Synthesis of norcarbovir analogues, the first examples of cyclobutene nucleosides unsubstituted at the vinylic position

Article abstract of DOI:10.1021/jo961451y

Two cyclobutene nucleosides, 27 and 29, analogous to the yet unknown norcarbovir, and with adenine and hypoxanthine as the base moieties, respectively, were synthesized starting from cis-3-cyclobutene-1,2-dicarboxylic anhydride (6). Its reduction to lacto

Full text of DOI:10.1021/jo961451y

2166
J . Org. Chem. 1997, 62, 2166-2172
Syn th esis of Nor ca r bovir An a logu es, th e F ir st Exa m p les of
Cyclobu ten e Nu cleosid es Un su bstitu ted a t th e Vin ylic P osition
Marie-Edith Gourdel-Martin and Franc¸ois Huet*
Laboratoire de Synthe`se Organique, URA-CNRS 482, Faculte´ des Sciences, Universite´ du Maine,
BP 535, F-72017 Le Mans Cedex, France
Received J uly 30, 1996 (Revised Manuscript Received J anuary 8, 1997X)
Two cyclobutene nucleosides, 27 and 29, analogous to the yet unknown norcarbovir, and with
adenine and hypoxanthine as the base moieties, respectively, were synthesized starting from cis-
3-cyclobutene-1,2-dicarboxylic anhydride (6). Its reduction to lactone 9 followed by reaction with
ammonia and then Hofmann rearrangement led to cyclic carbamate 15 which was the key
intermediate of these syntheses. Its tert-butoxycarbonyl derivative 17 led to the ring opening of
the heterocyclic moiety at low temperature. Compound 18 was thus obtained, and the successive
benzylation and then treatment with hydrochloric acid yielded hydrochloride 21. Construction of
bases was achieved in satisfying overall yields provided that mild experimental conditions from 21
to 27 or 29 were used to restrict the unwanted electrocyclic ring opening. Nitropyrimidine 31 was
also prepared from 21 via the intermediate 23.
In tr od u ction
The recognition that nucleosides and nucleoside ana-
logues can possess interesting antitumor and antiviral
properties has led to a great interest of chemists during
the past years.1 Peculiarly, (-)-carbovir (1), the carbocy-
clic analogue of 2′,3′-didehydro-2′,3′-dideoxyguanosine in
which the furan ring oxygen is replaced by a methylene,
was reported to be a potent inhibitor of reverse tran-
scriptase of HIV-1.2 This interesting biological activity
gave rise to a number of synthetical works from research
laboratories.3 As a further step in the evaluation of the
analogues of carbovir, we planned to remove this meth-
ylene and to obtain norderivatives. Besides the possible
interest of these compounds on the biological point of
view, we anticipated that special conditions would be
needed to synthesize these compounds. Cyclobutene
compounds with two cis substituents at the allylic
position have indeed almost never been prepared as
target molecules, and they rather are intermediates to
acyclic4 and cyclic5 (Z,E)-dienes. On the other hand only
one cyclobutene nucleoside (2) has been previously
prepared6a,7 as well as a few cyclobutane nucleosides with
an exocyclic double bond (3, 4)6 (Figure 1).
F igu r e 1.
Resu lt a n d Discu ssion
This paper deals with the first synthesis of cyclobutene
nucleosides unsubstituted at the vinylic position (5). The
synthetic way started from anhydride 6 prepared by
photocycloaddition of acetylene to maleic anhydride.8 In
early experiments the carboxylic group of the hemiester
7, obtained by methanolysis of 6, was converted into
amide or acyl azide in the usual experimental conditions
but the subsequent Hofmann or Curtius rearrangements
failed to yield the amino ester 8, or a protected related
product, due to the high thermal unstability of the
intermediates and the product. Fortunately replacement
of the methoxycarbonyl group by an hydroxymethyl group
resulted in an increased stability and the amido alcohol
10 was obtained in fair yield by reduction of anhydride
X Abstract published in Advance ACS Abstracts, March 1, 1997.
(1) For recent reviews, see the following. (a) Huryn, D. M.; Okabe,
M. Chem. Rev. 1992, 92, 1745. (b) Borthwick, A. D.; Biggadike, K.
Tetrahedron 1992, 48, 571. (c) Agrofoglio, L.; Suhas, E.; Farese, A.;
Condom, R.; Challand, S. R.; Earl, R. A.; Guedj, R. Tetrahedron 1994,
50, 10611.
(2) Coates, J . A. V.; Inggall, H. J .; Pearson, B. A.; Penn, C. R.; Storer,
R.; Williamson, C.; Cameron, J . M. Antiviral Res. 1991, 15, 161.
(3) For recent syntheses, see the following. (a) Trost, B. M.; Li, L.;
Guile, S. D. J . Am. Chem. Soc. 1992, 114, 8745. (b) Evans, C. T.;
Roberts, S. M.; Shoberu, K. A.; Sutherland, A. G. J . Chem. Soc., Perkin
Trans. 1 1992, 589. (c) Mac Keith, R. A.; Mc Cague, R.; Olivo, H. F.;
Palmer, C. F.; Roberts, S. M. J . Chem. Soc., Perkin Trans. 1 1993,
313. (d) J ung, M. E.; Rhee, H. Tetrahedron Lett. 1993, 34, 449. (e)
Asami, M.; Takahashi, J .; Inoue, S. Tetrahedron: Asymmetry 1994, 5,
1649. (f) Nokami, J .; Matsuura, H.; Nakasima, K.; Shibata, S. Chem.
Lett. 1994, 1071. (g) J ung, M. E.; Rhee, H. J . Org. Chem. 1994, 59,
4719. (h) Diaz, M.; Ibarzo, J .; J imenez, J . M.; Ortuno, R. M. Tetrahe-
dron: Asymmetry 1994, 5, 129. (i) Legraverend, M.; Aubertin, A. M.;
Obert, G.; Huel, C.; Bisagni, E. Nucleosides Nucleotides 1994, 13, 915.
(j) Hildebrand, S.; Troxler, T.; Scheffold, R. Helv. Chim. Acta 1994,
77, 1236. (k) Berranger, T.; Langlois, Y. Tetrahedron Lett. 1995, 36,
5523. (l) Crimmins, M. T.; King, B. W. J . Org. Chem. 1996, 61, 4192.
See also references therein.
(5) (a) Trost, B. M.; McDougal, P. G. J . Org. Chem. 1984, 49, 458.
(b) Tamm, C.; J eker, N. Tetrahedron 1989, 45, 2385. (c) Vos, G. J . M.;
Benders, P. H.; Reinhoudt, D. N.; Egberink, R. J . M.; Harkema, S.;
van Hummel, G. J . J . Org. Chem. 1986, 51, 2004.
(6) (a) Maruyama, T.; Hanai, Y.; Sato, Y. Nucleosides Nucleotides
1992, 11, 855. (b) Maruyama, T.; Hanai, Y.; Sato, Y.; Snoeck, R.;
Andrei, G.; Hosoya, M.; Balzarini, J .; De Clercq, E. Chem. Pharm. Bull.
1993, 41, 516.
(7) Gharbaoui, T.; Legraverend, M.; Bisagni, E. Tetrahedron Lett.
1992, 33, 7141.
(8) (a) Bloomfield, J . J .; Owsley, D. C. Org. Photochem. Synth. 1976,
2, 36. (b) Binns, F.; Hayes, R.; Ingham, S.; Saengchantara, S. T.;
Turner, R. W.; Wallace, T. W. Tetrahedron 1992, 48, 515. (c) Brauman,
J . I.; Archie, W. C., J r. J . Am. Chem. Soc. 1972, 94, 4262.
(4) Binns, F.; Hayes, R.; Hodgetts, K. J .; Saengchantara, S. T.;
Wallace, T. W.; Wallis, C. J . Tetrahedron 1996, 42, 3631.
