Metal chelation aptitudes of bis(o-azaheteroaryl)methanes as tuned by heterocycle charge demands

Article abstract of DOI:10.1021/jo025696o

We describe the synthesis of a number of 1,3-azol-2-yl-, 1,3-benzazol-2-yl-, and azinyl-based bis- (o-azaheteroaryl)methanes (LH, L^- = Het₂CH-) and their coordinating properties toward divalent transition metals (Zn, Cu, Co, Ni, Hg,

Full text of DOI:10.1021/jo025696o

Meta l Ch ela tion Ap titu d es of Bis(o-a za h eter oa r yl)m eth a n es As
Tu n ed by Heter ocycle Ch a r ge Dem a n d s1
Alessandro Abbotto, Silvia Bradamante, Antonio Facchetti, and Giorgio A. Pagani*
Department of Materials Science, University of Milano-Bicocca, via Cozzi 53, I-20125, Milano, Italy, and
CNR-Istituto di Scienze e Tecnologie Molecolari, via C. Golgi 19, I-20133 Milano, Italy
giorgio.pagani@mater.unimib.it
Received March 8, 2002
We describe the synthesis of a number of 1,3-azol-2-yl-, 1,3-benzazol-2-yl-, and azinyl-based bis-
-
-
(
2
o-azaheteroaryl)methanes (LH, L ) Het CH ) and their coordinating properties toward divalent
transition metals (Zn, Cu, Co, Ni, Hg, Pd). This extended investigation includes both symmetrical
and unsymmetrical ligands based on several substituted and/or unsubstituted thiazole, benzothia-
zole, benzoxazole, benzimidazole, pyridine, and quinoline derivatives. Depending on the structure
and electron properties of the ligand, a vast set of neutral chelates ML
2
were obtained, where the
ligand is present in its carbanionic form L . Additionally, we have prepared salt complexes [M(LH) ]-
, where the ligand is present as a neutral system. Neutral chelates were typically obtained by
-
n
X
m
the reaction of the ligand with metal acetates in alcoholic solution; salt complexes were formed by
reaction with other metal salts such as chlorides. By exploring the coordinating properties of several
bisheteroarylmethane ligands based on heteroaromatics of variable π-electron structure and
substitution pattern, we demonstrate that the formation of neutral chelates is strictly dependent
on the electron-withdrawing capacity (charge demand) of the heteroaromatic moiety. The latter
-
primarily dictates the efficiency by which the negative charge of the anionic ligand L is stabilized
2
by delocalization in ML and, therefore, the stability of the chelate itself. On the basis of the large
number and the variable nature of the nitrogen ligands used, we confirm the general validity of
the charge-demand-dependent formation of chelates. This key factor can therefore be used for the
efficient design of new π-deficient heteroaromatic nitrogen ligands in chelates of great potential in
many synthetic, catalytic, and technological fields.
In tr od u ction
pyridine-based structures, which appears as a serious
limitation to the strong potential coordinating properties
of other heteroaromatic structures, the bipyridine moiety
being by far the most widely used ligand.12 In contrast,
azole- and benzazole-based ligands have so far received
scant interest in their use as nitrogen ligands toward
transition metals.
Heteroaromatic nitrogen ligands2 find extended ap-
plications in several important research and technological
fields, including C-C bond formation, asymmetric ho-
mogeneous and heterogeneous catalysis, DNA binding,
3
4
5
6
use as diagnostic agents and drugs, radioimmuno-
7
8
9
therapy, tumor targeting, electroluminescent (LED)
Over the last few years, we have undertaken a sys-
tematic investigation on bisheteroarylmethanes 1 and
their corresponding deprotonated forms at the methylene
and nonlinear optical10 materials, and other applications
in electrooptical and photonic devices.11 Still, the vast
majority of heteroaromatic nitrogen ligands covers solely
-
bridge, 1 . Our primary interest was to elucidate and
*
To whom correspondence should be addressed at the University
of Milano-Bicocca.. Fax: (+39) 02 6448 5403.
1) Bisheteroarylmethanes. 9. Part 8: see ref 18. Part 7: see ref
9. Parts 6 and 5: see ref 17.
2) (a) Vila, J . M.; Gayoso, M.; Pereira, M. T.; Suarez, A.; Fernandez,
(
1
(
J . J .; Ortigueira, J . M.; Fernandez, A.; Torres, M. L. Trends Organomet.
Chem. 1997, 2, 21-37. (b) Alexander, V. Chem. Rev. 1995, 95, 273-
quantitatively rank the electron-acceptor properties of
3
42. (c) Steel, P. J . Coord. Chem. Rev. 1990, 106, 227-265.
(
(
3) Elsevier, C. J . Coord. Chem. Rev. 1999, 185-186, 809-822.
4) (a) Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem.
(8) (a) Parker, D. Chem. Br. 1990, 26, 942-945. (b) Parker, D. Chem.
Soc. Rev. 1990, 19, 271-291. (c) Morphy, J . R.; Parker, D.; Kataky,
R.; Eaton, M. A. W.; Millican, A. T.; Alexander, R.; Harrison, A.;
Walker, C. J . Chem. Soc., Perkin Trans. 2 1990, 4, 573-585.
(9) (a) Wang, S. Coord. Chem. Rev. 2001, 215, 79-98. (b) Balzani,
V.; J uris, A.; Venturi, M.; Campagna, S.; Serroni, S. Chem. Rev. 1996,
96, 759-833.
(10) Di Bella S. Chem. Soc. Rev. 2001, 30, 355-366.
(11) (a) Kalyanasundaram, K.; Gratzel, M. Coord. Chem. Rev. 1998,
177, 347-414. (b) Baxter, S. M.; J ones, W. E.; Danielson, E.; Worl, L.;
Strouse, G.; Younathan, J .; Meyer, T. J . Coord. Chem. Rev. 1991, 111,
47-71.
Rev. 2000, 100, 2159-2231. (b) Helmchen, G.; Pfaltz, A. Acc. Chem.
Res. 2000, 33, 336-345. (c) Helmchen, G.; Kudis, S.; Sennhenn, P.;
Steinhagen, H. Pure Appl. Chem. 1997, 69, 513-518. (d) Pfaltz, A. Acc.
Chem. Res. 1993, 26, 339-345.
(
5) (a) Sigman, D. S.; Mazumder, A.; Perrin, D. M. Chem. Rev. 1993,
9
2
3, 2295-2316. (b) J i, L.-N.; Zou, X.-H.; Liu, J .-G. Coord. Chem. Rev.
001, 216-217, 513-536. (c) McMilllin, D. R.; McNett, K. M. Chem.
Rev. 1998, 98, 1201-1219.
(
6) Caravan, P.; Ellison, J . J .; McMurry, T. J .; Lauffer, R. B. Chem.
Rev. 1999, 99, 2293-2352.
7) Alexander, V. Chem. Rev. 1995, 95, 273-342.
(
1
0.1021/jo025696o CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/09/2002
J . Org. Chem. 2002, 67, 5753-5772
5753

Abbotto et al.
π-deficient heteroaromatics using, as a method of choice,
multinuclear NMR investigation of anionic systems in
DMSO, and get a deep insight into their experimental
charge distribution mapping obtained by largely vali-
dated 13C and 15N shift/charge relationships.14,15 Among
other organic systems, we included in our multiyear
study the following heterocycles: azines (2- and 4-pyridyl,
TABLE 1. Ch a r ge Dem a n d s of Heter oa r yl a n d P r im a r y
Or ga n ic Su bstitu en ts (X)a
X
cXPh
cX
X
1
3
Phb
CONMe2
CO2Me
COMe
0.29
0.42
0.40
0.51
0.56
0.28
0.26
0.28
0.26
0.413-0.380
0.346
0.283
0.457-0.471
0.424-0.436
0.382
0.411
0.411
0.29
b
0.275
0.268
0.325
0.341
0.207
0.233
0.206
0.122
0.318
b
b
b
COPh
pyrazinyl, 4-pyrimidyl, 3-pyridazinyl, and 2- and 4-quino-
CNb
lyl),1
5a,16
1,3-azoles (2-oxazolyl, 2-thiazolyl, and 2-imida-
b
SOPh
1
7
18
zolyl and their benzo-fused analogues), triazoles, and
SO Phb
2
purines (8-purinyl).19
b
PO(OEt)2
c
2
2
-thiazolyl
Ranking of the π-electron-withdrawing (EW) power of
heterocycles was conveniently expressed in terms of the
charge demand c,20 defined as the fraction of π-charge
-oxazolylc
c
N-methylimidazol-2-yl
0.254
0.316
0.288
0.276
0.286
0.302
0.299
0.313
c
2
-benzothiazolyl
c
transferred from an adjacent negatively charged trigonal
2-benzoxazolyl
N-methylbenzimidazol-2-yl
carbon atom to the X group.1
3,14b,21
Charge demands are
c
d
e
1
2
4
2
,2,4-triazol-5-yl
-pyridyl
directly correlated to the π-electron density residing on
f,g
π
C
the trigonal carbanionic carbon q , as obtained from its
f,g
-pyridyl
0.408
1
3
14
C chemical shift and shift/charge relationships, using
-quinolylg
eqs 1 and 2.22
h
3-pyridazinyl
0.417
0.430
0.501
0.446
0.536
2
-pyrimidylh
h
X
X
π
4-pyrimidyl
c
) (2 - q C)/2
(1)
(2)
pyrazinylh
i
N-methylpurin-8-yl
0.305
X
π
c
) 2 - cPh - q
a
The cXX values are smaller than the cXPh values because of
Ph
C
saturation phenomena; the two sets of values are linearly related
b
c
(
refs 13, 15b, and 21). References 14b and 21. Reference 17a.
Depending on whether the capacity of delocalizing an
adjacent negative charge by the group X is measured in
d
Reference 19. e Reference 18. f Reference 13a. g Reference 16b.
Reference 15a. Reference 19.
h
i
-
X
symmetrical anions 1 (c
(
X
) or benzyl carbanions PhCH-X
X
c Ph), two sets of c values can be obtained. Table 1 lists
the values of charge demands for various heterocyclic
groups and, for comparison, primary organic functional-
ities.1
The table clearly shows that most of the listed azahet-
erocycles are as strong electron acceptors as common EW
primary organic functionalites. In particular, it can be
noted that the EW capacity of the thiazolyl ring is
comparable to that of an alkoxycarbonyl group. Benzo-
fusion further increases their charge demand: the ben-
zothiazolyl substituent is as powerful as the acetyl group.
The benzoxazolyl ring is located in the middle of these
two situations. In general, the following trend was found
in the EW power of azole derivatives: (a) thiazole >
oxazole > imidazole; (b) benzazole > azole. Analogously,
six-membered rings such as azines, diazines, and purine
are powerful EW systems. The charge demand of the
N-methylpurin-8-yl was found to be the highest among
the investigated azinyl and azolyl substituents and is
comparable to that of the strongest classical EW func-
tionalities.
4,21
(
12) Kaes, C.; Katz, A.; Hosseini, M. W. Chem. Rev. 2000, 100, 3553-
3
7
590.
(
13) (a) Bradamante S.; Pagani G. A. Pure Appl. Chem. 1989, 61,
09-716. (b) Bradamante, S.; Pagani, G. In Advances in Carbanion
Chemistry; Snieckus, V., Ed.; J AI Press: Greenwich, CT, 1996; Vol. 2,
pp 189-263.
(14) (a) Bradamante, S.; Pagani, G. A. J . Org. Chem. 1984, 49,
2
863-2870. (b) Bradamante S.; Pagani G. A. J . Chem. Soc., Perkin
Trans. 2 1986, 1035-1046.
15) (a) Abbotto, A.; Alanzo, V.; Bradamante, S.; Pagani, G. A. J .
(
Chem. Soc., Perkin Trans. 2 1991, 481-488. (b) Abbotto, A.; Brada-
mante, S.; Pagani, G. A. J . Org. Chem. 1993, 58, 444-448. (c) Abbotto,
A.; Bradamante, S.; Pagani, G. A. J . Org. Chem. 1993, 58, 449-455.
(
1
d) Gatti, C.; Ponti, A.; Gamba, A.; Pagani, G. A. J . Am. Chem. Soc.
992, 114, 8634-8644.
(16) (a) Berlin, A.; Bradamante, S.; Pagani, G. A. J . Chem. Soc.,
Perkin Trans. 2 1988, 1525-1530. (b) Abbotto, A.; Bradamante, S.;
Pagani, G. A.; Rzepa, H.; Stoppa, F. Heterocycles 1995, 40, 757-776.
These findings lead to the general expectation that
bisheteroarylmethanes 1 (X ) azinyl or azolyl substitu-
ent) behave as active methylene compounds, showing a
reactivity pattern close to that of â-diketones and malonic
esters toward electrophilic reagents. Indeed, we have
shown that these systems, for instance, bis(benzothiazol-
(
17) (a) Abbotto, A.; Bradamante, S.; Pagani, G. A. J . Org. Chem.
1
996, 61, 1761-1769. (b) Abbotto, A.; Bradamante, S.; Capri, N.; Rzepa,
H.; Williams, D. J .; White, A. J . Org. Chem. 1996, 61, 1770-1778.
18) Abbotto, A.; Bradamante, S.; Facchetti, A.; Pagani, G. A. J . Org.
Chem. 1999, 64, 6756-6763.
19) Abbotto, A.; Bradamante, S.; Facchetti, A.; Pagani, G. A. J . Org.
Chem. 1998, 63, 436-444.
20) One of the reviewers questioned the suitability of the term
charge demand” for describing the ability of a group or substituent
(
(
(
2
-yl)methane (2) and bis(benzoxazol-2-yl)methane (3), do
“
in distributing the electron density of a carbanionic carbon into an
extended π-array. While we concede that a better term might be “π-
charge demand” or “π-electron- withdrawing power” we emphasize that
c is a charge, and more specifically a π-charge because of its NMR
source. We stress that c provides a static picture of the charge
distribution and has little to do with “reactivity” substituent constants
undergo classical electrophilic reactions under mild
conditions, including azo-coupling with benzenediazo-
nium chloride, nitrosation, and crotonic-type condensa-
tions.1
9,23
The highly reactive nature of the central
methylene moiety of 1 was also revealed in an additional
number of reactions, such as oxidation to carbinols and
ketones, dimerization to ethane or ethene derivatives,
-
-
such as σ
R
as previously defined. Values of c and σ
R
are somewhat
1
3
linearly related but have a different implication. We thank the
reviewer for stimulating us in providing the general reader with a
caveat in avoiding any arbitrary use of the π-charge demand c values.
24
and metal-promoted coupling reactions.
(
21) Barchiesi, E.; Bradamante, S.; Ferraccioli, R.; Pagani, G. A. J .
Chem. Soc., Perkin Trans. 2 1990, 375-383.
22) cPh in eq 2 is the π-charge residing on the phenyl ring in
PhCH-X.
(
(23) Abbotto, A.; Bradamante, S.; Pagani, G. A. Gazz. Chim. Ital.
1994, 124, 301-308.
5
754 J . Org. Chem., Vol. 67, No. 16, 2002

