Diheteroarylmethanes. 5. E-Z isomerism of carbanions substituted by 1,3-Azoles: 13C and 15N π-charge/shift relationships as source for mapping charge and ranking the electron-withdrawing power of heterocycles

Article abstract of DOI:10.1021/jo951884l

Previously proposed π-charge/shift relationships have been applied to ¹³C and ¹⁵N shifts of the carbanions of 2-benzylazoles (thiazole, oxazole, and imidazole), their corresponding benzo-fused analogs, and bis(2-azolyl)methanes (azol

Full text of DOI:10.1021/jo951884l

J . Org. Chem. 1996, 61, 1761-1769
1761
Dih eter oa r ylm eth a n es. 5.1 E-Z Isom er ism of Ca r ba n ion s
Su bstitu ted by 1,3-Azoles: 13C a n d 15N π-Ch a r ge/Sh ift
Rela tion sh ip s a s Sou r ce for Ma p p in g Ch a r ge a n d Ra n k in g th e
Electr on -With d r a w in g P ow er of Heter ocycles
Alessandro Abbotto, Silvia Bradamante, and Giorgio A. Pagani*
Dipartimento di Chimica Organica e Industriale dell’Universita` di Milano and
Centro CNR Speciali Sistemi Organici, via Golgi 19, I-20133, Milano, Italy
Received October 23, 1995X
Previously proposed π-charge/shift relationships have been applied to 13C and 15N shifts of the
carbanions of 2-benzylazoles (thiazole, oxazole, and imidazole), their corresponding benzo-fused
analogs, and bis(2-azolyl)methanes (azolyl groups as above). In this way it is possible to rank the
π electron-withdrawing power of these heterocycles in terms of charge demands cX, a quantity
representing the fraction of π negative charge withdrawn (delocalized) by the ring. The results
indicate that cthiaz > coxaz > cimidaz; furthermore, benzoazoles are more efficient than monocyclic
systems in delocalizing the negative charge. The charge demand cX of imidazole is the smallest
among the heteroaromatics so far considered, being even smaller than that of the phenyl ring. As
a consequence, the negative charge in the anion of 2-benzyl-N-methylimidazole is predominantly
transferred from the carbanionic carbon to the phenyl group rather than to the imidazolyl residue.
The high double bond character of the bond linking the carbanionic and ipso phenyl ring carbons
leads to room temperature 13C shift anisochrony of the meta and meta′ and ortho and ortho′ positions
of the phenyl ring. In all of the other cases, hindered rotation is observed at room temperature
between the carbanionic carbon and position 2 of the heterocycle. A single set of resonances is
presented by the bis(heteroaryl)methyl carbanions. π-Charge/shift relationships allow for the
accurate π-charge mapping in these carbanionic systems, and the results point to considerable
delocalization of the electron pair(s) of the oxygen and pyrrolic nitrogen atoms at position 1 in
oxazole and imidazole toward the pyridic nitrogen at position 3 of the rings (in both the neutrals
and the carbanionic species). On the contrary, not only does the sulfur atom in thiazole derivatives
not delocalize any negative charge in the anions but it is barely involved in any π-donation to the
pyridic nitrogen atom at position 3 also in the neutrals.
Once the chemical shift of the carbanionic carbon and
the shielding contributions Ai3 of the i groups bonded to
it are known, the π-charge/13C-shift relationship (1)
depend on the system studied. In charge demand nota-
tion, the subscript identifies the group and the super-
script the system or family of carbanions. Thus, benzyl
carbanions PhCH-X (in which Y ) Ph) originated the
cPXh values,4 and symmetrically diactivated carbanions
X2CH- originated the cXX values.6 Strong electron-with-
drawing groups X or Y (with the exception of Y ) Ph)
have the same charge demands in X2CH- and XYCH-
allows empirical calculation of the π-electron density
qCπ
on a trigonal carbanionic carbon XYCH-.
3,4
δ13C ) 122.8 + ΣAi - 160(qπC - 1)
(1)
We have previously defined4-6 the charge demand c of
(cXX ) cY). The charge demands cX and cY are in turn
X
related to qπC. In diactivated carbanions X2CH-, the
charge demand cXX is related to the experimentally
obtained qπC by relationship 2; in benzyl carbanions
PhCH-X, the cPXh is related to the value of qπC by rela-
tionship 3.
a substituent group as the fraction of π-charge withdrawn
from an adjacent charged trigonal carbon atom and have
subsequently used charge demands as a measure of the
capacity of substituents to delocalize positive or negative
charges.4-10 The values of substituent charge demands
X Abstract published in Advance ACS Abstracts, February 15, 1996.
(1) For part 4, see ref 2a. For part 3, see ref 7b. For part 2, see ref
2b. For part 1, see ref 2c.
cXX ) (2 - qπC)/2
(2)
(3)
(2) (a) Bradamante, S.; Facchetti, A.; Pagani, G. Gazz. Chim. Ital.
In press. (b) Abbotto, A.; Bradamante, S.; Pagani, G. Gazz. Chim. Ital.
1994, 124, 301-308. (c) Abbotto, A.; Alanzo, V.; Bradamante, S.;
Pagani, G. A.; Rizzoli, C.; Calestani, G. Gazz. Chim. Ital. 1991, 121,
365-368.
cPXh ) 2 - cPh - qπC
In (3) cPh is the charge delocalized by the phenyl group
in PhCH-X. It varies with X but can be calculated4
according to relationship 4 by adding the local variations
(3) Bradamante, S.; Pagani, G. A. J . Org. Chem. 1984, 49, 2863-
2870.
(4) Bradamante, S.; Pagani, G. A. J . Chem. Soc., Perkin Trans. 2
1986, 1035-1045.
(5) Bradamante, S.; Pagani, G. A. Pure Appl. Chem. 1989, 61, 709-
716.
(8) Abbotto, A.; Alanzo, V.; Bradamante, S.; Pagani, G. A. J . Chem.
Soc., Perkin Trans. 2 1991, 481-488.
(6) Barchiesi, E.; Bradamante, S.; Ferraccioli, R.; Pagani, G. A. J .
Chem. Soc., Perkin Trans. 2 1990, 375-383.
(7) (a) Berlin, A.; Bradamante, S.; Pagani, G. A. J . Chem. Soc.,
Perkin Trans. 2 1988, 1525-1530. (b) Abbotto, A.; Bradamante, S.;
Pagani, G.; Rzepa, H.; Stoppa, F. Heterocycles 1994, 40, 757-776.
(9) Abbotto, A.; Bradamante, S.; Pagani, G. A. J . Org. Chem. 1993,
58, 444-448.
(10) Abbotto, A.; Bradamante, S.; Pagani, G. A. J . Org. Chem. 1993,
58, 449-455.
0022-3263/96/1961-1761$12.00/0 © 1996 American Chemical Society

1762 J . Org. Chem., Vol. 61, No. 5, 1996
Abbotto et al.
of the π-electron densities at all of the positions of the
phenyl ring. Analogously, after exploiting the π-charge/
We considered the bis(heteroaryl)methanes 7-11 at-
tractive for at least three reasons. First, unlike substi-
tuted diphenylmethanes, bis(heteroaryl)methanes of azines
and azoles are compounds that have so far received little
attention in the literature, notwithstanding their poten-
tially great interest as activated carbon acids.13 Indeed,
many of them manifest “active methylene behaviour” 2b
insofar as they undergo easy nitrosation, azo-coupling,
and condensation with carbonyl reagents. Second, we
cPh ) Σ∆qπC-ring ) -Σ∆δ13Cring/160
(4)
Ph
Het
15N-shift relationship (5),8-11 the charge demand c
of
an aromatic nitrogen heterocycle in benzyl carbanions
PhCH-X with X ) Het is given by the relationship 6.
Ph
Het
Het
wanted to compare the charge demands c
and c
of
Het
∆δ15N ) -366.34∆qπN
) Σ∆qπC-ring + Σ∆qπN
(5)
these heterocycles with the charge demand of the phenyl
ring cPPhh. Third, although bis(2-benzothiazolyl)methane
(bisBTzM) (9) and transition metal ions are known2c to
give neutral methanates [ML2] in which the ligand is
present as bis(2-benzothiazolyl)methyl carbanion, not all
bis(o-azaheteroaryl)methanes behave as good carbanionic
ligands.7b,15 As a rough estimate of the stability of the
carbanion, the charge demand of the heterocycle may
prove to be a valid discriminating threshold below which
the formation of neutral metal chelates can be prevented.
