Asymmetric direct aldol reaction catalysed by L-prolinethioamides

Article abstract of DOI:10.1002/ejoc.200600219

L-Prolinethioamides have been found to be active catalysts for direct aldol reactions of acetone with aromatic aldehydes, affording aldol products in good yields and with good enantioselectivities. They were prepared from L-proline and simple aliphatic and aromatic amines in optically pure form and in good overall yields. Studies employing ten catalysts allowed us to unequivocally establish the basic principles governing the outcome of the L-prolinethioamide-catalysed aldol reaction. In particular, the catalyst prepared from L-proline and (S)-phenylethylamine catalysed the reaction of acetone with 4-cyanobenzaldehyde in 57 % yield and 93 % ee (100% ee at -78°C). Most importantly, we found that steric interaction between the catalyst and a donor or an acceptor is crucial for the stereoselectivity of the aldol addition, while the unwanted formation of imidazolidinethione (from the catalyst and acetone or an aldehyde) was shown to decrease both the ee and the yield. The influence of the amine moiety (-CSNHR), different solvents and temperatures were studied, and we also found that there is a linear correlation between the optical purity of the catalyst and the ee of the aldol product, which supports the hypothesis that the reaction proceeds by the enamine-imine mechanism, involving only one molecule of the catalyst in the transition state. For the first time, the formation of 1,5-dihydroxypentan-3-one products (double addition products) was studied in detail. By precise optimisation we were able to show that the courses of the reactions of acetone with highly reactive aromatic aldehydes could be manipulated to give either the aldol products or 1,5-dihydroxypentan-3-one derivatives as the major product in moderate ee. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200600219

FULL PAPER
DOI: 10.1002/ejoc.200600219
Asymmetric Direct Aldol Reaction Catalysed by -Prolinethioamides
L
Dorota Gryko*[a] and Radosław Lipin´ski[a]
Keywords: Aldol reaction / Prolinethioamides / Asymmetric synthesis / Organocatalysis / Imidazolidinethione
L
-Prolinethioamides have been found to be active catalysts
both the ee and the yield. The influence of the amine moiety
(–CSNHR), different solvents and temperatures were studied,
and we also found that there is a linear correlation between
the optical purity of the catalyst and the ee of the aldol prod-
uct, which supports the hypothesis that the reaction proceeds
by the enamine–imine mechanism, involving only one mole-
cule of the catalyst in the transition state. For the first time,
the formation of 1,5-dihydroxypentan-3-one products
(double addition products) was studied in detail. By precise
optimisation we were able to show that the courses of the
reactions of acetone with highly reactive aromatic aldehydes
could be manipulated to give either the aldol products or 1,5-
dihydroxypentan-3-one derivatives as the major product in
moderate ee.
for direct aldol reactions of acetone with aromatic aldehydes,
affording aldol products in good yields and with good
enantioselectivities. They were prepared from L-proline and
simple aliphatic and aromatic amines in optically pure form
and in good overall yields. Studies employing ten catalysts
allowed us to unequivocally establish the basic principles
governing the outcome of the
aldol reaction. In particular, the catalyst prepared from
L-prolinethioamide-catalysed
L-pro-
line and (S)-phenylethylamine catalysed the reaction of ace-
tone with 4-cyanobenzaldehyde in 57% yield and 93% ee
(100% ee at –78 °C). Most importantly, we found that steric
interaction between the catalyst and a donor or an acceptor
is crucial for the stereoselectivity of the aldol addition, while
the unwanted formation of imidazolidinethione (from the cat-
alyst and acetone or an aldehyde) was shown to decrease
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
We have reported that the replacement of the amide
group with the thioamide functionality has a beneficial ef-
fect on both the yield and the stereoselectivity of the aldol
addition.[21] In that brief report we demonstrated that the
increased reactivity was due to the higher acidity of the NH
group (thioamide) relative to the amide NH functionality.
Moreover, it was found that the stereochemical outcome
and the chemical yields of the aldol additions were influ-
enced not only by the acidity of the thioamide group but
also by the steric interactions.
We now document a full, in-depth account on this topic,
including (a) the correlation between the -prolinethioam-
ide structure and the enantioselectivity and the yield, (b)
the synthetic scope of -prolinethioamide catalysis in the
aldol reaction, and (c) studies concerning the reaction
mechanism. Moreover, the aldol reactions of some highly
reactive aromatic aldehydes with acetone resulted predomi-
nately, depending on the reaction conditions, either in the
corresponding aldol product or in a 1,5-dihydroxypentan-
3-one compound.
Introduction
Asymmetric reactions catalysed by simple organic mole-
cules have attracted intense attention over the past few
years and their contribution toward organic synthesis has
become increasingly significant.[1–9] A wide variety of enan-
tioselective transformations can be performed with only
catalytic amounts of chiral promoter, providing highly eco-
nomical access to optically active compounds. Over the past
few years rapid progress has been made in the development
of the organocatalysed aldol reaction,[6–11] starting from the
pioneering observation by List et al.[12] that -proline itself
can catalyse the intermolecular aldol addition of acetone to
4-nitrobenzaldehyde, although only fair enantioselectivities
were obtained. Though proline itself is a very attractive cat-
alyst, its catalytic activity can be fine-tuned only by chang-
ing the reaction conditions. Since then, several proline-de-
rived catalysts have been prepared,[13–27] in most cases with
the carboxylic acid functionality having been modified. Un-
fortunately, none of them is a universal catalyst for aldol
reactions of various ketones with all types of aldehydes. Re-
cently, the use of -prolineamides derived from -proline
and different amines[14] – including diamines[26,27] and
amines with strongly electron-withdrawing groups[14c] – has
appeared promising for catalyst design.
Results and Discussion
Catalysts’ Synthesis
[a] Institute of Organic Chemistry, Polish Academy of Sciences,
Kasprzaka 44/52, 01-224 Warsaw, Poland
Fax: +48-22-6326681
All catalysts bearing thioamide functionalities were syn-
thesised by the general strategy presented in Scheme 1, in
overall yields ranging from 30 to 79%. The initial set of
E-mail: dgryko@icho.edu.pl
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Asymmetric Direct Aldol Reaction Catalysed by -Prolinethioamides
FULL PAPER
Scheme 1. Synthesis of -prolinethioamides.
thioamide catalysts was synthesised in four steps from - Asymmetric Aldol Reaction
proline and aniline, benzylamine and their simple analo-
gous compounds. N-Boc-proline (2) was transformed into
Novel catalysts 5e–j were tested in the direct aldol ad-
amides by the mixed anhydride method,[14b,21] and the fol- dition between acetone and 4-cyanobenzaldehyde (6a). The
lowing treatment with Lawesson’s reagent gave the pro- initial reaction conditions (a large excess of acetone and
tected -prolinethioamides (4).[28] In the last step, the Boc 20 mol-% of the catalyst relative to the aldehyde) were the
protecting group was removed under standard conditions same as reported in our preliminary communication.[21] All
to give catalysts 5a–d.[29] The intriguing results obtained reactions were carried out at +4 °C for 68 h, regardless of
with these catalysts inclined us to synthesise a broader the catalyst activity. The results are summarized in Table 1.
range of catalysts. The first class was made up of simple
As has previously been reported,[21] -prolinethioamide
analogous compounds of 5c, which had previously worked 5a was not used as a catalyst since all attempts to obtain
the best, and included derivatives synthesised from (R)-(α- it in an enantiomerically pure form failed. All remaining
ethylbenzyl)amine (5e) and (R)-[1-(4-methoxyphenyl)ethyl]- synthesised thioamides 5 catalysed the model aldol reaction
amine (5f). Because of the apparently fundamental role of of 4-cyanobenzaldehyde (6a) with acetone. N-Benzyl-
steric hindrance in the performance of the thioamide cata- amine derivative 5b gave aldol product 7a in only 20% yield
lysts, the second class of analogous compounds were deriva- and with low enantiomeric excess (Table 1, Entry 2). The
1
tives 5g–j of simple aliphatic amines. In our initial experi- main product formed in this reaction and detected by H
ments we chose the reaction of 4-cyanobenzaldehyde (6a) NMR (compound 8; Scheme 2) was a result of cyclocon-
with acetone as a model system, with four -proline thioam- densation between acetone and the catalyst 5b.
ides derived from aniline (5a), benzylamine (5b) and (R)- or
The two diastereoisomeric thioamides 5c and 5d, each
(S)-(1-phenylethyl)amine (5c and 5d, respectively) as cata- containing a methyl group in the α-position, catalysed the
lysts. It has been shown that small changes in the catalyst addition of acetone to 6a to give 7a in good yields and with
structure can have a profound effect on the catalytic activity good ees (Entries 3, 4). In the light of these intriguing re-
and we wanted to study this issue in greater detail. At this sults we synthesised the simple analogous compounds 5e–f,
stage of our research, we decided not to change the α-amino all of which gave results comparable to those obtained with
acid part in our catalysts and so, in the light of the above 5c. The replacement of the methyl group (catalyst 5c) with
findings, (R)-(α-ethylbenzyl)amine and (R)-[1-(4-meth- an ethyl group (catalyst 5e) only slightly improved the ee of
oxyphenyl)ethyl]amine were selected. By the previously de- aldol product 7a (Entry 5). The introduction of a methoxy
scribed approach shown in Scheme 1, new optically pure - substituent at the 4-position in the phenyl ring also had
prolinethioamides 5e and 5f were obtained in good yields. little influence, though the acidity of the N–H bond was
Furthermore, the optimised procedure also worked nicely changed (Entry 6). All the -prolinethioamides with the (R)
when a series of aliphatic amines were allowed to react with configuration in the amine part (5c, 5e, 5f; match pairs)
-proline to give amides 3, which were subsequently trans- gave a superior level of stereocontrol over compound 5d
formed into the corresponding prolinethioamides 5g–j. This with the (S) configuration (mismatch pair). Furthermore,
class of compounds was synthesised in order to explain we were intrigued by the question of whether the absence
some issues concerning the influence of the second ste- of the α-group in the amine part of the catalyst would nec-
reocenter present in the amine part, together with the for- essarily result in cyclic product formation, thus preventing
mation of the imidazolidinethione, on the stereochemical its good catalytic activity. n-Butylthioamide 5g was conse-
course of the aldol addition.
quently synthesised and used as the catalyst for the model
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Table 1. Direct aldol addition of acetone to 4-cyanobenzaldehyde (6a) catalysed by -prolinethioamides 5.[a]
[a] Conditions: 1 mmol aldehyde, 2 mL acetone, 20 mol-% catalyst. [b] Isolated yields. [c] Determined by HPLC on a Daicel AS-H column.
improve the enantioselectivity of the reaction, but the
thioamide 5i gave a lower yield and a smaller ee (Entry 9).
We can assume that the metal-free Zimmerman–Traxler-like
transition state is destabilised by steric interactions due to
the presence of the bulky tert-butyl group. Surprisingly, the
use of catalyst 5j, with the α-methyl group and an ad-
ditional stereocenter, gave results similar to those obtained
with 5g (Entries 7 and 10).
