An approach toward isoindolobenzazepines using the ammonium ylide/Stevens [1,2]-rearrangement sequence

Article abstract of DOI:10.1021/jo001684w

Ammonium ylides derived from the Cu(II)-catalyzed decomposition of α-diazo carbonyls tethered to tertiary amines underwent a benzylic Stevens [1,2]-rearrangement to give tetrahydroisoquinolines or benzazepines containing fused five-membered rings, a feature found in the cephalotaxus alkaloids. Model studies were also carried out toward the synthesis of lennoxamine, a member of the isoindolobenzazepine family of alkaloids. The approach utilized is based on the Rh(II)-catalyzed reaction of an α-diazo carbonyl compound containing an amido group in the γ-position. Treatment of several N,N-dialkyl-substituted amido diazo-esters with Rh₂(OAc)₄ in benzene at 80 °C in the presence of several dienophiles gave [4 + 2]-cycloadducts derived from the Diels-Alder reaction of a transient α-amino isobenzofuran intermediate. In the absence of an external trapping agent, no rearranged product derived from an ammonium ylide intermediate could be detected in the crude reaction mixture. In contrast to this result, reaction of the related diazo dihydroisoquinoline amide 46 with Rh₂(OAc)₄ afforded the isoindolobenzazepine ring system in high yield. Formation of the 5,7-fused skeleton was rationalized in terms of a spirocyclic ammonium ylide that underwent a preferential Stevens [1,2]-shift of the benzylic carbon atom. While we were ultimately thwarted in using the ammonium ylide/rearrangement cascade for a lennoxamine synthesis by an uncooperative diazo transfer reaction, the cascade sequence was shown to be useful for the preparation of various isoindolobenzazepines.

Full text of DOI:10.1021/jo001684w

2414
J . Org. Chem. 2001, 66, 2414-2421
An Ap p r oa ch tow a r d Isoin d oloben za zep in es Usin g th e Am m on iu m
Ylid e/Steven s [1,2]-Rea r r a n gem en t Sequ en ce
Albert Padwa,* L. Scott Beall, Cheryl K. Eidell, and Kimberly J . Worsencroft
Department of Chemistry, Emory University, Atlanta, Georgia 30322
chemap@emory.edu
Received November 29, 2000
Ammonium ylides derived from the Cu(II)-catalyzed decomposition of R-diazo carbonyls tethered
to tertiary amines underwent a benzylic Stevens [1,2]-rearrangement to give tetrahydroisoquinolines
or benzazepines containing fused five-membered rings, a feature found in the cephalotaxus alkaloids.
Model studies were also carried out toward the synthesis of lennoxamine, a member of the
isoindolobenzazepine family of alkaloids. The approach utilized is based on the Rh(II)-catalyzed
reaction of an R-diazo carbonyl compound containing an amido group in the γ-position. Treatment
of several N,N-dialkyl-substituted amido diazo-esters with Rh2(OAc)4 in benzene at 80 °C in the
presence of several dienophiles gave [4 + 2]-cycloadducts derived from the Diels-Alder reaction of
a transient R-amino isobenzofuran intermediate. In the absence of an external trapping agent, no
rearranged product derived from an ammonium ylide intermediate could be detected in the crude
reaction mixture. In contrast to this result, reaction of the related diazo dihydroisoquinoline amide
46 with Rh2(OAc)4 afforded the isoindolobenzazepine ring system in high yield. Formation of the
5,7-fused skeleton was rationalized in terms of a spirocyclic ammonium ylide that underwent a
preferential Stevens [1,2]-shift of the benzylic carbon atom. While we were ultimately thwarted in
using the ammonium ylide/rearrangement cascade for a lennoxamine synthesis by an uncooperative
diazo transfer reaction, the cascade sequence was shown to be useful for the preparation of various
isoindolobenzazepines.
Polycyclic nitrogen containing heterocycles form the
pharmacological point of view, since they incorporate
the [3]benzazepine moiety, an important biological phar-
macophore.8
basic skeleton of numerous alkaloids and physiologically
active drugs.1,2 Members of the botanical family Berberi-
daceae are known to be a rich source of alkaloids.3 Recent
studies of the Chilean Berberidaceae plant have provided
the isoindolobenzazepine class of alkaloids isolated from
Chilean barberries.4 These plants were gathered in the
vicinity of Ciudad Osorno, the southernmost region of
Chile. The designation “aporhoeadane” has been applied
to the family, connoting the close chemical kinship of the
isoindolo[1,2-b][3]benzazepines (i.e., 1) with the naturally
occurring rhoeadine and papaverrubine alkaloids.5 This
ring system is biogenetically related to the highly oxi-
dized protoberberine (2) alkaloids.6 Typically, the iso-
indolobenzazepines bear oxygenated substituents on the
benzene ring at positions 2, 3, 9, and 10 (usually two
methoxy groups and a methylenedioxy group).7 Such
structures are interesting from both a synthetic and
Lennoxamine (3) and chilenine (4), isolated from the
Chilean barberries species, represent the first examples
of this interesting class of alkaloids.6 Since their isolation
in 1984, a number of related isoindolobenzazepine natu-
ral products have also been discovered.4 Although mem-
bers of this alkaloid family do not appear to possess any
useful pharmacological activities, their unique structural
features render them attractive synthetic targets. The
ring system, which is accessible in vivo and in vitro by
oxidation of berbine alkaloids,6 has been the object of
several synthetic approaches based on biomimetic path-
ways,9 electrophilic alkylation,10 photochemistry of ena-
mides11 or vinyl azide chemistry.12
* Corresponding author.
(1) (a) Sza´ntay, C.; Blesko, G.; Hongy, K.; Do¨rnyei, G. In The
Alkaloids; Academic: Orlando, 1986; Vol. 27, pp 131-268. (b) Sza´ntay,
C. Pure Appl. Chem. 1990, 62, 1299-1302.
(2) Cordell, G. A. In Heterocyclic Compounds: The Monoterpenoid
Indole Alkaloids; Saxton, J . E., Ed.; Wiley: New York, 1983; Vol. 25,
Part 4, p 539.
(3) Shamma, M.; Rahimizadeh, M. J . Nat. Prod. 1986, 49, 398.
(4) (a) Fajardo, V.; Elango, V.; Cassels, B. K.; Shamma, M. Tetra-
hedron Lett. 1982, 23, 39. (b) Valencia, E.; Freyer, A. J .; Shamma, M.;
Fajardo, V. Tetrahedron Lett. 1984, 25, 599. (c) Valencia, E.; Weiss, I.;
Firdous, S.; Freyer, A. J .; Shamma, M.; Urzu´a, A.; Fajardo, V.
Tetrahedron 1984, 40, 3957.
(5) Shamma, M.; Moniot, J . L. Isoquinoline Alkaloid Research;
Plenum Press: New York, 1978.
(6) (a) Moniot, J . L.; Hindenlang, D. M.; Shamma, M. J . Org. Chem.
1979, 44, 4347. (b) Dorn, C. R.; Koszyk, F. J .; Lenz, G. R. J . Org. Chem.
1984, 49, 2642. (c) Teitel, S.; Klo¨tzer, W.; Borgese, J .; Brossi, A. Can.
J . Chem. 1972, 50, 2022.
(7) Napolitano, E.; Spinilli, G.; Fiaschi, R.; Marsili, A. J . Chem. Soc.,
Perkin Trans. 1 1986, 785.
(8) (a) Weinstock, J .; Hieble, J . P.; Wilson, J . W. Drugs Future 1985,
10, 645. (b) Csende, F.; Szabo, Z.; Stajer, G. Heterocycles 1993, 36, 1809.
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(10) Kessar, S. V.; Singh, T.; Vohra, R. Indian J . Chem. 1991, 30B,
299.
10.1021/jo001684w CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/06/2001

Isoindolobenzazepines
J . Org. Chem., Vol. 66, No. 7, 2001 2415
Sch em e 1
They are also accessible through (a) the cyclization of
2-arylbenzazepine derivatives ortho-substituted with car-
boxylate groups,13 (b) the ring-expansion of isoindolo-
isoquinoline derivatives obtained by cyclization of acyl-
iminium precursors,14 (c) the regioselective 7-endo-trig
radical cyclization of methylenephthalimidines,15 (d)
the Pummerer rearrangement of 3-phenylsulfanyliso-
indolinones followed by intramolecular electrophilic
aromatic substitution and desulfurization,16 and (e) the
reduction/cyclization of 3-arylmethylene-lactams.17
Almost all of the synthetic approaches to lennoxamine
3 involve either the formation of the isoindolinone
Sch em e 2
template or azepine ring system in the final step.18
A
strategy that we have found to be of some importance in
the design of complex alkaloids is to make use of the
tandem metallo-carbenoid generation/ylide rearrange-
ment cascade.19,20 The high efficiency and facility of this
process suggested that this method might also serve as
the basis for a new approach toward lennoxamine. Our
strategy, which is depicted in retrosynthetic Scheme 1,
is based on the Rh(II)-catalyzed reaction of diazoamide
7. This compound could be obtained from the condensa-
tion of amine 5 with the benzoic acid derivative 6 followed
by diazo transfer.21-24 The notion of using 7 as the key
starting material for lennoxamine was particularly
attractive since the transition metal-catalyzed cyclization
reaction was expected to produce the spirocyclic am-
monium ylide 8. A Stevens [1,2]-rearrangement would
then provide the desired isoindolo[1,2-b][3]benzazepine
ring system. In this paper we detail our observations
dealing with the Rh(II)-catalyzed reaction of several
R-diazo carbonyls tethered to both amino and amido
groups as well as the application of the method toward
the synthesis of lennoxamine.
