Reactions of 6-aminopyrimidines with biselectrophiles: Manipulation of product composition with solvent and pyrimidine substitution variation

Full text of DOI:10.1021/jo9713870

634
J . Org. Chem. 1999, 64, 634-638
Notes
phile, followed by ring closure between the 6-amino group
Rea ction s of 6-Am in op yr im id in es w ith
and the second electrophilic center. This experimental
observation is supported by computational studies using
AM1 and PM3 calculations, which reveal a direct cor-
relation between charge densities at the C5-carbon of the
above-mentioned 6-aminopyrimidines and their enamine-
like nucleophilicity toward enones.13 During the course
of our continued studies toward the synthesis of bicyclic
and tricyclic antifolates via utilization of this methodol-
ogy, we discovered an unexpected reaction pathway
leading to the formation of several novel, interesting
heterocycles, which is the subject of this note.
Biselectr op h iles: Ma n ip u la tion of P r od u ct
Com p osition w ith Solven t a n d P yr im id in e
Su bstitu tion Va r ia tion 1
Anil Vasudevan,*,† Farahnaz Mavandadi,‡
Lihua Chen,§ and Aleem Gangjee*
Division of Medicinal Chemistry, Graduate School of
Pharmaceutical Sciences, Duquesne University,
Pittsburgh, Pennsylvania 15282
Received J uly 28, 1997
Trimetrexate (TMQ) is a recently approved drug for
the treatment of opportunistic infections in patients with
acquired immunodeficiency syndrome (AIDS).14 As part
of a project aimed at synthesizing conformationally
restricted analogues of TMQ, the tricyclic analogue 5 was
sought, the seemingly trivial synthesis of which was
initially attempted via the reaction of 2,4,6-triamino-
pyrimidine (1) with ethyl 2-cyclohexanonecarboxylate (2)
in glacial acetic acid (Scheme 1). The expected mode of
reactivity involves nucleophilic attack by the C5-carbon
of 1 at the ketone moiety of 2 followed by ring closure
between the 6-amino moiety and the ethyl ester. Unex-
pectedly, this reaction afforded two products in a 1:1
ratio, none of which was 5. On the basis of the 1H NMR5,15
and the 13C NMR, the two compounds were identified as
3 and 4, which could be easily distinguished from one
another by the downfield shift of one of the 2-amino
protons of 3 which participates in a hydrogen bond with
the lactam carbonyl. The suggested pathway for the
formation of 3 and 4 via route i and route ii, respectively,
is depicted in Scheme 1, and involves ring-formation
between the N1-nitrogen and the 6-amino moiety. When
the same reaction was performed under thermal condi-
tions (diphenyl ether at 190 °C), 5 was obtained as the
sole product, as reported by Hitchings et al.11 This
influence of reaction conditions on product composition
in the reaction of 6-aminopyrimidines with â-keto esters
being a novel observation, warranted further investiga-
tion.
The reaction of 1 with a simple, acyclic keto ester, ethyl
acetoacetate 6, would be predicted to afford 9 if the
“normal" reactivity mode were followed (Scheme 2).
Refluxing a mixture of 1 and 6 in acetic acid afforded a
mixture of 7 and 8, with none of the anticipated product
9. When the same reaction was performed in diphenyl
ether at 190-200 °C (the conditions followed for the
synthesis of 5) or dioxane at 100-110 °C, the sole product
obtained was 9, with the diagnostic lactam NH resonat-
ing at 8.43 ppm and the absence of the H5 proton in the
1H NMR. Thus, in acetic acid, the N1-nitrogen of 1
behaves as the nucleophilic partner in lieu of the C5-
The one-step assembly of monocyclic as well as poly-
cyclic heterocycles represents a useful strategy in con-
temporary organic synthesis. Such reactions are of special
interest in combinatorial chemistry,2 since this allows the
generation of vast arrays of molecules (depending on the
substitution on the reactants) in an efficient manner. We
have reported the regiospecific synthesis of a number of
bicyclic and tricyclic as well as tetracyclic heterocycles
as potential inhibitors of the enzyme dihydrofolate re-
ductase (DHFR) via this synthetic strategy.3-9 An em-
pirical rule has emerged from our studies as well as those
of others,10-12 which dictates that in annulation reactions
involving substituted 6-aminopyrimidines (which have
multiple competing sites for potential ring-annulation)
and biselectrophiles such as â-keto aldehydes, â-keto
esters, and â-dialdehydes as well as R-halo ketones, the
5-position of the pyrimidine is the most nucleophilic and
attacks the most electrophilic carbon of the biselectro-
* To whom all correspondence should be addressed at Duquesne
University. Tel: (412)396-6070. Fax: (412)396-5130.
