A new and versatile synthesis of 5-substituted pyrrolo[2,3-d]pyrimidines

Article abstract of DOI:10.1016/S0040-4039(00)01491-X

We have developed a new methodology for the construction of 5-substituted pyrrolo[2,3-d]pyrimidines that involves the reduction of a nitroalkane to an oxime using the reducing ability of the Sn(SR₃)^- species, followed by mild, acid-catalysed deoximation of the resulting adduct using Dowex-H⁺ resin to form an intermediate aldehyde that spontaneously cyclises to the fused pyrrole ring. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01491-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8581–8585
A new and versatile synthesis of 5-substituted
pyrrolo[2,3-d]pyrimidines
Dolore`s Edmont and David M. Williams*
Department of Chemistry, Krebs Institute, University of Sheffield, Sheffield S3 7HF, UK
Received 30 August 2000; accepted 6 September 2000
Abstract
We have developed a new methodology for the construction of 5-substituted pyrrolo[2,3-d]pyrimidines
that involves the reduction of a nitroalkane to an oxime using the reducing ability of the Sn(SR3)− species,
followed by mild, acid-catalysed deoximation of the resulting adduct using Dowex-H+ resin to form an
intermediate aldehyde that spontaneously cyclises to the fused pyrrole ring. © 2000 Published by Elsevier
Science Ltd.
Keywords: oxime; Dowex; deoximation; cyclisation; pyrrolo[2,3-d]pyrimidines.
Substituted 2-aminopyrrolo[2,3-d]pyrimidin-4-ones (7-deazaguanines) occur naturally within a
number of minor nucleosidic constituents of tRNAs such as nucleoside Q1 and archaeosine.2
There are also several biologically active 2-aminopyrrolo[2,3-d]pyrimidin-4-ones, exemplified by
the anticancer agent LY231514 1.3 In each case, substitution at C5 is found. In addition,
nucleoside analogues incorporating C5-substituted pyrrolo[2,3-d]pyrimidines have been widely
studied as analogues of their purine counterparts, which permit the introduction of functional
groups into the major groove of DNA.4
* Corresponding author. Fax: 01142738673; e-mail: d.m.williams@sheffield.ac.uk
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01491-X

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We have been interested for some time in the syntheses of analogues of type 2,5 which are
derived from C5-substituted pyrrolo[2,3-d]pyrimidines. Whilst routes to such compounds using
palladium catalysed cross-coupling reactions with 5-iodo-pyrrolo[2,3-d]pyrimidines6 allows
access to these molecules, the 5-iodo-substituted precursors are sometimes not readily available.
Electrophilic substitution of 7-deazaguanine (2-aminopyrrolo[2,3-d]pyrimidin-4-one) occurs at
C67 and consequently we have investigated routes to such compounds exemplified in the
cyclisation of the pyrimidine acetal 3, which upon treatment with aqueous acid gives the
5-substituted pyrrolo[2,3-d]pyrimidine 4.
Recently, Taylor and Liu8 have reported a concise synthesis of 1 by Michael addition of
2,6-diamino-4(3H)-pyrimidinone 5 to a nitro olefin to produce 6, which cyclises to 7 under
conditions of the Nef reaction (Scheme 1). We envisaged applying a similar route for a general
synthesis of 5-substituted pyrrolo[2,3-d]pyrimidines such as 4, which we have described previ-
ously, but only in moderate yield.7
Scheme 1.
We report here a novel and efficient synthesis of 4 from commercially available 2,6-diamino-4-
(3H)-pyrimidinone 5 and an acyclic nitro alkene precursor, followed by subsequent acid
catalysed cyclisation of an oxime to give the pyrrolopyrimidine.
Thus, 1,3-propandiol was monobenzylated to give 8, which was oxidised to the corresponding
aldehyde 9.9 Aldol condensation of 9 with nitromethane,10 followed by dehydration11 with
methanesulfonyl chloride/triethylamine gave the nitro olefin 10. Michael addition12 of 5 to 10
gave 11 in good yield. Our initial attempts to effect cyclisation of 11 using the Nef reaction to
generate an intermediate aldehyde analogously to that described8 resulted in only poor yields
(29%) of the desired product. As an alternative route, we envisaged the generation of the
intermediate aldehyde from an oxime rather than from the nitro alkane 11. Thus, compound 11,
when treated with 1.5 equiv. of a mixture of SnCl2/3 PhSH/3 Et3N in acetonitrile readily gave
the oxime13 12 in 79% yield. The aldehyde intermediate was generated by deoximation14 using
Dowex-50 H+ form resin in water at neutral pH and spontaneously cyclised to the pyrrolo[2,3-
d]pyrimidine 13 (56% overall yield from 11). Debenzylation of 13 with boron trichloride15 gave
4 (Scheme 2).

