Cycloaddition chemistry of 2-vinyl-substituted indoles and related heteroaromatic systems

Article abstract of DOI:10.1021/jo047834a

(Chemical Equation Presented) The intramolecular Diels-Alder cycloaddition reaction (IMDAF) of several N-phenylsulfonylindolyl-substituted furanyl carbamates containing a tethered π-bond on the indole ring were examined as an approach to the iboga alkaloi

Full text of DOI:10.1021/jo047834a

Cycloaddition Chemistry of 2-Vinyl-Substituted Indoles and
Related Heteroaromatic Systems
Albert Padwa,* Stephen M. Lynch, Jose´ M. Mej´ıa-Oneto, and Hongjun Zhang
Department of Chemistry, Emory University, Atlanta, Georgia 30322
chemap@emory.edu
Received December 8, 2004
The intramolecular Diels-Alder cycloaddition reaction (IMDAF) of several N-phenylsulfonylindolyl-
substituted furanyl carbamates containing a tethered π-bond on the indole ring were examined as
an approach to the iboga alkaloid catharanthine. Only in the case where the tethered π-bond
contained two carbomethoxy groups did the [4 + 2]-cycloaddition occur. Push-pull dipoles generated
from the Rh(II)-catalyzed reaction of diazo imides, on the other hand, undergo successful
intramolecular 1,3-dipolar cycloaddition across both alkenyl and heteroaromatic π-bonds to provide
novel pentacyclic compounds in good yield and in a stereocontrolled fashion. The facility of the
cycloaddition was found to be critically dependent on conformational factors in the transition state.
Ligand substitution in the rhodium(II) catalyst markedly altered the product ratio between [3 +
2]-cycloaddition and intramolecular C-H insertion. The variation in reactivity reflects the difference
in electrophilicity between the various rhodium carbenoid intermediates. Intramolecular C-H
insertion is enhanced with the more electrophilic carbene generated using Rh(II) perfluorobutyrate.
SCHEME 1
Construction of azapolyheterocycles through cycload-
dition chemistry has been a particularly fruitful area of
investigation, and the synthesis of various types of
alkaloids by this approach has been carried out by
numerous investigators.1-13 Several years ago, we began
a synthetic program to provide general access to a variety
of alkaloids by [4 + 2]-cycloaddition chemistry of furanyl
carbamates.14 This approach, demonstrated by the cy-
clization of 1 to the intermediate oxabicycle 2 (Scheme
1) was limited to systems containing an angular sub-
stituent in the resultant azabicycle 3 or else aromatic
products were formed.15 Our experience with this domino
sequence prompted us to examine the method for an
eventual synthesis of the iboga alkaloid catharanthine
(4).16 The dense, pentacyclic skeleton of catharanthine
contains a tryptamine fragment substituted at the 2-po-
sition by a quaternary sp3 carbon and thereby represents
an attractive challenge for synthesis. (()-Catharanthine
(4) has been the target of numerous successful and formal
total syntheses.17 Despite the availability of many syn-
thetic methods for the iboga alkaloids, there still exists
a need to develop procedures more efficient and flexible
than those currently in existence.
Our synthetic plan for the synthesis of catharanthine
(4) is shown in retrosynthetic format in Scheme 2 and is
centered on the construction of the key benzo[2,3]azepino-
[4,5-b]indole intermediate 8, which, by analogy with
previous work in our laboratory14 should be available by
the cycloaddition-nitrogen assisted ring opening cascade
of indole 5 (R ) Et).18 In this paper, we give an account
(1) For reviews on the Diels-Alder reaction, see: (a) Petrzilka, M.;
Grayson, J. I. Synthesis 1981, 753. (b) Pindur, U.; Lutz, G.; Otto, C.
Chem. Rev. 1993, 93, 741. (c) Cycloaddition Reactions in Organic
Synthesis; Kobayashi, S., Jorgensen, K. A., Eds.; Wiley-VCH: Wein-
heim, 2002. (d) Carruthers, W. Cycloaddition Reactions in Organic
Synthesis; Tetrahedron Organic Chemistry Series; Pergamon Press:
New York, 1990; Vol. 8. (e) Fringuelli, F.; Taticchi, A. The Diels-Alder
Reaction: Selected Practical Methods; John Wiley & Sons: New York,
2002. (f) Brieger, G.; Bennett, J. N. Chem. Rev. 1980, 80, 63. (g)
Lipshutz, B. H. Chem. Rev. 1986, 86, 795. (h) Kappe, C. O.; Murphree,
S. S.; Padwa, A. Tetrahedron 1997, 53, 14179. (i) Vogel, P.; Cossy, J.;
Plumet, J.; Arjona, O. Tetrahedron 1999, 55, 13521. (j) Chiu, P.;
Lautens, M. In Topics in Current Chemistry; Metz, P., Ed.; Springer-
Verlag: Berlin, 1997; Vol. 190, pp 1-85.
10.1021/jo047834a CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/18/2005
2206
J. Org. Chem. 2005, 70, 2206-2218

Cycloaddition Chemistry of 2-Vinyl-Substituted Indoles
SCHEME 2
SCHEME 3a
a Reagents: (a) Cs2CO3, DMF/THF (4:1), 80 °C; (b) Bu4NHSO4,
NaOH, ClSO2C6H5, CH2Cl2, rt; (c) t-BuLi, pentane, -78 °C,
n-Bu3SnCl, pentane, -78 °C; (d) methyl R-bromoacrylate, DMF,
Pd(PPh3)4, CuI, 25 °C.
reaction of carbamate 9 with 3-(2-bromoethyl)indole (10)
using Cs2CO3 as the base afforded the expected NH-
indole 11 in 96% yield (Scheme 3). Subsequent N-
sulfonylation under phase transfer conditions produced
12 in 86% yield. The presence of a N-benzenesulfonyl
group on the indole nitrogen is known to facilitate
regioselective metalation at the 2-position of the het-
eroaromatic ring via a chelate-stabilized lithiated inter-
mediate.19 Our intention was to exploit this lithiation
reaction so as to eventually introduce the necessary
acrylate π-bond required for the cycloaddition. Indeed,
treatment of 12 with t-BuLi afforded the desired lithiate
which, after quenching with Bu3SnCl, afforded stannane
13 in 78% yield. This stannane derivative proved to be a
versatile intermediate as it allowed the introduction of
a variety of functional groups at the 2-position of the
indole ring by making use of palladium cross-coupling
chemistry.20 Thus, the reaction of 13 with methyl R-bro-
moacrylate in the presence of catalytic Pd(PPh3)4 and CuI
furnished the desired cycloaddition precursor 6 in 60%
yield.
of our efforts dealing with this unique cycloaddition
approach to assemble the polycyclic array of catharan-
thine.
Results and Discussion
The potential of using this methodology for the syn-
thesis of catharanthine and related iboga alkaloids
prompted us to first carry out some model studies to
prove the likelihood of the key intramolecular [4 +
2]-cycloaddition across the tethered acrylate π-bond. With
this in mind, we reasoned that it would be easier to
evaluate the IMDAF cycloaddition2 using the N-phenyl-
sulfonyl-indolyl furan 6 (R2 ) H) rather than the less
activated ethyl substituted furan 5 for the initial model
studies. After some experimentation, we found that the
(2) (a) Paulvannan, K.; Jacobs, J. W. Tetrahedron 1999, 55, 7433.
(b) Paulvannan, K.; Chen, T.; Jacobs, J. W. Synlett 1999, 1609. (c) Akai,
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Matsugi, M. Kita, Y. Chem. Eur. J. 2002, 8, 4255. (d) Mance, A. D.;
Sindler-Kulyk, M.; Jakopcic, K.; Hergold-Brundic, A.; Nagl, A. J.
Heterocycl. Chem. 1997, 34, 1315. (e) Hudlicky, T.; Butora, G.;
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C.; Nieto, J. J. Org. Chem. 2000, 65, 831. (g) Jacobi, P. A.; Li, Y. J.
Am. Chem. Soc. 2001, 123, 9307. (h) Padwa, A.; Brodney, M. A.; Liu,
B.; Satake, K.; Wu, T. J. Org. Chem. 1999, 64, 3595. (i) Padwa, A.;
Brodney, M. A.; Lynch, S. M. J. Org. Chem. 2001, 66, 1716. (j) Padwa,
A.; Straub, C. S. J. Org. Chem. 2003, 68, 227. (k) Cauwberghs, S.; De
Clercq, P. J.; Tinant, B.; Declercq, J. P. Tetrahedron Lett. 1988, 29,
2493. (l) Lee, M.; Moritomo, H.; Kanematsu, K. Tetrahedron 1996, 52,
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M. J. Org. Chem. 2002, 67, 3412. (n) Parker, K. A.; Adamchuk, M. R.
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Org. Chem. 1998, 63, 2968. (r) Rogers, C.; Keay, B. A. Can. J. Chem.
1993, 71, 611. (s) Hunt, I. R.; Rauk, A.; Keay, B. A. J. Org. Chem.
1996, 61, 751. (t) Sternbach, D. D.; Rossana, D. M. Tetrahedron Lett.
1982, 23, 303. (u) Sternbach, D. D.; Rossana, D. M.; Onan, K. D. J.
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Chem. 2003, 68, 7990.
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(13) Sparks, S. M.; Gutierrez, A. J.; Shea, K. J. J. Org. Chem. 2003,
68, 5274.
(14) (a) Padwa, A.; Dimitroff, M. A.; Waterson, A. G.; Wu, T. J. Org.
Chem. 1997, 62, 4088. (b) Padwa, A.; Brodney, M.; Dimitroff, M. J.
Org. Chem. 1998, 63, 5304. (c) Padwa, A.; Brodney, M. A.; Satake, K.;
Straub, C. S. J. Org. Chem. 1999, 64, 4617. (d) Bur, S. K.; Padwa, A.
Org. Lett. 2002, 4, 4135.
(15) Padwa, A.; Dimitroff, M.; Waterson, A. G.; Wu, T. J. Org. Chem.
1998, 63, 3986.
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N. J. J. Am. Pharm. Assoc. (Sci. Ed.) 1959, 48, 256. (b) Svoboda, G.
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659. (c) Neuss, N.; Gorman, M. Tetrahedron Lett. 1961, 206. (d)
Gorman, M.; Neuss, N.; Cone, N. J. J. Am. Chem. Soc. 1965, 87, 93.
(e) Bu¨chi, G.; Coffen, D. L.; Kocsis, K.; Sonnet, P. E.; Ziegler, F. E. J.
Am. Chem. Soc. 1966, 88, 3099. (f) The Alkaloids. Antitumor Bisindole
Alkaloids from Catharanthus roseus (L.); Brossi, A., Suffness, M., Eds.;
Academic Press: San Diego, 1990; Vol. 37.
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(17) For some leading references, see those cited in: Reding, M. T.;
Fukuyama, T. Org. Lett. 1999, 1, 973.
(6) Mans, D. M.; Pearson, W. H. Org. Lett. 2004, 6, 3305.
(18) The conversion of 7 to 4 via 8 would require a number of
additional steps including an oxabicyclic ring opening followed by
double-bond isomerization as well as an eventual intramolecular
nucleophilic N-C bond formation.
(7) Stockman, R. A.; Sinclair, A.; Arini, L. G.; Szeto, P.; Hughes, D.
L. J. Org. Chem. 2004, 69, 1598.
(8) O’Connor, P. D.; Mander, L. N.; McLachlan, M. M. W. Org. Lett.
2004, 6, 703.
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J. Org. Chem, Vol. 70, No. 6, 2005 2207

