Improved syntheses of 3H,5H-pyrrolo[3,2-d]pyrimidines

Full text of DOI:10.1021/jo990903e

J . Org. Chem. 1999, 64, 8411-8412
8411
Sch em e 1
Im p r oved Syn th eses of
3H,5H-P yr r olo[3,2-d ]p yr im id in es
Richard H. Furneaux and Peter C. Tyler*
Carbohydrate Chemistry Team,
Industrial Research Limited, P.O. Box 31310,
Lower Hutt, New Zealand
Sch em e 2a
Received J une 2, 1999
The synthesis of 3H,5H-pyrrolo[3,2-d]pyrimidines is of
renewed interest because both 2-amino-3H,5H-pyrrolo-
[3,2-d]pyrimidin-4-one (1, 9-deazaguanine) and its de-
amino derivative 2 (9-deazahypoxanthine) are potential
synthetic precursors of the newly discovered immucillins
3 and 4, which are extremely potent inhibitors of purine
nucleoside phosphorylase.1
a
Key: (a) (MeO)2CHNMe2, CH2Cl2, rt; (b) NaH, tBuCO2CH2Cl;
(c) (MeO)2CHNMe2, DMF, rt, (d) Na2S2O4; (e) NaOH, EtOH; (f)
(MeO)2CHNMe2, DMF, 100 °C.
There are relatively few routes to the pyrrolo[3,2-d]-
pyrimidine ring system,2 the most commonly used ap-
proach starting from pyrimidines with appropriate func-
tional groups at the 5 and 6 positions to allow elaboration
of the pyrrole ring (Scheme 1a). Otherwise, the pyrimi-
dine ring can be constructed onto a substituted pyrrole3
(Scheme 1b). Syntheses of compound 2 have previously
been carried out by methods following route a,4-6 and of
1 by routes a7-9 and b,3 but none of the methods is as
straightforward and efficient as was required.
this was N-protected using pivaloyloxymethyl chloride
to give compound 7 (60%). Treatment with DMF dimethyl
acetal in DMF at room temperature then gave the
enamine 8 (86%), reduction of which with dithionite led
to the pyrrolo[3,2-d]pyrimidine ring system of compound
9, presumably following reduction of the nitro group, ring
closure, and loss of dimethylamine. Alkaline N-depro-
tection of compound 9 gave the required 9-deazaguanine
(1) in 48% yield.
These earlier workers8,9 observed that the reaction of
compound 5 with DMF dimethyl acetal in DMF caused
the formation of the product 11 of N-methylation as well
as imine formation. The N-alkylation of the amide group
of heterocyclic bases using DMF dialkyl acetals has been
well documented.11-13 Our further investigation of the
reaction led to the finding that the product obtained when
the nitro derivative 5 was treated with 6 equiv of DMF
dimethyl acetal in DMF at 100 °C was compound 10
(80%) without any of the N-methyl analogue 11. When
fewer mole equivalents of DMF dimethylacetal were
used, the formation of some N-methyl compound 11 was
observed, suggesting that a sufficient excess of the acetal
is required for exclusive formation of 10. Dithionite
reduction of this product 10 in boiling water afforded
9-deazaguanine (1) in 61% isolated yield without chro-
matographic separation (Scheme 2).
We report here new, abbreviated, and facile syntheses
of compounds 1 and 2 that can be applied on a multigram
scale.
After the report of a 10-step procedure to synthesize
9-deazaguanine (1) in 0.86% efficiency,4 and of a further
method7 that could not be reproduced by others,8,9 the
latter workers developed a five-step, 20% efficient ap-
proach starting from 2-amino-6-methyl-5-nitropyrimidin-
4-one (5) which is readily made by the nitration of the
commercially available 2-amino-6-methylpyrimidin-4-
one.10 Their reaction of compound 5 with DMF dimethyl
acetal in CH2Cl2 gave the imine 6 in excellent yield, and
* To whom correspondence should be addressed. E-mail: p.tyler@
irl.cri.nz.
(1) Miles, R. W.; Tyler, P. C.; Furneaux, R. H.; Bagdassarian, C. K.;
Schramm, V. L. Biochemistry 1998, 37, 8615.
(2) Amarnath, V.; Madhav, R. Synthesis 1974, 837.
(3) Elliott, A. J .; Montgomery, J . A.; Walsh, D. A. Tetrahedron Lett.
1996, 37, 4339.
(4) Imai, K. Chem. Pharm. Bull. 1964, 12, 1030.
(5) Brakta, M.; Daves, G. D., J r. J . Chem. Soc., Perkin Trans. 1 1992,
1883.
(6) Ektova, L. V.; Preobrazhenskaya, M. N. Khim.-Pharm. Zh. 1988,
22, 860.
