Cyclic carbonates as sustainable solvents for proline-catalysed aldol reactions

Article abstract of DOI:10.1016/j.tetasy.2010.03.051

Ethylene and propylene carbonates, which can be prepared from epoxides and carbon dioxide, are effective solvents for the proline-catalysed, 100% atom economical, asymmetric aldol reaction between enolisable and non-enolisable carbonyl compounds. The opti

Full text of DOI:10.1016/j.tetasy.2010.03.051

Tetrahedron: Asymmetry 21 (2010) 1262–1271
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Cyclic carbonates as sustainable solvents for proline-catalysed aldol reactions
*
William Clegg, Ross W. Harrington, Michael North , Francesca Pizzato, Pedro Villuendas
School of Chemistry and University Research Centre in Catalysis and Intensified Processing, Newcastle University, Bedson Building, Newcastle upon Tyne, NE1 7RU, England, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Ethylene and propylene carbonates, which can be prepared from epoxides and carbon dioxide, are effec-
tive solvents for the proline-catalysed, 100% atom economical, asymmetric aldol reaction between enol-
isable and non-enolisable carbonyl compounds. The optimal cyclic carbonate to use for a particular aldol
reaction along with the need for water as a cosolvent appear to be determined by the polarities of the
various components present in the reaction mixture. Both cyclic and acyclic ketones can be used as
the enamine precursor and react best with electron-deficient aldehydes, such as 4-nitrobenzaldehyde
and pentafluorobenzaldehyde. Chemical yields of up to 99%, diastereoselectivities of up to 100% and
enantioselectivities of up to 99% can be obtained. The relative and/or absolute configuration of three of
the aldol products are determined unambiguously by X-ray diffraction.
Received 9 February 2010
Accepted 29 March 2010
Available online 23 May 2010
Dedicated to Professor Henri Kagan on the
occasion of his 80th birthday
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
maximise the environmental and economic benefits of utilising
organocatalysts, the solvent should also be sustainable. Organoca-
Asymmetric organocatalysis has a long history, which can be
traced back to 1912 when Bredig and Fiske reported the use of
alkaloids to catalyse the asymmetric addition of hydrogen cya-
nide to aldehydes.1 The first reports of proline being used as an
asymmetric catalyst come from two industrial laboratories in
the early 1970s.2,3 This intramolecular aldol reaction is now
known as the Hajos–Parrish–Eder–Sauer–Wiechert reaction
(Scheme 1). However, until the late 1990s the Hajos–Parrish–
Eder–Sauer–Wiechert reaction was considered as something of
an oddity since, although it involves an aldol reaction, the stereo-
chemistry arises from the differentiation of enantiotopic carbonyl
groups, rather than from the differentiation of the enantiotopic
faces of a single carbonyl group as would be required in a more
general intermolecular aldol reaction. It is only over the last ten
years that proline-catalysed aldol reactions have been general-
ised,4 and this has sparked an explosion of interest in asymmetric
organocatalysis in general.5
One of the main attractions of organocatalysis is that it offers
the possibility of carrying out key chemical transformations with-
out the need for expensive, toxic and scarce transition metal- or
lanthanide metal-based catalysts. However, to obtain the maxi-
mum benefit from this approach, the organocatalyst should be a
readily available natural product or easily prepared from a natural
product in one or two chemical steps using 100% atom economical
reactions. This requirement is most readily met by proline4 (and
other amino acids6) and by cinchona alkaloid derivatives.7 To
talysed reactions have been carried out in water8 and ionic liq-
uids,9 although the green credentials of both of these solvents
have been questioned.10 In some cases, reactions may be carried
out solvent-free,11 but in many cases DMF, DMSO, acetonitrile
and chlorinated solvents are employed.4–7
Cyclic carbonates, especially ethylene carbonate 1 and propyl-
ene carbonate 2, are attracting increasing interest as green sol-
vents for metal-catalysed reactions. Ethylene carbonate 1 is a
solid at room temperature (mp 36 °C) and has a boiling point
of 248 °C. Nevertheless, it can be used as a solvent at room tem-
perature as its melting point is depressed on addition of reac-
tants. Propylene carbonate
2 has an extremely wide liquid
range (mp ꢀ49 °C, bp 242 °C), making it an ideal solvent for reac-
tions carried out below, at or above room temperature. The high
boiling points mean that both cyclic carbonates have very low
vapour pressures which is also commercially advantageous. Both
solvents are known to be biodegradable, have high flash points
and low odour levels. In addition, as they are already used as
degreasers, paint strippers and in cleaning applications, their tox-
icities have been assessed and both solvents have low toxicity.12
Both ethylene and propylene carbonates have high dielectric con-
stants and so they can be considered as environmentally friendly
and sustainable replacements for traditional polar aprotic sol-
vents such as DMF, DMSO and HMPA. However, there is a signif-
icant difference in polarity between the two cyclic carbonates:
whereas ethylene carbonate has a dielectric constant of 90, pro-
pylene carbonate has a dielectric constant of just 65.13 Thus,
the solvent polarity can be tuned over a wide range by the choice
of the appropriate cyclic carbonate or by use of a mixture of the
two solvents.
* Corresponding author. Tel.: +44 191 222 7128; fax: +44 191 222 6929.
E-mail address: Michael.north@ncl.ac.uk (M. North).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.03.051

W. Clegg et al. / Tetrahedron: Asymmetry 21 (2010) 1262–1271
1263
O
O
O
Me
Me
Me
(S)-proline (3 mol%),
20 ºC, 20 hours
Me
100% yield, 93% ee
O
O
O
OH
O
Scheme 1. The Hajos–Parrish–Eder–Sauer–Wiechert reaction.
Herein we report in full the use of the natural product (S)-proline
3 as an asymmetric organocatalyst in conjunction with cyclic
carbonates as sustainable solvents. We show that, under these
conditions, catalysis of 100% atom economical cross-aldol reactions
can be achieved with high diastereoselectivity and enantioselec-
tivity.26
O
O
O
O
COOH
N
H
O
O
Me
1
2
3
2. Results and discussion
In 1996, Reetz showed that propylene carbonate could be used
as a solvent for palladium-catalysed Heck reactions14 while in
2002 Obst showed that platinum-catalysed hydrosilylations could
be carried out in mixed solvents including propylene carbonate.15
The most work, however, has been done by Börner et al. who have
shown that cyclic carbonates can be used as solvents for rhodium-
catalysed asymmetric hydrogenations16 and palladium-catalysed
allylic chemistry.17 Recently, we have shown that propylene car-
bonate makes an excellent solvent for asymmetric cyanohydrin
synthesis catalysed by VO(salen)NCS.18
Cyclic carbonates can be prepared by the 100% atom economical
reaction between carbon dioxide and ethylene or propylene oxide
(Scheme 2).19 The sustainability of propylene carbonate is en-
hanced by the commercialisation of a low-temperature route for
the synthesis of propylene oxide from propene and hydrogen per-
oxide,20 by the development of a greener synthesis of hydrogen
peroxide,21 and by the combination of these processes into a
one-pot synthesis of propylene oxide from propene, hydrogen
and oxygen.22 In addition, it has been shown that in the presence
of an appropriate catalyst, the reaction between ethylene oxide
or propylene oxide and carbon dioxide can be achieved at atmo-
spheric pressure and room temperature for batch processes23 and
at temperatures of 100 °C or below in a gas-phase continuous flow
reactor,24 thus facilitating the use of waste carbon dioxide from
major fixed site producers such as power stations,25 oil refineries
and chemical plants in this process.
To determine whether cyclic carbonates could function as effec-
tive alternative solvents for proline-catalysed reactions, the cross-
aldol reaction between cyclohexanone and 4-nitrobenzaldehyde
catalysed by (S)-proline was selected as a test reaction (Scheme 3).
This reaction would allow the chemical yield, diastereoselectivity
and enantioselectivity obtained in cyclic carbonate solvents to be
compared with those obtained in traditional solvents. Therefore,
the reaction was first carried out in DMSO27 to provide comparison
data. When distilled anhydrous DMSO was employed as solvent, no
product was obtained (Table 1, entry 1). However, the addition of
4 equiv of water to the reaction mixture resulted in the formation
of aldol products 4a and 5a in a combined yield of 91%, favouring
(7.8:1) the anti-isomer 4a. Both diastereomers were enantiomeri-
cally enriched, with the major, anti-isomer 4a being formed in a
respectable 89% enantiomeric excess as determined by chiral HPLC
analysis (Table 1, entry 2).
The use of anhydrous propylene carbonate 2 as the solvent was
more effective than the use of anhydrous DMSO, though the yield,
diastereoselectivity and enantioselectivity were all still unsatisfac-
tory (Table 1, entry 3). Addition of 1 equiv of water (relative to the
amount of 4-nitrobenzaldehyde) had a remarkably positive effect
on all the reaction parameters (Table 1, entries 4 and 5). The chem-
ical yield increased to 80–83% with the diastereomeric ratio
(7–8:1) equal to that obtained in wet DMSO (Table 1, entry 2).
The enantioselectivities of both the syn- and anti-diastereomers
of the product were also significantly higher than those obtained
in wet DMSO, reaching 98% for the major, anti-diastereomer 4a.
However, the amount of water added to propylene carbonate
was critical, since addition of increasing amounts (2–8 equiv) re-
sulted in a steady drop in both the chemical yield and diastereose-
lectivity, although the enantiomeric excess of the major
diastereomer 4a was essentially unaffected by the amount of water
(Table 1, entries 6–11).
O
O
+ CO2 catalyst
O
O
R
R
Scheme 2. Synthesis of cyclic carbonates from epoxides and CO2.
O
O
OH
O
OH
Ar
(S)-proline (cat)
solvent, water
r.t., 24 h
+ ArCHO
+
Ar
anti 4a-f
syn 5a-f
a: Ar = 4-O2NC6H4
b: Ar = C6H5
c: Ar = 4-BrC6H4
d: Ar = 4-F3CC6H4
e: Ar = 3-O2NC6H4
f: Ar = C6F5
Scheme 3. Proline-catalysed aldol reactions involving cyclohexanone.

