Stereochemical aspects of the iodine(III)-mediated aziridination reaction of some cyclic allylic carbamates.

Article abstract of DOI:10.1021/ol0259490

[reaction: see text] The iodine(III)-mediated aziridination reaction of an indolyl-substituted carbamate requires a Rh(II) catalyst and proceeds by a metallonitrene intermediate. Stepwise addition across the indole pi-bond followed by Rh(II) detachment ge

Full text of DOI:10.1021/ol0259490

ORGANIC
LETTERS
2002
Vol. 4, No. 13
2137-2139
Stereochemical Aspects of the
Iodine(III)-Mediated Aziridination
Reaction of Some Cyclic Allylic
Carbamates
Albert Padwa* and Thomas Stengel
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
Received March 29, 2002
ABSTRACT
The iodine(III)-mediated aziridination reaction of an indolyl-substituted carbamate requires a Rh(II) catalyst and proceeds by a metallonitrene
intermediate. Stepwise addition across the indole π-bond followed by Rh(II) detachment generates a metal-free zwitterion, which ultimately
leads to the observed products. In contrast, intramolecular aziridination of several cycloalkenyl carbamates does not require a Rh(II) catalyst
and occurs via an iminoiodinane intermediate.
Vicinal amino alcohols are found in a substantial number of
bioactive compounds1 and are also utilized for asymmetric
synthesis2 and as ligands for transition metal catalyzed
processes.3 This functionality not only is of importance in
the chemistry of aminosugars, carbohydrates, and nucleo-
sides4 but also has varied applications in organic synthesis.5
Considering the enormous potential of the â-amino alcohol
moiety for chemistry, it is not surprising that numerous
synthetic routes have been reported.6 Cyclic carbamates,
readily available from cyclocarbamation of allylic or homo-
allylic amines and alcohols,7 have often been used as crucial
intermediates for highly stereoselective construction of both
1,2- and 1,3-amino alcohol structures. Another useful strategy
is the ring opening of aziridines with oxygen nucleophiles.8
Although the transition metal catalyzed oxygen9 and
carbon transfer10 to olefins is a highly developed process,
significantly fewer reagents and procedures are available for
the analogous nitrogen atom transfer.11 On the basis of our
(6) Williams, D. R.; Osterhout, M. H.; Reddy, J. P. Tetrahedron Lett.
1993, 34, 3271. Barrett, A. G. M.; Seefeld, M. A. J. Chem. Soc., Chem.
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S. C.; Stanchina, D. M. J. Org. Chem. 1997, 62, 4449. Bruncko, M.;
Schlingloff, G.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1997, 36,
1483. Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798.
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1982, 104, 6465. Georges, M.; Mackay, D.; Fraser-Reid, B. J. Am. Chem.
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Tetrahedron Lett. 1982, 23, 619.
(8) Evans, D. A.; Faul, M. M.; Bilodeau, M. T.; Anderson, B. A.; Barnes,
D. M. J. Am. Chem. Soc. 1993, 115, 5328. Davis, F. A.; Zhou, P.; Reddy,
G. V. J. Org. Chem. 1994, 59, 3243. Pirrung, M. C.; Nunn, D. S. Bioorg.
Med. Chem. Lett. 1992, 2, 1489. Dehmlow, H.; Mulzer, J.; Seilz, C.;
Strecker, A. R.; Kohlmann, A. Tetrahedron Lett. 1992, 33, 3607. Legters,
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VCH: New York, 1993; Chapter 4.2. Brandes, B. D.; Jacobsen, E. N.
Tetrahedron Lett. 1995, 36, 5123.
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D. J. Nat. Prod. Rep. 2000, 17, 7. Huff, J. R. J. Med. Chem. 1991, 34,
2305.
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Ghosh, A. K.; Fidanze, S.; Senanayake, C. H. Synthesis 1998, 937.
(3) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley-
Interscience: New York, 1994. Gomez, M.; Muller, G.; Rocamora, M.
Coord. Chem. ReV. 1999, 193-195, 769. Seyden-Pene, J. Chiral Auxiliaries
and Ligands in Asymmetric Synthesis; Wiley-Interscience: New York, 1995.
(4) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed. Engl.
1996, 35, 1380. Gijsen, H. J. M.; Qiao, L.; Fitz, W.; Wong, C. H. Chem.
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Soc. 1997, 119, 3179. Herold, P. HelV. Chim. Acta 1988, 71, 354.
10.1021/ol0259490 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/29/2002

