Chemoselective reduction of 2-acyl-N-sulfonylpyrroles: Synthesis of 3-pyrrolines and 2-alkylpyrroles

Article abstract of DOI:10.1039/c1ob05111c

The partial reduction of pyrroles is not a common practice even though it offers a potential route to pyrroline building blocks, commonly used for synthesis. We have investigated the reduction of 2-acyl-N-sulfonylpyrroles and by varying the hydride source

Full text of DOI:10.1039/c1ob05111c

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2011, 9, 3948
www.rsc.org/obc
PAPER
Chemoselective reduction of 2-acyl-N-sulfonylpyrroles: Synthesis of
3-pyrrolines and 2-alkylpyrroles†
Hai Tao You, Andrew C. Grosse, James K. Howard, Christopher J. T. Hyland, Jeremy Just, Peter P. Molesworth
and Jason A. Smith*
Received 20th January 2011, Accepted 4th March 2011
DOI: 10.1039/c1ob05111c
The partial reduction of pyrroles is not a common practice even though it offers a potential route to
pyrroline building blocks, commonly used for synthesis. We have investigated the reduction of
2-acyl-N-sulfonylpyrroles and by varying the hydride source and solvent, achieved a chemoselective
reduction, leading to 3-pyrrolines and alkyl pyrroles in high yield.
The dearomatisation of aromatic and heteroaromatic rings is
an important source of functional building blocks for synthetic
chemistry.1,2 While most of these derivatives can be reduced by clas-
sical conditions such as the Birch reaction, pyrroles are typically
inert due to the high electron density of this heterocyclic system.
Recently Donohoe has demonstrated that reducing the electron
density by the addition of at least two electron withdrawing groups,
pyrrolic derivatives can be dearomatised to give the corresponding
3-pyrroline derivatives.3 This methodology has been exploited as
a key step in the synthesis of the polyhydroxylated pyrrolizidine
1-epiaustraline (3, Scheme 1).4
(Scheme 2).6 While the reaction is rapid and high yielding, the
harsh conditions required, zinc powder in refluxing methanol with
conc. hydrochloric acid, means that this method is incompatible
with many functional groups and thus milder reaction conditions
would be desirable.
Scheme 2 Reduction of 2-acylpyrroles to pyrrolines; (i) Zn, HCl (conc),
EtOH, reflux.
A potential alternative to these methods was reported by
Ketcha, who demonstrated that the less electron rich N-
phenylsulfonylpyrroles possessing alkyl or acyl groups at C-2 or
C-3 could be reduced to the corresponding 3-pyrrolines by the
action of sodium cyanoborohydride in trifluoroacetic acid (TFA)
(Scheme 3).7 Since this report there has been no application
of this methodology possibly due to the reported potential for
minor explosions during the addition. Herein we report our
investigation into the reduction of N-sulfonylpyrroles and the
potential application of this methodology to the synthesis of
pyrrolidine alkaloids.
Scheme 1 Synthesis of ( )-1-epiaustraline from a 3-pyrroline building
block.
It was demonstrated over a century ago by Knorr and Rabe
that the electron rich pyrroles can be reduced to 3-pyrrolines
by the action of zinc powder in 5 M hydrochloric acid.5 The
mechanism is assumed to proceed by protonation of pyrrole at C-
2 to form an iminium species which is then reduced. Recently we
reported an adaption of this method for the reduction of bicyclic
2-acylpyrroles (4) for the synthesis of indolizidine derivatives
Scheme 3 Reagents and conditions: (i) NaBH3CN, TFA, rt.
The initial focus was to investigate the reaction conditions
reported by Ketcha for the reduction of N-tosylpyrrole to identify
modifications that could be made to reduce the large excess of
sodium cyanoborohydride as well as the volume of trifluoroacetic
acid used as the solvent. The use of a co-solvent such as ethanol
or acetic acid had a dramatic effect in that no reaction occurred at
School of Chemistry, University of Tasmania, Hobart, Australia.
E-mail: Jason.Smith@utas.edu.au; Fax: 613 6226 2858; Tel: 613 6226 2182
† Electronic Supplementary Information (ESI) available. See http://
dx.doi.org/10.1039/b000000x/
3948 | Org. Biomol. Chem., 2011, 9, 3948–3953
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
all and neither could sodium cyanoborohydride be replaced with
sodium borohydride. However, we did find that for the simple N-
tosyl and N-methanesulfonylpyrroles the volume of trifluoroacetic
acid reported7 could be reduced by one third and only three
equivalents of reducing agent were required (Scheme 4).
cyanoborohydride to give 12 in 91%. Therefore the reduction of
acyl pyrroles to alkyl derivatives can now be carried out in a
practical one-pot procedure.
