Rearrangements of bicyclic nitrones to lactams: Comparison of photochemical and modified barton conditions

Article abstract of DOI:10.1021/jo035004b

The rearrangement of nitrones to lactams can be carried out by photochemical activation or by treatment with Tf₂O followed by KOH-promoted rearrangement (a modification of conditions originally introduced by Barton). Substrates in which the nit

Full text of DOI:10.1021/jo035004b

Rea r r a n gem en ts of Bicyclic Nitr on es to La cta m s: Com p a r ison of
P h otoch em ica l a n d Mod ified Ba r ton Con d ition s
Yibin Zeng, Brenton T. Smith, J ohn Hershberger, and J effrey Aube´*
Department of Medicinal Chemistry, 1251 Wescoe Hall Drive, Room 4070, Malott Hall,
University of Kansas, Lawrence, Kansas 66045-7852
jaube@ku.edu
Received J uly 11, 2003
The rearrangement of nitrones to lactams can be carried out by photochemical activation or by
treatment with Tf2O followed by KOH-promoted rearrangement (a modification of conditions
originally introduced by Barton). Substrates in which the nitrone is part of a fused bicyclic ring
system have traditionally proven problematic for this kind of reaction. In this study, a series of
mono-, bi-, and tricyclic ring-fused nitrones were prepared to investigate the dependence of products
on nitrone ring size and tether length. Results indicated that photochemical rearrangement of
nitrones in benzene afforded reasonably good yields (30-68%) of lactams, while the two-step
nonphotochemical process provided slightly better average yields (30-95%) of the same targets.
The photolysis of oximes to afford amides, the photo-
Beckmann rearrangement, and the corresponding reac-
tion of nitrones provides easy access to medium ring
lactams.1 In particular, these methods often have the
advantage of allowing successful ring expansions of
substrates that are sensitive to the acidic conditions of
the classical Beckmann rearrangement.2 In most cases,
the rearrangements of nitrones have been studied in
substrates containing the nitrone in an exocyclic orienta-
tion to a single ring (Figure 1a). Although these com-
pounds are readily prepared by the intermolecular reac-
tions of ketones with hydroxylamines, in most cases they
afford a mixture of regioisomeric lactams. This is because
the intermediate oxaziridine presumably forms nonste-
reoselectively from the starting nitrone, which may itself
be a mixture of isomers. An alternative to the photo-
chemical nitrone rearrangement was introduced by Bar-
ton et al., who described treatment of the nitrone with
toluenesulfonyl chloride, presumably to transform the
nitrone oxygen into a competent leaving group in the
presence of pyridine.3
F IGURE 1. Rearrangements of (a) exocyclic and (b) endocyclic
nitrones.
On the other hand, rearrangement of endocyclic, ring-
fused nitrones has attracted much less attention, despite
the fact that the bicyclic lactams formed by the rear-
rangement of such species are of considerable value for
alkaloid synthesis (Figure 1b). Of the few examples that
have been reported, yields are variable and sometimes
complex mixtures of products are obtained.4 Still, this
process has considerable potential due to the fact that
rearrangement of a single isomeric nitrone should afford
a single lactam due to the stereoelectronic principles that
govern the reactions of the intermediate oxaziridine (i.e.,
it is usually the group antiperiplanar to the lone pair on
nitrogen that migrates5). In practice, this advantage has
been lessened by the fact that many workers have
generated the nitrone or the oxaziridine by oxidation of
a secondary amine, which is not always regioselective.
In addition, we have also noted some advantages in using
this technique over a close synthetic equivalent (the
intramolecular Schmidt reaction of alkyl azides and
ketones6) because Lewis or protic acids are not involved.7
* Address correspondence to this author. Phone: 785.864.4496.
Fax: 785.864.5326.
(4) (a) Black, D. S. C.; Watson, K. G. Aust. J . Chem. 1973, 26, 2505-
2513. (b) Black, D. S. C.; J ohnstone, L. M. Aust. J . Chem. 1984, 37,
577-585. (c) Black, D. S. C.; J ohnstone, L. M. Aust. J . Chem. 1984,
37, 587-597. (d) J ohnson, G. P.; Marples, B. A. Tetrahedron Lett. 1985,
26, 4115-4118. (e) Bourguet, E.; Baneres, J .-L.; Girard, J .-P.; Parello,
J .; Vidal, J .-P.; Lusinchi, X.; Declercq, J .-P. Org. Lett. 2001, 3, 3067-
3070.
(1) (a) Lamchen, M. Mech. Mol. Migr. 1968, 1, 1-60. (b) Spence, G.
G.; Taylor, E. C.; Buchardt, O. Chem. Rev. 1970, 70, 231-265.
(2) Gawley, R. E. Org. React. 1988, 35, 1-420.
(3) Barton, D. H. R.; Day, M. J .; Hesse, R. H.; Pechet, M. M. J . Chem.
Soc., Chem. Commun. 1971, 945-946.
10.1021/jo035004b CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/10/2003
J . Org. Chem. 2003, 68, 8065-8067
8065

