Indium-Promoted Preparation of α-Methylene-γ-butyrolactams from 2-(Bromomethyl)acrylic Acid and Aldimines

Full text of DOI:10.1021/jo982311m

3376
J . Org. Chem. 1999, 64, 3376-3378
Sch em e 1
In d iu m -P r om oted P r ep a r a tion of
r-Meth ylen e-γ-bu tyr ola cta m s fr om
2-(Br om om eth yl)a cr ylic Acid a n d
Ald im in es†
Prabir K. Choudhury, Francisco Foubelo, and
Miguel Yus*
Departamento de Quı´mica Orga´nica, Facultad de Ciencias,
Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
Received November 24, 1998
R-Methylene-γ-butyrolactams1 are interesting com-
pounds from a biological point of view because they
exhibit less cytotoxic activity than the corresponding
R-methylene-γ-butyrolactones,2 making them suitable for
cancer treatment; in fact, this class of compounds con-
stitutes potential anticancer agents.3 Compared to R-
methylene-γ-buryrolactones, the preparation of the cor-
responding nitrogenated derivatives is the subject of
few reports in the literature. Among them, metal-
promoted syntheses (Zn,4-9 Pd,10,11 B,12 Rh13) as well as
anionic,14,15 radical,16 or other17 methodologies have been
used to prepare R-methylene-γ-butyrolactams: one dis-
advantage of many of these procedures is that together
with the expected compound the corresponding endocyclic
unsaturated lactam is obtained, resulting from an un-
desired isomerization. Despite the observed disadvan-
tages and because of our continuing interest in indium-
promoted reactions,18 we report here the use of this
metal19 for the preparation of R-methylene-γ-butyro-
lactams by addition of 2-(bromomethyl)acrylic acid to
aldimines.20
Equimolar amounts of indium powder, 2-(bromomethyl)-
acrylic acid, and the corresponding aldimine 2 were
refluxed in THF for 2-18 h (see Table 1) and then
quenched with saturated NH4Cl. After extraction and
evaporation, the crude residue was treated with dicyclo-
hexylcarbodiimide (DCC) and a catalytic amount of
4-pyrrolidinopyridine (4-PPY) in dichloromethane at
room temperature for 20-45 min (see Table 1) to give
the corresponding R-methylene-γ-butyrolactams 3a -i
(Scheme 1 and Table 1).
Treatment with DCC after the first step is necessary
in order to avoid the formation of a mixture of the
expected lactam 3 and the γ-amino acid 4. In only one
case, even with poor yield, no formation of the amino acid
was observed, so the second step was not necessary
(Table 1, entry 5). In this case, an aldimine (2e) derived
from an aliphatic amine was used as the imino compo-
nent, and in the other cases, aniline was always the
amine component. Other related systems, such as aldi-
mines derived from butylamine, cyclohexylamine, and
tert-butylamine, and benzaldehyde work with very poor
yields (<10%). Finally, ketimines were not reactive
enough to carry out the reaction shown in Scheme 1.
† This Paper is dedicated to Professor E. J . Corey on occasion of his
70th birthday.
(1) Kornet, M. J .; Crider, A. M.; Magarian, E. O. J . Med. Chem. 1977,
20, 1210-1213.
(2) Kornet, M. J . J . Pharm. Sci. 1979, 69, 350-353; Chem. Abstr.
1979, 91, 5060h.
(3) Hoffmann, H. M. R.; Rabe, J . Angew. Chem., Int. Ed. Engl. 1985,
24, 94-110.
(4) Belaud, C.; Roussakis, C.; Letourneux, Y.; El Alami, N.; Villie´ras,
J . Synth. Commun. 1985, 15, 1233-1243; Chem. Abstr. 1986, 105,
208706d.
(5) El Alami, N.; Belaud, C.; Villie´ras, J . Tetrahedron Lett. 1987,
28, 59-60.
(6) El Alami, N.; Belaud, C.; Villie´ras, J . Synth. Commun. 1988, 18,
2073-2081; Chem. Abstr. 1989, 110, 231369h.
(7) Dembe´le´, Y. A.; Belaud, C.; Hitchcock, P.; Villie´ras, J . Tetrahe-
dron: Asymmetry 1992, 3, 351-354.
(8) Dembe´le´, Y. A.; Belaud, C.; Villie´ras, J . Tetrahedron: Asymmetry
1992, 3, 511-514.
