Gold-catalyzed synthesis of benzil derivatives and α-keto imides via oxidation of alkynes

Article abstract of DOI:10.1021/ol200270t

An efficient process based on the gold-catalyzed redox reaction has been developed to oxidize 1,2-diarylacetylene or ynamide to 1,2-diaryldiketone or α-keto imide respectively. This process can tolerate a variety of functional groups and affords 1,2-dicarbonyl compounds in excellent yields under mild reaction conditions.

Full text of DOI:10.1021/ol200270t

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1556–1559
Gold-Catalyzed Synthesis of Benzil
Derivatives and r-Keto Imides via
Oxidation of Alkynes
Cheng-Fu Xu,† Mei Xu,† Yi-Xia Jia,‡ and Chuan-Ying Li*,†
Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou 310018, China, and
The State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology,
Zhejiang University of Technology, Hangzhou 310014, China
licy1218@gmail.com
Received January 27, 2011
ABSTRACT
An efficient process based on the gold-catalyzed redox reaction has been developed to oxidize 1,2-diarylacetylene or ynamide to 1,2-
diaryldiketone or R-keto imide respectively. This process can tolerate a variety of functional groups and affords 1,2-dicarbonyl compounds in
excellent yields under mild reaction conditions.
1,2-Dicarbonyl functionalities are found in numerous
bioactive natural products.1 Moreover, they are versatile
building blocks in a string of chemical transforma-
tions.2 Several synthetic strategies have been reported
to obtain this useful structure, such as oxidation of
carbon substituted alkynes3 or heteroatom substituted
alkynes,4 oxidation of R-hydroxyketones,5 substitution
of oxalyl chloride or R-keto acid chloride,6 and some
other transformations.7 However, several drawbacks
such as low chemoselectivity, high toxicity, and low
functionality tolerance are still issues in this area.
Consequently, the development of general and conve-
nient methods for construction of 1,2-dicarbonyl deri-
vatives are of great importance.
In the past decade, gold-catalyzed transformations have
attracted considerable attention due to their strong π
acidity for the activation of unsaturated carbon carbon
bonds toward nucleophilic attack.8 The stability of gold
catalysts to air and moisture renders gold catalysis a straight-
forward protocol in modern synthesis. Recently, gold-
catalyzed redox procedures using sulfoxide and amine-N-
oxide as the oxidant have been reported.9 In the reactions,
alkynes are employed as a precursor of R-carbonyl gold-
carbenoids, which bypasses the use of potentially explosive
diazo compounds (Scheme 1a). We envisioned that the
hypothetic R-carbonyl gold-carbenoids C could be oxidized
† Zhejiang Sci-Tech University.
‡ Zhejiang University of Technology.
(1) For selected examples, see: (a) Rozwadowska, M. D.; Chrzanowska,
M. Tetrahedron 1985, 41, 2885. (b) Angelstro, M. R.; Mehdi, S.; Burkhart,
J. P.; Peet, N. P.; Bey, P. J. Med. Chem. 1990, 33, 11. (c) Maurya, R.; Singh,
R.; Deepak, M.; Handa, S. S.; Yadav, P. P.; Mishra, P. K. Phytochemistry
2004, 65, 915. (d) Mahabusarakam, W.; Deachathai, S.; Phongpaichit, S.;
Jansakul, C.; Taylor, W. C. Phytochemistry 2004, 65, 1185. (e) Nicolaou,
K. C.;Gray, D. L. F.;Tae, J. J. Am. Chem. Soc. 2004, 126, 613. (f)Wadkins,
R. M.; Hyatt, J. L.; Wei, X.; Yoon, K. J. P.; Wierdl, M.; Edwards, C. C.;
Morton, C. L.;Obenauer, J. C.; Damodaran, K.;Beroza, P.;Danks, M. K.;
Potter, P. M. J. Med. Chem. 2005, 48, 2906.
(2) For recent examples, see: (a) Wolkenberg, S. E.; Wisnoski, D. D.;
Leister, W. H.; Wang, Y.; Zhao, Z.; Lindsley, C. W. Org. Lett. 2004, 6,
1453. (b) Shipe, W. D.; Yang, F.; Zhao, Z.; Wolkenberg, S. E.; Nolt,
M. B.; Lindsley, C. W. Heterocycles 2006, 70, 655. (c) Deng, X.; Mani, N.
Org. Lett. 2006, 8, 269. (d) Held, I.; Xu, S. J.; Zipse, H. Synthesis 2007,
1185. (e) Rong, F.; Chow, S.; Yan, S.; Larson, G.; Hong, Z.; Wu, J.
