Synthesis of 2-phenyl- and 2,2-diarylpyrrolidines through Stevens rearrangement performed on azetidinium ions

Article abstract of DOI:10.1002/ejoc.201301536

A set of azetidinium ions substituted at the nitrogen atom either by a benzyl group or a benzhydryl group were synthesized to delineate the scope of their ring expansion into 2-phenyl- or 2,2-diaryl-pyrrolidines through a Stevens rearrangement. Whereas th

Full text of DOI:10.1002/ejoc.201301536

FULL PAPER
DOI: 10.1002/ejoc.201301536
Synthesis of 2-Phenyl- and 2,2-Diarylpyrrolidines through Stevens
Rearrangement Performed on Azetidinium Ions
Bruno Drouillat,[a] Edouard d’Aboville,[a] Flavien Bourdreux,[a] and François Couty*[a]
Keywords: Nitrogen heterocycles / Small ring systems / Spiro compounds / Rearrangement / Cations / Ring expansion
A set of azetidinium ions substituted at the nitrogen atom
either by a benzyl group or a benzhydryl group were synthe-
sized to delineate the scope of their ring expansion into 2-
phenyl- or 2,2-diaryl-pyrrolidines through a Stevens re-
arrangement. Whereas the regioselectivity of the rearrange-
ment is very high, the diastereoselectivity is low when 2,3-
disubstituted pyrrolidines are produced, except in one case.
The major undesirable side-reaction is a Hofmann elimi-
nation leading to ring cleavage.
derived from this skeleton. In this work, we delineate the
scope of the Stevens rearrangement performed on N-
benzyl-substituted azetidinium ions 4 or N-benzhydryl-sub-
stituted azetidinium ions 5, leading to 2-phenylpyrrolidines
8 and 2,2-diarylpyrrolidines 9, respectively, via ylides 6 and
7 (Figure 2). It is clear from examination of the literature
that both of these aryl-substituted pyrrolidines suffer from
synthetic routes that are either lengthy and/or lacking in
generality,[3] although a major breakthrough has quite re-
cently been reported for the preparation of derivatives of 8
in enantioenriched form.[4]
Introduction
Considering the high number of nitrogen heterocycles in
pharmaceuticals, it is quite surprising to note that only two
drugs including a pyrrolidine ring are present in the top 200
pharmaceutical products by US retail sales in 2011 (Fig-
ure 1): the antiviral Telaprevir (1), and the antidiabetic Ong-
lyza (2),[1] which probably reflects the difficulties faced by
synthetic chemists when substituted pyrrolidines are targets.
This analysis is best illustrated when one considers nicotine
(3), which at first sight is a rather simple molecule. None-
theless, the search for an efficient route to prepare this drug
has stimulated huge amounts of difficult but innovative syn-
thetic work, from which quantities of analogues have been
synthesized and evaluated as CNS-focused drugs.[2]
Figure 1. Drugs including a pyrrolidine ring.
Figure 2. A synopsis of this work.
Therefore, innovative and robust synthetic routes to pyr-
rolidines are highly desirable and should be of interest for
medicinal chemists wishing to explore chemical diversity
The Stevens rearrangement of N-benzylazetidinium salts
has been reported[5] but the scope of this rearrangement
has, to the best of our knowledge, not been evaluated apart
from isolated issues involving problems of regio- and stereo-
selectivity.[6] The Stevens rearrangement starting from N-
benzhydrylazetidinium ions, on the other hand, has not
been reported.
[a] Institut Lavoisier de Versailles, UMR 8180, Université de
Versailles St-Quentin en Yvelines,
45, av. des Etats-Unis, 78035 Versailles Cedex, France
E-mail: couty@chimie.uvsq.fr
http://www.ilv.uvsq.fr/recherche/Syre/syre.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301536.
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B. Drouillat, E. d’Aboville, F. Bourdreux, F. Couty
FULL PAPER
Results and Discussion
Some representative azetidines 10–20 (Figure 3) bearing
an N-benzyl group (10–12), an N-benzhydryl group (13–18)
or a substituted N-benzhydryl group (19 and 20) were se-
lected for this study. Some of these substrates were either
monosubstituted or disubstituted at C-2 on the azetidine
ring to address problems of regio- and stereoselectivity dur-
ing the planned Stevens rearrangement. Among these
azetidines, only 13 is commercially available, and other sub-
strates were prepared by three distinct methods.
Scheme 2. Synthesis of azetidines 18–20.
Finally, the other substrates were prepared through our
previously reported procedure,[9] involving ring closure of
the azetidine ring by intramolecular alkylation of ester or
nitrile enolates. Scheme 3 outlines the synthesis of azetid-
ines that have not been described previously by using this
methodology.
Figure 3. Structures of the N-benzyl- and N-benzhydrylazetidines
selected for this study.
Azetidine 10 was prepared through anionic cyclization,
by adapting a recently described procedure[7] involving in-
tramolecular alkylation of a benzylic anion by an epoxide.
Thus N-dibenzyl ethanolamine 21 was first chlorinated to
afford 22 and cyclized to give a modest yield of 10 by treat-
ment with LIDA-KOR (a mixture of lithium diisoprop-
ylamide (LDA) and potassium tert-butoxide) at –78 °C
(Scheme 1). It should be noted that attempts to extend this
reaction to secondary benzylic chlorides such as 23 failed.
Scheme 3. Synthesis of azetidines 12 and 14–17.
Next, all of these azetidines were treated with methyl tri-
fluoromethane sulfonate (MeOTf, CH2Cl2, 0 °C, then room
temp., 3 h) to afford the corresponding azetidinium salts
30–39 in good yields, often with high diastereoselectivity,
producing single diastereoisomers 33–37 in which the rela-
tive configurations were not determined but which have al-
ready been discussed (Figure 4).[10] In the case of azetidines
with a quaternary center, the corresponding ammonium
Scheme 1. Synthesis of azetidine 10.
Azetidines 18–20 were prepared through reactions in- salts were, however, obtained with modest diastereoselectiv-
volving the formation of N–C bonds as the key step ity (33 and 39). Additionally, 13 was also reacted with ethyl
(Scheme 2), either through a two-step procedure consisting trifluoromethanesulfonate to give 40, however, this required
of reductive amination of the corresponding benzophen- prolonged reaction time (22 h) to complete the alkylation.
ones with propanolamine followed by mesylation and intra- Only 14 was found to be reluctant to undergo methylation
molecular alkylation to produce azetidines 19 and 20 in under these conditions, which might be due to deactivation
modest yields, or by double alkylation of 2,4-dibromo- of the nitrogen lone pair by an anomeric effect operating in
propane with benzhydrylamine to afford azetidine 18.[8]
the amino nitrile moiety.
