A Rh-catalyzed C-H insertion reaction for the oxidative conversion of carbamates to oxazolidinones

Article abstract of DOI:10.1002/1521-3773(20010202)40:3<598::AID-ANIE598>3.0.CO;2-9

Selective intramolecular alkane oxidations: an Rh^II carboxylate catalyzed C-H amination reaction facilitates the preparation of 1,2-amino alcohols from primary carbamates. The reaction is stereospecific, providing access to chiral α-branched amines from optically pure starting with no loss in enantiomeric excess (see scheme).

Full text of DOI:10.1002/1521-3773(20010202)40:3<598::AID-ANIE598>3.0.CO;2-9

COMMUNICATIONS
The crystalline indanol derivative 2 used for our initial studies
was afforded easily upon treatment of alcohol 1 with
CCl3C(O)NCO followed by K2CO3/MeOH (Scheme 1).[11]
A Rh-Catalyzed C H Insertion Reaction for
the Oxidative Conversion of Carbamates to
Oxazolidinones**
Christine G. Espino and J. Du Bois*
O
HN
b
Vicinal amino alcohols are common structural units in both
naturally occurring molecules and pharmaceutical agents.[1]
These groups also appear as auxiliaries in asymmetric syn-
thesis and in ligands for metal catalysts.[2, 3] The large and
varied number of applications for b-hydroxy amines in
synthetic, medicinal, materials, and coordination chemistry
has fueled interest in the development of methods for their
construction.[2a, 4] We have found a unique, metal-catalyzed
C H insertion process that makes possible the preparation of
such compounds from readily available carbamate starting
materials [Eq. (1)]. This methodology utilizes catalytic quan-
O
OR
3
1: R = H
a
2: R = CONH2
86% yield
Scheme 1. a) CCl3C(O)NCO; K2CO3/MeOH; b) 5 mol% [Rh2(OAc)4],
PhI(OAc)2, MgO, CH2Cl2, 408C, 12 hr.
Control experiments indicate that 2 does not react with
PhI(OAc)2 after >10 hr at 408C.[12] We were pleased to find,
however, that a stirred suspension of 2, PhI(OAc)2, and
5 mol% [Rh2(OAc)4] at 258C produced ꢀ15% of the desired
oxazolidinone 3. Analysis of the unpurified reaction mixture
by 1HNMR spectroscopy indicated that the sample comprised
mostly starting material 2. Subsequent studies demonstrated
that the conversion of 2 into 3 could be improved slightly by
warming the mixture of reactants to 408C, an observation that
intimated a possible problem with slow catalyst turnover.
Following a series of control experiments, we concluded that
AcOH, generated as a by-product from PhI(OAc)2, reduced
the catalytic activity of [Rh2(OAc)4]. The need to scavenge
AcOH from the reaction mixture prompted the screening of
K2CO3, Na2HPO4, 2,6-di-tert-butyl-4-methylpyridine, BaO,
and MgO as base additives. Of these reagents, MgO proved
uniquely effective and, in addition, was the most desirable
from a cost and convenience standpoint. Thus, the reaction of
2 performs optimally when a CH2Cl2 suspension containing
PhI(OAc)2 (1.4 equivalents), 5 mol% [Rh2(OAc)4], and MgO
(2.3 equivalents) is stirred for 12 hr at 408C (Scheme 1).[13]
Reactions conducted under these conditions on scales
>1.5 mmol furnish the product oxazolidinone 3 as analytically
pure material in 86% yield.
Extension of this method to other carbamate starting
materials illustrates the potential value of this C H oxidation
reaction (Table 1). Substrates containing both benzylic and
tertiary C H centers are cyclized to oxazolidinone products in
yields of 74 ± 84% (entries 1 ± 5). [Rh2(OAc)4] can be used as
the catalyst with a number of these starting materials; in some
cases, however, the readily prepared triphenylacetate (tpa)
complex, [Rh2(tpa)4],[14] is a more effective promoter at a
5 mol% loading. The enhanced performance of [Rh2(tpa)4] is
ascribed to its greater resistance towards oxidation under the
reaction conditions. As evident in entry 6, cyclization of less
reactive substrates such as n-butylcarbamate requires use of
this more robust catalyst.[15] By contrast, carbamates derived
from tertiary cycloalkanols with unactivated CH2 centers
(entries 7 and 8) are converted efficiently into oxazolidinones
with [Rh2(OAc)4].[16] Collectively, our findings indicate that
substrates having some degree of conformational constraint
generally afford superior results.
