Synthesis of 2,5-disubstituted pyrroles and pyrrolidines by intramolecular cyclization of 6-amino-3-keto sulfones

Article abstract of DOI:10.1055/s-2002-20025

Wittig reaction of 4-[(4-methylphenyl)sulfonyl]-1-(triphenylphosphoranylidene)butan-2-one (1) with N-protected α-amino aldehydes furnished N-protected γ-amino-α, β-unsaturated keto sulfones which have been conveniently utilized as precursors of both aromatic and non-aromatic 2,5-disubstituted five-membered heterocyclic compounds. While 2,5-disubstituted pyrroles are efficiently formed by cyclodehydration of the starting materials, 2,5-disubstituted pyrrolidines and pyrrolenines could be obtained by prior reduction of the conjugated double bond followed by acid-or base-mediated cyclization. The ready availability of the materials required for the whole sequence makes this methodology a convenient way to generate both aromatic and saturated 2,5-disubstituted five-membered heterocyclic compounds.

Full text of DOI:10.1055/s-2002-20025

PAPER
331
Synthesis of 2,5-Disubstituted Pyrroles and Pyrrolidines by Intramolecular
Cyclization of 6-Amino-3-keto Sulfones
Synthesis of 2,
i
5-Disu
m
bstituted Pyrroles
a
o
nd Pyrrolidin
n
e
s
etta Benetti,a Carmela De Risi,b Paolo Marchetti,b Gian P. Pollini,*b Vinicio Zaniratoc
a
Dipartimento di Chimica, Via L. Borsari 46, 44100 Ferrara, Italy
b
Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 19, 44100 Ferrara, Italy
Fax +39(532)291296; E-mail: pol@unife.it
c
Dipartimento Farmaco-Chimico-Tecnologico, Via A. Moro, 53100 Siena, Italy
Received 2 October 2001; revised 22 November 2001
Since the two double bonds adjacent to the carbonyl group
could be generated in separate steps, namely a Wittig re-
action with a suitable aldehyde and a base-promoted -
elimination of the sulfone group, we anticipated that
Abstract: Wittig reaction of 4-[(4-methylphenyl)sulfonyl]-1-
(triphenylphosphoranylidene)butan-2-one (1) with N-protected
-
amino aldehydes furnished N-protected -amino- , -unsaturated
keto sulfones which have been conveniently utilized as precursors
of both aromatic and non-aromatic 2,5-disubstituted five-mem- chiral non-racemic compounds like the -amino- , -un-
bered heterocyclic compounds. While 2,5-disubstituted pyrroles are
saturated keto sulfones 11–13 could provide diastereo-
efficiently formed by cyclodehydration of the starting materials,
meric 2-substituted piperidine nuclei. To test this
2,5-disubstituted pyrrolidines and pyrrolenines could be obtained
hypothesis, we have now prepared the derivatives 11–136
by prior reduction of the conjugated double bond followed by acid-
through Wittig alkenylation of 1 with suitably N-protected
or base-mediated cyclization. The ready availability of the materials
required for the whole sequence makes this methodology a conve-
amino aldehydes 8–10,7 in turn conveniently obtained by
LiAlH4 reduction of the corresponding N-methyl-N-meth-
oxyamides 5–7 of suitably N-protected amino acids 2–4
such as alanine, valine, phenylalanine and serine (Scheme
2).
nient way to generate both aromatic and saturated 2,5-disubstituted
five-membered heterocyclic compounds.
Key words: pyrroles, pyrrolidines, amino aldehydes, cyclodehy-
dration, sulfones
O
NH(OMe)Me HCl,
Et3N, DCC
CO2H
Me
R
The pyrrole subunit is a frequently found motif in many
naturally occurring compounds as well as in substances
with important biological activities. The importance of
pyrrole derivatives in pharmaceutical and agricultural de-
velopment, has created the need for efficient preparation
of this nucleus, usually constructed through the classical
Paal–Knorr synthesis starting from primary amines and
1,4-dicarbonyl compounds.1 More recent approaches uti-
lize conjugate addition of -aminoalkylcuprates to alky-
nyl ketones2 or aldol-type reactions between -amino
aldehydes and lithium enolates of various ketones3 or in-
tramolecular cyclodehydration of -substituted- , -un-
saturated ketone derivatives.4 We have recently
introduced 4-[(4-methylphenyl)sulfonyl]-1-(triphenyl-
phosphoranylidene)butan-2-one (1) as a versatile four-
carbon building block for substituted divinyl ketones able
to take part in a domino sequence initiated by a nitrogen- Scheme 2
centered nucleophile, allowing the construction of a vari-
ety of six-membered heterocyclic ring systems (Scheme
R
LiAlH4
N
NHP
OMe
NHP
77-78%
75-81%
5a-d: P = Boc
6a-d: P = Fmoc
7c: P = Z
2a-d: P = Boc
3a-d: P = Fmoc
4c: P = Z
O
CHO
R
1
NHP
64-89%
R
SO2p-Tol
8a-d: P =Boc
9a-d: P = Fmoc
10c: P = Z
NHP
11a-d: P = Boc
12a-d: P = Fmoc
13c: P =Z
a: R = Me; b: R = CH(Me)2;
c: R = Bn; d: R = CH2OC(Me)3
An accurate inspection of the polifunctionalized interme-
diates 11–13 revealed that their -amino- , -unsaturated
ketone moiety could take part in an intramolecular cyclo-
dehydratation leading to five-membered heterocycles.
The present paper deals with this useful synthetic strategy.
1).5
O
O
O
Ph3P
SO2p.Tol
R
N
R
Different nitrogen protective groups were utilized consid-
ering that they can be cleaved under different experimen-
1
R1
tal
conditions
(strongly
acidic,
basic
or
Scheme 1
hydrogenolytically), thus offering more options to obtain
aromatic and saturated 2,5-disubstituted five-membered
Synthesis 2002, No. 3, 18 02 2002. Article Identifier:
1437-210X,E;2002,0,03,0331,0338,ftx,en;E06401SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

332
S. Benetti et al.
PAPER
heterocyclic compounds with both free and protected ni-
trogen atom.
Table Synthesis of Vinylpyrroles 14 and Pyrrole Sulfones 15, 16
from -Amino- , -unsaturated Keto Sulfones 11–12
Thus, base induced deprotection of the amine function of
12a–d led to the formation of a mixture of the interesting
and quite rare vinyl pyrrole derivatives 14a–d and the ex-
pected pyrrole sulfones 15a–d. The ratio of the two com-
pounds depends on the base used in the deprotection step,
and piperidine, the classical base used for Fmoc removal,8
gave higher yields of vinyl pyrrole derivatives 14a–d.
Otherwise, mild acid treatment of 11a–d with trifluoro-
acetic acid (TFA) promoted a spontaneous intramolecular
cyclodehydration giving N-Boc 2,5-disubstituted pyrrole
sulfone derivatives 16a–d bearing the intact sulfone moi-
ety as an additional interesting functionality in the side
chain (Scheme 3 and Table).
Keto Sulfones 11, 12
Promoter
Time
(h)
14
15
16
R
Yield Yield Yield
(%)
-
(%)
-
(%)
11a Me
TFA
12
20
16
16
0.45
2.5
1
85
78
91
72
-
11b CH(Me)2
TFA
-
-
11c
Bn
TFA
-
-
11d CH2OC(Me)3
12a Me
TFA
-
-
piperidine
Et3N
61
20
53
-
35
73
32
-
-
12b CH(Me)2
piperidine
NaHCO3
IRA-420b
TMG
-
24a
24a
0.5
1.5
2
-
R
N
-
35
88
18
27
25
53
-
H
14a-d
+
53-64%
Base
-
-
O
12c
Bn
piperidine
Et3N
72
60
64
39
-
12a-d
SO2p-Tol
R
N
H
(CH2)2SO2p-Tol
R
-
27-73%
15a-d
NHP
11 or 12
12d CH2OC(Me)3
piperidine
Et3N
1
-
1.5
-
11a-d
a At reflux.
