Efficient synthesis of novel 2,4-[diaryl-3-azabicyclo[3.3.1]nonan-9-yl]-5- spiro-4-acetyl-2-(acetylamino)-δ2-1,3,4-thiadiazolines

Article abstract of DOI:10.1080/00397910903161694

2,4-[Diaryl-3-azabicyclo[3.3.1]nonan-9-yl]-5-spiro-4-acetyl-2-(acetylamino) -2-1,3,4-thiadiazoline derivatives (3a-h) have been synthesized by the cyclization of 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-one thiosemicarbazones (2a-h) under acetylating condition. The synthesized compounds were characterized by analytical and spectral (infrared, 1H NMR, and 13C NMR) studies. Copyright

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Efficient Synthesis of Novel 2,4-
[Diaryl-3-azabicyclo[3.3.1]nonan-9-
yl]-5-spiro-4-acetyl-2-(acetylamino)-Δ
2-1,3,4-thiadiazolines
M. Rani a , R. Ramachandran a & S. Kabilan a
a Department of Chemistry, Annamalai University, Annamalai Nagar,
Tamil Nadu, India
Version of record first published: 06 May 2010.
To cite this article: M. Rani , R. Ramachandran & S. Kabilan (2010): Efficient Synthesis of Novel 2,4-
2
[Diaryl-3-azabicyclo[3.3.1]nonan-9-yl]-5-spiro-4-acetyl-2-(acetylamino)-Δ -1,3,4-thiadiazolines,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
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Synthetic Communications1, 40: 1694–1700, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903161694
EFFICIENT SYNTHESIS OF NOVEL 2,4-[DIARYL-3-
AZABICYCLO[3.3.1]NONAN-9-YL]-5-SPIRO-4-ACETYL-
2-(ACETYLAMINO)-D2-1,3,4-THIADIAZOLINES
M. Rani, R. Ramachandran, and S. Kabilan
Department of Chemistry, Annamalai University, Annamalai Nagar,
Tamil Nadu, India
2,4-[Diaryl-3-azabicyclo[3.3.1]nonan-9-yl]-5-spiro-4-acetyl-2-(acetylamino)-D2-1,3,4-
thiadiazoline derivatives (3a–h) have been synthesized by the cyclization of 2,4-diaryl-3-
azabicyclo[3.3.1]nonan-9-one thiosemicarbazones (2a–h) under acetylating condition.
The synthesized compounds were characterized by analytical and spectral (infrared,
1H NMR, and 13C NMR) studies.
Keywords: Acetic anhydride; azabicyclo[3.3.1]nonan-9-ones; cyclization; thiadiazolines; thiosemicarbazones
INTRODUCTION
In recent decades, the synthesis of substituted thiadiazolines[1–3] has attracted
considerable attention because these compounds constitute the structural frameworks
of several naturally occurring alkaloids that show a wide range of pharmacological
activities.[4] The 1,3,4-thiadiazolines and 1,3,4-thiadiazoles exhibit antifungal,[5]
anti-inflammatory,[6] anticonvulsant,[7] antiviral,[8] plant-growth regulatory,[9]
hypotensive,[10] central nervous system depressant,[10] anticancer,[11] and carbonic
anhydrase inhibitory[12] activities.
However, piperidine derivatives possess a broad spectrum of pharmacological
activities. For instance, Lijinsky and Taylor reported[13] that introduction of an alkyl
substituent at the a-position of nitrogen creates significant biological activities.
Furthermore, several 2,6-diarylpiperidine derivatives have good antibacterial,
antifungal, and antitubercular activity. Apart from their biological importance, these
bridged bicyclic compounds exhibit twin-chair, chair–boat, or twin-boat conforma-
tions, which is interesting stereochemistry.
These activities are highly desirable and have been the goal of our ongoing
research program.[14–16] These observations prompted us to synthesize the deriva-
tives of thiadiazolines in piperidine-based bicyclic compounds.
Received March 28, 2009.
