The Aryne [2,3] Stevens Rearrangement

Article abstract of DOI:10.1021/acs.orglett.6b02809

Arynes are employed in the transition-metal-free and mild [2,3] Stevens rearrangement of tertiary allylic amines for the synthesis of functionalized homoallylic amines in moderate to good yield with a broad substrate scope. The key nitrogen ylide intermediate was generated by the N-arylation of allyl amines using arynes. Moreover, the reaction of chiral allyl amines with arynes resulted in the enantiospecific synthesis of homoallylic amines. In addition, preliminary studies on the [1,2] Stevens rearrangement is also presented.

Full text of DOI:10.1021/acs.orglett.6b02809

Letter
pubs.acs.org/OrgLett
The Aryne [2,3] Stevens Rearrangement
Tony Roy,†,§ Manikandan Thangaraj,†,§ Trinadh Kaicharla,†,§ Rupa V. Kamath,† 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: Arynes are employed in the transition-metal-
free and mild [2,3] Stevens rearrangement of tertiary allylic
amines for the synthesis of functionalized homoallylic amines
in moderate to good yield with a broad substrate scope. The
key nitrogen ylide intermediate was generated by the N-
arylation of allyl amines using arynes. Moreover, the reaction
of chiral allyl amines with arynes resulted in the enantiospecific
synthesis of homoallylic amines. In addition, preliminary
studies on the [1,2] Stevens rearrangement is also presented.
broad application of this method.5 Consequently, studies
he Stevens rearrangement involves the conversion of
Tammonium/sulfonium salts into complex nitrogen/sulfur toward the mild and general methods for the [1,2], and [2,3]
rearrangements are highly desirable. Transition-metal-catalyzed
methods have been utilized for the generation of nitrogen
ylides. The metal-catalyzed cross-coupling of tertiary allyl
amines with diazoesters is a convenient method for the direct
access to nitrogen ylides.6 In 2011, the Tambar group
demonstrated the Pd-catalyzed allylic amination strategy using
tertiary amino esters and allyl carbonates for the nitrogen ylide
generation, and the method was applied in a tandem ylide
generation/[2,3] rearrangement.7
containing products, usually taking place in the presence of a
strong base.1,2 The reaction proceeds via either [1,2] or [2,3]
sigmatropic rearrangement, and the key intermediate is a
nitrogen ylide.3 Traditionally, the nitrogen ylides for this
rearrangement are generated from the corresponding ammo-
nium salts (prepared from tertiary amines and alkyl halides) by
treatment with a base (Scheme 1).4 However, the harsh
reaction conditions needed for the synthesis of many
ammonium salt precursors and use of a strong base limit the
In this context, we envisioned the generation of nitrogen
ylide intermediates by the reaction of tertiary amino esters/
ketones with arynes8 followed by the [2,3] Stevens rearrange-
ment for the synthesis of functionalized homoallylic amines.
The addition of a tertiary amine to the aryne generated from
the 2-(trimethylsilyl) aryl triflate9 could generate the 1,3-
zwitterionic intermediate A, which could undergo an intra-
molecular proton transfer to form the key nitrogen ylide
intermediate B.10 The ylide B could undergo a [2,3] Stevens
rearrangement to afford the homoallylic amines (Scheme 1).
Herein, we report the mild and transition-metal-free [2,3]
Stevens rearrangement induced by arynes for the synthesis of
functionalized homoallylic amines.11 It may be noted in this
context that the aryne induced [3,3] sigmatropic rearrange-
ments of tertiary allyl amines for the synthesis of 2-allyl aniline
derivatives are reported by Greaney and co-workers.12,13
Inspired by our previous work on generating the nitrogen
ylides from arynes and electron-deficient aziridines,10a the
present study was commenced with the treatment of ethyl N-
allyl-N-phenylglycinate 1a with the aryne generated from the 2-
Scheme 1. [2,3] Stevens Rearrangement
Received: September 18, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02809
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Organic Letters
Letter
(trimethylsilyl)aryl triflate precursor 2a9 using KF in the
presence of an 18-crown-6 as additive in THF at 30 °C. To our
delight, under these reaction conditions, the homoallylic amine
3a derived from the [2,3] Stevens rearrangement of the initially
generated nitrogen ylide was formed in 87% yield (Scheme 2).
was replaced by a nitrile group, the reactivity was unaltered and
the α-amino cyano compound 3n was formed in 80% yield. In
addition, different alkoxy carbonyl groups including methyl,
benzyl, and tert-butyl as the electron-withdrawing group were
well tolerated in this rearrangement reaction (3o−3q).
