An improved synthesis of 9-deazaguanine

Article abstract of DOI:10.1081/SCC-120015398

A new, improved synthesis of 9-deazaguanine is described. The method involves use of the benzyloxymethyl group to protect the N³-position of 2-[(dimethylaminomethylene)-amino]-6-methyl-5-nitro-4(3H)-pyrimidinone, followed by treatment with DMF-dimethylacetal, reductive cyclization, treatment with ethanolic ammonia and removal of the protecting group by catalytic hydrogenation.

Full text of DOI:10.1081/SCC-120015398

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AN IMPROVED SYNTHESIS OF 9-DEAZAGUANINE
Mao-Chin Liu a , Mei-Zhen Luo a , Diane E. Mozdziesz a & Alan C. Sartorelli b
a Department of Pharmacology and Developmental Therapeutics Program, Cancer Center,
Yale University School of Medicine, New Haven, CT, 06520-8066, U.S.A.
b Department of Pharmacology and Developmental Therapeutics Program, Cancer Center,
Yale University School of Medicine, New Haven, CT, 06520-8066, U.S.A.
Version of record first published: 23 Aug 2006.
To cite this article: Mao-Chin Liu , Mei-Zhen Luo , Diane E. Mozdziesz & Alan C. Sartorelli (2002): AN IMPROVED SYNTHESIS
OF 9-DEAZAGUANINE, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 32:24, 3797-3802
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 24, pp. 3797–3802, 2002
AN IMPROVED SYNTHESIS OF
9-DEAZAGUANINE
Mao-Chin Liu, Mei-Zhen Luo, Diane E. Mozdziesz,
*
and Alan C. Sartorelli
Department of Pharmacology and Developmental
Therapeutics Program, Cancer Center, Yale University
School of Medicine, New Haven,
CT 06520-8066, USA
ABSTRACT
A new, improved synthesis of 9-deazaguanine is described.
The method involves use of the benzyloxymethyl group to
protect the N3-position of 2-[(dimethylaminomethylene)-
amino]-6-methyl-5-nitro-4(3H )-pyrimidinone, followed by
treatment with DMF-dimethylacetal, reductive cyclization,
treatment with ethanolic ammonia and removal of the
protecting group by catalytic hydrogenation.
Key Words: 9-Deazaguanine; 9-Deazapurine nucleosides
The carbon–carbon linked 9-deazapurine nucleosides are resistant to
cleavage by purine nucleoside phosphorylase[1] and several exhibit anti-
cancer,[2,3] antileishmanial,[4] and antitripanosomal[5] activity. As part of
an ongoing program to synthesize 9-deazapurine nucleosides as potential
*Corresponding author. E-mail: alan.sartorelli@yale.edu
3797
DOI: 10.1081/SCC-120015398
Copyright & 2002 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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3798
LIU ET AL.
anticancer and antiviral agents, we required 9-deazaguanine (1) as a starting
material. The methods reported earlier by Imai[6] and Klein et al.[7]
for the synthesis of 9-deazaguanine were either long and low-yielding[6]
or nonreproducible.[7,8] The most recent method described by Taylor and
coworkers[8,9] was a facile synthesis from 2-amino-6-methyl-5-nitro-4(3H )-
pyrimidinone, which was first converted into the 2-dimethylaminomethylene
derivative 2. Protection of N3-position of 2 with a pivaloyloxymethyl group
produced the N3-protected derivative 3 (60% yield) and 15% of the
O4-protected by-product 4. Further treatment of 3 with DMF-dimethylace-
tal, followed by reductive cyclization gave the protected 9-deazaguanine 5.
Basic removal of the protecting groups produced 9-deazaguanine (1).
However, selection of pivaloyloxymethyl as a protecting group was not
the optimum choice. First, it produced an O4-protected by-product which
needed to be removed, thereby reducing the yield of the product. Second,
the pivaloyloxymethyl protecting group is difficult to remove under mild
alkaline conditions, and the 9-deazaguanine ring is not stable in strong
basic solutions. Thus, treatment of 5 with a mixture of 1 N NaOHand
THF at room temperature for 4 days gave only 48% of 9-deazaguanine.[9]
We selected the benzyloxymethyl group to protect the N3-position of 2
instead of the pivaloyloxymethyl group, since the benzyloxymethyl group
not only produced solely the N3-protected product, but it also could be

