1,2-Aminohalogenation of arynes with amines and organohalides

Article abstract of DOI:10.1039/c9cc05505c

An unprecedented use of inexpensive organohalides as halogen electrophiles to trap the zwitterion intermediates generated from amines and arynes has been developed to access structurally diverse tertiary 2-haloanilines. Effective organohalides include carbon tetrachloride, hexachloroethane, N-chlorosuccinimide, carbon tetrabromide, fluorotribromomethane, N-bromosuccinimide, carbon tetraiodide, and N-iodosuccinimide.

Full text of DOI:10.1039/c9cc05505c

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1,2-Aminohalogenation of arynes with amines and organohalides
Sheng-Jun Lia, Lu Hana and Shi-Kai Tian*ab
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
An unprecedented use of inexpensive organohalides as halogen
electrophiles to trap the zwitterion intermediates generated from
amines and arynes has been developed to access structurally
diverse tertiary 2-haloanilines. Effective organohalides include
carbon tetrachloride, hexachloroethane, N-chlorosuccinimide,
R1
N
R2
R3
R2
R1
N
+
R
R
+
Nu
E
E
R1
N
R1
N
R2
R3
R2
R3
Nu-
carbon
tetrabromide,
fluorotribromomethane,
N-
Nu
E
Nu R3
R
R
bromosuccinimide, carbon tetraiodide, and N-iodosuccinimide.
E
(a) Previous work:
E = H, C
1,2-Difunctionalization of arynes with nucleophiles and
electrophiles constitutes a powerful strategy to access complex
aromatic compounds that are not readily synthesized by
alternative methods.1 In this regard, tertiary amines have been
identified as effective nitrogen nucleophiles to attack arynes to
generate zwitterions that can be trapped by proton2,3 or by
carbon electrophiles such as carbonyl compounds and CO2
(Scheme 1, (a)).4 Dealkylation of the resulting ammonium salts
yields tertiary aromatic amines. Herein, we report for the first
time the use of inexpensive organohalides as halogen
electrophiles to trap the zwitterion intermediates generated
from amines and arynes, delivering structurally diverse tertiary
2-haloanilines (Scheme 1, (b)).
(b) This work:
E = Cl, Br, I
Scheme 1 Three-component reactions of amines, arynes, and electrophiles.
analogues to afford tertiary 2-chloroanilines and 2-
bromoanilines in moderate to good yields.10
NH2
Cl
Cl
Cl
N
O
N
F
O
N
H
O
N
HO2C
N
aripiprazole (antipsychotic)
clinafloxacin (antibacterial)
The core structure of the tertiary 2-haloaniline products is
present in some biologically relevant compounds such as
aripiprazole,5 clinafloxacin,6 dichloromethotrexate,7 and
pirprofen (Scheme 2).8 A direct approach to access tertiary 2-
haloanilines is the electrophilic halogenation of tertiary anilines,
which, however, suffers from low regioselectivity.9 Moreover,
Wang and coworkers reported in 2013 the insertion of arynes
into the nitrogen-halogen bonds of N-halomorpholines and
H2N
N
N
N
Cl
Me Cl
N
N
N
CO2H
H
NH2
N
Me
Cl
O
CO2H
CO2H
dichloromethotrexate (anticancer)
pirprofen (analgesic)
Scheme 2 Representative bioactive molecules containing a tertiary 2-haloaniline
framework.
On the basis of our recent report that carbon tetrachloride
can serve as a halogen electrophile to trap the carbon anions
generated from imines and arynes (or alkynes),11 we envisioned
that it would be capable of forming C−Cl bonds with the
zwitterions generated from tertiary amines and arynes (Scheme
1, (b)). To broaden the scope of using carbon tetrachloride as an
inexpensive halogen electrophile,12 we tested our hypothesis by
a. Hefei National Laboratory for Physical Sciences at the Microscale, Center for
Excellence in Molecular Synthesis, and Department of Chemistry, University of
Science and Technology of China, Hefei, Anhui 230026, China.
