A convenient method for the synthesis of fluorinated α-cyanoacetates via phase-transfer catalysis

Article abstract of DOI:10.1080/00397911.2018.1473442

A simple and convenient method for the synthesis of fluorinated α-cyanoacetate derivatives has been developed by using electrophilic fluorination of allyl and benzyl substituted α-cyanoacetates with N-fluorobenzensulfonimide (NFSI) as electrophilic fluori

Full text of DOI:10.1080/00397911.2018.1473442

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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A convenient method for the synthesis of
fluorinated α-cyanoacetates via phase-transfer
catalysis
Kavita Jain & Kalpataru Das
To cite this article: Kavita Jain & Kalpataru Das (2018): A convenient method for the synthesis
of fluorinated α-cyanoacetates via phase-transfer catalysis, Synthetic Communications, DOI:
10.1080/00397911.2018.1473442
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https://doi.org/10.1080/00397911.2018.1473442
A convenient method for the synthesis of fluorinated
a-cyanoacetates via phase-transfer catalysis
Kavita Jain and Kalpataru Das
Department of Chemistry, School of Chemical Sciences and Technology, Dr. Harisingh Gour University
(
A Central University), Sagar, India
ABSTRACT
ARTICLE HISTORY
A simple and convenient method for the synthesis of fluorinated
a-cyanoacetate derivatives has been developed by using electrophilic
fluorination of allyl and benzyl substituted a-cyanoacetates with
N-fluorobenzensulfonimide (NFSI) as electrophilic fluorinating agent
via phase transfer catalysis. The reaction is transition metal free and
carried out in aqueous and mild reaction conditions in the presence
of readily available tetra-N-butylammonium iodide (TBAI) as phase-
transfer catalyst.
Received 5 April 2018
KEYWORDS
a-Cyanoacetates;
electrophilic fluorination;
organofluorine compounds;
phase-transfer catalysis;
quaternary ammonium salts
GRAPHICAL ABSTRACT
Introduction
Organofluorine compounds have attracted much attention to synthetic chemist owing to
[
1–4]
their widespread applications in pharmaceuticals, agrochemicals and materials.
The
strategic incorporation of fluorine atom(s) into biologically active molecules has been
exploited in drug discovery research to improve pharmacological properties of drug
[5]
molecules.
Accordingly, various strategy for the selective fluorination of organic
[6]
compounds have been developed in the past decade. In particular, the development of
new and efficient synthetic method for a-fluorination of a-cyanoacetates is very attractive
in the field of organic synthesis and medicinal chemistry. It has been reported that
a-cyano-a-fluoroacetates can serve as valuable building blocks for the synthesis of
biologically active heterocycles such as 3-fluoropiperidines which are very useful for the
[7]
treatment of various neurological disorders. Moreover, fluorinated a-cyanoacetate has
been identified as an important structural unit of various biologically active molecules
[
8–10]
those exhibit anticancer, antifungal, and antiviral activities.
On the other hand,
CONTACT Kalpataru Das
kdas@dhsgsu.ac.in
Department of Chemistry, School of Chemical Sciences and
Technology, Dr. Harisingh Gour University (A Central University), Sagar, Madhya Pradesh, 470 003, India
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
ß 2018 Taylor & Francis