Scheme 2. Cyclocondensation between catalyst 5b and acetone.
reaction and afforded aldol product 7a in only 36% yield
Since the catalyst 5c afforded good results (which could
and with 62% ee (Entry 7). Indeed, the presence of an α- be further improved by lowering the reaction temperature)
group in thioproline derivatives had a profound effect both and is less expensive than analogue 5e, -prolinethioamide
on the yield and on the enantioselectivity and ensured good 5c was chosen for further studies. Numerous data presented
catalytic activity in the -prolinethioamides. The reaction of in the literature showed a significant influence of solvents
4-cyanobenzaldehyde (6a) with acetone catalysed by on the stereoselectivity and yields of organocatalysed reac-
thioamide 5h, containing only one stereocenter (proline tions.[13c,17,24,30–35] In this context a solvent screen was per-
part), afforded the corresponding aldol product 7a with fair formed, and the results are summarised in Table 2. Regard-
yield and enantioselectivity (Entry 8), so we reasoned that less of the solvent used, the aldol reaction catalysed by 5c
a bulkier amino part such as the tBu group should further afforded 7a with much lower yields and enantioselectivities
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Asymmetric Direct Aldol Reaction Catalysed by -Prolinethioamides
FULL PAPER
than had been obtained from the reactions in acetone. The Table 3. Direct aldol reactions of acetone with arenecarbaldehydes
6b–i in the presence of 5c.
only exception was the reaction in the ionic liquid
(BMIM[BF4]), which gave optically pure 7a but unfortu-
nately in only 32% yield (Entry 11).
Table 2. Solvent screening.[a]
Entry
1
R
Product
Yield [%][a]
ee [%][b]
Entry
Solvent
Yield [%]
ee [%][c]
4-O2NC6H4
7b
62
81[c]
70
84
94
73
87
75
84
84
78
82
1
2
3
DMSO
DMF
NMP
–
–
–
23
76
9
37
–
2
3
4
5
6
7
8
2-ClC6H4
4-ClC6H4
2,6-Cl2C6H3
F5C6
4-FC6H4
4-BrC6H4
β-naphthyl
7c
7d
7e
7f
7g
7h
7i
61
4
5
6
7
MeOH
n.d.
23
0
35
–
33
68
100
86
iPrOH/H2O
CH3CN
THF
64[d]
30
20
60
8
9
dioxane
CH2Cl2
13
70
32
[a] Isolated yields. [b] Determined by HPLC on a Daicel AS-H or
AD-H column. [c] TFA·5c was used as the catalyst. [d] The 1,5-
dihydroxypentan-3-one derivative was isolated as a side product.
10
11
acetone/H2O
BMIM[BF4][b]
[a] Conditions: 1 mmol aldehyde, 0.8 mL acetone, 20 mol-% cata-
lyst, 4 mL solvent, room temp., 68 h. [b] The reaction was carried
out at +4 °C. [c] Determined by HPLC on a Daicel AS-H column.
During the course of these scope and limitation studies
The generality of 5c in catalysing direct aldol reactions we found that the reaction of the highly reactive pentafluo-
of acetone with a variety of aromatic and aliphatic alde- robenzaldehyde (6f) with acetone afforded the desired aldol
hydes was examined under optimal conditions: 20 mol-% of product 7f accompanied by a double addition product 9
catalyst relative to the aldehyde, 0.5  aldehyde in acetone, (i.e., the 1,5-dihydroxypentan-3-one derivative). These types
+4 °C, 68 h. The results are shown in Table 3.
of compounds had also been observed by Peng et al.[36] in
For most of the aromatic aldehydes the ees were higher pyrrolidine/p-nitrophenol-catalysed aldol reactions of
than or similar to those obtained in reactions catalysed by highly reactive aromatic aldehydes with aliphatic ketones.
-proline. Unfortunately, prolinethioamide 5c was not suit- Their highly functional catalyst allowed racemic aldol prod-
able for aldol additions with less reactive aromatic alde- ucts to be obtained with very good yields and chemoselec-
hydes or aliphatic aldehydes.
tivities and allowed the formation of unwanted products of
Table 4. Reaction of 6f with acetone catalysed by -prolinethioamide 5c.
Entry
Conc. of 6f
[][a]
Catalyst 5c
[mol-%]
Temp.
[°C]
Yield of 7f
ee of 7f
Yield of 9
Yield of 10
[%][b]
[%][c]
[%][b]
[%][b]
1
2
3
4
5
6
7
8
9
0.5
0.5
0.5
0.5
0.5
10
5
5
20
2.5
1.25
5
2.5
5
+4
+4
–18
–78
23
64
34
0
77
56
86
77
67
31
14
nd
84
86
–
96
96
96
96
98
81
92
32
18
24
0
22
14
not isolated
not isolated
not isolated
0
6
5
10
6
8
12
10
+4
0.5
+4
+4
+4
0.25
0.25
0.125
13.7
27
not isolated
22
12
40
44
+4
10
11
20
20
room temp.
room temp.
[a] Concentration of 6f in acetone. [b] Isolated yields. [c] Determined by HPLC on a Daicel AS-H column.
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D. Gryko, R. Lipin´ski
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type 9 to be suppressed. Moreover, a small amount of the
1,5-dihydroxypentan-3-one product derived from 4-ni-
trobenzaldehyde (7b) was isolated from the reaction cata-
lysed by -proline. To gain further insight into this issue we
studied the reaction of 6f with acetone in the presence of
5c in greater detail; the results are summarised in Table 4.
A decrease in the catalyst loading caused an increase
both in the yield and in the ee of 7f (Table 4, Entries 1, 2,
5, 6). The best result – 86% yield of 7f with 96% ee – was
achieved when the concentration of the aldehyde was 0.25 
instead of 0.5 , the catalyst loading 5 mol-%, and the reac-
tion temperature +4 °C (Entry 7). Further dilution some-
what diminished the yield but the ee reached 98% (Entry 9).
On the other hand, in order to obtain 9 as the main product
(40% yield), 20 mol-% of 5c had to be used and the [alde-
hyde]/[acetone] ratio had to be stoichiometric (2:1; En-
try 11). Unfortunately, we were not able to determine the
syn/anti ratio of the 1,5-dihydroxypentan-3-one product 9
regardless of the technique used. Treatment of 2-chloro-
benzaldehyde (6c) with the stoichiometric amount of ace-
tone at room temp. with catalysis by 5c afforded a mixture
(1:5) of 1,5-dihydroxypentan-3-one compounds 11 with an
anti preference in 39% total yield. In this case the dia-
stereomeric ratio was determined from the amounts of com-
pounds isolated. The relative configuration of the major
product anti-11 was assigned by X-ray analysis (Figure 1).
The anti product 11 was isolated in 94% ee but the single
crystal measured by X-ray analysis was shown to be race-
mic, thus preventing the assignment of the absolute config-
uration.
Scheme 3. Reaction of aldol product 7c with aldehyde 6c.
NЈ-benzyl-NЈ-prolylproline hydrazide (syn/anti = 75:25) and
to the best of our knowledge this is the best syn diastereo-
selectivity for the reaction described.
Scheme 4. Reaction of cyclopentanone (12) with 4-cyanobenzalde-
hyde (6a).
Mechanistic Considerations
We assume that the direct, asymmetric aldol reaction cat-
alysed by -prolinethioamides 5 proceeds through the same
Accordingly, the aldol product 7c (73% ee) was treated mechanism as proposed for proline (Scheme 5).[12,37,38] In
with 2-chlorobenzaldehyde (6c) in the presence of the cata- this mechanism, both a base and an acidic proton are re-
lyst 5c, affording diols 11 with the same diastereomeric ratio quired for effective catalysis. In our case the transferred pro-
as previously (Scheme 3). Since the remaining 2-hydroxy ton originates from the thioamide group. The assumption
ketone 7c was isolated in only 43% ee, partial kinetic reso- is supported by the fact that -proline-derived thioamides 5
lution had taken place.
gave better results than prolineamides itself, which implies
Finally, cyclopentanone (12) was explored as an aldol that the thioamide group is able to form a stronger hydro-
donor. The reaction of 12 with 6a afforded products 13 in gen bond with an aldehyde and, as a result, a tighter metal-
87% yield (Scheme 4). The diastereomeric ratio according free Zimmerman–Traxler-like transition state than the car-
1
to H NMR analysis was almost 2:1 with syn preference, boxylic acid functionality in -proline.
while the reactions catalysed by -proline led to anti prefer-
Furthermore, we also investigated the relationship be-
ence (1:1.7). Unfortunately, the enantioselectivity was low. tween the enantiomeric excess of the aldol product 7a and
Wu et al.[33] have recently reported diastereoselective ad- the enantiomeric purity of -prolinethioamide 5c. Plotting
dition of cyclopentanone to an aldehyde through the use of the enantiomeric excess of 5c against that of 7a showed a
Figure 1. Crystal structure of anti-11.
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Asymmetric Direct Aldol Reaction Catalysed by -Prolinethioamides
FULL PAPER
Scheme 5. Proposed mechanism for aldol reactions catalysed by 5.
linear correlation consistent with the involvement of only
Compound 14 was stable even in solution (CDCl3) at
one molecule of the amino acid derivative 5c in the asym- room temperature for several days. When isolated imidazol-
metric aldol reaction transition state (Figure 2).
idinethione 14 was treated with an equimolar amount of 4-
cyanobenzaldehyde (6a) in acetone, the reaction afforded
the aldol product 7a in 43% yield and with 46% ee
(Scheme 6). On the other hand, when 14 was used in a cata-
lytic amount in the model reaction, both the yield and the
selectivity increased (73%, 73% ee), reaching the same level
of stereocontrol as in the reaction catalysed by thioamide
derivative 5c. Since the above reactions gave different re-
sults, we can assume that the free form of thioamide 5c had
to catalyse the aldol addition before the formation of 14,
which diminished both the yield and the enantioselectivity.
1
Using H NMR techniques, List’s group[39] was able to
detect the oxazolidinone formation from proline and ace-
tone and to estimate the equilibrium constant. The influ-
ence of the oxazolidinone on the course of the aldol reac-
tion was not explained. Furthermore, they also demon-
strated that, in the proline-catalysed reaction of isobutyral-
dehyde with acetone in [D6]DMSO, the proline was initially
quantitatively engaged in the formation of the oxazolidi-
none (analogous to 15), and that the formation of this com-
pound diminished the rate but allowed for turnover. In our
case, we did not observe the cyclic compound 15 under the
standard reaction conditions (1H NMR), but the imidazol-
idinethione 15 was formed when 4-cyanobenzaldehyde (6a)
was allowed to react with catalyst 5c in CH2Cl2. It was not
stable enough for purification and was therefore used as
obtained in the reaction with acetone. After 3 d at room
temperature, the reaction had afforded 7a in 38% yield and
with 43% ee.
Figure 2. Linear effect in the aldol reaction of acetone with 4-cya-
nobenzaldehyde (6a).
As previously reported,[21] we believe that the level of ste-
reocontrol is influenced by the formation of imidazolidine-
1
thiones of type 14 and 15. By H NMR spectroscopy we
found that under standard reaction conditions, but in the
absence of an aldehyde, thioamide 5c would react with [D6]-
acetone to give analytically pure imidazolidinethione [D6]-
14 within 80 min (Scheme 6).
Our results contrast with the findings of Blackmond’s
group,[40] who showed that the formation of oxazolidinone-
type compounds in the α-aminoxylation reaction enhanced
the rate of the process since they were better catalysts of
the studied reaction than proline itself. In our studies of
the aldol reaction catalysed by thioamide 5c, the unwanted
formation of imidazolidinethiones derived both from ace-
tone – 14 – and the aldehyde – 15 – diminished the yield
and the enantioselectivity.
Furthermore, the progress of the reaction of a catalyst
1
with [D6]acetone was monitored by H NMR and it was
observed that the catalyst 5c converted into the correspond-
ing imidazolidinethione of type 14 within 80 min whereas
its diastereoisomer 5d and 5h required only approximately
25 min (Figure 3). Since it had been shown that the forma-
Scheme 6. Reactions of 5c with acetone and aldehyde 6a.
