CA2020648A1 - Aqueous alkylation process - Google Patents

Abstract

AQUEOUS ALKYLATION PROCESS
ABSTRACT OF THE DISCLOSURE

This invention relates to a process for alkylation at carbon and phosphorus sites in an aqueous medium using precious metal catalysts containing sulfonated triarylphosphines (STP) of the generic formula P(C6H4SO3-)X(C6H5)Y (X+Y=3).

Description

~J'33 ~

AOUEOUS A KYLATION PP~OCESS

~ÇKGROUND OF THE INVENTION
This invention relates to a process for alkylation at carbon and phosphorl-s sites in an aqueous medium using precious metal catalysts containing sulfonated triarylphosphines ~STP) of the generic formula P(C6HgSO3~)x(C6H5)y (X+Y~3)-A review of the use of sulphonated phosphines in homogeneous catalysis is Homogeneous Catalysis in Water" by Emile G. Kuntz, Chemtech, Sept. 1987, p. 570. Review of the Heck reaction and Pd catalyzed alkylations in non-aqueous media can be found in J. Oraangmet. Ch~m~, 1989, 360, 409, L. Hegedus;
Q~ganotransition Metal Chemist~Y: A~Plications_~_ Oraanic Svnthesis, Stephen Davies, Vol. 2, 1982, p. 218; Oraanic SYnthesis wih-glLLldium Compounds, Jiro Tsuji, 1980.
The use of sulphonated arylphosphines has been reported for unrelated catalytic processes in aqueous media. Hydrocyanation of unsaturated organic compounds utilizing sulphonated triarylphosphines (STP) and Ni or Ni/Pd compounds has been reported (U.S. 9,087,452). Hydroformylation of propene using Rh and STP (U.S. 4,684,750), and telomerization of dienes usincl STP and Pd has been described (U.S.
9,142,060). The coupling of butadienes to phenols in the presence of Rh complexes and STP has been disclosed (U.S. 4,594,460). Asymmetric hydrogenation, hydroformylation and oligomerization reactions using sulphonated chiral arylphosphines and transition metal compounds has been report~d (U.S.
4,654,176). The reduction of allyl chlorides to 2 ~ d~

alkenes using STP, Pd salts and sodium formate has been described (Çhem ~oc. Japan, 1986, 1463~. Allyl chlorides have also been carbonylated to ~arbo~ylic acids using STP and Pd salts (Chem. Soc. Jap~n, 198B, 957).
The Pd catalyzed akylation of aryl or vin~1 halides with alkynes, alkenes, and aryl or vinylboronic acids has been extensiv ly reported.
Sonogoshira and others have described the alkynylation of aryl ana vinyl halides with terminal acetylenes in the p~esence of Pd tripl~enylphosphine (TPP) comple~es, base and CuI in non-aqueous media (Te~. L~ters, 1975, 44~7; ~eterocycles, 1978, 9, 271). Robins and others have reported the coupling of iodonucleosides with ~erminal acetylenes under similar conditions in non-aqueous media (J. Or~.
Çhem,, 19~3, 48, 1854). Aryl and vinyl halides may also be alkylated by al~enes in the presence of Pd TPP comple~es and base in a non-aqueous medium in a reaction commonly known as the Heck reaction (J. Org.
Chem., 1977, 42, 3903).
In a variation of the Heck reaction, aryl and vinyl mercurials can be coupled with alkenes utilizing PdC142- (J. AmL-~h~L-sQ~ , 1968, 90, 5518). Mertes has reported the coupling of 5-mercurialuridine mono~hosphates with alkenes in aqueous media using this method (J~_~m,_~h~ln. Soc., 1980, 102, 2033).
Suzuki and others have carried out the alkylation of aryl or vinyl halides with aryl or vinyl boronic acids (RB~OH)2 where R-aryl, vinyl) utilizing Pd rPP comples~s and a base in two phase 35 systems where one phase comprises an aqueous phase (SYnth. Comm., 1981, 11, 513; ~hem. L~ , 1987, 3 ~ V ~