Metal Chelation Aptitudes of Bisheteroarylmethanes
-
SCHEME 1
form L , the acidity of the -CHW- bridge is expected to
play a strategic role, together with the stabilizing energy
of the metal-ligand coordination.
We have considered the following bisheteroarylmethane
ligands: (A) symmetrical and asymmetrical bis(benza-
zolyl)methanes, bis(benzothiazol-2-yl)methane (2), bis-
(
benzoxazol-2-yl)methane (3), bis(N-methylbenzimidazol-
-yl)methane (4), (benzothiazol-2-yl)(N-methylbenzimid-
azol-2-yl)methane (5), and bis(7-methylpurin-8-yl)methane
6); (B) unsubstituted and substituted bis(thiazol-2-yl)-
2
(
methanes, bis(thiazol-2-yl)methane (7), bis[4-(ethoxycar-
bonyl)thiazol-2-yl]methane (8), bis(4-phenylthiazol-2-yl)-
methane (9), bis[4-(p-nitrophenyl)thiazol-2-yl]methane
(
10), and bis(5-ethoxycarbonyl-4-methylthiazol-2-yl)-
methane (11); (C) mixed (benzothiazol-2-yl)(thiazol-2-yl)-
methanes, (benzothiazol-2-yl)(5-ethoxycarbonyl-4-meth-
ylthiazol-2-yl)methane (12), (benzothiazol-2-yl)(4-ethoxy-
carbonylthiazol-2-yl)methane (13), (benzothiazol-2-yl)(4-
hydroxycarbonylthiazol-2-yl)methane (14), (benzothiazol-
2
-yl)(thiazol-2-yl)methane (15), (benzothiazol-2-yl)(5-
hydroxycarbonyl-4-methylthiazol-2-yl)methane (16); (D)
bis(benzazolyl)methanes functionalized at the methylene
bridge, ligands 17-21; (E) mixed azine-azole bishet-
eroarylmethanes, (pyrid-2-yl)(benzothiazol-2-yl)methane
Given the remarkable similar reactivity of bishet-
eroarylmethanes with â-carbonyl derivatives, it is evident
that the -NdCsCH sCdN- fragment, present in bis-
2
o,o′-(azaheteroaryl)methanes, becomes particularly in-
teresting since it mimics, in its deprotonated form, the
well-known coordinating properties of â-diketonate moi-
eties. These heterocyclic systems can potentially behave
(
22) and (pyrid-2-yl)(benzoxazol-2-yl)methane (23); (F)
azine-based bisheteroarylmethanes, bis(pyrid-2-yl)methane
24), bis(pyrid-2-yl)acetonitrile (25), and bis(quinol-2-yl)-
(
methane (26).
-
as both neutral (LH) and anionic (L ) nitrogen ligands
toward transition-metal ions. In the former case, salt
m+
complexes of general formula [M(LH)
n
]
are obtained,
whereas the latter should lead to neutral chelates of the
type ML . The few known examples concerning the
coordinating properties of simple bisheteroarylmethanes
n
2
5
are basically limited to bis(quinol-2-yl)methane and bis-
2
6
(
pyrid-2-yl)methane. However, with very few excep-
2
7
tions, in none of these studies were neutral chelates
ML reported.
n
We herein report the first systematic and extensive
investigation on the coordinating properties of bishet-
eroarylmethanes, acting both as neutral ligands LH, to
m+
give salt complexes [M(LH)
n
]
, and as anionic ligands
(Scheme 1).
-
L , to afford neutral chelates ML
n
The latter can be formally obtained by preliminary
deprotonation of the ligand LH, followed by metal
coordination. To account for the formation of the neutral
n
complexes ML , where the ligand is present in its anionic
(
24) Bradamante, S.; Facchetti, A.; Pagani, G. A. Gazz. Chim. Ital.
996, 126, 329-337.
25) (a) Scheibe, G.; Daltrozzo, E. Adv. Heterocycl. Chem. 1966, 7,
53-181. (b) He, L.; Wang, X.; Gan, X.; Tang, N.; Tan, M. Chem. Abstr.
991, 114, 155978. (c) He, L.; Tang, N.; Gan, X.; Tan, M. Chem. Abstr.
991, 114, 177096.
1
(
1
1
1
(
26) (a) Black, D. S. C. Aust. J . Chem. 1967, 20, 2101-2107. (b)
Buehler, H. W.; Anderegg, G. Chimia 1970, 24, 433-436. (c) Urbach,
F. L.; Knopp, U.; Zuberbuehler, A. D. Helv. Chim. Acta 1978, 61, 1097-
1
106. (d) Canty, A. J .; Stevens, E. A. Inorg. Chim. Acta 1981, 55, L57-
L59. (e) Newkome, G. R.; Gupta, V. K.; Taylor, H. C. R.; Fronczek, F.
R. Organometallics 1984, 3, 1549-1554. (f) Canty, A. J .; Minchin, N.
J .; Skelton, B. W.; White, A. H. J . Chem. Soc., Dalton Trans. 1986,
The choice of heteroaromatic ligands was made to
elucidate electronic and structural effects in the forma-
tion of complexes. Ligands 2-6 are expected to lead to
1
0, 2205-2210. (g) Keene, F. R.; Snow, M. R.; Stephenson, P. J .;
Tiekink, E. R. T. Inorg. Chem. 1988, 27, 2040-2045. (h) Spodine, E.;
Manzur, J .; Garland, M. T.; Fackler, J . P. J .; Staples, R. J .; Trzcinska-
Bancroft, B. Inorg. Chim. Acta 1993, 203, 73-80. (i) Mock, C.; Puscasu,
I.; Rauterkus, M. J .; Tallen, G.; Wolff, J . E. A.; Krebs, B. Inorg. Chim.
Acta 2001, 319, 109-116.
stable neutral chelates ML
n
, due to the relevant charge
demand of the benzazolyl substituents, which should
stabilize the anionic structure of the ligand in the
complex. In this series, the stabilization of the anionic
ligand should reflect the different charge demands of the
27) A neutral chelate of the type ML
3
(M3 ) Gd , LH ) bis(pyrid-
+
3+
(
2
1
-yl)methane) was described: Mandel, A.; Magull, J . Z. Chem. Abstr.
995, 123, 101323.
J . Org. Chem, Vol. 67, No. 16, 2002 5755

Abbotto et al.
heterocyclic rings, which increases on going from N-me-
thylbenzimidazol-2-yl to N-methylpurin-8-yl. Similar
considerations prompted the design of ligands 7-11,
where ring substitution with EW groups should play a
SCHEME 2
-
-
-
stabilizing effect in L . Compound 11 differs from 8 in
the fact that the electron-wihdrawing substituent
CO Et is in a position that is analogous to the benzenoid
2
para one with respect to the negative charge on the
bridging carbon atom, supplying a more favorable sta-
bilizing delocalization. Following the same reasoning, we
have added ligands 12, 13, and 15 where the thiazole
ring is either unsubstituted or substituted with a strong
electron-acceptor group. A number of hydroxycarbonyl-
substituted systems, 14 and 16, and methylene-bridge-
functionalized bisbenzazolylmethanes, 17-21, were thus
introduced to investigate the formation of chelates with
potential additional properties such as improved solubil-
ity in protic solvents, a desirable property in view of
biodiagnostic applications, and to furnish a convenient
linking site for subsequent derivatization in DNA-bind-
ing28 and tumor-targeting applications. Finally, a num-
ber of azine-based derivatives, 22-26, were included to
compare the azine vs azole coordination properties
toward transition metals and the possible steric effect
exerted by the six- vs five-membered ring. Again, we have
designed different ligands reasoning on electronic effects.
The mixed systems 22 and 23 combine the commonly
used coordinating properties of the pyrid-2-yl moiety12
with that of two strong benzazolyl acceptors (see Table
SCHEME 3
remaining compounds were previously unknown, with
very few exceptions concerning 533 and 19.
34
8
The mixed benzothiazolyl-benzimidazolyl derivative
5 was obtained according to Scheme 2, where the two
heterocycle rings are formed in two subsequent steps.
The benzothiazolyl intermediate 27 was prepared by
condensation, under neat conditions, of 2-aminothiophe-
nol with ethyl cyanoacetate. The subsequent ring clo-
sure to benzimidazole was carried out, with low yields,
under conditions similar to those previously used for
the synthesis of 4,24 with no solvent and distilling off
the ethanol formed during the condensation with the
aid of a continuous flow of inert gas, to keep the reac-
tion temperature constant at the initial value (160 °C).
The crude product was purified by acid-base treat-
ment.
1
). Ligands 25 and 26 furnish an additional stabilizing
effect in the corresponding conjugate anions with respect
to the pyridine derivative 24 due to the presence of a
third acceptor group (CN) and a larger charge demand
of the azine ring, respectively.
Over the past few years, we have sporadically com-
municated a number of salt complexes and neutral
chelates based on bisheteroarylmethanes. We have pre-
liminarily reported the synthesis and characterization of
Ring-substituted bis(thiazol-2-yl) derivatives 9 and 10
were conveniently prepared in high yields according to
3
5
the general Hantzsch thiazole synthesis, by condensing
malonodithioamide23 with the corresponding phenacyl
bromides (Scheme 3). We have found that the replace-
ment of DMF, used in the Hantzsch synthesis of 8
2
9
30
19
16b
some complexes afforded by 2, 3, 5 and 6, 25, and
1
6b
30
29
2
6,
and explored their catalytic activity. X-ray,
3
1
17a
spectroscopic, and magnetic studies have shown that
neutral chelates of 2 and 3 with Ni(II), Cu(II), Co(II), and
Zn(II) present a distorted tetrahedral geometry. In the
(intermediate for 7), with the mixture acetone-water
(4:1) as a reaction solvent led to higher yields and lower
amounts of byproducts. Isolation of the practically pure
product is particularly easy for the nitrophenyl deriva-
tive, since it readily separates from the reaction mixture
thanks to its low solubility in the used solvent. It is worth
noting that whereas the parent unsubstituted derivative
7 is liquid at room temperature and rather unstable in
air (it must be stored, but only for short periods, under
nitrogen and in the cold),1 4-aryl derivatives 9 and 10
are stable, relatively high melting compounds.
case of the Cu(II) neutral chelate of 2 the data suggested
an oligo- or polynuclear structure.2
9,31
It is worth noting
that most of our previously published chelates have been
very recently patented by others in their use as elec-
troluminescent materials.32
7a
Resu lts
Syn th esis of Liga n d s. We have previously reported
the synthesis of bisheteroarylmethanes 4, 6-8, 11, and
Synthesis of the thiazolyl-benzothiazolyl ligand 12
implied conversion of the ester 27 to acetamide 28, and
then to thioacetamide 29, to apply the Hantzsch route
to the formation of the thiazolyl ring, as depicted in
Scheme 4. Both intermediates 2836 and 29 were re-
1
8-21, and prepared derivatives 2 and 3 according to
known methods (see the Experimental Section). All the
37
(
28) Abbotto, A.; Pagani, G. A.; Corradini, R.; Dossena, A.; Marchelli,
R. University of Milano-Bicocca, Italy, unpublished results.
29) Abbotto, A.; Alanzo, V.; Bradamante, S.; Pagani, G. A.; Rizzoli,
C.; Calestani, G. Gazz. Chim. Ital. 1991, 121, 365-368.
30) Ragaini, F.; Pizzotti, M.; Cenini, S.; Abbotto, A.; Pagani, G. A.;
Demartin, F. J . Organomet. Chem. 1995, 489, 107-112.
31) Abbotto, A.; Bruni, S.; Cariati, F.; Pagani, G. A. Spectrochim.
Acta, Part A 2000, 56, 1543-1552.
32) Hisashi, O. J apan Patent 2000008033, 2000; Chem. Abstr. 2000,
32, 100241.
(33) Chuiguk, V. A.; Fedotov, K. V. Chem. Abstr. 1981, 95, 24917.
(34) Kornilov, M. Yu.; Ruban, E. M. Chem. Abstr. 1978, 88, 51929.
(35) J oule, J . A.; Mills, K.; Smith, G. F. Heterocyclic Chemistry;
Chapman & Hall: London, 1984.
(36) (a) van Dormael, A. E.; de Smet, P. Chem. Abstr. 1952, 46,
26032. (b) Yakout, E. M. A.; Allam, Y. A.; Nawwar, G. A. M. Heteroat.
Chem. 1999, 10, 177-182.
(37) Elneairy, M. A. A.; Abdel-Rahman, T. M.; Hammad, A. M. J .
Chem. Res., Synop. 1998, 684-685.
(
(
(
(
1
5
756 J . Org. Chem., Vol. 67, No. 16, 2002

