Enantio- and Diastereoselective Hydrofluorination of Enals by N-Heterocyclic Carbene Catalysis

Article abstract of DOI:10.1002/anie.201902989

In contrast to well-established asymmetric hydrogenation reactions, enantioselective protonation is an orthogonal approach for creating highly valuable methine chiral centers under redox-neutral conditions. Reported here is the highly enantio- and diastereoselective hydrofluorination of enals by an asymmetric β-protonation/α-fluorination cascade catalyzed by N-heterocyclic carbenes (NHCs). The two nucleophilic sites of a homoenolate intermediate, generated from enals and an NHC, are sequentially protonated and fluorinated. The results show that controlling the relative rates of protonation, fluorination, and esterification is crucial for this transformation, and can be accomplished using a dual shuttling strategy. Structurally diverse carboxylic acid derivatives with two contiguous chiral centers are prepared in a single step with excellent d.r. and ee values.

Full text of DOI:10.1002/anie.201902989

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Accepted Article
Title: Enantio- and Diastereoselective Hydrofluorination of Enals via N-
Heterocyclic Carbene Catalysis
Authors: Leming Wang, Xinhang Jiang, Jiean Chen, and Yong Huang
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10.1002/anie.201902989
Angewandte Chemie International Edition
COMMUNICATION
Enantio- and Diastereoselective Hydrofluorination of Enals via N-
Heterocyclic Carbene Catalysis
Leming Wang,[a] Xinhang Jiang,[a] Jiean Chen,*[a] Yong Huang*[a]
Dedication ((optional))
Abstract: In contrast to well-established asymmetric hydrogenation
reactions, enantioselective protonation is an orthogonal approach to
create highly valuable methine chiral centers under redox-neutral
conditions. We report highly enantio- and diastereoselective
hydrofluorination of enals via an asymmetric β-protonation-α-
fluorination cascade catalyzed by N-heterocyclic carbene. The two
nucleophilic sites of a homoenolate intermediate, generated from
enals and an N-heterocyclic carbene, are sequentially protonated and
fluorinated. Our results show that controlling the relative rates of
protonation, fluorination and esterification is crucial for this
transformation, which can be accomplished using a dual shuttling
strategy. Structurally diverse carboxylic acid derivatives with two
continuous chiral centers are prepared in a single step with excellent
dr and ee.
ester enals, a reaction which was later extended to ,-aryl, alkyl
enals by the same group.[5] In 2017, our group reported
enantioselective hydrogenation of enals using bridgehead
nitrogen amines as
a
selective proton transfer agent.[6]
Subsequently, we discovered that the same transformation can
be accomplished with a broader substrate scope by using a
combination of an achiral NHC and a chiral phosphoric acid.[7] We
recently applied this strategy to the synthesis of -chiral amides,
hydrazides, acid, esters, peresters and heterocycles.[8] However,
all asymmetric -protonation reactions mentioned above are only
applicable to products lacking an -chiral center. We envisioned
that upon -protonation of the homoenolate intermediate, the
resulting acyl azolium species could be intercepted by an
electrophilic fluorinating agent under basic conditions, to give the
formal hydrofluorination product with continuous  and  chiral
centers (Scheme 2).
There are high interests in developement of general synthetic
strategies towards fluorine-containing compounds, due to their
broad applications of in pharmaceuticals and agrochemicals.[1]
Direct, asymmetric hydrofluorination is particularly attractive, due
to aboundance of common olefinic chemical feedstocks.[2]
However, introduction of two continuous chiral centers, one of
which being a fluorine-containg stereogenic center, in a single
process is very challenging. Asymmetric metal hydride addition to
olefins, followed by trapping of the corresponding organometallic
species with a fluorine source, has been reported (Scheme 1A).[3]
MacMillan et al. reported a formal asymmetric addition of H--F+ to
electron-deficient olefins using a cascade of iminium/enamine
catalysis (Scheme 1B).[4] These approaches use reducing
reagents for the hydride transfer and oxidative conditions for the
fluorination, which proceeds by a sequential or stepwise manner.
