Thermal and microwave-assisted conjugate additions of indole on electron-deficient nitro-olefins

Article abstract of DOI:10.1080/00397910500498788

Conjugate addition of indole on nitro-olefins was carried out by three different methods: (i) thermal heating in a sealed tube, (ii) reaction with indolyl magnesium iodide, and (iii) microwave irradiation. Comparison of the results indicated that the micr

Full text of DOI:10.1080/00397910500498788

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Thermal and Microwave‐Assisted Conjugate
Additions of Indole on Electron‐Deficient
Nitro‐olefins
Radhika S. Kusurkar a , Nabil A. H. Alkobati a , Anita S. Gokule a , Purnima
M. Chaudhari a & Prasad B. Waghchaure a
a Department of Chemistry, University of Pune, Pune, India
Published online: 16 Aug 2006.
To cite this article: Radhika S. Kusurkar , Nabil A. H. Alkobati , Anita S. Gokule , Purnima M. Chaudhari
& Prasad B. Waghchaure (2006) Thermal and Microwave‐Assisted Conjugate Additions of Indole on
Electron‐Deficient Nitro‐olefins, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 36:8, 1075-1081, DOI: 10.1080/00397910500498788
To link to this article: http://dx.doi.org/10.1080/00397910500498788
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Synthetic Communicationsw, 36: 1075–1081, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500498788
Thermal and Microwave-Assisted
Conjugate Additions of Indole on Electron-
Deficient Nitro-olefins
Radhika S. Kusurkar, Nabil A. H. Alkobati, Anita S. Gokule,
Purnima M. Chaudhari, and Prasad B. Waghchaure
Department of Chemistry, University of Pune, Pune, India
Abstract: Conjugate addition of indole on nitro-olefins was carried out by three
different methods: (i) thermal heating in a sealed tube, (ii) reaction with indolyl
magnesium iodide, and (iii) microwave irradiation. Comparison of the results
indicated that the microwave technique is most efficient.
Keywords: Conjugate additions, indole, microwave, nitro-olefins
Indole is an important system present in many biologically active and
naturally occurring compounds.[1] The increased nucleophilic reactivity of
the 3-position of the indole ring is used[2–4] for building up the subsequent
rings of indole alkaloids. One of the earlier methods to get the addition at
only the 3-position of the indole ring was the use of indolyl, Grignard
reagent.[5] Presence of protic solvents[6,7] or Lewis acids[8–11] was required
for the other methods such as nucleophilic Friedel–Crafts–type conjugate
addition of indole to alkylate indole at the 3-position. The earlier methods
required longer time and gave low yields of the products, which were due
to polymerization. Recently these reactions are reported using catalysts such
as bismuth triflate,[12] indium halides,[13,14] or ytterbium triflate[15]
recent report,[16] the
.
[Yb(OTf)3 3H2O] as Lewis acids. In
a
.
.
CeCl3 7H2O NaI-SiO2 system was used for the conjugate addition. As a
part of our interest in alkylation of indole at C-3, we studied direct alkylation
of indole with nitro-olefins under microwave irradiation. In addition, we have
Received September 7, 2005
Address correspondence to Radhika S. Kusurkar, Department of Chemistry,
University of Pune, Pune 411 007, India. E-mail: rsk@unipune.ernet.in
1075

1076
R. S. Kusurkar et al.
also carried out comparative studies involving thermal heating, Grignard
reagent–mediated reaction, and microwave irradiation.
Initially indole was treated with methyl magnesium iodide to get
indolyl magnesium iodide, which on treatment with nitrostyrene 1 at room
temperature gave the expected product 12 in 71% yield in 5 min
(Scheme 1). Furthermore, indole and nitrostyrene 1 in dry benzene were
heated at 120 8C in a sealed tube for 2 days. Compound 12 was isolated in
80% yield. Finally indole and nitrostyrene 1 were loaded on silica gel (60–
120 mesh) and then irradiated in a microwave oven for 2 min to get 12 in
almost quantitative yield.
1
The structure of 12 was supported by IR, H NMR, 13C NMR, DEPT
spectra, and elemental analysis. From this result, it was apparent that the
microwave-irradiation reaction was most efficient with respect to time and
yield. Various nitro-olefins (2–8) and indole provide products (13–19) in
good yields (see Tables 1 and 2).
Alkylation of indole with a-methyl nitro-alkenes (9–11) using
microwave irradiation furnished the corresponding Michael addition
1
products (20–22) (Scheme 1) in good yields (see Table 2). The H NMR of
20–22 revealed the presence of diastereomers in the ratio of 7:3 for 20,
1.1:1 for 21 and 1:1 for 22.
In summary, microwave irradiation is the method of choice for the
conjugate addition of indole to nitro-alkenes.
EXPERIMENTAL
General Remarks
Thin-layer chromatographic analysis was performed using silica gel on glass
1
plates and was detected under UV. The H and 13C NMR spectra were
recorded in CDCl3 on a Varian 300 S instrument. FT-IR spectra were
recorded on a Perkin-Elmer 1600. Mass spectra were recorded on a
Shimadzu QP 5050.
Scheme 1. 1, 12: Ar ¼ phenyl, R ¼ H; 2, 13: Ar ¼ 3,4-dimethoxyphenyl, R ¼ H; 3,
14: Ar ¼ 3,4-methylenedioxyphenyl, R ¼ H; 4, 15: Ar ¼ p-nitro phenyl, R ¼ H; 5, 16:
Ar ¼ 2-furyl, R ¼ H; 6, 17: Ar ¼ 2-thienyl, R ¼ H; 7, 18: Ar ¼ p-methoxyphenyl,
R ¼ H; 8, 19: Ar ¼ m-methoxyphenyl, R ¼ H; 9, 20: Ar ¼ 2-furyl, R ¼ CH3; 10,
21: Ar ¼ p-methoxyphenyl, R ¼ CH3; 11, 22: Ar ¼ p-nitro phenyl, R ¼ CH3.

