2-Trimethylsilylethyl sulfides in the von Braun cyanogen bromide reaction: Selective preparation of thiocyanates and application to nucleoside chemistry

Article abstract of DOI:10.1021/jo016200q

Mixed 2-(trimethylsilyl)ethyl sulfides were synthesized and used in the von Braun cyanogen bromide reaction for preparing selectively thiocyanates in high yield. We show here that this cleavage reaction is highly selective in methanol in comparison with the reaction of the corresponding non-silyl sulfide analogues. This reaction was applied to the synthesis of nucleosidic thiocyanates such as the new nucleosides 14 and 18 in the search for mechanism-based inhibitors of ribonucleoside diphosphate reductase and bioactive molecules. The selective cleavage is possible for sulfides bearing hydroxyl functions and aromatic rings. The reactions of cyanogen bromide as cyanating and brominating agent were observed for the first time under the same conditions with the naphthoxyhexyl 2-trimethylsilylethyl sulfide 7, which, treated with cyanogen bromide in dichloromethane, led selectively to the p-bromonaphthoxyhexyl thiocyanate 10 in 89% yield. Another reaction induced by cyanogen bromide was observed in dichloromethane with the 2-(trimethylsilylethyl)thio nucleoside 13, which gives the corresponding symmetrical disulfide 21 in good yield.

Full text of DOI:10.1021/jo016200q

1898
J . Org. Chem. 2002, 67, 1898-1904
2-Tr im eth ylsilyleth yl Su lfid es in th e von Br a u n Cya n ogen
Br om id e Rea ction : Selective P r ep a r a tion of Th iocya n a tes a n d
Ap p lica tion to Nu cleosid e Ch em istr y
Ste´phane Chambert, Franc¸ois Thomasson, and J ean-Luc De´cout*
Laboratoire de Chimie Bio-organique, De´partement de Pharmacochimie Mole´culaire,
UMR 5063 CNRS/ Universite´ J oseph Fourier-Grenoble I, Domaine de la Merci,
F-38706 La Tronche Cedex, France
J ean-Luc.Decout@ujf-grenoble.fr
Received October 16, 2001
Mixed 2-(trimethylsilyl)ethyl sulfides were synthesized and used in the von Braun cyanogen bromide
reaction for preparing selectively thiocyanates in high yield. We show here that this cleavage reaction
is highly selective in methanol in comparison with the reaction of the corresponding non-silyl sulfide
analogues. This reaction was applied to the synthesis of nucleosidic thiocyanates such as the new
nucleosides 14 and 18 in the search for mechanism-based inhibitors of ribonucleoside diphosphate
reductase and bioactive molecules. The selective cleavage is possible for sulfides bearing hydroxyl
functions and aromatic rings. The reactions of cyanogen bromide as cyanating and brominating
agent were observed for the first time under the same conditions with the naphthoxyhexyl
2-trimethylsilylethyl sulfide 7, which, treated with cyanogen bromide in dichloromethane, led
selectively to the p-bromonaphthoxyhexyl thiocyanate 10 in 89% yield. Another reaction induced
by cyanogen bromide was observed in dichloromethane with the 2-(trimethylsilylethyl)thio
nucleoside 13, which gives the corresponding symmetrical disulfide 21 in good yield.
Sch em e 1. Mod el Stu d y of th e Su lfid e Clea va ge
w ith Cya n ogen Br om id ea
In tr od u ction
Chemical modifications of naturally occurring nucleo-
sides and nucleotides have led to a large number of
analogues used for their therapeutic properties, especially
their antiviral and antitumoral activities.1 Among these
modified nucleosides and nucleotides, many sulfur-
containing molecules showed interesting biological activi-
ties and/or were used as tools for biochemical and
biological studies.2
In the search for new bioactive nucleotides, we have
shown that 2′-deoxy-2′-thiouridine 5′-diphosphate strongly
inactivates in vitro Escherichia coli ribonucleoside diphos-
phate reductase (RDPR).3 This enzyme catalyzes the
reduction of the four natural ribonucleotides to the
corresponding 2′-deoxyribonucleotides and thus is a key
enzyme in the synthesis of DNA.4 The thiol function of
the modified nucleotide interacts with a cysteine residue
at the active site to lead to a perthiyl radical on the
enzyme. This nucleotide was obtained using a mixed
propyl disulfide intermediate, which can be reduced
easily in situ with dithiothreitol to lead to the active
a
Key: (a) BrCN, MeOH, rt; (b) BrCN, DCM, rt.
compound.5 This protection appeared useful to introduce
a diphosphate function at the 5′-position.
To improve the synthesis of nucleosides and nucleo-
tides possessing a thiol function, we had previously
developed a method for preparing methyl disulfides of
thionucleosides such as 2′-thiouridine, cytidine, and 3′-
thiothymidine using 2-(trimethylsilyl)ethanethiol
1
* To whom correspondence should be addressed. Phone: (33) 4 76
63 74 57. Fax: (33) 4 76 51 86 67.
(Scheme 1).6 Stable methyl disulfides, precursors of easily
oxidable and unstable nucleosides possessing a thiol
function on the sugar, were obtained by treatment of
trimethylsilylethyl sulfide intermediates with dimethyl-
(methylthio)sulfonium tetrafluoroborate.7 These methyl
disulfides can be reduced under mild conditions to lead
to the corresponding thiols.
(1) Bergstrom, D.; Lin, X.; Wang, G.; Rotstein, D.; Beal, P.; Norrix,
K.; Ruth, J . Synlett. 1992, 179-188. Pe´rigaud, C.; Gosselin, G.; Imbach,
J .-L. Nucleosides Nucleotides 1992, 11, 903-945. Huryn, D. M.; Okabe,
M. Chem. Rev. 1992, 92, 1745-1768. Burgess, K.; Cook, D. Chem. Rev.
2000, 100, 2047-2059. De Clercq, E. Rev. Med. Virol. 2000, 10, 255-
277. J onckheere, H.; Anne´, J .; De Clercq, E. Med. Res. Rev. 2000, 20,
323-349. Fischer, B. Drug Dev. Res. 2000, 50, 338-354.
(2) For reviews, see: (a) Wnuk, S. F. Tetrahedron 1993, 49, 9877-
9936. (b) Chambert, S.; De´cout, J .-L. Org. Prep. Proced. Int. 2002, 34,
27-85. (c) Hamm, M. L.; Piccirilli, J . A. J . Org. Chem. 1997, 62, 3415-
3420 and references therein.
(3) Cove`s, J .; Le Hir de Fallois, L.; Lepape, L.; De´cout, J .-L.;
Fontecave, M. Biochemistry 1996, 35, 8595-8602.
(4) Stubbe, J .; van der Donk, W. A. Chem. Biol. 1995, 2, 793-801.
J ordan, A.; Reichard, P. Annu. Rev. Biochem. 1998, 67, 71-98.
Fontecave, M. Cell Mol. Life Sci. 1998, 1, 684-695. Robins, M. J .
