L-prolinethioamides - Efficient organocatalysts for the direct asymmetric aldol reaction

Article abstract of DOI:10.1002/adsc.200505247

A series of novel L-proline derived thioamides has been synthesised. They have been evaluated as organocatalysts in the direct asymmetric aldol reaction for the first time. Thioamides exhibit catalytic ability higher than proline itself and the model aldol reaction of 4-cyanobenzaldehyde with acetone proceeds well in the presence of 5 mol % of catalyst (ee up to 100%). Other aromatic aldehydes gave aldol products with high ees and moderate yields. Small changes in the catalyst's structure [e.g., N-Bn versus N-CH(CH₃)Ph] as well as the addition of an acid have a profound effect on their activity. The unexpected formation of the catalyst-derived cyclic adducts was observed and their reactivity was established giving valuable insight into the course of the reaction.

Full text of DOI:10.1002/adsc.200505247

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DOI: 10.1002/adsc.200505247
l-Prolinethioamides -- Efficient Organocatalysts for the Direct
Asymmetric Aldol Reaction
´
Dorota Gryko,* Radosław Lipinski
Institute of Organic Chemistry, Polish Academy of Science, Kasprzaka 44/52, 01-224 Warsaw, Poland
Fax: (þ48)-22-632-6681, e-mail: dgryko@icho.edu.pl
Received: June 16, 2005; Revised: September 8, 2005; Accepted: September 12, 2005
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A series of novel l-proline derived thio-
amides has been synthesised. They have been evalu-
ated as organocatalysts in the direct asymmetric al-
dolreaction for the first time. Thioamides exhibit
catalytic ability higher than proline itself and the
model aldol reaction of 4-cyanobenzaldehyde with
acetone proceeds well in the presence of 5 mol %
of catalyst (ee up to 100%). Other aromatic alde-
hydes gave aldol products with high ees and moder-
ate yields. Small changes in the catalystꢀs structure
[e.g., N-Bn versus N-CH(CH3)Ph] as well as the ad-
dition of an acid have a profound effect on their ac-
tivity. The unexpected formation of the catalyst-de-
rived cyclic adducts was observed and their reactivity
was established giving valuable insight into the
course of the reaction.
very expensive. The use of simple aliphatic or aromatic
prolinamides including those derived from chiral 1-phe-
nylethylamine resulted in good yields, albeit with low
enantioselectivities. It was observed that the enantiose-
lectivity increased with the increase in the acidity of the
ꢀ
amide N H bond and in the presence of a terminalhy-
droxy group. Moreover Arvidsson and Hartikka[8]
showed that the proline-derived tetrazolic acid was
much more effective than proline itself. The increase
in the reactivity and selectivity of the catalyst was attrib-
uted to the higher acidity of the tetrazolic group in com-
parison to the carboxylic acid functionality.
With this in mind we set out to design a more reactive
catalyst for the direct asymmetric aldol reaction. The
ꢀ
presence of the acidic amide N H bond seemed to be
crucial in the catalytic activity of prolinamide-derived
catalysts. The replacement of the amide functionality
with the thioamide group would increase the acidity of
ꢀ
Keywords: asymmetric aldol reaction; C C bond for-
ꢀ
mation; organic catalysis; proline; thioamides
the N H bond (for example, the pKa of CH3CSNH2 is
18.5 whereas the same value for CH3CONH2 is 25.5).[9]
Consequently, we expected that the thioamide group
would form a stronger hydrogen bond with the acceptor
than the amide group and effectively facilitate the re-
The aldol reaction is one of the most powerful methods quired proton transfer.
for the formation of complex polyol molecules.[1–5] In re-
Here we report a novel class of organic catalysts – (S)-
cent years many efforts have been spent on developing pyrrolidine-2-carboxythioamides – that efficiently cata-
its catalytic asymmetric versions.[2] One of the most in- lyse the direct aldol reaction of aromatic aldehydes in
teresting ways involves proline and its derivatives as or- neat acetone with high enantioselectivity (up to 100%)
ganocatalysts.[2,6] This approach avoids the use of pro- and in good yields.
tecting groups and metals, which can be both expensive
Since it has already been established that the acidity of
ꢀ
and toxic. However, proline itself has some drawbacks the N H bond is crucialfor the performance of a cata-
too, it is rather poorly soluble in most of organic solvents lyst, our initial target was a proline-derived thioamide
and a high catalyst loading is required, often up to 30%. with an aromatic amine. The synthesis of l-prolinethio-
Given all the above, the development of an efficient cat- amide 5a involved the coupling of N-Boc-l-proline[10]
alyst for the asymmetric catalytic direct aldol reaction is (2) with aniline[7b] followed by the reaction with the
a worthwhile endeavour. Recently Tang et al.[7] has Lawessonꢀs reagent[11] (Scheme 1). After removalof
shown that l-prolinamide derivatives are able to effi- the Boc group[12] the desired catalyst 5a was obtained
ciently catalyse intermolecular acetone aldolisation in a good yield, but unfortunately it was not optically
with high enantioselectivity. However, the best results pure (ee 26%). We found that the racemisation took
were obtained when the catalyst was prepared from l- place during the formation of 4a. All further attempts
proline and (1S,2S)-diphenyl-2-aminoethanol which is to obtain thioamide 5a in an optically pure form failed.
1948
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Adv. Synth. Catal. 2005, 347, 1948 – 1952

