Convenient synthesis of 5-aryl(alkyl)sulfanyl-1,10-phenanthrolines from 5,6-epoxy-5,6-dihydro-1,10-phenanthroline, and their activity towards fungal β-d-glycosidases

Article abstract of DOI:10.1016/j.tet.2011.07.058

A broad series of novel 5-aryl(alkyl)sulfanyl-1,10-phenanthrolines has been prepared by a new simple procedure: a treatment of the commercially available 5,6-epoxy-5,6-dihydro-1,10-phenanthroline with various thiols in the presence of a base. Other functional groups attached to the thiol allow a use of the products as building blocks in synthesis of versatile ligands and in functionalization of surfaces. The synthesized phenanthrolines showed a moderate ability as activators or inhibitors of fungal β-d-glucosidases and β-d-galactosidases.

Full text of DOI:10.1016/j.tet.2011.07.058

Tetrahedron 67 (2011) 7470e7478
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Convenient synthesis of 5-aryl(alkyl)sulfanyl-1,10-phenanthrolines from
5,6-epoxy-5,6-dihydro-1,10-phenanthroline, and their activity towards fungal
b- -glycosidases
D
*
Irina A. Dotsenko, Matthew Curtis, Nataliya M. Samoshina, Vyacheslav V. Samoshin
Department of Chemistry, University of the Pacific, 3601 Pacific Avenue, Stockton, CA 95211, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 June 2011
Received in revised form 12 July 2011
Accepted 20 July 2011
Available online 28 July 2011
A broad series of novel 5-aryl(alkyl)sulfanyl-1,10-phenanthrolines has been prepared by a new simple
procedure: a treatment of the commercially available 5,6-epoxy-5,6-dihydro-1,10-phenanthroline with
various thiols in the presence of a base. Other functional groups attached to the thiol allow a use of the
products as building blocks in synthesis of versatile ligands and in functionalization of surfaces. The
synthesized phenanthrolines showed a moderate ability as activators or inhibitors of fungal
sidases and -galactosidases.
b-D-gluco-
b-D
Keywords:
1,10-Phenanthroline
Ó 2011 Elsevier Ltd. All rights reserved.
Base-induced aromatization
Glycosidase activators/inhibitors
Epoxide deoxygenation
1. Introduction
and also easy to prepare in good yield by treatment of phen with
bleach.5,11,12
1,10-Phenanthroline (phen) is a classic chelating ligand for
transition metal ions, one of the most widely used ligands in
modern coordination chemistry.1e4 Phen derivatives with a pen-
dant arm containing functional group(s) are of special importance
for organic, inorganic and supramolecular chemistry as versatile
starting materials or building blocks for construction of complex
ligands with a variety of applications1e3 and for immobilization
onto/into support matrixes.1 A large number of phen derivatives
have been synthesized including some 5-substituted phens with
nitrogen, oxygen and carbon-based substituents.5 However, only
a few compounds were obtained with RS-groups at position 5 via
a nucleophilic substitution in 5-chloro-phen6 and in its Ru(II)
complexes,7,8 and at positions 5,6 via a palladium catalyzed cross-
coupling reaction in 5,6-dibromo-phen.9,10 The halogen de-
rivatives had to be prepared first from phen by a harsh treatment
(e.g., with Br2 in oleum10).
2. Results and discussion
Studying reaction of epoxide 1 with various thiols RSH in
presence of base, we found that the desired products of epoxide
cleavage (2) were difficult to isolate. They dehydrated easily in mild
conditions, and were completely or almost completely converted
into 5-aryl(alkyl)sulfanyl-1,10-phenanthroline derivatives (3e24)
by the time when the starting epoxide was consumed (Scheme 1,
Table 1). Similar results were obtained with commercially available
thiolates (products 18, 25 and 26).
Apparently, aromatization of the central ring is a driving force
for this elimination. Similar spontaneous dehydration was ob-
served when epoxide 1 reacted with KCN in water.5 However, de-
hydration of 5-methoxy- or 5-dialkylamino analogues of 2 was
achieved only by additional heating in the presence of a strong
base, such as NaH.5 The products of epoxide 1 cleavage with aro-
matic amines in presence of excess magnesium perchlorate did not
dehydrate even when refluxed in acetonitrile.4,13 On the contrary,
we did not have to apply harsh conditions or additional reagents for
preparation of sulfides 3e26, although moderate heating was
sometimes helpful (Table 1).
We suggest a simple, mild and inexpensive one-step synthesis
of 5-aryl(alkyl)sulfanyl-1,10-phenanthrolines with a variety of
possible aryl/alkyl groups starting with 5,6-epoxy-5,6-dihydro-
1,10-phenanthroline (1), which is commercially available (Aldrich)
Although simple, the synthesis of phen derivatives 3e26 may
require some tuning depending on the nature of the thiol (see
Experimental). For instance, the conditions suitable for preparation
* Corresponding author. Tel.: þ1 209 9462921; fax: þ1 209 9462607; e-mail
address: vsamoshin@pacific.edu (V.V. Samoshin).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.058

I.A. Dotsenko et al. / Tetrahedron 67 (2011) 7470e7478
7471
of compounds 3e17 (method A) yielded inseparable mixtures of
products when applied to dithiols. Therefore to obtain the
bis(phen) derivatives 19e24, we used a slow addition of a diluted
dithiol solution in ethanolic NaOEt to the concentrated solution of
epoxide 1 at elevated temperature under argon atmosphere
(method B). In another example, the use of Li2S instead Na2S im-
proved substantially the yield and purity of product 25. We found
also that variation of solvent (simple alcohols) may be beneficial for
the synthesis.
Noteworthy, the bis(phen) 22 was synthesized before, but in
a form of a binuclear complex with ruthenium(II), via substitution
in a ruthenium(II) complex of 5-chloro-phen.7 The simple synthesis
of the free bis-phenanthrolines 19e25 described here may be in-
strumental in preparation of other mono/binuclear complexes and
molecular assemblies.14,15
Synthesis of phen derivatives of cysteine was attempted starting
with
L-cysteine methyl ester hydrochloride or N-(tert-butox-
ycarbonyl)-L-cysteine methyl ester, but the reactions produced only
inseparable mixtures of products. A successful attachment of the
cysteine moiety to phen was achieved previously by substitution in
a ruthenium(II) complex of 5-chloro-phen.8
Unexpectedly, a deoxygenation occurred in the reaction of ep-
oxide 1 with a slight excess of sodium hydrosulfide at room tem-
perature (the conditions for synthesis of 2-mercaptoalcohols16),
Scheme 1. Syntheses of 5-aryl(alkyl)sulfanyl-1,10-phenanthrolines.
