Synthesis of Benzo-Fused 1-Azabicyclo[m.n.0]alkanes via the Schmidt Reaction: A Formal Synthesis of Gephyrotoxin

Article abstract of DOI:10.1021/jo0011383

The intramolecular capture of benzocyclobutyl, benzocyclopentyl, and benzocyclohexyl carbocations 7 by azides produces spirocyclic aminodiazonium ions 8, which undergo 1,2-C-to-N rearrangement with loss of dinitrogen to produce benzo-fused iminium ions resulting from either aryl (9) or alkyl (10) migration to the electron-deficient nitrogen atom. Reduction of the iminium ions affords regioisomeric benzo-fused 1-azabicyclo[m.n.0]alkanes, e.g., benzopyrrolizidines, benzoindolizidines, benzoquinolizidines, or perhydrobenzo[f]pyrrolo[1,2-α]azepines in two regioisomeric versions, anilines (e.g., 11-14) and benzylic amines (e.g., 15-18), the result of aryl and alkyl migrations, respectively. Generally, aryl migration is preferred, despite modeling that shows that the lowest energy aminodiazonium ions are those where the departing dinitrogen is preferentially antiperiplanar to the migrating alkyl group rather than the aryl group. The utility of this methodology was illustrated by a formal synthesis of the alkaloid gephyrotoxin 4. A dependence on the efficiency and regioselectivity of the Schmidt reaction upon subtle changes in the structure of the cation precursor was observed, necessitating the exploration of a variety of substrates. Fortunately, these materials were easily made. Ultimately, the azido-alkene 81 bearing a 2-bromoethyl side-chain was useful for the Schmidt reaction, producing the known benzo-fused indolizidine 49, which had been transformed by Ito et al. into gephyrotoxin 4. The synthesis of 49 required nine steps (five purifications) from commercially available 4-methoxy-1-indanone 60 and proceeded in 22% overall yield.

Full text of DOI:10.1021/jo0011383

7158
J . Org. Chem. 2000, 65, 7158-7174
Syn th esis of Ben zo-F u sed 1-Aza bicyclo[m .n .0]a lk a n es via th e
Sch m id t Rea ction : A F or m a l Syn th esis of Gep h yr otoxin
William H. Pearson* and Wen-kui Fang†
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055
wpearson@umich.edu
Received J uly 26, 2000
The intramolecular capture of benzocyclobutyl, benzocyclopentyl, and benzocyclohexyl carbocations
7 by azides produces spirocyclic aminodiazonium ions 8, which undergo 1,2-C-to-N rearrangement
with loss of dinitrogen to produce benzo-fused iminium ions resulting from either aryl (9) or alkyl
(10) migration to the electron-deficient nitrogen atom. Reduction of the iminium ions affords
regioisomeric benzo-fused 1-azabicyclo[m.n.0]alkanes, e.g., benzopyrrolizidines, benzoindolizidines,
benzoquinolizidines, or perhydrobenzo[f]pyrrolo[1,2-a]azepines in two regioisomeric versions,
anilines (e.g., 11-14) and benzylic amines (e.g., 15-18), the result of aryl and alkyl migrations,
respectively. Generally, aryl migration is preferred, despite modeling that shows that the lowest
energy aminodiazonium ions are those where the departing dinitrogen is preferentially antiperipla-
nar to the migrating alkyl group rather than the aryl group. The utility of this methodology was
illustrated by a formal synthesis of the alkaloid gephyrotoxin 4. A dependence on the efficiency
and regioselectivity of the Schmidt reaction upon subtle changes in the structure of the cation
precursor was observed, necessitating the exploration of a variety of substrates. Fortunately, these
materials were easily made. Ultimately, the azido-alkene 81 bearing a 2-bromoethyl side-chain
was useful for the Schmidt reaction, producing the known benzo-fused indolizidine 49, which had
been transformed by Ito et al. into gephyrotoxin 4. The synthesis of 49 required nine steps (five
purifications) from commercially available 4-methoxy-1-indanone 60 and proceeded in 22% overall
yield.
In tr od u ction
The benzo-fused 1-azabicyclo[m.n.0]alkanes 1 and 2
and their oxidized or reduced forms are found in a variety
of natural products and other pharmacologically impor-
tant compounds (Figure 1 and Scheme 1). For example,
the anticancer drug mitomycin C (3) is related to the
benzo-fused pyrrolizidine 11, gephyrotoxin (4) is a re-
duced form of the benzo-fused indolizidine 12, the pro-
toberberine alkaloid xylopinine (5) is an example of the
benzo-fused quinolizidine 17, and the perhydrobenzo[f]-
pyrrolo[1,2-a]azepine 6, an anxiolytic agent,1 is a deriva-
tive of the benzo-fused pyrrolidinoazepane 14.
On the basis of our earlier work on the intramolecular
Schmidt reactions of azides with carbocations,2,3 we
expected that the benzylic carbocation 7 would cyclize
† Current address: Allergan, Inc., Mail Code RD-3D, 2525 Dupont
Drive, Irvine, CA 92612.
(1) Ishihara, Y.; Kiyota, Y.; Goto, G. Chem. Pharm. Bull. 1990, 38,
3024-3030.
(2) (a) Pearson, W. H.; Schkeryantz, J . M. Tetrahedron Lett. 1992,
33, 5291-5294. (b) Pearson, W. H.; Walavalkar, R.; Schkeryantz, J .
M.; Fang, W.-k.; Blickensdorf, J . D. J . Am. Chem. Soc. 1993, 115,
10183-10194. (c) Pearson, W. H.; Fang, W.-k.; Kampf, J . W. J . Org.
Chem. 1994, 59, 2682-2684. (d) Pearson, W. H.; Fang, W.-k. J . Org.
Chem. 1995, 60, 4960-4961. (e) Pearson, W. H. J . Heterocycl. Chem.
1996, 33, 1489-1496. (f) Pearson, W. H.; Fang, W.-k. Isr. J . Chem.
1997, 37, 39-46.
(3) Aube´ has shown that aliphatic azides may participate in Schmidt
reactions with ketones and related electrophiles. See: (a) Aube´, J .;
Milligan, G. L. J . Am. Chem. Soc. 1991, 113, 8965-8966. (b) Aube´, J .;
Milligan, G. L.; Mossman, C. J . J . Org. Chem. 1992, 57, 1635-1637.
(c) Aube´, J .; Rafferty, P. S.; Milligan, G. L. Heterocycles 1993, 35, 1141-
1147. (d) Milligan, G. L.; Mossman, C. J .; Aube´, J . J . Am. Chem. Soc.
1995, 117, 10449-10459. (e) Forsee, J . E.; Aube´, J . J . Org. Chem. 1999,
64, 4381-4385.
F igu r e 1. Benzo-fused 1-azabicyclo[m.n.0]alkanes and rep-
resentative targets.
to the spirocyclic aminodiazonium ion 8, which would
produce the iminium ions 9 and 10 by migration of an
aryl or alkyl group, respectively (Scheme 1). Hydride
reduction of 9 and 10 would then afford the tricyclic
anilines 11-14 and the tricyclic benzylamines 15-18. A
key issue that arises is the regioselectivity of aryl vs alkyl
migration. Herein we report the Schmidt reactions of the
10.1021/jo0011383 CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/20/2000

1-Azabicyclo[m.n.0]alkanes via the Schmidt Reaction
J . Org. Chem., Vol. 65, No. 21, 2000 7159
Sch em e 1. Ben zo-F u sed
1-Aza bicyclo[m .n .0]a lk a n es via In tr a m olecu la r
Sch m id t Rea ction s
combination of 1-indanol 23 with n-butyl azide produces
three Schmidt products from the aminodiazonium ion 24
(eq 2).2d The aniline 25 is a result of aryl migration, while
the benzylic amines 26 and 27 are produced by alkyl and
hydrogen migration, respectively. Neglecting hydrogen
migration, which is not possible in the aminodiazonium
ion 8, alkyl migration in 24 is preferred over aryl
migration by a margin of 3.5:1. While the structure of
24 is very close to that of 8, once again the conformational
mobility of 24 about the benzylic C-N bond makes it
difficult to extrapolate the regioselectivity of its rear-
rangement to 8.
cation systems 7a -d , which produce the tricyclic amines
11-18 or their analogues. A formal synthesis of gephy-
rotoxin (4) using this method is described.
Since our prior results (eqs 1 and 2) do not provide
unequivocal guidance regarding the aryl vs alkyl migra-
tory preference of the aminodiazonium ions 8 (Scheme
1), we carried out molecular modeling on these interme-
diates using a combination of molecular mechanics and
semiempirical molecular orbital (AM1) methods in order
to gain some insight into this regioselectivity question.5
The aminodiazonium ions with the aryl group antiperi-
planar to the departing dinitrogen group were consistent-
ly 2-4 kcal/mol higher in energy than the invertomers
with the alkyl group antiperiplanar.6 A representative
result is shown in Figure 2. Thus, it might be expected
that alkyl migration would be preferred, leading to the
iminium ions 10 and thus the benzylic amines 15-18 as
the major Schmidt products (Scheme 1). However, as
stated above, such a stereoelectronic rationale is only one
factor to consider; the ability of the migrating group and
the migration origin to stabilize a positive charge are also
important factors. For example, neglecting stereoelec-
tronic issues, aryl groups have a higher migratory
Regarding the regioselectivity of the rearrangement of
the aminodiazonium ions 8 to the iminium ions 9 and
10, we have previously encountered the aryl vs alkyl
migration issue in intermolecular Schmidt reactions, as
shown in eqs 1 and 2.2d Reaction of the cyclic tertiary
benzylic alcohols 19 with n-butyl azide under acidic
conditions produced the anilines 21 and the benzylic
amines 22 as a result of aryl or alkyl migration, respec-
tively, in the aminodiazonium ions 20. The propensity
for aryl migration was found to increase smoothly as a
function of the size of the ring undergoing expansion. An
explanation for this trend was proposed based on the
conformation of the aminodiazonium ion about the ben-
zylic C-N bond in 20.2d As is often the case with 1,2-
rearrangements to electron-deficient centers, the regio-
selectivity of the migration is difficult to predict because
there are at least three factors that must be considered,
namely the inherent migratory aptitude of the migrating
group, the stability of the newly developing positive
charge at the migration origin, and stereoelectronic
factors (i.e., the migrating group and the leaving group
prefer an antiperiplanar geometry).2b,2d,4 Comparing 20
to 8 reveals that while both are secondary aminodiazo-
nium ions attached to tertiary benzylic carbon atoms,
there is a substantial difference in the conformational
flexibility of these intermediates about their benzylic
C-N bonds, making it difficult to extrapolate the regio-
selectivity of the rearrangement of 20 to that of 8. The
(5) For a discussion of the mechanism of the Schmidt reaction of
azides with carbocations, including structural and theoretical work on
aminodiazonium ions, see ref 2b. This paper also describes our
procedure for using molecular mechanics and semiempirical MO
methods to model aminodiazonium ions. See also: Fang, W.-k. Ph.D.
Thesis, University of Michigan, 1997.
(6) With respect to the nitrogen-containing ring, the lowest energy
aminodiazonium ions have the endocyclic alkyl group roughly anti-
periplanar to the departing dinitrogen group. Since such a migration
would result in ring contraction, often to a strained ring, we did not
expect this pathway to dominate. Hence, we focused on the higher
energy aminodiazonium ions where the exocyclic aryl or alkyl groups
are considered.
(4) Hoffman, R. V.; Kumar, A. J . Org. Chem. 1985, 50, 1859-1863.

7160 J . Org. Chem., Vol. 65, No. 21, 2000
Pearson and Fang
Sch em e 2. Sch m id t Rou te to Ben zo-F u sed
P yr r olizid in es
F igu r e 2. AM1 calculations on aminodiazonium ion 8b: A
representative result.
aptitude than alkyl groups in 1,2-rearrangements from
C to N,4,7 presumably due to their ability to bear positive
charge in the rearrangement in the form of phenonium
ion intermediates. Ideally, modeling of transition states
and other intermediates encountered on the rearrange-
ment pathway (e.g., phenonium ions) would be required
for a more useful prediction. With these caveats in mind,
we sought to explore the cyclizations of the cations 7 to
the amines 11-18.
Resu lts a n d Discu ssion
detected. Hence, the simple aminodiazonium ion 8a
rearranged primarily by aryl migration, despite modeling
studies that showed a preference for the aminodiazonium
ion with the alkyl group roughly antiperiplanar to the
departing dinitrogen group. This may be a reflection of
the greater ability of a migrating aryl group to carry a
positive charge in the transition state (i.e., as a phe-
nonium ion), as discussed above.
Ba sic Cycliza tion s Lea d in g to 1-Aza bicyclo[m .n .0]-
a lk a n es. For access the benzo-fused pyrrolizidines 11
and 15, we required a benzocyclobutyl cation (see 7a in
Scheme 1), which should be accessible from the azido
alkene 30 by protonation (Scheme 2). Formation and
O-silylation of the dianion of the phosphonium salt 27
followed by the reaction of the resultant silyloxy ylide8
with benzocyclobutenone 289 gave the hydroxy alkene 29
as a mixture of geometrical isomers after desilylation
with n-Bu4NF. A Mitsunobu reaction10 was then used to
prepare the key azide 30. Treatment of 30 with trifluo-
romethanesulfonic acid caused a Schmidt reaction via the
aminodiazonium ion 8a , producing the iminium ions 9a
and 10a (not isolated or observed directly). Reduction of
these ions with sodium borohydride gave the desired
benzopyrrolizidines 1111,12 and 1513 accompanied by the
indole 31,12,14,15 the result of deprotonation of 9a . All three
compounds are known; 11 and 31 were prepared in model
studies for the synthesis of mitocenes and mitomycins.
The ratio of aryl migration (31 + 11) to alkyl migration
(15) was 3:1. Reduction of the iminium ions 9a and 10a
under less basic conditions using borane gave only 11
and 15 in a 1.5:1 ratio, with none of the indole 31
A five-membered ring cation (see 7b in Scheme 1) was
then targeted in order to access the benzoindolizidines
12 and 16 (Scheme 3). Metalation of indene 32 with
Sch em e 3. Sch m id t Rou te to Ben zo-F u sed
In d olizid in es
(7) Smith, P. A. S. In Molecular Rearrangements; P. de Mayo, Ed.;
J ohn Wiley and Sons: New York, 1963; Vol. 1, pp 457-591.
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1987, 1561-1565.
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n-butyllithium16 followed by alkylation of the resultant
indenyllithium with 1-chloro-3-iodopropane gave a mix-
ture of alkenes, 1-(3-chloropropyl)indene and 3-(3-chlo-
3486.
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5880.
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(16) Collins, S.; Kuntz, B. A.; Taylor, N. J .; Ward, D. G. J .
Organomet. Chem. 1988, 342, 21-29.

