Substituent effects on the reactivity of benzo-1,2-dithiolan-3-one 1-oxides and their possible application to the synthesis of DNA-targeting drugs

Article abstract of DOI:10.1021/jo0508191

The efficiency of polysulfane product generation has been investigated for n-propyl thiol reactions with ortho- and para-substituted benzo-1,2-dithiolan-3- one 1-oxides in acetonitrile-water (7:3) mixtures. The reaction is facilitated by reducing the electron density at the para position or by placing substituents bearing lone pair electrons ortho to the dithiolanone-oxide (S1) reaction center. Through-space and through-bond effects both contribute to the conversion of polysulfane products.

Full text of DOI:10.1021/jo0508191

SCHEME 1
Substituent Effects on the Reactivity of
Benzo-1,2-dithiolan-3-one 1-Oxides and
Their Possible Application to the Synthesis
of DNA-Targeting Drugs
Nahed Sawwan, Edyta M. Brzostowska, and
Alexander Greer*
Department of Chemistry, Graduate Center & The City
University of New York (CUNY), Brooklyn College,
Brooklyn, New York 11210
SCHEME 2a
agreer@brooklyn.cuny.edu
Received April 22, 2005
a Reagents and conditions: (a) HCl, NaNO2, 5 °C. (b) (i) Na2S,
elemental S8, NaOH, 5 °C; (ii) Zn, glacial CH3CO2H, reflux, 48 h.
(c) H2SO4, CH3COSH, 24 °C, 15 min. (d) dimethyldioxirane, 0 °C,
2 h, 20-30%.
The efficiency of polysulfane product generation has been
investigated for n-propyl thiol reactions with ortho- and
para-substituted benzo-1,2-dithiolan-3-one 1-oxides in ac-
etonitrile-water (7:3) mixtures. The reaction is facilitated
by reducing the electron density at the para position or by
placing substituents bearing lone pair electrons ortho to the
dithiolanone-oxide (S1) reaction center. Through-space and
through-bond effects both contribute to the conversion of
polysulfane products.
initial attack of thiol or another nucleophile onto the
dithiolanone-oxide ring system.14-16 A structure-activity
study in which the structure of the benzene core of 1 is
varied by introduction of substituents may provide
insight into the factors influencing the thiol reaction with
dithiolanone-oxide drugs. We have examined ortho- [X
) Cl (3), CH3 (4), OCH3 (5)] and para-substituted [Y )
Cl (6), CH3 (7), OCH3 (8)] 1,2-dithiolan-3-one 1-oxides
that contain different substituent groups, which also
differ in being nearer to or farther from the sulfinate
sulfur (S1) (Scheme 2). The ortho and para positions are
relative to the sulfinyl sulfur (S1) and refer to the 3- and
5-positions of the fused benzene ring.
Benzo-1,2-dithiolan-3-one 1-oxide (1) contains a thio-
sulfinate ester heterocycle1 and possesses DNA-cleaving
activity, albeit reduced, compared to the natural product
leinamycin (2) (Scheme 1).2-5 DNA-cleaving activity2-5
and antitumor activity6-13 of leinamycin 2 and other
dithiolanone-oxide compounds are thought to arise by an
Preparation of dithiolanone-oxides 1 and 3-8 is shown
in Scheme 2 where a modification of the method of
Beaucage et al.17 was used. Treatment of a 3- or 5-sub-
stituted anthranilic acid with NaNO2 yielded the diazo
compound. Sodium sulfide and elemental sulfur were
added to the diazo compound to give the dithiosalicylic
acid derivative and, after reduction, thiolsalicylic acid.
Thiolacetic acid was then added to the thiosalicylic acid,
which after oxidation with dimethyldioxirane gave the
substituted benzodithiolanone-oxides 3-8 in 20-30%
yield (Scheme 2). The synthetic method gave higher
yields with structures possessing the methyl (30%) or
methoxy groups (25%) compared to the chloro substituent
* To whom correspondence should be addressed.
(1) Behroozi, S. J.; Kim, W., Gates, K. S. J. Org. Chem. 1995, 60,
3964-3966.
(2) Behroozi, S. J.; Kim, W.; Dannaldson, J.; Gates, K. S. Biochem-
istry 1996, 5, 1768-1774.
(3) Hara, M.; Saitoh, Y.; Nakano, H. Biochemistry 1990, 29, 5676-
56.
(4) Mitra, K.; Kim, W.; Daniels, J. S.; Gates, K. S. J. Am. Chem.
