Synthesis of 2,6,7-Trichloro-1-(β-D-ribofuranosyl)naphtho[2,3-d]imidazole: A Linear Dimensional Analogue of the Antiviral Agent TCRB

Article abstract of DOI:10.1021/jo971152o

Human cytomegalovirus (HCMV) remains a significant clinical problem in neonates and immunocompromised individuals such as those undergoing transplantation as well as individuals with acquired immune deficiency syndrome (AIDS). Recently in our laboratory, 2,5,6-trichloro-1-(β-D-ribofuranosyl)benzimidazole (TCRB, 1a) and 2-bromo-5,6-dichloro-l-(β-D-ribofuranosyl)benzimidazole (BDCRB, 1b) were found to have better activities in cell culture studies against HCMV than the clinically used agents ganciclovir and foscarnet. These benzimidazole compounds appear to act by a unique mechanism. However, as the biological target of TCRB and BDCRB has not been completely identified, 2,6,7-trichloro-1-(β-D-ribofuranosyl)naphtho[2,3-d]imidazole (2) was designed as a linear dimensional analogue of TCRB for a study on the spatial limitation of the binding site in the target enzyme. In the synthesis, a convenient route was developed for the synthesis of 2-substituted 6,7-dichloronaphtho[2,3-d]imidazoles involving a Diels-Alder reaction of 4,5-dichloro-o-quinodimethane (8) as the key step. 6,7-Dichloro-1,4-dihydro-2,3-benzoxathiin 3-oxide (15) was found to be an ideal precursor for the generation of the elusive intermediate 8. The ribosylation of 6,7-dichloronaphtho[2,3-d]imidazoles was influenced by the functional group at the 2-position and 6,7-dichloro-2-methylthionaphtho[2,3-d]imidazole (3c) was found to smoothly undergo ribosylation. The 2-methylthio group of the unprotected nucleoside 25 was converted into a chloro group under mild conditions to give nucleoside 2 in high yield.

Full text of DOI:10.1021/jo971152o

J . Org. Chem. 1998, 63, 977-983
977
Syn th esis of
2,6,7-Tr ich lor o-1-(â-D-r ibofu r a n osyl)n a p h th o[2,3-d ]im id a zole: A
Lin ea r Dim en sion a l An a logu e of th e An tivir a l Agen t TCRB
Zhijian Zhu, J ohn C. Drach, and Leroy B. Townsend*
Department of Chemistry, College of Literature, Sciences, and Arts, and Department of Medicinal
Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109-1065
Received J une 25, 1997X
Human cytomegalovirus (HCMV) remains a significant clinical problem in neonates and immu-
nocompromised individuals such as those undergoing transplantation as well as individuals with
acquired immune deficiency syndrome (AIDS). Recently in our laboratory, 2,5,6-trichloro-1-(â-D-
ribofuranosyl)benzimidazole (TCRB, 1a ) and 2-bromo-5,6-dichloro-1-(â-D-ribofuranosyl)benzimida-
zole (BDCRB, 1b) were found to have better activities in cell culture studies against HCMV than
the clinically used agents ganciclovir and foscarnet. These benzimidazole compounds appear to
act by a unique mechanism. However, as the biological target of TCRB and BDCRB has not been
completely identified, 2,6,7-trichloro-1-(â-D-ribofuranosyl)naphtho[2,3-d]imidazole (2) was designed
as a linear dimensional analogue of TCRB for a study on the spatial limitation of the binding site
in the target enzyme. In the synthesis, a convenient route was developed for the synthesis of
2-substituted 6,7-dichloronaphtho[2,3-d]imidazoles involving a Diels-Alder reaction of 4,5-dichloro-
o-quinodimethane (8) as the key step. 6,7-Dichloro-1,4-dihydro-2,3-benzoxathiin 3-oxide (15) was
found to be an ideal precursor for the generation of the elusive intermediate 8. The ribosylation
of 6,7-dichloronaphtho[2,3-d]imidazoles was influenced by the functional group at the 2-position
and 6,7-dichloro-2-methylthionaphtho[2,3-d]imidazole (3c) was found to smoothly undergo ribosy-
lation. The 2-methylthio group of the unprotected nucleoside 25 was converted into a chloro group
under mild conditions to give nucleoside 2 in high yield.
In tr od u ction
Recently in our laboratory, a series of polyhalogenated
benzimidazole ribonucleosides were found to have potent
activity and high selectivity against human cytomega-
lovirus (HCMV).9 The lead compounds, 2,5,6-trichloro-
1-(â-D-ribofuranosyl)benzimidazole (TCRB, 1a , Figure 1)
and 2-bromo-5,6-dichloro-1-(â-D-ribofuranosyl)benzimi-
dazole (BDCRB, 1b) were more active and less toxic than
ganciclovir and foscarnet in the cell culture studies.
Furthermore, both compounds appear to act by a unique
mechanism that does not involve the inhibition of DNA
synthesis but does involve the inhibition of DNA process-
ing.10
Human cytomegalovirus (HCMV) is a human herpes
virus that has a high order of genome sequence complex-
ity and a narrow host range.1 Although HCMV is
innocuous in the immunocompetent individual, it is a
significant pathogen in neonates and immunocompro-
mised individuals2 such as bone marrow3 and organ
transplant4 patients as well as individuals with acquired
immune deficiency syndrome (AIDS).5 Ganciclovir, fos-
carnet, and cidofovir are the only FDA approved drugs
for the treatment of HCMV infections. However, all of
them have exhibited poor bioavailability and undesirable
side effects.6 For ganciclovir and foscarnet, resistant
virus strains are also emerging.7 Moreover, coadminis-
tration of ganciclovir and AZT in AIDS patients was
found to cause synergistic toxicity.8 Consequently, there
is a need for better, more potent, and selective antiviral
drugs to treat HCMV infections.
(8) (a) Millar, A. R.; Millar, R. F.; Patou, G.; Mindel, A.; Marsh, R.;
Semple, S. J . G. Genitourin. Med. 1990, 66, 156-158. (b) Prichard, M.
M.; Prichard, L. E.; Baguley, W. A.; Nassiri, M. R.; Shipman, C., J r.
Antimicrob. Agents Chemther. 1991, 35, 1060-1065.
(9) (a) Townsend, L. B.; Drach, J . C., and co-workers. Presented at
the Fifth Int. Conf. Antiviral Res., Vancouver, BC, 1992, Abstracts 12,
105, 107, 108, 110. (b) Townsend, L. B.; Devivar, R. V.; Turk, S. R.;
Nassiri, M. R.; Drach, J . C. J . Med. Chem. 1995, 38, 4098-4105. (c)
Devivar, R. V.; Kawashima, E.; Revankar, G. R.; Breitenbach, J . M.;
Freske, E. D.; Drach, J . C.; Townsend, L. B. J . Med. Chem. 1994, 37,
2942-2949.
(10) (a) Underwood, M. R.; Biron, K. K.; Hemphill, M. L.; Miller, T.
J .; Stanat, S. C.; Drach, J . C.; Townsend L. B.; Harvey, R. J . The
Benzimidazole Riboside, 2-Bromo-5,6-dichloro-1-â-D-ribofuranosyl Ben-
zimidazole (BDCRB), Prevents Maturation of Concatemeric Viral DNA
in HCMV-Infected Cells. 4th International CMV Conference, Institut
Pasteur, Paris, France, April 1993. (b) Underwood, M. R.; Biron, K.
