Reaction of polychloroacetamides with amines: Reductive dechlorination and aziridine formation

Article abstract of DOI:10.3987/COM-05-10426

Treatment of trichloroacetamides with amines undergoes reductive dechlorination via single-electron transfer process to afford dichloroacetamides in good yields. Reaction of trichloro- and dichloroacetamides with DBU provides a new synthetic method of azi

Full text of DOI:10.3987/COM-05-10426

HETEROCYCLES, Vol. 65, No. 8, 2005
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HETEROCYCLES, Vol. 65, No. 8, 2008, pp. 1857 - 1869
Received, 8th April, 2005, Accepted, 13th May, 2005, Published online, 17th May, 2005
REACTION OF POLYCHLOROACETAMIDES WITH AMINES:
REDUCTIVE DECHLORINATION AND AZIRIDINE FORMATION
Takeaki Naito,* Ayako Saito, Masafumi Ueda, and Okiko Miyata
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558,
Japan e-mail: taknaito@kobepharma-u.ac.jp
Abstract – Treatment of trichloroacetamides with amines undergoes reductive
dechlorination via single-electron transfer process to afford dichloroacetamides
in good yields. Reaction of trichloro- and dichloroacetamides with DBU provides
a new synthetic method of aziridinopyrrolidines.
INTRODUCTION
Radical reactions have emerged as a valuable tool for organic chemists, exhibiting great advantages over
ionic chemistry.1-10 Free radical synthetic methods largely relied on toxic organomercury or organotin
chemistry. Therefore, the radical reactions including atom- and group-transfer processes or
single-electron transfer (SET) processes have been a subject of current interest. 1-10 Among known SET
reactions, there have been only a few examples11-14 using organic amines as an electron donor compared
with so many examples using metals. Synthetic methods using metals are not generally tolerant of the
removal of even a trace amount of metals which are often included in foods and drugs. Considering these
backgrounds, we investigated to develop an environmentally benign SET reaction employing amines as
an electron donor and found two types of novel reactions which are a novel reductive dehalogenation
reaction via SET and a simple method for preparing aziridine skeletons via aza-Darzens type reaction.
There have been several examples of cyclization of trichloroacetamides with olefins in which the first
step of cyclization proved to be SET reaction from metals such as ruthenium, 15 copper, 16 and nickel17 to
the trichloroacetamide group. Actually Nagashima16 and Zard17 groups provided novel method for
preparing pyrrolidones via the route involving transition-metal catalyzed radical cyclization of
trichloroacetamides. Ishibashi group14 has independently reported that upon treatment of
p-dihydroquinone and amine, trichloroacetamides carrying the enamide moiety undergo cyclization to
give hydroindolones via SET.

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HETEROCYCLES, Vol. 65, No. 8, 2005
RESULTS AND DISCUSSION
Aiming at the development of a new environmentally benign cyclization reaction via the route involving
SET process from organic molecule, we started to investigate the reaction of trichloroacetamide (1a)
under the same reaction conditions reported by Ishibashi group.14
OBn
Cl
Cl
N
Cl
Cl
Cl
NHOBn
NOBn
Cl
H
NOBn
Cl
Cl
DBU
+
+ BnOH
O
N
R
MeCN
rt
O
N
R
O
N
R
O
N
R
4
1a
2a
R: allyl
5
3a
Scheme 1
Table 1. Reaction of 1a with DBU
entry conc. DBU
temp.
yield (%)
time
(M)
0.02
0.02
0.02
0.02
0.1
(eq.)
2a
25
13
0
3a
0
4
23
9
1
2
3a
4b
5
1
3
3
3
3
3
reflux
10 (h)
18 (d)
19 (d)
3 (d)
rt
rt
rt
rt
rt
8
7
25
27
5
0
2
3 (d)
23
22
11
10
6
0.5
17 (h)
trace
aThe reaction was carried out in the dark.
bThe reaction was carried out in the presence of EtOH (3 eq.).
Employment of 1a as a substrate which carries two types of double bonds, olefin and oxime ether, would
lead to informative and instructive suggestions regarding each double bond as a radical acceptor (Scheme
1). However, the reaction conditions (p-dihydroquinone, DBU, reflux in MeCN) employed by Ishibashi14
led only to a very sluggish reaction that gave no isolable compounds from the reaction mixture. Therefore
we investigated the reaction of 1a with either hydroquinone or DBU. In the presence of hydroquinone,
trichloroacetamide (1a) was completely recovered while three products (2a, 3a) and benzyl alcohol (4)
were obtained from the reaction of 1a with DBU (entry 2). Product (2a) has the dichloroacetamide group
and another one (3a) was proved an aziridine compound from the spectral data. Intramolecularly cyclized
product (5) was not isolated.

