Effect of π-electron delocalization on tautomeric equilibria - Benzoannulated 2-phenacylpyridines

Article abstract of DOI:10.1002/ejoc.200500840

Most benzoannulated 2-methylpyridines react with phenyllithium and substituted alkyl benzoates to give the corresponding 2-phenacylpyridines. 3-Methylisoquinoline is transformed into 2-benzoyl-3-methyl-1-phenyl-1,2- dihydroisoquinoline under these conditions, but replacement of phenyllithium with lithium isopropylcyclohexylamide is effective for production of 3-phenacylisoquinolines. Except in the cases of some substituted 6-phenacylphenanthridines, tautomeric mixtures of benzoannulated 2-phenacylpyridines in chloroform solution always contain the ketimine forms. (Z)-2-(2-Hydroxy-2-phenylvinyl)pyridine (enolimine) forms also contribute if the pyridine ring is not benzoannulated or if such annulation is at positions 4,5. On the other hand, (Z)-2-benzoylmethylene-1,2-dihydropyridine (enaminone) forms exist in equilibrium with the ketimine tautomers if the pyridine ring is benzoannulated at positions 3,4 or 5,6, or at both of these locations. As well as the effectiveness of π-electron delocalization, other effects, such as the strength of the intramolecular hydrogen bonding, should also be considered in order to infer the tautomeric preferences. Strongly electron-donating substituents were found to stabilize the ketimine forms in each series. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200500840

FULL PAPER
DOI: 10.1002/ejoc.200500840
Effect of π-Electron Delocalization on Tautomeric Equilibria – Benzoannulated
2-Phenacylpyridines
Ryszard Gawinecki,*[a] Erkki Kolehmainen,[b] Hossein Loghmani-Khouzani,[c]
[a]
[d]
[e]
´
Borys Osmiałowski, Tamás Lovász, and Pavel Rosa
Keywords: Nitrogen heterocycles / Annulation / Aromaticity / Substituent effect / Tautomerism / Ketimine / Enolimine /
Enaminone / Hydrogen bond
Most benzoannulated 2-methylpyridines react with phenyl-
lithium and substituted alkyl benzoates to give the corre-
sponding 2-phenacylpyridines. 3-Methylisoquinoline is
transformed into 2-benzoyl-3-methyl-1-phenyl-1,2-dihy-
droisoquinoline under these conditions, but replacement of
if such annulation is at positions 4,5. On the other hand,
(Z)-2-benzoylmethylene-1,2-dihydropyridine (enaminone)
forms exist in equilibrium with the ketimine tautomers if the
pyridine ring is benzoannulated at positions 3,4 or 5,6, or at
both of these locations. As well as the effectiveness of π-elec-
phenyllithium with lithium isopropylcyclohexylamide is ef- tron delocalization, other effects, such as the strength of the
fective for production of 3-phenacylisoquinolines. Except in
the cases of some substituted 6-phenacylphenanthridines,
tautomeric mixtures of benzoannulated 2-phenacylpyridines
in chloroform solution always contain the ketimine forms.
(Z)-2-(2-Hydroxy-2-phenylvinyl)pyridine (enolimine) forms
also contribute if the pyridine ring is not benzoannulated or
intramolecular hydrogen bonding, should also be considered
in order to infer the tautomeric preferences. Strongly elec-
tron-donating substituents were found to stabilize the
ketimine forms in each series.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
same form [i.e., (benzo)-o-quinone monooxime] is present
in the solid state.[6–8]
Introduction
According to the concept of resonance,[1] π-electron delo-
calization is a very powerful phenomenon in suitably substi-
tuted, and especially in benzoannulated, molecules. This ef-
fect is a very important factor affecting the physical and
chemical properties of compounds, such as the stabilities of
tautomeric species.[2] Experimentally determined tauto-
meric constants indicate that benzoannulation at posi-
tions 3,4 or 5,6 increases the stabilities of 2-pyridone (1H-
pyridine-2-one) forms, whereas annulation at positions 4,5
shifts tautomeric equilibria towards the 2-hydroxypyridine
forms.[3] In solution, o-nitrosophenol exists in equilibrium
with its o-quinone monooxime tautomer.[4,5] On the other
hand, only the oxime tautomers of o-nitrosonaphthols were
found to be present in the gas phase and in solution.[6] The
Benzoannulation at positions 5,6 favors N-salicylidene-
amine (solutions in chloroform and acetonitrile) over its
NH tautomer [i.e., aminomethylene-1H-naphthalene-2-one
(2-oxo-1,2-dihydro-naphthylidene-1-amine)].[9] These com-
pounds and some tautomers of 2-acylmethylpyridines con-
tain structurally similar fragments. 2-Phenacylpyridines
(1K, Scheme 1) and their 5,6-benzo derivatives (3K) do not
