1,3-Dipolar cycloaddition of unstabilised azomethine ylides by Lewis base catalysis

Article abstract of DOI:10.1039/c2ob26047f

Lewis base catalysed 1,3-dipolar cycloaddition between α,β- unsaturated acyl fluorides and N-[(trimethylsilyl)methyl]amino ethers has been achieved using 1 mol% DMAP. Competition experiments and ¹⁹F-NMR studies indicate that the cycloaddition o

Full text of DOI:10.1039/c2ob26047f

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PAPER
1,3-Dipolar cycloaddition of unstabilised azomethine ylides by Lewis base
catalysis†
Shveta Pandiancherri, Sarah J. Ryan and David W. Lupton*
Received 31st May 2012, Accepted 7th August 2012
DOI: 10.1039/c2ob26047f
Lewis base catalysed 1,3-dipolar cycloaddition between α,β-unsaturated acyl fluorides and
N-[(trimethylsilyl)methyl]amino ethers has been achieved using 1 mol% DMAP. Competition
experiments and 19F-NMR studies indicate that the cycloaddition occurs preferentially between the
α,β-unsaturated acyl fluoride and the unstabilised azomethine ylide. In addition, an enantioselective
variant, using chiral isothiourea catalysts, has been achieved with 14% ee.
concept we recently commenced studies focused on establishing
the viability of Lewis base catalysis of the 1,3-dipolar cyclo-
Introduction
The 1,3-dipolar cycloaddition of unstabilised azomethine ylides
(i.e. 1) with electron poor dipolarophiles is a useful approach to
the stereoselective synthesis of pyrrolidines 2.1 While generation
of the unstabilised azomethine ylide can be achieved using a
number of methods, the desilylation of N-[(trimethylsilyl)-
methyl]amino ethers (i.e. 3) with metal fluorides,2 or trifluorace-
tic acid,3 remains a common strategy.4 Despite on-going appli-
cation of this reaction, realisation of a catalytic enantioselective
variant has received little attention. This is in contrast to stabil-
ized azomethine ylides, whose application in catalytic enantio-
selective transformations is well documented.5,6 From our
reading the only studies towards a catalytic enantioselective 1,3-
dipolar cycloaddition of unstabilised azomethine ylides have
been attempted using chiral Lewis acids, and unfortunately gave
only 2% ee.6,7 Presumably this lack of selectivity arose due to
unselective 1,3-dipolar cycloaddition of stoichiometrically
generated azomethine ylide 1 and the dipolarophile, in the
absence of the chiral Lewis acid.
To address this limitation we envisaged an orthogonal
approach to enantioselectivity, through the use of chiral Lewis
base catalysis.8 We postulated that by exploiting an α,β-unsatu-
rated acid fluoride such as 4,9,10 and an appropriate chiral Lewis
base, homochiral 5 could be generated, with concomitant for-
mation of the unstabilised azomethine ylide 1. Such a strategy
would ensure that ylide 1 was maintained at substoichiometric
levels and, provided the rate of cycloaddition between 5 and 1 is
more rapid than with 4, this should allow the development of an
enantioselective pyrrolidine synthesis (Scheme 1). To trial this
addition of unstabilised azomethine ylides. Herein, we report the
first example of Lewis base catalysis of the 1,3-dipolar cyclo-
addition of unstabilised azomethine ylides.
Results and discussion
Studies commenced with the identification of Lewis base cata-
lysts for the cycloaddition between cinnamoyl fluoride 4a and
ylide precursor 3a. N-Heterocyclic carbenes (NHCs) have been
shown to activate acyl fluorides,9 and provided a starting place
for optimisation. Bis-(2,4,6-trimethylphenyl)imidazol-2-ylidene,
IMes (A1), generated from the imidazolium salt precursor, was
able to catalyse the formation of pyrrolidine 2a, which was iso-
lated in 21% yield (Table 1, entry 1). Changing from toluene to
THF increased the yield moderately (Table 1, entry 1 cf. 2), as
did increasing the steric demand of the NHC through the use of
1,3-bis-(2,6-diisopropylphenyl)imidazol-2-ylidene IPr (A2)
(Table 1, entry 3). Finally generation of IPr (A2) by deprotona-
tion of the imidazolium in toluene followed by filtration to
remove salt byproducts increased the yield to 58% (Table 1,
entry 4). The role of endogenous metal salts and Lewis acid
additives is well documented.11
While this yield is serviceable, alternate nucleophilic catalysts
were trialled to improve the reaction. Although catalytic
DABCO (B)12 and isothiourea (C)13 provided 20 and 70% of
the expected pyrrolidine 2a (Table 1, entries 5 and 6), we were
pleased to find that 10 mol% DMAP (D) gave pyrrolidine 2a in
85% yield (Table 1, entry 7). Furthermore, the catalytic loading
could be decreased to 1 mol% with no detrimental effect on the
reaction (Table 1, entry 8). However, when performed with
0.1 mol% DMAP the reaction was very slow, and after 36 h had
failed to reach completion (Table 1, entry 9).
Monash University, Clayton 3800, Melbourne, Australia.
E-mail: david.lupton@monash.edu; Fax: +61 3 9905 4597;
Tel: +61 3 9902 0327
†Electronic supplementary information (ESI) available: 1H- and
13C-NMR spectra of all reported compounds as well as additional exper-
imental procedures. See DOI: 10.1039/c2ob26047f
With conditions that allowed nucleophilic catalysis of the
1,3-dipolar cycloaddition in hand, the generality of the
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Scheme 1 Reaction design.
(4 + 3) product formed.14 When the ylide precursor contained an
S-methyl benzyl group (i.e. 3l), pyrrolidine 2l formed with no
diastereoselectivity (Table 1, entry 5). This result is consistent
with other studies exploiting this chiral auxiliary that proceed
with modest diastereoselectivity.15 Similarly, menthol derived
ylide precursor 3m provided pyrrolidine 2m in good yield
(Table 1, entry 6), but with no diastereoselectivity (vide infra).
Table 1 Selected optimisation studies
Lewis base catalysis without α,β-unsaturated acyl fluorides
The low catalyst loading, mild conditions and short reaction
times, allow favourable comparison to more established
approaches. While the necessity of acyl fluorides 4 may be
viewed as a limitation, we have found these materials to be
easily prepared, and stable when stored appropriately. However,
to address this potential limitation modified reaction conditions
were developed exploiting commercially available benzoyl
fluoride as a sacrificial fluoride source.16 In this case Lewis base
mediated defluoronation generates benzoyl pyridinium and
fluoride, the later triggers the 1,3-dipolar cycloaddition with
turnover achieved through conversion of the former to the benzo-
ate ester. These reaction conditions were investigated using a
range of α,β-unsaturated esters 6. When methyl and ethyl cinna-
mates 6a–q were examined their dipolar cycloaddition with ylide
precursor 3a was complete at room temperature after 6 h
(Table 3, entry 1). In all cases yields were comparable to those
obtained starting with the acyl fluoride (Table 2, entry 2 cf.
