CA2562661A1 - Methods of preparing tertiary carbinamine compounds - Google Patents
Methods of preparing tertiary carbinamine compounds Download PDFInfo
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- CA2562661A1 CA2562661A1 CA002562661A CA2562661A CA2562661A1 CA 2562661 A1 CA2562661 A1 CA 2562661A1 CA 002562661 A CA002562661 A CA 002562661A CA 2562661 A CA2562661 A CA 2562661A CA 2562661 A1 CA2562661 A1 CA 2562661A1
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/24—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/44—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers
- C07C209/52—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers by reduction of imines or imino-ethers
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/16—Preparation of optical isomers
- C07C231/18—Preparation of optical isomers by stereospecific synthesis
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D211/58—Nitrogen atoms attached in position 4
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- C07C2602/00—Systems containing two condensed rings
- C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
- C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms
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Abstract
The present invention relates to a method for the preparation of tertiary carbinamine compounds from diastereoselective allylation and crotylation of N-unsubstituted imines derived from ketones.
Description
B&P File No. 14696-17 TITLE: METHODS OF PREPARING TERTIARY CARBINAMINE
COMPOUNDS
FIELD OF THE INVENTION
The present invention relates to a method for the preparation of tertiary carbinamine compounds, particularly the preparation of tertiary carbinamine compounds, from diastereoselective allylation and crotylation of N-unsubstituted imines derived from ketones.
BACKGROUND OF THE INVENTION
Research into the addition of allyl organometallics to carbonyl compounds and their derivatives continues to proceed unabated - a consequence of the fact that the resulting homoallylic products have proven to be valuable synthons [S. E. Denmark and N. G. Almstead, Modern Carbonyl Chemistry, ed. J. Otera, Wiley-VCH, Weinheim, 2000, ch. 10; Y. Yamamoto and N. Asao, Chem. Rev., 1993, 93, 2207; and W. R. Roush, Comprehensive Organic Synthesis, ed. B. M. Trost, I. Fleming and C. H. Heathcock, Pergamon, Oxford, 2nd edn., 1991, vol. 2, pp 1-53]. The majority of the research, however, has focused on the addition of these organometallics to aidehydes. For example, the reaction of ~ H 9 NH3, EtOH NH2 R ~ R\ ~ B'O ~
7/ v R ~
R~ R R
has previously been described by Kobayashi et al. [M. Sugiura, K. Hirano and S. Kobayashi, J. Am. Chem. Soc., 2004, 126, 7182; S. Kobayashi, K. Hirano, M. Sugiura, Chem. Commun., 2005, 104].
Although to a lesser extent, there have been some recent examples of allylation of ketones [L. F. Tietze, K. Schiemann, C. Wegner and C. Wulff, Chem. Eur. J., 1998, 4, 1862; S. Casolari, D. D'Addario and E. Tagliavini, Org. Left., 1999, 1, 1061; R. Hamasaki, Y. Chounan, H. Horino and Y.
Yamamoto, Tetrahedron Left., 2000, 41, 9883; R. M. Kamble and V. K. Singh, Tetrahedron Left., 2001, 42, 7525; J. G. Kim, K. M. Waltz, I. F. Garcia, D.
Kwiatkowski and P. J. Walsh, J. Am. Chem. Soc., 2004, 126, 12580; T. R.
Wu, L. Shen and J. M. Chong, Org. Lett., 2004, 6, 2701; and Y.-C. Teo, J.-D.
Goh and T.-P. Loh, Org. Lett., 2005, 7, 2743]. Until recently, the expansion of the substrate scope to include imines and their derivatives had received limited attention. Some recent examples of the addition of allylorganometallics to aldimine derivatives can be found in the following references [C. Bellucci, P. G. Cozzi and A. Umani-Ronchi, Tetrahedron Left., 1995, 36, 7289; H. Nakamura, K. Nakamura and Y. Yamamoto, J. Am. Chem.
Soc., 1998, 120, 4242; F. Fang, M. Johannsen, S. Yao, N. Gathergood, R. G.
Hazell and K. A. Jorgensen, J. Org. Chem., 1999, 64, 4844; T. Gastner, H.
Ishitani, R. Akiyama and S. Kobayashi, Angew. Chem., Int. Ed., 2001, 40, 1896; H. C. Aspinall, J. S. Bissett, N. Greeves and D. Levin, Tetrahedron Lett., 2002, 43, 323; M. Sugiura, F. Robvieux and S. Kobayashi, Synlett, 2003, 1749; R. A. Fernandes and Y. Yamamoto, J. Org. Chem., 2004, 69, 735; S.-W. Li and R. A. Batey, Chem. Commun., 2004, 1382; I. Shibata, K.
Nose, K. Sakamoto, M. Yasuda and A. Baba, J. Org. Chem., 2004, 69, 2185;
and C. Ogawa, M. Sugiura and S. Kobayashi, Angew Chem., Int. Ed., 2004, 43, 6491]. As for the addition of allylorganometallics to ketimine derivatives, some recent examples have also been reported [C. Ogawa, M. Sugiura and S. Kobayashi, J. Org. Chem., 2002, 67, 5359; S. Yamasaki, K. Fujii, R. Wada, M. Kanai and M. Shibasaki, J. Am. Chem. Soc., 2002, 124, 6536; R. Berger, K. Duff and J. L. Leighton, J. Am. Chem. Soc., 2004, 126, 5686; H. Ding and G. K. Friestad, Synthesis, 2004, 2216].
However, there is yet no known synthetic methodology for the preparation of tertiary carbinamine compounds through diastereoselective allylation and crotylation of N-unsubstituted ketimines. New methodologies to solve the difficulties associated with making these valuable tertiary carbinamine compounds will no doubt have a tremendous impact in organic synthesis and in the chemical industry. New methodologies may also provide a new class of tertiary carbinamine compounds that cannot be obtained using conventional protocols. For example, the recent report of aminoallylation of aldehydes by Kobayshi and coworkers has already had a tremendous impact in organic synthesis [M. Sugiura, K. Hirano and S. Kobayashi, J. Am. Chem.
Soc., 2004, 126, 7182; S. Kobayashi, K. Hirano, M. Sugiura, Chem.
Commun., 2005, 104].
Thus, there remains a need for an efficient diastereoselective synthesis of tertiary carbinamine compounds that requires mild reaction conditions and provides good yields.
SUMMARY OF THE INVENTION
A new method for the preparation of tertiary carbinamine compounds from the diastereoselective allylation and crotylation of in situ generated N-unsubstituted ketimines has been developed. The method has been shown to provide the homoallylic amines in good to excellent yields through simple acid-base extraction. Also, the crotylation of N-unsubstituted ketimines has been shown to be highly diastereoselective.
Accordingly, the present invention relates a method of preparing an amine of the formula Ia and/or lb comprising reacting a compound of formula II with a compound of formula III:
0 R5 o'R HzN R2 R5 H2N R2 R5 RRz + R s B \ O , R s NH3 or NH4'X- R1x Rs Ri) R7 Ra Rs R7 R4R3~R7 R4 R3 R6 II III la lb wherein R' and R2 are independently selected from C1_20alkyl, CI_20alkoxy, C2_ 20alkenyl, C3_20cycloalkyl, C3_20cycloalkoxy, aryl, aryloxy, heteroaryl and heteroaryloxy, all of which are optionally substituted and one or more of the carbons in Cl-20alkyl, Cl_20alkoxy, C2_20alkenyl, C3_20cycloalkyl, C3_ 2ocycloalkoxy, aryl, aryloxy, heteroaryl or heteroaryloxy is optionally replaced with a heteroatom selected from 0, S, N, NR10 and NR'0R";
or R' and R2 are linked to form an optionally substituted monocyclic or polycyclic ring system having 4 to 20 atoms including the carbonyl to which R' and R2 are bonded, and one or more of the carbons of the ring system is optionally replaced with a heteroatom selected from 0, S, N, NR10 and NR'0R";
R3 to R' are independently selected from H, Cl-20alkyl, C1_20alkoxy, C2_ 2oalkenyl, C3_20cycloalkyl, C3-20cycloalkoxy, aryl, aryloxy, heteroaryl and heteroaryloxy, the latter 9 groups being optionally substituted and one or more of the carbons in C1_20alkyl, Cl_20alkoxy, C2_20alkenyl, C3-20cycloalkyl, C3-2ocycloalkoxy, aryl, aryloxy, heteroaryl or heteroaryloxy is optionally replaced with a heteroatom selected from 0, S, N, NR10 and NR10R11;
R 8 and R9 are independently selected from H, Cl-20alkyl, C3_20cycloalkyl, aryl and heteroaryl, the latter 4 groups being optionally substituted;
or R8 and R9 are linked to form an optionally substituted monocyclic or polycyclic ring system having 4 to 20 atoms, including the B and 0 atoms to which R8 and R9 are bonded;
R10 and R" are independently selected from H, Cl-20alkyl, C3_20cycloalkyl, aryl and heteroaryl, the latter 4 groups being optionally substituted, in the presence of ammonia NHs or an ammonia equivalent of the formula NH4i'X", wherein X is an anionic ligand.
Other features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
DETAILED DESCRIPTION OF THE INVENTION
It has been demonstrated for the first time that tertiary carbinamine compounds can be efficiently and effectively generated through 5 diastereoselective allylation and crotylation of N-unsubstituted imines that are derived from a diverse range of ketones. The method has been shown to be a simple three-component reaction of a ketone, excess ammonia or ammonia salt and an allylorganometallic reagent.
Accordingly, the present invention relates a method of preparing an amine of the formula Ia and/or lb comprising reacting a compound of formula II with a compound of formula III:
0 R5 01R8 HzN R2 R5 H2N R2 R5 R, R2 + RsB,O,Rs NH3 or NHq*X Ri Rs R' R~
R4 Rs R7 R4 YR3~R7 R4YR3\YR6 II III la lb wherein R' and R2 are independently selected from C1_20alkyl, Cl_20alkoxy, CZ_ 20alkenyl, C3_20cycloalkyl, C3_20cycloalkoxy, aryl, aryloxy, heteroaryl and heteroaryloxy, all of which are optionally substituted and one or more of the carbons in C,_ZOalkyl, C,_20alkoxy, C2_20alkenyl, C3_20cycloalkyl, Cs_ 20cycloalkoxy, aryl, aryloxy, heteroaryl or heteroaryloxy is optionally replaced with a heteroatom selected from 0, S, N, NR10 and NR'0R";
or R' and R2 are linked to form an optionally substituted monocyclic or polycyclic ring system having 4 to 20 atoms including the carbonyl to which R' and R2 are bonded, and one or more of the carbons of the ring system is optionally replaced with a heteroatom selected from 0, S, N, NR10 and NR'0R";
R3 to R' are independently selected from H, Cl_20alkyl, Cl_20alkoxy, C2_ 2oalkenyl, C3_20cycloalkyl, C3_20cycloalkoxy, aryl, aryloxy, heteroaryl and heteroaryloxy, the latter 9 groups being optionally substituted and one or more of the carbons in Cl_20alkyl, Cl_20alkoxy, C2_20alkenyl, C3_20cycloalkyl, C3_ 20cycloalkoxy, aryl, aryloxy, heteroaryl or heteroaryloxy is optionally replaced with a heteroatom selected from 0, S, N, NR10 and NR'0R";
R8 and R9 are independently selected from H, Cl_20alkyl, C3_20cycloalkyl, aryl and heteroaryl, the latter 4 groups being optionally substituted;
or R8 and R9 are linked to form an optionally substituted monocyclic or polycyclic ring system having 4 to 20 atoms, including the B and 0 atoms to which R8 and R9 are bonded;
R10 and R" are independently selected from H, Cl_20alkyl, C3_20cycloalkyl, aryl and heteroaryl, the latter 4 groups being optionally substituted, in the presence of ammonia NH3 or an ammonia equivalent of the formula NH4+X", wherein X is an anionic ligand.
The term "Cl_nalkyl" as used herein means straight and/or branched chain alkyl groups containing from one to n carbon atoms and includes, depending on the identity of n, methyl, ethyl, propyl, isopropyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, hexadecyl, octadecyl, icosyl and the like and wherein n is an integer representing the maximum number of carbon atoms in the group.
The term "C3_ncycloalkyl" as used herein means saturated cyclic or polycyclic alkyl groups containing from three to n carbon atoms and includes, depending on the identity of n, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclohexadecyl, cyclooctadecyl, cycloicosyl, adamantyl and the like, and wherein n is an integer representing the maximum number of carbon atoms in the group.
The term "Cl_nalkoxy" as used herein means straight and/or branched chain alkoxy groups containing from one to n carbon atoms and includes, depending on the identity of n, methoxy, ethoxy, propyoxy, isopropyloxy, t-butoxy, pentoxy, hexoxy, heptoxy, octoxy, nonoxy, decoxy, undecoxy, dodecoxy, hexadecoxy, octadecoxy, icosoxy and the like, and wherein n is an integer representing the maximum number of carbon atoms in the group.
The term "C3_ncycloalkoxy" as used herein means saturated cyclic or polycyclic alkyoxy groups containing from three to n carbon atoms and includes, depending on the identity of n, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, cycloheptoxy, cyclooctoxy, cyclononoxy, cyclodecoxy, cycloundecoxy, cyclododecoxy, cyclohexadecoxy, cyclooctadecoxy, cycloicosoxy and the like, and wherein n is an integer representing the maximum number of carbon atoms in the group.
The term "C2_nalkenyl" as used herein means straight and/or branched chain alkenyl groups containing from two to n carbon atoms and one to six double bonds and includes, depending on the identity of n, vinyl, allyl, 1-butenyl, 2-hexenyl and the like, and wherein n is an integer representing the maximum number of carbon atoms in the group.
The term "aryl" as used herein means a monocyclic or polycyclic carbocyclic ring system containing one or two aromatic rings and from 6 to 14 carbon atoms and includes phenyl, naphthyl, anthraceneyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl and the like.
The term "heteroaryl" as used herein means mono- or polycyclic heteroaromatic radicals containing from 5 to 14 atoms, of which 1 to 4 atoms are a heteroatom selected from nitrogen, oxygen and sulfur and includes furanyl, thienyl, pyrrolo, pyridyl, indolo, benzofuranyl and the like.
The term "halo" as used herein means halogen and includes chloro, fluoro, bromo and iodo.
The term "one or more" as used herein means that from one to the maximum allowable substitutions are allowed.
The present invention includes combinations of groups and substituents that are permitted and would provide a stable chemical entity according to standard chemical knowledge as would be known to those skilled in the art.
COMPOUNDS
FIELD OF THE INVENTION
The present invention relates to a method for the preparation of tertiary carbinamine compounds, particularly the preparation of tertiary carbinamine compounds, from diastereoselective allylation and crotylation of N-unsubstituted imines derived from ketones.
BACKGROUND OF THE INVENTION
Research into the addition of allyl organometallics to carbonyl compounds and their derivatives continues to proceed unabated - a consequence of the fact that the resulting homoallylic products have proven to be valuable synthons [S. E. Denmark and N. G. Almstead, Modern Carbonyl Chemistry, ed. J. Otera, Wiley-VCH, Weinheim, 2000, ch. 10; Y. Yamamoto and N. Asao, Chem. Rev., 1993, 93, 2207; and W. R. Roush, Comprehensive Organic Synthesis, ed. B. M. Trost, I. Fleming and C. H. Heathcock, Pergamon, Oxford, 2nd edn., 1991, vol. 2, pp 1-53]. The majority of the research, however, has focused on the addition of these organometallics to aidehydes. For example, the reaction of ~ H 9 NH3, EtOH NH2 R ~ R\ ~ B'O ~
7/ v R ~
R~ R R
has previously been described by Kobayashi et al. [M. Sugiura, K. Hirano and S. Kobayashi, J. Am. Chem. Soc., 2004, 126, 7182; S. Kobayashi, K. Hirano, M. Sugiura, Chem. Commun., 2005, 104].
