Synthesis of CF3-Containing Linear Nitriles from α-(Trifluoromethyl)styrenes

Article abstract of DOI:10.1021/acs.orglett.1c01988

Four unprecedented base-catalyzed/mediated nucleophilic additions of TMSCN to α-(trifluoromethyl)styrenes and 2-trifluoromethyl enynes were developed. The reaction proceeded smoothly at room temperature under mild and transition-metal-free conditions with

Full text of DOI:10.1021/acs.orglett.1c01988

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Letter
Synthesis of CF3−Containing Linear Nitriles from
α‑(Trifluoromethyl)styrenes
Sixue Xu,‡ Yupian Deng,‡ Jingjing He, Qianding Zeng, Chuan Liu, Yi Zhang, Bin Zhu, and Song Cao*
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ABSTRACT: Four unprecedented base-catalyzed/mediated nu-
cleophilic additions of TMSCN to α-(trifluoromethyl)styrenes and
2-trifluoromethyl enynes were developed. The reaction proceeded
smoothly at room temperature under mild and transition-metal-
free conditions without affecting the trifluoromethyl group and
afforded the corresponding CF3-containing alkyl, alkynyl, and
butadienyl nitriles in moderate to excellent yields in a highly
regioselective manner, respectively.
Scheme 1. Reactions of α-(Trifluoromethyl)styrenes
he hydrofunctionalization and difunctionalization of
alkenes have received much attention due to their
T
potential applications in organic synthesis.1 Recently, vicinal
trifluoromethyl functionalization of alkenes has become an
attractive strategy for the construction of functionalized CF3-
containing compounds.2,3 Among these protocols, cyanotri-
fluoromethylation of styrenes provides a straightforward access
to β-trifluoromethylated nitriles in a single procedure.4
Although these methods are useful, they still suffer one or
more drawbacks, such as the use of expensive Togni’s reagents.
Furthermore, the scope of these methods limits to the
preparation of the CF3-containing branched alkyl nitriles.
Therefore, it is highly desirable to develop a general method
for the synthesis of CF3-containing linear alkyl nitriles.5
Trifluoromethylstyrenes are highly useful CF3-containing
building blocks in organic synthesis.6 The transformation of
trifluoromethylstyrenes into other fluorinated or nonfluori-
nated compounds has become a fascinating field in organic
chemistry.7 However, most research has been focused on the
development of efficient methods for the synthesis of the gem-
difluoroalkenes via cleavage of the C−F bonds in the
trifluoromethyl group,8 which might be ascribed to the fact
that trifluoromethylstyrenes are more prone to undergo β-
fluoride elimination under various reaction conditions
(Scheme 1a−e).9 The addition reaction of trifluoromethyl-
styrenes with retaining of three C−F bonds is a great challenge.
Considering the importance of the trifluoromethyl group in
organic synthesis and the relatively high cost of trifluorome-
thylated compounds, we envisage that the incorporation of a
trifluoromethyl group into organic molecules by utilizing
trifluoromethylstyrenes as inexpensive and readily available
CF3-containing building blocks without accompanying de-
fluorination of CF3 group is worthy of further exploration.
Until now, only a few examples with trifluoromethylstyrenes as
dipolarophiles for 1,3-diploar cycloaddition reactions have
been reported and several CF3-containing carbocycles and
Received: June 15, 2021
Published: July 23, 2021
https://doi.org/10.1021/acs.orglett.1c01988
Org. Lett. 2021, 23, 5853−5858
© 2021 American Chemical Society
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Letter
a
heterocycles have been synthesized, leaving the C−F bond
untouched (Scheme 1f).10 In addition, Ichikawa et al. reported
the synthesis of CF3-bearing heterocycles via nucleophilic 5-
endo-trig cyclization of 2-trifluoromethyl-1-alkenes (Scheme
1g).11 However, addition of α-(trifluoromethyl)styrenes with
nucleophiles without loss of the C−F bond of the CF3 group
remains a largely unexplored area.12 In this paper, we reported
an unprecedented base-catalyzed/mediated nucleophilic addi-
tion of TMSCN to α-(trifluoromethyl)styrenes and 2-
trifluoromethyl enynes under mild reaction conditions,
affording the CF3-containing alkyl, alkynyl and butadienyl
nitriles in moderate to excellent yields in an anti-Markovnikov
manner (Scheme 1h).