Table 3, entry 1). In addition the reaction was compatible with
esters bearing heteroaromatic motifs (Table 3, entry 2), while the
reaction with ethyl propiolate 6s could be achieved to yield the
dihydropyrrole 2s in good yield (Table 3, entry 3). This later
transformation could not be achieved from the acid fluoride due
to difficulties preparing the substrate. In all cases separation of
the pyrrolidine from the methyl benzoate byproduct was easily
achieved by flash column chromatography.
Entry
[mol%] cat.
Additives
Solvent
Yield 3aa
1
2
3
4
5
6
7
8
9
10% A1
10% A1
10% A2
10% A2b
10% B
10% C
10% D
10% KOtBu
Toluene
THF
THF
THF
THF
THF
THF
THF
THF
21
34
38
58
70
20
85
81
48c
10% KOtBu
10% KOtBu
—
—
—
—
—
—
1 mol% D
0.1 mol% D
a Isolated yield following flash column chromatography. b Generated
from the imidazolium and isolated from KCl. c Isolated yield after 36 h.
transformation was examined (Table 2). In contrast to other
cycloadditions exploiting unstabilised azomethine ylide 1, the
ether in precursor 3 is required for catalyst turnover, and is ulti-
mately found in the ester functionality of the pyrrolidine product
2 (see Scheme 1). Thus, studies began by examining the chem-
istry of ylide precursors 3a–d bearing methyl through to t-butyl
ethers (Table 1, entry 1). In all cases these ylide precursors
reacted smoothly with cinnamoyl fluoride 4a to provide pyrroli-
dines 2a–d in good yields. Even the hindered t-butyl ester con-
taining pyrrolidine 2d could be produced in 62% yield (Table 1,
entry 1d).
Next the scope with respect to the dipolarophile was exam-
ined, initially using a range of cinnamoyl fluorides (4e–i) with
differing electronic and steric demand. In all cases the pyrroli-
dines (2e–i) were formed in acceptable yields using the standard
reaction conditions (Table 1, entry 2). Heteroaromatic groups, in
the form of a 2-furyl, could be included at the β-position of the
α,β-unsaturated acyl fluoride (i.e. 4j) giving rise to pyrrolidine
2j in 79% yield (Table 1, entry 3). α,β,γ,δ-Unsaturated acyl
fluoride 4k was also viable providing only pyrrolidine 2k in
76% isolated yield (Table 1, entry 4), with none of the possible
Mechanistic studies
Having demonstrated the generality of the reaction attention was
directed towards an enantioselective variant. For this to be viable
the cycloaddition between acyl pyridinium 5 and ylide 1
(Scheme 2, Path A) must be faster than esterification of 5 to
provide 6t, and also cycloaddition between the α,β-unsaturated
acid fluoride 4e and ylide 1 (Scheme 2, Path B). To investigate
these questions a competition study between acyl fluoride 4e and
ester 6a was undertaken. The major product of this reaction was
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Table 2 Scope of the DMAP catalysed 1,3-dipolar cycloaddition
Entry
1
Acyl fluoride (4)
Ylide precursor 3
Product 2
Yielda
a
b
c
d
3a
3b
3c
3d
2a, R1 = Me
2b, R1 = Et
2c, R1 = iPr
2d, R1 = tBu
81
81
68
62
2
a
b
c
3a
3a
3a
2e, R = pMe
2f, R = pOMe
2g, R = oOMe
80
73
75
d
e
3
3a
3a
3a
2h, R = mBr
2i, R = oNO2
72
65
79
4
3a
76
5
6
3l
80b
80b
3m
a Isolated yield following flash column chromatography. b Isolated in a 1 : 1 ratio as determined by 1H-NMR analysis.
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pyrrolidine 2e. If this reaction proceeds via an ester intermediate
(i.e. 6t) then the major product would be pyrrolidine 2a, since
this can form directly from 6a (Scheme 1, Path C). The for-
mation of 2e as the major product indicates that the dipolarophile
in this reaction is either acyl pyridinium 5, or acyl fluoride 4e
and the reaction occurs via Path A or B.
ester 6u (Scheme 3). When reacted with ylide precursor 3a,
using conditions previously described in Table 3, pyrrolidine 2m
formed as a 2 : 1 mixture of diastereoisomers.17 In contrast when
pyrrolidine 2m was prepared from the menthol containing ylide
precursor 3m and cinnamoyl fluoride 4a a 1 : 1 mixture was
obtained (Table 2, entry 6). If menthol ester 6u was an inter-
mediate in the later transformation, then it should form with the
same diastereoselectivity in both cases.
Further support for cycloaddition via either Path A or B can
be gleaned from considering the reaction of homochiral menthol
To clarify whether the dipolarophile is acyl pyridinium 5 or
acyl fluoride 4e the competition described in Scheme 2 was
repeated using TFA to generate the ylide, followed by a work-up
to convert acyl fluoride pyrrolidine 7 to the ester. In this case the
acyl pyridinium intermediate 5 cannot form. When conducted
the same ratio of cycloadducts was obtained as in Scheme 2.
Combined, these results indicate that the 1,3-cycloaddition
between the acyl fluoride 4e and ylide precedes with at least the
same rate as the cycloaddition with the acyl pyridinium 5.
Further evidence for preferential cycloaddition between the
α,β-unsaturated acyl fluoride and the unstabilised azomethine
ylide was obtained by in situ 19F-NMR analysis of the reaction
mixture. If cycloaddition occurs solely via the pyridinium then
two fluorine-containing materials should be observed, the
α,β-unsaturated acyl fluoride and TMSF. In contrast, a third
fluorine-containing compound, i.e. 7, would be observable if the
1,3-dipolar cycloaddition occurs with the α,β-unsaturated acid
fluoride. In the event, a new signal was observed at 40.09 ppm
when the reaction was monitored by 19F-NMR (Scheme 4). This
signal is typical of an acyl fluoride, and was attributed to acyl
pyrrolidine 7 (Scheme 4).18
Table 3 Scope of the DMAP catalyzed 1,3-dipolar cycloaddition of
α,β-unsaturated esters
Entry
Ester 6
Product 2
Yielda
1a
b
c
d
e
f
g
6a, R = Me R4 = H
2a
2g
2i
2n
2o
2p
2q
89
93
65
91
82
91
72
6g, R = Me, R4 = o-Me
6i, R = Et, R4 = o-NO2
6n, R = Et, R4 = o-CH3
6o, R = Et, R4 = p-NO2
6p, R = Et, R4 = o-MeO
6q, R = Et, R4 = o-Br
2
67
3
90
a Isolated yield following flash column chromatography.