Nucleosides Nucleotides 1999, 18, 779-793.
(5) Le Hir de Fallois, L.; De´cout, J .-L.; Fontecave, M. J . Chem. Soc.,
Perkin Trans. 1 1997, 2587-2595.
(6) Chambert, S.; Gautier-Luneau, I.; Fontecave, M.; De´cout, J .-L.
J . Org. Chem. 2000, 65, 249-253.
(7) This method was first developed by Fuchs et al. for preparing
alkylthiols: Anderson, M. B.; Ranasinghe, M. G.; Fuchs, P. L. J . Org.
Chem. 1988, 53, 3125-3127.
10.1021/jo016200q CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/28/2002

von Braun Cyanogen Bromide Reaction
J . Org. Chem., Vol. 67, No. 6, 2002 1899
Cyanogen bromide is an interesting reagent that is able
to induce selective cleavage of the methionyl peptide bond
in proteins.8a It has been also used for sequence-specific
cleavage of single-strand DNA8c and for ligation of DNA
strands.8b Recently, homoserine lactone libraries were
obtained through a BrCN-mediated cyclization process
in the final cleavage step.8d
In the von Braun reaction, cyanogen bromide induces
a nonselective cleavage of tertiary amines to yield alkyl
bromides and disubstituted cyanamides.8e Alkyl sulfides
also undergo nonselective cleavage in the presence of
cyanogen bromide with formation of alkyl bromides and
thiocyanates.8e In this reaction, mixed 2-trimethylsilyl-
ethyl sulfides could be interesting intermediates able to
be cleaved selectively through a favored elimination of
the 2-trimethylsilylethyl group.
We show here that such 2-trimethylsilylethyl sulfides
are interesting reagents in the von Braun cyanogen
bromide reaction for preparing selectively thiocyanates,
especially nucleosidic thiocyanates in the search for
bioactive compounds, and that the nature of the products
can be dependent upon the solvent.
Thiocyanates undergo isomerization, substitution, elimi-
nation, addition, oxidation, and reduction reactions and,
thus, are interesting intermediates in organic synthesis.9
The photochemical homolytic fission of the S-CN bond
has been reported.10 As a consequence, nucleosides bear-
ing a thiocyanate function could be interesting precursors
in the search for nucleoside diphosphates that interfere
with the radical reactions at the active site of RDPR. This
function appears to be stable in vivo, for example,
introduction of a thiocyanate function as a polar end
group on aryloxyalkyl derivatives led to an improvement
on the inhibition of Trypanosoma cruzi proliferation
(Chagas’ disease).11 Thus, nucleosides bearing such a
function could exhibit interesting biological activities.
cyanogen bromide. The 2-trimethylsilylethyl sulfides 312
and 7 possessing an aromatic chromophore (Scheme 1)
were prepared in good yields by reaction of 1-bromo-3-
phenylpropane 2 and the naphthyloxybromoalkyl deriva-
tive 6, respectively, with 2-trimethylsilylethanethiol in
the presence of sodium hydride. To demonstrate an
orientation effect of the silyl group in the cleavage of such
sulfides with cyanogen bromide, the corresponding ana-
logues without a silicon atom, the mixed 2-methylbutyl
sulfides 4 and 8 were prepared by reaction of compounds
2 and 6 with 3-methylbutylthiol in the presence of sodium
hydride, respectively (72 and 93% yields, respectively).
Treatment of the 3-phenylpropyl 2-trimethylsilylethyl
sulfide 3 with 10 equiv of cyanogen bromide in methanol
at room temperature during 45 min led selectively to only
one aromatic compound (C18 reversed-phase HPLC,
detection by UV absorption). This product was identified
as the thiocyanate 5 (Scheme 1) by TLC and HPLC from
an authentical sample prepared by reaction at room
temperature of 1-bromo-3-phenylpropane 2 with 10 equiv
of potassium thiocyanate in the presence of 18-crown-6
in 77% yield according to a method described by Pakulski
et al.9d The bromide derivative formed in the cyanogen
bromide reaction was not detected under our analysis
conditions and was not isolated.
The same selectivity was observed in the cleavage of
the naphthylsilyl sulfide 7 with an excess of cyanogen
bromide in methanol at room temperature during 5 h
(HPLC). The thiocyanate 9 (Scheme 1) was detected as
the sole aromatic product and was isolated in 82% yield.
The characteristic IR asymmetric stretching vibrations
of the SCN group in compounds 5 and 9 were observed
at 2150 and 2160 cm-1, respectively.9a,13
Treatment with cyanogen bromide, under the condi-
tions previously used, of the close analogue of the silyl
sulfide 7, the 3-methylbutyl sulfide 8, without the silicon
atom, led to a mixture of two aromatic products (HPLC).
These products were characterized as the aromatic
bromide 6 and the thiocyanate 9 detected as a mixture
(65:35) by HPLC and isolated in 40 and 20% yields,
respectively.
Resu lts a n d Discu ssion
Mod el Rea ction s. We began this work with model
compounds in order to demonstrate the selectivity of
cleavage of mixed 2-trimethylsilylethyl sulfides with
The reactivities of the sulfides 7 and 8 were compared,
alone in solution or in mixture, at the same concentra-
tions, by HPLC (10 equiv of cyanogen bromide). Clearly,
the silyl sulfide 7 undergoes cleavage more rapidly than
its 3-methylbutyl sulfide analogue 8 (see HPLC profiles
in the Supporting Information: Figure 2). After stan-
dardization with naphthalene present in the reaction
solution as an unreactive internal reference, the areas
of the peaks detected by HPLC are proportional to the
concentrations of the corresponding compounds present
because (i) only the aromatic products in which the
substituent on the alkyl chain has been modified were
detected at 300 nm, and these modifications do not
modify the absorption, and (ii) the spectrum of the
aromatic chromophore is not affected by the composition
of the eluent (methanol-water). In Figure 1, these areas
were plotted as a function of the reaction time of the
sulfides 7 and 8 in (50:50) mixture. This figure, and the
other studies with the sulfides alone, revealed clearly the
highest reactivity of the trimethylsilylethyl sulfide 7.
(8) (a) Lawson, W. B.; Gross, E.; Foltz, C.; Witkop, B. J . Am. Chem.
Soc. 1961, 83, 1510-1511. Gross, E.; Witkop, B. J . Am. Chem. Soc.
1961, 83, 1510-1511. Hang, A. H.; Gross, J . Biochemistry 1970, 9,
796-804. Davies, M.; Bradley, M. Tetrahedron Lett. 1997, 38, 8565-
8568. (b) Iverson, B. L.; Dervan, P. B. J . Am. Chem. Soc. 1987, 109,
1241-1243. (c) Kanaya, E.; Yanagawa, H. Biochemistry 1986, 25,
7423-7430. Fedorova, O. A.; Gottikh, M. B.; Oretskaya, T. S.; Sha-
barova, Z. A. Nucleosides Nucleotides 1996, 15, 1137-1147. (d) Ko,
D.-H.; Kim, D. J .; Lyu, C. S.; Min, I. K.; Moon, H.-S. Tetrahedron Lett.
