Synthesis and unusual chemical reactivity of certain novel 4,5-disubstituted 7-benzylpyrrolo[2,3-d][1,2,3]triazines

Article abstract of DOI:10.1021/jo001499i

The fact that only two pyrrolo[2,3-d][1,2,3]triazines heterocycles had been reported in the literature prompted us to initiate studies designed to provide additional members of this ring system. Initial attempts to prepare additional derivatives of the 7-unsubstituted pyrrolo[2,3-d][1,2,3]triazin-4-ones were limited by their low chemical reactivity. Subsequently, 7-benzyl-5-carboxamidopyrrolo-[2,3-d][1,2,3]triazin-4-one (16) was prepared from diethyl 2-nitropyrrole-3,4,-dicarboxylate via an alkylation, ammonolysis, reduction and intramolecular diazocoupling sequence. Conversion of 16 into 7-benzyl-4-(1,2,4-triazol-1-yl)pyrrolo [2,3-d][1,2,3]triazine-5-carbonitrile (17) was accomplished, and nucleophilic displacements of the 4-triazol-1-yl group were studied. Treatment of 17 with NH₃/ CH₃CN gave a mixture of 4-amino-7-benzylpyrrolo[2,3-d][1,2,3]triazine-5-carbonitrile (19) and 2-amino-1-benzylpyrrole-3,4-dicarbonitrile (21). A mechanism to account for the formation of this mixture is described along with studies on the effect that ammonia concentration and a TFA catalyst have on the product ratio. Compound 19 was converted into the 5-carboxamide and 5-thioamide derivatives of 19.

Full text of DOI:10.1021/jo001499i

4776
J . Org. Chem. 2001, 66, 4776-4782
Syn th esis a n d Un u su a l Ch em ica l Rea ctivity of Cer ta in Novel
4,5-Disu bstitu ted 7-Ben zylp yr r olo[2,3-d ][1,2,3]tr ia zin es
Michael T. Migawa† and Leroy B. Townsend*
Department of Chemistry, College of Literature, Sciences and Arts, Department of Medicinal Chemistry,
College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109-1065
leroy.townsend@umich.edu
Received October 18, 2000
The fact that only two pyrrolo[2,3-d][1,2,3]triazines heterocycles had been reported in the literature
prompted us to initiate studies designed to provide additional members of this ring system. Initial
attempts to prepare additional derivatives of the 7-unsubstituted pyrrolo[2,3-d][1,2,3]triazin-4-
ones were limited by their low chemical reactivity. Subsequently, 7-benzyl-5-carboxamidopyrrolo-
[2,3-d][1,2,3]triazin-4-one (16) was prepared from diethyl 2-nitropyrrole-3,4,-dicarboxylate via an
alkylation, ammonolysis, reduction and intramolecular diazocoupling sequence. Conversion of 16
into 7-benzyl-4-(1,2,4-triazol-1-yl)pyrrolo[2,3-d][1,2,3]triazine-5-carbonitrile (17) was accomplished,
and nucleophilic displacements of the 4-triazol-1-yl group were studied. Treatment of 17 with NH3/
CH3CN gave a mixture of 4-amino-7-benzylpyrrolo[2,3-d][1,2,3]triazine-5-carbonitrile (19) and
2-amino-1-benzylpyrrole-3,4-dicarbonitrile (21). A mechanism to account for the formation of this
mixture is described along with studies on the effect that ammonia concentration and a TFA catalyst
have on the product ratio. Compound 19 was converted into the 5-carboxamide and 5-thioamide
derivatives of 19.
In tr od u ction
Many structural analogues of the naturally occurring
purine nucleosides, adenosine and guanosine, have been
synthesized and subsequently demonstrated to be useful
chemotherapeutic agents. These discoveries have prompted
an exceptional growth of research resulting in the
preparation of a vast number of purine ribo- and 2-deoxy-
ribonucleoside analogs.1 While modifications of the sugar
moiety, the heterocylic base and the exocyclic substitu-
ents have been reported, our major research interests
have been focused on modifications of the purine ring per
se. The preparation of these base-modified nucleosides
are synthetically challenging and can result in the
discovery of new classes of chemotherapeutic agents,
potentially with novel biological modes of action.2,3
In view of the important biological activity of many
purine analogues, it was of considerable interest that an
entire class of aza-deazapurine nucleoside analogs, the
pyrrolo[2,3-d][1,2,3]triazine nucleosides, had not been
reported in the literature. These pyrrolo[2,3-d][1,2,3]-
triazines are similar in structure to the imidazo[4,5-d]-
pyrimidines (2-azapurines), differing only in a carbon-
nitrogen ring substitution at C-5, and to the pyrrolo[2,3-
d]pyrimidine nucleosides, differing only in a nitrogen-
F igu r e 1.
carbon ring substitution at C-2. In fact, only two
pyrrolo[2,3-d][1,2,3]triazine heterocycles had been re-
ported4,5 in the literature (1 and 2, Figure 1).
However, the synthetic route for the preparation of 1
and 2 is very limited in regards to exocyclic functional
groups. This fact prompted us to initiate studies designed
to provide pyrrolo[2,3-d][1,2,3]triazines amenable toward
functional group modifications at the C-4, C-5, C-6, and
N-7 positions.
Resu lts a n d Discu ssion
A retrosynthetic disconnection of the pyrrolo[2,3-d]-
[1,2,3]triazine ring system (4) suggests two potential ring
disconnections (Scheme 1). First, disconnection of the
pyrrole ring gives the 1,2,3-triazine precursor (3) from
which the pyrrole portion could be constructed via a
cyclization reaction. Second, disconnection of the 1,2,3-
triazine ring gives a pyrrole precursor (5) from which the
1,2,3-triazine portion could be constructed. The first route
was rejected since a suitably substituted precursor would
be difficult to obtain6 and the monocyclic 1,2,3-triazines
are much more unstable than pyrroles.7 On the other
† Present address: Ibis Therapeutics, a Division of Isis Pharma-
ceuticals, Inc., 2292 Faraday Avenue, Carlsbad, CA 92008.
(1) (a) Chemistry of Nucleosides and Nucleotides; Townsend, L. B.,
Ed.; Plenum Press: New York, 1994; Vol. 3. (b) Chemistry of Nucleo-
sides and Nucleotides; Townsend, L. B., Ed.; Plenum Press: New York,
1991; Vol. 2.
(2) Kosalka, G. W.; Chamberlain, S. D.; Daluge, S. M.; Boyd, F. L.;
Tidwell, J . H.; Martin, M. T.; Harvey, R. J .; Frick, L. W.; Perkins, D.
G.; Wang, L. H.; Drach, J . C.; Townsend, L. B.; Biron, K. K. XII
International Roundtable: Nucleosides, Nucleotides and their Biologi-
cal Application; La J olla, CA, September, 1996.
