Three-component carboarylation of unactivated imines with arynes and carbon nucleophiles

Article abstract of DOI:10.1039/c6cc09311f

With 2-(trimethylsilyl)aryl triflates as aryne precursors, an unprecedented three-component carboarylation reaction of unactivated imines with arynes and carbon nucleophiles has been developed to access a variety of functionalized tertiary amines under transition metal-free conditions. Suitable carbon nucleophiles include chloroform, acetonitrile, and methyl propiolate.

Full text of DOI:10.1039/c6cc09311f

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Three-component carboarylation of unactivated imines with
arynes and carbon nucleophiles
Received 00th January 20xx,
Accepted 00th January 20xx
Jing-Kun Xu, Sheng-Jun Li, Hai-Yang Wang, Wen-Cong Xu and Shi-Kai Tian*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Previous work:
With 2-(trimethylsilyl)aryl triflates as aryne precursors, an
unprecedented three-component carboarylation reaction of
unactivated imines with arynes and carbon nucleophiles has been
developed to access a variety of functionalized tertiary amines
under transition metal-free conditions. Suitable carbon
nucleophiles include chloroform, acetonitrile, and methyl
propiolate.
R
N
R
N
R
Ar
N
CO2
Ar
+
Yoshida, Kunai2
O
Ar
R = alkyl
O
R = CH2EWG
(EWG = CO2R', CN)
Ph
N
C
X
Ph
(X = N, C)
Hwu3
Ar
EWG
Ar
N
EWG
X
Arynes are highly electrophilic species that serve as targets
toward nucleophilic addition in a number of cascade reactions
in the absence of transition metals, leading to complex organic
molecules.1 Notably, the scope of nucleophiles has been
expanded to some unusual ones such as unactivated imines,
addition of which to arynes provides convenient access to
iminium zwitterions having activated carbon-nitrogen double
bonds. In 2006, Yoshida, Kunai, and coworkers disclosed the
use of iminium zwitterions to capture carbon dioxide to yield
benzoxazinones (Scheme 1).2 Recently, Hwu and coworkers
reported that iminium zwitterions bearing electron-
withdrawing groups could undergo proton transfer to generate
azomethine ylides, which subsequently underwent [3+2]
cycloaddition with the original imines or electron-deficient
alkenes.3 In these cases, iminium zwitterion intermediates
were intercepted by double bonds to yield nitrogen-containing
heterocycles.4,5 Inspired by these reports, we envisioned that
iminium zwitterions could deprotonate some nucleophiles and
the resulting activated nucleophiles would undergo addition to
the activated carbon-nitrogen double bonds (Scheme 1).6
Clearly, it constitutes a formidable challenge to minimize or
even obviate the addition of nucleophiles to arynes in the
proposed three-component reaction of unactivated imines
with arynes and nucleophiles.
This work:
R'
N
R'
N
R'
N
R
R
+
R
Nu
Nu
H
H
R, R' = alkyl, aryl
Scheme 1 Three-component reactions involving unactivated imines
and arynes.
While chloroform, an inexpensive bulk chemical used
frequently as
a
solvent, traditionally serves as
a
dichlorocarbene source under basic conditions, sporadic
examples have shown that it can undergo deprotonation
followed by addition to activated imines, such as N-sulfonyl
imines and N-sulfinyl imines, to yield amine derivatives bearing
a
trichloromethyl group.7 It is noteworthy that the
trichloromethyl group exists in a number of biologically
relevant compounds.8 Consequently, we selected chloroform
as a nucleophile to develop the three-component reaction
proposed in Scheme 1. Using 2-(trimethylsilyl)phenyl triflate
(
2a) (1.2 equiv) as a benzyne precursor,9 we surveyed a few
fluoride sources, such as cesium fluoride, potassium fluoride,
sodium fluoride, and tetrabutylammonium fluoride, in the
model reaction of imine 1a and chloroform in dry acetonitrile
under nitrogen at 50 oC (eqn (1)) and found that the use of
cesium fluoride afforded 2,2,2-trichloroethanamine 3a in the
best yield (45%).10 Importantly, addition of chloroform to
benzyne was not observed at all. The yield was not enhanced
simply by screening a few other common solvents such as
toluene, 1,2-dichloroethane, chloroform, and tetrahydrofuran.
Elevating the temperature to 65 oC improved the yield to 68%,
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and moreover, increasing the amount of benzyne precursor 2a
to 1.5 equiv further improved the yield to 81%.
A
range of aliphatic and aromatic imines smoothly
underwent three-component carboarylation with benzyne
precursor 2a and chloroform in the presence of cesium
fluoride
to
afford
structurally
diverse
2,2,2-
trichloroethanamines in moderate to good yields (Scheme 2,
3a-r). Both acyclic and cyclic unactivated imines served as
suitable substrates. It is noteworthy that the reaction worked
well with sterically bulky imines, aromatic imines bearing
electron-donating groups, and unactivated imines bearing a
variety of N-substituents such as an alkyl group, a benzyl
group, an allyl group, a propargyl group, and an aryl group. In
some cases the yields were moderate simply owing to
unsatisfactory conversion of the starting imines judging by TLC
analysis. On the other hand, the chemistry was extended to a
few 2-(trimethylsilyl)aryl triflates bearing either electron-
donating groups or electron-withdrawing groups (Scheme 2,
3s-x). It is noteworthy that the regioselectivity highly depends
on the position of substituents in the in situ generated
unsymmetrical arynes. While the reaction with 4-
