Ketone synthesis under neutral conditions. Cu(I) diphenylphosphinate-mediated, palladium-catalyzed coupling of thiol esters and organostannanes

Article abstract of DOI:10.1021/ol034962x

(Matrix presented) A versatile approach to ketone synthesis is described. The reaction relies on the palladium-catalyzed, copper diphenylphosphinate-mediated coupling of thiol esters with organostannanes under neutral reaction conditions. This reaction complements the previously described coupling of thiol esters with boronic acids that used dual thiophilic-borophilic activation methodology.

Full text of DOI:10.1021/ol034962x

ORGANIC
LETTERS
2003
Vol. 5, No. 17
3033-3035
Ketone Synthesis under Neutral
Conditions. Cu(I)
Diphenylphosphinate-Mediated,
Palladium-Catalyzed Coupling of Thiol
Esters and Organostannanes
Ru1diger Wittenberg, Jiri Srogl, Masahiro Egi, and Lanny S. Liebeskind*
Emory UniVersity, Department of Chemistry, 1515 Pierce DriVe,
Atlanta, Georgia 30322
chemLL1@emory.edu
Received May 30, 2003
ABSTRACT
A versatile approach to ketone synthesis is described. The reaction relies on the palladium-catalyzed, copper diphenylphosphinate-mediated
coupling of thiol esters with organostannanes under neutral reaction conditions. This reaction complements the previously described coupling
of thiol esters with boronic acids that used dual thiophilic−borophilic activation methodology.
Transition-metal-catalyzed cross-coupling reactions represent
extremely powerful tools in organic synthesis.1 As one recent
example, thiol esters and boronic acids participate in a
palladium-catalyzed, copper-mediated cross-coupling reaction
to give ketones under neutral reaction conditions.2 This new
reaction relies upon the unique ability of a Cu(I) carboxylate
to effect transmetalation of the intermediate acylpalladium
thiolate (RCOPdL2SR′) and a boronic acid through simul-
taneous thiophilic activation of the palladium thiolate bond
and borophilic activation of the boronic acid.3 To present
the synthetic community with additional options for carbon-
carbon bond formation through cross-coupling protocols, we
now describe an extension of the thiophilic activation
methodology to the coupling of thiol esters with organostan-
nanes.4 This system represents a useful approach to ketone
synthesis under neutral reaction conditions from synthetically
versatile thiol esters and complements the previously de-
scribed coupling of thiol esters with boronic acids.2 Some
transformations of thiol esters to ketones are known, but they
proceed under basic reaction conditions and are not general.5
Other acylpalladium-based ketone syntheses are also known.6
The coupling reaction of thiol ester 1 with organostannane
2 was examined as a model system (Table 1). No observable
reaction occurred between the reaction partners in the
presence of various palladium catalysts alone. However, upon
addition of Cu(I) 3-methylsalicylate (CuMeSal) or Cu(I)
(4) See also: Egi, M.; Liebeskind, L. S. Org. Lett. 2003, 5, 801-802.
Alphonse, F.-A.; Suzenet, F.; Keromnes, A.; Lebret, B.; Guillaumet, G.
Org. Lett. 2003, 5, 803-805.
(1) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P.
J., Eds.; Wiley-VCH: Weinheim, 1998.
(2) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122, 11260-
11261.
(3) See also: Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2001, 3
(1), 91-93. Savarin, C.; Liebeskind, L. S. Org. Lett. 2001, 3 (14), 2149-
2152. Srogl, J.; Liebeskind, L. S. Org. Lett. 2002, 4 (6), 979-981. Kusturin,
C. L.; Liebeskind, L. S.; Neumann, W. L. Org. Lett. 2002, 4 (6), 983-985.
Liebeskind, L. S.; Srogl, J.; Savarin, C.; Polanco, C. Pure Appl. Chem.
2002, 74 (1), 115-122.
(5) Anderson, R. J.; Henrick, C. A.; Rosenblum, L. D. J. Am. Chem.