HETEROCYCLES, Vol. 65, No. 8, 2005
1859
Optimization of the reaction was attempted by changing concentration, amount of base, reaction
temperature and time as shown in Table 1. Stirring 0.5 M solution of trichloroacetamide (1a) and DBU (3
eq.) in acetonitrile for 17 h gave dichloroacetamide (2a) and aziridine (3a) in 22% and 10% yields,
respectively, with a small amount of benzyl alcohol (4) (entry 6).
Generality of this reaction was proved by the reaction of N-benzyl trichloroacetamide (1b) with either
DBU or other organic bases summarized in Table 2.
OBn
Cl
Cl
N
Cl
H
Cl
Cl
NOBn
NOBn
Cl
amine
+ BnOH
+
O
N
O
N
MeCN
rt
O
N
4
Bn
2b
Bn
1b
Bn
3b
Scheme 2
Table 2. Reaction of 1b with amines
entry
conc.
(M)
0.02
0.1
amine
(eq.)
time
(d)
1
yield (%)
3b
2b
44
21
25
36
4
1b
trace
trace
0
1
2
3
4
5
6
DBU (3)
DBU (3)
DBN (3)
TMG (3)
Et3N (3)
DABCO (3)
2
14
6
14
11
13
0
2.5
2
0.1
0.1
2
3
37
0.1
14
7
no reaction
no reaction
0.1
Product ratio and yield of three products (2b, 3b, and 4) are found to be slightly depending upon reaction
conditions used. It is worth to note that amines such as DBU, DBN, and TMG (tetramethylguanidine)
containing an amidine moiety in the molecule are effective in this reaction (entries 1-4). Bases carrying
the amidine group exhibit strong basicity and are also suitable for SET while DABCO carrying
bridgehead nitrogen would be unable to supply α-hydrogen of the nitrogen moiety.
In order to propose reaction pathway to three products, we next investigated reaction of the related
substrates, ketoxime ether (6) and acetamide (8) with DBU (Scheme 3). Upon treatment with DBU,
ketoxime ether (6) gave dichloroactamide (7) in 67% yield with no formation of benzyl alcohol (4).
Similar treatment of acetamide (8) with DBU gave nitrile (9) and benzyl alcohol (4) in 37% and 36%

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HETEROCYCLES, Vol. 65, No. 8, 2005
yields, respectively, with recovering 47% yield of starting material (8).
Cl
Me
H
2
Me
Cl
Cl
Cl
Cl
N
NOBn
DBU (3 eq.)
NOBn
NOBn
DBU (3 eq.)
1
1'
+ BnOH
MeCN
rt
2 d
AcN
Bn
9 37%
O
N
AcN
Bn
MeCN
rt
36 d
O
N
4
36%
Bn
6
Bn
7
8
67%
Scheme 3
We also extended reaction with DBU to dichloroacetamide (2b) in order to disclose the reaction pathway
to aziridine formation. Additionally, both E- and Z-oxime ethers (2b) were isolated and subjected to the
reaction as shown in Table 3.
OBn
N
Cl
Cl
H
N
Cl
OBn
DBU
+ BnOH
O
N
MeCN
rt
O
N
4
Bn
2b
Bn
3b
Scheme 4
Table 3. Reaction of 2b with DBU
entry
2b
(E/Z)
E
conc.
(M)
0.02
0.1
DBU
time
(d)
4
yield (%)
(eq.)
3b
29
51
27
27
29
4
trace
4
2b
18
3
1
2
3
4
5
3
6
6
3
6
E
3
Z
0.02
0.1
1.5
2
27
25
6
Z
26
Z
0.1
3
20
6
Reaction of E-2b with DBU gave the expected aziridine (3b) as a major product with a small amount of
benzyl alcohol (4) (entry 1). When 6 eq. of DBU and 0.1 M solution were employed, we obtained
aziridine (3b) in moderate yield (entry 2). On the other hand, under the same reaction conditions, Z-2b
gave almost same yield (27%) of aziridine (3b) and benzyl alcohol (4) (27%).
There are a few examples of reductive dehalogenation of α-halogenocarbonyl compounds with organic
11
amines but they are mostly focused on reaction mechanism using α-bromo ketones,

HETEROCYCLES, Vol. 65, No. 8, 2005
1861
α-chloroacetophenone, 12 and hexachloroacetone13 as a substrate.
Based on the results mentioned above and related works,11-13 we propose possible reaction pathway to
three products (2-4) as shown in Scheme 5.
Cl
H
Cl
Cl
Cl
Cl
Cl
Cl
DBU
SET
NOBn
NOBn
DBU
NOBn
Radical
pathway
O
N
R
O
N
Cl
O
N
R
R
A
2
1
H2O
DBU SET
DBU
DBU
Cl
Cl
Cl
NOBn
NOBn
Cl
H
Cl
Cl
Cl
N
OBn
Aza-
Darzens
O
N
R
C
O
N
R
D
O
N
R
B
DBU
OBn
N
N
H
Cl
Cl
N
Cl
O
N
Cl
+
BnOH
O
N
R
H
4
N
R
3
Scheme 5
SET from DBU to trichloroacetamide (1) occurs to form α-carbamoyl radical (A) that would be
hydrogenated by radical cation of DBU produced to afford dichloroacetamide (2). As another possible
pathway, product (2) would be formed via SET from DBU to intermediate radical (A) leading to the
formation of the corresponding anion (C) followed by its protonation.
In aziridine formation, two reaction pathways would be possible. Since dichloroacetamide (2) worked
well, 2 is first deprotonated by DBU to form anion (C) that would undergo aza-Darzens type of reaction
to afford aziridine (3). When trichloroacetamide (1) is used as a substrate, anion (C) is formed from
radical (A) and also by deprotonation of 2 with DBU.
Formation of by-product benzyl alcohol (4) would be explained in anti-elimination fashion from
Z-aldoxime ether group (B) with DBU.
Potentiality of reductive dechlorination of trichloroacetamides has been proved by two other reactions of
N-trichloroacetamides (10) and (12) prepared from tetrahydroquinoline and tetrahydroisoquinoline which
afforded the respective dichloroacetamides (11) and (13) in good yields (Scheme 6).