Metal Chelation Aptitudes of Bisheteroarylmethanes
SCHEME 4
SCHEME 5
methyl 2-pyridylacetate with o-aminothiophenol and
o-aminophenol, respectively, at ca. 160 °C under neat
conditions. Whereas the reaction with o-aminothiophe-
nol gave directly the corresponding bisheteroarylmethane
2
2 in 75% yield, in the case of the oxa analogue
condensation led to the isolation of the o-hydroxyanilide
3
9
3
5, which only subsequently could be cyclized to the
ported very few times in the literature. A synthesis of
final product 23 in 50% overall yield using polyphosphoric
acid as a condensing agent. The lower yield and higher
complexity of the latter procedure are likely due to the
instability of the benzoxazole ring under acidic conditions,
as described elsewhere.40 Indeed, the benzoxazole deriva-
tive 23 opens back to the anilide 35 in acidic aqueous
solution.
thioamide 29 was only recently communicated, employing
the reaction of H
2
S with benzothiazol-2-ylacetonitrile.37
We report here a much more convenient access in good
yields to 29 from carboxamide 28 and the simple action
of Lawesson’s reagent in boiling toluene, avoiding the use
of highly toxic hydrogen sulfide. Final ring closure was
accomplished by condensation of 29 with ethyl bromoac-
etoacetate. The use of the commercially available chlo-
roacetoacetate, in different solvents, afforded the product
in much less satisfactory yields.
Syn th esis of Neu tr a l Ch ela tes a n d Sa lt Com -
p lexes. Tables 2-4 and Tables 5 and 6 collect ex-
perimental details and microanalytical data for the
preparation and characterization of all of the novel
neutral chelates and salt complexes, respectively. Fur-
The series of ligands 13-15 was prepared by reaction
of 29 with ethyl bromopyruvate to give 13 in fair yields.
Subsequent acidic hydrolysis of 13 using 10% HCl gave
the corresponding carboxylic acid 14 (Scheme 5), which
precipitates in the reaction medium and can be easily
isolated in good yields. Decarboxylation of 14 upon
heating and subsequent distillation under reduced pres-
sure led to the ligand 15 in low yields. In general,
thiazole-4-carboxylic acids undergo decarboxylation less
easily than the corresponding 2- and 5-isomers,38 and
indeed severe conditions are needed for the decarboxy-
lation of 14.
1
13
ther characterization, including H and some C NMR
spectra of diamagnetic Zn and Pd chelates and UV-vis,
MS, and IR data can be found in the Experimental
Section.
A key choice concerned the solvent in which to carry
out the reaction with metal ions. This factor was found
to be critical for the successful obtainment of the neutral
and salt complexes and to greatly affect both yields and
chelate isolation and purity. Whenever possible, we
employed a solvent where the expected chelates are
insoluble but the starting inorganic salts and the organic
ligands are soluble. Following this approach, microana-
lytically pure chelates can be readily obtained usually
in high yields. Our initial attempts based on a two-phase
reaction, where an aqueous solution of the metal acetate
was vigorously shaken with a solution of the ligand in
All of the attempts to prepare 16 by hydrolysis of 12
failed, as shown in Scheme 6. Therefore, we prepared the
system 30, where the ethoxy group is replaced by the
more labile tert-butoxy one. In fact, PTSA treatment of
3
0 in benzene afforded 16 in excellent yields.
2 2 3
either CH Cl or CHCl , afforded, in the organic phase,
impure chelates in low yields.
In general, addition of either a methanol or ethanol
Synthetic access to R-heteroarylmethyl-substituted
ligands 17 and 18 (Scheme 7) exploited the behavior of
bis(benzazol-2-yl)methanes 2 and 3 as active methylene
compounds, which makes picolylidene derivatives 31 and
solution of a metal acetate, M(OAc)
Ni, Co, Pd), to a solution of ligands 2 (entries 1-5, Table
2
‚nH O (M ) Zn, Cu,
2
3
2, respectively, readily available.23 Catalytic hydrogena-
2
), 3 (entries 7-11, Table 2), 11 (entries 5-9, Table 3),
tion to picolyl derivatives 33 and 34 and subsequent
00% regioselective alkylation of the pyridine nitrogen
with methyl triflate in dry benzene afforded salts 17 and
8, which can be isolated as crystalline pure analytical
and 12 (entries 10-14, Table 3) in the same solvent
afforded all of the corresponding neutral chelates. From
1
2
and Hg(OAc)
2
the Hg(II) chelate was also successfully
‚nH
1
isolated (entry 6, Table 2). The reaction of M(OAc)
2
2
O
samples. When the triflate gegenion is replaced by iodide,
isolation of crystalline products is much more tedious and
difficult, whereas alkylation with dimethyl sulfate led to
mixtures of products, likely due to the simultaneous
monoalkylation of the azole nitrogen atoms and poly-
alkylation side reactions.
(
38) Katritzky A. R. Handbook of Heterocyclic Chemistry; Pergamon
Press: Oxford, 1983.
(39) The identification of the condensation product as the isomer
O-(o-aminophenyl)pyrid-2-ylacetate, which would derive from
transesterification reaction, has been excluded on the basis of IR data
a
-1
(
1690 cm , amidic CdO streching) and solubility in 10% aqueous
NaOH.
The synthetic approach to the mixed pyrid-2-yl-benz-
(40) Sainsbury, M. In Rodd’s Chemistry of Carbon Compounds;
1
,3-azol-2-yl derivatives 22 and 23, shown in Scheme 8,
Coffey, S., Ansell, M. F., Eds.; Elsevier: Amsterdam, 1986; Vol. IV,
Part C, Chapter 17, p 350.
employed the condensation of the commercially available
J . Org. Chem, Vol. 67, No. 16, 2002 5757

Abbotto et al.
SCHEME 6
SCHEME 7
SCHEME 8
scopic (IR) and microanalytical data suggested that
4
CuSO might have afforded a mixture of the two types
of complexes.
Attempts to prepare neutral chelates of “hydrophilic”
ligands 14, 16, and 18-21 were performed following the
general synthetic protocol depicted above. All of the
Zn(II), Cu(II), Ni(II), Co(II), and Pd(II) neutral chelates
of 17 (entries 3-7, Table 4) and 18 (entries 8-12, Table
4
) were isolated. However, both the ligand and metal
acetate should be dissolved in a minimal amount of
solvent to allow precipitation of the corresponding che-
late, which occurs either immediately or after partial
solvent removal. In fact, thanks to the improved ligand
solubility in alcohols, their chelates do not readily
precipitate and therefore are much more difficult to
isolate and purify. Ligand 19 gave both Zn(II) and
Pd(II) chelates (entries 13 and 14, Table 4). On the
contrary, neutral chelates of hydroxycarbonyl-containing
ligands 14, 16, and 20 could not be isolated.
(
M ) Zn, Cu, Ni, Co) with all of the other ligands in
methanol, ethanol, or DMF may or may not lead to the
formation of the neutral chelates. We isolated the Zn(II)
and Cu(II) chelates of 5 (entries 12 and 13, Table 2) and
1
3 (entries 1 and 2, Table 4), the Cu(II) and Co(II)
chelates of 10 (entries 3 and 4, Table 3), and the Cu(II)
chelates of 8 (entry 1, Table 3) and 9 (entry 2, Table 3).
Systems 7, 15, 22, and 23 failed to react with any metal
acetate, and the unreacted ligand was recovered. The
above results confirm that a positive reaction of bishet-
eroarylmethanes with azaphilic transition-metal acetates
gives the corresponding neutral chelates. The only no-
ticeable, but fully explainable, exception is the action of
some of the above acetates on ligand 4, which gives the
corresponding salt complexes (entries 1-4, Table 6). In
Oxid a t ion a n d Ma n ga n ese(II)-P r om ot ed Cou -
41
24
p lin g Rea ction s. We have previously reported that
the action of poorly azaphilic transition-metal acetates
such as manganese(II), iron(II), and lead(II) on ligands
2
-4 and 22 promotes their oxidation and/or dimerization
reactions instead of leading to the corresponding neutral
chelates (Scheme 9). Similarly, the reaction of the highly
1
9
this case we showed that to isolate neutral chelates
M(4 ) , the presence of a strong base, such as MeONa,
2
is needed.
coordinating ligands 6, 11, and 12 with Mn(OAc)
2
2
‚4H O
-
gives rise to variable yields of either pure or mixtures of
oxidation/dimerization products 36-39, according to
Scheme 10.
Reaction of an alcoholic (MeOH or EtOH) solution of a
number of metal chlorides, MCl
Ni, Co, Hg), with a solution of 2 (entries 1-5, Table 5),
3
1
6
2
‚nH
2
O (M ) Zn, Cu,
Unfortunately, separation and therefore analytical
characterization of the oxidation/dimerization products
(entries 7-10, Table 5), 6 (entries 5 and 6, Table 6),
2 (entries 7 and 8, Table 6), 22 (entries 9 and 10, Table
), and 23 (entry 11, Table 6), generates the correspond-
1
of 6 were not performed due to their poor solubility. H
NMR spectra of this mixture could not be recorded in
ing salt complexes. The action of metal sulfates MSO
nH O (M ) Zn, Cu, Ni, Co) was checked on ligand 2. They
were found to behave somehow between acetates and
chlorides. ZnSO and CuSO afforded the corresponding
neutral chelates Zn(2 ) , whereas NiSO gave
and Co(2-)
the salt complex Ni(2) SO (entry 6, Table 5). Spectro-
4
‚
(
41) We thank one of the reviewers for pointing out that the
2
formation of the coupling products could be envisioned as occurring
via a radical process. See for instance: Newkome, G. R.; J oo, Y. J .;
Evans, D. W.; Fronczek, F. R.; Baker, G. R. J . Org. Chem. 1990, 55,
714-19. In the original paper we neither investigated the reaction
mechanism nor hypothesized any carbanionic intermediate, with the
exception of the oxidation to ketones (ref 24).
4
4
5
-
2
2
4
2
4
5
758 J . Org. Chem., Vol. 67, No. 16, 2002

Metal Chelation Aptitudes of Bisheteroarylmethanes
TABLE 2. Exp er im en ta l a n d An a lytica l Da ta of Neu tr a l Ch ela tes of Liga n d s 2-4 w ith Differ en t Meta ls
preparation procedure
product
analytical data
EAa
protocol
(time)
yield
(%)
notes
b
entry LH mmol
metal salt
mmol
color
yellow
formula
C
H
N
(mp)
1
2
3
4
5
6
7
8
9
0
1
2
3
2
2
2
2
2
2
3
3
3
3
3
5
5
5.00
1.00
1.00
5.00
3.00
2.00
1.00
1.00
1.00
1.00
2.00
0.20
0.20
Zn(OAc)2‚2H2 O
2.50
0.50
0.50
2.50
1.50
1.00
0.50
0.50
0.50
0.50
1.00
0.10
0.10
A
94
96
78
68
84
90
85
89
73
94
94
81
40
C30H18N4S4Zn
57.08
2.85
8.86
(8.92)
8.67
(8.95)
9.18
(9.02)
8.79
(9.01)
8.54
(8.38)
7.24
(7.34)
10.12
(9.93)
9.82
c
(15 min)
(57.36) (2.89)
57.26 2.87
(57.53) (2.90)
57.78 2.97
(57.98) (2.92)
57.68 2.98
(57.95) (2.92)
53.25 3.01
(53.85) (2.71)
46.72 2.29
(47.20) (2.38)
64.12 3.31
(63.89) (3.22)
63.78 3.30
(64.10) (3.23)
64.91 3.34
Cu(OAc)2‚H2O
Ni(OAc)2‚4H2O
Co(OAc)2‚4H2O
Pd(OAc)2
A
green
C30H18N4S4Cu
C30H18N4S4Ni
C30H18N4S4Co
C30H18N4S4Pd
C30H18N4S4Hg
C30H18N4O4Zn
C30H18N4O4Cu
C30H18N4O4Ni
C30H18N4O4Co
C30H18N4O4Pd
C32H24N6S2Zn
C32H24N6S2Cu
(15 min)
A
dark green
dark purple
dark brown
orange
d
(30 min)
A
c
(15 min)
A
e
(30 min)
Hg(OAc)2
A
(245)
(15 min)
Zn(OAc)2‚2H2O
Cu(OAc)2‚H2O
Ni(OAc)2‚4H2O
Co(OAc)2‚4H2O
Pd(OAc)2
A
light brown
blue
(15 min)
A
(15 min)
(9.97)
9.93
A
dark green
red
d
f
(30 min)
(64.66) (3.26) (10.05)
64.68 3.27 9.76
(64.62) (3.26) (10.05)
1
1
1
1
A
(15 min)
A
red
59.78
(59.56) (3.34)
61.57 3.75
3.22
9.25
(9.26)
13.37
(30 min)
Zn(OAc)2‚2H2O
Cu(OAc)2‚H2O
A
yellow
(15 min)
(61.78) (3.90) (13.51)
63.56 3.63 13.69
D
green
(1 d)
(61.96) (3.91) (13.55)
a
Calculated values are reported in parentheses. b Melting points (°C) are >250 unless indicated in parentheses. These chelates can
c
also be obtained from the corresponding metal sulfates under similar conditions. The reaction was performed at 50 °C. e Under nitrogen.
This chelate was washed with warm MeOH.
d
f
TABLE 3. Exp er im en ta l a n d An a lytica l Da ta of Neu tr a l Ch ela tes of Liga n d s 8-12 w ith Differ en t Meta ls
preparation procedure
product
analytical data
EAa
H
protocol
(time)
yield
(%)
notes
(mp)
b
entry LH mmol
metal salt
mmol
color
brown
formula
C
N
1
2
3
4
5
6
7
8
9
0
1
2
3
4
8
9
1.00
1.00
1.00
1.00
2.80
1.70
5.00
1.00
1.00
1.20
0.80
0.80
0.90
1.00
Cu(OAc)2‚H2O
0.50
0.50
0.50
0.50
1.40
0.85
2.50
0.50
0.50
0.60
0.40
0.40
0.45
0.50
B
13
14
18
18
79
76
29
37
21
35
86
66
97
27
C26H26N4S4O8Cu
44.02
3.58
7.96
(7.84)
7.76
(5 h)
(43.72) (3.67)
62.38 3.54
(62.48) (3.59)
49.94 2.37
(50.12) (2.44) (12.31)
50.61 2.52 12.53
(50.38) (2.52) (12.37)
46.51 4.13 7.33
(46.66) (4.44)
46.75 4.39
(46.77) (4.45)
46.83 4.24
(47.06) (4.47)
47.20 4.48
(47.05) (4.48)
44.71 4.32
(44.31) (4.21)
51.25 3.86
(51.45) (3.75)
51.14 3.80
(51.59) (3.76)
51.66 3.61
(51.95) (3.78)
51.66 3.67
(51.93) (3.78)
48.15 3.24
(48.61) (3.54)
Cu(OAc)2‚H2O
Cu(OAc)2‚H2O
Co(OAc)2‚H2O
Zn(OAc)2‚2H2O
Cu(OAc)2‚H2O
Ni(OAc)2‚4H2O
Co(OAc)2‚4H2O
Pd(OAc)2
D
blue
C38H26N4S4Cu
c
(20 h)
(7.67) (160)
10
10
11
11
11
11
11
12
12
12
12
12
D
blue
C38H22N8O8S4Cu
C38H22N8O8S4Co
C30H34N4O8S4Zn
C30H34N4O8S4Cu
C30H34N4O8S4Ni
C30H34N4O8S4Co
C30H34N4O8S4Pd
C30H26N4O4S4Zn
C30H26N4O4S4Cu
C30H26N4O4S4Ni
C30H26N4O4S4Co
C30H26N4O4S4Pd
12.12
d
d
c
(2 h)
D
blue
(2 h)
A
orange
dark green
gray
(15 min)
(7.29) (208)
7.00
(7.27) (277)
7.34
(7.32) (202)
7.14
(7.32) (208)
7.02
(6.89) (247)
8.22
(8.00) (209)
A
c
(15 min)
A
c
(15 min)
A
purple
brown
red
c
(15 min)
A
c
(15 min)
1
1
1
1
1
Zn(OAc)2‚2H2O
Cu(OAc)2‚H2O
Ni(OAc)2‚4H2O
Co(OAc)2‚4H2O
Pd(OAc)2
A
c
(3 h)
A
brown
black
red
8.03
(8.02)
8.23
c
(1 h)
D
c
(24 h)
(8.08) (210)
8.12
(8.08) (162)
7.31
(7.56) (203)
A
c
(3 h)
B
brown
c
(4 d)
a
Calculated values are reported in parentheses. Melting points (°C) are >250 unless indicated in parentheses. c In EtOH instead of
b
d
MeOH. In DMF instead of MeOH.
common deuterated solvents. The IR spectra of the solid
arising from the reaction of manganese acetate with 6
shows a typical CdO stretching at 1684 cm-1, suggesting
the presence of ketone 36. However, elemental analysis
J . Org. Chem, Vol. 67, No. 16, 2002 5759

