Rhodium carbenoid induced cycloadditions of diazo ketoimides across indolyl π-bonds

Article abstract of DOI:10.1055/s-2007-967982

A series of diazo ketoimides prepared from (1H-indol-3-yl)acetyl chloride and alkyl 2-diazo-3-(3-substituted-2-oxopiperidin-3-yl)-3-oxopropanoates were treated with rhodium(II) acetate. Attack of the imido carbonyl oxygen at the resultant rhodium carbenoi

Full text of DOI:10.1055/s-2007-967982

LETTER
775
Rhodium Carbenoid Induced Cycloadditions of Diazo Ketoimides Across
Indolyl p-Bonds
Rhodium
Carbeno
u
id Induced
C
e
ycloadditio
c
nsof
D
iazo
h
Ketoimidesuan Hong, José M. Mejía-Oneto, Stefan France, Albert Padwa*
Department of Chemistry, Emory University, Atlanta, GA 30322, USA
Fax +1(404)7276629; E-mail: chemap@emory.edu
Received 15 September 2006
O
Abstract: A series of diazo ketoimides prepared from (1H-indol-3-
yl)acetyl chloride and alkyl 2-diazo-3-(3-substituted-2-oxopiperi-
din-3-yl)-3-oxopropanoates were treated with rhodium(II) acetate.
Attack of the imido carbonyl oxygen at the resultant rhodium car-
benoid center produced a transient push–pull carbonyl ylide dipole
which underwent an intramolecular dipolar cycloaddition across the
indole p-bond. In most cases, the resulting cycloadduct is the con-
sequence of endo-cycloaddition with respect to the dipole and this
is fully in accord with the lowest energy transition state. Interesting-
ly, when a tert-butyl acetate substituent is located at the ring junc-
ture of the starting diazo ketoimide, the exo-cycloadduct was the
exclusive product obtained. In this case, the bulky tert-butyl ester
functionality blocks the endo-approach thereby resulting in the
cycloaddition taking place from the less congested exo-face.
O
(CH2)n
(CH2)n
Rh(II)
A=B
RCO(CH2)nCOCHN2
R
–
O
A
R
O
+
1
B
2
3
Scheme 1
carbonyl ylide dipoles with tethered alkenes represents an
effective method for the synthesis of a variety of natural
products.
As an extension of these earlier studies, we developed a
new approach to the construction of the pentacyclic
skeleton of the aspidosperma ring system which involves
the use of a related cyclization–cycloaddition cascade
sequence.21–25 This strategy was successfully applied to
the synthesis of desacetoxy-4-oxo-6,7-dihydrovindor-
osine (4).21 The approach used is outlined in Scheme 2
and is centered on the construction of the key oxabicyclic
intermediate 5. We found that 4 was accessible by reduc-
tion of the N-acyliminium ion derived from 5, which in
turn was available by a tandem rhodium(II)-catalyzed
cyclization cycloaddition of a-diazoimide 6. Cycloaddi-
tion of the initially formed dipole across the pendant
indole p-system22 results in the simultaneous generation
of the CD-rings of the aspidosperma skeleton.23 The
Key words: rhodium(II), diazo, catalyst, carbonyl ylide, dipolar
cycloaddition, indole, kopsifoline, alkaloid
Nitrogen-containing heterocycles are abundant in nature
and exhibit diverse and important biological properties.1,2
Accordingly, novel strategies for the stereoselective syn-
thesis of azapolycyclic ring systems continue to receive
considerable attention in the field of synthetic organic
chemistry.3–9 Tandem methodology for heterocyclic
synthesis represents a powerful approach for the rapid
build-up of molecular complexity from potentially simple
starting materials.10–12 In the ongoing search for new dom-
ino processes, emphasis has been laid on sequential reac-
tions which proceed cleanly and without forming by-
products.13–15 In 1986, we started work in our laboratory
to synthesize bridged heterosubstituted bicycloalkanes
from the Rh(II)-catalyzed cyclization cascade of diazo
carbonyl compounds.16 The domino reaction was shown
to proceed by the formation of a rhodium carbenoid inter-
mediate and a subsequent transannular cyclization of the
electrophilic carbon onto an adjacent carbonyl group to
generate a cyclic carbonyl ylide dipole. This was followed
by a 1,3-dipolar-cycloaddition reaction17 (Scheme 1). The
primary spatial requirement for carbonyl ylide formation
is that the distance between the two reacting centers be
sufficiently close so that effective overlap of the lone pair
O
N
N
D
E
H
C
O
A
B
N
Et
Et
O
R
R
N
O
Me
Me CO2Me
HO
CO2Me
4
5
Cl
Me
N
OMe
N2
O
R
O
O
R
N
O
O
of electrons of the carbonyl group with the metallocar-
benoid can occur.18 The resulting cyclic dipole (i.e., 2)
always contains a carbonyl group within the ring. We19
and others20 have found that intramolecular trapping of
Me
7
N
+
Et
O
CH2CO2Me
6
HN
O
Et
SYNLETT 2007, No. 5, pp 0775–0779
Advanced online publication: 08.03.2007
1
6.
