Palladium-catalyzed coupling of thiol esters with aryl and primary and secondary alkyl organoindium reagents

Article abstract of DOI:10.1021/jo050110u

Thiol esters and organoindium reagents undergo palladium-catalyzed cross-coupling under mild conditions to give ketones in moderate to excellent yields. Aryl and primary/ secondary alkyl organoindium reagents can be used as coupling partners. This method has two advantages over the cross-coupling of thiol esters with boron and tin reagents: (1) no added copper reagent is required to mediate the reaction and (2) for the case of alkyl transfer, no added base is required to activate organoindium reagents for cross-coupling as is required for the coupling of alkyl boron reagents with thiol esters.

Full text of DOI:10.1021/jo050110u

could proceed directly with sufficiently thiophilic orga-
nometallic cross-coupling partners without the require-
ment of a stoichiometric Cu(I) carboxylate activator (eq
2).
Palladium-Catalyzed Coupling of Thiol
Esters with Aryl and Primary and
Secondary Alkyl Organoindium Reagents
Bryan W. Fausett and Lanny S. Liebeskind*
stoich
R1-SR′ + R2-B(OH)2 Cu(I)OCOR8 R1-R2 + Cu-SR′ +
Emory University, Department of Chemistry, 1515 Dickey
Drive, Atlanta, Georgia 30322
cat. Pd
RC(O)O-B(OH)2 (1)
chemLL1@emory.edu
cat. Pd
R1-SR′ + R2-M if M is thiophilic8 R1-R2 + M-SR (2)
Received January 19, 2005
Pursuing this analysis led to consideration of the
indium-sulfur bond, which is assumed to be strong on
the basis of the Pearson Hard-Soft Principle,5 and thus
to an exploration of the palladium-catalyzed coupling of
thiol esters with organoindium reagents.6 The latter are
versatile coupling partners in their own right.7,8 Initially
0.4 equiv of various triorganoindium reagents9 were
treated with S-4-chlorophenyl 4-methylbenzothioate in
the presence of 5% Pd(CH3CN)2Cl2 as precatalyst in THF
at 55 °C to probe the number of organic groups that
would transfer from indium to form the product ketone
(Table 1). These results demonstrated that aryl and
primary alkyl triorganoindium reagents easily trans-
ferred between 2 and 3 of the organic groups, while only
one secondary alkyl was readily transferred.10 Conversion
was high in all cases since unreacted thiol ester could be
recovered (entry 5). The coupling with vinyl- and al-
kynylindium reagents performed poorly, giving only a
trace of or no product.11 Control experiments without Pd
(entries 6-8) demonstrated that triphenylindium was
capable of transferring the first of its three phenyl groups
to the thiol ester in an uncatalyzed reaction to give 33%
yield of the corresponding ketone. This uncatalyzed
reactivity did not extend to either tri-n-butyl- or tri-sec-
Thiol esters and organoindium reagents undergo palladium-
catalyzed cross-coupling under mild conditions to give
ketones in moderate to excellent yields. Aryl and primary/
secondary alkyl organoindium reagents can be used as
coupling partners. This method has two advantages over the
cross-coupling of thiol esters with boron and tin reagents:
(1) no added copper reagent is required to mediate the
reaction and (2) for the case of alkyl transfer, no added base
is required to activate organoindium reagents for cross-
coupling as is required for the coupling of alkyl boron
reagents with thiol esters.
Thioorganics are excellent cross-coupling partners with
boronic acids1 and organostannanes2 under mild and
nonbasic conditions.3 The breadth of this methodology is
still being explored and has recently been extended to
the cross-coupling of thiol esters with alkyl boron re-
agents.4 With boronic acids in particular, the palladium-
catalyzed coupling of thioorganics relies on the unique
ability of a copper(I) carboxylate additive to labilize a
palladium thiolate ligand toward transmetalation, while
at the same time providing a stoichiometric quantity of
a borophilic carboxylate counterion to pair with the
-B(OH)2 moiety (eq 1). This understanding suggests that
the palladium-catalyzed cross-coupling of thioorganics
(5) Pearson, R. G. Chemical Hardness; Wiley-VCH Verlag GmbH:
Weinheim, Germany, 1997.
