An expeditious and solvent-free synthesis of 2-amino-substituted isoflav-3-enes using microwave irradiation

Full text of DOI:10.1021/jo980985r

8038
J . Org. Chem. 1998, 63, 8038-8041
view of our ongoing endeavors to conduct organic syn-
thesis under solvent-free conditions,4 we decided to adopt
an enamine-mediated approach for the one-pot assembly
of isoflav-3-enes substituted at the 2-position with various
cyclic amines.5
An Exp ed itiou s a n d Solven t-F r ee Syn th esis
of 2-Am in o-Su bstitu ted Isofla v-3-en es Usin g
Micr ow a ve Ir r a d ia tion †
Rajender S. Varma* and Rajender Dahiya‡
Enamines 4 are usually prepared by the condensation
of a carbonyl compound bearing an R-hydrogen atom 1
with a secondary amine 2 followed by the dehydration
of the resultant intermediate 3 (Scheme 1).6-8 The
azeotropic removal of water from the intermediate 3 is
the driving force for the reaction which is normally
catalyzed by reagents such as p-toluenesulfonic acid,6
titanium(IV) chloride,7 montmorillonite K-10 clay,8 etc.,
in a Dean-Stark setup requiring a large excess of
aromatic hydrocarbon solvents such as benzene or tolu-
ene. We have recently demonstrated the advantageous
attributes of microwave-assisted elimination of water in
the rapid and solvent-free synthesis of enamines4i,j and
nitroalkenes.4k
Department of Chemistry and Texas Research Institute for
Environmental Studies (TRIES), Sam Houston State
University, Huntsville, Texas 77341-2117
Received May 22, 1998
In tr od u ction
Isoflav-3-enes bearing a 2H-1-benzopyran nucleus form
an important class of chromene intermediates useful in
the synthesis of many natural products and medicinal
agents such as potassium-channel activating drugs.1
Their basic structural framework is a common feature
of many tannins and polyphenols2 found in fruits, veg-
etables, teas, and red wines which have gained popularity
because of their health-promoting effects. Additionally,
isoflav-3-enes are well-known estrogens,3 and several
derivatives of these oxygen heterocycles have attracted
the attention of medicinal chemists over the years. In
Since the appearance of the first paper on the applica-
tion of microwave irradiation in the chemical synthesis,9
the approach has blossomed into a useful technique for
a variety of applications in organic synthesis and func-
tional group transformations.4,10,11 The initial experi-
ments with microwave techniques centered around the
use of high dielectric solvents such as DMSO and DMF
in specialized Teflon vessels and sealed containers. The
rate enhancements in such reactions are now believed
to be essentially due to rapid superheating of these polar
solvents. The focus has now shifted to less cumbersome
solvent-free methods wherein the neat reactants, often
in the presence of mineral supports, undergo facile
reactions to provide high yields of pure products, thus
eliminating or minimizing the use of organic solvents.4,10f,11
The bulk temperature is relatively low in such solventless
reactions, although higher localized temperatures may
be reached during microwave irradiation.
* To whom correspondence should be addressed. Tel.: (409) 294-
1587. Fax: (409) 294-1585. E-mail: CHM_RSV@SHSU.EDU.
†Presented, in part, at the 16th International Congress of Hetero-
cyclic Chemistry (Abstract No. OP-V-8), Bozeman, MT, Aug 10-15,
1997.
‡ On leave of absence from M.L.N. College, Yamuna Nagar-135001,
Haryana, India.
(1) (a) Atwal, K. S.; Grover, G. J .; Ferrara, F. N.; Ahmd, S. Z.; Sleph,
P. G.; Dzwonczyk, S.; Normandin, D. E. J . Med. Chem. 1995, 38, 1966.
(b) Elomri, A.; Mitaku, S.; Michel, S.; Skaltsounis, A.-L.; Tillequin, F.;
Koch, M.; Pierre´, A.; Guilbaud, N.; Le´once, S.; Kraus-Berthier, L.;
Rolland, Y.; Atassi, G. J . Med. Chem. 1996, 39, 4762.
