Difluoro(trimethylsilyl)acetonitrile: Synthesis and fluoroalkylation reactions

Article abstract of DOI:10.1021/jo301094b

A new silicon reagent, difluoro(trimethylsilyl)acetonitrile, was prepared by insertion of difluorocarbene into silyl cyanide. The obtained silane served as a good cyanodifluoromethylating reagent toward aldehydes, N-tosylimines, N-alkylimines, and enamines under basic or acidic conditions.

Full text of DOI:10.1021/jo301094b

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Note
Difluoro(trimethylsilyl)acetonitrile: synthesis and fluoroalkylation reactions
Mikhail D. Kosobokov, Alexander D. Dilman, Vitalij V. Levin, and Marina I. Struchkova
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo301094b • Publication Date (Web): 18 Jun 2012
Downloaded from http://pubs.acs.org on June 18, 2012
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Difluoro(trimethylsilyl)acetonitrile: synthesis and fluoroalkylation reactions
Mikhail D. Kosobokov,† Alexander D. Dilman,*,† Vitalij V. Levin,† Marina I. Struchkova,†
†N. D. Zelinsky Institute of Organic Chemistry, 119991 Moscow, Leninsky prosp. 47, Russian
Federation
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adil25@mail.ru
A
H
A
CF2
Me3Si
CN
R
Me3SiCN
CN
R
F
F
F
F
A = O, NTs, NAlk
Abstract. A new silicon reagent, difluoro(trimethylsilyl)acetonitrile, was prepared by insertion of
difluorocarbene into silyl cyanide. The obtained silane served as a good cyanodifluoromethylating
reagent towards aldehydes, Nꢀtosylimines, Nꢀalkylimines, and enamines under basic or acidic
conditions.
The importance of organofluorine compounds for pharmaceutical and agrochemical industries have
stimulated intense research activity aimed at the development of new methods for the synthesis of
fluorinated substances.1 Though mechanistically diverse processes have been evaluated, reactions
employing silicon reagents have received particular attention, since they allow for the smooth
introduction of fluorinated carbanions.2ꢀ4 Indeed, silanes are typically air stable and easyꢀtoꢀhandle
compounds, with their nucleophilic reactivity being uncovered by Lewis basic activators.
While the major work on nucleophilic fluoroalkylation has been done with CF3ꢀ and higher alkyl
silanes,2 the efforts in the field are moving forward to study fluorinated silanes bearing a functional
group.3 Thus, silanes of possessing sulfur,4 phosphorus,5 halogen,6 as well as ester group,7 have been
prepared and used in various CꢀC bond forming processes (Figure 1). Herein we describe a new
silicon reagent, which contains nitrile substituent, and demonstrate that it can be successfully used in
fluoroalkylation reactions.
Lit.
this work
X = CN
X = SPh, SO2Ph
P(O)(OEt)2
CO2Et
Me3Si
X
F
F
Cl, Br
Figure 1. Silicon reagents.
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Our original plan to synthesize difluoro(trimethylsilyl)acetonitrile (1) was to silylate readily
available bromodifluoroacetonitrile (Scheme 1). However, attempts to perform this transformation
failed despite extensive variation of reaction conditions. Even in those cases when silane 1 was
detected by NMR spectroscopy, we could not isolate it in individual state. In an alternative approach,
we started from TMSCF3, which was converted to the corresponding difluoromethylsilane according
to a literature procedure.8 Subsequent radical bromination of TMSCHF2 using hydrogen bromide
/aqueous hydrogen peroxide system9 irradiating with household incandescent light bulb afforded
silane 2. Heating of silane 2 with trimethylsilyl cyanide in the presence of 5 mol % of
benzyltriethylammonium chloride lead to clean reaction providing an equimolar mixture of silane 1
and Me3SiBr. The bromosilane byꢀproduct was scavenged by styrene oxide,10 and subsequent
distillation allowed to isolate analytically pure silane 1 in 80% yield as a clear colorless liquid.11 As a
working hypothesis, we assume that the reaction proceeds through the chloride ion induced generation
of difluorocarbene from 2,12 and its insertion into Me3SiCN.
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Scheme 1. Synthesis of silane 1.
Me3SiX (X = Cl, OMs)
reducing agents:
Mg, Zn, P(NEt2)3
Br
CN
Me3Si
CN
F
F
F F
solvents:
ether, THF, DMF, NMP
1
NaBr, H2SO4
30% H2O2
F
F
NaBH4
Me3Si
Br
Me3Si CF3
Me3Si
F
F
hν
2, 80%
5% BnNEt3Cl
Me3Si
CN
Me3Si
Br
+ Me3SiCN
F
F
F
F
PhCN, 110 °C, 80 min
1, 80%
2
O
then
Ph
Having developed a convenient protocol for the preparation of multigram quantities of silane 1, we
focused on exploration of its chemistry. First, the interaction of benzaldehyde (3a), selected as a
model electrophile, with silane 1 (1.3 equiv) using THF as solvent was studied (Table 1). Employment
of 10 mol % of strong Lewis basic activators such as TBAT (Bu4NPh3SiF2), CsF, or Bu4NOAc
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induced rapid reactions leading to mixtures containing noticeable amounts of compound 6, which is
likely produced from the nucleophilic addition of 1 to primary product 4a.13 Use of alkaline acetate
salts allowed to decrease the amount of byꢀproduct 6, though longer reaction times were needed.
Lithium acetate proved to be optimal Lewis base furnishing the cleanest reaction, and virtually no byꢀ
product 6 could be detected. To achieve high conversion 2 equiv of the silane were used, and after
desilylative workꢀup with KHF2/trifluoroacetic acid and column chromatography the final product 5a
was isolated in 82% yield (entry 9). Finally, the fastest and leastꢀcostly procedure utilizing only 1.05
equiv of the silane was developed by carrying out the reaction at slightly elevated temperature (50 °C)
for 3 hours (entry 10).
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Table 1. Reaction of silane 1 with benzaldehyde.
