Nucleophilic bromodifluoromethylation of iminium ions

Article abstract of DOI:10.1021/jo501644m

A method for bromodifluoromethylation of iminium ions using Me₃SiCF₂Br is described. The reaction involves room temperature activation of the silicon reagent by HMPA to generate difluorocarbene, which upon interacting with excess of bromide ion provides bromodifluoromethyl carbanionic species. The iminium electrophiles are generated in situ from aldehydes, secondary amines, proton sponge, and silyl triflate. The reaction can be extended for introduction of chlorodifluoromethyl and iododifluoromethyl groups.

Full text of DOI:10.1021/jo501644m

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Nuchleophilic Bromodifluoromethylation of Iminium Ions
Artem V. Tsymbal, Mikhail D. Kosobokov, Vitalij V. Levin, Marina I. Struchkova, and Alexander D. Dilman
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo501644m • Publication Date (Web): 13 Aug 2014
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Nuchleophilic Bromodifluoromethylation of Iminium Ions
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Artem V. Tsymbal,†,‡ Mikhail D. Kosobokov,† Vitalij V. Levin,† Marina I. Struchkova,† Alexander
D. Dilman,*,†
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†N. D. Zelinsky Institute of Organic Chemistry, 119991 Moscow, Leninsky prosp. 47, Russian
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Federation
‡Moscow State University, Department of Chemistry, 119991, Moscow, Leninskie Gory 1ꢀ3,
Russian Federation
adil25@mail.ru
R1
R2
R1
R3
R2
(a) Me3SiOTf,
proton sponge
R1
R3
R2
N
H
N
N
Br
Br
O
Br
SiMe3
, HMPA, Br
C
(b)
F
F
R3
F
F
F
F
room temperature
Abstract. A method for bromodifluoromethylation of iminium ions using Me3SiCF2Br is described.
The reaction involves room temperature activation of the silicon reagent by HMPA to generate
difluorocarbene which upon interacting with excess of bromide ion provides bromodifluoromethyl
carbanionic species. The iminium electrophiles are generated in situ from aldehydes, secondary
amines, proton sponge, and silyl triflate. The reaction can be extended for introduction of
chlorodifluoromethyl and iododifluoromethyl groups.
Introduction
Methods for the synthesis of organofluorine compounds have witnessed intensive growth in
recent years.1 While major efforts were focused on the introduction of a fluorine atom and the CF3ꢀ
group, methodology for the synthesis of gemꢀdifluorinated compounds remains limited.2 For
example, it is difficult to obtain compounds bearing interhalogenated methyl group, CF2X (X = Br,
I). At the same time, this fragment can serve as a halogen bond donor,3 which may be important for
medicinal chemistry and crystal engineering, whereas the CꢀX bond can be further involved into
radical or ionꢀradical processes4 finally affording gemꢀdifluorinated products.
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Existing methods for direct introduction of CF2X group involve electrophilic
bromodifluoromethylation of terminal alkynes,5 radical atom transfer additions,6 formal
nucleophilic addition to carbonyl compounds using halogenation of JuliaꢀKocienski intermediates.7
Recently we reported a first method for direct nucleophilic bromoꢀ and iododifluoromethylation of
simple aldehydes using corresponding silicon reagents Me3SiCF2X (X = Br, I).8 The latter reaction
likely involves the intermediacy of difluorocarbene and proceeds at high temperatures (100 °C),
which is required for activation of SiꢀC bond by weakly basic bromide and iodide anions (Scheme
1). However, these conditions are too drastic to be applicable to labile electrophiles such as iminium
ions. Herein we propose a protocol for nucleophilic addition of the CF2X group to iminium salts
using corresponding silicon reagents which is carried out room (or lower) temperatures. The key
finding is that silanes Me3SiCF2X can be readily activated by neutral Lewis bases.
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Scheme 1. Nucleophilic halodifluoromethylation.
X
LB
Me3Si
X
C
F
X
F
F
F
F
F
O
X = Br, I
OH
F
, LB = X –, T = 100 °C
Previous work
R
X
R
F
R
R
R
N
R
R
R
N
, LB = HMPA, DMPU, T = rt
X
This work
F
F
Results and Discussion
Iminium salt 2a generated by methylation of imine 1a with methyl triflate in dichloromethane
was selected as a model substrate, and its reaction with (bromodifluoromethyl)trimethylsilane (3a)
in the presence of tetrabutylammonium bromide (1.1 equiv) was evaluated (Table 1). While no
reaction occurred in dichloromethane, the use of amide solvents at the bromodifluoromethylation
step provided product 4a (entries 3ꢀ6).9 Subsequent studies aimed at reducing the amount of the
amides allowed to identify HMPA as a Lewis basic activator, which is effective even in
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stoichiometric quantities (entries 9ꢀ10). Fortunately, only slight excess of the silicon reagent (1.5
3
4
5
equiv) proved to be sufficient to achieve 89% isolated yield of 4a (entry 10).
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Table 1. Bromodifluoromethylation of iminium salt 2a.