Address correspondence to S. Kabilan, Department of Chemistry, Annamalai University,
Annamalai Nagar 608 002, Tamil Nadu, India. E-mail: chemkabilan@rediffmail.com
1694

1,3,4-THIADIAZOLINES
1695
RESULTS AND DISCUSSION
The parent 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones (1a–h) and their
thiosemicarbazones (2a–h) were prepared by the methodology reported in the
literature.[17,18] However, these 1a–h and 2a–h compounds were characterized by
melting points and IR spectral analysis.
In the present study, the key intermediate 2,4-diaryl-3-azabicyclo[3.3.1]nonan-
9-one thiosemicarbazones (2a–h), upon cyclization with acetic anhydride, afforded
the target molecules (3a–h) with good yield. The aforementioned compounds
(3a–h) were characterized by spectral and analytical methods. The schematic
representation and analytical data of compounds 3a–h are given in Scheme 1 and
Table 1, respectively.
The IR spectra of 1,3,4-thiadiazolines (3a–h) showed absorption bands around
1690 cmꢀ1 and 1595 cmꢀ1, which are characteristic of NꢀC O and C N bond
=
=
Scheme 1. Reagent and conditions: (A) ethanol, warm; (B) thiosemicarbazide, Hþ; and (C) acetic anhydride,
reflux, 10–18 h.

1696
M. RANI, R. RAMACHANDRAN, AND S. KABILAN
Table 1. Analytical data for compounds 3a–h
Entry
R
R1
R2
Yield (%)
Mp (ꢁC)
3a
3b
3c
3d
3e
3f
H
Cl
H
H
H
H
H
H
H
H
H
H
90
80
90
75
65
60
80
75
166–168
160–162
154–156
152
F
H
OCH3
H
H
OCH3
CH3
Cl
155
H
164–166
168
158
3g
3h
H
H
F
stretching vibrations. A sharp and intense absorption band around 3300 cmꢀ1
showed the NH stretching frequency in acetyl amino group and piperidine
analogue. In addition, the appearance of NꢀCꢀS bending vibration around
1375 cmꢀ1 is evidence of the five-membered ring closure.
1
The H NMR spectra revealed that the ring proton signals (H-1e=H-5e and
H-2a=H-4a) of 3a–h resonated as symmetrical instead of the expected unsymmetrical
signals that appeared in 2a–h compounds. In addition, two new signals appeared
around 1.90 ppm and 2.30 ppm, denoting the presence of methyl protons in the
cyclized five-membered ring. Similarly, an NH proton signal in the deshielded region
(around 8–9 ppm), indicating that cyclization occurred in the thiosemicarbazone
unit. In our earlier work,[19] the N-acetylation also occurred in the piperidine
analogue, whereas in the present investigation, N-acetyl signals of compounds 3a
and 3e confirmed that N-acetylation has occurred on the piperidine analogue, but
for 3b–d and 3f–h, the signal around 1.70 ppm (NH proton signal) indicates the
absence of N-acetylation. Furthermore, the ring closure may be ascertained by
the disappearance of signal at 180 ppm corresponding to the thiocarbonyl function.
EXPERIMENTAL
Thin-layer chromatography (TLC) was carried out to monitor the course of the
reaction and the purity of the product. The melting points were recorded in open capil-
laries and are uncorrected. IR spectra were recorded on an Avatar-330 Fourier trans-
form (FT)–IR spectrophotometer (Thermo Nicolet), and only noteworthy absorption
levels (reciprocal centimeters) are listed. 1H NMR spectra were recorded at 400 MHz
on a Bruker AMX 400-MHz spectrophotometer using CDCl3=dimethylsulfoxide
(DMSO-d6) as solvent and tetramethylsilane (TMS) as an internal standard. 13C
NMR spectra were recorded at 100 MHz on a Bruker AMX 400-MHz spectrometer
in CDCl3 and DMSO-d6. Microanalyses were performed on Heraeus Carlo Erba
1108 CHN analyzer. All the reagents and solvents used were of high grade and
purchased from Fluka and Merck. All the solvents were distilled prior to use.