1998, 39, 297-300. (e) von Braun, J .; Engelbertz, P. Ber. 1923, 56,
1573-1577. von Braun, J .; Friedsam, A. Ber. 1930, 63, 2407-2413.
von Braun, J .; May, M.; Michaelis, R. Ann. 1931, 490, 189-200. For a
review, see: Hageman, H. A. In Organic Reactions; R. E. Krieger
Publishing Co.: Malabar, FL, 1975; Vol. VII, pp 198-262.
(9) The Chemistry of cyanates and their thio derivatives; Patai, S.,
Ed.; J . Wiley & Sons: Chichester, New York, Brisbane, Toronto, 1977;
Parts 1 and 2. Pal, B. C.; Schmidt, D. G. J . Am. Chem. Soc. 1974, 96,
5943-5944. Miller, J .; Kendall, F. H. J . Chem. Soc., Perkin Trans. 2
1974, 1645-1648. Pontecillo, G. S.; Hartman, R. D.; Lumma, W. C.,
J r.; Baldwin, J . J . J . Org. Chem. 1979, 44, 3080-3082. Ando, T.; Clark,
J . H.; Cork, D. G.; Fujita, M.; Kimura, T. J . Org. Chem. 1987, 52, 681-
685. J ia, X.; Zhang, Y.; Zhou, X. Tetrahedron Lett. 1994, 35, 8833-
8834. Bouchu, M.-N.; Large, S.; Steng, M.; Langlois, B.; Praly, J .-P.
Carbohydr. Res. 1998, 314, 37-45. Ohtani, N.; Murakawa, S.; Wa-
tanabe, K.; Tsuchimoto, D.; Sato, D. J . Chem. Soc., Perkin Trans. 2
2000, 1851-1856. Pakulski, Z.; Pierozynski, D.; Zamojski, A. Tetra-
hedron 1994, 50, 2975-2992.
(12) Compound 3 has been previously synthesized, but its charac-
teristics were not reported.7
(13) Tabulation of infrared spectral data; Dolphin, D., Wick, A., Eds.;
Wiley-Interscience: New York, London, Sidney, Toronto, 1977; pp 164-
166.
(10) Parks, T. E.; Spurlock, L. A. J . Org. Chem. 1973, 38, 3922-
3924.
(11) Szajnman, S. H.; Yan, W.; Bailey, B. N.; Docampo, R.; Elhalem,
E.; Rodriguez, J . B. J . Med. Chem. 2000, 43, 1826-1840.

1900 J . Org. Chem., Vol. 67, No. 6, 2002
Chambert et al.
phates possessing a thiocyanate function on the sugar
could interfere with the radical processes. To prepare a
uridine derivative bearing a thiocyanate function at the
2′-position, a precursor of a diphosphate potentially
mechanism-based inhibitor of RDPR, we used the 2′-(2-
trimethylsilylethyl)thiouridine derivative 13 prepared
previously.6 Its cleavage with cyanogen bromide in
methanol also appeared selective with formation of one
nucleoside detected by TLC (Scheme 2). However, after
complete reaction, during isolation of the product, de-
composition reactions were observed. The thiocyanate 14
was finally obtained in 34% yield by precipitation from
the reaction mixture and rapid chromatography on silica
gel. At room temperature, this compound was found to
be unstable in water, on silica gel, or on alumina; it
decomposes to lead to several products.16 Formation of
the thiocyanate 14 was not detected when 2,2′-anhydro-
uridine 15 was heated in the presence of potassium
thiocyanate and 18-crown-6 in DMF (80 °C, 120 °C, or
reflux).
F igu r e 1. Cyanogen bromide cleavage of a (50:50) mixture
of the model naphthyloxyalkyl sulfides 7 and 8 in methanol
at room temperature (0.03 M for each sulfide, 0.42 M cyanogen
bromide). Standardized areas of the HPLC peaks detected at
300 nm as a function of the reaction time. The silyl sulfide 7
leads selectively to the thiocyanate 9 more rapidly than its
nonsilyl sulfide analogue 8, which gives a mixture of the
bromide 6 and the thiocyanate 9.
To introduce a thiocyanate function in the xylo con-
figuration of the sugar that could interfere with the thiyl
radical of RDPR formed from the 439 cysteine, we
synthesized the corresponding 2-trimethylsilylethyl sul-
fide 17 using the interesting and versatile route described
recently by Reese and co-workers for preparing xylo 2′-
deoxy-2′-ethylthio and benzylthio uridine derivatives
(Scheme 2).17a 2,2′-Anhydrouridine 15 was first converted
into the 2′,3′-isomeric epoxide 16 by treatment with
sodium hydride in excess in DMF and then addition of
2-trimethylsilylethanethiol led to the xylo sulfide 17 in
78% yield. The presence of the alkylthio group in the xylo
configuration was confirmed by 1H NMR experiments.17b
The silyl sulfide 17 obtained was treated with an excess
of cyanogen bromide at room temperature in methanol
for obtaining selectively the corresponding new thiocy-
anate 18 in 69% yield.
Compound 7 is 22-fold more reactive than compound 8
under the initial conditions of reaction used (Figure 1).
This points out the strong effect of the silyl group.
A lack of selectivity in the cyanogen bromide cleavage
was also observed with the 3-methylbutyl sulfide 4,
analogue of the silyl sulfide 3, under the conditions used
previously. Two aromatic products were identified as
1-bromo-3-phenylpropane 2 and the thiocyanate 5 by
comparison with authentic samples and were detected
as a mixture (55:45) (HPLC). The kinetics of cleavage of
the sulfides 3 and 4 were compared by HPLC. This study
also showed a higher reactivity of the trimethylsilylethyl
sulfide 3 than the one of the corresponding non silylated
sulfide 4.
Under the same conditions, the silyl sulfides 3 and 7
are cleaved more rapidly than the corresponding 3-meth-
ylbutyl sulfides 4 and 8. These results indicate that,
probably, from the cyanosulfonium intermediate, the
2-trimethylsilylethyl group is removed rapidly to give
selectively a silylated carbenium ion intermediate sta-
bilized by the â-silicon effect.14
Ap p lica tion to Nu cleosid e Ch em istr y. Nucleosides
and nucleotides bearing a thiocyanate function could be
interesting bioactive agents and/or tools for biochemical
studies.
Previously, in the search for antiviral agents, 3′-deoxy-
3′-thiocyanatothymidine 12 has been prepared in 21%
yield by reaction of 1-(2-deoxy-3-O-mesyl-5-O-trityl-â-D-
threopentofuranosyl)thymine with potassium thiocyanate
in DMF at 100 °C and then deprotection. This nucleoside
showed very low protection of MT4 cells against HIV.15
The 3′-(2-trimethylsilylethyl)thiothymidine derivative 11
prepared by us previously6 was treated with an excess
of cyanogen bromide in methanol at room temperature
to form selectively one nucleoside that was characterized
as the thiocyanate 12 isolated in 77% yield (Scheme 2).
