Dipyrrolo pyrazines

Dipyrrolo[l,2- 2, l - ]pyrazines, for example, 47, and related dipyrrolopyrimidines can be partially reduced in the central diazine ring under Birch reduction conditions to give the corresponding dihydro derivative 48 (Equation 5) <2005JOC2054>. 

In 1960, Mold et al. (2592) reported the isolation and identification of the tricyclic A-heterocyclic 5H, QH-dipyrrolo[l,2-fl r,2 -(i]pyrazine-5,10-dione (pyrocoll) V (Figure XVlI.E-3) from CSC and demonstrated its relationship to its precursor in tobacco, the amino acid proline. Obviously, pyrocoll is not an aza-arene but an amide. Rodgman and Cook (3279) reported the identification of indole, carbazole, and several alkylated indoles and car-bazoles in CSC and confirmed the presence of 5H, QH-dipyrrolo[l,2-fl r,2 -(i]pyrazine-5,10-dione (pyrocoll) V described previously by Mold et al. (2592). Rodgman and Cook also assessed previously reported biological studies on indole, 3-methylindole (skatole), and carbazole None was reported to be tumorigenic in laboratory animals [Hartwell (1544), Shubik and Hartwell (3664)]. 

In his 1968 review of tobacco and tobacco smoke composition, Stedman (3797) discussed the identification of tumorigenic A-heterocyclic compounds [dibenz[fl,/t]acridine, dibenz[fl, ]acridine, and 7//-dibenzo[c, carbazole] reported by Van Duuren et al. (4027), as well as the identification of the following A-heterocyclic compounds 5//,10//-dipyrrolo[l,2-fl T,2 -(i]pyrazine-5,10-dione (pyrocoll), 9//-pyrido[3,4-fc] indole (norharman), l-methyl-9/f-pyrido[3,4-fc]indole (harman), and 9//-pyrido[2,3-fc]indole. 

Although not originally classified at the time as cooked food mutagens, several amino acid-derived iV-heterocyclic compounds were identified in cigarette smoke condensate (CSC) in the early 1960s 5//,10//-Dipyrrolo[l,2-a r,2 -(i] pyrazine-5,10-dione (pyrocoll) 1 by Mold et al. (2592) and 9H-pyrido[3,4-fc]indole (norharman) 11 and l-methyl-9-H-pyrido[3,4-fc ]indole (harman) 111 by Poindexter and Carpenter (2972) (Figure XVll.F-1). 

Proline is the precursor in tobacco of 57/,107/-dipyrrolo[l,2-fl r,2 -(i]pyrazine-5,10-dione (pyrocoll) 1 in tobacco smoke. Tryptophan is the major precursor in tobacco of 1-methyl-... 

Tf, 10Tf-Dipyrrolo[l, l-a-.V,T-d pyrazine-5,10-dione, methyl-I methylpyrocoll ... 

Tf,10Tf-Dipyrrolo[l,2-a l ,2 -ti] pyrazine-5,10-dione, l,2a,3,5a,8,10a-hexahydro-3-methyl-... 

Rodgman and Cook (3279) conflrmed the presence in CSC of 5//,10//-dipyrrolo[l,2-a r,2 -alkylated indoles and carbazoles. Rodgman and Cook (3279) also reviewed the previously reported biological studies on indole, 3-methylindole (skatole), and carbazole None of the three was reported to be tumorigenic. 

In a 1974 in-house report, a 1975 TCRC presentation, and a 1977 publication on their study of the water-soluble portion of CSC, Schumacher et al. (3553) reported the identifications of l-methyl-97/-pyrido[3,4-/>]indole (barman), 5H,10H-dipyrrolo[l,2-a r,2 -(f pyrazine-5,10-dione (pyrocoll), octahydro-5//,107/-dipyrrolo[l,2-a r,2 -]indole. 

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