Conjugate Additions of Indole
1077
Table 1. Time and yields for the products 12–17 using Grignard reaction, sealed tube
reaction, and microwave reaction
Grignard
reaction
Sealed tube
reaction
Microwave
reaction
Yield Time Yield Time Yield
(%) (min) (%)
Entry
1
Electrophile
Product Time
(%)
(h)
12
13
5 min
20 h
71
48a
80
53
2
95
80
2
3
4
73
73
35
72b
72b
48b
10
14
15
20 h
60
65
10
10
89
84
5 min
5
6
16
17
5 min
5 min
60
58
48a
48a
85
82
2
2
86
93
aHeating at 120 8C.
bHeating at 140 8C.
General Procedure for Reaction of Nitro-olefins (1–6) with Indolyl
Magnesium Iodide
Nitro-olefins (1–6) (0.003 mol) in dry toluene (5 ml) were slowly added to
freshly prepared indolyl magnesium iodide[17] in ether. After the reaction
was completed as judged by TLC, the reaction mixture was quenched by
adding water, extracted with dichloromethane, washed with brine, dried
over sodium sulphate, and evaporated. The residue was chromatographed
on silica gel using hexane–ethyl acetate as an eluent to give 12–17.
General Procedure for Reaction of Nitro-olefins (1–6) with Indole
in a Sealed Tube
Nitro-olefins (1–6) (0.003 mol) and indole (0.0032 mol) in dry benzene (5 ml)
were heated for two days at 120 8C. The crude product obtained after removal
of the solvent was chromatographed on silica gels using hexane–ethyl acetate
to get the pure product (12–17).

1078
R. S. Kusurkar et al.
Table 2. Time and yields for the products 18–22 using the microwave reaction
Entry
1
Electrophile
Product
Time (min)
10
Yield (%)
92
18
2
19
10
94
3
4
20
21
20
1
96
87
5
22
1
82
General Procedure for Reaction of Nitro-olefins (1–12) with Indole
using Microwave Irradiation
A mixture of indole (0.0012 mol) and nitro-olefin (0.001 mol) was loaded on
silica gel (60–120 mesh) and was irradiated in a microwave oven. The
completion of the reaction was confirmed by TLC. The same silica gel was
loaded on a silica-gel column, and chromatographic separation using
hexane–ethyl acetate furnished the products (12–22).
Data
Compound 12: Mp 99 8C. IR (Nujol): 3393 cm21 (NH), 1532 and 1373 cm21
1
(NO2). H NMR d 4.95 (dd, 1H, J ¼ 8.2, 12.3 Hz), 5.08 (dd, 1H, J ¼ 7.6,
12.3 Hz), 5.20 (t, 1H, J ¼ 8.2 Hz), 7.04–7.18 (m, 2H), 7.18–7.4 (m, 7H),
7.44 (d, 1H, J ¼ 7.9 Hz), 8.1 (bs, 1H). 13C NMR d 41.47, 76.58, 111.36,
114.22, 118.84, 119.86, 121.56, 122.61, 125.99, 127.51, 127.70, 128.86,
136.37, 139.09. C16H14N2O2: C, 72.16; H, 5.3. Found: C, 72.35; H, 5.45.
Compound 13: Mp 145 8C. IR (Nujol): 3343 cm21 (NH), 1551 and
1
1371 cm21 (NO2). H NMR d 3.80 (s, 3H), 3.84 (s, 3H), 4.89 (dd, 1H,
J ¼ 8.2, 12.1 Hz), 5.03 (t, 1H, J ¼ 7.1 Hz), 5.1 (dd, 1H, J ¼ 7.7, 15.6 Hz),
6.77–6.88 (m, 3H), 7.0 (d, 1H, J ¼ 2.5 Hz), 7.06 (t, 1H, J ¼ 7.7 Hz), 7.18
(t, 1H, J ¼ 7.1 Hz), 7.35 (d, 1H, J ¼ 8.2 Hz), 7.44 (d, 1H, J ¼ 7.7 Hz), 8.1
(bs, 1H). 13C NMR d 41.31, 55.89, 55.92, 79.73, 111.20, 111.35, 111.49,
114.55, 118.96, 119.73, 119.95, 121.65, 122.70, 126.1, 131.72, 136.56,
148.36, 149.18. C18H18N2O4: C, 66.24; H, 5.56. Found: C, 66.44; H, 5.60.

