Palladium-catalyzed allylic coupling of 1,2,3-triazolo[4,5-d]pyrimidines (8-azapurines)

Article abstract of DOI:10.1021/jo960815j

The palladium-catalyzed coupling of the sodium salt of 7-amino-1,2,3-triazolo[4,5-d]pyrimidine (8-azaadenine, 1) with allylic phosphates or carbonates resulted in mixtures of 2- and 3-substituted 1,2,3-triazolopyrimidines, which were separated by chromatography. 1-Substituted triazolopyrimidines were not isolated from these reactions. Regioselectivity (and stereoselectivity) was also observed for substitution of the allylic moiety when more than one isomer is possible from the reaction. The use of 5-amino-1,2,3-triazolo[4,5-d]pyrimidin-7-ones (8-azaguanine, 2), instead of 8-azaadenine, also resulted in mixtures. Alternate syntheses of the 3-allyl-1,2,3-triazolo[4,5-d]-pyrimidines confirmed the structures of these compounds.

Full text of DOI:10.1021/jo960815j

J . Org. Chem. 1996, 61, 6199-6204
6199
P a lla d iu m -Ca ta lyzed Allylic Cou p lin g of
1,2,3-Tr ia zolo[4,5-d ]p yr im id in es (8-Aza p u r in es)
Michael J . Konkel and Robert Vince*
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota,
308 Harvard Street, S.E., Minneapolis, Minnesota 55455-0343
Received May 3, 1996X
The palladium-catalyzed coupling of the sodium salt of 7-amino-1,2,3-triazolo[4,5-d]pyrimidine (8-
azaadenine, 1) with allylic phosphates or carbonates resulted in mixtures of 2- and 3-substituted
1,2,3-triazolopyrimidines, which were separated by chromatography. 1-Substituted triazolopyrim-
idines were not isolated from these reactions. Regioselectivity (and stereoselectivity) was also
observed for substitution of the allylic moiety when more than one isomer is possible from the
reaction. The use of 5-amino-1,2,3-triazolo[4,5-d]pyrimidin-7-ones (8-azaguanine, 2), instead of
8-azaadenine, also resulted in mixtures. Alternate syntheses of the 3-allyl-1,2,3-triazolo[4,5-d]-
pyrimidines confirmed the structures of these compounds.
Sch em e 1. Nu m ber in g System s a n d
Nom en cla tu r e for 8-Aza p u r in es
In tr od u ction
In the search for new lead compounds for a variety of
medicinal uses such as antiviral or antitumor therapy,
many syntheses of modified nucleosides have been re-
ported.1 The modifications include alterations to the
ribose, the base (purine or pyrimidine), or both. Replace-
ment of the C-8 of purines with a N gives 1,2,3-triazolo-
[4,5-d]pyrimidines (8-azapurines). The numbering sys-
tems for purines and triazolopyrimidines are shown in
Scheme 1. The triazolopyrimidines often display in-
creased toxicity and improved antitumor properties when
compared to those of the corresponding purines.2 Re-
ported methods of synthesizing substituted triazolopy-
rimidines, however, are limited.3 The most common
method, which proceeds through a condensation of ni-
trous acid with a 4,5-diaminopyrimidine (Traube syn-
thesis), requires a number of steps to build an 8-azaade-
nine or an 8-azaguanine moiety from an appropriate
amine.3 Reported methods of directly replacing leaving
groups (such as a halide) with triazolopyrimidines lead
to mixtures of three or more isomers4 with the N-2
substitution product often being the dominant isomer.4e
Therefore, an improved short synthesis of N-3-substi-
tuted triazolopyrimidines is desirable.
method of directly placing a purine onto a modified sugar.
Examples of this methodology include the key steps in
the syntheses of the natural product aristeromycin5 and
the antiviral compound carbovir.5b,6 The palladium-
catalyzed coupling gives substitution of a purine for a
carbonate or acetate. In addition to the predictable
regiospecific 9-substitition of the purine, these reactions
also give net stereochemical retention of configuration
and a predictable regiochemistry for the allylic moiety.
Thus, we decided to explore whether this chemistry could
be useful in the synthesis of substituted triazolopyrim-
idines.
Palladium-catalyzed coupling of purines with allylic
carbonates or acetates has been reported recently as a
X Abstract published in Advance ACS Abstracts, August 15, 1996.
(1) Reviews, see: (a) Marquez, V. E.; Lim, M.-I. Med. Res. Rev. 1986,
6, 1-40. (b) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48,
571-623. (c) Krayevsky, A. A.; Watanabe, K. A. Modified Nucleosides
as Anti-AIDS Drugs: Current Status and Perspectives; Bioinform:
Moscow, 1993. (d) Koomen, G. J . Recl. Trav. Chim. Pays-Bas 1993,
112, 51-65. (e) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.;
Challand, S. R.; Earl, R. A.; Guedj, R. Tetrahedron 1994, 50, 10611-
10670.
(2) (a) Bennett, L. L.; Vail, M. H.; Allan, P. W.; Laster, W. R. Cancer
Res. 1973, 33, 465-471. (b) Montgomery, J . A.; Elliott, R. D.; Thomas,
H. J . Ann. N.Y. Acad. Sci. 1975, 255, 292-305. (c) Vince, R.; Brownell,
J .; Daluge, S. J . Med. Chem. 1984, 27, 1358-1360. (d) Vince, R.;
Turakhia, R. H.; Shannon, W. M.; Arnett, G. J . Med. Chem. 1987, 30,
2026-2030. (e) Vince, R.; Hua, M. J . Med. Chem. 1990, 33, 17-21. (f)
Vince, R.; Peterson, M. J . Med. Chem. 1990, 33, 1214-1219.
(3) Review of the chemistry of 8-azapurines, see: Albert, A. Adv.
Heterocycl. Chem. 1986, 39, 117-180.
