Rhodium(I)-catalyzed nucleophilic ring-opening reactions of oxabicyclo adducts derived from the [4 + 2]-cycloaddition of 2-imido-substituted furans

Article abstract of DOI:10.1021/jo060238r

A series of 2-imido-substituted furans containing tethered unsaturation were prepared by the addition of the lithium carbamate of furan-2-ylcarbamic acid tert-butyl ester to a solution of the mixed anhydride of an appropriately substituted 3-butenoic acid

Full text of DOI:10.1021/jo060238r

Rhodium(I)-Catalyzed Nucleophilic Ring-Opening Reactions of
Oxabicyclo Adducts Derived from the [4 + 2]-Cycloaddition of
2-Imido-Substituted Furans
Albert Padwa* and Qiu Wang
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
ReceiVed February 6, 2006
A series of 2-imido-substituted furans containing tethered unsaturation were prepared by the addition of
the lithium carbamate of furan-2-ylcarbamic acid tert-butyl ester to a solution of the mixed anhydride of
an appropriately substituted 3-butenoic acid. The initially formed imido furans undergo a rapid
intramolecular [4 + 2]-cycloaddition at room temperature to deliver the Diels-Alder cycloadducts in
good to excellent yield. Isolation of the highly labile oxabicyclic adduct is believed to be a consequence
of the lower reaction temperatures employed as well as the presence of the extra carbonyl group, which
diminishes the basicity of the nitrogen atom, thereby retarding the ring cleavage/rearrangement reaction
generally encountered with related systems. By using a Rh(I)-catalyzed ring opening of the oxabicyclic
adduct with various nucleophilic reagents, it was possible to prepare highly functionalized hexahydro-
1H-indol-2(3H)-one derivatives in good yield. The major stereoisomer obtained possesses a cis-relationship
between the nucleophile and hydroxyl group in the ring-opened product. The stereochemistry was
unequivocally established by X-ray crystallographic analysis. Coordination of Rh(I) to the alkenyl π-bond
followed by a nitrogen-assisted cleavage of the carbon-oxygen bond occurs to furnish a π-allyl rhodium-
(III) species. Addition of the nucleophile then occurs from the least hindered terminus of the resulting
π-allyl rhodium(III) complex. Proton exchange followed by rhodium(I) decomplexation ultimately leads
to the cis-diastereomer.
Introduction
employing these intermediates involves the cleavage of the
oxygen bridge to produce functionalized cyclohexene deriva-
tives. Many groups have developed different approaches includ-
ing â-elimination of suitable derivatives,10 treatment with strong
acids,11 reductive elimination of endo functionalities,12 frag-
7-Oxabicyclo[2.2.1]heptenes are valuable intermediates in
organic synthesis.1,2 The large number of selective transforma-
tions possible with the oxabicyclic system endow this nucleus
with impressive versatility.3-9 A crucial synthetic transformation
(1) (a) Lautens, M. Synlett 1993, 177. (b) Chiu, P.; Lautens, M. Top.
Curr. Chem. 1997, 190, 1. (c) Lautens, M.; Fagnou, K.; Hiebert, S. Acc.
Chem. Res. 2003, 36, 48.
(2) (a) Vogel, P.; Fattori, D.; Gasparini, F.; Le Drian, C. Synlett 1990,
173. (b) Reymond, J.-L.; Pinkerton, A. A.; Vogel, P. J. Org. Chem. 1991,
56, 2128.
(3) (a) Renaud, P.; Vionnet, J.-P. J. Org. Chem. 1993, 58, 5895. (b) Dean,
F. M. AdV. Heterocycl. Chem. 1981, 30, 168. (c) Lipshutz, B. H. Chem.
ReV. 1986, 86, 795. (d) Woo, S.; Keay, B. A. Synthesis 1996, 669.
(4) Eggelte, T. A.; de Koning, H.; Huisman, H. O. J. Chem. Soc., Perkin
Trans. 1 1978, 980.
(5) Ogawa, S.; Iwasawa, Y.; Nose, T.; Suami, T.; Ohba, S.; Ito, M.;
Saito, Y. J. Chem. Soc., Perkin Trans. 1 1985, 903.
(7) Murai, A.; Takahashi, K.; Taketsuru, H.; Masamune, T. J. Chem.
Soc., Chem. Commun. 1981, 221.
(8) Kotsuki, H.; Nishizawa, H. Heterocycles 1981, 16, 1287.
(9) Cox, P. J.; Simpkins, N. S. Synlett 1991, 321.
(10) (a) Le Drian, C.; Vieira, E.; Vogel, P. HelV. Chim. Acta 1989, 72,
338. (b) Takahashi, T.; Iyobe, A.; Arai, Y.; Koizumi, T. Synthesis 1989,
189. (c) Guildford, A. J.; Turner, R. W. J. Chem. Soc., Chem. Commun.
1983, 466. (d) Yang, W.; Koreeda, M. J. Org. Chem. 1992, 57, 3836.
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M.; Jackson, B.; Prout, K.; Witt, F. J. Tetrahedron Lett. 1990, 31, 1885.
(c) Koreeda, M.; Jung, K.-Y.; Hirota, M. J. Am. Chem. Soc. 1990, 112,
7413. (d) Reynard, E.; Reymond, J.-L.; Vogel, P. Synlett 1991, 469. (e)
Ogawa, S.; Yoshikawa, M.; Taki, T. J. Chem. Soc., Chem. Commun. 1992,
406. (f) Ogawa, S.; Tsunoda, H. Liebigs Ann. Chem. 1992, 637.
(6) Just, G.; Kim, S. Tetrahedron Lett. 1976, 17, 1063.
10.1021/jo060238r CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/22/2006
3210
J. Org. Chem. 2006, 71, 3210-3220

Rh(I)-Catalyzed Ring-Opening Reactions of Oxabicyclo Adducts
SCHEME 1. Lauten’s Oxabicyclic Ring-Opening Protocol
SCHEME 2. IMDAF Reaction of Furanyl Carbamates
mentation,13 hydrolytic ring openings,14 and alkylative bridge
cleavage reactions.15 A significant advancement in the ring-
opening chemistry of oxabicyclic compounds occurred in the
early 1990s as a result of the elegant work of Lautens and co-
workers.16 This research team demonstrated that the ring opening
of unsymmetrical oxabicycloheptenes 1 is a highly regioselective
process giving rise to products 2 derived from attack of the
nucleophile distal to the bridgehead substituent.16 These reac-
tions were carried out with a range of nucleophiles including
hydride, stabilized and nonstabilized carbanions, alcohols,
amines, and carboxylates.1 Highly stereoselective reactions were
also observed to occur with organocuprates, silylcuprates,
organolithium reagents, and organomagnesium compounds,1c
and these processes were used for the synthesis of acyclic (and
cyclic compounds) 3 with multiple stereocenters (Scheme 1).1
The most general method for the synthesis of 7-oxabicyclo-
[2.2.1]heptenes relies on the Diels-Alder reaction of a furan
derivative with various dienophiles.17 Furan itself is not very
reactive as a diene due to the loss of aromaticity which
accompanies the cycloaddition.18 Among the solutions inves-
tigated to improve the [4 + 2]-cycloaddition reaction are
catalysis using Lewis acids,2c use of metal salts,19 silica gel,20
zeolites,21 centrifugation,22 ultrasound,23 and high-pressure
techniques.24 The placement of an electron-donor substituent
on the furan ring also significantly enhances its reactivity toward
dienophiles by raising its HOMO level. The intramolecular
version of the Diels-Alder reaction of furans (IMDAF) has
been described in several reviews,17,25 including an excellent
treatise by Keay and Hunt.26 For the IMDAF reaction to proceed
favorably, the aromatic character of the furan ring and the strain
associated with the oxabicyclic adduct must be overcome. Steric
factors, rather than electronic or solvent effects, appear to have
the greatest influence on the outcome of the [4 + 2]-cyclo-
addition.27 Electronically disfavored furan cycloadditions can
be brought about by creative functional group modifications.
Several years ago, we began a synthetic program to provide
general access to a variety of alkaloids by [4 + 2]-cycloaddition
chemistry of substituted 2-amidofurans.28 Our synthetic strategy
was to take advantage of an intramolecular Diels-Alder reaction
of an alkenyl-substituted furanyl carbamate derivative (IM-
DAF).29,30 Not only does this IMDAF reaction allow for the
preparation of aza-polycyclic ring compounds, but they proceed
at lower temperatures than their intermolecular counterparts.
Even more significantly, unactivated π-bonds are reactive
toward the internal cycloaddition reaction. We discovered that
the IMDAF reaction of a series of furanyl carbamates (i.e., 4)
occurred smoothly to furnish the cyclized indoline 6 as the only
isolable product in high yield when a monosubstituted alkenyl
tether (R ) H) was used (Scheme 2).28 When the alkenyl group
possesses a substituent other than hydrogen at the 2-position of
the π-bond, the thermal reaction furnished a rearranged hexa-
hydroindolinone (i.e., 8). With this system, the initially formed
cycloadduct 5 cannot aromatize. Instead, ring opening of the
oxabicyclic intermediate occurs to generate zwitterion 7, which
undergoes a subsequent proton elimination by tautomerization
to give the rearranged ketone 8.30
(12) (a) Jung, M. E.; Street, L. J. J. Am. Chem. Soc. 1984, 106, 8327.
(b) Mirsadeghi, S.; Rickborn, B. J. Org. Chem. 1985, 50, 4340.
(13) Grieco, P. A.; Lis, R.; Zelle, R. E.; Finn, J. J. Am. Chem. Soc. 1986,
108, 5908.
(14) (a) Takayama, H.; Hayashi, K.; Koizumi, T. Tetrahedron Lett. 1986,
27, 5509. (b) Hanessian, S.; Beaulieu, P.; Dube, D. Tetrahedron Lett. 1986,
27, 5071.
(15) (a) Arjona, O.; de Dios, A.; Fernandez de la Pradilla, R.; Plumet,
J.; Viso, A. J. Org. Chem. 1994, 59, 3906. (b) Lautens, M.; Dockendorff,
C.; Fagnou, K.; Malicki, A. Org. Lett. 2002, 4, 1311.
(16) (a) Lautens, M.; Fagnou, K.; Rovis, T. J. Am. Chem. Soc. 2000,
122, 5650. (b) Lautens, M.; Fagnou, K.; Taylor, M. Org. Lett. 2000, 2,
1677. (c) Lautens, M.; Fagnou, K. Tetrahedron 2001, 57, 5067. (d) Lautens,
M.; Chiu, P.; Ma, S.; Rovis, T. J. Am. Chem. Soc. 1995, 117, 532. (e)
Lautens, M.; Chiu, P.; Colucci, J. T. Angew. Chem., Int. Ed. Engl. 1993,
32, 281. (f) Lautens, M.; Di Felice, C.; Huboux, A. Tetrahedron Lett. 1989,
30, 6817.
(17) Kappe´, C. O.; Murphree, S. S.; Padwa, A. Tetrahedron 1997, 53,
14179.
(18) Sargent, M. V.; Dean, F. M. In ComprehensiVe Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984;
Vol. 4, p 599.
When furanyl carbamates such as 4 were used, the IMDAF
reaction required heating at 165 °C for several hours in order
to produce the rearranged product (i.e., 6 or 8). The Diels-
Alder adduct 5 that was first formed underwent reorganization
under the reaction conditions and could not be isolated or
detected in the crude reaction mixture. During the course of
investigating the general nature of this reaction, significant rate
differences were noticed when the alkenyl tether was incorpo-
rated onto the amido side chain. With these systems, the IMDAF
cycloaddition occurred at room temperature, and in some cases,31
it was possible to isolate the initially formed aza-oxabicyclo
(19) (a) Moore, J. A.; Partain III, E. M. J. Org. Chem. 1983, 48, 1105.
(b) Bailey, M. S.; Brisdon, B. J.; Brown, D. W.; Stark, K. M. Tetrahedron
Lett. 1983, 24, 3037.
