New chiral diamide ligands: synthesis and application in allylic alkylation

Article abstract of DOI:10.1016/j.tetasy.2008.01.018

A new family of chiral diamide ligands has been designed and synthesised. These ligands have been successfully applied to an asymmetric allylic substitution reaction. A palladium complex of one of the diamide ligands achieved enantioselectivities of up to 93% in the allylic alkylation of 1,3-diphenyl-3-acetoxyprop-1-ene.

Full text of DOI:10.1016/j.tetasy.2008.01.018

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 391–396
New chiral diamide ligands: synthesis and application in allylic
alkylation
Lorraine Bateman, Simon W. Breeden and Patrick O’Leary*
School of Chemistry, National University of Ireland, Galway, Ireland
Received 13 December 2007; accepted 14 January 2008
Abstract—A new family of chiral diamide ligands has been designed and synthesised. These ligands have been successfully applied to an
asymmetric allylic substitution reaction. A palladium complex of one of the diamide ligands achieved enantioselectivities of up to 93% in
the allylic alkylation of 1,3-diphenyl-3-acetoxyprop-1-ene.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
The AAS reaction is a versatile asymmetric transformation
since the same chiral catalyst can form several types of
bonds, for example, C–H, C–C, C–N, C–O, C–S, etc., by
varying either the substrate or the nucleophile.7
The formation of a new asymmetric carbon–carbon or car-
bon–heteroatom bond is of great synthetic value; hence,
the transition-metal-catalysed asymmetric allylic substitu-
tion (AAS) reaction is a very important synthetic organic
tool (Scheme 1).1 It uses milder conditions than normal
substitution reactions and involves varying degrees of che-
mo-, enantio- and regioselectivity.
The bis(picolinamide) ligand 1 reported by Trost8,9 (Fig. 1)
has been employed successfully with catalytic molybdenum
complexes used in AAS reactions. Numerous derivatives of
1 have been synthesised to probe its structure–behaviour
relationship, and it has been shown that only one pyridine
ring or even a picolinamide unit is required for the forma-
tion of an active catalytic complex.10 Similarly, further
studies demonstrated that a symmetric scaffold, as well as
two stereogenic centres were not necessary.11 Inspired by
the success of bis(picolinamide) ligand 1 in molybdenum-
catalysed asymmetric allylic substitution reactions, we have
developed a novel set of structurally related chiral diamide
ligands 2 and 3 (Fig. 1). Ligand 1 has been shown, during
In 1977, Trost and Strege developed a catalytic version of
the reaction with the ligand, DIOP.2 Since then, the trans-
formation has been developed to achieve high selectivities
with a range of substrates.1 Typically, acetates and carbon-
ates are used as leaving groups.3 A wide variety of transi-
tion metals have been used but palladium continues to be
the most common, closely followed by molybdenum.4
The AAS reaction has been exploited as a key enantioselec-
tive step in the synthesis of many complex molecular tar-
gets.5 Its use has been reported in over 50 total synthesis
of a wide array of natural products.6
O
O
HN
NH
N
N
X
Nu
Catalyst*, Nu-
1
X-
+
H
H
N
N
N
N
O
Scheme 1. Asymmetric allylic substitution.
O
N
N
O
H
H
O
CROSIDE
UNIFIDE
*
Corresponding author. Tel.: +353 0 91 492476; fax: +353 0 91 525700;
e-mail: patrick.oleary@nuigalway.ie
3
2
Figure 1. Novel pyridylamide ligands 2 and 3, and known bis(pyridyl)-
amide ligand 1.
Present address: Green Chemistry Centre of Excellence, Department of
Chemistry, The University of York, UK.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.01.018

392
L. Bateman et al. / Tetrahedron: Asymmetry 19 (2008) 391–396
its catalytic cycle, to coordinate to molybdenum using both
nitrogens of one pyridylamide unit as well as binding to the
remote carbonyl oxygen of the second pyridylamide unit
when the allyl substrate is present.12 We envisaged our
ligands 2 and 3 showing similar behaviour.
form 9. The corresponding amine 10 was obtained by the
hydrogenation of 9 before performing a DCC-mediated
coupling with 2-picolinic acid to afford 3 in 53% overall
yield.
