Tandem reactions of 1,2-allenic ketones leading to substituted benzenes and α,β-unsaturated nitriles

Article abstract of DOI:10.1021/ol201789z

One-pot double Michael addition/intramolecular aldol reaction/ decarboxylation of 1,2-allenic ketones with cyanoacetate offers an efficient and convenient approach to highly functionalized benzenes. With 2-substituted cyanoacetates, the reaction proceeds via a different tandem process to afford α,β-unsaturated nitriles effectively.

Full text of DOI:10.1021/ol201789z

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5024–5027
Tandem Reactions of 1,2-Allenic Ketones
Leading to Substituted Benzenes and
r,β-Unsaturated Nitriles
Xinying Zhang,* Xuefei Jia, Liangliang Fang, Nan Liu, Jianji Wang, and Xuesen Fan*
School of Chemistry and Environmental Science, Key Laboratory of Green Chemical
Media and Reactions, Ministry of Education, Henan Key Laboratory for Environmental
Pollution Control, Henan Normal University, Henan 453007, P. R. China
xuesen.fan@henannu.edu.cn; xinyingzhang@henannu.edu.cn
Received July 4, 2011
ABSTRACT
One-pot double Michael addition/intramolecular aldol reaction/decarboxylation of 1,2-allenic ketones with cyanoacetate offers an efficient and
convenient approach to highly functionalized benzenes. With 2-substituted cyanoacetates, the reaction proceeds via a different tandem process
to afford R,β-unsaturated nitriles effectively.
1,2-Allenic ketones are versatile and useful synthetic
intermediates.1,2 Meanwhile, the Michael addition reaction is
among the most powerful methods for the formation of
carbonÀcarbon or carbonÀheteroatom bonds.3 During
our studies in utilizing the Michael addition reactions
of allenic ketones to prepare compounds with biological
and synthetic interest,4 we serendipitously discovered
some unprecedented reactions of 1,2-allenic ketones with
cyanoacetate or 2-substituted cyanoacetates. From these
reactions, efficient and convenient syntheses of polysubsti-
tuted benzenes and R,β-unsaturated nitriles were successfully
developed.
Our initial objective was to prepare pyroneÀnucleoside
hybrids as potential antiviral candidates. The proposed
synthesis is based on an elegant strategy toward R-pyrones
developed by Ma et al.5 For this purpose, 1-(4-bromophenyl)-
buta-2,3-dien-1-one (1a) and diethyl malonate (2) were
used as model substrates, and they afforded the desired
R-pyrone (3) smoothly under standard conditions
(Scheme 1).5 When diethyl malonate was replaced by ethyl
cyanoacetate (4), however, we did not get the expected
cyano substituted R-pyrone (5). Surprisingly, a biphenyl,
1-(4-bromobenzoyl)-4-(4-bromophenyl)-3-cyano-2,6-di-
methyl benzene (6a) was obtained. The structure of 6a was
confirmed by its spectroscopic data together with X-ray
diffraction analysis (Figure 1).
(1) (a) Ma, S. Acc. Chem. Res. 2003, 36, 701. (b) Krause, N.; Hashmi,
A. S. K. Modern Allene Chemistry; WILEY-VCH: Weinheim: 2004; Vol. 2,
Chapter 10. (c) Ma, S. Chem. Rev. 2005, 105, 2829. (d) Ma, S.
Aldrichimica Acta 2007, 40, 91. (e) Schuster, H. F.; Coppola, G. M.
The unexpected formation of 6a not only reveals an
unprecedented and interesting transformation of allenic
ketones but also offers a promising pathway toward
€
Allenes in Organic Synthesis; Wiley: New York, 1984. (f) Hoffmann-Roder,
A.; Krause, N. Angew. Chem., Int. Ed. 2004, 43, 1196.
(2) (a) Alcaide, B.; Almendros, P.; del Campo, T. M. Chem.;Eur. J.