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Synthesis of 2-Phenyl- and 2,2-Diarylpyrrolidines
was a primary alcohol (35), then alkoxide formation com-
peted, and intramolecular attack led to epoxide 47, a pro-
cess that has been observed previously.[12]
Figure 4. Structures of the N-benzyl and N-benzhydrylazetidinium
salts selected for this study.
A brief screening of the best conditions to induce the
Stevens rearrangement of these substrates was carried out
by using 30 as substrate; this study led us to identify the
use of two equivalents of base (ROK) in tetrahydrofuran
(THF) at room temperature for 2 h as best conditions.
Using these standardized conditions, N-benzhydrylazetidin-
iums unsubstituted on the azetidine ring 30–32 and 40 gave
fair to good yields of the expected 2,2-diaryl-substituted
pyrrolidines, with no isolable side-products (Scheme 4). No
noticeable influence of either the nature of the R group (Me
or Et) or of the X group on the N-benzhydryl moiety could
be detected.
Scheme 5. Influence of the nature of the substituent at C-2 for the
Stevens rearrangement leading to 2,2-diarylpyrrolidines.
The nature of the substituent at C-2 also had a strong
influence on the rearrangement of N-benzylazetidinium
salts (Scheme 6). In the case of 2-phenyl-substituted azetid-
inium ion 37, an excellent yield of 2,3-diphenylpyrrolidines
50 and 51 was produced, demonstrating again the complete
regioselectivity for ylide formation and subsequent ring
cleavage but low stereoselectivity in the final recombination
Scheme 4. Stevens rearrangement leading to 2,2-diarylpyrrolidines
41–44.
When N-benzhydryl substrates substituted at C-2 (33–36)
were reacted under these conditions, the nature of the C-2
substituent was found to have a strong influence on the out-
come of the reaction (Scheme 5). In the case of a Me or
CH2OBn group (33 and 36), the Stevens rearrangement was
highly regioselective, leading to single regioisomers of 45 or
48, respectively, resulting from cleavage of the N–C2 bond.
However, a side product, 49, due to competitive Hofmann
elimination[11] was isolated in the case of 36, and the low
yield of 48 also reflects similar unwanted processes. When
the substituent at C-2 was an ester (34), only azetidine 46
was formed, resulting from the regioselective formation of
the ylide at C-2 followed by migration of the benzhydryl
Scheme 6. Stevens rearrangement of N-benzylazetidinium sub-
group without ring expansion. Finally, when the substituent strates.
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B. Drouillat, E. d’Aboville, F. Bourdreux, F. Couty
FULL PAPER
of radicals.[13] These isomers were conveniently separated
by flash chromatography, however, in spite of extensive
NOESY experiments performed on each compound, we
were unable to determine unambiguously their relative con-
figurations. In the case of 38 and 39, with a quaternary
center at C-2, regioselectivity was again total and afforded
pyrrolidines 52, 53 and 55 with low isolated yields because
Hofmann elimination becomes severely competitive, with
alkenes 54 and 56 isolated as major products. It is worth
noting for these examples that whereas 52 and 53 were
again produced without stereoselectivity, this was not the
case for 55, which was produced as a single diastereoisomer,
which was carefully checked by examination of the crude
reaction product by NMR spectroscopy. Relative configura-
tions of 52, 53 and 55 were assigned on the basis of NOESY
experiments (see the Supporting Information).
vacuo, the following azetidinium ions were obtained with yields
specified in Figure 4.
Azetidinium 30: Oil; Rf = 0.44 (CH2Cl2/MeOH, 9:1). 1H NMR
(300 MHz, CDCl3): δ = 7.62–7.58 (m, 4 H, ArH), 7.47–7.45 (m, 10
H, 2Ph), 6.06 (s, 1 H, CHPh2), 5.00–4.89 (m, 2 H, H-2), 4.18–4.09
(m, 2 H, H-2Ј), 3.37 (s, 3 H, Me), 2.85–2.75 (m, 1 H, H-3), 2.24–
2.14 (m, 1 H, H-3Ј) ppm. 13C NMR (75 MHz, CDCl3): δ = 132.3
(CqAr), 130.1, 130.0, 129.7 (CHAr), 78.2 (CH), 63.4 (CH2), 49.0
(CH ), 14.2 (CH ) ppm. IR (film): ν = 3035, 1497, 1452, 1259,
˜
max
3
2
1221, 1145 cm–1. HRMS (ESI, +ve): calcd. for C17H20N [M –
TfO–]+ 238.1596; found 238.1598.
Azetidinium 31: Oil; Rf = 0.11 (CH2Cl2/MeOH, 98:2). 1H NMR
(300 MHz, CDCl3): δ = 7.48 (d, J = 6 Hz, 2 H, ArH), 7.40–7.32
(m, 5 H, ArH), 7.14 (d, J = 8 Hz, 2 H, ArH), 5.88 (s, 1 H, CHPh2),
4.86–4.74 (m, 2 H, H-2), 3.99 (br. s, 2 H, H-2Ј), 3.23 (s, 3 H, Me),
2.77–2.61 (m, 1 H, H-3), 2.24 (s, 3 H, Me), 2.09–2.05 (m, 1 H, H-
3Ј) ppm. 13C NMR (75 MHz, CDCl3): δ = 140.3, 132.6 (CqAr),
130.3, 130.0, 129.9, 129.7, 129.6 (CHAr), 129.2 (CqAr), 78.0 (CH),
63.3, 63.2 (CH2), 48.7 (CH3), 21.1 (CH3), 14.1 (CH2) ppm. IR
(film): ν
= 3036, 1455, 1253, 1223, 1151, 1028 cm–1. HRMS
˜
max
Conclusions
(ESI, +ve): calcd. for C18H22N [M – TfO–]+ 252.1752; found
252.1749.
The set of experiments reported herein demonstrates that
Stevens rearrangement of N-benzyl and N-benzhydryl-
azetidinium ions constitutes an efficient route to 2-phenyl-
Azetidinium 32: Oil; Rf = 0.26 (CH2Cl2/MeOH, 9:1). 1H NMR
(300 MHz, CDCl3): δ = 7.58–7.44 (m, 9 H, 2Ph), 6.07 (s, 1 H,
and 2,2-diarylpyrrolidines. When 2-substituted and 2,2-di- CHPh2), 4.92–4.75 (m, 2 H, H-2), 4.12 (br. s, 2 H, H-2Ј), 3.35 (s, 3
H, Me), 2.82–2.68 (m, 1 H, H-2), 2.19 (br. s, 1 H, H-2Ј) ppm. 13C
NMR (75 MHz, CDCl3): δ = 132.8 (CHAr), 131.8 (CqAr), 131.6
(CHAr), 131.3 (CqAr), 130.3, 129.9, 129.8 (CHAr), 124.6 (CqBr),
76.6 (NCHPh2), 63.6 (CH2), 48.9 (CH3), 14.2 (CH2) ppm. IR
substituted azetidinium ions are involved, the rearrange-
ment is completely regioselective and often leads to mix-
tures of diastereoisomeric 2,3-disubstituted pyrrolidines. A
major identified side-reaction is Hofmann elimination lead-
ing to ring cleavage, and this reaction becomes the major
pathway in the case of quaternary azetidinium ions.
