Synthesis of Dihydropyrrole and Pyrrole Derivatives by Radical Cyclization of γ,δUnsaturated Ketone O-Acetyloximes

Article abstract of DOI:10.1246/bcsj.76.2003

Treatment of γδ-unsaturated ketone O-acetyloximes with a catalytic amount of 1,5-naphthalenediol or hydroquinone, acetic acid, and 1,4-cyclohexadiene affords various dihydropyrrole and pyrrole derivatives via radical cyclization induced by one-electron reduction of the oximes.

Full text of DOI:10.1246/bcsj.76.2003

Ó 2003 The Chemical Society of Japan
Bull. Chem. Soc. Jpn., 76, 2003–2008 (2003) 2003
Synthesis of Dihydropyrrole and Pyrrole Derivatives by Radical
Cyclization of ꢀ,ꢁ-Unsaturated Ketone O-Acetyloximes
ꢀ
Masayuki Yoshida, Mitsuru Kitamura, and Koichi Narasaka
Department of Chemistry, Graduate School of Science, The University of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033
Received April 10, 2003; E-mail: narasaka@chem.s.u-tokyo.ac.jp
Treatment of ꢀ,ꢁ-unsaturated ketone O-acetyloximes with a catalytic amount of 1,5-naphthalenediol or hydroqui-
none, acetic acid, and 1,4-cyclohexadiene affords various dihydropyrrole and pyrrole derivatives via radical cyclization
induced by one-electron reduction of the oximes.
Recently, we reported a new synthetic method of cyclic
imines from oxime derivatives by the intramolecular SN2-type
substitution on the sp2 nitrogen atom of oximes.1 For instance,
O-methylsulfonyloximes havingan active methine group are
converted to cyclic imines by treatment with 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU) (Eq. 1).1e,f Due to the stereospe-
cificity of SN2 reaction, only anti isomers2 of the oximes are
converted to cyclic imines. This stereospecificity, however,
causes a serious drawback in applyingthis reaction to organic
synthesis, because it is quite hard to prepare oxime derivatives
in a stereoselective manner.
ð2Þ
Based on these findings, intramolecular cyclization of ꢀ,ꢁ-
unsaturated ketone O-acetyloxime 2a was examined; we ex-
pected that 3,4-dihydro-2H-pyrroles 3a would be formed by
the nucleophilic substitution reaction of the acetoxy group of
2a with the intramolecular olefinic moiety via the cationic in-
termediate A, as depicted in Scheme 1.
ð1Þ
In fact, however, not only the nucleophilic cyclization prod-
uct, 2-acetoxymethyl-3,4-dihydro-2H-pyrrole 3a, but also un-
expected 2-methyl-3,4-dihydro-2H-pyrrole 4a was obtained
(Eq. 3).
It was expected that the both stereoisomers of oxime deriv-
atives could be employed for the cyclization if the syn–anti
isomerization occurs under the cyclization conditions. Oximes
themselves easily isomerize under acidic conditions,3a whereas
O-substituted oximes usually don’t isomerize under mild
conditions.3 We investigated the isomerization of O-acetylox-
imes and found that they could be isomerized by treatment
with acetic acid, but very slowly. For example, though (ꢁE)-
4-phenyl-2-butanone O-acetyloxime (1) isomerized at 80 C,
the isomerization had not attained equilibrium even after 2
h. It is noteworthy that the addition of a catalytic amount of
hydroquinone accelerated the isomerization and the syn:anti
ratio of 1:2.7 was attained at equilibrium, as shown in Eq. 2.
Scheme 1. Synthetic plan of 2H-pyrrol 3a from O-acetylox-
ime 2a.
Published on the web October 15, 2003; DOI 10.1246/bcsj.76.2003

2004 Bull. Chem. Soc. Jpn., 76, No. 10 (2003)
Dihydropyrroles and Pyrroles from Oximes
cyclization. In fact, the reaction in toluene-d8 without 1,4-cy-
clohexadiene gave the cyclic imine 4a in 17% yield containing
65% deuterium in the methyl group along with 26% yield of
3a (Eq. 4). In contrast, no cyclic imine containingdeuterium
was detected when a radical trappingreagent, 1,4-cyclohexa-
diene, was added.
ð3Þ
We have studied the formation of 4a, and found a new syn-
thetic method of 3,4-dihydro-2H-pyrroles, which was briefly
reported as a communication.4 This paper presents full ac-
counts of the syntheses of 3,4-dihydro-2H-pyrroles and pyrrole
derivatives from ꢀ,ꢁ-unsaturated ketone O-acetyloximes.
ð4Þ
Results and Discussion
A plausible mechanism of the formation of 4a by using1,5-
naphthalenediol is depicted in Scheme 2. One-electron trans-
fer occurs from 1,5-naphthalenediol to 2a, and the resulting
radical B cyclizes to generate alkyl radical C, which abstracts
hydrogen from 1,4-cyclohexadiene. The catalyst, 1,5-naphtha-
lenediol, is regenerated from hydroxynaphthalenoxyl radical
by hydrogen abstraction from 1,4-cyclohexadiene.
As shown in Table 2, various O-acetyloximes were cyclized
by the treatment with a 5 mol% amount of 1,5-naphtalenediol,
2 molar amounts of acetic acid, and 10 molar amounts of 1,4-
cyclohexadiene in refluxing1,4-dioxane. By the reaction of
O-acetyloxime 2 havingan electron-rich olefinic moiety, ace-
toxymethyl derivative 3 was yielded as a major product (En-
tries 2, 3). In contrast, only radical cyclization products 4d
and 4e were obtained from oximes 2d and 2e, which have
an electron-deficient olefinic moiety (Entries 4, 5). The reac-
tion of O-acetyloxime of phenyl ketone 2f gave radical cycli-
zation product 4f exclusively (Entry 6). As oxime 2f predom-
inantly exist in the syn forms.5 The nucleophilic attack of the
alkenyl group was suppressed to give only radical cyclization
products 4f. O-pivaloyl oxime of ꢂ-keto ester 2g6 gave only
radical cyclization product (Entry 7).