† Current address: Abbott Laboratories, Abbott Park, IL 60064.
‡ Current address: Centaur Pharmaceuticals, Sunnyvale, CA 94086.
§ Current address: Chemical and Physical Sciences, Dupont Merck
Pharmaceutical Co., Wilmington, DE 19880.
(1) (a) Taken in part from the dissertation submitted by A. V. to
the Graduate School of Pharmaceutical Sciences, Duquesne University,
in partial fulfillment of the requirements for the degree of Doctor of
Philosophy, J une 1996. (b) Taken in part from the dissertation
submitted by F. M. to the Graduate School of Pharmaceutical Sciences,
Duquesne University, in partial fulfillment of the requirements for the
degree of Doctor of Philosophy, J une 1995. (c) Taken in part from the
thesis submitted by L. C. to the Graduate School of Pharmaceutical
Sciences, Duquesne University, in partial fulfillment of the require-
ments for the degree of Master of Science, J une 1995.
(2) Gordon, E. M.; Gallop, M. A.; Patel, D. V. Acc. Chem. Res. 1996,
29, 144-154.
(3) Gangjee, A.; Devraj, R.; McGuire, J . J .; Kisliuk, R. L.; Queener,
S. F.; Barrows, L. R. J . Med. Chem. 1994, 37, 1169-1176.
(4) Gangjee, A.; Ohemeng, K. A. J . Heterocycl. Chem. 1987, 24, 123-
126.
(5) Gangjee, A.; Patel, J . J . Heterocycl. Chem. 1988, 25, 1597-1598.
(6) Gangjee, A.; Donkor, I. O. J . Heterocycl. Chem. 1989, 26, 705-
708.
(7) Gangjee, A.; Vasudevan, A.; Queener, S. F.; Kisliuk, R. L. J . Med.
Chem. 1996, 39, 1448-1456.
(8) Donkor, I. O.; Gangjee, A.; Kisliuk, R. L.; Gaumont, Y. J .
Heterocycl. Chem. 1991, 28, 1651-1655.
(9) Gangjee, A.; Ohemang, K. A.; Tulachka, J . J .; Lin, F. T.; Katoh,
A. J . Heterocycl. Chem. 1985, 22, 1149.
(10) Robins, R. K.; Hitchings, G. H. J . Am. Chem. Soc. 1958, 80,
3449.
(11) Hurlbert, B. S.; Ledig, K. W.; Stenbuck, P.; Valenti, B. F.;
Hitchings, G. H. J . Med. Chem. 1968, 11(4), 703-707.
(12) Secrist, J . A.; Liu, P. S. J . Org. Chem. 1978, 43, 3937-3941.
(13) Troschuetz, R.; Anders, E. Arch. Pharm. 1992, 325(6), 341-
348.
(14) News. Am. J . Hosp. Pharm. 1994, 51, 591-592.
(15) Gangjee, A.; O’Donnell, J . K.; Bardos, T. J .; Kalman, T. I. J .
Heterocycl. Chem. 1984, 21, 873-875.
10.1021/jo9713870 CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/15/1998

Notes
J . Org. Chem., Vol. 64, No. 2, 1999 635
Sch em e 1a
a
Reaction conditions: (a) CH3COOH, reflux 14 h; (b) diphenyl ether, 190 °C, 14 h.
Sch em e 2a
Sch em e 3a
a
Reaction conditions: (a) CH3COOH, reflux, 12 h; (b) diphenyl
ether, 190-200 °C, 12 h.
carbon, in contrast to the speculation that reactions
between â-dicarbonyl compounds and 1 (in acidic media)
proceed via initial acylation of the C5-carbon followed by
ring closure.10 These results taken together with the
observation that in reactions with 1, introduction of
substituents such as a methyl or phenyl group on 216 or
the use of a heterocyclic (piperidone or pyrrolidone) â-keto
ester17,18 afford tricyclics resulting from the participation
of the C5-carbon and the 6-amino group in both acetic
acid and diphenyl ether suggest that depending on the
substitution the reactivity of 1 with â-keto esters in
different solvents could be varied to afford products
cyclized either at the N1-nitrogen or the C5-carbon.
