Water in amine-mediated single electron transfer reaction of N-allylic trichloroacetamides

Article abstract of DOI:10.3987/COM-09-S(S)57

Water contaminating 1,4-dimethylpiperazine was thought to play an important role in effecting a single electron transfer reaction (radical cyclization) of N-allylic trichloroacetamides.

Full text of DOI:10.3987/COM-09-S(S)57

HETEROCYCLES, Vol. 80, No. 1, 2010
657
HETEROCYCLES, Vol. 80, No. 1, 2010, pp. 657 - 662. © The Japan Institute of Heterocyclic Chemistry
Received, 17th July, 2009, Accepted, 31st August, 2009, Published online, 1st September, 2009
DOI: 10.3987/COM-09-S(S)57
WATER IN AMINE-MEDIATED SINGLE ELECTRON TRANSFER
REACTION OF N-ALLYLIC TRICHLOROACETAMIDES
Tsuyoshi Taniguchi, Masamichi Sasaki, and Hiroyuki Ishibashi*
School of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and
Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192,
Japan. E-mail: isibasi@p.kanazawa-u.ac.jp
Abstract – Water contaminating 1,4-dimethylpiperazine was thought to play an
important role in effecting a single electron transfer reaction (radical cyclization)
of N-allylic trichloroacetamides.
We have recently reported that N-allylic trichloroacetamides (1), upon heating in 1,4-dimethylpiperazine
(1,4-DMP), gave -lactams (2) in good yields (Scheme 1). 1-3 These reactions might involve a single
electron transfer reaction of 1,4-dimethylpiperazine to 1. Compounds (1) gave dichloro-substituted
carbamoylmethyl radicals after removal of a mono-chlorine atom. Cyclization of these radicals to an
olefinic bond and successive addition reaction of a H-atom at the resulting terminal radical intermediates
gave -lactams (2). Our attention was next turned to the application of this method to synthesis of
(–)-kainic acid (3).4,5 We report herein that water contaminating 1,4-dimethylpiperazine plays an
important role in effecting a radical cyclization.
R2
Cl
R2
N
N
CO2H
Cl
Cl
HO2C
HN
Cl
Cl
N
R1
N
R1
O
O
1
2
3
Scheme 1
________________________________
This paper is dedicated to Prof. Emeritus Akira Suzuki (Hokkaido University) on the occasion of his 80th
birthday.

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HETEROCYCLES, Vol. 80, No. 1, 2010
We initiated our investigation by examining the cyclization of compound (8) giving (+)-kainic acid in
boiling 1,4-dimethylpiperazine in place of that giving the desired (–)-kainic acid. Synthesis of radical
precursor (8) was begun by conversion of L-serine (4) into (–)-Garner’s aldehyde (5).6
Horner-Wadsworth-Emmons reaction of compound (5) gave the known E-ester (6).7 After transformation
of compound (6) into 7, the hydroxy group of compound (7) was protected with a tert-butyldiphenylsilyl
(TBDPS) group and the nitrogen atom was trichloroacetylated to give radical precursor (8) (Scheme 2).
O
H
N
H
N
CHO
Boc
CO2Et
(EtO)2PCH2CO2Et
iPr2NEt, LiCl
H
CO2H
O
O
HO
ref. 6
MeCN, 0 °C
ref. 7
Boc
NH2
L-serine (4)
(-)-Garner's aldehyde (5)
6
CO2Et
1) AcCl, EtOH, 0 °C
2) PhCHO, Et3N, MgSO4
CH2Cl2, rt
1) TBDPSCl, Et3N
DMAP, DMF, rt
93%
H
H
CO2Et
TBDPSO
Cl
Cl
HO
BnN
3) NaBH4, MeOH, 0 °C
85% for 3 steps
2) Cl3CCOCl, Et3N
CH2Cl2, 0 °C
94%
NHBn
Cl
O
7
8
Scheme 2
When compound (8) was heated in 1,4-dimethylpiperazine (1,4-DMP), which is commercially available
and was used without further purification, the expected radical cyclization product (9) (stereoisomers’
ratio = 9:1) was obtained in 28-38% yield together with tert-butyldiphenylsilanol (10)８ after 10 min of
heating (Scheme 3).
CO2Et
CO2Et
Cl
N
N
H
TBDPSO
TBDPSO
Bn
Cl
Cl
(not distilled)
N
Cl
+
TBDPS OH
N
Bn
Cl
133 °C, 10 min
O
O
8
10
9 (28-37%)
dr 9:1
Scheme 3
The stereochemistry between C4 and C5 of the major isomer of compound (9) was probably
trans-configuration.９ We next carried out a similar reaction in pure 1,4-DMP, since reproducibility was