To apply relationship 1 to carbanions 1--10- and
obtain the cHet values, we needed to know the shielding
contributions Ai of the different azoles and benzoazoles.
Following a previous approach,6 the Ai terms were
calculated as the difference between the 13C chemical
shifts of the â carbon in styrene and those of the same
carbon atoms in the styryl derivatives 12-16.
Ph
Het
c
)
-[Σ∆δ13Cring/160 + Σ∆δ15N/366.34] (6)
We have so far been mainly involved in ranking the
resonance electron-withdrawing power of primary organic
functionalities,4-6 along with pyridyl7 and azine5,8 het-
erocyclic rings contiguous to a carbanionic center. In this
way, we have obtained two sets of values, cPXh and cXX, for
various X groups, depending on whether R-substituted
benzyl anions PhCH-X or diactivated systems X2CH- are
being considered. The ranking of electron-withdrawing
groups has allowed a precise prediction of the 13C shift
of the carbanionic carbon to be made in many di-9,10
and trisubstituted12 carbanions. It has also been pos-
sible to describe the variation in the π-electron density
between neutral and conjugated anionic species (charge
mapping).4-10 In particular, benzyl carbanions PhCH-Het
with Het ) 2- and 4-pyridyl and 2- and 4-quinolyl and
heterocyclic azine rings show E-Z isomerism for the bond
linking the heterocycle and the carbanionic carbon.7,8
We have now extended this approach to the carbanions
substituted by heterocyclic 1,3-azoles (oxazole, thiazole,
and imidazole) and their benzo-fused analogs. The
systems we have considered are 2-benzylthiazole (BnTz)
(1), 2-benzyloxazole (BnOx) (2), 2-benzyl-N-methylimi-
dazole (BnIm) (3), 2-benzylbenzothiazole (BnBTz) (4),
2-benzylbenzoxazole (BnBOx) (5), and 2-benzyl-N-meth-
ylbenzimidazole (BnBIm) (6). However, the extension
also covered the bis(heteroaryl)methanes, bis(2-thiazolyl)-
methane (bisTzM) (7), bis(N-methylimidazol-2-yl)methane
(bisImM) (8), bis(2-benzothiazolyl)methane (bisBTzM)
(9), bis(2-benzoxazolyl)methane (bisBOxM) (10), and
bis(N-methylbenzimidazol-2-yl)methane (bisBImM) (11).
Resu lts
Syn th esis of Neu tr a ls a n d P r ep a r a tion of Ca r -
b a n ion s. 2-Benzyloxazole (BnOx) (2) appears to be
unknown. It was prepared according to Scheme 1 fol-
lowing Cornforth’s approach17 for 2-substituted oxazoles.
Phenylacetimidoyl ethyl ether (17) was reacted with the
hydrochloride of glycine methyl ester to give substituted
imido ether 18 which, upon condensation with ethyl
formate under basic conditions, gave hydroxymethylene
sodium salt 19. Cyclization to 2-benzyl-4-(ethoxycarbo-
nyl)oxazole (20) was performed in refluxing glacial acetic
acid. Subsequent careful basic hydrolysis to acid 21 and
decarboxylation afforded 2 in an overall yield of 32%.
Compound 2 was also prepared using an alternative
route based on a recently reported synthesis of oxazole
derivatives.18 The mixture of 1- and 2-(phenylacetyl)-
1,2,3-triazoles (22 and 23) (respectively), as obtained from
the reaction of phenylacetyl chloride and 2-(trimethylsi-
lyl)-1,2,3-triazole (Scheme 2),was thermolyzed in sul-
folane.
Bis[4-(ethoxycarbonyl)thiazol-2-yl]methane (24) was
prepared (Scheme 3) according to the general Hantzsch
synthesis of thiazoles by condensing malonodithioamide2b
with ethyl bromopyruvate. Subsequent acidic hydrolysis
(13) Bordwell has reported14 particularly high carbon acidity for
2-benzylbenzothiazole in DMSO (pKa ) 20.8): since the phenyl ring
is much less electron-withdrawing than the benzothiazolyl ring, we
estimate that the pKa of bis(2-benzothiazolyl)methane is in the upper
region of the 10-20 pKa units.
(14) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456-463.
(15) We have reported2c that bis(2-benzothiazolyl)methane (9) acts
as a carbanionic ligand L- toward the acetates of divalent transition
metal ions [Zn(II), Cu(II), Co(II), Ni(II)], leading to neutral metal
methanates [MeL2]. Further work from this laboratory16 has shown
that this behavior is common to a number of other bis(o-azaheteroaryl)-
methanes, including bis(2-benzoxazolyl)methane (10). The aza analog
of the series, bis(N-methylbenzimidazol-2-yl)methane (11), fails to react
with metal acetates to give neutral methanates.
(11) Gatti, C.; Ponti, A.; Gamba, A.; Pagani, G. J . Am. Chem. Soc.
1992, 114, 8634-8644.
(12) Barchiesi, E.; Bradamante, S.; Ferraccioli, R.; Pagani, G. A. J .
Chem. Soc., Chem. Commun. 1987, 1548-1549.
(16) Abbotto, A. Ph.D. Thesis, University of Milano, 1993.
(17) Cornforth, J . W.; Fawaz, E.; Goldsworthy, L. J .; Robinson, R.
J . Chem. Soc. 1949, 1549-1553.
(18) Williams, E. L. Tetrahedron Lett. 1992, 33, 1033-1036.

Diheteroarylmethanes
J . Org. Chem., Vol. 61, No. 5, 1996 1763
Sch em e 1
Sch em e 4
Carbanions 1--10- were prepared in DMSO using
dimsylsodium as a base. We have documented the
reasons for our choice of DMSO as a solvent elsewhere.3-10
Under these conditions, the sodium salts should have the
form of solvent separated ion pairs or of free ions. The
insufficient solubility of the carbanion sodium salt of
compound 11 prevented us from obtaining its 13C and 15N
NMR spectra.
NMR Sh ift Assign m en ts. The 13C and 15N NMR
shifts of compounds 1-6 and 1--6- are shown in Table
1; those relating to compounds 7-11 and 7--10- are
given in Table 2. Here, we only provide a detailed
interpretation of NMR data when the assignments were
not straightforward.
Sch em e 2
(a ) 13C Sh ifts. The 13C shift assignments in the
neutral compounds 1-11 were based on coupling con-
stants19a and the known heteroatom substituent effects
operating in the heterocycles.19b Benzothiazole, benzox-
azole, and N-methylbenzimidazole20 were used as model
compounds for comparison. When ambiguities occurred,
a complete analysis of the spectrum was performed
and discrimination was based on the multiplicity of
patterns and the values of the long-range coupling
constants.
Sch em e 3
In compound 2 the assignments to Cpara, C(4), and
C(5) were as follows: 126.82 ppm, Cpara, double triplet,
3J C,H(ortho) ) 6.9 Hz; 127.03 ppm, C(4), double doublet,
1
1J C,H(4) ) 193.9 Hz, in line with J C,H(4) ) 195 Hz in
2
oxazole,19a J C,H(5) ) 16.0 Hz; 139.72 ppm, C(5), double
1
doublet, 1J C,H(5) ) 209.6 Hz, in line with J C,H(5) ) 209 Hz
in oxazole,19a 2J C,H(4) ) 18.5 Hz. In compound 3, the peak
at 121.23 ppm was attributed to C(5), given that this was
1
a double double quartet, J C,H(5) ) 188.5 Hz, in analogy
1
2
with J C,H(5) ) 189 Hz in imidazole,19a J C,H(5) ) 13.0 Hz,
3J C,H(Me) ) 3.0 Hz; at 126.39 ppm C(4) was present as a
1
2
double doublet, J C,H(4) ) 186.6 Hz, J C,H(5) ) 9.7 Hz.