SiMe3
Me3SiO
Ph
N
O
OY
1, activator
CN
CN
+
Ph
Ph
THF
F
F F F
3a
F
F
4a, Y = SiMe3
5a, Y = H
6
KHF2/TFA
#
activator
1, equiv. condtns. conversion 4a : 6
1
2
3
4
5
6
CsF, 10%
1.3
1.3
0 °C, 1 h 80%
0 °C, 1 h 87%
0 °C, 1 h 73%
0 °C, 1 h 18%
11 : 1
15 : 1
14 : 1
>30 : 1
14 : 1
6 : 1
TBAT, 10%
Bu4NOAc, 10% 1.3
AcONa, 10% 1.3
AcONa, 10% 1.3
rt, 24 h
rt, 18 h
96%
AcOK, 10%
1.3
1.3
1.3
2.0
1.05
>98%
7a AcOK, 10%
0 °C, 2 h 84%
5 : 1
8
9
AcOLi, 10%
AcOLi, 50%
rt, 24 h
rt, 18 h
78%
>30 : 1
93% (82%b) >30 : 1
10 AcOLi, 50%
50 °C, 3 h 95% (85%b) >30 : 1
a DMF as solvent.
b Isolated yield of 5a.
Under the optimized conditions a series of aldehydes were reacted with silane 1 (Table 2). All
tested substrates including aromatic, heteroaromatic, α,βꢀunsaturated, and aliphatic aldehydes gave
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good yields of products. Attempted reactions of acetophenone gave only about 70% conversion, while
providing complex mixtures, which is likely caused by decreased reactivity of the keto group along
with side reactions of primary product.
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Table 2. Fluoroalkylation of aldehydes.
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Me3Si
CN
F F
1
O
OH
0.5 equiv AcOLi
CN
R
R
THF
F F
3
5
then KF/TFA
Method A: 1 (2.0 equiv), rt, 18 h
Method B: 1 (1.05 equiv), 50 °C, 3 h
#
aldehyde
method
5
yield of 5,a %
O
1
2
A
B
5b
5b
70
77
O2N
O
3
A
5c
75
MeO
O
4
5
6
B
B
B
5d
5e
5f
60
84
72
Me2N
Br
O
O
O
O
7
8
B
A
5g
5h
73
72
N
S
O
9
A
5i
72
O
O
10
11
A
B
5j
5j
72
70
12
13
A
B
5k
5k
65
66
a Isolated yield.
Then we focused on reactions of silane 1 with substrates bearing C=N bond. NꢀTosylimines (7)
were first evaluated as electrophilic components. In this case, stoichiometric quantities of Lewis basic
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activator were required for complete conversion of starting imine. Reactions were performed using 1.3
equivalents of both lithium acetate and the silane at room temperature for 18ꢀ48 hours (Table 3).
Notably, no byꢀproducts originating from the consecutive nucleophilic addition at the nitrile group of
primary products were observed. This fact, as well as the need for stoichiometric amount of basic
activator, can be explained by the formation of stable anionic adduct after the addition of carbanion at
the C=N bond, which does not undergo silylation. High yields of products 8a-b were obtained starting
from nonꢀenolizable imines. At the same time, Nꢀtosylimines derived from hydrocinnamaldehyde and
isobutyraldehyde bearing acidic αꢀhydrogen gave complex mixtures. Unactivated imines (Nꢀmethyl
and Nꢀphenylimines of benzaldehyde) were completely unreactive and were recovered unchanged.
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Table 3. Reactions of N-tosylimines.
Me3Si
CN
(1.3 equiv)
1
F
F
Ts
Ts
HN
N
AcOLi (1.3 equiv)
CN
R
R
THF, rt
F
F
8
7
then aq. NaHSO4
#
1
imine
time, h
18
8
yield of 8,a %
N
Ts
8a
93
Ph
N
Ts
2
3
4
5
48
18
18
48
8b
8c
8d
8e
78
91
82
76
MeO
N
Ts
MeO2C
N
Ts
O
N
Ts
a Isolated yield.
It was also important to investigate applicability of silane 1 for reactions mediated by in situ
generated hydrofluoric acid, since this procedure significantly extends the scope of fluoroalkylation
process.14 Thus, unactivated imines and enamines were treated with silane 1 in the presence of
potassium bifluoride and trifluoroacetic acid in acetonitrile (Table 4). Reasonable yields were
achieved in all cases, though reactions of enamines proceeded faster and gave higher yields.
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Table 4. Fluoroalkylation under acidic conditions.
4
5
6
7
8
9
R2
R2
HN
R1
11
N
rt, 18 h
CN
R1
1 (1.5 equiv)
F
F
9
KHF2 (0.75 equiv)
CF3CO2H (1.25 equiv)
R3
R3
R1
R3
R2
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F
F
N
MeCN
R3
R1
12
N
CN
0 °C → rt, 2 h
R2
10
#
1
substrate
product
yield,a %
66
N
Me
11a
Ph
Ph
N
OMe
2
3
11b
68
78
N
N
11c
S
O
4
5
12a
95
82
12b
N
a Isolated yield.
Finally, we briefly investigated the behavior of obtained products (Scheme 2). Reduction of nitrile
group of product 5f with lithium aluminium hydride allowed to isolate amine 13 as hydrochloride salt.
We also attempted to liberate amino group by reductive removal of tosyl group from product 8a upon
treatment with hydrobromic acid in the presence of phenol. Disappointingly, even at room
temperature the hydration of electrophilic nitrile group occurred faster than the deprotection leading to
amide 14. An attempt to remove pꢀmethoxyphenyl group from product 11b using ceric ammonium
nitrate also failed resulting in complex mixture.
Scheme 2. Transformations of primary products.
OH
OH NH2·HCl
LiAlH4
CN
Et2O, r.t., 2 h
F
F
F F
5f
13, 95%
Ts
Ts
HN
Ph
HN
Ph
O
HBr, phenol
CN
NH2
AcOH, rt, 18 h
F
F
F F
14, 84%
8a
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In summary, we obtained a new fluorinated silicon reagent starting from readily available starting
materials.15 The silane works well in nucleophilic cyanodifluoromethylation of carbonyl compounds,
imines, and enamines under basic or acidic conditions.