(film): νmax = 3037, 2981, 2248, 1590, 1492, 1456, 1251, 1223, 1153,
˜
1076, 1027, 1010 cm–1. HRMS (ESI, +ve): calcd. for C16H19NBr
[M – TfO–]+ 316.0701; found 316.0698.
Azetidinium 33: Oil; Rf
= 0.62 (EtOAc/nBuOH/AcOH/H2O,
1:1:1:1). 1H NMR (300 MHz, CDCl3): δ = 7.68–7.60 (m, 4 H,
ArH), 7.42–7.23 (m, 11 H, 3Ph), 5.87 (s, 1 H, CHPh2), 5.20–5.12
(m, 1 H, H-2), 4.91–4.81 (m, 1 H, H-4), 4.49–4.39 (m, 2 H,
OCH2Ph), 3.92–3.84 (m, 1 H, H-4Ј), 3.79–3.72 (m, 1 H, CHHO),
3.44 (d, J = 15 Hz, 1 H, CHHO), 3.21 (s, 3 H, Me), 2.77–2.64 (m,
1 H, H-3), 2.29–2.18 (m, 1 H, H-3Ј) ppm. 13C NMR (75 MHz,
CDCl3): δ = 136.6, 132.4, 131.8 (CqAr), 131.0, 130.2, 130.0, 129.9,
129.7, 129.6, 128.6, 128.2, 128.1, 128.0, 127.8 (CHAr), 79.9 (CH),
73.4 (CH2), 72.5 (CH), 65.8, 60.9 (CH2), 42.5 (CH3), 17.1
Experimental Section
1
General Comments: H and 13C NMR spectra were recorded with
a Bruker Avance spectrometer at operating at 200 or 300 and 75
or 50 MHz, respectively; chemical shifts are reported in ppm from
TMS. All reactions were carried out under argon. Column
chromatography was performed on silica gel 230–400 mesh by
using various mixtures of diethyl ether (Et2O), ethyl acetate
(EtOAc), petroleum ether (PE), dichloromethane (CH2Cl2), and
methanol. TLC analyses were run on Merck Kieselgel 60F254
plates. Melting points are uncorrected. THF and toluene were dried
by a dehydrating system MB-SPS 800 (Mbraun). Dichloromethane
was distilled from calcium hydride. The mention of a “usual
workup” means: (i) decantation of the organic layer, (ii) extraction
of the aqueous layer with specified solvent, (iii) drying of the com-
bined organic layers over MgSO4, and (iv) solvent evaporation un-
der reduced pressure. Isomeric ratios were determined by NMR
analysis of crude reaction mixtures before purification. High-reso-
lution mass spectra (HRMS) were obtained with a Water Micro-
mass Q-Tof Micro instrument. Procedures for the synthesis of azet-
idines 10–20 are provided in the Supporting Information.
(CH ) ppm. IR (film): ν
= 3478, 3058, 2355, 1455, 1394, 1254,
˜
2
max
1223, 1151, 1027 cm–1. HRMS (ESI, +ve): calcd. for C25H28NO
[M – TfO–]+ 358.2172; found 358.2171.
Azetidinium 34: Oil; Rf
= 0.62 (EtOAc/nBuOH/AcOH/H2O,
1
1:1:1:1). H NMR (300 MHz, CDCl3): δ = 7.72 (br. s, 4 H, ArH),
7.46 (m, 6 H, ArH), 6.12 (s, 1 H, CHPh2), 5.61 (t, J = 8.3 Hz, 1
H, H-2), 5.08–4.98 (m, 1 H, H-4), 4.15–4.07 (m, 2 H, CH2O), 3.92–
3.85 (m, 1 H, H-4Ј), 3.35 (s, 3 H, Me), 3.08–2.95 (m, 1 H, H-3),
2.76–2.66 (m, 1 H, H-3Ј), 1.14 (t, J = 8.5 Hz, 3 H, Me) ppm. 13C
NMR (75 MHz, CDCl3): δ = 164.2 (CO), 131.3, 131.0 (CqAr),
130.9, 130.6, 130.4, 129.9, 129.7 (CHAr), 80.9, 69.4 (CH), 63.2,
62.2 (CH2), 43.5 (CH), 18.8 (CH2), 13.7 ppm. HRMS (ESI, +ve):
calcd. for C20H24NO2 [M – TfO–]+ 310.1807; found 310.1799.
General Procedure for the Synthesis of Azetidinium Ions 30–40: To
a solution of the required azetidine (1 mmol) in CH2Cl2 (10 mL)
was added methyl trifluoromethanesulfonate (223 μL, 2 mmol) and
the mixture was stirred at room temp. for 3 h. The solvent was
evaporated and the oily residue was triturated with small portions
of Et2O. For azetidinium 40, ethyl trifluoromethanesulfonate was
used, and reaction time was prolonged to 22 h. After drying in
Azetidinium 35: Oil; Rf
= 0.54 (EtOAc/nBuOH/AcOH/H2O,
1:1:1:1). 1H NMR (300 MHz, CDCl3): δ = 7.68–7.39 (m, 10 H,
2Ph), 5.75 (s, 1 H, CHPh2), 5.11–4.99 (m, 1 H, H-2), 4.86–4.76 (m,
1 H, H-4), 4.06–3.88 (m, 1 H, H-4Ј), 3.75–3.70 (m, 1 H, CHHOH),
3.46–3.10 (m, 1 H, CHHOH), 3.28 (s, 3 H, Me), 2.75–2.65 (m, 1
H, H-3), 2.18–2.12 (m, 1 H, H-3Ј) ppm. 13C NMR (75 MHz,
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Synthesis of 2-Phenyl- and 2,2-Diarylpyrrolidines
CDCl3): δ = 132.9 (CqAr), 131.6, 131.5, 131.2, 130.3, 130.0, 129.8,
129.7, 129.5, 129.2 (CHAr), 79.9, 73.4 (CH), 59.5, 59.0 (CH2), 43.0
1144, 1027 cm–1. HRMS (ESI, +ve): calcd. for C17H26NO2 [M –
TfO–]+ 276.1969; found 276.1964.