To further investigate the participation by the N1-
nitrogen of 6-aminopyrimidines in cyclizations with bi-
selectrophiles other than keto esters, R-halo carbonyls
were employed. Cyclocondensation of R-chloro carbonyls
with 4-hydroxy-6-aminopyrimidines in DMF or NaOAc/
H2O have been reported12,19-22 to yield pyrrolo[2,3-d]-
a
Reaction conditions: (a) NaOAc, H2O, 60 °C, 1.5 h; (b) DMF,
50 °C, 12 h; (c) dioxane, reflux, 12 h.
pyrimidines and/or furo[2,3-d]pyrimidines, resulting from
reaction between the C5-carbon and the 6-amino or
4-hydroxy group, respectively, with the biselectrophile.
However, to our knowledge, the literature does not
contain information regarding the cyclocondensation of
unsubstituted 2,4,6-triaminopyrimidines with R-chloro
carbonyl compounds. Reaction of 1 with 10 in solvents
typically used in such reactions,12,19-22 did not yield the
pyrrolo[2,3-d]pyrimidine 11, but rather imidazo[1,2-c]-
pyrimidines 12 or 13 (Scheme 3). When a mixture of 1
and 10 was heated in sodium acetate/water, 12 was
obtained exclusively. This corroborates literature re-
(19) Wellcome Foundation, British patent 812366, 1956; Chem.
Abstr. 1956, 54, 5921.
(20) Noell, C. W.; Robins, R. K. J . Heterocycl. Chem. 1964, 1, 34-
(16) Gangjee, A.; Patel, R. Unpublished results.
(17) Gangjee, A.; Mavandadi, F.; Queener, S. F. Adv. Exp. Med. Biol.
1993, 338, 441-444.
(18) Gangjee, A.; Shi, J .; Queener, S. F. J . Med.Chem. 1997, 40,
1930-1936.
41.
(21) Quijano, M. L.; Nogueras, M.; Sanchez, A.; Alvarez, G.; Mel-
garejo, M. J . Heterocycl. Chem. 1990, 27, 1079.
(22) Ramaswamy, K.; J oshi, R. V.; Robins, R. K.; Revankar, G. R.
J . Chem. Soc. Perkin. Trans. 1 1989, 2375-2384.

636 J . Org. Chem., Vol. 64, No. 2, 1999
Notes
ports12 that when aminopyrimidines annulate to form
imidazopyrimidines, the exocyclic amino group bonds to
the ketone of the R-halo carbonyl and the ring nitrogen
to the halogen-containing carbon, perhaps on account of
the intermolecular hydrogen bonding between the 6-ami-
no moiety and water, as a result of which the N1-nitrogen
reacts with the more reactive halogen-containing carbon.
However, performing the same reaction in DMF where
such strong intermolecular hydrogen bonding with the
solvent should be disrupted, 13 is formed regiospecifi-
cally. Further, when 1 and 10 were refluxed in a solvent
of lower polarity and solvation ability than water and
DMF such as dioxane23 for 12 h, no regiospecificity was
observed, and a 1:1 mixture of 12 and 13 was obtained.
None of the reaction conditions afforded the pyrrolo[2,3-
d]pyrimidine 11. Roth24 has reported the formation of a
thiazolo[3,2-c]pyrimidine as its sulfate via a similar N1-
cyclization in the reaction of 2,4-diamino-6-mercapto-
pyrimidine with an R-halo ketone in sulfuric acid. While
the possibility exists for the formation of 12 via the initial
formation of 13 followed by a Dimroth-type rearrange-
ment,25 the conditions required for such a rearrangement
(NaOH, reflux) are much too harsh compared to those
utilized in this study. Reaction of 10 with 2,6-diamino-
4-hydroxypyrimidine, which possesses an electron-with-
drawing group at the 4(6)-position in DMF12 or NaOAc-
H2O (data not shown) has been shown to afford a mixture
of a pyrrolo[2,3-d]pyrimidine and furo[2,3-d]pyrimidine,
suggesting that similar pyrimidines with electron-
withdrawing groups at the 4-position might possess the
requisite electron density at the C5-carbon to facilitate
cyclization to occur at the 5-position, in either DMF or
NaOAc-H2O. Surprisingly, the cyclocondensation of 2,6-
diamino-4-chloropyrimidine 14 with 10 in NaOAc-H2O
did not afford the desired pyrrolo[2,3-d]pyrimidine, but
instead gave the N1 cyclized compound 16 (Scheme 3).
No evidence for the presence any other regioisomer was
detected.
