Journal of the Korean Chemical Society Vol. 37, No. 5, 1993
Printed in the Republic of Korea 든? 슨j
Pyirolo[l,2-a]benzimidazole-5,8-dione 유도체의 합성
李彰熙* •白祜賑 강원대학교 자연과학대학 화학과
(1993. 2. 19 접수)
Synthesis of 2,3-Dihydro-lH-Pyrrolo[ 1,2-a]Benzimidazole-5,8-Diones and its Reduced Analogues
Chang Hee Lee* and Ho Jin Baik
Department of Chemistry, Kang Weon National University, Chun Cheon 200-701, Korea (Received February 19, 1993)
The synthesis and studies of heterocyclic qui
nones were important in conjunction with biore- ductive alkylation and the design of new alkylat
ing agents. The reductive alkylating agents are quinones functionalized with leaving groups so as to permit quinone methide formation upon reduc
tion.1'3 Reported here is the synthesis of pyrrolo Ll,2-a]benzimidazole-5,8-diones and its reduced analogues as model of potential reductive alkyla
ting agents. Although many pyrr이o[l,2-a]benzi- midazole have been synthesized6~8 and studied since 1955, there was only one report for the syn
thesis of pyrrolo[l,2-a]benzimidazoles bearing quinone moiety.4 Such derivatives may exhibit quinone mediated reactions such as reductive alk
ylation and redox reaction. We found that 6 was conveniently converted to 7 upon treatment with concentrated hydrobromic acid, which indicate that 6 possesses very high reduction potential.5 The synthetic sequence described in Scheme 1 may be a versatile route to these novel pyrrolo[l, 2-a]benzimidazole based hetdrocyclic quinone sy
stems. A. R. Freeman and coworkers have prepa
red various pyrroloEl,2-a]benzimidazole by anne- lation of the benzimidazole and pyrrole rings with an appropriately substituted benzene.6 Unfortuna
tely, such benzene derivatives are not always available which could be easily converted to a be
nzoquinone to ring annelation. We have attempted
the preparation of 6 starting from 2-amino-4-chlo- rotoluene. The reaction sequence leading to 6 and 7 is shown in Scheme 1. As is shown, the synthesis relies on the formation of 2 which could be cycli
zed to the purrolo[l,2-a]benzimidazole 3. Treat
ment of 2-amino-4-chlorotoluene with neat pyrro
lidine at reflux resulted substitution product 1 as well as amide hydrolysis product. The ratio of the two products. was 50/50 in this reaction. Subse
quent catalytic hydrogenation of the mixture to reduce nitro group followed by treatment with acetic anhydride afforded 2 as the sole product.
The 】H・NMR spectrum of 2 in DMSO-rf6 shows three different methyl groups indicating peracety- lation of reduced form of 1. Cyclization of 2 to pyrroloE l,2-a]benzimidazole 3 was accomplished by two different methods. Not only cyclization of 3 in the presence of performic acid gave desired product 4 but also thermal reaction in boiling n- butanol also gave desired product. The former cy
clization is thought to involve /-amine N-oxide fol
lowed by acetyl transfer to N-oxide and subse
quent elimination of acetyl group to give iminium ion which was then cyclized and oxidized.8 The latter cyclization is thought involve[ 1,5]-sigmatro
pic H-shift.9 The rate of reaction monitored by UV-Vis spectrometer seemed to depend on the substrate concentration. Detailed kinetic studies are under progress. Nitration of 3 proceeded -537-
538 李彰熙-白祜賑
애'广丫睥 너小 Pdg 어y
、
nhacHa아HC아1 어丫、N5人，p 2-A^O* A由A서〉70°C 乙*A사
IHNQ)
R①亏：冷揷气:g
. S *
Scheme 1.
smoothly to afford mononitrzated product 4 regio- selectively, which gave amino product 5 after ca
talytic reduction.
Treatment of 5 with refluxing formic acid affor
ded 8 indicating that original nitration occurred at 8-position of 3. Cyclization of 5 to 8 was evide
nced by 】H-NMR and IR spectroscopy. IR spect
rum clearly shows that there is no absorbance attributed to carbonyl stretching of 5. Far down
field shift of N-H proton from 8 8.87 to 6 12.30 indicate that N-H proton in the imidazole moiety has intramolecular hydrogen bonding.11 Only one tautomeric form was isofated in this reaction.