methylbenzyne gave poor regioselectivity (Scheme 2, 3s and
3s′), a single regioisomer was obtained from the reaction with
3-methoxybenzyne (Scheme 2, 3w).2
Scheme
2
Three-component reaction of imines, arynes, and
a
chloroform. Reaction conditions:
(0.60 mmol), chloroform (0.3 mL), acetonitrile (0.3 mL), 65 oC, 10 h.
Isolated yields were given. c Aryne precursors for the synthesis of 3s
4-methyl-2-(trimethylsilyl)phenyl triflate 2b), 4,5-dimethyl-2-
(trimethylsilyl)phenyl triflate 2c), 4,5-dimethoxy-2-
1 (0.20 mmol), 2 (0.30 mmol), CsF
b
-x:
(
(
(trimethylsilyl)phenyl triflate (2d), 4,5-difluoro-2-(trimethylsilyl)phenyl
triflate (2e), 3-methoxy-2-(trimethylsilyl)phenyl triflate (2f), and 3-
(trimethylsilyl)naphthalen-2-yl triflate (2g).
In contrast, 2,2-dichloroethenamines rather than 2,2,2-
trichloroethanamines were obtained from the reaction with
aromatic imines bearing electron-withdrawing groups such as
a trifluoromethyl group, a cyano group, a sulfonyl group, and a
nitro group (Scheme 3). In most cases the yields were
moderate due to unsatisfactory conversion of the starting
imines. Notably, the reaction was highly sensitive to the
position of an electron-withdrawing group on the benzene
ring. While para- and meta-substituted aromatic imines
reacted well with benzyne precursor 2a and chloroform to
afford
the
desired
2,2-dichloroethenamines,
the
corresponding reaction with an ortho-substituted one just
provided a complex mixture probably because of the steric
hindrance imposed on the formation of the carbon-carbon
double bond.
Scheme 3 Reaction with aromatic imines bearing electron-withdrawing
groups.
To gain insights into the reaction mechanism, we treated
imine 1a and benzyne precursor 2a with deuterated
chloroform under the standard conditions and observed
complete deuterium incorporation at the ortho-position of the
phenyl group in the desired product 3a-D1 according to 1H
NMR spectroscopic analysis and HRMS spectrometric analysis
(eqn (2)).10 This result substantially supports that the iminium
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zwitterion shown in Scheme 1 abstracts a proton from
chloroform during the reaction. While no 2,2-
dichloroethenamine product was obtained from the three-
component reaction with an aromatic imine bearing an
electron-donating group such as a methoxy group, we found
that treatment of 2,2,2-trichloroethanamine 3d with 2 equiv of
cesium fluoride led to the formation of 2,2-
dichloroethenamine 4g in 81% yield (eqn (3)). These results,
along with those shown in Scheme 3, suggest that electron-
withdrawing groups on the aromatic rings greatly accelerate
the elimination of HCl from 2,2,2-trichloroethanamines
generated during the reaction.
Scheme 5 Other carbon nucleophiles.
In summary, we have developed an unprecedented three-
component carboarylation reaction of unactivated imines with
arynes and carbon nucleophiles. A range of aliphatic and
aromatic imines underwent carboarylation with 2-
(trimethylsilyl)aryl triflates and chloroform in the presence of
cesium fluoride to afford structurally diverse 2,2,2-
trichloroethanamines in moderate to good yields. In the case
of aromatic imines having electron-withdrawing groups,
elimination of HCl occurred readily to afford 2,2-
dichloroethenamines. The scope of carbon nucleophiles for
the three-component reaction was successfully extended to
acetonitrile and methyl propiolate. These three-component
reactions are operationally simple and provide access to a
variety of functionalized tertiary amines under transition
metal-free conditions.
On the basis of the above experimental results and
previous studies, we proposed a reaction pathway as depicted
in Scheme 4. Nucleophilic attack of imine
generated in situ from 2-(trimethylsilyl)aryl triflate
presence of cesium fluoride, gives iminium zwitterion 6 2,3
which activates chloroform by deprotonation to yield iminium
. The resulting trichloromethyl anion undergoes nucleophilic
addition to iminium to afford 2,2,2-trichloroethanamine
1
on aryne
5,
2
in the
We are grateful for the financial support from the National
Natural Science Foundation of China (21472178 and
21232007), the National Key Basic Research Program of China
(2014CB931800), and the Strategic Priority Research Program
of the Chinese Academy of Sciences (XDB20000000).
,
7
7
3.
When the starting imine is an aromatic one having an electron-
withdrawing group, elimination of HCl occurs readily under the
standard conditions to afford 2,2-dichloroethenamine 4.
Notes and references
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Scheme 4 Proposed reaction pathway
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A few other types of carbon nucleophiles were examined in
the three-component reaction with unactivated imines and
arynes. To our delight, acetonitrile and methyl propiolate
served as suitable carbon nucleophiles and the corresponding
three-component reaction afforded functionalized tertiary
amines in moderate yields (Scheme 5). Nevertheless, the
three-component reaction was not applicable to bromoform,
nitromethane, acetone, activated methylene compounds such
as diethyl malonate, ethyl 3-oxobutanoate, and malononitrile,
and electron-rich aromatic compounds such as indole and 2-
naphthol under the standard conditions.
2
3
4
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10 For details, see the Supporting Information.
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