Microwave-assisted synthesis of azoniaspiro compounds using a novel catalyst, 1-azaphenothiazine

Article abstract of DOI:10.1080/00397910903576677

1-Azaphenothiazine catalyses the intramolecular cyclization of N-(bromoalkyl)phthalimides in the presence of anhydrous K₂CO ₃ to form spiro cyclic quaternary ammonium salts, namely azoniaspiro compounds, under microwave irradiation. A novel and ecofriendly method was developed for the synthesis of azoniaspiro compounds, and the role of azaphenothiazine as a catalyst in such reactions has been established for the first time. In the future, this protocol can be extended to the synthesis of various substituted N-heterocycles by hydrolyzing the resulting azoniaspiro compounds.

Full text of DOI:10.1080/00397910903576677

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Microwave-Assisted Synthesis of
Azoniaspiro Compounds Using a Novel
Catalyst, 1-Azaphenothiazine
a
a
a
Archana Gupta , Rajeev Sakhuja , Khushbu Kushwaha & Subhash
a
C. Jain
a
Department of Chemistry , University of Delhi , Delhi, India
Published online: 13 Jan 2011.
To cite this article: Archana Gupta , Rajeev Sakhuja , Khushbu Kushwaha & Subhash C. Jain (2011)
Microwave-Assisted Synthesis of Azoniaspiro Compounds Using a Novel Catalyst, 1-Azaphenothiazine,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 41:3, 411-416, DOI: 10.1080/00397910903576677
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1
Synthetic Communications , 41: 411–416, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903576677
MICROWAVE-ASSISTED SYNTHESIS OF
AZONIASPIRO COMPOUNDS USING A NOVEL
CATALYST, 1-AZAPHENOTHIAZINE
Archana Gupta, Rajeev Sakhuja, Khushbu Kushwaha, and
Subhash C. Jain
Department of Chemistry, University of Delhi, Delhi, India
1-Azaphenothiazine catalyses the intramolecular cyclization of N-(bromoalkyl)-
phthalimides in the presence of anhydrous K CO to form spiro cyclic quaternary
2
3
ammonium salts, namely azoniaspiro compounds, under microwave irradiation. A novel
and ecofriendly method was developed for the synthesis of azoniaspiro compounds, and
the role of azaphenothiazine as a catalyst in such reactions has been established for the first
time. In the future, this protocol can be extended to the synthesis of various substituted
N-heterocycles by hydrolyzing the resulting azoniaspiro compounds.
Keywords: 1-Azaphenothiazine; azoniaspiro; catalyst; microwave irradiation; N-(bromoalkyl)phthalimides
INTRODUCTION
Azaphenothiazines have recently attracted considerable attention of synthetic
[
1–4]
and medicinal chemists because of their varied biological activities.
Various
aminoalkylated azaphenothiazines have been synthesized and studied neuropharma-
cologically.
In view of this, an effort was made by us earlier to synthesize a series of 10-[n-
(phthalimido)alkyl]-1-azaphenothiazines under microwave irradiations as this method
offered tremendous advantages over classical methods, in the forms of reduction
in reaction time, operational simplicity, cleaner reaction, easy workup, and better
[5]
yields. We reported the desired N-alkylated product(s), 10-[(n-phthalimido)alkyl]-
1
-azaphenothiazine in 52–58% yields only, along with some unidentified product(s).
These unidentified products have been now identified and belong to a class
of spirocyclic quaternary ammonium salts, known in the literature as azoniaspiro
[
6]
compounds. This class of compounds, earlier prepared by a classical method, were
[
7]
evaluated as novel cholinergic agents for the control of blood pressure. Azonia-
[
8]
chalcone bromide obtained from azachalcone showed antibacterical activity.
Similarly, derivatives of 8-azoniabicyclo[3.2.1]octane have been reported as
b2-adrenoreceptor agonists, antihistamines, allergy inhibitors, and inflammation
Received October 6, 2009.
Address correspondence to Subhash C. Jain, Department of Chemistry, University of Delhi,
Delhi 110 007, India. E-mail: jainsc48@hotmail.com
4
11

