Improving catalyst activity in secondary amine catalysed transformations

Article abstract of DOI:10.1039/c4ob01916d

The effect on catalyst performance of altering substituents at the 2-position of the Macmillan imidazolidinone has been examined. Condensation of l-phenylalanine N-methyl amide with acetophenone derivatives results in a series of imidazolidinones whose sa

Full text of DOI:10.1039/c4ob01916d

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Improving catalyst activity in secondary amine
catalysed transformations†
Cite this: DOI: 10.1039/c4ob01916d
John B. Brazier,a Timothy J. K. Gibbs,a Julian H. Rowley,b Leopold Samulis,a
Sze Chak Yau,a Alan R. Kennedy,b James A. Plattsa and Nicholas C. O. Tomkinson*b
The effect on catalyst performance of altering substituents at the 2-position of the Macmillan imidazolidi-
none has been examined. Condensation of L-phenylalanine N-methyl amide with acetophenone deriva-
tives results in a series of imidazolidinones whose salts can be used to accelerate the Diels–Alder
cycloaddition. Electron withdrawing groups significantly increase the overall rate of cycloaddition
without compromise in selectivity. The most effective catalyst was shown to be efficient for a variety of
substrates and the applicability of this catalyst to alternative secondary amine catalysed transformations is
also discussed.
Received 9th September 2014,
Accepted 14th October 2014
DOI: 10.1039/c4ob01916d
www.rsc.org/obc
ment. Reducing levels of catalyst loading necessary to bring
about reaction at an effective rate would further increase this
Introduction
Catalyst design generally relies upon serendipity and extensive potential.6
high throughput screening which has frequently proved to be
Within the field of LUMO catalysis using secondary amines
effective in asymmetric synthesis. However, pressure to reduce a consistent mechanism has been accepted, the fundamental
financial and environmental footprints provides inspiration steps of which are outlined in Fig. 1.7–9 In Step 1 the secondary
for innovation. The use of predictive models represents the amine salt 1 condenses with the α,β-unsaturated carbonyl com-
future of asymmetric synthesis whereby bespoke catalysts can pound 2 to form the reactive iminium ion 3. In Step 2 the
be tailored to specific reactions with minimal laboratory diene 4 undergoes cycloaddition with the activated π-system of
screening. Current models, however, frequently fall short of 3 to form the iminium ion of the product 5. Finally, in Step 3
the accuracy required to be effective predictors of both activity the iminium ion 5 undergoes hydrolysis/solvolysis to release
and selectivity.1 An alternative approach is to draw inspiration the product (e.g. acetal 6) and regenerate the secondary amine
from mechanistic knowledge where a combination of kinetic salt 1.10
experiment and intelligent design allows interrogation,
reinforcing and underpinning of hypotheses.2
Amine catalysis represents an important area of contempor-
ary synthetic chemistry. Since their introduction the fields of
LUMO, HOMO and SOMO catalysis have been established as
the most significant areas of Organocatalysis.3 This is due, in
part, to the wide variety of reactions which have been develo-
ped using secondary amines along with the excellent yields
and outstanding levels of selectivity which are commonly
achieved in these transformations.4,5 The field also follows
some of the principles of Green chemistry which has further
enhanced applicability, particularly in the industrial environ-
aSchool of Chemistry, Main Building, Cardiff University, Park Place, Cardiff,
CF10 3AT, UK
bWestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde,
Glasgow, G1 1XL, UK. E-mail: Nicholas.Tomkinson@strath.ac.uk
†Electronic supplementary information (ESI) available: 1H and 13C spectra for
compounds reported. CCDC 1017471. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c4ob01916d
Fig. 1 Catalytic cycle for imidazolidinone catalysed Diels–Alder
cycloaddition.
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Fig. 4 Potential points of substitution in the imidazolidinone
architecture.
Fig. 2 Considerations within Step 1 of the catalytic cycle.
Scheme 1 Origins of stereoselectivity in the imidazolidinone catalysed
Diels–Alder cycloaddition.
1 was deemed crucial for influencing reactivity. Modelling
studies had previously shown the highest activation barrier
within iminium ion formation was Equilibrium 1 where the
ammonium salt 7·HX loses a proton (Fig. 2).18 When compar-
ing the imidazolidinone 13 and the diarylprolinol ether 14 it
was found proton affinity (PA) was a readily calculable theore-
tical measure of amine basicity to act as a predictor of catalyst
Fig. 3 Imidazolidinone and diarylprolinol ether catalysts.
For the Diels–Alder cycloaddition reaction, under literature activity.15 The benchmark imidazolidinone 13 has a PA of
optimised conditions, it has been shown the rate determining 943.1 KJ mol−1 whereas the diarylprolinol ether 14, which has
step of the catalytic cycle is iminium ion formation (Step 1).11 a lower level activity, has a PA of 998.6 KJ mol−1 (Fig. 3).15
Iminium ion formation consists of a number of mechanistic Therefore we sought to alter the basicity of 13 through substi-
steps, whereby distinct equilibria require the amine to have tution and determine the influence on reactivity within a
different properties.12 Fig. 2 shows a series of productive equi- benchmark Diels–Alder reaction, with the expectation that low-
libria from Step 1 leading to a reactive iminium ion 12. ering proton affinity would improve reactivity.
Reduced basicity of the amine 7 drives Equilibrium 1 and
The imidazolidinone architecture 15 offers a number of
Equilibrium 4 in the forward direction whereas amine nucleo- places for developing an understanding of the relationship
philicity is required for Equilibrium 3 to proceed forwards. It between structure and catalytic activity (Fig. 4). We elected to
is well established that the basicity of an amine is intimately examine the substituents R2 and R3 where it was thought ease
linked to its nucleophilicity, therefore, positively influencing of synthesis and proximity to the reactive nitrogen would
Equilibrium 1 and Equilibrium 4 by reducing basicity can engender the greatest effect on reaction outcome.
negatively impact Equilibrium 3 by reducing nucleophilicity.
