3,2-Hydroxypyridinone (3,2-HOPO) vinyl sulfonamide and acrylamide linkers: Aza-Michael addition reactions and the preparation of poly-HOPO chelators

Article abstract of DOI:10.1016/j.tetlet.2012.11.136

The HOPO vinyl sulfonamide 3 and the corresponding HOPO acrylamide 10 were easily prepared by short synthetic sequences. Investigation of the aza-Michael reactions of these linkers showed that they proceed at a higher rate in solvent systems containing water. The scope and limits of the aza-Michael reactions of 3 and 10 were examined. Reagents 3 and 10 reacted cleanly with piperazine to give the corresponding adducts which were deprotected to give the di-HOPO ligands 7 and 16. Reaction of HOPO acrylamide 10 with 1,4,7-triazacyclononane gave the tris-adduct 17 which was deprotected to give the desired tris-HOPO ligand 18. Overall, the aza-Michael reactions of 3 and 10 appear to be governed not only by the solvent but also by the nature of the amine and the solubility of the reaction intermediates.

Full text of DOI:10.1016/j.tetlet.2012.11.136

Tetrahedron Letters 54 (2013) 630–634
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
3,2-Hydroxypyridinone (3,2-HOPO) vinyl sulfonamide and acrylamide linkers:
aza-Michael addition reactions and the preparation of poly-HOPO chelators
⇑
Gloria Martinez, Jayanthi Arumugam, Hollie K. Jacobs, Aravamudan S. Gopalan
Department of Chemistry and Biochemistry, MSC 3C, New Mexico State University, Las Cruces, NM 88003-8001, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The HOPO vinyl sulfonamide 3 and the corresponding HOPO acrylamide 10 were easily prepared by short
synthetic sequences. Investigation of the aza-Michael reactions of these linkers showed that they proceed
at a higher rate in solvent systems containing water. The scope and limits of the aza-Michael reactions of
3 and 10 were examined. Reagents 3 and 10 reacted cleanly with piperazine to give the corresponding
adducts which were deprotected to give the di-HOPO ligands 7 and 16. Reaction of HOPO acrylamide
10 with 1,4,7-triazacyclononane gave the tris-adduct 17 which was deprotected to give the desired
tris-HOPO ligand 18. Overall, the aza-Michael reactions of 3 and 10 appear to be governed not only by
the solvent but also by the nature of the amine and the solubility of the reaction intermediates.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 2 November 2012
Revised 26 November 2012
Accepted 28 November 2012
Available online 5 December 2012
Keywords:
Aza-Michael reaction
Hydroxypyridinone
Metal ion chelators
Vinyl sulfonamide
Rate acceleration in water
There has been considerable interest in the synthesis, coordina-
tion chemistry, and biological applications of hydroxypyridinone
(HOPO) ligand systems.1 Tris-HOPO chelators have been shown
to form strong complexes with hard metal ions such as iron, gado-
linium, and gallium. A recent review on hydroxypyridinones as
‘privileged’ structures for the design of medicinal drugs has been
published.2 3,4-HOPO chelators have been extensively examined
for the treatment of iron overload diseases3 and cancer treatment.4
Another review5 discusses the use of HOPO chelators as contrast
agents in magnetic resonance imaging (MRI), a hot area of re-
search.6 HOPO chelators have been attached to dendrimers7 and
viral capsids.8 HOPO complexes of gallium (III) isotopes are also
being investigated for positron emission tomography (PET)
applications.9
The sulfonamide moiety is present in a wide array of drugs that
range from sulfa antibiotics to Viagra and Celebrex.10 Sulfonamides
have been used clinically to treat diseases like glaucoma, macular
edema, diverse neuromuscular disorders, and fungal infections.