(3) For recent examples on synthesis of 1,2-diketones, see: (a)
Katriszky, A. R.; Zhang, D.; Kirichenko, K. J. Org. Chem. 2005, 70,
3271. (b) Giraud, A.; Provot, O.; Peyrat, J.-F.; Alami, M.; Brion, J.-D.
Tetrahedron 2006, 62, 7667. (c) Wan, Z.; Jones, C. D.; Mitchell, D.; Pu,
J. Y.; Zhang, T. Y. J. Org. Chem. 2006, 71, 826. (d) Mousset, C.; Provot,
O.; Hamze, A.; Bignon, J.; Brion, J.-D.; Alami, M. Tetrahedron 2008, 64,
4287. (e) Niu, M.; Fu, H.; Jiang, Y.; Zhao, Y. Synthesis 2008, 2879. (f)
Tan, K. J.; Wille, U. Chem. Commun. 2008, 6239. (g) Chu, J.-H.; Chen,
Y.-J.; Wu, M.-J. Synthesis 2009, 2155. (h) Ren, W.; Xia, Y.; Ji, S.-J.;
Zhang, Y.; Wan, X.; Zhao, J. Org. Lett. 2009, 11, 1841. (i) Ren, W.; Liu,
J.; Chen, L.; Wan, X. Adv. Synth. Catal. 2010, 352, 1424. (j) Mori, S.;
Takubo, M.; Yanase, T.; Maegawa, T.; Monguchi, Y.; Sajiki, H. Adv.
Synth. Catal. 2010, 352, 1630.
ꢀ
Bioorg. Med. Chem. Lett. 2007, 17, 1663. (f) Herrera, A. J.; Rondon, M.;
ꢀ
Suarez, E. J. Org. Chem. 2008, 73, 3384. (g) Boyce, G. R.; Johnson, J. S.
Angew. Chem., Int. Ed. 2010, 49, 8930.
r
10.1021/ol200270t
Published on Web 02/18/2011
2011 American Chemical Society

Table 1. Optimization of Reaction Conditionsa
Scheme 1. Initial Hypothesis
by the same oxidant B (Scheme 1b, sulfoxide or amine-N-
oxide). Thus, 1,2-dicarbonyl compounds D can be synthe-
sized from alkynes and very mild oxidants, which offers a
new method to access useful 1,2-dicarbonyl compounds.10
catalyst
sulfoxide
(equiv)
temp yieldb
entry
(4 mol %)
solvent
(°C)
(%)
1
4
3a (3.0)
3a (3.0)
3a (3.0)
3a (3.0)
3a (3.0)
3a (3.0)
3a (3.0)
3a (3.0)
3b (3.0)
3c (3.0)
3d (3.0)
3e (3.0)
3a (2.0)
3a (4.0)
3a (3.0)
3a (3.0)
3a (3.0)
3a (3.0)
3a (3.0)
3a (3.0)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
rt
0
19
3
2
Ph3PAuCl/AgSbF6
5/AgSbF6
rt
(4) For recent reviews on synthesis and reaction of ynamides, see: (a)
Evano, G.; Coste, A.; Jouvin, K. Angew. Chem., Int. Ed. 2010, 49, 2840.
(b) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang,
Y.; Hsung, R. P. Chem. Rev. 2010, 110, 5064. For a recent example on
synthesis of R-keto imides, see: (c) Al-Rashid, Z. F.; Johnson, W. L.;
Hsung, R. P.; Wei, Y.; Yao, P.-Y.; Liu, R.; Zhao, K. J. Org. Chem. 2008,
73, 8780. For a related example on synthesis of R-keto amides, see:
(d) Zhang, C.; Jiao, N. J. Am. Chem. Soc. 2010, 132, 28.
(5) (a) Kirihara, M.; Ochiai, Y.; Takizawa, S.; Takahata, H.; Nemoto,
H. Chem. Commun. 1999, 1387. (b)Tymonko, S. A.; Nattier, B. A.;Mohan,
R. S. Tetrahedron Lett. 1999, 40, 7657. (c) Okimoto, M.; Takahashi, Y.;
Nagata, Y.; Sasaki, G.; Numata, K. Synthesis 2005, 705. (d) Joo, C.; Kang,
S.; Kim, S. M.; Han, H.; Yang, J. W. Tetrahedron Lett. 2010, 51, 6006.