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IMPROVED SYNTHESIS OF 9-DEAZAGUANINE
3799
Scheme 1.
removed readily by mild reduction under neutral conditions. Treatment of 2
with benzyl chloromethyl ether in DMF in the presence of 1,8-diaza-
bicyclo[5,4,0]undec-7-ene (DBU) at room temperature afforded compound
6 in 90% yield. Condensation of 6 with DMF-dimethylacetal in DMF gave
compound 7 (91%). Subsequent reductive cyclization of 7 produced the
protected 9-deazaguanine derivative 8 (95%). Treatment of 8 with ethanolic
ammonia at an elevated temperature gave compound 9 (95%), which was
converted to 9-deazaguanine (1) by catalytic hydrogenation in 90% yield
(Sch. 1).
In summary, we report an improved method for the synthesis of
9-deazaguanine (1) from the intermediate 2 with an overall yield of 66.5%.
EXPERIMENTAL SECTION
Melting points were determined with a Thomas-Hoover Unimelt
apparatus and are uncorrected. 1HNMR spectra were recorded on a

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3800
LIU ET AL.
Varian EM-390 (90 MHz) or Gemini-300 (300 MHz) NMR spectrometer
with Me4Si as the internal reference. Column chromatography was con-
ducted with Merck silica gel 60, 230–400 mesh. TLC was performed on
EM precoated silica gel sheets containing a fluorescent indicator.
Elemental analyses were carried out by the Baron Consulting Co.,
Orange, CT, USA.
3-Benzyloxymethyl-2-[(dimethylamino)methyleneimino]-6-methyl-5-nitro-
4(3H )-oxopyrimidine (6): To a suspension of compound 2 (11.25 g, 50 mmol)
in anhydrous DMF (250 mL) was added DBU (8.0 mL, 52 mmol) with
stirring. After the reaction mixture became a clear solution (ꢀ5 min),
benzyl chloromethyl ether (9.4 g, 60 mmol) was added dropwise to this
solution at 0–5ꢁC (ice-water bath). The reaction mixture was stirred at
room temperature until TLC showed the reaction was complete (ꢀ2 h). The
reaction mixture was evaporated in vacuo to dryness, and the residue was
dissolved in methylene chloride (400 mL), washed with water (2 ꢂ 100 mL),
dried (MgSO4), filtered and washed with methylene chloride. The filtrate and
washings were combined and evaporated in vacuo to dryness and the residue
was purified by silica gel column chromatography (CH2Cl2/EtOAc, 4 : 1, v/v)
to yield 6 (16.6 g, 90%) as yellow crystals: m.p. 93–95ꢁC; Rf 0.77
(CH2Cl2/EtOAc, 4 : 1, v/v); 1HNMR (CDCl 3) ꢀ 2.40 (s, 3H, CH3), 3.12 and
3.28 (two s, 6H, NMe2), 4.75 (s, 2H, CH2), 5.75 (s, 2H, CH2), 7.30 (m, 5H,
ArH), 8.70 (s, 1H, CH). Anal. calcd. for C16H19N5O4: C, 55.62; H, 5.55;
N, 20.28. Found: C, 55.67; H, 5.86; N, 19.90.
3-Benzyloxymethyl-2-[(dimethylamino)methyleneimino]-6-[(2-dimethyl-
amino)ethenyl]-5-nitro-4(3H )-oxopyrimidine (7): A mixture of 6 (6 g,
17.4 mmol) and DMF-dimethylacetal (11 mL) in 60 mL of anhydrous
DMF was stirred at room temperature until TLC showed that the reaction
was complete (ꢀ 40 h). The reaction mixture was evaporated in vacuo to
dryness and the residue was purified by silica gel column chromatography
(CH2Cl2/EtOAc, 4 : 1, v/v) to yield 7 (6.3 g, 91%) as yellow crystals: m.p.
195–196ꢁC; Rf 0.46 (CH2Cl2/EtOAc, 4:1, v/v); 1HNMR (DMSO-d 6)
ꢀ 2.80–3.10 (m, 12H, 2NMe2), 4.70 (s, 2H, CH2), 5.65 (d, 1H, ¼CH,
J ¼ 12.1 Hz), 5.67 (s, 2H, CH2), 7.30 (m, 5H, ArH), 7.95 (d, 1H, ¼CH,
J ¼ 12.1 Hz), 8.58 (s, 1H, CH¼N). Anal. calcd. for C19H24N6O4: C, 56.99;
H, 6.04; N, 20.99. Found: C, 56.65; H, 6.13; N, 20.69.
3-Benzyloxymethyl-2-[(dimethylamino)methyleneimino]-4(3H)-oxo-5H-
pyrrolo[3,2-d]pyrimidine (8): A suspension of 7 (4.9 g, 12.2 mmol), sodium
hydrosulfite (12.0 g), THF (180 mL) and water (90 mL) was stirred at room
temperature until the reaction mixture gradually became a clear orange
solution and TLC showed that the reaction was complete (ꢀ12 h). The
reaction mixture was evaporated in vacuo to dryness and the residue was
stirred with water (30 mL) for 20 min. The solid was collected, washed with