2.2. Allylic alkylation of rac-1,3-diphenyl-3-acetoxyprop-1-
ene
While our novel diamide ligands have been modelled upon
those which form effective molybdenum allylation cata-
lysts, we herein report on the reactivity of their palladium
complexes. Palladium pre-catalysts have traditionally been
applied to phosphorus-containing ligands13 and the present
study presents the novel application of chiral diamide Pd
complexes forming effective asymmetric allylation catalysts
with chiral diamide ligands. To the best of our knowledge,
there has been no report of asymmetric allylic alkylations
involving such simple chiral diamide–palladium complexes.
Preliminary screening of these ligands led us to test their
palladium complexes in the allylic alkylation of (rac)-1,3-
diphenyl-3-acetoxyprop-1-ene 11 (Scheme 4).
O
O
O
O
OAc
DMM, Base
Pd2(dba)3, 2/3
12
11
2. Results and discussion
2.1. Synthesis of ligands
Scheme 4. Asymmetric allylic alkylation of 11.
In all cases, the catalysts were generated in situ using
Pd2(dba)3 dimer as the metal source. Complexation was
carried out in toluene or THF, using 15 mol % ligand
and 10 mol % palladium. Separately, the nucleophile was
prepared from dimethyl malonate and base in the chosen
solvent. On formation of the nucleophile, substrate 11
was added followed by the active catalyst and the reaction
was carried out and monitored at intervals over of 48 h
(Table 1).
Ligands 2 and 3 were synthesised starting with (S)-(ꢀ)-
pyrrolidone-5-carboxylic acid 4. Esterification of 4, and
subsequent condensation with commercially available
2-pyridylamine, led to the formation of UNIFIDE 2 in
61% overall yield (Scheme 2).
H
N
(i)
N
(ii)
OEt
OH
O
O
O
N
N
N
H
H
H
O
O
O
Table 1. Pd-catalysed allylic alkylation of rac-1,3-diphenyl-3-acetoxy-
prop-1-ene using ligands 2 and 3, as outlined in Scheme 2
4
5
2
Scheme 2. Reagents and conditions: (i) EtOH, H2SO4, PhCH3, 72%;
(ii) 2-pyridylamine, EtOAc, 85%.
Entry
Ligand
Solvent
Temp (°C)
% Conv.
% ee (S)e
1a
3
3
2
2
2
2
2
2
PhCH3
THF
PhCH3
PhCH3
THF
PhCH3
PhCH3
PhCH3
85
60
85
85
60
85 and rt
rt
85
52
22
72
44
56
13
0
22
21
93
49
90
57
—
78
2a
3a
In the case of 3, a longer synthetic pathway is necessary
(Scheme 3). Following quantitative esterification of 4 the
resulting methyl ester 6 was reduced to the amido alcohol,
with no reduction of the amide being observed. The best
synthetic approach was found to be the isolation and puri-
fication of mesylate 8 before reaction with sodium azide to
4b
5a
6a,c
7a
8a,d
100
a Nucleophile generated using NaH as base.
b Nucleophile generated using BSA/NaOAc as base.
c Catalyst formation occurred at 85 °C, reaction at rt.
d Reaction carried out in round-bottomed flask instead of Schlenk tube.
e % ee determined by chiral HPLC analysis; Chiralcel OD column, 254 nm,
hexane (0.1% diethylamine)/isopropyl alcohol, 99:1, 0.5 ml/min,
t(R) = 19.3 min, t(S) = 21.2 min.
(iii)
(ii)
OMe
OH
OH
(i)
O
O
O
N
N
N
H
H
H
O
O
4
6
7
O
(iv)
(v)
NH2
Me
O
S
O
N3
O
O
O
N
N
N
Initially, a brief study was conducted using ligand 3 to gen-
erate the catalyst. The product was formed in 47% conver-
sion and 22% ee (Table 1) when toluene was used as the
solvent and the nucleophile was generated using sodium
hydride. On changing the reaction solvent to tetrahydro-
furan, the conversion to product more than halved to
22%. The enantioselectivity of the reaction system was
not altered with the product being isolated in 21% ee. Over-
all the catalyst derived from ligand 3 gave poor yields and
enantioselectivities, so we then focused on ligand 2.