In the phenyl ring of anions 1--6-, the carbon atoms
para to the carbanionic center showed the largest high-
field displacement in comparison with neutrals. In
anions 1--3-, 7-, and 8-, C(5) proved to be the most
shielded position of the heterocycle; in anions 4--6-, 9-,
and 10-, C(4), C(6), C(7), and C(8) showed shielding
effects to varying degrees. Anion 1- was present as a
mixture of the E and Z geometrical isomers in a ratio of
1:1, not interchangeable in the NMR time scale at room
temperature. Discrimination between the signals of the
two isomers was not possible because of the lack of ring
protons proximate to the carbanionic proton susceptible
to an NOE experiment. Two isomers were also present
and decarboxylation of acid 25 gave (bisTzM) (7). This
compound is rather unstable in air but can be stored for
some time and with little decomposition under nitrogen
and in the cold.
Bis(N-methylimidazol-2-yl)methane (bisImM) (8) was
prepared according to the method shown in Scheme 4.
Bis-malonimido ethyl ether 26 was reacted with (N-
methylamino)acetaldehyde diethyl acetal to give bis-
amidine 27; this compound was cyclized in hydrochloric
acid to bis(N-methylimidazol-2-yl)methane (bisImM) (8).
Because of the solubility of 8 in water, its isolation
required continuous extraction with hexane in a Kuma-
gawa apparatus from the basified, dry residue obtained
from the cyclization step.
(19) (a) Breitmaier, E.; Voelter, W. Carbon-13 NMR Spectroscopy;
VCH: Weinheim, 1987; pp 288-289. (b) Reference 19a, p 282.
(20) Stefaniak, L. Org. Magn. Reson. 1978, 11, 385-389.

1764 J . Org. Chem., Vol. 61, No. 5, 1996
Abbotto et al.
Ta ble 1. 13Ca a n d 15N NMR Sh iftsb (p p m ) of 2-Ben zyl-1,3-a zoles 1-6 a n d Con ju ga te Ca r ba n ion s 1--6- in DMSOc
azole ring positions
phenyl ring positions
ortho meta para
CH2/
CH- Hzd
1J /
other
groups
compd
1
2
3
4
5
6
7
8
9
ipso
1
1
170.12 316.82 142.60 120.36
165.83 231.56 141.61 93.58
163.92 230.98 140.00 93.26
162.64 245.35 127.03 139.72
168.48 190.2f 127.01 125.30
129.22 129.00 127.23 138.56 38.68 129.9
119.18 127.55 111.64 143.68 82.87 150.6
119.01 127.15 111.22 142.92 79.90 150.2
128.72 128.56 126.82 135.95 33.59 130.1
117.64 127.22 109.12 144.84 65.10g 150.6
128.30 128.38 126.21 137.89 32.30 128.2 CH3 ) 32.32
117.74g 127.52g 105.16 145.42 62.59 147.5 CH3 ) 31.47
114.70g 126.78g
- 50%e
50%
2
2-
3
155.78 146.17 257.72 126.39 121.23
122.54 154.73 216.40 124.22 111.56
3-
4
4
170.98 308.02 122.30 126.08 124.86 122.08 135.05 152.89 129.15 128.70 127.07 137.52 39.41
160.37 218.33 111.59 124.30 114.05 118.26 130.58 159.96 121.36 127.33 114.96 143.20 82.60 151.4
159.51 111.28 124.71 112.83 118.81 129.90 156.46 120.78 127.83 114.68 142.83 85.20 150.4
h
- 85%
15%
i
5
5
165.18 242.53 119.30 124.72 124.20 110.44 150.30 140.84 128.90 128.53 126.92 135.06 34.07 130.6
- 90%
10%
168.10 179.62 108.99 121.28 113.58 104.38 149.26j 148.88j 120.85 127.25 113.74 143.77 67.13 152.0
168.47
i
108.63 121.96 112.46 104.84 150.11k 147.59k 120.40 127.72 114.01 143.42 69.23 152.0
6
138.73 153.67 242.22 118.47 121.62 121.28 109.84 135.87 142.23 128.56 128.66 126.53 136.87 32.99 129.0 CH3 ) 29.78
109.54 158.52 193.49 108.63 117.81 112.72 102.08 136.88 148.20 119.89 127.04 111.10 145.05 65.86 148.0 CH3 ) 28.29
6-
a
b
Relative to Me4Si (0.0 ppm). Relative to liquid NH3 (0.0 ppm), 380.23 ppm from neat nitromethane. c 0.50 M solutions at 27 °C.
Relative to the benzylic methylene or methine group. e Values of corresponding positions in the two isomers can be exchanged. f Obtained
for a 1 M solution at 35 °C (broad peak at 27 °C). Broad. Covered by solvent peaks. Nitrogen of minor isomer was not detected.
Values can be exchanged. Values can be exchanged.
d
g
h
i
j
k
Ta ble 2. 13Ca a n d 15N NMR Sh iftsb (p p m ) of Bis-2-(1,3-a zolyl)m eth a n es 7-11 a n d Th eir Con ju ga te Ca r ba n ion s 7--10- in
DMSOc
azole ring positions
compd
1
2
3
4
5
6
7
8
9
CH2/CH-
1J /Hzd
other groups
7
7-
8e
165.54
166.63
143.69
154.55
166.30
164.76
160.60
168.71
150.51
319.04
247.52
259.43
201.94
311.22
241.32
245.72
187.10
242.16
142.42
140.49
126.20
123.93
122.55
115.43
119.62
114.20
118.51
120.76
100.41
121.48
112.02
126.28
124.42
125.30
122.30
121.77
35.88
79.91
25.30
47.10
37.78
81.42
28.58
55.81
26.73
135.0
156.9
129.0
149.5
133.8
157.8
133.8
160.2
130.1
157.46
122.60
CH3 ) 32.45
CH3 ) 31.40
8- e,f
9
125.28
117.45
124.57
118.16
121.27
122.21
119.62
110.75
107.01
109.82
135.25
132.11
150.46
148.59
135.90
152.58
155.97
140.58
145.65
142.13
9-
10
10-
11
140.50
CH3 ) 29.92
a
b
Relative to Me4Si (0.0 ppm). Relative to liquid NH3 (0.0 ppm), 380.23 ppm from neat nitromethane. c 0.50 M solutions at 27 °C.
Relative to the methylene or methine bridge. e 0.25 M solution. f 50 °C.
d
in the NMR spectrum of anions 4- and 5- with similar
ratios of respectively 85:15 and 90:10. Once again, it was
impossible to discriminate the signals of the two isomers.
In anion 2-, the assignment of the double doublets at
shift assignments of the two nitrogen atoms of the
imidazole ring in compounds 3 and 8, and of the benz-
imidazole ring in compounds 6 and 11, were based on
known nitrogen shieldings in simple heterocyclic sys-
tems.21 In anions 3-, 6-, and 8-, both nitrogen atoms
are shielded in relation to their corresponding atoms in
the neutrals. It is assumed that the pyrrolic nitrogen
atom remained at a higher field than the pyridic nitrogen
atom, as in the neutrals.
E-Z Isom er ism in th e An ion s. The 13C NMR
spectra of benzyl anions 1-, 2-, 4-, 5-, and 6- provide
evidence for a mixture of both the E and Z isomers along
the bond linking the carbanionic carbon and the hetero-
cycle. The carbanion of 2-benzyl-N-methylimidazole (3-)
is one of the rare cases in which there is evidence at room
temperature that hindered rotation is present along the
bond linking the carbanionic carbon and the phenyl ring.
Figure 1 shows the variations in the spectrum as the
sample temperature increased. In the other cases, no
evident variation was detected as the temperature was
increased to 55 °C; in view of the instability of the dimsyl
anion above 60 °C,22 we did not try higher temperatures.