Table 1
Synthesis of 5-RS-1,10-phenanthrolines 3e26
Product
Structure
Method
A
Time (h)
10
Temp (ꢀC)
Yield (%)
79
3
50
4
5
A
A
15
24
50
60
93
80
6
7
8
9
A
12
10
3
20
50
60
20
78
71
63
A
d
A
6
83
(continued on next page)

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I.A. Dotsenko et al. / Tetrahedron 67 (2011) 7470e7478
Table 1 (continued )
Product
Structure
Method
Time (h)
12
Temp (ꢀC)
Yield (%)
93
10
11
12
13
14
A
A
A
A
A
20
24
22
60
60
22
88
97
83
79
1
12
16
15
16
17
A
A
A
36
36
24
60
60
60
72
85
81
4
þ10
60
20
18
d
70
19
B
3
60
70

I.A. Dotsenko et al. / Tetrahedron 67 (2011) 7470e7478
7473
Table 1 (continued )
Product
Structure
Method
Time (h)
Temp (ꢀC)
Yield (%)
20
21
22
B
B
B
4
78
73
91
50
24
50
22
2
23
24
B
B
12
24
50
22
54
62
25
d
3
60
82
26
d
36
22
64
which yielded phen as the only isolated product (Scheme 2). The
same result was observed in the reaction with trithiocyanuric acid
trisodium salt both at low (5 ꢀC) and at high (60 ꢀC) temperature. We
obtained phen as a major product also in the reaction of epoxide 1
with thiourea in the standard conditions for preparation of thiir-
anes17 (Scheme 2). A plausible mechanism for the deoxygenation
may include formation and subsequent desulfurization of a thiirane.
Each of these transformations is well known.17e19 Aryl thiiranes
were shown to split off elemental sulfur simply on heating with
conversion to the corresponding olefins.17 The easy desulfurization
at room temperature that we found (Scheme 2) was apparently
stimulated by the aromatization of the central ring as in the case of
reactions described above. These observations may be of interest for
further research, because epoxides are used as protecting groups for
alkene double bonds, and their deprotection (deoxygenation) is
a useful tool in organic synthesis.19,20
Scheme 2. Deoxygenation of 5,6-epoxy-5,6-dihydro-1,10-phenanthroline 1.

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I.A. Dotsenko et al. / Tetrahedron 67 (2011) 7470e7478
Thioglycosides are known to be weak to moderate glycosidase
derivatives 13e17 and bis(phens) 20e22 had weaker and non-
systematic effects. To the best of our knowledge, an activation of
glycosidases by phen or its derivatives was never observed before.
Thus, our preliminary findings deserve further investigation.
inhibitors by beingnonhydrolyzable substrateanalogues, and assuch
theyare potential therapeutic compounds in thetreatmentof various
pathologies.21e24 Thereforewe assayedthenew
b-D-thioglucoside 26
as a possible b-D-glucosidase inhibitor by spectrophotometric mon-
itoring (at 400 nm) of the p-nitrophenol release from the corre-
sponding p-nitrophenyl glycosides according to procedures
described earlier.25,26 Indeed, the compound 26 (1 mM) decreased
3. Conclusion
We found that the nucleophilic cleavage of 1,10-phenanthroline
5,6-oxide 1 by various thiolates is immediately followed by spon-
taneous dehydration (aromatization). Based on this result, a novel
convenient approach has been developed to a variety of function-
alized 5-aryl(alkyl)sulfanyl-1,10-phenanthrolines that can be used
as building blocks and ligands in organic and inorganic synthesis.
The obtained compounds demonstrated an ability to activate or
the activity of
and Penicilliumcanescensby 75% and77%, respectively. Thusitmay be
considered as a moderately strong -glucosidase inhibitor. At the
same time it increased the activity of -galactosidases by 58% (A.
b-D-glucosidases isolated from fungi Aspergillus oryzae
b-D
b-D
oryzae) and 40% (P. canescens). Intrigued by this result we assayed
phen and several derivatives for a possible activity towards glycosi-
dases and found many cases of marked activation or inhibition of
enzymes (Fig. 1). Usually the glycosidase activity is not significantly
altered by the metal ionchelatorslike EDTA and 1,10-phenanthroline,
because these enzymes are not metalloenzymes.27e29 We found only
inhibit fungal b-D-glycosidases.
4. Experimental
4.1. General
two reports on inhibition by phen of some
Pediococcus sp.30 and A. oryzae31). According to our data, phen had an
opposite effect on -galactosidase from A. oryzae: it increased the
b-D-galactosidases (from
b-D
The chemicals used in this study were purchased from com-
mercial sources and used without additional purification. The ep-
oxide 1 was obtained from Aldrich. All solvents were purified by
conventional techniques prior to use. Column chromatography was
hydrolytic activity of this enzyme by a factor of two. The activation
turned out to be more common for these compounds than the in-
hibition, especially towards
b-D-glucosidases, for which only
b-D-
thioglucoside 26 was an inhibitor (Fig.1a). The effect on activity of
b
-
performed on silica gel (40e75 mm, Sorbent Technologies) and alu-
ꢀ
D-galactosidases appeared to be substituent-dependent (Fig. 1b).
minium oxide (activated basic, 58 A, Aldrich). The reactions were
monitored by TLC (silica gel or alumina, 8ꢁ2 cm plates with UV-
indicator (254 nm), Analtech Inc.). 1H NMR and 13C NMR spectra
were acquired on JEOL ECA-600 NMR-spectrometer (600 MHz for 1H
and 150 MHz for 13C). COSY and HMQC techniques were used to
assign the signals. High resolution mass spectra (HRMS) were
obtained on a JEOL AccuTOF time-of-flight mass spectrometer
(Peabody, MA) coupled with an Ionsense DART open-air ionization
source (Saugus, MA). The instrument was tuned to a resolving power
of 7000 with reserpine directly infused into the electrospray ioni-
zation source; this provides a stable ion current to tune the time-of-
flight parameters. Samples were introduced into the DART sample
gap with a glass melting point capillary by first dipping the closed
end of the capillary into the sample then immediately placing it into
the helium metastable beam. The helium gas temperature was set to
250 ꢀC to aid in the desorption of the analyte from the capillary. The
samples were held in the sample gap for 10e15 s to acquire several
mass spectra to average for an accurate m/z assignment.
While phen and its epoxide 1 were activators, the simple derivatives
3, 4, 6 and 7 caused a moderate inhibition. The aryl(hetaryl)sulfanyl
4.2. General procedure for preparation of compounds 3e7,
9e17 (method A)
A thiol (0.3 mmol) was dissolved in a sodium ethoxide solution
in ethanol (0.1 M, 2 mL). This mixture was added to a solution of 1
(50 mg, 0.255 mmol) in dry ethanol (2 mL) at room temperature.
The reaction mixture was stirred at 20e60 ꢀC for 1e36 h (Table 1)
until complete conversion of the epoxide, as monitored by TLC
(silica gel; EtOAc/CH3OH/NH4OH 10:1:0.5). The reaction mixture
was neutralized with 1 drop of 1 M HCl to pH w7, and the solvent
was removed on a rotary evaporator. The product was isolated ei-
ther by column chromatography or by crystallization.