By employing the literature precedent of Baliah et al.[17] all the parent 2,4-
diaryl-3-azabicyclo[3.3.1]nonan-9-ones were prepared by the condensation of cyclo-
hexanone, aldehydes, and ammonium acetate in a 1:2:1 ratio using ethanol as
solvent. The respective ketone thiosemicarbazones 2a–h were prepared in excellent
yields by condensing thiosemicarbazides with appropriate ketones in the presence
of a few drops of mineral acids.

1,3,4-THIADIAZOLINES
1697
General Procedure for Synthesis of 2,4-[Diaryl-3-azabicyclo[3.3.1]nonan-
9-yl]-5-spiro-4-acetyl-2-(acetylamino)-D2-1,3,4-thiadiazolines (3a–h)
Bicyclic ketone thiosemicarbazones 2a–h (0.01 mol) were refluxed with distilled
acetic anhydride (20–25 mL) for about 10–18 h on a water bath (90–100 ꢁC). After
the completion of reaction, the reaction mixture was kept in the freezer for 1 day,
and the separated solid was filtered, dried, and purified by column chromatography.
Characterization Data of Compounds 3a–h
N-Acetyl-2,4[diphenyl-3-azabicyclo[3.3.1]nonan-9-yl]-5-spiro-4-acetyl-2-
(acetylamino)-D2-1,3,4-thiadiazoline (3a). IR (KBr): 3215, 3140, 3028, 3046,
2954, 2875, 1681, 1633, 1594, 1492, 1452, 1372, 1325, 1293, 1234, 1142, 1074,
1
1031, 1002, 755, 703, 611, 546, 463. H NMR (CDCl3, 400 MHz): 6.13 (d, 2H,
H-2a and H-4a); 3.30 (d, 2H, H-1e and H-5e); 3.21 (m, 1H, H-7a); 1.70 (s, 5H,
H-6e, H-8e and CH3 at N at 3 in piperidine ring); 1.30 (d, 2H, H-6a and H-8a);
1.24 (m, 1H, H-7e); 9.67 (bs, 1H, spiro NH); 2.20, 1.90 (s, 3H, CH3 at NHCO and
NCO); 7.40 and 7.51 (t, bs, 10H aryl protons). 13C NMR (d ppm) CDCl3: 61.58
(C-2 and C-4); 41.25 (C-1 and C-5); 25.61 (C-6 and C-8); 22.36 (C-7); 87.28 (C-9);
27.23, 24.63, 18.30 (CH3 at NHCO and NCO and CH3 at N in piperidine ring);
=
176.20, 174.22, 169.55 (NHCO and NCO and NCO at 3); 155.60 (C N); 142.95,
142.18 (C-20 and C-40); 128.53, 126.59, 125.58 (other aryl carbons). Anal. calcd. for
C26H32N5O2S: C, 65.24; H, 6.74; N, 14.63. Found: C, 65.25; H, 6.74; N, 14.60.
2,4-[Bis(o-chlorophenyl)-3-azabicyclo[3.3.1]nonan-9-yl]-5-spiro-4-acetyl-
2-(acetylamino)-D2-1,3,4-thiadiazoline (3b). IR (KBr): 3200, 3123, 3063, 2929,
2860, 1697, 1587, 1469, 1439, 1318, 1273, 1227, 1117, 1042, 1014, 978, 917, 794,
1
758, 700, 568, 458. H NMR (DMSO-d6, 400 MHz): 4.98 (d, 2H, H-2a and H-4a);
2.81 (d, 2H, H-1e and H-5e); 2.97 (m, 1H, H-7a); 1.93 (m, 2H, H-6e and H-8e);
2.56 (m, 1H, NH at 3); 1.17 (m, 3H, H-6a, H-8a and H-7e); 11.75 (s, 1H, spiro
NH); 2.10, 2.07 (s, 3H, CH3 at NHCO and NCO); 7.44 (1d, 2s, 4H, aryl protons
meta to chlorine atom); 8.02 (d, 2H, aryl protons ortho to chlorine atom); 7.31
(3d, 2H, aryl protons para to chlorine atom). 13C NMR (d ppm) DMSO-d6: 59.30
(C-2 and C-4); 37.26 (C-1 and C-5); 23.19 (C-6 and C-8); 18.35 (C-7); 89.20 (C-9);
24.67, 22.73 (CH3 at NHCO and NCO); 171.96, 168.93 (NHCO and NCO);
00
156.32 (C N); 140.26 (C-2 and C-400); 131.27 (C-2000 and C-4000); 129.47, 129.07,
=
128.45, 127.02 (other aryl carbons).