Scheme 3 Diastereoselective 1,3-dipolar cycloaddition with menthol 6v.
Scheme 2 DMAP catalysed competition between α,β-unsaturated acyl fluoride 4e and ester 6a.
7906 | Org. Biomol. Chem., 2012, 10, 7903–7911 This journal is © The Royal Society of Chemistry 2012

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Conclusions
The 1,3-dipolar cycloaddition of unstabilised azomethine ylide 1
with electron poor olefins has been achieved using Lewis base
catalysis. Optimal conditions exploit 1 mol% DMAP and allow a
broad range of cycloadducts to be generated. In addition, use of
benzoyl fluoride as a sacrificial fluoride source allows the cyclo-
addition to be achieved with readily accessible α,β-unsaturated
esters. Together these procedures increase the flexibility with
which 1,3-dipolar cycloadditions of unstabilised azomethine
ylides can be achieved. Competition and 19F-NMR studies indi-
cate that, in the former reaction, the cycloaddition occurs prefer-
entially between the α,β-unsaturated acyl fluoride and the
azomethine ylide.
Scheme 4 Key signals from reactions monitored with 19F-NMR.
Studies with homochiral isothiourea catalyst C3 demonstrate
that low levels of enantioselectivity can be achieved. While these
are modest, they provide proof of principle for such a strategy.
Future studies are focused on the development of new chiral
Lewis base catalysts capable of delivering α,β-unsaturated Lewis
base adducts with greatly enhanced reactivity.
Experimental
General experimental
Proton (1H) and carbon (13C) NMR spectra were recorded at
400 MHz for proton, 100 MHz for carbon nuclei and 282 MHz
for fluorine. High resolution mass spectra (HRMS) (ESI) were
recorded using NaI for accurate mass calibration. Flash column
chromatography was performed on silica gel (LC60A, 40–63 μm
silica media) using compressed nitrogen. Thin layer chromato-
graphy (TLC) was performed using aluminium-backed plates
coated with 0.2 mm silica. Eluted plates were visualized using a
254 nm UV lamp and/or by treatment with a suitable stain fol-
lowed by heating. Tetrahydrofuran and dioxane were distilled
from sodium benzophenone ketyl, toluene from sodium metal,
and dichloromethane from calcium hydride. Azomethine ylide
precursors prepared using procedures communicated by Padwa2
and others.3 Starting acyl fluorides were prepared according to
the procedure of Chen et al.25 Starting esters 6 were prepared
according to procedures of Chuzel and Piva26 or Brooks and
Chan.27
Chart 1 Studies into the enantioselective 1,3-dipolar cycloadditiona,b
.
Enantioselective 1,3-dipolar cycloaddition of unstabilised
azomethine ylides
The facile cycloaddition between unstabilised azomethine ylide
1 and α,β-unsaturated acyl fluorides makes the development of
an enantioselective variant of this reaction challenging. Of
course the kinetics of the 1,3-dipolar cycloaddition will be con-
trolled by the nature of the specific catalyst. Thus, we decided to
screen a range of common chiral Lewis bases (Chart 1, eqn (4)).
When homochiral DMAP derivatives19 of Vedejs (D2 and D3)20
and Fu (D4)21 were exposed to the reaction conditions they
failed to induce any enantioselectivity. In addition known chiral
NHCs (A3 and A4)22 failed to induce asymmetry. Finally, chiral
isothioureas23 were investigated. When 10 mol% tetramisole
(C2) was trialled no enantioselectivity was observed. However,
with 100 mol% C2, and sequential addition of reagents, pyrroli-
dine 2a formed with 35% ee, although in moderate yield. The
enantioselectivity could be increased to 43% ee by exploiting
dioxane as the solvent. While an exhaustive study of isothioureas
was not undertaken we found that 10 mol% C324 provided pyr-
rolidine 2a in an improved 35% yield and 14% ee. By increasing
the catalyst loading to 50 mol% and adding the acyl fluoride 4a
over 14 h the enantioselectivity could be improved to 25%.
Although the selectivity and yield are clearly not optimal, results
using C3 suggest the possibility of an enantioselective Lewis-
base catalysed 1,3-dipolar cycloaddition.
General procedure for the 1,3-cycloaddition using
α,β-unsaturated acyl fluorides
A flame dried and N2 purged round bottom flask was charged
with a magnetic stirrer bar, acid fluoride 4a–k (0.2 mmol), ylide
precursor 3a–m (0.22 mmol) and THF (3 mL). The resultant sol-
ution was magnetically stirred and cooled to 0 °C as a solution
of DMAP (0.002 mmol, 0.24 mg) in THF (1 mL) was added.
The reaction was stirred at 0 °C for 1 h, then warmed to room
temperature over 10 min. Solvent was removed in vacuo, and the
residue purified via flash column chromatography to provide the
pyrrolidine 2a–m (Table 2).
(3S,4R)-Methyl
1-benzyl-4-phenylpyrrolidine-3-carboxylate
and (3R,4S)-methyl 1-benzyl-4-phenylpyrrolidine-3-carboxylate
(2a).28 Clear oil; Rf 0.39 (1 : 4 v/v ethyl acetate–hexanes); IR
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1
νmax 3080, 3030, 1745, 1676, 1450 cm−1; H NMR (400 MHz,
128.5, 128.4(9), 128.4(2), 127.2, 114.1, 62.0, 60.1, 57.5, 55.4,
52.0, 51.9, 46.5; HRMS (ESI) m/z found (M + H)+ 326.1753,
C20H24NO3 requires (M + H)+ 326.1751.
CDCl3) δ 7.35–7.20 (m, 10H), 3.70 (d, JAB = 13.0 Hz, 1H), 3.65
(d, JAB = 13.0 Hz, 1H), 3.66 (s, 3H), 3.11–2.99 (m, 4H),
2.89–2.87 (m, 1H), 2.78–2.74 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 174.8, 144.3, 138.9, 128.8, 128.7, 128.4, 127.6, 127.2,
126.7, 61.9, 60.1, 57.6, 52.1, 51.8, 47.1.