3
rt
4
AuCl3/AgSbF6
AuCl/AgSbF6
AuCl/AgSbF6
AuCl/AgSbF6
AuCl/AgSbF6
AuCl/AgSbF6
AuCl/AgSbF6
AuCl/AgSbF6
AuCl/AgSbF6
AuCl/AgSbF6
AuCl/AgSbF6
rt
11
63
73
81
93
68
0
5
rt
6
rt
7
DCE
60
85
85
85
85
85
85
85
85
85
85
85
85
85
8
DCE
9
DCE
10
11
12
13
14
15
16
17
18
19e
20e,f
DCE
DCE
9
DCE
17
67
91
69
96
7
DCE
ꢀ
ꢀ
(6) (a) Sanz, R.; Castroviejo, M. P.; Guilarte, V.; Perez, A.; Fananas,
F. J. J. Org. Chem. 2007, 72, 5113. (b) Maresh, J. J.; Giddings, L.-A.;
Friedrich, A.; Loris, E. A.; Panjikar, S.; Trout, B. L.; Stockigt, J.; Peters,
B.; O’Connor, S. E. J. Am. Chem. Soc. 2008, 130, 710. (c) Kashiwabara,
T.; Tanaka, M. J. Org. Chem. 2009, 74, 3958.
DCE
c
AuCl/AgSbF6
DCE
d
AuCl/AgSbF6
DCE
AuCl
DCE
(7) For recent examples, see: (a) Allais, C.; Constantieux, T.; Rodriguez,
J. Synthesis 2009, 2523. (b) Tada, N.; Shomura, M.; Nakayama, H.; Miura,
T.; Itoh, A. Synlett 2010, 1979. (c) Bouma, M.; Masson, G.; Zhu, J. J. Org.
Chem. 2010, 75, 2748. (d) Mossetti, R.; Pirali, T.; Tron, G. C.; Zhu, J. Org.
Lett. 2010, 12, 820.
AgSbF6
DCE
0
AuCl/AgSbF6
AuCl/AgSbF6
DCE
94
95
DCE
€
a All reactions were carried out under an atmosphere of nitrogen in
2 mL of dry solvent. The flask was covered by aluminum foil. 0.2 mmol
scale. b Isolated yield. c 2 mol % of catalysts. d 6 mol % of catalysts. e No
aluminum foil covered. f The reaction was conducted in the air with
solvent of technical grade.
(8) For selected reviews, see: (a) Furstner, A.; Davies, P. W. Angew.
Chem., Int. Ed. 2007, 46, 3410. (b) Hashmi, A. S. K. Chem. Rev. 2007,
107, 3180. (c) Shen, H. C. Tetrahedron 2008, 64, 3885. (d) Skouta, R.; Li,
C.-J. Tetrahedron 2008, 64, 4917. (e) Muzart, J. Tetrahedron 2008, 64,
5815. (f) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239. (g)
ꢀ
ꢀ
Arcadi, A. Chem. Rev. 2008, 108, 3266. (h) Jimenez- Nunez, E.;
Echavarren, A. M. Chem. Rev. 2008, 108, 3326. (i) Gorin, D. J.; Sherry,
B. D.; Toste, F. D. Chem. Rev. 2008, 108, 3351. (j) Hashmi, A. S. K.;
Rudolph, M. Chem. Soc. Rev. 2008, 37, 1766. (k) Michelet, V.; Toullec,
To test the feasibility of this idea, 1,2-diphenylacetylene
1a and 3 equiv of diphenylsulfoxide 3a were treated with
various gold and silver catalyst systems in CH2Cl2 at room
temperature (Table 1, entries 1-5). When 4 mol % of
AuCl/AgSbF6 was used, the benzil could be obtained in
63% yield (entry 5). Solvent also has a great impact on the
reaction yield;11 ClCH2CH2Cl was the optimal solvent
under our screened conditions (entry 6). The yield was
further improved to 93% by raising the reaction tempera-
ture to 85 °C (entry 8). Among the sulfoxides we examined,
the diphenylsulfoxide was the best one (entries 8-12). The
effect of the loading of catalyst and sulfoxide was also
investigated; 4 mol % of catalyst and 3 equiv of diphenyl-
sulfoxide gave the highest yield (entries 13-16). Control
experiments indicated that both AuCl and AgSbF6 were
^
€
P. Y.; Genet, J. P. Angew. Chem., Int. Ed. 2008, 47, 4268. (l) Furstner, A.
Chem. Soc. Rev. 2009, 38, 3208.