Resu lts a n d Discu ssion
We first examined the reactivity of the sodium salt of
7-amino-1,2,3-triazolo[4,5-d]pyrimidine (8-azaadenine, 1)
toward allyl phosphate 3 (Table 1) under palladium
catalysis. Tetrakis(triphenylphosphine)palladium(0), pal-
ladium(II) acetate, and tris(dibenzylideneacetone)dipal-
ladium(0)-chloroform adduct were examined as catalysts
for this reaction. Of these, the first catalyst gave the best
yield of triazolopyrimidine 4 and the cleanest product
after chromatography. Thus, this catalyst was used in
all subsequent palladium-catalyzed reactions that are
(4) (a) Davoll, J . J . Chem. Soc. 1958, 1593-1599. (b) Baker, D. A.;
Harder, R. A.; Tolman, R. L. J . Chem. Soc., Chem. Commun. 1974,
167-168. (c) Elliott, R. D.; Montgomery, J . A. J . Med. Chem. 1976,
19, 1186-1191. (d) Kazimierczuk, Z.; Binding, U.; Seela, F. Helv. Chim.
Acta 1989, 72, 1527-1536. (e) Beauchamp, L. M.; Tuttle, J . V.;
Rodriguez, M. E.; Sznaidman, M. L. J . Med. Chem. 1996, 39, 949-
956.
(5) (a) Trost, B. M.; Kuo, G.-H.; Benneche, T. J . Am. Chem. Soc.
1988, 110, 621-622. (b) Trost, B. M.; Li, L.; Guile, S. D. J . Am. Chem.
Soc. 1992, 114, 8745-8747.
(6) Vince, R.; Peterson, M. L.; Lackey, J . W.; Mook, R. A.; Partridge,
J . J . PCT Int. Appl. WO 91 15490, 1991 (Chem. Abstr. 1992, 116,
59910p).
S0022-3263(96)00815-8 CCC: $12.00 © 1996 American Chemical Society

6200 J . Org. Chem., Vol. 61, No. 18, 1996
Konkel and Vince
Ta ble 1. Isola ted P r od u cts fr om th e
P a lla d iu m -Ca ta lyzed Cou p lin g of 8-Aza a d en in e to a n
Allylic P h osp h a te a n d Allylic Ca r bon a tesa
a pure product due to contamination with triphenylphos-
phine oxide (a reproducible observation). The route by
which the triphenylphosphine is oxidized is not clear. The
amounts of triazolopyrimidine 10 and triphenylphosphine
1
oxide were calculated, based on the H NMR areas. The
triazolopyrimidine 10 was, subsequently, hydrolyzed, and
the triphenylphosphine oxide was separated from tri-
azolopyrimidine 11. The amount of triphenylphosphine
oxide found closely agreed with the amount calculated
to be contaminating triazolopyrimidine 10, and its iden-
tity was verified by comparison (including mixed melting
point) to an authentic sample. Triazolopyrimidines 14
and 16 were separated, but they were also contaminated
with impurities. These were each deprotected under
conditions that we have previously described,7 giving
triazolopyrimidines 15 and 17 in yields of 28 and 15%,
respectively, from carbonate 13.
Triazolopyrimidines 11, 12, 15, and 17 were each
isolated and found to be mixtures of major and minor
stereoisomers that were inseparable by chromatography.
Since the purine analogs of triazolopyrimidines 11 and
15 that were synthesized by palladium coupling were
accompanied by minor amounts of trans and cis isomers,
respectively,7,8a the appearance of the minor isomers of
triazolopyrimidines 11, 12, 15, and 17 was not surprising.
The regiochemistry of triazolopyrimidines 11 and 12
and the minor isomer of triazolopyrimidines 12, with
respect to the cyclohexyl ring, was determined by exami-
nation of COSY spectra of triazolopyrimidines 11 and 12.
Carbonate 9 did not give any detectable allylic rear-
rangement product even though the allylpalladium in-
termediate would allow such a formation. Only the less
sterically hindered products 10 and 12 and their minor
trans isomers were isolated. This is analogous to what
has been observed with purines in palladium-catalyzed
couplings.5-8 Determination of which is the major ste-
reoisomer and which is the minor stereoisomer for
triazolopyrimidines 11 and 12 was made by a comparison
of their 1H NMR spectra to the spectra of their purine
analogs which were assigned structures on the basis of
NOE experiments.8a Several features were noticed in the
1H NMR spectra of the purine analogs of 11 that were
useful in determination of the stereochemistry. The
chemical shift of the H-2 of the cyclohexyl ring is upfield
and the chemical shift of the H-3 is downfield for the cis
isomers when compared to those of the trans isomers. In
addition, the coupling between H-1 and the H-2 is
significantly larger for the trans isomers. Application of
these features gave the expected cis assignment to the
major isomers of triazolopyrimidines 11 and 12.
a
See Experimental Section for conditions. All yields are
isolated yields of purified products, except for 10 which was
contaminated with triphenylphosphine oxide. The yield of 10 was
calculated, on the basis of purity as determined by 1H NMR.
Compound 10 was hydrolyzed to 11 which was separated from
the impurity. The amount of the impurity isolated corresponded
to the amount calculated on the basis of the 1H NMR of 10. The
TBDMS groups were removed from 14 and 16 with TBAF and
HOAc, giving 15 and 17.
The symmetric nature of the allylpalladium intermedi-
ate formed from carbonate 13 allows for only one regio-
isomer, with respect to the cyclohexyl ring, for triazol-
opyrimidines 15 and 17. The stereochemistry of
triazolopyrimidine 15 was determined by comparison of
reported in this study. The palladium-catalyzed reaction
of 8-azaadenine with allyl phosphate 3 gave a mixture
of two compounds which were separated by column
chromatography. The faster eluting compound was
identified as the 3-substituted triazolopyrimidine 4 (29%),
and the slower eluting compound was identified as the
2-substituted triazolopyrimidine 5 (14%) (Table 1).