Although to a lesser extent, there have been some recent examples of allylation of ketones [L. F. Tietze, K. Schiemann, C. Wegner and C. Wulff, Chem. Eur. J., 1998, 4, 1862; S. Casolari, D. D'Addario and E. Tagliavini, Org. Left., 1999, 1, 1061; R. Hamasaki, Y. Chounan, H. Horino and Y.
Yamamoto, Tetrahedron Left., 2000, 41, 9883; R. M. Kamble and V. K. Singh, Tetrahedron Left., 2001, 42, 7525; J. G. Kim, K. M. Waltz, I. F. Garcia, D.
Kwiatkowski and P. J. Walsh, J. Am. Chem. Soc., 2004, 126, 12580; T. R.
Wu, L. Shen and J. M. Chong, Org. Lett., 2004, 6, 2701; and Y.-C. Teo, J.-D.
Goh and T.-P. Loh, Org. Lett., 2005, 7, 2743]. Until recently, the expansion of the substrate scope to include imines and their derivatives had received limited attention. Some recent examples of the addition of allylorganometallics to aldimine derivatives can be found in the following references [C. Bellucci, P. G. Cozzi and A. Umani-Ronchi, Tetrahedron Left., 1995, 36, 7289; H. Nakamura, K. Nakamura and Y. Yamamoto, J. Am. Chem.
Soc., 1998, 120, 4242; F. Fang, M. Johannsen, S. Yao, N. Gathergood, R. G.
Hazell and K. A. Jorgensen, J. Org. Chem., 1999, 64, 4844; T. Gastner, H.
Ishitani, R. Akiyama and S. Kobayashi, Angew. Chem., Int. Ed., 2001, 40, 1896; H. C. Aspinall, J. S. Bissett, N. Greeves and D. Levin, Tetrahedron Lett., 2002, 43, 323; M. Sugiura, F. Robvieux and S. Kobayashi, Synlett, 2003, 1749; R. A. Fernandes and Y. Yamamoto, J. Org. Chem., 2004, 69, 735; S.-W. Li and R. A. Batey, Chem. Commun., 2004, 1382; I. Shibata, K.
Nose, K. Sakamoto, M. Yasuda and A. Baba, J. Org. Chem., 2004, 69, 2185;
and C. Ogawa, M. Sugiura and S. Kobayashi, Angew Chem., Int. Ed., 2004, 43, 6491]. As for the addition of allylorganometallics to ketimine derivatives, some recent examples have also been reported [C. Ogawa, M. Sugiura and S. Kobayashi, J. Org. Chem., 2002, 67, 5359; S. Yamasaki, K. Fujii, R. Wada, M. Kanai and M. Shibasaki, J. Am. Chem. Soc., 2002, 124, 6536; R. Berger, K. Duff and J. L. Leighton, J. Am. Chem. Soc., 2004, 126, 5686; H. Ding and G. K. Friestad, Synthesis, 2004, 2216].
However, there is yet no known synthetic methodology for the preparation of tertiary carbinamine compounds through diastereoselective allylation and crotylation of N-unsubstituted ketimines. New methodologies to solve the difficulties associated with making these valuable tertiary carbinamine compounds will no doubt have a tremendous impact in organic synthesis and in the chemical industry. New methodologies may also provide a new class of tertiary carbinamine compounds that cannot be obtained using conventional protocols. For example, the recent report of aminoallylation of aldehydes by Kobayshi and coworkers has already had a tremendous impact in organic synthesis [M. Sugiura, K. Hirano and S. Kobayashi, J. Am. Chem.
Soc., 2004, 126, 7182; S. Kobayashi, K. Hirano, M. Sugiura, Chem.
Commun., 2005, 104].
Thus, there remains a need for an efficient diastereoselective synthesis of tertiary carbinamine compounds that requires mild reaction conditions and provides good yields.
SUMMARY OF THE INVENTION
A new method for the preparation of tertiary carbinamine compounds from the diastereoselective allylation and crotylation of in situ generated N-unsubstituted ketimines has been developed. The method has been shown to provide the homoallylic amines in good to excellent yields through simple acid-base extraction. Also, the crotylation of N-unsubstituted ketimines has been shown to be highly diastereoselective.
Accordingly, the present invention relates a method of preparing an amine of the formula Ia and/or lb comprising reacting a compound of formula II with a compound of formula III:
0 R5 o'R HzN R2 R5 H2N R2 R5 RRz + R s B \ O , R s NH3 or NH4'X- R1x Rs Ri) R7 Ra Rs R7 R4R3~R7 R4 R3 R6 II III la lb wherein R' and R2 are independently selected from C1_20alkyl, CI_20alkoxy, C2_ 20alkenyl, C3_20cycloalkyl, C3_20cycloalkoxy, aryl, aryloxy, heteroaryl and heteroaryloxy, all of which are optionally substituted and one or more of the carbons in Cl-20alkyl, Cl_20alkoxy, C2_20alkenyl, C3_20cycloalkyl, C3_ 2ocycloalkoxy, aryl, aryloxy, heteroaryl or heteroaryloxy is optionally replaced with a heteroatom selected from 0, S, N, NR10 and NR'0R";
or R' and R2 are linked to form an optionally substituted monocyclic or polycyclic ring system having 4 to 20 atoms including the carbonyl to which R' and R2 are bonded, and one or more of the carbons of the ring system is optionally replaced with a heteroatom selected from 0, S, N, NR10 and NR'0R";
R3 to R' are independently selected from H, Cl-20alkyl, C1_20alkoxy, C2_ 2oalkenyl, C3_20cycloalkyl, C3-20cycloalkoxy, aryl, aryloxy, heteroaryl and heteroaryloxy, the latter 9 groups being optionally substituted and one or more of the carbons in C1_20alkyl, Cl_20alkoxy, C2_20alkenyl, C3-20cycloalkyl, C3-2ocycloalkoxy, aryl, aryloxy, heteroaryl or heteroaryloxy is optionally replaced with a heteroatom selected from 0, S, N, NR10 and NR10R11;
R 8 and R9 are independently selected from H, Cl-20alkyl, C3_20cycloalkyl, aryl and heteroaryl, the latter 4 groups being optionally substituted;
or R8 and R9 are linked to form an optionally substituted monocyclic or polycyclic ring system having 4 to 20 atoms, including the B and 0 atoms to which R8 and R9 are bonded;
R10 and R" are independently selected from H, Cl-20alkyl, C3_20cycloalkyl, aryl and heteroaryl, the latter 4 groups being optionally substituted, in the presence of ammonia NHs or an ammonia equivalent of the formula NH4i'X", wherein X is an anionic ligand.
Other features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
DETAILED DESCRIPTION OF THE INVENTION
It has been demonstrated for the first time that tertiary carbinamine compounds can be efficiently and effectively generated through 5 diastereoselective allylation and crotylation of N-unsubstituted imines that are derived from a diverse range of ketones. The method has been shown to be a simple three-component reaction of a ketone, excess ammonia or ammonia salt and an allylorganometallic reagent.
Accordingly, the present invention relates a method of preparing an amine of the formula Ia and/or lb comprising reacting a compound of formula II with a compound of formula III:
0 R5 01R8 HzN R2 R5 H2N R2 R5 R, R2 + RsB,O,Rs NH3 or NHq*X Ri Rs R' R~
R4 Rs R7 R4 YR3~R7 R4YR3\YR6 II III la lb wherein R' and R2 are independently selected from C1_20alkyl, Cl_20alkoxy, CZ_ 20alkenyl, C3_20cycloalkyl, C3_20cycloalkoxy, aryl, aryloxy, heteroaryl and heteroaryloxy, all of which are optionally substituted and one or more of the carbons in C,_ZOalkyl, C,_20alkoxy, C2_20alkenyl, C3_20cycloalkyl, Cs_ 20cycloalkoxy, aryl, aryloxy, heteroaryl or heteroaryloxy is optionally replaced with a heteroatom selected from 0, S, N, NR10 and NR'0R";
or R' and R2 are linked to form an optionally substituted monocyclic or polycyclic ring system having 4 to 20 atoms including the carbonyl to which R' and R2 are bonded, and one or more of the carbons of the ring system is optionally replaced with a heteroatom selected from 0, S, N, NR10 and NR'0R";
R3 to R' are independently selected from H, Cl_20alkyl, Cl_20alkoxy, C2_ 2oalkenyl, C3_20cycloalkyl, C3_20cycloalkoxy, aryl, aryloxy, heteroaryl and heteroaryloxy, the latter 9 groups being optionally substituted and one or more of the carbons in Cl_20alkyl, Cl_20alkoxy, C2_20alkenyl, C3_20cycloalkyl, C3_ 20cycloalkoxy, aryl, aryloxy, heteroaryl or heteroaryloxy is optionally replaced with a heteroatom selected from 0, S, N, NR10 and NR'0R";
R8 and R9 are independently selected from H, Cl_20alkyl, C3_20cycloalkyl, aryl and heteroaryl, the latter 4 groups being optionally substituted;
or R8 and R9 are linked to form an optionally substituted monocyclic or polycyclic ring system having 4 to 20 atoms, including the B and 0 atoms to which R8 and R9 are bonded;
R10 and R" are independently selected from H, Cl_20alkyl, C3_20cycloalkyl, aryl and heteroaryl, the latter 4 groups being optionally substituted, in the presence of ammonia NH3 or an ammonia equivalent of the formula NH4+X", wherein X is an anionic ligand.
The term "Cl_nalkyl" as used herein means straight and/or branched chain alkyl groups containing from one to n carbon atoms and includes, depending on the identity of n, methyl, ethyl, propyl, isopropyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, hexadecyl, octadecyl, icosyl and the like and wherein n is an integer representing the maximum number of carbon atoms in the group.
The term "C3_ncycloalkyl" as used herein means saturated cyclic or polycyclic alkyl groups containing from three to n carbon atoms and includes, depending on the identity of n, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclohexadecyl, cyclooctadecyl, cycloicosyl, adamantyl and the like, and wherein n is an integer representing the maximum number of carbon atoms in the group.
The term "Cl_nalkoxy" as used herein means straight and/or branched chain alkoxy groups containing from one to n carbon atoms and includes, depending on the identity of n, methoxy, ethoxy, propyoxy, isopropyloxy, t-butoxy, pentoxy, hexoxy, heptoxy, octoxy, nonoxy, decoxy, undecoxy, dodecoxy, hexadecoxy, octadecoxy, icosoxy and the like, and wherein n is an integer representing the maximum number of carbon atoms in the group.
The term "C3_ncycloalkoxy" as used herein means saturated cyclic or polycyclic alkyoxy groups containing from three to n carbon atoms and includes, depending on the identity of n, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, cycloheptoxy, cyclooctoxy, cyclononoxy, cyclodecoxy, cycloundecoxy, cyclododecoxy, cyclohexadecoxy, cyclooctadecoxy, cycloicosoxy and the like, and wherein n is an integer representing the maximum number of carbon atoms in the group.
The term "C2_nalkenyl" as used herein means straight and/or branched chain alkenyl groups containing from two to n carbon atoms and one to six double bonds and includes, depending on the identity of n, vinyl, allyl, 1-butenyl, 2-hexenyl and the like, and wherein n is an integer representing the maximum number of carbon atoms in the group.
The term "aryl" as used herein means a monocyclic or polycyclic carbocyclic ring system containing one or two aromatic rings and from 6 to 14 carbon atoms and includes phenyl, naphthyl, anthraceneyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl and the like.
The term "heteroaryl" as used herein means mono- or polycyclic heteroaromatic radicals containing from 5 to 14 atoms, of which 1 to 4 atoms are a heteroatom selected from nitrogen, oxygen and sulfur and includes furanyl, thienyl, pyrrolo, pyridyl, indolo, benzofuranyl and the like.
The term "halo" as used herein means halogen and includes chloro, fluoro, bromo and iodo.
The term "one or more" as used herein means that from one to the maximum allowable substitutions are allowed.
The present invention includes combinations of groups and substituents that are permitted and would provide a stable chemical entity according to standard chemical knowledge as would be known to those skilled in the art.
The term "polycyclic" or "ring system" as used herein means a cyclic group containing more than one ring in its structure, and includes bicyclic, tricyclic, bridged and spiro ring systems and the like.
It is an embodiment of the invention that the compounds of formulae Ia, lb and II include those in which R' and R2 are independently selected from Cl_ loalkyl, C2_,oalkenyl, aryl and heteroaryl, all of which are optionally substituted.
In a further embodiment of the invention, R' and R2 in the compounds of the formulae Ia, lb and II are independently selected from methyl, ethyl, propyl, butyl, pentyl, ethene, styrene, phenyl, benzyl, thiophene and indole, all of which are optionally substituted.
It is another embodiment of the invention that the compounds of formulae Ia, lb and II include those in which R' and R2 are linked to form an optionally substituted monocyclic or polycyclic ring system having 6 to 16 carbon atoms including the carbonyl to which R' and R2 are bonded. In a further embodiment of the invention, one or more of the carbons of this ring system is optionally replaced with a heteroatom selected from 0, S, N, NR'o and NR10R", in which Rl0 and R" are independently selected from H, Cl_ 6alkyl and aryl. In a still further embodiment of the invention, R' and R2 in the compounds of the formulae Ia, lb and II are linked to form a ring system selected from cyclohexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]hept-2-ene and fluorene, all of which are optionally substituted, and/or one or more of the carbons of cyclohexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]hept-2-ene or fluorene is optionally replaced with a heteroatom selected from 0, S, and NR10; in which R'0 is H or benzyl.
In an embodiment of the invention, the optional substituents on R' and R2 in the compounds of the formulae Ia, lb and II are independently selected from OH, halo, CN, NO2, phenyl, benzyl, OCi-6alkoxy, C1_6alkyl, C1_6alkenyl, C,_6alkenyloxy, NH2, NH(C,_6alkyl), N(Cl_6alkyl)(C1_6alkyl), C(O)C,_6alkyl, C(O)OC1_6alkyl, S02CI_6alkyl, SO2NH2, SO2NHC,-6aIkyl, and SC1-4alkyl. More particularly, in another embodiment of the invention, the optional substituents on R' and R2 in the compounds of the formulae Ia, lb and II are independently selected from OH, F, Cl, Br, CN, NO2, phenyl and C1_4alkyl. Still more particularly, the optional substituents on R' and R2 in the compounds of the formulae Ia, lb and II further comprise at least one stereocenter.
It is an embodiment of the invention that R3 to R' in the compounds of the formulae Ia, lb and III are independently selected from H, Cl_loalkyl, C3_ 12cycloalkyl, aryl and heteroaryl, the latter 4 groups being optionally substituted. In another embodiment of the invention, one or more of the carbons in C,_10alkyl, C3_locycloalkyl, aryl or heteroaryl is optionally replaced with a heteroatom selected from 0, S, N, NR10 and NR'0R" in which R'0 and R" are independently selected from H and C1_6alkyl. In a particular embodiment of the invention, R3 to R' in the compounds of the formulae Ia, lb and III are independently selected from H and C1_6alkyl. In a more particular embodiment of the invention, R3 to R' in the compounds of the formulae Ia, lb and III are independently selected from H and methyl. Still further, in an embodiment of the invention, the optional substituents on R3 and R' in the compounds of the formulae Ia, lb and III are independently selected from OH, halo, CN, NO2, phenyl, benzyl, OC1_6alkoxy, CI_6alkyl, Cl_6alkenyl, Cl_ 6alkenyloxy, NH2, NH(Cl_6alkyl), N(Cl_6alkyl)(Cl_6alkyl), C(OP_6alkyl, C(O)OC1-6alkyl, SO2C,-6aIkyl, SO2NH2, SO2NHC1_6alkyl, and SCI-4alkyl.