(2) (a) Rochford, A. J .; Metzger, R.; Hobbs, L.; Capon, R. J . Aust. J .
Chem. 1996, 49, 1217. (b) J ankun, J .; Selman, S. H.; Swiercz, R.;
Skrzypczak-jankun, E. Nature 1997, 387, 561. (c) Covington A. D.
Chem. Soc. Rev. 1997, 111. (d) van Rensburg, H.; van Heerden, P. S.;
Bezuidenhoudt, B. C. B.; Ferreira, D. Tetrahedron Lett. 1997, 38, 3089.
(3) (a) Lawson, W. J . Chem. Soc. 1954, 4448. (b) Micheli, R. A.;
Booth, A. N.; Livingstone, A. L.; Bickoff, E. M. J . Med. Chem. 1962, 5,
321. (c) Durani, S.; Agarwal, A. K.; Saxena, R.; Setty, B. S.; Gupta, R.
C.; Kole, P. L.; Ray, S.; Anand, N. J . Steroid Biochem. 1979, 11, 67.
(d) Grese, T. A.; Pennington, L. D. Tetrahedron Lett. 1995, 36, 8913.
(e) Miksicek, R. J . Proc. Soc. Exp. Biol. Med. 1995, 208, 44.
(4) For cleavage-deprotection reactions, see: (a) Varma, R. S.;
Chatterjee, A. K.; Varma, M. Tetrahedron Lett. 1993, 34, 3207. (b)
Varma, R. S.; Chatterjee, A. K.; Varma, M. Tetrahedron Lett. 1993,
34, 4603. (c) Varma, R. S.; Varma, M.; Chatterjee, A. K. J . Chem. Soc.,
Perkin Trans. 1 1993, 999. (d) Varma, R. S.; Lamture, J . B.; Varma,
M. Tetrahedron Lett. 1993, 34, 3029. (e) Varma, R. S.; Saini, R. K.
Tetrahedron Lett. 1997, 38, 2623. (f) Varma, R. S.; Meshram, H. M.
Tetrahedron Lett. 1997, 38, 5427. (g) Varma, R. S.; Meshram, H. M.
Tetrahedron Lett. 1997, 38, 7973. (h) Varma, R. S.; Dahiya, R.; Saini,
R. K. Tetrahedron Lett. 1997, 38, 8819. For condensation-cyclization
reactions see: (i) Varma, R. S.; Dahiya, R.; Kumar, S. Tetrahedron
Lett. 1997, 38, 2039. (j) Varma, R. S.; Dahiya, R. Synlett 1997, 1245.
(k) Varma, R. S.; Dahiya, R.; Kumar, S. Tetrahedron Lett. 1997, 38,
5131. (l) Varma, R. S.; Saini, R. K. Synlett 1997, 857. (m) Varma, R.
S.; Saini, R. K.; Kumar, D. J . Chem. Res. Synop. 1998, 348. For
oxidation reactions, see: (n) Varma, R. S.; Dahiya, R. Tetrahedron Lett.
1997, 38, 2043. (o) Varma, R. S.; Saini, R. K.; Meshram, H. M.
Tetrahedron Lett. 1997, 38, 6525. (p) Varma, R. S.; Dahiya, R.; Saini,
R. K. Tetrahedron Lett. 1997, 38, 7029. (q) Varma, R. S.; Saini, R. K.;
Dahiya, R. Tetrahedron Lett. 1997, 38, 7823. (r) Varma, R. S.; Dahiya,
R.; Saini, R. K. Tetrahedron Lett. 1997, 38, 7029. (s) Varma, R. S.;
Dahiya, R. Tetrahedron Lett. 1998, 39, 1307. (t) Varma, R. S.; Dahiya,
R.; Kumar, D. Molecules Online 1998, 2, 82. (u) Varma, R. S.; Saini,
R. K. Tetrahedron Lett. 1998, 39, 1481. (v) Varma, R. S.; Saini, R. K.;
Dahiya, R. J . Chem. Res. Synop. 1998, 120. (w) Varma, R. S.; Naicker,
K. P. Molecules Online 1998, 2, 94. (x) Varma For reduction reactions,
see: (y) Varma, R. S.; Saini, R. K. Tetrahedron Lett. 1997, 38, 4337.
