NL2015814B1 - Pyridine-based isocyanides as novel reagents for multicomponent reactions. - Google Patents

Pyridine-based isocyanides as novel reagents for multicomponent reactions. Download PDF

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NL2015814B1
NL2015814B1 NL2015814A NL2015814A NL2015814B1 NL 2015814 B1 NL2015814 B1 NL 2015814B1 NL 2015814 A NL2015814 A NL 2015814A NL 2015814 A NL2015814 A NL 2015814A NL 2015814 B1 NL2015814 B1 NL 2015814B1
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isocyanopyridines
isocyanopyridine
substituted
nmr
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NL2015814A
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Van Der Heijden Gydo
Adrianus Wilhelmus Jong Jacobus
Vincenzo Antonio Orru Romano
Ruijter Eelco
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Stichting Vu-Vumc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates

Abstract

The present invention provide novel substituted 2-isocyanopyridines and their use in methods comprising reacting substituted isocyanopyridines of the general formula with a carbonyl-containing compound selected from the group consisting of an aldehyde and a ketone; in the presence of an acidic carbon compound selected from the group consisting of a carboxylic acid and a (thio)phenolic compound and/or a primary or secondary amine, including their use in Ugi, Passerini and Ugi-Smiles reactions, and conversion of the resulting secondary amide products to (thio)carboxylic acids, (thio)esters and amides.

Description

Title: Pyridine-based isocyanides as novel reagents for multicomponent reactions Technical Field [01] The present invention relates to substituted 2-isocyanopyridines, their preparation, the use of substituted 2-isocyanopyridines in various multicomponent reactions such as Ugi, Passerini and related reactions, and conversion of the resulting secondary amide products to (thio)carboxylic acids, (thio)esters and amides.
Background Art [02] Isocyanide-based multicomponent reactions (IMCRs) such as the Ugi reaction are of tremendous importance for the creation of compound libraries for e.g. drug discovery. Especially in this medicinal chemistry context, one of the most important limitations of this family of reactions is the lack of commercially available isocyanides (especially those with biologically relevant functionalities), and the lack of possibilities to diversify the functional group resulting from the isocyanide input (typically a secondary amide). For instance, the Ugi four-component reaction (Ugi, I; Meyr, R.; Fetzer, U.; Steinbrückner, C. (1959). "Versuche mit Isonitrilen". Angew. Chem. 71 (11): 386, U4CR, Scheme 1A) is a reaction between isocyanides, aldehydes (or ketones), primary amines, and carboxylic acids affording diamides 1.
Scheme 1:
An Ugi four-component reaction [03] One of the problems in the art is that only a limited number of R1 groups is available due to the limited commercial availability of isocyanides. Furthermore, in order to fully exploit the synthetic potential of such reactions, it would be desirable to have the opportunity to convert the secondary amide in 1 to the corresponding tertiary amides (2a), other secondary amides (2b), carboxylic acids (3) and (thio)esters (4).
Scheme 2:
Ugi four-component reaction and desired conversion products [04] In this regard, the carboxylic acids 3 are the most versatile intermediates, since standard methodologies allow their conversion to 2a, 2b and 4. In this light, several attempts to create so-called convertible isocyanides, that allow the conversion of an Ugi product 1 to the corresponding secondary amide (2, R5 = R6 = H), or carboxylic acid (3) have appeared in literature. Scheme 3 presents an overview of the competing approaches to date. All these isocyanides suffer from one or more of the following severe limitations:
Scheme 3:
Previously reported convertible isocyanides.
[05] The isocyanides require lengthy, tedious synthetic routes and they are instable/difficuIt to handle. The deprotection conditions are incompatible with various functional groups in the rest of the molecule. The functional groups in the isocyanide moiety are incompatible with various standard manipulations and cleavage of the convertible isocyanide require harsh reaction conditions or a multistep transformation.
Summary of Invention [06] The present inventors have developed a range of 2- and 4-isocyanopyridines having unexpected properties and applications.
21-isocyanopyridines (5) 4-isocyanopyridines (19)
Scheme 4:
Substituted 2-isocyanopyridines and 4-isocyanopyridines [07] The 2-isocyanopyridines 5 and the 4-isocyanopyridines 19 of the invention allow straightforward application in the Ugi reaction and other isocyanide-based multicomponent reaction (IMCRs). Furthermore, conversion of the resulting Ugi products 6 to 3 and 4, as well as to 2a and 2b. The isocyanides of the present invention do not present any of the problems of currently used convertible isocyanides as mentioned herein before. They are stable solids when properly stored, for instance at -20°C, that are readily available in multigram quantities by standard transformation of (commercially available) 2- and 4-aminopyridines (20 and 21, respectively). The isocyanopyridines of the invention find application in multicomponent reactions such as Ugi and Passerini reactions. The products from these multicomponent reactions compound can, due to the advantageous characteristics of the isocyanopyridine-based moiety be further converted in good yields and under mild conditions. For instance, the conversion of the resulting Ugi products 6 to the corresponding carboxylic acids 3,
(thio)esters 4 or tertiary/secondary amides 2a/2b proceeds under very mild conditions compatible with the presence of many common functional groups. In addition, and another aspect of the invention, is the demonstrated similar utility of convertible isocyanides 5 in other IMCRs such as the Passerini reaction. Among the investigated isocyanides, compound 5I (R = 6-Br) seems to be the most preferred: It is a stable solid at -20°C (as determined by NMR over 7 months) that is readily accessible in multigram quantities from a relatively inexpensive amine precursor. In addition, the cleavage proceeds most efficiently with this particular substitution on the pyridine ring. Moreover, many of the isocyanopyridines 5 and 19 have not been described in the literature and are hence another aspect of the invention. Importantly, the use of the isocyanopyridines of the invention is conceptually significantly different from existing approaches. Without being bound by theory, the present inventors believe that the design of the isocyanides of the present invention requires a delicate balance of electron-donating properties (ensuring sufficient nucleophilicity of the isocyanide in the IMCR) and electron-withdrawing properties of the substituent on the isocyanide (to allow mild cleavage of the amido moiety resulting from the isocyanide).
Description of the Invention [08] Thus in a first aspect the invention pertains to a method for performing an isocyanide-based multicomponent reaction (IMCR) comprising a step of reacting a substituted isocyanopyridine of the general formula 5 or 19, preferably 5,
5 19 with a carbonyl-containing compound selected from the group consisting of an aldehyde and a ketone; in the presence of an acidic carbon compound selected from the group consisting of (thio)carboxylic acids and (thio)phenolic compounds; and/or a primary or secondary amine, wherein R is selected from the group consisting of H, CrC4-alkyl such as Cr, C2-, n-C3-, i-C3-alkyl,, halogenated C1-C4 alkyl, halogen (F, Cl, Br, I), (thio)ethers, sulfoxides, sulfones, esters, (substituted) (hetero)aryl, (substituted) cycloalkyl, alkoxy/(hetero)aryloxy, and mono-di-alkyl/(hetero)arylamino.
[09] Using the substituted isocyanopyridines of the invention results in good yields and clean reactions. The substituted isocyanopyridines can be readily synthesised in multigram quantities and are stable solids. The result application in IMCRs is straightforward under mild conditions and tolerates a wide range of substituents. The products of the IMCRs are readily deprotected to remove the pyridyl-amide moiety.
[10] In certain embodiments of the invention, the acidic carbon compound is a carboxylic acid. The IMCR is then also known as the Passerini reaction, see also reaction scheme 10.
[11] In certain other embodiments, the reaction is the Ugi 4-component reaction and is performed in the presence of an acidic carbon compound and a primary amine.
[12] In certain other embodiments, the reaction is an Ugi 3-component reaction in the absence of an acidic carbon compound and in the presence of a secondary amine.
[13] In certain other embodiments, the reaction is the Ugi-Smiles reaction and the acidic carbon is a phenolic compound, i.e. an hydroxyl group directly attached to an aromatic ring.
[14] The substituent R used in the isocyanopyridines in the method of the invention can vary widely, but is preferably selected from the group consisting of H, Cr, C2-, n-C3-, i-C3-alkyl, halogen (F, Cl, Br, I), CF3 ,(thio)ethers, sulfoxides, sulfones, esters, (substituted) (hetero)aryl, (substituted) cycloalkyl, alkoxy/(hetero)aryloxy, and mono-di-alkyl/(hetero)arylamino. In certain preferred embodiments R is selected from the group consisting of Cr, C2-, n-C3-, /'-C3- alkyl, halogen (F, Cl, Br, I), CF3. A preferred substituted isocyanopyridine is a substituted 2-isocyanopyridine. In certain preferred embodiments for 2-isocyanopyridines, R is selected from the group consisting of 3-Me, 4-Me, 5-Me, 6-Me, 3-Br, 4-Br, 5-Br, 6-Br, 3-CI, 4-CI, 5-CI, 6-CI, 3-F, 4-F, 5-F, 6-F, 3-CF3,4-CF3,5-CF3, 6-CF3. In certain preferred embodiments for 2-isocyanopyridines R is selected from the group consisting of 3-Me, 4-Me, 5-Me, 6-Me, 3-Br, 4-Br, 5-Br, 6-Br, 3-CI, 4-CI, 5-CI, 6-CI 5-F, 5-CF3. Good results have been obtained and hence preferred substituents are 2-isocyanopyridines wherein R is selected from the group consisting of 3-Me, 4-Me, 5-Me, 6-Me, 3-Br, 4-Br, 5-Br, 5-CI, 5-CF3, 6-Br, 6-CI. The most preferred substituent for 2-isocyanopyridines R = Br. The most preferred position for 2-isocyanopyridines is the 6-position. The most preferred compound in the method of the invention is 6-bromo-2-isocyanopyridine.
[15] In certain preferred embodiments for4-isocyanopyridines , R is selected from the group consisting of 2-Me, 3-Me, 5-Me, 6-Me, 2-Br, 3-Br, 5-Br, 6-Br, 2-CI, 3-CI, 5-CI, 6-CI, 2-F, 3- F, 5-F, 6-F, 2-CF3,3-CF3, 5-CF3,6-CF3, the 5 and 6 positions being equivalent with the 3 and 2 position, respectively. In certain preferred embodiments for 4-isocyanopyridines, R is selected from the group consisting of 2-Me, 2-Br, 2-CF3, 2-CI.
[16] The position of the substituent R on the pyridine ring in the method of the invention may vary. Substituent positions refer to the parent compound 2-isocyanopyridine or 4-isocyanipyridine compound, respectively, although the systematic IUPAC nomenclature for each of the compound may be different depending on the priority of the substituent relative to the isocyano group. For 2-isocyanopyridines, the substituent R can be at the 3-position; at the 4- position; at the 5-positon; at the 6-position. For 4-isocyanopyridines, the monosubstituent R can be at the 2-position; at the 3-position; the 5-position and 6-position being equivalent to the 3- and 2- position, respectively. Two or more substituents R are possible, independently selected.
[17] The substituted 2-isocyanopyridines or 4-isocyanopyridines are another aspect of the invention. The 2-isocyanopyridines or 4-isocyanopyridines are prepared using conventional methods as exemplified in the experimental section. The invention thus also relates to substituted 2-isocyanopyridines having the general formula
or substituted 4-isocyanopyridines having the general formula
19 wherein R is selected from the group consisting of H, Ci-C4-alkyl such as Cr, C2-, n-C3-, i-C3- alkyl, halogenated C1-C4 alkyl, halogen (F, Cl, Br, I), (thio)ethers, sulfoxides, sulfones, esters, (substituted) (hetero)aryl, (substituted) cycloalkyl, alkoxy/(hetero)aryloxy, and mono-di-alkyl/(hetero)arylamino.
[18] For substituted 2-isocyanopyridines: In a preferred embodiment, R is selected from the group consisting of 3-Me, 4-Me, 5-Me, 6-Me, 3-Br, 4-Br, 5-Br, 6-Br, 3-CI, 4-CI, 5-CI, 6-CI, 3- F, 4-F, 5-F, 6-F, 3-CF3, 4-CF3,5-CF3,6-CF3. In a further preferred embodiment, R is selected from the group consisting of 3-Me, 4-Me, 5-Me, 6-Me, 3-Br, 4-Br, 5-CF3, 6-Br, 6-CI.
In a more preferred embodiment R is Brand more preferably 6-Br, i.e. 6-bromo-2-isocyanopyridine.
[19] For substituted 4-isocyanopyridines , R is selected from the group consisting of 2-Me, 3-Me, 2-Br, 3-Br, , 2-CI, 3-CI, , 2-F, 3-F, 2-CF3,3-CF3. In certain preferred embodiments for 4-isocyanopyridines, R is selected from the group consisting of 2-Me, 2-Br, 2-CF3, 2-CI.
[20] Thus the invention also relates to, independently: 3-chloro-2-isocyanopyridine; 4-chloro-2-isocyanopyridine; 5-chloro-2-isocyanopyridine; 6-chloro-2-isocyanopyridine; 3-bromo-2-isocyanopyridine; 4-bromo-2-isocyanopyridine; 5-bromo-2-isocyanopyridine; 6-bromo-2-isocyanopyridine; 3-fluoro-2-isocyanopyridine; 4-fluoro-2-isocyanopyridine; 5-fluoro- 2-isocyanopyridine; 6-fluoro-2-isocyanopyridine; 3-methyl-2-isocyanopyridine; 4-methyl-2-isocyanopyridine; 5-methyl-2-isocyanopyridine; 6-methyl-2-isocyanopyridine; 3-ethyl-2-isocyanopyridine; 4-ethyl-2-isocyanopyridine; 5-ethyl-2-isocyanopyridine; 6-ethyl-2-isocyanopyridine; 3-n-propyl-2-isocyanopyridine; 4-n-propyl-2-isocyanopyridine; 5-n-propyl-2-isocyanopyridine; 6-n-propyl-2-isocyanopyridine 3-i-propyl-2-isocyanopyridine; 4-i-propyl-2-isocyanopyridine; 5-i-propyl-2-isocyanopyridine; 6-i-propyl-2-isocyanopyridine; 3-trifluoromethyl-2-isocyanopyridine; 4-trifluoromethyl-2-isocyanopyridine; 5-trifluoromethyl-2-isocyanopyridine; 6-trifluoromethyl-2-isocyanopyridine; 2-chloro-4-isocyanopyridine;2 -bromo- 4- isocyanopyridine. For these individual compounds, substituent positions refer to the parent compound 2-isocyanopyridine or 4-isocyanipyridine compound, respectively, although the systematic IUPAC nomenclature for each of the compound may be different depending on the priority of the substituent relative to the isocyano group.
[21] Methods for the synthesis of isocyanopyridines are known in the art, For instance for R = H: Bioorganic and Medicinal Chemistry, 2009 , vol. 17, # 1 p. 74 - 84; Russian Journal of Organic Chemistry, 1999 , vol. 35, # 5 p.693 - 697.
