Arylation of rhodium(II) azavinyl carbenes with boronic acids

Article abstract of DOI:10.1021/ja3062453

A highly efficient and stereoselective arylation of in situ-generated azavinyl carbenes affording 2,2-diaryl enamines at ambient temperatures has been developed. These transition-metal carbenes are directly produced from readily available and stable 1-sulfonyl-1,2,3-triazoles in the presence of a rhodium carboxylate catalyst. In several cases, the enamines generated in this reaction can be cyclized into substituted indoles employing copper catalysis.

Full text of DOI:10.1021/ja3062453

Communication
pubs.acs.org/JACS
Arylation of Rhodium(II) Azavinyl Carbenes with Boronic Acids
Nicklas Selander, Brady T. Worrell, Stepan Chuprakov, Subash Velaparthi, and Valery V. Fokin*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
S
* Supporting Information
We recently demonstrated that readily available 1-sulfonyl-
ABSTRACT: A highly efficient and stereoselective
arylation of in situ-generated azavinyl carbenes affording
2,2-diaryl enamines at ambient temperatures has been
developed. These transition-metal carbenes are directly
produced from readily available and stable 1-sulfonyl-1,2,3-
triazoles in the presence of a rhodium carboxylate catalyst.
In several cases, the enamines generated in this reaction
can be cyclized into substituted indoles employing copper
catalysis.
1,2,3-triazoles 1 can serve as direct precursors to rhodium(II)
azavinyl carbenes 2.9 These structurally unique carbenes share
many similarities to the well-studied diazoester derivatives;
however, the ready availability and stability of the triazoles
allows for simple experimental setup and handling. Following
our recent success with the Rh(II)-catalyzed transformations of
1, we attempted a rhodium-catalyzed arylation utilizing
organoboronic acids. We hypothesized that the pendant
nitrogen lone pair of the sulfonyl imine of azavinyl carbene 2
could participate in the formation of a boronate complex;
subsequent transfer of the nucleophilic organic group could
then afford the arylated product. To this end, we examined the
reaction of phenylboronic acid 4a and triazole 1a in the
presence of a 0.5 mol % loading of various Rh(II) catalysts and
CaCl2 as an additive (Table 1). We were pleased to find that
arylated enamine 3a was formed at room temperature as the
single product.
tilization of diazo compounds as versatile reactive species
U
has become a cornerstone in modern organic synthesis.1
In particular, the diverse reactivity of rhodium carbene
complexes derived from diazo compounds has gained
considerable attention.2 Despite the multitude of reactions
developed for rhodium carbenes, there are only a few examples
of their direct arylation, which are limited to intramolecular
processes.3 The Wang4a and Barluenga4b groups recently
reported that diazo compounds (either directly or generated
in situ from tosylhydrazones)5 react with arylboron nucleo-
philes in the absence of a transition-metal catalyst (eq 1).
a
Table 1. Catalyst Optimization for the Arylation of 1a
b
entry
catalyst
yield (%)
1
2
3
4
5
Rh2(oct)4
<5
69
50
85
75
Rh2(piv)4
Rh2(esp)2
Rh2(S-PTAD)4
Rh2(S-NTTL)4
a
Performed on a 0.30 mmol scale using 0.5 mol % Rh catalyst and 1.0
equiv of 4a in 1.0 mL of CHCl3. Since previous studies identified
CHCl3 as the optimum solvent for the generation of Rh(II) azavinyl
b
carbenes, no solvent optimization was performed. Determined by
LC/MS using p-tolyl acetamide as an internal standard.
Furthermore, related arylation reactions of diazo compounds
via migratory carbene insertion6 into Pd−aryl intermediates
have been described (eq 2).7 Herein we report a stereoselective
Rh(II)-catalyzed reaction of arylboronic acids with azavinyl
carbenes derived from 1-sulfonyl-1,2,3-triazoles 1 that provides
access to a variety of functional enamine products 3 (eq 3).