The palladium-catalyzed reactions of 1 with three
allylic carbonates (6, 9, and 13) were studied, and the
results are shown in Table 1. In each case, 3-substituted
triazolopyrimidines (7, 10, and 14, 23-28%) and 2-sub-
stituted triazolopyrimidines (8, 11, and 15, 11-43%) were
isolated. Triazolopyrimidine 10 could not be obtained as
1
its H NMR spectrum to the spectrum of its cis analog
1
that was made by an unambiguous route.9 The H NMR
spectrum of the cis analogs matched the signals of the
minor isomer, leaving the trans stereochemistry for
assignment to the major isomer (as is shown in structure
15). In addition, the chemical shifts of the H-4 and H-5
of the cyclohexyl ring are consistently further downfield
(7) Konkel, M. J .; Vince, R. Tetrahedron 1996, 52, 8969-8978.
(8) (a) Konkel, M. J .; Vince, R. Tetrahedron 1996, 52, 799-808. (b)
Akella, L. B.; Vince, R. Tetrahedron 1996, 52, 2789-2794.
(9) Konkel, M. J .; Vince, R. Nucleosides Nucleotides 1995, 14, 2061-
2077.

Allylic Coupling of 8-Azapurines
Ta ble 2. Isola ted P r od u cts fr om th e
J . Org. Chem., Vol. 61, No. 18, 1996 6201
Ta ble 3. UV Sp ectr a of Su bstitu ted 8-Aza a d en in es
P a lla d iu m -Ca ta lyzed Cou p lin g of 8-Aza gu a n in e to a n
λ
max, nm (ꢀ × 10-3
)
Allylic P h osp h a te a n d a n Allylic Ca r bon a tea
8-azaadeninesa
pH 1
pH 7
1-(â-D-2-deoxyribofuranosyl)-b 262 (11.7) 287 (8.4)
2-(â-D-2-deoxyribofuranosyl)-b 285 (11.2) 254 (4.3), 297 (10.2)
3-(â-D-2-deoxyribofuranosyl)-b 263 (10.9) 278 (11.8)
4
5
7
8
11
12
15
17
263
282
262
282
263
283
262
282
278
255, 292
276
256, 290
278
255, 291
276
256, 290
a
b
1,2,3-Triazolo[4,5-d]pyrimidine numbering. Reference 4d.
The position of the substitution on the triazolopyrim-
idines was determined by the comparison of the UV data
to that of other literature triazolopyrimidines (Tables 3
and 4).4c-d,10 In addition to the λmax value, the relative
size of the absorbencies and the shape of the peaks was
also taken into account when determining the position
of the substitutions of the 5-amino-1,2,3-triazolo[4,5-d]-
pyrimidin-7-ones.
The novel triazolopyrimidines 4 and 18 were also
synthesized using conventional chemistry3 to confirm the
structural assignments. This synthetic route is shown
in Scheme 2. Triazolopyrimidines 4 and 18, synthesized
by these routes, were identical in all respects (except for
a higher mp for 18) to the triazolopyrimidines 4 and 18
synthesized by the palladium-catalyzed coupling. In
addition, mixed melting points were not depressed.
a
See Experimental Section for conditions. All yields are
isolated yields after chromatography.
for the trans isomers than for the cis isomers of purine
analogs of 15.7,9 In the H NMR spectra of both triazol-
1
opyrimidines 15 and 17, the chemical shifts for the major
isomers of the H-4 and H-5 are further downfield than
those for the minor isomers. Application of these features
gave the expected trans assignment to the major isomers
of triazolopyrimidines 15 and 17.
The palladium coupling chemistry of triazolopyrim-
idines resembles the palladium coupling chemistry of
purines in some respects. The cis:trans ratios for 10, 12,
15, and 17 were 9:1, 10:1, 1:3.5, 1:5.5, respectively. These
ratios are similar to the ratios that have been previously
observed for the purine analogs which were synthesized
by the allylic palladium-catalyzed coupling chemistry.7,8
A 1-substituted triazolopyrimidine was not isolated from
any of these reactions. This result is analogous to the
allylic palladium-catalyzed coupling reactions of purines
in which 7-substituted products are generally not
observed.5-8
Con clu sion s
In this study, we used commercially available 8-aza-
adenine (1) and 8-azaguanine (2) as the triazolopyrimi-
dine nucleophiles, since our desire was to find a short
route to triazolopyrimidine nucleosides. Although the
5-amino-1,2,3-triazolo[4,5-d]pyrimidin-7-one derivatives
were difficult to purify, the 2- and 3-substituted 7-amino-
1,2,3-triazolo[4,5-d]pyrimidine derivatives were synthe-
sized by palladium-catalyzed coupling in moderate yields
in one to two steps from easily prepared carbonates or
phosphates.
Exp er im en ta l Section
Gen er a l. 1H NMR spectra were recorded on 500 or 300
MHz spectrometers and referenced to the solvent. Chemical
shifts are expressed in ppm, and coupling constants are in
hertz. Melting points were measured in open capillary tubes
and are uncorrected. Column chromatography was performed
with Whatman 60 Å 230-400 mesh ASTM silica gel, and thin-
layer chromatography was performed with Whatman 60 Å K6F
250 µm silica gel. Elemental analysis were performed by
M-H-W Laboratories, Phoenix, AZ. Methyl 2-cyclohexenyl
carbonate (6),11 methyl cis-[4-[(methoxycarbonyl)oxy]-2-cyclo-
hexen-1-yl]methyl carbonate (9),8a and methyl [cis-5-(((tert-
butyldimethylsilyl)oxy)methyl)-2-cyclohexen-1-yl]carbonate (13)7
were prepared by reported procedures. Anhydrous DMF and
THF were obtained from Aldrich Chemical Co. All other
solvents and chemicals were reagent grade. All glassware was
oven-dried.
The use of the sodium salt of 5-amino-1,2,3-triazolo-
[4,5-d]pyrimidin-7-one (8-azaguanine, 2) as the nucleo-
phile in allylic palladium-catalyzed coupling reactions
was tested with one phosphate and one carbonate (Table
2). Phosphate 3 gave the 3-substituted triazolopyrimi-
dine 18 in only 8% yield. The major component isolated
(35%) was an inseparable mixture of two isomers in a
55:45 ratio. The isomers are tentatively assigned to be
the 1- and 2-substituted triazolopyrimidines, based on
UV, 1H NMR, and MS data. Carbonate 9 gave the
3-substituted triazolopyrimidine 19 in 20% yield, along
with the 2-substituted triazolopyrimidine 20 in 12% yield.