Ribonucleoside diphosphate reductase (RDPR) func-
tions through radical reactions4 and nucleoside 5′-diphos-
Some 5′-modified adenosine derivatives are mecha-
nism-based inhibitors of S-adenosyl-L-homocysteine hy-
drolase, and some of them present interesting antiviral
activities, for example, 5′-deoxy-5′-methylthioadeno-
sine.2a,b,18 To confirm the cleavage selectivity of 2-trimeth-
ylsilylethyl sulfides in nucleosides, the 5′-thiocyanato
adenosine derivative 20 was synthesized from 5′-deoxy-
5′-(2-trimethylsilylethanethio)adenosine 19. This latter
was prepared from the corresponding 5′-tosyl adenosine
derivative in 96% yield. The silyl sulfide 19 was treated
with an excess of cyanogen bromide in methanol at room
temperature for obtaining selectively the corresponding
nucleosidic thiocyanate 20 in 80% yield (Scheme 3).19
(16) The instability of thiocyanate 14 could be explained by an
intramolecular reaction of the 2′-thiocyano group with the 3′-hydroxyl
function. Such an instability was not observed for the xylo isomer of
compound 14 described here and has not been reported for 3′-deoxy-
3′-thiocyanatoarabinofuranosyl pyrimidine nucleosides previously pre-
pared: Hollenberg, D. H.; Watanabe, K. A.; Fox, J . J . J . Med. Chem.
1977, 20, 113-116.
(17) (a) Miah, A.; Reese, C. B.; Song, Q. J . Chem. Soc., Chem.
Commun. 1997, 407-408. (b) Chemical shifts analysis and homode-
coupling experiments showed the presence of the silylethylthio group
at the 3′-position of the sugar. In DMSO-d6, the 3′-H proton was
detected at 3.34 ppm as a pseudo triplet (doublet of doublet, J 3′,2′
)
J 3′,4′ ) 7.2 Hz). These data are close to those reported in the same
solvent for the corresponding benzylthio derivative, 1-(3-benzylthio-
â-D-xylofuranosyl)uracil described by Reese et al.a and characterized
by X-ray crystal analysis: Miah, A.; Reese, C. B.; Song, Q.; Sturdy, Z.;
Neidle, S.; Simpson, I. J .; Read, M.; Rayner, E. J . Chem. Soc., Perkin
Trans. 1 1998, 3277-3284.
(14) Wierschke, S. G.; Chandrasekhar, J .; J orgensen, W. L. J . Am.
Chem. Soc. 1985, 107, 1496-1500.
(15) Herdewijn, P.; Balzarini, J .; De Clercq, E.; Pauwels, R.; Baba,
M.; Broder, S.; Vanderhaeghe, H. J . Med. Chem. 1987, 30, 1270-1278.

von Braun Cyanogen Bromide Reaction
J . Org. Chem., Vol. 67, No. 6, 2002 1901
Sch em e 2. P r ep a r a tion of Th iocya n a tes 12, 14, a n d 18 by Cya n ogen Br om id e Clea va ge of th e
Cor r esp on d in g 2-Tr im eth ylsilyleth ylth io Der iva tives 11, 13, a n d 17a
a
Key: (a) BrCN, MeOH, rt.
Sch em e 3. P r ep a r a tion of Th iocya n a te 20 by
Cya n ogen Br om id e Clea va ge of th e Cor r esp on d in g
2-Tr im eth ylsilyleth ylth io Der iva tive 19
Sch em e 4. P r ep a r a tion of th e Sym m etr ica l
Disu lfid e 21 by Rea ction of th e
2-Tr im eth ylsilyleth ylth io Der iva tive 13 w ith
Cya n ogen Br om id e
Solven t Effects on th e Cya n ogen Br om id e Rea c-
tivity. The reactivity of the trimethylsilylethyl sulfides
prepared with cyanogen bromide was studied in dichlo-
romethane instead of methanol as a solvent.
was observed in dichloromethane. The low solubility of
these compounds in this solvent led us to conduct the
reaction with cyanogen bromide at reflux. A white
precipitate appeared slowly. The corresponding product
was purified by chromatography and obtained in 70%
yield. It was characterized as the symmetric uridine
disulfide 21 by comparison with an authentical sample
prepared (Scheme 4).5,21 This reaction is an alternative
to the preparation of reductible and stable precursors of
2′-thiouridine from compound 13.5,6,21
This behavior was also observed with the trimethyl-
silylethylthio nucleoside 17, which gave the correspond-
ing symmetrical disulfide in dichloromethane under the
same conditions but not selectively (1H NMR, LRMS).
Formation of the corresponding thiocyanates as minor
products was observed by CCM.
In dichloromethane, the phenyl sulfide 3 led selectively
to the thiocyanate 5 (HPLC), whereas the naphthyl
sulfide 7 led selectively to an aromatic compound differ-
ent of the thiocyanate 9 obtained in methanol. This
compound was isolated and characterized as the thiocy-
anate 10 (Scheme 1), which results from a selective
electrophilic bromination on the naphthyl ring at the
para position and a selective cleavage of the trimethyl-
silylethyl sulfide function (Scheme 1). It was isolated in
89% yield. Thus, in dichloromethane the polarization of
cyanogen bromide can be inverted to generate an elec-
trophilic bromine species. The brominating action of
cyanogen bromide has been reported previously, for
example, in the synthesis of R-bromo-â-aminoenones from
â-aminoenones.20
Concerning the trimethylsilylethylthio nucleosides pre-
pared, an interesting reaction of the 2′-uridine sulfide 13
Con clu sion
These results show that 2-trimethylsilylethyl sulfides
can be cleaved with cyanogen bromide in methanol to
lead selectively to the corresponding thiocyanates in
excellent yields. This reaction is possible and selective
for compounds possessing an aromatic ring such as
phenyl, alkoxynaphthyl, pyrimidine (uracil), and purine
(adenine) rings and in the presence of hydroxyl functions.
Different potentially bioactive nucleosides bearing a
thiocyanate function were prepared in good yields using
this method, among them the new xylo uridine derivative
18. 2′-Deoxy-2′-thiocyanatouridine 14 was also obtained
for the first time despite its instability under different
conditions.
(18) Palmer, J . L.; Abeles, R. H. J . Biol. Chem. 1979, 254, 1217-
1226. Yuan, C.-S.; Yeh, J .; Liu, S.; Borchardt, R. T. J . Biol. Chem. 1993,
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(19) During this work, Guillerm et al. synthesized this compound
using another way and showed that it is an irreversible inhibitor of
S-adenosyl-L-homocysteine hydrolase (unpublished results; for ex-
amples, see ref 18).
(20) Alberola, A.; Andre`s, C.; Ortega, A. G.; Pedrosa, R.; Vicente,
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J . Chem. Soc., Perkin Trans. 1 1990, 969-974.

