Synthesis of Novel Dispiro 1,4-Benzothiazine Hybrid Heterocycles Through 1,3-Dipolar Cycloaddition

Article abstract of DOI:10.1080/00397911.2014.965329

The 1,3-dipolar cycloaddition of azomethine ylides generated in situ from the reaction of acenaphthylene-1,2-dione or isatins and α-amino acids to (E)-methyl/ethyl 2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-2-ylidene)acetate led to the stereoselective f

Full text of DOI:10.1080/00397911.2014.965329

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Synthesis of Novel Dispiro 1,4-Benzothiazine Hybrid
Heterocycles Through 1,3-Dipolar Cycloaddition
Malathi Karuppiaha, Jeyachandran Veerappana, Kalaiselvan Karumpana & Raju Ranjith
Kumara
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University,
Madurai, Tamil Nadu, India
Accepted author version posted online: 04 Nov 2014.
To cite this article: Malathi Karuppiah, Jeyachandran Veerappan, Kalaiselvan Karumpan & Raju Ranjith Kumar
(2014): Synthesis of Novel Dispiro 1,4-Benzothiazine Hybrid Heterocycles Through 1,3-Dipolar Cycloaddition,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI:
10.1080/00397911.2014.965329
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SYNTHESIS OF NOVEL DISPIRO 1,4-BENZOTHIAZINE HYBRID
HETEROCYCLES THROUGH 1,3-DIPOLAR CYCLOADDITION
Malathi Karuppiah1, Jeyachandran Veerappan1, Kalaiselvan Karumpan1, Raju Ranjith
Kumar1
1Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University
Madurai, Tamil Nadu, India
Address correspondence to Raju Ranjith Kumar, Department of Organic Chemistry,
School of Chemistry, Madurai Kamaraj University, Madurai 625021, Tamil Nadu, India.
E-mail: raju.ranjithkumar@gmail.com
Abstract
The 1,3-dipolar cycloaddition of azomethine ylides generated in situ from the reaction of
acenaphthylene-1,2-dione or isatins and -amino acids to (E)-methyl/ethyl 2-(3-oxo-3,4-
dihydro-2H-benzo[b][1,4]thiazin-2-ylidene)acetate led to the stereoselective formation of
novel dispiro 1,4-benzothiazine hybrid heterocycles in good yields.
KEYWORDS: 1,3-Dipolar cycloaddition, Azomethine ylide, Dispiro oxindole,
Pyrrolidine, Pyrrolizine
INTRODUCTION
1,3-Dipolar cycloadditions form a subject of intensive research in organic synthesis in
view of their enormous synthetic applications.1 In particular, the cycloaddition of non-
stabilized azomethine ylides generated in situ from the decarboxylative condensation of
1

-amino acids and non-enolizable 1,2-diketones to exocyclic olefins represent one of the
most convergent approaches for the construction of novel dispiro oxindole or
acenaphthene–pyrrolidine, pyrrolizine, pyrrolothiazole or octahydroindolizine hybrid
heterocycles.2 Spiro oxindoles are present in many natural products such as coerulescine,
horsfiline and elacomine, which are endowed with wide range of biological activities.3
Furthermore, compounds constituting spiro pyrrolidine motif exhibit significant
biological activities such as anticonvulsant,4 potential antileukaemic,5 local anaesthetic6
and antiviral.7
On the other hand, 1,4-benzothiazines8 are significant class of heterocycles possessing
wide spectrum of biological activities such as analgesic,9 anticancer,10 antifungal,11
antibacterial,12 antitubercular,13 antithyroid14 and calcium antagonist.15 These
heterocycles form the core of antibiotic and cholesterol lowering drugs.16 In addition, 1,4-
benzothiazines are also known for their applications as dyes, photographic developers
and UV absorbers.17
The importance of spiro compounds and 1,4-benzothiazines, prompted us to
envisage the construct novel hybrids comprising the above motifs. In this context, the
present work discloses the outcome of 1,3-dipolar cycloaddition of azomethine ylides
generated in situ from the decarboxylative condensation of various -amino acids with
acenaphthenequinone or isatins to 1,4-benzothiazine dipolarophiles comprising an
excocyclic alkene. Acenaphthenequinone, though less explored in terms of biological
activity, is a versatile precursor for azomethine ylide cycloaddition as it reacts with -
2