The regiochemistry and stereochemistry for triazolopy-
rimidines 19 and 20 were determined as described above
for triazolopyrimidines 11 and 12. Both of the 3-substi-
tuted triazolopyrimidines 18 and 19, however, proved to
be difficult to purify. We have not been successful in
obtaining an acceptable elemental analysis for either of
these compounds when they are purified by chromatog-
raphy and recrystallization.
(10) (a) Noell, C. W.; Townsend, L. B.; Robins, R. K. Synth. Proced.
Nucleic Acid Chem. 1968, 1, 44-46. (b) Townsend, L. B.; Robins, R.
K. Synth. Proced. Nucleic Acid Chem. 1968, 1, 18-21. (c) Albert, A.;
Taguchi, H. J . Chem. Soc., Perkin Trans. 1 1972, 449-456.
(11) Brettle, R.; Sutton, J . R. J . Chem. Soc., Perkin Trans. 1 1975,
1947-1954.

6202 J . Org. Chem., Vol. 61, No. 18, 1996
Ta ble 4. UV Sp ectr a of Su bstitu ted 8-Aza gu a n in es
Konkel and Vince
λ
max, nm (ꢀ X 10-3
)
8-azaguaninesa
0.1 N HCl
pH 7
0.1 N NaOH
4-methyl-b
205 (25.7), 264 (7.39)
252 (5.65), 264 (sh, 4.16)
210 (23.5), 270 (5.37)
206 (26.8), 269 (8.84)
255 (13.4), 275 (sh, 9.34)
251,f 270 (sh)
213 (7.56), 249 (9.85), 267 (11.2)
249 (9.76), 267 (11.2)
6-methyl-c
1-methyl-d
210 (25.7), 240 (7.12), 296 (5.23)
211 (28.7), 241 (6.69), 292 (6.32)
256 (12.9), 275 (sh, 9.00)
252,f 270
219 (20.1), 245 (sh, 5.46), 297 (5.89)
218 (22.7), 250 (4.97), 296 (7.98)
221 (23.3), 278 (11.7)
215,f 280
2-methyl-d
9-â-D-ribofuranosyl-e
18
19
20
252,f 271 (sh)
252,f 271
219,f 278
212 (sh),f 267
209 (sh),f 243,g 297h
217,f 248,g 297h
1,2,3-Triazolo[4,5-d]pyrimidine numbering. Reference 10a. c Reference 10b. Reference 10c. e Reference 4c. f Major relative intensity.
a
b
d
g
h
Minor relative intensity. Medium relative intensity.
and the solvent was removed in vacuo. The resulting solid
was dissolved in EtOAc or EtOAc:MeOH, and any undissolved
material was filtered. The solvent was removed from the
filtrate under reduced pressure, and the residue was purified
by flash chromatography. The products were eluted with one
of the following solvent systems: (A) EtOAc; (B) a gradient of
hexane:PhH (3:1) to hexane:PhH:2-propanol (2:1:1) with a
constant PhH concentration; or (C) a gradient of PhH to PhH:
2-propanol (1:1).
Sch em e 2. Alter n a te Syn th eses of
3-Allyltr ia zolo[4,5-d ]p yr im id in esa
7-Am in o-3-(2-et h en yl)-3H -1,2,3-t r ia zolo[4,5-d ]p yr im i-
d in e (4) a n d 7-Am in o-2-(2-eth en yl)-2H-1,2,3-tr ia zolo[4,5-
d ]p yr im id in e (5). Reaction of 1 with 3 following the general
procedure (eluted with B) gave 4 as a white powder (71.9 mg,
0.41 mmol, 29%): mp 203.5-204 °C; Rf ) 0.32 (hexane:PhH:
2-propanol, 2:1:1); 1H NMR (DMSO-d6, 300 MHz) 8.42 (br s, 1
H, D2O exchangeable), 8.28 (s, 1 H), 8.09 (br s, 1 H, D2O
exchangeable), 6.07 (dddt, 1 H, J ) 17.1, 10.5, 1.5, 5.4), 5.22
(d q, 1 H, J ) 10.5, 1.5), 5.14 (d t, 1 H, J ) 5.4, 1.5), 5.07 (d q,
1 H, J ) 17.1, 1.5); MS (EI) m/ z (intensity) 176 (M+, 31), 148
(100). Anal. Calcd for C7H8N6: C, 47.72; H, 4.58; N, 47.70.
Found: C, 47.49; H, 4.80; N, 47.49.
Further elution gave a pink sticky material (42.3 mg) which
was further purified on a preparative TLC plate, giving 5 as
a white powder (34.6 mg, 0.20 mmol, 14%): mp 156-157 °C;
Rf ) 0.19 (hexane:PhH:2-propanol, 2:1:1); 1H NMR (DMSO-
d6, 300 MHz) 8.27 (s with br base, 2 H, br base is D2O
exchangeable), 8.04 (br s, 1 H, D2O exchangeable), 6.13 (m, 1
H), 5.33 (m with d in center, 4 H, J ) 7.8); MS (EI) m/ z
(intensity) 176 (M+, 100). Anal. Calcd for C7H8N6: C, 47.72;
H, 4.58; N, 47.70. Found: C, 47.73; H, 4.67; N, 47.51.
7-Am in o-3-(2-cycloh exen yl)-3H-1,2,3-tr ia zolo[4,5-d ]p y-
r im id in e (7) a n d 7-Am in o-2-(2-cycloh exen yl)-2H-1,2,3-
tr ia zolo[4,5-d ]p yr im id in e (8). Reaction of 1 with 6 following
the general procedure (eluted with B) gave 7 as white flakes
(88.7 mg, 0.41 mmol, 23%): mp 233-234 °C; Rf ) 0.43 (hexane:
PhH:2-propanol, 2:1:1); 1H NMR (DMSO-d6, 300 MHz) 8.40
(br s, 1 H, D2O exchangeable), 8.27 (s, 1 H), 8.06 (br s, 1 H,
D2O exchangeable), 6.05 (m, 1 H), 5.80 (m, 1 H), 5.46 (m, 1
H), 2.12 (m, 4 H), 1.85 (m, 1 H), 1.75 (m, 1 H); MS (CI) m/ z
(intensity) 217 (MH+, 100). Anal. Calcd for C10H12N6: C,
55.54; H, 5.59; N, 38.86. Found: C, 55.50; H, 5.77; N, 38.62.
