A straightforward route to piloty's acid derivatives: A class of potential nitroxyl-generating prodrugs

Article abstract of DOI:10.1055/s-0029-1217565

A series of Piloty's acid derivatives were easily prepared under mild and neutral conditions. The ease of isolation of the final product offers a marked advantage over well-known procedures. This methodology is particularly attractive as it cleanly provided low molecular weight aliphatic sulfohydroxamic acids, which are very interesting for their tendency to generate HNO under physiological conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217565

LETTER
2149
A Straightforward Route to Piloty’s Acid Derivatives: A Class of Potential
Nitroxyl-Generating Prodrugs
A
C
lass of Potentia
n
l
N
itroxyl-G
d
enerating Pr
r
odrugs ea Porcheddu,* Lidia De Luca, Giampaolo Giacomelli
Dipartimento di Chimica, Università degli Studi di Sassari, Via Vienna 2, 07100 Sassari, Italy
Fax +39(079)212069; E-mail: anpo@uniss.it
Received 22 April 2009
amides (using an amine instead of hydroxylamine),
sulfohydroxamic acids are obtained in quite low yields af-
ter several complex purification steps.16 Extensive studies
on the synthesis of sulfonamides have revealed that sulfo-
Abstract: A series of Piloty’s acid derivatives were easily prepared
under mild and neutral conditions. The ease of isolation of the final
product offers a marked advantage over well-known procedures.
This methodology is particularly attractive as it cleanly provided
low molecular weight aliphatic sulfohydroxamic acids, which are nylation of weakly nucleophilic amines (e.g. NH2OH) is
very interesting for their tendency to generate HNO under physio-
difficult; beside sulfonyl chlorides are highly reactive and
often unstable species.17
logical conditions.
Key words: Piloty’s acid, NO, HNO, MgO, sulfohydroxamic acids
O
S
O
S
base
+
HCl⋅NH2OH
R
Cl
R
NHOH
In the mid 1980’s,1 nitric oxide’s (NO) reputation was un-
expectedly elevated from that of harmful, polluting gas,
which is formed when nitrogen burns in automobile ex-
haust fumes, to a molecule of potential biological rele-
vance. In the past few years, NO has received intense
attention in the life sciences and medicine. In this context,
the biochemistry of nitroxyl2 (HNO), the one-electron re-
duction product of NO, has attracted considerable interest
as a new player in NO research for its remarkable biolog-
ical activity which has been until now largely ignored.3
O
O
R = alkyl, aryl
base = K2CO3, NaOEt, EtONa, Et3N
Scheme 1 Classical approach to sulfohydroxamic acids
Moreover, sulfohydroxamic acids18 having relatively
short alkyl hydrocarbon (1–6 carbon) chains are water sol-
uble and their purification by aqueous workup is elaborat-
ed and tedious. On the other hand, alternative
methodology, based on the use of leaving groups other
than chloride,19 does not avoid all the drawbacks of the
sulfonyl chlorides. In addition direct sulfonylation of hy-
droxylamine itself is well known to result in a mixture of
N- and O-sulfonylated as well as di- and trisulfonylated
products.14b
Nitroxyl is usually generated in solution4 by Angeli’s salt5
(Na2N2O3), a highly oxidizing compound that readily de-
– 6
composes to form HNO via oxyhyponitrite anion HN2O3 .
Another very interesting HNO donor is the benzenesulfo-
hydroxamic acid, well known as Piloty’s acid (PA).7
Some recent studies8 have highlighted that PA decompos-
es to HNO through a base-catalyzed deprotonation
mechanism9 or releases NO upon oxidation.2e,7b,10 In
1998, Shoeman and Nagasawa11 have also observed that
methanesulfohydroxamic acid (MHSA), the simplest
member of the aliphatic sulfohydroxamic acid series, was
able to decompose to HNO at a rate comparable to Ange-
li’s salt, and at physiological pH.12
Therefore, the development of a facile method for the syn-
thesis of ‘sulfonamide bond’, which takes place under
mild and neutral conditions, is strongly desired. In recent
years, mineral oxides have gained some attention because
of reaction rate enhancement, selectivity, easier workup
and the eco-friendly, green, reaction conditions.20
In this context, Rho et al.21 have recently developed an ef-
ficient and chemoselective N-sulfonylation of amino al-
cohols in the presence of MgO.22 The use of this metal
oxide23 becomes much more remarkable to overcome the
most of the problems associated with the synthesis of sul-
fohydroxamic acids. Therefore, we chose to exploit the
utility of MgO as base for the coupling of less reactive N-
hydroxylamine with sulfonyl chlorides.