amino acids generating reactive 1,3-dipoles. The present work also pertains to our
continuous effort in the synthesis of novel dispiro hybrid heterocycles employing 1,3-
dipolar cycloaddition reactions.18
RESULTS AND DISCUSSION
Initially, the dipolarophiles viz. (E)-methyl or ethyl 2-(3-oxo-3,4-dihydro-2H-
benzo[b][1,4]thiazin-2-ylidene)acetate 3 were synthesized from the reaction of 2-
aminothiophenol 1 with DMAD 2a or DEAD 2b respectively (Scheme 1) following a
literature procedure.19 The structure of the exocyclic dipolarophiles 3a and 3b was
elucidated with the help of NMR spectroscopy. The melting point and the NMR data of
these synthesized exocyclic dipolarophiles 3a and 3b agree well with those reported in
the literature.
Subsequently, the 1,3-dipolar cycloaddition of azomethine ylides generated in situ from
the reaction of sarcosine 5, phenylglycine 6, proline 7 or 1,3-thiazolane-4-carboxylic acid
8 with acenaphthenequinone 4 to the above dipolarophiles 3a and 3b afforded novel
dispiro 1,4-benzothiazine hybrid heterocycles 9–12 (Scheme 2). The cycloadditions were
effected by heating an equimolar mixture of the reactants to reflux in ethanol on a water
bath. After the reaction was complete as evident from TLC the reaction mixture was
poured into ice water and the resultant solid was subjected to column chromatography to
obtain pure product.
The reaction proceeds via the generation of azomethine ylide A in situ from the
3

decarboxylative condensation of acenaphthenequinone 4 and -amino acids, which then
reacts with the exocyclic dipolarophiles 3 to afford the dispiro hybrid heterocycles 9–12
(Scheme 3). It is well known that the azomethine ylide exists in resonance forms A and
B, either of which can react with the dipolarophile 3 to afford the respective isomers
(Scheme 3). However, the above cycloaddition occurs selectively involving the
dipolarophile A leading to the formation of 9. The other isomer 9′ arising from the
cycloadditon of dipole B is not obtained in the course of the reaction, which may
presumably be attributed to the steric factors. This selectivity is also apparent form the 1H
NMR spectrum of the product 9, wherein three triplets due to H-4′ and H-5′ are observed
in the range 3–4 ppm. If the other isomer 9′ was formed, a singlet would have been
expected due to H-3′ instead of a triplet. In addition, the above cycloaddition reaction
occur stereoselectively resulting in the exclusive formation of one diastereomer in all the
cases 9–12, although up to four new contiguous stereo centers are generated during the
course of the cycloaddition in a single step.
The structure of all the dispiro 1,4-benzothiazine hybrid heterocycles 9–12 was
elucidated with the help of one- and two- dimensional NMR spectroscopy. As a
representative case the 1H and 13C chemical shift assignment of 12b are discussed. In the
1H NMR spectrum of 12b, a triplet and a quartet at 1.28 and 4.23 ppm (J = 7.2 Hz) can be
readily assigned to the protons of the -OEt group. The C,H-COSY correlation of these
protons assigns the carbon signals at 13.3 and 60.5 ppm to -CH3 and -CH2 carbons
respectively. Further, the HMBC correlation of the above –CH2 protons assigns the signal
at 167.8 ppm to the carboxylate carbon. A doublet at 4.59 ppm with J value 10.2 Hz can
4

