Rapid access to azepine-fused oxetanols from alkoxy-substituted maleimides

Article abstract of DOI:10.1021/ol049645k

UV irradiation of alkoxy-substituted N-alkenylmaleimides induces a sequence involving a [5 + 2] cycloaddition followed by a Norrish-Yang cyclization. The resulting highly strained alkylidene oxetanol-fused azepines are formed in good yield and with high d

Full text of DOI:10.1021/ol049645k

ORGANIC
LETTERS
2004
Vol. 6, No. 9
1481-1484
Rapid Access to Azepine-Fused
Oxetanols from Alkoxy-Substituted
Maleimides
,†
Kevin I. Booker-Milburn,* James R. Baker,† and Ian Bruce‡
School of Chemistry, UniVersity of Bristol, Cantock’s Close, Bristol, BS8 1TS, UK,
and NoVartis Horsham Research Centre, Wimblehurst Road, Horsham,
West Sussex, RH12 5AB, UK
k.booker-milburn@bristol.ac.uk
Received February 27, 2004
ABSTRACT
UV irradiation of alkoxy-substituted N-alkenylmaleimides induces a sequence involving a [5 + 2] cycloaddition followed by a Norrish−Yang
cyclization. The resulting highly strained alkylidene oxetanol-fused azepines are formed in good yield and with high diastereoselectivities
Previously, we reported that N-pentenyl-substituted male-
imide derivatives 1 undergo an efficient formal [5 + 2]
cycloaddition reaction on UV irradiation.1 The reaction has
proved to be general for a range of maleimide derivatives
and has recently been used by us as a key step in alkaloid
synthesis.2 The reaction is related to similar photochemistry
described by Mazzocchi3 for phthalimide derivatives and is
thought to proceed by initial [2 + 2] cycloaddition to form
the zwitterion 2, which then undergoes fragmentation to the
azepine 3 (Scheme 1). One limitation is that when the parent
this communication, we describe the novel and unexpected
photochemical behavior of methoxy-substituted maleimides
and their potential advantages over previously studied
maleimides in synthesis.
We sought to explore a range of substituted maleimides
that would be amenable to further modification, thus render-
ing the resulting azepine products more useful in alkaloid
synthesis.
It was found that the chloromethoxy maleimide 4 could
be synthesized4 in one pot by addition of sodium methoxide
to the previously prepared N-pentenyl dichloromaleimide 1
(R ) Cl). Irradiation of 4 for 40 min indicated that all the
starting material had been consumed, and analysis of the
resulting photosylate showed an almost quantitative mass
balance of the tricyclic alkylidene oxetanol 5 and the [5 +
Scheme 1. [5 + 2] Photochemical Cycloaddition of
Maleimides
(1) Booker-Milburn, K. I.; Anson, E. A.; Clissold, C.; Costin, N. J.;
Dainty, R. F.; Murray, M.; Patel, D.; Sharpe, A. Eur. J. Org. Chem. 2001,
1473.
(2) (a) Booker-Milburn, K. I.; Dudin, L. F.; Anson, C. E.; Guile, S. D.
Org. Lett. 2001, 3, 3005. (b) Booker-Milburn, K. I.; Hirst, P.; Charmant, J.
P. H.; Taylor, L. H. J. Angew. Chem., Int. Ed. 2003, 42, 1642.
(3) (a) Mazzocchi, P. H.; Bowen, M.; Narain, N. J. Am. Chem. Soc. 1977,
99, 7063. (b) Mazzocchi, P. H.; Minamikana, S.; Wilson, P. J. Org. Chem.
1979, 44, 1186. (c) Mazzocchi, P. H.; Minamikana, S.; Wilson, P.; Bowen,
M.; Narain, N. J. Org. Chem. 1981, 46, 4846. (d) Mazzocchi, P. H.; Khachik,
F.; Wilson, P. J. Am. Chem. Soc. 1981, 103, 6498. (e) Mazzocchi, P. H.;
Wilson, P.; Khachik, F.; Klingler, L.; Minamikana, S. J. Org. Chem. 1983,
48, 2981.
maleimide 1 (R ) H) is used, then low yields of cycloadduct
3 (R ) H) result due to further [2 + 2] dimerization.1 In
† University of Bristol.
‡ Novartis Horsham Research Centre.
(4) See Supporting Information for preparation of alkoxy maleimides.
10.1021/ol049645k CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/06/2004

