Regloselectlve reduction of 2, 4-diacylpyrroles and the synthesis of a 2, 4-divinylpyrrole

Article abstract of DOI:10.1002/ejoc.200900331

Reduction of 2,4-diacylpyrroles followed by dehydration to prepare the divinylpyrroles has been studied. The N-phenylsulfonyl group exhibited directing ability at the 4-position during the reduction of 2,4-diacylpyrrole and complete regioselectivity was a

Full text of DOI:10.1002/ejoc.200900331

FULL PAPER
DOI: 10.1002/ejoc.200900331
Regioselective Reduction of 2,4-Diacylpyrroles and the Synthesis of a
2,4-Divinylpyrrole
Yan Li[a] and David Dolphin*[a]
Keywords: N Heterocycles / Pyrroles / Reduction / Regioselectivity
Reduction of 2,4-diacylpyrroles followed by dehydration to
prepare the divinylpyrroles has been studied. The N-phenyl-
sulfonyl group exhibited directing ability at the 4-position
during the reduction of 2,4-diacylpyrrole and complete re-
gioselectivity was achieved for formations of the 2- and 4-
carbinols; several new derivatives, including 2,4-divinylpyr-
role, have been prepared.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
have explored the reductions of 2,4-diacylpyrroles to pre-
pare 2,4-divinylpyrrole.
Introduction
C-Vinylpyrroles, such as 2- and 3-vinylpyrroles, are ex-
tensively present in natural products such as porphyrins, vi-
tamin B12, chlorophylls and hemoglobin; they are also im-
portant building blocks for a variety of compounds.[1] Com-
pared to those of functionalized C-vinylpyrroles, where the
Results and Discussion
According to the literature,[10] 2,4-diisobutyryl)-1H-pyr-
vinyl substituents are conjugated with aryl, ester and amide role (1) is easily prepared by a one-pot acylation of pyrrole
groups, the synthesis of unfunctionalized C-vinylpyrroles is with isobutyryl chloride in the presence of aluminum chlo-
more challenging due to the considerable reactivity of the ride (Scheme 1). Using boron boron trifluoride–diethyl
unfunctionalized vinyl groups.[2] In addition to Wittig reac- ether, diacylpyrrole 1 was treated with dimethoxymethane
tions of formyl- or acyl-pyrroles with alkylidenephosphor- to produce bis(2,4-diisobutyryl)-1H-pyrrol-5-yl) methane
anes, another effective method to prepare unfunctionalized (2) in moderate yield. Interestingly, this reaction did not
2- and 3-vinylpyrroles is reduction of the corresponding proceed with the use of trifluoroacetic acid, although tri-
acylpyrroles followed by dehydration.[3–8] However, while fluoroacetic acid was reported to catalyze the reactions of
several pyrroles of unfunctionalized 2,5-divinyl substituents 2-alkoxycarbonyl-4-benzoyl)-1H-pyrroles with dimeth-
have been prepared by Wittig reactions,[9] there are no re- oxymethane to provide the corresponding dipyrromethanes
ports of the reduction of diacylpyrroles as precursors of C- in 25–30% yields.[11]
divinylpyrroles. Also, due to the difference in electron densi-
The reduction of 2- and 3-acylpyrroles is generally car-
ties at the α- and β-positions of pyrrole, the reduction rates ried out using sodium borohydride and 2-propanol or lith-
of α- and β-acyl substituents should be different, and will ium aluminum hydride and ether, but the yields of the re-
presumably give rise to varying regioselectivity. Herein, we sulting carbinols are always low due to over reduction to
Scheme 1.