Further elution gave 8 as a white powder (165.3 mg, 0.76
mmol, 43%): mp 202-202.5 °C; Rf ) 0.24 (hexane:PhH:2-
a
Reagents and conditions: (a) 5-amino-4,6-dichloropyrimidine,
Et3N, BuOH; 94%; (b) NaNO2, HCl; 22, 74%, 23, 15%; 27, 53%;
(c) NH3, MeOH; 76%; (d) 2-amino-4,6-dichloropyrimidine, Et3N,
BuOH; 99%; (e) p-chlorophenyldiazonium chloride, H2O-HOAc,
NaOAc; 94%; (f) Zn, HOAc, H2O-EtOH; 56%; (g) 0.25 N NaOH;
88%.
Allyl d ip h en yl p h osp h a te (3) was prepared by a literature
method12 and by using Mitsunobu conditions.13 The latter
method was carried out as follows: DEAD (1.81 g, 10.4 mmol)
in THF (15 mL) were added over 20 min to a stirring solution
of allyl alcohol (300 mg, 5.17 mmol), triphenylphosphine (2.71
g, 10.3 mmol), and diphenyl phosphate (2.61 g, 10.5 mmol) in
THF (35 mL). After 21 h, the solvent was removed under
reduced pressure and the residue was purified by flash
chromatography, eluting with a gradient of hexane to hexane:
EtOAc (3:1). The solvent was removed from the first fraction
that was UV-active, leaving phosphate 3 as a clear oil (1.20 g,
4.14 mmol, 80%) that was identical in all respects to the
phosphate 3 prepared by the literature method.12
Gen er a l P r oced u r e for P a lla d iu m -Ca ta lyzed Cou -
p lin gs. 8-Azapurine (1 or 2, 1 equiv, 0.66-1.40 mmol) was
added to a stirring solution of NaH (95%, 0.95 equiv) in DMF
(15 mL) and heated in a 60 °C oil bath for 0.5-2 h. Then the
solution was cooled to rt and the allylic phosphate or allylic
carbonate (1 equivalent) in DMF (3 mL) and tetrakis(triphen-
ylphosphine)palladium(0) (0.15 equivalent) were added. The
solution was protected from light, put under N2, and stirred
at 60 °C for 2-3 h. The solution was then cooled and filtered,
1
propanol, 2:1:1); H NMR (DMSO-d6, 300 MHz) 8.26 (s, 1 H),
8.21 (br s, 1 H, D2O exchangeable), 7.98 (br s, 1 H, D2O
exchangeable), 6.08 (d m, 1 H, J ) 9.5), 5.89 (dm, 1 H, J )
9.5), 5.50 (m, 1 H), 2.20 (m, 1 H), 2.11 (m, 3 H), 1.82 (m, 1 H),
1.72 (m, 1 H); MS (CI) m/ z (intensity) 217 (MH+, 100). Anal.
Calcd for C10H12N6: C, 55.54; H, 5.59; N, 38.86. Found: C,
55.61; H, 5.49; N, 38.94.
cis-4-(7-Am in o-3H-1,2,3-tr ia zolo[4,5-d ]p yr im id in -3-yl)-
2-cycloh exen ylm eth an ol (11) an d Meth yl cis-[4-(7-Am in o-
2H -1,2,3-t r ia zolo[4,5-d ]p yr im id in -2-yl)-2-cycloh exen -1-
yl]m eth yl Ca r bon a te (12). Reaction of 1 with 9 following
the general procedure (eluted with A) gave a mixture of 10
and triphenylphosphine oxide as a white solid [262.1 mg, Rf
) 0.37 (EtOAc)]. 1H NMR areas indicate that 10 is ∼60% of
the mixture by weight.
Further elution gave 12 as a white powder (104.2 mg, 0.34
mmol, 26%): mp 118-124 °C; Rf ) 0.20 (EtOAc); 1H NMR
(DMSO-d6, 500 MHz) 8.42 (br s, 1 H, D2O exchangeable), 8.28
(12) Miller, J . A.; Wood, H. C. S. J . Chem. Soc. C 1968, 1837-1843.
(13) Review, see: Mitsunobu, O. Synthesis 1981, 1-28.

Allylic Coupling of 8-Azapurines
J . Org. Chem., Vol. 61, No. 18, 1996 6203
(s, 1 H), 8.07 (br s, 1 H, D2O exchangeable), 5.99 (dm, 1 H, J
) 10.0), 5.95 (dm, 1 H, J ) 10.0), 5.43 (m, 1 H), 4.12 (dd, 1 H,
J ) 10.5, 6.0), 4.07 (dd, 1 H, J ) 10.5, 8.0), 3.70 (s, 3 H), 2.57
(m, 1 H), 2.13 (m, 1 H), 1.90 (m, 1 H), 1.83 (m, 1 H), 1.69 (m,
1 H); MS (CI) m/ z (intensity) 305 (MH+, 100). Anal. Calcd
for C13H16N6O3: C, 51.31; H, 5.30; N, 27.62. Found: C, 51.51;
H, 5.46; N, 27.39.