(6) Recent syntheses of ketones via cross-coupling methods: (a)
Zhang, Y.; Rovis, T. J. Am. Chem. Soc. ASAP, Nov. 18, 2004, 126,
15964-15965. (b) Kells, K. W.; Chong, J. M. J. Am. Chem. Soc. 2004,
126, 15666-15667. (c) Tatamidani, H.; Yokota, K.; Kakiuchi, F.;
Chatani, N. J. Org. Chem. 2004, 69, 5615. (d) Tatamidani, H.;
Kakiuchi, F.; Chatani, N. Org. Lett. 2004, 6, 3597. (e) Fukuyama, T.;
Tokuyama, H. Aldrichim. Acta 2004, 37, 87. See also footnotes 1a, 2a,
and 3e.
(1) (a) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122,
11260. (b) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2001, 3,
91. (c) Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979. (d) Savarin,
C.; Liebeskind, L. S. Org. Lett. 2001, 3, 2149. (e) Kusturin, C. L.;
Liebeskind, L. S.; Neumann, W. L. Org. Lett. 2002, 4, 983. (f)
Liebeskind, L. S.; Srogl, J.; Savarin, C.; Polanco, C. Pure Appl. Chem.
2002, 74, 115. (g) Kusturin, C.; Liebeskind, L. S.; Rahman, H.; Sample,
K.; Schweizer, B.; Srogl, J.; Neumann, W. L. Org. Lett. 2003, 5, 4349.
(h) Lengar, A.; Kappe, C. O. Org. Lett. 2004, 6, 771.
(2) (a) Wittenberg, R.; Srogl, J.; Egi, M.; Liebeskind, L. S. Org. Lett.
2003, 5, 3033. (b) Egi, M.; Liebeskind, L. S. Org. Lett. 2003, 5, 801. (c)
Alphonse, F.-A.; Suzenet, F.; Keromnes, A.; Lebret, B.; Guillaumet,
G. Org. Lett. 2003, 5, 803.
(7) (a) Perez, I.; Sestelo, J. P.; Sarandeses, L. A. Org. Lett. 1999, 1,
1267. (b) Perez, I.; Sestelo, J. P.; Sarandeses, L. A. J. Am. Chem. Soc.
2001, 123, 4155. (c) Lee, P. H.; Sung, S.; Lee, K. Org. Lett. 2001, 3,
3201. (d) Lee, K.; Lee, J.; Lee, P. H. J. Org. Chem. 2002, 67, 8265. (e)
Lee, P. H.; Lee, S. W.; Seomoon, D. Org. Lett. 2003, 5, 4963. (f) Takami,
K.; Yorimitsu, H.; Shinokubo, H.; Matsubara, S.; Oshima, K. Org. Lett.
2001, 3, 1997.
(8) Organoindium reagents have been used to make ketones via
carbonylative cross-coupling procedures: (a) Pena, M. A.; Sestelo, J.
P.; Sarandeses, L. A. Synthesis 2003, 5, 780. (b) Lee, P. H.; Lee, S. W.;
Lee, K. Org. Lett. 2003, 5, 1103. (c) Lee, S. W.; Lee, K.; Seomoon, D.;
Kim, S.; Kim, H.; Kim, H.; Shim, E.; Lee, M.; Lee, S.; Kim, M.; Lee, P.
H. J. Org. Chem. 2004, 69, 4852.
(3) Organozinc reagents are also good partners for coupling with
thioorganics under mild reaction conditions: (a) Roberts, W. P.; Ghosh,
I.; Jacobi, P. A. Can. J. Chem. 2004, 82, 279. (b) Ghosh, I.; Jacobi, P.
