Rhodium(II)-catalyzed enantioselective C-H functionalization of indoles

Article abstract of DOI:10.1021/ja1093309

A catalytic, enantioselective method for the C-H functionalization of indoles by diazo compounds has been achieved. With catalytic amounts of Rh ₂(S-NTTL)₄, the putative Rh-carbene intermediates from α-alkyl-α-diazoesters react with indoles at C(3) to provide α-alkyl-α-indolylacetates in high yield and enantioselectivity. From DFT calculations, a mechanism is proposed that involves a Rh-ylide intermediate with oxocarbenium character.

Full text of DOI:10.1021/ja1093309

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pubs.acs.org/JACS
Rhodium(II)-Catalyzed Enantioselective C-H Functionalization of
Indoles
Andrew DeAngelis, Valerie W. Shurtleff, Olga Dmitrenko, and Joseph M. Fox*
Brown Laboratories, Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States
S Supporting Information
b
tetrakis[N-phthaloyl-(S)-tert-leucinate] [Rh2(S-PTTL)4], a cat-
alyst first described by Hashimoto.8 We7a and Charette9 have
ABSTRACT: A catalytic, enantioselective method for the
C-H functionalization of indoles by diazo compounds has
been achieved. With catalytic amounts of Rh2(S-NTTL)4,
the putative Rh-carbene intermediates from R-alkyl-R-
diazoesters react with indoles at C(3) to provide R-alkyl-
R-indolylacetates in high yield and enantioselectivity. From
DFT calculations, a mechanism is proposed that involves a
Rh-ylide intermediate with oxocarbenium character.
independently observed that Rh2(S-PTTL)4 and several other
phthalimide-derived complexes crystallize in the “chiral crown”
conformation. This conformation, in which the four phthalimide
groups are projected on one face of the complex, has also been
recently observed in crystalline Cu2(S-PTTL)410 and dirhodium-
(II) tetrakis[N-(1,8-naphthaloyl)-(S)-tert-leucinate [Rh2-
(S-NTTL)4].10,11 Models for asymmetric induction based on chiral
crown conformations have been proposed7a,9 and debated,12 and
factors that create bias for the chiral crown configuration over
competing conformations have been discussed.7a,9,10 With
this foundation, we hypothesized that enantioselective reac-
tions between indoles and R-alkyl-R-diazoesters could be
catalyzed by Rh complexes proposed to adopt chiral crown
conformations.
We began our investigation with the reaction of 1,2-dimethy-
lindole with a 2-fold excess of ethyl 2-diazohexanoate (Table 1).
A variety of Rh complexes derived from tert-leucine were screened,
as were Rh2(S-DOSP)4 and Rh2(R-PTAD)4. While many of the
catalysts screened gave 1 with good enantioselectivity, it was
found that Rh2(S-NTTL)4 in toluene at -78 °C was optimal in
terms of both yield and enantioselectivity, as 1 was formed in
95% yield and 95% ee. In line with our previous observations,7
the use of low temperature was critical to the success of the
reaction: the analogous reaction at higher temperature (0 °C)
gave 1 in only 36% yield and 85% ee (entry 7).
With the optimized reaction conditions in hand, we then
explored the scope of this transformation, and the results are
summarized in Table 2. High yields (82-96%) and enantios-
electivities (79-99% ee) are obtained across a wide array of
substrates. Diazoesters bearing a variety of R-alkyl substituents,
covering the range of methyl, ethyl, butyl, and isopentyl, led to
functionalized indoles with high yield and enantioselectivity.
Diazoesters with primary R-alkyl substitutents gave higher en-
antioselectivity than ethyl R-diazopropionate (compare 9 and 10).
The transformation is successful for reactions of indoles with
a range of functionality, including fluoro-, bromo-, methoxy-,
siloxy-, Boc-protected aniline and ester functional groups. Methyl
(compounds 1, 2, 5, 8), benzyl (compounds 3, 4, 6, 7), and aryl
(compounds 9-15) groups on nitrogen were well tolerated,
while indole itself gave the product of N-H insertion in low
enantiomeric excess.13a An attempt to react ethyl R-diazo-5-
methylhexanoate with 1,3-dimethylindole was also unsuccessful:
only intramolecular β-elimination was observed.
ndoles are important structural motifs in a myriad of biologi-
cally interesting natural products and pharmaceutical targets.1
I
Accordingly, several methods have been developed for the
generation of highly functionalized indoles.2 Among these stra-
tegies is the selective functionalization by metal carbenes derived
from R-diazocarbonyl compounds,3 a reactivity pattern that has
been utilized in various total syntheses4 as well as selective
tryptophan modification in peptides and proteins.5 However,
the only catalytic enantioselective reaction of indoles and tran-
sient metal carbenes is Davies’s [3þ2] annulation of indoles with
styryldiazoacetates (eq 1).6 While indol-3-yl acetate derivatives
with stereogenic centers positioned R to C-3 have high medicinal
value,1e,1f only one example of an enantioselective C-H functio-
nalization reaction of an indole has been reported, and the ee was
<5%.6 Described herein is a general Rh-catalyzed method for
enantioselective C-H functionalization of indoles by carbenoids
derived from R-alkyl-R-diazoesters (eq 2).
