Water versus solvent-free conditions for the enantioselective inter- and intramolecular aldol reaction employing l-prolinamides and l-prolinethioamides as organocatalysts

Article abstract of DOI:10.1002/adsc.200800814

Organocatalysts 1, derived from L-proline and (1S,2R)-cis-l-aminoindan-2-ol or (R)-l-aminoin-dane, are evaluated as promoters in the direct asymmetric aldol reaction between ketones and aromatic aldehydes in the presence of water and under solvent-free reaction conditions. L-Prolinethioamides 1c and 1d exhibited higher enantioselectivity than the corresponding prolinamides 1a and 1b in the model aldol reaction between cyclohexanone and 4-nitro-benzaldehyde in the presence of 4-nitrobenzoic acid as cocatalyst. In particular, L-prolinethioamide 1d (5 mol%), derived from L-proline and (R)-1-amino-indane, is shown as the most efficient organocatalyst studied promoting the direct aldol reaction of cyclo-alkyl, alkyl, and a-functionalized ketones with aromatic aldehydes in the presence of water and under solvent-free reaction conditions employing only 2 equivalents of nucleophile. Generally, anft-aldol products are obtained in high yields and excellent diastereo- and enantioselectivities (up to > 98/2 until syn, up to 98% ee). Solvent-free conditions give slightly higher dr and ee than using water as solvent. In addition, organocatalyst Id can be easily recovered by extractive work-up and reused. Prolinethio-amide Id (5 mol%) in combination with 4-NO2C6H4CO2H (5 mol%) is also a very effective or-ganocatalytic system for the asymmetric solvent-free intramolecular Haj os-Parrish-Eder-Sauer-Wiechert reaction with comparable or higher levels of enantioselectivity (up to 88% ee) to other reported catalysts in organic solvents.

Full text of DOI:10.1002/adsc.200800814

FULL PAPERS
DOI: 10.1002/adsc.200800814
Water versus Solvent-Free Conditions for the Enantioselective
Inter- and Intramolecular Aldol Reaction Employing
l-Prolinamides and l-Prolinethioamides as Organocatalysts
a
a,
a
Diana Alma s¸ i, Diego A. Alonso, * Andrea-Nekane Balaguer,
a
and Carmen Nꢀjera
Departamento de Quꢁmica Orgꢀnica and Instituto de Sꢁntesis Orgꢀnica (ISO), Facultad de Ciencias, Universidad de
Alicante, Apartado 99, 03080, Alicante, Spain
a
Fax : (+34)-96-590-3549; e-mail: diego.alonso@ua.es or cnajera@ua.es
Received: December 29, 2008; Revised: February 3, 2009
Dedicated to Professor Armin de Meijere on the occasion of his 70th birthday
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800814.
Abstract: Organocatalysts 1, derived from l-proline equivalents of nucleophile. Generally, anti-aldol
and (1S,2R)-cis-1-aminoindan-2-ol or (R)-1-aminoin- products are obtained in high yields and excellent
dane, are evaluated as promoters in the direct asym- diastereo- and enantioselectivities (up to >98/2 anti/
metric aldol reaction between ketones and aromatic syn, up to 98% ee). Solvent-free conditions give
aldehydes in the presence of water and under sol- slightly higher dr and ee than using water as solvent.
vent-free reaction conditions. l-Prolinethioamides 1c In addition, organocatalyst 1d can be easily recov-
and 1d exhibited higher enantioselectivity than the ered by extractive work-up and reused. Prolinethio-
corresponding prolinamides 1a and 1b in the model
ACHTUNGTRENUNNGa mide 1d (5 mol%) in combination with 4-
aldol reaction between cyclohexanone and 4-nitro- NO C H CO H (5 mol%) is also a very effective or-
2
6
4
2
benzaldehyde in the presence of 4-nitrobenzoic acid ganocatalytic system for the asymmetric solvent-free
as cocatalyst. In particular, l-prolinethioamide 1d intramolecular Hajos–Parrish–Eder–Sauer–Wiechert
(
5 mol%), derived from l-proline and (R)-1-amino- reaction with comparable or higher levels of enantio-
indane, is shown as the most efficient organocatalyst selectivity (up to 88% ee) to other reported catalysts
studied promoting the direct aldol reaction of cyclo- in organic solvents.