2,4-[Bis(m-fluorophenyl)-3-azabicyclo[3.3.1]nonan-9-yl]-5-spiro-4-acetyl-
2-(acetylamino)-D2-1,3,4-thiadiazoline (3c). IR (KBr): 3299, 3227, 3030, 2964,
2930, 2862, 1688, 1653, 1587, 1484, 1444, 1371, 1336, 1268, 1228, 1140, 1018, 976,
1
892, 789, 702, 460. H NMR (CDCl3, 400 MHz): 4.95 (s, 2H, H-2a and H-4a);
2.73 (s, 2H, H-1e and H-5e); 2.46 (m, 1H, H-7a); 1.74 (m, 2H, H-6e and H-8e);
1.62 (s, 1H, NH at 3); 1.34 (m, 2H, H-6a and H-8a); 1.28 (m, 1H, H-7e); 8.20 (s,
1H, spiro NH); 2.26, 2.22 (s, 3H, CH3 at NHCO and NCO); 7.32 (4dd, 6H, aryl pro-
tons ortho to fluorine function); 6.97 (3dd, 2H, aryl protons meta to fluorine func-
tion). 13C NMR (d ppm) CDCl3: 60.23 (C-2 and C-4); 41.90 (C-1 and C-5); 25.32
(C-6 and C-8); 19.33 (C-7); 92.13 (C-9); 25.71, 23.66 (CH3 at NHCO and NCO);
000
172.60, 167.84 (NHCO and NCO); 156.13 (C N); 164.21,161.77 (C-2 and C-4000);
=

1698
M. RANI, R. RAMACHANDRAN, AND S. KABILAN
146.49, 146.42 (C-200 and C-400); 145.79, 145.69 (C-20000 and C-40000); 129.87, 129.76,
129.68, 122.25, 122.33, 114.17, 113.73, 113.66, 113.62, 1125, 113.40. Anal. calcd.
for C26H30F2N5O2S: C, 60.68; H, 5.88; N, 13.61. Found: C, 60.68; H, 5.85; N, 13.60.
2,4-[Bis(m-methoxyphenyl)-3-azabicyclo[3.3.1]nonan-9-yl]-5-spiro-4-
acetyl-2-(acetylamino)-D2-1,3,4-thiadiazoline (3d). IR (KBr): 3299, 3224, 3034,
2935, 2858, 2833, 1684, 1652, 1587, 1485, 1460, 1437, 1370, 1334, 1270, 1232, 1155,
1
1082, 1046, 786, 678, 565, 460. H NMR (CDCl3, 400 MHz): 4.91 (s, 2H, H-2a and
H-4a); 2.73 (s, 2H, H-1e and H-5e); 2.67 (m, 1H, H-7a); 1.70 (m, 3H, H-6e, H-8e and
NH at 3); 1.26 (m, 3H, H-6a, H-8a and H-7e); 8.22 (s, 1H, spiro NH); 2.26, 2.21 (s,
3H, CH3 at NHCO and NCO); 7.26 (m, 6H, aryl protons para to OCH3 group); 6.80
(2dd, 2H, aryl protons ortho to OCH3 group); 3.85 (s, 6H, OCH3 group at C-2000 and
C-4000). 13C NMR (d ppm) CDCl3: 60.53 (C-2 and C-4); 42.06 (C-1 and C-5); 25.34
(C-6 and C-8); 19.40 (C-7); 87.70 (C-9); 25.87, 23.67 (0C00 H3 at NHCO and NCO);
173.18 (NHCO and NCO); 156.18 (C N); 159.62 (C-2 and C-4000); 145.74 (C-20000
=
and C-40000); 55.23 (OCH3 group at C-2000 and C-4000); 129.68, 129.18, 128.32,
119.17, 112.77, 113.40, 111.64 (other aryl carbons).