When the hydride source was changed to sodium borohyride
no reaction of the alcohol 11 was observed, however, changing
the acid to trifluoroacetic acid had a dramatic effect, forming the
3-pyrroline 10 in good yield (Scheme 5). This reaction was the first
example of the formation of a 3-pyrroline with a hydride source
other than sodium cyanoborohydride. This reaction represents
an effective alternative protocol to that reported by Ketcha7 and
by choice of solvent and hydride source, highly chemoselective
reductions of 2-acyl-N-sulfonylpyrroles can be achieved.
We chose to apply this methodology to the synthesis of the
pyrrolidine alkaloid anisomycin (13) as the benzyloxycarbonyl
protected 3-pyrroline 14 is the key intermediate in the majority
of syntheses (Scheme 6).10
Scheme 4 Reagents and conditions: (i) NaBH3CN, TFA, rt.
These conditions were also effective for the reduction of 2-acyl
derivatives such as 9 and it was found that dichloromethane could
be used as a co-solvent for these substrates giving the correspond-
ing 3-pyrroline 10 (R = n-propyl) in an 81% isolated yield (Scheme
5). However, there was no reaction when acetic acid was used
as the proton source. The synthesis of 2-acyl pyrrole derivatives
can be readily achieved by the reaction of the N-sulfonylpyrroles
with the appropriate carboxylic acid and trifluoroacetic anhydride
(TFAA).8 As for the reduction of the unsubstituted derivative
7a, the combination of sodium cyanoborohydride in acetic acid
gave no reaction and we hypothesised that the initial reduction
of the carbonyl to the alcohol was the limiting step. Protonation
of the carbonyl is most likely required for reduction with sodium
cyanoborohydride which is hindered due to the decreased electron
donation from the N-sulfonylpyrrole. An IR spectrum indicates
the carbonyl has vinylogous amide character with the carbonyl
showing a stretch at 1670 cm-1 instead of a more typical aromatic
ketone of 1690 cm-1. Hence a stronger acid source is required
for the initial reduction to occur. Therefore, we hypothesised
that initial reduction to an a-hydroxy derivative might be more
effective. Therefore 9 was reacted with sodium borohydride in
ethanol to give the stable a-hydroxy derivative 11 in quantitative
yield. When 11 was subjected to sodium cyanoborohydride in
acetic acid/dichloromethane the corresponding 2-alkyl pyrrole 12
was formed in 90% yield. This indicated that the reduction of the
carbonyl group is in fact the rate limiting step in these reactions.
While the reduction of keto groups attached to pyrroles to the
corresponding alkanes is well known,9 this method constitutes a
practical two step sequence. In fact, we also found that the reaction
can be carried out in the one flask by removal of the solvent
after borohydride reaction and addition of acetic acid/sodium
Scheme 6 Key intermediate (14) in the synthesis of anisomycin.
The reaction of N-tosylpyrrole 7a with anisic acid in the
presence of trifluoroacetic anhydride provided the carbon skeleton
15 in one step, but reduction of 15 to the 3-pyrroline 17 under
the standard conditions resulted in no reaction (Scheme 7). The
carbonyl in this instance is also conjugated to the aromatic ring
which hinders the first reduction step. Therefore, the ketone was
reduced to the alcohol 16 with sodium borohydride and then this
was subjected to the reduction conditions to give the desired 3-
pyrroline 17 as a 2 : 1 mixture with the fully reduced pyrrolidine
in a combined 88% yield over two steps. While this intermediate
could be converted directly to anisomycin11 we decide to confirm
the structure by conversion to the common intermediate 14.
Typically N-tosylamines are difficult to deprotect but reaction
with magnesium metal in methanol under sonication12 gave the
crude amine that was transformed to the protected 3-pyrroline
14 in 74% yield, therefore completing a relatively short formal
synthesis of the natural product.
Scheme 7 Reagents and conditions: (i) anisic acid, TFAA, CH2Cl2;
(ii) NaBH4, EtOH; (iii) NaBH3CN, TFA, CH2Cl2; (iv) Mg, CH3OH,
sonication; (v) CbzCl, toluene, 2 M NaOH.
Scheme 5 Reagents and conditions: (i) NaBH3CN, TFA, CH2Cl2; (ii)
NaBH4, EtOH; (iii) NaBH3CN, AcOH, CH2Cl2; (iv) NaBH4, TFA,
CH2Cl2.