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Experimental section
(Bromodifluoromethyl)trimethylsilane (2).6 The flask equipped with reflux condenser was charged
with NaBr (10.8 g, 105 mmol), 30% aqueous H2O2 (14.2 g, 125 mmol) and water (7 mL). The mixture
was cooled with ice/water bath, and concentrated sulfuric acid (6.7 mL, 125 mmol) was added
dropwise. The cooling bath was removed and TMSCHF2 (12.4 g, 100 mmol) was added to the
resulting dark mixture. The reaction flask was immersed into 40 °C water bath and stirred at this
temperature under irradiation with household incandescent light bulb (75W) until bromine color
almost disappeared (ca. 1 hour). Upper phase was separated, filtered through MgSO4, and distilled.
B.p. 106–108 °C. Yield 16.2 g (80%), colorless liquid.
Difluoro(trimethylsilyl)acetonitrile (1). A mixture of Me3SiCN (3.96 g, 40 mmol), silane 2 (8.12 g 40
mmol), BnNEt3Cl (372 mg, 2 mmol) and benzonitrile (15 mL) was heated at 110 °C for 80 min. The
mixture was cooled to 0 °C, styrene oxide (5.5 mL, 48 mmol) was added dropwise, and stirred for 1
hour at room temperature. The reaction flask was immersed into room temperature bath, and volatile
components were distilled off under vacuum (1 Torr) collecting into a cold trap (–100 °C). The
collected liquid was filtered through cotton wool plug, and fractionally distilled at atmospheric
pressure using Vigreux column. B.p. 106–108 °C. Yield 4.76 g (80%), colorless liquid. 1H NMR (300
MHz, CDCl3), δ: 0.34 (s, 9H). 13C NMR (75 MHz, CDCl3), δ: –5.8 (t, J = 1.5), 113.3 (t, J = 37.1),
116.4 (t, J = 264.9). 19F NMR (282 MHz, CDCl3), δ: –115.4 (s, 2F). Calcd for C5H9F2NSi (149.21): C,
40.25; H, 6.08; N, 9.39. Found: C, 40.50; H, 6.13; N, 9.62.
Mixture of compounds 4a and 6 (ratio 1.6 : 1). AcOK (220 mg, 2.25 mmol) was added to a solution of
benzaldehyde (159 mg, 1.5 mmol) and silane 1 (514 mg, 3.45 mmol), and the mixture as stirred for 18
h at room temperature. The volatile components were evaporated under vacuum in a bath not
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exceeding 25 °C, the residue was diluted with hexane (10 mL), and filtered. The filtrate was
concentrated under vacuum, and the residue was distilled in a short path apparatus at 85–100 °C (bath
1
temp.)/0.078 Torr to give 200 mg of the mixture of 4a and 6. Colorless oil. H NMR (300 MHz,
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CDCl3), δ: 0.09 (s, 9H), 0.20 (s, 14H), 0.36 (s, 9H), 4.99 (t, 2H, J = 8.5), 5.14 (dd, 1H, J = 17.8, 5.9),
7.39–7.57 (m, 13H). 13C NMR (75 MHz, CDCl3), δ: –0.34, –0.26, 0.1 (br), 75.3 (dddd, J = 32.2, 24.8,
2.9, 1.0), 75.6 (dd, J = 27.6, 25.9), 105.3 (t, J = 254.8), 111.0 (t, J = 259.6), 111.1 (tm, J = 44.1),
111.4 (t, J = 44.9), 116.1 (ddt, J = 259.1, 250.5, 2.0), 127.7, 128.17, 128.24, 128.5, 129.1, 129.7,
134.0 (dd, J = 3.5), 135.4 (d, J = 1.7), 151.5 (dddd, J = 56.4, 34.5, 28.4). 19F NMR (282 MHz,
CDCl3), δ: –89.6 (ddd, 1F, J = 308.4, 17.8, 8.5), –92.5 (dt, J = 308.4, 8.5), –98.2 (dd, J = 284.0, 8.5),
–102.9 (dd, J = 284.0, 8.5), –104.7 (ddd, J = 260.3, 17.8, 8.5), –114.1 (dm, J = 260.3).
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Reaction of silane 1 with aldehydes 3. General procedure.
Method A. AcOLi (17 mg, 0.25 mmol) was added to a solution of aldehyde 3 (0.5 mmol) and silane 1
(149 mg, 1.0 mmol) in dry THF (1 mL) at 0 °C, and the mixture was stirred for 18 h at room
temperature. For the workꢀup, the volatile components were evaporated under vacuum in a bath not
exceeding 25 °C, the residue was dissolved in acetonitrile (1 mL), treated with CF3CO2H (77 ꢁL, 1.0
mmol) and KHF2 (47 mg, 0.6 mmol), and stirred for 30 min. The mixture was diluted with water (5
mL), extracted with tertꢀbutyl methyl ether (3×3 mL). The organic phase was dried over Na2SO4,
concentrated, and the residue was purified by chromatography.
Method B. AcOLi (17 mg, 0.25 mmol) was added to a solution of aldehyde 3 (0.5 mmol) and silane 1
(78 mg, 0.525 mmol) in dry THF (1 mL) at room temperature, and the mixture was stirred for 3 h at
50 °C. The workꢀup is the same as that used in Method A.
2,2-Difluoro-3-hydroxy-3-phenylpropanenitrile (5a). Method A, 78 mg, 84% yield. Method B, 77 mg,
1
85% yield. Oil. Rf 0.31 (hexanes/EtOAc 5 : 1). B.p. 100–105 °C (bath temp.)/0.091 Torr. H NMR
(300 MHz, CDCl3), δ: 2.98–3.06 (br, 1H), 5.04 (t, 1H, J = 8.6), 7.43–7.56 (m, 5H). 13C NMR (75
MHz, CDCl3), δ: 74.9 (t, J = 26.2), 110.7 (t, J = 249.3), 111.0 (t, J = 44.6), 127.5, 128.9, 130.2,
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132.6. 19F NMR (282 MHz, CDCl3), δ: –99.4 (dd, 1F, J = 290.3, 8.6), –102.5 (dd, 1F, J = 290.3, 8.6).
Calcd for C9H7F2NO (183.15): C, 59.02; H, 3.85; N, 7.65. Found: C, 58.83; H, 3.65; N, 7.54.
