Stereoselective synthesis of α-fluoroacrylonitriles: Via organocatalytic cyanation of gem -difluoroalkenes and TMSCN

Article abstract of DOI:10.1039/c9nj02370d

An organocatalytic cyanation reaction of gem-difluoroalkenes was developed. Under the catalysis of 10 mol% DBU, gem-difluoroalkenes undergo a nucleophilic addition-β-elimination reaction with trimethylsilyl cyanide to provide α-fluoroacrylonitriles in 50-98% yields with excellent Z/E selectivity.

Full text of DOI:10.1039/c9nj02370d

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Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
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DOI: 10.1039/C9NJ02370D
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Stereoselective synthesis of α-fluoroacrylonitriles through
organocatalytic cyanation of gem-difluoroalkenes and TMSCN
Received 00th January 20xx,
Accepted 00th January 20xx
Yu-Chuan Ma, Yang Zhang, Cheng-Zhi Gu, Guang-Fen Du,* Lin He*
DOI: 10.1039/x0xx00000x
An organocatalytic cyanation reaction of gem-difluoroalkenes was developed. Under the catalysis of 10 mol% DBU, gem-
difluoroalkenes undergo nucleophilic addition-β-elimination reaction with trimethylsilyl cyanide to provide α-
fluoroacrylonitriles in 50%-98% yields with excellent Z/E selectivity.
prepared
a
stable
reagent
(1,3-benzothiazol-2-
Introduction
ylsulfonyl)fluoroacetonitrile via multistep reactions. In the
presence of 4.0 equivalents of DBU, this reagent can undergo
fluoro-Julia olefination with aldehydes to provide α-
fluoroacrylonitriles in high yields with good Z-selectivity
(Scheme 1, eq 2). Recently, Rolando and co-workers12
developed the copper-catalyzed coupling reaction of alkenyl
halide and potassium cyanide, which gave α-
fluoroacrylonitriles in high yield (Scheme 1, eq 3). Interestingly,
using benzyl nitrile as a cyanating reagent, Cao and co-
workers13 developed a highly stereoselective cyanation of
gem-difluoroalkenes (Scheme 1, eq 4).
The monofluoroalkene is an important structural motif found
in many agrochemicals, pharmaceuticals and functional
materials.1 Owing to its unique physical and chemical
properties, this fluorinated unit has been used widely in the
synthesis of peptide mimics2 and served as the amide
bioisosteres3 in medicinal chemistry. Moreover, they can also
serve as fluorinated building blocks in organic synthesis.4
Therefore, considerable efforts have been exerted to develop
new methods for the synthesis of these important
frameworks.5
organocatalysts catalyzed C-F bond functionalization of gem-
difluoroalkenes with different nucleophiles provides
Among
them,
transition-metal
and
Van der
2004
Gen,
FCH2CN
a
O
O
H
R
F
CN
F
LDA
RCHO
-78 °C-rt
(2.0 equiv)
-78 °C
Ph2PCl
Ph2P
(1)
(2)
powerful and effective strategy for the synthesis of
functionalized monofluoroalkenes.6 On the other hand, the
acrylonitrile is another common structural subunit existing in
different biologically active compounds and pharmaceuticals.7
The cyano group can feasibly transfer to other useful
functional moieties, such as amine, amidine and carboxylic
acid.8 The significance of this motif has attracted considerable
attention from organic chemists. In the past decade,
transition-metal catalyzed cyanation of alkenes and alkenyl
halides have been extensively developed, which provides facile
access to different acrylonitrile derivatives.9 Despite numerous
achievements accomplished in this research field, the
synthesis of fluorinated acrylonitriles remains far less
examined. In 2004, Van der Gen and co-workers10 reported a
THF,
CN
2008
Zajc,
O
H
F
N
S
O
DBU
CH2Cl2 -78 °C
,
(4.0 equiv)
S
CN
RCHO
-rt
R
CN
F
2012
Rolando,
H
F
H
F
−
Cu+BF4
(CH3CN)4
150 °C 18h
(3)
KCN
,
NMP,
R
CN
R
Br
2016
F
Cao,
H
H
F
t-BuOLi
(5.0 equiv)
rt
(4)
(5)
PhCH2CN
TMSCN
DMF, air,
R
CN
R
F
This work
H
R
F
DBU
H
F
(10 mol%)
rt
DMSO,
Horner-wittig
reaction
of
CN
R
F
(diphenylphosphinoyl)fluoroacetonitrile and aldehydes, which
produced α-fluoroacrylonitriles in moderate yield and low Z/E
selectivity (Scheme 1, eq 1). In 2008, Zajc and co-workers11
Scheme 1 Different synthesis methods of α-fluoroacrylonitriles
However, these methods often suffer from some
drawbacks, such as harsh reaction conditions, the use of highly
toxic cyanating reagent and the addition of excess of additives.