Padwa et al.
SCHEME 4
SCHEME 5
Unfortunately, all of our attempts to effect the [4 +
2]-cycloaddition of 6 resulted in the formation of dark tars
and we were not able to isolate any characterizable
product from the thermolysis reaction. In previous stud-
ies, structural features that facilitate the intramolecular
Diels-Alder reaction of amidofurans were discovered.21
On the basis of FMO considerations,22 we anticipated that
additional activation of the CdC double bond with
another electron withdrawing group would facilitate the
intramolecular [4 + 2]-cycloaddition.23 With this in mind,
the dicarbomethoxy substituted furanyl indole 14 was
prepared in 64% yield by the Stille coupling of stannane
13 and 3-bromodimethyl maleate. Heating a sample of
14 at 200 °C for 7 h did furnish cycloadduct 15, but only
in 38% yield (Scheme 4). The isolation of azepine 15 was
somewhat unexpected since related aza-substituted oxa-
bicyclic compounds generally tend to undergo ring open-
ing at elevated temperatures.24 The presence of the oxa-
bridge in 15 is especially striking and suggests that the
loss of isobutylene and CO2 from the N-Boc carbamate
occurs first and that the transient NH-furan undergoes
a subsequent cycloaddition across the diactivated π-bond.
Examination of molecular models indicates that this
particular seven-membered azepine adopts a severely
twisted conformation in which the nitrogen atom lone
pair resides nearly orthogonal to the oxygen bridge and
consequently cannot participate in the ring-opening
reaction.
For comparison purposes, we have also investigated
the thermal chemistry of the related N-phenylmaleimide
substituted indole 16. This compound was prepared in
76% yield by the Stille cross-coupling reaction20 of stan-
nane 13 with 3-bromo-1-phenylpyrrole-2,5-dione. As was
the case with indole 14, thermolysis of 16 at 200 °C (6 h)
resulted in the loss of isobutylene and CO2 and furnished
the nine-membered azacycle 17 as the only detectable
product in 45% yield. The structure of 17 was based on
its spectroscopic properties and was further validated by
single crystal X-ray analysis which clearly indicates the
trans-substitution pattern present at the fused succin-
imide ring juncture (Scheme 5). This interesting product
arises by conjugate addition of the furan on the activated
maleimide ring. More than likely the steric bulk of the
N-phenylmaleimide group interferes with the other sub-
stituents present in the two-plane orientation complex
required for the Diels-Alder reaction and thereby pre-
vents the cycloaddition from occurring. The bulky N-
phenylmaleimide group apparently causes the molecule
SCHEME 6
to adopt a conformation where conjugate addition by the
furan onto the activated π-bond becomes the preferred
pathway.
In earlier studies we had demonstrated that confor-
mational effects can have a dramatic impact on the rate
of the IMDAF reaction of amido-substituted furans.25
Specifically, the incorporation of a carbonyl group such
that an amide linkage joining the dienophile and furan
moieties resulted in a conformation of the tether that
brings the dienophile into closer proximity with the furan
and facilitates the cycloaddition reaction relative to the
simple amine tether. A recent example from our labora-
tory which illustrates this rate difference is seen in the
thermal chemistry of carbamate 18 vs amidofuran 19
(Scheme 6). Heating a sample of 18 at 200 °C gave no
sign of any product derived from a [4 + 2]-cycloaddition
reaction. In sharp contrast, 19 gave 20 in 82% isolated
yield when heated at 100 °C. In this case, the initially
formed Diels-Alder cycloadduct underwent ring opening
and subsequent loss of water to produce the aromatized
product 20.
In an attempt to exploit this conformational facilitating
effect in the indole series, we examined the thermal
behavior of indole 23 which could be formed by the base-
induced alkylation of N-H furan 21 with 3-bromo-2-
methyl-1-propene. In addition to the expected N-alky-
lated product 23, a substantial amount of azepino[4,5-
b]indole 22 was also isolated and is derived by conjugate
addition of the amide anion onto the adjacent acrylate
π-bond (Scheme 7). Unfortunately, all of our attempts to
effect the IMDAF cycloaddition of 23 failed and only the
starting furanyl indole was recovered. One possible
explanation that might account for the lack of reactivity
of 23 is that the presence of the amido group on the furan
ring lowers the HOMO energy thereby widening the gap
between the FMO levels and consequently diminishing
the overall rate of the cycloaddition.22
(21) Padwa, A.; Kappe, C. O.; Cochran, J. E.; Snyder, J. P. J. Org.
Chem. 1997, 62, 2786.
(22) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley: New York, 1976.
(23) (a) Fallis, A. G. Can. J. Chem. 1984, 62, 183. (b) Ciganek, E.
Org. React. 1984, 32, 1. (c) Craig, D. Chem. Soc. Rev. 1987, 16, 187.
(24) Padwa, A.; Brodney, M. A.; Lynch, S. M.; Rashatasakhon, P.;
Wang, Q.; Zhang, H. J. Org. Chem. 2004, 69, 3735.
Since the furanyl carbamate cycloaddition approach
toward catharanthine proved not to be feasible, we
(25) (a) Bur, S. K.; Lynch, S. M.; Padwa, A. Org. Lett. 2002, 4, 473.
(b) Lynch, S. M.; Bur, S. K.; Padwa, A. Org. Lett. 2002, 4, 4643.
2208 J. Org. Chem., Vol. 70, No. 6, 2005

Cycloaddition Chemistry of 2-Vinyl-Substituted Indoles
SCHEME 7
SCHEME 10
SCHEME 8
SCHEME 11
SCHEME 9
(II)-catalyzed cyclization to give the azapolycyclic cy-
cloadduct 31 in 92% yield. The cascade sequence was
extremely facile and took place at room temperature.
When the Rh(II)-catalyzed reaction was carried out at
50 °C or higher, the only product isolated corresponded
to the ring-opened pyridone 32. Control experiments
demonstrated that heating a pure sample of 31 in ether
provided 32 in 90% yield (Scheme 10).
Armed with these promising results, we set out to
explore the cycloaddition chemistry of the homologous
indolyl diazo imide 33, which is a more suitable model
for an eventual synthesis of catharanthine. Interestingly,
subjection of 33 to Rh(II) catalysis led exclusively to
cycloadduct 34 (95%) where cycloaddition of the 1,3-dipole
occurred preferentially across the indole π-bond rather
than with the tethered vinyl group (Scheme 11). Although
there are examples in the literature where the 2,3-double
bond of indole participates in [4 + 2]-cycloaddition
chemistry,28-30 the indole ring generally shows only a low
tendency to act as a dienophile with electron-rich
dienes.31,32 In bimolecular Diels-Alder reactions that
decided to explore the possibility of using the related
amido-substituted carbonyl ylide dipole for the critical
cycloaddition step. In earlier work, we had demonstrated
that push-pull 1,3-dipoles of type 26 were highly reactive
and synthetically useful intermediates for [3 + 2]-cy-
cloaddition chemistry.26 The potential of using carbonyl
ylide dipoles such as 26 for the synthesis of catharanthine
and related iboga alkaloids prompted us to first carry out
some model studies to prove the likelihood of the key
cycloaddition across a tethered vinyl group. The starting
diazo imide substrates (i.e., 25) were easily prepared by
treating the stable N-H diazo amides 24 with an ap-
propriate acid chloride in the presence of 4 Å molecular
sieves (Scheme 8). Formation of the push-pull dipole 26
was achieved by reaction of 25 with Rh2(OAc)4, which
afforded a rhodium carbenoid species that readily un-
derwent cyclization onto the neighboring imido carbonyl
to form the carbonyl ylide dipole.27 Subsequent intramo-
lecular cycloaddition across the tethered vinyl group in
the model system 27 furnished cycloadduct 28 in 95%
isolated yield, thereby demonstrating the facility of the
cascade sequence (Scheme 9).
(28) (a) Wenkert, E.; Piettre, S. R. J. Org. Chem. 1988, 53, 5850.
(b) Wenkert, E.; Moeller, P. D. R.; Piettre, S. R. J. Am. Chem. Soc.
1988, 110, 0, 7188.
(29) (a) Kraus, G. A.; Raggon, P. J.; Thomas, P. J.; Bougie, D.
Tetrahedron Lett. 1988, 29, 5605. (b) Kraus, G. A.; Bougie, D.; Jacobson,
R. A.; Su, Y. J. Org. Chem. 1989, 54, 2425.
(30) For a similar approach to the Vinca alkaloids using a tandem
intramolecular Diels-Alder/dipolar cycloaddition sequence of a 1,3,4-
oxadiazole across the indole double bond, see: Wilkie, G. D.; Elliott,
G. I.; Blagg, B. S. J.; Wolkenberg, S. E.; Soenen, D. R.; Miller, M. M.;
Pollack, S.; Boger, D. L. J. Am. Chem. Soc. 2002, 124, 11292.
(31) (a) Biolatto, B.; Kneeteman, M.; Paredes, E.; Mancini, P. M. E.
J. Org. Chem. 2001, 66, 3906.
(32) Indole is quite a good dienophile in inverse electron-demand
Diels-Alder cycloadditions; (a) Lee, L.; Snyder, J. K. Advances in
Cycloaddition Chemistry; Harmata, M., Ed.; JAI Press: 1999; Vol. 6,
p 119. (b) Padwa, A.; Hertzog, D. L.; Nadler, W. R. J. Org. Chem. 1994,
59, 7072.
We were pleased to find that the analogous vinylin-
dolyl-substituted diazoimide 29 underwent a related Rh-
(26) (a) Padwa, A.; Price, A. T. J. Org. Chem. 1995, 60, 6258. (b)
Padwa, A.; Price, A. T. J. Org. Chem. 1998, 63, 556. (c) Mej´ıa-Oneto,
J. M.; Padwa, A. Org. Lett. 2004, 6, 3241.
(27) (a) Padwa, A.; Weingarten, M. D. Chem. Rev. 1996, 96, 223.
(b) Padwa, A.; Hornbuckle, S. F. Chem. Rev. 1991, 91, 263.
J. Org. Chem, Vol. 70, No. 6, 2005 2209

Padwa et al.
SCHEME 12
SCHEME 13
occur with normal electron-demand, indole acts as a 2π-
substrate only if electron-withdrawing groups are present
in the 1 and 3-positions.28 Intramolecular cycloaddition
reactions, however, benefit from higher reactivity and
greater control of stereoselectivity relative to their in-
termolecular counterparts. More than likely, the initially
formed dipole derived from 33 resides in a conformation
where the 4π-array of the carbonyl ylide dipole is able to
better overlap in the traditional two-plane orientation
approach with the indolyl π-bond than with the vinyl
group, thereby controlling the periselectivity of the
cycloaddition.
SCHEME 14
Most interestingly, the placement of a carbomethoxy
group on the tethered vinyl group drastically altered the
regioselectivity of the cycloaddition. Thus, exposure of the
related diazo imide 35 to Rh2(OAc)4 at 90 °C furnished
cycloadduct 36 in 91% yield as the only product formed.
In this case, the initially generated carbonyl ylide dipole
undergoes exclusive cycloaddition across the more acti-
vated acrylate π-bond to furnish cycloadduct 36 rather
than undergoing addition across the indole system as was
encountered with diazo imide 33.
It would seem as though these indolyl substituted
systems are markedly sensitive to both conformational
and electronic factors in the key cycloaddition step
(Scheme 12).
In the context of extending the above cycloaddition to
other ring systems, we wondered whether the push-pull
dipole found in 26 might also undergo intramolecular
dipolar cycloaddition with different heteroaromatic
π-bonds. Five-membered-ring heteroaromatics such as
furan, thiophene and benzofurans have, despite their
aromaticity, frontier orbital energies and shapes similar
to those of cyclopentadiene.33 The reactivity of these
heteroaromatic dipolarophiles is, however, sharply de-
creased because of the loss of aromaticity in the cycload-
dition transition states. A vast amount of information is
available concerning the reactivity of heteroaromatics in
cycloadditions where the heteroaromatics function as 4πs
components,34 but a study of their dipolarophilic reactiv-
ity has not been extensively examined to date.32,35
Consequently, we initiated a study to determine whether
push-pull dipoles of type 26 would undergo cycloaddition
with several other heteroaromatic π-systems.
complete diastereospecificity. The regio- and relative
stereochemistry of 38 was assigned by 1H NMR and was
confirmed by single-crystal X-ray analysis. A similar
product (i.e., 40) was obtained in 95% yield using the
related indolyl-substituted diazo imide 39 (Scheme 13).26
Bolstered by these positive results, we next examined
the Rh(II)-catalyzed behavior of the cyclic diazo imide
containing a tethered furan ring. Treatment of 41 with
rhodium(II) pivalate at 90 °C furnished cycloadduct 42
but only in 35% yield. The lower yield encountered with
this system is probably related to its greater aromaticity
relative to the benzo-fused systems. Thiophene has a
lower lying HOMO level than does furan, which increases
the energy gap between the interacting FMO’s.31 This is
probably why so little is known about dipolar cycloaddi-
tions across thiophene rings. We found, however, that no
significant difference in yield occurred when the related
thiophenyl-substituted diazo imide 43 was treated with
Rh(II) pivalate. The major product formed in 38% yield
corresponded to cycloadduct 44 (Scheme 14). This result
stands in contrast to other literature reports, where it is
known that the greater aromatic character of thiophene
considerably limits its ability to undergo cycloaddition
chemistry.28 This example also represents the first
instance of an intramolecular [3 + 2]-cycloaddition of a
1,3-dipole across the thiophene 2,3-π-bond.
Our initial efforts focused on the Rh(II)-catalyzed
reaction of the benzofuranyl-substituted diazo imide 37.
Gratifyingly, treatment of 37 with rhodium(II) pivalate
at 100 °C in benzene using a microwave reactor afforded
the polyheterocyclic adduct 38 in 90% yield and with
While searching for optimal reaction conditions to
maximize the yield of cycloadduct 44, we found that
changing the ligand group on the rhodium catalyst
resulted in a major difference in the overall reaction
pathway.36 Thus, the only compound that was isolated
from the rhodium(II) perfluorobutyrate (Rh2(pfb)4) cata-
lyzed decomposition of 43 (90 °C microwave) was lactam
(33) Del Bene, J.; Jaffe´, H. H. J. Chem. Phys. 1968, 48, 4050.
(34) (a) Sauer, J. Angew Chem., Int. Ed. Engl. 1967, 6, 16. (b)
Carruthers, W. Cycloaddition Reactions in Organic Synthesis; Perga-
mon Press: Oxford, 1990.
(35) For some related work, see: Oguri, H.; Schreiber, S. L. Org.
Lett. 2005, 7, 47.
(36) Mej´ıa-Oneto, J. M.; Padwa, A. Tetrahedron Lett. 2004, 45, 9115.
2210 J. Org. Chem., Vol. 70, No. 6, 2005

