Preparation of the MacMillan imidazolidinones

Article abstract of DOI:10.1016/j.tet.2011.04.009

A general method for the preparation of the MacMillan imidazolidinones is described. Treatment of an α-amino amide with a carbonyl compound in refluxing chloroform in the presence of Yb(OTf)₃ (1 mol %) provides convenient access to the corresponding imidazolidinones.

Full text of DOI:10.1016/j.tet.2011.04.009

Tetrahedron 67 (2011) 4263e4267
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Preparation of the MacMillan imidazolidinones
*
Leopold Samulis, Nicholas C.O. Tomkinson
School of Chemistry, Main Building, Cardiff University, Park Place, Cardiff CF10 3AT, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A general method for the preparation of the MacMillan imidazolidinones is described. Treatment of an a-
Received 16 December 2010
Received in revised form 18 March 2011
Accepted 4 April 2011
amino amide with a carbonyl compound in refluxing chloroform in the presence of Yb(OTf)3 (1 mol %)
provides convenient access to the corresponding imidazolidinones.
Ó 2011 Elsevier Ltd. All rights reserved.
Available online 9 April 2011
1. Introduction
for reactions of a,b-unsaturated ketones that proceed via iminium
ion intermediates, expanding the substrate scope of known trans-
formations to encompass this important functionality.11 Trypto-
phan based catalysts (e.g., 4 and 5) provide a similar reactivity
profile to the phenylalanine derived catalysts and in certain cases
have resulted in higher levels of enantioselectivity.12 More recently,
the imidazolidinones 6 and 7 have been introduced for SOMO
catalysed transformations.13
Literature methods for the preparation of the imidazolidinones
1e3 are outlined in Scheme 1. Catalyst 1 is made by condensation of
acetone (9) with amide 8 using p-toluene sulfonic acid as the cat-
alyst.3 It has been reported that with alternative ketone and alde-
hyde substrates, Brønsted acid catalysed methods and elevated
temperatures lead to racemisation, limiting the applicability of this
method.14 For the alternative imidazolidinones it is necessary to
use Lewis acid catalysis. The pivaldehyde derived catalyst 2 is
Over the past decade imidazolidinones have been shown to
provide an efficient platform for the acceleration of iminium ion,
enamine and SOMO catalysed processes.1,2 From this privileged
structure seven principal imidazolidinone catalysts have been
reported (1e7) (Fig. 1).
Catalyst 1 is used for cycloaddition3 and closed transition state
conjugate addition reactions4 of
a
,b
-unsaturated aldehydes along
with several enamine catalysed processes.5,6 Catalyst 2 is the most
broad ranging scaffold and is effective for cycloaddition,7 conjugate
addition,8 enamine9 and SOMO10,13a catalysis. Catalyst 3 is efficient
O
O
O
N
N
N
N
H
N
H
N
H
O
Ph
Ph
Ph
1
2
3
O
O
H
Bn
N
p-TsOH, MeOH
O
N
O
O
N
O
Bn
Bn
+
+
N
H
N
N
Bn
Bn
,
18 h
N
H
NH2
N
H
N
H
8
9
1
4
5
O
O
O
N
FeCl3, 4Å MS
THF, r.t., 36 h
O
O
N
H
t
N
N
N
H
H
O
Bu
NH2
N
H
N
8
10
23%
2
H
6
7
O
Sm(OTf)3, 4Å MS
THF, r.t., 29 h
N
Bn
Fig. 1. Principal imidazolidinone catalysts for iminium ion, enamine and SOMO cata-
lysed transformations.
+
O
N
H
H
Bn
N
H
NH2
O
8
11
3
46%
* Corresponding author. Tel.: þ44 (0) 2920874068; fax: þ44 (0) 2920874030;
Scheme 1. Literature methods for the synthesis of 1e3.
e-mail address: tomkinsonnc@cardiff.ac.uk (N.C.O. Tomkinson).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.009

4264
L. Samulis, N.C.O. Tomkinson / Tetrahedron 67 (2011) 4263e4267
prepared from the same amide 8 using iron(III) chloride as the
Lewis acid (23%).8b The furan containing catalyst 3 is far more
challenging to prepare using air sensitive samarium(III) triflate,
freshly distilled aldehyde 11 and glove box techniques.11a Alterna-
tive methods for the preparation of imidazolidinones are available,
the most broad ranging being the two-step procedure developed by
Seebach.15
not required to access target material analytically pure. In addition
to the phenylalanine based catalysts, tryptophan derived systems
(e.g., 4, 26%; 5, 26%) were also accessible suggesting the method
should be applicable to alternative amino acid scaffolds with equal
efficiency. This was further exemplified by preparation of the ala-
nine and glycine derived imidazolidinones 6 (77%) and 7 (55%),
which have recently been used for SOMO catalysis.10,13a
Given the importance of 1e7 and the possibility that further
structural modification may lead to innovation and discovery we
sought to develop a standard, robust method for their preparation.
