Tandem dipolar cycloaddition - Mannich cyclization as an approach to tricyclic nitrogen heterocycles

Article abstract of DOI:10.1021/jo9607267

A series of 2-diazo-N-[2-(3,4-dimethoxyphenyl)ethyl]-N-hept-6-enoylmalonamides were prepared and treated with a catalytic amount of rhodium(II) perfluorobutyrate. The resultant carbenoids undergo facile cyclization onto the neighboring amide carbonyl oxyg

Full text of DOI:10.1021/jo9607267

J . Org. Chem. 1997, 62, 67-77
67
Ta n d em Dip ola r Cycloa d d ition -Ma n n ich Cycliza tion a s a n
Ap p r oa ch to Tr icyclic Nitr ogen Heter ocycles†
Albert Padwa,* Michael A. Brodney, J oseph P. Marino, J r., Martin H. Osterhout, and
Alan T. Price
Department of Chemistry, Emory University, Atlanta, Georgia 30322
Received April 19, 1996X
A series of 2-diazo-N-[2-(3,4-dimethoxyphenyl)ethyl]-N-hept-6-enoylmalonamides were prepared
and treated with a catalytic amount of rhodium(II) perfluorobutyrate. The resultant carbenoids
undergo facile cyclization onto the neighboring amide carbonyl oxygen atom to generate isomu¨nch-
none-type intermediates. Subsequent 1,3-dipolar cycloaddition across the pendant olefin affords
intramolecular cycloadducts in high yield. Exposure of these cycloadducts to boron trifluoride
etherate results in a Lewis acid-induced ring opening to generate N-acyliminium ions which then
undergo Mannich cyclization onto the neighboring π-framework attached to the amide nitrogen
atom. The cis stereochemistry of the resulting A/B ring fusion is analogous to similar erythrinane
products obtained via a Mondon-enamide-type cyclization. The stereochemical assignment of the
final cyclized products was determined by X-ray crystallography. Molecular mechanics calculations
show that the ground state energy of the cis-fused diastereomer is 4.6 kcal lower than that of the
trans diastereomer, and presumably some of this thermodynamic energy difference is reflected in
the transition state for cyclization. In certain cases, proton loss from the initially formed
N-acyliminium ion occurs prior to cyclization to give acyl enamides which subsequently cyclize
producing epimeric products.
In tr od u ction
tion has now emerged as a prominent synthetic
method.14-17 Carbon-carbon bond-forming reactions
involving N-acyliminium ions also play an extremely
Tandem or cascade processes belong to a growing
family of reactions which allow the regio- and stereocon-
trolled formation of several carbon-carbon bonds and/
or ring systems in a single operation.1-6 Important
contributions to this area have been realized utilizing a
combination of cationic,7 anionic,8 radical,9 carbenoid,10
and transition metal-catalyzed11 processes. In recent
years, consecutive pericyclic reactions12 involving at least
one cycloaddition have also been utilized for the synthesis
of complex polycyclic ring systems.13 In the realm of
synthesis, in which a premium is put on the rapid
construction of polyfunctional, highly bridged carbon and
heteroatom networks, the 1,3-dipolar cycloaddition reac-
(9) Motherwell, W. B.; Crich, D. Free Radical Reactions in Organic
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Fokas, D. J . Am. Chem. Soc. 1992, 114, 9688. Chen, Y.-J .; Chen, C.-
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58, 7228 and references therein. Iwasawa, N.; Funahashi, M.; Hay-
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D. C.; Pattenden, G. Tetrahedron Lett. 1992, 33, 2851. Grigg, R.;
Kennewell, P.; Teasdale, A. J . Tetrahedron Lett. 1992, 33, 7789 and
references therein. Batty, D.; Crich, D. J . Chem. Soc., Perkin Trans. 1
1992, 3205 and references therein. Trost, B. M.; Shi, Y. J . Am. Chem.
Soc. 1992, 114, 791 and references therein.
† This paper is dedicated to Rolf Huisgen on the occasion of his 75th
birthday.
X Abstract published in Advance ACS Abstracts, November 1, 1996.
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S0022-3263(96)00726-8 CCC: $14.00 © 1997 American Chemical Society

68 J . Org. Chem., Vol. 62, No. 1, 1997
Padwa et al.
Sch em e 1
Sch em e 2
4.24 This type of mesoionic oxazolium ylide corresponds
to the cyclic equivalent of a carbonyl ylide and readily
undergoes 1,3-dipolar cycloaddition with suitable
dipolarophiles.25-28 Construction of the prerequisite
diazo imides necessary for dipole generation was ac-
complished by the transformation of the corresponding
carboxylic acids to their respective amides. Conversion
to the diazo imides was straightforward using established
malonylacylation29 and diazotization procedures.30 For-
mation of the isomu¨nchnone ring proceeds by initial
generation of a rhodium carbenoid species, followed by
an intramolecular cyclization onto the neighboring car-
bonyl oxygen to form the dipole.31 The resultant iso-
mu¨nchnone may be trapped with electron rich or electron
deficient dipolarophiles to give the cycloadducts in high
yield.32
Several years ago our laboratory became interested in
using the intramolecular cycloaddition of isomu¨nchnones
for the construction of a variety of alkaloid systems.22
Intramolecular dipolar cycloadditions have been particu-
larly useful in natural product synthesis, as this reaction
results in the formation of an additional ring and exhibits
increased reactivity due to entropic factors.33-35 The
regiochemistry of the process is complicated by a complex
interplay of factors such as the nature of the 1,3-dipole,
alkene polarity, ring strain, and other nonbonded inter-
actions. In general, the intramolecular situation can be
assessed as a competition between bridged and fused
modes of cycloaddition.
We began our investigations of the sequential cycload-
dition-Mannich cyclization protocol by first examining
the Rh(II)-catalyzed reaction of diazo imide 6. Treatment
of 6 with a catalytic quantity of rhodium(II) perfluorobu-
tyrate (Rh2pfb4) in CH2Cl2 at 25 °C provided cycloadduct
7 in 98% isolated yield. The assignment of the stereo-
chemistry of 7 was based on the comparison of NMR
signals of related substrates.22 The formation of the
endo-cycloadduct with respect to the carbonyl ylide dipole
is in full accord with molecular mechanics calculations
which show a large ground state energy difference
between the two diastereomers. Exposure of 7 to BF3‚OEt2
important role in the synthesis of nitrogen hetero-
cycles.18-20 The elaboration of ring-fused polyhetero-
cycles, based on a sequential dipolar cycloaddition-N-
acyliminium ion cyclization process,21 would seem to offer
a unique opportunity for a rapid stereocontrolled syn-
thesis of a wide range of highly functionalized azapoly-
cyclic natural products. With this aim in mind, we have
investigated some of the general principles underlying
the synthetic design presented in Scheme 1.
Our earlier studies of the 1,3-dipolar cycloaddition
reactions of isomu¨nchnones22 derived from R-diazo imides
1 provided us with a uniquely functionalized cycloadduct
2 containing a “masked” N-acyliminium ion. By incor-
porating an internal nucleophile on the tether, annula-
tion of the original dipolar cycloadduct 2 would allow for
the construction of more complex nitrogen heterocyclic
systems, particularly B-ring homologues of the erythri-
nane family of alkaloids.23 By starting from simple
acyclic diazo imides 1, we have established a tandem
carbenoid cyclization-dipolar cycloaddition-cationic π-cy-
clization protocol as a method for the construction of
complex nitrogen polyheterocycles of type 3. We are
unaware of any previous examples in which the 1,3-
dipolar cycloaddition and N-acyliminium ion cyclization
are coupled in a one-pot sequence. The novelty of the
process lies in the method of N-acyliminium ion genera-
tion, which, to our knowledge, is unprecedented. Herein
the synthetic and mechanistic work are presented in full.
Resu lts a n d Discu ssion
The synthesis of 1,3-oxazolium-4-oxides (isomu¨nch-
nones) 5 (Scheme 2) is easily accomplished by the
rhodium(II)-catalyzed cyclization of a suitable diazo imide
(16) Padwa, A. In Comprehensive Organic Synthesis; Trost, B. M.,
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(18) Hiemstra, H.; Speckamp, W. N. In Comprehensive Organic
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1985, 41, 4367. Hiemstra, H.; Speckamp, W. N. In The Alkaloids;
Brossi, A., Ed.; Academic Press: New York, 1988; Vol. 32, p 271. Hart,
D. J . In Alkaloids: Chemical and Biological Perspectives; Pelletier, S.
W., Ed.; Wiley: New York, 1988; Vol. 6, p 227.
(24) Osterhout, M. H.; Nadler, W. R.; Padwa, A. Synthesis 1994,
123.
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J pn. 1969, 42, 2310.
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Veenstra, S. J .; Speckamp, W. N. J . Am. Chem. Soc. 1981, 103, 4645.
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Chem. 1981, 46, 3576. Hart, D. J .; Kanai, K. J . Org. Chem. 1982, 47,
1555. Hart, D. J .; Yang, T. K. Tetrahedron Lett. 1982, 23, 2671. Hart,
D. J .; Kanai, K. J . Am. Chem. Soc. 1983, 105, 1255.
(21) Padwa, A.; Weingarten, M. D. Chem. Rev. 1996, 96, 223.
(22) Padwa, A.; Marino, J . P., J r.; Osterhout, M. H. J . Org. Chem.
1995, 60, 2704. Padwa, A.; Hertzog, D. L; Nadler, W. R. J . Org. Chem.
1994, 59, 7072. Marino, J . P., J r.; Osterhout, M. H.; Price, A. T.;
Semones, M. A.; Padwa, A. J . Org. Chem. 1994, 59, 5518. Padwa, A.;
Hertzog, D. L.; Nadler, W. R.; Osterhout, M. H.; Price, A. T. J . Org.
Chem. 1994, 59, 1418. Hertzog, D. L.; Austin, D. J .; Nadler, W. R.;
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1972, 1000. Potts, K. T.; Marshall, J . L. J . Org. Chem. 1979, 44, 626.
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chi, M.; Ibata, T. Chem. Lett. 1975, 499.
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1315.
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J ohn Wiley: New York, 1973; Collect. Vol. 5, p 179.
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A.; Schoffstall, A. Advances in Cycloaddition; Curran, D. P., Ed.; J AI
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Press: Oxford, U.K., 1991; Chapter 4.10, p 111.

Tandem Dipolar Cycloaddition-Mannich Cyclization
J . Org. Chem., Vol. 62, No. 1, 1997 69
cloadducts 11 and 12 in 95% and 90% yield, respectively.
As in the case of cycloadduct 7, the BF3‚OEt2 induced
cyclization afforded products 13 (95%) and 14 (85%) as
(2 equiv in CH2Cl2 at 0 °C) gave the cyclized product 8
(91%), isolated as a single diastereomer. The structural
assignment was, in part, based, on the appearance of two
aromatic CH protons observed as two individual singlets,
each integrating for one proton. The proposed cis ster-
eochemistry of the A/B ring junction for 8 was assigned
by analogy to similar erythrinane products obtained via
a Mondon-enamide-type cyclization.36-38 The structure
of 8 was unequivocally established by a single-crystal
X-ray analysis.39
The formation of 8 is perfectly consistent with the
sequence of events proposed in Scheme 1. The critical
step in this transformation involves the Lewis acid-
assisted generation of an N-acyliminium ion. In the
initial studies, p-TsOH was utilized as the Lewis acid
promoter for the unmasking of the N-acyliminium ion.
Subsequent studies demonstrated that the cyclization
reactions were capricious with variable yields of product
being obtained. In order to overcome these difficulties,
a survey of diverse Lewis acids was carried out. Among
the many Lewis acids employed, BF3‚OEt2 routinely gave
the highest yield of the cyclized product 8.
single diastereomers whose structures were unequivo-
cally established by a single-crystal X-ray analysis.39 It
is noteworthy that in all three examples (i.e., 8, 13, and
14), the anti stereochemical relationship is still main-
tained between the hydroxyl stereocenter (from the
oxygen bridge) and the bridgehead proton (R2 ) H) or
methyl (R2 ) CH3) group.
Interestingly, when the dipolar cycloadduct 16 derived
from the unsubstituted alkenyl diazo imide 15 was
exposed to BF3‚OEt2, the cyclized product 17 (90%) was
identified as the all syn-tetracyclic lactam by a single-
crystal X-ray analysis.39 Thus, in contrast to the other
three systems, the ring junction proton of 17 is syn to
the newly formed hydroxyl group. We assume that the
The versatility of N-acyliminium ions for the synthesis
of a wide variety of nitrogenous materials underscores
the need to find new methods for their preparation.18-20
N-Acyliminium ions are traditionally generated from the
N-acylation of imines,40 N-protonation41 and oxidation42
of amides, electrophilic additions to enamides,43 and the
heterolysis of amides bearing a leaving group adjacent
to nitrogen.18 These reactive intermediates readily react
with a wide assortment of nucleophiles to effect an overall
R-amido alkylation. To further illustrate the scope and
utility of N-acyliminium ion formation from the ring
opening of an isomu¨nchnone cycloadduct, we examined
the tandem cycloaddition-cyclization reaction of R-diazo
imides 9 and 10. The Rh(II)-catalyzed reaction proceeded
uneventfully to provide the expected isomu¨nchnone cy-
intermediate N-acyliminium ions formed from the Lewis
acid-assisted ring opening of the isomu¨nchnone cycload-
ducts undergo rapid proton loss to produce tetrasubsti-
tuted enamides. Indeed, upon treatment of the isomu¨nch-
none cycloadduct 18 (containing one less methylene group
on the nitrogen tether) with BF3‚OEt2, a 4:1 mixture of
enamides 19 and 20 was formed in essentially quantita-
tive yield. In this case, proton loss from the initially
formed N-acyliminium ion occurs in preference to cy-
clization. We attribute this difference to the high strain
associated with cyclization of 18 leading to a five mem-
bered ring.