1-Azabicyclo[m.n.0]alkanes via the Schmidt Reaction
J . Org. Chem., Vol. 65, No. 21, 2000 7161
ropropyl)indene. Azide displacement of the chlorides
followed by thermal isomerization of the indene double
bond isomers afforded the azide 33 with the alkene in
the most substituted position. This type of double bond
isomerization is similar to those known for cyclopenta-
dienes and has been well documented for indene sys-
tems.17 Treatment of 33 with trifluoromethanesulfonic
acid followed by in situ reduction of the presumed
iminium ions 9b and 10b with sodium borohydride gave
a 2.3:1 mixture of the two tricyclic compounds 12 and
16 in excellent (92%) combined yield. The regioisomer 12
was isolated in 64% yield and was easily separated from
16 (28% yield) due to its greater mobility on silica gel.
The hexahydropyrroloquinoline 1215 and the hexahydro-
pyrroloisoquinoline 1618,19 are both known compounds.
Aryl migration rather than alkyl migration had occurred
in the rearrangement of the intermediate aminodiazo-
nium ion 8b to an extent similar to that observed above
for the rearrangement of 8a (Scheme 2).
dine 39,22 with none of the expected regioisomeric ben-
zylic amine 40 being detected. Aryl migration had thus
occurred exclusively in the aminodiazonium ion 38.
In an attempt to access an azepane, we targeted a six-
membered ring cation for the Schmidt reaction (see 7d
in Scheme 1), presumably accessible by protonation of
the azido alkene 45 (Scheme 5). Thus, cerium-promoted
Sch em e 5. Sch m id t Rou te to Ben zo-F u sed
P yr r olid in oa zep a n es
To access benzo-fused quinolizidines, we then studied
a system that retained a five-membered ring cation but
had a longer tether to the azide, resulting in a six-
membered ring aminodiazonium ion (38 in Scheme 4, cf.
Sch em e 4. Sch m id t Rou te to Ben zo-F u sed
Qu in olizid in es
addition21 of allylmagnesium chloride to R-tetralone 41
followed by mesylation and elimination of the mesylate
under acidic conditions gave the diene 42 as a mixture
of regio- and stereoisomers. Hydroboration/oxidation of
the terminal vinyl group of 42 gave an inseparable 1.3:1
mixture of the alcohols 4323 and 44, which were converted
to their azides using standard displacement methodology.
The resultant mixture of alkene isomers was subjected
to trifluoroacetic acid, which caused double bond isomer-
ization, producing a 10:1 mixture of 45 and another
alkene isomer (unidentified). Treatment of 45 with tri-
fluoromethanesulfonic acid followed by reduction of the
intermediate iminium ion gave the known benzo-fused
pyrrolidinoazepane 14,24 with none of the regioisomeric
amine 18 detected. Once again, aryl migration in the
aminodiazonium ion intermediate (i.e., 7d ) had occurred
preferentially.
The cyclizations in Schemes 2-5 clearly show that the
intramolecular Schmidt reaction of azides with cyclic
benzylic carbocations is an efficient process that affords
benzo-fused 1-azabicyclo[m.n.0]alkanes. The substrates
are easily prepared, and the regioselectivity of the
rearrangment favors aryl migration, producing anilines
as the major or exclusive products. The regioisomeric
anilines and benzylic amines that are produced are easily
separated by chromatography due to their substantially
different basicities. The regioselectivity observed is con-
trary to predictions based on the energies of the various
aminodiazonium ions encountered (e.g., Figure 2), where
the lower energy ion consistently has the ring alkyl group
antiperiplanar to the departing dinitrogen, indicating
that alkyl migration would be preferred over aryl migra-
tion. A more complete study would require modeling of
the transition states for rearrangement, i.e., alkyl migra-
8c in Scheme 1). Double metalation of 2-methylbenzyl
alcohol 34 using the method of Braun20 followed by
transmetalation to the cerium(III) salt21 and addition to
1-indanone 35 gave the diol 36. A Mitsunobu reaction10
was used to install an azido group selectively at the
primary benzylic position, affording the desired azide 37.
Treatment of 37 with trifluoromethanesulfonic acid fol-
lowed by reduction of the intermediate iminium ion with
sodium borohydride afforded only the known quinolizi-
(17) Kelly, T. R.; Bell, S. H.; Ohashi, N.; Armstrong-Chong, R. J . J .
Am. Chem. Soc. 1988, 110, 6471-6480.
(18) Maryanoff, B. E.; McComsey, D. F.; Gardocki, J . F.; Shank, R.
P.; Costanzo, M. J .; Nortey, S. O.; Schneider, C. R.; Setler, P. E. J .
Med. Chem. 1987, 30, 1433-1454.
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S.; Wooden, G. P. J . Am. Chem. Soc. 1989, 111, 2487-2496.
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(24) Meyers, A. I.; Milot, G. J . Org. Chem. 1993, 58, 6538-40.

7162 J . Org. Chem., Vol. 65, No. 21, 2000
Pearson and Fang
Sch em e 6. Retr osyn th etic An a lysis of
tion (46q) vs aryl migration (47q), as well as modeling of
additional intermediates along the reaction coordinate,
e.g., the phenonium ions 48. Without such computations,
we are left to conclude that aryl groups migrate selec-
tively because of their increased ability to stabilize a
positive charge during the migration, presumably via the
phenonium ion intermediates 48.
Gep h yr otoxin (4)
Ap p lica tion of th e Meth od ology: A F or m a l Syn -
th esis of Gep h yr otoxin . Given that the Schmidt reac-
tions outlined above produce anilines 1 rather than
benzylic amines 2 (see Figure 1 above), we wished to
determine whether this methodology would be useful for
accessing more complex examples of this core structure.
A formal synthesis of the alkaloid gephyrotoxin 4 is
described below, a compound that has a similar skeleton
to the benzo-fused indolizidine 12 synthesized in Scheme
3 above.25
Gephyrotoxin (4), originally isolated from Dendrobates
histrionicus,26 is a member of a class of alkaloids isolated
from the skins of tropical frogs of the genus Dendro-
bates.27 Its absolute configuration was determined to be
as shown by X-ray analysis.28 Gephyrotoxin is relatively
nontoxic. Mild muscarinic activity was originally reported
for this alkaloid,29 however recent studies30 have revealed
a more complex and interesting array of neurological
activities associated with gephyrotoxin. The low abun-
dance of gephyrotoxin in amphibians and its unusual
chemical and biological characteristics have led to syn-
thetic interest in several laboratories.31-39
reaction of the azido-alkene 52 proceeding through the
aminodiazonium ion 51 by aryl migration in a fashion
analogous to that shown above in Scheme 3, where the
azido-alkene 33 was cyclized to the benzoindolizidines
12 and 16, the former being the desired ring system for
gephyrotoxin. The azido-alkene 52 should be available
from the indene 53 by deprotonation and alkylation, as
was done in Scheme 3. The stereoselectivity of the
iminium ion reduction, the regioselectivity of the Schmidt
reaction, and the regioselectivity of the indene alkylation
are all interesting issues to be examined. Before disclos-
ing the formal synthesis of racemic gephyrotoxin, model
studies will be described that deal with the viability of
the basic Schmidt reaction for the assembly of the three
rings of this alkaloid.
Th e Use of a Secon d a r y Azid e in th e Sch m id t
R ea ct ion : St er eoselect ivit y of t h e Im in iu m Ion
Red u ction . While access to the basic ring skeleton
gephyrotoxin was described above in Scheme 3 (i.e.,
compound 12), a secondary rather than primary azide is
desirable in the Schmidt precursor in order to install the
2-hydroxyethyl group of this alkaloid. Given the ease of
assembly of the cyclization precursors using the indene
alkylation method, a simple model study was conducted
to ascertain whether a secondary azide can be used in
the intramolecular Schmidt reaction (Scheme 7). This
A retrosynthetic analysis of gephyrotoxin is shown in
Scheme 6. Ito and co-workers have prepared 49 and
converted it to gephyrotoxin 4.36 We planned to intercept
Ito’s intermediate by the stereoselective reduction of the
iminium ion 50, which would result from a Schmidt
(25) For a preliminary communication, see: Pearson, W. H.; Fang,
W.-k. Electron. Conf. Heterocycl. Chem., 1998, http://www.ch.ic.ac.uk/
ectoc/echet98/pub/013/index.htm.
(26) Tokuyama, T.; Uenoyama, K.; Brown, G.; Daly, J . W.; Witkop,
B. Helv. Chim. Acta 1974, 57, 2597-2604.
(27) Daly, J . W.; Brown, G. B.; Mensah-Dwumah, M.; Myers, C. W.
Toxicon 1978, 16, 163-188.
Sch em e 7. Mod el Cycliza tion of th e Azid e 56.
Ster eoselectivity of th e Im in iu m Ion Red u ction
(28) Daly, J . W.; Witcop, B.; Tokuyama, T.; Nishikawa, T.; Karle, I.
L. Helv. Chim. Acta 1977, 60, 1128-1140.
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Albuquerque, E. X. Mol. Pharmacol. 1984, 25, 384-400.
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study also addresses the stereoselectivity of the reduction
of the resultant iminium ion. Metalation of indene 32 and
alkylation with the chloride 5440 gave the alcohol 55 in

1-Azabicyclo[m.n.0]alkanes via the Schmidt Reaction
J . Org. Chem., Vol. 65, No. 21, 2000 7163
Sch em e 8. Attem p ts a t Regioselective Alk yla tion
of Meth oxyin d en e 53
F igu r e 3. New questions.
good yield. Mesylation followed by azide displacement
provided the desired azido-indene 56 in 58% yield.
Treatment of 56 with trifluoromethanesulfonic acid in
benzene afforded a mixture of iminium ions that were
reduced with sodium borohydride to give the desired
tricyclic aniline 57 (resulting from phenyl migration) and
the benzylic amine regioisomer 58 (resulting from alkyl
migration) in 72% combined yield. The iminium ion
reduction had proceeded with poor stereoselectivity,
producing 57 as a 1:1 mixture of diastereomers. However,
we hoped that a bulkier hydride reagent in combination
with a bulky alcohol protecting group on the 2-hydroxy-
ethyl side chain required for gephyrotoxin would lead to
an improvement in the stereoselectivity of the iminium
ion reduction. An alternate side-chain in conjunction with
the required methoxy-substituted indene might also alter
the low regioselectivity of the Schmidt rearrangement.
In itia l Effor ts to Syn th esize Gep h yr otoxin : Re-
gioselectivity of th e Alk yla tion of Un sym m etr ica l
In d en e An ion s. Moving from model systems to fully
functionalized compounds that may lead to gephyrotoxin,
two new issues arise (Figure 3). First, if we use the same
indene alkylation approach that we developed in the
model studies, methoxyindene (53) is needed as the
starting material, and the regioselectivity of its alkylation
becomes important. Second, we must choose a group R,
a synthetic equivalent of a 2-hydroxyethyl group, that
will survive the strongly acidic conditions of the Schmidt
reaction and perhaps promote greater regioselectivity.
Our initial efforts to address these issues are outlined
below.
dene alkylation (tert-butyllithium/TMSCl) could be used
to make the undesired indene 62 selectively.17
Pure 62, the “wrong” regioisomer, was subjected to the
Schmidt reaction (Scheme 9), producing 66 in moderate
Sch em e 9. Sch m id t Rea ction of Azid o-In d en e
Regioisom er s 61 a n d 62
The desired methoxyindene 53 was prepared from
commercially available 4-methoxy-1-indanone (60) by
sodium borohydride reduction and dehydration according
to Grieco’s selenoxide method41 (Scheme 8). We do not
know the location of the double bond in 53, although it
appears to be a single regioisomer. Metalation of 53 with
n-butyllithium followed by alkylation with 64, easily
prepared from commercially available 4-bromotetrahy-
dropyran (63),42,43 followed by azide displacement pro-
duced a 1:3 ratio of the desired indene 61 and the
undesired regioisomeric indene 62. Chelation of lithium
to the methoxy group may explain this regioselectivity,
which has been observed in other alkoxyindene metala-
tion/alkylations.17,44 Attempts to inhibit this internal
chelation and thus alter the regioselectivity of the alkyl-
ation [e.g., KN(TMS); NaH; silyloxy rather than methoxy]
were unsuccessful. Kelly’s method for regioselective in-
(40) Hamilton, R. J .; Mander, L. N.; Sethi, S. P. Tetrahedron 1986,
42, 2881-2892.
yield as a single regioisomer, the result of only aryl
migration in the intermediate aminodiazonium ion 67.
A sample of pure 61 could not be obtained by chroma-
tography, so a mixture of 61 and 62 was subjected to the
Schmidt reaction. Compound 66 (derived from 62) was
(41) Grieco, P. A.; Gilman, S.; Nishizawa, M. J . Org. Chem. 1976,
41, 1, 1485-1486.
(42) Hanschke, E. Chem. Ber. 1955, 88, 1053-1061.
(43) Kulkarni, S. U.; Patil, V. D. Heterocycles 1982, 18, 163-167.
(44) Mazzocchi, P. H.; Stahly, B. C. J . Med. Chem. 1981, 24, 457-
462.

7164 J . Org. Chem., Vol. 65, No. 21, 2000
Pearson and Fang
the only product; no 49 was detected, perhaps indicating
that 68 does not undergo rearrangement, although the
use of a mixture of compounds made the study of this
reaction more difficult. An alternate synthesis of the
cyclization precursor was thus sought in order to avoid
the lack of regiocontrol in the indene alkylation method.
Regiocon tr olled Rou tes to th e Cycliza tion P r e-
cu sor s: Avoid in g In d en e An ion Alk yla tion s. A single
regioisomer of the related azido-alkene 72 was synthe-
sized as shown in Scheme 10. Addition of dibromolithio-
be problematic in the more challenging cyclizations
involving migration of a m-methoxyaryl group. Regarding
regioselectivity, the more electron-rich aromatic ring will
be better able to compete with alkyl migration. Thus one
might expect the propensity for aryl migration (vs alkyl
migration) to decrease in the order given above. Indeed,
the o-methoxyaryl case is completely aryl selective, while
the nonmethoxy cases gave significant amounts of alkyl
migration. The lack of success in the m-methoxyaryl case
does not allow us to discuss these data point, although
it would be expected that a m-methoxyaryl group would
be a poorer migrator than an o-methoxyaryl or simple
aryl group.
Sch em e 10. Regiocon tr olled Alk en e Syn th esis a n d
Attem p ted Sch m id t Rea ction
The failure of the Schmidt reactions of the azides 61
and 72 might also be due in part to the choice of side-
chain; i.e., for the more difficult cyclizations involving
m-methoxyaryl cations, a more robust and perhaps less
electronegative side-chain than 2-(methoxymethoxy)ethyl
might be desirable. Thus, we chose to examine an allyl
group as the side-chain, since this group might be
transformed later into the desired 2-(hydroxy)ethyl group
of gephyrotoxin. The synthesis and cyclization of such a
compound (75) is shown in Scheme 11. A cerium-
Sch em e 11. An Allyl Sid e-Ch a in Allow s a
Su ccessfu l Sch m id t Rea ction
methane45 to the indanone 60 followed by treatment of
the resulting adduct with zinc dust46 gave the vinyl
bromide 69 as an inseparable 2:1 mixture of Z and E
isomers. Metal halogen exchange on 69 followed by Lewis
acid mediated opening47 of the epoxide 7048 provided the
alcohol 71 in good yield as a 1:1 mixture of E and Z
isomers. Replacement of the alcohol with azide was
accomplished by mesylation and azide displacement.
When the azido-alkene 72 was subjected to the usual
Schmidt reaction/iminium ion reduction sequence, no
identifiable products were obtained, consistent with the
observations in Scheme 9. Considering the data in
Schemes 9 and 10 and the model studies already de-
scribed (i.e., no methoxy on the ring, Schemes 3 and 7),
we concluded that the electron density in the aromatic
ring is an important influence in the success and regi-
oselectivty of the Schmidt migration. Regarding rate, one
might expect the most electron-rich aromatic ring to
migrate fastest, i.e., the o-methoxyaryl group (62/67,
Scheme 9), followed by a simple aryl group (33/8b,
Scheme 3; 56, Scheme 7), which should migrate faster
than a m-methoxyaryl group (61/68, Scheme 9 and 72/
68, Scheme 10), thus explaining why there is no cycliza-
tion for 61 or 72. The acid-sensitive MOM group may also
mediated21 addition of allylmagnesium chloride to meth-
oxyindanone 60 gave an alcohol, that was mesylated and
eliminated to furnish a diene (not shown). Selective
hydroboration/oxidation of the terminal double bond of
this alkene with 9-BBN49 provided the alcohol 73 in
excellent overall yield as a 1.3:1 mixture of endocyclic
and exocyclic alkenes 73a and 73b, respectively. Isomer
73b was a single alkene of undetermined geometry. A
one-pot Swern oxidation/organometallic addition using
Ireland’s method50 transformed 73 into 74, which was
isolated as a single isomer. The conversion of 74 to the
azide 75 was accomplished with standard displacement
chemistry. Schmidt reaction of 75 followed by hydride
(45) Taguchi, H.; Yamamoto, H.; Nozaki, H. J . Am. Chem. Soc. 1974,
96, 3010-3011.
(46) Williams, D. R.; Nishitani, K.; Bennett, W.; Sit, S. Y. Tetrahe-
dron Lett. 1981, 22, 3745-3748.
(47) Eis, M. J .; Wrobel, J . E.; Ganem, B. J . Am. Chem. Soc. 1984,
106, 3693-3694.
(49) Knight, E. F.; Brown, H. C. J . Am. Chem. Soc. 1968, 90, 5281-
5283.
(48) Mori, Y.; Kohchi, Y.; Noguchi, H.; Suzuki, M.; Carmeli, S.;
Moore, R. E.; Patterson, G. M. L. Tetrahedron 1991, 47, 4889-4904.
(50) Ireland, R. E.; Norbeck, D. W. J . Org. Chem. 1985, 50, 2198-
2200.

