A general and efficient synthesis of 3,6-diazabicyclo[3.2.1]octanes

Article abstract of DOI:10.1016/j.tet.2006.02.030

A convenient and efficient synthesis of N⁶-substituted 3,6-diazabicyclo[3.2.1]octanes (6a-c) has been achieved starting from suitably substituted lactams, which were converted to nitroenamines followed by reductive cyclization to afford 3,6-dia

Full text of DOI:10.1016/j.tet.2006.02.030

Tetrahedron 62 (2006) 4011–4017
A general and efficient synthesis of 3,6-diazabicyclo[3.2.1]octanes
Rakesh K. Singh,a,† Sanjay Jain,a, ,‡ Neelima Sinha,a,‡ Anita Mehta,a
*
Fehmida Naqvib and Nitya Ananda,
*
aMedicinal Chemistry Division, New Drug Discovery Research, Ranbaxy Laboratories Limited, R&D II, Plot # 20, Sector-18,
Udyog Vihar Industrial Area, Gurgaon 122 001, India
bDepartment of Chemistry, Jamia Millia Islamia, New Delhi 110 015, India
Received 28 October 2005; revised 18 January 2006; accepted 10 February 2006
Available online 3 March 2006
Abstract—A convenient and efficient synthesis of N6-substituted 3,6-diazabicyclo[3.2.1]octanes (6a–c) has been achieved starting from
suitably substituted lactams, which were converted to nitroenamines followed by reductive cyclization to afford 3,6-diazabicyclo[3.2.1]-
octane-2-ones in good yields. These bicyclic lactams were then reduced to the corresponding 3,6-diazabicyclo[3.2.1]octanes and converted
to the required N3,N6-disubstituted 3,6-diazabicyclo[3.2.1]octanes (7a–h), which were screened for a1-adrenoceptors antagonistic activities.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
workup generate hydrogen cyanide gas, and (c) poor yields
(18–40%). In this paper, we wish to report a convenient and
efficient synthesis of 3,6-diazabicyclo[3.2.1]octanes from
readily available 5-oxopyrrolidine-3-carboxylic acid methyl
ester. This method also provides an easy access to the
substitution at the N-3, N-6 and C-4 centre.
Lactams have been the subject of much study in this
laboratory for creation of molecular diversity, a useful
source of leads for potential bioactive agents/intermedi-
ates,1,2 through conversion to reactive intermediates such as
lactim ethers, lactim thioethers and lactam acetals, which
undergo facile reaction with both nucleophiles and
electrophiles and also with bifunctional reagents. In our
studies directed to the design of conformationally con-
strained prototypes incorporating the essential structural
features of important pharmacophores,3 we were interested
in the synthesis of 3,6-diazabicyclo[3.2.1]octanes (6).
2. Results and discussion
A retrosynthetic analysis of compound 6 (Scheme 1) indicated
the possibility of constructing 3,6-diazabicyclo[3.2.1]octanes
ring through reductive cyclization of a nitroenamine of
type II, which could in turn be obtained from lactam I, by
activation of the amide group followed by condensation with
nitroalkane.
A
literature survey revealed that 6-methyl-3,6-
diazabicyclo[3.2.1]octane 6a (Fig. 1) has been reported
once as a conformationally rigid ethylenediamine systems
from 2-azabicyclo[2.2.1]hept-5-ene via ozonolysis of the
double bond to a dialdehyde followed by reductive
amination using benzylamine.4 But this method has several
limitations: (a) ozonolysis is not a very convenient reaction
to carry out, (b) reductive amination was carried out in
presence of sodium cyanoborohydride, which during
1-Methyl-5-oxopyrrolidine-3-carboxylic acid methyl ester
1a and 1-(2-methoxyphenyl)-5-oxopyrrolidine-3-carboxylic
acid methyl ester 1b, prepared from itaconic acid following
R6
N
1
Keywords: 3,6-Diazabicyclo[3.2.1]octanes; Lactams; Itaconic acid; Nitro-
enamine; Reductive cyclization; RBx 2258.
4
3
R1
N
*
Corresponding authors. Tel.: C91 20 25126161; fax: C91 20 25171329;
H
e-mail addresses: sanjay.sjain@gmail.com; nityaanand@satyam.net.in
6a; R = Me, R1 = H
6b; R = R1 = Me
6c; R = 2-OMeC6H4, R1 = H
† Present address: Department of Pediatrics, Brown Medical School,
Kilguss Research Centre, Women and Infant Hospital, Providence, RI
02903, USA.
‡ Present address: Medicinal Chemistry Division, New Chemical Entity
Research, Lupin Research Park, 46/47A, Village Nande, Taluka Mulshi,
Pune 411 042, India.
Figure 1.
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.02.030

4012
R. K. Singh et al. / Tetrahedron 62 (2006) 4011–4017
R
R
N
N
CO2R"
CO2R"
CO2R"
O2N
R'
H2N
R'
O
N
R
II
N
R
N
R
R'
N
H
O
R'
N
H
I
IV
III
6
Scheme 1. Retrosynthetic approach to 3,6-diazabicyclo[3.2.1]octanes (6).
the procedure described in the literature,1d,5 were chosen as
the starting material for the synthesis of 3,6-diazabicyclo-
[3.2.1]octanes (6). The lactam 1a was treated with
Lawesson’s reagent to give the corresponding thiolactam
2a in almost quantitative yields. The thiolactam 2a was
converted to methylthioimonium iodide 3a with excess
methyl iodide in 96% yield, which on condensation with
nitromethane in DMF and excess of triethylamine yielded
the corresponding nitroenamine 4a in 45% yield (Scheme 2).
