α-Difluoromethylation on sp3 Carbon of Nitriles Using Fluoroform and Ruppert-Prakash Reagent

Article abstract of DOI:10.1021/acs.orglett.5b02438

Difluoromethylation on sp³ carbon of various nitrile compounds with lithium base and fluoroform (CF₃H), which is an ideal difluoromethylating reagent, is shown to provide the α-difluoromethylated nitrile products with an all-carbon q

Full text of DOI:10.1021/acs.orglett.5b02438

Letter
pubs.acs.org/OrgLett
α‑Difluoromethylation on sp3 Carbon of Nitriles Using Fluoroform
and Ruppert−Prakash Reagent
Kohsuke Aikawa, Kenichi Maruyama, Kazuya Honda, and Koichi Mikami*
Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology, O-okayama,
Meguro-ku, Tokyo 152-8552, Japan
S
* Supporting Information
ABSTRACT: Difluoromethylation on sp3 carbon of various
nitrile compounds with lithium base and fluoroform (CF3H),
which is an ideal difluoromethylating reagent, is shown to
provide the α-difluoromethylated nitrile products with an all-
carbon quaternary center in moderate to high yields. The Ruppert−Prakash reagent (CF3TMS) is also applicable to the reaction,
affording the α-siladifluoromethylated nitrile products, which can be utilized for sequential carbon−carbon bond-forming
reactions. These reactions using 1.1 equiv of lithium base, 1.5−2.0 equiv of CF3H or CF3TMS, and easily accessible nitrile
derivatives are completed in only a few minutes, resulting in the formation of valuable difluoromethylated compounds.
luoroform (also called trifluoromethane, CF3H, and HFC-
23) is mainly produced as a byproduct during chlorodi-
the presence of KOH as a base to give only low yield (30%).9
Herein, we present our α-difluoromethylation on sp3 carbon of
various nitrile compounds10 using fluoroform in the presence of
lithium base. The reaction is operationally simple and fast
(completed in a few minutes); only treatment of fluoroform
(1.5−2.0 equiv) and n-BuLi (1.1 equiv) to nitriles without
transition metal or other additives leads to the valuable α-
difluoromethylated products with a quaternary carbon center.
Significantly, the Ruppert−Prakash reagent (CF3TMS),11 which
is one of the most versatile and commercially available
trifluoromethylating reagents, is also applicable to the reaction
providing the α-siladifluoromethylated products,12 which can be
exploited for sequential carbon−carbon bond-forming reactions
to transform into the compounds bearing the difluoromethylene
(−CF2−) group regarding as a bioisostere to ethereal oxygen.
We initiated our research by examining the reaction between
fluoroform and 2,2-diphenylacetonitrile 1a in the presence of
lithium base as a model system to optimize the reaction
conditions (Table 1). Initially, following addition of 1.0 or 0.9
equiv of n-BuLi to 1a in THF, fluoroform (5.0 equiv) was
bubbled into the solution at −78 °C. However, the reaction did
not proceed at all, resulting in almost complete recovery of 1a
(entry 1). Significantly, employment of a slight excess of n-BuLi
(1.1 equiv) was found to provide the desirable difluoromethy-
lated product 2a in excellent yield (entry 2). Increasing the
amount of n-BuLi (2.0 equiv) did not cause a deleterious effect
(entry 3). As briefly illustrated, various lithium bases, such as
MeLi, LDA, LTMP, and LHMDS, were evaluated, and
consequently, n-BuLi was demonstrated to be the most efficient
lithium base (entries 2 vs 4−7). Surprisingly, the reaction was
completed within 1 min even at −78 °C, using even 1.5 equiv of
fluoroform (entry 10). THF was also found to be better solvent
than other coordinating solvents for this reaction.