As we have explained in Eq. 2, addition of hydroquinone
was effective for the isomerization of O-acetyloxime with ace-
tic acid. We therefore examined the cyclization of 2a in the
presence or absence of hydroquinone derivatives; the results
are summarized in Table 1. By treating 2a with 2 molar
amounts of acetic acid in refluxing1,4-dioxane for 24 h, we
obtained nucleophilic substitution product 3a in 19% yield
with 20% yield of 2-methyl-3,4-dihydro-2H-pyrrole 4a (Entry
1). The addition of 1,4-cyclohexadiene as a radical trapping
reagent improved the yield of imine 4a to 29% (Entry 2).
The reaction was finished within 6 h. The total yield of 3a
and 4a was increased to 85–86% when a catalytic amount of
hydroquinone or 1,5-naphthalenediol was added (Entries 3,
4). By the addition of 1,5-dimethoxynaphthalene, however,
the yield of imine 4a was not improved.
2-Methylcyclic imine 4a could not be formed by the SN2-
type mechanism, but was supposed to be generated by radical
Table 1. Influence of Additive in the Cyclization of O-
Acetyloxime 2aa)
Next, this method was applied to the preparation of pyrroles
from the O-acetyloximes havingan alkynyl moiety. First, 1-
phenyl-6-heptyn-3-one O-acetyloxime (5a) was treated with
Yield/%
Entry
Additive
Time/h
3a
4a
1b)
2
3
4
none
none
24
24
6
6
24
19
12
32
34
16
20
29
53
52
26
hydroquinone
1,5-naphthalenediol
1,5-dimethoxynaphthalene
5
a) 2a:AcOH:1,4-cyclohexadiene = 1:2:10. b) 1,4-Cyclohexa-
diene was not used.
Scheme 2. Plausible mechanism for formation of 4a.

M. Yoshida et al.
Table 2. Cyclization of Various O-Acetyloximes 2a)
Bull. Chem. Soc. Jpn., 76, No. 10 (2003) 2005
Entry
R1
R2
R3
Time/h
Yield/%
34 (3a)
1
2
3
4
5
6
7g)
PhCH2CH2
PhCH2CH2
PhCH2CH2
PhCH2CH2
PhCH2CH2
Ph
H
H
H
Me
H
H
(2a)b)
(2b)b,c)
(2c)b)
(2d)b)
(2e)e)
(2f)f)
6
6
6
12
12
8
52 (4a)
16 (4b)
5 (4c)
Me
Me
CN
CO2Et
H
67 (3b)d)
72 (3c)
0 (3d)
0 (3e)
69 (4d)
72 (4e)
75 (4f)
67 (4g)
H
H
0 (3f)
0 (3g)
Ph(CH2)3O2C
H
(2g)h)
6
a) Cyclization was carried out under the followingconditions: 1,5-naphthalenediol (5 mol%), acetic
acid (2 molar amounts), 1,4-cyclohexadiene (10 molar amounts). b) syn:anti = 1:1. c) The stereo-
chemistry of olefin moiety was E:Z = 5:1. d) Diastereomer mixture (2:1). e) syn:anti = 1:2. f) Only
syn-isomer was used. g) O-Pivaloyloxime was used instead of O-acetyloxime. h) Single isomer was
used. The stereochemistry is unknown. See Ref. 7.
a catalytic amount of hydroquinone, acetic acid, and 1,4-cyclo-
verted to 2,5-disubstituted pyrroles in good yields (Entries 1
and 2). No significant influence was observed on the substitu-
ents of the alkyne moiety, except for the phenyl group. That
is, acetylenic oximes havingelectron-donatingor -withdraw-
hexdiene; 2-methyl-5-phenethylpyrrole (6a) was obtained in
67% yield as a radical cyclization product without forminga
SN2-type reaction product (Eq. 5).
ingrgoups
5c and 5d gave the corresponding pyrroles 6c
and 6d in 72% and 83% yields, respectively (Entries 3, 4).
The one-electron reduction of ꢀ,ꢁ-olefinic and acetylenic
ketone O-acetyloximes with a catalytic amount of hydroqui-
none or 1,5-naphtalenediol leads to the cyclization to 3,4-dihy-
dro-2H-pyrroles and pyrroles via a radical process. Several
methods have been reported for radical cyclization of oxime
derivatives.8,9 For example, tributyltin hydride method,9c,d ox-
idation reaction,9a,b photochemical reaction,9c,i,10 and Weinreb’s
method9g were used for radical cyclization of olefinic oxime de-
rivatives via N–O bond dissociation. Zard et al. reported the
radical cyclization of O-acetyloximes based on the reduction
with an excess amount of nickel powder.9f The present reaction
developed in this article would provide a catalytic method for
the reductive cyclization of O-acetyloximes.