8
9
Me3SiCF2Br (3a)
Me
Ar
Bn
Bn
Me
Ar
Bn
N
N
N
Bu4NBr (1.1 equiv)
MeOTf
Br
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CH2Cl2
15 min
solv, LB
Ar
1a
TfO
F
F
0 °C, then rt
2a
4a
Ar = 4-MeOC6H4
3,
equiv
#
solva
LB (equiv) Time, h Yield of 4a, %b
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2
3
4
5
6
7
8
9
CH2Cl2 3.0
MeCN 3.0
HMPA 3.0
–
–
–
–
–
–
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18
18
24
20
2
0
0
42
46
DMF
NMP
3.0
3.0
61
DMPU 3.0
82 (77c)
68
DMPU 3.0 HMPA (3.0)
CH2Cl2 1.5 DMPU (3.0)
CH2Cl2 3.0 HMPA (3.0)
7
2
97 (89c)
95 (89c)
4
10 CH2Cl2 1.5 HMPA (3.0)
11 CH2Cl2 1.5 HMPA (0.1)
12d CH2Cl2 1.5 HMPA (3.0)
2
4
5
78
a
HMPA – hexamethylphosphoramide; DMF – dimethylformamide; NMP – Nꢀmethylꢀ2ꢀ
pyrrolidone; DMPU – N,N'ꢀdimethylꢀN,N'ꢀtrimethyleneurea.
b Determined by 19F NMR of reaction mixtures with PhCF3 as an internal standard.
c Isolated yield.
d 0.5 equiv of Bu4NBr was used.
In order to apply this protocol to iminium ions that could not be conveniently prepared by
alkylation of corresponding Schiff bases, we developed a procedure for their in situ generation.
Thus, treatment of secondary amines with silyl triflate and 1,8ꢀbis(dimethylamino)naphthalene
(proton sponge) in dichloromethane followed by interaction with aldehydes during one hour led to
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iminium salts 2.10,11 Subsequent addition of the silane, bromide ion, and HMPA effected
bromodifluormethylation (Table 2).
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Table 2. Coupling of amines, aldehydes and silane 3.
8
9
Me2N
NMe2
(1.1 equiv)
O
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R3
R1
R2
R1
R2
Me3SiOTf (2.5 equiv)
(1.0 equiv)
N
N
H
CH2Cl2, 0 °C to rt, 30 min
0 °C to rt, 1h
SiMe3
Me3SiCF2Br (3a, 1.5 equiv)
Bu4NBr (1.1 equiv)
HMPA (3 equiv)
R1
R2
R1
R2
N
N
Br
R3
R3
0 °C to rt, 2h
TfO
F
F
4
2
#
1
Aldehyde
Amine
4
Yield of 4, %a
O
Me
N
Ph
4a
88
H
MeO
O
2
3
4b
4c
88
85
N
H
N
H
O
OMe
4b
5
4d
4e
76
87
Me
N
H
Br
N
H
O
6
7
4f
4g
4h
94
63 (79с)
80
N
H
Cl
O
N
H
Ph
O
8b
N
H
O
Me
N
Ph
9
4i
74
H
S
a Isolated yield.
b The iminium ion was generated for 24 h.
Yield determined by 19F NMR. The decrease of yield upon isolation is due to volatility of the
c
product.
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According to this protocol, a variety of iminium ions generated from aromatic aldehydes and
alkyl, allyl, benzyl and aryl substituted secondary amines were bromodifluoromethylated affording
products 4 in good to excellent yields. In this oneꢀpot protocol, the complete generation of moisture
sensitive iminium ion is believed to be a limiting factor. For example, in case of moderately reactive
aldehyde/amine couples such as those in entry 4 (nonꢀnucleophilic amine) and entry 8 (hindered
aldehyde), longer time (24 hours) is needed for the formation of iminium salts. Interestingly, when
diallylamine was used, no cyclopropanation products were detected.
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Unfortunately, the oneꢀpot procedure was unsuccessful for
a
combination of
cyclohexanecarboxaldehyde and Nꢀbenzylmethylamine, presumably owing to enolization problem.
Nevertheless, product 4j could be obtained when the intermediate iminium ion was generated by
methylation of imine 1b (Scheme 2).
Scheme 2. Synthesis of product 4j.
Bn
Me
Bn
N
N
(a) MeOTf, rt, 15 min
Br
F
F
(b) Me3SiCF2Br (3a),
Bu4NBr, HMPA, rt, 2h
1b
4j, 82%
It was interesting to extend the same methodology to chloroꢀ and iododifluoromethylation.
Starting from iminium salt 2a generated by imine methylation, for the chloroꢀsubstituted silane
Me3SiCF2Cl (3b), good yield of product 5a was achieved only after 48 hours (Table 3, entry 4). In
contrast, iodinated counterpart Me3SiCF2I (3c), the use of less donating DMPU (N,N'ꢀdimethylꢀ
N,N'ꢀtrimethyleneurea) was found to be optimal12 (entry 7).
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Table 3. Variation of the silicon reagent.