(20) Moursounidis, J.; Wege, D. Aust. J. Chem. 1983, 36, 2473.
(21) Laszlo, P. Acc. Chem. Res. 1986, 19, 121.
(22) Dolata, D. P.; Bergman, R. Tetrahedron Lett. 1987, 28, 707.
(23) Saksena, A. K.; Girijavallabhan, V. M.; Chen, Y.-T.; Jao, E.; Pike,
R. E.; Desai, J. A.; Rane, D.; Ganguly, A. K. Heterocycles 1993, 35, 129.
(24) Matsumoto, K.; Sera, A. Synthesis 1985, 999.
(27) (a) Roush, W. R. AdV. Cycloaddit. 1990, 2, 91. (b) Fallis, A. G.
Can. J. Chem. 1984, 62, 183. (c) Craig, D. Chem. Soc. ReV. 1987, 16, 187.
(28) (a) Padwa, A.; Brodney, M. A.; Dimitroff, M. J. Org. Chem. 1998,
63, 5304. (b) Padwa, A.; Brodney, M. A.; Satake, K.; Straub, C. S. J. Org.
Chem. 1999, 64, 4617.
(29) (a) Sternbach, D. D.; Rossana, D. M.; Onan, K. D. J. Org. Chem.
1984, 49, 3427. (b) Klein, L. L. J. Org. Chem. 1985, 50, 1770. (c) Jung,
M. E.; Gervay, J. J. Am. Chem. Soc. 1989, 111, 5469.
(25) Oppolzer, W. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5, p 315.
(26) Keay, B. A.; Hunt, I. R. AdV. Cycloaddit. 1999, 6, 173.
(30) (a) Padwa, A.; Brodney, M. A.; Lynch, S. M. J. Org. Chem. 2001,
66, 1716. (b) Padwa, A.; Brodney, M. A.; Dimitroff, M.; Liu, B.; Wu, T.
J. Org. Chem. 2001, 66, 3119.
J. Org. Chem, Vol. 71, No. 8, 2006 3211

Padwa and Wang
SCHEME 4. IMDAF Cycloaddition of the 2-Imidofuran
SCHEME 3. Isolation of the Aza-oxabicyclic Cycloadduct
System
adduct. For example, the intramolecular [4 + 2]-cycloaddition
of amidofuran 9 afforded cycloadduct 10 in 77% yield when
the reaction was carried out at 25 °C (Scheme 3). Further heating
of a benzene solution of this cycloadduct at reflux provided
the rearranged tricyclic lactam 11 in 75% yield. The notion of
further functionalizing an aza-oxabicyclo adduct by a transition-
metal-catalyzed ring-opening reaction with various nucleophilic
reagents was most attractive to us since the resulting product-
(s) can be envisaged as precursors to a wide assortment of
alkaloids. In this paper, we detail our recent findings using a
series of alkenyl-substituted imidofurans where we address the
issues of (a) ease of access to the starting aza-oxabicyclo
adducts, (b) the efficiency of the IMDAF reaction, and (c) regio-
and stereocontrol in the metal-catalyzed ring-opening reaction.
SCHEME 5. More Heavily Substituted Systems
Results and Discussion
The aza-oxabicyclo[2.2.1] substrates employed in this study
were readily prepared from the corresponding imidofurans.
Initially, we had envisioned imidofuran 13 arising from the
simple acylation of furanyl carbamate 12a with the acid chloride
derived from 3-butenoic acid. However, under a variety of
conditions, 12a proved to be remarkably resistant toward
acylation. After some experimentation, we found that the
addition of lithiated carbamate 12b, formed by the action of
n-BuLi on 12a, to a solution of the mixed anhydride 14 provided
the expected imidofuran 13, which rapidly reacted at room
temperature to deliver the Diels-Alder cycloadduct 23 in 55%
isolated yield. Intrigued by the ease with which imidofuran 13
underwent the IMDAF cycloaddition, we investigated several
other systems containing related tethers as illustrated in Scheme
4. The mixed anhydrides 15 and 16 were subjected to the
acylation protocol and provided the desired imidofurans 19 and
20, which also underwent cycloaddition at 25 °C (12 h) to
furnish the aza-oxabridged cycloadducts 24 and 25. When the
more highly activated anhydride 17 was used, imidofuran 21
could not be observed because the [4 + 2]-cycloaddition
occurred too rapidly to preclude its detection, even at 0 °C. In
contrast, the more sterically congested anhydride 18 furnished
imidofuran 22, which required heating at 90 °C to give
cycloadduct 27.
Several more heavily substituted imidofuran substrates were
also found to rapidly undergo the intramolecular [4 + 2]-cyclo-
addition at room temperature and gave aza-oxabicyclo adducts
in good yield. Thus, the reaction of the mixed anhydride of
vinylacetic acid with lithiated carbamates 32 and 33 provided
the expected imidofurans as transient species which underwent
a subsequent IMDAF reaction at 25 °C to deliver cycloadducts
34 and 35 in 60% yield, respectively (Scheme 5). Interestingly,
the IMDAF cycloaddition of the somewhat labile imidofurans
36 and 37 (prepared in a similar manner) occurred with very
high diastereoselectivity (>20:1) producing the cis-substituted
cycloadducts 38 and 39 in 96% and 98% yield, respectively.
The increase in reactivity of these 2-imido-substituted furans
(0-90 °C) when compared to the related furanyl carbamates32
(>150 °C) is clearly related to the placement of the carbonyl
center within the dienophilic tether. Dramatic effects on the rate
of the Diels-Alder reaction were previously noted to occur
when an amido group was used to anchor the diene and
dienophile.33 The effect of amide-linked tethers on both the rate
and diastereoselectivity of intramolecular Diels-Alder reactions
were previously attributed to relative transition-state stabilities.33
The rate enhancement observed with the imidofuranyl system
probably originates from restricted rotation about the C-N bond,
producing a lower energy ground-state conformer that is more
energetically similar to the reactive conformer.34 Our ability to
isolate the highly labile aza-oxabicyclic adducts is presumably
(32) (a) Bur, S. K.; Lynch, S. M.; Padwa, A. Org. Lett. 2002, 4, 473.
(b) Ginn, J. D.; Padwa, A. Org. Lett. 2002, 4, 1515.
(33) For examples, see: (a) Oppolzer, W.; Fro¨stl, W. HelV. Chim. Acta
1975, 58, 590. (b) Oppolzer, W.; Fro¨stl, W.; Weber, H. P. HelV. Chim.
Acta 1975, 58, 593. (c) White, J. D.; Demnitz, F. W. J.; Oda, H.; Hassler,
C.; Snyder, J. P. Org. Lett. 2000, 2, 3313. (d) Tantillo, D. J.; Houk, K. N.;
Jung, M. E. J. Org. Chem. 2001, 66, 1938. (e) Weingarten, M. D.; Prein,
M.; Price, A. T.; Snyder, J. P.; Padwa, A. J. Org. Chem. 1997, 62, 2001.
(31) Padwa, A.; Ginn, J. D.; Bur, S. K.; Eidell, C. K.; Lynch, S. M. J.
Org. Chem. 2002, 67, 3412. (b) Wang, Q.; Padwa, A. Org. Lett. 2004, 6,
2189.
3212 J. Org. Chem., Vol. 71, No. 8, 2006

Rh(I)-Catalyzed Ring-Opening Reactions of Oxabicyclo Adducts
SCHEME 6. Rh(I)-Catalyzed Ring Opening of the
10-Oxa-2-azatricyclodecene System
a result of the lower reaction temperatures employed as well as
the presence of the extra carbonyl group, which diminishes the
basicity of the nitrogen atom thereby retarding the ring cleavage/
rearrangement reaction generally encountered with these sys-
tems.32 When exposed to more forcing conditions (i.e., >100
°C), the oxabridged cycloadducts 24-27 were smoothly trans-
formed (>90%) into the corresponding hexahydroindolinone
systems 28-31. It should also be noted that the IMDAF reaction
of these systems proceeds by a transition state where the sidearm
of the tethered alkenyl group is oriented exo with respect to the
oxygen bridge. Products resulting from an endo sidearm
transition state were neither detected nor isolated. This result
is quite reasonable since, in these mobile cycloaddition equi-
libria, the exo adducts are thermodynamically more stable. In
fact, the stereochemical results that we have encountered with
the IMDAF cycloaddition of these 2-imidofurans is consistent
with those reported by others for related systems possessing
short tethers.35 As a consequence of this preferred exo orienta-
tion, the oxido bridge is located anti to the substituent on the
bridgehead carbon. The cis-diastereoselectivity observed in the
cycloaddition of imidofurans 36 and 37 can be rationalized as
being the result of approach of the furan ring from the less
hindered π-face of the double bond.
SCHEME 7. Rh(I)-Catalyzed Ring-Opening Reactions
Using Carboxylates as the Nucleophile
Regioselective cleavage of the oxygen bridge of the 7-oxa-
bicyclo-[2.2.1]hept-2-ene skeleton to give functionalized cy-
clohexene derivatives is central to many synthetic strategies.36
Remote electronic effects mediated by an aromatic π-system
have been thoroughly investigated for the transformation of
substituted oxabenzonorbornadienes to the corresponding naph-
thols under protic conditions.37 The ring-opening reaction of
7-oxanorbornenes with organometallic reagents has also been
investigated in some detail by several research groups.38 Lautens
and co-workers demonstrated that a variety of oxabicyclo[2.2.1]-
heptene derivatives readily undergo Rh(I)-catalyzed nucleophilic
ring-opening,1 and this key reaction was employed for the
synthesis of highly functionalized acyclic polypropionate and
polyacetate chains using the related oxabicyclo[3.2.1] system.39
Our research plan was to explore the reactivity of the IMDAF-
derived aza-oxabicyclo adducts toward several nucleophilic
partners with the thought of eventually applying the resulting
methodology toward the synthesis of several alkaloid skeletons.
With a representative selection of 10-oxa-2-azatricyclo-
[5.2.1.01,5]decenes on hand, a standard set of ring-opening
conditions was employed. Our first set of experiments was
carried out with cycloadducts 23 and 24 using Lauten’s
conditions16 ([Rh(COD)Cl]2, DPPF). Phenol and N-methyl-
aniline were employed as the nucleophilic reagents. This led to
the ring-opened alcohols 40-43 in good yield (Scheme 6) and
with cis/trans ratios (Nu to OH) of 5:1 for 40 and 41 and 20:1
for 42 and 43. An X-ray crystal structure of the major
diastereomer of 41 unequivocally established the cis relationship
between the nucleophile and hydroxyl groups in the ring-opened
product. Interestingly, the stereochemical outcome of this
reaction was exactly opposite to that reported by Lautens for
the Rh(I)-catalyzed alcoholysis and aminolysis of oxabenzonor-
bornadiene.16 When oxabicyclo 24 was subjected to the Rh(I)-
catalyzed conditions using 2-bromobenzoic acid and NEt3, a
3:1 mixture of the ring-opened product 44 was obtained in 72%
yield (Scheme 7). The cis-stereochemical assignment of the
major diastereomer 44a was made on the basis of analogy with
substrate 41 where X-ray data had been obtained. Subsequent
experiments revealed that the reaction of the related oxabicyclo
adduct 23 with the Rh(I) catalyst in the presence of various
ammonium carboxylates16c generated the dienyl alcohol 45 in
80% isolated yield as the exclusive product. In the absence of
the Rh(I) catalyst, only starting material was recovered. On the
other hand, when the Rh(I)-catalyzed reaction was carried out
in the absence of ammonium carboxylate, oxindole 46 was
formed in 90% yield.
(34) Jung and Gervay, however, reported data for intramolecular Diels-
Alder reactions which suggest that substitution on the tether results in an
increase in the population of reactive rotamers. The rate enhancement was
suggested to originate from a restricted rotation, producing a lowest energy
ground state conformer that is more energetically similar to the reactive
conformer, see: (a) Jung, M. E.; Gervay, J. J. Am. Chem. Soc. 1991, 113,
224. See also: (b) Sternbach, D. D.; Rossana, D. M.; Onan, K. D.
Tetrahedron Lett. 1985, 26, 591. (c) Giessner-Prettre, C.; Hu¨kel, S.;
Maddaluno, J.; Jung, M. E. J. Org. Chem. 1997, 62, 1439.