[22] In a further aspect the invention relates to follow up transformations, i.e. reactions that follow the multicomponent reactions with the isocyanopyridines of the invention. The products of the multicomponent reactions described herein readily undergo a set of further conversions to yield valuable synthetic products that can be used in further transformations.
[23] Specifically, the invention also pertains to the saponification, hydrolysis, solvolysis, alcoholysis and/or transamidation of the product of the isocyanide-based IMCRs. In more detail, the invention pertains in one embodiment to the conversion of the N-2-pyridylamide-(or N-4-pyridylamide-, not shown here) containing product of an Ugi reaction to the corresponding carboxylic acid under basic conditions as exemplified below.
[24] The product compound from the multicomponent reaction using the substituted isocyanides of the present invention is converted under basic conditions, preferably in a solvent to a carboxylic acid by saponification of the N-2-pyrimidylamide or N-4-pyridylamide group. The basic conditions can be provided by the use of basic compounds such as LiOH, NaOH, KOH or sodium methoxide in aqueous and/or alcoholic solutions. Other solvents may be used.
[25] In another embodiment, the invention pertains to the nucleophilic substitution of the /V-2-pyridylamide or /V-4-pyridylamide-group of the /V-2-pyridylamide- or ΛΜ-pyridylamide-containing product of an Ugi reaction in the presence of a nucleophile under acidic or basic conditions, as exemplified below: or
[26] By contacting the product compound from the multicomponent reaction using the substituted isocyanides of the present invention with a nucleophile under acidic or basic conditions, the /V-2-pyridylamide or /V-4-pyridylamide group of the product compound is substituted with the nucleophile. The basic conditions are as outlined herein. The acidic conditions can be provided using mineral or organic acids such as HCI; or acetic acid. Solvents may be used. The resulting nucleophilic substitution products are obtained in good yields and purities. In preferred embodiments, the nucleophile is selected from the group consisting of water, alcohols, and thiols. More preferably, when the conditions are basic, the nucleophile is selected from the group consisting of water, primary Ci-C8-alcohols, primary CrCe alkylamines, secondary C2-C8 alkylamines and C4-C8 cycloalkylamines.
[27] In another embodiment, the conditions are acidic and the nucleophile is selected from the group consisting of water, alcohols, thiols. More preferably, the nucleophile is selected from the group consisting of water, primary CrC8-alcohols, primary CrC8- thiols, benzylic thiols.
[28] Further embodiments of the invention relate to the conversion of the Λ/-2-pyridylamide- (22) or /V-4-pyridylamide- containing products of the Passerini reaction under basic conditions to provide the corresponding alpha-hydroxy carboxylic acids 23, as exemplified below. The basic conditions may be as described herein elsewhere.
Brief Description of Drawings [29] Figure 1. Yields of various substituted 2-isocyanopyridines 5a-l from the corresponding amines (over two steps) for the various isocyanides.
[30] Figure 2. Yields of benchmark Ugi reactions with various substituted 2-isocyanopyridines with isobutyraldehyde, benzylamine and acetic acids to give 6a-l (R1 = CH3, R2 = Bn, R3 = /Bu) [31] Figure 3. Yields of hydrolysis of Ugi products 6a-l using 2.5 equiv. (light grey bars) or 5.0 equiv. (dark grey bars) of NaOH in MeOH/H20.
Description of Embodiments 1. Synthesis of convertible isocyanides [32] A range of substituted 2-aminopyridines 20a-l were converted to the corresponding 2-isocyanopyridines 5a-l via the formamides 24a-l using the following procedure (Scheme 5,
General Procedures I and II). Figure 1 discloses yields of various substituted 2-isocyanopyridines 5a-l from the corresponding amines over two steps.
Scheme 5.
Synthesis of substituted 2-isocyanopyridines, (a: R = 3-Me, b: R = 3-Br, c: R = 4-Me, d: R = 4-Br, e: R = 5-Me, f: R = 5-F, g: R = 5-CI, h: R = 5-Br, i: R = 5-CF3. j: R = 6-Me, k: R = 6-CI, I: R = 6-Br).
General procedure I: Synthesis of 2-formamidopyridines 24 [33] In a flame-fried roundbottom flask equipped with a reflux condenser formic acid (41 mmol, 2.05 eq.) was added dropwise to acetic anhydride (40 mmol, 2.0 eq.) and the resulting mixture refluxed at 65°C for 2-3 hours. The mixture was cooled to room temperature and slowly added to a cold solution of a 2-aminopyridine 20 (20 mmol, 1.0 eq.) in anhydrous THF (50 ml.) at 0°C. After 1 h, the reaction was allowed to warm up to RT and stirred for 2-3 more hours. The solvent and excess of acetic acid were evaporated and the residue was redissolved in EtOAc. The crude mixture was washed with a saturated NaHC03 and the water layer was extracted with EtOAc (2*). The organic layers were combined, washed with brine and dried over Na2S04. The solvent was evaporated to furnish the corresponding formamide.
General procedure II: Synthesis of 2-isocyanopyridines 5 [34] Unless stated otherwise: To a flame dried 3-neck flask a 2-formamidopyridine 24 (10 mmol, 1.0 eq.) was added and dissolved in anhydrous CH2CI2 (30 ml_). Then, Et3N (60 mmol, 6.0 eq.) was added and the solution was cooled to -78°C. POCI3 (11.5 mmol, 1.15 eq.) in anhydrous CH2CI2 (5 ml_)was added dropwise to the mixture. After 1 h, the mixture was warmed up to 0°C and stirred overnight. The crude reaction mixture was carefully quenched with saturated NaHC03(25 ml_). The layers were separated and the water layer was extracted with CH2CI2 (2x). The organic layers were combined and washed with brine, dried over Na2S04 and concentrated. The residue was purified by column chromatography (CH2CI2) to afford the 2-isocyanopiridine. The product was stored in the freezer at -18°C.
[35] The yields (over two steps) for the various isocyanides are depicted in Figure 1. [As an example, isocyanide 5I (R = 6-Br) was obtained in 71% yield over two steps after chromatography].
[36] The substituted 4-isocyanopyridines 19 were obtained analogously, starting from the corresponding substituted 4-aminopyridines 21.
[37] Analytical data:
2. Selection of the optimal convertible isocyanide [38] The synthesized isocyanopyridines were then used in the benchmark Ugi reaction with isovaleraldehyde, benzylamine and acetic acid (MeOH, RT, 24 h) to give Ugi products 6a-l, (scheme 6) which were then subjected to hydrolysis (2.5 or 5.0 eq. NaOH, MeOH/H20, 48h, rt) to give carboxylic acid 3. The yields for the Ugi reaction and the subsequent hydrolysis for various convertible isocyanides 5a-l are depicted in Figures 2 and 3, respectively. Reactions with 4-isocyanopyridnes give similar results.
Scheme 6.
Benchmark Ugi reaction with various substituted 2-isocyano pyridines and subsequent hydrolysis.
[39] The results in Figures 2 and 3 indicate that isocyanide 51 (R = 6-Br) is very effective in both the Ugi reaction and subsequent hydrolysis, and can be produced in relatively high yield from the corresponding amine (Figure 1).
[40] Analytical data: 6a: 1H NMR (CDCI3, 500 MHz) δ 8.92 (bs, 1H), 8.30 (d, J = 3.9 Hz, 1H), 7.51 (d, J = 7.4 Hz, 1H), 7.37-7.20 (m, 5H), 7.06 (t, J = 6.0 Hz, 1H), 5.19 (t, J = 7.5 Hz, 1H), 4.65 (s, 2H), 2.29 (s, 3H), 2.21 (s, 3H), 1.97 (m, 1H), 1.58 (m, 1H), 1.46 (m, 1H), 0.88- 0.86 (m, 6H). 13C NMR (CDCIs, 125 MHz) δ 173.6 (Cq), 169.0 (Cq), 149.3 (Cq), 146.0 (CH), 139.4 (CH), 137.1 (Cq), 128.8 (CH), 127.3 (CH), 126.8 (Cq), 126.0 (CH), 121.2 (CH), 57.1 (CH), 49.5 (CH2), 36.9 (CH2), 25.2 (CH), 22.9 (CH3), 22.4 (CH3), 22.2 (CH3), 17.9 (CH3). IR (neat): vmax (cm'1) = 2957 (w), 1674 (m), 1448 (s), 1420 (s), 633 (s), 534 (s), 496 (s), 401 (s). HRMS (ESI): m/z calculated for C2iH28N302(M+H) 354.2176, found 354.2193. 6b: 1H NMR (CDCI3, 500 MHz) δ 9.11 (broad s, 1H), 8.43 (d, J = 4.1 Hz, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.38-7.18 (m, 5H), 6.97 (dd, J= 7.6, 4.5 Hz, 1H), 5.22 (t, J= 6.5 Hz, 1H), 4.63 (s, 2H), 2.14 (s, 3H), 2.01 (m, 1H), 1.58 (m, 1H), 1.46 (m, 1H), 0.92 (d, J= 5.0 Hz, 3H), 0.88 (d, J = 5.0 Hz, 3H). 13C NMR (CDCI3, 125 MHz) δ 173.6 (Cq), 168.7 (Cq), 148.6 (Cq), 147.3 (CH), 141.3 (CH), 137.0 (Cq), 128.8 (CH), 127.4 (CH), 126.1 (CH), 121.2 (CH), 111.6 (Cq), 57.3 (CH), 49.5 (CH2), 36.5 (CH2), 25.2 (CH), 22.9 (CH3), 22.4 (CH3), 22.3 (CH3). IR (neat): vmax (cm'1) = 2956 (w), 1628 (m), 1497 (s), 1431 (m), 633 (s), 534 (s), 498 (s), 405 (s). HRMS (ESI): m/z calculated for C20H25BrN3O2(M+H) 418.1125, found 418.1130. 6c: 1H NMR (CDCI3, 500 MHz) δ 9.03 (bs, 1H), 8.14 (d, J= 4.8 Hz, 1H), 7.82 (s, 1H), 7.28- 7.17 (m, 5H), 6.84 (d, J = 4.6 Hz, 1H), 5.22 (t, J= 7.2 Hz, 1H), 4.66 (d, J= 17.5 Hz, 1H), 4.60 (d, J= 17.5 Hz, 1H), 2,31 (s, 3H), 2.14 (s, 3H), 1.95 (m, 1H), 1.56-1.45 (m, 2H), 0.88 (d, J = 6.5 Hz, 3H), 0.87 (d, J = 6.5 Hz, 3H). 13C NMR (CDCI3, 125 MHz) δ 173.2 (Cq), 169.5 (Cq), 151.2 (Cq), 149.5 (Cq), 147.6 (CH), 137.0 (Cq), 128.8 (CH), 127.3 (CH), 126.0 (CH), 120.9 (CH), 114.6 (CH), 56.8 (CH), 49.2 (CH2), 36.8 (CH2), 25.2 (CH), 22.8 (CH3), 22.3 (CH3), 22.3 (CH3), 21.3 (CH3). IR (neat): vmax (cm'1) = 2957 (w), 1697 (s), 1630 (m), 1568 (s), 1414 (s), 633 (s), 523 (s), 498 (s), 407 (s). HRMS (ESI): m/z calculated for C2iH28N302 (M+H) 354.2176, found 354.2185. 6d: 1H NMR(CDCI3, 500 MHz) δ 9.21 (bs, 1H), 8.19 (s, 1H), 8.10 (d, J= 5.0 Hz , 1H), 7.27-7.22 (m, 5H), 7.17 (d,J = 6.6 Hz, 1H), 5.17 (t, J= 6.8 Hz, 1H), 4.66 (d, J= 17.5 Hz, 1H), 4.57 (d, J= 17.5 Hz, 1H), 2.18 (s, 3H), 1.94 (m, 1H), 1.52 (m, 2H), 0.88 (m, 6H). 