Solvent-free cycloaddition reaction of 3-indolylimines with chloroacetyl chloride under microwave irradiation

Article abstract of DOI:10.1002/hc.10180

Solvent-free approach is developed for the rapid synthesis of spiro[azetidine-indoles] 6a-g on basic alumina supported potassium carbonate (K₂C O₃-Al₂O₃) from the cycloaddition reaction of indolylimines 3 and ch

Full text of DOI:10.1002/hc.10180

Heteroatom Chemistry
Volume 14, Number 5, 2003
Solvent-Free Cycloaddition Reaction of
3-Indolylimines with Chloroacetyl Chloride
Under Microwave Irradiation
Anshu Dandia, Ruby Singh, and Pragati Sharma
Department of Chemistry, University of Rajasthan, Jaipur 302004, India
Received 19 March 2003; revised 28 April 2003
biodynamic indole alkaloids [5,6]. Spiro[azetidine-
ABSTRACT: Solvent-free approach is developed for
indoles] have also shown unique antimicrobial ac-
the rapid synthesis of spiro[azetidine-indoles] 6a–
tion [7]. It has been observed that introduction of
g on basic alumina supported potassium carbon-
a fluorine atom or CF3 group to heterocycles may
ate (K2CO3–Al2 O3) from the cycloaddition reaction of
act as a pharmacophore enhancing pharmacological
indolylimines 3 and chloroacetyl chloride 4 as syn-
properties of the compounds as compared to their
thons using microwaves. The procedure neither re-
non-fluorinated analogues [8]. Incorporation of flu-
quired toxic and hazardous base nor volatile solvents.
orine atoms into the indole ring tends to increase
3 was synthesized in situ by the neat reaction of
drug persistence by increasing the solubility of the
indole-2,3-diones 1 and fluorinated anilines 2 un-
drug in lipoid material and fat deposits in body [9].
der microwave irradiation. Solvent-free aminoalkyla-
tion of spiro compounds 6a and 6b has been car-
ꢀ
C
ried out under microwaves.
2003 Wiley Periodicals,
RESULTS AND DISCUSSION
Inc. Heteroatom Chem 14:468–473, 2003; Published on-
line in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hc.10180
Conventional synthesis of spiro-azetidines involves
a long and tedious (80–82 h) two-step procedure
that uses dry benzene/dioxane as solvent and triethy-
lamine as basic catalyst, giving a product in just 55–
63% yield [7,10]. The synthesis of ꢀ-lactams under
microwave irradiation using the MORE (microwave-
induced organic reaction enhancement) technique
was extensively studied by Bose et al. [11], us-
ing N-methyl morpholine as basic catalyst in place
of triethylamine and chlorobenzene/DMF as a en-
ergy transfer media. However, microwave-enhanced
chemical reactions on inorganic solid supports un-
der solventless conditions have attracted attention
recently [12]. The advantages of these methods are
enhanced reaction rates, milder reaction conditions,
easier work-up, and organic syntheses are carried
out in open vessels with ecofriendly conditions on
a preparative scale.
INTRODUCTION
The ꢀ-lactam heterocycles are the most prescribed
antibiotics used in medicine [1], and various biolog-
ical activities are possessed by 3-chloromonocyclic
ꢀ-lactams [2,3]. They also function as enzyme in-
hibitors and are effective on the central nervous sys-
tem [4]. Moreover, 3-spiro indoline moieties also play
a vital role largely due to the wide range of biological
activities associated with them and their presence in
Correspondence to: Anshu Dandia; e-mail: dranshudandia@
eth.net.
Contract grant sponsor: UGC, New Delhi.
To the best of our knowledge there is no report
on solvent-free synthesis of spiro[azetidineindoles].