1902 J . Org. Chem., Vol. 67, No. 6, 2002
Chambert et al.
mmol) was added. The mixture was stirred for 15 h at room
temperature and then was cooled at 0 °C. An aqueous NaH2-
PO4 (10%, 200 mL) was added slowly, and the resulting
solution was extracted with dichloromethane (250 mL). The
organic layer was dried over Na2SO4 and then was evaporated
at room temperature. The residue was chromatographed on
silica gel in pentane-CH2Cl2 (9:1) to lead to compound 4
(liquid, 2.57 g, 72%): 1H NMR (200 MHz, CDCl3) δ 7.29-7.18
(5 H, m), 2.76 (2 H, t), 2.56 (4 H, m), 1.95 (2 H, m), 1.71 (1 H,
m), 1.50 (2 H, m), 0.94 (6 H, d); 13C NMR (50 MHz, CDCl3) δ
141.5, 128.4, 128.3, 125.8, 38.6, 34.8, 31.4, 31.1, 30.0, 29.6, 27.4,
22.2; LRMS (EI) m/z ) 222 [M]•+. Anal. Calcd for C13H22S: C,
75.61; H, 9.97; S, 14.42. Found: C, 75.51; H, 10.01; S, 14.94.
1-Br om o-6-(1-n a p h th oxy)h exa n e 6. To a solution of
1-naphthol (1 g, 6.9 mmol in acetonitrile (6 mL) were added
potassium carbonate (2 g, 14.5 mmol) and then 1,6-dibromo-
hexane (6.4 mL, 41.4 mmol). The mixture was stirred at 50
°C under nitrogen for 15 h. After filtration to remove the
mineral salts and evaporation, the residue was dissolved in
dichloromethane (100 mL). The solution was washed with
water (100 mL), dried over Na2SO4, and evaporated. The
residue was chromatographed on silica gel in pentane-CH2-
Cl2 (9:1) to lead to compound 6 (liquid, 1.935 g, 91%): 1H NMR
(200 MHz, CDCl3) δ 8.26 (1 H, m), 7.77 (1 H, m), 7.50-7.30
(4 H, m), 6.79 (1 H, d), 4.13 (2 H, t), 3.42 (2 H, t), 1.99-1.65
(4 H, m), 1.68-1.51 (4 H, m); 13C NMR (50 MHz, CDCl3)
δ 154.8, 134.5, 127.4, 126.3, 125.9, 125.7, 125.1, 122.0, 120.0,
104.6, 67.7, 33.7, 32.7, 29.1, 28.0, 25.5; LRMS (EI) m/z ) 308
[M(81Br)]•+, 306 [M(79Br)]•+, 144 [naphthol]•+. Anal. Calcd for
A study in another solvent, dichloromethane, revealed
the remarkable interest of cyanogen bromide in the
reaction of electron-rich, aromatic trimethylsilylethyl
sulfides, which can be selectively brominated on the
aromatic ring and cleaved at the sulfur atom to generate
a thiocyanate function as illustrated with the preparation
of compound 10 from compound 7 in 89% yield. Thus,
the dual reactivity of cyanogen bromide resulting from
opposite polarizations can be observed on a molecule
under the same conditions. Another interesting effect of
the solvent and temperature was observed with the
trimethylsilylethylthio nucleoside 13, which led in dichlo-
romethane to the symmetrical disulfide 21 in good yield.
In conclusion, cyanogen bromide is a powerful reagent
for selectively modifying trimethylsilylethyl sulfides. It
will be interesting to investigate the corresponding
reactions of trimethylsilylethylamines. 2-(Trimethylsilyl)-
ethyl sulfides are versatile intermediates that can be
selectively converted into their corresponding methyl
disulfides,6,7 thiols,6,22a and thioacetates.22b We show here
that they can also be selectively transformed to their
corresponding thiocyanates.
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points are reported uncor-
rected. Chemical shifts are in parts per million relative to the
residual signal of the solvent. NMR peak assigments and
conditions for the study of cyanogen bromide cleavage of the
model sulfides by HPLC (Figure 2) can be obtained as
Supporting Information.
C
16H19BrO: C, 62.55; H, 6.23. Found: C, 62.81; H, 6.32.
6-(1-Na p h th yl)oxyh exyl 2-(Tr im eth ylsilyl)eth yl Su l-
fid e 7. To a solution of the bromonaphthyl derivative 6 (1 g,
3.25 mmol) in DMF (5 mL) were added potassium carbonate
(2 g, 14.5 mmol) and then 2-(trimethylsilyl)ethanethiol (0.63
mL, 3.9 mmol). The mixture was stirred at 50 °C under
nitrogen for 15 h. After filtration to remove the mineral salts
and evaporation, the residue was dissolved in dichloromethane
(100 mL). The solution was washed with water (100 mL), dried
over Na2SO4, and evaporated. The residue was chromato-
graphed on silica gel in pentane-CH2Cl2 (8:2) to led to
compound 7 (liquid, 1.06 g, 90%): 1H NMR (200 MHz, CDCl3)
δ 8.26 (1 H, m), 7.77 (1 H, m), 7.50-7.29 (4 H, m), 6.78 (1 H,
dd), 4.13 (2 H, t), 2.54 (4 H, m), 1.92 (2 H, m), 1.71-1.45 (6 H,
m), 0.85 (2 H, m), 0.01 (9 H, s); 13C NMR (50 MHz, CDCl3) δ
154.8, 134.5, 127.4, 126.2, 125.8, 125.7, 125.0, 122.0, 120.0,
104.5, 68.0, 31.6, 29.5, 29.2, 28.7, 27.6, 25.9, 17.4, -1.8; LRMS
Syn th esis. 2-(Trimethylsilyl)ethanethiol (commercially avail-
able) was synthesized from vinyltrimethylsilane and thiolacetic
acid according to the procedures described previously.7,23 2,2′-
Anhydrouridine 15 was obtained using the method reported
by Hampton and Nichol and improved by Mofatt et al.24
3-P h en ylp r op yl 2-(Tr im eth ylsilyl)eth yl Su lfid e 3. To
a solution of 2-(trimethylsilyl)ethanethiol 1 (250 µL, 1.56
mmol) in THF (5 mL) was added sodium hydride (65%
suspension, 200 mg, 5.42 mmol). The mixture was stirred for
30 min at room temperature under nitrogen, and then 1-bromo-
3-phenylpropane (300 µL, 1.97 mmol) was added. The mixture
was stirred at room temperature for 15 h and then cooled at
0 °C. Water was added slowly (40 mL), followed by an aqueous
ammonium chloride solution (5 M, 5 mL). The resulting
solution was extracted with dichloromethane (150 mL). The
organic solution was dried over Na2SO4 and then evaporated
at room temperature. The residue was chromatographed on
silica gel in hexane-CH2Cl2 (9:1) to afford compound 3 (liquid,
269 mg, 68%): 1H NMR (200 MHz, CDCl3) δ 7.29-7.18 (5 H,
m), 2.73 (2 H, t), 2.55 (4 H, m), 1.91 (2 H, m, CH2), 0.65 (2 H,
m), 0.02 (9 H, s); 13C NMR (50 MHz, CDCl3) δ 141.7, 128.5,
128.3, 125.8, 34.9, 31.2, 31.1, 27.6, 17.4, -1.7; LRMS (DCI+,
(EI) m/z ) 360 [M]•+, 144 [naphthol]•+. Anal. Calcd for C21H32
OSSi: C, 69.94; H, 8.94. Found: C, 70.24; H, 9.07.