Table 1. Optimization of Reaction Conditions
b
entry
base (x mol %)
TMSCN (x equiv)
solvent
2a (%)
1
2
3
4
5
6
7
8
none
Et3N (20)
DABCO (20)
TMEDA (20)
DMAP (20)
DIPEA (20)
Na2CO3 (20)
NaOH (20)
LiOtBu (20)
K3PO4 (20)
NaOCH3 (20)
K2CO3 (20)
NaH (20)
CsF (20)
DBN (20)
DBU (20)
TMG (20)
Cs2CO3 (20)
Cs2CO3 (20)
Cs2CO3 (20)
Cs2CO3 (20)
Cs2CO3 (20)
Cs2CO3 (20)
Cs2CO3 (20)
Cs2CO3 (15)
Cs2CO3 (20)
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
0
0
0
0
0
0
2
5
5
6
6
7
7
30
48
64
82
99
0
c
c
c
c
Compared to a normal alkene (such as α-methylstyrene), α-
(trifluoromethyl)styrene is generally considered as activated
olefin due to the σ-electron-withdrawing character of the CF3
group. The trifluoromethyl group attached to a double bond
can slightly lower the LUMO energy levels of the olefins,
which renders the terminal carbon of α-(trifluoromethyl)-
styrene significantly more electrophilic poor than the
corresponding α-methylstyrene arene (weak nucleophi-
le).9g,12b,13 However, in comparison with other standard
electrophiles such as α,β-unsaturated ketone, α-
(trifluoromethyl)styrene exhibits lower reactivity toward to
nucleophiles due to the lack of a strong π-electron-withdrawing
group (ketone, nitro, cyano, or ester etc.) which is known to
dramatically decrease the LUMO energy level. In consideration
of the unique electrophilicity of α-(trifluoromethyl)styrene, we
question whether it is capable of undergoing nucleophilic
addition if the defluorination reaction is efficiently suppressed.
Based on the above-mentioned considerations, we envi-
sioned that the reaction of nucleophile with α-
(trifluoromethyl)styrenes via nucleophilic addition and not
via the typical SN2′ type of defluorinative addition−elimination
process might be feasible. Initially, the reaction of 1-methoxy-
4-(3,3,3-trifluoroprop-1-en-2-yl)benzene with TMSCN were
performed in the CuCl/NaOtBu/CH3CN system. Unfortu-
nately, a mixture of defluorinative product and unreacted
starting material was observed. Therefore, effective suppression
of the undesired defluorination reaction is a significant
problem we should solve. We began our investigation using
the nucleophilic addition of 1a with TMSCN as the model
reaction to optimize the reaction conditions without the
addition of transition metal catalyst (Table 1). No desired
products 2a was detected and the starting material 1a was
retained in the absence of base (entry 1). Among the various
bases tested (entries 2−18), Cs2CO3 was the most suitable for
the reaction, while other bases such as DBN, DBU, and TMG
gave lower yields. Screening of different solvents showed that
both CH3CN and DMF were effective for this reaction,
whereas the yields were reduced when THF, toluene, CH3OH,
NMP, and DMSO were used as solvent (entries 18−24).
Decreasing the amount of Cs2CO3 and TMSCN led to
significant decrease in the yields (entries 25 and 26). To our
delight, nucleophilic addition product 2a were detected as the
sole product, and no defluorinative product was observed in all
cases. Furthermore, the hydrocyanation reactions proceeded in
an anti-Markovnikov fashion, and no Markovnikov product
was found.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
c
c
c
toluene
CH3OH
NMP
DMSO
DMF
0
0
17
82
96
47
CH3CN
CH3CN
44
a
b
Reaction conditions: 1a (0.1 mmol), solvent (1 mL), rt, 1 h. Yields
c
are determined by GC analysis based on 1a. For the full names of
bases, see the Supporting Information. The reaction vial was sealed
with a septum.
Scheme 2. Cs2CO3-Catalyzed Hydrocyanation of α-
a
(Trifluoromethyl)styrenes
a
Reaction conditions: 1a−j (0.7 mmol), TMSCN (1.5 equiv, 1.05
mmol), Cs2CO3 (20 mol %), CH3CN (7 mL), rt, 0.5−4 h. The
reaction vial was sealed with a septum.
styrenes bearing electron-donating groups were unreactive and
failed to provide the desired products under the optimal
reaction conditions. Only those substrates having electron-
withdrawing groups could afford addition products in good
yields. A series of functional groups, such as halogen, cyano,
Subsequently, the scope of α-(trifluoromethyl)styrenes was
investigated (Scheme 2). The results indicated that the
electronic nature of the substituents on the benzene ring
played a significant role in the reaction. α-(Trifluoromethyl)-
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trifluoromethoxy, formyl, ester, trifluoromethyl, and nitro, were
well tolerated. α-(Trifluoromethyl)styrenes possessing sub-
stituent in the para- and meta-position on the benzene ring
proceeded smoothly (1a and 1b). However, the reaction of
ortho-substituted styrene did not proceed efficiently and only
small amounts of the desired product were observed (1c),
which might be due to the steric effect of the substituent
attached at the ortho-position.