Soc. 1997, 119, 11691-11692.
(5) Gates, K. S. Chem. Res. Toxicol. 2000, 13, 953-956.
(6) Kanda, Y.; Ashizawa, T.; Saitoh, Y.; Saito, H.; Gomi, K.; Okabe,
M. Bioorg. Med. Chem. Lett. 1998, 8, 909-912.
(7) Lee, A. H. F.; Chan, A. S. C.; Li, T. Tetrahedron 2003, 59, 833-
839.
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Yoshida, M.; Saitoh, Y., Okabe, M. J. Med. Chem. 1999, 42, 1330-
1332.
(9) Ashizawa, T.; Kawashima, K.; Kanda, Y.; Gomi, K.; Okabe, M.;
Ueda, K.; Tamaoki, T. Anti-Cancer Drugs 1999, 10, 829-836.
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H.; Saitoh, Y. J. Am. Chem. Soc. 1996, 118, 6802-6803.
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T.; Gates, K. S. J. Am. Chem. Soc. 2003, 125, 4996-4997.
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Bioorg. Med. Chem. Lett. 2001, 11, 1511-1515.
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(16) Breydo, L.; Zang, H.; Mitra, K.; Gates, K. S. J. Am. Chem. Soc.
2001, 123, 2060-2061.
(17) Iyer, R. P.; Phillips, L. R.; Egan, W.; Regan, J. B.; Beaucage, S.
L. J. Org. Chem. 1990, 55, 4693-4699.
10.1021/jo0508191 CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/20/2005
6968
J. Org. Chem. 2005, 70, 6968-6971

TABLE 1. Efficiency of Polysulfane Product Generation (%) Measured for Propyl Thiol Reactions with Substituted
Dithiolanone-oxides 1 and 3-8 by NMR Spectroscopy
a Reaction of compound 1 and ortho- [X ) Cl (3), CH3 (4), OCH3 (5)] and para-substituted [Y ) Cl (6), CH3 (7), OCH3 (8)] 1,2-dithiolan-
3-one 1-oxides (10 mM) was carried out in the presence of n-PrSH (20-40 mM) in 70% CD3CN-30% D2O. b Relative yields determined
by 1H NMR after 15 min at 25 °C are the average of two runs (see Experimental Section). c Ortho or para substituent positions are
relative to the sulfinate sulfur (S1) of compounds 1 and 3-8.
TABLE 2. Relationship between the CD3CN-D2O Ratio
(20%). A likely reason is that the generation of the diazo
for the Reaction of Substituted
group should depend on electron donation to add stabil-
ity. Compounds 3-8 were synthesized and characterized
as described in Experimental Section.18 The known
dithiolanone-oxide 11 was prepared by oxidation of com-
mercially available 3H-1,2-benzodithiolan-3-one with
dimethyldioxirane.
Experiments to analyze the substituent effect were
collected for the reaction of 1 and 3-8 with n-propyl thiol
in a mixture of CD3CN and D2O (Table 1). Thiol was
added to 1 and 3-8 in acetonitrile-water (7:3) mixtures.
We find that 3 decomposes in the presence of thiol with
an 83% conversion, while 7 decomposes to thiol with a
7% conversion. The lower yield of products is caused by
a lower rate, not by other reactions. We selected the
CD3CN-D2O (7:3) mixture for the study because it gave
rates such that, after 15 min, products arose in different
overall yields and the reactivity and substituent effect
could be assessed. No reaction takes place between 1,3-8
and n-PrSH over a 3 day period in CD3CN alone (entry
Benzodithiolanone-oxides 1 and 3-8 with n-Propyl
Thiola
entry CD3CN-D2O
comment
1
2
3
4
1:0
8:2
7:3
1:10
no reaction (after 3 days)
12 h to reach approximately 50% conversion
2 h to reach approximately 50% conversion
minutes to reach 100% conversion
a Perfomed with 10 mM 1 and 3-8 and 30 mM n-PrSH.
1, Table 2). The reaction rate increases upon increasing
the D2O content in CD3CN (entries 2-4) since the acidity
of n-PrSH is enhanced where n-PrS- ion can act as a
nucleophile; however, substrate solubility becomes a
problem at CD3CN-D2O 1:10 (entry 4).