From the above findings, the obvious starting material
for making 9-deazahypoxanthine (2) is the deamino
analogue of compound 5, but it is difficult to obtain, and
the alternative general approach to pyrrolo[3,2-d]pyrim-
idines (Scheme 1b), as exemplified by the conversion of
the C-nucleoside 12 on treatment with formamidine
(7) Klein, R. S.; Lim, M.-I.; Tam, S. Y-K.; Fox, J . J . J . Org. Chem.
1978, 43, 2536.
(8) Taylor, E. C.; Young, W. B.; Ward, C. C. Tetrahedron Lett. 1993,
34, 4595.
(9) Taylor, E. C.; Young, W. B. J . Org. Chem. 1995, 60, 7947.
(10) Mitchell, G.N.; McKee, R. L. J . Org. Chem. 1974, 39, 9, 176.
(11) Zemlicka, J . Collect. Czech. Chem. Commun. 1963, 28, 1060.
(12) Holy, A.; Chla´dek, S.; Zemlicka, J . Collect. Czech. Chem.
Commun. 1969, 34, 253.
(13) Zemlicka, J . Collect. Czech. Chem. Commun. 1970, 35, 3572.
10.1021/jo990903e CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/14/1999

8412 J . Org. Chem., Vol. 64, No. 22, 1999
Notes
Sch em e 3a
Exp er im en ta l Section
Gen er a l Meth od s. Microanalyses were performed by the
Campbell Laboratory, Otago University, New Zealand. Aluminum-
backed silica gel sheets (Merck or Riedel de Haen) were used
for TLC. Column chromatography was performed on silica gel
(230-400 mesh, Merck). Chromatography solvents were distilled
prior to use. Anhydrous solvents were obtained from Aldrich.
2-[(N,N-Dim eth yla m in o)m eth ylen e]a m in o-6-[(2-N,N-d i-
m eth yla m in o)vin yl]-5-n itr op yr im id in -4-on e (10). A mixture
of 510 (20 g, 117 mmol) with dry DMF (250 mL) and DMF
dimethyl acetal (75 mL, 700 mmol) was stirred at 100 °C for 24
h and then cooled. Acetone (500 mL) was added, and the mixture
was filtered and washed with acetone, affording 10 as an orange/
brown solid (26.3 g, 80%). A sample purified by chromatography
(CHCl3/EtOAc/MeOH 5:2:1) and crystallized from methanol had
mp ∼270 °C dec; 1H NMR (DMSO-d6) δ 8.59 (s, 1H), 7.81 (d,
J ) 12.5 Hz, 1H), 5.30 (d, J ) 12.5 Hz, 1H), 3.12 (s, 3H), 3.00 (s,
3H), 2.93 (s, 6H); 13C NMR (DMSO-d6) δ 168.4, 166.0, 159.2,
158.5, 149.5, 129.1, 90.6, 41.8, 35.7. Anal. Calcd for C11H16N6-
O3: C, 47.14; H, 5.75; N, 29.98. Found: C, 46.87; H, 5.72; N,
29.83.
a
Key: (a) H2NCHdNH‚HOAc.
Sch em e 4a
2-Am in o-3H,5H-p yr r olo[3,2-d ]p yr im id in -4-on e (1). A mix-
ture of 10 (24 g, 86 mmol) and sodium dithionite (48 g) in water
(240 mL) was heated under reflux for 2 h. The suspension was
hot filtered, cooled, and refiltered to give 1 (7.84 g, 61%) as a
yellow/brown solid. This material was suitable for synthetic
purposes but contained about 10% of inorganic material that
was difficult to remove. A portion (0.5 g) was chromatographed
(CHCl3/EtOAc/MeOH 5:2:2) on silica gel, and the material
obtained (0.42 g) was recrystallized from methanol affording
1
a
compound 1 as a white solid: mp > 300 °C; H NMR (DMSO-
Key: (a) NaOEt, EtOH; (b) H2NCHdNH‚HOAc.
d6) as previously reported;4 13C NMR (DMSO-d6) δ 155.9, 152.0,
146.6, 128.3, 113.6, 101.2. Anal. Calcd for C6H6N4O: C, 48.00;
H, 4.03; N, 37.32. Found: C, 47.57; H, 4.13; N, 36.87.
acetate to compound 13 (Scheme 3),14 was employed. For
the purpose of producing compound 2, the previously
unreported pyrrole 14 was therefore required, and the
first attempt to make it involved reaction of 3-ethoxy-
acrylonitrile (16) with diethyl aminomalonate (17, Scheme
4A) following the successful synthesis of pyrrole 15 by
condensation of ethyl (ethoxymethylene)cyanoacetate (18)
with the same malonate ester3 (Scheme 4B) but none of
the required product 14 was formed. However, when the
malonate 17 was treated with 3-oxopropionitrile (19),
formed from its isomer isoxazole (20) on treatment with
base,15 the required pyrrole (14) was obtained in 55%
yield based on malonate 17, presumably by way of the
3-aminoacrylonitrile compound 21. From the pyrrole 14
the required 9-deazahypoxanthine (2) was produced in
82% yield (without chromatography) following condensa-
tion in boiling ethanol with formamidine acetate (Scheme
4C).
