N-heterocyclic carbene catalyzed enantioselective α-fluorination of aliphatic aldehydes and α-chloro aldehydes: Synthesis of α-fluoro esters, amides, and thioesters

Article abstract of DOI:10.1002/anie.201409961

The asymmetric fluorination of azolium enolates that are generated from readily available simple aliphatic aldehydes or α-chloro aldehydes and N-heterocyclic carbenes (NHCs) is described. The process significantly expands the synthetic utility of NHC-catalyzed fluorination and provides facile access to a wide range of α-fluoro esters, amides, and thioesters with excellent enantioselectivity. Pyrazole was identified as an excellent acyl transfer reagent for catalytic amide formation.

Full text of DOI:10.1002/anie.201409961

Angewandte
Chemie
DOI: 10.1002/anie.201409961
Organocatalysis
N-Heterocyclic Carbene Catalyzed Enantioselective a-Fluorination of
Aliphatic Aldehydes and a-Chloro Aldehydes: Synthesis of a-Fluoro
Esters, Amides, and Thioesters**
Xiuqin Dong, Wen Yang, Weimin Hu, and Jianwei Sun*
Abstract: The asymmetric fluorination of azolium enolates
that are generated from readily available simple aliphatic
aldehydes or a-chloro aldehydes and N-heterocyclic carbenes
(NHCs) is described. The process significantly expands the
synthetic utility of NHC-catalyzed fluorination and provides
facile access to a wide range of a-fluoro esters, amides, and
thioesters with excellent enantioselectivity. Pyrazole was iden-
tified as an excellent acyl transfer reagent for catalytic amide
formation.
method to readily available aliphatic aldehydes to enhance its
synthetic utility. However, there are several compatibility
issues to be addressed. For example, the oxidative conditions
required for enolate generation should be compatible with
the oxidizable NHC catalyst. The competition between
substrate, oxidant, and electrophilic fluorination reagent to
react with the NHC should also be balanced. Herein, we
report the realization of the asymmetric synthesis of a-fluoro
esters, amides, and thioesters from both simple aldehydes and
a-chloro aldehydes (Scheme 1).
T
he development of efficient synthetic methods for chiral
organofluorine molecules has recently attracted substantial
interest, owing to the valuable applications of such com-
pounds in medicinal chemistry, agrochemistry, and materials
science.[1,2] The catalytic asymmetric a-fluorination of car-
bonyl compounds is of particular interest. Over the past
decade, significant progress has been made. Different metal
and organocatalytic systems have been developed, particu-
larly for easily enolizable carbonyl compounds, such as 1,3-
dicarbonyl derivatives, aldehydes, and ketones. In contrast,
efficient asymmetric methods for a-fluorine incorporation
into less activated monocarbonyl compounds, such as esters,
amides, and thioesters, remain to be developed.[3,4]
Scheme 1. Fluorination of azolium enolates generated from simple
aliphatic aldehydes and a-chloro aldehydes.
Catalytic systems that are based on N-heterocyclic
carbenes (NHCs) have proven to be versatile in particular
for establishing the a-stereogenic center of esters via key
azolium enolate intermediates.[5–8] Previously, we have
reported the mono- and bisfluorination of vinylogous azolium
enolates that were generated from a,b-unsaturated aldehydes
bearing a leaving group in the g position.[9,10] However, this
method not only suffered from a limited scope, but also
required a multistep substrate synthesis. Recently, the Rovis
and Chi groups have reported the successful generation of
azolium enolates from simple aliphatic aldehydes under
oxidative conditions.[11] Inspired by their pioneering work,
we envisioned the expansion of our asymmetric fluorination
We started the evaluation of our hypothesis with aldehyde
1a. After considerable efforts comparing different reagents
required for the reaction (e.g., precatalyst, base, fluorination
reagent, oxidant), we were pleased to find that the desired
a-fluoro ester 2a could be formed with both good efficiency
and enantioselectivity with Bode catalyst A [Eq. (1)].[12] It is
noteworthy that N-fluorobenzenesulfonimide (NFSI) served
not only as the electrophilic fluorination reagent but also an
excellent oxidant.[13] Other oxidants, including MnO2, Dess–
Martin periodinane (DMP), oxone, PhI(OAc)2, and 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), proved to
be inferior, presumably because of the excellent oxidation
strength of NFSI. It probably outcompetes these oxidants, and
[*] Dr. X. Dong, Dr. W. Yang, Dr. W. Hu, Prof. Dr. J. Sun
Department of Chemistry
The Hong Kong University of Science and Technology
Clear Water Bay, Kowloon, Hong Kong SAR (China)
E-mail: sunjw@ust.hk
Dr. X. Dong
Department of Chemistry, Jinan University
Guangzhou 510632 (China)
[**] Financial support was provided by HKUST and Hong Kong RGC
(ECS605812, M-HKUST607/12, and GRF604513).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201409961.
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thus its subsequent function as a fluorine source is affected
when one equivalent of NFSI is used in combination with
another oxidant (1 equiv). Furthermore, K2CO3 was identi-
fied as the base of choice. Other bases, such as NaOAc,
KOAc, and Et3N, all resulted in significantly diminished
yields. The suitable basicity not only ensures successful
enolization of the acyl triazolium intermediate, but also
suppresses the nonproductive aldol reaction and other side
reactions.
With the standard conditions in hand, we next examined
the substrate scope of the transformation (Scheme 2). Differ-