(CH ), 17.3 (CH ) ppm. IR (film): ν = 3432, 3060, 2357, 1450,
˜
max
3
2
Azetidinium 40: Oil; Rf = 0.6 (EtOAc/nBuOH/AcOH/H2O, 1:1:1:1).
1H NMR (300 MHz, CDCl3): δ = 7.58–7.43 (m 10 H, 2Ph), 5.60
(s, 1 H, NCHPh2), 4.86–4.76 (m, 2 H, H-2), 4.46–4.37 (m, 2 H, H-
2Ј), 3.74–3.67 (m, 2 H, CH2CH3), 2.59–2.47 (m, 1 H, H-3), 1.74–
1.66 (m, 1 H, H-3Ј), 1.37 (t, J = 11 Hz, 3 H, Me) ppm. 13C NMR
(75 MHz, CDCl3): δ = 132.3 (CqAr), 130.0, 129.9, 129.7, 129.5,
127.4 (CHAr), 74.4 (CH), 59.8, 57.5, 54.5, 14.3 (CH2), 8.2
1244, 1223, 1156, 1027 cm–1. HRMS (ESI, +ve): calcd. for
C18H22NO [M – TfO–]+ 268.1701; found 268.1701.
Azetidinium 36: Oil; Rf = 0.2 (CH2Cl2/MeOH, 9:1). 1H NMR
(300 MHz, CDCl3): δ = 7.77–7.68 (m, 4 H, ArH), 7.49–7.41 (m, 6
H, ArH), 6.17 (s, 1 H, CHPh2), 5.33–5.25 (m, 1 H, H-2), 5.01–4.91
(m, 1 H, H-4), 3.77–3.70 (m, 1 H, H-4Ј), 3.13 (s, 3 H, Me), 2.68–
2.58 (m, 1 H, H-3), 2.48–2.41 (m, 1 H, H-3Ј), 1.09 (d, J = 6 Hz, 3
H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 131.7, 131.6
(CqAr), 130.6, 130.4, 130.2, 129.7, 129.6 (CHAr), 79.6, 72.1 (CH),
62.3 (CH2), 39.3 (CH3), 22.8 (CH2), 15.7 (CH3) ppm. IR (film):
(CH ) ppm. IR (film): ν
= 3478, 3058, 2984, 1455, 1254, 1223,
˜
3
max
1027 cm–1. HRMS (ESI, +ve): calcd. for C18H22N [M – TfO–]+
252.1753; found 252.1752.
General Procedure for the Stevens Rearrangement: To a solution of
the required azetidinium salt (1 mmol) in anhydrous THF (10 mL)
at 0 °C was added tBuOK (224 mg, 2 mmol) and the mixture was
stirred at room temp. for 2 h. At this time, the reaction was
quenched by addition of saturated aqueous NH4Cl (5 mL) and the
reaction mixture was partitioned between water and EtOAc. Usual
workup was followed by purification by flash chromatography,
yielding the following compounds.
ν
max = 3432, 3060, 2357, 1450, 1244, 1223, 1156, 1027 cm–1. HRMS
˜
(ESI, +ve): calcd. for C18H22N [M – TfO–]+ 252.1752; found
252.1752.
Azetidinium 37: Oil; Rf = 0.4 (CH2Cl2/MeOH, 9:1). 1H NMR
(300 MHz, CDCl3): δ = 7.49–7.35 (m, 10 H, 2Ph), 6.16 (t, J = 9 Hz,
1 H, H-2), 5.01 (d, AB syst., J = 12 Hz, NCHHPh), 4.96 (m, 1 H,
H-4), 4.38 (d, AB syst., J = 12 Hz, NCHHPh), 3.66–3.60 (m, 1 H,
H-4), 3.24–3.14 (m, 1 H, H-3), 2.87–2.84 (m, 1 H, H-3Ј), 2.49 (s, 3
H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 132.0, 131.6
(CqAr), 130.8, 129.9, 129.7, 129.6, 128.7, 127.5 (CHAr), 77.2 (CH),
1
Pyrrolidine 41 (from 30): Oil; Rf = 0.6 (PE/EtOAc, 9:1). H NMR
(300 MHz, CDCl3): δ = 7.37–7.25 (m, 10 H, 2Ph), 2.79 (dd, J = 7,
7 Hz, 2 H, H-5), 2.47–2.41 (m, 2 H, H-3), 2.10–2.00 (m, 2 H, H-
4), 2.06 (s, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 143.9
(CqAr), 128.3, 127.5, 1263 (CHAr), 73.1 (Cq), 53.4, 41.9 (CH2),
67.2, 59.9 (CH ), 42.8 (CH ), 19.0 (CH ) ppm. IR (film): ν =
˜
max
2
3
2
3579, 3065, 2363, 1471, 1254, 1224, 1145, 1028 cm–1. HRMS (ESI,
+ve): calcd. for C17H20N [M – TfO–]+ 238.1596; found 238.1592.
36.6 (Me), 22.1 (CH ) ppm. IR (film): ν
= 3035, 1497, 1452,
˜
2
max
1259, 1221, 1145 cm–1. HRMS (ESI, +ve): calcd. for C17H20N [M
+ H]+ 238.1593; found 238.1596.
Azetidinium 38: Obtained as a mixture of stereoisomers (63:37) as
an oil; Rf = 0.6 (EtOAc/nBuOH/AcOH/NEt3, 1:1:1:1). 1H NMR
(300 MHz, CDCl3): δ = 7.47–7.28 (m, 10 H, 2Ph), 4.82 (d, AB syst.,
J = 12 Hz, 1 H, NCHHPh minor), 4.68 (s, 2 H, OCH2Ph, minor),
4.72–4.59 (m, 3 H, H-4 both isomers, NCHHPh major), 4.57 (s, 2
H, OCH2Ph, major), 4.42 (d, AB syst., J = 12 Hz, 1 H, NCHHPh
minor), 4.10 (d, AB syst., J = 12 Hz, 1 H, NCHHPh major), 4.05
(s, 2 H, CqCH2O major), 3.97 (d, AB syst., J = 12 Hz, 1 H,
CqCHHO minor), 3.72 (d, AB syst., J = 12 Hz, 1 H, CqCHHO
minor), 3.58–3.50 (m, 1 H, H-4Ј major), 3.40–3.39 (m, 1 H, H-4Ј
minor), 2.96 (s, 3 H, Me major), 2.92 (s, 3 H, Me minor), 2.85–
2.69 (m, 3 H, 2H-3 major, H-3 minor), 2.46–2.39 (m, 1 H, H-3Ј
Pyrrolidine 42 (from 31): Oil; Rf = 0.25 (PE/EtOAc, 95:5). 1H NMR
(300 MHz, CDCl3): δ = 7.31–7.24 (m, 9 H, 2Ph), 2.79–2.72 (m, 2
H, H-5), 2.43–2.39 (m, 2 H, H-3), 2.36 (s, 3 H, Me), 2.07–2.00 (m,
2 H, H-4), 2.02 (s, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ
= 144.2, 140.5, 135.7 (Cq Ar), 128.3, 128.2, 128.1, 127.4, 126.2
(CH Ar), 72.9 (Cq), 53.3, 41.9 (CH2), 36.6 (CH3), 22.0 (CH2), 21.0
(CH ) ppm. IR (film): ν
= 2967, 2921, 1693, 1444, 1230 cm–1.
max
˜
3
HRMS (ESI, +ve): calcd. for C18H22N [M + H]+ 252.1750; found
252.1752.