Resu lts a n d Discu ssion
The tandem ammonium ylide generation/rearrange-
ment sequence has been previously used in the prepara-
tion of various nitrogen-containing heterocycles.25
A
typical example involves the ring expansion reaction of
spirocyclic ammonium ylides such as 11 which have been
nicely exploited for the synthesis of a number of alkaloids.
For example, the key step in West and Naidu’s enantio-
selective synthesis of (-)-epilupinine26 involved the
ammonium ylide-Stevens [1,2]-rearrangement of the
L-proline derivative 9 which furnished the advanced
intermediate 12 in 84% yield and with 76% ee. Starting
from a related L-proline derivative 10 (R ) vinyl), Clark
and Hodgson synthesized the partial CE ring system 13
in their approach to the Mazamine A ring skeleton27 via
an ammonium ylide-[2,3]-sigmatropic rearrangement
(Scheme 2).28
(11) Bernhard, H. O.; Snieckus, V. Tetrahedron Lett. 1971, 4867.
(12) Moody, C. J .; Warrellow, G. J . Tetrahedron Lett. 1987, 28, 6089.
(13) Tertel, S.; Klo¨tzer, W.; Borgese, J .; Brossi, A. Can. J . Chem.
1972, 50, 2022.
(14) Koseki, Y.; Kusano, S.; Sakata, H.; Nagasaka, T. Tetrahedron
Lett. 1999, 40, 2169.
(15) Rodriguez, G.; Cid, M.; Saa, C.; Castedo, L.; Dominguez, D. J .
Org. Chem. 1996, 61, 2780.
(16) Ishibashi, H.; Kawanami, H.; Ikeda, M. J . Chem. Soc., Perkin
Trans. 1 1997, 817.
(17) Couture, A.; Deniau, E.; Grandclaudon, P.; Hoarau, C. Tetra-
hedron 2000, 56, 1491.
(18) For an exception, see: Rodriguez, G.; Casedo, L.; Dominguez,
D.; Saa, C. Tetrahedron Lett. 1998, 39, 6551.
(19) (a) Curtis, E. A.; Worsencroft, K. J .; Padwa, A. Tetrahedron Lett.
1997, 38, 3319. (b) Padwa, A.; Brodney, M. A.; Marino, J . P., J r.;
Sheehan, S. M. J . Org. Chem. 1997, 62, 78. (c) Padwa, A.; Price, A. T.
J . Org. Chem. 1998, 63, 556.
Our own investigations of the ammonium ylide cascade
sequence stemmed from an interest in using this strategy
for the assemblage of the 5,7-fused ring framework found
(20) Padwa, A.; Snyder, J . P.; Curtis, E. A.; Sheehan, S. M.;
Worsencroft, K. J .; Kappe, C. O. J . Am. Chem. Soc. 2000, 122, 8155.
(21) (a) Regitz, M. Angew. Chem., Int. Ed. Engl. 1967, 6, 733. (b)
Regitz, M.; Menz, F. Chem. Ber. 1968, 101, 2622. (c) Regitz, M.; Maas,
G. Diazo Compounds, Properties and Synthesis; Academic Press: New
York, 1986.
(22) (a) Taber, D. F.; Ruckle, R. E.; Hennessy, M. J . J . Org. Chem.
1986, 51, 4077. (b) Taber, D. F.; Gleeve, D. M.; Herr, R. J .; Moody, K.;
Hennessy, M. J . J . Org. Chem. 1995, 60, 2283.
(25) (a) Padwa, A.; Hornbuckle, S. F. Chem. Rev. 1991, 91, 263. (b)
Ye, T.; McKervey, A. M. Chem. Rev. 1994, 94, 1901.
(26) (a) West, F. G.; Naidu, B. N. J . Am. Chem. Soc. 1993, 115, 1177.
(b) West, F. G.; Glaeske, K. W.; Naidu, B. N. Synthesis 1993, 977. (c)
Naidu, B. N.; West, F. G. Tetrahedron 1997, 53, 16565.
(27) The Manzamine ring skeleton posseses a complex pentacyclic
core containing 5-, 6-, 8-, and 13-membered rings. For ring notation,
see ref 28.
(28) (a) Clark, J . S.; Hodgson, P. B. J . Chem. Soc., Chem. Commun.
1994, 2701. (b) Clark, J . S.; Hodgson, P. B. Tetrahedron Lett. 1995,
36, 2519. (c) Wright, D. L.; Weekly, R. M.; Groff, R.; McMills, M. C.
Tetrahedron Lett. 1996, 37, 2165.
(23) Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; Park, S. Z. J .
Org. Chem. 1990, 55, 1959.
(24) McGuiness, M.; Shechter, H. Tetrahedron Lett. 1990, 31, 4987.

2416 J . Org. Chem., Vol. 66, No. 7, 2001
Padwa et al.
in cephalotaxine (14).29 Cephalotaxine is the major
alkaloid constituent isolated from Cephalotaxus harring-
tonia,30 an evergreen tree native to Southern China. This
alkaloid is of considerable interest due to the biological
activity of its ester derivatives, harringtonine (HT) and
homoharringtonine (HHT)31 which have been used in the
treatment of certain types of carcinomas.32
Sch em e 3
Our plan was to use the ammonium ylide/rearrange-
ment sequence for the synthesis of the 5,7-fused ring
system found in both cephalotaxine and lennoxamine. We
first carried out some model studies in order to probe the
likelihood of creating the desired skeleton by this method.
Initial feasibility studies were conducted with amino keto
esters 20-23. We prepared diazo keto ester 15 using a
diazo transfer reaction of the corresponding R,â-unsatur-
ated keto ester.33 Addition of 15 to a solution of the
readily available amines 16-19 in CH2Cl2 at 25 °C
afforded the desired amino keto esters 20-23 in 78-96%
yield by conjugate addition. Early attempts at cycliza-
tions using rhodium-based catalyst systems were ob-
served to be sluggish, resulting in complex mixtures of
products due to extended reaction times. Copper catalysis
was found to be a superior alternative for effecting the
desired rearrangement.34 The Cu(acac)2-catalyzed de-
composition of the diazo compounds in toluene at reflux
for 1 h furnished the rearranged 5,7-fused systems 25-
28 in 68-77% yield as a 1:1-mixture of diastereomers.
The formation of these ring-expanded products can be
rationalized by the initial formation of ammonium ylide
24 followed by a preferential Stevens [1,2]-shift of the
benzylic carbon atom.35 Interestingly, in the case of 21,
it was possible to isolate ylide 24 (R ) H) as a white
crystalline solid. Further heating of the ylide in the
absence of the Cu-catalyst cleanly afforded 26 in high
yield. The reaction sequence worked well for both five
(16) and six-membered (17-19) ring amine precursors
leading to tetrahydroisoquinolines (25) or benzazepines
(26-28) (Scheme 3), respectively, which contain the
required fused 5,7-ring system present in many natural
product systems.36
Sch em e 4
delineated in Scheme 1 for the synthesis of lennoxamine
relies on a tandem ammonium ylide/Stevens rearrange-
ment of an appropriately substituted amido diazoester
(i.e., 7). To pursue this approach, it was necessary to first
probe whether the initially formed metallo-carbenoid
would lead to an ammonium ylide or result in isobenzo-
furan formation via a carbonyl ylide intermediate. There
are several reports in the literature where the metal-
induced decomposition of o-(diazomethyl)benzamide de-
rivatives preferentially gave benzannulated quinolines
(Scheme 4).37 Presumably, this reaction sequence involves
the initial formation of an aminoisobenzofuran interme-
diate (i.e., 30) that was trapped intramolecularly with
subsequent elimination of water as shown in Scheme 4.
Recent results from our laboratory have shown that
the Rh(II)-catalyzed reaction of R-diazoesters containing
an amido group in the γ-position can lead to either five-
membered ammonium or carbonyl ylides depending on
the reaction conditions used.20 The metallo-carbenoid
Unlike the cephalotaxine approach that required the
presence of a γ-amino-substituted diazoester, the strategy
(29) Beall, L. S.; Padwa, A. Tetrahedron Lett. 1998, 39, 4159.
(30) (a) Huang, L.; Xue, Z. In The Alkaloids; Brossi, A., Ed.;
Academic Press: New York, 1984; Vol. 23, Chapter 3. (b) Wick-
remesinhe, R. M.; Arteca, R. N. J . Liq. Chrom., Relat. Technol. 1996,
19, 889.
(31) Hudlicky, T.; Kwart, L. D.; Reed, J . W. In Alkaloids. Chemical
and Biological Perspectives; Pelletier, S. W., Ed.; Springer-Verlag: New
York, 1987; Vol. 5, Chapter 5.
(32) (a) Powell, R. G.; Weisleder, D.; Smith, C. R., J r. J . Pharm.
Sci. 1972, 61, 1227. (b) Zhou, D. C.; Zittoun, R.; Marie, J . P. Bull.
Cancer 1995, 82, 987.
(33) Zibuck, R.; Streiber, J . M. J . Org. Chem. 1989, 54, 4717.
