Stereoselective [3 + 2] cycloaddition reactions of azomethine ylides derived from 5-methylbenzo[B]thiophene-2,3-dione and piperidine-2-carboxylic acid

Article abstract of DOI:10.1080/10426500701610945

A series of spiropyrrolidines have been synthesized in 68-76% yield by 1,3 dipolar cycloaddition reaction of azomethine ylides generated by a decarboxylative route from 5-methylbenzo[b]thiophene and piperidine-2-carboxylic acid with different acetylenic and ethylenic dipolarophiles. The stereochemical course of the cycloaddition has been investigated by spectral data and AM1 quantum chemical method. The novel spiro compounds have been characterized by elemental analyses and spectroscopic techniques. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500701610945

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Stereoselective [3
+ 2] Cycloaddition
Reactions of Azomethine
Ylides Derived from 5-
Methylbenzo[B]thiophene-2,3-
dione and Piperidine-2-
Carboxylic Acid
Komal Arora a , Sonali Verma a , Densely Jose a ,
Pushpa Pardasani a & R. T. Pardasani a
a Department of Chemistry , University of
Rajasthan , Jaipur, India
Published online: 09 May 2008.
To cite this article: Komal Arora , Sonali Verma , Densely Jose , Pushpa Pardasani &
R. T. Pardasani (2008) Stereoselective [3 + 2] Cycloaddition Reactions of Azomethine
Ylides Derived from 5-Methylbenzo[B]thiophene-2,3-dione and Piperidine-2-Carboxylic
Acid, Phosphorus, Sulfur, and Silicon and the Related Elements, 183:5, 1168-1180,
DOI: 10.1080/10426500701610945
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Phosphorus, Sulfur, and Silicon, 183:1168–1180, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701610945
Stereoselective [3 + 2] Cycloaddition Reactions
of Azomethine Ylides Derived from
5-Methylbenzo[B]thiophene-2,3-dione
and Piperidine-2-Carboxylic Acid
Komal Arora, Sonali Verma, Densely Jose,
Pushpa Pardasani, and R.T. Pardasani
Department of Chemistry, University of Rajasthan, Jaipur, India
A series of spiropyrrolidines have been synthesized in 68–76% yield by 1,3 dipolar
cycloaddition reaction of azomethine ylides generated by a decarboxylative route
from 5-methylbenzo[b]thiophene and piperidine-2-carboxylic acid with different
acetylenic and ethylenic dipolarophiles. The stereochemical course of the cycload-
dition has been investigated by spectral data and AM1 quantum chemical method.
The novel spiro compounds have been characterized by elemental analyses and
spectroscopic techniques.
Keywords
1,3-Dipolar
cycloaddition;
5-methylbenzo[b]thiophene-2,3-dione;
piperidine-2-carboxylic acid; dipolarophiles; semiempirical stereoselectivity; spectral
characterization
INTRODUCTION
The 1,3-dipolar cycloaddition reaction has been established as “the
single most important method for the construction of heterocyclic
five membered rings in organic chemistry”.1,2 These reactions have
found widespread use as a high yielding and efficient, regio- and
sterecontrolled method for the synthesis of different heterocyclic com-
pounds. The 1,3-dipolar cycloaddition reactions of azomethine ylides
occupy a unique position in the synthesis of pyrrolidines3; an impor-
tant building block in the synthesis of many natural products and
pharmaceuticals.4 As an extension of our studies on 1,3-dipolar cycload-
ditions of isatin derivatives and acenaphthylene-1,2-dione,5 we have
Received 5 June 2007; accepted 20 July 2007.
The authors are thankful to the DAE/BRNS, Mumbai for financial assistance. We also
thank Dr. V. K. Goyal, Agarwal College, Jaipur for providing facility for measuring optical
rotations. Komal Arora is thankful to UGC, New Delhi for NET-JRF scholarship.
Address correspondence to Pushpa Pardasani, Department of Chemistry, University
of Rajasthan, Jaipur-302 004, India. E-mail: rtpardasani@gmail.com
1168

