Syntheses of 1,2-diamino and 1,2-aminoalcohol derivatives in the piperidine and pyrrolidine series as anti-amnesic agents

Article abstract of DOI:10.1016/S0968-0896(99)00079-6

Tacrine, one of the drugs available for Alzheimer's disease based on the cholinergic approach, suffers from considerable toxicity. Many analogues of tacrine has been prepared which retain the pharmacologically rich aminopyridine or aminoquinoline motifs. The current research is a continuation of our efforts in the area of 11-aminobenzoquinolizidines (4) and 10-aminobenzoindolizidines (5) (cf. ref 9). A serendipitous discovery led us to the biologically active open chain analogue 9, and we proceeded to elaborate on this molecule. Overall, the compounds we prepared were poor inhibitors of acetylcholinesterase as compared to tacrine. The single exception was compound 20 which exhibited an effect comparable to that of tacrine, but only at a dose in the order of 10^-3 M. However, despite the poor acetylcholinesterase inhibition by 9, this compound was found to be an effective antiamnesic agent. Copyright (C) 1999 Elsevier Science Ltd.

Full text of DOI:10.1016/S0968-0896(99)00079-6

Bioorganic & Medicinal Chemistry 7 (1999) 1647±1654
Syntheses of 1,2-Diamino and 1,2-Aminoalcohol Derivatives in the
Piperidine and Pyrrolidine Series as Anti-amnesic Agents
Shikai Zhao, a Jeremiah P. Freeman, a C. L. Bacon, b G. B. Fox, b E. O'Driscoll, b
A. G. Foley, b J. Kelly, b U. Farrell, b Ciaran Regan, b Stephen A. Mizsak c
and Jacob Szmuszkovicz a,*
aDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA
bDepartment of Pharmacology, University College Dublin, Dublin, Ireland
cPharmacia and Upjohn, Kalamazoo, MI 49001, USA
Received 13 November 1998; accepted 25 February 1999
AbstractÐTacrine, one of the drugs available for Alzheimer's diseasebased on the cholinergic approach, su€ersfrom considerable toxicity.
Many analogues of tacrine has been prepared which retain the pharmacologically rich aminopyridine or aminoquinoline motifs. The cur-
rentresearch isa continuation of our e€orts in the area of 11-aminobenzoquinolizidines (4) and 10-aminobenzoindolizidines (5) (cf. ref 9). A
serendipitous discovery led us to the biologically active open chain analogue 9, and we proceeded to elaborate on this molecule. Overall, the
compounds we prepared were poor inhibitors of acetylcholinesterase as compared to tacrine. The single exception was compound 20 which
exhibited an e€ect comparable to that of tacrine, but only at a dose in the order of 10 3 M. However, despite the poor acetylcholinesterase
inhibition by 9, this compound was found to be an e€ective antiamnesic agent. # 1999 Elsevier Science Ltd. All rights reserved.
Introduction
The cholinergic approach to Alzheimer's disease
received an encouraging signal due to the recent
approval of tacrine hydrochloride (Cognex1) as the ®rst
drug for the treatment of this disease; it was launched in
1993. Tacrine (1) is a complex pharmacological agent1
which also inhibits the enzyme acetylcholinesterase
(AcChE), thus maintaining synaptic residence of acet-
ylcholine (AcCh).2 Two other AcChE inhibitors have
been marketed recently: donezepil (Aricept1 (2)3 and
rivastigmine (Exelon) (3).4
Many analogues of tacrine have been prepared.8 Most of
these are structurally closely related to the parent com-
pound and retain the aminopyridine or aminoquinoline
moiety.
The de®ciency of tacrine as a drug is related to liver
toxicity and peripheral cholinomimetic actions.5 Tacrine
belongs to the well known structural class of aminopyr-
idines6 which represent an interesting group of potas-
sium channel blockers, but are toxic. It also incorporates
the template of 4-aminoquinoline, well known for
diverse pharmacological activity.7 Furthermore, tacrine
possesses a relatively ¯at aromatic structure which may
be prone to intercalation.
Our approach to the problem of maintaining the
AcChE inhibitory activity while diminishing the toxicity
is based on the incorporation of the 11-amino benzo-
quinolizidine (4) and 10-aminobenzoindolizidine (5)
moieties as the templates for AcChE inhibitors. In 4
and 5 we have eliminated the pyridine and quinoline
* Corresponding author. Fax: +1-219-631-6652.
0968-0896/99/$ - see front matter # 1999 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(99)00079-6

1648
S. Zhao et al. / Bioorg. Med. Chem. 7 (1999) 1647±1654
moieties while maintaining the two amino functional-
ities and rendering the molecule less ¯at. We have
recently reported the preparation of these two classes of
compounds.9
A pyrrolidine acetate analogue 17 was similarly synthe-
sized from commercially available (S)-(±)-1-benzyl-2-
pyrrolidinemethanol (16, Aldrich).
For the synthesis of the amino analogue, alcohol 14 was
treated with mesyl chloride and triethylamine followed
by reaction of the mesylate with methylamine to give
the desired amino derivative of N-benzylpiperidine 19
and a rearranged homopiperidine derivative 20 in a
ratio of about 1:1.11 For a detailed discussion of the
NMR analysis of 19 and 20, see Experimental. Both
products should be derived from the same aziridinium
intermediate 18.
During an attempt to cyclize compound 6 to the keto-
amide 7, using oxalyl chloride followed by stannic
chloride, the erroneous assumption was made that the
desired cyclization had taken place. Thus the crude
product was treated with benzylamine followed by
LiAlH4 at room temperature in order to generate com-
pound 8. As we discovered, the cyclization 6!7 had not
occurred and the acid chloride derivative of 6 reacted
with the amine to give the benzylamide which was
selectively reduced to compound 9. This compound was
subjected to biological evaluation and proved to be an
interesting lead.
The preparation of N-methylpiperidine 24 followed a
known procedure.12 2-Benzoylpyridine 21 was methy-
lated with methyl tri¯uoromethanesulfonate. The
resulting pyridinium salt 22 was hydrogenated in the
presence of rhodium on carbon. Both the pyridine ring
and the carbonyl were reduced to give product 23. The
alcohol was converted to a methylamine derivative 24
(as a mixture of diastereoisomers) by the generation of
mesylate followed by the reaction with methylamine.