S0022-3263(96)01451-X CCC: $14.00 © 1997 American Chemical Society

Synthesis of Norcarbovir Analogues
J . Org. Chem., Vol. 62, No. 7, 1997 2167
Sch em e 1
opening occurred. tert-Butoxycarbonyl derivative 18
reacted with hydrochloric acid at 0 °C and yielded the
pure crystallized hydrochloride 20. Similarly, benzyla-
tion of 18 followed by the same hydrochloric acid treat-
ment led to compound 21. Compounds 20 and 21 were
thus obtained in high purity and in 41% and 38% overall
yields, respectively, from 6, and difficulties due to the
unwanted thermal electrocyclic reactions were thus
practically circumvented.
We anticipated that the following steps would also need
mild experimental conditions for the same reasons.
Therefore, we used, in the first step of construction of
adenine, 4,6-dichloro-5-nitropyrimidine,13 which is more
reactive that the corresponding amino derivative. The
reactions worked at room temperature from hydrochlo-
rides 20 or 21, in the presence of triethylamine, and gave
the substitution products 22 and 23 in satisfactory yields.
Compound 22 was obtained in lower yield than 23.
Moreover the subsequent reduction of the nitro group of
22, in several experimental conditions, proved to give
complex mixtures instead of the expected product. There-
fore we pursued the synthesis from benzylated derivative
23. Its reduction with sodium hydrosulfite14 gave the
expected product 24 that could be easily purified; how-
ever, in these conditions, the yield was low (27%).15
Other reagents such as NaBH4-Pd/C16 and H3PO2-Pd/
C17 gave bad results. An attempt of reduction in the
presence of bakers’ yeast18 also failed. Finally the best
result was obtained with SnCl2‚2H2O13a,19 in ethanol.
Compound 24 was thus prepared in 62% yield at 60 °C
for 10 min. Further cyclization with triethyl orthofor-
mate gave the expected product 25 at room temperature.
It was treated with ammonia under pressure in a
stainless steel bomb for 48 h at 40 °C, and the reaction
yielded 26 in high yield. Subsequent debenzylation with
boron trichloride13a gave norcabovir A (27) (Scheme 3)
in 12 steps from 6 and in 15% overall yield. Fortunately
compounds 24, 25, 26, and 27 were less sensitive to
heating than the previous ones of this synthesis. For
instance, preparation of 24 needed a short heating at 60
°C, and only a small amount of the electrocyclic ring-
6 to lactone 94,9 followed by treatment with ammonia
(Scheme 1).
Reaction of the silyl or tetrahydropyranyl derivative,
11a or 11b, respectively, with bis(acetoxy)iodobenzene10
led to the expected methyl carbamates 12a and 12b
together with small amounts of the electrocyclic ring-
opening products. Attempts of separation by column
chromatography on silica gel failed and led to higher
yields of the opening products. On the other hand
heating of cyclobutene 12a at 110 °C in toluene for 12
min gave rise to 13 as the sole electrocyclic ring-opening
product. Other similar outward conrotation preferences
for nitrogen substituents were pointed out previously.11
In these experimental conditions, a part of compound 13
was isomerized into 14 (Scheme 2). These dienes were
characterized by 1H NMR (13, J H-1/H-2 ) 12.9 Hz; J H-3/H-4
) 9.9 Hz; strong NOE enhancement of H-4 upon satura-
tion of H-3 + H-4 at 5.95 ppm; 14, J H-1/H-2 ) 13.8 Hz;
J H-3/H-4 ) 15.3 Hz). The cyclobutene/diene ratio for the
1
1
opening product was detected by H NMR of the crude
product. It was removed in the course of the purification
by column chromatography.
Compound 29 with hypoxanthine as the base was
obtained by acidic hydrolysis of 25 followed by debenzy-
lation. We also prepared compound 31 by nucleophilic
substitution of ammonia to 23, followed by debenzylation
(Scheme 4). Compounds 30 and 31 were obtained
reaction from 11a was measured by integration of H
NMR signals corresponding to methylene groups of both
compounds (3.79 and 4.20 ppm for 12a and 13, respec-
tively). The same method was used for the following
products.
Compounds 12a and 12b were submitted to the usual
hydrolytic methods for methyl carbamates (e.g., heating
in basic or acidic conditions). However we could not thus
obtain the expected amino alcohols, and either recovery
of the starting materials or formation of unidentified
products occurred.
On the other hand the same reaction from the unpro-
tected 10 led to an interesting result. Cyclic carbamate
15 was thus obtained in high yield provided that the
reaction was run in a concentrated medium to reduce the
amount of methyl carbamate 16. When this compound
(15) was submitted to reaction with di-tert-butyl dicar-
bonate,12 the expected product 17 was easily obtained.
Its basic treatment in mild conditions led to compound
18, and only a small amount of the electrocyclic ring-
(12) (a) Ishizuka, T.; Kunieda, T. Tetrahedron Lett. 1987, 28, 4185.
(b) Taylor, S. J . C.; Mc Cague, R.; Wisdom, R.; Lee, C.; Dickson, K.;
Ruecroft, G.; O’Brien, F.; Littlechild, J .; Bevan, J .; Roberts, S. M.;
Evans, C. T. Tetrahedron: Asymmetry 1993, 4, 1117.
(13) (a) Marquez, V. E.; Lim, B. B.; Driscoll, J . S.; Snoek, R.;
Balzarini, J .; Ikeda, S.; Andrei, G.; De Clercq, E. J . Heterocycl. Chem.
1993, 30, 1393. (b) Agrofoglio, L.; Condom, R.; Guedj, R.; Challand,
R.; Selway, J . Tetrahedron Lett. 1993, 34, 6271. (c) Payne, A. N.;
Roberts, S. M. J . Chem. Soc., Perkin Trans. 1 1992, 2633. (d) Coe, D.
M.; Myers, P. L.; Parry, D. M.; Roberts, S. M.; Storer, R. J . Chem. Soc.,
Chem. Commun. 1990, 151. (e) Palmer, C. F.; Parry, K. P.; Roberts, S.
M. Tetrahedron Lett. 1990, 31, 279.
(14) (a) Louis-Andre, O.; Gelbard, G. Bull. Soc. Chim. Fr. 1986, 565.
(b) O’Hara Dempcy, R.; Skibo, E. B. J . Org. Chem. 1991, 56, 776.
(15) For a similar observation, see: Boothroyd, S. R.; Kerr, M. A.
Tetrahedron Lett. 1995, 36, 2411.
(16) Petrini, M.; Ballini, R.; Rosini, G. Synthesis 1987, 713.
(17) Entwistle, I. D.; J ohnstone, R. A. W.; Telford, R. P. J . Chem.
Soc., Perkin Trans. 1 1977, 443.
(18) (a) Baik, W.; Han, J . L.; Lee, K. C.; Lee, N. H.; Kim, B. H.;
Hahn, J .-T. Tetrahedron Lett. 1994, 35, 3965. (b) Davey, C. L.; Powell,
L. W.; Turner, N. J .; Wells, A. Tetrahedron Lett. 1994, 35, 7867.
(19) Bellamy, F. D.; Ou, K. Tetrahedron Lett. 1984, 25, 839.
(9) (a) Soai, K.; Yokoyama, S.; Mochida, K. Synthesis 1987, 647. (b)
Me´vellec, L.; Evers, M.; Huet, F. Tetrahedron 1996, 48, 15103.
(10) Moriarty, R. M.; Chany, C. J ., II; Vaid, R. K.; Prakash, O.;
Tuladhar, S. M. J . Org. Chem. 1993, 58, 2478.
(11) Gourdel-Martin, M.-E.; Huet, F. Tetrahedron Lett. 1996, 37,
7745 and references therein.

2168 J . Org. Chem., Vol. 62, No. 7, 1997
Gourdel-Martin and Huet
Sch em e 4
Sch em e 2
a
b
CF3CO2H, H2O, rt. BCl3, CH2Cl2, -78 °C. c NH3, MeOH, rt.
d
See b, Scheme 2.
DMSO-d6. NMR results and NOE experiments11 are in
agreement with the 1′Z,3′E stereochemistry.