2010, 16, 5836. (b) Zhou, C.-Y.; Chan, P. W. H.; Che, C.-M. Org. Lett.
2006, 8, 325. (c) Ma, S.; Yu, Z. Q. Angew. Chem., Int. Ed. 2002, 41, 1775.
(d) Wallace, D. J.; Sidda, R. L.; Reamer, R. A. J. Org. Chem. 2007, 72,
1051. (e) Malhotra, D.; Liu, L. P.; Hammond, G. B. Eur. J. Org. Chem.
2010, 6855. (f) Ma, S.; Zhang, J. Chem. Commun. 2000, 117. (g) Ma, S.;
Li, L. Org. Lett. 2000, 2, 941. (h) Dudnik, A. S.; Sromek, A. W.; Rubina,
M.; Kim, J. T.; Kel’in, A. V.; Gevorgyan, V. J. Am. Chem. Soc. 2008,
130, 1440. (i) Xia, Y.; Dudnik, A. S.; Gevorgyan, V.; Li, Y. J. Am. Chem.
Soc. 2008, 130, 6940.
(3) (a) Smith, M. B.; March, J. March’s Advanced Organic Chemistry,
6th ed.; Wiley: New York, 2007; pp 1105À1110. (b) Fang, L. C.; Chen, Y.;
Huang, J.; Liu, L. Z.; Quan, J. M.; Li, C. C.; Yang, Z. J. Org. Chem.
2011, 76, 2479. (c) Wang, X. F.; An, J.; Zhang, X. X.; Tan, F.; Chen,
J. R.; Xiao, W. J. Org. Lett. 2011, 13, 808.
(4) (a) Fan, X. S.; Wang, Y. Y.; Qu, Y. Y.; Xu, H. Y.; He, Y.; Wang,
J. J. J. Org. Chem. 2011, 76, 982. (b) Ma, S.; Li, L.; Xie, H. J. Org. Chem.
1999, 64, 5325. (c) Ma, S.; Yu, S. Org. Lett. 2005, 7, 5063.
r
10.1021/ol201789z
Published on Web 08/30/2011
2011 American Chemical Society

tried with various bases. Inorganic bases Na2CO3 and
NaOH exhibited similar efficiency as K2CO3 (entries
11À12). On the other hand, organic bases such as TBAF,
piperidine, DBU, DABCO, and TEA were much less
effective. In summary of the optimization, treatment of
1b and 4 with 0.5 equiv of K2CO3 in refluxing acetone for
15 min gave 6b in an optimum yield of 75% (entry 3).
Scheme 1. Reaction of Allenic Ketone 1a with 2 or 4
Table 1. Opimization of the Reaction Leading to 6ba
entry
base (equiv)
solvent
T (°C) t (min) yield (%)b
1
K2CO3 (0.1)
K2CO3 (0.2)
K2CO3 (0.5)
K2CO3 (1.0)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
Na2CO3 (0.5)
NaOH (0.5)
TBAF (1.0)
acetone
acetone
reflux
reflux
60
60
15
15
30
30
30
30
30
30
30
30
30
30
30
30
30
32
2
41
3
acetone reflux
75
76
4
acetone
CH2Cl2
THF
reflux
reflux
reflux
reflux
reflux
80
5
trace
65
6
7
CH3CN
EtOH
66
Figure 1. X-ray crystal structure of 6a.
8
70
9
DMF
48
substituted benzenes. It has been well documented that
benzenoid compounds are ubiquitous structural units in a
wide variety of naturally occurring compounds and a
plethora of pharmaceuticals. While direct functionaliza-
tion of aromatic precursors is often used to prepare sub-
stituted benzenes, selective construction of aromatic rings
from simple and readily available acyclic units constitutes
another efficient approach for this purpose.6 Based on the
above facts, we were interested in developing the reaction
of 1 and 4 into a general and efficient method for the
preparation of polysubstituted benzenes.
