G. Mladenova, E. Lee-Ruff / Tetrahedron Letters 48 (2007) 2787–2789
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2. Results
References and notes
1. Jeong, L. S.; Lee, J. A. Antivir. Chem. Chemoth. 2004, 15,
235–250.
2. Lee-Ruff, E.; Xi, F.-D.; Qie, J.-H. J. Org. Chem. 1996, 61,
1547–1550.
Cyclobutanones 1 were prepared by [2+2] cycloaddition
of the corresponding alkene with dichloroketene,
followed by dechlorination in 50–70% yield (Scheme 2).
3. Khalili, P.; Naimi, E.; Knaus, E. E.; Wiebe, L. I.
Biopharm. Drug Dispos. 2002, 23, 105–113.
4. Lamberth, C. Org. Prep. Proced. Int. 2002, 34, 151–
167.
Irradiation of CH2Cl2 solutions of ketones 1 (R = Bz,
TBDMS) (5 · 10ꢀ3 M) with malononitrile, methyl-
malononitrile or HCN (5 equiv) led to the formation
of adducts 2 and 3, respectively, in about 40% yields
and 16% for methylmalononitrile (Scheme 3).7 The
remaining products are derived from cycloelimination.
The stereoisomers of 3 could be separated and the
stereochemistry assigned based on NOESY analysis.
The trans-isomer was formed in a slightly higher yield
compared to the cis-isomer. The cis-isomer of 3 has
the more shielded anomeric hydrogen (d 4.68 ppm for
R = TBDMS and d 4.76 ppm for R = Bz) relative to
the trans-isomer (d 4.75 ppm for R = TBDMS and d
5. (a) Lee-Ruff, E.; Jiang, J.-L.; Wan, W.-Q. Tetrahedron
Lett. 1993, 34, 261–264; (b) Lee-Ruff, E.; Wan, W.-Q.;
Jiang, J.-L. J. Org. Chem. 1994, 59, 2114–2118;
(c) Lee-Ruff, E.; Xi, F.-D.; Qie, J. H. J. Org. Chem
1996, 61, 1547–1550; (d) Lee-Ruff, E.; Ostrowski, M.;
Ladha, A.; Stynes, D. V.; Vernik, I.; Jiang, J.-L.; Wan,
W.-Q.; Ding, S.-F.; Joshi, S. J. Med. Chem. 1996, 39,
5276–5280; (e) Lee-Ruff, E.; Margau, R. Nucleos. Nucleot.
Nucl. 2001, 20, 185–196; (f) Zhong, J.-H.; Fishman, A.;
Lee-Ruff, E. Organic Lett. 2002, 4, 4415–4417; (g)
Ghazi, H.; Lee-Ruff, E. J. Fluorine Chem. 2005, 126,
1565–1569.
1
4.86 ppm for R = Bz) in their H NMR spectra. The
stereoisomers of 2 could not be separated.
6. The insertion of siloxycarbenes, generated from acyl
silanes, to HCN and malononitrile has been previously
observed. Duff, J. M.; Brook, A. G. Can. J. Chem. 1973,
51, 2869–2883.
Condensation of 2 (R = H) with guanidine hydrogen
chloride salt, urea or thiourea according to the method
of Bio et al.8 did not give any heterocycle formation.
However, methylmalononitrile adduct
reacted with urea under the same conditions to give 4
7. Photolyses were carried out using a Hanovia 450 W
medium-pressure mercury arc lamp in a water-cooled
quartz immersion well. The photoproducts were purified
by chromatography (4:1 hexane–ethyl acetate) obtained as
colourless oils. Compound 3 (R = Bz) 1H NMR; d 2.20
(ddd, J = 7.68, 2.08, 6.28 Hz, 1H), 2.50 (ddd, J = 3.80,
3.36, 3.6 Hz, 1H), 3.03 (q, J = 6.16 Hz, 1H), 3.93 (dd,
J = 5.16, 5.16 Hz, 1H), 4.18 (t, J = 8.56, 7.92 Hz, 1H),
4.29 (dd, J = 7.12, 7.04 Hz, 1H), 4.35 (dd, J = 6.28,
6.4 Hz, 1H) 4.85 (dd, J = 3.52, 3.52 Hz, 1H), 7.48 (t,
J = 7.68 Hz, 2H), 7.61 (t, J = 7.2 Hz, 1H), 8.04 (d,
J = 7.48 Hz, 2H). Compound 30 (R = Bz) 1H NMR; d
2.23 (m, 1H), 2.59 (m, 1H), 2.87 (h, J = 7.92 Hz, 1H), 3.91
(t, J = 8.52, 8.04 Hz, 1H), 4.18 (t, J = 8.64, 7.64 Hz,
1H), 4.40 (dd, J = 7.24, 7.24 Hz, 1H), 4.47 (dd, J =
6.36, 6.36 Hz, 1H), 4.76 (dd, J = 5.64, 5.72 Hz, 1H), 7.48
(t, J = 7.68 Hz, 2H), 7.61 (t, J = 7.2 Hz, 1H), 8.07
(d, J = 7.68 Hz, 2H). Compounds 3 and 30 as well as
other photoproducts gave satisfactory elemental
analyses.
2 (R = Me)
in 80% yield (Scheme 4).
The HCN photoadducts 3 (trans) and 30 (cis) reacted
with 2,3-diaminopyridine and 4,5,6-triaminopyrimidine
to give the corresponding 1H-Imidazo[4,5-b]pyridines,
6 (trans) and 60 (cis), and purines 7 (trans) and 70 (cis),
respectively via imidate salt 5 (Scheme 4).9 Other
C-nucleoside analogues prepared in this study are the
tetrazole derivatives (Scheme 4). Reaction of the cyano
photoadduct 3 or 30, sodium azide and ammonium
chloride in DMF gave tetrazole furanoside 8 or 80
(75%).10
3. Summary
8. Bio, M. M.; Xu, F.; Waters, M.; Williams, J. M.; Savary,
K. A.; Cowden, C. J.; Yang, C.; Buck, E.; Song, Z. J.;
Tschaen, D. M.; Volante, R. P.; Reamer, R. A.;
Grabowski, E. J. J. J. Org. Chem. 2004, 69, 6257–
6266.
9. Miller, D. D.; Hamada, A.; Clark, M. T.; Adejare, A.;
Patil, P. N.; Shams, G.; Romstedt, K. J.; Kim, S. U.;
Intrasuksri, U. J. Med. Chem. 1990, 33, 1138–1144.
10. Popsavin, M.; Torovic, L.; Spaic, S.; Stankov, S.; Kapor,
A.; Tomic, Z.; Popsavin, V. Tetrahedron 2002, 58, 569–
580.
The photochemical ring-expansion of cyclobutanones
with malononitrile and hydrogen cyanide give photo-
adducts by direct insertion into the acidic C–H function.
These adducts can be condensed with appropriate
reagents to give heterocyclic C-furanosides, which are
analogues of C-nucleosides. Since cyclobutanones with
stereochemically defined ring-substituents are com-
monly available by classical synthetic methods, many
of which involve enantioselective reactions,11 these C-
nucleoside analogues can also be prepared in optically
enriched forms.
11. Mladenova, G.; Lee-Ruff, E. Chem. Rev. 2003, 103, 1449–
1483.