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D. Gryko, R. Lipin´ski
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tion of the unwanted cyclic product diminished the yield amides, are more effective catalysts. The reaction catalysed
and the enantioselectivity of the aldol reaction catalysed by by thioamides 5 showed a linear effect, supporting the in-
thioamides 5, we suggest that the slower the unwanted volvement of the imine–enamine mechanism and the transi-
imidazolidinethione formation between the catalyst and tion state proposed by Houk and List,[37–39] involving only
acetone, the higher the stereoselectivity in the aldol ad- one molecule of the catalyst. Perhaps of greater significance
1
dition. To corroborate this assumption, H NMR studies for the future is the fact that a new type of -proline deriva-
were conducted with 5f; this catalyst gave similar results to tives can be added to the repertoire of organocatalysts, thus
5c. Indeed, the reaction of 5f with [D6]acetone took longer inspiring chemists towards further developments in this
than that with 5d (approximately 2 h). Similar conclusions field.
were drawn by Arvidsson and Hartikka for the reaction cat-
alysed by the tetrazole catalyst.[13c] They confirmed by H
1
Experimental Section
NMR that the catalyst did not engage in parasitic bicyclic
oxazolidinone formation from an aldehyde and the catalyst.
Consequently, more catalyst is available for the formation
of the enamine intermediate, thus increasing the reactivity
of the catalyst in relation to -proline, which forms this type
of compound immediately.
General: All chemicals were used as received unless otherwise
noted. Reagent-grade solvents (CH2Cl2, hexane) were distilled
prior to use. All reported 1H NMR spectra were collected either
with a Bruker spectrometer at 500 (1H NMR) or 125 (13C NMR)
MHz or with a Varian Gemini spectrometer at 200 (1H NMR) and
50 (13C NMR) MHz. Chemical shifts are reported as δ values rela-
tive to TMS, defined as δ = 0.00 ppm (1H NMR) or δ = 0.0 ppm
(13C NMR). IR spectra were obtained with a Perkin–Elmer 1640
FTIR unit. Mass spectra were obtained with an AMD-604 Intectra
instrument by EI or with a Mariner PerSeptive Biosystem instru-
ment by the ESI technique. Chromatography was performed on
silica gel (Kieselgel 60, 200–400 mesh). Melting points were deter-
mined with a Kofler hot-stage apparatus and are uncorrected. The
ee values were determined by HPLC on Daicel OD-H, AS-H or
AD-H columns and the configuration was assigned as (R) by com-
parison of the retention time with the reported values.
General Procedure for the Preparation of L-Proline-Derived Amides:
N-Boc--proline (2, 10.0 mmol, 2.15 g) was dissolved in dry THF
(40 mL) and treated with triethylamine (10.0 mmol, 1.39 mL). The
reaction mixture was cooled to 0 °C and ethyl chloroformate
(10.0 mmol, 1.23 mL) was then added dropwise over 15 min. After
the mixture had been stirred for another 30 min, an amine
(10.0 mmol) was added over 15 min. The resulting solution was
stirred at 0 °C for 1 h and at room temperature for another 16 h
and was then heated at reflux for 3 h. After it had cooled, it was
filtered through a Celite pad and the solvents were evaporated. Col-
umn chromatography on silica gel (hexane/AcOEt) gave the desired
amides.
Figure 3. Graph showing the conversion of catalysts into imidazol-
idinethiones of type 14 as a function of time.
Conclusions
In summary, we present -proline-derived thioamides 5,
prepared from -proline and chiral and achiral amines, as
very efficient catalysts for direct aldol additions. Both the
yields and the enantioselectivities were low for tert-butyl-,
n-butyl- and benzylamine. The replacement of the N-benzyl
substituent by the analogous (R)-1-phenylethyl, (R)-α-eth-
ylbenzyl and (R)-1-(4-methoxyphenyl)ethyl moieties on the
amine part changes the outcomes of the reactions, while the
introduction of various alkylamines with two α-substituents
in the amine part also produced good reactivity and selec-
tivity. Moreover, we have tried in this paper to explain the
influence of the formation of the imidazolidinethiones 14
and 15 on the course of the model aldol reaction of acetone
with the aldehyde 6a. It was shown that the unwanted for-
mation of imidazolidinethione-type compounds 14 and 15
diminished both the yield and the ee, and that the slower
the unwanted imidazolidinethione formation between the
catalyst and acetone, the higher the stereoselectivity in the
aldol addition.
tert-Butyl 2-(Benzylcarbamoyl)pyrrolidine-1-carboxylate (3b): Yield:
78% (2.37 g, 7.80 mmol). White crystals; m.p. 121–122 °C (from
Et2O/hexane). [α]2D0 = –80.8 (c = 1.03, CH2Cl2), ref.[41] –80.2 (c =
0.6, CHCl3). 1H NMR (500 MHz, [D6]DMSO, 353 K): δ = 8.08
(brs, 1 H, CONH), 7.30–7.18 (m, 5 H, Ph), 4.33 (dd, J = 6.2 Hz,
J = 15.1 Hz, 1 H, CHaHbPh), 4.23 (dd, J = 5.8 Hz, J = 15.1 Hz, 1
H, CHaHbPh), 4.12 (m, 1 H, CH), 3.44–3.36 (m, 1 H, CHaHbN),
3.35–3.28 (m, 1 H, CHaHbN), 2.11 (m, 1 H, CHaHb), 1.90–1.72
(m, 3 H, CHaHb, CH2), 1.35 (s, 9 H, tBu) ppm. 13C NMR
(125 MHz, [D6]DMSO, 353 K): δ = 171.9, 153.2, 139.2, 127.7,
126.8, 126.2, 95.2, 78.2, 59.6, 46.2, 41.8, 27.7 ppm. IR (KBr): ν =
˜
3316, 2978, 2872, 1685, 1656, 1531, 1396, 1370, 1169, 1159 1129,
1016, 974, 725, 694 cm–1. HR ESI-MS: m/z calcd. for
[C17H24N2O3Na+] 327.1679; found 327.1695. C17H24N2O3
(304.07): calcd. C 67.08, H 7.95, N 9.20; found C 67.24, H 7.95, N
9.33.
tert-Butyl (2S)-2-{[(1R)-1-Phenylethyl]carbamoyl}pyrrolidine-1-car-
boxylate (3c): Yield: 89% (1.21 g, 3.81 mmol). White crystals; m.p.
84–85 °C (from Et2O/hexane). [α]2D0 = –70.6 (c = 1.04, CH2Cl2). 1H
NMR (500 MHz, [D6]DMSO, 353 K): δ = 7.89 (d, 1 H, CONH),
Our investigations confirmed that the organocatalysed
reactions often depend on essential hydrogen-bond stabili-
zation of the transition state, since the thioamides, with
more acidic N–H protons than those in the corresponding 7.34–7.30 (m, 2 H, Ph), 7.29–7.24 (m, 2 H, Ph), 7.21–7.16 (m, 1 H,
3870
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Eur. J. Org. Chem. 2006, 3864–3876

Asymmetric Direct Aldol Reaction Catalysed by -Prolinethioamides
FULL PAPER
Ph), 4.92 (quint, 1 H, CHPh), 4.12 (d, 1 H, CHCO), 3.41–3.35 (m, 8.4 Hz, 1 H, CHCO), 3.40–3.35 (m, 1 H, CHaHbN), 3.30–3.25 (m,
1 H, CHaHbN), 3.29 (dt, Jd = 10.2 Hz, Jt = 7.0 Hz, 1 H, CHaHbN), 1 H, CHaHbN), 3.10–3.00 (m, 2 H, CH2N), 2.10–2.00 (m, 1 H,
2.08 (brs, 1 H, CHaHb), 1.89–1.70 (m, 3 H, CHaHb, CH2), 1.37 (d, CHaHb), 1.90–1.70 (m, 3 H, CHaHb, CH2), 1.45–1.35 (m, 2 H,
3 H, CH3), 1.29 (brs, 9 H, tBu) ppm. 13C NMR (125 MHz, [D6]- CH2), 1.36 (s, 9 H, tBu), 1.30–1.25 (m, 2 H, CH2), 0.87 (t, J =
DMSO, 353 K): δ = 170.9, 153.2, 144.0, 127.6, 126.1, 125.7, 95.2,
7.3 Hz, 3 H, CH3) ppm. 13C NMR (125 MHz, [D6]DMSO, 353 K):
δ = 171.6, 153.2, 95.1, 78.0, 59.5, 46.1, 37.8, 30.9, 27.7, 22.9, 19.0,
78.1, 59.4, 47.4, 46.2, 27.7, 23.0, 21.6 ppm. IR (KBr): ν = 3302,
˜
3061, 2977, 2880, 1669, 1539, 1456, 1416, 1364, 1239, 1166, 1127,
13.0 ppm. IR (KBr): ν = 3289, 3248, 3089, 2975, 2932, 2875, 16.90,
˜
700 cm–1. HR ESI-MS: m/z calcd. for [C18H26N2O3Na+] 341.1836; 1651, 1567, 1404, 1363, 1256, 1245, 1173, 1117, 987, 909, 770 cm–1.
found 341.1825. C18H26N2O3 (318.18): calcd. C 67.90, H 8.23, N
8.80; found C 68.02, H 7.94, N 8.89.
HR ESI-MS: m/z calcd. for [C14H26N2O3Na+] 341.1836; found
341.1847. C18H26N2O3 (318.18): calcd. C 62.19, H 9.69, N 10.36;
found C 62.24, H 9.77, N 10.50.
tert-Butyl (2S)-2-{[(1S)-1-Phenylethyl]carbamoyl}pyrrolidine-1-car-
boxylate (3d): Yield: 89% (2.89 g, 9.09 mmol). White crystals; m.p.
97–99 °C (from Et2O/hexane). [α]2D0 = –106.5 (c = 1.01, CH2Cl2),
tert-Butyl
(2S)-2-(Isopropylcarbamoyl)pyrrolidine-1-carboxylate
(3h): Yield: 80% (2.05 g, 8.01 mmol). White crystals; m.p. 128–
129 °C (from Et2O/hexane). [α]2D0 = –98.1 (c = 1.3, CH2Cl2). 1H
NMR (500 MHz, [D6]DMSO, 353 K): δ = 7.16 (brs, 1 H, CONH),
4.01 (dd, J = 4.0 Hz, J = 8.5 Hz, 1 H, CHCO), 3.84 (m, 1 H,
CHiPr), 3.40–3.30 (m, 1 H, CHaHbN), 3.30–3.20 (m, 1 H,
CHaHbN), 2.10–2.00 (m, 1 H, CHaHb), 1.90–1.70 (m, 3 H, CHaHb,
CH2), 1.37 (s, 9 H, tBu), 1.06 (t-like, J = 6.7 Hz, 6 H, 2×CH3, iPr)
ppm. 13C NMR (125 MHz, [D6]DMSO, 353 K): δ = 170.7, 153.1,
1
ref.[41] –109.8 (c = 1.3, CHCl3). H NMR (500 MHz, [D6]DMSO,
353 K): δ = 7.92 (d, J = 6.0 Hz, 1 H, CONH), 7.31–7.26 (m, 4 H,
Ph), 7.20 (m, 1 H, Ph), 4.94 (q, J = 7.2 Hz, 1 H, CHPh), 4.12 (dd,
J = 3.0 Hz, J = 8.3 Hz, 1 H, CHCO), 3.40–3.35 (m, 1 H, CHaHbN),
3.30–3.25 (m, 1 H, CHaHbN), 2.15–2.06 (m, 1 H, CHaHb), 1.90–
1.70 (m, 3 H, CHaHb, CH2), 1.38 (s, 3 H, CH3), 1.37 (s, 9 H, tBu)
ppm. 13C NMR (125 MHz, [D6]DMSO, 353 K): δ = 170.9, 153.2,
144.2, 127.7, 126.1, 125.5, 95.2, 78.1, 59.4, 47.2, 46.2, 30.3, 27.7,
90.1, 77.9, 59.4, 46.1, 29.1, 27.6, 22.8, 21.7 ppm. IR (KBr): ν =
˜
3287, 2970, 2880, 1700, 1650, 1556, 1396, 1364, 1254, 1163, 1118,
922, 772 cm–1. HR ESI-MS: m/z calcd. for [C13H24N2O3Na+]
279.1679; found 279.1686. C13H24N2O3 (256.16): calcd. C 60.91, H
9.44, N 10.93; found C 60.83, H 9.29, N 10.85.