Following this propensity of sulfohydroxamic acids to re-
lease nitroxyl, we have thought to prepare a library of
Piloty’s acid derivatives reacting a sulfonyl chloride (tra-
ditionally used to synthesize sulfonamide) with hydroxyl-
amine hydrochloride in basic medium (Scheme 1).13
Unfortunately, perusal of the literature14 revealed that
there are several important problems associated with this
classical sulfonylation reaction (Scheme 1), which restrict Initially, we chose 4-methylbenzensulfonyl chloride (1a)
its scope.15 In fact, although the procedure is highly reac- and hydroxylamine hydrochloride (HCl·NH2OH), as the
tive and successful for the preparation of simple sulfon- model substrates for optimization of the reaction condi-
tions (Scheme 2). Hydroxylamine hydrochloride was ini-
tially deprotonated using one equivalent of MgO in
methanol–water. In the absence of H2O (required for a
partial solubilization of HCl·NH2OH and MgO), the
SYNLETT 2009, No. 13, pp 2149–2153
Advanced online publication: 15.07.2009
DOI: 10.1055/s-0029-1217565; Art ID: G10309ST
x
x
.x
x
.2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

2150
A. Porcheddu et al.
LETTER
hydroxylamine reacts very slowly with the sulfonylating Table 1 Chemoselective Synthesis of 2a under Various Reaction
Conditions
reagent and the yields are generally low. The sulfonyl
chloride 1a, dissolved in THF, and an additional equiva-
Entry Solvent
Basea
Time Yieldb
(%)
lent of MgO were then added to the hydroxylamine solu-
tion and the resulting mixture was vigorously stirred at
room temperature until the sulfonyl chloride has com-
pletely disappeared, as monitored by TLC. The reaction
was complete in about 12 hours (Scheme 2).
1
2
Py
Py
12
12
18
11
24
5
CH2Cl2
TEA (2.0)
3
MeOH–H2O (2:3)
MeOH–THF (3:2)
K2CO3 (1.0)14b 12
After the completion of the reaction, the mixture was fil-
tered first through a pad of Celite, and then on a short plug
of silica gel. The clear filtrate was dried over MgSO4 and
evaporated to dryness to give the resulting N-hydroxysul-
fonamide 2a (55%) as a crystalline solid. The purity, as
checked by analytical RP-HPLC, was satisfactory (91%).
All the spectroscopic analysis24 clearly revealed that no
traces of O-sulfonylated or N,O-bis-sulfonylated deriva-
tives were present under the conditions employed.
4
MgO (2.0)
12
6
5
MeOH–H2O–THF (3:2:30) MgO (2.0)
MeOH–H2O–THF (3:2:30) MgO (3.0)
MeOH–H2O–THF (3:2:30) MgO (5.0)
55
85
71
60
45
65
53
47
16
6
2
7
2
8
H2O–DME (2:30)
MgO (3.0)
MgO (3.0)
6
9
H2O–1,4-dioxane (2:30)
6
In a second set of experiments, various conditions includ-
ing solvent, bases, and reaction temperature were exam-
ined for this N-sulfonylation reaction (Table 1). Inferior
results, both in terms of yield and purity of the target com-
pound, were obtained when other solvents such as 1,2-
dimethoxyethane (DME), 1,4-dioxane or CH2Cl2 were
used. Other bases such as ZnO, CuO, NaHCO3, NaOH
(Schotten–Baumann conditions), TEA and pyridine were
also tried in the reaction, but MgO was demonstrated to be
the best choice. Although the sulfonylation reaction pro-
ceeded smoothly (in about 4 h) at a temperature higher
then 40 °C, we observed the collapse of the yields of 2a
(23%) and an increasing of the side products due to the de-
composition of the sulfonyl chloride. N,O-Bis-sulfonylat-
ed derivatives were observed as by-products too.