give the corresponding alkylpyrroles.[3–5,7] We have found
that using methanol as solvent for the reduction of diacyl-
pyrrole 1, and the fractional addition of sodium borohy-
dride at room temperature, produced a single product over
[a] Department of Chemistry, The University of British Columbia,
2036 Main Mall, Vancouver, B.C., V6T 1Z1, Canada
Fax: +1-604-822-9678
E-mail: david.dolphin@ubc.ca
3562
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3562–3566

Regioselective Reduction of 2,4-Diacylpyrroles
a period of several hours. After work-up and chromatog- used in place of phenylsulfonyl chloride, both bis(1-tert-but-
raphy on silica gel, 2-(1-hydroxyisobutyl)-4-isobutyryl)-1H- oxycarbonyl-2,4-diisobutyryl)-1H-pyrrol-5-yl)methane (7)
pyrrole (3) was obtained in 98% yield (Scheme 2). Carbinol and [1-(tert-butoxycarbonyl)-2,4-diisobutyryl)-1H-pyrrol-5-
1
3 was identified by H NMR and H-H NOSY, in which a yl](2,4-diisobutyryl)-1H-pyrrol-5-yl)methane
(8)
were
doublet signal for CHCH(OH) appears at δ = 4.49 ppm formed with a ratio of 1:1.2 (Scheme 4). Unfortunately, tet-
with integration for a single proton and has interactions raacyldipyrromethane 7 was deprotected under sodium
with only a single aromatic proton. Although 2,4-dibenzo- borohydride reduction condition and provided similar re-
ylpyrrole can be reduced to 2,4-bis(1-hydroxy-benzyl)pyr- sult as in the reduction of 2.
role by lithium aluminum hydride,[12] attempts to further
reduce the 4-acyl substituent of 3 failed even when a large
excess of sodium borohydride or lithium aluminum hydride
was used. A similar observation has been reported[7] for the
reduction of 3-acetylpyrrole by sodium borohydride, which
was unsuccessful even in refluxing dioxane and 2-propanol.
On the other hand, reduction of tetraacyldipyrromethane
2, by sodium borohydride, showed no regioselectivity. A
mixture of products identified by mass spectroscopy, as the
mono-, di-, tri- and tetra-carbinols were observed but
proved to be inseparable by chromatography.
Scheme 3.
Scheme 2.
It is well known that the N-phenylsulfonyl group has a
dramatic influence on electrophilic reactions of pyrrole by
“sequestering” the nitrogen lone pair resulting in reactions
at the β (3)-position for acylation[10,13] and sulfonation.[14]
In order to further investigate the reduction of 2,4-diacyl-
pyrroles, diacylpyrrole 1 was treated with phenylsulfonyl
chloride in the presence of a catalytic amount of 4-(dimeth-
ylamino)pyridine,[15] and 2,4-diisobutyryl-1-(phenylsulfon-
yl)pyrrole (4) was obtained in quantitative yield. Dramati-
cally, the N-phenylsulfonyl group preferentially displays di-
recting ability to the 4-position in the reduction of 2,4-di-
acylpyrrole 4. When sodium borohydride was added to a
solution of diacylpyrrole 4 in methanol at room tempera-
ture, 4-(1-hydroxyisobutyl)-2-isobutyryl-1-(phenylsulfonyl)-
pyrrole (5) was obtained as the major product (Scheme 3).
In the H NMR and H-H NOSY spectra of carbinol 5, a
Scheme 4.
1
doublet signal for CHCH(OH) appears at δ = 4.43 ppm
Dehydrations of carbinols at both the 2- and 3-positions
with integration for one proton and shows interactions with are generally carried out in the presence of catalytic
two aromatic proton signals. The fully reduced compound amounts of p-toluenesulfonic acid[6,16] or at high tempera-
2,4-bis(1-hydroxyisobutyl)-1-(phenylsulfonyl)pyrrole
(6) tures.[3,7] Since neither of these conditions are suitable for
was also formed in low yield, resulting from the further the carbinols described here we choose to use basic condi-
reduction of 5 since 2-(1-hydroxyisobutyl)-4-isobutyryl-1- tions[4] for all dehydrations. Upon refluxing the mixture of
(phenylsulfonyl)pyrrole was not observed. Excess sodium carbinol 5 and basic aluminum oxide in benzene with a
borohydride does reduce both 4 and 5 to the dicarbinol 6. Dean–Stark trap, 5 was cleanly converted to 4-isobutenyl-
Dicarbinol 6 was separated on a silica gel column as two 2-isobutyryl-1-(phenylsulfonyl)pyrrole (9) (Scheme 5). Fur-
pairs of racemic stereoisomers 6a and 6b in equal yields. ther reduction of acylpyrrole 9, with sodium borohydride,
They have the same 1H NMR spectra showing two doublet gave 2-(1-hydroxyisobutyl)-4-isobutenyl-1-(phenylsulfonyl)-
signals for two CHCH(OH) protons at δ = 4.5 and 4.3 ppm. pyrrole (10). Dehydration of both 6 and 10 with basic alu-
Surprisingly, tetraacyldipyrromethane 2 did not react with minum oxide in refluxing benzene provided 2,4-diisobu-
1
phenylsulfonyl chloride. When di-tert-butyl dicarbonate was tenyl-1-(phenylsulfonyl)pyrrole (11). In the H NMR spec-
Eur. J. Org. Chem. 2009, 3562–3566
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3563

Y. Li, D. Dolphin
FULL PAPER
Scheme 5.