usually appear in the solid (crystal) state,[10,11] while more
stable tautomers [i.e., (Z)-2-(2-hydroxy-2-phenylvinyl)pyri-
dines (1O) and (Z)-2-benzoyl-methylene-1,2-dihydropyri-
dines (3E)], are observed there.[10,11] In chloroform solution
2-phenacylpyridines (ketimines) substituted in the benzene
ring exist in equilibrium with (Z)-2-(2-hydroxy-2-phenylvi-
nyl)pyridines (enolimines) stabilized by the intramolecular
hydrogen bond.[10]
NMR studies show that 2-phenacylquinolines (ket-
imines) coexist in chloroform with similarly stabilized (Z)-2-
benzoylmethylene-1,2-dihydroquinolines (this enaminone
tautomer prevails independently of substitution present in
the benzoyl moiety).[11] DMSO solution contains exclu-
sively (Z)-6-(p-nitrobenzoyl)-methylene-5,6-dihydrophen-
anthridine [no 6-(p-nitrophenacyl)phenanthridine (5K, R7
= NO2) was detected].[12] 3-(p-Methylphenacyl)isoquinoline
(ketimine) definitely predominates over (Z)-3-(2-hydroxy-2-
phenylvinyl)isoquinoline (enolimine) in chloroform solu-
tion.[13] In DMSO solution, 1-(p-methylphenacyl)isoquino-
[a] Department of Chemistry, Technical & Agricultural University,
Seminaryjna 3, 85-326 Bydgoszcz, Poland
Fax: +48-052-3749005
E-mail: gawiner@mail.atr.bydgoszcz.pl
[b] Department of Chemistry, P. O. Box 35,
40014 University of Jyväskylä, Finland
[c] Department of Chemistry, Faculty of Sciences, University of
Isfahan,
Isfahan 81744, Iran
[d] Department of Organic Chemistry and CSOFSTM, Babes-
Bolyai University,
11 Aranyi Jànos Str., 3400 Cluj-Napoca, Romania
[e] ANIVEG CZ spol. s.r.o.,
8 kvetna 165, 410 02 Lovosice, Czech Republic
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2817

R. Gawinecki et al.
FULL PAPER
dines, the corresponding enolimine forms.[10] Benzoannu-
lation of the pyridine ring in these compounds affects the
tautomeric equilibria both qualitatively and quantita-
tively.[11] For the latter compounds a question arises regard-
ing the contribution of electron delocalization to increased
stability of the (Z)-2-benzoylmethylene-1,2-dihydroquino-
lines, the enaminone tautomers of 2-phenacylquino-
lines.[10,11] To discover whether the resonance effect is really
responsible for this increased stability of the enaminone
forms (and their increased contributions to the tautomeric
mixtures), different benzoannulated 2-phenacylpyridines
were studied.
Synthesis and Identification of Tautomers
Naming of compounds exhibiting tautomerism can be
somewhat
problematic.
Substituted
(Z)-2-benzoyl-
methylene-1,2-dihydroquinolines 3E are the only species
present in the crystalline state,[11] whereas 2-phenacylpyri-
dines 1K and (Z)-2-(2-hydroxy-2-phenylvinyl)pyridines 1O
have been detected when strongly electron-donating or elec-
tron-withdrawing substituents, respectively, are present in
the molecule.[10] Since no X-ray results are available for the
solid phenacyl derivatives of phenanthridine and isoquino-
line (the tautomer appearing in the solid product is not
known), double names (i.e., these of the potential tauto-
mers) are used in this paper for the solid reaction products.
The species present in solution were identified, so they are
named properly.
Scheme 1.
line (4K, R7 = Me) was found to exist in tautomeric equilib-
rium with (Z)-1-(p-methylbenzoylmethylene)-1,2-dihydro-
isoquinoline (4E, R7 = Me), previously erroneously formu-
lated as (Z)-1-(2-hydroxy-2-p-methylphenylvinyl)isoquino-
line (4O, R7 = Me).[14] It is also known that (1Z,3Z)-1,4-
bis(pyridin-2-yl)buta-1,3-diene-2,3-diol (enediol) coexists
2-Phenacylpyridines/(Z)-2-(2-hydroxy-2-phenylvinyl)pyr-
idines and 2-phenacylquinolines/(Z)-2-benzoylmethylene-
1,2-dihydroquinolines were prepared by treatment of
picolyllithium (2-lithio-methylpyridine) or quinaldyllithium
(2-lithiomethylquinoline) with substituted ethyl or methyl
with
(3Z)-3-hydroxy-1,4-bis(pyridin-2-yl)but-3-en-2-one
(ketimine-enolimine)[15] but dibenzoannulation is responsi-
ble for the exclusive presence of (3Z)-3-hydroxy-1,4-
bis(quinolin-2-yl)but-3-en-2-one in chloroform solution.[16]
Although these observations show that benzoannulation of
2-(acylmethyl)pyridines affects the tautomerism, the relative
stabilities of different tautomers present in solution are not
known. This prompted us to study the tautomeric equilibria
of phenacyl derivatives of pyridine, quinoline, isoquinoline,
and phenanthridine, and to find out how the presence and
location of benzene ring(s) in the molecules affects the pop-
ulations of the various tautomeric species of 2-phenacylpyr-
idines.