10
11
12
13
MeOH–H2O–THF (3:2:30) Ag2O (3.0)
MeOH–H2O–THF (3:2:30) CuO (3.0)
MeOH–H2O–THF (3:2:30) ZnO (3.0)
MeOH–H2O–THF (3:2:30) NaHCO3 (3.0)
6
6
6
12
a The molar equivalents are given in parentheses.
b Isolated yields.
(R = aliphatic residue). Aromatic sulfohydroxamic acids
containing various electron-donating and electron-with-
drawing substituents were obtained in good to excellent
yields (entries 1–6 and 7–9, Table 2). No remarkable elec-
tronic effects on the reaction were observed. No signifi-
cant steric effects were observed for the ortho-, meta-, and
para-substituted sulfonyl chloride (entries 4, 5 and 7–9,
Table 2). The reaction is not only limited to hydroxy-
lamine but works well also with N- and/or O-alkylated hy-
droxylamines (entries 9–11, Table 2). Moreover, when a
ketone and sulfonyl chloride groups are present in the
same substrate (1o, entry 15, Table 2), only the sulfonyl
chloride moiety is selectively transformed to the corre-
sponding N-hydroxyamide (2o, entry 15, Table 2).
Afterward, further experiments were carried out using dif-
ferent combinations of equivalents of HCl·NH2OH (from
1.0 to 3.0 equiv) and MgO (from 1.0 equiv to 3.0 equiv).
We observed that two equivalents of hydroxylamine hy-
drochloride and three equivalents of magnesium oxide in
a MeOH–H2O–THF (3:2:30) solution efficiently promot-
ed the sulfonylation reaction in only two hours at room
temperature giving the desired sulfohydroxamic acid 2a
in 85% yield (purity >95%).
All the sulfonyl hydroxamates were fully characterized by
NMR and ES-MS.25 These results show that the majority
of the synthesized compounds have purity higher than
95%. More importantly, no column purification was need-
ed for the isolation of the product.
Encouraged by our initial studies, we then investigated the
generality and versatility of this procedure using a series
of structurally different sulfonyl chlorides (commercially
available) under these optimized conditions. A combina-
torial library (parallel format) of sulfohydroxamic acids
was smoothly prepared in good to high yields and the re-
sults are summarized in Table 2.
The reason for N-sulfonylation induced by metal oxide
has not been entirely clarified; most probably the reaction
mechanism is analogous to that observed in the selective
N-acylation of amino alcohols.22 It seems likely that the
coordinating ability of magnesium ion26 to the double
The methodology is efficient and successful both with ar-
omatic and with aliphatic sulfonic chloride although the
yields are less satisfactory with the aliphatic substrates
O
O
MgO
Me
S
Cl
+
HCl⋅NH2OH
Me
S
NHOH
MeOH–H2O–THF
(3:2:30)
r.t., overnight
O
O
1a
2a
Scheme 2 Synthesis of N-hydroxy-4-methylbenzenesulfonamide
Synlett 2009, No. 13, 2149–2153 © Thieme Stuttgart · New York

LETTER
A Class of Potential Nitroxyl-Generating Prodrugs
2151
Table 2 Synthesis of Sulfohydroxamic Acids
Acknowledgment
OR3
R2
O
S
OR3
O
This work was financially supported by the University of Sassari,
and MIUR (Rome) within the project PRIN 2005: ‘Structure and
Activity Studies of DNA Quadruplexes through the Exploitation of
Synthetic Oligonucleotides and Analogues’.