The nitroenamine 4a appeared to be thermodynamically
stable as the E-isomer as shown by NMR studies; irradiation
of the olefinic proton resulted in 11% NOE enhancement for
the N-methyl protons. Catalytic transfer hydrogenation of
nitroenamine 4a over 10% Pd–C in presence of ammonium
formate in MeOH at reflux, resulted in reduction of both the
double bond and the nitro group followed by in situ
cyclization to furnish 6-methyl-3,6-diazabicyclo[3.2.1]-
octan-2-one 5a in 70% yield. Finally, this bicyclic lactam
5a was subjected to LAH reduction in THF at reflux, which
after chromatographic purification afforded 6-methyl-3,6-
diazabicyclo[3.2.1]octane (6a) in 68% yield (Scheme 2).
Analogously, the corresponding 4,6-dimethyl analogue 6b
and 6-(2-methoxyphenyl) analogue 6c were synthesized in
53 and 57% yield, respectively, by using the appropriate
lactams and nitroalkanes. Compound 6b (R1ZCH3) was
isolated as a mixture of diastereoisomers of unassigned
relative configuration.
In the light of the likely benefits of restricted flexibility6 on
the pharmacokinetic properties of bioactive agents, various
3-substituted 6-(2-methoxyphenyl)-3,6-diazabicyclo-
[3.2.1]octanes (7a–h) were prepared because of
the structural analogy of 6-(2-methoxyphenyl)-3,6-
diazabicyclo[3.2.1]octane nucleus (6c) with 1-(2-
methoxyphenyl)piperazine the structural unit present in
RBx 2258 (entry 9, Table 1), the analogue RBx 2258,7
R
R
R
(i)
(ii)
N
N
I
N
O
O
O
O
H3CS
S
OCH3
OCH3
OCH3
1a; R = Me
2a; R = Me; 98%
3a; R = Me; 96%
1b; R = 2-OMeC6H4
2b; R = 2-OMeC6H4; 91%
3b; R = 2-OMeC6H4; 90%
R
N
R
(iii)
(iv)
N
R1
O
R1
N
H
O
O2N
OCH3
5a; R = Me, R1 = H; 70%
5b; R = R1 = Me; 35%
4a; R = Me, R1 = H; 45%
4b; R = R1 = Me; 36%
5c; R = 2-OMeC6H4, R1 = H; 70%
4c; R = 2-OMeC6H4, R1 = H; 45%
R
N
(v)
R1
N
H
6a; R = Me, R1 = H, 68%
6b; R = R1 = Me, 53%
6c; R = 2-OMeC6H4, R1 = H, 57%
Scheme 2. Reagents and conditions: (i) Lawesson’s reagent, THF, rt, 3 h; (ii) CH3I, PhMe or PhH, rt, 24 h; (iii) R1CH2NO2, Et3N, DMF, rt, 24 h;
(iv) HCOONH4, 10% Pd–C, MeOH, reflux, 7–10 h; (v) LAH, THF, reflux, 18 h.

R. K. Singh et al. / Tetrahedron 62 (2006) 4011–4017
4013
which has shown good a1-adrenoceptor blocking activity
and appear promising for the treatment of benign prostatic
hyperplasia (BPH) is in phase II clinical trials.
The compounds 7a–h (Table 1) were prepared starting from
1-(3-halopropyl)dicarboximides (9), which in turn were
prepared by condensing various a,u-dicarboximides (8) and
1-bromo-3-chloropropane according to the procedure
described in literature.7 The compounds
9 were
Table 1. Preparation of 3-substituted 6-(2-methoxyphenyl)-3,6-diazabi-
cyclo[3.2.1]octanes (7a–h)
then condensed with 6-(2-methoxyphenyl)-3,6-diazabi-
cyclo[3.2.1]octane (6c) in presence of K2CO3 in DMF at
60–70 8C to give 1-[6-(2-methoxyphenyl)-3,6-diazabi-
cyclo[3.2.1]octan-3-yl]-3-[N-(a,u-dicarboximido)]pro-
panes 7a–h in good yields (Table 1). Compounds 6b–c and
7a–h are hitherto unknown in the literature and their
structures were confirmed on the basis of elemental and
spectroscopic analysis.
Ref. 7
N
H
N
O
O
O
O
X
8
9; X = Cl, Br
6c, K2CO3
DMF
60-70 oC
Receptor binding assays were performed for native a1-
adrenoreceptors. Rat submaxillary and liver membrane
preparations were used to assess the affinity for a1A and a1B
subtypes, respectively.8 Aliquots of membrane protein
(100–200 mg) were incubated in a final volume of 250 mL
assay buffer (50 mM Tris, 0.5 mM EDTA at pH 7.4) with
0.5 nM [3H]prazosin for 60 m at 28 8C. Reaction was
stopped by rapid filtration on Millipore filters. Filters were
dried and bound radioactivity counted. Non-specific binding
was determined in the presence of 0.3 mM prazosin. Protein
was assayed according to the method of protein estimation9
with minor modifications. All the newly synthesized
analogues of RBx 2258 were screened for a1A inhibition.
However, none of these compounds have shown any
remarkable activity.
N
O
O
MeO
N
15-18 h
N
7a−h
Entry
Product
Yield
(%)a
O
MeO
N
N
N
1
2
78
70
O
7a
O
MeO
N
N
N
O
7b
3. Conclusion
O
MeO
N
H
N
N
In conclusion, a convenient and new approach for the
synthesis of 3,6-diazabicyclo[3.2.1]octanes (6) has been
accomplished. The key step of the synthesis involves
catalytic hydrogenation, accompanied with spontaneous
cyclization, of the nitroenamine 4. These nitroenamine can
be conveniently prepared in large quantities from readily
available starting materials. In addition, various confor-
mationally constrained analogues of RBx 2258 have been
synthesized. However, derivatives of our novel 6-(2-
3
4
67
54
O
H
7c
O
MeO
N
N
N
Et
O
Me
7d
O
MeO
N
N
N
5
71
methoxyphenyl)-3,6-diazabicyclo[3.2.1]octane
ring
O2N
O
systems have not shown any activity against a1-adrenor-
eceptors. The lack of activity against a1-adrenoceptors may
be probably due to steric hindrance of the methylene bridge
in the ligands–receptor interaction.
