Nucleophilic β-Carbon Activation of Propionic Acid as a 3-Carbon Synthon by Carbene Organocatalysis

Article abstract of DOI:10.1002/chem.201501481

Direct β-carbon activation of propionic acid (C₂H₅CO₂H) by carbene organocatalysis has been developed. This activation affords the smallest azolium homoenolate intermediate (without any substituent) as a 3-carbon nucleophi

Full text of DOI:10.1002/chem.201501481

DOI: 10.1002/chem.201501481
Communication
&
Organocatalysis
Nucleophilic b-Carbon Activation of Propionic Acid as a 3-Carbon
Synthon by Carbene Organocatalysis
Zhichao Jin,[a] Ke Jiang,[b] Zhenqian Fu,[a] Jaume Torres,[b] Pengcheng Zheng,[c] Song Yang,[c]
Bao-An Song,*[c] and Yonggui Robin Chi*[c]
boxylic acids and their derivatives such as carboxylic esters
Abstract: Direct b-carbon activation of propionic acid
(C2H5CO2H) by carbene organocatalysis has been devel-
and acetyl halides is a versatile strategy.
Herein we report a carbene-catalyzed b-sp3 carbon activa-
oped. This activation affords the smallest azolium homoe-
tion of propionic acid (CH3CH2CO2H) to generate the smallest
nolate intermediate (without any substituent) as a 3-
homoenolate intermediate (bearing no substituent at the b-
carbon nucleophile for enantioselective reactions. Pro-
carbon) with a reactive nucleophilic b-carbon (Scheme 1a).
pionic acid is an excellent raw material because it is
cheap, stable, and safe. This approach provides a much
better solution to azolium homoenolate synthesis than
the previously established use of acrolein (enal without
any substituent), which is expensive, unstable, and toxic.
N-heterocyclic carbene (NHC) organocatalysts provide unique
opportunities in organic synthesis.[1] Raw materials widely ex-
plored under NHC organocatalysis include aldehydes and alde-
hyde derivatives such as a,b-unsaturated aldehydes (enals). In
particular, reactions of NHC catalysts with enals form a,b-unsa-
turated Breslow intermediates (homoenolates) and convert the
b-sp2 carbon as a reactive nucleophilic carbon, as first dis-
closed in 2004 by the groups of Glorius[2] and Bode.[3] We are
committed to developing new activation modes and effective
synthetic methods that use readily available, easy to handle,
and inexpensive substrates as starting materials. In the last few
years, we have realized carbene-catalyzed activation of carbox-
ylic esters and their derivatives.[4] We hope to offer comple-
mentary or better solutions that are not readily available with
the catalytic approaches using aldehyde substrates. Studies
Scheme 1. Carbene-catalyzed activation of C2H5CO2H as a 3-carbon nucleo-
phile.
from the groups of Romo,[5] Lectka,[6] Smith,[7] Lupton,[8] and
others[9] have also shown that organocatalytic activation of car-
[a] Z. Jin,+ Dr. Z. Fu
Mechanistically, condensation of propionic acid forms in situ
Division of Chemistry & Biological Chemistry, School of Physical &
a carboxylic anhydride that subsequently reacts with the NHC
catalyst to initiate the catalytic cycle (Scheme 1b). Urea addi-
tives were found to enhance reaction enantioselectivity consis-
tently. In practical application, our approach should be very at-
tractive when compared with the enal approach using acrolein
(enal without b-substituent)[10] as the substrate. For instance,
acrolein is unstable and usually needs to be prepared freshly
from its acrolein diethyl acetal precursor that costs over $790
per 500 g (TCI). In contrast, propionic acid is stable and very in-
expensive ($18 per 500 g, TCI). The high instability and reactivi-
ty of acrolein can also lead to undesired side reactions. In addi-
tion, acrolein is highly volatile and toxic.[11] Propionic acid is
much safer: it can even be used as a food additive.
Mathematical Sciences, Nanyang Technological University
Singapore 637371 (Singapore)
[b] Dr. K. Jiang,+ Prof. Dr. J. Torres
School of Biological Sciences, Nanyang Technological University
Singapore 637371 (Singapore)
[c] P. Zheng, Prof. Dr. S. Yang, Prof. Dr. B.-A. Song, Prof. Dr. Y. R. Chi
Laboratory Breeding Base of Green Pesticide and Agricultural
Bioengineering, Key Laboratory of Green Pesticide and Agricultural
Bioengineering, Ministry of Education, Guizhou University
Huaxi District, Guiyang 550025 (P. R. China)
E-mail: songbaoan22@yahoo.com
robinchi@ntu.edu.sg
[+] These authors contributed equally.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501481.