trum of divinylpyrrole 11, the doublet signals for displayed directing ability to the 4-position for the mono-
CHCH(OH) disappear and two singlet signals for two reduction of 2,4-diisobutyryl-1-(phenylsulfonyl)pyrrole;
HC=CMe2 protons appear at δ = 6.05 and 5.94 ppm.
complete regioselectivity was achieved since a 2-carbinol
Hydrolysis of the N-(phenylsulfonyl)-1H-pyrroles readily was formed directly from the reduction of 2,4-diisobutyryl-
gave the corresponding N-free pyrroles using previously re- pyrrole and a 4-carbinol from 2,4-diisobutyryl-1-(phenyl-
ported[10] basic conditions. Stirred with 6  sodium hydrox- sulfonyl)pyrrole; The 2,4-diisobutenyl-1-(phenylsulfonyl)-
ide, at room temperature, carbinol 5 was converted into 4- pyrrole reported here is the first example of a C-divinylpyr-
(1-hydroxyisobutyl)-2-isobutyryl-pyrrole (12) (Scheme 6). role synthesized by reduction of diacylpyrrole followed by
Carbinols 3 and 12, as constitutional isomers, have similar dehydration. Further investigation on regioselective re-
1
characteristics in their H NMR spectra and can be easily ductions of additional 2,4-diacylpyrroles and syntheses of
identified by H-H NOSY. The formations of carbinols 3 N-free stable pyrroles bearing unfunctionalized 2,4-divinyl
and 12 provide two paths to the mono-reduction of 2,4- substituents are underway.
diacylpyrroles with complete regioselectivity. Similarly,
vinylpyrrole 9 was hydrolyzed to give 4-isobutenyl-2-iso-
butyryl-pyrrole (13). Regrettably, attempts to hydrolyze di-
vinylpyrrole 11 and vinylpyrrole 10 failed as the solutions
rapidly decomposed during work-up.
Experimental Section
General: 1H and 13C NMR spectra were recorded in CDCl3 with a
Bruker AVANCE-400INV spectrometer; the chemical shifts (δ,
ppm) are quoted relative to tetramethylsilane (TMS). Low and
high-resolution EI mass spectra were measured with a Kratos
MS50 spectrometer. All reactions were performed under an argon
atmosphere. Dichloromethane was pre-dried with calcium hydride
and distilled prior to use. Methanol and anhydrous tetrahydrofuran
were used as received. Column chromatography was performed
using 230–400 mesh silica gel.
2,4-Diisobutyryl-1H-pyrrole (1): Under conditions similar to the lit-
erature,[10] to a mixture of pyrrole (5.90 mL, 0.084 mol) and anhy-
drous aluminum chloride (13.47 g, 0.101 mol) in dichloromethane
(1000 mL) was added isobutyryl chloride (9.98 mL, 0.094 mol)
dropwise at room temperature. The mixture was stirred for 30 min
to form a clear solution and then another portion of isobutyryl
chloride (9.98 mL, 0.094 mol) and anhydrous aluminum chloride
(13.47 g, 0.101 mol) was added. Followed by stirring at room tem-
Scheme 6.
