Three-Component Coupling Involving Arynes, Aromatic Tertiary Amines, and Aldehydes via Aryl-Aryl Amino Group Migration

Article abstract of DOI:10.1021/acs.orglett.5b03319

The transition-metal-free multicomponent coupling of arynes, aromatic tertiary amines, and aldehydes proceeding via the aryl to aryl amino group migration has been demonstrated. This protocol allows rapid access to ortho-functionalized tertiary amines in moderate to good yields. Moreover, activated ketones can also be used as the aldehyde component in the present reaction. The similarity of the aryl-aryl tertiary amino group migration with the Smiles rearrangement is striking.

Full text of DOI:10.1021/acs.orglett.5b03319

Letter
pubs.acs.org/OrgLett
Three-Component Coupling Involving Arynes, Aromatic Tertiary
Amines, and Aldehydes via Aryl−Aryl Amino Group Migration
Sachin Suresh Bhojgude,† Dnyaneshwar R. Baviskar,† Rajesh G. Gonnade,‡ and Akkattu T. Biju*,†
‡
†Organic Chemistry Division and Centre for Materials Characterization, CSIR-National Chemical Laboratory (CSIR-NCL),
Dr. Homi Bhabha Road, Pune 411008, India
S
* Supporting Information
ABSTRACT: The transition-metal-free multicomponent cou-
pling of arynes, aromatic tertiary amines, and aldehydes
proceeding via the aryl to aryl amino group migration has
been demonstrated. This protocol allows rapid access to ortho-
functionalized tertiary amines in moderate to good yields.
Moreover, activated ketones can also be used as the aldehyde
component in the present reaction. The similarity of the
aryl−aryl tertiary amino group migration with the Smiles rearrangement is striking.
ransition-metal-free multicomponent coupling (MCC)
involving arynes constitutes one of the convenient methods
amines (eq 2). Activated ketones can also be used as the third
component in this reaction. Mechanistically, this reaction
T
for the rapid access to 1,2-disubstituted benzene derivatives
having complexity and diversity.1,2 Traditionally, in aryne MCCs,
a nucleophile (having no acidic hydrogen) adds to the aryne
generating a transient aryl anion intermediate, which is sub-
sequently trapped by an electrophile (third-component) to form
the MCC product (eq 1). A wide variety of nucleophiles such as
proceeds via a unique aryl to aryl tertiary amino group migration
and is analogous to Smiles rearrangement.16
The present study commenced by the treatment of aryne
generated in situ from 2-(trimethylsilyl)aryl triflate 1a17 (using
KF and 18-crown-6) with 4-cyanobenzaldehyde 2a and 4-bromo
N,N-dimethylaniline 3a. Interestingly, under these conditions, a
facile reaction occurred resulting in the formation of O-arylated
2-(dimethylamino)benzhydrol 4a in 80% yield (Scheme 1).18 The
isocyanides,3 imines,4 N-heterocycles (such as pyridine and
isoquinoline),5 phosphines,6 and solvents (including THF,7
DMF,3c,8 and DMSO9) can trigger the aryne−nucleophile
zwitterion generation. The electrophilic coupling partners are
usually carbonyl compounds including CO2.10
Scheme 1. MCC Involving Aryne, 4-Cyanobenzaldehyde, and
4-Bromo-N,N-dimethylaniline
The use of amines as nucleophilic triggers in aryne MCCs has
received only limited attention. This is primarily due to the
spontaneous protonation of the aryl anion generated from amine
and aryne resulting in arylation of amines.11 In 2007, Yoshida and
co-workers reported the aryne MCCs initiated by silyl-protected
amines using aldehydes as the third-component leading to the
synthesis of 2-aminobenzyl alcohols.12 Apart from the work of
Yoshida, the synthetic utility of tertiary amines as nucleophilic
trigger in aryne MCCs remains underexplored.13 Notably, the
use of tertiary allylamines was utilized in an aryne aza-Claisen
rearrangement by Greaney and co-workers.14 We have recently
reported the transition-metal-free N-arylation of tertiary amines