TFA
b Fluka Amberlite basic anion exchange resin.
R
(CH2)2SO2p-Tol
N
72-91%
Boc
16a-d
obtained as above described to catalytic hydrogenation in
the presence of Pd/C. Thus, acid-promoted dehydration of
the resulting saturated compound 17c followed by hydro-
genation of the crude reaction mixture led to the formation
of the pyrrolidine sulfone 20c with a modest 53% de,
while double bond reduction of 12c followed by base
deprotection of the amine function of 18c produced the
optically active vinylpyrroline 21c (Scheme 4).
Scheme 3
It is likely that an acid- or base-induced trans/cis isomer-
ization of the double bond geometry is required to allow
the cyclodehydration, which, of course, occurr with loss
of the chirality of the starting amino acid due to the forma-
tion of the aromatic heterocyclic compounds.
As a logical extension of our method, we next explored
the possibility to obtain compounds in which the chirality
information could be preserved and transferred to eventu-
ally created new chiral centers. To this end, we decided to
anticipate the reduction of the double bond to the cycliza-
tion step, submitting the model compounds 11c and 12c
A much better result in term of induced chirality transfer
has been found when we applied the reduction/deprotec-
tion sequence to compound 13c, the saturated pyrrolidine
23c being formed in good chemical yield and satisfactory
de (81%, Scheme 5).
1) TFA
2) H2/Pd
NaOH
R
(CH2)2SO2p-Tol
N
+
R
(CH2)2SO2p-Tol
20c (de = 53%)
N
O
H
H
95%
78%
H
_
17c
CF3CO2
(S)-11c
19c
R
H2/Pd
SO2p-Tol
or
95-97%
NHP
(S)-12c
18c
piperidine
69%
17c: P = Boc
18c: P = Fmoc
R
N
21c
Scheme 4
Synthesis 2002, No. 3, 331–338 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 2,5-Disubstituted Pyrroles and Pyrrolidines
IR (KBr): 3318, 1720, 1232, 1190, 1089 cm–1.
333
H2/Pd,
pyrrolidine
(Ac)2O, Et3N
89%
1H NMR (200 MHz, CDCl3): = 1.21 (s, 9 H, CH2OC4H9-t), 1.35
(s, 9 H, CO2C4H9-t), 3.31 (s, 3 H, OCH3), 3.58 (t, 1 H, J = 7 Hz,
CH), 3.81 (s, 3 H, OCH3), 4.18–4.23 (m, 2 H, CH2), 5.61 (d, 1 H,
J = 7.9 Hz, NH).
13C NMR (50 MHz, CDCl3): = 27.2, 27.5, 45.4, 53.6, 61.2, 67.5,
73.7, 155.9, 169.5.
13c
R
Et
N
+
R
Et
N
79%
H
H
_
SO2p-Tol
Me
O
22c
23c (de = 81%)
Scheme 5
Anal. Calcd for C14H28N2O5 (304.4): C, 55.24; H, 9.27; N, 9.20.
Found: 54.32; H, 9.01; N, 9.35.
On the basis of NMR spectra we could not specify the ab-
solute configurations of the new chiral centers at C-5 of
pyrrolidines 20c and 23c however, assuming facial selec-
tivity in the cis-hydrogenation of pyrroline intermediates,
we suppose the cis-diastereomers are predominant in the
mixture.
[2-tert-Butoxy-(S)-1-(methoxymethylcarbamoyl)-1-ethyl]-
carbamic Acid 9H-Fluoren-9-ylmethyl Ester [(S)-6d]
Solid (75%); mp 131–132 °C; Rf 0.2 (EtOAc–hexane, 1:2); [ ]D
20
+14.5 (c = 1.00, CHCl3).
IR (KBr): 3309, 1723, 1652, 1450, 1247, 1195, 1099, 760, 741
cm–1.
In summary, the reaction of ylide 1 with easily available
N-protected -amino aldehydes opened a convenient ac-
cess to N-protected -amino- , -unsaturated keto sulfone
derivatives, which have been conveniently utilized as pre-
cursors of both aromatic and non-aromatic 2,5-disubsti-
tuted five-membered heterocyclic compounds. Moreover,
an appropriate choice of nitrogen protecting group allows
obtaining N-protected or free 2,5-disubstituted pyrroles as
well as 2,5-disubstituted pyrrolidines and pyrrolenines
simply by prior reduction of the conjugated double bond.
Interestingly, the ready availability of the starting materi-
als makes this methodology a convenient way to generate
both aromatic and saturated 2,5-disubstituted five-mem-
bered heterocyclic compounds and could find applica-
tions in the synthesis of natural products.
1H NMR (200 MHz, CDCl3): = 1.17 (s, 9 H, CH2Ot-C4H9), 3.35
(s, 3 H, OCH3), 3.64 (t, 1 H, J = 7.1 Hz, HNCH), 3.79 (s, 3 H,
OCH3), 4.20–4.27 (m, 2 H, t-BuOCH2), 4.37 (d, 2 H, J = 6.8 Hz,
CO2CH2), 4.81–4.92 (m, 1 H, OCH2CH), 5.70 (d, 1 H, J = 9 Hz,
NH), 7.27–7.78 (m, 8 Harom).
13C NMR (50 MHz, CDCl3): = 27.4, 47.2, 51.9, 61.5, 62.1, 67.1,
73.6, 120.0, 125.3, 127.1, 127.7, 141.3, 143.9, 144.1, 156.1, 170.7.
Anal. Calcd for C24H30N2O5 (426.5): C, 67.59; H, 7.09; N, 6.57.
Found: C, 67.40; H, 7.00; N, 6.83.
Aldehydes (S)-8d and (S)-9d; General Procedure
To an ice-cooled solution of (S)-5d or (S)-6d (3 mmol) in anhyd
Et2O (10 mL) was added LiAlH4 (125 mg, 3.3 mmol) in one portion
and the stirring was continued for 10 min at the same temperature.
The mixture was quenched with a few drops of aq 3% KHSO4, fil-
tered through Celite, washed with Et2O (2 5 mL) and dried. After
evaporation of the solvent, the crude residue was purified by col-
umn chromatography to give (S)-8d or (S)-9d.
Melting points were determined on a Reichert-Kofler apparatus and
are uncorrected. NMR spectra were recorded on a Brucker AC-200
spectrometer. Chemical shifts are given in parts per million ( )
downfield from tetramethylsilane as an internal standard. IR spectra
were recorded on a Perkin-Elmer FT-IR Paragon 500 spectrometer.
Optical rotations [ ] were determined using a Perkin-Elmer 241 po-
larimeter operating at 589 nm (sodium D line) at 20 °C. Organic so-
lutions were dried over anhyd MgSO4 and evaporated with a rotary
evaporator. PE (light petroleum) refers to the fractions boiling in the
range 40–60 °C. HPLC analysis was performed on a Gilson 119
variable wavelength detector. Chiral HPLC was run using two
Astec column systems with the appropriate eluents mixture: Chiro-
biotic V (column system 1) and Cyclobond 2000 (column system
2). TLC was done with precoated plates of silica gel (Merk F-254)
using the indicated solvent system. Flash chromatography was car-
ried out with Merck silica gel (230–400 mesh). Elemental analyses
were measured at the microanalytical laboratory of Dipartimento di
Chimica, University of Ferrara.
[2-tert-Butoxy-(S)-1-formylethyl]carbamic Acid tert-Butyl
Ester [(S)-8d]
Yellowish oil (78%); Rf 0.3 (EtOAc–hexane, 1:2); [ ]D20 +37.8 (c =
1.00, CHCl3).
IR (neat): 3442, 3310, 1728, 1710, 1237, 1081 cm–1.