Conjugate Additions of Indole
1079
Compound 14: Mp 145 8C. IR (Nujol): 3400 cm21 (NH), 1542 and
1
1376 cm21 (NO2). H NMR d 4.87 (dd, 1H, J ¼ 8.2, 12.1 Hz), 5.02 (t, 1H,
J ¼ 7 Hz), 5.12 (dd, 1H, J ¼ 7.9, 13.7 Hz), 5.9 (AB quartet, 2H, J ¼ 1.3,
4.9 Hz), 6.7–6.8 (m, 3H), 7.07–7.1 (m, 2H), 7.18 (t, 1H, J ¼ 7.9 Hz), 7.35
(d, 1H, J ¼ 7.9 Hz), 7.42 (d, 1H, J ¼ 7.9 Hz), 8.0 (bs, 1H). 13C NMR d
41.19, 55.78, 79.61, 111.06, 111.22, 111.36, 114.45, 118.85, 119.6, 119.84,
121.53, 122.59, 125.99, 131.58, 136.43, 148.24, 149.06. C17H14N2O4: C,
65.80; H, 4.55. Found: C, 65.83; H, 4.78.
Compound 15: Mp 142 8C. IR (Nujol): 3401 cm21 (NH), 1598, 1545, 1345,
1
and 1375 cm21 (NO2). H NMR d 4.98 (dd, 1H, J ¼ 8.8, 12.6 Hz), 5.08 (dd,
1H, J ¼ 7.1, 12.6 Hz), 5.26 (t, 1H, J ¼ 8.2 Hz), 7.02 (m, 2H), 7.21 (t, 1H,
J ¼ 8.5 Hz), 7.3–7.4 (m, 2H), 7.47 (d, 2H, J ¼ 8.8 Hz), 8.13 (d, 2H,
J ¼ 8.5 Hz), 8.22 (bs, 1H). 13C NMR d 41.17, 78.66, 111.62, 112.83,
118.45, 120.28, 121.58, 123.06, 124.14, 125.57, 128.73, 136.41, 146.67,
147.23. C16H13N3O4: C, 61.73; H, 4.21. Found: C, 61.57; H, 4.73.
Compound 16: Mp 69 8C. IR (Nujol): 3399 cm21 (NH), 1548 and 1376 cm21
1
(NO2). H NMR d 4.91 (dd, 1H, J ¼ 7.3, 12.6 Hz), 5.06 (dd, 1H, J ¼ 7.9,
12.6 Hz), 5.26 (t, 1H, J ¼ 7.6 Hz), 6.16 (d, 1H, J ¼ 3.2 Hz), 6.31 (t, 1H,
J ¼ 2.9 Hz), 7.13 (m, 2H), 7.23 (t, 1H, J ¼ 8.79 Hz), 7.38 (m, 2H), 7.56
(d, 1H, J ¼ 7.9 Hz), 8.14 (bs, 1H). 13C NMR d 35.65, 77.81, 107.34,
110.43, 111.51, 118.65, 120.01, 122.59, 122.69, 125.6, 136.22, 142.2,
152.1. C14H12N2O3: C, 65.62; H, 4.72. Found: C, 65.65; H, 5.01.
Compound 17: Mp 94 8C. IR (Nujol): 3412 cm21 (NH), 1548 and 1378 cm21
1
(NO2). H NMR d 4.96–5.10 (m, 2H), 5.47 (t, 1H, J ¼ 7.6 Hz), 6.93–7.0
(m, 2H), 7.2–7.26 (m, 4H), 7.38 (d, 1H, J ¼ 8.2 Hz), 7.52 (d, 1H,
J ¼ 8.2 Hz), 8.14 (bs, 1H). 13C NMR d 35.65, 76.57, 107.35, 110.43,
111.51, 118.65, 120.02, 122.6, 122.69, 125.61, 136.23, 142.22, 152.1.
C14H12N2O2S: C, 61.75; H, 4.44. Found: C, 61.65; H, 4.63.
Compound 18: Mp 150–152 8C. IR (Nujol): 3381 cm21 (NH), 1375 and
1548 cm21 (NO2). 1H NMR d 3.82 (s, 3H), 4.93 (dd, 1H, J ¼ 8.5, 12.36 Hz),
5.08 (dd, 1H, J ¼ 7.4, 12 Hz), 5.18 (t, 1H, J ¼ 7.9 Hz), 6.88 (d, 2H,
J ¼ 8.8 Hz), 7.06–7.14 (m, 2H), 7.21–7.3 (m, 3H), 7.4 (d, J ¼ 8.2 Hz), 7.4
(d, 1H, J ¼ 7.9 Hz), 8.13 (bs, 1H). 13C NMR d 40.32, 54.62, 79.24, 111.07,
112.92, 113.43, 117.92, 118.54, 121.23, 121.26, 125.35, 128.12, 130.89,
136.03, 157.94. MS: m/z 296 (Mþ), 249, 236, 44 (100).
Compound 19: Mp Oily liquid. IR (Nujol): 3423 cm21(NH), 1377 and
1550 cm21 (NO2). 1H NMR d 3.66 (s, 3H), 4.81 (dd, 1H, J ¼ 8.5,
12.37 Hz), 4.92 (dd, 1H, J ¼ 7.7, 12.37 Hz), 5.1 (t, 1H, J ¼ 7.9 Hz), 6.72
(dd, 1H, J ¼ 2.4, 8.2 Hz), 6.82 (m, 3H), 7.0 (t, 1H, J ¼ 6.87 Hz), 7.08–7.2
(m, 3H), 7.4 (d, 1H, J ¼ 7.9 Hz), 7.98 (bs, 1H). 13C NMR d 41.4, 55.08,

