X=Y-ZH systems as potential 1,3-dipoles. Part 61: Metal exchanged zeolites, silver(I) oxide, Ni(II) and Cu(I) complexes as catalysts for 1,3-dipolar cycloaddition reactions of imines generating proline derivatives

Article abstract of DOI:10.1016/j.tet.2005.06.110

A range of regio- and stereo-selective 1,3-dipolar reactions of imines of α-amino esters, generating polysubstituted prolines, catalysed by silver(I) exchanged zeolites or silver(I) supported on titania, both in combination with DBU, are described. The us

Full text of DOI:10.1016/j.tet.2005.06.110

Tetrahedron 61 (2005) 8677–8685
XZY–ZH systems as potential 1,3-dipoles.
Part 61: Metal exchanged zeolites, silver(I) oxide, Ni(II) and Cu(I)
complexes as catalysts for 1,3-dipolar cycloaddition reactions of
imines generating proline derivatives
a
b
b
a
Ronald Grigg,a, Daniel M. Cooper, Stephen Holloway, Simon McDonald, Emma Millington
*
and Mohammed A. B. Sarkera
aMolecular Innovation, Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry, Leeds University, Leeds LS2 9JT, UK
bDiscovery Chemistry, GlaxoSmithKline, Gunnels Wood Road, Stevanage, Herts, SG1 2NY, UK
Received 11 April 2005; revised 16 June 2005; accepted 30 June 2005
Abstract—A range of regio- and stereo-selective 1,3-dipolar reactions of imines of a-amino esters, generating polysubstituted prolines,
catalysed by silver(I) exchanged zeolites or silver(I) supported on titania, both in combination with DBU, are described. The use of a catalytic
amount of silver(I) oxide, Ni(II) complexes and cuprous iodide as catalysts for the cycloaddition reactions are also disclosed.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
knowledge, the use of silver exchanged zeolites as catalysts
for 1,3-dipolar cycloaddition reactions has not been
reported.
Metal exchanged zeolites are widely used for the catalysis
of a variety of reactions.1–9 For example, combination of
Co(II), Mn(II) and Ni(II) with certain types of zeolites, for
example, ZSM-5 and mordenite are active catalysts for the
reduction of NOX with methane in an oxidising atmosphere1
and Ag-ZSM-5 catalyst, prepared by an ion exchange
method, is an effective catalyst for the catalytic decompo-
sition of NOX in flue gases.2 Multifunctional metal-
exchanged zeolites are active catalysts for the conversion
of methyl halides to ethylene3 whilst complete catalytic
oxidations of low molecular weight chlorinated hydro-
carbons such as CH2Cl2, trichloroethane and CCl4 in air
over several cation-exchanged Y zeolites (Co–Y, Cr–Y and
Mn–Y) have been reported.4 Catalysts prepared by
impregnating samples of neutral chabazite and mordenite
zeolites with silver nitrate are active and selective for the
epoxidation of ethane5 whilst Cu(II) or Zn(II) exchanged
zeolites catalyse the rearrangement6 of (C)-pinene oxides.
Silver(I) exchanged zeolite Y catalyses the dimerization of
alkanes under UV–vis photochemical conditions at room
temperature7 and AgX and AgY are effective catalysts for
the formation of glycosyl linkages.8,9 However, to our
We introduced a facile and wide ranging Bronsted acid10 or
metal salt-tertiary amine catalysed 1,3-dipolar cyclo-
addition reaction of imines, activated by an appropriately
located carbanion stabilising substituent, with electro-
negative alkenes. The reaction, which proceedes via in situ
formation of metalloazomethine ylides, occurs at room
temperature or below, is highly regio- and stereo-selective
(Scheme 1) and furnishes polysubstituted pyrrolidines in
excellent yield.11
Scheme 1.
Keywords: Metallo-azomethine ylides; Cycloaddition; Silver-exchanged
zeolites; Silver oxide; Ni(II) catalysis; Cu(I) catalysis.
In the case of Bronsted acids the rate in toluene correlates
with pKa of a range of carboxilic acids.10 The metal salt
*
Corresponding author. Tel.: C44 11334336501; fax: C44 1133436530;
e-mail: r.grigg@chem.leeds.ac.uk
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.110

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R. Grigg et al. / Tetrahedron 61 (2005) 8677–8685
mediated process is compatible with a range of solvents
(toluene, CH2Cl2, THF, MeCN, DMF, DMSO), metal salts
[Ag, Li, Tl(I), Zn, Mg, Mn(II), Co(II), Ni(II)(vide infra),
Cu(I)(vide infra)]11 and bases (tertiary amines, DBU,
guanidines) and the regiochemistry is precisely reversed,
for room temperature reactions, when Ti(IV) catalysts are
employed12 whilst maintaining the stereoselectivity
(Scheme 1). The reaction tolerates a wide variation in
EWG1 [ester, nitrile, COR, P(O)(OR)2, 2-pyridyl,
9-thiazolyl, 9-fluorenyl]11 and EWG2. Asymmetric versions
of the reaction have been developed, which employ either a
chiral catalyst13 or a chiral auxiliary.13b,14,15
optimised conditions.
The mild reaction conditions, regio- and stereo-selectivity,
simple experimental protocol and high yields ensured it was
one of the first ring syntheses to be exploited by solid phase
combinatorial chemistry.16 Since then many further combi-
natorial chemistry applications have been developed17
including combinations with other core reactions such as
the Pictet–Spengler reaction and palladium catalysis.18 Very
large numbers of pyrrolidines have been made for biological
screening by pharmaceutical and agrochemical companies
using this chemistry. Recent applications in medicinal
chemistry include inhibitions of hepatitis C virus RNA-
dependent RNA polymerase19 and inhibitors of a4b1-
integrin-mediated hepatic melanoma metastasis.20
The applicability of the 100-mesh silver exchanged zeolite
catalyst was demonstrated by using it in a number of other
cycloaddition reactions involving imines 3 and 5a–i. The
cycloadditions proceeded regio- and stereo-specifically with
methyl acrylate in toluene at room temperature in the
presence of commercial silver exchanged zeolite and DBU
to give single cycloadducts 6a–i in 50–96% yield (Table 1).