It is an embodiment of the invention that R8 and R9 in the compound of the formula III are independently selected from H, C1_10alkyl, C3-12cycIoalkyl, aryl and heteroaryl, the latter 4 groups being optionally substituted. In a more particular embodiment of the invention, R8 and R9 in the compound of the formula III are independently selected from H or C1_6alkyl. In another embodiment of the invention, R 8 and R9 in the compound of the formula I I I
are linked to form an optionally substituted monocyclic or polycyclic ring system having 5 to 12 atoms, including the B and 0 atoms to which R8 and R9 are bonded. In a more particular embodiment of the invention, R8 and R9 in the compound of the formula III are linked to form an optionally substituted monocyclic or bicyclic ring system having 5 to 12 atoms, including the B and 0 atoms to which R8 and R9 are bonded. It is an embodiment of the invention that the optional substituents on R8 and R9 in the compound of the formula III
are independently selected from OH, halo, CN, NO2, phenyl, benzyl, OCj_ 6alkoxy, C1_6alkyl, Cl_6alkenyl, Cl_6alkenyloxy, NH2, NH(Cl_6alkyl), N(Cj_ 6alkyl)(C1_6alkyl), C(O)Cl_6alkyl, C(O)OC1_6alkyl, SO2C1_6alkyl, SO2NH2, 5 SO2NHC1_6alkyl, and SC1-4alkyl. Still further, it is an embodiment of the invention that the optional substituent on R8 and R9 in the compound of the formula III is C1_4alkyl.
In an embodiment of the invention, the method is performed in the presence of ammonia. In yet another embodiment of the invention, the 10 method is performed in the presence of an ammonia salt NH3+X- in which X is an anionic ligand. In a further embodiment of the invention, X is selected from halo, R12C00, R12S04 and BF4 in which R12 is selected from Cl_loalkyl, C3-20cycloalkyl, aryl and heteroaryl, all of which are optionally substituted. In an embodiment of the invention, X is selected from Cl, Br, R12C00, R12SOa and BF4 and in which R12 is selected from C1_4alkyl, C3_12cycloalkyl, aryl and heteroaryl, all of which are optionally substituted. In a still further embodiment of the invention, the optional substituents are independently selected from OH, halo, CN, NO2, phenyl, benzyl, OC1_6alkoxy, C1_6alkyl, C,_6alkenyl, C,_ 6alkenyloxy, NH2, NH(C1_6alkyl), N(C,_6alkyl)(C,_6alkyl), C(O)C1_6alkyl, C(O)OC1_6alkyl, SO2C,-6alkyl, SO2NH2, SO2NHC1_6alkyl, and SC1.4alkyl.
In an embodiment of the invention, the method is performed in an inert organic solvent. More particularly, the organic solvent is selected from methanol, ethanol, propanol, butanol, toluene, tetrahydrofuran, acetonitrile, benzene, methylene chloride. Still more particularly, the organic solvent is methanol.
Also within the scope of the invention, the method is performed at room temperature or above or below room temperature for example at a temperature of from -40 C to 100 C, suitably 0 C to 50 C more suitably 10 C
to 30 C. Suitably, the method is performed at room temperature. A person skilled in the art would appreciate that the reaction temperature may vary depending on a number of variables, including, but not limited to the structure of the starting materials (compounds of formulae II and III), the solvent, reaction pressure and the choice of ammonia or ammonia equivalent. A
person skilled in the art would be able to optimize the reaction temperature to obtain the best yields and overall performance of the reaction.
Although there are a number of methods which have been surveyed to synthesize and isolate N-unsubstituted ketimines of the compound of the formula IV [P. L. Pickard and T. L. Tolbert, J. Org. Chem., 1961, 26, 4886; D.
R. Boyd, K. M. McCombe and N. D. Sharma, Tetrahedron Left., 1982, 23, 2907; A. J. Bailey and B. R. James, Chem. Commun., 1996, 2343; Y.
Bergman, P. Perlmutter and N. Thienthong, Green Chem., 2004, 6, 539; and R. W. Layer, Chem. Rev., 1963, 63, 489], the present inventors have found that the three-component reaction of the ketone of the compound of the formula II, excess ammonia and the allylorganometallic of the compound of the formula III was the most efficient and effective protocol to generate the desired homoallylic amines of the compounds of formulae Ia and lb (Scheme I).
Rs M
R3Y~1IXR7 ONH3 NH R III R6 2N ~~ R2 Rs 1 R7 (or R6) R'~R2 MeOH R'~R2 R' R3 R4 4 R6 (or R') II IV Ia (or Ib) Scheme I
While not wishing to be limited by theory, it is believed that the N-unsubstituted ketimine of the compound of formula IV is formed in situ prior to its reaction with the allylorganometallic of the compound of formula III [M.
Sugiura, K. Hirano and S. Kobayashi, J. Am. Chem. Soc., 2004, 126, 7182; S.
Kobayashi, K. Hirano, M. Sugiura, Chem. Commun., 2005, 104; B. Davis, J.
Labelled Compd. Radiopharm., 1987, 24, 1221; and N. Haider, G. Heinisch, I.
It is an embodiment of the invention that the compounds of formulae Ia, lb and II include those in which R' and R2 are independently selected from Cl_ loalkyl, C2_,oalkenyl, aryl and heteroaryl, all of which are optionally substituted.
In a further embodiment of the invention, R' and R2 in the compounds of the formulae Ia, lb and II are independently selected from methyl, ethyl, propyl, butyl, pentyl, ethene, styrene, phenyl, benzyl, thiophene and indole, all of which are optionally substituted.
It is another embodiment of the invention that the compounds of formulae Ia, lb and II include those in which R' and R2 are linked to form an optionally substituted monocyclic or polycyclic ring system having 6 to 16 carbon atoms including the carbonyl to which R' and R2 are bonded. In a further embodiment of the invention, one or more of the carbons of this ring system is optionally replaced with a heteroatom selected from 0, S, N, NR'o and NR10R", in which Rl0 and R" are independently selected from H, Cl_ 6alkyl and aryl. In a still further embodiment of the invention, R' and R2 in the compounds of the formulae Ia, lb and II are linked to form a ring system selected from cyclohexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]hept-2-ene and fluorene, all of which are optionally substituted, and/or one or more of the carbons of cyclohexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]hept-2-ene or fluorene is optionally replaced with a heteroatom selected from 0, S, and NR10; in which R'0 is H or benzyl.
In an embodiment of the invention, the optional substituents on R' and R2 in the compounds of the formulae Ia, lb and II are independently selected from OH, halo, CN, NO2, phenyl, benzyl, OCi-6alkoxy, C1_6alkyl, C1_6alkenyl, C,_6alkenyloxy, NH2, NH(C,_6alkyl), N(Cl_6alkyl)(C1_6alkyl), C(O)C,_6alkyl, C(O)OC1_6alkyl, S02CI_6alkyl, SO2NH2, SO2NHC,-6aIkyl, and SC1-4alkyl. More particularly, in another embodiment of the invention, the optional substituents on R' and R2 in the compounds of the formulae Ia, lb and II are independently selected from OH, F, Cl, Br, CN, NO2, phenyl and C1_4alkyl. Still more particularly, the optional substituents on R' and R2 in the compounds of the formulae Ia, lb and II further comprise at least one stereocenter.
It is an embodiment of the invention that R3 to R' in the compounds of the formulae Ia, lb and III are independently selected from H, Cl_loalkyl, C3_ 12cycloalkyl, aryl and heteroaryl, the latter 4 groups being optionally substituted. In another embodiment of the invention, one or more of the carbons in C,_10alkyl, C3_locycloalkyl, aryl or heteroaryl is optionally replaced with a heteroatom selected from 0, S, N, NR10 and NR'0R" in which R'0 and R" are independently selected from H and C1_6alkyl. In a particular embodiment of the invention, R3 to R' in the compounds of the formulae Ia, lb and III are independently selected from H and C1_6alkyl. In a more particular embodiment of the invention, R3 to R' in the compounds of the formulae Ia, lb and III are independently selected from H and methyl. Still further, in an embodiment of the invention, the optional substituents on R3 and R' in the compounds of the formulae Ia, lb and III are independently selected from OH, halo, CN, NO2, phenyl, benzyl, OC1_6alkoxy, CI_6alkyl, Cl_6alkenyl, Cl_ 6alkenyloxy, NH2, NH(Cl_6alkyl), N(Cl_6alkyl)(Cl_6alkyl), C(OP_6alkyl, C(O)OC1-6alkyl, SO2C,-6aIkyl, SO2NH2, SO2NHC1_6alkyl, and SCI-4alkyl.
It is an embodiment of the invention that R8 and R9 in the compound of the formula III are independently selected from H, C1_10alkyl, C3-12cycIoalkyl, aryl and heteroaryl, the latter 4 groups being optionally substituted. In a more particular embodiment of the invention, R8 and R9 in the compound of the formula III are independently selected from H or C1_6alkyl. In another embodiment of the invention, R 8 and R9 in the compound of the formula I I I
are linked to form an optionally substituted monocyclic or polycyclic ring system having 5 to 12 atoms, including the B and 0 atoms to which R8 and R9 are bonded. In a more particular embodiment of the invention, R8 and R9 in the compound of the formula III are linked to form an optionally substituted monocyclic or bicyclic ring system having 5 to 12 atoms, including the B and 0 atoms to which R8 and R9 are bonded. It is an embodiment of the invention that the optional substituents on R8 and R9 in the compound of the formula III
are independently selected from OH, halo, CN, NO2, phenyl, benzyl, OCj_ 6alkoxy, C1_6alkyl, Cl_6alkenyl, Cl_6alkenyloxy, NH2, NH(Cl_6alkyl), N(Cj_ 6alkyl)(C1_6alkyl), C(O)Cl_6alkyl, C(O)OC1_6alkyl, SO2C1_6alkyl, SO2NH2, 5 SO2NHC1_6alkyl, and SC1-4alkyl. Still further, it is an embodiment of the invention that the optional substituent on R8 and R9 in the compound of the formula III is C1_4alkyl.
In an embodiment of the invention, the method is performed in the presence of ammonia. In yet another embodiment of the invention, the 10 method is performed in the presence of an ammonia salt NH3+X- in which X is an anionic ligand. In a further embodiment of the invention, X is selected from halo, R12C00, R12S04 and BF4 in which R12 is selected from Cl_loalkyl, C3-20cycloalkyl, aryl and heteroaryl, all of which are optionally substituted. In an embodiment of the invention, X is selected from Cl, Br, R12C00, R12SOa and BF4 and in which R12 is selected from C1_4alkyl, C3_12cycloalkyl, aryl and heteroaryl, all of which are optionally substituted. In a still further embodiment of the invention, the optional substituents are independently selected from OH, halo, CN, NO2, phenyl, benzyl, OC1_6alkoxy, C1_6alkyl, C,_6alkenyl, C,_ 6alkenyloxy, NH2, NH(C1_6alkyl), N(C,_6alkyl)(C,_6alkyl), C(O)C1_6alkyl, C(O)OC1_6alkyl, SO2C,-6alkyl, SO2NH2, SO2NHC1_6alkyl, and SC1.4alkyl.
In an embodiment of the invention, the method is performed in an inert organic solvent. More particularly, the organic solvent is selected from methanol, ethanol, propanol, butanol, toluene, tetrahydrofuran, acetonitrile, benzene, methylene chloride. Still more particularly, the organic solvent is methanol.
Also within the scope of the invention, the method is performed at room temperature or above or below room temperature for example at a temperature of from -40 C to 100 C, suitably 0 C to 50 C more suitably 10 C
to 30 C. Suitably, the method is performed at room temperature. A person skilled in the art would appreciate that the reaction temperature may vary depending on a number of variables, including, but not limited to the structure of the starting materials (compounds of formulae II and III), the solvent, reaction pressure and the choice of ammonia or ammonia equivalent. A
person skilled in the art would be able to optimize the reaction temperature to obtain the best yields and overall performance of the reaction.
Although there are a number of methods which have been surveyed to synthesize and isolate N-unsubstituted ketimines of the compound of the formula IV [P. L. Pickard and T. L. Tolbert, J. Org. Chem., 1961, 26, 4886; D.
R. Boyd, K. M. McCombe and N. D. Sharma, Tetrahedron Left., 1982, 23, 2907; A. J. Bailey and B. R. James, Chem. Commun., 1996, 2343; Y.
Bergman, P. Perlmutter and N. Thienthong, Green Chem., 2004, 6, 539; and R. W. Layer, Chem. Rev., 1963, 63, 489], the present inventors have found that the three-component reaction of the ketone of the compound of the formula II, excess ammonia and the allylorganometallic of the compound of the formula III was the most efficient and effective protocol to generate the desired homoallylic amines of the compounds of formulae Ia and lb (Scheme I).
Rs M
R3Y~1IXR7 ONH3 NH R III R6 2N ~~ R2 Rs 1 R7 (or R6) R'~R2 MeOH R'~R2 R' R3 R4 4 R6 (or R') II IV Ia (or Ib) Scheme I
While not wishing to be limited by theory, it is believed that the N-unsubstituted ketimine of the compound of formula IV is formed in situ prior to its reaction with the allylorganometallic of the compound of formula III [M.
Sugiura, K. Hirano and S. Kobayashi, J. Am. Chem. Soc., 2004, 126, 7182; S.
Kobayashi, K. Hirano, M. Sugiura, Chem. Commun., 2005, 104; B. Davis, J.
Labelled Compd. Radiopharm., 1987, 24, 1221; and N. Haider, G. Heinisch, I.
Kurzmann-Rauscher and M. Wolf, Liebigs Ann. Chem., 1985, 167]. The addition of a series of allyl organometallics to the in situ generated ketimine of the compound of formula IV (R'=4-BrC6H4, R2=Me) have been investigated.
The following non-limiting examples are illustrative of the present invention:
EXAMPLES
Materials and Methods:
All ketones in liquid form were distilled prior to use. All ketones in solid form were used as received. All other reagents were used as received (Aldrich, Acros, Strem). MeOH was dried over magnesium methoxide and distilled prior to use. 2 M solutions of allyl, (E)- and (Z)-crotylboronic acid in anhydrous MeOH were prepared just prior to use (exact molarities were confirmed by titration with benzaldehyde) [H. C. Brown, U. S. Racherla and P.
J. Pellechia, J. Org. Chem., 1990, 55, 1868].
Melting points were uncorrected and were measured on a Fisher-Johns melting point apparatus. 'H and 13C NMR were recorded at 300 or 500 MHz and 75 or 125 MHz respectively on a Bruker Spectrospin 300 or 500 MHz spectrometer. Proton chemical shifts were internally referenced to the residual proton resonance in CDCI3 (S 7.26). Carbon chemical shifts were internally referenced to the deuterated solvent signals in CDCI3 (S 77.00).
Infrared spectra were obtained on a Bruker VECTOR22 FT-IR spectrometer.
HRMS-Cl and HRMS-ESI were performed on a Waters/Micromass GCT time-of-flight mass spectrometer and a Waters/Micromass Q-TOF Global quadrupole time-of-flight mass spectrometer respectively.
Example 1: General Procedure for the Allylation of N-Unsubstituted Imines Derived from Ketones:
To the ketone (0.5 mmol) was added a solution of ammonia in methanol (ca.
7M in MeOH, 0.75 mL, ca. 10 equiv.). The resulting solution was stirred for 15 min at rt. A freshly prepared solution of allylboronic acid (5e) (2M in MeOH, 0.4 ml, 0.8 mmol) was then added dropwise over 5 min. The reaction mixture was subsequently stirred for 16 h at rt. All volatiles were removed in vacuo and the residue re-dissolved in Et20 (15 mL). The desired amine was then extracted with 1 N HCI (15 ml). The acidic aqueous extract was washed with Et20 (3 x 15 mL). The aqueous extract was next made alkaline by addition of solid NaOH (ca. 5 g). The alkaline aqueous layer was then extracted with dichloromethane (3 x 15 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the desired tertiary carbamine (6).
