Synthesis of a novel ring-expanded purine analogue containing a 5:8-fused imidazo[4,5-e][1,2,4]triazocine ring system amidst opportunistic rearrangements and ring transformations

Article abstract of DOI:10.1016/S0040-4020(02)01252-8

A novel 5:8-fused heterocycle containing the imidazo[4,5-e][1,2,4]triazocine ring system has been synthesized in ten steps commencing from 1-benzyl-5-methyl-4-nitroimidazole. The compound is a new member of the family of ring-expanded xanthine-xanthosine analogues reported from this laboratory. The synthesis led to the unraveling of a number of novel rearrangements and ring-transformations.

Full text of DOI:10.1016/S0040-4020(02)01252-8

Tetrahedron 58 (2002) 9567–9578
Synthesis of a novel ring-expanded purine analogue containing a
5:8-fused imidazo[4,5-e][1,2,4]triazocine ring system amidst
opportunistic rearrangements and ring transformations
*
Friedrick N. Burnett and Ramachandra S. Hosmane
Laboratory for Drug Design and Synthesis, Department of Chemistry and Biochemistry, University of Maryland UMBC, 1000 Hilltop circle,
Baltimore County, Baltimore, MD 21250, USA
Received 8 August 2002; accepted 2 October 2002
Abstract—A novel 5:8-fused heterocycle containing the imidazo[4,5-e][1,2,4]triazocine ring system has been synthesized in ten steps
commencing from 1-benzyl-5-methyl-4-nitroimidazole. The compound is a new member of the family of ring-expanded xanthine–
xanthosine analogues reported from this laboratory. The synthesis led to the unraveling of a number of novel rearrangements and ring-
transformations. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
fore, their structures shall only be assigned with due caution,
especially since a large number of reportedly alleged seven
and larger ring heterocycles were later discovered to be only
5- or 6-membered ring systems by X-ray diffraction
analyses.3 This report describes our synthetic studies on
the title imidazo[4,5-e][1,2,4]triazocine ring system (2).4
This 5:8-fused heterocyclic system proved to be just as or
even more synthetically challenging than many other
predecessor ring-expanded purine systems with a 5:7-
fusion.
Ring-expanded purine bases as well as their nucleoside and
nucleotide derivatives carry chemical, biochemical, bio-
physical, and medicinal significance.1 While chemical
significance concerns their synthesis and study of structure,
stability, acid-base properties, aromaticity, tautomeric
equilibria, etc. their biochemical significance derives from
their potential substrate–inhibitory activity against a host of
enzymes of purine metabolism, and enzymes that require
energy cofactors such as ATP or GTP. Endowed with
unique steric, electronic, and conformational character-
istics, they are also potentially excellent probes for
biophysical investigations of nucleic acid structure and
function. From a medicinal standpoint, they can be regarded
as analogues of purines with potential applications in
anticancer and antiviral therapy.
Often plagued with undesired, opportunistic rearrange-
ments, ring-expanded purine bases often present formidable
challenge especially when the target ring systems are
antiaromatic by Hu¨ckel standards. We have in fact reported
a few such rearrangements involving the 5:7-fused imi-
dazo[4,5-e][1,2,4]triazepine ring system (1).2 While most of
the target compounds of the latter system were found to be
remarkably stable when once synthesized, the steps leading
to their synthesis, more often than not, were prone to
unforeseen ring transformations and rearrangements. There-
2. Results and discussion
As was the case with 1, the logical targets for initial
synthetic explorations of the new heterocyclic system 2 are
the benzyl analogues 2b and 2c. The benzyl substitutions,
while being stable to both acidic and basic reaction
conditions, can be conveniently cleaved by catalytic
hydrogenation to produce the parent heterocycle that can
later be used for constructing the corresponding nucleoside
and nucleotide derivatives for eventual biological investi-
gations. In that context, the ring-expanded analogues of
Keywords: ring-expanded purine; ring transformations; 5:8-fused
heterocycles; rearrangements.
*
Corresponding author. Tel.: þ1-410-455-2520; fax: þ1-410-455-1148;
e-mail: hosmane@umbc.edu
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01252-8

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F. N. Burnett, R. S. Hosmane / Tetrahedron 58 (2002) 9567–9578
Scheme 1.
xanthine are also preferrred as they are the convenient
precursors to a wide variety of other purine analogues,
including adenine, guanine, isoguanine, hypoxanthine, and
2,6-diaminopurine.
The required synthetic precursor for the target 2b is
4-amino-1-benzylimidazole-5-glyoxal (N 2-methoxycarbo-
nyl)hydrazone (10) whose synthesis is outlined in Scheme
1. The synthesis commenced with 1-benzyl-5-methyl-4-
Figure 1. ORTEP view of 9 showing the atom numbering scheme that was employed.

F. N. Burnett, R. S. Hosmane / Tetrahedron 58 (2002) 9567–9578
9569
Scheme 2.
nitroimidazole (3),5 which was treated with dimethylforma-
mide dimethyl acetal, catalyzed by trifluoroacetic acid, to
form 1-benzyl-5-b-(N,N-dimethylaminoethylene-4-nitro-
imidazole (4) in 85% yield. The enamine 4 was converted
to the corresponding enol-acetate 5 in 70% yield by reaction
with acetic anhydride–ammonium acetate. When 5 was
treated with an equivalent of hydrazine, the product isolated
was the acetylhydrazone 7. Apparently, 5 undergoes initial
deacylation to form the intermediate aldehyde 6 and
acetohydrazide which further reacts to form 7. Based upon
this result, the desired 8 was prepared from 5 in 94% yield
by reaction with 2 equiv. or more of methylcarbazate. It was
later discovered that 8 could also be prepared directly from
4 and methylcarbazate in 95% yield. The 5-methylene group
of 8 was oxidized to the corresponding keto group of 9 by
treatment with sodium hydride in the presence of molecular
oxygen in 27% yield. In order to improve the yield of the
latter reaction, various alternative methods of oxidation
were attempted, including CrO3·(Pyr)2,6a MgO–KMnO4-
(HNO3–H2O),6b DDQ–MeOH,6c and NaH–O2–trimethyl
Scheme 3.