1080
R. S. Kusurkar et al.
79.28, 111.29, 112.25, 113.75, 113.82, 118.60, 119.64, 119.83, 121.44,
122.35, 125.81, 129.71, 136.15, 140.67, 159.57. MS: m/z 296 (Mþ), 249
(100), 236.
Compound 20: Mp 153–154 8C. IR (Nujol): 3415 cm21 (NH), 1546 and
1355 cm21 (NO2). Diasteriomeric ratio 7:3. 1H NMR d 1.48 (d, 3H,
J ¼ 6.6 Hz), 1.57 (d, 3H, J ¼ 6.6 Hz), 4.94 (m, 2H), 5.29 (m, 2H), 6.77
(m, 4H), 7.12 (m, 10H), 7.65 (d, 2H, J ¼ 7.7 Hz), 8.12 (bs, 2H). MS: m/z
270 (Mþ), 224, 223, 196 (100).
Compound 21 (one diastereomer): Mp 170–172 8C. IR (Nujol): 3381 cm21
1
(NH), 1375 and 1548 cm21 (NO2). H NMR d 1.6 (d, 3H, J ¼ 6.3 Hz), 3.72
(s, 3H), 4.7 (d, 1H, J ¼ 11 Hz), 5.36 (sextet, 1H), 6.76 (d, 2H, J ¼ 8.2 Hz),
7.08–7.58 (m, 6H), 7.6 (d, 1H, J ¼ 7.7 Hz), 8.10 (bs, 1H). 13C NMR d
19.32, 47.01, 55.2, 87.83, 111.3, 113.94, 114.76, 118.89, 119.9, 121.42,
122.51, 126.46, 128.5, 132, 135.99, 158.4. MS: m/z 310 (Mþ), 263, 249,
236 (100).
Compound 22: Mp 174–176 8C. IR (Nujol): 3406 cm21 (NH), 1548
and 1344 cm21 (NO2). 1H NMR d 1.6 (d, 3H, J ¼ 6.6 Hz), 1.8 (d, 3H,
J ¼ 6.6 Hz), 4.87 (d, 1H, J ¼ 11 Hz), 4.96 (d, 1H, J ¼ 10.17 Hz), 5.32
(m, 2H), 6.99 (m, 14H), 8.12 (m, 4H), 8.25 (bs, 2H). MS: m/z 325 (Mþ),
278, 251 (100), 252.
ACKNOWLEDGMENTS
We are grateful to A. P. Gadgil for IR spectra, J. P. Chaudhari for NMR
spectra, and V. S. Shinde and D. S. Shishupal for mass spectra.
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