1264
W. Clegg et al. / Tetrahedron: Asymmetry 21 (2010) 1262–1271
Table 1
Table 2
Synthesis of keto-alcohols 4a and 5aa
Synthesis of keto-alcohols 4b–f and 5b–fa
Entry Solventb
3
Waterb
(equiv)
Yield 4a:5ac 4a
(ee)d
5a
Entry
Solvent
Aldehyde
Yield
4:5b
4 (ee)c
5 (ee)c
(mol %)b
(ee)d
1
2
3
4
5
6
7
8
9
2
2
1
2
2
1
2
1
2
1
2
1
PhCHO
PhCHO
PhCHO
12
47d
44
18
60d
47
49
86
22
89
98
99
4.4:1
4.5:1
16:1
4.7:1
4.8:1
13:1
4.7:1
9:1
7.4:1
7.8:1
100:0
100:0
56
80
99
96
96
95
93
98
92
99
98
98
77
67
89
89
80
87
68
89
92
88
—
1
2
DMSO
DMSO
10
10
10
10
10
10
10
10
10
10
10
20
30
10
10
0
4
0
1
1
2
2
3
4
6
8
2
4
1
0
0
91
45
83
80
63
81
57
49
12
8
—
7.8:1
1:1
7.9:1
7.2:1
4.3:1
13:1
2.6:1
12.1
—
—
—
89
74
98
98
96
99
96
99
—
50
40
88
92
41
90
90
84
—
—
2
29
91
—
3
4
5
6
7
8
2
4-BrC6H4CHO
4-BrC6H4CHO
4-BrC6H4CHO
4-F3CC6H4CHO
4-F3CC6H4CHO
3-O2NC6H4CHO
3-O2NC6H4CHO
C6F5CHO
2e
2e
2
2f
2
9
2
10
11
12
10
11
12
13
14
15
2
2
—
—
C6F5CHO
—
2
71
72
92
6
5.8:1
2.0:1
9:1
97
95
98
—
a
2g
1
All reactions were carried out for 24 h (unless specified otherwise) at room
temperature with 2 equiv of cyclohexanone relative to aldehyde using 10 mol % of
(S)-proline and with 1 equiv of water added to the reaction mixture.
1
2:1
Determined by 1H NMR spectroscopy.
b
a
c
All reactions were carried out for 24 h at room temperature with 2 equiv of
Determined by chiral HPLC using a Chiralpak AD-H column prior to purification
cyclohexanone relative to 4-nitrobenzaldehyde.
of the product by silica gel chromatography. The major enantiomers had (S,R)- and
(S,S)-configurations, respectively, (as shown in Scheme 3) based on the correlation
of the HPLC retention times with the literature data.11,27,28
b
Relative to 4-nitrobenzaldehyde.
c
Determined by 1H NMR spectroscopy.
d
d
Determined by chiral HPLC using a Chiralpak AD-H column prior to purification
Reaction time six days.
of the product by silica gel chromatography. The major enantiomers had (S,R)- and
(S,S)-configurations, respectively, (as shown in Scheme 3) based on the correlation
of the HPLC retention times with the literature data.11,27,28
attached to the stereocentre adjacent to the carbonyl occurring
during the chromatography. Partial epimerisation of 4a (the major
product) gives the enantiomer of 5a and results in a large reduction
in the observed enantiomeric excess of 5a. In contrast, whilst
epimerisation of 5a gives the enantiomer of 4a, this only slightly
reduces the enantiomeric excess of 4a as only a small amount of
syn-diastereomer 5a is present in the reaction product.
e
Duplicated experiment to show reproducibility.
Reaction time 48 h.
Reaction time 60 h.
f
g
The influence of water on organocatalysed reactions has been
studied extensively.8,29 With regard to the catalysis of aldol reac-
tions by proline, there have been previous reports where the addi-
tion of water enhances the rate and/or enantioselectivity of the
reactions.30 However, recent work from Armstrong and Blackmond
based on a study of the reaction kinetics has shown that water is an
inhibitor of homogeneous aldol reactions catalysed by proline.31
Since the reactions shown in Table 1 are initially heterogeneous,
it appears that the beneficial effect of adding a small amount of
water is to enhance the solubility of proline in the reaction mix-
ture, resulting in an increase in the rate of reaction due to an in-
crease in the amount of catalyst present in solution, but that if
too much water is added then the detrimental effect of water on
the rate of reaction becomes increasingly apparent. This is consis-
tent with the results shown in Table 1, entries 6–7, which show
that the reaction is still in progress after 24 h as the yield increases
to 81% after 48 h.
Increasing the amount of (S)-proline used to 20 or 30 mol % did
not result in an increase in yield or stereoselectivity (Table 1, en-
tries 12–13), though this is probably due to the need to increase
the amount of water added to the reactions (to 2 and 4 equiv,
respectively) in order to dissolve the catalyst. Finally, the use of
ethylene carbonate as a solvent resulted in a significant improve-
ment in both chemical yield and diastereoselectivity (Table 1, com-
pare entries 4, 5 and 14). This is probably due to the greater
polarity of ethylene carbonate compared to propylene carbonate,13
which will help with solubilising the catalyst and stabilising
charged intermediates, though the presence of some water was
again essential (Table 1, entry 15).
On the basis of the results presented in Table 1, 10 mol % of (S)-
proline 3 and 1 equiv of water were selected as the optimal reac-
tion conditions (Table 1, entries 4 and 5). The use of cyclic carbon-
ates 1 and 2 as solvents for aldol reactions was then extended to
the reaction of other aromatic aldehydes with cyclohexanone
(Scheme 3) and the results are tabulated in Table 2. In line with
the previous work on proline-catalysed aldol reactions in other sol-
vents,4–6 the best substrates were found to be electron-deficient
aldehydes. Thus, in propylene carbonate, benzaldehyde gave a
low yield of aldol products 4b and 5b and poor enantioselectivity
(Table 2, entry 1). Both the yield and enantioselectivity could be
significantly improved by extending the reaction time to six days
(Table 2, entry 2). However, the best results were again obtained
using ethylene carbonate as solvent (Table 2, entry 3). This not only
improved the chemical yield from 12% to 44%, but gave excellent
levels of both enantioselectivity and diastereoselectivity. The same
dependence of chemical yield and diastereoselectivity on the
solvent was observed for reactions involving the conversion of
4-bromobenzaldehyde into keto-alcohols 4c and 5c (Table 2,
entries 4–6). However, in this case a similar, high level of enanti-
oselectivity was observed in all reactions.
4-Trifluoromethylbenzaldehyde gave
a significantly better
chemical yield of aldol products in propylene carbonate than had
been obtained from reactions with either benzaldehyde or 4-bromo-
benzaldehyde as substrate (Table 2, compare entries 1,4 and 7), but
again the yield of keto-alcohols 4d and 5d obtained in ethylene
carbonate was better still (Table 2, entry 8). The diastereoselectivity
and enantioselectivity were also better in ethylene carbonate than
in propylene carbonate. For reactions involving the use of
3-nitrobenzaldehyde, the chemical yield of products 4e and 5e again
increased dramatically on changing the solvent from propylene to
ethylene carbonate, although in this case only a slight increase in
diastereoselectivity and enantioselectivity of the anti-diastereomer
4e was observed (Table 2, entries 9 and 10). The best results,
however, were obtained with pentafluorobenzaldehyde as substrate
(Table 2, entries 11 and 12). Even using propylene carbonate as the
The results shown in Table 1 were reproducible as seen by en-
tries 4 and 5. However, all of the enantioselectivities reported in
Table 1 were determined prior to chromatographic purification
since the enantioselectivities of 4a and 5a were found to decrease
during silica gel chromatography. Thus, for example, when the
product obtained from entry 5 was purified, the anti-diastereomer
4a was found to have an enantiomeric excess of 95%, but the syn-
diastereomer 5a had an enantiomeric excess of just 32%. This is
consistent with epimerisation of the remaining acidic proton

W. Clegg et al. / Tetrahedron: Asymmetry 21 (2010) 1262–1271
1265
solvent, the anti-product 4f was formed as a single diastereomer in
almost quantitative yield and with 98% enantiomeric excess. In this
case, identical results were obtained in ethylene carbonate. In gen-
eral, the results for the formation of aldol adducts 4/5a–f were com-
parable to, or better than, those reported in the literature for proline-
To extend the scope of this reaction beyond cyclohexanone as
the enamine precursor, aldol reactions between acetone and aro-
matic aldehydes were investigated next (Scheme 4). The reaction
was again optimised by reactions using 4-nitrobenzaldehyde to
give aldol product 6a;11,32a,34 the results are tabulated in Table 3.
In this case, the addition of water to the reaction mixture was
found to be counterproductive and the best results (96% yield,
61% ee) were obtained when 8 equiv of acetone were used in anhy-
drous propylene carbonate (Table 3, entry 6). Also in this case, the
use of ethylene carbonate as a solvent was not beneficial to the
enantioselectivity (Table 3, entry 7).
Having optimised the reaction conditions for the use of acetone
as the enamine precursor, aldol reactions involving five other aro-
matic aldehydes were carried out under the same conditions to
give hydroxyketones 6b–f (Table 4).34 Electron-deficient aldehydes
again gave the highest chemical yields and pentafluorobenzalde-
hyde gave the best asymmetric induction. In contrast to the results
obtained using cyclohexanone as the enamine precursor, however
with acetone as the substrate, comparable chemical yields and
enantioselectivities were obtained in ethylene and propylene car-
bonates. The yields and enantioselectivities obtained and shown
in Tables 3 and 4 compare favourably with those obtained in con-
ventional solvents such as DMSO and DMF30a,30b,32a,35 or under sol-
vent-free conditions.11
The major enantiomer of keto-alcohols 6a–e was readily deter-
mined to have the (R)-configuration based on the comparison of
specific rotation data and order of elution of the peaks from a chiral
HPLC column with the literature data.11,32,34 However, keto-alcohol
6f has not previously been reported and was obtained as an oil.