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F. N. Burnett, R. S. Hosmane / Tetrahedron 58 (2002) 9567–9578
Figure 2. ORTEP view of (A) compound 16 and (B) compound 17.
phosphite,6d,e but the yield in each case was less than
desirable. The structure of 9 was confirmed by single-crystal
X-ray diffraction analysis. An ORTEP view of the molecule
along with the atom numbering scheme that we employed is
shown in Fig. 1. The atomic co-ordinates with thermal
motion parameters, bond lengths, bond angles, and selected
torsion angles are collected in tables of the Supplementary
Material. Data from the tables show that 9 contains a planar
imidazole ring with 1-benzyl, 4-nitro, and 5-keto sub-
stituents that are essentially coplanar with the ring. The
carbon or nitrogen atom of the substituents, directly
connected to the ring, does not deviate by more than 68
from planarity (180 or 08) as evidenced by torsion angles.
The orientation of the C7–N8 double bond with respect to
the C5–C6 bond is syn, whereas that of C6–C7 with respect
to N8–N9 is anti. Finally, the nitro group of 9 was reduced
by catalytic hydrogenation over Pd–C to obtain the desired
amino compound 10 in 73% yield.
benzylimidazole (11), in 88% yield. A tentative mechanism
(Scheme 2) for the formation of 11 involves the initial attack
of methoxide ion at the side chain carbamate carbonyl of 10
to produce 13. The latter, upon another attack by methoxide,
eliminates a molecule of gaseous nitrogen to form 14. The
subsequent acid work-up would produce the enol 15, which
tautomerizes to the ketone 11.
The protection of the side-chain hydrazino moiety with an
alkyl or aralkyl group was anticipated to lower the
likelihood of degradation of 10 to 11 as the two nitrogen
atoms could no longer be eliminated as the entropy-favored
nitrogen gas. To this end, we aimed to prepare the dibenzyl
analogue 16 (Scheme 3). Compound 16 was prepared either
from 10 using benzyl bromide–sodium hydride (48% yield)
or directly from 8 in a one-pot reaction using the same
reagents plus molecular oxygen (18%). However, the
attempted catalytic hydrogenation of 16 in order to reduce
its nitro group into the corresponding amino group, using
Pd–C–H2, only afforded the dimer 17 in 46% yield. The
structures of both 16 and 17 were confirmed by single-
crystal X-ray diffraction analysis (Fig. 2). Apparently, under
The attempted ring-closure of 10 to 2b with sodium
methoxide–methanol, followed by acid work-up, however,
produced only the degradation product, 5-acetyl-4-amino-1-
Scheme 4.

F. N. Burnett, R. S. Hosmane / Tetrahedron 58 (2002) 9567–9578
9571
Figure 3. ORTEP view of compound 19.
low pressure of hydrogen that was employed, the partially
formed amino group of the target compound reacts with the
intermediate nitroso compound to form the observed dimer
17.
proceed by way of the desired 5:8-fused system 2c as an
intermediate. The base-catalyzed ring-opening of 2c with
concomitant elimination of hydrogen cyanide, followed by
ring-closure would yield the observed 1,7-dibenzylxanthine
(19). The attempted ring-closure of 18 with sodium
methoxide in methanol at room temperature only resulted
in a product that lacked the methoxycarbonyl functionality
(see below).
The problem of dimer formation during catalytic reduction
was overcome by doubling the pressure of hydrogen gas,
which was anticipated to enhance the rate of reduction and
minimize the amount of unreacted nitroso species during the
course of reduction. Thus, at 30 psi of H2, 16 was reduced to
form the desired 18 in 62% yield. However, the attempted
ring-closure of 18 in sodium hydride–dimethyl sulfoxide at
50–608C gave only the rearranged 5:6-fused system
(Scheme 4), a xanthine derivative 19 instead of the desired
5:8-fused 2c. The structure of 19 was confirmed by single-
crystal X-ray diffraction analyses (Fig. 3). A tentative
mechanism for the transformation of 18 to 19 is outlined in
Scheme 5. As shown, the observed rearrangement might
It was thought that the reaction conditions were too drastic
for the desired ring-closure of 18 to 2c, and that the milder
reaction conditions were believed necessary. Therefore, the
same reaction was carried out at 08C. This time, two new
products were isolated from the reaction mixture, whose
FAB mass spectra exhibited the Mþ1 peaks at m/z 399 and
426. The determination of elemental composition of these
peaks by high resolution FAB pointed to molecular
formulae of C22H18N6O2 and C23H19N7O2, respectively.
Scheme 5.

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F. N. Burnett, R. S. Hosmane / Tetrahedron 58 (2002) 9567–9578
Scheme 6.
These mass spectral data, coupled with their NMR data,
led to the proposed structures 20 and 21 for these two
products (Scheme 6). Tentative reaction pathways for the
formation of the 20 and 21 have been outlined in
Schemes 7 and 8, respectively. Apparently, at a low
temperature, compound 18 could preferably exist in a
sterically less crowded form 18a. The latter is likely to
undergo intermolecular condensation, rather than intra-
molecular, with a loss of molecules of hydrogen
cyanide, methanol, and N-benzyl isocyanate, to form
the dimeric intermediate 22. Subsequent intramolecular
condensation of 22 with a loss of second molecule
each of hydrogen cyanide, methanol, and N-benzyl
isocyanate would produce the observed novel bis-
imidazodiazocinedione (20). The reaction pathway for
the formation of 21 is similar, with the exception that the
final intramolecular ring-closure of 22 occurs at the
hydrazone junction, instead of carbonyl, of the side-chain
(see Scheme 8).
The above results led us to the following conclusions: (a)
The employed 08C is too low for effecting the desired
intramolecular condensation of 18 to form 2c, and (b) the
electrophilicity of the concerned side-chain carbonyl group
where the ring-closure is supposed to take place, is
inadequate for nucleophilic attack as it is flanked by two
electron-donating methoxy and hydrazino functionalities
(viz a carbonate or a urea). To make the matter worse, the
concerned amino nucleophile attached to the imidazole ring
is also deactivated as it is conjugated to the carbonyl
group (viz amide). Accordingly, we decided to replace
the methoxycarbonyl group with the highly electrophilic
p-nitrophenoxycarbonyl functionality. Thus, compound 18
was treated with excess sodium methoxide in methanol to
form 23 (Scheme 9), which was further reacted with
p-nitrobenzene chloroformate to obtain the desired 24 in
84% yield. Finally, the latter was ring-closed at room
temperature in the presence of 4-dimethylaminopyridine
(DMAP) to afford the target 2c as a yellow solid in low
Scheme 7.

F. N. Burnett, R. S. Hosmane / Tetrahedron 58 (2002) 9567–9578
9573
Scheme 8.
yield (21%). A TLC of the initial reaction mixture
showed the presence of a number of other side
products besides the target 2c, one of which had an
identical Rf as that of the authentic xanthine analogue
19 isolated earlier. No further attempts were made to
isolate or purify these other products. The 1H and 13C
NMR, mass spectral, and microanalytical data of 2c
are consistent with the structure as assigned. Further
attempts to increase the yields of 2c as well as its
conversions into the corresponding nucleoside–
nucleotide analogues by sequential debenzylation,
and ribosylation–phosphorylation procedures that are
well established in this lab,1 are currently in
progress.
Finally, in an attempt to confirm the intermediacy of 2c in
the earlier observed rearrangement of 18 to 19 (see
Scheme 5), compound 2c was heated in a mixture of
sodium hydride and dimethyl sulfoxide at 508C. A TLC
comparison in three different solvents showed complete
conversion of 2c into 19 in less than an hour. The 1H NMR
of the product was identical to that of 19 obtained from 18.
Scheme 9.

