Use of a sterically demanding Lewis acid to direct ring expansion of monoactivated methylenecyclopropanes

Article abstract of DOI:10.1016/j.tet.2007.05.081

A novel synthetic route for the preparation of functionalized alkylidene pyrrolidines via a MAD/n-Bu₄NI-mediated ring expansion of monoactivated MCP was developed. The substrate scope for this reaction was found to be broad for a variety of ald

Full text of DOI:10.1016/j.tet.2007.05.081

Tetrahedron 63 (2007) 8469–8477
Use of a sterically demanding Lewis acid to direct ring
expansion of monoactivated methylenecyclopropanes
*
Catherine Taillier, Yann Bethuel and Mark Lautens
Department of Chemistry, Davenport Chemical Laboratories, 80 St George Street,
University of Toronto, Toronto, Ontario M5S 3H6, Canada
Received 13 March 2007; revised 30 April 2007; accepted 22 May 2007
Available online 26 May 2007
Abstract—A novel synthetic route for the preparation of functionalized alkylidene pyrrolidines via a MAD/n-Bu4NI-mediated ring expansion
of monoactivated MCP was developed. The substrate scope for this reaction was found to be broad for a variety of aldimines and symmet-
rically as well as unsymmetrically monoactivated MCPs yielding the corresponding five-membered heterocyclic compounds in good yields
(up to 92%). This methodology complements previous reports on the ring expansion of MCPs showing that selective syntheses of different
heterocyclic scaffolds could be achieved from the same MCP by just changing the catalyst system.
Crown Copyright Ó 2007 Published by Elsevier Ltd. All rights reserved.
I-
1. Introduction
NRR'
O
LA
Over the past few decades, nucleophilic ring opening of
distal bond
-
LA/I
electron deficient cyclopropyl derivatives and subsequent
use of the resulting enolate intermediates for the construc-
tion of heterocyclic compounds has received considerable
attention.1,2 However, the development of novel and simple
ring expansion methods constitutes a continuing challenge,
as five- and six-membered cycles are essential structural
units, which could serve as precursors to a variety of chem-
ically and biologically important compounds.3
cleavage
R''
O
TsN
γ
NRR'
R''
O
NRR' LA = MgI2
R''
OLA
NRR'
LA = MAD
I
α
N
N
Ts
Ts
γ-alkylation/cyclization
TsN
α-alkylation/cyclization
R''
I
Scheme 1. Divergent selectivity in the Lewis acid-mediated ring expansion
of monoactivated MCP amides.
Recently, we reported the syntheses of cyclic diazadienes4
and b,g-unsaturated lactams5 by Mg-mediated ring expan-
sion of methylenecyclopropyl (MCP) derivatives in the
absence of an electrophile. Interestingly, when the latter
transformation was conducted in the presence of aryl N-tosyl
aldimines, 2,3-disubstituted methylene pyrrolidines were
obtained.6 A key intermediate was proposed to be the tri-
functional vinylogous enolate I generated in situ from ring
opening of the MCP amide. We observed that addition of
the electrophile occurred exclusively at the a-position of the
vinylogous enolate in the presence of MgI2. We postulated
that use of a sterically demanding Lewis acid such as Yama-
moto’s MAD7 reagent might direct the reaction to the g-po-
sition and we now describe our success with this concept. As
a result, regioisomeric alkylidene pyrrolidines now become
readily available (Scheme 1).
2. Results and discussion
Inspired by the early work from Carreira and co-workers,2
ring opening of MCP amides promoted by MgI2 is believed
to occur through electrophilic activation of the carbonyl
group and simultaneous attack of iodide released from MgI2
(Scheme 1). To mimic the push–pull behaviour of MgI2 and
allow ring opening to occur, we envisioned using a Lewis
acid in combination with an external source of iodide. A pre-
liminary study focused on the screening of Lewis acids8 and
sources of iodide revealed that MAD [methylaluminum
bis[2,6-di-tert-butyl-4-methyl-phenoxide)] and n-Bu4NI were
the most effective. Indeed, this combination of reagents
was able to promote ring opening of MCP amide 1 in the
presence of imine 2a (Scheme 2). Moreover, we were par-
ticularly pleased to observe that the reaction led to the ex-
clusive formation of alkylidene pyrrolidine 3a (91%) as a
* Corresponding author. Tel.: +1 416 978 6083; fax: +1 416 946 8185;
e-mail: mlautens@alchemy.chem.utoronto.ca
0040–4020/$ - see front matter Crown Copyright Ó 2007 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.081

8470
C. Taillier et al. / Tetrahedron 63 (2007) 8469–8477
Table 1. Scope of the reaction with various N-tosyl aldimines
t-Bu
Me Al O
t-Bu
2
R''
TsN
Me
O
O
NPh2
NPh2
2
MAD (1.1 equiv)
NPh2
+
R''
n-Bu4NI (1.0 equiv)
O
NPh2
R''
1
N
N
O
O
CH2Cl2, toluene, rt
NPh2
NPh2
Ts
Ts
O
+
1
MAD (1.1 equiv)
+
Ph
3-exo
3-endo
n-Bu NI (1.0 equiv)
4
Ph
H
N
N
CH2Cl2,7h, rt
91%
Ts
Ts
Entry Imine R00
Time (h) Product Yielda (%) exo/endo
TsN Ph
2a
3a-exo
3a-endo
1
2
3
4
5
6
7
8
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2,4-Me2–C6H3
2-Naphthyl
4-MeO–C6H4
2-Br–C6H4
4-Br–C6H4
2-CF3–C6H4
4-CF3–C6H4
3-NO2–C6H4
2,4-Cl2–C6H3
2-Furyl
3-Furyl
2-(N-Me-pyrrole) 18
Cinnamyl
i-Bu
Cyclohexyl
12
5
8
24
8
18
8
14
12
8
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
61
92
64
41
89
58
67
61
89
86
38
46
81
59
35
4:1
>20:1
13:1
exo/endo = 5.25:1
Scheme 2. Preliminary results for the MAD/n-Bu4NI-promoted ring expan-
sion of MCP 1 in the presence of N-tosyl aldimine 2a.
8:1
4.25:1
4.5:1
2.85:1
5:1
mixture of two isomers, which would result from g-alkyl-
ation of a vinylogous enolate intermediate I. In addition,
it was shown that the major isomer 3a-exo was obtained
as only one geometric isomer of E configuration.9 The ob-
served regioselectivity might be explained by the size of the
Lewis acid, which would prevent alkylation from occurring
at the a-position.10 But it is not possible at this time to rule
out effects arising from the change in metal (Mg vs Al) or
reaction conditions. Furthermore, it is reasonable to think
that the 3a-exo product would be formed directly following
the postulated pathway, while the isomer 3a-endo would
arise from isomerization of 3a-exo. Indeed, when the exo-
regioisomer of 3a was subjected to the reaction conditions,
a partial isomerization was observed leading to a mixture of
3a-exo/3a-endo in a 1:1 ratio.
9
18:1
10
11
12
13
14
15
>20:1
8.5:1
>20:1
>20:1b
>20:1
>20:1
16
18
24
24
a
Isolated overall yields.
Isolated as an inseparable mixture of geometric isomers E/Z¼4.5:1.
b
aldimine 2m, the corresponding pyrrolidine 3m could be
isolated in 46% yield. In the cases where a heteroatom is
present at the 2-position, no isomerization of the exo-product
was observed. We also found that the reaction could be suc-
cessfully achieved with the conjugated aldimine 2n in 81%
yield (entry 13).
Among the changes that we made to optimize the reaction,
solvent, reaction time, temperature or quantity of MAD
and iodide, were varied but the original conditions [MCP
(1.0 equiv), aldimine (1.2 equiv), MAD (1.1 equiv), n-
Bu4NI (1.0 equiv), CH2Cl2, rt] proved to give the best over-
all yields and limit the competing isomerization reaction.11
To further expand the scope of the reaction, aliphatic aldi-
mines 2o and 2p were also tested (entries 14 and 15). Despite
lower reactivities, the ring expansion conditions allowed the
formation of expected alkyl-substituted pyrrolidines 3o and
3p in 59% and 35% yield, respectively. The success of these
reactions was governed by the size of the alkyl aldimines.
Indeed, reaction of the aldimine substituted with a tert-butyl
group failed completely.
The substrate scope for the MAD/n-Bu4NI-mediated ring
expansion of N,N-diphenyl MCP amide 1 was examined us-
ing a variety of aldimines. Representative results of the ring
expansion of MCP 1 with substituted aromatic, heteroaro-
matic and aliphatic aldimines using a mixture of MAD and
n-Bu4NI in dichloromethane at room temperature are shown
in Table 1. In all cases, the reactions proceeded smoothly
providing the g-alkylation products 3 in yields up to 92%.