(z) Varma, R. S.; Dahiya, R. Tetrahedron 1998, 54, 6293.
Earlier, we discovered a general route to isoflav-3-enes5
that, contrary to previous findings,12 proceeds readily via
(5) (a) Dean, F. M.; Varma, R. S. J . Chem. Soc., Perkin Trans. 1
1982, 1193. (b) Dean, F. M.; Varma, M.; Varma, R. S. J . Chem. Soc.,
Perkin Trans. 1 1982, 2771. (c) Dean, F. M.; Varma, R. S. Tetrahedron
Lett. 1981, 22, 2113.
(6) Cook, A. G. Enamines: Synthesis, Structure and Reactions, 2nd
ed.; Marcel Dekker: New York, 1988; p 103.
(7) (a) Stork, G.; Terrell, R.; Szmuszkovicz, J . J . Am. Chem. Soc.
1954, 76, 2029. (b) Stork, G.; Brizzolara, A.; Landesman, H.; Szmusz-
kovicz, J .; Terrell, R. J . Am. Chem. Soc. 1963, 85, 207.
(8) Dewan, S. K.; Varma, U.; Malik, S. D. J . Chem. Res., Synop.
1995, 21.
(9) Gedye, R.; Smith, F.; Westway, K.; Ali, H.; Baldisera, L.; Laberge,
L.; Rousell, J . Tetrahedron Lett. 1986, 27, 279.
(10) For recent reviews on microwave-assisted chemical reactions,
see: (a) Abramovich, R. A. Org. Prep. Proced. Int. 1991, 23, 683. (b)
Whittaker, A. G.; Mingos, D. M. P. J . Microwave Power Electromagn.
Energy 1994, 29, 195. (c) Majetich, G.; Hicks, R. J . Microwave Power
Electromagn. Energy 1995, 30, 27. (d) Caddick, S. Tetrahedron 1995,
51, 10403. (e) Strauss, C. R.; Trainor, R. W. Aust. J . Chem. 1995, 48,
1665. (e) Bose, A. K.; Banik, B. K.; Lavlinskaia, N.; J ayaraman, M.;
Manhas, M. S. Chemtech 1997, 27, 18. (f) Varma, R. S. Microwave-
Assisted Reactions under Solvent-Free “Dry” Conditions. In Micro-
waves: Theory and Application in Material Processing IV; Clark, D.,
Sutton, W., Lewis, D., Eds.; American Ceramic Society, Ceramic
Transactions: Westerville, 1997, Vol. 80, p 357.
(11) (a) Oussaid, A.; Thach, L. N.; Loupy, A. Tetrahedron Lett. 1997,
38, 2451. (b) Villemin, D.; Benalloum, A. Synth. Commun. 1991, 21,
63. (c) Lerestif, J . M.; Toupet, L.; Sinbandhit, S.; Tonnard, F.;
Bazureau, J . P.; Hamelin, J . Tetrahedron 1997, 53, 6351.
(12) Paquette, L. A.; Stucki, H. J . Org. Chem. 1966, 31, 1232.