perature for a further 30 min, the resulting solution was refluxed
for 24 h. After cooling, ice and saturated aqueous sodium hydrogen
carbonate were carefully added. The organic phase was separated
and the aqueous phase was extracted with dichloromethane
(3ϫ300 mL). The combined organic phases were dried with anhy-
drous sodium sulfate and evaporated under reduced pressure. The
residue was chromatographed on silica gel eluting with the mixture
of ethyl acetate and hexane (1:1) to provide the desired product
(11.02 g); yield 63%. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 9.71
(br., 1 H, NH), 7.61–7.59 [q, J = 3.24, 1.38 Hz, 1 H, CCHN (pyr-
Conclusions
A series of reactions, starting from 2,4-diacylpyrroles, in-
cluding reduction, dehydration, N-protection and N-depro-
tection, have been explored and 13 new stable derivatives
are reported in this work. The N-phenylsulfonyl group, a
3-directing group for acylation and sulfonation of pyrrole, role)], 7.33–7.32 [q, J = 2.41, 1.47 Hz, 1 H, CCHC (pyrrole)], 3.35–
3564 Eur. J. Org. Chem. 2009, 3562–3566
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Regioselective Reduction of 2,4-Diacylpyrroles
3.26 (m, 1 H, CHMe2), 3.26–3.16 (m, 1 H, CHMe2), 1.22 (d, J =
6.85 Hz, 6 H, 2 CH3), 1.21 (d, J = 6.84 Hz, 6 H, 2 CH3) ppm. EI
MS: m/z (%) = 207 (12) [M]+, 164 (100), 94 (35). HR-EI MS: m/z
calcd. for C12H17NO2: 207.1259; found 207.1262.
(phenyl)], 7.70 [d, J = 1.77 Hz, 1 H, CCHN (pyrrole)], 7.59 [d, J =
7.09 Hz, 1 H, p-HC (phenyl)], 7.52 [t, J = 7.39 Hz, 2 H, 2 m-HC
(phenyl)], 6.98 [d, J = 1.76 Hz, 1 H, CCHC (pyrrole)], 4.43 (d, J =
6.19 Hz, 1 H, CHOH), 3.18–3.09 (m, 1 H, CHC=O), 1.98–1.89 (m,
1 H, CHCHMe2), 1.67 (br., 1 H, OH), 1.08 (d, J = 6.84 Hz, 3 H,
CH3), 1.06 (d, J = 6.85 Hz, 3 H, CH3), 0.99 (d, J = 6.71 Hz, 3 H,
CH3), 0.90 (d, J = 6.78 Hz, 3 H, CH3) ppm. EI MS: m/z (%) = 349
(18) [M]+, 306 (100), 141 (16). HR-EI MS: m/z calcd. for
C18H23NO4S: 349.1348; found 349.1342.
Bis(2,4-diisobutyryl-1H-pyrrol-5-yl)methane (2): To a solution of di-
methoxymethane (1.61 mL, 0.013 mol) in dichloromethane
(200 mL) was added boron trifluoride–diethyl ether (18.09 mL,
0.144 mol) at room temperature. The solution was stirred for
10 min and then diacylpyrrole 1 (5.00 g, 0.024 mol) was added and
stirring continued for a further 48 h; the resulting mixture was
poured onto ice-water. The work-up process was similar to that in
the procedure for 1. The evaporated residue was chromatographed
on silica gel eluting with the mixture of ethyl acetate and hexane
(1:5) to provide the desired product (1.126 g), followed by the unre-
acted diacylpyrrole 1 (3.70 g); yield 22%. 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 10.57 (br., 2 H, 2 NH), 7.11 [d, J = 2.50 Hz, 2
H, 2 CCHC (pyrrole)], 4.52 (s, 2 H, CCH2C), 3.26–3.16 (m, 4 H,
4 CHMe2), 1.18 (s, 6 H, 2 CH3), 1.16 (s, 12 H, 4 CH3), 1.14 (s, 6
H, 2 CH3) ppm. EI MS: m/z (%) = 426 (64) [M]+, 356 (54), 313
(100), 227 (40). HR-EI MS: m/z calcd. for C25H34N2O4: 426.2519;
found 426.2522.