In the case of 16, this process is not operative as
witnessed by the formation of compound 17. Loss of the
bridgehead proton HA in 21 (dihedral angle 90° with
respect to the N-acyliminium ion π-bond) is fast relative
to π-cyclization. Intramolecular axial reprotonation of
enamide 23 from the â-face generates the diastereomeric
iminium ion 24 which then undergoes intramolecular
cationic π-cyclization from the least sterically congested
face to give the observed all-syn isomer 17. Molecular
mechanics calculations show that the ground state energy
(36) Mondon, A.; Hansen, K. F.; Boehme, K.; Faro, H. P.; Nestler,
H. J .; Vilhuber, H. G.; Bo¨ttcher, K. Chem. Ber. 1970, 103, 615. Mondon,
A.; Seidel, P. R. Chem. Ber. 1971, 104, 2937. Mondon, A.; Nestler, H.
J . Chem. Ber. 1979, 112, 1329.
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(38) Ishibashi, H.; Sato, K.; Ikeda, M.; Maeda, H.; Akai, S.; Tamura,
Y. J . Chem. Soc., Perkin Trans. 1 1985, 605.
(39) The authors have deposited coordinates for structures 8, 13,
14, and 17 with the Cambridge Crystallographic Data Centre. The
coordinates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
U.K.
(40) Bo¨hme, H.; Hartke, K. Chem. Ber. 1963, 96, 600. Hiemstra,
H.; Fortgens, H. P.; Stegenga, S.; Speckamp, W. N. Tetrahedron Lett.
1985, 26, 3151.
(41) Weinreb, S. M.; Levin, J . I. Heterocycles 1979, 12, 949. J en-
drzejewski, S.; Steglich, W. Chem. Ber. 1981, 114, 1337.
(42) Shono, T.; Hamaguchi, H.; Matsumura, Y. J . Am. Chem. Soc.
1975, 97, 4264.
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A.; Nowlan, V. J .; Tidwell, T. T. J . Am. Chem. Soc. 1979, 101, 974.
Brossi, A.; Dolan, L. A.; Teital, S. Org. Synth. 1977, 56, 3.

70 J . Org. Chem., Vol. 62, No. 1, 1997
Padwa et al.
systems were considered. Ultimately, substrates 26, 29,
33, and 36 were studied as they contain a range of
synthetically interesting and easily attainable functional-
ity. The synthesis of indoles bearing substituents at the
2- and 3-positions has been of interest for many years
due to the large number of biologically active natural
products having this substitution pattern.45 Conse-
quently, we decided to investigate the Rh(II)-catalyzed
behavior of R-diazo imide 26 where an indolyl tether has
been placed on the amide nitrogen as a method for
generating highly functionalized indoles. Treatment of
diazo imide 26 with Rh2(pfb)4 gave cycloadduct 27 (98%)
which was readily converted into 28 in 60% isolated yield
as a single diastereomer. The stereochemical assignment
was based on analogy to the tetracyclic system 17.
This sequential process provides a unique entry into
2,3-substituted indolo ring systems that would be ex-
tremely difficult to prepare by other methods. Two
of the cis-fused diastereomer is 4.6 kcal lower than that
of the trans diastereomer, and presumably some of this
thermodynamic energy difference is reflected in the
transition state for cyclization. The additional methyl
group present in the related 6,5-fused cycloadduct 22
promotes loss of the proton adjacent to it, and this results
in the formation of enamide 25. Stereoselective repro-
tonation from the least congested R-face regenerates 22,
which is then trapped intramolecularly by the aromatic
nucleus. Cyclization always occurs from the least hin-
dered side of the molecule, as has already been estab-
lished by Mondon and co-workers.36 Cationic cyclizations
additional systems involving o-allyl-substituted benza-
mides further illustrate the scope and variety of the
π-systems that may be employed in this tandem process
are outlined below. The Rh(II)-catalyzed reaction of diazo
imide 29 gave rise to a 4:1 mixture of cycloadduct 30 and
the conjugated indenyl enamide 31 in a combined yield
of 75%. Treatment of either 30 or 31 with BF3‚OEt2 in
CH2Cl2 at 0 °C afforded a 1:1 diastereomeric mixture of
tetracyclic lactams 32 in 84% yield. The formation of a
mixture of diastereomers is best understood in terms of
the initial conversion of 30 to 31. Nonstereoselective
protonation of the enamide π-bond followed by a Pictet-
Spengler cyclization then affords 32 as a mixture of
diastereomers.
The reactions of iminium ions with tethered alkenes
are among the most important methods for preparing
N-heterocyclic compounds.46 An antiperiplanar orienta-
tion of the developing nonbonded electron pair on nitro-
gen and the entering nucleophile is preferred, as are chair
topologies in cyclizations that form piperidine rings.46
Recent studies of this process have focused on the
development of new procedures for initiating these cy-
clizations and for controlling the regiochemistry and
product functionality of the cationic cyclization step.47-49
of this type are known to be governed by steric control.44
Cycloadduct 11 does not possess a bridgehead proton, and
therefore deprotonation can only occur from one direction.
We believe that the initially formed iminium ion derived
from 7 (i.e., 21b, n ) 2) undergoes fast π-cyclization prior
to proton loss. In this case, the deprotonation step is
significantly slower than in the 6,5-system due to the
larger dihedral angle (113°) between proton HA and the
π-system of the N-acyliminium ion. As before, the
stereochemical outcome in 8 is the result of a stereoelec-
tronic preference for axial attack by the aromatic ring of
the N-acyliminium ion from the least hindered side.
So that a cross section of additional information could
be obtained in regard to the tandem carbenoid cycliza-
tion-cycloaddition-cationic π-cyclization protocol, a se-
ries of R-diazo imides was needed representing a variety
of different π-bonds. Compounds ranging from substi-
tuted aromatics to indoles to simple alkenyl tethered
Owing principally to efforts by the Overman group,47
a
variety of useful procedures have evolved for hydropyri-
dine synthesis based on Mannich cyclization of iminium
ions that contain tethered olefinic π-bonds. Since the
earlier examples of our diazo imide cycloaddition reaction
(45) Gilchrist, T. L. Heterocyclic Chemistry; Pitman: London, 1981.
(46) Overman, L. E.; Ricca, D. J . In Comprehensive Organic Syn-
thesis; Trost, B. M.; Fleming. I., Eds.; Pergamon: Oxford, 1991; Vol.
2, Chapter 4.4.
(47) Overman, L. E. Lect. Heterocycl. Chem. 1985, 8, 59. Blumen-
kopf, T. A.; Overman, L. E. Chem. Rev. 1986, 86, 857. Overman, L. E.;
Ricca, D. J . Compr. Org. Syn. 1991, 2, 1007.
(48) Grieco, P. A.; Fobare, W. F. Tetrahedron Lett. 1986, 27, 5067;
J . Chem. Soc., Chem. Commun. 1987, 185.
(49) Zhang, X.; J ung, Y. S.; Mariano, P. S.; Fox, M. A.; Martin, P.
S.; Merkert, J . Tetrahedron Lett. 1993, 34, 5239.
(44) Dean, R. T.; Rapoport, H. A. J . Org. Chem. 1978, 43, 4183.

Tandem Dipolar Cycloaddition-Mannich Cyclization
J . Org. Chem., Vol. 62, No. 1, 1997 71
most effective Lewis acid to carry out this transformation.
With diazo imide 36, however, we found that BF3‚2AcOH
was a particularly effective Lewis acid, probably as a
consequence of its ability to serve in a dual capacity in
this reaction. First, it acts as a typical Lewis acid,
triggering the ring opening of the oxygen bridge of the
isomu¨nchnone cycloadduct. Second, once the Mannich
cyclization has occurred, BF3‚2AcOH functions as a protic
acid allowing for the thermodynamic equilibration of the
two regioisomers. Indeed, the same ratio of isomers (i.e.,
38/39 ) 4:1) was obtained upon subjecting either product
to the reaction conditions used to promote the cyclization.
Interestingly, when the cyclization reaction was carried
out using TMSOTf as the Lewis acid, the major regioi-
somer (80%) that formed corresponded to compound 39.
Under these conditions there was no interconversion of
the two isomeric products, thereby suggesting kinetic
control of the Mannich cyclization.
In conclusion, the results presented herein demon-
strate the potential of the tandem carbenoid cyclization-
dipolar cycloaddition-Mannich cyclization reaction of
diazo imides for the construction of polyheterocyclic ring
systems. This three-step protocol begins with the Rh-
(II)-catalyzed cyclization of an R-diazo imide to give rise
to an isomu¨nchnone 1,3-dipole. This is followed by an
intramolecular 1,3-dipolar cycloaddition. N-Acyliminium
ion formation is triggered by exposure of the cycloadduct
to a Lewis acid. The annulation is completed by Mannich
cyclization of a tethered π-bond onto the cationic inter-
mediate. The overall transformation represents a highly
effective means by which simple starting materials can
be converted to relatively complex products by using the
tandem chemistry of rhodium carbenoids. We have used
this strategy to carry out a formal synthesis of (()-
lycopodine which is described in the following article.
for promoting Mannich cyclization involve aromatic
π-bonds, we decided to study several systems which
possess a simple olefinic tether. Treatment of the acyclic
substrate 33 with rhodium(II) perfluorobutyrate in CH2-
Cl2 at 25 °C gave a single product that corresponded to
the indenyl enamide 34 in 85% yield. The anticipated
product of 1,3-dipolar cycloaddition of the intermediate
isomu¨nchnone dipole was not observed. Exposure of 34
to BF3‚OEt2 in CH2Cl2 at 40 °C resulted in a 3:2 mixture
of diastereomeric tetracyclic lactams 35 in 88% yield,
thereby demonstrating that tethered alkenes can also be
utilized in the third step of these cascade reactions.
Exp er im en ta l Section
In a further investigation of the sequential cycloaddi-
tion-π-cyclization process for the construction of nitrogen
heterocycles, we examined the Rh(II)-catalyzed reaction
of diazo imide 36. The reaction afforded cycloadduct 37
as a single diastereomer in 94% yield. Formation of 37
is again the consequence of endo-cycloaddition with
respect to the dipole. The resulting stereochemistry
features the methyl substituent in a syn relationship to
the angular hydrogen, in agreement with the previously
studied systems.22 Further exposure of cycloadduct 37
to a Lewis acid provided a mixture of the tetracyclic
lactams 38 and 39 in good yield. In our earlier cationic
cyclization studies, we determined that BF3‚OEt2 was the
Melting points are uncorrected. Mass spectra were deter-
mined at an ionizing voltage of 70 eV. Unless otherwise noted,
all reactions were performed in flame-dried glassware under
an atmosphere of dry nitrogen. Solutions were evaporated
under reduced pressure with a rotary evaporator, and the
residue was chromatographed on a silica gel column using an
ethyl acetate-hexane mixture as the eluent unless specified
otherwise.
Gen er a l P r oced u r e for th e Syn th esis of Dia zo Im id es.
A solution containing 5.0 mmol of the appropriate amide and
10.0 mmol of ethyl malonyl chloride in 15 mL of anhydrous
benzene was heated at reflux for 1 h. After being cooled to rt,
the reaction mixture was diluted with ether and washed with
10% aqueous NaOH and brine. The organic layer was dried

72 J . Org. Chem., Vol. 62, No. 1, 1997
Padwa et al.
over MgSO4 and concentrated under reduced pressure. The
residue was purified by flash chromatography on a silica gel
column. A variation of the procedure described by Taber and
co-workers50 was used to prepare the diazo imide system. To
a solution containing 2 mmol of the appropriate imide and 2.2
mmol of mesyl azide in 5 mL of acetonitrile or CH2Cl2 was
added 4.0 mmol of NEt3 under N2 at rt. After the solution
was stirred for 3 h, the solvent was removed under reduced
pressure and the residue was subjected to flash chromatog-
raphy on a silica gel column.
120.6, 130.7, 147.7, 148.9, 166.0, and 171.1; HRMS calcd for
C22H29NO6 403.1994, found 403.1981.