alkyl, alkyl, and a-functionalized ketones with aro-
matic aldehydes in the presence of water and under Keywords: aldol reaction; asymmetric organocataly-
solvent-free reaction conditions employing only 2 sis; prolinethioamides; solvent-free reaction; water
Introduction
as DMSO, DMF, and chlorinated solvents or using a
large excess of nucleophile which allows it to act as
[
1]
The direct asymmetric aldol reaction is one of the reaction medium as well. The necessity to further
most useful synthetic methods for the synthesis of reduce sources of pollution, such as the sometimes
chiral polyol derivatives. Asymmetric organocataly- employed chlorinated solvents, has prompted scien-
[2]
sis has recently devoted a great emphasis to the tists to search for organic reactions performed in the
[5]
[
4]
design of efficient chiral organocatalysts for the aldol presence of water or under solvent-free conditions.
reaction via in situ generated enamine intermedi- Organocatalysts that can perform in the presence of
[3]
ates. Organocatalyzed aldol reactions are very often water are of current interest because water is a desira-
environmentally friendly processes since no metal ble solvent with respect to environmental concerns,
[
6–8]
species are involved and the reactions can usually be safety, and cost.
On the other hand, organocata-
performed without the use of inert atmosphere and lyzed reactions under solvent-free conditions usually
anhydrous solvents. These reactions are typically per- need shorter reaction times and result in simple and
[
9]
formed under mild conditions in organic solvents such efficient work-up procedures. For these reasons, or-
Adv. Synth. Catal. 2009, 351, 1123 – 1131
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Diana Alma s¸ i et al.
FULL PAPERS
Figure 1. Prolineamide-derived organocatalysts for the
direct aldol reaction.
ganocatalyzed aldol reactions under solvent-free con-
ditions or employing water as solvent have become a
highly pursued goal in green chemistry.
Following our studies in the use of prolineamide-
derived organocatalysts as efficient promoters for CÀ
C bond forming processes, we have recently shown
that prolineamide 1a, derived from l-Pro and
(
1S,2R)-cis-1-amino-2-indanol (Figure 1), exhibits
good catalytic activity in the asymmetric conjugate
addition of ketones to nitrostyrenes in NMP as sol-
[11]
[10]
vent. On the other hand, we have communicated
that prolinethioamide 1d, derived from l-Pro and
R)-1-aminoindane (Figure 1), is a very efficient and
(
recyclable organocatalyst for the solvent-free direct
aldol reaction with excellent levels of anti-diastereose-
lectivity (up to >96%) and enantioselectivity (up to
Scheme 1. Synthesis of l-prolinethioamides 1c and 1d.
[12]
98% ee). Herein, we report a full account about the amined in the direct aldol reaction between cyclohex-
direct inter- and intramolecular aldol reactions cata- anone and 4-nitrobenzaldehyde in the presence of
lyzed by 1-aminoindane- and 1-aminoindanol-derived water (Method A) and under solvent-free conditions
prolinamides and prolinethioamides using water as with conventional magnetic stirring (Method B) at
solvent and under solvent-free conditions.
room temperature (Table 1). A preliminary study (see
Supporting Information) showed 4-nitrobenzoic acid
(
20 mol%) as the most efficient cocatalyst for the pro-
cess in the presence of water. As depicted in Table 1
entries 1–8) catalysts 1 exhibited high catalytic effi-
Results and Discussion
(
Prolinamides 1a and 1b were prepared in excellent ciency, especially prolinamide 1a under solvent-free
yields by reaction of N-Cbz-l-Pro with (1S,2R)-cis-1- conditions (Method B), which provided a very fast
aminoindan-2-ol and (R)-1-aminoindane, respectively, cross-aldol reaction (10 min) although with moderate
and final hydrogenolysis (see Supporting Informa- diastereo- and enantioselectivity (Table 1, entry 2). In
[10]
tion). On the other hand, catalysts 1c and 1d were general, the best results in terms of selectivity were
[
12]
prepared following reported procedures
from N- obtained when the reaction was carried out in the
Boc-l-Pro instead due to Cbz hydrogenolysis prob- presence of water (Method A) regardless of the cata-
lems associated with the presence of the thioamide lyst employed. The highest diastereo- and enantiose-
moiety. Thus, reaction of N-Boc-l-Pro with commer- lectivity was observed with prolinethioamide 1d
cially available (R)-1-aminoindane and (1S,2R)-cis-1- (Table 1, entry 7) still under a very short reaction
aminoindan-2-ol, led to N-Boc-l-prolinamide inter- time [anti/syn: 91/9, 89% ee (anti), 3 h] employing
mediates 2c and 2d, respectively (Scheme 1). Protec- water as solvent. Similar selectivities were observed
tion of the hydroxy function in 2c with TBDMSCl, for this catalyst under solvent-free conditions (entry 8,
followed by thiation with Lawessonꢃs reagent, and de- Method B), although a dramatic rate acceleration
protection of the amine and hydroxy functions with a took place and the reaction was completed after 1 h.