To explore suitable conditions, the reaction of 1b and 4
mediated by different solvents under the promotion of
various bases was investigated and the results are listed in
Table 1. First, it was found that increasing the amount of
K2CO3 from 0.1 to 0.5 equiv improved the reaction
remarkably. A further increase from 0.5 equiv did not give
an obvious improvement (Table 1, entries 1À4). With 0.5
equiv of K2CO3, the reaction was tried in several solvents
other than acetone. It was found that while THF, CH3CN,
and ethanol gave similar results as that of acetone (entries
6À8), CH2Cl2, DMF, and H2O had a deleterious effect on
this reaction (entries 5 and 9À10). The reaction was then
10
11
12
13
14
15
16
17
H2O
80
29
acetone
acetone
acetone
reflux
reflux
reflux
reflux
reflux
reflux
reflux
72
72
18
piperidine (1.0) acetone
49
DBU (1.0)
DABCO (1.0)
TEA (1.0)
acetone
acetone
acetone
28
45
trace
a Reaction conditions: 1b (1.0 mmol), 4 (0.5 mmol). b Isolated yields.
With the optimized reaction conditions, the scope of 1,
2-allenic ketones was studied. 1-Aryl substituted 1,2-allenic
ketones with various substituents on the aryl ring under-
went this reaction smoothly with good yields (Table 2,
entries 1À12). The reaction was found to be also compa-
tible with 1-alkyl-4-aryl, 1,4-diaryl, or 1-aryl-4-alkyl sub-
stituted allenic ketones (entries 13À22). It was noted that
various functional groups such as methyl, methoxyl, ha-
lides, and cyano are well tolerated.
A tentative pathway for the formation of 6 is depicted in
Scheme 2. First, base triggers the cascade process by
deprotonating 4 to give anion A, which undergoes a
Michael addition to 1 to afford the second anion B. The
Michael addition occurs again with B and 1 to give the
third anion C. Tautomerization of C affords the fourth
anion D, which undergoes an intramolecular aldol type
reaction to give the fifth anion E. Aromatization through
cleavage of an ethyl carbonate from intermediate F yields
the polysubstituted benzene to conclude the process.7
(5) (a) Ma, S. M.; Yu, S. C.; Yin, S. H. J. Org. Chem. 2003, 68, 8996.
(b) Ma, S. M.; Yin, S. H.; Li, L. T.; Tao, F. G. Org. Lett. 2002, 4, 505.
(6) For recent approaches for the synthesis of substituted benzenes, see: (a)
Gevorgyan, V.; Takeda, A.; Homma, M.; Sadayori, N.; Radhakrishnan, U.;
Yamamoto, Y. J. Am. Chem. Soc. 1999, 121, 6391. (b) Lian, J. J.; Odedra, A.;
Wu, C. J.; Liu, R. S. J. Am. Chem. Soc. 2005, 127, 4186. (c) Li, S.; Qu, H. M.;
Zhou, L. S.; Kanno, K. I.; Guo, Q. X.; Shen, B. J.; Takahashi, T. Org. Lett.
2009, 11, 3318. (d) Zhou, H. W.; Xing, Y. P.; Yao, J. Z.; Chen, J. H. Org. Lett.
2010, 12, 3674. (e) Ziffle, V. E.; Cheng, P.; Clive, D. L. J. J. Org. Chem. 2010,75,
8024. (f) Shen, Y. X.; Jiang, H. F.; Chen, Z. W. J. Org. Chem. 2010,75, 1321. (g)
Matsumoto, S.; Takase, K.; Ogura, K. J. Org. Chem. 2008, 73, 1726. (h) Wu,
C. Y.; Lin, Y. C.; Chou, P. T.; Wang, Y.; Liu, Y. H. Dalton Trans. 2011, 40,
3748. (i) Kim, S. C.; Lee, K. Y.; Lee, H. S.; Kim, J. N. Tetrahedron 2008,64, 103.