(9) For intramolecular reaction, see: (a) Gorin, D. J.; Davis, N. R.;
Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260. (b) Shapiro, N. D.;
Toste, F. D. J. Am. Chem. Soc. 2007, 129, 4160. (c) Li, G.; Zhang, L.
Angew. Chem., Int. Ed. 2007, 46, 5156. (d) Yeom, H.-S.; Lee, J.-E.; Shin,
S. Angew. Chem., Int. Ed. 2008, 47, 7040. (e) Cui, L.; Peng, Y.; Zhang, L.
J. Am. Chem. Soc. 2009, 131, 8394. (f) Davies, P. W.; Albrecht, S. J.-C.
Angew. Chem., Int. Ed. 2009, 48, 8372. (g) Cui, L.; Zhang, G.; Peng, Y.;
Zhang, L. Org. Lett. 2009, 11, 1225. (h) Yeom, H.-S.; Lee, Y.; Jeong, J.;
So, E.; Hwang, S.; Lee, J.-E.; Lee, S. S.; Shin, S. Angew. Chem., Int. Ed.
2010, 49, 1611. For intermolecular reaction, see: (i) Cuenca, A. B.;
Montserrat, S.; Hossain, K. M.; Mancha, G.; Lledos, A.; Medio-Simon,
M.; Ujaque, G.; Asensio, G. Org. Lett. 2009, 11, 4906. (j) Ye, L.; Cui, L.;
Zhang, G.; Zhang, L. J. Am. Chem. Soc. 2010, 132, 3258. (k) Ye, L.; He,
W.; Zhang, L. J. Am. Chem. Soc. 2010, 132, 8550. (l) Lu, B.; Li, C.;
Zhang, L. J. Am. Chem. Soc. 2010, 132, 14070. (m) Li, C.-W.; Pati, K.;
Lin, G.-Y.; Sohel, S. M. A.; Hung, H.-H.; Liu, R.-S. Angew. Chem., Int.
Ed. 2010, 49, 9891. For other recent reports on synthesis of R-keto
carbenoids from alkynes, see: (n) Couty, S.; Meyer, C.; Cossy, J. Synlett
2007, 2819. (o) Al-Rashid, Z. F.; Hsung, R. P. Org. Lett. 2008, 10, 661.
(10) 1,2-Diketones have been observed as byproducts in the reports
by the Zhang and Liu groups; for references, see ref 9l and 9m.
(11) A 24% yield was observed when the reaction was performed in
toluene. No benzil was obtained when the reaction was conducted in
THF or CH3CN.
Org. Lett., Vol. 13, No. 6, 2011
1557

necessary for the high yield (entries 17 and 18). It is
noteworthy that the reaction can be conducted in air with
solvent of technical grade (entry 20).
With the optimal conditions in hand, the substrate scope
was then examined. As shown in Table 2, high yield can be
observed when oxidizing the diarylalkynes and ynamides
to 1,2-diaryldiketones and R-keto imides respectively.
Functional groups such as methyl ether, bromide, fluoride,
and ketone are well tolerated. 1,2-Dicarbonyl compounds
bearing a bromide on the phenyl ring were obtained in
more than 90% yield (entries 4 and 12), which can be further
functionalized by a cross coupling reaction. The reaction
proceeded smoothly when the aryl group was substituted
with a methoxy group, but a slightly low yield compared to
other substrates was achieved (entries 3 and 11).
Table 2. Oxidation of Various 1,2-Diarylalkynes or Ynamides
to 1,2-Dicarbonyl Compoundsa
Scheme 2. Preliminary Study on Mechanism
To clarify the reaction mechanism, 10 equiv of styrene
were used to trap the hypothetic gold carbenoid (Scheme 2).