Cycloaddition of imines 3 and 5g with the chiral
dipolarophile (R)-5(1R)-menthyloxy-2-(5H)-furanone 7
resulted in cycloadducts in good yield and diastereo-
selectivity (Table 1, entries 10 and 11). The lower de in
the case of the glycine imine 5g reflects the well known
sensitivity of azomethine ylides derived from glycine
imines to stereomutation.11
An area experiencing rapid recent growth is the use of solid
phase reagents,21 which has many applications in solution
phase combinatorial chemistry. This encouraged us to
evaluate metal exchanged zeolites as potential hetero-
geneous catalysts for our pyrrolidine synthesis. This paper
describes our studies in this area and also reports the first
applications of Ni(II) and Cu(I) complexes/salts as catalysts
for Scheme 1.
The reaction of imine 3 with methyl acrylate was next
investigated with a combination of 20% silver chloride on
titania (donated by Johnson Matthey) and DBU in toluene
(25 8C, 5 h), which furnished an 85% yield of 4. Powdered
silver chloride alone was then tested, to see whether it was
effective in the absence of titania and was found to give a
quantitative yield of cycloadduct 4 in a few minutes. Thus,
the reaction was retarded by the titania support.
The 1,3-dipolar cycloaddition reaction of methyl
(2-naphthylidene)alanate 3 and methyl acrylate, which is
known to procede rapidly and in high yield with other Ag(I)
salts, was chosen as the standard reaction. The first reaction
(MeCN, DBU, 4 h, 25 8C) with a commercial 100-mesh
silver exchanged zeolite22 afforded only 12% of the
cycloadduct 4. When the reaction solvent was changed to
dichloromethane the yield of the cycloadduct increased to
56% and when toluene was used as solvent, the product 4
was isolated in 82% yield (Scheme 2). Two furthe0r0
commercial silver exchanged zeolites (20-mesh and 1/16
pellets) gave yields of 54 and 42%, respectively, under the
1.1. Silver oxide catalysis
Silver oxide (1 mol equiv) was examined as a potential
heterogeneous catalyst in the standard imine cycloaddition
reaction (Scheme 2) (toluene, DBU, 2 h, 25 8C). It was
found that when 1 mol equiv of silver oxide was used, the
Scheme 2.

R. Grigg et al. / Tetrahedron 61 (2005) 8677–8685
Table 1. Cycloaddition of imines 5a–i using AgAa as catalystb
8679
Entry
Imine
Dipolarophilec
R1
R2
Cycloadduct
Yield (%)
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
MA
MA
MA
MA
MA
MA
MA
MA
MA
7
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Pyridyl
p-MeOC6H4
Phenyl
2-Naphthyl
Cyclohexyl
Cyclohexyl
2-Naphthyl
2-Naphthyl
CH2Ph
CH2OH
CH2-2-indolyl
Me
6a
6b
6c
6d
6e
6f
6g
6h
6i
96
50
93
50
53
90
50
68
CH2Ph
Me
H
Me
9
10
11
CH2CH2SCH3
92
73 (100% de)14b d
97 (90% de)14b d
3
5g
Me
H
8a
8b
7
a The amount of commercial zeolite (100 mesh, 20% Ag) used was equivalent to 1 mol equiv of silver.
b Reaction conditions: imine (1 equiv), dipolarophile (1 equiv), DBU (1 equiv), toluene, 25 8C, 5 h.
c MAZmethyl acrylate.
d Determined by chiral HPLC—see Section 3.
reaction was over within 5 min and gave a quantitative yield
of cycloadduct 4. Moreover when 10 mol% silver oxide was
employed, the reaction was over within 2 h, affording 4 in
quantitative yield. Several reactions with different dipolaro-
philes were conducted to further test the efficacy of silver
oxide as a catalyst. Imines 5g,h and 5j–k reacted with
methyl acrylate in the presence of 10 mol% of Ag2O to
afford the corresponding cycloadducts in 92–100% yield.
Reactions with chiral dipolarophile (R)-5(1R)-menthyloxy-
2-(5H)-furanone 7 afforded the cycloadducts 8a–c in
excellent yield (95–100%) and diastereoselectivity
(90–100% de) (Table 2).
silver (I) to silver metal during the reaction/regeneration
cycle or it might arise from soluble silver species leaching
from the zeolite. Leaching of silver species may originate in
a number of ways, for example, in the preparation of the
silver exchanged zeolite, some of the silver nitrate, used in
the preparation of the silver exchanged zeolites will be
sorbed onto the zeolite and hence more readily transferred to
the bulk solution. Another possibility is that silver within the
exchanged zeolite is released due to some kind of structural
breakdown. For example, Kim and Seff23 discovered that
when Br2 is sorbed onto zeolite AgA it interacts with the
framework oxygen atoms and causes the decomposition of
hexasilver clusters with the oxidised silver ion migrating out
of the zeolite cavities.
1.2. Heterogeneous versus homogeneous nature of the
catalysis
It appeared likely that a leaching mechanism was
responsible for the observed catalysis in both the Ag zeolite
and Ag2O cases. Silver oxide is prepared from silver nitrate
and it generally contains traces of silver nitrate. We
demonstrated that 10 mol% silver nitrate catalysed the 1,
3-dipolar cycloaddition reaction under the same conditions
although the yields were lower and the time taken for the
completion of the reaction was longer. Fortunately, we were
able to obtain some silver oxide from Johnson Matthey,
which contained only 5 ppm of silver nitrate. At this level, it
was unlikely to be the major catalytic species when the
silver oxide was used as a catalyst.