The nature of the solvent dependence constraining
reductive thiol activation reported here may be of im-
portance for dithiolanone-oxide compounds capable of
noncovalently associating with DNA.19-21 The structure
of thiol may also play an important role in the activity
of dithiolanone-oxide drugs.22,23 Control experiments
show that the above dithiolanone-oxide decomposition is
a thiol-dependent process. There is no reaction of the
benzodithiolanone-oxides in the CD3CN-D2O (7:3) mix-
ture over 2 h in the absence of thiol. Each dithiolanone-
oxide (1 and 3-8)/n-PrSH reaction forms at least five
products (Table 1), which are similar to the product
distribution observed previously by Gates and co-workers
for the reaction of 1 with n-PrSH.1
(18) Synthetic and biosynthetic processes leading to dithiolanone-
oxide and related compounds have been reported. (a) Pattenden, G.;
Shuker, A. J. Tetrahedron Lett. 1991, 32, 6625-6628. (b) Pattenden,
G.; Shuker, A. J. J. Chem. Soc., Perkin Trans. 1 1992, 1215-1221. (c)
Kanda, Y.; Fukuyama, T. J. Am. Chem. Soc. 1993, 115, 8451-8452.
(d) Glass, R. S.; Liu, Y. Tetrahedron Lett. 1994, 35, 3887-3888. (e)
Marchan, V.; Gilbert, M.; Messeguer, A.; Pedroso, E.; Grandas, A.
Synthesis 1999, 43-45. (f) Cheng, Y. Q.; Tang, G.-L.; Shen, B. J.
Bacteriol. 2002, 184, 7013-7024. (g) Pattenden, G.; Sinclair, D. J. J.
Organomet. Chem. 2002, 653, 261-268. (h) Cheng, Y. O.; Tang, G.-L.;
Shen, B. Proc. Nat. Acad. Sci. 2003, 100, 3149-3154. (i) Du, L.; Chen,
M.; Zhang, Y.; Shen, B. Biochemistry 2003, 42, 9731-9740. (j) Lee, A.
H. F.; Chan, A. S. C.; Li, T. Tetrahedron 2003, 59, 833-839. (k) Salvetti,
R.; Martinetti, G.; Ubiali, D.; Pregnolato, M.; Pagani, G. Farmaco 2003,
58, 995-998. (l) Lee, A. H. F.; Chen, J.; Chan, A. S. C.; Li, T.
Phosphorus Sulfur Silicon Relat. Elem. 2003, 178, 1163-1174. (m)
Gargadennec, S.; Legouin, B.; Burgot, J.-L. Phosphorus Sulfur Silicon
Relat. Elem. 2003, 178, 1721-1726. (n) Garcia-Valverde, M.; Pascual,
R.; Torroba, T. Org. Lett. 2003, 5, 929-932. (o) Hutchinson, C. R. Proc.
Nat. Acad. Sci. 2003, 100, 3010-3012. (p) Tang, G.-L.; Cheng, Y.-Q.;
Shen, B. Chem. Biol. 2004, 11, 35-45. (q) Barriga, S.; Fuertes, P.;
Marcos, C. F.; Torroba, T. J. Org. Chem. 2004, 69, 3672-3682. (r)
Szila´gyi, A.; Pelyva´s, I. F.; Majercsik, O.; Herczegh, P. Tetrahedron
Lett. 2004, 45, 4307-4309. (s) Bentley, R. Chem. Soc. Rev. 2005, 34,
609-624.
The polysulfane products observed are proposed to
arise from the interconversion of sulfenic acid (A) and
(19) Galm, U.; Hager, M. H.; Van Lanen, S. G.; Ju, J.; Thorson, J.
S.; Shen, B. Chem. Rev. 2005, 105, 739-758.
(20) Paz, M. M.; Das, A.; Palom, Y.; He, Q.-Y.; Tomasz, M. J. Med.
Chem. 2001, 44, 2834-2842.
(21) Lopez-Larraza, D. M.; Moore, K., Jr.; Dedon, P. C. Chem. Res.
Toxicol. 2001, 14, 528-535.
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41, 897-905.