Therefore, to determine its absolute configuration, compound 6f
was treated with 4-bromophenyl isocyanate to give the crystalline
carbamate 7 (Scheme 5). X-ray analysis of carbamate 7 confirmed
that it possessed the (R)-configuration based on anomalous scat-
tering effects (Fig. 3). The N–Hꢁ ꢁ ꢁO hydrogen bonds connect mole-
cules of carbamate 7 together to form chains along the short
crystallographic a axis.
catalysed reactions under
a
range of different reaction
conditions.11,28b,32
In the case of aldol products 4/5a,b the preferential formation of
anti-diastereomer 4 in the reactions reported in Tables 1 and 2 was
based on 1H NMR and HPLC data reported in the literature11,27,28,32
which could be correlated back to X-ray structures of the anti-dia-
stereomers 4a,b.33 However, for aldol products 4/5c–f, although 1H
NMR and HPLC data were available in the literature,28 no X-ray
data were available. Therefore, to unambiguously confirm that
the major diastereomer obtained in these cases was indeed the
anti-diastereomer, X-ray structures of the fluorinated products
4d and 4f were obtained (Figs. 1 and 2) which confirmed the rela-
tive and absolute stereochemistry in each case. The molecular
structures are essentially as expected. Compound 4d forms hydro-
gen-bonded chains through O–Hꢁ ꢁ ꢁO(ketone) interactions between
molecules related by a screw axis. There are two independent mol-
ecules in the asymmetric unit of 4f; these are linked together as a
discrete dimer by O–Hꢁ ꢁ ꢁO(ketone) interactions, one of these
hydrogen bonds being approximately linear, while the other is
bent and is bifurcated with an intramolecular hydrogen bond.
The four O atoms of the dimer thus form an irregular quadrilateral.
The need to optimise the solvent system (structure of cyclic car-
bonate and presence or absence of water) can be explained on the
basis of the significantly different dielectric constants of propylene
and ethylene carbonates(65 and 90, respectively13) and the differing
amounts of cyclohexanone and acetone employed in the aldol reac-
tions. Proline-catalysed aldol reactions generally require a polar
reaction medium, hence solvents such as DMF and DMSO4–7 are
used to stabilise the transition states. As a result, ethylene carbonate
is expected to be the solvent of choice (accelerating the rate of the
proline-catalysed reaction relative to the background reaction, thus
giving higher yields and stereoselectivities) when using a very non-
polar ketone such as cyclohexanone as the enamine precursor. How-
ever, reactions with acetone as the enamine precursor require
8 equiv of acetone (as opposed to 2 equiv of cyclohexanone) and this
constitutes a third of the reaction mixture by volume. Thus, the ef-
fect of the polarity difference between ethylene and propylene car-
bonates is greatly diminished and comparable results are obtained
in both solvents. Water has a dielectric constant of 79,36 which is
intermediate between those of ethylene and propylene carbonates,
so its addition to reactions carried out in propylene carbonate may
also help to raise the polarity of the reaction mixture.
Figure 1. The molecular structure of keto-alcohol 4d with 40% probability
displacement ellipsoids and non-H atom labels.
Figure 2. The structure of one of the two crystallographically independent
molecules of keto-alcohol 4f with 40% probability displacement ellipsoids and
non-H atom labels.
a: Ar = 4-O2NC6H4
b: Ar = C6H5
c: Ar = 4-BrC6H4
d: Ar = 4-F3CC6H4
e: Ar = 3-O2NC6H4
f: Ar = C6F5
(S)-proline (cat)
solvent, water
r.t., 24 h
O
OH
Ar
O
+ ArCHO
6a-f
Scheme 4. (S)-Proline-catalysed cross-aldol reactions involving acetone.

1266
W. Clegg et al. / Tetrahedron: Asymmetry 21 (2010) 1262–1271
Table 3
(S)-Proline-catalysed synthesis of aldol product 6aa
Entry Solvent Acetoneb
(equiv)
(S)-Prolineb
(mol %)
Waterb
(equiv)
Yield 6a
(ee)c
1
2
3
4
5
6
7
2
2
2
2
2
2
1
2
2
2
2
4
8
8
10
10
10
20
10
10
10
0
1
2
2
0
0
0
37
28
27
29
58
96
97
—
—
—
—
66
61
58
a
b
c
All reactions were carried out for 24 h at room temperature.
Relative to 4-nitrobenzaldehyde.
Determined by chiral HPLC using a Chiralpak AS-H column. The major enan-
tiomer had an (R)-configuration based on the comparison of its specific rotation and
correlation of the chiral HPLC retention times with the literature data.11,32a,34
Table 4
Synthesis of keto-alcohols 6b–fa
Figure 3. The molecular structure of carbamate 7 with 40% probability displace-
ment ellipsoids and non-H atom labels.
Entry
Solvent
Aldehyde
Yield
6b–f (ee)b
1
2
3
4
5
6
7
8
9
2
1
2
1
2
1
2
1
2
1
PhCHO
PhCHO
58
72
76
71
94
95
84
95
85
99
60
62
75
69
73
76
55
65
82
99
bonate than in propylene carbonate (Table 5, entries 5 and 6).
Attempts to extend the chemistry to cyclobutanone or cyclohepta-
none were unsuccessful as no aldol products were formed with
these ketones.
4-BrC6H4CHO
4-BrC6H4CHO
4-F3CC6H4CHO
4-F3CC6H4CHO
3-O2NC6H4CHO
3-O2NC6H4CHO
C6F5CHO
As an example of an aldol reaction between two ketones, the
reaction between cyclohexanone and ethyl phenylglyoxalate was
investigated40 using both propylene and ethylene carbonates as
solvent (Scheme 7). The reaction was found to be highly enantiose-
lective and diastereoselective, giving only the anti-isomer of aldol
product 13 with up to 97% ee (Table 6). Reactions in propylene car-
bonate were extremely slow, requiring 20 days to proceed to 50%
yield even when 10 equiv of cyclohexanone and 50 mol % of (S)-
proline were used (entry 1). Addition of 1 equiv of water to the
reaction had a beneficial effect, allowing the amount of proline to
be reduced to 30 mol % and increasing the enantioselectivity to
97% (entry 2). However, addition of further equivalents of water
decreased both the reaction yield and enantioselectivity (entries
3 and 4). Reactions carried out in ethylene carbonate in the ab-
sence of water (entries 5 and 6) were much faster than those car-
ried out in propylene carbonate under identical conditions, giving
yields of 39% after a reaction time of three days and 54% after a
10-day reaction, whilst retaining the high level of asymmetric
induction. This rate acceleration is probably due to the greater
polarity of ethylene carbonate13 since it was necessary to use
10 equiv of cyclohexanone in these reactions. Addition of water
to reactions carried out in ethylene carbonate did not significantly
enhance the rate of reaction (entry 7).
10
C6F5CHO
a
All reactions were carried out for 24 h at room temperature with 8 equiv of
acetone relative to aldehyde using 10 mol % of (S)-proline.
b
Determined by chiral HPLC using a Chiralpak AD-H (6b,e,f) or AS-H (6c,d)
column. For products 6b–e, the major enantiomer was shown to have an (R)-con-
figuration based on the comparison of its specific rotation and correlation of the
chiral HPLC retention times with the literature data.34
To validate this hypothesis and to demonstrate the generality of
proline-catalysed aldol reactions in cyclic carbonates, reactions
with other cyclic and acyclic enamine precursors were carried
out. Initially, cyclohexanone derivatives 8 and 9 and cyclopenta-
none 10 were chosen as substrates. Compounds 8 and 10 were ex-
pected to be more polar than cyclohexanone, whilst compound 9
would be less polar. Reactions were carried out with 4-nitrobenz-
aldehyde in either ethylene or propylene carbonate in the presence
of 1 equiv of water and 10 mol % of (S)-proline to give aldol prod-
ucts 11/12a–c (Scheme 6). The results are summarised in Table 5;
it is apparent that for polar substrate 8, propylene carbonate is a
better solvent than ethylene carbonate (entries 1 and 2), whilst
for non-polar substrate 9, ethylene carbonate was a much better
solvent than propylene carbonate (entries 3 and 4). For both sub-
strates, the use of the appropriate cyclic carbonate solvent gave
excellent chemical yields and stereoselecivities. Cyclopentanone
10 was also an excellent substrate for proline-catalysed aldol
reactions in cyclic carbonate solvents, giving adducts 11/12a–c in
99% chemical yield in both solvents. However, the enantioselectiv-
ity and diastereoselectivity were both much higher in ethylene car-
To extend this methodology to hetero-aldol reactions, the reac-
tion between propanal and nitrosobenzene to give alcohol 14 after
a reductive work-up was investigated (Scheme 8). This reaction
has previously been performed in chloroform, DMF, DMSO, aceto-
nitrile and ionic liquids.41 A reaction carried out in propylene car-
bonate 2 at 0 °C for 2 h gave compound 14 with 98% enantiomeric
excess, but in only 33% yield. Raising the reaction temperature to
Br
O
CHCl3
5 days
O
OH
C6F5
+
N=C=O
Br
O
O
N
H
95%
C6F5
7
6f
Scheme 5. Synthesis of carbamate 7.

W. Clegg et al. / Tetrahedron: Asymmetry 21 (2010) 1262–1271
1267
O
O
O
(S)-proline
X
OH
X
OH
O
(10 mol%)
1 or 2,
+
+
water (1 equiv)
r.t., 24 h
X
NO2
NO2
anti 11a-c
a: X = O; b: X = CHtBu; c: X = -
NO2
syn 12a-c
8: X = O
9: X = CHtBu
10: X = -
Scheme 6. Aldol reactions involving cyclohexanone derivatives and cyclopentanone.
Table 5
Table 6
Synthesis of keto-alcohols 11a–c and 12a–ca
Synthesis of keto-alcohol 13a
Entry
Ketone
Solvent
Yield
11:12b
11 (ee)c
12 (ee)c
Entry
Solvent
Water (equiv)
3 (mol %)
Time (days)
Yield
eea
1
2
3
4
5
6
8
8
9
9
10
10
2
1
2
1
2
1
99
74
58
89
99
99
7:1
94
73
90
95
39
91
68
69
61
95
2
1
2
3
4
5
6
7
2
2
2
2
1
1
1
0
1
2
4
0
0
1
50
30
30
30
30
30
30
20
20
20
20
3
50
49
40
25
39
54
57
91
97
95
90
93
95
94
2.9:1
1.7:1
8.4:1
1.2:1
2.2:1
0
10
10
a
All reactions were carried out for 24 h at room temperature with 2 equiv of
a
cyclohexanone relative to 4-nitrobenzaldehyde.