Cycloaddition Reactions of Azomethine Ylides
1169
chosen benzo[b]thiophene nucleus with piperidine-2-carboxylic acid for
the present investigation because the former has been reported to pos-
sess active antiosteoporotic,6,7 antifungal8 properties, as well as has
been determined to be inhibitor of poliovirus,9 while the later is well
recognized as HIV protease inhibitor,10 analgesic and diuretic agent.11
Therefore, a molecule incorporating these two moieties might be ex-
pected to be an effective biomolecule.
RESULT AND DISCUSSION
Azomethine ylides can be generated in situ by the decarboxylation of
the intermediate iminium species and can be trapped as cycloadducts
in the presence of various dipolarophiles.12 Thus an equimolar mix-
ture of 5-methylbenzo[b]thiophene-2,3-dione (5-methylthioisatin)
I and piperidine-2-carboxylic acid (pipecolinic acid) II was refluxed
for 22 h in the absence of any dipolarophile, whereby it afforded
oxazolidinone derivative (6S, 9S) spiro-{1-aza-8-oxa-bicyclo[4,3,0]-
nonan-9,3ꢀ}-5ꢀ-methylbenzo[b]thiophene-7,2ꢀ-dione III in 74% yield.
Formation of such an oxazolidinone derivative has been previously
reported by Seebach et al.13 in the case of proline with pivaldehyde.
When the same reaction was carried out in the presence of differ-
ent ethylenic and acetylenic dipolarophiles, viz phenyl acetylene,
1-phenyl-1-propyne. diphenyl acetylene, ethylphenyl propiolate,
and methyl acrylate, it afforded (6S, 9R) spiro-{8-phenyl-1-aza-
bicyclo [4,3,0]-7-nonen-9,3ꢀ}-5ꢀ-methylbenzo[b]thiophene-2ꢀ-one V,
(6S, 9R)-spiro-{8-phenyl-7-methyl-1-aza- bicyclo [4,3,0]-7-nonen-9,3ꢀ}-
5ꢀ-methylbenzo[b]thiophene-2ꢀ-one VI, (6S, 9R) spiro-{7,8-diphenyl-1-
aza-bicyclo [4,3,0]-7-nonen-9,3ꢀ}-5ꢀ-methylbenzo[b] thiophene-2ꢀ-one
VII, and (6S, 9R) spiro-8-phenyl-7-ethoxycarbonyl-1-aza-bicyclo[4,3,0]-
7-nonen-9,3ꢀ}-5ꢀ-methylbenzo[b]thiophene-2ꢀone (VIII), and (6S, 8S,
9R) spiro-{8-methoxycarbonyl-1-aza-bicyclo [4,3,0]-nonane-9,3ꢀ}-5ꢀ-
methylbenzo[b]thiophene-2ꢀ-one IX, respectively, in 68–76% yields. The
reaction proceeds via formation of intermediate azomethine ylide IV
that subsequently undergoes 1,3-dipolar cycloadditions with various
dipolarophiles to afford spiro compounds (Scheme 1). The cycloadducts
20
V to IX are optically active and their specific rotations [α]D were in
the range 47◦–63◦.
The structure of the products was ascertained from their spectral
features. The IR spectrum of oxazolidinone derivative III showed ab-
sorption bands at 1720 and 1690 cm−1 due to lactonic C O and carbonyl
groups whereas absorptions at 1290 and 760 cm−1 were associated with
1
C-N and C-S stretching vibrations. Its H NMR spectrum showed fol-
lowing signals: δ 2.05 as a singlet for methylene protons (3-H to 5-H),

1170
K. Arora et al.
SCHEME 1 Reaction of 5-methylbenzo[b]thiophene,2.3-dione with piperidine-
2-carboxylic acid in absence and presence of different dipolarophiles.

