Preparation and reactivity of O2-sulfonated diazeniumdiolates

Article abstract of DOI:10.1021/jo026656n

We report the facile preparation of O²-sulfonated diazeniumdiolates and mechanistic investigation of their reactions with representative nucleophiles. This new class of compounds extends the range of O²-substituted diazeniumdiolates available for potential applications in research and medicine.

Full text of DOI:10.1021/jo026656n

SCHEME 1
P r ep a r a tion a n d Rea ctivity of
O2-Su lfon a ted Dia zen iu m d iola tes
Raechelle A. D’Sa,† Yuhong Wang,† Patrick H. Ruane,†
Brett M. Showalter,† J oseph E. Saavedra,‡
Keith M. Davies,§ Michael L. Citro,‡ Melissa N. Booth,
Larry K. Keefer, and J ohn P. Toscano*,†
Department of Chemistry, J ohns Hopkins University,
3400 North Charles Street, Baltimore, Maryland 21218,
Basic Research Program, SAIC Frederick, National Cancer
Institute at Frederick, Frederick, Maryland 21702,
Department of Chemistry, George Mason University,
Fairfax, Virginia 22030, and Chemistry Section,
SCHEME 2
Laboratory of Comparative Carcinogenesis, National
Cancer Institute at Frederick, Frederick, Maryland 21702
jtoscano@jhu.edu.
Received November 4, 2002
SCHEME 3
Abstr a ct: We report the facile preparation of O2-sulfonated
diazeniumdiolates and mechanistic investigation of their
reactions with representative nucleophiles. This new class
of compounds extends the range of O2-substituted diazeni-
umdiolates available for potential applications in research
and medicine.
Anions such as 1-(N,N-dialkylamino)diazen-1-ium-1,2-
diolates (1) are stable as solid salts, but release up to 2
mol of the important bioregulatory molecule nitric oxide
(NO) when dissolved in aqueous solution at physiologi-
cally relevant conditions.1 These compounds have been
converted to hydrolytically stable prodrug forms 2 by
reacting them with a variety of alkylating and arylating
agents to affix electrophilic1 or photosensitive2 groups to
the terminal oxygen (Scheme 1). Thus, extending the
range of synthetically accessible O2-substituted diazeni-
umdiolates is of significant interest to researchers in-
volved in the design of compounds for the controlled
release of NO.3
Reaction of primary alkyl halides with 1 is facile. For
example, O2-benzyl-substituted diazeniumdiolates can be
prepared in near quantitative yield by reaction of the
appropriate benzyl bromide with 1 equiv of diazenium-
diolate salt (Scheme 2). Problems arise, however, when
the alkyl halide is more sterically crowded. Indeed, we
found that the analogous reaction failed with tert-butyl
halides or benzhydryl halides (Scheme 2).
Because of this deficiency we have begun to investigate
other synthetic methodologies for the preparation of
hindered O2-substituted diazeniumdiolates. Herein, we
report the preparation and initial investigations concern-
ing the reactivity of O2-tosylated diazeniumdiolate 3.
Treatment of 1 (R ) Et) with p-toluenesulfonyl chloride
gave O2-tosylated diazeniumdiolate 3 in good yield.
Purification was easily achieved by column chromatog-
raphy. The corresponding mesylated derivative can be
similarly prepared. (See Supporting Information.)
We first examined the reaction of the sodium or
potassium salt of benzhydrol with 3 in 5:1 THF/DMF.
Unlike the unsuccessful reaction of 1 with benzhydryl
bromide described above, we obtained the desired coupled
product 4 in small (ca. 10%), but adequate, yield. Our
initial rationale to explain this result was simple nucleo-
philic attack at nitrogen and displacement of the tosylate
group (Scheme 3, N-attack). However, an alternate
mechanism, involving initial nucleophilic attack at sulfur
to produce 1 (R ) Et) and an intermediate tosyl ester 5
that subsequently alkylates the newly formed 1 ion, is
also possible (Scheme 3, S-attack).
* Corresponding author.
† J ohns Hopkins University.
‡ SAIC Frederick.
§ George Mason University.
National Cancer Institute.
(1) For a recent review of the chemistry of diazeniumdiolate deriva-
tives, see: Hrabie, J . A.; Keefer, L. K. Chem. Rev. 2002, 102, 1135-
1154.
(2) (a) Makings, L. R.; Tsien, R. Y. J . Biol. Chem. 1994, 269, 6282-
6285. (b) Srinivasan, A.; Kebede, N.; Saavedra, J . E.; Nikolaitchik, A.
V.; Brady, D. A.; Yourd, E.; Davies, K. M.; Keefer, L. K.; Toscano, J . P.
J . Am. Chem. Soc. 2001, 123, 5465-5472. (c) Ruane, P. H.; Bushan,
K. M.; Pavlos, C. M.; D’Sa, R. A.; Toscano, J . P. J . Am. Chem. Soc.
2002, 124, 9806-9811. (d) Bushan, K. M.; Xu, H.; Ruane, P. H.; D’Sa,
R. A.; Pavlos, C. M.; Smith, J . A.; Celius, T. C.; Toscano, J . P. J . Am.
Chem. Soc. 2002, 124, 12640-12641.
To differentiate between these two possible mecha-
nisms, the reaction was repeated with 18O-labeled ben-
zhydrol. As indicated in Scheme 3, the direct N-attack
pathway would lead to incorporation of the 18O-label in
(3) Keefer, L. K. Annu. Rev. Pharmacol. Toxicol. (Rev. Adv.) 2003,
43, 585-607.
10.1021/jo026656n CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/31/2002
656
J . Org. Chem. 2003, 68, 656-657