With pyrrole 14 now readily available, its condensation
with 1,3-bis(carbomethoxy)-S-methylisothiourea would
offer a further possible route to compound 2,16 but in our
opinion this option is unlikely to prove superior to our
new procedure.
In conclusion, we have developed a convenient, direct
synthetic route involving the condensation of isoxazole
and diethyl aminomalonate to the pyrrole derivative 14
(55%) from which 9-deazahypoxanthine (2) is readily
available by treatment with formamidine acetate (overall
yield 45%). An abbreviation of a published synthesis of
9-deazaguanine (1) from the readily available nitro
compound 5 (two steps, overall yield 49%) also makes this
compound much more accessible.
3-Am in o-2-et h oxyca r bon ylp yr r ole Hyd r och lor id e (14‚
HCl). A solution of sodium ethoxide in ethanol (2 M, 152 mL,
305 mmol) was added slowly to a stirred solution of isoxazole
20 (20 g, 290 mmol) in ethanol (80 mL) in an ice bath with a
reaction temperature of e8 °C. After an additional 0.5 h with
stirring, acetic acid (5.5 mL, 100 mmol), diethyl aminomalonate
hydrochloride (40.9 g, 193 mmol), and sodium acetate (16.4 g,
200 mmol) were added, and the mixture was stirred at rt for 2
d, after which most of the ethanol was removed under vacuum.
The residue was partitioned between chloroform and water, and
the organic phase was dried and filtered through a pad of silica
gel. Evaporation afforded a syrup that was dissolved in a solution
of sodium ethoxide in ethanol (0.5 M, 400 mL), and the solution
was stirred at room temperature for 3 d. Acetic acid (12 mL,
210 mmol) was added and the ethanol removed under vacuum.
The residue was dissolved in chloroform and washed with
NaHCO3 (aqueous, pH kept ∼7). The organic phase was dried
and filtered through a thick pad of silica gel to give crude syrupy
14 (16.4 g, 106 mmol), with clean 1H and 13C NMR spectra, that
was suitable for synthetic use. A portion in ether was treated
with HCl in dioxane to precipitate the hydrochloride salt 14‚
HCl (recrystallized from ethyl acetate/ethanol): mp 197-200
1
°C; H NMR (DMSO-d6) δ 7.02 (t, J ) 3.0 Hz, 1H), 6.34 (t, J )
2.5 Hz, 1H), 4.26 (q, J ) 7.1 Hz, 2H), 1.31 (t, J ) 7 Hz, 3H); 13
C
NMR δ 159.7, 123.2, 121.6, 114.7, 106.1, 60.6, 14.6. Anal. Calcd
for C7H11ClN2O5: C, 44.10; H, 5.82; N, 14.70. Found: C, 44.02;
H, 6.13; N, 14.55.
3H,5H-P yr r olo[3,2-d ]p yr im id in -4-on e (2). Formamidine
acetate (16.6 g, 158 mmol) was added to a solution of crude 14
(16.4 g, 106 mmol) in ethanol (150 mL), and the solution was
heated under reflux for 16 h and then cooled. The solid that
formed was isolated by filtration, washed with ethanol, and dried
to give 2 (11.8 g, 87 mmol) (recrystallized from water): mp >
1
300 °C; H NMR (DMSO-d6) as previously reported;4 13C NMR
(DMSO-d6) δ 154.0, 145.0, 141.8, 127.7, 118.2, 103.3. Anal. Calcd
for C6H5N3O: C, 53.33; H, 3.73; N, 31.10. Found: C, 53.41; H,
3.43; N, 31.21.
(14) Lim, M.-I.; Ren, W.-Y.; Otter, B. A.; Klein, R. S. J . Org. Chem.
1983, 48, 780.
(15) Ciller, J . A.; Martin, N.; Seoane, C.; Soto, J . L. J . Chem. Soc.,
Perkin Trans. 1 1985, 2581.
(16) Elliott, A. J .; Morris, P. E. J r.; Petty, S. L.; Williams, C. H. J .
Org. Chem. 1997, 62, 8071.
Ack n ow led gm en t. Dr. Herbert Wong kindly re-
corded the NMR spectra and Professor Robin Ferrier
assisted with the preparation of the manuscript.
J O990903E