2,4-Bis(1-hydroxyisobutyl)-1-(phenylsulfonyl)-1H-pyrrole (6): 6a and
6b were obtained in 28% yield (0.098 g) during the procedure to
prepare carbinol 5 or prepared in 79% yield, using the same pro-
cedure and a 1:8 molar ratio of diacylpyrrole 4 and sodium borohy-
dride.
1
6a: H NMR (300 MHz, CDCl3, 25 °C): δ = 7.77 [d, J = 7.32 Hz,
2 H, 2 o-HC (phenyl)], 7.59 [t, J = 4.81 Hz, 1 H, p-HC (phenyl)],
7.49 [t, J = 7.54 Hz, 2 H, 2 m-HC (phenyl)], 7.19 [d, J = 1.12 Hz,
1 H, CCHN (pyrrole)], 6.24 [d, J = 1.62 Hz, 1 H, CCHC (pyrrole)],
4.51 (d, J = 8.09 Hz, 1 H, CHCHMe2), 4.31 (d, J = 6.25 Hz, 1 H,
CHCHMe2), 2.39 (br., 1 H, OH), 2.09–1.99 (m, 1 H, CHCHMe2),
1.90–1.81 (m, 1 H, CHCHMe2), 1.79 (br., 1 H, OH), 0.99 (d, J =
6.59 Hz, 3 H, CH3), 0.91 (d, J = 6.70 Hz, 3 H, CH3), 0.80 (d, J =
6.78 Hz, 3 H, CH3), 0.67 (d, J = 6.70 Hz, 3 H, CH3) ppm. EI MS:
m/z (%) = 351 (6) [M]+, 308 (100), 141 (8). HR-EI MS: m/z calcd.
for C18H25NO4S: 351.1504; found 351.1507.
1H-2-(1-Hydroxyisobutyl)-4-isobutyryl)-1H-pyrrole (3): To a solu-
tion of diacylpyrrole 1 (3.31 g, 0.016 mol) in methanol (100 mL)
was added sodium borohydride (1.21 g, 0.032 mol) in small por-
tions over 3 h at room temperature. The reaction was monitored
by TLC with a developing solution of ethyl acetate and hexane
(1:1). After diacylpyrrole 1 disappeared, the reaction mixture was
evaporated to dryness and treated with 100 mL of water. The work-
up process was similar to that in the procedure for 1. The evapo-
rated residue was chromatographed on silica gel eluting with a mix-
ture of ethyl acetate and hexane (1:1) to provide the desired product
1
6b: H NMR (300 MHz, CDCl3, 25 °C): δ = 7.77 [d, J = 7.19 Hz,
2 H, 2 o-HC (phenyl)], 7.59 [t, J = 6.81 Hz, 1 H, p-HC (phenyl)],
7.48 [t, J = 7.54 Hz, 2 H, 2 m-HC (phenyl)], 7.18 [d, J = 1.31 Hz,
1 H, CCHN (pyrrole)], 6.25 [d, J = 1.66 Hz, 1 H, CCHC(pyrrole)],
4.52 (d, J = 8.07 Hz, 1 H, CHCHMe2), 4.31 (d, J = 6.22 Hz, 1 H,
CHCHMe2), 2.20 (br., 1 H, OH), 2.09–1.98 (m, 1 H, CHCHMe2),
1.92–1.81 (m, 1 H, CHCHMe2), 1.80 (br., 1 H, OH), 0.99 (d, J =
6.59 Hz, 3 H, CH3), 0.90 (d, J = 6.71 Hz, 3 H, CH3), 0.80 (d, J =
6.79 Hz, 3 H, CH3), 0.67 (d, J = 6.70 Hz, 3 H, CH3) ppm.
1
(3.30 g); yield 98%. H NMR (300 MHz, CDCl3, 25 °C): δ = 8.76
(br., 1 H, NH), 7.36 [s, 1 H, CCHN (pyrrole)], 6.44 [s, 1 H, CCHC
(pyrrole)], 4.49 (d, J = 6.05 Hz, 1 H, CHOH), 3.23–3.14 (m, 1 H,
CHC=O), 2.04–1.95 (m, 1 H, CHCHMe2), 1.63 (br., 1 H, OH),
1.18 (d, J = 6.81 Hz, 6 H, 2 CH3), 0.98 (d, J = 6.70 Hz, 3 H, CH3),
0.89 (d, J = 6.78 Hz, 3 H, CH3) ppm. EI MS: m/z (%) = 209 (54)
[M]+, 166 (100). HR-EI MS: m/z calcd. for C12H19NO2: 209.1416;
found 209.1419.