Within this paper we describe a simple and scalable protocol for
the preparation of the imidazolidinone architecture.
Confirmation of ee for the imidazolidinones 1e6 came from
their preparation using racemic amino amide starting materials
and comparison of HPLC traces (see Supplementary data for full
details). In each case, the ee was found to be >99%, showing this to
be a viable method for the preparation of imidazolidinones from
a
variety of amino acid and carbonyl substrates without
racemisation.
2. Results and discussion
Finally, to confirm the robust nature of this method the second
generation catalyst 2 was prepared from 5 g of amide 8. Thus,
imidazolidinone 2 was prepared in 22% yield and >99% ee (together
with the recyclable diastereoisomer 12; 46%) suggesting the
method should be scalable (Scheme 3).
Our investigations began with a broad survey of both Lewis and
Brønsted acid catalysts to promote the formation of imidazolidinone
2 using conductive and microwave heating. From these screens the
optimal method emerged to be that shown in Scheme 2. Treatment
of amide 8 with 2 equiv of pivaldehyde (10) in the presence of
Yb(OTf)3 (1 mol %) gave the diastereomeric imidazolidinones 2 and
12 in approximately a 1:2 ratio. These diastereoisomers could easily
be separated by chromatography to give the desired catalyst 2 (22%,
>99% ee). Recycling of the undesired diastereoisomer 12 was also
O
Yb(OTf)3 (1 mol%)
O
10 (2 equiv)
N
Bn
N
H
Bn
Δ
,
CHCl3,
N
H
NH2
8 h
8
2
possible (1 mol % Yb(OTf)3, CHCl3,
D), providing 2 with a small loss of
enantiopurity (26%, 98% ee).16
1.3 g (22%)
5.0 g
Scheme 3. Scale up of imidazolidinone synthesis.
O
N
Bn
Bn
N
H
3. Conclusion
O
Yb(OTf)3 (1 mol%)
Yb(OTf)3
CHCl3,
10 (2 equiv)
Bn
2 (22%)
N
H
In summary, we have developed a standard method for syn-
thesis of the principal MacMillan imidazolidinones 1e7 that have
demonstrated widespread use in LUMO, HOMO and SOMO accel-
erated transformations. The reactions are scalable and proceed
without loss of optical purity. In certain cases, the current method
offers distinct operational advantages over literature procedures
and importantly, provides a standard protocol to prepare the
structures. The methodology should be applicable to alternative
carbonyl substrates and provide opportunity to diversify the known
scaffolds, providing the impetus for further development in this
exciting and important area of contemporary research.
, 8 h
Δ
O
CHCl3,
NH2
Δ
,
N
8 h
(26%)
8
N
H
12 (46%)
Scheme 2. Standard method for the synthesis of 2.
Application of this standard method to alternative imidazolidi-
nones architectures (1 and 3e7) is summarised in Table 1. The first
generation catalyst 1 was effectively prepared by this method in
96% isolated yield (>99% ee). The synthetically more challenging
furan containing catalyst 3 was also accessed by this method (32%;
>99% ee). Although this yield is lower than the literature report,
glove box techniques and distillation of aldehyde precursor were
4. Experimental section
4.1. General
Table 1
Application of imidazolidinone synthesisa
Commercially available solvents and reagents were used with-
out further purification. Petroleum ether refers to the fraction with
bp 40e60 ꢀC and ether refers to diethyl ether. Flash chromatogra-
phy was carried out using Merck Kieselgel 60H silica or Matrex
silica 60. Analytical thin layer chromatography was carried out
using aluminium-backed plates coated with Merck Kieselgel
60 GF254 that were visualised under UV light (at 254 and/or
360 nm). Infra-red (IR) spectra were recorded in the range
4000e600 cmꢁ1 using KBr disks for solid samples and thin films
between NaCl plates for liquid samples or as a Nujol mull and are
reported in cmꢁ1. Nuclear magnetic resonance (NMR) spectra were
recorded in CDCl3 at 18 ꢀC and were reported in parts per million; J
values were recorded in Hertz and multiplicities were expressed by
the usual conventions. Low-resolution mass spectra (MS) were
determined using electrospray ionization (ES) unless otherwise
stated. APCI refers to atmospheric pressure chemical ionization, CI
refers to chemical ionization (ammonia) and EI refers to electron
ionization. High-resolution mass spectra were obtained courtesy of
the EPSRC Mass Spectrometry Service at University of Wales,
O
O
O
N
Yb(OTf)3 (1 mol%)
R2
R3
R1
N
H
+
R2
R3
CHCl3, Δ, 8 h
N
H
NH2
R1
Imidazolidinone
R1
R2
R3
% Yield
eec
1
2
3
Ph
Ph
Ph
Me
tBu
Me
H
96
22
32
>99%
>99%
>99%
H
O
4
5
3-Indolyl
N-Bn-3-indolyl
H
d
tBu
tBu
H
H
26
26
77
55
>99%
>99%
>99%
d
H
6
tBu
H
7b
tBu
a
Standard reaction conditions: Yb(OTf)3 (1 mol %); CHCl3 (0.5 M);
Catalyst 7 prepared under standard reaction conditions from glycine N-methyl-
D
; 8 h.