Compounds 27, 29, and 31 have been evaluated as
inactive in in vitro anti HIV-1 and HIV-2 screens (CEM
4 cells) and in in vitro antitumor tests (KB cells).
a tBuMe2SiCl, imidazole, DMF (11a ) or dihydropyrane, PPTS
(11b). Total yields (%) for the cyclobutene compounds and the
resulting electrocyclic ring-opening products that could not be
separated from this mixture. The numbers in parentheses refer
to the ratio cyclobutenes/dienes measured by 1H NMR.
b
Con clu sion
The main difficulty in obtaining the target molecules
was the easy thermal electrocyclic ring opening of cyclo-
butene compounds, which could even partly occur at room
temperature (e.g., 12a ,b, 18, and 19). Cyclobutene-
diene isomerization has already been studied.20 It has
been shown that the rate and the stereoselectivity of the
conrotatory electrocyclic reaction of cyclobutenes are
influenced to a large extent by the electronic effects of
the allylic substituents.11,21 In this paper, we describe
the first syntheses of carbocyclic nucleosides analogous
to carbovir but with a cyclobutene ring. These com-
pounds were obtained in fair overall yield when mild
experimental conditions were used.
Sch em e 3
Exp er im en ta l Section
1
NMR spectra were recorded at 400 and 100 MHz for H and
13C, respectively. Multiplicities in the 13C spectra were
determined by DEPT experiments, and numerous assignments
were obtained by 13C/1H cosy experiments. IR spectra were
recorded with a FT infrared spectrophotometer. Melting
points are uncorrected. Isomerization can occur in the course
of these measurements for cyclobutene compounds. Elemental
analyses were performed by the service de microanalyse,
CNRS ICSN, Gif sur Yvette. High-resolution mass measure-
ments were performed at the CRMPO (Rennes). The column
a
4,6-Dichloro-5-nitropyrimidine, Et3N, CH2Cl2, rt, 30 min.
(20) Durst, T.; Breau, L. Cyclobutene Ring Opening Reactions. In
Comprehensive Organic Synthesis; Trost, B. M., Flemming, I., Paquette,
L. A., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, Chapter 6.1 pp 665-
697.
SnCl2‚2H2O, EtOH, 60 °C, 10 min. c HC(OEt)3, HCl, rt. NH3,
b
d
MeOH, 10-11 bars, 48 h, 40 °C. e See b, Scheme 2. f BCl3, CH2Cl2,
-78 °C.
(21) (a) Binns, F.; Hayes, R.; Ingham, S.; Saengchantara, S. T.;
Turner, R. W.; Wallace, T. W. Tetrahedron 1992, 48, 515. (b) Houk, K.
N.; Li, Y.; Evanseck, J . D. Angew. Chem., Int Ed. Engl. 1992, 31, 682.
together with small amounts of dienes. The total conver-
sion of 31 into diene 32 was achieved in 1 h at 110 °C in

Synthesis of Norcarbovir Analogues
J . Org. Chem., Vol. 62, No. 7, 1997 2169
chromatographies were run on silica gel Gerudan SI 60, 230-
400 mesh, under 1-2 bars. The silica gel/crude product ratio
is indicated for each separation.
thus obtained: 1H NMR (CDCl3) δ 6.11 (d, 1H, H-3 or H-4,
J H-3/H-4) 2.4 Hz), 6.01 (d, 1H, H-4 or H-3, J ) 2.4 Hz), 5.75
(br d, 1H, NH), 4.81 (dd, 1H, H-1, J H-1/H-2 ) 4.2 Hz), J H-1/NH
) 9.6 Hz), 3.79 (m, 2H, H-5), 3.66 (s, 3H, CO2Me), 3.24 (m,
1H, H-2), 0.89 (s, 9H, Si(Me)2CMe3), 0.06 and 0.04 (2s, 6H,
Si(Me)2CMe3); 13C NMR (CDCl3) δ 157.00 (CdO), 138.60 and
138.03 (C-3 and C-4), 61.48 (C-5), 54.03 (C-1), 51.92 (CO2CH3),
50.47 (C-2), 25.80 (Si(CH3)2 C(CH3)3), 18.14 (Si(CH3)2C(CH3)3),
-5.46 and -5.49 (Si(CH3)2 C(CH3)3).
2-(H yd r oxym et h yl)cyclob u t -3-en eca r b oxa m id e (10).
Ammonia dried on KOH was bubbled for 1 h through a
solution, cooled to 0 °C, of lactone 94,9 (3.77 g, 34.24 mmol) in
MeOH (175 mL). The reaction mixture was stirred overnight
at room temperature. Evaporation led to crude 10, and
recrystallization in acetone provided 10 as white crystals
1
Refluxing of 12a in toluene during 12 min gave rise to dienes
13 and 14 in a 93:7 ratio.
(4.045 g, 93%): mp 148-150 °C; H NMR (DMSO-d6) δ 7.25
(s, 1H of NH2), 6.99 (s, 1H of NH2), 6.23 (ddd, 1H, H-3, J H-3/H-4
) 2.8 Hz, J H-3/H-1) 1.0 Hz, J H-3/H-2 ) 0.9 Hz), 6.17 (dd, 1H,
H-4, J H-4/H-3) 2.8 Hz, J H-4/H-1 ) 0.9 Hz), 3.64 (t, 1H, OH, J )
5.5 Hz), 3.55 (ddd, 1H, H-1, J H-1/H-2 ) 4.6 Hz, J H-1/H-3 ) 1.0
Hz, J H-1/H-4 ) 0.9 Hz), 3.53 (m, 1H, H-5, J H-5/H-5′ ) 10.8 Hz,
J H-5/H-2 ) 7.2 Hz, J H-5/OH ) 5.5 Hz), 3.39 (m, 1H, H-5′, J )
10.8, 7.5, 5.5 Hz), 3.09 (m, 1H, H-2, J ) 7.5, 7.2, 4.6, 0.9 Hz);
13C NMR (DMSO-d6) δ 173.07 (CdO), 140.02 (C-3), 135.63 (C-
4), 62.06 (C-5), 48.94 (C-1), 48.12 (C-2); IR (KBr disc) cm-1
3365, 3282, 3162, 3052, 1649, 1623, 1560, 1415, 1114, 1039,
746. Anal. Calcd for C6H9NO2: C, 56.68; H, 7.13; N, 11.02.
Found: C, 56.80; H, 7.01; N, 11.08.
Meth yl (1E,3Z)-[5-((ter t-bu tyld im eth ylsilyl)oxy)p en ta -
1,3-d ien yl]ca r ba m a te (13): 1H NMR (DMSO-d6) δ 9.62 (br
d, 1H, NH, J NH/H-1 ) 10.5 Hz), 6.67 (dd, 1H, H-1, J H-1/H2
)
12.9 Hz, J H-1/NH ) 10.5 Hz), 5.95 (m, 2H, H-2 and H-3), 5,23
(dt, 1H, H-4, J H-4/H-3 ) 9.9 Hz, J H-4/H-5 ) 6.5 Hz), 4.20 (d,
2H, H-5, J ) 6.5 Hz), 3.62 (s, 3H, CO2Me), 0.86 (s, 9H, Si-
(Me)2CMe3), 0.04 (s, 6H, Si(Me)2CMe3); 13C NMR (CDCl3) δ
153.87 (CdO), 127.65, 127.17 and 126.59 (C-1, C-2, and C-3),
106.69 (CO2
CH3), 59.71 (C-5), 25.94 (Si(CH3)2C(CH3)3), 18.35
(Si(CH3)2C(CH3)3), -5.08 (Si(CH3)2C(CH3)3).