0
3.
2
0
0
7
8
DOI: 10.1055/s-2007-967982; Art ID: S17206ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

776
X. Hong et al.
LETTER
O
stereospecific nature of the internal cycloaddition reaction
leads to the correct relative stereochemistry of the four
chiral centers about the C-ring.
O
N
Cl
HN
O
R2
n-BuLi
O
R2
O
+
45%
O
Prompted by our earlier studies dealing with the internal
dipolar-cycloaddition reaction of push–pull carbonyl
ylides for the synthesis of the aspidosperma skeleton, we
became interested in determining whether a related pro-
cess could be used to assemble the carbon framework of a
new group of hexacyclic monoterpenoid indoline alka-
loids known as the kopsifolines (i.e., 9).24 The key step in
our planned approach to this family of alkaloids involves
a 1,3-dipolar cycloaddition of a carbonyl ylide dipole de-
rived from diazo ketoimide 10 across the indole p-bond.25
Reductive ring opening of the resulting cycloadduct 11
followed by dehydration and N-deprotection would lead
to the key precursor 12 necessary for the final F-ring
closure (Scheme 3).26
EtO
N
R1
N
EtO
R1
13; R2 = H
14a; R1 = Me
15; R1 = Me; R2 = H
14b; R1 = SO2Ph
1. n BuMgCl
2. ethyl 2-diazo
malonyl chloride
O
N
59%
O
CO2Et
N2
O
N
CO2Et
16a; R1 = Me
R1
Scheme 4
N
N
H
H
appropriate indole acid chloride 14.28 By carrying out the
synthesis of the indolyl-substituted diazo imide in this
manner, the Regitz diazo-transfer reaction29 can be avoid-
ed in the final step thereby simplifying the synthesis.
Thus, piperidinones such as 17 and 18 were easily con-
verted to the corresponding diazo lactams 19 and 20 in ex-
cellent yield.29 These compounds, in turn, were treated
with an N-substituted indolyl acid chloride (i.e., 14)
which resulted in the formation of the desired diazo imi-
des 16a and 16b in 82% and 73% yield, respectively. A
related set of reactions was used to prepare the other
substituted diazo imides 16c–f outlined in Scheme 6.
R2
O
N
N
H
CO2Me
CO2Me
12; R2 = CH2CH2X
9; kopsifolines
O
O
N
N
R2
R2
O
O
N2
O
O
N
R1
N
H
CO2Me
10
CO2Me
R1
H
N
11
HN
MsN3
R2
Scheme 3
O
Et3N
R2
O
O
O
N2
We first carried out a model study using diazo ketoimide
16a in order to test the reliability of the key dipolar-cy-
cloaddition reaction. Several methods for preparing the
diazo imides necessary for dipole formation have been ex-
plored. One option that we have used involves treating the
commercially available 3-carboethoxy-2-piperidone (13)
with n-BuLi at –78 °C followed by the addition of an in-
dole acid chloride such as 14a. This results in the joining
of the two fragments to give imide 15 in 45% yield. A
subsequent reaction of 15 with n-butyl magnesium chlo-
ride in THF at 0 °C followed by the addition of ethyl 2-
diazomalonyl chloride27 afforded the indolyl-substituted
diazo imide 16a in 59% yield (Scheme 4).