2,2-Difluoro-3-hydroxy-3-(4-nitrophenyl)propanenitrile (5b). Method A, 80 mg, 70% yield. Method
B. 88 mg, 77% yield. Pale yellow crystals. M.p. 87–89 °C (hexanes). Rf 0.20 (hexanes/EtOAc 3 : 1).
1H NMR (300 MHz, CDCl3), δ: 3.37–3.47 (br, 1H), 5.24 (t, 1H, J = 8.4), 7.74 (d, 2H, J = 8.6), 8.31
(d, 2H, J =8.6). 13C NMR (75 MHz, CDCl3), δ: 73.9 (t, J = 27.1), 110.3 (t, J = 250.5), 110.4 (t, J =
44.3), 123.9, 128.7, 139.3, 149.0. 19F NMR (282 MHz, CDCl3), δ: –99.2 (dd, 1F, J = 290.3, 8.4), –
102.6 (dd, 1F, J = 290.3, 8.4). Calcd for C9H6F2N2O3 (228.15): C, 47.38; H, 2.65; N, 12.28. Found:
C, 47.60; H, 2.66; N, 12.35.
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2,2-Difluoro-3-hydroxy-3-(4-methoxyphenyl)propanenitrile (5c). Method A, 80 mg, 75% yield.
Colorless oil. Rf 0.32 (hexanes/EtOAc 3 : 1). B.p. 110–120 °C (bath temp.)/0.015 Torr. 1H NMR (300
MHz, CDCl3), δ: 3.04–3.10 (br, 1H), 3.84 (s, 3H), 4.98 (t, 1H, J = 8.6), 6.96 (d, 2H, J = 8.8), 7.43 (d,
2H, J = 8.8). 13C NMR (75 MHz, CDCl3), δ: 55.3, 74.5 (t, J = 26.8), 110.8 (t, J = 249.0), 111.1 (t, J =
44.6), 114.3, 124.7, 128.8, 160.9. 19F NMR (282 MHz, CDCl3), δ: –99.6 (dd, 1F, J = 288.2, 8.6), –
102.5 (dd, 1F, J = 288.2, 8.6). Calcd for C10H9F2NO2 (213.18): C, 56.34; H, 4.26; N, 6.57. Found: C,
56.23; H, 4.21; N, 6.51.
3-[4-(Dimethylamino)phenyl]-2,2-difluoro-3-hydroxypropanenitrile (5d). Method B, 68 mg, 60%
1
yield. Orange crystals. M.p. 56–58 °C (hexanes/EtOAc 10 : 1). Rf 0.28 (hexanes/EtOAc 2 : 1). H
NMR (300 MHz, CDCl3), δ: 2.99 (s, 6H), 3.15–3.39 (br, 1H), 4.87 (t, 1H, J = 8.7), 6.75 (d, 2H, J =
8.8), 7.33 (d, 2H, J = 8.8). 13C NMR (75 MHz, CDCl3), δ: 40.3, 74.7 (t, J = 26.8), 110.9 (t, J =
19
249.0), 111.4 (t, J = 44.9), 112.3, 120.0 (d, J = 3.6), 128.4, 151.6. F NMR (282 MHz, CDCl3), δ: –
99.4 (dd, 1F, J = 288.2, 8.7), –102.3 (dd, 1F, J = 288.2, 8.7). HRMS (ESI): Calcd for C11H13F2N2O
(M + H): 227.0990. Found: 227.0991.
3-(2-Bromophenyl)-2,2-difluoro-3-hydroxypropanenitrile (5e). Method B, 110 mg, 84% yield.
Colorless oil. Rf 0.35 (hexanes/EtOAc 5 : 1). B.p. 110–125 °C (bath temp.)/0.095 Torr. 1H NMR (300
MHz, CDCl3), δ: 3.02–3.10 (br, 1H), 5.70 (t, 1H, J = 7.6), 7.26–7.37 (m, 1H), 7.40–7.50 (m, 1H),
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7.60–7.68 (m, 1H), 7.71–7.79 (m, 1H). 13C NMR (75 MHz, CDCl3), δ: 73.0 (t, J = 27.0), 110.8 (t, J =
250.2), 111.0 (t, J = 44.3), 124.1, 128.1, 129.3, 131.5, 132.5 (d, J = 3.5), 133.2. 19F NMR (282 MHz,
CDCl3), δ: –98.2 (dd, 1F, J = 291.4, 7.6), –102.5 (dd, 1F, J = 291.4, 7.6). Calcd for C9H6BrF2NO
(262.05): C, 41.25; H, 2.31; N, 5.35. Found: C, 41.24; H, 2.24; N, 5.41.
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2,2-Difluoro-3-hydroxy-3-(1-naphthyl)propanenitrile (5f). Method B, 84 mg, 72% yield. Colorless
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crystals. M.p. 72–73 °C (hexanes). Rf 0.28 (hexanes/EtOAc 5 : 1). H NMR (300 MHz, CDCl3), δ:
3.08 (d, 1H, J = 4.0), 5.86–6.00 (m, 1H), 7.51–7.64 (m), 7.88–8.02 (m). 13C NMR (75 MHz, CDCl3),
δ: 70.5 (t, J = 27.4), 111.1 (t, J = 44.6), 111.6 (t, J = 250.5), 122.4 (d, J = 2.9), 125.2, 125.9, 126.1,
127.0, 128.8 (d, J = 3.5), 129.1, 130.7, 131.1, 133.6. 19F NMR (282 MHz, CDCl3), δ: –96.4 (dd, 1F, J
= 290.3, 8.5), –101.0 (dd, 1F, J = 288.2, 6.4). Calcd for C13H9F2NO (233.21): C, 66.95; H, 3.89; N,
6.01. Found: C, 66.81; H, 3.88; N, 5.96.
2,2-Difluoro-3-hydroxy-3-pyridin-2-ylpropanenitrile (5g). Method B, 67 mg, 73% yield. Colorless
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crystals. M.p. 56–61 °C (hexanes). Rf 0.23 (hexanes/EtOAc 2 : 1). H NMR (300 MHz, CDCl3), δ:
5.05 (t, 1H, J = 8.2), 5.63–5.82 (br, 1H), 7.39–7.53(m, 2H), 7.80–7.89 (m, 1H), 8.66–8.71 (m, 1H).
13C NMR (75 MHz, CDCl3), δ: 72.7 (t, J = 26.8), 110.7 (t, J = 250.8), 110.8 (t, J = 44.3), 123.1,
125.0, 137.5, 148.7, 149.7 (d, J = 5.2). 19F NMR (282 MHz, CDCl3), δ: –98.8 (dd, 1F, J = 292.5, 8.2),
–103.2 (dd, 1F, J = 290.3, 8.2). Calcd for C8H6F2N2O (184.14): C, 52.18; H, 3.28; N, 15.21. Found:
C, 52.39; H, 3.31; N, 15.32.