Soc. 1974, 96, 3654-3655. Cardellicchio, C.; Fiandanese, V.; Marchese,
G.; Ronzini, L. Tetrahedron Lett. 1987, 28, 2053-2056. Kawanami, Y.;
Katsuki, I.; Yamaguchi, M. Tetrahedron Lett. 1983, 24, 5131-5132.
Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T. Tetrahedron
Lett. 1998, 39, 3189-3192. Araki, M.; Sakata, S.; Takei, H.; Mukaiyama,
T. Bull. Chem. Soc. Jpn. 1974, 47, 1777-1780. Kim, S.; Lee, J. I. J. Chem.
Soc., Chem. Commun. 1981, 1231-1232.
10.1021/ol034962x CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/25/2003

yields (Table 1). Notably, after a simple workup and
chromatography, the desired product 3 was easily separated
from n-Bu3SnOP(O)Ph2 and the copper residues. Additional
improvements in yield were obtained using tri-2-furylphos-
phine (TFP) as a supporting ligand in combination with Pd2-
dba3, a catalyst system for which Farina had noted large rate
accelerations in Stille cross-coupling reactions.11,12
Table 1. Model System for the Coupling of Thiol Esters with
Organostannanes
To judge the generality of this new reaction, the cross-
coupling of S-p-tolyl thiol esters with various tri-n-butylor-
ganostannanes was investigated using between 0.65 and 2.5%
of a 1:8 Pd2dba3/TFP catalyst system and 1.2-2.2 equiv of
CuOP(O)Ph2. The results are depicted in Table 2; THF was
Pd source
Pd(PPh3)4
Cu(I) sourcea
yield
60
66
69
CuMeSal
CuMeSal
CuMeSal
CuTC
CuDPP
CuDPP
CuDPP
CuDPP
PdCl2(PPh3)2
PdCl(PPh3)2CH2Ph
PdCl(PPh3)2CH2Ph
Pd(PPh3)4
PdCl2(PPh3)2
PdCl(PPh3)2CH2Ph
Pd2(dba)3/TFPc
Table 2. Cross-Coupling of Thiol Esters and Organostannanes
71
89 (98)b
67 (92)b
88 (97)b
94
a CuTC ) Cu(I) thiophene-2-carboxylate; CuMeSal ) Cu(I) 3-methyl-
salicylate; CuDPP ) Cu(I) diphenylphosphinate. b Yield based on recovered
thiol ester. c TFP ) tri-2-furylphosphine.
entry thiol ester, R1
stannane, R2
p-tolyl
2-furyl
2-thienyl
3-pyridyl
4-pyridyl
2-pyridyl
R1COR2 yield (%)a
1b CH3(CH2)10
2b CH3(CH2)10
3b CH3(CH2)10
4b (E)-â-styryl
5b (E)-â-styryl
6b p-NO2C6H5
7b p-NO2C6H5
8c p-NO2C6H5
9d p-NO2C6H5
10d 2-benzofuranyl 2-pyrazyl
11d 1-adamantyl
12d 2-aminophenyl 2-benzofuranyl
13d 2-acetoxyacetyl 2-benzofuranyl
91
78
73
76
67
70
91
61
69
96
68
93
96
92
81
97
81
thiophene-2-carboxylate (CuTC), copper sources that had
earlier proven to be effective for the palladium-catalyzed
coupling of boronic acids with thiol esters,2 heteroaromatic
thioethers,7 or thioalkynes,8 ketone 3 was generated in
moderate to good yields after 24 h in THF at 45-50 °C.
Cu(I)Cl was ineffective as an additive, promoting only low
conversion to product with various side reactions. No
significant difference in efficiency was noted among the
palladium catalysts Pd(PPh3)4, PdCl2(PPh3)2, and PdCl-
(PPh3)2(CH2Ph), all of which produced ketone 3 in isolated
yields between 60 and 71%.