The NOE experiment8 that allowed the determination of
the double bond configuration in the case of the benzy-
lazine anions could not be used for anions 1-, 2-, 4-, 5-,
and 6- because of the lack of protons at the ortho,ortho′
125.30, 127.01, and 127.22 ppm to C(5), C(4) and Cmeta
respectively, was based on the different values of J C,H
,
1
1
2
(125.30 ppm, C(5), J C,H(5) ) 199.6 Hz, J C,H(4) ) 19.1 Hz;
1
2
127.01 ppm, C(4), J C,H(4) ) 181.7 Hz, J C,H(5) ) 15.5 Hz;
1
3
127.22 ppm, Cmeta, J C,H(meta) ) 151.5 Hz, J C,H(meta′) ) 7.0
Hz). In anion 3-, the long-range coupling with the
methyl group allowed the assignment to C(5) and C(4):
111.56 ppm, C(5), double double quartet, 1J C,H(5) ) 180.9
Hz, 2J C,H(4) ) 15.9 Hz, 3J C,H(Me) ) 3.2 Hz; 124.22 ppm, C(4),
1
2
double doublet, J C,H(4) ) 178.8 Hz, J C,H(5) ) 9.6 Hz. In
anion 7-, the different values of the J C,H allowed the
2
discrimination between C(4) and C(5): 100.41 ppm, C(5),
double doublet, 2J C,H(4) ) 15.0 Hz, could be compared with
2J C(5),H(4) ) 15.3 Hz in compound 7; and 140.49, C(4),
2
2
double doublet, J C,H(5) ) 5.5 Hz, with J C(4),H(5) ) 6.6 Hz
in compound 7. As with anion 3-, the discrimination
between C(5) and C(4) in anion 8- was based on the long-
range coupling constant with the methyl group: 112.02
2
ppm, C(5), double double quartet, J C,H(4) ) 15.6 Hz,
3J C,H(Me) ) 2.8 Hz; 123.93 ppm, C(4), double doublet,
2J C,H(5) ) 9.8 Hz.
(b) 15N Sh ifts. As expected from previous results
obtained investigating carbanions with pyridine-like
nitrogen atoms,7,8 the 15N shift underwent high-field
displacement when passing from the neutrals to the
carbanions. This must be related to the increase of π-
electron density on the nitrogen atoms in the anions. The
(21) Witanowski, M.; Stefaniak, L.; Webb G. A. In Annual Reports
on NMR Spectroscopy; Webb, G. A., Ed.; Academic Press; London:
1986; Vol. 18, pp 444-445.
(22) Corey, E. J .; Chaikowski, M. J . Am. Chem. Soc. 1965, 87, 1345-
1353.

Diheteroarylmethanes
J . Org. Chem., Vol. 61, No. 5, 1996 1765
Ta ble 3. Sh ield in g Con tr ibu tion s AX (p p m ) of
Heter oa r yl Su bstitu en ts a t C(â) in â-Su bstitu ted Styr en es
13C(â) shift
AX
a
substituent
H
113.2b
120.8
0.0
7.6
0.5c
1.4
8.7
0.5
1.2
thiazol-2-yl
oxazol-2-yl
N-methylimidazol-2-yl
benzothiazol-2-yl
benzoxazol-2-yl
114.6
121.9
113.7
114.4
N-methylbenzimidazol-2-yl
a
b
Positive values mean low-field displacements. Kalinowski,
H. O.; Berger, S.; Braun, S. Carbon-13 NMR Spectroscopy; J ohn
Wiley & Sons: Chichester, 1988; p 161. c The same value of the
corresponding benzo-fused substituent is assumed.
and meta to the benzyl residue. Therefore, as expected,
deprotonation of the benzylic methylene involves a much
greater high-field displacement of C(5) than C(4) (which
remains almost constant). Similarly, in benzo-fused
systems, only C(4), C(6), and, to a lesser extent, C(8)
undergo the greatest high-field shift. The nitrogen at
position 3 of the heterocycles is the nucleus that under-
goes the largest shift when passing from the neutrals to
carbanions. In benzyl derivatives, this increase amounts
to ca. 85-90 ppm for the thiazole ring, 50 ppm for the
oxazolyl derivatives, and 40 ppm for the imidazole ring.
The results are similar in the bis(heteroaryl)methanes.
A preliminary question arising before calculation of the
charge demands of the heterocycles concerns the reso-
nance contribution made to limit formulas (see below)
by the second heteroatom in thiazole, oxazole, and
imidazole derivatives (respectively sulfur, oxygen, and
nitrogen). In particular, do resonance ring structures
A-C make a substantial contribution to charge delocal-
ization in benzyl anions D-F? To answer this question
F igu r e 1. Temperature-dependent 13C NMR spectrum of the
carbanion of 2-benzyl-N-methylimidazole (3-) in DMSO (aro-
matic region).
positions of the heterocycle. In these anions, we found
that the phenyl ring prefers to stay syn to the ring
nitrogen atom, and it is possible that there is an
analogous preference in the case of benzyl azoles. The
anion of 2-benzylbenzothiazole has been reported23 to
react with benzaldehyde in THF to give the threo aldol
product with moderate diastereoselectivity (80%). Un-
fortunately, this result is of no help for the stereochemical
assignment of the E and Z isomers of 4- because the
lithium salt of the same anion was reported to be
unreactive in HMPA, that is, under conditions analogous
to those of the sodium salt in DMSO described herein.
Unlike the above benzyl carbanions, the 13C NMR
spectra of the anions of bis(heteroaryl)methanes 7--10-
show a single set of resonances and therefore indicate
either a single species [e.g., either the (E,E)-7-, the (E,Z)-
7-, or the (Z,Z)-7-] or a rapid (on the NMR time scale)
equilibrium between the three interconverting isomers.
it is worth noting, first, that the 15N chemical shift of
the nitrogen atom in thiazolyl derivatives is strictly
analogous to that of the pyridyl systems.21 Furthermore,
the high-field displacement of 15N following deprotonation
of 2-benzylthiazole and 2-benzylbenzothiazole is almost
the same as that found for 2-benzylpyridine24 and
2-benzylquinoline.7b It therefore seems that the -S- group
in neutral and carbanionic thiazole derivatives offers an
electronic and magnetic contribution which is no more
and no less than that offered by the sCHdCHs fragment
in pyridine.
Second, a totally different situation is presented by
oxazole and imidazole derivatives. The 15N shift at
position 3 of the neutrals (Tables 1 and 2) is considerably
more high field than that of thiazole. Although not
exclusively so, this result can be ascribed to the π
donation of X(1) to N(3) and regarded as providing
evidence for a considerable contribution of the limit
formula B for X ) O and NMe. In the anions, the
Discu ssion
Th e Na tu r e of X in Azoles a n d Deloca liza tion in
Ca r ba n ion s. Carbons C(5) and C(4) of monocyclic
benzyl azoles can be considered as being respectively para
(23) Epifani, E.; Florio, S.; Ingrosso, G. Tetrahedron 1987, 43, 1937-
1943.
(24) Barchiesi, E.; Bradamante, S. J . Phys. Org. Chem. 1990, 3,
139-142.

1766 J . Org. Chem., Vol. 61, No. 5, 1996
Abbotto et al.
Ta ble 4. Va r ia tion s of th e Loca l π-Electr on Den sities (m illielectr on s) for Ea ch ith P osition on Goin g fr om th e Neu tr a l
2-Ben zyl-1,3-a zoles 1-6 to th e Con ju ga te An ion s 1--6- a
azole ring positions
phenyl ring positions
compd
1
2
3
4
5
6
7
8
9
ortho
meta
para
ipso
1-
50%
50%
27
39
-36
-54
233
234
150
113
6
16
0
167
169
90
63
64
69
66
85
49
52
50
53
54
9
11
8
5
10
9
5
8
5
10
97
100
111
132
-32
-27
-56
-47
2-
3-
91
14
60
4-
5-
85%
15%
90%
10%
66
72
-18
-21
-30
245
172
133
67
69
64
67
62
11
9
22
17
24
68
75
66
73
54
24
20
38
35
48
28
32
6
1
-6
-44
-22
-50
-42
-37
76
77
82
81
96
-36
-33
-54
-52
-51
6-
80
a
Positive values correspond to an increment of π-electron density.