23.0, 21.6 ppm. IR (KBr): ν = 3301, 2973, 1697, 1650, 1547, 1398,
˜
1391, 1365, 1246, 1167, 1120, 761, 702, 536 cm–1. HR ESI-MS:
m/z calcd. for [C18H26N2O3Na+] 341.1836; found 341.1847.
C18H26N2O3 (318.18): calcd. C 67.90, H 8.23, N 8.80; found C
67.65, H 8.16, N 8.76.
tert-Butyl
(2S)-2-(tert-Butylcarbamoyl)pyrrolidine-1-carboxylate
(3i): Yield: 76% (3.82 g, 14.15 mmol). White crystals; m.p. 115–
116 °C (from AcOEt). [α]2D0 = –109.8 (c = 1.05, CH2Cl2). 1H NMR
(500 MHz, [D6]DMSO, 353 K): δ = 6.87 (brs, 1 H, CONH), 4.01
(dd, J = 3.5 Hz, J = 8.4 Hz, 1 H, CH), 3.35–3.25 (m, 2 H, CH2N),
2.10–2.00 (m, 1 H, CHaHb), 1.85–1.70 (m, 3 H, CHaHb, CH2), 1.38
(s, 9 H, tBu, Boc), 1.26 (s, 9 H, tBu) ppm. 13C NMR (125 MHz,
[D6]DMSO, 353 K): δ = 171.0, 153.2, 95.1, 77.9, 59.6, 49.4, 46.1,
tert-Butyl
(2S)-2-{[(1R)-1-Phenylpropyl]carbamoyl}pyrrolidine-1-
carboxylate (3e): Yield: 70% (4.30 g, 12.1 mmol). White crystals;
m.p. 101–103 °C (from AcOEt/hexane). [α]2D0 = –44.5 (c = 0.95,
1
CH2Cl2). H NMR (500 MHz, [D6]DMSO, 353 K): δ = 7.85 (d, J
= 6.9 Hz, 1 H, CONH), 7.35–7.25 (m, 4 H, Ph), 7.20–7.16 (m, 1
H, Ph), 4.70 (dd, J = 7.6 Hz, J = 15.5 Hz, 1 H, CHPh), 4.14 (d, J
= 6.4 Hz, 1 H, CHCO), 3.40–3.30 (m, 1 H, CHaHbN), 3.30–3.25
(m, 1 H, CHaHbN), 2.10–2.0 (brs, 1 H, CHaHb), 1.85–1.70 (m, 5
H, CHaHb, 2×CH2), 1.25 (brs, 9 H, tBu), 0.85 (t, J = 7.3 Hz, 3 H,
CH3) ppm. 13C NMR (125 MHz, [D6]DMSO, 353 K): δ = 171.3,
153.3, 143.1, 127.6, 126.2, 126.1, 95.2, 78.1, 59.4, 53.7, 46.2, 28.5,
30.0, 28.1, 27.6, 22.8 ppm. IR (KBr): ν = 3314, 2973, 2934, 2878,
˜
1694, 1661, 1548, 1461, 1403, 1362, 1262, 1250, 1163, 1119, 984,
862, 770, 662 cm–1. HR ESI-MS: m/z calcd. for [C14H26N2O3Na+]
293.1836; found 293.1831. C14H26N2O3 (270.18): calcd. C 62.19, H
9.69, N 10.36; found C 62.12, H 9.69, N 10.36.
27.7, 23.0, 10.4 ppm. IR (KBr): ν = 3295, 2974, 2931, 2876, 1700,
˜
1670, 1656, 1554, 1454, 1398, 1257, 1163, 1122, 1089, 886, 770,
699 cm–1. HR ESI-MS: m/z calcd. for [C19H28N2O3Na+] 355.1992;
found 355.2007. C19H28N2O3 (332.20): calcd. C 68.65, H 8.49, N
8.43; found C 68.65, H 8.66, N 8.26.
tert-Butyl (2S)-2-{[(1R)-1,2-Dimethylpropyl]carbamoyl}pyrrolidine-
1-carboxylate (3j): Yield: 62% (3.29 g, 11.59 mmol). White crystals;
m.p. 103–104 °C (from AcOEt/hexane). [α]2D0 = –122.2 (c = 0.98,
1
CH2Cl2). H NMR (500 MHz, [D6]DMSO, 353 K): δ = 7.11 (brd,
J = 7.3 Hz, 1 H), 4.08 (dd, J = 3.0 Hz, J = 8.5 Hz, 1 H, CHCON),
3.59 (dq, Jq = 6.7 Hz, Jd = 8.6 Hz 1 H, CHCH3), 3.40–3.34 (m, 1
H, CHaHbN), 3.33–3.27 (m, 1 H, CHaHbN), 2.05 (m, 1 H, CHaHb),
1.85–1.71 (m, 3 H, CH2 + CHaHb), 1.65 (m, 1 H, CHiPr), 1.37 (s,
9 H, tBu), 0.99 (d, J = 6.8 Hz, 3 H, CH3), 0.84 (d, J = 6.8 Hz, 6
H, 2×CH3, iPr) ppm. 13C NMR (125 MHz, [D6]DMSO, 353 K): δ
= 171.3, 153.3, 143.1, 127.6, 126.2, 126.1, 95.2, 78.1, 59.4, 53.7,
tert-Butyl (2S)-2-{[(1R)-1-(4-Methoxyphenyl)ethyl]carbamoyl}pyr-
rolidine-1-carboxylate (3f): Yield 87% (7.03 g, 20.2 mmol). White
crystals; m.p. 116–117 °C (from AcOEt/hexane). [α]2D0 = –43.5 (c =
1
0.98, CH2Cl2). H NMR (500 MHz, [D6]DMSO, 353 K): δ = 7.68
(d, J = 5.3 Hz, 1 H, CONH), 7.23 (m, 2 H, Ar), 6.84 (m, 2 H, Ar),
4.88(m, 1 H, CHAr), 4.10 (dd, J = 2.8 Hz, J = 8.6 Hz, 1 H,
CHCO), 3.72 (s, 3 H, OCH3), 3.40–3.35 (m, 1 H, CHaHbN), 3.35–
3.25 (m, 1 H, CHaHbN), 2.07 (m, 1 H, CHaHb), 1.85–1.70 (m, 3 H
CHaHb, CH2), 1.35 (d, J = 7.0 Hz, 3 H, CH3), 1.31 (s, 9 H,
tBu) ppm. 13C NMR (125 MHz, [D6]DMSO, 353 K): δ = 170.7,
157.8, 153.2, 136.0, 126.7, 113.2, 78.0, 59.3, 54.7, 46.7, 46.1, 27.6,
46.2, 28.5, 27.7, 23.0, 10.4 ppm. IR (KBr): ν = 3321, 2978, 2965,
˜
1670, 1545, 1421, 1365, 1237, 1169, 1126, 1089, 979, 772, 552 cm–1.
HR ESI-MS: m/z calcd. for [C15H28N2O3Na+] 307.1992; found
307.2005. C15H28N2O3 (284.20): calcd. C 63.38, H 9.86, N 9.86;
found C 63.48, H 9.96, N 9.78.
22.9, 21.4 ppm. IR (KBr): ν = 3324, 2977, 2952, 1670, 1541, 1514,
˜
1415, 1250, 1186, 1165, 1132, 1037, 1025, 835, 771 cm–1. HR ESI-
MS: m/z calcd. for [C19H28N2O4Na+] 371.1941; found 371.1928.
C19H28N2O4 (348.19): calcd. C 65.52, H 8.05, N 8.05; found C
65.49, H 8.12, N 7.97.
General Procedure for the Preparation of Thioamides: An amide 3
(3.47 mmol) and Lawesson’s reagent (1.74 mmol) in dry toluene
(40 mL) were heated at reflux until the amide 3 was consumed
(TLC, usually 2–3 h). The reaction mixture was cooled and was
then concentrated to dryness. Column chromatography on silica gel
gave pure thioamides 4.
tert-Butyl (2S)-2-(Butylcarbamoyl)pyrrolidine-1-carboxylate (3g):
Yield: 84% (2.62 g, 9.70 mmol). White solid; m.p. 56–58 °C. [α]2D0
= –88.8 (c = 0.98, CH2Cl2). 1H NMR (500 MHz, [D6]DMSO,
tert-Butyl (2S)-2-(Phenylthiocarbamoyl)pyrrolidine-1-carboxylate
353 K): δ = 7.41 (brs, 1 H, CONH), 4.03 (dd, J = 3.4 Hz, J = (4a): Column chromatography on silica (CH2Cl2 and then hexane/
Eur. J. Org. Chem. 2006, 3864–3876
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3871

D. Gryko, R. Lipin´ski
FULL PAPER
acetone gradually from 7:3 to 5:5) gave a white solid. Yield: 61%
NMR (125 MHz, CDCl3): δ = 202.0, 152.0, 141.2, 128.7, 127.7,
(2.47 g, 8.07 mmol). White crystals; m.p. 175–177 °C (from AcOEt/
hexane). ee = 26%. H NMR (500 MHz, [D6]DMSO, 353 K): δ =
126.4, 126.2, 80.9, 53.6, 47.7, 47.6, 28.3, 28.1, 23.7, 23.6, 20.0 ppm.
1
IR (KBr): ν = 3223, 3032, 2975, 1670, 1538, 1452, 1421, 1355, 1166,
˜
11.14 (brs, 1 H, CSNH), 7.60 (d, J = 7.9 Hz, 2 H, Ph), 7.38 (m, 2
1158, 1130, 876, 767, 755, 697 cm–1. HR ESI-MS: m/z calcd. for
H, Ph), 7.22 (t, J = 7.4 Hz, 1 H, Ph), 4.69 (dd, J = 4.2 Hz, J = [C18H26N2O2SNa+] 357.1607; found 357.1619. C18H26N2O2S
8.5 Hz, 1 H, CHCS), 3.60–3.50 (m, 1 H, CHaHbN), 3.50–3.40 (m,
1 H, CHaHbN), 2.30–2.20 (m, 1 H, C3HaHb), 2.00 (m, 2 H, C4H2),
1.80 (m, 1 H, C3HaHb), 1.36 (9 H, tBu) ppm. 13C NMR (125 MHz,
[D6]DMSO, 353 K): δ = 204.7, 152.9, 139.1, 127.8, 125.5, 123.2,
(334.16): calcd. C 64.64, H 7.84, N 8.38, S 9.59; found C 64.71, H
7.80, N 8.35, S 9.63.
tert-Butyl (2S)-2-{[(1R)-1-Phenylpropyl]thiocarbamoyl}pyrrolidine-
1-carboxylate (4e): Column chromatography on silica (hexane/
CH2Cl2 gradually from 8:2 to 6.5:4.5 and then hexane/AcOEt grad-
ually from 7:3 to 6:4) gave a white solid. Yield: 89% (2.34 g,
6.72 mmol). White crystals; m.p. 114–118 °C (from AcOEt/hexane).
78.2, 67.3, 46.6, 33.1, 27.8, 22.8 ppm. IR (KBr): ν = 3277, 3210,
˜
3053, 3038, 2975, 2874, 1657, 1558, 1498, 1411, 1367, 1321, 1163,
1129, 921, 761, 699 cm–1. HR ESI-MS: m/z calcd. for
[C16H22N2O2SNa+] 329.1294; found 329.1309. C16H22N2O2S
(306.13): calcd. C 62.72, H 7.24, N 9.14, S 10.74; found: C 62.50,
H 7.23, N 8.99, S 10.49.