Zeng et al.
SCHEME 1
SCHEME 2
In this paper we report studies on the utility of the
synthesis and rearrangement reactions of bicyclic ni-
trones. Nitrones were prepared by intramolecular addi-
tion of substituted hydroxylamines to ketones, to maxi-
mize regiochemical control in the nitrone formation step.
Rearrangement reactions with both photochemical means
and a new variant of the Barton protocol were then
compared across a series of substrates.
TABLE 1. Nitr on e Rea r r a n gem en ts
rearrange-
ment
nitrone, % method
yield of
yield of
lactam lactam, %
Resu lts a n d Discu ssion
entry nitrone
m
n
P r ep a r a tion of En d ocyclic Nitr on es. Despite a vast
number of literature methods available for the prepara-
tion of nitrones,8 many of themsespecially those based
on oxidation of a secondary amine directly to the nitrone
(as often used to generate endocyclic nitrones)sdo not
adequately control regiochemistry. A useful approach
that typically provides a single CdN double bond isomer
is the condensation of an N-substituted hydroxylamine
with a ketone. Surprisingly, intramolecular versions of
this reaction are rare.9 The direct installation of a
hydroxylamine protected as various bis-carbonates into
complex substrates is readily accomplished with either
halide displacement10 or Mitsunobu reaction.11 It was
anticipated that N,O-deprotection and subsequent con-
densation of bis-tert-butoxycarbonyl (Boc)-protected hy-
droxylamines with a ketone would directly afford the
nitrones of interest (Scheme 1).
The required iodoalkyl ketones were readily obtained
via hydrazone alkylation as previously described.6 Dis-
placement of the appropriate iodoalkyl ketone with N,O-
diBoc-hydroxylamine10 was followed by treatment with
trifluoroacetic acid in DCM (4 Å MS; followed by acid
neutralization with solid NaHCO3) or a protocol in which
the hydroxylamine was initially formed by treatment
with TFA in DCM, followed by evaporation, replacement
of the solvent with benzene, and reflux with a Dean-
Stark trap (see Supporting Information for details). In
general, the nitrones were purified and characterized
1
2
3
4
5
6
7
8
9
10
11
12
13
14
8
8
9
9
1
1
2
2
2
2
2
2
3
3
4
4
4
4
2
2
1
1
2
2
3
3
2
2
1
1
2
2
85
90
80
88
95
78
87
A
B
A
B
A
B
A
B
A
B
A
B
A
B
15
15
16
16
17
17
18
18
19
19
20
20
21
21
50
40
68
75
65
70
35
40
50
70
56
60
45
35
10
10
11
11
12
12
13
13
14
14
prior to the rearrangement step, although this precaution
is probably not necessary in many cases.
Nitr on e Rea r r a n gem en t. Two methods for the rear-
rangement of these bicyclic nitrones were examined. As
shown above (Figure 1), the photochemical rearrange-
ment of nitrone involves initial oxaziridine formation
followed by the migratory rearrangement to yield lac-
tams. These reactions were conveniently carried out in
a vintage Merry-Go-Round photolysis apparatus (0.02-
0.03 M, 254 nm, benzene, quartz tubes). Benzene has
been shown to be a useful solvent for some oxaziridine
rearrangements, possibly due to sensitization effects.12
Given the spotty history of this reaction as presented
in the literature,4 we thought it desirable to have a
nonphotochemical alternative for the rearrangement
step. Accordingly, we slightly modified Barton’s protocol
(treatment of nitrone with toluene-p-sulfonyl chloride in
pyridine)3 to a two-step process of trapping the nitrone
oxygen with Tf2O followed by a semipinacol-like KOH-
promoted rearrangement (Scheme 2). The results for
nitrones 8-14 are collected in Table 1.
(5) Lattes, A.; Oliveros, E.; Rivie`re, M.; Belzecki, C.; Mostowicz, D.;
Abramskj, W.; Piccinni-Leopardi, C.; Germain, G.; Van Meerssche, M.
J . Am. Chem. Soc. 1982, 104, 3929-3934.
(6) Milligan, G. L.; Mossman, C. J .; Aube´, J . J . Am. Chem. Soc. 1995,
117, 10449-10459.
(7) Smith, B. T.; Wendt, J . A.; Aube´, J . Org. Lett. 2002, 4, 2577-
2579.
(8) (a) Hamer, J .; Macaluso, A. Chem. Rev. 1964, 64, 473-495. (b)
Adams, J . P.; Paterson, J . R. J . Chem. Soc., Perkin Trans. 1 2000,
3695-3705. (c) J ones, R. C. F.; Martin, J . N. Chem. Heterocycl. Compd.
2002, 59, 1-81.
(9) Werner, K. M.; De los Santos, J . M.; Weinreb, S. M.; Shang, M.
J . Org. Chem. 1999, 64, 4865-4873.
In the bicyclic series, the photolysis process afforded
the desired bicyclic lactams with modestly reasonable
yields (35-68%). The lowest yields were associated with
(10) Mellor, S. L.; Chan, W. C. Chem. Commun. 1997, 2005-2006.
(11) (a) Stewart, A. O.; Brooks, D. W. J . Org. Chem. 1992, 57, 5020-
5023. (b) Knight, D. W.; Leese, M. P. Tetrahedron Lett. 2001, 42, 2593-
2595.
(12) (a) Post, A. J .; Nwaukwa, S.; Morrison, H. J . Am. Chem. Soc.
1994, 116, 6439-6440. (b) Wolfe, M. S.; Dutta, D.; Aube´, J . J . Org.
Chem. 1997, 62, 654-663.
8066 J . Org. Chem., Vol. 68, No. 21, 2003