A second fundamental requirement of the secondary amine
Therefore in order to influence Step 1 of the catalytic cycle the catalyst is the ability to control the stereochemical outcome of
electronics of the amine must be balanced through appropri- the transformation. It was crucial for any amine with improved
ate substitution.
activity over 13 maintained the exceptional levels of asymmetry
Within the literature there are two principal catalyst generally associated with this catalyst.7 Within the reaction of
scaffolds developed for accelerating the Diels–Alder reaction a secondary amine 13 and a α,β-unsaturated carbonyl com-
through iminium ion intermediates (Fig. 3): the imidazolidi- pound two potential iminium ions can be formed, the E- and
nones13 and the diarylprolinol ethers;14 the imidazolidinones the Z-isomers 16 and 17 (Scheme 1). Ratios of 16 and 17 have
having a higher level of activity in this reaction.15 We therefore been shown to be dictated by the steric requirements of the
elected to examine the imidazolidinone architecture to dis- substituents on the imidazolidinone ring.9
cover catalysts with higher levels of activity.16,17 Within this
For the imidazolidinone 13, following selective formation
manuscript we prepare a series of imidazolidinone structures of the E-iminium ion 16, the catalyst architecture renders sub-
based upon our mechanistic understanding of the reaction sequent Diels–Alder cycloaddition asymmetric, with the benzyl
and explore the reactivity of these catalysts.
arm of the catalyst directing approach of the diene from the
Understanding how substituents on the secondary amine lower face of the iminium ion as shown (Scheme 1). For any
can affect basicity, nucleophilicity, and hence the rate of Step alternative imidazolidinone structures it is essential that high
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levels of E/Z iminium control is observed to maintain levels of
selectivity.9a
Results and discussion
Based upon the hypothesis that introduction of an electron
withdrawing group α- to the reactive nitrogen (R2 and R3 in 15)
would reduce basicity and therefore enhance reactivity a series
of imidazolidinones 20–24 were prepared through conden-
sation of phenylalanine-N-methyl amide (18) and a substituted
acetophenone (Table 1). Reaction of 18 and 19 in toluene
under microwave irradiation in the presence of ytterbium tri-
flate gave the corresponding imidazolidinones 20–23 with a
variety of substitution on the aromatic ring.19 For preparation
of the imidazolidinone 24, derived from 4-nitroacetophenone,
it proved necessary to develop alternative conditions to access
the catalyst with high levels of ee. Reaction of 18 with the
ketone in DMF at 150 °C for 30 minutes in the presence of
methane sulfonic acid gave 24 enantiomerically pure (entry 6)
(see ESI† for full details of catalyst preparation). Proton affinity
(PA) for each catalyst was calculated using Gaussian 09 (B3LYP/
6-31+G(d,p)) which showed a clear influence on predicted basi-
city of the secondary nitrogen (entries 2–6) when compared to
the parent structure 13 (entry 1). Introduction of an aromatic
ring with an electron donating substituent displayed a raised
proton affinity (entry 2, 970 KJ mol−1) when compared to 13
(entry 1, 943 KJ mol−1). Whereas increasing the strength of
Scheme 2 Diels–Alder cycloaddition catalysed by 13·HCl.
Fig. 5 Relative rates of imidazolidinone catalysed Diels–Alder
cycloaddition.
electron withdrawing group progressively decreased the proton spectroscopy (see ESI† for full details). As can be seen in
affinity of the secondary amine (entries 3–6), with the lowest Fig. 5, introduction of an aromatic ring greatly increased the
value being shown for imidazolidinone 24 (R = 4-NO2C6H4, rate of the Diels–Alder cycloaddition when compared to the
PA = 924 KJ mol−1).
parent system 13·HCl ( ). This was the case for all acetophe-
The Diels–Alder cycloaddition of cinnamaldehyde and none derived catalysts examined. Subtleties in the electronic
cyclopentadiene was used to benchmark the acetophenone substitution of the aromatic ring had less influence on the
derived catalysts 20·HCl–24·HCl (Scheme 2).7 Each reaction overall rate than proton affinity predictions had suggested
was performed under literature optimised reaction con- (Table 1), showing a deficiency in this ground state prediction,
ditions (3 equiv. cyclopentadiene, MeOH–H2O (19 : 1), 25 °C, however, the significantly increased reaction rate observed was
5 mol% catalyst), monitoring reaction progress by 1H NMR exciting and warranted further investigation.
As stated previously, it was deemed essential that alongside
an increase in reaction rate we required the high levels of
Table 1 Preparation of potential imidazolidinone catalystsa,b
selectivity observed with the imidazolidinone 13·HCl. For
each reaction selectivities were determined for the Diels–Alder
adducts 26 and 27 (Table 2).20 Based upon these reaction out-
comes we selected the imidazolidinone derived from 4-nitro-
acetophenone 24 (entry 3) for further investigations due to the
high levels of enantioselectivity observed for both the endo
(95% ee) and exo (87% ee) isomers of the Diels–Alder product.
To profile the reactivity of the imidazolidinone 24 further
we examined a series of alternative dienophiles within the
Diels–Alder cycloaddition (Table 3). For cinnamaldehyde
derivatives (entries 1–4) high yields and enantioselectivities
were maintained for both electron withdrawing and electron
donating substituents on the aromatic ring. Reactions with ali-
phatic substituted substrates proceeded slower than reactions
with cinnamaldehyde derivatives, however, they still pro-
gressed cleanly and mass balance could be accounted for
Entry
R
Yield (%)
PA KJ mol−1
1
2
3
4
5
6c
Me (13)
4-OMeC6H4 (20)
C6H5 (21)
4-ClC6H4 (22)
4-CNC6H4 (23)
4-NO2C6H4 (24)
96
29
33
36
21
36
943
970
960
950
928
924
a PA = Proton affinity. b Reaction conditions: Yb(OTf)3, PhMe, 120 °C,
μw. c Reaction conditions: MsOH, DMF, 150 °C, μw, 30 min.
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Table 2 Imidazolidinone catalysed Diels–Alder cycloaddition
Entry
Catalyst
Yield (%)
endo : exoa
endo eeb
exo eeb
Fig. 6 X-ray structure of iminium ion derived from 24 and 4-iodo-
cinnamaldehyde.
1
2
3
4
5
6
13
20
24
21
22
23
57
96
97
97
95
97
1 : 1.32
1 : 1.20
1 : 1.05
1.24 : 1
1 : 1.18
1.08 : 1
93
95
95
96
90
83
93
84
87
82
78
73
a Determined by 1H NMR spectroscopy on crude reaction mixture.
b Determined by conversion to 2,4-dinitrophenylhydrazine derivative
and examination by HPLC.
Scheme 4 Conjugate addition of N-methyl pyrrole to cinnamaldehyde.
Table 3 Diels–Alder cycloaddition catalysed by 24·HCl
Crystals of an iminium ion suitable for X-ray analysis were
obtained through reaction of 24·HPF6 and 4-iodocinnamalde-
hyde (Fig. 6). A low energy solid-state conformation of the
E-iminium ion with the benzyl arm residing over the top of the
imidazolidinone ring was observed. Direction of the diene to
the bottom face of this iminium ion leads to the stereochemi-
cal outcome observed in reactions of 24.22 Consistent with
observations on the MacMillan catalyst 13, this suggests use of
24 as a catalyst in conjugate addition reactions would lead to
products with low levels of enantioselectivity,23 and increasing
the steric requirement of the methyl group on the β-face would
be necessary to prepare alternative catalysts to accelerate this
class of reaction.