F
fluoromethane manufacturing utilized in the production of
Teflon (DuPont) but also readily manufactured via fluorine/
chlorine exchange of chloroform.1 While a nontoxic and
nonozone-depleting gas (boiling point: −83 °C), it must be
destroyed or transformed to environmentally benign compounds
because it possesses a global warming potential 11700 times
higher than that of CO2.1 Therefore, the development of a
transformation of fluoroform to valuable and/or novel
fluoromethylated building blocks has attracted much attention
in view of not only pharmaceutical and agrochemical industries
but also synthetic challenges to its low reactivity. However, in the
past few years, the exploration of precise organic synthesis
employing fluoroform, which is an atom-economical, inex-
pensive, and most promising fluoromethylating reagent, remains
undeveloped,2,3 despite the explosive growth of synthetic
fluorine chemistry involving the development of practical and
reliable reactions and reagents.4
The selective introduction of the difluoromethyl (CF2H)
group into biologically active molecules is of particular interest in
pharmaceuticals and agrochemicals because the group can bring
about some useful effects, such as the enhancement of binding
affinity, bioavailability, and lipophilicity.5 Actually, the difluor-
omethyl group is known to act as a bioisostere of alcohols and
thiols, which is a lipophilic hydrogen bond donor. Common
syntheses of compounds containing the difluoromethyl group
can be conducted via the deoxofluorination of aldehydes with
SF4, DAST (N,N-diethylaminosulfur trifluoride), and its
derivatives as harsh reagents.6 The nucleophilic, electrophilic,
and radical difluoromethylations as an alternative approach have
been developed for the direct preparation of compounds
containing the difluoromethyl group;5,7 however, the difluor-
omethylation on sp3 carbon involving carbon−carbon bond
formation has scarcely been reported.2d,5,8 During our research
project, Dolbier and co-workers reported a single example of α-
difluoromethylation of nitrile with a large excess of fluoroform in
Received: August 24, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02438
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Having identified the optimal conditions of both the α-
difluoromethylation and α-siladifluoromethylation, we turned
our attention to evaluate the generality of these protocols (Figure
1). High yields were generally observed for 2,2-diarylacetonitrile
Table 1. α-Difluoromethylation with Fluoroform
b
entry
1
base
reaction conditions
yield (%)
n-BuLi
CF3H (5 equiv), −78 °C, 1 h
0
(0.9 or 1.0 equiv)
n-BuLi (1.1 equiv)
n-BuLi (2.0 equiv)
MeLi (1.1 equiv)
LDA (1.1 equiv)
LTMP (1.1 equiv)
2
3
4
5
6
7
CF3H (5 equiv), −78 °C, 1 h
CF3H (5 equiv), −78 °C, 1 h
CF3H (5 equiv), −78 °C, 1 h
CF3H (5 equiv), −78 °C, 1 h
CF3H (5 equiv), −78 °C, 1 h
CF3H (5 equiv), −78 °C, 1 h
98
92
96
0
73
0
LHMDS
(1.1 equiv)
8
9
n-BuLi (1.1 equiv)
n-BuLi (1.1 equiv)
CF3H (2 equiv), −78 °C, 1 h
CF3H (2 equiv), −78 °C, 5 min
95
93
c
10 n-BuLi (1.1 equiv) CF3H (2 equiv), −78 °C, 1 min
96 (85)
a
Conditions: After addition of lithium base to 1a in THF, CF3H was
bubbled to the mixture at −78 °C. The reaction was quenched with
b
H2O. Yields were determined by 19F NMR analysis using
c
benzotrifluoride as an internal standard. 1.5 equiv of CF3H was used.