saturated solution of hydrogen chloride in dioxane Similar results but with opposite enantioselectivity
led to prolinethioamide 1c in good yield (Scheme 1). were obtained when ent-1d was used as catalyst under
A similar procedure, except for the hydroxy protec- solvent-free conditions (entry 9). At this point, differ-
tion, was followed to prepare prolinethioamide 1d ent reaction parameters were also studied in order to
from intermediate 2d in a 51% yield (Scheme 1).
improve the selectivity of the process. For instance,
The efficacy of organocatalysts 1 (20 mol%) using a under solvent-free conditions (Method B), the effica-
carboxylic acid as cocatalyst (20 mol%) was first ex- cy of catalyst 1d was similar when the reaction was
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Water versus Solvent-Free Conditions for the Enantioselective Aldol Reaction
FULL PAPERS
Table 1. Aldol reaction of cyclohexanone with 4-nitrobenzaldehyde catalyzed by 1 in the presence of water (Method A) and
under solvent-free conditions (Method B).
[a]
[b]
[b]
[c]
Entry
1 [mol%]
Method
T [8C]
Time [h]
Conv. [%]
anti/syn
ee [anti]
1
2
3
4
5
6
7
8
9
1a (20)
1a (20)
1b (20)
1b (20)
1c (20)
1c (20)
1d (20)
1d (20)
ent-1d (20)
1d (20)
1d (20)
1d (20)
1d (20)
1d (5)
A
B
A
B
A
B
A
B
B
B
B
A
B
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
12
0
3
95
99
97
99
99
97
99
99
99
98
98
96
97
98
99
99
95
87/13
79/21
77/23
70/30
88/12
82/18
91/9
89/11
85/15
91/9
87/13
91/9
92/8
98/2
94/6
81
64
71
58
87
71
89
88
À88
86
74
89
88
94
93
95
93
10 min
3
3
3
3
3
1
1
1
1
5
5
8
8
8
24
[
[
d]
e]
10
11
12
13
14
15
16
17
A
12
0
12
0
1d (5)
1d (5)
1d (5)
B[
f]
A
94/6
98/2
[
g]
B
[
a]
Method A: a mixture of the corresponding organocatalyst, 4-NO C H CO H, and cyclohexanone (4 equiv.) was stirred in
2
6
4
2
À1
water (0.5 mLmmol aldehyde) for 20 min before addition of 4-nitrobenzaldehyde (1 equiv.). Then, the reaction mixture
was stirred for the time indicated in the table. Method B: a mixture of the corresponding organocatalyst, 4-
NO C H CO H, and cyclohexanone (2 equiv.) was stirred for 20 min before addition of 4-nitrobenzaldehyde (1 equiv).
2
6
4
2
Then, the reaction mixture was stirred for the time indicated in the table.
Determined by HNMR over the crude reaction mixture.
Determined by chiral phase HPLC analysis over the crude reaction mixture.
The reaction was performed in a ball mill at 400 rpm.
[
[
[
[
b]
1
c]
d]
e]
1
d, 4-NO C H CO H, and 4-nitrobenzaldehyde were first dissolved in THF, then the solvent was evaporated and cyclo-
2 6 4 2
hexanone (2 equiv.) was added to the mixture, which was stirred for 1 h.