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Scheme 2. Reagents and conditions: (a) PhCH2Br, NaH, DMF, Ref. 9; (b) PCC, CH2Cl2, Ref. 9; (c) CH3NO2/NaOH/
EtOH, 64% yield; (d) CH3SO2Cl/Et3N, 90% yield; (e) 5, 1:1 EtOAc/H2O, 50°C, 24 h, 69% yield; (f) 1.5 equiv. SnCl2/3
PhSH/3 Et3N, CH3CN, 79% yield; (g) H2O, Dowex-50, reflux, 71% yield; (h) CH2Cl2, 9 equiv. BCl3, −78°C, 51% yield
In summary, we have developed a new and simple methodology to synthesise 5-substituted-7-
deazaguanines which provides an alternative to the Nef-mediated cyclisation from a nitroalkane,
especially in circumstances where yields of the latter route are poor. The method employed for
the conversion of a nitroalkane into an aldehyde under mild and neutral conditions is envisaged
to be of general interest as an alternative to the Nef reaction.
Acknowledgements
We thank the EPSRC (GR/M44477) for financial support and Professor E. C. Taylor for
helpful discussions.
References
1. Kasai, H.; Ohashi, Z.; Harada, F.; Nishimura, S.; Oppenheimer, N. J.; Crain, P. F.; Liehr, J. D.; von Minden,
D. L.; McCloskey, J. A. Biochemistry 1975, 14, 4198–4208.
2. Gregson, J. M.; Crain, P. F.; Edmonds, C. G.; Gupta, R.; Hashizume, T.; Phillipson, D. W.; McCloskey, J. A.
J. Biol. Chem. 1993, 268, 10076–10086.
3. Taylor, E. C.; Kuhnt, D.; Shih, C.; Rinzel, S. M.; Grindley, G. B.; Barredo, J.; Jannatipour, M.; Moran, R. G.
J. Med. Chem. 1992, 35, 4450–4454.
4. For example see (a) Seela, F.; Zulauf, M. Helv. Chim. Acta 1999, 82, 1878–1898. (b) Ramzaeva, N.; Mittelbach,
C.; Seela, F. Nucleosides Nucleotides 1999, 18, 1439–1440. (c) Seela, F.; Zulauf, M. Chemistry—A European
Journal 1998, 4, 1781–1790. (d) Ramzaeva, N.; Mittelbach, C.; Seela, F. Helv. Chim. Acta 1997, 80, 1809–1822.
(e) Seela, F.; Chen, Y. M. Helv. Chim. Acta 1997, 80, 1073–1086.
5. (a) Williams, D. M.; Loakes, D.; Brown, D. M. J. Chem. Soc., Perkin Trans 1 1998, 3565–3570. (b) Williams, D.
M.; Yakovlev, D. Y.; Brown, D. M. J. Chem. Soc., Perkin Trans 1 1997, 1171–1178.
6. (a) Seela, F.; Zulauf, M. Synthesis 1996, 726–732. (b) Ramzaeva, N.; Seela, F. Helv. Chim. Acta 1996, 79,
1549–1558. (c) Seela, F.; Thomas, H. Helv. Chim. Acta 1995, 78, 94–108.
7. (a) Lu¨pke, U.; Seela, F. Chem. Ber. 1977, 110, 1462–1469. (b) Williams, D. M.; Brown, D. M. J. Chem. Soc.,
Perkin Trans 1 1995, 1225–1231.
8. Taylor, E. C.; Liu, B. Tetrahedron Lett. 1999, 40, 4023–4026.

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9. Baxter, A. D.; Binns, F.; Javed, T.; Roberts, S. M.; Sadler, P.; Scheinmann, F.; Wakefield, B. J.; Lynch, M.;
Newton, R. F. J. Chem. Soc., Perkin Trans. 1 1986, 889.