Cycloaddition Reactions of Azomethine Ylides
1171
δ 2.29 as a triplet for 2-H, δ 2.5 as a singlet due to methyl protons, δ
4.08 as a triplet for 6-H, aromatic protons were seen as multiplet in
the region δ 7.0–7.9 ppm. Its 13C NMR spectrum showed the C-2ꢀ car-
bonyl carbon signal at δ 180.18 ppm whereas the lactone ring carbon
resonated at δ 170.03; the benzenoid carbons appeared in the region δ
135.92–123.68 ppm; the chiral carbons C-9 and C-6 were observed at δ
80.82 and δ 60.12 ppm respectively; methylene carbons (C-3, C-5, C-2
and C-4) appeared at δ 47.58, δ 27.73 δ 25.20 δ 21.40 ppm, respectively,
and the methyl carbon appeared at δ 19.22 ppm.
The IR spectrum of the typical 1-phenyl-1-propyne cycloadduct VI
showed characteristic bands at 1710, 1290, and 790 cm−1 for >C O,
1
C-N and C-S stretching vibrations respectively. Its H NMR spectrum
showed a singlet at δ 2.0 for methylene protons (3-H to 5-H), a multiplet
at δ 2.18 for 6-H, a triplet at δ 2.29 for 2-H, a singlet at δ 2.40 for methyl
protons of thioisatin ring, a doublet at δ 2.54 for C-7 CH3 protons which
preferentially supports the formation of VIa over VIb and a multiplet
in the range of δ 6.99–7.85 ppm for aromatic protons. The stereochem-
ical course of the cycloaddition reaction was further supported by the
1H NMR spectrum of phenyl acetylene cycloadduct (Va/Vb), in which
a quartet appeared at δ 3.3 due to 6-H and a doublet at δ 2.3 for 7-H
supporting the structure Va (Scheme 3). The 13C NMR spectrum of VI
showed a signal at δ 181.42 for carbonyl carbon, aromatic carbons ap-
peared in the range δ 134.23–118.63 ppm, the olefenic carbons appeared
at δ 112.27 and 110.19, spiro carbon appeared at δ 78.28, C-6 at δ 54.17,
C-2 at δ 53.46, C-5 at 34.82, C-4 at δ 29.57 and C-3 at 24.49 ppm and
methyl carbons at δ 15.83 ppm. Additional evidence was gathered from
its mass spectrum. The molecular ion peak and base peaks were present
at m/z 361 and 245 respectively along with other prominent peaks. The
mass fragmentation pattern of VI has been depicted in Scheme 2. These
results are in good harmony with the observation of Grigg et al.,14 as
well as with the theoretical calculations. Physical and spectral data
have been tabulated in Table I and Table II respectively.
SEMIEMPIRICAL MOLECULAR ORBITAL STUDIES
The stereochemical course of the cycloaddition was ascertained by AM1
quantum chemical calculations on MOPAC 6 program. Oxazolidinone
derivative III contains two chiral centers and therefore a total of four
stereoisomers IIIa-IIId could be possible (Scheme 4).
Since III is formed by dehydration of the intermediate iminium
species, the stereochemistry at C-6 should remain unaltered with re-
spect to the piperidine ring. The configuration at C-6 and C-9 is there-
fore in analogy with the previously assigned configuration of the [3,3,0]

1172
K. Arora et al.
SCHEME 2 Mass fragmentation pattern of cycloadduct VI.
SCHEME 3 Stereoisomers of cycloadduct V and VI.
bicyclic N,O-acetal obtained by the condensation of proline and pivalde-
hyde as reported by Seebach et al.13On this basis, the possibility of
stereoisomers IIIa and IIIb may be ruled out. Out of the remaining
two isomers, IIIc has high ꢀHf (ꢀHf = −56.515 Kcal/mol) as compared
to isomer IIId (ꢀHf = −62.098 Kcal/mol). Hence, the expected product
is IIId.
The intermediate lactonic species may undergo decarboxylation to
give azomethine ylide IV that subsequently undergoes 1,3-dipolar