Abbotto et al.
TABLE 4. Exp er im en ta l a n d An a lytica l Da ta of Neu tr a l Ch ela tes of Liga n d s 13 a n d 17-19 w ith Differ en t Meta ls
preparation procedure
product
analytical data
EAa
H
protocol
(time)
yield
(%)
notes
(mp)
b
entry LH mmol
metal salt
mmol
color
yellow
formula
C
N
1
2
3
4
5
6
7
8
9
0
1
2
3
4
13
13
17
17
17
17
17
18
18
18
18
18
19
19
0.66
0.66
0.40
0.10
0.10
0.10
0.40
0.10
0.10
0.10
0.10
0.40
0.40
0.60
Zn(OAc)2‚2H2O
0.33
0.33
0.20
0.05
0.05
0.05
0.20
0.05
0.05
0.05
0.05
0.20
0.20
0.30
A
28
10
48
59
17
57
23
45
57
29
55
78
96
52
C28H22N4O4S4Zn
50.56
3.57
8.84
c
(30 min)
(50.04) (3.30) (8.34)
50.74 3.41 8.68
(50.17) (3.31) (8.36)
48.31 3.20 7.23
(48.52) (3.01) (7.38)
48.61 3.31 7.63
Cu(OAc)2‚H2O
Zn(OAc)2‚2H2O
Cu(OAc)2‚H2O
Ni(OAc)2‚4H2O
Co(OAc)2‚4H2O
Pd(OAc)2
A
green
yellow
green
green
C28H22N4O4S4Cu
C46H34F6N6O6S6Zn
C46H34F6N6O6S6Cu
C46H34F6N6O6S6Ni
C46H34F6N6O6S6Co
C46H34F6N6O6S6Pd
C46H34F6N6O10S2Zn
C46H34F6N6O10S2Cu
C46H34F6N6O10S2Ni
C46H34F6N6O10S2Co
C46H34F6N6O10S2Pd
C56H50N4S4Zn
c
c
(40 min)
C
(3 h)
D
(4 h)
(48.60) (3.02) (7.40) (114)
50.12 3.15 7.58
(48.84) (3.03) (7.43) (241)
48.54 3.28 7.64
(48.81) (3.03) (7.43) (163)
46.67 3.07 7.31
(46.83) (2.91) (7.13)
51.27 3.15 7.70
(51.42) (3.20) (7.82)
51.08 2.92 7.75
(51.51) (3.20) (7.84) (210)
51.94 3.33 7.65
(51.74) (3.22) (7.87) (160)
51.53 3.08 7.64
(51.73) (3.22) (7.87) (162)
49.64 3.09 7.72
(49.53) (3.08) (7.54)
62.73 4.97 5.14
(62.93) (4.73) (5.24) (214)
59.97 4.57 4.71
(60.61) (4.55) (5.05) (232)
D
(5 h)
D
brown-purple
light brown
yellow
c
(4 h)
B
(30 min)
Zn(OAc)2‚2H2O
Cu(OAc)2‚H2O
Ni(OAc)2‚4H2O
Co(OAc)2‚4H2O
Pd(OAc)2
C
(15 min)
C
green
(4 h)
1
1
1
1
1
D
green
(15 min)
D
brown
(4 h)
A
red-brown
yellow
(15 min)
Zn(OAc)2‚2H2O
Pd(OAc)2
A
(15 min)
A
light brown
C56H50N4S4Pd
(15 min)
a
Calculated values are reported in parentheses. b Melting points (°C) are >250 unless indicated in parentheses. c In EtOH instead of
MeOH.
TABLE 5. Exp er im en ta l a n d An a lytica l Da ta of Sa lt Com p lexes of Liga n d s 2 a n d 3 w ith Differ en t Meta ls
preparation procedure
product
analytical data
EAa
H
protocol
(time)
composition
(color)
yield
(%)
notes
(mp)
b
entry LH mmol
metal salt
ZnCl2
mmol
0.55
formula
C
N
1
2
3
4
5
6
7
8
9
0
2
2
2
2
2
2
3
3
3
3
1.10
1.10
1.10
1.10
5.00
2.00
1.20
1.20
1.20
1.20
A
Zn(LH)Cl2
69
65
96
63
13
16
68
65
92
63
C15H10Cl2N2S2Zn
C30H20Cl2N4S4Cu
C15H11ClN2OS2Ni
C15H10Cl2N2S2Co
C15H10Cl2N2S2Hg
C30H20N4O4S5Ni
C15H10Cl2N2O2Zn
C30H20Cl2N4O4Cu
C15H11ClN2O3Ni
C30H20Cl2N4O4Co
42.93
2.59
7.07
(
A
(
B
15 min) (light green)
Cu(LH)2Cl2
15 min) (dark green)
Ni(LH)OHCl
15 min) (yellow-brown)
(43.03) (2.41) (6.69)
51.38 2.99 7.69
(51.53) (2.89) (8.01)
45.77 2.82 7.12
(45.51) (2.91) (7.33)
43.92 2.63 6.73
(43.70) (2.44) (6.73)
32.05 2.09 4.78
(32.52) (1.82) (5.06)
49.67 3.02 7.67
(50.07) (2.81) (7.79)
46.27 2.58 7.67
(46.60) (2.56) (7.25)
56.54 3.00 9.01
(56.74) (3.18) (8.83)
49.63 2.94 7.50
(49.84) (3.07) (7.75)
57.39 3.41 9.32
(57.15) (3.20) (8.90)
CuCl2
0.55
0.55
0.55
2.50
1.00
0.60
0.60
0.60
0.60
NiCl2
(
CoCl2‚6H2O
HgCl2
A
Co(LH)Cl2
c
c
(15 min) (blue)
A
Hg(LH)Cl2
(15 min) (light green)
NiSO4‚6H2O
ZnCl2
A
Ni(LH)2SO4
(15 min) (green)
A
Zn(LH)Cl2
(
A
(
15 min) (light yellow)
Cu(LH)2Cl2
15 min) (yellow-brown)
CuCl2
NiCl2
C
Ni(LH)OHCl
(yellow-brown)
Co(LH)2Cl2
(48 h)
1
CoCl2‚6H2O
A
c
(15 min) (green)
a
Calculated values are reported in parentheses. b Melting points (°C) are >250 unless indicated in parentheses. c In EtOH instead of
MeOH.
indicates the presence of byproducts, probably arising
from coupling and dimerization reactions, which could
not be isolated. On the other hand, the reaction of
ethane dimer 37, whereas from 12 the ketone 38 and
dimer 39 can be isolated. Note that, due to the asym-
metry of the system 12, both (E)- and (Z)-39 diastereo-
1
Mn(OAc)
2
with the much more soluble systems 11 and
isomers were clearly detected in solution by H NMR, as
1
2 gives products which could be investigated in detail.
shown in Figure 1. In contrast to 6 and 12, the reaction
of manganese(II) acetate with 11 does not afford any
trace of the corresponding ketone 40. The latter can be
isolated only, leaving 11 to the action of air in a basic
Full analytical, spectroscopic, and mass spectrometric
characterization of products 37-39 allowed the assign-
ment of the above structures. Compound 11 gives the
5
760 J . Org. Chem., Vol. 67, No. 16, 2002

Metal Chelation Aptitudes of Bisheteroarylmethanes
TABLE 6. Exp er im en ta l a n d An a lytica l Da ta of Sa lt Com p lexes of Liga n d s 4, 6, 12, 22, a n d 23 w ith Differ en t Meta ls
preparation procedure
product
analytical data
EAa
H
protocol
mmol (time)
composition
(color)
yield
(%)
notes
(mp)
b
entry LH mmol
metal salt
formula
C
N
1
2
3
4
5
6
7
8
9
0
1
4
4
4
4
6
6
1.00 Zn(OAc)2‚2H2O 0.50
A
Zn(LH)(OAc)2‚1.5H2O 35
C21H24N4O5Zn
52.09
4.71
11.12
(15 min) (light green)
(52.13) (5.14) (11.58)
55.31 4.54 12.15
(55.06) (4.85) (12.23)
55.43 4.62 14.68
(55.65) (4.90) (12.36)
51.64 4.68 12.36
(51.53) (5.36) (11.45)
44.92 3.48 32.16
(44.81) (3.47) (32.16)
44.92 3.49 32.25
(44.93) (3.48) (32.24)
C15H14Cl2N2O2S2Zn 40.15 3.08 6.41
(39.68) (3.10) (6.16)
C30H28Cl2N4O4S4Cu 47.18 3.27 7.55
(46.71) (3.66) (7.26)
43.57 3.05 7.63
(43.06) (2.78) (7.73)
43.79 3.15 8.01
(43.28) (2.79) (7.77)
45.21 3.04 7.83
(45.06) (2.91) (8.09)
1.00 Cu(OAc)2‚H2O
0.50
A
Cu(LH)(OAc)2
70
39
17
62
14
39
24
65
44
86
C21H22N4O4Cu
C21H22N4O4Ni
C21H26N4O6Co
C26H24Cl2N16Zn
C26H24Cl2N16Cu
(15 min) (light blue)
1.00 Ni(OAc)2‚4H2O 0.50
1.00 Co(OAc)2‚4H2O 0.50
D
Ni(LH)(OAc)2
(gray)
(12 h)
D
Co(LH)(OAc)2‚2H2O
c
(3 h)
(pink)
0.54 ZnCl2
0.54 CuCl2
0.27
0.27
0.28
0.55
0.50
0.50
0.40
E
Zn(LH)2Cl2
(10 min) (orange)
E
Cu(LH)2Cl2
Zn(LH)Cl2
Cu(LH)2Cl2
Zn(LH)Cl2
(10 min) (light green)
12 0.56 ZnCl2
12 1.10 CuCl2
22 1.00 ZnCl2
22 1.00 CuCl2
23 0.80 ZnCl2
A
c
c
(15 min) (yellow)
A
(15 min) (green)
A
C13H10Cl2N2SZn
C13H10Cl2N2SCu
C13H10Cl2N2OZn
(15 min) (white)
1
1
B
Cu(LH)Cl2
(green)
(2 h)
A
Zn(LH)Cl2
(15 min) (light yellow)
a
Calculated values are reported in parentheses. b Melting points (°C) are >250 unless indicated in parentheses. c In EtOH instead of
MeOH.
SCHEME 9
MeONa/MeOH solution (Scheme 11). A similar result was
obtained for ligand 2.
metric ligand 12 and of the corresponding Zn(II) and Pd-
(II) chelates (Figure 3) provide insights into the struc-
tures of these chelates. The comparison of the two metal
complex spectra is clear evidence of the different ligand
arrangement around the metal center. We reported that
Discu ssion
Str u ctu r e of Neu tr al Ch elates: Mu ltin u clear NMR
In vestiga tion . Multinuclear NMR data provide un-
equivocal evidence of the existence of the ligand as an
29
the four-coordinated Zn(II) chelate of 2 is tetrahedral
-
and, accordingly, Zn(12 )
2
is a mixture of two enanti-
13
omers, giving rise to a single set of C NMR resonances.
Conversely, four-coordinated Pd(II) complexes, such as
those of many diketonates, are known to be square
-
anionic species, L , in the neutral chelates ML
2
. Table 7
1
13
15
collects relevant H, C, and N shifts of ligands 2-6,
1, 12, 25, and 26 and of the corresponding Zn(II) neutral
chelates. For comparison, NMR data of solvent-separated
1
42
planar, and indeed the Pd(II) chelate of 12, exhibiting
two set of resonances with different intensities, provides
evidence of the presence of two diastereoisomers in
different ratios. Similar conclusions can be drawn by
looking at the corresponding proton NMR spectra.
N-Coordination in the neutral chelates is also strongly
-
-
-
-
-
-
ion pair sodium carbanions 2 , 3 , 6 , 25 , and 26 (L //
+
1
Na ) are also reported. H NMR data clearly show the
formation of neutral chelates. The methylene (ligand) f
methine (chelate) conversion of the bridge after complex-
1
ation is evident from both H NMR integration (bridge
15
supported by the N NMR chemical shifts, which show
versus ring protons) and the low-field shift of the -CH-
resonance compared to the -CH2- resonance. The close
a significant difference (30-60 ppm) with respect to the
15
ligand anion. The N NMR shifts of the neutral systems
1
3
similarity of both the -CH- bridge and ring carbon
C
compared to the corresponding anions exhibit high-field
displacements. These resonances are further high-field-
1
-
+
NMR shifts and J (CH) coupling constants of L //Na and
the corresponding ZnL (shown in Figure 2 for L ) 3) is
2
1
shifted in the neutral chelates. Figure 4 shows the H-
further evidence that all of the ligands are present in the
chelates as anions. Note that the π-electronic distribution
of the carbon framework of the anionic ligands, as derived
from 13C NMR data, is almost identical to that of “free”
carbanions in DMSO. This is peculiar in view of the large
different properties and reactivity of these two classes
15
N HETCOR NMR spectrum of ligand 5 and of its Zn(II)
neutral chelate. Both azine nitrogen atoms (N(1) and
N(2)) and the pyrrole-like nitrogen (N(3)) can be clearly
(42) (a) Cotton, F. A.; Wilkinson, G.; Murillo, C. A.; Bochmann, M.
Advanced Inorganic Chemistry; Wiley: New York, 1999. (b) Thornton,
D. A. Coord. Chem. Rev. 1990, 104, 173-249.
1
3
of compounds. Finally, C NMR spectra of the asym-
J . Org. Chem, Vol. 67, No. 16, 2002 5761

Abbotto et al.
F IGURE 1. 1H NMR spectrum of the (E)- and (Z)-dimers of 12 in CDCl
.
3
SCHEME 10
2
detected. Our results on a series of pyridyl-based car-
banions and nitroanions showed that the increase of
π-electron density on an sp nitrogen atom conjugatively
sp electron pair on the nitrogen atom is donated to the
metal center in the neutral chelates, the net result is a
decreased σ-electron density, which leads to a further
high-field displacement of the 15N shifts in the chelates
2
linked to the anionic site is responsible for its high-field-
1
5
43
shifted N NMR signal. Conversely, an increased
(
43) (a) Barchiesi, E.; Bradamante, S. J . Phys. Org. Chem. 1990, 3,
39-142. (b) Bradamante, S.; Pagani, G. A. J . Chem. Soc., Perkin
Trans. 2 1986, 1055-1061.
2
σ-electron density resident on the nitrogen sp orbital
1
coplanar with the ring has an opposite effect. Since the
5
762 J . Org. Chem., Vol. 67, No. 16, 2002