H
H
H
10
8
9
H
N
(vi)
N
O
N
H
O
3
Scheme 3. Reagents and conditions: (i) Amberlyst 15+, MeOH, 99%; (ii)
NaBH4, EtOH, 99%; (iii) MsCl, TEA, DCM, 99%; (iv) NaN3, DMF, 71%;
(v) 10%Pd/C, EtOH, 30 psi, 98%; (vi) 2-pyridylamine, DCC, DCM, 78%.

L. Bateman et al. / Tetrahedron: Asymmetry 19 (2008) 391–396
393
The study conducted on the reactions using ligand 2 was
3. Conclusion
more extensive. Performing the entire reaction in toluene
at 85 °C led to the formation of the desired product 12 in
93% ee. The fact that such a high degree of stereocontrol
is observed for a structurally simple ligand with a single ste-
reogenic centre is intriguing. It was noted during the reac-
tion that the gelatinous nature of the nucleophile was
hindering the rapid formation of a uniform reaction mix-
ture. It took almost 24 h for this ‘biphasic’ mixture to
appear consistent/uniform. To test if the lack of homoge-
neity was affecting the overall conversion, we conducted
the reaction in a round-bottomed flask rather than a
narrow Schlenk tube improve mixing (Table 1, entry 8).
The product was formed in 100% conversion, but the
enantioselectivity had dropped to 78% ee. Without unifor-
mity, we postulate that the reaction was behaving more like
a heterogeneous system and the concentration of ‘avail-
able’ nucleophile, allylic acetate or catalyst was lower than
in the latter reaction. It is therefore plausible that this had a
bearing on the enantioselectivity of the reaction.
We have succeeded in creating simple chiral diamide
ligands, which contain only one stereocentre. In the case
of one ligand, the palladium complex is an active catalyst
and gives good enantiocontrol in asymmetric allylic
alkylation reactions. This work has been innovative in its
application of such small diamide ligands to palladium
complex-catalysed alkylation of diphenyl allyl acetate. We
are hopeful that further development of these ligand
systems will lead to highly selective catalyst systems and
work is currently underway to extend the use of these
ligands to other metals and reactions.
4. Experimental
4.1. General information
All chemicals were purchased from Aldrich Chemical
Company and generally used without further purification.
Any necessary reagent purification, along with the drying
and distillation of solvents, was carried out according to
the literature procedures.16 Melting points were measured
on a Stuart Scientific SMP3 apparatus. IR spectra were
measured on a Perkin Elmer Spectrum 1000 FT-IR, or a
Perkin Elmer Spectrum One FT-IR. Optical rotations were
measured on a Perkin Elmer 241 polarimeter at 589 nm
(Na) in a 10 cm cell. Thin layer chromatography (TLC)
was carried out on precoated silica gel plates (Merck 60
F254); column chromatography was conducted using
Merck silica gel 60 or Apollo Scientific silica gel
40–63 lm or alumina (activated, neutral, Brockmann I,
ca. 150 mesh). Elemental analysis was performed on a
Perkin Elmer 2400 analyser. 1H NMR (400 MHz), 13C
NMR (100 MHz), 31P NMR (162 MHz) and 15N NMR
(40.5 MHz) were recorded on a JEOL ECX-400 NMR
spectrometer. 15N NMR spectra were externally referenced
to nitromethane. All spectra were recorded at probe tem-
peratures (ꢁ20 °C) using tetramethylsilane as an internal
standard. All chiral liquid–liquid chromatography (HPLC)
was carried out on a Varian instrument, with an UV/vis
detector at the specified wavelength, with a Daicel CHI-
RALCEL OD 0.46 cm ꢂ 25 cm column, using isopropa-
nol/hexane (0.1% diethylamine) as the solvent, under
conditions described for each experiment.
When tetrahydrofuran was used as the solvent, the most
striking difference from the toluene reaction was the consis-
tency of the nucleophile solution (Table 1, entries 2 and 5).
A clear solution was observed unlike the gelatinous mix-
ture in toluene. It was anticipated that this solubility would
lead to a faster reacting system and in turn a higher conver-
sion. To our surprise, the conversion was lower than in tol-
uene at 56% but a high enantioselectivity of 90% was
achieved. The tetrahydrofuran reactions are run at 60 °C,
as opposed to 85 °C for toluene. While this decrease in tem-
perature did not seem to improve enantioselectivity, as one
might expect, it did influence the reactivity of the system.
