A simple and efficient synthesis of 8-methyl-3,8-diazabicyclo[3.2.1]octane (azatropane) and 3-substituted azatropanes therefrom using pyroglutamic acid

Article abstract of DOI:10.1016/j.tetlet.2006.11.141

8-Methyl-3,8-diazabicyclo[3.2.1]octane (3-azatropane) is synthesized efficiently from pyroglutamic acid making use of amide activation. The key step of the synthesis involves reduction and cyclization of a nitroenamine intermediate. Several 3-substituted

Full text of DOI:10.1016/j.tetlet.2006.11.141

Tetrahedron Letters 48 (2007) 545–548
A simple and efficient synthesis of
8-methyl-3,8-diazabicyclo[3.2.1]octane (azatropane) and
3-substituted azatropanes therefrom using pyroglutamic acid
Rakesh K. Singh,a,ꢀ Sanjay Jain,a,*,ꢁ Neelima Sinha,a,ꢁ Anita Mehta,a
Fehmida Naqvi,b Ashok K. Agarwalc 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
cIndustrial Toxicology Research Centre, PO Box 80, Mahatma Gandhi Marg, Lucknow 226 001, India
Received 31 August 2006; revised 16 November 2006; accepted 22 November 2006
Available online 12 December 2006
Abstract—8-Methyl-3,8-diazabicyclo[3.2.1]octane (3-azatropane) is synthesized efficiently from pyroglutamic acid making use of
amide activation. The key step of the synthesis involves reduction and cyclization of a nitroenamine intermediate. Several 3-substi-
tuted analogues of this azatropane were also synthesized via this methodology and evaluated for their affinity at D2 and 5-HT2A
receptors.
ꢀ 2006 Elsevier Ltd. All rights reserved.
In continuation of our systematic studies on the syn-
thetic utility of activated lactams derived from a-amino
acids,1 we report a simple and efficient method for the
synthesis of 8-methyl-3,8-diazabicyclo[3.2.1]octane I
(R = H, Fig. 1) and 3-substituted derivatives therefrom
starting from commercially available pyroglutamic acid.
Me
N
Me
N
N
R
X
I
X = CH2; tropane
X = NH; 3-azatropane
8-Methyl-3,8-diazabicyclo[3.2.1]octane, which is
a
bridged homopiperazine, is a common pharmacophore
in a number of biologically active compounds acting
on the CNS and CVS and as anthelmintics.2–5 A notice-
able feature of compounds of formula I is that they pos-
sess a 3-azatropane skeleton and therefore might display
promising pharmacological properties. Tropane alka-
loids have been important targets in organic synthesis
Figure 1.
because of their biological properties as well as to find
out their mode of action.6 Among them, cocaine and
its isomers are interesting tropane alkaloids and a num-
ber of their analogues have been synthesized.7 There are
only a few reports in the literature for the synthesis of
3-azatropane.8
Keywords: 8-Methyl-3,8-diazabicyclo[3.2.1]octane; 3-Azatropane;
DABCO; Pyroglutamic acid; Hydrogenation; Lactams.
8-Methyl-3,8-diazabicyclo[3.2.1]octane was synthesized
in six steps as shown in Scheme 1.
*
Corresponding authors. Tel.: +91 20 25126161; fax: +91 20 25171329
(S.J.); e-mail addresses: sanjay.sjain@gmail.com; nityaanand@
satyam.net.in
Commercially available pyroglutamic acid 1 was con-
verted to methyl 1-methyl-5-oxopyrrolidine-2-carboxyl-
ate 2 in one step following the procedure described in
the literature.9 Lactam 2 was then treated with Lawes-
son’s reagent in anhydrous THF to give the correspond-
ing thiolactam 3 in 78% yield. Thiolactam 3 was
ꢀ Present address: Department of Pediatrics, Kilguss Research Center,
Woman and Infant Hospital, Brown Medical School, Providence, RI
02903, USA.