Cl
O
7e
MeO
N
N
N
6
7
64
45
O
7f
O
MeO
4. Experimental
4.1. General
N
S
N
N
O
O
7g
O
MeO
N
Melting points were recorded on a Bu¨chi B-540 melting
point apparatus. Compounds were routinely checked for
their purity on silica gel 60 F254 TLC plates and their spots
were visualized by exposing them to iodine vapor, UV lamp
or by spraying the plates with Dragendorff’s or KMnO4
reagents. IR spectra (ymax in cmK1) were recorded on Perkin
Elmer Paragon-1000PC instrument and NMR (300 MHz)
spectra were recorded on Bruker 300-DRX instrument as
solutions using TMS as internal standard, and chemical
shifts are expressed in d units. Mass spectra were recorded
N
N
8
9
46
—
Me
Me
O
7h
O
N
N
OMe
N
O
RBx 2258
a The yields are based on products isolated by column chromatography over
silica gel.

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R. K. Singh et al. / Tetrahedron 62 (2006) 4011–4017
on API-3000 LCMS/MS using direct inlet system under
positive ion electrospray ionization source. Elemental
analyses were carried out with a Perkin Elmer 2400
analyzer and values found were within G0.4% of
theoretical values.
yield 22.91 g (91%), mp 92–93 8C; ymax (CH2Cl2) 1738,
1585, 1210 cmK1; dH (CDCl3) 3.47–3.50 (m, 3H), 3.78
(s, 3H), 3.84 (s, 3H), 4.17–4.27 (m, 2H), 7.01–7.06 (m, 2H),
7.26–7.39 (m, 2H); dC (CDCl3) 197.9, 174.4, 158.9, 126.5,
125.6, 125.0, 121.1, 114.5, 59.5, 56.0, 50.8, 48.5, 36.5; m/z
266 (MC1). Anal. Calcd for C13H15NO3S (265.33): C,
58.85; H, 5.70; N, 5.28. Found: C, 59.03; H, 5.86; N, 5.02%.
4.2. General method of lactam 1
4.4. General procedure for compounds 3
4.2.1. 1-Methyl-5-oxopyrrolidine-3-carboxylic acid
methyl ester (1a). This was prepared according to the
literature method1d,5 starting from itaconic acid in 87%
yield as a thick oil; ymax (CH2Cl2) 1736, 1689 cmK1; dH
(CDCl3) 2.67–2.71 (m, 2H), 2.87 (s, 3H), 3.26 (m, 1H),
3.56–3.76 (m, 2H), 3.76 (s, 3H); m/z 158 (MC1). Anal.
Calcd for C7H11NO3 (157.17): C, 53.49; H, 7.05; N, 8.91.
Found: C, 53.52; H, 6.99; N, 9.05%.
4.4.1. 3-Methoxycarbonyl-1-methyl-5-methylthio-3,4-
dihydro-2H-pyrrolium iodide (3a). A solution of the
thiolactam 2a (17.3 g, 100 mmol) and methyl iodide
(70.95 g, 500 mmol) was stirred at 25–30 8C for 2 h, the
formation of a yellow precipitate indicates the formation of
the methylthioimonium iodide. The excess of methyl iodide
was removed under reduced pressure, the residue taken up
in dry benzene, stirred for 10 min, the solid, which separated
out was filtered, washed well with dry benzene and dry ether
and dried under vacuum over P2O5 to give 3a as pale yellow
solid, yield 30.24 g (96%), mp 104–106 8C; ymax (KBr)
2363, 2344, 1735, 1617 cmK1; dH (CDCl3) 2.94 (s, 3H),
3.45 (s, 3H), 3.68–3.74 (m, 1H), 3.80 (s, 3H), 3.94–4.02 (m,
1H), 4.26 (dd, JZ10.2 Hz, 1H), 4.45 (dd, JZ4.5 Hz, 1H),
4.79 (t, JZ11.1 Hz, 1H); m/z 189 (MC1). Anal. Calcd for
C8H14INO2S (315.17): C, 30.49; H, 4.48; N, 4.44. Found: C,
30.59; H, 4.56; N, 4.50%.
4.2.2. 1-(2-Methoxyphenyl)-5-oxopyrrolidine-3-carb-
oxylic acid methyl ester (1b). To a cooled (K5 8C)
solution of MeOH (100 mL), freshly distilled thionyl
chloride (13.09 g, 0.11 mmol) was added dropwise over a
period of 0.5 h, after addition was completed the resulting
mixture stirred at the same temperature for 0.5 h. To this 1-
(2-methoxyphenyl)-5-oxopyrrolidine-3-carboxylic acid5a
(23.5 g, 0.10 mmol) was added portion wise, at the same
temperature, stirred for another 0.5 h and then temperature
was allowed to rise to 25–30 8C and then stirred for 3 h.
MeOH was removed completely under reduced pressure.
The residue was dissolved in CHCl3 (200 mL) and washed
with 20% aq NaHCO3 (3!50 mL), water (1!50 mL),
brine (1!25 mL), dried (Na2SO4) and filtered. The filtrate
was concentrated under reduced pressure to give 1b as white
powder, yield 23.8 g (96%), mp 82–83 8C; ymax (KBr) 3000,
2960, 1729, 1690, 1593, 1503, 1414 cmK1; dH (CDCl3)
2.74–2.94 (m, 2H), 3.35–3.46 (m, 1H), 3.77 (s, 3H), 3.85
(s, 3H), 3.94–3.97 (d, JZ7.7 Hz, 2H), 6.94–7.00 (m, 2H),
7.24–7.30 (m, 2H); dC (CDCl3) 174.4, 170.0, 153.9, 126.5,
125.0, 121.4, 121.0, 114.1, 56.3, 50.6, 42.5, 36.0, 31.1; m/z
250 (MC1). Anal. Calcd for C13H15NO4 (249.26): C, 62.64;
H, 6.07; N, 5.62. Found: C, 63.00; H, 6.13; N, 5.29%.
4.4.2.