K.; Hemphill, M. L.; Stanat, S. C.; Dornsife, R. E.; Drach, J . C.;
Townsend L. B.; Edwards, C. A.; Harvey, R. J . High Molecular Weight
HCMV DNA does not Properly Mature in the Presence of 2-Bromo-
5,6-dichloro-1-â-D-ribofuranosylbenzimidazole (BDCRB). Herpesvirus
Workshop, Pittsburgh, PA, J uly 1993. (c) Underwood, M. R.; Stanat,
S. C.; Drach, J . C.; Harvey, R. J .; Biron, K. K. Inhibition of HCMV
DNA Processing by a new class of Anti-HCMV Compounds is Mediated
through the UL89 Gene Product. Herpesvirus Workshop, Vancouver,
B.C., August 1994. (d) Underwood, M. R.; Stanat, S. C.; Townsend, L.
B.; Drach, J . C.; Biron, K. K. Inhibition of HCMV DNA Processing by
a New Class of Anti-HCMV Compounds (Benzimidazole Ribosides) is
Mediated through the UL89 Gene Product. 8th International Confer-
ence on Antiviral Research, Santa Fe, NM, April 1995.
* To whom correspondence should be addressed at the Department
of Medicinal Chemistry.
X Abstract published in Advance ACS Abstracts, December 1, 1997.
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S0022-3263(97)01152-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/03/1998

978 J . Org. Chem., Vol. 63, No. 4, 1998
Zhu et al.
Sch em e 1
Sch em e 2
F igu r e 1.
Structure-activity relationship studies of TCRB and
BDCRB have demonstrated that all of the three halo
groups and the ribosyl moiety are essential for antiviral
activity.11 As the target enzyme that TCRB and BDCRB
inhibit has not been completely identified, we elected to
explore the spatial limitation12 of the binding site of the
target enzyme by relocating the relative positions of the
key structural units of TCRB with certain spacers. As
part of this effort, 2,6,7-trichloro-1-(â-D-ribofuranosyl)-
naphtho[2,3-d]imidazole (2) was designed as a linear
dimensional analogue of TCRB with a benzene ring as
the spacer. This analogue retains the relative positions
of the imidazole and the ribosyl moieties while moving
the o-dichlorobenzene moiety 2.4 Å linearly toward the
periphery.
The synthesis of nucleoside 2 required the synthesis
of a derivative of 6,7-dichloronaphtho[2,3-d]imidazole (3)
with a functional group at the 2-position, e.g., 2-hydroxy
(3a ), 2-amino (3b), or 2-(methylthio) derivative (3c). The
functional group at the 2-position could be converted to
the chloro group at either the heterocycle or the nucleo-
side level. To the best of our knowledge, only a few 6,7-
disubstituted naphtho[2,3-d]imidazoles have been re-
ported.13 Due to the unfavorable substitution pattern,
the naphthalene moieties of all these 6,7-disubstituted
naphtho[2,3-d]imidazoles have been generated either by
stepwise Friedel-Crafts reactions13a or by Diels-Alder
reactions involving o-quinodimethane derivatives.13b,c
However, none of the above routes were ideal for the
preparation of our target compounds. We would now like
to report a new and convenient route for the preparation
of certain 6,7-disubstituted naphth[2,3-d]imidazoles that
are functionalized at the 2-position and their use in the
subsequent synthesis of the nucleoside 2.
Friedel-Crafts reactions14 starting from 4,5-dichlo-
rophthalic anhydride (5) and imidazolin-2-one15 (6)
(Scheme 1). Although, 6 was believed to be an exception
of imidazoles and apparently possesses sufficient activity
toward an electrophile under Friedel-Crafts conditions,16
the Friedel-Crafts reaction of 5 and 6 in the presence of
AlCl3 in nitrobenzene was found to be very sluggish and
afforded a low yield.
We then elected to pursue a route wherein the imida-
zole moiety would be constructed at the final stage of the
synthetic route. It was envisaged that a Diels-Alder
reaction between 4,5-dichloro-o-quinodimethane (8) and
ethyl (E)-3-nitroacrylate17 (9) would provide, after aro-
matization, ethyl 6,7-dichloro-3-nitro-2-naphthoate (7)
with the desired functionalities for a subsequent genera-
tion of the imidazole moiety (Scheme 2).
A variety of precursors have been reported in the
literature for the generation of o-quinodimethanes.18 We
were interested in precursors that are readily available,
amenable for scale-up, and would undergo a transforma-
tion to the corresponding o-quinodimethanes under mild
conditions. Initially, a retrosynthetic approach involving
1-acetoxy-4,5-dichlorobenzocyclobutene (12) was selected
since the electron-donating acetoxy group would facilitate
the thermal ring opening at a temperature slightly above
100 °C.19 1-Acetoxybenzocyclobutene has been prepared
readily through a [2 + 2] cycloaddition reaction from vinyl
(14) (a) Tominaga, Y.; Lee, M. L.; Castle, R. N. J . Heterocycl. Chem.
1981, 18, 967-972. (b) Dozen, Y.; Hatta, M. Bull. Chem. Soc. J pn. 1975,
48, 2842-2847.
(15) (a) Duschinsky, R.; Dolan, L. A. J . Am. Chem. Soc. 1946, 68,
2350-2355. (b) Huines, D. R.; Leonard, N. J .; Wiemer, D. F. J . Org.
Chem. 1982, 47, 478-482.
Resu lts a n d Discu ssion
Our initial approach for the synthesis of 6,7-dichlo-
ronaphtho[2,3-d]imidazol-2-one (3a ) involved sequential
(16) (a) Grimmett, M. R. in Comprehensive Heterocyclic Chemistry;
Katritzky, A., Rees, C., Eds.; Pergamon Press: New York, 1984; Vol.
5, p 402. (b) Schnettler, R. A.; Dage, R. C.; Grisar, J . M. J . Med. Chem.
1982, 25, 1477-1481.
(17) McMurry, J . E.; Musser, J . H. Org. Synth. 1977, 56, 65-68.
(18) Reviews on the generation of o-quinodimethanes: (a) Martin,
N.; Seoane, C.; Hanack, M. Org. Prepr. Proced. Int. 1991, 23, 239-
272. (b) Charlton, J . L.; Alauddin, M. M. Tetrahedron 1987, 43, 2873-
2889. (c) Oppolzer, W. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 5, pp 385-
396. (d) Oppolzer, W. Synthesis 1978, 793-795.
(11) (a) Zou, R.; Ayres, K. R.; Drach, J . C.; Townsend, L. B. J . Med.
Chem. 1996, 39, 3477-3482. (b) Zou, R.; Drach, J . C.; Townsend, L.
B. J . Med. Chem. 1997, 40, 811-818. (c) Zou, R.; Drach, J . C.;
Townsend, L. B. J . Med. Chem. 1997, 40, 802-810.
(12) (a) Leonard, N. J .; Hiremath, S. P. Tetrahedron 1986, 42, 1917-
1961. (b) Leonard, N. J . Acc. Chem. Res. 1982, 15, 128-135.
(13) (a) Renz, P.; Bauer-David, A. J . Z. Naturforsch. B Anorg. Chem.
Org. Chem. Biochem. Biophys. Biol. 1972, 27, 539-544. (b) Moder, K.
P.; Leonard, N. J . J . Am. Chem. Soc. 1982, 104, 2613-2624. (c)
Stevenson, T. M.; Leonard, N. J . J . Org. Chem. 1984, 49, 2158-2164.

Analog of the Antiviral Agent TCRB
J . Org. Chem., Vol. 63, No. 4, 1998 979
Sch em e 3
Sch em e 4a
a
Key: (1) HOCH2SONa‚2H2O, TBAB, DMF, 0 °C to rt quan-
titative; (2) ethyl (E)-3-nitroacrylate, benzene, reflux, 10 h, 71%;
(3) (a) NBS, chloroform, hν, 5 °C, (b) triethylamine, -15 °C to rt,
88% in two steps.
acetate and benzyne generated from anthranilic acid.20
Various reaction conditions21 have been reported for the
use of anthranilic acids in the generation of benzynes.