Pyrrolidine 43 (from 32): Oil; Rf = 0.25 (PE/EtOAc, 95:5). 1H NMR
(300 MHz, CDCl3): δ = 7.44 (d, J = 8 Hz, 2 H, ArH), 7.33–7.27
(m, 4 H, ArH), 7.22–7.13 (m, 4 H, ArH), 2.82–2.68 (m, 2 H, H-5),
2.49–2.27 (m, 2 H, H-3), 2.07–1.97 (m, 5 H, Me and H-4) ppm.
13C NMR (75 MHz, CDCl3): δ = 143.3, 142.9 (CqAr), 130.6, 129.9,
128.2, 127.5, 126.5 (CHAr), 120.1 (CqBr), 72.7, 53.3, 41.8 (CH2),
minor), 1.97 (s, 3 H, Me major), 1.67 (s, 3 H, Me minor) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 136.5, 136.3 (Cq Ar), 132.1, 131.8,
130.4, 129.4, 129.3, 128.7, 128.7, 128.4, 128.3, 128.2, 128.0, 127.8,
127.6 (CH Ar), 84.1, 83.6 (Cq), 73.6, 73.4, 71.6, 71.5, 62.2, 61.0,
59.5, 58.7 (CH2), 44.6, 43.4 (CH3), 25.3, 24.7 (CH2), 20.1, 19.7
36.4 (CH ), 22.0 (CH ) ppm. IR (film): ν = 3051, 2970, 2929,
˜
max
(CH ) ppm. IR (film): ν
= 3064, 2868, 1455, 1391, 1255, 1123,
˜
3
2
3
max
1153, 1095, 1012 cm–1. HRMS (ESI, +ve): calcd. for C20H26NO
2782, 1687, 1597, 1483, 1463, 1444, 1392, 1228, 1157, 1071,
1108 cm–1. HRMS (ESI, +ve): calcd. for C17H18NBr [M + H]+
316.0701; found 316.0704.
[M – TfO–]+ 296.2014; found 296.2018.
Azetidinium 39: Obtained as a mixture of stereoisomers (70:30) as
an oil; Rf = 0.6 (EtOAc/nBuOH/AcOH/H2O, 1:1:1:1). 1H NMR
(300 MHz, CDCl3): δ = 7.47–7.43 (m, 5 H, Ph), 5.04–4.94 (m, 1 H,
H-4 major), 4.82 (d, AB syst., J = 12 Hz, NCHHPh), 4.11 (d, AB
syst., J = 12 Hz, NCHHPh), 3.58–3.51 (m, 1 H, H-4Ј major), 3.46–
3.40 (m, 1 H, H-4 minor), 3.28–3.17 (m, 1 H, H-3), 2.94 (s, 3 H,
Me, major), 2.89 (s, 3 H, Me, minor), 2.40–2.33 (m, 1 H, H-3Ј),
2.15 (s, 3 H, Me, major), 2.12 (s, 3 H, Me, minor), 1.51 (s, 9 H,
tBu, major), 1.27 (s, 9 H, tBu, minor) ppm. 13C NMR (75 MHz,
CDCl3): δ = 167.9 (CO minor), 166.8 (CO major), 131.8, 131.7,
130.7, 129.6, 126.5 (CHAr), 86.3, 81.8 (Cq major), 81.7 (Cq minor),
1
Pyrrolidine 44 (from 40): Oil; Rf = 0.49 (PE/Et2O, 98:2). H NMR
(300 MHz, CDCl3): δ = 7.34–7.23 (m, 10 H, 2Ph), 2.81 (t, J =
12 Hz, 2 H, H-5), 2.42–2.37 (m, 2 H, H-3), 2.10–2.03 (m, 4 H, H-
4 and NCH2CH3), 1.15 (t, J = 9 Hz, 3 H, NCH2CH3) ppm. 13C
NMR (75 MHz, CDCl3): δ = 144.6 (CqAr), 128.2, 127.4, 126.2
(CHAr), 73.7 (Cq), 49.3, 44.5, 42.0, 22.1 (CH2), 14.3 (CH3) ppm.
IR (film): ν
= 3051, 2967, 2800, 2365, 1598, 1488, 1443, 1227,
˜
max
1161, 1074, 1059 cm–1. HRMS (ESI, +ve): calcd. for C18H22N [M
+ H]+ 252.1748; found 252.1752.
Pyrrolidine 45 (from 33): Oil; Rf = 0.64 (PE/EtOAc, 95:5). 1H NMR
62.0 (CH2 major), 61.5 (CH2 minor), 58.9 (CH2 major), 58.7 (CH2 (300 MHz, CDCl3): δ = 7.32–7.12 (m, 15 H, 3Ph), 4.21 (s, 2 H,
minor), 46.3 (CH3), 30.8 (CH3 minor), 27.6 (CH3 major), 25.4 OCH2Ph), 3.14–2.97 (m, 3 H, H-3, H-5 and CHCHHO), 2.82–2.78
(CH2 major), 25.2 (CH2 minor), 20.6 (CH3 major), 20.1 (CH3 (m, 1 H, CHCHHO), 2.38–2.26 (m, 2 H, H-4 and H-5Ј), 2.11–2.06
minor) ppm. IR (film): ν
= 2983, 1736, 1456, 1373, 1250, 1221, (m, 1 H, H-4Ј), 1.97 (s, 3 H, Me) ppm. 13C NMR (75 MHz,
˜
max
Eur. J. Org. Chem. 2014, 1103–1109
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1107

B. Drouillat, E. d’Aboville, F. Bourdreux, F. Couty
FULL PAPER
CDCl3): δ = 142.1, 140.0, 138.5 (CqAr), 129.3, 129.2, 128.2, 127.6,
NMR (75 MHz, CDCl3): δ = 128.5, 128.4, 128.0, 127.7, 126.6
127.6, 127.4, 127.3, 127.0, 126.5, 126.4 (CHAr), 75.1 (Cq), 74.4,
(CHAr), 80.0 (CH), 56.2 (CH2), 53.4 (CH), 39.9 (CH3), 31.3
72.9, 52.2 (CH ), 48.0, 36.2 (CH), 27.8 (CH ) ppm. IR (film): ν
(CH ) ppm. IR (film): ν
= 3399, 2952, 2449, 2671, 1456, 1419,
˜
˜
2
2
max
2
max
= 3027, 2931, 2844, 2789, 2353, 2493, 1443, 1363, 1027, 1090 cm–1.