1H NMR (200 MHz, CDCl3): = 1.20 (s, 9 H, CH2Ot-C4H9), 1.39
(s, 9 H, CO2t-C4H9), 4.29 (t, 1 H, J = 7.0, HNCH), 4.32–4.41 (m, 2
H, OCH2), 5.64 (d, 1 H, J = 7.8 Hz, NH), 9.64 (s, 1 H, COH).
13C NMR (50 MHz, CDCl3): = 26.9, 29.2, 48.1, 61.4, 66.3, 72.5,
158.4, 200.1.
Anal. Calcd for C12H23NO4 (245.3): C, 58.75; H, 9.45; N, 5.71.
Found: C, 58.48; H, 9.32; N, 5.70.
[2-tert-Butoxy-(S)-1-formylethyl]carbamic acid, 9H-Fluoren-9-
ylmethyl Ester [(S)-9d]
20
Oil (77%); Rf 0.37 (EtOAc–hexane, 1:2); [ ]D +31.4 (c = 1.00,
Compounds (S)-5d and (S)-6d; General Procedure
CHCl3).
DCC (1.135 g, 5.5 mmol) and the N-protected -amino acid 2d or
3d (5 mmol) were successively added to a stirred suspension of
N,O-dimethylhydroxylamine hydrochloride (537 mg, 5.5 mmol)
and Et3N (506 mg, 5.5 mmol) in anhyd CH2Cl2. After stirring at r.t.
for 40 min, the mixture was filtered through Celite and the solid
washed with CH2Cl2 (2 5 mL). Evaporation of the solvent and col-
umn chromatography of the residue yielded pure (S)-5d or (S)-6d.
IR (neat): 3440, 3318, 1725, 1695, 1506, 1450, 1364, 1247, 1088,
759, 741 cm–1.
1H NMR (200 MHz, CDCl3): = 1.16 (s, 9 H, CH2Ot-C4H9), 4.34
(t, 1 H, J = 7.0, HNCH), 4.38–4.95 (m, 5 H, t-BuOCH2, CO2CH2
and OCH2CH), 5.66 (d, 1 H, J = 8 Hz, NH), 7.25–7.78 (m, 8 H, flu-
orene), 9.62 (s, 1 H, CHO).
13C NMR (50 MHz, CDCl3): = 27.3, 47.2, 60.1, 60.6, 67.2, 73.9,
120.0, 125.2, 127.2, 127.8, 141.4, 143.9, 156.3, 199.2.
[2-tert-Butoxy-(S)-1-(methoxymethylcarbamoyl)-1-ethyl]-
carbamic Acid tert-Butyl Ester [(S)-5d]
Solid (81%); mp 125–126 °C; Rf 0.2 (EtOAc–hexane, 1:3); [ ]D
20
Anal. Calcd for C22H25NO4 (367.5): C, 71.91; H, 6.86; N, 3.81.
Found: C, 72.43; H, 6.91; N, 3.74.
+26.1 (c = 1.00, CHCl3).
Synthesis 2002, No. 3, 331–338 ISSN 0039-7881 © Thieme Stuttgart · New York

334
S. Benetti et al.
PAPER
Alkenes 11–13; General Procedure
1H NMR (200 MHz, CDCl3): = 0.88 (d, 3 H, J = 7.1 Hz, CH3CH),
0.91 (d, 3 H, J = 7.2 Hz, CH3CH), 1.85–1.95 (m, 1 H, CH), 2.43 (s,
3 H, C6H4CH3), 3.02 (t, 2 H, J = 7.8 Hz, COCH2), 3.35–3.50 (m, 3
H, CH2S and HCNH), 4.19 (t, 1 H, J = 6.9 Hz, OCH2CH), 4.44 (d,
2 H, J = 6.9 Hz, OCH2), 5.02 (br d, 1 H, J = 7.9 Hz, NH), 6.11 (d, 1
H, J = 15.9 Hz, OCCH=), 6.75 (dd, 1 H, J = 15.9, 6.2 Hz, NCCH=),
7.15–7.80 (m, 12 H, C6H4 and fluorene).
13C NMR (50 MHz, CDCl3): = 16.9, 20.2, 30.3, 33.3, 47.1, 59.5,
66.9, 119.6, 124.8, 125.1, 127.3, 127.9, 128.2, 128.8, 130.0, 135.9,
140.1, 141.8, 142.1, 143.7, 155.5, 199.9.
A mixture of the appropriate aldehyde 8–10 (1 mmol) and 1 (487
mg, 1 mmol) in anhyd toluene was refluxed until the reaction was
completed (TLC monitoring). After evaporation of the solvent the
crude residue was purified by column chromatography.
[(S)-1-Methyl-4-oxo-6-(toluene-4-sulfonyl)hex-2-enyl]carbamic
Acid tert-Butyl Ester [(S)-11a]
Solid (76%); Rf 0.2 (EtOAc–hexane, 1:1); mp 104–106 °C; [ ]D
–37.1 (c = 1.00, CHCl3).
IR (KBr): 3320, 1695, 1560, 1308, 1156 cm–1.
1H NMR (200 MHz, CDCl3): = 1.26 (d, 3 H, J = 7.1 Hz, NCCH3),
1.38 (s, 9 H, t-C4H9), 2.43 (s, 3 H, C6H4CH3), 2.98 (t, 2 H, J = 7.4
Hz, COCH2), 3.42 (t, 2 H, J = 7.4 Hz, CH2S), 4.35 4.42 (m, 1 H,
HCN), 4.80 (d, 1 H, J = 8 Hz, NH), 6.06 (d, 1 H, J = 15.2 Hz, OC-
CH=), 6.68 (dd, 1 H, J = 15.2, 5 Hz, NCCH=), 7.27–7.60 (m, 4
20
Anal. Calcd for C31H33NO5S (531.7): C, 70.03; H, 6.26; N, 2.63; S,
6.03. Found: C, 69.26; H, 6.02; N, 2.99; S, 6.41.
[(S)-1-Benzyl-4-oxo-6-(toluene-4-sulfonyl)hex-2-enyl]carbamic
Acid tert-Butyl Ester [(S)-11c]
20
Solid (69%); mp 121–124 °C; Rf 0.32 (EtOAc–hexane, 1:2); [ ]D
H
arom).
–5.1 (c = 1.00, CHCl3). HPLC with chiral column (system 1): iso-
cratic elution (MeCN–MeOH–Et3N–AcOH = 85:15:0.01:0.01);
t1 = 3.45; ee = 96%.
IR (KBr): 3351, 1690, 1683, 1525, 1313, 1171, 1144 cm–1.
1H NMR (200 MHz, CDCl3): = 1.40 (s, 9 H, t-C4H9), 2.46 (s, 3 H,
CH2C6H5), 2.89 (d, 2 H, J = 6.9 Hz, CH2C6H4), 2.99 (t, 2 H, J = 8.2
Hz, CH2CO), 3.38 (t, 2 H, J = 8.2 Hz, CH2S), 4.58 (br s, 2 H, NH
and NCH), 6.08 (d, 1 H, J = 15.9 Hz, OCCH=), 6.82 (dd, 1 H,
J = 15.9, 4.8 Hz, NCCH=), 7.13–7.80 (m, 9 H, C6H5 and C6H4).
13C NMR (50 MHz, CDCl3): = 21.7, 27.0, 28.3, 33.1, 40.7, 50.7,
52.5, 80.1, 127.1, 128.0, 128.1, 128.7, 129.3, 130.1, 136.0, 136.1,
145.0, 147.3, 155.0, 195.0.
13C NMR (50 MHz, CDCl3): = 20.3, 21.9, 28.6, 34.2, 50.9, 52.5,
80.0, 126.4, 128.6, 130.2, 135.8, 142.3, 145.2, 156.2, 197.4.