Entry
R
Yield (%)
endo : exoa
endo ee
exo ee
1
2
3
4
5
6
4-OMeC6H4
4-MeC6H4
4-ClC6H4
4-NO2C6H4
nPr
95
75
95
94
72
18
1 : 1.1
1 : 1
1.1 : 1
1.1 : 1
1.2 : 1
1 : 1
96b
94b
96b
94b
81c
80c
87b
86b
84b
86b
63c
64c
iPr
a Determined by 1H NMR spectroscopy on crude reaction mixture.
b Determined by reduction to corresponding alcohol and examination
by HPLC. c Determined by conversion to 2,4-dinitrophenylhydrazine
derivative and examination by HPLC.
The importance of knowing the rate determining step
of the catalytic cycle when altering catalyst structure is
highlighted by examination of an alternative transformation
which proceeds via iminium ion intermediates. For
example, Mayr has shown that in the conjugate addition
of electron rich heteroaromatics, such as N-methyl pyrrole 31,
to an α,β-unsaturated carbonyl compound, C–C bond
formation is rate determining.24 From this it could be
expected that the 4-nitroacetophenone derived catalyst 24
would not significantly alter the rate of addition of 31 to 25
(Scheme 4).
The addition of 31 to 25 catalysed by 13 and 24 under litera-
ture optimised conditions was monitored by 1H NMR spec-
troscopy (Fig. 7). Each reaction proceeded smoothly to
completion after 6 hours. As can be seen from Fig. 7 each
catalyst accelerates the reaction at a similar rate showing
that improved activity for 24 will only be observed in
transformations where iminium ion formation is rate
determining.
Scheme 3 Parasitic dienamine formation.
through recovered starting material. It is believed that parasitic
equilibria of the catalyst involving dienamine 30 21 formation
from the iminium intermediate 29 accounts for this observed
loss in reactivity (Scheme 3).
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mixture was heated under reflux for 18 h. The solvent was
removed under reduced pressure and the residue taken up in
chloroform (30 mL) and saturated sodium carbonate solution
(30 mL). The aqueous layer was extracted with chloroform
(2 × 30 mL) and the combined organics were dried over potass-
ium carbonate. The solvent was removed under reduced
pressure to give the target compound as a pale yellow oil
(2.40 g, quant.). [α]D20 = −33.5 (c = 1.3, MeOH); νmax (film)/cm−1
1
3473, 3329, 3060, 3030, 2975, 2929, 1685; H NMR (400 MHz,
CDCl3) δ 7.38–7.14 (5H, m), 3.82 (1H, dd, J = 6.5, 4.5 Hz),
3.17 (1H, dd, J = 14.2, 4.5 Hz), 3.03 (1H, dd, J = 14.2, 6.5 Hz),
2.77 (3H, s), 1.28 (3H, s), 1.18 (3H, s); 13C NMR (126 MHz,
CDCl3) δ 173.7, 137.6, 129.9, 129.0, 127.2, 75.9, 59.7, 37.7, 27.6,
25.7, 25.6; m/z (APCI): 219.2 (M + H+).
Fig. 7 Comparison of the reactivity of 13 and 24 in the conjugate
addition of N-methyl pyrrole to cinnamaldehyde.
Conclusions
General procedure for the preparation of imidazolidinones
20–23
In summary, we have presented a series of highly reactive
imidazolidinone catalysts, which significantly increase the rate
of Diels–Alder cycloaddition reactions. A low energy crystal
structure of a proposed iminium ion intermediate suggests
that salts of 24 induce asymmetry in a similar manner to the
MacMillan imidazolidinone 13. The catalysts described would
be predicted to accelerate cycloaddition reactions and conju-
gate addition reactions that proceed through a closed tran-
sition state and provide enhanced rates to those observed with
13 where iminium ion formation is the rate determining step
of the catalytic cycle. Central to this method of catalyst design
is a thorough understanding of reaction mechanism providing
an attractive and practical method to improve catalyst activity.
A toluene solution of L-phenylalanine-N-methyl amide (0.6 M),
the appropriate substituted acetophenone (0.9 eq.) and ytter-
bium(III) trifluoromethanesulfonate (0.05 eq.) were heated
under reflux for 16–69 h. The mixture was then allowed to cool
and diethyl ether (2 vol) was added. The solution was washed
with 4 M potassium carbonate (0.3 vol), water (0.3 vol), and
brine (0.3 vol). The volatiles were then removed under reduced
pressure and the desired products obtained by flash chromato-
graphy (ethyl acetate/heptane).
(2R,5S)-5-Benzyl-2-(4-methoxyphenyl)-2,3-dimethylimidazoli-
din-4-one 20. Prepared according to General Procedure. [α]D30
=
+36 (c 0.1, CH2Cl2); νmax (NaCl disk)/cm−1 3360, 2933, 1690,
1
1608, 1510; H NMR (500 MHz, CDCl3) δH 7.23–7.08 (7H, m),
6.78 (2H, d, J = 8.9 Hz), 3.81 (1H, dd, J = 7.2 Hz, 4.2 Hz), 3.71
(3H, s), 3.08 (1H, dd, J = 13. 9 Hz, 4.2 Hz), 2.93 (1H, dd, J =
13.9 Hz, 7.2 Hz), 2.64 (3H, s), 1.46 (3H, s); 13C NMR (125 MHz,
CDCl3) δC 173.6, 159.4, 137.7, 134.9, 129.7, 128.5, 126.7, 126.5,
114.1, 78.4, 59.4, 55.3, 38.4, 26.4, 26.1; LRMS m/z (ES) (M + H)+
= 311.2; HRMS m/z (ES) (M + H+) = 311.1753; HRMS m/z calc.
(M + H+) = 311.1760.
(2R,5S)-5-Benzyl-2,3-dimethyl-2-phenylimidazolidin-4-one 21.
Prepared according to General Procedure. [α]3D0 = +3.0 (c 0.1,
CH2Cl2); νmax (NaCl disk)/cm−1 1693, 1454; 1H NMR (500 MHz,
CDCl3) δH 7.23 (2H, t, J = 6.2 Hz), 7.20–7.09 (8H, m), 3.76 (1H,
dd, J = 7.1 Hz, 4.2 Hz), 3.05 (1H, dd, J = 13.9 Hz, 4.2 Hz), 2.91
(1H, dd, J = 13.9 Hz, 7.1 Hz), 2.63 (3H, s), 1.45 (3H, s); 13C
NMR (125 MHz, CDCl3) δC 173.7, 142.8, 137.6, 129.7, 128.9,
128.5, 128.1, 126.7, 125.1, 78.6, 59.3, 38.3, 26.3, 26.2; LRMS
m/z (ES) (M + H)+ = 281.2; HRMS m/z (ES) (M + H+) = 281.1646;
HRMS m/z calc. (M + H+) = 281.1654.