Cycloaddition Reactions of Azomethine Ylides
1173
SCHEME 4 Four possible stereoisomers of oxazolidinone III.
cycloaddition with various dipolarophiles to afford azabicycloadducts.
The optimized geometry of azomethine ylide IV indicates that it has
a planar structure wherein the piperidine ring lies in the same plane
as that of thioisatin moiety. It may exist in two isomeric forms one in
which >C O and C H of the dipole are syn to each other IVsyn and the
other one in which they are anti IVanti. (Figure 1).
TABLE I Physical and analytical data of cycloadducts
Elemental analysis
calcd/found
Compd.
no.
Physical
state
Molecular
formula
m.p.
◦C Yield [α]D
20
C
H
N
S
III
V
Chocolate brown C15H15NO3S 90
powder
74
75
76
68
74
70
—
52
50
48
63
47
62.28
5.19
4.84
(4.60)
4.03
(4.01)
3.87
(3.64)
3.30
(3.14)
3.61
(3.42)
4.22
11.07
(10.94)
9.22
(9.12)
8.86 (8.
14)
7.56
(7.10)
8.26
(61.12) (4.89)
76.08 6.05
(75.53) (5.97)
76.45 6.37
(76.11) (6.05)
79.43 5.91
(78.97) (5.87)
77.51 6.45
(76.17) (6.29)
65.25 6.34
(64.95) (5.98)
Bright yellow
powder
Shiny brown
powder
C22H21NOS 188
C23H23NOS 220
C28H25NOS 175
VI
VII
VIII
IX
Brown powder
Light brown
powder
Reddish brown
powder
C
25H25NO3S 200
18H21NO3S 180
(8.10)
9.66
(9.53)
C
(4.01)

1174
K. Arora et al.
TABLE II Spectral data of the cycloadducts
Compd
No.
IR (cm−1
)
1HNMR (δ ppm)
13CNMR (δ ppm
III
2920 (C-Haro), 2855
(C-Hali), 1720
(lactone >C O),
1690 (C O), 1290
(C-N), 1230 (C-O),
760 (C-S)
2.05 (s, 3-H+4-H+5-H, 6H), 180.18 (.C O), 170.03
2.29 (t, 2-H, 2H), 2.50 (s,
CH3, 3H), 4.08 (t, 6-H,
1H), 7.0–7.9 (m, ArH)
(O C O),
135.91-123.68 ( ArC),
80.82 (Spiro C), 60.12
(C-6), 47.58 (C-3), 27.73
(C-5), 25.20 (C-2), 21.40
(C-4), 19.22 (CH3)
V
3050 (C-Haro), 2925
(C-Hali), 1715
(>C O), 1295 (C-N),
780 (C-S)
2.1 (s, 3-H+4-H+5-H, 6H), 182.5 (C O),
2.2 (t, 2-H, 2H), 2.3 (d,
7-H, 1H), 2.4 (s, CH3,
3H), 3.3 (q, 6-H, 1H),
7.1-7.9 (m, ArH)
136.5–120.13 ( ArC),
114.1–112.2 (C C),
70.09 (Spiro C-9), 57.52
(C-6), 55.11 (C-2), 36.21
(C-5), 30.30 (C-4), 25.32
(C-3), 16.42 (CH3)
VI
VII
2930 (C-Haro), 2860
(C-Hali), 1710
(>C O), 1290 (C-N),
790 (C-S)
2.0 (s, 3-H+4-H+5-H, 6H), 181.42 (C O),
2.15 (t, 2-H, 2H), 2.3 (m,
6-H, 1H), 2.4 (s, CH3’,
3H), 2.5 (d, CH3, 3H),
6.9–7.8 (m, ArH)
134.23–118.63 ( ArC),
112.21–110.19 (C C),
78.28 (Spiro C-9), 54.17
(C-6), 53.46 (C-2), 34.82
(C-5), 29.57 (C-4), 24.49
(C-3), 15.83 (CH3)
3075 (C-Haro), 2930
(C-Hali), 1680
(>C O), 1280 (C-N),
765 (C-S)
1.4 (s, 3-H+4-H, 4H), 2.0
(q, 5-H, 2H), 2.3 (t, 2-H,
2H), 2.5 (t, 6-H, 1H), 2.54
(s, CH3, 3H), 6.9–8.0 (m,
ArH)
183.1 (C O), 134.9-119.5
(ArC), 110.7-109.2
(C C), 75.12 (Spiro
C-9), 52.2 (C-6), 50.7
(C-2), 32.9 (C-5), 27.8
(C-4), 22.4 (C-3), 18.1
(CH3)
VIII
IX
3060 (C-Haro), 2925
(C-Hali), 1675
1.2 (s, CH3), 2.0 (s,
3-H+4-H+ 5-H, 6H), 2.15
(t, 2-H, 2H), 2.27 (t, 6-H,
1H), 2.40 (s, CH3, 3H),
3.5 (q, OCH2), 6.8–7.8
(m, ArH)
(O
C O), 1650
(>C O), 1290 (C-N),
1225 (C-O), 760
(C-S)
3040 (C-Haro), 2915
(C-Hali), 1740
2.29 (s, 3-H+4-H+
5-H, 6H), 2.31 (t, 2-H,
2H), 2.37 (t, 6-H, 1H),
2.40 (s, CH3, 3H), 3.34 (t,
7-H, 2H), 4.03 (t, 8-H,
1H),4.25 (s, OCH3,3H),
6.7-7.5 (m, ArH)
(O
C O), 1710
(>C O), 1280 (C-N),
1230 (C-O), 755
(C-S)
Mass spectrum of VI m/z: 361 [C23H23NOS].+[M.+] (28%), 333 [M.+-CO](32%), 245
[M.+-C9H8](100%), 162 [M.+- C9H8,C5H9N], 150 [M.+-C15H17N](22%), 90
[M.+-C15H17N, SCO](30%).