The reaction workup was tedious, and removal of the tin
residues was not efficient under the conditions mentioned
above.9 In earlier work on Stille cross-coupling reactions
mediated only by copper(I) carboxylates,10 we had noted the
effectiveness of the Ph2P(O)O- counterion in facilitating the
separation of tin residues (as n-Bu3SnOP(O)Ph2) from the
reaction mixture. This led in the current study to the
consideration of Cu(I) diphenylphosphinate (CuDPP) as a
unique mediator for the palladium-catalyzed coupling of thiol
esters with organostannanes. In fact, CuOP(O)Ph2 mediated
the palladium-catalyzed coupling reaction of 1 with 2 in the
presence of 5% Pd(PPh3)4, PdCl2(PPh3)2, or PdCl(PPh3)2(CH2-
Ph) as catalysts to give ketone 3 in good to excellent isolated
1-methyl-2-pyrrolyl
2-pyrimidinyl
2-thiazolyl
3-formyl-4-pyridyl
14e CH3(CH2)10
15e o-tolyl
16e o-tolyl
17e CH3(CH2)10
2-methyl-1-propenyl
2-methyl-1-propenyl
2-thienyl
3-propenyl
a Isolated yields of purified products. b Conditions: 1% Pd2(dba)3, 8%
TFP, 1.2 equiv of CuDPP, THF, 50 °C, 7 h. c Conditions: 2.5% of
Pd2(dba)3, 20% TFP, 1.2 equiv of CuDPP, THF, 50 °C, 7 h. d Conditions:
0.65% Pd2(dba)3, 5.2% TFP, 1.3 equiv of CuDPP, 1:1 THF/hexanes, 40
°C, 18 h. e Conditions: 2.5% of Pd2(dba)3, 20% TFP, 2.2 equiv of CuDPP,
THF, 50 °C, 1-25 h.
used as the solvent. The reaction system shows excellent
generality and delivers good to excellent isolated yields of
ketones from alkyl, aryl, heteroaryl, and functionalized S-p-
tolyl thiol esters and from aryl, heteroaryl, and alkenylstan-
nanes. In general, very good yields are obtained even using
1.2-1.3 equiv of the Cu(I) mediator, although in a few cases
higher loadings were used. Some organotin compounds are
noticeably sensitive to copper-mediated side reactions such
as oxidative homocoupling and protodestannylation, probably
(6) Farina, V.; Krishnamurthy, V.; Scott, W. J. In Organic Reactions;
Paquette, L., Ed.; John Wiley & Sons: New York, 1997; Vol. 50, pp 1-652.
Mitchell, T. N. Synthesis 1992, 803-815. Haddach, M.; McCarthy, J. R.
Tetrahedron Lett. 1999, 40, 3109-3112. Bumagin, N. A.; Korolev, D. N.
Tetrahedron Lett. 1999, 40, 3057-3060. Miyaura, N.; Suzuki, A. Chem.
ReV. 1995, 95, 2457-2483. Goossen, L. J.; Ghosh, K. Angew. Chem., Int.
Ed. 2001, 40, 3458-3460. Yamamoto, A. Pure Appl. Chem. 2002, 74, 1-5.
(7) Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979-981.
(8) See Supporting Information for: Savarin, C.; Srogl, J.; Liebeskind,
L. S. Org. Lett. 2001, 3 (1), 91-93.
(11) Farina, V.; Krishnamurthy, V.; Scott, W. J. In Organic Reactions;
Paquette, L., Ed.; John Wiley & Sons: New York, 1997; Vol. 50, pp 1-652.
Mitchell, T. N. Synthesis 1992, 803-815. Stille, J. K. Angew. Chem., Int.
Ed. Engl. 1986, 25, 508-524.
(9) Neither the standard treatment with KF nor washing with an aqueous
NaOH solution was effective.
(10) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748-
2749.
(12) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585-9595.