(3S,4R)-Methyl 1-benzyl-4-(2′-methoxyphenyl)pyrrolidine-3-
carboxylate and (3R,4S)-methyl 1-benzyl-4-(2′-methoxyphenyl)-
pyrrolidine-3-carboxylate (2g).33 Clear oil; Rf 0.33 (1 : 4 v/v
ethyl acetate–hexanes); IR νmax 3027, 2949, 2835, 2795, 1733,
1437, 1052 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.37–7.16 (m,
7H), 6.93–6.89 (m, 1H), 6.84–6.82 (m, 1H), 4.03–3.97 (m, 1H),
3.77 (s, 3H), 3.72 (d, J = 13.0 Hz, 1H), 3.65 (s, 3H), 3.64 (d, J =
13.0 Hz, 1H), 3.16–3.12 (m, 1H), 3.02–2.98 (m, 2H), 2.93–2.89
(m, 1H), 2.78–2.74 (m, 1H); 13C NMR (100 MHz, CDCl3): δ
175.5, 157.3, 139.0, 131.6, 128.9, 128.4, 127.7, 127.1, 126.3,
120.8, 110.7, 60.1, 60.0, 57.6, 55.4, 51.9, 49.7, 41.7; HRMS
(ESI) m/z found (M + H)+ 326.1757, C20H24NO3 requires
(M + H)+ 326.1751.
(3S,4R)-Ethyl 1-benzyl-4-phenylpyrrolidine-3-carboxylate and
(3R,4S)-ethyl
(2b).29 Clear oil; Rf 0.46 (1 : 4 v/v ethyl acetate–hexanes); IR
νmax 3061, 3028, 2792, 1731, 1630, 1451 cm−1 1H NMR
(400 MHz, CDCl3) δ 7.13–7.04 (m, 10H), 4.02–3.94 (m, 2H),
3.57 (d, JAB = 13.0 Hz, 1H), 3.53–3.50 (m, 1H), 3.51 (d, JAB
1-benzyl-4-phenylpyrrolidine-3-carboxylate
;
=
13.0 Hz, 1H), 2.94–2.85 (m, 3H), 2.75–2.71 (m, 1H), 2.65–2.61
(m, 1H), 1.06 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 174.3, 144.4, 139.0, 128.8, 128.6, 128.4, 127.6, 127.1, 126.6,
61.9, 60.8, 60.1, 57.6, 52.0, 47.1, 14.3.
(3S,4R)-isoPropyl 1-benzyl-4-phenylpyrrolidine-3-carboxylate
and (3R,4S)-isopropyl 1-benzyl-4-phenylpyrrolidine-3-carboxy-
late (2c). Clear oil; Rf 0.37 (1 : 4 v/v ethyl acetate–hexanes); IR
(3S,4R)-Methyl
1-benzyl-4-(3′-bromophenyl)pyrrolidine-3-
carboxylate and (3R,4S)-methyl 1-benzyl-4-(3′-bromophenyl)-
pyrrolidine-3-carboxylate (2h). Clear oil; Rf 0.43 (1 : 4 v/v ethyl
νmax 3061, 3028, 1731, 1676, 1453 cm−1; H NMR (400 MHz,
acetate–hexanes); IR νmax 3061, 3027, 2793, 1733 cm−1 1H
;
1
CDCl3) δ 7.38–7.18 (m, 10H), 3.79 (sep, J = 6.0 Hz, 1H),
3.74–3.64 (m, 3H), 3.15–2.97 (m, 3H), 2.94–2.90 (m, 1H),
2.78–2.74 (m, 1H), 1.14 (d, J = 6.0 Hz, 3H), 1.13 (d, J =
6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.9, 144.2,
139.0, 128.8, 128.7, 128.4, 127.6, 127.2, 126.7, 88.1, 72.4,
62.0, 60.1, 57.4, 52.0, 47.0, 22.6; HRMS (ESI) m/z found
(M + H)+ 324.1963, C21H25NO2 requires (M + H)+, 324.1958.
NMR (400 MHz, CDCl3) δ 7.51–7.49 (m, 1H), 7.37–7.30 (m,
5H), 7.27–7.24 (m, 2H), 7.17–7.13 (m, 1H), 3.67 (s, 3H),
3.69–3.64 (m, 2H), 3.63–3.61 (m, 1H), 3.11–3.04 (m, 2H),
2.96–2.92 (m, 1H), 2.83–2.79 (m, 1H), 2.76–2.72 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 174.4, 146.9, 138.8, 130.6, 130.2,
129.8, 128.8, 128.5, 127.2, 126.3, 122.7, 61.5, 59.9, 57.4, 52.2,
51.7, 46.6; HRMS (ESI) m/z found (M + H)+ 374.0758,
C19H2079BrNO2 requires (M + H)+ 374.0750.
(3S,4R)-tertButyl 1-benzyl-4-phenylpyrrolidine-3-carboxylate
and (3R,4S)-tertbutyl 1-benzyl-4-phenylpyrrolidine-3-carboxy-
late (2d).30 Clear oil; Rf 0.47 (1 : 4 v/v ethyl acetate–hexanes);
(3S,4R)-Methyl 1-benzyl-4-(2′-nitrophenyl)pyrrolidine-3-car-
boxylate and (3R,4S)-methyl 1-benzyl-4-(2′-nitrophenyl)pyrroli-
dine-3-carboxylate (2i). Clear oil; Rf 0.2 (1 : 4 v/v ethyl acetate–
hexanes); IR νmax 3028, 1734, 1608, 1578, 1525, 1354 cm−1; 1H
NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 6.7 Hz, 1.3 Hz, 1H),
7.70 (dd, J = 6.7 Hz, 1.3 Hz, 1H), 7.57 (td, J = 6.7 Hz, 1.3 Hz,
IR νmax 3061, 3027, 2792, 1734, 1453 cm−1 1H NMR
;
(400 MHz, CDCl3) δ 7.31–7.18 (m, 10H), 3.71 (d, JAB
=
13.0 Hz, 1H), 3.64 (d, JAB = 13.0 Hz, 1H), 3.61–3.56 (m, 1H),
3.05–2.96 (m, 3H), 2.86–2.82 (m, 1H), 2.78–2.74 (m, 1H), 1.40
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 173.5, 144.3, 139.9,
128.8, 128.6, 128.4, 127.7, 127.1, 126.5, 80.7, 62.0, 60.1, 57.5,
52.9, 47.2, 28.2.