They have also been used in cancer treatment.11 Sulfonamide
derivatives are known to be inhibitors of carbonic anhydrase12
and matrix metalloproteinases.13
method for synthesizing sulfonamides is by reacting ammonia, pri-
mary or secondary amines with the desired sulfonyl chloride. Aro-
matic sulfonyl chlorides are often directly synthesized by
chlorosulfonylation and many are commercially available. How-
ever, aliphatic sulfonyl chlorides are not as easily accessed though
they can be prepared from the corresponding sulfonate salts. Re-
cently, some alternate routes for accessing aliphatic sulfonamides
have been published.14 A popular method involves the conversion
of thiols to a sulfonic acid chloride using oxidative chlorination fol-
lowed by in situ coupling with amines.15
In this paper, we disclose a convenient and convergent proce-
dure for the incorporation of HOPO ligands onto various amine
platforms using aza-Michael reactions of a new vinyl sulfon-
amide-HOPO reagent. The choice of primary sulfonamide in the
linker is relevant as it provides a site for H-bonding, metal ion11b
or anion bonding,16 and permits subsequent attachment to another
group via N-alkylation. Our interest in this area was further stim-
ulated by recent disclosures on vinyl sulfonamide reagents which
have been shown to be valuable ‘linchpins’ in diversity-oriented
synthesis as they undergo aza-Michael, Heck, and RCM reactions.17
We also report the results of the aza-Michael reaction of the corre-
sponding HOPO acrylamide, which allows access to amide analogs
for comparison purposes.
Given the importance of both the HOPO ligand and the sulfon-
amide bond, synthetic methodology to access molecules that
incorporate both these features are lacking. This could be due to
the fact that in comparison to the corresponding amides, non-aryl
sulfonamide systems are more difficult to prepare. The traditional
Our study began with the preparation of the HOPO vinyl sulfon-
amide reagent 3. It was also decided to prepare the simpler and
more easily accessible sulfonamide 1 to conduct some model stud-
ies on reactivity. Using a modification of a procedure reported by Li
et al.,18 the synthesis of vinylsulfonamide 1 was accomplished, in a
one-pot reaction, from commercially available 2-chloro-
⇑
Corresponding author. Tel.: +1 575 646 2589; fax: +1 575 646 2649.
E-mail address: agopalan@nmsu.edu (A.S. Gopalan).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.136

G. Martinez et al. / Tetrahedron Letters 54 (2013) 630–634
631
Table 1
ethanesulfonyl chloride. In our hands, the most convenient proce-
Reactions of vinyl sulfonamide 1 with amines
dure involved the addition of chloroethanesulfonyl chloride to a
solution of amylamine in dichloromethane in the presence of tri-
ethylamine at room temperature (Scheme 1). After aqueous
work-up and chromatographic purification, vinyl sulfonamide 1
was isolated in good yields. Similar reaction of HOPO amine 2,19
with chloroethanesulfonyl chloride gave HOPO vinyl sulfonamide
reagent 3 in 63% yield after purification.20
The aza-Michael addition of vinylsulfonamide 1 with a primary
amine was first examined. The desired addition showed little pro-
gress when a 1:1 mixture of benzyl amine with the vinylsulfona-
mide reagent 1 in acetonitrile was stirred at room temperature
for 8 days. However, better results were observed when excess
benzyl amine (4 equiv) was used in this reaction (85% yield over
8 days at rt). When a 1:1 mixture of benzyl amine and 1 was re-
fluxed in acetonitrile for 3 days, the desired adduct 4 was isolated
in 75% yield (Table 1, entry 1).
Entry
R
Solvent
Temp
Time
Yielda (%)
1
2
3
4
5
H
H
H
CH3
CH3
CH3CN
Reflux
rt
rt
Reflux
rt
3 d
18 h
4 d
3 d
18 h
75
62
87
79
83
2:3 MeOH:H2O
2:3 THF:H2O
CH3CN
2:3 THF:H2O
a
Isolated yield after work-up. TLC was homogeneous.
From our initial studies, it was clear that under traditional con-
ditions, aza-Michael addition reactions of primary amines to the
vinyl sulfonamide were slow. Our observation is not unique as
there are reports in the literature that primary vinyl sulfonamides
are not particularly reactive in aza-Michael reactions. This has
been ascribed to deprotonation of the acidic sulfonamide proton
to some degree reducing the reagent’s electrophilicity.21 In one
study that examined the Michael addition of 2-phenylethanethiol
to representative vinyl sulfonyl Michael acceptors, the sulfonamide
analog was found to be the least reactive while the phenyl vinyl
sulfonate ester was the most reactive.21 In another study, it was
found that no aza-Michael addition occurred in the absence of Le-
wis acids in both solution and solid phase, when excess 4-furoyl-
piperazine was contacted with vinyl sulfonamides on solid
support or in corresponding model studies.22 It became imperative
to identify more favorable conditions for the aza-Michael addition
reactions of amines/polyamines with reagent 1.