13C NMR (CDCI3, 125 MHz) δ 173.4 (Cq), 169.6 (Cq), 151.9 (Cq), 148.5 (CH), 136.6 (Cq), 134.1 (Cq), 128.8 (CH), 127.5 (CH), 126.2 (CH), 123.0 (CH), 117.1 (CH), 56.8 (CH), 49.4 (CH2), 36.6 (CH2), 25.1 (CH3), 22.8 (CH3), 22.4 (CH3), 22.3 (CH3). IR (neat): vmax (cm'1) = 2957 (w), 1628 (s), 1560 (s), 1396 (s), 633 (s), 536 (s), 498 (s), 401 (s). HRMS (ESI): m/z calculated for C2oH25BrN302 (M+H) 418.1125, found 418.1128. 6e: 1H NMR (CDCI3, 500 MHz) δ 8.98 (bs, 1H), 8.10 (s, 1H), 7.85 (d, J= 8.4 Hz, 1H), 7.44 (d, J= 8.4 Hz, 1H), 7.26-7.16 (m, 5H), 5.22 (m, 1H), 4.65 (d, J = 17.5 Hz, 1H), 4.59 (d, J= 17.5 Hz, 1H), 2.27 (s,3H),2.13(s, 3H), 1.92 (m, 1H), 1.55-1.48 (m, 2H), 0.88 (d, J = 6.5 Hz, 3H), 0.86 (d, J = 6.7 Hz, 3H). 13C NMR (CDCI3, 125 MHz) δ 173.2 (Cq), 169.2 (Cq) 149.0 (Cq), 147.8 (CH), 138.5 (CH), 137.0 (Cq), 129.0 (Cq), 128.7 (CH), 127.3 (CH), 126.0 (CH), 113.5 (CH), 56.7 (CH), 49.2 (CH2), 36.8 (CH2), 25.1 (CH), 22.7 (CH3), 22.4 (CH3), 22.4 (CH3), 17.8 (CH3). IR (neat): vmax (cm'1) = 2957 (w), 1630 (m), 1522 (s), 1385 (s), 1298 (s), 633 (s), 534 (m), 498 (s). HRMS (ESI): m/z calculated for C2iH28N302(M+H) 354.2176, found 354.2193. 6f: 1H NMR (CDCI3, 500 MHz) δ 9.17 (bs, 1H), 8.16 (s, 1H), 7.98 (dd, J= 9.1 Hz, 3.8 Hz, 1H), 7.37 (m, 1H), 7.28-7.17 (m, 5H), 5.21 (m, 1H), 4.67 (d, J= 17.5 Hz, 1H), 4.60 J= 17.5 Hz, 1H), 2.20 (3H), 1.96 (m, 1H), 1.56-1.53 (m, 2H), 0.91 (m, 6H). 13C NMR (CDCI3, 125 MHz) δ 173.4 (Cq), 169.1 (Cq) 156.2 (d, J = 250 Hz, Cq), 147.4 (Cq), 136.7 (Cq) 135.5 (d, J=25 Hz, CH), 128.8 (CH), 127.5 (CH), 126.1 (CH), 124.8 (d, J = 20 Hz, CH), 114.6 (CH), 56.7 (CH), 49.3 (CH2), 36.6 (CH2), 25.1 (CH), 22.7 (CH3), 22.4 (CH3), 22.4 (CH3). IR (neat): vmax (cm'1) = 2959 (w), 1630 (s), 1526 (s), 1472 (s), 1391 (s), 633 (s), 534 (s), 498 (s). HRMS (ESI): m/z calculated for C2oH25FN302(M+H) 358.1925, found 358.1932. 6g: 1H NMR (CDCI3, 500 MHz) δ 9.16 (bs, 1H), 8.24 (s, 1H), 7.92 (d, J= 8.9 Hz, 1H), 7.58 (d, J = 8.8 Hz), 7.26-7.15 (m, 5H), 5.18 (m, 1H), 4.65 (d, J= 17.4 Hz, 1H), 4.57 (d, J= 17.4 Hz, 1H), 2.18 (s, 3H), 1.94 (m, 1H), 1.56-1.51 (m, 2H), 0.89-0.87 (m, 6H). 13C NMR (CDCI3, 125 MHz) δ 173.4 (Cq), 169.4 (Cq) 149.5 (Cq), 146.6 (CH), 137.6 (CH) 136.6 (Cq), 128.8 (CH), 127.5 (CH), 126.6 (Cq), 126.1 (CH), 114.5 (CH), 56.8 (CH), 49.4 (CH2), 36.5 (CH2), 25.1 (CH), 22.7 (CH3), 22.4 (CH3), 22.4 (CH3). IR (neat): vmax (cm'1) = 2957 (w), 1628 (m), 1522 (m), 1375 (s), 1292 (s), 633 (s), 538 (s), 498 (s). HRMS (ESI): m/z calculated for C2oH25CIN302 (M+H) 374.1630, found 374.1633. 6h: 1H NMR (CDCI3, 500 MHz) δ 9.20 (bs, 1H), 8.34 (s, 1H), 7.89 (d, J= 8.8 Hz, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.27-7.17 (m, 5H), 5.20 (t, J = 6.7 Hz, 1H), 4.67 (d, J= 17.4 Hz, 1H), 4.59 (d, J= 17.4 Hz, 1H), 2.20 (s, 3H), 1.95 (m, 1H), 1.57-1.54 (m, 2H), 0.91-0.89 (m, 6H). 13C NMR (CDCI3, 125 MHz) δ 173.4 (Cq), 169.4 (Cq), 149.9 (Cq), 148.9 (CH), 140.4 (CH), 136.6 (Cq), 128.8 (CH) 127.5 (CH), 126.1 (CH), 115.1 (CH), 114.5(Cq), 56.8 (CH), 49.4 (CH2), 36.5 (CH2), 25.1 (CH), 22.7 (CH3), 22.4 (CH3), 22.4 (CH3). IR (neat): vmax (cm'1) = 2957 (w), 1626 (m), 1518 (m), 1367 (s), 1290 (s), 633 (s), 523 (m), 498 (s), 413 (s), 403 (s). HRMS (ESI): m/z calculated for C20H25BrN3O2(M+H) 418.1125, found 418.1138. 6i: 1H NMR (CDCI3, 500 MHz) δ 9.47 (bs, 1H), 8.56 (s, 1H), 8.08 (d, J = 8.7 Hz, 1H), 7.85 (d, J = 8.7 Hz, 1H), 7.28-7.17 (m, 5H), 5.21 (m, 1H), 4.68 (d, J= 17.4 Hz, 1H), 4.59 (d, J= 17.4 Hz, 1H), 2.23 (s, 3H), 1.97 (m, 1H), 1.60-1.55 (m, 2H), 0.92 (m, 6H). 13C NMR (CDCI3, 125 MHz) δ 173.5 (Cq), 169.8 (Cq) 153.8 (Cq), 145.4 (q, J= 3.7 Hz, CH), 136.5 (Cq), 135.3 (q, J = 3.7 Hz, CH), 128.8 (CH), 127.6 (CH), 126.2 (CH), 123.5 (q, J= 270 Hz, Cq), 122.3 (q, J= 31 Hz, Cq), 113.2 (CH), 56.9 (CH), 49.5 (CH2), 36.5 (CH2), 25.1 (CH), 22.7 (CH3), 22.4 (CH3), 22.4 (CH3). IR (neat): vmax (cm'1) = 2957 (w), 1626 (m), 1520 (s), 1325 (s), 908 (s), 731 (s), 633 (s), 532 (s), 496 (s). HRMS (ESI): m/z calculated for C2iH25F3N302(M+H) 408.1893, found 408.1909. 6j: 1H NMR (CDCI3, 500 MHz) δ 8.84 (bs, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.30-7.18 (m, 5H), 6.88 (d, J= 7.5 Hz, 1H), 5.28 (m, 1H), 4.68 (d, J= 17.6 Hz, 1H), 4.62 (d, J= 17.6 Hz, 1H), 2.46 (s, 3H), 2.16 (s, 3H), 1.93 (m, 1H), 1.57-1.48 (m, 2H), 0.91-0.81 (m, 6H). 13C NMR (CDCI3, 125 MHz) δ 173.1 (Cq), 169.2 (Cq), 157.0 (Cq), 150.4 (Cq), 138.3 (CH), 137.1 (Cq), 128.8 (CH), 127.3 (CH), 126.0 (CH), 119.2 (CH), 110.7 (CH), 56.5 (CH), 49.0 (CH2), 36.8 (CH2), 25.1 (CH), 24.0 (CH3), 22.8 (CH3), 22.4 (CH3), 22.3 (CH3). IR (neat): vmax (cm'1) = 2957 (w), 1630 (m), 1454 (s), 633 (s), 536 (s), 498 (s), 403 (s). HRMS (ESI): m/z calculated for C2iH28N302(M+H) 354.2176, found 354.2182. 6k: 1H NMR (CDCI3, 500 MHz) δ 8.98 (bs, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.58 (t, J = 7.9 Hz, 1H), 7.30-7.18 (m, 5H), 7.04 (d, J= 7.6 Hz, 1H), 5.23 (m, 1H), 4.67 (d, J= 17.4 Hz, 1H), 4.60 (d, J= 17.4 Hz, 1H), 2.20 (s, 3H), 1.94 (m, 1H), 1.57-1.52 (m, 2H), 0.91 (m, 6H). 13C NMR (CDCI3, 125 MHz) 5173.2 (Cq), 169.5 (Cq) 151.0 (Cq), 149.0 (Cq), 140.5 (CH), 136.7 (Cq), 128.8 (CH), 127.5 (CH), 126.1 (CH), 119.7 (CH), 112.0 (CH), 56.5 (CH), 49.2 (CH2), 36.7 (CH2), 25.1 (CH), 22.7 (CH3), 22.4 (CH3), 22.3 (CH3). IR (neat): vmax (cm'1) = 2957 (w), 1628 (s), 1572 (s), 1435 (s), 1157 (s), 633 (s), 536 (s), 498 (s), 424 (s), 413 (s), 403 (s). HRMS (ESI): m/z calculated for C20H25CIN3O2(M+H) 374.1630, found 374.1632. 61: 1H NMR (CDCI3, 500 MHz) δ 9.06 (bs, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.27-7.14 (m, 6H), 5.27 (m, 1H), 4.67 (d, J= 17.4 Hz, 1H), 4.60 (d, J= 17.4 Hz, 1H), 2.18 (s,3H), 1.92 (m, 1H), 1.54-1.48 (m, 2H), 0.88 (m, 6H). 13C NMR (CDCI3, 125 MHz) δ 173.1 (Cq), 169.5 (Cq) 151.2 (Cq), 140.1 (CH), 139.3 (Cq), 136.8 (Cq), 128.8 (CH), 127.4 (CH), 126.1 (CH), 123.4 (CH), 112.3 (CH), 56.4 (CH), 49.1 (CH2), 36.8 (CH2), 25.1 (CH), 22.7 (CH3), 22.3 (CH3), 22.3 (CH3). IR (neat): vmax (cm'1) = 2957 (w), 1624 (s), 1566 (s), 1429 (s), 1388 (s), 1155 (s), 633 (s), 530 (s), 496 (s), 403 (s). HRMS (ESI): m/z calculated for C2oH25BrN302 (M+H) 418.1125, found 418.1139. 3a: Two rotamers were present on NMR timescale (R1: R2 = 1 : 0.3). 1H NMR (CDCI3, 500 MHz) δ 11.40 (bs, 1.3H), 7.42-7.18 (m, 6.5H), 5.05 (d, J= 15.6 Hz, 0.3H), 4.75-4.70 (m, 2H), 4.51 (d, J = 17.3 Hz, 1H), 4.42 (m, 0.3H), 4.22 (d, J = 15.6 Hz, 0.3H), 2.30 (s, 0.9H), 2.17 (s, 3H), 1.92 (m, 1H), 1.73 (m, 0.3H), 1.65-1.49 (m, 2.3H), 1.36 (m, 0.3H), 0.89 (d, J= 6.5 Hz, 3H), 0.86 (d, J = 6.5 Hz, 0.9H), 0.75 (d, J = 6.6 Hz, 3H), 0.59 (d, J = 6.7 Hz, 0.9H). 13C NMR (CDCI3, 125 MHz) δ 175.4 (Cq), 174.4 (Cq), 173.3 (Cq), 173.0 (Cq), 138.2 (Cq), 136.5 (Cq), 128.8 (CH), 128.1 (CH), 127.8 (CH), 127.6 (CH), 126.9 (CH), 126.6 (CH), 59.5 (CH), 57.2 (CH), 51.7 (CH2), 47.5 (CH2), 38.4 (CH2), 38.1 (CH2), 25.2 (CH), 24.4 (CH), 22.2 (CH3), 22.2 (CH3), 22.2 (CH3), 22.0 (CH3), 22.0 (CH3), 21.7 (CH3). IR (neat): vmax (cm'1) = 2955 (w), 1735 (s), 1718 (s), 729 (s), 632 (s), 546 (s), 501 (s). HRMS (ESI): m/z calculated for Ci5H22N03 (M+H) 264. 1594, found 264.1603. 3. Evaluation of 5I as a convertible isocyanide in various MCRs and follow-up transformations [41] Next, we further evaluated the utility of isocyanide 5I in isocyanide-based MCRs and subsequent hydrolysis, solvolysis, transamidation, and other transformation. Because of its broad scope of application and its importance to medicinal chemistry, we started with the application in the Ugi reaction. Given the ease of transformation of carboxylic acids to various derivatives (amides, esters, etc.) we focused primarily on hydrolysis as a follow-up transformation of MCR products derived from 5I. 3.1 Ugi reactions with V-l [42] Isocyanide 5I was reacted with various aldehydes, amines, and carboxylic acids to give the corresponding Ugi products 25a-k (Scheme 7, General Procure III). The resulting Ugi products 25a-k were readily saponified to carboxylic acids 3a-k under mildly basic conditions.
Scheme 7:
Various Ugi reactions with isocyanide 5I and subsequent hydrolysis
Table 1. Yields of Ugi reactions with 5I and saponification of the resulting Ugi products 6l-w
a) The deprotection requires elevated temperatures or elongated reaction time.
General procedure III: Ugi reaction and subsequent hydrolysis [43] The amine (1.0 mmol, 1.0 eq.) and the aldehyde (1.0 mmol, 1.0 eq.) were dissolved in the appropriate solvent (3 ml.) and prestirred for 2 hours at room temperature. The carboxylic acid (1.5 mmol, 1.5 eq.) and 2-bromo-6-isocyanopyridine (220 mg, 1.2 mmol, 1.2 eq.) were added subsequently. Additional solvent (1 ml.) was added and the reaction mixture stirred for 48 hours at room temperature. The solvent was removed under reduced pressure and the crude mixture was purified by column chromatography (cyclohexane : EtOAc) to yield the dipeptide Ugi-products generally as a foamy solid.
[44] Unless stated otherwise: The Ugi product (0.1 mmol, 1.0 eq.) was dissolved in MeOH (0.75 ml.) and 2M NaOH (0.25 ml_, 5.0 eq.) was added. The resulting mixture stirred for 48 hours at room temperature. Conversion of the amide to the acid was monitored by TLC, indicated by formation of 6-bromopyridin-2-amine (a characteristic blue spot appears without stain). The crude mixture was acidified to pH=1 with 1M HCI and extracted with EtOAc. The organic layer was washed with 1M HCI and with brine, dried over Na2S04and concentrated under reduced pressure to yield the corresponding carboxylic acid.