ꢁ Present address: Medicinal Chemistry Division, NCER, Lupin
Research Park, 46/47A, Village Nande, Taluka Mulshi, Pune 411
042, India.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.141

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R. K. Singh et al. / Tetrahedron Letters 48 (2007) 545–548
(ii)
(iii)
(i)
CO2H
O
CO2Me
S
CO2Me
O
N
H
N
N
78%
95%
Me
Me
1
2
3
MeS
CO2Me
N
I
Me
Me
N
Me
4
N
O2N
(vi)
77%
(v)
(iv)
CO2Me
N
N
H
N
H
O
65%
79%
H
Me
6
5
7
Scheme 1. Reagents and conditions: (i) Ref. 9; (ii) Lawesson’s reagent, THF, rt, 3–4 h; (iii) CH3I, PhH, rt, 12 h; (iv) CH3NO2, Et3N, DMF, N2", rt,
24 h; (v) HCO2NH4, 10% Pd–C, MeOH, reflux, 2–4 h; (vi) LAH pellets, THF, reflux, 4–6 h.
converted to methylthioimonium iodide 4 with excess
CH3I, which on further condensation with CH3NO2 in
the presence of Et3N yielded the corresponding nitroen-
amine 5 in 65% yield (Scheme 1).10 Nitroenamine 5 was
found to be thermodynamically stable as the E-isomer,
as shown by NMR studies. Catalytic transfer hydroge-
nation of nitroenamine 5 over 10% Pd–C in the presence
of HCO2NH4 in absolute MeOH at reflux, resulted in
the reduction of both the double bond and the nitro
group followed by in situ cyclization to give 8-methyl-
3,8-diazabicyclo[3.2.1]octan-2-one (6)10 in 79% yield.
Finally, bicyclic lactam 6 was reduced to the desired
8-methyl-3,8-diazabicyclo[3.2.1]octane (7) in 77% yield
by refluxing with LAH pellets in anhydrous THF
(Scheme 1).11 This amine 7 was further converted to
its dihydrochloride salt by treatment with ethereal–
HCl and characterized by comparison of spectroscopic
(1H NMR, MS) and analytical data.12
Derivatives 8–1113 of 8-methyl-3,8-diazabicyclo[3.2.1]-
octane 7 were also prepared as described in Table 1 to
establish the validity of our synthetic route and to eval-
uate their affinity towards D2, 5-HT2A and muscarinic
receptors.
Affinities for D2, 5-HT2A and cholinergic-muscarinic
receptors were determined using [3H]-spiperone, [3H]-
ketanserin and [3H]-quinuclidinyl benzilate, respectively,
as radioligands. The synaptic membrane preparation
used in all receptor binding experiments was prepared
Table 1. Synthesis of 3-substituted 8-methyl-3,8-diazabicyclo[3.2.1]octanes (8–11)
RCl
Me
N
Me
N
Me
N
RCO H
2
K CO
2
(COCl)
3
2
DMF
60-65
7 h
DMF
o
DCM
o
C
N
R
N
H
N
0
C, 1 h
rt, 12 h
O
R
8
9-11
7
Compounds
R
Yielda (%)
Receptor binding affinityb
D2
48
5-HT2A
Cholinergic-muscarinic
8
9
49
72
53
81
80
43
28
36
30
Me
Me
10
38
63
71
41
11
23
40
N
H
a Yields of analytically pure products.
b % Inhibition.

R. K. Singh et al. / Tetrahedron Letters 48 (2007) 545–548
547
according to the method described by Agarwal et al.14
The known derivatives 8 and 9 have shown the previ-
ously reported5,15 anti-muscarinic activity. Interestingly,
these compounds have also shown 5-HT2A and anti-
dopaminergic activity, which was previously not de-
scribed. In particular, compound 8 appears to be a new
and promising 5-HT2A lead. Since all of these com-
pounds showed rather significant binding to the majority
of the neurotransmitters with altogether different thera-
peutic potential, these structures infer the existence of
certain common chemical space available within these
neurotransmitters, which participate in binding. This
chemical space can probably be effectively exploited to
identify leads for one or more of these neurotransmitters.