3
4
5
6
7
8
Me
Bn
R4NX (1.1 equiv)
LB (3 equiv)
N
Me
Ar
Bn
Me3Si
X
N
X
+
Ar
F
F
CH2Cl2
F
F
TfO
(1.5 equiv)
5a, X = Cl
6a, X = I
2a
Ar = 4-MeOC6H4
9
#
1
2
Xa
Cl
Cl
LB
t, °C
Time, h
Yield, %
traces
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TMUb
DMAPb
0 °C → rt
0 °C → rt
2
2
traces
12c
3
Cl
HMPA
0 °C → rt
2
4
Cl
HMPA 0 °C → rt
48
89d
66d
53c
5
I
HMPA
HMPA
DMPU
0 °C → rt
–42 °C
2
6
I
2
7
I
0 °C → rt
2
75d
a BnNEt3Cl (for X = Cl) or Bu4NI (for X = I) were used.
b TMU – tetramethylurea; DMAP – 4ꢀ(N,Nꢀdimethylamino)pyridine.
c Yield determined by 19F NMR.
d Isolated yield.
Chloroꢀ and iododifluoromethylation was also evaluated according to oneꢀpot protocol (Scheme
3), but the yields of products 5a and 6a were lower than those achieved with an authentic iminium
ion 2a.
Scheme 3 One-pot chloro- and iododifluoromethylation.
Me3Si
X
R1
Ar
R2
O
/ R4NX
R1
R2
i
F F
N
N
+
H
Ar
X
HMPA, 48h (for X = Cl)
DMPU, 2h (for X= I)
F
F
i: 1,8-bis(dimethylamino)naphthalene/Me3SiOTf
R1 = Me, R2 = Bn
R1 = Me, R2 = Bn
R1, R2 = Et, X = Cl
5a, 55%
6a, 64%
6b, 88%
Ar = 4-MeOC6H4
Ar = 4-MeOC6H4
Ar = 4-ClC6H4
X = Cl
X = I
X = I
The described halodifluoromethylation reactions are believed to proceed through the
intermediacy of difluorocarbene.8 It is of special note that by combining silanes Me3SiCF2X with
amides, the generation of difluorocarbene occurs at room temperature under virtually nonꢀbasic
conditions. For comparison, in previous reports, the decomposition of Me3SiCF2X (X = F, Cl, Br)
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to difluorocarbene was carried out either with highly reactive activators (fluoride, acetate) at room
(or lower) temperature13 or with nonꢀbasic chloride and bromide ions at 100 °C.14 To make use of
our mild activation conditions, we demonstrated the possibility of difluorocyclopropantion of
alkenes to be triggered simply by a proper amide additive (HMPA or DMPU) (Table 4). Indeed,
difluorocyclopropanation of 1,1ꢀdiphenylethylene with bromoꢀ and iodoꢀsubstituted silanes took
place at room temperature within two hours. To obtain a good isolated yield of product 7, three
equivalents of brominated silane were employed (entry 3). However, chlorinated silane Me3SiCF2Cl
gave only small amount of cyclopropane 7 while most of the silane (ca. 70%) remained unreacted.
The latter phenomenon was unexpected, since Me3SiCF2Cl successfully reacted with iminium salt
(vide supra). Such a discrepancy may suggest that, contrary to bromoꢀ and iodoꢀsubstituted silanes,
for which generation of difluorocarbene is fast, the reaction of Me3SiCF2Cl with iminium ion
proceeds as direct transfer of chlorodifluoromethyl group from pentacoordinate siliconate species.
Table 4. Difluorocyclopropanation reactions.
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F
F
Ph
Ph
LB (3 equiv)
CH2Cl2, rt
Me3Si
X
Ph
Ph
+
F
F
7
#
1
2
3
4
X
Cl
Br
Br
I
Equiv of silane
LB
Time, h Yield of 7, %
1.5
1.5
3
HMPA
HMPA
HMPA
DMPU
48
2
7a
54a
83b
39a
2
1.5
2
a Yield determined by 19F NMR.
b Isolated yield.
In summary, a method for direct bromodifluoromethylation of iminium ions with Me3SiCF2Br
furnishing αꢀbromodifluoromethylꢀsubstituted amines18 has been described. A oneꢀpot procedure
involving generation of iminium ions from aldehydes and secondary amines with their successive
coupling with the silane has been developed. The method can also be extended to the introduction
of CF2Cl and CF2I groups using corresponding silicon reagents. The activation of silanes by neutral
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Lewis bases such as HMPA and DMPU is believed to be the key factor responsible for reaction
efficiency.
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Experimental section
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General Methods. All reactions were performed in Schlenk flasks under an argon atmosphere.
