Solvent and ligand effects on selective mono- and dilithiation of 1-(chlorophenyl)pyrroles and 1-(methoxyphenyl)pyrroles

Article abstract of DOI:10.1039/b100008j

Novel methods for site-selective lithiation of 1-(chlorophenyl)pyrroles and 1-(methoxyphenyl)pyrroles are described. Mono- or dilithiations are governed by change of both the temperature and the solvent from tetrahydrofuran to diethyl ether. Regioselectiv

Full text of DOI:10.1039/b100008j

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Solvent and ligand effects on selective mono- and dilithiation
of 1-(chlorophenyl)pyrroles and 1-(methoxyphenyl)pyrroles†
Katalin Fogassy,a Krisztina Kovács,a György M. Keseru´´ , b László To´´ k e a and Ferenc Faigl*a
1
a Department of Organic Chemical Technology, Budapest University of Technology
and Economics, H-1521 Budapest, Hungary
b Department of Chemical Informatical Technology, Budapest University of Technology
and Economics, H-1521 Budapest, Hungary
Received (in Cambridge, UK) 2nd January 2001, Accepted 22nd March 2001
First published as an Advance Article on the web 18th April 2001
Novel methods for site-selective lithiation of 1-(chlorophenyl)pyrroles and 1-(methoxyphenyl)pyrroles are
described. Mono- or dilithiations are governed by change of both the temperature and the solvent from
tetrahydrofuran to diethyl ether. Regioselectivities could be influenced by the quality of the metallating agent.
Thus, 1-(4-chlorophenyl)pyrrole was dilithiated with activated butyllithium at 0 ЊC to afford a valuable
intermediate in a pyrrolobenzoxazepine synthesis.
N,N,NЈ,NЉ,NЉ-pentamethyldiethylenetriamine (PMDTA) in
tetrahydrofuran (THF) at Ϫ75 ЊC.8 Site-selective monolithi-
ation of 1-(fluorophenyl)pyrroles9 and of 1-[(trifluoromethyl)-
phenyl]pyrroles10 has also been reported by our laboratory.
Regiocontrolled metallation of ortho, meta and para isomers
of 1-(bromophenyl)pyrroles (4, 9, 18) and of 1-(chlorophenyl)-
pyrroles (5, 10, 19) is a new challenge. First of all, metal
halogenide elimination may easily occur during ortho
metallation. In addition, the electronic, steric and complex-
forming abilities of the halogen substituents are different from
those of the OMe group.
Introduction
Multifunctionalized derivatives of 1-phenylpyrrole are known
potent biologically active compounds. Cytostatic mytomycine
derivatives1 (1), central nervous system (CNS)-active pyrrolo-
benzoxazepines2 (2), the neopyrrolomycine3 3 and analogous
antibiotics and fungicides3 are among the known pharmaceut-
ically interesting compounds.
On the other hand, α,2 dilithiation of the model compounds
would be useful for simultaneous functionalization of the
pyrrole and the benzene rings, yielding valuable intermediates
for the synthesis of biologically active compounds (such as
1, 2 or 3). Substituents like Cl, Br or OMe may influence the
outcome of such reactions depending on their characters.
Therefore, comparison of dilithiations of the OMe-substituted
1-phenylpyrroles (6, 11 and 20) with the same reactions of the
halogen-containing model compounds is also interesting both
from theoretical and practical points of view.
Site-selective metallation methods would be useful tools
for the synthesis of these molecules. On the other hand, 1-
(substituted phenyl)pyrroles are quite interesting models for
the investigation of the directing effects during metallation.