412
A. GUPTA ET AL.
inhibitors for the treatment of muscarinic acetylcholine receptor–mediated diseases
[9]
of the respiratory tract. Also, some new azaspiro compounds, namely, 2-azaspiro
[
have effects on the peripheral and central nervous system.
4.4] nonanes, 3-azaspiro [5.5] undecanes, and 2-azaspiro [4.5] decanes, were found to
[
10]
Spasmex, an
azonia-bicyclo derivative, inhibited normal and suxamethonium-stimulated salva-
tions in humans about three times as strongly as atropine sulfate, thereby acting
[11]
as a spasmolytic agent.
Realizing the importance of these compounds, we were curious to synthesize
these azoniaspiro compounds as major product(s) rather than as side product(s) in
the reaction by optimizing experimental conditions. We report here a new and efficient
method for the synthesis of azoniaspiro compounds using microwave irradiation.
RESULTS AND DISCUSSION
The reaction of N-(bromoalkyl)phthalimides (1a–d) using catalytic amounts
of 1-azaphenothiazine (2a) and anhydrous K CO separately under microwave
2
3
irradiation yielded the corresponding azoniaspiro compounds (3a–d) in 76–81%
yields (Scheme 1).
Further, by modifying the conditions and using different reagents, we con-
cluded that the reaction takes place only in the presence of 1-azaphenothiazines,
thereby indicating that the latter acts as a catalyst in this reaction. Replacing
1
-azaphenothiazine by phenothiazine did not give the expected azoniaspiro com-
pound. Also, in the absence of 1-azaphenothiazine, N-(bromoalkyl)phthalimides
failed to cyclize. However, when the same reaction was repeated with different
halosubstituted 1-azaphenothiazines (2b–d), similar product(s) as expected from a
particular N-(bromoalkyl)phthalimide were obtained. It looks that the proper
Scheme 1. Synthesis of azoniaspiro compounds 3a–d.

MICROWAVE-ASSISTED SYNTHESIS OF AZONIASPIROS
413
Table 1. Synthesis of azoniaspiro compounds 3a–d from different N-(bromoalkyl)
phthalimides using 1-azaphenothiazine as catalyst under microwave irradiation
ꢁ
Entry
n
Temp. ( C)
Product
Yield (%)
1
2
3
4
2
3
4
5
100
100
110
110
3a
3b
3c
3d
76
78
79
81
positioning of two nitrogen atoms in the 1-azaphenothiazine ring has probably
helped it to act as a template in catalyzing this intramolecular reaction. It may be
worth mentioning here that other isomeric 2-, 3-, or 4-azaphenothiazines failed to
act as catalysts under these conditions. Several examples illustrating this procedure
are summarized in Table 1.
Thus, the role of 1-azaphenothiazine as a catalyst has been identified for the
first time in such intramolecular cyclization reactions under microwave irradiation.
The structures of 3a–d were assigned on the basis of their detailed spectral studies.
The main evidence of the formation of 3c came from the presence of a multiplet
1
at d3.73 in its H NMR spectrum, which was due to the four protons attached to
the nitrogen carrying a positive charge. Further, the absence of any peak for the cor-
responding methylene protons attached to the bromine in the reactant supported the
cyclization. Apart from this, the presence of only two multiplets for four aromatic
protons in the downfield region at d7.84 and 7.71 indicated the presence of the
four protons of only phthalimide nucleus, thereby ruling out the possibility of an
azaphenothiazine moiety in 3c. The mass spectra (MS) of the compound 3c showed
a molecular ion peak at m=z 281, which accounted for it having a molecular formula
of C H NO Br. The elemental analysis confirmed this. The infrared (IR) spectrum
1
2
12
2
ꢀ1
of compound 3c also showed two absorption bands at 1770 and 1711 cm for the
two carbonyls of the phthalimide nucleus. The presence of nitrogen and bromine
in the product were also confirmed by carrying out its qualitative analysis. On the
basis of spectral data and elemental analyses, 3c was identified as 6,9-dioxo-[7,8]-
benzo-5-azoniaspiro-[4,4]-nonane bromide.
Taking advantage of the presence of a phthalimide nucleus in our synthetic
azoniaspiro compounds, we thought of knocking it to obtain the corresponding
N-heterocycles. As a model experiment, we selected 7,10-dioxo-[8,9]-benzo-
6
detectable compound on hydrolysis. Therefore, 3d was hydrolyzed with hydrazine
-azoniaspiro-[5,4]-decane bromide (3d) because it would give piperidine, an easily
[
12]
hydrate in ethanol (Scheme 2), and the product obtained was analyzed as piperidine
Scheme 2. Hydrolysis of azoniaspiro 3d.