CH2Cl2 was distilled from CaH2 prior to use. HMPA, DMPU, TMU were distilled under vacuum
from CaH2 and stored over MS 4Å. Column chromatography was carried out employing silica gel
(230−400 mesh). Precoated silica gel plates Fꢀ254 were used for thinꢀlayer analytical
chromatography visualizing with UV and/or acidic aq. KMnO4 solution. High resolution mass
spectra (HRMS) were measured using electrospray ionization (ESI) and timeꢀofꢀflight (TOF) mass
analyzer. The measurements were done in a positive ion mode (interface capillary voltage – 4500
V) or in a negative ion mode (3200 V); mass range from m/z 50 to m/z 3000. Nꢀ[(4ꢀ
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methoxyphenyl)methylene]ꢀ1ꢀphenylmethanamine
(1b),16
(iododifluoromethyl)trimethylsilane (3c)8 were obtained according to literature procedures.
(1a),15
Nꢀ[cyclohexylmethylene]ꢀ1ꢀ
phenylmethanamine
(bromodifluoromethyl)trimethylsilane
(3a)14d
and
(Chlorodifluoromethyl)trimethylsilane (3b). Obtained from silane 3a by modified literature
procedure.17 (Bromodifluoromethyl)trimethylsilane (13.0 g, 64 mmol) was added to a suspension of
LiCl (4.1 g, 96 mmol) in diglyme (32 mL) at room temperature, and the mixture was stirred for 18 h
at room temperature. The reaction mixture was cooled with ice/water bath, and stirred for additional
2 h. Then, the volatile components were distilled off under vacuum (10 Torr) collecting into a cold
trap (liquid nitrogen) [upon distillation the distilling flask was slowly warmed from 0 to 35 °C]. To
the collected liquid, BnNEt3Cl (228 mg, 1 mmol) was added, and the mixture was subjected to
distillation at atmospheric pressure affording 7.56 g (74% yield) of the product as a clear colorless
liquid. Bp 86–88 °C. NMR spectra were identical to the reported data.17
General procedure 1. Halodifluoromethylation of iminium salts generated from aldehydes and
amines [preparation of 4a-i, 5a, 6a,b]. Amine (0.55 mmol) and TMSOTf (1.25 mmol, 230 ꢁL)
were added to a solution of 1,8ꢀbis(dimethylamino)naphthalene (0.55 mmol, 118 mg) in CH2Cl2 (1
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mL) at 0 °C. The cooling bath was removed and the reaction mixture was stirred for 30 min at room
temperature. Then, the mixture was cooled to 0 °C, aldehyde (0.50 mmol) was added. The cooling
bath was removed and the mixture was stirred at room temperature (1 h for preparation of 4a-c,e-
g,i, 5a,b, 6a; 24 h for preparation of 4d,h). For reaction with silanes, the obtained solution of
iminium salt was cooled to 0 °C, and ammonium salt (0.55 mmol; Bu4NBr for X = Br, Bu4NI for X
= I, BnNEt3Cl for X = Cl), silicon reagent Me3SiCF2X (0.75 mmol), a Lewis base (1.50 mmol,
HMPA for X = Br and Cl, DMPU for X = I) were successively added. The cooling bath was
removed and the mixture was stirred at room temperature (2 h for X = Br and I, 48 h for X = Cl).
For the workꢀup, the mixture was concentrated under vacuum and the residue was quenched with
0.3 M aqueous NH4OAc (5 mL). The aqueous phase was extracted with hexane/methyl tertꢀbutyl
ether (1:1, 10 mL; 3×3 mL). The combined organic phases were filtered through Na2SO4,
concentrated under vacuum, and the residue was purified by column chromatography.
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General procedure 2. Halodifluoromethylation of iminium salts generated by methylation of
imines [preparation of 4a,j, 5a, 6a]. MeOTf (0.55 mmol, 53 ꢁL) was added to a solution of imine
(1a,b, 0.5 mmol) in CH2Cl2 (1 mL) at 0 °C. The cooling bath was removed and the solution was
stirred for 15 min at room temperature to give a solution of iminium salts 2a,b. Reactions of the
iminium salts 2a,b with silanes was performed identically to General procedure 1.
Benzyl[2ꢀbromoꢀ2,2ꢀdifluoroꢀ1ꢀ(4ꢀmethoxyphenyl)ethyl]methylamine (4a). General procedure 1:
162.0 mg (88%). General procedure 2: 164.8 mg (89%). Colorless oil. Bp 135–140 °C (bath
1
temp.)/0.31 Torr. Rf 0.39 (EtOAc/hexanes, 1:10). H NMR (300 MHz, CDCl3) δ: 7.43–7.22 (m,
7H), 7.01–6.89 (m, 2H), 4.30 (t, J = 13.8, 1H), 3.85 (s, 3H), 3.80 (d, J = 13.6, 1H), 3.53 (d, J =
13.6, 1H), 2.32 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ: 159.8, 138.9, 131.2 (t, J = 1.5), 128.9,
128.5, 127.4, 125.8 (t, J = 313.9), 124.7, 113.9, 75.0 (dd, J = 21.6, 19.7), 59.9, 55.4, 39.0 (t, J =
2.3). 19F NMR (282 MHz, CDCl3) δ: −48.1 (dd, J = 161.0, 12.8, 1F), −49.3 (dd, J = 161.0, 14.8,
1F). Anal. Calcd. for C17H18BrF2NO (370.23): C, 55.15; H, 4.90; N, 3.78. Found: C, 55.19; H, 4.74;
N, 3.81.