However, our attempts to prepare 12 from 4,5-dichloro-
anthranilic acid (10) and vinyl acetate (11) gave less than
a 7% yield of 12 (Scheme 3). This failure to obtain 12
was disappointing but not surprising since, as reported
in the literature,21d the generation of benzynes from
anthranilic acids is strongly influenced by the substitu-
ents on the benzene moiety.
F igu r e 2.
for the sulfinates. However, Hoey and Dittmer have
developed25e a convenient one-step synthesis of 1,4-
dihydro-2,3-benzoxathiin 3-oxide, in high yield, from R,R′-
dihalo-o-xylene and rongalite (sodium hydroxymethane-
sulfinate) under mild conditions.26 This method made
the sulfinate approach ideal for the generation of 4,5-
dichloro-o-quinodimethane (8). 6,7-Dichloro-1,4-dihydro-
2,3-benzoxathiin 3-oxide (15) was prepared by the Ditt-
mer method in an essentially quantitative yield from 1,2-
bis(bromomethyl)-4,5-dichlorobenzene24 (14) and rongalite.
When 15 was heated in benzene at reflux in the presence
of ethyl (E)-3-nitroacrylate (9), ethyl 6,7-dichloro-3-nitro-
1,2,3,4-tetrahydro-2-naphthoate (16) was obtained in an
overall 71% yield from 14 (Scheme 4).
Our first attempts to aromatize27a 16 used the conven-
tional Barne’s method27b for tetralin. However, only a
40% yield of ethyl 6,7-dichloro-3-nitro-2-naphthoate (7)
was obtained after bromination of 16 with N-bromosuc-
cinimide (NBS) in the presence of benzoyl peroxide in
carbon tetrachloride at reflux followed by dehydrobro-
mination with potassium acetate. The major side product
was identified as ethyl 6,7-dichloro-2-naphthoate (17)
(Figure 2). Other aromatization methods, e.g., DDQ,27c
trityl trifluoroacetate,27d and bromine in pyridine,27e were
attempted without any major improvement. The nitro
group can undergo base-induced elimination of nitrous
acid if an electron-withdrawing group is present at the
adjacent position.28 However, we found that some 17 was
formed during the free-radical bromination with NBS in
carbon tetrachloride at reflux even before the introduc-
tion of a base. Compound 17 was also generated by NBS
bromination at rt with a tungsten light as the free-radical
initiator. However, by lowering the reaction temperature
This prompted us to reevaluate the other type of
precursors for the generation of 4,5-dichloro-o-quin-
odimethane (8). One of the most attractive methods was
the 1,4-elimination from o-xylene derivatives,18a,b,c such
as fluoride-induced elimination from [o-[(trimethylsilyl)-
methyl]benzyl]trimethylammonium halide22 and deha-
logenation of R,R′-dihalo-o-xylenes by metals.23 However,
these methods either require multistep synthesis of the
precursors or use reagents that would not be compatible
with reducible groups. We then evaluated an alternative
method involving the thermolysis of benzofused het-
erocycles.18a,b 1,3-Dihydro-5,6-dichlorobenzo[c]thiophene
S,S-dioxide (13) has been used24 for the generation of 4,5-
dichloro-o-quinodimethane (8). However, the cheletropic
elimination of sulfur dioxide from this sulfone (13)
required a temperature of 230 °C. In direct contrast to
sulfones (1,3-dihydrobenzo[c]thiophene S,S-dioxides), the
sulfinates25 (or sultines, 1,4-dihydro-2,3-benzoxathiin
3-oxides) undergo cheletropic elimination of sulfur dioxide
smoothly around 80 °C. The formation of o-quin-
odimethanes from sulfinates has not been fully explored,
presumably due to the required multistep synthesis25a,b,c
(19) Durst, T.; Greau, L. in Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 5, pp
691-696.
(20) (a) Wasserman, H. H.; Solodar, J . J . Am. Chem. Soc. 1965, 87,
4002-4003. (b) Bubb, W. A.; Sternhell, S. Aust. J . Chem. 1976, 29,
1685-1697.
(21) (a) Stiles, M.; Miller, R. G.; Burckharclt, U. J . Am. Chem. Soc.
1963, 85, 1792-1797. (b) Friedman, L.; Logullo, F. M. J . Am. Chem.
Soc. 1963, 85, 1549. (c) Logullo, F. M.; Seize, A. H.; Friedman, L. Org.
Synth. 1968, 48, 12-17. (d) Frideman, L.; Logullo, F. M. J . Org. Chem.
1969, 34, 3089-3092. (e) Roberts, R. M.; Gilgert, J . C.; Rodewald, L.
B.; Wingrove. A. S. An introduction to modern experimental organic
chemistry; Holt, Rinehart and Winston, New York, 1969; pp 196-201.
(f) Ardakan, M. A.; Wallace, T. W. Tetrahedron 1988, 44, 5939-5952.
(22) Ito, Y.; Nakatsuka, M.; Saegusa, T. J . Am. Chem. Soc. 1982,
104, 7609-7622.
(26) We were quite surprised to find that this method has not been
used for the generation of other sulfinates, except 1,4-dihydro-2,3-
benzoxathiin 3-oxide, and to some extent has been neglected (see ref
25f).
(27) (a) For a general review on aromatization: Fu, P. P.; Harvey,
R. G. Chem. Rev. 1978, 78, 317-360. (b) Barnes, R. A. J . Am. Chem.
Soc. 1948, 70, 145-147. (c) Braude, E. A.; Brook, A. G.; Linstead, R.
P. J . Chem. Soc. 1954, 3, 569-573. (d) Fu, P. P.; Harvey, R. G.
Tetrahedron Lett. 1974, 36, 3217-3220. (e) Martin, N.; Bechard, R.;
Hanack, M. J . Org. Chem. 1984, 54, 2563-2568.
(28) Ono, N. The nitro function as a leaving group in organic
synthesis. In Nitro Compounds, Recent Advances in Synthesis and
Chemistry; Feuer, H., Nieken, A. T., Eds.; VCH Publisher: New York,
1990; pp 1-127.
(23) (a) Han, B. H.; Boudjouk, P. J . Org. Chem. 1982, 47, 751-752.
(b) Rubottom, G. M.; Wey, J . E. Synth. Commun. 1984, 14, 507-513.
(c) Inaba, S.; Wehmeyer, R. M.; Forker, M. W.; Reike, R. D. J . Org.
Chem. 1988, 53, 339-344.
(24) Levy, L. Synth. Commun. 1983, 13, 639-648.
(25) (a) J ung, F.; Molin, M.; Van Den Elzen, R.; Durst, T. J . Am.
Chem. Soc. 1974, 96, 935-936. (b) Charlton, J . L.; Durst, T. Tetrahe-
dron Lett. 1984, 25, 5287-5290. (c) Durst, T.; Charlton, J . L. Can. J .
Chem. 1986, 64, 246-249. (d) Harpp, D. N.; Steliou, K.; Chan, T. H.
J . Am. Chem. Soc. 1978, 100, 1222-1228. (e) Hoey, M. D.; Dittmer,
D. C. J . Org. Chem. 1991, 56, 1947-1948. (f) Attardo, G.; Wang, W.;
Kraus, J .-L.; Belleau, B. Tetrahedron Lett. 1994, 35, 4743-4746.

980 J . Org. Chem., Vol. 63, No. 4, 1998
Zhu et al.