In today's climate of combinatorial libraries, multikilo
sample sophisticated screening procedures, computer-
ized rational design, and X-ray crystallographic ligand-
receptor determinations, it is instructive to be able to
®nd a lead by a serendipitous process such as described
above coupled with the absence of preconceived ideas
about structure±activity relationships.
In the present report, we describe the design and synth-
eses of open chain analogues of benzoquinolizine and
benzoindolizidine derivatives. A benzylpiperidine com-
pound (such as 11), and a methylpiperidine compound
(such as 12), were attractive target molecules obtained
by disconnecting bond a or b in structure 10.
For the synthesis of pyrrolidine analogue 29, N-benzyl-
pyrrolidone-5-carboxylic acid (25) was converted to acid
chloride 26 and then to benzylamide 27. Amide 27 was
reduced to the pyrrolidine amide 28 with LAH at room
temperature.
Chemistry
Ethyl N-benzylpipecolinate (13)10 was reduced with
LiAlH4 (LAH) to give an alcohol 14. The alcohol was
converted to an acetate 15.
Compound 27 was completely reduced to pyrrolidine 29
when it was re¯uxed in the presence of LAH in THF.

S. Zhao et al. / Bioorg. Med. Chem. 7 (1999) 1647±1654
1649
Synthesis of the piperidine analogue of compound 28 is
straightforward. Amidation of ethyl ester 13 with a
lithium aluminum amide reagent13 from LAH and
benzylamine gave benzylamide 30 directly.
Ki of 0.03 mM acetylthiocholine iodide substrate (Fig.
1). However, the inhibitory concentration of tacrine
(5 mM) was 100 times lower than that observed for 9
(500 mM) (data not shown for tacrine).
Within this series of piperidine and pyrrolidine deriva-
tives, 9 was found to be an e€ective anti-amnesic agent
in vivo despite lacking acetylcholinesterase inhibitory
actions (Fig. 2). Thus, this piperidine and pyrrolidine
series would appear to include agents with an anti-
amnesic action that is independent of an antic-
holinesterase e€ect. Moreover, 9 was devoid of any
overt behavioral toxicity when administered alone.
Similarly, this ester amidation reaction was used to
synthesize the analogues of prolinamide 28. Thus, dl-
proline was converted to the N-substituted ester 31 by
the reaction of proline with arylmethyl chloride and
potassium carbonate in DMF. Ester 31 was converted
to the amide 32 directly with the lithium aluminum
amide reagent. However, methoxybenzylated com-
pound 31d failed to give amidation product.
Biological Studies
Overall, these piperidine and pyrrolidine derivatives
were poor inhibitors of acetylcholinesterase, as com-
pared to that observed with tacrine (Table 1).
The single exception was 20 which exhibited an e€ect
comparable to that of tacrine, but only at a dose in the
3
order of 10 M. In general, cholinesterase inhibition
was similar to that determined for acetylcholinesterase.
However, in one case a stimulatory e€ect was observed
at higher concentrations (see compound 32a). Inhibition
of acetylcholinesterase by these piperidine and pyrroli-
dine derivatives appeared competitive in nature as
kinetic studies with 9 and tacrine revealed an equivalent
Figure 1. In¯uence of piperidine and pyrrolidine derivatives on rat
brain acetylcholinesterase activity. The data is illustrated as Line-
weaver±Burke plots for control (closed squares) and 9 (0.5 mM; closed
circles)
Table 1. Inhibition of rat cholinesterase and acetylcholinesterase activity by piperidine and pyrrolidine derivatives and tacrinea
Compd
Acetylcholinesteraseb
10 5M
Total cholinesteraseb
10 5M
10 3M
10 7M
10 3M
10 710M
15
17
9
29
24
19
20
27
34.59‹04.76
36.37‹02.90
68.41‹09.52
28.05‹00.81
82.00‹07.48
40.16‹08.81
09.75‹00.89
92.06‹05.14
88.19‹16.84
52.03‹10.43
93.67‹07.96
55.13‹07.64
55.15‹07.16
41.11‹10.90
87.78‹05.21
78.94‹16.66
05.42‹00.62
83.55‹07.07
71.34‹00.91
83.09‹13.71
108.58‹03.39
106.05‹12.99
94.28‹05.75
45.47‹21.80
96.78‹08.28
82.68‹03.46
93.00‹07.54
89.77‹08.46
87.41‹01.88
92.08‹04.26
60.32‹12.59
93.93‹03.20
94.46‹03.90
07.35‹00.05
77.09‹08.05
67.46‹01.65
92.13‹01.78
125.12‹14.24
106.79‹07.02
116.18‹17.00
54.94‹18.82
89.72‹09.89
94.56‹09.20
96.19‹11.01
106.18‹09.96
91.34‹00.93
98.28‹11.80
56.37‹13.39
86.70‹06.97
100.55‹18.25
42.81‹02.78
47.27‹05.89
60.57‹06.41
81.87‹11.92
29.54‹03.68
76.29‹07.83
43.43‹06.93
26.41‹03.29
107.51‹03.81
132.75‹34.44
59.41‹06.89
273.85‹23.09
46.99‹04.08
57.87‹05.42
35.58‹09.73
51.54‹20.35
68.86‹37.58
17.82‹00.91
79.70‹11.96
103.73‹03.52
100.63‹14.41
109.07‹05.67
110.04‹16.74
84.77‹08.35
42.13‹17.10
108.45‹04.06
95.76‹07.59
95.29‹10.40
106.63‹15.22
88.95‹10.52
101.04‹10.15
63.16‹16.76
128.43‹09.84
62.76‹00.63
14.93‹06.12
92.95‹05.63
102.71‹05.69
111.39‹03.49
118.58‹04.07
102.92‹13.73
100.99‹16.20
53.13‹14.26
96.03‹09.68
95.20‹07.88
97.54‹17.64
70.80‹32.34
92.49‹03.27
96.13‹05.01
60.09‹16.38
119.89‹20.62
62.11‹04.31
42.97‹04.50
30
31a
32a
31b
31c
32c
32b
31d
Tacrine
a
Values represent the mean‹Sem for three independent experiments.