We next envisioned that this strategy would be adaptable to α-
siladifluoromethylation using the Ruppert−Prakash reagent
(CF3TMS) in lieu of fluoroform as a difluoromethyl source
(Table 2). Similarly, no desired product was detected with 1.0 or
Table 2. α-Siladifluoromethylation with Ruppert−Prakash
a
Reagent
Figure 1. Substrate scope and functional group tolerance. Yields were
determined by 19F NMR analysis using benzotrifluoride as an internal
standard. (a) Method A: After addition of n-BuLi (0.55 mmol) to 1 (0.5
mmol) in THF (1.0 mL) at −78 °C, CF3H (1.0 mmol) was added at
−78 °C, and the mixture was stirred for 1−5 min at −78 °C. (b) Method
B: After addition of n-BuLi (0.55 mmol) to 1 (0.5 mmol) in THF (1.0
mL) at −78 °C, CF3TMS (1.0 mmol) was added at −78 °C, and the
mixture was stirred for 1 h at room temperature. (c) n-BuLi (1.0 mmol)
was used. (d) LTMP (1.0 mmol) instead of n-BuLi was used.
b)
3a/2a of yield
entry
base
reaction conditions
(%)
1
2
3
4
5
6
n-BuLi (0.9 or 1.0 equiv)
n-BuLi (1.1 equiv)
n-BuLi (1.1 equiv)
n-BuLi (1.1 equiv)
n-BuLi (1.1 equiv)
n-BuLi (1.1 equiv)
−78 °C, 1 h
−78 °C, 10 min
−78 °C, 1 h
−40 °C, 1 h
−20 °C, 1 h
rt, 10 min
0/<1
0/87
29/54
86/2
1b−d bearing not only electron-donating but also -withdrawing
substituents on the para-position. 2,2-Diarylacetonitrile 1d−f
with a chlorine substituent, regardless of the arene substitution
position (para-, meta-, and ortho-), could be converted to the
corresponding product, while a decrease in yield was observed
with ortho-substituted 1f. Nitrile 1g with a fluorene backbone was
also compatible with these reactions. As encouraged, not only
acyclic but also cyclic α-monoalkylated nitriles 1h−k were
applicable to these reactions, while yields were moderate,
respectively. The reactions of substrates 1l−m with the vinylic
substituent also occurred, resulting in the formation of the
desired α-(sila)difluoromethylated products, but along with the
γ-(sila)difluoromethylated byproducts in about 20% yields. Even
aliphatic nitrile 1n was allowed to react with CF3H and CF3TMS
by treatment of LTMP instead of n-BuLi, which reacted with 1n
to form n-BuLi adduct, providing the corresponding products 2n
and 3n, respectively.
The mechanisms of reactions with fluoroform and the
Ruppert−Prakash reagent was researched experimentally
(Scheme 1). At first, combination of 1a and n-BuLi (1.0 equiv)
in THF followed by quench with D2O resulted in the formation
of α-deuterated 1a-D (>95% D incorporation) quantitatively
without byproduct, while avoiding the addition reaction of n-
BuLi to the cyano group (eq 1). The reaction of 1a with
fluoroform under the optimized reaction conditions followed by
90/2
90/0
a
Conditions: After addition of base to 1a in THF, CF3TMS (2 equiv)
was added to the mixture at −78 °C. The reaction was quenched with
b)
H2O.
Yields were determined by 19F NMR analysis using
benzotrifluoride as an internal standard.
0.9 equiv of n-BuLi (entry 1). As expected, in the presence of 1.1
equiv of n-BuLi, the reaction of 1a with CF3TMS (2.0 equiv)
took place smoothly within 10 min but, however, did not provide
the desired α-siladifluoromethylated product 3a but instead the
α-difluoromethylated counterpart 2a selectively in 87% yield
(entry 2). Importantly, in the prolonged reaction time at −78 °C,
the mixtures of 2a and 3a were formed in totally 83% yield (entry
3). The elevated reaction temperature (−40 and −20 °C) led to
the almost single product 3a in 86% and 90% yields, respectively
(entries 4 and 5). These results imply that the reaction was
completed at −78 °C within 10 min, generating in situ the
reaction intermediate 7 which can be transformed to both 2a and
3a under the different reaction conditions (vide infra: Scheme 2).
Finally, the reaction was found to be completed at room
temperature within 10 min, providing only single product 3a in
90% yield (entry 6).