-
3-Meth ylbu tyl 6-(1-Na p h th yl)oxyh exyl Su lfid e 8. To a
solution of the bromonaphthyl derivative 6 (1 g, 3.25 mmol)
in DMF (5 mL) were added potassium carbonate (2 g, 14.5
mmol) and 3-methylbutanethiol (0.49 mL, 3.9 mmol). The
mixture was stirred at 50 °C under nitrogen for 15 h before
being filtered and evaporated to dryness. After filtration to
remove the mineral salts and evaporation, the residue was
dissolved in dichloromethane (100 mL). The solution was
washed with water (100 mL), dried over Na2SO4, and evapo-
rated. The residue was chromatographed on silica gel in
pentane-CH2Cl2 (8:2) to lead to compound 8 (liquid, 0.997 g,
93%): 1H NMR (200 MHz, CDCl3) δ 8.28 (1 H, m), 7.79 (1 H,
m), 7.52-7.31 (4 H, m), 6.80 (1 H, dd), 4.15 (2 H, t), 2.52 (4 H,
m), 1.95 (2 H, m), 1.72-1.39 (9 H, m), 0.91 (6 H, d); 13C NMR
(50 MHz, CDCl3) δ 154.8, 134.4, 127.3, 126.2, 125.8, 125.7,
124.9, 122.0, 120.0, 104.5, 68.0, 38.7, 32.0, 30.1, 29.6, 29.5, 29.2,
27.4, 25.9, 22.2; LRMS (DCI+, NH3 + isobutane) m/z ) 331
[M + H]+. Anal. Calcd for C21H30OS: C, 76.31; H, 9.15; S, 9.70.
Found: C, 76.18; H, 9.15; S 9.65.
Th iocya n a tes. 3-P h en ylp r op yl Th iocya n a te 5. To a
solution of 1-bromo-3-phenylpropane (200 µL, 1.32 mmol) in
acetone (2 mL) was added KSCN (1.3 g, 13.3 mmol) and 18-
crown-6 (350 mg, 1.32 mmol). The mixture was stirred for 15
h at room temperature under nitrogen. After filtration to
remove the mineral salts and evaporation, the residue was
dissolved in dichloromethane (50 mL). The solution was
washed with water (20 mL), dried over Na2SO4, and evapo-
NH3 + isobutane) m/z ) 253 [M + H]+. Anal. Calcd for C14H24
-
SSi: C, 66.60; H, 9.58; S, 12.70. Found: C, 66.49; H, 9.66; S,
12.82.
3-Meth ylbu tyl 3-P h en ylp r op yl Su lfid e 4. To a solution
of 3-methylbutanethiol (2 mL, 16 mmol) in THF (20 mL) was
added sodium hydride (65% suspension, 1 g, 27 mmol) at room
temperature. The mixture was stirred for 30 min under
nitrogen, and then 1-bromo-3-phenylpropane (3.65 mL, 25
(22) (a) Baum, G.; Kaiser, F.-J .; Massa, W.; Seitz, G. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 1163-1164. Takeda, H.; Shimada, S.; Ohnishi,
S.; Nakanishi, F.; Matsuda, H. Tetrahedron Lett. 1998, 39, 3701-3704.
Yu, C. J .; Chong, Y.; Kayyem, J . F.; Gozin, M. J . Org. Chem. 1999, 64,
2070-2079. (b) Grundberg, H.; Andergran, M.; Nilsson, U. J . Tetra-
hedron Lett. 1999, 40, 1811-1814.
(23) Gornowicz, G. A.; Ryan, J . W.; Speier, J . L. J . Org. Chem. 1968,
33, 2918-2924.
(24) Hampton, A.; Nichol, A. W. Biochemistry 1966, 5, 2076-2082.
Verheyden, J . P. H.; Wagner, D.; Moffatt, J . G. J . Org. Chem. 1971,
36, 250-254.

von Braun Cyanogen Bromide Reaction
J . Org. Chem., Vol. 67, No. 6, 2002 1903
rated. The residue was chromatographed on silica gel in
methanol (80:20) to afford the thiocyanate 14 (215 mg, 34%):
1
dichloromethane to lead to compound 5 (liquid, 180 mg, 77%):
mp dec; IRmax (KBr) 2150 cm-1; H NMR (300 MHz, DMSO-
1
IRmax (KBr) 2150 cm-1; H NMR (200 MHz, CDCl3) δ 7.35-
d6) δ 11.48 (1 H, d), 7.79 (1 H, d), 6.00 (1 H, d), 5.66 (1 H, dd),
5.28 (1 H, ls, 5′-OH), 5.18 (1 H, m), 4.55 (1 H, dd), 4.28 (1 H,
m), 3.65 (2 H, m), 3.16 (1 H, ls); 13C NMR (75 MHz, DMSO-d6)
δ 163.1, 150.5, 140.6, 110.5 (SCN), 101.9, 91.9, 86.1, 83.9, 60.7,
53.6; LRMS (DCI+, NH3 + isobutane) m/z ) 286 [M + H]+,
227 [M - HSCN + H]+, 113 [uracil + H]+; HRMS (FAB+, MCA)
calcd for [C10H12O5N3S + H]+ 286.0498, found 286.0495.