Anal. Calcd for C19H27NO5S (381.5): C, 59.82; H, 7.13; N, 3.67; S,
8.41. Found: C, 59.72; H, 7.18; N, 3.58; S, 8.50.
[(S)-1-Methyl-4-oxo-6-(toluene-4-sulfonyl)hex-2-enyl]carbamic
Acid 9H-Fluoren-9-ylmethyl Ester [(S)-12a]
Solid (81%); mp 121–123 °C; Rf 0.12 (EtOAc–hexane, 1:1.5);
[ ]D20 –32.9 (c = 1.00, CHCl3).
IR (KBr): 3323, 1690, 1684, 1534, 1315, 1264, 1145 cm–1.
1H NMR (200 MHz, CDCl3): = 1.28 (d, 3 H, J = 7 Hz, NCCH3),
2.43 (s, 3 H, C6H4CH3), 3.03 (t, 2 H, J = 7.8 Hz, COCH2), 3.39 (t, 2
H, J = 7.8 Hz, CH2S), 4.17–4.23 (m, 1 H, CHCH3), 4.37–4.45 (m, 3
H, OCH2 and OCH2CH), 4.88 (br d, 1 H, J = 8 Hz, NH), 6.10 (d, 1
H, J = 16 Hz, OCCH=), 6.74 (dd, 1 H, J = 16, 5.9 Hz, NCCH=),
7.26–7.80 (m, 12 H, fluorene and C6H4).
Anal. Calcd for C25H31NO5S (457.6): C, 65.62; H, 6.83; N, 3.06; S,
7.01. Found: C, 65.49; H, 6.79; N, 3.09; S, 7.11.
[(R,S)-1-Benzyl-4-oxo-6-(toluene-4-sulfonyl)hex-2-enyl]-
carbamic Acid tert-Butyl Ester [(R,S)-11c]
Solid (75%); mp 114–116 °C; Rf 0.32 (EtOAc–hexane, 1:2). HPLC
with chiral column (system 1): isocratic elution (MeCN–MeOH–
Et3N–AcOH = 85:15:0.01:0.01); t1 = 3.45; t2 = 4.94.
13C NMR: = 20.1, 21.6, 33.1, 47.2, 50.7, 66.7, 120.0, 124.9, 127.1,
127.4, 127.8, 128.0, 130.0, 135.9, 141.4, 143.8, 143.9, 145.1, 148.3,
155.4, 195.2.
Anal. Calcd for C29H29NO5S (503.6): C, 69.16; H, 5.80; N, 2.78; S,
6.37. Found: C, 69.45; H, 5.91; N, 2.82; S, 6.21.
[(S)-1-Benzyl-4-oxo-6-(toluene-4-sulfonyl)-hex-2-enyl]-
carbamic Acid 9H-Fluoren-9-ylmethyl Ester [(S)-12c]
Solid (89%) mp 150–152 °C; Rf 0.4 (EtOAc–hexane, 1:1.5); [ ]D
–10.2 (c = 1.00, CHCl3).
IR (KBr): 3326, 1690, 1534, 1315, 1258, 1146 cm–1.
20
[(S)-1-Isopropyl-4-oxo-6-(toluene-4-sulfonyl)hex-2-enyl]-
carbamic Acid tert-Butyl Ester [(S)-11b]
20
Solid (74%); mp 104–106 °C; Rf 0.3 (EtOAc–hexane, 1:1.5); [ ]D
–37.1 (c = 1.00, CHCl3).
IR (KBr): 3329, 1695, 1305, 1148 cm–1.
1H NMR (200 MHz, CDCl3): = 2.46 (s, 3 H, CH3C6H4), 2.91 (d, 2
H, J = 6.4 Hz, CH2C6H5), 2.99 (t, 2 H, J = 8 Hz, CH2CO), 3.38 (t, 2
H, J = 8 Hz, CH2S), 4.18 (t, 1 H, J = 6.6 Hz, HCCN), 4.38–4.47 (m,
2 H, CH2O), 4.50–4.52 (m, 1 H, HCCH2O), 4.81 (br d, 1 H, NH),
6.08 (d, 1 H, J = 16 Hz, OCCH=), 6.71 (dd, 1 H, J = 16, 5 Hz,
NCCH=), 7.10–7.80 (m, 17 H, fluorene, C6H4, C6H5).
13C NMR (50 MHz, CDCl3): = 20.3, 33.9, 46.9, 48.3, 50.8, 66.8,
121.1, 122.1, 124.5, 125.3, 126.9, 127.2, 127.7, 128.1, 128.3, 131.2,
136.0, 141.0, 141.3, 143.7, 143.9, 148.6, 155.9, 194.8.
1H NMR (200 MHz, CDCl3): = 0.87 (d, 3 H, J = 6.8 Hz, CH3CH),
0.92 (d, 3 H, J = 6.6 Hz, CH3CH), 1.36 (s, 9 H, t-C4H9), 1.80–1.93
(m, 1 H, CH), 2.44 (s, 3 H, C6H4CH3), 2.65–2.73 (m, 1 H, HCNH),
2.95 (t, 2 H, J = 7.1 Hz, COCH2), 3.35 (t, 2 H, J = 7.1 Hz, CH2S),
5.18 (d, 1 H, J = 8.3 Hz, NH), 6.16 (d, 1 H, J = 15.9 Hz, OCCH=),
6.74 (dd, 1 H, J = 15.9, 6.1 Hz, NCCH=), 7.35 (d, 2 H, J = 8 Hz,
C6H5), 7.80 (d, 2 H, J = 8 Hz, C6H5).
Anal. Calcd for C35H33NO5S (579.7): C, 72.52; H, 5.74; N, 2.42; S,
5.53. Found: C, 72.49; H, 5.70; N, 2.42; S, 5.65.
13C NMR (50 MHz, CDCl3): = 17.5, 20.8, 28.9, 32.9, 33.4, 47.9,
60.2, 68.9, 126.2, 127.8, 129.3, 135.2, 143.0, 143.3, 158.1, 198.7.
Anal. Calcd for C21H31NO5S (409.6): C, 61.59; H, 7.63; N, 3.42; S,
7.83. Found: C, 61.59; H, 7.61; N, 3.45; S, 7.86.
[(S)-1-Benzyl-4-oxo-6-(toluene-4-sulfonyl)hex-2-enyl]carbamic
Acid Benzyl Ester [(S)-13c]
Solid (70%); mp 106–108 °C; Rf 0.3 (EtOAc–hexane, 1:2); [ ]D
–19.9 (c = 1.00, CHCl3).
IR (KBr): 3328, 1690, 1684, 1535, 1315, 1261, 1143 cm–1.
1H NMR (200 MHz, CDCl3): = 2.46 (s, 3 H, CH3C6H4), 2.85 (d, 2
H, J = 7 Hz, CH2C6H5), 2.93 (t, 2 H, J = 8.1 Hz, CH2CO), 3.38 (t, 2
H, J = 8.1 Hz, CH2S), 4.62–4.70 (m, 1 H, CH), 4.86 (d, 1 H, J = 8
Hz, NH), 5.05–5.07 (m, 2 H, OCH2), 6.08 (d, 1 H, J = 15.8, OC-
20
[(S)-1-Isopropyl-4-oxo-6-(toluene-4-sulfonyl)hex-2-enyl]-
carbamic Acid 9H-Fluoren-9-ylmethyl Ester [(S)-12b]
Solid (85%); mp 113–115 °C; Rf 0.2 (EtOAc–hexane, 1:1.5); [ ]D
20
–40.5 (c = 1.00, CHCl3).
IR (KBr): 3326, 1689, 1539, 1302, 1143 cm–1.
Synthesis 2002, No. 3, 331–338 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 2,5-Disubstituted Pyrroles and Pyrrolidines
335
CH=), 6.79 (dd, 1 H, J = 15.8, 5 Hz, NCCH=), 7.12–7.80 (m, 14 H,
2-Isopropyl-5-vinyl-1H-pyrrole (14b)
2 C6H5, C6H4).
Oil (53%); Rf 0.13 (EtOAc–hexane, 1:4).