It was important to find out whether the silver zeolite and
silver oxide were acting in a heterogeneous or a
homogeneous manner. Calculations indicated the cyclo-
adduct was larger than the pore size of the zeolite. Hence
reactions inside the zeolite cavity would be non-productive.
However, heterogeneous catalysis by silver might occur by
coordination of the imine to silver ions located on the outer
surface of the zeolite. Alternatively, the reactants might
leach the silver from the zeolite affording a soluble silver
species, which catalyses the cycloaddition in the usual way.
It was observed that if the silver exchanged zeolite was
filtered from the reaction mixture after the reaction was
complete, then washed and reactivated by heating at 40 8C
in a high vacuum (1 mmHg) for 24 h and reused, its
catalytic activity was reduced. Thus, only 52% of 4 was
obtained with recycled catalyst in the same reaction time.
Deactivation of the zeolite might be due to reduction of
The standard imine cycloaddition reaction (Scheme 2) was
carried out in toluene using 10 mol% silver oxide containing
5 ppm silver nitrate. The reaction was followed by thin-
layer chromatography and was completed in 2 h. The
reaction mixture was filtered through acid washed Celite to
Table 2. Cycloaddition of imines 3 and 5g–k with dipolarophiles using Ag2O as catalysta
Entry
Imine
Dipolarophileb
R1
R2
Cycloadduct
Yield (%)
1
2
3
4
5
6
7
8
3
MA
MA
MA
MA
MA
7
2-Naphthyl
2-Naphthyl
Cyclohexyl
Cyclohexyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
Cyclohexyl
Me
H
Me
4
100
100
95
100
100
5g
5h
5j
5k
3
6g
6h
6j
6k
8a
8b
8c
H
CH2CH2SCH3
Me
H
Me
100 (100% de)14b c
97 (90% de)14b c
95 (99% de)14b c
5g
5h
7
7
a Reaction conditions: DBU/imine/dipolarophileZ1:1:2, Ag2O (10 mol%), toluene, 25 8C, 2 h.
b MAZmethyl acrylate.
c Determined by chiral HPLC—see Section 3.

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R. Grigg et al. / Tetrahedron 61 (2005) 8677–8685
Table 3. Filtration experiments for the reaction shown in Scheme 2
Reaction
Dipolarophile
DBU
Imine
Silver oxide
Time (h)
Conversion (%)
1
2
Yes
Yes
No
Yes
No
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
72
72
2
50
30
100
100
3
4a
Yes
2
a No filtration.
remove all the solids. If any silver was passed through the
Celite, it was assumed to be a soluble silver species. The
toluene filtrate was then evaporated to dryness under
reduced pressure and the residue sent for accurate silver
analysis. It was found that soluble silver had passed through
the Celite filtration and that the amount (0.44% Ag)
using equimolar amounts of the chiral Ni(II) complexes 9
and 10 and imine. When 9 was employed racemic 4 was
isolated in 49% yield after 27 h. The dramatic increase in
the reaction time, the large reduction in yield of the
cycloadduct and lack of enantioselectivity clearly relates to
the coordination chemistry of Ni(II).28 Octahedral and
distorted octahedral complexes are the most common but
numerous four-coordinate tetrahedral and square planar
complexes of Ni(II) are known, together with five-
coordinate square pyramidal and trigonal bipyramidal
complexes.29 Equilibria exist between the different struc-
tural types in solution and are frequently temperature and
concentration dependent. The absence of enantioselectivity
and the long reaction time indicates that the cycloaddition
reaction is catalysed by ‘free Ni(II)’ ions resulting from
equilibria involving dissociation of the chiral phosphine.
Similarly when equimolar amounts of chiral Ni(II) complex
10 and imine were reacted under the same reaction
conditions the product, isolated in 92% yield after 24 h,
was essentially racemic (4% ee).
exceeded that attributable to silver nitrate alone (11!10K5
%
Ag).
Using the same filtration technique the mode of solubil-
isation was examined in more detail. A series of reactions
was carried out for 2 h omitting one of the reagents. The
reaction mixture was then filtered through Celite and
the reagent, which was left out in the first stage was added
to the filtrate (Table 3). The reaction was then allowed to
proceed for the time shown in Table 3 and progress was
followed by thin layer chromatography.
The results in Table 3 demonstrate that both imine and DBU
are required for any appreciable solubilisation of silver
species from the silver oxide catalyst, and therefore rate
enhancement (reactions 3 and 4). When either DBU or
imine was omitted (reactions 1 and 2) the reaction was
substantially retarded and DBU alone effected a greater
solubilisation of Ag(I) than the imine alone. In conclusion,
both DBU and imine are required for effective solubilisation
of Ag(I) and catalysis.
1.4. Cu(I) salts as catalysts
The success of the Ag2O catalysed processes encouraged us
to evaluate Cu2O and other simple Cu(I) salts as catalysts
for Scheme 2. When imines 5f and 5l were reacted
separately with methyl acrylate in dichloromethane in the
presence of Cu2O (1 mol equiv) and DBU (1.12 mol equiv)
the products were the Michael adducts 11a30 and 11b
(82–83%) (Scheme 3).
1.3. Ni(II)–phosphine complexes as catalysts
Nickel(II) catalysed 1,3-dipolar cycloadditions of azo-
methine ylides were studied. It was found that both
NiCl2(dppe), or NiCl2(PPh3)2, in combination with Et3N
(1.5 mol equiv) efficiently promoted the cycloaddition
reactions of imine 3 with methyl acrylate to give the
cycloadduct 4 in 97% yield over 3 h (Scheme 2). The
reactions were performed in dichloromethane using
equimolar amounts of the Ni(II) complex and imine.
When the reaction was repeated with imine 5l and a
stoichiometric amount of CuCN replacing the Cu2O the
desired cycloadduct 6l31 was obtained in 72% yield.
However, the same reaction with 10 mol% of CuCN
afforded a 1:1 mixture of Michael adduct 11 and
cycloadduct 6l.
We then turned our attention to CuI as a possible catalyst.