[45] Analytical data: 61: 1H NMR (CDCI3, 500 MHz) δ 9.06 (bs, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.27-7.14 (m, 6H), 5.27 (m, 1H), 4.67 (d, J= 17.4 Hz, 1H), 4.60 (d, J= 17.4 Hz, 1H), 2.18 (s,3H), 1.92 (m, 1H), 1.54-1.48 (m, 2H), 0.88 (m, 6H). 13C NMR (CDCI3, 125 MHz) δ 173.1 (Cq), 169.5 (Cq) 151.2 (Cq), 140.1 (CH), 139.3 (Cq), 136.8 (Cq), 128.8 (CH), 127.4 (CH), 126.1 (CH), 123.4 (CH), 112.3 (CH), 56.4 (CH), 49.1 (CH2), 36.8 (CH2), 25.1 (CH), 22.7 (CH3), 22.3 (CH3), 22.3 (CH3). IR (neat): vmax (cm'1) = 2957 (w), 1624 (s), 1566 (s), 1429 (s), 1388 (s), 1155 (s), 633 (s), 530 (s), 496 (s), 403 (s). HRMS (ESI): m/z calculated for C20H25BrN3O2 (M+H) 418.1125, found 418.1139. 6m: 1H NMR (CDCI3, 500 MHz) δ 9.38 (bs, 1H), 7.78-6.97 (m, 13H), 5.04 (m, 1H), 4.75 (d, J = 15.0 Hz, 1H), 4.47 (m, 1H), 1.96 (m, 2H), 1.72 (m, 1H), 0.99 (m, 6H). 13C NMR (CDCI3, 125 MHz) δ 174.1 (Cq), 169.4 (Cq), 151.1 (Cq), 139.9 (CH), 139.2 (Cq), 135.8 (Cq), 135.2 (Cq), 130.3 (CH), 128.6 (CH), 128.4 (CH), 127.6 (CH), 127.5 (CH), 123.2 (CH), 112.3 (CH), 57.5 (CH), 51.5 (CH2), 36.3 (CH2), 24.9 (CH), 22.9 (CH3), 22.0 (CH3). IR (neat): vmax (cm'1) = 3252 (w), 2955 (w), 1697 (s), 1564 (s), 1522 (m), 1431 (s), 1155 (s), 787 (s), 698 (m). HRMS (ESI): m/z calculated for C25H27BrN302(M+H) 480.1281, found 480.1272. 6n: Two rotamers were present on NMR timescale (R1: R2 = 1 : 0.2). 1H NMR (CDCI3, 500 MHz) δ8.69 (bs, 1H), 8.22 (bs, 0.2H), 8.12 (d, J= 8.1 Hz, 0.2H), 8.08 (d, J= 7.7 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1,2H), 7.38-7-26 (m, 3.6H), 7.20 (dd, J = 4.9, 2.7, 2.4H), 4.70 (s, 2.4H), 4.14 (s, 2H), 4.04 (s, 0.4H), 2.30 (s, 3H), 2.19 (s, 0.6H). 13C NMR (CDCI3, 125 MHz) δ 172.4 (Cq), 167.4 (Cq), 151.0 (Cq), 140.4 (CH), 139.3 (Cq), 135.3 (Cq), 129.1 (CH), 128.9 (CH), 128.5 (CH), 128.1 (CH), 127.9 (CH), 126.6 (CH), 123.7 (CH), 112.4 (CH), 53.4 (CH2), 51.6 (CH2), 50.6 (CH2), 49.9 (CH2), 21.8 (CH3)21.4 (CH3). IR (neat): wnax (cm'1) = 3227 (w), 3040 (w), 1701 (s), 1623 (m), 1568 (s), 1431 (s), 1155 (s), 1128 (s), 789 (s), 729 (s). HRMS (ESI): m/z calculated for Ci6H17BrN302(M+H) 362.0499, found 362.0485. 6o: 1H NMR (CDCI3, 500 MHz) δ 8.23 (bs, 1H), 8.21 (d, J= 8.2 Hz, 1H), 7.52 (t, J= 7.9 Hz, 1H), 7.50-7.41 (m, 5H), 7.17 (d, J= 7.7 Hz, 1H), 6.78-6.74 (m, 4H), 6.19 (s, 1H), 3.75 (s, 3H), 3.45 (m, 2H), 2.62-2.43 (m, 3H), 2.10 (m, 1H), 1.20 (t, J= 7,3, 3H).13C NMR (CDCI3, 125 MHz) δ 175.0 (Cq), 168.9 (Cq), 158.2 (Cq), 151.2 (Cq), 140.4 (CH), 139.2 (Cq), 133.9 (Cq), 130.2 (CH), 130.1 (Cq), 129.4 (CH), 129.3 (CH), 129.2 (CH), 123.5 (CH), 113.9 (CH), 112.3 (CH), 63.5 (CH), 55.2 (CH3), 48.1 (CH2), 35.4 (CH2), 26.7 (CH2), 9.4 (CH3). IR (neat): wnax (cm'1) = 3238 (w), 2937 (w), 1705 (m), 1618 (s), 1568 (s), 1512 (s), 1431 (s), 1153 (s), 787 (m). HRMS (ESI): m/z calculated for C25H27BrN303(M+H) 496.1130, found 496.1123. 6p: 1H NMR(CDCI3, 500 MHz) δ 9.18 (bs, 7.83 (d, J= 8.1 Hz, 1H), 7.51 (d, J=2.5 Hz, 1H), 7.46-7.41 (m, 2H), 7.27-7.17 (m, 6H), (t, J=4.4 Hz, 1H), 5.04 (d, J=17.1 Hz, 1H), 5.02 (t, J = 7.3 Hz, 1H), 4.82 (d, J=16.8 Hz, 1H), 1.99 (m, 1H), 1.75 (m, 1H), 1.61 (m, 1H), 0.90 (m, 6H).13C NMR (CDCI3, 125 MHz) δ 169.3 (Cq), 166.7 (Cq), 151.2 (Cq), 140.1 (CH), 139.4 (Cq), 137.1 (Cq), 136.5 (Cq), 130.8 (CH), 130.0 (CH), 128.7 (CH), 127.7 (CH), 127.3 (CH), 127.2 (CH), 123.6 (CH), 112.5 (CH), 59.2 (CH), 51.5 (CH2), 37.1 (CH2), 25.2 (CH). 22.6 (CH3), 22.5 (CH3). IR (neat): wnax (cm'1) = 3240 (w), 2957 (w), 1697 (s), 1562 (s), 1517 (s), 1427 (s), 1387 (s), 1155 (s), 1120 (s), 727 (s). HRMS (ESI): m/z calculated for C23H25BrN302S (M+H) 486.0845, found 486.0831. 6q: 1H NMR (CDCI3, 500 MHz) δ 8.23 (bs, 1H), 8.20 (d, J= 8.3 Hz, 1H), 7.53 (t, J= 8 Hz, 1H), 7.34 (m, 2H), 7.27 (m, 3H), 7.18 (m, 4H), 6.98 (d, J= 7.3 Hz, 2H), 6.12 (s, 1H), 4.75 (d, J = 17.6 Hz, 1H), 4.53 (d, J= 17.6, 1H), 2.17 (s, 3H). 13C NMR (CDCI3, 125 MHz) δ 172.8 (Cq), 168.6 (Cq), 151.1 (Cq), 140.5 (CH), 139.2 (Cq), 137.1 (Cq), 133.3 (Cq), 130.1 (CH), 129.2 (CH), 129.1 (CH), 128.4 (CH), 127.0 (CH), 126.0 (CH), 123.6 (CH), 112.3 (CH), 63.9 (CH), 50.5 (CH2), 22.4 (CH3). IR (neat): wnax (cm'1) = 3238 9w), 3030 (w), 1703 (s), 1634 (s), 1568 (s), 1431 (m), 1153 (s), 698 (m), 631 (s), 530 (s), 500 (s). HRMS (ESI): m/z calculated for C22H2iBrN302 (M+H) 438.0812, found 438.0804. 6r: 1H NMR (CDCI3, 500 MHz) δ 9.04 (bs, 1H), 7.65 (d, J= 8.2 Hz, 1H), 7.43 (t, J= 8.0 Hz, 1H), 7.22-7.13 (m, 6H), 4.89 (d, J= 16.3 Hz, 1H), 4.66 (t, J = 7.4 Hz, 1H), 4.56 (d, J= 16.3 Hz, 1H), 1.85 (m, 1H), 1.69 (m, 1H), 1.54 (m, 1H), 1.38 (s, 9H), 0.91 (d, J= 6.6 Hz, 3H), 0.88 (d, J = 6.6, 3H). 13C NMR(CDCI3, 125 MHz) δ 180.3 (Cq), 169.8 (Cq), 151.2 (Cq), 140.0 (CH), 139.3 (Cq), 134.7 (Cq), 133.6 (Cq), 128.9 (CH), 128.8 (CH), 123.3 (CH), 112.3 (CH), 59.1 (CH), 49.9 (CH2), 40.2 (Cq), 36.7 (CH2), 28.9 (CH3), 24.9 (CH), 22.8 (CH3), 22.3 (CH3). IR (neat): wnax (cm'1) = 2957 (w), 1701 (s), 1562 (s), 1431 (s), 1155 (s), 787 (s). HRMS (ESI): m/z calculated for C23H30BrCIN3O2(M+H) 494.1204, found 494.1201. 6s: 1H NMR (CDCI3, 500 MHz) δ 9.26 (bs, 1H), 7.76 (d, J= 8.2 Hz, 1H), 7.41 (t, J= 7.9 Hz, 1H), 7.21-7.12 (m, 6H), 4.78 (m, 1H), 4.68 (d, J= M2 Hz, 1H), 4.61 J= M2 Hz, 1H), 2.28 (m, 1H), 2.17 (s, 3H), 1.75-1.60 (m, 6H), 1.20-1.14 (m, 2H), 1.03-0.99 (m, 2H). 13C NMR (CDCI3, 125 MHz) δ 173.2 (Cq), 168.8 (Cq), 151.2 (Cq), 140.2 (CH), 139.3 (Cq), 136.7 (Cq), 128.7 (CH), 127.3 (CH), 126.1 (CH), 123.5 (CH), 112.4 (CH), 60.4 (CH), 50.1 (CH2), 35.6 (CH), 30.2 (CH2), 28.9 (CH2), 26.2 (CH2), 25.6 (CH2), 25.5 (CH2), 22.4 (CH3). IR (neat): wnax (cm'1) = 3198 (w), 2924 (w), 1628 (s), 1568 (s), 1431 (s), 773 (m), 631 (s),534 (m), 494 (s), 405 (s). HRMS (ESI): m/z calculated for C22H27BrN302(M+H) 444.1281, found 444.1266. 6t: Product 1 (a white solid): m.p.: 158 °C. 1H NMR (CDCI3, 500 MHz) δ 10.45 (bs, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.49-7-31 (m, 5H), 7.17 (d, J = 7.6 Hz, 1H), 5.15 (q, J = 6.5 Hz, 1H), 3.75 (m, 1H), 2.49 (m, 1H), 2.35 (s, 3H), 1.66 (d, J = 7.0 Hz, 3H), 1.26 (m, 1H) 1.17 (m, 1H), 0.63 (d, J= 6.5 Hz, 3H), 0.41 (d, J= 6.5 Hz, 3H). 13C NMR (CDCI3, 125 MHz) δ 172.4 (Cq), 171.4 (Cq), 151.8 (Cq), 140.1 (CH), 139.5 (Cq), 138.8 (Cq), 128.8 (CH), 128.2 (CH), 127.3 (CH), 123.4 (CH), 112.5 (CH), 61.3 (CH), 57.3 (CH), 39.2 (CH2), 25.1 (CH), 23.9 (CH3), 23.0 (CH3), 21.0 (CH3), 17.6 (CH3). IR (neat): wnax (cm'1) = 2966 (w), 1693 (m), 1556 (s), 1529 (s), 1429 (s), 1391 (s), 1319 (m), 1155 (s), 1128 (s), 993 (m), 794 (s), 698 (s), 554 (m), 522 (m). HRMS (ESI): m/z calculated for C2iH27BrN302(M+H) 432.1281, found 432.1264. Product 2 (a light brown oil): 1H NMR (CDCI3, 500 MHz) δ 9.31 (bs, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.40-7.32 (m, 5H), 7.12 (d, J= 8.0 Hz, 1H), 5.17 (q,J = 7.0 Hz, 1H), 3.93 (bs, 1H), 2.49 (m, 1H), 2.27 (s, 3H), 1.71 (d, J= 7.0 Hz, 3H), 1.64 (m, 1H), 1.49 (m, 1H), 0.95 (m, 6H). 13C NMR (CDCI3, 125 MHz) δ 172.0 (Cq), 169.7 (Cq), 151.6 (Cq), 140.1 (CH), 139.3 (Cq), 139.1 (Cq), 129.2 (CH), 128.4 (CH), 126.9 (CH), 123.1 (CH), 112.2 (CH), 59.2 (CH), 56.6 (CH), 39.2 (CH2), 25.7 (CH), 23.6 (CH3), 23.3 (CH3), 22.1 (CH3), 17.5 (CH3). IR (neat): wnax (cm'1) = 3227 (w), 3040 (w), 1701 (s), 1623 (m), 1568 (s), 1431 (s), 1155 (s), 1128 (s), 789 (s), 729 (s). HRMS (ESI): m/z calculated for C2iH27BrN302(M+H) 432.1281, found 432.1272. 6u: 1H NMR (CDCI3, 500 MHz) δ 8.81 (bs, 1H), 8.17 (d, J= 8.0 Hz, 1H), 7.52 (t, J= 8.0 Hz, 1H), 7.33 (bs, 4H), 7.17 (d, J = 7.5, 1H), 6.11 (s, 1H), 3.25 (t, J = 8.0 Hz, 2H), 2.25 (s, 3H), 1.45 (m, 1H), 1.05 (m, 1H), 0.69 (t, J = 7.0 Hz, 3H). 13C NMR (CDCI3, 125 MHz) δ 172.1 (Cq), 168.6 (Cq), 151.2 (Cq), 140.4 (CH), 139.3 (Cq), 135.0 (Cq), 132.8 (Cq), 131.0 (CH), 123.6 (CH), 112.3 (CH), 62.6 (CH), 49.2 (CH2), 23.0 (CH2), 21.8 (CH3) 11.1 (CH3). IR (neat): wnax (cm'1) = 2968 (w), 1703 (m), 1616 (m), 1566 (s), 1533 (m), 1427 (s), 1391 (s), 1300 (m), 1155 (s), 1128 (s), 789 (s), 731 (s), 548 (s). HRMS (ESI): m/z calculated for Ci8H20BrN3O2(M+H) 424.0422, found 424.0418. 6v: 1H NMR (CDCI3, 500 MHz) δ 8.69 (bs, 1H), 7.69 (d, J= 8.5 Hz, 1H), 7.37 (t, J= 7.8 Hz, 1H), 7.18-7-04 (m, 6H), 5.36 (bs, 1H), 5.19 (d, J= 17.5 Hz, 1H), 4.74 (d, J= 17.5 Hz, 1H), 2.39 (m, 1H), 2.22 (m, 1H), 1.14 (s, 9H), 1.10 (t, J= 7.3 Hz, 3H). 13C NMR(CDCI3, 125 MHz) δ 176.7 (Cq), 168.3 (Cq), 150.8 (Cq), 140.2 (CH), 139.2 (Cq), 138.1 (Cq), 128.6 (CH), 126.7 (CH), 125.3 (CH), 123.6 (CH), 112.4 (CH) 49.6 (CH2), 36.7 (Cq), 27.6 (CH3), 27.4 (CH2), 9.8 (CH3). IR (neat): vmax (cm'1) = 2960 (w), 1630 (s), 1566 (s), 1529 (m), 1431 (s), 1389 (s), 1153 (s), 1128 (s), 789 (s), 731 (s). HRMS (ESI): m/z calculated for C2iH27BrN302(M+H) 432.1281, found 432.1267. 6w: 1H NMR (CDCI3, 500 MHz) δ 9.60 (bs, 1H), 8.17 (d, J= 8.0 Hz, 1H), 7.53 (t, J= 8.0 Hz, 1H), 7.19 (d,J = 7.5 Hz, 1H), 5.31 (bs, 1H), 4.17 (m, 1H), 3.85 (m, 1H), 3.65 (s, 3H), 2.63-2.56 (m, 2H), 2.34 (s, 3H), 1.11 (s, 9H). 13C NMR (CDCI3, 125 MHz) δ 172.8 (Cq), 171.3 (Cq), 169.1 (Cq), 151.3 (Cq), 140.4 (CH), 139.5 (Cq), 123.7 (CH), 112.6 (CH), 60.4 (CH2), 51.9 (CH), 36.5 (Cq), 34.6 (CH2), 27.8 (CH3), 21.9 (CH3). IR (neat): vmax (cm'1) = 2957 (w), 1735 (s), 1628 (s), 1568 (s), 1431 (s), 1153 (s), 764 (m), 631 (s), 534 (m), 498 (s), 401 (s). HRMS (ESI): m/z calculated for Ci7H25BrN304(M+H) 414.1023, found 414.1017. 