2,2-Difluoro-3-hydroxy-3-thien-2-ylpropanenitrile (5h). Method A, 68 mg, 72% yield. Colorless oil.
Rf 0.27 (hexanes/EtOAc 5 : 1). B.p. 80–100 °C (bath temp.)/0.075 Torr. 1H NMR (300 MHz, CDCl3),
δ: 3.04–3.19 (br, 1H), 5.25–5.39 (m, 1H), 7.05–7.19 (br, 1H), 7.23–7.35 (br, 1H), 7.42–7.52 (br, 1H).
13C NMR (75 MHz, CDCl3), δ: 71.6 (t, J = 27.9), 110.0 (t, J = 249.9), 110.8 (t, J = 44.6), 127.4,
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127.8, 127.9, 134.7 (d, J = 3.4). F NMR (282 MHz, CDCl3), δ: –99.9 (d, 1F, J = 288.2), –102.4 (d,
1F, J = 288.2). Calcd for C7H5F2NOS (189.19): C, 44.44; H, 2.66; N, 7.40. Found: C, 44.21; H, 2.55;
N, 7.27.
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(4E)-2,2-Difluoro-3-hydroxy-5-phenylpent-4-enenitrile (5i). Method A, 75 mg, 72% yield. Colorless
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oil. Chromatography was performed at –30 °C. Rf 0.29 (hexanes/EtOAc 5 : 1). H NMR (300 MHz,
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CDCl3), δ: 2.80–2.98 (br, 1H), 4.68 (q, 1H, J = 7.4), 6.19 (dd, 1H, J = 15.8, 7.4), 6.95 (d, 1H, J =
15.8), 7.34–7.51 (m, 5H). 13C NMR (75 MHz, CDCl3), δ: 73.7 (t, J = 26.8), 110.7 (t, J = 249.6), 111.2
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(t, J = 44.3), 119.1 (dd, J = 3.5, 1.7), 127.0, 128.8, 129.1, 135.0, 137.8. F NMR (282 MHz, CDCl3),
δ: –100.9 (dd, 1F, J = 290.3, 7.4), –103.7 (dd, 1F, J = 290.3, 7.4). Calcd for C11H9F2NO (209.19): C,
63.16; H, 4.34; N, 6.70. Found: C, 63.08; H, 4.45; N, 6.81.
2,2-Difluoro-3-hydroxy-5-phenylpentanenitrile (5j). Method A, 76 mg, 72% yield. Method B, 74 mg,
70% yield. Colorless oil. Rf 0.25 (hexanes/EtOAc 10 : 1). B.p. 90–100 °C (bath temp.)/0.051 Torr. 1H
NMR (300 MHz, CDCl3), δ: 1.91–2.25 (m, 2H), 2.41–2.58 (m, 1H), 2.72–2.88 (m, 1H), 2.92–3.10 (m,
1H), 3.84–4.08 (m, 1H), 7.20–7.42 (m, 5H). 13C NMR (75 MHz, CDCl3), δ: 30.7, 30.8 (dd, J = 2.3,
1.2), 71.8 (dd, J = 26.5, 25.3), 111.2 (t, J = 44.6), 111.5 (t, J = 247.9), 126.6, 128.4, 128.7, 139,8. 19F
NMR (282 MHz, CDCl3), δ: –101.7 (dd, 1F, J = 294.6, 10.6), –104.5 (dd, 1F, J = 292.5, 8.5). Calcd
for C11H11F2NO (211.21): C, 62.55; H, 5.25; N, 6.63. Found: C, 62.57; H,5.31; N, 6.61.
2,2-Difluoro-3-hydroxy-4,4-dimethyl-5-phenylpentanenitrile (5k). Method A, 78 mg, 65% yield.
Method B, 79 mg, 66% yield. Colorless oil. Rf 0.26 (hexanes/EtOAc 5 : 1). B.p. 90–100 °C (bath
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temp.)/0.078 Torr. H NMR (300 MHz, CDCl3), δ: 1.11 (s, 3H), 1.18 (s, 3H), 2.64 (d, 1H, J = 13.2),
2.75 (d, 1H, J = 6.6), 2.92 (d, 1H, J = 13.2), 3.70 (td, 1H, J = 10.8, 6.2), 7.16–7.45 (m, 5H). 13C NMR
(75 MHz, CDCl3), δ: 22.6, 23.3 (dd, J = 2.3, 4.0), 38.1, 45.9, 76.7 (t, J = 23.9), 112.2 (dd, J = 253.9,
247.0), 112.3 (t, J = 44.6), 126.6, 128.2, 130.7, 136.9. 19F NMR (282 MHz, CDCl3), δ: –91.1 (dd, 1F,
J = 296.7, 10.6), –98.6 (dd, 1F, J = 296.7, 10.6). Calcd for C13H15F2NO (239.26): C, 65.26; H, 6.32;
N, 5.85. Found: C, 65.21; H, 6.38; N, 5.68.
Reaction of silane 1 with N-tosylimines 7. General procedure.
AcOLi (43 mg, 0.65 mmol) was added to a solution of Nꢀtosylimine 7 (0.5 mmol) and silane 1 (97
mg, 0.65 mmol) in THF (1 mL) at 25 °C, and the mixture was stirred at room temperature for time
indicated in Table 3. The mixture was treated with saturated aq. NaHSO4 (1 mL), stirred for additional
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30 min. The mixture was diluted with water (5 mL), extracted with tertꢀbutyl methyl ether (3×3 mL).
The organic phase was dried over Na2SO4, concentrated, and the residue was purified by
chromatography.
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N-(2-cyano-2,2-difluoro-1-phenylethyl)-4-methylbenzenesulfonamide (8a). 156 mg, 93% yield.