b
amide and pivaldehyde as a racemic mixture.
c
Determined by HPLC on a chiral stationary phase. See Supplementary data for
full details.

L. Samulis, N.C.O. Tomkinson / Tetrahedron 67 (2011) 4263e4267
4265
25
Swansea, U.K. using the ionization methods specified. In vacuo re-
fers to evaporation at reduced pressure using a rotary evaporator
and diaphragm pump, followed by the removal of trace volatiles
using a vacuum (oil) pump.
solid (17.7 g, 43.4 mmol, 58%); mp 192e195 ꢀC; [
a]
þ4.6 (c 0.1,
D
CH2Cl2); nmax (NaCl disk)/cmꢁ1 1736, 1507, 1238, 734, 699; dH
(500 MHz, DMSO-d6) 8.81 (3H, s, NH3þ), 7.62 (1H, d, J 7.8, ArH), 7.42
(1H, d, J 7.1, ArH), 7.39 (1H, s, ArH), 7.31 (2H, t, J 7.5, ArH), 7.25 (1H, t, J
7.3, ArH), 7.21 (2H, d, J 7.0, ArH), 7.12 (1H, t, J 7.0, ArH), 7.05 (1H, t, J 7.0,
ArH), 5.39 (2H, t, J 16.5, PhCH2), 4.15 (1H, dd, J 7.9 and 5.4, COCH),
4.08e3.95 (2H, m, CH3CH2), 3.41 (1H, dd, J 14.6 and 5.2, CHCH2), 3.27
(1H, dd, J 14.6 and 7.9, CHCH2),1.00 (3H, t, J 7.1, CH2CH3); dC (125 MHz,
DMSO-d6) 169.8 (C), 138.6 (C), 136.5 (C), 128.9 (CH), 128.1 (C), 127.8
(CH), 127.5 (CH), 122.0 (CH), 119.4 (CH), 119.0 (CH), 110.7 (CH), 107.3
(C), 62.0 (CH2), 53.3 (CH), 49.5 (CH2), 26.7 (CH2),14.1 (CH3); m/z (EI):
323.2 (MþHþ); HRMS (ESþ): found MþHþ, 323.1758. C20H23N2O2
requires, 323.1760.
4.1.1. L L-Phenylalanine ethyl ester
-Phenylalanine N-methylamide3.