(4) Roth, H. J .; Eger, K. Arch. Pharm. (Weinheim, Ger.) 1975, 308,
(3) Ptak, R. G.; Borysko, K. Z.; Porcari, A. R.; Buthod, J . L.; Holland,
L. E.; Shipman, C., J r.; Townsend, L. B.; Drach, J . C. AIDS Res. Hum.
Retroviruses 1998, 14, 11315-1322.
186-189.
(5) Steinhilber, D.; Schmidt, K.; Eger, K.; Roth, H. J . Pharm. Res.
1986, 3, 271-277.
10.1021/jo001499i CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/16/2001

Disubstituted 7-Benzylpyrrolo[2,3-d][1,2,3]triazines
J . Org. Chem., Vol. 66, No. 14, 2001 4777
lation13 of pyrrole 6 resulted in very poor yields and some
decomposition of starting material. This is not surprising
since 2-aminopyrroles are well-known to undergo various
side reactions (oxidation, polymerization).14 We then
initiated an alternative approach for the preparation of
N-1-substituted 2-aminopyrrole-3,4-dicarboxamides. In
this approach, the amino group of the 2-amino-3-car-
boxamide precursor would be masked as a nitro group,
and then reduced immediately before the intramolecular
diazo-coupling reaction.
Sch em e 1
Sch em e 2
Therefore, diethyl 1-benzyl-2-nitropyrrole-3,4-dicar-
boxylate (13) was prepared by an alkylation of the
potassium salt of diethyl 2-nitropyrrole-3,4-dicarboxylate
(12) with benzyl bromide. The pyrrole diester 13 was then
treated with methanolic ammonia at 80 °C for 45 h to
obtain the desired dicarboxamide precursor, 1-benzyl-2-
nitropyrrole-3,4-dicarboxamide (14). The structural as-
signment for this compound as the diamide was based
on four D2O exchangeable protons in the 1H NMR
spectrum. A reduction of the nitro group of 14 was then
accomplished to give 2-amino-1-benzylpyrrole-3,4-dicar-
boxamide (15) in a 94% yield. The presence of two
hand, the chemistry of the pyrrole ring system has been
well explored, and the success of an intramolecular diazo-
coupling strategy, in the preparation of several 5:6 fused
systems, supported this method8-11 as our first choice for
the key step in the preparation of pyrrolo[2,3-d][1,2,3]-
triazines (4).
1
additional D2O exchangeable resonances in the H NMR
spectrum of 15 was used to determine that a complete
reduction of the nitro group had occurred.
Initially we chose to explore the reactivity of the N-1-
unsubstituted pyrrole, 2-amino-5-(methylthio)pyrrole-3,4-
dicarboxamide (6),12 toward the reported8 diazo-coupling
conditions. However, diazotization of pyrrole 6 under 6
N HCl/NaNO2 conditions resulted in significant decom-
position. By changing the conditions to tert-butylnitrite/
AcOH, we obtained reasonable yields of the pyrrolo[2,3-
d][1,2,3]triazin-4-one 8 (Scheme 2). Raney nickel reductive
desulfurization of 6 gave the 5-unsubstituted pyrrole 7
and diazotization of 7 gave the N7-unsubstituted pyrrolo-
[2,3-d][1,2,3]triazin-4-one 9.
Treatment of the pyrrolotriazine 8 and pyrrolotriazine
9 individually under a variety of conditions, e.g., POCl3,
POCl3/PCl5, POCl3/1,2,3-triazole/base, alkylation and gly-
cosylation, failed to give any functionalized product. It
was subsequently found that the 6-methylthio moiety of
pyrrolotriazine 8 could be converted to the sulfoxide 10
with hydrogen peroxide in the presence of KOH or to the
sulfone 11 with hydrogen peroxide in acetic acid at reflux
temperature (Scheme 3). Attempts to displace either the
sulfone with a nucleophile (e.g., NaN3, RNH2) or convert
10 or 11 to a precursor suitable for glycosylation failed
under a variety of conditions.
Compound 15 was diazotized15 at -45 °C using sodium
nitrite in 6 N HCl and then allowed to reach room
temperature. The precipitate was collected by filtration
and dried to give a 93% yield of 7-benzyl-5-carboxami-
dopyrrolo[2,3-d][1,2,3]triazin-4-one (16) without the need
for further workup. Lower yields were obtained when the
initial reaction temperature was allowed to rise above
-30 °C. Concomitant functionalization of both the 4- and
the 5-position of pyrrolo[2,3-d][1,2,3]triazine 16 was then
attempted under a variety of conditions. Treatment of
compound 16 with POCl3 and DMAP in acetonitrile15-17
for 10 min at room temperature, followed by quenching
with methanolic ammonia, produced only a trace of a
compound tentatively assigned the structure 7-benzyl-
5-cyanopyrrolo[2,3-d][1,2,3]triazin-4-one, based on the
lack of D2O exchangeable protons in the 1H NMR
spectrum and the presence of a characteristic cyano group
resonance at 115 ppm in the 13C NMR spectrum. Alter-
natively, quenching the aforementioned reaction, after
4 h, with methanolic ammonia or sodium methoxide/
methanol produced very low yields of 7-benzyl-4-meth-
oxypyrrolo[2,3-d][1,2,3]triazine-5-carbonitrile (18, vida
infra). Since POCl3/DMAP had proved unsuccessful, we
opted to try an alternative procedure18 in which a
heterocycle is added to a premixed suspension of POCl3,
1,2,4-triazole and triethylamine. Subjecting 16 to this
procedure gave a 49% yield of 7-benzyl-4-(1,2,4-triazol-
1-yl)pyrrolo[2,3-d][1,2,3]triazine-5-carbonitrile (17). The
presence of two separate triazole proton resonances in
As a result of some difficulty in functionalizing the N-7-
unsubstituted pyrrolo[2,3-d][1,2,3]triazines (i.e., 8, 10,
11), we elected to install a N-7 substituent prior to the
diazo-coupling step. Preliminary attempts at N-1 alky-
(6) Itoh, T.; Matsuya, Y.; Hasegawa, H.; Nagata, K.; Okada, M.;
Ohsawa, A. Chem. Pharm. Bull. 1995, 43, 881-883.
(7) Neunhoeffer, H. 1,2,3-Triazines. In The Chemistry of 1,2,3-
Triazines and 1,2,4-Triazines, Tetrazines, and Pentazines; Neunhoeffer,
H., Ed.; Wiley: New York, 1978.