Cycloaddition Chemistry of 2-Vinyl-Substituted Indoles
SCHEME 15
hydrolysis/decarboxylation reaction. Unfortunately, all of
our efforts to detect the expected intermediate 51 failed
to indicate its presence in the reaction mixture. Since it
was necessary to carry out the catalyzed reaction at
elevated temperatures (>90 °C) for the C-H insertion
to proceed, we assume that 51 is simply too labile to be
detected under the thermal conditions employed. Further
work is clearly necessary before this pathway can be
unequivocally established.
Earlier studies have shown that, despite their high
reactivity, rhodium carbenoid intermediates are often
highly chemoselective when two or more reaction path-
ways are open to them. Site selectivity has been found
to depend not only on the type of R-diazocarbonyl utilized,
but is also governed by steric,39-42 conformational,43 as
well as electronic factors.44-47 The earlier studies have
revealed some interesting ligand effects,38 and it is now
established that carboxylate ligands can effectively con-
trol chemoselectivity in competitive carbenoid transfor-
mations of R-diazocarbonyl compounds.48 To further
investigate the chemoselectivity of the reaction as a
function of the nature of the catalyst, we prepared the
N-but-3-enoyl-substituted imide 52, which possesses an
unactivated terminal π-bond. The rhodium(II) pivalate
catalyzed decomposition of 52 resulted in exclusive
carbonyl ylide formation and subsequent intramolecular
cycloaddition to give cycloadduct 53 in 98% yield (Scheme
17). No signs of any product derived from a C-H
insertion could be detected in the crude reaction mixture.
Virtually complete cycloaddition chemistry also occurred
when rhodium(II) caprolactomate (Rh2(cap)4) was used
as the catalyst. Although Rh(II) acetate (Rh2(OAc)4) and
Rh(II) mandelate (Rh2(man)4) also afforded cycloadduct
53 as the major product, small amounts of the C-H
SCHEME 16
45 (51%), which arose from a formal insertion of the
metal carbene into the C-H bond at the 5-position of the
lactam ring37 followed by an unusual ethoxy-decarboxy-
lation reaction (vide infra). No signs of the previously
isolated cycloadduct 44 were detected in the crude
mixture. The structure of lactam 45 was assigned on the
basis of its characteristic spectral data.
Formation of the 3-aza-bicyclo[3.2.1]octan-2,7-dione
ring system was found to be a general reaction that also
occurred with related R-diazo ketoamides just as long as
Rh2(pfb)4 was used as the catalyst. Thus, the rhodium-
(II) perfluorobutyrate catalyzed decomposition of diazo
ketoamide 46 at 100 °C in benzene afforded the analo-
gous insertion product 47 in 66% isolated yield (Scheme
15). When the reaction of 46 was carried out using Rh2-
(OAc)4 as the catalyst, there were no detectable quantities
of lactam 47 or any other characterizable product,
thereby attesting to the sensitivity of the C-H insertion
reaction to the nature of the ligand group attached to
the rhodium metal (Scheme 15).
(38) (a) Padwa, A.; Austin, D. J.; Hornbuckle, S. F.; Semones, M.
A.; Doyle, M. P.; Protopopova, M. N. J. Am. Chem. Soc. 1992, 114,
1874. (b) Padwa, A.; Austin, D. J.; Price, A. T.; Semones, M. A.; Doyle,
M. P.; Protopopova, M. N.; Winchester, W. R.; Tran, A. J. Am. Chem.
Soc. 1993, 115, 8669. (c) Padwa, A.; Austin, D. J.; Hornbuckle, S. F.;
Price, A. T. Tetrahedron Lett. 1992, 33, 6427. (d) Cox, G. G.; Moody,
C. J.; Austin, D. J.; Padwa, A. Tetrahedron 1993, 49, 5109. (e) Zaragoza,
F. Tetrahedron 1995, 51, 8829.
(39) (a) Taber, D. F.; Petty, E. H. J. Org. Chem. 1982, 47, 4808. (b)
Taber, D. F.; Amedio, J. C., Jr.; Sherrill, R. G. J. Org. Chem. 1986, 51,
3382. (c) Taber, D. F.; Ruckle, R. E., Jr. Tetrahedron Lett. 1985, 26,
3059. (d) Taber, D. F.; Amedio, J. C., Jr.; Raman, K. J. Org. Chem.
1988, 53, 2984. (e) Taber, D. F.; Hennessy, M. J.; Hoerrner, R. S.;
Raman, K.; Ruckle, R. E., Jr.; Schuchardt, J. S. In Catalysis of Organic
Reactions; Blackburn, D. W., Ed.; Marcel Dekker: New York, 1988;
Chapter 4, p 43. (f) Taber, D. F.; Ruckle, R. E., Jr. J. Am. Chem. Soc.
1986, 108, 7686.
(40) Doyle, M. P.; Westrum, L. J.; Wolthius, W. N. E.; See, M. M.;
Boone, W. P.; Bagheri, V.; Pearson., M. M. J. Am. Chem. Soc. 1993,
115, 958.
One conceivable route to account for aza-bicyclo lactam
formation involves the production of ethylene from the
initially formed rhodium carbenoid 49 followed by C-H
insertion and eventual extrusion of CO2 (Scheme 16, path
A). To test this mechanistic possibility, we prepared the
corresponding methyl ester (i.e., 48) and noted no sig-
nificant difference in the yield of product when 48 was
treated with the Rh2(pfb)4 catalyst. It is for this reason
that we propose the alternative mechanism (Scheme 16,
path B), which involves initial C-H insertion into the
5-position of the lactam ring followed by a subsequent
(41) Cane, D. E.; Thomas, P. J. J. Am. Chem. Soc. 1984, 10, 6, 5295.
(42) (a) Hashimoto, S.; Watanabe, N.; Ikegami, S. Tetrahedron Lett.
1992, 33, 2709. (b) Hashimoto, S.; Watanabe, N.; Ikegami, S. J. Chem.
Soc., Chem. Commun. 1992, 1508.
(43) (a) Doyle, M. P.; Shanklin, M. S.; Oon, S. M.; Pho, H. Q.; van
der Heide, F. R.; Veal, W. R. J. Org. Chem. 1988, 53, 3384. (b) Doyle,
M. P.; Pieters, R. J.; Taunton, J.; Pho, H. Q.; Padwa, A.; Hertzog, D.
L.; Precedo, L. J. Org. Chem. 1991, 56, 820.
(44) (a) Doyle, M. P.; Taunton, J.; Pho, H. Q. Tetrahedron Lett. 1989,
30, 5397. (b) Doyle, M. P.; Bagheri, V.; Pearson, M. M.; Edwards. J. D.
Tetrahedron Lett. 1989, 30, 7001.
(45) Taber, D. F.; Hennessy, M. J.; Louey, J. P. J. Org. Chem. 1992,
57, 436.
(46) Matsumoto, M.; Watanabe, N.; Kobayashi, H. Heterocycles 1987,
26, 1479.
(47) Sundberg, R. J.; Baxter, E. W.; Pitts, W. J.; Ahmed-Schofield,
R.; Nishiguchi, T. J. Org. Chem. 1988, 53, 5097.
(37) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds; John Wiley and Sons:
New York, 1998.
(48) Padwa, A.; Austin, D. J. Angew Chem., Int. Ed. Engl. 1994,
33, 1797.
J. Org. Chem, Vol. 70, No. 6, 2005 2211

Padwa et al.
(t, 2H, J ) 7.6 Hz), 5.91 (brs, 1H), 6.32 (s, 1H), 7.17 (d, 1H, J
) 1.2 Hz), 7.22-7.26 (m, 1H), 7.29-7.33 (m, 1H), 7.38 (s, 1H),
7.40-7.44 (m, 2H), 7.49-7.53 (m, 2H), 7.85-7.87 (m, 2H), and
7.98 (d, 1H, J ) 8.0 Hz); 13C NMR (CDCl3, 100 MHz) δ 24.7,
28.3, 48.3, 81.6, 101.2, 111.2, 113.9, 119.7, 120.0, 123.4, 123.6,
125.0, 126.9, 129.4, 131.1, 133.9, 135.4, 138.2, 138.5, 148.6,
and 153.7; HRMS calcd for C25H26N2O5S 466.1562, found
466.1547.
SCHEME 17
[2-(1-Benzenesulfonyl-2-tributylstannanyl-1H-indol-3-
yl)ethyl]furan-2-ylcarbamic Acid tert-Butyl Ester (13).
To a solution containing 2.0 g (4.3 mmol) of the above indole
12 in 40 mL of THF at -78 °C was added 3.6 mL (4.7 mmol)
of t-BuLi (1.3 M in pentane). The reaction mixture was stirred
at -78 °C for 1 h, and then 1.4 g (4.3 mmol) of tributyltin
chloride was added dropwise. The mixture was stirred at -78
°C for an additional 0.5 h and then quenched with saturated
aqueous NH4Cl and warmed to rt. The mixture was diluted
with H2O, extracted with EtOAc, dried over MgSO4, and
concentrated under reduced pressure. The residue was sub-
jected to flash silica gel chromatography (8% EtOAc in hexane)
to give 2.5 g (78%) of 13 as a colorless oil: IR (neat) 1716,
1618, 1449, 1362, and 1173 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 0.89 (t, 9H, J ) 7.2 Hz), 1.16-1.20 (m, 6H), 1.30-1.38 (m,
6H), 1.48 (s, 9H), 1.49-1.54 (m, 6H), 3.05-3.09 (m, 2H), 3.70-
3.74 (m, 2H), 5.99 (brs, 1H), 6.38 (s, 1H), 7.18-7.20 (m, 2H),
7.24 (d, 1H, J ) 1.2 Hz), 7.32 (t, 2H, J ) 8.0 Hz), 7.42-7.46
(m, 1H), 7.53-7.55 (m, 2H), 7.62 (brs, 1H), and 7.83-7.86 (m,
1H); 13C NMR (CDCl3, 100 MHz) δ 13.1, 13.9, 26.2, 27.5, 28.4,
29.2, 49.9, 81.4, 101.7, 111.3, 114.7, 119.2, 123.4, 124.5, 126.4,
129.0, 132.7, 132.9, 133.4, 138.4, 138.8, 139.4, 140.8, 148.7,
and 153.9; HRMS calcd for C37H52N2O5SSnLi 763.2779, found
763.2764.
insertion product 54 could be detected in the crude
reaction mixture. Catalysis by Rh(II) trifluoroacetate
(Rh2(tfa)4) or Rh2(pfb)4, on the other hand, gave signifi-
cant quantities of the insertion product 54 (22% and
32%). The variation in reactivity (yield) presumably
reflects the differences in electrophilicity between the
various rhodium carbenoid intermediates. Intramolecular
C-H insertion is enhanced with the more electrophilic
carbene generated using Rh2(pfb)4, as had been encoun-
tered earlier with allyl- and aryl-substituted 1-diazo-
pentanediones.38b Either charge or HOMO/LUMO control
or both may be operating in these Rh(II)-catalyzed
transformations (Scheme 16).
In conclusion, several trends have surfaced from our
investigations in this area. Furanyl carbamates possess-
ing a vinyl group tethered to an indole ring undergo
intramolecular [4 + 2]-cycloaddition only under forcing
conditions and in low yield. Push-pull dipoles generated
from the Rh(II)-catalyzed reaction of diazoimides, on the
other hand, undergo successful intramolecular 1,3-dipolar
cycloaddition across both alkenyl and heteroaromatic
π-bonds to provide novel pentacyclic compounds in good
to excellent yield and in a stereocontrolled fashion. The
facility of the cycloaddition is critically dependent on
conformational factors in the transition state. In addition,
ligand substitution in the rhodium(II) catalyst can mark-
edly alter the product ratio between [3 + 2]-cycloaddition
and intramolecular C-H insertion. We are currently
investigating the scope and limitations of the intramo-
lecular cycloaddition of these push-pull dipoles as a
potential method for the synthesis of various alkaloid
targets.
2-{1-Benzenesulfonyl-3-[2-(tert-butoxycarbonylfuran-
2-ylamino)ethyl]-1H-indol-2-yl}but-2-enedioic Acid Di-
methyl Ester (14). To a solution of 1.3 g (1.7 mmol) of
stannane 13 in 2.0 mL of DMF under argon was added a
solution of 0.44 g (2.0 mmol) of 3-bromodimethyl maleate in
1.0 mL of DMF followed by 0.09 g (0.08 mmol) of Pd(PPh3)4
and 0.06 g (0.33 mmol) of CuI. The reaction mixture was
stirred at room temperature for 1 h, diluted with 30 mL of
ether, and filtered over a pad of Celite. The filtrate was washed
with H2O, dried over anhydrous MgSO4, and concentrated
under reduced pressure. The residue was subjected to flash
silica gel chromatography (10% EtOAc in hexane) to provide
0.64 g (64%) of 14 as a pale yellow oil: IR (neat) 1736, 1710,
1613, 1449, 1367, and 1173 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 1.38 (s, 9H), 2.98 (t, 2H, J ) 7.6 Hz), 3.70 (brs, 2H), 3.77 (s,
3H), 3.89 (s, 3H), 5.87 (brs, 1H), 6.18 (brs, 1H), 6.28 (s, 1H),
7.09 (dd, 1H, J ) 2.0 and 0.8 Hz), 7.27-7.31 (m, 1H), 7.37-
7.41 (m, 3H), 7.51 (t, 1H, J ) 7.6 Hz), 7.57 (d, 1H, J ) 7.6
Hz), 7.76 (d, 2H, J ) 7.2 Hz), and 8.20 (d, 1H, J ) 8.4 Hz); 13
C
NMR (CDCl3, 100 MHz) δ 24.6, 28.2, 48.3, 52.6, 52.9, 81.7,
100.1, 111.2, 115.3, 120.3, 124.3, 126.3, 127.1, 128.0, 129.3,
130.4, 131.5, 131.7, 132.9, 134.2, 136.7, 137.8, 138.1, 148.5,
153.3, 164.8 and 165.7; HRMS calcd for C31H32N2O9S 608.1829,
found 608.1830.
Experimental Section
6-(Benzenesulfonyl[4,5-b]indole)-12-oxa-2-azatricyclo-
[7.2.1.01,7]dodeca-5,10-diene-7,8-dicarboxylic Acid Di-
methyl Ester (15). A solution of 0.005 g (0.08 mmol) of the
above indole 14 in 2 mL of toluene was heated in a sealed
pressure tube under argon at 200°C for 7 h. The reaction
mixture was cooled to room temperature and the solvent was
removed under reduced pressure. The residue was purified by
flash silica gel chromatography (8% EtOAc in hexane) to
provide 0.002 g (38%) of 15 as a colorless oil: IR (neat) 3370,
1731, 1613, 1449, and 1168 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 3.04-3.14 (m, 2H), 3.22-3.33 (m, 1H), 3.48-3.52 (m, 1H),
3.57 (s, 3H), 3.79 (s, 3H), 3.97-4.00 (m, 1H), 4.61 (d, 1H, J )
10.4 Hz), 5.50 (d, 1H, J ) 10.4 Hz), 5.96 (d, 1H, J ) 2.0 Hz),
6.55 (d, 1H, J ) 2.0 Hz), 7.09-7.19 (m, 2H), 7.36-7.42 (m,
3H), 7.46-7.52 (m, 2H), and 7.64-7.67 (m, 2H); 13C NMR
(CDCl3, 100 MHz) δ 28.9, 45.1, 45.2, 47.1, 52.4, 53.0, 102.2,
[2-(1-Benzenesulfonyl-1H-indol-3-yl)ethyl]furan-2-yl-
carbamic Acid tert-Butyl Ester (12). To a solution contain-
ing 1.4 g (4 mmol) of furan-2-yl-(2-(1H-indol-3-yl)ethyl)-
carbamic acid tert-butyl ester (11)24 in 50 mL of benzene at
rt was added 0.14 g (0.4 mmol) of tetrabutylammonium
hydrogensulfate in 10 mL of 50% aqueous NaOH solution. The
reaction mixture was stirred at rt for 10 min, and then 0.7
mL (5 mmol) of benzenesulfonyl chloride was added dropwise
to the solution. The mixture was stirred at rt for 3 h and then
diluted with H2O. The aqueous layer was extracted with
EtOAc, and the combined organic layer was washed with H2O,
dried over MgSO4, and concentrated under reduced pressure.
The residue was subjected to flash silica gel chromatography
(10% EtOAc in hexane) to afford 1.7 g (86%) of 12 as a colorless
oil: IR (neat) 1705, 1613, 1449, 1367, and 1173 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 1.39 (s, 9H), 2.97 (t, 2H, J ) 7.6 Hz), 3.86
2212 J. Org. Chem., Vol. 70, No. 6, 2005