(35) (a) Woo, S.; Keay, B. Tetrahedron: Asymmetry 1994, 5, 1411. (b)
Rogers, C.; Keay, B. A. Tetrahedron Lett. 1991, 32, 6477. (c) Rogers, C.;
Keay, B. A. Can. J. Chem. 1992, 70, 2929. (d) De Clercq, P. J.; Van Royen,
L. A. Synth. Commun. 1979, 9, 771. (e) Van Royen, L. A.; Mijngvheer,
R.; De Clercq, P. J. Bull. Soc. Chim. Belg. 1984, 93, 1019. (f) Fischer, K.;
Hunig, S. J. Org. Chem. 1987, 52, 564.
(36) (a) Vogel, P.; Cossy, J.; Plumet, J.; Arjona, O. Tetrahedron 1999,
55, 13521. (b) Vogel, P. Bull. Soc. Chim. Belg. 1990, 99, 395.
(37) Baker, R. W.; Baker, T. M.; Birkbeck, A. A.; Giles, R. G. F.;
Sargent, M. V.; Skelton, B. W.; White, A. H. J. Chem. Soc., Perkin Trans.
1 1991, 1589 and references therein.
(38) (a) Arjona, O.; Borrallo, C.; Iradier, F.; Medel, R.; Plumet, J.
Tetrahedron Lett. 1998, 39, 1977. (b) Arjona, O.; Fernandez de la Pradilla,
R.; Garcia, E.; Martin-Domenech, A.; Plumet, J. Tetrahedron Lett. 1989,
30, 6437. (c) Caple, R.; Chen, G. M.-S.; Nelson, J. D. J. Org. Chem. 1971,
36, 2874. (d) Jeffrey, A. M.; Yeh, H. J. C.; Jerina, D. M.; DeMarinis, R.
M.; Foster, C. H.; Piccolo, D. E.; Berchtold, G. A. J. Am. Chem. Soc. 1974,
96, 6929.
(39) (a) Lautens, M.; Belter, R. K. Tetrahedron Lett. 1992, 33, 2617.
(b) Lautens, M.; Chiu, P. Tetrahedron Lett. 1991, 32, 4827. (c) Lautens,
M.; Kumanovic, S. J. Am. Chem. Soc. 1995, 117, 1954.
A reasonable mechanism to account for the Rh(I)-catalyzed
reaction of the oxabicyclic adduct is outlined in Scheme 8.
J. Org. Chem, Vol. 71, No. 8, 2006 3213

Padwa and Wang
SCHEME 9. Rh(I)-Catalyzed Addition of Arylboronic
SCHEME 8. Proposed Mechanism for the Ru(I)-Catalyzed
Ring-Opening Reactions
Acids to the IMDAF Cycloadducts
Coordination of Rh(I) to the alkenyl π-bond followed by
nitrogen-assisted cleavage of the carbon-oxygen bond occurs
to furnish the π-allyl rhodium(III) species 47. Nucleophilic
addition then occurs from the least hindered terminus of 47 and
on the side opposite the rhodium complex.40 Proton exchange
of intermediate 48 followed by rhodium decomplexation
ultimately leads to the cis diastereromers 40-43. In the presence
of the basic ammonium carboxylate, intermediate 47 (R ) H)
undergoes preferential deprotonation and subsequent loss of
Rh(I) to generate a transient diene 49 which then isomerizes to
give 45. Without a base to induce double-bond isomerization,
intermediate 49 undergoes an aromatization reaction to furnish
oxindole 46.
and aminolysis experiments. When the Rh(I)-catalyzed reaction
was carried out with phenylboronic acid and without added base,
the ring-opened boronates 53 and 54 were obtained in excellent
yield (>95%). The cis-stereochemistry of 53 was unequivocally
established by an X-ray crystal structure. Both boronates were
cleaved to the corresponding diols,46 which were subsequently
transformed into dioxolanes 55 and 56 by reaction with 2,2-
dimethoxypropane. It was also possible to prepare the same 1,3-
dioxolanes (>90%) by treating oxabicyclic adducts 23 and 24
with catalytic anhydrous SnCl2 in acetone.47
In recent years, the Rh(I)-catalyzed addition of arylboronic
acids to olefins has become an active research area in organic
synthesis.41 Conjugate addition generally occurs with electron-
deficient olefins such as enone,42 alkenylphosphonates,43 and
nitroalkenes.44 The facile addition of boronic acids to oxaben-
zonorbornenes has also been achieved using a catalytic amount
of a rhodium(I) complex.45 A common step in these reactions
is the carborhodation of the carbon-carbon double bond
followed by hydrolysis of the organorhodium intermediate.
These earlier findings prompted us to examine whether a related
transformation might occur upon treating the IMDAF-derived
cycloadducts 23/24 with organoboronic acids in the presence
of a Rh(I) catalyst. With this in mind, the reaction of 5,5-
dimethyl-2-phenyl-1,3,2-dioxaborinane (50) with oxabicyclics
23 and 24, using 5 mol % of the Rh(I) catalyst and 2.0 equiv
of Cs2CO3 (5 M in H2O) in THF at 65 °C, led to the ring-
opened alcohols 51 and 52 in 70-80% yield (Scheme 9). The
cis isomer was formed exclusively (X-ray structure of 51 was
obtained) and parallels the results observed with the alcoholysis
The following mechanistic scheme is suggested to account
for the formation of the ring-opened alcohol 51 (or 52). Initially,
phenylrhodium(I) 57 is generated by transmetalation of a
rhodium(I) chloride or hydroxide with dioxaborinane 50. This
process might well be promoted by the presence of a base. The
resulting rhodium species 57 then undergoes exo-selective
carborhodation at the oxabicycle olefin to generate intermediate
58. Chelation of the rhodium metal with the olefin and oxygen
atom of the oxabicycle probably contributes to the high exo-
selectivity. â-Oxygen elimination, perhaps assisted by the
nitrogen lone pair, furnishes the ring-opened intermediate 59,
which undergoes eventual protonolysis with water to produce
the final product (i.e., 51) (Scheme 10). The rhodium(I) species
that is regenerated in this step is available to promote the next
catalytic cycle.
When phenylboronic acid is used without added base, the
oxabicyclic adduct 23 seemingly prefers to undergo a Rh(I)-
catalyzed oxygen elimination reaction as the first step, perhaps
as a consequence of the higher Lewis acidity of PhB(OH)2 vs
dioxaborinane 50, and gives the ring-opened intermediate 60.
This intermediate then undergoes reaction with the boronic
acid from the side opposite the rhodium metal to produce 61,
which eventually affords 53 (or 54) by cyclization and liberation
of rhodium(I) hydroxide (Scheme 11).
(40) With the oxabenzonorbornene system studied by the Lautens’
group,16 the rhodium metal undergoes initial exo-coordination with the
π-bond and this is followed by C-O insertion and then a subsequent
displacement of the allyl rhodium species via endo attack of the nucleophile.
(41) (a) Hayashi, T. Synlett 2001, 879. (b) Sakai, M.; Hayashi, H.;
Miyaura, N. Organometallics 1997, 16, 4229. (c) Senda, T.; Ogasawara,
M.; Hayashi, T. J. Org. Chem. 2001, 66, 6852.
(42) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N.
J. Am. Chem. Soc. 1998, 120, 5579.
(43) Hayashi, T.; Senda, T.; Takaya, Y.; Ogasawara, M. J. Am. Chem.
Soc. 1999, 121, 11591.
In summary, a highly convergent synthesis of hexahydro-
1H-indol-2-(3H)-one derivatives has been devised using an
IMDAF cycloaddition reaction of 2-imido-substituted furans.
(44) Hayashi, T.; Senda, T.; Ogasawara, M. J. Am. Chem. Soc. 2000,
122, 10716.
(45) Murakami, M.; Igawa, H. Chem. Commun. 2002, 390.
(46) Bertounesque, E.; Florent, J.-C.; Monneret, C. Synthesis 1991, 270.
(47) Vyvyan, J. R.; Meyer, J. A.; Meyer, K. D. J. Org. Chem. 2003, 68,
9144.
3214 J. Org. Chem., Vol. 71, No. 8, 2006

Rh(I)-Catalyzed Ring-Opening Reactions of Oxabicyclo Adducts
SCHEME 10. Rh(I)-Catalyzed Reaction of the Oxabicyclic
System Using 5,5-Dimethyl-2-phenyl-1,3,2-dioxaborinane (50)
was added dropwise via syringe to the above solution. After being
stirred at 0 °C for an additional 5 min, the reaction mixture was
quenched with H2O and extracted with EtOAc. The organic layer
was washed with a saturated aqueous NaHCO3 solution, dried over
MgSO4, and concentrated under reduced pressure. The residue was
subjected to flash silica gel chromatography to afford a colorless
oil which underwent spontaneous cycloaddition while standing at
room temperature for 12 h. The crude yellow solid was subjected
to flash silica gel chromatography to provide 0.09 g (55%) of 23
as a white solid: mp 126-127 °C; IR (neat) 1792, 1767, 1726,
1
1357, 1296, and 1157 cm-1; H NMR (CDCl3, 400 MHz) δ 1.52
(s, 9H), 1.65 (dd, 1H, J ) 11.6 and 7.6 Hz), 1.80 (dt, 1H, J ) 11.6
and 4.4 Hz), 2.05-2.13 (m, 1H), 2.41 (dd, 1H, J ) 17.2 and 10.0
Hz), 2.75 (dd, 1H, J ) 17.2 and 8.8 Hz), 5.02 (dd, 1H, J ) 4.4
and 2.0 Hz), 6.30 (dd, 1H, J ) 6.0 and 2.0 Hz), and 6.52 (d, 1H,
J ) 6.0 Hz); 13C NMR (CDCl3, 100 MHz) δ 28.2, 32.6, 35.9, 38.4,
77.6, 84.1, 102.0, 133.6, 134.7, 149.4, and 174.6. Anal. Calcd for
C13H17NO4: C, 62.14; H, 6.82; N, 5.57. Found: C, 62.01; H, 6.80;
N, 5.52.
SCHEME 11. Rh(I)-Catalyzed Reaction Using PhB(OH)2
tert-Butyl 5-Methyl-3-oxo-10-oxa-2-azatricyclo[5.2.1.01,5]dec-
8-ene-2-carboxylate (24). To a solution of 0.6 g (3.2 mmol) of
carbamate 12a in 10 mL of THF at 0 °C was added dropwise 1.6
mL (3.4 mmol) of n-BuLi (2.1 M in hexane). The reaction mixture
was stirred at 0 °C for 20 min. In a separate flask, 0.35 g (3.5
mmol) of 3-methylbut-3-enoic acid48 was dissolved in 10 mL of
THF at 0 °C, and 0.38 mL (3.5 mmol) of 4-methylmorpholine and
0.45 mL (3.5 mmol) of isobutyl chloroformate were added dropwise
to the above solution. After the mixture was stirred for 5 min, the
white precipitate was removed via filtration and washed with 4
mL of THF. The filtrate was cooled to 0 °C, and the preformed
lithiate was added dropwise via syringe. After being stirred at 0
°C for an additional 5 min, the reaction was quenched with H2O
and extracted with EtOAc. The organic layer was washed with a
saturated aqueous NaHCO3 solution, dried over MgSO4, and
concentrated under reduced pressure. The residue was subjected
to flash silica gel chromatography to afford a clear oil which
underwent spontaneous cycloaddition while standing at room
temperature for 12 h. The crude yellow oil was subjected to flash
silica gel chromatography to provide 0.5 g (56%) of 24 as a white
solid: mp 96-98 °C; IR (neat) 1793, 1767, 1730, 1353, 1306, and
The increase in reactivity of these imidofurans when compared
to the related furanyl carbamates is related to the placement of
the carbonyl center within the dienophilic tether. Isolation of
the highly labile aza-oxabicyclo adducts is a result of the lower
reaction temperatures used (ca. 25 °C) as well as the presence
of the extra carbonyl group, which diminishes the basicity of
the nitrogen atom, thereby retarding the thermal cleavage/
rearrangement reaction generally encountered with these sys-
tems. The Rh(I)-catalyzed ring-opening reactions of the IMDAF
cycloadducts were investigated using a variety of nucleophiles.
