Microwave-Assisted Henry Reaction:
Solventless Synthesis of Conjugated Nitroalkenes

Tetrahedron Letters, Vol. 38, No. 29, pp 5131-5134, 1997

Rajender S. Varma[TRIES, HARC], Rajender Dahiya[TRIES] and Sudhir Kumar[HARC]

Department of Chemistry and Texas Regional Institute for Environmental
Studies (TRIES), Sam Houston State University, Huntsville, Texas
77341-2117, USA Houston Advanced Research Center (HARC), 4800 Research
Forest Drive, The Woodlands, Texas 77381, USA

Key Words: Arylaldehydes; Nitroalkanes; Ammonium acetate; Conjugated
           nitroalkenes; Henry reaction; Microwave irradiation

Abstract: In a solventless system and under microwave irradiation,
nitroalkanes react with arylaldehydes in the presence of a catalytic amount
of ammonium acetate to afford, in one step, conjugated nitroalkenes without
the isolation of intermediary b-nitro alcohols.

Nitroalkenes are abundantly utilized for the preparation of a variety of
organic compounds[1] and possess significant biological activities such as
insecticidal[2,3] fungicidal,[3-6] bactericidal,[7, 8] rodent-repellent[9]
and antitumor agents.[10] The utility of nitroalkenes in organic synthesis
is largely due to their ease of conversion into a variety of
functionalities. They are strong dienophiles in Diels-Alder reactions and
alternatively, these electrophilic alkenes readily undergo addition
reactions with various nucleophiles thus providing an array of valuable
products.

The most versatile synthesis of nitroalkenes involves the Henry
condensation reaction of a carbonyl compound 1 with nitroalkane 2 to give
D-nitro alcohol 3 which undergoes dehydration affording conjugated
nitroalkene 4 (Eqn.).[11] This condensation reaction is usually
accomplished under mildly basic conditions.

R1.CO.R2  + R3.CH2.NO2  -->  R1R2C(OH).CR3(NO2)  -->  R1R2C=CR3(NO2) (Eqn.)

Cmp
1       R1.CO.R2
2       R3.CH2.NO2
3       R1R2C(OH).CR3(NO2)
4       R1R2C=CR3(NO2)

Several reagents such as phthalic anhydride,[12,13] methanesulfonyl
chloride,[14] dicyclohexylcarbodiirnide (DCC), [15] pivaloyl chloride, [16,
17] ammonium acetate-acetic acid [18, 19] and amines[7, 19] have been used
for the dehydration of the ensuing b-nitro alcohols. However, some of these
reactions require elevated temperature and may not be amenable to the
dehydration of functionalized nitroalcohol intermediates.

The significance of nitroalkenes in organic synthesis[1] and our continued
interest in the development of environmentally benign synthetic protocols
using microwave (MW) irradiation under solvent-free 'dry' conditions,[20]
prompted us to investigate the Henry reaction that involves the excessive
use of nitrohydrocarbons. We wish to report herein a solventless synthesis
of conjugated nitroalkenes using microwaves in the presence of catalytic
amount of ammonium acetate. The method reduces longer reaction times and
requirement of large quantities of nitrohydrocarbons that normally play the
dual role of a solvent as well as a reactant in the conventional solution
phase chemistry. Microwave heating has been used for a wide variety of
applications including the rapid synthesis of organic compounds.[21-24] The
useful solution phase chemistry utilizing microwaves[22] is finding
numerous applications under solventless 'dry' conditions where the MW
effect is more pronounced.[20, 23-24]

The environmentally benign aspect of the approach is obvious in view of the
elimination or reduction of solvents which are normally employed in large
amounts.

The condensation of aldehydes with nitroalkanes using a catalytic amount of
ammonium acetate (0.25 mmol/mmol of carbonyl compound used) coupled with
the pulsed microwave irradiation is found to be an ideal condition that
affords high yields of the conjugated nitroalkenes directly without the
isolation of the intermediary b-nitroalcohols. That the effect is not
purely thermal [25] is supported by the fact that using an alternate
heating mode (oil bath) at the same temperature of 90 C, the reaction
(a-naphthaldehyde, entry 8j) could be completed in 18 hours.

R-Ar.CHO  + R1.CH2.NO2  -->  R-Ar.CH(OH).CH(NO2)R1  -->  R-Ar.CH=C(NO2)R1

Cmp
5:      R.Ar.CHO
6:      R1.CH2.NO2
7:      R-Ar.CH(OH).CH(NO2)R1
8:      R-Ar.CH=C(NO2)R1
Ar:     substituted benzene ring

{Formatting details for table: Ariel font, size 10, tab stops at 0.5", 1.5", 2, 2.5", 3", 4"}