Cycloaddition Reactions of Azomethine Ylides
1175
FIGURE 1 Optimized geometries of azomethine ylide IV.
Attack of dipolarophile, such as 1-phenyl-1-propyne on syn or anti
azomethine ylide may produce a cycloadduct VI having two chiral cen-
ters and therefore a total of 4 + 4 = 8 stereoisomers could be possible
(Figure 2).
Frontside attack of phenyl propyne (Figure 3) on azomethine
ylide IVsyn results in the formation of products VIe-h. However, the
FIGURE 2 Possible stereoisomers of phenyl propyne cycloadduct VI.

1176
K. Arora et al.
FIGURE 3 Backside attack and frontside attack of phenyl propyne on amy IV.
transition state could not be located even in a single case. This may be
attributed to the steric hindrance between the thioisatin ring and the
piperidine ring because frontside attack results in the inward move-
ment of the piperidine ring towards the thioisatin ring making the sys-
tem unstable and hence failing to produce transition state geometry.
This leaves only four isomers VIa-VId for consideration. Of these
four possibilities, in two cases VIc and VId, where N and H atoms on
the adjacent carbons do not lie on the same side, the transition state
could not be located because a concerted mechanism is not possible
in such a situation. Out of the remaining two possibilities VIa and
VIb, we could optimize the transition state in the case of VIa only.
This can be explained using the FMO approach along with the endo
approach of the phenyl ring. The transition state of the concerted 1,3-
dipolar cycloadditions in usually controlled by Frontier Molecular Or-
bitals (FMO’s) of dipolarophiles and dipole (amy). From Figure 4, it may
be concluded that HOMOdipole-LUMOdipolarophile energy gap is lower than
FIGURE 4 Correlation diagram indicating HOMO and LUMO energies
of dipole and dipolarophiles and H-L and L-H energy gaps.

Cycloaddition Reactions of Azomethine Ylides
1177
FIGURE 5 Atomic orbital coefficients and overlapping of dipole (amy) and
dipolarophile (phenyl propyne).
the LUMOdipole-HOMOdipolarophile gap and therefore the dominant FMO
approach is HOMOdipole-LUMOdipolarophile
.
In the HOMO of amy (dipole), the orbital coefficient is larger at C1
(0.0747) than at C2 (−0.098). Similarly in the LUMO of 1-phenyl-1-
propyne the atomic orbital coefficient on the C-atom bearing the phenyl
group is larger (0.0015) than that of the atom away from it (0.00001)
(Figure 5).
An efficient orbital overlap between C of azomethine ylide and the C-
atom bearing the phenyl group results in the formation of product VI a,
ruling out the possibility of VI b. The optimized geometry of transition
state is shown in Figure 6. Thus cycloadduct VIa could be formed in
diastereoisomeric excess due to the endo approach of the phenyl ring
which is in good harmony with experimental results.
FIGURE 6 AM1 optimized geometry of transition state of cycloadduct VI.