1
the H NMR spectrum indicated that the 4-(triazol-1-yl)
(8) Montgomery, J . A.; Thomas, H. J . 4-Amino-7-â-D-ribofuranosyl-
7H-imidazo[4,5-d]-v-triazine (2-azaadenosine). In Nucleic Acid Chem-
istry, Improved and New Synthetic Procedures, Methods and Tech-
niques; Townsend, L. B., Tipson, R. S., Eds.; Wiley and Sons: New
York, 1978; Vol. 2.
(13) Bennett, S. M.; Nguyen-Ba, N.; Ogilvie, K. K. J . Med. Chem.
1990, 33, 2162-2173.
(14) Aminopyrroles, Pyrroles. Part Two.; Cirrincione, G., Almerico,
A. M., Aiello, E., Dattolo, G., Eds.; J ohn Wiley & Sons: New York, 1992.
(15) Kelly, J . L.; Wilson, D. C.; Styles, V. L.; Soroko, F. E.; Cooper,
B. R. J . Heterocycl. Chem. 1995, 32, 1417-1421.
(16) Adamiak, R. W.; Biala, E.; Skalski, B. Nucleic Acids Res. 1985,
13, 2989-3003.
(9) Woolley, D. W.; Shaw, E. J . Biol. Chem. 1951, 189, 401-410.
(10) Panzica, R. P.; Townsend, L. B. J . Heterocycl. Chem., 1972, 9,
623-628.
(11) Biraldi, P. G.; Garuti, L.; Roberti, M. Synthesis 1994, 1437-
(17) Adamiak, R. W.; Biala, E.; Skalaski, B. Angew. Chem., Int. Ed.
Engl. 1985, 24, 1054-1055.
(18) Perbost, M.; Hoshiko, T.; Morvan, F.; Swayze, E.; Griffey, R.
H.; Sanghvi, Y. S. J . Org. Chem. 1995, 60, 5150-5156.
1440.
(12) Gewalt, V. K.; Kleinert, M.; Thiele, B.; Hentschel, M. J . Prakt.
Chem. 1972, 2, 303-314.

4778 J . Org. Chem., Vol. 66, No. 14, 2001
Migawa and Townsend
Sch em e 3
Sch em e 4
regioisomer rather than the 4-(triazol-4-yl) regioisomer
was obtained.
We then initiated studies designed to explore the
reactivity of the 4-triazol-1-yl group toward nucleophilic
displacement. We reasoned that treatment of 17 with
ammonia should give an amino group at the 4-position
of the pyrrolo[2,3-d][1,2,3]triazine ring. However, treat-
ment of the pyrrolotriazine 17 with methanolic ammonia
at room temperature for 1 h gave 7-benzyl-4-methoxy-
pyrrolo[2,3-d][1,2,3]triazine-5-carbonitrile (18) as the only
product. Morever, treatment of compound 17 with meth-
anolic ammonia for 27 h at room temperature, followed
by 35 h at 45 °C, gave a 19% yield of 4-amino-7-
benzylpyrrolo[2,3-d][1,2,3]triazine-5-carbonitrile (19) and
a 34% yield of methyl 4-amino-7-benzylpyrrolo[2,3-d]-
[1,2,3]triazine-5-imidate (20), along with some decompo-
sition products. Longer reaction times and higher tem-
peratures resulted in lower yields of compounds 19 and
20. On the other hand, treatment of 17 with liquid
ammonia in a sealed tube at room temperature for 2 h
gave a 61% yield of 4-amino-7-benzylpyrrolo[2,3-d][1,2,3]-
triazine-5-carbonitrile (19) as the only product.
the pyrrole 21. Therefore, 15N-labeling studies19 have
suggested that this reaction may proceed by a retro
Diels-Alder reaction involving the elimination of N-2 and
N-3 from the imino tautomer of compound 19. This
prompted us to determine whether the 4-aminopyrrolo-
triazine 19 was being converted directly into the pyrrole
21 under milder conditions than we had previously19
used, i.e., close to room temperature rather than heating
at g250 °C. Therefore, we subjected the 4-aminopyrrolo-
[2,3-d][1,2,3]triazine 19 to essentially the same reaction
conditions that produced the mixture of 19 and 21 from
17, i.e., a 0.5 M solution of ammonia in acetonitrile at
45 °C. To our surprise, we recovered only the starting
material. This would suggest that both 19 and 21 arise
from a common intermediate. A mechanism that takes
these facts into account is proposed in Scheme 5.
It was of some interest that during our studies to
establish optimum reaction conditions for a clean conver-
sion of 17 to 19, we found that when the pyrrolo[2,3-d]-
[1,2,3]triazine 17 was treated with a dilute solution of
ammonia in acetonitrile, a mixture of pyrrolo[2,3-d][1,2,3]-
triazine 19 and 2-amino-1-benzylpyrrole-3,4-dicarboni-
trile (21) was obtained (Scheme 4).
Nucleophilic addition of ammonia results in the forma-
tion of a Meisenheimer complex (22). The formation of
this intermediate is followed by nitrogen elimination (22
to 23 (path b)) and 1,2,4-triazole elimination to give
pyrrole 21 or a simple elimination of the 1,2,4-triazole
We have recently reported19 that compound 19 under-
goes a thermal elimination of nitrogen at 250 °C to give
(19) Migawa, M. T.; Townsend, L. B. Org. Lett. 1999, 1, 537-539.

Disubstituted 7-Benzylpyrrolo[2,3-d][1,2,3]triazines
J . Org. Chem., Vol. 66, No. 14, 2001 4779
Sch em e 5
(path a) to give 4-aminopyrrolotriazine 19. In the case of
the thermal elimination, the aromaticity of the pyrrolo-
triazine ring must be disrupted in order to undergo the
concerted thermal elimination, while in the case of the
Meisenheimer complex, the 1,2,3-triazine portion of the
heterocycle already has disrupted aromaticity, allowing
a nitrogen elimination to occur at a lower temperature.
Similar to the thermal elimination, the reaction that
proceeds through the Meisenheimer complex is assumed
to lose nitrogen from the 2- and 3-positions of compound
17.
We next initiated studies to ascertain the effect that a
change in the ammonia concentration would have on the
pyrrolo[2,3-d][1,2,3]triazine 19/ pyrrole 21 product ratio
(Figure 2). As higher concentrations of ammonia were
used, the 4-aminopyrrolotriazine formation was favored
over pyrrole formation. In fact, a variation of the product
ratio (19/21) of 4 to 14 was observed over a concentration
range of 0.16-0.62 M.
results of subjecting compound 17 to various concentra-
tions of trifluoroacetic acid (TFA) in a 0.4 M NH3/
acetonitrile solution are shown in Figure 3. Adding TFA
as an acid catalyst dramatically increases the 19/21
product ratio. When 4 equiv of TFA was used, the 19/21
product ratio increased to 47:1 without any significant
change in total yield.