2,4-[Bis(p-methoxyphenyl)-3-azabicyclo[3.3.1]nonan-9-yl]-5-spiro-4-
acetyl-2-(acetylamino)-D2-1,3,4-thiadiazoline (3e). IR (KBr): 3063, 2992, 2956,
2837, 1677, 1629, 1510, 1463, 1372, 1304, 1248, 1173, 1110, 1035, 900, 833, 767, 609,
1
554. H NMR (CDCl3, 400 MHz): 6.11 (d, 2H, H-2a and H-4a); 3.22 (d, 2H, H-1e
and H-5e); 3.16 (m, 1H, H-7a); 1.68 (m, 2H, H-6e); 1.34 (d, 2H, H-6a and H-8a);
1.23 (m, 1H, H-7e); 9.73 (bs, 1H, spiro NH); 2.19, 1.90, 1.75 (s, 3H, CH3 NHCO,
NCO and CH3 at N in piperidine ring); 6.91 (d, 5H, aryl protons ortho to OCH3
group; 7.41 (bs, 3H, aryl protons meta to OCH3 group); 3.82 (s, 6H, OCH3 group
at C-20000 and C-40000). 13C NMR (d ppm) CDCl3: 61.09 (C-2 and C-4); 41.43 (C-1
and C-5); 25.60 (C-6 and C-8); 22.57 (C-7); 87.45 (C-9); 27.37, 24.65, 16.78 (CH3
at NHCO and NCO and CH3 at N in piperidine ring); 176.90, 174.01, 0010069.37
=
(NHCO and NCO and NCO at 3); 155.32 (C N); 158.21, 158.14 (C-2 and
C-40000); 134.94, 134.24 (C-20 and C-40); 126.70, 113.93 (other aryl carbons); 55.30
(OCH3 group at C-20000 and C-40000). Anal. calcd. for C28H36N5O4S: C, 62.43; H,
6.74; N, 13.00. Found: C, 62.41; H, 6.75; N, 13.00.
2,4-[Bis(p-methylphenyl)-3-azabicyclo[3.3.1])nonan-9-yl]-5-spiro-4-
acetyl-2-(acetylamino)-D2-1,3,4-thiadiazoline (3f). IR (KBr): 3222, 3134, 3036,
2924, 2856, 1684, 1644, 1589, 1438, 1369, 1320, 1112, 1020, 814, 729, 674, 581,
1
460. H NMR (CDCl3, 400 MHz): 4.89 (s, 2H, H-2a and H-4a); 2.69 (s, 2H, H-1e
and H-5e); 2.63 (bs, 1H, H-7a); 2.20 (s, 2H, H-6e and H-8e); 1.65 (d, 1H, NH at
3); 1.26 (m, 3H, H-6a, H-8a and H-7e); 8.08 (s, 1H, spiro NH); 2.26, 2.16 (s, 3H,
CH3 at NHCO and NCO); 7.16 (d, 4H, aryl protons ortho to CH3 group); 7.48
(d, 4H, aryl protons meta to CH3 group); 2.34 (s, 6H, CH3 group at C-20000 and
C-40000). 13C NMR (d ppm) CDCl3: 60.55 (C-2 and C-4); 42.16 (C-1 and C-5);
25.82 (C-6 and C-8); 19.45 (C-7);0080 6.91 (C-9); 30.90, 23.70 (CH3 at NHCO and
NCO); 156.18 (C N); 159.62 (C-2 and C-4000); 145.74 (C-20000 and C-40000); 129.68,
=
129.18, 128.32, 119.17, 112.77, 113.40, 111.64 (other aryl carbons); 36.57 (CH3 group
at C-20000 and C-40000). Anal. calcd. for C28H36N5O2S: C, 66.37; H, 7.16; N, 13.82.