During the course of our studies on the development of Rh-
catalyzed reactions of R-alkyl-R-diazoesters that are selective
over β-hydride elimination,7 we reported a method for enantio-
selective cyclopropanation of olefins.7a The most effective cata-
lyst for enantioselective cyclopropanation was dirhodium(II)
Received: October 16, 2010
Published: January 25, 2011
r
2011 American Chemical Society
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Table 1. Selected Enantioselective Indole Functionalization
Optimization Experimentsa
Table 2. Scope of the Reactionc
entry
solvent
catalyst
yield (%)b
ee (%)c
1
PhMe
PhMe
PhMe
PhMe
PhMe
CH2Cl2
PhMe
Rh2(S-PTTL)4
Rh2(S-TCPTTL)4
Rh2(S-NTTL)4
Rh2(R-PTAD)4
Rh2(S-DOSP)4
Rh2(S-NTTL)4
Rh2(S-NTTL)4
73
20
95
54
24
56
36
85
76
2
3
4
95
-91
20
5
6
7d
92
85
a Conditions: indole (0.2 M), Rh-cat (0.5 mol %) at -78 °C, R-
diazoester (0.67 M) added via syringe pump. b Isolated yield.
c Determined by chiral HPLC analysis. d Reaction run at 0 °C.
Optimal conditions in bold.
The nucleophilicity of the nitrogen atom plays a critical role.
While the reaction is successful for N-aryl or N-alkyl indole
derivatives, substituting strongly electron-withdrawing groups
on nitrogen (e.g., acetyl or Boc) completely shut down the
intermolecular reaction, and only the products of β-hydride
elimination of the carbenoid were observed. The reaction was
also highly sensitive to steric bulk at the indole C(2) position.
High yields and enantioselectivities were obtained when R2 was
small (R2 = H, Me); the highest enantioselectivities were gen-
erally observed when R2 = Me. Experiments with larger R2
substituents (Et, n-Bu, CF3, Ph, I) were unsuccessful. However,
indoles with N-to-C(2) ring fusion were excellent substrates, and
compounds 16 and 17 were obtained in good yield and high
enantioselectivity13b (Scheme 1).
a 5 equiv of diazoester was used. b Contained <5% of the product of
alkene cyclopropanation. c All yields and ee’s refer to the average of
two runs.
Scheme 1. Reactions of Fused Indoles
Previous mechanistic proposals for the indole C-H func-
tionalization reaction include a cyclopropanation/fragmentation
pathway3b,3c or an ylide formation/proton-transfer pathway.3d,3e,6
To rule out the former pathway, we carried out the reaction
between indole 18 and ethyl R-diazohexanoate in the presence of
racemic 19 and 20. Compounds 19 and 20 were prepared as an
inseparable 1:1 mixture from the Rh2(Piv)4-catalyzed reaction
between 1-phenylindole and ethyl R-diazo-5-methylhexanoate. In
the event, Rh2(S-NTTL)4 catalyzed the formation of 8 in 89%
yield and 84% ee, and compounds 19 and 20 were isolated in a 1:1
ratio with 97% mass recovery (Scheme 2). That cyclopropane 20
did not rearrange under the reaction conditions provides evidence
against the cyclopropanation/fragmentation mechanism.
2-methylindole and Et(EtO2C)CdRh2(O2CH)4 using the
B3LYP method with two basis sets: lanl2dz for Rh and 6-311þG-
(d,p) for other atoms. A lanl2dz effective core potential was
utilized. The calculations support the mechanism shown in
To investigate the plausibility of a mechanism that involves a
Rh-ylide, calculations were carried out for the reaction between
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Figure 2. (a) X-ray crystal structure of Rh2(S-NTTL)4. (b) Asymmetric
induction may be explained by approach of the indole to the si-face of the
Rh-carbene, with subsequent aromatization and stereoretentive pro-
tonation. (c) Alternatively, asymmetric induction may occur via dynamic
kinetic resolution, provided that equilibrium between diastereomeric
Rh-enolates G and G0 is fast relative to the rate of protonation.
synchronous. Thus, the C-C distance (2.457 Å, labeled a in
Scheme 2b) in D is considerably shorter than the C-O bond
distance (2.815 Å, labeled b in Figure 1b) in transition state D. By
contrast, the corresponding distances in ylide E (Scheme 2c) are
1.542 and 1.501 Å, respectively.
In transition state D, the C-1 methyl group projects toward
one of the formate ligands (3.299 Å separation, labeled c in
Figure 1b), whereas the nitrogen substituent projects away from
the Rh-carboxylate core. Thus, this model is consistent with the
observed sensitivity toward steric effects for substitution at C(2)
but tolerance of a broad range of substitution on the indole
nitrogen. IRC analysis indicates that transition state D leads to
ylide E, the structure of which is shown in Figure 1c.
Figure 1. (a) Proposed mechanism. (b) Calculated transition state (D)
for the reaction between 2-methylindole and Et(EtO2C)CdRh2-
(O2CH)4. (c) Calculated structure of ylide E.
