Rhodium catalyzed direct arylation of α-diazoimines

Article abstract of DOI:10.1021/ol500874p

An efficient rhodium catalyzed direct arylation of α-diazoimines, generated from readily accessible 1,2,3-triazole, has been accomplished for the synthesis of 2,2-diaryl enamides. The reaction involves the chemo- and regioselective insertion of rhodium az

Full text of DOI:10.1021/ol500874p

Letter
pubs.acs.org/OrgLett
Rhodium Catalyzed Direct Arylation of α‑Diazoimines
Dongari Yadagiri and Pazhamalai Anbarasan*
Department of Chemistry, Indian Institute of Technology Madras, Chennai − 600036, India
S
* Supporting Information
ABSTRACT: An efficient rhodium catalyzed direct arylation
of α-diazoimines, generated from readily accessible 1,2,3-
triazole, has been accomplished for the synthesis of 2,2-diaryl
enamides. The reaction involves the chemo- and regioselective
insertion of rhodium azavinyl carbene into aromatic C(sp2)−H
bonds. Utility of the developed methodology was demon-
strated in the synthesis of indole and tetrahydroisoquinoline
frameworks.
ransition metal catalyzed insertion of carbenes into various
the groups of Rovis,9 Glorius,10 Cui,11 and Wang12 have
TC−H bonds is one of the most widely practiced methods in demonstrated the study of diazo compounds in the Rh-catalyzed
organic synthesis.1 These reactions generally show high
functionalization of various directing group assisted C−H bonds.
These reactions are majorly limited to C(sp2)−H bonds of
specific substrates, such as acidic heterocyclic or chelation
assisted C−H bonds. Thus, the generally direct intermolecular
insertion of transition metal carbenes into C−H bonds of simple
arenes is highly warranted.
selectivity for the intramolecular reaction with either a C(sp3)−
H or C(sp2)−H bond, for the formation of small membered
rings.2 But, the intermolecular reaction of transition metal
carbenes with C−H bonds is rather nonselective. Particularly, the
reaction of metal carbenes with arenes affords the cyclo-
heptatriene, well-known as the Buchner reaction,3 instead of
the possible C(sp2)−H insertion (Scheme 1a).4
Use of 1,2,3-triazole as a source of α-diazoimines, which is
difficult to access through traditional routes,13 and its
functionalization to various nitrogen-based building blocks and
heterocycles, has gained reasonable attention in recent years.14
Recently, we disclosed the Rh-catalyzed denitrogenative [2,3]-
sigmatropic rearrangement of azavinylcarbene derived from
1,2,3-triazole with allyl aryl(alkyl) sulfides.15 Based on our
interest in the C−H functionalization of arenes16 and unique
reactivity of 1,2,3-triazole, we herein reveal the new Rh-catalyzed
direct arylation of α-diazoimines generated from N-sulfonyl-
1,2,3-triazole with arenes (Scheme 1d).
Scheme 1. Transition Metal Catalyzed Reaction of Diazo
Compounds and Arenes
At the beginning of our studies, we examined the rhodium
acetate (2 mol %) catalyzed reaction of 1,2,3-triazoles (1 equiv)
1a with various arenes (4 equiv) in chloroform at 70 °C.
Although a number of arenes such as xylene, mesitylene, and
anisole did not show a promising result,17 N,N-diethylaniline 2a
gave a detectable amount of product (21% yield) along with the
hydrated product, α-aminoketone. Analysis of the isolated
product proved the formation of enamide 4aa18 as a mixture of
Z/E isomers in a 1.6:1 ratio, instead of expected imine 3, which
may also arise from imine 3 through imine−enamine
tautomerism (Scheme 2). The formation of product 4aa was
further confirmed through hydrogenation over Pd/C to amide,
where amide 5 was isolated in 94% yield as the sole product.
The synthesis of a similar enamide was reported by Fokin and
co-workers from 1,2,3-triazoles employing arylboronic acid, a
prefunctionalized arene, as a coupling partner (Scheme 1d),19
but the present reaction utilizes the simple arene as a coupling
Recently, Wang et al.5 disclosed the Cu-catalyzed insertion of
metal carbene generated from N-tosylhydrazones to the acidic
C−H of 1,3-azoles. A similar reaction was later demonstrated
employing either a Ni- or Co-based catalyst (Scheme 1b).6 Rh-
catalyzed directing group assisted activation of the ortho C−H
bond of arene followed by insertion of the diazo compound was
reported by Yu et al.7 and Li et al.8 (Scheme 1c). Subsequently,
Received: March 24, 2014
Published: April 11, 2014
© 2014 American Chemical Society
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conditions were chosen for studying the generality of the present
methodology: 1 equiv of 1,2,3-triazole 1a, 4 equiv of arene 2a, 2
mol % of Rh2(Oct)4, toluene, 100 °C, 1 h.
Scheme 2. Rh-Catalyzed Arylation of Triazole 1a with N,N-
Diethylaniline 2a
After identifying the optimized conditions, the generality of
the present method was investigated with functionally different
triazoles and arenes. As can be seen in Scheme 3, various
Scheme 3. Rh-Catalyzed Arylation of Triazoles 1 with 2a
partner and forms the enamide through C−H insertion.