To probe the effect of temperature on the catalytic system,
we performed the toluene reaction at room temperature in-
stead of 85 °C (Table 1, entries 6 and 7). Initially, the entire
reaction was carried out at rt. No product could be de-
tected after 48 h. No product formed likely due to the inad-
equate formation of an active catalyst. Subsequently, a
reaction was performed, where the catalyst preparation
was conducted at 85 °C, for 2 h before being cooled and
the rest of the reaction carried out at rt. After 48 h, only
13% conversion to the desired product was obtained in
57% ee. This represents a TON of ꢁ1 indicating that the
active catalyst is not reformed at lower temperature. Low-
ering the reaction temperature decreased the enantioselec-
tivity and significantly reduced conversion. It appears
that elevated temperatures are critical to the efficiency
and enantioselectivity of the reactions, presumably due to
the inherent lack of reactivity of amides in comparison to
other metal complex ligands. In the case of 2, an alternative
method of nucleophile generation was also investigated,
that is, from dimethyl malonate, N,O-bis(trimethyl-
silyl)acetamide (BSA)14 and a catalytic amount of sodium
acetate (Table 1, entry 4). The BSA/dimethyl malonate
system has been reported to yield products with higher
enantioselectivities in shorter reaction times. It is reported
that BSA works as a silylating agent for the dimethyl
malonate anion, forming a ketene silyl acetal.15 However,
(entries 3 and 4) the effectiveness of a particular counterion
is specific to the reacting system, and in this case it appears
that the NaH/dimethyl malonate system works best.
4.1.1. (1R,2R)-N,N0-Bis(2-pyridine carboxamide)-1,2-cyclo-
hexane 1. Oxalyl chloride (6.5 g, 51.2 mmol) and dimeth-
ylformamide (5 drops) were added to a suspension of
picolinic acid (4.73 g, 38.4 mmol) in dichloromethane
(55 ml) at 0 °C. The resulting buff-coloured suspension
was warmed to room temperature and stirred for 5 h before
removing volatiles, including excess oxalyl chloride, in
vacuo. This acid chloride was resuspended in dichloro-
methane (73 ml) and cooled to 0 °C before the addition
of (ꢀ)-(1R,2R)-trans-1,2-diaminocyclohexane (1.46 g,
12.8 mmol) and triethylamine (17 ml, 12.3 g, 121.6 mmol).
The reaction mixture was stirred at 0 °C for 4 h and
then quenched by the addition of water (20 ml). The
organic layer was isolated and washed successively with
water (2 ꢂ 20 ml), saturated sodium hydrogen carbonate

394
L. Bateman et al. / Tetrahedron: Asymmetry 19 (2008) 391–396
20
(25 ml), water (20 ml) and brine (25 ml), dried and concen-
trated in vacuo. Recrystallisation from hot ethanol
(ꢁ20 ml) afforded product 7 as a colourless crystalline solid
(7.84 g, 63%); mp 172–173 °C (lit.,17 172–175 °C); 1H
NMR (CDCl3): 1.41–1.46 (m, 4H), 1.82 (m,2H), 2.15–
2.20 (m, 2H), 4.04 (br s, 2H), 7.30–7.33 (m, 2H),
7.69–7.73 (m, 2H), 8.03–8.05 (m, 2H), 8.21 (br s, 2H),
8.48–8.50 (m, 2H); 13C NMR (CDCl3) 24.9, 32.7, 53.3,
122.1, 126.0, 137.1, 148.2, 149.8, 164.6.18 IR (solid): 3345,
dichloromethane) {lit.,22 ½aꢃD ¼ ꢀ8:2 (c 1.0, dichlorometh-
1
ane)}; H NMR (CDCl3) 2.18–2.48 (m, 4H), 3.73 (s, 3H),
4.23 (dd, J 9.1, 5.5, 1H), 7.25 (br s, 1H); 13C NMR (CDCl3)
24.8, 29.4, 52.7, 55.6, 172.6, 178.5;23 IR (film) 3369, 1748,
1699, 1220 cmꢀ1
.