hydrochloride (100.8 g, 439 mmol) was stirred in a 33% w/w
ethanolic solution of methylamine (300 mL, 74.8 g, 2.41 mol) for
95 h. The solution was evaporated and the residue dissolved in
sodium hydrogen carbonate solution (saturated, 200 mL) then
extracted with chloroform (4ꢂ100 mL). The combined extracts
were dried over sodium carbonate and evaporated to give the crude
product, a white solid (52.4 g, 294 mmol, 67%). This was recrys-
tallised from ethyl acetate/hexanes (1:2, 600 mL) and dried in
vacuo to give the product as white crystals (42.7 g, 240 mmol, 55%);
4.1.4. 1-Benzyl- L-trypto-
-tryptophan N-methylamide19. 1-Benzyl-
L
mp 58e60 ꢀC [lit.17 mp 92e93 ꢀC]; [
a]
34 þ72.6 (c 0.1, CH2Cl2); nmax
phan ethyl ester hydrochloride (5.34 g, 14.9 mmol) was taken up in
potassium carbonate (4 M, 100 mL) and extracted with chloroform
(3ꢂ50 mL). The chloroform was evaporated and the residue was
stirred in an ethanolic methylamine solution (25 mL, 201 mmol) for
62 h then evaporated and dried to yield the desired product,
D
(NaCl disk)/cmꢁ1 3358, 1651, 1573, 1496, 1454, 1412; dH (500 MHz,
CDCl3) 7.33e7.21 (6H, m, ArH and NH), 3.61 (1H, dd, J 9.5 and 4.0,
COCH), 3.28 (1H, dd, J 13.7 and 4.0, CH2), 2.82 (3H, d, J 5.0, NCH3),
2.68 (1H, dd, J 13.7 and 9.5, CH2), 1.41 (2H, s, NH2); dC (125 MHz,
CDCl3) 174.8 (C), 138.0 (C), 129.3 (CH), 128.7 (CH), 126.8 (CH), 56.5
(CH), 41.1 (CH2), 25.8 (CH3); m/z (ESþ): 179.1 (MþHþ); HRMS (ESþ):
found MþHþ, 179.1181. C10H14N2O requires, 179.1184.
a cream solid (3.71 g, 12.1 mmol, 86%); mp 80e82 ꢀC; [
a
]
34 ꢁ51.8 (c
D
0.1, CH2Cl2); nmax (NaCl disk)/cmꢁ1 3362, 3059, 2935, 1655, 1537,
1467, 1333, 1178; dH (500 MHz, CDCl3) 7.55 (1H, d, J 7.9, ArH),
7.17e6.93 (9H, m, ArH), 6.83 (1H, s, ArH), 5.07 (2H, s, PhCH2), 3.54
(1H, dd, J 8.8 and 4.2, COCH), 3.22 (1H, dd, J 14.5 and 3.7, CHCH2),
2.78 (1H, dd, J 14.5 and 8.8, CHCH2), 2.62 (3H, d, J 5.0, CH3), 1.33 (2H,
br s, NH2); dC (125 MHz, CDCl3) 175.5 (C), 137.6 (C), 136.9 (C), 128.8
(CH), 128.4 (C), 127.7 (CH), 127.2 (CH), 126.9 (CH), 122.1 (CH), 119.4
(CH), 119.3 (CH), 111.1 (C), 109.9 (CH), 55.8 (CH), 49.9 (CH2), 30.9
(CH2), 25.9 (CH3); m/z (ESþ): 308.2 (MþHþ); HRMS (ESþ): found
MþHþ, 308.1756. C19H22N3O1 requires, 308.1763.
4.1.2.
16.3 g, 134 mmol) was added dropwise to ethanol (130 mL). The
solution was cooled to room temperature before -tryptophan
L
-Tryptophan N-methylamide18. Thionyl chloride (10.0 mL,
L
(9.7 g, 47.6 mmol) was added and the mixture stirred for 24 h then
evaporated. The residue was washed with ethyl acetate (1ꢂ300 mL,
1ꢂ100 mL) and petroleum ether (ca. 100 mL) then dried to yield
a cream solid. The solid was stirred in an ethanolic solution of
methylamine (70 mL, 560 mmol) for 120 h then evaporated, taken
up in sodium bicarbonate (saturated, 100 mL) and extracted with
chloroform (4ꢂ40 mL). The combined chloroform extract was dried
over sodium carbonate and evaporated to yield the desired product,
4.1.5. L . L-Alanine ethyl ester hydrochlo-
-Alanine N-methylamide20
ride (8.1 g, 52.4 mmol) was stirred in an ethanolic methylamine
solution (36 mL, 289 mmol) for 97 h then evaporated. The residue
was taken up in potassium carbonate (4 M, 30 mL) and sodium
bicarbonate (saturated, 20 mL) then extracted with chloroform
(5ꢂ25 mL), which was dried over sodium carbonate and evapo-
a yellow solid (6.1 g, 28 mmol, 59%); mp 123e125 ꢀC; [
a]
34 þ32.0 (c
D
0.1, CH3OH); nmax (NaCl disk)/cmꢁ1 3282, 1650, 1537, 1457, 1411,
1342, 1232, 1101; dH (500 MHz, DMSO-d6) 10.89 (1H, br s, NH),
7.84e7.83 (1H, m, NH), 7.57 (1H, d, J 8.1, ArH), 7.36 (1H, d, J 2.2, ArH),
7.17 (1H, s, ArH), 7.07 (1H, ddd, J 7.0, 7.0 and 0.9, ArH), 6.98 (1H, ddd,
J 7.0, 7.0 and 0.9, ArH), 3.44 (1H, dd, J 8.1 and 4.9, COCH), 3.09 (1H,
dd, J 14.1 and 4.9, CH2), 2.77 (1H, dd, J 14.1 and 8.1, CH2), 2.60 (3H, d,
J 4.7, CH3), 1.70 (1H, br s, NH2); dC (125 MHz, DMSO-d6) 175.7 (C),
136.7 (C), 128.0 (C), 124.2 (CH), 121.3 (CH), 119.0 (CH), 118.7 (CH),
111.8 (CH), 111.3 (C), 56.0 (CH), 31.7 (CH2), 26.0 (CH3); m/z (ESþ):
218.1 (MþHþ); HRMS (ESþ): found MþHþ, 218.1285. C12H16N3O1
requires, 218.1293.