Sch em e 5a
Sch em e 6a
a
Key: (1) SnCl2, EtOH, EtOAc, 70 °C, quantitative; (2) NaOH,
EtOH, 94%; (3) (PhO)2PON3, Et3N, benzene, reflux. Overall 80%
yield in three steps.
a
(a) NaOH, EtOH, rt, quantitative; (2) (a) (PhO)2PON3, Et3N,
DMF, rt, (b) H2O, 100 °C, 99%; (3) Pd/C, H2; (4) CNBr, MeOH,
H2O, rt, quantitative from 21.
to 4 °C during the NBS bromination with tungsten light,
a clean reaction was obtained to give, after dehydrobro-
mination at -15 °C with triethylamine, compound 7 in
an 88% yield.
Starting from 7, 6,7-dichloronaphtho[2,3-d]imidazol-
2-one (3a ) was prepared in three steps (Scheme 5). A
stannous chloride reduction of the nitro group was
followed by a hydrolysis of the ester group with 10%
sodium hydroxide to give 2-amino-6,7-dichloro-2-naph-
thoic acid (19). The order of reduction and hydrolysis
was found to be important since the reverse order
resulted in some difficulties during workup. The treat-
ment of 19 with diphenyl phosphorazidate in benzene at
reflux effected a Curtius rearrangement that was fol-
lowed by a subsequent intramolecular ring closure to give
3a in an 80% yield.
F igu r e 3. NOE of compound 25. The experiment was carried
out in DMSO-d6 at room temperature.
fusion method,35b and phase-transfer method33 were
unsuccessful. Ribosylation by the sodium salt method30
with 2,3,5-tri-O-benzyl-D-ribofuranosyl chloride34 gave a
mixture of R- and â-anomers with the R-anomer as the
major product.
Our attempts to convert 3a to 2,6,7-trichloronaphtho-
[2,3-d]imidazole (3d ) by the use of phosphorus oxychlo-
ride in the presence of N,N-dimethylaniline at reflux were
found to be unsuccessful. Furthermore, ribosylations of
3a by the Vorbruggen method29 with 1-O-acetyl-2,3,5-tri-
O-benzoyl-â-D-ribofuranose (TBAR) as well as the sodium
salt method30 with 2,3,5-tri-O-acetyl-â-D-ribofuranosyl
chloride31 were unsuccessful.
The ribosylation of some 2-substituted naphtho[2,3-d]-
imidazoles, e.g., the 2-methyl, 2-(trifluoromethyl), and
2-(methylthio) derivatives, have been reported.35 After
the unsuccessful ribosylation of both 3a and 3b, we
prepared 6,7-dichloro-2-(methylthio)naphtho[2,3-d]imi-
dazole (3c). The preparation of 3c started with the ring
closure of the diamine 22 by using (thiocarbonyl)-
diimidazole followed by an alkylation with methyl iodide.
In sharp contrast to the results for compound 3a and 3b,
the silylated 3c underwent ribosylation under Vor-
bruggen conditions with TBAR in the presence of tri-
methylsilyl (trifluoromethyl)sulfonate (TMSOTf) to give
6,7-dichloro-2-(methylthio)-1-(2,3,5-tri-O-benzoyl-â-D-ri-
bofuranosyl)naphtho[2,3-d]imidazole (24) in a 97% yield.
A removal of the benzoyl groups with methanolic am-
monia gave 6,7-dichloro-2-(methylthio)-1-(â-D-ribofura-
nosyl)naphtho[2,3-d]imidazole (25) in 96% yield. The
â-configuration of 25 was established by NOE experi-
ments as shown in Figure 3.
We assumed that the 2-oxo group might be the cause
of the unsuccessful ribosylations.32 In an effort to
overcome this problem, 2-amino-6,7-dichloronaphtho[2,3-
d]imidazole (3b) was prepared in four steps (Scheme 6).
Compound 7 was first converted to 2-amino-6,7-dichloro-
3-nitronaphthalene (21) in an overall 99% yield by the
hydrolysis of the ester with 10% NaOH followed by a
Curtius rearrangement using diphenylphosphorazidate.
Compound 21 was then reduced to the corresponding
diamine (22) by hydrogenation followed by ring-closure
using cyanogen bromide to give 3b in quantitative yield.
However, the ribosylation of 3b was also found to be
troublesome. Ribosylations by the Vorbruggen method,29
The direct transformation of a thio or methylthio group
to a chloro group on unprotected nucleosides has proven
to be an efficient and facile method for the generation of
chloro-substituted nucleosides.36 This appears to be an
ideal way to prepare 2 from 25. However, the naphtha-
lene moiety of 25 could be vulnerable to chlorination
under the literature reaction conditions where chlorine
(29) Vorbruggen method: (a) Vorbruggen, H.; Krolikiewicz, K.;
Bennua, B. Chem. Ber. 1981 114, 1234-1255. (b) Vorbruggen, H.;
Bennua, B. Chem. Ber. 1981, 114, 1279-1286. (c) Dudycz, L.; Wright,
G. E. Nucleosides Nucleotides 1984, 3, 33-44.
(30) Revankar, G. R.; Robins, R. K. Nucleosides and Nucleotides
1989, 8, 709-724.
(31) Earl, R. A.; Townsend, L. B. In Nucleic Acid Chemistry,
Improved and New Synthetic Procedures, Methods and Techniques;
Wiley Interscience: New York, N.Y., 1991, Townsend, L. B., Tipson,
R. S., Eds.; Part 1, pp 203-205.
(32) However, successful examples of ribosylation of 2-oxo deriva-
tives in benzimidazole, imidazo[4,5-b]quinoline, and imidazo[4, 5-b]-
quinoxaline systems have been observed. (a) Reference 9b. (b) Zhu,
Z.; Townsend, L. B. Unpublished results.
(33) Seela, F.; Bussmann, W. Nucleosides Nucleotides 1982, 1, 253-
261.
(34) Mead, E. A.; Wotring, L. L.; Drach, J . C.; Townsend, L. B. J .
Med. Chem. 1993, 36, 3834-3842.
(35) (a) Hijazi, A.; Pfleiderer, W. Nucleosides Nucleotides 1984, 13,
293-295. (b) Hijazi, A. Nucleosides Nucleotides 1986, 5, 529-537. (c)
Hijazi, A. Nucleosides Nucleotides 1988, 7, 537-547.

Analog of the Antiviral Agent TCRB
J . Org. Chem., Vol. 63, No. 4, 1998 981
Sch em e 7a
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points were taken on a
Thomas-Hoover apparatus and are uncorrected. Silica gel 60
230-400 mesh (E. Merck, Darmstadt, West Germany) was
used for chromatography. Thin layer chromatography (TLC)
was performed on prescored SilicAR 7GF plates (Analtech,
Newark, DE). Compounds were visualized by illumination
under UV light (254 nm). Evaporations were carried out under
reduced pressure (water aspirator) with the bath temperature
below 40 °C, unless specified otherwise. IR spectra were
obtained on a Nicolet 5DXB FT-IR spectrophotometer. UV
spectra were performed on a Hewlett-Packard 8450-A UV/vis
spectrophotometer. Nuclear magnetic resonance (NMR) spec-
tra were determined at 360 MHz with a Bruker WP 360 SY.
The chemical shift values are expressed in δ values (parts per
million) relative to the standard chemical shift of TMS or the
solvent used. Elemental analyses were performed by M-H-W
Laboratories, Phoenix, AZ.
a
Key: (1) (thiocarbonyl)diimidazole, benzene, reflux, 80%; (2)
6,7-Dich lor o-1,4-dih ydr o-2,3-ben zoxath iin 3-Oxide (15).