l-Prolinethioamides – Organocatalysts for Asymmetric Aldol Reaction
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Scheme 1. Synthesis of l-prolinethioamides 5 and their reaction with acetone.
Consequently it was not used as the catalyst in the aldol product would be less favourable. Consequently, it
reaction. would act as a better catalyst for the aldol reaction.
In the light of this result we turned our attention to the With this requirement complied the (R)- and (S)-phe-
less acidic N-benzylamine derivative 5b. An analogous nylethylamines – the simplest analogue of benzylamine.
route (Scheme 1) afforded optically pure 5b in 53% Thus, two diastereoisomeric thioamides 5c and 5d de-
overall yield. Subsequently it was used in a model reac- rived from l-proline were synthesised (Scheme 1).
tion of 4-cyanobenzaldehyde[7a] with acetone giving the
We were delighted to find out that the reaction of 4-cy-
desired aldol 7 in 22% yield and with low enantiomeric anobenzaldehyde (7a) with acetone in the presence of
excess. The main product formed in this reaction (de- 20% mol 5c or 5d at room temperature afforded aldol
tected by TLC) decomposed during the column chroma- 8a with good yield and enantioselectivity (Table 1, en-
1
tography. Using the H NMR technique we found that tries 1 and 2) and the formation of the analogous bicyclic
this compound was the result of the cyclocondensation inidazolidinethione 6c or 6d was not detected by TLC.
of the catalyst 5c with acetone (6b, Scheme1). Therefore The reaction was completed within 24 hours. When tem-
we thought that if the amine part contained a bulky sub- perature was lowered to þ48C both the yield as well as
stituent in the a-position the formation of the cyclic the enantioselectivity increased (entry 3). Further de-
Table 1. Aldol reaction of 4-cyanobenzaldehyde (7a) with acetone in the presence of 5c or 5d.
Entry
Catalyst
Amount of cat. [mol %]
Temperature [8C]
Time [h]
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
9
5c
5d
5c
5c
5c
5c
5c
5c
5d
5d
0.20
0.20
0.20
0.20
0.30
0.15
0.10
0.05
0.20
0.20
RT
RT
24
24
72
96
96
72
72
5d
72
13d
67
62
74
57
57
71
70
83
83
21
72
54
86
93
93
86
86
85
80
100
þ4
ꢀ18
ꢀ18
þ4
þ4
þ4
ꢀ18
ꢀ78
10
[a]
Yields of isolated products.
Determined by HPLC using an ODH column.
[b]
Adv. Synth. Catal. 2005, 347, 1948 – 1952
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1949