To compare this result with our zinc reduction methodology6 we
prepared the 2-aroylpyrrole 19, by reaction of the magnesium salt
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 3948–3953 | 3949
©

View Article Online
of pyrrole with the corresponding acid chloride, and subjected
it to the standard conditions (Scheme 8). The initial reduction
showed numerous products as well as the desired pyrroline by
1H NMR, therefore the crude mixture was treated with benzyl
chloroformate to give the protected pyrroline 14 in a 45% yield
over two steps. Therefore the hydride reaction methodology is
the preferred synthetic route to intermediates of this type as the
reactions and products are much cleaner.
as the platform for the formal synthesis of the anti-biotic natural
product anisomycin and can have application in the synthesis of
cis-2,5-disubstituted pyrrolidines.
Experimental
1H and 13C NMR spectra were recorded at 300 MHz and 75 MHz
respectively on a Varian Mercury 2000 spectrometer. Spectra
were run in CDCl3 unless otherwise stated. Chemical shifts are
measured in ppm and referenced internally to residual CHCl3 for
1H NMR (d 7.26) and the central peak of CDCl3 for 13C NMR (d
77.04). Coupling constants, J are recorded in Hz.
Infrared spectra were recorded on a Shimadzu FTIR 8400 s
spectrometer as thins flims on NaCl plates unless otherwise stated.
Mass spectroscopy was performed on a Kratos Concept ISQ mass
instrument.
Scheme 8 Reagents and conditions: (i) EtMgBr, THF 0 ◦C, then anisic
chloride (ii) Zn, HCl (conc), EtOH, reflux; (iii) CbzCl, toluene, 2 M NaOH.
A Unisonics Australia FXP12D ultrasonic bath was used
for reactions involving sonication. Flash chromatography was
performed according to the method of Still and co-workers using
silica gel 60 (32–63 mm).15 Solvents and reagents were obtained
from Aldrich, AJAX or BDH chemicals and used as supplied
or purified by standard laboratory methods if required. N-
Sulfonylpyrroles 7a16 and 7b17 were prepared by literature methods.
We also investigated the synthesis of the toxin pyrrolidine
197, which comes from the poison arrow frogs Dendrobates
histrionicus,13 as a platform to investigate the viability and
stereochemical outcome of the reduction of 2,5-disubstituted-
N-sulfonylpyrroles (Scheme 9). Acylation of 2-butylpyrrole 12,
prepared earlier, with heptanoic acid gave the desired carbon
skeleton of the target compound 20 in 73% yield. Reduction of 20
with sodium cyanoborohydride in trifluroacetic acid occurs to give
the 3-pyrroline 21 and the saturated pyrrolidine in an ~ 2 : 1 ratio
by 1H NMR. The compounds could not be separated by coloumn
chromotography therefore, the crude product was subjected to
catalytic hydrogenation to yield the known N-tosylpyrrolidines 22
and 2314 as an ~ 9 : 1 mixture of diastereoisomers as identified
1-(p-Toluenesulfonyl)-2,5-dihydropyrrole (8a)
To a stirred solution of 7a (0.210 g, 0.95 mmol) in trifluoroacetic
acid (5 mL) at room temp was added sodium cyanoborohydride
(0.21 g, 3.0 mmol), slowly in small portions and the mixture stirred
for 1 h. The solvent was removed under reduced pressure before
solid Na2CO3 was added to neutralize residual acid, water (10 mL)
added and the mixture extracted with dichloromethane (3 ¥
10 mL). The combined organic layers were dried with anhydrous
MgSO4, filtered through silica gel and the solvent removed under
reduced pressure yielding the desired product 8a (0.20 g, 94%), as
a pale yellow oil that crystallised on standing. The spectroscopic
data was consistent with the literature.18 dH (300 MHz, CDCl3)
2.35 (3H, s), 4.03 (4H, s), 5.58 (2H, s), 7.24 (2H, d, J 8.1), 7.63
(2H, d, J 8.1).
1
by H and 13C NMR. The major isomer was found to the cis
derivative 22 as determined by comparison with the literature.13
It is not unexpected that the cis-diastereomer is favoured as
hydride is delivered preferentially from the least hindered face
away from the second substituent. This is in contrast to the zinc
reduction chemistry which normally yields the trans derivatives.5,6
Therefore the hydride methodology is complementary to the zinc
reduction chemistry as either diastereomer of 3-pyrrolines could
be synthesised from a common intermediate.
1-Methanesulfonyl-2,5-dihydropyrrole (8b)
The above method was used to reduce 7b yielding 8b (80% yield)
as a colourless oil that solidified on standing. The spectroscopic
data was consistent with the literature.19 dH (300 MHz, CDCl3)
2.80 (3H, s), 4.14 (4H, s), 5.78 (2H, s); dC (75 MHz, CDCl3) 34.3,
54.8, 125.6.