10.1021/jo980985r CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/14/1998

Notes
J . Org. Chem., Vol. 63, No. 22, 1998 8039
Sch em e 1
Sch em e 3
Sch em e 2
Ta ble 1. On e-P ot Syn th esis of Isofla v-3-en es
entry
substitution at C-2
R1
R2
R3
R4
10a
10b
10c
10d
10e
10f
10g
10h
10i
morpholinyl
morpholinyl
morpholinyl
morpholinyl
morpholinyl
piperidinyl
piperidinyl
piperidinyl
pyrrolidinyl
pyrrolidinyl
pyrrolidinyl
H
H
H
OMe
H
H
H
H
H
H
H
H
H
OMe
H
H
H
H
H
Cl
NO2
H
H
H
Cl
NO2
H
Cl
H
H
H
H
OMe
H
H
H
H
the condensation of N-styrylamines with o-hydroxyary-
laldehydes to deliver 2-substituted isoflav-3-ene deriva-
tives. In an extension of our present program to develop
efficient solventless protocols,4 we decided to pursue the
synthesis of 2-amino(2-morpholino, 2-piperidino, and
2-pyrrolidino)-substituted isoflav-3-enes under solvent-
free conditions using microwaves. Herein, we report our
results that exploit the in situ generation of enamine
intermediates that can be further elaborated, in one-pot
protocol, to 2-substituted isoflav-3-enes 10a -k from
readily accessible phenyl acetaldehyde (5), cyclic amines
6a -c, and salicylaldehydes 8a -e in the presence of
ammonium acetate as a catalyst.
10j
10k
H
H
H
H
H
H
NO2
followed that entails irradiating the reaction mixture at
a lower power for successive intervals of 2 min each with
a cooling period of 1 min. This method is followed to
avoid overheating of reactants since the unmodified
household microwave oven lacks the special attributes
of commercial microwave reactors in terms of control of
temperature and power. This reproducible microwave
protocol, however, is much simpler and cleaner when
compared to conventional methods in terms of enhanced
reaction rates, higher yields, and the ease of manipula-
tion.
Resu lts a n d Discu ssion
In the first step, the enamines N-styrylmorpholine,
7a ,13 N-styrylpiperidine, 7b,14 and N-styrylpyrrolidine,
7c,15 are prepared within 2 min by irradiating a mixture
of phenyl acetaldehyde with respective cyclic amines
6a -c in open glass containers using an unmodified
household microwave oven (Scheme 2). The addition of
salicylaldehydes to the same reaction vessel, in the
second step, and further exposure to microwaves gener-
ates the desired isoflav-3-enes. The present procedure
considerably reduces the longer reaction time usually
encountered in traditional enamine synthesis, which
employs a large excess of aromatic hydrocarbon solvents
for the azeotropic removal of water using a Dean-Stark
apparatus.6-8
In our previously described solution-phase chemistry,
the reaction of enamine 7a with substituted salicylalde-
hydes 8a and 8d in benzene under an inert atmosphere
produced 2-morpholinoisoflav-3-ene 10a and 8-methoxy-
2-morpholinoisoflav-3-ene 10d in 55 and 45.6% yields,
respectively (Scheme 3).5 The same reactions under
solvent-free conditions using microwaves in the presence
of ammonium acetate as a catalyst (0.25 mmol), however,
provide the desired products expeditiously in 80 and 73%
yields, respectively. A pulsed microwave technique is
One-pot synthesis of 2-morpholinoisoflav-3-ene, 10a ,
is thus achieved by irradiating the mixture of 5 and 6a
for 2 min in a microwave oven followed by the reaction
of in situ generated 7a with salicylaldehyde 8a in the
presence of a catalytic amount of ammonium acetate
using pulsed microwave irradiation. The reaction is
monitored on TLC using hexane/EtOAc (9:1, v/v) as the
solvent system and the integrity of the product confirmed
by the spectral data obtained. The appearance of two
singlets, accounting for one proton each, at δ 5.74 (2-H)
and 7.04 (4-H) in its H NMR spectrum and its 13C NMR
1
data are in agreement with the assigned structure.