(j) Dumond, Y. R.; Negishi, E. Tetrahedron 2004, 60, 1345.
(7) Malakar, C. C.; Schmidt, D.; Conrad, J.; Beifuss, U. Org. Lett.
2011, 13, 1972.
(8) For reactions of 1,2-allenic ketones with 2-substituted diethyl
malonates, see: Ma, S. M.; Yu, S. C.; Qian, W. J. Tetrahedron 2005, 61,
4157.
Org. Lett., Vol. 13, No. 19, 2011
5025

substrates for the formation of 6. It was then of interest
to determine what kind of products would be formed from
the reaction of 1 with 7, which, to the best of our knowl-
edge, has not been studied yet.8 Thus, 1-(4-chlorophenyl)-
buta-2,3-dien-1-one (1) and ethyl 2-methyl cyanoacetate
(7a) were treated with K2CO3 in refluxing acetone for 1 h
(Scheme 3). Separation of the resulting mixture gave a β,
Table 2. Scope of the Reaction Leading to 6a
Scheme 2. Plausible Pathway for the Formation of 6
γ-unsaturated nitrile (8, 66%) together with an R,β-un-
saturated nitrile (9a, 10%). Further efforts were then made
to improve its selectivity and yield. During the optimiza-
tion, we found that the nature of solvents had remarkable
effects on the selectivity of this reaction. While the reaction
run in acetone mainly afforded 8, 9a was obtained as a
dominating product (78%) by treating 1 and 7a with
K2CO3 in DMF at 80 °C for 20 min. 9a was obtained as
a mixture ofstereoisomers (Z/E = 4:3, which are separable
by column chromatography). The configuration of the
carbonÀcarbon double bond of the more polar E-isomer
was determined on the basis of the X-ray diffraction
analysis (Figure 2).
Scheme 3. Reactions of R-Substituted Cyanoacetate with Alle-
nic Ketone in Different Solvents
a Reaction conditions: 1 (1.0 mmol), 4 (0.5 mmol), K2CO3 (0.5
equiv), acetone (5 mL), reflux, 15 min. b Isolated yields.
Based on the proposed mechanism, we noticed that
2-substituted cyanoacetates (7) would not be possible
Figure 2. X-ray crystal structure of (E)-9a.
Org. Lett., Vol. 13, No. 19, 2011
5026

Table 3. Synthesis of R,β-Unsaturated Nitrilesa
Scheme 4. Plausible Pathway for the Formation of 9
yield (%)b
entry
R1
R2
R3
R4
9
Z
E
1
p-ClC6H4
p-BrC6H4
o-FC6H4
H
H
CH3
CH3
CH3
CH3
CH3
CH3
Bn
9a
9b
9c
9d
9e
9f
44
45
35
49
47
41
44
43
41
43
36
48
44
34
34
31
35
38
30
32
32
32
36
26
32
30
2
H
H
H
H
H
H
H
H
H
H
H
A plausible pathway for the formation of 9 is shown in
Scheme 4. In the first phase of the tandem process, the
Michael addition of anion I with allenic ketone 1 and
subsequent isomerization and protonation yield a β,γ-un-
saturated nitrile 8. In the second stage, a base catalyzed
decarboxylationof8andthesubsequentisomerization and
protonation afford 9. The much improved selectivity
toward 9 by using DMF as the reaction medium may be
explained by the enhanced basicity of the carbonate in
DMF compared with that in acetone, which is essential for
the decarboxylation process.
Various allenic ketones and different R-substituted cya-
noacetates were then studied to determine the scope of the
above process leading to the synthetically and biologically
important R,β-unsaturated nitriles.9 Table 3 lists the suc-
cessful results of this reaction with a variety of substrates
under the optimized conditions.