Found: C, 66.38; H, 7.16; N, 13.84.

1,3,4-THIADIAZOLINES
1699
2,4-[Bis(p-chlorophenyl)-3-azabicyclo[3.3.1]nonan-9-yl]-5-spiro-4-acetyl-
2-(acetylamino)-D2-1,3,4-thiadiazoline (3g). IR (KBr): 3293, 3211, 3129, 3032,
2966, 2934, 2861, 2822, 1688, 1586, 1488, 1436, 1368, 1314, 1229, 1139, 1090,
1
1013, 824, 792, 723, 681, 579, 502, 459, 422: H NMR (CDCl3, 400 MHz): 4.92 (s,
2H, H-2a and H-4a); 2.68 (s, 2H, H-1e and H-5e); 2.60 (m, 1H, H-7a); 1.73 (m,
2H, H-6e and H-8e); 1.62 (s, 1H, NH at 3); 1.33 (m, 3H, H-6a, H-8a and H-7e);
8.13 (s, 1H, spiro NH); 2.29, 2.17 (s, 3H, CH3 at NHCO and NCO); 7.32 (2s, 4H,
aryl protons ortho to chlorine atom); 7.53 (d, 4H, aryl protons meta to chlorine
atom). 13C NMR (d ppm) CDCl3: 60.20 (C-2 and C-4); 41.90 (C-1 and C-5); 25.34
(C-6 and C-8); 19.35 (C-7); 92.25 (C-9); 25.63, 23.70 (CH3 at NHCO and NCO);
0000
173.39, 167.59 (NHCO and NCO); 156.01 (C N); 142.20 (C-2 and C-40000);
=
132.58 (C-2000 and C-4000); 128.41, 128.04 (other aryl carbons). Anal. calcd. for
C26H30Cl2N5O2S: C, 57.04; H, 5.52; N, 12.79. Found: C, 57.02; H, 5.55; N, 12.79.
2,4-[Bis(p-fluorophenyl)-3-azabicyclo[3.3.1]nonan-9-yl]-5-spiro-4-acetyl-
2-(acetylamino)-D2-1,3,4-thiadiazoline (3h). IR (KBr): 3299, 3234, 3156, 3037,
2931, 2860, 1657, 1586, 1507, 1458, 1438, 1372, 1334, 1280, 1222, 1091, 1015, 942,
1
832, 801, 727, 671, 519, 457. H NMR (CDCl3, 400 MHz): 4.92 (s, 2H, H-2a and
H-4a); 2.68 (s, 2H, H-1e and H-5e); 2.63 (m, 1H, H-7a); 1.72 (m, 2H, H-6e and
H-8e); 1.62 (d, 1H, NH at 3); 1.25 (s, 3H, H-6a, H-8a and H-7e); 8.12 (bs, 1H, spiro
NH); 2.26, 2.21 (s, 3H, CH3 at NHCO and NCO); 7.04 (t, 4H, aryl protons meta
fluorine function); 7.56 (t, 4H, aryl protons ortho to fluorine function). 13C NMR
(d ppm) CDCl3: 60.23 (C-2 and C-4); 42.01 (C-1 and C-5); 25.35 (C-6 and C-8);
19.38 (C-7); 92.43 (C-9); 25.63, 23.70 (CH3 at NHCO and NCO); 173.35, 167.66
0000
(NHCO and NCO); 156.13 (C N); 163.07, 160.64 (C-2 and C-40000); 139.39
=
(C-2000 and C-4000); 128.17, 128.09, 115.12, 114.91 (other aryl carbons).
ACKNOWLEDGMENT
Authors are thankful to the NMR Research Centre, Indian Institute of
Science, Bangalore for recording the NMR data.
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