(34) For reports regarding the superiority of copper catalysts for
generation of onium ylides, see: (a) West, F. G.; Naidu, B. N.; Tester,
R. W. J . Org. Chem. 1994, 59, 6892. (b) Clark, J . S.; Krowiak, S. A.;
Street, L. J . Tetrahedron Lett. 1993, 34, 4385.
(36) Further studies are currently underway to determine the scope
of the reaction with regard to ring size, ring substitution, catalytic
effects, and its further application to the synthesis of cephalotaxine
and related target molecules.
(37) (a) Peters, O.; Friedrichsen, W. Tetrahedron Lett. 1995, 36,
8581. (b) Bernabe´, P.; Castedo, L.; Dominguez, D. Tetrahedron Lett.
1998, 39, 9785. (c) Sarkar, T. K.; Ghosh, S. K.; Nandy, S. K.; Chow, T.
J . Tetrahedron Lett. 1999, 40, 397. (d) Sarkar, T. K.; Basak, S.; Ghosh,
S. K. Tetrahedron Lett. 2000, 41, 759.
(35) For a similar reaction in the 6,6-system, see: Zaragoza, F.
Synlett 1995, 237.

Isoindolobenzazepines
J . Org. Chem., Vol. 66, No. 7, 2001 2417
Sch em e 5
Sch em e 7
Sch em e 6a
The exclusive formation of isobenzofuran 40 from the
Rh(II)-catalyzed reaction of R-diazo ketoamides 37-39,
while not unprecedented,37 was disappointing for our
planned lennoxamine synthesis. We decided at this point
that the simplest adjustment to our model system would
be to incorporate a tetrahydroisoquinoline skeleton within
the amide moiety. This led us to study the Rh(II)-
catalyzed behavior of the cyclic diazo ketoamide 46, which
is a more accurate model system for lennoxamine. In
stark contrast to the acyclic o-(diazo)-benzamide series,
and for reasons that still remain obscure, the reaction
of 46 with Rh2(OAc)4 afforded the desired isoindolo-
benzazepine ring system in 83% yield. Formation of
the 5,7-fused skeleton can be attributed to the initial
formation of the spirocyclic ammonium ylide 47 followed
by a preferential Stevens [1,2]-shift of the benzylic carbon
atom to give 48 (Scheme 7).
With this encouraging result in hand, we proceeded
to apply this strategy to the synthesis of lennoxamine.
Amide 51 was readily prepared by conversion of the
known carboxylic acid 4940 into the corresponding acid
chloride followed by reaction with tetrahydro-1,2-dioxolo-
[4,5-g]isoquinoline.41 Unfortunately, all of our attempts
to carry out the critical diazo transfer reaction using a
wide variety of literature procedures did not give the
desired diazo amide 52. No tractable product was ever
isolated from these reactions. Attempts to find alternative
methods42 for the diazo transfer were not successful. The
failed diazo transfer of 51 to 52 may be attributed to the
presence of the methoxy group in the 5-position of the
aromatic ring that diminishes the acidity of the benzylic
protons. Diazo transfer reactions are known to be ex-
tremely sensitive to the nature of the substrate. Indeed,
conversion of the related amide 54 (R ) H), which is
devoid of the 5-methoxy group, to the corresponding
amido diazoester 55 proceeded in 88% yield without any
of the difficulties encountered with 51. With amido
diazoester 55 in hand, we carried out the Rh(II)-catalyzed
a
Reagents: (a) (COCl)2; (b) R1NHR2; (c) NaHMDS; (d) MsN3;
(e) DMAD; (f) N-phenylmaleimide.
intermediate generated in these reactions could either
interact with the lone pair of electrons on the amide
nitrogen (ammonium ylide formation) or the lone pair of
electrons on the carbonyl oxygen (carbonyl ylide forma-
tion) (Scheme 5). The experimental observations reflect
a catalyst-promoted system of equilibria with a thermo-
dynamic bias for the ammonium ylide. This chemo-
selectivity issue is important because the key step in
the planned lennoxamine synthesis requires selective
ammonium ylide formation.
To sort out the factors influencing the regiochemistry
of the cyclization, we opted to examine the Rh(II)-
catalyzed behavior of several simple acyclic o-diazo-
benzamides. These N,N-dialkyl-substituted amido diazo-
esters (37-39) were easily prepared from the readily
available carboxylic acid 3638 by the synthetic protocol
shown in Scheme 6. When these substrates were treated
with Rh2(OAc)4 at 80 °C in benzene with dimethyl
acetylenedicarboxylate (DMAD), cycloadducts 41-43 were
obtained in 85-97% yield. With N-phenylmaleimide as
the trapping agent, the ring-opened cycloadduct 44 was
isolated in 65% yield from the Rh(II)-catalyzed reaction
of 39. The formation of these products is easily rational-
ized in terms of a [4 + 2]-cycloaddition39 of an initially
formed amino isobenzofuran intermediate 40 with the
added dienophile. Most importantly, in the absence of an
external trapping agent, no rearranged product (i.e., 45)
derived from an ammonium ylide intermediate could be
detected in the crude reaction mixture. The reaction
mixture contained a significant amount of a dark tar
which resisted characterization.
(40) Scho¨pf, C.; J ack-Tettweiler, I.; Perry-Fehrenbauch, P.; Winter-
halder, L. J ustus Liebigs Ann. Chem. 1940, 77.
(41) Meyers, A. I.; Matulenko, M. A. J . Org. Chem. 1996, 61, 573.
(42) For reviews on diazo transfer reagents, see: (a) Bollinger, F.
W.; Tuma, L. D. Synlett 1996, 406. (b) Khare, A. B.; McKenna, C. E.
Synthesis 1991, 405. (c) Creary, X. Org. Synth. 1985, 64, 207. (d)
Monteiro, H. Synth. Commun. 1987, 17, 983. (e) Hendrickson, J . B.;
Wolff, W. A. J . Org. Chem. 1968, 33, 3610. (f) Cavender, C. J .; Shiner,
V. J . J . Org. Chem. 1972, 37, 3567. (g) Balli, H.; Low, R.; Muller, V.;
Rempfler, H.; Sezen-Gezgin, G. Helv. Chim. Acta 1978, 61, 97. (h)
Kokel, B.; Viehe, H. G. Angew. Chem. 1980, 92, 754. (i) Hazen, G. G.;
Weinstock, L. M.; Connell, R.; Bollinger, F. W. Synth. Commun. 1981,
11, 947. (j) Lombardo, L.; Mander, L. N. Synthesis 1980, 368.
(38) Hutchings, M. G.; Chippendale, A. M.; Ferguson, I. Tetrahedron
1988, 44, 3727.
(39) (a) Friedrichsen, W. Adv. Heterocycl. Chem. 1981, 26, 135. (b)
Hildebrandt, K.; Friedrichsen, W. Heterocycles 1989, 29, 1243.

2418 J . Org. Chem., Vol. 66, No. 7, 2001
Padwa et al.
Sch em e 8a
2-Dia zo-5-(1,3-d ih yd r oisoin d ol-2-yl)-3-oxop en t a n oic
Acid Eth yl Ester (20). Following the general procedure, the
reaction of 0.23 g (2.0 mmol) of 1,3-dihydroisoindole (16) and
diazoester 15 for 1 h gave 0.4 g (78%) of 20 as a pale yellow
oil: IR (neat) 3029, 2933, 2769, 2136, 1717, and 1655 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 1.33 (t, 3H, J ) 7.2 Hz), 3.08-
3.19 (m, 4H), 3.97 (s, 4H), 4.31 (q, 2H, J ) 7.2 Hz), and 7.17
(s, 4H); 13C NMR (CDCl3, 100 MHz) δ 14.3, 39.1, 50.6, 58.9,
61.4, 76.3, 122.2, 126.6, 139.9, 161.2, and 191.4. Anal. Calcd
for C15H17N3O3: C, 62.69; H, 5.97; N, 14.63. Found: C, 62.58;
H, 5.86; N, 14.41.
2-Dia zo-5-(3,4-d ih yd r o-1H-isoqu in olin -2-yl)-3-oxop en -
ta n oic Acid Eth yl Ester (21). Following the general proce-
dure, the reaction of 0.5 g (3.9 mmol) of tetrahydroisoquinoline
(17) and diazoester 15 for 1 h gave 1.0 g (96%) of 21 as a pale
yellow oil: IR (neat) 3065, 2919, 2136, 1717, and 1653 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 1.32 (t, 3H, J ) 7.2 Hz), 2.77 (t,
2H, J ) 6.1 Hz), 2.89-2.93 (m, 4H), 3.16 (t, 2H, J ) 7.2 Hz),
3.67 (s, 2H), 4.28 (q, 2H, J ) 7.2 Hz), and 6.99-7.10 (m, 4H);
13C NMR (CDCl3, 100 MHz) δ 14.2, 28.9, 37.5, 50.6, 52.7, 55.7,
61.2, 76.1, 125.4, 125.9, 126.4, 128.4, 134.0, 134.5, 161.1, and
191.5. Anal. Calcd for C16H19N3O3: C, 63.77; H, 6.36; N, 13.94.
Found: C, 63.89; H, 6.38; N, 13.93.