long-standing involvement with metallo carbenoids derived
from R-diazocarbonyl compounds,12 we naturally became
interested in the chemistry of the corresponding acyl ni-
trenoids. Addition of a metallo nitrene to an olefin followed
by aziridine ring opening (Scheme 1) represents an attractive
approach to a variety of medicinally important vicinal amino
alcohols.13
conditions to indole 5 provided oxazolidinone 6 as a single
diastereomer in 85% yield (Scheme 3). The expected
Scheme 3
Scheme 1
Inspired by Du Bois’ recently discovered Rh(II)-directed
intramolecular nitrogen C-H insertion reaction of carbamates
to oxazolidinones,14 we wondered whether this procedure
could be used for delivery of a nitrogen atom to a tethered
π-bond. When we started our studies in this area, the transi-
tion metal catalyzed delivery of nitrogen from a carbamoyl
nitrene to an olefin had not been described in the literature.15
Our plan was to utilize an intramolecular primary carbamate
cyclization to provide for the directed aziridination reaction
shown in Scheme 2. Nucleophilic ring opening would
aziridine 7 was not observed. Rather, simultaneous spiro-
cyclization of C3 and stereoselective acylation at C2 occurred,
leading to compound 6. The stereochemical assignment of
6 was unequivocally established by an X-ray crystallographic
study. The stereochemical outcome of the reaction was totally
unexpected and certainly incompatible with an SN2 opening
of a transient aziridine intermediate (i.e., 7), since nucleo-
philic attack of an acetate group on the three-membered ring
would lead to an anti-configuration of the substituent
groups.18 The experimental observations suggest a close
interaction of the acetate moiety with the metal fragment,
thereby favoring formation of the oxazolidinone with the syn-
configuration of substituents. Without the addition of the
Rh(II) catalyst, only recovered starting material was obtained.
Interestingly, when the above reaction was carried out using
iodosobenzene (PhIdO) rather than PhI(OAc)2 as the
oxidant19 in the presence of 5 equiv of an added alcohol,
indolines 12, 13, and 14 were formed in 64%, 65%, and 50%
isolated yield as single diastereomers (Scheme 4).20 Again,
Scheme 2
(10) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds; John Wiley & Sons: New
York, 1997. Davies, H. M. L. Tetrahedron 1993, 49, 5203. Davies, H. M.
L. Curr. Org. Chem. 1998, 2, 463. Davies, H. M. L.; Panaro, S. A.
Tetrahedron 2000, 56, 4871.
(11) Jeong, J. U.; Tao, B.; Sagasser, I.; Henniges, H.; Sharpless, K. B.
J. Am. Chem. Soc. 1998, 120, 6844. Dauban, P.; Dodd, R. H. Tetrahedron
Lett. 2001, 42, 1037. Evans, D. A.; Faul, M. M.; Bilodeau, M. J. J. Am.
Chem. Soc. 1994, 116, 2742. Dauban, P.; Sanie`re, L.; Tarrade, A.; Dodd,
R. H. J. Am. Chem. Soc. 2001, 123, 7707. Mu¨ller, P. Transition Metal-
Catalyzed Nitrene Transfer. In AdVances in Catalytic Processes; Doyle,
M. P., Ed.; JAI Press: Greenwich, CT, 1997; Vol. 2, pp 113-151.
(12) Padwa, A.; Weingarten, M. D. Chem. ReV. 1996, 96, 223.
(13) So¨dergren, M. J.; Alonso, D. A.; Bedekar, A. V.; Andersson, P. G.
Tetrahedron Lett. 1997, 38, 6897. Dauban, P.; Dod, R. H. J. Org. Chem.
1999, 64, 5304.
(14) Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem.
Soc. 2001, 123, 6935. Espino, C. G.; Du Bois, J. Angew. Chem., Int. Ed.
2001, 40, 598.
(15) While this work was in progress, Rojas and co-workers have
described the amidoglycosylation of allal 3-carbamates using metallo acyl
nitrenoids; see: Levites-Agababa, E.; Menhaji, E.; Perlson, L. N.; Rojas,
C. M. Org. Lett. 2002, 4, 863.
generate oxazolidinone 3, which we intended to use for the
stereospecific preparation of a variety of 1,2-amino alcohol
derivatives (3 f 4). Herein we describe the iodine(III)-
mediated aziridination reaction of a carbamoyl nitrene16 with
an indole π-bond, as well as a detailed study of this reaction
with several other cyclic alkenes.
Our initial studies involved the protected indolyl carbamate
5, which was synthesized in three steps17 [tosylation (82%),
reduction (77%), and carbamoylation (71%)] starting from
indole-3-carboxaldehyde. In a recent report, Du Bois and
Espino described the use of iodobenzene diacetate [PhI-
(OAc)2], MgO, and catalytic Rh2(OAc)4 for acyl nitrenoid
generation from primary carbamates.14 Application of these
(16) For a recent report of a transition metal catalyzed reaction of an
alkenylcarbonyl azide, see: Bach, T.; Schlummer, B.; Harms, K. Chem.
Eur. J. 2001, 7, 2581.
(17) Kocovsky, P. Tetrahedron Lett. 1986, 27, 5521.
(18) Padwa, A.; Woolhouse, A. D. ComprehensiVe Heterocyclic Chem-
istry, Lwowski, W., Ed.; Pergamon: Oxford, 1983; Vol. 7, pp 47-93.
2138
Org. Lett., Vol. 4, No. 13, 2002