3-Methoxycarbonyl-1-(2-methoxyphenyl)-5-
methylthio-3,4-dihydro-2H-pyrrolium iodide (3b). This
was obtained in 90% yield as creamish-white powder by
reacting methyl iodide with thiolactam 2b according to the
procedure described for compound 3a; mp 139–141 8C;
ymax (KBr) 2951, 1792, 1573, 1497 cmK1; dH (CDCl3) 2.84
(s, 3H), 3.66 (m, 1H), 3.82 (s, 3H), 3.90 (s, 3H), 4.28–4.29
(m, 1H), 4.58–4.68 (m, 1H), 4.72–4.80 (m, 2H), 7.04–7.15
(m, 2H), 7.48–7.54 (m, 2H); m/z 281 (MC1). Anal. Calcd
for C14H18INO3S (407.27): C, 41.29; H, 4.45; N, 3.44.
Found: C, 41.05; H, 4.65; N, 3.03%.
4.5. General procedure for compounds 4
4.3. General method of thiolactam 2
4.5.1. 1-Methyl-5-nitromethylene-pyrrolidine-3-carb-
oxylic acid methyl ester (4a). To a stirred solution of 3a
(7.88 g, 25 mmol) in dry DMF (50 mL), dry Et3N (2.78 g,
27.5 mmol) and distilled nitromethane (7.63 g, 125 mmol)
were added under nitrogen atmosphere. The reaction
mixture was stirred at 25–30 8C for 12 h. DMF and excess
of nitromethane were removed under reduced pressure to
give a crude product, which was purified by column
chromatography over silica gel (230–400 mesh) using
CHC13–MeOH (98/2) as eluent to afford nitroenamine 4a
as yellow solid, yield 2.27 g (45%), mp 76–78 8C; ymax
(KBr) 1733, 1590, 1359 cmK1; dH (CDCl3) 2.87 (s, 3H),
3.23–3.33 (m, 1H), 3.63–3.69 (m, 3H), 3.73 (s, 3H), 3.84–
3.89 (m, 1H), 6.63 (s, 1H); dC (CDCl3) 174.8, 161.5, 102.1,
57.5, 51.0, 46.1, 35.5, 33.5; m/z 201 (MC1). Anal. Calcd for
C8H12N2O4 (200.19): C, 48.00; H, 6.04; N, 13.99. Found: C,
47.98; H, 6.22; N, 14.10%.
4.3.1. 1-Methyl-5-thioxopyrrolidine-3-carboxylic acid
methyl ester (2a). This was prepared according to the
literature method1d starting from 1a in 98% yield as a thick
oil; ymax (CH2Cl2) 1736, 1210 cmK1; dH (CDCl3) 3.26
(s, 3H), 3.31–3.35 (m, 3H), 3.74 (s, 3H), 3.90–3.97 (m, 1H),
4.04–4.09 (m, 1H); m/z 174 (MC1). Anal. Calcd for
C7H11NO2S (173.23): C, 48.53; H, 6.40; N, 8.09. Found: C,
48.20; H, 6.55; N, 8.00%.
4.3.2. 1-(2-Methoxyphenyl)-5-thioxopyrrolidine-3-car-
boxylic acid methyl ester (2b). To a solution of lactam
1b (23.65 g, 95 mmol) in dry THF (100 mL) was added
Lawesson’s reagent (19.19 g, 47.5 mmol) portion wise
under stirring at 25–30 8C and resulting reaction mixture
stirred for 4–5 h at same temperature. THF was removed
under reduced pressure to obtain a viscous residue, which
was dissolved in EtOAc (200 mL), washed with 10%
NaHCO3 (5!50 mL), brine (30 mL), dried (Na2SO4) and
filtered. The filtrate was concentrated under reduced
pressure to give the thiolactam 2b as off white powder,
4.5.2. 1-Methyl-5-(1-nitroethylidene)-pyrrolidine-3-
carboxylic acid methyl ester (4b). This was obtained in
36% yield as thick oil by reacting nitroethane with 3a

R. K. Singh et al. / Tetrahedron 62 (2006) 4011–4017
4015
according to the procedure described for compound 4a; ymax
(CH2Cl2) 1738, 1581, 1376 cmK1; dH (CDCl3) 2.31 (s, 3H),
3.14 (s, 3H), 3.18–3.28 (m, 1H), 3.57–3.60 (m, 3H), 3.72 (s,
3H), 3.77–3.88 (m, 1H); dC (CDCl3) 174.9, 154.1, 111.5,
57.6, 50.6, 46.5, 35.8, 32.9, 10.8; m/z 215 (MC1). Anal.
Calcd for C9H14N2O4 (214.22): C, 50.46; H, 6.59; N, 13.08.
Found: C, 50.55; H, 6.51; N, 13.17%.
6.60–6.69 (m, 4H); dC (CDCl3) 179.6, 146.7, 130.3, 121.5,
119.1, 115.0, 114.3, 63.5, 56.1, 51.9, 48.7, 39.0, 30.2; m/z 233
(MC1). Anal. Calcd for C13H16N2O2 (232.28): C, 67.22; H,
6.94; N, 12.06. Found: C, 67.25; H, 6.89; N, 11.96%.
4.7. General procedure for compounds 6
4.7.1. 6-Methyl-3,6-diazabicyclo[3.2.1]octane (6a). To a
stirred suspension of pulverized lithium aluminum hydride
(2.96 g, 78 mmol) in dry THF (5 mL), a solution of bicyclic
lactam 5a (2.73 g, 19.5 mmol) in dry THF (10 mL) was
added under N2 atmosphere at 25–30 8C and the resulting
reaction mixture was refluxed under stirring for 18 h. After
completion of reaction, reaction mixture was cooled to
K5 8C and cautiously decomposed with water (15 mL).
