Preparation of 5-unsubstituted 4-formylpyrrole-2-carboxylates and conversion to cycloalkano-oligopyrroles

Article abstract of DOI:10.1039/b003360j

Ethyl 4-formylpyrrole-2-carboxylates were prepared from nitroacetaldehyde dimethyl acetal in 9-50% yields using the Barton-Zard reaction. These formylpyrroles were successfully transformed to cycloalkano-oligopyrroles. The conformation of cyclononatripyrroles in CDCl₃ was found to be a crown form based on the NMR analysis, while cyclododecatetrapyrroles were in two interconverting boat and chair conformations.

Full text of DOI:10.1039/b003360j

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Preparation of 5-unsubstituted 4-formylpyrrole-2-carboxylates
and conversion to cycloalkano-oligopyrroles†
Yumiko Fumoto,a Hidemitsu Uno,b Satoshi Ito,a Yuka Tsugumi,a Maki Sasaki,a
Yukiko Kitawakia and Noboru Ono*a
1
a Department of Chemistry, Faculty of Science, Ehime University, Matsuyama 790-8577, Japan.
Fax: ϩ81(89)9279590. E-mail: ononbr@dpc.ehime-u.ac.jp
b Advanced Instrumentation Center for Chemical Analysis, Ehime University,
Matsuyama 790-8577, Japan
Received (in Cambridge, UK) 26th April 2000, Accepted 10th July 2000
Published on the Web 4th August 2000
Ethyl 4-formylpyrrole-2-carboxylates were prepared from nitroacetaldehyde dimethyl acetal in 9–50% yields using
the Barton–Zard reaction. These formylpyrroles were successfully transformed to cycloalkano-oligopyrroles. The
conformation of cyclononatripyrroles in CDCl3 was found to be a crown form based on the NMR analysis, while
cyclododecatetrapyrroles were in two interconverting boat and chair conformations.
as the first target compounds. The Barton–Zard pyrrole syn-
Introduction
thesis8 was used for the preparation of the 4-formylpyrroles
(Scheme 1). The starting material, nitroacetaldehyde dimethyl
Recently, calixarenes,1 cyclophanes2 and cyclotriveratrylene
derivatives3 have been extensively studied as host molecules
capable of binding or including neutral, anionic and cationic
substances. Their interesting ability to form supramolecular
complexes such as caviplexes4 is expected to reveal new
chemical or physical functions. These host molecules are
usually prepared by simple oligocyclic condensation of aryl-
methyl units utilizing the electron-rich nature of phenol,
resorcinol and veratrole, respectively. Similarly, pyrroles have
been successfully utilized for the construction of host mole-
cules, and the binding ability of the so-called calixpyrroles
toward anions, metals and neutral molecules have been exten-
sively studied by Sessler’s and Floriani’s groups.5,6 The pyrrole
ring is very electron-rich and capable of reacting easily with
electrophiles even if the ring is already substituted by an
electron-withdrawing group. In contrast to the calixpyrroles,
the properties of cycloalkano-oligopyrroles,7 pyrrole versions
of cyclotriveratrylenes, have not been investigated, although
macrocyclic oligopyrroles are thought to be promising can-
didates for the recognition of negatively charged substances by
the acidic NH groups and for the formation of caviplexes4 by
the variety in the possible choice of substituents on the pyrrole
ring. The slow growth of studies in this area is due to the lack
of a reliable method to access the macrocycles: easily accessible
α-hydroxymethylpyrroles tend to oligomerize at the α-positions,
even if the other α-position is occupied by a substituent, and
no simple method for the preparation of α-unsubstituted
β-hydroxymethylpyrroles has been reported. Moreover, con-
trary to the conformation of cyclotriveratrylenes, the reported
conformations of cyclononatripyrroles7a and cyclononatri-
indoles7b are ambiguous. In this paper, we report an efficient
method to access the β-hydroxymethylpyrroles and their oligo-
cyclization leading to cycloalkano-oligopyrroles.