B
DOI: 10.1021/acs.orglett.5b02438
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Organic Letters
Letter
Scheme 1. Experiments for Consideration of Reaction
Mechanism
Figure 2. Transition state TS was computed at the B3LYP-D3/6-
31+G*/IEF-PCM level of theory in THF. Distances in Å. R1, R2 = Me, s
= Me2O in TS of Scheme 2. Unimportant hydrogen atoms are omitted.
2.06 Å; C2−F2, C2−F3: 1.34 Å; C1−C2: 3.25 Å) with Li−F
association.
In the case of the Ruppert−Prakash reagent (CF3R, R = TMS),
difluoromethyllithium 5 is also formed via the TS. However, 5
would afford not directly silylated 3 but also difluorocyclopro-
pane 6, and eventually silylated 7, due to steric demand around
the all-carbon quaternary center in 5. In fact, the corresponding
peak (δF: −125)17 of 7 was observed in 19F NMR analysis at
temperatures lower than −60 °C. Intramolecular transfer of the
silyl group in 7 or intermolecular reaction of 7 with CF3TMS at
temperatures higher than −78 °C (conditions A) selectively led
to α-siladifluoromethylated product 3 (Table 2, entries 2 vs 3−
6). On the other hand, difluoromethylated product 2(-D) is
selectively obtained at lower temperature (conditions B: −78 °C,
less than 10 min), as actually deuterated by D2O quench
(Scheme 1, eq 3).
quench with D2O did not afford deuterated 2a-D but 2a in 90%
yield (eq 2). In sharp contrast to the fluoroform system, the
reaction with the Ruppert−Prakash reagent at −78 °C for 10 min
followed by quench with D2O, and only difluoromethylated 2a-D
was obtained in 88% yield without the formation of 3a (eq 3). It
was also found that each product 2a and 3a underwent no H-D
and TMS-D exchange under each reaction conditions shown in
eqs 2 and 3, respectively (eq 4).
On the basis of these observations and DFT calculations,
mechanisms in difluoromethylation are visualized in Scheme 2.
With these successes in terms of the wide scope of nitriles, we
transformed the α-siladifluoromethylated product into valuable
compounds bearing various functional groups (Scheme 3). The
Scheme 2. Plausible Mechanism of α-Difluoromethylation
Scheme 3. Applications to Transforming Reactions
In the case of fluoroform (CF3R, R = H), the remaining n-BuLi
deprotonates fluoroform to give lithium carbenoid (CF3Li).1b,13
Subsequently, lithium carbenoid is allowed to react with lithium
ketene imine 4, which can be quantitatively generated by
combination of nitrile 1 and n-BuLi,14 leading eventually to
difluoroalkyllithium 5 via the proposed TS.15,16 Difluorome-
thyllithium 5 is more basic than 4 and can abstract a proton of
fluoroform to provide protonated product 2 without 2a-D
formation even by D2O quench (Scheme 1, eq 2). Similar to
mechanistic studies of the direct difluoromethylation of lithium
enolate and lithium carbenoid (CF3Li),15 the transition state was
found to be likely TS via the bimetallic carbenoid with dual
activation of the lithium nonbutterfly-shaped carbenoid (Figure
2). The lithium carbenoid rather than free difluorocarbene reacts
with 4 in SN2-type displacement via the angle obtuse enough
(C1−C2−F1: 167.0°) by the activation of C−F bond (C2−F1:
reductions of 3m in the presence of LiAlH4 or DIBAL-H
provided amine 8 and aldehyde 9, respectively, maintaining the
trimethylsilyl group. The oxidation of 3m using H2O2 and
K2CO3 led to amide 10, while protodesilylation occurred. The
methylation and esterification using MeI and ethyl chlorofor-
mate as electrophiles proceeded smoothly by virtue of the
reactive silyl functionality, providing the fluoroalkylated products
11 and 12, respectively. Moreover, 3m possessing a quaternary
carbon center was converted to the corresponding thioether 13
with disulfide using spray dry potassium fluoride.