J. Org. Chem, Vol. 70, No. 17, 2005 6969

SCHEME 3
TABLE 3. Calculated Structural Parameters for Substituted Benzo-1,2-dithiolan-3-one 1-Oxides (1 and 3-8)a,b
substituent
NBO charges
S2
X
Y
S1-S2
S1-O1
C1-S2
S2-S1-O1
θc
S1
O
1
3
4
5
6
7
8
H
H
2.215
2.213
2.202
2.218
2.217
2.217
2.222
1.497
1.493
1.499
1.495
1.496
1.497
1.497
1.822
1.815
1.821
1.817
1.819
1.822
1.818
113.1
110.9
111.9
111.1
113.1
113.1
113.1
113.1
104.7
110.1
105.9
113.2
112.9
112.9
1.150
1.155
1.138
1.159
1.154
1.150
1.153
0.007
0.020
0.016
0.005
0.017
0.004
0.007
-0.862
-0.853
-0.874
-0.862
-0.859
-0.863
-0.863
Cl
H
Me
OMe
H
H
H
H
H
Cl
Me
OMe
a Structures optimized at the B3LYP/6-31G(d) level. b Distances in Å, angles in degrees. c Dihedral angle θ ) O1-S1-S2-C1 is positive
for a clockwise movement from O1 to C1 as you look down from S1 to S2.
oxathiolane species (B) on the reaction surface (Scheme
3). A similar mechanism has been proposed previously
by Gates and co-workers for compound 1.1 Compounds
A and B are unstable intermediates and are not detected
directly in the reaction. Electrophilic oxathiolane B can
potentially undergo a reaction with PrS- or PrSS- to give
rise to 3- or 5-substituted 2-propyldisulfuranyl benzoic
acid (C) and 3- or 5-substituted 2-propyltrisulfuranyl
benzoic acid (D), respectively. Equilibrium and exchange
processes may also contribute to the production of C and
D. The reactive byproduct hydrodisulfide (PrSSH) will
likely undergo reactions in the presence of PrSH and O2
to account for formation of polysulfanes [di-n-propyl-
disulfane (E), di-n-propyl-trisulfane (F), and di-n-propyl-
tetrasulfane (G)]. Similar thiol-disulfide equilibria (redox)
processes have been observed in biological systems.24
A possible through-space effect emerges25 with sub-
stituents bearing lone pair electrons positioned near the
dithiolanone-oxide sulfinate sulfur (S1). ortho-Chloro- (3)
and -methoxy-substituted dithiolanone-oxides (5) yield
higher concentrations of polysulfane products (C-G)
compared to 1, 4, 7, and 8, which may be explained by
intramolecular S1-Cl or S1-O(methoxy) dipole-dipole in-
teractions that enhance the ease of ring opening of the
heterocycle. According to B3LYP/6-31G(d) calculations,
the 1,4-S-X interaction (X ) Cl, OMe) influences the
structure of dithiolanone-oxide 3 and 5 (Table 3). The
calculated S2-S1-O1 bond angle in 3 (110.9°) and 5
(111.1°) is less than that in other dithiolanone-oxides 1
(113.1°), 4 (111.9°), 6 (113.1°), 7 (113.1°), and 8 (113.1°).26
The 1,4-S-X interaction [X ) Cl (3), OMe (5)] influences
the S1-O1 and C1-S2 bond distances but has little or
no effect on the S1-S2 bond distance. We observe
decreases in the S1-O1 and C1-S2 bond distance when
comparing 3 and 5 with 1, 4, and 6-8. The S-X
interaction also influences the calculated dihedral angle
(θ ) O1-S1-S2-C1). The torsion angle θ in 3 (104.7°)
(25) Through-space effects to perturb the reactivity of chalcogen
centers have been reported: (a) Burling, F. T.; Goldstein, B. M. J. Am.
Chem. Soc. 1992, 114, 2313-2320. (b) Nagao, Y.; Hirata T.; Goto, S.;
Sano, S.; Kakehi, A.; Iizuka, K.; Shiro, M. J. Am. Chem. Soc. 1998,
120, 3104-3110. (c) Iwaoka, M.; Takemoto, S.; Okada, M.; Tomoda, S.
Chem. Lett. 2001, 2, 132-133. (d) Iwaoka, M.; Takemoto, S.; Okada,
M.; Tomoda, S. Bull. Chem. Soc. Jpn. 2002, 75, 1611-1625. (e) Iwaoka,
M.; Katsuda, T.; Tomoda, S.; Harada, J., Ogawa, K. Chem. Lett. 2002,
5, 518-519. (f) Iwaoka, M.; Takemoto, S.; Tomoda, S. J. Am. Chem.
Soc. 2002, 124, 10613-10620. (g) Iwaoka, M.; Komatsu, H.; Katsuda,
T.; Tomoda, S. J. Am. Chem. Soc. 2004, 126, 5309-5317. (h) Leriche,
P.; Turbiez, M.; Monroche, V.; Fre`re, P.; Blanchard, P.; Skabara, P.
