Incomparably easy migration of functionalized enol substituent in pyrrole ring

Article abstract of DOI:10.1134/s1070428008020097

Functionalized pyrrolebvbΕ enols, 2-(1-hydroxy-2.2-dicyanoethenyl)-1- methylpyrroles, at heating (75-135°C) unexpectedly readily rearranged in high yield into 3-isomers. Evidently the migration of the enol fragment involves a mesomeric zwitterion formed as a result of an intra- and intermolecular autoprotonation of the pyrrole ring by the acidic enol hydroxy group. Under similar conditions no migration of the ethenyl moiety occurred in 2-(1-hydroxy-2-carbamoyl-2-cyanoethenyl)-1-methylpyrroles. The quantum-chemical calculations (MP2/6-311G**) show a clear-cut distinction in the relative stability of 2- and 3-isomers of 1H- and 1- methylhydroxyethenylpyrroles: in the former case the 2-isomer is more stable, whereas in the 1-methyl-substituted compound, the 3-isomer.

Full text of DOI:10.1134/s1070428008020097

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 2, pp. 237−246. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © L.N. Sobenina, V.N. Drichkov, O.V. Petrova, I.A. Ushakov, T.V. Kashik, L.B. Krivdin, Yu.Yu. Rusakov, E.V. Zykova, A.I.
Mikhaleva, B.A. Trofimov, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 2, pp. 246−255.
Dedicated to the Full Member of the Russian Academy of Sciences
G.A. Tolstikov on occasion of his 75th anniversary
Incomparably Easy Migration of Functionalized
Enol Substituent in Pyrrole Ring
L. N. Sobenina, V. N. Drichkov, O. V. Petrova, I. A. Ushakov, T. V. Kashik, L. B. Krivdin,
Yu. Yu. Rusakov, E. V. Zykova, A. I. Mikhaleva, and B. A. Trofimov
Faworsky Irkutsk Institute of Chemistry, Siberian Division, Russian Academy of Sciences, Irkutsk, 664033 Russia
e-mail: boris_trofimov@irioch.irk.ru
Received January 30, 2007
Abstract—Functionalized pyrroleüνûε enols, 2-(1-hydroxy-2,2-dicyanoethenyl)-1-methylpyrroles, at heating (75–
135°C) unexpectedly readily rearranged in high yield into 3-isomers. Evidently the migration of the enol fragment
involves a mesomeric zwitterion formed as a result of an intra- and intermolecular autoprotonation of the pyrrole
ring by the acidic enol hydroxy group. Under similar conditions no migration of the ethenyl moiety occurred in 2-
(1-hydroxy-2-carbamoyl-2-cyanoethenyl)-1-methylpyrroles. The quantum-chemical calculations (MP2/6-311G**)
show a clear-cut distinction in the relative stability of 2- and 3-isomers of 1H- and 1-methylhydroxyethenylpyrroles:
in the former case the 2-isomer is more stable, whereas in the 1-methyl-substituted compound, the 3-isomer.
DOI: 10.1134/S1070428008020097
Our research in the field of the chemistry of func-
tionally-substituted C-ethenylpyrroles led to the develop-
ment of a simple and efficient preparation method for
stable enols of the pyrrole series, 2-(1-hydroxy-2-cyano-
ethenyl)pyrroles [5], important intermediates and models
of transformations in DNA and enzymes [6]. However
their regioisomers, 3-(1-hydroxy-2-cyanoethenyl)-
pyrroles, up till now were virtually inaccessible. The
development of synthetic method for these compounds
is an urgent target, the more so because it is far more
difficult to synthesize 3-substituted pyrroles than their
2-isomers for the majority of electrophilic substitution
reactions and the metallation of N- substituted pyrroles
occurs mainly at the α-position in the pyrrole ring.
We discovered recently an unexpected easy migration
of an enol function from the α- into the β-position of
the pyrrole ring on an example of 2-(1-hydroxy-2,2-
dicyanoethenyl)-1-methyl-4,5,6,7-tetrahydroindole [7].
This rearrangement in event of its general character
might open the route to highly functionalized etheny-
lpyrroles with an enol substituent in the position 3.
C-Ethenylpyrroles are extensively studied building
blocks for the synthesis of versatile members of the
pyrrole series, especially of fused heterocycles related
to pyrrole [1]. Their structure is present in the molecules
of many life-supporting systems (porphyrins, vitamin Β12,
bile pigments, prodigiosins, myoglobin and hemoglobin
performing oxygen transport in live bodies of mammals,
and chlorophyll playing the key role in photosynthesis
processes, i.e., in the photocatalytic transformation of
the solar energy [2]).
Taking in consideration the unique role of C-ethenyl-
pyrroles in the living matter the development of their
syntheses is an important task (especially procedures
for preparation of C-ethenylpyrroles with functional
groups attached to the double bond).