Finally, the observance of molecular ion peak at m/z
293.1418 (11.2%) confirms the structure as 10a . The
other isoflavenes (Table 1) are similarly prepared, and
their structures are confirmed by 1H NMR, 13C NMR and
high-resolution mass spectral data.
The formation of the products 10a -k is supported by
the mechanism delineated in Scheme 4, which is guided
by the neighboring group participation of the phenolic
hydroxyl function in salicylaldehyde, 8a , followed by the
dehydration of the ensuing intermediate 9a , a process
facilitated by the aryl moiety at position 3.
In conclusion, we have shown that the 2-amino-
substituted isoflav-3-enes can be expeditiously prepared
in a one-pot solvent-free operation using microwaves via
the in situ generation of enamines and their subsequent
(13) Ziegenbein, W.; Franks, W. Chem. Ber. 1957, 90, 2291.
(14) Domschke, G. J . Prakt. Chem. 1966, 32, 144; Chem. Abstr. 1966,
65, 12156d.
(15) Omote, Y.; Nakamura, T.; Kuo, K.-T.; Sugiyama, N.Nippon
Kagaku Zasshi 1966, 7, 888; Chem. Abstr. 1966, 65, 16928c.

8040 J . Org. Chem., Vol. 63, No. 22, 1998
Notes
1H, 2-H), 6.99 (d, 1H, J ) 8.7, 8-H), 7.11 (s, 1H, 4-H), 7.35-
7.48 (m, 3H, 3′-H, 4′-H, 5′-H), 7.69 (dd, 2H, J ) 1.8, 8.3, 2′-H,
Sch em e 4
6′-H), 8.08 (d, 1H, J ) 3, 5-H), 8.09 (dd, 1H, J ) 3, 8.7, 7-H); 13
C
NMR δ 46.9 (NCH2), 66.9 (OCH2), 92.2 (C-2), 115.3, 120.9, 121.8,
122.8, 125.4, 126.2, 128.6, 128.7, 130.5, 136.4, 141.4, 158.9;
HRMS (EI) calcd for C19H18N2O4 [M+] 338.1266, found 338.1263.
8-Meth oxy-2-m or p h olin oisofla v-3-en e (10d ): MW irradia-
tion for 4 min; yield 73%, as a gum; 1H NMR δ 2.66 (m, 2H,
NCH2), 3.09 (m, 2H, NCH2), 3.62 (m, 4H, CH2OCH2), 3.88 (s,
3H, OCH3), 5.87 (s, 1H, 2-H), 6.79 (dd, 1H, J ) 3, 9, 7-H), 6.84
(dd, 1H, J ) 3, 9, 5-H), 6.88 (m, 1H, 6-H), 7.09 (s, 1H, 4-H),
7.29-7.42 (m, 3H, 3′-H, 4′-H, 5′-H), 7.72 (dd, 2H, J ) 1.8, 8.7,
2′-H, 6′-H); 13C NMR δ 47.1 (NCH2), 56.1 (OCH3), 67.1 (OCH2),
90.7 (C-2), 112.2, 119.3, 120.4, 121.8, 123.3, 126.1, 127.8, 128.4,
128.5, 137.5, 142.6, 147.0; HRMS (EI) calcd for C20H21NO3 [M+]
323.1521, found 323.1525.
5,7-Dim eth oxy-2-m or p h olin oisofla v-3-en e (10e): MW ir-
radiation for 6 min; yield 75%, as a gum; 1H NMR δ 2.66 (m,
2H, NCH2), 3.08 (m, 2H, NCH2), 3.62 (m, 4H, CH2OCH2), 3.80
(s, 3H, OCH3), 3.83 (s, 3H, OCH3), 5.76 (s, 1H, 2-H), 6.07 (d,
1H, J ) 3, 6-H), 6.17 (d, 1H, J ) 3, 8-H), 7.22-7.40 (m, 3H,
3′-H, 4′-H, 5′-H), 7.42 (s, 1H, 4-H), 7.70 (dd, 2H, J ) 1.8, 8.7,
2′-H, 6′-H); 13C NMR δ 46.9 (NCH2), 55.3 (OCH3), 55.4 (OCH3),
67.1 (OCH2), 90.9 (C-2), 91.4, 92.2, 104.5, 117.8, 123.3, 125.7,
127.0, 128.4, 138.1, 155.6, 156.6, 161.6; HRMS (EI) calcd for
reactions with salicylaldehydes. This environmentally
friendly procedure does not require azeotropic removal
of water using large excess of aromatic hydrocarbon
solvents for the generation of enamines or the activation
of the catalyst.