A. J. Org. Chem. 2002, 67, 9304. (c) Angiolelli, M. E.; Casalnuovo, A.
L.; Selby, T. P. Synlett 2000, (6), 905. (d) Srogl, J.; Liu, W.; Marshall,
D.; Liebeskind, L. S. J. Am. Chem. Soc. 1999, 121, 9449. (e) Tokuyama,
H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T. Tetrahedron Lett.
1998, 39, 3189.
(9) Organoindium reagents were prepared from InCl3 and 3 equiv
of a Grignard reagent in THF at room temperature for 30 min.
(10) InR3 are more reactive than InR2X reagents. Wilkinson, G.;
Stone, F. G. A.; Abel, E. W. Comprehensive Organometallic Chemistry;
Pergamon Press: New York, 1982; Vol. I, p 711.
(11) Of related interest is a nickel-catalyzed coupling of aryl and
alkyl but not alkenyl or alkynyl Grignard reagents: Terao, J.;
Watanabe, H.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc.
2002, 124, 4222.
(4) Yu, Y.; Liebeskind, L. S. J. Org. Chem. 2004, 69, 3554.
10.1021/jo050110u CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/13/2005
J. Org. Chem. 2005, 70, 4851-4853
4851

TABLE 1. Coupling of Triorganoindium Reagents with
TABLE 2. Coupling of S-4-Chlorophenyl
4-Methylbenzothioate with Secondary Alkyl
Organoindium Reagents
S-4-Chlorophenyl 4-Methylbenzothioate
% isolated
entry
R
product
yield
% isolated
yield
entry
R
product
1
2
3
4
5
6
7
8
phenyl
2a
2b
2c
2d
2e
2a
2d
2e
89
p-methoxyphenyl
p-fluorophenyl
n-butyl
60
1
2
3
sec-butyl
cyclopentyl
cyclohexyl
2e
2f
2g
83
80
95
69
70
sec-butyl
53 (47a)
35
phenylb,c
n-butylc
<5
<5
TABLE 3. Coupling S-4-Chlorophenyl
4-Methylbenzothioate with t-Bu3-nInRn (n ) 1 or 2)
sec-butylc
a Recovered starting material. b 0.33 equiv of InPh3. c Control:
no Pd catalyst.
butylindium, perhaps reflecting the greater Lewis acidity
of the triphenyl- versus the trialkylindium reagents.
In the cross-coupling of thiol esters to form ketones the
organoindium reagents possess two specific attributes
that differentiate them from boronic acids and orga-
nostannanes. First, indium is thiophilic and, therefore,
like zinc,12 the reaction does not require an added Cu(I)
carboxylate to facilitate the coupling. Second, the use of
indium allows a facile coupling with primary and second-
ary alkyl groups. Alkyl cross-couplings are now known
for Grignard,13 9-BBN,14 trifluoroorganoborate,15 and
organozinc reagents.16 More recently conditions for the
transfer of alkyl groups from boronic acids have been
developed.17
% isolated
entry
reagent
product
yield
1
2
(t-Bu)2In(sec-butyl)
2e
2f
2g
2e
2f
2g
2b
2c
2d
2h
2i
73
69
65
64
83
77
72
85
83
55
60
(t-Bu)2In(cyclopentyl)
(t-Bu)2In(cyclohexyl)
(t-Bu)In(sec-butyl)2
3
4
5
(t-Bu)In(cyclopentyl)2
(t-Bu)In(cyclohexyl)2
(t-Bu)In(p-methoxyphenyl)2
6
a
7
a
8
(t-Bu)In(p-fluorophenyl)2
a
9
(t-Bu)In(n-butyl)2
a
10
11
(t-Bu)In(o-tolyl)2
a
(t-Bu)In(o-methoxyphenyl)2
a Using 0.6 equiv of (t-Bu)InR2.