1H), 7.38–7.24 (m, 6H), 4.10–4.06 (m, 1H), 3.71 (d, JAB
=
12.9 Hz, 1H), 3.67 (d, JAB = 12.9 Hz, 1H), 3.67 (s, 3H),
3.29–3.25 (m, 1H), 3.12–3.06 (m, 1H), 2.97–2.91 (m, 2H),
2.70–2.66 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 174.0,
149.9, 139.7, 138.7, 133.2, 129.3, 128.8, 128.5, 127.4, 127.3,
123.8, 61.6, 59.9, 57.6, 52.4, 52.2, 41.4; HRMS (ESI) m/z found
(M + H)+ 341.1501, C19H20N2O4 requires (M + H)+ 341.1496.
(3S,4R)-Methyl 1-benzyl-4-(p-tolyl)pyrrolidine-3-carboxylate
and (3R,4S)-methyl 1-benzyl-4-(p-tolyl)pyrrolidine-3-carboxy-
late (2e).31 Clear oil; Rf 0.38 (1 : 4 v/v ethyl acetate–hexanes);
IR νmax 3060, 3026, 2789, 1734, 1453 cm−1 1H NMR
;
(400 MHz, CDCl3) δ 7.36–7.10 (m, 9H), 3.71 (d, JAB
=
(3S,4S)-Methyl 1-benzyl-4-(furan-2′-yl)pyrrolidine-3-carboxy-
late and (3R,4S)-methyl 1-benzyl-4-(furan-2′-yl)pyrrolidine-3-
carboxylate (2j). Clear oil; Rf 0.37 (1 : 4 v/v ethyl acetate–
13.0 Hz, 1H), 3.66 (s, 3H), 3.66 (d, JAB = 13.0 Hz, 1H),
3.12–2.99 (m, 3H), 2.92–2.88 (m, 2H), 2.75–2.71 (m, 1H), 2.32
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 174.8, 141.2, 139.0,
136.2, 129.4, 128.8, 128.4, 127.4, 127.1, 62.0, 60.1, 57.5, 52.1,
52.0, 46.9, 21.2.
1
hexanes); IR νmax 3027, 2951, 1733 cm−1; H NMR (400 MHz,
CDCl3) δ 7.26–7.14 (m, 6H), 6.19 (dd, J = 2.0 Hz, 1.2 Hz, 1H),
6.00 (m, 1H), 3.73 (apparent q, J = 7.2, 1H), 3.61 (d, JAB
=
13.2 Hz, 1H), 3.61 (s, 3H), 3.55 (d, JAB = 13.2 Hz, 1H),
3.14–3.09 (m, 1H), 2.97–2.88 (m, 1H), 2.88–2.81 (m, 2H), 2.62
(dd, J = 7.2 Hz, 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 175.5, 157.1, 142.6, 139.7, 129.8, 129.4, 128.2, 111.3, 106.2,
60.8, 59.8, 57.9, 53.2, 49.3, 41.4; HRMS (ESI) m/z found
(M + H)+ 286.1444, C17H19NO3 requires (M + H)+ 286.1438.
(3S,4R)-Methyl 1-benzyl-4-(4′-methoxyphenyl)pyrrolidine-3-
carboxylate and (3R,4S)-methyl 1-benzyl-4-(4′-methoxyphenyl)-
pyrrolidine-3-carboxylate (2f).32 Clear oil; Rf 0.17 (1 : 4 v/v
ethyl acetate–hexanes); IR νmax 3029, 2951, 2835, 2793, 1732,
1438, 1079 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.37–7.29 (m,
4H), 7.25–7.23 (m, 3H), 6.84–6.82 (m, 2H), 3.78 (s, 3H), 3.70
(d, JAB = 13.2 Hz, 1H), 3.65 (s, 3H), 3.64 (d, JAB = 13.2 Hz,
1H), 3.06–2.97 (m, 4H), 2.89–2.87 (m, 1H), 2.73–2.69 (m, 1H);
13C NMR (100 MHz, CDCl3): δ 174.8, 158.4, 138.9, 136.3,
(3S,4R)-Methyl 1-benzyl-4-(2′-bromocyclohex-1-en-1-yl)pyrro-
lidine-3-carboxylate and (3R,4S)-methyl 1-benzyl-4-(2′-bromo-
cyclohex-1-en-1-yl)pyrrolidine-3-carboxylate (2k). Clear oil; Rf
7908 | Org. Biomol. Chem., 2012, 10, 7903–7911
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0.42 (1 : 4 v/v ethyl acetate–hexanes); IR νmax 3028, 2933, 2859,
2838, 1733, 1435 cm−1 1H NMR (400 MHz, CDCl3)
CDCl3) δ 7.30–7.10 (m, 9H), 4.15–4.08 (m, 2H), 3.70 (d, JAB
=
13.2 Hz, 1H), 3.65 (d, JAB = 13.2 Hz, 1H), 3.65–3.61 (m, 1H),
3.06–2.99 (m, 3H), 2.91–2.87 (m, 1H), 2.76–2.72 (m, 1H), 2.32
(s, 3H), 1.21 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
174.4, 141.4, 139.1, 136.2, 129.3, 128.8, 128.4, 127.5, 127.1,
62.0, 60.8, 60.1, 57.6, 52.0, 46.8, 21.1, 14.4.
;
δ 7.31–7.23 (m, 5H), 3.91–3.86 (m, 1H), 3.68 (s, 3H), 3.66 (d,
JAB = 12.8 Hz, 1H), 3.56 (d, JAB = 12.8 Hz, 1H), 2.94–2.88 (m,
2H), 2.80–2.71 (m, 2H), 2.53–2.48 (m, 3H), 2.19–2.15 (m, 2H),
1.73–1.61 (m, 4H); 13C NMR (100 MHz, CDCl3): δ 174.7,
138.9, 135.3, 128.7, 128.4, 127.1, 121.2, 60.0, 57.3(2), 57.2(5),
52.1, 48.0, 46.4, 37.2, 26.9, 24.9, 22.8; HRMS (ESI) m/z found
(M + H)+ 378.1068, C19H2479BrNO2 requires (M + H)+
378.1063.
