Synthesis of the bicyclic secondary amines via dimethylaminomethylene ketones from 3-pyrrolidone and 4-piperidone

Article abstract of DOI:10.3987/COM-01-S(K)25

The reaction of N-protected 3-pyrrolidone and 4-piperidone with N,N-dimethylformamide dimethyl acetal gave the dimethylaminomethylene ketones, which reacted with several types of hydrazines, amidines, and guanidine to afford the secondary amines having fused ring system.

Full text of DOI:10.3987/COM-01-S(K)25

HETEROCYCLES, Vol. 56, 2002, pp. 257 - 264, Received, 29th May, 2001
SYNTHESIS OF THE BICYCLIC SECONDARY AMINES
VIA DIMETHYLAMINOMETHYLENE KETONES FROM
3-PYRROLIDONE AND 4-PIPERIDONE
Hideto Fukui,* Kiyoshi Inoguchi, and Jun Nakano
Central Research Institute, Kaken Pharmaceutical Co., Ltd., Shinomiya, Minami-
kawara-cho, Yamashina-ku, Kyoto 607-8042, Japan
Abstract – The reaction of N-protected 3-pyrrolidone and 4-piperidone with
N,N-dimethylformamide dimethyl acetal gave the dimethylaminomethylene ketones,
which reacted with several types of hydrazines, amidines, and guanidine to afford
the secondary amines having fused ring system.
Since the introduction of antibacterial fluoroquinolones in the early 1980s, this class of compounds have
become one of the most attractive agents in the antiinfective chemotherapy field.1 The cyclic amine side
chain at the 7-position of the quinolone nucleus is known to be a very important part for its antibacterial
activity, and many groups are still researching novel compounds with potent antibacterial activity.2
Recently, moxifloxacin (Figure 1), having a bicyclic amine side chain at the 7-position of the quinolone
nucleus, was reported to possess potent antibacterial activity, especially against Gram-positive bacteria
including the drug resistant strains.3 We synthesized the secondary amines having a fused ring system
using a simple procedure via the common intermediates as follows.
O
F
COOH
·HCl
H
7
N
N
HN
OMe
H
Figure 1
Dedicated to Professor James P. Kutney in celebration of his 70th birthday.

The pyrrolidines and piperidines condensed with the pyrazole ring were prepared as shown in Scheme 1.
The reaction of ketones (1a) and (1b), easily obtained from the commercially available materials, with
N,N-dimethylformamide dimethyl acetal afforded the dimethylaminomethylene ketones (2a) and (2b) as
the common intermediates, respectively. By the reaction with hydrazine hydrate and the following acid
treatment, compounds (2a) and (2b) were converted into 3a and 3b in good yields, respectively. The
reaction of 2a with methylhydrazine and the following acid treatment gave 4a as a single product, which
had the methyl group at the 1-position of the pyrazole ring. The position of the methyl group was
determined by the NOE experiments (Figure 2). When the N1-Me signal (δ 3.77) of 4a was irradiated,
the C6-H2 signal (δ 4.38) was enhanced, indicating a proximal relationship. The same reaction of 2b
afforded a 4:1 mixture of the two isomers.5 However, the major product (4b), separated from the mixture
by washing with 2-propanol, had the methyl group at the 2-position of the pyrazole ring.6 When the
N2-Me signal (δ 3.79) of 4b was irradiated, in the NOE experiment, the C7-H2 signal (δ 2.85)
enhancement was not observed, but the C3-H signal (δ 7.57) was enhanced.
1
R
2 N
Me
Me
OMe
OMe
N
O
n
Me N CH
O
n
2
1) R1NHNH2
2) H+
N
1
n
N
N
N
reflux
H
·2HCl
Boc
Boc
1
1a
1b (n=2)
2a
2b (n=2)
3a
(R =H, n=1)
(n=1)
(n=1)
3b (R1=H, n=2)
4a (R1=1-Me, n=1)
1
4b
(R =2-Me, n=2)
Scheme 1
NOE
Me
N
2 N
Me
H
N
N
3
1
NOE
H
H
7
6
N
H
N
H
4a
4b
Figure 2