In this paper, we report a complementary strategy of formal
asymmetric addition of H+-F+ to enals via a enantioselective -
protonation, diastereoselective -fluorination and esterification
cascade (Scheme 1C). This redox neutral transformation
demonstrates wide tolerance to functional groups and structural
motifs.
Scheme 1. Asymmetric hydrofluorination of olefins.
Sun and Wang reported enantioselective -fluorination of
acyl azolium compounds using aliphatic aldehydes.[9] However,
their protocols cannot be extended to -protonation, due to the
absence of a proton source in the reaction. Mechanistically,
tethering -protonation and -fluorination presents several
challenges, with the first being chemoselectivity. In the proposed
catalytic cycle (Scheme 2), there are two reactive electrophiles,
H+ and F+, and the -carbon of the homoenolate needs a way to
differentiate between them. The second challenge is premature
esterification of the acyl azolium intermediate prior to -
fluorination. It has been demonstrated that esterification is facile
using alcohols as NHC turnover agents[10] and consequently, in
order to accomplish effective -fluorination, slowing down
esterification and increasing basicity of the reaction media are
necessary. However, once -fluorination is accelerated by
increasing the concentration of the enolate, the -protonation will
inevitably be compromised due to the low concentration of
protons. As a result, complications might arise from -fluorination
or direct oxidation of the homoenolate. We recently found that
oxidation of homoenolates to ,-unsaturated esters
predominates when the concentration of protons in the reaction
Recently, asymmetric protonation reactions catalyzed by N-
heterocyclic carbenes (NHC) emerged as a general, redox-
neutral strategy for the synthesis of -chiral carboxyl derivatives.
In 2015, Scheidt et al. reported asymmetric hydrogenation of -
[a]
Dr. L. Wang, Mr. X. Jiang, Prof. Dr. J. Chen and Prof. Dr. Y. Huang
State Key Laboratory of Chemical Oncogenomics, Key Laboratory
of Chemical Genomics, Peking University, Shenzhen Graduate
School
Shenzhen, 518055 China
E-mail: chenja@pkusz.edu, huangyong@pkusz.edu.cn
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201902989
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system is low.[11] This is consistent with reports that F+ is an
effective oxidant for Breslow-type of enols or homoenolates even
in an inert atmosphere.[9,12] In order to address these issues, we
propose introducing suitable proton and fluorine transfer agents,
as well as NHC turnover agents, which might help accomplish a
delicate kinetic balance for the desired -protonation--
fluorination cascade.
those in entry 4. A 4:1 mixture of toluene and dioxane promotes
high chemoselectivity, enantioselectivity and yield simultaneously.
Screening of other NHC scaffolds results compromised
conversion and ee value (with cat. 4b to 4f).
Table 1. Optimization of conditions for hydrofluorination of cinnamaldehyde.[a]
entry
solvent
base
yield (%)
3a/3a’
ee (%)
1
2
3
4
PhMe
K2CO3
12
93
34
86
5:1
88
92
93
96
PhMe
iPrCO2Li
iPrCO2Li
iPrCO2Li
3.3:1
33:1
17:1
1,4-dioxane
PhMe/dioxane (4:1)
[a] Reactions were performed using 0.1 mmol of 1a and 0.2 mmol of 2a in 1.0 mL
solvent under argon for 24 h at r.t. Total yield for 3a and 3a’. Ratio of 3a and 3a’
was determined by GC. Ee value was Determined by chiral HPLC.
Scheme 2. Plausible reaction pathways of asymmetric hydrofluorination via
NHC-mediated homoenolate intermediates.
We began our investigation using cinnamaldehyde (1a) as
substrate. The lack of the second β-substituent makes this
compound ideal for studying the α-fluorination step independently
without concern about the asymmetric control of the β-protonation.