Experimental
L-Phenylalanine N-methyl amide 18
L-Phenylalanine ethyl ester hydrochloride (30.0 g, 131 mmol)
was stirred in an ethanolic solution of methylamine 33 wt%
(150 mL, 1.2 mol) for 72 hours at ambient temperature. The
solvent was removed under reduced pressure. The resultant
slurry was taken up in saturated sodium carbonate (50 mL)
and extracted with chloroform (3 × 50 mL). The combined
organic extracts were dried over anhydrous potassium carbon-
ate and the solvent removed under reduced pressure to give a
white solid. The residue was recrystallized from ethyl acetate
and petroleum ether to give the product as white needles
(17.6 g, 75%). mp: 67–69 °C; [α]2D0 = −89.6 (c = 1, CHCl3); νmax
(film)/cm−1 3371, 3345, 3290, 2939, 2875, 1644; 1H NMR
(400 MHz, CDCl3) δ 7.47–7.12 (6H, m), 3.54 (1H, dd, J = 9.5,
3.9 Hz), 3.22 (1H, dd, J = 13.7, 3.9 Hz), 2.83 (3H, d, J = 5.0 Hz),
2.60 (1H, dd, J = 13.7, 9.5 Hz), 1.38 (2H, s); 13C NMR (101 MHz,
CDCl3) δ 174.8, 138.0, 129.3, 128.7, 126.8, 56.5, 41.0, 25.8; m/z
(ES): 179.1 (M + H+).
(2R,5S)-5-Benzyl-2-(4-chlorophenyl)-2,3-dimethylimidazolidin-
4-one 22. Prepared according to General Procedure. [α]D30
=
+5.2 (c 0.1, CH3OH); νmax (NaCl disk)/cm−1 3316, 2720, 1704,
1493; 1H NMR (500 MHz, CDCl3) δH 7.23–7.19 (4H, m),
7.16–7.14 (3H, m), 7.13–7.09 (2H, m), 3.76 (1H, dd, J = 6.9 Hz,
4.3 Hz), 3.06 (1H, dd, J = 14.0 Hz, 4.3 Hz), 2.95 (1H, dd, J =
(S)-5-Benzyl-2,2,3-trimethylimidazolidin-4-one 13
L-Phenylalanine-N-methyl amide (2.00 g, 11.2 mmol) was dis- 14.0 Hz, 6.9 Hz), 2.64 (3H, s), 1.44 (3H, s); 13C NMR (125 MHz,
solved in acetone (10 mL) and methanol (30 mL). A small CDCl3) δC 173.5, 141.4, 137.3, 134.1, 129.7, 129.0, 128.6, 126.8,
crystal of p-toluenesulfonic acid (<1 mg) was added and the 126.7, 78.2, 59.2, 38.0, 26.2, 21.0; LRMS m/z (ES) (M + H+) =
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315.1; HRMS m/z (ES) (M + H+) = 315.1253; HRMS m/z calc. LRMS m/z (ES) = 311.2 (M–Cl−); HRMS m/z (ES) (M–Cl−) =
(M + H+) = 315.1264.
311.1753; HRMS m/z calc. (M–Cl−) = 311.1760.
(2R,5S)-5-Benzyl-2,3-dimethyl-2-(4-cyanophenyl)imidazolidin-
(2R,5S)-5-Benzyl-2,3-dimethyl-2-phenylimidazolidin-4-one
hydrochloride 21·HCl. mp 139–141 °C; [α]3D0 = +7.6 (c 0.1,
4-one 23. Prepared according to General Procedure. [α]D20
=
+41.8 (c 0.1, CH3OH); νmax (NaCl disk)/cm−1 2228, 1695; 1H CH2Cl2); νmax (NaCl disk)/cm−1 3412, 2096, 1644; 1H NMR
NMR (500 MHz, CDCl3) δH 7.57 (2H, dt, J = 10.4 Hz, 1.7 Hz), (500 MHz, CD3OD) δH 7.60–7.55 (3H, m), 7.50–7.46 (2H, m),
7.31 (2H, dt, J = 10.4 Hz, 1.7 Hz), 7.24 (2H, t, J = 7. 5 Hz), 7.41 (2H, d, J = 7.6 Hz), 7.36 (2H, t, J = 7.6 Hz), 7.30 (1H, tt, J =
7.20–7.15 (3H, m), 3.72 (1H, dd, J = 6.3 Hz, 4.7 Hz), 3.07 (1H, 7.60 Hz, 2.4 Hz), 4.44 (1H, dd, J = 9.7 Hz, 4.0 Hz), 3.57 (1H, dd,
dd, J = 14.1 Hz, 4.7 Hz), 3.00 (1H, dd, J = 14.1 Hz, 6.3 Hz), 2.99 J = 15.2 Hz, 4.0 Hz), 3.24 (1H, dd, J = 15.2 Hz, 9.7 Hz), 2.94
(3H, s), 1.94 (1H, s), 1.45 (3H, s); 13C NMR (125 MHz, CDCl3) (3H, s), 2.21 (3H, s); 13C NMR (125 MHz, CD3OD) δC 167.6,
δC 173.6, 147.9, 136.8, 132.7, 129.6, 128.7, 127.0, 126.1, 118.3, 134.9, 134.3, 130.8, 129.5, 129.0, 128.8, 127.4, 126.9, 80.5, 58.6,
112.1, 78.2, 59.0, 37.6, 26.3, 25.8; LRMS m/z (APCI) (M + H+) = 34.0, 26.2, 19.4; LRMS m/z (ES) = 281.2 (M–Cl−); HRMS m/z
306.2; HRMS m/z (ES) (M + H+) = 306.1600; HRMS m/z calc. (ES) (M–Cl−) = 281.1646; HRMS m/z calc. (M–Cl−) = 281.1654.
(M + H+) = 306.1606.
(2R,5S)-5-Benzyl-2-(4-chlorophenyl)-2,3-dimethylimidazolidin-
(2R,5S)-5-Benzyl-2,3-dimethyl-2-(4-nitrophenyl)imidazolidin- 4-one hydrochloride 22·HCl. mp 133–135 °C; [α]3D0 = +38.0
4-one 24. L-Phenylalanine-N-methyl amide (3.86 g, 21.7 mmol) (c 0.1, CH3OH); νmax (NaCl disk)/cm−1 3414, 1720, 1495; 1H
was dissolved in DMF (20 mL). 4-Nitroacetophenone (3.96 g, NMR (500 MHz, CD3OD) δH 7.58 (2H, dt, J = 8.8 Hz, 1.9 Hz),
24 mmol) was added followed by methanesulfonic acid 7.47 (2H, dt, J = 8.8 Hz, 1.9 Hz), 7.42 (2H, d, J = 7.4 Hz), 7.36
(0.3 mL, 4.63 mmol, 20 mol%). The mixture was separated into (2H, t, J = 7.4 Hz), 7.30 (1H, t, J = 7.4 Hz), 4.46 (1H, dd, J =
two microwave vials and subjected to microwave irradiation at 9.7 Hz, 4.0 Hz), 3.57 (1H, dd, J = 15.2 Hz, 4.0 Hz), 3.25 (1H, dd,
150 °C for 30 minutes. The contents of the two vials were com- J = 15.24 Hz, 9.7 Hz), 2.93 (3H, s), 2.20 (3H, s); 13C NMR
bined and concentrated under reduced pressure. Chloroform (125 MHz, CD3OD) δC 167.3, 136.8, 134.9, 132.4, 129.6, 129.0,
(40 mL) and saturated sodium carbonate solution (40 mL) 128.7, 128.2, 127.3, 79.6, 58.0, 33.8, 25.5, 22.2; LRMS m/z
were added. The aqueous layer was extracted with chloroform (APCI) = 315.1 (M–Cl−); HRMS m/z (ES) (M–Cl−) = 315.1257;
(2 × 40 mL) and dried over anhydrous potassium carbonate. HRMS m/z calc. (M–Cl−) = 315.1264.