using arynes as the aryl source.15 Herein, we report the three-
component coupling of arynes, aromatic tertiary amines, and
aldehydes leading to the synthesis of ortho-functionalized tertiary
product formation took place via the migration of NMe2 group from
the amino aryl moiety of 3a to the aryl part of aryne. Notably, from a
product perspective, ortho-functionalization of aromatic tertiary
amines is difficult to realize compared to the para-derivatization.19
With the reaction conditions for the synthesis of ortho-
functionalized tertiary amines in hand, we then examined the
Received: November 18, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03319
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Organic Letters
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Scheme 2. MCCs Involving Arynes, Aldehydes, and Tertiary
Amines: Scope of Tertiary Amines*
Scheme 3. Scope of Aldehydes and Arynes*
*
General conditions: 1a (0.6 mmol), 2a (1.0 mmol), 3 (0.5 mmol),
KF (1.2 mmol), 18-crown-6 (1.2 mmol), THF (2.0 mL), −10 °C to rt,
a
12 h. Yields of the isolated products are given. 23% of N-arylated
b
c
product was also isolated. Reaction run at 60 °C for 12 h. Run on
*
General conditions: 1 (0.6 mmol), 2 (1.0 mmol), 3a (0.5 mmol), KF
(1.2 mmol), 18-crown-6 (1.2 mmol), THF (2.0 mL), −10 °C to rt,
0.25 mmol scale.
a
1
12 h. Yields of the isolated products are given. Given is H NMR
yield. Yield of N-arylated product. The regioisomer ratio was deter-
mined by H NMR analysis.
b
c
substrate scope of this reaction. First, the variation of tertiary
amine was evaluated (Scheme 2). A series of aromatic tertiary
amines with different substituents on the aromatic ring were well-
tolerated to furnish the 2-aminobenzhydrol derivatives in
moderate to good yields (4a−f).20 Moreover, variations at the
NMe2 moiety in 3 were possible, and these substrates afforded
the desired products when the reaction was performed at 60 °C
(4g−j). The naphthyl substrate and the donor−acceptor tertiary
amines also underwent smooth aryne MCCs with aryl−aryl
NMe2 migration (4k−m). Interestingly, the commonly used dye
leuco-malachite green afforded 2-fold MCC upon treatment with
1a and 2a forming the product 4n in 50% yield. Notably, tertiary
amines with electron-releasing groups on the aryl ring furnished
only moderate yields of the target compounds (4o,p) under the
present conditions.21
Next, we examined the scope of the aryne MCC with various
aldehydes and differently substituted arynes (Scheme 3). A series
of aromatic aldehydes with electron-releasing and -withdrawing
substituents at the 4-position of the ring are well-tolerated,
affording the 1,2-disubstituted arenes in good yields (4q−w).22
Moreover, 3-substituted and 2-substituted aldehydes underwent
smooth aryne MCCs to deliver the desired products in good
yields (4x−aa). 3,4-Dichloro, naphthyl, and furyl substitution did
not affect the outcome of the reaction (4ab−ad). Notably, linear
and branched aliphatic aldehydes resulted in a relatively low
yield of the product under the present conditions (4ae−af).
In addition, electronically different 4,5-disubstituted arynes
1
generated from the corresponding precursors afforded the func-
tionalized tertiary amines in moderate to good yields (4ag−ai).
In the case of the dimethyl derivative 4ag, the structure was
confirmed by X-ray analysis.23 In addition, the symmetrical and
unsymmetrical naphthalynes furnished the desired products
in moderate yields (4aj,ak). In the case of unsymmetrical
naphthalyne, the corresponding N-arylated product was also
observed 41% yield.15 Furthermore, the reaction of 2a and 3a
with unsymmetrical arynes (4-methyl- and 4-fluoroarynes)
resulted in the formation of a regioisomeric mixture of MCC
products in good yields (4al,am).