Furthermore, use of differently substituted benzoyl groups as
the electron-withdrawing group was feasible under the present
conditions and the corresponding rearranged products are
formed in good yields (3r−3t). In the case of compound 3r,
the structure was further confirmed by X-ray analysis.15
Scheme 2. Aryne Induced [2,3] Stevens Rearrangement
The feasibility of this [2,3] Stevens rearrangement was then
examined with differently substituted arynes (Table 1).
a
Table 1. Variation of the Aryne Moiety
Notably, the aza-Claisen product reported by Greaney and co-
workers was not formed under the present reaction
conditions.12 The use of CsF as the fluoride source (in
CH3CN as solvent) afforded 3a in 68% yield only. The use of
tetrabutyl ammonium fluoride (TBAF) resulted in a reduced
yield of 3a.
With the optimized reaction conditions in hand, we
evaluated the scope of amines in this reaction (Scheme 3).14
Scheme 3. Scope of Amines in the Aryne Induced [2,3]
a
Stevens Rearrangement
a
General conditions: 1a (0.50 mmol), 2 (0.75 mmol), KF (3.0 equiv),
18-crown-6 (3.0 equiv), THF (2.0 mL), 30 °C and 12 h. Yields of the
b
isolated products are given. The regioisomer ratio was determined by
1H NMR analysis of crude reaction mixture.
a
General conditions: 1 (0.50 mmol), 2a (0.75 mmol), KF (3.0 equiv),
Electronically dissimilar 4,5-disubstituted symmetrical arynes
generated from the corresponding triflate precursors 2b−d
readily furnished the respective homoallylic amines in good
yields (3u−3w). Moreover, the reaction of 1a with symmetrical
and unsymmetrical naphthalyne generated from the precursors
2e and 2f resulted in the formation of 2-naphthyl substituted
homoallyl amine 3x in good yield. In the case of unsymmetrical
naphthalyne, 3x was formed in high regioselectivity. In addition,
the unsymmetrical 4-methyl aryne generated from 2g afforded
the mixture of regioisomers 3y and 3y′ in 80% yield and a 1:1
ratio. Furthermore, the reaction of 1a with 4-fluoroaryne
resulted in the mixture of regioisomers 3z and 3z′ in 78% yield
and a 2:1 ratio thereby further expanding the scope of this
aryne [2,3] rearrangement reaction.
18-crown-6 (3.0 equiv), THF (2.0 mL), 30 °C and 12 h. Yields of the
isolated products are given.
Interestingly, various electronically different para-substituted
allylic anilines underwent smooth rearrangement under the
present reaction conditions to afford the N,N-diaryl homoallylic
amines in good yields (3b−3f). Moreover, meta-substituted
anilines were well tolerated furnishing the desired products in
good yields (3g−3i). Disappointingly, ortho-substituted anilines
afforded only traces of the expected product. Notably, various
3,4-disubstituted allylic anilines worked well under the present
reaction conditions giving the rearranged products in good
yields (3j−3l). It is noteworthy that the allylic amine derived
from 3,4,5-trimethoxy aniline also afforded the desired product
3m in 65% yield. When the electron-withdrawing ester group
Next, we examined the outcome of this rearrangement with
allyl amines having a substituent at the allylic position.