[α]2D0 = –54.5 (c = 1.2, CH2Cl2). H NMR (500 MHz, [D6]DMSO,
1
353 K): δ = 9.81 (brs, 1 H, CSNH), 7.36 (m, 2 H, Ph), 7.28 (m, 2
H, Ph), 7.22 (m, 1 H, Ph), 5.51 (m, 1 H, CHPh), 4.58 (dd, J =
3.7 Hz, J = 8.7 Hz, 1 H, CHCS), 3.50 (m, 1 H, CHaHbN), 3.36 (dt,
Jt = 7.1 Hz, Jd = 10.1 Hz, 1 H, CHaHbN), 2.26–2.18 (m, 1 H,
CHaHb), 1.95–1.80 (m, 4 H, 2×CH2), 1.78–1.70 (m, 1 H, CHaHb),
1.26 (brs, 9 H, tBu), 0.88 (t, J = 7.4 Hz, 3 H, CH3, Et) ppm. 13C
NMR (125 MHz, [D6]DMSO, 353 K): δ = 204.4, 153.1, 141.1,
127.7, 127.6, 126.6, 126.5, 95.2, 78.2, 66.4, 59.4, 46.7, 27.7, 27.5,
tert-Butyl
(2S)-2-(Benzylthiocarbamoyl)pyrrolidine-1-carboxylate
(4b): Column chromatography on silica (hexane/CH2Cl2 gradually
from 8:2 to 2:8 and then hexane/AcOEt, 6:4) gave a white solid.
Yield: 73% (1.52 g, 4.75 mmol). White crystals; m.p. 152–153 °C
(from AcOEt/hexane). [α]2D0 = –149.1 (c = 0.98, CH2Cl2). 1H NMR
(500 MHz, [D6]DMSO, 353 K): δ = 9.96 (brs, 1 H, CSNH), 7.35–
7.25 (m, 4 H, Ph), 7.25–7.20 (m, 1 H, Ph), 4.92 (dAB/2, J = 6.3 Hz,
J = 14.8 Hz, 1 H, CHaHbPh), 4.71(dAB/2, J = 5.5 Hz, J = 14.8 Hz,
1 H, CHaHbPh), 4.60 (dd, J = 3.6 Hz, J = 8.7 Hz, 1 H, CHCS),
3.50–3.45 [m, 1 H, C(5)HaHbN], 3.38 [dt, J = 6.9 Hz, J = 10.2 Hz,
1 H, C(5)HaHbN], 2.30–2.20 (m, 1 H, CH2), 1.95–1.85 (m, 2 H,
CH2), 1.80–1.70 (m, 1 H, CH2), 1.34 (s, 9 H, tBu) ppm. 13C NMR
(125 MHz, [D6]DMSO, 353 K): δ = 204.2, 152.6, 136.5, 127.1,
126.6, 126.0, 77.8, 66.3, 47.1, 46.1, 32.5, 27.2, 22.2 ppm. IR (KBr):
10.3 ppm. IR (KBr): ν = 3220, 3042, 2967, 2932, 2874, 1661, 1546,
˜
1419, 1363, 1357, 1322, 1255, 1165, 1129, 1098, 974, 917, 891, 764,
699 cm–1. HR ESI-MS: m/z calcd. for [C19H28N2O2SNa+]
371.1780; found 371.1764. C19H28N2O2S (348.18): calcd. C 65.48,
H 8.10, N 8.04, S 9.20; found C 65.22, H 7.96, N 8.03, S 9.17.
tert-Butyl (2S)-2-{[(1R)-1-(4-Methoxyphenyl)ethyl]thiocarbamoyl}-
pyrrolidine-1-carboxylate (4f): Column chromatography on silica
(hexane/CH2Cl2 gradually from 8:2 to 5:5 and then hexane/AcOEt
gradually from 8:2 to 7:3) gave a white solid. Yield: 70% (2.90 g,
7.97 mmol). White crystals; m.p. 134–135 °C (from AcOEt/hexane).
[α]2D0 = +24.3 (c = 0.98, CH2Cl2). 1H NMR (500 MHz, [D6]DMSO,
353 K): δ = 9.65 (brs, 1 H, CSNH), 7.29 (m, 2 H, Ar), 6.86 (m, 2
H, Ar), 5.67 (m, 1 H, CHAr), 4.54 (dd, J = 3.8 Hz, J = 8.7 Hz, 1
H, CHCS), 3.73 (s, 3 H, OCH3), 3.50–3.40 (m, 1 H, CHaHbN),
3.37 (dt, Jt = 7.1 Hz, Jd = 10.1 Hz, 1 H, CHaHbN), 2.20 (m, 1 H,
C3HaHb), 1.95–1.80 (m, 2 H, C4H2), 1.80–1.70 (m, 1 H, C3HaHb),
1.46 (d, J = 6.9 Hz, 3 H, CH3) 1.30 (s, 9 H, tBu) ppm. 13C NMR
(125 MHz, [D6]DMSO, 353 K): δ = 203.1, 158.1, 153.0, 133.9,
127.2, 113.3, 95.1, 78.1, 66.3, 54.7, 52.3, 46.6, 27.6, 22.6, 19.6 ppm.
ν = 3224, 3063, 3003, 2975, 2879, 1656, 1558, 1450, 1418, 1323,
˜
1165, 1127, 971, 734, 697 cm–1. HR ESI-MS: m/z calcd. for
[C17H24N2O2SNa+] 343.1451; found 343.1465. C17H24N2O2S
(320.15): calcd. C 63.72, H 7.55, N 8.99, S 10.01; found C 63.53,
H 7.58, N 8.79, S 10.26.
tert-Butyl (2S)-2-{[(1R)-1-Phenylethyl]thiocarbamoyl}pyrrolidine-1-
carboxylate (4c): Column chromatography on silica (hexane/
CH2Cl2 gradually from 8:2 to 2:8 and then hexane/acetone, 6:4)
gave a white solid. Yield: 72% (2.17 g, 6.44 mmol). White crystals,
m.p. 134–135 °C (from AcOEt/hexane). [α]2D0 = –31.1 (c = 1.1,
CH2Cl2). 1H NMR (CDCl3, 500 MHz): δ = 9.20 (brs, 0.5 H,
CSNH), 7.94 (brs, 0.5 H, CSNH), 7.35 (m, 2 H, Ph), 7.28 (m, 3
H, Ph), 5.77 (brs, 1 H, CHPh), 4.69 (dd, J = 3.2 Hz, J = 8.2 Hz, 1
H, CHCS), 3.46 (brs, 1 H, CHaHbN), 3.38 (m, 1 H, CHaHbN),
2.27 (brs, 2 H, CH2), 1.83 (m, 2 H, CH2), 1.58 (d, J = 6.9 Hz, 3
H, CH3), 1.45 (s, 9 H, tBu) ppm. 13C NMR (CDCl3, 125 MHz): δ
= 201.9, 152.0, 142.0, 128.8, 127.7, 126.2, 80.9, 49.0, 47.6, 28.3,
IR (KBr): ν = 3205, 3029, 2974, 2933, 1669, 1660, 1542, 1515, 1417,
˜
1361, 1293, 1253, 1179, 1130, 1094, 1030, 876, 833, 757 cm–1. HR
ESI-MS: m/z calcd. for [C19H28N2O3SNa+] 387.17129; found
387.1732. C19H28N2O3S (364.17): calcd. C 62.69, H 7.71, N 7.92,
S 8.90; found C 62.61, H 7.74, N 7.69, S 8.80.
tert-Butyl
(2S)-2-(Butylthiocarbamoyl)pyrrolidine-1-carboxylate
(4g): Column chromatography on silica (hexane/CH2Cl2 gradually
from 8:2 to 5:5 and then hexane/AcOEt gradually from 7:3 to 6:4)
gave a white solid. Yield: 86% (2.15 g, 7.52 mmol). White crystals;
m.p. 78–79 °C (from AcOEt/hexane). [α]2D0 = –125.3 (c = 1.1,
23.8, 21.0 ppm. IR (KBr): ν = 3205, 3032, 2980, 2880, 1672, 1656,
˜
1548, 1453, 1424, 1369, 1360, 1320, 1303, 1170, 1133, 763,
699 cm–1. HR ESI-MS: m/z calcd. [C18H26N2O2SNa+] 357.1607;
found 357.1625. C18H26N2O2S (334.16): calcd. C 64.64, H 7.84, N
8.38, S 9.59; found: C 64.58, H 7.78, N 8.22, S 9.53.
1
CH2Cl2). H NMR (500 MHz, [D6]DMSO, 353 K): δ = 9.47 (brs,
1 H, CSNH), 4.50 (dd, J = 3.6 Hz, J = 8.6 Hz, 1 H, CH), 3.60 (m,
1 H, CHaHbN), 3.51–3.40 (m, 2 H, CHaHbN, CHaHb), 3.40–3.30
(m, 1 H, CHaHb), 2.30–2.10 (m, 1 H, CHaHb), 1.90–1.80 (m, 2 H,
CH2), 1.80–1.70 (m, 1 H, CHaHb), 1.56 (q, J = 7.3 Hz, 2 H, CH2),
1.35 (s, 9 H, tBu), 1.40–1.30 (m, 2 H, CH2), 0.89 (t, J = 7.3 Hz, 3
H, CH3) ppm. 13C NMR (125 MHz, [D6]DMSO, 353 K): δ = 203.8,
153.0, 95.1, 78.2, 66.6, 46.6, 44.1, 33.0, 28.9, 27.7, 22.7, 19.1,
tert-Butyl (2S)-2-{[(1S)-1-Phenylethyl]thiocarbamoyl}pyrrolidine-1-
carboxylate (4d): Column chromatography on silica (hexane/
CH2Cl2 gradually from 8:2 to 4:6 and then hexane/AcOEt grad-
ually from 8:2 to 7:3) gave a white solid. Yield: 97% (2.12 g,
6.35 mmol). White crystals; m.p. 105–107 °C (from Et2O/hexane).
1
[α]2D0 = –221.8 (c = 1.1, CH2Cl2). H NMR (500 MHz, CDCl3): δ
= 8.92 (brs, 0.5 H, CSNH), 7.93 (brs, 0.5 H, CSNH), 7.36–7.32
13.0 ppm. IR (KBr): ν = 3242, 3027, 2980, 2966, 2933, 2874, 1667,
˜
(m, 4 H, Ph), 7.29–7.26 (m, 1 H, Ph), 5.79 (brs, 1 H, CHPh), 4.68 1554, 1416, 1365, 1299, 1170, 1121, 870, 771 cm–1. HR ESI-MS:
(dd, J = 3.8 Hz, J = 8.2 Hz, 1 H, CHCS), 3.50 (brs, 1 H, CHaHbN), m/z calcd. for [C14H26N2O2SNa+] 309.1607; found 309.1608.
3.44 (m, 1 H, CHaHbN), 2.34 (brs, 2 H, CH2), 1.86 (m, 2 H, CH2), C14H26N2O2S (286.16): calcd. C 58.65, H 9.15, N 9.78, S 11.19;
1.57 (d, J = 6.9 Hz, 3 H, CH3), 1.33 (brs, 9 H, tBu) ppm. 13C
found C 58.47, H 9.16, N 9.61, S 11.26.