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Colorless crystals. M.p. 166–168 °C (hexanes/EtOAc 10 : 1). Rf 0.29 (hexanes/EtOAc 3 : 1). H
NMR (300 MHz, CDCl3), δ: 2.35 (s, 3H), 4.96 (q, 1H, J = 11.0), 6.27 (d, 1H, J = 11.0), 7.11–7.36 (m,
7H), 7.64 (d, 2H, J = 8.2). 13C NMR (75 MHz, CDCl3), δ: 21.4, 61.6 (t, J = 25.6), 109.5 (t, J =
251.0), 111.0 (t, J = 44.6), 127.0, 128.1, 129.0, 129.6, 129.8, 130.3, 136.6, 144.1. 19F NMR (282
MHz, CDCl3), δ: –97.6 (dd, 1F, J = 287.2, 11.0), –99.1 (dd, 1F, J = 287.2, 11.0). Calcd for
C16H14F2N2O2S (336.36): C, 57.13; H, 4.20; N, 8.33. Found: C, 57.04; H, 4.20; N, 8.20.
N-[2-Cyano-2,2-difluoro-1-(4-methoxyphenyl)ethyl]-4-methylbenzenesulfonamide (8b). 143 mg, 78%
yield. Colorless crystals. M.p. 136–137 °C (hexanes/EtOAc 10 : 1). Rf 0.30 (hexanes/EtOAc 2 : 1). 1H
NMR (300 MHz, CDCl3), δ: 2.37 (s, 3H), 3.77 (s, 1H), 4.90 (td, 1H, J = 11.7, 9.7), 6.15 (d, 1H, J =
9.7), 6.77 (d, 2H, J = 8.8), 7.11 (d, 2H, J = 8.4), 7.17 (d, 2H, J = 8.2), 7.63 (d, 2H, J = 8.4). 13C NMR
(75 MHz, CDCl3), δ: 21.4, 55.3, 61.1 (t, J = 25.6), 109.6 (t, J = 251.1), 111.1 (t, J = 44.6), 114.5,
122.2, 127.0, 129.4, 129.6, 136.7, 144.0, 160.7. 19F NMR (282 MHz, CDCl3), δ: –98.5 (m, 2F).
HRMS (ESI): Calcd for C17H16F2N2O3SNa (M+Na): 389.0742, C17H16F2N2O3SK (M+K): 405.0481.
Found: 389.0734 (M+Na), 405.0473 (M+K).
Methyl 4-(2-Cyano-2,2-difluoro-1-{[(4-methylphenyl)sulfonyl]amino}ethyl)benzoate (8c). 179 mg,
91% yield. Colorless crystals. M.p. 175–176 °C (hexanes/EtOAc 10 : 1). Rf 0.37 (hexanes/EtOAc 1 :
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1). H NMR (200 MHz, CDCl3), δ: 2.33 (s, 3H), 3.92 (s, 3H), 5.06 (dt, 1H, J = 13.0, 10.2), 6.69 (d,
1H J = 10.2), 7.13 (d, 2H, J = 8.3), 7.30 (d, 2H, J = 8.3), 7.62 (d, 2H, J = 8.3), 7.91 (d, 2H, J = 8.3).
13C NMR (50 MHz, CDCl3), δ: 21.3, 52.4, 61.3 (t, J = 25.6), 109.2 (t, J = 251.2), 110.7 (t, J = 44.7),
126.9, 128.3, 129.7, 130.1, 131.4, 134.8, 136.3, 144.4, 166.1. 19F NMR (282 MHz, CDCl3), δ: –97.2
(dd, 1F, J = 288.2, 10.2), –99.5 (dd, 1F, J = 288.2, 14.8). Calcd for C18H16F2N2O4S (394.39): C,
54.82; H, 4.09; N, 7.10. Found: C, 54.72; H, 4.07; N, 7.16.
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N-[2-Cyano-2,2-difluoro-1-(2-furyl)ethyl]-4-methylbenzenesulfonamide (8d). 134 mg, 82% yield.
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Colorless crystals. M.p. 147–150 °C (hexanes/EtOAc 10 : 1). Rf 0.25 (hexanes/EtOAc 1 : 1). H
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NMR (300 MHz, CDCl3), δ: 2.39 (s, 3H), 5.12 (q, 1H, J = 10.3), 6.00 (d, 1H, J = 10.3), 6.27 (br, 1H),
6,31–6.37 (m, 1H), 7.23 (d, 2H, J = 8.1), 7.31 (br, 1H), 7.69 (d, 2H, J = 8.1). 13C NMR (50 MHz,
CDCl3), δ: 21.5, 55.7 (t, J = 27.7), 108.4 (t, J = 252.0), 110.9, 111.6, 127.0, 129.7, 136.5, 143.0,
144.3. 19F NMR (282 MHz, CDCl3), δ: –97.7 (dd, 1F, J = 286.1, 10.3), –99.0 (dd, 1F, J = 286.1, 10.3).
Calcd for C14H12F2N2O3S (326.32): C, 51.53; H, 3.71; N, 8.58. Found: C, 51.38; H, 3.80; N, 8.50.
N-(1-Cyano-1,1-difluoro-3,3-dimethylbutan-2-yl)-4-methylbenzenesulfonamide (8e). 120 mg, 76%
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yield. Colorless crystals. M.p. 157–159 °C (hexanes). Rf 0.27 (hexanes/EtOAc 5 : 1). H NMR (300
MHz, CDCl3), δ: 1.11 (s, 9H), 2.43 (s, 3H), 3.86 (dt, 1H, J = 13.2, 9.5), 5.24–5.39 (m, 1H), 7.30 (d,
2H, J = 8.3), 7.78 (d, 2H, J = 8.3). 13C NMR (75 MHz, CDCl3), δ: 21.5, 27.4, 34.5, 65.0 (t, J = 23.6),
111.0 (t, J = 251.6), 112.0 (t, J = 44.9), 126.9, 129.6, 138.0, 143.8. 19F NMR (282 MHz, CDCl3), δ: –
89.4 (dd, 1F, J = 292.5, 13.2), –92.5 (dd, 1F, J = 292.5, 10.1). Calcd for C14H18F2N2O2S (316.37): C,
53.15; H, 5.73; N, 8.85. Found: C, 53.14; H, 5.74; N, 8.79.
Reaction of silane 1 with imines 9. General procedure.