Metal Chelation Aptitudes of Bisheteroarylmethanes
SCHEME 11
To confirm this hypothesis, we submitted the salt
complex [Zn(2)]Cl to the action of the acetate base by
2
using two different stoichiometries, to take into account
the different molar ratios in ligand and metal in the salt
-
complex [Zn(2)]Cl
2
and in the neutral ligand Zn(2 )
2
(Scheme 13). In the first stoichiometry (reaction A) 50%
of the salt complex is necessarily disrupted to free the
second molecule of ligand to be embedded into the neutral
TABLE 7. Selected 1H, 13C, a n d 15N NMR Da ta of
Liga n d s 2-6, 11, 12, 25, a n d 26, Som e of th e
Cor r esp on d in g An ion s, a n d Zn (II) a n d P d (II) Neu tr a l
Ch ela tes
-
chelate Zn(2 )
2
. Alternatively (reaction B) a second
molecule of free ligand 2 can be added as reactant. In
both cases, the neutral chelate was successfully obtained
in very high yields, thus supporting the above consider-
ations. It should be noted, however, that when the
acceptor properties of the heteroaromatic substituents
are not strong enough to provide efficient delocalization
δ(13C)
1
δ( H)
compd
solvent
(CH
2
/CH) (CH
2
/CH) 1J (CH) δ(15N)a notes
2
2
DMSO-d
DMSO-d
6
6
37.78
81.42
80.65
28.58
55.81
58.90
61.65
26.73
53.53
33.62
4.94
133.8
165.0
157.8
133.8
160.0
169.0
172.1
131.1
156.7
131.8
311.2
241.3
185.5
245.7
187.1
152.9
171.0
242.2
154.6
309.1,
b, c
c
d, e
c
-
-
Zn(2 )
3
3
Zn(3 )
Pd(3 )
2
CDCl
3
5.99
4.68
-
of the negative charge in the anionic ligand L (vide
DMSO-d
DMSO-d
DMSO-d
6
6
6
-
infra), even the acetates of the salt complexes cannot be
deprotonated to chelates, as found for ligand 4.
c
-
2
5.46
5.24
4.68
4.60
4.82
-
2
CDCl
DMSO-d
3
Ch a r ge-Dem a n d -Dep en d en t F or m a tion of Neu -
tr a l Ch ela tes. Although we have investigated the for-
mation of many salt complexes, we were particularly
interested in the analogy with the important â-diketonate
chelates, where the ligand is anionic and the overall
charge of the coordination compound is neutral. In
particular, we focused our attention on the search for a
relationships between the formation of neutral chelates
4
6
c
-
Zn(4 )
5
2
2
CDCl
CDCl
3
3
2
42.0
178.2,
59.4
Zn(5-)
CDCl
68.33
5.41
4.93
160.5
3
1
6
6
DMSO-d
DMSO-d
DMSO-d
6
6
6
26.88
60.12
60.02
37.49
82.09
38.20
81.38
87.23,
131.8
153.4
153.7
133.3
162.7
132.9
163.5
167.1
246.0
202.5
f
f
-
-
Zn(6 )
1
Zn(11 )
1
Zn(12 )
Pd(12 )
2
5.28
4.60
5.78
4.80
5.87
5.62
f, g
1
CDCl
CDCl
CDCl
CDCl
CDCl
3
3
3
3
3
328.6
209.1
-
2
ML and the π-electron-acceptor properties of the anionic
2
2
-
2
heteroaromatic ligand 1 , exemplified by their charge
demands listed in Table 1. For this reason, our final aim
was far from providing a complete and exhaustive
compilation of the coordinating properties toward a high
number of transition metals, but rather to investigate
the coordinating properties with a proper set of ions,
depending on the charge demand values and expected
formation of neutral chelates containing the ligand in its
anionic form.
-
-
2
h
8
7.25
2
2
5
5
DMSO-d
DMSO-d
CDCl
3
DMSO-d
DMSO-d
CDCl
3
6
6
66.42
68.03
70.00
47.78
93.61
93.07
315.0
i
-
g, i
g, i
b, i
i, j
g, i
-
Zn(25 )
2
2
2
2
6
6
6
6
4.75
5.55
132.1
149.2
155.1
307.4
265.6
-
-
Zn(26 )
a
Azine nitrogen(s). H NMR in CDCl3. From ref 17a. d 15N
b 1
c
e
f
g 15
Our data clearly show that the π-electron delocalization
of the anionic ligand in the neutral chelates plays a
strategic role in the formation and stability of the latter.
These results are summarized in Charts 1-3. Ranking
of charge demand values provides evidence that the
capacity of the heterocyclic ring to delocalize an adjacent
negative charge is the key factor for determining the
stability of the anionic ligand in the neutral chelate and,
therefore, their formation. We have decided to investigate
in more detail the benzothiazolyl and benzoxazolyl
derivatives 2 and 3, respectively, not only for their ease
of formation, but also because the charge demand of the
corresponding heterocyclic substituents is ranked middle
to high and comparable to that of the ester and ketone
functionalities. Both ligands are able to form neutral
chelates with most of the divalent transition metals we
have considered (Chart 1A). Nonetheless, in the reaction
with Mn(II), Fe(II), and Pb(II) no chelate was observed
but rather the formation of dimerization and/or oxidation
products24 or the recovery of the unreacted ligand. The
higher charge demand of the benzothiazolyl ring with
respect to the benzoxazolyl ring is experimentally evi-
denced by the successful formation, in the former, and
unsuccessful formation, in the latter, of the Hg(II) neutral
chelate. The purinyl substituent, to which the largest
charge demand among the heterocycles listed in Table 1
has been associated, was expected to provide ligand 6
with high reactivity toward transition metals, resulting
NMR in THF-d8. From ref 29. From ref 19.
available due to low solubility. Mixture of two isomers. From
ref 16b. Major isomer.
N shifts not
h
i
j
compared to that of the “free” anionic ligands. Therefore,
coordination at the nitrogen atom can also be efficiently
monitored by 15N NMR spectroscopy.
F or m a tion of Neu tr a l Ch ela tes vs Sa lt Com -
p lexes. The reaction leading to neutral chelates, simply
carried out using a neutral ligand and a metal acetate
as starting partners, can in principle occur along two
routes (Scheme 12). Since the reaction is carried out in
a one-pot sequence, we do not know whether the generic
-
ligand 1 is first deprotonated to 1 and, only subse-
quently, metal coordination occurs (route A) or the ionic
2
+
complexes [M(LH)
n
]
are the intermediates in the for-
(route B). The
mation of the neutral chelates ML
2
experimental procedure would discard the hypothesis
that the weak acetate base is able to deprotonate bis-
heteroarylmethanes 1, which are in no doubt much less
acidic than acetic acid. Therefore, it is more likely that
deprotonation occurs at some intermediate stage: after
that coordination to the metal center has taken place.
This metal-coordinated intermediate, which can reason-
ably be identified as the salt complexes obtained in the
reaction with other metal salts such as chlorides, is
somewhat more acidic than the ligand itself, and could
be deprotonated by the acetate anion.
J . Org. Chem, Vol. 67, No. 16, 2002 5763

Abbotto et al.
F IGURE 2. 13C NMR spectra of ligand 3 and the corresponding anion 3- and Zn(II) neutral chelate in DMSO-d
at 25 °C.
6
in the easy formation of the corresponding neutral
chelates. Indeed, chelates with a number of metal ions
were promptly obtained, and further investigation on this
ligand was not considered essential for our purposes.
Replacing one and then both benzothiazolyl rings in 2
with the weaker acceptor benzimidazolyl ring, to give
ligands 5 and 4, respectively, correctly decreases the
somehow comparable to 12 from the electronic point of
view. Although the thiazole charge demand is lower than
that of benzothiazole, it is quite straightforward to
2
imagine that the presence of the acceptor CO Et in
position 5 increases the EW capacity to a value compa-
rable to that of the benzo-fused ring. Indeed, we found
that the capacity to bind metal ions in neutral chelates
stability of the anionic ligand in ML
2
, as probed by the
2
ML is almost identical in the compounds 11, 12, and 2.
unsuccessful reaction with divalent ions such as Co(II)
and Ni(II), under the same conditions where 2, 3, and 6
gave ready formation of the corresponding chelates.
The same conclusions are drawn by looking at the data
in Chart 1B, where the stability of the anionic ligand L
2
in ML is now independent of the charge demand values
listed in Table 1 and relies on simple, but unambiguous,
considerations based on the position and commonly
known EW strength of ring substituents. With this
reasoning, we have compiled a qualitative ranking of the
EW power of the thiazolyl groups in the series 7-11.
Once again, a definitive relationship between the forma-
On the opposite end, the parent thiazolyl derivative 7
does not lead to any formation of neutral chelates, in
accord with the expected lower charge demand of the
heterocycle. The remaining ligands 8-10, 13, and 15
present an intermediate behavior, as predicted by looking
at the acceptor properties of the methylene substituents.
Consistently, very few, or no, neutral chelates were
obtained. Note how the trend of ion coordination depen-
dence on π-acceptor properties is found for subseries of
systems with different structures. For instance, the
relative behavior within the pair 8-7 can also be found
for the benzothiazole-based pair 13-15. The “reproduc-
ibility” of these results and the use of more than one
azolyl framework provide a check for the accuracy of the
obtained data and suggest a general validity of these
conclusions.
-
tion of neutral chelates ML
2
and the ability of the
heterocyclic substituents to delocalize the central car-
banionic negative charge is clearly obtained. The most
-
effective ligand is undoubtedly compound 11 , where the
ethoxycarbonyl acceptor group is placed in the para
position with respect to the carbanionic center and can
efficiently delocalize the negative charge. Ligand 11 is
The reactivity of ligands 22-26 with metal ions to form
neutral chelates is somewhat more complex (Chart 2).
In these systems either one or both five-membered rings
5
764 J . Org. Chem., Vol. 67, No. 16, 2002

Metal Chelation Aptitudes of Bisheteroarylmethanes
F IGURE 3. 13C NMR spectra of ligand 12 and the corresponding Zn(II) and Pd(II) neutral chelates in CDCl
at 25 °C.
3
are sequentially replaced by a six-membered azinyl
group. The charge demand of the pyrid-2-yl substituent
is lower than that of benzothiazole and benzoxazole but
much higher than that of benzimidazole. Therefore, the
capacity of the heterocyclic rings in 22 and 23 to ef-
ficiently delocalize the negative charge in the correspond-
the stability of the corresponding anion 25- in the Zn-
(II), Cu(II), and Pd(II) neutral chelates. Also it should
-
-
be noted that anions 24 and 26 exist as a mixture of
geometric isomers (Scheme 14), as ascertained by multi-
1
6b
nuclear NMR and computational investigation. To form
coordination compounds, the (E,E)- and (E,Z)-isomers
must first convert to the geometrically favorable (Z,Z)-
conformer, through an energy barrier of ca. 10 kcal
-
ing deprotonated ligands L should be ranked between
those of 2 and 3 and that of 5. Despite this expectation,
ligands 22 and 23 do not form neutral chelates. We
believe that this behavior could be ascribed to an ad-
ditional structural factor associated with the six-mem-
bered geometry, which can result in an increased steric
hindrance around the metal center in the chelate or a
less favorable spatial arrangement of the two nitrogen
coordinating sites. The available experimental data for
ligands 24-26,1 also reported in Chart 2, support this
hypothesis. No chelates were obtained for the neutral bis-
-
1 16b
mol
.
Syn th esis of Wa ter -Solu ble Ch ela tes. The obtain-
ment of water-soluble bisheteroarylmethane-based neu-
tral chelates was exploited, keeping in mind the excellent
ligand properties exhibited by 2 and 3. Therefore, these
systems were considered the natural candidates of where
to introduce moieties containing solubilizing groups such
as N-methylpyridinium (ligands 17 and 18), hydroxycar-
bonyl (ligand 20), and sulfonyl (ligand 21). Chart 3
summarizes their coordinating capacities together with
those of the hydroxycarbonyl-containing systems 14 and
16. Indeed, systems 17 and 18 afforded all of the expected
neutral chelates. These results mean that both alkyl
fuctionalization at the methylene bridge and the pyri-
dinium substituent do not affect the ability of the 2 and
3 cores to coordinate transition-metal ions. A similar
6b
(quinol-2-yl)methane (26) in the same conditions where
five-membered ligands 2 and 3 easily react with metal
acetates. The Zn(II) chelate of 26 was obtained only when
NaOH or MeONa was added to the reaction mixture. An
even lower reactivity was observed for the pyrid-2-yl
ligand 24, but the presence of the cyano group on the
methine bridge of 25 is apparently sufficient to increase
J . Org. Chem, Vol. 67, No. 16, 2002 5765

Abbotto et al.
1
15
3
F IGURE 4. H- N HETCOR NMR spectra of ligand 5 and its Zn(II) neutral chelate in CDCl at 25 °C.
SCHEME 12
the Zn(II)-containing compounds do not provide any
useful information to clarify the molecular structure. We
believe that the hydroxycarbonyl group competes with
the -NdCsCsCdN- moiety in binding the metal center
(Scheme 15).
The result is probably the consequence of the formation
of polymeric mixed N-chelates/carboxylate salts, difficult
to characterize. This hypothesis is strongly supported by
the evidence that the starting ligands can be recovered
by treating these solids with dilute hydrochloric acid.
SCHEME 13
Con clu sion
The present extensive investigation on the coordinating
properties of bisheteroarylmethanes toward transition
metals expands our long-term study on the synthesis,
π-electron distribution, and reactivity of this important
class of heteroaromatic systems. We here provide abun-
dant and definitive evidence of the behavior of these
compounds as aromatic aza analogues of â-dicarbonyl
derivatives, one of the most important building blocks
in organic chemistry. We have already documented their
behavior as “active methylene compounds” in the reaction
toward electrophiles.23 In this work we show that several
bisheteroarylmethanes, based on 1,3-azolyl and azinyl
rings, are able to react with a variety of divalent
transition metals, affording salt complexes and neutral
chelates. The successful formation of neutral chelates,
where the ligand is present in its anionic form, is mostly
dependent on electronic parameters, associated with the
charge demand of the heterocyclic substituents. There-
fore, detailed and quantitative knowledge of the EW
capacity of heterocyclic systems allows prediction of the
formation of neutral chelates, a class of compounds that
could have a great potential interest in a number of
behavior was observed for ligand 19 (precursor of 20),
which further confirms the first of the above results. All
of the 17 and 18 neutral chelates are quite soluble in
water (up to 0.01 M), and both their formation and pH-
dependent stability were investigated by UV-vis spec-
troscopy.44 On the opposite side, we have no clear
evidence of the behavior of ligands 14, 16, 20, and 21
toward transition-metal ions. The reactions of these
systems with metal acetates in either degassed MeOH
or water afford quite insoluble precipitates. Microana-
lytical data of the collected solids disagree with neutral
chelate empirical formulas and with those of any reason-
1
able derivatives. When soluble, the H NMR spectra of
(44) Abbotto, A.; Facchetti, A.; Pagani, G. A. University of Milano-
Bicocca, Italy, unpublished results.
5
766 J . Org. Chem., Vol. 67, No. 16, 2002

