A new efficient synthetic strategy for N-(dialkylamino)azacycle as a tetrasubstituted hydrazine derivative using sodium triacyloxyborohydride

Article abstract of DOI:10.1016/j.tet.2008.04.114

A new efficient and convergent method has been developed to construct a N-(dialkylamino)azacyclic system as a tetrasubstituted hydrazine via reductive alkylation of the corresponding hydrazone using sodium triacyloxyborohydride [NaBH(OCOR)₃], which is tolerant of various substituents (e.g., phenol, conjugated olefin, amide, and thioamide) on the substrate and useful for organization of the N-aminoazacycle array.

Full text of DOI:10.1016/j.tet.2008.04.114

Tetrahedron 64 (2008) 6275–6280
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A new efficient synthetic strategy for N-(dialkylamino)azacycle as a
tetrasubstituted hydrazine derivative using sodium triacyloxyborohydride
*
Hideya Mizufune , Hiroaki Yamamoto, Minoru Nakamura, Shokyo Miki
Chemical Development Laboratories, Pharmaceutical Production Division, Takeda Pharmaceutical Company Limited, 2-17-85 Jusohonmachi,
Yodogawaku, Osaka 532-8686, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A new efficient and convergent method has been developed to construct a N-(dialkylamino)azacyclic
system as a tetrasubstituted hydrazine via reductive alkylation of the corresponding hydrazone using
sodium triacyloxyborohydride [NaBH(OCOR)3], which is tolerant of various substituents (e.g., phenol,
conjugated olefin, amide, and thioamide) on the substrate and useful for organization of the N-amino-
azacycle array.
Received 4 March 2008
Received in revised form 27 April 2008
Accepted 28 April 2008
Available online 1 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Sodium triacyloxyborohydride
Hydrazine
1. Introduction
(acylamino)azacycle, or alkylation of a protected N-aminoazacycle.7
Thus, the conventional methods require step-by-step alkylation
N-(Dialkylamino)azacycle is a tetrasubstituted hydrazine de-
rivative bearing a dialkylamino moiety at the nitrogen atom of al-
iphatic cyclic amine, and has often been installed to various
bioactive substances. For example, in a new drug discovery pro-
gram based on natural products, podophyllotoxin analogue 11
having N-aminopiperazine moiety has been studied as an antitu-
mor agent with DNA topoisomeraze II inhibition; and 9-azamor-
phinan 22 has been identified as an analgesic with antagonist effect
of morphine analgesia. In order to identify other new drug candi-
dates, a series of N-aminopiperazine derivatives 33 have been in-
vestigated as new compounds to treat multi-drug-resistant
tuberculosis; and naphthalene derivative 44 with N-amino-
morpholine has been studied as an oral-administrative antifungal
agent. In addition, although the N-amino moiety was not
substituted, the N-aminorhodanine system has been found as
a framework of sialyl Lewis X (sLex) biosynthesis inhibitor 5a5 as
well as other rhodanine derivatives, such as compound 5b. There-
fore, an extension of the N-aminorhodanine library by alkylation of
the amino moiety could be interesting to explore a new drug can-
didate (Fig. 1).
reactions from non-substituted N-aminoazacycle to avoid the for-
mation of a symmetrical N-dialkyl compound. Therefore, in order to
carry out effectively both medicinal and process research programs
on a new drug candidate bearing N-(dialkylamino)azacycle, an ef-
ficient and convergent method to construct the ring system as
a tetrasubstituted hydrazine system has been demanded.
On the other hand, G. W. Gribble and co-workers have explored
an unique alkylation method8a–d of amine or imine derivatives
using sodium triacyloxyborohydride [NaBH(OCOR)3] since their
first report8e on the reductive ethylation of indole with NaBH4 and
acetic acid in 1974. Although his and other groups have contributed
to expansion of the chemistry, the reductive alkylation of hydrazine
moiety has received less attention. To our knowledge, there is only
one report9 regarding alkylation of the protected phenylhydrazine
derivative. Herein, we report a new efficient and convergent
strategy for preparation of the N-(dialkylamino)azacyclic system, as
a tetrasubstituted hydrazine, utilizing NaBH(OCOR)3 alkylation.
According to our new synthetic strategy, shown in Scheme 1, the
target compound (A) would be prepared by NaBH(OCOR)3 alkyl-
ation of hydrazone derivative (B), which would be easily converted
from N-aminoazacycle (C) and carbonyl compounds (D).
Such a N-(dialkylamino)azacyclic system has been prepared via
alkylation1–4 of a N-(monoalkylamino)azacycle as a trisubstituted
hydrazine compound, derived by reduction2,4 of the correspond-
ing hydrazone, reduction6 of the amido moiety in N-
2. Results and discussion
First, reductive ethylation of hydrazone derivatives 7a–e, easily
prepared from various N-aminoazacycles 6a–e and piperonal, was
investigated by employing commercially available NaBH(OAc)3 in
acetic acid at room temperature (Scheme 2, Table 1, entries 1–5).
* Corresponding author.
E-mail address: mizufune_hideya@takeda.co.jp (H. Mizufune).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.114

6276
H. Mizufune et al. / Tetrahedron 64 (2008) 6275–6280
Me
N
N
NMe
2HCl
O
O
O
N
O2N
Me
N
O
N
N
N
Me
O
N
N
O
R
HO
OMe
MeO
2
3
R = Cl, OCF3, CF3
OH
1
Cl
Me
S
N
S
5a
O
R = NH2
=
O
N
N
R
N
O
5b
4
Me
O
Figure 1.
R2
R1
R2
NaBH(OCOR1)3
N
N
R2CHO
+
H2N
N
N
N
(A)
(D)
(B)
(C)
Scheme 1.