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HETEROCYCLES, Vol. 65, No. 8, 2005
DBU
MeCN
69%
DBU
N
N
N
CCl3
N
CHCl2
MeCN
60%
O
CCl3
O
CHCl2
O
O
10
12
13
11
Scheme 6
CONCLUSION
We have now established an effective method for preparing dichloroacetamides by simple treatment of
trichloroacetamides with DBU and found that reactions of tri- and dichloroacetamides carrying oxime
ether with DBU gave aziridine compounds via aza-Darzens reaction. The resulting aziridinopyrrolidines
are closely related to the partial structure of mitomycin-mitosene antitumor antibiotics.
EXPERIMENTAL
1
13
Melting points are uncorrected. H and C NMR spectra were recorded at 200, 300, or 500 MHz and at
75 or 125 MHz, respectively. IR spectra were recorded using FTIR apparatus. MS spectra were obtained
by EI method. Flash column chromatography (FCC) was performed using E. Merck Kieselgel 60
(230-400 mesh). Medium-pressure column chromatography (MCC) was performed using Lobar größe B
(E. Merck 310-25, Lichroprep Si60). Preparative TLC (PTLC) was performed on pre-coated Silica gel
60F-254 plates (0.5 mm thick, Merck). All extracts were dried over MgSO4 and then concentrated under
reduced pressure.
2,2,2-Trichloro-N-(2-phenylmethoxyiminoethyl)-N-(2-propenyl)acetamide
(1a)
To
2-chloroacetaldehyde O-phenylmethyloxime18 (25 g, 136 mmol) was added allylamine (38 mL, 507
mmol) with stirring under a nitrogen atmosphere at 0 °C. The mixture was stirred at rt for 2 days. Water
was added and then the mixture was extracted with AcOEt. The organic phase was dried and concentrated
at reduced pressure to give the residue. 1H-NMR spectrum of the residue proved the formation of desired
sec-amine (E : Z = 1 : 1) which without further purification was subjected to next acylation reaction.
1
(E/Z)-2-Propenylaminoacetaldehyde O-Phenylmethyloxime: H-NMR (300 MHz) δ : 7.47-7.31 (5H +
1/2H, m, ArH + iminoic H), 6.81 (1/2H, t, J=5.0 Hz, iminoic H), 5.90-5.66 (1H, m, olefinic H), 5.18-5.09
(2H, m, olefinic H), 5.08 (2/2H, s, OCH2Ph), 5.07 (2/2H, s, OCH2Ph), 3.20 (2H, d, J=6.2 Hz,
NCH2CH=CH2), 3.09 (2H, d, J=5.0 Hz, CH2CH=NOBn).
To a solution of sec-amine prepared above (26.7 g, 130 mmol) in CH2Cl2 (300 mL) were added dropwise
Et3N (14.5 mL, 254 mmol) and then TCAA (trichloroacetic anhydride) (23 mL, 127 mmol) under a