Results and discussion
Preparation of 4-formylpyrrole-2-carboxylates 6
Since hydroxymethyl- and alkoxymethyl-pyrroles are thought
to be unstable, the corresponding formylpyrroles were chosen
† Experimental procedures for the preparation of compounds 6a, 6b,
6d, 10b, 10d, 11b and 11d are available as supplementary data. For
direct electronic access see http://www.rsc.org/suppdata/p1/b0/
b003360j/
Scheme 1 a: R1 = H; b: R1 = Me; c: R1 = Ph; d: R1 = p-BrC6H4.
DOI: 10.1039/b003360j
J. Chem. Soc., Perkin Trans. 1, 2000, 2977–2981
This journal is © The Royal Society of Chemistry 2000
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Table 1 Synthesis of 4-formylpyrrole-2-carboxylates 6
Nitro aldol reaction
conditions
Comp.
R1
Yield of 6 (%)a
a
b
c
H
Me
Ph
p-BrC6H4
A
B
C
C
9
50
31
13
d
a The yield was based on the starting nitro acetal 1.
acetal (1), was readily prepared from methyl orthoformate and
nitromethane by the reported procedure.9 The nitro acetal 1
easily reacted with acetaldehyde with the aid of Amberlyst A-21
(condition B)10 to give the β-nitro alcohol 2b in 83% yield. A
similar reaction of 1 with formalin using Et3N gave a mixture
of the desired 2a and bishydroxymethylated by-product 3a.
Since the presence of 3a did not interfere with the following
reactions, this mixture was used without separation and the
calculated yield of 2a was 50%. On the other hand, poor results
were obtained in the reaction of 1 with aromatic aldehydes
under similar conditions. After several trials, use of Et3N,
TBSCl, and TBAF was found to be effective.11 Thus, the
reaction of 1 with benzaldehyde and p-bromobenzaldehyde
gave β-nitro alcohols 2c and 2d in 56% and 35% yield, respect-
ively (condition C).
Fig. 1 The methylene proton region of the 1H NMR spectrum of 10c
at 50 ЊC in CDCl3 and the crown conformation of cyclononatripyrrole
10c.
β-Nitro alcohols 2a–d were transformed to β-acetoxy nitro
compounds 4a–d by acetylation with Ac2O in the presence of
DMAP. The acetoxy nitro compounds 4b–d reacted with
ethyl isocyanoacetate in the presence of DBU to give 4-formyl-
pyrrole-2-carboxylates 6b–d in good yields after acidic work-up
(Scheme 1, Table 1). In the reaction of 4a, however, the corre-
sponding pyrrole 6a having no substituent at the 3-position was
obtained in lower yield than in other cases. A similar difficulty
was reported in preparations of 3-unsubstituted pyrroles by the
Barton–Zard method.8
Reaction of ethyl 4-formylpyrrole-2-carboxylates 6
The formyl group at the 4-position of the pyrroles was easily
converted to a hydroxymethyl group in quantitative yields by
treatment with NaBH4 in THF at 0 ЊC (Scheme 2). When 4-
hydroxymethylpyrrole 7c was treated with toluene-p-sulfonic
acid in the presence of ethanol and thiophenol, dehydration
followed by nucleophilic attack occurred to give 4-ethoxy-
methyl- and 4-phenylthiomethyl-pyrroles 8 and 9 in 79%
and 62% yields, respectively. On the other hand, when the
4-(hydroxymethyl)pyrroles 7b–d were treated with toluene-p-
sulfonic acid in the absence of a nucleophile, oligocyclization
took place to give mixtures of cyclononatripyrroles 10b–d,
cyclododecatetrapyrroles 11b–d and a small amount of by-
products. Separation of the macrocycles 10 and 11 was prob-
lematic. To our surprise, the macrocycles 10 and 11 could not be
separated either preparative gel permeation chromatography
(GPC) or recrystallization. For 10c and 11c only, separation
of these two macrocycles was achieved by repeated column
chromatography. Pure 10c and 11c were obtained in 58% and
7% yields, respectively.
Scheme 2 Reagents: a, NaBH4, EtOH; b, EtOH, p-TsOH, CHCl3; c,
PhSH, p-TsOH, CHCl3; d, p-TsOH, CHCl3.
