Carbene-Catalyzed Direct Functionalization of the β-sp3-Carbon Atoms of α-Chloroaldehydes

Article abstract of DOI:10.1002/chem.201903592

A direct functionalization of the β-sp³ carbon atom of α-chloro aldehyde has been developed. The reaction starts with the addition of a carbene catalyst to α-chloroaldehyde to eventually form the homoenolate intermediate. This overall redox-neu

Full text of DOI:10.1002/chem.201903592

A Journal of
Accepted Article
Title: Carbene-Catalyzed Direct Functionalization of β-sp³-Carbons of
α-Chloroaldehydes
Authors: Bin Liu, Guoyong Luo, Hongling Wang, Lin Hao, Song Yang,
Zhichao Jin, and Yonggui Robin Chi
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.201903592
Link to VoR: http://dx.doi.org/10.1002/chem.201903592
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3
Carbene-Catalyzed Direct Functionalization of -sp -Carbons of -
Chloroaldehydes
Bin Liu,†[a,c] Guoyong Luo,†[b,c] Hongling Wang,[a] Lin Hao, Song Yang, * Zhichao Jin, and Yonggui
[c]
[a]
[a]
Robin Chi[a,c]
*
3
Abstract: A direct functionalization of the -sp carbon of -chloro
aldehyde is developed. The reaction starts with the addition of a
carbene catalyst to -chloroaldehyde to eventually form homoenolate
intermediate. This overall redox-neutral process successfully converts
Here we disclose a new approach for the generation of
homoenolate intermediates by using -chloroaldehydes as the
substrates (Figure 1a). Our reaction starts with the formation of
an azolium ester enolate intermediate I from -chloroaldehyde
(1a) and NHC catalyst (Figure 1b), this process first reported by
Rovis and Bode.[9] In those previous reports,[9c] the azolium ester
enolate intermediates underwent further reactions with the -
carbons as the nucleophilic reaction centres. In our present study,
the -carbon of enolate intermediate I undergoes a deprotonation
to form homoenolate intermediate II for further asymmetric
reactions. The overall process converts the otherwise inert -sp3
carbon of -chloroaldehyde to a nucleophilic carbon. Bases and
acidic additives were found to have dramatic influences on
chemo-selectivity of the reactions (selection between - and -
carbon of the aldehyde substrates). Control experiments revealed
that -chloroaldehydes were not converted to enals under our
conditions and ruled out the possibilities for the involvement of
enals as substrates in our reactions.
3
the otherwise inert -sp -carbon of the aldehyde substrate to a
nucleophilic carbon for asymmetric reactions. This study constitutes
the first success in activating -chloroaldehydes to generate
homoenolate intermediates via carbene organic catalysis, and shall
encourage further explorations in using organic catalysis for
transforming inert chemical bonds.
Carbonyl compounds are among the most common substrates
involved in organic synthesis. Numerous methods have been
developed to functionalize the -carbons of saturated carbonyl
compounds or -sp -carbons of ,-unsaturated carbonyl
molecules. In contrast, strategies for direct functionalization of
2
[
1]
3