HETEROCYCLES, Vol. 65, No. 8, 2005
1863
nitrogen atmosphere at 0 °C. The mixture was stirred at rt for 23 h. Water was added and then the mixture
was extracted with CH2Cl2. The organic phase was dried and concentrated to give a residue which was
purified by FCC (hexane : AcOEt (20 : 1)) to afford 1a (24 g, 44%) as a colorless oil. 1H-NMR spectrum
showed the existence of a geometrical mixture (E : Z = 1 : 1) of the oxime ether group and rotational
isomer around the amide group. IR ν max cm-1 : 1682 (CON). 1H-NMR (300 MHz) δ : 7.44 (1/2H, t, J=5.7
Hz, iminoic H), 7.40-7.27 (10H, m, ArH), 6.84-6.66 (1/2H, br m, iminoic H), 5.86-5.70 (1H, m, olefinic
H), 5.30-5.16 (2H, br m, olefinic H), 5.13 (1H, s, OCH2Ph), 5.09 (1H, s, OCH2Ph), 4.66-3.99 (4H, br m,
NCH2CH=CH2 + CH2CH=NOBn). 13C-NMR (50 MHz) δ : 160.5, 147.1, 144.5, 137.1, 131.1, 130.4,
128.3, 128.24, 128.16, 128.0, 127.9, 127.8, 119.8, 118.8, 92.5, 92.4, 77.2, 76.4, 76.0, 53.4, 51.9, 50.3,
47.5, 46.2, 45.2, 44.2. MS m/z (relative intensity) : 354 (1.5), 352 (13.5), 350 (40.0), 348 (40.5). HRMS
m/z : Calcd for C14H15N2O2Cl3 (M+) 348.0198. Found : 348.0195.
2,2,2-Trichloro-N-(2-phenylmethoxyiminoethyl)-N-phenylmethylacetamide (1b) According to the
procedure given for 1a, the amide (1b) was prepared from 2-chloroacetaldehyde O-phenylmethyloxime18
(3.4 g, 18.3 mmol), benzylamine (4 mL, 36.6 mmol), and TCAA (4 mL, 22 mmol) via the
corresponding benzyliminoethylamine. The amide (1b) (3 g, 48%) obtained is colorless oil and found to
be a geometrical mixture (E : Z = 1 : 1) of the oxime ether group and rotational isomer around the amide
1
1
group from H-NMR spectrum. IR ν
cm-1 : 1685 (CON). H-NMR (300 MHz) δ : 7.42-7.18 (10H +
max
1/2H, m, ArH + iminoic H), 6.73 (1/2H, br s, iminoic H), 5.07 (2H, br s, OCH2Ph), 4.91 (2/2H, br s,
NCH2Ph), 4.61 (2/2H, br s, NCH2Ph), 4.46-3.96 (2H, br m, CH2CH=NOBn). 13C-NMR (50 MHz) δ :
160.9, 147.2, 144.5, 137.2, 137.1, 134.7, 128.8, 128.7, 128.3, 128.1, 128.0, 127.9, 92.7, 92.6, 76.4, 76.1,
65.4, 60.2. MS m/z (relative intensity) : 404 (0.7), 402 (6.5), 400 (18.0), 398 (18.0). HRMS m/z : Calcd
for C18H17N2O2Cl3 (M+) 398.0356. Found : 398.0350.
General Procedure for Reaction of Trichloroacetamides (1a, b) with DBU A solution of
trichloroacetoamides (1a, b) (140 mg, 0.4 mmol) and DBU in MeCN was stirred under the reaction
conditions shown in Tables 1 and 2. After the solution was concentrated, the residue was purified by
either FCC, MCC, or PTLC (hexane : AcOEt (3 : 1) to afford dichloroacetamide (2a, b), aziridine (3a, b),
benzyl alcohol (4), and starting compounds (1a, b) in the yields shown in Tables 1 and 2.
2,2-Dichloro-N-(2-phenylmethoxyiminoethyl)-N-(2-propenyl)acetamide (2a). Colorless oil. Spectral data
are collected as a geometrical mixture of the oxime ether group and rotational isomer around the amide
group (2 : 2 : 3 : 1). IR ν max cm-1 : 1685 (CON). 1H-NMR (300 MHz) δ : 7.46-7.32 (5H + 1/8H + 2/8H,
m, ArH + iminoic H), 6.77 (2/8H, t, J=4.5 Hz, iminoic H), 6.69 (3/8H, t, J=4.5 Hz, iminoic H), 6.25
(2/8H, s, COCCl2H), 6.19 (2/8H, s, COCCl2H), 6.17 (3/8H, s, COCCl2H), 6.15 (1/8H, s, COCCl2H),