The pyrrole ring is suitable for α metallation, while it works
as an ortho-directing group connected to the benzene ring and
this latter aromatic ring contains (an)other directing substi-
tuent(s) in different positions. Mono- and dimetallations of
1-alkylpyrroles have been extensively studied by Chakrabarti4
and Chadwick.5 However, few articles have discussed the
metallation of 1-arylpyrroles. Selective α lithiation of 1-phenyl-
pyrrole was observed first by Shirley,6 and α,2 dilithiation of
the same molecule was published by Cheeseman.7 Recently,
we have reported on the regioselective monolithiation of
1-(methoxyphenyl)pyrroles controlled by the appropriate
application of the di- or tridentate activating agents
Results and discussion
Consecutive treatment of the ortho-, meta- and para-substi-
tuted 1-phenylpyrroles 4–6, 9–11, 18–20 with organometallic
base and solid CO2 provided mono- and dicarboxylic acids as
mixtures or sole products depending on the reaction conditions
used. The reactions and the structures of the isolated products
are shown in Schemes 1–3. The reagents, product ratios and
yields are collected in Tables 1 and 2.
Multicomponent mixtures formed instead of the desired
products when the bromine-containing 4 and 9 substrates were
consecutively treated with lithium 2,2,6,6-tetramethylpiperidide
(LiTMP) and solid CO2. Failure of these reactions is due to
the special ease of elimination of lithium bromide from the
ortho-lithiated derivatives of 4 and 9. Metallation and con-
secutive carboxylation of the para isomer 18 afforded acid 21 as
the main product, but we could not avoid formation of 22 even
when 20% excess of 2,2,6,6-tetramethylpiperidine (TMP) was
used related to the amount of butyllithium. The selectivity
completely changed when a stronger base, potassium tert-
butoxide-activated LiTMP (LiTMP–KOR), was the reagent in
(N,N,NЈ,NЈ-tetramethylethylenediamine
(TMEDA)
or
† Electronic supplementary information (ESI) available. Details of
molecular modelling, yields, melting or boiling points, spectroscopic
data of the starting materials 4–6, 9–11, 18–20 and the known products
12, 14, 16, 22–25, 27, 28, 30. See http://www.rsc.org/suppdata/p1/b1/
b100008j/
DOI: 10.1039/b100008j
J. Chem. Soc., Perkin Trans. 1, 2001, 1039–1043
This journal is © The Royal Society of Chemistry 2001
1039

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the presence of the tridentate PMDTA ligand (Table 1, entry
12). The high selectivity of this reaction can be explained by
the stabilizing effect of PMDTA on the organometallic inter-
mediate of 23 and by the simultaneous fast elimination of alkali
bromide from the organometallic intermediate of 21 (if it was
formed).
Much higher yields were achieved during lithiation and
carboxylation of the chloro-substituted compounds (5, 10 and
19). The C–Cl bond was stable enough at Ϫ75 ЊC; neither
halogen–lithium exchange nor elimination of lithium chloride
was observed using butyllithium (BuLi) or its activated com-
plexes (BuLi–TMEDA and BuLi–PMDTA) in THF. The yields
of the isolated carboxylic acids 7, 12 and the mixture of 24 and
25 increased together with the reactivity of the metallating
agent. Change of TMEDA to PMDTA did not influence the
regioselectivities during metallation of 5 and 10; monocarb-
oxylic acids 7 and 12 were isolated as sole products, respectively
(Table 1, entries 2–4 and 7–9). A strong competition between
the C-2 and C-3 positions (activated by the chloro and the
pyrrolo substituents, respectively) was observed when 19 was
treated with the above-mentioned bases and mixtures of 24 and
25 were isolated.
The weaker, lithium amide-type base (LiTMP) reacted with
the chloro compounds (5, 10 and 19) in different ways: com-
pounds 5 and 19 could be transformed—after solid-CO2
quenching—into acids 7 and 24, respectively, with complete
regioselectivity and in good yields. The meta isomer 10 under-
went parallel lithiation on both halogen-adjacent positions (C-2
and C-4) with LiTMP, therefore a 1 : 2 mixture of 12 and 13
was isolated after the reaction with solid CO2. The C-2 position
is sterically more crowded than the C-4 position, but the bulki-
ness of LiTMP alone does not explain the result since BuLi–
TMEDA and BuLi–PMDTA are also bulky reagents and we
obtained the C-2 acid 12 regioselectively and in a high yield
using these bases (Table 1, entries 8–10).