1-[1-(p-Toluenesulfonyl)pyrrol-2-yl]butan-1-one (9)
n-Butyric acid (0.5 mL, 7.2 mmol) was added to a solution of
N-tosylpyrrole 7a (0.798 g, 3.6 mmol) in trifluoroacetic anhydride
(5 mL) and dichloromethane (10 mL) and the resulting solution
stirred overnight at room temp. The volatiles were removed under
reduced pressure, water (10 mL) added and the mixture extracted
with dichloromethane (3 ¥ 10 mL). The combined organic layers
were washed with saturated sodium carbonate and saturated brine
solutions, dried and filtered through a plug of silica gel eluting with
ethylacetate/hexane (20 : 80) yielding the desired product 9 (1.05 g,
97%) as a yellow oil which crystallized on standing. The product
Scheme 9 Reagents and conditions: (i) Heptanoic acid, TFAA, CH2Cl2;
(ii) NaBH3CN, TFA, CH2Cl2; (iii) H2, Pd/C, EtOH.
Conclusions
In conclusion, we have demonstrated that 2-acyl-N-
sulfonylpyrroles are useful synthetic building blocks and
that their reduction can be controlled to generate alkylpyrroles
and 3-pyrrolines in good yield. The methodology has been used
3950 | Org. Biomol. Chem., 2011, 9, 3948–3953
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
was used without further purification. nmax/cm-1 (film) 3152, 2964,
2875, 1677, 1596, 1440, 1123, 1090, 1063, 669; (300 MHz, CDCl3)
0.86 (3H, t, J 7.5), 1.61 (2H, sextet, J 7.5), 2.38 (3H, s), 2.62 (2H,
t, J 7.5), 6.29 (1H, at, J 3.3), 7.00 (1H, m), 7.27(2H, d, J 8.2),
7.76 (1H, m), 7.86 (2H, d, J 8.2); dC (75 MHz, CDCl3) 13.8, 18.5,
21.8, 41.5, 110.4, 123.4, 128.4, 129.5, 130.2, 133.6, 136.2, 144.8,
189.2; m/z (EI) 291.09269 (M+ C15H17NO3S requires 291.09291),
291 (3%), 248 (65), 155 (75) 91 (100).
oil. nmax/cm-1 (film) 3153, 2957, 2862, 1366, 1189, 1175, 1155,
1091, 668; dH (300 MHz, CDCl3) 0.87 (3H, t, J 7.7), 1.34 (2H,
sext., J 7.7), 1.52 (2H, quint., J 7.7), 2.40 (3H, s), 2.65 (2H, t, J
7.7), 5.97 (1H, m), 6.19 (1H, at, J 3.6), 7.26 (3H, m), 7.62 (2H, d, J
8.1); dC (75 MHz, CDCl3) 14.0, 21.8, 22.5, 27.0, 30.9, 111.4, 111.9,
122.3, 126.9, 130.1, 136.2, 136.7, 144.9; m/z (EI) 277.11366 (M+
C15H19NO2S requires 277.11365) 277 (12%), 234 (25), 155 (50), 91
(100).
2-Butyl-1-(p-toluenesulfonyl)-2,5-dihydropyrrole (10)
1-(p-Toluenesulfonyl)-2-(p-methoxybenzoyl)pyrrole (15)
Sodium cyanoborohydride (88 mg, 1.40 mmol) was added slowly
in small portions to a solution of pyrrole 9 (0.135 g, 0.465 mmol)
in◦dichloromethane (6 mL) and trifluoroacetic acid (3 mL) at
0 C. The mixture was stirred for 1 h before another portion of
sodium cyanoborohydride (88 mg, 1.40 mmol) was added and the
reaction mixture stirred overnight at room temp. The volatiles were
removed under reduced pressure, water (10 mL) added and the pH
adjusted to ~8–9 by the addition of solid sodium carbonate. The
solution was extracted with dichloromethane (3 ¥ 10 mL), and the
extracts combined and dried with MgSO4, filtered and the solvent
removed under reduced pressure to afford the pyrroline 10 (0.105 g,
81%) as a pale yellow oil. nmax/cm-1 (film) 2956, 2929, 2860, 1725,
1461, 1346, 1288, 1163, 1091, 667; dH (300 MHz, CDCl3) 0.89 (3H,
t, J 6.9), 1.27–1.76 (6H, m), 2.41 (3H, s), 4.10 (2H, apparent d, J
3.6), 4.45 (1H, m), 5.58 (2H, bs), 7.28 (2H, d, J 8.4), 7.70 (2H, d,
J 8.4); dC (75 MHz, CDCl3) 14.3, 21.7, 22.9, 26.9, 36.1, 55.8, 67.6,
124.8, 127.6, 129.9, 130.1, 135.1, 143.5; m/z (EI) 279.12831 (M+
C15H21NO2S requires 279.12930), 279 (14%), 222 (30), 167 (41),
149 (100).