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HETEROCYCLES, Vol. 65, No. 8, 2005
5.88-5.64 (1H, m, olefinic H), 5.30-5.17 (2H, m, olefinic H), 5.15 (2/8H, s, OCH2Ph), 5.13 (4/8H, s,
OCH2Ph), 5.10 (4/8H, s, OCH2Ph), 5.08 (6/8H, s, OCH2Ph), 4.41 (2/8H, d, J=4.5 Hz, CH2CH=NOBn),
4.26 (4/8H, d, J=4.5 Hz, CH2CH=NOBn), 4.18 (4/8H, d, J=5.4 Hz, CH2CH=NOBn), 4.10 (6/8H, d, J=5.4
13
Hz , CH2CH=NOBn), 4.09-3.97 (2H, m, NCH2CH=CH2). C-NMR (50 MHz) δ : 164.1, 163.6, 147.0,
146.8, 144.6, 137.2, 136.9, 131.6, 131.4, 131.1, 130.7, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9,
118.9, 118.8, 188.5, 76.7, 76.3, 76.0, 65.1, 64.9, 64.6, 64.5, 51.5, 50.1, 49.9, 49.3, 46.1, 45.3, 43.1, 43.0.
MS m/z (relative intensity) : 318 (7.0), 316 (43.0), 314 (64.0). HRMS m/z : Calcd for C14H16N2O2Cl2 (M+)
314.0606. Found : 314.0601.
1-Chloro-6-phenylmethoxy-3-(2-propenyl)-3,6-diazabicyclo[3.1.0]hexan-2-one (3a). Colorless oil. IR
ν
max cm-1 : 1714 (CON). 1H-NMR (300 MHz) δ : 7.38-7.34 (5H, m, ArH), 5.73-5.60 (1H, m, olefinic H),
5.24-5.16 (2H, m, olefinic H), 4.88 (2H, s, OCH2Ph), 3.85 (2H, m, NCH2CH=CH2), 3.49 (1H, dd, J=11.4,
13
4.2 Hz, 4-H), 3.39 (1H, d, J=11.4 Hz, 5-H), 3.27 (1H, d, J=4.2 Hz, 4-H). C-NMR (50 MHz) δ : 165.0,
135.8, 131.0, 129.0, 128.4, 128.3, 118.7, 76.0, 64.1, 47.1, 46.9, 45.6. MS m/z (relative intensity) : 280
(4.0), 278 (12.0). HRMS m/z : Calcd for C14H15N2O2Cl (M+) 278.0821. Found : 278.0824.
2,2-Dichloro-N-(2-phenylmethoxyiminoethyl)-N-phenylmethylacetamide (2b). Colorless oil. Spectral
data are collected as a geometrical mixture of the oxime ether group and rotational isomer around the
amide group (1 : 1 : 1 : 1). IR ν max cm-1 : 1674 (CON). 1H-NMR (300 MHz) δ : 7.39-7.13 (10H + 1/4H +
1/4H, m, ArH + iminoic H), 6.67 (1/4H + 1/4H, dt, J=9.9, 4.5 Hz, iminoic H), 6.30 (1/4H, s, COCCl2H),
6.24 (1/4H, s, COCCl2H), 6.21 (1/4H, s, COCCl2H), 6.19 (1/4H, s, COCCl2H), 5.11 (2/4H, s, OCH2Ph),
5.09 (2/4H, s, OCH2Ph), 5.06 (2/4H, s, OCH2Ph), 5.05 (2/4H, s, OCH2Ph), 4.71 (2/4H, s, NCH2Ph), 4.64
(2/4H, s, NCH2Ph), 4.61 (2/4H, s, NCH2Ph), 4.57 (2/4H, s, NCH2Ph), 4.35 (2/4H, d, J=4.5 Hz,
CH2CH=NOBn), 4.22 (2/4H, d, J=4.5 Hz, CH2CH=NOBn), 4.11 (2/4H, d, J=5.7 Hz, CH2CH=NOBn),
4.07 (2/4H, d, J=5.7 Hz, CH2CH=NOBn). 13C-NMR (50 MHz) δ : 164.2, 164.0, 144.5, 144.3, 137.2,
136.9, 135.4, 134.6, 129.0, 128.7, 128.4, 128.3, 128.27, 128.2, 128.0, 127.8, 126.7, 76.3, 76.0, 65.1, 64.6,
50.8, 49.6, 45.7, 45.0. MS m/z (relative intensity) : 368 (3.0), 366 (17.0), 364 (26.5). HRMS m/z : Calcd
for C18H18N2O2Cl2 (M+) 364.0744. Found : 364.0741.
1-Chloro-6-phenylmethoxy-3-phenylmethyl-3,6-diazabicyclo[3.1.0]hexan-2-one
(3b)
Colorless
crystals mp 107-108 °C (hexane / AcOEt). IR ν max (CHCl3) cm-1 : 1711 (CON). 1H-NMR (300 MHz) δ :
7.39-7.17 (10H, m, ArH), 4.89 (2H, s, OCH2Ph), 4.51, 4.30 (2H, ABq, J=14.7 Hz, NCH2Ph), 3.37 (1H,
dd, J=11.1, 4.2 Hz, 4-H), 3.27 (1H, d, J=11.1 Hz, 5-H), 3.22 (1H, d, J=4.2 Hz, 4-H). 13C-NMR (50 MHz)
δ : 165.3, 135.8, 134.9, 129.0, 128.8, 128.4, 128.0, 127.9, 76.1, 64.0, 47.1, 47.0, 46.8. MS m/z (relative