Trifluoroacetic acid (48 ꢁL, 0.625 mmol) was added to a mixture of imine 9 (0.5 mmol) and KHF2 (29
mg, 0.375 mmol) in acetonitrile (1.5 mL) at 0 °C, and the suspension was stirred for 5 min. Silane 1
(112 mg, 0.75 mmol) was added, the cooling bath was removed, and the mixture was stirred for 18 h
at room temperature. For the workꢀup, saturated aqueous Na2CO3 (1 mL) was added dropwise, the
mixture was stirred for an additional two minutes, diluted with water (7 mL) and extracted with
ether/hexane (1 : 1, 3×4 mL). The combined organic phase was filtered through Na2SO4, concentrated,
and the residue was purified by chromatography.
2,2-Difluoro-3-(methylamino)-3-phenylpropanenitrile (11a). 65 mg, 66% yield. Colorless oil. Rf 0.32
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(hexanes/EtOAc 20 : 1). B.p. 111–125 °C (bath temp.)/9 Torr. H NMR (300 MHz, CDCl3), δ: 1.67–
1.81 (br, 1H), 2.47 (s, 3H), 4.05 (t, 1H, J = 9.7), 7.42–7.48 (m, 5H). 13C NMR (75 MHz, CDCl3), δ:
34.6, 68.6 (t, J = 23.9), 111.88 (t, J = 44.9), 111.91 (t, J = 248.5), 128.6, 128.9, 129.7, 132.7 (d, J =
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3.5). 19F NMR (282 MHz, CDCl3), δ: –95.4 (dd, 1F, J = 288.2, 9.7), –99.0 (dd, 1F, J = 288.2, 9.7).
Calcd for C10H10F2N2 (196.20): C, 61.22; H, 5.14; N, 14.28. Found: C, 61.03; H, 5.03; N, 14.05.
2,2-Difluoro-3-[(4-methoxyphenyl)amino]-3-phenylpropanenitrile (11b). 98 mg, 68% yield. Colorless
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oil. Rf 0.35 (hexanes/EtOAc 10 : 1). B.p. 140–145 °C (bath temp.)/0.109 Torr. H NMR (300 MHz,
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CDCl3), δ: 3.76 (s, 3H), 4.17 (d, 1H, J = 8.5), 4.89 (dt, 1H, J = 13.2, 8.5), 6.70–6.78 (m, 2H), 6.78–
6.85 (m, 2H), 7.41–7.55 (m, 5H). 13C NMR (75 MHz, CDCl3), δ: 55.5, 64.1 (t, J = 24.5), 111.0 (t, J =
251.2), 111.9 (t, J = 45.2), 114.8, 116.7, 128.1, 129.0, 129.6, 132.6, 138.7, 153.9. 19F NMR (282
MHz, CDCl3), δ: –96.0 (dd, 1F, J = 287.5, 8.5), –100.5 (dd, 1F, J = 287.5, 13.2). Calcd for
C16H14F2N2O (288.29): C, 66.66; H, 4.89; N, 9.72. Found: C, 66.85; H, 4.82; N, 9.72.
3-(Cyclopropylamino)-2,2-difluoro-3-thien-2-ylpropanenitrile (11c). 89 mg, 78% yield. Colorless oil.
Rf 0.33 (hexanes/EtOAc 40 : 1). B.p. 98–105 °C (bath temp.)/0.67 Torr. 1H NMR (300 MHz, CDCl3),
δ: 0.47–0.66 (m, 4H), 2.17–2.41 (m, 2H), 4.51 (ddd, 1H, J = 16.7, 9.5, 7.5), 7.10 (dd, 1H, J = 5.1,
3.8), 7.19 (d, 1H, J = 3.8), 7.41 (d, 1H, J = 5.1). 13C NMR (75 MHz, CDCl3), δ: 6.9, 7.1, 29.3, 62.7 (t,
J = 25.6), 110.8 (t, J = 249.6), 112.0 (t, J = 44.9), 126.7, 127.3, 127.6, 136.0. 19F NMR (282 MHz,
CDCl3), δ: –94.8 (dd, 1F, J = 286.1, 7.5), –102.1 (dd, 1F, J = 284.0, 16.7). Calcd for C10H10F2N2S
(228.26): C, 52.62; H, 4.42; N, 12.27. Found: C, 52.54; H, 4.46; N, 12.17.
Reaction of silane 1 with enamines 10. General procedure.
Trifluoroacetic acid (48 ꢁL, 0.625 mmol) was added to a mixture of enamine 10 (0.5 mmol) and KHF2
(29 mg, 0.375 mmol) in acetonitrile (1.5 mL) at –30 °C, and the suspension was stirred for 5 min.
Silane 1 (112 mg, 0.75 mmol) was added, the cooling bath was replaced by ice/water bath, the mixture
was stirred for 1 h at 0°C, and then for an additional hour at room temperature. For the workꢀup,
saturated aqueous Na2CO3 (1 mL) was added dropwise, the mixture was stirred for an additional two
minutes, diluted with water (7 mL) and extracted with ether/hexane (1 : 1, 3×4 mL). The combined
organic phase was filtered through Na2SO4 and concentrated to give the crude material, which was
purified by chromatography.
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Difluoro(1-morpholin-4-ylcyclohexyl)acetonitrile (12a). 116 mg, 95% yield. Colorless oil. Rf 0.43
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(hexanes/EtOAc 20 : 1). B.p. 95–103 °C (bath temp.)/0.106 Torr. H NMR (300 MHz, CDCl3), δ:
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1.20–1.93 (m, 8H), 2.01–2.18 (m, 2H, J = 9.2), 2.88–3.09 (br, 4H), 3.60–3.84 (br, 4H). C NMR (75
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MHz, CDCl3), δ: 19.9, 25.4, 27.3, 46.6, 62.6 (t, J = 19.0), 68.3, 112.7 (t, J = 45.5), 116.1 (t, J =
258.1). 19F NMR (282 MHz, CDCl3), δ: –98.1 (s, 2F). Calcd for C12H18F2N2O (244.28): C, 59.00; H,
7.43; N, 11.47. Found: C, 58.93; H, 7.53; N, 11.34.