Cuprous iodide has found numerous applications in organic
synthesis including asymmetric Kharasch reactions,32
asymmetric conjugate addition of Grignard reagents,33
enantioselective oxidative biaryl coupling,34 and as an
additive in many Pd(0) catalysed cross-coupling processes,
for example, the Sonogashira rection.35
Previous success with chiral Co(II)13 and Ag(I)14 complexes
as catalysts for Scheme 2 encouraged us to explore chiral
Ni(II)–phosphine complexes. Such complexes have been
widely used in a range of catalytic reactions.24 Nickel(II)
halides are known to form a large number of complexes with
nitrogen or phosphorus donor ligands25 and Ni(II) aldimine
complexes are known.26 The square planar chiral nickel(II)
complexes 9 and 10 were prepared27 and evaluated in
Scheme 2. Reactions were carried out in dichloromethane
When Scheme 2 was carried out in dichloromethane with
10 mol% CuI in combination with DBU as base the desired
cycloadduct 4 was isolated in 87% yield after 4 h.
Analogous cycloadditions of imines 5a, 5c, and 5f afforded
the expected cycloadducts 6a, 6c and 6f in 83–92% yield
over 4–6 h. Repeating Scheme 2 with 10 mol% CuBr
afforded 4 in 64% yield. The coordination chemistry of CuI
with N-ligands is often complex36 and frequently involve

R. Grigg et al. / Tetrahedron 61 (2005) 8677–8685
8681
Scheme 3.
aggregates.37 However, in our studies up to 80% ee was
AD column (Daicel) eluting with 15% isopropanol in
hexane, a flow rate of 1 mL/min and UV detection. All
compounds were named using the ACD software version
8.0.
achieved with CuI and ligand 12.38 Asymmetric versions of
13d,e
this process employing chiral Cu(OTf)2
complexes
were reported after our own work was completed. Thus, it
would appear that both Cu(I) and Cu(II) salts are effective
catalysts with soft anions most effective for Cu(I) and hard
anions for Cu(II).
3.1. A. General procedure for preparation of imines
A mixture of amino acid methyl ester hydrochloride
(22 mmol), aldehyde (20 mmol), triethylamine (20 mmol)
and anhydrous magnesium sulfate (4 g) in dry DCM
(50 mL) was stirred at room temperature for 16 h. On
completion of the reaction (NMR monitoring), the mixture
was diluted with DCM (100 mL), washed with water (2!
100 mL), dried (MgSO4), filtered and the filtrate concen-
trated in vacuo to give the imine. Solid imines were purified
by crystallisation from ether–hexane, and liquid imines
were used in the next step without further purification
because attempted purification led to decomposition. Imines
3 and 5a,d–h,l were prepared following the literature
methods.14c,30,31,40
2. Summary
Silver exchanged zeolites have been demonstrated to
function as imine cycloaddition catalysts via leaching of
silver species and are thus sources of of homogeneous
catalytic silver salts. A leaching mechanism also operates in
the case of 20% AgCl on titania. In this case, the titania
support retards catalysis. The use of catalytic Ag2O in
toluene also involves soluble silver species and the solid/
solution phase transfer involves both the imine and the
amine base. Ni(II) complexes as shown to promote the
imine cycloaddition for the first time. However, the use of
chiral Ni(II)–phosphine complexes gives racemic cyclo-
adducts. This together with the rate retarding effects of some
chelating phosphines suggest the active Ni(II) catalyst is
essentially phosphine free. Cu(I) salts are also shown, for
the first time, to catalyse the imine cycloaddition. These
salts show interesting selectivity with respect to their
counterion. Thus, Cu2O gives Michael addition products
in good yield whilst CuCN gives either cycloadduct, when
used in stoichiometric amount, or a 1:1 mixture of
cycloadduct and Michael addition product when a sub-
stoichiometric amount (10 mol%) is employed. In contrast
10 mol% CuI proved an excellent catalyst whilst CuBr was
somewhat less effective. The catalytic efficacy of Cu(I) salts
of soft anions contrasts with that of the reported use of
Cu(II) salts of hard anions as catalysts for analogous
processes. The latter work13d,e appeared after completion of
our own studies.
3.1.1. Methyl (2E)-3-hydroxy-2-[(2-naphthylmethyl)
imino]propanoate 5b. Prepared by general procedure A
from serine methyl ester hydrochloride (3.42 g, 22 mmol),
2-naphthaldehyde (3.10 g, 20 mmol) and triethylamine
(2.8 mL, 20 mmol). Crystallisation from dichloromethane
afforded 5b (2.67 g, 52%) as colourless prisms, mp 79–
80 8C. (Found: C, 70.05; H, 5.75; N, 5.60. C15H15NO3
requires: C, 70.05; H, 5.85; N, 5.45%); d (CDCl3,
250 MHz): 8.39 (s, 1H, N]CH), 8.00–7.96 (m, 2H, Ar–
H), 7.82–7.67 (m, 3H, Ar–H), 7.53–7.43 (m, 2H, Ar–H),
4.22–4.02 (m, 3H, CHCO2Me and CH2OH) and 3.73 (s, 3H,
OMe); m/z (%): 257 (MC, 30), 198(100), 167(12) and
103(20).
3.1.2. Methyl (2E)-3-(2,3-dihydro-1H-indol-2-yl)-2-[(2-
naphthylmethyl)imino]propanoate 5c. Prepared by
general procedure A from tryptophan methyl ester
hydrochloride (5.60 g, 22 mmol), 2-naphthaldehyde
(3.10 g, 20 mmol) and triethylamine (2.8 mL, 20 mmol).