As previously mentioned, partial isomerization of the exo-
product was observed and variable ratio of exo/endo isomers
were obtained.
We also examined the reaction of other N,N-unsymmetri-
cally substituted MCP derivatives 4 and 5 with different tosyl
imines (2) (Table 2). An excess of MAD (2.2 equiv) gave the
expected alkylidene pyrrolidines 6 and 7 in excellent selec-
tivity but in moderate to low yields (28–55%). Neither elec-
tronic nor steric effects can be used to explain the dramatic
changes in the isomeric ratio. The exo-compound could eas-
ily be transformed into the more stable endo-derivative by
treatment with base suggesting that the exo-isomer is the ki-
netic product.12 The results obtained with the Weinreb amide
MCPs (5) were particularly gratifying since the analogous
MgI2-mediated ring expansion reactions yielding methylene
pyrrolidines is so far limited to N,N-diaryl MCP amides.
In the case of aromatic aldimines, the electronic nature of the
substituents seemed to have little or no influence on the suc-
cess or the rate of the ring expansion process (entries 1–9).
However, the presence of sterically demanding ortho-sub-
stituents on the aromatic ring tends to lower the reactivity
(entries 1, 4, 6). Longer reaction times were required in these
cases for complete conversion of the starting MCP 1.
In conclusion, we have developed a novel route for the prep-
aration of functionalized alkylidene pyrrolidines via MAD/
n-Bu4NI-mediated ring expansion of monoactivated methyl-
enecyclopropanes. This discovery complements previous
reports on the ring expansion of MCPs showing that selec-
tive syntheses of different pyrrolidine scaffolds could be
achieved from the same MCP by simply changing the cata-
lyst system.
Use of heteroaromatic aldimines was also found to be effec-
tive in the ring expansion of MCP 1 with MAD/n-Bu4NI as
the promoter (entries 10–12). For the furyl series, reaction
yields were found to be dependent on the position of the
heteroatom in the aromatic ring. On the other hand, when
the reaction was carried out with the 2-pyrrole-substituted

C. Taillier et al. / Tetrahedron 63 (2007) 8469–8477
Table 2. Use of monoactivated unsymmetrical MCP derivatives
8471
2
R''
TsN
O
O
MAD (2.2 equiv)
NRR'
NRR'
R''
n-Bu4NI (1.0 equiv)
NRR'
+
CH2Cl2, toluene, rt
O
R''
N
N
Ts
Ts
4-5
6-7-exo 6-7-endo
Entry
MCP
R
R0
R00
Product
Yielda (%)
exo/endo
1
2
3
4
5
6
7
8
4
4
4
4
4
5
5
5
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
2-Pyr
2-Pyr
2-Pyr
2-Pyr
2-Pyr
OMe
OMe
OMe
Ph
6a
6b
6c
6d
6e
7a
7b
7c
55
48
33
39
28
51
52
33
>20:1
<1:20
<1:20
>20:1
<1:20
>20:1
>20:1
<1:20
2-Naphthyl
4-CF3–C6H4
4-MeO–C6H4
2-(N-Me–pyrrole)
Ph
2-Naphthyl
4-CF3–C6H4
a
Isolated overall yields.
3. Experimental
3.2.1. 2-Methylenecyclopropane carboxylic acid diphen-
ylamide 1.6a To a solution of MCP carboxylic acid (3.96 g,
40 mmol) and triethylamine (5.58 mL, 40 mmol) in THF
(150 mL) was added isobutylchloroformate (5.19 mL,
40 mmol) at 0 ꢀC. The solution was stirred at 0 ꢀC for 15 min
followed by the addition of lithium diphenylamide, which
was prepared by adding n-BuLi (17.6 mL, 44 mmol, 2.5 M
solution in hexanes) into a solution of diphenylamine
(7.45 g, 44 mmol) in THF (20 mL) at ꢁ78 ꢀC and warming
to room temperature for 30 min. The resulting mixture was
stirred at room temperature for 4 h. After quenching with
saturated NH4Cl solution, the reaction mixture was extracted
with EtOAc (2ꢂ250 mL). The combined organic extracts
were washed with H2O (250 mL), brine (250 mL) and dried
over MgSO4, filtered and concentrated. Flash chromato-
graphy on silica gel (hexanes/EtOAc 8:1) furnished the prod-
uct 1 (6.5 g, 26 mmol, 65%) as a beige solid. Mp¼51–53 ꢀC;
Rf¼0.52 (hexanes/EtOAc 3:1); IR (CH2Cl2) n 3062, 3036,
2991, 1742, 1668, 1594, 1490, 1448, 1361, 1251, 1177,
1158, 1103, 1074, 1025, 1003, 971, 900, 754, 755, 700,
3.1. General
Allflaskswereflame-driedundera streamofargonandcooled
before use. All experiments were performed under anhydrous
conditions under an atmosphere of argon. Solvents and solu-
tions were transferred with syringes and cannulae using stan-
dard inert atmosphere techniques. Tetrahydrofuran (THF)
was distilled under nitrogen from Na/benzophenone immedi-
ately prior to use. Dichloromethane was distilled under nitro-
gen from CaH2 immediately before use. All reagents were
used as received from Sigma–Aldrich except n-Bu4NI, which
was recrystallized from toluene (5 mL/g) at 110 ꢀC by adding
hot hexanes (three-times the amount of toluene). Column
chromatography was carried out as ‘flash chromatography’
as reported by Still13 using neutral silica (Silicycle, Quebec,
Canada).
Melting points were recorded using a Fisher–Johns melting
point apparatus and are uncorrected. 1H and 13C NMR spec-
tra were recorded using either a Varian Gemini 300 or Mer-
cury Unity 400 MHz spectrometers in CDCl3 with chemical
shifts relative to tetramethylsilane (TMS, 0 ppm) unless
otherwise reported. Spectral features are tabulated in the fol-
lowing order: chemical shift (d, ppm); number of protons;
multiplicity (s-singlet, d-doublet, t-triplet, q-quartet, m-com-
plex multiplet); coupling constants (J, Hz). No special nota-
tion is used for equivalent carbons. IR spectra were obtained
using a Nicolet DX FTIR spectrometer as thin films on NaCl
plates. High-resolution mass spectra were obtained using a
VG 70-250S (double focusing) mass spectrometer at 70 eV.
1
616 cmꢁ1; H NMR (300 MHz, CDCl3) d 7.46–7.14 (10H,
m), 5.51–5.44 (2H, m), 2.24–2.15 (1H, m), 2.05–1.96 (1H,
m), 1.53–1.43 (1H, m); 13C NMR (75 MHz, CDCl3)
d 170.7, 142.9, 132.4, 129.4, 128.5, 127.9, 127.1, 103.4,
19.9, 11.5; HRMS calcd for C17H15NO (M)+ 249.1154,
found 249.1166.
3.2.2. 2-Methylenecyclopropane carboxylic acid phenyl-
pyridin-2-yl-amide 4. To a solution of MCP carboxylic
acid (3.96 g, 40 mmol, 1 equiv) and triethylamine (5.58 mL,
40 mmol, 1 equiv) in THF (150 mL) was added isobutyl-
chloroformate (5.19 mL, 40 mmol, 1 equiv) at 0 ꢀC. The so-
lution was stirred at 0 ꢀC for 15 min followed by the addition
of lithium N-phenyl(2-pyridyl)amide, which was prepared
by adding n-BuLi (17.6 mL, 2.5 M solution in hexanes,
44 mmol, 1.1 equiv) into a solution of N-phenyl(2-pyridyl)-
amine (7.45 g, 44 mmol, 1.1 equiv) in THF (20 mL) at
ꢁ78 ꢀC and warming to room temperature for 30 min. The
resulting mixture was stirred at room temperature for 6 h.