(3S,4R)-Ethyl
1-benzyl-4-(4′-nitrophenyl)pyrrolidine-3-car-
boxylate and (3R,4S)-ethyl 1-benzyl-4-(4′-nitrophenyl)pyrroli-
dine-3-carboxylate (2o).36 Clear oil; Rf 0.42 (1 : 4 v/v ethyl
acetate–hexanes); IR νmax 3028, 2980, 2793, 1729, 1600, 1517,
1492, 1450 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.16–8.14 (m,
2H), 7.52–7.50 (m, 2H), 7.36–7.26 (m, 5H), 4.17–4.12 (m, 2H),
(3S,4R,1′R)-Methyl 4-phenyl-1-(1′-phenylethyl)pyrrolidine-3-
carboxylate and (3R,4S,1′R)-methyl 4-phenyl-1-(1′-phenylethyl)-
pyrrolidine-3-carboxylate (2l).34 Clear oil; Rf 0.5 (1 : 4 v/v ethyl
3.78–3.74 (m, 1H), 3.72 (d, JAB = 10.0 Hz, 1H), 3.67 (d, JAB
=
acetate–hexanes); IR νmax 3060, 3027, 2780, 1734, 1453 cm−1
;
10.0 Hz, 1H), 3.21–3.17 (m, 1H), 3.07–3.02 (m, 1H), 2.97–2.93
(m, 1H), 2.85–2.76 (m, 2H), 1.23 (t, J = 6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 173.5, 152.7, 146.9, 138.7, 128.7, 128.5
(1), 128.4(6), 127.4, 124.0, 61.2, 61.1, 59.8, 57.4, 52.1,
46.7, 14.3.
1H NMR (400 MHz, CDCl3) δ 7.39–7.18 (m, 10H), 3.66 (s,
1.5H), 3.64 (s, 1.5H), 3.63–3.61 (m, 1H), 3.34–3.29 (m, 1H),
3.16–3.01 (m, 2H), 2.96–2.88 (m, 1H), 2.85–2.78 (m, 1.5H),
2.65–2.61 (m, 0.5H), 1.41 (d, J = 6.4 Hz, 1.5 H), 1.39 (d, J =
6.4 Hz, 1.5 H); 13C NMR (100 MHz, CDCl3) δ 174.8(0), 174.7
(6), 145.5, 145.3, 144.5, 144.2, 128.7, 128.6, 128.5, 128.5,
127.5(8), 127.5(7), 127.5(4), 127.3, 127.1(8), 127.1(5), 127.1
(0), 126.7, 65.4, 65.3, 60.8, 60.6, 56.6, 56.3, 52.0(3), 52.0(2),
52.0(1), 51.6, 47.0, 46.9, 23.3, 23.2.
(3S,4R)-Ethyl
1-benzyl-4-(2′-methoxyphenyl)pyrrolidine-3-
carboxylate and (3R,4S)-ethyl 1-benzyl-4-(2′-methoxyphenyl)pyrroli-
dine-3-carboxylate (2p).32 Clear oil; Rf 0.36 (1 : 4 v/v ethyl
acetate–hexanes); IR νmax 3061, 3029, 2957, 2834, 2790, 1729,
1448, 1034 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.33–7.23 (m,
7H), 6.85–6.83 (m, 2H), 4.16–4.10 (m, 2H), 3.78 (s, 3H),
3.72–3.59 (m, 3H), 3.07–2.97 (m, 3H), 2.90–2.86 (m, 1H),
2.75–2.71 (m, 1H), 1.21 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ 174.4, 158.3, 139.0, 136.4, 128.8, 128.5,
128.4, 127.1, 114.0, 62.0, 60.8, 60.1, 57.5, 55.4, 52.1, 46.4, 14.4
(2 signals overlapping or missing).
General procedure for the 1,3-cycloaddition with esters and
unstabilised ylides
A flame dried and N2 purged round bottom flask was charged
with a magnetic stirrer bar, benzoyl fluoride (0.2 mmol), ester
6a–t (0.2 mmol), ylide precursor 3a (0.22 mmol) and THF
(3 mL). The resultant solution was magnetically stirred and
cooled to 0 °C as a solution of DMAP (0.002 mmol) in THF
(1 mL) was added. The reaction was allowed to stir at 0 °C for
30 min, then warmed to room temperature over 6 h. Solvent was
removed in vacuo, and the residue purified via flash column
chromatography to yield desired pyrrolidines 2a–s (Table 3).
(3S,4R)-Ethyl
1-benzyl-4-(2′-bromophenyl)pyrrolidine-3-
carboxylate and (3R,4S)-ethyl 1-benzyl-4-(2′-bromophenyl)-
pyrrolidine-3-carboxylate (2q). Clear oil; Rf 0.44 (1 : 4 v/v ethyl
acetate–hexanes); IR νmax 3063, 3027, 2838, 1733 cm−1 1H
;
NMR (400 MHz, CDCl3): δ 7.55 (dd, J = 6.0 Hz, 1.6 Hz, 1H),
7.51 (dd, J = 6.8 Hz, 1.2 Hz, 1H), 7.38–7.23 (m, 6H), 7.07–7.03
(m, 1H), 4.19–4.11 (m, 3H), 3.72 (d, JAB = 12.8 Hz, 1H), 3.67
(d, JAB = 12.8 Hz, 1H), 3.21–3.17 (m, 1H), 3.09–3.04 (m, 1H),
3.01–2.97 (m, 1H), 2.81–2.77 (m, 2H), 1.23 (t, J = 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3): δ 174.1, 144.1, 139.0, 132.8,
128.8, 128.6, 128.4, 128.0(3), 128.0(2), 127.2, 124.6, 61.4,
61.0, 60.0, 57.5, 51.5, 46.1, 14.3; HRMS (ESI) m/z found
(M + H)+ 388.0914, C20H2279BrNO2 requires 388.0907.
(3R,4S,1′R,2′S,4′R)-2′-Isopropyl-4′-methylcyclohexyl 1-benzyl-4-
phenylpyrrolidine-3-carboxylate and (3S,4R,1′R,2′S,4′R)-2′-
isopropyl-4′-methylcyclohexyl 1-benzyl-4-phenylpyrrolidine-3-
carboxylate (2m). Clear oil; Rf 0.51 (1 : 9 v/v ethyl acetate–
1
hexanes); IR νmax 3027, 2933, 1734 cm−1; H NMR (400 MHz,
CDCl3) δ 7.38–7.18 (m, 10H), δ 4.70–4.62 (m, 1H), 3.76–3.61
(m, 3H), 3.10–3.00 (m, 3H), 2.92–2.85 (m, 1H), 2.79–2.74 (m,
1H), 1.97–1.94 (m, 1H), 1.75–1.60 (m, 4H), 1.51–1.42 (m, 1H),
1.34–1.24 (m, 2H), 1.07–0.97 (m, 1H), 0.88 (d, J = 6.8 Hz, 3H),
0.82 (d, J = 6.8 Hz, 1H), 0.79 (d, J = 6.8 Hz, 2H), 0.70 (d, J =
7.2 Hz, 1H), 0.67 (d, J = 7.6 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 173.9(9), 173.8, 144.4, 144.1, 139.1, 128.8, 128.7,
128.6, 128.4, 127.6(4), 127.6, 127.1, 126.6(2), 126.6, 74.7,
62.1, 60.1, 57.7, 52.3(2), 52.3, 47.6, 47.1(4), 47.1, 41.1, 41.0,
34.4, 31.5, 26.3, 26.1, 23.5, 23.4, 22.2, 20.9, 16.3 (14 signals
overlapping); HRMS (ESI) m/z found (M + H)+ 420.2897,
C28H37NO2 requires (M + H)+ 420.2902.