2-H yd r oxy-6,7-d im et h oxy-3-oxo-1,2,3,4,5,10,11,12,13,-
13a -d eca h yd r o-3a -a za ben zo[d ]p h en a n th r en e-2-ca r boxy-
lic Acid Eth yl Ester (8). To a solution containing 0.20 g (0.47
mmol) of cycloadduct 7 in 2 mL of CH2Cl2 at 0 °C was added
0.11 g (0.95 mmol) of BF3‚Et2O. After the reaction mixture
was stirredat rt for 3 h, the reaction was quenched with 2 mL
of MeOH and the reaction mixture was diluted with CH2Cl2.
The organic layer was washed with brine and dried over Na2-
SO4. The organic extracts were filtered and concentrated
under reduced pressure. The crude residue was subjected to
flash silica gel chromatography to give 183 mg (91%) of benzo-
[d]phenanthrene 8 as a white solid: mp 159-160 °C; IR (neat)
3420, 2935, 1750, 1643, and 1228 cm-1; 1H NMR (CDCl3, 300
MHz) δ 0.79 (t, 3H, J ) 7.2 Hz), 1.28-1.47 (m, 4H), 1.61-
1.76 (m, 3H), 1.97 (m, 1H), 2.27 (m, 2H), 2.52 (m, 2H), 3.02
(ddd, 1H, J ) 16.5, 12.0, and 7.8 Hz), 3.30 (ddd, 1H, J ) 19.5,
12.0, and 5.4 Hz), 3.74 (s, 3H), 3.78 (s, 3H), 3.85 (m, 2H), 3.94
(s, 1H), 4.64 (dd, 1H, J ) 13.5 and 7.8 Hz), 6.49 (s, 1H), and
6.61 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 13.3, 21.4, 25.9, 27.1,
27.3, 33.9, 35.4, 36.4, 41.0, 55.8, 56.2, 61.7, 61.8, 74.1, 106.3,
112.5, 127.0, 134.5, 147.2, 147.8, 170.9, and 172.9. Anal.
Calcd for C22H29NO6: C, 65.49; H, 7.26; N, 3.47. Found: C,
65.38; H, 7.29; N, 3.42.
P r ep a r a tion a n d Rh od iu m (II)-Ca ta lyzed Cycloa d d i-
tion of 2-Dia zo-N-[2-(3,4-d im eth oxyph en yl)eth yl]-N-h ep t-
6-en oylm a lon a m ic Acid Eth yl Ester (6). To a solution
containing 1.09 g (7.80 mmol) of 6-heptenoic acid51 in 50 mL
of CH2Cl2 was added 1.73 g (9.36 mmol) of 1,1′-carbonyldiimi-
dazole and the solution was stirred at rt for 2 h. The reaction
mixture was added to a solution of 2.02 g (8.97 mmol) of 3,4-
dimethoxyphenethylamine in 100 mL of CH2Cl2 at 0 °C. The
resulting solution was stirred at 25 °C for 10 h and concen-
trated under reduced pressure. The residue was subjected to
flash silica gel chromatography to give 2.01 g (89%) of hept-
6-enoic acid [2-(3,4-dimethoxyphenyl)ethyl]amide as a white
solid: mp 59-60 °C; IR (neat) 3302, 1639, 1514, 1233, and
1
1026 cm-1; H NMR (CDCl3, 300 MHz) δ 1.35 (quin, 2H, J )
7.2 Hz), 1.58 (quin, 2H, J ) 7.2 Hz), 2.01 (q, 2H, J ) 7.2 Hz),
2.09 (t, 2H, J ) 7.5 Hz), 2.72 (t, 2H, J ) 6.9 Hz), 3.46 (q, 2H,
J ) 6.9 Hz), 3.83 (s, 6H), 4.89-4.98 (m, 2H), 5.46 (brs, 1H),
5.74 (ddt, 1H, J ) 16.8, 10.2, and 6.6 Hz), 6.68 (m, 2H), and
6.77 (d, 1H, J ) 8.4 Hz); 13C NMR (CDCl3, 75 MHz) δ 25.2,
28.4, 33.4, 35.3, 36.6, 40.6, 55.9, 111.3, 111.9, 114.6, 120.6,
131.4, 138.3, 147.6, 149.0, and 172.9.
P r ep a r a tion a n d Rh od iu m (II)-Ca ta lyzed Cycloa d d i-
t ion of 2-Dia zo-N-[2-(3,4-d im et h oxyp h en yl)et h yl]-N-(5-
m eth ylh exen oyl)m a lon a m ic Acid Eth yl Ester (9). To a
solution containing 1.09 g (8.50 mmol) of 5-methyl-5-hexenoic
acid52 in 50 mL of CH2Cl2 was added 1.65 mg (10.02 mmol) of
1,1′-carbonyldiimidazole, and the solution was stirred at rt for
2 h. The reaction mixture was added to a solution of 1.69 g
(9.35 mmol) of 3,4-dimethoxyphenethylamine in 100 mL of
CH2Cl2 at 0 °C. This mixture was stirred at 25 °C for 10 h
and then concentrated under reduced pressure. The resulting
residue was subjected to flash silica gel chromatography to
give 2.05 g (85%) of 5-methylhex-5-enoic acid [2-(3,4-dimethox-
yphenyl)ethyl]amide as a white solid: mp 62-63 °C; IR (neat)
3305, 1641, 1515, and 1027 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 1.66 (s, 3H), 1.72 (quin, 2H, J ) 7.5 Hz), 1.98 (t, 2H, J ) 7.5
Hz), 2.08 (t, 2H, J ) 7.5 Hz), 2.73 (t, 2H, J ) 6.9 Hz), 3.47 (q,
2H, J ) 6.9 Hz), 3.83 (s, 6H), 4.61 (s, 1H), 4.67 (s, 1H), 5.44
(brs, 1H), 6.69 (m, 2H), and 6.77 (d, 1H, J ) 8.7 Hz); 13C NMR
(CDCl3, 75 MHz) δ 22.1, 23.4, 35.2, 35.9, 37.0, 40.6, 55.8, 110.5,
111.3, 111.8, 120.5, 131.3, 144.8, 147.6, 148.9, and 172.8.
N-Malonylacylation was carried out on the above amide in
the normal manner to give N-[2-(3,4-dimethoxyphenyl)ethyl]-
N-(5-methylhex-5-enoyl)malonamic acid ethyl ester as a clear
N-Malonylacylation was carried out on the above amide in
the normal manner to give N-[2-(3,4-dimethoxyphenyl)ethyl]-
N-hept-6-enoylmalonamic acid ethyl ester as
a clear oil
1
(85%): IR (neat) 2936, 1738, 1696, 1515, and 1028 cm-1; H
NMR (CDCl3, 300 MHz) δ 1.25 (t, 3H, J ) 7.2 Hz), 1.27 (m,
2H), 1.51 (quin, 2H, J ) 7.5 Hz), 1.98 (m, 2H), 2.28 (t, 2H, J
) 7.5 Hz), 2.81 (t, 2H, J ) 7.5 Hz), 3.77 (s, 2H), 3.84 (m, 8H),
4.16 (q, 2H, J ) 7.2 Hz), 4.93 (m, 2H), 5.73 (ddt, 1H, J ) 17.1,
10.2, and 6.9 Hz), 6.71 (d, 1H, J ) 8.7 Hz), 6.72 (s, 1H), and
6.77 (d, 1H, J ) 8.7 Hz); 13C NMR (CDCl3, 75 MHz) δ 14.0,
23.8, 28.1, 33.3, 34.6, 36.2, 46.3, 46.4, 55.9, 61.1, 111.4, 112.3,
114.7, 120.7, 130.8, 138.2, 147.9, 149.1, 167.4, 168.7, and 175.8.
The above compound was subjected to the standard diazo
transfer conditions to give 2-diazo-N-[2-(3,4-dimethoxyphenyl)-
ethyl]-N-hept-6-enoylmalonamic acid ethyl ester (6) as a yellow
oil (100%): IR (neat) 2938, 2136, 1718, 1647, 1512, and 1024
1
cm-1; H NMR (CDCl3, 300 MHz) δ 1.22 (t, 3H, J ) 7.2 Hz),
oil (86%): IR (neat) 2932, 1737, 1695, 1515, and 1029 cm-1
;
1.32 (quin, 2H, J ) 7.2 Hz), 1.56 (quin, 2H, J ) 7.2 Hz), 1.98
(q, 2H, J ) 7.2 Hz), 2.38 (t, 2H, J ) 7.2 Hz), 2.80 (t, 2H, J )
7.2), 3.78 (m, 8H), 4.17 (q, 2H, J ) 7.2 Hz), 4.89 (m, 2H), 5.72
(ddt, 1H, J ) 16.8, 10.2, and 6.6 Hz), 6.65 (s, 1H), 6.67 (d, 1H,
J ) 8.7 Hz), and 6.73 (d, 1H, J ) 8.7 Hz); 13C NMR (CDCl3, 75
MHz) δ 14.2, 24.4, 28.2, 33.3, 35.3, 35.8, 48.2, 55.8, 61.7, 72.4,
111.3, 112.3, 114.5, 120.9, 130.8, 138.3, 147.7, 148.9, 160.3,
166.3, and 175.2.
1H NMR (CDCl3, 300 MHz) δ 1.25 (t, 3H, J ) 6.9 Hz), 1.65
(m, 5H), 1.93 (t, 2H, J ) 7.5 Hz), 2.29 (t, 2H, J ) 7.5 Hz), 2.80
(t, 2H, J ) 7.5 Hz), 3.78 (s, 2H), 3.83 (m, 8H), 4.17 (q, 2H, J )
6.9 Hz), 4.62 (s, 1H), 4.70 (s, 1H), 6.70 (d, 1H, J ) 8.4 Hz),
6.71 (s, 1H), and 6.74 (d, 1H, J ) 8.4 Hz); 13C NMR (CDCl3,
75 MHz) δ 14.0, 21.9, 22.0, 34.6, 35.6, 36.7, 46.3, 46.5, 55.8,
61.1, 110.7, 111.4, 112.2, 120.7, 130.7, 144.6, 147.9, 149.1,
167.4, 168.6, and 175.7.
A solution of 0.99 g (2.23 mmol) of diazo imide 6 in 15 mL
of CH2Cl2 at rt was treated with 5 mg of rhodium(II) perfluo-
robutyrate. The reaction mixture was stirred for 24 h at rt
and was then concentrated under reduced pressure. The
resulting residue was purified by flash silica gel chromatog-
raphy to give 0.92 g (98%) of 10-[2-(2,3-dimethoxyphenyl)-
ethyl]-9-oxo-11-oxa-10-azatricyclo[6.2.1.01,6]undecane-8-car-
boxylic acid ethyl ester (7) as a clear oil: IR (neat) 2937, 1749,
1720, 1516, and 1263 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.15
(m, 2H), 1.33 (t, 3H, J ) 7.2 Hz), 1.57-1.84 (m, 7H), 2.15 (m,
2H), 2.75 (m, 2H), 3.25 (m, 1H), 3.42 (m, 1H), 3.83 (s, 6H),
4.34 (q, 2H, J ) 7.2 Hz), 6.71 (m, 2H), and 6.77 (d, 1H, J )
8.7 Hz); 13C NMR (CDCl3, 75 MHz) δ 14.2, 21.4, 24.5, 27.4,
32.5, 35.2, 36.8, 41.5, 42.0, 55.9, 62.0, 85.8, 96.6, 111.3, 112.0,
The above compound was subjected to the standard diazo
transfer conditions to give 2-diazo-N-[2-(3,4-dimethoxyphenyl)-
ethyl]-N-(5-methylhexenoyl)malonamic acid ethyl ester (9) as
a yellow oil (97%): IR (neat) 2936, 2137, 1718, and 1648 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 1.25 (t, 3H, J ) 7.2 Hz), 1.67 (s,
3H), 1.74 (quin, 2H, J ) 7.5 Hz), 1.99 (t, 2H, J ) 7.5 Hz), 2.41
(t, 2H, J ) 7.5 Hz), 2.84 (t, 2H, J ) 7.5 Hz), 3.83 (m, 8H), 4.21
(q, 2H, J ) 7.2 Hz), 4.64 (s, 1H), 4.70 (s, 1H), 6.69 (s, 1H),
6.70 (d, 1H, J ) 7.8 Hz), and 6.76 (d, 1H, J ) 7.8 Hz); 13C
NMR (CDCl3, 75 MHz) δ 14.2, 22.1, 22.6, 35.3, 35.4, 36.9, 48.2,
55.8, 61.7, 72.4, 110.6, 111.2, 112.2, 120.9, 130.7, 144.8, 147.7,
148.9, 160.3, 166.3, and 175.3.
To a mixture of 5 mg of rhodium(II) perfluorobutyrate in
10 mL of toluene at reflux was added a solution of 1.27 g (2.85
mmol) of diazo imide 9 in 5 mL of toluene. The reaction
mixture was heated at reflux for 24 h, cooled to rt, and
(50) Taber, D. F.; Ruckle, R. E., J r.; Hennesy, M. J . J . Org. Chem.