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4ꢀ[2ꢀBromoꢀ2,2ꢀdifluoroꢀ1ꢀ(4ꢀmethoxyphenyl)ethyl]morpholine (4b). 148.5 mg (88%). White
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crystals. Mp 34–37 °C. Bp 129–132 °C (bath temp.)/0.26 Torr. Rf 0.30 (EtOAc/hexanes, 1:5). H
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NMR (300 MHz, CDCl3) δ: 7.29 (d, J = 8.6, 2H), 6.92 (d, J = 8.6, 2H), 3.98 (dd, J = 13.4, 10.6,
1H), 3.83 (s, 3H), 3.70 (t, J = 4.6, 4H), 2.72–2.47 (m, 4H). 13C{1H} NMR (75 MHz, CDCl3) δ:
159.9, 131.2, 125.3 (dd, J = 310.7, 312.7), 124.6, 113.9, 77.2 (t, J = 20.8), 67.2, 55.3, 51.5. 19F
NMR (282 MHz, CDCl3) δ: −47.3 (dd, J = 162.8, 10.6, 1F), −48.6 (dd, J = 162.8, 13.4, 1F). Anal.
Calcd. for C13H16BrF2NO2 (336.17): C, 46.45; H, 4.80; N, 4.17. Found: C, 46.34; H, 4.88; N, 4.14.
[2ꢀBromoꢀ2,2ꢀdifluoroꢀ1ꢀ(4ꢀmethoxyphenyl)ethyl]bis(propꢀ2ꢀenꢀ1ꢀyl)amine (4c). 147.4 mg
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(85%). Paleꢀyellow oil. Bp 107–108 °C (bath temp.)/0.22 Torr. Rf 0.53 (EtOAc/hexanes, 1:20). H
NMR (300 MHz, CDCl3) δ: 7.27 (d, J = 8.6, 2H), 6.92 (d, J = 8.6, 2H), 5.85 (dddd, J = 15.0, 10.1,
7.8, 4.8, 2H), 5.30–5.13 (m, 4H), 4.46 (t, J = 14.3, 1H), 3.84 (s, 3H), 3.49 (dd, J = 14.3, 4.8, 2H),
2.86 (dd, J = 14.3, 7.8, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ: 159.6, 136.4, 131.1 (t, J = 1.5),
126.0 (t, J = 313.0), 125.0, 117.8, 113.9, 70.7 (dd, J = 22.2, 19.4), 55.3, 54.2 (t, J = 1.5). 19F NMR
(282 MHz, CDCl3) δ: −48.9 (dd, J = 161.1, 14.3, 1F), −50.2 (dd, J = 161.1, 14.3, 1F). Anal. Calcd.
for C15H18BrF2NO (346.21): C, 52.04; H, 5.24; N, 4.05. Found: C, 52.07; H, 5.19; N, 4.04.
Nꢀ[2ꢀBromoꢀ1ꢀ(4ꢀbromophenyl)ꢀ2,2ꢀdifluoroethyl]ꢀ4ꢀmethoxyꢀNꢀmethylaniline (4d). 165.0 mg
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(76%). Colorless oil. Rf 0.28 (EtOAc/hexanes, 1:20). H NMR (300 MHz, CDCl3) δ: 7.52 (d, J =
8.4, 2H), 7.26 (d, J = 8.4, 2H), 7.00–6.85 (m, 4H), 5.35 (t, J = 13.5, 1H), 3.81 (s, 3H), 2.71 (s, 3H).
13C{1H} NMR (75 MHz, CDCl3) δ: 153.7, 144.4, 132.2 (t, J = 1.5), 131.8, 130.5 (t, J = 2.1), 124.2
(dd, J = 316.1, 314.1), 122.7, 117.3, 114.8, 73.6 (dd, J = 22.4, 20.5), 55.7, 34.6 (t, J = 2.2). 19F
NMR (282 MHz, CDCl3) δ: −49.0 (dd, J = 163.6, 13.5, 1F), −50.4 (dd, J = 163.6, 13.5, 1F). HRMS
(ESI) Calcd. for C16H16Br2F2NO (М+Н): 433.9541. Found: 433.9533.
[2ꢀBromoꢀ1ꢀ(4ꢀbromophenyl)ꢀ2,2ꢀdifluoroethyl]bis(propꢀ2ꢀenꢀ1ꢀyl)amine (4e). 171.0 mg (87%).
