Diastereo- and enantioselective copper-catalyzed intramolecular carboamination of alkenes for the synthesis of hexahydro-1 H-benz[f]indoles

Article abstract of DOI:10.1021/ol102233g

A new method for the enantioselective synthesis of hexahydro-1H-benz[f] indoles is described. This copper-catalyzed enantioselective intramolecular alkene carboamination process can install vicinal tertiary and quaternary carbon stereocenters with high levels of diastereo- and enantioselectivity. The C-C bond-forming component of the reaction constitutes a C-H functionalization and no electronic activation of the aryl ring that undergoes addition is required. A known 5-HT_1A receptor antagonist was synthesized efficiently using this method.

Full text of DOI:10.1021/ol102233g

ORGANIC
LETTERS
2010
Vol. 12, No. 21
4739-4741
Diastereo- and Enantioselective
Copper-Catalyzed Intramolecular
Carboamination of Alkenes for the
Synthesis of
Hexahydro-1H-benz[f]indoles
Lei Miao, Imranul Haque, Maria R. Manzoni,† Weng Siong Tham, and
Sherry R. Chemler*
Department of Chemistry, The UniVersity at Buffalo, The State UniVersity of New York,
Buffalo, New York 14260, United States
schemler@buffalo.edu
Received September 17, 2010
ABSTRACT
A new method for the enantioselective synthesis of hexahydro-1H-benz[f]indoles is described. This copper-catalyzed enantioselective
intramolecular alkene carboamination process can install vicinal tertiary and quaternary carbon stereocenters with high levels of diastereo-
and enantioselectivity. The C-C bond-forming component of the reaction constitutes a C-H functionalization and no electronic activation
of the aryl ring that undergoes addition is required. A known 5-HT1A receptor antagonist was synthesized efficiently using this method.
The intramolecular carboamination of alkenes is an attractive
method for the synthesis of nitrogen heterocycles.1 This
reaction has benefited particularly from methods involving
palladium, copper and gold catalysis.2,3 In recent years, the
catalytic asymmetric carboamination has been actively
pursued. One approach involves the doubly intramolecular
enantioselective carboamination wherein intramolecular alk-
ene amination is followed by addition of the resulting reactive
carbon intermediate to a π-bond tethered through the
N-substituent. In this manner, Pd(II)2c and Cu(II)3a complexes
have catalyzed formation of chiral bicyclic lactams and
sultams, respectively.
† Current address: US Food and Drug Administration (FDA).
(1) Reviews: (a) Wolfe, J. P. Eur. J. Org. Chem. 2007, 571. (b) Wolfe,
J. P. Synlett 2008, 2913. (c) Chemler, S. R. Org. Biomol. Chem. 2009, 7,
3009.
We desired to apply the copper-catalyzed carboamina-
tion reaction to the synthesis of other nitrogen heterocycles
and believed that the proposed carbon radical interme-
diate,3c for example, A (Scheme 1), could add to other
nearby π-bonds.
(2) Recent palladium-catalyzed carboaminations/carbonylations: (a)
Tsujihara, T.; Shinohara, T.; Takenaka, K.; Takizawa, S.; Onitsuka, K.;
Hatanaka, M.; Sasai, H. J. Org. Chem. 2009, 74, 9274. (b) Mai, D. N.;
Wolfe, J. P. J. Am. Chem. Soc. 2010, 132, 12157. (c) He, W.; Yip, K.-T.;
Zhu, N.-Y.; Yang, D. Org. Lett. 2009, 11, 5626. (d) Scarborough, C. C.;
Stahl, S. S. Org. Lett. 2006, 8, 3251. (e) Houlden, C. E.; Bailey, C. D.;
Ford, J. G.; Gagne, M. R.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. J. Am.
Chem. Soc. 2008, 130, 10066. (f) Scarborough, C. C.; Bergant, A.; Sazama,
G. T.; Guzei, I. A.; Spencer, L. C.; Stahl, S. S. Tetrahedron 2009, 65, 5084.
(g) Rosewall, C. F.; Sibbald, P. A.; Liskin, D. V.; Michael, F. E. J. Am.
Chem. Soc. 2009, 131, 9488. A gold-catalyzed carboamination: (h) Zhang,
(3) Copper-catalyzed carboaminations: (a) Zeng, W.; Chemler, S. R.
J. Am. Chem. Soc. 2007, 129, 12948. (b) Sherman, E. S.; Chemler, S. R.
AdV. Synth. Catal. 2009, 351, 467. Cu(II)-promoted carboaminations: (c)
Sherman, E. S.; Fuller, P. H.; Kasi, D.; Chemler, S. R. J. Org. Chem. 2007,
72, 3896. (d) Fuller, P. H.; Chemler, S. R. Org. Lett. 2007, 9, 5477.
G.; Cui, L.; Wang, Y.; Zhang, L. J. Am. Chem. Soc. 2010, 132, 1474
.
10.1021/ol102233g  2010 American Chemical Society
Published on Web 09/28/2010