Determined by chiral HPLC using a Chiralpak AD-H column prior to purification
Consistent diastereoselectivities were obtained by 1H NMR spectroscopy and by
of the product by silica gel chromatography. The major enantiomer had (S,R)-
configuration (as shown in Scheme 7) based on the correlation of the HPLC reten-
tion times with the literature data.40
b
chiral HPLC analysis.
c
Determined by chiral HPLC using a Chiralpak AD-H (11/12a,b) or AS-H (11/12c)
column prior to purification of the product by silica gel chromatography. The major
enantiomers had (S,R)- and (S,S)-configurations, respectively, (as shown in
Scheme 6) based on the correlation of the HPLC retention times with the literature
data.11,27,28,32,37–39
then stored over molecular sieves. Liquid aldehydes were freshly
distilled prior to use. Other commercially available chemicals (Alfa
Aesar, Aldrich, Fluka, Acros) were used as received. Distillations
were carried out on a Büchi Kügelrohr GKR-50 apparatus. Chro-
matographic separations were performed using Silica Gel 60
(230–400 mesh, Davisil).
room temperature increased the chemical yield to 95%, but signif-
icantly decreased the enantioselectivity to 58%. Changing the sol-
vent to ethylene carbonate at room temperature resulted in a
good compromise between yield and enantioselectivity, giving
compound 14 in 85% isolated yield and with 80% enantiomeric
excess.
Infrared spectra were recorded at room temperature on a Perkin
Elmer Spectrum-1 FT-IR spectrometer or on a Varian 800 FT-IR
Scimitar series spectrometer, measuring specific absorbance
intensities as: broad (br), strong (s), medium (m) and weak (w).
Melting points were determined on a Stuart SMP3 system. Optical
rotation measurements were conducted on a Polaar 2001 Optical
Activity automatic polarimeter at the sodium D-line using 0.25
and 0.5 dm thermostated cuvettes and a suitable solvent that is
reported along with the concentration (g/100 mL). High- and
low-resolution electrospray ionisation (ES) mass spectra were re-
corded on a Waters LCT Premier LCMS spectrometer using direct
injection of the sample dissolved in MeOH. Low-resolution elec-
tron ionisation (EI) mass spectra were recorded on a Varian CP-
800-SATURN 2200 GC/MS ion-trap mass spectrometer using a Fac-
torFour (VF-5 ms) capillary column (30 m ꢂ 0.25 mm) with helium
as the carrier gas. The conditions used were initial temperature
60 °C, hold at initial temperature for 3 min then ramp rate 15 °C/
min to 270 °C; hold at final temperature for 5 min.
3. Conclusions
The cyclic carbonates 1 and 2 are sustainable alternatives to
conventional polar aprotic solvents such as DMF and DMSO and
for chlorinated solvents in proline-catalysed aldol reactions. The
polarity difference between cyclic carbonates 1 and 2 can be
exploited to optimise the reaction conditions for a particular
enamine precursor, with ethylene carbonate 1 generally being pref-
erable for reactions which require an excess of a non-polar substrate.
4. Experimental
4.1. Chemicals and instrumentation
Propylene carbonate was distilled from CaH2 under reduced
pressure, and acetone was distilled from CaCO3. Both solvents were
The 1H, 19F and 13C NMR spectra were recorded on JEOL Oxford
400 and JEOL Lambda 500 spectrometers at resonance frequencies
3 (30-50 mol%)
O
O
HO
CO2Et
Ph
O
1 or 2
3-20 days, r.t.
+
CO2Et
Ph
10 equivalents
13
Scheme 7. Aldol reaction involving ethyl phenylglyoxalate.

1268
W. Clegg et al. / Tetrahedron: Asymmetry 21 (2010) 1262–1271
OH
O
1) 3 (10 mol%), 1 or 2, 2 hours
2) NaBH4, EtOH
+ PhNO
Ph
O
H
N
H
14
3 equivalents
Scheme 8. Heteroaldol reaction between propanal and nitrosobenzene.
of 400 and 500 MHz for 1H, 100 and 125 MHz for 13C and 376 and
470 MHz for 19F, respectively. 1H and 13C NMR spectra were also
recorded on a Bruker Avance 300 spectrometer at resonance
frequencies of 300 and 75 MHz, respectively. All spectra were
recorded at room temperature in CDCl3 solution. Chemical shifts
are reported in ppm and for 1H and 13C spectra are relative to
TMS internally referenced to the residual solvent peak. 19F spectra
are externally referenced to CFCl3. The multiplicity of signals is
reported as singlet (s), doublet (d), triplet (t), quartet (q), multiplet
(m), broad (br) or a combination of any of these. DEPT 90 and DEPT
135 experiments were used to determine the number of hydrogen
atoms attached to each carbon atom.
Chiral HPLC was performed using a Varian Prostar system com-
prising binary pumping modules, a diode array detector and auto-
sampler and equipped with a Diacel Chiralpak AD-H or AS-H
column (25 cm by 4.6 mm), using a mixture of isopropanol and
hexane as eluent.
1.7–1.3 (4H, br, CH); dC(syn) 213.4 (CO), 149.2 (ArC), 147.4 (ArC),
126.7 (ArCH), 123.4 (ArCH), 70.3 (CH), 56.9 (CH), 42.6 (CH2), 27.7
(CH2), 26.1 (CH2), 24.9 (CH2); dC(anti) 214.1 (CO), 148.6 (ArC),
147.8 (ArC), 127.9 (ArCH), 123.4 (ArCH), 74.0 (CH), 57.3 (CH),
42.6 (CH2), 30.8 (CH2), 27.6 (CH2), 24.7 (CH2); HPLC: AD-H column,
hexane/iPrOH (95:5) as solvent system, flow rate 0.5 mL/min,
detection at 254 nm, tR syn = 63.0 (major) and 48.8 min (minor),
tR anti = 98.4 (major) and 70.1 min (minor).
4.2.2. (2S,10R)- and (2S,10S)-2-[10-Hydroxy-10-phenylmethyl]-
cyclohexanone 4b/5b27,28
Prepared according to the general procedure leaving the reac-
tion for six days instead of 24 h when using propylene carbonate
as solvent. The aldol product was isolated as a white solid in 44–
47% yield. dH 7.4–7.2 (5H, m, ArH), 5.39 (1H, d J 2.2 Hz, syn-CHOH),
4.78 (1H, d J 8.8 Hz, anti-CHOH), 4.1–4.0 (1H, br, OH), 2.7–2.6 (1H,
m, CH), 2.5–2.3 (2H, m, CH), 2.1–2.0 (1H, m, CH), 1.8–1.5 (5H, m,
CH); dC 214.7 (CO), 141.5 (ArC), 128.1 (ArCH), 126.9 (ArCH),
125.7 (ArCH), 70.6 (CH), 57.2 (CH), 42.6 (CH2), 27.9 (CH2), 26.0
(CH2), 24.9 (CH2); m/z(ES+) 227 (M+Na+, 45), 226 (100), 201 (85);
Found (ES+) 431.2185 and 227.1032, C26H32O4Na (2M+Na)+ re-
quires 431.2185, C13H16O2Na (M+Na)+ requires 227.1048; HPLC:
AD-H column, hexane/iPrOH (90:10) as solvent system, flow rate
0.5 mL/min, detection at 220 nm, tR syn = 20.5 (major) and
16.9 min (minor), tR anti = 27.6 (major) and 24.1 min (minor).
X-ray crystallographic data were collected on an Oxford Diffrac-
tion Gemini A Ultra diffractometer at 150 K with Cu K
a radiation
(k = 1.54184 Å) for 4d and 4f and at Diamond Light Source beam-
line I19 at 120 K with synchrotron radiation (k = 0.6889 Å) for a
very small rod-like crystal (0.12 ꢂ 0.03 ꢂ 0.01 mm) of 7. Standard
Oxford Diffraction and Rigaku control software was used, together
with Bruker APEX2 for the synchrotron data integration; the
structures were solved and refined with Bruker SHELXTL. Full
crystallographic results have been deposited at the Cambridge
Crystallographic Data Centre with the reference numbers CCDC
765263, 765264 and 765265 for 4d, 4f and 7, respectively.
4.2.3. (2S,10R)- and (2S, 10S)-2-[10-Hydroxy-10-(4-
bromophenyl)methyl]cyclohexanone 4c/5c27,28
Prepared according to the general procedure leaving the reac-
tion for six days instead of 24 h when using propylene carbonate
as solvent. The aldol product was isolated as a white solid in 47–
60% yield. dH 7.46 (2H, d J 8.4 Hz, ArH), 7.19 (2H, d J 8.3 Hz, ArH),
5.33 (1H, d J 2.0 Hz, syn-CHOH), 4.74 (1H, d J 8.7 Hz, anti-CHOH),
4.0–3.5 (1H, br, OH), 2.6–2.4 (2H, m, CH), 2.4–2.3 (1H, m, CH),
2.1–2.0 (1H, m, CH), 1.9–1.4 (5H, m, CH); dC (syn) 214.3 (CO),
140.7 (ArC), 131.2 (ArCH), 127.5 (ArCH),120.5 (ArCBr), 69.1
(CH), 56.8 (CH), 42.6 (CH2), 30.7 (CH2), 27.9 (CH2), 24.9 (CH2);
dC (anti) 215.2 (CO), 140.0 (ArC), 131.4 (ArCH), 128.7 (ArCH),
121.7 (ArCBr), 74.1 (CH), 57.3 (CH), 42.6 (CH2), 30.7 (CH2), 27.7
(CH2), 24.7 (CH2); m/z(ES+) 591 (2(81Br)M+Na+, 50), 589
(2(81Br+79Br)M+Na+, 100), 587 (2(79Br)M+Na+, 50), 454 (95), 347
(60), 185 (90); Found (ES+) 589.0390, C26H30O479Br81BrNa
(2M+Na)+ requires 589.0390; HPLC: AD-H column, hexane/iPrOH
(90:10) as solvent system, flow rate 0.5 mL/min, detection at
220 nm, tR syn = 20.7 (major) and 17.6 min (minor), tR anti = 32.6
(major) and 27.5 min (minor).
4.2. General procedure for (S)-proline-catalysed aldol reactions
involving cyclic ketones
To a mixture of (S)-proline 3 (11.5 mg, 10 mol %) and aldehyde
(1 mmol) were added propylene or ethylene carbonate (1 ml), cyc-
lic ketone (2 mmol) and water (18 mg, 1 mmol) under an inert
atmosphere. The resulting mixture was stirred at room tempera-
ture for 24 h. The reaction mixture was then poured into brine
(5 ml) and water (5 ml) and extracted with diethyl ether (10 ml).