Cycloaddition Chemistry of 2-Vinyl-Substituted Indoles
112.7, 114.1, 118.9, 123.4, 123.5, 125.3, 126.8, 128.4, 129.3,
132.6, 133.6, 135.6, 136.3, 139.7, 154.4, 171.7, and 175.6. Anal.
Calcd for C26H24N2O7S: C, 61.41; H, 4.76; N, 5.51. Found: C,
60.97; H, 4.83; N, 5.30.
(dd, 1H, J ) 17.2 and 10.8 Hz), 6.98 (dd, 1H, 2.0 and 1.2 Hz),
7.30 (m, 3H), and 7.58 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ
41.7, 95.7, 111.7, 117.9, 126.9, 128.7, 128.8, 131.1, 131.3, 133.7,
135.6, 137.9, 145.1, and 167.4; HRMS calcd for [(C14H13NO2)
+ Li]+ 234.1106, found 234.1098.
{2-[1-Benzenesulfonyl-2-(2,5-dioxo-1-phenyl-2,5-dihy-
dro-1H-pyrrol-3-yl)-1H-indol-3-yl]ethyl}furan-2-ylcar-
bamic Acid tert-Butyl Ester (16). To a solution of 2.6 g (3.4
mmol) of stannane 13 in 4.0 mL of DMF under argon was
added a solution of 0.9 g (3.7 mmol) of 3-bromo-1-phenylpyr-
role-2,5-dione49 in 3.0 mL of DMF followed by 0.2 g (0.2 mmol)
of Pd(PPh3)4 and 0.13 g (0.7 mmol) of CuI. The reaction
mixture was stirred at room temperature for 0.5 h, diluted
with 60 mL of ether, and filtered over a pad of Celite. The
filtrate was washed with H2O, dried over anhydrous MgSO4,
and concentrated under reduced pressure. The residue was
subjected to flash silica gel chromatography (10% EtOAc in
hexane) to provide 1.6 g (76%) of 16 as a pale yellow oil: IR
(neat) 1721, 1603, 1393, 1367, and 1178 cm-1; 1H NMR (CDCl3,
400 MHz) δ 1.38 (s, 9H), 3.04 (t, 2H, J ) 7.8 Hz), 3.76 (brs,
2H), 5.90 (brs, 1H), 6.32 (s, 1H), 6.86 (brs, 1H), 7.13 (d, 1H, J
) 1.2 Hz), 7.29 (t, 1H, J ) 7.6 Hz), 7.35-7.41 (m, 5H), 7.46-
7.51 (m, 4H), 7.57 (d, 1H, J ) 8.0 Hz), 7.69-7.71 (m, 2H), and
8.04 (d, 1H, J ) 8.0 Hz); 13C NMR (CDCl3, 100 MHz) δ 24.9,
28.3, 48.2, 82.0, 100.2, 111.5, 115.8, 120.4, 124.7, 125.5, 126.4,
127.0, 127.1, 128.0, 128.8, 129.3, 130.7, 130.9, 131.8, 134.2,
135.2, 137.2, 137.9, 138.7, 148.5, 153.5, 168.3 and 168.9; HRMS
calcd for C35H31N3O7SLi 644.2043, found 644.2048.
N-Furan-2-yl-N-(2-methylallyl)-2-(2-vinylphenyl)acet-
amide (19). To a solution of 0.1 g (0.3 mmol) of the above
furanyl amide in 2 mL of DMF at 0 °C was added 15 mg (0.36
mmol) of NaH (60% dispersion in mineral oil). After stirring
for 10 min, the mixture was warmed to room temperature and
stirred for an additional 30 min, and this was followed by the
addition of 0.05 mL (0.45 mmol) of 2- bromo-2-methylpropene.
The mixture was allowed to stir for 30 min, then quenched
with H2O and extracted with EtOAc. The organic layer was
washed with H2O, brine, dried over MgSO4 and concentrated
under reduced pressure. The resultant residue was subjected
to flash silica gel chromatography (7% EtOAc in hexane) to
give 0.09 g (80%) of 19 as a pale yellow oil: IR (neat) 2971,
2919, 1686, and 1367 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.73
(s, 3H), 3.61 (s, 2H), 4.20 (s, 2H), 4.77 (s, 1H), 4.83 (s, 1H),
5.28 (dd, 1H, J ) 11.2 and 1.2 Hz), 5.60 (dd, 1H, J ) 17.6 and
1.2 Hz), 6.07 (dd, 1H, J ) 3.2 and 0.8 Hz), 6.38 (dd, 1H, J )
3.2 and 2.0 Hz), 6.80 (dd, 1H, J ) 17.6 and 11.2 Hz), 7.07 (dd,
1H, J ) 6.8 and 1.6 Hz), 7.20 (m, 2H), 7.28 (dd, 1H, J ) 2.0
and 0.8 Hz) and 7.47 (dd, 1H, 7.2 and 2.0 Hz); 13C NMR
(CDCl3, 100 MHz) δ 20.3, 38.7, 54.4, 105.1, 111.4, 113.3, 116.4,
126.2, 127.5, 127.9, 130.6, 132.8, 134.7, 137.5, 140.4, 140.8,
148.5, and 172.0; HRMS calcd for C18H19NO2 281.1416, found
281.1418.
5-(2-Methylallyl)-5H,7H-dibenzo[b,d]azepin-6-one (20).
A solution of 0.08 g (0.2 mmol) of acetamide 19 in 2 mL of
toluene was heated at 200 °C in a sealed pressure vessel for
36 h. After cooling to room temperature, the reaction mixture
was concentrated under reduced pressure and was subjected
to flash silica gel chromato-graphy to give 0.066 g (82%) of 20
as a white solid: mp 82-83 °C; IR (neat) 2965, 1671, 1440,
1375, and 763 cm-1; 1H NMR (CDCl3, 600 MHz) δ 1.40 (s, 3H),
3.48 (d, 1H, J ) 12.0 Hz), 3.60 (d, 1H, J ) 12.0 Hz), 4.23 (d,
1H, J ) 16.8 Hz), 4.54 (d, 1H, J ) 16.8 Hz), 4.56 (d, 1H, J )
1.2 Hz), 4.70 (d, 1H, J ) 1.2 Hz), 7.30 (dt, 1H, J ) 7.8 and 1.8
Hz), 7.38-7.44 (m, 5H), and 7.57-7.59 (m, 2H); 13C NMR
(CDCl3, 150 MHz) δ 20.0, 42.4, 53.7, 111.9, 123.3, 125.7, 127.9,
128.0, 128.1, 128.5, 128.9, 130.3, 134.8, 135.7, 136.7, 140.6,
140.8, and 171.1; HRMS calcd for C18H17ON 263.1310, found
263.1299.
6,7-(1-Benzenesulfonyl-1H-indol-2,3-yl)-2,3-(furan-2,3-
yl)-4,5-(1-phenylpyrrolidine-2,5-dion-3,4-yl)-1-azacy-
clononane (17). A solution of 0.5 g (0.8 mmol) of indole 16 in
4 mL of toluene was heated in a sealed pressure tube under
argon at 200 °C for 6 h, and the tube was opened after cooling
in dry ice. The solvent was removed under reduced pressure,
and the residue was purified by flash silica gel chromatography
(10% EtOAc in hexane) to provide 0.18 g (45%) of 17 as a pale
yellow solid: mp 187-189°C; IR (neat) 1715, 1385, 1359, and
1
1172 cm-1; H NMR (CDCl3, 400 MHz) δ 2.69-2.77 (m, 1H),
2.85 (brs, 1H), 3.03-3.10 (m, 2H), 3.67-3.70 (m, 1H), 4.49 (d,
1H, J ) 6.8 Hz), 4.98 (brs, 1H), 6.47 (d, 1H, J ) 2.0 Hz), 7.16
(d, 1H, J ) 2.0 Hz), 7.25-7.28 (m, 2H), 7.40-7.57 (m, 9H),
7.69-7.71 (m, 1H), and 7.97-8.00 (m, 2H); 13C NMR (CDCl3,
100 MHz) δ 25.6, 45.2, 47.7, 48.7, 108.5, 110.8, 114.8, 119.1,
124.0, 124.2, 125.8, 127.3, 127.5, 128.9, 129.0, 129.4, 129.5,
131.8, 132.6, 134.2, 136.7, 137.9, 138.8, 151.6, 174.2, and 174.8;
HRMS calcd for C30H23N3O5S 537.1358, found 537.1359.
2-Diazo-3-(3-ethyl-2-oxopiperidin-3-yl)-3-oxopropion-
ic Acid Ethyl Ester (24). To a 1.6 g (9.4 mmol) sample of
3-ethyl-2-oxopiperidine-3-carboxylic acid26 in 20 mL of CH2-
Cl2 was added 1.8 g (11 mmol) of 1,1′-carbonyldiimidazole, and
the solution was allowed to stir at rt under an argon atmo-
sphere for 12 h. The resulting mixture was added dropwise to
a solution of 1.8 g (14 mmol) of hydrogen ethyl malonate and
22 mL (44 mmol) of 2 M isopropylmagnesium chloride in 75
mL of THF at rt. The mixture was stirred at rt for 12 h, and
then 30 mL of 1 N HCl was added. The organic layer was
separated, and the aqueous layer was extracted with ether.
The combined organic extracts were washed with a saturated
NaCl solution, dried over MgSO4, and concentrated under
reduced pressure. The residue was subjected to flash silica gel
chromatography (10% EtOAc in hexane) to give 1.3 g (61%) of
3-(3-ethyl-2-oxopiperidin-3-yl)-3-oxopropionic acid ethyl ester
as a yellow oil: IR (neat) 1742, 1701, 1655, and 1301 cm-1; 1H
NMR (400 MHz, CDCl3) δ 0.87 (t, 3H, J ) 7.2 Hz), 1.26 (t, 3H,
J ) 7.2 Hz), 1.47-1.99 (m, 5H), 2.42-2.49 (m, 1H), 3.28-3.31
(m, 2H), 3.71 (d, 1H, J ) 16.4 Hz), 3.88 (d, 1H, J ) 16.4 Hz),
4.14-4.20 (m, 2H) and 6.09 (brs, 1H); 13C NMR (100 MHz,
CDCl3) δ 8.8, 14.3, 20.0, 26.7, 29.6, 42.8, 45.5, 60.7, 61.4, 168.0,
171.6, and 202.0.
N-Furan-2-yl-2-(2-vinylphenyl)acetamide. To a solution
of 0.36 g (2.0 mmol) of furan-2-yl carbamic acid tert-butyl ester
in 5 mL of THF at 0 °C was added dropwise 0.9 mL (2.2 mmol)
of n-BuLi (2.5 M). The reaction mixture was stirred for 10 min
at 0 °C. To a solution of 0.3 g (2.0 mmol) of (2-vinylphenyl)-
acetic acid50 in 5 mL of THF at 0 °C was added 0.3 mL (2.4
mmol) of N-methylmorpholine followed by the dropwise addi-
tion of 0.3 mL (2.2 mmol) of isobutyl chloroformate. After
stirring for 5 min, the reaction mixture was filtered through
a short path of Celite and washed with 2 mL of THF. The
filtrate was cooled to 0 °, and the preformed 2-amidofuran
lithiate was added dropwise via syringe. After stirring at 0 °C
for an additional 10 min, the reaction was quenched with H2O
and extracted with EtOAc. The combined organic extracts were
washed with H2O, brine and dried over MgSO4. After removing
the solvent under reduced pressure, the resultant residue was
dissolved into 5 mL of CH3CN, and this was followed by the
addition of 0.2 g (0.1 mmol) of magnesium perchlorate. The
solution was heated to 50 °C for 2.5 h and then cooled to rt
and quenched with H2O. After extracting with EtOAc, the
combined organic layer was washed with H2O, and brine, dried
over MgSO4, and concentrated under reduced pressure. The
residue was subjected to flash silica gel chromatography to
give 0.25 g (40%) of the titled compound as a white solid: mp
To a 0.91 g (4 mmol) sample of the above ester in acetonitrile
(35 mL) was added 0.49 g (4.8 mmol) of triethylamine, and
the solution was vigorously stirred for 30 min. To this mixture
was added 0.91 g (8 mmol) of mesyl azide and the solution
1
115-116 °C; IR (neat) 3203, 1661, and 1560 cm-1; H NMR
(CDCl3, 400 MHz) δ 3.80 (s, 2H), 5.38 (dd, 1H, J ) 10.8 and
0.8 Hz), 5.71 (dd, 1H, J ) 17.2 and 0.8 Hz), 6.31 (m, 2H), 6.92
J. Org. Chem, Vol. 70, No. 6, 2005 2213