Among the functional vinyl compounds enols and their
reactive cationic intermediates are now the most
intensively investigated [3, 4]; therewith a great attention
is focused on heterocyclic enols [4].
The combination of an enol and a pyrrole moieties in
one molecule may result in a synergic effect of these
important chemical functions and can significally extend
the application limits of polyfunctional C-ethenylpyrrole
compounds.
The target of the present study was establishing the
application limits of this rearrangement, acquiring new
information on its rules and specific features, and also
extending the series of functionally substituted 3-(1-
237

SOBENINA et al.
238
hydroxy-2-cyanoethenyl)pyrroles, important key syn-
thetic intermediates for preparation of potential
pharmacophores and materials for optronics.
chemical evaluation of the relative stability of the
corresponding 2- and 3-isomers.
Two approaches were used in the synthesis of enols
IIa–IIi: the exchange of EtS group in 2-(2-cyano-1-
ethylsulfanylethenyl)pyrroles Ia–Ig (Scheme 1) and
substitution of cyano by hydroxy group in 2-(1,2,2-
tricyanoethenyl)-pyrroles Ih and Ii, (Scheme 2) by
procedures [5] and [8] respectively.
To this end we synthesized and tested under the
conditions of the rearrangement [7] NH- (IIa–IId) and
NMe- (IIe–IIi) -2-(1-hydroxy-2-cyanoethenyl)pyrroles,
measured their acidity, and carried out a quantum-
Scheme 1.
It was considered formerly that tricyanoethenylation
of 1-methylpyrrole with tetracyanoethylene (TCNE) in
acetone selectively provided 2-tricyanoethenylpyrrole
[8]. However we found that not only in acetone but also
in THF and DMSO this reaction resulted in a mixture of
2- and 3-tricyanoethenylpyrroles [the ratio Ih:Ij = 30:70
(acetone), 15:85 (THF), 75:25 (DMSO)] (Scheme 3).
R3
SEt
R2
N
R1
CN
X
Further in the synthesis of enols IIh and IIIh we used
the mixture prepared in acetone.After its hydrolysis (40–
45°C, 1 h) and workup the ratio of enols IIh:IIIh = 8:92.
_
Ià Ig
R3
The tricyanoethenylation of 1-methyl-2-propyl-3-
ethylpyrrole in DMSO proceeded selectively and
provided tricyanoethenylpyrrole (Ii) in 51% yield.
OH
NaOH
R2
N
R1
MeOH / H2O,
As mentioned above, 2-(1-hydroxy-2,2-dicyano-
ethenyl)-1-methyl-4,5,6,7-tetrahydroindole (IIe)
uncommonly easily rearranged into 3-(1-hydroxy-2,2-
dicyanoethenyl)-1-methyl-4,5,6,7-tetrahydroindole
(IIIe) (Scheme 4). At boiling pyrrole IIh unsubstituted
in positions 4 and 5 in benzene, toluene, and o-xylene
for 5 min was convertied into 3-isomer to 3, 4, and 8%
respectively (1H NMR data). At longer heating (1 h) in
toluene (105°C) and m-xylene (135°C) the conversion
of reagent IIh was respectively 60 and 95%. However
in the last case the rearrangement was accompanied with
tarring hampering the isolation of 3-isomer IIIh. The
latter was prepared by boiling in toluene for 1 h of the
mixture of 2- and 3-(1-hydroxy-2,2-dicyanoethenyl)-1-
methylpyrroles (IIh and IIIh), hydrolysis products of
the corresponding tricyanoethenylpyrroles Ih and Ij.
CN
o
_
40 45 C, 1 h
X
_
IIà IIg
R1 = H, R2 = Pr, R3 = Et, X = CN (a); R1 = H, R2 = Bu,
R3 = Pr, X = CN (b); R1 = R3 = H, R2 = Ph, X = CN (c);
R1 = R3 = H, R2 = Ph, X = CONH2 (d); R1 = Me, R2,R3
= (CH2)4, X = CN (e); R1 = Me, R2 = R3 = H, X = CONH2
(f); R1 = Me, R2,R3 = (CH2)4, X = CONH2 (g).
Scheme 2.
R3
R3
CN
TCNE
R2
R2
N
R1
N
R1
CN
The findings obtained suggest that the alkyl sub-
stituents in the pyrrole ring accelerate the isomerization.
NC
Ih, Ii
R3
Scheme 3.