rated to yield crude L-Alanine N-methylamide, a red oil (3.62 g,
35.5 mmol, 68%). A solution of the free amine (1.9 g, 18.5 mmol) in
diethyl ether (200 mL) was treated with hydrogen chloride gas for
10 min before the product was removed by filtration and washed
with diethyl ether to yield the hydrochloride salt, a clear crystalline
solid (2.2 g, 16.0 mmol, 86%). This was further purified by recrys-
tallisation from ethanol and hexane; mp 213e215 ꢀC; [ 25 19.6 (c
a]
D
0.1, CH3OH); nmax (NaCl disk)/cmꢁ1 3408, 1674, 1514, 1417, 1275,
1169; dH (400 MHz, D2O) 3.85 (1H, q, J 7.1, CH), 2.60 (3H, s, NCH3),
1.32 (3H, d, J 7.1, CCH3); dC (100 MHz, D2O) 174.1 (C), 51.2 (CH), 28.5
4.1.3. 1-Benzyl-
L
-tryptophan ethyl ester hydrochloride19. Iron(III)
(CH3), 19.2 (CH3). L-Alanine N-methylamide hydrochloride (0.58 g,
nitrate nonahydrate (0.31 g, 0.78 mmol) was dissolved in liquid
ammonia (500 mL). Sodium (3.95 g, 172 mmol) was dissolved and
4.17 mmol) and sodium carbonate (0.56 g, 5.30 mmol) were stirred
in ethanol (40 mL) at 60 ꢀC for 1 min, then cooled to room tem-
34
the ammonia was kept at reflux for 1 h before
L-tryptophan (15.4 g,
perature, filtered and evaporated to yield the desired product; [a]
D
75.4 mmol) was added, along with anhydrous diethyl ether (10 mL).
The reaction was refluxed for 60 min and benzyl chloride was added
dropwise (12.0 mL,13.2 g,104 mmol). The reaction mixturewas then
allowedto evaporateslowlyovernight and quenched bythe addition
of water (600 mL) then heated to precipitate a solid, which was re-
moved by filtration. The filtrate was treated with glacial acetic acid
(65 mL), cooled to around 10 ꢀC and the resultant white precipitate
filtered, washed with water (500 mL), ethanol (200 mL) and
40e60 ꢀC petroleum ether (200 mL) then dried in vacuo. It was then
refluxed for 23 h in an ethanolic solution of hydrogen chloride
formed by the cautious addition of thionyl chloride (30 mL) to eth-
anol (1.1 L). The solution was then evaporated and the residue
washed with 1:1 ethyl acetate/diethyl ether (300 mL) and copious
diethyl ether then dried to give the desired product, a fluffy white
þ2.0 (c 0.1, CH2Cl2); nmax (NaCl disk)/cmꢁ1 3364, 1646, 1575, 1456,
1413,1375,1318,1272,1160; dH (500 MHz, CDCl3) 7.29 (1H, br s, NH),
3.34 (1H, q, J 7.0, CH), 2.66 (3H, d, J 5.0, NCH3), 1.39 (2H, br s, NH2),
1.17 (3H, d, J 7.0, CHCH3); dC (125 MHz, CDCl3) 176.5 (C), 50.7 (CH),
25.7 (CH3), 21.6 (CH3); m/z (EIþ): 102.1 (Mþ); HRMS (EIþ): found
Mþ, 102.0788. C4H10N2O1 requires, 102.0793.