1). NaBH4/R1COOH
or NaBH(OAc)3
2). HCl/AcOEt
CHO
O
Qn
O
N
CH2
N
Qn
O
O
N
N
n
H2N
N
Q
R1
O
O
HCl
EtOH
7a-e
6a-e
R1= Me, n = 0, Q = CH2 : 8a
R
R
1 = Me, n = 1, Q = CH2 : 8b
1 = Me, n = 1, Q = O : 8c
R1 = Me, n = 1, Q = NMe : 8d
R1 = Me, n = 2, Q = CH2
:
8e
8f
1 = CH2OMe, n = 2, Q = CH2 : 8g
R
R
1 = H , n =2, Q = CH2
:
Scheme 2.
Table 1
Syntheses of various N-(dialkylamino)azacycles 8a–g by sodium triacyloxyborohydride
Entry
N-Aminoazacycle
Product
Yield (%)
NaBH4/R4COOH or NaBH(OCOR4)3
Product
Yield (%)
1
2
3
4
5
6
7
N-Aminopyrrolidine (6a)
N-Aminopiperidine (6b)
N-Aminomorpholine (6c)
N-Amino-N0-methylpiperazine (6d)
N-Aminohomopiperidine (6e)
7a
7b
7c
7d
7e
78
72
74
80
79
NaBH(OAc)3
NaBH(OAc)3
NaBH(OAc)3
NaBH(OAc)3
NaBH(OAc)3
NaBH4/HCOOH
NaBH4/MeOCH2COOH
8a
8b
8c
8d
8e
8f
77
91
80
67
84
82
78
8g
Five- to seven-membered aliphatic cyclic amine derivatives 8a–e,
including bisheteroatom-containing types such as morpholine and
piperazine, were conveniently obtained as N-ethylated derivatives
of crystalline hydrochloride in good yield. The other reductive al-
kylations of hydrazone 6e were then studied using NaBH(OCOR)3,
generated in-situ from NaBH4 and appropriate carboxylic acid
(Table 1, entries 6 and 7). Dropwise-addition of formic acid to
a suspension of NaBH4 and 6e in toluene at 0–25 ꢀC gave N-
methylated hydrazine derivative 8f. In the same manner, use of
methoxyacetic acid introduced the methoxyethyl moiety into N-
(dialkylamino)homopiperidine 8g.
Next, our interest focused on the compatibility of various
substituents on hydrazones with reductive alkylation methodol-
ogy (Schemes 3 and 4, Table 2). N-(Dialkylamino)homopiperidine
8h bearing a phenol moiety was furnished from the corresponding
hydrazone derivative 7h by reductive ethylation using NaBH(OAc)3
in acetic acid, the transformation of which was superior to SN2-
type alkylation due to no protective group for the phenol moiety
(Table 2, entry 1). The reductive alkylation of
a,b-unsaturated
hydrazone derivative 7i, derived from N-aminohomopiperidine 6e
and trans-cinnamaldehyde, afforded N-cinnamyl hydrazine de-
rivative 8i chemoselectively (Table 2, entry 2). Although it is

H. Mizufune et al. / Tetrahedron 64 (2008) 6275–6280
6277
OH
OH
HCl
MeO
1). NaBH(OAc)3/AcOH
MeO
2). HCl/AcOEt
N
N
N
N
Et
8h
7h
HCl
1). NaBH(OAc)3/AcOH
2). HCl/AcOEt
N
N
N
N
8i
7i
Et
Scheme 3.
MeO
MeO
CHO
S
OMe
S
H2N
N
9j
AcONa/EtOH
OMe
O
78%
S
S
N
Et
N
S
R2
R3
S
R2
S
N
R2
R3
NaBH(OAc)3
AcOH
N
N
O
S
m
m
m
H2N
R3
O
O
EtOH, r.t.
O
R2 = R3 = OMe, m = 0 : 7j
R2 = R3 = H, m = 1 : 7k
R2 = R3 = OMe, m = 0 : 8j
R2 = R3 = H, m = 1 : 8k
6j
Cl
S
CHO
O
S
O
Cl
N
N
Et
AcONa/EtOH
78%
10k
O
Scheme 4.
Table 2
Syntheses of various N-(dialkylamino)azacycles 8h–k by sodium triacyloxyborohydride
Entry
N-Aminoazacycle
Aldehyde
Product
Yield (%)
NaBH4/R4COOH or NaBH(OCOR4)3
Product
Yield (%)
1
2
3
4
6e
6e
o-Vaniline
7h
7i
7j
77
d
NaBH(OAc)3
NaBH(OAc)3
NaBH(OAc)3
NaBH(OAc)3
8h
8i
8j
67a
65b
64c
72c
Cinnamaldehyde
Veratraldehyde
Cinnamaldehyde
N-Aminorhodanine (6j)
6j
92
94
7k
8k
a
Isolated yield as a hydrochloride salt.
Isolated yield as a hydrochloride salt based on N-aminohomopiperidine (without isolation of 7i).
Isolated yield as a free base.
b
c
reported4 that alkylation of trisubstituted hydrazine with cin-
3. Conclusion
namyl chloride gave a mixture of the target N-cinnamyl de-
rivatives
and
N-(3-phenylpropynilidene-1-yl)-substituted
In conclusion, we have developed a new efficient and conver-
gent method for the preparation of a N-(dialkylamino)azacyclic
system via reductive alkylation of N-(alkylideneamino)azacyclic
derivative using sodium triacyloxyborohydride [NaBH(OCOR)3],
which is tolerant of various substituents (e.g., phenol, conjugated
olefine, amide, and thioamide). Furthermore, the method will
contribute to establish a N-(dialkylamino)azacyclic library with
high molecular diversity.
compound, migration of the olefin bond was not observed in our
process for 8i.