2
K. JAIN AND K. DAS
fluorinated a-cyanoacetate derivatives represent useful synthons in organic synthesis
because both ester and nitrile groups of a-cyanoacetate can be easily transformed
[
11–12]
into other functional groups.
A few examples are known in the literature for the
synthesis of substituted a-cyano-a-fluoroacetates using electrophilic fluorination,
[13–16]
however, these methods are mainly applicable to aryl substituted a-cyanoacetates.
De Kimpe et al. reported the electrophilic fluorination of haloalkyl substituted
a-cyanoacetate using very high boiling solvent such as DMF and K CO as base, while
2
3
[
17]
the reaction took 20 h to afford the corresponding fluorinated product.
The electro-
philic fluorination of substituted a-cyanoacetate has been carried out using acetonitrile as
ꢀ
a solvent and K CO as base at 50 C where a-cyanoacetate unit present as the side chain
of an acyclic nucleoside.
2
3
[
10]
Thus, most of these reported methods have one or several
drawbacks such as use of expensive catalyst systems, metal complexes, high boiling
solvent, high temperature, limited substrate scope and long reaction time. In addition to
that the systematic study towards catalytic fluorination of allyl and benzyl substituted
a-cyanoacetates have not yet been developed. Hence, it is desirable to develop a practical
method for the synthesis of such fluorinated a-cyanoacetate derivatives. In our research
efforts towards the development of green methods for chemical transformation, we
anticipated that simple phase-transfer catalyst would be promising catalysts for the syn-
thesis of organofluorine compounds in aqueous condition. Phase-transfer catalysts have
been extensively employed in organic synthesis in aqueous condition for various organic
[18]
transformations.
In this paper, we report a simple and convenient method for the
catalytic synthesis of a series of fluorinated a-cyanoacetate derivatives using electrophilic
fluorination of allyl and benzyl substituted a-cyanoacetates with N-fluorobenzensulfoni-
mide (NFSI) in aqueous and mild condition via phase-transfer catalysis in the presence
of tetra-N-butylammonium iodide (TBAI) as very cheap phase-transfer catalyst (PTC).
Experimental
General procedure for the synthesis of ethyl 2-cyano-2-fluoro-3-phenylpropanoate
(
2
2a): A round bottom flask equipped with a magnetic stir bar was charged with ethyl
-cyano-3-phenylpropanoate 1a (50 mg, 0.250 mmol), and then a mixure of diethylether
and water (2 mL) in 7:3 proportion was added via a glass syringe and followed by the
addition of TBAI (9.2 mg, 0.025 mmol) and solid K CO (86.4 mg, 0.625 mmol). The
2
3
resulting reaction mixture was stirred for 30 min at room temperature and then NFSI
86.7 mg, 0.275 mmol) was added. The reaction was allowed to stirred for another 2.5 h
(
and after completion of the reaction was quenched with water (5 ml) and extracted with
ethyl acetate (3 ꢁ 5 mL). The combined organic layers were washed with brine and dried
over anhydrous Na SO , filtered and solvent was evaporated under reduced pressure.
2
4
The crude product was purified by flash column chromatography over silica gel using
% ethyl acetate in petroleum ether as eluent to afford the pure product 2a in 75% yield
41.5 mg) as colorless oil, TLC R ¼ 0.50 (petroleum ether: EtOAc ¼9:1), IR m (KBr,
1
(
f
max
1
ꢂ1
cm ): 3035, 2940, 2250, 1774, 1497, 1457, 1272, 1107, 1041, 855, 701; H NMR
(
1
400 MHz, CDCl ): d 7.36–7.24 (m, 5H), 4.29 (q, J ¼ 8.0 Hz, 2H), 3.47–3.41 (m, 2H),
3
1
3
.26 (t, J ¼ 8.0 Hz, 3H); C NMR (100 MHz, CDCl ) d 163.2 (d, J ¼ 26.0 Hz), 130.6 (d,
3
J ¼ 2.0 Hz), 130.4, 128.9, 128.7, 114.0 (d, J ¼ 34.0 Hz), 87.0 (d, J ¼ 197 Hz), 64.2, 43.1, (d,