1986, 51, 1663. Regitz, M.; Hocker, J .; Leidhergener, A. Organic
Synthesis; J ohn Wiley: New York, 1973; Collect. Vol. 5, pp 179-183.
(51) Scarborough, R. M., J r.; Smith, A. B., III. Tetrahedron Lett.
1977, 18, 4361.
(52) Kappeler, H.; Stauffacher, D.; Eschenmoser, A.; Schinz, H. Helv.
Chim. Acta. 1954, 37, 957.

Tandem Dipolar Cycloaddition-Mannich Cyclization
J . Org. Chem., Vol. 62, No. 1, 1997 73
concentrated under reduced pressure. The crude residue was
purified by flash silica gel chromatography to give 0.50 g (95%)
of 9-[2-(3,4-dimethoxyphenyl)ethyl]-5-methyl-8-oxo-10-oxa-9-
azatricyclo[5.2.1.01,5]decane-7-carboxylic acid ethyl ester (11)
(m, 2H), 2.79 (m, 3H), 3.78 (m, 8H), 4.18 (q, 2H, J ) 7.2 Hz),
4.87-4.96 (m, 2H), 5.66 (ddt, 1H, J ) 16.8, 10.2, and 6.6 Hz),
and 6.37-6.65 (m, 3H); 13C NMR (CDCl3, 75 MHz) δ 14.1, 17.1,
30.9, 33.1, 35.1, 38.5, 48.4, 55.6, 55.7, 61.6, 72.3, 111.2, 112.3,
114.9, 120.9, 130.7, 137, 147.6, 148.7, 159.8, 166.5, and 178.5.
A solution of 0.73 g (1.70 mmol) of diazo imide 10 in 15 mL
of CH2Cl2 at rt was treated with 5 mg of rhodium(II) perfluo-
robutyrate. The reaction mixture was stirred at 25 °C for 24
h and was concentrated under reduced pressure. The resulting
residue was purified by flash silica gel chromatography to give
0.63 g (90%) of 9-[2-(2,3-dimethoxyphenyl)ethyl]-2-methyl-8-
oxo-10-oxa-9-azatricyclo[5.2.1.01,5]decane-7-carboxylic acid eth-
yl ester (12) as a clear oil: IR (neat) 2950, 1750, 1721, and
1
as a clear oil: IR (neat) 2956, 1748, 1719, and 1514 cm-1; H
NMR (CDCl3, 300 MHz) δ 0.91 (s, 3H), 1.32 (t, 3H, J ) 7.2
Hz), 1.57-1.91 (m, 8H), 2.18 (d, 1H, J ) 12.6 Hz), 2.76 (m,
2H), 2.97 (dt, 1H, J ) 13.8 and 7.8 Hz), 3.82 (s, 3H), 3.86 (s,
3H), 4.33 (q, 2H, J ) 7.2 Hz), 6.70 (m, 2H), and 6.77 (d, 1H, J
) 8.4 Hz); 13C NMR (CDCl3, 75 MHz) δ 14.1, 21.3, 21.6, 23.3,
35.6, 37.5, 42.6, 43.9, 53.6, 55.8, 55.9, 62.0, 87.2, 107.8, 111.3,
112.3, 120.7, 130.9, 147.7, 148.9, 166.1, and 170.1; HRMS calcd
for C22H29NO6 403.1994; found 403.1987.
1
1515 cm-1; H NMR (CDCl3, 300 MHz) δ 1.05 (d, 3H, J ) 6.9
2-Hyd r oxy-8,9-d im eth oxy-13a -m eth yl-3-oxo-2,3,5,6,11,-
12,13,13a -octa h yd r o-1H-cyclop en ta [2,3]p yr id o[2,1-a ]iso-
qu in olin e-2-ca r boxylic Acid Eth yl Ester (13). A solution
containing 0.12 g (0.29 mmol) of cycloadduct 11 and 0.10 g
(0.85 mmol) of BF3‚Et2O in 4 mL of CH2Cl2 was heated at
reflux for 24 h. The reaction mixture was cooled to rt, the
reaction was quenched with 2 mL of MeOH, and the reaction
mixture was diluted with CH2Cl2. The organic layer was
washed with brine and dried over Na2SO4. The organic
extracts were filtered and concentrated under reduced pres-
sure. The crude residue was subjected to flash silica gel
chromatography to give 75 mg (95%) of pyrido[2,1-a]isoquino-
line 13 as a white solid: mp 207-208 °C; IR (neat) 3338, 2932,
Hz), 1.29 (t, 3H, J ) 7.2 Hz), 1.35 (m, 1H), 1.63-2.31 (m, 7H),
2.76 (m, 2H), 3.25 (m, 1H), 3.36 (dt, 1H, J ) 6.9 Hz), 3.80 (s,
6H), 4.29 (q, 2H, J ) 7.2 Hz), and 6.67-6.76 (m, 3H); 13C NMR
(CDCl3, 75 MHz) δ 13.1, 14.1, 28.2, 32.0, 32.1, 34.7, 37.7, 41.9,
46.7, 55.9, 61.9, 87.7, 107.4, 111.4, 112.0, 120.5, 130.8, 147.8,
149.0, 166.0, and 171.7; HRMS calcd for C22H29NO6 403.1995;
found 403.2000.
2-Hyd r oxy-7,8-d im et h oxy-11-m et h yl-3-oxo-2,3,5,6,11,-
12,13,13a -octa h yd r o-1H-cyclop en ta [2,3]p yr id o[2,1-a ]iso-
qu in olin e-2-ca r boxylic Acid Eth yl Ester (14). To a solu-
tion containing 40 mg (0.10 mmol) of cycloadduct 12 in 2 mL
of CH2Cl2 at rt was added 29 mg (0.20 mmol) of BF3‚Et2O.
After the reaction mixture was stirred at rt for 3 h, the reaction
was quenched with 2 mL of MeOH and the reaction mixture
was diluted with CH2Cl2. The organic layer was washed with
brine and dried over Na2SO4. The organic extracts were
filtered and concentrated under reduced pressure. The crude
residue was subjected to flash silica gel chromatography to
give 36 mg (90%) of pyrido[2,1-a]isoquinoline 14 as a white
solid: mp 149-150 °C; IR (neat) 3401, 2951, 1743, 1640, and
1734, and 1627 cm-1 1H NMR (CDCl3, 300 MHz) δ 0.80 (s,
;
3H), 1.19 (t, 3H, J ) 7.2 Hz), 1.94-2.13 (m, 4H), 2.19 (d, 1H,
J ) 14.4 Hz), 2.31 (m, 1H), 2.34 (d, 1H, J ) 14.4 Hz), 2.50 (m,
2H), 2.81 (m, 2H), 3.82 (s, 3H), 3.83 (s, 3H), 4.11 (m, 2H), 4.28
(s, 1H), 4.98 (m, 1H), 6.55 (s, 1H), and 6.77 (s, 1H); 13C NMR
(CDCl3, 75 MHz) δ 13.7, 20.6, 22.9, 30.0, 40.4, 41.7, 42.5, 42.9,
44.3, 55.7, 56.0, 61.9, 72.5, 74.8, 110.1, 111.5, 129.1, 132.2,
147.0, 147.3, 167.6, and 172.0. Anal. Calcd for C22H29NO6:
C, 65.49; H, 7.25; N, 3.47. Found: C, 65.24; H, 7.26; N, 3.48.
1
1513 cm-1; H NMR (CDCl3, 300 MHz) δ 0.64 (t, 3H, J ) 6.9
Hz), 1.01 (d, 3H, J ) 7.2 Hz), 1.62 (m, 1H), 1.97 (m, 1H), 2.14
(m, 1H), 2.29-2.42 (m, 2H), 2.49-2.71 (m, 3H), 3.08 (m, 2H),
3.72 (m, 1H), 3.81 (s, 6H), 3.83 (m, 2H), 4.39 (s, 1H), 4.81 (m,
1H), and 6.53 (d, 2H, J ) 3.3 Hz); 13C NMR (CDCl3, 75 MHz)
δ 13.0, 17.2, 27.2, 29.8, 31.1, 39.0, 39.2, 39.6, 46.1, 55.8, 56.2,
61.6, 71.2, 73.4, 109.3, 111.5, 125.3, 136.3, 146.8, 147.8, 169.4,
and 171.0. Anal. Calcd for C22H29NO6: C, 65.49; H, 7.26; N,
3.47. Found: C, 65.41; H, 7.30; N, 3.45.
P r ep a r a tion a n d Rh od iu m (II)-Ca ta lyzed Cycloa d d i-
tion of 2-Dia zo-N-[2-(3,4-d im eth oxyp h en yl)eth yl]-N-h ex-
5-en oylm a lon a m ic Acid Eth yl Ester (15). To a solution of
1.06 g (9.28 mmol) of 5-hexenoic acid in 50 mL of CH2Cl2 was
added 1.65 g (10.20 mmol) of 1,1′-carbonyldiimidazole, and the
solution was stirred at rt for 2 h. The reaction mixture was
added to a solution of 1.85 g (10.20 mmol) of 3,4-dimethox-
yphenethylamine in 100 mL of CH2Cl2 at 0 °C. The resulting
solution was warmed to 25 °C, stirred for 10 h, and then
concentrated under reduced pressure. The crude residue was
subjected to flash silica gel chromatography to give 2.01 g
(83%) of hex-5-enoic acid [2-(3,4-dimethoxyphenyl)ethyl]amide
as a crystalline solid: mp 39-40 °C; IR (neat) 3306, 2936,
1641, 1234, and 1026 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.64
(quin, 2H, J ) 7.2 Hz), 1.95-2.12 (m, 4H), 2.69 (t, 2H, J ) 7.2
Hz), 3.41 (q, 2H, J ) 7.2 Hz), 3.78 (s, 6H), 4.87-4.94 (m, 2H),
5.71 (m, 2H), and 6.64-6.75 (m, 3H); 13C NMR (CDCl3, 75
MHz) δ 24.7, 33.0, 35.2, 35.8, 40.6, 55.8, 111.3, 111.8, 115.1,
120.5, 131.4, 137.8, 147.6, 148.9, and 172.7.
P r ep a r a tion a n d Rh od iu m (II)-Ca ta lyzed Cycloa d d i-
t ion of 2-Dia zo-N-[2-(3,4-d im et h oxyp h en yl)et h yl]-N-(2-
m eth ylh ex-5-en oyl)m a lon a m ic Acid Eth yl Ester (10). A
solution containing 1.0 g (7.80 mmol) of 2-methyl-5-hexenoic
acid53 in 50 mL of CH2Cl2 at rt was stirred with 1.73 g (9.36
mmol) of 1,1′-carbonyldiimidazole at rt for 1 h. The mixture
was added to a solution of 2.02 g (8.97 mmol) of 3,4-
dimethoxyphenethylamine in 100 mL of CH2Cl2 at 0 °C. The
solution was stirred at 25 °C for 10 h and then concentrated
under reduced pressure. The residue was subjected to flash
silica gel chromatography to give 2.01 g (89%) of 2-methylhex-
5-enoic acid [2-(3,4-dimethoxyphenyl)ethyl]amide as a white
solid: mp 76-77 °C; IR (neat) 3299, 1659, 1028, and 909 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 1.06 (d, 3H, J ) 6.9 Hz), 1.39
(m, 1H), 1.68 (m, 1H), 1.89-2.14 (m, 3H), 2.72 (t, 2H, J ) 6.9
Hz), 3.47 (m, 2H), 3.81 (s, 6H), 4.91 (m, 2H), 5.49 (brs, 1H),
5.70 (ddt, 1H, J ) 17.1, 10.5, and 6.6 Hz), and 6.67-6.78 (m,
3H); 13C NMR (CDCl3, 75 MHz) δ 17.8, 31.4, 33.2, 35.3, 40.5,
40.6, 55.7, 55.8, 111.3, 111.8, 114.8, 120.6, 131.4, 138.0, 147.5,
148.9, and 176.2.
N-Malonylacylation was carried out on the above amide in
the normal manner to give N-[2-(3,4-dimethoxyphenyl)ethyl]-
N-(2-methylhex-5-enoyl)malonamic acid ethyl ester as a clear
oil (70%): IR (neat) 2958, 1740, 1695, 1515, and 1027 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 1.04 (d, 3H, J ) 6.9 Hz), 1.25 (t,
3H, J ) 7.2 Hz), 1.39 (m, 1H), 1.70 (m, 1H), 1.96 (m, 2H), 2.68
(q, 1H, J ) 6.9 Hz), 2.81 (m, 2H), 3.77 (s, 2H), 3.83 (s, 3H),
3.85 (s, 3H), 3.88 (m, 2H), 4.17 (q, 2H, J ) 7.2 Hz), 4.98 (m,
2H), 5.70 (ddt, 1H, J ) 16.8, 10.2, and 6.6 Hz), and 6.69-6.80
(m, 3H); 13C NMR (CDCl3, 75 MHz) δ 13.9, 16.9, 30.9, 32.5,
34.8, 38.2, 46.0, 46.2, 55.7, 60.9, 111.4, 112.3, 115.3, 120.7,
130.5, 137.5, 147.8, 149.0, 167.2, 168.8, and 179.7.