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F. N. Burnett, R. S. Hosmane / Tetrahedron 58 (2002) 9567–9578
3. Conclusion
107, 91, 65. Anal. calcd for C14H16N4O2: C, 61.75; H, 5.92;
N, 20.57. Found: C, 61.83; H, 5.96; N, 20.46.
A novel ring-expanded congener of purine containing a 5:8-
fused imidazo[4,5-e][1,2,4]triazocine ring system has been
synthesized in 10 steps starting from an imidazole
derivative. The compound undergoes facile base-catalyzed
rearrangement to form a 5:6-fused xanthine analogue. The
undertaken synthetic approach unravelled a number of
interesting ring transformations.
4.1.2. 5-(2-Acetoxy)ethylene-1-benzyl-4-nitroimidazole
(5). To a dry 250 mL three-neck flask equipped with a
magnetic stirring bar, a condenser, and a guard tube, was
added 4 (2.00 g, 7.34 mmol). The solid was dissolved by the
addition of acetonitrile (100 mL). Added to this solution
was acetic anhydride (40.0 mL, 0.424 mol), followed by
ammonium acetate (0.85 g, 11.0 mmol). The reaction
mixture was refluxed for 10.5 h. The mixture was then
rotary evaporated to dryness and the residue was adsorbed
onto silica gel (40–63 mm particle size), using acetonitrile
(100 mL). This was loaded onto a flash silica gel column
(42 g) and eluted with chloroform. The combined fractions
were evaporated to dryness to give a golden yellow oil. The
1H NMR of the oil indicated the presence of cis and trans
isomers (1:1). The oil was covered with ethyl acetate and
allowed to stand in a refrigerator overnight to get the trans
isomer as a yellow crystalline solid. Evaporation of the
filtrate resulted in an oil which was covered with ethanol to
give the cis isomer as a yellow solid. Combined yield 1.47 g
4. Experimental
4.1. General
1H NMR spectra were recorded at 80, 300 or 500 MHz on an
IBM NR/80, a GE QE-300, or a GE GN-500 spectrometer,
respectively. 13C NMR spectra were run on the GE QE-300
spectrometer operating at 75 MHz. The reported spectral
data are relative to Me4Si as an internal reference standard.
Multiplicity is designated by the abbreviation, s¼singlet,
d¼doublet, dd¼doublet of doublets, t¼triplet, q¼quartet,
m¼multiplet, br¼broad, and ap¼apparent. Deuterium
oxide was used to verify the presence of exchangeable
protons. Electron impact (EI) or chemical ionization (CI)
mass spectra were recorded at 70 eV on a Hewlett Packard
5988A mass spectrometer. The fast atom bombardment
(FAB) mass spectra were recorded at the Mass Spectral
Facility, Department of Biochemistry, Michigan State
University, East Lansing, MI. Infrared spectra were
obtained on a Perkin–Elmer 1420 ratio recording instru-
ment. Ultraviolet spectra were recorded on a Gilford
Response UV–VIS spectrophotometer. X-Ray diffraction
analyses were carried out at the Department of Chemistry,
Southern Methodist University, Dallas, TX on an automatic
Nicolet R3m/V diffractometer. Elemental Microanalyses
were performed by Atlantic Microlab, INC., Norcross,
Georgia. Melting points were determined on a Thomas–
Hoover capillary melting point apparatus and are uncor-
rected. Dry solvents were prepared as follows: toluene was
distilled over sodium; tetrahydrofuran was first dried over
CaH2 and then distilled over sodium. Dry solvents were
1
(70%): cis isomer mp 82–848C; H NMR (DMSO-d6) d
8.01 (s, 1H, imidazole CH), 7.44 (d, 1H, J¼7.02 Hz, CH),
7.07–7.34 (m, 5H, PhH’s), 6.00 (d, 1H, J¼6.96 Hz, CH),
5.27 (s, 2H, CH2), 2.01 (s, 3H, CH3); trans isomer mp 129–
1
1308C; H NMR (DMSO-d6) d 8.07 (d, 1H, J¼12.8 Hz,
CH), 8.03 (s, 1H, imidazole CH), 7.07–7.34 (m, 5H,
PhH’s), 6.52 (d, 1H, J¼12.8 Hz, CH), 5.41 (s, 2H, CH2),
2.21 (s, 3H, CH3); MS (EI) m/z 287 (Mþ). Anal. calcd for
C14H13N3O4 (mixture of cis and trans): C, 58.53; H, 4.56;
N, 14.63. Found: C, 58.53; H, 4.61; N, 14.61.
4.1.3. 1-Benzyl-4-nitroimidazole-5-acetaldehyde (N 2-
acetyl)hydrazone (7). To a 100 mL two-neck round-
bottomed flask was added 5 (0.54 g, 1.88 mmol) and
acetonitrile (15 mL). The mixture was stirred until the
solid completely dissolved. The solution was cooled in an
ice-water bath, and hydrazine monohydrate (0.117 mL,
2.26 mmol) was added, when the color of the reaction
mixture turned reddish brown. The pale green solid that
separated after about 15–20 min was filtered out, and the
filtrate was allowed to stand in a refrigerator for about 6–
7 h. The colorless solid that separated was recrystallized
from acetonitrile to obtain 7 (0.51 g, 90%): mp 168–
169.58C; 1H NMR (DMSO-d6) d 10.75 (s, 1H, ex. w/D2O),
7.95 (s, 1H), 7.50–7.16 (m, 6H), 5.34 (s, 2H), 3.96 (s, 2H),
1.81 (s, 3H); IR (KBr) 3420 (NH), 1680 (CO), 1555
˚
stored over 4 A molecular sieves.
4.1.1. 1-Benzyl-5-b-(dimethylamino)ethylene-4-nitro-
imidazole (4). To a 250 mL three-neck, round-bottom
flask equipped with a condenser and guard tube was placed
3 (10.0 g, 0.046 mol). The solid was dissolved by the
addition of DMF (100 mL) before adding DMF–DMA
(6.00 g, 0.0504 mol) by a syringe. The reaction mixture was
stirred at room temperature and trifluoroacetic acid (TFA)
(0.1 mL) was added. The mixture was heated to reflux for
5–24 h until complete formation of a slower moving, UV-
absorbing compound as observed by TLC (silica gel,
CHCl3–acetone, 1:1). The mixture was then evaporated to
dryness resulting in a dark red oil. The oil was covered with
toluene and refrigerated overnight to form a crystalline
solid. The solid was recrystallized from toluene to give red
(NvCH), 1480 (NO2), 1420 (CH2), 1345 (NO2) cm21
.
Anal. calcd for C14H15N5O3: C, 55.81; H, 5.02; N, 23.24.
Found: C, 55.53; H, 5.12; N, 23. 28.
4.1.4. 1-Benzyl-4-nitroimidazole-5-acetaldehyde (N 2-
carbomethoxy)hydrazone (8). Method A. To an oven-
dried 100 mL two-neck roundbottom flask equipped with a
magnetic stirrer, a condenser, and a guard tube, was added 5
(1.50 g, 5.22 mmol), followed by acetonitrile (50 mL). To
the resulting yellow solution was added methyl carbazate
(1.18 g, 13.1 mmol), and the reaction mixture was heated to
reflux for 46 h. The mixture was allowed to cool, extracted
with chloroform (3£50 mL), and washed with water
(2£25 mL). The combined extracts were dried over
MgSO4, filtered through an acrodisc filter (0.45 mm), and
1
crystals; yield 10.6 g (85%): mp 148.5–149.58C; H NMR
(DMSO-d6) d 7.82 (d, 1H, J¼13.51 Hz, side-chain b-CH),
7.72 (s, 1H, imidazole CH), 7.32 (m, 5H, PhH’s), 5.31 (s,
2H, CH2), 5.13 (d, 1H, J¼13.20 Hz, sidechain a-CH), 2.83
(s, 6H, N(CH3)2; MS (EI) m/z 272 (Mþ), 255, 217, 181, 134,