Metal Chelation Aptitudes of Bisheteroarylmethanes
CHART 1. Liga n d P r op er ties of System s 2-6 (A) a n d 7-13 a n d 15 (B)
a
This work unless otherwise indicated. Metal in parentheses means that dimerization and/or oxidation product(s) were recovered.
b
c
Metal in brackets means that no reaction was observed and the ligand was recovered. Reference 19. Neutral chelates were communicated
in ref 29. Reference 24. Reference 30.
d
e
phenylglycolic acid (20),24 and o-[â,â-bis(benzothiazol-2-yl)-
ethyl]benzenesulfonic acid (21)24 were prepared according to
the literature.
important technological and biodiagnostic fields, in ad-
dition to material science. The use of different heterocy-
clic frameworks and the consistency of experimental
results within different sets of systems suggest a general
applicability of this approach to the investigation and
prediction of the coordinating properties of other aromatic
and aliphatic nitrogen ligands based on π-acceptor moi-
eties.
Eth yl 2-Ben zoth ia zolyla ceta te (27). A mixture of ethyl
cyanoacetate (6.00 g, 53.0 mmol) and 2-aminothiophenol (6.63
g, 53.0 mmol) was stirred for 2 h at 120 °C under a nitrogen
atmosphere. After the mixture was cooled to room tempera-
ture, the product was obtained practically pure as a yellow oil
(11.07 g, 50.0 mmol, 94%), and used without further purifica-
tion in the next step. An analytical sample was purified by
4
7
Exp er im en ta l Section
Kugelrohr distillation: bp 180 °C (0.6 mmHg) (lit. bp 90-95
1
°
(
2
C (0.1 mmHg)); H NMR (CDCl
d, 1H, J ) 8), 7.47 (t, 1H, J ) 8), 7.39 (t, 1H, J ) 8), 4.25 (q,
H, J ) 7.2), 4.16 (s, 2H), 1.30 (t, 3H, J ) 7.2). Anal. Calcd for
S: C, 59.70; H, 5.02; N, 6.33. Found: C, 59.54; H,
.99; N, 6.53.
B e n zo t h ia zo l-2-y l)(N -m e t h y lb e n zim id a zo l-2-y l)-
3
) δ 8.02 (d, 1H, J ) 8), 7.88
2 4
Extracts were dried over Na SO . Anhydrous toluene was
prepared by distillation over sodium sand, in the presence of
benzophenone and under nitrogen, until the blue color of
sodium ketyl was permanent. Benzene was dried over
Na SO or Drierite for a few days. Melting points are uncor-
2 4
rected. In the NMR data, coupling constants J are given in
11 2
C H11NO
4
(
2
4
m eth a n e (5). A mixture of N-methyl-o-phenylenediamine
hertz.
4
5
(1.86 g, 15.2 mmol) and 27 (3.37 g, 15.2 mmol) was refluxed
for 6 h at 160 °C under nitrogen. The EtOH formed in the
reaction was continuously distilled off to keep the refluxing
temperature at the initial value. The dark brown residue was
taken up with diethyl ether, leading to a yellow solid which
was separated by filtration and treated with 20% aqueous HCl
(300 mL). The acid solution was treated with decolorizing
activated charcoal, filtered off, and neutralized with a satu-
Syn th esis of Liga n d s. Bis(benzothiazol-2-yl)methane (2),
bis(benzoxazol-2-yl)methane (3), bis(N-methylbenzimidazol-
4
6
2
4
19
2
-yl)methane (4), bis(7-methylpurin-8-yl)methane (6), bis-
1
7a
(thiazol-2-yl)methane (7),
bis[4-(ethoxycarbonyl)thiazol-2-
1
7a
yl]methane (8), bis(5-ethoxy-4-methylthiazol-2-yl)methane
2
3
(
11), O-{o-[â,â-bis(benzothiazol-2-yl)]ethyl}phenylglycolic acid
24
tert-butyl ester (19), O-{o-[â,â-bis(benzothiazol-2-yl)]ethyl}-
(
(
45) Rai, C.; Braunwarth, J . B. J . Org. Chem. 1961, 26, 3434-3445.
46) Rai, C.; Braunwarth, J . B. U. S. Patent 3,250,780; Chem. Abstr.
(47) Klemm, L. H.; J ohnstone, S.; Tran, L. K. J . Heterocycl. Chem.
1989, 26, 1519-1522.
1
966, 65, 7180g.
J . Org. Chem, Vol. 67, No. 16, 2002 5767

Abbotto et al.
CHART 2. Liga n d P r op er ties of System s 22-26
CHART 3. Liga n d P r op er ties of System s 14 a n d
6-21
1
a
This work unless otherwise indicated. Metal in parentheses
means that dimerization and/or oxidation product(s) were recov-
ered. Metal in brackets means that no reaction was observed and
b
c
the ligand was recovered. Reference 16b. The dimer was also
d
isolated. Stoppa, F. Laurea Thesis, University of Milano, Italy,
1
994.
rated NaHCO
was collected by filtration, taken up with water, and extracted
with CHCl . The combined organic layers were dried and
3
aqueous solution to give a precipitate. The solid
3
evaporated to dryness under reduced pressure to leave the
a This work unless otherwise indicated. Metal in parentheses
pure product as a light yellow solid (0.266 g, 0.95 mmol, 6%):
means that dimerization and/or oxidation product(s) were recov-
ered. Metal in brackets means that no reaction was observed and
the ligand was recovered. Metal in braces means that the ligand
1
mp 131-133 °C; H NMR (CDCl
3
) δ 7.98 (d, 1H, J ) 8.1), 7.82-
7
7
.76 (m, 2H), 7.46 (t, 1H, J ) 8.1), 7.36 (t, 1H, J ) 8.1), 7.32-
.28 (m, 3H), 4.82 (s, 2H), 3.81 (s, 3H). Anal. Calcd for
S: C, 68.79; H, 4.69; N, 15.04. Found: C, 69.01; H,
b
was recovered after acidification according to Scheme 15. We have
C
16
H
13
N
3
evidence that oxidation of the methine bridge afforded the corre-
sponding carbinol: Ferluga, P. Laurea Thesis, University of
Milano, Italy, 1993.
4
.57; N, 15.27.
Bis(4-ph en ylth iazol-2-yl)m eth an e (9). A solution of phen-
2
acyl bromide (1.59 g, 8.00 mmol) in acetone-H O (4:1, 5 mL)
was added dropwise to a solution of malonodithioamide23 (0.54
g, 4.00 mmol) in the same solvent (55 mL). After the solution
was stirred for 16 h at room temperature, the acetone was
distilled off under a reduced pressure. The resulting mixture
SCHEME 14
was neutralized with aqueous NaHCO
CHCl . The solvent was removed from the dried combined
organic layers to leave a brown solid which was submitted to
flash chromatography (CH Cl2-AcOEt, 4:1) on silica gel and
then crystallized to a white solid (1.04 g, 3.11 mmol, 78%):
3
, and extracted with
3
2
mp 110-111 °C (toluene) (lit. mp 119-120 °C); 1H NMR
CDCl ) δ 7.91 (d, 4H, J ) 8.1), 7.47-7.31 (m, 8H), 4.84 (s,
H). Anal. Calcd for C19 : C, 68.22; H, 4.22; N, 8.37.
48
(
3
2
14 2 2
H N S
Found: C, 68.02; H, 3.79; N, 8.27.
Bis[4-(p-n itr op h en yl)th ia zol-2-yl]m eth a n e (10). A solu-
tion of p-phenacyl bromide (7.32 g, 30.0 mmol) in acetone-
H O (4:1, 10 mL) was added dropwise to a solution of
2
2
3
malonodithioamide (2.01 g, 15.0 mmol) in the same solvent
200 mL). The formation of a red precipitate was observed after
min. The reaction mixture was stirred for 4 h at room
temperature, and the solid collected by filtration to give the
light green product (4.70 g, 11.1 mmol, 74%): mp 196-197 °C
(
5
(DMF); H NMR (CDCl ) δ 8.32-8.08 (m, 8H), 7.67 (s, 2H),
1
3
19 12 4 4 2
4.85 (s, 2H). Anal. Calcd for C H N O S : C, 53.76; H, 2.86;
N, 13.20. Found: C, 53.38; H, 2.95; N, 12.94.
-Ben zoth ia zolyla ceta m id e (28). A mixture of 27 (11.60
g, 52.4 mmol) in 30% aqueous NH (40 mL) and EtOH (20 mL)
was stirred for 18 h at room temperature. The formed
2
(
48) Lehr, H.; Guex, W.; Herlenmeyer, H. Helv. Chim. Acta 1944,
3
2
7, 970-972.
5
768 J . Org. Chem., Vol. 67, No. 16, 2002

Metal Chelation Aptitudes of Bisheteroarylmethanes
SCHEME 15
precipitate was collected to give the practically pure product
as a yellow-green solid (8.01 g, 41.7 mmol, 80%): mp 168 °C
hydrochloric acid (10%, 15 mL) was refluxed for 8 h. After
cooling, the formed precipitate was collected, washed with
water, and finally dried to give the pure product as a dark
3
6a
1
(
EtOH) (lit. mp 171-172 °C); H NMR (CDCl ) δ 8.10-7.38
3
1
(m, 4H), 5.65 (br, 2H), 4.08 (s, 2H).
yellow solid (0.33 g, 1.19 mmol, 73%): mp 180 °C; H NMR
2
-Ben zoth ia zolylth ioa ceta m id e (29). A mixture of 28
(CDCl
7.3), 7.52 (t, 1H, J ) 7.25), 5.00 (s, 2H). Anal. Calcd for
O: C, 44.86; H, 4.08; N, 8.72. Found: C,
3
) δ 8.41 (s, 1H), 8.09 (d, 1H, J ) 7.25), 7.98 (d, 1H, J )
(
7.46 g, 38.8 mmol) and Lawesson’s reagent (7.84 g, 19.4 mmol)
in anhyd toluene (200 mL) was refluxed for 2 h, resulting in
an orange solution. The solvent was removed from the mixture
to leave a red residue which was taken up with abs EtOH,
leading to the practically pure product as an orange solid (4.04
g, 19.4 mmol, 50%) which was used without further purifica-
tion in the next step. An analytical sample (light orange solid)
was obtained after purification by flash chromatography
C
12
H
8
N
2
O
2
S
2
‚5H
2
44.59; H, 3.50; N, 9.16.
(Ben zoth ia zol-2-yl)(th ia zol-2-yl)m eth a n e (15). A mix-
ture of 14 (1.50 g, 5.43 mmol) and electrolytic copper powder
(1.60 g) was heated at 240 °C and 0.01 mmHg. The distillation
afforded a product which was chromatographed on silica gel
2
(CH Cl2-AcOEt 1:1) to give the pure product as a light yellow
1
(
1
(
3
CH
66 °C (AcOEt); H NMR (CDCl
9 8 2 2
m, 4H), 4.54 (s, 2H). Anal. Calcd for C H N S
2
Cl2-AcOEt, 1:1) on silica gel and crystallization: mp 164-
solid (0.14 g, 0.60 mmol, 11%): mp 86-90; H NMR (CDCl ) δ
3
1
3
) δ 9.18 (br, 2H), 8.06-7.27
: C, 51.89; H,
.88; N, 13.45. Found: C, 51.63; H, 3.82; N, 13.34.
8.03 (d, 1H, J ) 8.1), 7.85 (d, 1H, J ) 7.2), 7.79 (d, 1H, J )
3.4), 7.48 (t, 1H, J ) 7.4), 7.38 (t, 1H, J ) 7.9), 7.33 (d, 1H, J
) 3.4), 4.91 (s, 2H); HRMS m/z calcd for C11H N S 232.0129,
8 2 2
(
Ben zoth ia zol-2-yl)(5-eth oxyca r bon yl-4-m eth ylth ia zol-
found 232,0126.
4
9
2
(
-yl)m eth a n e (12). A solution of ethyl bromoacetoacetate
(Ben zot h ia zol-2-yl)(5-ter t-b u t yloxyca r b on yl-4-m et h -
ylth ia zol-2-yl)m eth a n e (30). A solution of tert-butyl chloro-
acetoacetate (2.56 g, 13.29 mmol) in acetone (5 mL) was
added dropwise to a solution of 29 (2.77 g, 13.29 mmol) in
0.627 g, 3.00 mmol) in acetone (1 mL) was added dropwise to
a solution of 29 (0.625 g, 3.00 mmol) in acetone-H O (11:1,
4 mL). After the solution was stirred for 30 min, the formed
precipitate was separated by filtration, taken up with a
saturated NaHCO aqueous solution, and extracted with
CH Cl . The dried organic layers were evaporated to dryness
2
2
acetone-H O (11:1, 40 mL). After the solution was stirred for
2
3
47 h, the formed precipitate was separated by filtration, taken
2
2
up with a saturated NaHCO aqueous solution, and extracted
3
to leave the crude product as a red-orange oil which was
purified by Kugelrohr distillation (0.490 g, 1.54 mmol, 51%):
bp 250 °C (0.2 mmHg); H NMR (CDCl
with CH Cl . The dried organic layers were evaporated to
2
2
dryness to leave the crude product as a red-orange oil which
was used for the next step without further purification (2.84
g, 8.20 mmol, 62%). An analytical sample was obtained by
1
3
) δ 8.06 (d, 1H, J )
7
)
3
.7), 7.88 (d, 1H, J ) 7.7), 7.51 (t, 1H, J ) 7.7), 7.41 (t, 1H, J
1
7.7), 4.80 (s, 2H), 4.32 (q, 2H, J ) 7.3), 2.77 (s, 3H), 1.35 (t,
: C, 56.57; H, 4.44;
Kugelrohr distillation: bp 250 °C (0.02 mmHg); H NMR
H, J ) 7.3). Anal. Calcd for C15
H
14
N
2
O
2
S
2
(CDCl ) δ 8.05 (dd, 1H, J ) 8.5, 1.3), 7.86 (dd, 1H, J ) 8.5,
3
N, 8.80. Found: C, 56.48; H, 4.56; N, 8.92.
Be n zot h ia zol-2-yl)(4-e t h oxyca r b on ylt h ia zol-2-yl)-
1.3), 7.49 (t, 1H, J ) 8.5), 7.39 (t, 1H, J ) 8.5), 4.77 (s, 2H),
•
+
(
2.71 (s, 3H), 1.55 (s, 9H); MS (EI) m/z 346 (M , 41), 290 (100);
-
1
m eth a n e (13). A solution of ethyl bromopiruvate (1.87 g, 9.60
mmol) in acetone (6 mL) was added dropwise to a solution of
9 (2.00 g, 9.60 mmol) in acetone-H
the solution was stirred for 4 h at room temperature, the
solvent was evaporated and the residue taken up with a
saturated NaHCO
extracted with CHCl
rated to dryness to leave a red-orange oil which was chro-
matographed on silica gel (CH Cl2-AcOEt 9:1) to give the pure
product as a light yellow solid (1.40 g, 4.60 mmol, 48%): mp
IR (Nujol) 1713, 1525, 1474, 1315 cm . Anal. Calcd for
C H N O S : C, 58.93; H, 5.24; N, 8.09. Found: C, 58.53; H,
1
7
18
2
2
2
2
2
O (11:1, 144 mL). After
5.07; N, 7.88.
(Ben zoth iazol-2-yl)(5-h ydr oxycar bon yl-4-m eth ylth iazol-
2-yl)m eth a n e (16). Under nitrogen, a solution of 30 (0.17 g,
0.49 mmol) and dry PTSA (0.10 g, 0.50 mmol) in benzene (15
mL) was refluxed for 5 h. After cooling, the precipitate was
collected and dissolved in a saturated NaHCO3 aqueous
solution, and the solution extracted with chloroform. Hydro-
chloric acid (10%) was added dropwise to the aqueous solution
until pH 2-3 was reached. The formed white solid was
collected, washed with water, and identified as the pure
3
aqueous solution, and the suspension was
3
. The dried organic layers were evapo-
2
1
6
7
1
3
3
8; H NMR (CDCl ) δ 8.15 (s, 1H), 8.03 (dd, 1H, J ) 8.1, 1.5),
.86 (dd, 1H, J ) 7.3, 1.5), 7.49 (td, 1H, J ) 8.1, 1.5), 7.49 (td,
H, J ) 7.3, 1.5), 4.90 (s, 2H), 4.44 (q, 2H, J ) 6.1), 1.42 (t,
1
product (0.10 g, 0.39 mmol, 79%): mp 210 °C (H O); H NMR
2
H, J ) 6.1). Anal. Calcd for C14
H
12
N
2
O
2
S
2
: C, 55.24; H, 3.98;
(DMSO-d ) δ 8.10 (d, 1H, J ) 8.1), 8.00 (d, 1H, J ) 8.1), 7.52
6
N, 9.20. Found: C, 55.21; H, 4.24; N, 9.84.
Ben zot h ia zol-2-yl)(4-h yd r oxyca r b on ylt h ia zol-2-yl)-
m et h a n e (14). A suspension of 13 (0.50 g, 1.64 mmol) in
(t, 1H, J ) 8.1), 7.44 (t, 1H, J ) 8.1), 4.93 (s, 2H), 2.61 (s, 3H).
Anal. Calcd for C H N O S : C, 53.78; H, 3.47; N, 9.65.
(
1
3
10
2
2
2
Found: C, 53.62; H, 3.24; N, 10.01.
4
-[â,â-Bis(ben zoth ia zol-2-yl)eth yl]p yr id in e (33). A solu-
2
3
(49) Br u¨ hl, J . W. Chem. Ber. 1903, 36, 1722.
tion of the picolylidene derivative 31 (2.10 g, 5.65 mmol) in
J . Org. Chem, Vol. 67, No. 16, 2002 5769

