Facile C-N cleavage in a series of bridged lactams

Article abstract of DOI:10.1021/ja050214m

A series of strained bi- and tricyclic amides has been shown to be unusually sensitive to cleavage of the C-N bond adjacent to the amide moiety. This bond undergoes facile breaking when subjected to treatment with H₂/Pd(OH)₂, MeI, and DDQ. In each case, the reaction is highly regioselective and mainly results in breaking the C-N bond that deviates the farthest from its natural planar state. Preliminary experiments that bear on the mechanisms of these reactions are described. Copyright

Full text of DOI:10.1021/ja050214m

Published on Web 03/10/2005
Facile C-N Cleavage in a Series of Bridged Lactams
Yao Lei, Aaron D. Wrobleski, Jennifer E. Golden, Douglas R. Powell, and Jeffrey Aube´*
Department of Medicinal Chemistry, 1251 Wescoe Hall DriVe, Room 4070, Malott Hall,
UniVersity of Kansas, Lawrence, Kansas 66045-7582
Received January 12, 2005; E-mail: jaube@ku.edu
Scheme 1
Twisted amides, in which the amide bond deviates significantly
from the planar conformation usually associated with this functional
group, are of interest from both a structural and reactivity
perspective.1 Such amides are markedly sensitive to hydrolysis of
the amide bond, they are subject to reactions that are more
commonly associated with ketones than amides, and they undergo
N- rather than O-protonation.2 These features have been ascribed
to loss of conjugation between the amide nitrogen and the CdO π
bond, although this interpretation is subject to continuing investiga-
tion from a theoretical perspective.3 Nonplanar amides are also
Scheme 2
interesting because they are encountered midway in the cis/trans
isomerization of peptide bonds.4 We wish to report a class of twisted
amides whose non-carbonyl, C-N σ bond is remarkably susceptible
to cleavage, even exhibiting a highly unusual sensitivity to catalytic
hydrogenolysis.
Twisted amides most commonly arise by the incorporation of
the amide bond into a ring system that prohibits the amide from
attaining its usual planar geometry.5,6 Recently, we encountered
lactam 1 as the minor component of a tandem intramolecular Diels-
Alder/Schmidt reaction sequence carried out in the context of a
total synthesis of stenine (Scheme 1).7 Wishing to verify the
structure of this byproduct, we sought to prepare a crystalline
derivative by removing the benzyl group by catalytic hydrogenation
(an act that also reduced the olefinic group in the compound) and
then making the p-bromobenzoyl ester of the resulting alcohol.
Although the product was indeed crystalline, it was not the tricyclic
amide that we had expected. Strikingly, the sole product resulted
from the regioselective, reductive cleavage of the C-N bond within
the seven-membered ring. None of the product resulting from
reaction at the C-N bond in the six-membered ring was observed.7,8
Although heightened reactivity of a twisted amide linkage is well-
known, the breaking of an otherwise unactivated C-N σ bond has
been reported in only a single specialized example.9 A series of
analogues of 1 was subjected to similar conditions, demonstrating
that this unusual reduction was not peculiar to 1 (Scheme 2; see
The C-N bond also underwent cleavage by treatment with
Supporting Information for substrate preparations). The successful
hydrogenolysis of two examples lacking an olefin demonstrated
that an alkene was not necessary for hydrogenolysis (e.g., by
migrating into an allylic position). In addition, two bicyclic
analogues were made and similarly challenged; one of these
underwent hydrogenolysis and one did not. Since compound 6
appears to have a similar extent of strain as 4, its lack of reactivity
is possibly due to increased steric hindrance, although this point
will require additional study. Although a number of conditions
afforded product, the yields of all of these reactions were dependent
on catalyst and solvent. The best results were obtained in ethanol
using Pearlman’s catalyst (Pd(OH)2), although reactions in non-
protic solvents also succeeded to a lesser extent (e.g., reaction of
1 in THF gave a 16-27% yield of the alcohol corresponding to
2).
methyl iodide (Scheme 3). This reaction, which is mechanistically
related to the dealkylation of tertiary amines with haloformates,10
was also completely regioselective. The C-N bond also proved
susceptible to oxidative cleavage using DDQ. This reaction, which
presumably involves initial single-electron transfer, afforded a ca.