The solvent was removed under reduced pressure and the
(2R,5S)-5-Benzyl-2,3-dimethyl-2-(4-cyanophenyl)imidazolidin-
residue purified by flash chromatography (20% ethyl acetate in 4-one hydrochloride 23·HCl. mp 109–111 °C; [α]2D6 = +43.6
petroleum ether) to give the title compound as an orange oil (c 0.1, CH3OH); νmax (NaCl disk)/cm−1 3415, 2534, 2231, 1722; 1H
(500 mg, 7%). [α]2D0 = +24.2 (c = 2.0, MeOH); νmax (ATR)/cm−1 NMR (500 MHz, CD3OD) δH 7.91 (2H, d, J = 8.6 Hz), 7.65 (2H,
3350, 3028, 2924, 2855, 1688; 1H NMR (400 MHz, CDCl3) d, J = 8.6 Hz), 7.40 (2H, d, J = 7.5 Hz), 7.34 (2H, t, J = 7.5 Hz),
δ 8.26–8.16 (2H, m), 7.51–7.44 (2H, m), 7.36–7.22 (5H, m), 3.83 7.28 (1H, t, J = 7.5 Hz), 4.44 (1H, dd, J = 9.6 Hz, 3.9 Hz), 3.55
(1H, app. t, J = 5.3 Hz), 3.18 (1H, dd, J = 14.1, 4.6 Hz), 3.11 (1H, dd, J = 15.2 Hz, 3.9 Hz), 3.23 (1H, dd, J = 15.2 Hz, 9.6 Hz),
(1H, dd, J = 14.1, 6.5 Hz), 2.80 (3H, s), 2.04 (1H, s), 1.57 (3H, s); 2.93 (3H, s), 2.21 (3H, s); 13C NMR (125 MHz, CD3OD) δC
13C NMR (101 MHz, CDCl3) δ 173.7, 150.0, 147.8, 136.9, 129.8, 167.4, 138.7, 134.9, 133.2, 129.0, 128.7, 127.7, 127.3, 117.3,
128.8, 127.1, 126.5, 124.2, 78.2, 59.1, 37.7, 26.4, 26.1; m/z 114.5, 79.3, 58.1, 33.8, 25.6, 22.1; LRMS m/z (APCI) = 306.1
(ES/APCI): 326.2 (M + H+).
(M–Cl−); HRMS m/z (ES) (M–Cl−) = 306.1597; HRMS m/z calc.
(M–Cl−) = 306.1606.
(2R,5S)-5-Benzyl-2,3-dimethyl-2-(4-nitrophenyl)imidazolidin-
4-one hydrochloride 24·HCl. mp 153–155 °C; [α]2D0 = +36.4 (c =
General procedure for imidazolidinone salt formation
1
A solution of the amine in diethyl ether was treated with 2.0, MeOH); νmax (ATR)/cm−1 1732; H NMR (400 MHz, CDCl3)
hydrogen chloride gas for 10 minutes. The precipitate was δ 8.26 (2H, d, J = 8.8 Hz), 7.58 (2H, d, J = 8.8 Hz), 7.44–7.27
recovered on a sinter, washed with diethyl ether and petroleum (5H, m), 4.28 (1H, app. t, J = 5.7 Hz), 3.43 (1H, dd, J = 15.1, 5.7
ether, then dried under reduced pressure.
Hz), 3.31 (1H, dd, J = 15.1, 5.7 Hz), 2.80 (3H, s), 1.82 (3H, s);
(S)-5-Benzyl-2,2,3-trimethylimidazolidin-4-one hydrochloride 13C NMR (101 MHz, CDCl3) δ 167.5, 149.3, 140.9, 134.3, 130.1,
13·HCl. mp: 104–106 °C; [α]2D0 = −71.5 (c = 1.3, MeOH); νmax 129.1, 128.3, 128.1, 124.6, 79.3, 58.0, 34.6, 26.6, 23.3; m/z
(ATR)/cm−1 3416, 3380, 1710; 1H NMR (400 MHz, MeOD) (ES/APCI): 326.1 (M-Cl−). HRMS (ES) calculated for
δ 7.49–7.27 (5H, m), 4.67 (1H, dd, J = 10.7, 3.5 Hz), 3.53 (1H, C18H20O3N3 326.1499 (M + H+), found 326.1498.
dd, J = 15.2, 3.5 Hz), 3.09 (1H, dd, J = 15.2, 10.7 Hz), 2.92 (3H,
General procedure for Diels Alder cycloaddition (Tables 2
and 3)
s), 1.75 (3H, s), 1.60 (3H, s); 13C NMR (101 MHz, MeOD)
δ 170.4, 139.2, 132.9, 132.7, 131.3, 81.7, 62.3, 37.5, 28.3, 26.9,
24.9; m/z (ES): 219.0 (M–Cl−).