Padwa et al.
was stirred at 25 °C for 10 h. The solution was concentrated
under reduced pressure and recrystallized from hexane/ether
to give 0.77 g (76%) of the titled compound as a pale yellow
solid: mp 100-101°C; IR (neat) 2134, 1720, 1669, 1480, 1318
and 1202 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.97 (t, 3H, J )
7.2 Hz), 1.28 (t, 3H, J ) 7.2 Hz), 1.70 (m, 1H), 1.80 (m, 1H),
2.05 (s, 3H), 2.25 (dt, 1H, J ) 13.0 and 4.4 Hz), 3.30 (m, 1H),
3.64 (dt, 1H, J ) 11.7 and 4.5 Hz), 4.22 (q, 2H, J ) 7.2 Hz),
and 5.59 (brs, 1H); 13C NMR (100 MHz, CDCl3) δ 10.0, 14.5,
18.9, 28.68, 28.71, 42.6, 57.6, 61.3, 76.6, 161.3, 173.0 and 191.5.
Anal. Calcd for C12H17N3O4: C, 53.92; H, 6.41; N, 15.72.
Found: C, 53.98; H, 6.45; N, 15.86.
mL) in THF (10 mL). After stirring for 8 h, the solvent was
removed under reduced pressure and the residue was dissolved
in ether, washed with sodium bicarbonate, basified to pH 10
with 10% NaOH, and washed with brine. The combined
organic phase was dried over MgSO4, filtered, and concen-
trated under reduced pressure. The crude material was
purified by flash column chromatography on silica gel (25%
EtOAc in hexane) to give 0.66 g (73%) of 29 as a white solid:
mp 139-142 °C; IR (neat) 2130, 1716, 1700, 1680, and 1470
1
cm-1; H NMR (400 MHz, CDCl3) δ 0.78 (t, 3H, J ) 7.2 Hz),
1.25 (t, 3H, J ) 7.2 Hz), 1.78 (m, 1H), 2.15 (m, 2H), 2.30 (dt,
1H, J ) 5.4 and 4.4 Hz), 3.70 (s, 1H), 4.00 (m, 1H), 4.20 (m,
3H), 5.60 (dd, 1H, J ) 13.8 and 1.2 Hz), 5.70 (dd, 1H, J ) 11.6
and 1.2 Hz), 6.90 (dd, 1H, J ) 13.8 and 11.6 Hz), 7.10 (m, 1H),
7.20 (m, 1H), 7.25 (m, 1H), and 7.60 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 9.8, 14.5, 19.6, 28.3, 30.3, 30.9, 46.3, 59.8, 61.5,
75.8, 109.7, 119.7, 121.2, 122.1, 122.9, 125.6, 137.1, 139.1,
161.4, 170.9, 172.2, and 190.8. Anal. Calcd for C24H26N4O5: C,
63.99; H, 5.82; N, 12.44. Found: C, 64.05; H, 5.88; N, 12.49.
2-Diazo-3-[3-ethyl-2-oxo-1-(2-vinylbenzoyl)piperidin-3-
yl]-3-oxopropionic Acid Ethyl Ester (27). A 0.25 g (3.4
mmol) sample of 2-vinylbenzoic acid51 was dissolved in CH2-
Cl2 (10 mL), and 1.28 g (10.1 mmol) of oxalyl chloride was
added dropwise. The mixture was stirred for 1 h, concentrated
under reduced pressure, and dissolved in THF (10 mL). This
solution was added dropwise over 1 h to a vigorously stirred
mixture containing 0.45 g (3.4 mmol) of 2-diazo-3-(3-ethyl-2-
oxopiperidin-3-yl)-3-oxopropionic acid ethyl ester and 3 g of 4
Å molecular sieves in THF (10 mL). After stirring for 8 h, the
mixture was filtered through a pad of Celite and concentrated
under reduced pressure. The crude material was purified by
flash column chromatography on silica gel (10% EtOAc in
hexane) to give 0.94 g (70%) of 27 as a clear oil: IR (neat)
3a-Ethyl-2,12c-epoxy-12c-methyl-3,7-dioxo-1,2,3a,4,5,6,-
7,12,12b,12c-decahydro-3H-6a,12-diazaindeno[2,1-a]-
phenalene-2-carboxylic Acid Ethyl Ester (31). A 0.07 g
(0.15 mmol) sample of the above diazo amide 29 was dissolved
in benzene (5 mL). Rhodium(II) acetate (6 mg) was added and
the solution was stirred for 3 days at room temperature. The
solution was filtered through a pad of Celite with ether (5 mL).
The mixture was concentrated under reduced pressure. The
crude material was purified by flash column chromatography
on silica gel to give 0.06 g of 31 as a white solid in 92% yield:
1
2136, 1711, 1680, 1327, 1260, 1178, and 1142 cm-1; H NMR
(400 MHz, CDCl3) δ 0.81 (t, 3H, J ) 7.2 Hz), 1.27 (t, 3H, J )
7.2 Hz), 1.75 (m, 1H), 2.05 (m, 4H), 2.29 (m, 1H), 3.90 (m, 1H),
4.20 (m, 3H), 5.26 (dd, 1H, J ) 11.2 and 0.8 Hz), 5.70 (dd, 1H,
J ) 17.4 and 0.8 Hz), 7.76 (dd, 1H, J ) 17.4 and 11.2 Hz),
IR (neat) 1767, 1736, 1654, 1490, 1475, and 1378 cm-1 1H
;
NMR (400 MHz, CDCl3) δ 1.09 (t, 3H, J ) 7.2 Hz), 1.14 (t, 3H,
J ) 7.2 Hz), 1.70 (m, 3H), 1.90 (m, 3H), 2.40 (m, 1H), 2.75 (m,
1H), 3.20 (m, 1H), 3.65 (s, 1H), 3.90 (m, 1H), 4.15 (q, 2H, J )
7.2 Hz), 4.50 (m, 1H), 7.20 (m, 3H), and 8.20 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 9.2, 14.3, 18.7, 24.1, 24.5, 30.9, 34.2, 35.8,
39.7, 50.9, 62.5, 85.1, 99.0, 103.5, 109.3, 121.6, 122.4, 123.1,
125.3, 137.8, 143.0, 164.9, 165.2, and 208.0.
7.11 (m, 1H), 7.20 (m, 1H), 7.32 (m, 1H), and 7.55 (m, 1H); 13
C
NMR (100 MHz, CDCl3) δ 9.8, 14.5, 19.4, 28.1, 30.7, 45.1, 59.7,
61.6, 76.0, 116.4, 125.2, 126.0, 127.2, 129.3, 134.4, 134.8, 161.6,
172.5, 174.1 and 190.3.
9-Aza-13-(ethoxycarbonyl)-16-oxa-8,14-dioxopentacy-
clo[13.2.1.02,7.09.17.013,14]-octadeca-2(3),4,5-triene-15-eth-
yl Ester (28). To an argon-filled round-bottom flask containing
0.08 g (0.2 mmol) of diazo amide 27 in benzene (10 mL) was
added 4 mg (5 mol %) of dirhodium(II) tetraacetate. After
stirring for 18 h, the mixture was filtered through a pad of
Celite and concentrated under reduced pressure. The crude
residue was purified by flash column chromatography on silica
gel (10% EtOAc in hexane) to give 0.07 g (95%) of 28 as a white
solid: mp 221-223 °C; IR (neat) 1767, 1742, 1700, and 1373
3a-Ethyl-2-hydroxy-12-methyl-3,7-dioxo-1,2,3a,4,5,6,7,-
12-octahydro-3H-6a,12-diaza-indeno[2,1-a]phenalene-2-
carboxylic Acid Ethyl Ester (32). A 0.06 g (0.14 mmol)
sample of cycloadduct 31 was heated at reflux in ether for 5
min. The mixture was allowed to cool and was stored at 0 °C
for 10 h. The solution was concentrated under reduced pres-
sure, and the crude material was purified by flash column
chromatography on silica gel (4% methanol in CH2Cl2) to give
pyridone 32 in 90% yield: mp 252-255 °C; IR (neat) 1767,
1721, 1629, and 1209 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.87
(t, 3H, J ) 7.2 Hz), 1.40 (t, 3H, J ) 7.2 Hz), 2.10 (m, 6H), 3.77
(d, 1H, J ) 16.0 Hz), 3.85 (d, 1H, J ) 16.0 Hz), 3.98 (m, 1H),
4.05 (s, 3H), 4.10-4.20 (m, 1H), 4.37 (dq, 1H, J ) 10.8 and
7.2 Hz), 4.47 (dq, 1H, J ) 10.8 and 7.2 Hz), 7.25 (m, 3H), and
8.40 (d, 1H, J ) 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ 8.9,
14.3, 19.2, 28.2, 31.2, 32.1, 33.4, 42.0, 52.1, 63.4, 75.6, 100.2,
107.4, 108.7, 121.8, 122.1, 124.3, 124.6, 140.3, 140.9, 143.5,
160.2, 171.5, and 205.4. Anal. Calcd for C24H26N2O5: C, 68.23;
H, 6.20; N, 6.63. Found: C, 68.41; H, 6.50; N, 6.34.
(2-Bromo-1-methyl-1H-indol-3-yl)acetic Acid Ethyl Es-
ter. A sample of (2-bromo-1H-indol-3-yl)-acetic acid ethyl
ester53 (1.7 g, 6 mmol) was taken up in acetonitrile (15 mL)
and then 60% sodium hydride (0.24 g, 6 mmol) was added.
The reaction mixture was stirred for 5 min and methyl iodide
(1 g, 7.2 mmol) was added in one portion and the solution was
stirred for 2 h. The mixture was diluted with water and the
aqueous layer was taken up in EtOAc. The organic phase was
collected and washed with sodium bicarbonate and brine. The
combined organic phase was dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude material was
purified by flash column chromatography on silica gel (10%
1
cm-1; H NMR (400 MHz, CDCl3) δ 1.16 (t, 3H, J ) 7.2 Hz),
1.31 (t, 3H, J ) 7.2 Hz), 1.72 (m, 3H), 1.95 (m, 3H), 2.53 (dd,
1H, J ) 13.6 and 4.8 Hz), 2.81 (dd, 1H, J ) 13.6 and 9.2 Hz),
3.27 (dt, 1H, J ) 13.2 and 4.0 Hz), 3.82 (m, 1H), 4.29 (m, 2H),
4.58 (m, 1H), 7.14 (m, 1H), 7.37 (m, 1H), 7.54 (m, 1H), and
8.18 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 9.1, 14.3, 18.5,
24.3, 37.0, 38.1, 40.5, 50.2, 62.4, 85.6, 96.6, 125.6, 127.1, 127.4,
128.9, 133.4, 139.6, 164.7, 165.2, and 207.6. Anal. Calcd for
C21H23NO5: C, 68.28; H, 6.28; N, 3.79. Found: C, 68.07; H,
6.34; N, 3.64.
2-Diazo-3-[3-ethyl-1-(1-methyl-2-vinyl-1H-indole-3-car-
bonyl)-2-oxopiperidin-3-yl]-3-oxopropionic Acid Ethyl
Ester (29). A 0.4 g sample (2 mmol) of 1-methyl-2-vinylindole-
3-carboxylic acid52 was dissolved in CH2Cl2 (20 mL). To this
solution was added oxalyl chloride (0.7 mL, 7 mmol) dropwise,
and the solution was stirred for 30 min, concentrated under
reduced pressure, and dissolved in THF (10 mL). This solution
was added dropwise over 1 h to a vigorously stirred mixture
of 0.56 g (3.4 mmol) of 2-diazo-3-(3-ethyl-2-oxopiperidin-3-yl)-
3-oxopropionic acid ethyl ester and triethylamine (0.61 g, 0.84
(49) Choi, D. S.; Huang, S.; Huang, M.; Barnard, T. S.; Adams, R.
D.; Seminario, J. M.; Tour, J. M. J. Org. Chem. 1998, 63, 2646.
(50) Ku¨ndig, E. P.; Perret, C. Helv. Chim. Acta 1981, 8, 2606.
(51) Chamoin, S.; Houldsworth, S.; Snieckus, V. Tetrahedron Lett.,
1998, 39, 4175.
(52) Laronze, M.; Laronze, J. Y.; Nemes, C.; Sapi, J. Eur. J. Org.
Chem. 1999, 9, 2285.
(53) Jirousek, M. R.; Paal, M.; Ruhter, G.; Schotten, T.; Stenzel, W.;
Takeuchi, K. Eur. Pat. Appl. 1999, EP 924209-A1; 19990623; US 97-
68195; 19971219. CAN 131:58827; AN 1999:401581.
2214 J. Org. Chem., Vol. 70, No. 6, 2005