Meth yl (1E,3E)-[5-((ter t-bu tyld im eth ylsilyl)oxy)p en ta -
2-(((ter t-Bu t yld im et h ylsilyl)oxy)m et h yl)cyclob u t -3-
en eca r boxa m id e (11a ). tBuMe2SiCl (4.268 g, 28.31 mmol)
and imidazole (4.016 g, 58.98 mmol) were added to a solution
of amido alcohol 10 (3 g, 23.59 mmol) in DMF (5.5 mL). The
reaction mixture was stirred overnight at room temperature,
and water (13 mL) was added. Extraction with Et2O (4 × 30
mL), drying (MgSO4), evaporation, and column chromatogra-
phy on silica gel (60:1, cyclohexane/Et2O 3:7) led to 11a as
white crystals (4.939g, 87%): mp 79-80 °C; 1H NMR (CDCl3)
δ 6.35 (br s, 1H of NH2), 5.47 (br s, 1H of NH2), 6.24 (s, 2H,
H-3 and H-4), 3.79 (d, 2H, H-5, J ) 7.0 Hz), 3.73 (d, 1H, H-1,
J H-1/H-2 ) 4.5 Hz), 4.25 (td, 1H, H-2, J ) 7.0, 4.5 Hz), 0.89 (s,
1,3-d ien yl]ca r ba m a te (14): 1H NMR (DMSO-d6) δ 9.57 (br
d, 1H, NH, J NH/H-1 ) 10.3 Hz), 6.60 (dd, 1H, H-1, J H-1/H2
)
13.8 Hz, J H-1/NH ) 10.3 Hz), 6.14 (dd, 1H, H-3, J H-3/H4 ) 15.3
Hz, J H-3/H-2 ) 11.8 Hz), 5.72 (dd, 1H, H-2, J ) 13.8, 11.8 Hz),
5.50 (dt, 1H, H-4, J ) 15.3, 5.4 Hz), 4.13 (d, 2H, H-5, J H-5/H-4
) 5.4 Hz), 3.61 (s, 3H, CO2CH3), 0.86 (s, 9H, Si(Me)2CMe3),
0.03 (s, 6H, Si(Me)2CMe3).
(Meth oxyca r bon yl)((2-tetr a h yd r op yr a n yloxy)m eth yl)-
cyclobu t-3-en yl)a m in e (12b). The same experimental pro-
cedure as above from 100 mg (0.47 mmol) of 11b and with
cyclohexane and then cyclohexane/AcOEt 8:2 as the chroma-
tography eluent led to an oil (86 mg, 75%) consisting of 12b
together with a small amount of the electrocyclic reaction
product (97:3): 1H NMR (CDCl3) δ 6.13 (m, 2H, H-3 and H-4),
5.61/5.55 (2 br d, 1H, NH), 4.86 (m, 1H, H-1), 4.63/4.57 (m,
1H, H-6), 3.92/3.84 (2m, 2H, H-5 and H-10), 3.66 (s, 3H, CH3),
3.50 (m, 2H, H-5′ and H-10′), 3.36 (m, 1H, H-2), 1.79/1.70 (2m,
2H), 1.56 (m, 4H); 13C NMR (CDCl3) δ 156.68 (CdO), 138.94/
138.82 and 138.19 (C-3 and C-4), 99.22/98.61 (C-6), 66.40/65.79
(C-10), 62.28 (C-5), 53.92 (C-1), 49.15 (CH3), 48.60 (C-2), 30.67/
30.36 (C-7), 25.97/25.31 (C-9), 19.50/19.41 (C-8).
2-Aza -4-oxa b icyclo[4.2.0]oct -7-en -3-on e (15). Amido
alcohol 10 (4.014 g, 32.09 mmol) and then bis(acetoxy)-
iodobenzene (≈90% of purity, 11.481 g, 32.09 mmol) were
added to a stirred solution of KOH (85% of purity, 4.5 g, 68.21
mmol) in MeOH (40 mL), cooled by an ice-water bath. The
reaction mixture was progressively warmed up to room tem-
perature. After 1.3 h MeOH was evaporated and then CH2-
Cl2 (100 mL) and water (60 mL) were successively added to
the residue under stirring. Decantation, extraction (CH2Cl2,
4 × 80 mL), drying (MgSO4), and then evaporation left a white
paste. Iodobenzene was removed under reduced pressure.
Recrystallization (AcOEt, light petroleum ether) provided 15
as white crystals (3.43 g, 87%): mp 95-96 °C; 1H NMR (CDCl3)
δ 6.22 (dd, 1H, H-7 or H-8, J H-7/H-8 ) 3.0 Hz), 6.17 (dd, 1H,
H-8 or H-7, J ) 3.0 Hz), 5.99 (br s, 1H, NH), 4.31 (m, 1H,
H-1), 4.25 (dd, 1H, H-5, J H-5/H-5′ ) 11.8 Hz, J H-5/H-6 ) 1.5 Hz),
4.14 (dd, 1H, H-5′, J ) 11.8, 3.4 Hz), 3.44 (m, 1H, H-6); 13C
NMR (CDCl3) δ 157.05 (CdO), 139.55 and 137.82 (C-7 and
C-8), 66.45 (C-5), 53.04 (C-1), 43.18 (C-6). IR (KBr disc) cm-1
3288, 3068, 1710, 1673, 1465, 1448, 1411, 1365, 1263, 1193,
1105, 1000, 811, 763. Anal. Calcd for C6H7NO2: C, 57.59; H,
5.64; N, 11.19. Found: C, 57.36; H, 5.45; N, 11.02
t
9H, Bu), 0.07 (s, 3H, Me), 0.06 (s, 3H, Me); 13C NMR (CDCl3)
δ 173.89 (CdO), 139.93 (C-3), 135.35 (C-4), 63.67 (CH2), 49.90
(C-1), 48.83 (C-2), 25.83 (C(CH3)3), 18.21 (C(CH3)3), -5.41
(CH3), -5.44 (CH3); IR (KBr disc) cm-1 3384, 3195, 3054, 2965,
2929, 2857, 1648, 1471, 1417, 1259, 1095, 1068, 836, 795.
Anal. Calcd for C12H23NO2Si: C, 59.71; H, 9.60; N, 5.80; Si
11.63. Found: C, 59.56; H, 9.53; N, 5.86; Si 10.90.
2-((Tetr a h yd r op yr a n yloxy)m eth yl)cyclobu t-3-en eca r -
boxa m id e (11b). Pyridinium p-toluenesulfonate (200 mg)
and a small amount of CH2Cl2 were added to a suspension of
amido alcohol 10 (1g, 7.87 mmol) in 3,4-dihydropyran (10 mL).
The reaction mixture was heated to 50 °C with stirring until
it became homogeneous (≈20 min). It was then cooled, and
brine (5 mL) and water (5 mL) were added. Extraction with
AcOEt (4 × 15 mL), drying (MgSO4), and evaporation led to
11b together with another tetrahydropyranyl derivative in a
79:21 ratio, respectively. Recrystallization (AcOEt/light pe-
troleum ether 1:1) led to pure 11b as white crystals (0.998 g,
62%): mp ) 116-117 °C, 1H NMR (CDCl3) δ 6.31/6.29 (2d,
1H, H-3 or H-4), 6.21 (s, 1H, H-4 or H-3), 5.97/5.70 (2s, 2H,
NH2), 4.58/4.55 (2s, 1H, H-6), 3.94 (m, 1H), 3.85 (m, 1H), 3.73
(m, 1H), 3.50 (m, 3H), 1.75 (m, 2H), 1.53 (m, 4H); 13C NMR
(CDCl3) δ 174.09 (CdO), 140.95/140.53 (C-3), 135.03/134.64
(C-4), 99.33/99.14 (C-6), 68.02/67.56 (C-10), 62.50/62.34 (C-5),
49.62/49.55 (C-1), 46.83/46.35 (C-2), 30.48/30.43 (C-7), 25.24
(C-9), 19.61/19.50 (C-8). Anal. Calcd for C11H17NO3: C, 62.54;
H, 8.11; N, 6.63. Found: C, 62.41; H, 7.96; N, 6.63.