3a: Two rotamers were present on NMR timescale (R1: R2 = 1 : 0.3). 1H NMR (CDCI3, 500 MHz) δ 11.40 (bs, 1.3H), 7.42-7.18 (m, 6.5H), 5.05 (d, J= 15.6 Hz, 0.3H), 4.75-4.70 (m, 2H), 4.51 (d, J = 17.3 Hz, 1H), 4.42 (m, 0.3H), 4.22 (d, J = 15.6 Hz, 0.3H), 2.30 (s, 0.9H), 2.17 (s, 3H), 1.92 (m, 1H), 1.73 (m, 0.3H), 1.65-1.49 (m, 2.3H), 1.36 (m, 0.3H), 0.89 (d, J= 6.5 Hz, 3H), 0.86 (d, J = 6.5 Hz, 0.9H), 0.75 (d, J = 6.6 Hz, 3H), 0.59 (d, J = 6.7 Hz, 0.9H). 13C NMR (CDCI3, 125 MHz) δ 175.4 (Cq), 174.4 (Cq), 173.3 (Cq), 173.0 (Cq), 138.2 (Cq), 136.5 (Cq), 128.8 (CH), 128.1 (CH), 127.8 (CH), 127.6 (CH), 126.9 (CH), 126.6 (CH), 59.5 (CH), 57.2 (CH), 51.7 (CH2), 47.5 (CH2), 38.4 (CH2), 38.1 (CH2), 25.2 (CH), 24.4 (CH), 22.2 (CH3), 22.2 (CH3), 22.2 (CH3), 22.0 (CH3), 22.0 (CH3), 21.7 (CH3). IR (neat): vmax (cm'1) = 2955 (w), 1735 (s), 1718 (s), 729 (s), 632 (s), 546 (s), 501 (s). HRMS (ESI): m/z calculated for Ci5H22N03 (M+H) 264. 1594, found 264.1603. 3b: Two rotamers were present on NMR timescale (R1: R2 = 1 : 0.7). 1H NMR (CDCI3, 500 MHz) δ 10.45 (bs, 1.7H), 7.59-7.16 (m, 17H), 5.19 (d, J= 14.3 Hz, 0.7H), 4.69 (d, J= 15.6 Hz, 1H), 4.4.49 (m, 1.7H), 4.21 (d, J= 14.6 Hz, 0.7H), 4.14 (m, 1H), 2.19 (m, 1H), 1.83-1.52 (m, 3.1 H), 1.30 (m, 1H), 0.98-0.82 (m, 6H), 0.60-0.40 (m, 4.2H). 13C NMR (CDCI3, 125 MHz) δ 176.0 (Cq), 175.5 (Cq), 173.7 (Cq), 173.6 (Cq), 138.3 (Cq), 135.8 (Cq), 135.7 (Cq), 135.2 (Cq), 130.3 (CH), 130.1 (CH), 129.7 (CH), 128.8 (CH), 128.4 (CH), 128.3 (CH), 128.1 (CH), 127.9 (CH), 127.4 (CH), 127.0 (CH), 126.6 (CH), 60.6 (CH), 58.7 (CH), 54.6 (CH2), 47.4 (CH2), 38.2 (CH2), 29.7 (CH2), 25.4 (CH), 24.2 (CH), 22.4 (CH3), 22.2 (CH3), 21.4 (CH3). IR (neat): vmax (cm'1) = 2957 (w), 1713 (m), 1593 (m), 1447 (m), 1246 (m), 733 (m), 633 (s), 536 (s), 494 (s), 403 (s). HRMS (ESI): m/z calculated for C20H24NO3 (M+H) 326.1751, found 326.1748. 3c: Two rotamers were present on NMR timescale (R1: R2 = 1 : 0.4). 1H NMR (CDCI3, 500 MHz) δ 8.60 (bs, 1.4H), 7.39-7.19 (m, 7H), 4.66 (s, 0.8H), 4.63 (s, 2H), 4.09 (s, 2H), 3.94 (s, 0.8H), 2.25 (s, 3H), 2.16 (s, 1.2H). 13C NMR (CDCI3, 125 MHz) δ 172.7 (Cq), 172.6 (Cq), 172.3 (Cq), 172.1 (Cq), 136.31 (Cq), 135.4 (Cq), 129.1 (CH), 128.7 (CH), 128.4 (CH), 128.0 (CH), 127.7 (CH), 126.7 (CH), 53.0 (CH2), 49.5 (CH2), 48.8 (CH2), 47.1 (CH2), 21.3 (CH3), 21.1 (CH3). IR (neat): wnax (cm'1) = 2927 (w), 1732 (m), 1599 (m), 1431 (m), 1201 (m), 633 (s), 532 (m), 498 (s), 403 (s). HRMS (ESI): m/z calculated for CnH14N03 (M+H) 208.0968, found 208.0964. 3d: Two rotamers were present on NMR timescale (R1: R2 = 1 : 0.14). 1H NMR (CDCI3, 500 MHz) δ 10.71 (bs, 1.14H), 7.42 (m, 5.7H), 6.75 (m, 4.56H), 6.03 (s, 1H), 5.74 (s, 0.14H), 3.75 (s, 3.42H), 3.65 (m, 0.14H), 3.42 (m, 1H), 3.35 (m, 1H), 3.17 (m, 0.14H), 2.75 (m, 0.14H), 2.58 (m, 1H), 2.50-2.31 (m, 2.28H), 2.13 (m, 1H), 1.92 (m, 0.14H), 1.16 (t, J =7.0 Hz, 3.42H). 13C NMR (CDCI3, 125 MHz) δ 175.6 (Cq), 174.0 (Cq), 158.2 (Cq), 133.9 (Cq), 129.9 (Cq), 129.8 (CH), 129.4 (CH), 128.9 (CH), 113.9 (CH), 62.5 (CH), 55.2 (CH3), 48.4 (CH2), 35.2 (CH2), 26.6 (CH2), 9.4 (CH3). IR (neat): wnax (cm'1) = 2937 (w), 1736 (m), 1610 (m), 1512 (s), 1421 (m), 1246 (s), 1178 (s), 1157 (s), 1036 (m), 727 (m), 702 (s). HRMS (ESI): m/z calculated for C2oH24N04(M+H) 342.1700, found 342.1687. 3e: 1H NMR (CDCI3, 500 MHz) δ 10.35 (bs, 1H), 7.49 (s, 1H), 7.47-7.30 (m, 6H), 7.00 (s, 1H), 4.99 (d, J =16.5 Hz, 1H), 4.79 (bs, 1H),4.16(bs, 1H),2.17(m, 1H), 1.65 (m, 2H), 0.91-0.63 (m, 6H). 13C NMR (CDCI3, 125 MHz) δ 175.8 (Cq), 166.4 (Cq), 136.9 (Cq), 129.5 (CH), 128.8 (CH), 127.8 (CH), 127.4 (CH), 127.2 (CH), 60.0 (CH), 38.3 (CH2), 29.7 (CH2), 25.3 (CH), 22.5 (CH3), 22.1 (CH3). IR (neat): wnax (cm'1) = 2957 (w), 1715 (s), 1591 (m), 1522 (s), 1425 (m), 1352 (m), 1319 (m), 1245 (m), 1173 (m), 968 (m), 908 (m), 858 (m), 729 (s). HRMS (ESI): m/z calculated for Ci8H22N03S (M+H) 332.1315, found 332.1305. 3f: 1H NMR (CDCI3, 500 MHz) δ 10.40 (bs, 1H), 7.37-7.17 (m, 8H), 6.99 (m, 2H), 5.92 (s, 1H), 4.68 (d, J = 17.6 Hz, 1H), 4.45 (d, J = 17.6 Hz, 1H), 2.13 (s, 3H). 13C NMR (CDCI3, 125 MHz) δ 173.8 (Cq), 173.4 (Cq), 136.7 (Cq), 133.5 (Cq), 129.9 (CH), 128.8 (CH), 128.7 (CH), 128.6 (CH), 127.1 (CH), 126.1 (CH), 62.6 (CH), 50.6 (CH2), 22.1 (CH3). IR (neat): wnax (cm'1) = 2922 (w), 1732 (m), 1597 (m), 1418 (m), 1204 (m), 729 (s), 698 (s), 634 (s), 530 (s), 496 (s), 401 (s). HRMS (ESI): m/z calculated for Ci7H18N03 (M+H) 284.1281, found 284.1274. 3g: 1H NMR (CDCI3, 500 MHz) δ 7.34 (d, J= 7.4 Hz, 1H), 7.28 (d, J= 7.4 Hz, 1H), 4.91 (d, J = 16.5 Hz, 1H), 4.55 (d, J= 15.0 Hz, 1H), 3.49 (m, 1H), 2.19 (m, 1H), 1.59 (m, 1H), 1.43 (m, 1H), 1.34 (s, 9H), 0.86 (d, J = 6.5 Hz, 1H), 0.73 (d, J = 6.5 Hz, 1H). 13C NMR (CDCI3, 125 MHz) δ 179.6 (Cq), 174.7 (Cq), 129.0 (CH), 128.9 (CH), 60.6 (CH), 39.3 (CH2), 38.7 (Cq), 29.7 (CH2), 28.4 (CH3), 25.4 (CH), 22.8 (CH3), 22.0 (CH3). IR (neat): vmax (cm'1) = 2959 (w), 1734 (m), 1716 (m), 1636 (m), 1493 (s), 1182 (m), 790 (m), 516 (s), 430 (s). HRMS (ESI): m/z calculated for Ci8H27CIN03(M+H) 140.1674, found 340.1650. 3h: Two rotamers were present on NMR timescale (R1: R2 = 1 : 0.2). 1H NMR (CDCI3, 500 MHz) δ 10.78 (bs, 1.2H), 7.38-7.11 (m, 6H), 4.74 (d, J= 16.8 Hz, 1H), 4.67 (d, J= 15.5 Hz, 0.2H), 4.60 (d, J= 15.5 Hz, 0.2H), 4.40 (d, J= 16.8 Hz, 1H), 3.99 (d, J= 11.0 Hz, 0.2H), 3.87 (d, J= 10.5 Hz, 1H), 2.32 (m, 1H), 2.26 (s, 0.6H), 2.20 (s, 3H), 1.93 (m, 0.2H), 1.81-1.56 (m, 4.8H), 1.48 (m, 0.2H), 1.36-1.04 (m, 4.6H), 1.01-0.68 (m, 2.4H). 13C NMR (CDCI3, 125 MHz) δ 174.7 (Cq), 173.5 (Cq), 172.5 (Cq), 171.8 (Cq), 137.9 (Cq), 135.2 (Cq), 129.0 (CH), 128.1 (CH), 128.0 (CH), 127.9 (CH), 126.8 (CH), 126.7 (CH), 70.6 (CH), 66.2 (CH), 55.4 (CH2), 46.2 (CH2), 36.7 (CH), 36.0 (CH), 30.3 (CH2), 30.1 (CH2), 29.7 (CH2), 29.3 (CH2), 26.1 (CH2), 26.0 (CH2), 25.6 (CH2), 25.5 (CH2), 25.3 (CH2), 22.6 (CH3), 22.3 (CH3). IR (neat): wnax (cm'1) = 2926 (m), 1728 (m), 1601 (s), 1450 (s), 1421 (m), 1240 (m), 1184 (m), 910 (m), 729 (s), 696 (s). HRMS (ESI): m/z calculated for Ci7H24N03(M+H) 290.1751, found 290.1733. 3i: 1H NMR (CDCI3, 500 MHz) δ 11.22 (bs, 1.1 H), 5.17 (m, 1.1H), 3.56 (m, 0.1 H), 3.47 (m, 1H), 2.34 (m, 4.4H), 1.67 (d, J=7.0 Hz, 3.3H), 1.26 (m, 1.1H), 0.91 (m, 0.6H), 0.76 (m, 1.1H), 0.60 (d, J =6.5 Hz, 3H), 0.22 (d, J =6.5 Hz, 3H). 13C NMR (CDCI3, 125 MHz) δ 174.4 (Cq), 173.0 (Cq), 172.8 (Cq), 172.6 (Cq), 138.0 (Cq), 137.9 (Cq), 128.8 (CH), 128.8 (CH), 128.4 (CH), 128.4 (CH), 127.7 (CH), 127.3 (CH), 58.0 (CH), 57.8 (CH), 57.7 (CH), 57.6 (CH), 39.9 (CH2), 39.2 (CH2), 25.6 (CH), 24.9 (CH), 23.5 (CH3), 23.3 (CH3), 23.0 (CH3), 22.7 (CH3), 21.7 (CH3), 20.5 (CH3), 17.6 (CH3), 16.9 (CH3). IR (neat): wnax (cm'1) = 2957 (w), 1715 (m), 1635 (m), 1593 (m), 1450 (m), 1313 (m), 1246 (m), 1205 (s), 904 (s), 725 (s), 648 (s). HRMS (ESI): m/z calculated for Ci6H24N03 (M+H) 278.1751, found 278.1738. 3j: Two rotamers were present on NMR timescale (R1: R2 = 1 : 0.1). 1H NMR (CDCI3, 500 MHz) δ 10.15 (bs, 1.1 H), 7.99 (d, J=7.5 Hz, 0.1 H), 7.42 (d, J=7.5 Hz, 0.1 H), 7.30 (m, 4H), 5.67 (s, 1H), 5.54 (s, 0.1 H), 3.37 (m, 0.1 H), 3.24 (m, 1H), 3.12 (m, 1H), 3.02 (m, 0.1 H), 2.20 (s, 3.3H), 1.45 (m, 1.1 H), 1.14 (m, 1.1H), 0.73 (t, J= 7.3 Hz, 3H), 0.63 (m, 0.3H). 13C NMR (CDCI3, 125 MHz) δ 172.8 (Cq), 172.7 (Cq), 172.4 (Cq), 170.1 (Cq), 140.1 (Cq), 134.6 (Cq), 132.8 (Cq), 131.5 (CH), 130.8 (CH), 130.2 (CH), 128.8 (CH), 127.9 (Cq), 64.1 (CH), 62.1 (CH), 49.9 (CH2), 47.3 (CH2), 29.7 (CH2), 22.6 (CH2), 22.2 (CH3), 21.4 (CH3), 11.3 (CH3), 11.1 (CH3). IR (neat): wnax (cm'1) = 2968 (w), 1734 (m), 1595 (s), 1493 (s), 1421 (m), 1194 (m), 1092 (s), 1016 (s), 734 (m). HRMS (ESI): m/z calculated for Ci3Hi7CIN03 (M+H) 270.0891, found 270.0886. 3k: 1H NMR (CDCI3, 500 MHz) δ 7.35 (t, J = 7.3 Hz, 2H), 7.28 (d, J= 7.3 Hz, 1H), 7.16 (d, J = 7.3 Hz, 2H), 4.96 (d, J= 17.0 Hz, 1H), 4.40 (d, J= 17.0 Hz, 1H), 4.29 (bs, 1H), 2.37 (m, 2H), 1.12 (m, 12H). 13C NMR (CDCI3, 125 MHz) δ 178.2 (Cq), 171.4 (Cq), 136.0 (Cq), 129.1 (CH), 127.8 (CH), 126.0 (CH), 36.9 (CH2), 29.7 (Cq), 28.4 (CH3), 28.0 (CH2), 9.5 (CH3). IR (neat): vmax (cm'1) = 2961 (w), 1733 (m), 1604 (m), 1465 (m), 1452 (m), 1213 (m), 1163 (s), 966 (m), 731 (s), 696 (s). HRMS (ESI): m/z calculated for Ci6H24N03 (M+H) 278.1751, found 278.1742. 3I: Two rotamers were present on NMR timescale (R1: R2 = 1 : 0.5). 1H NMR (MeOD, 500 MHz) δ 4.26 (bs, 0.5H), 3.95 (m, 1H), 3.63 (m, 2H), 2.82-2.58 (m, 3H), 2.17 (s, 4.5H), 1.14 (s, 4.5H), 1.10 (s, 9H). 13C NMR (MeOD, 125 MHz) δ 175.6 (Cq), 174.9 (Cq), 174.9 (Cq), 174.1 (Cq), 172.5 (Cq), 172.2 (Cq), 69.6 (CH), 69.5 (CH), 42.9 (CH2), 37.1 (CH2), 36.6 (CH2), 34.6 (CH2), 33.2 (Cq), 30.8 (Cq), 28.5 (CH3), 28.3 (CH3), 22.7 (CH3), 21.7 (CH3). IR (neat): vmax (cm'1) = 2962 (w), 1717 (m), 1607 (m), 1419 (m), 1367 (s), 1209 (m), 1165 (s), 797 (s), 540 (m). HRMS (ESI): m/z calculated for CnH2oN05(M+H) 246.1336, found 246.1327. 3.1.1 Transformations under basic conditions.