J.; Roncali, J. Tetrahedron Lett. 2003, 44, 649-652. (i) Wu, S.; Greer,
A. J. Org. Chem. 2000, 65, 4883-4887. (j) Reznik, R.; Greer, A. Chem.
Res. Toxicol. 2000, 13, 1193-1198. (k) Scho¨neich, C.; Pogocki, D.;
Wisniowski, P.; Hug, G. L.; Bobrowski, K. J. Am. Chem. Soc. 2000,
122, 10224-10225. (l) Pogocki, D.; Scho¨neich, C. J. Org. Chem. 2002,
67, 1526-1535. (m) Scho¨neich, C.; Pogocki, D.; Hug, G. L.; Bobrowski,
K. J. Am. Chem. Soc. 2003, 125, 13700-13713. (n) Bobrowski, K.; Hug,
G. L.; Marciniak, B.; Miller, B.; Scho¨neich, C. J. Am. Chem. Soc. 1997,
119, 8000-8011. (o) Pogocki, D.; Serdiuk, K.; Scho¨neich, C. J. Phys.
Chem. A. 2003, 107, 7032-7042.
(23) Wolkenberg, S. E.; Boger, D. L. Chem. Rev. 2002, 102, 2477-
2496.
(24) Buckberry, L. D.; Teesdale-Spittle, P. H. Sulfur-Hydrogen
Compounds in Biological Interactions of Sulfur Compounds; Mitchel,
S., Ed.; Taylor & Francis; London, 1996; pp 113-144.
(26) Calculated features of benzodithiolanone-oxide 1 compare well
with those obtained from its X-ray structure. Behroozi, S. J.; Barnes,
C. L.; Gates, K. S. J. Chem. Crystallogr. 1998, 28, 689-91.
6970 J. Org. Chem., Vol. 70, No. 17, 2005

Magna FI-IR 760 spectrometer. UV data were collected on a
Hitachi V-2001 spectrometer.
and 5 (105.9°) is reduced compared with that in 1
(113.1°), 4 (110.1°), 6 (113.2°), 7 (112.9°), and 8 (112.9°).
The para-chloro substituent in 6 yielded an unexpected
influence on product generation. A reason for the en-
hanced reactivity of 6 is a suggested thiol attack at S2,
which should depend on electron-withdrawing through-
bond effects in ortho or para positions to enhance
reactivity. There is a small reduction of electron density
at S2 when comparing the NBO positive charge in 3
(0.020) and 6 (0.017) with that in compounds 1 (0.007),
4 (0.016), 5 (0.005), 7 (0.004), and 8 (0.007) (Table 3). We
believe that the destabilizing substitution of chlorine in
the ortho or para position accounts for the increase in
the rate of thiol activation. Finally, a chemical conse-
quence from the perturbation of the sulfinyl center in 3
could be accounted for by combined through-space S-Cl
interaction and an electron-withdrawing substituent
effect responsible for increased product formation (Table
1). This is shown in 3, where unlike others in the series,
the through-bond and through-space effects both con-
tribute in the same direction to product conversion.
In conclusion, mechanistic evidence points to an elec-
tron-withdrawing chlorine substituent in the para posi-
tion or a neighboring group interaction involving lone
pair electrons on methoxy or chlorine substituents as
factors that enhance benzodithiolanone-oxide reactivity
toward thiol. Successful attempts to quantify substituent
effects have been made using an acetonitrile-water 7:3
solvent mixture, but up to now the only substrates
considered have had limited water solubility. The rela-
tionship between the substituent effect in thiol activation
of the dithiolanone-oxide heterocycle may be dramatic in
vivo because of substrate-DNA noncovalent associations
where dipolar aprotic and aqueous solvent environments
are both contributors. Using remote and nearby func-
tional groups as a mechanistic tool enables one to bias
the yield of the polysulfane products C-G. Polysulfane
autoxidation and subsequent Fenton chemistry can take
place. Oxygen radicals such as OH radical are produced
in a trace metal-dependent Fenton reaction previously
reported for the oxidative DNA cleavage by the antitumor
antibiotic leinamycin and synthetic dithiolanone-oxide
analogues.2,4,5,27,28 However, unlike compounds 1 and 3-8,
leinamycin 2 can also act as a DNA-alkylating agent
because of an intramolecular reaction of an alkene moiety
on the oxathiolane heterocycle.6,8,9,11-13,16,29
Dithiolanone-oxide Synthesis. The synthesis involved
adding a 3- or 5-substituted anthranilic acid (6.6 mmol) to a 4
mL water solution of 2 mL of concentrated HCl and NaNO2 (6.6
mmol) at 5 °C to generate the diazo compound. A separate
solution was prepared by mixing Na2S (7.3 mmol) with elemental
sulfur (7.3 mmol) at 24 °C, which was heated and made alkaline
by the addition of 10 M NaOH. Mixing the two solutions resulted
in a precipitate upon addition of HCl. The sulfurization gave
the dithiosalicylic acid derivative, which after purification was
then mixed and Zn dust in glacial acetic acid and refluxed,
yielding thiolsalicylic acid. Thiolacetic acid (0.110 mol) was
added to thiosalicyclic acid (0.005 mol) in concentrated H2SO4
at 24 °C. Oxidations of the benzo-substituted dithiolanone-oxides
were carried out with dimethyldioxirane.