To investigate the possible role of steric hindrance
imposed by a phenyl substitution on the R-halo ketone
on the direction of ring closure, the cyclocondensation of
1 and 2-bromo-4-phenylcyclohexanone 17 (obtained via
bromination of 4-phenylcyclohexanone) was performed.
Stirring 17 with 1 in DMF at 60 °C for 12 h afforded two
regioisomeric imidazo[1,2-c]pyrimidines 19 and 20 as an
inseparable mixture in a 2:3 ratio (Scheme 4), as deter-
mined by their 1H NMR. These results are especially
intriguing considering that the reaction of 2,4,6-triamino-
substituted pyrimidine with R-bromocyclohexanone af-
fords the product resulting from the condensation of the
C5-carbon and the 6-amino moiety with the R-halo
ketone.26 This observation clearly suggests that steric
factors play a role in determining the direction of ring
closure in the reaction of R-halo carbonyls with triamino-
pyrimidines. The reaction of 14 with 2-bromo-4-phenyl-
cyclohexanone 17 in DMF at 60 °C for 2 days resulted in
the formation of one of the two possible imidazo[1,2-c]-
Sch em e 4a
a
Reaction conditions: (a) DMF, rt, 24 h.
pyrimidines 21 or 22. (Scheme 4). No attempts were
made to identify the precise regiochemistry of the cy-
clization.
To our knowledge, this is the first report where
reaction of â-keto esters with 1 affords different regio-
isomers depending on acidic or thermal modes of cycliza-
tion. Robins and Hitchings,10 in their pioneering work
on the synthesis of pyrido[2,3-d]pyrimidines via the
reaction of 6-aminopyrimidines with â-dicarbonyl com-
pounds, did consider the possibility that N1-cyclized
products could indeed occur in such reactions. However,
in all cases reported by these workers, exclusive partici-
pation by the 5-position (in phosphoric acid) was ob-
served, to afford regiospecifically pyrido[2,3-d]pyrim-
idines. N1-Cyclizations observed by Edstrom et al.27 when
6-[(carboxymethyl)amino]pyrimidines were heated with
acetic anhydride were intramolecular cyclizations, where
the reactive electrophile was tethered to the pyrimidine
ring via the 6-amino moiety, which benefits from the
entropic advantage associated in constraining two reac-
tion partners. The most basic nitrogen in 1 is N1, and
its pKa is 6.72,28 implying that in acetic acid (pH ) 4-5),
the N1-nitrogen should be protonated, perhaps account-
ing for the reaction of the 6-amino moiety with the more
reactive ketone carbonyl of 2; however, subsequent ring
closure via participation of the N1-nitrogen (to afford 3)
as opposed to the C5-carbon is unprecedented. Con-
versely, initial nucleophilic attack by the N1-nitrogen of
the nonprotonated form of 1 on the ketone moiety of 2
followed by ring closure may account for the formation
of 4. The prediction that the nature of the product
composition is most probably a combination of all three
variables, namely the pyrimidine substitution and the
solvent as well as the biselectrophile employed, is borne
out by the fact that the presence of substitutents on the
cyclic keto ester 2 such as a methyl or a phenyl moiety16
or the use of a heterocyclic keto ester, such as a pyrroli-
done17 or piperidone keto ester,18 promotes the cyclization
to occur in acetic acid or phosphoric acid or diphenyl ether
(23) March, J . Advanced Organic Chemistry, 4th ed.; J ohn Wiley &
Sons: New York, 1992; p 361.
(24) Roth, B. J . Med. Chem. 1969, 12, 227-232.
(25) Guerret, P.; J acquier, R.; Maury, G. J . Heterocycl. Chem. 1971,
8, 643-650.
(26) Bundy, G. L.; Aeyer, D. E.; Banitt, L. S.; Balonga, K. L.; Mizsak,
S. A.; Palmer, J . R.; Tustin, J . M.; Chin, J . E.; Hall, E. D.; Linseman,
K. L.; Richards, I. M.; Scherch, H. M.; Sun, F. F.; Yonkers, P. A.;
Larson, P. G.; Lin, J . M.; Padbury, G. E.; Aaron, C. S.; Mayo, J . K. J .
Med. Chem. 1995, 38, 4161-4163.
(27) Edstrom, E. D.; Wei, Y.; Gordon, M. J . Org. Chem. 1994, 59,
2473-2481.
(28) Roth, B.; Strelitz, J . Z. J . Org. Chem. 1969, 34, 821-836.