benzoates.[10,11]
1-Phenacylisoquinolines/(Z)-1-benzoyl-
methylene-1,2-dihydroisoquinolines, 3-phenacylisoquino-
lines/(Z)-3-(2-hydroxy-2-phenylvinyl)isoquinolines, and 6-
phenacylphenanthridines/(Z)-6-benzoylmethylene-5,6-dihy-
drophenanthridines were obtained in a similar manner (see
Exp. Sect. and Table 1 for details). It is noteworthy that
other synthetic methods for these compounds are also
known: 1-phenacylisoquinoline can be prepared by treating
1-methylsulfonylisoquinoline[17] or 1-chloroisoquinoline[18]
with sodium amide and acetophenone, as well as by ad-
dition of water to 1-ethynylisoquinoline.[19] Reductive de-
benzoylation of 2-benzoyl-1-phenacyl-1,2-dihydroisoquino-
Results and Discussion
Low energy barrier rearrangements (reversible processes) line also affords 1-phenacylisoquinoline.[20] Some of its sub-
enable different isomeric species (e.g., tautomers) to exist in stituted derivatives can also be obtained from 1-methyliso-
equilibrium. This dynamics may involve only two species, quinoline when treated with phenyllithium and substituted
but very often the number of interconverting compounds benzonitrile,[14] with p-nitrobenzoyl cyanide[12] or with aryl-
is higher. Although there should be no doubt about high or alkyllithium and substituted alkyl benzoates.[21] 3-Phen-
contributions of more stable isomers, there are no definite acylisoquinoline can be prepared by addition of water to 3-
known rules to evaluate their stability. Different effects such ethynylisoquinoline.[19,22] 3-Methylisoquinoline can also be
as steric and electronic (inductive and resonance) interac- transformed into 3-phenacylisoquinoline by treatment with
tions have to be considered when looking for the labile tau- lithium isopropylcyclohexylamide and benzonitrile,[13] while
tomers. 2-Phenacylpyridines exist in equilibrium (solution 6-(p-nitrophenacyl)phenanthridine has been obtained from
in chloroform) with (Z)-2-(2-hydroxy-2-phenylvinyl)pyri- 6-methylphenanthridine and p-nitrobenzoyl cyanide.[12]
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Effect of π-Electron Delocalization on Tautomeric Equilibria
FULL PAPER
Table 1. Synthetic and physical data.
p-toluonitrile gives 3-(p-methylphenacyl)isoquinoline in low
yield.[13]
Series/R7
Alkyl[a]
Method[b] Yield (%) M.p. (°C)
The formation of different products in these reactions
had also been observed previously. Organolithium com-
pounds can add to the azomethine linkages in pyridine or
its benzo derivatives[25] and substitution of the lithium atom
in the reaction product allows 2-substituted 1,2-dihydropyr-
idines to be prepared.[25] Although 2-alkylpyridines may
undergo similar reactions, lithiation may also take place at
the alkyl group,[25] so in 2-alkylpyridines there is competi-
tion between lithiation at the ring nitrogen or at the exo
carbon atom.[25] In consequence, acylation of the lithium
byproducts produces 1-acyl-1,2-dihydro- and 2-(acyl-
methyl)pyridines, respectively (Scheme 3).[25]
2/p-N(CH2)4
2/p-CH3
4/p-N(CH2)4
4/p-NMe2
4/p-CH3
4/p-Br
Et
Et
Et
Et
Et
Et
Me
Et
Et
Et
Et
Et
Me
Et
Me
–
–
12
22
69
62
248–250
120–122[c]
169–170
131–133
98–100
B
B
A
A
A
–
–
–
–
–
8
21.5
16.5
80
10.5
76
147–149[d]
153–155
235–237
204–210
245–247
97–99
4/p-CF3
5/p-N(CH2)4
5/p-NMe2
5/p-OCH3
5/p-CH3
5/H
5/p-Cl
5/m-F
5/p-CF3
13
12.5
12.5
12
131–134
153–159
167–172
200–202
–
–
–
14
The ability of a methyl group to react with an organo-
lithium compound (R–CH3 + RЈLi Ǟ R–CH2Li + RЈH) is
governed by the acidity of the methyl hydrogen atoms.[25a]
It is well known that 2-methylpyridine, 2-methylquinoline,
1-methylisoquinoline, and 6-methylphenathridine undergo
C-lithiation.[11,25–27] 1-Aryl-2-benzoyl-1,2-dihydroisoquino-
lines (Reissert-type compounds) can be obtained by treat-
ment of isoquinoline with arylmagnesium halide and ben-
zoyl chloride[28] or, in some special cases, of 2-arylbenzoyl-
isoquinolinium salts with N,N-dialkylanilines.[29,13] The ac-
tivity of the methyl group in 3-methylisoquinoline when
treated with lithium isopropylcyclohexylamide and p-tol-
uonitrile has been demonstrated through the formation of
3-(p-methylphenacyl)isoquinoline in low yield.[13] It should
be mentioned, however, that a different acylmethyl deriva-
tive of this type, 2-isoquinolin-3-ylindan-1,3-dione, was ob-
tained through the action of phthalic anhydride on 3-meth-
ylisoquinoline itself.[30]
[a] In substrate, i.e. p-substituted alkyl benzoate (see Exp. Sect.).