F. N. Burnett, R. S. Hosmane / Tetrahedron 58 (2002) 9567–9578
9575
the filtrate was rotary evaporated to dryness, affording a
reddish-orange oil. The oil was further dried using a vacuum
pump (10 mm Hg) to obtain 8 as a foam; yield 1.56 g (94%):
1H NMR (DMSO-d6) d 10.08 (s, 1H, ex. w/D2O, NH), 7.91
(s, 1H, CH), 7.25–7.34 (m, 6H, PhH’s and CH), 5.32 (s, 2H,
benzyl CH2), 3.93 (d, 2H, J¼4.3 Hz, CH2), 3.60 (s, 3H,
OCH3); IR (KBr) 3420 (NH), 1735 (CvO), 1495 (NO2),
was evaporated to dryness onto flash silica gel (1 g, 40–
63 mm particle size). The residue was suspended in CHCl3
and the resulting slurry was loaded onto a flash chromato-
graphy column packed with 10.0 g of flash silica gel. The
column was eluted using a mixture of CHCl3–acetone (4:1)
and the appropriately combined fractions were rotary
evaporated to dryness. The resulting yellow solid was
triturated with a mixture of petroleum ether (bp 35–608C)
and MeOH (10:1) and filtered to yield 10; yield 123 mg
1350 (NO2), 1030 (C–N) cm21
.
Anal. calcd for
C14H15N5O4: C, 52.99; H, 4.76; N, 22.07. Found: C,
52.92; H, 4.80; N, 21.98.
1
(73%): mp 193.5–1958C (dec.); H NMR (DMSO-d6) d
11.56 (s, 1H, NH), 7.80 (s, 1H, imino CH), 7.45 (s, 1H,
imidazole CH), 7.07–7.33 (m, 7H, PhH’s and NH2), 5.44 (s,
2H, CH2), 3.73 (s, 3H, OCH3); IR (KBr) 3450 (NH2), 3390
(NH2), 3280 (NH), 3250, 1720 (CvO), 1650 (CvO), 1560,
1550, 1460, 1445, 1430, 1255, 1231, 1135 (C–O),
1080 cm21; UV lmax (MeOH) 254.0, 377.0 nm; MS (CI,
w/i-butane) m/z 302 (MHþ, 100). Anal. calcd for
C14H15N5O3: C, 55.81; H, 5.02; N, 23.24. Found: C,
55.82; H, 5.06; N, 23.15.
Method B. A flame-dried 250 mL-flask was charged with 4
(8.0 g, 0.029 mol) and to this solid was added acetonitrile
(150 mL). After allowing the solid to dissolve, methyl
carbazate (2.48 g, 0.018 mol) was added, and the dark red
solution was heated to reflux for 5 days. The mixture was
diluted with water (150 mL) and extracted with CHCl3
(2£100 mL). The combined organic extracts were then
washed with water (2£50 mL), dried over MgSO4, filtered,
and the filtrate evaporated in vacuo (10 mm Hg) to give 8 as
a foam in 95% yield. Spectral data and TLC behavior of this
compound were identical to that of 8 obtained by Method A
described above.
4.1.7. 5-Acetyl-4-amino-1-benzylimidazole (11). Com-
pound 10 (59 mg, 0.196 mmol) was placed into a flame-
dried 100 mL two-neck flask equipped with a magnetic
stirrer, a condenser, and a guard tube. The solid was
partially dissolved by the addition of MeOH (5 mL). Freshly
prepared solution of NaOMe in MeOH (0.051 g of Na
(2.21 mg.atom) in 10 mL MeOH) was added slowly and the
dark yellow solution was heated to reflux. A TLC (silica gel,
CHCl3–acetone, 1:1) of the reaction mixture after 16 h
indicated complete conversion of the starting material into a
new UV-absorbing spot with a lower Rf. The reaction
mixture was neutralized with 1N HCl and extracted with
CHCl3 (2£15 mL). The combined extracts were dried over
MgSO4, filtered, and the filtrate was evaporated to obtain a
brown solid. The solid was dissolved in MeOH and the
solution was treated with decolorizing carbon. Filtration and
evaporation of the solvent left a solid residue which upon
trituration with ether afforded an off white solid; yield
37 mg (87%): mp 161–1638C; 1H NMR (DMSO-d6) d 7.66
(s, 1H, imidazole CH), 7.09–7.33 (m, 5H, PhH’s), 5.90 (s,
2H, NH2, ex. w/D2O), 5.34 (s, 2H, CH2); IR (KBR) 3430
(NH2), 3390, 3320 (NH2), 1615 (CvO), 1530, 1470 (NO2),
1380 (NO2), 1310, 1235, 1085, 1070, 1030, 955 cm21; MS
(CI, w/i-butane) m/z 216 (MHþ, 100).
4.1.5. 1-Benzyl-4-nitroimidazole-5-glyoxal (N 2-methoxy-
carbonyl)hydrazone (9). In a flame-dried 50 mL two-neck
round-bottom flask was placed sodium hydride (0.15 g,
5.0 mmol). The solid was washed twice with dry toluene
(2 mL) before adding dry tetrahydrofuran (THF) (20 mL) to
the reaction flask. To this suspension was added a solution
of 8 (0.202 g, 0.636 mmol) in THF (5 mL). The suspension
went from a reddish orange color to dark red. While stirring,
O2 gas was passed through the reaction mixture for 3–5 h.
The mixture was allowed to stir overnight. It was
neutralized with 1N HCl, diluted with 30 mL of water,
and extracted with chloroform (3£25 mL). The combined
extracts were dried over anhydrous MgSO4 and then
purified by flash chromatography, using a 30 g flash silica
gel column. The product was eluted with chloroform–
acetone (9:1). The oil obtained from evaporation of the
appropriately combined fractions was crystallized from
acetone–petroleum ether (bp 35–608C) to yield white
needles or from methanol overnight to give a white
1
crystalline solid; yield 116 mg (27%): H NMR (DMSO-
d6) d 11.9 (s, 1H, NH, ex. w/D2O), 8.17 (s, 1H, imino CH),
7.63 (s, 1H, imidazole CH), 7.12–7.59 (m, 5H, PhH’s), 5.32
(s, 2H, CH2), 3.69 (s, 3H, OCH3); IR (KBr) 3180 (NH),
1755 (CvO), 1665 (CvO), 1550, 1520, 1440 (NO2), 1390,
1345 (NO2), 1245, 1215, 1180, 1090, 960, 910, 835, 750,
700 cm21; MS (CI, w/i-butane) m/z 332 (MHþ, 14), 285
(1.9), 256 (2.3), 218 (100), 204 (46). Anal. calcd for
C14H13N5O5: C, 50.75; H, 3.95; N, 21.14. Found: C, 50.64;
H, 4.00; N, 21.00.
4.1.8. 1-Benzyl-4-nitroimidazole-5-glyoxal (N 2-benzyl-
N 2-methoxycarbonyl)hydrazone (16). Method A. To a
flame-dried 50 mL two-neck round-bottom flask equipped
with a condenser, a magnetic stirrer, and a guard tube, was
added sodium hydride (0.0362 g, 1.51 mmol). The solid was
washed with dry toluene (2£2 mL) to remove the adhering
oil before adding dry THF (20 mL), followed by benzyl
bromide (0.216 mL, 1.81 mmol). The solution was cooled
with an ice bath. Compound 10 (0.205 g, 0.604 mmol) was
placed into a separate vial, and the vial was flushed with N2.
The solid was dissolved in THF (5 mL) and the resulting
yellow solution was cooled in an ice bath. The cold solution
was then added dropwise to the flask, using a syringe drive
(flow rate¼0.06 mL min21). The reaction mixture was
stirred at room temperature for 24 h, neutralized with
0.67N HCl, diluted with 30 mL of water, extracted with
CHCl3 (3£30 mL), and the combined extracts were dried
over MgSO4. After filtration and evaporation, the product
4.1.6. 4-Amino-1-benzylimidazole-5-glyoxal (N 2-meth-
oxycarbonyl)hydrazone (10). To a 100 mL round-bottom
flask was added 9 (0.186 g, 0.548 mmol) and the solid was
covered with methanol (50 mL). The flask was warmed to
form a uniform solution, and Pd–C (0.10 g) was added and
the resulting slurry was stirred for 0.5 h and filtered. The
filtrate was transferred to a hydrogenation bottle and Pd–C
(0.15 g) was added before hydrogenation at 30 psi for
21 min. The mixture was filtered in vacuo and the filtrate