Conformational consideration of cycloalkano-oligopyrroles
In the NMR spectrum of 10c in CDCl3 at 27 ЊC, the three pairs
of methylene protons appeared at δ 3.55 and δ 3.98 as a pair of
doublets (AB-quartet), which did not coalesce even at 50 ЊC,
and only one set of resonances for the ethyl ester and phenyl
groups was observed. These facts suggest that this macrocycle
exists in one rigid conformation, where each of the ester and
phenyl groups is equivalent. Therefore, the macrocycle is
deduced to be in the crown conformation with C3 symmetry.
The macrocycle, of course, exists as a mixture of enantiomers,
one of which is shown in Fig. 1. Although the precise ∆H‡
value for the ring flipping could not be estimated, the value was
far in excess of 63 kJ molϪ1. A similar NMR behaviour
was reported for tribenzocyclononanes and the crown motif
was confirmed.12 The ∆H‡ for the conformational barrier was
reported to be ca. 108–117 kJ molϪ1 13
On the other hand,
.
unambiguous conformational determination was not possible
from the reported data for the cyclononatripyrroles obtained by
the condensation of 3,4-unsubstituted pyrroles with formalin,
because the signal due to the methylene protons was reported to
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conformation has Ci. In 11c, the chair conformer should be less
polar because the dipolar moments of the functional groups are
counterbalanced with each other. The more stable conform-
ation whose equilibrium concentration increases in CD2Cl2
(more polar than CDCl3) would be a boat form in which the
methylene protons appeared as a pair of doublets at the low
temperature.
Conclusion
We report an efficient synthesis of 4-formylpyrroles 6a–d via
Barton–Zard reaction, which are difficult to prepare by other
methods. The conformation of macrocycle 10c in CDCl3 is, as
expected, the locked crown form with C3 symmetry. Since the
1
inversion energy is calculated to be over 63 kJ molϪ1 by H
NMR analysis, it appears that the chirality of macrocycle 10c is
stable enough for the macrocycle to be a promising candidate
for recognition of chiral molecules. On the other hand, the
macrocycle 11c exists as two interconverting boat and chair
conformers at Ϫ50 ЊC.
Experimental
Unless otherwise noted, NMR spectra were obtained with
a JEOL GSX-270 or JMN-400 spectrometer at ambient
temperature by using CDCl3 as solvent and TMS as internal
standard for 1H and 13C. J Values are given in Hz. Mass spectra
and HRMS were measured with a Hitachi M80B-LCAPI
spectrometer under the following ionizing conditions (20 eV for
EI and 70 eV for HRMS, high boiling perfluorokerosine as a
standard). Column chromatography and TLC were carried out
using C-200 (Wakogel) and Kieselgel 60 F254 (Merk), respect-
ively. Tetrahydrofuran was distilled from sodium benzophenone
ketyl under an inert atmosphere. Chloroform was washed with
water to remove EtOH, dried with Na2SO4 and distilled from
CaH2 under an inert atmosphere. EtOH was distilled from
CaH2 under an inert atmosphere. Other commercially available
materials were used without further purification. Ethyl iso-
cyanoacetate was prepared from ethyl N-formylglycinate using
POCl3 and triethylamine.15 Nitro acetal 1 was prepared from
nitromethane and orthoformate according to the literature
procedure as a pale yellow liquid: 63–65 ЊC (10 mmHg).9
Experimental procedures for the preparation of 6a, 6b, 6d, 10b,
10d, 11b and 11d are given in the Supplementary data.
Fig. 2 The 1H NMR spectra of methylene protons of cyclododeca-
tetrapyrrole 11c in CD2Cl2 at the indicated temperatures.
Fig. 3 (a) Chair and (b) boat conformations of cyclododecatetra-
pyrrole 11c.
Ethyl 4-formyl-3-phenylpyrrole-2-carboxylate (6c)
be a broad singlet even at Ϫ40 ЊC. This differing NMR
behaviour could be due to the difference in the substitution
pattern on the pyrrole ring.