N-Malonylacylation was carried out on the above amide in
the normal manner to give N-[2-(3,4-dimethoxyphenyl)ethyl]-
N-hex-5-enoylmalonamic acid ethyl ester as a clear oil (78%):
IR (neat) 2950, 1738, 1697, 1516, and 1028 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 1.25 (t, 3H, J ) 6.9 Hz), 1.61 (quin, 2H,
J ) 7.2 Hz), 1.98 (q, 2H, J ) 7.2 Hz), 2.30 (t, 2H, J ) 7.2 Hz),
2.80 (t, 2H, J ) 7.2 Hz), 3.78 (s, 2H), 3.83 (m, 8H), 4.17 (q,
2H, J ) 6.9 Hz), 4.94-5.00 (m, 2H), 5.69 (ddt, 1H, J ) 17.0,
10.2, and 7.0 Hz), and 6.69-6.79 (m, 3H); 13C NMR (CDCl3,
75 MHz) δ 14.0, 23.3, 32.7, 34.6, 35.5, 46.2, 46.4, 55.8, 61.1,
111.5, 112.3, 115.4, 120.8, 130.8, 137.5, 147.9, 149.1, 167.4,
168.6, and 175.7.
The above compound was subjected to standard diazo
transfer conditions to give 2-diazo-N-[2-(3,4-dimethoxyphenyl)-
ethyl]-N-(2-methylhex-5-enoyl)malonamic acid ethyl ester (10)
as a yellow oil (100%): IR (neat) 2939, 2135, 1719, 1693, and
1
1649 cm-1; H NMR (CDCl3, 300 MHz) δ 1.08 (d, 3H, J ) 6.9
Hz), 1.22 (t, 3H, J ) 7.2 Hz), 1.41 (m, 1H), 1.73 (m, 1H), 1.97
The above compound was subjected to the standard diazo
transfer conditions to give 2-diazo-N-[2-(3,4-dimethoxyphenyl)-
(53) J ellal, A.; Santelli, M. Tetrahedron Lett. 1980, 21, 4487.

74 J . Org. Chem., Vol. 62, No. 1, 1997
Padwa et al.
ethyl]-N-hex-5-enoylmalonamic acid ethyl ester (15) as a
The above compound was subjected to the standard diazo
transfer conditions to give 2-diazo-3-[(3,4-dimethoxybenzyl)-
hex-5-enoylamino]-3-oxopropionic acid ethyl ester as a yellow
oil (100%): IR (neat) 2940, 2139, 1723, and 1658 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 1.22 (t, 3H, J ) 7.2 Hz), 1.64 (quin, 2H,
J ) 7.2 Hz), 1.96 (q, 2H, J ) 7.2 Hz), 2.44 (t, 2H, J ) 7.2 Hz),
3.77 (s, 6H), 4.18 (q, 2H, J ) 7.2 Hz), 4.78 (s, 2H), 4.86-4.94
(m, 2H), 5.65 (ddt, 1H, J ) 16.8, 10.2, and 6.6 Hz), and 6.71-
6.84 (m, 3H); 13C NMR (CDCl3, 75 MHz) δ 14.1, 23.8, 32.7,
35.1, 48.7, 55.7, 55.8, 61.7, 72.7, 110.5, 111.1, 115.2, 119.4,
129.5, 137.6, 148.3, 149.1, 160.4, 166.2, and 175.4.
To a mixture of 5 mg of rhodium(II) perfluorobutryrate in
15 mL of benzene at 80 °C was added a solution of 1.50 g (3.72
mmol) of the above diazo imide in 2 mL of benzene. The
reaction was heated at reflux for 24 h and concentrated under
reduced pressure. The resulting residue was purified by flash
silica gel chromatography to give 1.04 g (75%) of 9-(3,4-
dimethoxybenzyl)-8-oxo-10-oxa-9-azatricyclo[5.2.1.01,5]decane-
7-carboxylic acid ethyl ester (18) as clear oil: IR (neat) 2944,
1750, 1719, 1515, and 1237 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 1.36 (t, 3H, J ) 7.2 Hz), 1.74 (m, 1H), 1.86 (m, 1H), 1.92-
2.04 (m, 5H), 2.15-2.21 (m, 2H), 3.85 (s, 6H), 4.38 (m, 4H),
and 6.78 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 14.1, 24.6, 25.1,
30.1, 35.6, 43.4, 47.7, 55.8, 55.9, 62.0, 88.5, 106.9, 110.7, 111.0,
119.9, 128.9, 148.6, 149.2, 165.9, and 170.8; HRMS calcd for
C20H25NO6; 375.1681; found 375.1692.
yellow oil (95%): IR (neat) 2958, 2135, 1717, 1649, and 1516
1
cm-1; H NMR (CDCl3, 300 MHz) δ 1.21 (t, 3H, J ) 6.9 Hz),
1.65 (quin, 2H, J ) 7.2 Hz), 1.99 (q, 2H, J ) 7.2 Hz), 2.38 (t,
2H, J ) 7.2 Hz), 2.80 (t, 2H, J ) 7.2 Hz), 3.78 (m, 8H), 4.16
(q, 2H, J ) 6.9 Hz), 4.89-4.98 (m, 2H), 5.68 (ddt, 1H, J )
16.8, 10.2, and 6.6 Hz), and 6.65-6.74 (m, 3H); 13C NMR
(CDCl3, 75 MHz) δ 14.2, 23.9, 32.9, 35.1, 35.4, 48.2, 55.8, 55.9,
61.7, 72.3, 111.3, 112.3, 115.2, 120.9, 130.7, 137.7, 147.7, 148.9,
160.3, 166.3, and 175.2.
A solution containing 0.99 g (2.26 mmol) of diazo imide 15
in 15 mL of CH2Cl2 at rt was treated with 5 mg of rhodium-
(II) perfluorobutyrate. The reaction mixture was stirred at
25 °C for 24 h and was then concentrated under reduced
pressure. The crude residue was purified by flash silica gel
chromatography to give 0.52 g (56%) of 9-[2-(2,3-dimethox-
yphenyl)ethyl]-8-oxo-10-oxa-9-azatricyclo[5.2.1.01,5]decane-7-
carboxylic acid ethyl ester (16) as a clear oil: IR (neat) 2936,
1739, 1666, 1514, and 1261 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 1.34 (t, 3H, J ) 7.2 Hz), 1.80-2.22 (m, 9H), 2.79 (m, 2H),
3.17 (m, 1H), 3.57 (m, 1H), 3.85 (s, 6H), 4.10 (m, 2H), and 6.71-
6.80 (m, 3H); 13C NMR (CDCl3, 75 MHz) δ 14.1, 24.6, 25.1,
30.2, 35.0, 35.6, 41.8, 47.9, 55.8, 62.0, 88.3, 106.9, 111.3, 112.0,
120.6, 130.8, 147.7, 148.9, 165.9, and 170.8; HRMS calcd for
C21H27NO6 389.1838; found 389.1819.
2-Hyd r oxy-7,8-d im eth oxy-3-oxo-2,3,5,6,11,12,13,13a -oc-
ta h yd r o-1H-cyclop en ta [2,3]p yr id o[2,1-a ]isoqu in olin e-2-
ca r boxylic Acid Eth yl Ester (17). To a solution containing
0.15 g (130 mmol) of cycloadduct 16 in 2 mL of CH2Cl2 at rt
was added 0.11 g (0.75 mmol) of BF3‚Et2O. After the reaction
mixture was stirred at rt for 3 h, the mixture was quenched
with 2 mL of MeOH and the reaction mixture was diluted with
CH2Cl2. The organic layer was washed with brine and dried
over Na2SO4. The organic extracts were filtered and concen-
trated under reduced pressure. The crude residue was sub-
jected to flash silica gel chromatography to give 0.13 g (90%)
of pyrido[2,1-a]isoquinoline 17 as a white solid: mp 142-143
°C; IR (neat) 3400, 1742, 1644, 1512, and 1257 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 0.68 (t, 3H, J ) 7.2 Hz), 1.69 (m, 4H),
2.12 (m, 2H), 2.32 (m, 2H), 2.60 (m, 2H), 2.99 (m, 1H), 3.22
(dt, 1H, J ) 12.3 and 4.5 Hz), 3.78 (m, 8H), 4.34 (s, 1H), 4.71
(dd, 1H, J ) 13.2 and 6.0 Hz), and 6.52 (s, 2H); 13C NMR
(CDCl3, 75 MHz) δ 13.1, 22.7, 27.5, 33.2, 36.4, 39.3, 40.3, 43.4,
55.8, 56.1, 61.6, 69.3, 73.5, 108.2, 111.7, 125.8, 135.0, 147.2,
147.8, 168.6, and 171.1. Anal. Calcd for C21H27NO6: C, 64.75;
H, 7.00; N, 3.59. Found: C, 64.47; H, 6.98; N, 3.49.
Lewis Acid Rin g-Open in g Reaction of 9-(3,4-Dim eth ox-
yb en zyl)-8-oxo-10-oxa -9-a za t r icyclo[5.2.1.01,5]d eca n e-7-
ca r boxylic Acid Eth yl Ester (18). To a solution of 1.01 g
(8.85 mmol) of 5-hexenoic acid in 50 mL of CH2Cl2 was added
1.70 g (10.48 mmol) of 1,1′-carbonyldiimidazole, and the
mixture was stirred at rt for 2 h. This reaction mixture was
added to a solution of 1.65 g (10.17 mmol) of 3,4-dimethoxy-
benzylamine in 100 mL of CH2Cl2 at 0 °C. This solution was
warmed to rt and stirred for 10 h. The solution was concen-
trated under reduced pressure, and the resulting residue was
subjected to flash silica gel chromatography to give 1.91 g
(82%) of hex-5-enoic acid (3,4-dimethoxybenzyl)amide as a
crystalline solid: mp 65-66 °C; IR (neat) 3309, 1637, 1545,
and 802 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.69 (quin, 2H, J
) 7.5 Hz), 2.03 (q, 2H, J ) 7.5 Hz), 2.14 (t, 2H, J ) 7.5 Hz),
3.79 (s, 6H),4.28 (d, 2H, J ) 5.7 Hz), 4.92 (m, 2H), 5.71 (ddt,
1H, J ) 16.8, 10.2, and 6.6 Hz), 5.97 (brs, 1H), 6.74 (s, 3H);
13C NMR (CDCl3, 75 MHz) δ 24.7, 33.1, 35.8, 43.3, 55.8, 111.1,
115.2, 120.0, 131.0, 137.8, 148.3, 149.0, and 172.6.
1-(3,4-Dim et h oxyb en zyl)-3-h yd r oxy-2-oxo-2,3,4,5,6,7-
h exa h yd r o-1H-[1]p yr in d in e-3-ca r boxylic Acid Eth yl Es-
ter (19). To a solution of 0.064 g (0.17 mmol) of cycloadduct
18 in 2.0 mL of CH2Cl2 at 0 °C was added 49 µL (0.34 mmol)
of BF3‚Et2O. After the reaction mixture was warmed to rt and
stirred for 2 h, the reaction was quenched with 1.0 mL of EtOH
and the reaction mixture was diluted with 10 mL of CH2Cl2.
The organic layer was washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure to give 60
mg (95%) of 19 in 80% yield together with lesser quantities
(20%) of the trisubstituted olefin 20 which could not be fully
separated from 19. The structure of 19 exhibited the following
spectral properties: IR (neat) 3428 (br), 1738, 1668, 1515, and
1
1261 cm-1; H NMR (CDCl3, 300 MHz) δ 1.20 (t, 3H, J ) 7.2
Hz), 1.84 (quin, 2H, J ) 7.2 Hz), 2.34 (m, 4H), 2.42 (d, 1H, J
) 15.4 Hz), 2.92 (d, 1H, J ) 15.4 Hz), 3.81 (s, 3H), 3.82 (s,
3H), 4.17 (q, 2H, J ) 7.2 Hz), 4.58 (s, 1H), 4.67 (d, 1H, J )
15.6 Hz), 4.76 (d, 1H, J ) 15.6 Hz), 6.75 (m, 2H), and 6.80 (m,
1H); HRMS (FAB/LSIMS) Calcd for C20H25NO6Li: 375.1682;
found 375.1684.