Crystallisation from ether–hexane afforded 5c (5.41 g, 76%)
as colourless plates, mp 155–157 8C. (Found: C, 77.30; H,
5.55; N, 7.65. C23H20N2O2 requires: C, 77.50; H, 5.60; N,
7.85%); d (CDCl3, 250 MHz): 7.93 (s, 1H, N]CH), 8.16–
7.23 (m, 12H, ArH), 4.36 (dd, 1H, JZ7.6, 4.7 Hz,
CHCO2Me), 3.81 (s, 3H, OMe), and 3.41 and 3.18 (2!
dd, 2!1H, JZ13.3, 4.7, 13.3, 7.6 Hz, CH2); m/z (%): 356
(MC, 48), 297(75), 202(24) and 130(100).
3. Experimental
General methods have been described previously.39
Analytical grade anhydrous silver salts were used a0s0
purchased. Silver exchanged zeolites (20-mesh, 1/16
pellets and 100-mesh) were purchased from Aldrich and
were dried at 40 8C and 1 mmHg for 24 h before use. AgCl/
TiO2 (loading, 20% Ag) and Ag2O containing 5 ppm
AgNO3 were supplied by Johnson Matthey. In all reactions
involving silver(I) salts the reaction flask was covered with
aluminium foil. Chiral HPLC was performed on a Chiralcel
3.1.3. Methyl (2E)-N-(cyclohexylmethylene)methionate
5i. Prepared by general procedure A from methionine

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R. Grigg et al. / Tetrahedron 61 (2005) 8677–8685
methyl ester hydrochloride (4.39 g, 22 mmol), cyclohexyl
carboxaldehyde (2.26 g, 20 mmol) and triethylamine
(2.8 mL, 20 mmol). The product (2.83 g, 55%) was obtained
as a colourless oil, which was used without further
purification. Found (HRMS, MCCH): 258.1525.
C13H23O2SN requires: 258.1528. d (CDCl3, 250 MHz):
7.55 (d, 1H, JZ5.6 Hz, N]CH), 3.90 (dd, 1H, JZ8.6,
5.0 Hz, CHCO2Me), 3.74 (s, 3H, OMe), 2.63–2.32 (m, 2H,
CH2), 212–210 (m, 2H, CH2), 2.08 (s, 3H, SMe) and 1.82–
1.21 (m, 11H, cyclohexyl–H); m/z (ES, %): 258 (MCCH).
filtered and the solvent removed under reduced pressure to
afford the pyrrolidine.
3.4. D. General procedure for cycloaddition reactions
catalysed by Ni(II)–phosphine complexes
Ni(II)–phosphine complex (1 equiv) was stirred for 5 min in
dichloromethane. Imine (1 equiv) was added and the
reaction mixture was stirred for 15 min. Methyl acrylate
(3 equiv) and triethylamine (1.5 equiv) were then added and
the reaction was stirred at room temperature until the
reaction was complete (TLC). The reaction mixture was
washed with water, the aqueous layer extracted with
dichloromethane and the combined fractions were dried
(MgSO4), filtered and evaporated under vacuum. Flash
chromatography afforded the cycloadducts.
3.1.4. Methyl (2E)-N-(cyclohexylmethylene)glycinate 5j.
Prepared by general procedure A from glycine methyl ester
hydrochloride (3.07 g, 22 mmol), cyclohexyl carboxalde-
hyde (2.26 g, 20 mmol) and triethylamine (2.8 mL,
20 mmol). The product (2.27 g, 62%) was obtained as a
colourless oil, which was used without further purification.
Found (HRMS, MCCH): 184.1336. C10H17O2N requires:
184.1337. d (CDCl3, 250 MHz): 7.54 (d, 1H, JZ5.1 Hz,
N]CH), 4.16 (s, 2H, CH2), 3.75 (s, 3H, OMe) and 2.35–
1.21 (m, 11H, cyclohexyl–H); m/z (ES, %): 184 (MCCH).
3.5. E. General procedure for copper(I) iodide catalysed
1,3-dipolar cycloaddition reactions
Cuprous iodide (0.112 mmol, 10 mol%) was added to a
stirred solution of imine (1.12 mmol) in dichloromethane
(15 mL). Methyl acrylate (1.68 mmol) and DBU
(1.12 mmol) were then added dropwise over 5 min. The
reaction was followed by TLC until the starting materials
had disappeared (4–6 h), then quenched (saturated aqueous
NH4Cl) and extracted with dichloromethane (3!10 mL).
The combined extracts were dried (MgSO4), filtered and the
solvent removed in vacuo. The crude pyrrolidine was
purified by flash column chromatography.
3.1.5. Methyl (2E)-N-(2-naphthylmethylene)methionate
5k. Prepared by general procedure A from methionine
methyl ester hydrochloride (4.39 g, 22 mmol),
2-naphthaldehyde (3.10 g, 20 mmol) and triethylamine
(2.8 mL, 20 mmol). Crystallisation from dichloromethane
afforded 5k (5 g, 83%) as colourless prisms, mp 52–54 8C.
(Found: C, 67.90; H, 6.05; N, 4.15; S, 10.90. C17H19NO2S
requires: C, 67.75; H, 6.30; N, 4.65; S, 10.65%); d (CDCl3,
250 MHz): 8.47 (s, 1H, N]CH), 8.09–7.47 (m, 7H, ArH),
4.28 (dd, 1H, JZ7.9, 5.4 Hz, CHCO2Me), 3.76 (s, 3H,
OMe), 2.39 (m, 2H, CH2S), 2.31 (m, 2H, CH2CH2S) and
2.09 (s, 3H, SMe); m/z (%): 301 (MC, 67), 242(100),
195(37) and 181(14).
3.5.1. Dimethyl 2-methyl-5-(2-naphthyl)pyrrolidine-2,4-
dicarboxylate 4. Prepared by general procedure B from 3
(2.89 g, 12 mmol) and methyl acrylate (2.24 g, 24 mmol).