Activity was determined as mmol/min/mg protein and is presented as percent of the control value.
b

1650
S. Zhao et al. / Bioorg. Med. Chem. 7 (1999) 1647±1654
Figure 2. Reversal of scopolamine-induced amnesia of a passive avoidance response by 9. The data is presented as box plots showing the median
and interquartile range (n=6). The box plot marked with an asterisk is signi®cantly di€erent (p < 0:05) from all other values. The dose of 9
employed was 30 mg/kg.
Structure±Activity Relationship
mixture was stirred overnight. It was quenched by
sequential addition of H2O (0.4 mL), NaOH (15%, 0.4
mL) and H2O (1.2 mL). The resulting suspension was ®l-
tered and the ®ltrate was concentrated in vacuo to give 14
as a pale-yellow oil (1.78 g, 87%): 1H NMR (300 MHz) d
7.30 (m, 5H), 4.06 (d, J=13.4 Hz, 1H), 3.84 (dd, J=10.8,
4.3 Hz, 1H), 3.52 (dd, J=10.8, 3.9 Hz, 1H), 3.31 (d,
J=13.4 Hz, 1H), 2.86 (m, 1H), 2.77 (br s, OH), 2.44 (m,
1H), 2.13 (m, 1H), 1.30±1.70 (m, 6H); 13C NMR (75.4
MHz) d 138.98 (s), 128.76 (d), 128.24 (d), 126.90 (d), 62.23
(t), 60.90 (d), 57.66 (t), 50.79 (t), 27.30 (t), 24.05 (t), 23.35
(t); MS (EI), m/e 174 (100), 91 (56); HRMS (FAB) calcd.
for (C13H19NO + H) 206.1545, found 206.1546.
The structure±activity relationship de®ning compound 9
as the antiamnesic lead may be summarized as follows:
(1) pyrrolidine ring is preferred to piperidine and (2) the
unsubstituted benzene ring, with benzyl group on the
pyrrolidine nitrogen, is preferred to a benzene ring with
electron-withdrawing substituents and to a naphthalene
ring.
Experimental
1H and 13C NMR spectra were recorded on a Varian
spectrometer at 300 MHz for proton and 75.4 MHz for
carbon in CDCl3 solution. The predicted carbon spectra
were obtained from the ACD Labs CNMR program.
Peak positions are indicated in ppm down®eld from
internal TMS in d units. Mass spectra were obtained on
a MAT CH-5-DF (FAB), and Finnigan 8230 B (EI)
mass spectrometers. IR spectra were recorded on a Per-
kin±Elmer 1420 Ratio Recording IR spectrophoto-
meter. Flash column chromatography was done on
silica gel (E. M. Merck silica gel 60, 230±400 mesh) in
the stated solvents. Melting points were obtained on a
Thomas±Hoover apparatus and are uncorrected. Pro-
duct purities were routinely checked by TLC. THF was
tested for peroxides (aqueous KI) prior to use and used
without further puri®cation or drying. All reactions
were performed under a nitrogen atmosphere in oven- or
¯ame-dried glassware unless otherwise noted. The mul-
tiplicities of the 13C signals were determined by DEPT
experiments; s=C; d=CH; t=CH2; q=CH3. Methyla-
mine was obtained from either a lecture bottle (Aldrich)
or aqueous solution (40%, Fluka) by distillation. Ethyl
pipecolinate was purchased from Aldrich.
1-(Phenylmethyl)-2-piperidinemethyl acetate (15).
A
solution of CH3COCl (1.27 mmol, 90 mL) in CH2Cl2 (2
mL) was added to a solution of alcohol 14 (1.16 mmol,
237 mg) and Et3N (1.27 mmol, 177 mL) in CH2Cl2
(5 mL) at 0ꢀC. The mixture was stirred at rt for 2 h and
then diluted with CH2Cl2 (50 mL). The solution was
washed with Na2CO3 (satd., 10 mL) and H2O (10 mL),
dried over Na2SO4 and concentrated in vacuo. The
residue was chromatographed on silica gel eluting with
CH2Cl2/MeOH/NH4OH (99/0.8/0.2) to give 15 as a yel-
1
low oil (256 mg): H NMR (300 MHz) d 7.30 (m, 5H),
4.27 (dd, J=11.5, 4.8 Hz, 1H), 4.20 (dd, J=11.5, 5.2 Hz,
1H), 3.99 (d, J=13.7 Hz, 1H), 3.34 (d, J=13.7 Hz, 1H),
2.75 (dt, J=11.9, 4.2 Hz, 1H), 2.58 (m, 1H), 2.13 (m, 1H),
2.06 (s, CH3), 1.30±1.80 (m, 6H); 13C NMR (75.4 MHz) d
171.00 (s), 139.42 (s), 128.74 (d), 128.09 (d), 126.72 (d),
65.70 (t), 59.51 (d), 58.70 (t), 51.56 (t), 28.97 (t), 25.19 (t),
23.06 (t), 20.98 (q); MS (FAB), m/e 248 (72, M+H), 174
(100); HRMS (FAB) calcd for (C15H21NO2+H)
248.1651, found 248.1648.
(S)-( )-1-Benzyl-2-pyrrolidinemethyl acetate (17).
A
1-(Phenylmethyl)-2-piperidinemethanol (14). A suspen-
sion of LAH (410 mg) in THF (50 mL) was re¯uxed for 30
min. It was cooled to rt, a solution of ester 13 (10 mmol,
2.47 g) in 5 mL of THF was added dropwise, and the
solution of CH3COCl (5.76 mmol, 410 mL) in CH2Cl2
(10 mL) was added to a solution of (S)-( )-1-benzyl-2-
pyrrolidinemethanol (Aldrich, 5.23 mmol, 1.00 g) and
Et3N (5.76 mmol, 803 mL) in CH2Cl2 (40 mL) at 0ꢀC.

