Highly efficient organocatalysts for the asymmetric aldol reaction

Article abstract of DOI:10.1039/c7nj04424k

A new class of bifunctional organocatalysts containing both thiazolidine/pyrrolidine and imidazole cycles was prepared via a readily available synthetic route. The highly efficient five step methodology did not require intermediary purification and provid

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Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
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Highly efficient organocatalysts for the asymmetric aldol reaction
C. G. Jacoby,a Pedro H. V. Vontobel,a M. F. Bacha and P. H. Schneidera
Received 00th January 20xx,
Accepted 00th January 20xx
A new class of bifunctional organocatalysts containing both thiazolidine/pyrrolidine and imidazole cycles was prepared in a
readily available synthetic route. The highly efficient five steps methodology did not require intermediary purification and
provided the compounds in high yields. The catalysts were successfully applied in the asymmetric direct aldol reaction
between aromatic aldehydes and cyclic ketones in aqueous media. Aldol adducts were obtained in high yields with perfect
stereoselectivities (up to >99% ee and >19:1 dr).
DOI: 10.1039/x0xx00000x
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bifunctional catalysis.11
Introduction
Given these considerations, this work presents the synthesis of
four new compounds containing both thiazolidine and
Organocatalysis has been used as an important tool in organic
synthesis, as a large number of asymmetric organic reactions
have been shown to be efficiently performed using this
methodology.1 Since the organocatalysed aldol reaction was
published by List, Barbas et al. in 2000,2 several research
groups have been directing their efforts to discover new
compounds and methodologies that can be used to improve
the yield and selectivity of many products, including those of
importance to the pharmaceutical industry.3
imidazole cycles. The design of these molecules was carefully
planned so they could act as good bifunctional catalysts. The
direct asymmetric aldol reaction between different ketones
and aldehydes was used as a probe to verify the performance
of these organocatalysts, looking to identify those with
superior catalytic activity.
Results and Discussion
A significant part of the publications in this area presents L-
proline or its derivatives as the organocatalyst.4 This natural
amino acid had been shown to catalyze a number of different
asymmetric reactions, inducing high selectivity, and it is now
considered one of the most important organocatalysts to be
discovered. These results have inspired researchers to study
other amino acids in organocatalysis, since they are good
sources of chirality and are readily available.5
The organocatalysts 5a-d were synthesized by a simple and
efficient five-step route, using the natural amino acid
cysteine as starting material (Scheme 1). At first, compound
L-
1
was obtained following a very well-established methodology,
in which the thiazolidine ring was obtained by cyclisation of
L
-
cysteine with formaldehyde, and further protected with
Boc2O12. The acid was then reacted with different
acetophenone derivatives affording esters 3a-d
, which
The sulfur analogue of L-proline, (R)-thiazolidine-4-carboxylic
acid and its derivatives are rarely used in asymmetric
synthesis.6 In spite of this, our group has published several
reports using thiazolidines as chiral ligands in organometallic
reactions.7 Recently we also reported the synthesis of a new
class of thiazolidine derivatives and their successful application
as organocatalysts in asymmetric aldol reactions.8
underwent cyclisation with ammonium acetate, generating the
Aromatic heterocycles, especially azoles, have been used as
substitutes for carboxylic acids in the structures of bifunctional
ligands and catalysts,9 showing some very relevant results. The
imidazole cycle is a promising scaffold for organocatalysis,
since in the few reports existing it has been shown to act
either as a basic group10 or as a hydrogen-bond donor in
Scheme1 Synthesis of organocatalysts 5a-d
.
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imidazole cycle. Finally, removal of the Boc group in acidic widely used in organocatalysis,14 the reaction furnished only
conditions led to compounds 5a-d. It is important to mention traces of the product (entry 4). Based on the literature15 and
that through this new methodology, the final compounds were our previously published results,8 in which the direct aldol
obtained without the need for purification of any of the reaction has been shown to be influenced, in terms of
intermediates. This is very important for the rapid stereoselectivity, by the use of a reaction system with equal
development of methodologies for obtaining enantiomerically amounts of water or brine and ketone, we performed some
enriched compounds. All the synthesized organocatalysts were experiments to evaluate this concept (Table 1, entries 5–8). In
obtained in good overall yields (39 to 54%).