HETEROCYCLES, Vol. 65, No. 8, 2005
1865
intensity) : 330 (4.0), 328 (11.5). HRMS m/z : Calcd for C18H17N2O2Cl (M+) 328.0978. Found : 328.0973.
Anal. Calcd for C18H17N2O2Cl: C, 65.75; H, 5.21; N, 8.52. Found : C, 65.92; H, 5.27; N, 8.48.
2,2,2-Trichloro-N-(2-phenylmethoxyiminopropyl)-N-phenylmethylacetamide (6) According to the
procedure given for 1b, alkylation of benzylamine (3.3 mL, 30 mmol) with chloroacetone
O-phenylmethyloxime (1.9 g, 10 mmol) afforded (E/Z)-1-phenylmethylamino-2-propanone
O-phenylmethyloxime which without purification was acylated with TCAA (1.8 mL, 10 mmol) to give 6
(1.3 g, 30%) as a colorless oil.
1
(E/Z)-1-Phenylmethylamino-2-propanone O-Phenylmethyloxime. H-NMR (300 MHz) δ : 7.34-7.22
(10H, m, ArH), 5.10 (2H, s, OCH2Ph), 3.70 (2H, s, NCH2Ph), 3.28 (2H, s, CH2C(Me)=NOBn), 1.89 (3H,
s, Me).
Spectral data of 6 are collected as a geometrical mixture of the oxime ether group and rotational isomer
around the amide group. IR ν max cm-1 : 1682 (CON). 1H-NMR (300 MHz) δ : 7.35-7.29 (8H, m, ArH),
7.10 (2H, br m, ArH), 5.07 (2H, br s, OCH2Ph), 4.85 (10/8H, br s, NCH2Ph), 4.56 (6/8H, br s, NCH2Ph),
4.33 (6/8H, br s, CH2C(Me)=NOBn), 4.02 (10/8H, br s, CH2C(Me)=NOBn), 1.83 (3H, br s, Me).
13C-NMR (50 MHz) δ : 160.9, 151.7, 138.0, 135.4, 134.9, 128.6, 128.2, 128.0, 127.7, 127.1, 92.9, 77.2,
75.7, 52.3, 51.8, 51.1, 49.8, 12.8. MS m/z (relative intensity) : 418 (0.3), 416 (2.5), 414 (8.0), 412 (8.0).
HRMS m/z : Calcd for C19H19N2O2Cl3 (M+) 412.0511. Found : 412.0513.
2,2-Dichloro-N-(2-phenylmethoxyiminopropyl)-N-phenylmethylacetamide (7) A solution of 6 (165
mg, 0.4 mmol) and DBU (0.18 mL, 1.2 mmol) in MeCN (20 mL) was stirred at rt for 2 days. The reaction
mixture was concentrated and the residue was purified by MCC (hexane : AcOEt (5 : 1)) to give 7 (102
mg, 67%) as a colorless oil and starting compound (6) (29 mg, 17%). Spectral data of 7 are collected as a
geometrical mixture of the oxime ether group and rotational isomer around the amide group (1 : 1). IR ν
1
cm-1 : 1679 (CON). H-NMR (300 MHz) δ : 7.34-7.27 (8H, m, ArH), 7.15-7.06 (2H, m, ArH), 6.32
max
(1/2H, s, COCCl2H), 6.22 (1/2H, s, COCCl2H), 5.08 (2/2H, s, OCH2Ph), 5.07 (2/2H, s, OCH2Ph), 4.56
(2/2H, s, NCH2Ph), 4.53 (2/2H, s, NCH2Ph), 4.08 (2/2H, s, CH2C(Me)=NOBn), 3.98 (2/2H, s,
CH2C(Me)=NOBn), 1.85 (3/2H, s, Me), 1.77 (3/2H, s, Me). 13C-NMR (50 MHz) δ : 164.6, 164.4, 152.5,
151.6, 138.0, 137.6, 135.7, 134.8, 129.0, 128.7, 128.35, 128.26, 128.0, 127.9, 127.8, 127.7, 126.5, 76.2,
75.7, 65.0, 64.8, 50.4, 50.2, 50.1, 49.1, 12.9, 12.6. MS m/z (relative intensity) : 382 (2.0), 380 (12.5), 378
(18.5). HRMS m/z : Calcd for C19H20N2O2Cl2 (M+) 378.0900. Found : 378.0906.
N-(2-Phenylmethoxyiminoethyl)-N-phenylmethylacetamide
(8)
Acetylation
of
(E/Z)-2-propenylaminoacetaldehyde O-phenylmethyloxime (1.3 g, 5 mmol) used for preparation of 1 with