(9) Nyzam, U.; Belaud, C.; Zammattio, F.; Villie´ras, J . Tetrahe-
dron: Asymmetry 1996, 7, 1835-1843.
(10) Mori, M.; Washioka, Y.; Urayama, T.; Yoshiura, K.; Chiba, K.;
Ban, Y. J . Org. Chem. 1983, 48, 4058-4067.
(11) Henin, F.; Muzart, J .; Pete, J . P. Tetrahedron Lett. 1986, 27,
6339-6340.
From a mechanistic point of view, an allylindium
sesquihalide of type 5 has been previously proposed18 in
other similar processes. The addition of this species to
the aldimine followed by cyclization would give the
obtained lactams 3.
(12) Chataigner, I.; Zammattio, F.; Lebreton. J .; Villie´ras, J . Synlett
1998, 275-276.
(13) Campi, E. M.; Chong, J . M.; J ackson, W. R.; Van Der Schoot,
M. Tetrahedron 1994, 50, 2533-2542.
(14) Tanaka, K.; Yoda, H.; Kaji, A. Synthesis 1985, 84-86.
(15) Patra, R.; Maiti, S. B.; Chatterjee, A. Tetrahedron Lett. 1991,
32, 1363-1366.
(20) For leading references on indium-promoted allylation of imines,
see, for instance: (a) Beuchet, P.; Le Marrec, N.; Mosset, P. Tetrahe-
dron Lett. 1992, 33, 5959-5960. (b) Kalyanam, N.; Rao, G. V.
Tetrahedron Lett. 1993, 34, 1647-1648. (c) Carda, M.; Castillo, E.;
Rodr´ıguez, S.; Murga, J .; Marco, J . A. Tetrahedron: Asymmetry 1998,
9, 1117-1120. (d) Babu, G.; Perumal, P. T. Tetrahedron 1998, 54,
1627-1638. (e) Lloyd-J ones, C. G.; Russell, T. Synlett 1998, 903-905.
(f) Capps, S. M.; Lloyd-J ones, C. G.; Murray, M.; Peakman, T. M.;
Walsh, K. E. Tetrahedron Lett. 1998, 39, 2853-2856. (g) Ho¨ppe, H.
A.; Lloyd-J ones, C. G.; Murray, M.; Peakman, T. M.; Walsh, K. E.
Angew. Chem., Int. Ed. Engl. 1998, 37, 1545-1547.
(16) Lee, E.; Kang, T. S. Bull. Korean Chem. Soc. 1993, 14, 431-
432; Chem. Abstr. 1994, 120, 134232g.
(17) Tarnchompoo, B.; Thebtaranonth, C.; Thebtaranonth, Y. Tet-
rahedron Lett. 1987, 28, 6675-6687.
(18) Choudhury, P. K.; Foubelo, F.; Yus, M. Tetrahedron Lett. 1998,
39, 3581-3584.
(19) For a monograph on indium and other metal-promoted reactions
in aqueous media, see: Li, C.-J .; Chan, T.-H. Organic Reactions in
Aqueous Media; J . Wiley & Sons: New York, 1997.
10.1021/jo982311m CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/16/1999

Notes
J . Org. Chem., Vol. 64, No. 9, 1999 3377
Ta ble 1. P r ep a r a tion of r-Meth ylen e-γ-bu tyr ola cta m s 3
a
b
All compounds 3 were >95% pure (GLC and/or 300 MHz 1H NMR). Isolated overall yield of pure (>95% from 300 MHz 1H NMR)
compounds after column chromatography (silica gel, hexane/ethyl acetate) and recrystallization based on the starting imine 2. c DCC
treatment was not necessary.
P r ep a r a tion of Com p ou n d s 3 fr om 2-(Br om om eth yl)-
a cr ylic Acid a n d Im in es. Gen er a l P r oced u r e. A mixture of
indium powder (0.126 g, 1.1 g mol) and 2-(bromomethyl)acrylic
acid (0.165 g, 1.0 mmol) in THF (3 mL) was heated at 66 °C for
15 min under nitrogen, and then an aldimine (0.1 mmol) THF
solution (3 mL) was added dropwise. The reaction mixture was
stirred at the same temperature for 2-18 h (reaction time was
confirmed from TLC observations and is given in Table 1). After
that, it was quenched with a saturated NH4Cl aqueous solution
(0.5 mL), filtered through a MgSO4 pad, and washed with ethyl
acetate. The filtrate was evaporated (15 mmHg), and a mixture
of the resulting residue, DCC (0.222 g, 1.1 mmol), and a catalytic
amount of 4-PPY (0.015 g) in dichloromethane (5 mL) was stirred
at room temperature for 30-45 min (the reaction was monitored
by TLC; see Table 1).24 The resulting mixture was hydrolyzed
with water and extracted with ethyl acetate. The organic layer
was dried over anhydrous Na2SO4 and evaporated (15 mmHg).