After stirring for 1 h at 25–30 8C, the reaction mass was
filtered, washed with THF, the filtrate was collected and
dried over Na2SO4, and filtered. The solvent was evaporated
to yield crude product, which was purified by column
chromatography over silica gel (100–120 mesh) using
CHC13–MeOH (95/5) as eluent to afford 1.68 g (68%) of
6-methyl-3,6-diazabicyclo[3.2.1]octane (6a) as a pale
yellow oil; ymax (CH2Cl2) 2908, 2805, 1490 cmK1; dH
(CDCl3) 1.65–1.78 (m, 2H), 1.85–1.95 (m, 1H), 2.20–2.25
(m, 2H), 2.31 (s, 3H), 2.58–2.70 (m, 1H), 2.75–2.90
(m, 4H); dC (CDCl3) 64.5, 54.3, 52.7, 51.5, 37.8, 36.9, 33.1;
m/z 127 (MC1). Anal. Calcd for C7H14N2 (126.20): C, 66.62;
H, 11.18; N, 22.20. Found: C, 66.75; H, 11.22; N, 21.95%.
4.5.3. 1-(2-Methoxyphenyl)-5-nitromethylene-pyrro-
lidine-3-carboxylic acid methyl ester (4c). This was
obtained in 45% yield as thick yellow oil by reacting
nitromethane with 3b according to the procedure described
for compound 4a; ymax (CH2Cl2) 2948, 1728, 1570, 1506,
1351 cmK1; dH (CDCl3) 3.40–3.50 (m, 1H), 3.79 (s, 3H),
3.84 (s, 3H), 3.85–3.92 (m, 3H), 4.03–4.23 (m, 1H), 6.38
(s, 1H), 6.99–7.04 (m, 2H), 7.35–7.40 (m, 2H); dC (CDCl3)
174.6, 153.7, 145.5, 129.1, 117.7, 114.6, 113.5, 103.5, 57.5,
56.1, 50.7, 45.5, 29.9; m/z 293 (MC1). Anal. Calcd for
C14H16N2O5 (292.29): C, 57.53; H, 5.52; N, 9.58. Found: C,
57.39; H, 5.65; N, 9.88%.
4.6. General procedure for compounds 5
4.6.1. 6-Methyl-3,6-diazabicyclo[3.2.1]octan-2-one (5a).
To a solution of nitroenamine 4a (3.0 g, 15.0 mmol) and
ammonium formate (18.9 g, 300 mmol) in MeOH (80 mL)
was added 10% Pd–C (2.25 g, wet) and the resulting
reaction mixture was refluxed under stirring for 10 h. After
completion of reaction, reaction mixture was cooled to
25–30 8C and filtered through Celite bed, washed with
MeOH (2!5 mL) and the combined filtrate was concen-
trated under reduced pressure to afford crude product, which
was dissolved in CHCl3 (10 mL). To this 10% NH3–CHCl3
(10 mL) was added and stirred for 0.5 h at 25–30 8C, solid
separated out was filtered off and filtrate was concentrated
under reduced pressure to obtain an oily residue, which was
purified by column chromatography over silica gel (100–
200 mesh) using CHCl3–MeOH (99.5/0.5)/(98/2) as
eluent to afford bicyclic lactam 5a as thick oil, yield
1.48 g (70%); ymax (CH2Cl2) 1682 cmK1; dH (CDCl3) 2.03–
2.16 (m, 2H), 2.58 (s, 3H), 2.85 (br s, 1H), 3.01–3.11
(m, 2H), 3.36 (br s, 1H), 3.24 (d, JZ11.5 Hz, 1H), 3.48 (d,
JZ11.2 Hz, 1H), 5.92 (br s, 1H); dC (CDCl3) 179.9, 63.6,
51.8, 49.2, 39.5, 35.8, 30.6; m/z 141 (MC1). Anal. Calcd for
C7H12N2O (140.18): C, 59.98; H, 8.63; N, 19.98. Found: C,
59.73; H, 8.56; N, 19.80%.
4.7.2. 4,6-Dimethyl-3,6-diazabicyclo[3.2.1]octane (6b).
This was obtained in 53% yield as thick oil from bicyclic
lactam 5b according to the procedure described for
compound 6a; ymax (CH2Cl2) 2890, 2800, 1495 cmK1; dH
(CDCl3) 1.38 (d, JZ7.2 Hz, 3H), 1.95 (br s, 3H), 2.18–2.22
(m, 2H), 2.30 (s, 3H), 2.45–2.50 (m, 1H), 2.70–2.85
(m, 2H), 3.22–3.30 (m, 1H); dC (CDCl3) 69.2, 54.8, 52.7,
49.2, 38.1, 36.7, 31.4, 18.6; m/z 141 (MC1). Anal. Calcd for
C8H16N2 (140.23): C, 68.52; H, 11.50; N, 19.98. Found: C,
68.25; H, 11.38; N, 20.10%.
4.7.3. 6-(2-Methoxyphenyl)-3,6-diazabicyclo[3.2.1]-
octane (6c). This was obtained in 57% yield as pale yellow
oil from bicyclic lactam 5c according to the procedure
described for compound 6a; ymax (CH2Cl2) 2900, 2815,
1498 cmK1; dH (CDCl3) 1.78–1.82 (m, 2H), 1.94–1.99
(m, 1H), 2.30 (br s, 1H), 2.62–2.67 (d, JZ9.6 Hz, 1H),
2.79–2.93 (dd, JZ9.9 Hz, 2H), 3.29–3.32 (d, JZ9.6 Hz,
1H), 3.60–3.65 (q, JZ4.8 Hz, 1H), 3.78 (s, 3H), 4.21–4.24
(t, JZ5.4 Hz, 1H), 6.67–6.73 (m, 2H), 6.82–6.88 (m, 2H);
dC (CDCl3) 146.5, 130.3, 121.9, 119.3, 115.6, 114.2, 63.6,
56.2, 53.9, 51.5, 50.0, 35.3, 31.9; m/z 219 (MC1). Anal.
Calcd for C13H18N2O (218.29): C, 71.53; H, 8.31; N, 12.83.
Found: C, 71.68; H, 8.11; N, 12.80%.