formed (ca. 80% yield) as expected for nucleophilic attack
at the three-membered ring. This stands in marked contrast
to the results encountered with indole carbamate 5 where
the reaction proceeded with complete syn-selectivity. A clue
to the differing behavior of these systems was gleaned when
it was noted that the reactions of 15 and 16 proceeded
smoothly in the absence of the Rh(II) catalyst. This would
suggest that the initially formed iminoiodinane 24 readily
reacts with the electron rich π-bond present in the cyclo-
alkene ring (Scheme 6). In the case of the indole system,
Scheme 4
Scheme 6
without the addition of the Rh(II) catalyst, only recovered
starting material was obtained. A reasonable mechanism that
accounts for the experimental findings involves initial
formation of an iminoiodinane intermediate (i.e., 8) followed
by catalyst (Rh(II))-promoted loss of iodobenzene to give
the metallonitrene 9 (Scheme 4).8 Stepwise addition across
the indole π-bond followed by Rh(II) detachment generates
the metal-free zwitterionic intermediate 11. Attack of the
neutral nucleophile will then occur on the side of the amide
anion because deprotonation of the nucleophile and nucleo-
philic attack on the N-sulfonyl iminium ion can occur
simultaneously to deliver indolines 12-14.
With the intention of exploring the scope, generality, and
synthetic opportunities of this metal-mediated nitrenoid
cyclization reaction, we extended our studies to include
several carbocyclic systems containing an allylic carbamate
subunit. When either of the two procedures used with the
indolyl system were applied to cycloalkenes 15 and 16,
tricyclic aziridines 17 and 18 were obtained in 71% and 75%
yield, respectively (Scheme 5). No ring-opened products were
however, addition of iminoiodinane 24 to the π-bond is much
slower, presumably as a result of its heteroaromatic character.
It’s only when 24 reacts with the Rh(II) catalyst that stepwise
addition to the indole π-bond occurs, eventually producing
acetate 6.
In summary, the iodine(III)-mediated aziridination reaction
of an indolyl substituted carbamate requires a Rh(II) catalyst
and proceeds in a stepwise manner via a metal-free zwitter-
ionic intermediate. In contrast, the intramolecular aziridina-
tion of several cycloalkenyl carbamates does not require a
Rh(II) catalyst and proceeds via an iminoiodinane intermedi-
ate. The full scope and limitations of this novel methodology
are currently under investigation.
Scheme 5
Acknowledgment. This research was supported by the
National Science Foundation (grant CHE-0132651). We
thank our colleague, Dr. Kenneth Hardcastle, for his as-
sistance with the X-ray crystallographic studies.
Supporting Information Available: Complete descrip-
tion of the synthesis and characterization of all compounds
prepared in this study and ORTEP drawings of compounds
6, 14, and 19. This material is available free of charge via
the Internet at http://pubs.acs.org.
observed with these systems. Although both aziridines were
stable to silica gel chromatography, they did undergo reaction
with various nucleophiles at room temperature in the
presence of either p-TsOH or LiClO4. In most cases the
addition of 1-5 equiv of the nucleophile was used. The
smooth and efficient reaction with aliphatic and aromatic
amines is potentially very useful since 1,2-diamines represent
an important subunit in many biological compounds.21
Notably, the ring-opened products (i.e., 19-23) were
completely anti-stereoselective;20 only the trans-isomers were
OL0259490
(19) Willgerodt, C. Chem. Ber. 1892, 25, 3494. White, R. E. Inorg. Chem.
1987, 26, 3916.
(20) The stereochemical assignment of 14 (and 19, vide infra) was
unequivocally established by X-ray crystallography.
(21) Reetz, M. T.; Jaeger, R.; Drewlies, R.; Hubel, M. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 103.
Org. Lett., Vol. 4, No. 13, 2002
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