3872
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3864–3876

Asymmetric Direct Aldol Reaction Catalysed by -Prolinethioamides
FULL PAPER
tert-Butyl (2S)-2-(Isopropylthiocarbamoyl)pyrrolidine-1-carboxylate
(4h): Column chromatography on silica (hexane/CH2Cl2 gradually
from 1:1 to 4:6 and then hexane/AcOEt gradually from 8:2 to 6:4)
gave a white solid. Yield: 94% (1.56 g, 5.74 mmol). White crystals.
m.p. 158–159 °C (from AcOEt). [α]2D0 = –132.8 (c = 1.0, CH2Cl2).
1H NMR (500 MHz, [D6]DMSO, 353 K): δ = 9.22 (brs, 1 H,
CSNH), 4.55 (m, 1 H, CH, iPr), 4.46 (dd, J = 4.2 Hz, J = 8.6 Hz,
1 H, CHCS), 3.48 (ddd, J = 5.5 Hz, J = 7.6 Hz, J = 10.2 Hz, 1 H,
CHaHbN), 3.37 (dt, Jd = 7.0 Hz, Jt = 10.2 Hz, 1 H, CHaHbN), 2.18
(m, 1 H, CHaHb), 1.95–1.85 (m, 1 H, CHaHb), 1.85–1.80 (m, 1 H,
CHaHb), 1.75–1.70 (m, 1 H, CHaHb), 1.36 (s, 9 H, tBu), 1.17 (t-
like, J = 6.7 Hz, 6 H, 2×CH3, iPr) ppm. 13C NMR (125 MHz,
[D6]DMSO, 353 K): δ = 202.6, 153.0, 95.1, 78.1, 66.3, 46.5, 45.8,
with NaSO4. After the removal of the solvent, catalyst 5 was ob-
tained as a colourless oil, which often solidified as noted.
(2S)-N-Phenylpyrrolidine-2-carbothioamide (5a): Yield: 98%
(160 mg, 0.79 mmol), ee = 26%. Solid; m.p. 56–57 °C. 1H NMR
(500 MHz, CDCl3): δ = 11.75 (brs, 1 H, CSNH), 7.94 (m, 2 H,
Ph), 7.40 (m, 2 H, Ph), 7.3–7.2 (m, 1 H, Ph), 4.28 (dd, J = 5.6 Hz,
J = 9.1 Hz, 1 H, CHCS), 3.15 (dt, Jt = 6.8 Hz, Jd = 10.1 Hz, 1 H,
CHaHbN), 3.05 (dt, Jt = 6.2 Hz, Jd = 10.1 Hz, 1 H, CHaHbN), 2.46
[ddt, Jt = 7.3 Hz, Jd = 9.0 Hz, Jd = 13.3 Hz 1 H, C(3)HaHb], 2.12
[m, 2 H, C(3)HaHb, NH], 1.75 [m, 2 H, C(4)H2] ppm. 13C NMR
(125 MHz, CDCl3): δ = 203.0, 138.4, 128.8, 126.3, 122.2, 69.6, 47.5,
34.8, 26.2 ppm. IR (KBr): ν = 3445, 3295, 2970, 2937, 2863, 1673,
˜
1589, 1519, 1442, 1417, 1368, 1279, 1165, 1110, 1076, 907, 764,
744, 729, 690 cm–1. HR ESI-MS: m/z calcd. for [C11H15N2S+]
207.095; found 207.0943. C11H14N2S (184.09): calcd. C 64.04, H
6.84, N 13.58, S 15.54; found: C 63.81, H 6.80, N 13.31, S 15.35.
32.9, 27.7, 22.6, 20.1, 20.0 ppm. IR (KBr): ν = 3247, 3058, 2970,
˜
2934, 2874, 1674, 1549, 1453, 1419, 1387, 1364, 1325, 1165, 1126,
923, 871, 765, 755, 688 cm–1. HR ESI-MS: m/z calcd. for
[C13H24N2O2SNa+] 295.1451; found 295.1436. C13H24N2O2S
(272.15): calcd. C 57.32, H 8.88, N 10.28, S 11.77; found C 57.39,
H 8.82, N 10.10, S 11.90.
(2S)-N-Benzylpyrrolidine-2-carbothioamide (5b): Yield: 92%
(350 mg, 1.59 mmol). Solid; m.p. 45–46 °C. [α]2D0 = –107.2 (c = 0.99,
1
CH2Cl2). H NMR (500 MH, CDCl3): δ = 10.08 (s, 1 H, CSNH),
tert-Butyl (2S)-2-(tert-Butylthiocarbamoyl)pyrrolidine-1-carboxylate
(4i): Column chromatography on silica (hexane/CH2Cl2 gradually
from 8:2 to 4:6) gave a white solid. Yield: 63% (1.32 g, 4.63 mmol).
7.4–7.3 (m, 5 H, Ph), 4.86 (d, J = 5.1 Hz, 2 H, CH2Ph), 4.25 (dd,
J = 5.5 Hz, J = 9.1 Hz, 1 H, CHCS), 3.05 (dt, Jt = 6.8 Hz, Jd
=
10.0 Hz, 1 H, CHaHbN), 2.88 (dt, Jt = 6.2 Hz, Jd = 10.0 Hz, 1 H,
CHaHbN), 2.45–2.35 [m, 1 H, C(3)HaHb], 2.06 [m, 1 H, C(3)HaHb],
1.91 (s, 1 H, NH), 1.69 [m, 2 H, C(4)H2] ppm. 13C NMR
(125 MHz, CDCl3): δ = 205.2, 136.6, 128.8, 127.9, 127.8, 68.1, 48.6,
White crystals. m.p. 166–167 °C (from AcOEt/hexane). [α]2D0
=
–128.5 (c = 1.30, CH2Cl2). 1H NMR (500 MHz, [D6]DMSO,
353 K): δ = 8.61 (brs, 1 H, CSNH), 4.45 (dd, J = 4.2 Hz, J =
8.6 Hz, 1 H, CH), 3.50–3.40 (m, 1 H, CHaHbN), 3.40–3.30 (m, 1
H, CHaHbN), 2.16 (m, 1 H, CHaHb), 1.91 (m, 2 H, CH2), 1.76–
1.68 (m, 1 H, CHaHb), 1.48 (s, 9 H, tBu), 1.37 (s, 9 H, tBu, Boc)
ppm. 13C NMR (125 MHz, [D6]DMSO, 353 K): δ = 203.2, 153.1,
47.4, 34.5, 26.0 ppm. IR (KBr): ν = 3302, 3162, 2961, 2941, 2915,
˜
2870, 1525, 1495, 1453, 1382, 1343, 1312, 1287, 1177, 1069, 962,
892, 758, 734, 695 cm–1. HR ESI-MS: m/z calcd. for [C12H17N2S+]
221.1107; found 221.1097. C12H16N2S (220.11): calcd. C 65.41, H
7.32, N 12.71, S 14.55; found: C 65.41, H 7.32, N 12.73, S 14.52.
95.1, 78.2, 67.3, 54.1, 46.6, 32.8, 27.7, 26.9, 22.6 ppm. IR (KBr): ν
˜
= 3276, 3062, 2980, 2968, 2875, 1675, 1550, 1416, 1363, 1325, 1216,
1165, 1119, 920, 768 cm–1. HR ESI-MS: m/z calcd. for
[C14H26N2O2SNa+] 309.16079; found 309.1622. C14H26N2O2S
(286.16): calcd. C 58.7, H 9.15, N 9.78, S 11.20; found C 58.67, H
8.92, N 9.90, S 11.11.
(2S)-N-[(1R)-1-Phenylethyl]pyrrolidine-2-carbothioamide
(5c):
=
Yield: 94% (385 g, 1.65 mmol). White solid; m.p. 39–40 °C. [α]2D0
+57.51 (c = 1.05, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 10.12
(brs, 1 H, CSNH), 7.35 (m, 2 H, Ph), 7.28 (m, 3 H, Ph), 5.72 (m,
1 H, CHPh), 4.22 (dd, J = 5.5 Hz, J = 9.0 Hz, 1 H, CHCS), 3.05
(dt, Jd = 10.0 Hz, Jt = 6.8 Hz, 1 H, CHaHbN), 2.89 (dt, J =
10.0 Hz, J = 6.2 Hz, 1 H, CHaHbN), 2.36 [m, 1 H, C(3)HaHb], 1.99
[m, 1 H, C(3)HaHb], 1.90 (brs, 1 H, NH), 1.68 [m, 1 H, C(4)HaHb],
1.62 [m, 1 H, C(4)HaHb], 1.59 (d, J = 6.9 Hz, 3 H, CH3) ppm. 13C
NMR (125 MHz, CDCl3): δ = 203.7, 144.0, 128.7, 127.4, 126.1,
tert-Butyl
(2S)-2-{[(1R)-1,2-Dimethylpropyl]thiocarbamoyl}pyr-
rolidine-1-carboxylate (4j): Column chromatography on silica (hex-
ane/CH2Cl2 gradually from 8:2 to 4:6 and then hexane/AcOEt
gradually from 8:2 to 7:3) gave a white solid. Yield: 80% (1.69 g,
5.63 mmol). White crystals; m.p. 124–125 °C (from AcOEt/hexane).
[α]2D0 = –125.1 (c = 1.03, CH2Cl2). 1H NMR (500 MHz, [D6]DMSO,
353 K): δ = 9.49 (d, J = 5.7 Hz, 1 H, CSNH), 4.51 (dd, J = 3.2 Hz,
J = 8.6 Hz, 1 H, CHCS), 4.32 (brs, 1 H, CHCH3), 3.49 (m, 1 H,
CHaHbN), 3.33 (m, 1 H, CHaHbN), 2.23 (brs, 1 H, CHaHb), 1.86
(m, 2 H, CHaHb + CHiPr), 1.74 (brs, 2 H, CH2), 1.33 (s, 9 H, tBu),
1.06 (bd, J = 5.2 Hz, 2 H, CH2), 0.88 (d, J = 6.8 Hz, 3 H, CH3,
iPr), 0.86 (d, J = 6.8 Hz, 3 H, CH3iPr) ppm. 13C NMR (125 MHz,
[D6]DMSO, 363 K): δ = 203.3, 153.2, 95.4, 78.3, 66.7, 55.8, 47.0,
68.2, 52.8, 47.4, 34.4, 26.0, 20.6 ppm. IR (KBr): ν = 3174, 2970,
˜
2929, 2869, 1510, 1453, 1379, 1277, 1073, 757, 698 cm–1. HR EI-
MS: m/z calcd. for [C13H18N2S] 234.11907; found 234.12003.
C13H18N2S (234.12): calcd. C 66.62, H 7.74, N 11.95, S 13.68;
found C 66.49, H 7.84, N 12.02, S 13.95.
(2S)-N-[(1S)-1-Phenylethyl]pyrrolidine-2-carbothioamide
(5d):
Yield: 95% (669 mg, 2.86 mmol). Solid; m.p. 43–44 °C. [α]2D0
=
–300.1 (c = 1.05, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 10.11
(brs, 1 H, CSNH), 7.36–7.26 (m, 5 H, Ph), 5.73 (m, 1 H, CHPh),
33.9, 31.4, 28.0, 22.7, 19.5, 18.4, 15.5 ppm. IR (KBr): ν = 3262,
˜
3055, 2969, 2933, 2870, 1675, 1546, 1453, 1416, 1364, 1323, 1249,
1161, 1121, 1105, 953, 921, 763, 687 cm–1. HR ESI-MS: m/z calcd.
for [C15H28N2O2SNa+] 323.17637; found 323.1772. C15H28N2O2S
(300.18): calcd. C 60.00, H 9.33, N 9.33, S 10.67; found C 59.87,
H 9.37, N 9.32, S 10.43.