MgO
R1
S
R
N
+
Cl
HCl⋅
HN
MeOH–H2O–THF
(3:2:30)
R2
O
O
1a–o
r.t., 2 h
2a–o (65–98%)
Entry R1
R2
H
H
H
H
H
R3
H
H
H
H
H
Product Yield (%) References and Notes
(1) (a) Furchgott, R. F.; Zawadzki, J. V. Nature (London) 1980,
288, 373. (b) Ignarro, L. J.; Buga, G. M.; Wood, K. S.;
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D. W.; Goon, J. W.; Nagasawa, H. T. Nitric Oxide: Biol.
Chem. 2001, 5, 278.
1
2
3
4
5
4-MeC6H4
2-MeC6H4
4-t-BuC6H4
2a
2b
2c
2d
2e
85%
74%
77%
90%
95%
2,4,6-(i-Pr)3C6H2
2,6-(MeO)2C6H3
6
H
H
2f
96%
S
7
8
2-O2NC6H4
H
H
2g
2h
2i
97%
95%
97%
97%
95%
65%
76%
71%
(3) (a) Fukuto, J. M.; Switzer, C. H.; Miranda, K. M.; Wink,
D. A. Ann. Rev. Pharmacol. Toxicol. 2005, 45, 335.
(b) Schmidt, H. H. H. W.; Hofman, H.; Schindler, U.;
Shutenko, Z. S.; Cunningham, D. D.; Feelisch, M. Proc.
Natl. Acad. Sci. U.S.A. 1996, 93, 14492.
3-O2NC6H4
4-O2NC6H4
4-t-BuC6H4
4-MeC6H4
Me
H
H
9
H
H
10
11
12
13
14
Me
H
Me
Bn
H
2j
(4) HNO can only be detected indirectly by means of
characteristic downstream products. The major hindrance
to the understanding of HNO chemistry is the quick
dehydrative dimerization of HNO, which yields N2O via a
transient hyponitrous acid: (a) Smith, P. A. S.; Hein, G. E.
J. Am. Chem. Soc. 1960, 82, 5731. (b) Kohout, F. C.;
Lampe, F. W. J. Am. Chem. Soc. 1965, 87, 5795.
(5) Angeli’s salt is cytotoxic at low millimolar concentrations:
Wink, D. A. Arch. Biochem. Biophys. 1998, 351, 66.
(6) Wink, D. A.; Miranda, K. M.; Katori, T.; Mancardi, D.;
Thomas, D. D.; Ridnour, L.; Espey, M. G.; Feelisch, M.;
Colton, C. A.; Fukuto, J. M.; Kass, D. A.; Paolocci, N. Am.
J. Physiol. Heart Circ. Physiol. 2003, 285, H2264.
(7) (a) Piloty, O. Ber. Dtsch. Ges. 1896, 29, 1559. (b) Piloty’s
acids have shown to be selective inhibitors of human
mitochondrial aldehyde dehydrogenase and potent
vasodilators. See: King, S. B.; Nagasawa, H. T. Chemical
approaches toward generation of nitroxyl (HNO), in
Methods in Enzymology; Packer, L., Ed.; Academic Press:
New York, 1998, 211–220.
2k
2l
H
Pr
H
H
2m
2n
Bu
H
H
O
15
H
H
2o
98%
bond of sulfonyl chloride activates the leaving ability of
chloride playing a crucial role in the selective N-sulfon-
ation of NH2OH.27 In the presence of MgO, only the more
nucleophilic amino group is able to react with activated
sulfonyl chloride.
In summary we have investigated the reactions of
HCl·NH2OH with structurally different sulfonyl chlorides
in the presence of MgO and found that they can be
chemoselectively converted to the corresponding N-sulfo-
hydroxamic acids under neutral and mild conditions. The
reaction does not require any aqueous workup, and N-sul-
fohydroxamic acids are isolated pure after a simple filtra-
tion. In comparison with other procedures, the use of
MgO in the place of tertiary amine or other bases gives ac-
cess to sulfohydroxamates more efficiently and in higher
yields (65–98%). All the compounds obtained showed
NMR and mass spectral data compatible with the assigned
structures. No side reactions/products were observed dur-
ing the course of the reaction. The technique described
could be easily used in a parallel synthesis format. The
whole protocol has potential use in the high throughput
synthesis for this class of compounds.