Gratifyingly, this aryne MCC is not limited to aldehydes as the
third component but instead worked well with cyclic and acyclic
activated ketones. For instance, reaction of aryne generated from
1a with N-methylisatin 5a and 3b resulted in the formation of
the oxindole derivative 6a in 72% yield (Scheme 4, eq 3).
N-Substitution as well as substitution at the carbocyclic ring of
isatin are well tolerated under the present conditions to furnish
the desired products in moderate to good yields (6b−e). The
structure of the oxindole derivative 6d was confirmed by X-ray
analysis.23 Moreover, the reaction using trifluoroacetophenone 7
as the carbonyl surrogate afforded the MCC product 8 in 62%
yield upon treatment with 3b and aryne generated from 1a (eq 4),
thereby further expanding the scope of the present reaction.
B
DOI: 10.1021/acs.orglett.5b03319
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Scheme 4. Aryne MCCs Employing Activated Ketones
Notably, the use of benzil 9 as the third-component returned the
MCC product 10 in 30% yield (eq 5).
The mechanism of this aryl−aryl amino group migration can
be delineated as follows (Scheme 5). The initial nucleophilic
Scheme 5. Tentative Mechanism for the MCC
product 17 was formed in 25% yield (eq 6). In this case, the
aryl−aryl amino group migration was not observed. Possibly, the
initially formed amine−aryne zwitterion adds to the aldehyde to
generate the intermediate 18, which undergoes an intramolecular
proton transfer (in preference to aryl−aryl amino migration) to
afford 16. Moreover, the reaction using 19 as the amine source
afforded the rearranged product 20 in 60% yield and the styrene
derivative 21 in 20% yield (eq 7). The styrene 21 was formed by
an intramolecular proton transfer of the initial amine−aryne−
aldehyde adduct without the amino group migration. In addition,
crossover experiments carried out using amines 3a and 3g
afforded the products 4a (60%) and 4g (57%). The crossover
products 4b and 4an were not formed under the reaction
conditions (eq 8). This clearly indicates that the present aryl−
aryl amino group migration is intramolecular in nature.
In conclusion, we have developed a three-component coupling
of arynes, aldehydes, and aromatic tertiary amines allowing the
rapid synthesis of 2-functionalized tertiary amines. The reaction
proceeds via the aryl−aryl amino group migration, which is
mechanistically similar to the Smiles rearrangement. Moreover,
activated ketones can also be used as the aldehyde component in
this reaction. Further studies in related aryne MCCs are ongoing
in our laboratory.
attack of tertiary amine on aryne generates the zwitterionic inter-
mediate 11, which adds to aldehyde forming the key tetrahedral
intermediate 12. The intermediate 12 in the absence of proton
source could undergo an intramolecular nucleophilic aromatic
substitution reaction (SNAr) resulting in the formation of the
desired product 4 via the σ-complex 13. It is interesting to note
the mechanistic similarity of the present amino group migration
with the Smiles rearrangement. The key intermediate in the
Smiles rearrangement is 14, and the rearrangement depends on
the electron deficiency of the ring (to facilitate SNAr), leaving
group ability of X, and nucleophilicity of Y.16 Usually, this
reaction proceeds via a five-membered intermediate but in rare
cases proceeds via six-membered intermediates.24 In our tertiary
amine triggered aryne MCC, the key intermediate is the
zwitterion 12. The presence of the quaternary ammonium salt
in 12 may be crucial for the aryl to aryl amino group migration,
and the reaction proceeds via the six-membered intermediate
13.25,26 In addition, the electronic nature of the tertiary amine is
also important as the substrates with electron-releasing groups
furnished moderate yield of the product (Scheme 2, 4o,p).
To gain insight into the aryl−aryl amino group migration,
we have carried out mechanistic experiments. When the reaction
was performed using the secondary amine 15, the benzhydrol
derivative 16 was formed in 67% yield and the N-arylated
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03319.