(i) 1-(4-Bromophenyl)-1-methylbut-3-enylamine (6a) 0 ~B(OH)2 Me NH2 ~ 5e Br I/ NH3 Br la MeOH 6a 6a was isolated as a clear, colorless oil: 'H NMR (CDCI3, 500 MHz) 8 7.44 (2H, d, J = 8.5 Hz), 7.35 (2H, d, J = 8.5 Hz), 5.55 (1 H, dddd, J = 18.0, 9.5, 8.0, 7.0 Hz), 5.09 - 5.04 (2H, m), 2.53 (1 H, dd, J = 13.5, 7.0 Hz), 2.38 (1 H, dd, J =
13.5, 8.0 Hz), 1.49 (2H, br s), 1.44 (3H, s); 13C NMR (CDCI3, 125 MHz) S
147.79, 133.89, 131.14, 127.26, 120.12, 118.81, 54.45, 49.64, 30.93; IR (film) v, 3423, 1638 cm-'; HRMS (CI) m/z calcd. for CjjH15BrN (MH+) 240.0388, found 240.0395.
(ii) 1,1-Diethylbut-3-enylamine (6b) ~ B(OH)2 Et2C=O
lb MeOH 6b 6b was isolated as a clear, colorless oil: 'H NMR (CDCI3, 300 MHz) S 5.77 (1 H, ddt, J = 16.0, 11.0, 7.5 Hz)), 5.04 (1 H, d, J = 11.0 Hz), 5.03 (1 H, d, J =
16.0 Hz), 2.03 (2H, d, J = 7.5 Hz), 1.32 (4H, q, J = 7.5 Hz), 1.18 (2H, br s), 0.81 (6H, t, J = 7.5 Hz); 13C NMR (CDCI3, 75 MHz) S 134.44, 117.69, 53.36, 43.85, 31.66, 7.70; IR (film) v 3420, 1636 cm '; HRMS (ESI) m/z calcd. for C$H18N (MH+) 128.1439, found 128.1444.
(iii) 2-Amino-2-methylpent-4-en-1-ol (6c) O ~B(OH)2 NH2 HO~ NH3 HO~.~'~/'~
1 c MeOH 6c 6c was isolated as a clear, colorless oil: 'H NMR (CDCI3, 300 MHz) S 5.79 (1 H, ddt, J = 16.5, 10.5, 7.5 Hz), 5.12 - 5.01 (2H, m), 3.30 (1 H, d, J =
10.5 Hz), 3.25 (1H, d, J = 10.5 Hz), 2.45 (3H, br s), 2.11 (2H, d, J = 7.5 Hz), 1.01 (3H, s); 13C NMR (CDCI3, 75 MHz) S 133.77, 118.51, 68.07, 52.70, 44.28, 24.53; IR (film) v 3345, 3157, 1639 cm '; HRMS (CI) m/z calcd. for C6H14NO
(MH') 116.1075, found 116.1072.
(iv) 1-Benzyl-l-phenylbut-3-enylamine (6d) O ~B(OH)2 Ph NH2 Ph Ph Ph id MeOH 6d 6d was isolated as a clear, colorless oil: 'H NMR (CDCI3, 300 MHz) S 7.38 -7.08 (8H, m), 6.90 - 6.84 (2H, m), 5.53 (1 H, dddd, J = 17.0, 10.0, 8.5, 5.5 Hz), 5.15 - 5.00 (2H, m), 3.12 (1 H, d, J = 13.0 Hz), 2.97 (1 H, d, J = 13.0 Hz), 2.86 (1 H, dd, J = 13.5, 5.5 Hz), 2.44 (1 H, dd, J = 13.5, 8.5 Hz), 1.50 (2H, br s); 13C
NMR (CDC13, 75 MHz) 8 146.52, 137.09, 134.08, 130.68, 128.07, 127.86, 126.46, 126.30, 126.19, 118.81, 57.97, 50.54, 47.62; I R(fi(m) v, 3401, 1677 cm-1; HRMS (ESI) m/z calcd. for C17H2ON (MH+) 238.1596, found 238.1585.
(v) 1-Methyl-1-(3-methylbutyl)but-3-enylamine (6e) 0 ~B(OH)2 Me NH2 ~ie NH3 6e MeOH
6e was isolated as a clear, colorless oil: 'H NMR (CDCI3, 300 MHz) 8 5.74 (1 H, ddt, J = 17.0, 10.0, 7.5 Hz), 5.05 - 4.93 (2H, m), 2.00 (2H, d, J = 7.5 Hz), 10 1.40 (1H, septet, J = 6.5 Hz), 1.29 - 1.20 (2H, m), 1.19 - 1.03 (4H, m), 0.95 (3H, s), 0.80 (6H, d, J = 6.5 Hz); 13C NMR (CDCI3, 75 MHz) S 134.50, 117.77, 51.14, 47.15, 40.36, 32.82, 28.45, 27.71, 22.53; IR (film) p3385, 1636 cm-1;
HRMS (ESI) m/z calcd. for CioH22N (MH+) 156.1752, found 156.1745.
The following non-limiting examples are illustrative of the present invention:
EXAMPLES
Materials and Methods:
All ketones in liquid form were distilled prior to use. All ketones in solid form were used as received. All other reagents were used as received (Aldrich, Acros, Strem). MeOH was dried over magnesium methoxide and distilled prior to use. 2 M solutions of allyl, (E)- and (Z)-crotylboronic acid in anhydrous MeOH were prepared just prior to use (exact molarities were confirmed by titration with benzaldehyde) [H. C. Brown, U. S. Racherla and P.
J. Pellechia, J. Org. Chem., 1990, 55, 1868].
Melting points were uncorrected and were measured on a Fisher-Johns melting point apparatus. 'H and 13C NMR were recorded at 300 or 500 MHz and 75 or 125 MHz respectively on a Bruker Spectrospin 300 or 500 MHz spectrometer. Proton chemical shifts were internally referenced to the residual proton resonance in CDCI3 (S 7.26). Carbon chemical shifts were internally referenced to the deuterated solvent signals in CDCI3 (S 77.00).
Infrared spectra were obtained on a Bruker VECTOR22 FT-IR spectrometer.
HRMS-Cl and HRMS-ESI were performed on a Waters/Micromass GCT time-of-flight mass spectrometer and a Waters/Micromass Q-TOF Global quadrupole time-of-flight mass spectrometer respectively.
Example 1: General Procedure for the Allylation of N-Unsubstituted Imines Derived from Ketones:
To the ketone (0.5 mmol) was added a solution of ammonia in methanol (ca.
7M in MeOH, 0.75 mL, ca. 10 equiv.). The resulting solution was stirred for 15 min at rt. A freshly prepared solution of allylboronic acid (5e) (2M in MeOH, 0.4 ml, 0.8 mmol) was then added dropwise over 5 min. The reaction mixture was subsequently stirred for 16 h at rt. All volatiles were removed in vacuo and the residue re-dissolved in Et20 (15 mL). The desired amine was then extracted with 1 N HCI (15 ml). The acidic aqueous extract was washed with Et20 (3 x 15 mL). The aqueous extract was next made alkaline by addition of solid NaOH (ca. 5 g). The alkaline aqueous layer was then extracted with dichloromethane (3 x 15 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the desired tertiary carbamine (6).
(i) 1-(4-Bromophenyl)-1-methylbut-3-enylamine (6a) 0 ~B(OH)2 Me NH2 ~ 5e Br I/ NH3 Br la MeOH 6a 6a was isolated as a clear, colorless oil: 'H NMR (CDCI3, 500 MHz) 8 7.44 (2H, d, J = 8.5 Hz), 7.35 (2H, d, J = 8.5 Hz), 5.55 (1 H, dddd, J = 18.0, 9.5, 8.0, 7.0 Hz), 5.09 - 5.04 (2H, m), 2.53 (1 H, dd, J = 13.5, 7.0 Hz), 2.38 (1 H, dd, J =
13.5, 8.0 Hz), 1.49 (2H, br s), 1.44 (3H, s); 13C NMR (CDCI3, 125 MHz) S
147.79, 133.89, 131.14, 127.26, 120.12, 118.81, 54.45, 49.64, 30.93; IR (film) v, 3423, 1638 cm-'; HRMS (CI) m/z calcd. for CjjH15BrN (MH+) 240.0388, found 240.0395.
(ii) 1,1-Diethylbut-3-enylamine (6b) ~ B(OH)2 Et2C=O
lb MeOH 6b 6b was isolated as a clear, colorless oil: 'H NMR (CDCI3, 300 MHz) S 5.77 (1 H, ddt, J = 16.0, 11.0, 7.5 Hz)), 5.04 (1 H, d, J = 11.0 Hz), 5.03 (1 H, d, J =
16.0 Hz), 2.03 (2H, d, J = 7.5 Hz), 1.32 (4H, q, J = 7.5 Hz), 1.18 (2H, br s), 0.81 (6H, t, J = 7.5 Hz); 13C NMR (CDCI3, 75 MHz) S 134.44, 117.69, 53.36, 43.85, 31.66, 7.70; IR (film) v 3420, 1636 cm '; HRMS (ESI) m/z calcd. for C$H18N (MH+) 128.1439, found 128.1444.
(iii) 2-Amino-2-methylpent-4-en-1-ol (6c) O ~B(OH)2 NH2 HO~ NH3 HO~.~'~/'~
1 c MeOH 6c 6c was isolated as a clear, colorless oil: 'H NMR (CDCI3, 300 MHz) S 5.79 (1 H, ddt, J = 16.5, 10.5, 7.5 Hz), 5.12 - 5.01 (2H, m), 3.30 (1 H, d, J =
10.5 Hz), 3.25 (1H, d, J = 10.5 Hz), 2.45 (3H, br s), 2.11 (2H, d, J = 7.5 Hz), 1.01 (3H, s); 13C NMR (CDCI3, 75 MHz) S 133.77, 118.51, 68.07, 52.70, 44.28, 24.53; IR (film) v 3345, 3157, 1639 cm '; HRMS (CI) m/z calcd. for C6H14NO
(MH') 116.1075, found 116.1072.
(iv) 1-Benzyl-l-phenylbut-3-enylamine (6d) O ~B(OH)2 Ph NH2 Ph Ph Ph id MeOH 6d 6d was isolated as a clear, colorless oil: 'H NMR (CDCI3, 300 MHz) S 7.38 -7.08 (8H, m), 6.90 - 6.84 (2H, m), 5.53 (1 H, dddd, J = 17.0, 10.0, 8.5, 5.5 Hz), 5.15 - 5.00 (2H, m), 3.12 (1 H, d, J = 13.0 Hz), 2.97 (1 H, d, J = 13.0 Hz), 2.86 (1 H, dd, J = 13.5, 5.5 Hz), 2.44 (1 H, dd, J = 13.5, 8.5 Hz), 1.50 (2H, br s); 13C
NMR (CDC13, 75 MHz) 8 146.52, 137.09, 134.08, 130.68, 128.07, 127.86, 126.46, 126.30, 126.19, 118.81, 57.97, 50.54, 47.62; I R(fi(m) v, 3401, 1677 cm-1; HRMS (ESI) m/z calcd. for C17H2ON (MH+) 238.1596, found 238.1585.
(v) 1-Methyl-1-(3-methylbutyl)but-3-enylamine (6e) 0 ~B(OH)2 Me NH2 ~ie NH3 6e MeOH
6e was isolated as a clear, colorless oil: 'H NMR (CDCI3, 300 MHz) 8 5.74 (1 H, ddt, J = 17.0, 10.0, 7.5 Hz), 5.05 - 4.93 (2H, m), 2.00 (2H, d, J = 7.5 Hz), 10 1.40 (1H, septet, J = 6.5 Hz), 1.29 - 1.20 (2H, m), 1.19 - 1.03 (4H, m), 0.95 (3H, s), 0.80 (6H, d, J = 6.5 Hz); 13C NMR (CDCI3, 75 MHz) S 134.50, 117.77, 51.14, 47.15, 40.36, 32.82, 28.45, 27.71, 22.53; IR (film) p3385, 1636 cm-1;
HRMS (ESI) m/z calcd. for CioH22N (MH+) 156.1752, found 156.1745.
15 (vi) 1-Ethyl-1 -(4-Methoxyphenyl)but-3-enylamine (6f) 0 Et NH2 B(OH)2 j\
MeO c NH3 MeO ~
if MeOH 6f 6f was isolated as a clear, colorless oil: 'H NMR (CDCI3, 500 MHz) S 7.31 (2H, d, J = 9.0 Hz), 6.86 (2H, d, J = 9.0 Hz), 5.53 (1 H, dddd, J = 17.5, 10.0, 8.5, 6.0 Hz), 5.06 (1H, d, J = 17.5 Hz), 5.03 (1H, d, J = 10.0 Hz), 3.80 (3H, s), 2.59 (1 H, dd, J = 13.5, 6.0 Hz), 2.36 (1 H, dd, J = 13.5, 8.5 Hz), 1.85 (1 H, dq, J
= 14.0, 7.5 Hz), 1.66 (1 H, dq, J = 14.0, 7.5 Hz), 1.52 (2H, br s), 0.71 (3H, t, J
= 7.5 Hz); 13C NMR (CDCI3, 75 MHz) S 157.72, 138.66, 134.32, 126.93, 118.34, 113.27, 57.06, 55.16, 48.37, 36.05, 8.04; IR (film) p3420, 1638, 1610, 1511, 1248 cm-'; HRMS (CI) m/z calcd. for C13H2ONO (MH+) 206.1545, found 206.1565.
(vii) 4-(1-Amino-1 -methylbut-3-enyl)benzonitrile (6g) O Me NH2 B(OH)2 NC ~ ~~
1 g MeOH 6g 6g was isolated as a clear, colorless oil: 'H NMR (CDCI3, 300 MHz) S 7.57 (4H, apparent s), 5.55 - 5.40 (1 H, m), 5.07 - 4.97 (2H, m), 2.51 (1 H, dd, J
=
13.5, 6.5 Hz), 2.36 (1 H, dd, J = 13.5, 8.0 Hz), 1.46 (2H, br s), 1.43 (3H, s); 13C
NMR (CDCI3, 75 MHz) 8 154.26, 133.32, 131.99, 126.36, 119.37, 119.03, 110.05, 54.94, 49.50, 30.85; IR (film) v3499, 2228, 1639 cm-1; HRMS (CI) m/z calcd. for C12H15N2 (MH+) 187.1235, found 187.1235.
(viii) 1-Methyl-1-(4-nitrophenyl)but-3-enylamine (6h) O Me NH2 I B(OH)2 ~
~
1 h MeOH 6h 6h was isolated as a clear, colorless oil: 'H NMR (CDCI3, 500 MHz) S 8.16 (2H, d, J = 9.0 Hz), 7.66 (2H, d, J = 9.0 Hz), 5.53 (1H, dddd, J = 17.0, 10.5, 8.0, 7.0 Hz), 5.07 (1H, d, J = 10.5 Hz), 5.06 (1H, d, J = 17.0 Hz), 2.57 (1H, dd, J = 13.5, 7.0 Hz), 2.42 (1 H, dd, J = 13.5, 8.0 Hz), 1.54 (2H, br s), 1.50 (3H, s);
13C NMR (CDCI3, 125 MHz) b 156.28, 146.47, 133.13, 126.45, 123.30, 119.43, 55.01, 49.55, 30.92; IR (film) v3375, 1639, 1526, 1351 cm-1; HRMS
(CI) m/z calcd. for C11H15N202 (MH+) 207.1134, found 207.1132.
MeO c NH3 MeO ~
if MeOH 6f 6f was isolated as a clear, colorless oil: 'H NMR (CDCI3, 500 MHz) S 7.31 (2H, d, J = 9.0 Hz), 6.86 (2H, d, J = 9.0 Hz), 5.53 (1 H, dddd, J = 17.5, 10.0, 8.5, 6.0 Hz), 5.06 (1H, d, J = 17.5 Hz), 5.03 (1H, d, J = 10.0 Hz), 3.80 (3H, s), 2.59 (1 H, dd, J = 13.5, 6.0 Hz), 2.36 (1 H, dd, J = 13.5, 8.5 Hz), 1.85 (1 H, dq, J
= 14.0, 7.5 Hz), 1.66 (1 H, dq, J = 14.0, 7.5 Hz), 1.52 (2H, br s), 0.71 (3H, t, J
= 7.5 Hz); 13C NMR (CDCI3, 75 MHz) S 157.72, 138.66, 134.32, 126.93, 118.34, 113.27, 57.06, 55.16, 48.37, 36.05, 8.04; IR (film) p3420, 1638, 1610, 1511, 1248 cm-'; HRMS (CI) m/z calcd. for C13H2ONO (MH+) 206.1545, found 206.1565.
