Substrate-Controlled Selectivity Switch in the Three-Component Coupling Involving Arynes, Aromatic Tertiary Amines, and CO2

Article abstract of DOI:10.1021/acs.orglett.6b02845

The transition-metal-free multicomponent coupling involving arynes, aromatic tertiary amines, and CO₂ is reported. The reaction exhibits switchable selectivity depending on the electronic nature of the aromatic amines used. With amines bearing electron-releasing/neutral groups as the nucleophilic trigger, the reaction afforded 2-arylamino benzoates via a nitrogen to oxygen alkyl group migration. Employing electron-deficient amines in the reaction furnished 2-aminoaryl benzoates proceeding via the aryl to aryl amino group migration resembling a Smiles rearrangement.

Full text of DOI:10.1021/acs.orglett.6b02845

Letter
pubs.acs.org/OrgLett
Substrate-Controlled Selectivity Switch in the Three-Component
Coupling Involving Arynes, Aromatic Tertiary Amines, and CO2
Sachin Suresh Bhojgude,†,§ Tony Roy,†,§ Rajesh G. Gonnade,‡ and Akkattu T. Biju*,†,§
‡
†Organic Chemistry Division, Centre for Materials Characterization, CSIR-National Chemical Laboratory (CSIR-NCL), Dr. Homi
Bhabha Road, Pune-411008, India
§Academy of Scientific and Innovative Research (AcSIR), New Delhi 110020, India
S
* Supporting Information
ABSTRACT: The transition-metal-free multicomponent coupling involving arynes, aromatic tertiary amines, and CO2 is
reported. The reaction exhibits switchable selectivity depending on the electronic nature of the aromatic amines used. With
amines bearing electron-releasing/neutral groups as the nucleophilic trigger, the reaction afforded 2-arylamino benzoates via a
nitrogen to oxygen alkyl group migration. Employing electron-deficient amines in the reaction furnished 2-aminoaryl benzoates
proceeding via the aryl to aryl amino group migration resembling a Smiles rearrangement.
Scheme 1. Aryne MCCs Triggered by Aromatic Tertiary
Amines
he efficient utilization of CO2 as a one-carbon feedstock is
Tone of the safest and most inexpensive methods for the
synthesis of value-added products, as CO2 is a cheap and readily
available gas.1 However, employing CO2 as a C1 source in
organic chemistry is limited mainly because of its high
thermodynamic stability and kinetic inertness.2 One way to
explore the synthetic transformations using CO2 involves the
use of CO2 along with high energy substrates/reactive
intermediates.3 In this regard, employing CO2 in reactions
using highly electrophilic aryne intermediates constitutes a
convenient method to install the CO2 moiety directly to the
aromatic ring.4 In 2006, Yoshida, Kunai and co-workers
demonstrated, for the first time, the incorporation of CO2 in
aryne multicomponent coupling (MCC)5 triggered by imines
for the straightforward synthesis of benzoxazinones.6 Sub-
sequently, the same group uncovered the synthesis of
anthranilic acids by the MCC involving arynes, secondary
amines, and CO2.7 We have reported the incorporation of CO2
in aryne MCCs triggered by isocyanides for the practical
synthesis of phthalimides.8 Moreover, Kobayashi and co-
workers disclosed the Cu-catalyzed aryne MCCs involving
terminal alkynes and CO2 for the synthesis of isocoumarin
derivatives.9 Apart from these works, the incorporation of CO2
in aryne reactions remains underexplored.
