Rhodium-catalyzed synthesis of 2,3-disubstituted indoles from β,β-Disubstituted stryryl azides

Article abstract of DOI:10.1002/anie.201006917

Rings la carte: Rhodium carboxylate complexes catalyze selective cascade reactions to produce a range 2,3-disubstituted indoles from β,β- disubstituted stryryl azides. The selective migration of aryl groups appears to originate from a putative phenonium ion reactive intermediate (see scheme).

Full text of DOI:10.1002/anie.201006917

Communications
DOI: 10.1002/anie.201006917
Heterocyclic Synthesis
Rhodium-Catalyzed Synthesis of 2,3-Disubstituted Indoles from
b,b-Disubstituted Stryryl Azides**
Ke Sun, Sheng Liu, Patryk M. Bec, and Tom G. Driver*
Transition metal-catalyzed migratorial processes that form
new carbon–carbon bonds can enable the formation of
complex products from readily accessible, simple starting
materials. Controlling the selectivity of the migration step is
critical to the success of these transformations.[1] Sequential
reaction processes that involve metal nitrenes are rare despite
their electrophilicity,[2] which enables reaction with carbon–
hydrogen bonds or olefins.[3–6] Our mechanistic study of
rhodium(II)-catalyzed carbazole formation from biaryl azides
disubstituted indoles—as single regioisomers—from readily
available b,b-disubstituted stryryl azides.
The effect of transition metal complexes on the desired
migration was investigated using a mixture of the E- and Z-
isomer of b,b-disubstituted aryl azide 8 (Table 1). This azide is
Table 1: Development of optimal conditions for indole formation.
À
À
which suggested that C N bond formation preceded C H
bond cleavage through a 4p-electron–5-atom electrocycliza-
tion.[7] Consequently, we anticipated that substrates lacking
[a]
À
functionalizable C H bonds might participate in a migratorial
Entry
LnMXm
T
[8C]
Yield
[%][b]
9:10[c]
À
process where a new C C bond is formed in addition to the
À
C N bond. In support of this hypothesis, rhodium octanoate
1
2
3
4
[Rh2(O2CCH3)4]
[Rh2(O2CC7H15)4]
[Rh2(esp)2]
[Rh2(O2CCF3)4]
[Rh2(O2CC3F7)4]
[Rh2(O2CC3F7)4]
[{(cod)Ir(OMe)}2]
[Co(tpp)]
70
70
70
70
70
70
70
80
65
70
65
65
8
–
96:4
98:2
99:1
100:0
100:0
–
–
–
–
–
–
catalyzed the conversion of b,b-diphenylstryryl azide 1 to 2,3-
93
98
86
95
80[e]
0
diphenylindole 3 (Scheme 1).[8] This result, however, does not
5
6[d]
7
8
0
9[f]
10
11
12
RuCl3·nH2O
Cu(OTf)2
trace
0
0
AgOTf
AuCl
0
[a] esp=a,a,a’,a’-tetramethyl-1,3-benzenedipropionate; cod=cyclooc-
tadiene; tpp=tetraphenylporphyrin. [b] Yield after Al2O3 chromatogra-
phy. [c] As determined by using 1H NMR spectroscopy. [d] 3 mol%
catalyst. [e] 10% aryl azide remained. [f] No molecular sieve added.
Scheme 1. Potential for selective 2,3-disubstituted indole formation.
indicate whether this process can be rendered selective for
styryl azides 4 that contain two different b-substituents to
form 2,3-disubstituted indoles. Because these N-heterocycles
are important pharmaceutical scaffolds,[9] new methods,
which streamline their synthesis, remain an ongoing
goal.[10,11] Herein, we report our initial studies that resulted
in the development of a general method to form 2,3-
readily accessible in two steps from commercially available 2-
nitrobenzaldehyde.[12] Examination of a range of dirhodi-
um(II) complexes revealed that selective formation of 9 was
obtained using with [Rh2(O2CC3F7)4],[8,13] [Rh2(O2CC7H15)4],
or [Rh2(esp)2][14] (Table 1, entries 1–7).[15] Importantly, both
the E- and Z-isomer of 8 were converted to indole 9 revealing
that the selectivity of the reaction did not depend on the
stereochemistry of the starting material. Other rhodium
carboxylate complexes provided attenuated selectivities or
reduced yields. Other transition metal complexes, such as
[(cod)Ir(OMe)2],[16] [Co(tpp)],[17] RuCl3,[18] or copper salts,[19]
known to decompose azides or p-Lewis acids,[20] did not
promote indole formation (Table 1, entries 8–13). Conse-
quently, the reaction conditions were further optimized using
rhodium hexaflourobutyrate, and incomplete conversions
were observed when either the catalyst loading or the
reaction temperature was lowered (< 5 mol%; < 708C). The
optimal solvent was found to be either toluene or dichloro-
ethane. Purification proved to be facile: analytically pure
[*] K. Sun, S. Liu, P. M. Bec, Prof. T. G. Driver
Department of Chemistry, University of Illinois at Chicago
845 W. Taylor St., Chicago (USA)
Fax: (+1)312-996-0431
E-mail: tgd@uic.edu
Homepage: http://www.chem.uic.edu/driver
[**] We are grateful to the National Institutes of Health NIGMS
(R01M984945) and the University of Illinois at Chicago for their
generous support. We also thank Prof. L. Anderson (UIC) for
insightful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201006917.
1702
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Angew. Chem. Int. Ed. 2011, 50, 1702 –1706