Preliminary survey revealed that 1-chloromethyl-4-fluoro-1,4-
diazoniabicyclo-[2.2.2]-octane bis(tetrafluoroborate) (Selectfluor)
is the preferred F+ reagent for this transformation.[13] β-
Fluorination and direct oxidation of the homoenolate are
effectively suppressed as a result of the low solubility of
Selectfluor in non-polar solvents. Other, more soluble F+ agents,
such as N-fluorobenzene sulfonimide (NSFI), cause significant
decomposition of 1a. When small-sized primary alcohols are used
as the catalyst turnover agent, premature esterification, yielding
the non-fluorinated by-product 3a’, is the dominant reaction
pathway. Bulkier secondary alcohols, such as cyclohexanol, lead
to formation of the desired α-fluoro product (3a) which is
generated in low yield with high enantioselectivity (Table 1, entry
1). We believe lack of a proton-transfer promotor is responsible
for the unproductive β-protonation. Significantly improved
conversion was obtained when lithium isobutyrate (iPrCO2Li) was
The scope of β-aryl enals under the optimized conditions
was studied (Table 2). Both electron-poor and electron-rich
substituents at various positions of the β-aryl group are well
tolerated, and give products 3a-3n. Minimal influence on yield and
ee was observed for o-substituted cinnamaldehydes, substrates
that often perform poorly in homoenolate chemistry (products 3d
and 3l). The presence of higher order aryls with fused rings do not
compromise the efficiency and selectivity of this reaction.
Structurally appealing β-aryl-α-fluoro esters (3o-3q) were
obtained. Heteroaryl containing substrates have been
demonstrated only rarely in previous reports of olefin
hydrofluorination. Electron-rich heteroarenes often compete for
metal hydride addition, while those containing one or more basic
nitrogens bind to transition metal catalysts. Our protocol can be
applied to a wide range of β-heteroaryl compounds, and chiral α-
fluoro esters with a β-pyridyl, furyl, benzofuryl, thienyl or
benzothienyl group (3r-3v) were formed with good yield and ee.
When cyclohexanol was replaced by cholesterol, the reaction
proceeded in high yield and with exclusive diastereoselectivity
(product 3w).
i
used (entry 2). It is hypothesized that PrCO2H is an effective
i
-
proton source that accelerates -protonation. The PrCO2 ion
might also serve as phase-transfer-catalyst to assist
a
Table 2. Scope of β-aryl enals in the enantioselective hydrofluorination.
solubilization of Selectfluor. Despite the dual role of iPrCO2Li, the
non-fluorinated product (3a’) was still formed in 22% yield. Much
higher chemoselectivity was observed when the solvent was
changed from toluene to dioxane, although the overall conversion
decreased (entry 3). A control experiment, in which Selectfluor
was absent, showed the β-protonation to be very slow in dioxane,
accounting for the poor conversion to 3a’. Based on this result,
we decided to examine conditions using solvent mixtures and
further investigate various carboxylates (see Table S1 for more
detials). Eventually, the optimal conditions were identified as
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10.1002/anie.201902989
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COMMUNICATION
tolerated, but transesterification was not observed for substrates
containing an ester or phosphate moiety (products 6k-6n). In
cases in which the esterification used 3-pentanol, a number of
side reaction pathways are suppressed. To demonstrate
applicability to late-stage drug modification, an estrone analogue
with a chiral fluorine-containing group (6o) was prepared in 70%
yield and 91% de.
Table 3. Scope of β-alkyl enals in the enantioselective hydrofluorination.