Bis(1-tert-butoxycarbonyl-2,4-diisobutyryl-1H-pyrrol-5-yl)methane
(7): To a solution of tetraacyldipyrromethane 2 (0.253 g,
0.593 mmol) in dichloromethane (20 mL) were added di-tert-butyl
dicarbonate (0.284 g, 1.305 mmol) and 4-(dimethylamino)pyridine
(0.014 g, 0.118 mmol). The mixture was stirred overnight and then
evaporated under reduced pressure. The residue was chromato-
graphed on silica gel eluting with a mixture of ethyl acetate and
hexane (1:4). Unreacted tetraacyldipyrromethane 2 was recovered
first and then product 7 was obtained in 36% yield (0.134 g). 1H
NMR (300 MHz, CDCl3, 25 °C): δ = 7.01 [s, 2 H, CCHC (pyr-
role)], 5.17 (s, 2 H, CCH2C), 3.32–3.04 (m, 4 H, 4 CHMe2), 1.44
[s, 18 H, 2 (CH3)3C], 1.15 [d, J = 6.90 Hz, 12 H, 2 (CH3)2CH], 1.08
[d, J = 6.71 Hz, 12 H, 2 (CH3)2CH] ppm. ESI MS: m/z (%) =
649 (100) [M]+. HR-ESI MS: m/z calcd. for C35H50N2O8 + Na+:
649.3465; found 649.3455.
2,4-Diisobutyry-1-(phenylsulfonyl)-1H-pyrrole (4): To a solution of
diacylpyrrole 1 (4.00 g, 0.019 mol) in dichloromethane (80 mL)
were added triethylamine (6.00 mL), 4-(dimethylamino)pyridine
(0.240 g, 0.002 mol) and phenylsulfonyl chloride (2.68 mL,
0.021 mol). The mixture was stirred overnight and monitored by
TLC with a developing solution of ethyl acetate and hexane (1:2).
After 1 disappeared, the reaction mixture was evaporated to dry-
ness under reduced pressure and the residue was chromatographed
on silica gel eluting with the mixture of ethyl acetate and hexane
1
(1:2) to provide the desired product (6.60 g); yield 99%. H NMR
(300 MHz, CDCl3, 25 °C): δ = 8.32 [d, J = 1.77 Hz, 1 H, CCHN
(pyrrole)], 8.05–8.02 [q, J = 7.36, 1.48 Hz, 2 H, 2 o-HC (phenyl)],
7.64 [d, J = 7.34 Hz, 1 H, p-HC (phenyl)], 7.56 [t, J = 7.53 Hz, 2
H, 2 m-HC (phenyl)], 7.38 [d, J = 1.76 Hz, 1 H, CCHC (pyrrole)],
3.29–3.13 (m, 2 H, 2 CHMe2), 1.24 (d, J = 6.84 Hz, 6 H, 2 CH3),
1.09 (d, J = 6.86 Hz, 6 H, 2 CH3) ppm. EI MS: m/z (%) = 347 (44)
[M]+, 304 (100), 141 (28). HR-EI MS: m/z calcd. for C18H21NO4S:
347.1191; found 347.1189.
(1-tert-Butoxycarbonyl-2,4-diisobutyryl-1H-pyrrol-5-yl)(2,4-diisobut-
yryl-1H-pyrrol-5-yl)methane (8): Obtained in 43% yield (0.132 g)
1
during the procedure to prepare tetraacyldipyrromethane 7. H
NMR (300 MHz, CDCl3, 25 °C): δ = 9.63 (br., 1 H, NH), 7.18 [s,
1 H, CCHC (pyrrole)], 7.16 [s, 1 H, CCHC (pyrrole)], 4.77 (s, 2 H,
CCH2C), 3.32–3.06 (m, 4 H, 4 CHMe2), 1.46 [s, 9 H, (CH3)3C],
1.23–1.15 [m, 24 H, 4 (CH3)2CH] ppm. EI MS: m/z (%) = 526 (2)
[M]+, 426 (58), 383 (23), 356 (53), 313 (100). HR-EI MS: m/z calcd.
for C30H42N2O6: 526.3043; found 526.3064.