Colorless oil. Bp 100–101 °C (bath temp.)/0.24 Torr. Rf 0.63 (EtOAc/hexanes, 1:20). 1H NMR (300
MHz, CDCl3) δ: 7.51 (d, J = 8.1, 2H), 7.22 (d, J = 8.1, 2H), 5.91–5.72 (m, 2H), 5.30–5.12 (m, 4H),
4.47 (t, J = 13.9, 1H), 3.46 (dd, J = 14.3, 4.8, 2H), 2.86 (dd, J = 14.3, 7.4, 2H). 13C{1H} NMR (75
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MHz, CDCl3) δ: 136.0, 132.2, 131.7, 131.4 (t, J = 1.5), 125.2 (t, J = 313.2), 122.7, 118.2, 70.5 (t, J
= 20.9), 54.1 (t, J = 1.5). 19F NMR (282 MHz, CDCl3) δ: −49.1 (dd, J = 162.5, 13.9, 1F), −50.5 (dd,
J = 162.5, 13.9, 1F). Anal. Calcd. for C14H15Br2F2N (395.08): C, 42.56; H, 3.83; N, 3.55. Found: C,
42.62; H, 3.89; N, 3.54.
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[2ꢀBromoꢀ1ꢀ(4ꢀchlorophenyl)ꢀ2,2ꢀdifluoroethyl]diethylamine (4f). 152.9 mg (94%). Colorless
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oil. Bp 70–75 °C (bath temp.)/0.16 Torr. Rf 0.42 (EtOAc/hexanes, 1:20). H NMR (300 MHz,
CDCl3) δ: 7.35 (br, 4H), 4.40 (dd, J = 15.5, 11.6, 1H), 2.82 (dq, J = 14.2, 7.1, 2H), 2.49 (dq, J =
13.7, 7.1, 2H), 1.06 (t, J = 7.1, 6H). 13C{1H} NMR (75 MHz, CDCl3) δ: 134.3, 133.0 (d, J = 2.2),
131.1 (t, J = 1.8), 128.6, 125.6 (dd, J = 315.1, 313.0), 72.5 (dd, J = 21.5, 19.7), 45.0 (t, J = 1.5),
13.9. 19F NMR (282 MHz, CDCl3) δ: −48.8 (dd, J = 161.1, 11.6, 1F), −50.8 (dd, J = 161.1, 15.5,
1F). Anal. Calcd. for C12H15BrClF2N (326.61): C, 44.13; H, 4.63; N, 4.29. Found: C, 44.09; H,
4.75; N, 4.28.
1ꢀ(2ꢀBromoꢀ2,2ꢀdifluoroꢀ1ꢀphenylethyl)pyrrolidine (4g). 92.0 mg (63%). Colorless oil. Bp 107–
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110 °C (bath temp.)/0.18 Torr. Rf 0.29 (EtOAc/hexanes, 1:20). H NMR (300 MHz, CDCl3) δ:
7.51–7.33 (m, 5H), 3.88 (dd, J = 13.4, 6.2, 1H), 2.77–2.49 (m, 4H), 1.89–1.63 (m, 4H). 13C{1H}
NMR (75 MHz, CDCl3) δ: 135.0 (t, J = 2.7), 129.9 (t, J = 1.1), 128.8, 128.3, 125.6 (dd, J = 313.0,
307.9), 76.8 (dd, J = 22.1, 20.6), 52.6, 23.4. 19F NMR (282 MHz, CDCl3) δ: −46.7 (dd, J = 162.8,
6.2, 1F), −48.8 (dd, J = 162.8, 13.4, 1F). Anal. Calcd. for C12H14BrF2N (290.15): C, 49.67; H, 4.86;
N, 4.83. Found: C, 49.54; H, 4.84; N, 5.03.
1ꢀ[2ꢀBromoꢀ2,2ꢀdifluoroꢀ1ꢀ(naphthalenꢀ1ꢀyl)ethyl]pyrrolidine (4h). 136.0 mg (80%). Paleꢀpink
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oil. Bp 120–125°C (bath temp.)/0.13 Torr. Rf 0.47 (EtOAc/hexanes, 1:20). H NMR (300 MHz,
CDCl3) δ: 8.22 (d, J = 8.4, 1H), 7.99 (d, J = 7.3, 1H), 7.96–7.86 (m, 2H), 7.65–7.47 (m, 3H), 4.88
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(dd, J = 14.8, 5.0, 1H), 2.88–2.59 (m, 4H), 1.97–1.67 (m, 4H). C{1H} NMR (75 MHz, CDCl3) δ:
134.0, 132.5, 131.3 (t, J = 2.9), 129.3, 129.1, 127.9 (d, J = 2.5), 126.5, 126.2 (dd, J = 315.3, 308.5),
125.6, 125.2, 123.3, 70.8 (m), 52.7 (t, J = 1.5), 23.6. 19F NMR (282 MHz, CDCl3) δ: −44.6 (br d, J
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= 160.5, 1F), −48.0 (dd, J = 161.0, 14.8, 1F). Anal. Calcd. for C16H16BrF2N (340.21): C, 56.49; H,
4.74; N, 4.12. Found: C, 56.34; H, 4.91; N, 4.09.