Sodium hydroxymethanesulfinate dihydrate (16.4 g, 106.4
mmol) was added in one portion to a solution of 4,5-dichloro-
1,2-bis(bromomethyl)benzene24 (14, 17.2 g, 53.2 mmol) and
tetrabutylammonium bromide (3.43 g, 10.6 mmol) in dry DMF
(110 mL) in an ice bath. The suspension was stirred for 7 h
in an ice bath and an additional 7 h at rt. The almost clear
solution was then poured into a 1000 mL separatory funnel,
and water (200 mL) was added to give a white suspension.
The white suspension was shaken gently and then extracted
with ether (400 mL and then 2 × 200 mL). The ether extracts
were combined, washed with water (3 × 100 mL), and dried
over anhydrous MgSO4. This slightly cloudy ether solution
was filtered to give a clear ether solution. The solvent was
evaporated, and the solid was dried under vacuum by an oil
pump at rt to give 6,7-dichloro-1,4-dihydro-2,3-benzoxathiin
3-oxide (15, 13.1 g, quantitative, contained 10% of DMF as
shown by 1H NMR) as a white powder. This sample was used
directly for the next step without further purification. A small
sample was recrystallized from ethyl acetate and hexane for
analysis: 1H NMR (DMSO-d6) δ 7.70 (s, 1H), 7.66 (s, 1H), 5.16
(d, J ) 14.1 Hz, 1H), 5.07 (d, J ) 14 Hz, 1H), 4.51 (d, J ) 15.4
Hz, 1H), 3.83 (d, J ) 15.5 Hz, 1H); 13C NMR (DMSO-d6) δ
134.5, 131.7, 130.6, 129.9, 127.8, 127.7, 62.1, 54.3. Anal. Calcd
for C8H6O2SCl2: C, 40.51; H, 2.53. Found: C, 40.72; H, 2.70.
Eth yl 6,7-Dich lor o-3-n itr o-1,2,3,4-tetr a h yd r o-2-n a p h -
th oa te (16). A solution of 6,7-dichloro-1,4-dihydro-2,3-ben-
zoxathiin 3-oxide (15, 11 g, 45.3 mmol) and ethyl (E)-3-
nitroacrylate (12.5 g, 86.2 mmol) in dry benzene (130 mL) was
heated at reflux for 14 h. The solvent was removed under
reduced pressure to give a brown solid that was recrystallized
from methanol to give ethyl 6,7-dichloro-3-nitro-1,2,3,4-tet-
rahydro-2-naphthoate (16, 10.42 g, 71%) as white needles: mp
124-125 °C; 1H NMR (DMSO-d6) δ 7.51 (s, 2H), 5.32 (m, 1H),
4.15 (q, J ) 7.1 Hz, 2H), 3.53-3.43 (m, 2H), 3.33-3.15 (m,
DMF, MeI, 81%; (3) (a) BSA, ClCH2CH2Cl, rt, (b) TBAR, TMSOTf,
50 °C, 97%; (4) NH3, MeOH, 96%; (5) Cl2, MeOH, -78 °C, 82%.
gas was bubbled into a methanol solution at -10 °C.
Indeed, when chlorine gas was bubbled into a solution
of 25 in methanol at -10 °C, a complex reaction mixture
was obtained with apparent overchlorination occurring
on the naphthalene moiety. In an effort to avoid over-
chlorination of the naphthalene moiety, we elected to use
a stoichiometric quantity of chlorine gas. A solution of
chlorine in carbon tetrachloride was first prepared, and
the concentration of chlorine was calculated through the
weight increase. When approximately 1 equiv of this
chlorine solution was added to a solution of 25 at -78
°C, a clean reaction was obtained and gave an 82% yield
of 2,6,7-trichloro-1-(â-D-ribofuranosyl)naphtho[2,3-d]imi-
dazole (2) with a recovery (12%) of starting material 25
(Scheme 7).
In conclusion, we have developed an efficient and
convenient route for the synthesis of 2-substituted 6,7-
dichloronaphtho[2,3-d]imidazoles. 6,7-Dichloro-1,4-dihy-
dro-2,3-benzoxathiin 3-oxide (15) was found to be an ideal
precursor for the generation of the corresponding o-
quinodimethane. This o-quinodimethane was then used
in a Diels-Alder reaction for a construction of the
naphthalene moiety of 6,7-dichloronaphtho[2,3-d]imida-
zoles. The ribosylation of 6,7-dichloronaphtho[2,3-d]-
imidazoles was found to be dependent on the substituent
at the 2-position, and the 2-methylthio derivative was
found to undergo the ribosylation smoothly. Mild reac-
tion conditions for the preparation of 2 from 25 was
developed in which 1 equiv of chlorine at -78 °C was
used. The extremely mild reaction conditions for the
transformation of a methylthio group to a chloro group
on an unprotected nucleoside should increase the useful-
ness of this method.
2H), 2.94 (dd, J ) 11, 17 Hz, 1H), 1.20 (t, J ) 7.1 Hz, 3H); 13
C
NMR (DMSO-d6) δ 171.4, 134.4, 133.4, 130.1, 129.9, 128.9,
128.7, 81.8, 61.1, 42, 31.9, 29.29, 13.9. Anal. Calcd for
C
13H13NO4Cl2: C, 49.06; H, 4.09; N, 4.40. Found: C, 48.89;
H, 3.97; N, 4.39.
Eth yl 6,7-Dich lor o-3-n itr o-2-n a p h th oa te (7). Ethyl 6,7-
dichloro-3-nitro-1,2,3,4-tetrahydro-2-naphthoate (16, 2 g, 6.29
mmol), NBS (3.36 g, 18.78 mmol), and dry chloroform (120 mL)
were stirred in a photoreaction flask with an exterior cooling
jacket under an atmosphere of argon. The suspension was
irradiated, with stirring, by a 60 W tungsten light 1 ft away
from the reaction flask for 36 h. The cooling jacket was cooled
by ice-water throughout the reaction. The orange reaction
suspension was transferred to a round-bottom flask under an
atmosphere of argon and immediately cooled to -15 °C.
Triethylamine (2.62 mL, 18.78 mmol) was then added drop-
wise, and the solution was continuously stirred while the
temperature was maintained under -15 °C for 3 h and then
at rt for about 12 h. The solvent was removed (first by a water
aspirator followed by oil pump at 0.05 mmHg), and the residue
was subjected to silica gel chromatography (5 × 10 cm) with
Antiviral evaluation revealed that compound 2 was less
active against HCMV than TCRB9b in plaque (IC50 ) 16
µM) and yield (IC90 9 µM) reduction assays and was more
cytotoxic (IC50’s ) 8-16 µM). This loss of specific
antiviral activity by the spatial change in the molecule
is surprising and now is under further investigation in
our laboratory.
(36) (a) Robins, R. K. J . Am. Chem. Soc. 1960 82, 2654-2655. (b)
Gerster, J . F.; J ones, J . W.; Robins, R. K. J . Org. Chem. 1963, 28, 945-
948. (c) Rousseau, R. J .; Robins, R. K.; Townsend, L. B. J . Am. Chem.
Soc. 1968, 90, 2661-2668. (d) Giner-Sorolla, A.; Nanos, C.; Burchenal,
J . H.; Dollinger, M.; Bendich, A. J . Med. Chem. 1968, 11, 52-54.

982 J . Org. Chem., Vol. 63, No. 4, 1998
Zhu et al.
elution by dichloromethane. The appropriate fractions were
collected, and the solvents were evaporated to give ethyl 6,7-
dichloro-3-nitro-2-naphthoate (7, 1.73 g, 88%) as a yellow
(bs, 2H), 8.18 (s, 2H), 7.37 (s, 2H); 13C NMR (DMSO-d6) δ 156,
132, 128.5, 127.8, 125.3, 102.8; UV [λmax nm (ꢀ)] (MeOH) 340.6
(10 800), 325.2 (6180), 246.8 (80 500). Anal. Calcd for
C11H6N2OCl2: C, 52.17; H, 2.37; N, 11.07. Found: C, 52.16;
H, 2.68; N, 11.18.