The ability to couple secondary alkyl groups by using
organoindium reagents prompted further exploration of
the reaction. Since only slightly more than one of the
three alkyl groups of tri(sec-butyl)indium was transferred
efficiently (entry 5, Table 1), the yield of ketone was
maximized by employing 1.2 equiv of the tri(sec-alkyl)-
indium reagent (Table 2). This produced very good yields
of ketone, but at the expense of requiring 3.6 equiv of a
secondary alkyl group.
To mitigate the need for an excess of the secondary
alkyl group and achieve high yields of ketone, a non-
transferring tert-butyl “dummy ligand” on indium was
employed. Two types of mixed organoindium reagents
were prepared: those bearing two nontransferring tert-
butyl groups and those bearing only one nontransferring
tert-butyl group. These reagents were generated in situ
by treating InCl3 with (3 - n) equiv of t-BuMgCl followed
by n equivalents of a secondary alkyl Grignard reagent
(n ) 1 and 2). The resulting mixed organoindium
reagents t-Bu3-nInRn were exposed to S-4-chlorophenyl
4-methylbenzothioate in the presence of 5% Pd(MeCN)2Cl2
in THF and produced the corresponding aryl sec-alkyl
ketones in good yields (Table 3). No evidence of tert-butyl
transfer was noted. Significantly, efficient production of
ketone could be achieved by using only 1.5 equiv of the
transferring secondary alkyl group with either of the new
reagent systems. Of the two reagents, that with only one
nontransferring tert-butyl group requires only 0.75 equiv
of indium and gives slightly better yields of ketone in
some cases. Applying this same technique to the aryl-
and n-butylorganoindium reagents shown earlier in Table
1 gave increased yields and required only 0.6 equiv of
indium. Using these same conditions ortho-substituted
arylindium reagents (entries 10 and 11) were less reac-
tive, which resulted in decreased yields.
Two additional observations are of synthetic interest.
Depicted in Scheme 1 is the selective coupling of an
indium reagent at a thiol ester in the presence of a
reactive aryl bromide and a demonstration of the use of
an aliphatic thiol ester in the coupling chemistry.
In conclusion, a new palladium-catalyzed coupling of
thiol esters with organoindium reagents has been devel-
oped. This protocol does not require a thiophilic additive
and is effective with arylindium and primary and second-
ary alkylindium reagents.
(12) Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T.
Tetrahedron Lett. 1998, 39, 3189.
(13) (a) Terao, J.; Watanabe, H.; Ikumi, A.; Kuniyasu, H.; Kambe,
N. J. Am. Chem. Soc. 2002, 124, 4222. (b) Tamao, K.; Sumitani, K.;
Kumada, M. J. Am. Chem. Soc. 1972, 94, 4374. (c) Furstner, A.;
Leitner, A. Angew. Chem., Int. Ed. 2002, 41, 609.
(14) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(15) Molander, G. A.; Ito, T. Org. Lett. 2001, 3, 393.
(16) Devasagayaraj, A.; Stuedemann, T.; Knochel, P. Angew. Chem.,
Int. Ed. 1995, 34, 2723.
(17) (a) Zhou, J.; Fu, G. J. Am. Chem. Soc. 2003, 125, 14726. (b)
Zhou, J.; Fu, G. J. Am. Chem. Soc. 2004, 126, 1340. (c) Powell, D. A.;
Fu, G. J. Am. Chem. Soc. 2004, 126, 7788.