13C NMR (50 MHz, CDCl3): = 19.9, 30.0, 41.2, 47.7, 54.3, 71.5,
123.6, 124.5, 127.2, 127.4, 127.8, 128.6, 128.8, 130.5, 130.7, 137.6,
138.5, 140.0, 145.3, 155.8, 198.2.
IR (neat): 3423, 1635, 1631, 1476, 980 cm–1.
1H NMR (200 MHz, CDCl3): = 1.27 (d, 6 H, J = 7 Hz, 2 CH3),
2.92 (sept, 1 H, J = 7 Hz, CH), 5.74–5.79 (m, 2 H, 2 =CH pyrrole),
7.24 (dd, 1 H, J = 15.6, 8.1 Hz, =CH), 7.75–7.81 (m, 2 H, =CH2),
10.15 (br s, 1 H, NH).
Anal. Calcd for C28H29NO5S (491.6): C, 68.41; H, 5.95; N, 2.85; S,
6.52. Found: C, 68.11; H, 5.81; N, 2.84; S, 6.58.
13C NMR (50 MHz, CDCl3): = 24.9, 34.8, 106.8, 107.0, 114.9,
118.0, 127.1, 136.8.
[(S)-1-tert-Butoxymethyl-4-oxo-6-(toluene-4-sulfonyl)hex-2-
enyl]carbamic Acid tert-Butyl Ester [(S)-11d]
Solid (64%); mp 102–103 °C; Rf 1.4 (EtOAc–hexane, 1:2.5); [ ]D
20
Anal. Calcd for C9H13N (135.2): C, 79.95; H, 9.69; N, 10.36. Found:
C, 79.95; H, 9.78; N, 10.21.
–51.3 (c = 1.00, CHCl3).
IR (KBr): 3320, 1692, 1652, 1314, 1274, 1236, 1143 cm–1.
2-Benzyl-5-vinyl-1H-pyrrole (14c)
1H NMR (200 MHz, CDCl3): = 1.18 (s, 9 H, Ot-C4H9), 1.35 (s, 9
H, CO2C4H9-t), 2.35 (s, 3 H, CH3C6H4), 3.12 (t, 2 H, J = 7.2 Hz,
CH2CO), 3.43 (t, 2 H, J = 7.2 Hz, CH2S), 3.51 (d, 2 H, J = 6.9 Hz,
OCH2), 4.01–4.20 (m, 1 H, HCCN), 5.31 (d, 1 H, J = 8.4 Hz, NH),
6.23 (d, 1 H, J = 15.8 Hz, OCCH=), 6.83 (dd, 1 H, J = 15.8, 5.3 Hz,
NCCH=), 7.40 (d, 2 H, J = 8.1 Hz, C6H4), 7.78 (d, 2 H, J = 8.1 Hz,
C6H4).
Oil (72%), Rf 0.2 (EtOAc–hexane, 1:4).
IR (neat): 3416, 1589, 1579, 1455, 987, 964 cm–1.
1H NMR (200 MHz, CDCl3): = 3.92 (s, 2 H, CH2), 5.72–5.75 (m,
2 H, 2 =CH pyrrole), 7.21–7.98 (m, 8 H, C6H5, CH=CH2), 10.04 (br
s, 1 H, NH).
13C NMR (50 MHz, CDCl3): = 35.4, 105.6, 107.8, 117.1, 119.1,
125.5, 125.9, 128.9, 130.0, 137.7, 138.9.
13C NMR (50 MHz, CDCl3): = 21.2, 27.9, 31.0, 32.9, 46.9, 52.7,
67.7, 69.8, 71.1, 122.5, 128.7, 131.3, 138.0, 141.2, 156.9, 198.2.
Anal. Calcd for C13H13N (183.3): C, 85.21; H, 7.15; N, 7.64. Found:
C, 85.61; H, 7.02; N, 7.55.
Anal. Calcd for C23H35NO6S (453.6): C, 60.90; H, 7.78; N, 3.09; S,
7.07. Found: C, 61.26; H, 7.93; N, 3.45; S, 6.86.
2-tert-Butoxymethyl-5-vinyl-1H-pyrrole (14d)
Oil (64%); Rf 0.1 (EtOAc–hexane, 1:4).
IR (neat): 3415, 1631, 1605, 1487, 1286, 1127, 987 cm–1.
[(S)-1-tert-Butoxymethyl-4-oxo-6-(toluene-4-sulfonyl)hex-2-
enyl]carbamic Acid 9H-Fluoren-9-ylmethyl Ester [(S)-12d]
Solid (68%); mp 87–89 °C; Rf 1.2 (EtOAc–hexane, 1:2.5); [ ]D
–61.8 (c = 1.00, CHCl3).
IR (KBr): 3317, 1695, 1648, 1337, 1274, 1258, 1153 cm–1.
1H NMR (200 MHz, CDCl3): = 1.17 (s, 9 H, Ot-C4H9); 2.45 (s, 3
H, CH3C6H4), 3.05 (t, 2 H, J = 7 Hz, CH2CO), 3.40 (t, 2 H, J = 7 Hz,
CH2S), 3.44–3.53 (m, 1 H, CH), 4.28 (t, 1 H, J = 7.2 Hz, HCCN),
4.39–4.48 (m, 4 H, 2 OCH2), 5.30 (br d, 1 H, NH), 6.2 (d, 1 H,
J = 14.2 Hz), 6.83 (dd, 1 H, J = 14.2, 6.9 Hz, NCCH=), 7.32–7.81
(m, 8 H).
20
1H NMR (200 MHz, CDCl3): = 1.19 (s, 9 H, t-C4H9), 4.72 (s, 2 H,
OCH2), 5.66–5.69 (m, 1 H, =CH pyrrole), 5.81–5.86 (m, 1 H, =CH
pyrrole), 7.19 (dd, 1 H, J = 15.3, 8.0 Hz, =CH), 7.81–7.89 (m, 2
H, =CH2), 9.92 (br s, 1 H, NH).
13C NMR (50 MHz, CDCl3): = 28.7, 69.1, 70.0, 105.4, 107.3,
117.7, 119.0, 131.5, 132.6.
Anal. Calcd for C11H17NO (179.3): C, 73.70; H, 9.56; N, 7.81.
Found: C, 72.74; H, 9.40; N, 7.76.
13C NMR (50 MHz, CDCl3): = 21.6, 27.3, 33.0, 47.2, 50.7, 52.3,
63.0, 66.9, 120.0, 124.9, 127.1, 127.7, 128.0, 128.9, 130.0, 135.7,
141.3, 143.7, 145.0, 145.8, 156.2, 194.9.
2-Methyl-5-[2-(toluene-4-sulfonyl)ethyl]-1H-pyrrole (15a)
Oil (73%); Rf 0.2 (EtOAc–hexane, 1:4).
IR (neat): 3450, 1320, 1115 cm–1.
1H NMR (200 MHz, CDCl3): = 2.23 (s, 3 H, CH3), 2.47 (s, 3 H,
CH3C6H4), 3.02 (t, 2 H, J = 7.3 Hz, CH2), 3.36 (t, 2 H, J = 7.3 Hz,
CH2S), 5.73–5.75 (m, 2 H, 2 =CH pyrrole), 7.38 (d, 2 H, J = 8.2 Hz,
C6H4), 7.80 (d, 2 H, J = 8.2 Hz, C6H4), 8.22 (br, 1 H, NH).
13C NMR (50 MHz, CDCl3): = 14.2, 21.9, 25.8, 57.9, 108.8,
109.8, 126.4, 129.3, 129.8, 130.1, 136.5, 138.4.