4.2.1. 5-Isopropylsulfanyl-1,10-phenanthroline (3). Compound 3 was
prepared by method A using isopropyl mercaptane and isolated as
a yellow oil (52 mg, 79%) by column chromatography (Al2O3; EtOAc/
MeOH 10:1). 1H NMR (CDCl3):
d
1.30 (d, J¼6.7 Hz, 6H; CH3), 3.43 (sep,
J¼6.7 Hz, 1H; CHMe2), 7.57 (dd, J¼8.0, 4.3 Hz, H8), 7.64 (dd, J¼8.3,
4.2 Hz, H3), 7.89 (s, H6), 8.13 (dd, J¼8.0, 1.6 Hz, H7), 8.83 (dd, J¼8.3,
1.7 Hz, H4), 9.11 (dd, J¼4.3, 1.7 Hz, H9), 9.16 (dd, J¼4.2, 1.6 Hz, H2);
Fig. 1. Percent change of (a) b-D-glucosidase activity and (b) b-D-galactosidase activity
in presence of 1,10-phenanthroline (phen) or its derivatives (1 mM). The enzyme
13C NMR (CDCl3):
d 23.25 (CH3), 38.92 (CH), 123.17 (C3), 123.49 (C8),
producers: -dP. canescens, ,dA. oryzae.
128.30,129.57 (C4a/C6a),130.62 (C6),132.20 (C5),134.34 (C4),135.42

I.A. Dotsenko et al. / Tetrahedron 67 (2011) 7470e7478
7475
(C7), 145.89, 146.44 (C10a/C10b), 150.39 (C9), 150.45 (C2); HRMS:
C15H14N2S requires [2MþH]þ m/z 509.1834, [MþH]þ m/z 255.0956;
observed m/z 509.1787, 255.0926.
8.32 (d, J¼8.0 Hz, H7), 8.77 (d, J¼8.3 Hz, H4), 9.04 (dd, J¼4.3, 1.3 Hz,
H9) 9.07 (dd, J¼4.2, 1.2 Hz, H2); 13C NMR (CD3OD):
d 123.57, 123.98
(C3/C8), 127.28 (C6H4), 128.48, 128.63 (C4a/C6a), 129.39, 130.16
(C6H4), 131.26 (C6), 134.42 (C5), 134.51 (C4), 136.42 (C7), 145.16,
145.79 (C10a/C10b), 150.01 (C2), 150.19 (C9); HRMS: C18H12N2S
requires [2MþH]þ m/z 577.1521, [MþH]þ m/z 289.0799; observed
m/z 577.1509, 289.0736.
4.2.2. 5-Octylsulfanyl-1,10-phenanthroline (4). Compound 4 was
prepared by method
a brownish solid (77 mg, 93%; mp 68e70 ꢀC) by column chroma-
tography (SiO2; EtOAc/MeOH 9:2). 1H NMR (CDCl3):
0.85 (t,
A using 1-octanethiol and isolated as
d
J¼6.9 Hz, 3H; CH3), 1.19e1.33 (m, J¼6.7 Hz, 8H; CH2, octyl), 1.46 (p,
J¼7.3 Hz, 2H; CH2, octyl), 1.72 (p, J¼7.5 Hz, 2H; CH2, octyl), 3.05 (p,
J¼7.5 Hz, 2H; CH2S), 7.58 (dd, J¼8.1, 4.3 Hz, H8), 7.66 (dd, J¼8.3,
4.2 Hz, H3), 7.70 (s, H6), 8.12 (dd, J¼8.1, 1.7 Hz, H7), 8.74 (dd, J¼8.3,
1.7 Hz, H4), 9.10 (dd, J¼4.3, 1.7 Hz, H9), 9.18 (dd, J¼4.3, 1.6 Hz, H2);
4.2.7. 5-p-Tolylsulfanyl-1,10-phenanthroline (10). Compound 10 was
prepared by method A using p-thiocresol and isolated as a yellowish
solid (72 mg, 93%; mp 132e133 ꢀC) by column chromatography
(SiO2; MeOH). 1H NMR (CDCl3):
d
2.33 (s, 3H; CH3), 7.12 (d, J¼7.9 Hz,
2H; C6H4), 7.24 (d, J¼8.0 Hz, 2H; C6H4), 7.59 (dd, J¼8.0, 4.3 Hz, H8),
7.63 (dd, J¼8.3, 4.3 Hz, H3), 7.74 (s, H6), 8.08 (dd, J¼8.1, 1.6 Hz, H7),
8.72 (dd, J¼8.3,1.6 Hz, H4), 9.14 (dd, J¼4.3,1.7 Hz, H9), 9.19 (dd, J¼4.3,
13C NMR (CDCl3):
d 14.16 (CH3, octyl), 22.71, 28.85, 29.00, 31.86 (CH2
octyl), 33.80 (CH2S) 123.00 (C3), 123.47 (C8), 125.40 (C6), 128.40,
128.54 (C4a/C6a), 133.42 (C4), 133.87 (C7), 134.98 (C5), 145.34,
146.26 (C10a/C10b), 149.95 (C9), 150.45 (C2); HRMS: C20H24N2S
requires [2MþH]þ m/z 649.3399, [MþH]þ m/z 325.1738; observed
m/z 649.3322, 325.1727.
1.6 Hz, H2); 13C NMR (CDCl3):
d 21.23 (CH3), 123.31 (C3), 123.51 (C8),
128.38, 128.46, 129.75, 130.45, 131.25, 132.52 (C6H4/C6/C4a/C6a),
133.96 (C4), 135.52 (C7), 137.86 (C5), 146.02, 146.59 (C10a/C10b),
150.56 (C9), 150.59 (C2); HRMS: C19H14N2S requires [2MþH]þ m/z
605.1834, [MþH]þ m/z 303.0956; observed m/z 605.1785, 303.0926.
4.2.3. 5-Benzylsulfanyl-1,10-phenanthroline (5). Compound 5 was
prepared by method A using benzyl mercaptane and isolated as
a brownish solid (62 mg, 80%; mp 48e50 ꢀC) by column chroma-
4.2.8. 5-(4-Chlorophenylsulfanyl)-1,10-phenanthroline (11). Compo-
und 11 was prepared by method A using 4-chlorobenzenethiol and
isolated as a white solid (72 mg, 88%; mp 228e230 ꢀC) by crystal-
tography (SiO2; EtOAc/MeOH 7:2). 1H NMR (CDCl3):
d 4.17 (s, 2H;
CH2Ph), 7.19 (m, 5H; Ph), 7.55 (dd, J¼8.0, 4.3 Hz, H8), 7.61 (dd, J¼8.3,
4.3 Hz, H3), 7.66 (s, H6), 8.03 (dd, J¼8.1, 1.6 Hz, H7), 8.70 (dd, J¼8.3,
1.7 Hz, H4), 9.10 (dd, J¼4.3, 1.7 Hz, H9), 9.16 (dd, J¼4.2, 1.6 Hz, H2);
lization from EtOAc. 1H NMR (CDCl3):
d 7.15 (m, 2H; C6H4), 7.21 (m,
2H; C6H4), 7.62 (dd, J¼8.0, 4.3 Hz, 2H; H3, H8), 7.92 (s, H6), 8.14 (dd,
J¼8.0, 1.6 Hz, H7), 8.64 (dd, J¼8.3, 1.6 Hz, H4), 9.18 (dd, J¼4.4, 1.6 Hz,
13C NMR (CDCl3):
d
39.31 (CH2),123.14 (C3),123.52 (C8),127.59 (C6),
2H; H2, H9); 13C NMR (CDCl3):
d 123.58, 123.71 (C3/C8), 128.31,
128.35, 128.61, 128.68, 129.01, 132.60 (C, CH, phenyl, C4a, C6a),
133.65 (C4), 135.28 (C7), 136.58 (C5), 145.63, 146.26 (C10a/C10b),
150.33 (C9), 150.46 (C2); HRMS: C19H14N2S requires [2MþH]þ m/z
605.1834, [MþH]þ m/z 303.0956; observed m/z 605.1752, 303.0936.