Recently, several publications have appeared on the rate
enhancement of Michael addition reactions in the presence of
water.23 Importantly, Naidu et al reported a dramatic increase in
both the rate and yields in the Michael addition of amines and thi-
ols to dehydroalanine amides upon using THF:water or metha-
nol:water as the solvent.24 A similar rate enhancement was
observed in the aza-Michael addition of cyclam to phenyl vinyl sul-
fone and phenyl vinyl sulfoxide when water was added to the reac-
tion mixture.25 However, in the case of vinyl sulfonamides, it was
not known if there is any rate acceleration of the aza-Michael addi-
tion in the presence of water in the solvent system. We decided to
examine whether the inclusion of water in the solvent system
could favorably impact the addition of amines to vinyl
sulfonamides.
the rate of reaction, when the reaction was run in a 2:3 mixture of
methanol/water for 18 hours. Adduct 4 was formed in 62% yield
(Table 1, entry 2). When the same reaction was run in a solution
of THF/water, the rate enhancement was significantly less but
the reaction did proceed at room temperature and a higher yield
of the adduct was isolated after 4 days (entry 3).
N-Methyl benzyl amine was used as a model to understand the
reactivity of secondary amines with 1. When a 1:1 mixture of the
amine and 1 was refluxed in acetonitrile for 3 days, sulfonamide
5 was isolated in 79% yield (entry 4). When a mixture of water
and THF was used as the solvent, the same reaction gave an 83%
yield of the product after only 18 hours (entry 5). The precise
explanation for the rate enhancement observed in Michael addi-
tions in aqueous solutions is unknown.26 Various factors such as
hydrogen bonding and/or hydrophobic effects have been invoked
as potential contributors to the rate enhancement. Further, in the
case of sulfonamides, solubility of both starting materials and
products in the reaction medium appear to impact the progress
of the reaction.
From the literature, aza-Michael reactions of primary amines in
aqueous solvent systems have been reported to give monoalkyla-
tion only23c or mixtures of mono and di-adducts.27 Hence, it was
not clear whether the reaction of vinyl sulfonamide 1 with a pri-
mary amine (benzyl amine) could be controlled to obtain the di-
adduct selectively and in good yields. A number of reaction condi-
tions were examined for this purpose using a three to one stoichi-
ometric ratio of vinyl sulfonamide 1 to benzyl amine (Scheme 2). In
all cases, we obtained product mixtures with varying ratios of the
mono to di, with the mono usually being the major product. These
reactions could easily be monitored by 1H NMR analysis. The ben-
zyl protons of the mono and di-adducts have well differentiated
chemical shifts, d 3.80 and 3.69, respectively, and could be easily
integrated to obtain the ratio of the mono to di in the crude
products.
Given the lack of aqueous solubility of sulfonamide 1, we
decided that mixed solvents such as THF:water or methanol:water
may be more appropriate for our reaction.24 Indeed, this proved to
be correct. In the aza-Michael addition of benzyl amine (1 equiv) to
vinyl sulfonamide 1 (1 equiv) we observed a significant increase in
1. Et3N (3eq), DCM,
2. ClCH2CH2SO2Cl,
rt, 5 h, 67 %
O
S
O
N
H
NH2
1
O
O
1. Et3N (3 eq), DCM,
2. ClCH2CH2SO2Cl,
rt, 5 h, 63 %
O
OBn
BnO
NH2
S
O
N
N
N
H
3
2
Scheme 1.

632
G. Martinez et al. / Tetrahedron Letters 54 (2013) 630–634
Scheme 2.