B
DOI: 10.1021/acs.orglett.6b02809
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Gratifyingly, the reaction of arynes with the tertiary cinnamyl
amine 1u under the present conditions afforded the
diastereoselective synthesis of functionalized homoallylic
the presence of 18-crown-6 as an additive in THF at 30 °C
resulted in the formation of the functionalized tertiary amine 9
in 41% yield (Scheme 6). Increasing the concentration of aryne
1
amine 4 in 74% yield and a >20:1 ratio (determined by H
NMR) for the syn isomer (Scheme 4, eq 1). Moreover, the
reaction of an aryne with the crotyl substituted substrate 1v
resulted in the formation of the desired product 5 in 81% yield
and 5:1 dr (eq 2).
Scheme 6. Aryne Induced [1,2] Stevens Rearrangement
Scheme 4. Aryne Induced Diastereoselective [2,3] Stevens
Rearrangement
did not improve the yield of 9 under the present conditions. It
is likely that the reaction proceeds via the initial generation of
nitrogen ylide from aryne and 8, which undergoes a [1,2]
rearrangement to afford the desired product 9.
In conclusion, we have developed a mild and transition-
metal-free procedure for the [2,3] Stevens rearrangement
induced by arynes for the synthesis of functionalized
homoallylic amines. The reaction proceeds via the generation
of the nitrogen ylide intermediate from arynes and tertiary allyl
amines. A variety of tertiary allyl amines were well tolerated
under the present reaction conditions. Formation of a new
carbon−carbon and carbon−nitrogen bond under mild and
strong-base-free reaction conditions, a broad substrate scope,
and high yields of products are the notable features of the
present reaction. The reaction of arynes with chiral allyl amines
afforded chiral homoallylic amines with retention of enantio-
purity and inversion in configuration. Further studies on related
sigmatropic rearrangements induced by arynes are ongoing in
our laboratory.
This aryne induced [2,3] rearrangement was also applied to
enantiomerically pure proline-derived allyl amines. Treatment
of the chiral methyl ester 6a (>99% ee) with the aryne
generated from 2a under the optimized reaction conditions for
2 h resulted in the formation of the N-aryl proline derivative 7a
bearing a quaternary stereocenter in 63% yield and 96% ee
(Scheme 5). The reaction proceeds via the retention of
Scheme 5. Aryne Induced Enantiospecific [2,3] Stevens
a
Rearrangement
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02809.
Experimental procedures, characterization data of the
1
products, copies of the H and 13C NMR spectra of
products, and HPLC data (PDF)
Crystallographic data for compound 3r (CIF)
a
General conditions: 6 (0.50 mmol), 2 (0.75 mmol), KF (3.0 equiv),
AUTHOR INFORMATION
■
18-crown-6 (3.0 equiv), THF (2.0 mL), 30 °C, and 2 h. Yields of the
isolated products are given, and the ee was determined by HPLC
analysis on a chiral column.
Corresponding Author
*E-mail: at.biju@ncl.res.in.
Notes
enantiopurity as well as the inversion of configuration.16 It is
noteworthy that the transfer of chirality from carbon to
nitrogen (up on N-arylation of 6 using arynes) and then back to
carbon (via the nitrogen ylide formation and subsequent [2,3]
Stevens rearrangement) has been observed.17 Moreover, the
ethyl ester 6b afforded the desired product 7b in 61% yield and
98% ee. Additionally, 4,5-disubstituted aryne generated from
the triflate precursor 2c also afforded the corresponding proline
derivative 7c in 61% yield and 88% ee.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for this work has been generously provided
by the CSIR-New Delhi (as part of the 12th Five-Year plan
program under ORIGIN-CSC0108). T.R. thanks DST for an
Inspire fellowship, and M.T. and T.K. thank CSIR for the
research fellowships. We thank Mr. Santigopal Mondal for the
HPLC analysis, Dr. P. R. Rajamohanan for the excellent NMR
support, and Dr. B. Santhakumari (all CSIR-NCL) for the
HRMS data.
We have also performed a preliminary study on the [1,2]
Stevens rearrangement. Treatment of N-benzyl aniline
derivative 8 with the aryne generated from 2a using KF in
C
DOI: 10.1021/acs.orglett.6b02809
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