The pyrrolidines and piperidines condensed with the pyrimidine ring were synthesized as shown in
Scheme 2. The two intermediates (2a) and (2b) reacted with two types of amidines (R2=H, Me) and
guanidine (R2=NH2) to afford six compounds (5a-7a and 5b-7b) after the following acid treatment,
respectively.
5a (R2=H, n=1)
2
R2
R
5b (R2=H, n=2)
N
1)HN C NH2
N
6a (R2=Me, n=1)
2a,b
6b (R2=Me, n=2)
7a (R2=NH2, n=1)
7b (R2=NH2, n=2)
2) H+
n
N
H
·2HCl
Scheme 2
In conclusion, we synthesized the secondary amines (3a-7a, 3b-7b) having a fused ring system using a
simple procedure via the common intermediates (2a and 2b), respectively. Some of them were then
introduced to the quinolone nucleus that produced potent antibacterial activity against Gram-positive
bacteria including the drug resistant strains.7
EXPERIMENTAL
1
Melting points were determined on a Yanaco MP-500D and are uncorrected. H-NMR spectra were
recorded on a JEOL JNM-EX270 (270 MHz) spectrometer. Chemical shifts are reported in δ (ppm)
relative to tetramethylsilane. IR spectra were recorded on a Shimazu FTIR-4200 infrared
spectrophotometer. MS spectra were measured on a JEOL HX-110A. Column chromatography was
performed using Merck 60 silica gel, 70-230 mesh.
N-tert-Butoxycarbonyl-4-dimethylaminomethylene-3-pyrrolidone (2a). N-tert-Butoxycarbonyl-3-
pyrrolidone (1a, 2.90 g, 15.7 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (15 mL),
and the solution was heated under reflux for 1 h and concentrated. The residue was triturated with
hexane, filtered, and washed with hexane to give 2a as a yellow powder (2.39 g, 64%): mp 136-139 °C;
1H-NMR (CDCl3) δ 1.48 (9H, s), 3.09 (6H, s), 3.81 (2H, s), 4.57 (2H, s), 7.31 (1H, s); IR (KBr) 1595,
1675, 1695 cm-1. HRFABMS Calcd for C12H21N2O3 (M+H)+: 241.1552. Found: 241.1572. Anal. Calcd