Treatment of 5 with Fremy's salt in pH 3 aqueous phosphate buffer provided quinone 6. The struc
tural data are as follows: mp. 219~220，C; IR (KBr, cnL) 3240(s), 1651(s), 1510(s); 】H・NMR (DMSO-J6) 8 9.54 (1H, s, amide-H), 4.14 (2H, t, ]—7.0 Hz, C(l)-methylene), 2.86 (2H, t, J=7.0 Hz, C(3)-methylene), 2.60 (2H, quint, J= 6.4 Hz, C(2)- methylene), 2.05 (3H, & 6-methyl), 1.83 (3Ht s, acetyl).
Hydroquinone 7 was obtained by catalytic redu
ction of 6 in methanol.12 The compound 7 was air stable and obtained as hydrochlorids salt. The distictive feature of hydroquinone was seen in 1H- NMR spectrum. The structural data for 7 are as follows: IR (KBr, cm l) 3380(s), 3140(s), 1660(s), 1490(s), 1290(m); 】H・NMR (DMS0M&) 8 9.46 (1H, s, amide-H), 9.43 and 9.21 (2H, 2s, two Ar-OHs, no assignment made), 4.44 (2H, quint, /=4.7Hz, C(2)-methylene), 2.50 (3H, s, 7-methyl), 2.10 (3H, s, acetyl).
Various attempt to introduce leaving groups at 3-position of 6 resulted in different products. As shown in Scheme 2, attempted allylic bromination
애咨 5，= 滲Br b
다* 8 애3 9
0H OH
8 — • 쓰%R〔g
OH 애
10 7
Scheme 2.
of 6 with N-bromosuccinimide (NBS) gave 10.
This result indicates that benzylic bromination is more favorable than allylic bromination in 6.
When 5 was treated with NBS, 9 was formed qua
ntitatively. Cyclization of acetamido group and aromatic bromination were evidenced by 】H-NMR and IR spectra. XH-NMR (CDC13) spectrum of 9 shows disappearance of aromatic proton and IR spectrum clearly shows that there is no absorba
nce attributed to carbonyl stretching of 5.13 Also only one tautomeric form of imidazole ring was isolated in this reaction. Treatment of 6 with NBS afforded 10 as sole product which was slowly de
composed in air. This hydroquinone could elimi
nate HBr to afford orthoquinone methide, which traps nucleophiles. Currently we are trying to characterize possible intermediates in this reac
tion.
AKNOWLEDGEMENT
This reaesrch was supported by the Basic Scie
nce Research Institute Program, Ministry of Edu
cation, 1992.
REFERENCES
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Journal of the Korean Chemical Society
Pyrrolo[l,2-a]benzimidazole-5,8-dione 유도체의 합성 539
Chem., 51, 4784 (1986).
6. M. D. Nair and R. Amams, J. Am. Chem. Soc., 83, 3581 (1961).
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Heterocycl, Chem., 3, 257 (1966).
8. 0. Meth-Cohn, J. Chem. Soc. (C), 1356 (1971).
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10. 0. Meth-C아in and H. Suszhitsky, Adv. Heterocycl.
Chem., 14, 211 (1972) and references are there in.
11. HNMR (DMS04, TMS) 8 12.23 (1H, s, N-H), 7.09 (1H, s, Ar-H), 4.29 (2H, t, •/=&() Hz, C(l)-me- thylene), 2.92 (2H, t, J= 8.0 Hz, C(3)-methylene),
2.65 (2H, quint./= 8.0 Hz, C(2)-methylene)f 2.53 and 2.50 (6H, 2-s, 6 and 8-methyls, no assignment made).
12. lH-NMR (DMSO4) 6 9.46 (1H, s, N・H), 9.43 and 9.23 (2Hs, two s, Ar-OHs, no assignment made), 4.44 (2H, t, ]= 6.8 Hz, C(2)-methylene), 3.25 (2H, t, J— 6.8 Hz, C(3)-methylene), 2.73 (2H, quint, J=
6.8 Hz, C(2)-methylene), 2.09 and 2.11 (6H, two s, methyls, no assignment made).
13. JH-NMR (CDC13) 8 4.32 (2H, t,丿=6.0 Hz, C(l)- methylene), 3.07 (2H, t, /=6.0 Hz, C(3)-methy- lene), 2.78 (2H, quint, J— 6.0 Hz, C(2)-methylene), 2.20 and 1.67 (6H, two s, methyls, no assignment made).
Vol. 37, No. 5, 1993