Ta ble 5. Va r ia tion s of th e Loca l π-Electr on Den sities
(m illielectr on s) for Ea ch ith P osition on Goin g fr om th e
Neu tr a l Bis-2-(1,3-a zolyl)m eth a n es 7-10 to th e Con ju ga te
An ion s 7--10- a
Ta ble 6. Exp er im en ta l π-Electr on Den sities q (electr on s)
for Con ju ga te An ion s 1--6- of 2-Ben zyl-1,3-a zoles 1-6
a
b
c
d
compd
qPh
qHet
6.433
6.458
qC
qPh + qHet + qC
1-
50% 6.209
50% 6.223
6.209
1.378 14.020
1.397 14.078
azole ring positions
compd
1
2
3
4
5
6
7
8
9
2-
3-
4-
6.204 (6.295)e
6.224
1.445 13.858 (13.949)e
1.466 13.941
6.251
7-
8-
-7
-68
10
195
157
191
160
12
14
44
34
127
59
12
85% 6.156 10.465
1.387 18.008
1.371 18.029
95
15% 6.158 10.500f
9-
49
40
16
23
20
12
-21
-32
5-
90% 6.144 10.300 (10.380)g 1.432 17.876 (17.956)g
10-
-51
19
10% 6.145 10.302f (10.382)g 1.419 17.866 (17.946)g
6-
6.173 10.328
1.445 17.946
a
Positive values correspond to an increment of π-electron
density.
a
b
π-Electron density resident on the phenyl ring. π-Electron
density resident on the azole ring. c π-Electron density resident
d
benzylic negative charge can partition between both N(3)
and X(1), and the high-field displacement of the 15N shift
of the NMe at position 1 of the anionic imidazolyl
derivatives confirms this interpretation. To have access
to a quantitative measure of the charge mapping in the
anions, we adopted the working hypothesis that relation-
ship 5 is a valid means of correlating the displacement
of the 15N shift with π-electron density variations not only
for the pyridine-like N(3) but also for the pyrrole-like N(1)
of the NMe group. The same trigonal electronic config-
uration at N(3) and at N(1) justifies this assumption and
predominantly ascribes the high-field displacement of
N(1) to the increase in π-electron density at this site.
The following approach in the evaluation of the charge
demands of the heterocycles takes all of this into account.
Azoles Ch a r ge Dem a n d s. Experimental access to
the empirical evaluation of how much negative charge
is delocalized by the heterocyclic rings in the carbanions
can be provided by two alternative calculations. The
first, through eq 3, provides cX values that are homoge-
neous with those previously4,5 obtained for a number of
other classic EWGs of organic chemistry (CO2R, C(O)R,
CN, SOnR, NO2, etc.) and whose uncertainty depends
on qπC. The second approach provides the cHet value
through eq 6 and involves a large number of terms in
the summation of all the local π-charge densities. The
calculation of cHet was based on the following premises:
(1) The sulfur atom in the carbanions of thiazole deriva-
tives does not delocalize any negative charge, this being
present only on the carbon and nitrogen skeleton ( in
short, (∆qπ)S(1) ) 0). (2) The 15N shift/π-charge relation-
ship (5) is valid not only for the pyridine but also for the
pyrrole-like nitrogen atoms of imidazole derivatives. (3)
The π-charge density variation at the oxygen atom in
oxazoles is identical to that at the pyrrole nitrogen atom
in imidazoles. In short, (∆qπ)O(1) ) (∆qπ)N(1) (this appears
reasonable in view of the close resemblance of the 15N
shift behavior of oxazolyl and imidazolyl derivatives). The
calculations reported in Tables 6 and 7 for the oxazolyl
on the carbanionic carbon. Total π-electron density of the anionic
system (to be compared with the theoretical value of 14 and 18
π-electrons for simple and benzo-fused derivatives, respectively).
e Value in parentheses calculated by assuming ∆qπ
equal to
O(1)
∆qπN(1) of corresponding imidazole derivative 3-. f Same ∆qπN(3) of
g
major isomer assumed. Value in parentheses calculated by
assuming ∆qπ
derivative 6-.
equal to ∆qπ
of corresponding imidazole
O(1)
N(1)
Ta ble 7. Exp er im en ta l π-Electr on Den sities q (electr on s)
for Con ju ga te An ion s 7--10- of
Bis-2-(1,3-a zolyl)m eth a n es 7-10
a
b
c
compd
qHet
qC
2qHet + qC
14.017
14.005
22.009
7-
8-
6.327
6.257
10.321
1.363
1.491
1.367
1.425
9-
10-
10.205 (10.300)d
21.835 (22.025)d
a
b
π-Electron density resident on the azole ring. π-Electron
density resident on the carbanionic carbon. c Total number of
π-electrons in the anionic system (to be compared with the
theoretical values of 14 and 22 π-electrons for monocyclic and
d
benzo-fused derivatives, respectively). Value calculated by as-
suming ∆qπO(1) equal to ∆qπN(1) of similar imidazole derivative 8-.
derivatives were performed considering either (∆qπ)O(1)
0 or (∆qπ)O(1)) (∆qπ)N(1) (numbers in parentheses).
)
In order to ascertain whether the above assumptions
were acceptable, we compared the theoretical number of
total π-electrons of the systems (14 in 1--3-, 7-, and 8-;
18 in the benzo-fused 4--6-, 9-, and 10-) and the total
number of electrons calculated by summing the electron
densities on the rings (the phenyl and the heterocycle in
PhCH-Het, or the two heterocycles in Het2CH-) and on
the carbanionic carbon CH- (eqs 7 and 8). Tables 6 and
qHπ et + qπPh + qCπ ) total number of π electrons (7)
2qπHet + qπC ) total number of π electrons
(8)
7 show that the agreement between the experimental and

Diheteroarylmethanes
J . Org. Chem., Vol. 61, No. 5, 1996 1767
Ta ble 8. Ch a r ge Dem a n d s of Heter oa r yl Su bstitu en ts in
croanalysis laboratory of our department. Melting points are
uncorrected. Anhydrous solvents were prepared by continuous
distillation over sodium sand, in the presence of benzophenone
and under nitrogen or argon, until the blue color of sodium
ketyl was permanent. Extracts were dried over Na2SO4.
Anions were prepared following the procedure already de-
scribed.3 2-Ben zylth ia zole (1),25 2-ben zylben zoth ia zole
(4),26 2-ben zylben zoxa zole (5),27 bis(2-ben zoth ia zolyl)-
m eth a n e (9),28 bis(2-ben zoxa zolyl)m eth a n e (10),29 bis(N-
m et h ylb en zim id a zol-2-yl)m et h a n e (11),2a 2-(â-st yr yl)-
ben zoth ia zole (14),30 [13C NMR (DMSO-d6) δ 166.54, 153.60,
137.53, 135.27, 134.19, 129.61, 129.01, 127.80, 126.61, 125.57,
122.68, 122.26, 121.93], and 2-(â-styr yl)ben zoxa zole (15)30
[13C NMR (DMSO-d6) δ 162.23, 149.72, 141.64, 139.32, 134.73,
129.72, 128.78, 127.73, 125.30, 124.54, 119.46, 113.67, 110.40]
were prepared according to the literature.
P h CH-X(cXPh) a n d in X2CH-(cXX)
X
cPXh
cXX
thiazol-2-yl
oxazol-2-yl
0.413-0.380a,b
0.346
0.318
N-methylimidazol-2-yl
benzothiazol-2-yl
benzoxazol-2-yl
0.283
0.254
0.316
0.288
0.457-0.471a
0.424-0.436a
0.382
N-methylbenzimidazol-2-yl
a
Values referred to the major and minor anionic geometric
b
isomer, respectively. 1:1 mixture of geometrical isomers.
theoretical values is excellent. In particular, the calcula-
tions for the thiazole and benzothiazole rings show that
no negative charge is delocalized onto the sulfur atom in
the anions of thiazoles 1- and 7- and benzothiazoles 4-
and 9-. The consequence of this is that the sulfur
electron pair in the neutral thiazole derivatives is barely
involved in delocalization toward the nitrogen or the
aromatic carbon atoms of the ring. Incorporation of
relationship 5 for N(1) of the imidazole derivatives into
qπHet of relationships 7 and 8 leads to a total “experi-
mental” number of electrons that is in excellent agree-
ment with theory. A similarly excellent result is obtained
for the oxazole systems if qπHet takes into account that
2-Ben zyl-4-(eth oxyca r bon yl)oxa zole (20). A mixture of
ethyl formate (2.90 g, 39.1 mmol) and N-((ethoxycarbonyl)-
methyl)phenylacetimidoyl ethyl ether (18)17 (6.09 g, 24.4 mmol)
was added to a suspension of potassium tert-butoxide (3.00 g,
26.7 mmol) in anhydrous diethyl ether (40.0 mL) at -4 °C.