1-Azabicyclo[m.n.0]alkanes via the Schmidt Reaction
J . Org. Chem., Vol. 65, No. 21, 2000 7165
reduction of the resultant iminium ion proceeded in
excellent yield to produce the easily separable amines 76
and 77 in 44% and 42% isolated yield, respectively. The
desired benzoindolizidine 76 proved to be a 2:1 mixture
of diastereomers, the major isomer having the desired
cis configuration with respect to the pyrrolidine ring, i.e.,
76a . The undesired amine 77 was produced as a single
diastereomer. Hence, the Schmidt reaction involving the
migration of a m-methoxyaryl group can proceed ef-
ficiently if a more robust side-chain and a more nucleo-
philic azide are used (compare with Schemes 10 and 11),
although the regioselectivity is poor, as predicted (vide
supra). Nonetheless, oxidative cleavage of the alkene of
76 and reduction of the resultant aldehyde would com-
plete a formal synthesis of gephyrotoxin by intercepting
Ito’s compound 49 (Scheme 6). However, all attempts at
oxidative transformations of 76 were unsuccessful, per-
haps due to interference by the highly electron-rich
aromatic ring. Thus, we sought an alternative side-chain
that would be stable to the strongly acidic Schmidt
conditions and would be readily transformed into the
2-hydroxyethyl group of gephyrotoxin.
gave the alcohol 79 in excellent yield. Mesylation of the
alcohol and subsequent displacement with tetrabutylam-
monium azide and desilylation furnished the hydroxy-
azide 80 in high yield. Mesylation of the primary alcohol
of 80 followed by bromide displacement afforded the
desired bromo-azide 81.
Sch em e 13. F or m a l Syn th esis of Gep h yr otoxin
A F or m a l Syn th esis of Gep h yr otoxin . Our search
for a useful 2-hydroxyethyl side-chain equivalent had so
far led us to uncover several important aspects of the
Schmidt reaction required for the synthesis of gephyro-
toxin, but each strategy had a fatal flaw. Ultimately, we
narrowed our search to a 2-bromoethyl group, which
would survive the acidic conditions of the Schmidt
reaction, but would be easily transformed into a 2-hy-
droxyethyl group without relying on an oxidative reac-
tion. We were initially concerned that the 2-bromoethyl
group might lead to complications arising from azeti-
dinium ion formation after the Schmidt reaction, since
γ-bromoamines are well-known to cyclize to such ions.51
However, since the product of the rearrangement would
produce an aniline-type nitrogen, this concern was
diminished.
As shown in Scheme 13, treatment of 81 with trifluo-
romethanesulfonic acid in benzene followed by sodium
borohydride reduction of the resultant iminium ions 82
and 83 generated a mixture of Schmidt products which
were subjected, without purification, to displacement by
acetate ion. Again without purification, the mixture of
acetates was reduced with lithium aluminum hydride to
produce a mixture of the desired alcohol 49, its stereo-
isomer 84, and the regioisomer 85 in good overall yield
from 81. As in earlier attempts, the stereoselectivity of
the reduction of the desired iminium ion was poor. We
were able to overcome the nonselective reduction by
switching to bulkier reducing agents. L-Selectride proved
to be the best choice, ultimately producing the desired
compound 49 as a single diastereomer (i.e., none of 84
was detected) accompanied by a small amount of the
regioisomer 85. The overall yield of 49 from 81 using this
procedure was 45%. Since the aromatic ring of 49 has
been reduced by Ito et al.36 to afford an advanced
intermediate in Kishi’s synthesis of gephyrotoxin,31 our
synthesis of 49 constitutes a formal total synthesis of
gephyrotoxin 4. The synthesis of 49 required nine steps
(five purifications) from commercially available 4-meth-
oxy-1-indanone 60 and proceeded in 22% overall yield.
Mech a n istic Con sid er a tion s. A summary of the
results from the Schmidt reactions of the azides 33
(Scheme 3), 56 (Scheme 7), 61/62 (Scheme 9), 72 (Scheme
10), 75 (Scheme 11), and 81 (Scheme 13), represented
by the generic azide 86, to the benzoidolizidine iminium
ions 90 and 93 are tabulated at the bottom of Scheme
14. No simple general explanation for the regioselectivity
of the rearrangment is apparent, especially when one
considers that the side-chain R in the cations 87 (where
Sch em e 12. In cor p or a tion of a 2-Br om oeth yl
Sid e-Ch a in
The synthesis of the Schmidt reaction precursor 81 is
presented in Scheme 12. Formation of the Grignard
reagent derived from 69 (see Scheme 10) followed by a
copper-catalyzed opening of the epoxide 7852 according
to a procedure similar to that reported by Kocienski53
(51) (a) Gibbs, C. F.; Marvel, C. S. J . Am. Chem. Soc. 1934, 56, 725-
727. (b) Gibbs, C. F.; Marvel, C. S. J . Am. Chem. Soc. 1935, 57, 1137-
1139. (c) Grob, C. A.; Waldner, A. Helv. Chim. Acta 1980, 63, 2152-
2158. (d) Ringdahl, B.; Roch, M.; J enden, D. J . J . Med. Chem. 1988,
31, 160-164.
(52) Hanessian, S.; Tehim, A.; Chen, P. J . Org. Chem. 1993, 58,
7768-7781.
(53) Street, S. D. A.; Yeates, C.; Kocienski, P.; Campbell, S. F. J .
Chem. Soc. Chem. Commun. 1985, 20, 1386-1388.

7166 J . Org. Chem., Vol. 65, No. 21, 2000
Pearson and Fang
Sch em e 14. Sch m id t P a th w a ys to
Gep h yr otoxin -typ e Com p ou n d s
substituent Y on the aryl ring would lead to unfavorable
steric interactions in 88, 89, and 92, leaving 91 to account
for the rearrangement, which would produce the aryl
migration product 93. The other rearrangements give
lower regioselectivities, and a simple explanation for the
trends shown at the bottom of Scheme 14 is not apparent.
In particular, the higher selectivity for aryl migration
when R ) 2-bromoethyl (81; 3.9:1 aryl:alkyl migration)
versus the nonselectivity when R ) Et (56) or R ) allyl
(75) is intriguing. Nonetheless, this selectivity has proven
useful for our application to the formal synthesis of
gephyrotoxin.
Con clu sion
The intramolecular Schmidt reaction of azides with
carbocations has proven to be an effective way to as-
semble a variety of benzo-fused 1-azabicyclo[m.n.0]-
alkanes. In general, aryl migration in the intermediate
aminodiazonium ion is preferred over alkyl migration,
leading to anilines rather than benzylic amines, which
are easily separated by column chromatography due to
their diverse polarities. The ease of synthesis of the
Schmidt cyclization precursors is another attractive
feature of this chemistry. The methodology was shown
to be useful for the synthesis of the tricyclic core of the
alkaloid gephyrotoxin, resulting in a formal total syn-
thesis of this compound. The aryl vs alkyl regioselectivity
proved to be subject to small changes in the structure,
but again, aryl migration was often preferred, producing
aniline-like benzo-fused indolizidines.
Exp er im en ta l Section 55
(7E)- a n d (7Z)-7-(3-Hyd r oxyp r op ylid en e)bicyclo[4.2.0]-
octa -1(6),2,4-tr ien e (29). n-Butyllithium (10.5 mL of a 2.5
M solution in hexane, 26.3 mmol) was added to a suspension
of (3-hydroxypropyl)triphenylphosphonium bromide (27)8 (10.26
g, 25.59 mmol) in THF (80 mL) at 0 °C. After warming the
mixture to room temperature over 10 min, it was recooled to
0 °C and treated with chlorotrimethylsilane (3.25 mL, 2.78 g,
25.6 mmol). After 10 min, benzocyclobutenone (28)9 (3.02 g,
25.56 mmol) in THF (10 mL) was added. After refluxing for
20 min, the mixture was cooled to 0 °C and treated with tetra-
n-butylammonium fluoride (30 mL of a 1.0 M solution in THF,
30 mmol). After 30 min at room temperature, the solution was
concentrated and diluted with water (50 mL) and then
extracted with ether (3×). The combined organic phases were
washed with brine (3×), then dried (MgSO4) and concentrated.
Chromatography (2:1 hexane/ether) gave 1.26 g (31%) of the
title compounds as an inseparable 2:1 mixture of E and Z
isomers as judged by 1H NMR, where the major isomer was
assigned as the E configuration based on the larger J allylic,transoid
(1.4 Hz) coupling constant (J allylic,cisoid ca. 0 Hz).56 Characterized
of the mixture: Rf ) 0.25 (2:1 hexane/ether): 1H NMR (CDCl3,
300 MHz) δ 7.27-7.19 (m, 6 H), 7.15-7.12 (m, 1 H), 5.74 (tt,
J ) 7.6, 1.4 Hz, 1 H), 5.34 (t, J ) 7.6 Hz, 0.7 H), 3.80-3.69
(m, 3.5 H), 3.63 (s, 2H), 3.60 (s, 1.5 H), 2.65 (q, J ) 6.5 Hz, 1.5
H), 2.43 (q, J ) 6.5 Hz, 2 H), 2.13-2.06 (m, 1.7 H); 13C NMR
(CDCl3, 75 MHz) δ 144.9, 144.8, 144.5, 143.8, 139.6, 138.9,
128.1, 127.1, 122.6, 119.8, 117.6, 116.6, 114.8, 62.2, 38.0, 36.8,
33.5, 32.4; IR (neat) 3334 (br s) cm-1; MS (CI with NH3) m/z
(rel int) 161 ([M + H]+, 100), 143 (21.7); HRMS (CI with NH3)
calcd for C11H12OH ([M + H]+) 161.0966, found 161.0961.
(7E)- a n d (7Z)-7-(3-Azid op r op ylid en e)bicyclo[4.2.0]-
octa -1(6),2,4-tr ien e (30). Diisopropyl azodicarboxylate (3.25
R * H) renders the faces of the carbocation diaste-
reotopic, resulting in two diastereomeric aminodiazonium
ion manifolds represented by 88/89 (2,5-cis) and 91/92
(2,5-trans). Is the regioselectivity of the rearrangement
related to the diastereoselectivity of the capture of the
cation by the azide, or is that step a rapid preequilibrium,
making the rearrangement step rate determining? As-
suming such a preequilibrium, we are still left with a
problem. Since it is known that pyramidal inversion in
aminodiazonium ions is a low-barrier (ca. 1 kcal/mol)
event,54,2b one can assume that N-inversion is rapid and
reversible, leaving the rearrangement of the four ions 88/
89 and 91/92 as the likely rate-determining steps. In the
2,5-cis manifold, models suggest that 88 would be pre-
ferred over 89 because of the steric interaction shown,
but according to the Curtin-Hammett principle, this
preference may be irrelevant, since the barrier to inter-
conversion of 88 and 89 is so much lower than the
expected barrier for the rearrangement to 90 and 93,
respectively. A similar analysis holds for 91 and 92 from
the 2,5-trans manifold, where 91 seems more favorable
than 92 according to models, but it may be irrelevant.
Thus, we are left with a very complex picture, made more
difficult by the lack of knowledge about the transition
states for aryl vs alkyl migration, as discussed previously.
At least one piece of data may be explained by the
analysis shown in Scheme 14, i.e., that azide 62 (Scheme
9) leads to aryl migration as the sole product, i.e., yielding
the iminium ion 93 in Scheme 14. The o-methoxy
(55) For general experimental issues, see: Pearson, W. H.; Hembre,
E. J . J . Org. Chem. 1996, 61, 5537-5545.
(56) Newsoroff, G. P.; Sternhell, S. Aust. J . Chem. 1972, 25, 1669-
1693.
(54) Glaser, R.; Choy, G. S.-C. J . Phys. Chem. 1991, 95, 7682-7693.

1-Azabicyclo[m.n.0]alkanes via the Schmidt Reaction
J . Org. Chem., Vol. 65, No. 21, 2000 7167
mL, 3.34 g, 16.52 mmol) was added to a mixture of the alcohols
29 (1.30 g, 8.11 mmol), triphenylphosphine (4.26 g, 16.23
mmol), and Zn(N3)2‚(pyridine)2 (2.00 g, 6.50 mmol) in toluene
(40 mL) at room temperature over 10 min.10 After 40 min, the
mixture was concentrated, and the residue was chomato-
graphed (2:1 hexane/ether) to give 1.16 g (77%) of the title
compounds as an inseparable 2:1 mixture of E and Z isomers
249 mg (49%) of an inseparable 1.5:1 mixture of 11 and 15 as
judged by H NMR spectroscopy as outlined above.
1
3-(3-Azid op r op yl)-1H-in d en e (33). n-Butyllithium (48.0
mL of a 2.5 M solution in hexane, 0.12 mol) was added to a
solution of indene (32, 11.62 g, 0.10 mol) in THF (200 mL) at
0 °C. After 30 min, the solution was cooled to -78 °C, 1-chloro-
3-iodopropane (16.1 mL, 30.7 g, 0.15 mol) was added, and the
resulting mixture was allowed to warm to room temperature.
After 14 h, saturated aqueous ammonium chloride was added,
and the mixture was extracted with ether (3×). The combined
organic phases were washed twice with brine, dried (MgSO4),
and concentrated to give the crude product, which was
dissolved in DMSO (250 mL) and treated with NaN3 (13.00 g,
0.20 mol). After 14 h at 40 °C, water was added, and the
resulting mixture was extracted with ether (3×). The combined
organic phases were washed with water (3×) and brine and
then dried (MgSO4) and concentrated. Chromatography (1:16
ether/hexane) gave 12.42 g (62%) of the title compound as a
clear oil, Rf ) 0.60 (1:7 ether/hexane): 1H NMR (CDCl3, 360
MHz) δ 7.51 (d, J ) 7.3 Hz, 1 H), 7.42-7.34 (m, 2 H), 7.26 (dt,
J ) 7.3, 1.4 Hz, 1 H), 6.29-6.28 (m, 1 H), 3.45-3.39 (m, 4 H),
2.70 (tt, J ) 5.2, 1.6 Hz, 2 H), 2.07-1.99 (m, 2 H); 13C NMR
(CDCl3, 90 MHz, J MOD) δ 145.0 (-), 144.5 (-), 143.0 (-), 128.5
(+), 126.1 (+), 124.7 (+), 123.8 (+), 118.8 (+), 51.0 (-), 37.7
(-), 27.2 (-), 24.7 (-); IR (neat) 2096 (s) cm-1; MS (EI, 70 eV)
m/z (rel int) 170 ([M - N2 - H]+, 100), 141 (14.1); HRMS calcd
for C12H12N ([M - N2 - H]+) 170.0970, found 170.0974.
1,2,3,3a,4,5-Hexah ydr opyr r olo[1,2-a ]qu in olin e (12)15 an d
1,2,3,5,6,10b-Hexah ydr opyr r olo[2,1-a ]isoqu in olin e (16).18,19
Trifluoromethanesulfonic acid (1.15 g, 7.68 mmol) was added
to a solution of the azido indene 33 (1.02 g, 5.13 mmol) in dry
benzene (250 mL) at 15 °C via syringe. After 10 min, the
mixture was cooled to 0 °C, and sodium borohydride (1164 mg,
30.77 mmol) in methanol (30 mL) was added. After 14 h at
room temperature, 15% NaOH (80 mL) was added, and the
resulting mixture was extracted with ether (3×). The combined
organic phases were washed with brine, dried (Na2SO4), and
concentrated. Chromatography (1:16 ether/hexane) gave 569
mg (64%) of 1215 as a clear oil, Rf ) 0.46. Compound 12 was
reported by Caddick and co-workers without spectral data,
thus full characterization is provided here: 1H NMR (CDCl3,
300 MHz) δ 7.05 (t, J ) 7.7 Hz, 1 H), 6.96 (d, J ) 7.1 Hz, 1 H),
6.53 (t, J ) 7.3 Hz, 1 H), 6.38 (d, J ) 8.0 Hz, 1 H), 3.44-3.35
(m, 1 H), 3.33-3.25 (m, 1 H), 3.23-3.15 (m, 1 H), 2.85-2.70
(m, 2 H), 2.14-1.99 (m, 3 H), 1.95-1.85 (m, 1 H), 1.52-1.34
(m, 2 H); 13C NMR (CDCl3, 75 MHz) δ 144.9, 128.3, 127.0,
121.3, 114.9, 110.0, 58.1, 47.0, 33.2, 28.3, 27.7, 23.9; IR (neat)
2604 (w), 1873 (w), 1748 (w), 1604 (s), cm -1; MS (CI with NH3)
m/z (rel int) 174 ([M + H]+, 100), 158 (2.3), 145 (15.1); HRMS
(CI with NH3) calcd for C12H15NH 174.1283, found 174.1270.
Further elution with 0.5:5:100 NH3/MeOH/ether gave 245
mg (28%) of 1618,19 as a clear oil, Rf ) 0.46 (0.5:5:100 NH3/
MeOH/ether): 1H NMR (CDCl3, 300 MHz) δ 7.15-7.10 (m, 3
H), 7.08-7.05 (m, 1 H), 3.40 (t, J ) 7.6 Hz, 1 H), 3.23-3.16
(m, 1 H), 3.13-3.06 (m, 2 H), 2.86-2.75 (m, 1 H), 2.67-2.58
(m, 1 H), 2.51 (q, J ) 8.5 Hz, 1 H), 2.41-2.29 (m, 1 H), 2.00-
1.82 (m, 2 H), 1.79-1.66 (m, 1 H); 13C NMR (CDCl3, 75 MHz)
δ 139.0, 134.2, 128.3, 125.9, 125.6, 125.5, 63.4, 53.4, 48.6, 30.3,
28.7, 22.3; IR (neat) 2783 (s), 2730 (s), 1605 (w), 1493 (s), 1452
(s) cm -1; MS (CI with NH3) m/z (rel int) 174 ([M + H]+, 100),
157 (1.1), 145 (23.7), 130 (5.0), 117 (9.4), 103 (1.0), 91 (2.3);
HRMS (CI with NH3) calcd for C12H15NH 174.1283, found
1
as judged by H NMR, where the major isomer was assigned
as the E configuration based on the larger J allylic,transoid (1.4 Hz)
coupling constant (J allylic,cisoid ca. 0 Hz).56 Characterized of the
mixture: Rf ) 0.62 (1:2 ether/hexane): 1H NMR (CDCl3, 300
MHz) δ 7.26-7.23 (m, 6.2 H), 7.18-7.15 (m, 1 H), 5.75 (t, J )
7.1 Hz, 1 H), 5.35 (t, J ) 7.5 Hz, 0.8 H), 3.66 (s, 2 H), 3.62 (s,
1.6 H), 3.46-3.38 (m, 3.6 H), 2.70 (q, J ) 7.1 Hz, 1.6 H), 2.49
(q, J ) 7.1 Hz, 2 H); 13C NMR (CDCl3, 75 MHz) δ 145.0, 144.7,
144.3, 143.8, 139.8, 139.1, 128.4, 127.2, 122.7, 119.8, 117.8,
116.0, 114.2, 51.2, 38.0, 36.7, 28.6; IR (neat) 2096 (s) cm-1
;
MS (CI with NH3) m/z (rel int) 203 ([M+NH4]+, 4.3), 158 (100);
HRMS (CI with NH3) calcd for C11H11N3NH4 ([M+NH4]+)
203.1297, found 203.1296.
2,3,8,8a-Tetr ah ydr o-1H-3a-azacyclopen ta[a ]in den e (11),
2,3,5,9b-Tetr a h yd r o-1H-p yr r olo[2,1-a ]isoin d ole (15), a n d
2,3-Dih yd r o-1H-3a -a za cyclop en ta [a ]in d en e (31). Meth od
A. Trifluoromethanesulfonic acid (254 mg, 1.68 mmol) was
added to a solution of the azidoalkene 30 (300 mg, 1.62 mmol)
in benzene (20 mL) at 0 °C. After 10 min, a solution of sodium
borohydride (400 mg, 10.57 mmol) in methanol (10 mL) was
added, and the mixture was warmed to room temperature for
14 h and treated with 15% aqueous sodium hydroxide (15 mL).
The mixture was extracted with ether (3×), and the combined
organic phases were washed with brine (3×), dried (MgSO4)
and concentrated. Chromatography (1:7 ether/hexane) gave 68
mg (27%) of the known indole 31,12,14,15 Rf ) 0.53: 1H NMR
(CDCl3, 360 MHz) δ 7.65 (d, J ) 7.7 Hz, 1 H), 7.33-7.29 (m,
1 H), 7.24-7.15 (m, 2 H), 6.26 (s, 1 H), 4.10 (t, J ) 6.9 Hz, 2
H), 3.08 (t, J ) 7.5 Hz, 2 H), 2.65 (qintet, J ) 7.1 Hz, 2 H); 13
C
NMR (CDCl3, 90 MHz) δ 144.5, 133.2, 132.4, 120.2, 120.0,
119.0, 109.3, 92.2, 43.5, 27.7, 24.2; IR (neat) 1616 (m), 1551
(m) cm-1; MS (EI, 70 eV) m/z (rel int) 157 (M+, 100), 129 (24.9);
HRMS calcd for C11H11N 157.0891, found 157.0886. These
spectral data were consistent with those reported in the
literature.12,14
Further elution gave 53 mg (21%) of an inseparable 1:1.3
mixture of 1111,12 and 15.13 The major isomer was assigned as
1
11 based on the doublet at δ 6.60 (J ) 7.8 Hz) in the H NMR
spectrum, which should result from the coupling of the benzylic
hydrogens with the bridgehead hydrogen in 11. An AB quartet
at δ 4.44 was assigned to the benzylic hydrogens in 15.
Characterization of the mixture of 11 and 15: Rf ) 0.30 (1:7
ether/hexane): 1H NMR (CDCl3, 360 MHz) δ 7.35-7.26 (m, 2
H), 7.20-7.12 (m, 3 H), 7.10-7.07 (m, 2 H), 6.75 (t, J ) 7.4
Hz, 1.5 H), 6.60 (d, J ) 7.8 Hz, 1.5 H), 4.90-4.88 (m, 1 H),
4.44 (ABq, ∆νAB ) 86.3 Hz, J AB ) 15.2 Hz, 2 H), 3.96-3.89
(m, 1.5 H), 3.47-3.39 (m, 3 H), 3.23-3.15 (m, 3 H), 3.00-2.93
(m, 3 H), 2.62-2.54 (m, 1 H), 2.29-2.22 (m, 1 H), 2.11-2.03
(m, 1 H), 1.94-1.75 (m, 5 H), 1.38-1.28 (m, 1 H); 13C NMR
(CDCl3, 90 MHz, J MOD) δ 154.6 (-), 141.2 (-), 135.7 (-), 129.8
(-), 128.3 (+), 128.1 (+), 127.4 (+), 124.7 (+), 122.6 (+), 122.5
(+), 119.1 (+), 110.8 (+), 78.2 (+), 68.2 (-), 65.1 (+), 63.0 (-),
52.1 (-), 33.8 (-), 31.2 (-), 30.6 (-), 25.7 (-), 24.3); IR (neat)
2365 (s), 2317 (s), 2270 (s), 1603 (s) cm-1; MS (EI, 70 eV) m/z
(rel int) 159 (M+, 100), 143 (5.3), 130 (77.3); HRMS calcd for
1
C
11H13N 159.1048, found 159.1043.
174.1275. The H NMR and IR spectral data were consistent
The overall ratio of aryl migration products (11+31) to alkyl
migration product (15) was thus 3:1.
with those reported in the literature.18,19 The overall yield
(12+16) was 92%.
Meth od B. Trifluoromethanesulfonic acid (475 mg, 3.17
mmol) was added to a solution of the azidoalkene 30 (594 mg,
3.21 mmol) in benzene (50 mL) at room temperature. After 10
min, the solution was cooled to 0 °C and treated with BH3‚
SMe2 (4.50 mL of a 2.0 M solution in THF, 9.00 mmol). After
being warmed to room temperature for 14 h, the solution was
treated with saturated aqueous sodium bicarbonate (20 mL),
and the mixture was extracted with ether (3×). The combined
organic phases were washed with brine (3×), dried (MgSO4),
and concentrated. Chromatography (1:7 ether/hexane) gave
1-[(2-Hydr oxym eth yl)ph en yl]m eth ylin dan -1-ol (36). Ce-
rium chloride heptahydrate (22.40 g, 60.12 mmol) was heated
to 140 °C in vacuo (<0.1 mmHg) for 3 h. Nitrogen was
introduced, the flask was cooled to 0 °C, and cold (0 °C) THF
(160 mL) was added. The resulting suspension was stirred at
room temperature for 14 h.21 In another flask, the dianion of
2-methylbenzyl alcohol (34) was prepared.20 Thus, 2-methyl-
benzyl alcohol (3.66 g, 30.0 mmol) was dissolved in THF (8.0
mL) and cooled to -78 °C. tert-Butyllithium (39.0 mL of a 1.7
M solution in pentane, 66 mmol) was slowly added. After the