Scheme 2. Evidence against a Cyclopropanation/Fragmen-
tation Mechanism
Computation was also used to consider the formation of an
ylide intermediate via an electrophilic aromatic substitution-type
mechanism. A transition state that does not possess oxocarbe-
nium character was also located (see Supporting Information)
and was found to be higher in energy than D by ΔΔE(ZPE)q =
1.8 kcal/mol. In this higher energy transition state, the benzene
ring of the indole is positioned above the ester functionality.
In our prior work on asymmetric cyclopropanation, we pro-
posed that alignment of the carbenoid in the chiral crown
cavity of Rh2(S-PTTL)4 leaves the si-face of the carbenoid more
accessible for reactivity.7a Rh2(S-NTTL)4 also has a crown
structure10,11 (Figure 2a), and it is possible that a similar model
for asymmetric induction may be in operation for the formation
of ylide E (Figure 2b); aromatization and stereoretentive pro-
tonation of the C-Rh bond would then provide the indole
product F. We consider that the conversion of E to F is stepwise,
as computations suggest that an intramolecular 1,2-hydride shift
for the conversion of E to F is not plausible (ΔE(ZPE)q = 30.2
kcal/mol) at -78 °C. An alternative possibility is that asymmetry
is induced via dynamic kinetic resolution of intermediate
Rh-enolates (e.g., G and G0 in Figure 2c) that are not config-
urationally stable.15 In this scenario, the enantio-determining
step would involve a dynamic equilibrium between G and G0 that
is faster than the rate of protonation (Figure 2c).
Figure 1a, in which the intermediate ylide E is a stabilized
oxocarbenium ion formed via transition state D. Relative to a
pre-reaction complex between the carbene and indole, transition
state D has a barrier of ΔE(ZPE)q = 8.8 kcal/mol (Figure 1b),
and the formation of ylide E is exothermic by E(ZPE) = 16.0
kcal/mol. Transition state D is formed by end-on approach14 of
the indole to the carbene, with only a minor change in the
Rh-Rh bond length in D (2.498 Å) relative to the carbene
(2.490 Å). While both C-C and C-O bonds are formed in this
process, the advancement of these bond formations is not
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To conclude, we have developed an enantioselective, Rh2(S-
NTTL)4-catalyzed method for C-H functionalization of indoles
by R-alkyl-R-diazoesters. From DFT calculations, a mechanism
is proposed that involves a Rh-ylide intermediate with oxocar-
benium character. Asymmetric induction may be explained by
approach of the indole to the si-face of the Rh-carbene, with
subsequent aromatization and stereoretentive protonation. Al-
ternatively, asymmetric induction may occur via dynamic kinetic
resolution of a rhodium enolate intermediate. Efforts to distin-
guish these mechanisms are ongoing.
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Chem. Soc. 2009, 131, 7230. (b) DeAngelis, A.; Taylor, M. T.; Fox, J. M.
J. Am. Chem. Soc. 2009, 131, 1101. (c) Panne, P.; DeAngelis, A.; Fox,
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’ ASSOCIATED CONTENT
1
S
Supporting Information. Full experimental details, H
b
and 13C NMR spectra, stereochemical assignments, computa-
tional details, complete ref 1f, and crystallographic (CIF) data.
This material is available free of charge via the Internet at http://
pubs.acs.org.
(13) (a) Known substrate limitations: indole with ethyl R-diazobu-
tanoate gave the product of N-H insertion in 29% yield and <1% ee;
6-(hydroxymethyl)-N-methylindole with ethyl R-diazo-5-methylhex-
anoate gave the product of O-H insertion in 41% yield and <1% ee;
1,2-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole
with ethyl R-diazo-5-methylhexanoate gave the desired C-H functio-
nalization product in 81% yield, but only 13% ee; 5-nitro-1,2-dimethy-
lindole with ethyl R-diazobutanoate did not give any intermolecular
products. (b) For the preparation of 16 and 17, it was important to use
only 1 equiv of diazoester. Enantioselectivity was lower and difficult to
reproduce when 2 equiv of diazoester was used. Azine side products7c
were formed when excess amounts of diazoesters were employed. We
believe that the azine acts as a base that epimerizes 16 and 17.
(14) Nowlan, D. T.; Gregg, T. M.; Davies, H. M. L.; Singleton, D. A.
J. Am. Chem. Soc. 2003, 125, 15902.
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Chem. Commun. 2004, 1984. (b) Frost, C. G.; Penrose, S. D.; Lambshead,
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Chem. Soc. 2006, 128, 2556. For a review, see: (e) Mohr, J. T.; Hong,
A. Y.; Stoltz, B. M. Nature Chem. 2009, 1, 359.
’ AUTHOR INFORMATION
Corresponding Author
jmfox@udel.edu
’ ACKNOWLEDGMENT
For financial support we thank NIGMS (NIH R01 GM068650).
NMR spectra were obtained with instrumentation supported by
NSF CRIF:MU, CHE 0840401. We thank Glenn Yap for X-ray
crystallography.
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