Contract grant sponsor: CSIR, New Delhi.
c
ꢀ
2003 Wiley Periodicals, Inc.
468

Cycloaddition Reaction of 3-Indolylimines with Chloroacetyl Chloride Under Microwaves 469
Hence in view of our interest on the synthe-
of change of mechanism under a given set of reaction
conditions. Recently, we have also reported the ef-
fect of power level on diastereoselective synthesis of
spiro oxirans [15]. Encouraged by this, we have stud-
ied the title cycloaddition reaction under different
conditions of conventional and microwave-mediated
synthesis using either triethylamine or K2CO3 as ba-
sic catalyst respectively. However, present studies
showed exclusive formation of only one diastere-
omer irrespective of different variables as shown in
Table 1.
sis of biodynamic heterocycles and fluorine con-
taining 3-spiro indolines using nonconventional
method of organic synthesis [13], we report here
the solvent-free synthesis of a series of new fluo-
rinated spiro[azetidine-indole]diones 6 by the cy-
cloaddition reaction of 3-arylimino indolinones 3
with chloroacetyl chloride 4, using basic alumina-
supported potassium carbonate (K2CO3–Al2O3) as in-
organic support under microwave irradiation. The
intermediates 3a–g were synthesized in situ by the
neat reaction of indole-2,3-diones 1 and substituted
anilines 2 under microwave irradiation in 30–50 s
without using any support or catalyst.
Comparative studies (Table 1) showed that the
reaction occurred successfully when basic alumina-
supported potassium carbonate was used as support,
Earlier reports mentioned the variable forma-
tion of cis and trans isomers of ꢀ-lactams [14,11a,c]
depending on the power level of microwave irradi-
ation or order of addition of reactants in conven-
tional synthesis, which was rationalized on the basis
eliminating the requirement of volatile solvent and
hazardous base triethylamine. In such cases the ba-
sicity of alumina (basic) is not sufficient to cause cy-
cloaddition as observed by earlier workers for the
synthesis of other ꢀ-lactams [16].
TABLE 1 Comparative Study for the Synthesis of 6a Using (A) Classical Method, (B) Microwave Irradiation (MW), (C) Con-
ventional Heating (Using Thermostated Oil Bath)
Method
Medium/Support
MW Power (W)
Time
82 h
10 min
7 min
25 min
6 min
6 min
Tempa (◦C)
Yieldb (%)
A
B
Triethylamine + dry benzene
(i) o-Dichlorobenzene + triethylamine
(ii) o-Dichlorobenzene + triethylamine
(iii) Basic alumina
(iv) K2CO3–Al2O3
K2CO3–Al2O3
–
40–45
61
78
76
Nil
90
30
275
480
640
640
–
154–156
154–156
135–137
138–140
138–140
C
aThe final temperature is measured at the end of microwave irradiation by introducing a glass thermometer in the reaction mixture.
bYield of the isolated product.

470 Dandia, Singh, and Sharma
Two mechanistic pathways A and B by which
imines 3 and acid chloride 4 combine to form ꢀ-
lactams have been proposed [17]. Path A involves
prior formation of ketene 4ꢁ by the reaction of acid
chloride with base and subsequent cycloaddition
with imine (the Staudinger reaction), perhaps via
zwitterionic intermediate 5, and path B involves di-
rect acylation of the imine with the acid chloride
giving N-acyliminium chloride 7, which may be in
equilibrium with chloro amide 8. Reaction of 7 or 8
with base then gives ꢀ-lactams 6.
(Tables 2 and 3). IR spectra of compounds 6a–g
showed characteristic absorption bands at the region
of 3260–3230, 1730–1725, and 1700–1690 cm−1 due
to NH and two carbonyl groups. The 1H NMR spec-
tra of products 6a–g showed signals at δ 4.27–4.30
(s, Cl CH) along with aromatic protons at 7.06–7.89
(m, Ar-H) and NH protons at δ 8.34–8.41 (bs, 1H, NH
exchangeable with D2O).
Formation of the spiro product was further
confirmed on the basis of 13C, 19F NMR, and mass
spectra. In the 13C NMR spectrum of 6a, sharp
signals were observed at δ 175.3 (C O), 163.8
(C O), 145.1, 143.3, 139.81, 138.2, 137.1, 136.5,
135.5, 134.2, 130.5, 129.1, 125.1, 119.6 (12 aromatic
carbons), 83.5 (spiro carbon), and 42.8 (Cl CH).