Scheme 1. Benz[f]indole via Carboamination Sequence
This reaction could in principle be (1) chemoselective,
choosing radical addition either to an N-arylsulfonyl ring (as
previously reported)3a or an aromatic ring at the allylic
position (as in Scheme 1), (2) diastereoselective, choosing
between formation of either a cis or trans ring fusion, and
(3) enantioselective, catalyzed by a chiral copper(II)•ligand
complex. The desired carboamination product 2 constitutes
an otherwise difficult to access hexahydro-1H-benz[f]indole
ring system and contains vicinal quaternary and tertiary
carbon stereocenters. Some benz[f]indoles have demonstrated
biological activity as dopamine antagonists4 and as anticancer
agents.5 Surprisingly few methods for the synthesis of
hexahydro-1H-benz[f]indoles have been reported.
Our initial forays into the copper-promoted carboamination
of N-mesyl substrate 1a were promising. Using 300 mol %
of Cu(OAc)2, the cis-fused hexahydrobenz[f]indole 2a was
obtained in 64% yield with >20:1 diastereoselectivity
(Scheme 1).6 Encouraged by this result, we submitted 1a to
catalytic, enantioselective conditions.3a To our delight, we
obtained a 99% yield and 82% ee, with >20:1 diastereose-
lectivity using 20 mol % Cu(OTf)2, 25 mol % (R, R)-Ph-
box, 300 mol % MnO2 at 120 °C in PhCF3 for 24 h (Figure
1, 2a).
The trimethylsilylethylsulfonyl substrate 1b (R ) SES)
underwent the reaction with equal efficiency (Figure 1, 2b).
Various arylsulfonyl substrates 1c-1g (R ) Bs, Ts, PMBS,
PCBS, Ns) provided hexahydro-1H-benz[f]indole adducts
2c-2g with even higher enantioselectivity (94-97% ee) and
no trace of the sultam3a regioisomer. Substrates 1h-1j with
para aryl ring substitution (X ) F, SMe, OMe) provided uni-
formly high yields and enantioselectivities. The meta-MeO
substrate 3a gave the benz[f]indoles 4 as a 1.5:1 mixture of
ortho and para regioisomers (with respect to aryl addition).3c
Interestingly, substrates with ortho substitution, 5a and 5b,
gave regioisomers 6 and 7 where 7 is the result of a
rearrangement where an aryl substituent has apparently
shifted to the meta-position. This can be explained by a
mechanism involving ipso-addition3d,7 followed by 1,2-alkyl
shift (Scheme 2). A similar rearrangement occurred with the
p-CF3-substituted substrate 1k, which gave a 3:1 mixture of
products 2k and 8, the rearrangement product.
Figure 1.
Enantioselective carboamination scope. a20 mol %
Cu(OTf)2 and 25 mol % (R,R)-Ph-Box were combined in PhCF3
(0.1 M w/r to 1) and heated at 60 °C for 2 h in a pressure tube,
then 1, K2CO3 (100 mol %), MnO2 (300 mol %) were added and
the reaction was heated at 120 °C for 24 h. Yield refers to product
isolated from flash chromatography on SiO2. Enantioselectivity
b
(%ee) was determined by chiral HPLC. Reaction run at 110 °C.
cYield is for combined regioisomeric mixture, dr and %ee were
the same for both isomers. SES ) trimethylsilylethlysulfonyl, Bs
) benzenesulfonyl, PMBS ) 4-methoxybenzenesulfonyl, PCBS
) 4-chlorobenzenesulfonyl, Ns ) 4-nitrobenzenesulfonyl.
Upon the basis of these examples, it appears the propensity
to undergo ipso rather than direct ortho substitution may be
influenced by steric (in the case of ortho substituted) and
electronic (in the case of the 4-CF3 substituent) factors. No
regioisomers were observed in products 2a-j and direct
substitution without going through an ipso intermediate is
inferred for these compounds. Ortho substitution causes a
decrease in available ortho addition sites while the highly
electron-withdrawing 4-CF3 group may influence the relative
size of the orbital coefficients at the carbons that undergo
addition of the electron-rich primary radical.
(4) Lin, C.-H.; Haadsma-Svensson, S. R.; Phillips, G.; Lahti, R. A.;
McCall, R. B.; Piercey, M. F.; Schreur, P. J. K. D.; Von Voigtlander, P. F.;
Smith, M. W.; Chidester, C. G. J. Med. Chem. 1993, 36, 1069.
(5) Park, H. J.; Lee, H.-J.; Min, H.-Y.; Chung, H.-J.; Suh, M. E.; Park-
Choo, H.-Y.; Kim, C.; Kim, H. J.; Seo, E.-K.; Lee, S. K. Eur. J. Pharmacol.
2005, 527–31, and references therein.
(6) Manzoni, M. R. Ph.D. Thesis, The University at Buffalo, SUNY,
2006.
(7) Gonzales-Lopez de Turiso, F.; Curran, D. P. Org. Lett. 2005, 7, 151
.
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Org. Lett., Vol. 12, No. 21, 2010