Anal. Calcd for C33H37NO6S (575.7): C, 68.85; H, 6.48; N, 2.43; S,
5.57. Found: C, 68.09; H, 6.30; N, 2.39; S, 5.29.
Vinylpyrroles 14a–d and Pyrrole Sulfones 15a–d; General
Procedure
A solution of 12 (1 mmol) in CH2Cl2 (10 mL) was treated with pip-
eridine (170 mg, 2 mmol) and stirring was continued until consump-
tion of the starting material (TLC monitoring). The solvent was
evaporated under reduced pressure and the residue purified by col-
umn chromatography.
Anal. Calcd for C14H17NO2S (263.4): C, 63.85; H, 6.51; N, 5.32; S,
11.00. Found: C, 63.75; H, 6.25; N, 5.39; S, 12.29.
2-Isopropyl-5-[2-(toluene-4-sulfonyl)ethyl]-1H-pyrrole (15b)
Oil (88%); Rf 0.28 (EtOAc–hexane, 1:4).
IR (neat): 3351, 1316, 1146 cm–1.
1H NMR (200 MHz, CDCl3): = 1.23 (d, 6 H, J = 6.8 Hz, 2 CH3),
2.47 (s, 3 H, CH3C6H4), 2.88 (sept, 1 H, CH), 3.06 (t, 2 H, J = 7.4
Hz, CH2), 3.40 (t, 2 H, J = 7.4 Hz, CH2S), 5.76–5.78 (m, 2 H, 2 =CH
pyrrole), 7.38 (d, 2 H, J = 8 Hz, C6H4), 7.83 (d, 2 H, J = 8 Hz, C6H4),
8.43 (br, 1 H, NH).
13C NMR (50 MHz, CDCl3): = 21.2, 21.9, 22.6, 27.1, 56.4, 102.8,
105.9, 125.9, 128.1, 130.0, 135.9, 139.1, 145.0.
2-Methyl-5-vinyl-1H-pyrrole (14a)
Oil (61%); Rf 0.11 (EtOAc–hexane, 1:2).
IR (neat): 3401, 1632, 1601, 1487, 987 cm–1.
1H NMR (200 MHz, CDCl3): = 2.06 (s, 3 H, CH3), 5.58–5.52 (m,
1 H, =CH, pyrrole), 5.57–5.62 (m, 1 H, =CH pyrrole), 7.24 (dd, 1
H, J = 15.6, 8.1 Hz, =CH), 7.75–7.81 (m, 2 H, =CH2), 10.1 (br s, 1
H, NH).
13C NMR (50 MHz, CDCl3): = 14.1, 106.9, 107.8, 115.0, 116.2,
129.9, 136.9.
Anal. Calcd for C7H9N (107.2): C, 78.46; H, 8.47; N, 13.07. Found:
C, 78.58; H, 8.57; N, 12,94.
Anal. Calcd for C16H21NO2S (291.4): C, 65.95; H, 7.26; N, 4.81; S,
11.00. Found: C, 65.83; H, 7.20; N, 4.79; S, 11.21.
Synthesis 2002, No. 3, 331–338 ISSN 0039-7881 © Thieme Stuttgart · New York

336
S. Benetti et al.
PAPER
2-Benzyl-5-[2-(toluene-4-sulfonyl)ethyl]pyrrole-1-carboxylic
2-Benzyl-5-[2-(toluene-4-sulfonyl)ethyl]-1H-pyrrole (15c)
Oil (27%); Rf 0.32 (EtOAc–hexane, 1:4).
Acid tert-Butyl Ester (16c)
Oil (91%); Rf 0.6 (EtOAc–hexane, 1:1.5).
IR (neat): 1729, 1598, 1322, 1150, 1111 cm–1.
IR (neat): 3365, 1652, 1324, 1144 cm–1.
1H NMR (200 MHz, CDCl3): = 2.46 (s, 3 H, CH3C6H4), 3.16 (t, 2
H, CH2), 3.24 (t, 2 H, CH2S), 3.62 (s, 2 H, CH2C6H5), 5.45–5.47 (m,
1 H, =CH pyrrole), 5.83–5.85 (m, 1 H, =CH pyrrole), 7.25 (s, 5 H,
C6H5); 7.33 (d, 2 H, J = 8 Hz, C6H4), 7.80 (d, 2 H, J = 8 Hz, C6H4),
8.41 (br, 1 H, NH).
13C NMR (50 MHz, CDCl3): = 21.7, 21.9, 35.9, 56.7, 102.6,
104.9, 124.8, 125.7, 128.7, 129.0, 129.5, 129.8, 130.5, 131.8.
1H NMR (200 MHz, CDCl3): = 1.40 (s, 9 H, t-C4H9), 2.46 (s, 3 H,
CH3C6H4), 3.18 (t, 2 H, J = 8.2 Hz, CH2), 3.41 (t, 2 H, J = 8.2 Hz,
CH2S), 4.10 (s, 2 H, CH2C6H5), 5.66 (d, 1 H, J = 3.3 Hz, =CH pyr-
role), 5.83 (d, 1 H, J = 3.3 Hz, =CH pyrrole), 7.03–7.83 (m, 9 H,
C6H5 and C6H4).
13C NMR (50 MHz, CDCl3): = 21.7, 23.6, 27.0, 27.8, 35.7, 55.9,
84.4, 110.8, 112.0, 126.1, 128.2, 128.3, 128.5, 129.9, 131.5, 134.6,
136.2, 139.9, 144.6, 149.8.
Anal. Calcd for C20H21NO2S (339.5): C, 70.77; H, 6.24; N, 4.13; S,
9.45. Found: C, 70.84; H, 6.37; N, 4.15; S, 9.45.
Anal. Calcd for C25H29NO4S (439.6): C, 68.31; H, 6.65; N, 3.19; S,
7.29. Found: C, 68.30; H, 6.67; N, 3.11; S, 7.22.
2-tert-Butoxymethyl-5-[2-(toluene-4-sulfonyl)-ethyl]-1H-
pyrrole (15d)
Oil (53%); Rf 0.48 (EtOAc–hexane, 1:2).
IR (neat): 3359, 1318, 1246, 1195, 1140 cm–1.
2-tert-Butoxymethyl-5-[2-(toluene-4-sulfonyl)ethyl]pyrrole-1-
carboxylic Acid tert-Butyl Ester (16d)
Oil (72%); Rf 0.49 (EtOAc–hexane, 1:2).
IR (neat): 1725, 1315, 1283, 1143 cm–1.
1H NMR (200 MHz, CDCl3): = 1.27 (s, 9 H, t-C4H9), 1.38 (s, 9 H,
t-C4H9), 2.46 (s, 3 H, CH3C6H4), 2.80–2.87 (m, 2 H, CH2), 3.19–
3.24 (m, 2 H, CH2S), 4.34 (s, 2 H, OCH2), 5.71 (d, 1 H, J = 2.8
Hz, =CH pyrrole), 5.85 (d, 1 H, J = 2.8 Hz, =CH pyrrole), 7.30 (d,
2 H, J = 8 Hz, C6H4), 7.81 (d, 2 H, J = 8 Hz, C6H4).
13C NMR (50 MHz, CDCl3): = 21.14, 27.5, 29.2, 31.5, 55.1, 57.6,
73.0, 79.3, 106.5, 107.2, 127.4, 128.8, 129.0, 130.8, 136.4, 145.8,
150.0.
1H NMR (200 MHz, CDCl3): = 1.27 (s, 9 H, t-C4H9), 2.47 (s, 3 H,
CH3C6H4), 2.87–2.96 (m, 2 H, CH2), 3.13–3.21 (m, 2 H, CH2S),
4.36 (s, 2 H, OCH2), 5.66–5.68 (m, 1 H, =CH pyrrole), 5.79–5.82
(m, 1 H, =CH pyrrole), 7.37 (d, 2 H, J = 8 Hz, C6H4), 7.79 (d, 2 H,
J = 8 Hz, C6H4), 8.83 (br, 1 H, NH).