The catalyzed reactions proceed in high yield under very mild
conditions and occur with excellent diasteroselectivity. Ap-
plication of this methodology to various alkaloid skeletons is
currently under investigation, the results of which will be
disclosed in due course.
1
1157 cm-1; H NMR (CDCl3, 400 MHz) δ 0.97 (s, 3H), 1.25 (d,
1H, J ) 11.6 Hz), 1.50 (s, 9H), 2.13 (dd, 1H, J ) 11.6 and 4.4
Hz), 2.39 (d, 1H, J ) 16.8 Hz), 2.67 (d, 1H, J ) 16.8 Hz), 4.93
(dd, 1H, J ) 4.4 and 2.0 Hz), 6.32 (dd, 1H, J ) 6.0 and 2.0 Hz),
and 6.48 (d, 1H, J ) 6.0 Hz); 13C NMR (CDCl3, 100 MHz) δ
24.3, 28.1, 39.9, 41.8, 46.5, 77.1, 84.0, 104.0, 132.8, 133.3, 149.7,
and 174.5. Anal. Calcd for C14H19NO4: C, 63.38; H, 7.22; N, 5.28.
Found: C, 63.33; H, 7.13; N, 5.24.
tert-Butyl 3-Oxo-5-phenyl-10-oxa-2-azatricyclo[5.2.1.01,5]dec-
8-ene-2-carboxylate (25). To a solution of 0.41 g (2.2 mmol) of
carbamate 12a in 8 mL of THF at 0 °C was added dropwise 1.7
mL (2.5 mmol) of n-BuLi (1.5 M in hexane). The reaction mixture
was stirred at 0 °C for 20 min. In a separate flask, 0.40 g (2.5
mmol) of 3-phenylbut-3-enoic acid49 was dissolved in 10 mL of
THF at 0 °C, and 0.27 mL (2.5 mmol) of 4-methylmorpholine and
0.32 mL (2.5 mmol) of isobutyl chloroformate were added
dropwise. After the mixture was stirred for 5 min, the white
precipitate was removed via filtration and washed with 4 mL of
THF. The filtrate was cooled to 0 °C, and the preformed lithiate
was added dropwise via syringe to the above solution. After being
stirred at 0 °C for an additional 5 min, the reaction was quenched
with H2O and extracted with EtOAc. The organic layer was washed
with saturated aqueous NaHCO3, dried over MgSO4, and concen-
trated under reduced pressure. The residue was subjected to flash
Experimental Section
tert-Butyl 3-Oxo-10-oxa-2-azatricyclo[5.2.1.01,5]dec-8-ene-2-
carboxylate (23). To a solution of 0.2 g (1.2 mmol) of tert-butyl
furan-2-ylcarbamate (12a) in 4 mL of THF at 0 °C was added
dropwise 0.8 mL (1.3 mmol) of n-BuLi (1.5 M in hexane). The
reaction mixture was stirred at 0 °C for 20 min. In a separate flask,
0.1 mL (1.2 mmol) of 3-butenoic acid was dissolved in 5 mL of
THF at 0 °C, and 0.13 mL (1.2 mmol) of 4-methylmorpholine and
0.15 mL (1.2 mmol) of isobutyl chloroformate were added
dropwise. After the mixture was stirred for 5 min, the white
precipitate was removed via filtration and washed with 2 mL of
THF. The filtrate was cooled to 0 °C, and the preformed lithiate
(48) Smith III, A. B.; Toder, B. H.; Branca, S. J.; Dieter, R. K. J. Am.
Chem. Soc. 1981, 103, 1996.
(49) Itoh, K.; Harada, T.; Nagashima, H. Bull. Chem. Soc. Jpn. 1991,
64, 3746.
J. Org. Chem, Vol. 71, No. 8, 2006 3215

Padwa and Wang
silica gel chromatography to afford a pale yellow oil which
underwent spontaneous cycloaddition while standing at room
temperature for 12 h. The crude yellow oil was subjected to flash
silica gel chromatography to provide 0.3 g (41%) of 25 as a clear
imidofuran 22 in 4 mL of toluene was heated at 90 °C for 4 h. The
solution was cooled to room temperature, and the solvent was
removed under reduced pressure. The residue was subjected to flash
silica gel chromatography to afford 0.15 g (71%) of 27 as a white
1
oil: IR (neat) 1798, 1762, 1726, 1357, and 1296 cm-1; H NMR
solid: mp 154-155 °C; IR (neat) 1792, 1357, 1255, and 1157 cm-1
;
(CDCl3, 400 MHz) δ 1.53 (s, 9H), 2.17 (d, 1H, J ) 12.0 Hz), 2.52
(dd, 1H, J ) 12.0 and 4.8 Hz), 2.84 (d, 1H, J ) 16.8 Hz), 3.02 (d,
1H, J ) 16.8 Hz), 5.10 (dd, 1H, J ) 4.8 and 2.0 Hz), 6.31 (dd,
1H, J ) 6.0 and 2.0 Hz), 6.36 (d, 1H, J ) 6.0 Hz), 7.11-7.14 (m,
2H), and 7.17-7.28 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ 28.2,
40.4, 48.4, 49.9, 77.0, 84.2, 104.5, 126.9, 127.1, 128.8, 133.0, 134.4,
143.2, 149.3, and 174.4. Anal. Calcd for C19H21NO4: C, 69.71; H,
6.47; N, 4.28. Found: C, 69.52; H, 6.37; N, 4.38.
1H NMR (CDCl3, 400 MHz) δ 1.20-1.26 (m, 1H), 1.32-1.40 (m,
1H), 1.53 (s, 9H), 1.55-1.79 (m, 4H), 2.51 (d, 1H, J ) 17.0 Hz),
2.76-2.81 (m, 1H), 2.96 (d, 1H, J ) 17.0 Hz), 4.88 (dd, 1H, J )
5.2 and 2.0 Hz), 6.41 (dd, 1H, J ) 6.0 and 2.0 Hz), and 6.59 (d,
1H, J ) 6.0 Hz); 13C NMR (CDCl3, 100 MHz) δ 27.2, 28.2, 29.2,
35.1, 46.9, 55.2, 56.7, 80.1, 84.1, 104.4, 133.9, 134.8, 149.6, and
174.8. Anal. Calcd for C16H21NO4: C, 65.96; H, 7.27; N, 4.81.
Found: C, 65.68; H, 7.20; N, 4.90.
tert-Butyl
3-Oxo-5-carbomethoxy-10-oxa-2-azatricyclo-
tert-Butyl 2,3,3a,4,5,6-hexahydro-3a-methyl-2,5-dioxoindole-
1-carboxylate (28). A solution containing 0.05 g (0.19 mmol) of
oxabicycle 24 in 2 mL of toluene in a sealed tube was heated at
140 °C for 4 h. Concentration under reduced pressure and
purification by silica gel chromatography provided 0.046 g (92%)
of 28 as a yellow oil: IR (neat) 1763, 1724, 1681, 1301, 1150 and
[5.2.1.01,5]dec-8-ene-2-carboxylate (26). To a solution of 0.36 g
(2.0 mmol) of tert-butyl furan-2-yl-carbamate (12a) in 8 mL of
THF at 0 °C was added dropwise 1.3 mL (2.2 mmol) of n-BuLi
(1.6 M in hexane). The reaction mixture was stirred at 0 °C for 20
min. In a separate flask, 0.37 g (2.6 mmol) of 3-carbomethoxybut-
3-enoic acid was dissolved in 10 mL of THF at 0 °C, and 0.28 mL
(2.6 mmol) of 4-methylmorpholine and 0.33 mL (2.6 mmol) of
isobutyl chloroformate were added dropwise. After the mixture was
stirred for 5 min, the white precipitate was removed via filtration
and washed with 4 mL of THF. The filtrate was cooled to 0 °C,
and the preformed lithiate was added dropwise via syringe to the
above soltuion. After being stirred at 0 °C for an additional 10
min, the reaction was quenched with H2O and extracted with
EtOAc. The organic layer was washed with saturated aqueous
NaHCO3, dried over MgSO4, and concentrated under reduced
pressure. The residue was subjected to flash silica gel chromatog-
raphy to afford 0.47 g (77%) of 26 as a yellow oil: IR (neat) 2971,
1
845 cm-1; H NMR (CDCl3, 400 MHz) δ 1.18 (s, 3H), 1.57 (s,
9H), 2.43 (d, 1H, J ) 17.2 Hz), 2.56 (d, 1H, J ) 14.6 Hz), 2.57
(d, 1H, J ) 17.2 Hz), 2.63 (d, 1H, J ) 14.6 Hz), 3.03 (d, 2H, J )
3.8 Hz), and 6.00 (t, 1H, J ) 3.8 Hz); 13C NMR (CDCl3, 100 MHz)
δ 25.8, 28.2, 37.8, 37.9, 46.0, 51.4, 84.7, 102.6, 142.0, 149.5, 171.8,
and 207.6; HRMS calcd for C14H19NO4 265.1314, found 265.1312.
tert-Butyl 2,5-Dioxo-3a-phenyl-2,3,3a,4,5,6-hexahydroindole-
1-carboxylate (29). A solution containing 0.02 g (0.06 mmol) of
hexahydroindolinone 25 in 1 mL of toluene was heated at 135 °C
for 14 h and then cooled to rt. Concentration of the solution under
reduced pressure followed by purification using silica gel chroma-
tography afforded 0.018 g (91%) of 29 as clear oil: IR (neat) 2986,
2955, 1801, and 1728 cm-1; H NMR (CDCl3, 400 MHz) δ 1.50
1
1
1766, 1725, 1298, 1149, and 707 cm-1; H NMR (CDCl3, 600
(s, 9H), 2.08 (dd, 1H, J ) 12.0 and 4.4 Hz), 2.28 (d, 1H, J ) 12.0
Hz), 2.67 (d, 1H, J ) 17.0 Hz), 2.89 (d, 1H, J ) 17.0 Hz), 3.63 (s,
3H), 5.03 (dd, 1H, J ) 4.4 and 2.0 Hz), 6.38 (dd, 1H, J ) 6.0 and
2.0 Hz), and 6.41 (d, 1H, J ) 6.0 Hz); 13C NMR (CDCl3, 100
MHz) δ 28.1, 36.7, 42.4, 51.7, 52.9, 77.4, 84.2, 103.2, 132.7, 134.8,
149.0, 172.3, and 172.9; FAB HRMS calcd for [(C15H19NO6) +
Li]+ 316.1372, found 316.1372.
MHz) δ 1.59 (s, 9H), 2.82 (dd, 1H, J ) 23.4 and 2.4 Hz), 2.84 (d,
1H, J ) 14.4 Hz), 2.94 (s, 2H), 3.01 (dd, 1H, J ) 23.4 and 5.4
Hz), 3.17 (d, 1H, J ) 14.4 Hz), 6.35 (dd, 1H, J ) 5.4 and 2.4 Hz),
7.23-7.26 (m, 3H), and 7.32 (t, 2H, J ) 7.8 Hz); 13C NMR (CDCl3,
150 MHz) δ 28.2, 38.2, 46.1, 47.8, 53.0, 84.9, 106.0, 126.0, 128.2,
129.6, 140.1, 141.0, 149.4, 171.2, and 206.6; HRMS calcd for
C19H21NO4 327.1471, found 327.1470.
tert-Butyl 2-(Cyclopent-1-enylacetyl)furan-2-yl)carbamate (22).