Reaction of Thiol with Substituted Dithiolanone-
oxides. Reactions of 1 and 3-8 (10 mM) were carried out in
the presence of n-PrSH (20-40 mM) in 70% CD3CN-30% D2O.
The volume of the reaction mixture was 5 or 10 mL, and the
internal standard was 1,3,5-trimethoxybenzene (4 mM). The
percent yield of products was determined after 15 min at 25 °C.
Reaction of 3 or 5 with n-propyl thiol in a CD3CN-D2O (1:10)
solvent mixture gave products too rapidly to discern a possible
substituent effect by NMR spectroscopy. 1H NMR data on the
dithiolanone-oxide (1, 3-8)-n-PrSH reaction provided evidence
for the formation of unsymmetrical and symmetrical sulfane
products similar to that observed previously by Gates for the
1-n-PrSH reaction.1 The assignment of unsymmetrical products
[3- or 5-substituted-2-propyl disulfanyl benzoic acid (C) and 3-
or 5-substituted-2-propyl trisulfanyl benzoic acid (D)] is based
on two sets of triplets; a downfield set at about δ 2.8 ppm (2H,
SCH2) and a downfield set at about δ 2.9 ppm (2H, SCH2),
respectively. The chemical shifts for â-methylene and methyl
protons are often obscured by reagent peaks. Downfield chemical
shifts of polysulfane neighboring protons with higher numbers
of sulfur atoms have been reported previously.30-32 In the case
for the reaction of 1 with n-PrSH, we utilized GC/MS data of
the polysulfane mixture to corroborate this method of analysis
by 1H NMR spectroscopy. The percent yields of C and D were
determined by analysis of products in the respective reaction
mixtures.
Acknowledgment. We thank Cliff Soll of the Hunter
College Mass Spectrometry Facility for help in deter-
mining the masses of some of the compounds and
Edlaine Lucien for synthetic work conducted in an early
phase of the project. The City University of New York
and PSC-CUNY provided financial support for this
work. We wish to dedicate this paper to the late
Professor Christopher S. Foote (1935-2005) who was
as an inspirational figure to us.
Experimental Section
Supporting Information Available: Characterization
data for 1, 3-8, 3C-8C, 3D-8D, and E-G and computational
data for 1 and 3-8. This material is available free of charge
via the Internet at http://pubs.acs.org.
Materials and Instrumentation. Reagents and solvents
[2-amino-3-methylbenzoic acid, 2-amino-3-methoxybenzoic acid,
2-amino-3-chlorobenzoic acid, 2-amino-5-methylbenzoic acid,
2-amino-5-chlorobenzoic acid, 2-amino-5-methoxybenzoic acid,
1,3,5-trimethoxybenzene, sodium nitrate, sodium sulfide, el-
emental sulfur (S8), sodium hydroxide, sodium bicarbonate, zinc
dust, hydrochloric acid solution (12 M), sulfuric acid solution (1
M), glacial acetic acid, thiolacetic acid, magnesium sulfate,
potassium bromide, acetone, ethanol, CHCl3, CDCl3, CH3CN,
CD3CN, hexane, propyl thiol] were obtained commercially and
used as received. Proton and carbon NMR data were acquired
on a Bruker 400 MHz NMR spectrometer. Mass spectrometry
data were collected on one of two GC/MS instruments, a Hewlett-
Packard GC/MS instrument consisting of a 6890 series GC and
a 5973N series mass selective detector, or a Hewlett-Packard
GC/MS instrument consisting of a 5890 series GC and a 5988A
series mass selective detector. IR data were collected on a Nicolet
JO0508191
(27) Burrows, C. J.; Muller, J. G. Chem. Rev. 1998, 98, 1109-1152.
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