13C NMR (50 MHz, CDCl3): = 21.04, 21.6, 27.6, 31.2, 56.0, 57.3,
73.6, 106.3, 106.7, 127.6, 128.1, 129.2, 129.9, 135.9, 144.8.
Anal. Calcd for C18H25NO3S (335.5): C, 64.45; H, 7.51; N, 4.18; S,
9.56. Found: C, 65.03; H, 7.62; N, 4.06; S, 9.41.
N-Boc-pyrrole Sulfones 16a–d; General Procedure
Anal. Calcd for C23H33NO6S (435.6): C, 63.42; H, 7.64; N, 3.22; S,
7.19. Found: C, 63.58; H, 7.80; N, 3.28; S, 7.19.
CF3CO2H (3 mmol) was added to a solution of 11 (1 mmol) in
CH2Cl2 (10 mL) at r.t. and the mixture was kept at the same temper-
ature until completion of the reaction (TLC monitoring). The sol-
vent was evaporated under reduced pressure and the residue was
subjected to column chromatography to give pure 16.
Compounds 17c and 18c; General Procedure
A solution of 11c or 12c (1 mmol) in EtOAc (10 mL) was hydroge-
nated during 5 h in a Parr apparatus at 75 psi in the presence of 10%
Pd/C as the catalyst. Filtration through Celite and evaporation of the
solvent gave 17c and 18c, respectively.
2-Methyl-5-[2-(toluene-4-sulfonyl)ethyl]pyrrole-1-carboxylic
Acid tert-Butyl Ester (16a)
Oil (85%); Rf 0.3 (EtOAc–hexane, 1:2).
[1-Benzyl-4-oxo-6-(toluene-4-sulfonyl)hexyl]carbamic Acid
tert-Butyl Ester (17c)
White solid (97%); mp 158–160 °C; Rf 0.3 (Et2O–PE, 3:1); [ ]D
–48.9 (c = 1.00, CHCl3).
IR (KBr): 3367, 1710, 1680, 1522, 1315, 1150 cm–1.
1H NMR (200 MHz, CDCl3): = 1.36 (s, 9 H, t-C4H9), 1.43–1.60
(m, 1 H), 1.78–1.90 (m, 1 H), 2.43 (s, 3 H, CH3C6H4), 2.48 (d, 2 H,
J = 7 Hz), 2.68–2.80 (m, 2 H), 2.81 (t, 2 H, J = 7.9 Hz, CH2CO),
3.34 (t, 2 H, J = 7.9 Hz, CH2S), 3.78 (m, 1 H), 4.34 (br s, 1 H, NH),
7.12–7.77 (m, 9 H, C6H5 and C6H4).
13C NMR (50 MHz, CDCl3): = 21.6, 28.1, 28.3, 35.3, 39.4, 41.9,
50.6, 51.0, 79.8, 126.4, 127.9, 128.4, 129.3, 130.0, 135.9, 137.6,
144.9, 155.6, 205.8.
IR (neat): 1737, 1319, 1110 cm–1.
20
1H NMR (200 MHz, CDCl3): = 1.4 (s, 9 H, t-C4H9), 2.20 (s, 3 H,
CH3), 2.50 (s, 3 H, CH3C6H4), 3.02 (t, 2 H, J = 7.4 Hz, CH2), 3.35
(t, 2 H, J = 7.4 Hz, CH2S), 5.69–5.72 (m, 2 H, 2 =CH pyrrole), 7.33
(d, 2 H, J = 8.2 Hz, C6H4), 7.83 (d, 2 H, J = 8.2 Hz, C6H4).
13C NMR (50 MHz, CDCl3): = 21.7, 25.8, 27.9, 36.6, 54.9, 83.7,
109.8, 111.1, 126.2, 128.3, 129.1, 129.8, 136.5, 145.2, 149.9.
Anal. Calcd for C19H25NO4S (363.5): C, 62.78; H, 6.93; N, 3.85; S,
8.82. Found: C, 62.88; H, 6.95; N, 3.83; S, 8.80.
2-Isopropyl-5-[2-(toluene-4-sulfonyl)ethyl]pyrrole-1-carbox-
ylic Acid tert-Butyl Ester (16b)
Oil (78%); Rf 0.5 (EtOAc–hexane, 1:4).
IR (neat): 1735, 1598, 1316, 1086 cm–1.
Anal. Calcd for C25H33NO5S (495.6): C, 65.33; H, 7.24; N, 3.05; S,
6.98. Found: C, 65.99; H, 7.48; N, 3.00; S, 6.80.
1H NMR (200 MHz, CDCl3): = 1.24 (d, 6 H, J = 7 Hz, 2 CH3),
1.44 (s, 9 H, t-C4H9), 2.47 (s, 3 H, CH3C6H4), 2.81–2.94 (m, 1 H,
CH), 3.05–3.12 (m, 2 H, CH2), 3.35–3.45 (m, 2 H, CH2S), 5.75–
5.78 (m, 2 H, 2 =CH pyrrole), 7.38 (d, 2 H, J = 7.2 Hz, C6H4), 7.81
(d, 2 H, J = 7.2 Hz, C6H4).
13C NMR (50 MHz, CDCl3): = 21.3, 21.9, 22.2, 22.9, 27.8, 57.0,
83.9, 102.6, 106.2, 125.4, 128.6, 130.2, 136.2, 140.3, 145.5, 150.2.
[1-Benzyl-4-oxo-6-(toluene-4-sulfonyl)hexyl]carbamic Acid
9H-Fluoren-9-ylmethyl Ester (18c)
Solid (95%); mp 128–130 °C; Rf 0.3 (Et2O–PE, 5:1); [ ]D20 –58.3
(c = 1.00, CHCl3).
IR (KBr): 3381, 1712, 1600, 1453, 1318, 1141 cm–1.
1H NMR (200 MHz, CDCl3): = 1.52–1.93 (m, 2 H), 2.40 (s, 3 H,
CH3C6H4), 2.46 (d, 2 H, J = 7.1 Hz), 2.72–2.85 (m, 4 H), 3.31 (t, 2
H, J = 7.6 Hz), 3.60–3.80 (m, 1 H), 4.13 (t, 1 H, J = 6.5 Hz), 4.20–
4.45 (m, 2 H), 4.60 (br d, 1 H, NH), 7.10–7.81 (m, 17 H).
Anal. Calcd for C21H29NO4S (391.5): C, 64.42; H, 7.47; N, 3.58; S,
8.19. Found: C, 64.45; H, 7.54; N, 3.50; S, 8.27.
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Synthesis of 2,5-Disubstituted Pyrroles and Pyrrolidines
337
13C NMR (50 MHz, CDCl3): = 21.1, 30.0, 32.1, 34.9, 36.5, 42.8,
48.9, 52.8, 72.0, 123.1, 123.9, 124.6, 126.8, 127.1, 128.5, 128.7,
129.9, 134.6, 136.6, 139.8, 143.5, 143.7, 155.2, 205.5.
Anal. Calcd for C13H15N (185.3): C, 84.28; H, 8.16; N, 7.56. Found:
C, 83.75; H, 8.41; N, 7.42.
2-Benzyl-5-ethylpyrrolidine p-Toluenesulfonate (22c)
A solution of 13c (491 mg, 1 mmol) and piperidine (425 mg, 5
mmol) in MeOH (10 mL) was hydrogenated for 5 h in a Parr appa-
ratus (75 psi) in the presence of 10% Pd/C as the catalyst. The mix-
ture was filtered through Celite and the solvent was evaporated. The
residue was purified by column chromatography to give 22c as a
white solid (247 mg, 79%); mp 178–180 °C; Rf 0.35 (EtOAc–
MeOH, 2:1).