(3S,4R)-Ethyl 1-benzyl-4-(furan-2′-yl)pyrrolidine-3-carboxy-
late and (3R,4S)-ethyl 1-benzyl-4-(furan-2′-yl)pyrrolidine-3-car-
boxylate (2r). Clear oil; Rf 0.39 (1 : 4 v/v ethyl acetate–
hexanes); IR νmax 3062, 3028, 2795, 1729 cm−1 1H NMR
;
(400 MHz, CDCl3) 7.26–7.14 (m, 6H), 6.13 (dd, J = 2.8 Hz,
1.2 Hz, 1H), 5.93 (d, J = 2.8 Hz, 1H), 4.01 (q, J = 7.2 Hz, 2H),
3.67 (apparent q, J = 7.2 Hz, 1H), 3.52 (d, JAB = 13.2 Hz, 1H),
3.49 (d, JAB = 13.2 Hz, 1H), 3.05–2.99 (m, 1H), 2.92–2.88 (m,
1H), 2.84–2.76 (m, 2H), 2.58 (dd, J = 7.2 Hz, 2.0 Hz, 1H), 1.10
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 174.0,
156.1, 141.5, 138.6, 128.8, 128.4, 127.2, 110.2, 105.2, 61.0,
59.8, 58.8, 56.8, 48.5, 40.4, 14.3; HRMS (ESI) m/z found
(M + H)+ 300.1598, C18H21NO3 requires (M + H)+ 300.1594.
(3S,4R)-Ethyl
1-benzyl-4-(p-tolyl)pyrrolidine-3-carboxylate
and (3R,4S)-ethyl 1-benzyl-4-(p-tolyl)pyrrolidine-3-carboxylate
(2n).35 Clear oil; Rf 0.42 (1 : 4 v/v ethyl acetate–hexanes); IR
1
νmax 3060, 3027, 2789, 1730, 1451 cm−1; H NMR (400 MHz,
This journal is © The Royal Society of Chemistry 2012
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Ethyl 1-benzyl-4-phenyl-2,5-dihydro-1H-pyrrole-3-carboxy-
late (2s).37 Clear oil; Rf 0.35 (1 : 4 v/v ethyl acetate–hexanes);
Notes and references
1 For a review of 1,3-dipolar cycloadditions, see: (a) Synthetic Applications
of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and
Natural Products, ed. A. Padwa and W. H. Pearson, John Wiley and
Sons, Hoboken, NJ, 2003. For a review on intramolecular 1,3-dipolar
cycloadditions; (b) I. Coldham and R. Hufton, Chem. Rev., 2005, 105,
2765.
2 For key contributions see: (a) A. Padwa and Y.-Y. Chen, Tetrahedron
Lett., 1983, 33, 3447; (b) A. Padwa and W. Dent, J. Org. Chem., 1987,
52, 235.
1
IR νmax 3059, 3027, 2978, 2789, 1715, 1452 cm−1; H NMR
(400 MHz, CDCl3) δ 7.35–7.26 (m, 10H), 4.10 (q, J = 7.2 Hz,
2H), 3.92 (br s, 4H), 3.85 (s, 2H), 1.14 (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 171.4, 156.6, 144.0, 138.8,
133.2, 133.1, 132.9, 132.5, 132.2, 131.6, 130.2, 64.4, 60.2,
58.9, 58.8, 8.9.
3 For key contributions see: (a) Y. Terao, H. Kotaki, N. Imai and
K. Achiwa, Chem. Pharm. Bull., 1985, 33, 2762; (b) Y. Terao, H. Kotaki,
N. Imai and K. Achiwa, Chem. Pharm. Bull., 1985, 33, 896.
4 For selected applications of this ylide precursor: (a) A. D’Souza,
N. Spiccia, J. Basutto, P. Jokisz, L. S.-M. Wong, A. G. Meyer,
A. B. Holmes, J. M. White and J. H. Ryan, Org. Lett., 2011, 13, 486. For
total synthesis see: (b) M. E. Kopach, A. H. Fray and A. I. Meyers,
J. Am. Chem. Soc., 1996, 118, 9876; (c) G. Pandey, P. Banerjee,
R. Kumar and V. G. Puranik, Org. Lett., 2005, 7, 3713. For medicinal
chemistry: (d) V. S. Yarmolchuk, I. L. Mukan, O. O. Grygorenko,
A. A. Tolmachev, S. V. Shishkina, O. V. Shishkin and I. V. Komarov,
J. Org. Chem., 2011, 76, 7010.
5 For early examples: (a) J. M. Longmire, B. Wang and X. Zhang, J. Am.
Chem. Soc., 2002, 124(1), 3400; (b) A. S. Gothelf, K. V. Gothelf,
R. G. Hazell and K. A. Jørgensen, Angew. Chem., Int. Ed., 2002, 41,
4236.
6 For reviews see: (a) J. Adrio and J. C. Carretoro, Chem. Commun., 2011,
47, 6784; (b) L. M. Stanley and M. P. Sibi, Chem. Rev., 2008, 108, 2887;
(c) H. Pellissier, Tetrahedron, 2007, 63, 3235; (d) G. Pandey, P. Banerjee
and S. R. Gadre, Chem. Rev., 2006, 106, 4484; (e) K. V. Gothelf and
K. A. Jorgensen, Chem. Rev., 1998, 98, 863.
Procedure for competition studies
A flame dried and N2 purged round bottom flask was charged
with a magnetic stirrer bar, acid fluoride (0.2 mmol), ester
(0.2 mmol), ylide precursor (0.22 mmol) and 5 ml of anhydrous
THF. The resultant solution was magnetically stirred and cooled
to 0 °C and a solution of DMAP (0.002 mmol) in THF was
added. The reaction was allowed to stir at 0 °C for 1 h, before
being warmed to room temperature and stirred for a further 1 h.