4.1.6. Glycine N-methylamide21. Glycine ethyl ester hydrochloride
(5.23 g, 37.5 mmol) was stirred in a 33% w/w ethanolic solution of
methylamine (25 mL, 6.24 g, 201 mmol) at 50 ꢀC for 30 min before
sodium hydroxide (1.61 g, 40.4 mmol) was added and stirring con-
tinued for 3 min. The mixture was evaporated to give a slurry then
extracted with ethyl acetate (2ꢂ50 mL), which was filtered and re-
moved in vacuo to yield the desired product, a clear oil (2.56 g,

4266
L. Samulis, N.C.O. Tomkinson / Tetrahedron 67 (2011) 4263e4267
29.1 mmol, 77%); nmax (NaCl disk)/cmꢁ1 3353, 3101, 2947,1659,1564,
1414,1312,1161; dH (500 MHz, DMSO-d6) 7.79 (1H, br s, CONH), 3.06
(2H, s, CH2), 2.61 (3H, d, J 4.7, CH3), 1.89 (2H, s, NH2); dC (125 MHz,
DMSO-d6) 173.9 (C), 45.3 (CH2), 25.7 (CH3); m/z (EIþ): 88.1 (Mþ);
HRMS (EIþ): found MþHþ, 88.0634. C3H8N2O1 requires, 88.0637.
ArH), 4.00 (1H, s, CH3CCH), 3.75e3.65 (1H, m, COCH), 3.34 (1H, dd, J
14.7 and 4.2, CH2), 3.15 (1H, dd, J 14.7 and 6.4, CH2), 2.88 (3H, s,
NCH3), 1.81 (1H, br s, NH), 0.70 (9H, s, CCH3); dC (125 MHz, CDCl3)
176.2 (C),136.3 (C),128.1 (C),123.2 (CH),122.1 (CH),119.6 (CH),118.9
(CH), 111.2 (C), 111.2 (CH), 82.6 (CH), 59.5 (CH), 34.7 (C), 30.7 (CH3),
27.1 (CH2), 25.3 (CH3); m/z (ESþ): 286.2 (MþHþ); HRMS (ESþ):
found MþHþ, 286.1925. C17H24N3O1 requires, 286.1919.
4.2. Standard procedure for imidazolidinone synthesis
Recrystallised amino amide (1 equiv), aldehyde/ketone (2 equiv)
and ytterbium trifluromethane sulfonate (0.01 equiv) were refluxed
in chloroform (10 mL/mmol amino amide) for 8 h after which time
the mixture was allowed to cool and the solvent evaporated. The
products were purified by column chromatography.
4.3.5. (2S,5S)-5-((1-Benzyl-1H-indol-3-yl)methyl)-2-tert-butyl-3-
methylimidazolidin-4-one 5. Colourless oil; Rf¼0.14 (ethyl acetate);
[a
]
30 ꢁ11.4 (c 0.1, CH3OH); nmax (NaCl disk)/cmꢁ1 2962, 1720, 1468,
D
1397,1262, 740; dH (500 MHz, CDCl3) 7.63 (1H, d, J 7.7, ArH), 7.21e7.14
(4H, m, ArH), 7.09 (1H, td, J 8.2 and 1.0, ArH), 7.05e7.02 (3H, m, ArH),
6.97 (1H, s, ArH), 5.17 (2H, s, PhCH2), 3.91 (1H, s, CH3CCH), 3.64 (1H, t,
J 4.9, COCH), 3.25 (1H, dd, J 14.7 and 4.2, CH2), 3.09 (1H, dd, J 14.7 and
6.3, CH2), 2.79 (3H, s, NCH3), 0.60 (9H, s, CCH3); dC (125 MHz, CDCl3)
176.2 (C), 137.6 (C), 136.6 (C), 128.8 (CH), 128.7 (C), 127.6 (CH), 127.3
(CH), 126.9 (CH), 121.9 (CH), 119.4 (CH), 119.2 (CH), 110.4 (C), 109.7
(CH), 82.6 (CH), 59.4 (CH), 50.0 (CH2), 34.6 (C), 30.6 (CH3), 26.9 (CH2),
25.3 (CH3); m/z (ESþ): 376.2 (MþHþ); HRMS (ESþ): found MþHþ,
376.2380. C24H30N3O1 requires, 376.2389.
4.3. Standard method for the isomerisation of trans-isomers
(2R,5S)-5-Benzyl-2-tert-butyl-3-methylimidazolidin-4-one(1.11g,
4.51mmol, 99%ee)andytterbiumtrifluoromethanesulfonate (0.028 g,
0.045 mmol) were refluxed in chloroform for 24 h. The reaction
mixture was evaporated, and the diastereoisomers separated via col-
umn chromatography to yield (2R,5S)-5-benzyl-2-tert-butyl-3-
methylimidazolidin-4-one (0.62 g, 2.52 mmol, 56%, 98% ee) and
(2S,5S)-5-benzyl-2-tert-butyl-3-methylimidazolidin-4-one (0.29 g,
1.18 mmol, 26%, 98% ee).