Cycloaddition Chemistry of 2-Vinyl-Substituted Indoles
EtOAc in hexane) to give 1.7 g (97%) of the titled compound
for 15 min. At the end of this time, the mixture was filtered
through a pad of Celite. The solvent was removed under
reduced pressure and the crude material was purified by flash
column chromatography on silica gel (25% EtOAc in hexane)
to give 0.009 g (95%) of 34 as a clear oil: IR (neat) 1775, 1726,
1598, 1496, 1358, and 1291 cm-1; 1H NMR (400 MHz, CDCl3)
δ 0.49 (m, 1H), 0.76 (t, 3H, J ) 7.2 Hz), 0.84 (m, 1H), 1.36 (t,
3H, J ) 7.2 Hz), 1.59 (m, 2H), 1.77 (m, 1H), 1.95 (m, 2H), 2.44
(d, 1H, J ) 17.5 Hz), 3.01 (s, 3H), 3.08 (dd, 1H, J ) 17.5 and
0.4 Hz), 3.22 (dt, 1H, J ) 13.0 and 4.8 Hz), 3.90 (dd, 1H, J )
5.6 and 1.6 Hz), 4.37 (dq, 2H, J ) 7.2 and 1.6 Hz), 5.08 (d, 1H,
J ) 17.6 Hz), 5.41 (d, 1H, J ) 11.6 Hz), 5.66 (dd, 1H, J ) 17.6
and 11.6 Hz), 6.35 (d, 1H, J ) 7.6 Hz), 6.61 (dt, 1H, J ) 7.6
and 0.8 Hz), 6.89 (dd, 1H, J ) 7.6 and 0.8 Hz), and 7.19 (dt,
1H, J ) 7.6 and 0.8 Hz); 13C NMR (100 MHz, CDCl3) δ 9.28,
14.4, 17.9, 25.1, 30.1, 39.1, 41.7, 51.4, 62.5, 65.7, 85.0, 95.5,
103.1, 105.3, 117.2, 118.9, 124.0, 126.2, 130.6, 132.8, 151.6,
164.8, 176.8, and 205.1.
as a white solid: mp 49-51 °C; IR (neat) 1731, 1470, 1373,
1337, and 1163 cm-1 1H NMR (400 MHz, CDCl3) δ 1.27 (t,
;
3H, J ) 7.2 Hz), 3.77 (s, 3H), 3.79 (s, 1H), 4.18 (q, 4H, J ) 7.2
Hz), 7.15 (m, 1H), 7.23 (m, 1H), 7.29 (m, 1H), and 7.57 (d, 1H,
J ) 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ 14.4, 31.7, 31.8,
61.0, 107.8, 109.5, 115.0, 118.6, 120.1, 122.2, 127.2, 137.0, and
171.2.
(1-Methyl-2-vinyl-1H-indol-3-yl)acetic Acid Ethyl Es-
ter. A 2.5 g sample of the above indole (8.5 mmol) together
with tributylvinyl tin (5 g, 15 mmol), tetrabutylammonium
bromide (3.3 g, 10.2 mmol), bis(triphenylphosphine)palladium-
(II) chloride (0.3 g, 0.42 mmol, 5 mol %) was taken up in DMF
(30 mL) in a 60 mL microwave vessel. The solution was
subjected to microwave irradiation at 100 W for 25 min. The
resulting mixture was diluted with water and extracted with
in EtOAc. The organic layer was collected and washed with
sodium bicarbonate and brine. The combined organic phase
was dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude material was purified by flash
column chromatography on silica gel (10% EtOAc in hexane)
to give 1.45 g (70%) of the titled compound as a clear oil: IR
2-(1-Benzenesulfonyl-3-{2-[3-(2-diazo-2-ethoxycarbo-
nylacetyl)-3-ethyl-2-oxopiperidin-1-yl]-2-oxoethyl}-1H-
indol-2-yl)acrylic Acid Methyl Ester (35). To a solution of
0.34 g (0.87 mmol) of 2-[1-benzenesulfonyl-3-(2-hydroxyethyl)-
1H-indol-2-yl]acrylic acid methyl ester in 7 mL of acetone at
0 °C was added dropwise 2.2 mL (2.2 mmol) of Jones’ reagent
(1.0 M). The reaction mixture was allowed to stir at rt for an
additional 2 h. To this mixture was added isopropyl alcohol
until the reaction mixture turned from a brown to a green color
indicative of quenching the excess Jones’ reagent. After
filtering through a layer of Celite, the filtrate was concentrated
and extracted with EtOAc. The combined organic layers were
washed with H2O and brine and dried over MgSO4. Removal
of the solvent under reduced pressure left a solid residue which
was dissolved in 20 mL of ether. To this solution was added
0.22 g (1.0 mmol) of phosphorus pentachloride at 0 °C. The
reaction mixture was allowed to stir for 2 h at rt and was then
filtered through a pad of Celite. After removing the solvent
under reduced pressure, the residue was taken up in 15 mL
of THF. This solution was added dropwise over 1 h to a
vigorously stirred mixture of 0.26 g (0.96 mmol) of 2-diazo-3-
(3-ethyl-2-oxopiperidin-3-yl)-3-oxopropionic acid ethyl ester
and 4 Å molecular sieves (1 g) in 20 mL of THF. After stirring
for 20 h, the mixture was filtered and the solvent was removed
under reduced pressure. The crude material was purified by
flash column chromatography on silica gel (20% EtOAc in
hexane) to give 0.35 g (62%) of 35 as a white solid: mp 134-
136 °C; IR (neat) 2139, 1711, 1704, 1700, 1651, 1447, and 1148
1
(neat) 1731, 1469, 1366, and 1160 cm-1; H NMR (400 MHz,
CDCl3) δ 1.25 (t, 3H, J ) 7.2 Hz), 3.72 (s, 2H), 3.82 (s, 2H),
4.15 (q, 2H, J ) 7.2 Hz), 5.60 (dd, 1H, J ) 11.5 and 1.4 Hz),
5.75 (dd, 1H, J ) 17.6 and 1.4 Hz), 6.79 (dd, 1H, J ) 17.6 and
11.5 Hz), 7.11 (m, 1H), 7.23 (m, 2H), and 7.63 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 14.4, 30.7, 31.6, 60.9, 106.2, 109.3,
119.3, 119.7, 120.2, 122.4, 125.7, 127.9, 136.3, 137.2, and 172.3.
2-Diazo-3-{3-ethyl-1-[2-(1-methyl-2-vinyl-1H-indol-3-
yl)acetyl]-2-oxopiperidin-3-yl}-3-oxopropionic Acid Eth-
yl Ester (33). A 0.6 g (2.4 mmol) sample of the above
2-vinylindole-3-acetic acid ethyl ester and 85% potassium
hydroxide pellets (12 mmol) in ethanol (50 mL) were stirred
overnight at room temperature. The solvent was removed
under reduced pressure, and the residue was dissolved in
water. The solution was washed with ether and acidified to
pH 2. The aqueous phase was extracted with EtOAc, and the
combined organic phase was dried over MgSO4, filtered, and
concentrated under reduced pressure. A 0.1 g (0.46 mmol)
sample of the crude indole acetic acid and 0.1 g (0.48 mmol)
of phosphorus pentachloride were combined in anhydrous
ether (2.5 mL) at 0 °C under argon, and the mixture was
stirred for 30 min until all the solid had dissolved. The solvent
was concentrated under reduced pressure, and cold hexane (6
mL) was added. The solution was rapidly filtered through a
pad of Celite and concentrated under reduced pressure. The
residue was dissolved in THF (5 mL), and this solution was
added dropwise over 1 h to a vigorously stirred mixture of
2-diazo-3-(3-ethyl-2-oxopiperidin-3-yl)-3-oxopropionic acid eth-
yl ester (0.46 mmol) and 4 Å molecular sieves (2 g) in THF
(10 mL). After stirring for 8 h, the solvent was removed under
reduced pressure. The crude material was purified by flash
column chromatography on silica gel (20% EtOAc in hexane)
to give 0.13 g (60%) of 33 as a white solid: mp 112-115 °C;
IR (neat) 2131, 1711, 1682, 1311, and 1148 cm-1; 1H NMR (400
MHz, CDCl3) δ 0.91 (t, 3H, J ) 7.2 Hz), 1.29 (t, 3H, J ) 7.2
Hz), 1.72 (m, 1H), 1.90 (m, 3H), 2.25 (m, 1H), 3.72 (s, 3H),
3.75 (m, 1H), 4.15 (m, 1H), 4.23 (m, 2H), 4.32 (s, 2H), 5.50 (m,
2H), 6.75 (dd, 1H, J ) 18.2 and 11.4 Hz), 7.06 (m, 1H), 7.18
(m, 1H), 7.25 (m, 1H), and 7.42 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 10.0, 14.5, 19.6, 28.1, 30.0, 30.8, 35.9, 44.6, 60.1, 61.7,
76.0, 107.8, 109.3, 118.9, 119.3, 122.3, 126.2, 128.0, 136.1,
137.4, 161.5, 174.0, 176.8 and 190.8. Anal. Calcd for C25H28-
N4O5: C, 64.64; H, 6.08; N, 12.06. Found: C, 64.44; H, 5.88;
N, 11.84.
1
cm-1; H NMR (400 MHz, CDCl3) δ 0.90 (m, 3H), 1.27 (t, 3H,
J ) 7.2 Hz), 1.72 (m, 1H), 1.84-2.08 (m, 4H), 2.21 (dt, 1H, J
) 12.4 and 5.2 Hz), 3.60-3.74 (m, 1H), 3.77 (s, 1H), 3.82-
4.38 (m, 3H), 4.20 (q, 2H, J ) 7.2 Hz), 5.77 (br s, 1H), 6.66 (d,
1H, J ) 1.6 Hz), 7.20 (t, 1H, J ) 7.6 Hz), 7.24-7.38 (m, 4H),
7.45 (t, 1H, J ) 7.6 Hz), 7.67 (d, 2H, J ) 7.6 Hz), and 8.08 (d,
1H, J ) 8.4 Hz); 13C NMR (100 MHz, CDCl3) δ 10.1, 14.5, 19.4,
28.2, 29.7, 31.8, 44.5, 52.6, 60.0, 61.7, 76.0, 115.0, 118.9, 123.9,
125.6, 126.8, 129.2, 130.4, 130.9, 133.1, 133.9, 136.3, 138.5,
161.6, 166.2, 174.1, 174.6, and 190.3. Anal. Calcd for C32H32-
N4O9S: C, 59.25; H, 4.91; N, 8.64. Found: C, 59.18; H, 4.96;
N, 8.64.
Rh(II)-Catalyzed Cycloaddition of 2-(1-Benzenesulfo-
nyl-3-{2-[3-(2-diazo-2-ethoxycarbonylacetyl)-3-ethyl-2-
oxopiperidin-1-yl]-2-oxoethyl}-1H-indol-2-yl)acrylic Acid
Methyl Ester (36). A 10 mL microwave vessel was charged
with 4 Å molecular sieves (1 g) and 2.7 mg of rhodium(II)
acetate. The mixture was heated at 100 °C for 10 min and
flushed with argon. A 0.04 g (0.062 mmol) sample of diazo
amide 35 dissolved in 4 mL of benzene was syringed into the
vessel, and the mixture was heated at 90 °C for 2 h (150 W)
in a microwave reactor. At the end of this time, the mixture
was filtered through a pad of Celite and concentrated under
reduced pressure. The crude residue was recrystallized from
CH2Cl2-pentane to give 0.035 g (91%) of cycloadduct 36 as a
white solid: mp 240-244 °C; IR (neat) 1768, 1732, 1718, 1702,
3a-Ethyl-5,12b-epoxy-6-trimethyl-4,12-dioxo-5a-vinyl-
2,3,3a,4,5,5a,6,11,12,12b-decahydro-1H-6,12a-diazaindeno-
[7,1-cd]fluorene-5-carboxylic Acid Ethyl Ester (34). A
0.01 g (0.021 mmol) sample of diazo amide 33 was stirred with
rhodium(II) acetate (1 mg) in toluene (4 mL) in a 10 mL
microwave vessel. The mixture was heated at 100 °C (125 W)
J. Org. Chem, Vol. 70, No. 6, 2005 2215