In the mass spectrum of 6a, the appearance of
molecular ion peak m/z (M+) at 380 and at 382 (M+ +
2) due to chlorine isotopic peak showed the forma-
tion of spiro compound. The presence of fluorine
in all synthesized compounds was confirmed by 19F
NMR spectra. Single fluorine attached to the indole
However, in the present investigation, the title
reaction proceeds via path A, which is confirmed by
IR spectral studies carried out during monitoring the
progress of reaction [17]. A strong band at 2290 cm−1
is assigned to intermediate ketene 4ꢁ which is
well resolved from carbonyl bands of acid chloride
(1800 cm−1) and the ꢀ-lactams 6 (1730 cm−1), leading
to formation of only one diastereomer.
The identification of spiro compounds is based
on their spectral studies and elemental analyses
TABLE 2 Physical and Analytical Data of 6a–g and 7a–b
Analysis (%): Calcd (Found)
Time
(min)
m.p.
(◦C)
Yield
(%)
a
X
Y
Rf
Molecular Formula
C
N
6a
6b
6c
6d
6e
6f
6g
7a
7b
5-CH3
5-Cl
5,7-diCH3
5-F
5-Cl
5-NO2
H
2-CF3
3-Cl
2-CF3
3-CF3
2-CF3
3-Cl
6
6
7
6
7
8
7
3
4
172
158
160
95
75
98
190
212
223
92
90
91
88
91
85
89
86
89
0.61
0.54
0.53
0.63
0.62
0.58
0.61
0.69
0.61
C18H12ClF3N2O2
56.78 (56.92)
52.28 (52.09)
57.81 (57.62)
53.07 (52.93)
50.90 (50.79)
50.82 (50.68)
50.90 (50.76)
57.57 (57.35)
54.04 (54.25)
7.36 (7.33)
7.62 (7.58)
7.10 (7.07)
7.28 (7.24)
6.98 (6.95)
11.11 (11.07)
6.98 (7.02)
8.76 (8.73)
9.00 (8.98)
C
16H9Cl3N2O2
H
14
C19 ClF3N2O2
C17H9ClF4N2O2
C17H9Cl2F3N2O2
C16H9Cl2N3O4
C17H9N2O2Cl2F3
C23H21F3ClN3O3
3-CF3, 4-Cl
2-CF3
3-Cl
5-CH3
5-Cl
C
21H18N3O3Cl3
aUsing solvent system benzene/ethyl acetate (8:2).

Cycloaddition Reaction of 3-Indolylimines with Chloroacetyl Chloride Under Microwaves 471
TABLE 3 Infrared and 1H NMR Data of Compounds 6a–g and 7a–b
IR (cm−1
)
1H NMR (δ, ppm)
19F NMR (δ, ppm)
−63.29 (s, CF3)
6a
3250 (NH), 1725, 1695 (two C O), 760 (C Cl)
δH 2.25 (s, 3H, CH3), 4.30 (s, 1H, CH Cl),
7.06–7.89 (m, 7H, Ar H), 8.38 (bs, 1H,
NH)
6b
6c
3240 (NH), 1730, 1690 (two C O), 740 (C Cl)
3230 (NH), 1730, 1698 (two C O), 765 (C Cl)
δH 4.28 (s, 1H, CH Cl), 7.29–7.70 (m, 7H,
Ar H), 8.34 (bs, 1H, NH)
δH 2.15 (s, 3H, CH3), 2.22 (s, 3H, CH3),
4.29 (s, 1H, CH Cl), 7.31–7.76 (m,
6H, Ar H), 8.40 (bs, 1H, NH)
−64.04 (s, CF3)
6d
6e
6f
3250 (NH), 1725, 1693 (two C O), 748 (C Cl)
3245 (NH), 1728, 1697 (two C O), 740 (C Cl)
3240 (NH), 1730, 1700 (two C O), 740 (C Cl)
3250 (NH), 1727, 1698 (two C O), 760 (C Cl)
δH 4.28 (s, 1H, CH Cl), 7.11–7.76 (m,7H,
Ar H), 8.39 (bs, 1H, NH)
δH 4.30 (s, 1H, CH Cl), 7.09–7.70 (m, 7H,
Ar H), 8.41 (bs, 1H, NH)
δH 4.31 (s, 1H, CH Cl), 7.18–7.71 (m, 7H,
Ar H), 8.39 (bs, 1H, NH)
δH 4.28 (s, 1H, CH Cl), 7.09–7.70 (m, 7H,
Ar H), 8.40 (bs, 1H, NH)
δH 2.20 (s, 3H, CH3), 2.70–2.83 (t, 4H,
N(CH2)2), 3.40–3.55 (t, 4H, O(CH2)2),
4.12 (s, 2H, N CH2 N) 4.34 (s, 1H,
CH Cl), 6.98–7.91 (m, 7H, Ar H)
δH 2.71–2.85 (t, 4H, N(CH2)2), 3.41–
3.56 (t, 4H, O(CH2)2), 4.17 (s, 2H,