ð5Þ
The preparation of pyrroles from various acetylenic O-ace-
tyloximes 5 was examined as shown in Table 3. Both alkyl
and aryl ketoxime havinga terminal alkynyl group were con-
Experimental
Table 3. Cyclization of Various O-Acetyloximes 5a)
General. 1H NMR (500 MHz) spectra were recorded on a
Bruker DRX 500 and a Bruker AVANCE 500 spectrometers in
CDCl3 usingTMS ( ꢁ ¼ 0:00) as internal standard. 13C NMR
(125 MHz) spectra were recorded on Bruker DRX 500 and Bruker
AVANCE 500 spectrometers in CDCl3 usingCHCl 3 (ꢁ ¼ 77:0) as
internal standard. IR spectra were recorded on a Horiba FT 300-S
and Perkin Elmer SPECTRUM 1000 spectrophotometer on KBr
(neat). High-resolution mass spectra were obtained with a JEOL
JMS-700P mass spectrometer. The meltingpoints were un-
corrected. Elemental analyses were carried out at The Elemental
Analysis Laboratory, Department of Chemistry, Faculty of Sci-
ence, The University of Tokyo. Flash column chromatography
was performed on silica gel (Merck Silica gel 60, and Kanto
Chemical Co., Inc. Silica gel 60N (spherical, neutral)), and prepar-
ative thin-layer chromatography was carried out using Wakogel
B-5F. Dehydrated 1,4-dioxane was purchased from Kanto Chem-
ical Co., Inc. and was used as freshly distilled from LiAlH4 under
an argon atmosphere. Hydroquinone and 1,5-naphthalenediol
Entry
R1
R2
Time/h Yield/%
b)
1
2
3
4
5
PhCH2CH2
Phc)
H
H
Me
(5a)
(5b)
(5c)
24
24
24
28
6
67 (6a)
67 (6b)
72 (6c)
83 (6d)
32 (6e)
Phc)
Phc)
Med)
CO2Et (5d)
Ph (5e)
a) Cyclization was carried out under the followingconditions:
hydroquinone (5 mol%), acetic acid (2 molar amounts), 1,4-
cyclohexadiene (10 molar amounts). b) syn:anti = 1:1. c)
Only syn-isomer was used. d) Only anti-isomer was used.

2006 Bull. Chem. Soc. Jpn., 76, No. 10 (2003)
Dihydropyrroles and Pyrroles from Oximes
1367, 1203, 1000, 929, 748, 700 cmÀ1 1H NMR ꢁ 2.15 (1.5H,
s), 2.18 (1.5H, s), 2.31–2.34 (1H, m), 2.37–2.43 (1H, m), 2.46–
2.53 (2H, m), 2.63–2.73 (2H, m), 2.83–2.95 (2H, m), 5.29–5.36
(1H, m), 6.60–6.67 (1H, m), 7.16–7.36 (5H, m); 13C NMR ꢁ
19.5, 27.8, 28.9, 29.2, 31.5, 31.86, 31.90, 32.2, 32.7, 36.0, 31.7,
126.4, 126.6, 128.1, 128.2, 128.5, 128.6, 139.8, 140.1, 152.8,
153.5, 166.0, 146.0, 146.5, 166.0, 166.2, 168.3, 168.5. Found:
C, 70.97; H, 6.83; N, 10.26%. Calcd for C16H18N2O2: C, 71.09;
H, 6.71; N, 10.36%.
were recrystallized from benzene and dried under reduced
pressure. 1,4-Cyclohexadiene was purchased from Tokyo Chem-
ical Industry Co., Ltd. and used without purification. Configura-
tions of O-acetyloximes (syn or anti) were determined by the
13C NMR of the O-acetyloximes or the correspondingoximes
(N-hydroxy).11
;
Preparation of ꢀ,ꢁ-Unsaturated Ketone O-Acetyloximes.
Experimental procedures for the preparation of ꢀ,ꢁ-unsaturated
ketone O-acetyloximes are shown below as a typical example
for the synthesis of 1-phenyl-6-hepten-3-one O-acetyloxime (2a).
To a solution of 1-phenyl-6-hepten-3-one oxime (760 mg, 3.74
mmol) and triethylamine (1.02 mL, 7.48 mmol) in dichlorometh-
ane (15 mL) was slowly added a solution of acetic anhydride (572
mg, 5.61 mmol) in dichloromethane (5 mL), and this mixture was
stirred at room temperature for 12 h. After the reaction was
quenched with sat. NaHCO3, the mixture was extracted twice
with dichloromethane. The combined extracts were washed with
sat. NaHCO3, and the dichloromethane solution was dried over
anhydrous sodium sulfate. Dichloromethane was removed in va-
cuo, and the crude materials were purified by flash column chro-
matography (silica gel, hexane:ethyl acetate = 10:1) to give 1-
phenyl-6-hepten-3-one O-acetyloxime (2a) (780 mg, 3.22 mmol,
93%).
Spectral Data for ꢀ,ꢁ-Unsaturated Ketone O-Acetyloximes.
1-Phenyl-6-hepten-3-one O-Acetyloxime (2a): E:Z = 1:1 mix-
ture; Colorless oil; IR (KBr) 3028, 1768, 1639, 1454, 1365, 1207,
999, 920, 748, 700 cmÀ1; 1H NMR ꢁ 2.13 (3H, s), 2.24–2.39 (3H,
m), 2.49–2.52 (1H, m), 2.63–2.70 (2H, m), 2.82–2.85 (1H, m),
2.89–2.92 (1H, m), 4.99–5.08 (2H, m), 5.74–5.84 (1H, m),
7.18–7.32 (5H, m); 13C NMR ꢁ 19.5, 19.6, 29.0, 29.8, 30.1,
31.4, 31.9, 32.3, 33.7, 36.0, 115.6, 115.8, 126.2, 126.4, 128.1,
128.2, 128.4, 128.5, 136.4, 136.6, 140.2, 140.6, 167.9, 168.0,
168.6, 168.7. Found: C, 73.46; H, 7.70; N, 5.77%. Calcd for
C15H19NO2: C, 73.44; H, 7.81; N, 5.71%.
Ethyl 6-Acetyloxyimino-8-phenyl-2-octenoate (2e): E:Z =
1:1 mixture; Colorless oil; IR (KBr) 2981, 1766, 1718, 1657,
;
1454, 1367, 1268, 998, 927, 748, 700 cmÀ1 1H NMR ꢁ 1.27–
1.30 (3H, m), 2.13 (3H, s), 2.37–2.43 (2H, m), 2.44–2.50 (1H,
m), 2.53–2.55 (1H, m), 2.63–2.70 (2H, m), 2.83–2.86 (1H, m),
2.90–2.93 (1H, m), 4.16–4.21 (2H, m), 5.81–5.85 (1H, m),
6.88–6.93 (1H, m), 7.17–7.32 (5H, m); 13C NMR ꢁ 14.1, 19.6,
28.2, 31.7, 32.0, 32.3, 33.0, 36.0, 60.2, 60.3, 122.3, 122.5,
126.3, 126.5, 128.1, 128.2, 128.5, 128.6, 140.0, 140.3, 146.0,
146.5, 166.0, 166.2, 167.0, 167.0, 168.5, 168.5. Found: C,
67.87; H, 7.24; N, 4.47%. Calcd for C18H23NO2: C, 68.12; H,
7.30; N, 4.41%.