The residue was then purified by column chromatography (silica
gel; hexane/ethyl acetate) and recrystallized to yield pure product
As a conclusion, we report here a new route to
preparation of R-methylene-γ-butyrolactams starting
from easily available materials and promoted by indium
metal. Even considering that the overall yields (of
recrystallized compounds) are only moderate, we think
that this methodology can be useful for the preparation
of this type of interesting molecules.
Exp er im en ta l Section
Gen er a l Meth od s. The general experimental information is
similar to that recently described.21 Starting aldimines 2a -c22
as well as 2d -h 23 were prepared according to the literature
procedures.
(21) (a) Almena, J .; Foubelo, F.; Yus, M. J . Org. Chem. 1994, 59,
3210-3215. (b) Alonso, E.; Ramo´n, D. J .; Yus, M. J . Org. Chem. 1997,
62, 417-421.
(22) Savoia, D.; Tromboni, C.; Umani-Ronchi, A. J . Org. Chem. 1978,
43, 2907-2910.
(23) Taguchi, K.; Westheimer, F. H. J . Org. Chem. 1971, 36, 1570-
1572.
(24) Tanner, D.; Somfai, P. Tetrahedron 1988, 44, 613-168.

3378 J . Org. Chem., Vol. 64, No. 9, 1999
Notes
3a -i. Yields, Rf, and mp data are included in Table 1; analytical
and spectroscopic data as well as literature references follow.
5-Isopr opyl-3-m eth ylen e-1-ph en yl-2-pyr r olidin on e (3a):25
Rf 0.55 (silica gel; hexane/ethyl acetate 2/1); mp 140-144 °C
(pentane/dichloromethane); IR (KBr) 2960, 2922, 1677, 1653, 803
(pentane/dichloromethane); IR (KBr) 3154, 3066, 1677, 1655,
1595, 1596, 740 cm-1; 1H NMR δ 2.91-3.04 (m, 1H), 3.18-3.31
(m, 1H), 5.27 (dd J ) 8.5, 3.7 Hz, 1H), 5.48 (br s, 1H), 6.10 (d,
J ) 2.4 Hz, 1H), 6.17-6.25 (m, 2H), 7.10-7.47 (m, 6H); 13C NMR
δ 31.8, 54.6, 107.8, 110.3, 117.4, 122.8, 125.7, 128.7, 137.9, 138.6,
142.4, 152.7, 166.9; MS m/z 239 (M+, 23), 40 (100). Anal. Calcd
for C15H13NO2: C, 75.29; H, 5.47; N, 5.85. Found: C, 75.96; H,
5.51; N, 5.88.
1
cm-1; H NMR δ 0.67 (d, J ) 6.7 Hz, 3H), 0.90 (d, J ) 7.3 Hz,
3H), 1.98-2.09 (m, 1H), 2.57-2.70 (m, 1H), 2.83 (ddt, J ) 17.7,
8.5, 3.1 Hz, 1H), 4.27 (dt, J ) 8.7, 3.6 Hz, 1H), 5.41 (t, J ) 2.4
Hz, 1H), 6.10 (t, J ) 2.4 Hz, 1H) 7.17-7.52 (m, 5H); 13C NMR δ
13.6, 18.3, 24.6, 28.3, 60.6, 116.3, 123.7, 125.8, 128.9, 137.7,
140.1, 167.2; MS m/z 215 (M+, 5), 53 (100); HRMS calcd for
5-(4-Ch lor op h en yl)-3-m eth ylen e-1-p h en yl-2-p yr r olid in -
on e (3g): Rf 0.47 (silica gel; hexane/ethyl acetate 2/1); mp 129-
133 °C (pentane/dichloromethane); IR (KBr) 3061, 2922, 2852,
1685, 1658, 1260 cm-1 1H NMR δ 2.67 (dq, J ) 16.8, 2.4 Hz,
;
C14H17NO 215.1310, found 215.1313. Anal. Calcd for C14H17
-
NO: C, 78.10; H, 7.96; N, 6.50. Found: C, 76.46; H, 7.98; N,
6.20.