N-Tosylpyrrole 7a was reacted with anisic acid (1.5 equiv.) by the
method described for compound 9 to give the desired product 15
as a white solid (90%). nmax/cm-1 (film) 2954, 2923, 2853, 1742,
1461, 1377, 722; dH (300 MHz, CDCl3) 2.42 (3H, s), 3.84 (3H, s),
6.32 (1H, at, J 3.3), 6.66 (1H, m), 6.90 (2H, d, J 8.4 Hz), 7.34 (2H,
d, J 8.1), 7.71 (m, 1H), 7.82 (2H, d, J 8.7), 8.00 (2H, d, J 8.4).
(4-Methoxyphenyl)-[1-(p-toluenesulfonyl)pyrrol-2-yl]methanol (16)
Sodium borohydride (82 mg, 2.17 mmol) was added slowly to a
solution of pyrrole 15 (255 mg, 0.717 mmol) in ethanol (20 mL) at
0 ◦C. The reaction was warmed slowly to room temp and stirred
for 18 h. Further sodium borohydride (90 mg, 2.37 mmol) was
added and the reaction stirred for a further 18 h. The volatiles
were removed under reduced pressure and the residue taken up in
water (30 mL) and extracted with dichloromethane (3 ¥ 10 mL).
The organic extracts were washed with water (20 mL), dried
on magnesium sulphate, filtered and the solvent removed under
reduced pressure, yielding the title compound 16 (234 mg, 91%)
as an oil that solidified on standing. nmax/cm-1 (film) 3386, 2955,
2934, 1512, 1362, 1172; dH (300 MHz, CDCl3) 2.41 (3H, s), 3.15
(1H, d, J 4.6), 3.79 (3H, s), 5.82–5.86 (1H, m), 6.02 (1H, d, J 4.5),
6.18 (1H, at, J 3.3), 6.80 (2H, d, J 8.7), 7.16 (2H, d, J 8.7), 7.25
(2H, d, J 7.0), 7.30 (1H, dd, J = 3.3, 1.7), 7.59 (2H, d, J 8.3 Hz);
dC (75 MHz, CDCl3) 21.9, 55.5, 68.0, 111.7, 113.7, 115.5, 124.1,
126.9, 128.1, 130.2, 133.2, 136.3, 138.5, 139.9, 159.3; m/z (EI)
357.10289 (M+ C19H19NO4S requires 357.10348) 357 (15%), 201
(100), 170 (83), 155 (20), 135 (78), 91 (81).
1-[1-(p-Toluenesulfonyl)pyrrol-2-yl]butan-1-ol (11)
Sodium borohydride (1.17 g, 30.1 mmol) was added to a solution
of pyrrole 9 (2.96 g, 10.2 mmol) in ethanol (37 mL) and
dichloromethane (13 mL) at 0 ◦C and the mixture stirred for 2 h
at room temp. The volatiles were removed under reduced pressure,
water added (130 mL) and extracted with dichloromethane (3 ¥
50 mL). The extracts were combined dried on MgSO4 and filtered
and evaporated to afford the alcohol 11 (2.76 g, 93%) as colourless
oil. nmax/cm-1 (film) 3568, 3527, 2959, 2872, 1363, 1152, 1088, 1057,
672; dH (300 MHz, CDCl3) 0.85 (3H, t, J 7.2), 1.36 (2H, m), 1.73
(2H, m), 2.40 (3H, s), 2.78 (1H, br s), 4.82 (1H, dd, J 7.9 5.7),
6.24 (2H, m), 7.29 (3H, m), 7.67 (2H, d, J 8.7); dC (75 MHz,
CDCl3) 13.9, 19.5, 21.8, 37.3, 65.1, 111.8, 112.4, 123.6, 126.8,
130.3, 136.5, 138.5, 145.4; m/z (EI) 293.10856 (M+ C15H19NO3S
requires 293.10856), 293 (5%), 275 (10), 250 (100), 155 (75), 91
(50).