OH
NC
CN
CN
NaOH/ H2O
R2
N
_
40 45oC, 1 h
CN
R1
TCNE
CN
NC
IIh, IIi
N
+
N
N
Me
CN
NC
Ih
Me
Me
Ij
R1 = Me, R2 = R3 = H (h); R1 = Me, R2 = Pr, R3 = Et (i).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 2 2008

INCOMPARABLY EASY MIGRATION OF FUNCTIONALIZED ENOL SUBSTITUENT
239
This is confirmed by the high yield (90%) of 3-(1-hy-
Scheme 4.
droxy-2,2-dicyanoethenyl)-1-methylpyrrole (IIIi), obtain-
ed by heating in toluene (105°C, 1 h) its 2-isomer IIi.
HO
CN
CN
R3
R3
The observed rearrangement is unique for pyrrole
chemistry since the thermal migration of substituents
occurs at considerably higher temperature and as a rule
led to the prevailing formation of α-isomers [9]. The
migration from the α- into the β-position of the pyrrole
ring proceeded relatively easily only in the presence of
acids and was characteristic of mainly electron-acceptor
moieties [10]. We showed that acid addition did not
increase the conversion of α- into β-isomer. For instance,
pyrrole IIh isomerization on boiling in benzene in the
presence of a catalytic quantity of HCl proceeded
similarly to the reaction without acid, approximately to
3–5%. At the same time in the presence of HCl degrada-
tion process of the pyrrole ring intensified (1H NMR
data).
OH
Δ
R2
R2
N
CN
N
NC
Me
Me
IIIe, IIIh, IIIi
IIe, IIh, IIi
functionalized enol substituent (due to the effect of two
strong electron-acceptor groups).Actually, as showed our
measurements (see the table), enols IIa–IIc, IIe, IIh,
and IIi proved to be strong acids (pKa 5–6) comparable
in the acidity with the picric acid (pKa in methanol 4.8
[11]).
Therefore the rearrangement mechanism may be
represented by Scheme 5:An intramolecular autoprotona-
tion of the α-position of the pyrrole ring leads to the
formation of a zwitterion A that through the isomer form
B transforms into zwitterion C. The process is completed
by a proton transfer in the zwitterion C from position 3
of the pyrrole ring to the oxygen atom.
Apparently the ready migration of the enol fragment
from the α- into the β-position originated from the
sensitivity of the pyrrol ring to protonation combined
with the enhanced acidity of the hydroxy group of the
Acidity constants of enols in methanol
R
R
OH
OH
OH
Ph
N
H
N
H
N
CONH2
CN
CN
Me
NC
IId
NC
NC
_
IIe, IIh, IIi
IIà IIc
HO
CN
CN
HO
CN
CN
R
R
R
OH
Me
N
N
H
N
CONH2
Me
NC
Me
IIå, IIg
IIIk, IIIl
IIIe, IIIh, IIIi
Compd. no.
pKa
Compd. no.
pKa
5.37
5.50
5.28
8.76
5.67
8.35
9.04
5.25
5.72
6.09
5.79
6.69
6.77
6.35
IIa
IIb
IIc
IId
IIe
IIf
IIh
IIi
IIIe
IIIh
IIIi
IIIk
IIIl
IIg
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 2 2008

SOBENINA et al.
240
Scheme 5.
R3
R2
R3
R2
H
R3
O_
O_
O
R2
N
CN
N
N
CN
CN
H
H
Me
Me
Me
NC
NC
NC
II
A
O_
CN
CN
N
O_
H
H
N
R3
R2
C
R3
R2
III
CN
N
Me
B
Me
C
The relative stability of 2- and 3-isomers was
An intermolecular protonation of a pyrrole ring of
one molecule by the enol hydroxyl of another molecule
also cannot be excluded.
estimated by quantum-chemical calculation of relative
energies of pyrrole IIh and IIIh in four possible
conformations (Fig. 1).
The importance of the hydroxy proton in the
course of the rearrangement was proved by no
isomerization at heating ethylsulfanyl- (Ia–Ig) or cyano
(Ih and Ii) analogs.