[
[
f]
2
1
equiv. of ketone were used.
equiv. of ketone was used.
g]
[
9a,b]
performed in a ball mill
(Table 1, entry 10). Re- Method B: 94/6 anti/syn, 93% ee) when reducing the
cently, a remarkable rate acceleration of solvent-free catalyst and cocatalyst loading to 5 mol% under low
organic reactions has been described by Otera et al. temperature conditions and longer reaction times
by immediate solvent evaporation due to the en- (Table 1, entries 14 and 15). Notably, reducing the
hancement of molecule to molecule contacts between amount of nucleophile to 2 equivalents in the case of
[13]
reactants. In our case, under conventional magnetic using water as solvent, and to 1 equivalent when
stirring with a pre-formed solution in THF and imme- working under solvent-free conditions (Table 1, en-
diate evaporation of the solvent, similar rate and tries 16 and 17) was sufficient to afford the reaction in
lower diastereo- (anti/syn: 87/13) and enantioselectivi- high yield and selectivity, although 8 and 24 h were
[
14]
ty (74% ee) were observed (Table 1, entry 11). The necessary for completion, respectively.
effect of the temperature in the process was also stud- The mechanism of the direct asymmetric aldol reac-
ied. When the reaction was perfored at lower temper- tion catalyzed by l-prolinethioamides has been previ-
1
ature (128C for Method A and 08C for Method B) no ously studied by H NMR and electrospray-ionization
improvement of the enantioselectivity was detected mass spectrometry (ESI-MS) techniques revealing
(
compare entries 7 and 8 with 12 and 13, respective- that the reaction proceeds through an enamine-imini-
[
15]
ly). Finally, we were pleased to observe an improve- um pathway. This could be confirmed for the aldol
ment of diastereo- and enantioselectivity for the both reaction between cyclohexanone and 4-nitrobenzalde-
methodologies (Method A: 98/2 anti/syn, 94% ee; hyde catalyzed by 1d/4-NO C H CO H in the pres-
2
6
4
2
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Diana Alma s¸ i et al.
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Table 2. Match/mismatch effect of prolinethioamides.
[
[
a]
b]
1
Determined by H NMR over the crude reaction mixture.
Determined by chiral-HPLC analysis over the crude reaction mixture.
ence of water (Method A) since the ESI-MS spectrum where the reaction time was too long in its absence.
in positive ion mode clearly displayed (see Supporting Under these conditions, the direct cross-aldol reaction
Information) a peak at m/z=327 probably corre- of other several acceptor aromatic aldehydes with ali-
sponding to the iminium intermediate.
phatic donor ketones was examined in order to study
Diastereomeric catalyst 4, prepared from l-Pro and the reaction scope using water as solvent and under
S)-1-aminoindane (see Supporting Information) was solvent-free conditions (Table 3). Reactions of cyclo-
(
also tested as promoter of the reaction in order to hexanone with a variety of electron-deficient aromatic
test possible match/mismatch effects in the process aldehydes containing a variety of substitution patterns
(
Table 2). It was found that, under optimized reaction provided the desired anti-aldol products in high isolat-
conditions, there was not a significant match/mis- ed yields (70–98%) with excellent diastereo- (95/5 to
match effect in the reaction between cyclohexanone >98/2 anti/syn) and enantioselectivities (88–98% ee)
(
2 equiv.) and 4-nitrobenzaldehyde (1 equiv.) (Table 2, (Table 3, entries 1–12). In general, under solvent-free
entries 1–4) the enantioselectivity of the process being conditions, slightly better stereoselectivities were ob-
controlled by the proline moiety. tained for all the studied reactions. The same trend
With respect to the recyclability of 1d, it is worthy was also observed for non-activated and deactivated
to mention that this organocatalyst could be easily re- aldehydes, such as benzaldehyde, 2-naphthaldehyde,
covered from the reaction mixture (Method A: 90% and 4-methylbenzaldehyde. In those cases, the aldol
recovery; Method B: 91% recovery) after extractive reaction proceeded smoothly with longer reaction
acid/base work-up (HCl/NaOH) and reused with simi- times even in the presence of 4-nitrobenzoic acid as
lar results since no loss of optical activity was detect- cocatalyst to give the aldol products 3ah, 3ai, and 3aj,
ed in the organocatalyst (see Supporting Informa- respectively, in moderate yields, high diastereoselec-
tion).