Imidazolidinone hydrochloride salt (0.1 mmol, 5 mol%) was
(2R,5S)-5-Benzyl-2-(4-methoxyphenyl)-2,3-dimethylimidazoli- dissolved in a 19 : 1 methanol–water mixture (2 mL). The flask
din-4-one hydrochloride 20·HCl. mp 117–119 °C; [α]3D0 = +36.0 was placed into a 25 °C oil bath. The appropriate aldehyde
(c 0.1, CH3OH); νmax (NaCl disk)/cm−1 3418, 1715, 1608; 13C (2.0 mmol) was added and the mixture was stirred for
NMR (125 MHz, CD3OD) δC 165.8, 160.1, 133.4, 127.3, 127.1, 10 minutes before freshly distilled cyclopentadiene (420 µL,
126.3, 125.8, 123.6, 113.1, 78.5, 55.4, 53.1, 32.4, 23.9, 20.1; 5.0 mmol) was added in one portion. The reaction mixture was
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stirred for 6 h and then the volatiles were removed under δ 9.92 (1H, d, J = 2.1 Hz, CHO), 7.10–7.06 (2H, m), 6.83–6.79
reduced pressure. The residue was taken up into chloroform (2H, m), 6.35 (1H, dd, J = 5.6, 3.2 Hz), 6.08 (1H, dd, J =
(10 mL) and water (10 mL) and the aqueous layer was extracted 5.6, 2.9 Hz), 3.78 (3H, s), 3.67 (1H, dd, J = 5.1, 3.7 Hz),
with chloroform (2 × 10 mL). The combined organics were 3.22 (1H, s), 3.18 (1H, s), 2.56–2.53 (1H, m), 1.64–1.60 (1H, m),
dried over sodium sulfate and the solvent was removed under 1.58–1.54 (1H, m); endo 1H NMR (500 MHz, CDCl3) δ 9.59
reduced pressure. Chloroform (2 mL), water (1 mL) and TFA (1H, d, J = 2.3 Hz, CHO), 7.22–7.18 (2H, m), 6.88–6.84 (2H, m),
(1 mL) were added and the biphasic mixture was vigorously 6.42 (1H, dd, J = 5.6, 3.2 Hz), 6.17 (1H, dd, J = 5.6, 2.8 Hz),
stirred for 2 hours. Potassium carbonate (20 mL) was added 3.80 (3H, s), 3.33 (1H, s), 3.08 (1H, s), 3.04 (1H, d, J =
and the mixture was extracted with chloroform (3 × 10 mL). 4.5 Hz), 2.96–2.93 (1H, m), 1.80 (1H, app. d, J = 8.7 Hz),
The combined organics were dried over sodium sulfate and 1.64–1.60 (1H, m); endo–exo mixture 13C NMR (126 MHz,
the solvent was removed under reduced pressure. The products CDCl3) δ 203.8, 203.0, 158.3, 158.1, 139.4, 136.7, 136.4, 135.7,
were isolated using flash chromatography (10% ethyl acetate 134.8, 133.8, 128.9, 128.4, 114.1, 113.7, 61.0, 59.8, 55.4, 55.4,
in petroleum ether) as oils.
48.8, 48.7, 47.7, 47.2, 45.6, 45.2, 45.2, 44.9; due to fragmenta-
tion, mass spectrometric analysis of the parent aldehydes
was not possible; m/z of corresponding alcohols (CI): 231.1
(M + H+).
Monitoring Diels–Alder cycloaddition between
cinnamaldehyde and cyclopentadiene (Fig. 5)
Secondary amine salt (0.25 mmol, 5 mol%) was dissolved in
endo-3-(4-Methylphenyl)bicyclo[2.2.1]hept-5-ene-2-carbaldehyde
methanol (4.75 mL) and water (0.25 mL). The mixture was and exo-3-(4-methylphenyl)bicyclo[2.2.1]hept-5-ene-2-carbalde-
stirred at 25 °C. After 5 minutes, cinnamaldehyde (630 µL, hyde Table 3 entry 2. endo–exo mixture νmax (film)/cm−1: 2968,
5 mmol) was added. After another 10 minutes, freshly distilled 2941, 2918, 2874, 2912, 2710, 1715; exo: 1H NMR (500 MHz,
cyclopentadiene (1020 µL, 12.5 mmol) was added and the reac- CDCl3) δ 9.92 (1H, d, J = 2.1 Hz, CHO), 7.09–7.03 (4H, m), 6.34
tion timer started. 100 µL aliquots were periodically removed (1H, dd, J = 5.7, 3.2 Hz), 6.08 (1H, dd, J = 5.7, 2.9 Hz), 3.69 (1H,
and concentrated under reduced pressure (25 °C, 15 torr, dd, J = 5.2, 3.2 Hz), 3.24–3.19 (2H, m), 2.57 (1H, app. dt, J =
10 minutes). Water (5 mL) was added and extracted with 5.2, 1.8 Hz), 2.31 (3H, s), 1.64–1.53 (2H, m); endo: 1H NMR
diethyl ether (3 × 5 mL). The combined organics were concen- (500 MHz, CDCl3) δ 9.60 (1H, d, J = 2.3 Hz), 7.20–7.11 (4H, m),
trated under reduced pressure. Chloroform (2 mL) was added 6.42 (1H, dd, J = 5.6, 3.2 Hz), 6.17 (1H, dd, J = 5.6, 2.8 Hz), 3.33
followed by a mixture of TFA–water 1 : 1 (2 mL). The biphasic (1H, s), 3.10 (1H, s), 3.05 (1H, d, J = 4.6 Hz), 2.98–2.95 (1H, m),
mixture was vigorously stirred for 2 h. The reaction was 2.33 (3H, s), 1.81 (1H, app. d, J = 8.7 Hz), 1.64–1.53 (1H, m);
quenched with saturated sodium carbonate solution (5 mL) endo–exo mixture: 13C NMR (126 MHz, CDCl3) δ 203.7, 203.0,
and extracted with diethyl ether (3 × 5 mL). The combined 140.6, 139.7, 139.3, 136.7, 136.4, 136.0, 135.9, 133.9, 129.4,
organics were dried over magnesium sulfate and the solvent 129.0, 127.9, 127.4, 60.9, 59.6, 48.7, 48.5, 47.7, 47.2, 45.6, 45.5,
was removed under reduced pressure to give a yellow oil. 45.2, 21.0; due to fragmentation, mass spectrometric analysis
1H NMR (CDCl3) was used to assess reaction conversion from of the parent aldehydes was not possible; m/z of corresponding
the CHO resonances: exo 9.93 ppm (1H, d, J = 2.0 Hz, CHO), alcohol (CI): 215.1 (M + H+).
cinnamaldehyde 9.71 ppm (1H, d, J = 7.7 Hz, CHO) and endo
endo-3-(4-Chlorophenyl)bicyclo[2.2.1]hept-5-ene-2-carbaldehyde
9.60 ppm (1H, d, J = 2.2 Hz, CHO). The Diels–Alder adducts and exo-3-(4-chlorophenyl)bicyclo[2.2.1]hept-5-ene-2-carbalde-
can be isolated by flash chromatography (20% ethyl acetate in hyde Table 3 entry 3. endo–exo mixture νmax (film)/cm−1: 3061,
1
petroleum ether) to give a pale yellow viscous oil.