(vii) 4-(1-Amino-1 -methylbut-3-enyl)benzonitrile (6g) O Me NH2 B(OH)2 NC ~ ~~
1 g MeOH 6g 6g was isolated as a clear, colorless oil: 'H NMR (CDCI3, 300 MHz) S 7.57 (4H, apparent s), 5.55 - 5.40 (1 H, m), 5.07 - 4.97 (2H, m), 2.51 (1 H, dd, J
=
13.5, 6.5 Hz), 2.36 (1 H, dd, J = 13.5, 8.0 Hz), 1.46 (2H, br s), 1.43 (3H, s); 13C
NMR (CDCI3, 75 MHz) 8 154.26, 133.32, 131.99, 126.36, 119.37, 119.03, 110.05, 54.94, 49.50, 30.85; IR (film) v3499, 2228, 1639 cm-1; HRMS (CI) m/z calcd. for C12H15N2 (MH+) 187.1235, found 187.1235.
(viii) 1-Methyl-1-(4-nitrophenyl)but-3-enylamine (6h) O Me NH2 I B(OH)2 ~
~
1 h MeOH 6h 6h was isolated as a clear, colorless oil: 'H NMR (CDCI3, 500 MHz) S 8.16 (2H, d, J = 9.0 Hz), 7.66 (2H, d, J = 9.0 Hz), 5.53 (1H, dddd, J = 17.0, 10.5, 8.0, 7.0 Hz), 5.07 (1H, d, J = 10.5 Hz), 5.06 (1H, d, J = 17.0 Hz), 2.57 (1H, dd, J = 13.5, 7.0 Hz), 2.42 (1 H, dd, J = 13.5, 8.0 Hz), 1.54 (2H, br s), 1.50 (3H, s);
13C NMR (CDCI3, 125 MHz) b 156.28, 146.47, 133.13, 126.45, 123.30, 119.43, 55.01, 49.55, 30.92; IR (film) v3375, 1639, 1526, 1351 cm-1; HRMS
(CI) m/z calcd. for C11H15N202 (MH+) 207.1134, found 207.1132.
(ix) 1-Methyl-1 E-styrylbut-3-enylamine (6i) B(OH)2 I ~ \ \
O N\/\
1 i MeOH 6i 6i was isolated as a clear, colorless oil: 'H NMR (CDCI3, 300 MHz) 8 7.45 -7.15 (5H, m), 6.46 (1 H, d, J = 16.0 Hz), 6.28 (1 H, d, J = 16.0 Hz), 5.87 -5.72 (1 H, m), 5.18 - 5.05 (2H, m), 2.31 (1 H, dd, J = 16.5. 7.5 Hz), 2.23 (1 H, dd, J =
16.5, 8.0 Hz), 1.41 (2H, br s), 1.27 (3H, s); 13C NMR (CDCI3, 75 MHz) S
138.42, 137.22, 133.95, 128.39, 128.27, 127.06, 126.14, 118.45, 52.96, 48.00, 28.57; IR (film) v 3545, 1638 cm"'; HRMS (CI) m/z calcd. for C13H18N
(MH+) 118.1439, found 118.1449.
(x) 9-Allyl-9H-fluoren-9-ylamine (6j) 0::~O ~B(OH)2 NH3 _ \ I I/
1j MeOH 6j 6j was isolated as a clear, colorless oil: 'H NMR (CDCI3, 500 MHz) S 7.66 (2H, d, J = 7.5 Hz), 7.51 (2H, d, J = 7.0 Hz), 7.38 - 7.30 (4H, m), 5.57 (1 H, ddt, J = 17.0, 10.0, 7.5 Hz), 5.01 (1 H, dd, J = 17.0, 1.5 Hz), 4.96 (1H, d, J
=
10.0 Hz), 2.70 (2H, d, J = 7.5 Hz), 1.81 (2H, br s);13C NMR (CDCI3, 125 MHz) 8 150.86, 139.28, 133.22, 128.00, 127.53, 123.26, 119.85, 118.60, 64.71, 45.46; IR (film) v3360, 1640 cm-'; HRMS (ESI) m/z calcd. for C16H16N (MH+) 222.1283, found 222.1278.
O N\/\
1 i MeOH 6i 6i was isolated as a clear, colorless oil: 'H NMR (CDCI3, 300 MHz) 8 7.45 -7.15 (5H, m), 6.46 (1 H, d, J = 16.0 Hz), 6.28 (1 H, d, J = 16.0 Hz), 5.87 -5.72 (1 H, m), 5.18 - 5.05 (2H, m), 2.31 (1 H, dd, J = 16.5. 7.5 Hz), 2.23 (1 H, dd, J =
16.5, 8.0 Hz), 1.41 (2H, br s), 1.27 (3H, s); 13C NMR (CDCI3, 75 MHz) S
138.42, 137.22, 133.95, 128.39, 128.27, 127.06, 126.14, 118.45, 52.96, 48.00, 28.57; IR (film) v 3545, 1638 cm"'; HRMS (CI) m/z calcd. for C13H18N
(MH+) 118.1439, found 118.1449.
(x) 9-Allyl-9H-fluoren-9-ylamine (6j) 0::~O ~B(OH)2 NH3 _ \ I I/
1j MeOH 6j 6j was isolated as a clear, colorless oil: 'H NMR (CDCI3, 500 MHz) S 7.66 (2H, d, J = 7.5 Hz), 7.51 (2H, d, J = 7.0 Hz), 7.38 - 7.30 (4H, m), 5.57 (1 H, ddt, J = 17.0, 10.0, 7.5 Hz), 5.01 (1 H, dd, J = 17.0, 1.5 Hz), 4.96 (1H, d, J
=
10.0 Hz), 2.70 (2H, d, J = 7.5 Hz), 1.81 (2H, br s);13C NMR (CDCI3, 125 MHz) 8 150.86, 139.28, 133.22, 128.00, 127.53, 123.26, 119.85, 118.60, 64.71, 45.46; IR (film) v3360, 1640 cm-'; HRMS (ESI) m/z calcd. for C16H16N (MH+) 222.1283, found 222.1278.
(xi) 4-Allyl-l-benzylpiperidin-4-ylamine (6k) O H2N ~
B(OH)2 Bn MeOH Bn 1k 6k 6k was isolated as a clear, colorless oil: 'H NMR (CDCI3, 300 MHz) 8 7.32 -7.15 (5H, m), 5.81 (1 H, ddt, J 17.0, 10.0, 7.5 Hz), 5.12 - 5.01 (2H, m), 3.48 (2H, s), 2.58 - 2.48 (2H, dq, J 12.0, 4.0 Hz), 2.30 (2H, dt, J = 11.0, 3.0 Hz), 2.09 (2H, d, J = 7.5 Hz), 1.61 (2H, ddd, J = 13.0, 10.5, 4.0 Hz), 1.41 - 1.31 (2H, m), 1.08 (2H, br s); 13C NMR (CDCI3, 75 MHz) S 138.43, 133.51, 128.88, 127.95, 126.69, 118.29, 63.08, 49.39, 48.67, 47.60, 37.83; IR (film) v3422, 1639 cm '; HRMS (ESI) m/z calcd. for C15H23N2 (MH+) 231.1861, found 231.1862.
(xii) 1-Phenyl-l-thiophen-2-ylbut-3-enylamine (61) B(OH)2 H2N
O NH3 / I \
s MeOH
61 was isolated as a clear, colorless oil: 'H NMR (CDCI3, 500 MHz) 8 7.49 (2H, dt, J 7.5, 1.0 Hz), 7.33 (2H, t, J = 8.0 Hz), 7.27 - 7.17 (2H, m), 6.94 (1H, dd, J 5.0, 3.5 Hz), 6.90 (1H, dd, J = 3.5, 1.0 Hz), 5.62 (1H, ddt, J =
17.0, 10.0, 7.0 Hz), 5.19 (1 H, d, J = 17.0, 1.5 Hz), 5.13 (1H, ddd, J = 10.0, 1.5, 1.0 Hz), 3.08 (1 H, dd, J = 14.0, 7.0 Hz), 3.01 (1 H, dd, J = 14.0, 7.5 Hz), 2.09 (2H, br s); 13C NMR (CDCI3, 75 MHz) 8 154.78, 147.10, 133.63, 128.15, 126.77, 126.50, 126.01, 124.22, 123.64, 119.55, 59.32, 49.15; IR (film) v3410, 1639 cm-1; HRMS (CI) m/z calcd. for C14H16NS (MH+) 230.1003, found 230.1017.
(xiii) 1-(1 H-Indol-3-yl)-1-methylbut-3-enylamine (6m) O H2N Me O~N ~ B(OH)2 ~ NH I I
MeOH H
1m 6m 6m was isolated as a clear, colorless oil: 'H NMR (CDCI3, 500 MHz) 8 8.03 (1 H, br s), 7.84 (1 H, d, J = 8.0 Hz), 7.37 (1 H, d, J = 8.0 Hz), 7.19 (1 H, dt, J =
7.5, 1.0 Hz), 7.12 (1 H, dt, J = 7.5, 1.0 Hz), 7.07 (1 H, d, J = 2.5 Hz), 5.65 (1 H, ddt, J = 17.5, 10.0, 7.5 Hz), 5.06 (1H, d, J = 17.5 Hz), 5.03 (1H, d, J = 10.0 Hz), 2.79 (1 H, dd, J = 13.5, 7.5 Hz), 2.63 (1 H, dd, J = 13.5, 7.5 Hz), 1.85 (2H, br s), 1.61 (3H, s); 13C NMR (CDCI3, 75 MHz) 8 137.30, 134.93, 125.20, 124.74, 121.77, 120.91, 120.51, 119.21, 117.92, 111.35, 52.39, 48.20, 30.00;
IR (film) v3205, 1639 cm-'.
(xiv) 1-Allyl-4-tert-butylcyclohexylamine (6n) 0 B(OH)2 NH2 / ~
t Bu~ NH3 t-Bu 1 n MeOH 6n 6n was isolated as a clear, colorless oil (d.r. = 87:13). The diastereomeric ratio was determined by'H NMR of the crude sample. Main diastereomer:'H
NMR (CDCI3, 300 MHz) 8 5.83 (1 H, ddt, J = 17.0, 10.5, 7.5 Hz), 5.08 - 4.98 (2H, m), 2.02 (2H, d, J = 7.5 Hz), 1.60 - 1.40 (4H, m), 1.34 - 1.00 (6H, m), 0.90 - 0.83 (1H, m), 0.83 (9H, s); 13C NMR (CDCI3, 75 MHz) S 134.26, 117.87, 50.16, 49.94, 48.11, 38.43, 32.30, 27.50, 22.42; IR (film) v3368, 1638 cm-'; HRMS (CI) m/z calcd. for C13H26N (MH+) 196.2065, found 196.2068.The stereochemistry of 6n (axial NH2) was confirmed by converting it 5 (allylbromide, iPr2NEt, CH2CI2; 49%) to the previously known compound N-Allyl-l-Allyl-4-tert-butylcyclohexylamine (axial NHCH2CH=CH) [D. L. Wright, J.
P. Schulte, II and M. A. Page, Org. Left., 2000, 2, 1847].
(xv) 2-Allyl-bicyclo[2.2.1]hept-2-ylamine (6o) B(OH)2 O MeOH NH2 1o 6o 6o was isolated as a clear, colorless oil (d.r. = 94:6). The diastereomeric ratio was determined by 'H NMR of the crude sample. Main diastereomer: 'H
NMR (CDCI3, 300 MHz) S 5.78 (1 H, ddt, J = 17.0, 10.5, 7.5 Hz), 5.08 - 4.97 (2H, m), 2.10 (2H, d, J = 7.5 Hz), 1.88 (1 H, d, J = 3.5 Hz), 1.78 (1 H, ddt, J =
12.5, 9.0, 3.0 Hz), 1.60 - 1.42 (3H, m), 1.24 - 1.08 (6H, m), 0.82 (1 H, dd, J
=
12.5, 3.0 Hz); 13C NMR (CDCI3, 75 MHz) S 134.57, 117.95, 57.99, 47.41, 46.69, 46.48, 38.30, 37.54, 28.43, 22.92; IR (film) p3400, 1638 cm-1; HRMS
(CI) m/z calcd. for CjoH1$N (MH+) 152.1439, found 152.1435.
(xvi) 2-Amino-1,2-diphenylpent-4-en-1-ol (6p) p B(OH)2 H2N
Ph'j~' Ph NH3 Ph~Ph OH MeOH OH
ip 6p 6p was isolated as a clear, colorless crystalline solid. The diastereomeric ratio (d.r. = 88:12) was determined by 'H NMR of the crude sample. Main diastereomer: m.p. = 85-86 C (CH2CI2);'H NMR (CDCI3, 300 MHz) 8 7.30 -7.06 (8H, m), 6.90 - 6.85 (2H, m), 5.56 - 5.40 (1 H, m), 5.12 (1 H, d, J =
17.0 Hz), 5.00 (1 H, d, J = 10.0 Hz), 4.74 (1 H, s), 2.95 (1 H, dd, J = 14.0, 5.5 Hz), 2.65 (1H, dd, J = 14.0, 9.0 Hz), 2.08 (3H, br s); 13C NMR (CDCI3, 75 MHz) 8142.54, 140.02, 133.74, 127.62, 127.42, 127.24, 127.10, 126.71, 126.50, 118.96, 79.91, 61.70, 43.45; IR (film) p3422, 1638 cm'; HRMS (CI) m/z calcd. for C17H2ONO (MH+) 254.1545, found 254.1543.
(xvii) (1 S*,2R*,5R*)-2-Allyl-4,6,6-trimethylbicyclo[3. 1. 1 ]hept-3-en-2-ylamine (6q) O B(OH)2 H2N
MeOH
1q 6q 6q was isolated as a clear, colorless oil (d.r. = 97:3). The diastereomeric ratio was determined by'H NMR of the crude sample. 'H NMR (CDCI3, 300 MHz) S 5.85 (1 H, ddt, J = 17.5, 10.5, 7.5 Hz), 5.13 - 5.02 (3H, m), 2.36 (1 H, dt, J =
9.0, 5.5 Hz), 2.20 (1 H, dd, J = 13.5, 7.0 Hz), 2.13 (1 H, dd, J = 13.5, 8.0 Hz), 1.98 - 1.88 (2H, m), 1.68 (3H, d, J = 1.5 Hz), 1.60 - 1.35 (3H, m), 1.33 (3H, s), 1.05 (3H, s);13C NMR (CDCI3, 75 MHz) S 143.51, 133.89, 124.42, 118.23, 57.24, 52.84, 47.64, 45.88, 41.87, 33.78, 27.36, 23.85, 22.77; IR (film) v3410, 1713, 1681, 1623 cm-'; HRMS (ESI) m/z calcd. for C13H22N (MH+) 192.1752, found 192.1756.
Example 2: Results for the Allylation of N-Unsubstituted Imines Derived from Ketones:
The allylboron class of reagents were demonstrably superior in terms of reactivity and chemoselectivity [W. R. Roush, in Houben-Weyl, Stereoselective Synthesis, ed. G. Heimchen, R. W. Hoffmann, J. Mulzer and E. Schaumann, Georg Thieme Verlag, Stuttgart, 1995, vol. E21b, pp 1410-1486; D. S. Matteson, in Stereodirected Synthesis with Organoboranes, Springer-Verlag, Berlin, 1995]. In order to ascertain the reagent of choice, the present inventors have investigated the addition of a range of allylboron compounds to N-unsubstituted ketimines which are derived from ketones.
The results are shown in Table 1. As can be seen from the Table, the more reactive allylboron reagents, 5d and 5e [H. C. Brown, U. S. Racherla and P. J.