II
Table 3: Scope of Rh2 -catalyzed 2,3-disubstituted indole formation.
indole was obtained by filtering the reaction mixture through
a pipette of alumina.
Using these optimized conditions, the scope and limita-
tions of the rhodium(II)-catalyzed formation of 2,3-disubsti-
tuted indoles from b,b-disubstituted stryryl azides was exam-
ined (Table 2). In every example, only aryl group migration
Entry
1
14,
17
Styryl azide
Indole product
Yield
[%][a]
II
Table 2: Scope of Rh2 -catalyzed migratorial reactions.
a
b
88
78
Entry
11
R1
R2
R3
Yield
[%][a]
12:13[b]
2
1
2
3
a
b
c
d
e
f
MeO
H
H
H
H
H
H
H
H
MeO
Cl
MeO2C
F3C
MeO2S
H
H
H
H
H
H
H
Br
MeO2C
96
97
99
94
90
95
95
95
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
4[c]
5
3
4
c
92
94
6[d]
7
g
h
8[d]
H
[a] Yield after Al2O3 chromatography. [b] As determined by using 1H NMR
spectroscopy. [c] X-ray structure of product indole obtained. [d] 5 mol%
of [Rh2(esp)2] used.
d
5
6
e
f
91
93
was observed even if the electronic nature of the aryl azide
moiety was modulated. High yields were observed with
electron-donating substituents such as methoxide (Table 2,
entries 1 and 2). Electron-withdrawing groups also did not
lower the reaction yield or migration selectivity (Table 2,
entries 3–8). Among these, azides bearing potentially reactive
bromides, esters, or sulfones were competent substrates in our
process. The reaction was also not sensitive to the steric
nature around the azide: nearly quantitative yield of 12a was
observed with 11a, which contained two ortho-substituents.
Purification of every 2,3-disubstituted indole by simple
filtration through alumina further underscores the synthetic
utility of our reaction.
The nature of the migrating group on the aryl azide was
subsequently investigated (Table 3). For these substrates, only
aryl group migration was observed. While rhodium perfluor-
obutyrate was a competent catalyst, [Rh2(esp)2] provided the
highest yields of the reaction. Only indole 15a was observed
when the tether was shortened (Table 3, entry 1). Appending
the electron-withdrawing trifluoromethyl group or the elec-
tron-donating methoxy group to the migrating arene did not
change the outcome of the reaction (Table 3, entries 2 and 3).
In both cases, only aryl group migration was observed. High
yields and selective formation of indole 15d was obtained
when an oxygen atom was incorporated into the tether. The
reaction was not limited to ring expansion: despite changing
the electronic nature of the migrating aryl group, only indoles
15e and 15 f were formed from azides 14e and 14 f.
7
8
a
b
98
93
9
c
93
10
11
12
d
e
f
18[b,c]
quant.
quant.
The effect of ring size on the reaction efficiency was
further examined using styryl azides 17. For this series of
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Table 3: (Continued)
enhanced reactivity of azides with unsaturated ortho-sub-
stituents.
We performed several experiments to test the validity of
À
our mechanism. To examine whether N2 was lost before C N
bond formation, we performed an intermolecular competition
experiment between azides 11a and 8 (Scheme 3). Our
previous Hammett correlation study indicated that N2
extrusion occurred faster with electron-rich aryl azides.[7]