5:1 mixture of aldehydes from the unsubstituted ring system 2a
but exclusively 7c from 2c.
We obtained an X-ray structure of bridged lactam 2c (Figure
1). As expected, the nitrogen atom is nearly pyramidal, with bond
angles ranging from 110 to 119°. It is also evident that the labile
C10-N bond is further from the carbonyl plane than the C11-N
bond. However likely that this feature is related to the observed
regiochemistry, it is unclear whether the underlying reason is related
only to strain or if improved overlap of the labile bond with the
carbonyl π system is also a factor.
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C O M M U N I C A T I O N S
from 4 to 11 afforded only recovered starting material. We think
that hydration or hydrolysis does occur but the amide re-forms due
to the transannular relationship of the amine and ketone groups in
the ring-opened analogue.
Figure 1. (a) Ball-and-stick depiction of the X-ray-derived structure of
compound 2c. (b) Close-up of the amide region, showing dihedral angles
of C10-N-C1-O ) 62.9° and C11-N-C1-O ) -152.9° (which
corresponds to a 27.1° deviation from planarity).
This work shows that the C-N bond adjacent to a twisted amide
can undergo interesting strain-activated chemistry. Future work will
systematically address the effect of amide structure on reactivity
in this class of lactams.
Scheme 3
Acknowledgment. We thank the NIH (GM-49093) for support
of this work, David Vander Velde and Sarah Neuenswander for
assistance with NMR spectroscopy, and Jerry Murry for suggesting
the D2 experiment. J.E.G. acknowledges a Madison A. and Lila
Self Fellowship, and A.D.W. thanks the American Chemical Society
Division of Organic Chemistry and Abbott Laboratories for a
fellowship.
Supporting Information Available: Experimental procedures and
compound characterizations (PDF, CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
References
(1) For reviews of twisted amides: see (a) Greenberg, A. Mol. Struct. Energ.
1988, 7, 139-178. (b) Greenberg, A.; Breneman, C. M.; Liebman, J. F.
Amide Linkage: Selected Structural Aspects in Chemistry, Biochemistry,
and Materials Science; Wiley: New York, 2000.
(2) (a) Somayaji, V.; Skorey, K. I.; Brown, R. S. J. Org. Chem. 1986, 51,
4866. (b) Wang, Q. P.; Bennett, A. J.; Brown, R. S.; Santarsiero, B. D. J.
Am. Chem. Soc. 1991, 113, 5757-5765. (c) Kirby, A. J.; Komarov, I. V.;
Feeder, N. J. Chem. Soc., Perkin Trans. 2 2001, 522-529. (d) Lopez,
X.; Mujika, J. I.; Blackburn, G. M.; Karplus, M. J. Phys. Chem. A 2003,
2304-2315.
Scheme 4
(3) (a) Wiberg, K. B.; Breneman, C. M. J. Am. Chem. Soc. 1992, 114, 831-
840. (b) Greenberg, A.; Venanzi, C. A. J. Am. Chem. Soc. 1993, 115,
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1990, 55, 4984-4986. (c) Brown, R. S.; Bennet, A. J.; Slebocka-Tilt, H.
Acc. Chem. Res. 1992, 25, 481-488.
(5) Recent reports of bridged amides include: (a) Williams, R. M.; Lee, B.
H.; Miller, M. M.; Anderson, O. P. J. Am. Chem. Soc. 1989, 111, 1073-
1081. (b) Lease, T. G.; Shea, K. J. J. Am. Chem. Soc. 1993, 115, 2248-
2260. (c) Kirby, A. J.; Komarov, I. V.; Kowski, K.; Rademacher, P. J.