CO2Et
CO2Et
17; R2 = CO2Et
18; R2 = CH2CH2OBn
19; R2 = CO2Et, 93%
20; R2 = CH2CH2OBn, 96%
14
O
N
R2
O
O
N2
N
CO2Et
R1
16a; R1 = Me, R2 = CO2Et, 82%
16b; R1 = SO2Ph, R2 = CH2CH2OBn, 73%
Since the overall yield of diazo imide 16a obtained by this
method was somewhat low, we opted to study an alternate
procedure to prepare several of the starting diazo sub-
strates of interest. With this in mind, diazo imide 16a
could also be synthesized in the manner outlined in
Scheme 5. This involved the initial preparation of a meth-
yl 2-diazo-3-(3-substituted 2-oxopiperidin-3-yl)-3-oxo-
propanoate (i.e., 19 or 20) and then coupling it with the
Scheme 5
Gratifyingly, heating a sample of 16a with Rh2(OAc)4 in
benzene at 80 °C afforded cycloadduct 21a in 90% yield
as a single diastereomer (Scheme 6). Bolstered by this
positive result, we next examined the Rh(II)-catalyzed be-
havior of several related indolyl-substituted diazo amides
Synlett 2007, No. 5, 775–779 © Thieme Stuttgart · New York

LETTER
Rhodium Carbenoid Induced Cycloadditions of Diazo Ketoimides
777
O
O
N
N
Rh2(OAc)4
R2
O
CO2R3
R2
O
O
endo
cycloaddition
N2
O
N
R1
N
R1
H
CO2R3
21a; R1 = Me, R2 = CO2Et , R3 = Et, 90%
21b; R1 = SO2Ph, R2 = CH2CH2OBn, R3 = Et, 90%
21c; R1 = Me, R2 = Et, R3 = Me, 95%
16a; R1 = Me, R2 = CO2Et , R3 = Et
16b; R1 = SO2Ph, R2 = CH2CH2OBn, R3 = Et
16c; R1 = Me, R2 = Et, R3 = Me
21d; R1 = Me, R2 = CH2CH2OBn, R3 = Me, 96%
21e; R1 = SO2p-tol, R2 = CH2CH2OBn, R3 = Me, 90%
21f; R1 = SO2p-tol, R2 = CH2CO2Me, R3 = Me, 98%
16d; R1 = Me, R2 = CH2CH2OBn, R3 = Me
16e; R1 = SO2p-tol, R2 = CH2CH2OBn, R3 = Me
16f; R1 = SO2p-tol, R2 = CH2CO2Me, R3 = Me
Scheme 6
(16b–f) and were pleased to find that the Rh(II)-catalyzed ketoimide 25 (Scheme 8). In marked contrast to the results
cycloadditions proceeded in excellent yield (i.e., 90– encountered with diazo ketoimides 16a–f, the exo-cy-
98%). All of the cycloadducts are formed with complete cloadduct 26 was the exclusive product isolated from this
diastereoselectivity and correspond to endo cycloaddition reaction. The relative stereochemistry of 26 was assigned
with respect to the dipole and anti with respect to the sub- on the basis of an X-ray crystal structure of the ring-
stituent group at the ring juncture. The endo diastereose- opened alcohol.30 In this case, the bulky tert-butyl ester
lection for the dipolar cycloaddition can be attributed to a functionality blocks the endo-approach thereby resulting
conformation (strain) preference dictated by the dipolaro- in the cycloaddition taking place from the less congested
phile tether since it mirrors the relative energy of the four exo-face. Interestingly, intermolecular cycloaddition of
possible products. The stereochemical assignment was five-membered cyclic carbonyl ylides with indole was
unambiguously established by an X-ray crystal structure30 also found to proceed by an exo-cycloaddition31 attesting
of the ring-opened alcohol 24 derived from cycloadduct to the sensitivity of the dipolar-cycloaddition reaction to
21c (Scheme 7). Thus, treatment of 21c with Lawesson’s steric factors in the transition state.