Change of the temperature from Ϫ75 ЊC to 0 ЊC and of the
solvent from THF to diethyl ether resulted in significant differ-
ences in the metallation reactions. The lithio derivatives of
the 1-(bromophenyl)pyrroles 4, 9 and 18 and of the ortho and
meta 1-(chlorophenyl)pyrroles (5 and 10) were unstable under
these conditions; we could not isolate any halogen-containing
mono- or dicarboxylic acid from these reactions. However,
1-(4-chlorophenyl)pyrrole 19 underwent α,2 dimetallation even
when only one equivalent butyllithium was added to the model
compound (Table 2, entry 7). The yield of the isolated dicarb-
oxylic acid 26 became three–four-times higher when two
equivalents of butyllithium was used even in THF at 0 ЊC (entry
9). Metallation with two equivalents of BuLi–TMEDA gave the
best result in this series of experiments (Table 2, entry 10) while
the reaction with BuLi–PMDTA yielded—after solid-CO2
quenching—a mixture of monocarboxylic (25) and dicarb-
oxylic (26) acids. It has to be mentioned that we could not
isolate any α-substituted product from this reaction. (This is
in accord with the monolithiation reactions at Ϫ75 ЊC, Table 1,
entries 13–15.)
Scheme 1
For comparison, monolithiations of the OMe-group-contain-
ing model compounds (6, 11 and 20) were also accomplished
at 0 ЊC. Two-fold excess of BuLi–TMEDA was necessary for
ortho metallation of 6, providing the monocarboxylic acid 8
with reasonable yield (Table 2, entry 1). During metallation of
11 and 20 ortho lithiation occurred (products 14 and 27) with
BuLi–TMEDA reagent, but the thermodynamically favored α
lithiation dominated in the presence of PMDTA (formation of
acids 16 and 28, respectively). In diethyl ether, the consecutive
reactions of 11 with BuLi–PMDTA and solid CO2 resulted
in a mixture of 16 and 17. Appearance of the dicarboxylic
acid 17 might be due to the co-ordination of the α-lithiated
compound with another molecule of base and in this aggregate
hydrogen–lithium exchange could occur at the activated
C-2 position. Better solvation in THF prevents the α-lithiated
compound from forming such a type of aggregate, there-
fore clean α lithiation of 11 could be achieved even at 0 ЊC.
The dicarboxylic acid 17 formed in good yield when 11 was
treated with two equivalents amount of BuLi–TMEDA in
diethyl ether at 0 ЊC followed by quenching with solid CO2
(Table 2, entry 6).
Scheme 2
Scheme 3
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J. Chem. Soc., Perkin Trans. 1, 2001, 1039–1043

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Table 1 Reagents and results of the consecutive lithiation and carboxylation reactions in THF at Ϫ75 ЊC
Starting material
Product
Entry
No.
X
Base (equivalents)
No. (ratio)a
Yield (%)b
c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
4
5
Br
Cl
Cl
Cl
Cl
Br
Cl
Cl
Cl
Cl
Br
Br
Cl
Cl
Cl
Cl
LiTMP (1)
BuLi (1)
BuLi–TMEDA (1)
BuLi–PMDTA (1)
LiTMP (1)
LiTMP (1)
BuLi (1)
BuLi–TMEDA (1)
BuLi–PMDTA (1)
LiTMP (1)
LiTMP (1)
LiTMP–KOR ϩ PMDTA (1)
BuLi (1)
BuLi–TMEDA (1)
BuLi–PMDTA (1)
LiTMP (1)
7
7
7
7
18
54
55
5
5
5
59
c
9
10
10
10
10
18
18
19
19
19
19
12
69
58
75
34
32
17
58
64
66
67
12
12
12 ϩ 13 (1 : 2)
21 ϩ 22 (2 : 1)
23
24 ϩ 25 (1 : 3)
24 ϩ 25 (1 : 3)
24 ϩ 25 (1 : 1)
24
a Compositions of the isolated crude products were determined by 1H NMR. b Yields of the isolated products. c Multicomponent mixtures formed.