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We started by using a-ketobenzhydryl ester[12] 2a as
a model electrophile substrate (Table 1). The indanol-derived
triazolium catalyst A, first reported by Bode and co-workers,[13]
could mediate the formation of proposed product 3a in low
Table 2. Scope of a-ketoesters.[a]
Table 1. Optimization of conditions.[a]
Entry NHC dehydrating reagent solvent
base Yield [%][b] e.r.[c]
1
2
3
4
5
6
7
A
B
C
C
C
C
C
C
C
EDC·HCl
EDC·HCl
EDC·HCl
DCC
MsCl or CDI
EDC·HCl
EDC·HCl
EDC·HCl
EDC·HCl
THF
THF
THF
THF
THF
DBU 28
DBU
DBU 35
DBU 26
79:21
–
80:20
89:11
–
94:6
94:6
95:5
95:5
0
DBU
0
mesitylene DBU 86
mesitylene TEA 88
mesitylene K2CO3 99
mesitylene K2CO3 98
8
9[d]
[a] Reaction conditions, unless otherwise stated:
1
(5 equiv), 2a
(0.1 mmol, 1 equiv), NHC (20 mol%), base (2 equiv), dehydrating reagent
(4 equiv), solvent (1 mL), RT (248C), 24 h; [b] yield of product isolated by
column chromatography; [c] e.r. was determined by HPLC using a chiral
stationary phase. [d] 4 Eq of 1 was used.
[a] Reactions were carried out under the conditions outlined in Table 1,
entry 9 for the indicated time; yields refer to product isolated by column
chromatography; e.r. was determined by HPLC using a chiral stationary
phase.
but encouraging 28% yield when using 1-ethyl-3-(3-dimethyla-
minopropyl)carbodiimide hydrochloride (EDC·HCl) as a dehy-
drating reagent (to convert the propionic acid 1 into anhydride
1–A in situ; Scheme 1b) and 1,8-Diazabicyclo[5.4.0]undec-7-
ene (DBU) as the base (Table 1, entry 1). NHC precatalyst B,
with a N-phenyl substituent, first used by Rovis and co-work-
ers,[14] was ineffective in our reaction (Table 1, entry 2). We then
found that triazolium C, introduced by Scheidt and co-work-
ers,[15] performed better in terms of both yield and e.r. (Table 1,
entry 3). Evaluation of dehydrating reagents showed that
EDC·HCl worked better than N,N’-dicyclohexylcarbodiimide
(DCC), and the use of N,N’-carbonyldiimidazole (CDI) or metha-
nesulfonyl chloride (MsCl) led to no formation of 3a (Table 1,
entries 3–5). We found mesitylene to be a much better solvent
than THF, leading to 3a in 86% yield and 94:6 e.r. (Table 1,
entry 6). Last we found that by using K2CO3 as the base and 4
equivalent of propionic acid 1, quantitative conversion of a-ke-
toester 2a could be achieved with the formation of 3a in ex-
ceptional 98% yield and 95:5 e.r. (Table 1, entry 9).
To further expand the utility of our method, we next demon-
strated that isatins 4[16] could be used as effective ketone elec-
trophiles to react with the b-carbon of propionic acid
1 (Table 3). A search for conditions (see the Supporting Infor-
Table 3. Scope of isatins.[a]
Having established acceptable conditions, we next examined
the substrate scope of the reaction (Table 2). We first studied
the substituents on the ketone moiety of the a-ketoesters 2.
Both aryl (3a–l) and alkyl (3m) groups on the ketone moiety
worked well. The use of an electron-rich substituent (3h, i) on
the aryl ring or placing a substituent at the ortho-position of
the aromatic ketone (3d, g, j) slowed down the reaction, likely
for electronic and steric reasons respectively. We then exam-
ined the ester moiety of the a-ketoesters 2. Under the same
conditions, various esters (3n–r) could be used, although the
yields and enantioselectivities slightly varied.
[a] 1 (5 equiv), 4 (0.1 mmol; 1 equiv), C (10 mol%), DBU (2 equiv), EDC·HCl
(4 equiv), THF (1 mL), RT (248C), 12 h; yields refer to product isolated by
column chromatography; e.r. was determined by HPLC using a chiral sta-
tionary phase.