reagent furnished the expected thiolactam in 85% yield
which was cleanly reduced to pyrrolidine 22 on treatment
O
O
N
N
O
with Raney-Ni at 25 °C in THF. A subsequent hydrogena-
tion of 22 over PtO2 in acidic methanol gave 24 in 94%
yield as a single diastereomer. The overall reduction pro-
ceeds by an acid-catalyzed ring opening of the N,O-acetal
to generate a transient iminium ion 23 which is hydro-
genated from the least congested face. We have also in-
vestigated the Rh(II)-catalyzed cycloaddition of diazo
CH2CO2t-Bu
O
CH2CO2t-Bu
N2
O
O
N
N
Rh(II)
H
CO2Me
CO2Me
Me
Me
25
26 (exo cycloaddition)
Scheme 8
O
In conclusion, we have demonstrated that the Rh(II)-cata-
lyzed reaction of diazo ketoimides containing tethered
indolyl groups undergo successful 1,3-dipolar cycloaddi-
tions across the heteroaromatic p-bond to provide novel
oxa-bicyclic compounds. This tandem intramolecular cy-
clization–cycloaddition sequence is particularly attractive
for the synthesis of the kopsifoline class of alkaloids as
four stereocenters and two carbon–carbon bonds are
formed in a single step with a high degree of stereocontrol
under mild experimental conditions. Further studies on
transforming the cycloadducts to the kopsifoline family of
alkaloids are in progress and will be reported at a later
date.
1. Lawesson's
reagent
N
O
N
O
Et
Et
2. Ra-Ni
O
O
N
N
H
H
CO2Me
22
CO2Me
Me
Me
21c
H2, PtO2
MeOH–HCl
+
N
N
Et
Et
O
H
O
N
N
H
HO
H
HO
CO2Me
CO2Me
Me
Me
Acknowledgment
24
23
We appreciate financial support provided by the National Institutes
of Health (GM059284) and the National Science Foundation (CHE-
0450779).
Scheme 7
Synlett 2007, No. 5, 775–779 © Thieme Stuttgart · New York

778
X. Hong et al.
LETTER
1992, 114, 1874. (b) Padwa, A.; Austin, D. J.; Price, A. T.;
Semones, M. A.; Doyle, M. P.; Protopopova, M. N.;
Winchester, W. R. 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) Padwa, A. Acc. Chem.
Res. 1991, 24, 22. (e) Padwa, A.; Carter, S. P.; Nimmesgern,
H. J. Org. Chem. 1986, 51, 1157. (f) Padwa, A.; Carter, S.
P.; Nimmesgern, H.; Stull, P. D. J. Am. Chem. Soc. 1988,
110, 2894. (g) Padwa, A.; Stull, P. D. Tetrahedron Lett.
1987, 28, 5407. (h) Padwa, A.; Fryxell, G. E.; Zhi, L. J. Org.
Chem. 1988, 53, 2877. (i) Padwa, A.; Chinn, R. L.; Zhi, L.
Tetrahedron Lett. 1989, 30, 1491. (j) Padwa, A.;
Hornbuckle, S. F.; Fryxell, G. E.; Stull, P. D. J. Org. Chem.
1989, 54, 817. (k) Dean, D. C.; Krumpe, K. E.; Padwa, A. J.
Chem. Soc., Chem. Commun. 1989, 921. (l) Padwa, A.;
Chinn, R. L.; Hornbuckle, S. F.; Zhi, L. Tetrahedron Lett.