Chem. Soc., Perkin Trans. 2 1999, 1313-1316. (d) Greenberg, A. Amide
Linkage 2000, 47-83. (e) Bashore, C. G.; Samardjiev, I. J.; Bordner, J.;
Coe, J. W. J. Am. Chem. Soc. 2003, 125, 3268-3272. (f) Aszodi, J.;
Rowlands, D. A.; Mauvais, P.; Collette, P.; Bonnefoy, A.; Lampilas, M.
Bioorg. Med. Chem. Lett. 2004, 14, 2489-2492. (g) Sparks, S. M.; Chow,
C. P.; Zhu, L.; Shea, K. J. J. Org. Chem. 2004, 69, 3025-3035.
(6) Twisted amides are also observed when incorporating steric features that
are relieved by rotation around the amide bond. (a) Yamada, S. Angew.
Chem. 1993, 105, 1128-1130. (b) Yamada, S. ReV. Heterocycl. Chem.
1998, 19, 203-236. (c) Duspara, P. A.; Matta, C. F.; Jenkins, S. I.;
Harrison, P. H. M. Org. Lett. 2001, 3, 495-498.
(7) Golden, J. E.; Aube´, J. Angew. Chem., Int. Ed. 2002, 41, 4316-4318.
(8) The identity of 1 was confirmed by making a bis-bromobenzoylated
analogue that was subjected to X-ray analysis (Supporting Information).
(9) Cleavage of a C(Me)2-NC(O) bond in a [2.2.2]bicyclic lactam has been
attributed to carbocation formation: Levkoeva, E. I.; Nikitskaya, E. S.;
Yakhontov, L. N. Dokl. Akad. Nauk SSSR, 1970, 192, 342-345. In
contrast, another twisted amide incorporating a tert-butyl proline moiety
underwent clean hydrogenation with Pd/C in MeOH without fragmenta-
tion: Halab, L.; Lubell, W. D. J. Am. Chem. Soc. 2002, 124, 2474-
2484.
While the mechanism of the MeI-mediated cleavage reaction
almost certainly involves initial formation of the amidinium species
followed by SN2 displacement by iodide, we considered the
possibility that the hydrogenolysis reaction might instead involve
a McClafferty-type rearrangement (possibly Pd-promoted) to afford
an olefin that was subsequently reduced (Scheme 4). This idea lost
favor when it was shown that no change occurred when the twisted
amides were subjected to Pd(OH)2/EtOH treatment under a non-
hydrogen atmosphere. In addition, carrying out the reaction using
D2/EtOD11 resulted in the incorporation of a single D atom at the
end of the propyl chain, which is consistent with a direct
displacement either by Pd-activated hydride or by metal insertion
followed by reductive elimination. In either case, the NH proton
undergoes exchange when the compound is isolated. The preference
for a protic solvent in the hydrogenolysis likely indicates a role
for hydrogen bonding to nitrogen in the cleavage reaction.
(10) (a) Kametani, T.; Shiotani, S.; Mitsuhashi, K. Chem. Pharm. Bull. 1976,
24, 342-349. (b) Campbell, A. L.; Pilipauskas, D. R.; Khanna, I. K.;
Rhodes, R. A. Tetrahedron Lett. 1987, 28, 2331-2334.
(11) The source of the isotope in hydrogenation reactions carried out in protic
solutions is the solvent and not the gas: Lee, T. R.; Whitesides, G. M. J.
Am. Chem. Soc. 1991, 113, 369-370. Thus, when the Scheme 4
experiment was run with H2 in EtOD or d6-ethanol, the same results were
obtained.
Finally, we note that, in contrast to many other examples of
twisted amides, none of these lactams readily form the correspond-
ing seco acid. Thus, incubation in aqueous THF with pH ranging
JA050214M
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