The mechanism proposed in Scheme 6 accounts for the
observed variation in the 19/21 product ratio (Figure 2)
resulting from an increased ammonia concentration and
the observed increase in the 19/21 product ratio resulting
from the addition of TFA (Figure 3).
A protonation or deprotonation (or both) of intermedi-
ate 22 would result in the formation of intermediates 26
or 27, respectively. This catalytic effect would favor
triazole elimination (i.e., path a) over nitrogen elimina-
tion (i.e., path b).
Therefore, the mechanism proposed in Scheme 5 suc-
cessfully accounts for the conversion of the pyrrolo[2,3-
d][1,2,3]triazine 17 into 4-aminopyrrolo[2,3-d][1,2,3]-
triazine 19 and pyrrole 21 and explains the apparent
Additionally, we sought to determine the effect that
an acid catalyst would have on the product ratios. The
F igu r e 2. Reaction was run at 45 °C for 7 days. Ratios were
determined by integration of the 1H NMR methylene reso-
nances. Starting material was recovered in the case where
[NH3] is 0.16 (32%) and 0.31 (6%).
F igu r e 3. Reaction was run in 0.4 M NH3 at 45 °C for 7 days.
Ratios and yields were determined by integration of the 1H
NMR methylene resonances. Total yields were 80% ( 5% with
starting material being recovered in each case (8% ( 3%).

4780 J . Org. Chem., Vol. 66, No. 14, 2001
Migawa and Townsend
Sch em e 6
spectroscopy and elemental analyses were performed by the
University of Michigan Chemistry Department or by MHW
Laboratories, Phoenix, AZ.
Sch em e 7
2-Am in op yr r ole-3,4-d ica r boxa m id e (7). A stirred mix-
ture of isopropyl alcohol (110 mL), commercial grade Raney
nickel (10 g), and 2-amino-5-(methylthio)pyrrole-3,4-dicar-
boxamide12 (6, 2.14 g, 10.0 mmol) was heated at reflux
temperature for 24 h. At that time, the reaction mixture was
filtered (hot) through Celite. The Celite was resuspended in
2-propanol (70 mL) and then filtered through another bed of
Celite. The solvent portions were combined and evaporated
under reduced pressure, and the resultant solid was dried
under reduced pressure at 78 °C for 16 h to yield 1.10 g (65%)
of a dark product. This solid was recrystallized from hot water
and dried under reduced pressure at 78 °C for 24 h to yield
0.79 g (47%) of 7 as purple needles: mp > 210 °C (dec); Rf )
0.46 (40:9:1, EtOAc/MeOH/H2O); 1H NMR (DMSO-d6, 300
MHz) δ 10.51 (bs, 1H, D2O exchangeable, NH), 9.83 (bs, 1H,
D2O exchangeable, CONH2), 7.51 (bs, 1H, D2O exchangeable,
CONH2), 6.97 (bs, 2H, collapses to s, 1H upon D2O addition,
CONH2 and ArH), 6.44 (bs, 1H, D2O exchangeable, CONH2),
6.11 (bs, 2H, D2O exchangeable, NH2); 13C NMR (DMSO-d6,
75 MHz) δ 168.6, 168.4, 147.8, 116.4, 113.6, 93.2. Anal. Calcd
for C6H8N4O2: C, 42.86; H, 4.80; N, 33.32. Found: C, 42.89;
H, 4.77; N, 32.94.
discrepancy between the previously reported19 thermal
elimination of compound 19 and this recent observation.
Finally, two additional modifications of the 5-position
of the pyrrolo[2,3-d][1,2,3]triazine system were accom-
plished. Compound 19 was treated with a presaturated
solution of hydrogen sulfide gas, in a mixture of methanol
and sodium methoxide, in a sealed vial at 90 °C to give
the thioamide 28 as a hemihydrate (Scheme 7). Alter-
natively, the preparation of the amide 29 has been
accomplished in excellent yield by treating the 4-ami-
nopyrrolotriazine 19 with 30% hydrogen peroxide in
ethanol and ammonium hydroxide.
In conclusion, we have developed a general route for
the synthesis of 4,5-disubstituted 7-benzylpyrrolo[2,3-d]-
[1,2,3]triazines. Additionally, a novel nitrogen elimina-
tion was discovered which may serve to explain some of
the interesting chemical reactivity of this novel ring
system. We are currently expanding this methodology to
prepare novel pyrrolo[2,3-d][1,2,3]triazine nucleosides.
5-Ca r b oxa m id o-6-(m e t h ylt h io)p yr r olo[2,3-d ][1,2,3]-
t r ia zin -4-on e (8). A stirred mixture of 2-amino-5-(methyl-
thio)pyrrole-3,4-dicarboxamide12 (6, 2.14 g, 10.0 mmol), AcOH
(glacial, 100 mL), and H2O (50 mL) was cooled to 0 °C (ice
bath), and tert-butylnitrite (3.17 mL, 24.0 mmol) was added
over a 5 min period. The reaction was allowed to stir at 0 °C
for 15 min and then at room temperature for 90 min. At that
time, the flask was covered and allowed to stand for 16 h. The
resultant mixture was then reduced to one-half of its original
volume and cooled at 10 °C for 1 h, and the precipitate was
collected by filtration, washed with H2O (100 mL), and dried
under reduced pressure at 78 °C for 24 h to give 1.41 g (64%)
of 8 as a purple solid. An analytical sample was prepared by
dissolving 530 mg of 8 in NH4OH (conc, 60 mL), treating with
charcoal, filtering, and reprecipitating with HCl (conc). The
precipitate was collected by filtration and dried under reduced
pressure at 78 °C for 24 h to give 236 mg (45% recovery) of 8
as a white solid: mp > 200 °C (dec); 1H NMR (DMSO-d6, 300
MHz) δ 15.03 (bs, 1H, D2O exchangeable, NH),13.31 (bs, 1H,
D2O exchangeable, NH), 9.31 (bs, 1H, D2O exchangeable,
CONH2), 7.29 (bs, 1H, D2O exchangeable, CONH2), 2.60 (s,
3H, CH3); 13C NMR (DMSO-d6, 75 MHz) δ 164.1, 156.0, 145.8,
Exp er im en ta l Section
Melting points were determined on a Thomas-Hoover ap-
paratus and are uncorrected. Silica gel, SilicAR 40-63 µm
230-400 mesh was used for chromatography. Flash column
chromatography refers to the chromatography technique
described by Still et al. (J . Org. Chem. 1978, 43, 2923-2925).