be assigned to H-7′ on the basis of its multiplicity. This proton shows C,H-COSY
correlation with a carbon signal at 51.6 ppm assigning it to 7′-C. From the HMBC
correlation of H-7′ the 3-C amide carbonyl carbon appears at 161.7 ppm. Further, H-7′
has a H,H-COSY correlation with a multiplet at 4.84–4.87 ppm, which can be assigned to
H-7a′. The C,H-COSY correlation of H-7a′ assigns the carbon signal at 66.9 ppm to 7a′-
C. It is evident from the H,H-COSY correlation of H-7a′ that the doublets of doublets at
3.11 and 3.33 ppm (J = 11.1, 6.3 Hz) are due to 1′-CH2 and from the C,H-COSY
spectrum it is clear that 1′-CH2 carbon appears at 35.0 ppm. The two doublets at 3.42 and
3.78 ppm with J = 8.7 Hz which can be assigned to 3′-CH2 protons show (i) C,H-COSY
correlation with a carbon signal at 50.5 ppm due to 3′-C and (ii) HMBC correlation with
one of the spiro carbons 5′-C at 79.6 ppm thereby assigning the carbon signal at 63.0 to
the other spiro carbon 6′-C. The NH of the 1,4-benzothiazine ring appears as singlet at
9.74 ppm and shows HMBC correlation with the 2-C spiro carbon at 63.0 ppm. The
doublet at 5.89 ppm (J = 7.8 Hz) and the triplet at 6.70 ppm (J = 7.8 Hz) can be assigned
to H-5 and H-7 respectively on the basis of the shielding effect of NH through resonance.
The H,H-COSY correlations of the above protons assigns the triplet and doublet at 6.79
and 7.08 ppm (J = 7.5 Hz) to 6-C and 8-C respectively whereas the C,H-COSY
correlations assigns the carbon signals at 115.2, 122.3, 126.9 and 127.6 ppm to 5-C to 8-
C respectively. The two doublets observed at 7.26 ppm (J = 6.9 Hz) and 7.91 ppm (J =
7.2 Hz) can be assigned to 8′′- and 3′′-CH protons respectively from the fact that the
former shows HMBC correlation with the C-1′′ carbonyl carbon at 200.1 ppm and the
latter shows with the spiro carbon 5′-C at 79.6 ppm. Further, from the H,H-COSY
correlation the triplets at 7.61 ppm (J = 8.1 Hz) and 7.46 ppm (J = 7.5 Hz) are due to 4′′-
5

and 7′′-CH protons and the doublets at 7.83 ppm (J = 8.4 Hz) and 7.98 ppm (J = 6.9 Hz)
are due to 5′′- and 6′′-CH protons respectively. The C,H-COSY correlations of these
protons assigns the carbon signals at 126.4, 125.0, 130.5, 126.8 and 119.4 ppm to 3′′-C to
8′′-C carbons respectively. The 1H and 13C chemical shifts of 12b are shown in Figure 1.
The structure of 12b elucidated from NMR spectroscopy was further confirmed from
single crystal X-ray studies. The ORTEP diagram shoen in Figure 220 reveal that the 7′-H
and 8′-H are trans and the two carbonyls attached to C-5′ and C-2 are also trans.
Similarly, by straightforward considerations the 1H and 13C chemical shift assignments
for all the other dispiro 1,4-benzothiazine hybrid heterocycles 9–12 were done and the
data are given in the experimental section.
Then the cycloaddition of azomethine ylides generated in situ from the reaction of -
amino acids and isatins 13 to these dipolarophiles 3 was investigated with a view to
synthesize novel dispiro oxindole–1,4-benzothiazine hybrid heterocycles 14–16 (Scheme
4). The reaction under similar conditions afforded excellent yields of the products.
However, the reaction failed to occur in the case of proline. The structure of these
compounds was elucidated with one- and two-dimensional NMR spectroscopy as done
for the above cases. As a representative example, the 1H and 13C NMR chemical shifts of
14b are shown in Figure 3.
EXPERIMENTAL
General Procedure For The Synthesis Of Dispiro 1,4-Benzothiazine Hybrid
Heterocycles
6

A mixture of (3, 1 mmol), acenaphthylene-1,2-dione or isatins (4 or 13, 1.2 mmol) and
the respective -amino acid (5–8, 1.5 mmol) in ethanol (10 mL) was heated to reflux on a
water bath for 3 h. After completion of the reaction as evident from TLC, the mixture was
poured into crushed ice and the resulting solid was filtered off and purified by column
chromatography on silica gel employing ethyl acetate/petroleum ether (10:90 v/v) as
eluent to obtain pure products 9–12 and 14–16.
Compound 12b
Obtained as pale white solid; Yield 71%; m.p. 222–224°C; Anal. Calcd. for
C27H22N2O4S2: C, 64.52; H, 4.41; N, 5.57; S, 12.76. Found: C, 64,59; H, 4.34; N, 5.63; S,
12.68. 1H NMR (300 MHz, DMSO-D6/CDCl3) δH: 1.28 (t, J=7.2Hz, 3H), 3.30-3.36 (m,
1H), 3.42 (d, J=8.7Hz, 1H), 3.77 (d, J=8.7Hz, 1H), 4.23 (dd, J=14.1, 7.2Hz, 2H), 4.59 (d,
J=10.2Hz, 1H), 4.83–4.9 (m, 1H), 5.84 (d, J=7.8Hz, 1H),6.68 (t, J=7.8Hz, 1H), 6.79 (t,
J=7.5Hz, 1H), 7.08 (d, J=7.5Hz, 1H), 7.26 (d, J=6.9Hz 1H), 7.46 (t, J=7.5Hz, 1H), 7.59–
7.64 (m, 1H), 7.83 (d, J=8.4Hz, 1H), 7.91 (d, J=7.2Hz, 1H), 7.98 (d, J=8.1Hz, 1H), 9.74
(s, 1H). 13C NMR (75 MHz, CDCl3) δC: 13.3, 35.0, 38.1, 50.5, 51.6, 60.5, 63.0, 66.9,
79.6, 115.2, 116.5, 119.4, 122.3, 123.5, 125.0, 126.4, 126.8, 126.9, 127.6, 128.8, 130.0,
130.4, 132.4, 135.6, 139.6, 161.7, 167.8, 200.1.
Compound 14b
Obtained as pale white solid; Yield 70%; m.p. 279–281°C; Anal. Calcd. for
C22H21N3O4S: C, 62.40; H, 5.00; N, 9.92, S, 7.57. Found: C, 62.32; H, 4.93; N, 9.98; S,
7.49. 1H NMR (300 MHz, DMSO-D6/CDCl3) δH: 1.29 (t, J=7.2Hz, 3H), 2.05 (s, 3H),
7