Work up afforded a colourless solid, which was purified by
column chromatography eluting with 3:2 v/v ether–hexane
to give 4 (3.73 g, 100%), which crystallised from
dichloromethane–hexane as colourless needles, mp 83–
85 8C. (Found: C, 69.50; H, 6.25; N, 4.55. C19H21NO4
requires: C, 69.70; H, 6.45; N, 4.30%); d (CDCl3,
250 MHz): 7.84–7.76 (m, 4H, ArH), 7.48–7.37 (m, 3H,
ArH), 4.81 (d, 1H, JZ7.3 Hz, 5-H), 3.85 (s, 3H, OMe), 3.44
(ddd, 1H, JZ7.5, 7.3, 4.8 Hz, 4-H), 3.12 (s, 3H, OMe), 2.79
(dd, 1H, JZ13.5, 4.8 Hz, 3-Ha), 2.11 (dd, 1H, JZ13.5,
7.5 Hz, 3-Hb) and 1.55 (s, 3H, Me); m/z (%): 327 (MC, 61),
269(13), 268(62) and 209(100).
3.2. B. General procedure for silver exchanged zeolite
catalysed 1,3-dipolar cycloaddition reactions
Dried silver exchanged zeolite (9.72 g or 4.32 g based on 20
or 45% silver in partially and fully exchanged zeolite,
respectively) was added to a solution of imine (12 mmol) in
toluene (20 mL). The mixture was stirred for 5 min before
the dipolarophile (24 mmol) and DBU (12 mmol) were
added and stirring was continued until the starting materials
had disappeared (TLC). The reaction mixture was quenched
with saturated aqueous ammonium chloride, filtered and the
filtrate extracted with dichloromethane (3!20 mL). The
combined extracts were dried (MgSO4), filtered and
the solvent removed under reduced pressure to afford the
pyrrolidine.
3.5.2. Dimethyl 2-benzyl-5-(2-naphthyl)pyrrolidine-2,4-
dicarboxylate 6a. Prepared by general procedure B from 5a
(3.8 g, 12 mmol) and methyl acrylate (2.24 g, 24 mmol).
Work up afforded a colourless solid, which was purified by
column chromatography eluting with 1:1 v/v ether–hexane
to give 6a (4.64 g, 96%), which crystallised from
dichloromethane–hexane as colourless prisms, mp 108–
109 8C. (Found: C, 74.50; H, 6.05; N, 3.55. C25H25NO4
requires: C, 74.45; H, 6.20; N, 3.45%); d (CDCl3,
250 MHz): 7.81–7.22 (m, 13H, ArH), 4.64 (d, 1H, JZ
7.5 Hz, 5-H), 3.74 (s, 3H, OMe), 3.28 (m, 1H, 4-H), 3.16 (d,
1H, JZ13.1 Hz, CH2Ph), 3.09 (s, 3H, OMe), 2.95 (d, 1H,
JZ13.1 Hz, CH2Ph), 2.79 (dd, 1H, JZ13.6, 4.8 Hz, 3-Ha)
and 2.25 (dd, 1H, JZ13.6, 7.5 Hz, 3-Hb); m/z (%): 403
(MC, 67), 344(100), 285(45) and 194(54).
3.3. C. General procedure for silver(I) oxide catalysed 1,
3-dipolar cycloaddition reactions
A mixture of imine (12 mmol) and silver oxide (0.28 g,
1.2 mmol, 10 mol%) in toluene (20 mL) was stirred for
5 min, dipolarophile (24 mmol) and DBU (12 mmol) added
and stirring continued until TLC monitoring showed all the
starting materials had disappeared. The reaction mixture
was quenched with a saturated solution of ammonium
chloride (20 mL) and extracted with dichloromethane (3!
20 mL). The combined extracts were dried (MgSO4),

R. Grigg et al. / Tetrahedron 61 (2005) 8677–8685
8683
3.5.3. Dimethyl 2-hydroxymethyl-5-(2-naphthyl)pyrroli-
dine-2,4-dicarboxylate 6b. Prepared by general procedure
B from 5b (3.08 g, 12 mmol) and methyl acrylate (2.24 g,
24 mmol). Work up afforded a colourless solid, which was
purified by column chromatography eluting with 4:1 v/v
ether–hexane to give 6b (2.06 g, 50%), which crystallised
from ether as colourless needles, mp 117–119 8C. (Found:
C, 66.30; H, 6.30; N, 3.90. C19H21NO5 requires: C, 66.45;
H, 6.10; N, 4.10%); d (CDCl3, 250 MHz): 7.82–7.75 (m,
4H, ArH), 7.50–7.33 (m, 3H, ArH), 5.29 (br, 1H, OH), 4.65
(d, 1H, JZ6.8 Hz, 5-H), 3.87 (s, 3H, OMe), 3.79 and 3.54
(2!d, 2!1H, JZ10.7 Hz, CH2OH), 3.35 (m, 1H, 4-H),
3.14 (s, 3H, OMe), 2.62 (dd, 1H, JZ13.9, 3.3 Hz, 3-Ha) and
2.09 (dd, 1H, JZ13.9, 7.4 Hz, 3-Hb); m/z (%): 343 (MC,
57), 284(100), 225(58) and 194(39).
Work up afforded a colourless solid, which was purified by
column chromatography eluting with 1:2 v/v ether–hexane
to give 6f (2.99 g, 90%) as a colourless oil. (Found: C,
64.95; H, 6.90; N, 5.15. C15H19NO4 requires: C, 65.00; H,
6.85; N, 5.05%); d (CDCl3, 250 MHz): 7.31–7.22 (m, 5H,
ArH), 4.65 (d, 1H, JZ7.5 Hz, 5-H), 3.82 (s, 3H, OMe), 3.52
(m, 1H, 4-H), 3.20 (s, 3H, OMe), 2.72 (dd, 1H, JZ13.6,
5.3 Hz, 3-Ha), 2.05 (dd, 1H, JZ13.6, 7.5 Hz, 3-Hb) and 1.50
(s, 3H, Me); m/z (%): 277 (MC, 61), 269(13), 268(61) and
209(100).
3.5.8. Dimethyl 5-(2-naphthyl)pyrrolidine-2,4-dicar-
boxylate 6g. Prepared by general procedure C from 5g
(2.24 g, 12 mmol) and methyl acrylate (2.24 g, 24 mmol).