C
21H23NO4 [M+] 353.1627, found 353.1632.
Exp er im en ta l Section
2-P ip er id in oisofla v-3-en e (10f): MW irradiation for 5 min;
yield 72%, as a gum; 1H NMR δ 1.49 (m, 6H, CH2CH2CH2), 2.62
(m, 2H, NCH2), 3.04 (m, 2H, NCH2), 5.78 (s, 1H, 2-H), 6.89-
6.96 (m, 2H, 6-H, 8-H), 7.07 (s, 1H, 4-H), 7.14-7.22 (m, 2H, Ar-
H), 7.32-7.41 (m, 3H, Ar-H), 7.74 (dd, 2H, J ) 1.8, 7.2, 2′-H,
6′-H); 13C NMR δ 24.6 (CH2), 26.2 (CH2), 47.9 (NCH2), 91.7 (C-
2), 114.8, 120.3, 121.4, 123.2, 126.3, 127.0, 127.5, 128.4, 129.2,
129.4, 138.1, 154.1; HRMS (EI) calcd for C20H21NO [M+]
291.1623, found 291.1627.
Gen er a l. All reagents were purchased from Aldrich Chemi-
cal Co. or Lancaster Synthesis Inc. and were used as received.
A simple household microwave (MW) oven (900 W) equipped
with a turntable was used for microwave heating. An alumina
bath (neutral alumina: 125 g, mesh ∼150, Aldrich; bath: 5.7
cm diameter) was used as a heat sink inside the MW oven to
irradiate the reaction mixtures. TLC was performed on silica
gel plates supplied by Analtech, Inc., using hexane/EtOAc (9:1,
v/v) as the solvent system. Basic alumina (∼150 mesh, 58 Å,
surface area 155 m2/g) supplied by Aldrich Chemical Co. was
used for purification of the products. Melting points were
determined on a hot-stage apparatus using 51 K/J digital
thermometer and are uncorrected. All NMR spectra were
6-Ch lor o-2-p ip er id in oisofla v-3-en e (10g): MW irradiation
1
for 4 min; yield 88%; mp 128-129 °C; H NMR δ 1.49 (m, 6H,
CH2CH2CH2), 2.61 (m, 2H, NCH2), 3.01 (m, 2H, NCH2), 5.77 (s,
1H, 2-H), 6.87 (d, 1H, J ) 9, 8-H), 6.98 (s, 1H, 4-H), 7.12 (d, 1H,
J ) 2.8, 5-H), 7.13 (dd, 1H, J ) 2.8, 9.0, 7-H), 7.32-7.42 (m,
3H, 3′-H, 4′-H, 5′-H), 7.72 (dd, 2H, J ) 1.9, 8.1, 2′-H, 6′-H); 13C
NMR δ 24.5 (CH2), 26.1 (CH2), 47.9 (NCH2), 91.9 (C-2), 116.1,
122.0, 122.6, 124.9, 126.3, 127.9, 128.1, 128.4, 128.9, 130.4, 137.6,
152.6; HRMS (EI) calcd for C20H20ClNO [M+] 325.1233, found
325.1229 and 327.1198.
recorded in deuteriochloroform (CDCl3) on
a spectrometer
operating at 300 MHz (1H NMR) and 75.4 MHz (13C NMR) using
TMS as an internal standard. Coupling constants (J values)
are given in Hz. The peak assignments, whereever possible,
were made on the basis of multiplicity, coupling constants,
DEPT, and shielding and deshielding effects of the substituents.
