Palladium-catalyzed decarboxylation of allenyl 3-oxoalkanoates: An efficient synthesis of 3,4-allenyl ketones

Article abstract of DOI:10.1021/ol202786y

An efficient synthesis of 3,4-allenyl ketones via the Pd-catalyzed decarboxylative coupling of the readily available 3-oxoalkanoates is reported. The C-C bond forming reaction occurs under mild conditions producing CO ₂ as the only byproduct.

Full text of DOI:10.1021/ol202786y

ORGANIC
LETTERS
2012
Vol. 14, No. 1
46–49
Palladium-Catalyzed Decarboxylation
of Allenyl 3-Oxoalkanoates: An Efficient
Synthesis of 3,4-Allenyl Ketones
Baoqiang Wan,† Guochen Jia,*,‡ and Shengming Ma*,†,§
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032,
Department of Chemistry, the Hong Kong University of Science and Technology,
Clear Water Bay, Kowloon, Hong Kong, and Shanghai Key Laboratory of Green
Chemistry and Chemical Process, Department of Chemistry, East China Normal
University, 3663 North Zhongshan Lu, Shanghai 200062, P. R. China
*masm@sioc.ac.cn; chjiag@ust.hk
Received October 17, 2011
ABSTRACT
An efficient synthesis of 3,4-allenyl ketones via the Pd-catalyzed decarboxylative coupling of the readily available 3-oxoalkanoates is reported.
The CꢀC bond forming reaction occurs under mild conditions producing CO2 as the only byproduct.
Allenyl ketones are particularly attractive due to the
complementary reactivity of the carbonyl and allenyl groups
and used as versatile intermediates in various reactions,1 such
as electrophilic additions,2 nucleophilic additions,3 transition
metal-catalyzed cycloisomerizations,4 and electrochemical
reductive cyclization,5 etc. Thus, the development of new
methods for the synthesis of allenyl ketones is of high interest.
On the other hand, decarboxylative coupling reactions6 have
become a powerful method for the construction of CꢀC
(5) Pattenden, G.; Robertson, G. M. Tetrahedron Lett. 1983, 24,
4617.
† Chinese Academy of Sciences.
‡ The Hong Kong University of Science and Technology.
§ East China Normal University.
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€
r
10.1021/ol202786y
Published on Web 12/16/2011
2011 American Chemical Society

