Photochemical radical cyclization of γ,δ-unsaturated ketone oximes to 3,4-dihydro-2H-pyrroles

Article abstract of DOI:10.1016/j.tetlet.2005.02.062

3,4-Dihydro-2H-pyrroles are synthesized from γ, δ-unsaturated oximes by photochemical radical cyclization with 1,5-dimethoxynaphthalene (DMN) as the sensitizer. The cyclization of alkyl ketone O-acetyloximes proceeds via photosensitized electron transfer

Full text of DOI:10.1016/j.tetlet.2005.02.062

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2373–2376
Photochemical radical cyclization of c,d-unsaturated ketone
oximes to 3,4-dihydro-2H-pyrroles
Mitsuru Kitamura, Yutaka Mori and Koichi Narasaka*
Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 7 January 2005; revised 9 February 2005; accepted 14 February 2005
Dedicated to Professor Iwao Ojima on the occasion of his 60th birthday
Abstract—3,4-Dihydro-2H-pyrroles are synthesized from c,d-unsaturated oximes by photochemical radical cyclization with 1,5-
dimethoxynaphthalene (DMN) as the sensitizer. The cyclization of alkyl ketone O-acetyloximes proceeds via photosensitized elec-
tron transfer in the presence of acetic acid, while conjugated oximes of aryl and a,b-unsaturated ketones are cyclized via energy
transfer.
Ó 2005 Elsevier Ltd. All rights reserved.
For the synthesis of nitrogen heterocycles, iminyl radical
is employed as one of the reactive intermediates to pre-
pare cyclic imines.1 Several radical cyclization methods
have been reported using iminyl radical species gener-
ated from oxime derivatives.2–5 For example, Zard and
co-workers reported the radical cyclization of O-acetyl-
oximes2e by reduction with excess amount of nickel
powder, Winreband co-workers have developed the
cyclization of O-2,6-dimethylbenzenesulfinyloximes by
applying Hudson reaction.2f Although iminyl radicals
are known to be generated from oximes by photo-
induced energy transfer4,6 or photochemical electron
transfer,5,7 these photochemical processes have not been
utilized to radical cyclization except for few examples.4,5
CN
NC
hν >320 nm
O
cat. DMN
CHD
O
N
N
R
CH3CN, rt
R
1
R = Ph(CH2)2
2
Me
N
N
CHD
R
R
3
4
75%
DMN = 1,5-dimethoxynaphthalene
CHD = 1,4-cyclohexadiene
Scheme 1. Photochemical cyclization of O-(p-cyanophenyl)oxime 1.
During the course of our study on radical cyclization with
oximes,3 it was found that c,d-unsaturated ketone O-(p-
cyanophenyl)oxime 1 cyclizes to 3,4-dihydro-2H-pyrrole
4 by radical process initiated by the single electron trans-
fer from excited-1,5-dimethoxynaphthalene (DMN)
(Scheme 1).5 Thus formed anion radical 2 cyclizes to alkyl
radical intermediate 3 with the elimination of p-cyano-
phenoxide, and 3 is trapped with 1,4-cyclohexadiene to
yield cyclic imine 4. To make electron transfer efficient,
p-cyanophenyl group is introduced as a substituent of
the oxime oxygen. It was desired to replace the cyanophen-
yl group to a small substituent in the sense of atom econ-
omy and for the availability of the starting material. In
this letter, we wish to report an alternative photochemi-
cal cyclization of c,d-unsaturated oximes having acetyl
(Ac) or methyl group on their oxime oxygen.
The photochemical radical cyclization of 3-butenyl
phenethyl ketone O-acetyloxime (5a) was examined
under UV irradiation in the presence of 1,5-dimethoxy-
naphthalene (DMN) as a sensitizer8 in acetonitrile,
using a 400 W high pressure lamp equipped with a UV
cutoff filter (hm > 300 nm). Although O-acetyloxime 5a
was less reactive than O-(p-cyanophenyl)oxime 1 (entry
Keywords: Oxime; Radical cyclization; Photoinduced electron transfer;
Photoinduced energy transfer.
*
Corresponding author. Tel.: +81 3 5841 4343; fax: +81 3 5800
6891; e-mail: narasaka@chem.s.u-tokyo.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.062