Padwa et al.
1
1367, and 1172 cm-1; H NMR (400 MHz, CDCl3) δ 0.41 (d,
and 204.6. Anal. Calcd for C22H23NO6: C, 66.49; H, 5.83; N,
3.52. Found: C, 66.26; H, 5.64; N, 3.42.
1H, J ) 15.0 Hz), 0.83 (t, 3H, J ) 7.2 Hz), 0.87-1.08 (m, 2H),
1.31 (t, 3H, J ) 7.2 Hz), 1.46-1.57 (m, 1H), 1.63-1.76 (m, 1H),
1.80-1.92 (m, 2H), 2.72 (d, 1H, J ) 15.0 Hz), 3.11 (dt, 1H, J
) 12.8 and 2.8 Hz), 3.28 (d, 1H, J ) 17.2 Hz), 3.44 (d, 1H, J
) 17.2 Hz), 3.85-3.93 (m, 1H), 4.20-4.30 (m, 2H), 6.98-7.06
(m, 2H), 7.30-7.39 (m, 3H), 7.50-7.59 (m, 3H) and 7.78 (d,
1H, J ) 5.0 Hz); 13C NMR (150 MHz, CDCl3) δ 8.2, 14.2, 18.0,
22.5, 24.5, 36.4, 38.5, 44.4, 50.0, 52.7, 61.9, 63.1, 83.7, 99.0,
119.1, 122.9, 123.7, 126.3, 127.9, 128.5, 129.3, 129.4, 134.6,
134.7, 137.1, 138.9, 143.0, 166.4, 169.1, 174.0, and 209.9;
HRMS (FAB) calcd for C32H32N2O9S (M + Li) 627.1989, found
627.1959. Anal. Calcd for C32H32N2O9S: C, 61.92; H, 5.20; N,
4.51. Found: C, 61.75; H, 5.19; N, 4.47.
3-[1-(2-Benzofuran-3-yl-acetyl)-3-ethyl-2-oxopiperidin-
3-yl]-2-diazo-3-oxopropionic Acid Ethyl Ester (37). Ben-
zofuran-3-acetic acid ethyl ester54 (0.6 g, 2.4 mmol) and 85%
potassium hydroxide pellets (12 mmol) in ethanol (50 mL) were
stirred overnight. The solvent was removed under reduced
pressure, and the residue was dissolved in water. The solution
was washed with ether and acidified to pH 2. The aqueous
phase was extracted with EtOAc and the combined organic
phase was dried over MgSO4, filtered, and concentrated under
reduced pressure. A 0.21 g (1 mmol) sample of benzofuran-3-
yl-acetic acid was dissolved in CH2Cl2 (10 mL) and oxalyl
chloride (0.3 mL, 3.5 mmol) was added followed by two drops
of DMF. The solution was stirred for 1 h at rt, concentrated
under reduced pressure, and dissolved in THF (5 mL). This
solution was added dropwise over 1 h to 0.25 g (1 mmol) of a
vigorously stirred mixture of 2-diazo-3-(3-ethyl-2-oxopiperidin-
3-yl)-3-oxopropionic acid ethyl ester and 4 Å molecular sieves
(3 g) in THF (10 mL). After stirring for 8 h, the solvent was
removed under reduced pressure. The crude material was
purified by flash column chromatography on silica gel (10%
EtOAc in hexane) to give 0.37 g (86%) of 37 as a white solid:
mp 102-104 °C; IR (neat) 2141, 1705, 1690, 1650, 1450, 1368,
1316 and 1150 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.94 (t, 3H,
J ) 7.2 Hz), 1.28 (t, 3H, J ) 7.2 Hz), 1.70-1.80 (m, 1H), 1.80-
2.10 (m, 4H), 2.25 (dt, 1H, J ) 12.8 and 4.8 Hz), 3.74 (dt, 1H,
J ) 12.8 and 4.8 Hz), 4.15-4.30 (m, 5H), 7.21-7.31 (m, 2H),
7.65 (d, 1H, J ) 8.0 Hz), 7.54 (d, 1H, J ) 8.0 Hz), and 7.61 (s,
1H); 13C NMR (100 MHz, CDCl3) δ 10.1, 14.5, 19.4, 28.2, 29.8,
34.5, 44.5, 60.1, 61.8, 76.0, 111.6, 114.1, 120.0, 122.7, 124.4,
128.3, 143.4, 155.2, 161.6, 174.0, 174.6, and 190.6. Anal. Calcd
for C22H23N3O6: C, 62.11; H, 5.45; N, 9.88. Found: C, 62.10;
H, 5.54; N, 9.71.
2-Diazo-3-[3-ethyl-1-(2-furan-3-ylacetyl)-2-oxopiperidin-
3-yl]-3-oxopropionic Acid Ethyl Ester (41). To a 0.12 g
(0.93 mmol) sample of furan-3-ylacetic acid55 dissolved in CH2-
Cl2 (10 mL) was added 0.24 mL of oxalyl chloride followed by
two drops of DMF. The solution was stirred for 2 h and was
concentrated under reduced pressure and dissolved in THF
(10 mL). This solution was added dropwise over 1 h to a
vigorously stirred mixture of 0.23 g (0.85 mmol) of 2-diazo-3-
(3-ethyl-2-oxopiperidin-3-yl)-3-oxopropionic acid ethyl ester
and 4 Å molecular sieves (3 g) in THF (10 mL). After stirring
for 8 h, the mixture was filtered and the solvent was removed
under reduced pressure. The crude material was purified by
flash column chromatography on silica gel (10% EtOAc in
hexane) to give 0.21 g (60%) of 41 as a clear oil: IR (neat)
1
2140, 1702, 1689, 1649, 1468, 1371, 1317, and 1146 cm-1; H
NMR (400 MHz, CDCl3) δ 0.95 (t, 3H, J ) 7.2 Hz), 1.28 (t, 3H,
J ) 7.2 Hz), 1.70-1.78 (m, 1H), 1.83-1.98 (m, 2H), 2.02 (q,
4H, J ) 7.2 Hz), 2.25 (dt, 1H, J ) 12.0 and 5.3 Hz), 3.74 (dt,
1H, J ) 12.0 and 4.9 Hz), 3.92 (d, 1H, J ) 17.2 Hz), 4.02 (d,
1H, J ) 17.2 Hz), 4.17-4.26 (m, 3H), 6.37 (m, 1H), and 7.36-
7.38 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 10.1, 14.5, 19.5,
28.2, 29.9, 35.5, 44.4, 60.2, 61.8, 112.0, 118.5, 140.9, 142.8,
161.5, 173.9, 175.3, and 190.7.
Rh(II)-Catalyzed Cycloaddition of 2-Diazo-3-[3-ethyl-
1-(2-furan-3-ylacetyl)-2-oxopiperidin-3-yl]-3-oxopropi-
onic Acid Ethyl Ester (42). A 10 mL microwave vessel was
charged with 4 Å molecular sieves (0.5 g) and rhodium(II)
pivalate (4 mg, 5 mol %). The container was placed in an oven
at 100 °C for 10 min. The vessel was capped and flushed with
argon and 0.05 g (0.13 mmol) of furanyl diazo amide 41
dissolved in benzene (2 mL) was syringed into the vessel, and
the mixture was heated in the microwave reactor for 40 min
at 90 °C (140 W). The mixture was filtered through a pad of
Celite and concentrated under reduced pressure. The crude
residue was purified by flash column chromatography on silica
gel (10% EtOAc in hexane) to give cycloadduct 42 (0.015 g,
35%) as a clear oil: IR (neat) 1772, 1746, 1722, 1455, 1372,
1260, and 1022 cm-1 1H NMR (600 MHz, CDCl3) δ 1.07 (t,
;
3H, J ) 7.2 Hz), 1.37 (t, 3H, J ) 7.2 Hz), 1.81-1.85 (m, 1H),
1.90-2.04 (m, 1H), 2.12-2.22 (m, 3H), 2.56 (d, 1H, J ) 17.7
Hz), 2.78 (d, 1H, J ) 17.7 Hz), 3.18 (dt, 1H, J ) 13.0 and 4.6
Hz), 3.86 (dd, 1H, J ) 13.0 and 5.1 Hz), 4.34-4.40 (m, 2H),
4.90 (d, 1H, J ) 2.7 Hz), 5.04 (s, 1H), and 6.32 (d, 1H, J ) 2.7
Hz); 13C NMR (150 MHz, CDCl3) δ 9.2, 14.3, 18.0, 22.9, 24.7,
38.8, 42.5, 52.4, 60.7, 62.9, 92.1, 98.3, 104.2, 104.9, 148.5, 165.3,
176.0, and 197.2; HRMS (FAB) calcd for C18H21NO6 (M + Li)
354.1529, found 354.1523.
3a-Ethyl-5,12b-epoxy-4,12-dioxo-2,3,3a,5,5a,11,12,12b-
octahydro-1H,4H-6-oxa-12a-azaindeno[7, 1-cd]fluorene-
5-carboxylic Acid Ethyl Ester (38). A 10 mL microwave
reactor was charged with 4 Å molecular sieves (1 g) and 4 mg
of rhodium(II) pivalate. The container was heated at 100 °C
for 10 min and flushed with argon. A 0.05 g (0.117 mmol)
sample of the above diazo amide 37 dissolved in benzene (4
mL) was syringed into the vessel and the mixture was heated
in the microwave apparatus for 2 h at 70 °C (120 W). The
mixture was filtered through a pad of Celite and concentrated
under reduced pressure. The crude residue was purified by
flash column chromatography on silica gel (10% EtOAc in
hexane) to give 0.045 g (90%) of cycloadduct 38 as a white
solid: mp 185-187 °C; IR (neat) 1772, 1731, 1730, 1598, 1480,
2-Diazo-3-[3-ethyl-2-oxo-1-(2-thiophen-3-ylacetyl)pi-
peridin-3-yl]-3-oxopropionic Acid Ethyl Ester (43). To a
0.14 g (1 mmol) sample of thiophen-3-ylacetic acid dissolved
in CH2Cl2 (10 mL) was added oxalyl chloride (0.3 mL, 3.5
mmol) followed by two drops of DMF. The solution was stirred
for 1 h, concentrated under reduced pressure, and dissolved
in THF (5 mL). This solution was added dropwise over 1 h to
a vigorously stirred mixture of 0.25 g (1 mmol) of 2-diazo-3-
(3-ethyl-2-oxopiperidin-3-yl)-3-oxopropionic acid ethyl ester
and 4 Å molecular sieves (3 g) in THF (10 mL). After stirring
for 8 h, the solvent was removed under reduced pressure. The
crude residue was purified by flash column chromatography
on silica gel (10% EtOAc in hexane) to give 0.38 g (97%) of 43
as a yellow oil: IR (neat) 2137, 1705, 1686, 1649, 1371, 1315,
and 1143 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.91 (t, 3H, J )
7.2 Hz), 1.28 (t, 3H, J ) 7.2 Hz), 1.70-1.78 (m, 1H), 1.80-
2.10 (m, 4H), 2.25 (dt, 1H, J ) 12.4 and 5.5 Hz), 3.74 (dt, 1H,
J ) 12.8 and 4.8 Hz), 4.10-4.30 (m, 5H), 7.01 (dd, 1H, J ) 4.8
and 1.2 Hz), 7.10 (dd, 1H, J ) 2.8 and 1.2 Hz), and 7.25 (dd,
1H, J ) 4.8 and 2.8 Hz); 13C NMR (100 MHz, CDCl3) δ 10.0,
14.5, 19.4, 28.1, 29.9, 40.2, 44.4, 60.1, 61.7, 76.0, 123.1, 125.3,
129.1, 135.0, 161.5, 173.8, 175.3, and 190.7.
1455, 1358, 1315, 1265 and 1142 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 0.24-0.34 (m, 1H), 0.78 (t, 3H, J ) 7.2 Hz), 0.83-
0.91 (m, 1H), 1.40 (t, 3H, J ) 7.2 Hz), 1.52-2.12 (m, 4H), 2.86
(d, 1H, J ) 17.6 Hz), 3.10 (d, 1H, J ) 17.6 Hz), 3.22 (dt, 1H,
J ) 12.8 and 4.4 Hz), 3.91 (dt, 1H, J ) 13.2 and 5.6 Hz), 4.36-
4.50 (m, 2H), 5.39 (s, 1H), 6.86-6.96 (m, 2H), 7.04-7.08 (m,
1H), and 7.21-7.30 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
9.1, 14.4, 17.9, 20.4, 24.8, 39.3, 43.4, 52.1, 59.3, 63.0, 90.1, 92.3,
104.8, 111.6, 122.2, 124.4, 126.3, 131.0, 160.7, 165.0, 176.4,
(54) Deshpande, A. R.; Paradkar, M. V. Synth. Commun. 1990, 20,
809.
(55) Potvin, S.; Canonne, P. Tetrahedron: Asymmetry 1996, 7, 2821.
2216 J. Org. Chem., Vol. 70, No. 6, 2005