2-Dia zo-5-(1-m eth yl-3,4-d ih yd r o-1H-isoqu in olin -2-yl)-
3-oxop en t a n oic Acid E t h yl E st er (22). Following the
general procedure, the reaction of 0.35 g (2.3 mmol) of
1-methyltetrahydroisoquinoline (18) and diazoester 15 for 5
h gave 0.5 g (78%) of 22 as a pale yellow oil: IR (neat) 3049,
2971, 2821, 2135, 1712, and 1644 cm-1; 1H NMR (CDCl3, 300
MHz) δ 1.28-1.35 (m, 6H), 2.69-3.20 (m, 8H), 3.90 (q, 1H, J
) 6.6 Hz), 4.30 (q, 2H, J ) 7.1 Hz), and 7.05-7.13 (m, 4H);
13C NMR (CDCl3, 75 MHz) δ 14.4, 19.6, 27.2, 29.2, 37.8, 38.4,
44.5, 49.2, 50.8, 53.0, 56.0, 56.6, 61.4, 76.3, 125.6, 125.7, 125.8,
126.1, 126.6, 127.3, 128.6, 128.8, 134.2, 134.3, 140.3, 161.3,
and 192.0. Anal. Calcd for C17H21N3O3: C, 64.74; H, 6.71; N,
13.32. Found: C, 64.47; H, 6.66; N, 13.26.
a
Reagents: (a) (COCl)2; (b) DBU, TsN3; (c) Rh2(OAc)4.
reaction and were pleased to note that the desired ring
expanded lactam 56 was formed in 75% yield. While we
were ultimately thwarted in using the ammonium ylide/
rearrangement cascade for a lennoxamine synthesis by
an uncooperative diazo transfer reaction, there is no
question that the method has shown its potential for the
synthesis of 5,7-fused nitrogen heterocycles. In one
operation, the isoindolo-benzazepine ring system was
prepared in high yield from readily available starting
materials. Application of this method to the synthesis of
a number of related alkaloids is currently being explored
and will be reported on at a later date.
2-Dia zo-3-oxo-5-(1-p r op en yl-3,4-d ih yd r o-1H-isoqu in o-
lin -2-yl)-p en ta n oic Acid Eth yl Ester (23). Following the
general procedure, the reaction of 1.9 g (11 mmol) of 1-pro-
penyltetrahydroisoquinoline (19) and diazoester 15 for 12 h
gave 3.0 g (82%) of 23 as a pale yellow oil: IR (neat) 3018,
2911, 2805, 2129, 1716, and 1652 cm-1; 1H NMR (CDCl3, 300
MHz) δ 1.33 (t, 3H, J ) 7.1 Hz), 1.75 (d, 1H, J ) 6.2 Hz), 1.87
(d, 2H, J ) 6.7 Hz), 2.55-3.25 (m, 8H), 4.05 (d, 0.67H, J ) 8.6
Hz), 4.29 (q, 2H, J ) 7.1 Hz), 4.45 (d, 0.33H, J ) 9.8 Hz), 5.37-
5.45 (m, 1H), 5.66-5.83 (m, 1H), and 7.01-7.12 (m, 4H); 13C
NMR (CDCl3, 75 MHz) δ 13.6, 14.5, 17.9, 29.2, 29.7, 37.7, 37.8,
46.8, 47.7, 49.5, 49.7, 59.6, 61.4, 65.6, 76.2, 125.5, 125.7, 126.1,
126.8, 127.7, 128.4, 128.7, 129.1, 132.2, 132.3, 134.6, 134.7,
137.3, 137.5, 161.4, and 192.1. Anal. Calcd for C19H23N3O3: C,
66.84; H, 6.79; N, 12.31. Found: C, 66.84; H, 6.84; N, 12.24.
1-Oxo-2,3,5,10-tetr ah ydr o-1H-pyr r olo[1,2-b]isoqu in olin e-
10a -ca r boxylic Acid Eth yl Ester (25). A 0.1 g (0.35 mmol)
sample of 2-diazo-5-(1,3-dihydroisoindol-2-yl)-3-oxopentanoic
acid ethyl ester (20) and 0.05 g of Cu(acac)2 in 10 mL of xylene
was heated at reflux for 15 min to give 0.06 g (68%) of 25 as
a pale yellow solid after silica gel chromatography: mp 85-
Exp er im en ta l Section
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 argon. 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 other-
wise. All solids were recrystallized from ethyl acetate/hexane
for analytical data.
2-Dia zo-3-oxo-p en t-4-en oic Acid Eth yl Ester (15). To a
solution of 3.2 g (22 mmol) of 3-oxo-pent-4-enoic acid ethyl
ester,33 2.7 g (22 mmol) of mesyl azide, and 100 mL of CH2Cl2
at 0 °C was added dropwise 6.3 mL (45 mmol) of Et3N. After
the addition was complete, the solution was allowed to warm
to room temperature and was stirred for 2 h. The solvent was
removed under reduced pressure, and the residue was sub-
jected to flash silica gel chromatography to give 2.3 g (61%) of
15 as a yellow oil: IR (neat) 2983, 2137, 1717, 1650, and 1606
87 °C; IR (neat) 2980, 2927, 2851, 1761, and 1729 cm-1 1H
;
NMR (CDCl3, 400 MHz) δ 1.16 (t, 3H, J ) 7.2 Hz), 2.50-2.70
(m, 2H), 2.87 (d, 1H, J ) 15.9 Hz), 3.25 (dt, 1H, J ) 10.6 and
4.1 Hz), 3.38-3.48 (m, 2H), 4.01 (d, 1H, J ) 15.3 Hz), 4.11 (q,
2H, J ) 7.2 Hz), 4.17 (d, 1H, J ) 15.3 Hz), and 7.06-7.16 (m,
4H); 13C NMR (CDCl3, 100 MHz) δ 14.1, 32.1, 35.8, 46.9, 50.2,
61.4, 70.1, 126.1, 126.4, 126.5, 129.2, 132.3, 133.4, 168.8, and
209.8. Anal. Calcd for C15H17NO3: C, 69.48; H, 6.61; N, 5.40.
Found: C, 69.41; H, 6.58; N, 5.33.
cm-1; H NMR (CDCl3, 300 MHz) δ 1.34 (t, 3H, J ) 7.0 Hz),
1
4.30 (q, 2H, J ) 7.0 Hz), 5.73 (dd, 1H, J ) 10.4 and 1.7 Hz),
6.44 (dd, 1H, J ) 17.1 and 1.7 Hz), and 7.38-7.47 (m, 1H);
13C NMR (CDCl3, 75 MHz) δ 14.2, 61.4, 128.1, 128.2, 131.4,
160.9, and 181.6. Anal. Calcd for C7H8N2O3: C, 50.00; H, 4.80;
N, 16.66. Found: C, 49.79; H, 4.70; N, 16.36.
1-Oxo-2,3,6,11-tetr a h yd r o-1H,5H-ben zo[d ]p yr r olo[1,2-
a ]a zep in e-11a -ca r boxylic Acid Eth yl Ester (26). A 0.3 g
(1.0 mmol) sample of 2-diazo-5-(3,4-dihydro-1H-isoquinolin-2-
yl)-3-oxopentanoic acid ethyl ester (21) and 0.07 g of Cu(acac)2
in 10 mL of xylene was heated at reflux for 15 min to give 0.2
g (73%) of 26 as a pale yellow oil: IR (neat) 3023, 2933, 2856,
Gen er a l P r oced u r e for Con ju ga te Ad d ition Rea ction .
To a 0.1 M solution of the appropriate amine in CH2Cl2 was
added dropwise 0.9 equiv of 2-diazo-3-oxo-pent-4-enoic acid
ethyl ester (15) as a solution in CH2Cl2. After the reaction was
complete, the solvent was removed under reduced pressure,
and the crude product was purified by flash silica gel chro-
matography.
1764, and 1726 cm-1 1H NMR (CDCl3, 400 MHz) δ 1.08 (t,
;
3H, J ) 7.2 Hz), 2.43-2.58 (m, 2H), 2.75-2.81 (m, 1H), 3.00
(d, 1H, J ) 14.3 Hz), 3.04-3.11 (m, 2H), 3.22-3.43 (m, 3H),

Isoindolobenzazepines
J . Org. Chem., Vol. 66, No. 7, 2001 2419
3.46 (d, 1H, J ) 14.3 Hz), 3.94 (q, 2H, J ) 7.2 Hz), and 7.07-
7.18 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ 14.1, 34.9, 36.0,
40.6, 47.4, 48.5, 60.9, 73.3, 126.2, 126.9, 129.0, 130.9, 136.0,
141.3, 167.4, and 208.3. Anal. Calcd for C16H19NO3: C, 70.31;
H, 7.01; N, 5.12. Found: C, 70.37; H, 7.01; N, 5.10.