To a solution of 0.5 g (2.6 mmol) of furanyl carbamate 12a in 8
mL of THF at 0 °C was added dropwise 1.9 mL (2.8 mmol) of
n-BuLi (1.5 M in hexane). The reaction mixture was stirred at 0
°C for 20 min. In a separate flask, 0.36 g (2.8 mmol) of 2-cyclopent-
1-enylacetic acid50 was dissolved in 10 mL of THF at 0 °C, and
0.3 mL (2.8 mmol) of 4-methylmorpholine and 0.36 mL (2.8 mmol)
of isobutyl chloroformate were added dropwise. After the mixture
was stirred for 5 min, the white precipitate was removed via
filtration and washed with 4 mL of THF. The filtrate was cooled
to 0 °C, and the preformed lithiate was added dropwise via syringe
to the above solution. After the mixture was stirred at 0 °C for an
additional 5 min, the reaction was quenched with H2O and extracted
with EtOAc. The organic layer was washed with saturated aqueous
NaHCO3 solution, dried over MgSO4, and concentrated under
reduced pressure. The residue was subjected to flash silica gel
chromatography to afford 0.43 g (58%) of 22 as a white solid: mp
1-tert-Butyl 3a-Methyl-2,5-dioxo-2,3,3a,4,5,6-tetrahydro-1H-
indole-1,3a(4H)-dicarboxylate (30). A solution containing 0.04 g
of oxabicycle 26 in 2 mL of toluene in a sealed tube was heated at
140 °C for 14 h. Concentration under reduced pressure and
purification by silica gel chromatography provided 0.035 g (90%)
of 30 as a yellow solid: mp 101-103 °C; IR (neat) 2980, 1774,
1
1736, 1302, 1153, and 842 cm-1; H NMR (CDCl3, 600 MHz) δ
1.58 (s, 9H), 2.42 (d, 1H, J ) 16.2 Hz), 2.54 (d, 1H, J ) 17.4 Hz),
3.01 (d, 1H, J ) 16.2 Hz), 3.02 (dd, 1H, J ) 22.8 and 6.0 Hz),
3.11 (d, 1H, J ) 17.4 Hz), 3.15 (dd, 1H, J ) 22.8 and 2.4 Hz),
3.73 (s, 3H), and 6.27 (dd, 1H, J ) 6.0 and 2.4 Hz); 13C NMR
(CDCl3, 100 MHz) δ 28.2, 37.2, 41.0, 46.7, 47.0, 53.7, 85.0, 106.4,
135.5, 149.2, 170.7, 171.3, and 204.7; HRMS calcd for C15H19-
NO6 309.1212, found 309.1214.
tert-Butyl 2,6-Dioxo-1,2,5,6,6a,7,8,9-octahydro-3-azacyclopen-
ta[d]indene-3-carboxylate (31). A solution containing 0.03 g (0.1
mmol) of oxabicycle 27 in 2 mL of toluene in a sealed tube was
heated at 140 °C for 3 h. Concentration under reduced pressure
and purification by silica gel chromatography provided 0.027 g
(90%) of 31 as a yellow oil: IR (neat) 1767, 1728, 1683, 1295,
and 1151 cm-1; 1H NMR (CDCl3, 600 MHz) δ 1.47-1.57 (m, 1H),
1.58 (s, 9H), 1.65-1.73 (m,1H), 1.84-2.75 (m, 2H), 2.40-3.45
(m, 1H), 2.45 (d, 1H, J ) 16.8 Hz), 2.49 (dd, 1H, J ) 16.8 and 1.6
Hz), 2.54 (d, 1H, J ) 7.2 Hz), 3.05 (dd, 1H, J ) 21.6 and 4.8 Hz),
3.10 (dd, 1H, J ) 21.6 and 3.6 Hz), and 5.99 (dd, 1H, J ) 4.8 and
3.6 Hz); 13C NMR (CDCl3, 150 MHz) δ 21.6, 24.8, 28.2, 37.5,
37.7, 45.0, 49.0, 56.7, 84.6, 102.6, 139.7, 149.5, 171.9, and 208.6;
HRMS calcd for C16H21NO4 291.1471, found 291.1470.
1
55-56 °C; IR (neat) 1792, 1746, 1608, 1265, and 1147 cm-1; H
NMR (CDCl3, 400 MHz) δ 1.42 (s, 9H), 1.85-1.92 (m, 4H), 2.33
(t, 2H, J ) 7.4 Hz), 3.57 (s, 2H), 5.52 (s, 1H), 6.14 (dd, 1H, J )
3.2 and 0.8 Hz), 6.41 (dd, 1H, J ) 3.2 and 2.4 Hz), and 7.32 (dd,
1H, J ) 2.4 and 0.8 Hz); 13C NMR (CDCl3, 100 MHz) δ 23.7,
27.9, 32.8, 35.4, 39.8, 84.0, 106.1, 111.4, 128.4, 137.1, 140.7, 144.1,
151.6, and 173.0. Anal. Calcd for C16H21NO4: C, 65.96; H, 7.27;
N, 4.81. Found: C, 65.83; H, 7.14; N, 4.88.
tert-Butyl 5,6-Cyclopentyl-3-oxo-10-oxa-2-azatricyclo[5.2.1.01,5]-
dec-8-ene-2-carboxylate (27). A solution of 0.2 g (0.7 mmol) of
tert-Butyl (3-Ethylfuran-2-yl)carbamate (32). A modification
(50) Miyashi, T.; Nishizawa, Y.; Fujii, Y.; Yamakawa, K.; Kamata, M.;
Akao, S.; Mukai, T. J. Am. Chem. Soc. 1986, 108, 1617.
of the procedure of Burness51 was used to prepare methyl
3216 J. Org. Chem., Vol. 71, No. 8, 2006

Rh(I)-Catalyzed Ring-Opening Reactions of Oxabicyclo Adducts
3-ethylfuran-2-carboxylate. To a mixture containing 23 g (156
mmol) of 1,1-dimethoxy-3-pentanone,52 22 mL (250 mmol) of
methyl chloroacetate, and 125 mL of dry Et2O at -10 °C was added
13.5 g (250 mmol) of freshly prepared powdered NaOMe in small
portions over 30 min maintaining an internal temperature below
-5 °C. The reaction mixture was stirred for an additional 2 h at
-10 °C and then warmed to room temperature overnight. The slurry
was cooled to 0 °C and quenched by the slow addition of a solution
of 3 mL of AcOH in 50 mL of H2O, and then the aqueous layer
was extracted with Et2O. The combined organic layers were washed
with a dilute NaHCO3 solution and brine, dried over anhydrous
MgSO4, and concentrated under reduced pressure. The crude residue
was transferred to a flask equipped with a 5 in. Vigreux column
and distillation head and was heated at 170 °C until MeOH
distillation ceased. The mixture was cooled to room temperature
and distilled under reduced pressure to afford 11.7 g (49%) of
3-ethyl-furan-2-carboxylic acid methyl ester as a colorless oil: bp
80-95 °C (15 mm); IR (neat) 1716, 1598, 1490, 1434, 1301, and
the white precipitate was removed by filtration and was washed
with 2 mL of THF. The filtrate was cooled to 0 °C, and the
preformed lithiate was added dropwise via syringe. After the
mixture was stirred at 0 °C for an additional 5 min, the reaction
was quenched with H2O and extracted with EtOAc. The organic
layer was washed with a saturated aqueous NaHCO3 solution, dried
over MgSO4. and concentrated under reduced pressure. The residue
was subjected to flash silica gel chromatography to afford the
expected imidofuran as a labile oil which underwent spontaneous
cycloaddition while standing at room temperature for 12 h. The
crude colorless oil was subjected to flash silica gel chromatography
to afford 0.21 g (60%) of 34 as a colorless oil: IR (neat) 1798,
1762, 1731, 1296, and 1157 cm-1; 1H NMR (CDCl3, 400 MHz) δ
1.09 (t, 3H, J ) 7.2 Hz), 1.53 (s, 9H), 1.68 (dd, 1H, J ) 11.6 and
8.0 Hz), 1.79 (dt, 1H, J ) 11.6 and 4.0 Hz), 1.92-2.06 (m, 2H),
2.29-2.37 (m, 1H), 2.40 (dd, 1H, J ) 17.2 and 10.4 Hz), 2.74
(dd, 1H, J ) 17.2 and 8.8 Hz), 4.99 (d, 1H, J ) 4.0 Hz), and 5.89
(q, 1H, J ) 2.0 Hz); 13C NMR (CDCl3, 100 MHz) δ 11.4, 18.8,
28.0, 35.0, 35.4, 38.3, 77.5, 84.0, 103.3, 126.5, 149.6, 150.0, and
175.1. Anal. Calcd for C15H21NO4: C, 64.48; H, 7.58; N, 5.02.
Found: C, 64.36; H, 7.35; N, 5.37.
1
1198 cm-1; H NMR (CDCl3, 400 MHz) δ 1.18 (t, 3H, J ) 7.6
Hz), 2.81 (q, 2H, J ) 7.6 Hz), 3.87 (s, 3H), 6.40 (d, 1H, J ) 1.6
Hz) ,and 7.43 (d, 1H, J ) 1.6 Hz); 13C NMR (CDCl3, 100 MHz)
δ 14.3, 19.1, 51.7, 113.5, 137.8, 139.5, 145.2, and 160.1; HRMS
calcd for C8H10O3 154.0630, found 154.0631.
tert-Butyl 7-Methyl-3-oxo-10-oxa-2-azatricyclo[5.2.1.01,5]dec-
8-ene-2-carboxylate (35). To a solution of 0.3 g (1.5 mmol) of
the known tert-butyl (5-methylfuran-2-yl)carbamate53 in 5 mL of
THF at 0 °C was added dropwise 1.2 mL (1.7 mmol) of n-BuLi
(1.4 M in hexane). The reaction mixture was stirred at 0 °C for 20
min so as to generate the lithiated carbamate 33. In a separate flask,
0.14 mL (1.7 mmol) of vinylacetic acid was dissolved in 5 mL of
THF at 0 °C, and 0.18 mL (1.7 mmol) of 4-methylmorpholine and
0.22 mL (1.7 mmol) of isobutyl chloroformate were added
dropwise. After the mixture was stirred for 5 min, the white
precipitate that formed was removed by filtration and washed with
2 mL of THF. The filtrate was cooled to 0 °C, and the preformed
lithiate was added dropwise via syringe. After the mixture was
stirred at 0 °C for an additional 5 min, the reaction was quenched
with H2O and extracted with EtOAc. The organic layer was washed
with a saturated aqueous NaHCO3 solution, dried over MgSO4, and
concentrated under reduced pressure. The residue was subjected
to flash silica gel chromatography to afford the expected imidofuran
as a labile oil which underwent spontaneous cycloaddition while
standing at room temperature for 12 h. The crude yellow solid was
subjected to flash silica gel chromatography to give 0.3 g (68%)
of 35 as a white solid: mp 86-87 °C; IR (neat) 1796, 1763, 1731,
A suspension of 4.0 g (26 mmol) of the above 3-ethylfuran-2-
carboxylic acid methyl ester in 30 mL of a 10% aqueous NaOH
solution was heated at reflux for 2 h. The homogeneous reaction
mixture was cooled to 0 °C and was slowly acidified with concd
HCl. The resultant white precipitate was collected by filtration,
washed with several portions of cold H2O, and dried under high
vacuum to afford 3.4 g (94%) of 3-ethylfuran-2-carboxylic acid as
a white solid: mp 106-107 °C; IR (neat) 3139, 1675, 1593, 1490,
1
and 1285 cm-1; H NMR (CDCl3, 400 MHz) δ 1.22 (t, 3H, J )
7.6 Hz), 2.85 (q, 2H, J ) 7.6 Hz), 6.46 (d, 1H, J ) 1.6 Hz), 7.52
(d, 1H, J ) 1.6 Hz), and 12.31 (brs, 1H); 13C NMR (CDCl3, 100
MHz) δ 14.2, 19.4, 113.9, 138.9, 140.3, 146.5, and 165.0. Anal.
Calcd for C7H8O3: C, 59.99; H, 5.75. Found: C, 59.82; H, 5.74.