4.6.2. 4,6-Dimethyl-3,6-diazabicyclo[3.2.1]octan-2-one
(5b). This was obtained in 35% yield as thick oil from 4b
according to the procedure described for compound 5a; ymax
(CH2Cl2) 1680 cmK1; dH (CDCl3) 1.58 (d, JZ6.3 Hz, 3H),
1.92 (br s, 3H), 2.49 (s, 3H), 2.79 (br s, 2H), 3.28–3.38 (m,
2H), 5.30 (br s, 1H); dC (CDCl3) 179.8, 67.5, 52.2, 48.6,
39.5, 36.3, 27.9, 17.1; m/z 155 (MC1). Anal. Calcd for
C8H14N2O (154.21): C, 62.31; H, 9.15; N, 18.17. Found: C,
62.57; H, 8.99; N, 18.06%.
4.8. General procedure for compounds 7
4.8.1. 1-{3-[6-(2-Methoxyphenyl)-3,6-diazabicyclo-
[3.2.1]oct-3-yl]propyl}piperidine-2,6-dione (7a). A mix-
ture of 1-(3-chloropropyl)piperidine-2,6-dione (0.834 g,
4.4 mmol), 6-(2-methoxyphenyl)-3,6-diazabicyclo[3.2.1]oc-
tane (6c, 0.863 g, 3.96 mmol, 0.9 equiv), K2CO3 (0.303 g,
2.2 mmol, 0.5 equiv) and KI (0.146 g, 0.88 mmol, 0.2 equiv)
in DMF (15 mL) was heated at 60–70 8C under stirring for
4.6.3. 6-(2-Methoxyphenyl)-3,6-diazabicyclo[3.2.1]-
octan-2-one (5c). This was obtained in 70% yield as thick
oil from 4c according to the procedure described for
compound 5a; ymax (CH2Cl2) 1685 cmK1; dH (CDCl3) 2.04–
2.11 (m, 2H), 2.97 (br s, 1H), 3.28–3.33 (m, 1H), 3.55–3.72
(m, 3H), 3.83 (s, 3H), 4.62 (br s, 1H), 5.40 (br s, 1H),

4016
R. K. Singh et al. / Tetrahedron 62 (2006) 4011–4017
18 h. After cooling the reaction mixture to ambient
temperature, water (75 mL) was added and extracted with
CH2Cl2 (2!50 mL). The combined organic phase was
washed with water (2!50 mL) and dried (Na2SO4), filtered
and concentrated under reduced pressure to give crude
product, which was purified by column chromatography
over silica gel (100–120 mesh) using CHCl3–MeOH (99/1)/
(97/3) as eluent to afford 7a as thick oil, yield 1.15 g (78%);
ymax (CH2Cl2) 2945, 1771, 1710, 1594, 1503, 1395 cmK1; dH
(CDCl3) 1.52–1.55 (m, 2H), 1.84–1.96 (m, 4H), 2.00–2.08 (br
d, 1H), 2.32–2.41 (br d, 4H), 2.57 (t, JZ6.3 Hz, 4H), 2.95 (d,
JZ9.3 Hz, 2H), 3.45–3.54 (m, 3H), 3.74 (d, JZ7.5 Hz, 1H),
3.78 (s, 3H), 4.39 (br s, 1H), 6.61–6.84 (m, 4H); dC (CDCl3)
172.6, 146.5, 130.3, 121.6, 119.0, 115.1, 114.4, 61.5, 56.2,
54.7, 53.7, 51.3, 38.9, 33.7, 32.8, 32.0, 28.6, 18.1; m/z 372
(MC1). Anal. Calcd for C21H29N3O3 (371.47): C, 67.90; H,
7.87; N, 11.31. Found: C, 68.03; H, 8.01; N, 11.38%.
3.57 (m, 3H), 3.79 (br s, 4H), 4.40 (t, JZ4.2 Hz, 1H), 6.61–
6.84 (m, 4H); dC (CDCl3) 174.2, 148.2, 131.4, 123.3, 120.0,
116.2, 115.5, 63.3, 57.8, 57.1, 56.2, 55.0, 52.3, 45.6, 40.1,
34.0, 33.4, 33.0, 30.1, 25.3, 22.4, 10.5; m/z 414 (MC1).
Anal. Calcd for C24H35N3O3 (413.55): C, 69.70; H, 8.53; N,
10.16. Found: C, 70.01; H, 8.68; N, 10.01%.
4.8.5. 5-Chloro-2-{3-[6-(2-methoxyphenyl)-3,6-diazabi-
cyclo[3.2.1]oct-3-yl]propyl}-6-nitro-isoindole-1,3-dione
(7e). This was obtained in 71% yield as thick oil by reacting
5-chloro-2-(3-chloropropyl)-6-nitro-isoindole-1,3-dione
with 6c according to the procedure described for compound
7a; ymax (CH2Cl2) 3447, 2944, 1767, 1708, 1627, 1592,
1520 cmK1; dH (CDCl3) 1.94 (d, JZ10.6 Hz, 1H), 2.06–
2.13 (m, 3H), 2.58 (br s, 1H), 2.88–2.95 (m, 1H), 3.11
(d, JZ9.3 Hz, 1H), 3.26 (t, JZ13.2 Hz, 2H), 3.46–3.60 (m,
4H), 3.77 (t, JZ6.6 Hz, 2H), 3.88 (s, 3H), 4.43–4.44
(m, 1H), 6.62–6.64 (m, 1H), 6.73–6.84 (m, 2H), 6.89–6.91
(m, 1H), 7.57 (s, 1H), 8.09 (s, 1H); dC (CDCl3) 167.5, 154.3,
148.5, 141.6, 133.4, 132.3, 131.2, 129.7, 125.2, 122.7,
120.0, 116.4, 115.5, 63.1, 57.4, 57.0, 55.7, 54.9, 52.4, 40.5,
33.9, 33.1, 29.9; m/z 485 (MC1). Anal. Calcd for
C24H25ClN4O5 (484.93): C, 59.44; H, 5.20; N, 11.55.