It should be mentioned first of all that 3-(1-hydroxy-
2,2-dicyanoethenyl)-1-methylpyrrole (IIIh) is by 2.2 kcal
mol−1 more stable than the corresponding 2-isomer IIh
Fig. 1. Relative energies and deviation from planar structire of rotation conformations of 2- and 3-(1-hydroxy-2,2-
dicyanoethenyl)-1-methylpyrroles IIh and IIIh optimized by method MP2/6-311G**.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 2 2008

INCOMPARABLY EASY MIGRATION OF FUNCTIONALIZED ENOL SUBSTITUENT
241
(if both isomers are taken in their preferred conforma-
tions: s-trans-s-cis for IIh and s-cis-s-cis for IIIh) leading
to the equilibrium isomers ratio in the reaction mixture
~5:95 (T 350 K). The observed equilibrium ratio of the
isomers is comparable with the calculated one. For
instance, at heating reagent IIe in benzene-d6 (75°C,
1.5 h) whose intermolecular interaction with the enol
was insignificant the ratio IIe:IIIe reached 6:94
(1H NMR data). At heating under the similar conditions
isomer IIIe a mixture of compounds IIe and IIIe formed
in a ratio 4:96. Thus the α,β-migration of the enol
function in the pyrrol ring under consideration is
thermodynamically favorable and according to the
experimental findings it is governed by the
thermodynamical control. A higher thermodynamic
stability of 3-(1-hydroxy-2,2-dicyanoethenyl)-1-methyl-
pyrrole compared to its 2-isomer apparently, in particular,
originates from the destabilization of the 2-isomer by
a spatial interaction of the N-methyl group with the
ethenyl fragment. This is revealed by a considerable
deviation of the ethenyl fragment from the plane of the
pyrrole ring in all possible conformations of 2-(1-hy-
droxy-2,2-dicyanoethenyl)-1-methylpyrrole, from ~30 deg
in the preferable s-trans-s-cis-conformation to nearly
70 deg in the s-cis-s-trans-conformation possessing the
highest energy (Fig. 1). On the other hand, these steric
interactions in the 3-isomer are virtually lacking in the
preferable s-cis-s-cis-conformation that is virtually planar
(0.4 deg) and to notably lesser extent appear in the con-
formations of higher energy, s-trans-s-cis-, s-cis-s-trans- ,
and s-trans-s-trans-conformations (~10–30 deg) (Fig. 1).
a charge transfer) of the pyrrole part of the molecule
(strond π-donor) with strongly electron-deficient enol
part of the molecule is stronger in the 3-isomers than in
the 2-isomers. Thus the higher thermodynamic stability
of the 3-isomers can be ascribed to the stronger
conjugation of the pyrrole ring with the enol substituent.
The variation of enols pKa in the series IIe, IIh, IIi is
well consistent with the electronic effects of the
substituents in the pyrrole ring.Actually, the introduction
of electron-donor substituents in the molecule of 2-(1-
hydroxy-2,2-dicyanoethenyl)-1-methylpyrrole in
positions 4 and 5 of the pyrrole ring results in the decrease
in the acidity of the hydroxy function in the series IIh >
IIe > IIi; seemingly, the rate of the rearrangement should
have decelerate in this sequence. However taking into
account that the ease of the migration of the enol
substituent is affected also by the proton affinity of the
pyrrole ring that grows in this enol series IIh, IIe, IIi the
competition of the two influences should be expected.
The experimental results suggest that the growing proton
affinity of the pyrrole ring is the prevailing factor
governing the capability of α-enols to rearrange into
β-enols. Actually, as was already shown above and also
according to NMR data [the relative fraction of 3-isomer
after 1 h of heating (DMSO-d6, 110°C) was 57, 39, and
12% for IIIe, IIIi, and IIIh respectively] the
rearrangement rate increased in the series IIh < IIi <
IIe. Note that the rearrangement in DMSO-d6 proceeded
slower than in benzene due apparently to the concurrent
bonding of the hydroxy group by the solvent.
At heating (in benzene-d6, toluene-d8, DMSO-d6,
m-xylene-d10, 75–135°C) pyrroles IIf and IIg having at
the double bond instead of one cyano group a less
electron-acceptor carbamoyl substituent no migration of
the ethenyl fragment occurred. At heating pyrrole IIf in
m-xylene (130–135°C, 1 h) in the H NMR spectrum
signals appeared belonging to the product of its
destruction, 1-methyl-pyrrole (Scheme 6).
Besides the higher stability of isomers with the enol
substituent in the position 3 is in agreement with the
reduction in the acidity of their hydroxy group [about
0.5 log unit (compounds IIIe, IIIi, IIIh, IIIk, and IIIl)
compared with the α-isomer (see the table)]. The latter
fact means also that the 3-pyrrolyl fragment is a more
strong donor with respect to enol substituent than the
corresponding 2-pyrrolyl, namely, the conjugation (with
1
Scheme 6.
CONH2
OH
NC
R3
R3
NC
NH2
R2 = R3= H
R2
O
R2
X
N
N
N
O
H
Me
Me
Me
IIf, IIg
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SOBENINA et al.
