Because amino alcohol 8 is a 1:1 mixture of diastereomers,
the 3:1 ratio of cis-9 to trans-9 must result from the
equilibration of the C(1) or C(4) center at some point in the
acid-mediated cyclization. The available evidence indicates
that this occurs via formation of the benzylic cation at C(1),
followed by cyclization to form the product 3-benzazepine,
rather than via epimerization of the C(1) or C(4) center after
cyclization. First, resubjecting cis-9 to cyclization conditions
provides no trace of trans-9, thereby ruling out the possibility
of a postcyclization C(1) or C(4) epimerization. A second
piece of supporting evidence is a previous study10b of the
formation of 1-phenyl-3-benzazepines (e.g., 3, where R2 )
H) from the corresponding amino alcohol precursor. In that
case, an enantiomerically pure (>95% ee) amino alcohol
(e.g., 4, R2 ) H) was subjected to the standard cyclization
conditions, and the resulting 3-benzazepine product was
found to possess a very low ee (6%). Taken together, these
results suggest that the C(4) center is unaffected by the
cyclization conditions. Consequently, if the C(4) substituent
could be introduced stereoselectively in amino alcohol 8, then
the resulting cis and trans 3-benzazepines would be expected
to be enantiomerically pure.11
to be the [6,6]-spiropiperidine dienone trans-17a. Neither
the trans diastereomer of 16a nor the cis diastereomer of
17a could be detected by H NMR of the crude cyclization
1
product. Entries 15-18 of Table 1 summarize the 3-benz-
azepines synthesized via the opening of oxazolidine 13.
The synthesis of a spiropiperidine dienone similar to trans-
17a has been reported,12 and it is noteworthy that although
the cyclization precursor is very similar to amino alcohol
15a, the formation of a 3-benzazepine product was not
observed. Moreover, the product spiropiperidine dienone was
reported to be unstable in strong acid or base and rapidly
reverted to starting material upon exposure to 0.1 N aqueous
HCl. We did not observe trans-17a to be unstable.
In summary, we have developed two general and efficient
methods for the synthesis of 1,4-disubstituted-3-benz-
azepines. The reductive amination route (Scheme 1) allows
the rapid analoging of the N(3) position of 3, while the
oxazolidine route (Scheme 3) offers rapid entry into C(4)
analogues of 3. Depending upon the substitution pattern of
the aryl ring of the Weinreb amide precursor (5 or 12), one
of two possible minor products is formed in addition to the
major cis-1,4-disubstituted-3-benzazepine: starting from 5,
the corresponding trans-1,4-disubstituted-3-benzazepine is
provided in ∼10% yield; starting from 12, the corresponding
trans-1,4-disubstituted spiropiperidine dienone is afforded
in ∼20% yield. While side products are generally undesirable
in organic synthesis, the unusual divergence in reaction
pathways reflected by the formation of either trans-1,4-
disubstituted-3-benzazepines or trans-1,4-disubstituted spiropi-
peridine dienones merits further investigation.
We next turned our attention to the synthesis of C(7)-
unsubstituted 3-benzazepines via oxazolidine 13. As outlined
in Scheme 4, addition of methylmagnesium bromide to 13
afforded the corresponding amino alcohol 15a. Treatment
of 15a with neat methanesulfonic acid at 0 °C provided two
products in a 1.8:1 ratio: the desired cis-1,4-disubstituted-
3-benzazepine (cis-16a) and an unanticipated minor product
which, after extensive spectroscopic analysis, was determined
Acknowledgment. The authors thank Judd Berman,
Darryl McDougald, Michael Rabinowitz, Ron Sherrill, and
Jim Veal for helpful discussions and Randy Rutkowske for
2-D NMR experiments. J.S.S. was supported by a Glaxo
Wellcome summer internship (1995).
Scheme 4
Supporting Information Available: Synthetic procedures
for the preparation of 9a from 4a and 16a from 10. This
information is available free of charge via the Internet at
OL0067641
(11) Our asymmetric synthesis of 1,4-disubstituted-3-benzazepines will
be disclosed in a subsequent publication.
(12) Sill, A. D.; Housmyer, C. L.; Gibboney, K. Tetrahedron 1987, 43,
1177.
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Org. Lett., Vol. 2, No. 25, 2000