(X% EtOAc/Hex, Y cm × Z cm) means the solvent system that
is used as the eluent, the diameter of the column (Y) and the
height of silica gel (Z). Solvent systems are expressed as a
percentage of the more polar component with respect to total
volume (v/v %). Thin-layer chromatography (TLC) was per-
formed on prescored SilicAR 7GF plates (Analtech, Newark,
DE). Compounds were visualized by illuminating with UV
light (254 nm) or by spraying with 10% methanolic sulfuric
acid followed by charring on a hot plate. Evaporations were
carried out under reduced pressure (water aspirator) with the
bath temperature not exceeding 50 °C, unless specified oth-
erwise. The 1H (300 MHz) and 13C (75 MHz) NMR spectra were
recorded and the chemical shifts are expressed in parts per
one million relative to the standard chemical shift of the
solvent for DMSO-d6, 2.50 ppm (1H NMR), 39.50 ppm (13C
NMR), and relative to tetramethylsilane as an internal
standard for CDCl3 (1H NMR), and relative to the standard
chemical shift of the solvent for 13C NMR (77.0 ppm). Mass
144.7, 108.6, 107.4, 12.26; IR (KBr) 3386, 3333, 1598 cm-1
;
Anal. Calcd for C7H7N5O2S: C, 37.33; H, 3.13; N, 31.09.
Found: C, 37.50; H, 2.86; N, 30.85.
5-Ca r b oxa m id op yr r olo[2,3-d ][1,2,3]t r ia zin -4-on e (9).
Compound 9 was prepared in a 38% (673 mg) yield from 7
following the procedure used for the preparation of 8: mp >
1
200 °C (dec); H NMR (DMSO-d6, 300 MHz) δ 15.11 (bs, 1H,
D2O exchangeable, NH),13.60 (bs, 1H, D2O exchangeable, NH),
9.21 (bs, 1H, D2O exchangeable, CONH2), 8.06 (s, 1H, H-6),
7.48 (bs, 1H, D2O exchangeable, CONH2); 13C NMR (DMSO-
d6, 75 MHz) δ 162.8, 157.0, 145.6, 130.7, 114.9, 105.5; HRMS
(70 eV) calcd for C6H5N5O2 179.0443, found 179.0450.
5-Ca r boxa m id o-6-su lfin ylp yr r olo[2,3-d ][1,2,3]tr ia zin -
4-on e (10). A solution of 5-carboxamido-6-(methylthio)pyrrolo-
[2,3-d][1,2,3]triazin-4-one (8, 500 mg, 2.2 mmol), 1 N KOH (10
(20) Duffy, T. D.; Wibberley, D. G. J . Chem. Soc., Perkin Trans. 1
1974, 1921-1929.

Disubstituted 7-Benzylpyrrolo[2,3-d][1,2,3]triazines
J . Org. Chem., Vol. 66, No. 14, 2001 4781
mL) and 30% H2O2 (2 mL) was allowed to stir at room
temperature. After 1 h, an additional portion of 30% H2O2 (2
mL) was added, then another portion of 30% H2O2 (2 mL) was
added after 2 h, and the reaction was allowed to stir for an
additional 1 h. At that time, the pH of the reaction mixture
was adjusted to 5 with 5 N HCl. The precipitate was collected
by filtration and dried under reduced pressure at 50 °C for 24
h to give 361 mg (67%) of 10 which was slightly colored but
pure by 1H NMR. An analytical sample was prepared by
dissolving 210 mg in 1 N KOH (30 mL), treating with charcoal,
filtering, and reprecipitating with 4 N HCl. The precipitate
was collected by filtration and dried under reduced pressure
at 50 °C for 48 h to give 140 mg (67% recovery) of 10 as a
white solid: mp > 250 °C (dec); 1H NMR (DMSO-d6, 300 MHz)
δ 15.28 (bs, 1H, D2O exchangeable, NH),14.38 (bs, 1H, D2O
exchangeable, NH), 9.30 (bs, 1H, D2O exchangeable, CONH2),
7.81 (bs, 1H, D2O exchangeable, CONH2), 3.02 (s, 3H, CH3);
13C NMR (DMSO-d6, 75 MHz) δ 162.9, 156.6, 147.5, 145.8,
111.9, 107.0, 42.2. Anal. Calcd for C7H7N5O3S: C, 34.85; H,
2.92; N, 29.03. Found: C, 34.73; H, 3.14; N, 28.86.
5-Ca r boxa m id o-6-m eth ylsu lfon ylp yr r olo[2,3-d ][1,2,3]-
t r ia zin -4-on e (11). A solution of 5-carboxamido-6-(methyl-
thio)pyrrolo[2,3-d][1,2,3]triazin-4-one (8, 1.29 g, 5.73 mmol),
AcOH (glacial, 20 mL) and 30% H2O2 (10 mL) was heated at
reflux temperature for 3 h. At that time, the reaction mixture
was cooled to 10 °C. The precipitate was collected by filtration,
washed with H2O (20 mL) and MeOH (20 mL). and dried under
reduced pressure at 50 °C for 48 h to give 910 mg (62%) of 11
as a white solid: mp > 200 °C (dec); 1H NMR (DMSO-d6, 300
MHz) δ 15.31 (bs, 1H, D2O exchangeable, NH),14.0 (bs, 1H,
D2O exchangeable, NH), 9.37 (bs, 1H, D2O exchangeable,
CONH2), 7.81 (bs, 1H, D2O exchangeable, CONH2), 3.66 (s,
3H, CH3); 13C NMR (DMSO-d6, 75 MHz) δ 161.6, 156.6, 143.7,
137.6, 115.9, 107.0, 43.5. Anal. Calcd for C7H7N5O4S: C, 32.69;
H, 2.74; N, 27.23. Found: C, 32.72; H, 2.80; N, 27.15.
2-Am in o-1-ben zylp yr r ole-3,4-d ica r boxa m id e (15). Five
drops of 12 N HCl was added to a stirred mixture of 1-benzyl-
2-nitropyrrole-3,4-dicarboxamide (14, 726 mg, 2.52 mmol), iron
(reduced, 844 mg, 15 mmol), and 50% ethanol (aq, 25 mL).
The suspension was heated at reflux temperature in the dark
for 1 h, at which time it was filtered hot through a bed of Celite
and washed with hot 50% ethanol (aq, 100 mL). The solvent
was evaporated under reduced pressure until a volume of 5
mL was obtained. After cooling the mixture to 0 °C, the
precipitate was collected by filtration and then washed with
cold water (5 mL). Drying under reduced pressure at 78 °C
for 48 h gave 612 mg (94%) of 15 as a brown-red solid: mp
220 °C; 1H NMR (DMSO-d6, 300 MHz) δ 9.84 (bs, 1H, CONH2,
D2O exchangeable), 7.52 (bs, 1H, CONH2, D2O exchangeable),
7.3-7.0 (m, 6H, colapses to 5H upon addition of D2O), 7.06 (s,
1H, ArH), 6.40 (bs, 1H, CONH2, D2O exchangeable), 6.21 (bs,
2H, D2O exchangeable) 5.00 (s, 2H, CH2); 13C NMR (DMSO-
d6, 75 MHz) δ 168.1 (2 carbons), 147.4, 137.1, 128.6, 127.5,
127.2, 119.6, 113.5, 93.5, 47.5. Anal. Calcd for C13H14N4O2: C,
60.45; H, 5.46; N, 21.69. Found: C, 60.23; H, 5.68; N, 21.51.