In the case of 9, only 1-(3-carboxyphenyl)pyrrole was isolated (20%) from the mixture in spite of the excess of TMP (20% relative to butyllithium).
Table 2 Reagents and results of the consecutive lithiation and carboxylation reactions at 0 ЊC
Starting material
Product
Entry
No.
X
Base (equiv.), solventa
No. (ratio)b
Yield (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
6
11
11
11
11
11
19
19
19
19
19
20
20
20
20
OMe
OMe
OMe
OMe
OMe
OMe
Cl
Cl
Cl
Cl
Cl
BuLi–TMEDA (2), Et2O
BuLi (1), Et2O
BuLi–TMEDA (1), Et2O or THF
BuLi–PMDTA (1), Et2Oe
BuLi–PMDTA (1), THF
BuLi–TMEDA (2), Et2O
BuLi (1), Et2O
8
55d
24
62d
62
68
88
14
51
55
70
49
72
67d
32
66
14 ϩ 15 (1 : 3)
14
16 ϩ 17 (2 : 1)
16
17
26
BuLi (2), Et2O
BuLi (2), THF
26
26
BuLi–TMEDA (2), Et2O
BuLi–PMDTA (2), Et2O
BuLi–TMEDA (2), Et2O
BuLi–TMEDA (1), THF
BuLi–PMDTA (1), Et2O
BuLi–PMDTA (2), Et2O
26
25 ϩ 26 (4 : 3)
OMe
OMe
OMe
OMe
27 ϩ 29 (1 : 1)
27
28
29
1
a Et2O:diethyl ether, THF:tetrahydrofuran. b Compositions of the isolated crude products were determined by H NMR. c Yields of the isolated
products. d The yields were >95% when D2O was used as electrophilic reagent. e The metallation was carried out at Ϫ20 ЊC.
In the reaction of 20 with BuLi–TMEDA, a 1 : 1 mixture of
27 and 29 could be isolated after solid-CO2 quenching. Clean
α lithiation was accomplished with BuLi–PMDTA in diethyl
ether to afford 28, and the pure dicarboxylic acid 29 was formed
when two equivalents of BuLi–PMDTA were used (Table 2,
entries 14 and 15).
Efficient preparation of dicarboxylic acid 26 was the starting
point of the novel, convenient synthesis of a known, CNS-
active pyrrolobenzoxazepine2 (30, Scheme 4). In the two-step
methods (use of P2O5 or other strong acid) initiate serious
side-reactions of the pyrrole moiety.
In order to help rationalization of the observed reactivities
and selectivities, molecular modelling and quantum chemical
calculations were also carried out. Details of the calculations
are reported in the deposited Supplementary Data. These data
may be helpful for prediction of ortho lithiation adjacent to
the halogen or OMe group. However, the solvent- and ligand-
dependent site selectivities as well as the formation of the
dilithiated species (intermediates of dicarboxylic acids 17, 26
and 29) indicate the complexity of these reactions. Detailed
investigations have confirmed11 that lithium (in the complex
BuLi–TMEDA) may co-ordinate to the OMe group of anisole-
type molecules (Ar-H), but this intermediate does not account
for the facilitated ortho lithiation as such.11 Instead, it has
been shown by ab initio calculations12 and systematic kinetic
measurements12,13 that TMEDA-activated butyllithium may
react in a dimeric form of structure (BuLi)2(TMEDA)2. The
transition structures of stoichiometry [(BuLi)2(TMEDA)2-
(Ar-H)]‡ as well as formation of triple ions in the rate-limiting
steps have been discussed by Collum and co-workers.12 On the
other hand, they have demonstrated that activating ligands and
solvents may influence both the rate and the mechanism of
metallations by correlated solvation. Thus, construction of a
cogent mechanistic model is difficult.14
Scheme 4
synthesis the dicarboxylic acid 16 was reduced to the diol,
then this was treated with silica gel. Silica is acidic enough to
promote elimination of water under mild conditions. In this
way, 30 could be prepared conveniently while the known
J. Chem. Soc., Perkin Trans. 1, 2001, 1039–1043
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Conclusions
compositions are given in Tables 1 and 2. Analytical samples of
the products were recrystallized; the type of solvent is given
below. When D2O was the electrophile, the organic phase of
the reaction mixture was collected after hydrolysis, then was
dried, and concentrated in vacuo. The position of the inserted
deuterium was observed by 1H NMR spectroscopy.