With the useful information obtained from our model studies
with vinyl sulfonamide 1, we began to explore the aza-Michael
reaction of the HOPO vinylsulfonamide 3, for the preparation of
sulfonamide-linked HOPO chelators. Of particular interest to us
was the reaction of 3 with azacyclic polyamines. The syntheses
of chelators in which the HOPO ligands have been appended to
piperazine and 1,4,7-triazacyclononane have been reported and
they have been shown to be strong chelators of iron.28
Based on our results, we expected that secondary amines would
undergo efficient aza-Michael addition with 3. We were particu-
larly optimistic with piperazine as our substrate, since it is known
that cyclic amines react more readily with various Michael accep-
tors than their acyclic analogs.29 When piperazine was reacted
with sulfonamide 3 (2.1 equiv) in refluxing acetonitrile, the rate
of addition was slow (8 days) but the sulfonamide-linked bisHOPO
compound 6 was obtained in 48% yield. However, when the same
reaction was run in 2:3 THF/water at room temperature for 1 day,
the product 6 was isolated in excellent yield after chromatographic
purification (Scheme 3).30 Clearly, the addition of water improved
both the yield and rate of the reaction in this case. Deprotection of
6 using 1:1 HBr/acetic acid gave the sulfonamide-linked bisHOPO
Scheme 4.
The coupling of HOPO amine, 2, with acryloyl chloride in the
presence of excess triethylamine in dichloromethane gave the
HOPO acrylamide reagent 10 in 57% yield after purification
(Scheme 5). The difference in reactivity between the vinyl sulfon-
amide 1 and HOPO acrylamide 10 became quickly apparent, in
the reaction of 10 with benzyl amine. No significant product for-
mation was observed when benzyl amine (1 equiv) was refluxed
with 10 (1 equiv) for 3 days in acetonitrile. Minor adduct formation
was observed by proton NMR analysis when this reaction was con-
ducted in 2:3 methanol/water for 2 days at room temperature. In
contrast to the reaction with 1, when a 1:1 mixture of N-methyl-
benzyl amine and HOPO acrylamide 10 was refluxed in acetonitrile
for 2 days, no product formation was observed. However, when the
same reaction was carried out in 2:3 methanol/water at room tem-
perature for 3 days, the aza-Michael product 12 was isolated in 71%
yield after chromatographic purification. Though the reaction was
slow, the use of methanol/water as a solvent did result in good
yields of 12.
The difference in reactivity of the HOPO acrylamide 10 with
benzyl amine and N-methyl benzyl amine was surprising. To fur-
ther establish the difference in reactivity (primary vs secondary
amine), the reagent 10 (1 equiv) was reacted with N-methylethy-
lenediamine (5 equiv) in 2:3 methanol/water. After 1 day, only
the mono adduct, 13, from addition at the secondary amine, was
isolated in 86% yield after column chromatography (Scheme 6).
The secondary amine shows a surprising selectivity over the pri-
mary amine for addition to 10 and there is no obvious explanation
for this unexpected behavior. It has been reported23d that second-
ary amines undergo aza-Michael additions in higher yields than
primary amines though no competitive studies like ours have been
published. It is likely that both the solubility and the steric and
hydrophobic nature of the amine are key factors that affect the rate
chelator
7 as the hydrobromide salt in 92% yield after
lyophilization.31
The successful reaction of HOPO vinyl sulfonamide 3 with
piperazine encouraged us to explore the corresponding reaction
of sulfonamide 3 with 1,4,7-triazacyclononane. When triazacyclo-
nonane was stirred with 3 equiv of vinyl sulfonamide 3 in 2:3
THF/water it was observed that there was very little product for-
mation after 1 day at rt. Subsequently, the reaction mixture was re-
fluxed for 5 days adding THF as necessary to maintain
homogeneity. After purification by preparative TLC on alumina,
the desired tris-adduct 8 was obtained in 56% yield contaminated
with small amounts of the di-adduct, 9 (Scheme 4). In addition to
spectral analysis, LCMS confirmed the presence of the major tris-
adduct (1175, [MH]+) and also the minor di-adduct (827, [MH]+).
Given the success of the reaction of 3 with piperazine, our results
with 1,4,7-triazacyclononane were unexpected. It is clear that both
the solubility of the starting materials and the intermediates play a
critical role in the success of this reaction.