2970, 2872, 2810, 2712, 1715; exo: H NMR (500 MHz, CDCl3)
endo-3-Phenylbicyclo[2.2.1]hept-5-ene-2-carbaldehyde 26 and δ 9.91 (1H, d, J = 1.8 Hz, CHO), 7.24–7.20 (2H, m), 7.10–7.06
exo-3-phenylbicyclo[2.2.1]hept-5-ene-2-carbaldehyde 27. endo– (2H, m), 6.36 (1H, dd, J = 5.6, 3.2 Hz), 6.06 (1H, dd, J = 5.6,
exo mixture νmax (film)/cm−1 3414, 2972, 1717; exo 1H NMR 2.9 Hz), 3.71 (1H, dd, J = 5.1, 3.6 Hz), 3.26–3.22 (1H, m), 3.19
(500 MHz, CDCl3) δ 9.93 (1H, d, J = 2.0 Hz), 7.41–7.12 (5H, m), (1H, br. s), 2.52–2.55 (1H, m), 1.62–1.56 (2H, m); endo: 1H
6.35 (1H, dd, J = 5.5, 3.5 Hz), 6.09 (1H, dd, J = 5.5, 2.9 Hz), NMR (500 MHz, CDCl3) δ 9.60 (1H, d, J = 2.1 Hz), 7.30–7.26
3.77–3.72 (1H, m), 3.26–3.21 (2H, m), 2.62–2.58 (1H, m), (2H, m), 7.22–7.19 (2H, m), 6.42 (1H, dd, J = 5.7, 3.2 Hz), 6.18
1.66–1.55 (2H, m); endo 1H NMR (500 MHz, CDCl3) δ 9.61 (1H, (1H, dd, J = 5.7, 2.8 Hz), 3.36 (1H, s), 3.12–3.08 (1H, m), 3.07
d, J = 2.2 Hz), 7.38–7.11 (5H, m), 6.43 (1H, dd, J = 5.6, 3.2 Hz), (1H, d, J = 4.1 Hz), 2.95–2.90 (1H, m), 1.77 (1H, app. d, J =
6.19 (1H, dd, J = 5.6, 2.8 Hz), 3.35 (1H, br. s), 3.16–3.09 (1H, 8.7 Hz), 1.67–1.63 (1H, m); endo–exo mixture: 13C NMR
m), 3.03–2.96 (1H, m), 1.60–1.55 (2H, m); endo–exo mixture (126 MHz, CDCl3) δ 203.1, 202.4, 142.2, 141.2, 139.3, 136.6,
13C NMR (126 MHz, CDCl3) δ 203.4, 202.8, 143.6, 142.7, 139.3, 136.4, 133.9, 132.2, 132.1, 129.3, 128.8, 128.8, 128.3, 61.1, 59.7,
136.6, 136.4, 133.9, 128.7, 128.2, 127.9, 127.4, 126.4, 126.3, 48.5, 48.4, 47.7, 47.2, 45.6, 45.2, 45.2, 44.9; m/z (EI): 232.0 (M+);
60.9, 59.5, 48.5, 48.4, 47.6, 47.2, 45.8, 45.5, 45.5, 45.2; m/z (EI): HRMS (EI) calculated for C14H13OCl35 232.0649 (M+), found
198.1 (M+).
232.0652.
endo-3-(4-Methoxyphenyl)bicyclo[2.2.1]hept-5-ene-2-carbaldehyde
endo-3-(4-Nitrophenyl)bicyclo[2.2.1]hept-5-ene-2-carbaldehyde
and
exo-3-(4-methoxyphenyl)bicyclo[2.2.1]hept-5-ene-2-carb- and exo-3-(4-nitrophenyl)bicyclo[2.2.1]hept-5-ene-2-carbalde-
aldehyde Table 3 entry 1. endo–exo mixture νmax (film)/cm−1
:
hyde Table 3 entry 4. endo–exo mixture νmax (film)/cm−1: 3063,
1
1
2965, 2934, 2907, 2833, 1712; exo H NMR (500 MHz, CDCl3) 2972, 2943, 2872, 2818, 2717, 1713, 1514, 1342; exo: H NMR
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(500 MHz, CDCl3) δ 9.90 (1H, d, J = 1.4 Hz, CHO), 8.07 (2H, d, pressure (100 mbar, 25 °C). Water (20 mL) and diethyl ether
J = 8.7 Hz), 7.28 (2H, d, J = 8.7 Hz), 6.39 (1H, dd, J = 5.6, (20 mL) were added to the residue and the aqueous layer
3.2 Hz), 6.03 (1H, dd, J = 5.6, 2.8 Hz), 3.88–3.84 (1H, m), 3.28 extracted with diethyl ether (2 × 20 mL). The organics were
(1H, s), 3.24 (1H, s), 2.61 (1H, app. d, J = 5.1 Hz), 1.59 (2H, br. dried over sodium sulfate and the solvent removed under
1
s); endo: H NMR (500 MHz, CDCl3) δ 9.62 (1H, d, J = 1.4 Hz, reduced pressure (100 mbar, 25 °C). Chloroform (4 mL) was
CHO), 8.13 (2H, d, J = 8.6 Hz), 7.41 (2H, d, J = 8.6 Hz), 6.42 added to the residue followed by a 1 : 1 water and TFA mixture
(1H, dd, J = 0.6, 3.3 Hz), 6.18 (1H, dd, J = 5.6, 3.0 Hz), 3.41 (1H, (4 mL). The biphase was vigorously stirred for 2 hours. The
s), 3.19 (1H, d, J = 4.9 Hz), 3.17 (1H, s), 2.96–2.93 (1H, m), reaction was then quenched with saturated sodium carbonate
1.77–1.66 (2H, m); endo–exo mixture: 13C NMR (126 MHz, solution and the aqueous layer extracted with diethyl ether
CDCl3) δ 202.2, 201.6, 151.7, 150.7, 146.6, 146.5, 139.1, 137.1, (3 × 20 mL). The combined organics were dried over sodium
136.1, 134.1, 128.8, 128.3, 123.9, 123.4, 61.2, 59.6, 48.5, 48.0, sulfate and the solvent removed under reduced pressure
47.7, 47.2, 45.7, 45.6, 45.2, 45.1; due to fragmentation, (100 mbar, 25 °C). The product was isolated by flash chromato-
mass spectrometric analysis of the parent aldehydes was graphy (5% diethyl ether in petroleum ether) to give a colour-
not possible; m/z of corresponding alcohol (CI): 246.1 less oil. νmax (ATR)/cm−1:2957, 2911, 2895, 2870, 1701; exo
(M + H+).