´
Dorota Gryko, Radosław Lipinski
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creases in the reaction temperature improved enantio-
selectivity but at the cost of the yield (entry 4). The
use of a larger catalyst loading (30% mol) did not influ-
ence the yield (entry 5). Surprisingly the decrease in the
catalyst loading improved the yield although leaving the
ee at the same level (entries 6–8). Since the catalyst 5d
was more active than 5c at room temperature we
thought that its use would improve the yield. Indeed
the reaction catalysed by 5d at ꢀ188C was faster than
those promoted by 5c although the enantiomeric purity
of aldol 8a was a little bit lower (entry 9). The decrease in
the temperature to ꢀ78 8C afforded optically pure aldol
8a albeit in low yield (entry 10).
The results indicate that the catalyst 5c afforded a bet-
ter level of stereocontrol to its diastereoisomer 5d which
means that the (R) configuration at the amine part
matched the (S)-proline to enhance the enantiocontrol
of the aldol reaction. The same situation was observed
by Tangꢀs group,[7] but the enantiomeric excess was sig-
nificantly lower when the respective amide was used in-
stead of thioamide 5c. This proved the correctness of our
hypothesis that the thioamide group would enhance the
enantioselectivity of the direct aldol reaction due to the
ꢀ
Scheme 2.
more acidic N H bond. The use of secondary thioa-
mides with the chiral N-alkyl groups gave the same re-
sults as the use of the most active amide with the addi-
tional OH group (ee 93 versus 88), but the catalyst load- one (analogous to 9), and that the formation of this com-
ing can be lowered considerably (5% mol). pound diminished the rate but allowed for turnover. In
We believe that the level of stereocontrol was influ- our case, we did not observe the cyclic compound 9 un-
enced by the formation of the imidazolidinethiones 6. der the standard reaction conditions (1H NMR). How-
1
Using the H NMR technique we found that, under ever, when 4-cyanobenzaldehyde was allowed to react
standard reaction conditions but in the absence of alde- with catalyst 5c in CH2Cl2, imidazolidinethione 9 was
hyde, thioamide 5c did reacted with acetone-d6 to give formed. It was not stable enough for purification and
analytically pure imidazolidinethione 6c-d6 within 80 therefore it was used as obtained in the reaction with
minutes (Scheme 2).
Compound 6c was stable even in solution (CDCl3) at action afforded 8a in 38% yield and with 43% ee.
room temperature for severaldays. When isolated imi-
Investigations by Blackmondꢀs group[14] have shown
acetone. After 3 days at room temperature the aldol re-
dazolidinethione 6c was treated with an equimolar that the formation of oxazolidinone-type compounds
amount of 4-cyanobenzaldehyde (7a) in acetone the re- in the a-aminoxylation reaction enhanced the rate of
action afforded aldol 8a in 43% yield and 46% ee the process since they were better catalysts of the stud-
(Scheme 2). On the other hand when 6c was used in a ied reaction than proline itself. In contrast, we have
catalytic amount in the model reaction, both the yield showed that in the aldol reaction catalysed by thioamide
and the selectivity increased (73%, ee 73%, respective- 5c the unwanted formation of imidazolidinethiones de-
ly) reaching the same level of stereocontrol as for the re- rived both from acetone/6c and the aldehyde/9 diminish-
action catalysed by thioamide derivative 5c. Since the ed the yield and the enantioselectivity.
above-mentioned reactions gave different results, we as-
Encouraged by the above results we performed the di-
sume that the thioamide 5c had to catalyse the aldol ad- rect aldol reaction with a variety of aromatic aldehydes
dition before the formation of 6c which diminished both (7b–i) (Table 2). The prolinethioamide 5c catalysed
the yield and the enantioselectivity.
these reactions with high ees and moderate yields. We
Using a 1H NMR technique Listꢀs group[13] was able to found that in the aldol reaction of the highly reactive
detect the formation of oxazolidinones from proline and pentafluorobenzaldehyde (7f) with acetone the desired
acetone and to estimate the equilibrium constant. The aldol 8f was accompanied by a double aldol addition
influence of the oxazolidinone on the course of the aldol product (i.e., 1,5-dihydroxy-3-ketone). To the best of
reaction was not explained. Furthermore, they proved our knowledge this type of compound was not obtained
that in the proline-catalysed reaction of isobutyralde- in the organocatalysed aldol reaction. On the other hand
hyde with acetone in DMSO-d6, proline was initially the catalyst 5c was not suitable for aldol additions em-
quantitatively engaged in the formation of oxazolidin- ploying less reactive aromatic aldehydes or aliphatic al-
1950
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Adv. Synth. Catal. 2005, 347, 1948 – 1952

l-Prolinethioamides – Organocatalysts for Asymmetric Aldol Reaction
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Table 2. Prolinethioamide 5c-catalysed aldol reactions.
standing the aldol addition mediated by proline-type or-
ganocatalysts.
Experimental Section
Entry
R
Product
Yield [%][a]
ee [%][b]
General Procedure for the Aldol Reaction
1
2
3
4
5
6
7
8
9
4-NO2C6H4
4-NO2C6H4
2-ClC6H4
4-ClC6H4
2,6-Cl2 C6H3
F5C6
4-FC6H4
4-BrC6H4
b-naphthyl
8b
8b
8c
8d
8e
8f
8g
8h
8i
62
84
94
73
87
75
84
84
78
82
81[c]
70
The catalyst was dissolved in acetone (2 mL) and then 4-cyano-
benzaldehyde (1 mmol, 131 mg) was added. The resultant sol-
ution was stirred at the temperature indicated in Table 1 until
the disappearance of the aldehyde. The reaction was diluted
with saturated aqueous NH4Clsoultion and extracted with
AcOEt. The organic layers were dried over Na2SO4, evaporat-
ed and purified by silica-gel column chromatography (hexanes/
AcOEt mixtures).
61
86
64[d]
30
20
60
[a]
Yields of isolated products.
Determined by HPLC using ASH or ADH column.
5c·TFA was used as the catalyst.
1,5-Dihydroxy-3-ketone was isolated as a side product.
[b]
[c]
[d]
Acknowledgements
We would like to thank Prof. Janusz Jurczak and Dr. Jacek Mły-
narski for extensive help.
dehydes. In the reaction of cyclohexanecarboxaldehyde
with acetone the catalyst was almost quantitatively
transformed into the respective imidazolidinethione
(type 9) thereby preventing the aldol reaction.
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of 5c·TFA salt and we were delighted to find out that
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direct aldol reaction and the catalyst loading has been
lowered to 5% mol. The reactivity of the catalyst could
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ꢀ
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ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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´
Dorota Gryko, Radosław Lipinski
COMMUNICATIONS
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1952
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ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2005, 347, 1948 – 1952