7-Ben zyl-5-ca r boxa m id op yr r olo[2,3-d ][1,2,3]tr ia zin -4-
on e (16). A stirred solution of 2-amino-1-benzylpyrrole-3,4-
dicarboxamide (15, 258 mg, 1.0 mmol) in 6 N HCl (10 mL)
was cooled to -45 °C in a dry ice/acetonitrile bath. A solution
of sodium nitrite (120 mg, 2.0 mmol in 2 mL water) was then
added dropwise over a period of 5 min (2 mL of ethanol was
added to facilitate stirring). The reaction was allowed to
proceed at room temperature for 2 h at which time the
precipitate was collected by filtration and washed with cold
water (10 mL). Drying the solid under reduced pressure at 78
°C for 24 h gave 249 mg (93%) of 16 which was sufficiently
pure for further reactions. An analytical sample was prepared
by adding 234 mg of 16 to a 50% aqueous ethanol solution
(125 mL) at reflux temperature. Allowing the solution to stand
for 12 h at room temperature, collecting the precipitate by
filtration, and drying as before, gave 180 mg (77% recovery)
of 16: mp 234-235 °C; 1H NMR (DMSO-d6, 300 MHz) δ 15.24
(bs, 1H, D2O exchangeable, NH), 9.14 (bs, 1H, D2O exchange-
able, CONH2), 8.24 (s, 1H, ArH), 7.52 (bs, 1H, D2O exchange-
able, CONH2), 7.4-7.3 (m, 5H, ph), 5.63 (s, 2H, CH2); 13C NMR
(DMSO-d6, 75 MHz) δ 162.5, 156.7, 144.1, 136.4, 133.4, 128.8,
128.1, 127.8, 114.4, 106.0, 49.1. Anal. Calcd for C13H11N5O2:
C, 57.99; H, 4.12; N, 26.01. Found: C, 58.11; H, 4.38; N, 26.33.
7-Be n zyl-4-(1,2,4-t r ia zol-1-yl)p yr r olo[2,3-d ][1,2,3]-
tr ia zin e-5-ca r bon itr ile (17). A stirred suspension of 1,2,4-
triazole (18.4 g, 266 mmol) in CH3CN (150 mL), under argon,
was treated with phosphorus oxychloride (5.5 mL, 59 mmol),
and then the white suspension was cooled to 0 °C. Triethy-
lamine (37 mL, 266 mmol) was added, and the mixture was
allowed to stir at 0 °C for 1 h, at which time 7-benzyl-5-
carboxamidopyrrolo[2,3-d][1,2,3]triazin-4-one (16, 2.0 g, 7.4
mmol) was added in one portion. The reaction mixture was
stirred for 4.5 h at room temperature and filtered through
Celite, and the filter cake was washed with CH3CN (100 mL).
The filtrate and washing were evaporated under reduced
pressure, and the oily residue was dissolved in CHCl3 (250
mL) and washed successively with sodium bicarbonate solution
(2 × 100 mL), H2O (100 mL), and brine (100 mL). The organic
layer was dried (MgSO4) and filtered, and the filtrate was
evaporated under reduced pressure to give a brown solid,
which was purified by flash chromatography (CHCl3, 4 cm ×
20 cm). The resultant solid, Rf ) 0.39 (50% EtOAc/hexanes),
was recrystallized from CHCl3/petroleum ether and dried
under reduced pressure at 78 °C for 24 h to give 1.10 g (49%)
of 17 as light blue needles: mp 238-240 °C; 1H NMR (DMSO-
d6, 300 MHz) δ 9.85 (s, 1H), 9.32 (s, 1H), 8.61 (s, 1H), 7.4-7.3
(m, 5H, ph), 5.81 (s, 2H, CH2); 13C NMR (DMSO-d6, 75 MHz)
δ 154.3, 149.5, 145.7, 144.6, 144.4, 135.4, 128.9, 128.3, 128.0,
114.2, 103.1, 85.1, 49.5. Anal. Calcd for C15H10N8: C, 59.60;
H, 3.33; N, 37.07. Found: C, 59.69; H, 3.49; N, 37.21.
Dieth yl 1-Ben zyl-2-n itr op yr r ole-3,4-d ica r boxyla te (13).
A suspension of DMSO (20 mL) and KOH (powdered, 499 mg,
8.9 mmol) was stirred for 75 min under argon, at which time
a clear solution was observed. Diethyl 2-nitropyrrole-3,4-
dicarboxylate20 (12, 1.5 g, 5.9 mmol) was added to the solution
in one portion, followed by the dropwise addition of benzyl
bromide (1.06 mL, 8.9 mmol) over a 5 min period. After 2.5 h,
the reaction mixture was poured onto H2O (150 mL), extracted
with EtOAc (2 × 75 mL), dried (MgSO4), and filtered. The
filtrate was evaporated under reduced pressure, hexanes (20
mL) was added to the oil, and the resulting precipitate was
collected by filtration. Drying this solid under reduced pressure
at 50 °C for 24 h gave a quantitative yield of 13 as a yellow
powder. Recrystallization of this powder from methanol and
drying under reduced pressure at 78 °C for 48 h yielded 1.21
g (61%) of a white solid. An additional 505 mg (25%) of 13
was obtained from the mother liquor for a total yield of 1.72 g
1
(86%): mp 118-119 °C; Rf ) 0.45 (30% EtOAc/hexanes); H
NMR (DMSO-d6, 300 MHz) δ 8.22 (s, 1H, ArH), 7.4-7.2 (m,
5H, Ph), 5.64 (q, 2H, CH2), 5.60 (s, 2H, CH2), 4.24 (q, 2H, CH2),
1.27 (t, 3H, CH3), 1.25 (t, 3H, CH3); 13C NMR (DMSO-d6, 75
MHz) δ 162.3, 161.0, 135.9, 132.9, 132.7, 128.8, 128.0, 126.8,
121.3, 112.3, 61.7, 60.7, 53.3, 14.0, 13.7. Anal. Calcd for
C
17H18N2O6: C, 58.96;, 5.24; N, 8.09. Found: C, 58.83; H, 5.16;
N, 8.02.