S. Zhao et al. / Bioorg. Med. Chem. 7 (1999) 1647±1654
1651
The mixture was stirred at rt for 5 h and then diluted with
CH2Cl2 (100 mL). The solution was washed with Na2CO3
(satd., 20 mL) and H2O (20 mL), dried over Na2SO4 and
concentrated in vacuo. The residue was chromatographed
on silica gel eluting with CH2Cl2/MeOH/NH4OH (99/0.8/
a three bond correlation of both the C-7 methylene
protons to the C-7 methine carbon; also cross peaks can
be seen from both C-8 methylene protons to the N-CH3
carbon. The HMBC spectrum of 20 showed a three
bond correlation of the N-CH3 protons to the C-3
methine carbon, a three bond correlation of the C-8
protons to the C-2 methylene carbon, and both C-2
methylene protons to the C-8 carbon. That the N-CH3
protons are correlated to a CH2 group in 19 and a CH
group in 20 clearly de®nes the two structures. Calcu-
lated shifts obtained from the ChemIntosh C-13 NMR
module helped assign the signals for C-4, C-5 and C-6
where the lack of resolution did not permit the exact
assignment of the large number of cross peaks (see
Tables 2 and 3).
1
0.2) to give 17 as a yellow oil (717 mg, 65%): H NMR
(300 MHz) d 7.31 (m, 5H), 4.06 (m, 3H), 3.41 (d, J=13.2
Hz, 1H), 2.92 (m, 1H), 2.81 (m, 1H), 2.25 (m, 1H), 2.05 (s,
CH3), 1.95 (m, 1H), 1.70 (m, 3H); 13C NMR (75.4 MHz) d
171.04 (s), 139.48 (s), 128.78 (d), 128.15 (d), 126.83 (d),
67.12 (t), 61.79 (d), 59.43 (t), 54.40 (t), 28.40 (t), 22.89 (t),
20.94 (q); MS (FAB), m/e 234 (84, M + H), 160 (100);
HRMS (FAB) calcd for (C14H19NO2+H) 234.1494,
found 234.1506.
1-Benzyl-2-(N-methylaminomethyl)piperidine (19) and 1-
benzyl-3-(N-methylamino)hexahydroazepine (20). Tri-
ethylamine (3.61 mmol, 503 mL) was added to a solution
of alcohol 14 (3.28 mmol, 673 mg) followed by the
addition of MeSO2Cl (3.61 mmol, 279 mL). The mixture
was stirred for 3 h and concentrated in vacuo. The resi-
due was transferred to a bomb and MeNH2 (20 mL)
was added. It was heated at 110ꢀC for 14 h. NaOH
(1 N, 10 mL) was added and the layers were separated.
The aqueous layer was extracted with CH2Cl2 (2 Â 30
mL), and the combined extracts were washed with brine
(20 mL), dried over Na2SO4 and concentrated in vacuo
to give a red oil. It was chromatographed on silica gel
(CH2Cl2/MeOH/NH4OH=150/8/1) to give 19 as a yel-
low oil (115 mg), 20 as a yellow oil (84 mg) and also a
mixture of both isomers as a yellow oil (350 mg).
Synthesis of 24. Compound 24 was prepared accord-
ing to the literature8 starting from 21. The crude pro-
duct was chromatographed on silica gel eluting with
CH2Cl2/MeOH/NH4OH (150/8/1) to give pure 24 as an
oily mixture of diastereoisomers. 1H NMR (300 MHz) d
7.15 (m, 5H), 5.15 (d, J=3.0 Hz), 3.49 (d, J=9.3 Hz),
Table 2. 13C Found and calculated values for compound 19
1
Assignments
Found
Calcda
Á
19. H NMR (300 MHz) d 7.32 (m, 5H), 3.97 (d, J=13.7
Hz, 1H), 3.28 (d, J=13.7 Hz, 1H), 2.80 (dt, J=12.2, 4.2
Hz, 1H), 2.74 (d, J=4.4 Hz, 1H), 2.42 (m, 1H), 2.36 (s,
CH3), 2.08 (ddd, J=12.7, 9.2, 3.3 Hz, 1H), 1.25±1.76 (m,
6H, including NH); 13C NMR (75.4 MHz) d 139.90 (s),
128.62 (d), 128.16 (d), 126.65 (d), 60.70 (d), 57.70 (t), 54.02
(t), 51.86 (t), 36.93 (q), 29.09 (t), 24.61 (t), 23.79 (t); MS
(FAB), m/e 219 (100, M + H), 188 (9), 174 (16), 129 (3),
84 (3); HRMS (FAB) calcd for (C14H22N2+H) 219.1861,
found 219.1866.
4
5
23.33
24.09
28.31
36.28
51.40
53.21
57.59
59.64
25.7
27.9
29.7
37.1
51.7
61.3
59.9
53.7
+2.4
+3.8
+1.4
+0.8
+0.3
+8.1
+2.3
5.9
3
NCH3
6
8
7
2
a
From ChemIntosh C-13 NMR module calculation.
20. 1H NMR (300 MHz) d 7.23 (m, 5H), 3.64 (s, 2H),
2.52±2.71 (m, 5H), 2.18 (s, 3H), 1.25±1.87 (m, 6H); 13C
NMR (75.4 MHz) d 140.07 (s), 128.82 (d), 128.10 (d),
126.77 (d), 63.75 (t), 59.37 (d), 58.31 (t), 56.60 (t), 34.33
(t), 33.83 (q), 29.28 (t), 22.63 (t); HRMS (EI) calcd for
(C14H22N2+H) 218.1783, found 218.1778.
Table 3. 13C Found and calculated values for compound 20
NMR Analysis of 19 and 20. The 13C and DEPT spectra
showed one CH3, one CH and 6 CH2 groups for a total
1
of 8 aliphatic signals in both 19 and 20. The H NMR
and 13C NMR were correlated by means of a HSQC
(heteronuclear single-quantum correlation) spectrum. In
Assignment
Found
Calcd
Á
5
6
22.54
29.12
33.04
33.48
57.71a
56.48a
63.63
59.25
22.6
29.4
30.7
34.6
53.2
56.5
59.7
56.2
+0.1
+0.3
2.3
+1.2
4.5
0
3.9
3.1
1
the H spectrum of 19 the methylene (C-7) is an AB (d
3.9 and 3.3) suggesting crowding; in 20 the methylene
protons are equivalent (d 3.65). The 13C spectra of 19
and 20 show the C-7 methylene signal (d 6.02) further
up®eld in 19 also suggesting steric crowding (g e€ect) C-
8 methylene. The HMBC (heteronuclear multiple bond
correlation) spectrum of 19 showed a three bond corre-
lation of the NCH3 proton to the C-8 methylene carbon,
4
NCH3
7
2
8
3
a
May be interchanged.