Interestingly, excellent selectivity is observed for the function-
alization of para C−H bonds, which is not accessible through the
chelation assisted strategy, over possible other C−H bonds in
arenes and the known α-C(sp3)−H functionalization of
alkylamines.20
Encouraged by the result, various other critical parameters
were investigated to improve the yield of 4aa. As shown in Table
1, increasing the temperature to 90 °C as well as changing the
Table 1. Rh-Catalyzed Arylation of Triazole 1a with 2a:
a
Optimization
b
entry
Rh(II)-catalyst
solvent
temp (°C)
yield (%)
c
1
2
3
4
5
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(Oct)4
CHCl3
DCE
70
21
90
52
d
toluene
toluene
C6H5Cl
toluene
toluene
toluene
toluene
100
120
120
100
100
100
100
71 (70)
69
substituted triazoles were subjected under the Rh-catalyzed
arylation conditions with 2a to afford the enamides 4 as a mixture
of isomers in a variable ratio (see Supporting Information).
Changing the sulfonyl moiety of triazole to mesyl or
benzenesulfonyl gave the corresponding enamide 4ba and 4ca
in comparable yield. Alkyl (methyl, ethyl, tert-butyl) substituted
aryl containing triazole underwent smooth arylation to furnish
the enamides (4da−4ga) in good yield. Sterically hindered ortho
substituted enamides (4ha and 4na) were synthesized in
moderate to good yield. Interestingly, electron-rich anisyl
substituted triazole also afforded the enamide 4ia in 70% yield.
Synthetically useful halogen substituted aryl containing enamides
(4ja−4na) were also synthesized in good yield. In addition,
thiophene, a sulfur-containing heterocyclic substituted triazole,
also tolerated the optimized conditions and afforded the enamide
4oa in 72% yield. Tetrasubstituted enamide 4pa was achieved in
75% yield from the corresponding 4,5-disubstituted triazole and
2a.
46
e
6
45
7
8
9
70
Rh2(TBSP)4
Rh2(DOSP)4
34
49
a
Triazole 1a (0.17 mmol, 1 equiv), arene 2a (0.66 mmol, 4 equiv),
b
Rh(II)-catalyst (2 mol %), solvent (1 mL), temp, 1 h. Isolated yields,
Z/E ratio ∼1.6:1. 16 h. 1.7 mmol of 1a was used. 2 equiv of 2a.
c
d
e
solvent to 1,2-dichloroethane (DCE) showed a positive influence
on the outcome of reaction and 4aa was isolated in 52% yield in 1
h (Table 1, entry 2). A similar trend was observed with toluene at
100 °C, where the formation of 4aa was observed in 71% yield
(Table 1, entry 3). No arylated product derived from toluene was
observed. However, a further change in either the temperature or
solvent did not show any improvement (Table 1, entries 4 and
5). Screening other Rh-catalysts revealed Rh2(Oct)4 furnished
4aa in comparable yield (70%), but other bulky catalysts,
Rh2(TBSP)4 and Rh2(DOSP)4, gave 4aa in 34% and 49% yield,
respectively (Table 1, entries 7−9). Similarly, decreasing the
equivalents of arene to 2 decreased the yield of 4aa (Table 1,
entry 6).
The Rh-catalyzed arylation of vinyl substituted triazole 1q and
diethylaniline 2a under the optimized conditions furnished 6, as a
single product (Scheme 4). The formation of 6 can be explained
through the rearrangement of formed enamide to the
conjugatively more stable azadiene.
Increasing the scale of the reaction by 10-fold furnished 4aa in
70% yield, which is highly important in the synthetic application
(Table 1, entry 3). From the optimization studies, the following
Subsequently, the scope of arenes in the Rh-catalyzed arylation
of triazole 1a was examined (Scheme 5). Symmetrically
substituted aniline derivatives on reaction with 1a gave the
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Scheme 4. Rh-Catalyzed Arylation of Triazoles 1q with 2a
Scheme 6. Chemoselective Rh-Catalyzed Arylation of 1a
Scheme 5. Rh-Catalyzed Arylation of Triazole 1a with Arenes
2
Enamides are present as key subunits in various natural
products and pharmaceutically important molecules22 and are
vital intermediates in organic synthesis having diverse synthetic
utilities.23 With the ready accessibility of various enamides
established, next, the synthetic application was demonstrated
through the synthesis of a pharmaceutically important N-based
heterocyclic system such as 3-arylindole and 4-arylisoquinolines
(Scheme 7). 3-Arylindole 7 was achieved from the Cu-catalyzed
Scheme 7. Synthetic Utility of Enamide 4
C−N cross-coupling24 of the ortho brominated enamide 4na.
Consequently, hydrogenation of enamide 4aa over palladium on
carbon afforded the 2,2-diarylethylamide 5 in excellent yield.