for C12H20N2O3·1/8H2O: C, 59.42; H, 8.40; N, 11.55. Found: C, 59.45; H, 8.32; N, 11.54.
N-tert-Butoxycarbonyl-3-dimethylaminomethylene-4-piperidone (2b). This compound was obtained
from N-tert-butoxycarbonyl-4-piperidone (1b) in the same way as 2a. A yellow powder: yield 9.00 g
(71%); mp 72-75 °C; 1H-NMR (CDCl3) δ 1.48 (9H, s), 2.44 (2H, t, J = 6.3 Hz), 3.11 (6H, s), 3.60 (3H, t,
J = 6.4 Hz), 4.55 (2H, s), 7.49 (1H, s); IR (KBr) 1545, 1655, 1695 cm-1. HRFABMS Calcd for
C13H23N2O3 (M+H)+: 255.1709. Found: 255.1723. Anal. Calcd for C13H22N2O3·1/2H2O: C, 59.29; H,
8.80; N, 10.64. Found: C, 59.21; H, 8.87; N, 10.37.
1,4,5,6-Tetrahydropyrrolo[3,4-c]pyrazole dihydrochloride (3a). To a solution of 2a (3.00 g, 12.5
mmol) in MeOH (60 mL) was added hydrazine hydrate (98%, 0.73 mL, 15.1 mmol), and the solution
was heated under reflux for 1 h and concentrated. The residue was purified by column chromatography
eluting with CHCl3:2-propanol (10:1) to give a colorless powder. It was dissolved in TFA (50 mL) at
0 °C, and the solution was stirred at rt for 1 h and concentrated. The residue was dissolved in EtOH and
treated with concentrated HCl (3 mL). After removing the solvent, the resultant solid was triturated with
2-propanol, filtered, and washed with 2-propanol and Et2O to give 3a (2.01 g, 88%) as an orange
powder: mp 132-134 °C; 1H-NMR (DMSO-d6) δ 4.25 (4H, t, J = 5.1 Hz), 7.60 (1H, s), 10.51 (2H, br s),
11.39 (2H, br s); IR (KBr) 1455, 1560, 3000 cm-1. HRFABMS Calcd for C5H8N3 (M+H)+: 110.0718.
Found: 110.0721. Anal. Calcd for C5H9 N3Cl2: C, 32.99; H, 4.98; N, 23.08. Found: C, 32.80; H, 4.98; N,
22.79.
4,5,6,7-Tetrahydro-1H-pyrazolo[4,3-c]pyridine dihydrochloride (3b). This compound was obtained
1
from 1b in the same way as 3a. A pale yellow powder: yield 2.51 g (51%); mp 239-242 °C; H-NMR
(DMSO-d6) δ 2.95 (2H, t, J = 6.1 Hz), 3.34-3.36 (2H, m), 4.12 (2H, t, J = 4.1 Hz), 7.69 (1H, s), 9.72 (2H,
br s), 12.42 (2H, br s); IR (KBr) 1585, 1640, 2800 cm-1. HRFABMS Calcd for C6H10N3 (M+H)+:
124.0875. Found: 124.0868. Anal. Calcd for C6H11N3Cl2·1/8H2O: C, 36.34; H, 5.72; N, 21.19. Found: C,
36.24; H, 5.46; N, 21.02.
1,4,5,6-Tetrahydro-1-methylpyrrolo[3,4-c]pyrazole dihydrochloride (4a). To a solution of 2a (10.0

g, 41.7 mmol) in MeOH (120 mL) was added methylhydrazine (2.37 g, 51.5 mmol), and the solution
was heated under reflux for 2.5 h and concentrated. The residue was purified by column
chromatography eluting with CHCl3:2-propanol (50:1) to give a yellow oil. It was dissolved in TFA (200
mL) at 0 °C, and the solution was stirred at rt for 1 h and concentrated. The residue was dissolved in
EtOH and treated with concentrated HCl (12 mL). After removing the solvent, the resultant solid was
triturated with 2-propanol, filtered, and washed with 2-propanol and Et2O to give 4a (7.26 g, 89%) as a
1
pale brown powder: mp 181-186 °C; H-NMR (DMSO-d6) δ 3.77 (3H, s), 4.20 (2H, m), 4.38 (2H, m),
7.25 (1H, s), 7.61 (1H, br s), 10.64 (2H, br s); IR (KBr) 1470, 1560, 1635, 2700 cm-1. HRFABMS Calcd
for C6H10N3 (M+H)+: 124.0875. Found: 124.0882. Anal. Calcd for C6H11N3Cl2·1/4H2O: C, 35.93; H,
5.78; N, 20.95. Found: C, 35.88; H, 6.03; N, 21.94.
4,5,6,7-Tetrahydro-2-methyl-2H-pyrazolo[4,3-c]pyridine dihydrochloride (4b). This compound
was obtained from 1b in the same way as 4a. A pale yellow powder: yield 1.35 g (43%); mp
258-261 °C; 1H-NMR (DMSO-d6) δ 2.85 (2H, t, J = 6.1 Hz), 3.32-3.35 (2H, m), 3.79 (3H, s), 4.09 (2H,
t, J = 4.3 Hz), 6.91 (1H, br s), 7.57 (1H, s), 9.45 (2H, br s); IR (KBr) 1560, 1640, 2800 cm-1. HRFABMS
Calcd for C7H12N3 (M+H)+: 138.1031. Found: 138.1027. Anal. Calcd for C7H13N3Cl2·1/8H2O: C, 39.59;
H, 6.28; N, 19.79. Found: C, 39.66; H, 6.32; N, 19.77.
6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidine dihydrochloride (5a). To a solution of 2a (10.0 g, 41.7
mmol) in EtOH (200 mL) was added formamidine acetate (21.7 g, 209 mmol), and the solution was
heated under reflux for 36 h and concentrated. The residue was extracted with CHCl3 and washed with
water. The organic layer was dried over anhydrous MgSO4 and evaporated. The residue was purified by
column chromatography eluting with CHCl3:hexane (4:1) to give a pale yellow powder. It was dissolved
in TFA (75 mL) at 0 °C, and the solution was stirred at rt for 1 h and concentrated. The residue was
dissolved in 2-propanol and treated with concentrated HCl (5 mL). The precipitated solid was filtered
and washed with 2-propanol and Et2O to give 5a (5.71 g, 71%) as an orange powder: mp 141-145 °C;
1H-NMR (DMSO-d6) δ 4.54 (2H, t, J = 5.4 Hz), 4.64 (2H, t, J = 4.8 Hz), 7.48 (2H, br s), 8.87 (1H, s),
9.16 (1H, s), 10.35 (2H, br s); IR (KBr) 1460, 1535, 1595, 1640, 2900 cm-1. HRFABMS Calcd for
C6H8N3 (M+H)+: 122.0718. Found 122.0711. Anal. Calcd for C6H9N3Cl2·1/8H2O: C, 36.71; H, 4.75; N,