After stirring for 2 h at -4 °C, anhydrous ether (20 mL) was
added, and then the yellow mixture was kept overnight at 4
°C. The white precipitate was rapidly separated under a
nitrogen stream and washed with anhydrous diethyl ether (20
mL) to give the very hygroscopic hydroxymethylene potassium
salt 19 (6.94 g, 22.0 mmol, 90.2%): 1H NMR (CDCl3) δ 8.50
(s, 1 H), 7.35-7.10 (m, 5 H), 4.00 (q, 2 H, J ) 7.5), 3.90 (q, 2
H, J ) 7.5), 1.11-1.09 (m, 6 H). The product was treated
almost immediately in the subsequent reaction. Potassium
salt 19 (6.94 g, 22.0 mmol) was added to refluxing glacial AcOH
(50.0 mL), and after refluxing for 1 h, AcOH was removed at
reduced pressure to leave a residue that was neutralized with
a saturated aqueous solution of NaHCO3 (20.0 mL) and
extracted with diethyl ether (5 × 15 mL). The solvent was
removed from the dried extracts to give the product as a brown
solid (4.07 g, 17.6 mmol, 80.0%), mp 63 °C, which was used
without any further purification in the next step. An analyti-
cal sample was purified to give a white solid: mp 72 °C (EtOH)
(∆qπ)O(1)) (∆qπ)N(1)
Data in Table 8 show that the charge demands of the
heterocycles decrease in the series cthiaz > coxaz > cimid
.
.
The result that N(3) of imidazole is more reluctant than
that of oxazole and, even more so, that of thiazole to
accept negative charge from the carbanionic carbon is due
to the already very efficient “internal” donation to N(3)
from N(1) in imidazole and from O(1) in oxazole. Benzo-
fused rings are more efficient than monocyclic rings in
delocalizing the charge.
1
(lit.17 mp 74-75 °C); H NMR (CDCl3) δ 8.15 (s, 1 H), 7.35-
The charge demand of the 2-imidazolyl group is not
only the smallest of the values of the 1,3-azoles but is
also quite small on an absolute scale. While the thiazolyl
ring in anion 1- of 2-benzylthiazole accepts more charge
(qHet ) 6.44) (Table 6) than the phenyl ring (qPh ) 6.215),
in anion 3- of 2-benzyl-N-methylimidazole, the amount
7.20 (m, 5 H), 4.35 (q, 2 H, J ) 7.5), 4.15 (s, 2 H), 1.40 (t, 3 H).
2-Ben zyl-4-ca r boxyoxa zole (21). A mixture of 2-benzyl-
4-(ethoxycarbonyl)oxazole (20) (3.07 g, 13.2 mmol) and 6%
aqueous KOH (12 mL) in H2O (6 mL) was refluxed for 10 min,
cooled, and acidified to pH 4 with 1 N H2SO4. The resulting
pale yellow precipitate was separated to give the product as
monohydrate, used without any further purification in the
next step (2.66 g, 12.0 mmol, 90.9%), mp 153 °C. A sample
was purified to give a white solid: mp 153 °C (H2O, charcoal)
(lit.17 mp 156-158 °C); 1H NMR (CDCl3) δ 8.20 (s, 1 H),
7.40-7.20 (m, 5 H), 4.20 (s, 2 H), 3.00 (broad). The peak
at δ 3.00 disappears upon deuteration. Anal. Calcd for
C11H9NO3‚H2O: C, 59.73; H, 5.01; N, 6.33. Found: C, 59.41;
H, 4.70; N, 5.95.
2-Ben zyloxa zole (2). Meth od A. A mixture of 2-benzyl-
4-carboxyoxazole‚H2O (21) (1.66 g, 7.5 mmol) and electrolytic
copper powder (3.32 g) was heated at 250 °C in a Kugelrohr
apparatus. The pale green oil that distilled (bp 250 °C/25
mmHg) was taken up with diethyl ether (15 mL) and washed
with saturated aqueous NaHCO3 (10 mL). The solvent was
removed from the dried organic layer to leave the practically
pure product as a pale green oil (0.54 g, 3.4 mmol, 45.3%),
which was further purified by distillation in Kugelrohr to give
a colorless oil, bp 135-145 °C/0.08 mmHg: 1H NMR (CDCl3)
δ 7.56 (d, 1 H, J ) 0.8), 7.36-7.22 (m, 5 H), 7.04 (d, 1 H), 4.10
(s, 2 H); MS (EI) m/z 159 (M+•, 100), 130 (27), 103 (20), 91
(80). Anal. Calcd for C10H9NO: C, 75.44; H, 5.71; N, 8.80.
Found: C, 75.15; H, 5.69; N, 9.02.
of negative π-charge accepted by the phenyl ring (qPh
)
6.251) is greater than that accepted by the imidazole ring
(qHet ) 6.224). Consequently, whereas the thiazolyl ring
is a good competitor of the phenyl ring in delocalizing
the negative charge, the imidazolyl ring is not. The net
result is that hindered rotations occur along different
bonds in the two cases. The anion of 2-benzylimidazole
has high double bond character along the bond linking
the carbanionic carbon and the ipso carbon of the phenyl
ring, leading to the exceptional result of room tempera-
ture anisochrony of the ortho and meta positions. In
contrast, the anion of 2-benzylthiazole has high double
bond character along the bond linking the carbanionic
carbon and C(2) of the heterocycle. The results of the
benzo-fused systems can be rationalized on similar
grounds.
Exp er im en ta l Section
1H NMR spectra were recorded on a Bruker AC-300 instru-
ment operating at 300 MHz. 13C and 15N NMR spectra were
recorded at 27 °C on a Varian XL-300 spectrometer, operating
at 75.47 and 30.45 MHz, respectively, and using 0.50 M
solutions in DMSO. Spectral parameters and calibrations
have been previously reported.8 Coupling constant values, J ,
are given in hertz throughout. Elemental analyses were
performed on a Perkin-Elmer 240 instrument by the mi-
(25) Burger, A.; Ullyot, G. E. J . Org. Chem. 1947, 12, 342-355.
(26) Hamer, F. M. J . Chem. Soc. 1956, 1480-1498.
(27) Higginbottom, R.; Suschitzky, H. J . Chem. Soc. 1962, 2367-
3270.
(28) Rai, C.; Braunwarth, J . B. J . Org. Chem. 1961, 26, 3434-3445.
(29) Rai, C.; Braunwarth, J . B. U. S Patent 3,250,780; Chem. Abstr.
1966, 65, 7180g.
(30) Dryanska, V.; Ivanov, C. Synthesis 1976, 37-38.

1768 J . Org. Chem., Vol. 61, No. 5, 1996
Abbotto et al.
Meth od B. A procedure reported for the synthesis of
2-substituted oxazoles was adopted.18 A solution in anhydrous
sulfolane (70 mL) of a 95:5 mixture of 1-(phenylacetyl)-1,2,3-
triazole (22) and 2-(phenylacetyl)-1,2,3-triazole (23) as ob-
tained in the preparation described below (2.24 g, 12.0 mmol)
was stirred for 4.5 h at 160 °C under nitrogen. The originally
colorless solution became dark red. The mixture was cooled
to room temperature, poured into H2O (100 mL), and extracted
with diethyl ether (3 × 100 mL). The combined organic layers
were washed with H2O (2 × 500 mL) to eliminate the sulfolane,
dried, and evaporated to dryness to give a brown oil which
was submitted to Kugelrohr distillation, affording the product
as a colorless oil (1.61 g, 10.1 mmol, 84%), bp 130 °C/0.08
mmHg.
2-(Tr im eth ylsilyl)-1,2,3-tr ia zole. A procedure reported
in the literature for the synthesis of 1-(trimethylsilyl)tetrazole
was used.31 To a solution of 1,2,3-triazole (1.02 g, 14.8 mmol)
and Et3N (1.62 g, 16.0 mmol) in anhydrous benzene (20 mL)
was added dropwise trimethylsilyl chloride (1.59 g, 14.6 mmol),
maintaining the temperature below 10 °C. A white precipitate
was formed. The reaction mixture was stirred for 24 h at room
temperature and then cooled to 0 °C and the triethylammo-
nium chloride filtered off (2.00 g, 14.5 mmol, 99%). The
obtained benzene solution of the product was used for the next
step. After removal of the solvent at atmospheric pressure, a
sample was obtained by distillation at reduced pressure, bp
68 °C/20 mmHg (lit.32 bp 147-149 °C): 1H NMR (CDCl3) δ
7.73 (s, 2 H), 0.53 (s, 9 H).