E-mail: tiansk@ustc.edu.cn
b. Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
†Electronic Supplementary Information (ESI) available: General information,
experimental procedures, characterization data, and copies of NMR spectra. See
DOI: 10.1039/x0xx00000x
using 2-(trimethylsilyl)phenyl triflate (2a) as
a benzyne
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precursor,13 and surveyed a number of readily available fluoride obtained from the reaction with 3-methylbenzyne (in the
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DOI: 10.1039/C9CC05505C
sources to generate benzyne in situ in its reaction with tertiary synthesis of 4o).
amine 1a and carbon tetrachloride (3a) in tetrahydrofuran at 65
Me
oC for 6 h (Table 1, entries 1-6), and found that the combined
KF/18-crown-6
THF, 65 C
TMS
OTf
N
Me
R1
R1
use of KF and 18-crown-6 afforded tertiary 2-chloroaniline 4a in
the highest yield (90%; Table 1, entry 5). We then examined a
number of solvents and failed to achieve a higher yield (Table 1,
entries 7-13). Finally, prolonging the reaction time from 6 h to
10 h improved the yield to 95% (Table 1, entry 14).
CCl4
Me
+
R
N
+
R
Cl
4a-s
1a-n
2
3a
Me
Me
Me Me
N
N
N
Me
Table 1 Optimization of the reaction conditions.a
Cl
X
Cl
Cl
Me
4i
4j
, 78%
Me
, 92%
4a
4b
4c
4d
4e
4f
4g
4h
, X = H, 95%
, X = Me, 90%
, X = CN, 80%
, X = CO2Et, 62%
, X = NO2, 85%
, X = F, 92%
[F], solvent
65 C
TMS
OTf
N
N
Me
N
Me
CCl4
+
+
Cl
4a
OH
Me
Me
H
1a
2a
3a
Cl
O
Yieldb (%)
H
Entry
1
[F]
Solvent
, X = Cl, 92%
, X = Br, 91%
NH4F
Bu4NF
NaF
THF
THF
THF
THF
THF
THF
0
0
0
0
4k
, 67%
2
3
4
5
6
7
8
9
Me
N
Me
Me
N
KF
N
KF/18-crown-6
CsF
90
54
82
65
86
33
87
85
79
95
Cl
Cl
4m
Cl
4n
, 78%
KF/18-crown-6
KF/18-crown-6
KF/18-crown-6
KF/18-crown-6
KF/18-crown-6
KF/18-crown-6
KF/18-crown-6
KF/18-crown-6
1,4-Dioxane
Toluene
DCE
4l
, 91%
, 52%
Me
N
Me
N
Me
N
10
11
12
13
14c
CCl4
Me
MeCN
DMF
DMSO
THF
Cl
Me
4o
Cl
4p/4p'
Me
Cl
, 91%
(55:45), 90%
a
Reaction conditions: 1a (0.20 mmol), 2a (0.30 mmol), 3a (0.10 mL), [F] (0.60
Me
N
Me
Me
N
mmol), solvent (0.20 mL), 65 oC, 6 h. b Isolated yield. c The reaction was run for 10
h.
Me
Me
MeO
MeO
N
Cl
Cl
Cl
4q
4r
4s
, 85%
, 90%
, 57%
A range of N,N-dimethylarylamines were examined in the
three-component reaction with 2-(trimethylsilyl)phenyl triflate
(2a) and carbon tetrachloride (3a) in the presence of KF/18-
crown-6, and the corresponding tertiary 2-chloroanilines 4a-l
were isolated in good to excellent yields (Scheme 3). The
reaction permitted the introduction of various functional
groups, such as cyano, ester, nitro, fluoro, chloro, bromo,
hydroxy, ketone, alkene, and alkyne, into the final products. The
functional group tolerance was substantially demonstrated in
the modification of mifepristone, a commercial antiprogestin
(in the synthesis of 4k). The three-component reaction also
proceeded well with N,N-dimethylalkylamines such as N,N-
Scheme 3 Three-component reaction of tertiary amines, arynes, and carbon
tetrachloride. Reaction conditions: 1a-n (0.20 mmol), 2 (0.30 mmol), 3a (0.10 mL),
KF (0.60 mmol), 18-crown-6 (0.60 mmol), THF (0.20 mL), 65 oC, 10 h. Isolated yields
are given. Aryne precursors for the synthesis of 4o-s: 2-methyl-6-
(trimethylsilyl)phenyl triflate (2b), 4-methyl-2-(trimethylsilyl)phenyl triflate (2c),
4,5-dimethyl-2-(trimethylsilyl)phenyl
(trimethylsilyl)phenyl triflate (2e), and 3-(trimethylsilyl)-2-naphthyl triflate (2f).