128.51, 129.68, 130.33, 130.88, 132.30, 132.35, 133.16 (C6H4/C6/C4a/
C6a), 133.77 (C4), 134.17 (C7), 135.79 (C5), 146.44, 146.80 (C10a/
C10b), 150.74 (C9), 151.00 (C2); HRMS: C18H11ClN2S requires
[2MþH]þ m/z 645.0741, [MþH]þ m/z 323.0410; observed m/z
645.0636, 323.0341.
4.2.4. 5-(2-Hydroxyethylsulfanyl)-1,10-phenanthroline (6). Compo-
und 6 was prepared by method A using 2-mercaptoethanol and
isolated as a white solid (51 mg, 78%; mp 175e176 ꢀC) by crystalli-
4.2.9. 5-(4-Acetamidophenylsulfanyl)-1,10-phenanthroline
(12). Compound 12 was prepared by method
A using 4-
zation from EtOAc. 1H NMR (CD3OD):
d
3.23 (t, J¼6.5 Hz, 2H; CH2S),
acetamidothiophenol and isolated as a white solid (85 mg, 97%;
3.79 (t, J¼6.5 Hz, 2H; CH2O), 7.66 (dd, J¼8.1, 4.3 Hz, H8), 7.74 (dd,
J¼8.4, 4.3 Hz, H3), 7.87 (s, H6), 8.27 (dd, J¼8.1, 1.6 Hz, H7), 8.77 (dd,
J¼8.3, 1.6 Hz, H4), 8.95 (dd, J¼4.3, 1.7 Hz, H9), 9.04 (dd, J¼4.3, 1.6 Hz,
mp 241e243 ꢀC) by gradient column chromatography (SiO2; EtOAc/
MeOH (2:1) to MeOH). 1H NMR (DMSO):
d 2.00 (s, CH3), 7.33 (d,
J¼8.6 Hz, 2H; C6H4), 7.58 (d, J¼8.6 Hz, 2H; C6H4), 7.72 (dd, J¼8.1,
4.3 Hz, H8), 7.78 (dd, J¼8.3, 4.2 Hz, H3), 7.95 (s, H6), 8.39 (dd, J¼8.1,
1.5 Hz, H7), 8.67 (dd, J¼8.3, 1.4 Hz, H4), 9.04 (dd, J¼4.2, 1.4 Hz, H9),
H2); 13C NMR (CD3OD):
d 35.37 (CH2S), 59.88 (CH2O), 123.19 (C3),
123.72 (C8), 125.48 (C6), 128.17, 128.68 (C4a/C6a), 133.18 (C5), 133.44
(C4),135.53 (C7),144.21,145.25 (C10a/C10b),149.16(C9),149.67 (C2);
HRMS: C14H12N2OS requires [2MþH]þ m/z 513.1419, [MþH]þ m/z
257.0749; observed m/z 513.1353, 257.0725.
9.10 (dd, J¼4.2, 1.3 Hz, H2), 10.10 (s, NH); 13C NMR (DMSO):
d 24.54
(CH3), 120.57,120.66 (C6H4),124.21 (C3),124.39 (C8),126.76,128.08,
128.69 (C6H4/C4a/C6a), 130.59 (C6), 131.91(C5), 132.36 (C6H4),
133.86 (C4), 136.48 (C7), 139.79 (C6H4), 145.73, 146.47 (C10a/C10b),
150.85 (C2), 150.94 (C9), 169.05 (C]O); HRMS: C20H15N3OS re-
quires [MþH]þ m/z 346.1014; observed m/z 346.0980.
4.2.5. 5-(2-Aminoethylsulfanyl)-1,10-phenanthroline
(7). Compo-
und 7 was prepared by method A using 2-aminoethanethiol hy-
drochloride and sodium ethoxide solution in ethanol (0.3 M, 2 mL),
and was isolated as a yellow oil (46 mg, 71%) by column chroma-
4.2.10. 5-(2-Naphthalenylsulfanyl)-1,10-phenanthroline
(13). Compound 13 was prepared by method A using 2-
tography (SiO2; MeOH/NH4OH 20:1). 1H NMR (CDCl3):
d
1.55 (br s,
2H, NH2), 2.99 (t, J¼6.3 Hz, 2H; CH2S), 3.15 (t, J¼6.3 Hz, 2H; CH2N),
7.61 (dd, J¼8.0, 4.3 Hz, H8), 7.69 (dd, J¼8.3, 4.3 Hz, H3), 7.83 (s, H6),
8.15 (dd, J¼8.1, 1.7 Hz, H7), 8.80 (dd, J¼8.3, 1.6 Hz, H4), 9.13 (dd,
J¼4.3, 1.6 Hz, H9), 9.20 (dd, J¼4.3, 1.6 Hz, H2); 13C NMR (CDCl3):
mercaptonaphtaline and isolated as a brownish solid (71 mg,
83%; mp 163e164 ꢀC) by column chromatography (SiO2; MeOH). 1H
NMR (CD3OD):
d 7.34 (m, 1H; naphthyl), 7.43 (m, 2H; naphthyl),
7.66 (m, 1H; naphthyl), 7.70 (m, 2H; H3, H8), 7.78 (m, 3H; CH,
d
38.10 (CH2N), 40.90 (CH2S), 123.21 (C3), 123.59 (C8), 127.34 (C6),
naphthyl), 7.99 (s, H6), 8.28 (d, J¼8.0 Hz, H7), 8.79 (d, J¼8.2 Hz, H4),
128.39, 128.59 (C4a/C6a), 132.43 (C5), 133.61 (C4), 135.17 (C7),
145.60, 146.41 (C10a/C10b), 150.32 (C9), 150.56 (C2); HRMS:
C14H13N3S requires [2MþH]þ m/z 511.1739, [MþH]þ m/z 256.0908;
observed m/z 511.1718, 256.0852.
9.05 (m, 2H, H2, H9); 13C NMR (CD3OD):
d 123.57, 123.95 (C3/C8),
126.28, 126.66, 127.06, 127.32, 127.49, 128.45, 128.64, 129.05, 129.10,
131.25, 131.50, 131.68 (naphthyl/C4a/C6a), 132.51 (C6), 134.00 (C4),
134.40 (C5), 136.39 (C7), 145.19, 145.81 (C10a/C10b), 150.03, 150.18
(C2/C9); HRMS: C17H11N2S requires [2MþH]þ m/z 677.1834,
[MþH]þ m/z 339.0956; observed m/z 677.1660, 339.0916.