bonds, in part because these reactions may occur under
neutral conditions and produce CO2 as the only byproduct.
Notable examples of Pd-catalyzed decarboxylative coupling
reactions include decarboxylative alkylation,7 decarboxyl-
ative Heck coupling,8 aldol addition,9 decarboxylative cross-
coupling,10 etc. In 2008, Chung et al. reported the synthesis of
2-alkynyl buta-1,3-dienes by decarboxylation of buta-2,3-
dienyl 20-alkynoates (Scheme 1).11 We envisioned that such
a strategy of decarboxylation of allenyl 3-oxoalkanoates
would allow a convenient route to dienyl or allenyl ketones
via an R-methylene π-allylpalladium intermediate
(Scheme 1).6d,7o To the best of our knowledge, the synthesis
of 3,4-allenyl ketones has not been well established: they may
be prepared by the reactions of enolates1c or imines5 with the
alkylating agents, usually allenic chlorides or tosylates, using
a strong base at low temperature. For the alcohol-oxidation
approach, it is difficult to synthesize the corresponding 3,4-
allenyl carbinols.12 Thus, there is still a strong need for the
development of a convergent synthesis of 3,4-allenyl ketones
under mild conditions from readily available starting materials.
Herein, we disclose such an efficient protocol to construct
3,4-allenyl ketones under mild conditions from the easily
available allenyl 3-oxoalkanoates.
1,3-dienyl ketone 3a (Table 1, entry 1). An initial catalyst
screening revealed that Pd(OAc)2/PPh3, Pd(dba)2/PPh3,
and Pd(dba)2/LB-phos systems show similar results as Pd-
(PPh3)4 (Table 1, entries 2ꢀ4). However, the reaction
afforded the allenyl ketone 2a in 33% isolated yield as the
only product by using Pd(dba)2/dppf as the catalyst
(Table 1, entry 5). Encouraged by this result, a series of
ligands, such as dppe, binap, MeOBIPHEP, Xantphos, and
DPEphos were screened for this transformation (Table 1,
entries 6ꢀ10). Among them, DPEphos was shown to be the
best with 2a being formed in 59% isolated yield, and the
formation of dienyl ketone 3a was not observed. In this case,
1-vinylalkyne 4a was also formed in 17% NMR yield
(Table 1, entry 10).
Using 5 mol % Pd(dba)2 and 5 mol % DPEphos as the
catalyst, subsequent comprehensive study on the solvent
effect indicated that the reaction may proceed smooth-
ly in all the tested solvents (Table 2): the reaction in
t-BuOH afforded the best result with 2a being formed
in 66% isolated yield (Table 2, entry 10). By conducting
the reaction at 25 °C, the yield of 2a was improved to
77% although the reaction time was longer. In addition,
the formation of 4a was reduced to 6% NMR yield
(Table 2, entry 11). Thus, the following optimized
reaction conditions, i.e., 5 mol % Pd(dba)2, 5 mol %
DPEphos, t-BuOH, and 25 °C (Table 2, entry 11), were
established for further study.
Scheme 1. Decarboxylation Reactions via an R-Methylene
π-Allylpalladium Intermediate
Table 1. Effect of Catalysts on the Decarboxylation of 1aa
NMR yield (%)b
ligand
time
(h)
entry
catalyst
(x/mol %)
2a
4a
1
2
Pd(PPh3)4
Pd(OAc)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
ꢀ
21
complicated
complicated
complicated
complicated
(33)c
PPh3 (15)
21
To test our hypothesis, allenyl 3-oxoalkanoate 1a was
conveniently synthesized from readily available β-methy-
lene-β-lactone13 and the allenyl alcohol. When it was heated
in THF at 50 °C in the presence of Pd(PPh3)4, the reaction
failed to afford either the expected allenyl ketone 2a or the
3
PPh3 (15)
21
4
LB-phos (15)
dppf (5)
33
5
5.5
2.2
2.3
1.5
1.2
0.5
ꢀ
6
dppe (5)
<14
ꢀ
7
binap (5)
30
19
16
16
17
8
MeOBIPHEP (5)
Xantphos (5)
DPEphos (5)
<48
9
57
66 (59)c
(8) (a) Myers, A. G.; Tanaka, D.; Mannion, M. R. J. Am. Chem. Soc.
2002, 124, 11250. (b) Tanaka, D.; Myers, A. G. Org. Lett. 2004, 6, 433.
(9) Lou, S.; Westbrook, J. A.; Schaus, S. E. J. Am. Chem. Soc. 2004,
126, 11440.
(10) (a) Goossen, L. J.; Rodriguez, N.; Melzer, B.; Linder, C.; Deng,
G.; Levy, L. M. J. Am. Chem. Soc. 2007, 129, 4824. (b) Becht, J.-M.;
Catala, C.; Drian, C. L.; Wagner, A. Org. Lett. 2007, 9, 1781.
(c) Goossen, L. J.; Melzer, B. J. Org. Chem. 2007, 72, 7473.
(11) Sim, S. H.; Park, H.-J.; Lee, S. L.; Chung, Y. K. Org. Lett. 2008,
10, 433.
10
a Under argon, a mixture of 1a (0.2 mmol) and the indicated catalyst
in 2 mL of THF was stirred at 50 °C. b The yield was determined by 1H
NMR analysis using 1,3,5-trimethylbenzene as the internal standard.
c The numbers shown in the parentheses are the isolated yields of 2a.
(12) (a) Lotesta, S. D.; Hou, Y.; Williams, L. J. Org. Lett. 2007, 9,
869. (b) Zhang, X.; Ko, R. Y. Y.; Li, S.; Miao, R.; Chiu, P. Synlett 2006,
1197.
(13) (a) Wilson, S. R.; Augelli, C. E. Org. Synth. 1990, 68, 210.
(b) Wan, B.; Jia, G.; Ma, S. Adv. Synth. Catal. 2011, 353, 1763.
Org. Lett., Vol. 14, No. 1, 2012
47