Details on experimental procedures and characterization
data of all compounds (PDF)
X-ray data for 4ag (CIF)
X-ray data for 6d (CIF)
C
DOI: 10.1021/acs.orglett.5b03319
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Letter
Kohtani, S.; Miyabe, H. Org. Lett. 2013, 15, 3938. (d) Yoshioka, E.;
Kohtani, S.; Miyabe, H. Org. Lett. 2010, 12, 1956. (e) Yoshida, H.; Ito,
Y.; Ohshita, J. Chem. Commun. 2011, 47, 8512.
AUTHOR INFORMATION
Corresponding Author
■
(9) (a) Li, H.-Y.; Xing, L.-J.; Lou, M.-M.; Wang, H.; Liu, R.-H.; Wang,
B. Org. Lett. 2015, 17, 1098. (b) Liu, F.-L.; Chen, J.-R.; Zou, Y.-Q.; Wei,
Q.; Xiao, W.-J. Org. Lett. 2014, 16, 3768.
(10) For selected reports using CO2, see: (a) Kaicharla, T.; Thangaraj,
M.; Biju, A. T. Org. Lett. 2014, 16, 1728. (b) Yoo, W.-J.; Nguyen, T. V.
Q.; Kobayashi, S. Angew. Chem., Int. Ed. 2014, 53, 10213. (c) Yoshida,
H.; Morishita, T.; Ohshita, J. Org. Lett. 2008, 10, 3845.
(11) For the N-arylation of amines using arynes, see: (a) Liu, Z.;
Larock, R. C. Org. Lett. 2003, 5, 4673. (b) Liu, Z.; Larock, R. C. J. Org.
Chem. 2006, 71, 3198.
(12) (a) Yoshida, H.; Morishita, T.; Ohshita, J. Org. Lett. 2008, 10,
3845. (b) Yoshida, H.; Morishita, T.; Fukushima, H.; Ohshita, J.; Kunai,
A. Org. Lett. 2007, 9, 3367. For a related report, see: (c) Morishita, T.;
Fukushima, H.; Yoshida, H.; Ohshita, J.; Kunai, A. J. Org. Chem. 2008,
73, 5452.
(13) For aryne MCCs triggered by N-substituted aziridines, see:
(a) Stephens, D.; Zhang, Y.; Cormier, M.; Chavez, G.; Arman, H.;
Larionov, O. V. Chem. Commun. 2013, 49, 6558. (b) Roy, T.; Baviskar,
D. R.; Biju, A. T. J. Org. Chem. 2015, 80, 11131.
(14) (a) Cant, A. A.; Bertrand, G. H. V.; Henderson, J. L.; Roberts, L.;
Greaney, M. F. Angew. Chem., Int. Ed. 2009, 48, 5199. See also: (b) Aoki,
T.; Koya, S.; Yamasaki, R.; Saito, S. Org. Lett. 2012, 14, 4506.
(15) Bhojgude, S. S.; Kaicharla, T.; Biju, A. T. Org. Lett. 2013, 15, 5452.
(16) For reviews, see: (a) Snape, J. Chem. Soc. Rev. 2008, 37, 2452.
(b) Truce, W. E.; Kreider, E. M.; Brand, W. W. Org. React. 1970, 18, 99.
(17) (a) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983,
*E-mail: at.biju@ncl.res.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous financial support from the Science and Engineering
Research Board (SERB-DST), Government of India (Grant No.
SR/S1/OC/12/2012), is kindly acknowledged. A.T.B. thanks
the Alexander von Humboldt Foundation for an equipment
grant. S.S.B. thanks CSIR and D.R.B. thanks UGC for the
research fellowships. We thank Dr. P. R. Rajamohanan (CSIR-
NCL) for the excellent NMR support and Dr. B. Santhakumari
(CSIR-NCL) for the HRMS data.
DEDICATION
■
Dedicated with best regards to Dr. Vijay Nair on the occasion of
his 75th birthday.
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