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3
1
9
J ¼ 22.0 Hz), 13.9; F NMR (376 MHz, CDCl ) d –157.4 (t, J ¼ 22.5 Hz, 1F); HRMS
3
þ
(
ESIþ): m/z calcd for C H FNO [M þ H] : 222.0930; found: 222.0925.
1
2
12
2
Ethyl-(E)-2-cyano-2-fluoro-5-phenylpent-4-enoate (2k): Yield: 71%, 43.8 mg;
1
colorless oil, TLC R ¼ 0.38 (Petroleum ether: EtOAc ¼9:1); H NMR (400 MHz,
f
CDCl ): d 7.38–7.27 (m, 5H), 6.63 (d, J ¼ 16.0 Hz, 1H), 6.16–6.09 (m, 1H), 4.36 (q,
3
13
J ¼ 8.0 Hz, 2H), 3.08 (dd, J ¼ 8.0, 20.0 Hz, 2H), 1.34 (t, J ¼ 8.0 Hz, 3H); C NMR
(
100 MHz, CDCl ) d 163.2 (d, J ¼ 26.0 Hz), 137.4, 136.0, 128.8, 128.5, 126.7, 117.6 (d,
3
J ¼ 4.0 Hz), 114.1 (d, J ¼ 34.0 Hz), 86.5 (d, J ¼ 197.0 Hz), 64.2, 40.8 (d, J ¼ 23.0 Hz) 14.1;
1
9
F NMR (376 MHz, CDCl ) d -158.7 (t, J ¼ 18.8 Hz, 1F).
3
Results and discussion
To demonstrate our methodology, we required allyl and benzyl substituted a-cyanoacetates
[19]
as substrates, which were synthesized by following known literature methods.
The
structure of substrates 1a-k was confirmed by spectroscopic data and comparison with
literature data. To optimize the reaction condition via electrophilic fluorination under
phase-transfer catalysis, we initially investigated the role of phase-transfer catalyst and
screened various tetraalkylammonium salts. As shown in Table 1, a-benzyl ethyl cyanoace-
tate 1a (R¼ Ph) was chosen as model substrate and subjected to electrophilic fluorination
with NFSI as electrophilic fluorinating agent using solid K CO (5 equiv.) as mild base
2
3
and diethyl ether-water as mixed solvent at room temperature in the presence of 10 mol%
benzyltriethylammonium chloride (BTEAC) as a phase-transfer catalyst. The progress of
the reaction was monitored by TLC and after 5 h the fluorinated product 2a was obtained
in 65% yield (Table 1, entry 1). The formation of fluorinated product 2a was confirmed by
1
13
19
its H, C, F NMR and mass spectrometric data.
To improve the yield of 2a, the reaction was performed using a series of quaternary
ammonium salts as PTCs and it was found that the reaction was completed within
a
Table 1. Screening of PTC for electrophilic fluorination of 1a.
b
Entry
PTC
Time (h)
Yield (%)
1
2
3
4
5
6
BTEAC
BTEAB
BTBAC
TMAB
TBAB
TBAI
5
3
3
65
66
75
54
65
80
73
6
4.5
2.5
19
31
c
7
8
BTBAC
–
c
d
74
a
Reaction condition: Unless otherwise noted 1a (0.250 mmol), NFSI (0.275 mmol), PTC
O-H CO (1.25 mmol) were used at r.t.
Yield of 2a was determined by HNMR spectrum of the crude reaction mixture.
(
0.025 mmol), Et
2
2
O ¼ 2 mL (7:3), K
2
3
b
c
1
Reaction was carried out in the absence of water.
d
Isolated yield of 2a.
BTEAC ¼ Benzyltriethylammonium chloride; BTEAB ¼ Benzyltriethylammonium brom-
ide; BTBAC ¼ Benzyltributylammonium chloride; TMAB ¼ Tetramethylammonium
bromide; TBAB ¼ Tetrabutylammonium bromide; TBAI ¼ Tetrabutylammonium iodide.

4
K. JAIN AND K. DAS
a
Table 2. Optimization for electrophilic fluorination of 1a.
b
Entry
Base
Cs CO
Na CO
Equiv.
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
2
3
5
5
Et
2
Et
2
Et
2
Et
2
O
O
O
O
5
3
2.5
6
6
8
8
6
67
54
80
52
64
40
38
65
2
3
K
K
K
K
K
K
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
3
3
3
3
3
3
2.5
1
2.5
2.5
2.5
2.5
PhMe
CH Cl
CHCl
Et
2
2
3
c
8
a
2
O
Reaction condition: Unless otherwise noted 1a (0.250 mmol), NFSI (0.275 mmol), TBAI
0.025 mmol, 10 mol%), solvent: water ¼2 mL (7:3) were used at r.t.
(
b
c
1
Yield of 2a was determined by HNMR spectrum of the crude reaction mixture.
5
mol % TBAI was used.
2
.5 h, when 10 mol% tetra-N-butylammonium iodide (TBAI) was used as phase-transfer
catalyst and chemical yield of 2a was improved to 80% (Table 1, entry 6). Under the
same reaction condition, when water was not used as co-solvent the rate of fluorination
was found to be very slow (Table 1, entry 7).
We have also carried out the reaction in the absence of PTC and water. We found
that the reaction takes place, but required very long reaction time for completion
(Table 1, entry 8). However, in the absence of PTC when water was used as co-solvent
in combination with diethyl ether in 7:3 ratios, the formation of a complex mixture
with trace amount of desired product was observed in the TLC after 20 h. From these
results, it was evident that in the presence of water, PTC actively participates in the
reaction to enhance the reaction rate and completing the reaction in a short period of
time (Table 1, entry 6). Thus, during screening of PTC for reaction optimization, it was
clear that the combination of water and PTC have significant role to accelerate the rate
of electrophilic fluorination.
Encouraged by the results indicated in Table 1, we further screened the reaction
condition with respect to different base, equiv. of base, solvent systems and catalyst
loading to improve the reaction efficiency in the presence of TBAI as PTC. Inorganic
bases such as Cs CO and Na CO were found to be less efficient than K CO as
2
3
2
3
2
3
indicated by the observed low yields of 2a (Table 2, entry 1–2). Using strong bases like
KOH, NaOH and CsOH, a complex reaction mixture was obtained as observed from
1
the HNMR of the crude reaction mixture. From these experiments, we found that
K CO is best suited among different inorganic bases and required 2.5 equiv. of K CO
3
2
3
2
as optimum concentration (Table 2, entry 3). We also examined various solvent systems
such as toluene, chloroform, dichloromethane, diethyl ether in combination with water
as cosolvent. The best result was obtained when diethyl ether and water was used as
mixed solvent in 7:3 ratio for electrophilic fluorination of 1a.
Other electrophilic fluorinating agent, such as Selectfluor, gave a complex reaction
mixture. The reaction also proceeded with lower catalyst loading (5 mol%); however, the
rate of fluorination was found to be slow (Table 2, entry 8). The higher concentration