N-(P h en yla cetyl)-1,2,3-tr ia zoles 22 a n d 23. The prepa-
ration follows a procedure reported18 in the literature for
N-acyltriazoles. Phenylacetyl chloride (2.20 g, 14.4 mmol) was
added to the benzene solution of 2-(trimethylsilyl)-1,2,3-
triazole as obtained in the previous step. The temperature
raised spontaneously to 35 °C, and the formation of a white
precipitate was observed. The solid was filtered off, and the
solvent was removed to give the crude product (2.49 g, 13.3
mmol, 93%) as a pale pink oil. The product is a mixture of
the two isomers 1-(phenylacetyl)-1,2,3-triazole and 2-(pheny-
lacetyl)-1,2,3-triazole (95:5): 1H NMR (CDCl3) δ 8.26 (d, 0.95
H, J ) 1.4), 7.89 (s, 0.1 H), 7.74 (d, 0.95 H), 7.41-7.22 (m),
4.61 (s, 1.90 H), 4.52 (s, 0.1 H).
(s, 2 H), 3.42 (s, 3 H); MS (EI, 10 eV) m/e 172 (M+•, 100), 171
(100), 157 (40), 91 (60), 81 (65). Anal. Calcd for C11H12N2: C,
76.71; H, 7.02; N, 16.27. Found: C, 76.64; H, 6.97; N, 16.18.
2-Ben zyl-N-m eth ylben zim id a zole (6). Powdery pheny-
lacetimidoyl ethyl ether hydrochloride (1.60 g, 8.2 mmol) was
added to a solution of N-methyl-o-phenylenediamine34 (1.00
g, 8.2 mmol) in absolute EtOH (8 mL); the temperature
spontaneously rose to 50 °C. The reaction mixture was stirred
for 10 min at room temperature, the reaction was quenched
with H2O (15 mL), and then the mixture was extracted with
diethyl ether (5 × 10 mL). The solvent was removed from the
dried extracts to leave the product as a dark solid (1.45 g, 6.5
mmol, 79.3%) that was first purified by Kugelrohr distillation
to give a pink-orange solid [(0.95 g, 4.3 mmol, 52.4%), bp 195
°C/0.5 mmHg, mp 68 °C], and then crystallized to a pale pink
solid (0.7 g, 3.2 mmol, 30.0%), mp 72 °C (cyclohexane): 1H
NMR (CDCl3) δ 7.75 (m, 1 H), 7.35-7.15 (m, 8 H), 4.35 (s, 2
H), 3.60 (s, 3 H). Anal. Calcd for C15H14N2: C, 81.05; H, 6.35;
N, 12.60. Found: C, 81.00; H, 6.21; N, 12.45.
Bis[4-(eth oxyca r bon yl)th ia zol-2-yl]m eth a n e (24).
A
solution of ethyl bromopyruvate (26.10 g, 133.8 mmol) in DMF
(10 mL) was added dropwise to a solution of malono-
dithioamide2b (9.00 g, 67.0 mmol) in DMF (40 mL), maintain-
ing the temperature below 25 °C. The reaction mixture was
stirred for 24 h at room temperature, treated with an aqueous
solution (100 mL) of stoichiometric NaHCO3, and extracted
first with diethyl ether-AcOEt 2:1 (100 mL) and then with
diethyl ether-AcOEt 1:1 (100 mL). After washing several
times with H2O and drying the combined extracts, elimination
of the solvent left a dark oil that was extracted with diethyl
ether (4 × 50 mL). The residue obtained after evaporation of
the solvent from the combined extracts (yellowish solid, 13.40
g) was submitted to flash chromatography (CH2Cl2-AcOEt,
2:1) on silica gel to give the product as a yellowish solid (8.31
g, 25.4 mmol, 37.9%): mp 94-97 °C (a white sample was
obtained by recrystallization from H2O with no mp increase);
1H NMR (CDCl3) δ 8.06 (s, 2 H), 4.77 (s, 2 H), 4.34 (q, 4 H, J
) 7.1), 1.32 (t, 6 H); MS (EI) m/e 326 (M+•, 40), 281 (59), 254
(100), 208 (30), 182 (56). Anal. Calcd for C13H14N2O4S2: C,
47.84; H, 4.32; N, 8.58. Found: C, 48.17; H, 4.16; N, 8.46.
Bis(4-ca r boxyth ia zol-2-yl)m eth a n e (25). A suspension
of bis[(4-(ethoxycarbonyl)thiazol-2-yl]methane (24) (5.00 g,
15.3 mmol) in 10% HCl (50 mL) was refluxed for 10 h. After
1 h from the homogeneous solution at reflux temperature a
yellowish precipitate was observed, turning to light brown
during the reaction. After cooling to room temperature, the
brownish precipitate was collected and dried over CaCl2 at
reduced pressure, overnight, and at room temperature, and
then for further 30 min at 60 °C, to afford the product (3.73 g,
2-Ben zyl-N-m eth ylim id a zole (3). Powdery phenylace-
timidoyl ethyl ether hydrochloride33 (3.60 g, 18.0 mmol) was
added to a solution of (methylamino)acetaldehyde dimethyl
acetal (2.15 g, 18.0 mmol) in absolute EtOH (20 mL), main-
taining the temperature between 0 and 5 °C. After stirring
for 2.5 h at room temperature, anhydrous diethyl ether (100
mL) was added, giving N-m eth yl-N-(2,2-d im eth oxyeth yl)-
p h en yla ceta m id in e h yd r och lor id e as a white precipitate
(3.65 g, 13.4 mmol, 74.4%): mp 162 °C; 1H NMR (CDCl3), two
rotamers in the 30:70 ratio; 30% isomer, δ 10.5 (broad, 1 H),
9.9 (broad, 1 H), 7.37-7.25 (m, 5 H), 4.75 (t, 1 H, J ) 5.6),
4.20 (s, 2 H), 3.88 (d, 2 H, J ) 5.6), 3.48 (s, 3 H), 3.05 (s, 3 H);
70% isomer, δ 10.5 (broad, 1 H), 10.0 (broad, 1 H), 7.37-7.25
(m, 5 H), 4.27 (s, 2 H), 4.17 (t, 1 H, J ) 5.6), 3.38 (s, 3 H), 3.37
(d, 2 H, J ) 5.6), 3.35 (s, 3 H). Anal. Calcd for C13H20N2O2‚
HCl: C, 57.24; H, 7.76; N, 10.27. Found: C, 57.41; H, 7.55;
N, 9.98. A solution of the hydrochloride (2.47 g, 9.0 mmol) in
37% HCl (1.10 g) and glacial AcOH (30 mL) was refluxed for
2 h. The solvent was removed at reduced pressure to leave a
pale green residue that was taken up with diethyl ether (20
mL) and 30% NaOH (25 mL). The organic layer was separated
and the aqueous layer extracted with diethyl ether (4 × 15
mL). The solvent was removed from the dried combined
organic extracts to leave the product as a brown solid (1.31 g,
7.6 mmol, 84.4%) that was purified by Kugelrohr distillation
(bp 135 °C/0.6 mmHg) to give the compound as a white solid
1
13.8 mmol, 90.2%): mp > 220 °C; H NMR (DMSO-d6) δ 13
(broad, 2 H), 8.45 (s, 2 H), 4.92 (s, 2 H). Anal. Calcd for
C9H6N2O4S2: C, 40.00; H, 2.24; N, 10.36. Found: C, 40.15;
H, 2,27; N, 10.13.
Bis(2-th ia zolyl)m eth a n e (7). A mixture of bis(4-carbox-
ythiazol-2-yl)methane (25) (2.37 g, 8.8 mmol) and electrolytic
copper powder (3.00 g) was heated in a Kugelrohr apparatus
at 260-270 °C at 25 mmHg. The distilled oil (0.99 g) resulted
a mixture of the reactant and of the product; it was taken up
with CH2Cl2 (20 mL) and washed with saturated aqueous
NaHCO3 (20 mL). The solvent was removed from the dried
organic layer to leave a dark brown oil (0.52 g) that was
submitted to Kugelrohr distillation, affording the product as
a pale yellow oil (0.43 g, 2.4 mmol, 27.3%): bp 145 °C/0.05
1
mmHg; H NMR (CDCl3) δ 7.77 (d, 2 H, J ) 3.0), 7.28 (d, 2
H), 4.80 (s, 2 H); MS (EI) m/e 182 (M+•, 100), 137 (63), 124
(16), 98 (24), 58 (100). Anal. Calcd for C7H6N2S2: C, 46.13;
H, 3.32; N, 15.37. Found: C, 45.75; H, 3.08; N, 14.99. The
compound is unstable to air and must be stored under
nitrogen.