1989, 30, 301. (m) Padwa, A.; Sandanayaka, V. P.; Curtis,
E. A. J. Am. Chem. Soc. 1994, 116, 2667. (n) Curtis, E. A.;
Sandanayaka, V. P.; Padwa, A. Tetrahedron Lett. 1995, 36,
1989.
References and Notes
(1) Comprehensive Heterocyclic Chemistry; Katritzky, A.;
Rees, C. W.; Scriven, E. F., Eds.; Elsevier Science: Oxford,
UK, 1996.
(2) (a) Martin, S. F. In The Alkaloids, Vol. 30; Brossi, A., Ed.;
Academic Press: New York, 1987, 251–377. (b) Lewis, J.
R. Nat. Prod. Rep. 1994, 11, 329. (c) Jeffs, P. W. In The
Alkaloids, Vol. 19; Rodrigo, R. G. A., Ed.; Academic Press:
New York, 1981, 1–80.
(3) (a) Kuehne, M. E.; Matsko, T. H.; Bohnert, J. C.; Motyka,
L.; Oliver-Smith, D. J. Org. Chem. 1981, 46, 2002.
(b) Kuehne, M. E.; Earley, W. G. Tetrahedron 1983, 39,
3707. (c) Kuehne, M. E.; Brook, C. S.; Xu, F.; Parsons, R.
Pure Appl. Chem. 1994, 66, 2095. (d) Nkiliza, J.;
Vercauteren, J. Tetrahedron Lett. 1991, 32, 1787.
(e) Rawal, V. H.; Michoud, C.; Monestel, R. F. J. Am. Chem.
Soc. 1993, 115, 3030.
(4) (a) Overman, L. E.; Sworin, M.; Burk, R. M. J. Org. Chem.
1983, 48, 2685. (b) Overman, L. E.; Sugai, S. Helv. Chim.
Acta 1985, 68, 745. (c) Overman, L. E.; Robertson, G. M.;
Robichaud, A. J. J. Org. Chem. 1989, 54, 1236.
(5) (a) Gallagher, T.; Magnus, P.; Huffman, J. C. J. Am. Chem.
Soc. 1983, 105, 4750. (b) Magnus, P.; Gallagher, T.; Brown,
P.; Pappalardo, P. Acc. Chem. Res. 1984, 17, 35.
(6) (a) Rigby, J. H.; Qabar, M. N. J. Org. Chem. 1993, 58, 4473.
(b) Rigby, J. H.; Qabar, M.; Ahmed, G.; Hughes, R. C.
Tetrahedron 1993, 49, 10219. (c) Rigby, J. H.; Hughes, R.
C.; Heeg, M. J. J. Am. Chem. Soc. 1995, 117, 7834.
(d) Rigby, J. H.; Mateo, M. E. Tetrahedron 1996, 52, 10569.
(e) Rigby, J. H.; Laurent, S.; Cavezza, A.; Heeg, M. J. J. Org.
Chem. 1998, 63, 5587.
(7) (a) Kraus, G. A.; Thomas, P. J.; Bougie, D.; Chen, L. J. Org.
Chem. 1990, 55, 1624. (b) Sole, D.; Bonjoch, J.
Tetrahedron Lett. 1991, 32, 5183. (c) Bonjoch, J.; Sole, D.;
Bosch, J. J. Am. Chem. Soc. 1993, 115, 2064. (d) Schultz,
A. G.; Holoboski, M. A.; Smyth, M. S. J. Am. Chem. Soc.
1993, 115, 7904. (e) Schultz, A. G.; Guzzo, P. R.; Nowak,
D. M. J. Org. Chem. 1995, 60, 8044. (f) Schultz, A. G.;
Holoboski, M. A.; Smyth, M. S. J. Am. Chem. Soc. 1996,
118, 6210.
(8) (a) Pearson, W. H.; Postich, M. J. J. Org. Chem. 1994, 59,
5662. (b) Padwa, A.; Price, A. T. J. Org. Chem. 1995, 60,
6258.