(8) Miranda, K. M. Coord. Chem. Rev. 2005, 249, 433; and
references cited therein.
(9) (a) Bonner, F. T.; Ko, Y. Inorg. Chem. 1992, 31, 2514.
(b) Fukuto, J. M.; Hszieh, R.; Gulati, P.; Chiang, K. T.;
Nagasawa, H. T. Biochem. Biophys. Res. Commun. 1992,
187, 1367.
(10) (a) Grzesiok, A.; Weber, H.; Zamora Pino, R.; Feelisch, M.
In The Biology of Nitric Oxide; Moncada, S.; Feelisch, M.;
Busse, R.; Higgs, E. A., Eds.; Portland Press: London, 1994,
238–241. (b) Zamora, R.; Grzesiok, A.; Weber, H.; Feelisch,
M. Biochem. J. 1995, 312, 333. (c) Nagasawa, H. T.;
Kawle, S. P.; Elberling, J. A.; DeMaster, E. G.; Fukuto, J. M.
J. Med. Chem. 1995, 38, 1865. (d) Granik, V. G.; Grigor’ev,
N. B. Russ. Chem. Bull. Int. Ed. 2002, 51, 1375.
(e) Wilkins, P. C.; Jacobs, H. K.; Michael, D.; Johnson,
M. D.; Gopalan, A. S. Inorg. Chem. 2004, 43, 7877;
references cited therein.
(11) (a) Shoeman, D. W.; Nagasawa, H. T. Nitric Oxide 1998, 2,
66. (b) Shirota, F. S.; DeMaster, E. G.; Lee, M. J. C.;
Nagasawa, H. T. Nitric Oxide 1999, 3, 445.
Synlett 2009, No. 13, 2149–2153 © Thieme Stuttgart · New York

2152
A. Porcheddu et al.
LETTER
(12) Recently, Toscano et al. have demonstrated that a series of
aromatic and nonaromatic N-hydroxysulfonamide
derivatives release nitroxyl at a controlled rate under
physiological conditions: Toscano, J. P.; Brookfield, F. A.;
Cohen, A. D.; Courtney, S. M.; Frost, L. M.; Kalish, V. J.
US Patent, 20070299107A1, 2007.
(13) Blackburn, M.; Mann, B. E.; Taylor, B. F.; Worrall, A. F.
Eur. J. Biochem. 1985, 153, 553.
(14) (a) Gattermann, L. Laboratory Methods of Organic
Chemistry; The Macmillan Company: New York, 1937.
(b) Scolz, J. N.; Engel, S. P.; Glidewell, C.; Whitmire, K.
Tetrahedron 1989, 45, 7695.
(15) During the recrystallization of benzenesulfohydroxamic
acid previously prepared via a classical sulfonylation
procedure Engel et al. (ref. 14b) have isolated and
characterized several side products such as, for example:
PhSO3– + H3NNHSO2Ph and PhSH (accounted for the
reduction of PhSO2Cl by NH2OH).
(16) (a) Fujimoto, M.; Sakai, M. Chem. Pharm. Bull. 1965, 13,
248. (b) Keasling, H. H.; Schumann, E. L.; Veldkamp, W.
J. Med. Chem. 1965, 8, 548.
(25) General Procedure for the Sulfonylation of
Hydroxylamine in the Presence of MgO; N-Hydroxy-2-
methylbenzenesulfonamide (2b): Hydroxylamine
hydrochloride (0.72 g, 10 mmol) in MeOH–H2O (3:2, 5 mL)
was treated with MgO (0.34 g, 8.6 mmol), then a solution of
o-toluenesulfonyl chloride (1a; 0.8 g, 4.3 mmol) in THF (30
mL), and MgO (0.17 g, 4.3 mmol) were added. The reaction
was vigorously stirred at r.t. until the sulfonyl chloride had
completely disappeared (TLC: EtOAc–hexane, 1:1; 2 h).
