Copper-mediated cross-coupling of aryl boronic acids and alkyl thiols

Article abstract of DOI:10.1021/ol005832g

matrix presented The cross-coupling of aryl boronic acids and alkanethiols mediated by copper(II) acetate and pyridine in anhydrous dimethylformamide affords aryl alkyl sulfides in good yield with a wide variety of substituted aryl boronic acids. The method is applicable to the synthesis of aryl sulfides of cysteine.

Full text of DOI:10.1021/ol005832g

ORGANIC
LETTERS
2000
Vol. 2, No. 14
2019-2022
Copper-Mediated Cross-Coupling of Aryl
Boronic Acids and Alkyl Thiols
Prudencio S. Herradura,† Kathleen A. Pendola,† and R. Kiplin Guy*
,†,‡
Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology,
UniVersity of California at San Francisco, 513 Parnassus AVenue, San Francisco,
California 94143-0446
rguy@cgl.ucsf.edu
Received March 18, 2000
ABSTRACT
The cross-coupling of aryl boronic acids and alkanethiols mediated by copper(II) acetate and pyridine in anhydrous dimethylformamide affords
aryl alkyl sulfides in good yield with a wide variety of substituted aryl boronic acids. The method is applicable to the synthesis of aryl sulfides
of cysteine.
Alkyl aryl sulfides have a long and rich history as intermedi-
ates in organic synthesis.1 Numerous methods exist for
synthesizing these sulfides, typically involving the condensa-
tion of activated aryl halides with thiols under strongly basic
conditions.2 However, such methods are not applicable to
the synthesis of sulfides containing readily epimerizable
stereocenters. The recent advent of nelfinavir (Figure 1, 1),
a potent inhibitor of HIV protease,3 has highlighted the need
for more gentle methods for the production of these
compounds. This need is further underscored by the presence
of such linkages in several other biologically interesting
molecules such as kynureninase inhibitors4 and the toxins
Figure 1. HIV protease inhibitor Nelfinavir (1).
produced by Amanita phalloidies.5 Recently, the conversion
of unactivated aryl halides to aryl alkyl sulfides has been
catalysis by palladium.7 However, both methods still require
a strong inorganic base and an aryl halide. In the case of the
copper-mediated reaction, yields are low.
We were recently faced with the need to form an alkyl
sulfide from a π rich heterocycle and the thiol group of
accomplished with stoichiometric amounts of copper6 or
† Department of Pharmaceutical Chemistry.
‡ Department of Cellular and Molecular Pharmacology.
(1) Tiecco, M. Synthesis 1988, 749.
(2) Sasaki, N. A.; Hashimoto, C.; Potier, P. Tetrahedron Lett. 1987, 28,
6069.
(3) Kaldor, S. W.; Kalish, V. J.; Davies, J. F., II; Shetty, B. V.; Fritz, J.
E.; Appelt, K.; Burgess, J. A.; Campanale, K. M.; Chirgadze, N. Y.;
Clawson, D. K.; Dressman, B. A.; Hatch, S. D.; Khalil, D. A.; Kosa, M.
B.; Lubbehusen, P. P.; Muesing, M. A.; Patick, A. K.; Reich, S. H.; Su, K.
S.; Tatlock, J. H. J. Med. Chem. 1997, 40, 3979.
(4) Dua, R. K.; Taylor, E. W.; Phillips, R. S. J. Am. Chem. Soc. 1993,
115, 1264.
(6) Hickman, R. J. S.; Christie, B. J.; Guy, R. W.; White, T. J. Aus. J.
Chem. 1985, 38, 899.
(7) (a) Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett. 1995, 36,
4133. (b) Arnould, J. C.; Didelot, M.; Cadilhac, C.; Pasquet, M. J.
Tetrahedron Lett. 1996, 37, 4523. (c) Zheng, N.; McWilliams, J. C.; Fleitz,
F. J.; Armstrong, J. D., III; Volante, R. P. J. Org. Chem. 1998, 63, 9606.
(d) Belokon, Y. N.; Sagyan, A. S.; Djamgaryan, S. M.; Bakhmutov, V. I.;
Belikov, V. M. Tetrahedron 1988, 44, 5507.
(5) Wieland, T. Peptides of Poisonous Amanita Mushrooms; Springer-
Verlag: New York, 1986.
10.1021/ol005832g CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/10/2000