HETEROCYCLES, Vol. 80, No. 1, 2010
659
not observed, and the yield of product (9) was relatively low. However, the yield of 9 from compound (8)
in distilled (pure) 1,4-DMP was found to be lower (7%) than that using non-distilled
1,4-dimethylpiperazine (Table 1, Entry 1). In this case, silanol (10) was obtained as a major product in
67% yield.
We soon found that the yield of compound (9) was improved to 57% by addition of 5 equiv of water to
distilled 1,4-DMP (Table 1, Entry 2). The addition of 0.2 equiv of water gave a similar result (56% yield
of 9) (Table 1, Entry 3). However, when 100 equiv of water was added to 1,4-DMP, compound (9) was
obtained in only 19% yield with an increase in the yield of silanol (10) (80%) (Table 1, Entry 4).
Therefore, an appropriate quantity of water was found to play an important role in effecting a single
electron transfer reaction (radical cyclization).
Table 1. Effect of water in amine-mediated radical cyclization of 8
N
N
CO2Et
CO2Et
Cl
H
N
(distilled from CaH)
H2O
TBDPSO
TBDPSO
Bn
Cl
Cl
N
Cl
TBDPS OH
Bn
Cl
133 °C, 10 min
O
O
8
9
10
Yield (%)
10
Entry
H2O (equiv)
9
1
2
3
4
none
5
7
67
11
11
80
57
56
19
0.2
100
It was thought that the formation of silanol (10) might involve elimination of 8 to give diene (11), which
CO2Et
CO2Et
in the absence of
H2O
H
Cl
Cl
TBDPSO
Bn
Cl
Cl
decomposed
N
N
Bn
Cl
Cl
O
O
8
11
10
in the presence of H2O
9
Figure 1

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was decomposed under the present reaction conditions (Figure 1). The presence of a small quantity of
water might accelerate the radical cyclization to give compound (9) in good yield. The exact reason,
however, is not clear at the moment.
We found that water contaminating 1,4-dimethylpiperazine played an important role in effecting a single
electron transfer reaction (radical cyclization).
EXPERIMENTAL
Ethyl (ER)-4-(N-benzylamino)-5-hydroxy-2-pentenoate (7) Acetyl chloride (2.30 g, 29.4 mmol) was
added dropwise to EtOH (20 mL) at 0 °C over 5 min, and the mixture was stirred at the same temperature
for 10 min. To the resultant solution was added dropwise a solution of 6 (4.40 g, 14.7 mmol) in EtOH (10
mL) at 0 °C over 5 min. After the mixture was stirred at room temperature for 20 h, the solution was
concentrated to give brown oil. To a solution of the reside in CH2Cl2 (70 mL) were added successively
Et3N (1.50 g, 14.7 mmol), MgSO4 (4.40 g, 36.7 mmol) and benzaldehyde (2.30 g, 22.0 mmol) at 0 °C and
the mixture was stirred at room temperature for 3 h. The reaction mixture was filtered through Celite® and
the filtrate was concentrated. The residual yellow oil was diluted with MeOH (50 mL) and to the resultant
solution was added NaBH4 (4.50 g, 36.7 mmol) in portion at 0 °C. The reaction was quenched by addition
of water and the reaction mixture was extracted with AcOEt. The organic phase was washed with brine,
dried (Na2SO4), and concentrated. The residue was chromatographed on silica gel (hexane/AcOEt, 3:1 to
1:1 to 1:2) to give 7 (3.10 g, 85%) as an yellow oil: []2D4 -63.8 (c 2.4, CHCl3); IR (CHCl3)  1715 cm-1; 1H
NMR (270 MHz, CDCl3) 1.30 (3H, t, J = 7.1 Hz), 2.39 (2H, br s), 3.33-3.41 (1H, m), 3.44 (1H, dd, J =
10.1, 7.4 Hz), 3.64 (1H, dd, J = 10.1, 3.6 Hz), 3.64 (1H, d, J = 13.0 Hz), 3.84 (1H, d, J = 13.0 Hz), 4.20 (2H,
13
q, J = 7.1 Hz), 6.00 (1H, dd, J = 15.8, 0.8 Hz), 6.79 (1H, dd, J = 15.8, 7.3 Hz), 7.25-7.35 (5H, m); C
NMR (67.8 MHz, CDCl3)  14.1, 51.0, 60.1, 60.5, 63.8, 123.4, 127.2, 128.1, 128.4, 139.4, 146.5, 166.0;
HRMS calcd for C14H19NO3: 249.1365. Found: 249.1363.
Ethyl (E,R)-4-(N-benzyl-N-trichloroacetylamino)-5-(t-butyldiphenylsilyloxy)-2-pentenoate (8) To a
solution of 7 (500 mg, 2.01 mmol) in DMF (2 mL) were added Et3N (507 mg, 5.02 mmol), DMAP (25.0
mg, 0.201 mmol) and TBDPSCl (1.10 g, 4.01 mmol) and the mixture was stirred at room temperature for
2 h. The resultant suspension was diluted with a saturated aqueous solution of NaHCO3 and the mixture
was extracted with Et2O. The organic phase was washed with brine, dried (Na2SO4), and concentrated.
The residue was chromatographed on silica gel (hexane/AcOEt, 1:0 to 40:1 to 20:1 to 8:1) to give ethyl
(R)-4-(N-benzylamino)-5-(t-butyldiphenylsilyloxy)-2-pentenoate (910 mg, 93%) as a colorless oil: []2D5
-32.4 (c 1.5, CHCl3); IR (CHCl3)  1715 cm-1; 1H NMR (270 MHz, CDCl3)  1.04 (9H, s), 1.28 (3H, t, J =
7.1 Hz), 2.10 (1H, s), 3.36-3.43 (1H, m), 3.60 (1H, dd, J = 10.1, 3.1 Hz), 3.63 (1H, d, J = 13.5 Hz), 3.68