414
A. GUPTA ET AL.
(
(
4) by its Co-GLC with a standard sample of piperidine. The gas chromatography
GC)–MS, when recorded, further supported this analysis.
CONCLUSIONS
In summary, we have described a novel and ecofriendly method for the
synthesis of azoniaspiro compounds under microwave irradiation. In addition, we
have identified the role of 1-azaphenothiazine as a catalyst in these intramolecular
cyclization reactions. This protocol can be extended in the future for the synthesis
of various substituted nitrogen heterocycles.
EXPERIMENTAL
Melting points were determined in a capillary tube in a sulfuric acid bath and are
uncorrected. IR spectra were recorded on a Shimadzu model IR-435 spectrophot-
1
13
ometer. H NMR spectra were recorded on a Bruker AC (300MHz), and C NMR
spectra were recorded on a Bruker AC (75.47MHz) in CDCl . Elemental analyses were
3
performed on a Perkin-Elmer series 11 2400 CHNS=O analyzer. Mass spectra were
recorded on Jeol-JMS-DX 303 mass spectrometer. The GLC was recorded on GC
17A Shimadzu instrument using capillary column and flame ionization detector (FID).
General Procedures for the Synthesis of Azoniaspiro
Compounds (3a–d)
A mixture of N-(bromoalkyl)phthalimide (1a–d) (1.0 mmol) anhydrous K CO
2
3
(0.5 mmol), and 1-azaphenothiazine (2a) (5 mg) was irradiated in a microwave in an
open vessel for 8 min at 100–110 C. The reaction mixture showed a major spot on
ꢁ
thin-layer chromatography (TLC) in chloroform=methanol (98:2). The products
3
a–d were purified by column chromatography and recrystallized from ethanol.
Procedure for the Hydrolysis of 7,10-Dioxo-[8,9]-benzo-6-
azoniaspiro-[5,4]-decane Bromide (3d)
7,10-Dioxo-[8,9]-benzo-6-azoniaspiro-[5,4]-decane bromide (3d) (0.16 mmol)
was refluxed with hydrazine hydrate (0.32 mmol) in ethanol for 2 h, after which
ꢁ
the mixture was cooled to ꢀ15 C, and the precipitate was filtered off. The filtrate
was concentrated under reduced pressure, and CHCl was added to the residue.
3
The insoluble part was again filtered off, and the solvent was removed on a rotava-
por. The GLC record of the resultant residue showed a major peak that corre-
sponded to standard piperidine with respect to the retention time. The
confirmation of formation of piperidine (4) came from Co-GLC of the residue with
the standard sample of piperidine and also by recording the GC–MS.
Data
Spectral data for 4,7-dioxo-[5,6]-benzo-3-azoniaspiro-[2,4]-heptane
ꢀ1
ꢁ
bromide (3a). Yield: 76%; mp 175–176 C; IR (KBr) cm : 2924, 2853, 1773,