Then, the mixture was filtered first through a pad of Celite,
and then on a short plug of silica gel. The clear filtrate was
dried over MgSO4 and evaporated to dryness to give the
resulting N-hydroxysulfonamide 2b (0.59 g, 74%) as a
crystalline white solid (96% purity); mp 178–180 °C. 1H
NMR (CDCl3): d = 7.93 (d, J = 8.0 Hz, 1 H), 7.75 (br s, 1 H),
7.42 (t, J = 7.3 Hz, 1 H), 7.27 (t, J = 7.5 Hz, 2 H), 2.62 (s, 3
H). 13C NMR (CDCl3): d = 138.3, 134.8, 133.1, 132.3, 130.7,
125.9, 20.5. HRMS (ESI): m/z [M + H+] calcd for
C7H10NO3S: 188.0381; found: 188.0377. Anal. Calcd for
C7H9NO3S: C, 44.91; H, 4.85; N, 7.48. Found: C, 44.83; H,
4.71; N, 7.57.
(17) Although sulfonyl chlorides are widely used for N-sulfo-
nylation of amines, their drawbacks are the instability and
the too strong reactivity: Kim, H.-K.; Park, Y.-D.; Lee,
M.-H.; Chung, H.-A.; Kweon, D.-H.; Cho, S.-D.; Yoon,
Y.-J. Bull. Korean Chem. Soc. 2003, 24, 1655.
(18) Low molecular weight aliphatic sulfohydroxamic acids are
the most important compounds for their tendency to generate
HNO under physiological condition (at about pH 7, see
Scheme 1).
4-tert-Butyl-N-hydroxybenzenesulfonamide (2c):
According to the procedure previously described for 2b, the
sulfohydroxamic acid 2c was isolated as a white waxy solid
in 77% yield (98% purity). 1H NMR (DMSO): d = 9.53 (s, 1
H), 7.52 (d, J = 8.5 Hz, 2 H), 7.32 (d, J = 8.4 Hz, 2 H), 1.24
(s, 9 H). 13C NMR (DMSO): d = 156.4, 134.7, 125.9, 125.5,
35.1, 31.3. HRMS (ESI): m/z [M + H+] calcd for
C10H16NO3S: 230.0851; found: 230.0857. Anal. Calcd for
C10H15NO3S: C, 52.38; H, 6.59; N, 6.11. Found: C, 52.44; H,
6.39; N, 6.01.
(19) (a) Graham, S. L.; Scholz, T. H. Synthesis 1986, 1031.
(b) Boruah, A.; Baruah, M.; Prajapati, D.; Sandhu, J. S.
Synlett 1997, 1253. (c) Iyer, S.; Sattar, A. K. Synth.
Commun. 1998, 28, 1721. (d) Chan, W. Y.; Berthelette, C.
Tetrahedron Lett. 2002, 43, 4537. (e) Baskin, J. M.; Wang,
Z. Tetrahedron Lett. 2002, 43, 8479. (f) Caddick, S.;
Wilden, J. D.; Bush, H. D.; Wadman, S. N.; Judd, D. B. Org.
Lett. 2002, 4, 2549. (g) Caddick, S.; Wilden, J. D.; Judd, D.
B. J. Am. Chem. Soc. 2004, 126, 1024. (h) Katritzky, A. R.;
Rodriguez-Garcia, V.; Fair, S. K. J. Org. Chem. 2004, 69,
1849. (i) Caddick, S.; Wilden, J. D.; Judd, D. B. Chem.
Commun. 2005, 2727. (j) Wilden, J. D.; Judd, D. B.;
Caddick, S. Tetrahedron Lett. 2005, 46, 7637. (k) Massah,
A.; Kazemi, F.; Azadi, D.; Farzaneh, S.; Aliyan, H.;
Naghazh, H. J.; Momeni, A. R. Lett. Org. Chem. 2006, 3,
235. (l) Chantarasriwong, O.; Jang, D. O.; Chavasiri, W.