242
2-cyanoethenyl)-1H-pyrroles (IV) and (V) (Fig. 2) with
the previously considered 2- and 3-(1-hydroxy-2-cyano-
ethenyl)-1-methylpyrroles (IIh) and (IIIh) (Fig. 1). First
of all our attention is arrested by the fundamental
difference in the stability of 2- and 3-isomers in 1H- and
1-methyl-substituted pyrrole of this series: in the former
pair the more stable is 2-isomer IV, whereas in the latter
case of 1-methyl-substituted pyrroles IIh and IIIh the
pattern is reversed, namely, the more stable is 3-isomer
IIIh. The reason of this difference we presume to be in
additional stabilization of 2-isomer IV owing to the
formation of a weak intramolecular hydrogen bond
involving the NH proton of the pyrrole ring and the
nitrogen of the cyano group located in the cis-position
with respect to the pyrrole fragment. This suggestion is
According to X-ray diffraction analysis [5] in enols
IIf and IIg the hydroxy group formed a stromg
intramolecular hydrogen bond with the carbonyl group.
This hydrogen bond was conserved also in solutions of
enols IId, IIf and IIg, in particular, in methanol, as seen
from the abnormal low acidity of these compounds
compared with enols containing two cyano groups IIa–
IIc, IIe, IIh, and IIi. The electron-acceptor ability of
CN and CONH2 groups expressed through the nucleo-
–
–
–
philic constants σ (σCN 1.0, σCONH2 0.627 [12]) is not
strongly different (0.37 log unit). At the same time the
variation of pKa in pairs IIf–IIh, IIg–IIe, IId–IIc
amounts to a large value, 3.3 log unit, that cannot be
ascribed only to the decreased electron-acceptor effect
of the CONH2 group compared with CN.
In keeping with Hammett’s equation pKa = pKO + ρσ
the difference in the pKa values for two members of the
reaction series (ΔpKa) divided by the difference in the
values of polar effects of the substituents in the mentioned
members Δσ can characterize the value of the reaction
constant ñ that is known to have definite values. For
instance, in the series of substituted phenols which may
be regarded as models of the enols under study the value
ρ in question is in methanol 2.8.
supported by the short distance C≡N···H−N (dN···H
≈
2.3 Å) and by the significant deviation from the linear
structure of the C−C≡N fragment located in the cis-posi-
tion with respect to the pyrrole ring (bond angle CCN ≈
3.0 deg), but to the greater extent just by the fact of
s-cis-s-cis-conformation of isomer (IV) being the
preferable one, where the presence of the hydrogen bond
C≡N···H−N is expectable. Note for comparison that in
the 2-isomer of 1-methyl-substituted pyrrole IIh where
the formation of such intramolecular hydrogen bond is
impossible the preferable conformation is s-trans-s-cis
(Fig. 1). The preferred low-energy conformations of
both isomers of 1-hydroxy-2,2-dicyanoethenyl-1H-
pyrrole in contrast to 1-hydroxy-2,2-dicyanoethenyl-1-
methyl-pyrrole are nearly ideally planar (Fig. 2)
evidencing the absence of sterical interactions of the
pyrrole and ethenyl fragments in the former case whereas
the presence of N-methyl group in 2- and 3-isomers of
1-hydroxy-2,2-dicyanoethenyl-1-methyl-pyrrole results
in strong deviation of the structure of both its isomers
from planarity (see above).
The approximate estimate of the ρ parameter for enols
dissociation in methanol considering the above given
–
–
values ΔpKa 3.3 and Δσ 0.37 (ρ = ΔpKa/Δσ ) equals
8.92. As far as we know this value has no analogs in the
series of acids with the oxygen-centered anion. This fact
indicates that in methanol solution in the molecules of
carbamoyl-containing enols alongside the electronic
effect operates an additional structural factor consider-
ably reducing the acidity of these compounds. This factor
is evidently just the mentioned stong intramolecular
hydrogen bond that is conserved also in methanol.
–
Solving the reverse problem, namely, ΔpKa = ρΔσ where
–
ρ 2.8, Δσ 0.37 we get a value ΔpKa 1.04 that shows to
what extent the carbamoyl-containing enols (in keeping
only with their electronic effects) would be less strong
acids than their CN-substituted analogs. For instance,
the expected for compound IIg pKa value would be 6.29,
whereas the experiment gives 8.35.
The energy difference of 2- and 3-isomers of 1-hy-
droxy-2-cyanoethenyl-1H-pyrroles (IV) and (V) taken
in their preferable conformations (Fig. 2) amounts to
0.9 kcal mol−1 that would correspond to their ratio in the
reaction mixture ~77:23 (T 380 K). Thus the fundamental
difference in the occurrence of the rearrangement for 1H-
and 1-methyl-substituted pyrroles of this series can be
attributed to thermodynamic reasons; hence the α,β-
migration of the enol function in the pyrrole ring is
thermodynamically controlled.
N-Unsubstituted tricyanoethenylpyrrole IIa was
stable under the rearrangement conditions: at heating in
m-xylene (135°C, 4 h) no migration of the enol
substituent was observed, and in DMSO (110°C, 4 h)
the rearrangement occurred only to 6% (1H NMR data).