Notes
J . Org. Chem., Vol. 64, No. 2, 1999 637
161.6, 163.5, 164.4, 172.7. Anal. Calcd for C11H13N5O‚0.7H2O:
C, 54.18; H, 5.95; N, 28.72. Found: C, 53.81; H, 5.58; N, 28.37.
1,3-Dia m in o-7,8,9,10-tetr a h yd r o-5H-p yr im id o[4,5-c]iso-
qu in olin -6-on e (5). To a suspension of 1 (1.0 g, 8.0 mmol) in
diphenyl ether at 190 °C in a three-necked flask fitted with a
Dean-Stark trap was added ethyl 2-cyclohexanonecarboxylate
(1.63 g, 9.6 mmol) and the mixture heated for 14 h. At the end
of this period, the mixture was cooled and 100 mL of methanol
added. The mixture was filtered and the residue on the funnel
washed repeatedly with warm methanol to remove unreacted
starting materials to afford 0.59 g (32%) of 5. Appearance:
in the normal, anticipated manner, away from the N1-
nitrogen, and at the C5-position. This unequivocally
indicates that both steric as well as electronic effects
operate in dictating the direction of ring closure. Previous
studies12 have suggested that a certain critical electron
density (or HOMO coefficient) is necessary to facilitate
reaction at the C5-carbon. The results obtained in this
study conclusively indicate that not only is the electron
density at the C5-carbon important, but the solvents
utilized as well as the substitutions on the biselectrophile
control the regiochemistry of the pyrimidine-annulated
products. While it is reasonable to assume that the
nucleophiliity of the C5-carbon in 2,6-diamino-4-hydroxy-
pyrimidine and 14 are attenuated compared to 1 on
account of the electron-withdrawing nature of the sub-
stitutent at the 4-position, participation by the N1-
nitrogen in similar cyclizations, has not been reported.
Further studies are underway to explore the application
of this observed phenomenon in the synthesis of novel
heterocycles and will be the subject of future communica-
tions.
1
brownish solid. mp > 300 °C. H NMR (DMSO-d6, 300 MHz) δ
1.54 (br m, 4 H), 2.34 (br m, 2 H), 2.88 (br m, 2 H), 6.28 (br s, 2
H), 6.42 (br s, 2 H), 8.27 (br s, 1 H). Anal. Calcd C11H13N5O: C,
57.13; H, 5.67; N, 30.28. Found: C, 57.14; H, 5.30; N, 30.08.
N1-Cycliza tion of 2,4,6-Tr ia m in op yr im id in e w ith Eth yl
Acetoa ceta te. 2,4,6-Triaminopyrimidine 1 (1.00 g, 8 mmol) was
dissolved in 40 mL of glacial acetic acid, and ethyl acetoacetate
6 (1.04 g, 8 mmol) was added. The solution was refluxed for 12
h. TLC analyses (CHCl3:CH3OH:NH4OH 5:1:0.5) indicated the
presence of two new products (Rf ) 0.34, 0.51) along with some
unreacted 1. The acetic acid was evaporated to afford a black,
gummy residue, which was suspended in water and neutralized
with 1 N Na2CO3, and the residue was filtered. The solid was
then dissolved in a large amount (∼ 100 mL) of methanol, 1.0 g
silica gel added, and the methanol evaporated to afford a dry
plug. This plug was applied on the surface of a silica gel column
(1.05 in. × 23 in.) and eluted with CHCl3:CH3OH (5:1), and
individual fractions were collected to afford 7 and 8 in a 1:1 ratio.
6,8-Diam in o-4-m eth ylpyr im ido[1,6-a ]pyr im idin -2-on e (7).
Appearance: white solid, 0.44 g, 29%. mp ) 240-244 °C (dec).
1H NMR (DMSO-d6, 300 MHz) δ 2.05 (s, 3 H), 5.43 (overlapping
s, 2 H), 6.84 (br s, 2 H), 7.95 (s, 1 H), 9.96 (s, 1 H). Anal. Calcd
for C8H9N5O‚0.9H2O: C, 46.33; H, 5.25; N, 33.77. Found: C,
46.05; H, 5.13; N, 33.41.
Exp er im en ta l Section
Melting points were determined on a Fisher-J ohns melting
point apparatus or a Mel Temp apparatus and are uncorrected.