When the substrate scope is extended to β-alkyl enals, the
chemoselectivity of hydrofluorination vs. hydrogenation
deteriorates considerably. Preliminary optimization of the
conditions showed that premature esterification competes with α-
fluorination using cyclohexanol. Potassium carbonate, in
combination with 20 mol% of sodium pivalate as a dual
protonation/fluorination buffer, leads to a mixture of products 6
and 6’ in a ratio of 1.6/1 (Table 3). We tested bulky, acyclic
secondary alcohols, hoping to further slowdown the esterification
while maintaining good catalyst turnover. As expected, reactions
using i-propanol significantly improve the ratio of 6/6’ and with the
bulkier 3-pentanol, product 6 is formed exclusively. A series of -
alkyl enals were evaluated and generally, good yields and ee
were obtained (Table 3). Increasing steric hindrance at the
neighboring γ-carbon does not affect the reaction efficiency and
selectivity (product 6d). Alkyl chains containing a heterocyclic
moiety, such as thiophene, pyridine and piperidine, are well
tolerated, giving products 6e-6f and 6i. A number of functional
groups were introduced to the -alkyl group, with no effect on the
selectivity, giving products 6g-6o. The reaction proceeds
smoothly for enals with a terminal alkyne or olefin which often
interfere with transition-metal-catalyzed, reductive reactions,
leading to products 6g and 6h. Despite the presence in the
reaction of two electrophiles, a number of nucleophilic groups are
-Fluoro esters containing two continuous chiral centers are
essential building blocks for synthetic and medicinal chemistry.
Synthetic approaches to these molecules are rare.[14] Our
hydrofluorination strategy offers a straightforward approach to -
fluoro esters with additional chiral centers from readily available
-substituted cinnamaldehydes. With these substrates, however,
further challenges are presented. The rate of -protonation might
be affected by the extra -substituent so that neither cyclohexanol
or 3-pentanol might be able to preclude the premature
esterification. As expected, an inseparable non-fluorinated
product (8’) was formed in significant quantities from reactions
employing cyclohexanol and 3-pentanol. After further screening,
it was found that 2,3-dihydro-1H-inden-2-ol (2d) is an excellent
scavenger for NHC turnover, with little formation of compound 8’
(Table S2).
After solving the chemoselectivity issue, diastereoselectivity
appears as a more serious problem. Although the NHC precursor
(4) induces excellent discrimination in the -fluorination step,
asymmetric control of the -protonation is likely to be
compromised when a carboxylate is used as a proton transfer
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10.1002/anie.201902989
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COMMUNICATION
was measured by 1H-NMR; ee was measured by chiral HPLC. [b] The reaction
was performed at 0 oC for 12 h and another 24 h at rt.
agent. Our previous reports showed that only bridgehead
nitrogens can serve as highly enantioselective proton sources
and low ee’s were observed when carboxylate is used as a
protonation promotor.[6] If the -protonation occurs with low
enantioselectivity for β,β-disubstitued enals,
a mixture of
The optimized conditions are generally applicable for a broad
scope of ,-disubstituted enals (Table 5). Aromatic substitution,
giving products 8b-8c is widely tolerated for the β-aryl moiety. A
decrease in the electron density of the β-aryl group resulted in
diminished yield of products 8d and 8e and dr, probably due to
the slow -protonation. Substrates containing a β-heterocyclic
group, especially those with basic nitrogen atoms, do not disrupt
this delicate -protonation--fluorination cascade (products 8g-
8i), and both the ee and dr remain high. The β-methyl group can
be extended to diverse aliphatic structures (products 8j-8n). Enals
with an exocyclic double bond react smoothly in good yield with
excellent dr and ee (8o). Functional groups, including labile
halides on the -alkyl chain, are not affected, yielding extra
handles for further synthetic manipulations (products 8p-8r). One
limitation to this protocol is its failure with β-dialkyl enals. No
desired hydrofluorination product was obtained when using
cyclopropylideneacetaldehyde (8u). Compounds with elaborated
-alkyl groups, for example L-menthol and cholesterol, allow
access to structurally complicated chiral -fluoro esters (products
8s-8t).
diastereomeric products will be formed despite a highly selective
-fluorination event (Table 4). Indeed, the reaction involving β-
methyl cinnamaldehyde yielded the desired hydrofluorination
product 8a in 25% yield, 1.4:1 dr and 96% ee using the optimized
conditions in Table 2 (Table 4, entry 1). The conditions used for
Table 3 also lead to poor yield and dr (entry 2). To address this
issue, we decided to introduce two separate modifiers for -
protonation and -fluorination, respectively. A combination of
quinuclidine and carboxylic acid should be the most promising.