In this connection it is interesting to compare the
relative thermodynamic stability of 2- and 3-(1-hydroxy-
Besides the π-donor properties of the N-unsubstituted
ring with respect to the π-acceptor enol system (in
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 2 2008

INCOMPARABLY EASY MIGRATION OF FUNCTIONALIZED ENOL SUBSTITUENT
243
Fig. 2. Relative energies and deviation from planar structire of rotation conformations of model 2- and 3-(1-hydroxy-2,2-dicyanoethenyl)-
1H-pyrroles (IV) and (V), optimized by method MP2/6-311G**.
compound IV) are weaker in the N-methyl-substituted
analog IIh leading to the decrease in the energy of the
intramolecular donor-acceptor interaction (charge trans-
fer) in the former molecule. Probably just this is the
principal reason of the difficulty for the enol substituent
migration from the position 2 into position 3.
COSY and NOESY. The resonance signals of carbon
atoms were assigned based on the analysis of 2D spectra
HSQC and HMBC.
Dissociation constants of enols in anhydrous methanol
were established by the potentiometric titration [12] using
universal ion meter EV-74 equipped with glass-calomel
electrodes system. The calomel reference electrode was
filled with a saturated methanol solution of KCl.As titrant
0.1N solution of NaOH in methanol was used. The
measurements were performed at enols concentrations
enolOβ 0.005–0.01 mol l−1. Benzoic acid was applied as
reference whose dissociation constant was measured in
methanol by several methods and equaled pKa 9.4 [11].
The investigation of enol substituents migration in
the pyrrole ring is a fundamental supplement to the
existing concepts on the rearrangement processes
involving pyrrolium cations, and it significantly extends
the synthetic prospects of functionalized C-ethenyl-
pyrroles.
EXPERIMENTAL
The quantum-chemical calculations were carried out
using GAMESS software [13]. The optimization of
geometric parameters and calculation of relative energies
of rotation conformations of compounds IIh, IIIh, IV,
IR spectra of synthesized compounds in the region
400–4000 cm–1 were recorded on a spectrophotometer
Bruker IFS-25 from KBr pellets. 1H and 13C NMR spectra
were registered on a spectrometer Bruker DPX 400
[400.13 (1H) and 100. 6 (13C) MHz]; solvent CDCl3,
DMSO-d6, m-xylene-d10, internal reference HMDS. The
assignment of signals in 1H NMR spectra was performed
with the help of 2D homonuclear correlation procedures
and V were performed in the framework of the Mοller –
/
Plesset second order perturbation theory MP2 [14] using
correlation-consistent Pople basis sets expanded with the
polarization d-functions for the atoms of the second
period and polarization p-functions for hydrogen atoms,
6-311G** [15].
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SOBENINA et al.
244
2-(1-Methyl-1H-pyrrol-2-yl)- (Ih) and 2-(1-methyl-
mixture was stirred for 3 h at the mentioned temperature.
The methanol was removed in a vacuum, the residue was
acidified with 10% HCl till pH 3. The separated
precipitate was filtered off, washed with water, and dried.
Yield 0.110 g (53%), mp 183°C (from benzene). IR
spectrum, ν, cm–1: 3293, 3158, 2930, 2850, 2222, 2205,
1637, 1589, 1541, 1506, 1480, 1457, 1406, 1374, 1299,
1277, 1235, 1204, 1083, 1063, 1003, 851, 797, 760, 718,
1H-pyrrol-3-yl)ethylene-1,1,2-tricarbonitrile (Ij).
A mixture of 0.406 g (5 mmol) of 1-methylpyrrole and
0.640 g (5 mmol) of tetracyanoethylene in 20 ml of
acetone was stirred at room temperature for 1 h, then
diluted with water (100 ml), extracted with ether, and
the extracts were dried with potassium carbonate. On
removing the solvent we obtained 0.650 g (71%) of a
mixture of pyrroles Ih and Ij in a ratio 30:70 (1H NMR
data). Pyrrole Ih. 1H NMR spectrum (DMSO-d6), δ,
ppm: 3.96 s (3H, Me), 6.46 d.d (1H, H4, J 4.65, 2.45
Hz), 7.40 d.d (1H, H3, J 4.65, 1.70 Hz), 7.60 d.d (1H,
H5, J 2.45, 1.70 Hz). 13C NMR spectrum (DMSO-d6),
δ, ppm: 36.6, 50.3, 112.6, 112.7, 113.6, 113.8, 122.6,
1
688, 668, 611. H NMR spectrum (DMSO-d6), δ, ppm:
6.59 d.d (1H, H4, J 2.9, 1.8 Hz), 6.98 d.d (1H, H3,
J 2.9, 2.0 Hz), 7.22 m (1Hï), 7.36 m (2HO), 7.79 m (2Hm),
11.46 br.s (1H, NH). 13C NMR spectrum (DMSO-d6),
δ, ppm: 53.3, 109.4, 117.5, 119.3, 121.5, 124.2, 127.7,
128.8, 131.2, 137.8, 178.5. Found, %: C 71.27; H 3.90;
N 17.40. C14H9N3O. Calculated, %: C 71.48; H 3.86;
N 17.86.
