A new method for the synthesis of 2,6-dinitro and 2-halo-6-nitrostyrenes

Article abstract of DOI:10.1016/S0040-4039(00)01101-1

A new method for the synthesis of 2-halo-6-nitrostyrenes from 2-halo-6-nitrotoluenes is disclosed. Also described is a one-pot process for the synthesis of 2,6-dinitristyrene from 2,6-dinitrotoluene. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01101-1

Tetrahedron Letters 41 (2000) 6319±6321
A new method for the synthesis of 2,6-dinitro and
2-halo-6-nitrostyrenes
Sreenivasa R. Mundla*,y
Procter & Gamble Pharmaceuticals, Chemical Development, Woods Corners, PO Box 191, Norwich, NY 13815, USA
Received 12 May 2000; revised 23 June 2000; accepted 26 June 2000
Abstract
A new method for the synthesis of 2-halo-6-nitrostyrenes from 2-halo-6-nitrotoluenes is disclosed. Also
described is a one-pot process for the synthesis of 2,6-dinitristyrene from 2,6-dinitrotoluene. # 2000
Elsevier Science Ltd. All rights reserved.
Keywords: 2,6-dinitrotoluene; 2,6-dinitrostyrene; 2-halo-6-nitrostyrenes and p-formaldehyde.
During our e€orts to develop an economical process for the production of 5-amino-4-ethyl-
benzimidazole 1, we were interested in evaluating 2,6-dinitrostyrene 2a as a possible key
intermediate.1 We reasoned that the styrene derivatives 2a±f might serve as key intermediates for
a variety of heterocyclic compounds. We envisioned that these styrene derivatives 2 might easily
be synthesized by hydroxymethylation of the corresponding 2-nitrotoluenes2 3a±f followed by
elimination of the resulting hydroxyl group. A literature search revealed that Hegedus and
Harrington3 reported the synthesis of 2-bromo-6-nitrostyrene 2c from 2-bromo-6-nitro toluene 3c
via a three-step sequence in which they used the Wittig ole®nation reaction as the key step. By
using a similar three-step sequence, Soderberg and Shriver4 recently reported the synthesis of 2,6-
dinitrostyrene 2a from 2,6-dinitrotoluene 3a with an overall yield of 65%. They also developed a
new approach to the synthesis of various indoles from the corresponding styrenes.4 This prompted
us to report on our one-pot process for the synthesis of 2,6-dinitrostyrene and the results related
to the synthesis of various 2-halo-6-nitro styrene derivatives 2.
As shown in Scheme 1 and Table 1, treatment of the toluene derivatives 3a±d with p-form-
aldehyde at room temperature either in dimethylsulfoxide (entry 1) or in N,N-dimethyl-acetamide
(DMAC) (entries 2±5) in the presence of a catalytic amount of potassium hydroxide furnished the
hydroxyethyl derivatives 4a±d. Surprisingly, under similar reaction conditions, the 2-halo-5,6-dinitro
* Corresponding author. E-mail: mundlasr@pg.com
y
Current address: P&G Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Rd, Mason,
OH 45040, USA.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01101-1

6320
Scheme 1. Reagents and conditions: (i) (HCHO)n, KOH, N,N-dimethylacetamide, rt; (ii) TEA, MsCl, CH2Cl2 or
DMAC 0±25ꢀC; (iii) TEA or DABCO, CH2Cl2 re¯ux or DMAC, 65±90ꢀC
Table 1
derivatives5 3e,f gave no expected products and remained intact, even after prolonged reaction
time. Exposure of the crude hydroxyethyl derivatives 4a±d to triethylamine and methanesulfonyl
chloride either in dichloromethane (entry 1) or in DMAC (entries 2±5) gave the mesylate
derivatives 5a±d. Heating of the mesylate derivative 5a with excess triethylamine in the same pot
either in dichloromethane at re¯ux (entry 1) or in DMAC at 70±75ꢀC (entry 2) gave the 2,6-
dinitrostyrene 2a in excellent yield. The styrene 2a was isolated from the DMAC reaction mixture
by simply pouring into water followed by ®ltration. When we used the above-described reaction
conditions to e€ect the elimination of mesylate from 5b to furnish 2b, the reaction was found to
be very sluggish and incomplete even after 16 h. But exposure of 5b to DABCO in DMAC at 70±90ꢀC
cleanly furnished 2b. By using these modi®ed reaction conditions, the mesylate derivatives5 5e
and 5f were also converted into the corresponding styrene derivatives 2e and 2f.
General 3-step procedure: (i) To a solution of 3 (14.3 mmol) and p-formaldehyde (17.8 mmol) in
dimethylacetamide (20 ml) was added powdered potassium hydroxide (1.4 mmol). The reaction
mixture was stirred at room temperature for 4±6 h. The product 4 was either isolated after
standard work-up2 or directly used in the next step without any work-up or isolation; (ii) To a
stirred solution of hydroxy derivative 4 either in dichloromethane or in DMAC (20 ml) at 0ꢀC
was added methanesulfonyl chloride (20 mmol) and triethylamine (45 mmol). The reaction
mixture was allowed to warm up to room temperature and stirred until the reaction was
complete. The mesylate derivative 5 was either isolated after the usual work up or subjected to the
next step without doing any work up; (iii) To a solution of mesylate 5 either in dichloromethane
or in DMAC (20 ml) was added either TEA or DABCO, as shown in Table 1 (40 mmol). The
reaction mixture was stirred at 65±90ꢀC until the reaction was complete. The styrene 2 was
isolated after standard work-up and chromatographic puri®cation.6
In conclusion, a general method for the synthesis of 2-halo-6-nitrostyrenes 2 from 2-halo-6-
nitro toluenes 3 has been developed. In addition, we have also developed a one-pot process for the
synthesis of 2,6-dinitrostyrene from 2,6-dinitrotoluene. This process was found to be advantageous

6321
over the existing method as this method eliminates the use of environmentally unfriendly reagents
and is more suitable for large scale synthesis.4
Acknowledgements
The author would like to thank the P&GP management for their support and encouragement
and Drs. David E. Portlock, Patricia A. Matson and Thomas L. Cupps for their comments
during the preparation of this manuscript.
References
1. Cupps, T. L.; Bogdan, S. E. US 5478858, and references cited therein.
2. (a) Florvall, L.; Kumar, Y.; Ask, A. L.; Fagervall, I.; Renyi, L.; Ross, S. B. J. Med. Chem. 1986, 29, 1406;
(b) Tsuji, Y.; Kotachi, S.; Huh, K. T.; Watanabe, Y. J. Org. Chem. 1990, 55, 580.
3. Harrington, P. J.; Hegedus, L. S. J. Org. Chem. 1984, 49, 2657.
4. Soderberg, B. C.; Shriver, J. A. J. Org. Chem. 1997, 62, 5838.
5. For the preparation of compounds 5e & 5f, see: Mundla, S. R. Tetrahedron Lett. 2000, 41, 4277.
6. All products were identi®ed by proton NMR and Ms spectral data.