(20). Reaction of 2 with 9 following the general procedure
[neutralized with NH4Cl, resolved twice with hexane:PhH:2-
propanol (3:1:1) on a preparative TLC plate] gave 20 as an
off-white solid (25.6 mg, 0.08 mmol, 12%): mp 294-296 °C;
1H NMR (DMSO-d6, 300 MHz) 10.90 (br s, 1 H, D2O exchange-
able), 6.49 (br s, 2 H, D2O exchangeable), 5.95 (m, 2 H), 5.24
(m, 1 H), 4.08 (m, 2 H), 3.69 (s, 3 H), 2.49 (m, 1 H + DMSO),
2.09 (m, 2 H), 1.76 (m, 1 H), 1.59 (m, 1 H); MS (FAB) 321
(MH+). Anal. Calcd for C13H16N6O4: C, 48.75; H, 5.03; N,
26.24. Found: C, 49.00; H, 5.20; N, 26.35.
Further elution with EtOAc:MeOH (4:1) brought a band off
the baseline. The band was extracted with EtOAc:MeOH (4:
1), giving 19 as a pale yellow powder (42.8 mg, 0.13 mmol,
20%): mp 199.5-200.5 °C; 1H NMR (DMSO-d6, 300 MHz)
11.10 (br s, 1 H, D2O exchangeable), 6.96 (br s, 2 H, D2O
exchangeable), 5.93 (d, 1 H, J ) 10.3), 5.87 (d, 1 H, J ) 10.3),
5.06 (m, 1 H), 4.09 (m, 2 H), 3.68 (s, 3 H), 2.47 (m, 1 H +
DMSO), 1.98 (m, 2 H), 1.75 (m, 1 H), 1.65 (m, 1 H); MS (FAB)
321 (MH+).
5-Am in o-6-ch lor o-4-(2-eth en yla m in o)p yr im id in e (21).
A solution of 5-amino-4,6-dichloropyrimidine (0.25 g, 1.52
mmol) in allylamine (10 mL) and triethylamine (3 mL) was
stirred for 21 h at rt. The solvents were removed under
reduced pressure, and the residue was purified by flash
chromatography (eluting with a gradient of hexane to EtOAc),
giving 21 as a tan solid (265.5 mg, 1.44 mmol, 94%): mp 88-
89 °C; Rf ) 0.61 (EtOAc); 1H NMR (DMSO-d6, 300 MHz) 7.70
(s, 1 H), 6.96 (t, 1 H, J ) 5.4, D2O exchangeable), 5.90 (dddt,
1 H, J ) 17.4, 10.5, 1.5, 5.4), 5.22 (dq, 1 H, J ) 10.2, 1.5), 5.07
(dq, 1 H, J ) 10.2, 1.5), 5.04 (s, 2 H, D2O exchangeable), 5.07
(tt, 2 H, J ) 5.4, 1.5); MS (EI) m/ z (intensity) 186 (M+ + 2,
15), 184 (M+, 43), 169 (100). Anal. Calcd for C7H9N4Cl: C,
45.54; H, 4.91; N, 30.35. Found: C, 45.55; H, 5.07; N, 30.50.
A solution of impure 10 (100 mg) in THF (10 mL) and 0.20
N NaOH (5 mL) was stirred for 3 h at rt. The solvent was
removed under reduced pressure, and the residue was purified
by flash chromatography. Elution with a gradient of hexane
to EtOAc gave triphenylphosphine oxide (60.9 mg). Elution
was continued with EtOAc:MeOH (9:1), giving 11 as a white
solid (23.5 mg, 0.096 mmol, 74% from calcd amount of 10):
mp 229-230 °C; Rf ) 0.53 (EtOAc:MeOH, 4:1); 1H NMR
(DMSO-d6, 500 MHz) 8.39 (br s, 1 H, D2O exchangeable), 8.27
(s, 1 H), 8.05 (br s, 1 H, D2O exchangeable), 6.04 (d m, 1 H, J
) 9.9), 5.85 (d m, 1 H, J ) 9.9), 5.41 (m, 1 H), 4.74 (t, 1 H, J
) 5.3, D2O exchangeable), 3.42 (m, 2 H), 2.28 (m, 1 H), 2.11
(m, 1 H), 2.03 (m, 1 H), 1.77 (m, 1 H), 1.69 (m, 1 H); MS (CI)
m/ z (intensity) 247 (MH+, 100). Anal. Calcd for C11H14N6O:
C, 53.65; H, 5.73; N, 34.13. Found: C, 53.80; H, 5.90; N, 34.01.
tr a n s-3-(7-Am in o-3H-1,2,3-tr ia zolo[4,5-d ]p yr im id in -3-
yl)-4-cycloh exen ylm eth a n ol (15) a n d tr a n s-3-(7-Am in o-
2H -1,2,3-t r ia zolo[4,5-d ]p yr im id in -2-yl)-4-cycloh exen yl-
m eth a n ol (17). Reaction of 1 with 13 following the general
procedure (eluted with B) gave 14 [177.1 mg, Rf ) 0.54
(hexane:PhH:2-propanol, 2:1:1)] as an impure white solid and
16 [96.6 mg, Rf ) 0.36 (hexane:PhH:2-propanol, 2:1:1)] as an
impure white tacky solid.
Tetrabutylammonium fluoride (1 M in THF, 1.00 mL) was
added to a solution of 14 in THF (4 mL) and HOAc (0.12 mL)
and stirred for 20 h at rt. Silica gel was added, and the solvent
was removed under reduced pressure. The silica gel was
placed on a column of silica gel, and the contents were eluted
with hexane:PhH:2-propanol (2:1:1) until the first band was
removed from the column. Then the column was eluted with
THF, giving a white solid (105.4 mg) which slowly turned pale
yellow. The solid was triturated with a small amount of MeOH
and filtered, giving 15 as a pale yellow powder (45.8 mg, 0.19
7-Ch lor o-3-(2-eth en yl)-3H-1,2,3-tr ia zolo[4,5-d ]p yr im i-
d in e (22) a n d 3-(2-Eth en yl)-3H-1,2,3-tr ia zolo[4,5-d ]p yr im -
id in -7-on e (23). A cooled solution of NaNO2 (92 mg, 1.33
mmol) in H2O (2 mL) was added over 3 min to a solution of 21
(190 mg, 1.03 mmol) in H2O (15 mL) and HOAc (5 mL) at 0
°C. The resulting solution was stirred for 2 h and then brought
to rt and stirred for an additional 1 h. The solvent was
removed, and the residue was purified by flash chromatogra-
phy (eluting with a gradient of hexane to EtOAc), giving 22
as a pale yellow oil which slowly solidified (149.0 mg, 0.76
1
mmol, 28% from 13): mp 226.5-227.5 °C; H NMR (DMSO-
d6, 300 MHz, major isomer) 8.40 (br s, 1 H, D2O exchangeable),
8.28 (s, 1 H), 8.06 (br s, 1 H, D2O exchangeable), 6.13 (m, 1
H), 5.81 (m, 1 H), 5.44 (m, 1 H), 4.52 (t, 1 H, J ) 5.0, D2O
exchangeable), 3.32 (m, 2 H), 2.22 (m, 1 H), 2.05 (m, 2 H), 1.87
(m, 1 H), 1.84 (m, 1 H); MS (CI) m/ z (intensity) 247 (MH+,
100). Anal. Calcd for C11H14N6O: C, 53.65; H, 5.73; N, 34.13.