amines proceeding via the aryl to aryl amino group migration
similar to the Smiles rearrangement.13 Inspired by this finding,
we envisaged the use of CO2 in aryne MCCs triggered by
aromatic tertiary amines. When the reaction was performed
using electron-releasing/neutral tertiary amines as the nucleo-
philic trigger, 2-arylamino benzoates are formed via a unique
nitrogen to oxygen alkyl group migration (eq 2). Interestingly,
with electron-deficient tertiary amines, the reaction afforded 2-
In the context of our interest in developing transition-metal-
free MCCs involving arynes,4a,10 we have recently reported the
aryne MCCs triggered by aromatic tertiary amines using
aldehydes/activated ketones as the third component (Scheme
1, eq 1).11,12 The reaction afforded ortho-functionalized tertiary
Received: September 21, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02845
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Organic Letters
Letter
aminoaryl benzoates via an aryl to aryl amino group migration
(mechanistically similar to Smiles rearrangement).14 Herein, we
report this substrate-controlled switchable selectivity observed
in the aryne MCCs involving CO2 and aromatic tertiary amines.
Notably, related anthranilic acid derivatives are endowed with
interesting biological properties.15
Scheme 3. Scope of Aryne MCCs for the Synthesis of 2-
Arylamino Benzoates
a
Our present study commenced with the treatment of an
aryne generated in situ from 2-(trimethylsilyl) aryl triflate 1a16
(using KF and 18-crown-6) with N,N-dimethyl aniline 2a in
THF under an atmosphere of CO2 (balloon). Under these
conditions, we expected the 2-aminoaryl benzoate derivative 4
formed by the aryl to aryl NMe2 migration.11a But delightfully,
the 2-arylamino benzoate 3a was isolated in 87% yield (Scheme
2). The product 3a was formed by the N-arylation of 2a
Scheme 2. MCC Involving Aryne, N,N-Dimethylaniline, and
CO2
followed by quenching of the aryl anion using CO2 and a
subsequent nitrogen to oxygen methyl group migration.17 The
reactions performed using other common fluoride sources such
as CsF and tetrabutylammonium fluoride (TBAF) resulted in a
reduced yield of 3a.
a
With optimized conditions in hand, we then examined the
substrate scope with respect to the aryne and aniline substrates
(Scheme 3). A series of N,N-dimethyl anilines with differently
substituted electron-releasing/neutral/moderately electron-
poor groups are tolerated under the reaction conditions
furnishing the 2-arylamino benzoate derivatives in good yields
(3b−j). Moreover, the NMe2 moiety present in donor−
acceptor system 2k furnished the MCC product in 56% yield
(3k) and leuco-malachite green underwent efficient twofold
MCC with a methyl group transfer leading to the formation of
desired product 3l in 84% yield. Additionally, this alkyl group
migration reaction is not limited to N,N-dimethyl aniline
derivatives; delightfully, N,N-diethyl aniline 2m and N-benzyl-
N-methyl aniline 2n resulted in the ethyl and benzyl group
migration respectively to afford the target products in high
yields (3m, 3n) thus demonstrating the versatility of the
present method. Furthermore, electronically diverse 4,5-
disubstituted symmetrical arynes generated from their
precursors readily afforded the 1,2-disubstituted arene deriva-
tives in good yields (3o−q). It is noteworthy that both
symmetrical and unsymmetrical naphthalyne worked well and
the corresponding MCC products are formed in good yields
(3r, 3s). Finally, the reaction of 2a and CO2 with 4-
methylbenzyne generated from the triflate precursor resulted
in the formation of an inseparable mixture of regioisomers (3t
and 3t′) in 64% yield and 1.4:1 selectivity.
General conditions: 1 (0.6 mmol), 2 (0.5 mmol), KF (1.2 mmol), 18-
crown-6 (1.2 mmol), THF (2.0 mL), under an atmosphere of CO2
(balloon), −10 °C to rt, 12 h, then stirred at 60 °C for 12 h. Yields of
b
the isolated products are given. Reaction stirred at 100 °C for 12 h
c
d
instead of 60 °C. Run on 0.25 mmol scale. The regioisomer ratio
1
was determined by H NMR analysis.
well with various electron-poor aromatic tertiary amines, and in
all cases, the desired product was formed in moderate to good
yields (4b−e). In the case of 4-trifluoromethyl derivative 4b,
the structure was confirmed by single-crystal X-ray analysis.18 In
addition, this MCC worked well with electronically different
symmetrically substituted aryne precursors, and the expected
Smiles rearrangement products were isolated in good yields
(4f−i). Notably, the unsymmetrical naphthalyne generated
from the triflate precursor afforded a single regioisomer 4j in
62% yield. Besides, attempted CO2 incorporation MCC with 4-
methylbenzyne furnished an inseparable mixture of re-
gioisomers (4k and 4k′) in 61% yield with 1.7:1 selectivity.