1
solid: mp 121-123 °C; H NMR (CDCl3) δ 8.33 (s, 1H), 8.17
(s, 1H), 8.12 (s, 1H), 8.10 (s, 1H), 4.44 (q, J ) 7.13 Hz, 2H),
1.39 (t, J ) 7.18 Hz, 3H); 13C NMR (CDCl3) δ 164.7, 146.5,
135.1, 134.8, 132.4, 130.3, 129.9, 129.6, 125.5, 123.9, 62.7, 13.9.
Anal. Calcd for C13H9NO4Cl2: C, 49.68; H, 2.87; N, 4.46.
Found: C, 49.47; H, 2.80; N, 4.24.
6,7-Dich lor o-3-n itr o-2-n a p h th oic Acid (20). A 10% so-
dium hydroxide solution (4.5 mL) was added dropwise to a
suspension of ethyl 6,7-dichloro-3-nitro-2-naphthoate (7, 1.73
g, 5.52 mmol) in ethanol (36 mL). The mixture was stirred at
rt for 6 h to give a yellow suspension, at which time TLC
showed the absence of starting material. A hydrogen chloride
solution (5 N) was added until the solution was completely
acidic. The ethanol was removed under reduced pressure, and
the residue was stirred in water (50 mL) at rt for 1 h. The
solid was collected by filtration, washed with water, and dried
under vacuum at 78 °C to give 6,7-dichloro-3-nitro-2-naphthoic
acid (20, 1.58 g, quantitative) as a yellow solid. A small sample
was recrystallized from a mixture of ethanol and acetonitrile
for analysis: mp dec above 280 °C; 1H NMR (DMSO-d6) δ 14.0
(bs, 1H), 8.70 (s, 1H), 8.62 (s, 1H), 8.58 (s, 1H), 8.54 (s, 1H);
13C NMR (DMSO-d6) δ 165.6, 146.5, 132.8, 132.6, 132.4, 131.7,
130.6, 130.4, 130.2, 125.4, 123.8. Anal. Calcd for C11H5NO4-
Cl2: C, 46.15; H, 1.75; N, 4.90. Found: C, 46.01; H, 2.07; N,
4.57.
2-Am in o-6,7-d ich lor o-3-n itr on a p h th a len e (21). Diphe-
nyl phosphorazidate (1.78 mL, 8.28 mmol) was added to a
solution of 6,7-dichloro-3-nitro-2-naphthoate (20, 1.58 g, 5.52
mmol) and triethylamine (4.5 mL, 8.28 mmol) in dry DMF (40
mL). After the mixture was stirred at 25 °C for 3 h, water
(3.5 mL) was added to the solution, and the solution was then
heated at 100 °C for 1 h. The solution was concentrated under
reduced pressure and diluted with ethyl acetate (300 mL). The
ethyl acetate solution was washed sequentially with water (3
× 100 mL), and a saturated sodium chloride solution (50 mL)
and then dried over anhydrous sodium sulfate. The ethyl
acetate was removed by evaporation and the solid was dried
under vacuum at rt to give 2-amino-6,7-dichloro-3-nitronaph-
thlene (21, 1.4 g, 99%) as a red solid that was directly used in
the next step with out further purification: 1H NMR (DMSO-
d6) δ 8.77 (s, 1H), 8.25 (s, 1H), 7.98 (s, 1H), 7.24 (s, 1H), 7.00
(bs, 2H); 13C NMR (DMSO-d6) δ 142.3, 136.2, 135.1, 132.6,
130.5, 126.5, 126.2, 125, 122.8, 110.9.
Eth yl 6,7-Dich lor o-2-n a p h th oa te (17). When the aro-
matization reaction of ethyl 6,7-dichloro-3-nitro-1,2,3,4-tet-
rahydro-2-naphthoate (16) with NBS was carried out in the
presence of benzoyl peroxide (BPO) in CCl4 at reflux or at rt
under the irradiation of a tungsten light, ethyl 6,7-dichloro-
2-naphthoate (17) was formed as a side product. After
purification by silica gel chromatography with elution by
hexane/ethyl acetate (10/0.4, v/v), a solid was obtained. The
solid was recrystallized from hexane to give colorless needle
crystals: 1H NMR (CDCl3) δ 8.50 (m, 1H), 8.09 (dd, J ) 8.6,
1.6 Hz, 1H), 8.06 (s, 1H), 7.99 (s, 1H), 7.79 (d, J ) 8.7 Hz,
1H), 4.45 (q, J ) 7.1 Hz, 2H), 1.45 (t, J ) 7.1 Hz, 3H); 13C
NMR (CDCl3) δ 166.1, 134.2, 132.7, 131.4, 131.1, 130, 129.7,
129, 128.7, 127.1, 126.6, 61.4, 14.3. Anal. Calcd for
C
13H10O2Cl2‚0.25H2O: C, 57.08; H, 3.84. Found: C, 57.25; H,
4.09.
Eth yl 3-Am in o-6,7-d ich lor o-2-n a p h th oa te (18). Ethyl
6,7-dichloro-3-nitro-2-naphthoate (7, 1,14 g, 3.63 mmol) was
dissolved in a mixture of ethanol (16 mL) and ethyl acetate
(16 mL). Tin(II) chloride (3.44 g, 18.2 mmol) was added, and
the yellow solution was stirred for 30 min at 70 °C under an
atmosphere of argon. After being cooled to rt, the reaction
solution was poured into 100 mL of ice-water and neutralized
by the addition of sodium bicarbonate (solid). The yellow
suspension was then extracted with ethyl acetate (3 × 100
mL), and the combined ethyl acetate extracts were washed
with a saturated sodium chloride solution and dried over
anhydrous sodium sulfate. The solvent was evaporated to give
ethyl 3-amino-6,7-dichloro-2-naphthoate (18, 1.04 g, quantita-
tive) as a yellow solid. Without further purification, this solid
was used for the next step: 1H NMR (DMSO-d6) δ 8.46 (s, 1H),
8.16 (s, 1H), 7.89 (s, 1H), 7.01 (s, 1H), 6.67 (bs, 2H), 4.35 (q, J
) 7.04 Hz, 2H), 1.36 (t, J ) 7.07 Hz, 3H).
3-Am in o-6,7-d ich lor o-2-n a p h th oic Acid (19). A 10%
sodium hydroxide solution (2.5 mL) was added dropwise to a
mixture of ethyl 3-amino-6,7-dichloro-2-naphthoate (18, 1.04
g, 3.63 mmol) in ethanol (55 mL) under an atmosphere of
argon. The mixture was stirred at rt for 12 h to give a dark
brown solution, at which time TLC showed the absence of
starting material. A hydrogen chloride solution (5 N) was
added through a syringe until the solution became acidic (as
indicated by the change of the color from dark brown to yellow).
The ethanol was removed under reduced pressure, and the
residue was stirred in water (60 mL) while the pH was
adjusted to approximately 6 by the addition of sodium bicar-
bonate. The solid was collected by filtration, washed with
water, and dried under vacuum at rt to give 3-amino-6,7-
dichloro-2-naphthoic acid (19, 0.874 g, 94%) as a yellow solid.