tities of a RhII carboxylate complex and an inexpensive
commercial oxidant, PhI(OAc)2. The product oxazolidinones
are versatile, crystalline materials that can be opened under
hydrolytic conditions to furnish 1,2-amino alcohols.[5, 6]
Transition metal promoted methods for the oxidative
conversion of saturated hydrocarbons to amines or amine
derivatives have limited precedence.[7, 8] In one seminal
example, both iron and rhodium catalysts were found to react
with the iodoimine of 2,5-diisopropylbenzenesulfonamide to
furnish a substituted benzisothiazoline product.[9] This reac-
tion is believed to occur through intramolecular metal ± ni-
trene insertion into an isopropyl methine C H bond, though
no mechanistic data has been offered in support of this
claim.[10] More recently, reports of metal-catalyzed intermo-
ˆ
lecular allylic and benzylic C H oxidation with PhI NSO2Ar
reagents have been described.[7c±e,h±k] These processes are
hampered, however, by the poor shelf life of the iodoimine
starting materials, a restricted substrate profile, and the need
to often employ large excesses of hydrocarbon substrates.
We wished to explore the use of simple carbamate materials
as precursors for the synthesis of substituted oxazolidinones.
[*] Prof. Dr. J. Du Bois, C. G. Espino
Department of Chemistry
Stanford University
Stanford, CA 94305-5080 (USA)
Fax : (‡1)650-725-0259
E-mail: jdubois@leland.stanford.edu
[**] We thank Professors Brauman, Stack, Trost, and Wender for many
helpful discussions. C.G.E. is the recipient of an NSF Predoctoral
Fellowship. J.D.B. gratefully acknowledges the Camille and Henry
Dreyfus Foundation for a New Faculty Award. Special thanks are
extended to Merck Research Laboratories, Johnson Matthey, Profes-
sor Michael P. Doyle, and Stanford University for generous gifts and
financial support.
The carbamate prepared from (S)-2-methyl-1-butanol (4)
was employed as a probe to examine the mechanism of
oxazolidinone formation (Figure 1).[17] Direct insertion of a
nitrene or nitrenoid intermediate into the methine center of 4
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
598
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
1433-7851/01/4003-0598 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2001, 40, No. 3

COMMUNICATIONS
Table 1. Oxidative cyclization of carbamates.
makes possible the synthesis of chiral a,a-disubstituted alkyl
amines from enantiomerically pure, b-branched primary
alcohols.[20] The potential of this method is considerable given
the limited number of asymmetric methods available for
preparing this important class of compounds and related
quaternary a-amino acids.[21]
Entry
Substrate
Product
Catalyst[a]
Yield[b]
74
1
B
Carbamoylnitrenes, generated in thermolytic or photolytic
decomposition reactions of azidoformates, react as powerful,
indiscriminate oxidants.[17c, 18a,b] In the Rh-catalyzed process,
the regioselective formation of a single product from sub-
strates capable of generating other oxazolidinone and/or
oxazinone derivatives (e.g., entries 2, 4, and 6, Table 1) is
evidence against a free nitrene intermediate.[17c, 18a, 22] Addi-
tional data that strongly support this conclusion were
obtained from reactions with carbamate 6 [Eq. (2)]. The use
2
B
77[c]
83
3
4
A
A
B
A
B
B
77
79
82
84
44
5
6
7
of [Rh2(OAc)4] as a catalyst to effect the cyclization of 6
afforded a 2:1 mixture of diastereomeric products, 7a and 7b
(79%). In contrast, the [Rh2(tpa)4] complex yielded 7a and 7b
in a 1:2.6 ratio (74%).[23] Collectively, these observations
confirm that the Rh catalyst is in some way mediating C N
bond formation, and that a free carbamoylnitrene is not the
active oxidant. Such a reaction mechanism, in which the metal
complex influences the actual C H insertion step, has
significant ramifications for the future development of
catalyst systems that enable control over reaction chemo-,
regio-, and stereoselectivity.[24] We believe that our findings
represent the most compelling experimental documentation
recorded to date for a concerted, metal-directed N-atom
insertion process.[10]
A
A
82
8
83[d]
[a] Catalyst: A ˆ [Rh2(OAc)4], B ˆ [Rh2(tpa)4]. [b] All reactions conducted for
12 h with 5 mol% of catalyst, 1.4 equiv PhI(OAc)2, and 2.3 equiv MgO in
CH2Cl2 at 408C (ꢀ0.2m in substrate). [c] Exclusive product as determined by
1H NMR spectroscopy of the unpurified reaction mixture; cis stereochemistry
assigned based on 1H coupling constants. [d] Product isolated as an 8:1 mixture
of cis:trans isomers; cis stereochemistry established by X-ray crystallography.
Full experimental details are in the Supporting Information.
