NHC-catalyzed C-O or C-N bond formation: Efficient approaches to α,β-unsaturated esters and amides

Article abstract of DOI:10.1039/c2cc32862c

Simple and efficient NHC-catalyzed transformations of bromoenal or α,β-dibromoenal into α,β-unsaturated esters or amides with high stereoselectivity through C-O or C-N bond formation have been demonstrated. The NHC-catalyzed processes occur under mild con

Full text of DOI:10.1039/c2cc32862c

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NHC-Catalyzed C-O or C-N Bond Formation: Efficient Approaches to
α,β-Unsaturated Esters and Amides
Bo Zhang, a Peng Feng, a Yuxin Cui, a Ning Jiao*a,b
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Simple and efficient NHC-catalyzed transformations of
bromoenal or α,β-dibromoenal into α,β-unsaturated esters or
amides with high stereoselectivity through C-O or C-N bond
10 formation have been demonstrated. The NHC-catalyzed
processes occur under mild conditions. The ready availability
of the starting materials, avoidance of external oxidants and
the usefulness of the products all make the strategy quite
attractive.
15 Carboxylic acid esters and amides represent an important
class of compounds found in numerous bioactive products as
well as in medicines and materials.1 In addition, carboxylic
acid esters and amides are versatile building blocks in organic
synthesis and of significant importance for industrial
20 application.2,3 In general, synthetic methods for esters and
amides bond formation utilize acids and alcohols or amines as
coupling partners and rely on the stoichiometric preparation of
an activated carboxylate followed by nucleophilic
Scheme 1. NHC-Catalyzed Approaches to α,β-Unsaturated Esters and
50 Amides
Moreover, by the use of NHC/Fe cooperative catalysis, Gois
and co-workers realized an aerobic oxidative esterification of
aldehydes (c, Scheme 1).7h However, the process was shown
to be effective only with phenols as nucleophiles. Hence, a
55 simple, efficient and practical protocol for NHC-catalyzed
ester and amide bond formation is still highly desired. α,β-
unsaturated acylazolium ions III (Scheme 1) is a key
intermediate for ester and amide bond formation in above
transformations. Inspired by this intermediate, we envisioned
60 that α,β-unsaturated acylazolium ions III could be readily
generated from bromoenal and NHC through a3-d3 umpolung
and subsequent debromination, which should react with
alcohols or amines without any external oxidants.9 Herein, we
describe a novel NHC-catalyzed C-Br bond cleavage and C-O
65 or C-N bond formation for the synthesis of α,β-unsaturated
esters and amides under mild conditions (d, Scheme 1).
The study was initiated by investigating the reaction of
commercially available α-bromocinnamaldehyde 1a with
benzyl alcohol 2a in the presence of NHCs. The results
70 showed that imidazolium salt A is an effective organocatalyst
for this transformation which gave the desired product 3aa in
78% yield with high stereoselectivity (only E-isomer was
obtained) (see entry 1, Table S1). The various solvents were
surveyed and revealed dioxane to be the best choice (see entry
75 13, Table S1). Finally, base screening showed that Cs2CO3
substitution.1a-b,4
However,
some
disadvantages
of
25 conventional method are obvious, including the formation of
copious byproducts, extensive protection of other functional
group and harsh reaction condition. Therefore, the
development of catalytic process for ester and amide bond
formation under mild reaction conditions is highly desirable
30 and challenging.
In recent years, a number of catalytic methods for ester and
amide bond formation have been successfully established.5,6
Among them, N-heterocyclic carbene (NHC)-catalyzed redox
esterification and amidation of aldehydes with alcohol and
35 amine have become a powerful strategy for ester and amide
bond formation.7,8 However, in these NHC-catalyzed reactions,
synthetic methods for α,β-unsaturated esters and amides bond
formation are rare.7f-h,8c In 2006, Zeitler reported a NHC-
catalyzed redox esterification of alkynyl aldehydes by internal
40 redox process (a, Scheme 1).7f However, the yield was
moderate and alkynyl aldehydes as the substrate were not
readily available. More recently,
a
significant direct
esterification or amidation of α,β-unsaturated aldehydes were
realized by Studer, Grimme, and coworkers in the presence of
45 an external oxidant (b, Scheme 1).7g,8c Despite its
breakthrough in ester and amide bond formation, the use of
equivalent oxidant may reduce this process sustainability.