[46] The nucleophilic displacement of the 2-amino-6-bromopyridine moiety from the Ugi products under basic conditions gave good results, therefore other transformations were evaluated starting from the Ugi product of 5I, acetic acid, isovaleraldehyde and benzylamine.
It was found that this Ugi product (6I) was readily converted to the corresponding methyl ester 3a, as well as secondary and tertiary amides (2ba and 2aa, respectively).
Scheme 8:
Nucleophilic substitution of Ugi product 6I with various nucleophiles under basic conditions.
Table 2. Yields of nucleophilic substitution of Ugi product 6I with various nucleophiles under basic conditions.
[47] Analytical data: 4a: Two rotamers were present on NMR timescale (R1: R2 = 1 : 0.35). 1H NMR (CDCI3, 500
MHz) δ 7.42-7.17 (m, 6.75H), 4.95 (t, J=6.9 Hz, 1H), 4.66 (d, J = 17.6 Hz, 1.35H), 5.51 (d, J = 17.6 Hz, 1.35H), 4.41 (dd, J = 8.6 Hz, 6.1 Hz, 0.35H), 3.60 (s, 3H), 3.49 (s, 1.05H), 2.28 (s, 1.05H), 2.13 (s, 3H), 1.86-1.74 (m, 1.35H), 1.66 (m, 0.35H), 1.54 (m, 2H), 1.41 (m, 0.35H), 0.90 (m, 4.05H), 0.79 (d, J= 6.3Hz, 3H), 0.71 (d, J= 6.7 Hz, 1.05H). 13C NMR (CDCI3, 125 MHz) δ 172.2 (Cq), 171.9 (Cq), 171.7 (Cq), 171.3 (Cq), 138.0 (Cq), 137.0 (Cq), 128.6 (CH), 128.1 (CH), 128.0 (CH), 127.4 (CH), 127.0 (CH), 126.4 (CH), 58.8 (CH), 55.6 (CH), 52.1 (CH3), 51.9 (CH3), 50.5 (CH2), 46.2 (CH2), 38.3 (CH2), 29.6 (CH2), 25.1 (CH), 24.3 (CH), 22.4 (CH3), 22.4 (CH3), 22.2 (CH3), 22.2 (CH3), 22.1 (CH3), 21.9 (CH3). IR (neat): vmax (cm'1) = 2955 (m), 1738 (s), 1649 (s), 1410 (s), 1200 (s), 729 (s), 633 (s), 498 (s). HRMS (ESI): m/z calculated for Ci6H24N03 (M+H) 278.1751, found 278.1742. 2ba: Two rotamers were present on NMR timescale (R1: R2 = 1 : 0.1). 1H NMR (CDCI3, 500 MHz) δ 7.32 (t, J = 7.6 Hz, 2H), 7.26 (t, J = 7.4 Hz, 1H), 7.17 (d, J = 7.5 Hz, 2H), 6.56 (bs, 1H), 5.04 (m, 1H), 4.65 (d, J= 17.8 Hz, 1H), 4.59 (d, J= 17.7 Hz, 1H), 3.23-3.11 (m, 2H), 2.06 (s, 3H), 1.84 (m, 1H), 1.51-1.34 (m, 4H), 1.33-1.28 (m, 2H), 0.92 (t, J= 7.3 Hz, 3H), 0.86 (d, J = 6.6 Hz, 3H), 0.84 (d, J= 6.6 Hz, 3H). 13C NMR (CDCI3, 125 MHz) δ 172.9 (Cq), 170.6 (Cq), 137.5 (Cq), 128.6 (CH), 127.2 (CH), 125.9 (CH), 55.7 (CH), 48.9 (CH2), 38.9 (CH2), 37.0 (CH2), 31.4 (CH2), 25.1 (CH), 22.8 (CH3), 22.4 (CH3), 22.3 (CH3), 20.0 (CH2), 13.7 (CH3). IR (neat): vmax (cm'1) = 3298 (m), 2957 (m), 1630 (s), 1547 (s), 633 (s), 532 (s), 498 (s). HRMS (ESI): m/z calculated for Ci9H31N202(M+H) 319.2380, found 319.2369. 2aa: Two rotamers were present on NMR timescale (R1: R2 = 1 : 0.16). 1H NMR (CDCI3, 500 MHz) δ 7.39-7.08 (m, 5.8H), 5.58 (t, J = 7.0 Hz, 1H), 5.08 (d, J = 15.0 Hz, 0.16H), 4.73 (d, J = 17.5 Hz, 1H), 4.68 (d, J= 17.5 Hz, 1H), 4.27 (m, 0.16H), 4.05 (d, J= 15.0 Hz, 0.16H), 3.71 (m, 1H), 3.51 (m, 1H), 3.35 (m, 1H), 3.21 (m, 0.32H), 3.12 (m, 0.16H), 3.00 (m, 1H), 2.70 (m, 0.16H), 2.35 (m, 0.16H), 2.27 (s, 0.48H), 2.07 (s, 3H), 2.00-1.69 (m, 5.64H), 1.63-1.41 (m, 2.32H), 0.99-0.80 (m, 6.96H). 13C NMR (CDCI3, 125 MHz) δ 171.9 (Cq), 170.7 (Cq), 168.9 (Cq), 166.0 (Cq), 138.4 (Cq), 138.0 (Cq), 128.4 (CH), 128.4 (CH), 127.8 (CH), 126.9 (CH), 126.8 (CH), 125.8 (CH), 57.8 (CH), 52.1 (CH), 47.9 (CH2), 46.4 (CH2), 45.7 (CH2), 45.6 (CH2), 45.4 (CH2), 45.1 (CH2), 39.2 (CH2), 38.6 (CH2), 25.9 (CH2), 25.6 (CH2), 24.8 (CH), 24.6 (CH), 24.0 (CH2), 23.4 (CH3), 23.4 (CH2), 22.9 (CH3), 22.6 (CH3), 22.3 (CH3), 21.8 (CH3), 21.7 (CH3). IR (neat): vmax (cm'1) = 2955 (m), 1636 (s), 1439 (m), 1408 (m), 698 (m), 621 (m). HRMS (ESI): m/z calculated for Ci9H29N202(M+H) 317.2224, found 317.2200.
General procedure IV: Nucleophilic substitution of Ugi products derived from 5I under basic conditions.
[48] To a flame dried Schlenk 3A MS, NaOMe in MeOH (0.5M, 5 ml_, 2.5 mmol, 5.0 eq.) and a nucleophile (2.5 mmol, 5.0 eq.) were added and predried for 1 hour under nitrogen atmosphere. The Ugi-product 2-(/V-benzylacetamido)-/V-(6-bromopyridin-2-yl)-4-methylpenta-namide (209 mg, 0.5 mmol, 1.0 eq.) was added and the mixture was stirred for 24h at 50°C. The crude mixture was cooled to 0°C and acidified at once to pH=1 with 6M HCI and extracted with EtOAc. The organic layer was washed with 1M HCI and brine, dried over Na2S04and concentrated under reduced pressure. The crude mixture was purified by column chromatography (cyclohexane : EtOAc) to yield the corresponding product. 3.1.2 Transformations under acidic conditions [49] The 2-amino-6-bromopyridine moiety in the above Ugi products may also be displaced by non-basic nucleophiles under acidic conditions (scheme 9). It was found that conversion of Ugi product 61 to various esters 4a-d was efficient (quantitative yield). Also thioesters 4e and 4f were obtained in this manner.
61 3a, 4a-f
Scheme 9:
Nucleophilic substitution of Ugi product 61 with various nucleophiles under acidic conditions.
Table 3. Yields of nucleophilic substitution of Ugi product 61 with various nucleophiles under acidic conditions.
a) 2 Equivalents of the corresponding alcoho were used, b) EtSH was used as a co-solvent, c) 4A MS were added to the reaction mixture.
General procedure V: Nucleophilic substitution of Ugi products derived from 51 under acidic conditions.
[50] The Ugi-product 2-(/V-benzylacetamido)-/V-(6-bromopyridin-2-yl)-4-methylpentanamide (209 mg, 0.5 mmol, 1.0 eq.) was dissolved in CH2CI2 (2 ml.) and HCI in Et20 solution (1M, 2.5 ml_, 2.5 mmol, 5.0 eq.) was added. Subsequently, the nucleophile (2.5 mmol, 5.0 eq.) was added and the resulting mixture stirred for 16 hours at room temperature. The crude mixture was acidified to pH=1 with 1M HCI and extracted with CH2CI2. The organic layer was washed with 1M HCI and brine, dried over Na2S04and concentrated under reduced pressure to yield the corresponding product.
Analytical data: 4b: Two rotamers were present on NMR timescale (R1: R2 = 1 : 0.4). 1H NMR (CDCI3, 500 MHz) δ 7.34-7.12 (m, 7H), 4.80 (t, J = 6.6 Hz, 1H), 4.65 (m, 1.4H ), 4.43 (m, 1.4H), 4.37 (m, 0.4H), 4.00 (m, 1H), 3.93 (m, 1,4H), 3.76 (m, 0.4H), 2.23 (s, 1.2H), 2.06 (s, 3H), 1.82-1.75 (m, 1.4H), 1.56-1.43 (m, 5.6H), 1.33-1.24 (m, 2.8H), 0.89-0.83 (m, 8.4H), 0.73 (d, J= 6.5 Hz, 3H), 0.65 (d, J = 6.7 Hz, 1.2H). 13C NMR (CDCI3, 125 MHz) δ 171.8 (Cq), 171.7 (Cq), 171.5 (Cq), 170.8 (Cq), 137.9 (Cq), 137.0 (Cq), 128.5 (CH), 128.0 (CH), 127.8 (CH), 127.3 (CH), 126.8 (CH), 126.3 (CH), 65.1 (CH2), 64.7 (CH2), 58.9 (CH), 56.00 (CH2), 50.6 (CH2), 46.3 (CH2), 38.3 (CH2), 38.1 (CH2), 30.3 (CH2), 30.1 (CH2), 25.0 (CH), 24.3 (CH), 22.2 (CH3), 22.1 (CH3), 22.0 (CH3), 21.9 (CH3), 21.8 (CH3), 18.9 (CH2), 18.9 (CH2), 13.5 (CH3), 13.5 (CH3). IR (neat): vmax (cm'1) = 2957 (m), 1734 (s), 1653 (s), 633 (s), 536 (s), 498 (s). HRMS (ESI): m/z calculated for Ci9H30NO3 (M+H) 320.2220, found 320.2206. 4c: Two rotamers were present on NMR timescale (R1: R2 = 1 : 0.4). 1H NMR (CDCI3, 500 MHz) δ 7.40-7.15 (m, 7H), 4.94 (septet, J = 6.3 Hz, 1H), 5.89-5.80 (m, 1.8H), 4.70 (d, J= 17.5 Hz, 1H), 4.47 (d, J= 17.5 Hz, 1H), 4.33 (t, J = 6.3 Hz, 0.4H), 4.28 (d, J= 15.5 Hz, 0.4H), 2.56 (s, 1,2H), 2.09 (s, 3H), 1.84 (m, 1H), 1.73 (m, 0.4H), 1.64-1.35 (m, 2.8H), 1.21 (d, J= 6.0 Hz, 6H), 1.19 (d, J = 6.0 Hz, 1.2H), 1.13 (d, J= 6.0 Hz, 1.2H), 0.88 (m, 4.2H), 0.78 (d, J= 6.5 Hz, 3H), 0.67 (d, J = 6.5 Hz, 1,2H). 13C NMR (CDCI3, 125 MHz) δ 172.0 (Cq), 171.9 (Cq), 171.2 (Cq), 170.5 (Cq), 138.4 (Cq), 137.4 (Cq), 128.7 (CH), 128.2 (CH), 127.9 (CH), 127.4 (CH), 126.9 (CH), 126.5 (CH), 69.3 (CH), 68.6 (CH), 59.5 (CH), 56.5 (CH), 50.8 (CH2), 46.8 (CH2), 38.6 (CH2), 25.3 (CH), 24.5 (CH), 22.5 (CH3), 22.4 (CH3), 22.3 (CH3), 22.3 (CH3), 22.2 (CH3), 22.0 (CH3), 21.7 (CH3), 21.6 (CH3), 21.5 (CH3). IR (neat): vmax (cm'1) = 2957 (m), 1730 (s), 1653 (s), 1410 (m), 1177 (m), 1105 (s), 968 (m), 727 (s), 698 (s). HRMS (ESI): m/z calculated for Ci8H28N03(M+H) 306.2064, found 306.2051. 4d: Two rotamers were present on NMR timescale (R1: R2 = 1 : 0.35). 1H NMR (CDCI3, 500 MHz) δ 7.42-7.18 (m, 6.75H), 4.77 (t, J= 7.0 Hz, 1H), 4.75 (m, 1.35H), 4.50 (m, 1.35H), 4.41 (t, J = 7.0 Hz, 0.35H), 4.13 (m, 2H), 4.03 (m, 0.35H), 3.87 (m, 0.35H), 2.48 (m, 2H), 2.39 (m, 0.70H), 2.29 (s, 1H), 2.12 (s, 3H), 1.99 (s, 1.05H), 1.98 (0.35H), 1.89 (m, 1H), 1.78 (m, 0.35H), 1.71-1.38 (m, 2.7H), 0.89 (d, J= 6.5 Hz ,4.05H), 0.78 (d, J= 6.5 Hz, 3H), 0.73 (d, J = 6.5 Hz, 1.05H). 13C NMR (CDCI3, 125 MHz) δ 171.9 (Cq), 171.8 (Cq), 171.4 (Cq),170.7 (Cq), 138.1 (Cq), 137.1 (Cq), 128.7 (CH), 128.2 (CH), 128.1 (CH), 127.6 (CH), 127.0 (CH), 126.6 (CH), 80.1 (Cq), 70.2 (CH), 69.8 (CH), 62.8 (CH2), 62.6 (CH2), 58.9 (CH), 56.2 (CH), 51.1 (CH2), 46.3 (CH2), 38.4 (CH2), 38.2 (CH2), 25.2 (CH), 24.4 (CH), 22.5 (CH3), 22.4 (CH3), 22.4 (CH3), 22.3 (CH3), 22.2 (CH3), 22.0 (CH3), 18.8 (CH2), 18.7 (CH2). IR (neat): vmax (cm'1) = 3279 (m), 2957 (m), 1736 (s), 1647 (s), 1410 (m), 1240 (m), 1171 (m), 729 (s), 698 (s), 638 (m), HRMS (ESI): m/z calculated for Ci9H26N03(M+H) 316.1907, found 316.1892. 4e: Two rotamers were present on NMR timescale (R1: R2 = 1 : 0.4). 1H NMR (CDCI3, 500 MHz) δ 7.42-7.18 (m, 7H), 5.30 (t, J = 7.0 Hz, 1H), 5.10 (d,J = 15.5 Hz, 0.4H), 4.70 (d, J = 17.5 Hz, 1H), 4.44 (d, J= 17.5 Hz, 1H), 4.40 (t, J= 7.0 Hz, 0.4H), 4.02 (d, J= 15.5 Hz, 0.4H), 2.85 (m, 2.8H), 2.29 (s, 1.2H), 2.13 (s, 3H), 1.80 (m, 1.4H), 1.54 (m, 1.4H), 1.43 (m, 1H), 1.3 (m, 0.4H), 1.23 (m, 4.2H), 0.88 (d, J= 6.5 Hz, 3H), 0.84 (d, J= 6.5 Hz, 1.2H), 0.74 (d, J= 6.5 Hz, 3H), 0.53 (d, J= 6.5 Hz, 1.2H). 13C NMR (CDCI3, 125 MHz) δ 199.4 (Cq), 199.2 (Cq), 172.4 (Cq), 171.9 (Cq), 138.5 (Cq), 137.3 (Cq), 128.7 (CH), 128.3 (CH), 127.8 (CH), 127.4 (CH), 127.0 (CH), 126.2 (CH), 66.9 (CH), 62.1 (CH), 50.2 (CH2), 47.7 (CH2), 38.3 (CH2), 37.8 (CH2), 25.3 (CH), 24.5 (CH), 23.6 (CH2), 23.4 (CH2), 22.4 (CH3), 22.4 (CH3), 22.3 (CH3), 21.8 (CH3), 14.4 (CH3). IR (neat): vmax (cm'1) = 2957 (m), 1681 (m), 1655 (s), 1402 (s), 972 (m), 727 (s), 698 (s). HRMS (ESI): m/z calculated for Ci7H26N02S (M+H) 308,1679, found 308,1659. 4f: Two rotamers were present on NMR timescale (R1: R2 = 1 : 0.4). 1H NMR (CDCI3, 500 MHz) δ 7.29-7.11 (m, 14H), 5.24 (m, 1H), 5.05 (d, J= 15.5 Hz, 0.4H), 4.63 (d, J= 17.6, 1H), 4.36 (m, 1.4H), 4.03 (m, 3.2H), 2.21 (s, 1.2H), 2.06 (s, 3H), 1.81-1.70 (m, 1.4H), 1.54-1.36 (m, 2.8H), 0.82 (d, J = 6.5 Hz, 3H), 0.77 (d, J = 6.5 Hz, 1,2H), 0.67 (d, J = 6.6 Hz, 3H), 0.46 (d, J = 6.6 Hz, 1.2H). 13C NMR(CDCI3, 125 MHz) δ 198.9 (Cq), 198.6 (Cq), 172.3 (Cq), 171.8 (Cq), 138.3 (Cq), 137.1 (Cq), 136.9 (Cq) 136.6 (Cq), 128.8 (CH), 128.8 (CH), 128.7 (CH), 128.6 (CH), 128.5 (CH), 128.2 (CH), 127.8 (CH), 127.4 (CH), 127.4 (CH), 127.2 (CH), 127.0 (CH), 126.14 (CH), 66.8 (CH), 62.2 (CH), 50.3 (CH2), 47.8 (CH), 38.2 (CH2), 37.8 (CH2), 33.5 (CH2), 33.3 (CH2), 25.2 (CH), 24.4 (CH), 22.4 (CH3), 22.3 (CH3), 22.3 (CH3), 22.2 (CH3), 22.2 (CH3), 21.7 (CH3). IR (neat): vmax (cm'1) = 2957 (m), 1684 (s), 1655 (s), 1240 (s), 606 (s), 579 (s), 459 (s). HRMS (ESI): m/z calculated for C22H28N02S (M+H) 370.1835, found 370.1821.