4.3.6. (2R,5S)-5-Methyl-2-tert-butyl-3-methylimidazolidin-4-one
6. Colourless oil; Rf¼0.16 (ethyl acetate); [
a
]
25 ꢁ1.8 (c 0.1, CH3OH);
D
nmax (NaCl disk)/cmꢁ1 3419, 2981, 1664, 1479, 1404; dH (500 MHz,
CD3OD) 4.92 (1H, s, CH3CCH), 4.29 (1H, q, J 7.1, COCH), 3.08 (3H, s,
NCH3), 1.58 (1H, d, J 7.1, CHCH3), 1.18 (9H, s, CHCCH3); dC (125 MHz,
CD3OD) 168.1 (C), 78.9 (CH), 51.9 (CH), 34.6 (C), 29.5 (CH3), 22.4
(CH3), 11.8 (CH3); m/z (APCI): 171.2 (MþHþ); HRMS (ESþ): found
MþHþ, 171.1492. C9H19N2O1 requires, 171.1497.
4.3.1. (S)-5-Benzyl-2,2,3-trimethylimidazolidin-4-one 13. Colourless
oil;Rf¼0.32 (ethyl acetate); [
a
]
30 ꢁ57.8 (c0.1, CH3OH) [lit.22
[
a
]
25 ꢁ48.7
D
D
(c 2.92, EtOH)]; nmax (NaCl disk)/cmꢁ1 3318, 2975, 1682, 1428, 1400,
1148,1090, 748, 702; dH (500 MHz, CDCl3) 7.24e7.14 (5H, m, ArH), 3.72
(1H, dd, J 6.8 and4.5, COCH), 3.07 (1H, dd, J 14.2and 4.5, CH2), 2.94(1H,
dd, J 14.2 and 6.8, CH2), 2.68 (1H, s, NCH3),1.19 (3H, s, CCH3),1.09 (3H, s,
CCH3); dC (125 MHz, CDCl3) 173.4 (C), 137.2 (C), 129.5 (CH), 128.6 (CH),
126.8 (CH), 75.5 (C), 59.3 (CH), 37.4 (CH2), 27.3 (CH3), 25.4 (CH3), 25.2
(CH3); m/z (ESþ): 219.1 (MþHþ); HRMS (ESþ): found MþHþ, 219.1492.
C13H19N2O1 requires, 219.1497.
4.3.7. 2-tert-Butyl-3-methylimidazolidin-4-one 724. Colourless oil;
Rf¼0.30 (ethyl acetate/methanol 4:1); nmax (NaCl disk)/cmꢁ1 3339,
2957,1694,1483,1432,1400,1322,1260; dH (500MHz, DMSO-d6)4.05
(1H, s, CH), 3.35 (1H, br s, NH), 3.21 (2H, s, CH2), 2.82 (3H, s, NCH3),
0.89 (9H, s, CCH3); dC (125 MHz, DMSO-d6) 174.6 (C), 84.5 (CH), 49.2
(CH2), 37.8(C), 31.1 (CH3), 25.9 (CH3);m/z (ESþ):157.1 (MþHþ);HRMS
(ESþ): found MþHþ, 157.1334. C8H17N2O1 requires, 157.1341.
4.3.2. (2S,5S)-5-Benzyl-2-tert-butyl-3-methylimidazolidin-4-one
28b. White solid; Rf¼0.22 (ethyl acetate/petroleum ether 3:1); mp
30
25
78e80 ꢀC; [
a
]
D
ꢁ48.6 (c 0.1, CH3OH) [lit.23
[
a
]
þ71.8 (CHCl3)];
D
nmax (NaCl disk)/cmꢁ1 3354, 2975, 1676, 1392, 1340, 1106; dH
(400 MHz, CDCl3) 7.24e7.14 (5H, m, ArH), 3.99 (1H, s, CH3NCH), 3.64
(1H, dd, J 7.1 and 3.8, COCH), 3.09 (1H, dd, J 13.7 and 4.0, CH2), 2.89
(1H, dd, J 13.7 and 7.6, CH2), 2.85 (3H, s, NCH3), 1.64 (1H, s, NH), 0.77
(9H, s, CCH3); dC (125 MHz, CDCl3) 175.2 (C), 137.9 (C), 129.6 (CH),
128.5 (CH), 126.6 (CH), 82.5 (CH), 59.4 (CH), 38.3 (CH2), 35.0 (C),
30.7 (CH3), 25.3 (CH3); m/z (ESþ): 247.2 (MþHþ); HRMS (ESþ):
found MþHþ, 247.1810. C15H23N2O1 requires, 247.1810.