[b] See Exp. Sect. for details. [c] Literature m.p. 106–110 °C.[13]
[d] Yellow oil, according to Gnichtel and Möller.[14]
The general synthetic strategy for 1-methylisoquinoline
(for use in syntheses of 1-phenacylisoquinolines) was in
principle that of Schlittler and Müller.[23] 1-Phenylethylam-
ine was condensed with dimethoxyacetaldehyde [(MeO)2-
CHCHO; originally diethoxyacetaldehyde was used],[23] and
the obtained (2,2-dimethoxyethylidene)-(1-phenylethyl)-
amine [Ph–CH(CH3)N=CHCH(OMe)2] was cyclized under
acidic conditions.
Successive treatment of 3-methylisoquinoline with phen-
yllithium and ethyl p-methylbenzoate gave 3-methyl-2-(p-
methylbenzoyl)-1-phenyl-1,2-dihydroquinoline (Scheme 2
and Exp. Sect.). The molecular structure of this unexpected
reaction product was confirmed by NMR and X-ray crys-
tallography.[24] It is known that similar treatment of 3-meth-
ylisoquinoline with lithium isopropylcyclohexylamide and
Effect of Substituents and Temperature on the Contents of
Tautomeric Mixtures
1
The integrated intensities of 7-H signals in the H NMR
spectra were used to calculate the contents of the different
forms in solution.[10,11] As can be seen in Table 2, the tauto-
meric mixtures, except in the cases of some congeners in
series 5, always contain the K forms, which coexist with the
O forms if the pyridine rings are not benzoannulated
(series 1) or if such annulation is at positions 4,5 (series 2).
On the other hand, the E forms exist in equilibrium with
the K tautomers if the pyridine rings are 3,4- (series 4) or
Scheme 2.
Scheme 3.
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2819

R. Gawinecki et al.
FULL PAPER
5,6-benzoannulated (series 3), or if benzoannulation is pres- for quinolin-2-yl and isoquinolin-1-yl derivatives than for
ent at both of these positions (series 5). One should keep in pyridin-2-yl and isoquinolin-3-yl derivatives and are excep-
mind that 6-phenacylphenanthridine, owing to the presence tionally low for dibenzoannulated (i.e., phenanthridin-6-yl)
of two nonequivalent benzene rings in its system, has struc- derivatives (these compounds are both benzoannulated
tural fragments similar to both benzoannulated 2-phen- quinolin-2-yl and isoquinolin-1-yl derivatives).
acylquinoline and 1-phenacylisoquinoline. There is a ques-
When dissolved in chloroform, 2-phenacylpyridines exist
tion as to how the benzene ring(s) in the molecule influ- in equilibrium with (Z)-2-(2-hydroxy-2-phenylvinyl)pyri-
ence(s) the contributions of different species in solution. π- dines.[10] The character of the substituent on the benzene
Electron delocalization has been found to be responsible for ring significantly affects the tautomeric equilibrium [the
tautomeric preferences in numerous cases,[2] but other ef- amounts of the enolimine forms stabilized by intramolecu-
fects, such as strengths of intramolecular hydrogen bonds, lar hydrogen bonding are 1% for R = p-N(CH2)4 and 92%
should also be taken into account. Theoretical calcula- for p-NO2]. The negative logarithm of the tautomeric equi-
tions[32] indicate that the hydrogen bond in 7O (Scheme 4) librium constant (KT) is linearly dependent on the Hammett
is considerably stronger than that in 7E, so the strength of σ substituent constants;[10] the dependence of KT on tem-
this bond is responsible for the higher stability of 1O and perature is exponential: the more electron-withdrawing the
2O relative to 1E and 2E.
substituent, the more distinct is the influence of tempera-
ture.[10] The reaction K Ǟ O is exothermic for all pyridin-2-
yl derivatives except for those bearing strongly electron-do-
nating substituents.[10]
Table 2. K form contents (%)[a] (solutions in chloroform, 303 K).
R7
Series
1 [b,c]
2[b]
3[d,e]
4 [d]
5 [d]
NMR studies (Table 3) show that 2-phenacylquinolines
coexist in chloroform solutions with the (Z)-enaminone
forms, stabilized by intramolecular hydrogen bonding (these
tautomers prevail for all substituents studied).[11] Electron-
donating substituents in the phenacyl part of the molecule
increase the amount of the ketimine form (Table 2).[11,31]
Variable-temperature 1H NMR measurements show that
higher temperatures have the same effect.[11] The negative
logarithm values of the equilibrium constants (pKT) were
found to be linearly dependent on Hammett σ substituent
constants for these equilibria; pKT vs. temperature corre-
lation has linear character.[11] In general, strongly electron-
withdrawing substituents cause transformation from the ket-
imine to enaminone forms to become more exothermic, but
the values of the heats of reaction for the 2-phenacylquinol-
ines studied are not linearly dependent on σ.[11]
p-N(CH2)4 99.0
Ն 99
–
39.3[f]
33.0
24.6
11.1
6.7
4.8
4.7
4.2
2.1
2.2
1.8
1.5
1.0
48.2
26.3
–
–
5.2
–
–
–
2.5
–
–
4.0
2.0
–
1.2
0.0
–
0.0
–
–
0.0
0.0
–
0.0
–
p-NMe2
p-NH2
p-OMe
p-Me
m-Me
H
p-F
p-Br
p-Cl
m-F
95.7
90.8
84.8
72.5
64.4
58.1
56.8
50.6
45.5
34.0
32.5
18.6
7.8
–
–
60.7[g]
–
–
–
–
–
–
–
–
–
m-Br
p-CF3
p-NO2
–
1.5
–
–
[a] Based on integral intensities of 7-H signals in the 1H NMR spec-
trum, accuracy: 0.5%. [b] Another tautomer present: O. [c] Ref.[10]
[d] Another tautomer present: E. [e] Ref.[11] [f] Ref.[31] [g] 60.6%
based on intensities of 6-H signals.