We have described a unique catalytic method for the
oxidative cyclization of carbamates to oxazolidinones. The
reaction is performed conveniently on the benchtop using
readily accessible substrates and catalysts, an inexpensive
commercial oxidant, and a common absorbent. C H insertion
is stereospecific, thereby facilitating the preparation of a-
branched alkylamines from optically pure alcohol starting
materials. Importantly, our data indicate that the active
oxidizing species does not display the indiscriminate reactivity
patterns characteristic of a carbamoylnitrene. The ability to
use simple Rh carboxylate complexes to perform selective
intramolecular alkane oxidations has created myriad oppor-
tunities for investigations in catalyst design, mechanism, and
target-directed synthesis. Efforts along each of these lines are
currently in progress.
Figure 1. Cyclization of 4 into 5. Gas chromatograms of the oxazolidinone
5 from racemic (top) and optically pure (bottom) carbamate 4.
should occur with retention of configuration.[18, 19] Alterna-
tively, cyclization of 4 through a pathway involving a discrete
tertiary radical species is likely to produce a mixture of
enantiomeric oxazolidinones. Chiral GC analysis of the
product obtained from 4 displayed only a single peak in the
chromatogram (Figure 1). This result provides definitive
evidence that C N bond formation is stereospecific. More-
over, the observed reactivity is consistent with that of a
nitrene-type oxidant. In practice, stereospecific C H insertion
Received: October 4, 2000 [Z15910]
[1] a) P. N. Craig in Comprehensive Medicinal Chemistry, Vol. 6 (Ed.: C. J.
Drayton), Pergamon, Oxford, 1990, pp. 237 ± 991; b) R. E. Babine,
S. L. Bender, Chem. Rev. 1997, 97, 1359 ± 1472; c) M. G. Moloney, Nat.
Prod. Rep. 1999, 16, 485 ± 498; d) D. J. Faulkner, Nat. Prod. Rep. 2000,
17, 7 ± 55.
Angew. Chem. Int. Ed. 2001, 40, No. 3
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
1433-7851/01/4003-0599 $ 17.50+.50/0
599

COMMUNICATIONS
[2] a) D. J. Ager, I. Prakash, D. R. Schaad, Chem. Rev. 1996, 96, 835 ± 876;
b) A. G. Myers, B. H. Yang, H. Chen, L. McKinstry, D. J. Kopecky,
J. L. Gleason, J. Am. Chem. Soc. 1997, 119, 6496 ± 6511, and refs
therein; c) A. K. Ghosh, S. Fidanze, C. H. Senanayake, Synthesis 1998,
937 ± 961.
uct conversions under otherwise identical reaction conditions (carba-
mate, Rh catalyst, MgO). These results are ascribed to the poor
solubility and/or instability of these reagents. Control experiments
show that none of these oxidants react with carbamates to give
oxazolidinone products in the absence of catalyst.
[3] a) R. Noyori, Asymmetric Catalysis in Organic Synthesis, Wiley-
Interscience, New York, 1994; b) J. Seyden-Penne, Chiral Auxiliaries
and Ligands in Asymmetric Catalysis, Wiley, New York, 1995; c) K.
[14] [Rh2(tpa)4] is prepared easily from [Rh2(OAc)4] and Ph3CCO2H, see:
S.-i. Hashimoto, N. Watanabe, S. Ikegami, Tetrahedron Lett. 1992, 33,
2709 ± 2712. For a general review of RhII carboxylate compounds, see:
T. R. Felthouse, Prog. Inorg. Chem. 1982, 29, 73 ± 166.
Â
Soai, S. Niwa, Chem. Rev. 1992, 92, 833 ± 856; d) M. Gomez, G. Muller,
M. Rocamora, Coord. Chem. Rev. 1999, 193 ± 195, 769 ± 835.
[4] For some leading references, see: a) R. D. Tillyer, C. Boudreau, D.
Tschaen, U.-H. Dolling, P. J. Reider, Tetrahedron Lett. 1995, 36, 4337 ±
4340; b) J. F. Larrow, S. E. Schaus, E. N. Jacobsen, J. Am. Chem. Soc.
1996, 118, 7420 ± 7421; c) A. E. Rubin, K. B. Sharpless, Angew. Chem.
1997, 109, 2751 ± 2754; Angew. Chem. Int. Ed. Engl. 1997, 36, 2637 ±
2640; d) S. Kobayashi, H. Ishitani, M. Ueno, J. Am. Chem. Soc. 1998,
120, 431 ± 432; e) G. Zhu, A. L. Casalnuovo, X. Zhang J. Org. Chem.