4.2.6. 5-Phenylsulfanyl-1,10-phenanthroline (9). Compound 9 was
prepared by method A using thiophenol and isolated as a yellowish
solid (61 mg, 83%; mp 54e56 ꢀC) by column chromatography (SiO2;
4.2.11. 5-(2-Pyridinylsulfanyl)-1,10-phenanthroline (14). Compound
14 was prepared by method Ausing 2-mercaptopyridine and isolated
as a white solid (58 mg, 79%; mp 227e229 ꢀC) by column
EtOAc/MeOH 7:2). 1H NMR (CD3OD):
d
7.25 (m, 1H; Ph), 7.30 (d,
J¼4.1 Hz, 4H; Ph), 7.73 (dd, J¼8.1, 4.4 Hz, 2H; H3, H8), 7.98 (s, H6),

7476
I.A. Dotsenko et al. / Tetrahedron 67 (2011) 7470e7478
chromatography (Al2O3; EtOAc/MeOH 9:2). 1H NMR (CDCl3):
d
6.74
a rotary evaporator. The product was isolated by column chroma-
tography or crystallization.
(dt, J¼8.1, 0.9 Hz, 1H; pyridyl), 6.97 (ddd, J¼7.4, 4.9, 1.0 Hz, 1H; pyr-
idyl), 7.36 (ddd, J¼8.1, 7.4, 1.9 Hz, 1H; pyridyl), 7.60 (dd, J¼8.3, 4.2 Hz,
H3), 7.66 (dd, J¼8.0, 4.3 Hz, H8), 8.24 (dd, J¼8.0, 1.6 Hz, H7), 8.30 (s,
H6), 8.36 (ddd, J¼4.9, 1.8, 0.9 Hz, 1H; pyridyl), 8.68 (dd, J¼8.3, 1.6 Hz,
H4), 9.18 (dd, J¼4.2,1.6 Hz, H2), 9.23 (dd, J¼4.3, 1.7 Hz, H9); 13C NMR
4.3.1. 1,2-Bis(1,10-phenanthrolin-5-ylsulfanyl)ethane (19). Compound
19 was prepared by method B using 1,2-ethandithiol and a sodium
isopropoxide solution in isopropanol (0.01 M, 15 mL). It was isolated
as a brownish solid (40 mg, 70%; mp 235e237 ꢀC) by column chro-
(CDCl3):
d 120.37, 121.33 (pyridyl), 123.65, 123.71 (C3/C8), 127.27,
128.36, 129.56 (C4a/C6a/C5), 135.01 (C4), 136.25 (C6/C7), 137.03
(pyridyl), 147.03, 147.13 (C10a/C10b), 149.94 (pyridyl), 150.77 (C2),
151.63 (C9),160.02 (pyridyl); HRMS: C17H11N2S requires [2MþH]þ m/
z 579.1426, [MþH]þ m/z 290.0752; observed m/z 579.1356, 290.0639.
matography (Al2O3; EtOAc/MeOH 9:2). 1H NMR (CDCl3):
d 3.24 (s,
4H; CH2CH2), 7.57 (dd, J¼8.0, 4.3 Hz, 2H; H8, H80), 7.61 (dd, J¼8.3,
4.3 Hz, 2H; H3, H30), 7.68 (s, 2H; H6, H60), 7.86 (dd, J¼8.1, 1.7 Hz, 2H;
H7, H70), 8.72 (dd, J¼8.3, 1.6 Hz, 2H; H4, H40), 9.14 (dd, J¼4.3, 1.7 Hz,
2H; H9, H90), 9.18 (dd, J¼4.3, 1.6 Hz, 2H; H2, H20); 13C NMR (CDCl3):
4.2.12. 5-(4H-1,2,4-Triazol-3-ylsulfanyl)-1,10-phenanthroline
(15). Compound 15 was prepared by method A using 4-amino-3-
hydrazino-5-mercapto-1,2,4-triazole (‘purpald’) and isolated as
a brown solid (51 mg, 72%; mp >300 ꢀC) by crystallization from
d
33.61 (CH2CH2), 123.29 (C3, C30), 123.68 (C8, C80), 128.12, 128.68
(C4a/C6a, C4a0/C6a0), 128.90 (C6, C60), 131.13 (C5, C50), 133.65 (C4,
C40), 135.22 (C7, C70), 145.78, 146.47 (C10a/C10b, C10a0/C10b0), 150.69
(C9/C2, C90/C20); HRMS: C26H18N4S2 requires [MþH]þ m/z 451.1051;
observed m/z 451.1048.
EtOAc. 1H NMR (CD3OD):
d
7.62 (s, H6), 7.65 (dd, J¼8.1, 4.4 Hz, H8),
7.76 (dd, J¼8.3, 4.4 Hz, H3), 8.03 (s, 1H; NCHNH), 8.18 (dd, J¼8.1,
1.6 Hz, H7), 8.87 (dd, J¼8.4, 1.6 Hz, H4), 8.94 (dd, J¼4.4, 1.7 Hz, H9),
4.3.2. 1,6-Bis(1,10-phenanthrolin-5-ylsulfanyl)hexane (20). Compound
20 was prepared by method B using 1,6-hexanedithiol and isolated as
a yellow solid (47 mg, 73%; mp 96e97 ꢀC) by crystallization from
9.05 (dd, J¼4.4, 1.6 Hz, H2); 13C NMR (CD3OD):
d 123.20 (C8), 123.71
(C3), 126.56 (C6), 127.93, 128.76 (C4a/C6a), 133.58, 133.69 (C4/C5),
135.87 (C7), 144.48, 145.37 (C10a/C10b), 149.21 (C9), 149.65 (C2),
150.57 (NCHNH), 152.00 (NC(NH)S); HRMS: C14H9N5S requires
[MþH]þ m/z 280.0657; observed m/z 280.0592.
CHCl3/MeOH (3:1). 1H NMR (CDCl3):
d 1.52 (m, 4H; CH2, hexenyl), 1.73
(m, 4H, CH2, hexenyl), 3.05 (m, 4H; 2CH2S), 7.58 (dd, J¼8.0, 4.3 Hz, 2H;
H8, H80), 7.66 (dd, J¼8.2, 4.2 Hz, 2H; H3, H30), 7.71 (s, 2H; H6, H60), 8.11
(dd, J¼8.0, 1.5 Hz, 2H; H7, H70), 8.73 (dd, J¼8.3, 1.6 Hz, 2H; H4, H40),
9.11 (dd, J¼4.3, 1.6 Hz, 2H; H9, H90), 9.19 (dd, J¼4.3, 1.5 Hz, 2H; H2,
4.2.13. 5-(1H-Benzimidazol-2-ylsulfanyl)-1,10-phenanthroline
(16). Compound 16 was prepared by method A using mercapto-
benzimidazole and isolated as a white solid (71 mg, 85%; mp
286e288 ꢀC) by crystallization from EtOAc. 1H NMR (CDCl3/CD3OD
H20); 13C NMR (CDCl3):
d 28.47 (hexenyl), 28.71 (hexenyl), 33.76
(CH2S, hexenyl), 123.08 (C3,C30), 123.53 (C8,C80), 125.87 (C6, C60),
128.42, 128.48 (C4a/C6a, C4a0/C6a0), 133.42 (C4, C40), 133.53 (C7, C70),
135.00 (C5, C50), 145.40, 146.29 (C10a/C10b, C10a0/C10b0), 150.07 (C9,
C90), 150.52 (C2, C20); HRMS: C30H26N4S2 requires [MþH]þ m/z
507.1677; observed m/z 507.1563.