1-Phenyl-4-penten-1-one (E)-O-Acetyloxime (2f): Colorless
oil; IR (KBr) 2935, 1770, 1641, 1444, 1365, 1201, 998, 931, 771,
694 cmÀ1; 1H NMR ꢁ 2.27 (3H, s), 2.30–2.34 (2H, m), 2.95 (2H, t,
J ¼ 7:9 Hz), 5.01–5.07 (2H, m), 5.78–5.86 (1H, m), 7.39–7.47
(3H, m), 7.69–7.71 (2H, m); 13C NMR ꢁ 20.0, 27.7, 30.6, 115.8,
127.3, 128.6, 130.5, 134.0, 136.5, 165.6, 169.0. Found: C,
71.88; H, 6.91; N, 6.45%. Calcd for C13H15NO2: C, 71.87; H,
6.96; N, 6.45%.
3-Phenylpropyl (E)-Pivaloyloxyimino-5-hexenoate (2g):
Colorless oil; IR (KBr) 2975, 1772, 1726, 1641, 1479, 1454,
1207, 1155, 1095, 1024, 920, 752, 700 cmÀ1 1H NMR ꢁ 1.32
;
(9H, s), 2.04–2.11 (2H, m), 2.31–2.35 (2H, m), 2.71–2.74 (2H,
m), 2.76–2.79 (2H, m), 4.29–4.31 (2H, m), 4.98–5.09 (2H, m),
5.75–5.85 (1H, m), 7.18–7.20 (3H, m), 7.26–7.30 (2H, m);
13C NMR ꢁ 26.8, 27.1, 29.8, 30.3, 31.9, 38.7, 65.8, 116.3,
126.1, 128.36, 128.44, 136.0, 140.8, 159.4, 163.0, 173.9. Found:
C, 69.42; H, 7.89; N, 3.86%. Calcd for C20H27NO4: C, 69.54; H,
7.88; N, 4.05%.
1-Phenyl-6-octen-3-one O-Acetyloxime (2b): Diastereomer
mixture (6E)-(E)-oxime:(6E)-(Z)-oxime:(6Z)-(E)-oxime:(6Z)-
(Z)-oxime = 5:5:1:1; Colorless oil; IR (ZnSe) 3029, 2933,
1760, 1633, 1496, 1454, 1365, 1199, 1041, 1029, 998, 966, 925,
1
873, 748, 700 cmÀ1; H NMR ꢁ 1.58–1.66 (m, 3H), 2.13 (s) and
2.14 (s) and 2.16 (s) and 2.17 (s) (3H), 2.17–2.30 (m, 2H),
2.30–2.35 (m, 1H), 2.43–2.48 (m, 1H), 2.61–2.72 (m, 2H),
2.80–2.86 (m, 1H), 2.87–2.94 (m, 1H), 5.30–5.57 (m, 2H),
7.17–7.23 (m, 3H), 7.26–7.32 (m, 2H); 13C NMR (major two dia-
stereomers) ꢁ 17.80, 17.84, 19.63, 19.69, 28.8, 29.2, 29.7, 31.4,
32.0, 32.4, 34.4, 36.1, 126.2, 126.3, 126.4, 126.6, 128.15,
128.26, 128.48, 128.56, 129.0, 129.2, 140.3, 140.6, 168.3, 168.4,
168.7, 168.9. HRMS (FAB) Found m=z 260.1623. Calcd for
C16H22NO2, (M + H)þ 260.1651.
1-Phenyl-6-heptyn-3-one O-Acetyloxime (5a): E:Z = 1:1
mixture; Colorless oil; IR (ZnSe) 3290, 2933, 1763, 1637, 1603,
1496, 1198, 999, 931, 885, 752, 698 cmÀ1 1H NMR ꢁ 1.98–
;
2.02 (1H, m), 2.16 (3H, s), 2.43–2.49 (2H, m), 2.60–2.64 (2H,
m), 2.69–2.74 (2H, m), 2.82–2.94 (2H, m), 7.17–7.23 (3H, m),
7.25–7.31 (2H, m); 13C NMR ꢁ 15.2, 15.5, 19.57, 19.64, 28.5,
31.6, 31.9, 32.2, 32.4, 33.3, 36.3, 37.5, 69.4, 69.8, 82.0, 82.5,
126.2, 126.5, 128.1, 128.5, 128.6, 140.0, 140.4, 166.65, 166.71,
168.6. Found: C, 74.02; H, 7.28; N, 5.70%. Calcd for
C15H17NO2: C, 74.05; H, 7.04; N, 5.76%.
7-Methyl-1-phenyl-6-octen-3-one O-Acetyloxime (2c): E:Z
= 1:1 mixture; Colorless oil; IR (KBr) 2929, 1768, 1635, 1454,
;
1365, 1203, 998, 927, 750, 700 cmÀ1 1H NMR ꢁ 1.60 (1.5H,
1-Phenyl-4-pentyn-1-one (E)-O-Acetyloxime (5b): White
needles, mp 73–74 ꢁC; IR (ZnSe) 2958, 1770, 1699, 1392,
1
s), 1.61 (1.5H, s), 1.68 (1.5H, s), 1.69 (1.5H, s), 2.14 (1.5H, s),
2.19 (1.5H, s), 2.19–2.31 (3H, m), 2.40–2.43 (1H, m), 2.62–2.70
(2H, m), 2.82–2.85 (1H, m), 2.89–2.92 (1H, m), 5.07–5.11 (1H,
m), 7.18–7.24 (3H, m), 7.28–7.32 (2H, m); 13C NMR ꢁ 17.6,
17.7, 19.7, 24.5, 24.9, 25.6, 29.8, 31.4, 32.1, 32.5, 34.5, 36.2,
122.3, 122.5, 126.3, 126.5, 128.2, 128.3, 128.5, 128.6, 133.0,
133.5, 140.4, 140.7, 168.4, 168.4, 168.6, 168.7. Found: C,
74.75; H, 8.46; N, 5.16%. Calcd for C17H23NO2: C, 74.69; H,
8.48; N, 5.12%.