P r ep a r a tion a n d Rh od iu m (II)-Ca ta lyzed Cycloa d d i-
tion of N-[2-(1-Ben zyl-1H-in d ol-3-yl)eth yl]-2-d ia zo-N-h ex-
5-en oylm a lon a m ic Acid Eth yl Ester (26). To a solution
containing 1.40 g (12.30 mmol) of 5-hexenoic acid in 50 mL of
CH2Cl2 was added 2.0 g (12.30 mmol) of 1,1′-carbonyldiimi-
dazole, and the solution was stirred at rt for 1 h. To this
reaction mixture was added a solution of 2.90 g (11.6 mmol)
of 1-benzyltryptamine54 in 25 mL of CH2Cl2, and the solution
was allowed to stir for 1 h at rt. The solvent was removed
under reduced pressure, and the residue was taken up in ether
and washed with 10% aqueous HCl and brine. The organic
layer was dried over anhydrous MgSO4, filtered, and concen-
trated under reduced pressure. The resulting residue was
purified by flash silica gel chromatography to give 1.22 g (30%)
of hex-5-enoic acid [2-(1-benzyl-1H-indol-3-yl)ethyl]amide as
a yellow oil: IR (neat) 3299, 1642, 1553, 1468, and 741 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 1.67 (m, 2H), 2.05 (m, 4H), 2.96
(t, 2H, J ) 6.8 Hz), 3.58 (q, 2H, J ) 6.4 Hz), 4.95 (m, 2H),
5.26 (s, 2H), 5.52 (brs, 1H), 5.73 (m, 1H), 6.93 (s, 1H), and
7.05-7.65 (m, 9H); 13C NMR (CDCl3, 75 MHz) δ 24.7, 25.3,
33.1, 36.0, 39.8, 49.9, 109.8, 112.3, 115.2, 119.0, 119.3, 122.0,
126.1, 126.9, 127.7, 128.0, 128.8, 136.8, 137.9, and 172.9.
N-Malonylacylation was carried out on the above amide in
the normal manner to give N-[2-(1-benzyl-1H-indol-3-yl)ethyl]-
2-diazo-N-hex-5-enoylmalonamic acid ethyl ester as a clear oil
N-Malonylation was carried out on the above amide in the
normal manner to give 3-[(3,4-dimethoxybenzyl)hex-5-enoy-
lamino]-3-oxopropionic acid ethyl ester as a clear oil (68%);
IR (neat) 2935, 1737, 1701, 1519, and 1029 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 1.22 (t, 3H, J ) 7.2 Hz), 1.62 (quin, 2H,
J ) 7.2 Hz), 1.95 (m, 2H), 2.47 (t, 2H, J ) 7.2 Hz), 3.80 (s,
3H), 3.81 (s, 3H), 3.86 (s, 2H), 4.15 (q, 2H, J ) 7.2 Hz), 4.85-
4.91 (m, 4H), 5.62 (ddt, 1H, J ) 17.1, 10.5, and 6.6 Hz), and
6.67 (m, 3H); 13C NMR (CDCl3, 75 MHz) δ 14.0, 23.3, 32.6,
35.7, 46.3, 46.5, 55.9, 61.2, 109.6, 111.4, 115.3, 118.2, 129.0,
137.4, 148.3, 149.3, 167.4, 168.8, and 176.1.
1
(68%): IR (neat) 2979, 1740, 1696, and 1333 cm-1; H NMR
(CDCl3, 300 MHz) δ 1.25 (t, 3H, J ) 7.1 Hz), 1.53 (m, 2H),
(54) J ahangir; Brook, M. A.; Maclean, D. B.; Holland, H. L.
Tetrahedron 1987, 43, 5761.

Tandem Dipolar Cycloaddition-Mannich Cyclization
J . Org. Chem., Vol. 62, No. 1, 1997 75
1.84 (q, 2H, J ) 7.0 Hz), 2.31 (t, 2H, J ) 7.4 Hz), 3.04 (t, 2H,
J ) 7.3 Hz), 3.80 (s, 2H), 3.95 (t, 2H, J ) 7.3 Hz), 4.17 (q, 2H,
J ) 7.1 Hz), 4.91 (m, 2H), 5.60 (m, 1H), 5.24 (s, 2H), 6.96 (s,
1H), and 7.05-7.70 (m, 9H); 13C NMR (CDCl3, 75 MHz) δ 14.1,
23.4, 24.6, 32.7, 35.6, 45.2, 46.6, 50.0, 61.2, 109.9, 111.2, 115.4,
118.7, 119.3, 122.1, 126.9, 127.7, 127.9, 128.8, 136.6, 137.4,
137.6, 167.5, 168.8, and 175.9.
give 1.10 g (88%) of 2-allyl-N-[2-(3,4-dimethoxyphenyl)ethyl]-
benzamide as a white solid: mp 98-99 °C; IR (CDCl3) 3320,
1675, and 1530 cm-1 1H NMR (CDCl3, 300 MHz) δ 2.87 (t,
;
2H, J ) 6.8 Hz), 3.50 (d, 2H, J ) 6.3 Hz), 3.68 (dd, 2H, J )
13.0 and 6.8 Hz), 3.86 (s, 6H), 4.90-5.05 (m, 2H), 5.85 (brs,
1H), 5.80-6.00 (m, 1H), 6.75-6.83 (m, 3H), and 7.20-7.33 (m,
4H); 13C NMR (CDCl3, 75 MHz) δ 35.2, 37.4, 40.9, 55.8, 55.9,
111.4, 111.9, 115.9, 120.7, 126.3, 127.1, 130.0, 130.4, 131.3,
136.5, 137.5, 147.7, 149.1, and 169.8.
The above compound was subjected to the standard diazo
transfer conditions to give N-[2-(1-benzyl-1H-indol-3-yl)ethyl]-
2-diazo-N-hex-5-enoylmalonamic acid ethyl ester (26) as a
bright yellow oil (98%): IR (neat) 3031, 2136, 1708, and 1370
N-Malonylacylation was carried out on the above amide in
the normal manner to give 3-[(2-allylbenzoyl)-[2-(3,4-dimethox-
yphenyl)ethyl]amino]-3-oxopropionic acid ethyl ester as a
cm-1 1H NMR (C6D6, 300 MHz) δ 0.69 (t, 3H, J ) 7.2 Hz),
;
colorless oil (93%): IR (neat) 1738, 1687, 1510, and 1446 cm-1
;
1.65 (m, 2H), 1.81 (q, 2H, J ) 6.8 Hz), 2.31 (t, 2H, J ) 7.3
Hz), 3.12 (t, 2H, J ) 6.9 Hz), 3.67 (q, 2H, J ) 7.2 Hz), 3.96 (t,
2H, J ) 7.0 Hz), 4.58 (s, 2H), 4.88 (m, 2H), 5.54 (m, 1H), 6.48
(s, 1H), and 6.72-7.62 (m, 9H); 13C NMR (C6D6, 75 MHz) δ
13.7, 24.0, 25.7, 32.9, 35.0, 46.9, 49.4, 60.9, 73.8, 109.8, 111.2,
114.9, 118.9, 119.3, 121.8, 126.6, 127.2, 128.2, 128.4, 136.8,
137.6, 137.9, 160.1, 166.0, and 174.9.
1H NMR (CDCl3, 300 MHz) δ 1.26 (t, 3H, J ) 7.1 Hz), 2.74 (t,
2H, J ) 7.6 Hz), 3.30 (d, 2H, J ) 6.6 Hz), 3.60-3.72 (m, 4H),
3.79 (s, 3H), 3.87 (s, 3H), 4.18 (q, 2H, J ) 7.1 Hz), 4.99-5.06
(m, 2H), 5.75-5.90 (m, 1H), 6.35-6.69 (m, 3H), and 7.06-7.38
(m, 4H); 13C NMR (CDCl3, 75 MHz) δ 14.1, 34.3, 37.1, 46.7,
48.5, 55.8, 55.9, 61.3, 111.3, 112.0, 117.0, 120.9, 126.4, 126.7,
130.2, 130.6, 135.0, 135.8, 137.2, 147.7, 148.9, 167.3, 168.8,
and 173.6.
To a mixture of 3 mg of rhodium(II) perfluorobutyrate in
10 mL of benzene at 80 °C was added a solution of 0.27 g (0.56
mmol) of diazo imide 26 in 5 mL of benzene. After being
heated at reflux for 30 min, the solution was cooled to rt and
concentrated under reduced pressure. The residue was sub-
jected to flash silica gel chromatography to give 0.25 g (98%)
of 9-[2-(1-benzyl-1H-indol-3-yl)ethyl]-8-oxo-10-oxa-9-azatricyclo-
[5.2.1.01,5]decane-7-carboxylic acid ethyl ester (27) as a clear
oil: IR (neat) 2942, 1753, 1718, 1468, and 847 cm-1; 1H NMR
(C6D6, 300 MHz) δ 0.87 (t, 3H, J ) 7.1 Hz), 0.95 (m, 1H), 1.05-
1.63 (m, 6H), 1.87 (ddd, 2H, J ) 12.6, 7.9, and 3.5 Hz), 2.85
(m, 2H), 3.05 (m, 1H), 3.42 (m, 1H), 3.97 (q, 2H, J ) 7.1 Hz),
4.60 (s, 2H), 6.56 (s, 1H), 6.70-7.20 (m, 8H), and 7.55 (m, 1H);
13C NMR (CDCl3, 75 MHz) δ 14.3, 24.8, 25.1, 25.2, 30.4, 35.6,
40.9, 48.1, 50.0, 62.1, 88.4, 109.9, 111.6, 118.8, 119.3, 122.0,
126.3, 126.9, 127.6, 127.8, 128.8, 136.6, 137.5, 166.1, and 170.9;
HRMS (FAB/LSIMS) Calcd for C28H30N2O4Li 465.2366; found
465.2378.
The above compound was subjected to the standard diazo
transfer conditons to give 3-[(2-allylbenzoyl)-[2-(3,4-dimethox-
yphenyl)ethyl]amino]-2-diazo-3-oxopropionic acid ethyl ester
(29) as a bright yellow oil (78%): IR (neat) 2129, 1716, 1687,
1
and 1637 cm-1; H NMR (CDCl3 300 MHz) δ 1.19 (t, 3H, J )
7.1 Hz), 2.88 (t, 2H, J ) 7.8 Hz), 3.49 (d, 2H, J ) 6.4 Hz), 3.79
(s, 3H), 3.81 (s, 3H), 3.89 (t, 2H, J ) 7.8 Hz), 4.14 (q, 2H, J )
7.1 Hz), 5.00-5.10 (m, 2H), 5.85-6.00 (m, 1H), 6.59-6.74 (m,
3H), and 7.19-7.40 (m, 4H); 13C NMR (CDCl3, 75 MHz) δ 14.2,
34.8, 37.2, 48.9, 55.8, 55.9, 61.6, 111.2, 112.1, 116.5, 120.9,
125.8, 128.1, 130.5, 130.7, 130.9, 134.3, 136.7, 139.9, 147.7,
148.9, 160.2, 166.4, and 172.0.
A mixture containing 0.25 g (0.54 mmol) of diazo imide 29
and 4 mg of rhodium(II) perfluorobutyrate in 3 mL of CH2Cl2
was allowed to stir at rt for 12 h. The solution was concen-
trated under reduced pressure, and the residue was subjected
to flash silica gel chromatography. The first fraction isolated
(60%) was assigned as N-[(3,4-dimethoxyphenyl)ethyl]-3-car-
bethoxy-3,9b-epoxy-1,4,4a,5-tetrahydroindeno[1,2-b]pyridin-2-
one (30) on the basis of its spectral properties: IR (neat) 1745,
1716, 1510, and 1460 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.32
(t, 3H, J ) 7.1 Hz), 2.16 (dd, 1H, J ) 12.6 and 4.1 Hz), 2.33
(dd, 1H, J ) 12.6 and 7.6 Hz), 2.60-2.75 (m, 2H), 2.80-2.95
(m, 2H), 3.10 (dd, 1H, J ) 14.7 and 7.2 Hz), 3.20-3.60 (m,
2H), 3.76 (s, 3H), 3.81 (s, 3H), 4.34 (q, 2H, J ) 7.1 Hz), 6.60-
6.76 (m, 3H), and 7.10-7.41 (m, 4H); 13C NMR (CDCl3, 75
MHz) δ 14.2, 34.3, 35.1, 35.7, 43.5, 49.3, 55.8, 56.0, 62.1, 89.5,
107.2, 111.4, 112.1, 120.8, 125.3, 126.1, 127.1, 131.0, 131.2,
131.5, 147.2, 147.8, 149.0, 165.6, and 171.8; HRMS calcd for
C25H27NO6 437.1838; found 437.1829.