4.1.5. (S)-5-(Hydroxymethyl)-2-pyrrolidone 7. Sodium
borohydride (3.78 g, 100 mmol) was added portionwise,
over 15 min, to a solution of methyl-(S)-2-pyrrolidinone-
5-carboxylate 6 (14.22 g, 99.4 mmol) in ethanol (130 ml)
and the mixture stirred overnight. The reaction was
quenched with dilute hydrochloric acid (10%, 20 ml) and
concentrated in vacuo. The residue was dissolved in dis-
tilled water (60 ml) and the solution passed down an ion ex-
change column (Amberlite IR 120+, strong cation
exchange). The water was removed in vacuo and the
remaining solid azeotropically dried with methanol afford-
2151, 1650, 1513, 1154, 750, 689 cmꢀ1
.
4.1.2. (S)-5-Oxopyrrolidine-2-carboxylic acid ethyl ester
(8.33 g,
5. (S)-(ꢀ)-2-Pyrrolidone-5-carboxylic acid
4
64.5 mmol), concentrated sulfuric acid (0.16 ml), ethanol
(20 ml) and toluene (6.4 ml) were combined and the mix-
ture was refluxed for 2.5 h in a flask fitted with a Dean–
Stark apparatus to collect water formed in situ.The mixture
was cooled, carbon tetrachloride (65 ml) and potassium
carbonate (2.3 g, 16.7 mmol) were added and stirring was
continued for 30 min before filtering and removing the sol-
ing 7 as a colourless gum (11.43 g, 99%); no further purifi-
20
cation was necessary (>98% pure by GC); ½aꢃD ¼ þ29:2 (c
20
5.0, ethanol) {lit.,24 ½aꢃD ¼ þ28:0 (c 5.0, ethanol)}; 1H
vent in vacuo. The crude product was purified by Ku-
¨
NMR (CDCl3) 1.75–1.83 (m, 1H), 2.10–2.21 (m, 1H),
2.31–2.44 (m, 2H), 3.45 (dd, J 11.0, 6.8, 1H), 3.73 (dd, J
11.0, 3.1, 1H), 3.80 (m, 1H), 4.56 (br s, 1H), 7.60 (br s,
gelrøhr distillation (oven temp 206 °C; 0.1 mmHg) (lit.,19
180 °C, 0.1 Torr), giving a clear oil which solidified to a
13
colourless solid on standing (7.23 g, 72%); mp 51–52 °C
1H); C NMR (CDCl3) 22.6, 30.4, 56.9, 65.6, 179.7;23
20
(lit.,19 49–50 °C); ½aꢃD ¼ þ2:4 (c 10, ethanol) {lit.,20
IR (film) 3318, 1676, 1419, 1047 cmꢀ1
.
20
1
½aꢃD ¼ þ2:4 (c 10, ethanol)}; H NMR (CDCl3): 1.29 (t,
J 4.8, 3H), 2.17–2.32 (m, 1H), 2.34–2.52 (m, 3H), 4.22
(m, 3H), 6.75 (br s, 1H); 13C NMR (100 MHz) 14.0, 24.7,
29.2, 55.4, 61.6, 172.0, 178.0.21 IR (solid): 2983, 1732,
4.1.6. (2S)-5-Oxopyrrolidin-2-yl methyl methanesulfonate
8. Methanesulfonyl chloride (6.60 ml, 9.78 g, 85.40
mmol) and triethylamine (15.7 ml, 11.38 g, 112.5 mmol)
were added to a suspension of (S)-5-(hydroxymethyl)-2-
pyrrolidone, 7 (6.47 g, 56.26 mmol) in dichloromethane
(30 ml) at 0 °C. The reaction mixture was stirred at 0 °C
for 1.5 h at which stage water (1.5 ml) was added and the
mixture concentrated in vacuo. The crude product was
purified by flash column chromatography (ethyl acetate/
methanol, 10:1), affording the desired product 8 as a col-
ourless solid (9.99 g, 92%); mp 75–77 °C (lit.,24 75.5–
1684, 1198 cmꢀ1
.