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2,2-Difluoro-4-methyl-3-pyrrolidin-1-ylpentanenitrile (12b). 83 mg, 82% yield. Colorless oil. Rf 0.64
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(hexanes/EtOAc 20 : 1). B.p. 90–100 °C (bath temp.)/9 Torr. H NMR (300 MHz, CDCl3), δ: 0.97–
1.16 (m, 6H), 1.72–1.90 (m, 4H), 2.12–2.29 (m, 1H), 2.86–3.10 (m, 5H). 13C NMR (75 MHz, CDCl3),
δ: 19.6 (dd, J = 2.3, 4.6), 21.1, 24.8, 26.9, 49.0, 68.3 (t, J = 22.2), 113.5 (t, J = 44.9), 114.4 (dd, J =
255.7, 258.0). 19F NMR (282 MHz, CDCl3), δ: –85.8 (d, 1F, J = 288.2), –98.2 (dd, 1F, J = 288.2,
19.1). Calcd for C10H16F2N2 (202.24): C, 59.39; H, 7.97; N, 13.85. Found: C, 59.14; H, 7.75; N,
13.72.
3-Amino-2,2-difluoro-1-(1-naphthyl)propan-1-ol hydrochloride (13). A solution of nitrile 5f (117 mg,
0.5 mmol) in Et2O (1 mL) was added dropwise to a solution of LiAlH4 (34 mg, 0.85 mmol) in Et2O (1
mL) at 0 °C, and the mixture was stirred for 2 h at room temperature. The mixture was cooled to 0 °C,
and water (40 ꢁL), NaOH (30 ꢁL of 20% aq. solution) and water (140 ꢁL) were successively added.
The solid material was filtered, washed with ether (3×1 mL), and the filtrate was treated with HCl
(314 ꢁL, 1.74 M in dioxane, 0.55 mmol). The precipitate was filtered, washed with ether (1 mL), and
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dried under vacuum. Yield 130 mg (95%). Colorless crystals. M.p. 216–220 °C (dec). H NMR (300
MHz, CD3OD), δ: 3.58–3.87 (m, 2H), 4.72–5.35 (br, 3H), 6.00 (dd, 1H, J = 14.6, 7.0), 7.45–7.60 (m,
3H), 7.85–7.95 (m, 3H), 8.23 (d, 1H, J = 8.4). 13C NMR (75 MHz, CD3OD), δ: 42.5 (t, J = 26.2), 70.6
(dd, J = 29.4, 25.3), 121.6 (dd, J = 250.5, 247.0), 124.7 (t, J = 2.3), 126.1, 126.6, 127.2, 127.3, 129.7,
130.3, 132.9, 133.8 (d, J = 2.3), 135.0. 19F NMR (282 MHz, CD3OD), δ: –111.5 (ddt, 1F, J = 252.2,
23.3, 7.0), –117.4 (dddd, 1F, J = 252.2, 23.3, 14.6, 8.5). Calcd for C13H14ClF2NO (273.71): C, 57.05;
H, 5.16; N, 5.12. Found: C, 57.10; H, 5.20; N, 5.13.
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2,2-Difluoro-3-{[(4-methylphenyl)sulfonyl]amino}-3-phenylpropanamide (14). A solution of nitrile 8a
(168 mg, 0.5 mmol) and phenol (94 mg, 1 mmol) in 33% HBr/AcOH (1.5 g) was stirred for 18 h at
room temperature. The mixture was poured into Et2O (10 mL), the precipitate was filtered. The
collected solid was dissolved in minimal amount of refluxing methanol (ca. 5 mL), cooled to room
temperature followed by dropwise addition of Et2O (ca. 10 mL). The precipitate was filtered and
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dried. Yield 149 mg (84%). Colorless crystals. M.p. 260–265 °C. H NMR (300 MHz, DMSOꢀd6), δ:
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2.21 (s, 3H), 3.77–3.85 (br, 3H), 5.05 (t, 1H, J = 14.7), 7.04–7.23 (m, 7H), 7.43 (d, 2H, J = 8.1). C
NMR (75 MHz, DMSOꢀd6), δ: 20.8, 58.5 (t, J = 24.6), 115.1 (t, J = 258.5), 126.3, 127.9, 128.2,
128.6, 129.0, 132.7, 137.9, 142.5, 164.1 (t, J = 27.9). 19F NMR (282 MHz, DMSOꢀd6), δ: –112.1 (m,
2F). Calcd for C16H16F2N2O3S (354.37): C, 54.23; H, 4.55; N, 7.91. Found: C, 54.18; H, 4.57; N, 7.83.
Acknowledgement
This work was supported by the Ministry of Science (project MDꢀ1151.2011.3), and the Russian
Academy of Sciences (program # 8).
Supporting Information
Copies of NMR spectra for all compounds and free induction decay (FID) files for the mixture of
compounds 4a + 6. This material is available free of charge via the Internet at http://pubs.acs.org.
Dedication
This paper is dedicated to Professor Vladimir Tartakovsky on the occasion of his 80th birthday.
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(11) In case the styrene oxide scavenger is not applied, it was difficult to completely separate 1 and
Me3SiBr by fractional distillation.
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(12) Generation and trapping of difluorocarbene from silanes Me3SiCF2X (X = Cl, Br) in the
presence of chloride ion has been reported, see: Wang, F.; Zhang, W.; Zhu, J.; Li, H.; Huang,
K.ꢀW.; Hu, J. Chem. Commun. 2011, 47, 2411–2413.
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(13) Attempts to obtain compound 6 as dominating component using excess of silane 1 and Lewis
base failed leading to complex mixtures. Compound 6 cannot be isolated by silica gel
chromatography owing to decomposition. At best, the mixture of 4a and 6 containing 40% of 6
was obtained after vacuum distillation of crude reaction mixture. The structure of 6 was deduced
from 1H, 19F, and 13C NMR spectra.
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(14) (a) Levin, V. V.; Dilman, A. D.; Belyakov, P. A.; Struchkova, M. I.; Tartakovsky, V. A. Eur. J.
Org. Chem. 2008, 5226–5230. (b) Gritsenko, R. T.; Levin, V. V.; Dilman, A. D.; Belyakov, P.
A.; Struchkova, M. I.; Tartakovsky, V. A. Tetrahedron Lett. 2009, 50, 2994–2997. (с)
Kosobokov, M. D.; Dilman, A. D.; Struchkova, M. I.; Belyakov, P. A.; Hu, J. J. Org. Chem.
2012, 77, 2080–2086.
(15) The immediate precursor, Me3SiCF2Br, is commercially available from several companies.
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