In summary, highly selective methods for mono- and dimetal-
lation of (bromo)-, chloro- and methoxy-substituted 1-phenyl-
pyrroles have been developed. Thus 1-(chlorophenyl)pyrroles
could be lithiated with activated butyllithium at low temper-
ature with good yields.
Special effects influenced the metallations in diethyl ether
at 0 ЊC. Site-selective monolithiation of 1-(2-methoxyphenyl)-
pyrrole 6 could be achieved with two equivalents of BuLi–
TMEDA, only. Selective dimetallations of meta and para
methoxy analogs (11 and 20) with two equivalents of BuLi–
PMDTA and efficient α,2 dilithiation of 1-(4-chlorophenyl)-
pyrrole 19 were also accomplished. In the latter case, simple
butyllithium or its TMEDA-activated form was suitable
for dimetallation. Synthetic utility of these metallation
reactions was demonstrated by the preparation of a pyrrolo-
benzoxazepine derivative.
1-(4-Bromo-3-carboxyphenyl)pyrrole 21. Mp 138–142 ЊC
(from hexane) (Found: C, 49.61; H, 3.12; N, 5.17. C11H8BrNO2
requires C, 49.65; H, 3.03; N, 5.26%); νmax(KBr)/cmϪ1 3446
(OH), 1710, 1648 (CO); δH(CDCl3) 6.38 (2H, t, J 1.9, β- ϩ
βЈ-H), 7.10 (2H, t, J 1.9, α- ϩ αЈ-H), 7.42 (1H, dd, J 8.6, 2.5,
6-H), 7.75 (1H, d, J 8.6, 5-H), 8.03 (1H, d, J 2.5, 2-H).
1-(3-Carboxy-2-chlorophenyl)pyrrole 7. Mp 156–157 ЊC (from
dichloromethane) (Found: C, 59.63; H, 3.71; N, 6.48.
C11H8ClNO2 requires C, 59.61; H, 3.64; N, 6.32%); νmax(KBr)/
cmϪ1 3446 (OH), 1696 (CO); δH(CDCl3) 6.36 (2H, t, J 2.1,
β- ϩ βЈ-H), 6.88 (2H, t, J 2.1, α- ϩ αЈ-H), 7.43 (1H, t, J 7.9,
5-H), 7.50 (1H, dd, J 7.9, 2.0, 6-H), 7.88 (1H, dd, J 7.9, 2.0,
4-H).
Experimental
Generalities
1-(4-Carboxy-3-chlorophenyl)pyrrole 13. Mp 166–168 ЊC
(from dichloromethane–hexane) (Found: C, 59.62; H, 3.61;
N, 6.32. C11H8ClNO2 requires C, 59.61; H, 3.64; N 6.32%);
νmax(KBr)/cmϪ1 3446 (OH), 1708 (CO); δH(CDCl3) 6.40 (2H, t,
J 2.0, β- ϩ βЈ-H), 7.15 (2H, t, J 2.0, α- ϩ αЈ-H), 7.36 (1H, dd,
J 8.9, 2.5, 6-H), 7.52 (1H, d, J 2.5, 2-H), 8.10 (1H, d, J 8.9, 5-H).