4.19 (dd, J = 5.6 Hz, J = 9.0 Hz, 1 H, CHCS), 3.07 (dt, Jd
=
10.1 Hz, Jt = 6.9 Hz, 1 H, CHaHbN), 2.96 (dt, Jd = 10.1 Hz, Jt =
6.2 Hz, 1 H, CHaHbN), 2.45–2.30 [m, 1 H, C(3)HaHb], 2.18 (brs,
1 H, NH), 2.05–1.95 [m, 1 H, C(3)HaHb], 1.75–1.65 [m, 2 H, C(4)
H2], 1.57 (d, J = 6.9 Hz, 3 H, CH3) ppm. 13C NMR (125 MHz,
CDCl3): δ = 203.5, 141.7, 128.8, 127.6, 126.5, 68.1, 53.1, 47.4, 34.5,
General Procedure for the Removal of the N-Boc-Amino Group: N-
Boc-thioamide 4 (1.4 mmol) was dissolved in dry CH2Cl2 (2.8 mL)
and was treated with TFA (18.2 mmol, 1.40 mL) and then with
Et3SiH (3.30 mmol, 0.55 mL). After 3 h, the solvent and volatile
compounds were removed. The remaining oil was treated with
Et2O and in most cases a white solid precipitated and was filtered
off (sometimes addition of hexane was necessary). The precipitate
was dissolved in CHCl3, washed with saturated NaHCO3 and dried
26.0, 20.5 ppm. IR (film): ν = 3176, 2971, 2940, 2869, 1509, 1451,
˜
1378, 1278, 1176, 1073, 758, 698 cm–1. HR ESI-MS: m/z calcd. for
[C13H19N2S+] 235.1263; found 235.1260. C13H18N2S (234.12):
calcd. C 66.62, H 7.74, N 11.95, S 13.68; found. C 66.52, H 8.03,
N 11.80, S 13.46.
(2S)-N-[(1R)-1-Phenylpropyl]pyrrolidine-2-carbothioamide
(5e):
Yield: 81% (1.08 g, 4.35 mmol). White solid, m.p. 46–48 °C. [α]2D0
Eur. J. Org. Chem. 2006, 3864–3876
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3873

D. Gryko, R. Lipin´ski
6.8 Hz, Jd = 10.0 Hz, 1 H, CHaHbN), 2.95 (dt, Jt = 6.2 Hz, Jd
FULL PAPER
= +48.6 (c = 1.09, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ =
=
10.19 (brs, 1 H, CSNH), 7.35–7.30 (m, 2 H, Ph), 7.30–7.20 (m, 3 10.0 Hz, 1 H, CHaHbN), 2.38 [m, 1 H, C(3)HaHb], 2.19 (brs, 1 H,
H, Ph), 5.49 (dd, J = 7.2 Hz, J = 15.6 Hz, 1 H, CHPh), 4.23 (dd,
J = 5.5 Hz, J = 9.0 Hz, 1 H, CHCS), 3.07 (dt, Jt = 6.8 Hz, Jd
10.0 Hz, 1 H, CHaHbN), 2.92 (dt, Jt = 6.2 Hz, Jd = 10.0 Hz, 1 H,
NH), 1.96 [m, 1 H, C(3)HaHb], 1.68 [m, 2 H, C(4)H2], 1.55 (s, 9 H,
=
tBu) ppm. 13C NMR (125 MHz, CDCl3): δ = 202.8, 69.5, 54.2,
47.4, 34.6, 27.6, 26.0 ppm. IR (KBr): ν = 3304, 3092, 2965, 2878,
˜
CHaHbN), 2.33 (ddt, Jt = 7.3 Hz, Jd = 9.0 Hz, Jd = 13.0 Hz, 1 H, 1532, 1402, 1380, 1364, 1290, 1217, 1113, 1069, 901, 833, 799,
CHaHb), 2.05–1.95 (m, 2 H, CH2), 1.95–1.85 (m, 2 H, CHaHb, 773 cm–1. HR ESI-MS: m/z calcd. for [C9H19N2S+] 187.12635;
NH), 1.67 (m, 1 H, CHaHb), 1.58 (m, 1 H, CHaHb), 0.91 (t, J =
found 187.1255. C9H18N2S (186.13): calcd. C 58.02, H 9.74, N
7.4 Hz, 3 H, CH3, Et) ppm. 13C NMR (125 MHz, CDCl3): δ = 15.04, S 17.21; found C 58.21, H 9.58, N 14.99, S 17.19.
204.0, 140.8, 128.6, 127.3, 126.6, 68.3, 58.9, 47.4, 34.4, 28.5, 26.0,
(2S)-N-[(1R)-1,2-Dimethylpropyl]pyrrolidine-2-carbothioamide (5j):
10.5 ppm. IR (KBr): ν = 3327, 3131, 2972, 2940, 2923, 2855, 1516,
˜
Yield: 89% (148 mg, 0.74 mmol). Oil. [α]2D0 = –146.6 (c = 1.14,
CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 9.84 (brs, 1 H, CSNH),
4.40 (m, 1 H, CHCH3), 4.18 (dd, J = 5.3 Hz, J = 9.1 Hz, 1 H,
CHCS), 3.09 (dt, Jt = 6.9 Hz, Jd = 10.0 Hz, 1 H, CHaHbN), 2.94
(dt, Jt = 6.1 Hz, Jd = 10.1 Hz, 1 H, CHaHbN), 2.40–2.30 [m, 1 H,
C(3)HaHb], 2.04 [m, 1 H, C(3)HaHb], 1.94 (brs, 1 H, NH), 1.90 [m,
1 H, C(4)HaHb], 1.72 [m, 1 H, C(4)HaHb], 1.64 (m, 1 H, CH, iPr),
1.17 (d, J = 6.7 Hz, 3 H, CH3), 0.92 (t-like, J = 7.0 Hz, 6 H,
2×CH3, iPr) ppm. 13C NMR (125 MHz, CDCl3): δ = 203.3, 68.2,
1380, 1364, 1311, 1290, 1260, 1099, 1058, 903, 893, 870, 796, 765,
703 cm–1. HR ESI-MS: m/z calcd. for [C14H21N2S+] 249.1420;
found 249.1408. C14H20N2S (248.14): calcd. C 67.74, H 8.06, N
11.29, S 12.91; found C 67.84, H 8.19, N 11.30, S 13.05.
(2S)-N-[(1R)-1-(4-Methoxyphenyl)ethyl]pyrrolidine-2-carbothio-
amide (5f): Yield 67% (208 mg, 0.79 mmol). White solid, m.p. 42–
43 °C. [α]2D0 = +128.8 (c = 0.98, CH2Cl2). 1H NMR (500 MHz,
CDCl3): δ = 10.04 (brs, 1 H, CSNH), 7.24 (m, 2 H, Ar), 6.88 (m,
2 H, Ar), 5.67 (m, 1 H, CHAr), 4.20 (dd, J = 5.5 Hz, J = 9.0 Hz,
54.4, 47.4, 34.5, 32.4, 25.9, 18.5, 18.4, 15.8 ppm. IR (film): ν =
˜
3301, 3178, 2963, 2937, 2871, 1518, 1458, 1382, 1279, 1108, 1071,
1048, 896, 767, 746 cm–1. HR ESI-MS: m/z calcd. for [C10H21N2S+]
201.1420; found 201.1429. C10H20N2S (200.14): calcd. C 59.95, H
10.06, N 13.98, S 16.01; found C 60.02, H 10.06, N 13.85, S 15.92.
1 H, CHCS), 3.80 (s, 3 H, OCH3), 3.04 (dt, Jt = 6.8 Hz, Jd
=
10.1 Hz, 1 H, CHaHbN), 2.87 (dt, Jt = 6.2 Hz, Jd = 10.0 Hz, 1 H,
CHaHbN), 2.35 [ddt, Jt = 7.3 Hz, Jd = 9.0 Hz, Jd = 13.1 Hz, 1 H,
C(3)HaHb], 1.98 [m, 1 H, C(3)HaHb], 1.88 (brs, 1 H, NH), 1.70–
1.65 [m, 1 H, C(4)HaHb], 1.65–1.57 [m, 1 H, C(4)HaHb], 1.56 (d, J
= 6.9 Hz, 3 H, CH3) ppm. 13C NMR (CDCl3, 125 MHz): δ = 203.3,
158.9, 134.0, 127.3, 114.0, 68.1, 55.2, 52.3, 47.4, 34.4, 26.0,
(7aS)-2-Benzyl-3,3-dimethylhexahydro-1H-pyrrolo[1,2-c]imidazole-
1-thione (8): Yield: 99% (209 mg, 0.80 mmol). White solid; m.p. 78–
81 °C. [α]2D0 = –76.0 (c = 0.99, CH2Cl2). 1H NMR (500 MHz,
CDCl3): δ = 7.42–7.24 (m, 5 H, Ph), 5.28 (AB/2, J = 15.1 Hz, 1 H,
CHaHbPh), 4.61 (AB/2, J = 15.1 Hz, 1 H, CHaHbPh), 4.28 (m, 1
H, CHCS), 2.83 (dd, J = 6.5 Hz, J = 8.4 Hz, 1 H, CHaHbN), 2.50–
2.40 [m, 2 H, C(3)H2], 2.34 (ddd, J = 5.7 Hz, J = 8.6 Hz, J =
11.8 Hz, 1 H, CHaHbN), 1.90–1.70 [m, 2 H, C(4)H2], 1.34 (s, 3 H,
CH3), 1.30 (s, 3 H, CH3) ppm. 13C NMR (CDCl3, 125 MHz): δ =
204.1, 136.8, 128.6, 127.6, 127.4, 87.1, 74.6, 48.5, 48.1, 29.3, 26.8
25.0, 22.4 ppm. HR ESI-MS m/z calcd. for [C15H21N2S+] 261.142;
found 261.1432.
20.3 ppm. IR (KBr): ν = 3305, 3176, 2966, 2933, 2869, 1611, 1512,
˜
1455, 1377, 1286, 1248, 1179, 1101, 1031, 832, 763 cm–1. HR ESI-
MS: m/z calcd. for [C14H21N2OS+] 265.13691; found 265.1357.
C14H20N2OS (264.14): calcd. C 63.64, H 7.58, N 10.61, S 12.12;
found C 63.67, H 7.59, N 10.45, S 11.99.
(2S)-N-Butylpyrrolidine-2-carbothioamide (5g): Yield: 98 %
(472 mg, 2.51 mmol), 95% purity. [α]2D0 = –129.8 (c = 1.00, CH2Cl2).
1H NMR (500 MHz, CDCl3): δ = 9.86 (brs, 1 H, CSNH), 4.19 (dd,
J = 5.6 Hz, J = 9.0 Hz, 1 H, CHCS), 3.65 (m, 2 H, NCH2, Bu),
3.08 (dt, Jt = 6.8 Hz, Jd = 10.0 Hz, 1 H, CHaHbN), 2.94 (dt, Jt =
6.2 Hz, Jd = 10.0 Hz, 1 H, CHaHbN), 2.37 [m, 1 H, C(3)HaHb],
2.22 (brs, 1 H, NH), 2.00 [m, 1 H, C(3)HaHb], 1.70–1.60 (m, 4 H,
2×CH2), 1.39 (m, 2 H, CH2), 0.96 (t, J = 7.4 Hz, 3 H, CH3) ppm.
13C NMR (125 MHz, CDCl3): δ = 204.3, 67.9, 47.3, 44.3, 34.3,
(7aS)-3,3-Dimethyl-2-[(1R)-1-phenylethyl]hexahydro-1H-pyrrolo-
[1,2-c]imidazole-1-thione (14): Yield: 99 % (329 mg, 1.20 mmol).