triflate
(2d),
4,5-dimethoxy-2-
In addition to the methyl group, the benzyl group, the allyl
group, the propargyl group, and the ethyl group were found to
serve as effective leaving groups in three-component reaction
of tertiary amines 1o-v, 2-(trimethylsilyl)phenyl triflate (2a), and
carbon tetrachloride (3a) under the standard conditions
(Scheme 4). Only one methyl group was kept untouched in the
dimethyl-3-phenylpropan-1-amine
(1m)
and
N,N-
dimethylcyclohexanamine (1n), in which only one methyl group
served as the leaving group (in the synthesis of 4m and 4n). On
the other hand, we successfully extended the three-component
reaction to several arynes including substituted benzynes and
2-naphthyne to afford the corresponding chlorinated aromatic
amines 4o-s in good to excellent yields. In the cases of
unsymmetrical arynes, the regioselectivity highly depends on
the position of substituents. The reaction with 4-
methylbenzyne exhibited poor regioselectivity (in the synthesis
of 4p and 4p'), and in sharp contrast, a single regioisomer was
reaction
with
N,N-dimethylbenzylamine
(1r),
N,N-
dimethylallylamine (1s), or N,N-dimethylpropargylamine (1t),
and the resulting chlorinated N-methyldiarylamine 4t was
obtained in higher yields by employing CsF as the fluoride
source instead of KF/18-crown-6. The reaction with 1-
benzhydrylazetidine (1w) witnessed the opening of the
azetidine ring and the trichloromethyl group of carbon
tetrachloride (3a) was also introduced into the final product 4w.
To our surprise, the three-component reaction was successfully
extended to secondary amines 1x-z albeit they have an N-H
2 | J. Name., 2012, 00, 1-3
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bond, which was not found to serve as a proton source to trap (3i) and N-iodosuccinimide (NIS, 3j) were identified as suitable
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DOI: 10.1039/C9CC05505C
the zwitterion intermediates generated from benzyne and organoiodides for the synthesis of tertiary 2-iodoaniline 7a.
secondary amines 1x-z. In sharp contrast, the reaction with
primary amine 1aa did not afford a secondary 2-chloroaniline
product. Instead, diphenylamine (5) was isolated in 82% yield.
Me
NMe2
KF/18-crown-6
THF, 65 C, 10 h
TMS
OTf
N
RX
+
+
X
Me
N
Me
N
1a
2a
3
4
, X, yield
KF/18-crown-6
THF, 65 C, 10 h
TMS
OTf
3b
3c
3d
3e
3f
3g
3h
4a
4a
4a
, CCl3CN
, CCl3CCl3
, NCS
, CCl3Br
, CBr4
, CBr3F
, NBS
, CI4
, Cl, 33%
, Cl, 69%
, Cl, 77%
, Cl/Br, 38%/30%
, Br, 83%
, Br, 50%
, Br, 64%
, I, 57%
R
CCl4
+
+
Cl
2a
3a
1
4a
, R
4a/6a
1o
1p
1q
, benzyl
, allyl
, propargyl
90%
complex
45%
6a
6a
6a
7a
7a
Me Cl
3i
3j
TMS
OTf
, NIS
, I, 55%
N
Me
CsF, THF, 65 C, 12 h
CCl4
+
Scheme 5 Reaction of various organohalides. Reaction conditions: 1a (0.20 mmol),
2a (0.30 mmol), 3 (0.60 mmol), KF (0.60 mmol), 18-crown-6 (0.60 mmol), THF (0.20
mL), 65 oC, 10 h. Isolated yields are given.