HRMS (ESI, +ve): calcd. for C25H28NO [M + H]+ 358.2168; found
358.2171.
1157, 1095 cm–1. HRMS (ESI, +ve): calcd. for C17H20N [M + H]+
238.1596; found 238.1596.
Pyrrolidine 52, 53 and Alkene 54 (from 38); Compound 52: Oil; Rf
= 0.43 (PE/EtOAc, 1:1). 1H NMR (300 MHz, CDCl3): δ = 7.41–
7.27 (m, 10 H, 2Ph), 4.65–4.56 (m, 2 H, OCH2Ph), 3.32–3.18 (m,
5 H, H-2 H-5 CH2O), 2.41–2.32 (m, 1 H, H-5Ј), 2.21 (s, 3 H, Me),
2.14–2.07 (m, 1 H, H-4), 1.71–1.61 (m, 1 H, H-4Ј), 0.63 (s, 3 H,
Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 139.8, 138.8 (Cq Ar),
128.7, 128.3, 127.8, 127.5, 127.4, 126.7 (CHAr), 76.8 (CH2), 73.2
(CH), 55.2 (CH2), 46.2 (Cq), 41.3 (CH3), 35.2 (CH2), 22.9
Azetidine 46 (from 34): Oil; Rf = 0.8 (CH2Cl2/MeOH, 98:2). 1H
NMR (300 MHz, CDCl3): δ = 7.22–7.05 (m, 10 H, 2Ph), 4.37 (s, 1
H, CHPh2), 4.03–3.86 (m, 2 H, OCH2CH3), 2.98–2.91 (m, 2 H, H-
4), 2.61–2.54 (m, 1 H, H-3), 2.21 (s, 3 H, Me), 2.18–2.08 (m, 1 H,
H-3Ј), 0.90 (t, J = 6 Hz, 3 H, Me) ppm. 13C NMR (75 MHz,
CDCl3): δ = 171.4 (CO), 141.4, 140.9 (CqAr), 130.9, 128.9, 128.3,
127.4, 126.4, 126.2 (CHAr), 76.5 (Cq), 60.1 (CH2), 54.5 (CH), 52.6
(CH ) ppm. IR (film): ν
= 3027, 2962, 2936, 2837, 2776, 1491,
˜
3
max
(CH ), 38.5 (CH ), 23.7 (CH ), 14.0 (CH ) ppm. IR (film): ν =
˜
max
2
3
2
3
1452, 1361, 1249, 1092, 1027 cm–1. HRMS (ESI, +ve): calcd. for
2921, 1693, 1444, 1230, 1074 cm–1. HRMS (ESI, +ve): calcd. for
C20H26NO [M + H]+ 296.2017; found 296.2014.
C20H23NO2 [M + H]+ 252.1752; found 252.1750.
Compound 53: Oil; Rf = 0.17 (PE/EtOAc, 1:1). 1H NMR (300 MHz,
CDCl3): δ = 7.32–7.17 (m, 10 H, 2Ph), 4.29–4.18 (m, 2 H,
OCH2Ph), 3.25–3.19 (m, 1 H, H-5), 3.16 (d, AB syst., J = 9 Hz, 1
H, CHHO), 2.92 (s, 1 H, H-2), 2.65 (d, AB syst., J = 9 Hz, 1
CHHO), 2.40–2.31 (m, 1 H, H-5Ј), 2.19 (s, 3 H, Me), 2.15–2.09 (m,
1 H, H-4), 1.65–1.58 (m, 1 H, H-4Ј), 1.21 (s, 3 H, CH3) ppm. 13C
NMR (75 MHz, CDCl3): δ = 138.9, 138.7 (CqAr), 128.1, 127.9,
127.7, 127.3, 127.1, 126.9 (CHAr), 81.2 (CH), 77.2, 73.0, 55.0
Epoxide 47 (from 35): Oil; Rf = 0.29 (PE/EtOAc, 9:1). 1H NMR
(300 MHz, CDCl3): δ = 7.43 (d, J = 7 Hz, 4 H, ArH), 7.32–7.27
(m, 4 H, ArH), 7.23–7.18 (m, 2 H, ArH), 4.40 (s, 1 H, CHPh2),
2.99 (br. s, 1 H, CCHO), 2.78–2.75 (m, 1 H, CHHO), 2.58–2.53 (m,
2 H, CH2N), 2.47–2.45 (m, 1 H, CHHO), 2.19 (s, 3 H, Me), 1.82–
1.69 (m, 2 H, NCH2CH2) ppm. 13C NMR (75 MHz, CDCl3): δ =
143.1, 143.0 (CqAr), 128.4, 127.9, 126.9 (CHAr), 75.8 (CH), 51.9
(CH2), 51.0 (CH), 47.1 (CH), 40.1 (CH3), 30.5 (CH2) ppm. IR
(CH ), 45.9 (CH ), 35.0 (CH ), 24.5 (CH ) ppm. IR (film): ν =
˜
max
2
3
2
3
(film): νmax = 3023, 2962, 2786, 1593, 1490, 1451, 1266, 1078, 1027,
˜
3027, 2950, 2836, 2772, 1602, 1492, 1450, 1360, 1250, 1201, 1096,
1027 cm–1. HRMS (ESI, +ve): calcd. for C20H26NO [M + H]+
296.2017; found 296.2014.
1010 cm–1. HRMS (ESI, +ve): calcd. for C18H22NO [M + H]+
268.1701; found 268.1701.
Pyrrolidine 48 and Alkene 49 (from 36); Compound 48: Oil; Rf =
0.45 (PE/EtOAc, 9:1). 1H NMR (300 MHz, CDCl3): δ = 7.23–7.09
(m, 10 H, 2Ph), 2.82–2.75 (m, 1 H, H-5), 2.69–2.59 (m, 1 H, H-3),
2.42–2.34 (m, 1 H, H-5Ј), 2.28–2.17 (m, 1 H, H-4), 1.86 (s, 3 H,
Me), 1.64–1.52 (m, 1 H, H-4Ј), 0.59 (d, J = 9 Hz, 3 H, Me) ppm.