Furthermore, our methodology has contributed to the orga-
nization of highly molecular diversity of the N-aminorhodanine
scaffold (Scheme 4, Table 2). Namely, although condensation of
N-aminorhodanine 6j and an aldehyde in the presence of a base
or by heating under reflux gave C5-alkylidene product 9j, the
condensation reaction without a base at room temperature se-
lectively afforded N-alkylidene product10 7j and 7k. The reductive
alkylation of 7j and 7k using NaBH(OAc)3 provided N-(di-
alkylamino)rhodanine 8i and 8k (Table 2, entries 3 and 4),
without reduction of their carbonyl and thiocarbonyl moiety. The
Knoevenagel reaction of 8k and 2-furaldehyde derivative afforded
N-(dialkylamino)rhodanine 10k, further functionalized at its 5-
positon.
4. Experimental
4.1. General remarks
Melting points were recorded on Buchi B-540 micromelting
apparatus and are uncorrected. IR spectra were recorded on a Shi-
madzu IR Prestige-21 spectrophotometer. 1H NMR spectra were

6278
H. Mizufune et al. / Tetrahedron 64 (2008) 6275–6280
recorded on a Bruker DPX-300 spectrometer. Elemental analyses
and mass spectra were analyzed by Takeda Analytical Research Ltd.
HPLC conditions: Inertsil ODS-2 column (150 mmꢁ4.6 mm I.D.)
with 0.05 M KH2PO4 in water and acetonitrile (50:50) at 25 ꢀC.
Detection was effected with a Hitachi spectrophotometric detector
at 254 nm.
108–110 ꢀC; 1H NMR (CDCl3, TMS, 300 MHz)
d (ppm): 2.44 (3H, s),
2.70 (4H, t, J¼5.0 Hz), 3.27 (4H, t, J¼5.2 Hz), 6.00 (2H, s), 6.86 (1H, d,
J¼8.0 Hz), 7.04 (1H, dd, J¼8.0 and 1.5 Hz), 7.34 (1H, d, J¼1.5 Hz), 7.57
(1H, s); 13C NMR (DMSO-d6, TMS, 75.5 MHz)
d (ppm): 46.41, 51.67,
54.87, 101.93, 105.26, 109.10, 121.85, 131.89, 136.06, 148.09, 148.57;
MS (EI, m/z): (Mþ) 247. Elemental analysis: calcd for C13H17N3O2, C:
63.14, H: 6.93, N: 16.99; found, C: 63.05, H: 6.89, N: 17.07.
4.2. General procedure for the synthesis of N-
(alkylindeneamino)azacycle, represented by N-(1,3-
benzodioxol-5-ylmethylene)azepan-1-amine (7e) (method A)
4.2.5. 2-(Azepan-1-ylimino)methyl-6-methoxyphenol (7h)
Following method A, compound 6h (687 mg, 6.02 mmol) was
treated with piperonal (904 mg, 6.02 mmol) to give the title com-
pound (1.15 g, yield 77%) as a colorless crystalline powder: mp 78–
A mixture of 1-aminohomopiperidine (6e) (1.78 g, 15.6 mmol),
piperonal (2.34 g, 15.6 mmol), and ethanol (23 ml) was stirred un-
der reflux for 7.5 h. After cooling to room temperature and then ice-
cold temperature, the resulting crystals were filtered and dried in
vacuo at 40 ꢀC to give the title compound (2.87 g). From the mother
liquor, the second crop (149 mg) was obtained as a colorless crys-
talline powder: total yield 79%, mp 79–80 ꢀC; 1H NMR (CDCl3, TMS,
79 ꢀC; 1H NMR (CDCl3, TMS, 300 MHz)
d
(ppm): 1.6–1.9 (8H, m),
3.58 (4H, t, J¼5.7 Hz), 3.99 (3H, s), 6.7–6.9 (3H, m), 7.31 (1H, s), 12.0
(1H, s); 13C NMR (DMSO-d6, TMS, 75.5 MHz)
(ppm): 27.44, 28.53,
d
53.58, 56.66, 111.74, 119.38,120.82, 122.11, 131.21, 146.10, 148.48; MS
(EI, m/z): (Mþ) 248. Elemental analysis: calcd for C14H18N2O2, C:
67.71, H: 8.12, N: 11.28; found, C: 67.67, H: 8.06, N: 11.29.
300 MHz)
s), 6.84 (1H, d, J¼8.0 and 1.5 Hz), 7.14 (1H, s), 7.28 (1H, d, J¼1.4 Hz);
13C NMR (DMSO-d6, TMS, 75.5 MHz)
(ppm): 27.91, 28.79, 53.83,
101.62, 104.50, 109.04, 119.98, 127.08, 133.51, 146.67, 148.47; MS (EI,
m/z): (Mþ) 246. Elemental analysis: calcd for C14H18N2O2; C: 68.27,
H: 7.37, N: 11.37; found, C: 68.38, H: 7.25, N: 11.44.
d
(ppm): 1.6–1.9 (8H, m), 3.59 (4H, t, J¼5.7 Hz), 6.02 (2H,
4.3. General procedure for the synthesis of N-(dialkylamino)-
azacycle, represented by N-(1,3-benzodioxol-5-ylmethyl)-N-
methylazepan-1-amine hydrochloride (8f) (method B)
d
To a stirred suspension of 7e (500 mg, 2.03 mmol), toluene (5 ml),
and NaBH4 (768 mg, 20.3 mmol) was added formic acid (3 ml)
dropwise at ice-cold temperature under N2 atmosphere. After stir-
ring at the same temperature for 1 h, the mixture was stirred at room
temperature for 2 days. After the addition of NaBH4 (386 mg,
10.2 mmol) and formic acid (2.5 ml), stirring was continued for more
than 1 day. To the reaction mixture were added 4 M NaOH (35 ml)
and water (20 ml), followed by extraction with ethyl acetate three
times. The combined organic layers were washed with water
(150 ml), dried over anhydrous MgSO4, and concentrated in vacuo.