After quenching with saturated NH4Cl solution, the reaction
mixture was extracted with EtOAc (2ꢂ250 mL). The com-
bined organic extracts were washed with H2O (250 mL),
brine (250 mL) and dried over MgSO4, filtered and
3.2. Preparation of starting materials
p-Toluenesulfonyl (tosyl) aromatic and aliphatic aldimines
2a–p were prepared in moderate to good yields according to
known procedures.14 2-Methylenecyclopropane carboxylic
acid diphenylamide 1, 2-methylenecyclopropane carboxylic
acid phenyl-pyridin-2-yl-amide 4 and 2-methylenecyclopro-
pane carboxylic acid methoxymethylamide 5 were prepared
from 2-methylenecyclopropane carboxylic acid ethyl ester
and 2-methylenecyclopropane carboxylic acid.15

8472
C. Taillier et al. / Tetrahedron 63 (2007) 8469–8477
concentrated. Flash chromatography on silica gel (hexanes/
EtOAc 8:1) furnished the product 4 (6.3 g, 25 mmol, 63%)
as a pale yellow solid. Mp¼61–63 ꢀC; Rf¼0.45 (hexanes/
EtOAc 3:1); IR (CH2Cl2) n 3032, 3011, 2989, 1673, 1585,
1491, 1466, 1432, 1356, 1239, 1185, 1105, 904, 778,
699 cmꢁ1; 1H NMR (400 MHz, CDCl3) d 8.42 (1H, dm, J¼
4.0 Hz), 7.73 (1H, tm, J¼7.2 Hz), 7.56 (1H, d, J¼8.0 Hz),
7.48–7.30 (5H, m), 7.11 (1H, m), 5.03 (1H, m), 5.47 (1H,
m), 2.22–2.17 (1H, m), 2.05–1.97 (1H, m), 1.54–1.45 (1H,
m); 13C NMR (100 MHz, CDCl3) d 171.6, 155.3, 149.0,
141.8, 137.9, 132.3, 129.7, 129.0, 127.8, 121.4, 103.7,
20.2, 11.6; HRMS calcd for C16H14N2O (M)+ 249.1028,
found 249.1022.
3.3.1.1. (E)-N,N-Diphenyl-2-[5-phenyl-1-(toluene-4-
sulfonyl)pyrrolidin-3-ylidene]acetamide 3a-exo. White
solid (78 mg, 76%). Mp¼168–170 ꢀC; Rf¼0.28 (hexanes/
EtOAc¼3:1); IR (thin film) n 3061, 2923, 1666, 1596,
1491, 1384, 1348, 1268, 1164, 1093, 759, 736, 701,
1
667 cmꢁ1; H NMR (400 MHz, CDCl3) d 7.60–7.54 (2H,
m), 7.39–7.04 (17H, m), 5.76 (1H, m), 5.03 (1H, dd,
J¼8.8, 3.1 Hz), 4.17 (1H, d, J¼16.6 Hz), 4.07 (1H, dm,
J¼16.6 Hz), 3.40 (1H, dm, J¼18.7 Hz), 3.11 (1H, br
dd, J¼18.7, 8.8 Hz), 2.41 (3H, s); 13C NMR (75 MHz,
CDCl3) d 163.4, 154.2, 143.6, 142.3, 141.1, 134.7, 129.6,
128.4, 127.4, 127.3, 126.3, 114.7, 63.3, 53.7, 39.6, 21.5;
HRMS calcd for C31H28N2O3S (M)+ 508.1821, found
508.1831.
3.2.3. 2-Methylenecyclopropanecarboxylicacidmethoxy-
methylamide 5. To a solution of MCP acid (0.59 g,
6.0 mmol, 1 equiv) in CH2Cl2 (50 mL) were added DMAP
(0.15 g, 1.2 mmol, 20 mol %) and N,O-dimethylhydroxyl-
amine hydrochloride (0.87 g, 9.0 mmol, 1.5 equiv). After
complete dissolution, the solution was cooled to 0 ꢀC and
diisopropylamine (1.56 mL, 9.00 mmol, 1.5 equiv) and
EDCI (1.71 g, 9.00 mmol, 1.5 equiv) were added. After
30 min of stirring at 0 ꢀC and 16 h at room temperature,
the reaction mixture was washed with a saturated aqueous
solution of NaHCO3. The aqueous layer was extracted
with EtOAc (3ꢂ15 mL) and the combined organic extracts
were washed with H2O, dried over MgSO4, filtered and con-
centrated. Flash chromatography on silica gel (hexanes/
EtOAc 5:1) furnished the product 5 (0.45 g, 3.2 mmol,
55%) as a colourless oil. Rf¼0.31 (hexanes/EtOAc 3:1); IR
(CH2Cl2) n 3502, 3076, 2971, 2938, 1741, 1641, 1493,
3.3.1.2. N,N-Diphenyl-2-[5-phenyl-1-(toluene-4-sulfon-
yl)-2,5-dihydro-1H-pyrrol-3-yl]acetamide 3a-endo. Col-
ourless oil (15 mg, 15%). Rf¼0.21 (hexanes/EtOAc¼3:1);
IR (CH2Cl2) n 3062, 2921, 1667, 1596, 1494, 1338, 1161,
1
1075, 757, 701, 672 cmꢁ1; H NMR (400 MHz, CDCl3)
d 7.49–7.05 (19H, m), 5.48 (1H, br s), 5.33 (1H, br s),
4.35–4.22 (2H, m), 3.13 (2H, s), 2.36 (3H, s); 13C NMR
(100 MHz, CDCl3) d 168.9, 143.0, 140.4, 135.6, 132.4,
129.4, 128.4, 127.7, 127.5, 127.3, 127.2, 70.2, 56.8, 35.8,
21.4; HRMS calcd for C31H28N2O3S (M)+ 508.1821, found
508.1827.
General procedure A was followed (stirring at rt for 12 h)
using N-(2,4-dimethyl-benzylidene)-4-methyl-benzenesul-
fonamide (69 mg, 0.24 mmol, 1.2 equiv).
1
1417, 1385, 1180, 1110, 989, 908, 887 cmꢁ1; H NMR
3.3.1.3.
(E)-2-[5-(2,4-Dimethylphenyl)-1-(toluene-4-
(400 MHz, CDCl3) d 5.51 (1H, m), 5.46 (1H, m), 3.78
(3H, s), 3.23 (s, 3H), 2.81 (br s, 1H), 1.88 (m, 1H), 1.61
(m, 1H); 13C NMR (100 MHz, CDCl3) d 171.5, 131.3,
103.7, 61.6, 32.5, 15.6, 10.2; HRMS calcd for C7H12NO2
(M+H)+ 142.0862, found 142.0869.
sulfonyl)pyrrolidin-3-ylidene]-N,N-diphenylacetamide3b-
exo. White solid (52 mg, 49%). Mp¼192–194 ꢀC; Rf¼0.25
(hexanes/EtOAc¼3:1); IR (CH2Cl2) n 3059, 2921, 1669,
1643, 1596, 1491, 1382, 1348, 1267, 1164, 1093, 735, 701,
1
665 cmꢁ1; H NMR (400 MHz, CDCl3) d 7.62–7.54 (2H,
m), 7.33–6.84 (15H, m), 5.77 (1H, m), 5.15 (1H, dd, J¼8.8,
3.7 Hz), 4.19 (2H, br s), 3.25 (1H, br dd, J¼18.5, 8.8 Hz),
3.11 (1H, br d, J¼18.5 Hz), 2.42 (3H, s), 2.29 (3H, s), 2.28
(3H, s); 13C NMR (100 MHz, CDCl3) d 165.4, 154.0, 143.6,
142.3, 137.1, 136.6, 134.8, 134.0, 131.3, 129.6, 129.4,
127.4, 126.5, 125.3, 114.8, 60.7, 54.4, 39.7, 21.5, 20.9, 19.3;
HRMS calcd for C33H32N2O3S (M)+ 536.2134, found
536.2133.
3.3. MAD/n-Bu4NI-mediated ring expansion of MCPs
3.3.1. General procedure A. To a solution of 2,6-di-tert-
butyl-4-methylphenol (97 mg, 0.44 mmol, 2.2 equiv) in tol-
uene (0.45 mL) at room temperature was added a solution of
trimethylaluminum (0.11 mL, 2 M in toluene, 0.22 mmol,
1.1 equiv) dropwise. After 1 h of stirring at room tempera-
ture, the resulting solution was cooled to 0 ꢀC and a solution
of MCP 1 (0.20 mmol, 50 mg, 1 equiv), N-tosyl aldimine
(0.24 mmol, 1.2 equiv) and n-Bu4NI (74 mg, 0.2 mmol,
1 equiv) in CH2Cl2 (2 mL) was added dropwise. The result-
ing yellow solution was stirred at 0 ꢀC for 30 min and al-
lowed to warm to room temperature. Reaction completion
was monitored by TLC. The reaction mixture was poured
into a saturated aqueous solution of NH4Cl and the aqueous
layer was extracted with EtOAc (three-times 25 mL). The
combined organic extracts were washed with H2O (15 mL)
and brine (15 mL), dried over Na2SO4, filtered and concen-
trated in vacuo. Purification of the resulting oil by chromato-
graphy on silica gel (gradient hexanes/EtOAc; 5:1–3:1) gave
the expected products.
