Synthesis of dihydropyrrole derivatives by copper-catalyzed cyclization of γ, δ-unsaturated ketone O-methoxycarbonyloximes

Article abstract of DOI:10.1246/cl.2002.784

2-Bromomethyl-3,4-dihydro-2H-pyrroles are prepared from γ, δ-unsaturated ketone O-methoxycarbonyloximes by treatment with a catalytic amount of CuBr·SMe₂ and LiBr.

Full text of DOI:10.1246/cl.2002.784

784
Chemistry Letters 2002
Synthesis of Dihydropyrrole Derivatives by Copper-Catalyzed Cyclization of
ꢀ; ꢁ-Unsaturated Ketone O-Methoxycarbonyloximes
Yohei Koganemaru, Mitsuru Kitamura, and Koichi NarasakaÃ
Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033
(Received May 13, 2002; CL-020409)
2-Bromomethyl-3,4-dihydro-2H-pyrroles are prepared from
ꢀ; ꢁ-unsaturated ketone O-methoxycarbonyloximes by treatment
ꢀ
with a catalytic amount of CuBr SMe2 and LiBr.
out in the presence of diphenyl disulfide, cyclized products 2b and
2a was obtained in 41% and 14% yield, respectively (Run 3). In
the presence of LiBr, the cyclization product, 2-bromomethyldi-
hydropyrrole 2c, was obtained in high yield (86%, Run 4). 2-
Chloromethyldihydropyrrole 2d was prepared in 57% yield by
ꢀ
using CuCl instead of CuBr SMe2 in the presence of lithium
chloride (Run 5).
Recently, we reported the radical cyclization of ꢀ; ꢁ-
unsaturated ketone O-2,4-dinitrophenyloximes to 3,4-dihydro-
2H-pyrroles.1 The reaction is initiated by one electron reduction
of oximes with sodium hydride and 3,4-methylenedioxyphenol,
followed by radical cyclization with eliminating 2,4-dinitrophen-
oxide (Scheme 1). This procedure has drawbacks as a synthetic
method; the use of large excess amounts of NaH and a bulky
leaving group such as 2,4-dinitrophenoxy group.
Table 1. Copper-catalyzed cyclization of O-methoxycarbony-
loxime 1a
Scheme 1. Cyclization of O-2,4-dinitorophenyloxime.
In addition to O-methoxycarbonyloxime 1, O-pentafluor-
obenzoyloxime 3 was transformed into 2c in high yield, but the
corresponding O-2,4-dinitrophenyl and O-acetyloxime were not
It was expected that one electron reduction of oxime
derivatives would proceed by treatment with low valent transition
metal compounds. Such an example was reported by Zard. That
is, the treatment of ꢀ; ꢁ-unsaturated O-acetyloximes with nickel
powder and acetic acid in 2-propanol leads to the cyclization to
dihydropyrroles.2 The reaction, however, requires large excess
amounts of nickel powder. It is desirable to conduct such a
transformation in a catalytic manner. We would like to report
herein a copper-catalyzed transformation of ꢀ; ꢁ-unsaturated
ketone O-methoxycarbonyloximes to dihydropyrrole derivatives.
By using copper compounds3 as metal catalysts, we
examined the cyclization of various ꢀ; ꢁ-unsaturated oximes.
After screening the substituents on the oxime nitrogen atom (vide
infra), O-methoxycarbonyloximes were found to be suitable for
the transformation of ꢀ; ꢁ-unsaturated oximes to dihydropyrroles.
ꢀ
appropriate for the CuBr SMe2-LiBr-catalyzed cyclization. The
syn and anti-isomers of 1 were hard to separate, whereas syn and
anti-3 were separable by recrystallization.7 The influence of the
stereochemistry of oximes was hence examined by the reaction of
each isomer of 3, which gave the cyclization product 2c in 86%
and 91% yield from the syn and anti isomers, respectively. Thus
the cyclization proceeds irrespective of the stereochemistry of
oximes.
When a syn/anti (1 : 1) mixture4 of O-methoxycarbonyloxime 15
6
and 5 mol% of CuBr SMe2 in 1,4-dioxane was heated to 80 ꢁC,
ꢀ
The reaction probably proceeds as shown in Scheme 2.
Electron transfer from copper(I) salt to the oxime 1 generates
anion radical A. Successively, the N–O bond of A cleaves with
elimination of methyl carbonate anion and the cyclization occurs
simultaneously to give 2c.8 Lithium bromide plays a role for
cyclic imine 2a was obtained in 39% yield (Table 1, Run 1). Thus