water the results were almost the same as those obtained in
With this easily accessible set of organocatalysts, available in dichloromethane. However, the use of brine proved to be
large quantities, our attention turned towards the evaluation more interesting, since both yield and stereoselectivity were
of their catalytic activity. The compounds 5a–d were employed improved. The product was obtained with 54% yield and
in the direct asymmetric aldol reaction, which is widely applied almost perfect stereocontrol with 94% e.e. and
a
to evaluate organocatalysts,13 with the aim of controlling the diastereoisomeric ratio up to 19:1 (Table 1, entry 6). The
stereochemistry of the two stereocenters formed during the reaction time was also varied, but any reduction led to a
reaction. In order to determine the best conditions to carry out dramatic drop in yield.
the aldol reactions, we investigated the effect of several After the preliminary investigations of the reaction conditions,
parameters on the yields and the selectivities obtained, using we studied the influence on the reaction of the catalyst
initially the compound 5d as catalyst and cyclohexanone and loading, the amount of ketone and the presence of additives.
benzaldehyde as reactants, as a model reaction (Table 1).
The decrease of the catalyst loading caused a decrease in yield
Initially, we tested the reaction at two temperatures, and the as well as in stereoselectivity. On the other hand, the increase
best results concerning stereoselectivity were obtained at 0 °C, to 15 mol% did not generate significant improvement in the
despite the slight decrease in yield (Table 1, entry 1 vs 2). The yield; however the stereoselectivity was seriously affected
other parameter investigated was the reaction media; for that, (Table 2, entries 1–3). As can be seen from Table 2, the
the reaction was performed in different organic and aqueous concentration of the ketone is also an important feature, as
solvents. Using cyclohexanone and dichloromethane the better results were obtained when 10 equivalents were used.
results were very similar in terms of yield, enantiomeric excess Finally, the use of an acidic additive was also investigated, as it
(e.e.) and diastereoisomeric ratio (d.r.) (Table 1, entries 2 and is well established in the literature that it could help during the
3). However, when performed in DMSO, which is a solvent catalytic cycle in the formation of the enamine, as well as on
Table1 Optimisation of the reaction conditionsa
Table
2 Effect of catalyst loading, ketone amount and additives on the
asymmetric aldol reactiona
Temp.
(°C)
Time Yieldb e.e.c
d.r.d
Entry
Solvent
Catalyst
(mol %)
Ketone
Yield
(%)
e.e.
d.r.
(h)
(%)
(%)
(anti:syn)
Entry
Additive
(eq.)
(%)
(anti:syn)
1
2
3
4
5
6
7
8
25
0
Cyclohexanone
Cyclohexanone
CH2Cl2
120
47
74
2:1
6:1
1
2
3
4
5
6
7
8
10
5
10
-
51
37
55
40
43
40
61
81
97
95
>19:1
13:1
7:1
120
120
120
120
120
72
30
32
95
93
-
10
10
1
-
0
5:1
15
10
10
10
10
10
-
92
0
DMSO
Traces
31
-
-
-
91
>19:1
18:1
14:1
11:1
>19:1
0
H2O
94
97
94
95
8:1
5
94
0
Brine
51
>19:1
>19:1
>19:1
10
10
10
HCl
>99
>99
>99
0
Brine
22
TFA
0
Brine
96
30
PhCOOH
aReactions performed using 0.5 mmol (0.05 mL) of benzaldehyde, 5 mmol
(0.52 mL) of cyclohexanone, 0.05 mmol (0.014 g) of organocatalyst 5d and
0.5 mL of solvent; bIsolated yield; cDetermined by HPLC using chiral
stationary phase; dDetermined by 1H NMR spectroscopy of the crude
product.
aReactions performed using 0.5 mmol (0.05 mL) of benzaldehyde, 0.5–5
mmol of cyclohexanone, 0.025–0.075 mmol of organocatalyst 5d and 0.5
mL of brine; bIsolated yield; cDetermined by HPLC using chiral stationary
phase; dDetermined by 1H NMR spectroscopy of the crude product.
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the hydrolysis of the final iminium (Table 2, entries 6–8). Three Once the reaction conditions were optimized and the best
additives were tested and with 10 mol% of benzoic acid we catalyst was chosen, the versatility of the catalytic system was
observed a significant increase in the reaction yield from 51 to evaluated by extending this methodology to different
81%, as well as in the steroselectivity (Table 2, compare entries aldehydes and ketones, and the results can be seen in Table 4.