3.3.1.4. 2-[5-(2,4-Dimethylphenyl)-1-(toluene-4-sulfon-
yl)-2,5-dihydro-1H-pyrrol-3-yl]-N,N-diphenylacetamide
3b-endo. Colourless oil (13 mg, 12%). Rf¼0.16 (hexanes/
EtOAc¼3:1); IR (thin film) n 3062, 2921, 1672, 1596, 1491,
1
1346, 1162, 1096, 671 cmꢁ1; H NMR (400 MHz, CDCl3)
d 7.54–7.05 (15H, m), 6.92–6.87 (2H, m), 5.68 (1H, m),
5.25 (1H, m), 4.37–4.24 (2H, m), 3.09 (2H, s), 2.38 (3H, s),
2.33 (3H, s), 2.27 (3H, s); 13C NMR (100 MHz, CDCl3)
d 168.9, 143.0, 137.0, 135.6, 135.5, 134.5, 131.6, 131.2,
129.4, 127.6, 127.3, 127.1, 127.0, 67.0, 57.0, 35.8, 21.5, 21.0,
19.0; HRMS calcd for C33H32N2O3S (M)+ 536.2134, found
536.2129.
General procedure A was followed (stirring at rt for 7 h)
using N-benzylidene-4-methyl-benzenesulfonamide (62 mg,
0.24 mmol, 1.2 equiv).
General procedure A was followed (stirring at rt for 5 h)
using 4-methyl-N-naphthalen-1-ylmethylene-benzenesulfon-
amide (74 mg, 0.24 mmol, 1.2 equiv).

C. Taillier et al. / Tetrahedron 63 (2007) 8469–8477
8473
3.3.1.5. (E)-2-[5-Naphthalen-1-yl-1-(toluene-4-sulfon-
yl)-pyrrolidin-3-ylidene]-N,N-diphenylacetamide 3c-exo.
Colourless oil (102 mg, 92%). Rf¼0.25 (hexanes/
EtOAc¼3:1); IR (thin film) n 3059, 2921, 1669, 1643, 1597,
1490, 1382, 1348, 1292, 1270, 1163, 1093, 735, 701,
3.35 (1H, dm, J¼18.7 Hz), 3.12 (1H, m), 2.43 (3H, s); 13C
NMR (75 MHz, CDCl3) d 165.6, 153.7, 144.1, 142.6, 140.5,
134.9, 131.8, 130.0, 129.8, 128.4, 127.7, 121.7, 115.1, 63.1,
54.0, 39.8, 21.8; HRMS calcd for C31H27BrN2O3S (M)+
586.0926, found 586.0935.
1
669 cmꢁ1; H NMR (300 MHz, CDCl3) d 7.92–7.62 (5H,
m), 7.51–6.98 (16H, m), 5.84–5.74 (2H, m), 4.41–4.23 (2H,
m), 3.42–3.34 (2H, m), 2.41 (3H, s); 13C NMR (75 MHz,
CDCl3) d 165.6, 154.3, 144.1, 142.6, 137.5, 135.3, 134.2,
130.2, 130.0, 129.8, 129.2, 128.4, 127.7, 126.6, 126.5,
125.3, 123.5, 123.1, 115.2, 61.6, 54.6, 40.5, 21.8; HRMS
calcd for C35H30N2O3S (M)+ 558.1977, found 558.1976.
3.3.1.9. 2-[5-(4-Bromo-phenyl)-1-(toluene-4-sulfonyl)-
2,5-dihydro-1H-pyrrol-3-yl]-N,N-diphenylacetamide 3f-
endo. Colourless oil (20 mg, 17%). Rf¼0.22 (hexanes/
EtOAc¼3:1); IR (thin film) n 3061, 1664, 1595, 1491,
1341, 1162, 1096, 702, 669 cmꢁ1 1H NMR (400 MHz,
;
CDCl3) d 7.60–7.07 (18H, m), 5.42 (1H, s), 5.31 (1H, s),
4.32–4.24 (2H, m), 3.13 (2H, s), 2.38 (3H, s); 13C NMR
(75 MHz, CDCl3) d 169.0, 143.5, 139.7, 135.7, 133.3,
131.7, 129.7, 129.4, 127.4, 127.2, 121.9, 69.8, 57.1, 36.0,
21.7; HRMS calcd for C31H27BrN2O3S (M)+ 586.0926,
found 586.0922.
General procedure A was followed (stirring at rt for 8 h)
using N-(4-methoxy-benzylidene)-4-methyl-benzenesulfon-
amide (69 mg, 0.24 mmol, 1.2 equiv).
3.3.1.6. (E)-2-[5-(4-Methoxyphenyl)-1-(toluene-4-sul-
fonyl)pyrrolidin-3-ylidene]-N,N-diphenylacetamide 3d-
exo. Yellow solid (64 mg, 59%). Mp¼126–128 ꢀC; Rf¼
0.26 (hexanes/EtOAc¼3:1); IR (CH2Cl2) n 3061, 2925,
1668, 1644, 1596, 1513, 1490, 1383, 1347, 1293, 1249,
General procedure A was followed (stirring at rt for 18 h)
using 4-methyl-N-(2-trifluoromethyl-benzylidene)-benz-
enesulfonamide (78 mg, 0.24 mmol, 1.2 equiv).
1163, 1092, 1033, 732, 701, 665 cmꢁ1
;
1H NMR
3.3.1.10. (E)-N,N-Diphenyl-2-[1-(toluene-4-sulfonyl)-5-
(2-trifluoromethylphenyl)pyrrolidin-3-ylidene]acetamide
3g-exo. Pale yellow solid (55 mg, 48%). Mp¼158–160 ꢀC;
Rf¼0.23 (hexanes/EtOAc¼3:1); IR (CH2Cl2) n 3062, 2925,
1670, 1643, 1597, 1491, 1387, 1353, 1313, 1275, 1164,
(400 MHz, CDCl3) d 7.83–7.53 (2H, m), 7.41–7.08 (14H,
m), 6.84–6.78 (2H, m), 5.76 (1H, br s), 4.95 (1H, m),
4.18–4.01 (2H, m), 3.79 (3H, s), 3.37 (1H, br d,
J¼18.7 Hz), 3.08 (1H, br dd, J¼18.7, 8.8 Hz), 2.42 (3H,
s); 13C NMR (100 MHz, CDCl3) d 163.4, 154.4, 143.6,
143.5, 142.4, 139.1, 134.8, 133.2, 129.7, 129.6, 129.2, 127.7,
127.4, 126.4, 114.5, 113.8, 63.0, 55.3, 53.7, 39.6, 21.5;
HRMS calcd for C32H30N2O4S (M)+ 538.1926, found
538.1928.
1
1119, 756, 701, 665 cmꢁ1; H NMR (400 MHz, CDCl3)
d 7.70–7.07 (18H, m), 5.82 (1H, m), 5.19 (1H, dd, J¼9.4,
4.6 Hz), 4.33 (1H, br d, J¼15.6 Hz), 4.06 (1H, m), 3.40
(1H, br dd, J¼19.1, 9.0 Hz), 3.12 (1H, br d, J¼19.1 Hz),
2.44 (3H, s); 13C NMR (100 MHz, CDCl3) d 165.3, 152.3,
144.1, 142.3, 133.1, 132.1, 129.8, 129.7, 127.8, 127.4,
127.3, 125.8, 125.7, 115.1, 59.7, 55.3, 41.4, 21.5; HRMS
calcd for C32H27F3N2O3S (M)+ 576.1694, found 576.1685.
General procedure A was followed (stirring at rt for 24 h)
using N-(2-bromo-benzylidene)-4-methyl-benzenesulfon-
amide (81 mg, 0.24 mmol, 1.2 equiv).
3.3.1.11. N,N-Diphenyl-2-[1-(toluene-4-sulfonyl)-5-(2-
trifluoromethylphenyl)-2,5-dihydro-1H-pyrrol-3-yl]acet-
amide 3g-endo. Colourless oil (12 mg, 10%). Rf¼0.16
(hexanes/EtOAc¼3:1); IR (thin film) n 3060, 2923, 1674,
1597, 1492, 1454, 1350, 1313, 1272, 1163, 1118, 1058,
3.3.1.7. (E)-2-[5-(2-Bromophenyl)-1-(toluene-4-sulfon-
yl)pyrrolidin-3-ylidene]-N,N-diphenylacetamide 3e-exo.