2-[(4-Methoxyphenyl)methyl]-1-(p-toluenesulfonyl)-2,5-
dihydropyrrole (17)
Using the method described above for the reduction of 10,
sodium cyanoborohydride (494 mg, 7.86 mmol) was reacted
with pyrrole 16 (234 mg, 0.654 mmol) in dichloromethane
(12 mL)/trifluoroacetic acid (12 mL). The product was purified by
column chromatography on silica gel (eluent: dichloromethane) to
yield the pyrroline 17 and the saturated pyrroline as an inseparable
2 : 1 mixture (218 mg, 97%) as a colourless solid. Compound
17 nmax/cm-1 (film) 2954, 1611, 1512, 1336, 1247, 1161, 665; dH
(300 MHz, CDCl3) 2.41 (3H, s), 2.90 (1H, dd, J 13.2 8.7), 3.07–
3.30 (1H, m), 3.78 (3H, s), 3.83–4.16 (2H, m), 4.55–4.65 (1H, m),
5.42–5.57 (2H, m), 6.80–6.86 (2H, m), 7.12–7.17 (2H, m), 7.25–
7.32 (2H, m), 7.71–7.78 (2H, m); dC (75 MHz, CDCl3) 21.8, 42.4,
55.4, 56.0, 68.8, 113.8, 114.0, 125.3, 127.7, 129.4, 130.0, 131.1,
134.9, 143.7, 158.4; m/z (EI) 343.12368 (M+ C19H21NO3S requires
343.12421), 343 (2%), 222 (100), 155 (95), 121 (40), 91 (97)
2-Butyl-1-(p-toluenesulfonyl)pyrrole (12)
Sodium cyanoborohydride (163 mg, 2.6 mmol) was added care-
fully to a solution of alcohol 11 (255 mg, 0.87 mmol) in
◦
dichloromethane (1.5 mL) and acetic acid (4.5 mL) at 0 C and
the mixture allowed to warm to room temp over 5 h. The volatiles
wer removed under reduced pressure, water (10 mL) added and the
pH adjusted to ~8–9 by the addition of solid sodium carbonate.
The solution was extracted with dichloromethane (3 ¥ 10 mL),
and the extracts combined and dried with MgSO4, filtered and
evaporated to afford the pyrrole 12 (216 mg, 90%) as a pale yellow
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 3948–3953 | 3951
©

View Article Online
Benzyl 2-[(4-methoxyphenyl)methyl]-2,5-dihydropyrrole-1-
carboxylate (14)
6.88–6.91 (1H, m), 6.95–7.00 (1H, m), 7.12–7.14 (2H, m), 7.91–
7.96 (2H, m), 10.05 (1H, bs); dC (75 MHz, CDCl3) 55.7, 111.1,
113.8, 119.0, 119.4, 125.1, 131.1, 131.4, 163.0, 184.0; m/z (EI)
201.07893 (M+ C12H11NO2 requires 201.07898) 201 (100%), 170
(23), 135 (46), 94 (33).
Method 1. Zinc dust (102 mg, 1.59 mmol) then concentrated
HCl (3 mL) were added in five portions to a hot solution of 19
(30.0 mg, 0.149 mmol) such that reflux was maintained. After the
reaction had ceased the mixture was cooled and the zinc salts
dissolved using concentrated ammonia, before extraction with
dichloromethane (3 ¥ 10 mL). The organic extracts were dried with
sodium sulphate, filtered and the solvent removed under reduced
pressure. Without further characterisation the crude pyrroline was
immediately dissolved in toluene (5 mL)/triethylamine (0.1 mL),
chilled to 0 ◦C and benzyl chloroformate (50 mL) added. After 3 h
the reaction mixture was washed with water, and the organic layer
dried and the solvent removed under reduced pressure. The title
compound was purified by column chromatography on silica gel
(eluent ethyl acetate/hexanes, 1 : 4), to give carbamate 14 (20 mg,
42%) as a colourless oil. The spectral properties were consistent
with that previously reported.10
1-[5-Butyl-1-(p-toluenesulfonyl)pyrrol-2-yl]heptan-1-one (20)
n-Heptanoic acid (0.240 mL, 1.67 mmol) was added to a solution
of pyrrole 12 (0.232 g, 0.84 mmol) in dichloromethane (5 mL)
and trifluoroacetic anhydride (0.48 mL). The resulting mixture
was treated as described for 9, yielding the title compound
(quantitative) as a colourless oil. nmax/cm-1 (film) 2925, 1704, 1669,
1368, 1173, 1091, 1042; dH (300 MHz, CDCl3) 0.88 (6H, m), 1.23–
1.68 (12H, m), 2.42 (3H, s), 2.74 (2H, t, J 7.5), 2.88 (2H, t, J 7.8),
6.00 (1H, d, J 3.6), 6.75 (1H d, J 3.6), 7.30 (2H, d, J 7.8), 7.92
(2H, d, J 8.4); dC (75 MHz, CDCl3) 14.1, 14.3, 21.9, 22.7 (2C),
25.2, 28.7, 29.1, 31.2, 31.8, 41.4, 111.1, 120.9, 127.7, 129.7, 136.8,
137.1, 144.8, 145.6, 192.3; m/z (EI) 389.20241 (M+ C22H31NO3S
requires 389.20246), 389 (8%), 304 (70), 255 (79), 234 (100), 150
(83), 91 (93).