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mation for details) showed that by using 10 mol% of NHC pre-
catalyst C, EDC·HCl as the dehydrating reagent, and DBU as
the base in THF as the solvent, the desired lactone products 5
could be obtained in acceptable yields and enantioselectivities
(5a–j). It is worth noting that the use of the electron-rich and
sterically bulky trityl (Trt) unit as the N-protecting group was
necessary to achieve high enantiomeric control. The use of
other N-protecting groups for isatins led to products with
good yields but unsatisfactory enantioselectivities (5k–m).
To understand the reaction mechanism, we monitored the
a direct use of carboxylic acid as the starting material always
performed better (1e and 2e).
The products from our catalytic reactions (e.g., 3e, 5a)
could be readily transformed into other synthetic building
blocks or bioactive functional molecules (Scheme 3). For exam-
1
catalytic reaction with H NMR (see the Supporting Information
for details). Our results showed that the acid substrate 1 was
quickly converted into anhydride 1–A (Scheme 1b) in less than
1 h. Anhydride 1–A then reacted with the NHC catalyst via a b-
activation process, as previously reported by our group,[4g,h,i] to
form the smallest azolium homoenolate intermediate III
(Scheme 1b), which subsequently underwent formal [3+2] cy-
cloaddition reaction with the ketone electrophile to furnish the
lactone product and regenerate the NHC catalyst.
In addition to anhydride 1–A, our reaction mixture con-
tained carboxylic acid 1 and urea 6 formed from EDC·HCl
during anhydride generation (Scheme 2). Acid and urea may
Scheme 3. Synthetic transformation of chiral products.
ple, the ester moiety of 3e could be easily removed by TFA
(trifluoroacetic acid) to give the corresponding acid 7 without
loss of e.r. The chiral acid product 7 could be converted into
nucleoside analogues showing bioactivities on the central
nervous system.[17] The N-trityl protecting group of catalytic
product 5a could be removed under mild conditions to give
spirocyclic lactone 9, which is the synthetic precursor for 5-HT6
receptor antagonist.[18] Ester exchange of 5a in methanol effec-
tively afforded g-hydroxyester 10 bearing a quaternary alcohol.
In summary, we have developed a direct b-carbon activation
of propionic acid to generate the smallest azolium homoeno-
late intermediate. The majority of recent reaction develop-
ments have focused on substrates bearing various substitu-
ents. However, the synthetic potentials of many of the “small-
est” substrates, such as CO, CO2, HCHO, CH3OH, or CH3COOH,
have not been well appreciated largely due to the lack of ef-
fective activation strategies for such “small” substrates. Our
present study, with unusually cheap and safe 3-carbon carbox-
ylic acid as the starting material, should encourage further in-
vestigation in this direction.
Scheme 2. Reaction starting with anhydride or acid as the substrate and ef-
fects of additives.
interact with the ketone substrate or other intermediates of
our reaction. We therefore decided to study how the acid and
urea affected the reaction outcome. We first found that reac-
tions using pre-prepared anhydride 1–A as the substrate gave
3a and 5a in around 70% yield with 92:8 e.r. (Scheme 2, 1a
and 2a) that were much lower values than for the approach
starting with acid 1 as the substrate (99% yield and >95:5 e.r.;
1e and 2e) under otherwise identical conditions. Acid 1 and
urea 6 as additives were consistently found to improve the e.r.
values of corresponding products, although they have different
influences on the reaction yields with different electrophiles
(1b to 1d, 2b to 2d). We also found that the approach with
Acknowledgements
We acknowledge financial support by Singapore’s National Re-
search Foundation (NRF), the Ministry of Education (MOE), Na-
nyang Technological University (NTU), China’s National Key Pro-
gram for Basic Research (No. 2010CB 126105), Thousand Talent
Plan, National Natural Science Foundation (No. 21132003; No.
21472028), Guizhou Province Returned Oversea Student Sci-
ence and Technology Activity Program, and Guizhou University.
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Communication
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We thank Dr. R. Ganguly and Y. Li (NTU) for assistance with X-
ray structure analysis.
Keywords: asymmetric synthesis · b-activation · N-heterocyclic
carbenes · organocatalysis · propionic acid
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Received: April 16, 2015
Published online on May 26, 2015
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