White solid (43 mg, 37%). Mp¼198–200 ꢀC; Rf¼0.24 (hex-
anes/EtOAc¼3:1); IR (CH2Cl2) n 3061, 2924, 1669, 1643,
1595, 1491, 1384, 1351, 1292, 1267, 1165, 1093, 755, 701,
1
1036, 733, 702, 672 cmꢁ1; H NMR (400 MHz, CDCl3)
1
665 cmꢁ1; H NMR (400 MHz, CDCl3) d 7.74–7.66 (2H,
d 7.82–7.65 (2H, m), 7.63–7.48 (2H, m), 7.37–7.01 (14H,
m), 5.74 (1H, br s), 5.17 (1H, s), 4.45 (1H, dd, J¼14.2,
5.3 Hz), 4.32 (1H, d, J¼14.2 Hz), 3.05 (2H, s), 2.40 (3H,
s); 13C NMR (100 MHz, CDCl3) d 168.7, 143.7, 140.7,
134.0, 132.4, 131.7, 129.8, 129.7, 129.0, 127.9, 127.6,
127.3, 126.4, 125.4, 125.3, 66.3, 57.6, 35.9, 21.5; HRMS
calcd for C32H27F3N2O3S (M)+ 576.1694, found 576.1694.
m), 7.54–7.06 (16H, m), 5.77 (1H, s), 5.24 (1H, dd, J¼9.4,
4.4 Hz), 4.27 (1H, dd, J¼15.8, 1.3 Hz), 4.11 (1H, d, J¼
15.8 Hz), 3.86 (1H, br dd, J¼18.9, 9.2 Hz), 3.15 (1H, dm,
J¼18.9 Hz), 2,45 (3H, s); 13C NMR (100 MHz, CDCl3)
d 165.3, 152.8, 144.0, 142.3, 141.4, 133.6, 132.9, 129.8,
129.2, 128.8, 127.8, 127.5, 127.4, 115.0, 63.2, 55.0, 39.8,
21.6; HRMS calcd for C31H27BrN2O3S (M)+ 586.0926,
found 586.0924.
General procedure A was followed (stirring at rt for 8 h)
using 4-methyl-N-(4-trifluoromethyl-benzylidene)-benz-
enesulfonamide (78 mg, 0.24 mmol, 1.2 equiv).
General procedure A was followed (stirring at rt for 8 h)
using N-(4-bromo-benzylidene)-4-methyl-benzenesulfon-
amide (81 mg, 0.24 mmol, 1.2 equiv).
3.3.1.12. (E)-N,N-Diphenyl-2-[1-(toluene-4-sulfonyl)-5-
(4-trifluoromethylphenyl)pyrrolidin-3-ylidene]acetamide
3h-exo. White solid (57 mg, 50%). Mp 154–156 ꢀC; Rf¼
0.25 (hexanes/EtOAc¼3:1); IR (CH2Cl2) n 3062, 2925,
1668, 1644, 1596, 1491, 1384, 1326, 1268, 1164, 1123,
3.3.1.8. (E)-2-[5-(4-Bromophenyl)-1-(toluene-4-sulfon-
yl)pyrrolidin-3-ylidene]-N,N-diphenylacetamide 3f-exo.
Yellow solid (84 mg, 72%). Mp¼188–190 ꢀC; Rf¼0.28 (hex-
anes/EtOAc¼3:1); IR (CH2Cl2) n 3061, 1668, 1640, 1595,
1
1067, 737, 701, 667 cmꢁ1; H NMR (300 MHz, CDCl3)
1490, 1384, 1348, 1268, 1163, 1093, 758, 701, 667 cmꢁ1
;
d 7.59–7.48 (4H, m), 7.45–7.07 (14H, m), 5.80 (1H, m), 5.02
(1H, dd, J¼8.8, 3.8 Hz), 4.23–4.04 (2H, m), 3.38 (1H, m),
3.20 (1H, m), 2.41 (3H, s); 13C NMR (75 MHz, CDCl3)
1H NMR (400 MHz, CDCl3) d 7.59–7.02 (18H, m), 5.77
(1H, m), 4.93 (1H, dd, J¼8.8, 3.5 Hz), 4.18–4.03 (2H, m),

8474
C. Taillier et al. / Tetrahedron 63 (2007) 8469–8477
d 165.5, 153.4, 144.2, 142.5, 134.8, 130.0, 127.6, 127.0,
125.7, 115.2, 63.2, 54.2, 40.0, 21.7; HRMS calcd for
C32H27F3N2O3S (M)+ 576.1694, found 576.1696.
21.5; HRMS calcd for C31H26Cl2N2O3S (M)+ 576.1041,
found 576.1032.
3.3.1.17. 2-[5-(2,4-Dichlorophenyl)-1-(toluene-4-sulfon-
yl)-2,5-dihydro-1H-pyrrol-3-yl]-N,N-diphenylacetamide
3j-endo. Pale yellow oil (5 mg, 5%). Rf¼0.18 (hexanes/
EtOAc¼3:1); IR (thin film) n 3063, 2922, 1672, 1595,
3.3.1.13.
N,N-Diphenyl-2-[1-(toluene-4-sulfonyl)-5-
(4-trifluoromethylphenyl)-2,5-dihydro-1H-pyrrol-3-yl]-
acetamide 3h-endo. Colourless oil (20 mg, 17%). Rf¼0.19
(hexanes/EtOAc¼3:1); IR (thin film) n 3064, 2923, 1672,
1596, 1492, 1346, 1325, 1162, 1124, 1066, 733, 702,
1491, 1347, 1163, 1097, 815, 736, 703, 671 cmꢁ1 1H
;
NMR (300 MHz, CDCl3) d 7.84–7.65 (3H, m), 7.47–7.05
(14H, m), 5.77 (1H, br s), 5.29 (1H, s), 4.40–4.27 (2H, m),
3.08 (2H, s), 2.41 (3H, s); 13C NMR (100 MHz, CDCl3)
d 168.7, 143.8, 137.2, 134.2, 133.7, 132.8, 132.2, 129.8,
129.7, 129.0, 127.6, 126.4, 125.8, 66.8, 57.4, 35.8, 21.5;
HRMS calcd for C31H26Cl2N2O3S (M)+ 576.1041, found
576.1036.
1
672 cmꢁ1; H NMR (300 MHz, CDCl3) d 7.84–7.76 (2H,
m), 7.54–7.10 (16H, m), 5.51 (1H, br s), 5.34 (1H, m),
4.38–4.30 (2H, m), 3.15 (2H, br s), 2.35 (3H, s); 13C NMR
(75 MHz, CDCl3) d 169.1, 143.7, 139.4, 135.6, 133.6,
129.9, 129.7, 127.9, 127.4, 127.0, 126.6, 125.6, 69.9, 57.3,
35.9, 21.6; HRMS calcd for C32H27F3N2O3S (M)+
576.1694, found 576.1769.
General procedure A was followed (stirring at rt for 8 h)
using N-furan-2-ylmethylene-4-methyl-benzenesulfonamide
(60 mg, 0.24 mmol, 1.2 equiv).
General procedure Awas followed (stirring at rt for 14 h) us-
ing 4-methyl-N-(3-nitro-benzylidene)-benzenesulfonamide
(73 mg, 0.24 mmol, 1.2 equiv).
3.3.1.18. (E)-2-[5-Furan-2-yl-1-(toluene-4-sulfonyl)-
pyrrolidin-3-ylidene]-N,N-diphenylacetamide
3.3.1.14. (E)-2-[5-(3-Nitrophenyl)-1-(toluene-4-sulfon-
yl)pyrrolidin-3-ylidene]-N,N-diphenylacetamide 3i-exo.
Yellow oil (56 mg, 51%). Rf¼0.17 (hexanes/EtOAc¼3:1);
IR (thin film) n 3062, 2924, 1670, 1643, 1596, 1530, 1491,
3k-exo.
Orange oil (86 mg, 86%). Rf¼0.26 (hexanes/EtOAc¼3:1);
IR (thin film) n 3061, 2922, 1672, 1643, 1596, 1491, 1383,
1347, 1268, 1164, 1093, 735, 702 cmꢁ1
;
1H NMR
1384, 1350, 1267, 1163, 1093, 738, 702, 665 cmꢁ1
;
1H
(400 MHz, CDCl3) d 7.57–7.08 (15H, m), 6.25–6.21 (2H,
m), 5.79 (1H, m), 5.14 (1H, dd, J¼8.8, 2.2 Hz), 4.17 (1H,
d, J¼16.0 Hz), 3.98 (1H, d, J¼16.0 Hz), 3.51 (1H, dm,
J¼18.9 Hz), 3.11 (1H, ddm, J¼18.9, 8.8 Hz), 2.39 (3H, s);
13C NMR (100 MHz, CDCl3) d 165.4, 154.5, 153.1, 143.3,
142.4, 142.2, 134.8, 129.5, 129.3, 127.3, 127.2, 114.2, 110.0,
107.5, 56.8, 52.9, 36.9, 21.4; HRMS calcd for C29H26N2O4S
(M)+ 498.1613, found 498.1590.
NMR (300 MHz, CDCl3) d 8.14–7.94 (2H, m), 7.69–6.96
(16H, m), 5.85 (1H, m), 5.02 (1H, dd, J¼8.2, 4.4 Hz),
4.22–4.13 (2H, m), 3.45–3.21 (2H, m), 2.41 (3H, s); 13C
NMR (75 MHz, CDCl3) d 165.5, 152.8, 144.1, 142.5, 134.5,
133.2, 130.0, 129.8, 127.6, 122.9, 121.4, 115.5, 62.9, 54.3,
40.1, 21.7; HRMS calcd for C31H27N3O5S (M)+ 553.1672,
found 553.1678.