4.1.3. (2S)-5-Oxo-N-(pyridin-2-ylmethyl)pyrrolidine-2-car-
boxamide (UNIFIDE) 2. 2-(Aminomethyl)pyridine
(2.50 ml, 2.62 g, 24.25 mmol) was slowly added to a solu-
tion of (S)-5-oxopyrrolidine-2-carboxylic acid ethyl ester
5 (3.81 g, 24.25 mmol) in ethyl acetate (20 ml). The solution
was stirred at room temperature for 48 h before filtering
and concentrating in vacuo. The crude solid obtained was
triturated with acetone to give a creamy white solid, which
20
20
77.5 °C); ½aꢃD ¼ þ15:8 (c 1, ethanol) {lit.,24 ½aꢃD ¼ þ16:2
1
(c 1.02, ethanol)}; H NMR (CDCl3) 1.84–1.95 (m, 1H),
upon drying gave a colourless solid (4.50 g, 85%); mp 93–
20
95 °C; ½aꢃD ¼ ꢀ22:2 (c 0.5, chloroform); 1H NMR (CDCl3)
2.25–2.49 (m, 3H); 3.07 (br s, 3H), 4.03–4.28 (m, 3H),
7.34 (br s, 1H); 13C NMR (CDCl3) 22.6, 29.7, 37.6, 53.5,
71.1, 178.9;24 IR (film) 3227, 2937, 1686, 1347, 1168,
2.13–2.28 (m, 2H), 2.32–2.48 (m, 2H), 4.22 (dd, J 8.7, 5.0,
1H), 4.40 (dd, J 15.6, 5.5, 1H), 4.54 (dd, J 15.6, 5.5, 1H),
7.06 (dd, J 7.3, 5.5, 1H), 7.23 (d, J 7.8, 1H), 7.57 (dt, J
7.8, 1.8, 1H), 8.04 (br s, 1H), 8.16 ( t, J 5.5, 1H), 8.27 (d,
J 4.1, 1H); 15N NMR (40 MHz, CDCl3) ꢀ75.6, ꢀ255.8,
ꢀ269.1; 13C NMR (CDCl3) 25.6, 29.4, 44.2, 57.4, 122.3,
122.6, 136.8, 148.7, 156.4, 172.7, 179.6; IR (film) 3681,
3665, 2943, 1702, 1655, 1054 cmꢀ1; m/z [EI]; found
(HRMS, EI): m/z 219.1014 (<1%), Rt 10.27 min.
C11H13N3O2 (M+) requires 219.1008; 135 (88%), 93
[CH2(C5H4)NH+, 100%], 92 (57%), 84 (43%). Anal. Calcd
for C11H13N3O2: C, 60.26; H, 5.98; N, 19.17. Found: C,
59.85; H, 5.92; N, 18.87.
944 cmꢀ1
.
4.1.7. (S)-5-(Azidomethyl)-2-pyrrolidone 9. A solution of
(2S)-5-oxopyrrolidin-2-yl methyl methanesulfonate
8
(9.92 g, 51.39 mmol) in dimethylformamide (100 ml) was
stirred for 15 min before the portionwise addition of so-
dium azide (16.84 g, 259.1 mmol). The reaction mixture
was heated to 80 °C and stirred for 36 h, during which time
it was monitored through IR assays. On completion of the
reaction, it was cooled and concentrated in vacuo. The
resulting residue was resuspended in chloroform (250 ml),
filtered and concentrated in vacuo. The crude product
was purified by flash column chromatography (chloro-
form/methanol, 19:5), affording the desired product 9 as
a colourless solid (5.18 g, 71%); mp 62–63 °C (lit.,25 62–
4.1.4. Methyl-(S)-2-pyrrolidinone-5-carboxylate 6. Amber-
lyst 15 resin (5.0 g wet) was added to a solution of (S)-(ꢀ)-
2-pyrrolidone-5-carboxylic acid 4 (12.92 g, 0.1 mol) in
methanol (50 ml). The mixture was refluxed for 24 h,
cooled, filtered and concentrated in vacuo affording the
20
30
63 °C); ½aꢃD ¼ þ72:8 (c 5.0, ethanol) {lit.,25 ½aꢃD ¼ þ72:0
1
(c 5.0, ethanol)}; H NMR (CDCl3) 1.74–1.82 (m, 1H),
product as a yellow oil (14.22 g, 99%); no further purifica-
tion was necessary (>99% pure by GC); ½aꢃD ¼ ꢀ8:4 (c 1.0,
2.16–2.42 (m, 3H), 3.26 (dd, J 12.4, 6.5, 1H), 3.41 (dd, J
20
12.4, 4.8, 1H), 3.79 (m, 1H), 7.28 (br s, 1H); 13C NMR

L. Bateman et al. / Tetrahedron: Asymmetry 19 (2008) 391–396
395
(CDCl3) 24.0, 29.9, 53.7, 55.9, 178.8; IR (film) 3226, 2932,
2096, 1672 cmꢀ1
for a further 15 min. The catalyst solution was transferred
to the substrate–nucleophile mixture via a gas-tight syr-
inge, along with a toluene rinse (1 ml). The resulting mix-
ture was stirred at 85 °C for 48 h. Saturated ammonium
chloride solution (10 ml) was added, the organic layer sep-
arated and the aqueous layer extracted with diethyl ether
(3 ꢂ 10 ml). The combined organics were washed with
brine (10 ml), dried, filtered and concentrated in vacuo,
affording the crude product. The conversion to product
.