To a solution of 2.0 g (14.3 mmol) of the above acid in 60 mL
of CH2Cl2 were added 1.5 mL (17 mmol) of oxalyl chloride and 1
drop of DMF. The reaction mixture was stirred at rt for 1 h and
then concentrated under reduced pressure. The crude residue was
dissolved in 40 mL of Et2O, and a solution of 1.1 g (17 mmol) of
NaN3 in 20 mL of H2O was added. The biphasic reaction mixture
was stirred vigorously for 3 h, and then the organic layer was
separated, dried over MgSO4, and concentrated under reduced
pressure. The crude residue was dissolved in 40 mL of t-BuOH
and heated at reflux for 12 h. The reaction mixture was cooled to
rt and concentrated under reduced pressure. The residue was
subjected to flash silica gel chromatography to afford 1.6 g (52%)
of tert-butyl (3-ethyl-furan-2-yl)carbamate (32) as a pale yellow
1
1295, and 1160 cm-1; H NMR (CDCl3, 400 MHz) δ 1.46 (dd,
1H, J ) 7.6 and 4.4 Hz), 1.49 (s, 9H), 1.60 (s, 3H), 1.71 (dd, 1H,
J ) 11.6 and 7.6 Hz), 2.12-2.19 (m, 1H), 2.40 (dd, 1H, J ) 17.0
and 10.2 Hz), 2.70 (dd, 1H, J ) 17.0 and 8.6 Hz), 6.10 (d, 1H, J
) 5.8 Hz), and 6.49 (d, 1H, J ) 5.8 Hz); 13C NMR (CDCl3, 100
MHz) δ 19.5, 28.1, 38.5, 38.9, 39.0, 83.8, 85.2, 101.2, 135.2, 136.6,
149.4, and 174.6. Anal. Calcd for C14H19NO4: C, 63.38; H, 7.22;
N, 5.28. Found: C, 63.45; H, 7.32; N, 5.33.
1
oil: IR (neat) 3313, 1716, 1644, 1511, 1244, and 1157 cm-1; H
NMR (CDCl3, 400 MHz) δ 1.13 (t, 3H, J ) 7.6 Hz), 1.46 (s, 9H),
2.34 (q, 2H, J ) 7.6 Hz), 6.09 (brs, 1H), 6.25 (d, 1H, J ) 2.0 Hz),
and 7.13 (d, 1H, J ) 2.0 Hz); 13C NMR (CDCl3, 100 MHz) δ
14.2, 17.7, 28.3, 81.2, 111.8, 119.2, 138.9, 139.3, and 154.0; HRMS
calcd for C11H17NO3 211.1208, found 211.1215.
tert-Butyl 9-Ethyl-3-oxo-10-oxa-2-azatricyclo[5.2.1.01,5]dec-8-
ene-2-carboxylate (34). To a solution of 0.27 g (1.2 mmol) of the
above furan in 4 mL of THF at 0 °C was added dropwise 1.0 mL
(1.4 mmol) of n-BuLi (1.4 M in hexane). The reaction mixture
was stirred at 0 °C for 20 min so as to generate the lithiated
carbamate 32. In a separate flask, 0.12 mL (1.4 mmol) of vinylacetic
acid was dissolved in 5 mL of THF at 0 °C, and 0.15 mL (1.4
mmol) of 4-methylmorpholine and 0.18 mL (1.4 mmol) of isobutyl
chloroformate were added dropwise. After being stirred for 5 min,
tert-Butyl 4-Methyl-3-oxo-10-oxa-2-azatricyclo[5.2.1.01,5]dec-
8-ene-2-carboxylate (38). To a solution of 0.7 g (4.1 mmol) of
tert-butyl furan-2-ylcarbamate (12a) in 12 mL of THF at 0 °C was
added dropwise 2.1 mL (4.3 mmol) of n-BuLi (2.1 M in hexane).
The reaction mixture was stirred at 0 °C for 20 min. In a separate
flask, 0.47 mL (4.5 mmol) of 2-methylbut-3-enoic acid was
dissolved in 15 mL of THF at 0 °C, and 0.5 mL (4.5 mmol) of
4-methylmorpholine and 0.58 mL (4.5 mmol) of isobutyl chloro-
formate were added dropwise. After the mixture was stirred for 5
min, the white precipitate that formed was removed by filtration
and washed with 2 mL of THF. The filtrate was cooled to 0 °C,
and the preformed lithiate was added dropwise via syringe to the
above solution. After being stirred at 0 °C for an additional 10
min, the reaction mixture was quenched with H2O and extracted
with EtOAc. The organic layer was washed with a saturated aqueous
(51) Burness, D. M. Organic Syntheses; Wiley: New York, 1963; Collect.
Vol. IV, p 649.
(52) Harayama, T.; Cho, H.; Inubushi, Y. Chem. Pharm. Bull. 1978, 26,
1201.
(53) Padwa, A.; Brodney, M. A.; Liu, B.; Satake, K.; Wu, T. J. Org.
Chem. 1999, 64, 3595.
J. Org. Chem, Vol. 71, No. 8, 2006 3217

Padwa and Wang
NaHCO3 solution, dried over MgSO4, and concentrated under
reduced pressure. The residue was subjected to flash silica gel
chromatography to afford 0.69 g (65%) of furan 36 as a colorless
oil which underwent spontaneous cycloaddition while standing at
room temperature for 12 h. The 1H NMR spectra revealed the
presence of a 20:1 mixture of two diastereomers. The crude residue
was subjected to flash silica gel chromatography to provide 0.66 g
(96%) of the major cis diastereomer 38 as a white solid: mp 102-
104 °C; IR (neat) 2979, 1794, 1766, 1731, and 1159 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 1.24 (d, 3H, J ) 6.8 Hz), 1.52 (s, 9H), 1.64
(dd, 1H, J ) 11.2 and 7.2 Hz), 1.73 (ddd, 1H, J ) 10.0, 7.2 and
3.2 Hz), 1.81 (ddd, 1H, J ) 11.2, 4.4 and 3.2 Hz), 2.43 (dq, 1H,
J ) 10.0 and 6.8 Hz), 5.03 (dd, 1H, J ) 4.4 and 2.0 Hz), 6.31 (dd,
1H, J ) 6.0 and 2.0 Hz), and 6.50 (d, 1H, J ) 6.0 Hz); 13C NMR
(CDCl3, 100 MHz) δ 14.3, 28.2, 31.7, 44.0, 44.5, 77.7, 83.9, 100.0,
133.8, 134.6, 149.6, and 177.0. Anal. Calcd for C14H19NO4: C,
63.38; H, 7.22; N, 5.28. Found: C, 63.44; H, 7.32; N, 5.30.
tert-Butyl 3-Oxo-4-phenyl-10-oxa-2-azatricyclo[5.2.1.01,5]dec-
8-ene-2-carboxylate (39). To a solution of 0.35 g (1.9 mmol) of
carbamate 12a in 10 mL of THF at 0 °C was added dropwise 1.1
mL (2.2 mmol) of n-BuLi (2.1 M in hexane). The reaction mixture
was stirred at 0 °C for 20 min. In a separate flask, 0.37 g (2.3
mmol) of 2-phenylbut-3-enoic acid54 was dissolved in 15 mL of
THF at 0 °C, and 0.25 mL (2.3 mmol) of 4-methyl-morpholine
and 0.3 mL (2.3 mmol) of isobutyl chloroformate were added
dropwise. After the mixture was stirred for 5 min, the white
precipitate that formed was removed by filtration and washed with
2 mL of THF. The filtrate was cooled to 0 °C, and the preformed
lithiate was added dropwise via syringe to the above solution. After
being at 0 °C for an additional 10 min, the reaction mixture was
quenched with H2O and extracted with EtOAc. The organic layer
was washed with a saturated aqueous NaHCO3 solution, dried over
MgSO4, and concentrated under reduced pressure. The residue was
subjected to flash silica gel chromatography to afford 0.34 g (55%)
of furan 37 as a colorless oil, which underwent spontaneous
cycloaddition while standing at room temperature for 12 h. The
1H NMR spectrum of the solid showed a 30:1 mixture of two
diastereomers. The crude residue was subjected to flash silica gel
chromatography to provide 0.34 g (98%) of the major cis isomer
39 as a white solid: mp 124-125 °C; IR (neat) 1793, 1732, 1296,
and 1157 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.54 (s, 9H), 1.63
(dd, 1H, J ) 12.0 and 8.0 Hz), 1.94 (dt, 1H, J ) 12.0 and 3.6 Hz),
2.27 (ddd, 1H, J ) 10.8, 8.0 and 3.6 Hz), 3.63 (d, 1H, J ) 10.8
Hz), 5.09 (dd, 1H, J ) 3.6 and 2.0 Hz), 6.36 (dd, 1H, J ) 6.0 and
2.0 Hz), 6.59 (d, 1H, J ) 6.0 Hz), and 7.22-7.36 (m, 5H); 13C
NMR (CDCl3, 100 MHz) δ 28.1, 31.9, 44.9, 55.6, 77.8, 84.2, 99.7,
127.7, 128.6, 128.9, 134.1, 134.4, 136.5, 149.5, and 174.4. Anal.
Calcd for C19H21NO4: C, 69.71; H, 6.47; N, 4.28. Found: C, 69.76;
H, 6.42; N, 4.22.
8.0 Hz); 13C NMR (CDCl3, 100 MHz) δ 28.1, 32.5, 34.9, 37.7,
68.7, 72.6, 84.7, 104.4, 116.2, 122.0, 130.0, 143.6, 149.2, 157.8,
and 172.3; HRMS calcd for C19H23NO5 345.1576, found 345.1574.
tert-Butyl 5-Hydroxy-3a-methyl-2-oxo-6-phenoxy-2,3,3a,4,5,6-
hexahydroindole-1-carboxylate (41). To a solution containing 0.06
g (0.22 mmol) of oxabicycle 24 in 0.5 mL of THF were added 3
mg (0.007 mmol) of [Rh(COD)Cl]2, 7 mg (0.014 mmol) of DPPF,
and 0.22 g (2.3 mmol) of phenol. The mixture was heated at 80 °C
for 2 h, cooled to rt, and diluted with ether. The organic layer was
washed with a 4% aqueous NaOH solution and dried over MgSO4.
The solvent was removed under reduced pressure, and a NMR
spectrum of the crude reaction mixture showed the presence of a
5:1 mixture of isomeric products. Purification by flash silica gel
chromatography afforded 0.06 g (75%) of the major isomer 41 as
a white solid: mp 126-128 °C; IR (neat) 3508, 1774, 1732, 1302,
and 1153 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.29 (s, 3H), 1.52
(s, 9H), 1.95 (t, 1H, J ) 12.1 Hz), 2.02 (dd, 1H, J ) 12.1 and 4.1
Hz), 2.36 (d, 1H, J ) 16.2 Hz), 2.47 (d, 1H, J ) 16.2 Hz), 2.57 (d,
1H, J ) 10.5 Hz), 4.14-4.23 (m, 1H), 4.94 (t, 1H, J ) 4.7 Hz),
6.15 (d, 1H, J ) 4.7 Hz), 6.97-7.01 (m, 3H), and 7.28-7.32 (m,
2H); 13C NMR (CDCl3, 100 MHz) δ 25.9, 28.1, 38.8, 38.9, 47.4,
66.1, 72.3, 84.5, 104.6, 116.2, 122.0, 129.9, 147.2, 149.5, 157.8,
and 171.8; HRMS calcd for C20H25NO5 359.1733, found 359.1733.