To probe the mechanism of the alkyl group migration, a
series of experiments were performed. The reaction of 2a with
the aryne generated from 1a and CO2 followed by quenching
the reaction mixture with TfOH resulted in formation of the
ammonium salt 5.HOTf (Scheme 5, eq 3). Treatment of
5.HOTf with K2CO3 afforded the methyl ester 3a in 25% yield
(two steps). This indicates the intermediacy of the ammonium
salt in the reaction. To gain insight into the nature of the alkyl
group migration, we performed several mechanistic experi-
ments.17 The reaction of the aryne generated from 1a and CO2
with 2a and 2m afforded a mixture of four products (3a, 3m,
3u, and 3v) in the ratio 26:23:23:28 (eq 4). The products 3a
and 3m could be formed by the intramolecular alkyl group
migration. Interestingly, the formation of 3u and 3v clearly
Interestingly, treatment of 4-carboethoxy N,N-dimethyl
aniline with aryne generated from 1a (using KF and 18-
crown-6) under an atmosphere of CO2 (balloon) −10 °C
afforded the ortho-functionalized tertiary amine 4a in 75% yield
(Scheme 4). The product formation took place via the aryl to
aryl migration of the NMe2 group and is analogous to the
Smiles rearrangement. This rearrangement reaction worked
B
DOI: 10.1021/acs.orglett.6b02845
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Organic Letters
Letter
The mechanism of this substrate-controlled switchable
selectivity in aryne MCCs can be elucidated as follows (Scheme
6). The initial addition of aromatic tertiary amine 2 to the aryne
Scheme 4. Scope of Aryne MCCs Involving CO2 and
Electron-Poor Tertiary Amines
a
Scheme 6. Tentative Mechanism of the Substrate-Controlled
Switchable MCCs
formed from 1 generates the 1,3-zwitterionic intermediate 7. In
the absence of a proton source, the aryl anion intermediate 7
adds to CO2 generating the key dimethyl phenyl ammonium
benzoate intermediate 5. With electron-rich/-neutral amines,
the intermediate 5 could undergo a methyl group transfer to
furnish the 2-arylamino benzoate 3. However, in the case of
tertiary amines having an electron-poor group attached, the
intermediate 5 could undergo an intramolecular nucleophilic
aromatic substitution reaction (SNAr) resulting in the aryl to
aryl NMe2 group migration leading to the formation of 2-
aminoaryl benzoate 4 via the σ-complex 8.
a
General conditions: 1 (0.6 mmol), 2 (0.5 mmol), KF (1.2 mmol), 18-
crown-6 (1.2 mmol), THF (2.0 mL), under an atmosphere of CO2
(balloon), −10 °C, 24 h. Yields of the isolated products are given.
b
c
d
Reaction run at −10 °C to rt for 12 h. Given is 1H NMR yield. The
1
regioisomer ratio was determined by H NMR analysis.
Scheme 5. Mechanistic Experiments
Furthermore, the synthetic utility of the present alkyl group
migration MCC has been demonstrated in the transition-metal-
free synthesis of biologically important acridones and
benzoxazinones. 2-Arylaminobenzoate 3a was converted to 2-
arylamino benzaldehyde 9 by a reduction−oxidation sequence.