4-(1-Hydroxyisobutyl)-2-isobutyryl-1-(phenylsulfonyl)-1H-pyrrole
(5): Prepared using the same procedure as for 3, using diacylpyrrole
4 (0.347 g, 0.001 mol), sodium borohydride (0.151 g, 0.004 mol)
4-Isobutenyl-2-isobutyryl-1-(phenylsulfonyl)-1H-pyrrole (9): A mix-
ture of carbinol 5 (1.53 g, 4.384 mmol) and basic aluminum oxide
(4.40 g) in benzene (100 mL) was refluxed for 2 h using a Dean–
1
and methanol (20 mL); yield 63% (0.220 g). H NMR (300 MHz,
CDCl3, 25 °C): δ = 8.00–7.97 [q, J = 7.20, 1.28 Hz, 2 H, 2 o-HC
Eur. J. Org. Chem. 2009, 3562–3566
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Y. Li, D. Dolphin
FULL PAPER
Stark trap protected with anhydrous calcium chloride. After cool-
ing, the mixture was evaporated to dryness under reduced pressure
and the aluminum oxide residue was poured onto the top of a silica
gel column. Elution with a mixture of ethyl acetate and hexane
(1:4) gave the desired product in 82 % yield (1.19 g). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 7.99 [d, J = 7.16 Hz, 2 H, 2 o-HC
(phenyl)], 7.66 [s, 1 H, CCHN (pyrrole)], 7.58 [d, J = 7.11 Hz, 1 H,
p-HC (phenyl)], 7.52 [t, J = 7.37 Hz, 2 H, 2 m-HC (phenyl)], 6.95
[d, J = 1.55 Hz, 1 H, CCHC (pyrrole)], 5.98 (s, 1 H, CH=CMe2),
3.18–3.09 (m, 1 H, CHMe2), 1.90 [s, 6 H, (CH3)2C=C], 1.08 [d, J
= 6.86 Hz, 6 H, (CH3)2CH] ppm. EI MS: m/z (%) = 331 (55) [M]
+, 288 (100). HR-EI MS: m/z calcd. for C18H21NO3S: 331.1242;
found 331.1246.
m/z (%) = 209 (19) [M]+, 166 (100). HR-EI MS: m/z calcd. for
C12H19NO2: 209.1416; found 209.1416.
1H-4-Isobutenyl-2-isobutyryl)-1H-pyrrole (13): Prepared using the
same procedure as for 12, using 4-vinylpyrrole
9 (30.0 mg,
0.090 mmol), dioxane (6 mL) and 6  sodium hydroxide (1.5 mL);
yield 89% (15.3 mg). 1H NMR (300 MHz, CDCl3, 25 °C): δ = 9.27
(s, 1 H, NH), 6.97 [s, 1 H, CCHN (pyrrole)], 6.87 [s, 1 H, CCHC
(pyrrole)], 6.07 (s, 1 H, CH=CMe2), 3.31–3.24 (m, 1 H, CHC=O),
1.90 [d, J = 6.10 Hz, 6 H, (CH3)2C=C], 1.22 [d, J = 6.86 Hz, 6 H,
(CH3)2CH] ppm. EI MS: m/z (%) = 191 (49) [M]+, 147 (100). HR-
EI MS: m/z calcd. for C12H17NO: 191.1310; found 191.1305.
Acknowledgments
2-(1-Hydroxyisobutyl)-4-isobutenyl-1-(phenylsulfonyl)-1H-pyrrole
(10): Prepared using the same procedure as for 3, using acylpyrrole
9 (1.19 g, 3.595 mmol), sodium borohydride (0.544 g, 0.014 mol)
This work is supported by QLT Inc., Vancouver, BC, and the Natu-
ral Sciences and Engineering Research Council (NSERC) of
Canada. We thank the NMR and mass spectroscopy labs of the
Chemistry Department at the University of British Columbia.