Our focus then turned to the corresponding HOPO acrylamide
10. It was relevant to examine its reactivity with secondary amines
and determine whether a similar rate of acceleration in aqueous
solvents would be observed. Also the studies would provide amide
analogs of the sulfonamides for comparison purposes.
O
O
O
O
N
N
3 (2.1 eq)
RO
OR
HN
NH
N
N S
S N
N
H
O
H
O
, R = Bn
2:3 THF:H2O
rt, 24 h, 94%
6
1:1 HBr:AcOH
rt, 24 h, 92%
7, R = H
Scheme 3.

G. Martinez et al. / Tetrahedron Letters 54 (2013) 630–634
633
solvent systems (e.g., THF/water or methanol/water). This finding
is consistent with the rate of acceleration observed in the presence
of water in aza-Michael addition studies of various acrylate deriv-
atives. Both benzyl amine and N-methyl benzyl amine gave good
yields of the desired mono adducts with 1. In contrast, the reaction
of benzyl amine with excess sulfonamide 1 could not be controlled
to give only the di-adduct. Piperazine undergoes efficient addition
with vinyl sulfonamide 3 to give the di-adduct 6 in good yields.
However, our results from the reaction of 3 with 1,4,7-triazacyclo-
nonane suggest that solubility considerations of the intermediates
may play a role in driving this reaction to completion. In contrast
to HOPO vinyl sulfonamide 3, the corresponding HOPO acrylamide,
10, appears to be less reactive under comparable conditions with
both primary and secondary amines. However, the higher reactiv-
ity of 10 with secondary amines over primary amines is clearly
seen in its reaction with N-methyl ethylenediamine, which reacts
preferentially at the secondary amine site. In spite of its reduced
reactivity, reagent 10 does add efficiently to secondary amines
including piperazine. The reaction of HOPO acrylamide 10 with
1,4,7-triazacyclononane does proceed, albeit slowly, to give the de-
sired tris-adduct 17 in good yields. Overall, the aza-Michael reac-
tions appear to be governed not only by the solvent but by the
nature of the amine and the solubility of the reaction intermedi-
ates. While HOPO vinyl sulfonamide 3 does react more readily than
acrylamide 10, its use to prepare poly-HOPO derivatives from the
corresponding polyamines may be limited due to solubility consid-
erations. Finally, this work resulted in the successful synthesis of a
new bis-3,2-HOPO sulfonamide chelator 7 and its amide analog 16.
We also prepared tris-3,2-HOPO amide linked chelator 18 to dem-
onstrate the potential applicability of our new methodology. The
usefulness of reagents 3 and 10 in Heck and metathesis reactions,
which can further enhance the value of these new linkers, remains
to be examined.
Scheme 5.
of this reaction. When N,N0-dimethyl ethylenediamine was treated
with 10 (2 equiv) in methanol/water for 3 days, the dialkylated
product 14 was isolated in 53% yield after purification.
The aza-Michael addition of acrylamide-HOPO reagent 10 with
piperazine was also examined (Scheme 7). Treatment of piperazine
with acrylamide 10 (2 equiv) in methanol/water for 3 days gave
the desired dialkylated product 15 in 87% yield after purification.
Deprotection of the benzyl groups using HBr/acetic acid gave the
water-soluble amide linked bisHOPO chelator 16 as the hydrobro-
mide salt in good yield.32 The reaction of 1,4,7-triazacyclononane
with HOPO acrylamide 10 (3 equiv) in methanol/water was slow
but gave the tris-HOPO product 17 in good yield after purification
(Scheme 7). In contrast to the corresponding vinyl sulfonamide
addition, this reaction goes to completion. Deprotection using
HBr/acetic acid gave the water-soluble tris-HOPO chelator 18 as
the hydrobromide salt in good yield.33
Acknowledgment
In conclusion, the aza-Michael reaction of vinyl sulfonamides
has received little attention as a synthetic tool. In this Letter, the
aza-Michael reaction of vinyl sulfonamide 1 was shown to be very
slow in refluxing acetonitrile but occurs more rapidly in aqueous
This research was supported by Grants from NIH S06 GM08136
and 1SC3GM084809 and NIH-RISE GM61222 (fellowship to G.M.).
