Destruction and Construction: Application of Dearomatization Strategy in Aromatic Carbon-Nitrogen Bond Functionalization

Article abstract of DOI:10.1002/anie.201508161

The formation of carbon-carbon bonds through the functionalization of aromatic carbon-nitrogen bonds is a highly attractive synthetic strategy in the synthesis of aromatic molecules. In this paper, we report a novel aromatic carbon-nitrogen bond functionalization reaction by using a simple dearomatization strategy. Through this process para-substituted anilines serve as a potential aryl source in the construction of a range of functionalized aromatic molecules, such as quaternary carbon centers, α-keto esters, and aldehydes.

Full text of DOI:10.1002/anie.201508161

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201508161
German Edition: DOI: 10.1002/ange.201508161
Synthetic Methods
Destruction and Construction: Application of Dearomatization
Strategy in Aromatic Carbon–Nitrogen Bond Functionalization
Shuo-En Wang, Linfei Wang, Qiuqin He,* and Renhua Fan*
Dedicated to Professor Xue-Long Hou on the occasion of his 60th birthday
Abstract: The formation of carbon–carbon bonds through the
functionalization of aromatic carbon–nitrogen bonds is
a highly attractive synthetic strategy in the synthesis of aromatic
molecules. In this paper, we report a novel aromatic carbon–
nitrogen bond functionalization reaction by using a simple
dearomatization strategy. Through this process para-substi-
tuted anilines serve as a potential aryl source in the construc-
tion of a range of functionalized aromatic molecules, such as
quaternary carbon centers, a-keto esters, and aldehydes.
T
he formation of carbon–carbon bonds by the functionali-
zation of aromatic carbon–nitrogen bonds is an attractive
synthetic strategy because of the wide availability of ani-
lines,[1] and organic chemists have devoted significant efforts
to exploring effective methods to implement this strategy. An
example is the copper(I)-mediated arylation of olefins by
arenediazonium salts, the so-called Meerwein reaction.[2]
However, the narrow scope of this reaction has restricted its
application. A breakthrough in this area has been the
Matsuda–Heck reaction of arenediazonium salts.[3] Work on
this reaction has led to an extensive investigation into the
palladium-catalyzed cross-coupling reactions of arenediazo-
nium salts.[4] In recent reports, other aniline derivatives such
as areneammonium salts,[5] triazenes[6] or imidazoles[7] have
also proved to be suitable reaction partners in transition
metal-catalyzed cross-coupling reactions. The ruthenium-
catalyzed direct functionalization of the aromatic carbon–
nitrogen bonds of o-acylanilines has been developed.[8] Such
elegant transition metal-catalyzed synthetic tactics have
enabled the rapid synthesis of a range of aryl, alkenyl or
alkyl-substituted aromatic molecules. In this communication,
we report a novel aromatic carbon–nitrogen bond function-
alization reaction by using a dearomatization strategy. This
protocol provides a simple and direct way to convert para-
substituted anilines to quaternary carbon centers, a-keto
esters or aldehydes (Scheme 1).
Scheme 1. Functionalization of the carbon–nitrogen bonds in anilines.
Scheme 2. Construction of cyano-substituted a-aryl quaternary carbon
centers.
alize the aromatic carbon–nitrogen bonds through simple
conversions. The underlying principle is depicted in Scheme 2.
The transformation of the electron-rich aromatic system of
anilines to the electron-deficient cyclohexadienimine system
through oxidative dearomatization might be followed by
a Knoevenagel-type condensation with active nitriles. Sub-
sequent allylic rearrangement might restore the aromaticity
and complete the construction of cyano-substituted a-aryl
quaternary carbon centers, which are attractive synthetic
targets owing to the remarkable biological activities.[12,13]
Challenges to the implementation of this strategy were the
competition between the Knoevenagel-type condensation
and the 1,4-additions related to the electrophilicity of the C-4
carbon atom of the cyclohexadienimine system. Secondary
amines such as l-proline catalyzed condensation of a,b-
unsaturated system and might be suitable for our proposed
process. To avoid potential oxidation of the N-atom of l-
proline, an oxidant should be added to facilitate oxidative
dearomatization before adding l-proline. In testing this
strategy, we were delighted to find that the reaction of p-
toluidine 1 with ethyl 2-cyanoacetate in the presence of 1.1
equivalents of iodosylbenzene (PhIO)[14] and 20 mol% of l-
proline in methanol afforded the desired quaternary product
2 in 23% yield [Eq. (1)]. However, when pyrrolidine was used
The dearomatization[9] of anilines provides an economical
and efficient way to prepare nitrogen-containing complex
molecules by selective ortho[10] or meta substitutions.[11] We
originally conceived that the dearomatization of anilines
might also offer a unique strategic opportunity to function-
[*] S.-E. Wang, L. Wang, Dr. Q. He, Prof. Dr. R. Fan
Department of Chemistry, Fudan University
220 Handan Road, Shanghai, 200433 (China)
E-mail: rhfan@fudan.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201508161.