To the residue were added ethyl acetate (7.5 ml) and 4 M HCl/ethyl
acetate (1.02 ml, 4.08 mmol). After the resulting slurry was stirred at
ice-cold temperature, the crystals were filtered, washed with cold
ethyl acetate, and dried in vacuo at room temperature to give the
title compound (496 mg, yield 82%) as a colorless crystal: mp 194 ꢀC
4.2.1. N-(1,3-Benzodioxol-5-ylmethylene)pyrrolidin-1-amine (7a)
Following method A, compound 6a (738 mg, 6.02 mmol) was
treated with piperonal (904 mg, 6.02 mmol) to give the title com-
pound (1.01 g, yield 78%) as a colorless crystalline powder: mp 101–
103 ꢀC; 1H NMR (CDCl3, TMS, 300 MHz)
d (ppm): 1.9–2.0 (4H, m),
3.33 (4H, t, J¼6.6 Hz), 5.96 (2H, s), 6.77 (1H, d, J¼8.0 Hz), 6.91 (1H,
dd, J¼8.0 and 1.5 Hz), 7.14 (1H, s), 7.20 (1H, d, J¼1.5 Hz); IR (ATR,
cmꢂ1): 1604, 1560, 1498, 1382, 1338, 1253, 1036; MS (EI, m/z): (Mþ)
218. Elemental analysis: calcd for C12H14N2O2, C: 66.04, H: 6.47, N:
12.84; found, C: 66.10, H: 6.46, N: 12.90.
4.2.2. N-(1,3-Benzodioxol-5-ylmethylene)piperidin-1-amine (7b)
Following method A, compound 6b (615 mg, 6.02 mmol) was
treated with piperonal (904 mg, 6.02 mmol) to give the title com-
pound (1.04 g, yield 74%) as a colorless crystalline powder: mp 64–
(decomposed); 1H NMR (CDCl3, TMS, 300 MHz)
d (ppm): 1.6–1.9 (6H,
m), 2.3–2.4 (2H, br), 2.56 (3H, s), 3.2–3.3 (2H, m), 3.7–3.9 (2H, m),
4.14 (2H, s), 5.95 (2H, s), 6.7–6.9 (3H, m), 13.6 (1H, br); 13C NMR
65 ꢀC; 1H NMR (CDCl3, TMS, 300 MHz)
d (ppm): 1.5–1.8 (6H, m),
(DMSO-d6, TMS, 75.5 MHz) d (ppm): 22.78, 26.10, 35.50, 51.61, 56.10,
3.14 (4H, t, J¼5.6 Hz), 5.97 (2H, s), 6.79 (1H, d, J¼8.0 Hz), 6.95 (1H,
101.19, 108.19, 109.42, 122.56, 129.56, 147.01, 147.52; MS (EI, m/z):
(Mþ) 262. Elemental analysis: calcd for C16H25N2O2Cl; C: 60.29, H:
7.76, N: 9.38; found, C: 60.19, H: 7.82, N: 9.36.
dd, J¼8.0 and 1.6 Hz), 7.27 (1H, d, J¼1.5 Hz), 7.50 (1H, s); 13C NMR
(DMSO-d6, TMS, 75.5 MHz)
d (ppm): 24.57, 25.55, 52.59, 101.87,
105.18, 109.07, 121.58, 132.26, 134.83, 147.87, 148.55; MS (EI, m/z):
(Mþ) 232. Elemental analysis: calcd for C13H16N2O2, C: 67.22, H:
6.94, N: 12.06; found, C: 67.26, H: 6.89, N: 12.10.
4.3.1. N-(1,3-Benzodioxol-5-ylmethyl)-N-(2-methoxyethyl)azepan-
1-amine hydrochloride (8g)
Following method B, compound 7e (500 mg, 2.03 mmol) was
treated with NaBH4 (768 mg, 20.3 mmol) and methoxyacetic acid
(5 ml) at room temperature for 4 days to give the title compound
(541 mg, yield 78%) as a colorless crystalline powder: mp 148–
4.2.3. N-(1,3-Benzodioxol-5-ylmethylene)morpholin-4-amine (7c)
Following method A, compound 6c (603 mg, 6.02 mmol) was
treated with piperonal (904 mg, 6.02 mmol) to give the title com-
pound (1.01 g, yield 72%) as a colorless crystalline powder: mp 76–
149 ꢀC; 1H NMR (CDCl3, TMS, 300 MHz)
d (ppm): 1.6–2.1 (6H, m),
78 ꢀC; 1H NMR (CDCl3, TMS, 300 MHz)
d (ppm): 3.15 (4H, t,
2.3–2.4 (2H, br), 3.0–3.4 (9H, m), 3.6–3.9 (2H, m), 4.29 (2H, s), 5.95
J¼4.8 Hz), 3.90 (4H, t, J¼4.8 Hz), 5.98 (2H, s), 6.80 (1H, d, J¼8.0 Hz),
(2H, s), 6.7–6.9 (3H, m), 13.3 (1H, br); 13C NMR (DMSO-d6, TMS,
6.97 (1H, dd, J¼8.0 and 1.6 Hz), 7.27 (1H, d, J¼1.5 Hz), 7.50 (1H, s);
75.5 MHz)
d (ppm): 23.74, 26.53, 51.64, 53.99, 56.50, 58.89, 70.76,
13C NMR (DMSO-d6, TMS, 75.5 MHz)
d (ppm): 52.63, 66.55, 101.99,
101.92, 108.88, 110.14, 123.00, 131.26, 147.69, 148.19; MS (EI, m/z):
(Mþ) 306. Elemental analysis: calcd for C16H25N2O2Cl, C: 59.55, H:
7.94, N: 8.17; found, C: 59.33, H: 7.81, N: 8.04.