Nuclear magnetic resonance spectra were recorded on a Brucker
WH-300 (300 MHz). Low resolution mass spectra were obtained
on an LKB-9000 instrument. Thin-layer chromatography was
performed on silica gel plates with fluorescent indicator and were
visualized with light at 254 and 366 nm, unless indicated
otherwise. Column chromatography was performed with 230-
400 mesh silica gel purchased from Aldrich Chemical Co.,
Milwaukee, WI. Elution was performed using a gradient, and
10 mL fractions were collected, unless mentioned otherwise. All
anhydrous solvents were purchased from Aldrich Chemical Co.
and were used without further purification. Samples for micro-
analysis were dried in vacuo over phosphorus pentoxide at 70
°C or 110 °C. Microanalysis were performed by Atlantic Micro-
labs, Norcoss, GA. All samples for elemental analyses were dried
for 24-48 h, in vacuo at 110 °C. Traces of solvents present in
the analytical data could not be removed and were confirmed,
where possible, by their presence in the NMR spectra.
N-Acetyltr ia m in op yr im id in e (8). Appearance: cream solid,
1
0.41 g, 31%. mp ) 200-204 °C (softens). H NMR (DMSO-d6) δ
2.00 (s, 3 H), 5.29 (s, 2 H), 6.15 (s, 2 H), 6.50 (s, 1 H), 9.73 (s, 1
H). Anal. Calcd for C6H9N5O: C, 43.11; H, 5.43; N, 41.89.
Found: C, 43.02; H, 5.33; N, 41.53.
2,4-Dia m in o-5-m eth ylp yr id o[2,3-d ]p yr im id in -7-on e (9).
2,4,6-Triaminopyrimidine 1 (1.00 g, 8.00 mmol) was suspended
in 50 mL of diphenyl ether and ethyl acetoacetate (1.04 g, 8.00
mmol) added. The mixture was heated at 190-200 °C for 12 h
in a three-neck flask equipped with a Dean-Stark trap to
facilitate continuous removal of water and ethanol. TLC analyses
(CHCl3:CH3OH 5:1) at the end of 12 h indicated the presence of
N1-Cycliza tion of 2,4,6-Tr ia m in op yr im id in e w ith Eth yl
2-Cycloh exa n on eca r b oxyla t e. To a solution of 2,4,6-tri-
aminopyrimidine 1 (1.0 g, 8.0 mmol) in glacial acetic acid was
added ethyl 2-cyclohexanonecarboxylate 2 (1.36 g, 8.0 mmol) and
the mixture refluxed for 14 h. TLC (CHCl3:CH3OH:NH4OH 4:1:
0.5) indicated the presence of two new products (Rf ) 0.62 and
0.46) along with some unreacted triaminopyrimidine. The acetic
acid was evaporated and the residue basified to pH 8 with
NH4OH. The solid obtained was collected by filtration, washed
with hexanes, and dissolved in methanol with heating (50 °C).
A 1.0 g amount of silica gel was added to the solution and the
solvent evaporated to afford a dry plug. This plug was chro-
matographed on a 1.05 in. × 23 in. silica gel column using CHCl3:
CH3OH 10:1 as the eluant. Fractions containing pure product
were pooled and evaporated to afford 3 and 4 in a 1:1 ratio.
1,3-Diam in o-5,6,7,8-tetr ah ydr o[2,9-a ]10-tr iazaan th r acen -
9-on e (3). Appearance: cream solid, 0.57 g, 31%. TLC [CHCl3:
CH3OH (4:1) Rf ) 0.62]. mp ) 251-254 °C. 1H NMR (DMSO-
d6, 300 MHz) δ 1.62 (br s, 4 H), 2.25 (br s, 2 H), 2.37 (br s, 2 H),
5.36 (s, 1 H), 6.74 (br s, 2 H), 7.96 (br s, 1 H), 9.93 (br s, 1 H).
13C NMR (DMSO-d6, 75 MHz) 21.1, 22.0, 31.3, 81.0, 105.6, 152.5,
153.0, 158.0, 159.9, 162.1, 172.1. Anal. Calcd for C11H13N5O‚0.2
H2O: C, 56.26; H, 5.75; N, 29.82. Found: C, 56.40; H, 5.40; N,
29.81.
a
new product. The reaction mixture was cooled to room
temperature and the residue collected by filtration. It was then
dissolved in 250 mL of boiling methanol, 1.0 g silica gel was
added, and the solvent was evaporated to afford a dry plug.