7168 J . Org. Chem., Vol. 65, No. 21, 2000
Pearson and Fang
solution was allowed to warm to 0 °C over 30 min, an
additional portion of THF (100 mL) was added, and the
resultant red solution of the dianion was transferred via
cannula to the CeCl3 suspension prepared above, which had
been cooled to -78 °C. After 1 h, a solution of 1-indanone (35,
2.64 g, 19.98 mmol) in THF (40 mL). After 1 h, the mixture
was allowed to warm to room temperature over 2 h and then
quenched by the addition of 10% aqueous acetic acid (150 mL).
The mixture was extracted with ether (3×), and the combined
organic phases were washed with saturated sodium bicarbon-
ate (4×) and brine (2×) and then dried (MgSO4) and concen-
trated. Chromatography (2:1 ether/hexane) gave 4.66 g (92%)
of the title compound as a colorless oil, Rf ) 0.20 (2:1 ether/
hexane): 1H NMR (CDCl3, 300 MHz) δ 7.26-7.12 (m, 6 H),
7.00 (d, J ) 7.5 Hz, 1 H), 6.90 (d, J ) 7.1 Hz, 1 H), 4.48 (ABq,
∆νAB ) 27.9 Hz, J AB ) 11.8 Hz, 2 H), 3.90 (br s, 2 H), 3.09
(ABq, ∆νAB ) 59.9 Hz, J AB ) 14.0 Hz, 2 H), 2.92-2.88 (m, 2
H), 2.47-2.42 (m, 1 H), 1.93 (dd, J ) 12.7, 9.0 Hz, 1 H); 13C
NMR (CDCl3, 75 MHz) δ 147.2, 142.2, 140.1, 135.7, 132.1,
130.1, 128.1, 127.3, 126.8, 126.2, 124.7, 123.6, 83.2, 63.1, 42.0,
41.1, 29.2; IR (neat) 3285 (s) cm-1; MS (EI, 70 eV) m/z (rel int)
chloride (10.0 mL of a 2.0 M solution in THF, 20 mmol) was
added via syringe. After 30 min, triethylamine (10 mL, 7.3 g,
72 mmol) and methanesulfonyl chloride (1.55 mL, 2.29 g, 20.0
mmol) were added sequentially. After this mixture was
warmed to room temperature over 1 h, concentrated hydro-
chloric acid (10 mL) and water (10 mL) were added. After 30
min, the mixture was extracted with ether (3×), and the
combined organic phases were washed twice with saturated
aqueous sodium bicarbonate and once with brine and then
dried (MgSO4) and concentrated to afford the crude dienes 42.
To this material was added 9-BBN (40 mL of a 0.5 M solution
in THF, 20 mmol) at room temperature.49 The resultant
solution was kept at 80 °C for 1 h, cooled to room temperature,
and carefully treated with 5 N sodium hydroxide (10 mL) and
hydrogen peroxide (30% in water, 10 mL). The resultant
mixture was heated to 60 °C for 1 h and then cooled to room
temperature. The aqueous layer was saturated with solid
potassium carbonate, and the organic phase was separated,
dried (MgSO4), and concentrated. Chromatography (1:2 ether/
hexane) gave 1.44 g (77%) of the title compounds as a colorless
oil, Rf ) 0.29 (1:2 ether/hexane), which was found to be an
inseparable 1.3:1 mixture of the endo- and exocyclic alkene
regioisomers 43 and 44, respectively, by 1H NMR spectroscopy.
The endocyclic alkene regioisomer 43 is known in the litera-
ture,23 but no spectral data were reported. Data on the mixture
of isomers: 1H NMR (CDCl3, 300 MHz) δ 7.66-7.63 (m, 0.43
H), 7.33-7.12 (m, 3.57 H), 6.07 (t, J ) 7.3 Hz, 0.43 H), 5.93 (t,
J ) 4.5 Hz, 0.57 H), 3.79-3.68 (m, 2 H), 2.84-2.76 (m, 3 H),
2.60-2.49 (m, 2 H), 2.33-2.26 (m, 1 H), 1.92-1.78 (m, 2 H),
1.75-1.52 (m,1 H); 13C NMR (CDCl3, 75 MHz) δ 137.1, 136.5,
135.8, 134.6, 128.6, 127.4, 126.4, 126.1, 125.8, 125.3, 124.8,
123.5, 122.4, 119.6, 62.3, 62.1, 31.7, 31.3, 30.4, 28.8, 28.4, 26.6,
23.2, 23.1; IR (neat) 3332 (br s) cm-1; MS (EI, 70 eV) m/z (rel
int) 188 (M+, 37.3), 157 (68.2), 144 (91.0), 129 (100); HRMS
calcd for C13H16O 188.1201, found 188.1198.
236 ([M - H2O]+, 12.6), 104 (100); HRMS calcd for C17H16
O
([M - H2O]+) 236.1201, found 236.1192.
1-[(2-Azid om eth yl)p h en yl]m eth ylin d a n -ol (37). Diiso-
propyl azodicarboxylate (7.17 mL, 7.36 g, 36.4 mmol) was
slowly added to a mixture of the diol 36 (4.56 g, 17.93 mmol),
triphenylphosphine (9.41 g, 35.88 mmol), and Zn(N3)2‚(pyridine)2
(6.50 g, 21.13 mmol) in toluene (90 mL) at room temperature
over 15 min.10 After 1 h, the solution was concentrated, and
the residue was chomatographed (2:1 hexane/ether) to give
4.35 g (87%) of the title compound, Rf ) 0.39 (2:1 hexane/
ether): 1H NMR (CDCl3, 360 MHz) δ 7.32-7.24 (m, 6 H), 7.14
(dt, J ) 7.6, 2.1 Hz, 1 H), 6.85 (d, J ) 7.6 Hz, 1 H), 4.08 (ABq,
∆νAB ) 14.8 Hz, J
) 13.8 Hz, 2 H), 3.90 (br s, 2 H), 3.13
AB
(ABq, ∆νAB ) 50.1 Hz, J AB ) 14.0 Hz, 2 H), 2.95 (ddd, J )
16.1, 8.7, 5.8 Hz, 1 H), 2.88-2.81 (m, 1 H), 2.45-2.39 (m, 1
H), 2.08-1.99 (m, 1 H), 1.34-1.31 (m, 1 H); 13C NMR (CDCl3,
90 MHz, J MOD) δ 146.7 (-), 142.1 (-), 135.7 (-), 134.8 (-),
132.1 (+), 129.2 (+), 128.1 (+), 127.7 (+), 126.8 (+), 126.2 (+),
124.7 (+), 123.2 (+), 83.6 (-), 52.4 (-), 41.6 (-), 41.2 (-), 29.1
(-); IR (neat) 3431 (br s), 2098 (s) cm-1; MS (CI with NH3)
m/z (rel int) 262 ([M - H2O + H]+, 1.5), 234 (100); HRMS (CI
with CH4) calcd for C17H16N ([M - N2 - OH]+) 234.1283, found
234.1284.
1-(3-Azid op r op yl)-3,4-d ih yd r on a p h th a len e (45). Meth-
anesulfonyl chloride (2.9 mL, 4.3 g, 37 mmol) was added to a
solution of the alcohols 43 and 44 (3.50 g, 18.59 mmol, a
mixture of endocyclic and exocyclic double bond isomers), and
triethylamine (7.8 mL, 5.6 g, 56 mmol) in CH2Cl2 (50 mL) at
0 °C. After 1.4 h, the mixture was diluted with ether and
washed with brine, and then dried (MgSO4) and concentrated
to give the crude mesylate, which was dissolved in DMSO (80
mL) and treated with sodium azide (3.63 g, 55.84 mmol) at
room temperature. After 14 h, the mixture was diluted with
water and then extracted with ether (3×). The combined
organic phases were washed twice with water and once with
brine and then dried (MgSO4) and concentrated. The crude
azidoalkene was then dissolved in CH2Cl2 (30 mL) and treated
with trifluoroacetic acid (1.43 mL, 2.12 g, 18.6 mmol) at room
temperature to induce double bond isomerization. After 30
min, the solution was concentrated, and the residue was
chromatographed (hexane) to give 2.82 g (71%) of the title
compound as a clear oil, which was found to be a 10:1 ratio of
45 and another alkene isomer, presumably the exocyclic
6,6a ,7,12-Tet r a h yd r o -5H -12a -a za b en zo[a ]a n t h a cen e
(39). Trifluoromethanesulfonic acid (339 mg, 2.26 mmol) was
added to a solution of the azide 37 in benzene (30 mL) at room
temperature. After 10 min, the solution was cooled to 0 °C and
treated with borane dimethyl sulfide complex (3.0 mL of a 2.0
M solution in THF, 6.0 mmol). After the mixture was warmed
to room temperature for 14 h, 15% aqueous sodium hydroxide
(15 mL) was added, and the resulting mixture was extracted
with ether (3×). The combined organic phases were washed
with brine, dried (MgSO4), and concentrated. Chromatography
(1:7 ether/hexane) gave 307 mg (67%) of the known title
compound 39,22 Rf ) 0.40. Ochiai and Suzuki22 reported only
elemental analysis for this compound, thus full characteriza-
tion is provided: 1H NMR (CDCl3, 300 MHz) δ 7.21-7.12 (m,
5 H), 7.00 (d, J ) 7.3 Hz, 1 H), 6.83 (d, J ) 8.2 Hz, 1 H), 6.71-
6.66 (m, 1 H), 4.76 (d, J ) 15.8 Hz, 1 H), 4.22 (d, J ) 15.8 Hz,
1 H), 3.38-3.30 (m, 1 H), 2.96-2.65 (m, 4 H), 2.11-2.01 (m, 1
H), 1.96-1.87 (m, 1 H); 13C NMR (CDCl3, 75 MHz) δ 146.1,
134.8, 134.2, 128.3, 128.2, 127.1, 126.3, 126.1, 126.0, 125.2,
1
1
alkene, as judged by H NMR spectroscopy, Rf ) 0.34. The H
NMR signals from the minor isomer overlapped with those of
the major isomer; therefore, only the resonances for the major
isomer are provided here: 1H NMR (CDCl3, 300 MHz) δ 7.26-
7.17 (m, 4 H), 5.93-5.90 (m, 1 H), 3.35 (t, J ) 6.8 Hz, 12 H),
2.77 (dd, J ) 8.7, 7.7 Hz, 2 H), 2.60-2.53 (m, 2 H), 2.32-2.25
(m, 2 H), 1.90-1.81 (m, 2 H); 13C NMR (CDCl3, 75 MHz) δ
136.8, 135.2, 134.4, 127.7, 126.8, 126.4, 125.8, 122.5, 51.2, 29.9,
28.6, 27.8, 23.3; IR (neat) 2095 (s), cm-1; MS (EI, 70 eV) m/z
(rel int) 213 (M+, 2.2), 184 (100); HRMS calcd for C13H15N3
213.1266, found 213.1260.
117.2, 112.1, 53.1, 50.3, 37.5, 29.7, 26.7; IR (neat) 1603 (s) cm-1
;
MS (EI, 70 eV) m/z (rel int) 235 (M+, 100), 220 (11.1), 84 (95.8);
HRMS (EI, 70 eV) calcd for C17H17N 235.1361, found 235.1352.
1-(3-Hyd r oxyp r op yl)-3,4-d ih yd r on a p h th a len e (43) a n d
1-(3-H yd r oxyp r op ylid en e)-1,2,3,4-t et r a h yd r on a p h t h a -
len e (44). Cerium chloride heptahydrate (5.60 g, 15.00 mmol)
was dried at 137 °C in vacuo (<0.1 mmHg) for 3 h. Nitrogen
was introduced, the flask was cooled to 0 °C, and cold THF
(40 mL, 0 °C) was added.21 After the 14 h, a solution of
R-tetralone (41, 1.46 g, 10.00 mmol) in dry THF (15 mL) was
added, and the mixture was warmed to room temperature for
1 h. After this mixture was cooled to 0 °C, allylmagnesium
2,3,3a ,4,5,6-Hexa h yd r o-1H-b en zo[f]p yr r olo[1,2-a ]a ze-
p in e (14). Trifluoromethanesulfonic acid (950 mg, 6.33 mmol)
was added to a solution of the azidoalkene 45 (894 mg, 4.19
mmol) in dry benzene (25 mL) at 15 °C. After 10 min, the
mixture was cooled to 0 °C and treated with a solution of
sodium borohydride (950 mg, 25.11 mmol) in methanol (15
mL). The resultant mixture was warmed to room temperature
for 14 h and then treated with saturated aqueous sodium
bicarbonate (20 mL). The mixture was extracted with ether