3
H
4
p-CH3C6H4
p-CH3OC6H4
C6H5
H
5
H
6
H
7
p-BrC6H4
p-CH3C6H4
p-CH3OC6H4
p-CH3OC6H4
C6H5
H
9g
9h
9i
8
H
Bn
9
H
Bn
10
11
12
13
H
Allyl 9j
CH3 9k
C6H5
H
C6H5
CH3 CH3
CH3 CH3
9l
p-ClC6H4
H
9m
a Reaction conditions: 1 and 7 (1.0 mmol), K2CO3 (1 equiv), DMF (5
mL), 80 °C, 20 min. b Isolated yields.
Scheme 5. Synthesis of Biphenyl Tetrazole from 6b
Finally, the cyano group, which had played a key role as
a reactivitycontrolling element during the aboveprocesses,
could be used as a convenient chemical handle for the
preparation of other useful compounds. It is well-known
that biphenyl tetrazole is an important and powerful
pharmacophore.10 Compounds with this framework
have shown various pharmacological and biological
activities.11,12 We noticed that most of the products in-
cluded in Table 1 are ready substrates toward biphenyl
tetrazole derivatives. As an example, 6b was treated with
Me3SiN3 and a catalytic amount of n-Bu2SnO for 50 h at
90 °C in o-xylene.10a The corresponding biphenyl tetrazole
(10) was obtained in 75% yield (Scheme 5). This results in a
convenient and efficient sequence of reactions toward
biphenyl tetrazoles from the readily accessible allenic
ketones without using any transition metal catalysts.
In conclusion, we have developed an efficient and novel
protocol for the preparation of polysubstituted benzenes
and an effective synthetic method toward R,β-unsaturated
nitriles via tandem reactions of 1,2-allenic ketones with
cyanoacetate or 2-substituted cyanoacetates. Remarkable
advantages of these new strategies include high efficiency,
readily available starting materials, and mild reaction
conditions. In addition, the resulting cyano substituted
biphenyls can be smoothly functionalized to the pharma-
ceutically interesting biphenyl tetrazole. Further explora-
tion of the reaction scope and elaboration of the resulting
products are currently underway.
Acknowledgment. We are grateful to the Natural
Science Foundation of China (20972042, 20911140238),
Innovation Scientist and Technician Troop Construction
Projects of Henan Province (104100510019) and PCSIRT
(IRT1061) for financial support.
Supporting Information Available. Experimental de-
tails and NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(9) (a) Janey, J. M.; Orella, C. J.; Njolito, E.; Baxter, J. M.; Rosen,
J. D.; Palucki, M.; Sidler, R. R.; Li, W. J.; Kowal, J. J.; Davies, I. W. J.
Org. Chem. 2008, 73, 3212. (b) Yoo, K.; Kim, H.; Yun, J. J. Org. Chem.
2009, 74, 4232.
(11) (a) Wang, P.; Zheng, G.-J.; Wang, Y.-P.; Wang, X.-J.; Li, Y.;
Xiang, W.-S. Tetrahedron 2010, 66, 5402. (b) Dickstein, K.; Timmermans,
P.; Segal, R. Exp. Opin. Invest. Drugs 1998, 7, 1897.
€
(10) (a) Kivrakidou, O.; Brase, S.; Hulshorst, F.; Griebenow, N. Org.
Lett. 2004, 6, 1143. (b) Toney, J. H.; Cleary, K. A.; Hammond, G. G.;
Yuan, X. L.; May, W. J.; Hutchins, S. M.; Ashton, W. T.; Vanderwall,
D. E. Bioorg. Med. Chem. Lett. 1999, 9, 2741.
(12) Smith, R. G.; Cheng, K.; Schoen, W. R.; Pong, S.-S.; Hickey, G.;
Jacks, T.; Butler, B.; Chan, W. W.-S.; Chaung, L.-Y. P.; Judith, F.;
Taylor, J.; Wyvratt, M. J.; Fisher, M. H. Science 1993, 260, 1640.
Org. Lett., Vol. 13, No. 19, 2011
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