1 and 8).
All the aldehydes employed led to the product with excellent
Having established the optimized conditions, the synthesized stereoselectivity, showing a decrease in yield only when
catalysts 5a-d were applied in the test reaction, in order to electron-donating substituents were present, but with
investigate how the different electronic and steric quantitative yields when employing substrates with electron-
characteristics of the compounds would influence their withdrawing groups in their structures. The scope was also
catalytic potential and asymmetric induction power (Table 3). extended to meta- and ortho-substituted benzaldehydes with
When substituents of the phenyl portion were varied, all the excellent yields and stereoselectivities, proving that steric
synthesized organocatalysts led to a high stereoselectivity in hindrance in the aldehydes does not affect the reaction. When
the aldol reaction. The lowest e.e. and d.r. were obtained using a smaller ketone was used, good yield and selectivity were still
the nonsubstituted catalyst 5a, probably because of the obtained with three different aldehydes, which is not
diminution of steric hindrance. On the other hand, the commonly observed in organocatalysis and evidence the
reaction yield showed a clear dependence on the acidity of the importance of this class of catalysts. When using
imidazolic hydrogen. Compounds containing electron- cycloheptanone the product was not observed, probably due
withdrawing groups, which increase the hydrogen acidity, to the difficulty in forming the enamine. These results proved
furnished the aldol product in higher yields than did the that we have developed a robust catalytic system, which can
nonsubstituted catalyst, while a donating group in the phenyl be applied to a variety of substrates.
portion led to a dramatic decrease in yield. In order to The stereoselectivity obtained can be explained analyzing the
investigate the role of the thiazolidine ring in the catalytic proposed transition states for this reaction (Chart 1). The
process, we synthesized the L-proline derivative 5e, in which hydrogen of the imidazole group coordinates with the
the sulfur atom was replaced by carbon. When this compound aldehyde, improving the reactivity of the carbonyl group and
was applied as catalyst, both yield and stereoselectivity orienting its approach, having a crucial role in the transition
decreased, indicating that the insertion of a heteroatom state. This way, the enamine attack occurs on the re-face of
modifies the conformation of the transition state and the aldehyde, since the attack to the si-face is disfavored by
influences the course of the reaction.
the steric hindrance between the aryl group of the substrate
Table3 Application of synthesized compounds as catalysts in the asymmetric aldol reactiona
Entry
Catalyst
Yield (%)
e.e. (%)
d.r. (anti:syn)
1
81
>99
>19:1
2
3
4
5
70
34
45
20
>99
97
18:1
>19:1
8:1
96
77
5:1
aReactions performed using 0.5 mmol (0.05 mL) of benzaldehyde, 5 mmol (0.52 mL) of cyclohexanone, 0.05 mmol of the specified organocatalyst, 0.05 mmol
(0.006 g) of benzoic acid and 0.5 mL of brine; bIsolated yield; cDetermined by HPLC using chiral stationary phase; dDetermined by 1H NMR spectroscopy of the crude
product.
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Table4 Extension of reaction scope to other aldehydes and ketonesa
Entry
Product
Yield (%)
e.e. (%)
d.r. (anti:syn)
1
42
>99
>19:1
2
3
4
99
92
98
98
99
96
>19:1
8:1
>19:1
5
6
7
93
99
81
>99
>99
>99
>19:1
>19:1
3:1
8
99
99
3:1
9
99
>99
5:1
10
-
-
-
aReactions performed using 0.5 mmol of aldehyde, 5 mmol of ketone, 0.05 mmol (0.014 g) of organocatalyst 5d, 0.05 mmol (0.006 g) of benzoic acid and 0.5 mL
of brine; bIsolated yield; cDetermined by HPLC using chiral stationary phase; dDetermined by 1H NMR spectroscopy of the crude product.
4 | J. Name., 2012, 00, 1-3
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Experimental Section
General procedure for the synthesis of compounds 5a-e
Ammonium acetate (1.54 g, 20 mmol) was added to a solution
of the corresponding phenacyl ester (2 mmol) in toluene (20
mL). The mixture was refluxed with a Dean-Stark trap for 19 h.