4.3.8. (2R,5S)-5-Benzyl-2-tert-butyl-3-methylimidazolidin-4-one
128b. White solid; Rf¼0.36 (ethyl acetate/petroleum ether 3:1); mp
30
86e88 ꢀC; [
a
]
ꢁ51.2 (c 0.1, CH3OH); nmax (NaCl disk)/cmꢁ1 2956,
D
1691, 1454, 1397, 1104, 702; dH (500 MHz, CDCl3) 7.31e7.22 (5H, m,
ArH), 3.86e3.84 (1H, m, COCH), 3.81 (1H, s, (CH3)3CCH), 3.11 (1H, dd,
J 14.1 and 4.2, CH2), 2.92e2.89 (1H, m, CH2), 2.87 (3H, s, NCH3), 1.91
(1H, br s, NH), 0.90 (9H, s, CCH3); dC (125 MHz, CDCl3) 175.3 (C),137.5
(C), 129.5 (CH), 128.5 (CH), 126.7 (CH), 83.4 (CH), 59.5 (CH), 38.6
(CH2), 37.7 (C), 31.3 (CH3), 25.6 (CH3); m/z (ESþ): 247.2 (MþHþ);
HRMS (ESþ): found MþHþ, 247.1802. C15H23N2O1 requires, 247.1810.
4.3.3. (2S,5S)-5-Benzyl-3-methyl-2-(5-methylfuran-2-yl)imidazol-
idin-4-one 311a. Colourless oil; Rf¼0.22 (ethyl acetate); [
a
]
30 ꢁ151.0
D
(c 0.1, CH3OH); nmax (NaCl disk)/cmꢁ1 3331, 2920, 1694, 1454, 791,
702; dH (500 MHz, CDCl3) 7.20e7.11 (5H, m, PhH), 6.02 (1H, d, J 3.1,
OCCH), 5.80 (1H, d, J 3.1, OCCH), 5.09 (1H, s, ArCH), 3.68 (1H, dd, J
7.5 and 4.2, COCH), 3.15 (1H, dd, J 14.2 and 4.2, CH2), 2.99 (1H, dd, J
14.2 and 7.7, CH2), 2.54 (3H, s, NCH3), 2.11 (1H, br s, NH), 2.11 (3H, s,
ArCH3); dC (125 MHz, CDCl3) 173.7 (C), 153.3 (C), 148.7 (C), 137.2 (C),
129.4 (CH), 128.6 (CH), 126.7 (CH), 110.8 (CH), 106.4 (CH), 70.9 (CH),
60.1 (CH), 37.6 (CH2), 27.0 (CH3),13.5 (CH3); m/z (ESþ): 271.2 (MþHþ);
HRMS (ESþ): found MþHþ, 271.1444. C16H19N2O2 requires, 271.1447.
Acknowledgements
The authors thank the EPSRC for financial support, and the Mass
Spectrometry Service, Swansea for high-resolution spectra.
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2011.04.009.
4.3.4. (2S,5S)-5-((1H-Indol-3-yl)methyl)-2-tert-butyl-3-methyl-
imidazolidin-4-one 4. White solid; Rf¼0.15 (ethyl acetate); mp
References and notes
178e181 ꢀC; [
a
]
D
30 ꢁ85.8 (c 0.1, CH3OH); nmax (NaCl disk)/cmꢁ1 3299,
1. For an overview on the scope of imidazolidinone catalysts see: Lelais, G.;
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ArH), 7.69 (1H, d, J 7.8, ArH), 7.34 (1H, d, J 8.0, ArH), 7.18 (1H, td, J
7.6 and 0.8, ArH), 7.12 (1H, td, J 7.2 and 0.8, ArH), 7.08 (1H, d, J 2.2,

L. Samulis, N.C.O. Tomkinson / Tetrahedron 67 (2011) 4263e4267
4267
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