105.35, 109.13, 122.07, 131.63, 136.60, 148.27, 148.61; MS (EI, m/z):
(Mþ) 234. Elemental analysis: calcd for C12H14N2O3, C: 61.53, H:
6.02, N: 11.96; found, C: 61.38, H: 5.94, N: 12.01.
4.4. General procedure for the synthesis of N-(dialkylamino)-
azacycle, represented by N-(1,3-benzodioxol-5-ylmethyl)-N-
ethylazepan-1-amine hydrochloride (8e) (method C)
4.2.4. N-(1,3-Benzodioxol-5-ylmethylene)-4-methylpiperazin-1-
amine (7d)
Following method A, compound 6d (693 mg, 6.02 mmol) was
treated with piperonal (904 mg, 6.02 mmol) to give the title
compound (1.19 g, yield 74%) as a colorless crystalline powder: mp
To a stirred suspension of 7e (500 mg, 2.03 mmol) and AcOH
(10 ml) was added sodium triacetoxyborohydride (4.30 g,

H. Mizufune et al. / Tetrahedron 64 (2008) 6275–6280
6279
20.3 mmol) at room temperature under N2 atmosphere. After stir-
ring at the same temperature for 34 h, water (20 ml) and 4 M NaOH
(75 ml) were added to the reaction mixture and extracted with
ethyl acetate (3ꢁ50 ml). The combined organic layers were washed
with water (100 ml), dried over anhydrous MgSO4, and concen-
trated in vacuo to give a free base as yellow oil. 1H NMR (CDCl3,
temperature for 24 h to give the title compound (435 mg, yield 67%)
as a colorless crystalline powder: mp 157 ꢀC (decomposed); 1H
NMR (CDCl3, TMS, 300 MHz) d (ppm): 1.24 (3H, br), 2.7–3.0 (7H, m),
3.1–3.7 (6H, m), 3.92 (2H, br), 5.97 (2H, s), 6.7–7.1 (3H, m), 13.0 (1H,
br); IR (ATR, cmꢂ1): 1502, 1444,1259, 1236, 1035; MS (EI, m/z): (Mþ)
277. Elemental analysis: calcd for C15H24N3O2Cl$2.5H2O, C: 50.20,
H: 8.15, N: 11.71; found, C: 50.49, H: 8.09, N: 11.68.
TMS, 300 MHz)
(2H, t, J¼7.0 Hz), 2.81 (4H, t, J¼5.9 Hz), 3.52 (2H, s), 5.9 (2H, s), 6.6–
6.8 (2H, m), 6.89 (1H, m); 13C NMR (CDCl3, TMS, 75.5 MHz)
(ppm):
d
(ppm): 1.03 (3H, t, J¼7.0 Hz), 1.5–1.6 (8H, m), 2.41
d
4.4.5. 2-{[Azepan-1-yl(ethyl)amino]methyl}-6-methoxyphenol
hydrochloride (8h)
Following method C, compound 7h (500 mg, 2.01 mmol) was
treated with sodium triacetoxyborohydride and acetic acid at room
temperature for 32 h to give the title compound (420 mg, yield
67%) as a colorless crystalline powder: mp 131 ꢀC (decomposed); 1H
13.97, 27.31, 29.01, 45.50, 51.60, 54.36, 101.05, 107.94, 109.56, 121.84,
135.11, 146.43, 147.75. To the residual free base were added ethyl
acetate (3 ml) and 4 M HCl/ethyl acetate (1.02 ml, 4.08 mmol). After
the resulting slurry was stirred at ice-cold temperature, the crystals
were filtered, washed with cold ethyl acetate, and dried in vacuo at
room temperature to give the title compound (534 mg, yield 84%)
as a colorless crystalline powder: mp 198 ꢀC (decomposed); 1H
NMR (CDCl3, TMS, 300 MHz) d (ppm): 0.6–2.1 (9H, br), 3.0–3.6 (6H,
br), 3.89 (3H, s), 4.3 (2H, br), 6.0–7.8 (4H, br), 12.9 (1H, br); IR (ATR,
cmꢂ1): 1496, 1448, 1244, 1203, 1070; MS (EI, m/z): (Mþ) 258. Ele-
mental analysis: calcd for C16H27N2O2Cl, C: 61.04, H: 8.64, N: 8.90;
found, C: 60.72, H: 8.30, N: 8.79.
NMR (CDCl3, TMS, 300 MHz)
d
(ppm): 0.99 (3H, t, J¼6.3 Hz), 1.4–1.9
(7H, m), 2.2–2.4 (1H, br), 2.9–3.4 (5H, m), 3.7–3.9 (1H, br), 4.1–4.3
(2H, m), 5.95 (2H, s), 6.7–7.0 (2H, m), 7.1–7.4 (1H, m), 13.3 (1H, br);
IR (ATR, cmꢂ1): 1490, 1444, 1382, 1255, 1242, 1041; MS (EI, m/z):
(Mþ) 276. Elemental analysis: calcd for C16H25N2O2Cl, C: 61.43, H:
8.05, N: 8.95; found, C: 61.15, H: 7.91, N: 8.74.