Pellechia, J. Org. Chem., 1990, 55, 1868] displayed the highest efficacy in terms of isolated yields of homollylic amine 6a (entries 4 and 5). A major issue of concern in all these reactions-chemoselectivity of imine versus ketone addition-was addressed by analyzing the organic extracts from the acid-base workup of 6a (entries 4,5). It was determined that the corresponding homoallylic alcohol of 6a was formed in minor amounts (55%).
Due to the ease of the preparation of the allylboron reagent 5e and the simple purification of the resulting products, the present inventors have further investigated a series of ketones with reagent 5e in methanolic ammonia (Table 2). Aliphatic (entries 1-4), electron rich aromatic (entry 5), electron deficient aromatic (entries 6 and 7), a,(3-unsaturated (entry 8), cyclic (entries 9 and 10) and heterocyclic-substituted (entries 11 and 12) ketones were successfully allylated under the standard conditions. The resulting homoallylic amines (6) were easily isolated in high yields through simple acid-base extraction, and in all cases but one, did not require any further purification. A variety of functional groups were also found to be tolerated in the reaction sequence including the nitro (entry 7), cyano (entry 6), unprotected hydroxy (entry 2) and amino groups (entry 12).
Still further, the present inventors have expanded the scope of the study to include the allylation of ketones containing a pre-existing stereocenter. The substrates (ln-q) were subjected to the standard set of reaction and work-up conditions, the results of which are shown in Table 3.
Good to excellent yields of tertiary carbinamines 6n-q were obtained in all cases, while the observed diastereoselectivities, as determined by 'H NMR, varied from modest for the reaction of 4-tert-butylcyclohexanone, norchamphor, and benzoin (equations 1, 2 and 3 respectively) to excellent for verbenone (equation 4).
Example 3: General Procedure for the Crotylation of N-Unsubstituted Imines Derived from Ketones:
The protocol for the allylation of N-unsubstituted imines derived from ketones was followed with the exception that the boron reagent was changed to either either (E)- or (Z)-crotylboronic acid (2M in MeOH, 0.5 mL, 1.00 mmol).
(i) (1S*,2S*)-1,2-Dimethyl-l-(4-trifluoromethylphenyl)but-3-enylamine (4a) 0 B(OH)z J3~
Me F3C NH3 F3C Me Me OH 4a 4a was isolated as a clear, colorless oil (d.r. = 97:3). The diastereomeric ratio was determined by'H NMR of the crude sample. 'H NMR (CDCI3, 300 MHz) S 7.60 (2H, d, J = 9.0 Hz), 7.56 (2H, d, J = 9.0 Hz), 5.66 - 5.53 (1 H, m), 5.10 -5.00 (2H, m), 2.53 ('H, pentet, J = 7.0 Hz), 1.49 (2H, br s), 1.46 (3H, s), 0.91 (3H, d, J = 7.0 Hz); 13C NMR (CDCI3, 75 MHz) S 152.45, 139.63, 128.52 (q, J
= 30 Hz), 126.37, 124.79 (q, J = 3.5 Hz), 124.64 (q, J = 270 Hz), 116.45, 55.96, 48.82, 27.13, 14.30; IR (film) v3378, 1636 cm-1 ; HRMS (ESI) m/z calcd. for C13H17F3N (MH+) 244.1313, found 244.1305.
(ii) (1 S*,2R*)-1,2-Dimethyl-l-(4-trifluoromethylphenyl)but-3-enylamine (4b) j 0 H' ~ B(OH)2 H2N Me F3C NH3 F3C Me MeOH 4b 4b was isolated as a clear, colorless oil (d.r. = 96:4). The diastereomeric ratio was determined by'H NMR of the crude sample. 'H NMR (CDCI3, 300 MHz) S 7.56 (4H, apparent s), 5.75 (1 H, ddd, J = 18.5, 10.5, 8.0 Hz), 5.13 - 5.03 (2H, m), 2.53 (1 H, pentet, J = 7.5 Hz), 1.58 (2H, br s), 1.43 (3H, s), 0.78 (3H, d, J = 7.5 Hz); 13C NMR (CDCI3, 75 MHz) S 152.10, 139.46, 128.02 (q, J = 30 Hz), 126.23, 125.83 (q, J = 270 Hz), 124.73 (q, J = 3.5 Hz), 116.34, 55.56, 48.65, 29.51, 14.51; IR (film) v3390, 1637 cm '; HRMS (ESI) m/z calcd. for C13H17F3N (MH+) 244.1313, found 244.1304.
(iii) (2S*,3S*)-2-Amino-3-methyl-2-phenylpent-4-enoic acid amide (4c) B(OH)2 H2N CONH2 I ~ C02Me H_ I \ _ \
/ NH3 / Me MeOH 4c 4c was isolated as a clear, colorless, crystalline solid (d.r. = 97:3): m.p =
C (CH2CI2); 'H NMR (CDCI3, 300 MHz) S 7.65 - 7.58 (2H, m), 7.35 - 7.18 (4H, m), 6.20 (1 H, br s), 5.46 (1 H, ddd, J = 17.5, 10.0, 6.5 Hz), 5.05 -4.95 (2H, m), 3.59 (1 H, pentet, J = 6.5 Hz), 1.59 (2H, br s), 1.08 (3H, d, J = 6.5 Hz); 13C NMR (CDCI3, 75 MHz) S 176.99, 141.60, 138.23, 128.16, 127.04, 125.64, 116.69, 65.54, 42.58, 12.27; IR (film) v3441, 3207, 1710, 1620, 1637 cm '; HRMS (CI) m/z calcd. for CjjH17N20 (MH+) 205.1341, found 205.1332.
(iv) (2S*,3R*)-2-Amino-3-methyl-2-phenylpent-4-enoic acid amide (4d) 0 H\ ~ /B(OH)2 H2N CONH2 C02Me 71/
NH3 / Me MeOH 4d 4d was isolated as a clear, colorless, crystalline solid (d.r. = 96:4): m.p =
C (CH2CI2); 'H NMR (CDCI3, 500 MHz) 8 7.64 - 7.60 (2H, m), 7.35 - 7.24 (4H, m), 6.02 (1 H, ddd, J = 17.5, 10.5, 5.0 Hz), 5.59 (1 H, br s), 5.26 (1 H, dt, J
= 10.5, 1.5 Hz), 5.17 (1 H, dt, J = 17.5, 1.5 Hz), 3.76 - 3.69 (1 H, m), 1.63 (2H, 10 br s), 0.73 (3H, d, J = 7.0 Hz); 13C NMR (CDCI3, 125 MHz) b 177.15, 141.16, 139.07, 128.24, 127.06, 125.54, 117.21, 65.47, 41.87, 10.97; IR (film) v3432, 3170, 1715, 1633 cm '; HRMS (CI) m/z calcd. for CjjH17N20 (MH+) 205.1341, found 205.1337.
15 (v) (1S*,2S*)-1,2-Dimethyl-l-phenylbut-3-enylamine (4e) 0 B(OH)2 H2N Me H~
I i NH3 IMe MeOH 4e 4e was isolated as a clear, colorless oil (d.r. = 97:3). The diastereomeric ratio 20 was determined by'H NMR of the crude sample. 'H NMR (CDCI3, 300 MHz) S 7.42 - 7.10 (4H, m), 5.65 -5.55 (1 H, m), 4.96 - 5.02 (2H, m), 2.45 (1 H, dq, J
= 7.0 Hz), 1.50 (2H, br s), 1.38 (3H, s), 0.83 (3H, d, J = 7.0 Hz); 13C NMR
(CDCI3, 75 MHz) S 148.22, 140.30, 127.87, 126.13, 125.79, 115.90, 56.81, 49.02, 26.68, 14.49 [C. Ogawa, M. Sugiura and S. Kobayashi, J. Org. Chem., 25 2002, 67, 5359].
(vi) 2-Amino-2,3-dimethylpent-4-enoicacid amide (4f) 0 Y~B~OH~2 H2N CONH2 H _ ~~I
C02Me NH3 Me if MeOH 4f 4f was isolated as a clear, colorless oil (d.r. = 60:40). The diastereomeric ratio was determined by 'H NMR of the crude sample. Main diastereomer:'H
NMR (CDCI3, 300 MHz) S 7.41 (1H, br s), 5.95 - 5.60 (2H, m), 5.15 - 5.05 (2H, m), 2.81 (1 H, pentet, J = 6.5 Hz), 1.28 (3H, s), 1.26 (2H, br s), 0.99 (3H, d, J = 6.5 Hz); 13C NMR (CDCI3, 75 MHz) S 180.06, 139.33, 116.28, 59.62, 43.29, 25.10, 11.88; IR (film) u3444, 3250, 1691, 1654, 1557 cm-1; HRMS
(CI) m/z calcd. for C7H14N20 (MH+) 143.1184, found 143.1186.
Example 4: Results for the Crotylation of N-Unsubstituted Imines Derived from Ketones:
The crotylation of a select number of ketones was examined under a slightly modified set of conditions (2.0 equiv of 5e, 10 equiv. of NH3, rt, 24 h) (Table 4). Excellent diastereoselectivities were obtained with acetophenone derivatives (entries 1-4). The anti diastereomer (4a/c) was formed when (E)-crotylboronic acid (7a) was employed as the reagent, while (Z)-crotylboronic acid (7b) afforded the syn diastereomer (4b/d). The stereochemistry of the crotylated products 4 were assigned based upon the reaction of 7a with acetophenone (entry 5) which afforded the previously known anti diastereomer 4e in moderate yield and excellent diastereoselectivity (d.r. =
97:3) [C. Ogawa, M. Sugiura and S. Kobayashi, J. Org. Chem., 2002, 67, 5359]. Crotylation of methylpyruvate (entry 6), on the other hand, was not diastereoselective likely due to the similar steric sizes of the methyl and methylformate groups. The results from entries 3-5 also constitute a convenient route to a-allylated amino acid derivatives.
While the present invention has been described with reference to what are presently considered to be the preferred examples, it is to be understood that the invention is not limited to the disclosed examples. To the contrary, the invention is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.
All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term.
Table 1: Addition of allyl boron reagents (5) to N-unsubstituted ketimine derived from la.
0 ~BR2 H2N Me ~ 5 (1.6 equiv.) ~
I/ NH3 (ca. 10 equiv.) Br I/
Br MeOH, rt, 16 h 1a 6a Entry 5 Yield of 6a (%)a O
1 B (5a) 35 ~_o 2 10 k (5b) 29 B_O
3 6(O'Pr)2 (5c) 43 4 0 70b' i ~ ~ (sd) BO
B(oH)2 (se) 79b a Isolated yield after acid-base extraction. b Anal sis (H NMR, 2.4,6-trimethylbenzene standard) of the organic phase from the acid-base work-up revealed <~% of the , correspondin homoaIlylic alcohol- Isolated ield after aci -base extraction and preparative W.
Table 2: Reaction of N-unsubstituted imines derived from ketones with allylboronic acid (5e)a.
5e '5~B(OH)2 O (1.6 equiv) H2N R2 R'R2 NH3 (10 equiv.) R1 " \
1 MeOH, rt, 16 h 6 Entry Ketone Yield (%)b 1 Et2C=O (1 b) 73 (6b) O
2 HOI-lk (I c) 80 (6c) O
3 Ph'-APh (ld) 78 (6d) O
4 (le) 85 (6e) 4- (1f) 72 (6f) MeOC6H4C(O)CH2CH3 6 4-NCC6H4C(O)CH3 (lg) 80 (6g) 7 4-O2NC6H4C(O)CH3 (1h) 87 (6h) O
8 Ph (11) 70 (61)c O
9 0 0 (1J) 78 (6J) (1 k) 92(6k) N
Bn 11 s Ph (11) 75(61) O
m) 80 (6m) 12 07N (l H
Standard reaction conditions: A solution of the ketone (0.5 mmol), ammonia (ca. 7N in MeOH
5 0.75 mL ca. 10 eguiv.) and alTylboronic acid (5ej ~2M in N~ebOH, 0.40 rnL, 0.80 mmol) was stirred for 6 h at rt. Isolated ield after acid-base extraction.
Isolated yield attyer acid-base extraction, and preparative 1 LC.
Table 3: Reaction of N-unsubstituted imines derived from ketones with allylboronic acid (5e) in which the ketones contain a pre-existing stereocentre.
5e (1.6 equiv.) NH2 NH3, MeOH
t Bu \~~ ~
t-Bu16 h, rt 1n 6n 95%, d.r. = 87:13 5e (1.6 equiv.) NH3, MeOH
(2) 16h,rt 0 NH2 1o 6o 91 %, d.r. = 94:6 O 5e (1.6 equiv.) H2N -//
~Ph NH3, MeOH ~e; Ph (3) Ph 16 h, rt Ph/ \~
OH OH
1p 6p 81 %, d. r. = 88:12 NHz 5e (1.6 equiv.) NH3, MeOH
16 h, rt (4) lq 6q 84%, d.r. = 97:3 Table 4: Reaction of N-unsubstituted ketimines with (E)- and (Z)-crotylboronic acid (7a/b)a R3r B(OHh (2.0equfv.) ) O 7a: R3 = Me, R4 = H H2N R2 R, R2 7b:R3=H,R4=Me NH3 (10 equiv.) Rg R
MeOH, rt, 24 h Entry Crotyl Product Yield d.r.
reagent (%)"
1 7a F3CJ\ \ 80 (4a) 97:3 / =
2 7b F3C I\ \ 73 (4b)' 96:4 /
e~z 3 7a 95 (4c) 97:
4 7b I\ \ 92 (4d)'" 96:4 H2N :
7a I\ _\ 50 (4e) 97:3 6 7a 88 (41)' 60:40 Standard reaction conditions: ketone (0.5 mmol)- ammonia (ca. 7N in MeOH,, 0.75 5 mL, ca.,10 e uiv.) and crot~lboronic acid (7a(b) (2M 'n MeOH, 0;50 n~L, 1.00 mmol~
were stirred ~or 24 h at rt. Isolated yiela aTter acid-pase extraction.
Isolated yiel after acio-base extraction, and preparative, TLC. ~Viethyl benzoylformate wa em lo ea as the starting ketone and aminol sis oT the _ ester was observed.
Mepthy~pyruvate was empoyed as the startmg ketyone, and ammolysis of the ester was observed.
B(OH)2 Bn MeOH Bn 1k 6k 6k was isolated as a clear, colorless oil: 'H NMR (CDCI3, 300 MHz) 8 7.32 -7.15 (5H, m), 5.81 (1 H, ddt, J 17.0, 10.0, 7.5 Hz), 5.12 - 5.01 (2H, m), 3.48 (2H, s), 2.58 - 2.48 (2H, dq, J 12.0, 4.0 Hz), 2.30 (2H, dt, J = 11.0, 3.0 Hz), 2.09 (2H, d, J = 7.5 Hz), 1.61 (2H, ddd, J = 13.0, 10.5, 4.0 Hz), 1.41 - 1.31 (2H, m), 1.08 (2H, br s); 13C NMR (CDCI3, 75 MHz) S 138.43, 133.51, 128.88, 127.95, 126.69, 118.29, 63.08, 49.39, 48.67, 47.60, 37.83; IR (film) v3422, 1639 cm '; HRMS (ESI) m/z calcd. for C15H23N2 (MH+) 231.1861, found 231.1862.
(xii) 1-Phenyl-l-thiophen-2-ylbut-3-enylamine (61) B(OH)2 H2N
O NH3 / I \
s MeOH
61 was isolated as a clear, colorless oil: 'H NMR (CDCI3, 500 MHz) 8 7.49 (2H, dt, J 7.5, 1.0 Hz), 7.33 (2H, t, J = 8.0 Hz), 7.27 - 7.17 (2H, m), 6.94 (1H, dd, J 5.0, 3.5 Hz), 6.90 (1H, dd, J = 3.5, 1.0 Hz), 5.62 (1H, ddt, J =
17.0, 10.0, 7.0 Hz), 5.19 (1 H, d, J = 17.0, 1.5 Hz), 5.13 (1H, ddd, J = 10.0, 1.5, 1.0 Hz), 3.08 (1 H, dd, J = 14.0, 7.0 Hz), 3.01 (1 H, dd, J = 14.0, 7.5 Hz), 2.09 (2H, br s); 13C NMR (CDCI3, 75 MHz) 8 154.78, 147.10, 133.63, 128.15, 126.77, 126.50, 126.01, 124.22, 123.64, 119.55, 59.32, 49.15; IR (film) v3410, 1639 cm-1; HRMS (CI) m/z calcd. for C14H16NS (MH+) 230.1003, found 230.1017.