1998, 63, 8100 ± 8101; f) N. A. Petasis, I. A. Zavialov, J. Am. Chem.
Soc. 1998, 120, 11798 ± 11799; g) J. A. Marshall, K. Gill, B. M.
Seletsky, Angew. Chem. 2000, 112, 983 ± 986; Angew. Chem. Int. Ed.
2000, 39, 953 ± 956.
[15] 1HNMR spectroscopy shows a ꢀ1:1 mixture of unreacted n-butylcar-
bamate and the corresponding 4-ethyloxazolidinone. The higher
product yields for carbamates having either benzylic or tertiary
C H centers suggest that substrate reactivities parallel the C H
homolytic bond strengths. Additional results from our studies,
however, do not necessarily support this conclusion. Details will be
provided in a full account of this work.
[16] Carbamates prepared from some secondary alcohols, such as cyclo-
hexanol, yield only small amounts of the corresponding ketones. We
are exploring conditions under which such substrates can react to
afford oxazolidinone products and will report these findings in due
course.
[5] a) D. A. Evans, Aldrichimica Acta 1982, 15, 23 ± 32; b) D. J. Ager, I.
Prakash, D. R. Schaad, Aldrichimica Acta 1997, 30, 3 ± 12; c) J. M.
Takacs, M. R. Jaber, A. S. Vellekoop, J. Org. Chem. 1998, 63, 2742 ±
2748.
[17] (S)-2-methylbutyl azidoformate has been used in related studies, see:
a) G. Smolinsky, B. I. Feuer, J. Am. Chem. Soc. 1964, 86, 3085 ± 3088;
b) S. Terashima, S.-i. Yamada, Chem. Pharm. Bull. 1968, 16, 1953 ±
1971; c) O. Meth-Cohn, Acc. Chem. Res. 1987, 20, 18 ± 27.
[6] Oxazolidinone hydrolysis is performed conveniently with Ba(OH)2,
see ref. [5c]. N-tert-Butoxycarbonylated oxazolidin-2-ones may be
opened with catalytic base at 258C, see: T. Ishizuka, T. Kunieda,
Tetrahedron Lett. 1987, 28, 4185 ± 4188.
[18] a) W. Lwowski in Nitrenes (Ed.: W. Lwowski), Interscience, New
York, 1970, pp. 185 ± 224; b) C. J. Moody in Comprehensive Organic
Synthesis, Vol. 7 (Eds.: B. M. Trost, I. Fleming, S. V. Ley), Pergamon,
Oxford, 1991, pp. 21 ± 38. For a review on the use of chiral substrates to
probe C H oxidation mechanisms, see: H. G. Floss, S. Lee, Acc.
Chem. Res. 1993, 26, 116 ± 122.
[19] Metal-catalyzed diazoalkane C H insertion reactions have been
shown to proceed with retention of configuration, see: a) D. F. Taber,
E. H. Petty, K. Raman, J. Am. Chem. Soc. 1985, 107, 196 ± 199; b) M. P.
Doyle in Comprehensive Organometallic Chemistry II, Vol. 12 (Eds.:
E. W. Abel, F. G. A. Stone, G. Wilkinson), Pergamon, Oxford, 1995,
pp. 421 ± 468.
[7] a) D. S. Breslow, M. F. Sloan, Tetrahedron Lett. 1968, 5349 ± 5352;
b) D. H. R. Barton, R. S. Hay-Motherwell, W. B. Motherwell, J. Chem.
Soc. Perkin Trans. 1 1983, 445 ± 451; c) J. P. Mahy, G. Bedi, P. Battioni,
D. Mansuy, Tetrahedron Lett. 1988, 29, 1927 ± 1930; d) D. A. Evans,
M. M. Faul, M. T. Bilodeau, J. Am. Chem. Soc. 1994, 116, 2742 ± 2753,
and refs therein; e) I. Nägeli, C. Baud, G. Bernardinelli, Y. Jacquier,
M. Moran, P. Müller, Helv. Chim. Acta 1997, 80, 1087 ± 1105; f) Y.
Kohmura, K.-i. Kawasaki, T. Katsuki, Synlett 1997, 1456 ± 1458; g) S.-
M. Au, S.-B. Zhang, W.-H. Fung, W.-Y. Yu, C.-M. Che, K.-K. Cheung,
Chem. Commun. 1998, 2677 ± 2678; h) D. P. Albone, P. S. Aujla, P. C.
Taylor, S. Challenger, A. M. Derrick, J. Org. Chem. 1998, 63, 9569 ±
9571; i) S.-M. Au, J.-S. Huang, W.-Y. Yu, W.-H. Fung, C.-M. Che, J.