The data collected in Table 4 show that reductions in the
temperatures of chloroform solutions of 1-phenacylisoquin-
olines decrease the K form contents, so this temperature
effect on the contribution of the ketimine tautomer K is of
the same type as that observed for solutions of 2-phenacyl-
pyridines bearing electron-donating substituents.[10] On the
other hand, the amounts of the K forms increase with re-
ductions in temperature both for solutions of 2-phenacylpyr-
Scheme 4.
On the other hand, although intramolecular hydrogen idines bearing electron-withdrawing substituents[10] and for
bonding in 3E, 4E, and 5E is much weaker than in the cor- 2-phenacylquinolines.[11]
responding enolimine tautomers, π-electron delocalization
It is noteworthy that the “non-aromatic” tautomer E
in these molecules is very effective. Electron-withdrawing (Scheme 5) would not be expected to be preferred for
substituents increase the acidic character of methylene hy- isoquinolin-3-yl derivatives (and indeed, this form was not
drogen atoms in the K forms and in consequence their detected in chloroform solution).
transfer to the aza atoms in these compounds is easier. If
The contributions of different tautomeric forms (K, O,
the pyridine ring is not annulated in the correct position and E) can be evaluated by comparing the integrated inten-
1
(series 3–5), the formed tautomer O is not very stable and sities of their H7 signals in the H NMR spectra of the
it is transformed into E.
tautomeric mixtures (Table 4). These numbers enable the
It can be seen (Table 2) that the dependence of K (%) calculation of the relative experimental energies of the tau-
(content of the K form) on substitution is of the same na- tomers.[10,11] For the K form in series 4 the following results
ture in each series: electron-withdrawing substituents de- were obtained: 8.4, 8.7, 16.5, and 21.6 kJmol–1 for R7 = 4-
crease the amount of ketimine form in the tautomeric mix- N(CH2)4, 4-NMe2, 4-Me, and 4-Br, respectively (energy
tures. In general, the populations of this tautomer are lower with respect to form 4E), so it can be seen that the K form
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Effect of π-Electron Delocalization on Tautomeric Equilibria
FULL PAPER
1
Table 3. Selected H, 13C, and 15N NMR chemical shifts (δ) of 1-
It can be seen (Table 2) that the presence of electron-
donating substituents in the phenacyl part of the molecule
favors the K form (Scheme 6). The pyridine ring in this tau-
tomer still has an aromatic character.
phenacylisoquinolines, 3-phenacylisoquinolines, 6-phenacylphen-
anthridines, and their tautomers for 0.1–0.2  solutions in CDCl3
at 303 K.[a]
Tautomer
NH or
OH
7-H
7-C
8-C
1-N
2K/p-N(CH2)4
2K/p-Me
2O/p-Me
4K/p-N(CH2)4
4E/p-N(CH2)4
4K/p-NMe2
4E/p-NMe2
4K/p-Me
–
–
4.55
4.60
6.20
4.90
6.71
4.90
6.74
4.97
6.75
5.00
6.75
4.97
6.69
5.00
6.77
4.98
6.76
4.99
6.69[c]
6.80[c]
6.81[c]
6.75
6.77
6.76
47.59
48.01
95.10
46.64
83.58
46.55
83.61
46.50
195.15
196.89
160.07
194.23
184.64
194.29
–69.2
–73.1
–105.6
–72.6
–234.2
–72.7
–233.7
–72.1
14.41
–
15.99
–
16.02
–
16.19
–
16.31
–
16.21
–
15.63
–
15.65
–
184.35
[b]
Scheme 6.
4E/p-Me
4K/p-Br
4E/p-Br
84.62
184.29
–229.3
[b]
[b]
[b]
Notwithstanding that the forms E and O are stabilized
by intramolecular hydrogen bonds, those carrying electron-
donating substituents are not stable because neither the
pyridine nor the benzene rings in these molecules are aro-
matic (Scheme 7).