O
O
10 (1 eq)
OBn
O
H2N
5 eq
NH
CH3
N
H2N
O
N
N
N
H
2:3 MeOH:H2O
rt, 1 d, 86 %
CH3
13
O
O
10 (2 eq)
2:3 MeOH:H2O
BnO
OBn
HN
CH3
NH
CH3
N
CH3
N
N
N
H
N
H
CH3
rt, 3 d, 53 %
14
Scheme 6.
10 (2 eq)
N
R'
R'
N
HN
NH
2:3 MeOH:H2O
rt, 3 d, 87%
15
, R = Bn
1:1 HBr:AcOH
rt, 24 h, 80%
16, R = H
R'
HN
10 (3 eq)
N
N
N
O
O
NH
2:3 MeOH:H2O
rt, 8 d, 84%
OR
N
H
N
HN
O
17
, R = Bn
O
R'
1:1 HBr:AcOH
rt, 24 h, 81%
OR
R' =
N
N
H
18, R = H
Scheme 7.

634
G. Martinez et al. / Tetrahedron Letters 54 (2013) 630–634
NaHCO3 (2 ꢀ 15 mL), dried (MgSO4), filtered and the solvent was removed in
vacuo. The crude product was purified by radial chromatography to give 3
(0.328 g, 63%) as a viscous oil: IR (neat) 3168, 1651, 1596 cmꢁ1 1H NMR
(200 MHz, CDCl3) d 7.40–7.33 (m, 5H), 6.89 (dd, J = 1.4, 6.9 Hz, 1H), 6.67 (dd,
J = 1.6, 7.5 Hz, 1H), 6.58 (dd, J = 8.7, 16.8 Hz, 1H), 6.19 (d, J = 16.4 Hz, 1H), 6.10
(t, J = 7.1 Hz, 1H), 6.01 (t, J = 6.4 Hz, 1H), 5.85 (d, J = 10.2 Hz, 1H), 5.12 (s, 2H),
4.13 (t, J = 6.0 Hz, 2H), 2.96 (q, J = 6.1 Hz, 2H), 1.96 (quin, J = 5.9 Hz, 2H); 13C
NMR (200 MHz, CDCl3) d 158.4, 148.5, 136.2, 135.9, 128.8, 128.4, 127.9, 127.2,
125.6, 115.7, 105.5, 70.6, 46.1, 39.2, 29.8; Anal. Calcd for C17H20N2O4S: C,
58.60; H, 5.79; N, 8.04. Found: C, 58.24; H, 5.47; N, 7.84.
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T.; Nawaz, S.; Mullen, G. E. D.; Hider, R. C.; Blower, P. J. Chem. Commun. 2011,
47, 7068; (b) Chaves, S.; Mendonca, A. C.; Marques, S. M.; Prata, M. I.; Santos, A.
C.; Martins, A. F.; Geraldes, C. F. G. C.; Santos, M. A. J. Inorg. Biochem. 2011, 105,
31.
26. Jung, Y.; Marcus, R. A. J. Am. Chem. Soc. 2007, 129, 5492.
27. Loh, T.-P.; Wei, L.-L. Synlett 1998, 975.
28. Harrington, J. M.; Chittamuru, S.; Dhungana, S.; Jacobs, H. K.; Gopalan, A. S.;
Crumbliss, A. L. Inorg. Chem. 2010, 49, 8208.
29. Rulev, A. Y. Russ. Chem. Rev. 2011, 80, 197.
30. Synthesis of disulfonamide 6. To
a solution of HOPO vinyl sulfonamide 3
(0.050 g, 0.143 mmol) in 2:3 THF/H2O (5 mL) was added piperazine (0.006 g,
0.068 mmol) and the solution stirred at rt for 24 h. The solvent was removed in
vacuo and the resulting residue was extracted into dichloromethane
(3 ꢀ 10 mL). The combined organic extracts were dried (MgSO4), filtered, and
the solvent removed in vacuo. The crude product was purified by radial
chromatography to give 6 (0.051 g, 94%) as a white solid: mp 46–48 °C; IR (KBr)
3435, 1650, 1598 cmꢁ1 1H NMR (400 MHz, CDCl3) d 1.97 (quin, J = 6.1 Hz, 4H),
;
10. (a) Wilden, J. D. J. Chem. Res. 2010, 541; (b) Block, J. H.; Brackett, C. C.; Singh, H.;
Block, P. D. Pharmacotherapy 2004, 24, 856.