Anal. Calcd for C35H35NO5S (581.7): C, 72.26; H, 6.06; N, 2.41; S,
5.51. Found: C, 72.29; H, 6.12; N, 2.52; S, 5.43.
2-Benzyl-5-{2-[(4-methylphenyl)sulfonyl]ethyl}pyrrolidinium
Trifluoroacetate (19c)
A solution of 17c (738 mg, 1.6 mmol) and CF3CO2H (0.37 mL, 4.8
mmol) in CH2Cl2 (10 mL) was stirred at r.t. for 24 h. The solvent
was removed under reduced pressure and the crude residue was im-
mediately dissolved in MeOH. The solution thus obtained was hy-
drogenated for 19 h in a Parr apparatus at 75 psi using 10% Pd/C as
the catalyst. Filtration through Celite and evaporation of the solvent
yielded a brown solid which was triturated with a mixture EtOAc–
Et2O (1:2) and filtered to give 19c as a white solid (570 mg, 78%);
mp 174–177 °C.
IR (KBr): 3370, 2507, 1598, 1455, 1391, 1015, 962 cm–1.
1H NMR (200 MHz, DMSO-d6): = 0.93 (t, 3 H, J = 7 Hz, CH3),
1.25–2.15 (m, 4 H), 2.35 (s, 3 H, CH3C6H4), 2.68–2.91 (m, 2 H),
3.15–3.70 (m, 4 H), 6.28 (br, 2 H, NH2), 7.04–7.63 (m, 9 H, C6H5
and C6H4).
13C NMR (50 MHz, DMSO-d6): = 11.0, 21.4, 26.2, 29.8, 30.0,
60.0, 60.4, 124.4, 126.8, 128.6, 129.1, 137.3, 137.5, 139.3, 153.8.
IR (KBr): 3360, 2495, 1603, 1456, 1385, 1010, 977 cm–1.
1H NMR (200 MHz, DMSO-d6): = 1.50–1.62 (m, 2 H), 1.75–2.02
(m, 3 H), 2.42–2.50 (m, 4 H), 2.85 (dd, 1 H, J = 12, 7.8 Hz), 3.12
(dd, 1 H, J = 12, 7.8 Hz), 3.40–3.47 (m, 2 H), 3.57–3.78 (m, 2 H),
7.30 (s, 5 H, C6H5), 7.48 (d, 2 H, J = 7.8 Hz, C6H4), 7.79 (d, 2 H,
J = 7.9 Hz, C6H4), 9.45 (br s, 2 H, NH2).
13C NMR (50 MHz, DMSO-d6): = 21.1, 25.1, 29.4, 29.6, 37.3,
51.9, 57.2, 59.8, 126.7, 127.8, 128.5, 129.0, 130.0, 131.1 (q, CF3,
J = 259.3), 135.8, 137.2, 144.5.
Anal. Calcd for C20H27NO2S (313.5): C, 69.53; H, 7.88; N, 4.05; S,
9.28. Found: C, 69.24; H, 7.81; N, 3.89; S, 9.72.
1-(2-Benzyl-5-ethylpyrrolidin-1-yl)ethanone (23c)
Et3N (0.2 mL, 1.45 mmol) and Ac2O (0.06 mL, 0.6 mmol) were suc-
cessively added to a stirred suspension of 22c (100 mg, 0.29 mmol)
in anhyd CH2Cl2 (5 mL). After stirring for 6 h, the mixture was
evaporated and the oily residue subjected to column chromatogra-
phy to yield 23c as an oil (60 mg, 89%); Rf 0.2 (Et2O–PE, 4:1);
de 81% (by 1H NMR spectroscopy).
Anal. Calcd for C22H26F3NO4S (457.5): C, 57.76; H, 5.73; N, 3.06;
S, 7.01. Found: C, 57.98; H, 6.00; N, 3.31; S, 7.29.
IR (neat): 1684, 1605, 1555, 1463 cm–1.
2-Benzyl-5-[2-(toluene-4-sulfonyl)ethyl]pyrrolidine (20c)
A solution of 19c (100 mg, 0.29 mmol) in H2O (3 mL) was treated
with NaOH (23 mg, 0.4 mmol) and stirred at r.t. for 0.5 h. Addition-
1H NMR (200 MHz, CDCl3): (for the major isomer) = 0.88 (t, 3
H, J = 7.1 Hz, CH3CH2), 1.32–2.04 (m, 4 H), 2.14 (s, 3 H, CH3CO),
2.45–2.98 (m, 2 H), 3.26 (dd, 1 H, J = 12, 3 Hz), 3.52–3.69 (m, 1
H), 3.92–4.13 (m, 1 H), 4.25–4.39 (m, 1 H), 7.14–7.32 (m, 5 H,
C6H5).
13C NMR (50 MHz, CDCl3): (for the major isomer) = 10.5, 15.8,
24.8, 25.5, 26.8, 40.2, 51.1, 52.7, 126.0, 128.0, 128.5, 138.4, 169.9.
al H2O (7 mL) was added and the mixture extracted with Et2O (3
5
mL). The combined organic phases were dried and evaporated to
give 20c as a colourless oil (94 mg, 95%); Rf 0.65 (CH2Cl2–tolu-
ene–MeOH, 17:2:1); de = 53% as determined by chiral HPLC
(system 1): isocratic elution (MeCN–MeOH–Et3N–AcOH,
85:15:0.01:0.01); tR2 = 4.45, tR1 = 3.54.
Anal. Calcd for C15H21NO (231.3): C, 77.88; H, 9.15; N, 6.05.
Found: C, 77.85; H, 9.13; N, 6.11.
IR (KBr): 3367, 1552, 1450, 1315, 1150 cm–1.
1H NMR (200 MHz, CDCl3): (for the major isomer) = 1.20–1.50
(m, 2 H), 1.71–2.02 (m, 4 H), 2.43 (s, 3 H), 2.55–2.81 (m, 2 H),
3.07–3.49 (m, 5 H), 7.13–7.79 (m, 9 H, C6H5 and C6H4).
13C NMR (50 MHz, CDCl3): (for the major isomer) = 21.6, 29.8,
31.6, 31.8, 42.4, 54.3, 56.0, 58.4, 126.0, 126.2, 128.1, 128.3, 128.4,
129.0, 129.9, 136.3.
Acknowledgments
This work was financially supported by Consiglio Nazionale delle
Ricerche (CNR) and the Ministero dell’Università e della Ricerca
Scientifica e Tecnologica (Cofin 2000).
Anal. Calcd for C20H25NO2S (343.5): C, 69.93; H, 7.34; N, 4.08; S,
9.34. Found: C, 69.90; H, 7.29; N, 4.00; S, 9.48.
References
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2-Benzyl-5-vinyl-3,4-dihydro-2H-pyrrole (21c)
A solution of 18c (459 mg, 1 mmol) and piperidine (425 mg, 5
mmol) in CH2Cl2 (5 mL) was refluxed for 5 h, and then the solvent
was evaporated. Purification of the crude oil by column chromatog-
raphy afforded 21c as an oil (128 mg, 69%); Rf 0.4 (EtOAc–hexane,
2:1 + 2% Et3N); [ ]D20 +27.2 (c = 1.00, CHCl3).
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IR (KBr): 1645, 1598, 1465, 980 cm–1.
1H NMR (200 MHz, CDCl3): = 1.45–1.69 (m, 2 H), 2.28–2.71 (m,
2 H), 2.48 (d, 2 H, J = 7.3 Hz), 4.31–4.48 (m, 1 H), 5.58–5.72 (m, 2
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13C NMR (50 MHz, CDCl3): = 20.0, 28.1, 42.3, 59.9, 121.6,
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Synthesis 2002, No. 3, 331–338 ISSN 0039-7881 © Thieme Stuttgart · New York

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PAPER
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Synthesis 2002, No. 3, 331–338 ISSN 0039-7881 © Thieme Stuttgart · New York