Org. Chem. 1961, 26, 2747; (c) Cignarella, G.; Occelli, E.;
Maffii, G.; Testa, E. J. Med. Chem. 1963, 6, 385.
9. Pascal, C.; Benoit, R.; Dominique, F.; Daniel, C. J.
Heterocycl. Chem. 1991, 28, 1143.
10. Compounds 3–6 were prepared according to the method-
ology1 developed by us using methyl 1-methyl-5-oxopyrr-
olidine-2-carboxylate 2 as a starting material.
11. Preparation of 8-Methyl-3,8-diazabicyclo[3.2.1]octane 7.
To a suspension of LAH pellets (5.1 g, 0.134 mol) in
anhydrous THF (10 mL), a solution of bicyclic amide 6
(5.0 g, 0.036 mol) in anhydrous THF (15 mL) was added
dropwise under stirring and refluxing. After the addition
was complete, the resulting reaction mixture was refluxed
for 24 h. After completion of the reaction, the mixture was
cooled to room temperature and chilled in an ice bath and
carefully transferred to a pre-chilled conical flask contain-
ing EtOAc (100 mL) and stirred at 0 ꢁC for 30 min. To the
above suspension was added EtOAc (100 mL) and water
(10 mL) portion-wise, and stirring continued until the
suspension turned white. The reaction mixture was filtered
through Celite, which was washed with THF (3 · 20 mL)
and MeOH (3 · 20 mL). The combined organic layer was
concentrated under reduced pressure to give an oily
residue, which was purified by column chromatography
over silica gel (100–200 mesh) using CHCl3–MeOH–Et3N
(94:5:1) as the eluent to afford 7 as a yellow oil (3.5 g, 77%).
12. Analytical data for compounds 3, 5–7. Compound 3: thick
yellow oil (78%); mmax (CH2Cl2) 1744 cmꢀ1; dH (300 MHz,
CDCl3) 2.39–2.47 (m, 2H), 2.78–2.79 (m, 1H), 2.88 (s, 3H),
3.72 (s, 3H), 3.81–3.83 (br s, 1H), 4.11 (m, 1H); m/z 174
[M+1]. Anal. Calcd for C7H11NO2S (173.23): C, 48.53; H,
6.40; N, 8.09. Found: C, 48.77; H, 6.68; N, 8.13.
Compound 5: yellow solid (65%), mp 111–113 ꢁC; mmax
In conclusion, a simple and efficient method for the syn-
thesis of 8-methyl-3,8-diazabicyclo[3.2.1]octane (7) has
been accomplished. Several 3-substituted analogues of
8-methyl-3,8-diazabicyclo[3.2.1]octane have also been
synthesized. In addition to the previously reported
anti-muscarinic activity, these compounds have also
shown 5-HT2A and anti-dopaminergic activity.
Acknowledgements
We thank CSIR New Delhi, for a Research Fellowship
to R.K.S. and financial support for this work. We are
also grateful to the Analytical Chemistry Division for
IR, 1H NMR and mass spectroscopy and to CDRI,
Lucknow for the elemental analyses of all the com-
pounds synthesized.
(CH2Cl2) 1733, 1573, 1540, 1478, 1358 cmꢀ1
; dH
(300 MHz, CDCl3) 2.14–2.22 (m, 1H), 2.34–2.42 (qnt,
1H, J = 9.6 Hz), 2.88 (s, 3H), 3.28–3.38 (q, 1H,
J = 9.6 Hz), 3.55–3.69 (q, 1H, J = 6.0 Hz), 3.78 (s, 3H),
4.26–4.30 (dd, 1H, J = 3.3, 6.1 Hz), 6.70 (s, 1H); m/z 201
[M+1]. Anal. Calcd for C8H12N2O4 (200.19): C, 48.00; H,
6.04; N, 13.99. Found: C, 47.88; H, 6.11; N, 14.24.