White solid; m.p. 83–87 °C. [α]2D0 = +314.5 (c = 0.98, CH2Cl2). H
1
NMR (500 MHz, CDCl3): δ = 7.36–7.30 (m, 4 H, Ph), 7.28–7.24
(m, 1 H, Ph), 6.61 (m, 1 H, CHPh), 4.26 (dd, J = 9.5 Hz, J =
4.4 Hz, 1 H, CHCS), 2.68 (t-like, J = 7.5 Hz, 1 H, CHaHbN), 2.55–
2.45 [m, 1 H, C(3)HaHb], 2.45–2.35 [m, 1 H, C(3)HaHb], 2.09 (ddd,
J = 12.1 Hz, J = 8.4 Hz, J = 5.9 Hz, 1 H, CHaHbN), 1.87–1.82 [m,
1 H, C(4)HaHb], 1.79 (d, J = 7.4 Hz, 3 H, CHCH3), 1.77–1.70 [m,
30.0, 25.9, 20.1, 13.6 ppm. IR (KBr): ν = 3296, 3190, 2959, 2932,
˜
2871, 1528, 1461, 1385, 1287, 1107, 1066, 894, 751, 736 cm–1. HR
ESI-MS: m/z calcd. for [C9H19N2S+] 187.12635; found 187.1269.
(2S)-N-Isopropylpyrrolidine-2-carbothioamide (5h): Yield: 93%
1
1 H, C(4)HaHb], 1.54 (s, 3 H, CH3), 1.02 (brs, 3 H, CH3) ppm. 13
C
(587 mg, 3.41 mmol). [α]2D0 = –108.5 (c = 1.03, CH2Cl2). H NMR
NMR (125 MHz, CDCl3): δ = 204.4, 140.5, 128.7, 128.4, 127.5,
126.5, 126.3, 88.4, 74.1, 53.0, 48.2, 47.3, 34.4, 30.9, 29.8, 25.9, 24.7,
22.7, 20.6, 16.2 ppm. HR ESI-MS: m/z calcd. for [C16H23N2S+]
275.1576; found 275.1581. C16H22N2S (274.16): calcd. C 70.03, H
8.08, N 10.21, S 11.69, found C 69.90 H 7.91, N 10.38, S 11.83.
(500 MHz, CDCl3): δ = 9.65 (brs, 1 H, CSNH), 4.61 (m, 1 H,
CHiPr), 4.16 (dd, J = 5.7 Hz, J = 9.0 Hz, 1 H, CHCS), 3.07 (dt, Jt
= 6.8 Hz, Jd = 10.0 Hz, 1 H, CHaHbN), 2.93 (dt, Jt = 6.2 Hz, Jd =
10.0 Hz, 1 H, CHaHbN), 2.38 [m, 1 H, C(3)HaHb], 2.03 (brs, 1 H,
NH), 1.99 [m, 1 H, C(3)HaHb], 1.68 [m, 2 H, C(4)H2], 1.26 (d, J =
6.6 Hz, 3 H, CH3, iPr), 1.25 (d, J = 6.6 Hz, 3 H, CH3, iPr) ppm.
13C NMR (125 MHz, CDCl3): δ = 204.3, 67.9, 47.3, 44.3, 34.3,
4-{(7aS)-2-[(1R)-1-phenylethyl]-1-thioxohexahydro-1H-pyrrolo-
[1,2-c]imidazol-3-yl}benzonitrile (15): Yellowish solid. 1H NMR
(200 MHz, CDCl3): δ = 7.40–7.10 (m, 7 H, Ar), 6.89 (d, J = 7.6 Hz,
2 H, Ar), 6.40 (q, J = 7.2 Hz, 1 H, CHCH3), 5.93 (d, J = 1.6 Hz,
1 H, CHNN), 4.29 (m, 1 H, CHCS), 2.51–2.25 (m, 4 H, CH2N,
CH2), 1.83–1.62 (m, 2 H, CH2), 1.55 (d, J = 7.2 Hz, 3 H, CH3)
ppm. 13C NMR (50 MHz, CDCl3): δ = 207.2, 140.1, 138.4, 131.7,
130.4, 128.6, 128.1, 127.7, 113.1, 84.7, 77.8, 55.4, 49.0, 31.1, 25.7,
15.2 ppm. ESI-MS: m/z = 348 [M+ + H].
30.0, 25.9, 20.1, 13.6 ppm. IR (film): ν = 3300, 3182, 2968, 2938,
˜
2870, 1518, 1459, 1389, 1374, 1284, 1168, 1068, 739 cm–1. HR EI-
MS: m/z calcd. for [C8H16N2S+] 172.1034; found 172.1039.
C8H16N2S (172.10): calcd. C 55.77, H 9.36, N 16.26, S 18.61; found
C 55.55, H 9.36, N 16.13, S 18.38.
(2S)-N-(tert-Butyl)pyrrolidine-2-carbothioamide (5i): Yield: 96%
(250 mg, 1.34 mmol). White solid, m.p. 34–35 °C. [α]2D0 = –185.3 (c
= 1.25, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 9.82 (brs, 1 H,
General Procedure for the Aldol Reaction Catalysed by L-Proline-
CSNH), 4.08 (dd, J = 5.8 Hz, J = 8.9 Hz, 1 H, CH), 3.08 (dt, Jt = thioamides 5: An aldehyde 6 (1 mmol) was added at 0 °C to a solu-
3874 Eur. J. Org. Chem. 2006, 3864–3876
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Asymmetric Direct Aldol Reaction Catalysed by -Prolinethioamides
FULL PAPER
tion of thioamide 5 (0.2 mmol) in acetone (2 mL). The resulting
solution was stirred at +4 °C for 68 h. After this time, the solution
was quenched with saturated aqueous ammonium chloride and ex-
tracted with ethyl acetate (3×). The combined organic layers were
dried with NaSO4 and filtered, and the solvents were evaporated
in vacuo. Purification by column chromatography (hexane/AcOEt)
gave aldol product 7.
and analysis were carried out with the Oxford Diffraction pro-
grams.[43] The structure was solved by direct methods[44] and re-
fined by use of SHELXL.[45] The refinement was based on F2 for
all reflections except those with very negative F2. Weighted R fac-
tors wR and all goodness-of-fit S values are based on F2. Conven-
tional R factors are based on F with F set to zero for negative F2.
The Fo2 Ͼ 2σ(Fo2) criterion was used only for calculating R factors
and is not relevant to the choice of reflections for the refinement.
The R factors based on F2 are about twice as large as those based
on F. All hydrogen atoms were located geometrically and their posi-
tions and temperature factors were refined. Scattering factors were
taken from Tables 6.1.1.4 and 4.2.4.2.[46] CCDC-600255 contains
the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
General Procedure for the Synthesis of 1,5-Dihydroxypentan-3-one
Derivatives: An aldehyde 6 (1 mmol) was added at 0 °C to a solu-
tion of thioamide 5 (0.2 mmol) in acetone (37 µL). The resulting
solution was stirred at room temp. for 1 h. After this time, the solu-
tion was quenched with saturated aqueous ammonium chloride
and extracted with ethyl acetate (3×). The combined organic layers
were dried with NaSO4 and filtered, and the solvents were evapo-
rated in vacuo. Purification by column chromatography (hexane/
AcOEt) gave the 1,5-dihydroxypentan-3-one derivatives as a fourth
band.
Acknowledgments
1,5-Dihydroxy-1,5-bis(perfluorophenyl)pentan-3-one Mixture (9-
anti/9-syn): Yield: 44% (100 mg, 0.22 mmol). White crystals; m.p.
142–144 °C. 1H NMR (500 MHz, CDCl3): δ = 5.42 (dt, Jt = 5.3 Hz,
Jd = 7.8 Hz, 2 H, CH), 3.93 (d, J = 5.1 Hz, 2 H, OH), 3.22 (dd, J
= 8.0 Hz, J = 17.3 Hz, 2 H, CHaHb), 2.97 (dd, J = 5.7 Hz, J =
17.3 Hz, 2 H, CHaHb) ppm. 13C NMR (50 MHz, [D6]acetone): δ
= 206.5, 146.0, 144.1, 141.9, 139.9, 138. 6, 136.7, 62.2, 50.3 ppm. IR
The X-ray measurements were undertaken in the Crystallographic
Unit of the Physical Chemistry Laboratory at the Chemistry De-
partment of the University of Warsaw.
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1754.
(KBr): ν = 3512, 1702, 1529, 1506, 1395, 1130, 1092, 994, 948 cm–1.
˜
C17H8F10O3 (450.25): calcd. C 45.35, H 1.79, F 42.20; found C
45.41, H 1.62, F 41.99.
anti-1,5-Bis(2-chlorophenyl)-1,5-dihydroxypentan-3-one
(11-anti):
Yield: 33% (50 mg, 0.15 mmol). White crystals; m.p. 129–131 °C.
1H NMR (500 MHz, CDCl3): δ = 7.62 (dd, J = 1.7 Hz, J = 7.7 Hz,
Ar), 7.35–7.25 (m, 4 H, Ar), 7.22 (td, Jd = 1.7 Hz, Jt = 7.6 Hz, 2
H, Ar), 5.56 (dt, Jt = 2.9 Hz, Jd = 9.6 Hz, 2 H, CH), 3.34 (d, J =
3.5 Hz, 2 H, OH), 2.97 (dd, J = 2.4 Hz, J = 17.1 Hz, 2 H, CHaHb),
2.77 (dd, J = 9.6 Hz, J = 17.1 Hz, 2 H, CHaHb) ppm. 13C NMR
(125 MHz, CDCl3): δ = 210.8, 139.9, 131.2, 129.4, 128.7, 127.3,
127.0, 66.6, 49.9 ppm. IR (KBr): ν = 3459, 1698, 1474, 1402, 1370,
˜
1200, 1084, 1036, 895, 750 cm–1. HR ESI-MS: m/z calcd. for
[C17H16O3Cl2Na+] 361.03687; found 361.0386. C17H16Cl2O3
(338.05): calcd. C 60.19, H 4.75, Cl 20.90; found C 60.16, H 4.79,
Cl 21.04. ee = 94%, determined by HPLC (Daicel Chiralpak AS-
H, iPrOH/hexane, 10:90), λ = 207 nm, flow rate 1 mL·min–1, minor
isomer tR = 17.0 min, major isomer tR = 18.6 min.
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syn-1,5-Bis(2-chlorophenyl)-1,5-dihydroxypentan-3-one
(11-syn):
Yield: 6% (10 mg, 0.03 mmol). White crystals; m.p. 113–114 °C. 1H
NMR (500 MHz, CDCl3): δ = 7.62 (dd, J = 1.7 Hz, J = 7.7 Hz, 2
H, Ar), 7.35–7.25 (m, 4 H, Ar), 7.22 (td, Jd = 1.7 Hz, Jt = 7.7 Hz,
2 H, Ar), 5.58 (dt, Jt = 2.8 Hz, Jd = 9.7 Hz, 2 H, CH), 3.26 (d, J
= 3.5 Hz, 2 H, OH), 3.02 (dd, J = 2.4 Hz, J = 17.2 Hz, 2 H,
CHaHb), 2.74 (dd, J = 9.7 Hz, J = 17.2 Hz, 2 H, CHaHb) ppm. 13
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C
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127.3, 127.1, 66.8, 50.0 ppm. IR (KBr): ν = 3553, 3329, 3271, 1697,
˜
1474, 1437, 1403, 1388, 1369, 1195, 1080, 1032, 895, 755, 700 cm–1.
HR ESI-MS: m/z calcd. for [C17H16O3Cl2Na+] 361.03687; found
361.0362. C17H16Cl2O3 (338.05): calcd. C 60.19, H 4.75, Cl 20.90;
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Eur. J. Org. Chem. 2006, 3864–3876
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3875

D. Gryko, R. Lipin´ski
FULL PAPER
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Received: March 13, 2006
Published Online: June 29, 2006
3876
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3864–3876