Then the reaction was cooled to room temperature and
poured into water (20 mL). The organic layer was washed with
saturated aqueous NaHCO3 solution (20 mL) and water (20
mL), dried over Na2SO4, filtrated and concentrated under
reduced pressure. The residue was dissolved in ethyl acetate
(2 mL) and a solution of TFA (4 mL) in ethyl acetate (4 mL) was
added. The mixture was stirred at room temperature and the
reaction was monitored by TLC. After 1-2 h, the mixture was
neutralized with K2CO3 and the aqueous layer was extracted
with ethyl acetate (3 x 5 mL). The organic extracts were
combined, washed with water, dried over Na2SO4, filtrated and
concentrated under reduced pressure. The product was
purified with flash column cromatography on silica gel using
ethyl acetate.
Chart 1Proposed transition states for the organocatalysed reaction.
and the catalyst, in addition to the interaction with the ketone
in pseudo-axial position.
The catalytic system was successfully extended to the
asymmetric Michael reaction. When 10 mol % of catalyst 5d
was used in the addition of cyclohexanone to trans-β-
nitrostyrene, the product was obtained as
stereoisomer (Scheme 2).
a single
(R)-4-(5-phenyl-1H-imidazol-2-yl)thiazolidine (5a)
The product was obtained as a yellow solid. Yield: 91 %. Mp
ͦͤ
ʞ ʟ
178-182 °C.
= -19 (c 0.3, CH2Cl2). IR (KBr): 3042, 2979,
ꢀ
2945, 1684, 1441, 1208, 1140. 1H NMR (400 MHz, DMSO-d6) δ:
12.3 (bs, 1H), 7.74 (d, J = 7.2 Hz, 2H), 7.48 (s, 1H), 7.33 (t, J =
7.7 Hz, 2H), 7.17 (t, J = 7.4 Hz, 1H), 4.40 (t, J = 6.4 Hz, 1H), 4.17
(s, 2H), 3.23 (dd, J = 9.8; 6.4 Hz, 1H), 3.16 (dd, J = 9.8; 6.4 Hz,
1H). 13C NMR (100 MHz, DMSO-d6) δ: 147.1, 133.9, 128.5,
126.0, 124.2, 113.9, 61.9, 53.9, 37.4. HRMS calculated for
[C12H13N3S+H]+: 232.0909, obtained: 232.0986.
Conclusions
Five new organocatalysts containing both imidazole and
thiazolidine/pyrrolidine rings were synthesized by a highly
efficient route and without the necessity for purification of any
intermediate. This work showed the potential of this type of
structure in organocatalysis, since aldol reactions were
performed with near-perfect yields and stereoselectivities,
generating only one of four possible products. This class of
compounds also presented great modulability, as different
substituents caused substantial changes in the catalytic
activity. In this way, further exploration would demonstrate a
variety of applications for these molecules and their
derivatives.
(R)-4-(5-(4-methoxyphenyl)-1H-imidazol-2-yl)thiazolidine (5b)
The product was obtained as a brown solid. Yield: 83 %. Mp
ͦͤ
ʞ ʟ
166-169 °C.
= -50 (c 0.3, CH2Cl2). IR (KBr): 3055, 2946,
ꢀ
2887, 1687, 1208, 1141. 1H NMR (400 MHz, CDCl3) δ: 7.65-7.40
(m, 2H), 7.08 (s, 1H), 6.93-6.65 (m, 2H), 4.32-4.05 (m, 1H),
3.90-3.55 (m, 5H), 3.50-2.95 (m, 2H). 13C NMR (100 MHz,
DMSO-d6) δ: 157.9, 130.2, 126.6, 125.6, 114.2, 114.0, 55.2,
55.0. HRMS calculated for [C13H15N3OS+H]+: 262.1014,
obtained: 262.1082.
(R)-4-(5-(4-bromophenyl)-1H-imidazol-2-yl)thiazolidine (5c)
The product was obtained as a yellow solid. Yield: 93 %. Mp
ͦͤ
ʞ ʟ
174-178 °C.