13C NMR (75 MHz, CDCl3): δ = 142.2, 141.7 (CqAr), 129.7, 129.2,
127.1, 127.0, 126.3, 126.0 (CHAr), 52.3 (CH2), 43.8 (CH), 36.5
Compound 54: Oil; Rf = 0.30 (PE/EtOAc, 1:1). 1H NMR (300 MHz,
CDCl3): δ = 7.26–7.17 (m, 10 H, 2Ph), 5.00 (s, 1 H, C=CHH), 4.87
(s, 1 H, C=CHH), 4.39 (s, 2 H, OCH2Ph), 3.87 (s, 2 H, CCH2O),
3.42 (s, 2 H, NCH2Ph), 2.49–2.44 (m, 2 H, NCH2), 2.27–2.22 (m,
2 H, CH2C=C), 2.19 (s, 3 H, Me) ppm. 13C NMR (75 MHz,
CDCl3): δ = 144.5 (Cq), 139.1, 138.4 (CqAr), 129.0, 128.4, 128.2,
127.7, 127.5, 126.9 (CHAr), 112.7, 73.1, 71.9, 62.2, 55.8 (CH2), 42.0
(CH ), 31.9 (CH ), 20.1 (CH ) ppm. IR (film): ν = 2958, 1695,
˜
max
3
2
3
(CH ), 30.9 (CH ) ppm. IR (film): ν = 3027, 2839, 1452, 1364,
˜
max
3
2
1487, 1443, 1233, 1217 cm–1. HRMS (ESI, +ve): calcd. for
1093, 1073 cm–1. HRMS (ESI, +ve): calcd. for C20H26NO
C18H22N [M + H]+ 252.1755; found 252.1752.
[M + H]+ 296.2016; found 296.2014.
Compound 49: Oil; Rf = 0.54 (PE/EtOAc, 9:1). 1H NMR (300 MHz,
CDCl3): δ = 7.33 (d, J = 7 Hz, 4 H, ArH), 7.22–7.17 (m, 6 H,
ArH), 7.12–7.07 (m, 2 H, ArH), 5.75–5.61 (m, 1 H, CH=CH2),
4.95–4.86 (m, 2 H, CH=CH2), 4.30 (s, 1 H, CHPh2), 2.37–2.33 (m,
2 H, NCH2), 2.23–2.17 (m, 2 H, CH2CH), 2.09 (s, 3 H, Me) ppm.
13C NMR (75 MHz, CDCl3): δ = 128.3, 128.0, 126.7 (CHAr), 75.6
Pyrrolidine 55 and Alkene 56 (from 39); Compound 55: Oil; Rf =
0.75 (PE/EtOAc, 8:2). 1H NMR (300 MHz, CDCl3): δ = 7.34–7.24
(m, 5 H, Ph), 3.31–3.25 (m, 1 H, H-5), 3.02 (s, 1 H, H-2), 2.80–
2.69 (m, 1 H, H-4), 2.47–2.39 (m, 1 H, H-5Ј), 2.19 (s, 3 H, Me),
1.59–1.49 (m, 1 H, H-4Ј), 1.37 (s, 3 H, Me), 1.00 (s, 9 H, tBu) ppm.
13C NMR (75 MHz, CDCl3): δ = 173.9 (CO), 139.6 (Cq), 128.6,
127.8, 127.1 (CHAr), 82.0 (CH), 79.6 (Cq), 55.0 (Cq), 54.9 (CH2),
(CH), 54.7 (CH ), 40.1 (CH ), 31.6 (CH ) ppm. IR (film): ν =
˜
max
2
3
2
2958, 1695, 1487, 1443, 1233, 1217 cm–1. HRMS (ESI, +ve): calcd.
40.8 (CH ), 35.6 (CH ), 27.3, 25.8 (CH ) ppm. IR (film): ν =
˜
max
3
2
3
for C18H22N [M + H]+ 252.1755; found 252.1752.
2975, 2777, 1720, 1452, 1365, 1247, 1144, 1120 cm–1. HRMS (ESI,
+ve): calcd. for C17H26NO2 [M + H]+ 276.1976; found 276.1964.
Pyrrolidine 50 and 51 (from 37); Compound 50 (or 51): Oil; Rf =
0.52 (CH2Cl2/MeOH, 9:1). 1H NMR (300 MHz, CDCl3): δ = 6.95–
6.84 (m, 10 H, 2Ph), 3.57–3.44 (m, 3 H, H-2, H-3 and H-5), 2.52–
2.44 (m, 1 H, H-5Ј), 2.38–2.27 (m, 1 H, H-4), 2.23 (s, 3 H, Me),
2.19–2.13 (m, 1 H, H-4Ј) ppm. 13C NMR (75 MHz, CDCl3): δ =
129.0, 128.3, 127.4, 127.3, 126.3, 125.6 (CHAr), 75.9 (CH), 56.3
Compound 56: Oil; Rf = 0.41 (PE/EtOAc, 8:2). 1H NMR (300 MHz,
CDCl3): δ = 7.33–7.28 (m, 5 H, Ph), 6.09 (d, J = 1 Hz, 1 H,
C=CHH), 5.49 (d, J = 1 Hz, 1 H, C=CHH), 3.54 (s, 2 H,
NCH2Ph), 2.57–2.52 (m, 4 H, NCH2CH2), 2.25 (s, 3 H, Me), 1.49
(s, 9 H, tBu) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.4 (CO),
140.6, 139.1 (Cq), 129.0, 128.2, 126.9 (CHAr), 124.6 (CH2), 80.5
(Cq), 62.1, 56.5 (CH2), 42.0 (CH3), 29.8 (CH2), 28.0 (CH3) ppm.
(CH ), 50.7 (CH), 41.0 (CH ), 30.9 (CH ) ppm. IR (film): ν =
˜
max
2
3
2
3023, 2924, 2776, 1678, 1601, 1493, 1447, 1197, 1153, 1071,
1027 cm–1. HRMS (ESI, +ve): calcd. for C17H20N [M + H]+
238.1596; found 238.1596.
IR (film): ν
= 2976, 2786, 1708, 1453, 1366, 1310, 1147 cm–1.
˜
max
HRMS (ESI, +ve): calcd. for C17H26NO2 [M + H]+ 276.1962;
found 276.1964.