(Meth oxyca r bon yl)(2-((ter t-bu tyld im eth ylsiloxy)m eth -
yl)cyclobu t-3-en yl)a m in e (12a ). Amido ether 11a (0.400 g,
1.66 mmol) and then bis(acetoxy)iodobenzene (≈90% of purity,
587 mg, 1.64 mmol) were added to a stirred solution of KOH
(85% of purity, 232 mg, 3.51 mmol) in MeOH (13 mL), cooled
by an ice-water bath. The reaction mixture was progressively
warmed up to room temperature. After 1.15 h MeOH was
evaporated and then water (10 mL) and CH2Cl2 (5 mL) were
successively added to the residue with stirring. Decantation,
extraction (CH2Cl2, 3 × 5 mL), washing of the combined
organic phases (brine, 5 mL), drying (MgSO4), and then
evaporation gave the crude product that was chromatographed
on silica gel (60:1, cyclohexane then cyclohexane/AcOEt 92:
8). An oil (376 mg, 67%) consisting of 12a together with a
small amount of the electrocyclic reaction product (92:8) was
N-(ter t-Bu toxyca r bon yl)-2-a za -4-oxa bicyclo[4.2.0]oct-
7-en -3-on e (17). Triethylamine (4.2 mL, 30.09 mmol) and
4-(dimethylamino)pyridine (334 mg, 2.74 mmol) were added
under argon to a solution of carbamate 15 (3.422g, 27.35 mmol)
in THF (7 mL). The mixture was cooled to 0 °C, and a solution
of di-tert-butyl dicarbonate (7.162g, 41.16 mmol) in THF (7 mL)
was added dropwise at the same temperature. The reaction
mixture was stirred for 2 h at room temperature. Evaporation,
stirring of residue with CH2Cl2 (80 mL), washing successively
with 0.3 M KHSO4 (2 × 15 mL), water (15 mL), and brine (30
mL), drying (MgSO4), and evaporation left the crude product.

2170 J . Org. Chem., Vol. 62, No. 7, 1997
Gourdel-Martin and Huet
Recrystallization led to 5.840 g (95%) of 17 as yellow crystals:
led to 21 as a powder (4.07 g, 89%): mp 129-130 °C; 1H NMR
(CDCl3) δ 8.61 (br s, 3H, NH3+), 7.32 (m, 5H, Ph), 6.25 (s, 1H,
H-3 or H-4), 6.23 (s, 1H, H-4 or H-3), 4.67 (d (AB system), 1H,
H-6, J ) 11.8 Hz), 4.53 (d (AB system), 1H, H-6′, J ) 11.8
Hz), 4.44 (br s, 1H, H-1), 4.05 (br d, 1H, H-5), 3.84 (dd, 1H,
H-5′, J H-5′/H-5 ) 10.6 Hz, J H-5′/H-2 ) 4.2 Hz), 3.38 (br s, 1H,
H-2); 13C NMR (CDCl3) δ 141.25 (C-3 or C-4), 137.24 (quat C
of Ph), 134.74 (C-4 or C-3); 128.40, 127.83 and 127.79 (aromatic
CH), 73.14 (C-6), 67.38 (C-5), 52.88 (C-1), 46.11 (C-2); IR (KBr
disc) cm-1 3100-2700, 1608, 1481, 1455, 1374, 1087, 748, 701;
HRMS calcd for the corresponding amine (C12H15NO) 189.1154,
found 189.1148.
4-[[2′-(Hydr oxym eth yl)cyclobu t-3′-en yl]am in o]-6-ch lor o-
5-n itr op yr im id in e (22). Triethylamine (290 µL, 2.07 mmol)
was added dropwise and with stirring to a cooled suspension
(0 °C) of hydrochloride 20 (140 mg, 1.034 mmol) and of 4,6-
dichloro-5-nitropyrimidine (413 mg, 2.07 mmol) in CH2Cl2 (3
mL). The reaction mixture was allowed to slowly warm up to
room temperature. After 0.5 h, evaporation then chromatog-
raphy on silica gel (60:1, CH2Cl2/Et2O 95:5 then 8:2) led to 22
as orange crystals (179 mg, 67%): mp 96-98 °C; 1H NMR
(CDCl3) δ 8.39 (br s, 2H, NH and H-2), 6.27 (d (AB system),
1H, H-3′ or H-4′, J H-3′/H-4′ ) 2.5 Hz), 6.23 (d (AB system), 1H,
H-4′ or H-3′, J ) 2.5 Hz); 5.42 (dd, 1H, H-1′, J H-1′/H-2′ ) 4.2
Hz, J H-1′/NH ) 7.6 Hz), 3.93 (dd, 1H, CH2OH, J ) 11.3, 4.9
Hz), 3.86 (br d, 1H, CH2OH), 3.48 (ddd, 1H, H-2′), 1.94 (s, 1H,
OH); 13C NMR (CDCl3) δ 157.92 (C-2), 155.46 and 154.64 (C-4
and C-6), 138.65 and 138.54 (C-3′ and C-4′), 127.35 (C-5), 61.00
(CH2), 54.12 (C-1′), 50.32 (C-2′); IR (KBr disc) cm-1 3361, 3228,
2954, 2940, 2898, 2879, 1596, 1525, 1482, 1330, 1222, 1068,
970, 858, 784, 752. Anal. Calcd for C9H9ClN4O3: C, 42.12;
H, 3.54; N, 21.83; Cl, 13.81. Found: C, 42.09; H, 3.54; N,
21.67; Cl, 14.11.
1
mp 86-87 °C; H NMR (CDCl3) δ 6.21 (s, 2H, H-7 and H-8),
5.05 (d, 1H, H-1, J H-1/H-6 ) 4.4 Hz), 4.23 (dd, 1H, H-5, J H-5/J -5′
) 11.3 Hz, J H-5/H-6 ) 2.0 Hz), 4.16 (dd, 1H, H-5′, J ) 11.3, 3.4
t
Hz), 3.55 (br s, 1H, H-6), 1.53 (s, 9H, Bu); 13C NMR (CDCl3)
δ 152.31 and 151.63 (CdO), 138.45 and 138.37 (C-7 and C-8),
83.59 (C(CH3)3), 66.03 (C-5), 55.06 (C-1), 44.85 (C-6), 27.90
(C(CH3)3); IR (KBr disc) cm-1 3060, 2983, 2970, 2940, 1750,
1718, 1558, 1394, 1367, 1303, 1265, 1151, 1116, 1089, 806, 761.
Anal. Calcd for C11H15NO4: C, 58.66; H, 6.71; N, 6.22.
Found: C, 58.85; H, 6.76; N, 6.25.
(ter t-Bu t oxyca r b on yl)(2-(h yd r oxym et h yl)cyclob u t -3-
en yl)a m in e (18). Lithium hydroxide (0.93 g, 22.20 mmol) was
added to a suspension of 17 (1g, 4.44 mmol) in a 1:1 MeOH/
H2O mixture (20 mL) at -10 °C. The reaction mixture was
stirred for 1.5 h at the same temperature, and then CH3CO2H
(11 mL) was added. Partial evaporation, extraction (AcOEt,
4 × 20 mL), drying, and evaporation led to white crystals (885
mg, 100%) consisting of 18 together with a small amount of
the electrocyclic reaction product (97:3): mp (for the mixture)
72 °C; 1H NMR (CDCl3) δ 6.13 (dd, 1H, H-4, J H-4/H-3 ) 2,8
Hz, J H-4/H-1 ) 0,9 Hz), 6.09 (dd, 1H, H-3, J ) 2.8, 0.9 Hz),
5.33 (br s, 1H, NH), 4.70 (dd, 1H, H-1, J H-1/NH ) 7.8 Hz,
J H-1/H-2 ) 3.4 Hz), 3.74 (m, 2H, H-5), 3.32 (m, 1H, H-2), 2.28
t
(br s, 1H, OH), 1.45 (s, 9H, Bu); 13C NMR (CDCl3) δ 156.18
(CdO), 138.50 and 138.19 (C-3 and C-4), 79.82 (C(CH3)3) ,
61.35 (C-5), 53.64 (C-1), 51.79 (C-2), 28.30 (C(CH3)3); IR (KBr
disc) cm-1 3359, 3052, 2983, 2935, 1675, 1567, 1511, 1270,
1168, 1052, 1027, 738. The crude product gave good analytical
data. Anal. Calcd for C10H17NO3: C, 60.28; H, 8.60; N, 7.03.
Found: C, 60.15; H, 8.51; N, 6.85.