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instead of l-proline, the reactions only provided the Knoe-
venagel condensation product in 47% yield. This result
indicated that the presence of an acid might be essential for
the formation of the quaternary product. Therefore, various
combinations of secondary amines and acids were examined
(see Table S1 in the Supporting Information). When
0.2 equivalents of piperidine were used together with 1 equiv-
alent of BF3·Et2O, compound 2 was obtained in 31% yield.
However, while the addition of acids promotes the allylic
rearrangement, it also promotes the 1,4-additions of cyclo-
hexadienimine by MeOH or cyanoacetate. Further optimiza-
tion revealed that a one-pot stepwise procedure could be
employed to avoid the deleterious side reactions. Toluidine
was treated with iodosylbenzene in methanol (0.1m) at room
temperature for 5 minutes. After removal of the methanol in
vacuum, acetonitrile, 2-cyanoacetate, and piperidine were
added. The resulting mixture was stirred at room temperature
for 3 h, and then BF3·Et2O was added. This reaction afforded
compound 2 in 74% yield.
suitable reaction partners in this process and gave a set of
quaternary products, isolable in moderate to good yields.
In an experiment designed to elucidate the reaction
pathway, 1 equivalent of CD3OD was added to the model
reaction, leading to incorporation of the OCD3 group into
compound 2. This result indicated that an added nucleophile
might be incorporated into the structure of quaternary carbon
centers. To evade competition between the added nucleophile
and methanol, the oxidative dearomatization was conducted
in the less nucleophilic 2,2,2-trifluoroethanol. First, a reaction
using water as the added nucleophile was examined. The one-
pot reaction conducted under the previously established
conditions not only gave rise to the desired tertiaryalcohol 18
in 27% yield, but also produced the CF3CH2O-substituted
compound 19 in 11% yield and the TsNH-substituted
compound 27 in 13% yield (Ts = tosyl = toluene-sulfonyl).
To inhibit the formation of the latter two by-products,
a simple workup process was used to remove the residual
CF3CH2OH and the generated TsNH2 before adding water
and BF3·Et2O. In this way, the tertiary alcohol 18 was obtained
in 78% yield.
As shown in Scheme 3, reactions of a range of anilines
with 2-cyanoacetate proceeded smoothly. The para-substitu-
A wide range of nucleophilic reagents could serve as the
added nucleophile in this transformation (Scheme 4). For
oxygen nucleophiles (alcohols and acids), and sulfur nucleo-
philes (thiols and thiophenols), the reactions proceeded
smoothly affording the corresponding quaternary products
in moderate to good yields. For nitrogen nucleophiles, the
reaction of 4-methylbenzenesulfonamide gave rise to com-
pound 27 in 57% yield, but the reaction of butylamine or
Scheme 3. Investigation of the scope of anilines and nitriles.
ent in the anilines could be a linear or branched alkyl group,
an aryl group, or a methoxy group. The oxidative dearoma-
tization of 4-iodoaniline was complex. With multi-substituted
anilines, the desired products were formed in reasonable
yields but the steric hindrance caused by a 2-substituent in
substrates tended to diminish the reaction yield. For example,
compared with the reaction of 3,4-dimethylbenzenamine, the
reaction of 2,4-dimethylbenzenamine or 2,4,6-trimethylben-
zenamine afforded products in lower yields. The unsubsti-
tuted benzenamine could also be used as substrate. The
reaction, in which 2.1 equivalents of PhIO were used to
facilitate the oxidative dearomatization, provided the same
product as the reaction of 4-methoxy benzenamine [Eq. (2)].
With respect to other nitriles, 3-oxo-3-phenylpropanenitrile,
3-oxobutanenitrile, diethyl cyanomethylphosphonate, malo-
nonitrile, and 2-cyano-N-(2-hydroxyphenyl)acetamide were
Scheme 4. Investigation of the scope of nucleophiles.