Dia zo-(2-d ieth ylca r ba m oylp h en yl)a cetic Acid Meth yl
Ester (37). To a stirred solution of 0.5 g (2.0 mmol) of the
above amido ester in 5 mL of THF at -78 °C was added 2.4
mL (2.4 mmol) of a 1.0 M THF solution of lithium bis-
(trimethylsilyl) amide dropwise over a 20 min period. The
mixture was stirred at -78 °C for 1 h, and 0.5 g (2.2 mmol) of
MsN3 in 7 mL of THF was added in one portion. The solution
was stirred at -78 °C for 1 h, warmed to room temperature,
and stirred at room temperature for an additional 3 h. The
mixture was quenched with 30 mL of a phosphate buffer
solution (pH ) 7.0) and extracted with CH2Cl2. The combined
organic extracts were washed with 50 mL of a saturated NaCl
solution, dried over Na2SO4, and filtered, and the solvent was
removed under reduced pressure. The crude residue was
purified by flash chromatography on silica gel to afford 0.18 g
(40%) of 37 as a pale yellow oil which was used in the next
step without further purification; IR (neat) 2096, 1744, 1704,
11-Met h yl-1-oxo-2,3,6,11-t et r a h yd r o-1H ,5H -b en zo[d ]-
p yr r olo[1,2-a ]a zep in e-11a -ca r boxylic Acid Eth yl Ester
(27). A 0.5 g (1.6 mmol) sample of 2-diazo-5-(1-methyl-3,4-
dihydro-1H-isoquinolin-2-yl)-3-oxopentanoic acid ethyl ester
(22) and 0.08 g of Cu(acac)2 in 10 mL of xylene was heated at
reflux for 1 h to give 27 as a 1:1-mixture of diastereomers.
The two diastereomers were separated by silica gel chroma-
tography. The first fraction contained 0.17 g (37%) of a white
solid, mp 63-65 °C; IR (neat) 3060, 2977, 2934, 2856, 1762,
1
and 1719 cm-1; H NMR (CDCl3, 300 MHz) δ 1.0 (t, 3H, J )
7.2 Hz), 1.17 (d, 3H, J ) 7.2 Hz), 2.45-2.50 (m, 2H), 2.61-
2.67 (m, 1H), 3.04-3.11 (m, 1H), 3.28-3.49 (m, 4H), 3.76 (q,
1H, J ) 7.2 Hz), 3.80-3.94 (m, 2H), and 7.00-7.21 (m, 4H);
13C NMR (CDCl3, 75 MHz) δ 14.0, 14.8, 36.3, 36.8, 46.0, 48.7,
49.0, 60.9, 78.1, 126.4, 126.6, 130.9, 131.5, 139.9, 141.7, 167.8,
and 210.3. Anal. Calcd for C17H21NO3: C, 71.06; H, 7.37; N,
4.87. Found: C, 71.22; H, 7.26; N, 4.75.
1631, and 1153 cm-1 1H NMR (CDCl3, 400 MHz) δ 1.05 (t,
;
3H, J ) 6.8 Hz), 1.25 (t, 3H, J ) 6.8 Hz), 3.16-3.18 (m, 2H),
3.20-3.30 (m, 2H), 3.81 (s, 3H), 7.29 (dd, 1H, J ) 7.6 and 1.2
Hz), 7.34 (td, 1H, J ) 7.6 and 1.2 Hz), 7.42 (td, 1H, J ) 7.6
and 1.6 Hz), and 7.51-7.53 (m, 1H); 13C NMR (CDCl3, 100
MHz) δ 12.6, 13.7, 38.8, 42.8, 52.1, 52.9, 126.9, 128.2, 129.2,
130.6, 131.3, 136.6, 169.4 and 171.2.
The other diastereomer was also isolated as a white solid,
mp 65-67 °C; IR (neat) 3061, 2979, 2932, 2854, 1761, and 1721
cm-1; H NMR (CDCl3, 300 MHz) δ 1.10 (t, 3H, J ) 7.1 Hz),
8-Diet h yl-11-oxa -t r icyclo[6.2.1.02,7]u n d eca -2(7),3,5,9-
tetr a en e-1,9,10-tr ica r boxylic Acid Tr im eth yl Ester (41).
To a stirred solution of 0.05 g (0.18 mmol) of diazoester 37 in
10 mL of benzene were added 0.03 mL (0.27 mmol) of dimethyl
acetylenedicarboxylate and 2 mg of rhodium(II) acetate, and
the mixture was heated at reflux for 2 h. The mixture was
cooled to room temperature, and the solvent was removed
under reduced pressure. Purification of the crude residue by
flash chromatography on silica gel gave 0.03 g (44%) of 41 as
a yellow oil; IR (neat) 1740, 1734, 1703, 1235, 1155, and 1057
cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.14-1.25 (m, 6H), 3.15-
3.21 (m, 2H), 3.63 (s, 3H), 3.75 (s, 6H), 3.87 (d, 1H, J ) 6.4
Hz), 3.93 (d, 1H, J ) 6.4 Hz), and 7.43-8.23 (m, 4H); 13C NMR
(CDCl3, 100 MHz) δ 13.1, 16.5, 29.6, 44.8, 45.8, 50.6, 52.8, 53.3,
82.8, 126.1, 126.2, 126.5, 127.2, 127.3, 130.1, 134.2, 153.7,
166.1, 166.8, and 168.3. Anal. Calcd for C20H23NO7: C, 61.67;
H, 5.96; N, 3.60. Found: C, 61.58; H, 5.79; N, 3.62.
1
1.55 (d, 3H, J ) 7.4 Hz), 2.50 (t, 2H, J ) 6.7 Hz), 2.66 (dd, 1H,
J ) 13.7 and 5.4 Hz), 3.08-3.21 (m, 2H), 3.33-3.48 (m, 3H),
3.71 (q, 1H, J ) 7.4 Hz), 3.86-4.03 (m, 2H), and 7.05-7.23
(m, 4H); 13C NMR (CDCl3, 75 MHz) δ 14.1, 16.5, 33.4, 35.2,
39.5, 46.3, 48.7, 61.0, 75.2, 126.4, 126.8, 127.9, 128.8, 140.8,
141.1, 167.6, and 207.2. Anal. Calcd for C17H21NO3: C, 71.06;
H, 7.37; N, 4.87. Found: C, 71.10; H, 7.35; N, 4.95.
1-Oxo-11-p r op en yl-2,3,6,11-tetr a h yd r o-1H,5H-ben zo[d ]-
p yr r olo[1,2-a ]a zep in e-11a -ca r boxylic Acid Eth yl Ester
(28). A 3.0 g (8.8 mmol) sample of 2-diazo-3-oxo-5-(1-propenyl-
3,4-dihydro-1H-isoquinolin-2-yl)-pentanoic acid ethyl ester (23)
and 0.1 g of Cu(acac)2 in 10 mL of toluene was heated at reflux
for 1 h to give 2.1 g (77%) of 28 as a yellow solid after silica
gel chromatography: mp 69-71 °C; IR (neat) 3059, 2979, 2933,
2854, 1763, and 1720 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.98-
1.27 (m, 3H), 1.58 (d, 1H, J ) 6.5 Hz), 1.70 (dd, 1H, J ) 6.8
and 1.6 Hz), 2.41-2.74 (m, 4H), 2.97-3.14 (m, 1H), 3.27-3.48
(m, 4H), 3.83-4.16 (m, 2H), 4.28 (d, 0.5H, J ) 6.6 Hz), 4.59
(d, 0.5H, J ) 9.5 Hz), 5.25-5.35 (m, 0.5H), 5.45-5.55 (m,
0.5H), 5.64-5.71 (m, 0.5H), 6.00-6.08 (m, 0.5H), and 7.00-
7.23 (m, 4H); 13C NMR (CDCl3, 75 MHz) δ 13.3, 13.9, 18.0,
35.8, 36.0, 36.6, 36.8, 48.6, 48.7, 48.9, 49.0, 54.5, 60.8, 77.5,
77.9, 126.0, 126.1, 126.2, 126.4, 126.5, 126.7, 127.7, 127.9,
130.6, 130.7, 131.6, 131.9, 139.3, 139.7, 139.9, 140.1, 167.3,
167.5, 208.9, and 209.3. Anal. Calcd for C19H23NO3: C, 72.82;
H, 7.40; N, 4.47. Found: C, 72.71; H, 7.36; N, 4.40.
[2-(Ben zylm eth ylca r ba m oyl)p h en yl]a cetic Acid Meth -
yl Ester . To a stirred solution of 5.0 g (26 mmol) of carboxylic
acid 36 in 125 mL of CH2Cl2 were added 6.8 mL (78 mmol) of
oxalyl chloride and two drops of DMF. The mixture was stirred
at room temperature for 2 h, and the solvent and excess oxalyl
chloride were removed under reduced pressure. The crude acid
chloride was dissolved in 15 mL of CH2Cl2, and this was added
to a solution of 5.2 mL (65 mmol) of N-benzylmethylamine in
125 mL of CH2Cl2 at 0 °C. The reaction mixture was allowed
to warm to room temperature and was stirred for an additional
2 h. The mixture was quenched with 150 mL of water, the
organic layer was separated, washed with a saturated NaCl
solution, dried over anhydrous MgSO4, and filtered, and the
solvent was removed under reduced pressure. Purification of
the crude residue by flash chromatography on silica gel
gave 4.1 g (53%) of the title compound as a pale yellow oil;
(2-Dieth ylca r ba m oylp h en yl)a cetic Acid Meth yl Ester .