Toste reported carboxylic/phosphoric acids accelerate fluorine
transfer from Selectfluoro, via phase transfer catalysis.[15] In this
scenario, a proper choice of carboxylic acids may also facilitate
highly selective α-fluorination. Compared to other carboxylic acids,
1-adamantanecarboxylic acid (1-AdCO2H) quickly emerged as a
superior fluorination promotor for this transformation. However,
the overall yield of 8a and the dr remained unsatisfactory, and this
can be attributed to the low acidity of 1-AdCO2H, from which a
proton is not fully transferred to quinuclidine (entry 3). As a result,
rate of -protonation is attenuated and the enantioselectivity is
compromised by direct, non-selective proton-transfer from 1-
AdCO2H. In order to generate a sufficient concentration of
protonated quinuclidine as the proton source, strong Brønsted
acids were added and it was found that introduction of 1.0 eq. TFA
simultaneously improved the yield, dr and ee (entry 4). Performing
-protonation at 0C and -fluorination at room temperature led
to hydrofluorined products with 70% yield, >20/1 dr and >99% ee
(entry 5). The low temperature used for the -protonation step
Table 5. Scope of β-alkyl-β-aryl enals in the diastereo- and enantioselective
hydrofluorination.
enhances
enantioselectivity
and
prevents
destructive
homoenolate oxidation. Both dr and ee are significantly improved
using the stepped temperature procedure, compared to room
temperature only. (see Table S3 for more detials)
Table 4. Optimization of conditions for hydrofluorination of ꞵ-methyl
cinnamaldehyde.[a]
entry
solvent
PTA
FTA (eq.)
yield (%)
(dr)
ee
(%)
1
2
3
4
Conditions for Table 2
Conditions for Table 3
25 (1.4:1)
13 (1:1.2)
30 (4:1)
96
97
PhMe
PhMe
quinuclidine
1-AdCO2H (1.0)
1-AdCO2H (1.0)
+ TFA (1.0)
98
quinuclidine
quinuclidine
53 (7:1)
>99
1-AdCO2H (0.5)
+ TFA (1.0)
5[b]
mesitylene
70 (>20:1)
>99
[a] Reactions were performed using 0.1 mmol 7a, 0.25 mmol 2d, 0.12 mmol
Selectfluor, 0.6 mmol proton transfer agent (PTA) and the indicated amount of
fluorine transfer agent (FTA) in 1.0 mL solvent at rt for 24 h; GC yield; dr value
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10.1002/anie.201902989
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In summary, a general asymmetric hydrofluorination reaction of
enals has been accomplished via NHC catalysis. This method
represents a universal protocol for the synthesis of chiral -fluoro
esters from readily available enals. A dual promotor strategy is
essential in the reaction to control the chemo-, diastereo- and
enantioselectivity. The key factor for this transformation lies in
striking a balance between the relative rates of -protonation and
the subsequent -fluorination. A number of side reaction
pathways can be suppressed by an appropriate choice of
modifiers. Carboxylates serve as a dual promotor for efficient
asymmetric hydrofluorination of -aryl and -alkyl enals. A
combination of quinuclidine, TFA and 1-AdCO2H, is identified as
competent additives that promote reactions involving more
challenging ,-disubstituted enals in good yield, excellent dr and
ee. The continuous - and -chiral centers are dictated by a single
NHC catalyst in two separate events.
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This work was financially supported by the National Natural
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Keywords: shuttling catalysis • diastereoselectivity • asymmetric
hydrofluorination • redox neutral • homoenolate intermediate • N-
heterocyclic carbene
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Leming Wang,[a] Xinhang Jiang,[a] Jiean
Chen,*[a] Yong Huang*[a]
Enantio- and Diastereoselective
Hydrofluorination of Enals via N-
Heterocyclic Carbene Catalysis
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