Table: Microwave-assisted synthesis of conjugated nitroalkenes.
----------------------------------------------------------------------------------------------
Entry   R       		R1      Time    Yield   m.p. (Lit)      Ref.
----------------------------------------------------------------------------------------------
8a      H       		H       8.0     80      58 (58-9)       19
8b      4-OH    		H       4.0     88      165 (168-9)     19
8c      3-MeO,4-OH      H       3.0     89      166 (167-8)     19
8d      3,4-(MeO)2      H       2.5     90      139 (141-2)     19
8e      H       		CH3     7.0     83      64 (64-5)       19
8f      4-OH    		CH3     3 5     89      124 (124-5)     19
8g      3-MeO,4-OH      CH3     3.0     91      100 (100-1)     19
8h      3,4-(MeO)2      CH3     3.0     92      66 (67-8)       19
8i      4-MeO   		CH3     4.0     90      44 (44-5)       19
8j      1-Naphthyl      H       8.0     80      76 (72-74)      26
8k      2-Naphthyl      H       7.5     83      121 (121-2)     27
----------------------------------------------------------------------------------------------
(Time is in mins, Yield as %, m.p. in degrees C)

Although we have not used any special safety equipment because of adequate
air ventilation of the microwave cavity but prudent care is recommended in
view of the flammable and irritant nature of the nitrocompounds.

Unoptimized yields of the products that exhibited physical and spectral
characteristics in accord with the assigned structures.

In a typical synthetic procedure, a mixture of benzaldehyde 5a (0.106 g, 1
mmol) and nitromethane 6a (0.061 g, 1 mmol) is placed in a glass tube
containing ammonium acetate (0.019 g, 0.25 mmol) and is exposed to pulsed
microwave irradiation[28] in an alumina bath for 2 min using an unmodified
microwave oven operating at its 40% power.[25] The reaction mixture is
cooled to room temperature (~ 1 min) and is irradiated again for 2 min.
After two such successive irradiations (2 min) and cooling (~ 1 min)
sequences, another 1 mmol of nitromethane is added to the reaction mixture
that is further irradiated for two similar successions. After completion of
the reaction (followed by TLC), the reaction mixture is passed through a
short silica gel column using hexane:AcOEt (9:1,v/v) as an eluent. The
evaporation of the solvent on a rotary evaporator affords p-nitrostyrene
(8a). Other nitroalkenes prepared following this general procedure are
summarized in the Table.

In conclusion, we have developed an environmentally benign method for the
rapid synthesis of  conjugated nitroalkenes that avoids the use of
excessive nitrohydrocarbons and proceeds in high yields.

Acknowledgements: We are grateful to the Texas Advanced Research Program
(ARP) in chemistry (Grant # 0036060-023), Houston Environmental Initiative
Program (HARC), and Office of Naval Research/SERDP (Grant #
N00014-96-1-1067) for the financial support. SK thanks Department of
Science and Technology, Government of India, for a BOYSCAST fellowship.

REFERENCES AND NOTES

RD is currently on academic leave from M.L.N. College, Yamuna Nagar-135
001, Haryana, India.

A part of this work was presented in First World Congress on Microwave
Processing, Abstr. # XIV-3, Lake Buena Vista, Florida, 5-9 January, 1997;
For commentary on this congress proceedings see: Dagani, D. Chem. Eng. News
February 10,1997, 26.

1.  (a) Varma, R. S.; Kabalka, G. W. Heterocycles 1986, 24, 2645;
    (b) Barrett, A. G. M.; Graboski, G. G.  Chem. Rev. 1986, 86, 751;
    (c) Kabalka, G. W.; Varma, R. S. Org. Prep. Proc. Int. 1987,19, 283;
    (d) Kabalka, G. W.; Guindi, L. H. M.; Varma, R. S. Symposia-in-print
        Tetrahedron 1990, 46, 7443;
    (e) Barrett, A. G. W. Chem. Soc. Rev. 1991, 20, 95.

2.  Brown, A. W. A.; Robinson, D. B. W.: Hurtig, H.; Wenner, B. J. Can. J.
    Res. 1948, 26D, 177.

3.  Bousquet, E. W.; Kirby, J. E.; Searle, N. E. U. S. Patent 2,335,384
    1943; Chem. Abstr. 1944, 38, 2834.

4.  Brian, P. W.; Grove, J. F.; McGowan, J. C. Nature 1946,158, 876.

5.  McGowan, J. C.; Brian, P. W.; Hemming, H. G. Ann. Appl. Biol. 1948,
    35, 25.

6.  Bocobo, F. C.; Curtis, A. C.; Block, W. D.; Harrell, E. R.; Evans, E.
    E.; Haines, R. F. Antibiol.  Chemother. 1956, 6, 385.