Protection of NH as a MOM group followed by TMSOTf
mediated cyclization through an iminium ion furnished the 4-
arylisoquinoline 8 in 47% overall yield.
corresponding enamides 4ab, 4ac, and 4ad in 64%, 61%, and
51% yield, respectively. Unsymmetrically substituted nitrogen in
aniline also afforded the enamides 4ae and 4af in good yield.
Furthermore, meta-methyl and bromo substituted aniline
derivatives furnished the corresponding enamides 4ag and 4ah
in moderate to good yield. But, the ortho-substituted aniline
derivatives did not afford the expected enamides (4ai and 4aj).
Interestingly, the reaction of N-based heterocyclic arene (indole,
indoline, tetrahydroquinoline, and dibenzoazepine), which
contains the ortho-substitution in the fused form, with 1a giving
the corresponding enamides (4ak−4an) in good yield.
Furthermore, enamide 4ao was achieved from the arylation of
1a with a naphthalene derivative.
A plausible mechanism for the direct arylation of triazole 1
with arene 2 to enamide 4 is shown in Scheme 8. The catalytic
Scheme 8. Plausible Mechanism
After establishing the scope of the developed methodology,
the chemoselectivity of the Rh-catalyzed arylation reaction was
investigated employing allyl substituted aniline derivatives, which
is prone to other possible reactions such as cyclopropanation,
[2,3]-sigmatropic rearrangement, and α-C−H insertion reac-
tions. To our delight, the reaction of 1a under the Rh-catalyzed
arylation conditions with 2p and 2q selectively afforded the
C(sp2)−H inserted product, enamides 4ap and 4aq in excellent
yield, respectively (Scheme 6). The structure of 4aq was
unambiguously confirmed by X-ray analysis (see Supporting
Information).21 This demonstrates that the present method is
highly selective for the arene C−H insertion over other possible
reactions.
cycle starts with the formation of reactive rhodium carbenoid II
from α-diazoimine I with the extrusion of nitrogen, which in turn
is derived from triazole 1 via ring−chain isomerism. The
formation of product 4 from II with an arene can be realized by
two pathways. The concerted direct insertion of II into a C−H
bond of arene would lead to the formation of 3, which upon
tautomerization affords the enamide 4 (Path A). Alternatively,
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(5) Zhao, X.; Wu, G.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2011, 133,
3296.
(6) Yao, T.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed.
the addition of 2 to an electrophilic metal carbene center with the
assistance of a nitrogen lone pair would furnish the zwitterion III.
The direct formation of 4 from III can be achieved by loss of a
proton and rearomatization (Path B). Among them, path B can
be a preferable pathway: (1) formation of III is favored with
electron-rich arenes (aniline derivatives) over the neutral
(toluene) and moderately electron-rich arene (anisole deriva-
tive), and (2) since involvement of a nitrogen lone pair is
important to increase the nucleophilicity of the arene and
formation of III, electrophilic substitution occurs at the para
instead of the ortho position, and ortho-substituted (methyl and
iodo) aniline derivatives were not successful under the present
optimized conditions (Scheme 5). Similarly, attempts toward the
functionalization of an ortho C−H bond with para-substituted
N,N-diethyl-p-methylanilines were also unsuccessful. With the
plausible mechanism, the present method complements and
possesses an advantage over traditional acid mediated electro-
philic aromatic alkylation/acylation, where electron-rich aniline
derivatives are shown to be the least reactive.
In conclusion, we developed an efficient strategy for the direct
arylation of azavinyl carbenes, derived from 1,2,3-triazole with
various arenes. This strategy involves chemo- and regioselective
arene C(sp2)−H insertion and offers electronically and sterically
different substituted enamides, which are of high synthetic
importance. Furthermore, the utility of enamides was demon-
strated through the synthesis of N-based heterocycles, such as
indole and isoquinolines.
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ASSOCIATED CONTENT
* Supporting Information
Experimental methods, characterizations data, and H and 13C
■
S
1
NMR spectra of isolated compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: anbarasansp@iitm.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Department of Science and Technology (DST), New
Delhi for funding this work. D.Y. thanks IITM for an HTRA
fellowship. We thank Mr. Ramkumar (IIT Madras) for single
crystal analysis support.
(19) Selander, N.; Worrell, B. T.; Chuprakov, S.; Velaparthi, S.; Fokin,
V. V. J. Am. Chem. Soc. 2012, 134, 14670.
(20) For selected examples on α-C−H insertion of ethers and amines,
see: (a) Davies, H. M. L.; Beckwith, R. E. J.; Antoulinakis, E. G.; Jin, Q. J.
Org. Chem. 2003, 68, 6126. (b) Davies, H. M. L.; Hansen, T.; Churchill,
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M. n. V. A.; Aouad, E. Org. Lett. 2001, 3, 1475. (d) Davies, H. M. L.; Jin,
Q. Org. Lett. 2004, 6, 1769.
(21) CCDC 979169 (4aq) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via http://www.
ccdc.cam.ac.uk/data_request/cif.
(22) (a) Yet, L. Chem. Rev. 2003, 103, 4283. (b) Muller, K.; Sellmer, A.;
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(b) Carbery, D. R. Org. Biomol. Chem. 2008, 6, 3455.
(24) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2010, 1, 13.
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