85.22
182.18
–226.4
[b]
[b]
[b]
4K/p-CF3
4E/p-CF3
5K/p-N(CH2)4
5E/p-N(CH2)4
5K/p-NMe2
5E/p-NMe2
5K/p-OMe
5E/p-OMe
5E/p-Me
84.57
182.73
–228.2
–73.7
–250.5
–73.5
[b]
[b]
84.4
186.89
[b]
[b]
84.54
186.78
–250.1
[b]
[b]
[b]
15.67
15.83
15.87
15.93
15.89
15.88
84.66
85.14[d]
85.34
85.43
85.05
85.22
186.20
187.06
187.11
184.95
185.55
185.24
–247.8
–246.9
–246.2
–243.9
–245.4
–244.9
5E/H
5E/p-CF3
5E/p-Cl
5E/m-F
[a] See refs.[10,11] respectively, for the corresponding chemical shifts
in the series 1 and 3. [b] These signals were not found due to low
amounts of the tautomeric form in question. [c] There is a very
weak signal for 7-H in the K form at about 5 ppm. [d] There is a
very weak signal for 7-C in the K form at about 45 ppm.
Table 4. 1-Phenacylisoquinoline 4K contents (%)[a] in chloroform
solutions at different temperatures.
Temp. (K)
p-N(CH2)4 p-NMe2
p-Me
p-Br
303
293
283
273
263
253
243
48.2
44.6
42.2
38.7
35.6
31.9
31.6
26.3
23.9
20.7
18.4
16.3
13.1
10.7
5.2
4.2
3.4
2.5
1.8
1.2
0.7
–
2.5
1.9
1.4
0.9
0.6
–
Scheme 7.
[a] Based on integral intensities of 7-H signals in 1H NMR spec-
trum. Accuracy: 0.5%.
Conclusions
Benzoannulation affects the prototropic tautomerism of
2-phenacylpyridines. Except in the cases of some substi-
tuted 6-phenacylphenanthridines, tautomeric mixtures of
benzoannulated 2-phenacylpyridines in chloroform solu-
tions always contain the ketimine forms, coexisting with
(Z)-2-(2-hydroxy-2-phenylvinyl)pyridines (enolimine forms)
Scheme 5.
is only slightly less stable than the E form for strongly elec- if the pyridine ring is not benzoannulated or if such annu-
tron-donating substituents in this series (experimental re- lation is at positions 4,5. On the other hand, (Z)-2-
sults confirm this conclusion). Since lower temperatures benzoylmethylene-1,2-dihydropyridines exist in equilibrium
favor the E form, reaction K Ǟ E has an exothermic char- with ketimine forms if the pyridine ring is annulated at posi-
1
acter. Insignificant effects of temperature on the H NMR tions 3,4 or 5,6, or at both of these positions. Besides π-
spectra show that 5E is much more stable than 5K (not the electron delocalization in these molecules, other contri-
case in other series).
butions, such as the strengths of intramolecular hydrogen
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2821

R. Gawinecki et al.
FULL PAPER
tion of n-butyllithium in n-hexane). After 1 h the substituted alkyl
benzoate (7.2 mmol) was added to the flask and the reaction mix-
ture was allowed to warm to room temperature overnight. It was
then worked up by addition of water (60 mL) and extraction with
ether. The extracts were dried (Na2SO4), the solvent was evapo-
rated, and the residue was purified by column chromatography [sil-
ica gel (230–400 mesh), eluent: n-hexane/ethyl acetate, 3:1] and
recrystallized from ethanol.
bonds, should also be considered in order to infer tauto-
meric preferences. The dependence of the ketimine form
content on substitution is of the same nature in each series:
electron-withdrawing substituents decrease the amount of
ketimine forms in the tautomeric mixtures. On the other
hand, strongly electron-donating substituents stabilize the
ketimine forms. In general, the contributions of this tauto-
mer are lower for quinolin-2-yl and isoquinolin-1-yl deriva-
tives than for pyridin-2-yl and isoquinolin-3-yl derivatives
and are the lowest for dibenzoannulated (i.e., phen-
anthridin-6-yl) derivatives. The transformation of the ket-
imine into the enaminone form is exothermic in character
and strongly electron-withdrawing substituents enhance this
effect. Electron-withdrawing substituents increase the acidic
character of the methylene hydrogen atoms in the ketimine
forms and facilitate their transfer to the aza atoms.
p-N(CH2)4: C21H20N2O (316.39): calcd. C 79.71, H 6.37, N 8.86;
found C 79.41, H 6.49, N 8.99.
p-CH3: C18H15NO (261.31): calcd. C 82.73, H 5.79, N 5.36; found
C 82.63, H 5.59, N 5.24.
1-Phenacylisoquinolines/(Z)-1-Benzoylmethylene-1,2-dihydroiso-
quinolines (4). Method A: Phenyllithium was obtained by heating
a magnetically stirred reaction mixture containing lithium (0.1 g,
13 mmol) and freshly distilled bromobenzene (1.0 g, 6.5 mmol) at
reflux in absolute diethyl ether (40 mL, standard procedure: the
reflux condenser was equipped with a CaCl2 tube and the reaction
was usually initiated by addition of 1–2 crystals of iodine). The
obtained solution was treated dropwise with 1-methylisoquinoline
(0.83 g, 5.8 mmol) and heated at reflux for ca. 1 h to provide 1-
methylisoquinolyllithium (1-methyllithioisoquinoline). The substi-
tuted alkyl benzoate (5.8 mmol) diluted with absolute ethyl ether
(5 mL) was then added to the reaction vessel and the obtained mix-
ture was heated at reflux for 1 h. The reaction was quenched by
addition of water (20 mL), the product was extracted from the
water layer with ether, the combined extracts were dried (K2CO3),
and the ether was evaporated to provide the solid, which was usu-
ally recrystallized twice from ethanol.