3.3.1.15. 2-[5-(3-Nitrophenyl)-1-(toluene-4-sulfonyl)-
2,5-dihydro-1H-pyrrol-3-yl]-N,N-diphenylacetamide 3i-
endo. Yellow foam (11 mg, 10%). Mp¼178–180 ꢀC; Rf¼
0.11 (hexanes/EtOAc¼3:1); IR (CH2Cl2) n 3063, 2922,
2866, 1672, 1596, 1529, 1491, 1349, 1162, 1094, 738,
General procedure A was followed (stirring at rt for 16 h)
using N-furan-3-ylmethylene-4-methyl-benzenesulfonamide
(60 mg, 0.24 mmol, 1.2 equiv).
3.3.1.19. (E)-2-[5-Furan-3-yl-1-(toluene-4-sulfonyl)-
pyrrolidin-3-ylidene]-N,N-diphenylacetamide
1
703, 669 cmꢁ1; H NMR (300 MHz, CDCl3) d 8.12–8.00
3l-exo.
Yellow oil (34 mg, 34%). Rf¼0.29 (hexanes/EtOAc¼3:1);
(2H, m), 7.71–7.14 (16H, m), 5.53 (1H, m), 5.35 (1H, m),
4.41–4.26 (2H, m), 3.14 (2H, s), 2.37 (3H, s); 13C NMR
(75 MHz, CDCl3) d 168.5, 148.5, 144.0, 143.2, 135.2, 134.2,
133.8, 129.9, 129.8, 127.5, 126.4, 123.0, 122.3, 69.7, 57.5,
35.8, 21.7; HRMS calcd for C31H27N3O5S (M)+ 553.1672,
found 553.1672.
IR (thin film) n 3061, 2924, 1662, 1642, 1596, 1491, 1384,
1346, 1273, 1163, 1093, 1026, 759, 735, 701, 668 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d 7.65–7.57 (2H, m), 7.42–
7.08 (14H, m), 6.27 (1H, m), 5.77 (1H, m), 5.04 (1H, dd,
J¼8.6, 1.8 Hz), 4.14 (1H, dm, J¼16.7 Hz), 3.95 (1H, dt,
J¼16.7, 1.8 Hz), 3.41 (1H, dm, J¼18.4 Hz), 2.87 (1H,
ddm, J¼18.4, 7.7 Hz), 2.43 (3H, s); 13C NMR (100 MHz,
CDCl3) d 165.5, 154.6, 143.7, 143.5, 142.4, 139.6, 135.1,
129.7, 129.5, 127.4, 127.3, 126.4, 125.9, 114.7, 109.2,
56.0, 52.8, 37.9, 21.5; HRMS calcd for C29H26N2O4S
(M)+ 498.1613, found 498.1614.
General procedure A was followed (stirring at rt for 12 h)
using N-(2,4-dichloro-benzylidene)-4-methyl-benzenesul-
fonamide (78 mg, 0.24 mmol, 1.2 equiv).
3.3.1.16. (E)-2-[5-(2,4-Dichlorophenyl)-1-(toluene-4-
sulfonyl)pyrrolidin-3-ylidene]-N,N-diphenylacetamide 3j-
exo. Yellow solid (97 mg, 84%). Mp¼182–184 ꢀC; Rf¼0.28
(hexanes/EtOAc¼3:1); IR (CH2Cl2) n 3062, 2923, 1668,
1644, 1591, 1490, 1386, 1353, 1292, 1268, 1165, 1094, 701,
General procedure A was followed (stirring at rt for 18 h)
using 4-methyl-N-(1-methyl-1H-pyrrol-2-ylmethylene)-
benzenesulfonamide (63 mg, 0.24 mmol, 1.2 equiv).
1
667, 613 cmꢁ1; H NMR (400 MHz, CDCl3) d 7.69–7.62
(2H, m), 7.42–7.06 (15H, m), 5.78 (1H, br s), 5.18 (1H, dd,
J¼9.0, 4.2 Hz), 4.24 (1H, d, J¼16.3 Hz), 4.09 (1H, d, J¼
16.3 Hz), 3.35 (1H, dd, J¼19.1, 9.3 Hz), 3.15 (1H, br d,
J¼19.1 Hz), 2.44 (3H, s); 13C NMR (100 MHz, CDCl3)
d 165.1, 152.4, 144.1, 142.2, 138.5, 133.6, 133.4, 132.4,
129.8, 129.3, 128.4, 127.6, 127.1, 115.0, 60.6, 54.7, 39.5,
3.3.1.20. (E)-2-[10-Methyl-1-(toluene-4-sulfonyl)-1,2,3,5-
tetrahydro-10H-[2,20]bipyrrolyl-4-ylidene]-N,N-diphenyl-
acetamide 3m-exo. Yellow oil (47 mg, 46%). Rf¼0.22
(hexanes/EtOAc¼3:1); IR (thin film) n 3061, 2923, 1668,
1641, 1596, 1491, 1383, 1343, 1291, 1269, 1162, 1091, 735,
1
702, 671 cmꢁ1; H NMR (300 MHz, CDCl3) d 7.44–7.11

C. Taillier et al. / Tetrahedron 63 (2007) 8469–8477
8475
(16H, m), 6.56 (1H, m), 5.97 (1H, dd, J¼3.5, 2.9 Hz), 5.86
(1H, m), 5.73 (1H, m), 5.25 (1H, dd, J¼8.5, 1.8 Hz), 4.12
(1H, m), 3.91 (1H, br d, J¼17.3 Hz), 3.76 (3H, s), 2.44
(3H, s); 13C NMR (100 MHz, CDCl3) d 165.5, 155.8,
143.8, 142.5, 135.4, 129.9, 129.8, 127.5, 123.5, 113.8,
107.8, 106.6, 56.5, 52.3, 37.1, 34.5, 21.6; HRMS calcd for
C30H29N3O3S (M+H)+ 512.2002, found 512.1999.
J¼10.1 Hz), 2.46–2.08 (2H, m), 2.44 (3H, s), 1.82–0.88
(10H, m); 13C NMR (100 MHz, CDCl3) d 165.6, 156.7,
143.6, 142.5, 135.2, 129.8, 129.6, 129.4, 127.4, 127.3,
113.9, 65.8, 54.0, 42.7, 33.1, 29.5, 28.2, 26.2, 26.1, 26.0,
21.5; HRMS calcd for C31H34N2O3S (M)+ 514.2290, found
514.2296.
3.3.2. General procedure B. To a solution of 2,6-di-tert-bu-
tyl-4-methylphenol (194 mg, 0.88 mmol, 4.4 equiv) in tolu-
ene (0.90 mL) at room temperature was added a solution of
trimethylaluminium (0.22 mL, 2 M in toluene, 0.44 mmol,
2.2 equiv) dropwise. After 1 h of stirring at room tempera-
ture, the resulting solution was cooled to 0 ꢀC and a solution
of MCP (0.20 mmol, 1 equiv), N-tosyl aldimine (0.24 mmol,
1.2 equiv) and n-Bu4NI (74 mg, 0.2 mmol, 1 equiv) in
CH2Cl2 (2 mL) was added dropwise. The resulting yellow
solution was stirred at 0 ꢀC for 30 min and allowed to
warm to room temperature and stirred for 24 h. The reaction
mixture was poured into a saturated aqueous solution of
NH4Cl and the aqueous layer was extracted with EtOAc
(three-times 25 mL). The combined organic extracts were
washed with H2O (15 mL) and brine (15 mL), dried over
Na2SO4, filtered and concentrated in vacuo. Purification of
the resulting oil by chromatography on silica gel (gradient
hexanes/EtOAc; 5:1–4:1) gave the expected products.
General procedure A was followed (stirring at rt for 18 h)
using 4-methyl-N-(3-phenyl-allylidene)-benzenesulfon-
amide (68 mg, 0.24 mmol, 1.2 equiv).