1652
S. Zhao et al. / Bioorg. Med. Chem. 7 (1999) 1647±1654
2.60±3.03 (m), 2.46 (s, CH3), 2.24 (s, CH3), 2.19 (td,
J=11.4, 3.6 Hz), 2.06 (dt, J=11.4, 6.3 Hz), 0.90±1.70
(m); 13C NMR (75.4 MHz) d 142.05, 141.28, 128.30,
128.08, 127.84, 126.98, 126.56, 125.67, 70.44, 68.28,
66.00, 65.15, 57.23, 52.59, 43.03, 37.66, 34.70, 25.69,
23.78, 23.26, 23.22, 20.12, 19.29; MS (FAB), m/e 219
(100, M+H), 206 (33), 168 (32); HRMS (FAB) calcd
for (C14H22N2+H) 219.1861, found 219.1854.
J=13.2 Hz, 1H), 2.92 (m, 1H), 2.60±2.75 (m, 3H), 2.18
(q, J=8.6 Hz, 1H), 1.60±2.00 (m, 4H), NH is not dis-
cernible; 13C NMR (75.4 MHz) d 140.71, 139.94,
128.68, 128.28, 128.16, 128.02, 126.74, one aromatic
signal is not discernible, 63.74, 59.23, 54.59, 54.22,
52.05, 29.01, 22.95; MS (FAB), m/e 281 (65, M + H),
160 (100); The amine was converted to the hydrochlo-
ride. The resulting solid softens gradually on melting:
ꢁ
Anal. calcd for C19H24N2 2HClꢁ 1.5H2O: C, 60.00; H,
Synthesis of 27. Oxalyl chloride (12 mmol, 6 mL of 2
M solution in CH2Cl2) and DMF (0.3 mL) was added
to a solution of N-benzyl-2-oxopyrrolidine-5-carboxylic
acid (25, 10.7 mmol, 2.34 g). The mixture was stirred at
rt for 1.5 h, and then benzylamine (42.7 mmol, 4.67 mL)
was added. The mixture was washed with ice-cold HCl
(1 N, 10 mL), NaHCO3 (10%, 10 mL) and H2O (20
mL). The organic phase was dried over MgSO4 and
concentrated. The residue was chromatographed on
silica gel eluting with CH2Cl2/MeOH/NH4OH (400/10/
7.69; Cl, 18.64; N, 7.36. Found: C, 60.17; H, 7.45; Cl,
18.25; N, 7.51.
Synthesis of 30. A mixture of LAH (10 mmol) in THF
(20 mL) was re¯uxed for 90 min. It was cooled to 25ꢀC
and benzylamine (50 mmol, 5.46 mL) was added drop-
wise with stirring. Stirring was continued at 25ꢀC until
precipitation was complete. Ethyl ester 13 (10 mmol,
2.47 g) was added to the suspension dropwise and the
mixture was stirred at 25ꢀC overnight. The reaction was
then carefully quenched by successive addition of H2O
(0.4 mL), NaOH (15%, 0.4 mL) and H2O (1.2 mL).
Stirring was continued until the new precipitate became
white and powdered. After ®ltration, the precipitate was
carefully rinsed with CH2Cl2 (2Â10 mL) and the com-
bined organic phase were dried over Na2SO4 and con-
centrated in vacuo to give an oil. It was
chromatographed on silica gel eluting with CH2Cl2/
MeOH/NH4OH (400/10/1) to give a colorless solid
(2.18 g, 70%): mp 68±71ꢀC; 1H NMR (300 MHz) d
7.10±7.30 (m, 10H), CH2NH is an AB of an ABX pat-
tern, 4.48 (dd, JB=13 Hz, JNH=5.7 Hz, 1H), 4.45 (dd,
JA=13 Hz, JNH=5.7 Hz, 1H), 3.85 (d, J=13.8 Hz,
1H), 3.15 (d, J=13.8 Hz, 1H), 2.88 (m, 2H), 1.20±2.10
(m, 8H, including NH); 13C NMR (75.4 MHz) d 174.88,
138.34, 137.90, 128.70, 128.51, 128.31, 127.80, 127.45,
127.09, 67.78, 60.84, 51.66, 43.12, 30.42, 24.75, 23.48;
MS (FAB), m/e 309 (75, M+H), 174 (100), 91 (52);
Anal. calcd for C20H24N2O: C, 77.89; H, 7.84; N, 9.08.
Found: C, 78.11; H, 7.80; N, 9.08. The free base was
converted to the hydrochloride and crystallized from 2-
PrOH/MeOH/ether to give a colorless solid: mp 170±
172ꢀC; Anal. calcd for C20H24N2Oꢁ HCl: C, 69.65; H,
7.31; Cl, 10.28; N, 8.12. Found: C, 69.70; H, 7.15; Cl,
10.10; N, 8.15.
1
1) to give 27 as a solid (2.11 g): H NMR (300 MHz) d
7.12±7.40 (m, 10H), 5.88 (br s, NH), 5.01 (d, J=14.7
Hz, 1H, 4.46 (dd, J=14.6, 6.1 Hz, 1H), 4.30 (dd,
J=14.6, 5.5 Hz, 1H), 3.90 (d, J=14.3 Hz, 1H), 3.85 (dd,
J=8.8, 4.0 Hz, 1H), 2.02±2.66 (m, 4H); 13C NMR (75.4
MHz) d 175.79, 170.92, 137.61, 135.68, 128.83, 128.81,
128.40, 127.92, 127.82, 127.79, 60.73, 45.82, 43.58,
29.68, 23.54; MS (FAB), m/e 309 (100, M+H), 174 (20),
ꢁ
91 (95); Anal. calcd for C19H20N2O2 0.1H2O: C, 73.57;
H, 6.56; N, 9.03. Found: C, 73.37; H, 6.51; N, 9.22.