Tetrahedron Lett. 2006, 47, 7489. (m) Harmata, M.; Zheng,
P.; Huang, C.; Gomes, M. G.; Ying, W.; Ranyanil, K.-O.;
Balan, G.; Calkins, N. L. J. Org. Chem. 2007, 72, 683.
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Caddick, S. Chem. Commun. 2007, 1074.
(20) (a) Sharghi, H.; Hosseini, M. Synthesis 2002, 1057.
(b) Sarvari, H. M.; Sharghi, H. J. Org. Chem. 2004, 69,
6953. (c) Varma, R. S. Green Chem. 1999, 1, 43.
(21) Kang, H. H.; Rho, H. S.; Kim, D.-H.; Oha, S.-G.
Tetrahedron Lett. 2003, 44, 7225.
(22) Among these metal-mediated reactions, magnesium oxide
has received considerable interest because of its novel
surface catalytic properties: Kim, D.-H.; Rho, H.-S.; Youb,
J. W.; Lee, J. C. Tetrahedron Lett. 2002, 43, 277.
(23) Babu et al. have demonstrated the advantages obtained by
the use of magnesium oxide in the synthesis of N-Fmoc-
protected amino acid hydroxamates: Vasanthakumar, G .-R.;
Babu, V. V. S. Tetrahedron Lett. 2003, 44, 4099.
(24) The structure of 2a was verified by 1H NMR and 13C NMR
and mass spectroscopy.
N-Hydroxy-2,4,6-triisopropylbenzenesulfonamide (2d):
According to the procedure previously described for 2b, the
sulfohydroxamic acid 2d was isolated as a crystalline white
solid in 90% yield (96% purity); mp 212–213 °C (dec.). 1H
NMR (DMSO): d = 7.51 (br s, 2 H), 6.92 (s, 2 H), 4.53 (m,
2 H), 2.75 (m, 1 H), 1.13 (d, J = 6.9 Hz, 6 H), 1.07 (d, J = 6.8
Hz, 12 H). 13C NMR (DMSO): d = 147.4, 146.9, 141.8,
121.5, 33.4, 28.2, 24.9, 23.9. HRMS (ESI): m/z [M + H+]
calcd for C15H26NO3S: 300.1633; found: 300.1626. Anal.
Calcd for C15H25NO3S: C, 60.17; H, 8.42; N, 4.68. Found: C,
60.23; H, 8.49; N, 4.45.
N-Hydroxy-2,6-dimethoxybenzenesulfonamide (2e):
According to the procedure previously described for 2b, the
sulfohydroxamic acid 2e was isolated as a crystalline white
solid in 95% yield (97% purity); mp 158–160 °C. 1H NMR
(DMSO): d = 8.59 (d, J = 3.5 Hz, 1 H), 7.96 (d, J = 3.5 Hz,
1 H), 6.82 (d, J = 8.7 Hz, 1 H), 5.83 (m, 2 H), 3.02 (d, J = 6.6
Hz, 6 H). 13C NMR (DMSO): d = 164.8, 158.3, 132.9, 116.4,
105.2, 56.2, 55.8. HRMS (ESI): m/z [M + H+] calcd for
C8H12NO5S: 234.0436; found: 234.0430. Anal. Calcd for
C8H11NO5S: C, 41.20; H, 4.75; N, 6.01. Found: C, 41.31; H,
4.70; N, 6.12.
N-Hydroxythiophene-2-sulfonamide (2f): According to
the procedure previously described for 2b, the sulfo-
hydroxamic acid 2f was isolated as a waxy solid in 96%
yield (97% purity). 1H NMR (CDCl3): d = 7.75 (m, 1 H),
7.71 (m, 1 H), 7.35 (br s, 2 H), 7.16 (m, 1 H). 13C NMR
(CDCl3): d = 134.5, 133.9, 127.5, 116.5. HRMS (ESI): m/z
[M + H+] calcd for C4H6NO3S2: 179.9789; found: 179.9793.