1:1): d 7.18 (m, 2H; benzimidazolyl), 7.43 (br s, 2H; benzimidazolyl),
7.70 (dd, J¼8.4, 4.3 Hz, H3), 7.74 (dd, J¼8.0, 4.4 Hz, H8), 8.34 (dd,
J¼8.2, 1.7 Hz, H7), 8.35 (s, H6), 8.81 (dd, J¼8.4, 1.6 Hz, H4), 9.05 (dd,
J¼4.3, 1.6 Hz, H2), 9.11 (dd, J¼4.4, 1.7 Hz, H9); 13C NMR (CDCl3/
CD3OD 1:1):
d
122.69, 123.76, 123.87, 123.97 (benzimidazolyl/C3/
4.3.3. 1,4-Bis(1,10-phenanthrolin-5-ylsulfanyl)butane-2,3-diol
C8), 126.13 (C6), 128.32, 129.02 (C4a/C6a), 134.34 (C5), 134.92(C4),
136.64(C7), 146.09, 146.21(C10a/C10b), 147.60 (NC(NH)S), 150.10
(C2),150.86 (C9); HRMS: C17H11N2S requires [MþH]þ m/z 329.0861;
observed m/z 329.0785.
(21). Compound 21 was prepared by method B using dl-dithio-
threitol and isolated as
a yellowish solid (59 mg, 91%; mp
210e211 ꢀC) by crystallization from EtOAc. 1H NMR (DMSO):
d
3.25e3.37 (m, 4H; CH2S), 3.89 (m, 2H; CHOH), 7.67 (dd, J¼8.0,
4.3 Hz, 2H; H8, H80), 7.72 (dd, J¼8.4, 4.2 Hz, 2H; H3, H30), 7.93 (s, 2H;
H6, H60), 8.25 (dd, J¼8.1, 1.6 Hz, 2H; H7, H70), 8.57 (dd, J¼8.3, 1.6 Hz,
2H; H4, H40), 8.97 (dd, J¼4.3, 1.7 Hz, 2H; H9, H90), 9.06 (dd, J¼4.2,
4.2.14. 5-(1,3-Benzothiazol-2-ylsulfanyl)-1,10-phenanthroline
(17). Compound 17 was prepared by method
A using 2-
mercaptobenzothiazole and isolated as a white solid (71 mg, 81%;
1.6 Hz, 2H; H2, H20); 13C NMR (DMSO):
d 39.71 (CH2S), 70.86
mp 181e182 ꢀC) by column chromatography (SiO2; EtOAc/MeOH
(CHOH), 123.84 (C3, C30), 124.25 (C8, C80), 124.87 (C6, C60), 127.86,
128.86 (C4a/C6a, C4a0/C6a0), 133.04 (C4, C40), 133.44 (C5, C50),
135.63 (C7, C70), 144.71, 145.87 (C10a/C10b, C10a0/C10b0), 149.96
(C9, C90), 150.59 (C2, C20); HRMS: C30H26N4S2 requires [MþH]þ m/z
511.1262; observed m/z 511.1451.
9:2). 1H NMR (CDCl3):
d
7.23 (t, J¼7.6 Hz, 1H; benzothiazolyl), 7.38
(dd, J¼8.1, 7.4 Hz, 1H; benzothiazolyl), 7.54 (d, J¼7.9 Hz, 1H; ben-
zothiazolyl), 7.65 (dd, J¼8.3, 4.3 Hz, H3), 7.71 (dd, J¼8.0, 4.4 Hz, H8),
7.84 (d, J¼8.3 Hz, 1H; benzothiazolyl), 8.30 (d, J¼7.8 Hz, H7), 8.44 (s,
H6), 8.81 (d, J¼8.3 Hz, H4), 9.22 (d, J¼4.0 Hz, H2), 9.28 (d, J¼4.2 Hz,
H9); 13C NMR (CDCl3):
d
120.00, 122.17 (benzothiazolyl), 123.87,
4.3.4. 1,5-Bis(1,10-phenanthrolin-5-ylsulfanyl)-3-oxapentane
(22). Compound 22 was prepared by method B using bis(2-
mercaptoethyl) ether and isolated as a white solid (32 mg, 50%;
mp 279e281 ꢀC) by column chromatography (Al2O3; EtOAc/MeOH
124.02 (C3/C8), 124.75, 126.15 (benzothiazolyl), 126.47, 128.07,
129.17, 134.57 (benzothiazolyl/C5/C4a/C6a) 135.66 (C4), 136.60
(C7),137.33 (C6),147.10,147.43 (C10a/C10b),151.10 (C2),152.25 (C9),
153.76 (benzothiazolyl), 167.49 (NC(S)S); HRMS: C19H11N3S2 re-
quires [2MþH]þ m/z 691.0867, [MþH]þ m/z 346.0473; observed m/z
691.0740, 346.0462.
9:2). 1H NMR (CDCl3):
d
3.20 (t, J¼6.4 Hz, 4H; CH2S), 3.69 (t,
J¼6.4 Hz, 4H; CH2O), 7.55 (dd, J¼8.1, 4.3 Hz, 2H; H8, H80), 7.65 (dd,
J¼8.4, 4.2 Hz, 2H; H3, H30), 7.82 (s, 2H; H6, H60), 8.08 (dd, J¼8.1,
1.6 Hz, 2H; H7, H70), 8.75 (dd, J¼8.3, 1.6 Hz, 2H; H4, H40), 9.11 (dd,
J¼4.3, 1.7 Hz, 2H; H9, H90), 9.18 (dd, J¼4.2, 1.6 Hz, 2H; H2, H20); 13C
4.3. General procedure for preparation of compounds 19e24
(method B)
NMR (CDCl3): d
34.31 (CH2S), 69.44 (CH2OH), 123.20 (C3, C30),
123.60 (C8, C80), 128.36 (C6, C60), 128.58, 132.50 (C4a/C6a, C4a0/
C6a0), 133.64 (C4, C40), 135.22 (C7, C70), 135.82(C5, C50), 145.57,
146.29 (C10a/C10b, C10a0/C10b0), 150.33 (C9, C90), 150.55 (C2, C20);
HRMS: C28H22N4OS2 requires [2MþH]þ m/z 989.2548, [MþH]þ m/z
495.1313; observed m/z 989.2567, 495.1235.