On e-P ot Syn th esis of Su bstitu ted Isofla v-3-en es. Syn-
thesis of 2-morpholinoisoflav-3-ene, 10a , is representative of the
general procedure employed. A mixture of phenyl acetaldehyde
(0.6 g, 5 mmol) and morpholine (0.48 g, 5.5 mmol) was placed
in a small beaker and irradiated in an unmodified household
MW oven at its full power (900 W) for 2 min. Salicylaldehyde
(0.61 g, 5 mmol) and ammonium acetate (0.02 g, 0.25 mmol) were
then added to the same reaction vessel, and the reaction mixture
was further irradiated in the MW oven at its 50% power for 5
min using a pulse technique.16 Upon completion of the reaction,
followed by TLC, the reaction mixture was passed through a
bed of basic alumina using hexane/ether (9:1, v/v) as an eluent
to afford pure 2-morpholinoisoflav-3-enes (10a ): yield 80%; mp
103-105 °C (lit.5a mp 105 °C).
6-Nitr o-2-p ip er id in oisofla v-3-en e (10h ): MW irradiation
1
for 2 min; yield 85%, mp 137-138 °C; H NMR δ 1.49 (m, 6H,
CH2CH2CH2), 2.61 (bs, 2H, NCH2), 3.01 (bs, 2H, NCH2), 5.93 (s,
1H, 2-H), 6.96 (d, 1H, J ) 8.1, 8-H), 7.07 (s, 1H, 4-H), 7.32-
7.44 (m, 3H, 3′-H, 4′-H, 5′-H), 7.70 (dd, 2H, J ) 1.8, 8.7, 2′-H,
6′-H), 8.07 (d, 1H, J ) 2.7, 5-H), 8.08 (dd, 1H, J ) 2.7, 8.1, 7-H);
13C NMR δ 24.4 (CH2), 26.0 (CH2), 47.8 (NCH2), 93.4 (C-2), 115.2,
121.1, 121.6, 122.8, 125.2, 126.4, 128.4, 128.6, 131.3, 136.8, 141.1,
159.4; HRMS (EI) calcd for C20H20N2O3 [M+] 336.1474, found
336.1464.
2-P yr r olid in oisofla v-3-en e (10i): MW irradiation for 4 min;
yield 71%, as a gum; 1H NMR δ 1.71 (m, 4H, CH2CH2), 2.84 (m,
2H, NCH2), 3.14 (m, 2H, NCH2), 6.07 (s, 1H, 2-H), 6.88-6.96
(m, 2H, 6-H, 8-H), 7.00 (s, 1H, 4-H), 7.15-7.23 (m, 2H, Ar-H),
7.32-7.44 (m, 3H, Ar-H), 7.70 (dd, 2H, J ) 1.5, 8.1, 2′-H, 6′-
H); 13C NMR δ 24.4 (CH2), 46.3 (NCH2), 87.1 (C-2), 114.8, 120.3,
121.5, 122.0, 125.0, 127.9, 127.6, 128.5, 129.2, 130.5, 138.0, 154.4;
HRMS (EI) calcd for C19H19NO [M+] 277.1466, found 277.1458.