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Table 1. The reaction scope for NHC-catalyzed ester bond formationa, b
5aa was obtained in 13% yield by employing imidazole as the
40 additives (see entry 2, Table S2). Benzimidazole and
pentafluorophenol (PFPOH) as the additives suppressed the
formation of amide 5aa (see entries 3 and 7, Table S2). The
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reactions in the presence of DMAP, HOBt and HOAt did not
produce the desired product 5aa (see entry 4-6, Table S2).
45 Gratifyingly, when hexafluoroisopropanol (HFIP) was used as
the additives in this reaction, the yield of 5aa was improved to
50% (see entry 8, Table S2). The catalytic amounts of HFIP
provided low efficiency (see entry 9, Table S2). A range of
NHCs were then screened. The results showed that catalyst A
50 is an effective organocatalyst for this transformation (see
Table S3). Solvent and base screening were subsequently
performed and showed that THF and Cs2CO3 were preferable.
Finally, the yield increased to 81% by raising the loading of
4a to 2.0 equiv (see entry 16, Table S2). When 3.0 equiv 4a
55 was employed, the same result was observed (see entry 17,
Table S2). We also tested the possibility of the addition of
benzylamine at the beginning of this reaction. However, the
reaction exhibited lower efficiency (see entry 18, Table S2).
The scope of this reaction with different amines was then
60 investigated (Table 2). Amines containing alkyl, heterocycle
and alkyne proceeded efficiently and afforded the desired
products 5ab-5ad in moderate to good yields (42-82%; Table
2). For the sterically more hindered amine, the amidations
were slower (5ae-5ag, 55-70%; Table 2). Moreover,
65 pyrrolidine and morpholine were suitable substrates, affording
5ah and 5ai in 88% and 66% yield, respectively (Table 2).
Various bromoenal was then examined (table 2). Bromoenals
containing electron-rich or electron-deficient phenyl groups
were suitable partners in this reaction, affording 5ba-5ea in
70 good yields (66-72%; Table 2).
a
b
e
Reacion condition: see entry 13, Table S1. Isolated yields. 3.0 equiv
of 2 was used.
5
was preferable (see entry 13, Table S1).
With the optimized conditions in hand, the scope of this
reaction with different alcohols was then investigated (Table
1). A wide range of aliphatic alcohols smoothly underwent
this transformation generating the desired products 3aa-3ad in
10 moderate to good yield (63-81%, Table 1). Moreover,
reactions worked well with some simple alcohols such as
methanol and ethanol to give 3ae and 3af in 84% and 63%
yield, respectively. Alcohols containing olefin, alkyne,
halogen and heterocycle were compatible with good yields
15 (3ag-3al, 65-80%; Table 1). It is noteworthy that α-
bromocinnamaldehyde 1a with the sterically more hindered
isopropanol and cyclohexanol also gave the desired product
3am and 3an in 33% and 52%, respectively (Table 1). This
method proved to be effective for phenol containing an
20 electron-rich or electron-deficient group, leading to moderate
to good yield (3ao-3aq, 50-75%; Table 1).
Intriguingly, when α,β-dibromoaldehyde 6 was employed in
place of the α-bromocinnamaldehyde 1a in the reaction, the
final product 3a and 5a were efficiently generated in 78% and
76% yield, respectively (Eq. 1 and Eq. 2; also see SI).
75 Table 2. The reaction scope for NHC-catalyzed amide bond formationa,b
We then examined the scope of various bromoenal (Table
1). Bromoenals containing electron-rich or electron-deficient
phenyl groups were tolerated in this reaction, affording the
25 desired products 3ba-3ea with good yields (60-70%; Table 1).
Moreover, naphthyl-derived bromoenalenal also underwent
this transformation well generating the desired products 3fa in
74% yield (Table 1).
Encouraged by the aforementioned ester bond formation,
30 we extended the reaction to amide bond formation by using
amines as the nucleophiles. Disappointingly, the reaction of α-
bromocinnamaldehyde 1a with benzylamine 4a in the
presence of catalyst
A and Cs2CO3 in THF at room
temperature did not afford the desired product 5aa (see entry
35 1, Table S2). The intermediate acylazolium ions Ⅲ did not
react fast enough with benzylamine 4a, leading to the
formation of imine. Thus, we then tested a number of
additives in this reaction. Interestingly, the desired product
a Reacion condition: see entry 16, Table S2. b Isolated yields. c Amidation
for 6 h. d Amidation at 50 ℃.