Method 2. Magnesium turnings (310 mg, 12.75 mmol) were
added to a solution of pyrroline 19 (218 gm, 0.634 mmol) in dry
methanol (10 mL) under a nitrogen atmosphere and sonicated for
4.5 h. The solvent was removed under reduced pressure and ethyl
acetate (15 mL) added to the residue. The resulting suspension
was stirred for 5 min. then filtered through a plug of celite and
the solvent removed under reduced pressure yielding the interme-
diate 2-[(4-methoxyphenyl)methyl]-2,5-dihydro-(1H)-pyrrole as a
colourless oil. The intermediate was immediately dissolved in
toluene (15 mL)/2 M sodium hydroxide (15 mL), chilled to 0◦ C
and benzyl chloroformate (0.275 mL, 1.902 mmol) added. After 2
h the organic phase was separated and the aqueous extracted with
ethyl acetate (10 mL). The combined organic extracts were washed
with water, dried and the solvent removed under reduce pressure.
The title compound was purified by column chromatography on
silica gel (eluent ethyl acetate/hexanes, 1 : 4), to give carbamate
14 (152 mg, 74%) as a colourless oil. The spectroscopic data was
cis-2-Butyl-5-heptyl-1-(p-toluenesulfonyl)-2,5-dihydropyrrole (21)
The procedure described for the reduction of pyrrole10 was carried
out on pyrrole 20 to give an ~ 2 : 1 mixture of the pyrroline 21
and the saturated pyrrolidine 22 as a pale-yellow oil (58% yield)
that was used in the next reaction without further purification.
Compound 21 dH (300 MHz, CDCl3) 0.88 (6H, m), 1.16–1.85
(18H, m), 2.39 (3H, s), 4.28 (2H, dd, J 4.5, 8.1), 5.56 (2H, br s),
7.27 (2H, d, J 8.4), 7.67 (2H, d, J 8.4); dC (75 MHz, CDCl3) 14.2,
14.3, 22.9, 25.8, 27.9, 29.4, 29.5, 29.7, 29.8, 32.0, 37.6, 37.9, 68.11,
68.13, 127.7, 129.1, 129.7, 129.7, 135.0, 143.4.
cis-2-Butyl-5-heptyl-1-(p-tolylsulfonyl)pyrrolidine (22)
To a solution of crude pyrroline 21 (0.1964 g, 0.56 mmol) in
methanol (10 mL) was added Pd/C (10% w/w, 50 mg) and then
hydrogenated under an atmosphere of hydrogen (40psi) on a Parr
shaker hydrogenator for 3.5 h. The reaction mixture was filtered
through a plug of Celite, the solvent removed under reduced
pressure and purified by column chromatography on silica gel
(dichloromethane) to afford a 9 : 1 mixture of pyrrolidines 22 and
2313 (178 mg, 91%) as a colourless oil. Compound 22 dH (300 MHz,
CDCl3) 0.87 (6H, m), 1.28–1.86 (22H, m), 2.41 (3H, s), 3.54 (2H,
m), 7.27 (2H, d, J 8.3), 7.68 (2H, d, J 8.3); dC (75 MHz, CDCl3)
14.28, 14.31, 21.7, 22.8, 22.9, 26.5, 28.7, 29.5, 29.7, 29.8 (2C), 32.0,
37.2, 37.5, 61.8, 61.9, 127.7, 129.7, 135.5, 143.2; m/z (APCI) 380
(100%), EI+ 322 (22), 280 (32), 155 (65), 91 (100).
consistent with the literature.10 max/cm-1 (film) 3032, 2933, 1696,
n
1512, 1412, 1247, 1103, 698; dH (300 MHz, CDCl3) 2.75–2.94 (1H,
m), 2.99–3.17 (1H, m), 3.38–3.45 (1H, m), 3.77 (3H, s), 4.12–4.24
(1H, m), 4.71–4.82 (1H, m), 5.16–5.31 (2H, m), 5.63–5.73 (2H, m),
6.75–6.80 (2H, m), 6.93 (1H d, J 8.4), 7.03 (1H, d, J 8.4), 7.30–7.50
(5H, m); m/z (EI) 323.1505 (M+ C20H21NO3 requires 323.1524),
323 (1%), 202 (10), 158 (13), 121 (22), 91 (100).