1H NMR (400 MHz, CDCl3) δ 9.78 (1H, d, J = 2.6 Hz, CHO), 6.19
endo-3-Propylbicyclo[2.2.1]hept-5-ene-2-carbaldehyde
and (1H, dd, J = 5.6, 3.1 Hz), 6.15 (1H, dd, J = 5.6, 2.8 Hz),
exo-3-propylbicyclo[2.2.1]hept-5-ene-2-carbaldehyde Table
3
3.04–3.00 (1H, m), 2.96 (1H, s), 1.92–1.84 (2H, m), 1.51–1.40
entry 5. Secondary amine salt (0.1 mmol, 1 mol%) was dis- (2H, m), 1.08–0.97 (1H, m), 0.94 (3H, d, J = 6.2 Hz), 0.84 (3H,
1
solved in methanol (9.5 mL) and water (0.5 mL). The mixture d, J = 6.4 Hz); endo H NMR (400 MHz, CDCl3) δ 9.36 (1H, d,
was stirred at 25 °C. trans-2-Hexenal (1.16 mL, 10 mmol) was J = 3.4 Hz, CHO), 6.26 (1H, dd, J = 5.7, 3.3 Hz), 6.06 (1H, dd, J =
added and the mixture stirred for 10 minutes before freshly 5.7, 2.8 Hz), 3.11 (1H, s, CH), 2.87–2.83 (1H, m), 2.51–2.47 (1H,
distilled cyclopentadiene (2.00 mL, 25 mmol) was added. After m), 1.51–1.39 (1H, m), 1.34–1.29 (1H, m), 1.01 (1H, d, J =
18 h the solvent was removed under reduced pressure 6.5 Hz), 0.91 (1H, d, J = 6.6 Hz); endo–exo mixture 13C NMR
(100 mbar, 25 °C). Water (20 mL) and diethyl ether (20 mL) (101 MHz, CDCl3) δ 205.4, 204.3, 139.1, 136.4, 135.9, 133.2,
were added to the residue and the aqueous layer extracted with 58.8, 58.1, 50.4, 50.2, 47.0, 46.6, 45.3, 45.3, 45.1, 45.1, 32.9,
diethyl ether (2 × 20 mL). The organics were dried over sodium 32.6, 22.1, 22.1, 21.9, 21.6; m/z (CI): 181 (M+ + CH5), 163
sulfate and the solvent removed under reduced pressure (M–H−).
(100 mbar, 25 °C). Chloroform (4 mL) was added to the
residue followed by a 1 : 1 water and TFA mixture (4 mL). The
biphase was vigorously stirred for 2 hours. The reaction was
then quenched with saturated sodium carbonate solution and
General procedure for monitoring reaction between
cinnamaldehyde and N-methyl pyrrole
the aqueous layer extracted with diethyl ether (3 × 20 mL). The
(S)-3-(1-Methyl-1H-pyrrol-2-yl)-3-phenylpropan-1-ol. Second-
combined organics were dried over sodium sulfate and the ary amine salt (10 mol%, 0.21 mmol) was dissolved in THF
solvent removed under reduced pressure (100 mbar, 25 °C). (4 mL) and water (0.6 mL). The mixture was stirred at 25 °C
The product was isolated by flash chromatography (5% diethyl and after 5 minutes cinnamaldehyde (250 µL, 2 mmol) was
ether in petroleum ether) to give a colourless oil. νmax (ATR)/ added. Stirring was continued for 10 minutes before N-methyl
1
cm−1: 2957, 2918, 2870, 1717; exo H NMR (400 MHz, CDCl3) pyrrole (530 µL, 5.97 mmol) was added in one portion. Ali-
δ 9.77 (1H, d, J = 2.7 Hz, CHO, 6.20 (1H, dd, J = 5.6, 3.1 Hz), quots (100 µL) were periodically taken and added to a mixture
6.13 (1H, dd, J = 5.6, 2.9 Hz), 3.01 (1H, s, J = 1.3 Hz), 2.87 (1H, of sodium borohydride (5 mg, 0.13 mmol) in ethanol (1 mL).
s), 2.32–2.24 (1H, m), 1.77–1.73 (1H, m), 1.55–1.04 (6H, m), After 15 minutes the reduction was quenched with saturated
1
0.90 (3H, t, J = 7.1 Hz); endo H NMR (400 MHz, CDCl3) δ 9.36 sodium bicarbonate solution (5 mL) and extracted with
(1H, d, J = 3.4 Hz), 6.27 (1H, dd, J = 5.7, 3.2 Hz), 6.05 (1H, dd, dichloromethane (2 × 10 mL). The organics were dried over
J = 5.7, 2.8 Hz), 3.11 (1H, s), 2.66 (1H, d, J = 1.5 Hz), 2.37 (1H, sodium sulfate and the solvent removed under reduced
1
dd, J = 7.8, 3.4 Hz), 1.71–1.65 (1H, m), 1.56–1.03 (6H, m), 0.90 pressure. The residue was analysed by H NMR to determine
(3H, t, J = 7.1 Hz). endo and exo mixture: 13C NMR (101 MHz, reaction conversion using resonances: 4.33 ppm (2H, dd,
CDCl3) δ 205.2, 204.1, 138.9, 136.2, 136.2, 132.9, 60.2, 58.9, CH2OH) from cinnamyl alcohol and 4.15 (1H, t, PhCH) from
47.4, 47.2, 46.6, 45.2, 42.1, 38.2, 36.6, 21.8, 21.7, 14.3; m/z (CI): the product. The product was isolated using flash chromato-
181 (M+ + CH5), 163 (M–H−).
graphy (16% ethyl acetate in petroleum ether) as a colourless
endo-3-Isopropylbicyclo[2.2.1]hept-5-ene-2-carbaldehyde and oil. νmax (ATR)/cm−1 3246, 2965, 2930, 2864; 1H NMR
exo-3-isopropylbicyclo[2.2.1]hept-5-ene-2-carbaldehyde Table 3 (500 MHz, CDCl3) δ 7.34–7.28 (2H, m, CH), 7.24–7.17 (3H, m,
entry 6. Secondary amine salt (0.1 mmol, 1 mol%) was dis- CH), 6.58–6.54 (1H, m, CH), 6.20–6.14 (2H, m, CH), 4.15 (1H,
solved in methanol (9.5 mL) and water (0.5 mL). The mixture app. t, J = 7.6 Hz, PhCH), 3.74–3.57 (2H, m, CH2OH), 3.32 (3H,
was stirred at 25 °C. trans-4-Methyl-2-hexenal (1.16 mL, s, NCH3), 2.42–2.31 (1H, m, CHH), 2.17–2.07 (1H, m, CHH),
10 mmol) was added and the mixture stirred for 10 minutes 1.78 (1H, s, OH); 13C NMR (126 MHz, CDCl3) δ 143.6, 135.0,
before freshly distilled cyclopentadiene (2.00 mL, 25 mmol) 128.6, 128.0, 126.4, 121.9, 106.4, 105.8, 60.6, 39.5, 39.0, 33.9;
was added. After 18 h the solvent was removed under reduced m/z (ES): 216.0 (M + H+).
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11 J. B. Brazier, K. M. Jones, J. A. Platts and
N. C. O. Tomkinson, Angew. Chem., Int. Ed., 2011, 50,
1613.
Acknowledgements
The authors thank EPSRC for financial support and the
National Mass Spectrometry Facility, Swansea, U.K., for high- 12 W. P. Jencks, Catalysis in Chemistry and Enzymology,
resolution spectra.
McGraw Hill Text, New York, 1969.
13 For a review on the use of imidazolidinone catalysts see:
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