It is known that certain 1,2,3-triazoles can undergo ring−
chain tautomerization in solution to form the corresponding
diazo imines.8,9f Initially we attempted to capture the diazo
tautomer of 1 by reaction with phenylboronic acid, effectively
mimicking the Barluenga and Wang reaction (eq 1). However,
no reaction was observed, even under forcing conditions. We
attribute the failure of this transformation to a low
concentration of the putative diazo tautomer in solution.
Although most of the rhodium(II) carboxylate complexes
were effective for the arylation of 1a, Rh2(S-PTAD)4 was
10
found to be the optimal catalyst (85% yield of 3a; Table 1,
entry 4). During optimization of the reaction conditions we
discovered that CaCl2 is an essential additive for the success of
this transformation.11 A short desiccation period (30 min) was
found to be necessary for the formation of an arylboroxine
trimer, (ArBO)3, which is likely the active arylating species (see
below). Moreover, in the absence of CaCl2, we observed the
Received: June 26, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja3062453 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Table 2. Substrate Scope of the Rh(II)-Catalyzed Formation of Substituted Enamines
a
General reaction conditions: 1 (1.0 equiv, 0.50 mmol), 4 (1.1 equiv, 0.55 mmol), and CaCl2 (4.0 equiv, 2.0 mmol) in 2.0 mL of dry CHCl3 at 75 °C
for 30 min, then Rh2(S-PTAD)4 (0.5 mol %) in 0.5 mL of dry CHCl3 at rt for 1−36 h. Values in parentheses are isolated yields. Enamines 3 were
1
isolated in ≥10:1 isomeric purity (by H NMR) unless otherwise stated. For the majority of the substrates used, the reaction reached completion
b
c
within 4 h; however, some exceptions were noted (3c, 3p, 3r, and 3s; see the SI for details). CaCl2 was not used. With p-fluorophenylboroxine.
significant formation of side products12 and catalyst deactiva-
tion.
containing (3k and 3m) boronic acids worked effectively (72−
94% yield) for the construction of diversely functionalized 2,2-
diaryl enamines. Although ortho-substituted arylboronic acids
underwent this arylation process, the reactions were sluggish
and led to low conversions. Furthermore, employing triazoles 1
bearing different aryl groups at the C4 position furnished the
corresponding enamine products 3n−s in high yields. Both
electron-donating (3n and 3o) and electron-withdrawing (3p−
s) substituents were tolerated in the arylation reaction with a
series of substituted arylboronic acids (Table 2).
With the optimized conditions in hand, we examined the
scope of this new reaction with respect to variously substituted
1-sulfonyl-1,2,3-triazoles 1 and arylboronic acids 4, leading to
enamine products 3 (Table 2). Variation of the 1-sulfonyl
group at N1 of triazole 1 did not affect the efficiency of the
reaction. Accordingly, both aliphatic (3a and 3f) and aromatic
(3b−e) sulfonyl groups were tolerated in the reaction with
phenylboronic acid (85−97% yield).
The reaction of 1-mesyl-4-phenyl-1,2,3-triazole 1a with
substituted arylboronic acids 4 to produce unsymmetrical 2,2-
diaryl enamines 3 raised the question of the stereoselectivity of
the process. To our delight, we found that the enamine
products 3g−m were obtained in high isomeric purity,
indicating a highly stereoselective arylation reaction. The
geometry of the double bond was assigned by performing a
single-crystal X-ray analysis of enamine 3g (Figure 1).13
As shown in Table 2, sterically encumbered (3g), electron-
deficient (3h, 3j, and 3l), electron-rich (3i), and halogen-
Although this arylation reaction proceeded with high
stereoselectivity, we noted that in several cases (cf. Table 2)
mixtures of isomers were obtained upon isolation (9:1 to 5:1 by
NMR). The apparent reduction of stereoselectivity likely arose
from facile tautomerization of an initial syn product. Rapid
isolation of the products was required in order to obtain
enamines of high isomeric purity [see the Supporting
Information (SI)].
Enamines are endowed with a wealth of reactivity and can
serve as versatile precursors for the construction of heterocyclic
frameworks.14 Accordingly, we envisioned that the 2,2-diaryl
enamine products 3 could be employed in the synthesis of aryl-
substituted indoles via metal-catalyzed cyclization. To this end,
we subjected triazole 1b to the Rh-catalyzed arylation with a
series of arylboronic acids, followed by a Cu(I)-catalyzed
intramolecular N-arylation of the enamine intermediate (Table
3).