tivities and good enantioselectivities (Table 3, en-
Considerations of stereoselectivity and reaction tries 13–18).
time led us to focus our next study under the optimal
Heterocyclic cyclohexanones such as tetrahydro-
reaction conditions for Methods A and B, as follows: 4H-pyran-4-one, tetrahydro-4H-thiopyran-4-one, and
Method A: ketone (2 equiv.), aldehyde (1 equiv.), 1d N-Boc-4-piperidone reacted with 4-nitrobenzaldehyde
(
(
5 mol%), 4-nitrobenzoic acid (5 mol%), and H O leading to the corresponding anti-aldol adducts with
0.5 mLmmol aldehyde) at 128C or room tempera- high diastereo- and enantioselectivities (Table 3, en-
2
À1
ture; Method B: ketone (2 equiv.), aldehyde tries 19–24). Good results were obtained in the pres-
1 equiv.), and 1d (5 mol%) at 08C or room tempera- ence of water and under solvent-free conditions in
ture, and 4-nitrobenzoic acid (5 mol%) in those cases terms of yield and selectivity, though under the latter
(
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Water versus Solvent-Free Conditions for the Enantioselective Aldol Reaction
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Table 3. Aldol reactions of cycloalkanones with aldehydes catalyzed by 1d
in water (Method A) and under solvent-free conditions (Method B).
[
[
[
[
[
[
[
[
[
a]
b]
c]
d]
e]
f]
Isolated yield after flash chromatography.
Determined by H NMR over the crude reaction mixture.
1
Determined by chiral HPLC analysis of the crude reaction mixture.
Reaction carried out in the absence of 4-NO C H CO H.
A 19% yield of dehydrated product was also obtained.
A 15% yield of dehydrated product was also obtained.
An 8% yield of dehydrated product was also obtained.
ee (syn)=60%.
2
6
4
2
g]
h]
i]
ee (syn)=43%.
conditions a minor or negligible impact of the aldol ee values after flash chromatography purification of
condensation reaction was observed. Aldol adduct substrates 3 fitted with the results observed before
3
da (Table 3, entries 23 and 24) showed a marked ten- isolation with the exception of the above-mentioned
dency to racemize during the purification process. It aldol 3da.
is important to mention that the HPLC ee determina-
Under solvent-free conditions, the reaction between
tion was performed over the crude reaction mixture 4-nitrobenzaldehyde and tetrahydro-4H-thiopyran-4-
for all the synthesized aldol adducts. In general, the one or N-Boc-4-piperidone (Table 3, entries 22 and
Adv. Synth. Catal. 2009, 351, 1123 – 1131
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Table 4. Aldol reactions of ketones with 4-nitrobenzaldehyde catalyzed by 1d in water
Method A) and under solvent-free conditions (Method B).
(
[
[
[
[
[
[
a]
Isolated yield after flash chromatography.
b]
Regioisomeric ratio (3/5) determined by 1HNMR over the crude reaction mixture.
c]
d]
e]
f]
1
Determined by H NMR over the crude reaction mixture.
Determined by chiral HPLC analysis over the crude reaction mixture.
Reaction carried out in the absence of 4-NO C H CO H.
A 4% yield of diaddition product was also obtained.
2
6
4
2
2
4) took place with purely solid reactants through an
ACHTUNGTRENNGNUo xyacetone and methoxyacetone (Table 4). With the
[
11]
intermediate melt. This implies the existence of a exception of acetone, using water as solvent (Method
eutectic mixture with a fusion temperature below am- A) led to higher enantioselectivities than under sol-
bient temperature and over 08C since at this latter vent-free conditions (Method B) with the substrates
temperature the aldol reactions did not work. On studied. Thus, when acetone was used as donor
the other hand, when solid aldol products where (Table 4, entries 1 and 2), the aldol product 3fa was
formed from liquid ketones it was generally possible obtained after 2 d at room temperature in the absence
to see the evolution of the process since the initial of cocatalyst with good yield (80%) and 80% ee
heterogeneous mixture of the ketone, aldehyde, cata- under solvent-free conditions (entry 2). Prolinethio-
[
16]
lyst and cocatalyst evolved to a partially homogene-
ous honey-like reaction mixture where the aldol prod- reaction with butanone under Method A and B reac-
uct was already formed. tion conditions (Table 4, entries 3 and 4). Using water
ACHTUNGTRENNUaGN mide 1d was a very enantioselective catalyst for the
The appearance of the reaction mixture when the as solvent, this challenging substrate provided aldol
1
d-catalyzed aldol reactions were performed in the adduct 3ga in only 20% yield and 89% ee. However,
presence of water was rather different. Under solvent-free conditions afforded 3ga in 86% yield, 83/
Method A conditions, phase separation was normally 17 anti-favored dr, and 80% ee (Table 4, entry 4). The
observed, the enantioselective aldol reaction probably regioselectivity of the process was moderate since
[
7e]
taking place in the formed organic phase.