1329, 928, 760, 729 cmÀ1; H NMR ꢁ 1.98 (1H, t, J ¼ 2:7 Hz),
2.26 (3H, s), 2.45 (2H, dt, J ¼ 2:7, 7.7 Hz), 3.08 (2H, t, J ¼ 7:7
Hz), 7.38–7.44 (3H, m), 7.70–7.72 (2H, m); 13C NMR ꢁ 15.9,
19.8, 27.2, 69.7, 81.9, 127.3, 128.9, 130.6, 133.4, 164.0, 168.7.
Found: C, 72.67; H, 6.29; N, 6.35%. Calcd for C13H13NO2: C,
72.54; H, 6.09; N, 6.51%.
1-Phenyl-4-hexyn-1-one (E)-O-Acetyloxime (5c): Colorless
oil; IR (ZnSe) 2917, 1766, 1703, 1444, 1190, 995, 931, 893, 768,
692 cmÀ1; 1H NMR ꢁ 1.72 (3H, t, J ¼ 2:5 Hz), 2.28 (3H, s), 2.40–
2.44 (2H, m), 3.05 (2H, t, J ¼ 7:7 Hz), 7.39–7.45 (3H, m), 7.73–
7.74 (2H, m); 13C NMR ꢁ 3.32, 16.4, 19.8, 28.0, 76.96, 76.99,
6-Acetyloxyimino-8-phenyl-2-octenenitrile (2d): E:Z = 1:1
mixture; Colorless oil; IR (KBr) 2933, 1768, 1760, 1633, 1454,

M. Yoshida et al.
Bull. Chem. Soc. Jpn., 76, No. 10 (2003) 2007
ꢀ
32.7, 35.3, 37.5, 37.8, 72.8, 72.9, 75.3, 76.0, 126.02,
ꢀ
ꢀ
127.4, 128.6, 130.6, 133.8, 164.7, 168.8. Found: C, 73.23; H,
6.77; N, 5.91%. Calcd for C14H15NO2: C, 73.34; H, 6.59; N,
6.11%.
Ethyl (E)-6-Acetyloxyimino-6-phenyl-2-hexynoate (5d):
Colorless oil; IR (ZnSe) 2924, 2237, 1768, 1703, 1250, 1186,
1074, 1186, 1074, 769, 692 cmÀ1 1H NMR ꢁ 1.29 (3H, t,
;
J ¼ 7:0 Hz), 2.29 (3H, s), 2.62 (2H, t, J ¼ 7:4 Hz), 3.16 (2H, t,
J ¼ 7:4 Hz), 4.21 (2H, q, J ¼ 7:0 Hz), 7.43–7.46 (3H, m),
7.71–7.73 (2H, m); 13C NMR ꢁ 14.0, 16.2, 19.8, 26.2, 61.9,
74.1, 86.1, 127.2, 128.8, 130.9, 133.0, 153.3, 163.2, 168.5. Found:
C, 66.95; H, 6.14; N, 4.77%. Calcd for C16H17NO4: C, 66.89; H,
5.96; N, 4.88%.
major isomer) ꢁ 16.5, 16.8, 21.33, 21.37, 24.2, 24.6, 32.6,
ꢀ
ꢀ
ꢀ
ꢀ
126.06, 128.25, 128.28, 128.39, 128.41, 141.19, 141.27,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
170.6, 170.7, 178.7, 178.9. HRMS (FAB) Found m=z
260.1643. Calcd for C16H22NO2, (M + H)þ 260.1651.
2-Ethyl-5-phenethyl-3,4-dihydro-2H-pyrrole (4b): Color-
less oil; IR (ZnSe) 3025, 2958, 2921, 1644, 1602, 1496, 1454,
1428, 1376, 1315, 1270, 1078, 937, 750, 700 cmÀ1 1H NMR ꢁ
;
0.94 (3H, t, J ¼ 7:4 Hz), 1.37–1.46 (2H, m), 1.71–1.80 (m, 1H),
1.98–2.05 (1H, m), 2.37–2.51 (2H, m), 2.64 (2H, t, J ¼ 6:3 Hz),
2.87–2.97 (2H, m), 3.86–3.92 (1H, m), 7.17–7.23 (3H, m),
7.26–7.31 (2H, m); 13C NMR ꢁ 10.8, 18.0, 29.2, 32.8, 35.4,
37.4, 73.9, 126.0, 128.3, 128.4, 141.5, 176.38. HRMS (FAB)
Found m=z 202.1593. Calcd for C14H20N, (M + H)þ 202.1596.
2-(1-Acetoxy-1-methylethyl)-5-phenethyl-3,4-dihydro-2H-
pyrrole (3c): Colorless oil; IR (neat) 2978, 2935, 1730, 1367,
6-Phenyl-5-hexyn-2-one (E)-O-Acetyloxime (5e): Colorless
oil; IR (ZnSe) 2910, 1763, 1693, 1643, 1365, 1196, 999, 930, 756,
1
692 cmÀ1; H NMR ꢁ 2.07 (3H, s), 2.18 (3H, s), 2.65 (2H, t, J ¼
7:1 Hz), 2.71 (2H, t, J ¼ 7:1 Hz), 7.27–7.38 (5H, m); 13C NMR ꢁ
15.6, 16.8, 19.6, 34.8, 81.8, 87.8, 123.4, 127.8, 128.1, 131.5,
164.6, 168.8. Found: C, 73.17; H, 6.84; N, 6.10%. Calcd for
C14H15NO2: C, 73.34; H, 6.59; N, 6.11%.