4.1.8. (S)-5-(Aminomethyl)-2-pyrrolidone 10. Ten percent
palladium on carbon (899 mg) was added, to a solution
of (S)-5-(azidomethyl)-2-pyrrolidone 11 (6.29 g, 43.6
mmol) in ethanol (200 ml). The mixture was agitated under
hydrogen (30 psi) in a Parr apparatus, which had been
purged with air, for 6 h. The crude reaction mixture was fil-
tered through a short column of Celite using ethanol
(30 ml) as eluant, to remove the hydrogenation catalyst,
and the volatiles were removed in vacuo. The crude prod-
uct was purified by column chromatography (chloroform/
methanol, 19:5) to give the product 10 as a yellow oil
1
was indicated by H NMR spectral analysis of this mate-
rial. The crude product was then purified by flash column
chromatography (silica gel; petrol/ethyl acetate, 19:1)
yielding the product 12 as pale yellow oil, which solidified
on standing (210.6 mg, 65% yield). The enantiomeric excess
was established by HPLC analysis [Daicel Chiralcel OD,
254 nm, hexane (0.1% diethylamine)/isopropyl alcohol,
99:1, 0.5 ml/min], t(R) = 19.3 min, t(S) = 21.2 min, and
21
25
(4.92 g, 98%); ½aꢃD ¼ þ33:4 (c 5.0, ethanol) {lit.,26 ½aꢃD
¼
1
þ37:2 (c 2.0, ethanol)}; H NMR (CDCl3) 1.66–1.75 (m,
1H), 1.78 (br s, 2H), 2.15 (m, 1H), 2.29–2.33 (m, 2H),
2.61 (dd, J 12.8, 7.6, 1H), 2.80 (dd, J 12.8, 4.4, 1H), 3.63
(m, 1H), 7.41 (br s, 1H); 13C NMR (CDCl3) 24.2, 30.3,
1
confirmed by chiral shift NMR. H NMR (CDCl3) 3.52
(s, 3H), 3.70 (s, 3H), 3.96 (d, J 11.0, 1H), 4.27 (dd, J
11.0, 8.7, 1H), 6.33 (dd, J 15.6, 8.7, 1H), 6.48 (d, J 15.6,
1H), 7.20–7.34 (m, 10H); 13C NMR (CDCl3) 49.2, 52.5,
52.6, 57.7, 126.4, 126.6, 127.2, 127.6, 127.9, 128.5, 129.1,
131.9, 136.8, 140.2, 167.8, 168.2. The product 12 was
formed in 72% conversion and was found to have 93% ee
(S).
47.4, 57.0, 179.0.26 IR (film) 3238 br, 2926 w, 1667 s cmꢀ1
.