25). In these systems, the Pd TPP complex and the aryl or vinyl halide are insoluble in the aqueous phase and soluble in the organic phase.
Alkylation at phosphorus has been observed by Hirao and Xu when aryl halides are treated with dialkylphosphites or dialkylphosphine oxides in the presence of base and Pd TPP complexes in non-aqueous media (~ nthesis, 1981, 56; J. Chem. Soc., Chem.
Comm~n~, 1986, 1606).
The above catalysts are to be sure valuable but present significant problems; namely, these catalysts do not operate effectively in an aqueous medium on lS substrates which are soluble in an aqueous phase and relatively insoluble in an organic phase.
SV~ y-iE-~E-l~yENTIoN
According to this invention, it has unexpectedly been found that aqueous soluble precious metal catalysts (Group VIII), particularly palladium, platinum, and nickel catalysts, containing arylsulfonated phosphine ligands will catalyze, in the aqueous phase, a variety of alkylation processes, particularly aryl-alkenyl, aryl-alkynyl coupling as well as aryl-aryl coupling. In addition, alkenyl-alkenyl and alkenyl-alkynyl coupling, additionally, aryl or alkenyl phosphorous coupling may take place. The reactions take place under standard alkylation conditions which will be apparent to one skilled in the art. Typically, temperatures will vary between 0-100C and pressures which are, of course, preferred to be ambient but may vary between sub-atmospheric to super-atmospheric. Reaction times may vary from a few minutes, e.g. 2 to q, up to 48 hours. Here again, there is no criticality and 4 2 ~

proper reaction time will be apparent to one skilled in the art.

PETAlLED DESCR~T~ON OF THE I~vENTION
The present invention provides a catalytic process for preparing aryl or vinylalkynes, biaryls, arylalkenes, alkenylphosphonates or arylphosphonates, comprising reacting an aryl or vinyl halide compound or group of formula:

lS

R~ or )~(X

wherein R is hydrocarbon, hydrocarboyl, preferably Cl-C10 alkyl, heteroatoms, etc.;
X iS a halide preferebly bromide or iodide;
Rl-R3 are independently selected from R;
with a compound or group of formula HC= CR, )G( ~ ~( R~

1l nnd H- P( OR) 2 . .. .: . .

, . `,, , .~

' . ' "~, ' ' '.' ' ' :' ':

wherein R is the same as above;
R5-Rlo are independently selected from R;
Y and Z are independently selected from groups which can be hydrolyzed in water, preferred would be OH;
in the presence of a catalytic amount, preferably 1-20 mol %, of a low-valent Pd complex selected from the group consisting of: ~a) PdAnBm; (b) PdAn; and (c) precursors which are converted to complexes of the above formulae during the process wherein A is a sulphonated aryl phosphine ligand moiety;
B is a phosphine, arsine, or olefin preferably Cl-C20 olefin;
n and m are less than or equal to 4;
and may also contain a catalytic amount of a copper(I) salt of the formula: (a) CuX; (b) precursors which are converted to complexes of the above formulas during the process wherein X is an anion such as a halide (I), nitrate, etc.; and may also contain a base.

The above description can be illustrated by the following equations:

R~X C~ t . i~
1. ~ HC= CE~
~?2 R3 }3~9 e,CuI R2 R3 R~X~l~R5 C~ t . 5~R6 ;
R2 R3R4 R5 E~s Cl Rz R3 2 5 R3CI(R ~ ~C3( ~M Ra ~ e Rl R3 30 The catalytic process may also be extended to include the reaction of aryl or vinyl halides with dialkylphosphites in aqueous media. This process can be described by the following equation:

7 ~2~

O pl~OR"
~ V 3=~ ~ C~ t . 3~ OR~s R2 R3 OR, E~2 R3 The catalyst employed is a low valent group VIII
metal, preferably Pd, comple~ or precursor containing sulphonated aryl phosphine ligand moieties and may also contain a copper(I) salt as a co-catalyst. The base may be any general base such as trialkylamines, MOH, M2CO3 or a buffered basic solution. The base should have a pH in water of greater than 8, preferably greater than 10. The solvent system contains water and may contain a co-solvent forming a single phase, such as an alcohol, or may contain an organic co-solvent forming two or more phases.
DUSTRIAL UTILITY
The present invention allows group VIII metal, preferably Pd, catalyzed alkylations to be carried out in an aqueous medium on molecules whose solubility is generally restricted to aqueous solvent systems without the use of protecting groups.
Of particular interest are processes for the preparation of biomolecules such as nucleotides, amino acids, enzymes and DNA. A specific e~ample, shown in E~ample l, is the synthesis of the . - .. ....

.~ , .