4.4.6. N-Ethyl-N-[(2E)-3-phenylprop-2-en-1-yl]piperidin-1-amine
hydrochloride (8i)
A mixture of 1-aminohomopiperidine (687 mg, 6.02 mmol),
trans-cinnamaldehyde (796 mg, 6.02 mmol), and ethanol (8 ml)
was stirred under reflux for 8 h. After cooling to room temperature,
the reaction mixture was concentrated in vacuo. The crude
hydrazone compound was treated with sodium triacetoxyborohy-
dride and acetic acid at room temperature for 3 days, following
method C, to give the title compound (1.16 g, yield 65% based on 1-
aminohomopiperadine) as a colorless crystalline powder: mp
4.4.1. N-(1,3-Benzodioxol-5-ylmethyl)-N-ethylpyrrolidin-1-amine
hydrochloride (8a)
Following method C, compound 7a (450 mg, 2.06 mmol) was
treated with sodium triacetoxyborohydride and acetic acid at room
temperature for 48 h, to give the title compound (453 mg, yield
77%) as a colorless crystalline powder: mp 160–161 ꢀC; 1H NMR
(CDCl3, TMS, 300 MHz)
d
(ppm): 1.13 (3H, t, J¼6.8 Hz), 1.8–2.2 (4H,
m), 3.10 (3H, t, J¼6.9 Hz), 3.0–3.5 (2H, br), 3.7–3.9 (1H, br), 4.1 (2H,
127 ꢀC (decomposed); 1H NMR (CDCl3, TMS, 300 MHz)
d (ppm):
br), 5.95 (2H, s), 6.7–7.0 (3H, m), 13.6 (1H, br); 13C NMR (DMSO-d6,
1.1–2.5 (11H, m), 3.0–3.5 (4H, m), 3.6–4.2 (2H, m), 6.1–6.8 (2H, m),
TMS, 75.5 MHz)
d
(ppm): 13.52, 23.59, 47.02, 51.69, 54.38, 101.94,
7.2–7.6 (5H, m), 13.1–13.6 (1H, br); 13C NMR (DMSO-d6, TMS,
109.01,109.85,122.83,131.32,147.61,148.26; MS (EI, m/z): (Mþ) 248.
Elemental analysis: calcd for C14H21N2O2Cl, C: 59.05, H: 7.43, N:
9.84; found, C: 59.03, H: 7.28, N: 9.79.
75.5 MHz) d (ppm): 26.37, 27.60, 47.53, 51.20, 53.60, 120.66, 127.42,
129.29, 129.67, 136.63, 137.68; MS (EI, m/z): (Mþ) 258. Elemental
analysis: calcd for C17H27N2Cl, C: 69.25, H: 9.23, N: 9.50; found, C:
69.06, H: 9.18, N: 9.42.
4.4.2. N-(1,3-Benzodioxol-5-ylmethyl)-N-ethylpiperidin-1-amine
hydrochloride (8b)
Following method C, compound 7b (500 mg, 2.15 mmol) was
treated with sodium triacetoxyborohydride and acetic acid at room
temperature for 33 h, to give the title compound (583 mg, yield 91%)
as a colorless crystalline powder: mp 200 ꢀC (decomposed); 1H NMR
4.4.7. 3-Amino-5-(3,4-dimethoxybenzylidene)-2-thioxo-1,3-
thiazolidin-4-one (9j)
A mixture of 6j (892 mg, 6.02 mmol), 3,4-dimethoxybenz-
aldehyde (1.00 g, 6.02 mmol), sodium acetate (19.7 mg,
0.24 mmol), and ethanol (23 ml) was stirred under reflux for 3 h.
After cooling to room temperature, the resulting crystals were fil-
tered, washed with ethanol and water, and then dried in vacuo at
room temperature to give the title compound (1.39 g, yield 78%) as
an orange crystalline powder: mp 175 ꢀC (decomposed); 1H NMR
(CDCl3, TMS, 300 MHz) (ppm): 3.86 (3H, s), 3.88 (3H, s), 5.98 (2H, s),
7.1–7.3 (3H, m), 7.83 (1H, s); 13C NMR (DMSO-d6, TMS, 75.5 MHz)
(CDCl3, TMS, 300 MHz) d (ppm): 1.0–2.1 (8H, br), 2.60 (1H, br), 2.8–3.2
(5H, br), 3.58 (1H, br), 4.18 (2H, br), 5.95 (2H, s), 6.79 (1H, d, J¼7.5 Hz),
6.7–7.4 (2H, m), 13.4 (1H, br); IR (ATR, cmꢂ1): 1490, 1448, 1255, 1041;
MS (EI, m/z): (Mþ) 262. Elemental analysis: calcd for C15H23N2O2Cl, C:
60.29, H: 7.76, N: 9.38; found, C: 60.20, H: 7.66, N: 9.35.
4.4.3. N-(1,3-Benzodioxol-5-ylmethyl)-N-ethylmorpholin-4-amine
hydrochloride (8c)
d (ppm): 56.50, 56.69, 113.16, 114.60, 117.87, 125.92, 126.60, 134.89,
150.00, 152.41, 164.60, 188.03; MS (EI, m/z): (Mþ) 296. Elemental
analysis: calcd for C12H12N2O3S2; C: 48.63, H: 4.08, N: 9.45; found,
C: 48.99, H: 4.05, N: 9.34.