Compound 51 (or 50): Oil; Rf = 0.35 (CH2Cl2/MeOH, 9:1). 1H
NMR (300 MHz, CDCl3): δ = 7.21–7.11 (m, 8 H, ArH), 7.04–7.01
(m, 2 H, ArH), 3.43–3.38 (m, 1 H, H-5), 3.22–3.14 (m, 1 H, H-3),
3.07–3.04 (m, 1 H, H-2), 2.64–2.56 (m, 1 H, H-5Ј), 2.53–2.39 (m,
Supporting Information (see footnote on the first page of this arti-
cle): Procedures for the synthesis of azetidines 10–20. Copies of 1H
and 13C NMR spectra for all new compounds. NOESY data for
1 H, H-4), 2.18 (s, 3 H, Me), 2.03–1.93 (m, 1 H, H-4Ј) ppm. 13C 52, 53, and 55.
1108
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1103–1109

Synthesis of 2-Phenyl- and 2,2-Diarylpyrrolidines
14919; r) K. Griffin, C. Montagne, C. T. Wang, G. J. Clarkson,
M. Shipman, Org. Biomol. Chem. 2012, 10, 1032–1039; s) H.
Huang, X. Ji, W. Wu, H. Jiang, Chem. Commun. 2013, 49,
3351–3353.
a) T. K. Beng, J. S. Woo, R. E. Gawley, J. Am. Chem. Soc. 2012,
134, 14764–14771; b) N. S. Sheikh, D. Leonori, G. Barker, J. D.
Firth, K. R. Campos, A. J. H. M. Meijer, P. O’Brien, I.
Coldham, J. Am. Chem. Soc. 2012, 134, 5300–5308.
a) A. G. Anderson Jr, M. T. Wills, J. Am. Chem. Soc. 1968,
90, 3046–3050; b) M. T. Wills, I. E. Wills, L. Von Dollen, B. L.
Butler, J. Porter, A. G. Anderson Jr, J. Org. Chem. 1980, 45,
2489–2498.
a) F. Couty, F. Durrat, G. Evano, J. Marrot, Eur. J. Org. Chem.
2006, 4214–4223. For other uses of the Stevens rearrangement
of azetidinium ylides, see: b) T. M. Bott, J. A. Vanecko, F. G.
West, J. Org. Chem. 2009, 73, 2823–2836; c) B. N. Naidu, F. G.
West, Tetrahedron 1997, 53, 16565–16574; d) J. A. Vanecko,
F. G. West, Org. Lett. 2005, 7, 2949–2952.
F. Faigl, E. Kovács, G. Turczel, Á. Szöllösy, A. Mordini, L.
Balázs, T. Holczbauer, M. Czugler, Tetrahedron: Asymmetry
2012, 22, 1607–1614.
Acknowledgments
The University of Versailles St-Quentin-en-Yvelines and the Centre
National de la Recherche Scientifique (CNRS) are acknowledged
for financial support.
[4]
[5]
[6]
[1] N. A. McGrath, M. Brichacek, J. T. Njadarson, J. Chem.
Educ. 2010, 87, 1348–1349. See also the website: http://
cbc.arizona.edu/njardarson/group/top-pharmaceuticals-poster.
[2] For a review, see: S. R. Breining, Curr. Top. Med. Chem. 2004,
4, 609–629.
[3] For representative syntheses focused on 2-phenylpyrrolidine,
see: a) L. C. Craig, J. Am. Chem. Soc. 1933, 55, 2543–2550; b)
L. D. Quin, G. L. Roof, J. Org. Chem. 1962, 27, 4451–4454; c)
A. I. Meyers, J. M. Marra, Tetrahedron Lett. 1985, 26, 5863–
5866; d) F. D. Lewis, G. D. Reddy, S. Schneider, M. Gahr, J.
Am. Chem. Soc. 1989, 111, 6465–6466; e) C. J. Dunsmore, R.
Carr, T. Fleming, N. J. Turner, J. Am. Chem. Soc. 2006, 128,
2224–2225; f) G.-H. Hou, J.-H. Xie, P.-C. Yan, Q.-L. Zhou, J.
Am. Chem. Soc. 2009, 131, 1366–1367. For syntheses of 2,2-
diaryl pyrrolidines, see: g) J. G. Smith, C. D. Veach, Can. J.
Chem. 1966, 44, 2245–2257; h) J. G. Smith, D. J. Mitchell, J.
Am. Chem. Soc. 1977, 99, 5045–5050; i) H. Ludt, C. R. Hauser,
J. Org. Chem. 1971, 36, 1607–1613; j) G. J. Hitchings, M. D.
Thomas, J. D. Vernon, J. Chem. Soc. Perkin Trans. 1 1992, 895–
[7]
[8]
B. R. Neustadt, E. H. Gold, US Patent 4-304-790, 1981.
[9] a) C. Agami, F. Couty, G. Evano, Tetrahedron: Asymmetry
2002, 13, 297–302; b) For the preparation of azetidine 11, see:
B. Drouillat, K. Wright, O. David, F. Couty, Eur. J. Org. Chem.
2012, 6005–6012.
898; k) J.-U. Turner, W. Richter, H. Köppel, G. Tomaschewski, [10] F. Couty, F. Durrat, G. Evano, D. Prim, Tetrahedron Lett. 2004,
A. Hauser, G. Van Binst, J. Prakt. Chem. 1988, 330, 213–228;
l) A. Mertens, H. Zilch, B. Koenig, W. Shaefer, T. Poll, W.
Kampe, H. Seidel, U. Leser, H. Leinart, J. Med. Chem. 1993,
36, 2526–2535; m) R. Halim, P. J. Scammells, B. J. Flynn, Org.
Lett. 2008, 10, 1967–1970; n) Q. A. Best, R. Xu, M. E. Mc Car-
roll, L. Wang, D. J. Dyer, Org. Lett. 2010, 12, 3219–3221; o)
K. S. Chan, X. Z. Li, L. Sin, Organometallics 2010, 29, 2850–
2856; p) K. Smith, G. A. Hel-Hiti, A. Hegazy, A. Fekri, Het-
erocycles 2010, 80, 941–956; q) S. G. Newman, J. K. Howell, N.
Nicolaus, M. Lautens, J. Am. Chem. Soc. 2011, 133, 14916–
45, 7524–7528.
[11] M. DЈhooghe, W. Van Brabandt, N. De Kimpe, J. Org. Chem.
2004, 69, 2703–2710.
[12] F. Couty, O. David, F. Durrat, G. Evano, S. Lakhdar, J. Marrot,
M. Vargas-Sanchez, Eur. J. Org. Chem. 2006, 3479–3490.
[13] For an example of the enantioselective Stevens rearrangement
and a discussion on the mechanism, see: M.-H. Gonçalves-
Farbos, L. Vial, J. Lacour, Chem. Commun. 2008, 829–831.
Received: October 9, 2013
Published Online: December 2, 2013
Eur. J. Org. Chem. 2014, 1103–1109
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