To a stirred solution of 5.0 g (26 mmol) of carboxylic acid 3620
in 125 mL of CH2Cl2 were added 4.5 mL (52 mmol) of oxalyl
chloride and two drops of DMF. The mixture was stirred at
room temperature for 2 h, and the solvent and excess oxalyl
chloride were removed under reduced pressure. The crude acid
chloride was dissolved in 10 mL of CH2Cl2, and this was added
to a solution of 6.7 mL (65 mmol) of diethylamine in 125 mL
of CH2Cl2 at 0 °C. The reaction was allowed to warm to room
temperature and was stirred for an additional 24 h. The
mixture was quenched with 100 mL of water and the organic
layer was separated and washed with 100 mL of a 10% HCl
solution, 100 mL of a saturated NaHCO3 solution, and 100
mL of a saturated NaCl solution. The solution was dried over
anhydrous MgSO4, filtered, and the solvent was removed
under reduced pressure. The crude residue was chromato-
graphed on silica gel to give 3.8 g (60%) of the title compound
as a pale yellow oil; IR (neat) 3061, 2967, 1737, 1630, and 1603
IR (neat) 1737, 1635, 1600, 1265, 1170, and 1068 cm-1 1H
;
NMR (CDCl3, 400 MHz) δ 2.77 (s, 3H), 3.58 (s, 3H), 3.80 (s,
2H), 4.76 (s, 2H), and 7.17-7.37 (m, 9H); 13C NMR (CDCl3,
100 MHz) δ 36.4, 38.1, 50.3, 51.9, 126.4, 126.8, 127.1, 127.5,
128.3, 128.6, 128.8, 129.1, 129.3, 131.1, 136.6, 136.9, 170.8,
and 171.6; HRMS Calcd for C18H19NO3: 297.1364. Found:
297.1365.
[2-(Ben zylm eth ylca r ba m oyl)p h en yl]d ia zoa cetic Acid
Meth yl Ester (38). To a stirred solution of 0.5 g (1.6 mmol)
of the above amido ester in 15 mL of THF at -78 °C was added
1.9 mL (1.9 mmol) of a 1.0 M THF solution of sodium
bis(trimethylsilyl)amide dropwise over a 20 min period. The
mixture was stirred at -78 °C for 1 h, and 0.2 mL (1.9 mmol)
of mesyl azide in 1 mL of THF was added in one portion. The
solution was stirred at -78 °C for 2 h, warmed to room
temperature, and stirred for an additional 2 h. The mixture
was quenched with 30 mL of a phosphate buffer solution (pH
) 7.0) and extracted with CH2Cl2. The combined organic
1
cm-1; H NMR (CDCl3, 400 MHz) δ 1.08 (t, 3H, J ) 7.2 Hz),
1.23 (t, 3H, J ) 7.2 Hz), 3.13-3.18 (m, 2H), 3.67 (s, 3H), 3.72-
3.88 (m, 4H), and 7.20-7.36 (m, 4H); 13C NMR (CDCl3, 100
MHz) δ 12.5, 13.8, 37.9, 38.6, 42.8, 51.9, 125.6, 126.9, 128.8,
130.8, 137.2, 170.1, and 171.6; HRMS Calcd for C14H19NO3:
249.3124. Found: 249.3124.

2420 J . Org. Chem., Vol. 66, No. 7, 2001
Padwa et al.
extracts were washed with a saturated NaCl solution, dried
over Na2SO4, and filtered, and the solvent was removed under
reduced pressure. The crude residue was purified by flash
chromatography on silica gel to give 0.3 g (63%) of 38 as a
pale yellow oil which was used in the next step without further
purification; IR (neat) 2103, 1744, 1631, 1697, 1598, and 1199
8-(Met h ylp h en yla m in o)-11-oxa -t r icyclo[6.2.1.02,7]u n -
d eca -2(7),3,5,9-t et r a en e-1,9,10-t r ica r b oxylic Acid Tr i-
m eth yl Ester (43). To a stirred solution of 0.05 g (0.16 mmol)
of diazo amido-ester 39 in 10 mL of benzene were added 0.03
mL (0.24 mmol) of dimethyl acetylenedicarboxylate and 2 mg
of rhodium(II) acetate, and the reaction was heated at reflux
for 24 h. The mixture was cooled to room temperature, and
the solvent was removed under reduced pressure. Purification
of the crude residue by flash chromatography on silica gel gave
0.06 g (94%) of 43 as a pale yellow solid; mp 185-186 °C; IR
(neat) 1747, 1734, 1633, 1593, 1216, and 1176 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 3.46 (brs, 3H), 3.84 (s, 3H), 3.97 (s, 3H),
1
cm-1; H NMR (CDCl3, 400 MHz) δ 2.78 (s, 3H), 3.71 (s, 3H),
4.72 (d, 1H, J ) 14.8 Hz), 4.85 (d, 1H, J ) 14.8 Hz), and 7.18-
7.49 (m, 9H); 13C NMR (CDCl3, 100 MHz) δ 36.5, 50.4, 52.9,
61.7, 126.8, 127.6, 127.7, 127.9, 128.3, 128.4, 128.7, 128.8,
128.9, 129.7, 136.3, 136.6, 169.4, and 169.8.
8-(Ben zylm et h yla m in o)-11-oxa -t r icyclo[6.2.1.02,7]u n -
d eca -2(7),3,5,9-t et r a en e-1,9,10-t r ica r b oxylic Acid Tr i-
m eth yl Ester (42). To a stirred solution of 0.05 g (0.15 mmol)
of diazo amido-ester 38 in 10 mL of benzene were added 0.03
mL (0.2 mmol) of dimethyl acetylenedicarboxylate and 2 mg
of rhodium(II) perfluorobutyrate, and the reaction mixture was
heated at reflux for 24 h. The mixture was cooled to room
temperature, and the solvent was removed under reduced
pressure. The crude residue was purified by flash chromatog-
raphy on silica gel to provide 0.06 g (97%) of 42 as a clear oil;
4.03 (brs, 3H), 6.96-7.19 (m, 8H), and 7.43-7.49 (m, 1H); 13
C
NMR (CDCl3, 100 MHz) δ 37.8, 52.6, 53.4, 53.5, 62.6, 126.3,
126.7, 128.3, 129.1, 129.5, 130.2, 130.5, 131.0, 135.4, 139.3,
143.7, 158.9, 160.4, 167.5, and 168.8. Anal. Calcd for C23H21NO7:
C, 65.24; H, 5.00; N, 3.31. Found: C, 65.16; H, 4.86; N, 3.35.
4-Hyd r oxy-9-(m eth ylp h en yla m in o)-1,3-d ioxo-2-p h en yl-
2,3,3a ,4-t et r a h yd r o-1H -b en zo[f]isoin d ole-4-ca r b oxylic
Acid Met h yl E st er (44). To a stirred solution of 0.05 g
(0.16 mmol) of diazo amido-ester 39 in 10 mL of benzene were
added 0.04 g (0.24 mmol) of N-phenylmaleimide and 2 mg of
rhodium(II) perfluorobutyrate, and the reaction was heated
at reflux for 48 h. The mixture was cooled to room tempera-
ture, and the solvent was removed under reduced pressure.
Purification of the crude residue by flash chromatography on
silica gel gave 0.05 g (65%) of the ring opened cycloadduct 44
IR (neat) 1754, 1735, 1634, 1602, 1221, 1177, and 1063 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 2.66 (s, 3H), 3.81 (s, 3H), 3.96
(s, 3H), 3.97 (s, 3H), 4.51 (d, 1H, J ) 14.4 Hz), 4.76 (d, 1H, J
) 14.4 Hz), and 7.01-7.57 (m, 9H); 13C NMR (CDCl3, 100 MHz)
δ 32.9, 36.6, 50.4, 52.7, 53.5, 62.9, 126.1, 126.5, 126.9, 127.5,
128.2, 128.6, 129.3, 129.8, 130.0, 130.4, 135.9, 136.5, 139.6,
158.6, 160.2, 167.4, 169.5, and 170.2. Anal. Calcd for C24H23NO7:
C, 65.88; H, 5.30; N, 3.20. Found: C, 65.72; H, 5.29; N, 3.02.
[2-(Meth ylp h en ylca r ba m oyl)p h en yl]a cetic Acid Meth -
yl Ester . To a stirred solution of 5.0 g (26 mmol) of carboxylic
acid 36 in 125 mL of CH2Cl2 were added 4.5 mL (52 mmol) of
oxalyl chloride and two drops of DMF. The mixture was stirred
at room temperature for 2 h, and the solvent and excess oxalyl
chloride were removed under reduced pressure. The crude acid
chloride was dissolved in 15 mL of CH2Cl2, and this was added
to a solution of 7.0 mL (65 mmol) of N-methylaniline in 125
mL of CH2Cl2 at 0 °C. The reaction was allowed to warm to
room temperature and was stirred at room temperature for
an additional 18 h. The mixture was quenched with 100 mL
of water, the organic layer was separated and washed with
150 mL of a 10% HCl solution, 150 mL of a saturated NaHCO3
solution, and 150 mL of a saturated NaCl solution, dried over
anhydrous MgSO4, and filtered, and the solvent was removed
under reduced pressure. The crude residue was purified by
flash chromatography on silica gel to give 3.8 g (51%) of the
titled compound as a yellow oil; IR (neat) 1735, 1646, 1595,
1215, 1164, and 1031 cm-1; 1H NMR (CDCl3, 400 MHz) δ 3.48
(brs, 3H), 3.73 (s, 3H), 3.88 (s, 2H), 6.96 (brs, 2H), and 7.06-
7.21 (m, 7H); 13C NMR (CDCl3, 100 MHz) δ 37.6, 38.4, 51.9,
126.1, 126.3, 128.6, 128.8, 128.9, 130.8, 132.3, 135.5, 144.0,
169.9, and 171.7; HRMS Calcd for C17H17NO3: 283.1208.