Following method C, compound 7c (500 mg, 2.13 mmol) was
treated with sodium triacetoxyborohydride and acetic acid at room
temperature for 22 h, to give the title compound (583 mg, yield
80%) as a colorless crystalline powder: mp 165 ꢀC (decomposed);
4.4.8. 3-{[(3,4-Dimethoxyphenyl)methylene]amino}-2-thioxo-1,3-
thiazolidin-4-one (7j)
1H NMR (CDCl3, TMS, 300 MHz)
d (ppm): 1.48 (3H, br), 3.0–3.4 (2H,
br), 3.76 (4H, br), 4.1–4.4 (2H, br), 5.98 (2H, s), 6.79 (1H, d,
J¼8.0 Hz), 7.0–7.3 (2H, m), 13.7 (1H, br); IR (ATR, cmꢂ1): 1494, 1444,
1255, 1238, 1101, 1035; MS (EI, m/z): (Mþ) 264. Elemental analysis:
calcd for C16H27N2O2Cl; C: 55.91, H: 7.04, N: 9.31; found, C: 55.45, H:
7.04, N: 9.14.
A mixture of 6j (892 mg, 6.02 mmol), 3,4-dimethoxybenz-
aldehyde (1.00 g, 6.02 mmol), and ethanol (10 ml) was stirred at
room temperature for 5 h. The resulting crystals were filtered,
washed with ethanol and water, and dried in vacuo at room tem-
perature to give the title compound (1.07 g, yield 94%) as a yellow
crystalline powder: mp 152–154 ꢀC; 1H NMR (CDCl3, TMS,
4.4.4. N-(1,3-Benzodioxol-5-ylmethyl)-N-ethyl-4-methylpiperazin-
1-amine hydrochloride (8d)
Following method C, compound 7d (500 mg, 2.02 mmol) was
treated with sodium triacetoxyborohydride and acetic acid at room
300 MHz)
d
(ppm): 3.94 (6H, s), 4.06 (2H, s), 6.91 (1H, d, J¼8.3 Hz),
7.29 (1H, dd, J¼8.3 and 1.9 Hz), 7.57 (1H, d, J¼1.9 Hz); 13C NMR
(DMSO-d6, TMS, 75.5 MHz) d (ppm): 35.16, 56.07, 56.31, 109.89,
112.07, 124.87, 125.38, 149.66, 153.69, 170.29, 171.11, 197.26; MS (EI,

6280
H. Mizufune et al. / Tetrahedron 64 (2008) 6275–6280
m/z): (Mþ) 296. Elemental analysis: calcd for C12H12N2O3S2, C:
48.63, H: 4.08, N: 9.45; found, C: 48.76, H: 4.18, N: 9.49.
water (100 ml), dried over anhydrous MgSO4, and concentrated in
vacuo. The resulting residual solid was dried in vacuo at room
temperature to give the title compound (400 mg, yield 72%) as
yellow wax: HPLC purity: 94.5%; 1H NMR (CDCl3, TMS, 300 MHz)
4.4.9. 3-[(3,4-Dimethoxybenzyl)(ethyl)amino]-2-thioxo-1,3-
thiazolidin-4-one (8j)
d
(ppm): 1.10 (3H, t, J¼7.2 Hz), 3.45 (2H, t, J¼7.2 Hz), 3.77 (2H, dd,
To a stirred suspension of 7j (634 mg, 2.14 mmol) and AcOH
(8 ml) was added sodium triacetoxyborohydride (4.54 g,
21.4 mmol) at room temperature under N2 atmosphere. After stir-
ring at the same temperature for 5 days, sodium triacetoxyboro-
hydride (10.2 g, 48.1 mmol) and acetic acid (7 ml) were added. After
an additional reaction at room temperature for 5 days, water
(15 ml) and 4 M NaOH (50 ml), 2 M NaOH (50 ml) and NaOH
(3.00 g) were added to the reaction mixture to give precipitates.
After stirring at ice-cold temperature for 1 h, the resulting crystals
were filtered and washed with water and dried in vacuo at room
temperature to give the title compound (456 mg, yield 64%) as
a yellow crystalline powder: mp 92–94 ꢀC; 1H NMR (CDCl3, TMS,
J¼26.9 and 18.1 Hz), 4.0–4.2 (2H, m), 6.1–6.3 (1H, m), 6.56 (1H, d,
J¼15.8 Hz), 7.2–7.4 (5H, m); MS (FAB, m/z): (Mþ) 293. Elemental
analysis: calcd for C14H16N2OS2, C: 57.50, H: 5.52, N: 9.58; found, C:
57.65, H: 5.42, N: 9.51.
4.4.12. 5-{[5-(4-Chlorophenyl)-2-furyl]methylene}-3-{ethyl[(2E)-3-
phenylprop-2-en-1-yl]amino}-2-thioxo-1,3-thiazolidin-4-one (10k)
A mixture of 8k (338 mg,1.16 mmol), 5-(4-chlorophenyl)furfural
(240 mg, 1.16 mmol), sodium acetate (3.8 mg, 0.0464 mmol), and
ethanol (23 ml) was stirred under reflux for 1.5 h. After cooling to
room temperature, the resulting crystals were filtered, washed
with ethanol and dried in vacuo at room temperature to give the
title compound (435 mg, yield 78%) as an orange crystalline pow-
der: mp 89–91 ꢀC (decomposed); 1H NMR (CDCl3, TMS, 300 MHz)
300 MHz)
d
(ppm): 1.07 (3H, t, J¼7.2 Hz), 3.2–3.4 (2H,m), 3.74 (1H,
dd, J¼32 and 18 Hz), 3.84 (2H, s), 3.86 (2H, s), 4.38 (1H, dd, J¼54 and
12 Hz), 6.74 (1H, d, J¼8.1 Hz), 6.86 (1H, dd, J¼8.1 and 1.6 Hz), 7.16
d
(ppm): 1.13 (2H, t, J¼7.2 Hz), 3.4–3.7 (2H, m), 4.1–4.2 (2H, m), 6.2–
(1H, d, J¼1.7 Hz); 13C NMR (DMSO-d6, TMS, 75.5 MHz)
d
(ppm):
6.4 (2H, m), 6.56 (2H, d, J¼15.8 Hz), 6.81 (1H, d, J¼3.7 Hz), 6.90 (1H,
12.98, 32.62, 46.93, 55.83, 55.95, 58.04, 111.75, 113.22, 121.34,
129.77, 148.68, 148.93, 173.92, 203.00; MS (EI, m/z): (Mþ) 326.