2] cycloaddition regioisomer 6 (3.5:1). It was found that 5
was actually derived from the initially formed [5 + 2]
regioisomer 7, as irradiation of 4 for just 10 min gave a
mixture of 5-7. Subsequent irradiation of isolated regio-
isomer 7 gave 5 in good yield (Scheme 2).
maleimides studied. For example, 4 undergoes complete [5
+ 2] cycloaddition in under 10 min, whereas 1 (R ) Me)
requires 2.5 h of irradiation for complete conversion. This
may be explained by the fact that the key absorption for 1
(R ) Me) is in general a weak band observed in the UV
spectra at around 300 nm, which is probably excited by the
relatively weak 302 and 313 nm emissions from the medium-
pressure mercury source used in this study. The same absorp-
tion in 4 is shifted to a maximum at around 330 nm with a
continuum >370 nm. As this lies close to the most powerful
Hg lamp emission at 365 nm, it is therefore likely that the
excited state of 4 is populated much more efficiently than
1. It is also likely that the weak emission at 334 nm
contributes.
Scheme 2. Methoxymaleimide [5 + 2]/Norrish II Cascadea
We then set out to explore the scope of this reaction by
synthesizing a range of alkoxy maleimide derivatives and
investigating their photocycloaddition reactions (Table 1).
The photosubstrates were prepared by either Mitsunobu
alkylation of monomethoxy maleimide7 or by alkoxylation
of the N-alkylated dichloromaleimides.8 Generally, the
various maleimides displayed the same trend with oxetane
formation predominating. Excellent stereocontrol was ob-
served in the formation of the cycloadducts where up to four
contiguous centers could be formed in a single irradiation
(e.g., entry 3).
The five-membered alkene substrate 10 (entry 7) proved
to be very interesting, as no oxetane product was isolated.
With care, the [5 + 2] enol 11 could be isolated in up to
60% yield. It is likely that the ketone carbonyl in the initially
formed [5 + 2] cycloadduct 12 undergoes photoenolization
faster than Norrish-Yang oxetane formation.9 This in
essence protects the ketone carbonyl from undergoing further
photoreactions. This photoenolization may occur through a
diradical intermediate such as 13, where 1,5-hydrogen atom
abstraction leads to enol formation instead of the oxetane
(Scheme 3).
a Conditions: (a) hν, Pyrex, MeCN, 40 min; (b) hν, Pyrex,
MeCN, 10 min; (c) hν, Pyrex, MeCN, 2 h.
It is most likely that 5 is formed from 7 by the Norrish-
Yang sequence described in Scheme 2. Further excitation
of 7 results in the formation of 8, which undergoes 1,5-hy-
drogen atom abstraction (Norrish II) from the methoxy group
to give the diradical 9, which then undergoes recombination
to 5. A related reaction was observed by Feigenbaum5 for
methoxy-substituted cholestenones. Intermolecular [2 + 2]
photocycloaddition onto methoxy-substituted chromones, fol-
lowed by oxetane formation, has also been reported by Mal
and Venkateswaran.6 There are several noteworthy features
concerning this overall sequence. First, recombination of 9
is highly stereoselective (>99% de), presumably a result of
the methylene radical approaching the R-hydroxy radical
from the least hindered, convex face of the azulene ring sys-
tem. The methoxy group in 4 is clearly exerting a powerful
directing effect on the initial [5 + 2] cycloaddition, resulting
in the predominance of regioisomer 7 and ultimately 5. In
the case of 4, cycloaddition could proceed via the two pos-
sible amide bonds “a” and “b”. Cycloaddition via bond a
leads to the major regioisomer 7, whereas reaction through
bond b leads to the minor isomer 6. As carbonyl b can be
considered a vinylogous carbamate, then the cycloaddition
selectivity is likely to be a result of absorption differences
between these two carbonyls, although detailed modeling is
likely to be required to explain these differences. Mazzocchi
also observed regioselective alkene insertion reactions with
methoxy phthalimide, although it is interesting to note that
in a vinylogous sense, the regioselectivity obtained was oppo-
site that of the methoxy maleimides in this study.1d,e The
initial [5 + 2] reaction of 4 is much faster than previous
Scheme 3. Proposed Mechanism for Photoenolization
When the six-membered alkene substrate 14 was irradi-
ated, only the oxetane 15 and the regioisomer 16 were
obtained, and no sign of the enol was observed. However,
(5) Feigenbaum, A.; Pete, J. P. Tetrahedron Lett. 1972, 13, 2767.
(6) (a) Mal, J.; Venkateswaran, R. V. J. Org. Chem. 1998, 63, 3855. (b)
See also: Wender, P. A.; Rawlins, D. B. Tetrahedron 1992, 48, 7033.
(7) (a) Nicolaus, R. A.; Nicoletti, R. Rend. Accad. Sci. Fis. Mat., Naples
1959, 26, 148. (b) Walker, M. A. J. Org. Chem. 1995, 60, 5352.
(8) Lynch, D. M.; Crovetti, A. J. J. Heterocycl. Chem. 1972, 9, 1027.
(9) For reference to photoenolization during Norrish-Yang cyclization,
see: Wagner, P. J. In CRC Handbook of Organic Photochemistry and
Photobiology, 2nd ed.; CRC Press: Boca Raton, FL, 2004, Chapter 58, pp
1-70.
1482
Org. Lett., Vol. 6, No. 9, 2004