Gratifyingly, triazole 1b underwent the Rh(II)-catalyzed
arylation reaction efficiently, although an increased temperature
(50 °C), extended reaction time (12 h), and higher catalyst
loading (1.0 mol %) were required. After filtration, the derived
enamine products agreeably cyclized into the anticipated N-
sulfonyl-3-arylindoles 5 when the copper(I)-catalyzed con-
ditions developed by Buchwald and co-workers15 were
employed (Table 3). This cyclization requires a syn orientation
Figure 1. Crystal structure of enamine 3g.
B
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Journal of the American Chemical Society
Communication
sulfonylimine nitrogen in 2 reversibly coordinates to the empty
2pz orbital of the boron atom,16 forming complex 6. The active
arylation species is believed to be a trimeric arylboroxine
complex since compounds 3a, 3m, and 5b were obtained from
commercially available arylboroxines without the use of CaCl2.
The stereochemical outcome of this reaction is likely dictated
by the irreversible facial-selective delivery of the aryl group
from intermediate 6 to obtain 7. Finally, dissociation of
rhodium and subsequent protonolysis affords the enamine
product 3. The alternative, a concerted arylation mechanism
that also accounts for the observed stereochemical outcome,
cannot currently be ruled out.
Table 3. Synthesis of 3-Arylindoles via an Arylation/
Cyclization Sequence
a
The mild, efficient, and stereoselective Rh(II)-catalyzed
arylation of 1-sulfonyl-1,2,3-triazoles described here provides
convenient access to 2,2-diaryl enamines. This sequence of two
reliable steps (synthesis of 1-sulfonyl-1,2,3-triazoles followed by
their arylation with boronic acids) in effect carboaminates
alkynes regio- and stereoselectively, introducing two functional
groups into the acetylenic backbone. The synthetic utility of the
enamine products was demonstrated by using a copper-
catalyzed cyclization to form a range of 3-arylindoles. Further
studies of the scope and mechanism of this reaction are
underway in our laboratory and will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterization data, NMR spectra,
and crystallographic data (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
■
a
S
General reaction conditions: 1b (1.0 equiv, 0.50 mmol), 4 (1.1 equiv,
0.55 mmol), and CaCl2 (4.0 equiv, 2.0 mmol) in 2.0 mL of dry CHCl3
at 75 °C for 30 min, then Rh2(S-PTAD)4 (1.0 mol %) in 0.5 mL of dry
CHCl3, followed by CuI (5.0 mol %), N,N′-dimethylethylenediamine
(10 mol %), and K3PO4 (2.0 equiv, 1.0 mmol) in 2.0 mL of dry
toluene at 75 °C for 1 h. Values in parentheses are isolated yields from
AUTHOR INFORMATION
Corresponding Author
fokin@scripps.edu
b
■
1b. CaCl2 was not used; with p-fluorophenylboroxine.
of the o-bromophenyl substituent and the N-sulfonyl amino
group, which was readily achieved by a rapid isomerization of
the enamine double bond (see above). As demonstrated in
Table 3, several arylboronic acids 4 were tolerated in this two-
pot synthetic sequence. Thus, halogen-containing indoles 5b
and 5d, acetyl derivative 5e, and heteroaryl-substituted indole
5h were obtained in good yields.
A plausible mechanism for this novel Rh(II)-catalyzed
arylation reaction is shown in Figure 2. The ring−chain
tautomerization of triazole 1 delivers diazoimine 1′, which then
reacts with the rhodium carboxylate catalyst to form azavinyl
carbene complex 2. We propose that the lone pair of the
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
(CHE-0848982) and the National Institute of General Medical
Sciences, National Institutes of Health (GM-087620). N.S. also
acknowledges a postdoctoral fellowship from the Swedish
Research Council (VR). We also acknowledge Prof. A.
Rheingold and Dr. C. Moore for X-ray crystallographic
assistance.
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D
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