Without further purification, this solid was used for the next
2,3-Dia m in o-6,7-d ich lor on a p h th a len e (22). 2-Amino-
6,7-dichloro-3-nitronaphthalene (21, 1.11 g, 4.3 mmol), Raney
nickel (0.1 g), ethyl acetate (80 mL) and ethanol (30 mL) were
placed in a Parr hydrogenation apparatus under hydrogen (40
psi) for 15 h to give a yellow suspension. Acetone (50 mL)
was added to the suspension, and a clear brown solution was
obtained. The Raney nickel was removed by filtration through
a bed of Celite. The filtrate was evaporated under reduced
pressure, and the solid was dried under vacuum by an oil
pump at rt to give 2,3-diamino-6,7-dichloronaphthalene (22,
0.97 g, quantitative) as a brown solid that was used directly
in the next step without further purification: 1H NMR (DMSO-
d6) δ 7.61 (s, 2H), 6.77 (s, 2H), 5.3 (bs, 4H); 13C NMR (DMSO-
d6) δ 138.8, 127.7, 125.1, 122.7, 105.3. 2,3-Dia m in o-6,7-
d ich lor on a p h th a len e w a s fou n d to u n d er go oxid a tion
ver y ea sily, a n d sid e p r od u cts w er e gen er a ted a fter
exp osu r e to a ir for a sh or t p er iod of tim e.
1
step: mp dec above 280 °C; H NMR (DMSO-d6) δ 8.85 (bs,
2H), 8.46 (s, 1H), 8.14 (s, 1H), 7.87 (s, 1H), 6.97 (s, 1H); 13C
NMR (DMSO-d6) δ 168.8, 148.3, 135.9, 132.5, 131, 130.2, 125.7,
123.6, 123.3, 115.7, 107.4. Anal. Calcd for C11H7NO4Cl2: C,
51.56; H, 2.73; N, 5.47. Found: C, 51.64; H, 3.00; N, 5.33.
6,7-Dich lor on a p h th o[2,3-d ]im id a zol-2-on e (3a ). Tri-
ethylamine (0.85 mL, 6.0 mmol) was added to a suspension of
3-amino-6,7-dichloro-2-naphthoic acid (19, 0.78 g, 3.05 mmol)
in dry benzene (90 mL), and the mixture was stirred until a
clear brown solution was obtained. Diphenyl phosphorazidate
(1.31 mL, 6.1 mmol) was added, and the solution was heated
at reflux for 3 h to give a yellow suspension. The reaction
was cooled to rt, and the solid was collected by filtration,
washed with benzene and dried under vacuum to give 6,7-
dichloronaphtho[2,3-d]imidazol-2-one (3a , 0.615 g, 80%) as a
yellow solid. A small sample was recrystallized from DMF and
acetonitrile: mp above 340 °C, 1H NMR (DMSO-d6) δ 11.02
2-Am in o-6,7-dich lor on aph th o[2,3-d]im idazole (3b). 2,3-
Diamino-6,7-dichloronaphthalene (22, 0.97 g, 4.27 mmol) was
suspended in freshly distilled THF (10 mL), and then methanol
(25 mL) and water (25 mL) were added sequentially. Cyano-
gen bromide (0.94 mL, 4.7 mmol) was added dropwise to this
suspension over a period of 15 min. The mixture was stirred
at rt for 36 h, and an additional amount of cyanogen bromide
(0.3 mL, 1.5 mmol) was then added. The reaction mixture was
stirred at rt for an additional 2 d. Another portion of cyanogen
bromide (0.03 mL, 0.15 mmol) was added, and the reaction
mixture was stirred continuously for an additional day to give
an almost clear solution. TLC showed that the reaction was
complete, and the insoluble solid was removed by filtration.
The orange filtrate was concentrated under reduced pressure
to about 20 mL and diluted with water (50 mL) to give an
orange suspension. The orange suspension was neutralized

Analog of the Antiviral Agent TCRB
J . Org. Chem., Vol. 63, No. 4, 1998 983
by the addition of a saturated sodium bicarbonate solution to
give a yellow suspension. The solid was collected by filtration,
washed with water, and then dried under vacuum at 78 °C to
give 2-amino-6,7-dichloronaphtho[2,3-d]imidazole (3b, 1.08 g,
quantitative) as a slightly brown solid: mp dec above 250 °C;
1H NMR (DMSO-d6) δ 12.90 (bs, 1H), 9.10 (bs, 2H), 8.36 (s,
2H), 7.84 (s, 2H); 13C NMR (DMSO-d6) δ 152.9, 131.2, 128.7,
128.2, 126.6, 106.4; UV [λmax nm (ꢀ)] (MeOH) 345.6 (8560),
338.2 (7920), 255.2 (59 300), 230.2 (27 300). Anal. Calcd for
δ 8.31-6.92 (m, 19H), 6.46 (d, J ) 7.36 Hz, 1H), 6.19-6.10
(m, 2H), 5.00 (q, J ) 12.4, 2.0 Hz), 4.85 (q, J ) 12.4, 2.9 Hz),
4.77 (m, 1H), 2.83 (s, 3H). Anal. Calcd for C38H28N2O7SCl2:
C, 62.72; H, 3.85; N, 3.85. Found: C, 62.80; H, 3.67; N, 3.74.
6,7-Dich lor o-2-(m eth ylth io)-1-(â-D-r ibofu r a n osyl)n a p h -
t h o[2,3-d ]im id a zole (25). 6,7-Dichloro-2-(methylthio)-1-
(2,3,5-tri-O-benzoyl-â-D-ribofuranosyl)naphtho[2,3-d]imida-
zole (24, 0.32 g) was added to saturated methanolic ammonia
(140 mL) and stirred at rt for 24 h. The solvent was
evaporated, and the solid was triturated with hexane (3 × 50
mL). The hexane was decanted, and the solid was dried under
0.01 mmHg/78 °C for 24 h to give 6,7-dichloro-2-(methylthio)-
1-(â-D-ribofuranosyl)naphtho[2,3-d]imidazole (25, 0.173 g, 96.3%)
as a brown solid. A small sample was recrystallized from
2-propanol for analysis: mp 244-246 °C; 1H NMR (DMSO-
d6) δ 8.38 (s, 1H), 8.33 (s, 1H), 8.23 (s, 1H), 8.12 (s, 1H), 5.76
(d, J ) 7.46 Hz, 1H), 5.46 (d, J ) 6.29 Hz, 1H), 5.34 (m, 1H),
5.27 (d, J ) 4.31 Hz, 1H), 4.62 (q, J ) 6.57, 6.23 Hz, 1H), 4.18
(m, 1H), 4.01 (m, 1H), 3.78 (m, 2H); 13C NMR (DMSO-d6) δ
159.5, 144.5, 135.6, 128.8, 128.6, 128.5, 128.2, 126.2, 125.8,
113.2, 107.6, 88.9, 85.8, 70.6, 70, 61.5, 14.5; UV [λmax nm (ꢀ)]
(MeOH) 347.0 (18 100), 330.5 (14 900), 269.0 (75 000), 262.5
(71 100), 237.0 (40 300). Anal. Calcd for C17H16N2O4SCl2: C,
49.16; H, 3.86; N, 6.75. Found: C, 49.17; H, 4.04; N, 6.66.
C
11H7N3Cl2: C, 52.38; H, 2.78; N, 16.67. Found: C, 52.16; H,
2.91; N, 16.51.
6,7-Dich lor on a p h th o[2,3-d ]im id a zol-2-th ion e (23). 2,3-
Diamino-6,7-dichloronaphthalene (22, 1.3 g, 5.7 mmol) and
(thiocarbonyl)diimidazole (1.23 g, 6.9 mmol) were heated for
8 h in dry benzene at reflux under an atmosphere of argon.