Synthesis of 28. Amide 27 (1.28 mmol, 397 mg) was
added to a suspension of LAH (140 mg) in THF (10
mL). The mixture was stirred at rt overnight, and
quenched by the successive addition of H2O (140 mL),
NaOH (aqueous, 15%, 140 mL) and H2O (420 mL). The
suspension was ®ltered and the ®ltrate was con-
centrated. The residue was chromatographed on silica
gel eluting with CH2Cl2/MeOH/NH4OH (400/10/1) to
give 28 as an oil (319 mg, 85%): 1H NMR (300 MHz) d
7.71 (br s, NH), 7.13±7.36 (m, 10H), 4.40 (d, J=6.0 Hz,
2H), 3.85 (d, J=12.6 Hz, 1H), 3.48 (d, J=13.2 Hz, 1H),
3.28 (dd, J=10.2, 4.8 Hz, 1H), 2.99 (ddd, J=8.9, 6.8,
2.1 Hz, 1H), 1.60±2.41 (m, 5H); 13C NMR (75.4 MHz) d
174.47, 138.50, 138.47, 128.71, 128.67, 128.42, 127.60,
127.35, 127.24, 67.39 (d), 59.96 (t), 53.95 (t), 42.96 (t),
30.71 (t), 24.16 (t); MS (FAB), m/e 295 (85, M+H), 160
(100); The amine was converted to the hydrochloride
and crystallized from 2-PrOH/MeOH/ether to give a
solid: mp 157±159ꢀC; Anal. calcd for C19H22
N2Oꢁ HClꢁ 0.1H2O: C, 68.60; H, 7.03; Cl, 10.66; N, 8.42.
Found: C, 68.45; H, 7.00; Cl, 10.52; N, 8.29.
Synthesis of 31a. A mixture of 4-nitrobenzyl bromide
(22 mmol, 4.75 g), potassium carbonate (11 mmol, 1.52
g) and dl-proline (10 mmol, 1.15 g) in DMF (50 mL)
was heated at 60ꢀC for 2 days. It was cooled to room
temperature, diluted with ether (50 mL) and ®ltered.
The ®ltrate was acidi®ed (pH=4) by the addition of
aqueous HCl (15%) and extracted with ether (2Â50
mL). The aqueous layer was basi®ed (pH=9) by the
addition of NaOH, extracted with ether (3Â100 mL),
dried over Na2SO4 and concentrated in vacuo to give a
yellow solid. The solid was washed with EtOAc to give
31a as a pale-yellow solid (2.53 g, 68%): mp 88±90ꢀC
Synthesis of 29. A solution of amide 27 (1.62 mmol,
0.50 g) in THF (5 mL) was added dropwise to a sus-
pension of LAH (710 mg) in THF (30 mL). The mixture
was re¯uxed for 12 h and then quenched by the succes-
sive addition of H2O (0.7 mL), aqueous NaOH (15%,
0.7 mL) and H2O (2.1 mL). The suspension was ®ltered
and the ®ltrate was concentrated in vacuo. The residue
was chromatographed on silica gel eluting with CH2Cl2/
MeOH/NH4OH (150/8/1) to give 29 as a yellow oil (327
mg): 1H NMR (300 MHz) d 7.30 (m, 9H), 3.93 (d,
J=12.9 Hz, 1H), 3.78 (d, J=4.8 Hz, 2H), 3.27 (d,
1
(EtOAc); H NMR (300 MHz) d 8.21 (br d, J=8.7 Hz,
2H), 8.14 (br d, J=8.4 Hz, 2H), 7.51 (br d, J=8.1 Hz,
2H), 7.50 (br d, J=8.4 Hz, 2H), 5.22 (d, J=13.5 Hz,
1H), 5.19 (d, J=13.2 Hz, 1H), 4.05 (d, J=13.8 Hz, 1H),
3.66 (d, J=13.8 Hz, 1H), 3.43 (dd, J=9.0, 5.7 Hz, 1H),
3.03 (m, 1H), 2.44 (q, J=8.7 Hz, 1H), 2.20 (m, 1H),

S. Zhao et al. / Bioorg. Med. Chem. 7 (1999) 1647±1654
1653
1.80±2.10 (m, 3H); 13C NMR (75.4 MHz) d 173.32,
147.75, 147.15, 146.61, 142.95, 129.28, 128.40, 123.79,
123.47, 65.22, 64.81, 57.91, 53.29, 29.36, 23.30; MS
(FAB), m/e 386 (100, M + H), 251 (4), 249 (5), 205 (97);
Anal. calcd for C19H19N3O6: C, 59.22; H, 4.97; N,
10.90. Found: C, 59.29; H, 5.02; N, 10.84.
room temperature, diluted with ether (50 mL) and ®l-
tered. The ®ltrate was acidi®ed (pH=4) by the addition
of aqueous HCl (15%) and extracted with ether (2Â50
mL). The aqueous layer was basi®ed (pH=9) by the
addition of NaOH, extracted with ether (3Â100 mL),
dried over Na2SO4 and concentrated in vacuo. The
residue was chromatographed on silica gel eluting with
EtOAc/Skelly F (1/1) to give 31d as a yellow oil (1.98 g,
Synthesis of 31b. A mixture of 3-chlorobenzyl chloride
(14.9 mmol, 1.89 mL), potassium carbonate (7.43 mmol,
1.03 g) and dl-proline (6.76 mmol, 778 mg) in DMF (10
mL) was heated at 60ꢀC for 2 days. It was cooled to
room temperature, diluted with ether (50 mL) and ®l-
tered. The ®ltrate was acidi®ed (pH=4) by the addition
of aqueous HCl (15%) and extracted with ether (2Â50
mL). The aqueous layer was basi®ed (pH=9) by the
addition of NaOH, extracted with ether (3Â100 mL),
dried over Na2SO4 and concentrated in vacuo. The
residue was chromatographed on silica gel eluting with
EtOAc/Skelly F (1/1) to give 31b as a yellow oil (989
1
61%): H NMR (300 MHz) d 7.28 (d, J=8.7 Hz, 2H),
7.18 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 6.80
(d, J=8.6 Hz, 2H), 5.06 (d, J=12.0 Hz, 1H), 5.02 (d,
J=12.0 Hz, 1H), 3.82 (d, J=12.7 Hz, 1H), 3.78 (s,
OCH3), 3.76 (s, OCH3), 3.48 (d, J=12.7 Hz, 1H), 3.23
(dd, J=8.8, 6.0 Hz, 1H), 3.00 (m, 1H), 2.36 (q, J=8.7 Hz,
1H), 1.67±2.15 (m, 4H); 13C NMR (75.4 MHz) d 173.85,
159.49, 158.57, 130.15, 129.93, 128.38, 128.10, 113.77,
113.40, 65.85, 64.85, 57.59, 55.09, 55.05, 52.87, 29.14,
22.87; MS (FAB), m/e 356 (52, M+H), 190 (50), 121
(100); HRMS (FAB) m/e calcd for (C21H25NO4+H)
356.1862, found 356.1868.