(xiii) 1-(1 H-Indol-3-yl)-1-methylbut-3-enylamine (6m) O H2N Me O~N ~ B(OH)2 ~ NH I I
MeOH H
1m 6m 6m was isolated as a clear, colorless oil: 'H NMR (CDCI3, 500 MHz) 8 8.03 (1 H, br s), 7.84 (1 H, d, J = 8.0 Hz), 7.37 (1 H, d, J = 8.0 Hz), 7.19 (1 H, dt, J =
7.5, 1.0 Hz), 7.12 (1 H, dt, J = 7.5, 1.0 Hz), 7.07 (1 H, d, J = 2.5 Hz), 5.65 (1 H, ddt, J = 17.5, 10.0, 7.5 Hz), 5.06 (1H, d, J = 17.5 Hz), 5.03 (1H, d, J = 10.0 Hz), 2.79 (1 H, dd, J = 13.5, 7.5 Hz), 2.63 (1 H, dd, J = 13.5, 7.5 Hz), 1.85 (2H, br s), 1.61 (3H, s); 13C NMR (CDCI3, 75 MHz) 8 137.30, 134.93, 125.20, 124.74, 121.77, 120.91, 120.51, 119.21, 117.92, 111.35, 52.39, 48.20, 30.00;
IR (film) v3205, 1639 cm-'.
(xiv) 1-Allyl-4-tert-butylcyclohexylamine (6n) 0 B(OH)2 NH2 / ~
t Bu~ NH3 t-Bu 1 n MeOH 6n 6n was isolated as a clear, colorless oil (d.r. = 87:13). The diastereomeric ratio was determined by'H NMR of the crude sample. Main diastereomer:'H
NMR (CDCI3, 300 MHz) 8 5.83 (1 H, ddt, J = 17.0, 10.5, 7.5 Hz), 5.08 - 4.98 (2H, m), 2.02 (2H, d, J = 7.5 Hz), 1.60 - 1.40 (4H, m), 1.34 - 1.00 (6H, m), 0.90 - 0.83 (1H, m), 0.83 (9H, s); 13C NMR (CDCI3, 75 MHz) S 134.26, 117.87, 50.16, 49.94, 48.11, 38.43, 32.30, 27.50, 22.42; IR (film) v3368, 1638 cm-'; HRMS (CI) m/z calcd. for C13H26N (MH+) 196.2065, found 196.2068.The stereochemistry of 6n (axial NH2) was confirmed by converting it 5 (allylbromide, iPr2NEt, CH2CI2; 49%) to the previously known compound N-Allyl-l-Allyl-4-tert-butylcyclohexylamine (axial NHCH2CH=CH) [D. L. Wright, J.
P. Schulte, II and M. A. Page, Org. Left., 2000, 2, 1847].
(xv) 2-Allyl-bicyclo[2.2.1]hept-2-ylamine (6o) B(OH)2 O MeOH NH2 1o 6o 6o was isolated as a clear, colorless oil (d.r. = 94:6). The diastereomeric ratio was determined by 'H NMR of the crude sample. Main diastereomer: 'H
NMR (CDCI3, 300 MHz) S 5.78 (1 H, ddt, J = 17.0, 10.5, 7.5 Hz), 5.08 - 4.97 (2H, m), 2.10 (2H, d, J = 7.5 Hz), 1.88 (1 H, d, J = 3.5 Hz), 1.78 (1 H, ddt, J =
12.5, 9.0, 3.0 Hz), 1.60 - 1.42 (3H, m), 1.24 - 1.08 (6H, m), 0.82 (1 H, dd, J
=
12.5, 3.0 Hz); 13C NMR (CDCI3, 75 MHz) S 134.57, 117.95, 57.99, 47.41, 46.69, 46.48, 38.30, 37.54, 28.43, 22.92; IR (film) p3400, 1638 cm-1; HRMS
(CI) m/z calcd. for CjoH1$N (MH+) 152.1439, found 152.1435.
(xvi) 2-Amino-1,2-diphenylpent-4-en-1-ol (6p) p B(OH)2 H2N
Ph'j~' Ph NH3 Ph~Ph OH MeOH OH
ip 6p 6p was isolated as a clear, colorless crystalline solid. The diastereomeric ratio (d.r. = 88:12) was determined by 'H NMR of the crude sample. Main diastereomer: m.p. = 85-86 C (CH2CI2);'H NMR (CDCI3, 300 MHz) 8 7.30 -7.06 (8H, m), 6.90 - 6.85 (2H, m), 5.56 - 5.40 (1 H, m), 5.12 (1 H, d, J =
17.0 Hz), 5.00 (1 H, d, J = 10.0 Hz), 4.74 (1 H, s), 2.95 (1 H, dd, J = 14.0, 5.5 Hz), 2.65 (1H, dd, J = 14.0, 9.0 Hz), 2.08 (3H, br s); 13C NMR (CDCI3, 75 MHz) 8142.54, 140.02, 133.74, 127.62, 127.42, 127.24, 127.10, 126.71, 126.50, 118.96, 79.91, 61.70, 43.45; IR (film) p3422, 1638 cm'; HRMS (CI) m/z calcd. for C17H2ONO (MH+) 254.1545, found 254.1543.
(xvii) (1 S*,2R*,5R*)-2-Allyl-4,6,6-trimethylbicyclo[3. 1. 1 ]hept-3-en-2-ylamine (6q) O B(OH)2 H2N
MeOH
1q 6q 6q was isolated as a clear, colorless oil (d.r. = 97:3). The diastereomeric ratio was determined by'H NMR of the crude sample. 'H NMR (CDCI3, 300 MHz) S 5.85 (1 H, ddt, J = 17.5, 10.5, 7.5 Hz), 5.13 - 5.02 (3H, m), 2.36 (1 H, dt, J =
9.0, 5.5 Hz), 2.20 (1 H, dd, J = 13.5, 7.0 Hz), 2.13 (1 H, dd, J = 13.5, 8.0 Hz), 1.98 - 1.88 (2H, m), 1.68 (3H, d, J = 1.5 Hz), 1.60 - 1.35 (3H, m), 1.33 (3H, s), 1.05 (3H, s);13C NMR (CDCI3, 75 MHz) S 143.51, 133.89, 124.42, 118.23, 57.24, 52.84, 47.64, 45.88, 41.87, 33.78, 27.36, 23.85, 22.77; IR (film) v3410, 1713, 1681, 1623 cm-'; HRMS (ESI) m/z calcd. for C13H22N (MH+) 192.1752, found 192.1756.
Example 2: Results for the Allylation of N-Unsubstituted Imines Derived from Ketones:
The allylboron class of reagents were demonstrably superior in terms of reactivity and chemoselectivity [W. R. Roush, in Houben-Weyl, Stereoselective Synthesis, ed. G. Heimchen, R. W. Hoffmann, J. Mulzer and E. Schaumann, Georg Thieme Verlag, Stuttgart, 1995, vol. E21b, pp 1410-1486; D. S. Matteson, in Stereodirected Synthesis with Organoboranes, Springer-Verlag, Berlin, 1995]. In order to ascertain the reagent of choice, the present inventors have investigated the addition of a range of allylboron compounds to N-unsubstituted ketimines which are derived from ketones.
The results are shown in Table 1. As can be seen from the Table, the more reactive allylboron reagents, 5d and 5e [H. C. Brown, U. S. Racherla and P. J.
Pellechia, J. Org. Chem., 1990, 55, 1868] displayed the highest efficacy in terms of isolated yields of homollylic amine 6a (entries 4 and 5). A major issue of concern in all these reactions-chemoselectivity of imine versus ketone addition-was addressed by analyzing the organic extracts from the acid-base workup of 6a (entries 4,5). It was determined that the corresponding homoallylic alcohol of 6a was formed in minor amounts (55%).
Due to the ease of the preparation of the allylboron reagent 5e and the simple purification of the resulting products, the present inventors have further investigated a series of ketones with reagent 5e in methanolic ammonia (Table 2). Aliphatic (entries 1-4), electron rich aromatic (entry 5), electron deficient aromatic (entries 6 and 7), a,(3-unsaturated (entry 8), cyclic (entries 9 and 10) and heterocyclic-substituted (entries 11 and 12) ketones were successfully allylated under the standard conditions. The resulting homoallylic amines (6) were easily isolated in high yields through simple acid-base extraction, and in all cases but one, did not require any further purification. A variety of functional groups were also found to be tolerated in the reaction sequence including the nitro (entry 7), cyano (entry 6), unprotected hydroxy (entry 2) and amino groups (entry 12).
Still further, the present inventors have expanded the scope of the study to include the allylation of ketones containing a pre-existing stereocenter. The substrates (ln-q) were subjected to the standard set of reaction and work-up conditions, the results of which are shown in Table 3.
Good to excellent yields of tertiary carbinamines 6n-q were obtained in all cases, while the observed diastereoselectivities, as determined by 'H NMR, varied from modest for the reaction of 4-tert-butylcyclohexanone, norchamphor, and benzoin (equations 1, 2 and 3 respectively) to excellent for verbenone (equation 4).
Example 3: General Procedure for the Crotylation of N-Unsubstituted Imines Derived from Ketones:
The protocol for the allylation of N-unsubstituted imines derived from ketones was followed with the exception that the boron reagent was changed to either either (E)- or (Z)-crotylboronic acid (2M in MeOH, 0.5 mL, 1.00 mmol).
(i) (1S*,2S*)-1,2-Dimethyl-l-(4-trifluoromethylphenyl)but-3-enylamine (4a) 0 B(OH)z J3~
Me F3C NH3 F3C Me Me OH 4a 4a was isolated as a clear, colorless oil (d.r. = 97:3). The diastereomeric ratio was determined by'H NMR of the crude sample. 'H NMR (CDCI3, 300 MHz) S 7.60 (2H, d, J = 9.0 Hz), 7.56 (2H, d, J = 9.0 Hz), 5.66 - 5.53 (1 H, m), 5.10 -5.00 (2H, m), 2.53 ('H, pentet, J = 7.0 Hz), 1.49 (2H, br s), 1.46 (3H, s), 0.91 (3H, d, J = 7.0 Hz); 13C NMR (CDCI3, 75 MHz) S 152.45, 139.63, 128.52 (q, J
= 30 Hz), 126.37, 124.79 (q, J = 3.5 Hz), 124.64 (q, J = 270 Hz), 116.45, 55.96, 48.82, 27.13, 14.30; IR (film) v3378, 1636 cm-1 ; HRMS (ESI) m/z calcd. for C13H17F3N (MH+) 244.1313, found 244.1305.
(ii) (1 S*,2R*)-1,2-Dimethyl-l-(4-trifluoromethylphenyl)but-3-enylamine (4b) j 0 H' ~ B(OH)2 H2N Me F3C NH3 F3C Me MeOH 4b 4b was isolated as a clear, colorless oil (d.r. = 96:4). The diastereomeric ratio was determined by'H NMR of the crude sample. 'H NMR (CDCI3, 300 MHz) S 7.56 (4H, apparent s), 5.75 (1 H, ddd, J = 18.5, 10.5, 8.0 Hz), 5.13 - 5.03 (2H, m), 2.53 (1 H, pentet, J = 7.5 Hz), 1.58 (2H, br s), 1.43 (3H, s), 0.78 (3H, d, J = 7.5 Hz); 13C NMR (CDCI3, 75 MHz) S 152.10, 139.46, 128.02 (q, J = 30 Hz), 126.23, 125.83 (q, J = 270 Hz), 124.73 (q, J = 3.5 Hz), 116.34, 55.56, 48.65, 29.51, 14.51; IR (film) v3390, 1637 cm '; HRMS (ESI) m/z calcd. for C13H17F3N (MH+) 244.1313, found 244.1304.
(iii) (2S*,3S*)-2-Amino-3-methyl-2-phenylpent-4-enoic acid amide (4c) B(OH)2 H2N CONH2 I ~ C02Me H_ I \ _ \
/ NH3 / Me MeOH 4c 4c was isolated as a clear, colorless, crystalline solid (d.r. = 97:3): m.p =
C (CH2CI2); 'H NMR (CDCI3, 300 MHz) S 7.65 - 7.58 (2H, m), 7.35 - 7.18 (4H, m), 6.20 (1 H, br s), 5.46 (1 H, ddd, J = 17.5, 10.0, 6.5 Hz), 5.05 -4.95 (2H, m), 3.59 (1 H, pentet, J = 6.5 Hz), 1.59 (2H, br s), 1.08 (3H, d, J = 6.5 Hz); 13C NMR (CDCI3, 75 MHz) S 176.99, 141.60, 138.23, 128.16, 127.04, 125.64, 116.69, 65.54, 42.58, 12.27; IR (film) v3441, 3207, 1710, 1620, 1637 cm '; HRMS (CI) m/z calcd. for CjjH17N20 (MH+) 205.1341, found 205.1332.
(iv) (2S*,3R*)-2-Amino-3-methyl-2-phenylpent-4-enoic acid amide (4d) 0 H\ ~ /B(OH)2 H2N CONH2 C02Me 71/
NH3 / Me MeOH 4d 4d was isolated as a clear, colorless, crystalline solid (d.r. = 96:4): m.p =
C (CH2CI2); 'H NMR (CDCI3, 500 MHz) 8 7.64 - 7.60 (2H, m), 7.35 - 7.24 (4H, m), 6.02 (1 H, ddd, J = 17.5, 10.5, 5.0 Hz), 5.59 (1 H, br s), 5.26 (1 H, dt, J
= 10.5, 1.5 Hz), 5.17 (1 H, dt, J = 17.5, 1.5 Hz), 3.76 - 3.69 (1 H, m), 1.63 (2H, 10 br s), 0.73 (3H, d, J = 7.0 Hz); 13C NMR (CDCI3, 125 MHz) b 177.15, 141.16, 139.07, 128.24, 127.06, 125.54, 117.21, 65.47, 41.87, 10.97; IR (film) v3432, 3170, 1715, 1633 cm '; HRMS (CI) m/z calcd. for CjjH17N20 (MH+) 205.1341, found 205.1337.
15 (v) (1S*,2S*)-1,2-Dimethyl-l-phenylbut-3-enylamine (4e) 0 B(OH)2 H2N Me H~
I i NH3 IMe MeOH 4e 4e was isolated as a clear, colorless oil (d.r. = 97:3). The diastereomeric ratio 20 was determined by'H NMR of the crude sample. 'H NMR (CDCI3, 300 MHz) S 7.42 - 7.10 (4H, m), 5.65 -5.55 (1 H, m), 4.96 - 5.02 (2H, m), 2.45 (1 H, dq, J
= 7.0 Hz), 1.50 (2H, br s), 1.38 (3H, s), 0.83 (3H, d, J = 7.0 Hz); 13C NMR
(CDCI3, 75 MHz) S 148.22, 140.30, 127.87, 126.13, 125.79, 115.90, 56.81, 49.02, 26.68, 14.49 [C. Ogawa, M. Sugiura and S. Kobayashi, J. Org. Chem., 25 2002, 67, 5359].
(vi) 2-Amino-2,3-dimethylpent-4-enoicacid amide (4f) 0 Y~B~OH~2 H2N CONH2 H _ ~~I
C02Me NH3 Me if MeOH 4f 4f was isolated as a clear, colorless oil (d.r. = 60:40). The diastereomeric ratio was determined by 'H NMR of the crude sample. Main diastereomer:'H
NMR (CDCI3, 300 MHz) S 7.41 (1H, br s), 5.95 - 5.60 (2H, m), 5.15 - 5.05 (2H, m), 2.81 (1 H, pentet, J = 6.5 Hz), 1.28 (3H, s), 1.26 (2H, br s), 0.99 (3H, d, J = 6.5 Hz); 13C NMR (CDCI3, 75 MHz) S 180.06, 139.33, 116.28, 59.62, 43.29, 25.10, 11.88; IR (film) u3444, 3250, 1691, 1654, 1557 cm-1; HRMS
(CI) m/z calcd. for C7H14N20 (MH+) 143.1184, found 143.1186.