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IMPROVED SYNTHESIS OF 9-DEAZAGUANINE
3801
water and purified by silica gel column chromatography (CH2Cl2/EtOH,
15 : 1, v/v) to yield 8 (3.8 g, 95%) as an off-white solid: m.p. 195–196ꢁC;
1
Rf 0.28 (CH2Cl2/EtOAc, 1 : 1, v/v); HNMR (CDCl 3) ꢀ 3.05 and 3.12 (two
s, 6H, NMe2), 4.80 (s, 2H, CH2), 5.97 (s, 2H, CH2), 6.30 (d, 1H, ¼CH,
J ¼ 2.0 Hz), 7.22 (d, 1H, ¼CH, J ¼ 2.0 Hz), 7.30 (m, 5H, ArH), 8.50 (s, 1H,
CH¼N), 11.50 (br s, 1H, NH, D2O exchangeable). Anal. calcd. for
C17H19N5O2: C, 62.75; H, 5.88; N, 21.53. Found: C, 62.70; H, 5.80; N, 21.32.
1-Benzyloxymethyl-9-deazaguanine (9):
A mixture of 8 (0.7 g,
2.2 mmol) and ethanolic ammonia (60 mL, saturated at 0ꢁC) was heated
in a steel bomb at 165–170ꢁC with stirring for 4 h, then cooled in an ice
bath. The cold reaction mixture was evaporated in vacuo to dryness and the
residue was purified by silica gel column chromatography (CH2Cl2/EtOH,
15 : 1, v/v) to yield 9 (0.55 g, 95%) as a white solid: m.p. 204–205ꢁC; Rf 0.36
1
(CH2Cl2/EtOAc, 1 : 1, v/v); HNMR (DMSO-d 6) ꢀ 4.57 (s, 2H, CH2), 5.54
(s, 2H, CH2), 5.97 (d, 1H, ¼CH, J ¼ 2.1 Hz), 6.20 (br s, 2H, NH2, D2O
exchangeable), 7.21 (d, 1H, ¼CH, J ¼ 2.1 Hz), 7.34 (m, 5H, ArH), 11.52
(br s, 1H, NH, D2O exchangeable). Anal. calcd. for C14H14N4O2: C,
62.21; H, 5.22; N, 20.73. Found: C, 62.05; H, 4.98; N, 20.43.
9-Deazaguanine (1): To a solution of 9 (0.3 g, 1.1 mmol) in methanol
(100 mL) was added palladium hydroxide on carbon (0.2 g), and the mixture
was hydrogenated (H2, 50 psi) for 5 h. The catalyst was removed by filtration,
washed with methanol, and the filtrate and washings were combined and
evaporated in vacuo to dryness. The residue was recrystallized from 50%
ethanol to give 0.15 g of 1 (90%) as a white solid: m.p. gradually darkens
over 310ꢁC; (lit.[6] m.p.>300ꢁC; lit.[9] 310–315ꢁC dec); 1HNMR (DMSO-d 6)
ꢀ 5.95 (d, 1H, ¼CH, J ¼ 2.8 Hz), 5.95 (br s, 2H, NH2, D2O exchangeable),
7.15 (d, 1H, ¼CH, J ¼ 2.8 Hz), 10.70 (br s, 1H, NH, D2O exchangeable),
11.51 (br s, 1H, NH, D2O exchangeable). Anal. Calcd. for C6H6N4Oꢃ0.6H2O:
C, 44.77; H, 4.51; N, 33.81. Found: C, 44.74; H, 4.13; N, 34.85.
ACKNOWLEDGMENT
This research was supported in part by Connecticut Innovations, Inc.
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Received in the USA December 7, 2001