1
124.5, 138.4, 180.8. Pyrrole Ij. H NMR spectrum
(DMSO-d6), δ, ppm: 3.77 s (3H, Me), 6.90 d.d (1H, H4,
J 3.18, 1.60 Hz), 7.15 d.d (1H, H5, J 3.18, 1.60 Hz), 8.20
d.d (1H, H2, J 1.60, 1.60 Hz). 13C NMR spectrum
(DMSO-d6), δ, ppm: 36.7, 78.3, 108.3, 113.3, 113.4,
114.2, 117.1, 128.5, 133.6, 133.7.
Enols IIa, IIb, IId–IIg were obtained by the same
procedure. Their spectral and physicochemial
characteristics were reported in [5].
2-[Hydroxy(1-methyl-1H-pyrrol-3-yl)methylene]-
malononitrile (IIIh). To a mixture of 0.150 g
(0.82 mmol) of 2-(1-methyl-1H-pyrrol-2-yl)- (Ih) and 2-
(1-methyl-1H-pyrrol-3-yl)ethylene-1,1,2-tricarbonitrile
(Ij) was added 1.3 ml (3.7 mmol) of 10% NaOH solution,
and the reaction mixture was stirred for 15 min at 40–
45°C. On cooling to room temperature 1.5 ml of 10%
HCl was added to the reaction mixture. The formed loose
precipitate was filtered off, washed with water, and dried.
We obtained 0.073 g (51%) of a mixture of 2- and 3-iso-
mers IIh and IIIh in a ratio 8:92. The mixture was heated
for 1 h in 3 ml of toluene at 103–105°C. On cooling the
separated crystals were filtered off and dried in a vacuum
to obtain 0.070 g (96%) of pyrrole IIIh, mp 166–167°C.
IR spectrum, ν, cm–1: 3437, 3127, 2961, 2923, 2851,
2226, 2212, 1569, 1633, 1453, 1415, 1364, 1343, 1291,
1236, 1163, 1090, 1075, 993, 970, 856, 846, 819, 720,
646, 547. 1H NMR spectrum (DMSO-d6), δ, ppm: 3.70 s
(3H, Me), 6.63 d.d (1H, H4, J 2.9, 1.8 Hz), 6.90 d.d (1H,
H5, J 2.9, 2.0 Hz), 7.60 d.d (1H, H2, J 2.0, 1.8 Hz).
13C NMR spectrum (DMSO-d6), δ, ppm: 13.7, 16.2, 17.9,
22.9, 25.1, 33.8, 54.3, 113.7, 116.3, 118.1, 121.8, 125.5,
131.2, 181.1. Found, %: C 62.40; H 4.02; N 24.20.
C9H7N3O. Calculated, %: C 62.42; H 4.07; N 24.26.
2-(1-Methyl-5-propyl-4-ethyl-1H-pyrrol-2-yl)-
1,1,2-ethylenetricarbonitrile (Ii). A mixture of 0.220 g
(1.72 mmol) of 1-methyl-2-propyl-3-ethylpyrrole and
0.260 g (1.72 mmol) of tetracyanoethylene in 4 ml of
DMSO was stirred at room temperature for 1 h, then
diluted with water (40 ml), extracted with ether, and the
extracts were dried with MgSO4. On removing the solvent
the residue was dried in a vacuum and recrystallized from
methanol. Yield 0.221 g (51%), mp 109OC. IR spectrum,
ν, cm–1: 2972, 2928, 2877, 2228, 2195, 1544, 1513, 1494,
1475, 1464, 1456, 1430, 1421, 1374, 1314, 1169, 1160,
1
1091, 1023, 969, 836, 745, 724, 675, 555, 541. H NMR
spectrum (DMSO-d6), δ, ppm: 0.93 t (3H, Me), 1.12 t
(3H, Me), 1.52 m (2H, CH2), 2.44 m (2H, CH2), 2.70 m
(2H, CH2), 3.81 C (3H, NMe), 7.36 s (1H, H3). 13C NMR
spectrum (DMSO-d6), δ, ppm: 13.7, 14.3, 18.4, 21.6,
26.4, 33.5, 73.7, 113.7, 114.6, 114.9, 121.5, 125.3, 128.9,
150.3, 165.5. Found, %: C 71.05; H 6.29; N 22.55.
C15H16N4. Calculated, %: C 71.40; H 6.39; N 22.21.