9576
F. N. Burnett, R. S. Hosmane / Tetrahedron 58 (2002) 9567–9578
was purified by flash chromatography by first eluting the
column with CHCl3 and then with CHCl3–acetone (19:1).
The yellow oil obtained after evaporation of the appro-
priately combined fractions was crystallized from toluene–
petroleum ether (bp 35–608C) to yield 16 as a white solid;
two CH2), 5.42 (s, 4H, two CH2), 3.74 (s, 6H, two OCH3);
IR (KBr) 1720 (CvO), 1650 (CvN), 1550, 1515, 1495,
1440, 1400, 1330, 1160, 1125, 1060, 1010, 945, 905, 900,
885, 795, 765, 735, 695 cm21; UV lmax (MeOH): 274.5,
391.0 nm. Anal. calcd for C42H38N10O6: C, 64.77; H, 4.91;
N, 17.98. Found: C, 64.77; H, 4.92; N, 17.97.
1
yield 0.123 g (48%): mp 128–1308C; H NMR (CDCl3) d
7.04–7.43 (m, 12H, imidazole CH, imino CH, PhH’s), 5.19
(s, 3H, OCH3); IR (KBr) 1725 (CvO), 1670 (CvO), 1560,
1510, 1445 (NO2), 1390, 1340 (NO2), 1310, 1280, 1275,
1175 (C–O), 1080 cm21; MS (CI, w/i-butane) m/z 422
(MHþ, 23), 390 (3.2). Anal. calcd for C21H19N5O5: C,
59.85; H, 4.54; N, 16.62. Found: C, 59.95; H, 4.57; N, 16.58.
4.1.10. 4-Amino-1-benzylimidazole-5-glyoxal (N 2-ben-
zyl-N 2-methoxycarbonyl)hydrazone (18). Compound 16
(0.403 g, 0.956 mmol) was dissolved in methanol (125 mL)
with gentle warming and to this was added 10% Pd–C
(0.10 g). This suspension was allowed to stir for 0.5 h and
the Pd–C was filtered off. The filtrate was placed into a
hydrogenation bottle over Pd–C (0.15 g) and the mixture
was hydrogenated at 30 psi for 20–40 min. The suspension
was filtered in vacuo and the filtrate was evaporated to
dryness to obtain a yellow solid. The solid was triturated
with methanol and recrystallized from an excess of
methanol to give yellow crystals; yield 0.231 g (62%): mp
176–1778C; 1H NMR (DMSO-d6) d 7.81 (s, 1H, imino CH),
6.99–7.40 (m, 13H, PhH’sþimidazole CHþNH2 ex.
w/D2O), 5.38 (s, 2H, amide benzyl CH2), 5.16 (s, 2H,
imidazole benzyl CH2), 3.89 (s, 3H, OCH3); IR (KBr) 3370
(NH2), 3290 (NH2), 1725 (CvO), 1625, 1610, 1605,1565,
1535, 1450, 1435, 1405, 1375, 1305, 1210 (C–O), 1175,
1135, 765, 740, 695 cm21. Anal. calcd for C21H21N5O3: C,
64.44; H, 5.41; N, 17.89. Found: C, 64.34; H, 5.43; N, 17.77.
Method B. In a flame-dried 50 mL two-neck flask equipped
with a guard tube and a magnetic stirrer, was placed sodium
hydride (11 mg, 0.454 mmol). The solid was washed with
dry toluene (2£2 mL) to remove the adhering oil before
covering with dry THF (30 mL). Benzyl bromide
(0.357 mL, 3.15 mmol) was added and the mixture was
cooled in an ice bath. To the cold solution was added 8
(0.100 g, 0.315 mmol) at which point the colorless solution
became red. The solution was allowed to come to room
temperature and O2 gas was passed through the solution for
3–5 h. The reaction mixture was stirred for an additional
10 h, neutralizing with 1N HCl, and diluted with water
(25 mL). The resulting bilayered solution was extracted
with CHCl3 (3£30 mL), and the combined extracts were dried
over MgSO4. After filtration, the compound was directly
adsorbed onto flash silica gel (40–63 mm particle size) and
then loaded onto a 25-g flash silica gel column. The column
was eluted with hexanes–ethyl acetate (2:1) to give a yellow
oil, which was crystallized by dissolving in ethyl acetate and
adding hexanes until the solution became turbid. After
allowing this solution to stand for some time, a white
crystalline solid was formed; yield 24 mg (18%). Spectral
data, melting point, and TLC behavior of this solid were
identical to that of 16 obtained by Method A described above.
4.1.11. 1,7-Dibenzylxanthine (19). A 50-mL three-neck
flask, equipped with a reflux condenser, a thermometer, a
guard tube, and a magnetic stirring bar, was charged with
60% NaH (7.66 mg, 0.319 mmol). After washing the NaH
with dry toluene (1.5 mL), DMSO (15 mL) was added to the
reaction flask through a syringe. In a separate 50-mL flask
was placed 18 (50 mg, 0.13 mmol), and after flushing the
flask with a stream of nitrogen, the solid was dissolved in
DMSO (15 mL). The yellow solution was transferred to the
reaction flask using a syringe, and added dropwise over a
50-minute period. The reaction mixture was heated to 508C
and maintained at less than 608C for about 2 h. The reaction
mixture became reddish brown in color and eventually
changed back to a light yellow color. The work-up consisted
of adding 1N HCl until neutral. The resulting solution was
poured into ice-water, and extracted with EtOAc
(4£50 mL). The combined organic extract was washed
with water (8£75 mL), and dried over anhydrous MgSO4.
The solution was filtered in vacuo and the filtrate was
evaporated to dryness, and the resulting solid was triturated
with MeOH to give an off-white solid. The solid was
recrystallized from MeOH to afford nearly colorless crystals
of 19; yield 17 mg (40%): mp 223.5–2258C; 1H NMR
(DMSO-d6) d 12.02 (s, 1H, NH, exchangeable with D2O),
8.19 (s, 1H, CH), 7.21–7.32 (m, 10H, Ph-H’s), 5.45 (s, 2H,
CH2), 4.99 (s, 2H, CH2); IR (KBr) 3440 (NH), 1710 (CvO),
1555, 1485, 1445, 1415, 1380, 1345, 1310, 1255, 1205,
1110, 1050, 760, 745, 720, 705, 690, 630 cm21; UV
(MeOH) lmax 270.5 nm. Anal. calcd for C19H16N4O2: C,
68.66; H, 4.85; N, 16.85. Found: C, 68.66; H, 4.90; N, 16.91.
4.1.9. N,N0-Bis[(1-benzylimidazole-5-glyoxal (N 2-benzyl-
N 2-methoxycarbonyl)hydrazone)-4-yl]-diimide
(17).
Compound 16 (0.9 g, 2.14 mmol) was dissolved in MeOH
(150 mL), and to this solution was added 10% Pd–C
(0.20 g). This suspension was allowed to stir for 0.5 h and
the Pd–C was filtered off. The filtrate was placed into a
hydrogenation bottle over Pd–C (0.40 g) and the mixture
was hydrogenated at 10–15 psi for 1 h. A TLC (silica gel,
CHCl3–acetone, 4:1) of the reaction mixture showed the
formation of a UV-absorbing, slower moving compound as
compared to the starting material. The suspension was
transferred to a 250 mL beaker and heated while stirring for
20–25 min. The color of the suspension changed from
yellow to orange and the TLC (silica gel, CHCl3–acetone,
4:1) at this point showed a single spot that had an
approximately equal Rf as compared to the starting material,
but a higher Rf as compared to the intermediate spot
observed before heating. The suspension was filtered,
concentrated, and allowed to crystallize while standing in
the refrigerator overnight. Orange-red needles were recov-
ered after filtration which could be recrystallized from
toluene–petroleum ether (35–608) or acetonitrile–MeOH
to give orange needles; yield 0.380 g (46%): mp 212–
4.1.12. 1,6-Dibenzyl-4,5,9,10-tetrahydroimidazo[4,5-
b:40,50-f][1,5]diazocine-5,10-dione (20) and 10-amino-
1,6-dibenzyl-4,5,11-trihydrodiimidazo[4,5-f:40,50-b]-
1
2148C; H NMR (DMSO-d6) d 8.57 (s, 2H, two CH), 8.44
(s, 2H, two CH), 7.17–7.34 (m, 20H, PhH’s), 5.60 (s, 4H,
[1,5]diazocine-5,11-dione (21).
A
25-mL two-neck