(ter t-Bu toxyca r bon yl)(2-((ben zyloxy)m eth yl)cyclobu t-
3-en yl)a m in e (19). NaH (60% dispersion in oil, 1.809 g, 45.2
mmol) and nBu4NI (1.894 g, 5.13 mmol) were added under
argon and with stirring to a cooled solution (-15 °C) of
compound 18 (5.11g, 25.64 mmol) in dry THF (40 mL). Benzyl
bromide (3.75 mL, 30.77 mmol) was then added dropwise at
the same temperature. The reaction was allowed to proceed
for 4 h with a progressive increasing of temperature (-15 f
5 °C). MeOH (40 mL) was then added. Evaporation and then
chromatography on silica gel (20:1, cyclohexane/AcOEt 95:5
then 8:2) led to a colorless oil (5.85 g, 79%) that crystallized
on standing. It consisted of 19 together with a small amount
of the electrocyclic reaction product (94:6): mp (for the
mixture) 36-37 °C; 1H NMR (CDCl3) δ 7.34 (m, 5H, Ph), 6.13
(d (AB system), H-3 or H-4, J H-3/H-4 ) 3.0 Hz), 6.10 (d (AB
system), H-4 or H-3, J ) 3.0 Hz), 5.31 (br s, 1H, NH), 4.79 (m,
1H, H-1), 4.53 (m, 2H, H-6), 3.63 (dd, 1H, H-5, J H-5/H-5′ ) 9.8
Hz, J H-5/H-2 ) 4.9 Hz), 3.57 (dd, 1H, H-5′, J ) 9.8, 3.9 Hz),
3.34 (m, 1H, H-2), 1.45 (s, 9H, tBu); 13C NMR (CDCl3) δ 155.57
(CdO), 138.80 and 138.28 (C-3 and C-4), 138.02 (quat C of Ph);
128.40, 127.80 and 127.68 (CH of Ph), 79.07 (C(CH3)3), 73.36
(C-6) , 69.27 (C-5), 53.61 (C-1), 49.13 (C-2), 28.39 (C(CH3)3).
IR (KBr disc) cm-1 3415, 3345, 3031, 2977, 2929, 2859, 1714,
4-[[2′-((Ben zyloxy)m et h yl)cyclob u t -3′-en yl]a m in o]-6-
ch lor o-5-n itr op yr im id in e (23). Triethylamine (620 µL, 4.44
mmol) was added dropwise and with stirring to a cooled
suspension (0 °C) of hydrochloride 21 (500 mg, 2.22 mmol) and
of 4,6-dichloro-5-nitropyrimidine (885 mg, 4.44 mmol) in CH2-
Cl2 (10 mL). The reaction mixture was allowed to warm up
to room temperature. After 15 min, evaporation then chro-
matography on silica gel (60:1, cyclohexane/AcOEt 95:5 and
then 9:1) led to 23 as an orange oil (768 mg, 84%): 1H NMR
(CDCl3) δ 8.35 (s, 1H, H-2), 8.30 (br s, 1H, NH), 7.31 (m, 5H,
Ph), 6.22 (s, 2H, H-3′ and H-4′), 5.36 (dd, 1H, H-1′), J H-1′/NH
)
7.4 Hz, J H-1′/H-2′ ) 3.9 Hz), 4.63 (d (AB system), 1H, benzylic,
J ) 11.8 Hz), 4.49 (d (AB system), 1H, benzylic, J ) 11.8 Hz),
3.65 (m, 2H, CH2O), 3.49 (m, 1H, H-2′); 13C NMR (CDCl3) δ
157.86 (C-2), 155.53 and 154.63 (C-4 and C-6), 139.55 and
137.29 (C-3′ and C-4′), 137.48 (quat C of Ph); 128.38, 127.82
and 127.80 (CH of Ph), 127.21 (C-5), 73.36 (benzylic C), 68.73
(CH2O), 54.26 (C-1′), 48.49 (C-2′); IR (film) cm-1 3326, 3060,
3031, 1594, 1519, 1492, 1334, 1224, 1062, 858, 786, 750, 698;
HRMS calcd for C16H15ClN4O3 346.0833, found 346.0848.
4-[[2′-((Ben zyloxy)m et h yl)cyclob u t -3′-en yl]a m in o]-5-
a m in o-6-ch lor op yr im id in e (24). A solution of 23 (1.187 g,
3.423 mmol) and of SnCl2‚2H2O (3.864 g, 17.12 mmol) in EtOH
(7 mL) was heated for 10 min at 60 °C. The reaction mixture
was then cooled and poured into cooled water (250 mL). The
suspension thus obtained was neutralized (pH 7-8) by adding
a NaHCO3 aqueous solution (≈45 mL). Extraction (AcOEt, 4
× 160 mL), drying (MgSO4), evaporation, and chromatography
on silica gel (60:1, CH2Cl2/Et2O 95:5 and then 8:2) yielded 22
as an oil (0.676, 62%): 1H NMR (CDCl3) δ 8.03 (s, 1H, H-2),
7.33 (m, 5H, Ph), 6.23 (s, 2H, H-3′ and H-4′), 5.84 (br d, 1H,
NH, J NH/H-1′ ) 8.4 Hz), 5.31 (dd, 1H, H-1′, J ) 8.4, 3.9 Hz),
4.54 (s, 2H, benzylic), 3.74 (dd, 1H, CH2O, J ) 10.3, 4.9 Hz),
3.69 (dd, 1H, CH2O, J ) 10.3, 3.5 Hz), 3.49 (m, 1H, H-2′), 3.15
(br s, 2H, NH2); 13C NMR (CDCl3) δ 149.10 (C-2); 154.30,
142.08 and 121.98 (quat C of base), 139.01 and 138.09 (C-3′
and C-4′), 137.73 (quat C of Ph); 128.44, 127.83 and 127.66
(CH of Ph), 73.33 (benzylic C), 69.27 (CH2O), 54.23 (C-1′), 48.96
(C-2′); IR (film) cm-1 3357, 3249, 3060, 3031, 1643, 1573, 1494,
1455, 1419, 1218, 740, 698; HRMS calcd for C16H17ClN4O
316.1091, found 316.1094.
1506, 1455, 1367, 1245, 1164, 736, 698; HRMS calcd for C17H23
NO3 289.1678, found 289.1683.
-
(2-(Hyd r oxym eth yl)cyclobu t-3-en yl)a m in e Hyd r och lo-
r id e (20). Compound 18 (1.5 g, 7.53 mmol) was added to a 2
M solution of HCl in MeOH (150 mL). The mixture was stirred
for 4 h (-5 f 15 °C), and then argon was bubbled through
the solution. Evaporation and several additions of Et2O
followed by evaporation, drying under vacuum (P2O5), and two
successive recrystallizations (EtOH/Et2O 1:1) yielded 20 as a
powder (0.78 g, 76%): mp 119-120 °C; 1H NMR (D2O) δ 6.35
(d, 1H, H-3, J H-3/H-4 ) 2.7 Hz), 6.20 (d, 1H, H-4, J ) 2.7 Hz),
4.35 (d, 1H, H-1, J ) 3.9 Hz), 3.89 (d, 2H, H-5, J ) 4.9 Hz),
3.37 (dt, 1H, H-2); 13C NMR (D2O) δ 142.12 (C-3), 134.60 (C-
4), 59.45 (C-5), 52.41 (C-1), 47.19 (C-2); IR (KBr disc) cm-1
3400, 2400, 1619, 1589, 1469, 1374, 1301, 1151, 1114, 1056,
1037, 973, 844, 786, 736. Anal. Calcd for C5H10ClNO: C,
44.29; H, 7.43; N, 10.33; Cl, 26.15. Found: C, 44.22; H, 7.13;
N, 10.19; Cl, 26.41.
(2-((Ben zyloxy)m eth yl)cyclobu t-3-en yl)a m in e Hyd r o-
ch lor id e (21). Compound 19 (5.83 g, 20.14 mmol) reacted
under the same experimental conditions as 18, except that a
3 M solution of HCl was used. Recrystallization (CH2Cl2/Et2O)
9-[2′-((Ben zyloxy)m et h yl)cyclob u t -3′-en yl]-6-ch lor o-
p u r in e (25). A solution of 24 (667 mg, 2.08 mmol) and of 12

Synthesis of Norcarbovir Analogues
J . Org. Chem., Vol. 62, No. 7, 1997 2171
M HCl (210 µL) in triethyl orthoformate (5.6 mL) was stirred
for 5 h at room temperature. The reaction mixture was cooled
and then poured into cooled water (15 mL). Neutralization
(pH 7-8) by adding a NaHCO3 aqueous solution (≈3 mL),
extraction (AcOEt 4 × 25 mL), drying (MgSO4), evaporation
and chromatography on silica gel (60:1, cyclohexane/AcOEt 8:2
and then 7:3) led to 25 as an oil that crystallized on standing
(white crystals; 550 mg, 80%): mp 76-77 °C; 1H NMR (CDCl3)
δ 8.65 and 8.18 (2s, 2H, H-2 and H-8), 7.21 (m, 3H, Ph), 6.82
8 mL of a 3:1 CF3CO2H/H2O mixture cooled to 0 °C. The
reaction mixture was stirred at room temperature for 48 h.