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5
a
Table 3. Synthesis of ethyl a-cyano-a-fluoroacetates under phase-transfer catalysis.
Entry
1
1
R
2
Time (h)
2.5
Yield (%)
75
1a
6 5
C H
2
1b
4-ClC
H
6 4
2.5
76
3
4
5
6
1c
1d
1e
1f
3-BrC
6
H
4
2
2
1
1
72
69
67
79
6 4
4-FC H
2 6 4
4-NO C H
3 6 4
4-CF C H
7
1g
6
4-MeOC H
4
3.5
80
8
9
1h
1i
4-MeC
6
H
4
5
4
77
75
3 6 2
3,4,5-(MeO) C H
1
0
1j
CH
2 2
¼CH ¼CH–
5
65
(
continued)

6
K. JAIN AND K. DAS
Table 3. Continued.
Entry
1
R
2
Time (h)
Yield (%)
1
1
1k
PhCH¼CH–
6
71
a
Reaction condition: Unless otherwise noted 1 (0.250 mmol), NFSI (0.275 mmol), TBAI (0.025 mmol), Et
CO (0.625 mmol) were used at r.t.
Isolated yield of 2 by flash column chromatography.
2
O: H
2
O ¼ 2 mL
(
7:3), K
2
3
b
of catalyst did not affect much on the rate of fluorination and yield of the product.
We thus optimized 10 mol% TBAI is the optimum catalyst concentration and other
parameters as summarized in Tables 1–2. Under optimized conditions, a range of allyl
and benzyl substituted a-cyanoacetates 1a-k underwent electrophilic fluorination with
NFSI and afforded the corresponding ethyl a-cyano-a-fluoro acetates 2a-k in good
yields as shown in Table 3. However, the rate of electrophilic fluorination is dependent
on the the nature of substituents present in the substrate 1. We found that the reaction
was facilitate by electron withdrawing groups such as –NO and –CF groups compared
2
3
with electron donating groups like –OMe or –Me groups present in the aromatic ring of
benzyl substituted cyanoacetates 1a-i. On the other hand, allyl and cinnamyl substituted
ethyl cyanoacetate 1j and 1k proceeded the electrophilic fluorination to afford the
correspoding fluorinated product 2j and 2k, respectively, however, with slower reaction
rate compared to 1a. The results are summarized in Table 3. The stucture of all new
1
13
19
products 2a-k was determined and confirmed from their H, C, F NMR and mass
spectrometric data.
[
18]
Based on the above experimental results and literature reports,
a plausible mechan-
ism for electrophilic fluorination via phase-transfer catalysis was illustrated in Scheme 1.
Initially, metal enolate intermediate 3 is generated from the deprotonation of active
methylene proton of 1 by K CO and consequently, metal enolate 3 interacted with
2
3
ammonium cation of PTC through electrostatic interaction and thus intermediate 4 is
generated. The intermediate 4 subsequently reacts with electrophilic fluorinating agent
NFSI to afford the corresponding fluorinated product 2.
Conclusion
In conclusion, we have demonstrated a convenient and practical method for the synthe-
sis of a variety of a-cyano-a-fluoroacetate derivatives via electrophilic fluorination of
allyl and benzyl l under aqueous and mild condition using commercially available and
very cheap catalyst such as TBAI as phase-transfer catalyst. The synthesized a-cyano-
a-fluoroacetate derivatives could be valuable precursor for the synthesis of a range of
important compounds including b-amino acids, b-peptides and b-lactams. The

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7
Scheme 1. A proposed mechanism for the electrophilic fluorination under phase-transfer catalysis.
development for the synthesis of biologically active molecules via this methodology is
under investigation in our laboratory.
Acknowledgments
The authors thank Sophisticated Instrumentation Center, Dr. Harisingh Gour University, Sagar,
and IISER Bhopal for recording NMR spectral data and HRMS of our compounds. KJ is thankful
to UGC for the award of MANF research fellowship.
Funding
The authors are grateful to the University Grants Commission (UGC), New Delhi for Start-up
grant (No. F.30-56/2014 BSR) and Science and Engineering Research Board (SERB), Govt. of
India for EMR grant (EMR/2017/000234) as financial support.
ORCID
Kalpataru Das
http://orcid.org/0000-0003-4592-8796
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