F. N. Burnett, R. S. Hosmane / Tetrahedron 58 (2002) 9567–9578
9577
round-bottomed flask, equipped with a stirring bar and a
guard tube, was charged with NaH (24 mg, 1.04 mmol)
(1.5 equiv., 60%). After washing the solid with dry toluene
(1.5 mL), a mixture of DMSO (2 mL)–THF (2 mL) was
added to the flask by a syringe. The reaction flask was
cooled to 08C. In a separate 25 mL flask was placed 18
(160 mg, 0.41 mmol) and this flask was then flushed with a
stream of nitrogen gas before dissolving the solid by the
addition of a mixture of DMSO (6 mL)–THF (6 mL). The
yellow solution of 18 was transferred by a syringe to the
reaction flask containing NaH–DMSO by a syringe drive at
a rate of 3.9 mL h21. After the addition of the starting
material was complete, the temperature of the reaction
mixture was allowed to reach room temperature very
slowly. The color of the reaction mixture changed from
yellow to orange, and then to dark red. After 16 h, a TLC
(silica gel) showed two slower moving, UV-absorbing spots
as compared with the starting material, which was no longer
present. The reaction solution was transferred to another
flask, and evaporated to dryness on a Ku¨gelrohr apparatus at
a temperature lower than 358C. Ice water was added to the
residue, and to this aqueous solution was added 1N HCl
dropwise until the solution became neutral (litmus). The
resulting aqueous solution was extracted with EtOAc(4£25
mL). The combined organic layer was washed with water
(3£50 mL), and dried over anhydrous MgSO4. The organic
layer was concentrated to near dryness, which resulted in an
orange precipitate. The filtration of the precipitate yielded
52 mg (32%) of 20, mp 197–2008C (dec.); 1H NMR
(DMSO-d6) d 8.04 (s, 1H, CH), 7.92 (s, 1H, CH), 7.66 (s,
1H, NH, ex. w/D2O), 7.39–7.06 (m, 10H, Ph H¼s), 5.56 (s,
2H, CH2), 5.50 (s, 2H, CH2); IR (KBr) 3405 (NH), 1660
(CvO), 1640, 1605, 1530, 1525, 1500, 1450, 1365, 1340,
1110, 995, 690 cm21; UV (MeOH) lmax 441 nm; HRMS
(FAB) m/z: MHþ calcd for C22H19N6O2, 399.1569; found,
399.1568; Anal. calcd for C22H18N6O2: C, 66.32; H, 4.55;
N, 21.09. Found: C, 66.48, H, 4.68; N, 21.23.
solution was added dropwise to the reaction flask by a
syringe, and the reaction mixture was stirred at room
temperature. A TLC (silica gel, CHCl3–acetone, 4:1) taken
after 5.5 h showed complete conversion to a new spot with a
lower Rf as compared to the starting material. The reaction
was neutralized with 1N HCl and extracted with ethyl
acetate (2£15 mL). The organic extracts were dried over
MgSO4, filtered, and the filtrate evaporated to dryness. The
residue was triturated with ethyl acetate–petroleum ether
(35–608C) to give 23 as a solid, yield 16 mg (93%): mp
1
152–154.58C; H NMR (DMSO-d6) d 8.91 (t, 1H, NH ex.
w/D2O), 7.66 (s, 1H, imidazole CH), 7.00–7.47 (m, 11H,
PhH’s and hydrazone–CHv), 6.23 (s, 2H, NH2 ex. w/D2O),
5.37 (s, 2H, imidazole benzyl CH2) 4.37 (d, 2H, CH2); MS
(FAB) 334 (MHþ); Anal. calcd for C19H19N5O: C, 68.45; H,
5.74; N, 21.01. Found: C, 68.30; H, 5.83; N, 20.88.
4.1.14. 4-Amino-1-benzylimidazole-5-glyoxal (N 2-ben-
zyl-N 2-p-nitrophenoxycarbonyl)-hydrazone (24). To a
solution of p-nitrophenyl chloroformate (72 mg,
0.36 mmol) in dry acetonitrile (40 mL), contained in a 50-
mL three-neck flask maintained under N2 atmosphere, was
added 23 (96 mg, 0.29 mmol). A precipitate began to form
in the yellow solution in 5–10 min. The reaction mixture