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Ac2O under the usual reaction conditions afforded 8 (1.1 g, 76%) as a colorless oil. Spectral data are
collected as a geometrical mixture of the oxime ether group and rotational isomer around the amide group
(3 : 4 : 4 : 6). IR ν max cm-1 : 1658 (CON). 1H-NMR (300 MHz) δ : 7.42-7.10 (10H + 6/17H + 4/17H, m,
ArH + iminoic H), 6.70 (4/17H, t, J=4.2 Hz, iminoic H), 6.55 (3/17H, t, J=4.2 Hz, iminoic H), 5.08
(6/17H, s, OCH2Ph), 5.06 (16/17H, s, OCH2Ph), 5.04 (12/17H, s, OCH2Ph), 4.59 (6/17H, s, NCH2Ph),
4.56 (8/17, s, NCH2Ph), 4.50 (8/17H, s, NCH2Ph), 4.45 (12/17H, s, NCH2Ph), 4.25 (8/17H, d, J=4.2 Hz,
CH2CH=NOBn), 4.13 (6/17H, d, J=4.2 Hz, CH2CH=NOBn), 4.09 (12/17H, d, J=5.7 Hz, CH2CH=NOBn),
3.89 (8/17H, d, J=5.7 Hz, CH2CH=NOBn), 2.17 (12/17H, s, COMe), 2.14 (18/17H, s, COMe), 2.12
13
(12/17H, s, COMe), 2.09 (9/17H, s, COMe). C-NMR (50 MHz) δ : 170.6, 170.5, 170.3, 170.0, 148.3,
147.6, 145.5, 144.7, 137.0, 136.6, 135.7, 128.4, 128.2, 128.1, 127.8, 127.7, 127.6, 127.5, 127.33, 127.29,
127.2, 127.0, 126.1, 126.0, 75.9, 75.5, 75.3, 52.4, 50.8, 48.9, 48.0, 46.0, 43.4, 41.6, 21.0, 20.9, 20.8.
HRMS m/z : Calcd for C18H20N2O2 (M+) 296.1524. Found : 296.1530.
Reaction of N-(2-Phenylmethoxyiminoethyl)-N-phenylmethylacetamide (8) with DBU According to
the procedure given for 7, reaction of 8 (296 mg, 1 mmol) with DBU (0.45 mL, 3 mmol) for 36 days
afforded 9 (70 mg, 37%), benzyl alcohol (4) (39 mg, 36%), and 8 (140 mg, 47%).
N-Cyanomethyl-N-phenylmethylacetamide (9). Colorless oil. IR ν
cm-1 : 2254 (CN), 1662 (CON).
max
1H-NMR (200 MHz) δ : 7.41-7.20 (5H, m, ArH), 4.66 (2H, s, NCH2Ph), 4.25 (2H, s, CH2CH=NOBn),
2.25 (3H, s, NCOMe). 13C-NMR (50 MHz) δ : 170.7, 134.4, 129.3, 129.0, 128.5, 126.8, 115.3, 32.6, 30.9,
21.2. HRMS m/z : Calcd for C11H12N2O (M+) 188.0949. Found : 188.0947.
(E/Z)-2,2-Dichloro-N-(2-phenylmethoxyiminoethyl)-N-phenylmethylacetamide (2b) To a solution of
(E/Z)-2-phenylmethylaminoacetaldehyde O-phenylmethyloxime (3.04 g, 12 mmol) and Et3N (3.3 mL,
24 mmol) in CHCl3 (50 mL) was added dropwise dichloroacetyl chloride (1.27 mL, 13.2 mmol) at 0 °C
and then the mixture was stirred at rt for 2 h. Water was added and the mixture was extracted with
CHCl3. The extract was dried and concentrated to give a residue which was purified with FCC (hexane :
AcOEt (5 : 1)) to afford 2b (2.2 g, 50%) as colorless oil and as a geometrical mixture of the oxime ether
group and rotational isomer around the amide group (1 : 1 : 1 : 1). Further purification by MCC
(hexane : AcOEt (7 : 1)) gave E- and Z-oxime ethers as a single geometrical isomer. Both NMR spectral
data were collected as a 1 : 1 mixture of rotational isomer around the amide group.
E-Oxime ether. Colorless oil. IR ν max cm-1 : 1682 (CON). 1H-NMR (300 MHz) δ : 7.39-7.13 (10H + 1H,
m, ArH + iminoic H), 6.30 (1/2H, s, COCCl2H), 6.21 (1/2H, s, COCCl2H), 5.08 (2/2H, s, OCH2Ph), 5.05
(2/2H, s, OCH2Ph), 4.64 (2/2H, s, NCH2Ph), 4.57 (2/2H, s, NCH2Ph), 4.11 (2/2H, d, J=5.7 Hz,
CH2CH=NOBn), 4.07 (2/2H, d, J=5.7 Hz, CH2CH=NOBn). 13C-NMR (50 MHz) δ : 164.3, 164.1, 146.6,

HETEROCYCLES, Vol. 65, No. 8, 2005
1867
144.5, 144.4, 137.0, 135.5, 134.7, 129.1, 128.9, 128.8, 128.5, 128.42, 128.37, 128.3, 128.1, 128.0, 126.9,
126.8, 76.8, 76.5, 76.1, 65.2, 65.0, 64.8, 52.5, 50.9, 50.7, 49.7, 45.8, 45.2, 43.1, 42.9.
HRMS m/z : Calcd for C18H18N2O2Cl2 (M+) 364.0744. Found : 364.0741.
1
Z-Oxime ether. Colorless oil. IR ν
cm-1 : 1682 (CON). H-NMR (300 MHz) δ : 7.39-7.15 (10H, m,
max
ArH), 6.69 (1/2H, t, J=4.5 Hz, iminoic H), 6.65 (1/2H, t, J=4.5 Hz, iminoic H), 6.24 (1/2H, s, COCCl2H),
6.19 (1/2H, s, COCCl2H), 5.11 (2/2H, s, OCH2Ph), 5.06 (2/2H, s, OCH2Ph), 4.71 (2/2H, s, NCH2Ph),
4.60 (2/2H, s, NCH2Ph), 4.35 (2/2H, d, J=4.5 Hz, CH2CH=NOBn), 4.22 (2/2H, d, J=4.5 Hz,
13
CH2CH=NOBn). C-NMR (50 MHz) δ : 164.4, 164.2, 146.7, 144.5, 144.4, 135.5, 134.7, 129.1, 128.9,
128.8, 128.5, 128.42, 128.38, 128.30, 128.2, 128.1, 128.0, 126.9, 126.8, 76.8, 76.4, 76.1, 65.2, 65.0, 64.8,
52.5, 50.9, 50.7, 49.7, 45.8, 45.2, 43.1. HRMS m/z : Calcd for C18H18N2O2Cl2 (M+) 364.0745. Found :
364.0748.
General Procedure for Reaction of Dichloroacetamide (2b) with DBU A solution of E- or Z-oxime
ether (2b) (365 mg, 1 mmol) and DBU in MeCN was stirred under the reaction conditions shown in Table
3. After the solution was concentrated, the residue obtained was purified by either FCC, MCC, or PTLC
(hexane : AcOEt (3 : 1) to afford aziridine (3b), benzyl alcohol (4), and starting compound (2b) in the
yields shown in Tables 3. Both aziridine (3b) and benzyl alcohol (4) were identical with the respective
products obtained from 1b.
1-Trichloroacetyl-1,2,3,4-tetrahydroquinoline (10) To a solution of 1,2,3,4-tetrahydroquinoline (3.76
mL, 30 mmol) and Et3N (8.4 mL, 60 mmol) in CHCl3 (60 mL) was added TCAA (8.1 mL, 46 mmol)
under a nitrogen atmosphere at 0 °C. The mixture was stirred at rt for 30 h. Water was added and the
mixture was extracted with CHCl3. The extract was dried and concentrated to give a solid which was
recrystallized with hexane / AcOEt to give colorless needles of 6 (4.57 g, 55%), mp 117-118 °C. IR ν max
(CHCl3) cm-1 : 1683 (CON). 1H-NMR (200 MHz) δ: 7.72 (1H, d, J=7.4 Hz, 8-H), 7.35-7.23 (3H, m, ArH),
4.18 (2H, t, J=7.4 Hz, 2-H2), 3.00 (2H, t, J=7.4 Hz, 4-H2), 2.24 (2H, quint, J=7.4 Hz, 3-H2). 13C-NMR (50
MHz) δ: 159.4, 139.0, 131.0, 129.1, 126.0, 125.8, 125.1, 93.7, 47.5, 25.5, 23.0. MS m/z (relative
intensity) : 283 (0.9), 281 (8.0), 279 (25.0), 277 (25.5). HRMS m/z : Calcd for C11H10Cl3NO (M+)
276.9827. Found : 276.9828. Anal. Calcd for C11H10NOCl3 : C, 47.43; H, 3.62; N, 5.03. Found : C, 47.53;
H, 3.63; N, 5.02.
Reaction of 1-Trichloroacetyl-1,2,3,4-tetrahydroquinoline (10) with DBU According to the procedure
given for reaction of 1, reaction of 10 (111 mg, 0.4 mmol) with DBU (0.06 mL, 0.4 mmol) for 24 h
afforded 11 (67 mg, 69%) and 10 (7 mg, 6%).