The minor isomer (0.01 g (15%)) was obtained as a clear oil:
IR (neat) 1786, 1733, 1301, and 1148 cm-1; 1H NMR (CDCl3, 400
MHz) δ 1.37 (s, 3H), 1.44(s, 9H), 1.86 (t, 1H, J ) 16.8 Hz), 2.15
(dd, 1H, J ) 16.8 and 5.2 Hz), 2.35-2.46 (m, 3H), 4.28-4.38 (m,
1H), 4.91 (dd, 1H, J ) 9.6 and 4.0 Hz), 5.98 (d, 1H, J ) 4.0 Hz),
6.96-7.00 (m, 3H), and 7.26-7.32 (m, 2H); 13C NMR (CDCl3,
100 MHz) δ 26.5, 28.1, 28.2, 38.3, 40.8, 47.6, 68.8, 81.0, 84.5,
105.1, 116.6, 121.8, 129.9, 145.1, 157.8, and 173.4; HRMS calcd
for C20H25NO5 359.1733, found 359.1730.
tert-Butyl 6-(N-Methyl-N-phenylamino)-5-hydroxy-2-oxo-2,3,-
3a,4,5,6-hexahydroindole-1-carboxylate (42). To a solution con-
taining of 0.06 g (0.24 mmol) of oxabicycle 23 in 1 mL of THF
were added 3 mg (0.007 mmol) of [Rh(COD)Cl]2, 8 mg (0.014
mmol) of DPPF, 0.13 mL (1.2 mmol) of N-methylaniline, and 0.44
g (1.2 mmol) of tetrabutylammonium iodide. The mixture was
heated at reflux for 12 h, cooled to rt, diluted with water, and
extracted with CHCl3. The organic layer was dried over MgSO4
and concentrated under reduced pressure. A 1H NMR spectrum of
the crude reaction mixture indicated a 20:1 mixture of two isomeric
products. Purification by silica gel chromatography afforded 0.03
g (33%) of the major isomer 42 as a clear oil: IR (neat) 3451,
1786, 1732, 1306, and 1150 cm-1; 1H NMR (CDCl3, 400 MHz) δ
1.51 (s, 9H), 1.67 (q, 1H, J ) 12.0 Hz), 2.29 (dd, 1H, J ) 16.8
and 12.0 Hz), 2.36 (dt, 1H, J ) 10.0 and 4.0 Hz), 2.51 (brs, 1H),
2.64 (dd, 1H, J ) 16.8 and 8.8 Hz), 2.78 (s, 3H), 2.88-2.97 (m,
1H), 4.01 (ddd, 1H, J ) 12.0, 8.8 and 4.0 Hz), 4.49 (dt, 1H, J )
8.8 and 2.8 Hz), 5.64 (t, 1H, J ) 2.8 Hz), 6.80 (t, 1H, J ) 7.6 Hz),
6.95 (d, 2H, J ) 7.6 Hz), and 7.25 (t, 2H, J ) 7.6 Hz); 13C NMR
(CDCl3, 100 MHz) δ 28.2, 32.8, 34.1, 38.3, 66.1, 68.4, 84.73, 107.5,
115.2, 118.8, 129.5, 140.1, 148.9, 151.1, and 172.8; HRMS calcd
for C20H26N2O4 358.1892, found 358.1892.
tert-Butyl 2,3,3a,4,5,6-Hexahydro-5-hydroxy-2-oxo-6-phen-
oxyindole-1-carboxylate (40). To a solution containing 0.05 g (0.2
mmol) of oxabicycle 23 in 0.5 mL of THF was added 3 mg (0.006
mmol) of [Rh(COD)Cl]2, 6 mg (0.012 mmol) of 1,1′-bis(diphen-
ylphosphino)ferrocene (DPPF), and 0.19 g (2.0 mmol) of phenol.
The mixture was heated at 80 °C for 12 h, cooled to rt, and diluted
with ether. The organic layer was washed with a 4% aqueous NaOH
solution and dried over MgSO4. The solvent was removed under
tert-Butyl 6-(N-Methyl-N-phenylamino)-5-hydroxy-3a-methyl-
2-oxo 2,3,3a,4,5,6-hexahydroindole-1-carboxylate (43). To a
solution containing 0.05 g (0.19 mmol) of oxabicycle 24 in 1 mL
of THF were added 3 mg (0.006 mmol) of [Rh(COD)Cl2]2, 6 mg
(0.012 mmol) of DPPF, 0.13 g (0.94 mmol) of N-methylaniline,
and 0.13 g (0.94 mmol) of Et3NHCl. The mixture was heated at
80 °C for 10 h, cooled to rt, diluted with water, and extracted with
CHCl3. The organic layer was dried over MgSO4 and concentrated
under reduced pressure. A 1H NMR spectrum of the crude mixture
showed the presence of two isomeric products in a ratio of 10:1.
Purification by silica gel chromatography afforded 0.04 g (58%)
of the major isomer 43 as a clear oil: IR (neat) 3462, 1786, 1733,
1301, and 1149 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.34 (s, 3H),
1.51 (s, 9H), 1.82 (t, 1H, J ) 12.4 Hz), 2.17 (dd, 1H, J ) 12.4 and
4.0 Hz), 2.36 (d, 1H, J ) 16.4 Hz), 2.36 (brs, 1H), 2.43 (d, 1H, J
1
reduced pressure, and a H NMR spectrum of the crude mixture
showed the presence of a 5:1 mixture of isomeric products.
Purification by flash silica gel chromatography afforded 0.02 g
(62%) of the major isomer 40 as a clear oil: IR (neat) 3448, 1771,
1
1732, 1300, and 1152 cm-1; H NMR (CDCl3, 400 MHz) δ 1.50
(s, 9H), 1.82 (d, 1H, J ) 11.6 Hz), 2.18 (dt, 1H, J ) 11.6 and 4.4
Hz), 2.43 (dd, 1H, J ) 16.8 and 11.6 Hz), 2.57 (d, 1H, J ) 11.6
Hz), 2.66 (dd, 1H, J ) 16.8 and 8.4 Hz), 2.76-2.88 (m,1H), 3.96
(tt, 1 H, J ) 11.6 and 4.4 Hz), 4.94 (t, 1H, J ) 4.4 Hz), 6.21 (dd,
1H, J ) 4.4 and 2.4 Hz), 6.97-7.00 (m, 3H), and 7.29 (t, 2H, J )
(54) Friedrich, L. E.; Cormier, R. A. J. Org. Chem. 1971, 36, 3011.
3218 J. Org. Chem., Vol. 71, No. 8, 2006

Rh(I)-Catalyzed Ring-Opening Reactions of Oxabicyclo Adducts
) 16.4 Hz), 2.80 (s, 3H), 4.19 (ddd, 1H, J ) 12.0, 8.8 and 4.0
Hz), 4.47 (dd,1H, J ) 8.8 and 2.8 Hz), 5.60 (d, 1H, J ) 2.8 Hz),
6.80 (t, 1H, J ) 7.6 Hz), 6.95 (d, 2H, J ) 7.6 Hz), and 7.25 (t, 2H,
J ) 7.6 Hz); 13C NMR (CDCl3, 100 MHz) δ 26.5, 28.2, 32.9, 38.2,
41.1, 47.9, 66.0, 66.4, 84.2, 107.9, 115.1, 118.7, 129.5, 143.7, 149.2,
151.0, and 172.4; HRMS calcd for C21H28N2O4 372.2049, found
372.2048.
combined organic layer was dried over MgSO4. The solvent was
removed under reduced pressure, and the residue was subjected to
the flash silica gel chromatography to afford 0.06 g (72%) of 51
as a white solid: mp 175-176 °C; IR (neat) 3437, 1777, 1724,
1
1292, and 705 cm-1; H NMR (CDCl3, 400 MHz) δ 1.05 (d, 1H,
J ) 10.2 Hz), 1.51-1.55 (m, 1H), 1.55 (s, 9H), 1.99 (ddd, 1H, J
) 12.0, 5.2 and 3.2 Hz), 2.37 (d, 1H, J ) 17.2 Hz), 2.71 (dd, 1H,
J ) 17.2 and 8.8 Hz), 2.92-2.95 (m, 1H), 3.91-3.95 (m,1H),
4.12-4.20 (m, 1H), 5.91 (dd, 1H, J ) 4.4 and 2.4 Hz), 7.25-7.28
(m, 2H), and 7.30-7.40 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ
28.2, 32.6, 38.6, 46.0, 68.7, 84.3, 109.1, 127.9, 128.7, 130.7, 138.2,
138.8, 149.4, and 172.8. Anal. Calcd for C19H23NO4: C, 69.28; H,
7.04; N, 4.25. Found: C, 69.19; H, 7.07; N, 4.21.
tert-Butyl 6-(2-Bromobenzoyloxy)-5-hydroxy-3a-methyl-2-
oxo-2,3,3a,4,5,6-hexahydroindole-1-carboxylate (44a). To a solu-
tion containing 0.05 g (0.19 mmol) of oxabicycle 24 in 1 mL of
THF was added 3 mg (0.006 mmol) of [Rh(COD)Cl]2, 6 mg (0.012
mmol) of DPPF, 0.38 g (1.9 mmol) of 2-bromobenzoic acid, and
0.26 mL (1.9 mmol) of Et3N. The mixture was heated at 80 °C for
10 h, cooled to room temperature, diluted with water, and extracted
with ether. The organic layer was dried over MgSO4 and concen-
trated under reduced pressure. A NMR spectrum of the crude
mixture showed the presence of two isomeric products in a ratio
of 10:3. Purification by silica gel chromatography afforded 0.06 g
(72%) of the major cis-isomer 44a as a clear oil: IR (neat) 3487,
tert-Butyl 5-Hydroxy-3a-methyl-2-oxo-6-phenyl-2,3,3a,4,5,6-
hexahydroindole-1-carboxylate (52). To a solution containing 0.05
g (0.19 mmol) of oxabicycle 24, 3.0 mg (0.006 mmol) of [Rh-
(COD)Cl]2, and 2.0 µL (0.012 mmol) of P(OEt)3 in 1 mL of THF
were added 0.07 g (0.4 mmol) of 5,5-dimethyl-2-phenyl-1,3,2-
dioxaborinane (50) and 0.08 mL (0.38 mmol) of Cs2CO3 (5 M in
H2O). The reaction mixture was heated at 65 °C for 2 h, cooled to
rt, and quenched with water. The aqueous layer was extracted with
EtOAc, and the combined organic layer was dried over MgSO4.
The solvent was removed under reduced pressure, and the residue
was subjected to flash silica gel chromatography to afford 0.05 g
(80%) of 52 as a white solid: mp 170-173 °C; IR (neat) 3491,
1
1786, 1732, and 1148 cm-1; H NMR (CDCl3, 600 MHz) δ 1.33
(s, 3H), 1.54 (s, 9H), 1.85 (t, 1H, J ) 12.0 Hz), 2.19 (dd, 1H, J )
12.0 and 4.8 Hz), 2.37 (d, 1H, J ) 16.2 Hz), 2.45 (d, 1H, J ) 16.2
Hz), 3.26 (brs, 1H), 4.32 (ddd, 1H, J ) 12.0, 7.2 and 4.8 Hz), 5.58
(dd, 1H, J ) 7.2 and 3.6 Hz), 5.96 (d, 1H, J ) 3.6 Hz), 7.34 (td,
1H, J ) 7.8 and 1.8 Hz), 7.37 (td, 1H, J ) 7.8 and 1.8 Hz), 7.66
(dd, 1H, J ) 7.8 and 1.8 Hz) and 7.80 (dd, 1H, J ) 7.8 and 1.8
Hz); 13C NMR (CDCl3, 150 MHz) δ 26.1, 28.2, 37.6, 41.6, 47.2,
68.8, 80.6, 84.7, 104.4, 121.9, 127.5, 131.7, 132.2, 133.1, 134.6,
146.8, 149.2, 167.9, and 172.0; HRMS calcd for C21H24NO6Br
465.0787, found 465.0784.