1-Azabicyclo[m.n.0]alkanes via the Schmidt Reaction
J . Org. Chem., Vol. 65, No. 21, 2000 7169
(3×), and the combined organic phases were washed twice with
brine, dried (Na2SO4), and concentrated. Chromatography (1:7
ether/hexane) gave 563 mg (72%) of the known24 title com-
pound, Rf ) 0.58, 1H NMR (CDCl3, 300 MHz) δ 7.25-7.16 (m,
2 H), 6.96-6.84 (m, 2 H), 3.40-3.22 (m, 3 H), 3.11-3.02 (m, 1
H), 2.77 (ddd, J ) 14.2, 10.1, 2.2 Hz, 1 H), 2.32-2.19 (m, 1 H),
2.12-1.92 (m, 4 H), 1.82-1.78 (m, 2 H), 1.63-1.51 (m, 1 H);
13C NMR (CDCl3, 75 MHz) δ 149.5 (-), 132.8 (-), 130.4 (+),
126.4 (+), 119.3 (+), 114.5 (+), 61.8 (+), 51.6 (-), 37.6 (-),
90 MHz, J MOD) δ 144.0 (-), 143.8 (-), 129.1 (+), 128.3 (+),
127.0 (+), 126.6 (+), 121.7 (-), 114.7 (+), 114.1 (+), 110.8 (+),
109.4 (+), 59.8 (+), 58.6 (+), 58.2 (+), 32.3 (-), 30.6 (-), 30.3
(-), 30.0 (+), 28.6 (-), 28.5 (-), 28.4 (-), 28.0 (-), 27.4 (-),
26.1 (-), 25.3 (-), 10.8 (+), 9.8 (+); IR (neat) 1602 (s) cm-1
;
MS (EI, 70 eV) m/z (rel int) 201 (M+, 20.1), 172 (100); HRMS
(EI, 70 eV) calcd for C14H19N 201.1517, found 201.1526.
Further elution with 1:3 ether/hexanes gave 146 mg (35%)
of the tricyclic compound 58 as a clear oil. Assignment of the
relative configuration of 58 is based on the stereoelectronic
model proposed for reduction of analogous iminium ions.57-59
Data for 58: 1H NMR (CDCl3, 360 MHz) δ 7.13-7.09 (m, 3
H), 7.07-7.03 (m, 1 H), 3.33 (ddd, J ) 10.8, 7.2, 1.1 Hz, 1 H),
3.25-3.09 (m, 2 H), 2.87 (dd, J ) 16.9, 4.7 Hz, 1 H), 2.34 (dd,
J ) 11.3, 5.0 Hz, 1 H), 2.31-2.21 (m, 2 H), 2.12-2.01 (m, 1
H), 1.89-1.79 (m, 1 H), 1.73-1.62 (m, 1 H), 1.61-49 (m, 1 H),
1.36-1.26 (m, 1 H), 0.94 (t, J ) 7.5 Hz, 3 H); 13C NMR (CDCl3,
90 MHz, J MOD) δ 139.2 (-), 134.3 (-), 128.4 (+), 126.1 (+),
125.5 (+), 124.9 (+), 65.7 (+), 65.6 (+), 47.7 (-), 29.7 (-), 28.6
(-), 27.4 (-), 26.0 (-), 10.6 (+); IR (neat) 1493 (s), 1460 (s)
cm-1; MS (CI with NH3) m/z (rel int) 202 ([M + H]+, 100);
HRMS (CI with CH4) calcd for C14H19NH([M + H]+) 202.1596,
found 202.1590.
4- or 7-Meth oxy-1H-in d en e (53). Sodium borohydride
(2.33 g, 61.59 mmol) was added in small portions to a solution
of commercially available 4-methoxyindanone (60, 10.00 g,
61.66 mmol) in methanol (50 mL) at 0 °C. After 10 min, water
(50 mL) was added, and the mixture was concentrated and
diluted with ether. The organic phase was washed twice with
brine, dried (MgSO4), and concentrated. The crude 4-meth-
oxyindan-1-ol thus obtained was dissolved in THF (150 mL)
and treated with o-nitrophenyl selenocyanate (18.12 g, 85.03
mmol) at room temperature,41 followed by the slow addition
of tri-n-butylphosphine (19.8 mL, 16.1 g, 79.6 mmol). After 1
h, the reaction mixture was cooled to 0 °C and treated with
hydrogen peroxide (16 mL, 4.8 g, 141 mmol). The resulting
mixture was slowly warmed to room temperature over 3 h and
then diluted with ether. The organic layer was washed with
brine (3×, and then dried (MgSO4) and concentrated. Chro-
matography (1:7 ether/hexanes) yielded 6.62 g (80%) of the title
compound as a light yellow oil, Rf ) 0.58: 1H NMR (CDCl3,
360 MHz) δ 7.29 (t, J ) 5.5 Hz, 1 H), 7.09 (d, J ) 5.4 Hz, 1 H),
6.90 (br s, 1 H), 6.78 (d, J ) 8.0 Hz, 1 H), 6.60 (br s, 1 H), 3.94
(s, 3 H), 3.40 (br s, 2 H); 13C NMR (CDCl3, 90 MHz) δ 155.3,
146.6, 134.3, 131.8, 130.5, 127.9, 114.2, 107.0, 55.2, 36.5; IR
(neat) 1596 (s) cm-1; MS (EI, 70 eV) m/z (rel int) 146 (M+, 100),
131 (50.4); HRMS calcd for C10H10O 146.0732, found 146.0739.
The spectral data of this compound support a single position
of the indene double bond, but we have not assigned its
position.
35.4 (-), 34.0 (-), 25.7 (-), 24.1 (-); IR (neat) 1597 (s) cm-1
;
MS (EI, 70 eV) m/z (rel int) 187 (M+, 100), 170 (9.3), 158 (74.1);
HRMS calcd for C13H17N 187.1361, found 187.1357. These data
are consistent with those reported by Meyers.24
3-(3-Azid op en t yl)-1H -in d en e (56). Methyllithium (21.3
mL of a 1.40 M solution in ether, 29.8 mmol) was added to a
solution of indene (32, 2.89 g, 24.89 mmol) in THF (40 mL) at
0 °C. After 30 min, 3-chloro-3-(trimethylsilyloxy)pentane (54)40
(2.89 g, 16.59 mmol) was added. After 14 h at room temper-
ature, the mixture was treated with water (40 mL), and the
organic phase was separated and washed with brine, dried
(MgSO4), and concentrated to give an oil, which was dissolved
in THF (60 mL) and treated with tetra-n-butylammonium
fluoride (20 mL, 1.0 M in THF, 20 mmol) at room temperature.
After 10 min, the mixture was diluted with ether, and the
organic phase was separated and washed twice with brine,
dried (MgSO4), and concentrated. Chromatography (1:1 ether/
hexane) gave 1.68 g (50%) of 3-(3-hydroxypentyl)-1H-indene
(55), which was dissolved in CH2Cl2 (15 mL), cooled to -50
°C, and treated with methanesulfonyl chloride (1.22 mL, 1.81
g, 16.6 mmol) and triethylamine (3.50 mL, 2.54 g, 25.1 mmol).
After 2 h, the mixture was diluted with ether, and then the
organic phase was separated and washed with brine, dried
(MgSO4), and concentrated to give the crude mesylate, which
was dissolved in DMSO (30 mL) and treated with sodium azide
(1.62 g, 24.93 mmol) at room temperature. After 14 h, the
mixture was diluted with water and extracted with ether (3×).
The combined organic phases were washed with water and
brine and then dried (MgSO4) and concentrated. Chromatog-
raphy (1:2 ether/hexane) gave 1.10 g (58% based on the indenyl
alcohol 55) of the title compound, Rf ) 0.63: 1H NMR (CDCl3,
360 MHz) δ 7.50 (d, J ) 7.3 Hz, 1 H), 7.41 (d, J ) 7.4 Hz, 1
H), 7.34 (t, J ) 7.3 Hz, 1 H), 7.25 (dt, J ) 7.3, 1.2 Hz, 1 H),
6.27 (br s, 1 H), 3.37 (s, 2 H), 3.33-3.31 (m, 1 H), 2.77-2.66
(m, 2 H), 1.96-1.87 (m, 2 H), 1.71-1.62 (m, 2 H), 1.04 (t, J )
7.4 Hz, 3 H); 13C NMR (CDCl3, 90 MHz, J MOD) δ 145.0 (-),
144.4 (-), 143.3 (-), 128.3 (+), 126.0 (+), 124.6 (+), 123.8 (+),
64.1 (+), 37.7 (-), 32.4 (-), 27.5 (-), 24.3 (-), 10.5 (+); IR (neat)
2095 (s), 1610 (w) cm-1; MS (EI, 70 eV) m/z (rel int) 198 ([M-
N2-H]+, 100), 170 (12.0); HRMS (EI, 70 eV) calcd for C14H16
([M-N2-H]+) 198.1283, found 198.1282. Anal. Calcd for
14H17N3: C, 73.98; H, 7.54; N, 18.49. Found: C, 73.61; H,
N
C
1,3-Dibr om o-5-(m eth oxy)m eth oxyp en ta n e (64). Boron
tribromide (45 mL of a 1.0 M solution in CH2Cl2, 45 mmol)
was added to 4-bromotetrahydropyran42 (63, 2.486 g, 15.06
mmol) at 0 °C, and then the solution was heated at reflux for
14 h. After being cooled to room temperature, the mixture was
concentrated and slowly treated with methanol (50 mL). After
heating at reflux for 30 min, the mixture was cooled and
concentrated to yield the crude dibromo alcohol43 which was
dissolved in dimethoxymethane (30 mL) and treated with
lithium bromide (1.95 g, 22.45 mmol) and p-toluenesulfonic
acid monohydrate (280 mg, 1.47 mmol) at room temperature.60
After 1 h, the mixture was diluted with brine and extracted
twice with ether. The combined organic phases were washed
with brine and then dried (MgSO4) and concentrated to give
3.898 g (89%) of the title compound as a clear oil, which was
shown by 1H NMR to be pure enough for further use and thus
carried on to the next reaction without further purification:
7.53; N, 18.18.
(1R*,3a R*)- a n d (1R*,3a S*)-1-Eth yl-1,2,3,3a ,4,5-h exa h y-
d r op yr r olo[1,2-a ]qu in olin e (57) a n d (1R*,10bS*)-1-Eth yl-
1,2,3,5,6,10b-h exa h yd r op yr r olo [2,1-a ]isoqu in olin e (58).
Trifluoromethanesulfonic acid (390 mg, 2.58 mmol) was added
to a solution of the azide 56 (477 mg, 2.10 mmol) in benzene
(100 mL) at 5 °C. After 15 min, the solution was cooled to 0
°C, and sodium borohydride (477 mg, 12.61 mmol) in methanol
(20 mL) was added. After 14 h at room temperature, saturated
aqueous sodium bicarbonate (40 mL) was added, and the
mixture was extracted with ether (3×). The combined organic
phases were washed twice with brine, dried (Na2SO4), and
concentrated to give the crude product. Chromatography (1:
16 ether/hexanes) gave 157 mg (37%) of an inseparable 1:1
mixture of diastereomeric amines 57 as a clear oil. The ratio
of diastereomers was judged by 1H NMR based on the
integration of the multiplet at 3.65-3.56 (m, 0.5 H). Data for
the mixture of diastereomers of 57: Rf ) 0.36 (1:16 ether/
1
(57) Stevens, R. V. Acc. Chem. Res. 1984, 17, 289-296.
(58) Stevens, R. V.; Lee, A. W. M. J . Am. Chem. Soc. 1979, 101,
hexanes); H NMR (CDCl3, 360 MHz) δ 7.06-6.90 (m, 2 H),
6.53-6.43 (m, 1 H), 6.36-6.31 (m, 1 H), 3.65-3.56 (m, 0.5 H),
3.55-3.48 (m, 1 H), 3.36-3.27 (m, 0.5 H), 2.95-2.82 (m, 0.5
H), 2.80-2.70 (m, 0.5 H), 2.66-2.61 (m, 0.5 H), 2.20-2.03 (m,
2 H), 1.98-1.85 (m, 2 H), 1.82-1.73 (m, 1 H), 1.66-1.29 (m, 3
H), 1.19-1.04 (m, 0.5 H), 0.95-0.85 (m, 3 H); 13C NMR (CDCl3,
7032-7035.
(59) Polniaszek, R. P.; Belmont, S. E. J . Org. Chem. 1990, 55, 4688-
4693.
(60) Gras, J .-L.; Chang, Y.-Y. K. W.; Guerin, A. Synthesis 1985, 74-
75.