(9) (a) Takano, S.; Inomata, K.; Ogasawara, K. Chem. Lett.
1992, 443. (b) Uesaka, N.; Saitoh, F.; Mori, M.; Shibasaki,
M.; Okamura, K.; Date, T. J. Org. Chem. 1994, 59, 5633.
(c) Mori, M.; Kuroda, S.; Zhang, C. S.; Sato, Y. J. Org.
Chem. 1997, 62, 3263.
(10) (a) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl.
1993, 32, 131. (b) Tietze, L. F. Chem. Rev. 1996, 96, 115.
(11) (a) Ho, T. L. Tandem Organic Reactions; Wiley: New York,
1992. (b) Bunce, R. A. Tetrahedron 1995, 51, 13103.
(c) Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. Rev.
1996, 96, 195.
(12) Ziegler, F. E. In Comprehensive Organic Synthesis,
Combining C–C p-Bonds, Vol. 5; Paquette, L. A., Ed.;
Pergamon Press: Oxford, 1991, Chap. 7.3.
(17) Padwa, A.; Hornbuckle, S. F. Chem. Rev. 1991, 91, 263.
(18) Padwa, A.; Weingarten, M. D. Chem. Rev. 1996, 96, 223.
(19) (a) Padwa, A.; Brodney, M. A.; Marino, J. P. Jr.; Sheehan, S.
M. J. Org. Chem. 1997, 62, 78. (b) Padwa, A.; Precedo, L.;
Semones, M. J. Org. Chem. 1999, 64, 4079. (c) Padwa, A.;
Curtis, E. A.; Sandanayaka, V. P. J. Org. Chem. 1997, 62,
1317.
(20) (a) Kinder, F. R. Jr.; Bair, K. W. J. Org. Chem. 1994, 59,
6965. (b) Chen, B.; Ko, R. Y. Y.; Yuen, M. S. M.; Cheng,
K.-F.; Chiu, P. J. Org. Chem. 2003, 68, 4195. (c) Hodgson,
D. M.; Avery, T. D.; Donohue, A. C. Org. Lett. 2002, 4,
1809. (d) Dauben, W. G.; Dinges, J.; Smith, T. C. J. Org.
Chem. 1993, 58, 7635.
(21) (a) Padwa, A.; Price, A. T. J. Org. Chem. 1995, 60, 6258.
(b) Padwa, A.; Price, A. T. J. Org. Chem. 1998, 63, 556.
(22) Padwa, A.; Hertzog, D. L.; Nadler, W. R. J. Org. Chem.
1994, 59, 7072.
(23) (a) Cordell, G. A. In The Alkaloids, Vol. 17; Manske, R. H.
F.; Rodrigo, R. G. A., Eds.; Academic Press: New York,
1979, 199–384. (b) Saxton, J. E. Nat. Prod. Rep. 1993, 10,
349.
(24) (a) Kam, T.-S.; Choo, Y.-M. Tetrahedron Lett. 2003, 44,
1317. (b) Kam, T.-S.; Choo, Y.-M. Phytochemistry 2004,
65, 2119. (c) Kam, T.-S.; Choo, Y.-M. Helv. Chim. Acta
2004, 87, 991.
(25) (a) Mejía-Oneto, J. M.; Padwa, A. Tetrahedron Lett. 2004,
45, 9115. (b) Mejia-Oneto, J. M.; Padwa, A. Org. Lett. 2004,
6, 3241. (c) Padwa, A.; Boonsombat, J.; Rashatasakhon, P.;
Willis, J. Org. Lett. 2005, 7, 3725. (d) Padwa, A.; Lynch, S.
M.; Mejia-Oneto, J. M.; Zhang, H. J. Org. Chem. 2005, 70,
2206.
(26) For an early approach toward the kopsifolines, see: Hong,
X.; France, S.; Mejia-Oneto, J. M.; Padwa, A. Org. Lett.