1
1785, 1729, 1302, and 714 cm-1; H NMR (CDCl3, 400 MHz) δ
1.34 (s, 3H), 1.54 (s, 9H), 1.61 (t, 1H, J ) 12.4 Hz), 1.82 (dd, 1H,
J ) 12.4 and 3.6 Hz), 2.42 (d, 1H, J ) 16.0 Hz), 2.49 (d, 1H, J )
16.0 Hz), 3.93 (dd, 1H, J ) 6.4 and 4.4 Hz), 4.27-4.37 (m,1H),
5.85 (d, 1H, J ) 4.4 Hz), 7.22 (d, 2H, J ) 7.2 Hz), 7.31 (t, 1H, J
) 7.2 Hz), and 7.36 (t, 2 H, J ) 7.2 Hz); 13C NMR (CDCl3, 100
MHz) δ 26.4, 28.2, 38.9, 39.0, 46.1, 48.2, 66.2, 84.2, 109.5, 127.9,
128.7, 130.6, 137.9, 142.4, 149.7, and 172.4. Anal. Calcd for C20H25-
NO4: C, 69.95; H, 7.34; N, 4.08. Found: C, 69.67; H, 7.26; N,
4.01.
tert-Butyl 5-Hydroxy-2-oxo-2,4,5,6-tetrahydroindole-1-car-
boxylate (45). To the mixture of 0.18 g (0.72 mmol) of oxabicycle
23, 7 mg (0.014 mmol) of [Rh(COD)Cl]2, and 4.9 µL (0.029 mmol)
P(OEt)3 in 2 mL of THF was added 0.28 g (3.6 mmol) of
ammonium acetate. The reaction mixture was heated at reflux for
12 h and cooled to rt. The mixture was poured into a saturated
NaHCO3 aqueous solution and was extracted with EtOAc. The
combined organic layer was washed with brine and dried over
MgSO4. The solvent was removed under reduced pressure, and the
residue was subjected to flash column chromatography to give 0.14
g (80%) of 45 as a white solid: mp 167-168 °C; IR (neat) 3452,
1733, 1326, and 818 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.56 (s,
9H), 2.34 (brs, 1H), 2.44 (ddd, 1H, J ) 17.6, 8.4 and 4.0 Hz),
265-2.71 (m, 2H), 2.92 (dd, 1H, J ) 16.8 and 4.0 Hz), 4.15 (m,
tert-Butyl 2,3,3a,4,5,6-Hexahydro-2-oxo-5,6-phenylboronate-
indole-1-carboxylate (53). To a solution containing 0.1 g (0.4
mmol) of oxabicycle 23, 6 mg (0.01 mmol) of [Rh(COD)Cl]2, and
4.0 µL (0.02 mmol) of P(OEt)3 in 2 mL of THF was added 0.07 g
(0.6 mmol) of phenylboronic acid. The reaction mixture was heated
at 65 °C for 2 h, cooled to rt, and quenched with water. The aqueous
layer was extracted with EtOAc, and the combined organic layer
was washed with a saturated aqueous NaHCO3 solution and dried
over MgSO4. The solvent was removed under reduced pressure,
and the residue was subjected to the flash silica gel chromatography
to afford 0.14 g (98%) of 53 as a white solid: mp 139-141 °C; IR
1H), 5.77 (s, 1H), and 6.54 (ddd, 1H, J ) 5.6, 4.0 and 1.6 Hz); 13
C
NMR (100 MHz, CDCl3) δ 28.3, 33.7, 33.8, 66.2, 83.9, 115.2,
117.1, 136.0, 149.4, 149.7, and 168.2. Anal. Calcd for C13H17-
NO4: C, 62.14; H, 6.82; N, 5.57. Found: C, 61.73; H, 6.79; N,
5.41.
1
(neat) 1798, 1736, 1340, 1150, and 702 cm-1; H NMR (CDCl3,
400 MHz) δ 1.42 (q, 1H, J ) 12.0 Hz), 1.58, (s, 9H), 2.28 (dd,
1H, J ) 20.0 and 13.6 Hz), 2.45 (ddd, 1H, J ) 12.0, 5.6 and 4.0
Hz), 2.61-2.68 (m, 1H), 2.68 (dd, 1H, J ) 20.0 and 9.2 Hz), 4.67
(ddd, 1H, J ) 12.0, 7.6 and 5.6 Hz), 5.07 (ddd, 1H, J ) 7.6, 3.2
and 2.0 Hz), 6.24 (dd, 1H, J ) 4.0 and 2.0 Hz), 7.37 (t, 2H, J )
7.2 Hz), 7.47 (tt, 1H, J ) 7.2 and 1.6 Hz), and 7.80 (dd, 2H, J )
7.2 and 1.6 Hz); 13C NMR (CDCl3, 100 MHz) δ 28.1, 31.1, 33.8,
36.9, 73.7, 74.6, 84.8, 104.9, 128.0, 131.8, 135.0, 142.5, 148.9,
and 172.6; HRMS calcd for C19H22BNO5 355.1591, found 355.1593.
tert-Butyl 2,3,3a,4,5,6-Hexahydro-3a-methyl-2-oxo-5,6-phen-
ylboronateindole-1-carboxylate (54). To a solution containing 0.05
g (0.19 mmol) of oxabicycle 24, 2 mg (0.003 mmol) of [Rh(COD)-
Cl]2, and 1.0 µL (0.02 mmol) of P(OEt)3 in 1 mL of THF was
added 0.035 g (0.28 mmol) of phenylboronic acid. The reaction
mixture was heated at 65 °C for 2 h, cooled to rt, and quenched
with water. The aqueous layer was extracted with EtOAc, and the
combined organic layer was washed with a saturated aqueous
NaHCO3 solution and dried over MgSO4. The solvent was removed
under reduced pressure, and the residue was subjected to the flash
silica gel chromatography to afford 0.06 g (95%) of 54 as a white
solid: mp 136-137 °C; IR (neat) 1771, 1735, 1369, 1153, and
tert-Butyl 2-Oxo-2,3-dihydroindole-1-carboxylate (46). To a
solution of 0.18 g (0.72 mmol) of oxabicycle 23 in 2 mL of THF
was added 7 mg (0.014 mmol) of [Rh(COD)Cl]2 and 4.9 µL (0.029
mmol) of P(OEt)3. The reaction mixture was heated at reflux for 2
h and cooled to room temperature. The solvent was removed under
reduced pressure. The residue was subjected to flash silica gel
chromatography to give 0.16 g (90%) of 46 as a colorless oil: 1H
NMR (CDCl3, 400 MHz) δ 1.59 (s, 9H), 3.61 (s, 2H), 7.12 (t, 1H,
J ) 7.6 Hz), 7.23 (d, 1H, J ) 7.6 Hz), 7.28 (t, 1H, J ) 7.6 Hz),
and 7.77 (d, 1H, J ) 7.6 Hz); 13C NMR (CDCl3, 100 MHz) δ
28.3, 33.7, 84.6, 115.3, 123.4, 124.4, 128.3, 141.2, 149.4, and 173.3;
HRMS calcd for C13H15NO3 233.1052, found 233.1050.
tert-Butyl
5-Hydroxy-2-oxo-6-phenyl-2,3,3a,4,5,6-hexa-
hydroindole-1-carboxylate (51). To a solution containing 0.06 g
(0.24 mmol) of oxabicycle 23, 3 mg (0.007 mmol) of [Rh(COD)-
Cl]2, and 2.5 µL (0.014 mmol) of P(OEt)3 in 1 mL THF was added
0.09 g (0.48 mmol) of 5,5-dimethyl-2-phenyl-1,3,2-dioxaborinane
(50) and 0.1 mL (0.48 mmol) of Cs2CO3 (5 M in H2O). The reaction
mixture was heated at 65 °C for 2 h, cooled to rt, and quenched
with water. The aqueous layer was extracted with EtOAc, and the
1
692 cm-1; H NMR (CDCl3, 400 MHz) δ 1.23 (s, 3H), 1.56 (t,
J. Org. Chem, Vol. 71, No. 8, 2006 3219

Padwa and Wang
1H, J ) 12.0 Hz), 1.59, (s, 9H), 2.37 (d, 1H, J ) 16.4 Hz), 2.39
(dd, 1H, J ) 12.0 and 6.0 Hz), 2.45 (d, 1H, J ) 16.4 Hz), 4.89
(ddd, 1H, J ) 12.0, 7.6 and 6.0 Hz), 5.13 (dd, 1H, J ) 7.6 and 3.2
Hz), 6.21 (d, 1H, J ) 3.2 Hz), 7.38 (t, 2H, J ) 7.6 Hz), 7.48 (tt,
1H, J ) 7.6 and 1.6 Hz), and 7.80 (dd, 2H, J ) 7.6 and 1.6 Hz);
13C NMR (CDCl3, 100 MHz) δ 25.3, 28.2, 36.6, 40.0, 46.3, 73.3,
73.6, 84.8, 104.8, 128.0, 131.9, 135.0, 146.1, 149.3, and 172.0.
Anal. Calcd for C20H24BNO5: C, 65.06; H, 6.55; N, 3.79. Found:
C, 64.80; H, 6.57; N, 3.73.
tert-Butyl 2,3,3a,4,5,6-Hexahydro-5,6-acetonide-2-oxoindole-
1-carboxylate (55). To a solution containing 0.1 g (0.39 mmol) of
oxabicycle 23 in acetone was added 5 mg (0.03 mmol) of anhydrous
stannous chloride. After the mixture was stirred at rt for 15 min,
the solvent was removed under reduced pressure and the residue
was subjected to the flash silica gel chromatography to afford 0.11
g (91%) of 55 as a white solid: mp 103-105 °C; IR (neat) 1794,
1731, 1370, and 727 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.39 (s,
3H), 1.45 (q, 1H, J ) 11.6 Hz), 1.48 (s, 3H), 1.55 (s, 9H), 2.17
(ddd, 1H, J ) 11.6, 5.6 and 4.0 Hz), 2.25-2.33 (m, 1H), 2.62-
2.69 (m, 2H), 4.22 (dt, 1H, J ) 11.6 and 5.6 Hz), 4.68-4.71 (m,
1H), and 6.09 (dd, 1H, J ) 4.0 and 2.0 Hz); 13C NMR (CDCl3,
100 MHz) δ 25.9, 28.1, 28.5, 32.1, 32.8, 37.1, 71.5, 73.1, 84.6,
103.4, 109.2, 143.1, 148.9, and 172.9. Anal. Calcd for C16H23NO5:
C, 62.12; H, 7.49; N, 4.53. Found: C, 61.96; H, 7.46; N, 4.53.
tert-Butyl 2,3,3a,4,5,6-Hexahydro-3a-methyl-5,6-acetonide-2-
oxoindole-1-carboxylate (56). To a solution containing 0.1 g (0.38
mmol) of oxabicycle 24 in 2 mL of acetone was added 5 mg (0.03
mmol) of anhydrous stannous chloride. After the mixture was stirred
at rt for 15 min, the solvent was removed under reduced pressure
and the residue was subjected to flash silica gel chromatography
to afford 0.11 g (92%) of 56 as a white solid: mp 118-120 °C;
1H NMR (CDCl3, 400 MHz) δ 1.18 (s, 3H), 1.40 (s, 3H), 1.48 (s,
3H), 1.56 (s, 9H), 1.51-1.58 (m,1H), 2.11 (dd, 1H, J ) 12.4 and
6.0 Hz), 2.32 (d, 1H, J ) 16.4 Hz), 2.42 (d, 1H, J ) 16.4 Hz),
4.44 (dt, 1H, J ) 12.0 and 6.0 Hz), 4.73 (dd, 1H, J ) 6.0 and 4.0
Hz), and 6.05 (d, 1H, J ) 4.0 Hz); 13C NMR (CDCl3, 100 MHz)
δ 25.4, 25.6, 28.2, 28.3, 34.5, 38.8, 46.7, 71.1, 71.6, 84.6, 103.4,
109.1, 146.6, 149.3, and 172.4; HRMS calcd for C17H25NO5
323.1733, found 323.1735.
Acknowledgment. We appreciate the financial support
provided by the National Science Foundation (Grant No. CHE-
0450779) and the National Institutes of Health (GM 059384).
We thank our colleague, Dr. Kenneth Hardcastle, for his
assistance with the X-ray crystallographic studies.
Supporting Information Available: 1H and 13C NMR data of
various key compounds lacking CHN analyses together with an
ORTEP drawing for compounds 41, 51, and 53 as well as the
corresponding CIFs for these compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO060238R
3220 J. Org. Chem., Vol. 71, No. 8, 2006