2374
M. Kitamura et al. / Tetrahedron Letters 46 (2005) 2373–2376
Table 1. Photochemical reaction of O-acetyloxime 5aa
DMN is electron rich photosensitizer and has been used
as a photochemical electron transfer reagent,8 and O-
acetyloxime 5a may suffer from the reduction more eas-
ily by the protonation with AcOH. Thus, this cyclization
is considered to proceed via photosensitized electron
transfer as depicted in Scheme 2. Single electron transfer
(SET) from excited DMN to protonated oxime 5a af-
fords cation radical of DMN C and radical species of
protonated oxime 9. Successively, cyclization occurs
with the cleavage of the N–O bond to give alkyl radical
species 3. Back electron transfer (BET) from 3 to cation
radical C regenerates the catalyst, DMN, generating cat-
ion species like 10, which is trapped with AcOH imme-
diately to give cyclic imine 6a. Dihydropyrrole 7a or 8
may be formed from radical species 3 by the capture
of hydrogen or chloro atom from 1,4-cyclohexadiene
or 1,2-dichloroethane, respectively.
OAc
Me
OAc
hν >300 nm
N
N
N
DMN, AcOH, CHD
+
R
CH3CN, rt
R
R
5ab
6a
7a
R = Ph(CH2)2
Entry
DMN/
equiv
AcOH/
equiv
CHD/
equiv
Time/h
Yield/%
6a 7a
1c
2
0.2
0.2
None
3.0
10
3.0
0.2
0.2
0.2
20
20
12
20
4
4
67
74
—
6
3
4d
0.2
None
9
—
3.0
a DMN = 1,5-dimethoxynaphthalene; CHD = 1,4-cyclohexadiene.
bE:Z = 1:1.
c Oxime 5a was recovered in 86% yield.
d Oxime 5a was recovered quantitatively.
The photochemical reaction was examined for various
alkyl c,d-unsaturated O-acetyloximes as shown in Table
2. Although cyclization of 5a having the terminal olefin
gave cyclic imine 6a and hydrogenated 7a (entry 1), oxi-
mes 5b–d having internal olefin gave exclusively acet-
oxymethyl imines 6b–d in high yields (entries 2–4).
From c-methyl substituted oxime 5e, pyridine 12 was
formed via 6-endo cyclization in 15% with 58% total
yield of 5-exo products 6e and 7e (entry 5).
1), addition of acetic acid (AcOH, 3 equiv) accelerated
the reaction and dihydropyrrole 6a was obtained in
67% yield (entry 2). When 10 equiv of AcOH was added,
the cyclization finished after 12 h and the yield of 6a was
increased to 74% (entry 3). In both entries 2 and 3, a
small amount of 1,4-cyclohexadiene was added, which
reproduced the product yields of the cyclized products
6a and 7a satisfactorily, though the reason is not clear.
The reaction did not proceed at all in the absence of
the photosensitizer, DMN (entry 4, Table 1).
Next, the cyclization of aryl ketone oximes was exam-
ined instead of alkyl ketone oximes (Table 3). When
phenyl ketone O-acetyloxime 13a was irradiated under
the same conditions, 13a was consumed within 30 min
and cyclization product 16a and ketone 17 were
obtained in 46% and 5% yields, respectively (entry 1).
Without AcOH, the yield of dihydropyrrole 16a was in-
creased to 77% in the presence of excess amounts of 1,4-
cyclohexadiene (entry 2). The reaction hardly proceeded
in the absence of 1,5-dimethoxynaphthalene (entry 3).
Interestingly, O-methyloxime 14a and oxime 15 also
cyclized to 16a in good yields (entries 4 and 5).
In 1,2-dichloroethane instead of acetonitrile, 2-chloro-
methyl dihydropyrrole 8 was obtained as a major prod-
uct in 70% yield with a small amount of 2-acetoxymethyl
derivative 6a (Eq. 1). This result gave an important in-
sight to consider the mechanism of this photochemical
reaction as follows.
hν >300 nm
OAc
Cl
+
OAc
20 mol% DMN, CHD
300 mol% AcOH
N
N
N
R
ClCH2CH2Cl, rt, 20 h
R
R
5a R = Ph(CH2)2
8 70%
6a 7%
Thus the reactions of phenyl ketone oximes 13–15 did
not afford 2-(acetoxymethyl)dihydropyrrole and the
addition of AcOH was not essential. These indicate that
the cyclization of phenyl ketone oximes does not pro-
DMN = 1,5-dimethoxynaphthalene
CHD = 1,4-cyclohexadiene
ð1Þ
OAc
OAc
N
N
hν
N
AcOH
*
(DMN)
(DMN)
R
R
R
B
A
5a
10
6a
R = Ph(CH2)2
H+
(OAc)
X
or
Cl(CH2)2Cl
H
N
N
N
(DMN)
(DMN)
- AcOH
R
R
R
C
C
9
3
7a X = H
X = Cl
8
Scheme 2. Plausible mechanism of photochemical cyclization of 5a.