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Benzyl[2ꢀbromoꢀ2,2ꢀdifluoroꢀ1ꢀ(thiophenꢀ2ꢀyl)ethyl]methylamin (4i). 128.1 mg (74%). Yellow
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oil. Bp 112–115 °C (bath temp.)/0.18 Torr. Rf 0.54 (EtOAc/hexanes, 1:20). H NMR (300 MHz,
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CDCl3) δ: 7.49–7.27 (m, 6H), 7.19–7.05 (m, 2H), 4.67 (t, J = 13.1, 1H), 3.88 (d, J = 13.6, 1H), 3.64
(d, J = 13.6, 1H), 2.40 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ: 138.5, 133.7, 129.0, 128.64 (t, J
= 1.2), 128.55, 127.5, 126.9, 126.2, 124.6 (t, J = 314.1), 70.8 (dd, J = 22.6, 21.1), 59.8 (t, J = 1.7),
38.6 (t, J = 2.2). 19F NMR (282 MHz, CDCl3) δ: −49.3 (dd, J = 161.7, 13.1, 1F), −50.3 (dd, J =
161.7, 13.1, 1F). Anal. Calcd. for C14H14BrF2NS (346.23): C, 48.57; H, 4.08; N, 4.05. Found: C,
48.57; H, 4.17; N, 4.08.
Benzyl(2ꢀbromoꢀ1ꢀcyclohexylꢀ2,2ꢀdifluoroethyl)methylamine (4j). 142.0 mg (82%). Colorless oil.
Mp 52–64°C. Bp 114–118 °C (bath temp.)/0.16 Torr. Rf 0.64 (EtOAc/hexanes, 1:20). 1H NMR (300
MHz, CDCl3) δ: 7.39–7.20 (m, 5H), 4.02 (d, J = 13.7, 1H), 3.90 (d, J = 13.7, 1H), 3.03 (td, J = 10.2,
8.3, 1H), 2.44 (s, 3H), 2.14 (d, J = 13.2, 1H), 2.03–1.62 (m, 5H), 1.49–1.05 (m, 5H). 13C{1H} NMR
(75 MHz, CDCl3) δ: 139.8, 128.7, 128.4, 127.2, 127.1 (dd, J = 323.4, 321.8), 76.5 (t, J = 17.3),
61.0, 38.7, 36.9, 30.9 (dd, J = 3.3, 1.7), 30.8 (d, J = 1.0), 26.5, 26.4. 19F NMR (282 MHz, CDCl3) δ:
–39.5 (dd, J = 159.9, 8.3, 1F), –42.1 (dd, J = 159.9, 10.2, 1F). Anal. Calcd. for C16H22BrF2N
(346.25): C, 55.50; H, 6.40; N, 4.05. Found: C, 55.31; H, 6.31; N, 4.04.
Benzyl[2ꢀchloroꢀ2,2ꢀdifluoroꢀ1ꢀ(4ꢀmethoxyphenyl)ethyl]methylamine (5a). General procedure 1:
89.4 mg (55%). General procedure 2: 145.5 mg (89%). Paleꢀyellow oil. Bp 128–129 °C (bath
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temp.)/0.31 Torr. Rf 0.36 (EtOAc/hexanes, 1:20). H NMR (300 MHz, CDCl3) δ: 7.48–7.23 (m,
7H), 6.99 (d, J = 8.7, 2H), 4.31 (dd, J = 13.6, 12.1, 1H), 3.87 (s, 3H), 3.84 (d, J = 13.6, 1H), 3.55 (d,
J = 13.6, 1H), 2.37 (s, 3H). 13С{1H} NMR (50 MHz, CDCl3) δ: 159.7, 138.9, 131.1 (t, J = 1.8),
128.8, 128.5, 127.4, 124.6 (d, J = 1.3), 113.8, 73.0 (dd, J = 23.8, 22.4), 59.8 (t, J = 1.7), 55.3, 39.0
(t, J = 2.1). 19F NMR (282 MHz, CDCl3) δ: –54.2 (dd, J = 165.0, 12.1), –55.3 (dd, J = 165.0, 13.6).
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Anal. Calcd. for C17H18ClF2NO (325.78): C, 62.67; H, 5.57; N, 4.30. Found: C, 62.83; H, 5.84; N,
4.27.
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Benzyl[2,2ꢀdifluoroꢀ2ꢀiodoꢀ1ꢀ(4ꢀmethoxyphenyl)ethyl]methylamine (6a). General procedure 1:
132.9 mg (64%). General procedure 2: 156.1 mg (75%). White crystals. Mp 63–65 °C (hexanes). Rf
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0.33 (EtOAc/hexanes, 1:20). H NMR (300 MHz, CDCl3) δ: 7.48–7.26 (m, 7H), 6.96 (d, J = 8.6,
2H), 4.21 (t, J = 15.0, 1H), 3.86 (s, 3H), 3.79 (d, J = 13.4, 1H), 3.53 (d, J = 13.4, 1H), 2.32 (s, 3H).
13C{1H} NMR (75 MHz, CDCl3) δ: 159.8, 138.8, 131.4 (t, J = 1.6), 129.0, 128.4, 127.4, 124.2,
113.9, 109.1 (t, J = 321.1), 77.5 (dd, J = 20.6, 18.2), 59.9 (t, J = 1.9), 55.3, 39.0 (t, J = 2.4). 19F
NMR (282 MHz, CDCl3) δ: −41.4 (dd, J = 177.7, 15.0, 1F), −42.3 (dd, J = 177.7, 15.0, 1F). Anal.