11. (a) Supuran, C. T.; Vullo, D.; Franchi, M.; Gallori, E.; Antel, J.; Scozzafava, A. J.
Med. Chem. 2004, 47, 1272; (b) Macías, B.; García, I.; Villa, M. A.; Borrás, J.;
Castiñerias, A.; Sanz, F. Z. Anorg. Allg. Chem. 2003, 629, 255.
2.46 (br s, 8H), 2.81 (t, J = 7.0 Hz, 4H), 3.13–3.04 (m, 8H), 4.09 (t, J = 6.2 Hz, 4H),
5.09 (s, 4H), 6.10 (t, J = 7.1 Hz, 4H), 6.68 (dd, J = 1.6, 7.4 Hz, 2H), 6.91 (dd, J = 1.7,
6.8 Hz, 2H), 7.43–7.30 (m, 10H); 13C NMR (50 MHz, CDCl3) d 30.5, 39.5, 49.0,
46.2, 52.1, 52.7, 70.7, 105.4, 115.7, 127.3, 128.0, 128.5, 128.8, 136.0, 148.7,
158.5. Anal. Calcd for C38H50N6O8S2ꢂH2O: C, 56.98; H, 6.54; N, 10.49. Found: C,
56.95; H, 6.12; N, 10.09.
12. Supuran, C. T.; Innocenti, A.; Casini, A.; Alcar, M. C.; Papini, A. M.; Scozzafava, A.
J. Med. Chem. 2004, 47, 5224.
31. Synthesis of diHOPO 7. A solution of 1:1 48% HBr/AcOH (3 mL) was added to
protected HOPO sulfonamide 6 (0.051 g, 0.065 mmol) and the solution stirred
at rt for 18 h. The solvent was removed in vacuo. The residue was washed with
CHCl3 (2 ꢀ 5 mL), and EtOAc (2 ꢀ 5 mL). The washed product was dissolved in
nanopure water and lyopholized to give the diHOPO 7 (0.046 g, 92%) as a white
13. Tanakit, A.; Rouffet, M.; Martin, D. P.; Cohen, S. M. Dalton Trans. 2012, 41, 6507.
14. (a) García Ruano, J. L.; Parra, A.; Marzo, L.; Yuste, F.; Mastranzo, V. M.
Tetrahedron 2011, 67, 2905; (b) Caddick, S.; Wilden, J. D.; Bush, H. D.; Wadman,
S. N.; Judd, D. B. Org. Lett. 2002, 4, 2549; (c) Caddick, S.; Wilden, J. D.; Judd, D. B.
J. Am. Chem. Soc. 2004, 126, 1024; (d) Berthelette, C.; Chan, W. Y. Tetrahedron
Lett. 2002, 43, 4537.
15. (a) Bahrami, K.; Khodaei, M. M.; Abbasi, J. Tetrahedron 2012, 68, 5095; (b)
Massah, A. R.; Sayadi, S.; Ebrahimi, S. RSC Adv. 2012, 2, 6606; (c) Gareau, Y.;
Pellicelli, J.; Laliberté, S.; Gauvreau, D. Tetrahedron Lett. 2003, 44, 7821.
16. Chen, C.; Chen, Q. Tetrahedron Lett. 2004, 45, 3957.
17. (a) Zang, Q.; Javed, S.; Porubsky, P.; Ullah, F.; Neuenswander, B.; Lushington, G.
H.; Basha, F. Z.; Organ, M. G.; Hanson, P. R. ACS Comb. Sci. 2012, 14, 211; (b)
Ullah, F.; Zang, Q.; Javed, S.; Porubsky, P.; Neuenswander, B.; Lushington, G. H.;
Hanson, P. R.; Organ, M. G. Synthesis 2012, 44, 2547; (c) Fenster, E.; Long, T. R.;
Zang, Q.; Hill, D.; Neuenswander, B.; Lushington, G. H.; Zhou, A.; Santini, C.;
Hanson, P. R. ACS Comb. Sci. 2011, 13, 244; (d) Rolfe, A.; Lushington, G. H.;
Hanson, P. R. Org. Biomol. Chem. 2010, 8, 2198; (e) Morris, J.; Wishka, D. G. J.