Abbotto et al.
AcOEt (120 mL) was subjected to hydrogenation (10% Pd-C)
at room temperature and pressure. After 8 h (152 mL of
hydrogen volume consumed, 6.22 mmol), the mixture was
filtered and evaporated to dryness under reduced pressure to
J ) 5.1), 7.78 (t, 1H, J ) 7.0), 7.38-7.28 (m, 3H), 7.09 (t, 1H,
J ) 6.9), 7.00 (d, 1H, J ) 7.7), 6.85 (d, 1H, J ) 7.0), 3.93 (s,
2H); IR (Nujol) 1690 (CdO). Anal. Calcd for C13
12 2 2
H N O : C,
68.39; H, 5.31; N, 12.27. Found: C, 68.21; H, 5.18; N, 12.06.
(P yr id -2-yl)(ben zoxa zol-2-yl)m eth a n e (23). 35 (4.49 g,
19.7 mmol) was added to polyphosphoric acid (40 mL) at 70
°C under mechanical stirring. The reaction mixture was stirred
for 5 h at 160 °C, then cooled to 40 °C, poured onto ice, and
treated with 15% aqueous NH3 to pH 9-10. The resulting
afford the product as a yellow solid (2.11 g, 5.65 mmol, 100%):
1
mp 70-75 °C; H NMR (CDCl
3
) δ 8.45-8.41 (m, 2H) 8.06 (d,
2
H, J ) 8.1), 7.81 (d, 2H, J ) 8.1), 7.49 (t, 2H, J ) 8.1), 7.37
(
(
t, 2H, J ) 8.1), 7.24-7.20 (m, 2H), 5.33 (t, 1H, J ) 7.8), 3.87
d, 2H, J ) 7.8). An analytical sample was purified as
styphnate: yellow solid, mp 175-177 °C. Anal. Calcd for
mixture was extracted with CHCl . The combined organic
3
C
27
H
18
N
6
O
8
S
2
: C, 52.41; H, 2.94; N, 13.59. Found: C, 52.73;
layers were filtered over Celite, washed with water, dried, and
evaporated to dryness to leave a dark oil which was submitted
to Kugelrohr distillation, affording the pure product as a yellow
H, 3.16; N, 13.88.
4
-[â,â-Bis(b en zot h ia zol-2-yl)et h yl]-1-m et h ylp yr id in i-
1
u m Tr ifla te (17). A solution of methyl triflate (0.883 g, 5.38
oil (2.47 g, 11.7 mmol, 60%): bp 195 °C (0.6 mmHg); H NMR
mmol) in dry benzene (34 mL) was added to a solution of
(CDCl
1H, J ) 8.0), 7.37-7.28 (m, 3H), 7.22 (dd, 1H, J ) 7.6, 4.7),
4.48 (s, 2H). Anal. Calcd for C13 O: C, 74.26; H, 4.80; N,
3
) δ 8.58 (d, 1H, J ) 4.7), 7.72-7.63 (m, 2H), 7.48 (t,
3
3 (2.01 g, 5.38 mmol) in the same solvent (50 mL). After
the solution was stirred for 6 h at room temperature, the
formed precipitate was separated by filtration, providing the
10 2
H N
13.33. Found: C, 74.04; H, 4.71; N, 13.56.
product as a yellow solid (2.07 g, 3.85 mmol, 72%): mp 182-
Syn th esis of Sa lt Com p lexes a n d Neu tr a l Ch ela tes.
Reaction solvents (MeOH, EtOH, H O, and DMF) and metal
2
acetates, sulfates, and chlorides were used as received without
further purification. Experimental details (molar amount of
ligand and metal salt, type of metal salt, and reaction times)
for each preparation and microanalytical data (elemental anal-
1
1
2
85 °C; H NMR (DMSO-d
6
) δ 8.82 (d, 2H, J ) 6.6), 8.18 (d,
H, J ) 6.6), 8.08 (d, 2H, J ) 7.5), 8.02 (d, 2H, J ) 7.5), 7.53
(
td, 2H, J ) 7.5, 0.5), 7.46 (td, 2H, J ) 7.5, 0.5), 6.04 (t, 1H, J
7.6), 4.20 (s, 3H), 4.15 (d, 2H, J ) 7.6). Anal. Calcd for
: C, 51.38; H, 3.38; N, 7.82. Found: C, 51.04;
H, 3.42; N, 7.65.
)
23 18 3 3 3 3
C H F N O S
2 n m
ysis) of neutral chelates ML and salt complexes M(LH) X
4
-[â,â-Bis(ben zoxa zol-2-yl)eth yl]p yr id in e (34). A solu-
are reported in Tables 2-4 and Tables 5 and 6, respectively.
The following are general synthetic protocols for neutral and
salt complex preparation.
2
3
tion of the picolylidene derivative 32
mmol) in AcOEt (170 mL) was subjected to hydrogenation
(2.30 g, 6.78
(
(
10% Pd-C) at room temperature and pressure. After 4 h
Meth od A. A solution of metal salt in methanol was added
dropwise to a solution of ligand LH dissolved in the mini-
mal amount of the same solvent. A precipitate was im-
mediately formed. This solid was collected, washed several
times with methanol, and finally dried under vacuum at
40-60 °C. Elemental analysis was performed without further
purification.
Meth od B. Under nitrogen, a solution of metal salt in
methanol was added dropwise to a solution of ligand LH in
the same solvent. After the solution was stirred for the
specified time, the precipitate was collected, washed a few
times with methanol, and finally dried under vacuum at
40-60 °C. Elemental analysis was performed without further
purification.
170 mL of hydrogen volume consumed, 6.96 mmol), the
mixtured was filtered and evaporated to dryness under
reduced pressure to leave a brown residue which was taken
up with diisopropyl ether to afford the product as a brown solid
(
1.82 g, 5.30 mmol, 79%): mp 125-127 °C (H
2
O-EtOH 1:1);
) δ 8.45 (d, 2H, J ) 5), 7.74-7.68 (m, 2H),
.52-7.45 (m, 2H), 7.37-7.28 (m, 4H), 7.21 (d, 2H, J ) 5),
.06 (t, 1H, J ) 7.8), 3.85 (d, 2H, J ) 7.8). Anal. Calcd for
: C, 73.92; H, 4.43; N, 12.32. Found: C, 73.70; H,
.56; N, 12.31.
-[â,â-Bis(b e n zoxa zol-2-yl)e t h yl]-1-m e t h ylp yr id in i-
1
H NMR (CDCl
3
7
5
21 15 3 2
C H N O
4
4
u m Tr ifla te (18). A solution of methyl triflate (0.827 g, 5.04
mmol) in dry benzene (35 mL) was added to a solution of 34
(
1.72 g, 5.04 mmol) in the same solvent (50 mL). After the
Meth od C. Under nitrogen, a solution of metal salt in
methanol was added dropwise to a solution of ligand LH in
the same solvent. After the solution was stirred for the
indicated time, the reaction solvent was evaporated until a
precipitate was formed. This solid was collected, washed a few
times with cold methanol, and finally dried under vacuum at
40-60 °C. Elemental analysis was performed without further
purification.
Meth od D. Under nitrogen, a solution of metal salt in
methanol was added dropwise to a solution of ligand LH in
the same solvent. After the solution was stirred for the
indicated time, the solvent was removed under reduced
pressure. The residue was taken up with water, and the solid
was collected, washed with chloroform, THF, or cold methanol,
and finally dried under vacuum at 40-60 °C. Elemental
analysis was performed either without further purification or
after recrystallization (see the notes in Tables 1-5).
Meth od E. A solution of metal salt in water was added
dropwise to a boiling solution of ligand LH in the same solvent.
A precipitate immediately formed. The solid was collected,
washed with warm water, and dried under vacuum at 80 °C.
Elemental analysis was performed without further purifica-
tion.
solution was stirred for 2 h at room temperature, the precipi-
tate was collected by filtration to provide the product as a light
yellow solid (2.45 g, 4.85, 96%): mp 202-203 °C; H NMR
(
7
3
5
1
6
DMSO-d ) δ 8.86 (d, 2H, J ) 6.6), 8.19 (d, 2H, J ) 6.6), 7.81-
.69 (m, 4H), 7.49-7.34 (m, 4H), 5.79 (t, 1H, J ) 7.8), 4.24 (s,
H), 4.10 (d, 2H, J ) 7.8). Anal. Calcd for C23 S: C,
4.64; H, 3.60; N, 8.31. Found: C, 54.95; H, 3.52; N, 8.50.
P yr id -2-yl)(ben zoth ia zol-2-yl)m eth a n e (22). A mixture
18 3 3 5
H F N O
(
of methyl 2-pyridylacetate (3.83 g, 25.3 mmol) and 2-ami-
nothiophenol (3.17 g, 25.3 mmol) was stirred for 5 h at 160 °C
under a nitrogen atmosphere. The reaction mixture was cooled
to room temperature, leaving an orange oil which was submit-
ted to Kugelrohr distillation, affording the pure product as a
yellow oil (4.30 g, 19.0 mmol, 75%): bp 220 °C/0.5 mmHg; H
NMR (CDCl
7
8
2
1
3
) δ 8.60 (d, 1H, J ) 4.7), 7.99 (d, 1H, J ) 7.7),
.80 (d, 1H, J ) 8.2), 7.64 (t, 1H, J ) 7.8), 7.43 (t, 1H, J )
.2), 7.38-7.28 (m, 2H), 7.18 (dd, 1H, J ) 7.7, 4.6), 4.63 (s,
H). Anal. Calcd for C13 S: C, 68.98; H, 4.46; N, 12.38.
10 2
H N
Found: C, 68.56; H, 4.36; N, 12.27.
N-(o-Hyd r oxyp h en yl)p yr id -2-yla ceta m id e (35). A mix-
ture of methyl 2-pyridylacetate (3.78 g, 25.0 mmol) and
2
-aminophenol (2.73 g, 25.0 mmol) was stirred for 5 h at 165
°
C under a nitrogen atmosphere. The reaction mixture was
Sp ectr oscop ic a n d Sp ectr om etr ic Ch a r a cter iza tion of
1
allowed to cool to room temperature, leaving a solid which was
taken up with diethyl ether, providing the practically pure
product as a brown solid, used without further purification in
the subsequent step (4.81 g, 21.1 mmol, 84%). Recrystallization
gave an analytical sample (light brown solid): mp 152-154
°
Sa lt Com p lexes a n d Neu tr a l Ch ela tes. LH ) 2. Zn L
NMR (CDCl
(td, 4H, J ) 6.7, 1.7), 5.99 (s, 2H); C NMR (CDCl
2
:
H
3
) δ 7.47 (d, 4H, J ) 7.6), 7.06-6.97 (m, 8H), 6.94
13
3
) δ 166.32,
150.94, 128.50, 122.10, 120.92, 115.32, 80.65; N (THF-d ) δ
: MS (CI)
1
5
8
•
+
185.5; MS (CI) m/z 631 (MH , 7), 283 (100). Cu L
2
1
•+
•+
C (EtOH); H NMR (CDCl
3
) δ 10.4 (br), 10.0 (br), 8.60 (d, 1H,
2
m/z 283 (MH , 18), 256 (100). NiL : MS (EI) m/z 622 (M ,
5
770 J . Org. Chem., Vol. 67, No. 16, 2002