-sp -carbons of saturated carbonyl substrates are less
developed. Much progress in catalytic direct functionalization on
3
the -sp -carbons of carbonyl compounds comes from transition
metal-mediated carbon-hydrogen bond activations.[2] The use of
organic catalysts (such as amines) in combination with transition
metal photo catalysts[3] or oxidants[4] have also shown impressive
3
success in activating otherwise inert -sp carbons of saturated
carbonyl compounds. In 2013, our laboratory showed that with N-
heterocyclic carbine (NHC) used as the organic catalysts,[5]
saturated carboxylic esters can be activated to generate
homoenolate intermediates via an overall redox-neutral process
[
6]
(
Figure 1a). This unusual activation catalytically converts the -
3
sp carbon of ester to a reactive nucleophilic carbon of
asymmetric reactions.[7] As an important note, these homoenolate
intermediates were traditionally generated by using enals as the
substrates under NHC catalysis, as pioneered by Bode, Glorius,
and others (Figure 1a).[8]
[
a]
B. Liu, H. Wang, Prof. Dr. Z. Jin, Prof. Dr. S. Yang, 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, People’s Republic of China.
E-mail: robinchi@ntu.edu.sg
Figure 1. NHC-catalyzed direct -sp3 carbon functionalization of α-chloro
aldehydes via homoenolate intermediates
jhzx.msm@gmail.com
[
†]
These authors contributed equally to this work.
Dr. G. Luo
[
b]
Guizhou University of Traditional Chinese Medicine, Guiyang
Key results of condition optimization by using -chloro
aldehyde 1a and isatin 2a as the model substrates are
summarized in Table 1. The amino indanol-derived triazolium
NHC pre-catalyst, first reported by Bode,[10] was found as a
suitable catalyst. When the reaction was carried out with DIEA as
the base and THF as the solvent, the -carbon reaction product
was obtained in low while encouraging 10% yield and the -
5
50025, China
[
c]
B. Liu, Dr. G. Luo, Dr. L. Hao, Prof. Dr. Y. R. Chi
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore.
.
Supporting information for this article is available on the WWW
under http://www.XXXX.org.
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Chemistry - A European Journal
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COMMUNICATION
Table 2. Scope of reactions.[a]
carbon reaction product 3a’ was afforded as the main adduct in
42% yield (entry 1). Replacing DIEA with DMAP as the base
improved the chemo-selectivity of the - over -carbon reactions,
with the -carbon reaction product 3a obtained in 68% yield (entry
2
). In NHC-catalyzed reaction of enals, earlier studies from
Bode[ and us[12] found that bases could influence the -carbon
protonation process and thus converted homoenolate to enolate
intermediates. In this present study, it appears that the bases can
have profound impacts on the -carbon deprotonation process
and thus convert enolate to homoenolate intermediates
11]
(
intermediates I to II, Figure 1). We next studied the effects of
additives and found that HOBt could dramatically improve the -
carbon reaction yield and product dr (entries 3-8). For example,
the yield of -carbon reaction product (3a) could be improved from
68% to 95% when HOBt additive was added to the reaction with
DMAP as the base (entries 2-3). This beneficial effect of HOBt is
quite general when different bases were used (entries 3-8).
Inorganic bases (such as K CO ) and other solvent (such as
2 3
EtOAc) could be used as well to afford 3a with excellent yield and
dr and er values. It is worth noting that in the absence of HOBt the

-carbon reaction product (3a) was obtained in a low yield under
otherwise identical conditions (e.g., entry 9; also see SI). In all
cases with HOBt as an additive, the -carbon reaction product
was dramatically suppressed. The exact roles of HOBt remain
unclear. It appears HOBt can have hydrogen bonding interactions
with the isatin substrate (2a)[7d] to facilitate the -carbon reactions.
The use of HOBt also led to small while consistent improvements
on reaction diastereo- and enantio-selectivities.[4e,7b,13]
Table 1. Optimization of reaction conditions.[a]
[a] General conditions (unless otherwise specified): 1 (0.20 mmol), 2 (0.10
mmol), NHC (0.02 mmol), K CO (0.30 mmol), HOBt (0.02 mmol), EA (2.0
2
3
mL), RT, 24 h. [b] Isolated yield of 3. [c] The dr values were estimated via
H NMR analysis. [d] Er was determined via HPLC on chiral stationary
phase.
3
a (3a’)
3a
dr[c]
--
3a
er[d]
1
Entry
Base, Solvent
additive
Yield [%][b]
1
2
3
4
5
6
7
8
9
DIEA, THF
DMAP, THF
DMAP, THF
DIEA, THF
-
~10 (42)
--
-
68 (11)
3:1
94:6
97:3
97:3
96:4
98:2
99:1
99:1
83:17
With an optimized reaction condition in hand (Table 1, entry
7), we next examined the generality of our -sp carbon reaction
strategy with different -chloroaldehydes (1) and isatins (2)
Scheme 2). Placing substituents (e.g. halogens, methyl or
methyoxyl groups) on the para-carbons of the -phenyl rings of
the -chloroaldehydes were well tolerated (3b-f). These
sbustituents could also be installed on the meta-carbon of the -
phenyl rings of the aldehydes (3g-j). Variations on the isatins
substrates were all well tolerated, as examplified in products 3k-
v. As a technical note, when -chloroaldehyde with a -alkyl
substituent was used, the corresponding -carbon reaction
product (3w) was not observed likely due to the low acidity of the
3
HOBt
HOBt
HOBt
HOBt
HOBt
HOBt
-
95 (trace)
92 (trace)
84 (trace)
86 (trace)
92 (trace)
78 (trace)
29 (trace)
6:1
13:1
13:1
15:1
17:1
8:1
(
K
2
CO
DIEA, EtOAc
CO , EtOAc
DMAP, EtOAc
CO , EtOAc
3
, THF
K
2
3
K
2
3
8:1
[
a] General conditions (unless otherwise specified): 1a (0.10 mmol), 2a (0.05
mmol), NHC (0.01 mmol), base (0.15 mmol), solvent (1.0 mL), HOBt (0.01
mmol), RT, 24 h. [b] Isolated yield. [c] The dr values were determined via 1
NMR analysis. [d] Er values were determined via HPLC on chiral stationary
phase. Trt = Triphenylmethyl, DIEA = N,N-diisopropyl-ethylamine, DMAP = 4-
dimethylaminepyridine.
H