The organic phase was washed with water (3 ꢂ 10 ml), dried
(Na2SO4) and the solvent was removed in vacuo. The residue at this
stage was analysed by 1H NMR spectroscopy and chiral HPLC to ob-
tain the diasteroselectivity and enantioselectivity. The residue was
then purified by evaporation of benzaldehyde in vacuo to give 4/5a
or by column chromatography on silica gel (gradient from hexane/
EtOAc 4:1 to 1:1) to give aldol products 4/5b-f and 11/12a-c. Race-
mic HPLC standards were prepared by a literature procedure.42
4.2.1. (2S,10R)- and (2S,10S)-2-[10-Hydroxy-10-(4-nitrophenyl)-
methyl]cyclohexanone 4a/5a11,27,28
4.2.4. (2S,10R)- and (2S,10S)-2-[10-Hydroxy-1’-(4-trifluoromethyl
phenyl)methyl]cyclohexanone 4d/5d28
Obtained as yellow crystals in 83–92% yield. dH(syn) 8.20 (2H, d
J 8.8 Hz, ArH), 7.50 (2H, d J 8.4 Hz, ArH), 5.48 (br, 1H, CHOH), 3.17
(1H, d J 3.3 Hz, OH), 2.7–2.6 (1H, br, CH), 2.5–2.3 (2H, br, CH2), 2.2–
2.1 (1H, br, CH), 1.9–1.8 (1H, br, CH), 1.7–1.4 (4H, br, CH); dH(anti)
8.20 (2H, d J 8.7 Hz, ArH), 7.50 (2H, d J 8.6 Hz, ArH), 4.90 (1H, dd, J
3.1, 8.4 Hz, CHOH), 4.07 (1H, d J 3.2 Hz, OH), 2.6–2.5 (2H, br, CH),
2.4–2.3 (1H, br, CH), 2.2–2.1 (1H, br, CH), 1.9–1.8 (1H, br, CH),
Obtained as a white solid in 49–86% yield. Crystals of the anti-
diastereomer suitable for X-ray analysis were obtained by recrys-
tallisation from EtOAc/hexane. dH(syn) 7.59 (2H, d J 8.5 Hz, ArH),
7.42 (2H, d J 7.9 Hz, ArH), 5.44 (1H, br, CHOH), 3.09 (1H, br, OH),
2.6–2.5 (1H, m, CH), 3.1–2.3 (2H, m, CH), 2.2–2.0 (1H, m, CH),
1.9–1.5 (5H, m, CH); dH(anti) 7.61 (2H, d J 8.3 Hz, ArH), 7.44 (2H,
d J 7.6 Hz, ArH), 4.84 (1H, d J 8.6 Hz, CHOH), 4.02 (1H, br, OH),

W. Clegg et al. / Tetrahedron: Asymmetry 21 (2010) 1262–1271
1269
2.6–2.5 (1H, m, CH), 3.1–2.3 (2H, m, CH), 2.1–2.0 (1H, m, CH), 1.9–
1.5 (5H, m, CH); dC(syn) 214.5 (CO), 145.7 (ArC), 129.1 (q J 40.5 Hz,
CF3), 126.2 (ArCH), 125.3 (ArCH), 120.0 (q J 4.2 Hz, ArCCF3), 70.3
(CH), 57.0 (CH), 42.7 (CH2), 27.9, (CH2), 26.0 (CH2), 24.9 (CH2);
dC(anti) 215.2 (CO), 145.1 (ArC), 130.2 (q J 40.4 Hz, CF3), 127.5
(ArCH), 125.4 (ArCH) 122.5 (q J 4.5 Hz, ArCCF3), 74.3 (CH), 57.3
(CH), 42.7 (CH2), 30.8 (CH2), 27.8 (CH2), 24.8 (CH2); dF(syn)
ꢀ77.8; (s); dF(anti) ꢀ78.0 (s); m/z(ES+) 273 (MH+, 100); Found
(ES+) 273.1112, C14H16O2F3 MH+ requires 273.1102; HPLC: AD-H
column, hexane/iPrOH (90:10) as solvent system, flow rate
0.5 mL/min, detection at 254 nm, tR syn = 16.3 (major) and
13.8 min (minor), tR anti = 26.0 (major) and 21.3 min (minor). Crys-
tal data for 4d: C14H15F3O2, M = 272.3, orthorhombic, P212121,
a = 5.7230(6), b = 8.6129(11), c = 25.751(3) Å, V = 1269.3(3) Å3,
Z = 4, 3292 measured data, 1962 unique, Rint = 0.020, 177 refined
CHCO), 3.1–2.3 (3H, m, CH2CO + OH); m/z(ES+) 525 (2M+Na+, 15),
454 (60), 413 (60), 347 (100), 306 (90), 263 (100); Found (ES+)
525.1473, C24H26N2O10Na (2M+Na+) requires 525.1485; HPLC:
AD-H column, hexane/iPrOH (80:20) as solvent system, flow rate
1.0 mL/min, detection at 254 nm, tR syn = 38.0 (major) and
45.2 min (minor), tR anti = 58.8 (major) and 50.6 min (minor).
4.2.8. (2S,1’R)- and (2S,10S)-2-[10-Hydroxy-10-(4-nitrophenyl)-
methyl]4-tert-butylcyclohexanone 11b/12b11b,37a,e,38
Obtained as a white solid in 58–89% yield. dH(syn): 8.15 (2H, d J
8.4 Hz, ArH), 7.43 (2H, d J 8.5 Hz, ArH), 5.36 (1H, br, CHOH), 3.08
(1H, br, OH), 2.8–2.6 (1H, m, CH), 2.5–2.0 (3H, m, CH), 2.0–1.4
(4H, m, CH), 0.72 (9H, s, (CH3)3); dH(anti) 8.16 (2H, d J 8.6 Hz,
ArH), 7.48 (2H, d J 8.6 Hz, ArH), 4.92 (1H, d J 9.0 Hz, CHOH), 3.65
(1H, br, OH), 2.6–2.5 (1H, m, CH), 2.5–2.0 (3H, m, CH), 2.0–1.4
(4H, m, CH), 0.72 (9H, s, (CH3)3); m/z(ES+) 305 (M+, 10), 257 (40),
185 (100); Found (ES+) 305.1627, C17H23NO4 (M+) requires
305.1627; HPLC: AD-H column, hexane/iPrOH (85:15) as solvent
system, flow rate 1.0 mL/min, detection at 254 nm, tR syn = 9.5
(minor) and 12.9 min (major), tR anti = 10.4 (minor) and 19.4 min
(major).
parameters, R(F, F2 > 2 ) = 0.039, Rw(F2, all data) = 0.105, goodness
r
of fit = 1.06, final difference map extremes +0.34 and ꢀ0.19 e Åꢀ3
.
4.2.5. (2S,10R)-and (2S,10S)-2-[10-Hydroxy-10-(3-nitrophenyl)-
methyl]cyclohexanone 4e/5e11,27,28
Obtained as a yellow oil in 22–89% yield. dH(syn) 8.2–8.1 (2H, m,
ArH), 7.67 (1H, d J 7.7 Hz, ArH), 7.52 (1H, t J 7.9 Hz, ArH), 5.47 (1H,
d J 2.0 Hz, CHOH), 3.16 (1H, br, OH), 2.7–2.6 (1H, m, CH), 2.5–2.3
(2H, m, CH), 2.2–2.0 (1H, m, CH), 1.9–1.5 (5H, m, CH); dH(anti)
8.2–8.1 (2H, m, ArH), 7.67 (1H, d J 7.7 Hz, ArH), 7.52 (1H, t J
7.9 Hz, ArH), 4.89 (1H, d J 8.5 Hz, CHOH), 4.10 (1H, br, OH), 2.7–
2.6 (1H, m, CH), 2.5–2.3 (2H, m, CH), 2.2–2.1 (1H, m, CH), 1.9–1.5
(5H, m, CH); m/z(ES+) 521 (2M+Na+, 100), 454 (30), 347 (25), 226
(60); Found (ES+) 521.1887, C26H30N2O4Na (2M+Na)+ requires
521.1900; HPLC: AD-H column, hexane/iPrOH (95:5) as solvent
system, flow rate 0.5 mL/min, detection at 254 nm, tR syn = 63.0
(major) and 48.8 min (minor), tR anti = 98.4 (major) and 70.1 min
(minor).
4.2.9. (2S,10R)- and (2S,10S)-2-[10-Hydroxy-10-(4-nitrophenyl)-
methyl]cyclopentanone 11c/12c11a,27,28a,32c,39
Obtained as an orange solid in 99% yield. dH(syn): 8.21 (2H, d J
8.9 Hz, ArH), 7.51 (2H, d J 8.4 Hz, ArH), 5.42 (1H, br, CHOH), 2.70
(1H, br, OH), 2.5–2.0 (4H, m, CH), 2.0–1.4 (3H, m, CH); dH(anti)
8.21 (2H, d J 8.9 Hz, ArH), 7.53 (2H, d J 8.9 Hz, ArH), 4.84 (1H, d J
9.1 Hz, CHOH), 4.78 (1H, br, OH), 2.5–2.0 (3H, m, CH), 2.0–1.4
(4H, m, CH). HPLC: AS-H column, hexane/iPrOH (85:15) as solvent
system, flow rate 0.8 mL/min, detection at 254 nm, tR syn = 18.7
(major) and 36.5 min (minor), tR anti = 20.1 (minor) and 24.6 min
(major).