3.2 Passerini reactions with 5I
[51] We next investigated the utility of 5I in the Passerini reaction (scheme 10). Subsequent basic hydrolysis of the Passerini products 22 obviously also cleaves the ester moiety to give the corresponding α-hydroxy carboxylic acids 23.
Scheme 10:
Passerini reactions with 5I and subsequent saponification to α-hydroxy acids 23
Table 4. Passerini reactions with 51 and subsequent saponification to α-hydroxy acids
General procedure VI: Passerini reaction and subsequent saponification to a-hydroxy acids [52] The aldehyde (1.0 mmol, 1.0 eq.) was dissolved in CH2CI2 (3 ml_), acetic acid (86 μΙ_, 1.5 mmol, 1.5 eq.) and 2-bromo-6-isocyanopyridine (201 mg, 1.1 mmol, 1.1 eq.)were added subsequently. Additional CH2CI2 (1ml_) was added and the resulting mixture stirred for 48 hours at room temperature. The solvent was removed under reduced pressure and the crude mixture was purified by column chromatography (cyclohexane : EtOAc) to yield the Passerini-products.
[53] The Passerini product (0.2 mmol, 1.0 eq.) was dissolved in MeOH (0.9 ml.) and 10M NaOH (0.1 ml_, 1 mmol, 5.0 eq.) was added. The resulting mixture stirred at room temperature for 48 hours. Conversion of the amide to the α-hydroxy acid was monitored by TLC, indicated by formation of 6-bromopyridin-2-amine (a characteristic blue spot appears without stain). Waterwas added to the crude reaction mixture. The water later was washed with EtOAc (2x), acidified to pH=1 with 1M HCI and extracted with EtOAc (3x). The organic layer was dried over Na2S04and concentrated under reduced pressure to yield the corresponding α-hydroxy carboxylic acid.
[54] Analytical data: 22a: 1H NMR (CDCI3, 500 MHz) δ 8.29 (bs, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 5.17 (d, J=4.5 Hz, 1H), 2.36-2.29 (m, 1H), 2.24 (s, 3H), 1.02 (d, J = 3.8 Hz, 3H), 0.99 (d, J= 3.6 Hz, 3H). 13C NMR (CDCI3, 125 MHz) δ 169.7 (Cq), 168.2 (Cq), 150.5 (Cq), 140.7 (CH), 139.3 (Cq), 124.1 (CH), 112.5 (CH), 78.1 (CH), 31.0 (CH3), 21.0 (CH), 18.6 (CH3), 17.1 (CH3). IR (neat): vmax (cm'1) = 3296 (w), 1743 (m), 1708 (s), 1566 (s), 1519 (m), 1429 (s), 1389 (m), 1232 (m), 789 (m). HRMS (ESI): m/z calculated for Ci2H16BrN203 (M+H) 315.0339, found 315.0314. 22b: 1H NMR (CDCI3, 500 MHz) δ 8.35 (bs, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.25 (d, J = 7.5 Hz, 1H), 5.26 (t, J = 6.0 Hz), 2.23 (s, 3H), 1.90 (m, 2H), 1.37-1.27 (m, 8H), 0.87 (t, J=7.0 Hz, 3H). 13C NMR (CDCI3, 125 MHz) δ 169.6 (Cq), 168.7 (Cq), 150.6 (Cq), 140.7 (CH), 139.3 (Cq), 124.1 (CH), 112.6 (CH), 74.1 (CH), 32.0 (CH2), 31.5 (CH2), 28.8 (CH2), 24.6 (CH2), 22.5 (CH2), 21.1 (CH3), 14.0 (CH3). IR (neat): vmax (cm'1) = 2928 (w), 1717 (m), 1568 (s), 1431 (s), 787 (m), 631 (s), 536 (s), 498 (s). HRMS (ESI): m/z calculated for Ci5H22BrN203(M+H) 357.0808, found 357.0800. 23a: 1H NMR (CDCI3, 500 MHz) δ 4.15 (d, J= 3,4 Hz, 1H), 2.16 (m, 1H), 1.05 (d, J= 7.0 Hz, 1H), 0.91 (d, J = 7.0 Hz, 1H). 13C NMR (CDCI3, 125 MHz) δ 179.3 (Cq), 74.8 (CH), 31.9 (CH), 18.8 (CH3), 15.9 (CH3). 23b: 1H NMR (CDCI3, 500 MHz) δ 4.28 (dd, J = 7.5, 4.2 Hz, 1H), 1.87 (m, 1H), 1.72 (m, 1H), 1.47-1.41 (m, 8H) 0.88 (t, J = 6.6 Hz, 3H). 13C NMR (CDCI3, 125 MHz) δ 179.6 (Cq), 70.2 (CH), 34.2 (CH2), 31.6 (CH2), 28.9 (CH2), 24.7 (CH2), 22.5 (CH2), 14.0 (CH3).
3.3 Other MCRs with 5I
[55] Isocyanides of the present invention such as 5I are also suitable for other IMCRs such as the Ugi-Smiles reaction (scheme 11).
Scheme 11. Ugi-Smiles reactions with 5I
[56] Table 5. Yields of Ugi-Smiles reactions with 5I
General procedure VII: Ugi-Smiles reactions (scheme 11) [57] Under nitrogen atmosphere benzylamine (109 μΙ_, 1.0 mmol, 1.0 eq.) and isovaleraldehyde (108 μΙ_, 1.0 mmol, 1,0 eq.) were dissolved in the MeOH (3 ml.) and prestirred for 2 hours at room temperature. The nitrophenol (1.5 mmol, 1.5 eq.) and 2-bromo-6-isocyanopyridine (220 mg, 1.2 mmol, 1.2 eq.) were added subsequently. Additional MeOH (1 ml.) was added and the resulting mixture was refluxed for 72 hours. The solvent was removed under reduced pressure and the crude mixture was purified by column chromatography (cyclohexane : EtOAc) to yield the Ugi-Smiles products as foamy solids.
CLAIMS 1. Method for performing isocyanide-based multicomponent reaction (IMCR) comprising a step of reacting a substituted 2- or 4-isocyanopyridine of the general formula 5 or 19, preferably 5,
5 19 with a carbonyl-containing compound selected from the group consisting of an aldehyde and a ketone; in the presence of an acidic carbon compound selected from the group consisting of a (thio)carboxylic acid and a (thio)phenolic compound and/or a primary or secondary amine, wherein R is selected from the group consisting of H, halogen, Ci-C4-alkyl such as Cr, C2-, n-C3-, i-C3- alkyl,, halogenated C1-C4 alkyl, halogen (F, Cl, Br, I), (thio)ethers, sulfoxides, sulfones, esters, (substituted) (hetero)aryl, (substituted) cycloalkyl, alkoxy/(hetero)aryloxy, and mono-di-alkyl/(hetero)arylamino. 2. Method according to claim 1, wherein the acidic carbon compound is a carboxylic acid (Passerini reaction). 3. Method according to claim 1, wherein further a primary amine is present (Ugi reaction). 4. Method according to claim 1, wherein the acidic carbon compound is a phenolic compound (Ugi-Smiles reaction). 5. Method according to claim 1, wherein R is positioned at the 3, 4 ,5 and/or 6 position in the 2-isocyanopyridine or wherein R is positioned at the 2, 3, 5 or 6 position in the 4-isocyanopyridine. 6. Method according to claim 1, wherein R is selected from the group consisting of Cr, C2-, n-C3-, /'-C3- alkyl, halogen (F, Cl, Br, I), CF3. 7. Method according to claim 6, wherein, for 2-isocyanopyridines, R is selected from the group consisting of 3-Me, 4-Me, 5-Me, 6-Me, 3-Br, 4-Br, 5-Br, 6-Br, 3-CI, 4-CI, 5-CI, 6-CI, 3-F, 4-F, 5-F, 6-F, 3-CF3, 4-CF3,5-CF3,6-CF3 and wherein for 4-isocyanopyridines , R is selected from the group consisting of 2-Me, 3-Me, 5-Me, 6-Me, 2-Br, 3-Br, 5-Br, 6-Br, 2-CI, 3-CI, 5-CI, 6-CI, 2-F, 3-F, 5-F, 6-F, 2-CF3, 3-CF3, 5-CF3,6-CF3. 8. Method according to claim 7, wherein, for 2-isocyanopyridines, R is selected from the group consisting of 3-Me, 4-Me, 5-Me, 6-Me, 3-Br, 4-Br, 5-Br, 5-CI, 5-CF3, 6-Br, 6-CI. 9. Method according to claim 8, wherein R is Br, preferably 6-Br. 10. Substituted 2-isocyanopyridine or 4-isocyanopyridine having the general formula or
5 19 wherein R is selected from the group consisting of H, Ci-C4-alkyl such as Cr, C2-, n-C3-, i-C3- alkyl,, halogenated CrC4 alkyl, halogen (F, Cl, Br, I), (thio)ethers, sulfoxides, sulfones, esters, (substituted) (hetero)aryl, (substituted) cycloalkyl, alkoxy/(hetero)aryloxy, and mono-di-alkyl/(hetero)arylamino. 11. Substituted 2-isocyanopyridine or 4-isocyanopyridine according to claim 10, wherein for 2- isocyanopyridines, R is selected from the group consisting of 3-Me, 4-Me, 5-Me, 6-Me, 3- Br, 4-Br, 5-Br, 6-Br, 3-CI, 4-CI, 5-CI, 6-CI, 3-F, 4-F, 5-F, 6-F, 3-CF3, 4-CF3,5-CF3,6-CF3 and wherein for 4-isocyanopyridines , R is selected from the group consisting of 2-Me, 3-Me, 2-Br, 3-Br, 2-CI, 3-CI, 2-F, 3-F, 2-CF3, 3-CF3. 12. Substituted 2-isocyanopyridine or 4-isocyanopyridine according to claim 11, wherein for 2- isocyanopyridines, R is selected from the group consisting of 3-Me, 4-Me, 5-Me, 6-Me, 3- Br, 4-Br, 5-BR, 5-CI 5-CF3, 6-Br, 6-CI and wherein for 4-isocyanopyridines R is selected from the group consisting of 2-Me, 2-Br, 2-CF3, 2-CI. 13. Substituted 2-isocyanopyridine or 4-isocyanopyridine according to claim 12, wherein for 2-isocyanopyridines R is Br, preferably 6-Br and wherein for wherein for 4-isocyanopyridines is R is Br or Cl, preferably 2-Br or Cl. 14. Method for the conversion of the /V-2-pyridylamide- or /V-4-pyridylamide- containing product of the Ugi reaction of claim 3 to the corresponding carboxylic acid under basic conditions. 15. Method for the nucleophilic substitution of the /V-2-pyridylamide or ΛΜ-pyridylamide-group of the /V-2-pyridylamide- or /V-4-pyridylamide- containing product of the Ugi reaction of claim 3 in the presence of a nucleophile under acidic or basic conditions. 16. Method according to claim 15, wherein the nucleophile is selected from the group consisting of water, alcohols, thiols, primary or secondary amines. 17. Method according to claim 15 or 16, wherein the conditions are basic and the nucleophile is selected from the group consisting of water, primary CrC4-alcohols, primary CrC8 alkylamines, secondary C2-C8 alkylamines and C4-C8 cycloalkylamines. 18. Method according to claim 15 or 16, wherein the conditions are acidic and the nucleophile is selected from the group consisting of water, primary CrC4-alcohols, secondary C3-C8-alcohols, alkylthiols, benzylthiols. 19. Method for the conversion of the /V-2-pyridylamide- or /V-4-pyridylamide- containing product of the Passerini reaction of claim 2 under basic conditions to provide the corresponding alpha-hydroxy carboxylic acid. 20. Use of substituted 2-isocyanopyridines or substituted 4-isocyanopyridines as defined in claim 10 in multicomponent reactions.