Org. Chem. 1991, 56, 3549.
solid: mp 92–94 °C (dec); IR (KBr) 3368, 3119, 2532, 1674, 1583 cmꢁ1 1H NMR
;
(300 MHz, D2O) d 2.02 (quin, J = 6.7 Hz, 4H), 3.16 (t, J = 6.7 Hz, 4H), 3.67–3.47
(m, 16H), 4.10 (t, J = 6.9 Hz, 4H), 6.39 (t, J = 7.2 Hz, 2H), 7.00 (dd, J = 1.8, 7.3 Hz,
2H), 7.19 (dd, J = 1.6, 6.8 Hz, 2H); 13C NMR (100 MHz, D2O) d 29.7, 40.7, 46.9,
48.2, 50.2, 51.4, 109.3, 119.4, 130.1, 146.1, 159.3. Anal. Calcd for
C
24H38N6O8S2ꢂ3HBrꢂ3H2O: C, 32.05; H, 5.27; N, 9.34. Found: C, 31.90; H, 5.14;
N, 9.32.
32. Bis-HOPO 16. Mp 105–110 °C; IR (KBr) 3251, 1645, 1613, 1557 cmꢁ1 1H NMR
;
(200 MHz, CD3OD) d 1.60–1.73 (quin, 4H), 2.49 (t, J = 5.5 Hz, 4H), 2.81 (t,
J = 6.24 Hz, 4H), 3.27 (t, J = 6.22 Hz, 4H), 3.52 (br s, 8H), 3.90 (t, J = 6.96 Hz, 4H),
6.27 (t, J = 6.96 Hz, 2H), 6.79 (d, J = 7.32 Hz, 2H), 7.14 (d, J = 6.24 Hz, 2H); 13C
NMR (50 MHz, D2O) d 27.8, 29.3, 36.22, 47.1, 48.7, 52.8, 108.9, 118.8, 129.0,
145.3, 158.2, 170.6. Anal. Calcd for C26H38N6O6ꢂ3HBrꢂ2.5H2O: C, 38.16; H, 5.66;
N, 10.27. Found: C, 38.02; H, 5.30; N, 9.97.
18. Li, M.; Wu, R. S.; Tsai, J. S. C.; Salamone, S. J. Bioorg. Med. Chem. Lett. 2003, 13,
383.
33. Tris-HOPO 18. Mp 60–65 °C; IR (KBr) 3391, 1651, 1550 cmꢁ1
;
1H NMR
1.81–1.91 (m, 6H), 2.67 (t, J = 6.45 Hz, 6H), 3.13 (t,
(300 MHz, D2O)
d
19. Arumugam, J.; Brown, H. A.; Jacobs, H. K.; Gopalan, A. S. Synthesis 2011, 57.
20. Synthesis of HOPO vinylsulfonamide 3: 2-Chloroethanesulfonyl chloride (0.242 g,
1.49 mmol) was added to a solution of triethylamine (0.46 mL, 4.46 mmol) and
HOPO amine 2 (0.461 g, 1.78 mmol) in dichloromethane (6 mL) at rt and the
solution stirred for 5 h. The reaction mixture was diluted with
dichloromethane (20 mL) and washed with 1 M HCl (10 mL), saturated
J = 6.75 Hz, 6H), 3.39–3.44 (m, 18H), 3.94 (t, J = 7.05 Hz, 6H), 6.29 (t,
J = 7.32 Hz, 3H), 6.91 (dd, J = 1.77, 7.62 Hz, 3H), 7.09 (dd, J = 1.77, 7.05 Hz,
3H); 13C NMR (50 MHz, D2O) d 27.8, 29.6, 36.5, 47.6, 49.3, 53.2, 108.4, 118.3,
129.0, 145.3, 158.1, 172.7. Anal. Calcd for C39H57N9Oꢂ5HBr: C, 39.02; H, 5.21; N,
10.50. Found: C, 39.18; H, 5.44; N, 10.32.