Direct aryl-aldehyde Csp2−Csp2 bond formation via PhI-
(OAc)2-mediated intramolecular cross-dehydrogenative cou-
pling of 9 furnished the acridone 10 in 49% yield (Scheme 7, eq
Scheme 7. Synthetic Utility of 2-Arylamino Benzoates
6).19 In addition, benzoate 3a was hydrolyzed to acid 11 under
basic conditions followed by intramolecular Csp3−O bond
formation has been accomplished in the presence of PhI-
(OAc)2/NaN3 leading to the formation of benzoxazinone 12 in
96% yield (eq 7).20
indicates the possibility of the intermolecular alkyl group
migration in the present reaction. Moreover, performing the
reaction using N-ethyl N-methyl aniline 6 under the present
reaction conditions furnished four products (3a, 3u, 3v, and
3m) in the ratio 23:18:33:26 shedding further light on the
possibility of the intermolecular nature of the present alkyl
group migration (eq 5).
In conclusion, we have demonstrated switchable selectivity in
the aryne MCCs involving aromatic tertiary amines and CO2.
The selectivity depends on the electronic nature of the aromatic
amine used. The reaction of aromatic amines bearing electron-
releasing/-neutral groups, arynes, and CO2 furnished 2-
arylamino benzoates via a nitrogen to oxygen alkyl group
migration. Interestingly, the selectivity was switched to the
C
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Organic Letters
Letter
(5) (a) Bhojgude, S. S.; Biju, A. T. Angew. Chem., Int. Ed. 2012, 51,
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formation of 2-aminoaryl benzoates (via an aryl to aryl amino
group migration) employing electron-deficient amines as
nucleophiles in aryne MCCs using CO2 as the third
component. A reasonable mechanism for the switchable
reactions is provided. Further studies on related aryne MCCs
using CO2 are ongoing in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02845.
Details on experimental procedures, characterization data
of all compounds (PDF)
X-ray data for 4b (CIF)
AUTHOR INFORMATION
Corresponding Author
■
(11) (a) Bhojgude, S. S.; Baviskar, D. R.; Gonnade, R. G.; Biju, A. T.
Org. Lett. 2015, 17, 6270. For a related N-arylation of tertiary amines
using arynes, see: (b) Bhojgude, S. S.; Kaicharla, T.; Biju, A. T. Org.
Lett. 2013, 15, 5452.
*E-mail: at.biju@ncl.res.in.
Notes
The authors declare no competing financial interest.
(12) For the application of related MCCs for the synthesis of 9- and
10-membered oxaza heterocycles, see: Okuma, K.; Kinoshita, H.;
Nagahora, N.; Shioji, K. Eur. J. Org. Chem. 2016, 2264.
(13) For a related aryne reaction proceeding via the Smiles
rearrangement, see: (a) Holden, C. M.; Sohel, S. M. A.; Greaney,
M. F. Angew. Chem., Int. Ed. 2016, 55, 2450. For a related aryne
reaction proceeding via migration of the aryl group from sulfur to
nitrogen, see: (b) Yoshida, S.; Yano, T.; Misawa, Y.; Sugimura, Y.;
Igawa, K.; Shimizu, S.; Tomooka, K.; Hosoya, T. J. Am. Chem. Soc.
2015, 137, 14071.
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Proschak, E.; Schubert-Zsilavecz, M. Bioorg. Med. Chem. 2015, 23, 499.
(b) Walsh, C. T.; Haynes, S. W.; Ames, B. D. Nat. Prod. Rep. 2012, 29,
37.
ACKNOWLEDGMENTS
■
Generous financial support by Science and Engineering
Research Board (SERB-DST), Government of India (Grant
No. SR/S1/OC/12/2012) is kindly acknowledged. S.S.B.
thanks CSIR for the fellowship, and T.R. acknowledges DST
for the Inspire fellowship. We thank Dr. P. R. Rajamohanan
(CSIR-NCL) for the excellent NMR support and Dr. B.
Santhakumari (CSIR-NCL) for the HRMS data.
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