4.2.6. (2S,10R)-2-[10-Hydroxy-10-pentafluorophenylmethyl]
cyclohexanone 4f28b
4.3. General procedure for (S)-proline-catalysed aldol reactions
involving acetone
Obtained as a white solid in 98–99% yield. Crystals of the anti-
diastereomer suitable for X-ray analysis were obtained by recrys-
tallisation from EtOAc/hexane. Mp 99–101 °C (lit.28b, 85–87 °C);
To a mixture of (S)-proline 3 (11.6 mg, 10 mol %) and aldehyde
(1 mmol) were added propylene or ethylene carbonate (1 ml) and
dry acetone (464 mg, 8 mmol) under an inert atmosphere. The
resulting mixture was stirred at room temperature for 24 h. The
reaction mixture was then poured into brine (5 ml) and water
(5 ml) and extracted with diethyl ether (10 ml). The organic phase
was washed with water (3 ꢂ 10 ml), dried (Na2SO4) and the sol-
vent was removed in vacuo. The residue was then purified by col-
umn chromatography on silica gel (hexane/EtOAc gradient from
4:1 to 1:1) to give aldol products 6a-f. Racemic HPLC standards
were prepared by a literature procedure.43
½
a 2D0
ꢃ
¼ ꢀ19:0 (c 0.1, CHCl3), (lit.28b
½
a 2D5
ꢃ
¼ ꢀ15:0 (c 1.78, CHCl3));
dH 5.26 (1H, d J 9.6 Hz, CHOH), 4.00 (1H, br, OH), 3.0–2.9 (1H, m,
CH), 2.6–2.5 (1H, m, CH), 2.1–2.0 (1H, m, CH), 1.9–1.7 (2H, m,
CH), 1.7–1.5 (3H, m, CH), 1.3–1.2 (1H, m, CH); dC 214.0 (CO),
145.2 (ddd, J 311.6, 10.5, 4.9 Hz, ortho-ArCF), 140.8 (dtt, J 317.9,
16.8, 6.5 Hz, para-ArCF), 137.5 (dtt, J 316.1, 15.8, 4.8 Hz, meta-
ArCF), 113.7 (td, J 19.4, 3.8 Hz, ArC), 65.8 (CH), 54.2 (CH), 42.3
(CH2), 30.1 (CH2), 27.5 (CH2), 24.4 (CH2); dF –176.5 (2F, d J
21.1 Hz ortho-CF), –192.6 (1F, t J 23.6 Hz, para-CF), –201.9 (2F, br,
meta-CF); m/z(ES+) 317 (M+Na+, 12), 270 (20), 258 (30), 226 (70),
185 (100); Found (ES+) 317.0573, C13H11F5O2Na (M+Na)+ requires
317.0577; HPLC: AD-H column, hexane/iPrOH (88:12) as solvent
system, flow rate 0.5 mL/min, detection at 210 nm, tR anti = 13.9
(major) and 17.2 min (minor). Crystal data for 4f: C13H11F5O2,
M = 294.2, monoclinic, C2, a = 16.1976(18), b = 5.5004(7),
c = 27.518(4) Å, b = 95.313(11)°, V = 2441.2(5) Å3, Z = 8, 6314 mea-
sured data, 3737 unique, Rint = 0.027, 369 refined parameters, R(F,
4.3.1. (R)-4-Hydroxy-4-(4-nitrophenyl)-2-butanone 6a11,32a,34
Obtained as yellow crystals in 96–97% yield. Mp 59–61 °C (lit.43
59–61 °C); ½a 2D0
ꢃ
¼ þ45:7 (c 0.1, CHCl3), (lit.34a
½
a 2D2
ꢃ
¼ þ66:2 (c 0.5,
CHCl3)); dH 8.21 (2H, d J 8.8 Hz, ArH), 7.54 (2H, d J 8.4 Hz, ArH),
5.27 (1H, m, CHOH), 3.58 (1H, d J 3.2 Hz, OH), 2.8–2.9 (2H, m,
CH2CHOH), 2.22 (3H, s, CH3); HPLC: AS-H column, hexane/iPrOH
(70:30) as solvent system, flow rate 0.5 mL/min, detection at
254 nm, tR = 25.1 (major) and 32.0 min (minor).
F2 > 2 ) = 0.036, Rw(F2, all data) = 0.088, goodness of fit = 1.08, final
r
difference map extremes +0.17 and ꢀ0.21 e Åꢀ3
.
4.3.2. (R)-4-Hydroxy-4-phenyl-2-butanone 6b34
4.2.7. (2S,10R)- and (2S,10S)-2-[10-Hydroxy-10-(4-nitrophenyl)-
methyl]4-oxocyclohexanone 11a/12a28b,37
Obtained as a white solid in 74–99% yield. dH(syn): 8.14 (2H, d J
8.6 Hz, ArH), 7.50 (2H, d J 8.6 Hz, ArH), 5.45 (1H, br, CHOH), 4.0–3.7
(2H, m, 2 ꢂ CHO), 3.21 (1H, br, OH), 2.7–2.3 (5H, m, CH); dH(anti)
8.14 (2H, d J 8.6 Hz, ArH), 7.50 (2H, d J 8.6 Hz, ArH), 4.93 (1H, d J
8.1 Hz, CHOH), 4.3–3.7 (4H, m, CH2OCH2), 3.43 (1H, t J 9.8 Hz,
Obtained as a yellow oil in 58–72% yield. ½a D20
¼ þ40:8 (c 0.1,
ꢃ
CHCl3), (lit.44
½
a 2D0
ꢃ
¼ þ58:6 (c 0.39, CHCl3)); dH 7.4–7.2 (5H, m,
ArH), 5.15 (1H, dd J 8.8, 3.6 Hz, CHOH), 3.19 (1H, br, OH), 2.88
(1H, dd J 17.5, 8.8 Hz, CH2CHOH), 2.79 (1H, dd J 17.5, 3.5 Hz,
CH2CHOH), 2.18 (3H, s, CH3); m/z(EI) 164 (M+, 5), 147 (30), 131
(20), 105 (100), 77(10); Found (ES+) 187.0721, C10H12O2Na
(M+Na+) requires 187.0735; HPLC: AD-H column, hexane/iPrOH

1270
W. Clegg et al. / Tetrahedron: Asymmetry 21 (2010) 1262–1271
(97:3) as solvent system, flow rate 1.0 mL/min, detection at
215 nm, tR = 23.1 (major) and 26.2 min (minor).
compound 7 (643 mg, 95%) suitable for X-ray analysis. Mp 155–
156 °C; ½a 2D0
¼ þ56:0 (c 0.1, CHCl3); mmax 3349 (m), 3118 (w),
ꢃ
2985 (w), 1751 (s), 1717 (s), 1537 (s) and 1534 cmꢀ1 (s); dH 7.39
(2H, d J 8.8 Hz, ArH), 7.23 (2H, d J 8.8 Hz, ArH), 6.67 (1H, br, NH),
6.45 (1H, t J 7.0 Hz, CH), 3.41 (1H, dd J 7.8, 17.8 Hz, CH2), 3.05
(1H, dd J 6.2, 17.8 Hz, CH2), 2.21 (3H, s, CH3); dC 203.5 (CO),
151.8 (NCO2), 145.2 (dddd J 315, 20, 10, 6 Hz, ortho-ArCF), 137.6
(dtt J 319, 17, 6 Hz, para-ArCF), 136.3 (ArC), 132.1 (ArCH), 120.3
(ArC), 116.6 (dtd J 319, 15, 6 Hz, meta-ArCF), 113.0 (t J 18 Hz,
ArC) dF ꢀ176.6 (2F, d J 18 Hz), ꢀ191.2 (1F, br), ꢀ201.5 (2F, br);
m/z(ES+) 475 (20), 473 (36), 347 (100), 185 (20); Found (ES+)
473.9727 C17H1179BrNO3F5Na (M+Na+) requires 473.9740. Crystal
4.3.3. (R)-4-Hydroxy-4-(4-bromophenyl)-2-butanone 6c34
Obtained as a yellow oil in 71–76% yield. ½a D20
¼ þ43:1 (c 0.1,
ꢃ
CHCl3), (lit.34b
½
a 2D7
ꢃ
¼ þ48:3 (c 0.8, CHCl3)); dH 7.45 (2H, dd J 8.4,
2.5 Hz, ArH), 7.21 (2H, dd J 8.4, 2.1 Hz, ArH), 5.1–5.2 (1H, m, CHOH),
3.17 (1H, br, OH), 2.8–2.9 (2H, m, CH2CHOH), 2.18 (3H, s, CH3); m/
z(ES+) 267 ((81Br)M+Na, 12), 265 ((79Br)M+Na, 12), 258
((81Br)MꢀOH+OCH3, 100), 256 ((79Br)MꢀOH+OCH3, 100), 185
(70); Found (ES+) 264.9834, C10H11O279BrNa (M+Na)+ requires
264.9840. HPLC: AS-H column, hexane/iPrOH (85:15) as solvent
system, flow rate 0.5 mL/min, detection at 220 nm, tR = 20.6 (ma-
jor) and 23.8 min (minor).
data:
C
17H11BrF5NO3,
M = 452.2,
orthorhombic,
P212121,
a = 5.657(4), b = 16.574(12), c = 19.058(13) Å, V = 1787(2) Å3,
Z = 4, 10358 measured data, 2845 unique, Rint = 0.047, 246
refined parameters, R(F, F2 > 2 ) = 0.051, Rw(F2, all data) = 0.144,
r
4.3.4. (R)-4-Hydroxy-4-(4-trifluoromethylphenyl)-2-butanone
goodness of fit = 1.07, final difference map extremes +0.57 and
6d34a
ꢀ0.31 e Åꢀ3
.
Obtained as a yellow oil in 94–95% yield. ½a D20
ꢃ
¼ þ44:8 (c 0.1,
CHCl3), (lit.34a
½
a 2D2
ꢃ
¼ þ57:6 (c 0.51, CHCl3));
m
max(neat) 3435
(br), 2980 (w), 2925 (w) and 1711 cmꢀ1 (m); dH 7.58 (2H, d J
8.2 Hz, ArH), 7.45 (2H, d J 8.2 Hz, ArH), 5.18 (1H, dd J 7.7,
4.6 Hz, CHOH), 3.67 (1H, br, OH), 2.8–2.9 (2H, m, CH2), 2.17
(3H, s, CH3); dC 208.7 (CO), 146.7 (ArC), 129.5 (q J 4.3 Hz, ArC),
125.9 (ArCH), 125.4 (ArCH), 124.4 (q J 40.6 Hz, CF3); dF ꢀ78;
m/z(EI) 232 (M+, 5), 215 (42), 199 (25), 173 (93), 145 (73);
Found (ESꢀ) 231.0636 C11H10O2F3 (MꢀH)ꢀ requires 231.0633.
HPLC: AS-H column, hexane/iPrOH (85:15) as solvent system,
flow rate 0.5 mL/min, detection at 210 nm, tR = 13.8 (major)
and 15.5 min (minor).