In summary, we have succeeded in the α-difluoromethylation
on the sp3 carbon of various nitrile compounds with a slight
excess amount of n-BuLi (1.1 equiv) and fluoroform (2.0 equiv),
which is an ideal fluoromethylating reagent, to provide the
corresponding α-difluoromethylated products with quaternary
carbon center in moderate to high yields. The reaction is
C
DOI: 10.1021/acs.orglett.5b02438
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Synlett 2011, 2011, 1052. (d) Liu, Y.-L.; Yu, J.-S.; Zhou, J. Asian J. Org.
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completed within 1 min and operationally simple without
transition-metal and other additives. The Ruppert−Prakash
reagent is also applicable to the reaction to selectively provide the
α-siladifluoromethylated and α-difluoromethylated products
depending on the reaction temperature. Development of
valuable and novel catalytic difluoromethylations using fluoro-
form and the Ruppert−Prakash reagent is ongoing in our
laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02438.
́
Dixon, D. D.; Rodriguez, R. A.; Baxter, R. D.; Herle, B.; Sach, N.; Collins,
M. R.; Ishihara, Y.; Baran, P. S. Nature 2012, 492, 95. (g) Shen, X.; Ni,
C.; Gu, Y.; Hu, J. J. Am. Chem. Soc. 2012, 134, 16999. (h) Fier, P. S.;
Hartwig, J. F. Angew. Chem., Int. Ed. 2013, 52, 2092. (i) Kosobokov, M.;
Levin, V. V.; Zemtsov, A. A.; Struchkova, M. I.; Korlyukov, A. A.;
Arkhipov, D. E.; Dilman, A. D. Org. Lett. 2014, 16, 1438. (j) Su, Y.-M.;
Hou, Y.; Yin, F.; Xu, Y.-M.; Li, Y.; Zheng, X.; Wang, X.-S. Org. Lett. 2014,
16, 2958. (k) Xu, P.; Guo, S.; Wang, L.; Tang, P. Angew. Chem., Int. Ed.
2014, 53, 5955. (l) Gu, Y.; Leng, X.-B.; Shen, Q. Nat. Commun. 2014, 5,
Experimental procedures and compound characterization
data (PDF)
X-ray crystallographic data (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: mikami.k.ab@m.titech.ac.jp.
́
5405. (m) Ilchenko, N. O.; Tasch, B. O. A.; Szabo, K. J. Angew. Chem.,
Notes
Int. Ed. 2014, 53, 12897.
(8) (a) Ilies, M.; Di Costanzo, L.; Dowling, D. P.; Thorn, K. J.;
Christianson, D. W. J. Med. Chem. 2011, 54, 5432. (b) Yang, Y.-D.; Lu,
X.; Liu, G.; Tokunaga, E.; Tsuzuki, S.; Shibata, N. ChemistryOpen 2012,
1, 221. (c) Liu, G.; Wang, X.; Lu, X.; Xu, X.-H.; Tokunaga, E.; Shibata, N.
ChemistryOpen 2012, 1, 227. (d) Wang, X.; Liu, G.; Xu, X.-H.; Shibata,
N.; Tokunaga, E.; Shibata, N. Angew. Chem., Int. Ed. 2014, 53, 1827.
(9) Thomoson, C. S.; Wang, L.; Dolbier, W. R. J. Fluorine Chem. 2014,
168, 34.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by a grant program “Advanced
Catalytic Transformation program for Carbon utilization (ACT-
C)” from the Japan Science and Technology Agency (JST). We
thank TOSOH F-TECH, Inc., for the gift of CF3H and CF3TMS.
(10) Vanadium-catalyzed α-trifluoromethylation of nitriles using
electrophilic trifluoromethylating reagent: Fruh, N.; Togni, A. Angew.
Chem., Int. Ed. 2014, 53, 10813.
̈
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DOI: 10.1021/acs.orglett.5b02438
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