1
(0.78 g, 4.5 mmol, 50.0%): mp 50-52 °C; H NMR (CDCl3) δ
7.30-7.10 (m, 5 H), 6.95 (d, 1 H, J ) 0.8), 6.78 (d, 1 H), 4.10
Bis(N-m eth ylim id a zol-2-yl)m eth a n e (8). Powdery ma-
lonodiimidoyl diethyl ether dihydrochloride35 (2.50 g, 10.8
mmol) was added to a solution of (methylamino)acetaldehyde
(31) Birkofer, L.; Ritter, A.; Richter, P. Chem. Ber. 1963, 96, 2750-
2757.
(32) Peterson, W. R., J r.; Arkles, B.; Washburne, S. S. J . Organomet.
Chem. 1976, 121, 285-291.
(33) McElvain S. M.; Nelson, J . W. J . Am. Chem. Soc. 1942, 64,
1825-1827.
(34) Roeder, C. H.; Day, A. R. J . Org. Chem. 1941, 6, 25-35.
(35) Kenner, G. W.; Lythgoe, B.; Todd, A. R.; Topham, A. J . Chem.
Soc. 1943, 574-575.

Diheteroarylmethanes
J . Org. Chem., Vol. 61, No. 5, 1996 1769
dimethyl acetal (2.62 g, 22.0 mmol) in absolute EtOH (18 mL),
maintaining the temperature below 10 °C. After stirring for
4 h at room temperature, the solvent was removed to give
crude N1,N3-d im eth yl-N1,N3-bis(2,2-d im eth oxyeth yl)m a -
lon a m id in e d ih yd r och lor id e (27) as a brown oil (3.50 g,
9.3 mmol, 86.1%), which was used without any further
purification in the next step: 1H NMR (CDCl3) δ 8.30 (broad,
4 H), 4.85 (t, 2 H, J ) 5.1), 3.35 (s, 12 H), 2.95 (d, 4 H), 2.65
(s, 6 H). A solution of hydrochloride 27 (9.00 g, 23.8 mmol) in
37% HCl (20 mL) was refluxed for 2 h and then made strongly
alkaline with 30% aqueous NaOH. The solvent was removed
to leave a residue that was submitted to continuous extraction
with hexane in a Soxhlet apparatus. The product was obtained
as a white precipitate upon concentration of the solution (0.25
g, 1.4 mmol, 5.9%): mp 135-142 °C (lit.36 mp 143-148 °C);
1H NMR (CDCl3) δ 6.90 (d, 1 H, J ) 1.1), 6.80 (d, 1 H), 4.20 (s,
2 H), 3.65 (s, 6 H).
2-(â-Styr yl)-N-m eth ylim id a zole (13). A procedure simi-
lar to that used for the synthesis of 2-benzyl-N-methylimida-
zole (3) was employed. From (methylamino)acetaldehyde
dimethyl acetal (1.67 g, 14.0 mmol) and cinnamimidoyl ethyl
ether hydrochloride (2.96 g, 14.0 mmol) (prepared following a
general procedure)33 N-m eth yl-N-(2,2-d im eth oxyeth yl)cin -
n a m a m id in e h yd r och lor id e (1.87 g, 6.6 mmol, 47.1%), mp
180-183 °C, was obtained: 1H NMR (CDCl3) δ 10.1 (broad, 1
H), 9.7 (broad, 1 H), 8.20 (d, 1 H, J ) 17.5), 7.65 (m, 2 H), 7.35
(m, 3 H), 6.70 (d, 1 H), 4.50 (t, 1 H, J ) 5.1), 3.60 (d, 2 H), 3.50
(s, 3 H), 3.40 (s, 6 H). Anal. Calcd for C14H20N2O2‚HCl: C,
59.05; H, 7.43; N, 9.84. Found: C, 58.97; H, 7.18; N, 9.96.
From N-methyl-N-(2,2-dimethoxyethyl)cinnamamidine hydro-
chloride (1.83 g, 6.4 mmol) crude product 13 was obtained as
an orange solid (0.91 g, 4.9 mmol, 76.6%): mp 70-72 °C (mp
1
80 °C, hexane); H NMR (CDCl3) δ 7.65-7.18 (m, 5 H), 7.60
(d, 1 H, J ) 16.5), 7.07 (d, 1 H, J ) 1.1), 6.90 (d, 1 H), 6.87 (d,
1 H), 3.75 (s, 3 H); 13C NMR (DMSO-d6) δ 144.90, 136.60,
130.40, 128.63, 128.16, 127.85, 126.67, 122.21, 114.64, 32.22.
Anal. Calcd for C12H12N2: C, 78.23; H, 6.56; N, 15.20.
Found: C, 78.23; H, 6.57; N, 15.21.
2-(â-Styr yl)th ia zole (12). A procedure reported in the
literature for the preparation of 2-(â-styryl)benzothiazole and
2-(â-styryl)benzoxazole30 was used. Aqueous 50% NaOH (1
mL) was added dropwise to a solution in DMSO (4 mL) of
benzaldehyde (0.53 g, 5.0 mmol) and 2-methylthiazole37 (0.50
g, 5.0 mmol) (prepared from pure chloroacetaldehyde hy-
drate).38 The yellow mixture turned to orange, and the
formation of a precipitate was observed. After stirring for 24
h at room temperature, the reaction mixture was poured into
H2O (15 mL) and extracted with diethyl ether (2 × 25 mL).
The solvent was removed from the dried extracts to leave a
yellowish oil (0.24 g) that was submitted to flash chromatog-
raphy (CH2Cl2-AcOEt, 3:1) on silica gel to provide the product
as a yellow solid (30 mg, 0.2 mmol, 4%): mp 55-59 °C (lit.39
2-(â-Styr yl)-N-m eth ylben zim id a zole (16). A procedure
similar to that used for the synthesis of 2-benzyl-N-methyl-
benzimidazole (6) was employed. From N-methyl-o-phe-
nylenediamine34 (1.16 g, 9.5 mmol) and cinnamimidoyl ethyl
ether hydrochloride (2.01 g, 9.5 mmol) the crude product was
obtained as a dark oil (1.33 g, 5.7 mmol, 60.0%), which was
purified by flash chromatography (CH2Cl2-AcOEt, 2:1) on
silica gel to provide the pure product as a white solid (0.39 g,
1.7 mmol, 17.9%): mp 114 °C (cyclohexane) (lit.40 mp 113-
114 °C); 1H NMR (CDCl3) δ 7.96 (d, 1 H, J ) 15.7), 7.82-7.72
(m, 1 H), 7.60 (dd, 1 H, J ) 7.5, J ) 1.8), 7.44-7.18 (m, 6 H),
7.10 (d, 1 H), 3.85 (s, 3 H); 13C NMR (DMSO-d6) δ 150.91,
142.77, 136.03, 135.97, 135.82, 128.87, 128.78, 127.43, 122.03,
121.95, 118.43, 114.37, 110.11, 29.55. Anal. Calcd for
C16H14N2: C, 82.02; H, 6.02; N, 11.96. Found: C, 82.06; H,
6.02; N, 11.88.
1
mp 59 °C); H NMR (CDCl3) δ 7.81 (d, 1 H, J ) 3.4), 7.66-
7.17 (m, 8 H); 13C NMR (CDCl3) δ 166.70, 142.86, 135.14,
133.81, 128.29, 128.24, 126.47, 120.79, 117.66.
(36) Byers, P. K.; Canty, A. J . Organometallics 1990, 9, 210-220.
(37) Erlenmeyer, H.; Weber, O.; Schmidt, P.; Ku¨ng, G.; Zinsstag C.;
Prijs, B. Helv. Chim. Acta 1948, 31, 1142-1158.
(38) Kurkjv, R. P.; Brown, E. V. J . Am. Chem. Soc. 1952, 74, 5778-
5779.
J O951884L
(39) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici A.; Pedrini, P.
Tetrahedron 1988, 44, 2021-2031.
(40) Pushkina, L. N.; Mazalov, S. A.; Postovskii, I. Y. Chem. Abstr.
1963, 58, 9050c.