-CH.
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Scheme 1. Control experiments to understand reaction mechanism.
To understand the reaction pathway and the role of HOBt,
multiple control experiments were performed. Under the current
optimized reaction condition, elimination of -chloroaldehyde 1a
to form ,-unsaturated aldehyde 5a was not observed. We then
used a mixture of -chloroaldehyde and saturated ester (4a) from
HOBt (1:1 molar ratio) to react with isatin (1a) under the optimal
condition (Scheme 1b and 1c). Our results showed that the -
carbon reaction products (e.g., 3a or 3f) mainly came from the -
chloroaldehydes. These experiments support that the -carbon
activation and homoenolate intermediate formation are directly
-carbons of -chloroaldehydes. Chloroaldehydes exhibit high
reactivities with carbene catalysts, and therefore we expect this
approach to offer complimentary and, in some cases, better
solutions for homoenolate reactions. Further studies for direct
activation of other inert chemical bonds via carbene organic
catalysis are in progress in our laboratory.
Acknowledgements
resulted from -chloroaldehydes (not via the saturated esters with
as proposed in Figure 1b. We also ruled out the
possibility for the involvement of -unsaturated aldehydes (e.g,
We acknowledge financial support from the National Natural
Science Foundation of China (No. 21772029, 21801051),
National Key Technologies R&D Program (No. 2014BAD23B01),
HOBt),[
9d,9e]
5a or 5b) as key intermediates in our reaction (Scheme 1d and
“
Thousand Talent Plan”, The 10 Talent Plan (Shicengci) of
1e). Specifically, when the corresponding -unsaturated
Guizhou Province, Guizhou Province Returned Oversea Student
Science and Technology Activity Program, Guizhou University,
the Guizhou Province First-Class Disciplines Project (Yiliu Xueke
Jianshe Xiangmu)-GNYL(2017)008, Guizhou University of
Traditional Chinese Medicine (China). Singapore National
Research Foundation (NRF-NRFI2016-06), the Ministry of
Education of Singapore (MOE2013-T2-2-003; MOE2016-T2-1-
aldehydes were used as substrates under the present conditions
optimized for the -chloroaldehyde reactions), the corresponding
(
-lactam products (e.g., 3a or 3f) were not formed.
In summary, we have developed the first carbene-catalyzed
3
direct -sp -carbon functionalization of -chloroaldehydes. Key
steps in this catalytic process include azoium ester enolate
formation followed by -CH deprotonation to form homoenolate
intermediate for direct -carbon reactions. The use of HOBt
additive significantly alters the chemo-selectivity between - and
0
(
32; RG108/16), A*STAR Individual Research Grant
A1783c0008), Nanyang Research Award Grant, and Nanyang
Technological University.
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Layout 2:
COMMUNICATION
†
†
Bin Liu, Guoyong Luo, Hongling Wang,
Lin Hao, Song Yang,* Zhichao Jin, and
Yonggui Robin Chi*
Page No. – Page No.
Carbene-Catalyzed Direct
3
Inert carbon activation: direct functionalization of the -sp3 carbons of -chloro
aldehydes under the influence of NHC organic catalyst is realized.
Functionalization of -sp -Carbons of
α-Chloroaldehydes
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