1H), 3.37 (ddt, J ) 16.5, 8.5, 3.1 Hz, 1H), 5.24 (dd, J ) 8.8, 3.0
Hz, 1H), 5.46 (t, J ) 2.5 Hz, 1H), 6.22 (t, J ) 3.1 Hz, 1H), 7.04-
7.17 (m, 3H), 7.20-7.33 (m, 4H), 7.42-7.52 (m, 2H); 13C NMR δ
35.2, 59.9, 117.8, 122.1, 125.3, 127.2, 128.7, 129.2, 133.6, 137.9,
138.5, 140.1, 167.4; MS m/z 283 (M+, 15), 40 (100). Anal. Calcd
for C17H14ClNO: C, 71.95; H, 4.97; N, 4.93. Found: C, 71.63; H,
4.85; N, 4.67.
5-ter t-Bu tyl-3-m eth ylen e-1-p h en yl-2-p yr r olid in on e (3b):
25
Rf 0.44 (silica gel; hexane/ethyl acetate 2/1); mp 153-155 °C
(pentane/dichloromethane); IR (KBr) 3068, 2961, 1679, 1659, 807
cm-1 1H NMR δ 0.76 (s, 9H), 2.77 (dq, J ) 17.4, 2.1 Hz, 1H),
;
2.93 (ddt, J ) 17.1, 8.5, 3.1 Hz, 1H), 4.14 (dd, J ) 8.7, 2.1 Hz,
1H), 5.38 (t, J ) 2.3 Hz, 1H), 6.06 (t, J ) 2.4 Hz, 1H), 7.15-7.46
(m, 5H); 13C NMR δ 26.5, 28.2, 37.0, 65.6, 115.7, 124.9, 126.0,
128.7, 140.1, 140.2, 167.7; MS m/z 229 (M+, 12), 53 (100); HRMS
calcd for C15H19NO 229.1466, found 229.1464. Anal. Calcd for
5-(1,3-Ben zod ioxol-5-yl)-3-m eth ylen e-1-p h en yl-2-p yr r o-
lid in on e (3h ): Rf 0.43 (silica gel; hexane/ethyl acetate 2/1); mp
194-195 °C (pentane/dichloromethane); IR (KBr) 3055, 2909,
1684, 1655, 1482, 1035 cm-1; 1H NMR δ 2.58-2.77 (m, 1H), 2.32
(ddt, J ) 16.5, 8.5, 3.1 Hz, 1H), 5.16 (dd, J ) 8.5, 3.1 Hz, 1H),
5.44 (t, J ) 2.4 Hz, 1H), 5.89 (d, J ) 1.2 Hz, 2H), 6.20 (t, J ) 3.1
Hz, 1H), 6.60-6.74 (m, 3H), 7.01-7.14 (m, 1H), 7.19-7.35 (m,
2H), 7.42-7.58 (m, 2H); 13C NMR δ 35.4, 60.3, 101.1, 105.8,
108.4, 117.5, 119.4, 122.2, 125.1, 128.6, 135.5, 138.1, 138.9, 167.4;
MS m/z 293 (M+, 21), 77 (100). Anal. Calcd for C18H15NO3: C,
73.70; H, 5.15; N, 4.77. Found: C, 73.18; H, 5.14; N, 4.70.
C
15H19NO: C, 78.56; H, 8.35; N, 6.10. Found: C, 77.30; H, 8.32;
N, 5.71.
5-Cycloh exyl-3-m eth ylen e-1-ph en yl-2-pyr r olidin on e (3c):
Rf 0.49 (silica gel; hexane/ethyl acetate 2/1); mp 137-140 °C
(pentane/dichloromethane); IR (KBr) 3055, 2926, 2853, 1680,
1
1657, 930 cm-1; H NMR δ 0.78-1.78 (m, 11H), 2.65-2.76 (m,
1H), 2.86 (ddt, J ) 17.4, 8.5, 2.7 Hz, 1H), 4.23 (quintet, J ) 3.3
Hz, 1H), 5.39 (t, J ) 2.2 Hz, 1H), 6.08 (t, J ) 3.1 Hz, 1H), 7.15-
7.54 (m, 5H); 13C NMR δ 24.3, 25.5, 26.15, 26.2, 26.4, 29.0, 39.0,
60.5, 116.1, 123.7, 125.8, 128.9, 137.8, 140.2, 167.2; MS m/z 255
(M+, 3), 53 (100). Anal. Calcd for C17H21NO: C, 79.96; H, 8.29;
N, 5.48. Found: C, 80.08; H, 8.36; N, 5.20.