Solvent was removed in vacuo, and the residue purified via flash
column chromatography (1 : 4, v/v ethyl acetate–hexanes) with
both pyrrolidine products collected without seperation. The ratio
1
of products formed were determined by H NMR analysis, with
comparison to previously reported data.
7 S. Karlsson, F. Han, H.-E. Högberg and P. Caldirola, Tetrahedron: Asym-
metry, 1999, 10, 2605.
8 For a review: S. E. Denmark and G. L. Beutner, Angew. Chem., Int. Ed.,
2008, 47, 1560.
General procedure for the 1,3-cycloaddition with esters and
unstabilised ylides using chiral catalysts
9 (a) S. J. Ryan, L. Candish and D. W. Lupton, J. Am. Chem. Soc., 2009,
131, 14176; (b) L. Candish and D. W. Lupton, Org. Lett., 2010, 12,
4836; (c) S. J. Ryan, L. Candish and D. W. Lupton, J. Am. Chem. Soc.,
2011, 133, 4694; (d) L. Candish and D. W. Lupton, Org. Biomol. Chem.,
2011, 9, 8182; (e) S. J. Ryan, L. Candish and D. W. Lupton, Synlett,
2011, 2275; (f) L. Candish and D. W. Lupton, Chem. Sci., 2012, 3, 380;
(g) S. J. Ryan, A. S. Stasch, M. N. Paddon-Row and D. W. Lupton,
J. Org. Chem., 2012, 77, 1113.
10 For other studies with α,β-unsaturated acyl fluorides: E. Bappert,
P. Müller and G. Fu, Chem. Commun., 2006, 2604.
11 See ref. 9c and f for examples. For cooperative catalysis using Lewis
acids and nucleophilic carbenes: D. T. Cohen and K. A. Scheidt, Chem.
Sci., 2012, 3, 53 and references therein.
12 DABCO activation of carbonate oxidation state carbonyls: W.-C. Shieh,
S. Dell, A. Bach, O. Repic and T. J. Blacklock, J. Org. Chem., 2003, 68,
1954.
13 Isothioureas with acyl fluorides: P. A. Woods, L. C. Morrill, T. Lebl,
A. M. Z. Slawin, R. A. Bragg and A. D. Smith, Org. Lett., 2010, 12,
2660.
A flame dried and N2 purged round bottom flask was charged
with a magnetic stirrer bar, acid fluoride 4a (0.2 mmol), ylide
precursor 3a (0.22 mmol) and THF (3 mL). The resulting stirred
solution was cooled to 0 °C in an ice bath and a solution of the
chiral catalyst (0.02 mmol) in THF (1 mL) was added in one
portion. The reaction was allowed to warm to room temperature
over the course of 14 h. Solvent was removed in vacuo, and the
residue was purified via flash column chromatography (1 : 4 v/v
ethyl acetate–hexanes) to yield pyrrolidine 2a.
When using NHC catalysts A3 and A4: A flame dried and N2
purged round bottom flask was charged with a magnetic stirrer
bar, the NHC precursor (0.02 mmol) and THF (2 ml). The
resulting stirred mixture was treated with KOtBu (0.02 mmol)
and allowed to stir for 1 h. The reaction vessel was then cooled
to −20 °C and a solution of acid fluoride (0.2 mmol) and ylide
precursor (0.2 mmol) in THF (3 ml) added dropwise. The reac-
tion was allowed to warm to room temperature and then stirred
overnight. Solvent was removed in vacuo, and the residue
purified via flash column chromatography (1 : 4 v/v ethyl
acetate–hexanes) to yield pyrrolidine 2a. Enantiomeric
excess was determined by HPLC analysis, Daicel AD-H, λ =
238 nm, hexane–i-PrOH = 98 : 2; 0.5 ml min−1, fraction tr =
13.78 min (major enantiomer) and 15.18 (minor enantiomer)
(see ESI†).
14 For examples of (4 + 3) products see: T. Tanaka, Y. Nakamura, N. Aratani
and A. Osuka, Tetrahedron Lett., 2008, 49, 3308.
15 For examples: (a) A. Padwa, Y.-Y. Chen, U. Chiacchio and W. Dent,
Tetrahedron, 1985, 41, 3529; (b) A. R. Haight, A. E. Bailey, W. S. Baker,
M. H. Cain, R. R. Copp, J. A. DeMattei, K. L. Ford, R. F. Henry,
M. C. Hsu, R. F. Keyes, S. A. King, M. A. McLaughlin, L. M. Melcher,
W. R. Nadler, P. A. Oliver, S. I. Parekh, H. H. Patel, L. S. Seif,
M. A. Staeger, G. S. Wayne, S. J. Wittenberger and W. Zhang, Org.
Process Res. Dev., 2004, 8, 897; (c) S. Karlsson and H.-E. Högberg,
J. Chem. Soc., Perkin Trans. 1, 2002, 1076.
16 For benzoyl fluoride in cooperative catalysis see: (a) J. A. Kalow and
A. G. Doyle, J. Am. Chem. Soc., 2011, 133, 16001; (b) J. A. Birrell,
J.-N. Desrosiers and E. N. Jacobsen, J. Am. Chem. Soc., 2011, 133,
13872 and references therein.
17 The major diastereoisomer was not determined. For diastereoselective
reactions with O-linked chiral auxiliaries see: M. Kissane and
A. R. Maguire, Chem. Soc. Rev., 2010, 39, 845 and references therein.
18 The 19F-NMR of cinnamoyl fluoride was first reported by Servis:
(a) F. S. Lin and K. L. Servis, J. Am. Chem. Soc., 1972, 94, 5794. As a
singlet at 25.63 in CCl4. More recently it was assigned at −135.9, ref. 10,
Acknowledgements
We acknowledge financial support from the Australian Research
Council (DP120101315) and Monash University (Research
Accelerator Program).
7910 | Org. Biomol. Chem., 2012, 10, 7903–7911
This journal is © The Royal Society of Chemistry 2012

View Online
an atypical value for an acyl fluoride. Assignment of pyrrolidine acyl
fluoride 7 at 40.09, is viable. For example acetyl fluoride has a 19F-NMR
chemical shift of 50.4 ppm; (b) J. Emsley, V. Gold, F. Hibbert and
W. T. A. Szeto, J. Chem. Soc., Perkin Trans. 2, 1988, 923.
25 C. Chen, C.-T. Chien and C.-H. Su, J. Fluorine Chem., 2002, 115, 75.
26 O. Chuzel and O. Piva, Synth. Commun., 2003, 33, 393.
27 M. A. Brook and T. H. Chan, Synthesis, 1983, 3, 201.
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