1
and methanol (50 mL); yield 73% (0.873 g). H NMR (300 MHz,
CDCl3, 25 °C): δ = 7.75 [d, J = 7.22 Hz, 2 H, 2 o-HC (phenyl)],
7.50 [d, J = 7.10 Hz, 1 H, p-HC (phenyl)], 7.41 [t, J = 7.35 Hz, 2
H, 2 m-HC (phenyl)], 7.14 [s, 1 H, CCHN (pyrrole)], 6.26 [s, 1 H,
CCHC (pyrrole)], 5.90 (s, 1 H, CH=CMe2), 4.55 (d, J = 7.79 Hz,
1 H, CHOH), 2.60 (br., 1 H, OH), 2.06–1.96 (m, 1 H, CHMe2),
1.81 [s, 6 H, (CH3)2C=C], 0.97 (d, J = 6.50 Hz, 3 H, CH3CH), 0.67
(d, J = 6.60 Hz, 3 H, CH3CH) ppm. EI MS: m/z (%) = 333 (23)
[M]+, 290 (100), 148 (40). HR-EI MS: m/z calcd. for C18H23NO3S:
333.1399; found 333.1389.
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2,4-Diisobutenyl-1-(phenylsulfonyl)-1H-pyrrole (11): Prepared using
the same procedure as for 9, using dicarbinol
6 (1.30 g,
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1
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yield 67% (0.781 g). H NMR (300 MHz, CDCl3, 25 °C): δ = 7.73
[d, J = 7.79 Hz, 2 H, 2 o-HC (phenyl)], 7.54 [t, J = 7.37 Hz, 1 H,
p-HC (phenyl)], 7.43 [t, J = 7.75 Hz, 2 H, 2 m-HC (phenyl)], 7.18
[s, 1 H, CCHN (pyrrole)], 6.33 [s, 1 H, CCHC (pyrrole)], 6.05 (s, 1
H, HC=CMe2), 5.94 (s, 1 H, HC=CMe2), 1.86 [s, 6 H, (CH3)2C],
1.85 (s, 3 H, CH3C), 1.52 (s, 3 H, CH3C) ppm. EI MS: m/z (%) =
315 (100) [M]+, 174 (69). HR-EI MS: m/z calcd. for C18H21NO2S:
315.1293; found 315.1301.
1H-4-(1-Hydroxyisobutyl)-2-isobutyryl)-1H-pyrrole (12): Using
similar conditions to those reported in the literature,[10] to a solu-
tion of carbinol 5 (20.1 mg, 0.057 mmol) in dioxane (4 mL) was
added 6  sodium hydroxide (1 mL). The resulting mixture was
stirred for 30 h at room temperature and then poured into water
(20 mL). The aqueous solution was extracted with chloroform
(3ϫ20 mL). The combined organic phase was dried with anhy-
drous sodium sulfate and evaporated under reduced pressure. The
residue was chromatographed on silica gel eluting with a mixture
of ethyl acetate and hexane (1:3) to provide the desired product
(11.3 mg); yield 94%. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 9.61
(br., 1 H, NH), 6.94 [t, J = 1.36 Hz, 1 H, CCHN (pyrrole)], 6.86
[s, 1 H, CCHC (pyrrole)], 4.38 (d, J = 6.57 Hz, 1 H, CHOH), 3.30–
3.21 (m, 1 H, CHC=O), 2.00–1.91 (m, 1 H, CHCHMe2), 1.70 (br.,
1 H, OH), 1.18 [d, J = 6.85 Hz, 6 H, (CH3)2C], 0.98 (d, J = 6.53 Hz,
3 H, CH3CH), 0.85 (d, J = 6.76 Hz, 3 H, CH3CH) ppm. EI MS:
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7907–7915.
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2268.
Received: March 26, 2009
Published Online: June 16, 2009
3566
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Eur. J. Org. Chem. 2009, 3562–3566