7170 J . Org. Chem., Vol. 65, No. 21, 2000
Pearson and Fang
1H NMR (CDCl3, 360 MHz) δ 4.61 (s, 2 H), 4.37 (septet, J )
4.7 Hz, 1 H), 3.76-3.69 (m, 2 H), 3.61-3.54 (m, 2 H), 3.37 (s,
3 H), 2.34 (dd, J ) 7.5, 1.4 Hz, 2 H), 2.17-2.02 (m, 2 H); 13C
NMR (CDCl3, 90 MHz) δ 96.5, 65.0, 55.3, 51.7, 41.6, 38.8, 30.9;
IR (neat) 1434 (s) cm-1; MS (CI with CH4) m/z (rel int) 291
([M + H]+, 3.2), 259 (23.1), 229 (100); HRMS (EI, 70 eV) calcd
for C7H1379Br81BrO2 ([M - H]+) 288.9262, found 288.9273.
phase was separated and washed with water and brine and
then dried (MgSO4) and concentrated. Chromatography (1:7
ether/hexanes) gave 343 mg (72%) of the single compound 62
as a light yellow oil whose spectral data matched those
reported above.
(1R*,3a R*)- a n d (1R*,3a S*)-1-(2-Hyd r oxyeth yl)-9-m eth -
oxy-1,2,3,3a ,4,5-h exa h yd r op yr r olo[1,2-a ]qu in olin e (66).
Trifluoromethanesulfonic acid (102 mg, 0.68 mmol) was added
to a solution of the azide 62 (139 mg, 0.44 mmol) in benzene
(25 mL) at 10 °C. After 5 min, sodium borohydride (100 mg,
2.64 mmol) in methanol (5 mL) was added, and the mixture
was warmed to room temperature. After 14 h, saturated
aqueous sodium bicarbonate was added, and the mixture was
extracted with ether (3×). The combined organic phases were
washed with brine, dried (Na2SO4), and concentrated to give
the crude product. Chromatography (ether) gave 51 mg (47%)
of an inseparable 1.2:1 mixture of diastereomeric amines 66
as a clear oil, as judged by integration of methyl singlets in
3-[3-Azid o-5-(m eth oxy)m eth oxy]p en tyl-4-m eth oxy-1H-
in d en e (62) a n d 3-[3-Azid o-5-(m eth oxy)m eth oxy]p en tyl-
7-m eth oxy-1H-in d en e (61). Meth od A: n-Butyllithium (8.0
mL of a 2.0 M solution in hexane, 16.0 mmol) was added to a
solution of 7-methoxy-1H-indene (53, 1.98 g, 14.76 mmol) in
THF (25 mL) at 0 °C. After 30 min, the solution was cooled to
-78 °C and treated with a solution of the dibromide 64 in THF
(10 mL). After 14 h at room temperature, saturated aqueous
ammonium chloride was added, and the mixture was extracted
with ether (3×). The combined organic phases were washed
twice, dried (MgSO4), and concentrated to give a crude mixture
of 3-[3-bromo-5-(methoxymethoxy)]pentyl-4-methoxy-1H-in-
dene and 3-[3-bromo-5-(methoxymethoxy)]pentyl-7-methoxy-
1H-indene, which was dissolved in 10 mL of THF and treated
with tetra-n-butylammonium azide (30 mL of a 1.0 M solution
in THF, 30 mmol)61 at room temperature. After 14 h, the
mixture was diluted with ether, and the organic phases were
washed with water and brine, dried (MgSO4), and concen-
trated. Chromatography (1:7 ether/hexane) gave 2.54 g (80%)
of a 3:1 mixture of the azido indenes 62 and 61 as a light yellow
oil, Rf ) 0.30. Compound 62 was assigned by comparison with
the pure 62 prepared using method B below. The 3:1 ratio of
1
the H NMR spectrum. Rf ) 0.65; 1H NMR (CDCl3, 300 MHz)
δ 6.72-6.66 (m, 5 H), 6.65-6.58 (m, 1 H), 4.52-4.41 (m, 1 H),
4.12-4.02 (m, 1 H), 3.96-3.85 (m, 1 H), 3.83 (s, 3 H), 3.78 (s,
3 H), 3.77-3.64 (m, 2 H), 3.62-3.52 (m, 3 H), 3.51-3.42 (m, 1
H), 2.88-2.75 (m, 2 H), 2.74-2.58 (m, 2 H), 2.26-2.12 (m, 2
H), 2.10-1.99 (m, 3 H), 1.98-1.87 (m, 2 H), 1.85-1.75 (m, 2
H), 1.74-1.62 (m, 4 H), 1.60-1.43 (m, 2 H), 1.42-1.32 (m, 1
H), 1.31-1.20 (m, 1 H); 13C NMR (CDCl3, 90 MHz) δ 149.9,
149.7, 136.3, 133.9, 128.1, 126.8, 122.5, 121.8, 119.0, 118.3,
110.1, 110.0, 63.0, 62.0, 61.3, 58.1, 57.1, 55.8, 55.7, 55.5, 37.7,
36.0, 30.3, 29.7, 29.6, 28.9, 28.4, 26.6, 25.4; IR (neat) 3355 (br
s) cm-1; MS (EI, 70 eV) m/z (rel int) 247 (M+, 24.0), 202 (100);
HRMS calcd for C15H21NO2 247.1572, found 247.1560.
1
62 and 61 was determined by H NMR based on integration
of the olefinic hydrogens at δ 6.08 and 6.24 ppm in the mixture.
Complete separation of the two isomers was not possible with
conventional flash chromatography. Analytical samples of 62
and 61 were obtained by HPLC62 (silica gel, 3% EtOAc/
hexanes): Data for 62: 1H NMR (CDCl3, 300 MHz) δ 7.16 (t,
J ) 7.6 Hz, 1 H), 7.07 (d, J ) 7.4 Hz, 1 H), 6.79 (d, J ) 8.1 Hz,
1 H), 6.08 (br s, 1 H), 4.63 (s, 2 H), 3.86 (s, 3 H), 3.69-3.64 (m,
2 H), 3.60-3.53 (m, 1 H), 3.31 (br s, 2 H), 3.05-2.86 (m, 2 H),
2.83-2.72 (m, 1 H), 1.98-1.88 (m, 2 H), 1.86-1.73 (m, 1 H);
13C NMR (CDCl3, 75 MHz) δ 127.3, 125.9, 116.9, 108.8, 96.7,
(E)- an d (Z)-1-(Br om om eth ylen e)-4-m eth oxyin dan (69).
Taguchi’s method for the synthesis of polyhalomethyllithium
carbonyl adducts was followed.45 Thus, n-butyllithium (100 mL
of a 2.0 M solution in hexane, 200 mmol) was added to a
solution of dicyclohexylamine (36.20 g, 200 mmol) in THF (60
mL) at 0 °C. After 10 min, the lithium dicyclohexylamide thus
generated was transferred via cannula to a solution of dibro-
momethane (60 mL) and 4-methoxyindanone (60, 16.20 g, 100
mmol) in THF (200 mL) at -78 °C. After 1 h, 6 N HCl (200
mL) was added. The solids formed were washed with ether
(3×), and the combined organic materials were washed twice
with brine, dried (MgSO4) and concentrated to give the crude
adduct, which was dissolved in CH2Cl2 (300 mL), and treated
with acetic acid (24 mL) and zinc dust (10 g) according to
Williams’s protocol.46 After refluxing for 1 h, the mixture was
cooled to room temperature and diluted with ether. The
organic phases were washed with saturated aqueous sodium
bicarbonate (3×) and brine (2×) and then dried (MgSO4) and
concentrated. Chromatography (1:7 ether/hexane) gave 16.54
g (69% or 93% based on 4.10 g of 4-methoxyindanone recovered
after further elution) of the title compound as an inseparable
2:1 ratio of geometric isomers. The major isomer was assigned
as the Z isomer based on a larger allylic coupling (2.7 Hz) than
in the E isomer (1.9 Hz) in the 1H NMR spectrum.56 The 2:1
64.6, 60.1, 55.3, 38.0, 34.8, 34.6, 27.3; IR (neat) 2099 (s) cm-1
;
MS (CI with NH3) m/z (rel int) 318 ([M + H]+, 3.1), 304 (7.2),
290 (100); HRMS (CI with NH3) calcd for C17H23N3O3H
318.1818, found 318.1811. Data for 61: 1H NMR (CDCl3, 300
MHz) δ 7.30 (t, J ) 7.9 Hz, 1 H), 7.02 (d, J ) 7.5 Hz, 1 H),
6.77 (d, J ) 8.1 Hz, 1 H), 6.24 (br s, 1 H), 4.62 (s, 2 H), 3.84 (s,
3 H), 3.70-3.63 (m, 2 H), 3.61-3.57 (m, 1 H), 3.35 (s, 3 H),
3.30 (d, J ) 1.8 Hz, 2 H), 2.80-2.61 (m, 2 H), 1.96-1.78 (m, 4
H); 13C NMR (CDCl3, 75 MHz) δ 143.2, 128.4, 127.8, 112.2,
107.6, 96.7, 64.4, 59.9, 55.4, 35.3, 34.9, 33.4, 24.5; IR (neat)
2100 (s) cm-1; MS (CI with NH3) m/z (rel int) 290 ([M - N2
+
H]+, 75.3), 243 (30.9), 97 (100); HRMS (CI with NH3) calcd for
C
17H23NO3H ([M - N2 + H]+) 290.1756, found 290.1762.
Meth od B: tert-Butyllithium (4.70 mL of a 1.4 M solution
in pentane, 6.58 mmol) was added to a solution of the indene
53 (4.3 mg, 3.00 mmol) in THF (3 mL) at -78 °C.17 After 10
min, chlorotrimethylsilane (0.19 mL, 163 mg, 1.50 mmol) was
added. After 30 min, a solution of dibromide 64 (435 mg, 1.50
mmol) in THF (5 mL) was added, and the mixture was allowed
to warm to room temperature for 14 h. Saturated aqueous
ammonium chloride was added and the mixture was extracted
with ether (3×). The combined organic phases were washed
with brine, dried (MgSO4), and concentrated to give crude 3-[3-
bromo-5-(methoxymethoxy)]pentyl-7-methoxy-1H-indene, which
was treated with tetra-n-butylammonium azide (5.0 mL of a1.0
M solution in THF, 5.0 mmol)61 at room temperature for 14 h.
After diluting the solution with ether and water, the organic
1
ratio was determined by H NMR based on integration of the
olefinic hydrogens at δ 6.61 and 6.17 ppm. Characterization
of the mixture of diastereomers: 1H NMR (CDCl3, 300 MHz)
δ 8.02 (d, J ) 7.8 Hz, 0.5 H), 7.31-7.26 (m, 0.5 H), 7.22-7.17
(m, 1 H), 7.00 (d, J ) 7.8 Hz, 1 H), 6.83 (d, J ) 8.0 Hz, 0.5 H),
6.74 (d, J ) 8.0 Hz, 1 H), 6.61 (t, J ) 2.7 Hz, 1 H), 6.17 (t, J
) 1.9 Hz, 0.5 H), 3.87 (s, 3 H), 3.86 (s, 1.5 H), 2.99-2.91 (m,
3 H), 2.87-2.80 (m, 3 H); 13C NMR (CDCl3, 75 MHz) δ 156.9,
148.8, 145.4, 141.0, 140.8, 135.5, 128.2, 127.6, 118.1, 112.7,
110.8, 109.9, 97.4, 94.8, 55.3, 34.0, 31.9, 27.1, 26.4; IR (neat)
1587 (s), 1481 (s) cm-1; MS (EI, 70 eV) m/z (rel int) 238 (M+,
93.2), 207 (4.7), 159 (100); HRMS calcd for C11H11BrO 237.9993,
found 237.9985.
(E)- a n d (Z)-1-[3-Hyd r oxy-5-(m eth oxy)m eth oxy]p en -
tylid en e-4-m eth oxyin d a n (71). tert-Butyllithium (12.4 mL
of a 1.7 M solution in pentane, 21.1 mmol) was added to a
solution of a mixture of E and Z isomers of the vinyl bromide
69 (2.52 g, 10.54 mmol) in THF (40 mL) at -78 °C. After 15
min, boron trifluoride etherate (1.34 mL, 1.50 g, 10.6 mmol)47
was added, followed immediately by a solution of 4-(methoxy)-
(61) Bra¨ndstro¨m, A.; Lamm, B.; Palmertz, I. Acta Chem. Scand. B
1974, 28, 699-701.
(62) High performance liquid chromatography (HPLC) was per-
formed on a Rainin Rabbit HP instrument equipped with an ISCO V4
absorption detector (Wavelength: 254 nm) using a Dynamax-60 Å
column composed of silica (SiO2). General conditions were fixed solvent
system, flow rate: 1.0 mL/min.

1-Azabicyclo[m.n.0]alkanes via the Schmidt Reaction
J . Org. Chem., Vol. 65, No. 21, 2000 7171
methoxy-1,2-epoxybutane48 (70, 700 mg, 5.30 mmol) in THF
(15 mL). This mixture was kept at -78 °C for 15 min before
saturated aqueous sodium bicarbonate. The resulting mixture
was extracted with ether (3×), and the combined organic
phases were washed twice with brine and then dried (MgSO4)
and concentrated. Chromatography (2:1 ether/hexane) gave
894 mg (58%) of the title compound as an inseparable 1:1
mixture of geometric isomers as determined by integration of
the olefinic hydrogens at δ 5.98-5.89 and 5.60-5.52 ppm in
the 1H NMR spectrum. Characterization of the mixture: 1H
NMR (CDCl3, 300 MHz) δ 7.28-7.25 (m, 0.5 H), 7.16 (q, J )
7.9 Hz, 1 H), 7.06 (d, J ) 7.6 Hz, 0.5 H), 6.69 (dd, J ) 16.6,
8.0 Hz, 1 H), 5.98-5.89 (m, 0.5 H), 5.60-5.52 (m, 0.5 H), 4.64
(s, 2 H), 3.95 (br s, 1 H), 3.83 (s, 3 H), 3.81-3.64 (m, 2 H), 3.36
(s, 3 H), 2.96-2.80 (m, 2 H), 2.79-2.71 (m, 2 H), 2.70-2.60
(m, 1 H), 2.44-2.35 (m, 1 H), 1.92-1.73 (m, 2 H); 13C NMR
(CDCl3, 75 MHz) δ 156.5, 156.2, 145.1, 143.5, 143.1, 142.1,
136.0, 133.9, 127.8, 127.5, 118.0, 117.0, 114.7, 112.4, 109.1,
108.8, 96.5, 70.7, 70.3, 69.5, 66.0, 65.9, 64.9, 55.2, 39.2, 37.7,
36.5, 36.3, 34.8, 33.7, 28.1, 26.7, 26.6; IR (neat) 3442 (br s)
cm-1; MS (CI with NH3) m/z (rel int) 293 ([M + H]+, 9.7), 278
(18.3), 261 (100); HRMS (CI with CH4) calcd for C17H24O4H
([M + H]+) 293.1753, found 293.1758.
in water, 10 mL). The mixture was then heated to 60 °C for 1
h. After being cooled to room temperature, the water layer was
saturated with solid potassium carbonate, and the organic
phase was separated, dried (MgSO4), and concentrated. Chro-
matography (2:1 ether/hexane) gave 3.89 g (95%) of the title
compounds as a light yellow oil, Rf ) 0.41 (2:1 ether/hexane),
which was found to be an inseparable 1.3:1 mixture of regio-
isomers 73a and 73b by integration of the olefinic hydrogens
1
at δ 6.23 (0.6 H) and 5.95-5.86 (0.4 H) in the H NMR spec-
trum. The major isomer was assigned as the indene derivative
73a based on the appearance and chemical shift of the indenyl
hydrogen at C2 (δ 6.23 ppm). The geometry of 73b was not
determined. Characterization of the mixture: 1H NMR (CDCl3,
360 MHz) δ 7.31 (t, J ) 7.6 Hz, 0.6 H), 7.18 (t, J ) 7.8 Hz, 0.4
H), 7.10-7.04 (m, 1 H), 6.78)d, J ) 8.1 Hz, 0.6 H), 6.69 (d, J
) 7.9 Hz, 0.4 H), 6.23 (t, J ) 1.6 Hz, 0.6 H), 5.95-5.86 (m, 0.4
H), 3.91 (s, 1.7 H), 3.85 (s, 1.3 H), 3.73 (q, J ) 6.4 Hz, 2 H),
3.32 (q, J ) 1.7 Hz, 1 H), 2.98-2.92 (m, 1 H), 2.80-2.73 (m, 1
H), 2.67-2.60 (m, 1 H), 2.47 (q, J ) 6.6 Hz, 1 H), 2.38 (br s, 1
H), 2.00-1.92 (m, 1 H); 13C NMR (CDCl3, 90 MHz, J MOD) δ
156.5 (-), 155.3 (-), 147.2 (-), 145.3 (-), 143.8 (-), 143.1 (-),
134.0 (-), 131.2 (-), 128.0 (+), 127.9 (+), 127.8 (+), 115.0 (+),
112.4 (+), 112.3 (+), 108.7 (+), 107.2 (+), 62.4 (-), 62.2 (-),
55.2 (+), 55.1 (+), 35.1 (-), 33.0 (-), 31.0 (-), 27.9 (-), 26.7
(-), 24.1 (-); IR (neat) 3363 (br s) cm-1; MS (CI with NH3)
m/z (rel int) 205 ([M + H]+, 100), 187 (4.7); HRMS (CI with
NH3) calcd for C13H16O2H ([M + H]+) 205.1229, found 205.1232.
3-(3-Hyd r oxy-5-h exen yl)-7-m eth oxy-1H-in d en e (74). Di-
methyl sulfoxide (2.13 mL, 2.35 g, 30.08 mmol) was added
slowly to oxalyl chloride (2.63 mL, 3.83 g, 30.15 mmol) in THF
(40 mL) at -78 °C.63 After 20 min, the indenyl alcohol 73 in
THF (25 mL) was added. The resultant mixture was warmed
to -30 °C over 20 min and then treated with triethylamine
(10.0 mL, 7.26 g, 71.8 mmol). After the solution was warmed
to room temperature over 20 min and recooled to -78 °C,
allylmagnesium chloride (40 mL of a 2.0 M solution in THF,
80 mmol) was added.50 The mixture was stirred at -78 °C for
2 h and allowed to warm to room temperature over 30 min.
Acetic acid (10% aqueous, 80 mL) was added, and the mixture
was extracted with ether (3×). The combined organic phases
were washed twice with saturated aqueous sodium bicarbonate
and brine and then dried (MgSO4) and concentrated. Chro-
matography (2:1 ether/hexane) gave 3.09 g (70%) of the title
(E)- a n d (Z)-1-[3-Azid o-5-(m eth oxy)m eth oxy]p en tyl-
id en e-4-m eth oxyin d a n (72). Methanesulfonyl chloride (0.10
mL, 148 mg, 1.29 mmol) and triethylamine (0.30 mL, 218 mg,
2.15 mmol) were added to the alcohol 71 (178 mg, 0.61 mmol)
in CH2Cl2 (50 mL) at -50 °C. After 2 h, ether was added, and
the organic phase was collected and washed with saturated
aqueous sodium bicarbonate and brine, and then dried (Mg-
SO4) and concentrated to give the crude mesylate, which was
dissolved in THF (5 mL) and treated with tetra-n-butylam-
monium azide (2.0 mL of a 1.0 M solution in THF, 2.0 mmol)61
at room temperature. After warming to 50 °C for 2 h, the
solution was concentrated, and the residue was chromato-
graphed (2:1 hexanes/ether) to give 158 mg (81%) of the title
compound as an inseparable 1:1 mixture of geometric isomers
as judged by integration of the olefinic hydrogens at δ 5.98-
1
5.89 and 5.39-5.50 ppm in the H NMR spectrum, Rf ) 0.47.
1H NMR (CDCl3, 300 MHz) δ 7.26-7.20 (m, 1 H), 7.16 (d, J )
7.8 Hz, 0.4 H), 7.08 (d, J ) 7.6 Hz, 0.6 H), 6.75 (d, J ) 4.8 Hz,
0.4 H), 6.69 (d, J ) 7.8 Hz, 0.6 H), 5.98-5.89 (m, 0.6 H), 5.58-
5.50 (m, 0.4 H), 4.63 (s, 2 H), 3.85 (s, 3 H), 3.72-3.60 (m, 3 H),
3.37 (s, 3 H), 2.95 (t, J ) 6.3 Hz, 1 H), 2.90-2.83 (m, 1 H),
2.81-2.73 (m, 3 H), 2.49 (t, J ) 6.8 Hz, 1 H), 2.01-1.86 (m, 1
H), 1.84-1.70 (m, 1 H); 13C NMR (CDCl3, 75 MHz) δ 156.5,
156.4, 145.6, 144.2, 142.9, 141.9, 134.1, 127.9, 127.7, 117.1,
116.9, 113.8, 112.5, 109.3, 109.0, 96.6, 64.4, 60.2, 60.0, 55.2,
34.9, 34.5, 34.4, 33.8, 33.7, 28.1, 26.8, 26.7; IR (neat) 2099 (s)
cm-1; MS (CI with NH3) m/z (rel int) 290 ([M - N2 + H]+, 17.1),
218 (100); HRMS (CI with CH4) calcd for C17H23NO3H ([M -
N2 + H]+) 290.1756, found 290.1764.
1
compound as a single isomer based on H NMR, Rf ) 0.41: 1H
NMR (CDCl3, 360 MHz) δ 7.32 (t, J ) 8.0 Hz, 1 H), 7.07 (d, J
) 7.5 Hz, 1 H), 6.79 (d, J ) 8.1 Hz, 1 H), 6.25 (br s, 1 H),
5.94-5.79 (m, 1 H), 5.20-5.12 (m, 2 H), 3.91 (s, 3 H), 3.85 (br
s, 1 H), 3.80-3.75 (m, 1 H), 3.33 (d, J ) 1.8 Hz, 2 H), 2.81-
2.58 (m, 2 H), 2.43-2.32 (m, 1 H), 2.30-2.18 (m, 1 H), 1.94-
1.80 (m, 2 H); 13C NMR (CDCl3, 90 MHz, J MOD) δ 155.4 (-),,
147.3 (-), 144.1 (-), 134.8 (+), 131.3 (-), 128.1 (+), 127.9 (+),
118.3 (-), 112.4 (+), 107.3 (+), 70.4 (+), 55.3 (+), 42.1 (-),
35.3 (-), 35.2 (-), 24.1 (-); IR (neat) 3421 (br s) cm-1; MS (CI
with CH4) m/z (rel int) 245 ([M + H]+, 86.3), 227 (100); HRMS
(CI with CH4) calcd for C16H20O2H 245.1542, found 245.1537.
3-(3-Azid o-5-h exen yl)-7-m eth oxy-1H-in d en e (75). Meth-
anesulfonyl chloride (1.51 mL, 2.23 g, 19.5 mmol) and triethyl-
amine (4.09 mL, 2.97 g, 29.4 mmol) were added to the alcohol
74 (2.39 g, 9.77 mmol) in CH2Cl2 (40 mL) at -50 °C. After 2
h, ether was added, and the solution was washed with
saturated aqueous sodium bicarbonate and brine and then
dried (MgSO4) and concentrated to give the crude mesylate,
which was treated with tetra-n-butylammonium azide (30 mL
of a 1.0 M solution in THF, 30 mmol)61 at room temperature.
After 14 h, the mixture was diluted with ether and washed
twice with water and brine and then dried (MgSO4) and
concentrated. Chromatography (pentane) gave 1.62 g (62%) of
the title compound as a light yellow oil, Rf ) 0.41: 1H NMR
(CDCl3, 360 MHz) δ 7.32 (dd, J ) 8.0, 7.6 Hz, 1 H), 7.04 (dd,
J ) 7.6, 0.6 Hz, 1 H), 6.79 (d, J ) 8.1 Hz, 1 H), 6.25 (t, J ) 1.5
Hz, 1 H), 5.88-5.81 (m, 1 H), 5.21-5.14 (m, 2 H), 3.89 (s, 3
H), 3.46-3.44 (m, 1 H), 3.32 (dd, J ) 3.6, 1.8 Hz, 2 H), 2.78-
3-(3-Hyd r oxyp r op yl)-7-m eth oxy-1H-in d en e (73a ) a n d
3-(3-Hydr oxypr opyliden e)-7-m eth oxy-1H-in dan (73b). Ce-
rium chloride heptahydrate (11.20 g, 30.00 mmol) was dried
at 137 °C in vacuo (<0.1 mmHg) for 3 h. Nitrogen was
introduced, the flask was cooled to 0 °C, and cold THF (80 mL,
0 °C) was added.21 After the suspension was stirred for 14 h,
a solution of 4-methoxyindan-1-one (60, 3.24 g, 20.00 mmol)
in dry THF (32 mL) was added, and the mixture was stirred
for 1 h at room temperature and then recooled to 0 °C and
treated with allylmagnesium chloride (20 mL of a 2.00 M
solution in THF, 40 mmol) in a dropwise fashion. After 30 min
at 0 °C, triethylamine (8.4 mL, 6.1 g, 60 mmol) and methane-
sulfonyl chloride (3.00 mL, 4.44 g, 38.8 mmol) were added
sequentially. After 1 h, the mixture was warmed to room
temperature over 30 min, quenched with saturated aqueous
ammonium chloride, and extracted with ether (3×). The
combined organic phases were washed twice with saturated
aqueous ammonium bicarbonate and brine (3×) and then dried
(MgSO4) and concentrated. The crude diene was then treated
with 9-BBN (80 mL of a 0.5 M solution in THF, 40 mmol).49
After being warmed to 80 °C for 1 h, the solution was cooled
to room temperature and treated carefully with aqueous
sodium hydroxide (10 mL, 5 M) and hydrogen peroxide (30%
(63) Mancuso, A. J .; Huang, S.-L.; Swern, D. J . Org. Chem. 1978,
43, 2480-2482