both Methods A and B led to large amounts of the
Whereas cyclohexanone gave almost exclusively the iso-5 regioisomer. Alkoxy ketone nucleophiles such as
anti adduct product in high ee in the presence of methoxy- and benzyloxyacetone were excellent sub-
water and under solvent-free conditions (Table 1), strates providing with high regioselectivity CÀC bond
only the latter (Method B) were suitable conditions formation at the alkoxy group-substituted a-position
for an enantioselective aldol reaction of cyclopenta- affording, as expected for a secondary amine-derived
none and 4-nitrobenzaldehyde (Table 3, entries 25 organocatalyst, the corresponding anti-aldol adduct in
and 26) affording a 1:1 mixture of anti/syn-3ea iso- high enantioselectivities (Table 4, entries 5–8). Thus,
mers with a 92% ee for the anti isomer (entry 26).
methoxyacetone furnished aldol adduct 3ha with a
The optimized catalytic system also worked out for 87% yield, 80/20 anti favored dr, and 87% ee after 3 d
acyclic alkyl ketones such as acetone, butanone, as at room temperature under solvent-free conditions
well as other a-alkoxy ketone donors such as, benzyl- (Table 4, entry 6), whereas higher ee (92%) was ob-
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Water versus Solvent-Free Conditions for the Enantioselective Aldol Reaction
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Table 5. Intramolecular aldol reaction catalyzed by 1 in the presence of water (Methd A) and under solvent-free conditions
Method B).
(
[a]
[b]
Entry
Cat.
Method
6
n
R
T [8C]
Time [d]
7
Conv. [%]
ee
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1d
1d
1d
1d
B
B
B
B
6a
6a
6a
6a
6a
6a
6b
6c
6a
2
2
2
2
2
2
1
1
2
Me
Me
Me
Me
Me
Me
Me
Et
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
1
1
1
1
1
1
5.5
6
3
7a
7a
7a
7a
7a
7a
7b
7c
7a
98
87
100
100 (99)
65
66
76
74
86
82
80
88
84
61
[c]
B
A
B
B
B
86
100 (71)
100 (99)
46
l-Pro
Me
[
a]
1
Reaction conversion determined by H NMR over the crude reaction mixture. In brackets isolated yield after flash chro-
matography.
[
[
b]
c]
Determined by chiral-phase HPLC analysis over the crude reaction mixture.
Reaction performed in the absence of 4-NO C H CO H.
2
6
4
2
tained using water as solvent but in a very low 36% ditions, since lower yields and enantioselectivities
yield (entry 5). Reaction of benzyloxyacetone was were obtained employing l-Pro as catalyst under the
even more efficient providing, both in the presence of solvent-free reaction conditions for substrate 7a (com-
water (95% yield, anti/syn: 88/12, 94% ee for anti-3ia) pare entries 4 and 9).
and under solvent-free conditions (90% yield, anti/
syn: 89/11, 91% ee for anti-3ia), excellent yields and
enantioselectivities (Table 4, entries 7 and 8).