Compound 6: off white solid (79%); mp 95–96 ꢁC (lit.16 mp
96–97 ꢁC); mmax (KBr) 1665 cmꢀ1; dH (300 MHz, CDCl3)
1.74–1.79 (t, 1H, J = 9.6 Hz), 2.03–2.09 (t, 1H,
J = 9.9 Hz), 2.17–2.29 (m, 2H), 2.52 (s, 3H), 2.98–3.02
(m, 1H), 3.36–3.41 (t, 2H, J = 5.2 Hz), 3.66–3.71 (dd, 1H,
J = 3.6, 5.3 Hz), 6.01 (br s, 1H); m/z 141 [M+1]. Anal.
Calcd for C7H12N2O (140.18): C, 59.98; H, 8.63; N, 19.98.
Found: C, 59.67; H, 8.60; N, 20.05. Compound 7: thick oil
(77%); dH (300 MHz, CDCl3) 1.75–1.77 (br s, 2H), 2.01–
2.05 (q, 2H, J = 6.0 Hz), 2.31 (s, 3H), 2.61–2.66 (dd, 2H,
J = 10.0, 3.0 Hz), 3.09–3.13 (d, 4H, J = 9.6 Hz), 4.57 (br s,
1H); m/z 127 [M+1]. An analytical sample was obtained as
a dihydrochloride salt, which was prepared by dissolving
80 mg of 7 in a 1.4 mL solution of 1 M HCl–Et2O, mp
308–310 ꢁC (lit.8a 314–315 ꢁC). Anal. Calcd for
C7H14N2Æ2HCl (199.12): C, 42.22; H, 8.10; N, 14.07.
Found: C, 42.56; H, 8.21; N, 13.92.
References and notes
1. (a) Jain, S.; Sujatha, K.; Rama Krishna, K. V.; Roy, R.;
Singh, J.; Anand, N. Tetrahedron 1992, 48, 4985; (b)
Singh, R. K.; Sinha, N.; Jain, S.; Salman, M.; Naqvi, F.;
Anand, N. Synthesis 2005, 2765; (c) Singh, R. K.; Sinha,
N.; Jain, S.; Salman, M.; Naqvi, F.; Anand, N. Tetra-
hedron 2005, 61, 8868; (d) Singh, R. K.; Jain, S.; Sinha, N.;
Mehta, A.; Naqvi, F.; Anand, N. Tetrahedron 2006, 62,
4017.
2. Zhang, Y.; Rothman, R. B.; Dersch, C. M.; de Costa, B.
R.; Jacobson, A. E.; Rice, K. R. J. Med. Chem. 2004, 43,
4840.
3. Henry, D. W.; Sturm, P. A. U.S. Patent US3947445, 1976;
Chem. Abstr. 1976, 85, 5689.
4. Sturm, P. A.; Henry, D. W. J. Med. Chem. 1974, 17, 481.
5. Cignarella, G.; Occelli, E.; Maffii, G.; Testa, E. J. Med.
Chem. 1963, 6, 29.
6. (a) Lounasmaa, M. Alkaloids 1988, 33, 1; (b) Fodor, G.;
Dharanipragada, R. Nat. Prod. Rep. 1991, 603.
7. (a) Neumeyer, J. L.; Wang, S.; Milius, R. A.; Baldwin, R.
M.; Zea-Ponce, Y.; Hoffer, P. B.; Sybirska, E.; Al-Tikriti,
M.; Charney, D. S.; Malison, R. T.; Laruelle, M.; Innis, R.
B. J. Med. Chem. 1991, 34, 3144; (b) Lewin, A. H.; Gao,
Y.; Abraham, P. A.; Boja, J. W.; Kuhar, M. J.; Carroll, F.