Found: C, 59.51; H, 5.22; N, 11.50%.
4.8.2. 2-{3-[6-(2-Methoxyphenyl)-3,6-diazabicyclo-
[3.2.1]oct-3-yl]propyl}isoindole-1,3-dione (7b). This was
obtained in 70% yield as thick oil by reacting 2-(3-
chloropropyl)isoindole-1,3-dione with 6c according to the
procedure described for compound 7a; ymax (CH2Cl2) 2947,
1777, 1698, 1503, 1450 cmK1; dH (CDCl3) 1.67–1.71
(m, 2H), 1.95–1.99 (br d, 2H), 2.15 (d, JZ10.2 Hz, 2H),
2.35 (t, JZ6.6 Hz, 2H), 2.41 (d, JZ3.9 Hz, 1H), 2.88–3.12
(m, 2H), 3.42 (d, JZ6.3 Hz, 1H), 3.46 (t, JZ5.1 Hz, 2H),
3.68–3.70 (m, 1H), 3.78 (s, 3H), 4.39 (d, JZ3.9 Hz, 1H),
6.60–6.75 (m, 1H), 6.78–6.81 (m, 3H), 7.65–7.69 (m, 2H),
7.70–7.80 (m, 2H); dC (CDCl3) 167.2, 148.2, 133.4, 133.0,
131.1, 128.4, 122.9, 120.1, 116.2, 115.5, 62.8, 57.6, 57.0,
55.7, 54.9, 52.5, 40.2, 33.9, 33.2, 30.1; m/z 406 (MC1).
Anal. Calcd for C24H27N3O3 (405.49): C, 71.09; H, 6.71; N,
10.36. Found: C, 70.94; H, 6.80; N, 10.13%.
4.8.6. 1-{3-[6-(2-Methoxyphenyl)-3,6-diazabicyclo-
[3.2.1]oct-3-yl]propyl}pyrrolidine-2,5-dione hydrochlo-
ride (7f). This was obtained by reacting 1-(3-chloropropyl)-
pyrrolidine-2,5-dione with 6c according to the procedure
described for compound 7a, which was converted to
corresponding hydrochloride salt by treating with 1 equiv
ethanolic-HCl, 64% yield, mp 114–116 8C; ymax (KBr)
3428, 2958, 1769, 1694, 1593, 1502 cmK1; dH (D2O) 1.96–
2.07 (m, 2H), 2.77 (s, 4H), 2.83 (br s, 1H), 3.18 (t, JZ
7.8 Hz, 2H), 3.26 (br d, JZ12.0 Hz, 2H), 3.51–3.54 (m,
4H), 3.84 (br s, 4H), 3.90 (s, 3H), 4.30 (br s, 1H), 6.97–7.07
(m, 4H); dC (D2O) 175.5, 148.2, 132.4, 122.7, 120.6, 117.3,
116.1, 63.6, 58.5, 57.9, 55.7, 55.2, 52.3, 40.6, 34.2, 33.6,
30.8, 28.8; m/z 358 (MC1). Anal. Calcd for C20H27N3-
O3$HCl (393.91): C, 60.98; H, 7.16; N, 10.67. Found: C,
60.61; H, 7.52; N, 10.35%.
4.8.3. 2-{3-[6-(2-Methoxyphenyl)-3,6-diazabicyclo-
[3.2.1]oct-3-yl]propyl}-3a,4,7,7a-tetrahydroisoindole-
1,3-dione (7c). This was obtained in 67% yield as thick oil
by reacting 2-(3-chloropropyl)-3a,4,7,7a-tetrahydroisoin-
dole-1,3-dione with 6c according to the procedure described
for compound 7a; ymax (CH2Cl2) 3976, 3396, 2949, 1722,
1671, 1590, 1505, 1350 cmK1; dH (CDCl3) 1.51–1.59
(m, 4H), 1.65–1.70 (m, 2H), 1.94 (d, JZ9.9 Hz, 2H), 2.13
(dd, JZ10.5 Hz, 2H), 2.26 (t, JZ6.6 Hz, 2H), 2.39 (br s,
1H), 2.52–2.57 (m, 1H), 2.92–2.93 (m, 1H), 2.97 (t, JZ
6.6 Hz, 2H), 3.18–3.25 (m, 2H), 3.45–3.47 (t, JZ6.3 Hz,
2H), 3.78 (s, 3H), 4.39 (br s, 1H), 5.83–5.84 (d, JZ2.4 Hz,
2H), 6.61–6.84 (m, 4H); dC (CDCl3): d 179.1, 147.8, 132.8,
131.4, 123.0, 120.1, 115.2, 114.9, 63.1, 57.6, 57.1, 55.8,
54.8, 52.5, 44.1, 40.1, 33.2, 33.0, 29.8, 28.0; m/z 410 (MC
1). Anal. Calcd for C24H31N3O3 (409.52): C, 70.39; H, 7.63;
N, 10.26. Found: C, 70.49; H, 7.68; N, 10.30%.
4.8.7. 2-{3-[6-(2-Methoxyphenyl)-3,6-diazabicyclo-
[3.2.1]oct-3-yl]propyl}-1,1-dioxo-1,2-dihydro-1-
benzo[d]isothiazol-3-one (7g). This was obtained in
45% yield as thick oil by reacting 2-(3-chloropropyl)-1,1-
dioxo-1,2-dihydro-1-benzo[d]isothiazol-3-one with 6c
according to the procedure described for compound 7a;
ymax (CHCl3) 3417, 2915, 1731, 1594, 1502, 1457,
1332 cmK1; dH (CDCl3) 1.94 (br s, 2H), 2.31 (t, JZ
6.9 Hz, 2H), 2.84 (br s, 1H), 3.08 (d, JZ6.6 Hz, 1H), 3.30–
3.39 (m, 5H) 3.64–3.68 (m, 2H), 3.75–3.80 (m, 5H), 4.26 (br
s, 1H), 6.90–6.95 (m, 4H), 7.84–8.11 (m, 4H); dC (CDCl3)
170.2, 148.2, 139.9, 134.5, 132.8, 131.5, 132.1, 129.4,
126.8, 123.5, 121.3, 116.8, 115.6, 63.5, 57.3, 57.0, 55.8,
54.9, 53.0, 38.9, 33.8, 33.0, 30.1; m/z 442 (MC1). Anal.