SCHEME 4
SCHEME 5
the coupled product 4. Mass spectral analysis, however,
revealed no evidence for 18O-incorporation, indicating
that attack of the nucleophile on compound 2 proceeds
exclusively at sulfur. (Mass spectral data are included
as Supporting Information.)
With this information in hand, we prepared tosyl ester
5 and reacted it directly with 1 (R ) Et). The observed
yield of adduct 4 approximately doubled when compared
to the reaction of Scheme 3.
high yield without appreciable formation of disulfides (k1
> k2).4c
The leaving group ability of diazeniumdiolates has
previously been demonstrated to be intermediate between
that of chloride and fluoride.5 The rate constants, there-
fore, in Scheme 4 for the reaction of 3 with thiols should
more closely resemble those of sulfonyl chlorides (i.e., k1
< k2), consistent with our lack of observation of inter-
mediate 6.
No evidence has been obtained for the N-attack mech-
anism. The use of bulkier thiols such as diphenyl-
methanethiol and triphenylmethanethiol resulted in no
reaction.
These results are also consistent with the report by
Stevens6,7 that tosylated carbon-bound diazeniumdi-
olate 8 reacts with methoxide to give ultimately com-
pound 9, produced by an analogous S-attack mechanism
(Scheme 5).
In summary, we have reported the facile preparation
of O2-sulfonated diazeniumdiolates. Mechanistic inves-
tigations with a variety of nucleophiles have revealed
that this class of compounds reacts by an S-attack
pathway. We have used O2-tosylated diazeniumdiolate
3 to synthesize benzhydryl derivative 4, which had been
previously inaccessible by standard halide coupling reac-
tions. Further use of O2-sulfonated diazeniumdiolates
should extend the range of synthetically accessible
O2-substituted diazeniumdiolates for potential applica-
tions in research and medicine.
Similarly, coupling of methoxide ion with O2-tosylated
diazeniumdiolate 3, again in 5:1 THF/DMF, led to only
trace amounts of O2-methyl-substituted diazeniumdiolate
2 (R ) Et, R′ ) Me); however, a 78% yield was obtained
when diazeniumdiolate 1 (R ) Et) was directly coupled
with methyl tosylate. Presumably, in the reaction of
methoxide with 3, the initially produced methyl tosylate
reacted with excess methoxide to generate dimethyl
ether.
Further evidence in support of a general S-attack
pathway was obtained when the reaction of phenoxide
and 2,4,6-trimethylphenoxide anions with 3 gave the
tosyl esters in high yield with no production of the
corresponding O2-aryl-substituted diazeniumdiolates 2 (R
) Et, R′ ) Ar).
Mechanistic investigations with thiols as the nucleo-
phile were also carried out. O2-Tosylated diazeniumdi-
olate 3 was treated in dimethyl sulfoxide-d6 with ethyl,
tert-butyl, and phenyl thiolate, respectively, and the
1
reaction was followed in situ by H NMR spectroscopy.
Sulfinic acid 7 was observed (and its identity confirmed
by spiking with an authentic sample), consistent with an
S-attack mechanism (Schemes 3 and 4) as described
below. The sulfinic acid was completely transformed in
a slow oxidation step to the more stable tosic acid over
the course of a 24-h period.
Sulfonyl halides are known to react with thiols to afford
disulfides and sulfinic acids 7; thiosulfonic esters 6 have
been identified as intermediates.4 As indicated in Scheme
4, the product disulfides are produced at the expense of
the initially formed thiosulfonic esters 6 and the observa-
tion of 6 will be dependent on the relative magnitudes of
the two rate constants k1 and k2 shown. Since sulfonyl
chlorides are less reactive with thiols than thiosulfonic
esters (k1 < k2), 6 is not observed in the reaction of
p-toluenesulfonyl chloride with thiols.4 On the other
hand, analogous transformations with the more reactive
p-toluenesulfonyl bromide give thiosulfonic esters 6 in
Ack n ow led gm en t. J .P.T. gratefully acknowledges
the National Institutes of Health (Grant R01 GM58109),
a Camille Dreyfus Teacher-Scholar Award, and an
Alfred P. Sloan Research Fellowship for generous sup-
port of this research. Work was supported in part by
NIH Contract No. NO1-CO12400.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal procedures and compound characterization. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O026656N
(5) Saavedra, J . E.; Srinivasan, A.; Bonifant, C. L.; Chu, J .; Shanklin,
A. P.; Flippen-Anderson, J . L.; Rice, W. G.; Turpin, J . A.; Davies, K.
M.; Keefer, L. K. J . Org. Chem. 2001, 66, 3090-3098.
(6) Stevens, T. E. J . Org. Chem. 1964, 29, 311-315.
(7) See also: Maskill, H.; J encks, W. P. J . Am. Chem. Soc. 1987,
109, 2062-2070.
(4) (a) Cipris, D.; Pouli, D. Synth. Commun. 1979, 9, 207-213. (b)
Palumbo, G.; Caputo, R. Synthesis 1981, 888-890. (c) Ranasinghe, M.
G.; Fuchs, P. L. Synth. Commun. 1988, 18, 227-232.
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