cysteine. Such heterocyclic iodoarenes can prove capricious
in their tendency to decompose before undergoing productive
reaction. Therefore, we set out to develop a method for the
formation of alkyl aryl sulfides that both involved a more
stable precursor and was suitable for application in racem-
ization-sensitive chiral systems.
Recent work in the Chan,8 Cundy,9 and Evans10 labora-
tories has revealed the efficacy of copper(II) acetate in
mediation of the cross-coupling of aryl boronic acids and
phenols or amines to give biaryl ethers and aryl alkylamines.
We sought to develop a similar procedure for the formation
of aryl alkyl sulfides and report herein the success of this
approach. In general, this reaction (Scheme 1) proceeds as
proceeded very cleanly, giving only the desired product.11
Carrying out the reaction under an atmosphere of argon
abated the formation of dithiane but did not significantly
enhance the rate, even at 45 °C in a sealed tube (entry 2).
Switching to a more polar solvent and higher temperatures
did increase the reaction rate (entries 3 and 4), but failure to
exclude oxygen continued to lower the overall yield as a
result of sequestration of the thiol by dithiane formation
(entry 3). In each case, no significant side reactions were
observed other than dithiane formation, and the problem
seemed to be a slow reaction rate. The use of refluxing DMF
as solvent allowed the rapid formation of the desired product
with no observable side products (entry 5). These studies
revealed that the optimal conditions for the reaction were 2
equiv of aryl boronic acid, 3 equiv of pyridine, 1.5 equiv of
copper(II) acetate, and 75 wt % of 4 Å molecular sieves in
DMF under argon.
Scheme 1. Cross-Coupling of Cyclohexane Thiol with Aryl
Boronic Acids
We set out to explore the scope of the methodology with
respect to the substitution of the aryl ring (Table 2). In
general, the reaction is unaffected by electronic factors but
moderately affected by steric hindrance of the reaction center.
Table 2. Substituent Effects in the Cross-Coupling of
Cyclohexane Thiol with Aryl Boronic Acids
follows: Aryl boronic acids (2-2.2 equiv) are allowed to
react with a limiting quantity of alkanethiols (1 equiv) with
the mediation of copper(II) acetate and pyridine in anhydrous
DMF to give alkyl sulfides in 40-90% yield. The reaction
proceeds facilely with a variety of aryl boronic acids.
Initially, we began with the Evans conditions for the
formation of biaryl ethers. In this case, the reaction proceeds
in methylene chloride at 25 °C and is accelerated by the
presence of oxygen. In the cross-coupling of p-toluene
boronic acid and cyclohexane thiol (Table 1, entry 1), these
Table 1. Optimization of Reaction Conditions for
Cross-Coupling
conditions did yield the expected product, but the rate of
reaction was very sluggish and progression was hindered by
the oxidation of free thiol to dithiane. However, other than
the competitive oxidation of thiol to dithiane, the reaction
2020
Org. Lett., Vol. 2, No. 14, 2000

