Radical cyclizations in 1,4-dimethylpiperazine

Article abstract of DOI:10.1016/j.tetlet.2006.05.146

N-Allylic or N-vinylic α,α,α-trichloroacetamides, upon heating in 1,4-dimethylpiperazine, undergo radical cyclization to give the corresponding γ-lactams.

Full text of DOI:10.1016/j.tetlet.2006.05.146

Tetrahedron Letters 47 (2006) 6263–6266
Radical cyclizations in 1,4-dimethylpiperazine
Hiroyuki Ishibashi,a,* Shigeki Haruki,a Masahiko Uchiyama,a
Osamu Tamurab and Jun-ichi Matsuoa
aDivision of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University,
Kakuma-machi, Kanazawa 920-1192, Japan
bShowa Pharmaceutical University, 3-3165 Higashi-tamagawagakuen, Machida, Tokyo 194-8543, Japan
Received 10 May 2006; revised 23 May 2006; accepted 24 May 2006
Available online 18 July 2006
Abstract—N-Allylic or N-vinylic a,a,a-trichloroacetamides, upon heating in 1,4-dimethylpiperazine, undergo radical cyclization to
give the corresponding c-lactams.
Ó 2006 Elsevier Ltd. All rights reserved.
Much interest has been shown in radical cyclizations for
the synthesis of a variety of carbo- and heterocyclic
compounds, including natural products.1 A combina-
tion of a radical initiator such as AIBN [azobis(isobuty-
ronitrile)] and a hydrogen donor such as Bu3SnH has
frequently been used for radical reactions. There are,
however, some disadvantages in using Bu3SnH such as
its toxicity and the difficulty of product purifications.
Therefore, several substitutes for the use of Bu3SnH
have been studied in recent years.2
photoirradiation in the presence of triethylamine and
alkyl bromides.8
As an initial study for the cyclization, N-allylic a,a,a-tri-
chloroacetamide 1 was heated in boiling triethylamine
for 30 min but gave no reaction product. A similar treat-
ment in boiling tripropylamine, however, afforded 2 in
2% yield along with the starting material 1 (82%)
(Scheme 1). On the other hand, when compound 1 was
treated in boiling cumene, the boiling point of which
(155 °C) is almost the same as that of tripropylamine
(156 °C), no cyclization product was obtained after
90 min of heating. These results strongly suggested that
the cyclization of 1 giving 2 would proceed by heating in
amine having a high boiling point.
Herein we report that radical cyclization of N-allylic and
N-vinylic a,a,a-trichloroacetamides can be performed
by heating in 1,4-dimethylpiperazine (1,4-DMP) used
as a solvent to give the corresponding c-lactams in good
yields.
We next examined the cyclization of 1 in boiling amine
in more detail (Table 1). When compound 1 was heated
in a secondary amine such as dibutylamine (bp: 159 °C)
for 30 min, the cyclization product 2 was obtained in
44% yield (entry 3). The use of a primary amine such
as heptylamine (bp: 157 °C) gave a complex mixture of
products (entry 4). A cyclic secondary amine such as
piperidine gave an undesired compound 3 (34% yield)
Organic amines are known to work as electron donors in
single electron transfer (SET) reactions, and they have
been used for reductive dehalogenation of a-halo
carbonyl compounds; that is, N,N-dimethylaniline,3
1,3-dimethyl-2-phenylbenzimidazoline (DMBI),4 1-benz-
yl-1,4-dihydropyridines,5 morpholine6 and 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU)7 have been employed for
dehalogenation via a radical mechanism. However, no
example was reported for the formation of radical cycli-
zation product even when appropriate radical acceptors
were tethered to the molecules, except for the case of
Cl
Cl
Cl
Cl
O
Me
Cl
O
in amine
N
N
Ph
1
Ph
2
Keywords: N-allylic a,a,a-trichloroacetamide; Anion radical; 1,4-Di-
methylpiperazine; Radical cyclization; Single electron transfer.
*
Scheme 1. Cyclization of 1.
Corresponding author. E-mail: isibasi@p.kanazawa-u.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.146