To a stirred solution of Bu4NFؒ3H2O (7.5 mL, 7.5 mmol) in
THF (12 mL) at 0 ЊC were sequentially added nitro compound
1 (4.05 g, 30 mmol), benzaldehyde (2 mL, 20 mmol), Et3N (2.8
mL, 20 mmol) and a solution of tBuMe2SiCl (4.5 g, 30 mmol) in
THF (20 mL). After 2 h, the reaction mixture was filtered
through a Celite pad, which was washed with EtOAc (3 × 50
mL). The organic layer was separated and the aqueous layer
was extracted with EtOAc (2 × 20 mL). The combined organic
layers were washed with water (5 × 50 mL) and brine (30 mL),
dried over Na2SO4 and concentrated. The residue was chroma-
tographed on silica gel (20%, EtOAc–hexane) to give 4.49 g
(62%) of crude 1,1-dimethoxy-2-nitro-3-phenylpropan-3-ol (2c)
as an orange liquid: νmax(neat)/cmϪ1 3471, 2941, 2841 and 1554;
δH 3.13 (d, 1H, J = 8.3, major isomer), 3.43 (s, 3H, major
isomer), 3.44 (s, 3H, minor isomer), 3.45 (s, 3H, major
isomer), 3.47 (s, 3H, minor isomer), 3.62 (d, 1H, J = 1.9, minor
isomer), 4.50 (d, 1H, J = 7.3, minor isomer), 4.70 (m, 1H, both
isomers), 5.03 (d, 1H, J = 7.3, major isomer), 5.13 (dd, 1H,
J = 7.3, 1.9, minor isomer) and 5.26 (dd, 1H, J = 8.3, 4.2, major
isomer); δC 54.6, 54.9, 55.6, 55.9, 71.9, 73.2, 91.1, 92.1, 101.9,
103.2, 125.6, 126.9, 128.6, 128.7, 128.8 and 129.1.
In contrast to the rigid macrocycle 10c, the methylene
absorption of 11c appeared as a rather broader singlet (δ 3.60)
at room temperature in CD2Cl2, and this signal became broader
as the temperature was lowered (Fig. 2). At Ϫ50 ЊC, two con-
formers were observed and the methylene protons appeared as a
pair of doublets (δ 3.64 and δ 3.81) and a new broad singlet.
The coalescence temperature between the two conformers was
ca. Ϫ20 ЊC in CDCl3 and Ϫ10 ЊC in CD2Cl2. The integral ratios
of the methylene signals at Ϫ50 ЊC were ca. 3:2 in CDCl3 and
6:1 in CD2Cl2. The ∆G values between the two conformers at
Ϫ40 ЊC in CDCl3 and CD2Cl2 were 0.79 and 3.47 kJ molϪ1
,
respectively. The new broad singlet signal did not coalesce even
at Ϫ90 ЊC in CD2Cl2. These facts suggest that there are two
stable conformations of macrocycle 11c in CDCl3 and CD2Cl2
(Fig. 3). The structures of similar tetrabenzocyclododecanes
have been fully explored by 1H NMR analysis.14 Dodeca-
methoxytribenzocyclododecane exists as two conformers, boat
and chair conformers, in CDCl3 and C6D5NO2 even at 25 ЊC.
The aromatic protons in each conformer appeared as a pair
of singlets in both solvents. The equilibrium concentration of
the boat and chair (sofa) conformers depended on the solvent
polarity. The boat conformation has C2 symmetry and the chair
To a stirred solution of the crude nitro alcohol 2c (4.49 g,
18.6 mmol) in THF (10 mL) were added acetic anhydride (1.8
mL) and DMAP (0.01 g) at 0 ЊC. The mixture was warmed to
J. Chem. Soc., Perkin Trans. 1, 2000, 2977–2981
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10 ЊC and stirred for 18 h. Aqueous saturated NaHCO3 (10 mL)
and EtOAc (20 mL) were added. The organic layer was separ-
ated and the aqueous layer was extracted with EtOAc (3 × 10
mL). The combined organic layers were washed with water
(2 × 20 mL) and brine (20 mL), dried over Na2SO4 and concen-
trated to give 4.06 g (77%) of crude 1-acetoxy-3,3-dimethoxy-2-
nitro-1-phenylpropane (4c) as a yellow oil: νmax(neat)/cmϪ1
2939, 2841, 1753 and 1558; δH 2.07 (s, 3H, major isomer), 2.15
(s, 3H, minor isomer), 3.23 (s, 3H, major isomer), 3.37 (s, 3H,
minor isomer), 3.38 (s, 3H, major isomer), 3.42 (s, 3H, minor
isomer), 4.58 (d, 1H, J = 6.8, major isomer), 4.65 (d, 1H,
J = 7.8, minor isomer), 4.99 (dd, 1H, J = 7.8, 6.8, major iso-
mer), 5.10 (dd, 1H, J = 7.8, 6.0 minor isomer), 6.26 (d, 1H,
J = 6.0, minor isomer), 6.29 (d, 1H, J = 7.8, major isomer) and
7.37 (m, 5H); δC (typical signals) 20.8, 20.9, 54.6, 55.8, 55.03,
56.0, 72.0, 72.8, 88.5, 90.3, 101.1, 101.5, 153.1, 154.6, 155.0,
155.8, 156.0, 169.0 and 169.9.