7.  Schales, O.; Graefe, H. A. J. Am. Chem. Soc. 1952, 74, 4486.

8.  Dann, O.; Moller, E. F. Chem. Ber 1949, 82, 76.

9.  Harker, R. J. U. 5. Patent 2,889,2461959; Chem. Abstr. 1959, 53, 17414i.

10. Zee-Cheng, K.; Cheng, C. J. Med. Chem. 1969,12, 157.

11. (a) Bauer, H. H.; Urbas, L. The Chemistry of the Nitro and Nitroso
        Group, Feuer, H., Ed., Interscience, New York 1970, Part 2, pp 75-200;
    (b) Seebach, D.; Colvin, E. W.; Lehar, F.; Weller, T. Chimia 1979, 31, 1;
    (c) Schickh, O. V.; Apel, G.; Padeken, H. G.; Schwartz, H. H.; Segnitz, A.
        In Houben-Weyl: Methoden der Organische Chemie, Muller, E., Ed,
        George Thieme Verlag, Stuttgart 1971,10/1, pp 9-462;
    (d) Rajappa, S. Tetrahedron 1981, 37, 1453;
    (e) For review of extensive Russian work on nitroalkene chemistry see:
        Perekalin, V. V. J. Org. Chem. USSR (Engl. Transl.) 1985, 21, 1011;
    (f) Ballini, R.; Castagnani, R.; Petrini, M. J. Org. Chem. 1992, 57, 2160
        and references cited therein.

12.  Buckley, G. D.; Caife, C. W. J. Chem. Soc. 1947, 1471.

13.  Ranganathan, D.; Rao, C. B.; Ranganathan, S.; Mehrotra, A.; Iyengar,
     R. J. Org. Chem. 1980, 45, 1185.

14  (a) Miyashita, M.; Yamaguchi, R.; Yoshikoshi, A. Chem. Lett. 1982, 1505;
    (b) Melton, J.; McMurry, J. E. J. Org. Chem. 1975, 40, 2138.

15.  Knochel, P.; Seebach, D. Synthesis 1982, 1017.

16.  Knochel, P.; Seebach, D. Tetrahedron Lett. 1982, 23, 3897.

17.  Seebach, D.; Knochel, P. Helv. Chim Acta 1984, 67, 261.

18.  Karmarkar, S. N.; Kelkar, S. L.; Wadia, M. S. Synthesis 1985, 510.

19.  Gairaud, C. B.; Lappin, G.R. J. Org. Chem. 1953,18,1.

20.  (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. (I) 1993, 999; (d) Varma, R. S.;
     Lamture, J. B.; Varma, M. Tetrahedron Lett. 1993, 34, 3029; (e) Varma,
     R. S.; Dahiya, R.; Kumar, S. Tetrahedron Lett. 1997, 38, 2039; (f)
     Varma, R. S.; Dahiya, R. Tetrahedron Lett. 1997, 38, 2043; (g) Varma,
     R. S.; Saini, R. K. Tetrahedron Lett. 1997, 38, in press.

21.  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) For commentary on the First World Congress on Microwave
     Processing, see Dagani, D. Chem. Eng. News February 10, 1997, 26.

22.  (a) Giguere, R. J.; Namen, A. M.; Lopez, B. O.; Arepally, A.; Ramos,
     D. E.; Majetich, G.; Defauw, J. Tetrahedron Lett. 1987, 28, 6553 and
     references cited therein; (b) Bose, A. K.; Manhas, M. S.; Ghosh, M.;
     Raju, V. S.; Tabei, K.; Urbanczyk-Lipkowska, Z. Heterocycles 1990, 30,
     741; (c) Bose, A. K.; Jayaraman, M.; Okawa, A.; Bari, S. S.; Robb, E.
     W.; Manhas, M. S. Tetrahedron Lett. 1996, 37, 6989 and references of
     this group cited therein.

23.  (a) Bram, G.; Loupy, A.; Majdoub, M.; Gutierrez, E.; Ruiz-Hitzky, E.
     Tetrahedron 1990, 46, 5167; (b) Marrero-Terrero, A. L.; Loupy, A.
     Synlett 1996, 245.

24.  (a) Benalloum, A.; Labiad, B.; Villemin, D. J. Chem. Soc., Chem.
     Commun. 1989, 386; (b) Villemin, D.; Labiad, B. Synth. Commun. 1990,
     20, 3325 and 3333; (c) Villemin, D.; Benalloum, A. Synth. Commun.
     1991, 21, 1 and 63.

25.  For a critical evaluation of activation process by microwaves see:
     Raner, K. D.; Strauss, C. R.; Vyskoc, F.; Mokbel, L. J. Org. Chem.
     1993, 58,950. The temperature of the reaction mixture inside the
     alumina bath (heat sink) in a Sears Kenmore microwave oven (2450 MHz)
     equipped with a turntable at its 40 % power level (full power level
     being 900 Watts) reached ~90 C after 2 minute of irradiation.

26.  Trehan, I. R.; Bala, K.; Singh, J. B. Indian J. Chem. 1979, 18B, 295.

27.  Koremura, M.; Oku, H.; Shono, T.; Nakanishi, T. Takamine Kenkyusho
     Nempo 1961,13, 216.

28.  Pulse sequence (2 min heating with 1 min interval) is needed only for
     the volatile nitroalkanes used.