Found: C, 53.80; H, 5.90; N, 34.01.
1
mmol, 74%): mp 39.5-41.5 °C; Rf ) 0.74 (EtOAc); H NMR
(CDCl3, 500 MHz) 8.89 (s, 1 H), 6.09 (dddt, 1 H, J ) 17.0, 10.0,
1.5, 6.0), 5.35 (dq, 1 H, J ) 10.0, 1.5), 5.33-5.30 (m, 3 H); MS
(EI) m/ z (intensity) 197 (M+ + 2, 1), 195 (M+, 2), 41 (100).
Further elution with EtOAc gave 23 as a white solid (27.3
mg, 0.15 mmol, 15%) which was recrystallyzed from MeOH,
giving clear crystals (26.5 mg, 0.15 mmol, 15%): mp 164-164.5
16 was treated and purified by chromatography as described
above for 14, giving a yellow paste. The paste was dissolved
in hot EtOAc with the aid of a small amount of MeOH, hexane
was added until cloudy, and the solution was placed in a
freezer for several hours. The solution was filtered, giving 17
as an off-white powder (25.5 mg, 0.10 mmol, 15% from 13):
mp 193.5-195 °C; 1H NMR (DMSO-d6, 300 MHz, major
isomer) 8.27 (s, 1 H), 8.20 (br s, 1 H, D2O exchangeable), 7.98
(br s, 1 H, D2O exchangeable), 6.16 (m, 1 H), 5.95 (m, 1 H),
5.50 (m, 1 H), 4.55 (m, 1 H, D2O exchangeable), 3.27 (m, 2 H),
2.19 (m, 2 H), 1.90 (m, 3 H); MS (CI) m/ z (intensity) 247 (MH+,
100). Anal. Calcd for C11H14N6O‚2/5MeOH: C, 52.85; H, 6.07;
N, 32.44. Found: C, 52.82; H, 5.96; N, 32.53.
5-Am in o-3-(2-eth en yl)-3H-1,2,3-tr iazolo[4,5-d]pyr im idin -
7-on e (18). Reaction of 2 with 3 following the general
procedure (eluted with C) gave 18 as a white powder (19.1 mg,
0.10 mmol, 7%, mp 228-231 °C. This sample was identical
in all respects, except for a few minor peaks in the 1H NMR
and a lower mp, to the sample of 18 obtained from 27. A mixed
melting point was not depressed (238-250 °C).
1
°C; Rf ) 0.26 (EtOAc); H NMR (DMSO-d6, 500 MHz) 12.69
(br s, 1 H, D2O exchangeable), 8.23 (s, 1 H), 6.07 (dddt, 1 H, J
) 17.0, 10.5, 1.5, 5.5), 5.24 (dq, 1 H, J ) 10.5, 1.5), 5.15 (dt, 2
H, J ) 5.5, 1.5), 5.35 (dm, 1 H, J ) 17.5); MS (EI) m/ z
(intensity) 177 (M+, 43), 120 (100). Anal. Calcd for
C7H7N5O: C, 47.45; H, 3.98; N, 39.53. Found: C, 47.50; H,
4.06; N, 39.41.
7-Am in o-3-(2-et h en yl)-3H -1,2,3-t r ia zolo[4,5-d ]p yr im i-
d in e (4). A solution of 22 (94.4 mg, 0.483 mmol) in MeOH
(10 mL) and NH3 (∼50 mL) was stirred in a bomb at 60 °C for
42 h and then cooled to rt. The NH3 was carefully vented.
The residue was triturated in H2O and filtered, giving 4 as a
light tan solid (64.4 mg, 0.366 mmol, 76%, mp 203.5-204.5
°C). This sample was identical in all respects to the 4 obtained
through the palladium-catalyzed coupling route and a mixed
melting point was not depressed (203-203.5 °C).
2-Am in o-6-ch lor o-4-(2-eth en yla m in o)p yr im id in e (24)
was prepared as described for 21, except 2-amino-4,6-dichlo-
ropyrimidine (1.00 g, 6.10 mmol) was used as the pyrimidine
and 20 mL of allylamine was used, giving 24 as a white solid
(1.11 g, 6.01 mmol, 99%): mp 116.5-117 °C; Rf ) 0.63 (EtOAc);
1H NMR (DMSO-d6, 300 MHz) two isomers (2:1 ratio), peaks
for major isomer 7.25 (br s, 1 H, J ) 5.4, D2O exchangeable),
6.40 (br s, 2 H, D2O exchangeable), 5.89-5.67 (m, 2 H), 5.19-
4.98 (m, 2 H), 3.80 (m, 2 H); MS (EI) m/ z (intensity) 186 (M+
The filtered undissolved solid was adsorbed to silica gel and
eluted with C, giving a pale yellow powder (72.5 mg) which
1H NMR showed to be a 55:45 mixture of isomers. Neither
isomer was 18.
Meth yl cis-[4-(5-Am in o-7-oxo-3H-1,2,3-tr ia zolo[4,5-d ]-
p yr im id in -3-yl)-2-cycloh exen -1-yl]m eth yl Ca r bon a te (19)
a n d Met h yl cis-[4-(5-Am in o-7-oxo-2H-1,2,3-t r ia zolo[4,5-
d ]p yr im id in -2-yl)-2-cycloh exen -1-yl]m et h yl Ca r b on a t e

6204 J . Org. Chem., Vol. 61, No. 18, 1996
Konkel and Vince
+ 2, 10), 184 (M+, 31), 169 (100). Anal. Calcd for C7H9N4Cl:
C, 45.54; H, 4.91; N, 30.35. Found: C, 45.41; H, 4.98; N, 30.20.