10. 4-(Benzyloxy)-1-nitro-2-butanol: A solution of nitromethane (4.92 g, 80.69 mmol) and 99 (13.25 g, 80.69 mmol)
in EtOH (15 ml) was stirred at 0°C and an aqueous NaOH solution (3.16 g in 7.9 ml) was slowly added,
maintaining the temperature below 10°C. The solution was warmed to room temp. over 3 h, then ice was added,
followed by glacial acetic acid until the precipitate dissolved and the pH was 6. The crude product was extracted
into EtOAc, which was washed with water, dried (MgSO4) and evaporated. Purification by chromatography
(CH2Cl2) gave a pale yellow oil (7.6 g, 64%); lH (CDCl3) 1.78–1.85 (2H, m, CH2), 3.43 (1H, s, OH), 3.65–3.71
(3H, m, CH and CH2O), 4.41 (2H, dd, J 6.41 and 1.22 Hz, CH2NO2), 4.51 (2H, s, CH2Ph), 7.29–7.36 (5H, m,
Ph); lC (CDCl3) 33.26 (CH2), 67.17 (CH2O), 67.71 (CHOH), 73.43 (CH2Ph), 80.47 (CH2NO2), 127.79 (2C, Ph),
128.00 (1C, Ph), 128.58 (2C, Ph), 137.52 (1Cq, Ph).
11. {[(3E)-4-Nitro-3-butenyl]oxy}methyl)benzene 10: Methanesulfonyl chloride (2.7 ml, 33.77 mmol) was added in
one portion to a stirred solution of 4-(benzyloxy)-1-nitro-2-butanol (7.6 g, 33.77 mmol) in CH2Cl2 (34 ml) at 0°C
under nitrogen. Et3N (9.35 ml, 67.54 mmol) was then added via a syringe pump over 1.5 h and the mixture stirred
for 15 min at 0°C. (Note: poor yields result if addition is too rapid). CH2Cl2 (40 ml) was then added, the mixture
transferred to a separating funnel and the organic layer was washed with water, 5% aqueous HCl, and brine.
After evaporation, the product (6.3 g, 90%) was used without further purification; lH (CDCl3) 2.5–2.59 (2H, m,
CH2), 3.61 (2H, t, J 5.8 Hz, CH2O), 4.52 (2H, s, CH2Ph), 7.04 (1H, td, J 1.22 and 13.73 Hz, H2), 7.24–7.37 (6H,
m, H1 and Ph); lC (CDCl3) 28.97 (CH2), 67.29 (CH2O), 73.22 (CH2Ph), 127.74 (2C, Ph), 127.92 (C2), 128.08
(1C, Ph), 128.54 (2C, Ph), 137.67 (1Cq, Ph), 139.59 (C1).
12. 2,6-Diamino-5-[3-(benzyloxy)-1-(nitromethyl)propyl]-4(3H)-pyrimidinone 11: A solution of 2,6-diamino-4(3H)-
pyrimidinone (3.63 g, 27.66 mmol) and 10 (6.3 g, 30.43 mmol) in 50% EtOAc/H2O (60 ml) was heated at 50°C
overnight. The crude product was extracted into EtOAc, which was washed with water, dried (MgSO4) and
evaporated. Purification by column chromatography (9:1 CH2Cl2/MeOH) gave a pale yellow solid (6.37 g, 69%);
Rf (8:2 CH2Cl2/MeOH), 0.62. The compound can be recrystallised from CH3CN; mp 95.3°C; lH (DMSO-d6)
1.65–1.85 (1H, m, CH2), 1.95–2.15 (1H, m, CH2), 3.35–3.62 (3H, m, CH and CH2O), 4.41 (2H, q, J 3.05 and 11.6
Hz, CH2Ph), 4.76 (1H, dd, J 6.1 and 12.51 Hz, CH2NO2), 5.03 (1H, dd, J 3.66 and 12.51 Hz, CH2NO2), 5.81 (2H,
s, NH2), 6.06 (2H, s, NH2), 7.29–7.34 (5H, m, Ph), 9.81 (1H, s, NH); lC (DMSO-d6) 30.02 (CH2), 32.56 (CH),
68.40 (CH2O), 72.34 (CH2Ph), 78.08 (CH2NO2), 84.34 (Cq), 127.79 (1C, Ph), 127.97 (2C, Ph), 128.67 (2C, Ph),
138.98 (1Cq, Ph), 154.01 (Cq), 162.33 (Cq), 163.28 (CꢀO); m/z (FAB+) 334.152277 (M+H+; calc. for
C15H20N5O4, 334.151529).