Conclusions
Finally, organocatalysts 1 were also tested in the in-
tramolecular aldol condensation of triketones 6 l-Prolinamide and thioamide derivatives 1 are excel-
(
Table 5). A preliminary catalyst study under solvent- lent catalysts for the asymmetric direct aldol inter-
free conditions (Method B, Table 5, entries 1–4) con- and intramolecular reaction using water as solvent
firmed prolinethioamide 1d as the most effective or- and under solvent-free conditions. These catalysts are
ganocatalyst for the intramolecular reaction as well, easily prepared in a few high yielding steps, so they
affording after 24 h at room temperature, the Wie- are easily accessible. In general, l-prolinethioamides
land–Miescher ketone 7a in a 99% isolated yield and 1c and 1d derived from l-Pro and (1S,2R)-cis-1-ami-
86% ee (Table 5, entry 4). Catalyst 1d was less effi- noindan-2-ol and (R)-1-aminoindane, respectively, are
cient when the reaction was performed in the absence more efficient catalysts than the corresponding l-pro-
of cocatalyst (Table 5, entry 5) or in the presence of linamides 1a and 1b in the inter- and intramolecular
water (Method A, entry 6) affording ketone 7a in a aldol in the presence of water and under solvent-free
6
8
5% conversion and 82% ee and 86% conversion and conditions. In particular, l-prolinethioamide 1d, pre-
0% ee, respectively, after 1 d at room temperature. pared from l-proline and (R)-1-aminoindane, is a
Therefore, under solvent-free conditions and in the robust, recyclable, and highly enantioselective catalyst
presence of 4-NO C H CO H, the intramolecular for the anti-aldol reaction between ketones and aro-
2
6
4
2
aldol reaction was applied to substrates 6b and 6c matic aldehydes in the presence of water and under
where the ring size and/or substitution in the 2 posi- solvent-free conditions. Generally, catalyst 1d per-
tion of the cycloalkanedione were varied. As shown formed better under solvent-free conditions for the
in entries 6 and 7, bicyclic diketones 7b and 7c were intermolecular aldol reaction between cyclic ketones
obtained in high isolated yields and good enantiose- and aromatic aldehydes affording the corresponding
lectivities. The results obtained in this study of the aldol adducts in higher yields and selectivities than in
solvent-free version of the Hajos–Parrish–Eder– the presence of water. However, prolinethioamide 1d
Sauer–Wiechert reaction clearly demonstrated the was more selective in the presence of water for the
high activity of prolinethioamide 1d under these con- aldol reaction of acyclic ketones and aromatic alde-
Adv. Synth. Catal. 2009, 351, 1123 – 1131
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1129

Diana Alma s¸ i et al.
FULL PAPERS
hydes. Prolinethioamide 1d has been also shown as
the most efficient catalyst for the enantioselective sol-
vent-free Hajos–Parrish–Eder–Sauer–Wiechert reac-
tion.
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Experimental Section
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Typical Procedure for the Enantioselective Aldol
Reaction Catalyzed by 1d
A mixture of 1d (30 mg, 0.122 mmol), 4-nitrobenzoic acid
(
20.5 mg, 0.122 mmol) and cyclohexanone (508 mL,
4.88 mmol) was stirred in water (1.22 mL) (Method A) or
without solvent (Method B) for 20 min at 128C (Method A)
or at 08C (Method B). Then, 4-nitrobenzaldehyde
(
368.4 mg, 2.44 mmol) was added and the reaction mixture
5
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After separation, the organic layer was dried over anhy-
drous MgSO , filtered and the solvent was evaporated under
4
8
reduced pressure to give the crude reaction mixture that
was purified by flash chromatography (silica gel, hexane/
EtOAc: 1/6) to afford pure product anti-3aa.
hedron: Asymmetry 2007, 18, 2249–2293.
[
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The aqueous layer was treated with 10% NaOH solution
(
2
480 mL, 1.464 mmol) and then extracted with EtOAc (3ꢄ
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2
D
0
{
[a] : +113 (c 1.0, CH Cl }.
2 2
Supporting Information
Synthesis of organocatalysts 1 and 4, experimental proce-
dures, spectral data for new compounds and intermediates,
as well as ESI-MS experiments, HPLC separation conditions
and retention times for compounds 3, 5 and 7 are available
as Supporting Information.
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Acknowledgements
Financial support from the MEC (Projects CTQ2004-00808/
BQU, CTQ2007–62771/BQU and Consolider INGENIO
2010 CSD2007-00006), from the Generalitat Valenciana
(
GRUPOS05/11, GV05/144, GV/2007/142) and the Universi-
ty of Alicante are acknowledged. D. A. thanks the EU and
the Spanish MEC for a predoctoral fellowship.
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