M. Kitamura et al. / Tetrahedron Letters 46 (2005) 2373–2376
Table 2. Photochemical cyclization of various O-acetyl oximes 5a,b
2375
Table 4. Photochemical cyclization of conjugated ketone oximesa,b
Me
R2
R2 OAc
R3
H
OR2
R3
R4
hν >300 nm
OAc
N
hν >300 nm
DMN, AcOH, CHD
R4
R2
DMN, CHD
CH3CN, rt
N
N
N
N
R1
R1
+
R1
R3
R1
R1
CH3CN, rt
13-14
16
E:Z Time/h Yield/%
5c
R1 = Ph(CH2)2
R4
6
7
Entry R1
R2
Ac (13a)
Me (14a) 1:0
1
2
Ph
1:0
0.5
3
77 (16a)
79 (16a)
Entry
R2
R3
R4
Time/h
Yield/%
1
H
H
H (5a)
H (5b)d
H (5c)
H (5d)
Me (5e)
12
13
10
10
10
73 (6a)
82 (6b)e
76 (6c)f
80 (6d)
47 (6e)
9 (7a)
0 (7b)
0 (7c)
0 (7d)
11 (7e)
Ph
O
3
3
4
Piv (13b) 1:0
Me (14b) 1:0
2
5
56 (16b)
53 (16b)
2
H
Me
Ph
Me
H
3
H
O
4g
5h
Me
H
5
6
Ac (13c) 3:7
Me (14c) 3:5
2
9
12 (16c)
56 (16c)
Ph
Ph
a DMN = 1,5-dimethoxynaphthalene; CHD = 1,4-cyclohexadiene.
b Oxime:DMN:AcOH:CHD = 1:0.2:10:0.2.
c E:Z = 1:1.
d The stereochemistry of olefin moiety was E:Z = 10:3.
e Diastereomer mixture (4:1).
f Diastereomer mixture (7:3).
g 11 was obtained in 10% yield.
7c
8d
Ac (13d)
Me (14d) 6:11 20
3:8
5
63 (16d)
0 (16d)
a DMN = 1,5-dimethoxynaphthalene;
Piv = pivaloyl.
b Oxime:DMN:CHD = 1:0.2:10.
c 18 was obtained in 12% yield.
CHD = 1,4-cyclohexadiene;
Me
N
N
d 18 was obtained in 5% yield.
18
R1
11
followed by hydrogen abstraction from 1,4-cyclohexa-
diene affords methyl dihydropyrrole 16a.
h 12 was obtained in 15% yield.
Me
N
R1
The photochemical cyclization of some conjugated oxi-
mes of aryl ketone, a-keto ester, and a,b-unsaturated ke-
tone was examined as shown in Table 4. Cyclic imines
16a,b were obtained from phenyl ketone and a-keto
ester O-acyloximes 13a,b and O-methyloximes 14a,b in
moderate yields (entries 1–4). The cyclization of a,b-
unsaturated ketone O-methyloxime 14c proceeded,
while the cyclization yield of O-acetyloxime of a,b-
unsaturated ketone 13c was low because the produced
cyclic imine 16c was not stable enough to the resulting
acetic acid (entries 5 and 6). The reaction of O-meth-
yloxime of styryl ketone 14d did not afford the cycliza-
tion product 16d, probably due to the excitation
energy of styryl ketone O-methyloxime 14d, which was
not sufficient enough to cleave N–O bond of O-meth-
yloxime 14d (entry 8). Actually, cyclic imine 16d was ob-
tained in 63% yield from O-acetyloxime of styryl ketone
13d, having a weaker N–O bond6i than the O-meth-
yloxime 14d, along with quinoline 18 produced via 6p
cyclization (entry 7).
12
Table 3. Cyclization of phenyl ketone oximes 13–15a
hν >300 nm
20 mol% DMN
Additive
Me
OR
N
O
N
+
Ph
Ph
CH3CN, rt
Ph
13-15b
16a
17
Entry
R
Additive (equiv)
Time/h
Yield/%
16a 17
1
Ac (13a) CHD (3), AcOH (10)
Ac (13a) CHD (10)
Ac (13a) CHD (10)
0.5
0.5
10
46
77
18
79
61
5
2
3c
9
6
4
Me (14a) CHD (10)
H (15)
3
13
0
Trace
5
CHD (10)
a DMN = 1,5-dimethoxynaphthalene; CHD = 1,4-cyclohexadiene.
b Only E isomers were used.
c The reaction was carried out in the absence of DMN. 13a was
recovered in 69% yield.
In conclusion, dihydropyrroles were synthesized from
O-acetyl and O-methyl c,d-unsaturated oximes by two
types of photochemical processes. Cyclization of alkyl
ketone oximes is induced by the photochemical electron
transfer from exited DMN, while conjugated ketone oxi-
mes are cyclized by the energy transfer from photoacti-
vated DMN.
ceed by the electron transfer process. It is known that
N–O bonds of aryl ketone O-acyloximes and aryl alde-
hyde O-alkyloximes are cleaved homolytically by photo-
excitation,6 and the absorption wavelength of the
conjugated oximes is longer and the excitation energy
is lower than those of saturated oximes generally.9
Therefore, methyl dihydropyrrole 16a is considered to
be formed by energy transfer from the excited 1,5-
dimethoxynaphthalene to phenyl ketone oxime 13–
15.10 When the homolytic cleavage of the N–O bond
occurs generating iminyl radical, the radical cyclization
Acknowledgments
This research was supported by a Grant-in-Aid for
The 21st Century COE Program for Frontiers in

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M. Kitamura et al. / Tetrahedron Letters 46 (2005) 2373–2376
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