21.40. Found: C, 36.94; H, 4.65; N, 21.12.
5,6,7,8-Tetrahydropyrido[4,3-d]pyrimidine dihydrochloride (5b). This compound was obtained
1
from 1b in the same way as 5a. A yellow powder: yield 3.29 g (20%); mp 236 °C (decomp); H-NMR
(DMSO-d6) δ 3.12 (2H, t, J = 6.4 Hz), 3.44-3.49 (2H, m), 4.34 (2H, t, J = 4.5 Hz), 7.63 (2H, br s), 8.69
(1H, s), 9.03 (1H, s), 9.92 (2H, br s); IR (KBr) 1460, 1530, 1595, 1630, 2750 cm-1. HRFABMS Calcd
for C7H10N3 (M+H)+: 136.0875. Found 136.0869. Anal. Calcd for C7H11N3Cl2·1/8H2O: C, 39.97; H,
5.39; N, 19.98. Found: C, 39.92; H, 5.43; N, 19.97.
6,7-Dihydro-2-methyl-5H-pyrrolo[3,4-d]pyrimidine dihydrochloride (6a). To a solution of 2a
(8.00 g, 33.3 mmol) in EtOH (80 mL) were added acetamidine hydrochloride (15.8 g, 167 mmol) and
Et3N (23.5 mL, 169 mmol), and the solution was heated under reflux for 42 h and concentrated. The
residue was extracted with AcOEt and washed with water. The organic layer was dried over anhydrous
MgSO4 and evaporated. The residue was purified by column chromatography eluting with
hexane:AcOEt (1:2) to give a pale yellow powder. It was dissolved in TFA (30 mL) at 0 °C, and the
solution was stirred at rt for 0.5 h and concentrated. The residue was dissolved in 2-propanol and treated
with concentrated HCl (5 mL). After removing the solvent, the resultant solid was triturated with EtOH,
filtered, and washed with EtOH and Et2O to give 6a (5.39 g, 79%) as a pale yellow powder: mp 250 °C
(decomp); 1H-NMR (DMSO-d6) δ 2.67 (3H, s), 4.51 (2H, m), 4.61 (2H, m), 8.77 (1H, s), 10.51 (1H, br
s), 10.59 (1H, br s); IR (KBr) 1520, 1620, 1650, 2600 cm-1. HRFABMS Calcd for C7H10N3 (M+H)+:
136.0875. Found 136.0883. Anal. Calcd for C7H11N3Cl2·3/8H2O: C, 39.13; H, 5.51; N, 19.56. Found: C,
39.07; H, 5.75; N, 19.56.
5,6,7,8-Tetrahydro-2-methylpyrido[4,3-d]pyrimidine dihydrochloride (6b). This compound was
obtained from 1b in the same way as 6a. A yellow powder: yield 4.11 g (14%); mp 160 °C (decomp);
1H-NMR (DMSO-d6) δ 2.59 (3H, s), 3.04 (2H, t, J = 6.3 Hz), 3.48 (2H, m), 4.29 (2H, m), 8.58 (1H, s),
9.61 (2H, brs); IR (KBr) 1610, 1635, 2950 cm-1. HRFABMS Calcd for C8H12N3 (M+H)+: 150.1031.
Found 150.1035.