Anal. Calcd for C4H5NO3S2: C, 26.81; H, 2.81; N, 7.82.
Found: C, 26.74; H, 2.90; N, 7.74.
N-Hydroxy-2-nitrobenzenesulfonamide (2g): According
to the procedure previously described for 2a, the sulfo-
hydroxamic acid 2g was isolated as a crystalline yellow solid
in 97% yield (99% purity); mp 154–157 °C. 1H NMR
(DMSO): d = 7.83 (d, J = 7.8 Hz, 1 H), 7.55 (m, 3 H).
Synlett 2009, No. 13, 2149–2153 © Thieme Stuttgart · New York

LETTER
A Class of Potential Nitroxyl-Generating Prodrugs
2153
13C NMR (DMSO): d = 130.7, 130.0, 129.1, 122.4. HRMS
MeOH). 1H NMR (DMSO): d = 9.65 (s, 1 H), 9.05 (s, 1 H),
2.96 (d, J = 14.8 Hz, 1 H), 2.49 (m, 1 H), 2.32 (m, 2 H), 2.05
(t, J = 4.7 Hz, 1 H), 1.92 (m, 2 H), 1.43 (m, 2 H), 1.02 (s, 3
H), 0.80 (s, 3 H). 13C NMR (DMSO): d = 185.76, 176.39,
59.40, 49.44, 45.45, 43.07, 42.75, 26.99, 26.88, 19.88, 19.3.
HRMS (ESI): m/z calcd for C10H17NO4: 247.0878; found:
247.0871. Anal. Calcd for C10H17NO4S: C, 48.57; H, 6.93;
N, 5.66. Found: C, 48.52; H, 6.87; N, 5.71.
(ESI): m/z [M + H+] calcd for C6H7N2O5S: 219.0076; found:
219.0065. Anal. Calcd for C6H6N2O5S: C, 33.03; H, 2.77; N,
12.84. Found: C, 32.91; H, 2.81; N, 12.92.
4-tert-Butyl-N-methoxy-N-methylbenezenesulfonamide
(2j): According to the procedure previously described for
2b, the sulfohydroxamic acid 2j was isolated as a crystalline
white solid in 97% yield (99% purity); mp 112–114 °C. 1H
NMR (CDCl3): d = 7.80 (d, J = 8.3 Hz, 2 H), 7.57 (d, J = 8.3
Hz, 2 H), 3.82 (s, 3 H), 2.79 (s, 3 H), 1.36 (s, 9 H). 13C NMR
(CDCl3): d = 157.6, 129.5, 129.2, 125.8, 63.7, 39.2, 35.2,
31.0. HRMS (ESI): m/z calcd for C12H19NO3S: 257.1086;
found: 257.1081. Anal. Calcd for C12H19NO3S: C, 56.01; H,
7.44; N, 5.44. Found: C, 55.89; H, 7.48; N, 5.37.
(26) (a) Hanzlik, R. P. Inorganic Aspects of Biological and
Organic Chemistry; Academic Press: New York, 1976, 215.
(b) Comins, D.; Meyers, A. I. Synthesis 1978, 403. (c) Eiki,
T.; Horiguchi, T.; Ono, M.; Kawada, S.; Tagaki, W. J. Am.
Chem. Soc. 1982, 104, 1986. (d) Hanessian, S.; Kagotani,
M.; Komaglou, K. Heterocycles 1989, 28, 1115.
(7,7-Dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)-N-
hydroxymethanesulfonamide (2o): According to the
procedure previously described for 2b, the sulfohydroxamic
acid 2o was isolated as a crystalline white solid in 98% yield
(98% purity); mp 122–124 °C; [a]20D +27.89 (c = 0.384,
(e) Sammakia, T.; Jacobs, J. S. Tetrahedron Lett. 1999, 40,
2685.
(27) Guo, Z.; Dowdy, E. D.; Li, W.-S.; Polniaszek, R.; Delaney,
E. Tetrahedron Lett. 2001, 42, 1843.
Synlett 2009, No. 13, 2149–2153 © Thieme Stuttgart · New York

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