1254, 700 cmÀ1 1H NMR ꢁ 1.35 (3H, s), 1.56 (3H, s), 1.66–
;
1.71 (1H, m), 1.86–1.94 (1H, m), 1.95 (3H, s), 2.37–2.53 (2H,
m), 2.63–2.73 (2H, m), 2.87–2.97 (2H, m), 4.27–4.34 (1H, m),
7.15–7.28 (5H, m); 13C NMR ꢁ 21.9, 22.4, 23.6, 32.7, 35.2,
37.7, 79.8, 83.8, 125.9, 128.2, 128.3, 141.2, 141.2, 170.4, 178.2.
HRMS (FAB) Found m=z 274.1804. Calcd for C17H24NO2, (M
+ H)þ 274.1807.
General Procedure for the Synthesis of 3,4-Dihydro-2H-
pyrroles and Pyrroles. Into a flask containing O-acetyloxime
(2a) (254.3 mg, 1.04 mmol) in 1,4-dioxane (4 mL) was added hy-
droquinone (289 mg, 0.250 mmol), acetic acid (131 mg, 2.08
mmol) and 1,4-cyclohexadiene (0.984 mL, 10.4 mmol) at room
temperature under an argon atmosphere. The mixture was imme-
diately heated to reflux. After 6 h, the reaction was quenched with
sat. Na2CO3. The mixture was extracted three times with ethyl
acetate and the combined extracts were dried over anhydrous so-
dium sulfate. The solvent was removed in vacuo, and the crude
product was purified by thin-layer chromatography (hexane:ethyl
acetate = 1:1) to afford 2-acetoxymethyl-5-phenethyl-3,4-dihy-
dro-2H-pyrrole (3a) (100 mg, 0.541 mmol) in 52% yield and 2-
methyl-5-phenethyl-3,4-dihydro-2H-pyrrole (4a) (86.9 mg, 0.355
mmol) in 34% yield, respectively.
2-Isopropyl-5-phenethyl-3,4-dihydro-2H-pyrrole
Colorless oil; IR (neat) 1643, 1495, 1454, 750, 700 cmÀ1
(4c):9h
;
1H NMR ꢁ 0.85 (3H, d, J ¼ 6:8 Hz), 1.00 (3H, d, J ¼ 6:8 Hz),
1.50–1.58 (1H, m), 1.85–1.95 (2H, m), 2.38–2.50 (2H, m), 2.69
(2H, t, J ¼ 8:0 Hz), 2.94 (2H, t, J ¼ 8:0 Hz), 3.80–3.86 (1H,
m), 7.18–7.25 (3H, m), 7.28–7.33 (2H, m); 13C NMR ꢁ 18.0,
19.8, 24.8, 32.9, 35.3, 37.6, 78.3, 126.0, 128.3, 128.4, 141.4,
176.7.
2-Cyanomethyl-5-phenethyl-3,4-dihydro-2H-pyrrole (4d):9h
Colorless oil; IR (neat) 2925, 2247, 1646, 1495, 1454, 1423,
1311, 1290, 754, 701 cmÀ1 1H NMR ꢁ 1.67–1.75 (1H, m),
;
Spectral Data for 3,4-Dihydro-2H-pyrroles.
methyl-3,4-dihydro-5-phenethyl-2H-pyrrole (3a):
2-Acetoxy-
Colorless
2.18–2.26 (1H, m), 2.52–2.60 (1H, m), 2.62–2.77 (5H, m),
2.92–3.02 (2H, m), 4.25–4.31 (1H, m), 7.18–7.24 (3H, m),
7.28–7.33 (2H, m); 13C NMR ꢁ 24.4, 27.7, 32.5, 35.1, 38.2,
67.9, 117.8, 126.1, 128.2, 128.5, 140.9, 179.8.
2-(Ethoxycarbonyl)methyl-5-phenethyl-3,4-dihydro-2H-
pyrrole (4e):9h Colorless oil; IR (neat) 2935, 1734, 1643, 1495,
1373, 1315, 1261, 1180, 1028, 752, 702 cmÀ1 1H NMR ꢁ 1.26
;
oil; IR (neat) 2948, 1737, 1641, 1234, 1039, 752, 700 cmÀ1
;
1H NMR ꢁ 1.58 (1H, dddd, J ¼ 6:6, 7.4, 10.0, 13.1 Hz), 2.03
(1H, dddd, J ¼ 5:1, 8.0, 9.6, 13.1 Hz), 2.06 (3H, s), 2.45 (1H,
m), 2.54 (1H, dddd, J ¼ 2:0, 5.1, 10.0, 17.4 Hz), 2.68 (2H, t, J ¼
8:2 Hz), 2.93 (2H, t, J ¼ 8:2 Hz), 4.11 (1H, dd, J ¼ 5:9, 11.0 Hz),
4.19 (1H, dd, J ¼ 4:9, 11.0 Hz), 4.22–4.28 (1H, m), 7.16–7.20
(3H, m), 7.24–7.28 (2H, m); 13C NMR ꢁ 20.9, 25.4, 32.7, 35.3,
37.6, 67.2, 70.9, 126.0, 128.2, 128.4, 141.2, 171.0, 179.0. Found:
C, 73.19; H, 7.89; N, 5.67%. Calcd for C15H19NO2: C, 73.44; H,
7.81; N, 5.71%.
(3H, t, J ¼ 7:2 Hz), 1.48–1.57 (1H, m), 2.10–2.20 (1H, m), 2.33
(1H, dd, J ¼ 8:7, 15.4 Hz), 2.44–2.60 (2H, m), 2.64 (2H, t,
J ¼ 8:0 Hz), 2.80 (1H, dd, J ¼ 5:6, 15.4 Hz), 2.92 (2H, t,
J ¼ 8:0 Hz), 4.16 (2H, q, J ¼ 7:2 Hz), 4.35–4.41 (1H, m),
7.19–7.24 (3H, m), 7.28–7.32 (2H, m); 13C NMR ꢁ 14.2, 28.5,
32.6, 35.3, 37.7, 41.0, 60.3, 68.8, 126.0, 128.2, 128.4, 141.2,
171.9, 177.8.