4.1.9. N-{[(2S)-5-Oxopyrrolidin-2-yl]methyl}pyridine-2-car-
boxamide CROSIDE 3. (S)-5-(Aminomethyl)-2-pyrroli-
done 10 (1.64 g, 14.39 mmol) and 2-picolinic acid (1.77 g,
14.39 mmol) were suspended in dichloromethane (18 ml)
and cooled to 0 °C before the slow addition of a dicyclo-
hexylcarbodiimide (2.97 g, 14.39 mmol) solution in dichloro-
methane (18 ml). The reaction mixture was stirred at
0 °C for 1 h, allowed to warm to room temperature and
stirred overnight before filtering through Celite and wash-
ing with dichloromethane (10 ml). The combined organics
were concentrated in vacuo. The crude product was puri-
fied by column chromatography using gradient elution
(ethyl acetate–methanol; Rf 0.31 (silica) ethyl acetate/meth-
anol, 10:1) affording 3 as a colourless solid (3.08 g, 78%);
4.3. Alternative nucleophile generation
The reaction was carried out according to Section 4.2, ex-
cept that the dimethyl malonate nucleophile species was
generated as follows: a flame-dried Schlenk tube was
charged with dimethyl malonate (0.25 ml, 291 mg,
2.2 mmol), N,O-bis(trimethylsilyl)acetamide (0.55 ml,
447 mg, 2.2 mmol), and sodium acetate (2.5 mg) in toluene
(8 ml). The resulting solution was stirred at 85 °C for
15 min and the rest of the reaction was performed as de-
scribed. Product 12 was formed in 44% conversion and
was found to have 49% ee (S).
20
1
mp 140–141 °C; ½aꢃD ¼ þ41:1 (c 5.0, ethanol); H NMR
(CDCl3) 1.80–1.89 (m, 1H), 2.17–2.36 (m, 3H), 3.46–3.62
(m, 2H), 3.89–3.95 (m, 1H), 7.08 (br s, 1H), 7.34 (ddd, J
7.6, 4.8, 1.4, 1H), 7.76 (dt, J 7.8, 1.4, 1H), 8.08 (d, J 7.8,
1H), 8.40 (t, J 5.5, 1H), 8.44 (d, J 4.6, 1H); 15N NMR
(40 MHz, CDCl3) ꢀ76.6, ꢀ253.3, ꢀ276.1; 13C NMR
(CDCl3) 24.3, 29.8, 43.9, 54.2, 122.2, 126.2, 137.2, 148.0,
149.4, 165.0, 178.6; IR (film) 3346, 3218, 2967, 1665,
1645, 1537, 1286, 1253 cmꢀ1. Anal. Calcd for C11H13-
N3O2: C, 60.26; H, 5.98; N, 19.17. Found: C, 59.85; H,
6.06; N, 18.84.
1
4.4. Determination of enantiomeric excess by chiral shift H
NMR
The purified reaction product, 12 (7 mg, 0.024 mmol) was
dissolved in chloroform-D (0.8 ml) before the addition of
(+)-Eu(hfc)3 (13 mg, 0.0106 mmol). The resulting solution
was then transferred to an NMR tube. The 1H NMR spec-
trum displayed two singlets and a doublet in the region of
4 ppm. Each antipode of one of the methyl groups causes
the singlets, while the doublet arises from the non-baseline
resolved signal for the other methyl group. The integration
of the doublet is equivalent to the sum of the integrations
of both singlets. The relative integrals of the singlets are
used to give the enantiomeric excess. The singlet, which ap-
pears furthest downfield, corresponds to the (R)-enantio-
mer, when the (+)-antipode is used.27
4.2. Typical procedure for Pd(0)-catalysed asymmetric
allylic alkylation of 11
A flame-dried Schlenk tube was charged with UNIFIDE, 2
(32.8 mg, 0.15 mmol, 15 mol %) and tris(dibenzylideneace-
tone)dipalladium (45.5 mg, 0.05 mmol, 10 mol % Pd)
before being degassed. Toluene (3 ml) was added to this
and the resulting mixture heated to 85 °C for 2 h. Sepa-
rately, a flame-dried Schlenk tube was charged with sodium
hydride (60% dispersion in mineral oil, 80.0 mg, 2.0 mmol)
and was degassed before toluene (8 ml) and dimethyl
malonate (0.25 ml, 291 mg, 2.2 mmol) were added. The
resulting gel was stirred at 85 °C for 15 min, before the
addition of ( )-(E)-1,3-diphenyl-3-acetoxyprop-1-ene, 11,27
(252.0 mg, 1.0 mmol), in toluene (1 ml), and was stirred
Acknowledgements
We thank Enterprise Ireland, Limerick County Council
and Science Faculty, NUI, Galway for supporting this
work.

396
L. Bateman et al. / Tetrahedron: Asymmetry 19 (2008) 391–396
14. El Gihani, M. T.; Heaney, H. . Synthesis 1998, 357–375.
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