2-(p-Methoxybenzoyl)pyrrole (19)
Pyrrole (0.110 mL, 1.59 mmol) was added drop wise to a chilled
(0 ◦C) solution of 3.0 M methylmagnesium bromide (0.56 mL,
1.68 mmol) in anhydrous toluene (30 mL) before heating at 60 ◦C
for 1 h. After cooling to 0 ◦C, a solution of 4-methoxybenzoyl
chloride (217 mg, 1.27 mmol) in anhydrous toluene (15 mL) was
added drop wise and the reaction stirred at room temp for 18 h.
The reaction was quenched with saturated ammonium chloride
(10 mL) and extracted with ethyl acetate (3 ¥ 15 mL). The
organic extracts were washed with water (15 mL), 2 M sodium
carbonate (15 ml), dried and the solvent removed under reduced
pressure yielding the title compound (232 mg, 90%) as a pale solid.
Acknowledgements
The authors are thankful to the University of Tasmania and
The School of Chemistry for support. PPM is thankful to the
University of Tasmania and the Thomas Crawford Foundation
for a postgraduate scholarship and JJ is thankful to the School of
Chemistry and the Faculty of Science Engineering and Technology
for an Undergraduate Summer Research Scholarship. The authors
thank Dr Noel Davies from the Central Science Laboratory at the
University of Tasmania for assitance with mass spectrometery.
n
max/cm-1 (film) 3275, 2965, 1600, 1423, 1398, 1336, 1256, 1169,
1029, 892; dH (300 MHz, CDCl3) 3.88 (3H, s), 6.25–6.35 (1H, m),
3952 | Org. Biomol. Chem., 2011, 9, 3948–3953
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
10 D. P. Schumacher and S. S. Hall, J. Am. Chem. Soc., 1982, 104, 6076;
A. I. Meyers and B. Dupre, Heterocycles, 1987, 25, 113; P. Q. Huang
and X. Zheng, ARKIVOC, 2003, 7.
11 Pyrroline 17 has been reported previously but no spectral data was
reported; S. Hirner and P. Somfai, Synlett, 2005, 20, 3099.
12 Y. Yokoyama, T. Matsumoto and Y. Murakami, J. Org. Chem., 1995,
60, 1486; B. Nyasse, L. Grehn and U. Ragnarsson, Chem. Commun.,
1997, 1017; S. R. Angle, D. Bensa and D. S. Belanger, J. Org. Chem.,
2007, 72, 5592.
Notes and references
1 T. J. Donohoe, R. Garg and C. A. Stevenson, Tetrahedron: Asymmetry,
1996, 7, 317.
2 G. S. R. Subba Roa, Pure Appl. Chem., 2003, 75,
1443.
3 T. J. Donohoe and P. M. Guyo, J. Org. Chem., 1996, 61, 7664; T. J.
Donohoe, P. M. Guyon, R. L. Beddoes and M. Helliwell, J. Chem.
Soc., Perkin Trans. 1, 1998, 667.
4 T. J. Donohoe, H. O. Sintim and J. Hollinshead, J. Org. Chem., 2005,
70, 7297.
5 L. Knorr and P. Rabe, Ber. Dtsch. Chem. Ges., 1901, 34, 3491.
6 B. S. Gourlay, J. H. Ryan and J. A. Smith, Beilstein J. Org. Chem., 2008,
4(3).
13 J. W. Daly, T. F. Spande, N. Whittaker, R. J. Highet, D. Feigl, N.
Nishimori, T. Tokuyama and C. W. Myers, J. Nat. Prod., 1986, 49, 265.
14 J. Ba¨ckvall, H. E. Schink and Z. D. Renko, J. Org. Chem., 1990, 55,
826.
15 W. C. Still, M. Kahn and A. Mitra, J. Org. Chem., 1978, 43, 2923.
16 C. Zonta, F. Fabris and O. De Lucchi, Org. Lett., 2005, 7, 1003.
17 D. Krajewska, M. Dabrowska, P. Jakoniuk and A. Rozanski, Acta
Polonie Pharm., 2002, 59, 127.
18 M. Sukeda, S. Ichikawa, A. Matsuda and S. Shuto, J. Org. Chem., 2003,
68, 3465.
19 L. A. Paquette, C. S. Ra, J. D. Schloss, S. M. Leit and J. C. Gallucci, J.
Org. Chem., 2001, 66, 3564.
7 D. M. Ketcha, K. P. Carpenter and Q. Zhou, J. Org. Chem., 1991, 56,
1318.
8 C. Song, D. W. Knight and M. A. Whatton, Org. Lett., 2006, 8, 163–
166.
9 R. Greenhouse, C. Ramirez and J. M. Muchowski, J. Org. Chem., 1985,
50, 2961; L. J. Dolby, S. J. Nelson and D. Senkovich, J. Org. Chem.,
1972, 37, 3691.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 3948–3953 | 3953
©