8 ~ri~D~ 7 /~

chemically modified uridine nucleotide part of the family of chain terminators used in current DNA
sequencing methodology.
Traditional Pd phosphine catalysts employed for alkylations described above are insoluble in water and alcohol and are ineffective in aqueous media when highly hydrophilic substrates such as these biomolecules are used. In addition, alkylations involving hydrophobic substrates can be run in two phase systems, allowing easier separation of catalyst from product.
The illustrations above, Equations I-IV, demonstrate the process of the invention for alkenyl halides. It should be apparent to one skilled in the art that aryl halides or a compound containing an aryl halide moiety can be readily substituted as evidenced by the following e~amples.
PreParation of CatalYst The preparation of low valent group VIII
comple~es containing sulphonated aryl phosphines, including the preparation of sulphonated aryl phosphines, has been described elsewhere ~U.S.
9,219,677, U"S. 4,087,452, U.S. 4,483,802). The catalysts employed in the process described herein may be prepared in a similar fashion. In the e~amples described below, the Pd catalyst employed was synthesi;~ed and isolated as a Pd(O) complex using these methods and techniques apparent to one skilled in tlle art.

~AMp~Es In the following examples all reactions were run under a nitrogen atmosphere using degassed solvents.

In the following e~amyles, L refers to the sulphonated triarylphosphine ligand P(C6H5)2(m C6H5SO3Na). In example 1, "dye~ refers to a terminal alkyne covalently linked to a fluorescein dye and T-505 refers to the resulting alknylated nucleotide as shown below-0~ NH~
1l 1l }iC'-CCH2NHCCH2NMeCCH2CH~O
dye~ \~
~ NH4-HN~U) f dye o/ ~N
0~
~V T-505 In example 2, the isolated product is the benzofuran derivative shown below. Formation of the 1 0 . ~ J j i benzofuran derivative results from cyclization of the initial alkynylated amino acid.

O--\~ NH2 ~XAMPLE I
~~nthesis of T-505 Chain Terminator To a solution of 5-Iododideoxyuridine-5'-triphosphate (100 ~mol) and PdL4 (.035 9, 22 ~mol) in 3 ml of water was added a solution of the dye (125 ~mol), and triethylamine ~.020 9, 200 ~mol) in 3 ml of an acetonitrile/water mixture (2:1 v:v). To the resulting bright yellow solution was added dropwise a solution of CuI (.010 9, 50 ~mol~ in 1 ml of acetonitrile. The solution was stirred for two hours at 25C under Nz, the solvent removed in vacuo, and then remaining residue chromatographed (DEAE Sephadex A-25-120 ion e~change column, bead size 40-120~) with an aqueous solution of triethylammonium carbonate buffer (pH ~ 7.6, .1 1 M gradient). The product was collected by U.v. monitoring at 500 nm and then liophil;zed. Yield 97% (by U.V. measurement). The identity of the product was confirmed by comparison to an authentic sample of ~-505 and by bioassay as a chain terminating reagent.

EXAM L~
~se of ~n rot~ted Amino A~id To a solution of iodotyrosine (.158 9, .5 mmol), PdL~ (.078 9, .05 mmol), triethylamine (.101 9, 1 mmol) and propargylamine (.055 9, 1 mmol) in 5 ml of a water/acetonitrile mi~ture (3:2 v:v) was added dropwise a solution of CuI (.019 9, .1 mmol) in 1 ml of acetonitril~. The resulting dark solution was stirred overnight at Z5~C, spiked with phenylalanine as an internal standard and then analyzed by HPLC. The yield was calculated from a standard plot of the pure benzofuran product and phenylalanine. Yield: 82~.

UsQ of a_HydroDhobic ArYl IQ~id~ and Alkyne To a solution of p-Iodotoluene (.109 g, .5 mmol), phenylacetylene (.102 9, 1 mmol~, triethylamine (.101 g, 1 mmol) and PdL4 (.077 9, .05 mmol) in 8 ml of a water/acetonitrile mixture t3:5 v:v) was added dropwise a solution of CuI (.009 g, .05 mmol) in 1 ml of acetonitrile. The solution was stirred for 3 hours at 25C. GC analysis using diphenylacetylene as an internal standard indicated a complete consumption of the p-tolyl iodide and a 103%
yield of p-tolyphenylacetylene. The identity of the product was confirmed by high resolution GC/MS.
~XAMPLE 4 UseQ f_~a Hvdro~hobic ALY~-~Odide and Alkene (Heck ~eac~ion~
A mixture of iodotoluene (.224 9, 1 mmol), ethyl acrylate (.400 9, 9 mmol), triethylamine (.202 g, 2 mmol) and PdL4 (.125 9, .08 mmol) in 6 ml of a 50% aqueous acetonitrile mixture was heated at 80C
overnight. The formation of Pd metal was noted after about 1 hour of heating. GC analysis of the reaction mixture indicated a 63% yield of trans-3 (p-tolyl)acrylic acid ethyl ester, 13% yield of toluene and 7~ unreacted iodotoluene based on allyl cinnamate as an internal standard. The authenticity of the product was verified by GC~MS and by lH NMR of the isolated product.