HRMS: calcd for C14H18N2O3S2, 325.06866; found, 325.06866.
d, J¼3.7 Hz), 7.2–7.5 (8H, m), 7.66 (2H, d, J¼8.6 Hz); 13C NMR
(DMSO-d6, TMS, 75.5 MHz)
d (ppm): 13.36, 48.42, 56.80, 111.68,
116.51, 119.25, 124.10, 126.01, 126.92, 127.12, 128.23, 128.58, 129.51,
130.30, 133.96, 134.64, 137.23, 150.45, 157.85, 166.37, 194.32; MS (EI
m/z): (Mþ) 480. Elemental analysis: calcd for C25H21N2O2SCl, C:
62.42, H: 4.40, N: 5.82; found, C: 62.06, H: 4.36, N: 5.67.
4.4.10. 3-{[(2E)-3-Phenylprop-2-en-1-ylidene]amino}-2-thioxo-
1,3-thiazolidin-4-one (7k)
A mixture of compound 6k (892 mg, 6.02 mmol), trans-cinna-
maldehyde (796 mg, 6.02 mmol), and ethanol (8 ml) was stirred at
room temperature for 5 h. The resulting crystals were filtered and
dried in vacuo at room temperature to give the title compound
(1.45 g, yield 92%) as a yellow crystalline powder: mp 144 ꢀC
References and notes
1. Terada, T.; Fujimoto, K.; Nomura, M.; Yamashita, J.; Wierzba, K.; Yamazaki, R.;
Shibata, J.; Sugimoto, Y.; Yamada, Y. J. Med. Chem. 1993, 36, 1689.
2. (a) Kametani, T.; Kigasawa, K.; Hiiragi, M.; Wagatsuma, N.; Uryu, T.; Araki, K. J.
Med. Chem. 1973, 16, 301; (b) Kametani, T.; Kigasawa, K.; Hiiragi, M.;
Wagatsuma, N.; Kuama, O.; Uryu, T. Chem. Pharm. Bull. 1976, 24, 2563.
3. Tsubouchi, H.; Sasaki, H.; Itotani, M.; Haraguchi, Y.; Miyamura, S.; Matsumoto,
M.; Hashizume, H.; Tomishige, T.; Kawasaki, M.; Ohguro, K.; Shimada, T.;
Hasegawa, T.; Tanaka, K.; Takemura, I. WO2005-042542, 2005; Chem. Abstr.
2005, 142, 463728.
4. Fukuzaki, K. JP1993-201990, 1993; Chem. Abstr. 1993, 120, 134446.
5. Kobayashi, K.; Nishiyama, T.; Nakade, M. JP1999-302280, 1999; Chem. Abstr.
1999, 131, 299442.
6. Cusic, J. W.; LeVon, E. F. USP3159635, 1964; Chem. Abstr. 1964, 62, 51734.
7. Wu, S.; Janusz, J. M.; Sheffer, J. B. Tetrahedron Lett. 2000, 41, 1159.
8. (a) Gribble, G. W. Org. Process Res. Dev. 2006, 10, 1062; (b) Gribble, G. W. Chem.
Soc. Rev. 1998, 27, 395; (c) Gribble, G. W. Chemtech 1996, 8, 26; (d) Gribble,
G. W.; Nutaitis, C. F. Org. Prep. Proc. Int. 1985, 17, 317; (e) Gribble, G. W.;
Lord, P. D.; Skotnicki, J.; Dietz, S. E.; Eaton, J. T.; Johnson, J. L. J. Am.
Chem. Soc. 1974, 96, 7812.
(decomposed); 1H NMR (CDCl3, TMS, 300 MHz)
d (ppm): 3.94 (6H,
s), 4.06 (2H, s), 6.91 (1H, d, J¼8.3 Hz), 7.29 (1H, dd, J¼8.3 and
1.9 Hz), 7.57 (1H, d, J¼1.9 Hz); 13C NMR (DMSO-d6, TMS, 75.5 MHz)
d
(ppm): 35.61, 124.16, 129.08, 129.89, 131.31, 135.71, 148.56, 170.59,
173.04, 197.71; MS (FAB, m/z): (Mþ) 262. Elemental analysis: calcd
for C12H10N2OS2, C: 54.94, H: 3.84, N: 10.68; found, C: 54.89, H: 3.81,
N: 10.75.
4.4.11. 3-{Ethyl[(2E)-3-phenylprop-2-en-1-yl]amino}-2-thioxo-1,3-
thiazolidin-4-one (8k)
To a stirred suspension of 7k (500 mg, 1.91 mmol) and AcOH
(10 ml) was added sodium triacetoxyborohydride (4.05 g,
19.1 mmol) at room temperature under N2 atmosphere. After stir-
ring at the same temperature for 40 h, water (70 ml) and NaOH
(10 g) were added to the reaction mixture and extracted with ethyl
acetate (2ꢁ50 ml). The combined organic layers were washed with
9. Verardo, G.; Toniutti, N.; Giumanini, G. Can. J. Chem. 1998, 76, 1180.
10. Petlichnaya, L. I.; Turkevich, N. M. Chem. Heterocycl. Comp. (Engl. Transl.) 1968,
4, 57.