Work up afforded a colourless solid, which was purified by
column chromatography eluting with 1:1 v/v ether–hexane
to give 6f (3.57 g, 100%) as colourless plates, mp 161–
163 8C. (Found: C, 68.90; H, 6.20; N, 4.40. C18H19NO4
requires: C, 69.00; H, 6.10; N, 4.45%); d (CDCl3,
250 MHz): 7.85–7.26 (m, 7H, ArH), 4.65 (d, 1H, JZ
8.1 Hz, 5-H), 4.04 (dd, 1H, JZ8.8, 7.3 Hz, 2-H), 3.82 (s,
3H, OMe), 3.38 (m, 1H, 4-H), 3.12 (s, 3H, OMe) and 2.43–
2.85 (m, 2H, 3-Ha/Hb); m/z (%): 313 (MC, 60), 254(100),
240(62) and 195(10).
3.5.4. Dimethyl 2-(1H-indol-2-ylmethyl)-5-(2-naphthyl)
pyrrolidine-2,4-dicarboxylate 6c. Prepared by general
procedure B from 5c (3.85 g, 12 mmol) and methyl acrylate
(2.24 g, 24 mmol). Work up afforded a colourless solid,
which was purified by column chromatography eluting with
3:2 v/v ether–hexane to give 6c (5.05 g, 93%), which
crystallised from dichloromethane–hexane as colourless
prisms, mp 116–118 8C. (Found: C, 73.20; H, 5.70; N, 6.50.
C27H26N2O4 requires: C, 73.30; H, 5.90; N, 6.35%); d
(CDCl3, 250 MHz): 8.10 (br, 1H indole NH), 7.79–7.65 (m,
4H, ArH), 7.44–7.06 (m, 7H, ArH), 4.71 (d, 1H, JZ7.2 Hz,
5-H), 3.70 (s, 3H, OMe), 3.47 (m, 1H, 4-H), 3.22 (s, 2H,
CH2), 3.09 (s, 3H, OMe), 2.78 (dd, 1H, JZ13.4, 5.5 Hz,
3-Ha) and 2.28 (dd, 1H, JZ13.4, 7.6 Hz, 3-Hb); m/z (%):
443 (MC, 53), 383(100), 324(19) and 194(33).
3.5.9. Dimethyl 5-cyclohexyl-2-methylpyrrolidine-2,4-
dicarboxylate 6h. Prepared by general procedure C from
5h (2.36 g, 12 mmol) and methyl acrylate (2.24 g,
24 mmol). Work up afforded a colourless solid, which was
purified by column chromatography eluting with 1:1 v/v
ether–hexane to give 6h (3.26 g, 95%) as colourless plates,
mp 125–127 8C. (Found: C, 63.35; H, 9.00; N, 4.70.
C15H25NO4 requires: C, 63.60; H, 8.85; N, 4.95%); d
(CDCl3, 250 MHz): 3.72 and 3.61 (2!s, 2!3H, 2!OMe),
2.90–2.96 (m, 2H, 5-H and 4-H), 2.68 (m, 1H, 3-Ha), 2.57
(m, 1H, 3-Hb), 1.40 (s, 3H, Me) and 2.05–0.90 (m, 11H,
cyclohexyl-H); m/z (%): 283 (MC, 21), 224(100), 165(47)
and 150(17).
3.5.5. Dimethyl 2-methyl-5-pyridin-2-ylpyrrolidine-2,4-
dicarboxylate 6d. Prepared by general procedure B from 5d
(2.3 g, 12 mmol) and methyl acrylate (2.24 g, 24 mmol).
Work up afforded the crude product, which was purified by
column chromatography eluting with ether to 10% methanol
in ether to give 6d (2.77 g, 80%) as a yellow oil. (Found: C,
60.30; H, 6.25; N, 10.30. C14H18N2O4 requires: C, 60.45; H,
6.45; N, 10.05%); d (CDCl3, 250 MHz): 8.52–5.16 (m, 4H,
ArH), 4.68 (d, 1H, JZ7.6 Hz, 5-H), 3.81 (s, 3H, OMe), 3.41
(m, 1H, 4-H), 3.27 (s, 3H, OMe), 2.70–2.75 (m, 2H, 3-Ha/
Hb) and 1.51 (s, 3H, Me); m/z (%): 278 (MC, 32), 219(100),
160(17) and 145(28).
3.5.10. Dimethyl 5-cyclohexyl-2[2-(methylthioethyl]pyr-
rolidine-2,4-dicarboxylate 6i. Prepared by general pro-
cedure B from 5i (3.08 g, 12 mmol) and methyl acrylate
(2.24 g, 24 mmol). Work up afforded a colourless solid,
which was purified by column chromatography eluting with
3:2 v/v ether–hexane to give 6i (3.79 g, 92%) as a colourless
viscous oil. (Found: C, 59.50; H, 8.50; N, 4.15; S, 9.05.
C17H29NO4S requires: C, 59.45; H, 8.45; N, 4.10; S,
9.350%); d (CDCl3, 250 MHz): 3.77 and 3.63 (2!s, 2!3H,
OMe), 2.95–2.83 (m, 2H, 5-H and 4-H), 2.65–2.50 (m, 3H.
SCH2 and 3-Ha), 2.26 (m, 1H, 3-Hb), 2.07 (s, 3H, SMe),
2.04–0.84 (m, 13H, CH2 and cyclohexyl-H); m/z (%): 343
(MC, 16), 296(80), 284(100) and 225(21).