To a stirred solution of the crude β-nitro acetate 4c (4.06 g,
14.3 mmol) in anhydrous THF (20 mL) were added dropwise
ethyl isocyanoacetate (1.5 mL, 14.5 mmol) and DBU (4.1 mL,
29 mmol) at 0 ЊC. After the mixture was warmed to 10 ЊC and
stirred for 18 h, 1 mol LϪ1 HCl (10 mL) and CHCl3 (10 mL)
were added. The organic layer was separated and the aqueous
layer was extracted with CHCl3 (3 × 20 mL). The combined
organic layers were washed with saturated NaHCO3 (20 mL),
water (3 × 20 mL) and brine (20 mL), dried over Na2SO4 and
concentrated. The residue was chromatographed on silica gel
(10%, EtOAc–hexane) to give crude 6c. Recrystallization from
EtOAc–hexane afforded 1.91 g (55%) of pure 6c as yellow crys-
tals: mp 83–84 ЊC; νmax(neat)/cmϪ1 3268 and 1672; δH 1.15 (t,
3H, J = 7.1), 4.2 (q, 2H, J = 7.1), 7.4 (m, 5H), 7.65 (d, 1H, J = 3.4)
and 9.65 (s, 1H); δC 14.0, 60.8, 120.6, 125.1, 126.1, 127.7, 127.9,
130.7, 131.5, 133.1, 160.6 and 187.0; MS (EI) 243 (Mϩ, 67%),
196 (100) and 169 (89). Anal. Calcd for C14H13NO3: C, 69.12;
H, 5.39; N, 5.76. Found: C, 69.23; H, 5.49; N, 5.82%.
extracted with CHCl3 (3 × 10 mL). The combined organic
layers were washed with saturated NaHCO3 (20 mL), water
(3 × 10 mL) and brine (20 mL), dried over Na2SO4 and concen-
trated. The residue was chromatographed on silica gel (CHCl3)
to give crude 9. Recrystallization from EtOAc–hexane afforded
86 mg (62%) of pure 9 as yellow crystals: mp 65 ЊC; νmax(KBr)/
cmϪ1 3304, 2980, 1672 and 1292; δH 1.11 (t, 3H, J = 7.1), 3.90 (s,
2H), 4.14 (q, 2H, J = 7.33), 6.86 (d, 1H, J = 2.9), 7.27 (m, 10H)
and 9.21 (br s, 1H); δC 14.0, 29.2, 60.1, 119.1, 120.8, 121.4,
126.1, 127.0, 127.6, 128.7, 129.6, 130.4, 130.7, 133.8, 136.6 and
161.0; MS (EI) 228 (Mϩ, 100%), 182 (98) and 154 (28). Anal.
Calcd for C20H18NO2S: C, 71.19; H, 5.68; N, 4.15. Found: C,
70.64; H, 5.81; N, 4.06%.