As is known, enallenes, allenynes, and bisallenes are
useful substrates in organic synthesis.14ꢀ17 The enallenes
2eꢀ2i could be obtained in moderate to good yields
starting from 2-allylic substituted substrates 1eꢀ1i (Table 4).
The diastereoisomer ratio of 2eꢀ2g is about 1:1.
Table 2. Effect of Solvent on the Decarboxylation of 1aa
Table 4. Synthesis of 2-Allylic Substituted 3,4-Allenyl Ketones
by Decarboxylative Coupling of 1a
NMR yield (%)b
time
entry
solvent
(h)
2a
4a
1
THF
0.5
0.6
0.6
0.6
0.6
0.6
0.6
0.6
8
66 (59)c
63
17
18
18
13
15
19
15
18
4
2
Dioxane
DME
3
62
4
Toluene
Benzene
CH3CN
MTBE
DMF
59
1
5
58
6
66
time
(h)
isolated yield
entry
R1
R2
of 2 (%)
7
59
8
65
1
n-C9H19
cyclohexyl
tert-butyl
H
H (1e)
4
72 (2e)
74 (2f)
48 (2g)
70 (2h)
60 (2i)
9
EtOH
55
2
H (1f)
5.5
0.8
7.5
3
10
11d
t-BuOH
t-BuOH
0.6
6.5
70 (66)c
80 (77)c
10
6
3b
4
H (1g)
Ph (1h)
CO2Me (1i)
a Under argon, the reaction was carried out with 1a (0.2 mmol),
Pd(dba)2 (5 mol %), and DPEphos (5 mol %) in solvent (2 mL). b The
yield was determined by 1H NMR analysis using 1,3,5-trimethylbenzene
as the internal standard. c The numbers shown in the parentheses are the
isolated yields. d The reaction was carried out at 25 °C.
5
H
a Under argon, the reaction was carried out with 1 (0.4 mmol),
Pd(dba)2 (5 mol %), and DPEphos (5 mol %) in solvent (2 mL). b THF
was used as the solvent.
Then the substrate scope and generality of the reaction was
investigated (Table 3): the reaction of allenyl 3-oxoalkanoates
bearing a substituent at the terminal position of allenyl moieties
1aꢀ1c afforded the corresponding 3,4-allenyl ketones 2aꢀ2c
as a mixture of ∼1:1 diastereoisomers in 63ꢀ76% isolated
yields; the reaction of 1d with a terminal allene unit afforded
the corresponding 3,4-allenyl ketone in 62% isolated yield; in
addition, the reaction of 1a proceeded smoothly to afford the
allenyl ketone 2a on a 1 g scale in 77% yield (Table 3, entry 2).
Allenyne 2j could be obtained in 45% isolated yield
when THF was used as the solvent instead of t-BuOH
(Scheme 2). In addition, the 2-(2,3-allenyl) substituted
oxoalkanoate 1k could be applied in the transformation
affording the bisallene 2k as a mixture of ∼1:1 diaster-
eoisomers in 67% yield (Scheme 2).
Scheme 2. Synthesis of Allenyne 2j and Bisallene 2k by
Decarboxylative Coupling of 1j and 1k
Table 3. Decarboxylative Coupling of 2-Oxoalkanoate 1a
1
time
(h)
isolated yield
entry
R1
R2
of 2 (%)
1
n-C9H19
n-C9H19
n-C9H19
n-C4H9
H
CH3 (1a)
CH3 (1a)
Bn (1b)
Bn (1c)
Bn (1d)
5
76 (2a)
77 (2a)
65 (2b)
63 (2c)
62 (2d)
(15) For selected examples of cyclization of enallenes, see: (a) Teller,
€
2b
3
3
€
H.; Flugge, S.; Goddard, R.; Furstner, A. Angew. Chem., Int. Ed. 2010,
€
49, 1949. (b) Alcarazo, M.; Stork, T.; Anoop, A.; Thiel, W.; Furstner, A.
4
Angew. Chem., Int. Ed. 2010, 49, 2542. (c) Zhao, J.-F.; Loh, T.-K.
Angew. Chem., Int. Ed. 2009, 48, 7232.
(16) For selected examples of cyclization of allenynes, see: (a) Inagaki,
F.; Sugikubo, K.; Miuashita, Y.; Mukai, C. Angew. Chem., Int. Ed. 2010,
49, 2206. (b) Siebert, M. R.; Osbourn, J. M.; Brummond, K. Y.; Tatillo,
D. J. J. Am. Chem. Soc. 2010, 132, 11952. (c) Saito, N.; Tanala, Y.; Sato, Y.
Org. Lett. 2009, 11, 4124.
4
4.5
2.5
5
a Under argon, the reaction was carried out with 1 (0.4 mmol),
Pd(dba)2 (5 mol %), and DPEphos (5 mol %) in solvent (2 mL). b The
reaction was carried out on a 1 g scale.
(17) For selected examples of cyclization of bisallenes, see: (a) Ma, S.;
Lu, P.; Lu., L.; Hou, H.; Wei, J.; He, Q.; Gu, Z.; Jiang, X.; Jin, X. Angew.
Chem., Int. Ed. 2005, 44, 5275. (b) Jiang, X.; Cheng, X.; Ma, S. Angew.
Chem., Int. Ed. 2005, 45, 8009. (c) Lu., L.; Ma, S. Org. Lett. 2007, 9, 2095.
(14) Ma, S. Chem. Rev. 2005, 105, 2829.
48
Org. Lett., Vol. 14, No. 1, 2012