Rearrangements of Bicyclic Nitrones to Lactams
SCHEME 3
SCHEME 4
gave poor yields (10-20%) with both rearrangement
conditions. Interestingly, under photolytic conditions, this
was the only substrate that produced isolable oxaziridine
(33) in this study, indicating that the problem is with
the further reactivity of this species (as opposed to its
formation). Also, the unexpected vinylogous amide 35
was formed during the photochemical reaction; extended
photolysis for two additional hours led to 35 as the
difficult ring sizes (entries 7, 8, 13, and 14). Only fused
(as opposed to bridged) lactams were isolated, in accord
with stereoelectronically preferred bond migrations as-
sociated with the intermediate oxaziridines (see Figure
1).5 In comparison, the average yields of lactam formation
using Method B were slightly better. In neither case were
discrete byproducts isolated. It is noteworthy that two
medium ring lactams (18 and 21) obtained here in
reasonably good yields were inaccessible from the in-
tramolecular Schmidt reaction, further establishing the
present route as an alternative to that method.6
1
exclusive product by examination of the crude H NMR
spectrum. One possible mechanism for the formation of
35 is given, based on the idea that the presence of the
double bond facilitates initial C-O bond cleavage of the
oxaziridine. Presumably, the lactam 34 decomposes upon
extended photolysis. However, these points have not been
carefully examined due to the lack of synthetic utility of
this reaction.
Several more examples were assayed to further estab-
lish the scope of the reaction. For example, two acyclic
ω-hydroxylamino ketones were prepared as above (Scheme
3; the preferred method is shown in the scheme, but
yields of both ring expansion methods are reported for
these examples in the Supporting Information). Ring
expansion of each gave exclusively ring-contracted amides
24 and 27 shown as a direct consequence of selective
migration of bond antiperiplanar to the lone pair of
nitrogen electrons in the intermediate oxaziridine. This
particular example was also chosen to emphasize the
utility of intramolecular nitrone formation as opposed to
secondary amine oxidation; for example, oxidation of
2-phenyl-6-methylpiperidine would be expected to afford,
possibly exclusively, the isomer of nitrone 26. We also
note the very good yields obtained with the norbornane-
based tricyclic compound 29.
Su m m a r y
The rearrangement reactions of endocyclic nitrones
were examined by using photochemical techniques and
modified Barton conditions. Both methods afforded good
yields of the isomeric lactams. Thus, the overall conver-
sion of an ω-iodoalkyl ketone to the corresponding N,O-
bis-Boc-hydroxylamine followed by rearrangement pro-
vides an attractive alternative to synthetically equivalent
methods such as the intramolecular Schmidt reaction.
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM-49093) for support of this work.
J .H. was a 2002 National Science Foundation REU
student.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization of compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
As enones are also reluctant participants in the in-
tramolecular Schmidt reaction, nitrone 32 was prepared
and examined (Scheme 4). Unfortunately, compound 32
J O035004B
J . Org. Chem, Vol. 68, No. 21, 2003 8067