Partial evaporation, neutralization by 30 mL of a 10:1 MeOH/
NH4OH mixture cooled to 0 °C, evaporation, and then chro-
matography on silica gel (40:1, CH2Cl2/MeOH 98:2 to 9:1) led
to 28 as white crystals (270 mg, 95%): mp 155-156 °C; 1H
NMR (DMSO-d6) δ 12.26 (br s, 1H, NH), 8.01 and 7.97 (2s,
2H, H-2 and H-8), 7.20 (m, 3H, Ph), 6.88 (m, 2H, Ph), 6.48 (d
(AB system), 1H, H-3′ or H-4′, J H-3′/H-4′ ) 2.5 Hz), 6.45 (d (AB
system), 1H, H-4′ or H-3′, J ) 2.5 Hz), 5.57 (d, 1H, H-1′,
J H-1′/H-2′ ) 3.9 Hz), 4.10 (d (AB system), 1H, benzylic, J ) 11.8
Hz), 3,89 (d (AB system), 1H, benzylic, J ) 11.8 Hz), 3.56 (m,
1H, H-2′), 3.42 (dd, 1H, CH2O, J ) 10.3, 3.9 Hz), 3.15 (dd, 1H,
CH2O, J ) 10.3, 9.3 Hz); 13C NMR (DMSO-d6) δ 156.73, 148.61
and 124.17 (quat C of base), 145.24 and 139.15 (C-2 and C-8),
141.45 and 134.71 (C-3′ and C-4′), 137.85 (quat C of Ph);
127.91, 127.18 and 126.99 (CH of Ph); 71.93 (benzylic C), 68.72
(CH2O), 54.88 (C-1′), 49.19 (C-2′); IR (KBr disc) cm-1 1698,
1589, 1415, 1342, 1207, 1097; HRMS calcd for C17H16N4O2
308.1273, found 308.1269.
(m, 2H, Ph), 6.51 (d (AB system), 1H, H-3′ or H-4′, J H-3′/H-4′
)
3.0 Hz), 6.42 (d (AB system), 1H, H-4′ or H-3′, J ) 3.0 Hz),
5.78 (d, 1H, H-1′, J H-1′/H-2′ ) 3.5 Hz), 4.07 (d (AB system), 1H,
benzylic, J ) 11.8 Hz), 3.86 (d (AB system), 1H, benzylic, J )
11.8 Hz), 3.75 (ddd, 1H, H-2′), 3.45 (dd, 1H, CH2O, J ) 10.3,
4.2 Hz), 3.16 (dd, 1H, CH2O, J ) 10.3, 8.9 Hz); 13C NMR δ
151.73 and 144.50 (C-2 and C-8), 142.80 and 133.28 (C-3′ and
C-4′), 136.84 (quat C of Ph); 152.10, 150.72 and 131.67 (quat
C of base); 128.18, 127.69 and 127.46 (CH of Ph), 73.13
(benzylic C), 68.32 (CH2O), 55.75 (C-1′), 50.00 (C-2′); IR (KBr
disc) cm-1 3124, 3064, 3029, 2859, 2833, 2784, 1590, 1560,
1550, 1488, 1455, 1332, 1218, 950, 821, 744, 694. Anal. Calcd
for C17H15ClN4O: C, 62.48; H, 4.63; N, 17.14; Cl, 10.85.
Found: C, 62.21; H, 4.84; N, 16.95; Cl, 10.81.
9-[2′-((Ben zyloxy)m eth yl)cyclobu t-3′-en yl]aden in e (26).
A mixture of NH3 and MeOH (1:1) was prepared at -78 °C. It
was introduced into a cooled stainless steel bomb containing
chloropurine 25 (361 mg, 1.11 mmol). The bomb was closed,
and the reaction mixture was heated to 40 °C for 48 h under
10-11 bars of pressure. Evaporation led to a mixture of 26
and of the electrocyclic reaction product in a 92:8 ratio,
respectively. This ratio became 95:5 after chromatography on
silica gel (60:1, CH2Cl2, CH2Cl2/MeOH 98:2 and then 95:5).
White crystals (302 mg, 89%) corresponding to this mixture
were thus obtained: mp (for a pure sample obtained after
several triturations in the CH2Cl2/Et2O mixture) 150-151 °C;
1H NMR (CDCl3) δ 8.34 and 7.87 (2s, 2H, H-2 and H-8), 7.22
(m, 3H, Ph), 6.93 (m, 2H, Ph), 6.50 (d (AB system), 1H, H-3′
or H-4′, J H-3′/H-4′ ) 3.0 Hz), 6.39 (d (AB system), 1H, H-4′ or
H-3′, J ) 3.0 Hz), 5.75 (br s, 2H, NH2), 5.71 (d, 1H, H-1′,
J H-1′/H-2′ ) 3.9 Hz), 4.09 (d (AB system), 1 H, benzylic, J )
11.8 Hz), 3.98 (d (AB system), 1H, benzylic, J ) 11.8 Hz), 3.72
(ddd, 1H, H-2′), 3.38 (dd, 1H, CH2O, J ) 9.8, 4.9 Hz), 3.23 (dd,
1H, CH2O, J ) 9.8, 8.4 Hz); 13C NMR (CDCl3) δ 152.90 and
139.90 (C-2 and C-8), 142.67 and 133.68 (C-3′ and C-4′), 137.42
(quat C of Ph); 155.48, 150.38 and 119.72 (quat C of base);
128.16 and 127.47 (CH of Ph); 73.08 (benzylic C), 68.69 (CH2O),
55.31 (C-1′), 49.96 (C-2′); IR (KBr disc) cm-1 3278, 3120, 3033,
1675, 1602, 1573, 1307, 1211, 744, 696; HRMS calcd for
C17H17N5O 307.1433, found 307.1420.
9-[2′-(Hyd r oxym eth yl)cyclobu t-3′-en yl]a d en in e (27). A
solution of compound 26 (202 mg, 0.66 mmol) in dry CH2Cl2
(42 mL) was cooled under argon to -78 °C. A 1 M solution of
BCl3 in CH2Cl2 (5.25 mL) was then added. The reaction
mixture was stirred at the same temperature for 4 h. The
cooling bath was removed, and MeOH (30 mL) was added
slowly. Evaporation and three successive MeOH additions and
evaporations led to the crude product. MeOH (20 mL) was
added, and the resulting solution was neutralized by a
saturated solution of NH3 in MeOH. The suspension thus
obtained was evaporated. Chromatography on silica gel (60:
1, CH2Cl2, CH2Cl2/MeOH 95:5 and then 8:2) led to a white solid
that was recrystallized in MeOH (93 mg, 66%): mp 164-165
°C; 1H NMR (DMSO-d6) δ 8.12 and 8.03 (2 s, 2H, H-2 and H-8),
7.21 (br s, 2H, NH2), 6.53 (d (AB system), 1h, H-3′ or H-4′,
J H-3′/H-4′ ) 3.0 Hz), 6.49 (d (AB system), 1H, H-4′ or H-3′, J )
3.0 Hz), 5.50 (d, 1H, H-1′, J H-1′/H-2′ ) 3.9 Hz), 4.33 (t, 1H, OH,
J ) 4.9 Hz), 3.39 (m, 1H, H-2′), 3.16 (m, 2H, CH2O); adding of
CF3CO2H led to 3.23 (dd, 1H, CH2O, J ) 10.8, 6.4 Hz), 3.15
(dd, 1H, CH2O, J ) 10.8, 5.9 Hz); 13C NMR (DMSO-d6) δ 152.24
and 139.71 (C-2 and C-8), 142.58 and 134.37 (C-3′ and C-4′),
155.86, 149.67 and 118.75 (quat C of base), 60.23 (CH2O), 54.33
(C-1′), 51.23 (C-2′); IR (KBr disc) cm-1 3411, 3289, 3124, 1675,
1608, 1338, 1299, 1045, 796, 736, 647; HRMS calcd for
C10H11N5O 217.0963, found 217.0969.