2-(2-Methyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-1,1,2-
ethylenetricarbonitrile and 2-(2-methyl-5-phenyl-1H-
pyrrol-3-yl)-1,1,2-ethylenetricarbonitrile were similarly
prepared, their spectral and physicochemial character-
istics were reported in [16].
2-[Hydroxy(1-methyl-5-propyl-4-ethylpyrrol-2-
yl)methylene]malononitrile (IIi). A dispersion of
0.100 g (0.40 mmol) of reagent Ii in 0.65 ml of 10%
solution of NaOH was stirred for 70 min at 40–45°C.
The reaction mixture was diluted with water (2 ml), and
carbon dioxide was passed through till the solution get
2-[Hydroxy(5-phenyl-1H-pyrrol-2-yl)methylene]-
malononitrile (IIc). To a solution of 0.280 g (1 mmol)
of 2-(2,2-dicyano-1-ethylsulfanylethenyl)-5-phenylpyr-
role in 2 ml of MeOH heated to 60°C was added a solu-
tion of 0.080 g (2 mmol) of NaOH in 1 ml of H2O, the
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INCOMPARABLY EASY MIGRATION OF FUNCTIONALIZED ENOL SUBSTITUENT
245
turbid (pH 4). Then it was extracted with benzene (4 ×
3 ml), the extracts were dried with MgSO4, the solvent
was removed, the residue was dried in a vacuum. Yield
0.083 g (86%), dark red crystals, mp 204°C. IR spectrum,
ν, cm–1: 3437, 2960, 2931, 2870, 2205, 2167, 1627, 1570,
1526, 1446, 1426, 1401, 1331, 1310, 1184, 913, 744,
0.050 g (0.21 mmol) of reagent IIi was heated for 1 h at
103–105°C. On removing the solvent the separated
crystals were washed with hexane and dried in a vacuum.
Yield 0.045 g (90%), dark red crystals, mp 147°C. IR
spectrum, ν, cm–1: 3139, 2960, 2932, 2872, 2223, 2206,
1574, 1538, 1470, 1453, 1417, 1242, 1212, 1176, 1137,
1113, 1077, 1063, 1034, 909, 849, 807, 797, 752, 712,
1
559. H NMR spectrum (DMSO-d6), δ, ppm: 0.90 t (3H,
1
Me), 1.05 t (3H, Me), 1.43 m (2H, CH2), 2.32 m (2H,
CH2), 2.47 m (2H, CH2), 3.57 s (3H, NMe), 6.50 s (1H,
H3). 13C NMR spectrum (DMSO-d6), δ, ppm: 13.9, 15.8,
18.6, 22.7, 25.6, 31.9, 45.4, 112.0, 119.9, 122.6, 123.8,
128.8, 132.8, 179.4. Found, %: C 68.95; H 6.99; N 17.38.
C14H17N3O. Calculated, %: C 69.11; H 7.04; N 17.27.
694, 620. H NMR spectrum (CDCl3), δ, ppm: 0.98 t
(3H, Me), 1.07 t (3H, Me), 1.51 m (2H, CH2), 2.48 m
(2H, CH2), 2.57 m (2H, CH2), 3.60 C (3H, NMe), 7.66 s
(1H, H2). 13C NMR spectrum (DMSO-d6), δ, ppm: 13.70,
16.19, 17.90, 22.91, 25.13, 33.83, 54.23, 113.68, 116.30,
118.10, 121.80, 125.49, 131.17, 181.58. Found, %: C 68.90;
H 7.08; N 17.40. C14H17N3O. Calculated, %: C 69.11;
H 7.04; N 17.27.
Pyrroles IIIk and IIIl were similarly prepared.
2-[Hydroxy(2-methyl-4,5,6,7-tetrahydro-1H-
indol-3-yl)methylene]malononitrile (IIIk). Yield 79%,
mp 170–171°C (from benzene). IR spectrum, ν, cm–1:
3330, 3214, 2931, 2851, 2222, 1610, 1561, 1465, 1441,
1377, 1355, 1310, 1288, 1219, 1172, 1112, 1032, 1006,
The study was carried out under a financial support
of the Russian Foundation for Basic Research (grant no.
05-03-32231a).
1
963, 949, 896, 798, 724, 668, 563. H NMR spectrum
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CH2), 10.98 br.s (1H, NH). 13C NMR spectrum (DMSO-
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(2CN), 116.0, 126.3, 130.0, 182.3. Found, %: C 68.50;
H 5.70; N 18.20. C13H13N3O. Calculated, %: C 68.71; H
5.77; N 18.49.
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3-[Hydroxy(1-methyl-5-propyl-4-ethylpyrrol-2-
yl)methylene]malononitrile (IIIi). In 3 ml of toluene
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