was stirred at room temperature for 24 h, neutralized with
2% aq.NaHCO3, and extracted with EtOAc (2£50 mL). The
combined extracts were dried over anhydrous Na2SO4,
filtered, and the filtrate evaporated to dryness on a rotary
evaporator. The residual golden brown oil was adsorbed
onto flash silica gel (40–63 mm particle size) by coevapora-
tion with EtOAc (25 mL), and loaded onto a flash silica gel
column (6 g). The column was eluted with a 2:1 mixture of
EtOAc–hexanes (bp 68–698C), and the appropriate UV-
absorbing fractions with an approximate Rf¼0.2 were
pooled and evaporated. The yellow residue was triturated
with a mixture of EtOAc–petroleum ether (bp 30–658C) to
yield a bright yellow solid which was recrystallized from the
same solvent system to give 24; yield 39 mg (32%): mp
139–1418C; 1H NMR (DMSO-d6) d 8.35 (d, 2H, J¼8.5 Hz,
NO2PhH’s), 7.83 (s, 1H, imidazole CH), 7.66 (d, 2H,
J¼8.5 Hz, NO2PhH’s), 7.38–7.02 (m, 13H, PhH’sþ–
NvCH of side-chain, þNH2 ex. w/D2O), 5.39 (s, 2H,
CH2), 5.31 (s, 2H, CH2); IR (KBr) 3400 (NH2), 3280 (NH2),
1730 (CvO), 1605, 1560 cm21; MS (FAB) m/z 499 (MHþ);
Anal. calcd for C26H22N6O5·0.5H2O: C, 61.48; H, 4.53; N,
16.48. Found: C, 61.07; H, 4.68; N, 16.26.
The remaining filtrate was further purified by column
chromatography (silica gel, 40–63 mm particle size),
eluting with (CHCl3–MeOH, 14:1). The corresponding
UV-absorbing fractions were pooled and evaporated to
dryness. The resulting yellow solid was recrystallized from
EtOAC-petroleum ether (bp 40–608C) to yield 50 mg
1
(29%) of 21 as a bright yellow solid, mp 277–2798C; H
NMR (DMSO-d6) d 12.03 (s, 1H, NH, ex. w/D2O), 8.52 (s,
1H, CH), 7.96 (s, 1H, CH), 7.51–6.93 (m, 12H, Ph H¼s and
NH2 ex. w/D2O), 5.58 (s, 2H, CH2), 5.43 (s, 2H, CH2); IR
(KBr) 3490 (NH), 3420 (NH2), 3390 (NH2), 1685 (CvO),
1670, 1565, 1550, 1520, 1445, 1380, 1215, 1140, 1130, 880,
870, 740, 710, 695, 685, 665 cm21; UV (MeOH) lmax 377,
327, 312, 256.5 nm; (pH 1) lmax 360.5 nm; (pH 12) lmax
329, 273.5, 243 nm; HRMS (FAB) m/z: MHþ calcd for
C23H20N7O2, 426.1678; found, 426.1697; Anal. calcd for
C23H19N7O2: C, 64.93; H, 4.50; N, 23.05. Found: C, 65.14,
H, 4.63; N, 23.18.
4.1.15. 1,6-Dibenzylimidazo[4,5-e][1,2,4]triazocine-5,9-
dione (2c). A mixture of 24 (390 mg, 0.78 mmol) and
DMAP (200 mg, 1.6 mmol) in dry toluene (20 mL) was
stirred at room temperature under N2 atmosphere for 3 h.
The solid precipitate that separated was filtered and purified
by flash chromatography on a column of silica gel (20 g,
40–63 mm particle size), packed with CHCl3, eluting with a
mixture of CHCl3–acetone (1:1). The appropriate UV-
absorbing fractions were pooled and evaporated to obtain a
bright yellow solid which was recrystallized from aceto-
nitrile–petroleum ether (bp 30–658C) to obtain yellow
4.1.13. 4-Amino-1-benzylimidazole-5-glyoxal (N 2-ben-
zyl)hydrazone (23). A solution of NaOMe–MeOH was
prepared by dissolving Na (6.8 mg, 0.296 mg.atom) in
MeOH (7 mL). Compound 18 (20 mg, 0.0516 mmol) was
placed in a separate vial and flushed with a stream of N2
before dissolving it in a minimum quantity of MeOH. This
1
crystals of 2c; yield 59 mg (21%): mp.2508C; H NMR
(DMSO-d6) d 11.84 (s, 1H, ex. w/D2O, NH), 8.15 (s, 1H),
7.30–7.82 (m, 11H, PhHþCH), 5.53 (s, 2H, CH2), 5.14 (s,
2H, CH2); 13C NMR (DMSO-d6) d 184.62 (CvO), 156.71
(CvO), 153.87, 150.19, 138.45, 134.52, 134.15, 132.62,