Am. Chem. Soc. 1999, 121, 9120 ± 9132; j) X.-Q. Yu, J.-S. Huang, X.-G.
Zhou, C.-M. Che, Org. Lett. 2000, 2, 2233 ± 2236; k) P. Dauban, R. H.
Dodd, Org. Lett. 2000, 2, 2327 ± 2329. The azidonation of activated
C H bonds with PhIO/Me3SiN3 has been described, see: P. Magnus, J.
Lacour, P. A. Evans, M. B. Roe, C. Hulme, J. Am. Chem. Soc. 1996,
118, 3406 ± 3418.
[8] The amination of acetylenic, olefinic, and allenic p bonds is possible
under a variety of conditions, see: a) Y. Tamaru, M. Kimura, Synlett
1997, 749 ± 757, and refs therein; b) G. Li, H.-X. Wei, S. H. Kim, M.
Neighbors, Org. Lett. 1999, 1, 395 ± 398; c) P. OꢁBrien, Angew. Chem.
1999, 111, 339 ± 342; Angew. Chem. Int. Ed. 1999, 38, 326 ± 329;
d) K. C. Nicolaou, Y.-L. Zhong, P. S. Baran, Angew. Chem. 2000, 112,
639 ± 642; Angew. Chem. Int. Ed. 2000, 39, 625 ± 628; e) T. Bach, B.
Schlummer, K. Harms, Chem. Commun. 2000, 287 ± 288; f) H. M.
Senn, P. E. Blöchl, A. Togni, J. Am. Chem. Soc. 2000, 122, 4098 ± 4107,
and refs therein. Also, see refs. [4c] and [7d,k].
[20] Optically pure, b-branched primary alcohols are readily available; for
leading references, see [2b] and [5a].
[21] a) A. B. Charette, A. Gagnon, Tetrahedron: Asymmetry 1999, 10,
1961 ± 1968; b) D. A. Cogan, G. Liu, J. Ellman, Tetrahedron 1999, 55,
8883 ± 8904; c) B. M. Trost, X. Ariza, J. Am. Chem. Soc. 1999, 121,
10727 ± 10737; d) P. Vachal, E. N. Jacobsen, Org. Lett. 2000, 2, 867 ±
870, and refs therein; e) C. Cativiela, M. D. Díaz-de-Villegas, Tetra-
hedron: Asymmetry 2000, 11, 645 ± 732, and refs therein.
[22] Irradiation of a 0.2m CH2Cl2 solution of cyclohexylmethylcarbamoyl
azide at ꢀ258C (450 W medium pressure Hg arc lamp, H2O cooled)
afforded a complex mixture that included both oxazolidinone and
oxazinone products.
1
[23] Diastereomeric product ratios were determined by HNMR spectro-
scopy. The stereochemical assignments for compounds 7a and 7b are
based on difference nuclear overhauser effect (nOe) measurements.
[24] Numerous examples illustrate the influence of catalyst structure on
reaction selectivity in the analogous C H insertion reactions of
diazoalkanes. For a comprehensive reference, see: M. P. Doyle, M. A.
McKervey, T. Ye, Modern Catalytic Methods for Organic Synthesis
with Diazo Compounds, Wiley-Interscience, New York, 1998.
[9] R. Breslow, S. H. Gellman, J. Am. Chem. Soc. 1983, 105, 6728 ± 6729.
Also, see: R. Breslow, S. H. Gellman, J. Chem. Soc. Chem. Commun.
1982, 1400 ± 1401.
[10] For preliminary mechanistic studies on [Rh2(O2CR)4]-catalyzed,
ˆ
intermolecular C H insertion reactions with PhI NSO2Ar, see
ref. [7e]. Also, see: P. Müller, Adv. Cat. Proc. 1997, 2, 113 ± 151.
[11] P. Kocovsky, Tetrahedron Lett. 1986, 27, 5521 ± 5524.
[12] A suspension of 2, PhI(OAc)2, and MgO in CD2Cl2 was heated in an
NMR tube. 1HNMR spectroscopy indicated only the presence of
starting materials. Interestingly, carboxamides react rapidly with
PhI(OAc)2 to afford isocyanates, see: R. M. Moriarty, C. J. Chany II,
R. K. Vaid, O. Prakash, S. M. Tuladhar, J. Org. Chem. 1993, 58, 2478 ±
2482.
ˆ
[13] Substitution of PhI(OAc)2 with other iodine(iii) oxidants (PhI O,
PhI(O2CCF3)2, PhI(OMe)2, 2-iodosobenzoic acid) gave inferior prod-
600
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
1433-7851/01/4003-0600 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2001, 40, No. 3