Scheme 2
.
Addition and Rearrangement
Scheme 4. Diastereoselective Carboaminations
substituent in a pseudoequatorial position, rationalizes the
formation of the major diastereomers. The ortho-substituted
9b does not form products resulting from ipso substitution
and rearrangement. This is likely because the formation of
a trans-fused five-membered ring intermediate involved in
this ipso substitution is more difficult to form than the trans-
fused six-membered ring that would result from direct ortho
addition that leads to the observed product. In the case of 5,
a more favorable cis-fused spirocyclic intermediate (Scheme
2) can be formed.
Conversion of ortho-methoxy adduct 10b to the known
5-HT1A receptor antagonist4 11 was accomplished by removal
of the mesyl group with Red-Al followed by N-alkylation
(63%, two steps). Our synthesis of (()-11 is 8 steps from
γ-butyrolactone (24% overall yield) an improvement over
its previous synthesis.4
Transition state B and intermediate A can be used to
rationalize the enantio- and diastereoselectivity of the reaction
(Scheme 3). This model of enantioinduction is consistent with
Scheme 3. Transition State Model for Enantioselectivity
In conclusion, this intramolecular alkene carboamination
provides hexahydro-1H-benz[f]indoles in a concise and
enantioselective manner. New vicinal quaternary and tertiary
stereocenters can be formed in this reaction. The aromatic
rings that undergo addition do not require any specific
activating functionality and the C-C bond-forming step
constitutes a C-H functionalization.
our other copper-catalyzed reactions where the N-substituent
minimizes interaction with the closest bis(oxazoline)
substituent.3a,8 The diastereoselectivity arises from the carbon
radical of A adding to the aryl ring it is cis to. The structures
of 2a, 6a, 7a and 8 were assigned by X-ray crystallography.
The absolute and relative stereochemistry of the other adducts
in Table 2 were assigned by NOE and by analogy (see
Supporting Information).
We also explored the catalytic, diastereoselective car-
boamination reactions of the monobenzylated alkenyl sul-
fonamides 9 (Scheme 4). It was necessary to use the N-mesyl
derivatives of these substrates as the N-tosyl group competes
successfully for addition of the carbon radical intermediate
in these cases. The N-mesyl substrates 9a and 9b provided
the trans-fused carboamination products 10 as the major
diastereomers. Transition state C, which places the benzyl
Acknowledgment. We thank the National Institutes of
Health (NIGMS R01 078383) for support of this work and
William W. Brennessel and the X-ray Crystallographic
Facility at the University of Rochester for the X-ray structures
of 2a, 6a, 7a and 8 and Dr. Cara L. Nygren and Dr. Stephan
Scheins (SUNY-AB) for the X-ray structures of 10a and 10b.
No official support or endorsement of this article by the Food
and Drug Administration is intended or should be inferred.
Supporting Information Available: Full experimental
details. This material is available free of charge via the
Internet at http://pubs.acs.org.
(8) Fuller, P. H.; Kim, J.-W.; Chemler, S. R. J. Am. Chem. Soc. 2008,
130, 17638
.
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