Synthesis and Reactions of Benzofurazan-I -oxide Deborah L. Terrian, Melissa A. Houghtaling, and James R. ~ m e s ' University of Michigan-Flint, Flint, MI 48502 Laboratory experiments and the discussions of hetemyclic compounds often are not included in the average introductory organic chemistry course, even though beterocycles comprise over half the entries i n Beilstein. Heterocyclica make up a large share of pharmaceuticals, medicinals, and alkaloid natural products-materials that many students will encounter in their professional careers. These compounds also play a vital role in metabolism (1). Many introductory texts treat the subject in special topics chapters, or a t later stages of the book (2);Wolthuis suggests that they be discussed in the introductory course a t the expense of other aspects of organic chemistry (3a). Within the past few years, there have been several published syntheses of nitrogen containing heterocycles in this Journal (3).However, few may he considered appropriate for the introductory course, and fewer have included the preparation and reactions of these materials. To compensate for the need of an elementary experiment that can be used to familiarize students with the synthesis and reactions of nitrogen heterocycles, we have compiled the following sequence (eqs 1-2) for the preparation of quinoxaline di-N-oxides (&NO),a great number of which possess antibacterial as well as other pharmacological properties (4-6), in our sophomore level organic laboratory.
N
b
Fi
+
RCOCH,R.
-
for periods of up to a week, e.g., yields of la and l b were 75%and 31%,respectively. Thus, it is possible to have several reactions going simultaneously that allow for a more efficient use of student lab time as recently sueeested bv ~ i c k e r i n ~ ( lEach 0 . student prepares benzofura&-l-oxide ~RFOJvia the dchvdrocenation of o-nitroaniline with nodiumhypochlorite"(3afin the fwst meeting. Students are then divided into groups with each group synthesizing one of the products; in many cases there is no need for purification. The yellow to yellow-orange products displayed strong IR absorption in the 1300 to 1350 cm-' region, attributable to the N-oxide function. Other compounds such as phenazine di-N-oxides also are possible (9).Unlike the more common method for the preparation of quinoxaline N-oxides, which utilizes hydrogen peroxide in acetic acid or peracid (101, this reaction, referred to as the Beirut reaction, employs a one-pot synthesis of pmducts rather difficult to obtain by previous methods.
.
Precautions AU reactions should be performed under the hood oNitroaniline is a highly toxic imtant. Sodium hyphlorite
and sodium hydroxide are corrosive. Waah with large amounts of water if contact occurs. Triethylamine may be irritating to skin and mucous membranes. Procedures The melting points and percent yields cited are the averages of the results obtained by the students.
base
BFO
(a)R=CH,; R%OCH, lb) R=CH,: R%O,CH,
In addition to involving simple procedures, this series of reactions also allows one to discuss biologically active molecules, and the electronic similarities between enamines and enolate anions. Enamines and enolates have traditionally been introduced in lab texts in the synthesis of tetrapheuylcyclopentadienone (7a) and 2-acetylcyclohexanone (76). The procedures are written to be performed with extended periods of stirring. The mixtures also can be stored
Benzofurazan-I-oxide [BFOI (3a) Measure 53 mL of methanol into a 250-mL Erlenmeyer flask. While swirling the flask, add 4.5 mL of 50% sodium hydroxide solution followed by 3 g o-nitroaniline. Warm the mixture to dissolve both the base and the amine. Insert a thermometer into the flask a&d cool to 5 'C with an icewater bath. From a dropping funnel, add 60 mL chlorine bleach ("Chlorox") over 20-25 min, while keeping the temperature a t 5-10 'C. Keep the solution well mixed. Stir 10 min longer a t 5-10 'C and then vacuum filter. Wash the yellow residue with three 30-mL portions of water, followed by 30 mL 1-2% hydrochloric acid, and fmally 30 mL of water. Dry the product and recrystallize from a very small amount of methanol (mp 69-71'C, 75%yield).
2-Methyl-3-acetylquinomline-1,4-dioxi& [la1 (11) Suspend 1.7 g BFO and 1.4 g 2,4-pentanedione in 7 mL triethylamine. Heat the solution with stirring until solid dissolves. Remove heat and continue stirring 18 h. Collect yellow precipitate by vacuum filtration. Wash with ice cold methanol. Recrystallize product from methanol (mp 153154 'C, 42% yield).
2-Methyl-3-carbomtho~quinoxalim-I,4-dioxide [Ibl Add 1.7 gbenzofurazan-l-oxide to 1.7 gmethylacetoacetate in 12 mL triethylamine. Heat with stirring until solid dissolves. Remove heat and continue stirring 30 h. Collect Author to whom correspondence should be addressed. Volume 69 Number 7 July 1992
589
product by vacuum filtration and wash with water. Recrystallize from methanol (mp 169-170 'C; lit. mp 167-169 'C (12)30% yield).