4.5. Ethyl (R)-2-hydroxy-((S)-2-oxocyclohexyl)-2-phenylacetate 13
To a mixture of (S)-proline 3 (30–50 mol %) and ethyl phen-
ylglyoxalate (178 mg, 1 mmol) were added ethylene or propylene
carbonate (1 ml) and cyclohexanone (980 mg, 10 mmol) under an
inert atmosphere. The resulting mixture was stirred at room tem-
perature for 3–20 days. The reaction mixture was then poured into
brine (5 ml) and water (5 ml) and extracted with diethyl ether
(10 ml). The organic phase was washed with water (3 ꢂ 10 ml),
dried (Na2SO4) and the solvent was removed in vacuo. The residue
at this stage was analysed by 1H NMR spectroscopy to obtain the
diasteroselectivity. The residue was then purified by column chro-
matography on silica gel (hexane/iPrOH 1:5) to give aldol product
4.3.5. (R)-4-Hydroxy-4-(3-nitrophenyl)-2-butanone 6e34b,c
Obtained as a yellow oil in 84–95% yield. ½a D20
¼ þ54:2 (c 0.1,
ꢃ
13 as a pale yellow oil in 49–57% yield. ½a D20
¼ ꢀ138:8 (c 0.1,
ꢃ
CHCl3), (lit.44
½
a 2D7
ꢃ
¼ þ58:9 (c 0.45, CHCl3)); dH 8.23 (1H, t J
CHCl3), (lit.40a
½
a 2D5
ꢃ
¼ ꢀ139:6 (c 1.0, CHCl3) for 96% ee); dH 7.59
1.9 Hz, ArH), 8.13 (1H, ddd J 8.1, 2.2, 1.0 Hz, ArH), 7.71 (1H, d J
7.7 Hz, ArH), 7.52 (1H, t J 7.9 Hz, ArH), 5.2–5.3 (1H, m, CHOH),
3.62 (1H, d J 2.8 Hz, OH), 2.8–2.9 (2H, m, CH2), 2.22 (3H, s, CH3);
m/z(ES+) 228 (MH+H2O+, 40), 226 (100), 185 (50); Found (ES+)
418.1360, C20H22N2O8 (2M+) requires 418.1376; HPLC: AD-H col-
umn, hexane/iPrOH (95:5) as solvent system, flow rate 0.5 mL/
min, detection at 254 nm, tR = 65.4 (major) and 70.6 min (minor).
(2H, d J 8.4 Hz, ArH), 7.4–7.2 (3H, m, ArH), 4.3–4.1 (2H, m, CH2CH3),
3.88 (1H, s, OH), 3.41 (1H, dd J 11.1, 6.2, CHCOH), 2.5–2.3 (2H, m,
CH2), 2.1–2.0 (1H, m, CH), 1.8–1.7 (1H, m, CH), 1.7–1.5 (4H, m, 2
CH2), 1.23 (3H, t J 7.1 Hz, CH2CH3); HPLC: AD-H column, hex-
ane/iPrOH (90:10) as solvent system, flow rate 0.5 mL/min, detec-
tion at 210 nm, tR anti = 29.8 (major) and 23.0 min (minor). A
racemic HPLC standard was prepared by a literature procedure,40a
but using racemic proline as a catalyst.
4.3.6. (R)-4-hydroxy-4-(pentafluorophenyl)-2-butanone 6f
Obtained as a yellow oil in 85–99% yield. ½a D20
¼ þ6:7 (c 0.1,
ꢃ
4.6. (R)-2-(Phenylaminooxy)propan-1-ol 14
CHCl3); mmax 3400 (br), 2950 (w), 2910 (w), 1715 (m) and
1500 cmꢀ1 (s); dH 5.55 (1H, dd J 9.6, 3.2 Hz, CHOH), 3.32 (1H, br,
OH), 3.31 (1H, dd J 18.1, 9.6 Hz, CH2CHOH), 2.83 (1H, dd J 18.1,
3.3 Hz, CH2CHOH), 2.23 (3H, s, CH3); dC 207.5 (CO), 145.1 (dddd J
310, 20, 11, 5 Hz, ortho-ArCF), 141.1 (dtt J 319, 16, 7 Hz para-ArCF),
137.8 (dtd J 315, 20, 6 Hz, meta-ArCF), 115.2 (t J 20 Hz, ArC), 61.4
(CHOH), 48.5 (CH2CO), 30.5 (CH3); dF –177.9 (2F, d J 21 Hz),
ꢀ192.9 (1F, t J 24 Hz), ꢀ201.9 (2F, br); m/z(ESꢀ) 507 ((2MꢀH)ꢀ,
10), 253 ((MꢀH)ꢀ, 20); Found (ESꢀ) 253.0284, C10H6O2F5 (MꢀH)ꢀ
requires 231.0288; HPLC: AD-H column, hexane/iPrOH (98:2) as
solvent system, flow rate 0.5 mL/min, detection at 210 nm,
tR = 44.1 (major) and 53.1 min (minor).
To a suspension of (S)-proline 3 (12 mg, 0.1 mmol) and nitroso-
benzene (107 mg, 1.0 mmol) in ethylene or propylene carbonate
(0.66 ml) at 0–20 °C under nitrogen, propanal (0.22 ml, 3.0 mmol)
was added. The reaction mixture was stirred for 2 h, and then
the product was extracted with EtOAc (2 ꢂ 5 ml) and washed with
water (5 ꢂ 10 ml). The solvent was removed in vacuo and the res-
idue was dissolved in EtOH (1 ml) and added dropwise to a suspen-
sion of NaBH4 (400 mg) in EtOH (3 ml) at 0 °C. The resulting
suspension was stirred for 30 min, then a saturated aqueous solu-
tion of KHCO3 (10 ml) was added. The reaction mixture was ex-
tracted with EtOAc (2 ꢂ 10 ml), washed with brine (2 ꢂ 10 ml),
dried over Na2SO4 and evaporated in vacuo to leave an oil, which
was purified by column chromatography (hexane/EtOAc, 4:1) to
give alcohol 14 as a yellow oil in 33–85% yield. dH 7.3–7.2 (2H,
m, ArH), 7.0–6.9 (3H, m, ArH), 4.2–4.1 (1H, m, CHCH3), 3.8–3.7
(2H, m, CH2OH), 1.26 (3H, d J 6.4 Hz, CHCH3). HPLC: AD-H column,
hexane/iPrOH (95:5) as solvent system, flow rate 0.5 mL/min,
detection at 244 nm, tR = 17.1 (major) and 14.4 min (minor). A
racemic HPLC standard was prepared by a literature procedure,41
but using racemic proline as catalyst.
4.4. O-[(R)-1-(Pentafluorophenyl)-3-oxobutyl]-N-(4-bromo-
phenyl) carbamate 7
A mixture of compound 6f (381 mg, 1.5 mmol) and 4-bromo-
phenyl isocyanate (297 mg, 1.5 mmol) in CHCl3 (7 ml) was stirred
at room temperature for five days. The solvent was removed in va-
cuo and the residue was washed with diethyl ether to give a white
powder which was recrystallised from CHCl3 to give crystals of

W. Clegg et al. / Tetrahedron: Asymmetry 21 (2010) 1262–1271
1271
26. For a preliminary report of some of this work see: North, M.; Pizzato, F.;
Villuendas, P. ChemSusChem 2009, 2, 862–865.
Acknowledgements
27. Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III J.
Am. Chem. Soc. 2006, 128, 734–735.
28. (a) Wu, Y.; Zhang, Y.; Yu, M.; Zhao, G.; Wang, S. Org. Lett. 2006, 8, 4417–4420;
(b) Gruttadauria, M.; Giacalone, F.; Marculescu, A. M.; Meo, P. L.; Riela, S.; Noto,
R. Eur. J. Org. Chem. 2007, 4688–4698.
29. For reviews see: (a) Paradowska, J.; Stodulski, M.; Mlynarski, J. Angew. Chem.,
Int. Ed. 2009, 48, 4288–4297; (b) Raja, M.; Singh, V. K. Chem. Commun. 2009,
6687–6703.
30. (a) Nyberg, A. I.; Usano, A.; Pihko, P. M. Synlett 2004, 1891–1896; (b) Pihko, P.
M.; Laurikainen, K. M.; Usano, A.; Nyberg, A. I.; Kaavi, J. A. Tetrahedron 2006, 62,
317–328; (c) Angelici, G.; Corrêa, R. J.; Garden, S. J.; Tomasini, C. Tetrahedron
Lett. 2009, 50, 814–817.
31. (a) Zotova, N.; Franzke, A.; Armstrong, A.; Blackmond, D. G. J. Am. Chem. Soc.
2007, 129, 15100–15101; (b) Zotova, N.; Broadbelt, L. J.; Armstrong, A.;
Blackmond, D. G. Bioorg. Med. Chem. Lett. 2009, 19, 3934–3937; (c) Zotova, N.;
Moran, A.; Armstrong, A.; Blackmond, D. G. Adv. Synth. Catal. 2009, 351, 2765–
2769.
32. (a) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III J. Am. Chem. Soc. 2001, 123,
5260–5267; (b) Sekiguchi, Y.; Sasaoka, A.; Shimomoto, A.; Fujioka, S.; Kotsuki,
H. Synlett 2003, 1655–1658; (c) Wu, Y. S.; Chen, Y.; Deng, D.-S.; Cai, J. Synlett
2005, 1627–1629; (d) Kucherenko, A. S.; Struchkova, M. I.; Zlotin, S. G. Eur. J.
Org. Chem. 2006, 2000–2004; (e) Hayashi, Y.; Aratake, S.; Itoh, T.; Okano, T.;
Sumiya, T.; Shoji, M. Chem. Commun. 2007, 957–959; (f) Zhou, W.; Xu, L.-W.;
Qiu, H.-Y.; Lai, G.-Q.; Xia, C.-G.; Jiang, J.-X. Helv. Chim. Acta 2008, 91, 53–59.
33. (a) Kitamura, M.; Nakano, K.; Miki, T.; Okada, M.; Noyori, R. J. Am. Chem. Soc.
2001, 123, 8939–8950; (b) Kitamura, M.; Nakano, K. Cryst. Growth Des. 2003, 3,
25–34; (c) Wu, Y.-S.; Shao, W.-Y.; Zheng, C.-Q.; Huang, Z.-L.; Cai, J.; Deng, Q.-Y.
Helv. Chim. Acta 2004, 87, 1377–1384.