6-Ch lor o-2-p yr r olid in oisofla v-3-en e (10j): MW irradiation
for 2 min; yield 79%, as a gum; 1H NMR δ 1.72 (m, 4H, CH2-
CH2), 2.79 (m, 2H, NCH2), 3.06 (m, 2H, NCH2), 6.08 (s, 1H, 2-H),
6.88 (d, 1H, J ) 9.0, 8-H), 6.92 (s, 1H, 4-H), 7.14 (dd, 1H, J )
2.7, 9.0, 7-H), 7.15 (d, 1H, J ) 2.7, 5-H), 7.32-7.46 (m, 3H, 3′-
H, 4′-H, 5′-H), 7.69 (dd, 2H, J ) 1.8, 8.4, 2′-H, 6′-H); 13C NMR
δ 24.5 (CH2), 46.3 (NCH2), 87.4 (C-2), 116.2, 120.9, 122.8, 125.9,
126.1, 126.5, 128.0, 128.6, 128.8, 131.7, 137.5, 152.9; HRMS (EI)
calcd for C19H18ClNO [M+] 311.1077, found 311.1072 and
313.1047.
6-Ch lor o-2-m or p h olin oisofla v-3-en e (10b): MW irradia-
1
tion for 4 min; yield 81%; mp 137-138 °C; H NMR δ 2.65 (m,
2H, NCH2), 3.02 (m, 2H, NCH2), 3.62 (m, 4H, CH2OCH2), 5.77
(s, 1H, 2-H), 6.88 (d, 1H, J ) 8.2, 8-H), 7.01 (s, 1H, 4-H), 7.12
(d, 1H, J ) 2.7, 5-H), 7.14 (dd, 1H, J ) 2.7, 8.2, 7-H), 7.32-7.44
(m, 3H, 3′-H, 4′-H, 5′-H), 7.69 (dd, 2H, J ) 1.5, 8.4, 2′-H, 6′-H);
13C NMR δ 47.1 (NCH2), 67.0 (OCH2), 90.8 (C-2), 116.2, 122.3,
122.3, 125.3, 126.1, 126.4, 128.1, 128.6, 129.2, 129.6, 137.1, 152.2;
HRMS (EI) calcd for C19H18ClNO2 [M+] 327.1026, found 327.1022
and 329.1001.
6-Nitr o-2-m or p h olin oisofla v-3-en e (10c): MW irradiation
1
for 6 min; yield 82%; mp 161-163 °C; H NMR δ 2.66 (m, 2H,
NCH2), 3.02 (m, 2H, NCH2), 3.63 (m, 4H, CH2OCH2), 5.94 (s,
6-Nitr o-2-p yr r olid in oisofla v-3-en e (10k ): MW irradiation
for 2.5 min; yield 83%; mp 126-127 °C; 1H NMR δ 1.72 (m, 4H,
CH2CH2), 2.88 (bs, 4H, NCH2), 6.22 (s, 1H, 2-H), 6.95 (d, 1H, J
) 9.0, 8-H), 6.99 (s, 1H, 4-H), 7.32-7.44 (m, 3H, 3′-H, 4′-H, 5′-
(16) The reaction mixture is irradiated in a microwave oven for
successive intervals of 2 min with a cooling of 1 min after every
irradiation to avoid overheating of reactants.

Notes
J . Org. Chem., Vol. 63, No. 22, 1998 8041
H), 7.64 (dd, 2H, J ) 1.8, 8.4, 2′-H, 6′-H), 8.07 (dd, 1H, J ) 2.7,
9.0, 7-H), 8.08 (d, 1H, J ) 2.7, 5-H); 13C NMR δ 24.4 (CH2), 46.2
(NCH2), 89.2 (C-2), 115.1, 120.4, 121.1, 122.8, 125.1, 126.1, 128.4,
128.7, 132.5, 136.7, 141.0, 159.8; HRMS (EI) calcd for C19H18N2O3
[M+] 322.1317, found 322.1310.
Neena Rani, University of Illinois, Chicago, and Dr. R.
K. Saini, Rice University, for NMR and mass spectral
determinations.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of
10b-k (23 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS: see
any current masthead page for ordering information.
Ack n ow led gm en t. We are grateful to the Texas
Advanced Research Program (ARP) in chemistry (Grant
No. 003606-023), the Retina Research Foundation, and
Texas Research Institute for Environmental Studies
(TRIES) for financial support. We are thankful to Dr.
J O980985R