A dithiol (0.12 mmol) was dissolved in a sodium ethoxide so-
lution in ethanol (0.01 M, 15 mL). This solution was added dropwise
during 1 h to a solution of epoxide 1 (50 mg, 0.255 mmol) in dry
ethanol (1 mL) at room temperature in an argon atmosphere. The
reaction mixture was stirred at 22e78 ꢀC for 2e24 h (Table 1) until
complete conversion of the epoxide as monitored by TLC (silica gel;
EtOAc/CH3OH/NH4OH 10:1:0.5). The solvent was removed on
4.3.5. 1,8-Bis(1,10-phenanthrolin-5-ylsulfanyl)-3,6-dioxaoctane
(23). Compound 23 was prepared by method B using 3,6-dioxa-

I.A. Dotsenko et al. / Tetrahedron 67 (2011) 7470e7478
7477
1,8-octanedithiol and isolated as a white solid (37 mg, 54%; mp
(ddd, J¼8.3, 7.6, 1.2 Hz, 1H; pyridyl), 7.01 (ddd, J¼7.6, 6.6, 1.8 Hz, 1H;
pyridyl), 7.66 (dd, J¼8.2, 4.2 Hz, H3), 7.72 (dd, J¼7.9, 4.3 Hz, H8),
8.29 (br s, 1H; pyridyl), 8.30 (m, H7), 8.38 (s, H6), 8.66 (dd, J¼8.3,
1.5 Hz, H4), 9.24 (d, J¼3.0 Hz, H2), 9.29 (d, J¼3.1 Hz, H9); 13C NMR
296e298 ꢀC) by column chromatography (Al2O3; EtOAc/MeOH 9:2).
1H NMR (CDCl3):
d
3.22 (t, J¼6.6 Hz, 4H; CH2S), 3.55 (s, 4H; OCH2
-
CH2O), 3.70 (t, J¼6.6 Hz, 4H; OCH2CH2S), 7.57 (dd, J¼8.1, 4.3 Hz, 2H;
H8, H80), 7.65 (dd, J¼8.3, 4.3 Hz, 2H; H3, H30), 7.82 (s, 2H; H6, H60),
8.11 (dd, J¼8.1, 1.7 Hz, 2H; H7, H70), 8.75 (dd, J¼8.3, 1.6 Hz, 2H; H4,
H40), 9.11 (dd, J¼4.3, 1.7 Hz, 2H; H9, H90), 9.18 (dd, J¼4.3, 1.7 Hz, 2H;
(CDCl3):
d 121.34, 122.47 (pyridyl), 123.93 (C8), 124.15 (C3), 125.25
(C5), 125.94 (pyridyl), 128.29, 129.14 (C4a/C6a), 134.43 (C4), 136.41
(C7), 137.69 (C6), 138.70 (pyridyl), 147.11, 147.34 (C10a/C10b), 151.27
(C2), 152.16 (pyridyl), 152.27 (C9); HRMS: C17H11N3OS requires
[MþH]þ m/z 306.0701; observed m/z 306.0684.
H2, H20); 13C NMR (CDCl3):
d 33.69 (CH2S), 69.68 (SCH2CH2O), 70.55
(OCH2CH2O), 123.16 (C3, C30), 123.57 (C8, C80), 127.30 (C6, C60),
128.39, 128.59 (C4a/C6a, C4a0/C6a0), 133.58 (C5, C50), 133.66 (C4,
C40), 135.20 (C7, C70), 145.60, 146.32 (C10a/C10b, C10a0/C10b0),
150.30 (C9, C90), 150.55 (C2, C20); HRMS: C30H26N4O2S2 requires
[MþH]þ m/z 539.1575; observed m/z 539.1520.
4.6. Preparation of bis(1,10-phenanthrolin-5-yl)sulfide (25)
A solution of Li2S (15 mg, 0.2 mmol) in 15 mL of tert-butanol was
added dropwise during 1 h to a suspension of epoxide 1 (55 mg,
0.28 mmol) in tert-butanol (2 mL) at 60 ꢀC in an argon atmosphere.
The reaction mixture was stirred at 60 ꢀC for 2 h until complete
conversion of the epoxide as monitored by TLC (silica gel; EtOAc/
CH3OH/NH4OH 10:1:0.5). The solvent was removed on a rotary
evaporator. Residue was dissolved in 20 mL of chloroform and
washed with 10 mL of satd. NH4Cl. The water layer was extracted
with chloroform (3ꢁ5 mL). The organic extracts were combined and
dried over Na2SO4. The solvent was removed on a rotary evaporator.
The product 25 was isolated as a yellowish solid (45 mg, 82%; mp
>300 ꢀC) by crystallization from MeOH/H2O (2:1). 1H NMR (CDCl3):
4.3.6. 2,6-Bis(1,10-phenanthrolin-5-ylsulfanyl)pyrimidine-4,5-
diamine (24). Compound 24 was prepared by method B using 4,5-
diamino-2,6-dimercaptopyrimidine; the precipitation was filtered
off and washed with EtOAc yielding 24 as a brown solid (42 mg,
62%; mp >310 ꢀC). 1H NMR (DMSO):
d
7.34 (dd, J¼8.3, 4.2 Hz, 1H),
7.46 (dd, J¼8.3, 4.2 Hz, 1H), 7.64 (m, 2H), 7.74 (s, 1H), 7.93 (s, 1H),
8.06 (dd, J¼8.1, 1.6 Hz, 1H), 8.13 (dd, J¼8.2, 1.7 Hz, 1H), 8.16 (dd,
J¼8.1, 1.6 Hz, 1H), 8.22 (dd, J¼8.3, 1.5 Hz, 1H), 8.69 (dd, J¼4.2, 1.5 Hz,
1H), 8.79 (dd, J¼4.2, 1.5 Hz, 1H), 9.01 (m, 2H); 13C NMR was not
obtained due to very low solubility of the compound; HRMS:
C30H26N4O2S2 requires [MþH]þ m/z 531.1174; observed m/z
531.1110.
d
7.52 (dd, J¼8.0, 4.3 Hz, 2H; H8, H80), 7.67 (dd, J¼8.3, 4.3 Hz, 2H; H3,
H30), 7.68 (s, 2H; H6, H60), 8.00 (dd, J¼8.1, 1.6 Hz, 2H; H7, H70), 8.76
(dd, J¼8.3, 1.6 Hz, 2H; H4, H40), 9.18 (dd, J¼4.4, 1.6 Hz, 2H; H9, H90),
4.4. Preparation of 5-methoxycarbonylmethylsulfanyl-1,10-
phenanthroline (8)
9.25 (dd, J¼4.3, 1.6 Hz, 2H; H2, H20); 13C NMR (CDCl3):
d 123.63 (C3,
C30), 123.73 (C8, C80), 127.91, 128.40 (C4a/C6a, C4a0/C6a0), 130.32 (C6,
C60, C5, C50), 133.58 (C4, C40), 135.59 (C7, C70), 146.09, 146.72 (C10a/
C10b, C10a0/C10b0), 151.00 (C2, C20, C9, C90); HRMS: C24H14N4S re-
quires m/z [MþH]þ 391.1017; observed m/z 391.1022.