13. 4-(Benzyloxy)-2-(2,4-diamino-6-oxo-1,6-dihydro-5-pyrimidinyl)butanal oxime 12: Benzene thiol (1.65 ml, 16.06
mmol) and Et3N (2.5 ml, 17.93 mmol) were added to a stirred solution of anhydrous SnCl2 (1 g, 5.26 mmol) in
dry CH3CN (54 ml) at room temp. Then, 11 (1.2 g, 3.60 mmol) in dry CH3CN (73 ml) was added. After 30 min,
the reaction mixture was evaporated and the crude product was purified by column chromatography eluting with
95:5 CH2Cl2/MeOH (eluting PhSH, PhSSPh) and then 9:1 CH2Cl2/MeOH to afford a white solid (901 mg, 79%)
1
as an E/Z mixture (2:1.5 by H NMR); Rf (8:2 CH2Cl2/MeOH), 0.41; spectral data of isomer E: lH (DMSO-d6)
1.9–2.05 (2H, m, CH2), 3.45 (2H, t, J 7.05 Hz, CH2O), 3.40–3.50 (1H, m, CH), 4.32 (2H, s, CH2Ph), 5.75 (2H,
s, NH2), 6.07 (2H, s, NH2), 7.2–7.4 (5H, m, Ph), 7.55 (1H, d, J 8.6 Hz, CHꢀN), 9.81 (1H, s, NH), 10.21 (1H,
s, OH); lC (DMSO-d6) 30.73 (CH2), 32.94 (CH), 68.71 (CH2O), 72.35 (CH2Ph), 86.69 (Cq), 126.28 (1C, Ph),
127.74 (2C, Ph), 128.66 (2C, Ph), 139.13 (1Cq, Ph), 152.49 (CHꢀN), 153.92 (Cq), 154.24 (Cq), 162.37 (CꢀO);
m/z (FAB+) 318.158495 (M+H+; calc. for C15H20N5O3, 318.156615).
14. Cyclisation with Dowex-50 H+: 12 (324 mg, 1.02 mmol) was heated for 3 h at reflux with Dowex-50 (H+ form,
160 mg) in water (30 ml). The reaction mixture was then diluted with MeOH, and the Dowex resin filtered. The
methanol was evaporated under vacuum and the precipitate was filtered and washed with water to give 13 as a
white solid (206 mg, 71%); Rf (8:2 CH2Cl2/MeOH), 0.52; lH (DMSO-d6) 2.91 (2H, t, J 7.02 Hz, CH2), 3.71 (2H,
t, J 7.02 Hz, CH2O), 4.53 (2H, s, CH2Ph), 6.06 (2H, s, NH2), 6.48 (H, s, H-6), 7.30–7.45 (5H, m, Ph), 10.21 (1H,
s, NH), 10.76 (1H, s, NH); lC (DMSO-d6) 27.0 (CH2), 71.1 (CH2O), 72.1 (CH2Ph), 99.3 (Cq), 114.6 (C6), 114.9
(Cq), 127.7 (1C, Ph), 127.8 (2C, Ph), 128.6 (2C, Ph), 139.3 (Cq), 151.6 (Cq), 152.6 (Cq), 159.7 (CꢀO); m/z
(Fab+) 285.137312 (MH+; calc. for C15H17N4O2, 285.135151).
15. 2-Amino-5-(2-hydroxyethyl)-3,7-dihydro-7H-pyrrolo[2,3-d]pyrimidin-4-one 4: A solution of boron trichloride (1
M) in heptane (26 ml, 23.4 mmol) was added to a solution of 13 (700 mg, 2.46 mmol) in CH2Cl2 (90 ml) at −78°C
with exclusion of moisture. The mixture was stirred for 6 h at −78°C and a solution of CH2Cl2/EtOH (1:1; 90
ml) was added dropwise while the mixture was allowed to warm to room temp. The mixture was then evaporated,

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redissolved in a small volume of EtOH, and neutralised with a 1N NaOH solution. The residue was adsorbed
onto silica gel and chromatographed eluting with 9:1 and 8:2 CH2Cl2/MeOH to give a white solid (244 mg, 51%);
Rf (8:2 CH2Cl2/MeOH), 0.18; lH (DMSO-d6) 2.71 (2H, t, J 7.02 Hz, CH2), 3.56 (1H, t, J 7.02 Hz, CH2O), 3.60
(1H, d, J 5.19 Hz, CH2O), 4.64 (1H, t, J 5.19, OH), 6.06 (2H, s, NH2), 6.37 (1H, s, H-6), 10.25 (1H, s, NH),
10.69 (1H, s, NH); lC (DMSO-d6) 30.5 (CH2), 62.6 (CH2O), 99.3 (Cq), 114.5 (C6), 115.6 (Cq), 151.7 (Cq), 152.6
(Cq), 159.9 (CꢀO).
.