Example 4: Results for the Crotylation of N-Unsubstituted Imines Derived from Ketones:
The crotylation of a select number of ketones was examined under a slightly modified set of conditions (2.0 equiv of 5e, 10 equiv. of NH3, rt, 24 h) (Table 4). Excellent diastereoselectivities were obtained with acetophenone derivatives (entries 1-4). The anti diastereomer (4a/c) was formed when (E)-crotylboronic acid (7a) was employed as the reagent, while (Z)-crotylboronic acid (7b) afforded the syn diastereomer (4b/d). The stereochemistry of the crotylated products 4 were assigned based upon the reaction of 7a with acetophenone (entry 5) which afforded the previously known anti diastereomer 4e in moderate yield and excellent diastereoselectivity (d.r. =
97:3) [C. Ogawa, M. Sugiura and S. Kobayashi, J. Org. Chem., 2002, 67, 5359]. Crotylation of methylpyruvate (entry 6), on the other hand, was not diastereoselective likely due to the similar steric sizes of the methyl and methylformate groups. The results from entries 3-5 also constitute a convenient route to a-allylated amino acid derivatives.
While the present invention has been described with reference to what are presently considered to be the preferred examples, it is to be understood that the invention is not limited to the disclosed examples. To the contrary, the invention is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.
All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term.
Table 1: Addition of allyl boron reagents (5) to N-unsubstituted ketimine derived from la.
0 ~BR2 H2N Me ~ 5 (1.6 equiv.) ~
I/ NH3 (ca. 10 equiv.) Br I/
Br MeOH, rt, 16 h 1a 6a Entry 5 Yield of 6a (%)a O
1 B (5a) 35 ~_o 2 10 k (5b) 29 B_O
3 6(O'Pr)2 (5c) 43 4 0 70b' i ~ ~ (sd) BO
B(oH)2 (se) 79b a Isolated yield after acid-base extraction. b Anal sis (H NMR, 2.4,6-trimethylbenzene standard) of the organic phase from the acid-base work-up revealed <~% of the , correspondin homoaIlylic alcohol- Isolated ield after aci -base extraction and preparative W.
Table 2: Reaction of N-unsubstituted imines derived from ketones with allylboronic acid (5e)a.
5e '5~B(OH)2 O (1.6 equiv) H2N R2 R'R2 NH3 (10 equiv.) R1 " \
1 MeOH, rt, 16 h 6 Entry Ketone Yield (%)b 1 Et2C=O (1 b) 73 (6b) O
2 HOI-lk (I c) 80 (6c) O
3 Ph'-APh (ld) 78 (6d) O
4 (le) 85 (6e) 4- (1f) 72 (6f) MeOC6H4C(O)CH2CH3 6 4-NCC6H4C(O)CH3 (lg) 80 (6g) 7 4-O2NC6H4C(O)CH3 (1h) 87 (6h) O
8 Ph (11) 70 (61)c O
9 0 0 (1J) 78 (6J) (1 k) 92(6k) N
Bn 11 s Ph (11) 75(61) O
m) 80 (6m) 12 07N (l H
Standard reaction conditions: A solution of the ketone (0.5 mmol), ammonia (ca. 7N in MeOH
5 0.75 mL ca. 10 eguiv.) and alTylboronic acid (5ej ~2M in N~ebOH, 0.40 rnL, 0.80 mmol) was stirred for 6 h at rt. Isolated ield after acid-base extraction.
Isolated yield attyer acid-base extraction, and preparative 1 LC.
Table 3: Reaction of N-unsubstituted imines derived from ketones with allylboronic acid (5e) in which the ketones contain a pre-existing stereocentre.
5e (1.6 equiv.) NH2 NH3, MeOH
t Bu \~~ ~
t-Bu16 h, rt 1n 6n 95%, d.r. = 87:13 5e (1.6 equiv.) NH3, MeOH
(2) 16h,rt 0 NH2 1o 6o 91 %, d.r. = 94:6 O 5e (1.6 equiv.) H2N -//
~Ph NH3, MeOH ~e; Ph (3) Ph 16 h, rt Ph/ \~
OH OH
1p 6p 81 %, d. r. = 88:12 NHz 5e (1.6 equiv.) NH3, MeOH
16 h, rt (4) lq 6q 84%, d.r. = 97:3 Table 4: Reaction of N-unsubstituted ketimines with (E)- and (Z)-crotylboronic acid (7a/b)a R3r B(OHh (2.0equfv.) ) O 7a: R3 = Me, R4 = H H2N R2 R, R2 7b:R3=H,R4=Me NH3 (10 equiv.) Rg R
MeOH, rt, 24 h Entry Crotyl Product Yield d.r.
reagent (%)"
1 7a F3CJ\ \ 80 (4a) 97:3 / =
2 7b F3C I\ \ 73 (4b)' 96:4 /
e~z 3 7a 95 (4c) 97:
4 7b I\ \ 92 (4d)'" 96:4 H2N :
7a I\ _\ 50 (4e) 97:3 6 7a 88 (41)' 60:40 Standard reaction conditions: ketone (0.5 mmol)- ammonia (ca. 7N in MeOH,, 0.75 5 mL, ca.,10 e uiv.) and crot~lboronic acid (7a(b) (2M 'n MeOH, 0;50 n~L, 1.00 mmol~
were stirred ~or 24 h at rt. Isolated yiela aTter acid-pase extraction.
Isolated yiel after acio-base extraction, and preparative, TLC. ~Viethyl benzoylformate wa em lo ea as the starting ketone and aminol sis oT the _ ester was observed.
Mepthy~pyruvate was empoyed as the startmg ketyone, and ammolysis of the ester was observed.
Claims (22)
1. Accordingly, the present invention relates a method of preparing an amine of the formula Ia and/or Ib comprising reacting a compound of formula II with a compound of formula III:
wherein R1 and R2 are independently selected from C1-20alkyl, C1-20alkoxy, C2-20alkenyl, C3-20cycloalkyl, C3-20cycloalkoxy, aryl, aryloxy, heteroaryl and heteroaryloxy, all of which are optionally substituted and one or more of the carbons in C1-20alkyl, Cl-20alkoxy, C2-20alkenyl, C3-20cycloalkyl, C3-20cycloalkoxy, aryl, aryloxy, heteroaryl or heteroaryloxy is optionally replaced with a heteroatom selected from O, S, N, NR10 and NR10R11;
or R1 and R2 are linked to form an optionally substituted monocyclic or polycyclic ring system having 4 to 20 atoms including the carbonyl to which R1 and R2 are bonded, and one or more of the carbons of the ring system is optionally replaced with a heteroatom selected from O, S, N, NR10 and NR10R11;
R3 to R7 are independently selected from H, C1-20alkyl, C1-20alkoxy, C2-20alkenyl, C3-20cycloalkyl, C3-20cycloalkoxy, aryl, aryloxy, heteroaryl and heteroaryloxy, the latter 9 groups being optionally substituted and one or more of the carbons in C1-20alkyl, Cl-20alkoxy, C2-20alkenyl, C3-20cycloalkyl, C3-20cycloalkoxy, aryl aryloxy, heteroaryl or heteroaryloxy is optionally replaced with a heteroatom selected from O, S, N, NR10 and NR10R11;
R8 and R9 are independently selected from H, C1-20alkyl, C3-20cycloalkyl, aryl and heteroaryl, the latter 4 groups being optionally substituted;
or R8 and R9 are linked to form an optionally substituted monocyclic or polycyclic ring system having 4 to 20 atoms, including the B and O atoms to which R8 and R9 are bonded;
R10 and R11 are independently selected from H, C1-20alkyl, C3-20cycloalkyl, aryl and heteroaryl, the latter 4 groups being optionally substituted, in the presence of ammonia NH3 or an ammonia equivalent of the formula NH4+X-, wherein X is an anionic ligand.
wherein R1 and R2 are independently selected from C1-20alkyl, C1-20alkoxy, C2-20alkenyl, C3-20cycloalkyl, C3-20cycloalkoxy, aryl, aryloxy, heteroaryl and heteroaryloxy, all of which are optionally substituted and one or more of the carbons in C1-20alkyl, Cl-20alkoxy, C2-20alkenyl, C3-20cycloalkyl, C3-20cycloalkoxy, aryl, aryloxy, heteroaryl or heteroaryloxy is optionally replaced with a heteroatom selected from O, S, N, NR10 and NR10R11;
or R1 and R2 are linked to form an optionally substituted monocyclic or polycyclic ring system having 4 to 20 atoms including the carbonyl to which R1 and R2 are bonded, and one or more of the carbons of the ring system is optionally replaced with a heteroatom selected from O, S, N, NR10 and NR10R11;
R3 to R7 are independently selected from H, C1-20alkyl, C1-20alkoxy, C2-20alkenyl, C3-20cycloalkyl, C3-20cycloalkoxy, aryl, aryloxy, heteroaryl and heteroaryloxy, the latter 9 groups being optionally substituted and one or more of the carbons in C1-20alkyl, Cl-20alkoxy, C2-20alkenyl, C3-20cycloalkyl, C3-20cycloalkoxy, aryl aryloxy, heteroaryl or heteroaryloxy is optionally replaced with a heteroatom selected from O, S, N, NR10 and NR10R11;
R8 and R9 are independently selected from H, C1-20alkyl, C3-20cycloalkyl, aryl and heteroaryl, the latter 4 groups being optionally substituted;
or R8 and R9 are linked to form an optionally substituted monocyclic or polycyclic ring system having 4 to 20 atoms, including the B and O atoms to which R8 and R9 are bonded;
R10 and R11 are independently selected from H, C1-20alkyl, C3-20cycloalkyl, aryl and heteroaryl, the latter 4 groups being optionally substituted, in the presence of ammonia NH3 or an ammonia equivalent of the formula NH4+X-, wherein X is an anionic ligand.
2. The method according to claim 1, wherein R1 and R 2 in the compounds of the formulae Ia, Ib and II are independently selected from C1-10alkyl, C2-10alkenyl, aryl and heteroaryl, all of which being optionally substituted; or and R2 are linked to form an optionally substituted monocyclic or polycyclic ring system having 6 to 16 carbons including the carbonyl to which R1 and R2 are bonded and one or more of the carbons of the ring system is optionally replaced with a heteroatom selected from O, S, N, NR10 and NR10R11, in which R10 and R11 are independently selected from H, C1-6alkyl and aryl.
3. The method according to claim 1 or 2, wherein R1 and R2 in the compounds of the formulae Ia, Ib and II are independently selected from methyl, ethyl, propyl, butyl, pentyl, ethene, styrene, phenyl, benzyl, thiophene and indole, all of which are optionally substituted.
4. The method according to claim 1 or 2, wherein R1 and R2 in the compounds of the formulae Ia, Ib and II are linked to form a ring system selected from cyclohexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]hept-2-ene and fluorene, all of which are optionally substituted, and one or more of the carbons of cyclohexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]hept-2-ene or fluorene is optionally replaced with a heteroatom selected from O, S, and NR10; in which R10 is H or benzyl.
5. The method according to any one of claims 1 to 4, wherein the optional substituents on R1 and R2 in the compounds of the formulae Ia, Ib and II are independently selected from OH, halo, CN, NO2, phenyl, benzyl, OC1-6alkoxy, C1-6alkyl, C1-6alkenyl, C1-6alkenyloxy, NH2, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), C(O)C1-6alkyl, C(O)OC1-6alkyl, SO2C1-6alkyl, SO2NH2, SO2NHC1-6alkyl, and SC1-4alkyl.
6. The method according to claim 5, wherein the optional substituents on R1 and R2 in the compounds of the formulae Ia, Ib and II are independently selected from OH, F, Cl, Br, CN, NO2, phenyl and C1-4alkyl.
7. The method according to any one of claims 1 to 6, wherein the optional substituents on R1 and R2 in the compounds of the formulae Ia, Ib and II
further comprise at least one stereocenter.
further comprise at least one stereocenter.
8. The method according to any one of claims 1 to 7, wherein R3 to R7 in the compounds of the formulae Ia, Ib and III are independently selected from H, C1-10alkyl, C3-12cycloalkyl, aryl and heteroaryl, the latter 4 groups being optionally substituted and one or more of the carbons in C1-10alkyl, C3-10cycloalkyl, aryl or heteroaryl is optionally replaced with a heteroatom selected from O, S, N, NR10 and NR10R11 in which R10 and R11 are independently selected from H and C1-6alkyl.
9. The method according to claim 8, wherein R3 to R7 in the compounds of the formulae Ia, Ib and III are independently selected from H and C1-6alkyl.
10. The method according to claim 9, wherein R3 to R7 in the compounds of the formulae Ia, Ib and III are independently selected from H and methyl.
11. The method according to any one of claims 1 to 10, wherein the optional substituents on R3 and R7 in the compounds of the formulae Ia, Ib and III are independently selected from OH, halo, CN, NO2, phenyl, benzyl, OC1-6alkoxy, C1-6alkyl, C1-6alkenyl, C1-6alkenyloxy, NH2, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), C(O)C1-6alkyl, C(O)OC1-6alkyl, SO2C1-6alkyl, SO2NH2, SO2NHC1-6alkyl, and SC1-4alkyl.
12. The method according to any one of claims 1 to 11, wherein R 8 and R9 in the compound of the formula III are independently selected from H, C1-10alkyl, C3-12cycloalkyl, aryl and heteroaryl, the latter 4 groups being optionally substituted; or R8 and R9 in the compound of the formula III are linked to form an optionally substituted monocyclic or polycyclic ring system having 5 to 12 atoms, including the B and O atoms to which R8 and R9 are bonded.
13. The method according to claim 12, wherein R8 and R9 in the compound of the formula III are independently selected from H or C1-6alkyl; or R8 and in the compound of the formula III are linked to form an optionally substituted monocyclic or bicyclic ring system having 5 to 12 atoms, including the B and O atoms to which R8 and R9 are bonded.
14. The method according to any one of claims 1 to 13, wherein the optional substituents on R 8 and R9 in the compound of the formula III are independently selected from OH, halo, CN, NO2, phenyl, benzyl, OC1-6alkoxy, C1-6alkyl, C1-6alkenyl, C1-6alkenyloxy, NH2, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), C(O)C1-6alkyl, C(O)OC1-6alkyl, SO2C1-6alkyl, SO2NH2, SO2NHC1-6alkyl, and SC1-4alkyl.
15. The method according to claim 14, wherein the optional substituent on R8 and R9 in the compound of the formula III is C1-4alkyl.
16. The method according to any one of claims 1 to 15, wherein X is selected from halo, R12COO, R12SO4 and BF4 in which R12 is selected from C1-10alkyl, C3-20cycloalkyl, aryl and heteroaryl, all of which are optionally substituted; and wherein the optional substituents are independently selected from OH, halo, CN, NO2, phenyl, benzyl, OC1-6alkoxy, C1-6alkyl, C1-6alkenyl, C1-6alkenyloxy, NH2, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), C(O)C1-6alkyl, C(O)OC1-6alkyl, SO2C1-6alkyl, SO2NH2, SO2NHC1-6alkyl, and SC1-4alkyl.
17. The method according to any one of claims 1 to 16, wherein the method is performed in the presence of ammonia.
18. The method according to any one of claims 1 to 17, wherein the method is performed in an organic solvent.
19. The method according to claim 18, wherein the organic solvent is selected from methanol, ethanol, propanol, butanol, toluene, tetrahydrofuran, acetonitrile, benzene and methylene chloride.
20. The method according to claim 19, wherein the organic solvent is methanol.
21. The method according to any one of claims 1 to 20, wherein the method is performed at a temperature of from -40°C to +100°C.
22. The method according to claim 21, wherein the method is performed at room temperature.
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