MICROWAVE-ASSISTED SYNTHESIS OF AZONIASPIROS
415
1
713, 1618, 1509, 1466, 1432, 1392, 1358, 1318, 1190, 1076, 993; H NMR (CDCl ):
1
3
13
þ
d ¼ 4.01 [s, 4H, N -(CH ) ], 7.68 (m, 2H, 2 ꢂ ArH), 7.78 (m, 2H, 2 ꢂ ArH);
C
2
2
þ
NMR (CDCl ): d ¼ 32.0, 125.7, 136.3, 137.2, 188.2; EIMS: m=z ¼ 255 (M þ 2,
3
þ
1
C, 47.17; H, 3.20; N, 5.46.
5), 253 (M , 16). Anal. calcd. for C H NO Br: C, 47.27; H, 3.17; N, 5.51. Found:
1
0
8
2
Spectral data for 5,8-dioxo-[6,7]-benzo-4-azoniaspiro-[3,4]-octane
ꢀ1
ꢁ
bromide (3b). Yield: 78%; mp 177–178 C; IR (KBr) cm : 2923, 2854, 1769,
1
1
708, 1614, 1508, 1460, 1395, 1352, 1186, 1072, 996; H NMR (CDCl ): d ¼ 2.10
3
þ
(
2
m, 2H), 3.75 [t, 4H, J ¼ 6.4 Hz, N -(CH ) ], 7.72 (m, 2H, 2 ꢂ ArH), 7.84 (m, 2H,
2
2
1
3
ꢂ ArH); C NMR (CDCl ): d ¼ 28.0, 37.7, 124.9, 136.2, 137.6, 188.4; EIMS:
þ þ
11 10 2
3
m=z ¼ 269 (M þ 2, 14), 267 (M , 15). Anal. calcd. for C H NO Br: C, 49.28;
H, 3.76; N, 5.22. Found: C, 49.20; H, 3.78; N, 5.20.
Spectral data for 6,9-dioxo-[7,8]-benzo-5-azoniaspiro-[4,4]-nonane
ꢀ1
ꢁ
bromide (3c). Yield: 79%; mp 171–172 C; IR (KBr) cm : 2925, 2854, 1770,
1
1
711, 1621, 1594, 1566, 1509, 1459, 1414, 1397, 1371, 1246, 1082, 923; H NMR
þ
(
(
CDCl ): d ¼ 1.76 (m, 4H), 3.73 [m, 4H, N -(CH ) ], 7.71 (m, 2H, 2 ꢂ ArH), 7.84
3
2 2
1
3
m, 2H, 2 ꢂ ArH); C NMR (CDCl ): d ¼ 26.3, 40.7, 123.6, 132.5, 134.2, 188.7;
3
þ
þ
EIMS: m=z ¼ 283 (M þ 2, 11), 281 (M , 10). Anal. calcd. for C H NO Br: C,
1
2
12
2
5
1.09; H, 4.29; N, 4.96. Found: C, 51.01; H, 4.30; N, 4.90.
Spectral data for 7,10-dioxo-[8,9]-benzo-6-azoniaspiro-[5,4]-decane
ꢀ1
ꢁ
bromide (3d). Yield: 81%; mp 87–88 C; IR (KBr) cm : 2925, 2854, 1772, 1711,
1
1
4
464, 1397, 1368, 1259, 1054, 925; H NMR (CDCl ): d ¼ 1.45 (m, 2H), 1.71 (m,
3
H), 3.69 (t, 2H, J ¼ 7.0 Hz), 4.10 (t, 2H, J ¼ 6.5 Hz), 7.70 (m, 2H, 2 ꢂ ArH), 7.84
1
3
(m, 2H, 2 ꢂ ArH); C NMR (CDCl ): d ¼ 23.4, 28.7, 47.9, 123.5, 132.5, 134.2,
3
þ
þ
1
C, 52.72; H, 4.76; N, 4.73. Found: C, 52.70; H, 4.74; N, 4.70.
88.7; EIMS: m=z ¼ 297 (M þ 2, 12), 295 (M , 12). Anal. calcd. for C H NO Br:
1
3
14
2
ACKNOWLEDGMENTS
We thank the Department of Science and Technology, New Delhi, India, for
financial support and the Council of Scientific and Industrial Research, New Delhi,
India, for providing senior research fellowships to K. K. and R. S. respectively.
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