All commercial starting materials were purchased from Fluka
AG and Merck-Shuchardt and were used without further
purification. Butyllithium was supplied by Chemetall GmbH
Lithium Division, Frankfurt. Anhydrous diethyl ether and
THF were obtained by distillation from sodium wire after
the characteristic blue color of in situ-generated sodium
diphenylketyl had been found to persist. TMEDA and PMDTA
were also distilled from sodium wire before use. The concen-
tration of the butyllithium solution was determined by the
double-titration method.15 All experiments were carried out in
Schlenk flasks under dry nitrogen atmosphere. Solid CO2–
acetone-baths were used to achieve Ϫ75 ЊC during metallation
reactions. NMR spectra were recorded in deuteriochloroform
or hexadeuteriodimethyl sulfoxide solution at 250 MHz.
Chemical shifts refer to tetramethylsilane (δ = 0 ppm); coupling
constants (J) are given in Hz. Assignments for the proton
signals are given in all cases; the numbers and greek letters refer
to the numbering of the carbon skeleton (shown in Scheme 2).
Compounds 4–6, 9–11, 18–20 are known from the literature.
These materials were prepared from the corresponding sub-
stituted aniline and cis,trans-2,5-dimethoxytetrahydrofuran
in glacial acetic acid according to Gross’ general procedure.16
Several end-products (12, 14, 16, 22–25, 27, 28, 30) are also
known from the literature. The yields, physical and spectro-
scopic data of all the above-mentioned products are available in
the deposited Supplementary Data.
1-(2-Carboxy-4-chlorophenyl)pyrrole-2-carboxylic acid 26.
Mp 173–174 ЊC (from chloroform) (Found: C, 54.32; H, 3.03;
N, 5.27. C12H8ClNO4 requires C, 54.26; H, 3.04; N, 5.27%);
νmax(KBr)/cmϪ1 3445 (OH), 1706 (CO); δH(DMSO-d6) 6.25 (1H,
dd, J 4.0, 2.4, βЈ-H), 6.90 (1H, dd, J 4.0, 1.8, β-H), 7.04 (1H,
t-like dd, J 2.4, 1.8, α-H), 7.36 (1H, d, J 8.7, 6-H), 7.68 (1H, dd,
J 8.7, 2.5, 5-H), 7.85 (1H, d, J 2.5, 3-H).
1-(3-Carboxy-2-methoxyphenyl)pyrrole 8. Mp 104–106 ЊC
(from hexane) (Found: C, 66.26; H, 5.11; N, 6.38. C12H11NO3
requires C, 66.33; H, 5.11; N, 6.45%); νmax(KBr)/cmϪ1 3434
(OH), 1693 (CO); δH(CDCl3) 3.49 (3H, s, OMe), 6.40 (2H, t,
J 2.1, β- ϩ βЈ-H), 7.03 (2H, t, J 2.1, α- ϩ αЈ-H), 7.35 (1H, t,
J 7.9, 5-H), 7.59 (1H, dd, J 7.8, 2.0, 6-H), 8.18 (1H, dd, J 8.0,
2.0, 4-H).
1-(2-Methoxy[3-2H]phenyl)pyrrole. Oil, δH(CDCl3) 3.81 (3H,
s, OMe), 6.30 (2H, t, J 2.0, β- ϩ βЈ-H), 6.99 (2H, t, J 2.0,
α- ϩ αЈ-H), 7.00 (1H, t, J 7.8, 5-H), 7.27 (1H, dd, J 7.8, 1.7,
4-H), 7.30 (1H, dd, J 7.8, 1.7, 6-H).