The unsubstituted phenyl boronic acid undergoes the reaction
with equal facility as the p-toluene boronic acid used in the
initial studies (entry 1). The reaction is sensitive to sterics
surrounding the boronic acid as demonstrated by the
lengthened reaction times and reduced yields for the naph-
thalene (entry 2) and o-toluene (entry 3) boronic acids.
However, more distal steric bulk has, as expected, little effect
upon reactivity as demonstrated by the m-toluene (entry 4),
p-toluene (entry 5), and p-tert-butylbenzene (entry 6) boronic
acid cases. More strongly electron-donating or electron-
withdrawing substitutions do not significantly affect the
reaction rates or overall yields, with m-nitro (entry 7),
p-methoxy (entry 8), p-cyano (entry 9), and p-chloro (entry
10) benzene boronic acids all producing good yield of the
expected product within a reasonable time. Thus, the reaction
is applicable to the synthesis of a wide variety of substituted
phenyl sulfides and does not seem to be extremely sensitive
to electronic effects. These results are at odds with the trends
observed in the palladium-catalyzed cross-coupling of aryl
iodides with thiols, where both strongly electron-withdrawing
and electron-donating groups (p-methoxy and p-nitro) sig-
nificantly inhibited the reaction.7c Therefore, the conditions
reported herein provide advantage for such substrates.
We also examined the scope of the methodology with
respect to the nature of the thiol nucleophile. These studies
revealed that most thiols would enter into cross-coupling with
phenyl boronic acid under the standard conditions (Table
3). Thus, this method can afford the diphenyl sulfide (entry
1), the product of coupling of a primary thiol (entry 2), and
the product of coupling of a chiral secondary thiol with
retention of chirality at the sulfur center (entry 3). The
method can also be used with substrates that can be viewed
as a protected thiol (entry 4), thus giving access to thiophe-
nols. However, the method does not work well with tertiary
thiols (entry 5), giving some product but in very low yields.
The method is also inapplicable to the cross-coupling of thio
acids (entry 6) or to the production of R-carboxy thiols (entry
7). Thus, the conditions reported herein tolerate a wide
variety of thiols as nucleophiles but cannot be applied to
the generation of tertiary alkyl aryl sulfides or aryl thioesters.
Of particular note is the preservation of chirality at the sulfur
containing stereocenter.
We next turned our attention to applying this method to
the synthesis of S-aryl cysteine derivatives. As a convenient
test case, we targeted the synthesis of N-benzyloxycarbonyl-
(S-phenyl)-L-cysteine 2, a key intermediate in the synthesis
of Nelfinavir (Figure 1, 1).12
Toward this end, S-tert-butylthio-L-cysteine (Scheme 2,
3) was orthogonally protected by sequential blocking of the
Scheme 2. Synthesis of
N-Benzyloxycarbonyl-(S-phenyl)-L-cysteine
Table 3. Substituent Effects in the Cross-Coupling of Thiols
with Phenyl Boronic Acid
amino functionality as a carboxybenzoate and the acid
functionality as an allyl ester to afford 4. Compound 4 reacted
cleanly under our standard conditions to afford the phenyl
sulfide 5 in 79% yield. Selective removal of the allyl group
using palladium catalysis afforded N-benzyloxycarbonyl-(S-
phenyl)-L-cysteine 2. The optical rotation of this material
revealed that the reaction proceeded without epimerization
of the R-carbon of the amino acid. Thus, this method is
readily applicable to the synthesis of optically enriched
cysteine sulfides.
In conclusion, we have discovered a copper-mediated
method for the formation of alkyl aryl sulfides from thiols
(8) (a) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P.
Tetrahedron Lett. 1998, 39, 2933. (b) Lam, P. Y. S.; Clark, C. G.; Saubern,
S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron
Lett. 1998, 39, 2941.
(9) Cundy, D. J.; Forsyth, S. A. Tetrahedron Lett. 1998, 39, 7979.
(10) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39,
2937.
(11) All compounds were purified to homogeneity and structurally
1
characterized by H and 13C NMR, IR, and HRMS.
(12) (a) Rieger, D. L. J. Org. Chem. 1997, 62, 8546. (b) Inaba, T.;
Birchler, A. G.; Yamada, Y.; Sagawa, S.; Yokota, K.; Ando, K.; Uchida, I.
J. Org. Chem. 1998, 63, 7582.
Org. Lett., Vol. 2, No. 14, 2000
2021

and aryl boronic acids that proceeds in good to excellent
yield with most substrates. The method is tolerant of all
substitutions on the aryl ring with only modest changes in
rate being attributable to steric effects. Additionally, this
method works well with a variety of thiols including
potentially sensitive chiral thiols and is directly applicable
to the synthesis of cysteine sulfides. This new method nicely
complements the existing methodologies based upon the
coupling of aryl halides to thiols.
Acknowledgment. We thank the Sidney Kimmel Cancer
Research Foundation and the HHMI Research Resources
Program (Grant 76296-549901) for funding this research and
Thomas Scanlan and Stephen Kahl for helpful comments.
Supporting Information Available: A complete experi-
mental procedure for a typical coupling reaction and an-
notated spectral data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL005832G
2022
Org. Lett., Vol. 2, No. 14, 2000