Experimental Section
Syntheses
Ethyl p-(Pyrrolidino)benzoate: A solution of ethyl p-fluorobenzoate
(3.36 g, 20 mmol) and pyrrolidine (4.26 g, 60 mmol) in DMSO
(35 mL) was stirred at 95 °C for 24 h and then poured into water
(700 mL). The product was extracted with ethyl ether, the extract
was dried (K2CO3), and the solvent was evaporated to provide the
solid, which after crystallization from ethanol melts at 114–116 °C
(literature m.p. 103–104 °C).[33] Yield 3.81 g (87%).
(2,2-Dimethoxyethylidene)-(1-phenylethyl)amine: Toluene (200 mL)
and 1-phenylethylamine (50 mL, 47.00 g, 0.39 mol) were added to a
solution of dimethoxyacetaldehyde in water (60%, 67 mL, 77.05 g,
0.44 mol, Aldrich) and the obtained mixture was heated under ni-
trogen in a flask fitted with a Dean–Stark trap until 37 mL of water
had been collected, after which 73.70 g (92%) of a product boiling
at 135–145 °C/1 Torr was collected. C12H17NO2 (207.27): calcd. C
69.53, H 8.27, N 6.76; found C 69.31, H 8.49, N 6.54.
Method B: A solution of n-butyllithium in n-hexane (2 , 4.0 mL,
8.0 mmol) was added (by syringe) to a stirred solution of 1-methyl-
isoquinoline (1.02 g, 7.2 mmol) in dry ethyl ether (45–50 mL) under
nitrogen atmosphere (the reaction mixture was cooled with an ice/
salt bath during addition). After 30 min a saturated solution of the
substituted alkyl benzoate (7.2 mmol) in dry ethyl ether was added
dropwise to the flask. The cooling bath was removed after 1 h and
the contents of the flask were stirred for another 2–3 h. Water
(50 mL) was then slowly added to the reaction mixture with stir-
ring. The organic layer was then combined with the ether extract
of the aqueous phase and dried (Na2SO4). The solvent was evapo-
rated, and the residue was purified by column chromatography [sil-
ica gel (230–400 mesh), toluene/acetone (10:1) or hexane/ethyl ace-
tate (9:1)] and recrystallized from ethanol.
1-Methylisoquinoline: Concd. sulfuric acid (168.6 mL) was added
dropwise at 0 °C to (2,2-dimethoxyethylidene)(1-phenylethyl)amine
(32.60 g, 0.16 mol), the contents of the flask (fitted with a reflux
condenser) being stirred magnetically during addition. At the be-
ginning the reaction mixture was so viscous that stirring was not
efficient and shaking of the flask by hand was necessary. More acid
(281 mL) was then added in one portion at room temperature and
the flask was heated until the temperature of the reaction mixture
reached 160 °C. After two more minutes at this temperature the
contents of the flask were poured into crushed ice (400 g), made
basic with concd. aqueous sodium hydroxide, and steam distilled.
The distillate was extracted with ethyl ether and dried (Na2CO3) to
provide 1-methylisoquinoline (13.74 g, 61%, b.p. 114–115 °C/
8 Torr, literature b.p. 81 °C/1 Torr)[34,35] after evaporation of the
solvent and distillation of the residue.
p-N(CH2)4: C21H20N2O (316.39): calcd. C 79.71, H 6.37, N 8.86;
found C 79.69, H 6.47, N 8.59.
p-NMe2: C19H18N2O (290.35): calcd. C 78.59, H 6.25, N 9.65;
found C 78.31, H 5.99, N 9.56.
p-CH3: C18H15NO (261.31): calcd. C 82.73, H 5.79, N 5.36; found
C 82.53, H 5.50, N 5.16.
p-Br: C17H12BrNO (326.20): calcd. C 62.59, H 3.71, N 4.29; found
C 62.72, H 3.90, N 4.01.
6-Methylphenanthridine: A known synthetic method was used.[36]
After recrystallization from heptane the product melted at 82–
83 °C (literature m.p. 84 °C).[36]
p-CF3: C18H12F3NO (315.20): calcd. C 68.59, H 3.81, N 4.44;
found C 68.68, H 3.81, N 4.66.