1-Ben zyl-2-n it r op yr r ole-3,4-d ica r b oxa m id e (14). Di-
ethyl 1-benzyl-2-nitropyrrole-3,4-dicarboxylate (13, 1.05 g, 3.03
mmol) in methanolic ammonia (40 mL, saturated at 0 °C) was
heated in a sealed vial at 80 °C for 45 h. The reaction was
then cooled to -15 °C, and the precipitate was collected by
filtration, washed with methanol (20 mL), and dried under
reduced pressure at 78 °C for 2 days to give 726 mg (83%) of
14 as white crystals: mp > 295 °C (dec); 1H NMR (DMSO-d6,
300 MHz) δ 8.03 (bs, 1H, CONH2, D2O exchangeable), 7.90 (s,
1H, ArH), 7.68 (bs, 1H, CONH2, D2O exchangeable), 7.4-7.2
(m, 7H, Ph, 2-CONH2, collapses to 5H upon addition of D2O),
5.56 (s, 2H, CH2); 13C NMR (DMSO-d6, 75 MHz) δ 164.8, 162.8,
136.3, 133.1, 130.6, 128.8, 127.9, 126.9, 123.3, 117.1, 53.0.
Anal. Calcd for C13H12N4O4: C, 54.17; H, 4.20; N, 19.44.
Found: C, 54.11; H, 4.33; N, 19.39.
7-Ben zyl-4-m eth oxyp yr r olo[2,3-d ][1,2,3]tr ia zin e-5-ca r -
bon itr ile (18). Methanolic ammonia (15 mL, sat. at 0 °C) was
added to 7-benzyl-4-(1,2,4-triazol-1-yl)pyrrolo[2,3-d][1,2,3]-
triazine-5-carbonitrile (17, 342 mg, 1.13 mmol) in a pressure
tube and the tube was sealed. The reaction was stirred for 1

4782 J . Org. Chem., Vol. 66, No. 14, 2001
Migawa and Townsend
h at room temperature. The solvent was then removed under
reduced pressure and subjected to silica gel chromatography
(20% EtOAc/hexanes, 30% EtOAc/hexanes, and then 35%
EtOAc/hexanes, 2 cm × 20 cm). The resultant solid, Rf ) 0.76
(50% EtOAc/hexanes), was recrystallized from EtOAc/hexanes
and dried under reduced pressure at 78 °C for 36 h to give 40
mg (13%) of 18 as a white solid (note: this product decomposes
on the column!): mp 177-178 °C; Rf ) 0.76 (50% EtOAc/
(KBr) 3389-3219, 2217, 1655 cm-1. Anal. Calcd for C13H10N4:
C, 70.26; H, 4.54; N, 25.21. Found: C, 70.13; H, 4.82; N, 25.31.
Nu cleop h ilic Disp la cem en t Meth od . A pressure tube
containing 1-benzyl-4-(triazol-1-yl)pyrrolo[2,3-d][1,2,3]triazine-
5-carbonitrile (17, 20 mg, 0.06 mmol) and NH3 (0.4 M in CH3-
CN, 3 mL) was sealed and stirred at 45 °C for 7 days. At that
time the solvent was evaporated to a yellow oil which was
dissolved in EtOAc (5 mL) and washed successively with H2O
(5 mL) and brine (20 mL). The aqueous layers were back
extracted with EtOAc (20 mL), and the combined organic
layers were dried (Na2SO4), filtered through a 0.5 in. plug of
silica gel, and then evaporated under reduced pressure to give
1
hexanes); H NMR (DMSO-d6, 300 MHz) δ 8.93 (s, 1H, ArH),
7.34 (m, 5H, Ph), 5.72 (s, 2H, CH2), 4.28 (s, 3H, OCH3); 13C
NMR (DMSO-d6, 75 MHz) δ 158.3, 148.1, 140.6, 135.8, 128.8,
128.2, 127.8, 113.8, 102.8, 82.0, 55.5, 49.4. Anal. Calcd for
C14H11N5O: C, 63.39; H, 4.18; N, 26.40. Found: C, 63.22; H,
3.90; N, 26.15.
1
a yellow oil which was identified by H NMR as a mixture of
compounds 19 and 21.
4-Am in o-7-ben zylp yr r olo[2,3-d ][1,2,3]tr ia zin e-5-ca r bo-
n itr ile (19). Ammonia (15 mL) was condensed into a steel tube
containing 7-benzyl-4-(1,2,4-triazol-1-yl)pyrrolo[2,3-d][1,2,3]-
triazine-5-carbonitrile (17, 472 mg, 1.56 mmol). The tube was
sealed, and the mixture was stirred for 2 h at room temper-
ature. At that time the ammonia was slowly evaporated, and
the resultant solid was subjected to column chromatography
(CHCl3 then EtOAc, 2 cm × 20 cm). The resultant solid, Rf )
0.18 (50% EtOAc/hexanes), was recrystallized from H2O/
methanol and dried under reduced pressure at 78 °C for 24 h
to give 235 mg (60%) of 19 as a white solid: mp 225-226 °C;
Rf ) 0.18 (50% EtOAc/hexanes); 1H NMR (DMSO-d6, 300 MHz)
δ 8.68 (s, 1H, ArH), 7.43 (s, 2H, D2O exchangeable, NH2), 7.33
(m, 5H, Ph), 5.59 (s, 2H, CH2); 13C NMR (DMSO-d6, 75 MHz)
δ 152.8, 146.1, 138.2, 136.2, 128.8, 128.1, 127.7, 114.3, 98.7,
81.8, 48.8. Anal. Calcd for C13H10N6: C, 62.39; H, 4.03; N,
33.58. Found: C, 62.21; H, 4.08; N, 33.31.
Meth yl 4-Am in o-7-ben zylp yr r olo[2,3-d ][1,2,3]tr ia zin e-
5-im id a te (20). Methanolic ammonia (15 mL, saturated at 0
°C) was added to 7-benzyl-4-(1,2,4-triazol-1-yl)pyrrolo[2,3-d]-
[1,2,3]triazine-5-carbonitrile (17, 206 mg, 0.68 mmol) in a
pressure tube, and the tube was sealed. The reaction mixture
was stirred for 27 h at room temperature, followed by 35 h at
45 °C. The solvent was then removed under reduced pressure
and subjected to silica gel chromatography (20% EtOAc/
hexanes, 30% EtOAc/hexanes, and then EtOAc, 2 cm × 20 cm),
and the fractions containing the product, Rf ) 0.22 (EtOAc),
were evaporated to dryness, suspended in MeOH (5 mL),
collected by filtration, and dried under reduced pressure at
78 °C for 36 h to give 66 mg (34%) of 20 as a white solid.