Cycloaddition Chemistry of 2-Vinyl-Substituted Indoles
Rh(II)-Catalyzed Cycloaddition of 2-Diazo-3-[3-ethyl-
2-oxo-1-(2-thiophen-3-ylacetyl)piperidin-3-yl]-3-oxopro-
pionic Acid Ethyl Ester (44). A 10 mL microwave vessel
was charged with 4 Å molecular sieves (0.5 g) and 7 mg of
rhodium(II) pivalate. The mixture was heated at 100 °C for
10 min and flushed with argon. A 0.05 g (0.12 mmol) sample
of the above diazo amide 43 dissolved in benzene (1.6 mL) was
syringed into the vessel and the mixture was heated at 90 °C
for 40 min (140 W). At the end of this time, the mixture was
filtered through a pad of Celite and concentrated under
reduced pressure. The crude material was purified by flash
column chromatography on silica gel (20% EtOAc in hexane)
to give 0.017 g (38%) of 44 as a clear oil: IR (neat) 1772, 1746,
on silica gel (10% EtOAc in hexane) to give 47 as a clear oil
(0.024 g, 66% yield): IR (neat) 1772, 1751, 1717, 1282, 1253,
and 1151 cm-1; 1H NMR (600 MHz, CDCl3) δ 0.84 (t, 3H, J )
7.2 Hz), 1.50 (s, 9H), 1.72 (dt, 1H, J ) 15.0 and 7.2 Hz), 2.06
(ddd, 1H, J ) 12.0, 3.0 and 1.5 Hz), 2.10-2.14 (m, 1H), 2.19
(dd, 1H, J ) 12.0 and 3.0 Hz), 2.39 (dd, 1H, J ) 19.0 and 2.4
Hz), 2.55 (dd, 1H, J ) 19.0 and 7.8 Hz), 2.87-2.90 (m, 1H),
3.59 (dd, 1H, J ) 12.5 and 1.5 Hz) and 3.85 (dd, 1H, J ) 12.5
and 3.0 Hz); 13C NMR (150 MHz, CDCl3) δ 9.3, 21.9, 28.2, 28.6,
33.3, 43.7, 53.7, 63.5, 83.7, 152.8, 166.3, and 209.5; HRMS
(FAB) calcd for C14H21NO4 (M + Li) 274.1631, found 274.1634.
2-Diazo-3-(3-ethyl-2-oxo-piperidin-3-yl)-3-oxopropion-
ic Acid Methyl Ester. To a solution of 3-(3-ethyl-2-oxopi-
peridin-3-yl)-3-oxopropionic acid methyl ester26 (0.55 g, 2.4
mmol) in 35 mL of acetonitrile was added triethylamine (0.41
g, 2.9 mmol), and the mixture was vigorously stirred for 30
min. To this mixture was added mesyl azide (0.37 g, 4.8 mmol),
and the resulting mixture was stirred at rt for 10 h. The
solution was concentrated under reduced pressure and the
white solid that precipitated was recrystallized from hexanes-
ether to give the titled compound in 76% yield: mp 103-105
°C; IR (neat) 2136, 1721, 1664, 1654, 1316, and 1202 cm-1; 1H
NMR (400 MHz, CDCl3) δ 1.00 (t, 3H, J ) 7.2 Hz), 1.78-1.88
(m, 1H), 1.89-2.16 (m, 4H), 2.25 (dt, 1H, J ) 13.0 and 4.4
Hz), 3.40 (m, 1H), 3.68 (dt, 1H, J ) 11.7 and 4.5 Hz), 3.80 (s,
3H) and 5.44 (brs, 1H); 13C NMR (100 MHz, CDCl3) δ 10.1,
18.8, 28.4, 42.4, 52.4, 65.2, 76.6, 161.9, 173.0, and 191.1. Anal.
Calcd for C12H17N3O4: C, 52.17; H, 5.97; N, 16.59. Found: C,
52.01; H, 5.94; N, 16.51.
3-(2-Diazo-2-methoxycarbonylacetyl)-3-ethyl-2-oxopi-
peridine-1-carboxylic Acid tert-Butyl Ester (48). A sample
of di-tert-butyl dicarbonate (0.57 g, 2.6 mmol) was added to a
solution of the above diazo amide (0.5 g, 2.0 mmol) and
4-(dimethylamino)pyridine (0.012 g, 0.10 mmol) in 25 mL of
acetonitrile. The solution was stirred for 12 h at 25 °C, and
the mixture was concentrated under reduced pressure. The
crude residue was purified by flash column chromatography
on silica gel (20% EtOAc in hexane) to give 48 as a clear oil
(0.53 g, 75% yield): IR (neat) 2134, 1764, 1720, 1654, 1317,
and 1152 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.87 (t, 3H, J )
7.2 Hz), 1.44 (s, 9H), 1.57-1.66 (m, 1H), 1.76-1.86 (m, 1H),
1.87-2.09 (m, 3H), 2.21 (dt, 1H, J ) 13.2 and 4.8 Hz), 3.72 (s,
1H) and 3.74-3.90 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 9.8,
19.7, 27.9, 28.1, 30.6, 46.0, 52.3, 60.2, 75.9, 82.5, 154.0, 161.7,
171.8, and 190.7.
1
1727, 1462, 1402, 1360, and 1137 cm-1; H NMR (400 MHz,
CDCl3) δ 1.06 (t, 3H, J ) 7.2 Hz), 1.35 (t, 3H, J ) 7.2 Hz),
1.70-1.76 (m, 1H), 1.80 (m, 1H), 2.00-2.14 (m, 3H), 2.59 (d,
1H, J ) 17.2 Hz), 2.81 (d, 1H, J ) 17.2 Hz), 3.17 (dt, 1H, J )
12.8 and 4.5 Hz), 3.86 (dd, 1H, J ) 12.8 and 4.8 Hz), 4.36-
4.50 (dq, 2H, J ) 7.2 and 1.6 Hz), 4.48 (s, 1H), 5.35 (d, 1H, J
) 6.0 Hz), and 6.08 (d, 1H, J ) 6.0 Hz); 13C NMR (100 MHz,
CDCl3) δ 9.4, 14.3, 18.0, 21.7, 24.9, 39.1, 45.0, 52.2, 60.8, 62.9,
67.45, 91.8, 105.5, 122.2, 128.9, 165.3, 176.0 and 205.2; HRMS
(FAB) calcd for C18H21NO5S (M + Li: 370.1300, found 370.1302.
1-Ethyl-3-(2-thiophen-3-ylacetyl)-3-azabicyclo[3.2.1]-
octane-2,7-dione (45). A 10 mL microwave vessel was loaded
with 4 Å molecular sieves (0.7 g) and rhodium(II) perfluorobu-
tyrate (0.01 g, 10 mol %). The container was placed in an oven
at 100 °C for 10 min and was flushed with argon. Diazo amide
43 (0.037 g, 0.094 mmol) in 2 mL of benzene was added to the
tube, and the solution was subjected to microwave radiation
for 45 min at 90 °C (up to 120 W). The mixture was filtered
through a pad of Celite and concentrated under reduced
pressure. The crude residue was purified by flash column
chromatography on silica gel to give 45 as a clear oil (0.014 g)
in 51% yield: IR (neat) 1750, 1697, 1459, 1382, 1245, and 1141
1
cm-1; H NMR (400 MHz, CDCl3) δ 0.86 (t, 3H, J ) 7.2 Hz),
1.73 (dt, 1H, J ) 14.8 and 7.2 Hz), 2.10-2.18 (m, 2H), 2.20
(ddd, 1H, J ) 12.4, 3.2 and 1.2 Hz), 2.33 (dd, 1H, J ) 19.0
and 2.8 Hz), 2.57 (ddd, 1H, J ) 19.0, 7.2 and 1.2 Hz), 2.93-
2.98 (m, 1H), 3.71 (ddd, 1H, J ) 13.0. 1.8 and 1.6 Hz), 3.84
(ddd, 1H, J ) 13.0, 4.4 and 1.2 Hz), 4.20 (d, 1H, J ) 16.4 Hz),
4.27 (d, 1H, J ) 16.4 Hz), 7.01 (dd, 1H, J ) 4.8 and 1.2 Hz),
7.10 (dd, 1H, J ) 2.8 and 1.2 Hz) and 7.25 (dd, 1H, J ) 4.8
and 2.8 Hz); 13C NMR (150 MHz, CDCl3) δ 9.3, 21.9, 28.5, 33.5,
40.5, 43.8, 52.8, 63.6, 123.4, 125.6, 129.0, 134.2, 168.8, 175.4,
and 209.2; HRMS calcd for C15H17NO3S 291.09292, found
291.09334.
3-(1-But-3-enoyl-3-ethyl-2-oxopiperidin-3-yl)-2-diazo-
3-oxopropionic Acid Ethyl Ester (52). A sample of but-3-
enoyl chloride56 (0.3 g, 2.8 mmol) in THF (10 mL) was added
dropwise over 1 h to a vigorously stirred mixture of diazo
amide 10 (0.6 g, 2.4 mmol) and 4 Å molecular sieves (0.5 g) in
15 mL of THF. After stirring for 8 h, the solvent was removed
under reduced pressure and the residue was dissolved in ether
and filtered through a fritted glass tube. Removal of the
solvent left a residue which was purified by flash column
chromatography on silica gel (20% EtOAc in hexane) to give
52 (0.56 g, 71% yield) as a clear oil: IR (neat) 1711, 1689, 1650,
3-(2-Diazo-2-ethoxycarbonylacetyl)-3-ethyl-2-oxopi-
peridine-1-carboxylic Acid tert-Butyl Ester (46). A sample
of di-tert-butyl dicarbonate (0.11 g, 0.51 mmol) was added to
a solution of 2-diazo-3-(3-ethyl-2-oxopiperidin-3-yl)-3-oxopro-
pionic acid ethyl ester (0.1 g, 0.4 mmol) and 4-(dimethylamino)-
pyridine (0.0024 g, 0.02 mmol) in 5 mL of acetonitrile. The
mixture was stirred for 12 h at 25 °C and was concentrated
under reduced pressure. The crude residue was purified by
flash column chromato-graphy on silica gel (20% EtOAc in
hexane) to give 46 as a clear oil (0.11 g, 75% yield): IR (neat)
1316, and 1152 cm-1 1H NMR (400 MHz, CDCl3) δ 0.98 (t,
;
1
2137, 1767, 1714, 1652, 1315, and 1150 cm-1; H NMR (400
3H, J ) 7.2 Hz), 1.28 (t, 3H, J ) 7.2 Hz), 1.69-1.77 (m, 1H),
1.82-1.95 (m, 2H), 1.98-2.15 (m, 2H), 2.20-2.30 (m, 1H),
3.44-3.55 (m, 1H), 3.64-3.74 (m, 2H), 4.15-4.28 (m, 3H),
5.09-5.18 (m, 2H) and 5.96-6.08 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 10.2, 14.5, 19.5, 28.3, 30.0, 44.1, 44.2, 60.2, 61.7, 75.9,
118.2, 131.8, 161.5, 173.8, 175.7, and 190.7.
MHz, CDCl3) δ 0.93 (t, 3H, J ) 7.2 Hz), 1.27 (t, 3H, J ) 7.2
Hz), 1.94 (s, 9H), 1.63-1.69 (m, 1H), 1.82-1.90 (m, 1H), 1.92-
2.03 (m, 2H), 2.04-2.16 (m, 1H), 2.27 (dt, 1H, J ) 13.2 and
4.8 Hz), 3.78-3.92 (m, 2H), and 4.16-4.30 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 9.9, 14.4, 19.9, 28.1, 28.2, 30.8, 46.2, 60.3,
61.6, 82.6, 154.3, 161.4, 171.9, and 191.0.
6a-Ethyl-8,9b-epoxy-2,7-dioxodecahydropyrrolo[3,2,1-
ij]quinoline-8-carboxylic Acid Ethyl Ester (53). A 10 mL
microwave vessel containing 4 Å molecular sieves (0.5 g) and
rhodium(II) pivaloate (0.0025 g, 5 mol %) was flushed with
argon. A solution of the above diazo compound 52 (0.027 g,
0.082 mmol) dissolved in 1 mL of benzene was added to the
1-Ethyl-2,7-dioxo-3-azabicyclo[3.2.1]octane-3-carbox-
ylic Acid tert-Butyl Ester (47). A sample of the above diazo
ketoamide 46 in 2 mL of benzene together with Rh2(pfb)4 as
the catalyst (5 mol %) and 4 Å molecular sieves (0.7 g) was
subjected to microwave radiation at 90 °C for 45 min. After
the reaction was complete, the mixture was filtered through
a pad of Celite and concentrated under reduced pressure. The
crude residue was purified by flash column chromatography
(56) Marson, C. M.; Grabowska, U.; Fallah, A.; Walsgrove, T.;
Eggleston, D. S.; Baures, P. W. J. Org. Chem. 1994, 59, 291.
J. Org. Chem, Vol. 70, No. 6, 2005 2217

Padwa et al.
vessel, and the solution was subjected to microwave radiation
for 30 min. at 80 °C (up to 120 W). The mixture was filtered
through a pad of Celite and concentrated under reduced
pressure. The crude material was purified by flash column
chromatography on silica gel (10% EtOAc in hexane) to give
0.023 g (91%) of 53 as a white solid: mp 103-106 °C; IR (neat)
2.23 (ddd, 1H, J ) 12.4, 3.2 and 1.2 Hz), 2.37 (dd, 1H, J )
19.0 and 3.2 Hz), 2.59 (ddd, 1H, J ) 19.0, 7.2 and 1.2 Hz),
2.87-2.90 (m, 1H), 3.58-3.74 (m, 2H), 3.85 (ddd, 1H, J ) 13.2,
4.4 and 1.2 Hz), 5.10-5.18 (m, 2H), and 5.91-6.05 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 9.3, 21.9, 28.5, 33.4, 43.9, 44.5,
52.5, 63.6, 118.6, 131.0, 168.7, 175.7, and 209.3. Anal. Calcd
for C13H17NO3: C, 66.36; H, 7.28; N, 5.95. Found: C, 66.21;
H, 7.22; N, 5.82.
1
1769, 1746, 1722, 1372, and 1036 cm-1; H NMR (400 MHz,
CDCl3) δ 1.16 (t, 3H, J ) 7.2 Hz), 1.33 (t, 3H, J ) 7.2 Hz),
1.43-1.62 (m, 3H), 1.76-1.83 (m, 1H), 1.97-2.03 (m, 2H),
2.15-2.21 (m, 1H), 2.34-2.47 (m, 2H), 2.60-2.72 (m, 2H), 3.11
(dt, 1H, J ) 13.0 and 3.9 Hz), 3.83 (m, 1H), and 4.28-4.36
(dq, 2H, J ) 7.2 and 0.8 Hz); 13C NMR (100 MHz, CDCl3) δ
8.65, 14.4, 18.4, 23.0, 23.5, 34.0, 36.5, 37.2, 38.2, 48.9, 62.4,
88.8, 102.6, 165.8, 176.1, and 206.6.
Acknowledgment. We appreciate the financial sup-
port provided by the National Science Foundation
(Grant No. CHE-0132651) and the National Institutes
of Health (GM 059384-24) for generous support of this
work. We thank our colleague, Dr. Kenneth Hardcastle,
for his assistance with the X-ray crystallographic studies
and the University Research Committee of Emory
University for funds to acquire a microwave reactor.
3-But-3-enoyl-1-ethyl-3-azabicyclo[3.2.1]octane-2,7-di-
one (54). A sample of diazo ketoamide 52 was subjected to
microwave radiation as described above but using rhodium-
(II) perfluorobutyrate as the catalyst. The mixture was then
filtered through a pad of Celite and concentrated under
reduced pressure. The residue was purified by flash column
chromatography on silica gel (10% EtOAc in hexane) to give
two products. The major product isolated was identified as
cycloadduct 53 and was obtained in 62% yield (0.015 g). The
minor product was obtained as a clear oil (0.0058 g, 30% yield)
and was recrystallized from ether-pentane to give 54 as a
white solid: mp 76-78 °C; IR (neat) 1752, 1697, 1175, and
Supporting Information Available: Spectroscopic and
experimental procedures for compounds 6, 18, and 21-23. 1H
and 13C NMR spectra for new compounds lacking elemental
analyses together with an ORTEP drawing for structures 17
and 38. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
1143 cm-1; H NMR (400 MHz, CDCl3) δ 0.88 (t, 3H, J ) 7.2
Hz), 1.74 (dt, 1H, J ) 14.8 and 7.2 Hz), 2.10-2.18 (m, 2H),
JO047834A
2218 J. Org. Chem., Vol. 70, No. 6, 2005