7172 J . Org. Chem., Vol. 65, No. 21, 2000
Pearson and Fang
2.66 (m, 1 H), 2.65-2.57 (m, 1 H), 2.41-2.31 (m, 2 H), 1.95-
1.84 (m, 2 H); 13C NMR (CDCl3, 90 MHz, J MOD) δ 155.3 (-),
147.0 (-), 143.1 (-), 133.7 (+), 131.2 (-), 128.5 (+), 127.8 (+),
118.3 (-), 112.2 (+), 107.3 (+), 61.8 (+), 55.2 (+), 38.8 (-),
35.1 (-), 32.5 (-), 24.3 (-); IR (neat) 2098 (s) cm -1; MS (CI
with NH3) m/z (rel int) 270 ([M + H]+, 3.8), 242 (100); HRMS
(CI with NH3) calcd for C16H19N3OH 270.1606, found 270.1593.
(1R*,3aS*)-6-Meth oxy-1-(2-pr open yl)-1,2,3,3a,4,5-h exah y-
d r op yr r olo[1,2-a ]qu in olin e (76a ), (1R*,3a R*)-6-Meth oxy-
1-(2-p r op en yl)-1,2,3,3a ,4,5-h exa h yd r op yr r olo[1,2-a ]qu in -
olin e (76b), a n d (1R*,10bR*)-7-Meth oxy-1-(2-p r op en yl)-
1,2,3,5,6,10b-h exa h yd r op yr r olo[2,1-a ]isoq u in olin e (77).
Trifluoromethanesulfonic acid (339 mg, 2.25 mmol) was added
to a solution of the azide 75 (490 mg, 1.82 mmol) in benzene
(30 mL) at room temperature. After 10 min, the solution was
cooled to 0 °C, and sodium borohydride (413 mg, 10.92 mmol)
in methanol (10 mL) was added. After to room temperature
for 5 h, saturated aqueous sodium bicarbonate was added, and
the mixture was extracted with ether (3×). The combined
organic phases were washed twice with brine and then dried
(Na2SO4) and concentrated to give the crude product. Chro-
matography (1:7 ether/hexanes) gave 194 mg (44%) of an
inseparable 2:1 mixture of 76a and 76b as a clear oil, Rf )
0.61, as judged by integration of the hydrogens at δ 3.12-3.04
(E)- an d (Z)-1-[5-(ter t-Bu tyldiph en ylsilyl)oxy-3-h ydr oxy]-
p en tylid en e-4-m eth oxyin d a n (79). A solution of (E)- and
(Z)-1-(bromomethylene)-4-methoxyindan (69, 5.02 g, 21.0 mmol)
in THF (10 mL) was added to a suspension of magnesium
turnings (612 mg, 25.2 mmol) in THF (50 mL) at room
temperature. After 14 h, this Grignard reagent was transferred
by syringe to a solution of the epoxide 78 (3.27 g, 10.02 mmol)
in THF (10 mL) at 0 °C, followed by addition of anhydrous
cuprous iodide (400 mg, 2.10 mmol). After 30 min, the solution
was warmed to room temperature and kept for 2 h before
saturated aqueous ammonium chloride was added. The mix-
ture was filtered though Celite, washing twice with ether. The
water layer was separated from the filtrate and extracted twice
with ether. The combined organic phases were washed twice
with brine and then dried (MgSO4) and concentrated. Chro-
matography (1:2 ether/hexane) gave 4.10 g (84%) of the title
compounds as an inseparable 1:1 mixture of geometrical
isomers as judged by integration of the olefinic hydrogens at
1
δ 6.04-5.95 and 5.66-5.57 in the H NMR spectrum. Data on
the mixture of isomers: Yellow oil, Rf ) 0.32; 1H NMR (CDCl3,
300 MHz) δ 7.72 (dd, J ) 7.3, 1.5 Hz, 4 H), 7.53-7.39 (m, 6
H), 7.33-7.10 (m, 2 H), 6.72 (dd, J ) 17.9, 7.9 Hz, 1 H), 6.04-
5.95 (m, 0.5 H), 5.66-5.57 (m, 0.5 H), 4.13-4.10 (m, 1 H),
3.98-3.86 (m, 2 H), 3.86 (s, 1.5 H), 3.85 (s, 1.5 H), 3.36 (br s,
1 H), 2.89-2.85 (m, 2 H), 2.83-2.63 (m, 3 H), 2.53-2.38 (m, 1
H), 1.84-1.76 (m, 2 H), 1.10 (s, 9 H); 13C NMR (CDCl3, 75 MHz)
δ 156.6, 156.3, 144.9, 143.3, 142.3, 136.0, 135.5, 133.3, 129.7,
127.7, 118.3, 117.2, 115.0, 112.5, 109.2, 108.8, 71.5, 71.1, 63.2,
63.0, 55.3, 38.5, 37.7, 36.6, 33.7, 28.2, 27.0, 26,8, 26.7, 19.2;
IR (neat) 3461 (br s) cm-1; MS (CI with NH3) m/z (rel int) 469
([M-H2O+H]+, 22.4), 409 (91.7), 163 (100); HRMS (CI with
NH3) calcd for C31H36O2SiH ([M - H2O + H]+) 469.2563, found
469.2544.
1
(m, 0.5 H) and 2.96 (dd, J ) 17.3, 5.6 Hz, 1 H) in the H NMR
spectrum. The relative configuration of the major diastereomer
was proposed to be as indicated for 76a based on the stereo-
electronic model proposed for the reduction of analogous
iminium ions.57-59 Further elution yielded 184 mg (42%) of the
tricyclic compound 77 as a clear oil, Rf ) 0.61, whose relative
configuration was also proposed based on the same stereo-
electronic model. Data for 76a /b: 1H NMR (CDCl3, 360 MHz)
δ 7.08 (t, J ) 8.2 Hz, 1 H), 6.27-6.22 (m, 2 H), 5.92-5.81 (m,
1 H), 5.19-5.11 (m, 2 H), 3.95-3.89 (m, 0.5 H), 3.88 (s, 2 H),
3.87 (s, 1 H), 3.77 (t, J ) 7.2 Hz, 1 H), 3.55-3.48 (m, 0.5 H),
3.42-3.32 (m, 1 H), 3.12-3.04 (m, 0.5 H), 2.96 (dd, J ) 17.3,
5.6 Hz, 1 H), 2.65-2.53 (m, 1 H), 2.52-2.40 (m, 0.5 H), 2.25-
2.09 (m, 2 H), 2.06-1.89 (m, 2 H), 1.80-1.59 (m, 1 H), 1.57-
1.32 (m, 1 H); 13C NMR (CDCl3, 90 MHz, J MOD) δ 158.0 (-),
157.4 (-), 144.9 (-), 144.7 (-), 136.1 (+), 135.5 (+), 127.0 (+),
126.9 (+), 117.1 (-), 116.8 (-), 109.9 (-), 109.5 (-), 1.4.7 (+),
104.2 (+), 98.0 (+), 58.5 (+), 58.3 (+), 57.1 (+), 56.9 (+), 55.5
(+), 55.3 (+), 37.8 (-), 37.6 (-), 31.8 (-), 30.6 (-), 29.2 (-),
28.6 (-), 28.5 (-), 27.4 (-), 22.1 (-), 21.2 (-); IR (neat) 1603
(s) cm-1; MS (EI, 70 eV) m/z (rel int) 243 (M+, 21.5), 202 (100);
HRMS calcd for C16H21NO 243.1623, found 243.1634. Data for
77: 1H NMR (CDCl3, 300 MHz) δ 7.12 (t, J ) 8.0 Hz, 1 H),
6.70 (d, J ) 8.0 Hz, 2 H), 5.93-5.79 (m, 1 H), 5.15-5.02 (m, 2
H), 3.81 (s, 3 H), 3.45-3.39 (m, 1 H), 3.24 (br t, J ) 6.8 Hz, 1
H), 2.92-2.87 (m, 2 H), 2.60-2.52 (m, 1 H), 2.48-2.36 (m, 1
H), 2.35-2.22 (m, 2 H), 2.18-2.09 (m, 1 H), 2.06-1.98 (m, 1
H), 1.75-1.59 (m, 2 H); 13C NMR (CDCl3, 75 MHz, J MOD) δ
157.1 (-), 140.4 (-), 135.7 (+), 126.0 (+), 123.4 (-), 117.1 (+),
115.9 (-), 107.8 (+), 65.3 (+), 63.4 (+), 55.2 (+), 47.4 (-), 37.9
(-), 28.8 (-), 27.8 (-), 24.6 (-); IR (neat) 1640 (m), 1585 (s)
cm-1; MS (CI with CH4) m/z (rel int) 244 ([M + H]+, 100), 202
(19.8); HRMS (CI with CH4) calcd for C16H21NOH([M + H]+)
244.1701, found 244.1694.
(E)- a n d (Z)-1-(3-Azid o-5-h yd r oxy)p en tylid en e-4-m eth -
oxyin d a n (80). Methanesulfonyl chloride (0.31 mL, 459 mg,
4.01 mmol) and triethylamine (0.90 mL, 653 mg, 6.46 mmol)
were added to the alcohol 79 (974 mg, 2.00 mmol) in CH2Cl2
(10 mL) at 0 °C. After 1 h, ether was added, and the solution
was washed with water and brine and then dried (MgSO4) and
concentrated. The crude mesylate was then treated with tetra-
n-butylammonium azide (8 mL of a 1.0 M solution in THF, 8
mmol)61 at room temperature. After 14 h, ether was added,
and the solution was washed with water and brine and then
concentrated. The crude silyl ether was then treated with
tetra-n-butylammonium fluoride (8 mL of a1.0 M in THF, 8
mmol) at room temperature. After 6 h, ether was added, and
the mixture was washed with water and brine and then dried
(MgSO4) and concentrated. Chromatography (1:2 ether/hexane)
gave 454 mg (83%) of the title compounds as an inseparable
1:1 mixture of geometrical isomers as judged by integration
of the olefinic hydrogens at δ 5.98-5.86 and 5.57-5.52 in the
1H NMR spectrum. Data on the mixture of isomers: Yellow
1
oil, Rf ) 0.35; H NMR (CDCl3, 300 MHz) δ 7.23-7.21 (m, 1
H), 7.17 (d, J ) 7.8 Hz, 0.5 H), 7.09 (d, J ) 7.6 Hz, 0.5 H),
6.76 (t, J ) 4.2 Hz, 1 H), 6.70 (d, J ) 7.8 Hz, 0.5 H), 5.98-
5.86 (m, 0.5 H), 5.57-5.52 (m, 0.5 H), 3.85 (s, 1.5 H), 3.84 (s,
1.5 H), 3.80-3.76 (m, 2 H), 3.72-3.69 (m, 1 H), 2.98-2.93 (m,
1 H), 2.90-2.86 (m, 1 H), 2.81-2.73 (m, 3 H), 2.55-2.46 (m, 1
H), 2.21 (s, 1 H), 1.95-1.83 (m, 1 H), 1.81-1.68 (m, 1 H); 13C
NMR (CDCl3, 75 MHz) δ 156.4, 156.28, 145.6, 144.2, 142.8,
141.7, 136.2, 134.0, 127.8, 127.6, 116.8, 113.6, 112.4, 109.3,
109.0, 60.2, 60.0, 59.6, 55.1, 36.6, 34.7, 33.6, 28.0, 26.7, 26.6;
IR (neat) 3362 (br s), 2102 (s) cm-1; MS (CI with CH4) m/z (rel
int) 274 ([M + H]+, 7.3), 246 ([M - N2 + H]+, 47.7), 231 (38.5),
173 (100),; HRMS (CI with NH3) calcd for C15H19NO2H ([M -
N2 + H]+) 246.1494, found 246.1487.
4-(ter t-Bu tyld ip h en ylsilyl)oxy-1,2-ep oxybu ta n e (78).52
4-(N,N-Dimethylamino)pyridine (300 mg, 2.46 mmol) was
added to a solution of but-3-en-1-ol (5.00 g, 69.34 mmol), tert-
butyldiphenylsilyl chloride (15.88 g, 57.78 mmol), and imida-
zole (5.19 g, 76.23 mmol) in CH2Cl2 (300 mL) at room
temperature. After 4 h, the mixture was diluted with ether
and washed twice with water and brine. The organic phase
was dried (MgSO4) and concentrated to give the crude silylated
alcohol, which was dissolved in CH2Cl2 (200 mL) and treated
with m-chloroperbenzoic acid (17.60 g, 85% purity, 86.69
mmol). After 3 h at room temperature, the mixture was diluted
with ether, washed with 20% aqueous NaOH (3×) and brine
(2×), dried (MgSO4), and concentrated to give 23.0 g (∼100%)
(E)- a n d (Z)-1-(3-Azid o-5-br om o)p en tylid en e-4-m eth -
oxyin d a n (81). Methanesulfonyl chloride (1.40 mL, 2.07 g,
18.1 mmol) and triethylamine (3.70 mL, 2.69 g, 26.6 mmol)
were added to the azido alcohol 80 (2.41 g, 8.82 mmol) in CH2-
Cl2 (50 mL) at 0 °C. After 1 h, ether was added, and the
mixture was washed with water and brine and then dried
(MgSO4) and concentrated. The crude mesylate was then
treated with tetra-n-butylammonium bromide (8.53 g, 26.46
mmol) and THF (40 mL) at room temperature. After 14 h,
1
of the title compound, which was found by H NMR spectros-
copy to be pure enough to use in the next step without
1
purification. The H NMR data for this material matched the
literature values.52