Compound 19 was also isolated (33 mg, 19%). Imidate 20: mp
207-208 °C; Rf ) 0.22 (EtOAc); 1H NMR (DMSO-d6, 300 MHz)
δ 9.78 (bs, 1H, D2O exchangeable), 8.29 (bs, 1H, D2O exchange-
able), 8.11 (bs, 1H), 7.77 (bs, 1H, D2O exchangeable), 7.32 (bs,
5H, Ph), 5.55 (s, 2H, CH2), 3.77 (s, 3H, CH3); 13C NMR (DMSO-
d6, 75 MHz) δ 159.8, 154.1, 146.6, 137.0, 131.2, 128.7 (2
carbons), 127.8, 127.7, 109.1, 97.2, 52.0. Anal. Calcd for
4-Am in o-7-b en zylp yr r olo[2,3-d ][1,2,3]t r ia zin e-5-t h io-
ca r boxa m id e (28). For 30 min, hydrogen sulfide (g) was
passed through a solution of sodium methoxide (97 mg, 1.8
mmol) in methanol maintained at 0 °C in an ice bath. This
solution was then transferred to a pressure flask containing
4-amino-7-benzylpyrrolo[2,3-d][1,2,3]triazine-5-carbonitrile (19,
180 mg, 0.72 mmol), and the flask was sealed and heated at
90 °C for 3 h. The solution was then cooled to room temper-
ature, and the pH was adjusted to 7 with 1 N HCl. The solvent
was evaporated under reduced pressure, the resultant solid
was dissolved in DMF (40 mL), and H2O (120 mL) was then
added rapidly to give a precipitate which was collected by
filtration and dried under reduced pressure at 60 °C for 24 h.
The resultant solid was washed with Et2O (10 mL) and EtOAc
(10 mL) and dried as before. After suspending in hot methanol,
cooling to room temperature, collecting by filtration, and
drying as before, 190 mg (90%) of 28 was obtained as a
1
hemihydrate: mp 241-242 °C; Rf ) 0.66 (EtOAc); H NMR
(DMSO-d6, 300 MHz) δ 9.76 (bs, 1H, D2O exchangeable), 9.60
(bs, 1H, D2O exchangeable), 8.30 (s, 2H, D2O exchangeable),
8.23 (s, 1H, H-6), 7.34 (m, 5H, Ph), 5.56 (s, 2H, CH2); 13C NMR
(DMSO-d6, 75 MHz) δ 191.9, 153.5, 146.9, 136.5, 129.8, 128.8,
127.9, 127.8, 119.9, 97.3, 48.2. Anal. Calcd for C13H12N6S‚
0.5H2O: C, 53.23; H, 4.47; N, 28.65. Found: C, 53.44; H, 4.27;
N, 28.32.
4-Am in o-7-b en zylp yr r olo[2,3-d ][1,2,3]t r ia zin e-5-ca r -
boxa m id e (29). A solution of NH4OH (conc, 5 mL), ethanol
(2 mL), 30% hydrogen peroxide (2 mL), and 4-amino-7-
benzylpyrrolo[2,3-d][1,2,3]triazine-5-carbonitrile (19, 300 mg,
1.20 mmol) was allowed to stir at room temperature for 3 h.
The precipitate that formed during the course of the reaction
was collected by filtration, washed with H2O (20 mL), and
dried at 60 °C under reduced pressure to give 298 mg (93%)
of 29 as a yellow solid. This solid was suspended in EtOH/
H2O (1:1, 50 mL), and the suspension was heated on a steam
bath for 10 min. The flask was cooled to room temperature,
and the precipitate was collected by filtration and dried as
before to give 285 mg (96% recovery) of pure 29: mp 289-290
°C; Rf ) 0.30 (10% MeOH/chloroform); 1H NMR (DMSO-d6,
300 MHz) δ 8.30 (s, 1H, H-6), 8.5-7.5 (bs, 2H, D2O exchange-
able), 8.09 (bs, 1H, D2O exchangeable, CONH2), 7.54 (bs, 1H,
D2O exchangeable, CONH2), 7.3 (m, 5H, ph), 5.58 (s, 2H, CH2);
13C NMR (DMSO-d6, 75 MHz) δ 165.4, 153.8, 146.7, 136.8,
131.1, 128.9, 128.0, 127.7, 109.9, 97.9, 48.1. Anal. Calcd for
C
14H11N6O: C, 59.56; H, 5.00; N, 29.77 Found: C, 59.70; H,
5.12; N, 29.87.
2-Am in o-1-ben zylp yr r ole-3,4-d ica r bon itr ile (21) a n d /
or 4-Am in o-7-ben zylp yr r olo[2,3-d ][1,2,3]tr ia zin e-5-ca r -
bon itr ile (19). Th er m a l Meth od . A 50 mL Pyrex glass test
tube was charged with 4-amino-7-benzylpyrrolo[2,3-d][1,2,3]-
triazine-5-carbonitrile (19, 200 mg, 0.66 mmol) and slowly
heated neat at 250 °C for 30 s. During this time a very rapid
gas evolution commenced. When the vigorous gas release
ceased, the resultant amber liquid was cooled to room tem-
perature. The solidified compound was dissolved in 10%
MeOH/chloroform (25 mL) and filtered, and the filtrate was
evaporated under reduced pressure to dryness. Chloroform/
Et2O (1:1, 25 mL) was added, and after the filtrate was filtered
and evaporated to dryness, 131 mg (89%) of compound 21 was
C
13H12N6O: C, 58.20; H, 4.51; N, 31.33. Found: C, 58.61; H,
4.63; N, 31.08.
Ack n ow led gm en t. The authors would like to thank
Mr. J ack Hinkley for the large-scale preparation of
compounds 6, 7, and 12, Professor Rich Lawton for
useful discussions, and Ms. Kimberly Barrett for as-
sistance in the preparation of this manuscript. This
research was supported by research grants U19-
AI31718 and 5-R01-AI-36872 from the National Insti-
tute of Allergy and Infectious Diseases, the National
Institutes of Health.
1
obtained as a tan solid, which was pure by H NMR and TLC,
Rf ) 0.51 (5% MeOH/chloroform). An analytical sample was
prepared by recrystallization from methanol/water and drying
under reduced pressure at 78 °C to give 86 mg of a tan solid
(66% recovery): mp 199-201 °C; Rf ) 0.51 (5% MeOH/
chloroform); 1H NMR (DMSO-d6, 300 MHz) δ 7.4-7.3 (m, 5H,
ArH), 7.17 (m, 1H), 6.63 (s, 2H, D2O exchangeable, NH2), 5.06
(s, 2H, CH2); 13C NMR (DMSO-d6, 75 MHz) δ 148.4, 136.2,
129.1, 128.2, 127.5, 125.8, 115.5, 115.1, 90.6, 70.1, 48.8; ; IR
J O001499I