the reaction proceeded catalytically. Addition of radical trapping
reagents such as tris(trimethylsilyl)silane did not improve the
yield of cyclization products (Run 2). When the reaction carried
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
785
regeneration of CuBr from copper(I) carbonate.
ꢀ,ꢁ-Unsaturated ketone O-methoxycarbonyloximes were
converted into dihydropyrrole derivatives by using
CuBr Á SMe2-catalyst in the presence of LiBr. 5-Membered
cyclic imines are thus prepared catalytically, whereas the
formation of 6-membered imines is hard to proceed from ꢁ; "-
unsaturated ketone oximes.
Very recently was reported a copper-catalyzed radical
cyclization
of
unsaturated
N-benzoyloxyamines
to
pyrrolidines.10 Totally, various dihydropyrrols and pyrrolidines
can be prepared by copper-catalyzed radical cyclization pro-
cesses.
This research was supported by a Grant-in-Aid for Scientific
Research on Priority Areas (A) ‘‘Exploitation of Multi-Element
Cyclic Molecules’’ from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
Scheme 2. Mechanism of Cu(I)-catalyzed cyclization of 1.
ꢀ
As listed in Table 2, the catalytic system with CuBr SMe2-
LiBr could be applied to the cyclization of various ꢀ,ꢁ-
unsaturated ketone O-methoxycarbonyloximes. Cyclization of
4a and 4b having disubstituted olefin moiety proceeded to give
cyclic imines 5a and 5b in 85% and 74% yield, respectively (Runs
1, 2). 5,5-Disubstituted dihydropyrrole 5c was obtained in 53%
yield from ꢀ-methylsubstituted oxime 4c along with 16% yield of
disubstituted pyridine 6 (Run 3).9 Oxime derivatives of phenyl
ketone 4d and keto ester 4e were smoothly transformed into 2-
phenyl and 2-ethoxycarbonyl dihydropyrroles 5d and 5e,
respectively (Runs 4, 5).
References and Notes
1
2
3
K. Uchiyama, Y. Hayashi, and K. Narasaka, Chem. Lett.,
1998, 1261.
J. Boivin, A.-M. Schiano, S. Z. Zard, and H. Zhang,
Tetrahedron Lett., 40, 4531 (1999).
In recent years, there have been some reports on the radical
addition of trichloromethyl carbonyl compounds to intramo-
lecular olefin moiety mediated by a catalytic amount of
copper
complexes
of
bipyridine,3a,b
N-alkyl-2-
pyridylmetanimine,3c,d or multidentate amines3c,e,f as redox
catalysts. a) H. Nagashima, Y. Isono, and S. Iwamatsu, J. Org.
Chem., 66, 315 (2001). b) S. Iwamatsu, H. Kondo, K.
Matsubara, and H. Nagashima, Tetrahedron, 55, 1687 (1999).
c) A. J. Clark, R. P. Filik, and G. H. Thomas, Tetrahedron
Lett., 40, 4885 (1999). d) A. J. Clark, R. P. Filik, D. M.
Haddleton, A. Radique, C. J. Sanders, G. H. Thomas, and M.
E. Smith, J. Org. Chem., 64, 8954 (1999). e) A. J. Clark, F. de
Campo, R. J. Deeth, R. P. Filik, S. Gatard, N. A. Hunt, D.
Table 2. Cyclization of several O-methoxycarbonyloximea
´
Lastecoueres, G. H. Thomas, J.-B. Verlhac, and H. Wongtap,
J. Chem. Soc., Perkin Trans 1, 2000, 671. f) F. de Campo, D.
`
´
Lastecoueres, and J.-B.Verlhac, Chem. Commun., 1998,
2117.
`
4
5
6
In this paper, syn isomer means the oxime having a leaving
group on the oxime nitrogen and the olefin moiety in the same
side of the oxime C=N bond; anti isomer means the other.
O-Methoxycarbonyloximes were prepared by treatment of
the corresponding oximes with methyl chloroformate and
NaH in THF.
Some other copper compounds such as Cu powder, CuBr,
CuCN, CuI and their amine complexes were employed in the
ꢀ
cyclization of 1. Among them, CuBr SMe2 was most suitable
for this reaction.
7
O-Pentafluorobenzoyloxime 3 could be separated into the
syn-and anti-isomers by recrystallization (EtOH). syn-3
crystallized first, and then anti-3 was purified by repeating
recrystallization (EtOH).
8
9
a) J. Cassayre, D. Dauge, and S. Z. Zard, Synlett, 4, 471
(2000). b) B. B. Snider, Chem. Rev., 96, 339 (1996). c) J. K.
Kochi, Acc. Chem. Res., 7, 351 (1974).
Probably pyridine 6 was formed by 6-endo cyclizaiton,
dehydrobromination, and successive oxidation.
10 M. Noack and R. Gottlich, Chem. Commun., 2002, 536.
¨