+
N
R
Me
Cl
2a
3a
1
4t
, R
1r
1s
, benzyl
, allyl
87%
51%
47%
In the absence of an amine, we found that the solvent,
1t
, propargyl
tetrahydrofuran, participated in
a
reaction with 2-
Et
N
KF/18-crown-6
THF, 65 C, 10 h
TMS
Et
(trimethylsilyl)phenyl triflate (2a) and carbon tetrachloride (3a)
under the standard conditions to afford polychlorinated alkyl
aryl ether 8 in 56% yield (Scheme 6).14 Gratifyingly, such formal
insertion of benzyne and tetrahydrofuran into a C−Cl bond was
hardly observed in the above three-component reaction of
amines, arynes, and organohalides, probably due to the much
higher nucleophilicity of the amine relative to that of
tetrahydrofuran. Moreover, addition of 2 and 10 equiv of
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) to the reaction
mixture of amine 1a, 2-(trimethylsilyl)phenyl triflate (2a), and
carbon tetrachloride (3a) afforded tertiary 2-chloroaniline 4a in
81% and 37% yields, respectively, indicating large excess of
TEMPO failed to completely inhibit the desired three-
component reaction. This result is not in line with a radical
process and substantially support the reaction pathway
proposed in Scheme 1 (b), wherein carbon tetrachloride serves
as a halogen electrophile to trap the zwitterions generated from
amines and arynes.11
R
CCl4
+
N
+
Et
R
OTf
Cl
2a
3a
1
4
4u
4v
, R
1u
1v
, Ph
, Et
, 93%
, 82%
Ph
Ph
Ph
Ph
KF/18-crown-6
THF, 65 C, 10 h
TMS
N
CCl4
+
+
N
CCl3
OTf
Cl
2a
3a
1w
4w
, 65%
R1
KF/18-crown-6
THF, 65 C, 10 h
R1
N
TMS
OTf
N
R2
CCl4
+
+
H
R2
Cl
1
2
2a
3a
1
4
, R , R
1x
1y
1z
4a
4x
4y
, Ph, Me
, benzyl, benzyl
, allyl, allyl
, 72%
, 82%
, 76%
H
NH2
KF/18-crown-6
THF, 65 C, 10 h
TMS
Cl
N
KF/18-crown-6
THF, 65 C, 10 h
TMS
CCl4
+
O
+
CCl3
CCl4
+
OTf
H
OTf
2a
3a
1aa
5
, 82%
2a
3a
8
, 56%
Scheme 4 Reaction of various amines.
Me
N
Me
N
We then examined a few organochlorides in addition to
carbon tetrachloride (3a). As demonstrated by the results
summarized in Scheme 5, the use of trichloroacetonitrile (3b),
hexachloroethane (3c), and N-chlorosuccinimide (NCS, 3d) led
to the formation of tertiary 2-chloroaniline 4a in moderate to
good yields. Likewise, the corresponding tertiary 2-
bromoaniline 6a was obtained in good yields from reaction with
organobromides such as carbon tetrabromide (3f),
fluorotribromomethane (3g), and N-bromosuccinimide (NBS,
3h) under the standard conditions. Competing chlorination and
bromination of the zwitterion intermediate generated from
benzyne and tertiary amine 1a were observed in the reaction
with bromotrichloromethane (3e). Finally, carbon tetraiodide
TMS
TEMPO (x equiv)
Me
CCl4
+
+
KF/18-crown-6
THF, 65 C, 10 h
OTf
Cl
1a
2a
3a
4a
x
yield (%)
0
2
10
95
81
37
Scheme 6 Control experiments.
In summary, we have developed an unprecedented protocol
for the 1,2-difunctionalization of arynes with tertiary amines
and organohalides. With 2-(trimethylsilyl)aryl triflates as aryne
precursors, a range of tertiary amines smoothly reacted with
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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3
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arynes and organohalides to afford structurally diverse tertiary
2-haloanilines in moderate to excellent yields. Effective
organohalides include carbon tetrachloride, hexachloroethane,
NCS, carbon tetrabromide, fluorotribromomethane, NBS,
carbon tetraiodide, and NIS. The reaction tolerated a variety of
functional groups such as cyano, ester, nitro, fluoro, chloro,
bromo, hydroxy, ketone, alkene, and alkyne. Moreover,
secondary amines were also found to participate in the 1,2-
aminohalogenation of arynes.
We are grateful for the financial support from the National
Natural Science Foundation of China (21772182), the Strategic
Priority Research Program of the Chinese Academy of Sciences
(XDB20000000), and the Fundamental Research Funds for the
Central Universities.
4
Conflicts of interest
There are no conflicts to declare.
5
6
Notes and references
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DOI: 10.1039/C9CC05505C
1,2-Aminohalogenation of arynes with amines and organohalides
Sheng-Jun Li, Lu Han and Shi-Kai Tian*
R1
N
R4
R4
KF/18-crown-6
THF, 65 C
R2
TMS
R2
R1
N
+
RX
+
R3
X
OTf
RX = CCl4, CCl3CCl3, NCS
RX = CBr4, CBr3F, NBS
RX = CI4, NIS
X = Cl
X = Br
X = I
An unprecedented three-component reaction of amines, arynes, and organohalides provides convenient access to
structurally diverse tertiary 2-haloanilines.