Chromatography of the plug on a 1.05 in. × 23 in. silica gel
column afforded 9 (0.78 g, 51%). mp > 300 °C. 1H NMR (DMSO-
d6, 300 MHz) δ 2.45 (s, 3 H), 5.23 (s, 1 H), 6.45 (br s, 2 H), 6.98
(s, 2 H), 8.91 (s, 1 H). Anal. Calcd for C8H9N5O‚0.3H2O: C, 48.88;
H, 4.92; N, 35.62. Found: C, 48.57; H, 4.61; N, 35.24.
Reaction of 2,4,6-Tr iam in opyr im idin e with Eth yl 2-Ch lo-
r oa cetoa ceta te. 2,4,6-Triaminopyrimidine (1.00 g, 8.00 mmol)
was heated in dioxane at 100 °C. At this temperature, ethyl
2-chloroacetoacetate was added and the reaction mixture heated
at 100 °C for 24 h. The mixture was cooled to room temperature
and filtered and the filtrate washed with 100 mL of methanol.
Separation of the two components via silica gel chromatography
afforded two analytically pure products which were similar in
all respects to those obtained via the alternate conditions
described below for the synthesis of 12 and 13.
5,7-Dia m in o-2-m et h ylim id a zo[1,2-c]p yr im id in e-3-ca r -
boxylic Acid Eth yl Ester (12). A solution of 2,4,6-triamino-
pyrimidine 1 (1.26 g, 10.0 mmol) in water (15 mL) containing
NaOAc (0.80 g, 9.70 mmol) was heated to 60 °C. Ethyl 2-chlo-
roacetoacetate 10 (1.37 mL, 10.0 mmol) was added to this warm
solution, and the reaction mixture was heated at 60 °C for an
additional 90 min after which it was cooled to room temperature
and filtered. The residue was dissolved in 25 mL of MeOH and
filtered and the filtrate evaporated to dryness to yield 0.64 g
(27%) of 12 as a yellow solid: MS m/z 235 (M+); TLC Rf 0.75
(CHCl3/MeOH 9:4, silica gel), 0.49 (CHCl3/EtAc/MeOH, 5:1:1,
2,4-Dia m in o-5,6,7,8-t et r a h yd r o[3,4-a ]10-t r ia za p h en a n -
th r en -9-on e (4). Appearance: cream solid, 0.55 g, 30%. TLC
[CHCl3:CH3OH (4:1) Rf ) 0.46]. mp ) 231-234 °C. 1H NMR
(DMSO-d6, 300 MHz) 1.63 (br s, 4 H), 2.26 (br s, 2 H), 2.37 (br
s, 2 H), 5.23 (s, 1 H), 5.86 (br s, 2 H), 8.62 (br s, 2 H). 13C NMR-
(DMSO-d6, 75 MHz) 21.5, 22.1, 31.9, 77.7, 106.8, 151.0, 155.7,

638 J . Org. Chem., Vol. 64, No. 2, 1999
Notes
1
silica gel); mp ) 236-240 °C. H NMR (DMSO-d6, 300 MHz) δ
triaminopyrimidine
1
(0.25 g, 1.98 mmol) and 2-bromo-4-
1.28 (t, 3H), 2.42 (s, 3H), 4.25 (q, 2H), 5.64 (s, 1H), 6.22 (s, 2H),
8.23 (bs, 2H). Anal. Calcd for C10H13N5O2‚1.5H2O: C, 45.80; H,
6.15; N, 26.70. Found: C, 45.49; H, 5.76; N, 27.09.
phenylcyclohexanone 17 (0.50 g, 1.98 mmol) in DMF (12 mL)
was stirred at room-temperature overnight. The resulting solu-
tion was concentrated under reduced pressure, and the residue
was purified on a silica gel column with gradient 10%, 12.5%,
15%, and 17.5% of MeOH/CH2Cl2. The fractions with Rf ) 0.5
(20% MeOH/ CH2Cl2) were pooled and concentrated to give two
products (19 and 20) (0.25 g, 46%) in a 2:3 ratio, as determined
by 1H NMR.
1,3-Dia m in o -8-p h e n y l-6,7,8,9-t e t r a h yd r ob e n zo [4,5]-
im id a zo[1,2-c]p yr im id in e (19) a n d 1,3-Dia m in o-7-p h en yl-
6,7,8,9-tetr a h yd r oben zo[4,5]im id a zo[1,2-c]p yr im id in e (20).
1H NMR (DMSO-d6, 300 MHz) δ 7.37-7.30 (m, 5H), 7.21-6.70
(br m, 4H, exchanges with D2O), 5.70 (s, 2/5 H), 5.54 (s, 3/5 H),
3.32-2.65 (m, 5H), 2.00 (m, 2H). HRMS calcd for C16H17N5
279.1484, found 279.1434.