In addition, the reaction of 2-unsubstituented 3-oxo-
alkanoates 1l afforded the monoallenylation product 2l
together with the diallenylation product 2m in 41% and
27% isolated yields, respectively (eq 1).18
Scheme 3. Decarboxylative Coupling of Cyclic Substrates
1pꢀ1r
Unfortunately, reactions of the substrates 1mꢀ1o were
complicated and failed to afford the corresponding de-
carboxylation products (Figure 1).
both the carbonyl and allenyl moieties as well as the
unsaturated CꢀC bond introduced by the substitu-
tion at the 2-position, this method will be useful for
further application in organic synthesis. Further stud-
ies in this area including asymmetric synthesis of 3,4-
allenyl ketones via this protocol are ongoing in our
laboratory.
Figure 1. Other 3-oxoalkanoates tested for decarboxylation.
While the previous examples have focused on alkyl-
ation of acyclic 3-oxoalkanoates, the decarboxylative
coupling of cylic substrates is also investigated. To our
delight, the reaction of 3-oxoalkanoates 1pꢀ1r also af-
forded the corresponding allenyl ketones 2nꢀ2p in 71%,
74%, and 71% isolated yields, respectively (Scheme 3).
In conclusion, we have developed an efficient Pd-
catalyzed decarboxylative coupling protocol for the
synthesis of 3,4-allenyl ketones. The reaction occurs
under mild conditions without external bases and pro-
duces CO2 as the only byproduct. Due to the existence of
Acknowledgment. Financial support from National Ba-
sic Research Program of China (2011CB808700) and
National Nature Science Foundation of China (NO.
20732005) is greatly appreciated. We thank B. Guo in
our group for reproducing the results of entry 4 in Table 3,
entry 5 in Table 4, 2k in Scheme 2, and 2o in Scheme 3
presented in this study.
Supporting Information Available. Analytical data
for all products not listed in the text. This material is
available free of charge via the Internet at http://
pubs.acs.org.
(18) The formation of diallylated product in decarboxylation allyl-
ation has been reported by Tsuji and co-workers; see ref 7b.
Org. Lett., Vol. 14, No. 1, 2012
49