1-Azabicyclo[m.n.0]alkanes via the Schmidt Reaction
J . Org. Chem., Vol. 65, No. 21, 2000 7173
ether was added, and the mixture was washed with water and
brine and then dried (MgSO4) and concentrated. Chromatog-
raphy (1:7 ether/hexane) gave 2.69 g (91%) of the title
compounds as an inseparable 1:1 mixture of geometrical
isomers as judged by integration of the olefinic hydrogens at
stereoelectronic model proposed for the reduction of analogous
iminium ions.57-59 Data for 85: 1H NMR (CDCl3, 300 MHz) δ
7.13 (t, J ) 7.8 Hz, 1 H), 6.72-6.65 (m, 2 H), 4.79 (br s, 1 H),
4.00 (dt, J ) 11.0, 2.9 Hz, 1 H), 3.82 (s, 3 H), 3.78-3.75 (m, 1
H), 3.65 (tt, J ) 11.0, 4.2 Hz, 1 H), 3.56 (ddd, J ) 14.6, 6.0,
2.6 Hz, 1 H), 3.24 (dd, J ) 10.6, 6.1 Hz, 1 H), 2.86-2.75 (m, 2
H), 2.35-2.25 (m, 2 H), 2.17-1.96 (m, 2 H), 1.94-1.80 (m, 1
H), 1.78-1.66 (m, 1 H), 1.63-1.52 (m, 1 H); 13C NMR (CDCl3,
75 MHz, J MOD) δ 157.1 (-), 139.7 (-), 126.3 (+), 123.2 (-),
117.0 (+), 108.0 (+), 65.6 (+), 62.4 (+), 59.6 (-), 55.3 (+), 47.4
(-), 31.6 (-), 28.4 (-), 26.6 (-), 24.6 (-); IR (neat) 3336 (br s)
cm-1; MS (CI with NH3) m/z (rel int) 248 ([M + H]+, 100), 202
(86.3); HRMS (CI with NH3) calcd for C15H21NO2H([M + H]+)
248.1651, found 248.1652.
Meth od B. Trifluoromethanesulfonic acid (102 mg, 0.68
mmol) was added to a solution of the azide 81 (162 mg, 0.48
mmol) in benzene (10 mL) at 10 °C. After for 10 min, the
solution was cooled to 0 °C and treated with diisobutylalumi-
num hydride (DIBAL-H, 2.0 mL of a 1.5 M solution in toluene,
3.0 mmol). After the mixture was warmed to room temperature
for 30 min, 15% aqueous NaOH (0.1 mL) and water (0.3 mL)
were carefully added, and the resulting mixture was filtered
though a pad of Celite, washing the solids twice with ether.
The filtrate was concentrated to give a mixture of (1R*,3aR*)-
1-(2-bromoethyl)-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quino-
line, (1R*,3aS*)-1-(2-bromoethyl)-1,2,3,3a,4,5-hexahydropyrrolo-
[1,2-a]quinoline, and (1R*,10bR*)-1-(2-bromoethyl)-1,2,3,5,6,10b-
hexahydropyrrolo[2,1-a]isoquinoline, which was dissolved in
THF (10 mL), and treated with tetra-n-butylammonium
acetate (434 mg, 1.44 mmol) at room temperature. After 14 h,
ether was added, and the solution was washed with water and
brine and then dried (Na2SO4) and concentrated. The resultant
oil was dissolved in THF (10 mL) and transferred to a
suspension of lithium aluminum hydride (50 mg, 1.32 mmol)
in THF (5 mL) at 0 °C. After the mixture was warmed to room
temperature for 1 h, 15% aqueous sodium hydroxide (0.2 mL)
and water (0.5 mL) were slowly added in a sequential fashion.
The mixture was filtered, washing the solids with ether (3×).
The filtrate was dried (Na2SO4) and concentrated. Chroma-
tography (2:1 ether/hexanes) of the residue gave 56 mg (47%)
of an inseparable mixture of 49 and 84 as a clear oil, Rf )
0.43, that was shown by 1H NMR spectroscopy to be a 2:1
mixture of diastereomers as judged by integration of hydrogens
at δ 4.02-3.96 and 3.94-3.86. Comparison of the 13C NMR
data with the literature data36 showed that the major diaste-
reomer was 49, i.e., the (1R*,3aR*) isomer. Further elution
as above gave 15.4 mg (13%) of the isomeric amine 85, whose
spectral data matched those reported above.
1
δ 5.95-5.87 and 5.58-5.49 in the H NMR spectrum. Data on
the mixture of isomers: Yellow oil, Rf ) 0.51; 1H NMR (CDCl3,
360 MHz) δ 7.26-7.17 (m, 1.5 H), 7.09 (d, J ) 7.6 Hz, 0.5 H),
6.76 (dd, J ) 7.0, 1.7 Hz, 0.5 H), 6.71 (d, J ) 9.5 Hz, 0.5 H),
5.95-5.87 (m, 0.5 H), 5.58-5.49 (m, 0.5 H), 3.86 (s, 1.5 H),
3.85 (s, 1.5 H), 3.80-3.73 (m, 1 H), 3.54-3.50 (m, 2 H), 2.96
(t, J ) 6.3 Hz, 1 H), 2.89-2.86 (m, 1.5 H), 2.81-2.74 (m, 3 H),
2.55-2.46 (m, 0.5 H), 2.11-2.02 (m, 2 H); 13C NMR (CDCl3,
90 MHz) δ 156.4, 146.1, 144.7, 141.7, 136.3, 134.1, 128.0, 127.8,
116.8, 116.3, 113.1, 112.5, 109.3, 109.0, 61.0, 60.8, 55.2, 37.0,
36.9, 34.4, 33.7, 33.3, 29.9, 28.1, 26.7, 26.6; IR (neat) 2100 (s)
cm-1; MS (CI with NH3) m/z (rel int) 336 ([M + H]+, 3.7), 308
(25.7), 173 (100); HRMS (CI with NH3) calcd for C15H18N3BrOH
([M + H]+) 336.0711, found 336.0699.
(1R*,3a R*)-1-(2-Hyd r oxyeth yl)-6-m eth oxy-1,2,3,3a ,4,5-
h exa h yd r op yr r olo[1,2-a ]qu in olin e (49), (1R*,3a S*)-1-(2-
Hyd r oxyeth yl)-6-m eth oxy-1,2,3,3a ,4,5-h exa h ydr op yr r olo-
[1,2-a ]qu in olin e (84), an d (1R*,10bR*)-1-(2-Hydr oxyeth yl)-
7-m eth oxy-1,2,3,5,6,10b-h exa h yd r op yr r olo[2,1-a ]isoqu in -
olin e (85). Meth od A. Trifluoromethanesulfonic acid (356 mg,
2.37 mmol) was added to a solution of the bromo azide 81 (490
mg, 1.82 mmol) in benzene (40 mL) at 10 °C. After 10 min,
the mixture was cooled to 0 °C and treated with sodium
borohydride (359 mg, 9.49 mmol) in methanol (10 mL). After
warming to room temperature for 14 h, saturated aqueous
sodium bicarbonate was added, and the mixture was extracted
with ether (3×). The combined organic phases were washed
twice with brine and then dried (Na2SO4) and concentrated to
give a mixture of (1R*,3aR*)-1-(2-bromoethyl)-1,2,3,3a,4,5-
hexahydropyrrolo[1,2-a]quinoline, (1R*,3aS*)-1-(2-bromoethyl)-
1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoline, and (1R*,10bR*)-
1-(2-bromoethyl)-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquin-
oline, which was dissolved in THF (10 mL), and treated with
tetra-n-butylammonium acetate (1.43 g, 4.74 mmol) in THF
(5 mL) at room temperature. After 4 h, ether was added, and
the solution was washed with water and brine and then dried
(Na2SO4) and concentrated. The crude acetates were dissolved
in THF (10 mL) and transferred to a suspension of lithium
aluminum hydride (100 mg, 2.64 mmol) in THF (5 mL) at 0
°C. After warming to room temperature for 1 h, 15% aqueous
sodium hydroxide (0.2 mL) was carefully added, followed by
water (0.5 mL). The mixture was filtered, washing the solids
with ether (3×). The filtrate was dried (Na2SO4) and concen-
trated. Chromatography of the residue (2:1 ether/hexanes)
gave 218 mg (56%) of an inseparable mixture of 49 and 84 as
a clear oil, Rf ) 0.43, that was shown by 1H NMR spectroscopy
to be a 1:1 mixture of diastereomers as judged by integration
of hydrogens at δ 4.02-3.96 and 3.94-3.86. The 13C NMR
spectral data for the mixture of 49 and 84 was consistent with
that reported for a mixture of the same two compounds by Ito
and co-workers.36 Data for the mixture of 49 and 84: 1H NMR
(CDCl3, 300 MHz) δ 7.06 (t, J ) 8.2 Hz, 1 H), 6.32-6.23 (m, 2
H), 4.02-3.96 (m, 0.5 H), 3.94-3.86 (m, 0.5 H), 3.79 (s, 1.5
H), 3.78 (s, 1.5 H), 3.77-3.63 (m, 2 H), 3.56-3.45 (m, 0.5 H),
3.30 (tdd, J ) 10.8, 4.7, 2.1 Hz, 0.5 H), 3.05 (ddd, J ) 16.5,
4.3, 2.6 Hz, 0.5 H), 2.93 (dd, J ) 17.4, 5.1 Hz, 0.5 H), 2.50
(ddd, J ) 19.3, 12.7, 6.7 Hz, 0.5 H), 2.42 (ddd, J ) 17.5, 13.3,
5.0 Hz, 0.5 H), 2.25-2.12 (m, 3 H), 2.11-1.95 (m, 2 H), 1.89-
Meth od C. Trifluoromethanesulfonic acid (339 mg, 2.26
mmol) was added to a solution of azide 81 (500 mg, 1.49 mmol)
in benzene (25 mL) at 10 °C. After 10 min, the solution was
cooled to 0 °C and treated with L-Selectride (6.0 mL of a 1.0
M solution in THF, 6.0 mmol) was added. The mixture was
warmed to reflux for 1 h and then cooled to room temperature
and treated carefully with 15% aqueous sodium hydroxide (5
mL). Potassium carbonate was added until the aqueous layer
was saturated, and then the organic phase was separated,
dried (Na2SO4), and concentrated. The crude bromide was
dissolved in THF (5 mL) and treated with tetra-n-butylam-
monium acetate (1.80 g, 5.97 mmol) at room temperature.
After 14 h, the solution was diluted with ether, washed with
water and brine, dried (Na2SO4), and concentrated. The
resulting acetate was dissolved in THF (5 mL) and added to a
suspension of lithium aluminum hydride (113 mg, 2.98 mmol)
in THF (5 mL) at 0 °C. After warming to room temperature
for 1 h, 15% aqueous sodium hydroxide (0.5 mL) and water
(0.5 mL) were carefully added in a sequential fashion. The
mixture was filtered, washing the solids twice with ether. The
filtrate was concentrated, and the residue was chromato-
graphed (2:1 ether/hexane) to give 166 mg (45%) of 49, which
was found to be a single compound as judged by 1H NMR
spectroscopy, The 13C NMR spectrum of this material was
consistent with the partial data reported by Ito and co-
1.78 (m, 0.5 H), 1.72-1.41 (m, 3 H), 1.39-1.28 (m, 0.5 H); 13
C
NMR (CDCl3, 75 MHz, J MOD) δ 157.7 (-), 157.0 (-), 144.9
(-), 144.7 (-), 126.8 (+), 126.6 (+), 110.1 (-), 109.6 (-), 104.7
(+), 104.3 (+), 98.3 (+), 98.1 (+), 60.6 (-), 60.3 (-), 58.3 (+),
56.7 (+), 55.3 (+), 55.2 (+), 54.7 (+), 36.2 (-), 36.0 (-), 31.6
(-), 30.7 (-), 29.9 (-), 29.5 (-), 28.5 (-), 27.1 (-), 21.9 (-),
20.9 (-); IR (neat) 3356 (br s) cm-1; MS (CI with NH3) m/z
(rel int) 2482 ([M + H]+, 42.4), 202 (100); HRMS (CI with NH3)
calcd for C15H21NO2H 248.1651, found 248.1642.
Eluting further with 1:10:200 NH3/MeOH/ether gave 63 mg
(16%) of the amine 85 as a clear oil, Rf ) 0.42 (1:10:200 NH3/
MeOH/ether). The relative configuration is based on the
1
workers.36 The H NMR spectral data for this compound was
consistent with data on similar compounds reported by Hart

7174 J . Org. Chem., Vol. 65, No. 21, 2000
Pearson and Fang
and co-workers.34 Data for 49: Rf ) 0.43 (2:1 ether/hexanes),
1H NMR (CDCl3, 300 MHz) δ 7.03 (t, J ) 8.2 Hz, 1 H, Ar-H),
6.25 (t, J ) 5.2, 2 H, Ar-H), 3.95-3.83 (m, 1 H), 3.79 (s, 3 H,
Ar-OCH3), 3.77-3.65 (m, 2 H, HOCH2-), 3.35-3.23 (m, 1 H,
benzylic H), 2.89 (dd, J ) 16.9, 5.2 Hz, 1 H, benzylic H), 2.54
(ddd, J ) 19.3, 12.4, 6.7 Hz, 1 H, H(1)), 2.25-2.14 (m, 1 H,
bridgehead H), 2.07-1.95 (m, 2 H), 1.90-1.80 (m, 1 H), 1.73-
1.51 (m, 3 H), 1.49-1.38 (m, 1 H); 13C NMR (CDCl3, 75 MHz)
δ 157.8, 145.0, 126.8, 110.1, 105.0, 98.7, 60.8, 58.5, 55.3, 55.1,
36.3, 30.8, 29.7, 28.6, 22.0; IR (neat) 3362 (br s) cm-1; MS (EI,
70 eV) m/z (rel int) 247 (M+, 19.5), 229 (3.2), 202 (100); HRMS
calcd for C15H21NO2 247.1572, found 247.1582. Further elution
with (1:10:200 NH3:MeOH:ether) gave 37 mg (10%) of tricyclic
amine 85, whose spectral data matched those reported above.
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM-35572) for funding this research.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
all compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O0011383