2006, 8, 5141.
(27) Marino, J. P. Jr.; Osterhout, M. H.; Price, A. T.; Sheehan, S.
M.; Padwa, A. Tetrahedron Lett. 1994, 35, 849.
(28) In a typical general procedure, 1.1 equiv of the appropriate
3-indoleacetic acid was dissolved in CH2Cl2 and 4.0 equiv of
oxalyl chloride was added dropwise. The solution was
stirred overnight and then concentrated under reduced
pressure. The resulting solid was taken up in THF, which
was immediately added to a vigorously stirred mixture
containing 1.0 equiv of the diazo lactam (i.e. 19 or 20) and
4 Å MS in THF. After stirring for 12 h, the mixture was
filtered through a pad of Celite® and concentrated under
reduced pressure. The crude material was purified by flash
silica gel column chromatography to give the desired
(13) Waldmann, H. Domino Reactions In Organic Synthesis
Highlights II; Waldmann, H., Ed.; VCH: Weinheim, 1995,
193–202.
(14) Curran, D. P. In Comprehensive Organic Synthesis, Vol. 4;
Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991,
779.
(15) Frontiers in Organic Synthesis; Wender, P. A., Ed.; Chem.
Rev. 1996, 96, 1–600.
(16) (a) Padwa, A.; Austin, D. J.; Hornbuckle, S. F.; Semones, M.
A.; Doyle, M. P.; Protopopova, M. N. J. Am. Chem. Soc.
Synlett 2007, No. 5, 775–779 © Thieme Stuttgart · New York

LETTER
coupled product. Using this procedure, 3-{3-(2-
Rhodium Carbenoid Induced Cycloadditions of Diazo Ketoimides
779
To a solution of 0.2 g of the diazoimide 16d in 10 mL of
benzene under N2 was added 2 mg rhodium(II) acetate, and
the mixture was heated at reflux for 1 h. The mixture was
allowed to cool to r.t. and was filtered through a pad of
Celite®. The solvent was removed under reduced pressure
and the residue was subjected to flash silica gel chromatog-
raphy to give 0.16 g (96%) of the dipolar-cycloaddition
product 21d.
benzyloxyethyl)-1-[2-(1-methyl-1H-indol-3-yl)acetyl]-2-
oxopiperidin-3-yl}-2-diazo-3-oxopropionic acid methyl
ester (16d) was obtained as a colorless oil in 82% yield. IR
(neat): 2143, 1718, 1685, 1332, 1146 cm–1. 1H NMR (400
MHz, CDCl3): d = 1.65–1.75 (m, 1 H), 1.85–2.02 (m, 2 H),
2.19–2.30 (m, 3 H), 3.46–3.53 (m, 1 H), 3.61–3.80 (m, 2 H),
3.70 (s, 3 H), 3.76 (s, 3 H), 4.15–4.21 (m, 1 H), 4.24 (s, 2 H),
4.37 (d, 1 H, J = 15.8 Hz), 4.41 (d, 1 H, J = 15.8 Hz), 6.88
(s, 1 H), 7.07–7.11 (m, 1 H), 7.17–7.32 (m, 7 H), 7.54 (d, 1
H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3): d = 19.5, 30.2,
32.7, 34.7, 35.5, 44.5, 52.5, 59.3, 67.2, 73.0, 107.9, 109.3,
119.1, 119.2, 121.6, 127.6, 127.7, 128.2, 128.3, 128.5,
136.9, 138.4, 161.6, 173.6, 176.4, 190.8.
(29) (a) Regitz, M. Chem. Ber. 1966, 99, 3128. (b) Regitz, M.;
Hocker, J.; Liedhegener, A. Org. Synth. 1973, 5, 179.
(30) The X-ray crystal structure analysis will be reported
elsewhere.
(31) Muthusamy, S.; Gunanatha, C.; Babu, S. A. Tetrahedron
Lett. 2001, 42, 523.
Synlett 2007, No. 5, 775–779 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.