1-(3-(2-(Tr im et h ylsilyl)et h yl)-â-D-xylofu r a n osyl)u r a -
cil 17. To a suspension of 2,2′-anhydrouridine 15 (2 g, 8.84
mmol) in anhydrous DMF (50 mL) was added sodium hydride
(65% suspension, 4 g, 108 mmol). The mixture was stirred for
3 h at room temperature under nitrogen, and then 2-(tri-
methylsilyl)ethanethiol (2.5 mL, 13.2 mmol) was added. The
mixture was stirred for 3 h at room temperature, and then,
after cooling at 0 °C, an aqueous ammonium chloride solution
(10%, 20 mL) was added slowly. The mixture was evaporated
to dryness. The residue was dissolved in dichloromethane (300
mL). The solution was washed with water (100 mL), and the
aqueous layer was extracted with dichloromethane (2 × 200
mL). The combined organic extracts were dried over Na2SO4
and evaporated. The residue was chromatographed on silica
gel in dichloromethane-methanol (95:5) to lead to the silyl
sulfide 17 (2.47 g, 6.85 mmol, 78%): mp 165-167 °C; 1H NMR
(300 MHz, DMSO-d6) δ 11.33 (1 H, s), 7.91 (1 H, d), 5.79 (1 H,
d), 5.68 (1 H, d), 5.66 (1 H, d), 5.04 (1 H, t, J ) 4 Hz, 5′-OH),
4.28 (1 H, m, 4′-H), 4.11 (1 H, m, 2′-H), 3.62 (2 H, m, 5′-H),
3.34 (1 H, t), 2.63 (2 H, m), 0.81 (2 H, m), -0.01 (9 H, s); 13C
NMR (75 MHz, DMSO-d6) δ 163.1, 150.8, 140.8, 101.8, 88.0,
80.3, 78.6, 61.4, 50.5, 27.8, 17.2, -1.6; LRMS (FAB+, glycerol)
m/z ) 721 [2M + H]+, 361 [M + H]+. Anal. Calcd for
7.19 (5 H, m), 2.93 (2 H, t), 2.81 (2 H, t), 2.17 (2 H, m); 13C
NMR (50 MHz, CDCl3) δ 139.6, 128.5, 128.2, 126.3, 111.7
(SCN), 33.5, 32.9, 31.0; LRMS (EI) m/z ) 177 [M]•+. Anal. Calcd
for C10H11NS: C, 67.75; H, 6.25; N, 7.90; S, 18.09. Found: C,
67.92; H, 6.22; N, 7.99; S, 17.82.
Gen er a l P r oced u r e for th e Cya n ogen Br om id e Clea v-
a ge. To a solution of sulfide (∼0.6 mmol) in methanol (4 mL)
was added cyanogen bromide (∼6 mmol). The mixture was
stirred for 5-15 h at room temperature, and then aqueous
phosphate buffer (0.5 M, pH 7, 4 mL) was added. The mixture
was stirred for 30 min, and water (20 mL) was added. The
solution was extracted with dichloromethane (150 mL), and
the organic phase was dried over Na2SO4. The residue was
chromatographed on silica gel to afford the corresponding
thiocyanate.
6-(1-Na p h th oxy)h exyl Th iocya n a te 9. Starting silyl sul-
fide 7: 205 mg, 0.59 mmol; cyanogen bromide (630 mg, 5.95
mmol); reaction time, 5 h; eluent for chromatography, pen-
tane-dichloromethane (50:50). Thiocyanate 9: 139 mg, 82%;
mp 44-45 °C; IRmax(KBr) 2160 cm-1 1H NMR (200 MHz,
;
CDCl3) δ 8.27 (1 H, m, Ar-H), 7.80 (1 H, m, Ar-H), 7.50-7.29
(4 H, m, Ar-H), 6.81 (1 H, dd, Ar-H), 4.16 (2 H, t), 2.98 (2 H,
t), 2.04-1.64 (4 H, m), 1.75-1.54 (4 H, m); 13C NMR (50 MHz,
CDCl3) δ 154.7, 134.5, 127.5, 126.3, 125.8, 125.7, 125.1, 121.9,
120.1, 112.3 (SCN), 104.6, 67.7, 33.9, 29.8, 29.1, 27.7, 25.7;
LRMS (EI) m/z ) 285 [M]•+, 144 [naphthol]•+. Anal. Calcd for
C
17H19ONS: C, 71.54; H, 6.71; N, 7.91; S, 11.24. Found: C,
71.47; H, 6.75; N, 7.93; S, 11.53.
Clea va ge of th e Su lfid e 8. Starting sulfide 8: 195 mg, 0.59
mmol; cyanogen bromide (650 mg, 6.13 mmol); reaction time,
15 h. Bromide 6: eluent, pentane-dichloromethane (70:30);
70 mg, 40%. Thiocyanate 9: eluent, pentane-dichloromethane
(50:50); 34 mg, 60%.
C
14H24O5N2SiS: C, 46.64; H, 6.71; N, 7.77; S, 8.89. Found: C,
46.26; H, 6.71; N, 7.72; S, 8.88.
1-(3-Th iocya n a to-â-D-xylofu r a n osyl)u r a cil 18. To a so-
lution of sulfide (100 mg, 0.28 mmol) in methanol (1.5 mL)
was added cyanogen bromide (500 mg, 4.72 mmol) in parts.
The mixture was stirred for 48 h at room temperature, and
then aqueous phosphate buffer (0.5 M, pH 7, 4 mL) and water
(10 mL) were added. The mixture was extracted with dichlo-
romethane (60 mL) and then ethyl acetate (150 mL). The ethyl
acetate solution obtained were dried over Na2SO4 and evapo-
rated. The residue was chromatographed on silica gel in
dichloromethane-methanol (50:50) to afford to the thiocyanate
6-(1-(4-Br om on a p h th yl)oxy)h exyl Th iocya n a te 10. To
a solution of the silyl sulfide 7 (360 mg, 1 mmol) in dichloro-
methane (10 mL) was added cyanogen bromide (1 g, 9.4 mmol).
Monitoring of the reaction by HPLC revealed the formation
of only one compound absorbing in the UV. The mixture was
stirred for 20 h at room temperature, and then aqueous
phosphate buffer (0.5 M, pH 7, 15 mL) was added. The mixture
was stirred for 30 min, and water (10 mL) was added. The
mixture was extracted with dichloromethane (100 mL). The
organic layer was dried over Na2SO4 and evaporated. The resi-
due was chromatographed on silica gel in pentane-dichlo-
romethane (50:50) to lead to the thiocyanate 10 (325 mg,
18 (55 mg, 69%): mp 176-178 °C dec; IRmax (KBr) 2150 cm-1
;
1H NMR (200 MHz, DMSO-d6) δ 11.33 (1 H, s), 7.81 (1 H, d),
6.26 (1 H, d), 5.75 (1 H, d), 5.69 (1 H, d), 5.54 (1 H, t), 4.47 (1
H, m), 4.17 (2 H, m), 3.68 (2 H, m); 13C NMR (50 MHz, DMSO-
d6) δ 162.9, 150.7, 140.1, 113.0 (SCN), 102.2, 86.5, 77.8, 77.7,
60.9; LRMS (DCI+, NH3 + isobutane) m/z ) 303 [M + NH3 +
H]+, 286 [M + H]+, 113 [uracil + H]+, (DCI-, NH3 + isobutane)
m/z ) 569 [2M - H]-, 284 [M - H]-. Anal. Calcd for
89%): mp 64-66 °C; IRmax (KBr) 2160 cm-1 1H NMR (300
;
MHz, CDCl3) δ 8.28 (1 H, m), 8.25 (1 H, m), 7.63-7.48 (3 H,
m), 6.64 (1 H, d), 4.09 (2 H, t), 2.93 (2 H, t), 1.97-1.82 (4 H,
m), 1.65-1.54 (4 H, m); 13C NMR (75 MHz, CDCl3) δ 154.5,
132.4, 129.4, 127.7, 126.8, 126.7, 125.9, 122.4, 113.0, 112.2
(SCN), 105.2, 67.9, 33.9, 29.8, 28.9, 27.7, 25.6; LRMS (FAB+,
NBA) m/z ) 365 [M(81Br) + H]+, 363 [M(79Br) + H]+, 224
[(naphthol - Br)+H]+. Anal. Calcd for C17H18BrONS: C, 56.05;
H, 4.98; N, 3.84; S, 8.80. Found: C, 56.05; H, 4.96; N, 3.89; S,
8.55.