Claims (20)

1. Methode voor het uitvoeren van isocyanide gebaseerde multicomponent reactie (IMCR) bestaande uit een stap van het laten reageren van een gesubstitueerd 2 - of 4-isocyanopyridine van de algemene formule 5 of 19, bij voorkeur 5,Method for carrying out isocyanide-based multicomponent reaction (IMCR) consisting of a step of reacting a substituted 2- or 4-isocyanopyridine of the general formula 5 or 19, preferably 5, 5 19 met een carbonyl-bevattende stof geselecteerd uit de groep bestaande een aldehyde of een keton; in aanwezigheid van een zure koolstof verbinding geselecteerd uit de groep bestaande uit een (thio) carbonzuur en een (thio) fenolische verbinding en/of een primair of secundair amine, waarin R wordt geselecteerd uit de groep bestaande uit H, halogeen, C1-C4-alkyl zoals Cr, C2-, n-C3-, /'-C3- alkyl gehalogeneerde C1-C4 alkyl, halogeen (F, Cl, Br, I), (thio) ethers, sulfoxiden, sulfonen , esters, (gesubstitueerd) (hetero) aryl, (gesubstitueerd) cycloalkyl, alkoxy / (hetero) aryloxy en mono-di-alkyl / (hetero) arylamino.With a carbonyl-containing substance selected from the group consisting of an aldehyde or a ketone; in the presence of an acidic carbon compound selected from the group consisting of a (thio) carboxylic acid and a (thio) phenolic compound and / or a primary or secondary amine, wherein R is selected from the group consisting of H, halogen, C1 -C4 alkyl such as C 1, C 2, n-C 3, / 'C 3 alkyl halogenated C 1 -C 4 alkyl, halogen (F, Cl, Br, I), (thio) ethers, sulfoxides, sulfones, esters, (substituted) (hetero) aryl, (substituted) cycloalkyl, alkoxy / (hetero) aryloxy and mono-di-alkyl / (hetero) arylamino. 2. De methode volgens conclusie 1, waarin de zure koolstof verbinding een carbonzuur is (Passerini reactie).The method of claim 1, wherein the acidic carbon compound is a carboxylic acid (Passerini reaction). 3. De methode volgens conclusie 1, waarin verder een primair amine aanwezig is (Ugi reactieThe method of claim 1, further comprising a primary amine (Ugi reaction 4. De methode volgens conclusie 1, waarin de zure koolstof verbinding een fenolische verbinding is (Ugi-Smiles reactie).The method of claim 1, wherein the acidic carbon compound is a phenolic compound (Ugi-Smiles reaction). 5. De methode volgens conclusie 1, waarin R gelegen is op de 3, 4, 5 of 6 positie in de 2-isocyanopyridine of waarin R gelegen is op de 2, 3, 5 of 6 positie in de 4-isocyanopyridine.The method of claim 1, wherein R is at the 3, 4, 5 or 6 position in the 2-isocyanopyridine or wherein R is at the 2, 3, 5 or 6 position in the 4-isocyanopyridine. 6. Methode volgens conclusie 1, waarin R is geselecteerd uit de groep bestaande uit Cr, C2-, n-C3-, /'-C3- alkyl, halogeen (F, Cl, Br, I), CF3.The method of claim 1, wherein R is selected from the group consisting of Cr, C 2, n-C 3, / 'C 3 alkyl, halogen (F, Cl, Br, I), CF 3. 7. De methode volgens conclusie 6, waarin, voor 2-isocyanopyridines, R is geselecteerd uit de groep bestaande uit 3-Me, 4-Me, 5-Me, 6-Me, 3-Br, 4-Br, 5-Br, 6-Br, 3-CI, 4-CI, 5-CI, 6-CI, 3-F, 4-F, 5-F, 6-F, 3-CF3, 4-CF3,5-CF3,6-CF3 en waarin voor4-isocyanopyridines , R is geselecteerd uit de groep bestaande uit -Me, 3-Me, 5-Me, 6-Me, 2-Br, 3-Br, 5-Br, 6-Br, 2-CI, 3-CI, 5-CI, 6-CI, 2-F, 3-F, 5-F, 6-F, 2-CF3,3-CF3, 5-CF3,6-CF3.The method of claim 6, wherein, for 2-isocyanopyridines, R is selected from the group consisting of 3-Me, 4-Me, 5-Me, 6-Me, 3-Br, 4-Br, 5-Br , 6-Br, 3-CI, 4-CI, 5-CI, 6-CI, 3-F, 4-F, 5-F, 6-F, 3-CF3, 4-CF3.5-CF3.6 -CF 3 and wherein for 4-isocyanopyridines, R is selected from the group consisting of -Me, 3-Me, 5-Me, 6-Me, 2-Br, 3-Br, 5-Br, 6-Br, 2-CI , 3-CI, 5-CI, 6-CI, 2-F, 3-F, 5-F, 6-F, 2-CF3.3-CF3, 5-CF3.6-CF3. 8. De methode volgens conclusie 7, waarin, voor 2-isocyanopyridines, R is geselecteerd uit de groep bestaande uit 3-Me, 4-Me, 5-Me, 6-Me, 3-Br, 4-Br, 5-Br, 5-CI, 5-CF3, 6-Br, 6-Cl.The method of claim 7, wherein, for 2-isocyanopyridines, R is selected from the group consisting of 3-Me, 4-Me, 5-Me, 6-Me, 3-Br, 4-Br, 5-Br 5-CI, 5-CF 3, 6-Br, 6-Cl. 9. De methode volgens conclusie 8, waarin R is Br, bij voorkeur 6-Br.The method of claim 8, wherein R is Br, preferably 6-Br. 10. Gesubstitueerde 2-isocyanopyridine of 4-isocyanopyridine met de algemene formule or10. Substituted 2-isocyanopyridine or 4-isocyanopyridine of the general formula or 5 19 waarin R is geselecteerd uit de groep bestaande uit H, Ci-C4-alkyl such as Cr, C2-, n-C3-, i-C3- alkyl, gehalogeneerde C1-C4 alkyl, halogeen (F, Cl, Br, I), (thio)ethers, sulfoxides, sulfonen, esters, (gesubstitueerde) (hetero)aryl, (gesubstitueerde) cycloalkyl, alkoxy/(hetero)aryloxy, en mono-di-alkyl/(hetero)arylamino.Wherein R is selected from the group consisting of H, C 1 -C 4 alkyl such as Cr, C 2, n-C 3, i-C 3 alkyl, halogenated C 1 -C 4 alkyl, halogen (F, Cl, Br, I), (thio) ethers, sulfoxides, sulfones, esters, (substituted) (hetero) aryl, (substituted) cycloalkyl, alkoxy / (hetero) aryloxy, and mono-di-alkyl / (hetero) arylamino. 11. Gesubstitueerde 2-isocyanopyridine of 4-isocyanopyridine volgens conclusie 10, waarin voor 2-isocyanopyridines, R is geselecteerd uit de groep bestaande uit 3-Me, 4-Me, 5-Me, 6-Me, 3-Br, 4-Br, 5-Br, 6-Br, 3-CI, 4-CI, 5-CI, 6-CI, 3-F, 4-f, 5-F, 6-F, 3-CF3, 4-CF3,5-CF3, 6-CF3 en waarin voor 4-isocyanopyridines, R is geselecteerd uit de groep bestaande uit, 3-Me, 2-Br, 3-Br, 2-CI, 3-CI, 2-F, 3-F, 2-CF3, 3-CF3.A substituted 2-isocyanopyridine or 4-isocyanopyridine according to claim 10, wherein for 2-isocyanopyridines, R is selected from the group consisting of 3-Me, 4-Me, 5-Me, 6-Me, 3-Br, 4- Br, 5-Br, 6-Br, 3-CI, 4-CI, 5-CI, 6-CI, 3-F, 4-f, 5-F, 6-F, 3-CF3, 4-CF3, 5-CF3, 6-CF3 and wherein for 4-isocyanopyridines, R is selected from the group consisting of, 3-Me, 2-Br, 3-Br, 2-CI, 3-CI, 2-F, 3-F , 2-CF3, 3-CF3. 12. Gesubstitueerde 2-isocyanopyridine of 4-isocyanopyridine volgens conclusie 11, waarin voor 2-isocyanopyridines, R is geselecteerd uit de groep bestaande uit 3-Me, 4-Me, 5-Me, 6-Me, 3-Br, 4-Br, 5-CF3, 6-Br, 6-CI en waarin voor 4-isocyanopyridines R is geselecteerd uit de groep bestaande uit 2-Me, 2-Br, 2-CF3, 2-CI.A substituted 2-isocyanopyridine or 4-isocyanopyridine according to claim 11, wherein for 2-isocyanopyridines, R is selected from the group consisting of 3-Me, 4-Me, 5-Me, 6-Me, 3-Br, 4- Br, 5-CF3, 6-Br, 6-CI and wherein for 4-isocyanopyridines R is selected from the group consisting of 2-Me, 2-Br, 2-CF3, 2-CI. 13. Gesubstitueerde 2-isocyanopyridine of 4-isocyanopyridine volgens conclusie 12, waarin voor 2-isocyanopyridines R is Br, bij voorkeur 6-Br en waarin voor 4-isocyanopyridines R is Br of Cl , bij voorkeur 2-Br of 2-CI.Substituted 2-isocyanopyridine or 4-isocyanopyridine according to claim 12, wherein for 2-isocyanopyridines R is Br, preferably 6-Br and wherein for 4-isocyanopyridines R is Br or Cl, preferably 2-Br or 2-CI. 14. Methode voor de omzetting van de N-2-pyridylamide - of N-4-pyridylamide-bevattende product van de Ugi reactie van conclusie 3 tot de overeenkomstige carbonzuur onder basische condities.A method for the conversion of the N-2-pyridylamide - or N-4-pyridylamide-containing product of the Ugi reaction of claim 3 to the corresponding carboxylic acid under basic conditions. 15. Methode voor de nucleofiele substitutie van de N-2-pyridylamide of N-4-pyridylamide-groep van het N-2-pyridylamide - of N-4-pyridylamide- product van de Ugi reactie van conclusie 3 in aanwezigheid van een nucleofiel onder zure of basische condities.Method for the nucleophilic substitution of the N-2-pyridylamide or N-4-pyridylamide group of the N-2-pyridylamide - or N-4-pyridylamide product of the Ugi reaction of claim 3 in the presence of a nucleophile under acidic or basic conditions. 16. De methode volgens conclusie 15, waarin het nucleofiel is geselecteerd uit de groep bestaande uit water, alcoholen, thiolen, primaire of secundaire amines.The method of claim 15, wherein the nucleophile is selected from the group consisting of water, alcohols, thiols, primary or secondary amines. 17. Methode volgens conclusie 15 of 16, waarin de condities basisch zijn en het nucleofiel is geselecteerd uit de groep bestaande uit water, primaire CrC4-alcoholen, primaire CrC8 alkylaminen, secundaire C2-C8 alkylaminen en C4-C8 cycloalkylamines.The method of claim 15 or 16, wherein the conditions are basic and the nucleophile is selected from the group consisting of water, primary C 1 -C 4 alcohols, primary C 1 -C 8 alkylamines, C 2 -C 8 alkylamines secondary and C 4 -C 8 cycloalkylamines. 18. Methode volgens conclusie 15 of 16, waarin de voorwaarden zuur zijn en het nucleofiel is geselecteerd uit de groep bestaande uit water, primaire Ci-C4-alcoholen, secundaire C3-C8-alcoholen, alkylthiolen, benzylthiolen.A method according to claim 15 or 16, wherein the conditions are acidic and the nucleophile is selected from the group consisting of water, primary C 1 -C 4 alcohols, secondary C 3 -C 8 alcohols, alkylthiols, benzylthiols. 19. Methode voor de omzetting van het N-2-pyridylamide - of N-4-pyridylamide- product van de Passerini reactie van conclusie 2 onder basische condities om het overeenkomstige alpha-hydroxy carbonzuur te verkrijgen.A method for the conversion of the N-2-pyridylamide or N-4-pyridylamide product of the Passerini reaction of claim 2 under basic conditions to obtain the corresponding alpha-hydroxy carboxylic acid. 20. Toepassing van gesubstitueerde 2-isocyanopyridines of gesubstitueerde 4-isocyanopyridines zoals gedefinieerd in conclusie 10 in multicomponent reacties.Use of substituted 2-isocyanopyridines or substituted 4-isocyanopyridines as defined in claim 10 in multicomponent reactions.
NL2015814A 2015-11-19 2015-11-19 Pyridine-based isocyanides as novel reagents for multicomponent reactions. NL2015814B1 (en)

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