9578
F. N. Burnett, R. S. Hosmane / Tetrahedron 58 (2002) 9567–9578
129.25, 128.43, 128.1, 127.71, 127.41, 115.73, 56.58, 55.23;
MS (FAB) 360 (MHþ); Anal. calcd for C20H17N5O2: C,
66.85; H, 4.73; N, 19.50. Found: C, 66.70; H, 4.67; N, 19.38.
supported, in part, by a grant from the Biotechnology
Research Technology Program, National Center for
Research Resources, National Institutes of Health.
4.2. Single-crystal X-ray diffraction analyses
An appropriate crystal was mounted on a Nicolet R3m/V
diffractometer. Final unit cell parameters were obtained by a
least-squares fit of the angles of 24 accurately centered
reflections (16,2u,268). Intensity data were collected in
the range of 3.5#2u#42.08 at 2438C using graphite
References
1. (a) Hosmane, R. S. Ring-Expanded (Fat) Nucleosides as Broad-
Spectrum Anticancer and Antiviral Agents. Current Topics in
Medicinal Chemistry: Recent Developments in Antiviral
Nucleosides, Nucleotides, and Oligonucleotides, Hosmane,
R. S., Ed.; Bentham Science, 2002; Vol. 2, pp 1093–1109.
(b) Sood, R. K.; Bhadti, V. S.; Fattom, A. I.; Naso, R. B.; Korba,
B. E.; Kern, E.; Hosmane, R. S. Antiviral Res. 2002, 53, 159.
(c) Wang, L.; Hosmane, R. S. Bioorg. Med. Chem. Lett. 2001,
11, 2893. (d) Chen, H.-M.; Hosmane, R. S. Molecules 2001, 6,
203. (e) Gill, J.; Bretner, M.; Newman, R.; Kyprianou, N.;
Hosmane, R. S. Nucleosides Nucleotides 2001, 20, 1043.
(f) Chen, H.-M.; Hosmane, R. S. J. Heterocycl. Chem. 2000, 37,
951. (g) Bretner, M.; Beckett, D.; Sood, R.; Hosmane, R. S.
Bioorg. Med. Chem. 1999, 7, 2931. (h) Rajappan, V. P.;
Hosmane, R. S. Bioorg. Med. Chem. Lett. 1998, 8, 3649.
(i) Hosmane, R. S.; Hong, M. Biochem. Biophys. Res. Commun.
1997, 236, 88.
˚
monochromated Mo Ka (l¼0.71073 A) radiation. The
scan was u/2u, 2117 reflections were collected with 1916
unique with Rint¼0.023. Three standard reflections moni-
tored after every 150 reflections did not show any significant
change in intensity during the data collection. The data were
corrected for Lorentz and polarization effects, but not for
absorption. The structure was solved by direct-methods with
SHELXTL-Plus package.7 Bloc-diagonal least-squares
refinement was performed. Scattering factors were taken
from the International Tables for X-ray Crystallography.8
Hydrogen atoms, except those for methyl, were located on
DF maps and refined with fixed isotopic temperature factors
2
˚
(U¼0.08 A ). Details of analyses for each compound are
given in the supplementary material.
2. (a) Hosmane, R. S.; Lim, B. B.; Burnett, F. N. J. Org. Chem.
1988, 53, 382. (b) Hosmane, R. S.; Lim, B. B.; Summers, M. F.;
Siriwardane, U.; Hosmane, N. S.; Chu, S. C. J. Org. Chem.
1988, 53, 5309. (c) Hosmane, R. S.; Lim, B. B. Heterocycles
1988, 27, 31. (d) Hosmane, R. S.; Lim, B. B. Synthesis 1988,
242. (e) Afshar, C.; Berman, H. M.; Sawzik, P.; Lessinger, L.;
Lim, B. B.; Hosmane, R. S. J. Crystallogr. Spectrosc. Res.
1987, 17, 533.
Crystallographic data for 9. C14H13N5O5, Mr¼363.3, P1,
˚
a¼9.387(4), b¼9.898(4), c¼11.265(5) A, a¼103.80(3)8,
3
˚
b¼112.75(3)8, g¼101.42(3)8, V¼886.8(7) A , Z¼2,
21
r¼1.36 g cm23, (Mo Ka)¼0.71073 A, m¼1.00 cm
.
˚
Final R¼0.057 for 1494 reflections (I.3.0s(I)).
Crystallographic data for 16. C21H19N5O5, Mr¼421.4,
˚
P2(1)/c, a¼14.122(3), b¼8.560(2), c¼17.710(4) A,
3. (a) Freedman, J.; Huber, E. W. J. Heterocycl. Chem. 1990, 27,
343. (b) Peet, N. P. Synthesis 1984, 1065. and the references
cited therein. (c) Scheiner, P.; Frank, L.; Giusti, I.; Arwin, S.;
Pearson, S. A.; Excellent, F.; Harper, A. P. J. Heterocycl. Chem.
1984, 21, 1817. (d) Bridson, P. K.; Davis, R. A.; Renner, L. S.
J. Heterocycl. Chem. 1985, 22, 753. (e) Peet, N. P.; Sunder, S.
J. Heterocycl.Chem. 1984, 21, 1807.
3
23
˚
b¼103.76(2)8, V¼2079.6(7) A , Z¼2, r¼1.37 g cm
,
(Mo Ka)¼0.71073 A, m¼1.00 cm21. Final R 0.039 for
˚
1428 reflections (I.3.0s(I)).
Crystallographic data for 17. C42H40N10O6, Mr¼780.8,
˚
P21/n, a¼14.932(4), b¼5.806(1), c¼21.992(5) A,
3
23
˚
b¼95.40(2)8, V¼1898.8(8) A , Z¼2, r¼1.37 g cm
,
(Mo Ka)¼0.71073 A, m¼0.88 cm21. Final R¼0.053 for
4. A preliminary account of this work was presented at the 11th
International Round Table on Nucleosides Nucleotides, and
Their Biological Applications, Katholieke Universiteit Leuven,
Belgium, September 7–11, 1994 (Abstr. No. P-41); see the
proceedings of the Round Table: Burnett, F. N.; Lim, B.;
Hosmane, R. S. Nucleosides Nucleotides 1995, 14, 325.
5. Hosmane, R. S.; Bhan, A.; Rauser, M. E. J. Org. Chem. 1985,
50, 5892.
˚
1148 reflections (I.3.0s(I)).
Crystallographic data for 19. C19H16N4O2, Mr¼332.4,
˚
C2/c, a¼24.665(6), b¼5.749(2), c¼23.010(4) A,
3
23
˚
b¼103.94(2)8, V¼3167(2) A , Z¼8, r¼1.394 g cm
,
(Mo Ka)¼0.71073 A, m¼0.094 cm21. Final R¼0.028 for
˚
1346 reflections (I.3.0s (I)).
6. (a) Dauben, W. G.; Lorber, M.; Fullerton, C. S. J. Org. Chem.
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Acknowledgements
This paper is dedicated to Professor Nelson J. Leonard on
the occasion of his 86th birthday. We thank Dr Hongming
Zhang and Dr Narayan Hosmane for single-crystal X-ray
diffraction analyses of compounds 9, 16, 17, and 19. The
research presented herein was supported by grants from the
National Institutes of Health (#CA 71079 and # 9 R01
AI55452). FAB mass spectral data were obtained at the
Michigan State University Mass Spectral Facility which is
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