C
10H11O5N3S: C, 42.10; H, 3.89; N, 14.73; S, 11.24. Found: C,
41.80; H, 4.10; N, 14.70; S, 11.19.
5′-Deoxy-5′-(2-(tr im eth ylsilyl)eth yl)a d en osin e 19. To a
solution of 5′-tosyladenosine (500 mg, 1.19 mmol) in anhydrous
DMF (10 mL) were added potassium carbonate (1 g, 7.23
mmol) and then 2-(trimethylsilyl)ethanethiol (0.4 mL, 2.49
mmol). The mixture was stirred at 50 °C under nitrogen for
15 h. After filtration to remove the mineral salts and evapora-
tion, the residue was chromatographed on silica gel in dichlo-
romethane-methanol (90:10) to afford compound 19 (438 mg,
96%). This compound was finally crystallized from methanol:
3′-Deoxy-3′-th iocya n a toth ym id in e 12. Starting silyl sul-
fide 11: 100 mg, 0.28 mmol; methanol (1.5 mL), cyanogen
bromide (300 mg, 2.83 mmol); reaction time, 24 h; eluent,
dichloromethane-methanol (95:5). Thiocyanate 12: 61 mg,
1
77%; mp 112-113 °C; IRmax (KBr) 2160 cm-1; H NMR (200
1
MHz, pyridine-d5) δ 7.56 (1 H, s), 6.65 (1 H, dd), 4.53-4.04 (4
H, m), 2.85 (2 H, m), 1.83 (3 H, s); 13C NMR (75 MHz, pyridine-
d5) δ 164.7, 151.6, 136.3, 111.0 (SCN), 110.6, 86.4, 84.7, 60.3,
43.0, 39.1, 12.6; LRMS (FAB+, glycerol) m/z ) 284 [M + H]+,
127 [thymine + H]+.
mp 125-127 °C; H NMR (200 MHz, DMSO-d6) δ 8.31 (1 H,
s), 8.13 (1 H, s), 7.22 (2 H, s), 5.86 (1 H, d), 5.43 (1 H, d), 5.23
(1 H, d), 4.75 (1 H, m), 4.14 (1 H, m), 3.99 (1 H, m), 2.84 (2 H,
m), 2.50 (2 H, m), 0.71 (2 H, m), -0.12 (9 H, s); 13C NMR (50
MHz, DMSO-d6) δ 156.0, 152.5, 149.4, 139.8, 119.2, 87.5, 84.5,
72.6, 72.5, 33.6, 27.5, 16.6, -1.9; LRMS (FAB+, glycerol)
m/z ) 384 [M + H]+, 136 [adenine + H]+. Anal. Calcd for
2-Deoxy-2′-th iocya n a tou r id in e 14. To a solution of the
silyl sulfide 13 (800 mg, 1.26 mmol) in methanol (3 mL) was
added cyanogen bromide (1.35 g, 12.7 mmol). The mixture was
stirred for 48 h at room temperature and then was poured
slowly into diethyl ether (250 mL). The precipitate was
collected by filtration and washed with diethyl ether. It was
rapidly flash chromatographed on silica gel in dichloromethane-
C
15H25O3N5SiS‚1/2MeOH: C, 46.59; H, 6.81; N, 17.53; S, 8.03.
Found: C, 46.39; H, 6.75; N, 17.53; S, 8.53.
5′-Deoxy-5′-th iocya n a toa d en osin e 20. Starting silyl sul-
fide 19: 100 mg, 0.26 mmol; methanol (2 mL); cyanogen
bromide (500 mg, 4.7 mmol); reaction time 15 h; chromatog-

1904 J . Org. Chem., Vol. 67, No. 6, 2002
Chambert et al.
raphy on C18 reversed-phase, eluent water-methanol (70:30).
Thiocyanate 20: 64 mg, 80%: mp 103-105 °C; IRmax (KBr)
2160 cm-1; 1H NMR (200 MHz, DMSO-d6) δ 8.33 (1 H, s), 8.14
(1 H, s), 7.23 (2 H, s), 5.93 (1 H, d), 5.55 (1 H, d), 5.46 (1 H, d),
4.78 (1 H, m), 4.25 (1 H), 4.12 (1 H, m), 3.51 (2 H, m); 13C
NMR (50 MHz, DMSO-d6) δ 156.0, 152.5, 149.2, 139.9, 119.2,
112.9 (SCN), 87.7, 82.5, 72.6, 72.3, 35.7; LRMS (DCI+,
NH3 + isobutane) m/z ) 309 [M + H]+, 136 [adenine + H]+;
HRMS (FAB+, MCA) calcd for [C11H12O3N6S + H]+ 309.0770,
found 309.0788. Anal. Calcd for C11H12O3N6S‚2/3H2O: C, 41.24;
H, 4.20; N, 26.24; S, 10.01. Found: C, 41.41; H, 4.17; N, 25.92;
S, 10.29.
Bis(2′-d eoxyu r id in -2′-yl) Disu lfid e 21. To a solution of
the silyl sulfide 13 (200 mg; 0.55 mmol) in dichloromethane
(3 mL) was added a cyanogen bromide solution in dichloro-
methane (3 M; 0.7 mL; 2.1 mmol) at reflux under nitrogen.
The resulting solution was stirred for 48 h at 40 °C. From this
solution, the disulfide 21 precipitated slowly. After evapora-
tion, the residue was dissolved in water, and the disulfide 21
was chromatographed on a reversed-phase column (C18-Sep-
Pak, 10 g cartridge) in water-methanol (90:10) (98 mg; 0.19
mmol; 70%): mp 160-163 °C (lit.5,20b mp 157-158 °C, lit.20a
mp 161-164 °C); 1H NMR (200 MHz, DMSO-d6) δ 11.29 (1 H,
s), 7.76 (1 H, d), 6.15 (1 H, d), 5.74 (1 H, d), 5.67 (1 H, d), 5.04
(1 H, t), 4.15 (1 H, m), 3.81 (1 H, m), 3.53 (2 H, m); 13C NMR
(75 MHz, DMSO-d6) δ 163.0; 150.8; 140.5; 102.4; 87.8; 86.6;
72.1; 61.3; 55.3; LRMS (FAB+, glycerol) m/z ) 519 [M + H]+.
Ack n ow led gm en t. This work has been supported
by a grant from the “Ligue Nationale contre le Cancer,
Comite´ de la Droˆme”. This financial support is gratefully
acknowledged.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
data for all compounds synthesized and conditions for the
study of cyanogen bromide cleavage of the model sulfides by
HPLC (Figure 2). This material is available free of charge via
the Internet at http://pubs.acs.org.
J O016200Q