The orange suspension was cooled to rt and allowed to stand
at 5 °C overnight. The yellow solid was collected by filtration
and washed with benzene. The crude solid product was stirred
in 70 mL of water for 2 h, collected by filtration, washed with
water and then dried under vacuum over P2O5 at 78 °C to give
6,7-dichloronaphtho[2,3-d]imidazol-2-thione (23, 1.23 g, 80%)
as a brown solid: mp above 320 °C; 1H NMR (DMSO-d6) δ
12.80 (bs, 2H), 8.31 (s, 2H), 7.26 (s, 2H); 13C NMR (DMSO-d6)
δ 172.8, 133.9, 128.9, 128.4, 126.3, 104; UV [λmax nm (ꢀ)]
(MeOH) 357.2 (35 000), 342.0 (19 400, shoulder), 282.0 (61 400),
230.2 (47 500), 203.0 (16 800). Anal. Calcd for C11H6N2-
SCl2‚1.5 H2O: C, 44.59; H, 3.04; N, 9.46. Found: C, 44.73; H,
3.27; N, 9.10.
2,6,7-Tr ich lor o-1-(â-D-r ibofu r a n osyl)n a p h th o[2,3-d ]im -
id a zole (2). Chlorine in carbon tetrachloride (0.92 mL, 0.972
M, 0.88 mmol) was added through a gastight syringe to a
suspension of 6,7-dichloro-2-(methylthio)-1-(â-D-ribofuranosyl)-
naphtho[2,3-d]imidazole (25, 0.33 g, 0.795 mmol) in dry
methanol (33 mL) at -78 °C under an atmosphere of argon.
The suspension became clear a short while after the addition
of chlorine. The solution was stirred at -78 °C for 1 h and
diluted with ethyl acetate (300 mL). The ethyl acetate solution
was washed with a mixture of a saturated sodium chloride
solution and a saturated sodium bicarbonate solution (3 × 100
mL, 1/1, v/v), and a saturated sodium chloride solution (50 mL)
and then dried over anhydrous sodium sulfate. The solution
was evaporated, and the residue was subjected to silica gel
chromatography (5 × 18 cm) and eluted with 4% methanol in
chloroform. The appropriate fractions, as determined by TLC
(Rf ) 0.35, chloroform/methanol, 10/0.5, v/v), were collected,
and the solvents were removed under reduced pressure to give
2,6,7-trichloro-1-(â-D-ribofuranosyl)naphtho[2,3-d]imidazole (2,
0.262 g, 81.9%) as a white solid. Some starting material (0.042
g, 12.1%) was also recovered from the column. The total yield,
after the recovery of the starting material, was 90.4%: mp
179-182 °C; 1H NMR (DMSO-d6) δ 8.609 (s, 1H), 8.408 (s, 1H),
8.287 (s, 1H), 8.266 (s, 1H), 5.973 (d, J ) 7.57 Hz, 1H), 5.525
(d, J ) 6.37 Hz, 1H), 5.415 (t, J ) 4.45 Hz, 1H), 5.309 (d, J )
4.22 Hz, 1H), 4.635 (q, 1H), 4.200 (m, 1H), 4.047 (m, 1H), 3.801
(m, 2H); 13C NMR (DMSO-d6) δ 145.4, 142.2, 133.9, 129.1,
128.8, 128.7, 128.7, 127.1, 126.5, 115.2, 109, 89.3, 86.1, 70.7,
69.9, 61.4; UV [λmax nm (ꢀ)] (MeOH) 323.0 (8730), 249.0
(93 900); MS EI m/e 402 (M+, 8.9%); HRMS calcd for
6,7-Dich lor o-2-(m et h ylt h io)n a p h t h o[2,3-d ]im id a zole
(3c). Methyl iodide (0.449 mL, 7.2 mmol) was added to a
solution of 6,7-dichloronaphtho[2,3-d]imidazole-2-thione (23,
1.76 g, 6.55 mmol) in dry DMF (25 mL) in an ice bath and
stirred for 30 min in an ice bath and then about 12 h at rt.
The reaction solution was concentrated under reduced pres-
sure to about 5 mL and diluted with ethyl acetate (300 mL).
The ethyl acetate solution was washed with a saturated
sodium carbonate solution (3 × 100 mL), water (2 × 100 mL),
and a saturated sodium chloride solution (50 mL) and then
dried over anhydrous sodium sulfate. The solvent was evapo-
rated, and the residue was subjected to silica gel chromatog-
raphy (5 × 10 cm) with elution first by 0.5% methanol in
chloroform and then by 3% methanol in chloroform. The
appropriate fractions, as determined by TLC (Rf ) 0.4, 0.2%
methanol in chloroform), were collected, and the solvents were
removed under reduced pressure to give 6,7-dichloro-2-(me-
thylthio)naphtho[2,3-d]imidazole (3c, 1.5 g, 81%) as a yellow
1
solid: mp 215-217 °C; H NMR [DMSO-d6 (50 °C)] δ 12.77
(bs, 1H), 8.27 (s, 2H), 7.96 (s, 2H), 2.76 (s, 3H); UV [λmax nm
(ꢀ)] (MeOH) 346.4 (18 500), 331.4 (13 600), 267.8 (63 200), 261.2
(63 800), 235.4 (38 400). Anal. Calcd for C12H8N2SCl2: C,
50.88; H, 2.83; N, 9.89. Found: C, 50.73; H, 2.76; N, 9.69.
6,7-Dich lor o-2-(m eth ylth io)-1-(2,3,5-tr i-O-ben zoyl-â-D-
r ib ofu r a n osyl)n a p h t h o[2,3-d ]im id a zole (24). N,O-Bis-
(trimethylsilyl)acetamide (BSA, 0.45 mL, 1.86 mmol) was
added to a suspension of 6,7-dichloro-2-(methylthio)naphtho-
[2,3-d]imidazole (3c, 0.262 g, 0.93 mmol) in dry 1,2-dichloro-
ethane (13 mL) under an atmosphere of argon and stirred at
rt for 30 min. 1-O-Acetyl-2,3,5-tri-O-benzoyl-â-D-ribofuranose
(0.68 g, 1.39 mmol) was added to this mixture, followed by the
addition of trimethylsilyl (trifluoromethyl)sulfonate (TMSOTf,
0.287 mL, 1.48 mmol), and the reaction was stirred at 50 °C
for 3 d. The reaction solution was diluted with ethyl acetate
(100 mL). The ethyl acetate solution was washed with a
saturated sodium bicarbonate solution (2 × 100 mL) and a
saturated sodium chloride solution (50 mL) and then dried over
anhydrous sodium sulfate. The solvent was removed under
reduced pressure, and the residue was subjected to silica gel
chromatography (5 × 10 cm) with elution by 0.5% methanol
in chloroform. The appropriate fractions, as determined by
TLC (Rf ) 0.4, chloroform), were collected, and the solvents
were removed under reduced pressure to give 6,7-dichloro-2-
(methylthio)-1-(2,3,5-tri-O-benzoyl-â-D-ribofuranosyl)naphtho-
[2,3-d]imidazole (24, 0.65 g, 96.6%) as a brown solid. A small
sample was recrystallized from a mixture of chloroform and
C
16H13N2O4Cl3 401.9941, found 401.9928. Anal. Calcd for
C16H13N2O4Cl3: C, 47.58; H, 3.22; N, 6.94. Found: C, 47.39;
H, 3.10; N, 6.75.
Ack n ow led gm en t. This research was supported by
research Grant No. U19-AI-31718 from the National
Institute of Allergy and Infectious Disease, National
Institutes of Health. The authors would like to thank
Mr. J ack Hinkley for the large-scale preparation of
compound 15 and to Ms. Marina Savic for the prepara-
tion of this manuscript.
1
methanol for analysis: mp 241-243 °C; H NMR (DMSO-d6)
J O971152O