Experimental Section
General Procedures. All cross-coupling reactions were
performed under an atmosphere of dry N2 or Ar. THF was dried
over 4 Å molecular sieves and titrated for water level with a
4852 J. Org. Chem., Vol. 70, No. 12, 2005

SCHEME 1. Selectivity and Generality of Thiol Ester/Organoindium Cross-Coupling
Fisher Coulomatic K-F titrater and purged with dry N2 or Ar
before use. Et3N was dried over KOH pellets. 1H NMR and 13C
NMR spectra were taken at room temperature in CDCl3 and
internally referenced to CDCl3 (7.26, 77.23 ppm).
mmol, 44 mg) was placed in a flask with a vacuum attachment
and stirring bar. This was heated with a heat gun while stirring
under vacuum for several minutes to ensure dryness. After
heating the flask was filled with Ar and then reevacuated; this
was repeated 3 times before filling the flask a final time with
Ar. Next, THF (1.5 mL) was added via syringe. Once the indium-
(III) chloride was dissolved, PhMgCl (0.6 mmol) was added
dropwise and allowed to stir for 0.5 h. This reagent was used
directly in the coupling reaction.
Starting Materials: 4-Methylthiobenzoic Acid S-(4-Chlo-
rophenyl) Ester, 1.18 p-Chlorothiophenol (50 mmol, 7.23 g) and
p-toluoyl chloride (50 mmol, 7.73 g) were added to 115 mL of
THF and cooled in an ice bath. To this solution triethylamine
(100 mmol, 10.12 g) was added dropwise. The reaction was
allowed to warm to room temperature and stirred overnight.
Diethyl ether (100 mL) was added and the precipitated salts that
resulted were filtered off. The solvent was then evaporated and
the product was recrystallized from acetone to give a white solid
(9.48 g, 72% yield). Mp 119-120 °C. 1H NMR (600 MHz, CDCl3)
δ 7.91 (d, J ) 8.4 Hz, 2 H), 7.43 (m, 4 H), 7.29 (d, J ) 9.0 Hz, 2
H), 2.44 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 189.4, 145.1,
136.6, 136.1, 134.0, 129.7, 127.8, 126.2, 22.0. IR (neat) 1671 (s)
cm-1. Anal. Calcd for C14H11S: C, 64.00; H, 4.22; S, 12.20.
Found: C, 64.04; H, 4.42; S, 12.15.
tert-Butyl(cyclopentyl)2indium. Indium(III) chloride (0.375
mmol, 83 mg) was placed in a flask with a vacuum attachment
and stirring bar. This was heated with a heat gun while stirring
under vacuum for several minutes to ensure dryness. After
heating, the flask was filled with Ar and then reevacuated; this
was repeated 3 times before filling the flask a final time with
Ar. Next, THF (1.5 mL dry/degassed) was added via syringe.
Once the indium(III) chloride was dissolved t-BuMgCl (0.375
mmol, 1.9 M in diethyl ether, 0.20 mL) was added dropwise and
allowed to stir for 0.5 h giving a slightly milky reaction mixture.
To this was added cyclopentylMgCl (0.75 mol, 1.96 M in diethyl
ether, 0.39 mL) dropwise and the resulting solution was stirred
another 0.5 h to give a solution of tert-butyl(cyclopentyl)2indium.
This reagent used directly in the coupling reaction.
4-Bromothiobenzoic Acid S-(4-Chlorophenyl) Ester, 3.19
p-Chlorothiophenol (10 mmol, 1.45 g) and 4-bromobenzoyl
chloride (10 mmol, 2.19 g) were added to 30 mL of THF and
cooled in an ice bath. To this solution triethylamine (20 mmol,
2.02 g) was added dropwise. The reaction was allowed to warm
to room temperature and stirred overnight. Diethyl ether (20
mL) was added and the precipitated salts that resulted were
filtered off. The solvent was then evaporated and the product
recrystallized from acetone giving a white solid (2.36 g, 72%
yield). Mp 145-146 °C. 1H NMR (600 MHz, CDCl3) δ 7.88 (d, J
) 8.4 Hz, 2 H), 7.65 (d, J ) 8.4 Hz, 2 H), 7.44 (s, 4 H). 13C NMR
(150 MHz, CDCl3) δ 189.0, 136.5, 136.4, 135.4, 132.4, 129.8,
129.23, 129.16, 125.6. IR (neat) 1675 (s) cm-1. Anal. Calcd for
C13H8S: C, 47.66; H, 2.46; S, 9.79. Found: C, 47.42; H, 2.55; S,
9.80.