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1-Dichloroacetyl-1,2,3,4-tetrahydroquinoline (11) Colorless oil. IR ν
cm-1 : 2951 (Ar), 1679 (CON).
max
1H-NMR (200 MHz) δ : 7.24 (4H, br s, ArH), 6.49 (1H, s, COCCl2H), 3.87 (2H, t, J=6.6 Hz, 2-H), 2.76
13
(2H, t, J=6.6 Hz, 4-H), 2.03 (2H, quint, J=6.6 Hz, 3-H). C-NMR (50 MHz) δ : 163.8, 137.4, 129.0,
126.9, 122.9, 64.0, 44.0, 26.2, 23.5. MS m/z (relative intensity) : 247 (5.0), 245 (29.0), 243 (44.5). HRMS
m/z : Calcd for C11H11NOCl2 (M+) 243.0217. Found : 243.0216.
2-Trichloroacetyl-1,2,3,4-tetrahydroisoquinoline (12) According to the procedure given for 10,
acylation of 1,2,3,4-tetrahydroisoquinoline (3.75 mL, 30 mmol) with TCAA (6.1 mL, 33 mmol) gave
colorless crystals of 12 (5.7 g, 69%), mp 69-70 °C (hexane / AcOEt). Spectral data are collected as a
geometrical mixture of rotational isomer around the amide group. IR ν
(CHCl3) cm-1 : 1673 (CON).
max
1H-NMR (300 MHz) δ : 7.25-7.11 (4H, m, ArH), 5.10-4.70 (2H, br m, 1-H), 4.20-3.82 (2H, br m, 3-H),
4.20-3.82 (2H, br m, 4-H). 13C-NMR (50 MHz) δ : 159.3, 133.3, 131.8, 128.4, 126.9, 126.5, 126.1, 92.9,
77.2, 49.8, 47.6, 45.4, 28.2. MS m/z (relative intensity) : 283 (0.2), 281 (1.5), 279 (5.0), 277 (5.0). Anal.
Calcd for C11H10NOCl3: C, 47.43; H, 3.62; N, 5.03. Found : C, 47.52; H, 3.53; N, 5.04.
Reaction of 2-Trichloroacetyl-1,2,3,4-tetrahydroisoquinoline (12) with DBU According to the
procedure given for reaction of 1, reaction of 12 (278 mg, 1 mmol) with DBU (0.45 mL, 3 mmol) for 3
days afforded 1319 (144 mg, 60%) and 12 (32 mg, 12%).
2-Dichloroacetyl-1,2,3,4-tetrahydroisoquinoline (13). Colorless crystals, mp 87-88 °C (hexane / AcOEt)
(lit.,19 86-87 °C). Spectral data were identical with those of authentic sample. 19
ACKNOWLEDGEMENTS
We thank Grant-in Aids for Scientific Research (B) (T. N.) and Scientific Research (C) (O. M.) from
Japan Society for the Promotion of Science and for Young Scientists (B) (M. U.) from the Ministry of
Education, Culture, Sports, Science and Technology of Japan. Our thanks are also directed to the Science
Research Promotion Fund of the Japan Private School Promotion Foundation for research grant.
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