N CH2 N), 4.38 (s, 1H, CH Cl),
7.05–7.76 (m, 7H, Ar H)
−63.78 (s, CF3)
−119.52 (s, F)
−64.78 (s, CF3)
6g
7a
−62.98 (s, CF3)
−64.25 (s, CF3)
1730, 1690 (two C O), 1180 (C O C), 1460,
750
7b
1728, 1690 (two C O), 1180 (C O C), 1450,
770
Note: IR spectra were obtained in KBr disc; NMR spectra were obtained in CDCl3 solution.
ring and the CF3 group attached to the phenyl ring
appeared as singlets at δ −119.52 and −62.98 to
−64.78 ppm, respectively.
Bruker-DRX-300 spectrometer using CDCl3 as a sol-
vent at 300.13, 75.47, and 282.37 MHz, respectively.
1
TMS was used as internal reference for H and 13C
Further, in view to improve bioactivity,
aminoalkylation of spiro compounds 6a and
6b were carried out under microwave irradiation.
Under a conventional manner, it requires several
hours of heating, using organic solvents. Faced
with this dilemma, we explored a more effective
and much faster route (lasting a few minutes) for
the implementation of aminoalkylation of the spiro
compounds in solvent-free conditions.
NMR and TFA as external reference for 19F NMR.
Mass spectrum of the representative compound 6a
was recorded on a Kratos-30 spectrometer. Elemen-
tal analyses for C and N were performed on a Her-
aeus Carlo Erba 1108 analyzer and found within
3% of theoretical value. Progress of the reaction
was monitored by TLC using silica gel “G”-coated
glass plates and benzene/ethyl acetate (8:2) as elu-
ent. The microwave-induced reactions were carried
out in a BMO-7OOT modified domestic oven fitted
with a condenser and a magnetic stirrer. Indole-2,3-
diones were prepared according to the literature pro-
cedures [18]. Inorganic solid support (K2CO3–Al2O3)
was used immediately after activation under mi-
crowave irradiation.
Aminoalkylation occurs exclusively at indole
nitrogen, and formation of mannich base from
the corresponding spiro compound has been con-
firmed by appearance of new resonance signals cen-
tered at δ 2.71–2.85, 3.40–3.56, and 4.12–4.17 ppm
in 1H NMR spectrum because of morpholino
group.
3-Chloro-1-(2-trifluoromethylphenyl)-5ꢁ-methyl-
spiro[azetidine-2,3ꢁ[3H]-indole]-2ꢁ,4(1ꢁH)-dione(6a)
was prepared by two routes: (1) conventional syn-
thesis and (2) microwave-assisted procedure.
EXPERIMENTAL
Conventional Synthesis
Melting points were determined on a Toshniwal
melting point apparatus and are uncorrected. IR
spectra were recorded in KBr on a Perkin-Elmer In-
fracord spectrophotometer model 577 (νmax in cm−1),
1H, 13C, and 19F NMR spectra were recorded on a
It involves two steps:
1. Synthesis of 3-(2-trifluoromethylphenyl)-imino-
5-methyl-2H-indol-2-one (3a): An equimolar

472 Dandia, Singh, and Sharma
mixture (0.01 mol) of 5-methyl-indole-2,3-dione
1a and 2-trifluoromethyl aniline 2a was refluxed
in dry toluene for 4 h. Crystals separated out
on cooling were dried and recrystallized from
ethanol (yield = 70%; m.p. 165◦C [19]).