3.5.6. Dimethyl 2-benzyl-5-(4-methoxyphenyl)pyrroli-
dine-2,4-dicarboxylate 6e. Prepared by general procedure
B from 5e (3.4 g, 12 mmol) and methyl acrylate (2.24 g,
24 mmol). Work up afforded a colourless solid, which was
purified by column chromatography eluting with 1:1 v/v
ether–hexane to give 6e (3.81 g, 86%) as a colourless
viscous oil. (Found: C, 68.40; H, 6.35; N, 3.60. C21H23NO5
requires: C, 68.30; H, 6.25; N, 3.80%); d (CDCl3,
250 MHz): 7.26–7.15 (m, 7H, ArH), 6.81 (m, 2H, ArH),
4.47 (d, 1H, JZ7.5 Hz, 5-H), 3.77, 3.75 and 3.22 (3!s, 3!
3H, 3!OMe), 3.15 (m, 1H, 4-H), 3.10 and 2.92 (2!d, 2!
1H, JZ13.1 Hz, ArCH2), 2.74 (dd, 1H, JZ5.2, 13.7 Hz,
3-Ha) and 2.18 (dd, 1H, JZ7.5, 13.7 Hz, 3-Hb); m/z (%):
369 (MC, 53), 310(100), 262(19) and 251(33).
3.5.11. Dimethyl 5-cyclohexylpyrrolidine-2,4-dicar-
boxylate 6j. Prepared by general procedure C from 5j
(2.2 g, 12 mmol) and methyl acrylate (2.24 g, 24 mmol).
Work up afforded a colourless solid, which was purified by
column chromatography eluting with 1:1 v/v ether–hexane
to give 6j (3.07 g, 95%) as colourless plates, mp 35–37 8C.
(Found: C, 62.35; H, 8.75; N, 5.05. C14H23NO4 requires: C,
62.45; H, 8.55; N, 5.20%); d (CDCl3C2 drops C6D6,
250 MHz): 3.83 (dd, 1H, JZ5.5, 10.0 Hz, 2-H), 3.76 and
3.64 (2!s, 2!3H, 2!OMe), 2.94 (ddd, 1H, JZ1.7, 5.8,
3.5.7. Dimethyl 2-methyl-5-phenylpyrrolidine-2,-4-
dicarboxylate 6f. Prepared by general procedure B from
5f (2.29 g, 12 mmol) and methyl acrylate (2.24 g, 24 mmol).

8684
R. Grigg et al. / Tetrahedron 61 (2005) 8677–8685
7.3 Hz, 4-H), 2.82 (dd, 1H, JZ5.8, 9.5 Hz, 5-H), 2.39–2.15
(m, 2H, 3-Ha/Hb), and 2.20–1.15 (m, 11H, cyclohexyl-H);
m/z (%): 269 (MC, 21), 210(100), 186(47) and 150(17).
GlaxoSmithKline and the EPSRC for support. We thank
the EPSRC, Leeds University and the Royal Society for
support.
3.5.12. Dimethyl 2-(2-methylthioethyl)-5-(2-naphthyl)
pyrrolidine-2,4-dicarboxylate 6k. Prepared by general
procedure C from 5k (3.61 g, 12 mmol) and methyl acrylate
(2.24 g, 24 mmol). Work up afforded a colourless solid,
which was purified by column chromatography eluting with
1:1 v/v ether–hexane to give 6h (4.5 g, 100%) as colourless
needles, mp 176–178 8C. (Found: C, 65.00; H, 6.50; N, 3.70;
S, 8.35. C21H25NO4S requires: C, 65.10; H, 6.45; N, 3.60; S,
8.250%); d (CDCl3, 250 MHz): 7.75–7.68 (m, 4H, ArH),
7.39–7.27 (m, 3H, ArH), 4.63 (d, 1H, JZ6.9 Hz, 5-H), 3.79
(s, 3H, OMe), 3.28 (ddd, 1H, JZ7.4, 6.9, 3.9 Hz, 4-H), 3.04
(s, 3H, OMe), 2.71–2.60 (m, 2H, CH2SMe and 3-Ha), 2.32
(m, 1H, CH2SMe), 2.17–2.01 (m, 2H, CH2CH2SMe and
3-Hb), 2.03 (s, 3H, SMe) and 1.88 (m, 1H, CH2CH2SMe);
m/z (%): 387 (MC, 56), 328(100), 369(31) and 222(46).
References and notes
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bicyclo[3.3.0]octane-2-carboxylate 8c. Prepared by
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3.5.16.
2-Methyl-2-{[1-pyridin-3-yl-methylidene]-
amino}-pentanedioic acid dimethyl ester 11b. Prepared
by general procedure E from imine 5l (215 mg, 1.12 mmol)
and methyl acrylate (0.15 mL, 1.68 mmol). Purification by
flash column chromatography (ether) afforded the product
(21 mg, 82%) as a colourless gum. HRMS: [MC
H]CC14H19N2O4 requires 279.1345; found 279.1347. d
(500 MHz): 8.87 (br, m, 1H, PyH), 8.66 (br, s, 1H, PyH),
8.34 (s, 1H, N]CH), 8.15 (dt, 1H, JZ8.2, 1.8 Hz, PyH),
7.37 (dd, 1H, JZ8.2, 5.2 Hz, PyH), 3.76 (s, 3H, CO2CH3),
3.65 (s, 3H, CO2CH3), 2.54–2.34 (m, 3H, CHCH2CO2CH3),
2.17 (ddd, 1H, JZ13.6, 9.3, 6.6 Hz, CHCH2CO2CH3) and
1.54 (s, 3H, CH3). d 13C: 191.2 (C]N), 2!174.1 (C]O),
157.7, 152.2, 150.9, 135.0 and 124.0 (PyC), 68.1 (4 8C),
52.7 and 52.0 (CO2CH3), 35.4 and 29.8 (CH2) and 23.7
(CH3). n (film, cmK1): 3055 (C–Hstretch), 1732 (C]Oester),
1647 (C]N) and 1591 (C]Caromatic); m/z (ESC, %): 279
([MCH]C, 100).
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Acknowledgements
We thank the Mary and Alice Smith Memorial Fund (E.M.)
and the Commonwealth Scholarship Commision in the UK
(M.A.B.S.) for scholarships and Leeds University,
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