Metallation (general procedure)
1-(4-Carboxy-3-methoxyphenyl)pyrrole 15. Mp 118–120 ЊC
(from hexane) (Found: C, 66.38; H, 5.15; N, 6.43. C12H11NO3
requires C, 66.33; H, 5.11; N, 6.45%); νmax(KBr)/cmϪ1 3433
(OH), 1710 (CO); δH(CDCl3) 4.04 (3H, s, OMe), 6.39 (2H, t-like
m, J 2.0, β- ϩ βЈ-H), 6.92–7.20 (4H, m, 2-, 6-, α- ϩ αЈ-H), 8.19
(1H, d, J 7.8, 5-H).
A 1-(substituted phenyl)pyrrole 4–6, 9–11, 18–20 (10.0 mmol)
and the activating agent (10.0 mmol, TMEDA: 1.16 g;
PMDTA: 1.73 g, or the double amount) were dissolved in dry
THF or diethyl ether (25.0 ml) and cooled to 0 or Ϫ75 ЊC.
Buthyllithium (11.0 mmol; 7.3 ml or the double amount) in
hexane was added dropwise to the solution. When LiTMP was
used as a base, it was prepared from TMP (13.0 mmol, 1.83 g)
and butyllithium (11.0 mmol, 7.3 ml) before addition of the
model compound. The reaction mixture was stirred for 60 min
(in the case of 6 15 min), then was poured into a solid CO2–
diethyl ether slurry. At 20 ЊC, 20 ml of water was added, the
phases were separated, and the aqueous solution was washed
with diethyl ether (3 × 15 ml). The aqueous solution was acidi-
fied with 10% aq. citric acid. The product precipitated from the
solution in the form of an oil or as crystals. In the case of the
oil the aqueous phase was extracted with dichloromethane
(3 × 25 ml). The collected dichloromethane solutions were dried
over sodium sulfate and concentrated in vacuo. The residue was
treated with hexane to give crystalline material. The yields and
1-(2-Carboxy-3-methoxyphenyl)pyrrole-2-carboxylic acid 17.
Mp 146–148 ЊC (from chloroform–hexane) (Found: C, 59.73;
H, 4.30; N, 5.45. C13H11NO5 requires C, 59.77; H, 4.24;
N, 5.36%); νmax(KBr)/cmϪ1 3428 (OH), 1713, 1654 (CO);
δH(DMSO-d6) 3.85 (3H, s, OMe), 6.19 (1H, dd, J 3.9, 2.8, βЈ-H),
6.75 (1H, dd, J 3.9, 2.0, β-H), 6.82 (1H, d, J 7.7, 4-H), 6.88 (1H,
dd, J 2.8, 2.0, αЈ-H), 7.13 (1H, d, J 7.7, 6-H), 7.36 (1H, t, J 7.7,
5-H).
1-(2-Carboxy-4-methoxyphenyl)pyrrole-2-carboxylic acid 29.
Mp 171–172 ЊC (from chloroform–hexane) (Found: C, 59.82;
H, 4.31; N, 5.43. C13H11NO5 requires C, 59.77; H, 4.24; N,
5.36%); νmax(KBr)/cmϪ1 3430 (OH), 1686, 1654 (CO);
1042
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δH(DMSO-d6) 3.83 (3H, s, OMe), 6.19 (1H, dd, J 3.5, 2.9,
βЈ-H), 6.88 (1H, dd, J 3.5, 1.9, β-H), 6.96 (1H, dd, J 2.9, 1.9,
αЈ-H), 7.15 (1H, dd, J 8.2, 3.0, 5-H), 7.23 (1H, d, J 8.2, 6-H),
7.35 (1H, d, J 3.0, 3-H).
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30
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A solution of 26 (3.8 mmol, 0.84 g) in THF (10 ml) was added
dropwise to a suspension of lithium aluminium hydride (9.4
mmol, 0.35 g) in THF (30 ml) at 0 ЊC. The mixture was stirred
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2-(hydroxymethyl)phenyl]-2-(hydroxymethyl)pyrrole2
(yield
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Acknowledgements
This work was supported by the National Research Foundation
of Hungary, Budapest (OTKA grant No. T-030803).
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