Methyl mercaptoacetate (0.025 mL, 0.27 mmol) was dissolved in
a sodium methoxide solution in methanol (0.02 M, 10 mL), and the
mixture was added dropwise to a solution of 1 (50 mg, 0.255 mmol)
in dry methanol (2 mL) at 60 ꢀC in an argon atmosphere. The re-
action mixture was stirred at 60 ꢀC for 1 h. Then additional sodium
methoxide in methanol (0.05 M, 8 mL) was added dropwise during
2 h to a reaction mixture at 60 ꢀC until complete conversion of the
epoxide and the intermediate product as monitored by TLC (silica
gel; EtOAc/CH3OH/NH4OH 10:1:0.5). The reaction mixture was
neutralized with a few drops of 1 M HCl to pH w7, and solvent was
removed on a rotary evaporator. The product 8 was isolated as
a brown solid (45 mg, 63%; mp 162e163 ꢀC) by column chroma-
4.7. Preparation of 5-(b-D-glucopyranosylsulfanyl)-1,10-
phenanthroline (26)
Sodium salt of 1-thio-b-D-glucose (65.5 mg, 0.3 mmol) in 2 mL
of dry ethanol was added to a solution of epoxide 1 (50 mg,
0.255 mmol) in dry ethanol (2 mL) and stirred at room temperature
for 36 h until complete conversion of the epoxide as monitored by
TLC (silica gel; CH3OH/NH4OH 20:1). The precipitate was filtered off
and recrystalized from EtOH affording product 26 as a yellowish
tography (SiO2; EtOAc/MeOH 8:2). 1H NMR (CD3OD):
d
3.62 (s,
solid (61 mg, 64%; mp 154e155 ꢀC). 1H NMR (DMSO):
d 3.08 (t,
OCH3), 3.94 (s, SCH2), 7.76 (dd, J¼8.0, 4.4 Hz, H8), 7.84 (dd, J¼8.3,
4.4 Hz, H3), 8.07 (s, H6), 8.40 (dd, J¼8.1, 1.4 Hz, H7), 8.88 (dd, J¼8.3,
1.3 Hz, H4), 9.02 (d, J¼4.4 Hz, H9), 9.09 (d, J¼4.4 Hz, H2); 13C NMR
J¼9.2 Hz, 1H; H4, glu), 3.17 (dd, J¼9.6, 8.8 Hz, H2, glu), 3.23 (t,
J¼8.7 Hz, 1H; H3, glu), 3.30 (ddd, J¼9.6, 6.5, 2.0 Hz, 1H; H5, glu),
3.41 (dd, J¼11.8, 6.4 Hz, 1H; H6a, glu), 3.69 (dd, J¼11.7, 1.9 Hz, 1H;
H6b, glu), 4.79 (d, J¼9.7 Hz, 1H; H1, glu), 7.74 (dd, J¼8.1, 4.3 Hz, H8),
7.80 (dd, J¼8.3, 4.2 Hz, H3), 8.29 (s, H6), 8.36 (dd, J¼8.1, 1.6 Hz, H4),
8.79 (dd, J¼8.4, 1.6 Hz, H7), 9.02 (dd, J¼4.3, 1.6 Hz, H9), 9.09 (dd,
(CD3OD):
d 35.35 (SCH2), 51.81 (OCH3), 123.57 (C3), 124.00 (C8),
128.37, 128.69 (C6/C5, C4a/C6a), 133.93 (C4), 136.27 (C7), 144.68,
145.31 (C10a/C10b), 149.95 (C9), 150.02 (C2), 169.97 (C]O); HRMS:
C15H12N2O2S requires [2MþH]þ m/z 569.1317, [MþH]þ m/z
285.0698; observed m/z 569.1359, 285.0649.
J¼4.2, 1.6 Hz, H2); 13C NMR (DMSO):
d 61.57 (CH2OH), 70.36 (C4,
glu), 73.17(C2, glu), 79.74 (C3, glu), 81.75 (C5, glu), 87.46 (C1, glu),
123.91 (C3), 124.29 (C8), 128.73, 128.82 (C4a, C6a), 129.13 (C6),
131.44 (C5), 134.13 (C4), 136.34 (C7), 145.20, 145.86 (C10a/C10b),
150.48, 150.55 (C2/C9). HRMS: C30H26N4O2S2 requires m/z [MþH]þ
375.1015; observed m/z 375.1022.
4.5. Preparation of 5-(1-oxypyridin-2-ylsulfanyl)-1,10-
phenanthroline (18)
A solution of 2-mercaptopyridine N-oxide sodium salt (45 mg,
0.3 mmol) in 2 mL of dry ethanol was added to a solution of epoxide
1 (50 mg, 0.255 mmol) in dry ethanol (2 mL) and the mixture was
stirred at 60 ꢀC for 4 h until complete conversion of the epoxide as
monitored by TLC (silica gel; EtOAc/CH3OH/NH4OH 10:1:0.5). Then
sodium ethoxide in ethanol (0.02 M, 10 mL) was added dropwise to
a reaction mixture at room temperature and the mixture was stir-
red for another 10 h. The solvent was removed on a rotary evapo-
rator. The product 18 was isolated as a white solid (54 mg, 70%; mp
253e255 ꢀC) by column chromatography (Al2O3; EtOAc/MeOH
4.8. General procedure for the glycosidase activation and
inhibition assay
The enzyme activities (b-D-galactosidases and b-D-glucosidases)
were assayed using multi-enzyme complexes isolated from fungi P.
canescens and A. oryzaeusing somewhatmodified procedures of prior
studies.25,26 All assays were performed in a standard way by moni-
toring spectrophotometrically the release of p-nitrophenol from the
corresponding p-nitrophenyl glycosides at 30 ꢀC. One unit of enzyme
10:2). 1H NMR (CDCl3):
d
6.24 (dd, J¼8.4, 1.6 Hz, 1H; pyridyl), 6.88
activity was defined as the amount of enzyme that releases 1 mmol of

7478
I.A. Dotsenko et al. / Tetrahedron 67 (2011) 7470e7478
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were selected so that the degree of hydrolysis was never more than
20%, and in most cases was less than 10%, over the course of the assay.
The method used to measure the rate of the reaction assumes that the
amount of the substrate is high enough, such that the disappearance
over a given period is insignificant, that is the rate of the reaction is
close to linear for the first stage of the reaction. Enzyme solutions
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(100
m
L with activities 750ꢂ150
mU) were mixed with a set of in-
L,10 mM), then diluted with 700 mL
hibitor/activator solutions (100
m
of 0.2 M acetic buffer (pH 4.6), and the mixture was incubated for 1 h
at30 ꢀC. The reactionwasinitiatedwith additionofa propersubstrate
(100 mL of 20 mM p-nitrophenyl glycopyranoside), and aliquots were
taken after 5 and 10 min. The reaction was terminated by addition of
1 mLof1 M Na2CO3 to 0.5 mLofaliquot solution. Theconcentration of
the released p-nitrophenol was determined at 400 nmwith Beckman
Du-65 spectrophotometer using molar extinction coefficient
18.3 mMꢃ1 cmꢃ1. The inhibition/activation was estimated as a loss/
increase of enzymatic activity in % (Fig. 1).
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Acknowledgements
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The National Science Foundation Major Research In-
strumentation Grant (CHE-0722654) is gratefully acknowledged for
the funding of a JEOL ECA-600 NMR-spectrometer.
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