34. (a) Tang, Z.; Yang, Z.-H.; Chen, X.-H.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-
Z. J. Am. Chem. Soc. 2005, 127, 9285–9289; (b) Zhou, Y.; Shan, Z. Tetrahedron:
Asymmetry 2006, 17, 1671–1677; (c) Chandrasekhar, S.; Reddy, N. R.; Sultana,
S. S.; Narsihmulu, C.; Reddy, K. V. Tetrahedron 2006, 62, 338–345.
35. (a) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 2395–2396;
(b) Martin, H. J.; List, B. Synlett 2003, 1901–1902; (c) Mossé, S.; Alexakis, A. Org.
Lett. 2006, 8, 3577–3580; (d) Zhou, Y.; Shan, Z. J. Org. Chem. 2006, 71, 9510–
9512; (e) Hosseini, M.; Stiasni, N.; Barbieri, V.; Kappe, C. O. J. Org. Chem. 2007,
72, 1417–1424.
The authors thank Newcastle University for financial support
and a studentship to F.P., EPSRC for funding for a diffractometer
and for the National Crystallography Service, and Diamond Light
Source for access to synchrotron facilities.
References
1. Bredig, G.; Fiske, P. S. Biochem. Z. 1912, 46, 7.
2. Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971, 10, 496–497.
3. Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615–1621.
4. (a) List, B. Synlett 2001, 1675–1686; (b) Gröger, H.; Wilken, J. Angew. Chem., Int.
Ed. 2001, 40, 529–532; (c) List, B. Tetrahedron 2002, 58, 5573–5590; (d) List, B.
Acc. Chem. Res. 2004, 37, 548–557; (e) Kazmaier, U. Angew. Chem., Int. Ed. 2005,
44, 2186–2188.
5. (a) Pellissier, H. Tetrahedron 2007, 63, 9267–9331; (b) Gaunt, M. J.; Johansson,
C. C. C.; McNally, A.; Vo, N. T. Drug Discovery Today 2007, 12, 8–27; (c) Dondoni,
A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638–4660; (d) Melchiorre, P.;
Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138–6171.
6. Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58, 2481–2495.
7. Kacprzak, K.; Gawron´ ski, J. Synthesis 2001, 961–998.
8. (a) Brogan, A. P.; Dickerson, T. J.; Janda, K. D. Angew. Chem., Int. Ed. 2006, 45,
8100–8102; (b) Hayashi, Y. Angew. Chem., Int. Ed. 2006, 45, 8103–8104; (c)
Gruttadauria, M.; Giacalone, F.; Noto, R. Adv. Synth. Catal. 2009, 351, 33–57.
ˇ
9. Toma, S.; Meciarova, M.; Šebesta, R. Eur. J. Org. Chem. 2009, 321–327.
10. (a) Blackmond, D. G.; Armstrong, A.; Coombe, V.; Wells, A. Angew. Chem., Int. Ed.
2007, 46, 3798–3800; (b) Wu, B.; Liu, W.; Zhang, Y.; Wang, H. Chem. Eur. J.
2009, 15, 1804–1810.
11. (a) Rodríguez, B.; Rantanen, T.; Bolm, C. Angew. Chem., Int. Ed. 2006, 46, 6924–
6926; (b) Rodríguez, B.; Bruckmann, A.; Bolm, C. Chem. Eur. J. 2007, 13, 4710–
4722.
12. Clements, J. H. Ind. Eng. Chem. Res. 2003, 42, 663–674.
13. Silva, L. B.; Freitas, L. C. G. J. Mol. Struct. THEOCHEM 2007, 806, 23–34.
14. Reetz, M. T.; Lohmer, G. Chem. Commun. 1996, 1921–1922.
15. (a) Behr, A.; Naendrup, F.; Obst, D. Adv. Synth. Catal. 2002, 344, 1142–1145; (b)
Behr, A.; Naendrup, F.; Obst, D. Eur. J. Lipid Sci. Technol. 2002, 104, 161–166.
16. (a) Bayardon, J.; Holz, J.; Schäffner, B.; Andrushko, V.; Verevkin, S.; Preetz, A.;
Börner, A. Angew. Chem., Int. Ed. 2007, 46, 5971–5974;(b)Preetz, A.; Drexler, H.-J.;
Fischer, C.; Dai, Z.; Börner, A.; Baumann, W.;Spannenberg, A.; Thede, R.; Heller, D.
Chem. Eur. J. 2008, 14, 1445–1451; (c) Schnäffner, B.; Holz, J.; Verevkin, S. P.;
Börner, A. Tetrahedron Lett. 2008, 49, 768–771; (d) Schäffner, B.; Andrushko, V.;
Holz, J.; Verevkin, S. P.; Börner, A. ChemSusChem 2008, 1, 934–940.
17. Schnäffner, B.; Holz, J.; Verevkin, S. P.; Börner, A. ChemSusChem 2008, 1, 249–
253.
36. Fowler, F. W.; Katritzky, A. R.; Rutherford, R. J. D. J. Chem. Soc. (B) 1971, 3, 460–
469.
37. (a) Dinér, P.; Amedjkouh, M. Org. Biomol. Chem. 2006, 2091–2096; (b) Chen, J.
R.; Li, X. Y.; Xing, X. N.; Xiao, W. J. J. Org. Chem. 2006, 71, 8198–8202; (c) Long,
H.; Jiang, J.; Tang, Z.; Cui, X.; Mi, A. Q.; Jiang, Y. Z.; Gong, L. Z. Tetrahedron:
Asymmetry 2007, 18, 265–270; (d) Russo, A.; Botta, G.; Lattanzi, A. Tetrahedron
2007, 63, 11886–11892; (e) Li, X.-J.; Zhang, G.-W.; Wang, L.; Hua, M.-Q.; Ma, J.-
A. Synlett 2008, 1255–1259; (f) Guillena, G.; del Carmen Hita, M.; Nájera, C.;
Viózquez, S. F. J. Org. Chem. 2008, 73, 5933–5943.
18. North, M.; Omedes-Pujol, M. Tetrahedron Lett. 2009, 50, 4452–4454.
19. For reviews of the synthesis of cyclic carbonates see: (a) Yoshida, M.; Ihara, M.
Chem. Eur. J. 2004, 10, 2886–2893; (b) Sun, J.; Fujita, S.-i.; Arai, M. J. Organomet.
Chem. 2005, 690, 3490–3497; (c) Zevenhoven, R.; Eloneva, S.; Teir, S. Catal.
Today 2006, 115, 73–79; (d) Chankeshwara, S. V. Synlett 2008, 624–625; (e) Dai,
W.-L.; Luo, S.-L.; Yin, S.-F.; Au, C.-T. Appl. Catal., A 2009, 366, 2–12; (f) Sakakura,
T.; Kohno, K. Chem. Commun. 2009, 1312–1330.
20. (a) Tullo, A. H.; Short, P. L. Chem. Eng. News 2006, 84, 22–23; See also: (b)
Meiers, R.; Dingerdissen, U.; Hölderich, W. F. J. Catal. 1998, 176, 376–386; (c)
Jenzer, G.; Mallat, T.; Maciejewski, M.; Eigenmann, F.; Baiker, A. Appl. Catal., A
2001, 208, 125–133; (d) Li, G.; Wang, X.; Yan, H.; Chen, Y.; Su, Q. Appl. Catal., A
2001, 218, 31–38; (e) Taylor, B.; Lauterbach, J.; Blau, G. E.; Delgass, W. N. J.
Catal. 2006, 242, 142–152.
21. Chen, Q.; Beckman, E. J. Green Chem. 2007, 9, 802–808.
22. (a) Chen, Q.; Beckman, E. J. Green Chem. 2008, 10, 934–938; See also: (b)
Sheldon, R. A. Chem. Commun. 2008, 3352–3365.
23. (a) Meléndez, J.; North, M.; Pasquale, R. Eur. J. Inorg. Chem. 2007, 3323–3326;
(b) Meléndez, J.; North, M.; Pasquale, R. Angew. Chem., Int. Ed. 2009, 48, 2946–
2948; (c) Meléndez, J.; North, M.; Villuendas, P. Chem. Commun. 2009, 2577–
2579.
24. North, M.; Villuendas, P.; Young, C. Chem. Eur. J. 2009, 11454–11457.
25. Metcalfe, I. S.; North, M.; Pasquale, R.; Thursfield, A. Energy Environ. Sci. 2010, 3,
212–215.
38. Jiang, J.; He, L.; Luo, S.-W.; Cun, L.-F.; Gong, L.-Z. Chem. Commun. 2007, 736–
738.
39. (a) Yang, H.; Carter, R. G. Org. Lett. 2008, 10, 4649–4652; (b) Gandhi, S.; Singh,
V. K. J. Org. Chem. 2008, 73, 9411–9416; (c) Da, C.-S.; Che, L.-P.; Guo, Q.-P.; Wu,
F.-C.; Ma, X.; Jia, Y.-N. J. Org. Chem. 2009, 74, 2541–2546; (d) Shiomi, T.; Adachi,
T.; Ito, J.; Nishiyama, H. Org. Lett. 2009, 11, 1011–1014.
40. (a) Tokuda, O.; Kano, T.; Gao, W.-G.; Ikemoto, T.; Maruoka, K. Org. Lett. 2005, 7,
5103–5105; (b) Cordova, A.; Zou, W.; Dziedzic, P.; Ibrahem, I.; Reyes, E.; Xu, Y.
Chem. Eur. J. 2006, 5383–5397.
41. (a) Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247–4280; (b) Merino, P.; Tejero,
T. Angew. Chem., Int. Ed. 2004, 43, 2995–2997; (c) Brown, S. P.; Brochu, M. P.;
Sinz, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 10808–10809; (d)
Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M. Tetrahedron Lett. 2003, 44,
8293–8296; (e) Córdova, A.; Sundén, H.; Bøgevig, A.; Johansson, M.; Himo, F.
Chem. Eur. J. 2004, 3673–3684; (f) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.;
Hibino, K.; Shoji, M. J. Org. Chem. 2004, 69, 5966–5973; (g) Huang, K.; Huang,
Z.-Z.; Li, X.-L. J. Org. Chem. 2006, 71, 8320–8323.
42. Billimoria, J. D. J. Chem. Soc. 1955, 1126–1129.
43. Shokat, K.; Uno, T.; Schultz, P. G. J. Am. Chem. Soc. 1994, 116, 2261–2270.
44. Zhou, Y.; Shan, Z. Tetrahedron 2006, 62, 5692–5696.