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H. Ishibashi et al. / Tetrahedron Letters 47 (2006) 6263–6266
Table 1. Reaction of 1 in boiling amines
Entry
Amine
Bp
89
156
159
157
Time (min)
Yield of 2a (%)
1
2
3
4
Et3N
Pr3N
Bu2NH
CH3(CH2)6NH2
30
30
30
30
0 (97)
2 (82)
44 (32)
—
5
6
106
106
20
90
34b (0)
NH
18 (77)
NMe
7
8
116
133
90
2
46 (33)
75 (0)
O
NMe
MeN
NMe
Me
N
9
Me
162
90
2 (0)
N
N
Me
N
10
11
122
145
30
30
17 (32)
26 (58)
N
N
N
a Numbers in parentheses are % yields of the starting material.
b Yield of compound 3.
Me
N
N
O
Ph
3
(entry 5), which might be formed from 2 since com-
pound 3 was obtained in 79% yield by treating 2 in boil-
ing piperidine for 30 min. Of the cyclic tertiary amines
examined (entries 6–9), 1,4-dimethylpiperazine (1,4-
DMP) (bp: 133 °C) was found to be best for the cycliza-
tion of 1 (entry 8). The reaction of 1 in boiling 1,4-DMP
was completed within 2 min to give product 2 in 75%
yield. Acyclic diamines such as tetramethylethylene-
diamine and tetramethylpropanediamine gave product
2 in poor yields (entries 10 and 11).
However, surprisingly, the cyclization of 1 occurred at
room temperature by using dimethyl sulfoxide (DMSO)
as a co-solvent. When compound 1 was treated in a 1:1
mixture of 1,4-DMP and DMSO at room temperature
for 6 h, compound 2 and the dechlorinated product 11
were obtained in 50% and 17% yields, respectively, along
with the starting material 1 (13%).
Nitromethane, acetonitrile, or dimethyl formamide
could also be used as a co-solvent to give almost the
same result as that obtained when DMSO was used.
However, no reaction occurred when dichloromethane
or benzene was used as a co-solvent. These results sug-
gest that the cyclization of 1 at room temperature can
occur only when a co-solvent having a high dielectric
constant is used.10
The effects of reaction temperature in 1,4-DMP on the
cyclization of 1 were next examined in more detail.
When the cyclization of 1 was carried out at 100 °C in-
stead of at reflux (at 133 °C for 2 min, entry 8 in Table
1), compound 2 was obtained in 77% yield after
15 min of heating. Treatment of 1 at 65 °C also gave 2
in 81% yield after 120 min of heating.9 These results
strongly indicate that product 2 was labile at a high tem-
perature and that the cyclization of 1 took place at a rel-
atively low temperature when 1,4-DMP was used as a
solvent. Unfortunately, at a lower temperature such as
room temperature, no cyclization of compound 1
occurred.
The cyclization of N-allylic acetamide 4 also proceeded
smoothly for 5 min in 1,4-DMP at reflux to give com-
pound 5 and the partially dechlorinated compound 6
in 69% and 19% yields, respectively (Scheme 2). N-
(Cyclohex-2-eny-1-yl)acetamides 7 and 8 gave the corre-
sponding cyclization products 9 and 10 in 72% and 74%
yields, respectively.

H. Ishibashi et al. / Tetrahedron Letters 47 (2006) 6263–6266
6265
Cl
cyclizations, and application of this method to the syn-
thesis of a variety of cyclic compounds are under intense
investigation.
Cl
Cl
Cl
Cl
Cl
O
+
N
O
N
N
O
Me
N
N
Me
Ph
Ph
4
Ph
reflux, 5 min
6: 19%
5: 69%
Acknowledgments
Cl
H
Cl
Cl
Cl
Cl
O
The present work was supported by a Grant–in-Aid
for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology of Japan.
N
N
R
O
Me
N
N
Me
H
R
reflux, 5 min
7: R = Ph
8: R = CH2Ph
9: R = Ph: 72%
10: R = CH2Ph: 74%
Supplementary data
Scheme 2. Reactions of 4, 7 and 8.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.05.146.
H
Cl
Cl
O
Cl
N
N
O
Me
N
N Me
Ph
11
Ph
References and notes
reflux, 3 h
12: 12%
H
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Cl
O
H
Cl
Cl
O
N
N
H
Me
N
N Me
CH2Ph
13
CH2Ph
14: 13%
reflux, 3 h
Scheme 3. Reactions of 11 and 13.
N-Allylic a,a-dichloroacetamides were also found to
give the desired products, but the cyclization was slug-
gish. Compound 11 in 1,4-DMP gave 1211 in 12% yield
along with a considerable amount of the starting mate-
rial (80%) after 3 h of heating (Scheme 3). Under similar
conditions, compound 13 gave 14 in 13% yield along
1
with the starting material (69%). The H NMR spectra
of compound 14 showed it to be a single stereoisomer.
The orientation of its chlorine atom and the hydrogen
atom at C-3a was tentatively assigned to be cis in the
same manner as 12.
3. Giumanini, G. A. Chimia 1967, 21, 464.
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ucts 1612 and 1712 were obtained in 49% and 24% yields,
respectively (Scheme 4).
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In conclusion, radical cyclization of N-allylic or vinylic
trichloroacetamides proceeded smoothly in 1,4-DMP.
Neither heavy metals (Sn, Ni,13 Mn,14 etc.) nor photo-
chemical conditions were required in the present radical
reactions. Furthermore, easy purification of cyclized
products was realized by the use of volatile 1,4-DMP.
Elucidation of mechanistic problems for the radical
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(1) (141 mg, 0.5 mmol) was added to 1,4-dimethylpiper-
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120 min. The solvent was removed and the residue was
chromatographed on silica gel (hexane/AcOEt = 4:1) to
afford 3,3-dichloro-4-methyl-1-phenylpyrrolidin-2-one (2)
(99 mg, 81% yield).
10. It has been reported that SET reaction from a secondary
amine to [60]fullerene can be promoted by addition of
DMSO to the reaction mixture Isobe, H.; Tanaka, T.;
Nakanishi, W.; Lemiegre, L.; Nakamura, E. J. Org. Chem.
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Ph
Ph
Ph Cl
Cl
O
Cl
O
Cl
Cl
O
+
N
N
N
Bn
15
Me
N
N Me
Bn
Bn
reflux, 90 min
16: 49%
17: 24%
Scheme 4. Reaction of 15.

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H. Ishibashi et al. / Tetrahedron Letters 47 (2006) 6263–6266
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