3-Phenacylisoquinolines/(Z)-3-(2-Hydroxy-2-phenylvinyl)isoquino-
lines (2): A solution of 3-methylisoquinoline (1.0 g, 7.0 mmol, Ald-
rich) in dry ether (40 mL) was added slowly at –78 °C under nitro-
gen to a freshly prepared solution of lithium isopropylcyclohex-
6-Phenacylphenanthridines/(Z)-6-Benzoylmethylene-5,6-dihydro-
phenathridines (5): These compounds were prepared similarly to 1-
phenacylisoquinolines (Method A; 6-methylphenathridine was
used instead of 1-methylisoquinoline). The product was extracted
ylamide (from 1.18 mL, 1.02 g, 7.30 mmol of distilled isopropyl- from the water layer with chloroform, the combined extracts (di-
cyclohexylamine in 50 mL of dry ether and 1.8 mL of a 2  solu- ethyl ether + chloroform) were dried with Na2SO4, and the solvents
2822
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Eur. J. Org. Chem. 2006, 2817–2824

Effect of π-Electron Delocalization on Tautomeric Equilibria
FULL PAPER
were evaporated to provide the solid, which was usually recrys-
tallized twice from ethanol.
composite pulse decoupling (Waltz-16) was used to remove proton
couplings. An exponential window function of the spectral resolu-
tion was used prior to FT. The 13C NMR chemical shifts are refer-
enced to the central peak of the solvent [D6]DMSO (δ = 39.50 ppm
from TMS).
p-N(CH2)4: C25H22N2O (366.45): calcd. C 81.93, H 6.05, N 7.65;
found C 81.66, H 5.83, N 7.38.
p-NMe2: C23H20N2O (340.43): calcd. C 81.14, H 5.92, N 8.23;
found C 80.91, H 6.17, N 8.02.
The number of data points in PFG 1H,13C HMQC and HMBC
measurements was 1024 (f2)×256 (f1). This matrix was zero-filled
to 2048×512 and apodized by a shifted sine bell window function
along both axes prior to FT.
p-OCH3: C22H17NO2 (327.37): calcd. C 80.71, H 5.24, N 4.28;
found C 80.60, H 5.25, N 4.49.
1
In PFG H,15N HMBC experiments a 100 ms delay was used for
p-CH3: C22H17NO (311.37): calcd. C 84.86, H 5.50, N 4.50; found
evolution of long-range couplings. The number of data points was
1024 (f2)×512 (f1: 15N). This matrix was zero-filled to 2048×1024
and apodized by a shifted sine bell window function along both
axes prior to FT.
C 84.63, H 5.45, N 4.74.
H: C21H18NO (300.36): calcd. C 83.97, H 6.04, N 4.66; found C
83.69, H 6.29, N 4.63.
p-Cl: C21H14ClNO (331.79): calcd. C 76.01, H 4.25, N 4.22; found
C 76.12, H 4.03, N 4.01.
15N NMR chemical shifts are referenced to the signal of external
CH3NO2 (δ = 0.0 ppm) in a capillary (1 mm diameter) inserted
coaxially within an NMR tube with 5 mm diameter. All acquisition
and processing parameters are available from E. K. on request.
m-F: C21H14FNO (315.33): calcd. C 79.98, H 4.47, N 4.44; found
C 79.89, H 4.26, N 4.22.
p-CF3: C22H14F3NO (365.34): calcd. C 72.32, H 3.86, N 3.83;
found C 72.52, H 3.94, N 3.63.
Acknowledgments
3-Methyl-2-(p-methylbenzoyl)-1-phenyl-1,2-dihydroisoquinoline (6):
A solution of 3-methylisoquinoline (Aldrich, 7.0 mmol) in absolute
ethyl ether (10 mL) was added dropwise with stirring to a solution
of phenyllithium [obtained by a standard method from freshly dis-
tilled bromobenzene (1.57 g, 10 mmol), absolute diethyl ether
(50 mL), and lithium (0.14 g, 20 mmol)]. The reaction mixture was
stirred at room temperature for an additional 2 h. Ethyl benzoate
(7.0 mmol) diluted with absolute ethyl ether (5 mL) was then added
to the reaction vessel and the obtained mixture was heated at reflux
for 2 h. The reaction was quenched by addition of water (20 mL),
the product was extracted from the water layer with ether, the com-
bined extracts were dried (K2CO3), and the ether was evaporated
to provide the crude solid product. This was purified by column
chromatography [silica gel (230–400 mesh), toluene/ethyl acetate
(20:1)] and recrystallized from the eluent. Yield 0.16 g (11%), m.p.
B. O. gratefully acknowledges receipt of a Fellowship from the
Foundation for Polish Science (FNP). We thank Spec. Lab. Tech-
nician Reijo Kauppinen for his help in running the NMR spectra.
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170–172 °C. H NMR (CDCl3): δ = 7.53 (t, 1 H, 14-H), 7.20–7.35
(m, 12 H, 5-H, 6-H, 7-H, 8-H, 12-H, 13-H, 20-H, 21-H), 6.79 (s, 1
H, 1-H), 6.07 (s, 1 H, 4-H), 2.39 (s, 3 H, 17-H), 1.62 (s, 1 H, 25-
H) ppm. 13C NMR (CDCl3): δ = 169.80 (18-C), 141.40 (22-C),
140.39 (11-C), 135.68 (3-C), 133.98 (19-C), 132.93 (10-C), 131.69
(9-C), 129.02 (21-C), 128.38 (20-C), 128.05 (12-C), 127.87 (14-C),
127.12 (13-C), 127.23, 126.96, 126.80 (6-C, 7-C, 8-C), 124.65 (5-C),
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Eur. J. Org. Chem. 2006, 2817–2824
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2823

R. Gawinecki et al.
FULL PAPER
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