3034
Org. Lett., Vol. 5, No. 17, 2003

a result of transmetalation from tin to copper.13 For these
cases, it proved to be highly beneficial to reduce the effective
concentration of Cu(I) in solution by the use of a 1:1 THF/
hexanes solvent mixture in which the copper(I) salts are
minimally soluble. For example, no ketonic product was
observed in the coupling of 2-(tri-n-butylstannyl)thiazole with
p-nitrobenzoic acid S-p-tolyl ester in THF alone as a solvent,
while with 1:1 THF/hexanes, the product was obtained in
69% isolated yield.
The requirement in this reaction for a stoichiometric Cu-
(I) carboxylate or diphenylphosphinate suggests that, at a
minimum, thiophilic activation of the acylpalladium(II)
thiolate is a necessary prerequisite for transmetalation from
tin to palladium (Scheme 1). Since CuCl does promote a
Scheme 1
For the most part, the reaction of thiol esters with
organostannanes follows the same reactivity pattern as the
previously described cross-coupling of thiol esters with
boronic acids; however, there are some differences that justify
the use of an organotin reaction system. For example, no
product was detected in several attempted couplings of
boronic acids with 2-amino-thiobenzoic acid S-p-tolyl ester,
while the corresponding organotin version of the reaction
furnished the desired product in high yield. Furthermore,
while various R-heteroatom heteroarylboronic acids are
problematic in cross-couplings (i.e, 2-pyridinylboronic acid),
the corresponding organostannanes couple efficiently.
Notably, the cross-coupling of S-lauroyl-4-mercaptotoluene
with 3-propenyl-tri-n-butylstannane at 50 °C for 1 h afforded
the desired â,γ-unsaturated ketone in 81% yield, although a
significantly diminished yield of the ketone resulted from
longer reaction times (37% after 18 h). The easy isolation
of the â,γ-unsaturated ketone using the present reaction
conditions underscores the utility of this new ketone syn-
thesis.14
low-yield conversion to ketone, it is unclear if concomitant
activation of the organostannane by the diphenylphosphinate
counterion is responsible for the superior yields in this
system.
In conclusion, a mild synthesis of ketones has been
described that takes place under neutral reaction conditions.
The reaction system consists of thiol esters and tri-n-
butylorganostannanes that couple in the presence of low
loadings of 1:8 Pd2(dba)3/TFP as the catalyst system and
1.2-2.2 equiv of Cu(I) diphenylphosphinate.
Acknowledgment. The National Institutes of General
Medical Sciences, DHHS, supported this investigation
through grant No. GM066153.
Supporting Information Available: Complete descrip-
tion of experimental details and product characterization. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L. S.
J. Org. Chem. 1994, 59, 5905-5911.
(14) Typical Experimental Procedure for (4-Nitrophenyl)-thiazol-2-
yl-methanone. 2-(Tri-n-butylstannyl)thiazole (131 mg, 1.1 equiv, 0.35
mmol), 4-nitrothiobenzoic acid S-p-tolyl ester (87 mg, 0.32 mmol), CuDPP
(120 mg, 1.2 equiv, 0.38 mmol), tri-2-furylphoshine (14 mg, 20 mol %, 64
µmol), and Pd2(dba)3 (7 mg, 2.5 mol %, 8 µmol) were placed in a Schlenk
tube under argon. A 1:1 mixture of dry THF and hexanes (2.5 mL each)
sparged with argon was added, and the mixture was heated to 40 °C. After
7 h, the mixture was filtered through a plug of Celite (washed with ether,
15 mL) and then evaporated. The residue was taken up in ethyl acetate (20
mL) and washed with aqueous NH3 solution (10%) and brine (20 mL each).
OL034962X
The organic phase was dried over MgSO4 and concentrated. Purification
of the residue by silica gel flash chromatography (hexanes f hexanes/
CH2Cl2 5:1 f hexanes/CH2Cl2 1:1) afforded 52 mg (69%) of the ketone
as a pale yellow solid: mp 121 °C; TLC (50% dichloromethane in hexanes,
Rf ) 0.42). Full spectroscopic details are provided in Supporting Information.
Org. Lett., Vol. 5, No. 17, 2003
3035