ent aliphatic aldehydes all reacted smoothly to provide the
corresponding a-fluoro esters in moderate to good yield and
Scheme 3. Reaction scope with a-chloro aldehydes. Reaction condi-
tions: 3 (0.50 mmol), A (0.10 mmol), K2CO3 (0.75 mmol), NFSI
(0.53 mmol), R’OH (1.3 mmol), CHCl3 (5.0 mL). Yields of isolated
products are given.
the acyl transfer from acyl triazolium intermediates to amines
(relative to that to alcohols).[14,15] To overcome this challenge,
the groups of Rovis and Bode pioneered the use of additives
(e.g., 1-hydroxy-azobenzotriazole (HOAt), imidazole) as
relay shuttles for acyl transfer to amines. Unfortunately,
these known additives proved to be ineffective when used in
combination with our asymmetric fluorination method
(Table 1). However, additional screening identified pyrazole
as a compatible and excellent additive. Thus, the one-pot
synthesis of highly enantioenriched a-fluoro amides from
both aniline and benzyl amine was achieved. It is noteworthy
that phenyl hydrazine could also react to form the desired
product 4c. With the same method, a-fluoro thioesters could
also be successfully synthesized in excellent enantiomeric
excess.
Scheme 2. Variation of the aliphatic aldehyde coupling partner. Reac-
tion conditions: 1 (0.50 mmol), A (0.10 mmol), K2CO3 (1.5 mmol),
R’OH (0.56 mmol), CHCl3 (2.5 mL). Yields of isolated products are
given. Bn=benzyl, Fmoc=9-fluorenylmethoxycarbonyl.
with excellent enantioselectivity. Various functional groups,
such as Fmoc-protected amines, esters, ethers, and alkynes,
were tolerated. Heterocycles, such as the easily oxidizable
pyridine and thiophene, were also compatible with the
strongly oxidative reaction conditions.
Aside from simple aliphatic aldehydes, we also examined
the feasibility of using a-chloro aldehydes as the starting
materials (Scheme 3). According to the proposed mechanism,
an external oxidant is not required in this case. Indeed, with
only one equivalent of NFSI under otherwise almost identical
conditions, comparable results were obtained. The enantio-
selectivity remained excellent, which is consistent with the
involvement of the same azolium enolate intermediates.
Alcohols other than methanol were also suitable nucleo-
philes.
Considering the importance and challenges of catalytic
amide formation, we were also interested in extending the
fluorination process to the synthesis of a-fluoro amides.
However, when the alcohol nucleophile was simply replaced
with an amine, the desired product was not formed under the
above-described standard conditions. The formation of
amides by NHC catalysis is a known challenge that is
presumably due to complications arising from competing
non-productive imine formation reactions between the
amines and aldehydes as well as the intrinsic reluctance of
Whereas simple aliphatic aldehydes are suitable sub-
strates for our oxidative fluorination reaction, b,g-unsatu-
rated aldehydes might not be as practical owing to their
Table 1: One-pot synthesis of a-fluoro amides and thioesters.[a]
Entry
NuH
Product
Yield[b] [%]
ee [%]
1
2
3
BnNH2
PhNH2
PhNHNH2
4a
4b
4c
72
67
62
97
96
96
4
5
4d
4e
63
52
95
95
[a] 3a (0.50 mmol), A (0.10 mmol), K2CO3 (0.75 mmol), NFSI
(0.53 mmol), pyrazole (1.0 mmol), CHCl3 (5.0 mL). After stirring for
approximately 12 hours, the nucleophile (1.0 mmol) was added.
[b] Yields of isolated products.
2
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Chemie
relative instability. As the oxidative conditions for aldehyde
synthesis from the corresponding alcohol should be compat-
ible with our fluorination reaction, we envisaged the combi-
nation of the two steps into a one-pot process, thereby
obviating the need for isolation of the potentially labile
aldehyde. Therefore, alcohol 5 was initially treated with DMP.
Without work-up, the reaction mixture was then directly
subjected to the asymmetric fluorination conditions
(Scheme 4). The desired b,g-unsaturated a-fluoro ester 7
was obtained with reasonable overall efficiency and excellent
enantioselectivity.
tioenriched fluorinated products were shown to be precursors
to other useful fluorine-containing chiral building blocks.
Received: October 10, 2014
Revised: October 30, 2014
Published online: && &&, &&&&
Keywords: asymmetric catalysis · enolates · fluorine ·
.
N-heterocyclic carbenes · organocatalysis
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Scheme 5. Further transformations of an a-fluoro ester.
In summary, we have developed an efficient asymmetric
a-fluorination of azolium enolates that were generated from
simple aliphatic aldehydes and a-chloro aldehydes. With
a suitable combination of precatalyst, oxidant, base, and
fluorination reagent, the reaction proceeded smoothly to
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with excellent enantioselectivity. NFSI served as both the
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Organocatalysis
Two roles for NFSI: The N-heterocyclic
carbene (NHC) catalyzed asymmetric
fluorination of readily available simple
aliphatic aldehydes, a-chloro aldehydes,
and even alcohols proceeds via azolium
enolates and yields a wide range ofa-
fluoro esters, amides, and thioesters with
excellent enantioselectivity. N-Fluoroben-
zenesulfonimide (NFSI) acts as both
a fluorinating reagent and an oxidant in
this transformation.
X. Dong, W. Yang, W. Hu,
J. Sun*
&&&& — &&&&
N-Heterocyclic Carbene Catalyzed
Enantioselective a-Fluorination of
Aliphatic Aldehydes and a-Chloro
Aldehydes: Synthesis of a-Fluoro Esters,
Amides, and Thioesters
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