Triethyl 3,7,11-triphenylcyclonona[1,2-b:4,5-bЈ:7,8-bЉ]tripyr-
role-2,6,10-tricarboxylate (10c) and tetraethyl 3,7,11,15-tetra-
phenylcyclododeca[1,2-b:4,5-bЈ:7,8-bЉ:10,11-bٞ]tetrapyrrole-
2,6,10,14-tetracarboxylate (11c)
To a stirred solution of crude 7c prepared from the formyl
pyrrole 6c (100 mg, 0.41 mmol) as above in anhydrous CHCl3
(1 mL) was added p-TsOH (16.0 mg). After for 18 h, water
(10 mL) and CHCl3 (20 mL) were added. The organic layer was
separated and the aqueous layer was extracted with CHCl3
(3 × 10 mL). The combined organic layers were washed with
saturated NaHCO3 (20 mL), water (3 × 10 mL) and brine
(20 mL), dried over Na2SO4 and concentrated. The residue was
chromatographed on silica gel (20%, EtOAc–hexane) to give 77
mg (83%) of 10c and 7 mg (7%) of 11c. Recrystallization of
both materials from EtOAc–hexane afforded pure 10c and pure
11c. 10c: colorless crystals; mp 203–205 ЊC; νmax(KBr)/cmϪ1
3577, 2960 and 1678; δH 1.07 (t, 9H, J = 7.2), 3.55 (d, 3H,
J = 15.1), 3.98 (d, 3H, J = 15.1), 4.05 (q, 6H, J = 7.2), 4.06 (m,
15H) and 7.72 (br s, 3H); MS (EI) 681 (Mϩ, 100%) and 608 (7).
11c: colorless crystals; mp >300 ЊC; νmax(KBr)/cmϪ1 3440, 2979
and 1687; δH 1.10 (t, 12H, J = 6.8), 3.58 (br s, 8H), 4.07 (q,
8H, J = 6.8), 7.28 (m, 20H) and 7.99 (br s, 4H); MS (EI) 908
(Mϩ, 68%), 666 (100) and 241 (23). Anal. Calcd for (C14H13-
NO2)n (mixture of 10c and 11c): C, 73.99; H, 5.77; N, 6.16.
Found: C, 73.70; H, 6.00; N, 5.99%.
Ethyl 4-ethoxymethyl-3-phenylpyrrole-2-carboxylate (8)
To a stirred solution of the formyl pyrrole 6c (100 mg, 0.41
mmol) in EtOH (8 mL) was added NaBH4 (150 mg, 4 mmol) at
0 ЊC. After 3 h, 1 mol LϪ1 HCl was added (pH = 7–8) and then
CHCl3 (20 mL) was added. The organic layer was separated and
the aqueous layer was extracted with CHCl3 (3 × 10 mL). The
combined organic layers were washed with saturated NaHCO3
(20 mL), water (3 × 10 mL) and brine (30 mL), dried over
Na2SO4 and concentrated to give crude ethyl 4-hydroxymethyl-
3-phenylpyrrole-2-carboxylate (7c). To a stirred solution of
crude 7c in EtOH (1 mL) was added p-TsOH (16.0 mg). After
11 h, water (10 mL) and CHCl3 (20 mL) were added. The
organic layer was separated and the aqueous layer was
extracted with CHCl3 (3 × 30 mL). The combined organic
layers were washed with saturated NaHCO3 (20 mL), water
(3 × 10 mL) and brine (20 mL), dried over Na2SO4 and concen-
trated. The residue was chromatographed on silica gel (20%,
EtOAc–hexane) to give 69 mg (62%) of 8 as a yellow oil: mp
65 ЊC; νmax(neat)/cmϪ1 3309, 2954, 2885 and 1689; δH 1.17 (t,
3H, J = 6.8), 1.21 (t, 3H, J = 6.8), 3.44 (q, 2H, J = 6.8), 4.16
(q, 2H, J = 6.8), 4.24 (s, 2H), 6.99 (d, 1H, J = 2.9), 7.37 (m, 5H)
and 9.61 (br s, 1H); δC 13.9, 15.1, 60.0, 63.9, 65.2, 119.0, 122.0,
122.2, 126.8, 127.2, 130.4, 131.1, 133.9 and 161.3; MS (EI) 273
(Mϩ, 54%), 244 (46), 229 (62), 198 (530, 182 (100) and 154 (45);
HRMS calcd for Mϩ (C16H19NO3): 273.1365, found 273.1351.
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Ethyl 3-phenyl-4-(phenylthiomethyl)pyrrole-2-carboxylate (9)
To a stirred solution of crude 7c prepared from the formyl
pyrrole 6c (100 mg, 0.41 mmol) as above in anhydrous CHCl3
(1 mL) was added thiophenol (0.04 mL, 0.4 mmol) in the
presence of p-TsOH (16.0 mg). After the mixture was refluxed
for 18 h, water (10 mL) and CHCl3 (20 mL) were added. The
organic layer was separated and the aqueous layer was
2980
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