HETEROCYCLES, Vol. 80, No. 1, 2010
661
(1H, dd, J = 10.1, 4.8 Hz), 3.85 (1H, d, J = 13.5 Hz), 4.18 (2H, q, J = 7.1 Hz), 5.99 (1H, dd, J = 15.8, 1.0
Hz), 6.78 (1H, dd, J = 15.8, 7.4 Hz), 7.23-7.45 (11H, m), 7.58-7.62 (4H, m); 13C NMR (67.8 MHz, CDCl3)
14.2, 19.2, 26.8, 51.2, 60.1, 60.3, 65.8, 123.3, 126.9, 127.7, 128.0, 128.4, 129.8, 132.9, 133.0, 135.50,
135.51, 140.1, 147.4, 166.2; HRMS calcd for C30H37NO3Si: 487.2543. Found: 487.2545.
To a solution of thus obtained amine (910 mg, 1.87 mmol) in CH2Cl2 (20 mL) were added Et3N (378 mg,
3.73 mmol) and trichloroacetyl chloride (441 mg, 2.43 mmol) at 0 °C and the mixture was stirred at room
temperature for 30min. The reaction was quenched with a saturated aqueous solution of NaHCO3 and the
reaction mixture was extracted with CH2Cl2. The organic phase was dried (Na2SO4) and concentrated.
The residue was chromatographed on silica gel (hexane/AcOEt, 20:1) to give 8 (1.11 g, 94%) as a
1
13
colorless oil: []2D5 -38.8 (c 0.45, CHCl3); IR (CHCl3)  1680, 1715 cm-1; H and C NMR spectra of 8
1
showed it to contain two rotamers. H NMR (270 MHz, CDCl3)  1.01 (s), 1.06 (total 9H, both s),
1.20-1.35 (3H, m), 3.75-3.85, 4.00-4.40 (total 5H, both m), 4.88 (br d, J = 16.0 Hz), 5.38 (d, J = 16.2 Hz),
5.52 (d, J = 16.2 Hz), 6.03 (br d, J = 15.5 Hz), 6.95 (br dd, J = 16.0, 6.3 Hz), 7.07-7.60 (15H, m); HRMS
calcd for C32H3635Cl3NO4Si: 631.1480. Found: 631.1481.
(4S,5R)-1-Benzyl-5-(t-butyldiphenylsilyloxymethyl)-3,3-dichloro-4-(ethoxycarbonylmethyl)pyrroli
din-2-one (9) A mixture of 8 (30.0 mg, 0.0474 mmol), 1,4-dimethylpiperazine (541 mg, 4.74 mmol) and
H2O (4.30 mg, 0.237 mmol) was heated at reflux for 10 min. After cooling, the reaction mixture was
diluted with a saturated aqueous solution of NH4Cl and the mixture was extracted with CH2Cl2. The
organic phase was dried (Na2SO4) and concentrated. The residue was purified by preparative thin layer
chromatography (hexane/AcOEt, 3:1) to give 9 (16.2 mg, 57%) as a colorless oil: IR (CHCl3)  1725,
1730 cm-1; 1H NMR (500 MHz, CDCl3, for a major isomer)  1.09 (9H, s), 1.26 (3H, t, J = 7.1 Hz), 2.45
(1H, dd, J = 15.9, 6.1 Hz), 2.89 (1H, dd, J = 15.9, 6.8 Hz), 3.08 (1H, dt, J = 8.1, 2.4 Hz), 3.57-3.64 (3H, m),
3.73 (1H, dd, J = 12.0, 2.4 Hz), 4.14-4.22 (2H, m), 5.10 (1H, d, J = 15.1 Hz), 6.81-6.83 (2H, m), 7.19-7.21
(3H, m), 7.38-7.42 (2H, m), 7.44-7.47 (3H, m), 7.50-7.53 (1H, m), 7.61-7.63 (2H, m), 7.68-7.69 (2H, m);
13C NMR (125 MHz, CDCl3, for a major isomer)  14.0, 19.1, 26.7, 32.7, 44.3, 46.7, 58.2, 59.8, 61.1, 85.6,
127.6, 127.7, 127.8, 128.0, 128.7, 130.0, 130.2, 132.3, 132.3, 134.6, 135.6, 135.8, 167.0, 170.3; HRMS
calcd for C32H3735Cl2NO4Si: 597.1869. Found: 597.1860, calcd for C32H3737Cl2NO4Si: 601.1810. Found:
601.1812.
ACKNOWLEDGEMENT
This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology of Japan.
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