3.3.1.21. (E)-N,N-Diphenyl-2-[5-styryl-1-(toluene-4-
sulfonyl)pyrrolidin-3-ylidene]acetamide 3n-exo. Insepa-
rable mixture of geometric isomers (E/Z¼4.5:1). White solid
(86 mg, 81%). Mp¼110–112 ꢀC; Rf¼0.22 (hexanes/
EtOAc¼3:1); IR (CH2Cl2) n 3059, 1670, 1644, 1596,
1494, 1450, 1385, 1345, 1267, 1162, 1093, 966, 816, 735,
698, 666, 614 cmꢁ1
;
1H NMR (mixture E/Z¼4.5:1,
400 MHz, CDCl3) d 7.72–7.63 (2H, m), 7.42–7.08 (17H,
m), 6.52 (1HE, dd, J¼15.8, 1.1 Hz), 6.49 (1HZ, d,
J¼15.6 Hz), 5.99 (1HE, dd, J¼15.8, 6.8 Hz), 5.88 (1HZ,
dd, J¼15.6, 7.5 Hz), 5.78 (1H, m), 4.60 (1HZ, m), 4.49
(1HE, m), 4.08–3.96 (2H, m), 3.23 (1HE, dm, J¼18.7 Hz),
3.05 (1HE, ddm, J¼18.7, 8.1 Hz), 2.75 (1HZ, ddm,
J¼16.9, 8.1 Hz), 2.45–2.38 (1HZ, m), 2.38 (3H, s); 13C
NMR (E isomer, 100 MHz, CDCl3) d 165.4, 154.0, 143.6,
142.3, 136.2, 134.6, 131.0, 129.6, 129.4, 128.4, 128.2,
127.8, 127.7, 127.6, 126.5, 114.5, 62.0, 53.3, 37.8, 21.4;
HRMS calcd for C33H30N2O5S (M)+ 534.1977, found
534.1974.
General procedure B was followed using N-benzylidene-4-
methyl-benzenesulfonamide (62 mg, 0.24 mmol, 1.2 equiv).
3.3.2.1. (E)-N-Phenyl-2-[5-phenyl-1-(toluene-4-sulfo-
nyl)pyrrolidin-3-ylidene]-N-pyridin-2-ylacetamide 6a-
exo. Dark yellow oil (56 mg, 55%). Rf¼0.25 (hexanes/
EtOAc¼3:1); IR (thin film) n 3061, 2958, 1669, 1642, 1585,
1492, 1466, 1432, 1381, 1347, 1266, 1163, 1093, 699,
General procedure Awas followed (stirring at rt for 24 h) us-
ing 4-methyl-N-(3-methyl-butylidene)-benzenesulfonamide
(57 mg, 0.24 mmol, 1.2 equiv).
1
666 cmꢁ1; H NMR (400 MHz, CDCl3) d 7.72–6.93 (18H,
m), 5.77 (1H, s), 5.00 (1H, m), 4.77–4.64 (2H, m), 2.94
(1H, br dd, J¼16.9, 9.0 Hz), 2.57 (1H, br d, J¼16.9 Hz),
2.38 (3H, s); 13C NMR (100 MHz, CDCl3) d 165.7, 156.1,
149.0, 143.2, 141.4, 137.9, 135.2, 129.5, 128.5, 128.3, 127.6,
127.5, 126.4, 125.5, 121.5, 121.2, 114.7, 61.3, 52.5, 42.7,
30.3, 21.5; HRMS calcd for C30H28N3O3S (M+H)+
510.1851, found 510.1861.
3.3.1.22. (E)-2-[5-Isopropyl-1-(toluene-4-sulfonyl)pyr-
rolidin-3-ylidene]-N,N-diphenylacetamide 3o-exo. Beige
solid (58 mg, 59%). Mp¼130–132 ꢀC; Rf¼0.35 (hexanes/
EtOAc¼3:1); IR (CH2Cl2) n 3061, 2956, 2868, 1673,
1644, 1596, 1492, 1385, 1344, 1266, 1162, 1091, 1031, 758,
735, 701, 667, 613 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d 7.70–7.64 (2H, m), 7.41–7.12 (12H, m), 5.72 (1H, br s),
4.05–3.90 (3H, m), 2.98 (1H, d, J¼18.7 Hz), 2.61 (1H, br
dd, J¼18.7, 8.1 Hz), 2.44 (3H, s), 1.79–1.49 (2H, m), 1.24
(1H, m), 0.96 (3H, d, J¼6.6 Hz), 0.91 (3H, d, J¼6.6 Hz);
13C NMR (100 MHz, CDCl3) d 165.6, 155.6, 143.6, 142.4,
134.9, 129.8, 129.2, 127.4, 114.0, 59.3, 53.1, 44.7, 36.6,
24.9, 22.8, 22.3, 21.5; HRMS calcd for C29H32N2O3S
(M)+ 488.2134, found 488.2125.
General procedure B was followed using 4-methyl-N-naphtha-
len-1-ylmethylene-benzenesulfonamide (74 mg, 0.24 mmol,
1.2 equiv).
3.3.2.2. 2-[5-Naphthalen-1-yl-1-(toluene-4-sulfonyl)-
2,5-dihydro-1H-pyrrol-3-yl]-N-phenyl-N-pyridin-2-ylacet-
amide 6b-endo. Light yellow oil (54 mg, 48%). Rf¼0.2
(hexanes/EtOAc¼2:1); IR (thin film) n 3058, 2928, 2853,
General procedure Awas followed (stirring at rt for 24 h) us-
ing N-cyclohexylmethylene-4-methyl-benzenesulfonamide
(64 mg, 0.24 mmol, 1.2 equiv).
1674, 1582, 1341, 1157, 1093, 913 cmꢁ1 1H NMR
;
(400 MHz, CDCl3) d 8.37–8.35 (1H, m), 7.96–7.93 (1H,
m), 7.85–7.82 (1H, m), 7.73 (1H, d, J¼8 Hz), 7.62–7.53
(4H, m), 7.48–7.38 (3H, m), 7.32–7.25 (3H, m), 7.18–7.10
(5H, m), 7.08–7.04 (1H, m), 6.19 (1H, s), 5.44 (1H, s), 4.52
(1H, d, J¼14 Hz), 4.42 (1H, dd, J¼14.5, 4.2 Hz), 3.21 (2H,
s), 2.35 (3H, s); 13C NMR (100 MHz, CDCl3) d 169.7, 155.0,
149.0, 143.5, 141.5, 138.2, 136.3, 135.3, 134.0, 131.9, 130.5,
129.7, 129.1, 128.5, 128.3, 128.1, 127.7, 127.6, 126.3, 125.9,
125.6, 125.2, 122.8, 121.9, 121.3, 67.8, 57.5, 36.5, 21.7;
HRMS calcd for C34H30N3O3S (M+H)+ 560.2002, found
560.2018.
3.3.1.23. (E)-2-[5-Cyclohexyl-1-(toluene-4-sulfonyl)-
pyrrolidin-3-ylidene]-N,N-diphenylacetamide
3p-exo.
Colourless oil (36 mg, 35%). Rf¼0.31 (hexanes/
EtOAc¼3:1); IR (thin film) n 2926, 2852, 1670, 1643,
1596, 1491, 1384, 1345, 1269, 1162, 1092, 701, 667 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d 7.75–7.64 (2H, m), 7.42–
7.07 (12H, m), 5.66 (1H, m), 4.04 (1H, d, J¼17.4 Hz),
3.89 (1H, dm, J¼17.4 Hz), 3.80 (1H, m), 3.20 (1H, dm,

8476
C. Taillier et al. / Tetrahedron 63 (2007) 8469–8477
General procedure B was followed using 4-methyl-N-(4-
trifluoromethyl-benzylidene)-benzenesulfonamide (78 mg,
0.24 mmol, 1.2 equiv).
(hexanes/EtOAc¼3:1); IR (CH2Cl2) n 2936, 1669, 1634,
1598, 1456, 1419, 1386, 1347, 1162, 1091, 700, 667 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d 7.62–7.55 (2H, m), 7.31–
7.13 (7H, m), 6.31 (1H, br s), 5.01 (1H, dd, J¼8.8,
3.3 Hz), 4.34 (1H, d, J¼16.7 Hz), 4.26 (1H, br d, J¼
16.7 Hz), 3.63 (3H, s), 3.37 (1H, br d, J¼18.9 Hz), 3.15
(3H, s), 3.09 (1H, m), 2.40 (3H, s); 13C NMR (75 MHz,
CDCl3) d 166.5, 155.6, 144.1, 141.6, 135.3, 130.1, 130.0,
129.0, 128.0, 127.9, 126.9, 111.1, 64.0, 62.1, 54.5, 39.1,
32.5, 22.0; HRMS calcd C21H25N2O4S (M+H)+ 401.1535,
found 401.1538.
3.3.2.3. N-Phenyl-N-pyridin-2-yl-2-[1-(toluene-4-sul-
fonyl)-5-(4-trifluoromethylphenyl)-2,5-dihydro-1H-pyrrol-
3-yl]acetamide 6c-endo. Light yellow oil (38 mg, 33%). Rf¼
0.11 (hexanes/EtOAc¼3:1); IR (thin film) n 3058, 2922, 2867,
1681, 1585, 1490, 1463, 1432, 1324, 1161, 1120, 1066, 1018,
1
665 cmꢁ1; H NMR (400 MHz, CDCl3) d 8.42 (1H, d, J¼
4.9 Hz), 7.68 (1H, td, J¼7.6, 1.6 Hz), 7.49–7.13 (15H, m),
5.5 (1H, s), 5.36 (1H, s), 4.36 (2H, s), 3.25 (2H, d,
J¼4.3 Hz), 2.36 (3H, s); 13C NMR (100 MHz, CDCl3)
d 169.7, 149.1, 144.6, 143.6, 141.5, 138.4, 135.7, 133.6,
130.0, 129.8, 129.7, 128.5, 128.2, 128.0, 127.4, 127.1, 125.61,
125.57, 123.3, 122.1, 121.3, 69.8, 57.3, 26.3, 21.6; HRMS
calcd for C31H27F3N3O3S (M+H)+ 578.1719, found 578.1718.