Therefore, the development of more convenient and mild
method for the synthesis of α-fluoroacrylonitriles is still highly
significnce. In line with our continue interest of the
functionalization of C-F bonds of gem-difluoroalkenes14 and N-
heterocyclic carbene-catalyzed activation of silylated
a. Key Laboratory for Green Processing of Chemical Engineering of Xinjiang
Bingtuan/School of Chemistry and Chemical Engineering, Shihezi University,
Xinjiang Uygur Autonomous Region, 832000, People’s Republic of China. E-mail:
duguangfen@shzu.edu.cn; helin@shzu.edu.cn
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reagents,15 we envisioned that NHCs or other strong Brønsted
bases could catalyze the cyanation reaction of gem-
difluoroalkenes and TMSCN to produce fluorinated
acrylonitriles (Scheme 1, eq 5). And herein, we wish to report
this result.
9
DBU (10 mol%), DMSO
12
12
12
12
12
24
24
24
2
84 View Articl>e2O0n:1line
10
11
12
13
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16
TBD (10 mol%), DMSO
Cs2CO3 (10 mol%), DMSO
K2CO3 (10 mol%), DMSO
KF(10 mol%), DMSO
DBU (5 mol%), DMSO
DBU (10 mol%), DMSO
No base, DMSO
2DOI: 10.610739/C9NJ0>22307:10D
2
2
2
2
64
59
64
70
72
0
>20:1
>20:1
>20:1
>20:1
>20:1
/
1.5
2
Experimental
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a
b
1a (0.2 mmol), base (10 mol%), solvent (2.0 mL). Isolated total yield of two
Our initial studies were carried out with the readily
diastereomers. c Determined by 19F NMR analysis of the crude product.
available gem-difluoroalkene 1a and TMSCN as the model
substrates. In the presence of 10 mol% NHC A 16
, the reaction
With the optimized reaction conditions in hand, we then
evaluated the substrate scope of the cyanation reaction and
the results are summarized in Table 2. gem-Difluoroalkenes
with electron-withdrawing substituents on the aryl rings gave
the corresponding products in higher yields than those bearing
electron-donating substituents (Table 2, entries 1-4). In
addition, different positions of the substituents can be well
tolerated for the reaction (Table 2, entries 5-9). Interestingly,
when the strong electron-withdrawing nitro group substituted
gem-difluoroalkene 1j was used for the reaction, the desired
product was obtained in high yield but with opposite Z/E
selectivity (Table 2, entry 10). We reasoned that the nitro
group can stablize the benzyl anion intermediate and facilate
the β-elimination of fluoride, and as a result, giving the
thermodynamically favorable Z-isomer as the major product.
Both α-naphthyl and β-naphthyl substituted gem-
difluoroalkenes performed very well to produce the
corresponding products 3l and 3m in 70% and 77% yields
(Table 2, entries 11 and 12). Biphenyl substituted substrate
was proven to be a good candidate for the reaction, affording
3p in 85% yield (Table 2, entry 13). Heteroaryl substituted
gem-difluoroalkene underwent the reaction to provide 3q in
83% yield (Table 2, entry 14). Electron-donating,-neutral and -
hardly proceeded in THF and only trace amount of fluorinated
acrylonitrile 3a was observed by GC-MS (Table 1, entry 1). The
following studies indicated that the reaction media has
obvious influence on the reaction yield and the polar aprotic
solvents, DMF and DMSO are suitable for the transformation
(Table 1, entries 2-5). Basesd on these results, a series of
organic bases and inorganic bases were then screened for the
reaction. Both triethylamine and Hunig’s base showed low
efficiency (Table 1, entries 6 and 7. Strong Brønsted bases,
such as t-BuOK, DBU and TBD, catalyzed the reaction
efficiently and DBU gave the highest yield (Table 1, entries 8-
10). Carbonates and fluorides can also catalyze the reaction in
good efficiency (Table 1, entries 11-13). Reducing the DBU
loading to 5 mol% or lowering the amount of TMSCN to 1.5
equivalents led to prolonged reaction time and decreased
reaction yield (Table 1, entries 14 and 15). Finally, the control
experiment showed that in the absence of a Brønsted base,
the reaction was unsuccessful (Table 1, entry 16). The
configurations of Z- and E-isomers were determined by the
comparison of their 1H NMR data with literature reports.12 The
3JH-F coupling constant of the Z-isomer are generally more than
30 Hz, while the 3JH-F coupling constant of the E-isomer are less
than 20 Hz.11
withdrawing
groups
substituted
symmetrical
gem-
difluoroalkenes were all suitable for the reaction, giving the
corresponding products in excellent yields (Table 2, entries 15-
18).