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benzenamine was more complex. An azido group could be
incorporated into the quaternary carbon center by use of
azidotrimethylsilane. For tetrabutylammonium halides, the
reaction of tetrabutylammonium chloride or tetrabutylam-
monium bromide provided the chloro or the bromo-substi-
tuted quaternary product in 84% and 78% yield, respectively.
This strategy could also be used to construct all-carbon
quaternary centers which, given the steric congestion between
the carbon substituents, is challenging. For example, a methyl
or ethyl group can be incorporated into the quaternary
centers with organozinc reagents, and an allyl group can be
introduced with allyltrimethylsilane as the added nucleophile.
Interestingly, the reaction of benzyltrimethylsilane under the
same conditions failed to produce the benzyl-substituted
product, but instead afforded a phenyl-substituted compound
34 in 81% yield. Indeed, a range of diaryl quaternary centers
were formed in good yields when electron-rich aromatic or
heteroaromatic compounds were employed. When pyrrole or
indole was employed as nucleophile, the reaction was
complex. When some reactions were performed on 2 mmol
scale, the corresponding products were obtained in acceptable
yields.
Scheme 6. Conversion of para-substituted anilines to aromatic alde-
hydes.
be readily converted into other quaternary compounds. For
example, the hydrolysis of compound 32 under acid con-
ditions produced the amide 60, and reduction afforded b-
amino ester 61 (Scheme 7).
To further investigate the scope of this transformation,
other active methylene compounds were examined. The
reactions of malonates, b-keto esters or 1,3-diones gave rise to
3-substituted anilines, the products of the corresponding 1,4-
addition to cyclohexadienimine. When 2-isocyanoacetates
was used instead of 2-cyanoacetate, the reaction under the
previously established conditions gave rise to a-keto ester 43
in 32% yield. It is proposed that this compound was
generated from the decomposition of the unstable a-isocyano
quaternary product. Further optimization improved the yield
to 75% (Scheme 5). When 2-aminophenol was introduced
into this reaction at the third step, the reaction afforded
benzoxazinone 53 in 61% yield [Eq. (3)].
Scheme 7. Transformation of cyano-substituted quaternary carbon
center.
In conclusion, we have developed an aromatic carbon–
nitrogen bond functionalization reaction by using a simple
dearomatization strategy. Through this process para-substi-
tuted anilines serve as a potential aryl source in the
construction of a range of functionalized aromatic molecules,
such as quaternary carbon centers, a-keto esters, and
aldehydes. The limitation at this stage is that this strategy
may apply only para-substituted aniline system. The exten-
sion of this strategy to other aniline system and the
applications of this strategy to the synthesis of natural
products are in progress.
Experimental Section
Representative procedure: PhIO (0.22 mmol) was added to a solution
of N-Ts p-toluidine (1) (0.2 mmol) in MeOH (2.0 mL) at 258C. After
5 min, the reaction mixture was concentrated in vacuo. The resulting
mixture was mixed with 2-cyanoacetate (0.24 mmol) and piperidine
(0.04 mmol) in MeCN (2 mL). The reaction was stirred at room
temperature for 3 h, then BF3·Et2O (0.2 mmol) was added. After the
substrate was completely consumed (monitored by TLC analysis), the
reaction was quenched with saturated NaHCO3 (25 mL), and
extracted with EtOAc (25 mL ” 3). The organic layer was dried over
Na2SO4, and concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel (eluent: petroleum ether/
EtOAc) to furnish the desired compound 2.
Scheme 5. Conversion of para-substituted anilines to a-keto esters.
Moreover, nitromethane was also a suitable reaction
partner in this transformation. With the aid of 1 equivalent of
BF3·Et2O, the one-pot stepwise reaction with nitromethane
converted para-substituted anilines to the corresponding
aromatic aldehydes in moderate to good yields (Scheme 6).
Through the manipulation of the cyano group, the cyano-
substituted quaternary centers obtained in this reaction can
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Acknowledgements
We are grateful to the National Science Foundation of China
(grant numbers 21332009 and 21302021), the Shanghai
Science and Technology Committee (grant number
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Keywords: cyanides · dearomatization ·
functionalization of carbon–nitrogen bonds ·
quaternary carbon centers · synthetic methods
How to cite: Angew. Chem. Int. Ed. 2015, 54, 13655–13658
Angew. Chem. 2015, 127, 13859–13862
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Received: August 31, 2015
Published online: October 12, 2015
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