Found: 283.1208.
as a pale yellow oil: IR (neat) 1709, 1649, 1595, and 1201 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 3.55 (s, 3H), 3.85 (s, 3H), 5.31
(s, 1H), 5.74 (brs, 1H), and 6.84-7.52 (m, 14H); 13C NMR
(CDCl3, 100 MHz) δ 29.7, 38.2, 53.2, 57.8, 61.9, 87.9, 125.8,
126.2, 126.8, 127.2, 127.8, 128.7, 128.9, 129.2, 130.1, 131.2,
131.8, 133.6, 134.3, 139.0, 146.9, 166.2, 167.7, and 169.8. Anal.
Calcd for C27H22N2O5: C, 71.34; H, 4.88; N, 6.17. Found: C,
71.25; H, 4.87; N, 6.09.
[2-(3,4-Dih yd r o-1H -isoq u in olin e-2-ca r b on yl)p h en yl]-
a cetic Acid Meth yl Ester . To a stirred solution of 10 g (52
mmol) of carboxylic acid 36 in 150 mL of THF was added 8.4
g (52 mmol) of carbonyl diimidazole. The reaction mixture was
stirred at room temperature for 1 h, and 6.5 mL (52 mmol) of
1,2,3,4-tetrahydroisoquinoline was added. The mixture was
stirred at room temperature for an additional 18 h. The solvent
was removed under reduced pressure, and the residue was
dissolved in 200 mL of ether and consecutively washed with
100 mL of a 10% HCl solution, 100 mL of a saturated NaHCO3,
100 mL of water, and a saturated NaCl solution. The combined
organic extracts were dried over MgSO4 and filtered, and the
solvent was removed under reduced pressure. The crude
residue was purified by flash chromatography on silica gel to
give 13 g (82%) of the titled compound as a yellow oil which
consisted of a 1:1 mixture of rotomers; IR (neat) 1735, 1633,
1602, 1259, 1158, and 1005 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 2.77 (brs, 2H), 2.90 (brs, 2H), 3.21 (s, 3H), 3.46-3.52 (m,
4H), 3.57 (s, 3H), 3.62-3.95 (m, 4H), 4.40 (s, 2H), 4.62-5.01
Dia zo-[2-(m eth ylp h en ylca r ba m oyl)p h en yl]a cetic Acid
Meth yl Ester (39). To a stirred solution of 2.0 g (7.1 mmol)
of the above amido ester in 45 mL of THF at -78 °C was added
7.8 mL (7.8 mmol) of a 1.0 M THF solution of sodium
bis(trimethyl-silyl)amide dropwise over a 30 min period. The
mixture was stirred at -78 °C for 1 h, and 1.0 mL (7.8 mmol)
of mesyl azide in 2 mL of THF was added in one portion. The
solution was stirred at -78 °C for 2 h, warmed to room
temperature, and stirred at room temperature for an ad-
ditional 2 h. The mixture was quenched with 50 mL of a
phosphate buffer solution (pH ) 7.0) and extracted with
CH2Cl2. The combined organic extracts were washed with a
saturated NaCl solution, dried over Na2SO4, and filtered,
and the solvent was removed under reduced pressure. The
crude residue was purified by flash chromatography on silica
gel to afford 1.0 g (47%) of 39 as a yellow oil which was used
in the next step without further purification; IR (neat) 2108,
1743, 1635, 1594, 1203, 1115, and 1007 cm-1; 1H NMR (CDCl3,
400 MHz) δ 3.53 (brs, 3H), 3.82 (s, 3H), and 6.96-7.35 (m,
9H); 13C NMR (CDCl3, 100 MHz) δ 37.6, 52.8, 61.6, 126.5,
126.7, 127.7, 127.9, 128.1, 129.0, 129.4, 132.7, 135.7, 143.8,
168.9, and 169.6.
(m, 2H), 6.82 (d, 1H, J ) 7.6 Hz), and 7.06-7.34 (m, 15H); 13
C
NMR (CDCl3, 100 MHz) δ 28.3, 29.2, 37.9, 38.0, 39.7, 44.2,
44.7, 49.0, 51.5, 51.8, 125.8, 125.9, 126.1, 126.2, 126.4, 126.5,
127.0, 128.4, 128.7, 129.1, 129.2, 131.0, 131.1, 131.4, 131.5,
132.6, 132.7, 133.8, 134.3, 136.2, 136.3, 169.4, 169.4, 171.2,
and 171.6; HRMS Calcd for C19H19NO3: 309.1365. Found:
309.1365.
Diazo-[2-(3,4-dih ydr o-1H-isoqu in olin e-2-car bon yl)ph en -
yl]a cetic Acid Meth yl Ester (46). To a stirred solution of
0.5 g (1.6 mmol) of the above amido-ester 50 in 15 mL of
acetonitrile was added 0.8 mL (5.3 mmol) of 1,8-diazabicyclo-
[5.4.0]undec-7-ene followed by 0.9 mL (6.0 mmol) of p-toluene-
sulfonyl azide. After stirring for 48 h in the dark at room
temperature, another 0.25 mL (1.6 mmol) of p-toluenesulfonyl
azide was added. The reaction was stirred for an additional
24 h and concentrated under reduced pressure. The crude
residue was purified by flash chromatography on silica gel to
give 0.44 g (85%) of 46 as a yellow oil that consisted of a 1:1
mixture of rotomers and which was used in the next step
without further purification; IR (neat) 2106, 1740, 1633, 1606,
1260, 1206, and 1013 cm-1; 1H NMR (CDCl3, 400 MHz) δ 2.77-

Isoindolobenzazepines
J . Org. Chem., Vol. 66, No. 7, 2001 2421
2.99 (m, 4H), 3.44-3.74 (m, 10H), 4.27-4.30 (m, 1H), 4.40 (s,
1H), 4.61-4.68 (m, 1H), 4.95-5.05 (m, 1H), 6.81-6.83 (m, 1H),
and 7.09-7.53 (m, 15H); 13C NMR (CDCl3, 100 MHz) δ 28.1,
29.0, 39.6, 44.2, 44.5, 48.8, 51.7, 51.8, 122.5, 122.8, 125.7, 125.9,
126.2, 126.3, 126.4, 126.5, 127.0, 127.4, 127.6, 127.9, 128.3,
128.7, 129.3, 129.4, 129.5, 129.8, 132.3, 132.3, 133.6, 134.1,
134.8, 165.2, 165.4, 168.2, and 169.2.
5-Oxo-8,13-d ih yd r o-5H ,7H -b en zo[4,5]a zep in o[2,1-a ]-
isoin d ole-13a -ca r boxylic Acid Meth yl Ester (48). To a
refluxing solution of 0.01 g of rhodium(II) acetate in 200 mL
of toluene was added 0.8 g (2.5 mmol) of diazoester 46 in 50
mL of toluene dropwise over a 30 min period. The mixture was
heated at reflux for 1 h and cooled to room temperature. The
solvent was removed under reduced pressure, and the crude
residue was subjected to flash chromatography on silica gel
to give 0.27 g (35%) of 48 as a yellow oil; IR (neat) 3024, 2951,
1740, and 1694 cm-1; 1H NMR (CDCl3, 400 MHz) δ 2.84-3.03
(m, 2H), 3.07-3.10 (m, 1H), 3.25-3.32 (m, 1H), 3.55 (s, 3H),
3.75-3.79 (m, 1H), 4.81-4.87 (m, 1H), 7.15-7.30 (m, 4H), and
7.59-7.95 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ 35.7, 39.5,
44.9, 52.6, 70.4, 122.3, 123.8, 126.7, 127.7, 129.3, 129.4, 130.9,
131.2, 132.0, 134.4, 141.3, 143.5, 167.2, and 169.2. Anal. Calcd
for C19H17NO3: C, 74.24; H, 5.58; N, 4.56. Found: C, 74.13;
H, 5.66; N, 4.31.
[2-(7,8-Dih yd r o-5H -[1,3]d ioxolo[4,5-g]isoq u in olin e -
6-ca r b on yl)-3,4-d im et h oxyp h en yl]a cet ic Acid Met h yl
Ester (51). To a stirred solution of 0.5 g (1.9 mmol) of
carboxylic acid 4940 in 5 mL of CH2Cl2 were added 0.3 mL (3.9
mmol) of oxalyl chloride and two drops of DMF. The mixture
was stirred at room temperature for 2 h, and the solvent and
excess oxalyl chloride were removed under reduced pressure.