2-Methyl-5-phenethyl-3,4-dihydro-2H-pyrrole (4a):9h Col-
orless oil; IR (neat) 2960, 1643, 1603, 1496, 1454, 1288, 750,
700 cmÀ1; H NMR ꢁ 1.24 (3H, d, J ¼ 6:8 Hz), 1.30–1.39 (1H,
2-Methyl-5-phenyl-3,4-dihydro-2H-pyrrole (4f):9d
less oil; IR (neat) 3058, 2962, 2866, 1614, 1576, 1495, 1448,
1340, 1018, 906 cmÀ1
Color-
1
m), 2.02–2.09 (1H, m), 2.41 (1H, ddd, J ¼ 8:7, 8.7, 17.2 Hz),
2.47–2.54 (1H, m), 2.61 (2H, t, J ¼ 7:8 Hz), 2.91 (2H, dt,
J ¼ 4:5, 7.8 Hz), 4.01–4.07 (1H, m), 7.15–7.20 (3H, m), 7.24–
7.28 (2H, m); 13C NMR ꢁ 22.0, 30.6, 32.7, 35.3, 37.7, 67.7,
125.9, 128.2, 128.3, 141.4, 176.1.
;
1H NMR ꢁ 1.36 (3H, d, J ¼ 6:8 Hz),
1.56 (1H, dddd, J ¼ 7:3, 7.5, 9.9, 12.6 Hz), 2.25 (1H, dddd,
J ¼ 4:8, 7.3, 9.7, 12.6 Hz), 2.88 (1H, dddd, J ¼ 2:0, 7.5, 9.7,
17.0 Hz), 3.06 (1H, dddd, J ¼ 2:0, 4.8, 9.9, 17.0 Hz), 4.25–4.33
(1H, m), 7.37–7.42 (3H, m), 7.83–7.86 (2H, m); 13C NMR ꢁ
22.1, 30.7, 35.2, 68.4, 127.6, 128.4, 130.2, 134.7, 171.8.
2-(1-Acetoxyethyl)-5-phenethyl-3,4-dihydro-2H-pyrrole
(3b): Diastereomer mixture (2:1); Pale yellow oil; IR (ZnSe)
2933, 1731, 1644, 1496, 1456, 1428, 1371, 1240, 1141, 1060,
2-Methyl-5-(3-phenylpropyloxycarbonyl)-3,4-dihydro-2H-
pyrrole (4g): Colorless oil; IR (neat) 1743, 1720, 1454, 1251,
1
1031, 937, 750, 700 cmÀ1; H NMR ꢁ 1.23 (d, J ¼ 6:4 Hz) and
1.24 (d, J ¼ 6:4 Hz) (3H), 1.45–1.70 (m, 1H), 1.91–2.00 (m,
1H), 2.01 (s) and 2.04 (s) (3H), 2.39–2.54 (m, 2H), 2.62–2.73
(m, 2H), 2.87–2.98 (m, 2H), 4.07–4.16 (m, 1H), 4.97–5.06 (m,
1H), 7.18–7.24 (m, 3H), 7.26–7.30 (m, 2H); 13C NMR (ꢀ means
1126, 1030, 750, 700 cmÀ1
;
1H NMR ꢁ 1.37 (3H, d, J ¼ 6:9
Hz), 1.45–1.56 (1H, m), 2.05–2.12 (2H, m), 2.16–2.24 (1H, m),
2.70–2.79 (3H, m), 2.87–2.95 (1H, m), 4.25–4.37 (3H, m),
7.17–7.22 (3H, m), 7.25–7.31 (2H, m); 13C NMR ꢁ 21.4, 29.9,

2008 Bull. Chem. Soc. Jpn., 76, No. 10 (2003)
Dihydropyrroles and Pyrroles from Oximes
30.0, 32.1, 35.6, 65.2, 69.8, 126.0, 128.33, 128.42, 140.9, 163.0,
166.8. Found: C, 73.52; H, 7.87; N, 5.49%. Calcd for
C15H19NO2: C, 73.44; H, 7.81; N, 5.71%.
Uchiyama, M. Yoshida, Y. Hayashi, and K. Narasaka, Chem.
Lett., 1998, 607. f) M. Yoshida, K. Uchiyama, and K. Narasaka,
Heterocycles, 52, 681 (2000).
Spectral Data for Pyrroles. 2-Methyl-5-phenethylpyrrole
(6a):12 Yellow oil; IR (ZnSe) 3367, 2924, 1601, 1593, 1512,
2
In this manuscript, syn isomers mean the oximes having
leaving group on oxime nitrogen and nucleophile or olefin on
the same side of the oxime carbon–nitrogen double bond and anti
isomers mean the opposite.
1452, 1038, 748, 698 cmÀ1 1H NMR ꢁ 2.21 (3H, s), 2.87–2.92
;
(4H, m), 5.77–5.81 (2H, m), 7.20–7.22 (3H, m), 7.29–7.32 (2H,
m), 7.48 (1H, brs); 13C NMR ꢁ 12.9, 29.7, 36.2, 105.1, 105.5,
123.3, 126.0, 126.1, 128.3, 128.3, 130.5, 141.7.
3
a) C. R. Hauser and D. S. Hoffenberg, J. Org. Chem., 20,
1491 (1955). b) C. G. McCarty, ‘‘The Chemistry of the Carbon–
Nitrogen Double Bond,’’ in ‘‘The Chemistry of Functional
Groups,’’ ed by S. Patai, Interscience, New York (1970).
4
2002, 144.