as it led to significant amounts of the dealkoxylated [5 + 2]
product 18 on irradiation. Other products included the
isopropoxy adduct 19, the corresponding oxetane, and the
other [5 + 2] regioisomer (47% yield as a mixture). A plau-
sible mechanism is shown in Scheme 4 and would involve
Table 1. Photochemical Cascade Reactions of
Methoxymaleimidesa
Scheme 4. Photodealkoxylation of Isopropoxy [5 + 2] Adduct
initial formation of 19 followed by Norrish II to the diradical
20. Presumably due to increased steric demands, ring closure
to the oxetane is slower than normal and a significant
proportion of this diradical undergoes â-scission to the seven-
membered hydroxy-allene 21. This then would undergo
tautomerization to 18. Highly strained seven-membered
allenes are not without precedent; for example, 1,2-cyclo-
heptadiene has been prepared and trapped out in situ as a
Diels-Alder adduct.10 Although this type of fragmentation
is a well-known process in Norrish II reactions of saturated
alkoxy-ketones,11 we believe that this is the first report of
such a Norrish II cleavage on a vinyl group.
Finally, we investigated reduction12 of the alkylidene
oxetanol ring system in 22, which initially proved to be
resistant to cleavage by hydrogenation over Pd.13 Hydroge-
nation under Pt catalysis using conditions described by Laffan
for the cleavage of 3-methoxy enones14 eventually yielded
the diol 23 in high yield. Oxidative cleavage of the diol with
periodate gave the keto-amide 24 in excellent overall yield
(Scheme 5).
Scheme 5. Oxetane Cleavage
a Reactions carried out in 100 mL of MeCN at a 0.01 M concentration
using a 150 mL standard immersion well (Pyrex) apparatus with a 125 W
medium-pressure Hg lamp. b Contains minor oxetane diastereomer (>10:
1). c Contains minor oxetane diastereomer (4:1). d Contains minor oxetane
diastereomer (6.5:1). e 15 was obtained as a 1:1 mixture of diastereomers.
The reduced azepine product 24 has previously been
sourced from Zn/AcOH reduction of the dichloromaleimide
the 1:1 mixture of oxetane epimers obtained may indicate
that the enol may also be formed photochemically but
equilibrates to the more stable keto form in this case. It is
interesting to note that this phenomenon would appear to be
limited to methoxy maleimides, as the dimethyl analogue
of 12 showed no evidence of epimerization or enolization.1
The isopropoxy derivative 17 proved to be very interesting,
(10) Bottini, A. T.; Hilton, L. L. Tetrahedron 1975, 31, 2003.
(11) Sonawane, R. H.; Bellur, N. S.; Nazeruddin, G. M. Tetrahedron
1995, 51, 11281.
(12) Reductive cleavage of saturated hydroxyoxetanes has been reported
previously using metal hydride reagents; see: Bach, T.; Kather, K. J. Org.
Chem. 1996, 61, 3900.
Org. Lett., Vol. 6, No. 9, 2004
1483

adduct 3 (R ) Cl).1 Recently, however, we have found that
dichloromaleimides bearing more complex alkene substitu-
ents have proved to be troublesome [5 + 2] substrates, with
much photodegradation of the products observed. It is
possible, therefore, that more complicated analogues of 24
will be accessible via methoxy maleimide adducts using this
oxetane cleavage sequence.
In summary, a new maleimide [5 + 2]/Norrish-Yang
cascade has been reported that results in the stereoselective
formation of highly functionalized azepine-fused oxetanes
from simple alkoxymaleimide building blocks. One of the
most important aspects of this cascade is that, unlike unsub-
stituted maleimides, it yields cycloadducts that do not under-
go further synthetically unproductive dimerizations. These
findings are likely to have a significant impact in the appli-
cation of the [5 + 2] cycloaddition in alkaloid synthesis.
Acknowledgment. We thank the EPSRC (GR/R02382/
01) and Novartis for a CASE award to J.R.B. We also thank
Merck Sharp and Dohme and Pfizer, Ltd., for additional
funding.
Supporting Information Available: Experimental pro-
cedures and characterization for all new compounds prepared.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Feigenbaum et al. report small amounts of reductively cleaved
products on Pd-catalyzed hydrogenation of an alkylideneoxetane. The major
product was the saturated hydroxyoxetane; see: Arnould, J. C.; Enger, A.;
Feigenbaum, A.; Pete, J. P. Tetrahedron 1979, 35, 2501.
(14) Laffan, D. D. P.; Banziger, M.; Duc, L.; Evans, A. R.; McGarrity,
J. F.; Meul, T. HelV. Chim. Acta 1992, 75, 892.
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