I. J. Med. Chem. 1992, 35, 135; (c) Abraham, P. A.; Pitner,
J. B.; Lewin, A. H.; Boja, J. W.; Kuhar, M. J.; Carroll, F.
I. J. Med. Chem. 1992, 35, 141; (d) Carroll, F. I.; Lewin, A.
H.; Boja, J. W.; Kuhar, M. J. J. Med. Chem. 1992, 35, 969.
8. (a) Cignarella, G.; Nathansohn, G. J. Org. Chem. 1961,
26, 1500; (b) Cignarella, G.; Nathansohn, G.; Occelli, E. J.
13. Compounds 8–11 were prepared according to the proce-
dure described in the literature.5,15 Compound 8: white
solid (49%); mp 113–115 ꢁC; mmax (KBr) 2900, 2800,
1493 cmꢀ1; dH (300 MHz, CDCl3) 2.08–2.18 (m, 5H), 2.48
(s, 3H), 2.52 (br s, 1H), 2.68–2.73 (dd, 2H, J = 9.3,
2.1 Hz), 3.36 (br s, 2H), 4.37 (s, 1H), 7.21–7.49 (m, 10H);
m/z 293 [M+1]. Anal. Calcd for C20H24N2 (292.42): C,
82.15; H, 8.27; N, 9.58. Found: C, 82.06; H, 8.26; N, 9.71.
Compound 9: off white solid (72%); mp 129–131 ꢁC; mmax
(CH2Cl2) 1633, 1432 cmꢀ1; dH (300 MHz, CDCl3) 1.82 (br
s, 2H), 2.05 (br s, 3H), 2.69 (s, 3H), 3.07–3.11 (t, 1H,
J = 6.8 Hz), 3.59 (s, 1H), 3.77–3.84 (br s, 1H), 4.38–4.60

548
R. K. Singh et al. / Tetrahedron Letters 48 (2007) 545–548
(dd, 2H, J = 14.4, 3.5 Hz), 5.50 (s, 1H), 7.11–7.36 (m,
1.72 (br s, 2H), 1.96 (br s, 2H), 2.37 (s, 3H), 2.91–3.21 (m,
2H), 3.46–3.48 (d, 2H, J = 6.3 Hz), 3.72 (br s, 2H), 5.29 (s,
1H), 7.14–7.72 (m, 4H), 9.61 (br s, 1H); m/z 270 [M+1].
Anal. Calcd for C16H19N3O (269.34): C, 71.35; H, 7.11; N,
15.60. Found: C, 71.09; H, 7.10; N, 15.69.
10H); m/z 321 [M+1]. Anal. Calcd for C21H24N2O
(320.43): C, 78.71; H, 7.55; N, 8.74. Found: C, 78.82; H,
7.76; N, 8.97. Compound 10: thick oil (38%); mmax
(CH2Cl2) 1629 cmꢀ1; dH (300 MHz, CDCl3) 2.02 (m,
4H), 2.34 (br s, 9H), 3.06–3.11 (br s, 2H), 3.28 (br s,
1H), 3.38 (br s, 1H), 3.41–3.44 (m, 2H), 6.97–7.03 (m, 3H);
m/z 259 [M+1]. Anal. Calcd for C16H22N2OÆHCl (294.82):
C, 65.18; H, 7.86; N, 9.50. Found: C, 65.37; H, 7.60; N,
9.33. Compound 11: white solid (63%); mp 110–111 ꢁC;
mmax (CH2Cl2) 3452, 1636 cmꢀ1; dH (300 MHz, CDCl3)
14. Agrawal, A. K.; Squibb, R. E.; Bondy, S. C. Toxicol. Appl.
Pharmacol. 1981, 58, 89.
15. Kirchner, F. K. U.S. Patent US3328396, 1967; Chem.
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Farmaco 1969, 24, 418; Chem. Abstr. 1969, 70, 115125.