2-Phenyl-3-benzoylquinoxaline-1,4-dwxi&[lcl(11) Dissolve 1.7 g of benzofurazan-l-oxide and 2.8 g dibenzoylmethane in 13 mL of warm triethylamine. Allow the solution t o stand at room temperature for 24 h. If necessary, add triethylamine to thin the resulting precipitate and collect yellow crystals by vacuum fdtration. Recrystallize from methanol (mp 229 'C, 18%yield).
2-Phenyl-3-benzylquinoxaline-1,4-dioxide lldl A 1.7 g sample of BFO and 3.2 g of l,3-diphenyld-pmpanone were dissolved in 13 mL of triethylamine. The solution was stirred at room temperature for 30 h. The yellow product was filtered and washed with methanol to yield 0.61 g (14%).Recrystallization from ethanol resulted in a m p of 187-188 'C; lit. mp (13)191 'C.
2,3-Diphenylquimxaline-1,4-dioxze [le] A mixture of benzofurazan-l-oxide (2.04 g), deoxybenzoin (3.53 g), sodium hydroxide (0.06 g), and ethanol (10 mL) were refluxed for 2 h and then stirred overnight at room temperature. The solid that formed was filtered and recrystallized from methanol (mp 208-210 T;lit. mp (141, 21&21lT, 25% yield). 2-Phenylquinoxaline-1,4-diazide (11) Compound l c (0.25 g) was suspended in 2% methanolic KOH (11mL). The mixture was heated until the solid dissolved and then cooled with stirring. The resulting precip-
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Journal of Chemical Education
itate was wllected and washed thoroughly with methanol (mp 200-20l0C, 65%yield).
1,2,3,4-Tetmhydrophenazine-5,lO-dioxide 121 (15) To a warm (35 'C) methanolic (19 mL) solution of BFO (2.04 g), 3.01 g of l-morpholino-l-cyclohexene was added, with stirring, over 5 min. Continue to stir the mixture at 35 'C for 1.5 h. Cool the solution in the refrigerator overnight. Collect product by vacuum filtration, washing with cold methanol. Recrystallize from methanol (mp 188 'C, 44% yield). Literature Cited 1. campaigne, E.J Chem Edvc Ism, w, -3. 2. Forexamplesee:(a)Solomom,TW. G.OrgonlcChIsf'y.4thed.; Wky:NewY~rL, 1988.(blMeMurry, J. OrgonicChamishy.Znded.; BmoWCoIe:PadfleGmue,CA 19M
3. (a) Wolthuia, E. J. Cham Edue. 1979,56, 343344. (b) Lub, W B. J Cham Educ. 1490, 67, 11 (el Bahin, P; Devaur, G. J. Ch~m.Edue 1889,66, 522-523. (d) Awaltani R.;Sakzadeh,K.; Gablie1sen.B.J. Cham. Educ 1986,6.3,112-176. (el Panbake, M.C.;Small, L.,J. Cham. E d w . 1496,63, 650. (0lskander, M. N.; Andnws,P R J Chem. Educ. 1985,62,913. 4. Franeia, J.;Landquiat,J.K.;Lavi,A.A.:Silk, J.A;Thmp,J. M.Bioehem J. ISM, c, " C Z " C , "",-"-",.
5. Jones,W. R.;h d q l u s t . J. K: Stewart, G.T. Br J. P h m o l 1958,8,28&269. 6. See: Haddadin, M . J.;lssidotides,C. H. HetomcyelPa 1976,4,761-816. 7. Pavia, D.L.;Lampman, G. M.; Knz, G. S. Inboductlon to ogonic Lab,&,, Tednulues A Confempomry A p p m h , 3rd 4.:Saunders: Philadelphia, 1938:(a) pp ad,. ... ,(h,nnRb? ,. , rr ... . 8. Pickering, M. J. Cham E d w . 1491,66,232-234. 9. Ley, K.; Seng, E; Eholzer, U.;Nssf, R.; Schubert, R A n g w . Cham ht. Edn. Engl.
1969,8,596591. 10. Landquisf,J.K.J. Cham. Soe. 1963,28162821. 11. Issidondea, C.H.; Haddadin, M. J. J. Or& Cham 1868,31,4061-4068. 136&U64. 12. Dirlam, J.P;MeFarlsnd,J. W. J 0% Cham. IlYI?,42, 13. Hadda&n,M.J;Zahr,G.E.;Rawdah,TN.;ChelhofN.C.;lspidorides,C.H.Totmh d r m 1914,30,659666. 14. Gmwnstein, E.;Postman, W.; Taylor, J. W. J. 0% Cham 1980.25,6&13. 15. Haddadin, M.L: Issidmides, C.H. lhtmhrdmnLatL IWS,36,325-256,