= -34 (c 0.3, CH2Cl2). IR (film): 3261, 3035,
ꢀ
2981, 2943, 2893, 1687, 1476, 1435, 1208, 1140. 1H NMR (400
MHz, CDCl3) δ: 7.54 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H),
7.18 (s, 1H), 4.45 (t, J = 6.8 Hz, 1H), 4.20 (s, 2H), 3.33 (dd, J =
10.3; 6.8 Hz, 1H), 3.28 (dd, J = 10.3; 6.8 Hz, 1H). 13C NMR (100
MHz, CDCl3) δ: 148.7, 147.4, 132.0, 131.8, 126.4, 120.9, 114.6,
61.4, 50.7, 37.4. HRMS calculated for [C12H12BrN3S+H]+:
310.0013, obtained: 309.9938.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
The authors are grateful to CAPES, CNPq, INCT-CMN and
FAPERGS (PRONEX) forfinancial support and fellowship
awards.
(R)-4-(5-(4-nitrophenyl)-1H-imidazol-2-yl)thiazolidine (5d)
The product was obtained as a yellow solid. Yield: 95 %. Mp
ͦͤ
ʞ ʟ
185-190 °C.
= -23 (c 0.2, CH2Cl2). IR (KBr): 3265, 3021,
ꢀ
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2981, 2946, 2885, 1588, 1506, 1333, 1146, 1111. 1H NMR (400
MHz, CDCl3) δ: 8.18 (d, J = 8.9 Hz, 2H), 7.89 (d, J = 8.9 Hz, 2H),
7.50 (s, 1H), 4.99-4.92 (m, 1H), 4.34-4.30 (m, 2H), 3.64 (dd, J =
11.2; 8.4 Hz, 1H), 3.47 (dd, J = 11.1; 6.3 Hz, 1H). 13C NMR (100
MHz, DMSO-d6) δ: 148.5, 145.1, 141.6, 137.8, 124.6, 124.1,
116.8, 61.8, 53.9, 37.2. HRMS calculated for [C12H12N4O2S+H]+:
277.0759, obtained: 277.0804.
Voutyritsa, G. Galiatsatou and C. G. Kokotos, Tetrahedron,
2015, 71, 932.
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6
7
(S)-5-phenyl-2-(pyrrolidin-2-yl)-1H-imidazole (5e)
A. Wessjohann and P. H. Schneider, Tetrahedron, 2002, 58
,
ͦͤ
ʞ ʟ
38 (c 0.2, CH2Cl2). IR (film): 3036, 2948, 2913, 1655, 1450,
10413; (c) P. H. Schneider, H. S. Schrekker, C. C. Silveira, L. A.
Wessjohann and A. L. Braga, Eur. J. Org. Chem., 2004, 2715;
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The product was obtained as a brown oil. Yield: 81 %.
= -
ꢀ
1
1402, 1290, 1186. H NMR (400 MHz, CDCl3) δ: 7.85 (s, 1H),
7.70 (d, J = 7.6 Hz, 2H), 7.39 (t, J = 7.4 Hz, 2H), 7.30 (t, J = 7.6
Hz, 1H), 4.54 (t, J = 6.7 Hz, 1H), 3.29-3.19 (m, 1H), 3.17-3.07
(m, 1H), 2.35-2.19 (m, 1H), 2.18-2.07 (m, 1H), 2.03-1.86 (m,
3H). 13C NMR (100 MHz, CDCl3) δ: 140.6, 133.9, 130.9, 128.8,
128.2, 125.6, 55.2, 46.3, 30.9, 25.2. HRMS calculated for
[C13H15N3+2H]+: 215.1422, obtained: 215.1365.
8
9
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General procedure for organocatalytic asymmetric direct aldol
reaction
A solution of organocatalyst 5d (0.014 g, 0.05 mmol),
benzoic acid (0.006 g, 0.05 mmol) and the corresponding
ketone (5 mmol) was stirred at room temperature for 0.5 h.
Then the system was cooled to 0 °C, the aldehyde (0.5 mmol)
was added and the reaction mixture was stirred for 120 h. The
solution was returned to room temperature, treated with
saturated aqueous NH4Cl solution (1 mL) and extracted with
dichloromethane (3 x 2 mL). The organic extracts were
combined, dried over Na2SO4, filtrated and concentrated
under reduced pressure. The product was purified with flash
column cromatography on silica gel using ethyl acetate and
hexane (20:80).
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Lacoste, Y. Landais, K. Schenk, J.-B. Verlhac and J.-M.
Vincent, Tetrahedron Lett., 2004, 45, 8035; (g) K. R. Reddy, G.
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