3.32 (t, J=8.7Hz, 1H), 4.06 (t, J=9.0Hz, 1H), 4.21 (dd, J=14.4, 7.2Hz, 2H), 4.81 (t,
J=8.7Hz, 1H), 6.22 (d, J=7.5Hz, 1H), 6.28 (d, J=7.8Hz, 1H), 6.75 (t, J=6.3Hz, 2H), 6.79–
6.88 (m, 2H), 7.06 (d, J=7.2Hz, 1H), 7.14 (d, J=6.9Hz, 1H), 9.52 (s, 1H), 10.26 (s, 1H).
13C NMR (75 MHz, CDCl3) δC: 12.8, 33.7, 44.6, 52.0, 55.2, 59.2, 76.6, 107.2, 113.9,
115.2, 119.6, 121.1, 123.2, 124.3, 125.6, 128.0, 135.0, 141.7, 164.4, 168.3, 173.3.
CONCLUSIONS
The 1,3-dipolar cycloaddition of unstabilized azomethine ylides generated in situ from
the decarboxylative condensation of acenaphthylene-1,2-dione/ isatins and -amino acids
to (E)-ethyl/methyl 2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]-thiazin-2-ylidene)acetate
resulted in the formation of novel dispiro 1,4-benzothiazine hybrid heterocycles. These
cycloadditions proceeded stereo-selectively affording a single isomer of the product in
excellent yields. The structure of all the dispiro heterocycles was elucidated with the help
of one and two dimensional NMR spectroscopy. The prominent advantages of this
reaction comprise a facile one-pot three-component protocol, formation of two C–C and
one C–N bonds in a single step in addition to the generation of four new contiguous
stereo centers.
FUNDING
RRK, KM, VJ and KK would like to thank the University Grants Commission, New
Delhi for funds through Major Research Project F. No. 42-242/2013 (SR) and the
Department of Science and Technology, New Delhi for the funds under IRHPA
programme for providing high resolution NMR facility in the Department. VJ thanks the
8

University Grants Commission, New Delhi for funds under UGC-BSR meritorious
fellowship.
SUPPLEMENTARY INFORMATION
Full experimental detail, characterization data for all compounds, and copies of 1H and
13C NMR spectra for this article can be accessed on the publisher’s website.
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Crystallographic data (excluding structure factors) for compound 12b has been
deposited with the Cambridge Crystallographic Data Center as supplementary publication
number CCDC 1021459. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44 (0) 1223
762911 or e-mail: deposit@ccdc.cam.ac.uk].
12

Scheme 1. Synthesis of dipolarophiles 3
13

Scheme 2. Synthesis of dispiro acenaphthene1,4-benzothiazine hybrid heterocycles 9–12
14

Scheme 3. Formation of azomethine ylides via decarboxylative route and the
cycloaddition
15

Scheme 4. Synthesis of dispiro oxindole 1,4-benzothiazine hybrid heterocycles 14–16
16

Figure 1. 1H and 13C NMR chemical shifts of 12b
17

Figure 2. ORTEP diagram of 12b
18

Figure 3. 1H and 13C NMR chemical shifts of 14b
19