Cyclohexanecarbothioic Acid S-(4-Chlorophenyl) Ester,
5. p-Chlorothiophenol (10 mmol, 1.45 g) and cyclohexanecarbonyl
chloride (10 mmol, 1.47 g) were added to 30 mL of THF and
cooled in an ice bath. To this solution triethylamine (20 mmol,
2.02 g) was added dropwise. The reaction was allowed to warm
to room temperature and stirred overnight. Diethyl ether (20
mL) was added and the precipitated salts that resulted were
filtered off. The solvent was then evaporated and the product
recrystallized from acetone giving a white solid (2.33 g, 91%
yield). Mp 34-35 °C. 1H NMR (400 MHz, CDCl3) δ 7.34 (m, 4
H), 2.60 (m, 1 H), 2.01-1.27 (m, 10 H). 13C NMR (100 MHz,
CDCl3) δ 200.3, 136.0, 135.7, 129.5, 126.6, 52.7, 29.6, 25.7, 25.6.
IR (neat) 1702 (s) cm-1. Anal. Calcd for C13H15S: C, 61.28; H,
5.93; S, 12.59. Found: C, 61.02; H, 5.98; S, 12.40.
Representative Procedure for Cross-Coupling: 4-Meth-
ylbenzophenone. 4-Methylthiobenzoic acid S-(4-chlorophenyl)
ester (0.50 mmol, 131 mg) was added with Pd(MeCN)2Cl2 (5 mol
%, 6.5 mg) to a flask that was subsequently flushed with Ar.
THF (0.5 mL) was added to the flask followed immediately by a
solution of triphenylindium (0.2 mmol) as prepared above.
Finally, the reaction mixture was heated in an oil bath at 55 °C
and stirred for 16 h. The reaction mixture was diluted with 5
mL of 1:1 diethyl ether/hexanes and 3 mL of water was added.
The organics were removed and the resultant aqueous slurry
was washed with three 5 mL portions of 1:1 diethyl ether/
hexanes. The organics were combined and filtered through a plug
of silica gel and the solvent was evaporated. After preparative
plate chromatography (1:1 CH2Cl2/hexanes) 4-methylbenzophe-
1
none was obtained (87 mg, 89%). H NMR (600 MHz, CDCl3) δ
7.77 (d, J ) 7.2 Hz, 2 H), 7.71 (d, J ) 7.8 Hz, 2 H), 7.56 (m, 1
H), 7.46 (m, 2 H), 7.27 (d, J ) 8.4 Hz, 2 H), 2.42 (s, 3 H). 13C
NMR (150 MHz, CDCl3) δ 196.7, 143.4, 138.1, 135.0, 132.3, 130.5,
130.1, 129.1, 128.4, 21.8. IR (neat) 1656 (s) cm-1
.
Full characterization details of the cross-coupling products
2a-i and 4 are provided in the Supporting Information.
Acknowledgment. The National Institutes of Gen-
eral Medical Sciences, DHHS supported this investiga-
tion through Grant No. GM066153.
Representative Procedures for Preparing Triorgano-
indium Reagents: Triphenylindium. Indium(III) chloride (0.2
Supporting Information Available: A complete descrip-
tion of the synthesis and characterization data of all com-
pounds prepared in this study. This material is available free
of charge via the Internet at http://pubs.acs.org.
(18) Kingsbury, C. A.; Ebert, G. Phosphorus, Sulfur Silicon Relat.
Elem. 1980, 9, 315.
(19) Komives, T.; Marton, A. F.; Dutka, F. J. Prakt. Chem. 1976,
318, 248.
JO050110U
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