Synthesis of Mannich Base of Spiro
Compounds 7a/7b
A mixture of appropriate spiro compound 6a/6b
(1 mmol), formaldehyde (1.5 mmol, 40%), and mor-
pholine (1 mmol) was irradiated in a microwave oven
at power output at 640 W for the period indicated in
Table 2 (TLC). The resultant residue after crystalliza-
tion from methanol gave 7a/7b.
2. Synthesis of spiro product: To a well stirred
solution of 3a (0.005 mol) and triethylamine
(0.005 mol) in dry benzene (10 ml) was
added chloroacetyl chloride (0.005 mol) drop-
wise at room temperature. After the addition of
chloroacetyl chloride, the mixture was further
stirred for 3 days. The precipitated triethylamine
hydrochloride was filtered off and washed thor-
oughly with dry benzene. The solvent from the
filtrate was evaporated in vacuo and the residue
was recrystallized from benzene-pet-ether.
ACKNOWLEDGMENT
We are thankful to CDRI, Lucknow, India, for spec-
troscopic data and elemental analyses.
REFERENCES
[1] Manas, M. S.; Bose, A. K. Synthesis of Penicillin,
Cephalosporin and Analogs; Marcel Dekker, Inc.: New
York, 1969; p. 13.
[2] Doherty, J. B.; Down, C. P. PCT Int Appl WO
94,10,193, 1994; Chem Abstr 1995, 122, 160362k.
[3] Khalafallah, A. K.; Selim, M. A.; Abu, R. M.;
Elmaghraby, M. A.; Soleiman, H. A.; Raslan, M. A.
Indian J Chem 1995, 34B, 1060.
Microwave-Assisted Synthesis (Synthesis of 3a)
An equimolar mixture (0.01 mol) of 1a and 2a was
irradiated under microwave irradiation for 30 s at
640 W (monitored by TLC). The intermediate 3a was
so obtained in reasonable purity (TLC) (confirmed by
mixed mp with authentic sample), and used as such
for the next step for the synthesis of spiro[indole-
azetidine] 6a by following two methods to study the
role of power level, medium, and base.
Using the MORE technique: An equimolar
mixture (0.005 mol) of 3a, triethylamine, and
chloroacetyl chloride in o-dichlorobenzene (5 ml) in
an erlenmeyer flask was irradiated inside a domes-
tic microwave oven at power 30% (275 W) and 70%
(480 W) for 10 and 7 min respectively to check the ef-
fect of power level. Progress of the reaction was mon-
itored by TLC. Reaction mixture was cooled down
and the precipitate of triethylamine hydrochloride
was filtered off and washed thoroughly with benzene,
and the excess solvent was evaporated on a rotary-
evaporator to give a solid that was found to be pure
by TLC.
Using inorganic solid support: K2CO3 (2 mmol,
i.e., 376 g) was coground with 4 g of basic alumina
in an agate mortar. To this, a mixture of intermedi-
ate 3a (2 mmol) and chloroacetyl chloride 4 (3 mmol)
was added, mixed thoroughly, and irradiated under
microwave irradiation at 640 W for 6 min. The prod-
uct was obtained by desorption with methanol and
found to be pure by TLC.
The identity of compound 6a synthesized by
various methods, i.e., conventionally and under
microwave irradiation by changing power level,
medium, and base, was confirmed by mixed mps
and spectral studies. Other compounds 6b–g listed
in Table 2 were similarly prepared under solvent-free
conditions using (K2CO3–Al2O3) as support.
[4] Vashi, B. S.; Mehta, D. S.; Shah, V. H. Indian J Chem
1995, 34B, 802.
[5] Edmondson, S.; Danishefsky, J. S.; Sepp-Lorenzino,
L.; Rosen, N. J Am Chem Soc 1999, 121, 2147.