(Z)-3-Meth ylen e-1-p h en yl-5-(2-p h en yl-1-eth en yl)-2-p yr -
r olid in on e (3i):25 Rf 0.50 (silica gel; hexane/ethyl acetate 2/1);
mp 162-165 °C (pentane/dichloromethane); IR (KBr) 3055, 2922,
1680, 1656, 1595, 969 cm-1; 1H NMR δ 2.64-2.78 (m, 1H), 3.22
(ddt, J ) 17.1, 8.5, 2.4 Hz, 1H), 4.85 (sextet, J ) 3.7 Hz, 1H),
5.46 (t, J ) 2.4 Hz, 1H), 6.07 (dd, J ) 15.8, 7.9 Hz, 1H), 6.18 (t,
J ) 3.0 Hz, 1H), 6.51 (d, J ) 15.9 Hz, 1H), 7.07-7.65 (m, 10H);
13C NMR δ 32.8, 59.1, 117.3, 122.7, 125.4, 126.5, 128.0, 128.6,
128.8, 129.0, 132.5, 135.8, 138.1, 138.9, 167.1; MS m/z 275 (M+,
20), 77 (100); HRMS calcd for C19H17NO 275.1310, found
275.1311. Anal. Calcd for C19H17NO: C, 82.88; H, 6.22; N, 5.08.
Found: C, 81.13; H, 6.20; N, 5.02.
3-Meth ylen e-1,5-d ip h en yl-2-p yr r olid in on e (3d ):4 Rf 0.58
(silica gel; hexane/ethyl acetate 2/1); mp 147.5-148 °C (pentane/
dichloromethane); IR (KBr) 2932, 2858, 1682, 1658, 944 cm-1
;
1H NMR δ 2.67-2.76 (m, 1H), 3.37 (ddt, J ) 16.8, 8.8, 2.7 Hz,
1H), 5.25 (dd, J ) 8.5, 3.4 Hz, 1H), 5.45 (t, J ) 2.1 Hz, 1H), 6.22
(t, J ) 2.4 Hz, 1H), 7.04-7.09 (m, 1H), 7.18-7.35 (m, 7H), 7.48-
7.61 (m, 2H); 13C NMR δ 35.4, 60.5, 117.5, 122.1, 125.1, 125.7,
127.8, 128.7, 129.0, 138.3, 138.9, 141.3, 167.6; MS m/z 249 (M+,
26), 77 (100).
1-Ben zyl-3-m eth ylen e-5-p h en yl-2-p yr r olid in on e (3e): Rf
0.45 (silica gel, hexane/ethyl acetate 2/1); IR (KBr) 2389, 1693,
Ack n ow led gm en t. This project was financially sup-
ported by DGICYT from the Spanish Ministerio de
Educacio´n y Cultura (MEC) (project no. 1514) and by
the Generalitat Valenciana (project no. GV-C-CN-09-
066-96). P.K.C. thanks the MEC for a postdoctoral
fellowship.
1
1662, 1080 cm-1; H NMR δ 2.47-2.62 (m, 1H), 3.05 (ddt, J )
17.4, 8.5, 2.4 Hz, 1H), 3.45 (d, J ) 14.6 Hz, 1H), 4.32 (dd, J )
8.5, 3.7 Hz, 1H), 5.10 (d, J ) 14.6 Hz, 1H), 5.31 (t, J ) 2.5 Hz,
1H), 6.06 (t, J ) 2.7 Hz, 1H), 6.99-7.09 (m, 4H), 7.16-7.34 (m,
6H); 13C NMR δ 34.6, 44.7, 58.0, 116.2, 126.7, 127.5, 128.2, 128.5,
128.6, 129.0, 136.1, 138.8, 140.7, 168.1; MS m/z 263 (M+, 43%),
91 (100); HRMS calcd for C18H17NO 263.1310, found 263.1346.
5-(2-F u r yl)-3-m eth ylen e-1-p h en yl-2-p yr r olid in on e (3f):
Rf 0.45 (silica gel, hexane/ethyl acetate 2/1); mp 178-179 °C
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H (300
MHz) and 13C (75 MHz) NMR spectra of new compounds
lacking microanalyses (3e) or with no precise microanalyses
(3a ,b,i).
(25) For compounds 3a ,b,i, it was not possible to obtain more
accurate % C figures after several attempts.
J O982311M