2-Methyl-5-phenylpyrrole (6b):12
Yellow oil; IR (ZnSe)
3398, 2916, 1603, 1510, 1213, 904, 746, 727, 687 cmÀ1; 1H NMR
ꢁ 2.32 (3H, s), 5.95 (1H, br s), 6.39 (1H, br s), 7.15 (1H, t, J ¼ 7:3
Hz), 7.32 (2H, m), 7.42 (2H, m), 8.09 (1H, brs); 13C NMR ꢁ 13.2,
106.1, 107.9, 123.3, 125.6, 128.8, 129.0, 130.7, 132.9.
M. Yoshida, M. Kitamura, and K. Narasaka, Chem. Lett.,
5
Marini, J. Chem. Soc., Perkin Trans. 1, 1993, 1989.
M. Tiecco, L. Testaferri, M. Tingoli, L. Bagnoli, and F.
2-Ethyl-5-phenylpyrrole (6c):12 Yellow oil; IR (ZnSe) 3390,
2966, 1604, 1514, 1333, 1205, 1039, 912, 750, 690 cmÀ1
;
6
Because 3-phenylpropyl acetyloxyimino-5-hexenoate was
1H NMR ꢁ 1.29 (3H, t, J ¼ 7:6 Hz), 2.68 (2H, q, J ¼ 7:6 Hz),
5.98 (1H, br s), 6.42 (1H, br s), 7.16 (1H, t, J ¼ 7:3 Hz), 7.33
(2H, dt, J ¼ 7:5, 7.3 Hz), 7.43 (2H, t, J ¼ 7:5 Hz), 8.13 (1H,
brs); 13C NMR ꢁ 13.6, 21.0, 106.0, 106.2, 123.4, 125.4, 128.8,
130.6, 133.0, 135.6.
easily hydrolyzed, O-pivaloyloxime 2g was used instead of the
O-acetyloxime.
7 About the stereochemsistry of oximes of ꢂ-ketoester, see;
a) H. Reinheckel, A. Jovtscheff, and S. Spassov, Monatsh. Chem.,
96, 1185 (1965). b) L. Ernest, J. Phys. Chem., 65, 491 (1961).
8
Ethyl (5-phenyl-2-pyrrolyl)acetate (6d):12 Yellow oil; IR
(ZnSe) 3371, 2981, 1716, 1616, 1512, 1221, 1151, 1026, 750,
For a recent review of alkylideneaminyl radicals: a) S. Z.
Zard, Synlett, 1996, 1148. b) A. G. Fallis and I. M. Brinza, Tetra-
hedron, 53, 17543 (1997).
690 cmÀ1
;
1H NMR ꢁ 1.27 (3H, t, J ¼ 7:1 Hz), 3.68 (2H, s),
4.17 (2H, q, J ¼ 7:1 Hz), 6.06 (1H, br s), 6.40 (1H, br s), 7.16
(1H, t, J ¼ 7:3 Hz), 7.32 (2H, dd, J ¼ 7:3, 7.6 Hz), 7.44 (2H, d,
J ¼ 7:6 Hz), 9.06 (1H, brs); 13C NMR ꢁ 14.1, 33.3, 61.2, 105.8,
109.1, 123.6, 124.5, 125.9, 128.7, 132.1, 132.7, 171.2.
9
a) A. R. Forrester, M. Gill, J. S. Sadd, and R. H. Thomson,
J. Chem. Soc., Perkin Trans. 1, 1979, 612. b) S. Atmaram, A. R.
Forrester, M. Gill, and R. H. Thomson, J. Chem. Soc., Perkin
Trans. 1, 1981, 1721. c) J. Boivin, E. Fouquet, A.-M. Schiano,
and S. Z. Zard, Tetrahedron, 50, 1769 (1994). d) J. Boivin,
A.-C. Callier-Dublanchet, B. Quiclet-Sire, A.-M. Schiano, and
S. Z. Zard, Tetrahedron, 51, 6517 (1995). e) K. Uchiyama, Y.
Hayashi, and K. Narasaka, Chem. Lett., 1998, 1261. f) J. Boivin,
A.-M. Schiano, S. Z. Zard, and H. Zhang, Tetrahedron Lett., 40,
4531 (1999). g) X. Lin, D. Stien, and S. M. Weinreb, Org. Lett.,
1, 637 (1999). h) K. Uchiyama, Y. Hayashi, and K. Narasaka, Tet-
rahedron, 55, 8915 (1999). i) T. Mikami and K. Narasaka, Chem.
Lett., 2000, 338. j) Y. Koganemaru, M. Kitamura, and K.
Narasaka, Chem. Lett., 2002, 784.
2-Benzyl-5-methylpyrrole (6e):13
Yellow oil; IR (ZnSe)
3228, 2922, 1766, 1603, 1496, 1454, 1369, 1203, 1038, 914,
746, 698 cmÀ1; H NMR ꢁ 2.19 (3H, s), 3.91 (2H, s), 5.78 (1H,
1
m), 5.84 (1H, m), 7.21–7.24 (3H, m), 7.29–7.32 (2H, m), 7.47
(1H, brs); 13C NMR ꢁ 13.0, 34.2, 105.7, 106.5, 126.3, 127.0,
128.5, 128.6, 129.2, 139.8.
This research was supported by a Grant-in-Aid for Scientific
Research on Priority Areas (A) ‘‘Exploitation of Multi-Ele-
ment Cyclic Molecules’’ from the Ministry of Education, Cul-
ture, Sports, Science and Technology.
10 A. J. McCarroll and J. C. Walton, J. Chem. Soc., Perkin
Trans. 2, 2000, 1868.
11 G. E. Hawkes, K. Herwig, and J. D. Roberts, J. Org.
Chem., 39, 1017 (1974); R. M. Silverstein and F. X. Webster,
‘‘Spectrometric Identification of Organic Compounds,’’ John Wi-
ley & Sons, New York (1998).
12 H. Tsutsui, M. Kitamura, and K. Narasaka, Bull. Chem.
Soc. Jpn., 75, 1451 (2002).
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