Metal Chelation Aptitudes of Bisheteroarylmethanes
2
5), 282 (100). CoL
NMR (CDCl ) δ 7.17-7.12 (m, 4H), 6.84-6.78 (m, 4H), 6.66-
.58 (m, 4H), 5.72 (s, 2H). HgL
2
: MS (EI) m/z 621 (M•+, 100). P d L
2
: 1
H
7.7), 6.60-6.75 (m, 8H), 4.45 (s, 4H), 4.35 (s, 6H); IR (Nujol)
-1
3
1642, 1525, 1510, 1219 cm .
1
6
2
: MS (CI) m/z 323 (53), 284
LH ) 18. Zn L : H NMR (DMSO-d ) δ 8.88 (d, 4H, J )
2
6
(100).
6.6), 8.26 (d, 4H, J ) 6.6), 7.45-7.53 (m, 4H), 7.00-7.14 (m,
LH ) 3. Zn L
2
: 1H NMR (CDCl
.92 (m, 8H), 6.91-6.80 (m, 4H), 5.46 (s, 2H); C NMR (CDCl
3
) δ 7.36-7.24 (m, 4H), 7.05-
8H), 6.90-6.67 (m, 4H), 4.50 (s, 4H), 4.20 (s, 6H); IR (Nujol)
1
3
-1
6
3
)
2
1620, 1504, 1350, 1260 cm . Cu L : IR (Nujol) 1651, 1582,
δ 168.22, 147.47, 138.65, 124.63, 122.06, 109.57, 58.90; 5N
1
-1
-1
1522, 1256 cm . NiL
CoL : IR (Nujol) 1655, 1573, 1348, 1261 cm . P d L
(DMSO-d
2
: IR (Nujol) 1651, 1605, 1582, 1261 cm
.
•
+
-1
1
(DMSO-d
6
) δ 152.9; MS (EI) m/z 566 (M , 44), 562 (100).
2
2
:
H NMR
Cu L : MS (EI) m/z 556 (20), 250 (100). NiL
2
2
: MS (CI) m/z
6
) δ 8.87 (d, 4H, J ) 6.4), 8.24 (d, 4H, J ) 6.4), 7.32
•
+
•+
5
2
6
4
1
58 (MH , 15), 119 (100). CoL
2
: MS (EI) m/z 557 (M , 100),
(d, 4H, J ) 8.0), 6.84 (t, 4H, J ) 7.8), 6.49 (t, 4H, J ) 7.9),
1
50 (64). P d L : H NMR (CDCl ) δ 7.14 (dd, 4H, J ) 7.8, 1.2),
2
3
6.27 (d, 4H, J ) 7.8), 4.45 (s, 4H), 4.30 (s, 6H); IR (Nujol) 1628,
-
1
.78 (td, 4H, J ) 7.8, 1.2), 6.48 (td, 4H, J ) 7.7, 1.2), 6.22 (dd,
1582, 1325, 1155 cm .
1
3
1
H, J ) 7.6, 1.2), 5.24 (s, 2H); C NMR (CDCl
3
) δ 165.90,
2 3
LH ) 19. Zn L : H NMR (CDCl ) δ 7.44 (d, 4H, J ) 7.5),
48.80, 138.27, 122.88, 121.26, 108.65, 61.65.
7.40 (dd, 2H, J ) 7.5), 7.24 (td, 2H, J ) 7.3), 7.12 (d, 4H,),
7.04 (td, 4H, J ) 7.0), 6.95 (t, 4H, J ) 6.5), 6.92 (t, 2H, J )
1H NMR (CDCl
LH ) 5. Zn L
2
:
3
) δ 7.36 (d, 2H, J ) 7.6),
7
.2), 6.86 (d, 2H, J ) 8.1), 4.75 (s, 4H), 4.28 (s, 4H), 1.58 (s,
7
1
1
1
1
1
.05 (d, 2H, J ) 7.8), 6.96 (td, 2H, J ) 6.7, 1.7), 6.93-6.78 (m,
1
0H), 5.41 (s, 2H), 3.62 (s, 6H); 13C NMR (CDCl
) δ 166.24,
18H). P d L :
H NMR (CDCl ) δ 7.61 (d, 2H, J ) 6.4), 7.26
2
3
3
(
6
td, 2H, J ) 5.5), 7.06-7.12 (m, 4H), 6.89 (t, 2H, J ) 7.4), 6.82-
54.65, 151.87, 140.35, 134.10, 128.06, 125.99, 121.64, 120.49,
20.31, 114.50, 113.36, 107.20, 68.33, 29.25; IR (Nujol) 1922,
.89 (m, 6H), 6.53-6.60 (m, 8H), 4.75 (s, 4H), 4.15 (s, 4H), 1.55
-
1
(s, 18H).
2
472, 1344, 1302 cm . Cu L : IR (Nujol) 1626, 1592, 1401,
-
1
: 1H NMR (CDCl
317 cm
LH ) 8. Cu L
Nujol) 1698, 1530, 1288, 1224 cm
: MS (FAB) m/z 729 (M•+, 8), 154 (100).
LH ) 9. Cu L
LH ) 10. Cu L : MS (FAB) m/z 424 (22), 246 (100). CoL
MS (FAB) m/z 460 (3), 307 (100).
LH ) 11. Zn L
1H NMR (CDCl
.
LH ) 22. Zn (LH)Cl ) δ 8.95 (d, 1H, J )
4.6), 8.07-7.97 (m, 2H), 7.64-7.56 (m, 3H), 7.53-7.46 (m, 2H),
2
3
: MS (FAB) m/z 713 (M•+, 5), 136 (100); IR
2
-
1
4.79 (s, 2H).
(
.
2 3
LH ) 23. Zn (LH)Cl ) δ 8.93 (d, 1H, J )
: 1H NMR (CDCl
.7), 8.07-7.96 (m, 2H), 7.65-7.56 (m, 3H), 7.53-7.45 (m, 2H),
.78 (s, 2H).
2
4
4
2
2
:
Oxid a tion a n d /or Dim er iza tion Rea ction s. Rea ction
2
:
3
) δ 5.80 (s, 2H), 4.25 (q,
of 11 w ith Mn (OAc)
2
‚4H
2
O. A solution of Mn(OAc)
2
‚4H
2
O
8
H, J ) 7.1), 2.25 (s, 12H), 1.37 (t, 12H, J ) 7.1); MS (FAB)
(0.10 g, 0.42 mmol) in EtOH (5 mL) was added to a solution of
•
+
m/z 774 (M , 67), 770 (100); UV-vis (CH
ꢀ
Cu L
Cl
1
1
2
Cl
2
) λmax ) 464 nm,
bis(5-ethoxy-4-methylthiazol-2-yl)methane (11) (0.30 g, 0.85
mmol) in the same solvent (17 mL). After the solution was
stirred at room temperature for 6 h, a precipitate formed. This
solid was collected, washed with EtOH, and dried under
vacuum to give 1,1,2,2-tetra(5-ethoxy-4-methylthiazol-2-yl)-
-
1
-1
-1
) 140500 M cm ; IR (Nujol) 1704, 1554, 1499, 1316 cm
.
•
+
2
: MS (FAB) m/z 771 (M , 65), 154 (100); UV-vis (CH
2
-
-
1
-1
2
) λmax ) 445 nm, ꢀ ) 135000 M cm ; IR (Nujol) 1704,
-
1
•+
620, 1446, 1428 cm . NiL
33 (100); UV-vis (CH Cl
2
: MS (FAB) m/z 766 (M , 24),
-
1
2
2
) λmax ) 448 nm, ꢀ ) 130500 M
ethene (37) as a yellow solid (0.12 g, 0.17 mmol, 40.5%): mp
-
1
-1
cm ; IR (Nujol) 1705, 1555, 1499, 1366 cm . CoL
2
: MS (FAB)
1
1
1
1
57 °C; H NMR (CDCl
3
) δ 4.32 (q, 8H, J ) 7.1), 2.64 (s, 12H),
•+
m/z 765 (M , 100); UV-vis (CH
2
Cl
cm ; IR (Nujol) 1704, 1555, 1495, 1306 cm . P d L
NMR (CDCl ) δ 5.58 (s, 2H), 4.20 (q, 8H, J ) 7.1), 2.21 (s, 12H),
.34 (t, 12H, J ) 7.1).
LH ) 12. Zn L
1H NMR (CDCl
2
) λmax ) 438 nm, ꢀ ) 169000
13
.34 (t, 12H, J ) 7.1); C NMR (CDCl
60.36, 132.35, 125.66, 61.52, 17.36, 14.20; MS (EI) m/z 704
3
) δ 164.96, 161.76,
-
1
-1
-1
1
M
2
: H
3
•+
(M
, 40), 587 (100). Anal. Calcd for C30
H, 4.58; N, 7.95. Found: C, 51.02; H, 4.53; N, 7.83.
R ea ct ion of 12 w it h Mn (OAc) ‚4H O. A solution of
Mn(OAc) ‚4H O (0.16 g, 0.64 mmol) in EtOH (4 mL) was added
to a solution of (benzothiazol-2-yl)(5-ethoxy-4-methylthiazol-
-yl)methane (12) (0.41 g, 1.29 mmol) in the same solvent (7
mL). After the solution was stirred at room temperature for
2 h, a precipitate formed. This solid was collected and
chromatographied on silica gel (CH Cl :AcOEt ) 9:1). Two
32 4 4 8
H N S O : C, 51.11;
1
2
:
3
) δ 7.48 (d, 2H, J ) 8.0),
2
2
7
7
6
1
8
1
.08 (t, 2H, J ) 7.8), 6.99 (t, 2H, J ) 7.9), 6.91 (d, 2H, J )
.6), 5.87 (s, 2H), 4.22 (q, 4H, J ) 7.4), 2.26 (s, 6H), 1.27 (t,
2
2
1
3
H, J ) 7.1); C NMR (CDCl ) δ 166.83, 165.87, 162.22,
3
2
56.59, 150.59, 128.50, 126.63, 122.29, 121.09, 115.02, 108.74,
1.38, 60.75, 16.05, 14.35. Cu L
54 (100). NiL : MS (FAB) m/z 287 (88), 132 (100). CoL
•
+
2
: MS (FAB) m/z 697 (M , 2),
: MS
2
: Two isomers (A, 66%; B, 33%)
1
2
2
2
2
•+
(FAB) m/z 693 (M , 100). P d L
fractions were isolated. (A) Benzothiazol-2-yl 5-ethoxy-4-
1
were detected in solution. Isomer A: H NMR (CDCl
3
) δ 7.36
methylthiazol-2-yl ketone (38), yellow solid (0.14 g, 0.421
(d, 2H, J ) 7.5), 7.02 (td, 2H, J ) 7.5, 1.5), 6.93 (td, 2H, J )
1
mmol, 32.7%): mp 179 °C (EtOH); H NMR (CDCl
(
3
) δ 8.39
7
7
1
.6, 1.5), 6.87 (d, 2H, J ) 7.6), 5.62 (s, 2H), 4.07 (q, 4H, J )
dd, 1H, J ) 8.0, 2.4), 8.07 (dd, 1H, J ) 6.7, 2.5), 7.68-7.60
.6), 1.73 (s, 6H), 1.21 (t, 6H, J ) 7.6); 13C NMR (CDCl
) δ
3
(
m, 2H), 4.45 (q, 2H, J ) 7.9) 2.93 (s, 3H), 1.46 (t, 3H, J )
63.33, 161.18, 160.49, 157.69, 148.75, 129.75, 125.71, 122.28,
•+
7
1
3
.9); MS (EI) m/z 332 (M , 100); IR (Nujol) 1713, 1656,
1
20.93, 116.63, 110.66, 87.25, 60.34, 17.36, 14.38. Isomer B:
-1
266, 1094 cm . Anal. Calcd for C15
12 2 2 3
H N S O : C, 54.20; H,
1
H NMR (CDCl
3
) δ 7.13-7.09 (m, 2H), 6.68-6.56 (m, 6H), 5.62
.64; N, 8.43. Found: C, 53.66; H, 3.86; N, 8.66. (B) 1,2-Bis-
(s, 2H), 4.24 (q, 4H, J ) 7.5), 2.26 (s, 6H), 1.32 (t, 6H, J )
(
benzothiazol-2-yl)-1,2-bis(5-ethoxy-4-methylthiazol-2-yl)-
1
3
7
1
1
3
.5); C NMR (CDCl ) δ 162.93, 161.51, 161.00, 157.36, 148.87,
ethene (39), mixture of (E)- and (Z)-isomers, red solid (0.03
29.02, 125.17, 121.75, 120.23, 116.07, 111.00, 87.23, 60.66,
7.00, 14.32.
•+
mg, 0.05 mmol, 3.7%): mp 220 (dioxane); MS (EI) m/z 632 (M ,
-1
1
5), 515 (100); IR (Nujol) 1715, 1599, 1518, 1169 cm . Anal.
LH ) 13. Zn L
2
:
1H NMR (DMSO-d
6
) δ (d, 2H, J ) 7.2),
30 24 4 4 4
Calcd for C H N S O : C, 56.94; H, 3.82; N, 8.86. Found: C,
1
7
5
.31 (s, 2H), 7.01 (td, 2H, J ) 7.2, 1.4), 6.92-6.85 (m, 4H),
57.11; H, 4.03; N, 8.82. (Z)-39: H NMR (CDCl ) δ 8.09 (d,
3
.87 (s, 2H), 4.10 (q, 4H, J ) 7.3), 1.05 (t, 6H, J ) 7.3); IR
1H, J ) 8.6), 7.90 (d, 1H, J ) 8.6), 7.56-7.48 (m, 2H), 4.42 (q,
-
1
1
(Nujol) 1698, 1530, 1288, 1224 cm . Cu L
2
: IR (Nujol) 1712,
2H, J ) 8.2) 2.68 (s, 3H), 1.34 (t, 3H, J ) 8.2). (E)-39:
H
1
561, 1239, 1107 cm-1
LH ) 17. Zn L
1H NMR (DMSO-d
.6), 8.20 (d, 4H, J ) 6.6), 7.81 (d, 2H, J ) 7.5), 7.19 (t, 4H, J
7.4), 7.08 (t, 4H, J ) 7.6), 7.00 (d, 4H, J ) 8.0), 4.50 (s, 4H),
.
NMR (CDCl ) δ 8.02 (d, 1H, J ) 8.6), 7.80 (d, 1H, J ) 8.6),
3
:
6
) δ 8.90 (d, 4H, J )
7.48-7.38 (m, 2H), 4.25 (q, 2H, J ) 8.2) 2.52 (s, 3H), 1.27 (t,
3H, J ) 8.2).
2
6
)
4
Rea ction of 11 w ith Air . A solution of EtONa in EtOH (1
M, 0.3 mL) was added to a warm solution (40 °C) of 11 (0.50
g, 1.41 mmol) in EtOH (10 mL). After the solution was stirred
for 1 h at room temperature, a brown solid precipitated. This
solid was collected, washed with EtOH, dried under vacuum
at 50 °C, and identified as bis(5-ethoxy-4-methylthiazol-2-yl)
-
1
2
.33 (s, 6H); IR (Nujol) 1642, 1578, 1316, 1270 cm . Cu L :
-1
IR (Nujol) 1646, 1568, 1523, 1265 cm . NiL
2
: IR (Nujol) 1649,
: IR (Nujol) 1651, 1527, 1521,
H NMR (DMSO-d ) δ 8.93 (d, 4H, J ) 6.3),
.25 (d, 4H, J ) 6.2), 7.42 (d, 4H, J ) 7.5), 6.82 (d, 4H, J )
-
1
1
1
8
537, 1558, 1260 cm . CoL
2
-
1
1
224 cm . P d L
2
:
6
J . Org. Chem, Vol. 67, No. 16, 2002 5771

Abbotto et al.
1
1
ketone (40) (0.25 g, 0.60 mmol, 48%): mp 127; H NMR (CDCl
3
)
mmol, 82.1%). The H NMR spectrum was identical to that of
an authentic sample.
δ 4.40 (q, 8H, J ) 8.5), 2.90 (s, 6H), 1.40 (t, 6H, J ) 8.5); 3C
1
NMR (CDCl
7.58, 14.24; MS (EI) m/z 368 (M , 100); IR (Nujol) 1667 cm
Anal. Calcd for C15 : C, 48.90; H, 4.38; N, 7.60.
Found: C, 48.78; H, 4.32; N, 7.46.
Con ver sion of Zn (2)Cl to Zn (2 )
15.1 mg, 0.184 mmol) was added to a suspension of Zn(2)Cl
70 mg, 0.167 mmol) in MeOH (7 mL). After the suspension
3
) δ 173.39, 161.66, 161.59, 161.23, 130.06, 62.02,
Rea ction B. AcONa (21.4 mg, 0.262 mmol) was added to a
suspension of Zn(2)Cl
.119 mmol) in MeOH (5 mL). After the suspension was stirred
overnight at room temperature, the solid was collected, washed
•+
-1
1
.
2
(50 mg, 0.119 mmol) and 2 (33.6 mg,
16 2 2 5
H N S O
0
-
2
2
. Rea ction A. AcONa
with MeOH, and finally dried under vacuum at 80 °C for 2 h
(
(
2
-
to give Zn(2 )
2
as a yellow solid (68.3 mg, 0.108 mmol, 91.4%).
The H NMR spectrum was identical to that of an authentic
sample.
1
was stirred overnight at room temperature, the solid was
collected, washed with MeOH, and finally dried under vacuum
-
at 80 °C for 2 h to give Zn(2 )
2
as a yellow solid (43.1 mg, 0.068
J O025696O
5
772 J . Org. Chem., Vol. 67, No. 16, 2002