9-[2′-(Hyd r oxym eth yl)cyclobu t-3′-en yl]h yp oxa n th in e
(29). The same experimental procedure as for 26 starting from
28 (242 mg, 0.76 mmol) led to 224 mg of a white solid after
chromatography on silica gel (60:1, CH2Cl2/MeOH 95:5 and
then 8:2). Recrystallization in methanol yielded 88 mg (57%)
of 29 (white crystals): mp 220-221 °C; 1H NMR (DMSO-d6) δ
12.17 (br s, 1H, NH), 8.02 and 7.98 (2 s, 2H, H-2 and H-8),
6.52 and 6.45 (2 s, 2H, H-3′ and H-4′), 5.50 (d, 1H, H-1′,
J H-1′/H-2′ ) 3.4 Hz), 4.32 (t, 1H, OH, J ) 4.43 Hz), 3.37 (m,
1H, H-2′), 3.18 (m, 2H, CH2O); 13C NMR (DMSO-d6) δ 156.74,
148.59 and 124.09 (quat C of base), 145.30 and 139.24 (C-2
and C-8), 142.72 and 134.23 (C-3′ and C-4′), 60.22 (CH2O),
54.74 (C-1′), 51.22 (C-2′); IR (KBr disc) cm-1 3372, 3100, 3050,
1687, 1596, 1413, 1347, 1047, 609; HRMS calcd for C10H10N4O2
218.0804, found 218.0817.
6-Am in o-4-[[2′-((b en zyloxy)m et h yl)cyclob u t -3′-en yl]-
a m in o]-5-n itr op yr im id in e (30). A saturated solution of NH3
in MeOH (15 mL) was added to a cooled (-15 °C) solution of
compound 23 (416 mg, 1,20 mmol) in MeOH (2 mL). The
reaction mixture was stirred for 2 h (-15 f rt). Evaporation
and then chromatography on silica gel (70:1, cyclohexane/
AcOEt 8:2 and then 1:1) led to an orange solid (331 mg, 84%)
consisting of 30 together with a small amount of the electro-
cyclic reaction product (94:6): mp (for the mixture) 155 °C;
1H NMR (CDCl3) δ 9.69 (br d, 1H, NH, J ) 6.4 Hz), 8.55 and
6.30 (2 br s, 2H, NH2), 8.03 (s, 1H, H-2), 7.29 (m, 5H, Ph),
6.26 (d (AB system), 1H, H-3′ or H-4′, J H-3′/H-4′ ) 3.0 Hz), 6.23
(d (AB sytem), 1H, H-4′ or H-3′, J ) 3.0 Hz), 5.39 (dd, 1H,
H-1′, J H-1′/NH ) 6.9 Hz, J H-1′/H-2′ ) 4.18 Hz), 4.62 (d (AB
system), 1H, benzylic, J ) 12.3 Hz), 4.50 (d (AB system), 1H,
benzylic, J ) 12.3 Hz), 3.64 (m, 2H, CH2O), 3.51 (m, 1H, H-2′);
13C NMR (CDCl3) δ 159.44 (C-2), 159.20 and 156.81 (C-4 and
C-6), 139.49 and 137.64 (C-3′ and C-4′), 137.80 (quat C of Ph),
128.26, 127.76 and 127.57 (CH of Ph), 112.96 (C-5), 73.27
(benzylic C), 69.13 (CH2O), 53.78 (C-1′), 48.67 (C-2′); IR (KBr
disc) cm-1 3446, 3336, 3280, 3108, 3033, 1654, 1596, 1513,
1353, 1290, 1234, 1112, 1002, 794, 750, 696. Anal. Calcd for
C16H17N5O3: C, 58,71; H, 5.24; N, 21.39. Found: C, 58.37; H,
5.68; N, 21.42.
6-Am in o-4-[[2′-(h ydr oxym eth yl)cyclobu t-3′-en yl]am in o]-
5-n itr op yr im id in e (31). The same experimental procedure
as for 26 starting from 30 (270 mg, 0.76 mmol) led to the crude
product that was added to 30 mL of MeOH and neutralized
by a satured solution of NH3 in MeOH. Evaporation and
chromatography on silica gel (80:1, CH2Cl2 and then CH2Cl2/
MeOH 99:1 to 95:5) led to an orange solid (159 mg, 81%)
consisting of 31 together with a small amount of the electro-
cyclic reaction product (96:4): mp (for the mixture) 196-200
1
°C; H NMR (DMSO-d6) δ 9,69 (d, 1H, NH, J ) 7.4 Hz), 8.60
and 8.54 (2 s, 2H, NH2), 7.98 (s, 1H, H-2), 6.26 (s, 2H, H-3′
and H-4′), 5.27 (dd, 1H, H-1′, J H-1′-NH ) 7.4 Hz, J H-1′/H-2′
)
3.9 Hz), 4.79 (t, 1H, OH, J ) 4.7 Hz), 3.61 (m, 2H, CH2O),
3.28 (m, 1H, H-2′); 13C NMR (DMSO-d6) δ 159.41 (C-2), 158.81
and 156.46 (C-4 and C-6), 140.20 and 137.57 (C-3′ and C-4′),
111.90 (C-5), 60.31 (CH2O), 53.02 (C-1′), 50.12 (C-2′); IR (KBr
9-[2′-((Ben zyloxy)m et h yl)cyclob u t -3′-en yl]h yp oxa n -
th in e (28). Compound 25 (300 mg, 0.92 mmol) was added to

2172 J . Org. Chem., Vol. 62, No. 7, 1997
Gourdel-Martin and Huet
disc) cm-1 3446, 3330, 3286, 1654, 1596, 1513, 1353, 1288,
1236, 1043, 1002, 794; HRMS calcd for C9H11N5O3 237.0862,
found 237.0860.
6-Am in o-4-[[(1′E,3′Z)-5′-h yd r oxyp en ta -1′,3′-d ien yl]a m i-
n o]-5-n itr op yr im id in e (32). Compound 31 was heated at
110 °C in DMSO-d6 during 1 h and led only to diene 32: 1H
NMR (DMSO-d6) δ 10.72 (d, 1H, NH, J NH/H-1′ ) 10.5 Hz), 8.65
(br s, 2H, NH2), 8.05 (s, 1H, H-2), 7.48 (dd, 1H, H-1′, J H-1′/H-2′
Ack n ow led gm en t. We thank Drs. E. Bisagni and
M. Legraverend for useful suggestions and for one
experiment, Dr. D. Planchenault for its participation to
the beginning of this work, French MRE ministry for a
fellowship (M.-E. G.-M.), and Drs. J .-F. Riou, A. Bous-
seau, and J .-F. Ferron (Rhoˆne-Poulenc Rorer Co.) for
the biological tests.
) 13.8 Hz, J H-1′/NH ) 10.5 Hz), 6.67 (dd, 1H, H-2′, J H-2′/H-1′
13.8 Hz, J H-2′/H-3′ ) 11.5 Hz), 6.07 (dd, 1H, H-3′, J H-3′/H-2′
11.5 Hz, J H-3′/H-4′ ) 10.8 Hz), 5.43 (dt, 1H, H-4′, J H-4′/H-3′
10.8 Hz, J H-4′/H-5′ ) 6.6 Hz), 4.66 (t, OH, J OH/H-5′ ) 5.3 Hz),
4.13 (dd, 2H, H-5′, J H-5′/H-4′ ) 6.6 Hz, J H-5′/OH ) 5.3 Hz); 13C
NMR (DMSO-d6) δ 158.69, 152.54 and 112.14 (C-4, C-5 and
C-6), 159.11 (C-2), 130.10, 126.55, 126.30 and 112.14 (C-1′,
C-2′, C-3′, and C-4′), 57.33 (C-5′).
)
)
)
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
12-14, 19, 21, 23, 24, 26 to 29, 31, and 32 (26 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
J O961451Y