1
mg, 50%): H NMR (300 MHz) d 7.10±7.30 (m, 8H),
5.07 (m, 2H), 3.89 (d, J=13.2 Hz, 1H), 3.52 (d, J=12.9
Hz, 1H), 3.32 (dd, J=8.8, 5.6 Hz, 1H), 3.03 (m, 1H),
2.40 (q, J=8.7 Hz, 1H), 1.50±2.40 (m, 4H); 13C NMR
(75.4 MHz) d 173.60, 140.77, 137.85, 134.45, 134.05,
129.83, 129.43, 128.89, 128.35, 128.17, 127.22, 127.00,
126.16, 65.33, 65.09, 58.02, 53.21, 29.29, 23.14; MS
(FAB), m/e 364 (88, M + H), 194 (100), 125 (56);
HRMS (FAB) m/e calcd for (C19H19Cl2NO2+H)
364.0871, found 364.0847.
Synthesis of 32a. A suspension of LAH (3.19 mmol,
121 mg) in THF (20 mL) was re¯uxed for 1 h and then
cooled to room temperature. Benzylamine (16.0 mmol,
1.7 mL) was added and the mixture was stirred for 1 h.
A solution of 31a (3.19 mmol, 1.23 g) in THF (10 mL)
was added and the mixture was stirred overnight at
room temperature. The reaction was quenched by the
addition of H2O (0.12 mL), NaOH (0.12 mL, 15%) and
additional H2O (0.36 mL). The precipitate was ®ltered
and the ®ltrate was concentrated in vacuo. The residue
was chromatographed on silica gel elutingꢀwith EtOAc/
Synthesis of 31c.
A
mixture of 2-(bromo-
methyl)naphthalene (15.5 mmol, 3.43 g), potassium
carbonate (7.73 mmol, 1.07 g) and dl-proline (7.03
mmol, 809 mg) in DMF (10 mL) was heated at 60ꢀC for
2 days. It was cooled to room temperature, diluted with
ether (50 mL) and ®ltered. The ®ltrate was acidi®ed
(pH=4) by the addition of aqueous HCl (15%) and
extracted with ether (2 Â 50 mL). The aqueous layer
was basi®ed (pH=9) by the addition of NaOH, extrac-
ted with ether (3Â100 mL), dried over Na2SO4 and
concentrated in vacuo. The residue was chromato-
graphed on silica gel eluting with EtOAc/Skelly F (1/1) to
1
Skelly F to give 32a as a solid: mp 80±82 C; H NMR
(300 MHz) d 8.07 (br d, J=8.7 Hz, 2H), 7.49 (br s, NH),
7.20±7.36 (m, 7H), 4.49 (dd, J=14.4, 6.6 Hz, 1H), 4.33
(dd, J=14.7, 5.1 Hz, 1H), 3.91 (d, J=13.5 Hz, 1H), 3.59 (d,
J=13.8 Hz, 1H), 3.30 (dd, J=10.2, 5.4 Hz, 1H), 3.01 (ddd,
J=9.2, 6.7, 2.4 Hz, 1H), 2.20±2.40 (m, 2H), 1.65±2.00 (m,
3H); 13C NMR (75.4 MHz) d 173.76, 147.07, 145.83,
138.26, 129.19, 128.66, 127.56, 127.51, 123.58, 67.69, 59.21,
54.10, 42.94, 30.59, 24.11; MS (FAB), m/e 340 (100, M +
H), 205 (68); Anal. calcd for C19H21N3O3: C, 67.24; H,
6.24; N, 12.38. Found: C, 67.18; H, 6.28; N, 12.37.
1
give 31c as a yellow oil (1.91 g, 70%): H NMR (300
MHz) d 7.70±7.90 (m, 8H), 7.35±7.50 (m, 6H), 5.24 (d,
J=12.0 Hz, 1H), 5.17 (d, J=12.3 Hz, 1H), 4.08 (d,
J=12.6 Hz, 1H), 3.70 (d, J=12.6 Hz, 1H), 3.37 (dd,
J=8.7, 6.0 Hz, 1H), 3.07 (m, 1H), 2.44 (q, J=8.3 Hz, 1H),
1.70±2.20 (m, 4H); 13C NMR (75.4 MHz) d 173.98,
136.22, 133.32, 133.27, 133.13, 133.06, 132.71, 128.29,
127.95, 127.75, 127.71, 127.64, 127.56, 127.48, 127.42,
127.36, 126.19, 125.88, 125.79, 125.49, one aromatic signal
is not discernible, 66.35, 65.26, 58.78, 53.33, 29.36, 23.12;
The hydrochloride was prepared with ethereal HCl and
was crystallized from MeOH/2-PrOH/ether: mp>123ꢀC
(softens); MS (FAB), m/e 396 (100, M+H), 141 (78);
Synthesis of 32b. A suspension of LAH (1.26 mmol, 48
mg) in THF (20 mL) was re¯uxed for 1.5 h and then
cooled to room temperature. Benzylamine (6.3 mmol, 0.69
mL) was added and the mixture was stirred for 1 h. A
solution of 31b (1.26 mmol, 460 mg) in THF (10 mL) was
added and the mixture was stirred overnight at room
temperature. The reaction was quenched by the addition
of H2O (50 mL), NaOH (50 mL, 15%) and additional H2O
(150 mL). The precipitate was ®ltered and the ®ltrate was
concentrated in vacuo. The residue was chromatographed
on silica gel eluting with EtOAc/Skelly F to give 32b as a
yellow oil (323 mg, 71%): 1H NMR (300 MHz) d 7.63 (br
s, NH), 7.14±7.36 (m, 8H), 7.01 (dt, J=7.2, 1.7 Hz, 1H),
4.44 (dd, J=14.7, 6.3 Hz, 1H), 4.38 (dd, J=14.7, 5.7 Hz,
1H), 3.80 (d, J=12.9 Hz, 1H), 3.43 (d, J=12.9 Hz, 1H),
3.25 (dd, J=10.2, 4.8 Hz, 1H), 2.98 (ddd, J=9.2, 6.9, 2.4
Hz, 1H), 2.18±2.37 (m, 2H), 1.94 (m, 1H), 1.64±1.83 (m,
2H); 13C NMR (75.4 MHz) d 174.07, 140.41, 138.27,
134.13, 129.59, 128.63, 128.58, 127.46, 127.33, 126.68, one
ꢁ
.