General procedure B was followed using4-methyl-N-naphthal-
en-1-ylmethylene-benzenesulfonamide (74 mg, 0.24 mmol,
1.2 equiv).
3.3.2.7. (E)-N-Methoxy-N-methyl-2-[5-naphthalen-1-
yl-1-(toluene-4-sulfonyl)pyrrolidin-3-ylidene]acetamide
7b-exo. Colourless oil (47 mg, 52%). Rf¼0.34 (hexanes/
EtOAc¼2:1); IR (thin film) n 3051, 2962, 2928, 1670,
General procedure B was followed using N-(4-methoxy-benz-
ylidene)-4-methyl-benzenesulfonamide (69 mg, 0.24 mmol,
1.2 equiv).
1633, 1599, 1385, 1348, 1161, 1089, 800, 780, 665 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d 7.93–7.91 (1H, m), 7.85–
7.82 (1H, m), 7.73–7.67 (3H, m), 7.52–7.45 (3H, m),
7.38–7.33 (1H, m), 7.28–7.23 (2H, m), 6.32 (1H, s), 5.78
(1H, dd, J¼7.8, 4.9 Hz), 4.50 (2H, s), 3.58 (3H, s), 3.07
(3H, s), 2.41 (3H, s); 13C NMR (100 MHz, CDCl3) d 166.5,
155.0, 144.0, 137.3, 135.2, 134.2, 130.0, 129.2, 128.3, 127.7,
126.5, 125.8, 125.4, 123.4, 123.3, 111.3, 61.8, 61.7, 54.8,
40.3, 32.2, 21.8; HRMS calcd for C25H27N2O4S (M+H)+
451.1686, found 451.1699.
3.3.2.4. (E)-2-[5-(4-Methoxy-phenyl)-1-(toluene-4-sul-
fonyl)pyrrolidin-3-ylidene]-N-phenyl-N-pyridin-2-ylacet-
amide 6d-exo. Light yellow oil (42 mg, 39%). Rf¼0.15
(hexanes/EtOAc¼2:1); IR (thin film) n 3065, 2915, 2860,
1
1677, 1585, 1511, 1344, 1246, 1157, 1093 cmꢁ1; H NMR
(400 MHz, CDCl3) d 8.41 (1H, dd, J¼4.7, 1.2 Hz), 7.68
(1H, td, J¼8.0, 1.9 Hz), 7.45–7.13 (13H, m), 6.77 (2H, d,
J¼8.6 Hz), 5.43 (1H, s), 5.32 (1H, s), 4.27 (2H, m), 3.78
(3H, s), 3.24 (2H, s), 2.35 (3H, s); 13C NMR (100 MHz,
CDCl3) d 169.9, 159.5, 155.1, 149.1, 143.1, 141.5, 138.3,
136.0, 132.8, 132.3, 129.8, 129.6, 129.0, 128.6, 128.2,
127.9, 127.4, 122.0, 121.3, 114.0, 69.9, 56.9, 55.5, 36.4,
21.7; HRMS calcd for C31H29N3O4S (M)+ 539.1879, found
539.1864.
General procedure B was followed using 4-methyl-N-(4-
trifluoromethyl-benzylidene)-benzenesulfonamide (78 mg,
0.24 mmol, 1.2 equiv).
3.3.2.8.
N-Methoxy-N-methyl-2-[1-(toluene-4-sul-
fonyl)-5-(4-trifluoromethylphenyl)-2,5-dihydro-1H-pyr-
rol-3-yl] 7c-endo. Colourless oil (31 mg, 33%). Rf¼0.12
(hexanes/EtOAc¼3:1); IR (thin film) n 3024, 2928, 2860,
1664, 1616, 1419, 1381, 1324, 1157, 1123, 1106, 1069,
General procedureB wasfollowedusing4-methyl-N-(1-meth-
yl-1H-pyrrol-2-ylmethylene)-benzenesulfonamide (63 mg,
0.24 mmol, 1.2 equiv).
1
668 cmꢁ1; H NMR (400 MHz, CDCl3) d 7.49 (2H, d, J¼
3.3.2.5. 2-[10-Methyl-1-(toluene-4-sulfonyl)-2,5-dihy-
dro-1H,10H-[2,20]bipyrrolyl-4-yl]-N-phenyl-N-pyridin-2-
ylacetamide 6e-endo. Light yellow oil (29 mg, 28%). Rf¼
0.17 (hexanes/EtOAc¼2:1); IR (thin film) n 3065, 2928,
2853, 1677, 1582, 1490, 1463, 1429, 1337, 1297, 1256,
8.4 Hz), 7.45 (2H, d, J¼8.2 Hz), 7.36 (2H, d, J¼8.2 Hz),
7.15 (2H, d, J¼8.4 Hz), 5.53 (1H, s), 5.47 (1H, s), 4.37–
4.34 (2H, m), 3.65 (3H, s), 3.29 (2H, s), 3.16 (3H, s), 2.37
(3H, s); 13C NMR (100 MHz, CDCl3) d 144.6, 143.6,
135.7, 133.4, 129.7, 128.0, 127.4, 127.1, 125.7, 125.6,
123.0, 69.9, 61.6, 57.4, 32.5, 21.6; HRMS calcd for
C22H23N2O4F3S (M)+ 468.1336, found 468.1331.
1
1157, 1093 cmꢁ1; H NMR (400 MHz, CDCl3) d 8.4 (1H,
d, J¼3.7 Hz), 7.67 (1H, td, J¼7.9, 1.8 Hz), 7.41–7.09
(11H, m), 6.4 (1H, m), 6.0–5.94 (2H, m), 5.65 (1H, s),
5.35 (1H, s), 4.31 (1H, d, J¼13.8 Hz), 4.20 (1H, dd,
J¼12.9, 5.0 Hz), 3.35 (3H, s), 3.21 (2H, d, J¼7.2 Hz), 2.3
(3H, s); 13C NMR (100 MHz, CDCl3) d 169.8, 149.1,
142.9, 141.5, 138.3, 136.4, 132.7, 129.8, 129.4, 129.2, 128.5,
128.2, 127.2, 126.3, 123.8, 122.0, 121.3, 110.3, 107.0, 63.1,
56.1, 36.3, 34.1, 21.6; HRMS calcd for C29H29N4O3S
(M+H)+ 513.1954, found 513.1972.
Acknowledgements
This work is supported by NSERC (Canada), Merck Frosst
(IRC) and the University of Toronto.
Supplementary data
General procedure B was followed using N-benzylidene-4-
methyl-benzenesulfonamide (62 mg, 0.24 mmol, 1.2 equiv).
1H NMR–ROESY experiments are available for compounds
3a-exo and 3a-endo. This material is available free of
charge. Supplementary data associated with this article
can be found in the online version, at doi:10.1016/j.tet.
2007.05.081.
3.3.2.6. (E)-N-Methoxy-N-methyl-2-[5-phenyl-1-(tolu-
ene-4-sulfonyl)pyrrolidin-3-ylidene]acetamide 7a-exo.
White foam (41 mg, 51%). Mp¼148–150 ꢀC; Rf¼0.21

C. Taillier et al. / Tetrahedron 63 (2007) 8469–8477
8477
7. (a) Maruoka, K.; Itoh, T.; Yamamoto, H. J. Am. Chem. Soc.
1985, 107, 4573–4576; (b) Maruoka, K.; Itoh, T.; Sakurai,
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8. Reagents such as Et2AlI, TMSI and TiCl4/n-Bu4NI, which
have been used as halogen sources as well as promoters in
ring opening reaction of activated cyclopropanes were also
examined but failed to produce the desired g-alkylation re-
gioisomer. For leading examples, see: (a) Han, Z.; Uehira, S.;
Tsuritani, T.; Shinokubo, H.; Oshima, K. Tetrahedron 2001,
57, 987–995; (b) Miller, R. D.; McKean, D. R. J. Org. Chem.
1981, 46, 2412–2414.
9. Configuration and position of the double bond for both isomers
were confirmed by 1H NMR–ROESY experiments.
10. For previous report on the selectivity of bulky aluminum Lewis
acids, see: Saito, S.; Yamamoto, H. Chem. Commun. 1997,
1585–1592 and references cited therein.
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