Scheme 4. Cs2CO3-Catalyzed Hydrocyanation of 2-CF3
Enynes
a
Encouraged by the above success, we then turned our
attention to the hydrocyanation of α-(trifluoromethyl)styrenes
bearing electron-donating groups. With further screening of
the reaction conditions, we were delighted to find that the use
of strong organic base (DBU) and DMF as solvent could
significantly promote the hydrocyanation reaction and afford
the cyanation products in good to excellent yields (Scheme 3).
Scheme 3. DBU-Mediated Hydrocyanation of α-
a
(Trifluoromethyl)styrenes
a
Reaction conditions: 3a−s (0.7 mmol), TMSCN (1.5 equiv, 1.05
mmol), Cs2CO3 (5 mol %), CH3CN (7 mL), rt, 0.5 h, Ar. The
reaction vial was sealed with a septum. Performed at 10 mmol scale.
b
difference in the yields of the products. Aliphatic 2-CF3 enyne
(3s) was also found to be a suitable substrate, and the
corresponding addition product was afforded in moderate
yield.
When the reaction of 2-CF3 enynes with TMSCN was
carried out in the presence of 20 mol % DBU, the reactions
also proceeded rapidly within 40 min at room temperature and
afforded the unexpected cyanated CF3-substituted 1,3-
butadienes in fair to excellent yields (Scheme 5). The reactions
Scheme 5. DBU-Catalyzed Hydrocyanation of 2-CF3
a
Enynes
a
Reaction conditions: 1a, 1d−t (0.7 mmol), TMSCN (4.0 equiv, 2.8
mmol), DMF (7 mL), rt, 16 h. The reaction vial was sealed with a
septum. Performed at 8 mmol scale.
b
Both substrates bearing strong electron-donating group (OMe,
1r) and strong electron-withdrawing group (NO2, 1j) on the
benzene ring are compatible with the modified reaction
conditions. Substrates that bear a reactive site, such as halogen,
cyano, formyl, ester, nitro, and amino groups, remained intact,
providing synthetic opportunities for further transformation.
Recently, 2-CF3 enynes have attracted much attention for
their potential application in the construction of fluorinated or
nonfluorinated heterocycles and CF3-containing compounds.14
Functionalization of 2-CF3-1,3-enynes is a significant, yet
difficult, task because they possess five possible highly reactive
sites. In addition, the side reactions relating to fluorine
elimination are still a great challenge in these trans-
formations.12b,15 To further verify the generality of the
above-mentioned hydrocyanation reaction, the addition
reaction of various 2-CF3 enynes with TMSCN in the presence
of 5 mol % Cs2CO3 was performed, and the results are shown
in Scheme 4. In most cases, the reaction proceeded efficiently
via a 1,2-addition pattern and provided the 1,2-hydrocyanation
products in good to excellent yields with high regioselectivity,
irrespective of the nature of the substituent present in the
aromatic ring. Changing the aryl ring of the 2-CF3 enynes to
pyridine ring (3q) or thiophene ring (3r) did not make much
a
Reaction conditions: 3a−c, 3f, 3h, 3j−r (0.7 mmol), TMSCN (1.5
equiv, 1.05 mmol), DBU (20 mol %), CH3CN (7 mL), rt, 40 min.
The reaction vial was sealed with a septum. Performed at 10 mmol
scale.
b
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Letter
could tolerate various functional groups such as methoxy,
amino, halogen, and cyano. A mixture of (2E,4Z)/(2E,4E)-1,3-
butadienes was formed but with low E/Z-selectivity.
Fortunately, the (2E,4Z)- and (2E,4E)-isomers could be
isolated by column chromatography. The structures of
(2E,4E)-5k and (2E,4Z)-5p were determined by X-ray
diffraction (see the Supporting Information).
To demonstrate the practicality of these new developed
protocols, three scale-up reactions were performed. Without
further optimization, the hydrocyanation of 1p and 3a could be
scaled up to gram scale; however, the expected products were
obtained in slightly lower yields (Scheme 3, 1p; Scheme 4, 3a;
Scheme 5, 3a).
To elucidate the source of the hydrogen in the hydro-
cyanation products, a series of deuterium-labeling and some
control experiments were performed (see Schemes S1 and S2).