2-Am in o-6-ch lor o-5-[(4-ch lor op h e n yl)a zo]-4-(2-e t h -
en yla m in o)p yr im id in e (25). A solution of NaNO2 (451 mg,
6.54 mmol) in H2O (10 mL) was added dropwise to a solution
of 4-chloroaniline (777 mg, 6.09 mmol) in H2O (10 mL) and
concd HCl (4 mL) at 0 °C and stirred for 45 min. The resulting
solution was stirred for 2 h, brought to rt, and stirred for an
additional 1 h. The resulting solution was added over 10 min
to a solution of 24 (850 mg, 4.61 mmol) in H2O (100 mL) and
HOAc (100 mL) at 0 °C. The solution was allowed to reach
rt, stirred for 2 d, and then set in a refrigerator for 2 d. The
solution was filtered, giving 25 as a bright yellow solid (752.8
mg, mp 195-198 °C). Several additional crops were obtained
over several days after the volume of the filtrate was reduced
to 50 mL, and the solution was set in a refrigerator. An
analytical sample (mp 217-218 °C) was obtained by recrys-
tallization from EtOAc:hexane, but the crude material was
sufficiently pure for use in the next step: total 1.40 g, 4.33
mmol, 56%): mp 120.5-121 °C; Rf ) 0.24 (CHCl3:EtOAc, 1:1);
1H NMR (DMSO-d6, 300 MHz) 6.64 (br s, 1 H, D2O exchange-
able), 5.89 (m, 1 H), 5.62 (br s, 2 H, D2O exchangeable), 5.16
(d m, 1 H, J ) 17.4), 5.07 (d m, 1 H, J ) 9.6), 3.95 (m, 4 H, 2
H are D2O exchangeable); MS (EI) m/ z (intensity) 201 (M+
+
2, 28), 199 (M+, 100). Anal. Calcd for C7H10N5Cl: C, 42.11;
H, 5.05; N, 35.08. Found: C, 42.16; H, 5.17; N, 35.19.
5-Am in o-7-ch lor o-3-(2-eth en yl)-3H-1,2,3-tr ia zolo[4,5-d ]-
p yr im id in e (27) was prepared as described for 22, except 26
(273.7 mg, 1.37 mmol) was used as the pyrimidine. The crude
product was recrystallyzed from H2O, giving 27 as pale yellow
needles (152.4 mg, 0.72 mmol, 53%): mp 141-142 °C; Rf )
1
0.76 (EtOAc); H NMR (DMSO-d6, 300 MHz) 7.69 (br s, 2 H,
D2O exchangeable), 6.05 (ddt, 1 H, J ) 17.4, 10.5, 5.4), 5.22
(d, 1 H, J ) 10.2), 5.04 (m, 3 H); MS (EI) m/ z (intensity) 210
(M+, 35), 181 (100). Anal. Calcd for C7H7N6Cl: C, 39.92; H,
3.35; N, 39.90. Found: C, 40.10; H, 3.17; N, 39.70.
5-Am in o-3-(2-eth en yl)-3H-1,2,3-tr iazolo[4,5-d]pyr im idin -
7-on e (18). A solution of 27 (110 mg, 0.52 mmol) in 0.25 N
NaOH was warmed at ∼80 °C. After 90 min, the solution was
cooled to 0 °C and 1 N HCl was added to pH 3. The resulting
solid was filtered and rinsed with H2O, giving 18 as an off-
white solid (88.7 mg, 0.46 mmol, 88%): mp 275.5-277 °C; 1H
NMR (DMSO-d6, 300 MHz) 10.94 (s, 1 H, D2O exchangeable),
6.93 (br s, 2 H, D2O exchangeable), 6.01 (dddt, 1 H, J ) 17.1,
10.2, 1.3, 5.4), 5.20 (dq, 1 H, J ) 10.2, 1.2), 4.99 (dq, 1 H, J )
17.1, 1.2), 4.89 (dt, 1 H, J ) 5.4, 1.5); MS (EI) m/ z intensity
192 (M+, 56), 43 (100). Anal. Calcd for C7H8N6O: C, 43.75;
H, 4.20; N, 43.73. Found: C, 44.00; H, 4.03; N, 43.46.
1
mmol, 94%; Rf ) 0.59 (hexane:EtOAc, 1:1); H NMR (DMSO-
d6, 500 MHz) two isomers (7:3 ratio), peaks for major isomer
10.36 (br s, 1 H), 7.76 (d d, 2 H, J ) 7.0, 2.0), 7.63-7.53 (m, 4
H), 5.99 (ddt, 1 H, J ) 17.0, 10.5,, 5.5), 5.16 (m, 2 H), 4.16 (m,
2 H); MS (EI) m/ z (intensity) 326 (M+ + 4, 3), 324 (M+ + 2,
19), 322 (M+, 28), 196 (100). Anal. Calcd for C13H12N6Cl2: C,
48.31; H, 3.74; N, 26.00. Found: C, 48.21; H, 3.85; N, 25.87.
6-Ch lor o-2,5-d ia m in o-3-(2-et h en yla m in o)p yr im id in e
(26). HOAc (1.6 mL) was added to a stirring solution of 25
(1.22 g, 3.77 mmol) and Zn dust (2.52 g) in H2O (40 mL) and
EtOH (40 mL) under N2 at rt and then brought to reflux. After
3 h, the solution was cooled back to rt and rapidly filtered
through sintered glass, and the residue was rinsed with a
small portion of EtOH. The solvents were removed under
reduced pressure, and the residue was purified by flash
chromatography [eluting with a gradient of CHCl3 to CHCl3:
MeOH (30:1)], giving 26 as a white flakes (421.4 mg, 2.11
Ack n ow led gm en t. This work was supported by
Public Health Service Grant CA23263 from the National
Cancer Institute.
J O960815J