2
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a
catalyst A (10 mol%)
Cs2CO3 (2.2 equiv.)
dioxane, rt, 3h
Br
Br
O
O
O
State Key Laboratory of Natural and Biomimetic Drugs, Peking
University, School of Pharmaceutical Sciences, Peking University, Xue
Yuan Rd. 38, Beijing 100191, China. Fax: (+86)-010-8280-5297; Tel:
35 (+86) 01082805297; E-mail: jiaoning@bjmu.edu.cn
(1)
(2)
Ph
Ph
H +
Ph
Ph
Ph
Ph
O
HO
Ph
Br
b Shanghai Key Laboratory of Green Chemistry and Chemical Processes,
6
2a
4a
3aa (78%)
catalyst A (10 mol%)
Cs2CO3 (2.2 equiv.)
HFIP (1.5 equiv)
View Online
Department of Chemistry, East China Normal University, Shanghai
200062, China
† Electronic Supplementary Information (ESI) available: See
40 DOI: 10.1039/b000000x/
O
H+
N
H
H2N
Ph
THF, rt, 3h
Br
6
5aa (76%)
1
(a) J. M. Humphrey, A. R. Chamberlin, Chem. Rev. 1997, 97, 2243;
(b) J. Otera, Esterification: Methods, Reaction and Application;
Wiley: New York, 2003; (c) C. W. Lindsley, Curr. Top. Med. Chem.
2008, 8, 12; (d) E. Armelin, L. Franco, A. Rodriguez-Galan, J.
Puiggali, Macromol. Chem. phys. 2002, 203, 48; (e) M. A. Glomb,
C. Pfahler, J. Biol. Chem. 2001, 276, 41638; (f) L. H. Hu, H. B. Zou,
J. X. Gong, H. B. Li, L. X. Yang, S. W. Cheng, C. X. Zhou, H. Bai,
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Lurton, J. Boustie, L. Girre, F. Sauvager, M. Cormier, J. Nat. Prod.
1994, 57, 644.
For selected examples on synthetic application of carboxylic acid
esters, see: (a) T. Hayashi, K. Yamasaki Chem. Rev. 2003, 103,
2829; (b) D. H. Ryu, E. J. Corey, J. Am. Chem. Soc. 2003, 125,
6388; (c) F. López, S. R. Harutyunyan, A. Meetsma, A. J. Minnaard,
B. L. Feringa, Angew. Chem. Int. Ed. 2005, 44, 2752; (d) K. Inanaga,
K. Takasu, M. Ihara, J. Am. Chem. Soc. 2005, 127, 3668.
For selected examples on synthetic application of carboxylic acid
amides, see: (a) K. Ishihara, Y. Furuya, H. Yamamoto, Angew.
Chem. Int. Ed. 2002, 41, 2983; (b) C.-W. Kuo, J.-L. Zhu, J.-D. Wu,
C.- M. Chu, C.-F. Yao, K.-S. Shia, Chem. Commun. 2007, 301; (c)
G. W. Wang, T. T. Yuan, D. D. Li, Angew. Chem. Int. Ed. 2011, 50,
1380; (d) X. X. Zhang, W. T. Teo, P. W. H. Chan, J. Organomet.
Chem. 2011, 696, 331.
(1) R. C. Larock, Comprehensive Organic Transformations; VCH:
New York, 1999; (2) J. W. Bode, Curr.Opin. Drug Discovery Dev.
2006, 9, 765.
A plausible mechanism for this reaction is illustrated in
Scheme 2. The addition of the NHC to bromoenals 1 affords
the Breslow intermediates Ⅰafter addition and rearrangement,
which are the tautomer of the intermediates Ⅱ. The leaving of
the bromide generates the α,β-Unsaturated acylazolium ions
III as the key intermediates. Subsequent nucleophilic attack
by the alcohols 2 affords the esters 3 with the regeneration of
the NHC catalysts (Scheme 2). In the amidation process, the
10 activated esters Ⅳ are produced by attack of HFIP with the
formation of NHC to complete the catalytic cycle. Subsequent
substitution reaction with the amines 4 affords the amides 5.
In summary, we have demonstrated a simple and efficient
NHC-catalyzed transformation of bromoenal into α,β-
15 unsaturated esters or amides with high stereoselectivity
through C-Br bond cleavage and C-O or C-N bond formation.
The NHC-catalyzed processes occur under mild conditions.
More, the ready availability of the starting materials,
avoidance of external oxidants and the usefulness of the
20 products all make this strategy quite attractive. Further studies
on the scope, and the synthetic applications are ongoing in our
laboratory.