3-Ch lor o-7(or 8)-p h en yl-6,7,8,9-tetr a h yd r oben zo[4,5]-
im id a zo[1,2-c]-p yr im id -1-yla m in e, 21 (22). A mixture of
4-chloro-2,6-diaminopyrimidine 14 (0.71 g, 4.91 mmol) and
2-bromo-4-phenylcyclohexanone 17 (1.24 g, 4.90 mmol) in DMF
(12 mL) was heated to 60 °C for 3 days. The resulting precipitate
was collected by filtration to give the product as an off-white
solid (0.47 g, 32%): 1H NMR (DMSO-d6, 300 MHz) δ 8.34 (br s,
2H), 7.39-7.12 (m, 5H), 6.47 (s, 1H), 3.48-3.10 (m, 3H), 2.82
(m, 2H), 2.09-2.02 (m, 2H). HRMS calcd for C16H15ClN4
298.0985, found 298.0983.
5,7-Dia m in o-3-m et h ylim id a zo[1,2-c]p yr im id in e-2-ca r -
boxylic Acid Eth yl Ester (13). A mixture of 2,4,6-triamino-
pyrimidine 1 (1.26 g, 10.0 mmol) and ethyl 2-chloro acetoacetate
10 (1.37 mL, 10.0 mmol) in DMF (15 mL) was stirred at 50 °C
for 26 h. The reaction mixture was cooled to room temperature,
and the resulting suspension was filtered and washed with DMF.
The residue was dissolved in hot MeOH (50 mL) and filtered.
The filtrate was refrigerated and the resulting precipitate
filtered, washed with acetone, and dried under vacuum over P2O5
to yield 0.58 g (23%) of 13 as a buff solid: TLC Rf 0.2 (CHCl3/
EtAc/MeOH 5:1:1, silica gel), mp ) 201-203 °C, 1H NMR
(DMSO-d6, 300 MHz) δ 1.33 (t, 3H), 2.48 (s, 3H), 4.30 (q, 2H),
5.54 (s, 1H), 7.01 (s, 2H), 8.28 (s, 2H). Anal. Calcd for C10H13N5O2‚
0.5H2O: C, 49.17; H, 5.78; N, 28.67. Found: C, 48.78; H, 5.40;
N, 29.06.
5-Am in o-7-ch lor o-2-m eth ylim id a zo[1,2-c]p yr im id in e-3-
ca r boxylic Acid Eth yl Ester (16). To a solution of 2,6-diamino-
4-chloropyrimidine 14 (1.44 g, 10.0 mmol) in water (30 mL)
containing NaOAc (0.60 g, 7.30 mmol) and heated to 100 °C was
added ethyl 2-chloroacetoacetate 10 (1.37 mL, 10.0 mmol). After
heating at 100 °C for 5 h the reaction was complete. It was then
cooled to room temperature, filtered, and washed with hot water.
The residue was dissolved in 25 mL of MeOH and filtered, and
the filtrate was concentrated to yield 0.38 g (15%) of 16 as white,
crystalline needles: mp >160 °C; TLC Rf 0.76 (CHCl3/MeOH/
NH4OH 9:4:0.1, silica gel); 1H NMR (DMSO-d6, 300 MHz) δ 1.35
Ack n ow led gm en t. This work was supported in part
by grants from the NIH, National Institute of General
Medical Sciences (GM40998), and the National Institute
of Allergy and Infectious Diseases (AI41743). We would
like to thank Dr. Fu-Tyan Lin (University of Pittsburgh)
for the 13C NMR spectra.
1
(t, 3H), 2.66 (s, 3H), 4.35 (q, 2H), 6.89 (s, 1H), 8.89 (bs, 2H); H
NMR (TFA-d, 300 MHz) δ 1.39 (t, 3H), 2.71 (s, 3H), 4.49 (q, 2H),
6.96 (s, 1H). Anal. Calcd for C10H11N4O2Cl: C, 47.16; H, 4.35;
N, 22.00; Cl, 13.92. Found: C, 47.22; H, 4.36; N, 22.02; Cl, 13.95.
Rea ction betw een 2,4,6-Tr ia m in op yr im id in e a n d 2-Br o-
m o-4-p h en ylcycloh exa n on e (19, 20). A mixture of 2,4,6-
J O9713870