Calcd. for C17H18F2INO (417.23): C, 48.94; H, 4.35; N, 3.36. Found: C, 49.07; H, 4.51; N 3.21.
[1ꢀ(4ꢀChlorophenyl)ꢀ2,2ꢀdifluoroꢀ2ꢀiodoethyl]diethylamine (6b). 164.1 mg (88%). Colorless oil.
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Rf 0.49 (EtOAc/hexanes, 1:20). H NMR (300 MHz, CDCl3) δ: 7.35 (d, J = 8.6, 2H), 7.29 (d, J =
8.6, 2H), 4.27 (t, J = 15.0, 1H), 2.81 (dq, J = 14.0, 7.1, 2H), 2.45 (dq, J = 14.0, 7.1, 2H), 1.09 (t, J =
7.1, 6H). 13C{1H} NMR (75 MHz, CDCl3) δ: 134.3, 132.3, 131.3 (t, J = 1.7), 128.6, 109.6 (t, J =
321.3), 74.9 (dd, J = 20.8, 17.9), 45.0 (t, J = 1.6), 13.8. 19F NMR (282 MHz, CDCl3) δ: −42.2 (dd, J
= 177.9, 15.0, 1F), −43.2 (dd, J = 177.9, 15.0, 1F). HRMS (ESI) Calcd. for C12H16ClF2IN (М+Н):
373.9979. Found: 373.9975.
(2,2ꢀDifluoroꢀ1ꢀphenylcyclopropyl)benzene (7). Me3SiCF2Br (1.50 mmol, 304 mg) and HMPA
(1.50 mmol, 260 ꢁL) were successively added to a solution of 1,1ꢀdiphenylethylene (0.5 mmol, 90
mg) in CH2Cl2 at 0 °C. The cooling bath was removed and the mixture was stirred at room
temperature 2 h. Saturated aqueous Na2CO3 (5 mL) was added, and the mixture was extracted with
hexane/methyl tertꢀbuthyl ether (1:1, 10 mL; 3×3 mL). The combined organic phases were filtered
through Na2SO4, concentrated under vacuum, and the residue was purified by column
chromatography affording 95.7 mg (83% yield) of compound 7 as a colorless oil. NMR spectra
were identical to the reported data.13a
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Acknowledgement
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This work was supported by the Russian Science Foundation (project 14ꢀ13ꢀ00034).
Supporting Information
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Copies of NMR spectra for all compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
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References
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X.; Fu, Y. Tetrahedron Lett. 2014, 55, 585–594. (d) Chu, L.; Qing, F.ꢀL. Acc. Chem. Res.
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Wang, M.; Liu, Q. Chem. Rev. 2014, ASAP. DOI: 10.1021/cr400473a.
(2) (a) Tozer, M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619–8683. (b) Qing, F.ꢀL.; Zheng, F.
Synlett 2011, 1052–1072.
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Chem. Res. 2005, 38, 386–395. (с) Metrangolo, P.; Resnati, G. Chem. Eur. J. 2001, 7, 2511–ꢀ
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1065. (b) Zhang, C.ꢀP.; Cao, H.ꢀP.; Wang, Z.ꢀL.; Zhang, C.ꢀT.; Chen, Q.ꢀY.; Xiao, J.ꢀC.
Synlett 2010, 1089–1092. (c) Liu, G.; Mori, S.; Wang, X.; Noritake, S.; Tokunaga, E.;
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(6) (a) Li, A.ꢀR.; Chen, Q.ꢀY. Synthesis 1997, 333–336. (b) Li, A.ꢀR.; Chen, Q.ꢀY. Synthesis
1997, 1481–1488. (c) Yang, Z.ꢀY. J. Org. Chem. 2004, 69, 2394–2403. (d) Fang, X.; Yang,
X.; Yang, X.; Mao, S.; Wang, Z.; Chen, G.; Wu, F. Tetrahedron 2007, 63, 10684–10692.
(7) Zhao, Y.; Gao, B.; Hu, J. J. Am. Chem. Soc. 2012, 134, 5790–5793.
(8) Kosobokov, M. D.; Levin, V. V.; Struchkova, M. I.; Dilman, A. D. Org. Lett. 2014, 16, 3784–
3787.
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(9) For solvent exchange, a dichloromethane solution of 2a was concentrated under vacuum
followed by addition of another solvent.
(10) The use of conventional tertiary amines instead of 1,8ꢀbis(dimethylamino)naphthalene was
unsuccessful.
(11) For the generation of iminium ions from Nꢀsilylamines, carbonyl compounds and silylating
reagents, see (a) Levin, V. V.; Kozlov, M. A.; Song, Y.ꢀH.; Dilman, A. D.; Belyakov, P. A.;
Struchkova, M. I.; Tartakovsky, V. A. Tetrahedron Lett. 2008, 49, 3108–3111. (b) Schroth,
W.; Jahn, U. J. Prakt. Chem. 1998, 340, 287–299.
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