Table 1. Optimization of the reaction conditionsa
F
CN
F
catalyst
TMSCN
rt
solvent,
F
Table 2. Evaluation of the substrate scope a
Br
Br
1a
2
3
NC
F
F
F
10 mol% DBU
rt
Ar
TMSCN
N
N
N
N
DMSO,
Ar
H
Ar
H
N
N
N
E
2
H
1
(
)-3
Ar
DBU
TBD
A
i
Entry
Product
Yield of 3(%)b
E/Z c
=
Ar
C6H3
2,6-( Pr)2
1
Time/h 2 (equiv) Yield(%)b
E/Zc
NC
F
Entry
Conditions
3a, 84
>20:1
H
1
2
3
4
5
6
7
8
A (10 mol%), THF
A (10 mol%), DCM
A (10 mol%), CH3CN
A (10 mol%), DMF
A (10 mol%), DMSO
Et3N (10 mol%), DMSO
DIPEA (10 mol%), DMSO
24
24
24
12
12
12
12
12
2
2
2
2
2
2
2
2
< 10
18
27
53
66
34
34
70
/
Br
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
2
NC
F
3b, 75
>20:1
H
Cl
t-BuOK (10 mol%), DMSO
2 | J. Name., 2012, 00, 1-3
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3o, 9D6OI: 10.1039/C9NJ/02370D
NC
NC
NC
F
NC
NC
F
3c, 59
3d, 52
>20:1
H
Me
16
F
F
3p, 93
3q, 98
3r, 95
/
/
/
>20:1
H
10
11
12
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Me
Me
MeO
Br
17
5
6
NC
NC
F
F
F
3e, 77
3f, 65
>20:1
H
Cl
Cl
18
NC
F
>20:1
H
Br
Br
Br
7
8
a
NC
F
Reaction conditions: 1 (0.20 mmol), 2 (0.4 mmol), DBU (10 mol%), DMSO (2.0
3g, 87
3h, 81
>20:1
>20:1
mL), 12 h, room temperature. b Isolated total yield of two diastereomers. E/Z
c
MeO
was determined by 19F NMR analysis of the crude reaction mixture.
H
Based on previous literature report,17 a plausible reaction
mechanism was proposed as depicted in Scheme 2. The
Brønsted base attacks the silicon atom of TMSCN to generate
NC
F
H
the reactive hypervalent silicon species I, which might trigger
OMe
the following nucleophilic addition with gem-difluoroalkene to
form carbanion intermediate II, and after the β-elimination of
the fluoride anion, to produce the final product.
9
NC
F
3i, 50
3j, 84
13:1
1:5
MeO
MeO
H
Me3Si
F
Base
H
Base
TMSCN
F
10
NC
F
Si Base
SiMe3
NC
H
O2N
(I)
Ar
11
12
13
H
F
H
F
F
CN
F
NC
F
-F
3k, 70
3l, 77
>20:1
>20:1
>20:1
F
Ar
CN
Ar
H
(II)
Scheme 2 Proposed mechanism.
NC
F
The rotation of intermediate II would form two possible
conformational intermediates III and IV (Figure 1). In order to
minimize the electronic repulsion13 between the fluoride atom
and the aryl group, the elimination process of intermediate II
preferentially proceeds via model III and as a result, to
produce the E-isomer as the major product.
H
NC
F
3m, 85
H
14
NC
3n, 83
>20:1
F
O
H
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Hamel, J-F. Paquin, Synlett 2016, 27, 821.
H
Ar
E-isomer
(major)
F
NC
Ar
H
F
III
(
)
rotation
CN
F
H
F
Ar
F
II
( )
(a) W. Dai, H. Shi, X. Zhao, S. Cao, Org. Lett., 2016, 18, 4284.
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Z-isomer
(minor)
CN
IV
(
)
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Figure 1 Two possible conformational models
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In conclusion, an organocatalytic functionalization of gem-
difluoroalkenes has been described. The mild and transition-
metal free conditions, simple procedure and generally high
yield and excellent Z/E selectivity provide a new protocol for
the synthesis of fluorinated acrylonitriles.
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Acknowledgements
This work was supported by the National Natural Science
Foundation of China (No.21662029), the Young Scientists
Foundation of Shihezi University (Nos. RCZX201546,
2015ZRKXJQ05), the Excellent Young Teachers Plan of Bingtuan
(2017CB001, CZ027203) and the International Cooperation
Project of Shihezi University (No.GJHZ201801)
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New Journal of Chemistry
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DBU-catalyzed cyanation of gem-difluoroalkenes with TDMOI:S10C.10N39/C9NJ02370D
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highly stereoselective synthesis of α-fluoroacrylonitriles
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Ar
H
Ar
CN
F
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F
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10 mol% DBU
DMSO, rt
TMSCN
H
18 examples
yield up to 98%
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transition-metal free  mild conditions
readily available of starting materials 
high Z/E selectivity