Calcd for C23H27N3O4S (441.54): C, 62.56; H, 6.16; N,
9.52. Found: C, 62.25; H, 5.99; N, 9.50%.
4.8.4. 4-Ethyl-1-{3-[6-(2-methoxyphenyl)-3,6-diazabi-
cyclo[3.2.1]oct-3-yl]propyl}-4-methyl-piperidine-2,6-
dione (7d). This was obtained in 54% yield as thick oil by
reacting 1-(3-chloropropyl)-4-ethyl-4-methylpiperidine-
2,6-dione with 6c according to the procedure described for
compound 7a; ymax (CH2Cl2) 3970, 3394, 2943, 1724, 1673,
1592, 1510 cmK1; dH (CDCl3) 0.83–0.88 (t, JZ7.5 Hz, 3H),
0.95 (s, 3H), 1.25–1.33 (m, 2H), 1.52–1.67 (m, 4H), 1.97
(d, JZ10.8 Hz, 2H), 2.12 (br s, 1H), 2.30–2.34
(t, JZ7.2 Hz, 2H), 2.42 (s, 4H), 2.88–3.12 (m, 2H), 3.46–
4.8.8. 1-{3-[6-(2-Methoxyphenyl)-3,6-diazabicyclo-
[3.2.1]oct-3-yl]propyl}-4,4-dimethylpiperidine-2,6-dione
(7h). This was obtained in 46% yield as thick oil by reacting
1-(3-chloropropyl)-4,4-dimethylpiperidine-2,6-dione with

R. K. Singh et al. / Tetrahedron 62 (2006) 4011–4017
4017
6c according to the procedure described for compound 7a;
References and notes
ymax (CHCl3) 2954, 2764, 1723, 1672, 1594, 1503,
1358 cmK1; dH (CDCl3) 1.01 (s, 6H), 1.51–1.63 (m, 5H),
1.97 (d, JZ10.2 Hz, 1H), 2.10 (d, JZ9.9 Hz, 1H), 2.32 (t,
JZ6.9 Hz, 2H), 2.43 (s, 4H), 2.91–3.01 (m, 2H), 3.52 (t,
JZ7.5 Hz, 2H), 3.73 (d, JZ9.3 Hz, 2H), 3.78 (s, 3H), 4.39
(br s, 1H), 6.16–6.81 (m, 4H); dC (CDCl3) 174.8, 148.2,
131.6, 123.1, 121.5, 116.8, 115.5, 63.3, 57.8, 57.0, 55.7,
55.1, 52.7, 48.0, 39.9, 34.2, 33.6, 30.3, 27.7, 19.8; m/z 400
(MC1). Anal. Calcd for C23H33N3O3 (399.53): C, 69.14; H,
8.33; N, 10.52. Found: C, 69.22; H, 8.50; N, 10.53%.
1. (a) Sinha, N.; Jain, S.; Saxena, A. K.; Anand, N.; Saxena, R. M.;
Dubey, M. P.; Patnaik, G. K.; Ray, M. (Council of Sci. Ind. Res.).
US 6084097, 2000; Chem. Abstr. 2000, 133, 74036. (b) Sinha, N.;
Jain, S.; Anand, N. Teterahedron Lett. 2005, 46, 153. (c) Singh,
R. K.; Sinha, N.; Jain, S.; Salman, M.; Naqvi, F.; Anand, N.
Synthesis 2005, 2765. (d) Singh, R. K.; Sinha, N.; Jain, S.; Salman,
M.; Naqvi, F.; Anand, N. Tetrahedron 2005, 61, 8868.
2. (a) Anand, N.; Jain, S.; Sinha, N. J. Indian Chem. Soc. 1997, 74,
948. (b) Anand, N.; Singh, J. Tetrahedron 1988, 44, 5975.
3. Jain, S.; Sujatha, K.; Rama Krishna, K. V.; Roy, R.; Singh, J.;
Anand, N. Tetrahedron 1992, 48, 4985.
4.8.9. 1-(3-Halopropyl)dicarboximides (9). These were
prepared according to the literature procedure7 by conden-
sing various commercially available a,u-dicarboximides
(8) and 1-bromo-3-chloropropane.
4. Fray, A. H.; Augeri, D. J.; Kleinman, E. F. J. Org. Chem. 1988,
53, 896.
5. (a) Paytash, P. L.; Sparrow, E.; Gathe, J. C. J. Am. Chem. Soc.
1950, 72, 1415. (b) Sysko, R. J.; Tate, B. E. Eur. Patent Appl.
EP69512, 1983; Chem. Abstr. 1983, 98, 166765.
6. Veber, D. F.; Johnson, S. R.; Cheng, H.-Y.; Smith, B. R.;
Ward, K. W.; Kopple, K. D. J. Med. Chem. 2002, 45, 2615.
7. Anand, N.; Sinha, N.; Jain, S.; Mehta, A.; Saxena, A. K.;
Gupta, J. B. (Ranbaxy Laboratories Limited). WO
200005205, 2000 and references cited therein; Chem.
Abstr. 2000, 132, 107963.
Acknowledgements
We thank CSIR New Delhi, for Research Fellowship to
R.K.S. and financial support for this work. We are also
grateful to Pharmacology Division for receptor binding
assay and Analytical Chemistry Division for IR, 1H and 13
8. Michel, A. D.; Loury, D. N.; Whiting, R. L. Br. J. Pharmacol.
1989, 98, 883.
C
NMR, mass spectroscopy, and elemental analyses of all the
compounds synthesized.
9. U’Prichard, D. C.; Charness, M. E.; Robertson, D.; Snyder,
S. H. Eur. J. Pharmacol. 1978, 50, 87.