Only 40% of the 1,2-dicarbonyl compound 2i could be
obtained without any cyclopropane product, which may
suggest that no free gold carbenoid was formed. In the
gold-catalyzed redox reactions, Toste9b and Zhang9c have
previously proposed a gold carbenoid intermediate in the
intramolecular reactions. However, in the crossover experi-
ments performed by Ujaque, Asensio,9i and Liu group,9m
no products which incorporate the external sulfides were
detected, thus excluding the formation of an R-carbonyl
gold-carbenoid. We synthesized the substrate 1m and
subjected it to the optimal reaction conditions, and
Scheme 3. Proposed Catalytic Cycle
a The reaction was conducted in the air with solvent of technical
grade. 0.2 mmol substrate and 0.6 mmol diphenylsulfoxide in 2.0 mL of
ClCH2CH2Cl. b Isolated yield.
1558
Org. Lett., Vol. 13, No. 6, 2011

cyclobutene derivative 6, the same product that resulted
forthe Liugroup,9m was obtainedin49% yield (Scheme2),
which means our oxidation procedure should have a
similar mechanism as that reported by Liu. Furthermore,
O2 should not be the oxidizing species since similar results
were achieved when the reaction proceeded either in the air
or in the N2 atmosphere (Table 1, entry 8 vs 20).
Based on the above facts, we envision that coordination
of the cationic Au(I) to the alkyne facilitates the attack of
sulfoxide, which results in the formation of vinyl gold
species F (Scheme 3). The nucleophilic addition of another
molecule of sulfoxide to F12 followed by the loss of
diphenyl sulfide would afford intermediate G. Subse-
quently, Au(I)-assisted sulfide release produces the 1,2-
dicarbonyl compound 2 and regenerates the catalyst.
In summary, we have developed an efficient process for
oxidizing alkynes to the 1,2-dicarbonyl compounds based
on the gold-catalyzed redox reaction. Various 1,2-diaryl-
diketones or R-keto imides bearing sensitive functional
groups can be obtained in high to excellent yields under
mild reaction conditions. Furthermore, due to easy access
to a variety of substrates by Sonogashira coupling13 or
copper mediated amidation of bromoalkynes or terminal
acetylenes,14 this work provides a very straightforward
method to achieve useful 1,2-dicarbonyl functionality
from simple materials. Further investigation on details of
the mechanism is ongoing in our laboratory.
(12) For a related report on nucleophilic attack on vinyl gold species,
see 9m.
(13) (a) Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara,
N. Synthesis 1980, 8, 627. (b) Doucet, H.; Hierso, J.-C. Angew. Chem.,
ꢀ
Int. Ed. 2007, 46, 834. (c) Chinchilla, R.; Najera, C. Chem. Rev. 2007,
107, 874.
(14) For copper mediated amidation of bromoalkynes, see: (a)
Frederick, M. O.; Mulder, J. A.; Tracey, M. R.; Hsung, R. P.; Huang,
J.; Kurtz, K. C. M.; Shen, L.; Douglas, C. J. J. Am. Chem. Soc. 2003, 125,
2368. (b) Dunetz, J. R.; Danheiser, R. L. Org. Lett. 2003, 5, 4011. (c)
Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz, K. C. M.; Vera, E. L.
Org. Lett. 2004, 6, 1151. (d) Riddell, N.; Villeneuve, K.; Tam, W. Org.
Lett. 2005, 7, 3681. (e) Zhang, X.; Zhang, Y.; Huang, J.; Hsung, R. P.;
Kurtz, K. C. M.; Oppenheimer, J.; Petersen, M. E.; Sagamanova, I. K.;
Tracey, M. R. J. Org. Chem. 2006, 71, 4170. (f) Kohnen, A. L.; Dunetz,
J. R.; Danheiser, R. L. Org. Synth. 2007, 84, 88. (g) Sagamanova, I. K.;
Kurtz, K. C. M.; Hsung, R. P. Org. Synth. 2007, 84, 359. (h) Dooleweerdt,
K.; Birkedal, H.; Ruhland, T.; Skrydstrup, T. J. Org. Chem. 2008, 73, 9447.
For copper mediate amidation of terminal acetylenes, see: (i) Hamada, T.;
Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833.
Acknowledgment. This work was generously sup-
ported by the National Natural Science Foundation
of China (21002091) and Zhejiang Sci-Tech University
(11432732611043, 11110032251010).
Supporting Information Available. Experimental pro-
cedures, characterization data, and NMR spectra for new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 6, 2011
1559