1178
K. Arora et al.
FIGURE 7 Stabilization energy and activation energy of amy (IV) with phenyl
propyne and diphenyl acetylene.
The energy profile diagrams for the reactions of amy IV with phenyl
propyne and phenyl acetylene is depicted in Figure 7. Parallel calcu-
lations have been performed on other cycloadducts and the following
conclusions may be drawn:
1. Geometry optimization of the amy indicated that it has an almost
planar structure.
2. The dominant FMO approach is HOMOdipole-LUMOdipolarophile as this
energy group is lower than the LUMOdipolar-HOMOdipolarophile group
(Figure 4).
3. The endo approach is favored and the phenyl group lies towards the
thioisatin ring.
EXPERIMENTAL
The uncorrected melting points were taken in open glass capillaries.
The IR spectra were recorded on a Nicolet Magna IR Spectrometer
Model 550 in KBr pellets and band positions are reported in wave
numbers (cm−1). The 1H NMR spectra and 13C NMR spectra have been
recorded on a Bruker DRX-300 MHz and 75.47 MHz model respectively
in CDCl3using tetramethylsilane as an internal standard. The chemi-
cal shifts are given in δ ppm values. The mass spectra were recorded
on a JEOL-SX 102 (FAB). Most of the spectra were recorded at CDRI,
Lucknow, India. Elemental analyses were performed on a Perkin Elmer
Series C, H, N, S Analyzer 2400. The solvents were purified by standard
procedures.15,16 The optical rotations were measured on a D line of Na
lamp at 5893 A◦ wavelength, at 20◦C in 1g concentration.Acetonitrile

Cycloaddition Reactions of Azomethine Ylides
1179
was dried by refluxing with anhydrous calcium chloride for 5–6 h and
then distilling it. Pipecolinic acid were purchased from Merck and
Aldrich and used as supplied. Column chromatography was performed
on silica gel 60 (Merck).
Computational Details
All calculations have been carried out at MOPAC 6 program using AM1
hamiltonians on PCL-Pentium 4, PC MODEL for windows, version 5.13
Serena software was used as a graphical interface for drawing and
visualizing all structures and for preparing input files for MOPAC6.
The energy terms has been given in Kcal/mol.
Synthesis of Oxazolidione Derivative III
A reaction mixture of 5-methylthioisatin I (0.36 g; 2.0 mmol) and
pipecolinic acid II (0.260 g; 2.0 mmol) in the equimolar ratio was re-
fluxed under a nitrogen atmosphere for 22 h in dry acetonitrile. It was
then allowed to stand overnight, but no crystallization occurred. Hence,
it was further concentrated to half its volume and allowed to crystal-
lize whereby it afforded oxazolidinone derivative III as chocolate brown
powder (75%), m.p. 90◦C.
A Representative Method for the Synthesis of Cycloadduct VI
A mixture of 5-methylthioisatin I (0.36 g; 2.0 mmol) pipecolinic acid II
(0.260 g; 2.0 mmol) and phenyl propyne (0.232 g, 2.0 mmol) in equimolar
amount was refluxed under a nitrogen atmosphere for 20 h in dry ace-
tonitrile. The completion of reaction was monitored by TLC. The crude
product was column chromatographed over silica gel, whereby chloro-
form/ethylacetate (3:1) fraction afforded the cycloadduct VI as shiny
brown solid (0.63 g, 75%), m.p. 220◦C.
The cycloadducts V to IX are optically active and their specific rota-
tions [α]D were in the range 47◦–63◦.
20
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1180
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