11-N-Ben zyl-2-ca r b et h oxy-2-h yd r oxy-3-oxo-2,3,6,11,-
12,13,14,14a -octa h yd r o-1H,5H-cyclop en t[i]in d olo[2,3-a ]-
qu in olizin e (28). To a solution of 0.12 g (0.26 mmol) of
cycloadduct 27 in 5.0 mL of CH2Cl2 at 0 °C was added 74 mg
(0.52 mmol) of BF3‚Et2O. After the reaction mixture was
warmed to rt and stirred for 6 h, the reaction was quenched
with a saturated aqueous NaHCO3 solution and the reaction
mixture was diluted with ether. The ether layer was washed
with brine, dried over MgSO4, filtered, and concentrated under
reduced pressure. The resulting residue was purified by flash
silica gel chromatography to give 61 mg (60%) of indolo[2,3-
a]quinolizine 28 as a white solid: mp 72-73 °C; IR (CHCl3)
1
3380, 1750, 1646, 1466, and 1346 cm-1; H NMR (C6D6, 300
MHz) δ 0.64 (t, 3H, J ) 7.0 Hz), 0.83 (t, 2H, J ) 7.2 Hz), 1.38
(m, 1H), 1.45-1.85 (m, 1H), 1.90 (m, 1H), 2.04 (m, 1H), 2.23
(dd, 1H, J ) 14.1 and 5.3 Hz), 2.35 (dd, 1H, J ) 15.3 and 3.1
Hz), 2.68 (m, 1H), 2.80 (dt, 1H, J ) 12.3 and 3.7 Hz), 3.00
(ddd, 1H, J ) 15.1, 12.0, and 5.2 Hz), 3.75 (dq, 1H, J ) 10.7
and 7.1 Hz), 3.80 (m, 2H), 4.52 (s, 1H), 4.84 (s, 2H), 4.98 (dd,
1H, J ) 12.5 and 4.8 Hz), and 6.55-7.40 (m, 9H); 13C NMR
(CDCl3, 75 MHz) δ 13.8, 21.7, 23.6, 30.7, 31.3, 38.7, 39.5, 42.2,
48.1, 62.4, 70.2, 74.1, 110.6, 112.3, 118.2, 119.9, 122.4, 125.3,
126.5, 127.5, 129.0, 136.0, 137.5, 137.9, 169.1, and 172.5. Anal.
Calcd for C28H30N2O4: C, 73.33; H, 6.60; N, 6.11. Found: C,
73.34; H, 6.60; N, 6.01.
P r ep a r a tion a n d Rh od iu m (II)-Ca ta lyzed Cycloa d d i-
tion of 3-[(2-Allylben zoyl)[2-(3,4-d im eth oxyp h en yl)eth yl]-
a m in o]-2-d ia zo-3-oxop r op ion ic Acid Eth yl Ester (29). To
a solution of 0.68 g (3.80 mmol) of 2-allylbenzoic acid55 in 25
mL of CH2Cl2 was added 0.75 g (4.60 mmol) of 1,1′-carbonyl-
diimidazole, and the solution was stirred at rt for 2 h. This
mixture was added to a solution of 1.40 g (7.7 mmol) of 3,4-
dimethoxyphenethylamine in 25 mL of CH2Cl2 at 0 °C. The
solution was allowed to warm to rt, was stirred for 12 h at 25
°C, and was concentrated under reduced pressure. The crude
residue was subjected to flash silica gel chromatography to
The second fraction isolated (15%) from the column was
assigned as N-[(3,4-dimethoxyphenyl)ethyl]-3-carbethoxy-3-
hydroxy-4,5-dihydroindeno[1,2-b]pyridin-2-one (31) on the ba-
sis of its spectral properties: IR (neat) 3417, 1735, 1666, and
1
1517 cm-1; H NMR (CDCl3, 300 MHz) δ 1.09 (t, 3H, J ) 7.1
Hz), 2.65 (d, 1H, J ) 16.6 Hz), 2.80-3.40 (m, 5H), 3.80 (s, 3H),
3.83 (s, 3H), 4.07 (q, 2H, J ) 7.1 Hz), 4.15-4.50 (m, 2H), 4.65,
(s, 1H), 6.73-6.79 (m, 3H), and 7.20-7.50 (m, 4H); HRMS
calcd for C25H27NO6 437.1838; found 437.1850.
2-Ca r bet h oxy-8,9-d im et h oxy-2-h yd r oxy-3-oxo-5,6,13,-
13a -t et r a h yd r o-1H -cyclop en t a [2,3]p yr id o[11,12]b en zo-
[2,1-a ]isoqu in olin e (32). To a solution of 50 mg (0.11 mmol)
of cycloadduct 30 in 5 mL of CH2Cl2 at 0 °C was added 30 mg
(0.22 mmol) of BF3‚Et2O, and the mixture was stirred at 25
°C for 4 h. The reaction was quenched with brine, and the
solution was diluted with CH2Cl2. The organic layer was
washed with brine, dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The resulting residue
was subjected to flash silica gel chromatography to give 40
mg (80%) of benzo[2,1-a]isoquinoline 32 as a 1:1 mixture of
diastereomers which could be separated by HPLC. Diastere-
omer 32a exhibited the following spectral properties: IR (neat)
3400, 1720, 1630, 1510, and 1340 cm-1; 1H NMR (CDCl3, 300
MHz) δ 1.11 (t, 3H, J ) 7.1 Hz), 2.15 (dd, 1H, J ) 14.8 and
3.5 Hz), 2.43 (dd, 1H, J ) 14.8 and 3.5 Hz), 2.71 (dd, 1H, J )
(55) Padwa, A.; Ku, A. J . Am. Chem. Soc. 1978, 100, 2181.

76 J . Org. Chem., Vol. 62, No. 1, 1997
Padwa et al.
16.1 and 3.5 Hz), 3.05-3.55 (m, 4H), 3.72 (s, 3H), 3.70-3.80
(m, 1H), 3.88 (s, 3H), 4.07 (s, 1H), 4.00-4.25 (m, 2H), 4.57 (dd,
1H, J ) 13.1 and 5.8 Hz), 6.52 (s, 1H), 6.67 (s, 1H), 6.80 (d,
1H, J ) 7.5 Hz), and 7.05-7.35 (m, 3H); 13C NMR (CDCl3, 75
MHz) δ 13.7, 28.5, 30.2, 34.5, 37.4, 42.8, 55.9, 56.0, 62.5, 72.5,
74.2, 107.9, 111.6, 124.9, 126.1, 126.2, 128.3, 128.6, 128.9,
143.0, 146.8, 147.5, 148.3, 167.4, and 172.9; HRMS calcd for
C25H27NO6 437.1838; found 437.1854.
Diastereomer 32b exhibited the following spectral proper-
ties: IR (neat) 3390, 1720, 1620, 1500, and 1340 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 1.13 (t, 3H, J ) 7.1 Hz), 2.02 (dd, 1H, J
) 14.0 and 6.2 Hz), 2.65-2.75 (m, 2H), 3.00-3.60 (m, 4H),
3.62 (s, 3H), 3.70-3.80 (m, 1H), 3.84 (s, 3H), 3.98 (q, 1H, J )
7.1 Hz), 4.02 (q, 1H, J ) 7.1 Hz), 4.53 (s, 1H), 4.81-4.85 (m,
1H), 6.28 (s, 1H), 6.61 (s, 1H), 7.05 (d, 1H, J ) 7.6 Hz), and
7.11-7.27 (m, 3H); 13C NMR (CDCl3, 75 MHz) δ 13.7, 28.2,
33.6, 37.0, 39.8, 43.3, 55.8, 56.0, 62.0, 72.7, 73.0, 108.5, 111.4,
124.9, 125.4, 127.1, 128.7, 131.8, 141.6, 146.8, 148.0, 148.1,
169.8, and 170.6; HRMS calcd for C25H27NO6 437.1838; found
437.1854.
P r ep a r a tion a n d Rh od iu m (II)-Ca ta lyzed Cycloa d d i-
tion of 3-[(2-Allylben zoyl)(3-m eth ylbu t-3-en yl)a m in o]-2-
d ia zo-3-oxop r op ion ic Acid Eth yl Ester (33). To a solution
of 0.63 g (3.8 mmol) of 2-allylbenzoic acid55 in 50 mL of CH2-
Cl2 was added 0.75 g (4.6 mmol) of 1,1′-carbonyldiimidazole,
and the solution was allowed to stir at rt for 2 h. This mixture
was added to a solution of 0.58 g (5.8 mmol) of 1-amino-3-
methyl-3-butene56 in 25 mL of CH2Cl2 at 0 °C. The solution
was allowed to stir at 25 °C for 12 h and was concentrated
under reduced pressure. The resulting residue was subjected
to flash silica gel chromatography to give 0.25 g (28%) of
2-allyl-N-(3-methylbut-3-enyl)benzamide as a colorless oil: IR
(neat) 3300, 1655, and 1550 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 1.72 (s, 3H), 2.26 (t, 2H, J ) 6.8 Hz), 3.40-3.60 (m, 4H),
4.73 (s, 1H), 4.79 (s, 1H), 4.90-5.10 (m, 2H), 5.90-6.00 (m,
2H), and 7.10-7.35 (m, 4H); 13C NMR (CDCl3, 75 MHz) δ 21.9,
37.3, 37.4, 37.5, 112.4, 115.9, 126.2, 127.2, 129.9, 130.3, 136.6,
137.6, 142.5, and 169.8.
112.1, 118.7, 121.6, 124.5, 125.1, 126.6, 137.2, 137.9, 142.1,
143.1, 169.3, and 169.7; HRMS calcd for C20H23NO4 341.1627;
found 341.1633.
6-Hyd r oxy-2-m eth yl-5-oxo-4,5,6,7,7a ,8-h exa h yd r o-1H-
4a -a za b en zo[d ]flu or en e-6-ca r b oxylic Acid E t h yl E st er
(35). To a solution containing 80 mg (0.23 mmol) of enamide
34 in 5 mL of CH2Cl2 at rt was added 65 mg (0.46 mmol) of
BF3‚Et2O, and the mixture was heated at reflux for 12 h. After
the reaction mixutre was cooled to rt, the reaction was
quenched with brine and diluted with CH2Cl2. The organic
layer was washed with brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude residue was
subjected to flash silica gel chromatography to give 70 mg
(88%) of azabenzo[d]fluorene 35 as a 3:2 mixture of diastere-
omers. Recrystallization from CH2Cl2/hexane gave the major
diastereomer as a white solid: mp 108-109 °C; IR (CDCl3)
3389, 1741, 1634, and 1422 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 1.13 (t, 3H, J ) 7.1 Hz), 1.68 (s, 3H), 1.81 (dd, 1H, J ) 13.6
and 4.6 Hz), 1.89 (dd, 1H, J ) 17.1 and 3.6 Hz), 2.13-2.40 (m,
2H), 2.58 (d, 1H, J ) 16.0 Hz), 2.70-2.80 (m, 1H), 3.35 (dd,
1H, J ) 16.0 and 6.8 Hz), 3.37 (dt, 1H, J ) 12.5 and 3.6 Hz),
4.08 (q, 2H, J ) 7.1 Hz), 4.00-4.20 (m, 1H), 4.90-4.95 (m,
1H), 5.36 (s, 1H), and 7.18-7.39 (m, 4H); 13C NMR (CDCl3, 75
MHz) δ 13.8, 23.1, 28.8, 33.5, 35.6, 39.2, 41.3, 62.4, 70.0, 74.3,
123.9, 124.2, 125.9, 127.2, 128.0, 131.7, 139.9, 144.8, 167.8,
and 172.0; HRMS calcd for C20H23NO4 341.1627; found 341.1624.
P r ep a r a tion a n d Rh od iu m (II)-Ca ta lyzed Cycloa d d i-
tion of 2-Dia zo-N-(3,7-d im eth yloct-6-en oyl)-N-(3-m eth -
ylbu t-3-en yl)m a lon a m ic Acid Eth yl Ester (36). To a
solution containing 5.0 g (35.20 mmol) of citronellic acid in
125 mL of benzene were added 15.6 g (123.10 mmol) of oxalyl
chloride and 0.14 mL (1.76 mmol) of DMF. The solution was
stirred at rt for 2 h and concentrated under reduced pressure.
The resulting oil was taken up in 20 mL of CH2Cl2 and was
added to a solution of 3.59 g (42.2 mmol) of 1-amino-3-methyl-
3-butene56 in 150 mL of CH2Cl2 at 0 °C. The solution was
stirred at 25 °C for 12 h and concentrated under reduced
pressure. The residue was subjected to flash silica gel chro-
matography to give 3.61 g (44%) of 3,7-dimethyloct-6-enoic acid
(3-methylbut-3-enyl)amide as a clear oil: IR (neat) 3297, 1645,
and 1551 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.93 (d, 3H, J )
6.3 Hz), 1.17-1.24 (m, 1H), 1.30-1.41 (m, 1H), 1.59 (s, 3H),
1.68 (s, 3H), 1.74 (s, 3H), 1.86-2.03 (m, 4H), 2.15-2.02 (m,
1H), 2.21 (t, 2H, J ) 6.8 Hz), 3.39 (t, 2H, J ) 6.6 Hz), 4.74 (s,
1H), 4.82 (s, 1H), 5.06-5.11 (m, 1H), and 5.39 (brs, 1H); 13C
NMR (CDCl3, 75 MHz) δ 17.7, 19.6, 22.1, 25.6, 30.5, 37.0, 37.1,
37.6, 44.6, 112.2, 124.5, 131.4, 142.7, and 172.7.