~ AMPLE 5 Use of an Iodonucleoside ~nd an Alkenvlboronic Acid A mi~ture of 5-iododeoxyuridine (.163 9, .46 mmol), ~-phenylethenylboronic acid (.172 g, 1.17 mmol) and sodium carbonate (.127 9, 1.20 mmol) were dissolved in 7 ml of a water/ethanol mixture (7:2 v:v). To this solution was added PdL4 (.050 9, .03 mmol) in 1 ml of water and the reaction mi~ture then heated at 80C for 3 hours. The solution was cooled, filtered, the solvent removed in vacuo and the resulting residue analyzed by lH NMR in CD30D.
Complete consumption of iododeoxyuridine was observed. Two products were observed in the following distribution:
trans-5-~-phenylethenyldeoxyuridine 55~ and deoxyuridine 45~.

Biaryl Co~Plinq Usina Hvdrophilic Arvlbr~mides To a mixture of sodium p-bromobenzenesulfonate (.388 9, 1.5 mmol), p-tolyboronic acid (.136 9, 1 mmol) and PdL4 (.239 g,.15 mmol) was added 5 ml of water and 2 ml o~ 1 M sodium carbonate. The reaction 13 ~ h ~J ~ 2 '~

mixture was heated at 80C under N2 ~or seven hours.
The resulting deep brown reaction mixture was cooled and filtered to collect .321 9 of crude biaryl. The biaryl was washed with benzene, diethyl ether and dried in _ac~o to give .263 9 (97%) of sodium 9-(p-tolyl)benzenesul~onate. lH NMR (CD3OD/D2O, 9:1): 2.36, s, 3H, CH3; 7.26, d, 8.0 ~z, 2H, ArH;
107.53, d, 8.1, 2H, ArH; 7.65, d, 8.4, 2H, ArH; 7.85, d, 8.4, 2~. ArH.

2~

Claims (7)

1. An improved alkylation process wherein an aqueous soluble Group VIII catalyst containing an arylsulfonated phosphine ligand is contacted under catalytic conditions, in the aqueous phase with an alkylatable compound.

2. The method of Claim 1 wherein the alkylatable compound contains a coupling selected from aryl-alkenyl, aryl-alkynyl or aryl-aryl.

3. The process of Claim 1 wherein the coupling is selected from alkenyl-alkenyl, alkenyl-alkynyl or aryl or alkenyl-phosphorous.

4. A catalytic process for preparing aryl or vinylalkynes, biaryls, arylalkenes, alkenyl-phosphonates or arylphosphonates, comprising reacting an aryl or vinyl halide compound or group of a formula selected from:

or ;

wherein R is hydrocarbon, hydrocarboyl, preferably C1-C10 alkyl, heteroatoms, etc.;
X is a halide;

R1-R3 are independently selected from R;
with a compound or group of a formula selected from HC= R, , , and ;

wherein R is the same as above;
R5-R10 are independently selected from R;
Y and Z are OH or are independently selected from groups which can be hydrolyzed in water to OH
in the presence of a catalytic amount of a low-valent Pd complex selected from the group consisting of: (a) PdAnBm; (b) PdAn; and (c) precursors which are converted to complexes of the above formulas during the process wherein A is a sulphonated aryl phosphine ligand moiety;
B is a phosphine, arsine, or olefin preferably C1-C20 olefin:
n and m are less than or equal to 4.

5. The process of Claim 4 wherein the catalyst may contain a catalytic amount of a copper(I) salt of the formula: (a) CuX'; (b) precursors which are converted to complexes of the above formulas during the process wherein X' is an anion and may optionally a base.

6. The process of Claim 4 wherein the catalytic amount of palladium is 1-20 mol %.

7. The process of Claim 4 wherein the halide is bromide or iodide.