Anal. calcd for C27H25NO2 HCl H2O: C, 72.07; H, 6.27;
Cl, 7.88; N, 3.11. Found: C, 72.02; H, 6.58; Cl, 7.99; N,
3.07.
Synthesis of 31d. A mixture of 4-methoxybenzyl chlo-
ride (22 mmol, 2.98 mL), potassium carbonate (11
mmol, 1.52 g) and dl-proline (10 mmol, 1.15 g) in DMF
(50 mL) was heated at 60ꢀC for 2 days. It was cooled to

1654
S. Zhao et al. / Bioorg. Med. Chem. 7 (1999) 1647±1654
aromatic signal is not discernible, 67.35, 59.27, 53.82,
42.90, 30.54, 24.01; MS (FAB), m/e 329 (100, M + H),
194 (28), 125 (13); The hydrochloride was prepared with
ethereal HCl and was crystallized from MeOH/2-PrOH/
ether: mp 175±177ꢀC; Anal. calcd for C19H21ClN2Oꢁ HCl:
C, 62.47; H, 6.07; Cl, 19.41; N, 7.67. Found: C, 62.37; H,
6.04; Cl, 19.29; N, 7.63.
References
1. (a) Cacabelos, R.; Nordberg, A.; Caamano, J.; Franco-
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Synthesis of 32c. A suspension of LAH (3.82 mmol, 145
mg) in THF (30 mL) was re¯uxed for 1.5 h and then cooled
to room temperature. Benzylamine (19.1 mmol, 2.09 mL)
was added and the mixture was stirred for 1 h. A solution
of 31c (3.82 mmol, 1.51 g) in THF (10 mL) was added and
the mixture was stirred overnight at room temperature.
The reaction was quenched by the addition of H2O (0.15
mL), NaOH (0.15 mL, 15%) and additional H2O (0.45
mL). The precipitate was ®ltered and the ®ltrate was con-
centrated in vacuo. The residue was chromatographed on
silica gel eluting with EtOAc/Skelly F (1/1) to give 32c as a
yellow oil (308 mg, 24%): 1H NMR (300 MHz) d 7.20±7.80
(m, 13 H), 4.41 (dd, J=15.0, 6.0 Hz, 1H), 4.36 (dd,
J=14.7, 5.7 Hz, 1H), 3.99 (d, J=12.9 Hz, 1H), 3.62 (d,
J=12.6 Hz, 1H), 3.34 (dd, J=10.5, 4.8 Hz, 1H), 3.00 (ddd,
J=9.0, 6.6, 2.4 Hz, 1H), 2.40 (td, J=10.2, 6.6 Hz, 1H),
2.27 (m, 1H), 1.60±2.00 (m, 3H); 13C NMR (75.4 MHz) d
174.42, 138.39, 135.94, 133.25, 132.62, 128.63, 128.06,
127.65, 127.57, 127.55, 127.34, 127.25, 126.78, 126.05,
125.74, 67.42, 60.10, 53.99, 42.96, 30.65, 24.13; The hy-
drochloride was prepared with ethereal HCl and was
crystallized from MeOH/2-PrOH/ether: mp 191±193ꢀC;
MS (FAB), m/e 345 (100, M+H), 210 (9), 141 (33); Anal.
calcd for C23H24N2Oꢁ HCl: C, 72.52; H, 6.62; Cl, 9.31; N,
7.35. Found: C, 72.12; H, 6.66; Cl, 9.33; N, 7.23.
7. O'Neill, P.M.; Bray, P. G.; Hawley, S. R.; Ward, S. A.;
Park, B. K. Pharmacol. Ther. 1998, 77, 29.
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1980, 76, 12: CA 94, 139584c.
Determination of cholinesterase and acetylcholinester-
ase activities. The methods are described in ref 9.
11. cf. Morie, T.; Kato, S.; Haradsa, H.; Fujiwara, I.; Wata-
nabe, K.; Matsumoto, J. J. Chem. Soc., Perkin Trans 1 1994,
2565. These authors describe the reaction of 1-benzyl-2-chlor-
omethylpiperidine with NaN3, followed by reduction with
sodium bis(2-methoxyethoxy)aluminum hydride and acetyla-
tion to give a mixture of 2-(acetylamino)methyl-1-benzylpi-
peridine and 3-acetylamino-1-benzylhexahydro-1H-azepine.
12. Cheeseman, R. S.; Kezaar, H. S. III.; Scribner, R. M. PCT
Int. Appl. WO 92 12,128, 1992.
Passive avoidance training. The methods are described
in ref 9.
Acknowledgements
We thank American Biogenetic Sciences for support of
this research and Mr. James Carolan, a summer under-
graduate researcher.
13. Solladie-Cavallo, A.; Bencheqroun, M. J. Org. Chem.
1992, 57, 5831.