N-Malonylacylation was carried out on the above amide in
the normal manner to give 3-[(2-allylbenzoyl)(3-methylbut-3-
enyl)amino]-3-oxopropionic acid ethyl ester as a colorless oil
1
(90%): IR (neat) 1760, 1710, 1670, and 1460 cm-1; H NMR
(CDCl3, 300 MHz) δ 1.24 (t, 3H, J ) 7.1 Hz), 1.48 (s, 3H), 2.18
(t, 2H, J ) 7.7 Hz), 3.40 (d, 2H, J ) 6.7 Hz), 3.63 (t, 2H, J )
7.7 Hz), 3.82 (s, 2H), 4.16 (q, 2H, J ) 7.1 Hz), 4.52 (s, 1H),
4.65 (s, 1H), 5.00-5.10 (m, 2H), 5.80-6.00 (m, 1H), and 7.20-
7.45 (m, 4H); 13C NMR (CDCl3, 75 MHz) δ 14.1, 22.1, 36.5,
37.1, 45.3, 46.0, 61.3, 112.5, 117.0, 126.4, 126.7, 130.4, 130.7,
134.9, 135.9, 137.4, 141.9, 167.3, 168.8, and 173.6.
N-Malonylacylation was carried out on the above amide in
the normal manner to give 2.16 g (73%) of N-(3,7-dimethyloct-
6-enoyl)-N-(3-methylbut-3-enyl)-malonamic acid ethyl ester as
The above compound was subjected to the standard diazo
transfer conditions to give 3-[(2-allylbenzoyl)(3-methylbut-3-
enyl)amino]-2-diazo-3-oxopropionic acid ethyl ester (33) as a
bright yellow oil (90%): IR (neat) 2185, 1745, 1710, 1660, and
a clear oil: IR (neat) 1743, 1699, and 1140 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 0.95 (d, 3H, J ) 6.6 Hz), 1.18-1.28 (m,
1H), 1.27 (t, 3H, J ) 7.2 Hz), 1.32-1.39 (m, 1H), 1.60 (s, 3H),
1.68 (s, 3H), 1.79 (s, 3H), 1.97-2.10 (m, 3H), 2.27 (t, 2H, J )
7.7 Hz), 2.36 (dd, 1H, J ) 16.2 and 8.1 Hz), 2.57 (dd, 1H, J )
16.2 and 5.4 Hz), 3.79 (t, 2H, J ) 7.7 Hz), 3.81 (s, 2H), 4.18 (q,
2H, J ) 7.2 Hz), 4.74 (s, 1H), 4.82 (s, 1H), and 5.06-5.11 (m,
1H); 13C NMR (CDCl3, 75 MHz) δ 14.2, 17.7, 19.8, 22.6, 25.5,
25.7, 29.5, 36.8, 36.9, 43.2, 43.9, 46.5, 61.2, 112.5, 124.2, 131.6,
142.1, 167.4, 168.7, and 175.3.
1
1460 cm-1; H NMR (CDCl3, 300 MHz) δ 1.19 (t, 3H, J ) 7.2
Hz), 1.66 (s, 3H), 2.34 (t, 2H, J ) 7.6 Hz), 3.50 (d, 2H, J ) 6.5
Hz), 3.83 (t, 2H, J ) 7.6 Hz), 4.12 (q, 2H, J ) 7.2 Hz), 4.65 (s,
1H), 4.72 (s, 1H), 5.00-5.10 (m, 2H), 5.80-6.00 (m, 1H), and
7.20-7.50 (m, 4H); 13C NMR (CDCl3, 75 MHz) δ 14.2, 22.2,
37.0, 37.2, 45.8, 61.5, 112.4, 116.4, 125.7, 128.2, 130.5, 131.0,
134.3, 136.8, 140.0, 142.2, 160.2, 166.4, and 171.8.
The above compound was subjected to the standard diazo
transfer conditions to give 1.75 g (94%) of 2-diazo-N-(3,7-
dimethyloct-6-enoyl)-N-(3-methylbut-3-enyl)malonamic acid
ethyl ester (36) as a yellow oil: IR (neat) 3077, 2140, 1726,
A mixture containing 0.14 g (0.38 mmol) of diazo imide 33
and 4 mg of rhodium(II) perfluorobutyrate in 5 mL of CH2Cl2
was allowed to stir at rt for 12 h. The solution was concen-
trated under reduced pressure, and the residue was subjected
to flash silica gel chromatography to give 0.11 g (85%) of N-(3-
methylbut-3-enyl)-3-carbethoxy-3-hydroxy-4,5-dihydroindeno-
[1,2-b]pyridin-2-one (34) as a white solid: mp 83-84 °C; IR
1
1700, and 1654 cm-1; H NMR (CDCl3, 300 MHz) δ 0.92 (d,
3H, J ) 6.6 Hz), 1.16-1.24 (m, 1H), 1.24-1.36 (m, 1H), 1.28
(t, 3H, J ) 7.2 Hz), 1.57 (s, 3H), 1.65 (s, 3H), 1.73 (s, 3H),
1.94-2.04 (m, 3H), 2.31 (dd, 1H, J ) 15.7 and 8.1 Hz), 2.30 (t,
2H, J ) 8.0 Hz), 2.51 (dd, 1H, J ) 15.7 and 5.4 Hz), 3.75 (t,
2H, J ) 8.0 Hz), 4.24 (q, 2H, J ) 7.2 Hz), 4.69 (s, 1H), 4.77 (s,
1H), and 5.06 (t, 1H, J ) 6.9 Hz); 13C NMR (CDCl3, 75 MHz)
δ 14.4, 17.8, 19.8, 22.5, 25.6, 25.8, 30.2, 37.0, 37.5, 43.4, 45.2,
61.9, 112.6, 124.4, 131.6, 142.4, 160.5, 166.7, and 174.6.
A solution of 1.70 g (4.50 mmol) of diazo imide 36 in 100
mL of CH2Cl2 at rt was treated with 5 mg of rhodium(II)
perfluorobutyrate. The reaction mixture was stirred for 4 h
(CDCl3) 3400, 1735, 1670, and 1410 cm-1 1H NMR (CDCl3,
;
300 MHz) δ 1.08 (t, 3H, J ) 7.0 Hz), 1.79 (s, 3H), 2.29-2.50
(m, 2H), 2.75 (d, 1H, J ) 16.6 Hz), 3.32 (d, 1H, J ) 16.6 Hz),
3.35-3.39 (m, 2H), 4.07 (q, 2H, J ) 7.0 Hz), 4.10-4.40 (m,
2H), 4.70 (s, 2H), 4.82 (s, 1H), and 7.20-7.45 (m, 4H); 13C NMR
(CDCl3, 75 MHz) δ 13.8, 22.5, 31.1, 36.4, 37.9, 42.3, 61.9, 74.3,
(56) Tietze, L. F.; Bratz, M.; Pretor, M. Chem. Ber. 1989, 122, 1955.

Tandem Dipolar Cycloaddition-Mannich Cyclization
J . Org. Chem., Vol. 62, No. 1, 1997 77
at rt and was then concentrated under reduced pressure. The
resulting residue was purified by flash silica gel chromatog-
raphy to give 1.49 g (94%) of 3,7,7-trimethyl-10-(3-methylbut-
3-enyl)-9-oxo-11-oxa-10-azatricyclo[6.2.1.01,6]undecane-8-car-
boxylic acid ethyl ester (37) as a white solid; mp 90-91 °C; IR
(neat) 1751, 1728, and 1113 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 0.89-0.92 (m, 1H), 0.97 (d, 3H, J ) 6.6 Hz), 1.04 (s, 3H),
1.20 (s, 3H), 1.34 (t, 3H, J ) 7.1 Hz), 1.30-1.38 (m, 1H), 1.43-
1.47 (m, 1H), 1.51-1.57 (m, 1H), 1.68-1.74 (m, 3H), 1.77 (s,
3H), 2.17-2.26 (m, 3H), 3.23-3.41 (m, 2H), 4.36 (q, 2H, J )
7.1 Hz), 4.80 (s, 1H), and 4.73 (s, 1H); 13C NMR (CDCl3, 75
MHz) δ 14.6, 21.1, 22.4, 22.6, 26.4, 26.6, 28.5, 33.2, 36.9, 37.8,
38.6, 44.7, 51.7, 61.8, 92.1, 96.0, 112.5, 142.5, 165.5, and 169.4.
Anal. Calcd for C20H31NO4: C, 68.74; H, 8.94; N, 4.01.
Found: C, 68.64; H, 8.91; N, 3.98.
8-H yd r oxy-3,9,9,13-t et r a m et h yl-7-oxo-6-a za t r icyclo-
[8.4.0.01,6]tetr a d ec-3-en e-8-ca r boxylic Acid Eth yl Ester
(38) a n d 8-Hyd r oxy-3,9,9,13-tetr a m eth yl-7-oxo-6-a za tr i-
cyclo[8.4.0.01,6]t et r a d ec-2-en e-8-ca r boxylic Acid E t h yl
Ester (39). To a solution of 0.30 g (0.86 mmol) of cycloadduct
37 in 20 mL of CH2Cl2 at rt was added 1.61 mL (8.56 mmol)
of a BF3‚2AcOH complex. The reaction mixture was stirred
at 25 °C for 10 h, and the reaction was then quenched with 2
mL of EtOH. The solution was taken up in 50 mL of CH2Cl2
and extracted with water. The organic layer was dried over
Na2SO4, filtered, and concentrated under reduced pressure.
The resulting residue was subjected to flash silica gel chro-
matography to give 0.24 g (80%) of 8-hydroxy-3,9,9,13-tetram-
ethyl-7-oxo-6-azatricyclo[8.4.0.01,6]tetradecene-8-carboxylic acid
ethyl ester as a 4:1 mixture of olefinic regioisomers. The major
isomer was assigned as 8-hydroxy-3,9,9,13-tetramethyl-7,6-
azatricyclo[8.4.0.01,6]tetradec-3-ene-8-carboxylic acid ethyl es-
ter (38) on the basis of its spectral properties: mp 110-111
°C; IR (neat) 3424, 1746, 1720, 1629, and 1234 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 0.92 (d, 3H, J ) 6.3 Hz), 0.97 (s, 3H),
0.99-1.09 (m, 2H), 1.00 (s, 3H), 1.30 (t, 3H, J ) 7.2 Hz), 1.34-
1.44 (m, 1H), 1.68 (s, 3H), 1.70-1.75 (m, 2H), 1.87-1.91 (m,
1H), 2.16-2.22 (d, 1H, J ) 16.8 Hz), 2.23 (dd, 1H, J ) 12.1
and 2.1 Hz), 2.28 (dd, 1H, J ) 12.1 and 4.5 Hz), 2.54 (d, 1H,
J ) 17.7 Hz), 3.46 (d, 1H, J ) 18.2 Hz), 4.23 (q, 2H, J ) 7.2
Hz), 4.27 (s, 1H), 4.98 (d, 1H, J ) 18.2 Hz), and 5.38 (s, 1H);
13C NMR (CDCl3, 75 MHz) δ 14.4, 20.5, 21.0, 22.7, 23.8, 24.7,
29.2, 34.0, 35.6, 38.4, 39.2, 43.5, 46.3, 58.9, 62.2, 81.7, 117.6,
131.4, 168.1, and 172.1. Anal. Calcd for C20H31NO4: C, 68.74;
H, 8.94; N, 4.01. Found: C, 68.74; H, 8.90; N, 4.02.
When the reaction was carried out in the presence of 10
equiv of TMSOTf, a 1:6 mixture of the olefinic isomers 38/39
was isolated. Flash silica gel chromatography afforded 8-hy-
droxy-3,9,9,13-tetramethyl-7-oxo-6-azatricyclo[8.4.0.01,6]tetradec-
2-ene-8-carboxylic acid ethyl ester (39) as a crystalline solid:
mp 113-114 °C; IR (neat) 3434, 1744, 1633, 1457, and 1243
cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.78 (s, 3H), 0.92 (m, 6H),
0.95-1.07 (m, 2H), 1.29 (t, 3H, J ) 7.2 Hz), 1.61 (m, 6H), 1.86
(m, 2H), 2.13 (dd, 1H, J ) 11.5 and 2.7 Hz), 2.30 (m, 1H), 2.46
(dd, 1H, J ) 11.5 and 2.7 Hz), 3.32 (dt, 1H, J ) 12.5 and 5.4
Hz), 4.21 (m, 2H), 4.35 (s, 1H), 4.50 (dd, 1H, J ) 13.3 and 6.9
Hz), and 5.83 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 14.4, 18.9,
20.7, 22.8, 23.6, 23.8, 28.8, 29.1, 35.4, 36.5, 38.9, 46.0, 50.0,
60.3, 62.0, 81.7, 125.8, 132.0, 169.7, and 171.8. Anal. Calcd
for C20H31NO4: C, 68.74; H, 8.94; N, 4.01. Found: C, 68.70;
H, 8.92; N, 3.99.
Ack n ow led gm en t. We gratefully acknowledge the
National Cancer Institute (Grant CA-26751), DHEW,
for generous support of this work. We also thank Mark
A. Semones for determining the X-ray crystal structure
of compounds 8, 13, 14, and 17. Use of the high-field
NMR spectrometer used in these studies was made
possible through equipment grants from the NIH and
NSF.
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra for all compounds with high-resolution mass
spectra together with ORTEP drawings for structures 8, 13,
14, and 17 (16 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O9607267