These results indicated that the proton at the 4- and 5-position
of 5a was originated from a trace amount of water in CH3CN
and the methylene group, respectively. The transformation of
4a to 1,3-butadiene 5a might proceed via an intramolecular
proton migration.
V, and VI with DBU-H+ furnishes the 1,3-butadienes 5. The
non-nucleophilic, strong tertiary amine base, DBU acts as
hydrogen-bonding acceptor, whereas DBU-H+ acts as a proton
donor. In addition, on the basis of our labeling experiments
(see Schemes S1 and S2), the DBU-catalyzed rearrangement of
4 to the 1,3-butadienes 5 involves the intramolecular migration
of two hydrogen atoms, one at the propargyl and the other at
the methylene position. Importantly, these reaction conditions
suppress the defluorination reaction, and the defluorinative
product is not observed.
In summary, we have developed four unprecedented base-
catalyzed/mediated nucleophilic additions of TMSCN to α-
(trifluoromethyl)styrenes and 2-CF3 enynes. The nucleophilic
addition proceeded efficiently at room temperature, and the
undesired defluorination reaction was suppressed completely.
A variety of CF3-containing alkyl, alkynyl and butadienyl
nitriles were obtained in moderate to excellent yields. The
results suggested that α-(trifluoromethyl)styrenes could be
used as the moderate electrophiles and were sufficiently
electrophilic to undergo nucleophilic addition. The mechanism
of the DBU-catalyzed hydrocyanation of 2-CF3 enynes involves
nucleophilic 1,2-addition, propargyl-allenyl isomerization,
intramolecular proton migration, and protonation. We
anticipate that this strategy may provide a new method for
the synthesis of valuable functionalized CF3-containing
compounds from readily available α-trifluoromethylstyrenes.
Finally, a plausible reaction mechanism for the DBU-
catalyzed hydrocyanation of 2-CF3 enynes is proposed in
Scheme 6. First, the reaction is initiated by a catalytic amount
Scheme 6. Proposed Mechanism of the DBU-Catalyzed
Hydrocyanation of 2-Trifluoromethyl Enynes
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01988.
Experimental details and spectral data for all new
compounds (1H NMR, 13C NMR, and HRMS) (PDF)
Accession Codes
CCDC 2053222 and 2053257 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Song Cao − Shanghai Key Laboratory of Chemical Biology,
School of Pharmacy, East China University of Science and
Technology (ECUST), Shanghai 200237, China;
orcid.org/0000-0002-3231-6136; Email: scao@
ecust.edu.cn
of DBU. The reaction of DBU with a trace amount of water in
the CH3CN or reaction system produces the [DBU-H]+−OH−
complex.16 This complex coordinates to the silicon atom of
TMSCN to activate TMSCN and the reactive hypervalent
silicon species I is formed. The cleavage of the silicon−CN
bond in I could afford CN−, DBU-H+, and TMSOH
(detectable).17 Subsequently, nucleophilic 1,2-addition of
CN− to the 1-position of 2-CF3 enyne produces the key
propargyl anion II. The active trifluoromethylated propargyl
anion II is unstable due to the strong negative inductive effect
of the trifluoromethyl group and it undergoes propargyl-allenyl
isomerization with the assistance of DBU to generate the
allenyl anion III.18 The allenyl anion III could be transformed
into butadienyl anions IV, V, and VI through hydride
migration.19 Finally, protonation of the butadienyl anions IV,
Authors
Sixue Xu − Shanghai Key Laboratory of Chemical Biology,
School of Pharmacy, East China University of Science and
Technology (ECUST), Shanghai 200237, China
Yupian Deng − Shanghai Key Laboratory of Chemical
Biology, School of Pharmacy, East China University of
Science and Technology (ECUST), Shanghai 200237, China
Jingjing He − Shanghai Key Laboratory of Chemical Biology,
School of Pharmacy, East China University of Science and
Technology (ECUST), Shanghai 200237, China
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Qianding Zeng − Shanghai Key Laboratory of Chemical
Biology, School of Pharmacy, East China University of
Science and Technology (ECUST), Shanghai 200237, China
Chuan Liu − Shanghai Key Laboratory of Chemical Biology,
School of Pharmacy, East China University of Science and
Technology (ECUST), Shanghai 200237, China
Yi Zhang − Shanghai Key Laboratory of Chemical Biology,
School of Pharmacy, East China University of Science and
Technology (ECUST), Shanghai 200237, China
Bin Zhu − Shanghai Key Laboratory of Chemical Biology,
School of Pharmacy, East China University of Science and
Technology (ECUST), Shanghai 200237, China
Complete contact information is available at:
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Author Contributions
‡S.X. and Y.D. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (Grant Nos. 21472043).
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