The crude acid chloride was dissolved in 10 mL of CH2Cl2, and
0.5 g (3.9 mmol) of DMAP was added. The mixture was stirred
at room temperature for 15 min, 0.4 g (1.9 mmol) of amine
5041 was added, and the solution was heated at reflux for 18
h. The reaction mixture was cooled to room temperature,
quenched with 35 mL of a saturated NaHCO3 solution, and
extracted with CH2Cl2. The combined organic extracts were
washed with a saturated NaCl solution, dried over Na2SO4,
and filtered, and the solvent was removed under reduced
pressure. The crude residue was purified by flash chromatog-
raphy on silica gel to give 0.45 g (60%) of 51 as a pale yellow
solid which consisted of a 1:1 mixture of rotomers; mp 139-
141 °C; IR (neat) 1745, 1650, 1556, 1272, 1252, 1029, and 1002
cm-1; 1H NMR (CDCl3, 400 MHz) δ 2.58-2.66 (m, 1H), 2.80-
2.87 (m, 3H), 3.32 (s, 2H), 3.35-3.52 (m, 2H), 3.62 (s, 2H),
3.64-3.72 (m, 2H), 3.77-3.81 (m, 6H), 3.88-3.90 (m, 6H),
3.97-4.06 (m, 6H), 4.12-4.35 (m, 2H), 4.69-4.71 (d, 1H, J )
17.4 Hz), 4.92-4.97 (d, 1H, J ) 17.4 Hz), 5.87 (dd, 2H, J )
3.2 and 1.6 Hz), 5.92 (s, 2H), 6.37 (s, 1H), 6.56 (s, 1H), 6.61 (s,
1H), 6.65 (s, 1H), 6.89 (d, 1H, J ) 2.4 Hz), 6.92 (d, 1H, J ) 2.4
Hz), and 7.03 (t, 2H, J ) 7.4 Hz); 13C NMR (CDCl3, 100 MHz)
δ 27.9, 28.9, 37.3, 40.1, 44.2, 44.3, 48.3, 52.4, 52.6, 55.7, 56.3,
61.6, 100.9, 105.9, 106.4, 108.4, 108.5, 114.8, 119.7, 121.7,
124.8, 126.7, 127.2, 146.5, 151.0, 151.2, 153.7, 155.8, 161.1,
161.2, 164.1, and 164.3. Anal. Calcd for C22H23NO7: C, 63.92;
H, 5.61; N, 3.39. Found: C, 63.79; H, 5.68; N, 3.36.
[2-(7,8-Dih yd r o-5H -[1,3]d ioxolo[4,5-g]isoq u in olin e-6-
ca r b on yl)-3-m et h oxyp h en yl]a cet ic Acid Met h yl E st er
(54). To a stirred solution of 1.5 g (6.7 mmol) of carboxylic acid
5343 in 15 mL of CH2Cl2 were added 1.2 mL (13 mmol) of oxalyl
chloride and two drops of DMF. The mixture was stirred at
room temperature for 2 h, and the solvent and excess oxalyl
chloride were removed under reduced pressure. The crude acid
chloride was dissolved in 15 mL of CH2Cl2, and 1.6 g (13 mmol)
of DMAP was added. The mixture was stirred at room
temperature for 15 min, 1.2 g (6.7 mmol) of amine 50 was
added, and the solution was heated at reflux for 18 h. The
reaction mixture was cooled to room temperature, quenched
with 40 mL of a saturated NaHCO3 solution, and extracted
with CH2Cl2. The combined organic extracts were washed with
a saturated NaCl solution, dried over Na2SO4, and filtered,
and the solvent was removed under reduced pressure. The
crude residue was purified by flash chromatography on silica
gel to give 1.2 g (50%) of 54 as a pale yellow oil which consisted
of a 1:1 mixture of rotomers; IR (neat) 1729, 1649, 1596, 1268,
1
and 1034 cm-1; H NMR (CDCl3, 400 MHz) δ 2.61-2.77 (m,
2H), 2.83 (t, 2H, J ) 6.0 Hz), 3.36-3.80 (m, 20H), 4.21-4.32
(m, 2H), 4.68 (d, 1H, J ) 17.2 Hz), 4.94 (d, 1H, J ) 17.2 Hz),
5.88 (s, 2H), 5.92 (s, 2H), 6.37 (s, 1H), 6.57 (s, 1H), 6.62 (s,
1H), 6.65 (s, 1H), 6.82 (dd, 2H, J ) 8.0 and 2.0 Hz), 6.93 (t,
2H, J ) 8.0 Hz), and 7.31 (dt, 2H, J ) 8.0 and 2.0 Hz); 13C
NMR (CDCl3, 100 MHz) δ 28.3, 29.0, 37.7, 37.8, 39.4, 43.8,
47.6, 51.5, 51.7, 55.3, 100.5, 100.6, 105.6, 106.2, 107.9, 108.2,
109.2, 109.3, 122.7, 122.8, 125.3, 125.8, 126.9, 127.0, 127.4,
129.6, 129.7, 132.2, 132.4, 145.8, 145.9, 146.0, 146.1, 155.2,
155.3, 166.6, 167.1, 171.0, and 171.3. Anal. Calcd for C21H21NO6:
C, 65.77; H, 5.52; N, 3.65. Found: C, 65.64; H, 5.50; N, 3.47.
Dia zo-[2-(7,8-d ih yd r o-5H -[1,3]d ioxolo[4,5-g]isoq u in o-
lin e-6-ca r bon yl)-3-m eth oxyp h en yl]a cetic Acid Meth yl
Ester (55). To a stirred solution of 0.5 g (1.2 mmol) of ester
54 in 15 mL of acetonitrile was added 0.6 mL (4.0 mmol) of
1,8-diazabicyclo[5.4.0]undec-7-ene followed by 0.7 mL (4.6
mmol) of p-toluenesulfonyl azide. After stirring for 48 h in the
dark at room temperature, another 0.2 mL (1.2 mmol) of
p-toluenesulfonyl azide was added. The reaction mixture was
stirred for an additional 24 h and concentrated under reduced
pressure. The crude residue was purified by flash chromatog-
raphy on silica gel to give 0.4 g (88%) of 55 as a yellow oil that
consisted of a 1:1 mixture of rotomers and which was used in
the next step without further purification; IR (neat) 2087,
1705, 1638, 1591, 1255, and 1034 cm-1; 1H NMR (CDCl3, 400
MHz) δ 2.58-2.65 (m, 1H), 2.71-2.93 (m, 3H), 3.32-3.38 (m,
1H), 3.44-3.50 (m, 1H), 3.59 (s, 3H), 3.65-3.73 (m, 2H), 3.75
(s, 3H), 3.76 (s, 3H), 3.81 (s, 3H), 4.19-4.31 (m, 2H), 4.62 (d,
1H, J ) 17.2 Hz), 4.95 (d, 1H, J ) 17.2 Hz), 5.88 (s, 2H), 5.92
(s, 2H), 6.34 (s, 1H), 6.56 (s, 1H), 6.63 (s, 1H), 6.65 (s, 1H),
6.89 (dd, 2H, J ) 8.0 and 1.2 Hz), 7.13 (dd, 1H, J ) 8.0 and
0.8 Hz), 7.18 (dd, 1H, J ) 8.0 and 0.8 Hz), and 7.38 (dt, 2H, J
) 8.0 and 1.2 Hz); 13C NMR (CDCl3, 100 MHz) δ 28.3, 29.2,
39.7, 43.9, 44.1, 47.9, 51.8, 51.9, 55.6, 55.7, 100.6, 100.7, 105.6,
106.4, 108.0, 108.5, 110.2, 110.5, 122.6, 122.9, 123.6, 123.9,
125.4, 125.7, 126.8, 127.1, 127.6, 129.5, 129.6, 130.0, 130.1,
145.9, 146.2, 155.7, 155.8, 165.5, 165.6, 165.7 and 166.1.
Meth yl 11-Aza-8-m eth oxy-17,19-dioxa-10-oxopen tacyclo-
[12.7.0.03,11.04,9.016,20]h en icosa -1(21),4(9),5,7,14(15),16(20)-
h exa en e-3-ca r boxyla te (56). To a refluxing solution of 2 mg
of rhodium(II) acetate in 30 mL of toluene was added 0.2 g
(0.5 mmol) of diazoester 55 in 5 mL of toluene dropwise over
a 1 h period. The mixture was heated at reflux for 15 min and
cooled to room temperature. The solvent was removed under
reduced pressure, and the crude residue was subjected to flash
chromatography on silica gel to give 0.1 g (75%) of 56 as a
clear oil; IR (neat) 1738, 1691, 1604, 1276, and 1034 cm-1; 1H
NMR (CDCl3, 400 MHz) δ 2.72-2.89 (m, 2H), 2.97 (d, 1H, J )
14.4 Hz), 3.11-3.17 (m, 1H), 3.59 (s, 3H), 3.97 (s, 3H), 4.72-
4.77 (m, 2H), 5.91 (d, 1H, J ) 10.0 Hz), 5.94 (d, 1H, J ) 10.0
Hz), 6.64 (s, 1H), 6.74 (brs, 1H), 6.95 (d, 1H, J ) 8.0 Hz), 7.31
(d, 1H, J ) 7.6 Hz), and 7.35 (t, 1H, J ) 8.0 Hz); 13C NMR
(CDCl3, 100 MHz) δ 35.6, 39.2, 44.8, 52.7, 55.9, 69.7, 100.9,
109.9, 111.6, 111.7, 114.2, 118.2, 127.7, 133.5, 135.0, 145.9,
146.0, 146.6, 157.3, 165.9, and 169.5. Anal. Calcd for C21H19NO6:
C, 66.12; H, 5.02; N, 3.67. Found: C, 66.08; H, 4.97; N, 3.53.
Ack n ow led gm en t. We gratefully acknowledge the
National Institutes of Health (GM-59384-21) for gener-
ous support of this work. L.S.B. is pleased to acknowl-
edge the National Institute of Health for a postdoctoral
fellowship (CA 74500-01A1).
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for new compounds lacking elemental analyses. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(43) Harris, T. M.; Harris, C. M.; Oster, T. A.; Brown, L. E.; Lee, J .
Y. J . Am. Chem. Soc. 1988, 110, 6180.
J O001684W