45
50
55
60
65
70
5
2
3
4
5
For some selected catalytic approaches to ester bond formation, see:
(a) A. Sato, Y. Nakamura, T. Maki, K. Ishihara, H. Yamamoto, Adv.
Synth. Catal. 2005, 347, 1337; (b) C.-T. Chen, Y. S. Munot, J. Org.
Chem. 2005, 70, 8625; (c) K. Ishihara, S. Nakagawa, A. Sakakura, J.
Am. Chem. Soc. 2005, 127, 4168; (d) S. Magens, M. Ertelt, A.
Jatsch, B. Plietker, Org. Lett. 2008, 10, 53; (e) B. Maji, S.
Vedachalan, X. Ge, S. Cai, X.-W. Liu, J. Org. Chem. 2011, 76,
3016.
75 6
For some selected catalytic approaches to amide bond formation,
see: (a) W.-J. Yoo, C.-J. Li, J. Am. Chem. Soc. 2006, 128, 13064; (b)
Chan, J. Baucom, K. D. Murry, J. A. J. Am. Chem. Soc. 2007, 129,
14106; (c) A. J. A. Watson, A. C. Maxwell, J. M. J. Williams, Org.
Lett. 2009, 11, 2667; (d) B. Gnanaprakasam, D. Milstein, J. Am.
Chem. Soc. 2011, 133, 1682; (e) C. Qin, W. Zhou, F. Chen, Yang.
Ou, N. Jiao, Angew. Chem. Int. Ed. 2011, 50, 12595.
80
7
For some selected redox esterification of aldehydes by NHC
catalysis, see: (a) K. Y.-K. Chow, J. W. Bode, J. Am. Chem. Soc.
2004, 126, 8126; (b) N. T. Reynolds, J. R. D. Alaniz, T. Rovis, J.
Am. Chem. Soc. 2004, 126, 9518; (c) S. S. Sohn, J. W. Bode, Org.
Lett. 2005, 7, 3873; (d) N. T. Reynolds, T. Rovis, J. Am. Chem. Soc.
2005, 127, 16406; (e) Audrey. Chan, K. A. Scheidt, Org. Lett. 2005,
7, 905; (f) K. Zeitler, Org. Lett. 2006, 8, 637; (g) S. D. Sarkar, S.
Grimme, A. Studer, J. Am. Chem. Soc. 2010, 132, 1190; (h) R. S.
Reddy, J. N. Rosa, L. F. Veiros, S. Caddick, P. M. P. Gois, Org.
Biomol. Chem. 2011, 9, 3126; (i) B. Maji, S. Vedachalan, X. Ge, S.
Cai, X.-W. Liu, J. Org. Chem. 2011, 76, 3016; (j) S. S. Sohn, J. W.
Bode, Angew. Chem. Int. Ed. 2006, 45, 6021; (k) C. A. Rose. K.
Zeitler, Org. Lett. 2010, 12, 4552.
85
90
Scheme 2. Proposed Catalytic Cycles for NHC-catalyzed ester and amide
25 bond formation
Financial support from National Basic Research Program of
China (973 Program) (Grant No. 2009CB825300), National
Science Foundation of China (No 21172006), and Peking
University are greatly appreciated. We thank Yang Ou in this
30 group for reproducing the results of 3ah and 5ae.
95 8
For redox amidation of aldehydes by NHC catalysis, see: (a) H. U,
Vora, T. Rovis, J. Am. Chem. Soc. 2007, 129, 13796; (b) J. W. Bode,
S. S. Sohn, J. Am. Chem. Soc. 2007, 129, 13798; (c) S. D. Sarkar, A.
Studer, Org. Lett. 2010, 12, 1992.
9
During the preparation of this manuscript, a N-heterocyclic carbene
catalyzed reactions of bromoenal with 1,3-dinucleophilic reagents
was reported: C. Yao, D. Wang, J. Lu, T. Li, W. Jiao, C. Yu, Chem.
Eur. J. 2012, 18, 1914.
100
Notes and references
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ARTICLE TYPE
B. Zhang, Peng Feng, Y. Cui and
N. Jiao*
NHC-Catalyzed C-O or C-N Bond
Formation: Efficient Approaches to
α,β-Unsaturated Esters and Amides
Simple and efficient NHC-catalyzed transformations of bromoenal or α,β-dibromoenal
into α,β-unsaturated esters or amides with high stereoselectivity through C-O or C-N
bond formation have been demonstrated. The NHC-catalyzed processes occur under
mild conditions. The ready availability of the starting materials, avoidance of external
oxidants and the usefulness of the products all make the strategy quite attractive.
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 4