[6] Keplinger, K.; Wagner, H.; Kreutz-Kamp, B. PCT Int
86,00,524, 1986; Chem Abstr 1986, 105, 146231j.
[7] Joshi, K. C.; Jain, R.; Sharma, V. J Indian Chem Soc
1986, 63, 430.
[8] Filler, R. Chem Tech 1974, 4, 752.
[9] Whittle, B. A.; Youny, E. H. P. J Med Chem 1963, 6,
378.
[10] (a) Hassan, K. M.; El-Shavei, A. K.; El-Kashev, H.
S. Z Naturforsch B 1978, 33, 1515; (b) Joshi, K. C.;
Dandia, A.; Bhagat, S. J Fluorine Chem 1990, 48,
169; (c) Awad, I. M. A.; Abdel-Hafez, A. A.; Hassan,
K. M. Stud Org Chem 1988, 35, 201; (d) Kumar, R.;
Giri, S.; Nizamuddin, J. Agric Food Chem 1989, 37,
10946.
[11] (a) Bose, A. K.; Banik, B. K.; Manhas, M. S. Tetrahe-
dron Lett 1995, 36, 213; (b) Bose, A. K.; Jayaraman,
M.; Okawa, A.; Bari, S. S.; Robb, E. B.; Manhas, M.
S. Tetrahedron Lett 1996, 39, 6989; (c) Banik, B. K.;
Manhas, M. S.; Rebb, E. W.; Bose, A. K. Tetrahedron
Lett 1997, 44, 403.
[12] (a) Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet,
F.; Jacquault, P.; Mathe, D. Synthesis 1998, 1231;
(b) Varma, R. S. Green Chem 1999, 1, 43.
[13] (a) Dandia, A.; Sachdeva, H.; Singh, R.; Sharma, C. S.
Indian J Chem 2003, 42, 140; (b) Dandia, A.; Sati, M.;
Arya, K.; Loupy, A. Heterocycles 2003, 60(3), 563; (c)
Dandia, A.; Sati, M.; Loupy, A. Green Chem 2002, 4,
599; (d) Dandia, A.; Singh, R.; Sachdeva, H.; Arya,
K. J Fluorine Chem 2001, 111, 61; (e) Dandia, A.;
Sachdeva, H.; Singh, R. J Chem Res (S) 2000, 272; (f)
Dandia, A.; Sachdeva, H.; Singh, R. Synth Commun
2000, 31, 87; (g) Dandia, A.; Saha, M.; Taneja, H. J
Fluorine Chem 1998, 90, 17; (h) Dandia, A.; Upreti,

Cycloaddition Reaction of 3-Indolylimines with Chloroacetyl Chloride Under Microwaves 473
M.; Rani, B.; Pant, U. C. J Chem Res (S) 1998, 752; (i)
Dandia, A.; Upreti, M.; Rani, B.; Pant, U. C. J Chem
Res (M) 1998, 3348.
[17] Lynch, J. E.; Riseman, S. M.; Laswell, W. L.; Tschaen,
D. M.; Volante, R. P.; Smith, G. B.; Shinkai, I. J Org
Chem 1989, 54, 3792, and references cited therein.
[18] (a) Piozzi, F.; Favini, G. Atti Accad Naz Lincei Cl Sci
Fis, Mat Nat Rend 18, 1955, 647; (b) Dandia, A.; Saha,
M.; Rani, B. J Chem Res (S) 1998, 360; (c) Dandia, A.;
Saha, M.; Rani, B. J Chem Res (M) 1998, 1425.
[19] Dandia, A.; Saha, M.; Shivpuri, A. Indian J Chem
Technol 1997, 4, 201.
[14] Bose, A. K.; Chiang, Y. H.; Manhas, M. S. Tetrahedron
Lett 1972, 40, 4091.
[15] Dandia, A.; Singh, R.; Saha, M.; Shivpuri, A. Phar-
mazie 2002, 57, 9.
[16] Kidwai, M.; Venkataramanan, R.; Kohli, S. Synth
Commun 2000, 30, 989.