Acceleration of metallonitrene formation was attributed to
the ability of the electron-donating group to assist in N2 loss
(24 to 25). In contrast, if N2 loss occurred simultaneously with
13
14
g
h
88
97
À
C N bond formation, we anticipated that 8 would react faster
because the azide moiety was more electrophilic than in 11a.
To test these assertions, a 1:1 mixture of styryl azides 11a and
8 were exposed to reaction conditions. Despite the increased
steric pressure around the azide, the more electron-rich
substrate reacted faster to produce indole 12a as the major
product to support our proposed electrocyclization mecha-
nism.
[a] Yield after Al2O3 chromatography. [b] As determined by using 1H NMR
spectroscopy. [c] 35% remaining 17d. DCE=dichloroethane.
substrates, rhodium octanoate proved to be the most reliable
catalyst. While ring-expanded products were formed from 4-,
5-, and 6-membered substrates, poor conversion was observed
for 7-membered 17d (Table 3, entries 7–10). Varying the
electronic nature of the aryl azide did not attenuate the yield
of the reaction (Table 3, entries 11–13). Oxygen atoms were
tolerated in the tether without lowering the yield of the ring
expansion (Table 3, entry 14).
While many mechanisms are possible to explain the
reaction outcome, our data suggests that the migration occurs
once an intermediate (21) is generated with positive charge on
the benzylic carbon. We propose that this intermediate is
formed by the mechanism outlined in Scheme 2. Coordina-
If the migration mechanism involved the formation of a
partial positive charge on the a-carbon, we anticipated that
electron-rich aryl groups would migrate preferentially. To test
this hypothesis, a series of styryl azides, which systematically
varied the identity of the para-substituent R, were exposed to
reaction conditions (Figure 1). Examination of the product
Scheme 3. Intermolecular competition experiment.
Scheme 2. Potential mechanisms for indole formation.
tion of the rhodium carboxylate complex to the azide
produces either a-19 or g-19.[21] Extrusion of N2 from 19
forms rhodium nitrene 20,[22] which participates in a 4p-
electron–5-atom electrocyclization to establish the carbon–
nitrogen bond in 21.[7] Aryl migration forms the more stable
tertiary iminium ion 22, which tautermizes to produce 9.
Alternatively, the ortho-double bond could assist in N2
extrusion to form the intermediate 23, or this intermediate
could be formed from [2+1] cycloaddition of the pendant
double bond with the electrophilic metallonitrene 20. While
23 is strained,[23] its intermediacy would account for the
Figure 1. Correlation of product ratios with the Hammett equation.
y=À1.49x+0.17; R2 =0.98.
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In conclusion, we have demonstrated that rhodium
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stituted indoles. Our data suggests that the selectivity of the
migratorial process is controlled by the formation of a
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Received: November 4, 2010
Published online: January 14, 2011
Keywords: 1,2-shift · azides · indoles · nitrenes ·
.
rhodium complexes
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