2-Amino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine dihydrochloride (7a). To a solution of 2a (10.0
g, 41.7 mmol) in EtOH (250 mL) were added guanidine carbonate (30.0 g, 167 mmol) and sodium
acetate (27.4 g, 334 mmol), and the solution was heated under reflux for 48 h. The reaction mixture was
filtered, and the insoluble material was extracted with CHCl3 and washed with water. The organic layer
was dried over anhydrous MgSO4 and evaporated. The resultant solid was triturated with 2-propanol,
filtered, and washed with 2-propanol and Et2O to give a colorless powder. It was dissolved in TFA (70
mL) at 0 °C, and the solution was stirred at rt for 1 h and concentrated. The residue was dissolved in
2-propanol and treated with concentrated HCl (6.5 mL). The precipitated solid was filtered and washed
with 2-propanol and Et2O to give 7a (6.73 g, 90%) as a colorless powder: mp 260 °C (decomp);
1H-NMR (DMSO-d6) δ 4.37 (2H, m), 4.43 (2H, m), 7.09 (3H, br s), 8.35 (1H, s), 10.25 (2H, br s); IR
(KBr) 1540, 1655, 1675, 2650, 3150 cm-1. HRFABMS Calcd for C6H9N4 (M+H)+: 137.0827. Found
137.0820. Anal. Calcd for C6H10N4Cl2·1/4H2O: C, 33.74; H, 4.96; N, 26.23. Found: C, 33.96; H, 4.90; N,
26.25.
2-Amino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine dihydrochloride (7b). This compound was
obtained from 1b in the same way as 7a. A yellow powder: yield 3.13 g (39%); mp 274-278 °C;
1H-NMR (DMSO-d6) δ 2.98 (2H, t, J = 6.3 Hz), 3.42 (2H, m), 4.14 (2H, m), 5.67 (3H, br s), 8.33 (1H, s),
9.71 (2H, br s); IR (KBr) 1525, 1635, 1670, 2650, 3150 cm-1. HRFABMS Calcd for C7H11N4 (M+H)+:
151.0984. Found 151.0987. Anal. Calcd for C7H12N4Cl2·1/4H2O: C, 36.94; H, 5.53; N, 24.62. Found: C,
36.79; H, 5.36; N, 24.33.
ACKNOWLEDGEMENTS
We thank Ms. Miyako Ohara for doing the NOE experiments and Ms. Kazumi Sumita for the MS and IR
spectral measurements.
REFERENCES AND NOTES
1. S. Mitsuhashi, Ed. Fluorinated Quinolones-New Quinolone Antimicrobials. In Progress in Drug
Reseach, Birkhäuser Verlag, Basel, 1992, 38, 10.
2. D. TW. Chu, Exp. Opin. Ther. Patent, 1996, 6, 711.

3. J. A. B. Balfour and L. R. Wiseman, Drugs, 1999, 57, 363.
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5. N. P. Peet and M. E. LeTourneau, Heterocycles, 1991, 32, 41.
6. The reaction of N-tert-butoxycarbonyl-3-formyl-4-piperidone with methylhydrazine also gave a
mixture of the two isomers; T. Takaya, H. Tsutsumi, K. Matsuda, H. Sakai, and M. Murata, J pn
Kokai Tokkyo Koho JP 60166681 (Chem. Abstr., 1986, 104, 109495).
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