TABLE 3. Direct Asymmetric Mannich Reaction between Ketone
combination with increased catalyst loadings) resulted in faster
reactions. Gratifyingly, also under those conditions, a reduction
of the catalyst loading was possible. For example, at 45-50
°C, the use of 1 mol % of (S)-proline afforded 82% of the
product after 23 h (Table 3, entry 1), while at 75-77 °C, the
desired product was obtained in high yield (84%) after only 6
h (Table 3, entry 13). In both reactions, the enantioselectivities
were excellent (97-98% ee), confirming the previously ob-
served high-temperature tolerance. Above a critical point,
however, the enantioselectivities deceased significantly, and in
reactions performed at 84-86 °C and 90-93 °C with 10 mol
% of catalyst, the products had only moderate enantiomeric
excesses (Table 3, entries 14 and 15).
The only main difference to the MW experiment was the
required reaction time, which under thermal conditions had to
be extended to achieve comparable conversion and yield.
However, the observed rate enhancement could be a conse-
quence of the fast heating of the reaction mixtures when
irradiated in a MW field. For example, in those experiments,
which were ran at 64-66 °C with 5 and 10 mol % of catalyst,
the reaction was found to be almost complete after 4.5 h (see
Table 3, entries 2-5). Thus, it has been proved that this direct
asymmetric Mannich reaction catalyzed by (S)-proline is
thermally accelerated. It allows the reduction of the reaction
times and, most importantly, the catalyst amount. Concretely,
the use of constant MW irradiation at low power (10-15 W)
in conjunction with simultaneous cooling appears to access a
reaction window, which is well-balanced for achieving both a
high reaction rate and an excellent enantioselectivity.19 In this
particular organocatalytic case, previously unseen low catalyst
loadings could be employed. Although no specific MW effect
has been found,20 the results are synthetically promising and
guided us to examine other organocatalytic asymmetric trans-
formations on their sensitivity toward temperature.
1a, Formaldehyde (2a), and Aniline (3a) Catalyzed by (S)-Prolinea
mol % of
catalyst
temp
(°C)
time
(h)
yieldb
(%)
eec
(%)
entry
1
2
3
4
5
6
7
8
1
10
10
5
5
1
1
10
5
1
10
5
45-50
64-66
64-66
64-66
64-66
64-66
64-66
69-71
69-71
69-71
75-77
75-77
75-77
84-86
90-93
23
3
4.5
3
4.5
4
8
4.5
4.5
4.5
6
6
6
82
70
79
67
82
55
68
64
69
71
72
75
84
72
68
97
97
96
98
98
98
98
96
98
97
95
98
98
85
78
9
10
11
12
13
14
15
1
10
10
4.5
4
a Reaction conditions: same as those described in footnote a of Table
1, but in a preheated oil bath with the given reaction temperature. b See
footnote b of Table 1. c See footnote c of Table 1.
conditions with DMF as solvent and using 100 W of MW power
led to the corresponding product in only poor yield (44% yield,
Table 2, entry 1). However, positive effects on both yield and
enantioselectivity were observed, when the MW power was
reduced to 15 or 10 W (Table 2, entries 2 and 3). Finally, the
use of DMSO as solvent led to consistently high yields and
excellent enantioselectivities. For example, with 10 mol % of
(S)-proline and a MW power of 15 W, the product was isolated
(after only 2.5 h) in 96% yield, having an ee of 98% (Table 2,
entry 5). The most important observation concerned the catalyst
loading. Here, it was found that even with 0.5 mol % of (S)-
proline, 83% of the product with 98% ee could be obtained
(Table 2, entry 9)! Under the same MW conditions, substituted
anilines 3b and 3c reacted similarly and gave the corresponding
products in up to 84 and 88% yields, respectively (Table 2,
entries 10-16). To our delight, no decrease in enantioselectivity
was observed even with only 1 or 0.5 mol % of catalyst (Table
2, entries 12 and 16).
Experimental Section
General Experimental Procedures. See the Supporting Infor-
mation.
General Procedure for the Proline-Catalyzed Asymmetric
Mannich Reaction under Microwave Irradiation. Preparation
of (1R,2S)-2-Phenylaminomethyl-1-cyclohexanol (anti-5a)21 as
a Detailed Representative Example. In a 10 mL vessel was placed
cyclohexanone (1a, 3.0 mL, 2.9 mmol, 2.6 equiv), formaldehyde
(2a, 90 µL, 36% aq solution, 1.2 mmol, 1.1 equiv), aniline (3a,
0.10 mL, 1.1 mmol, 1.0 equiv), (S)-proline (13 mg, 0.11 mmol, 10
mol %), DMSO (4 mL), and a magnetic stir bar. The vessel was
sealed with a septum, placed into the MW cavity, and locked with
the pressure device. Constant MW irradiation of 15 W as well as
simultaneous air-cooling (0.7 bar, 10 psi) were used during the entire
reaction time (2.5 h). After cooling to room temperature, an aliquot
of the crude reaction mixture (0.1 mL) was quenched with
phosphate buffer pH 7.2, and was then extracted with ethyl acetate
(3 × 0.5 mL). The combined organic phases were dried over
MgSO4, and volatile organic materials were removed under reduced
pressure. The ee was 97%, as determined by HPLC analysis of the
crude Mannich product 4a7 (Daicel Chiralpak AD; heptane/
2-propanol, 98:2, 0.5 mL/min, λ ) 254 nm; major isomer, tS )
To further evaluate the beneficial effect of MW irradiation
and to the determine its real impact on the catalysis, we
performed comparative studies using conventional oil bath
heating.18 In these experiments, aniline (3a) was used as the
amine component in the coupling with cyclohexane (1a) and
formaldehyde (2a). As a result of the potential inaccuracy of
the measurement by IR sensor,16 a wide temperature range was
scanned (Table 3). As expected, higher temperatures (also in
(16) In our setup, all temperatures were measured externally by an IR
sensor. The temperature indicated in Table 2 corresponds to the maximum
temperature reached during the experiment. Attempts to use a Discover
CoolMate reactor from CEM Corporation equipped with an internal fiber-
optic sensor device failed due to the temperature limitation (Tmax ) 40 °C)
of the instrument. Thus, at the present stage, a reliable error margin of the
given temperatures (Table 2) cannot be given. This should, however, not
affect the reproducibility of the experiments. For a comparative study of
temperature determinations under MW irradiations, see: Ondruschka, M.
N. B.; Weiâ, D.; Beckert, R.; Bonrath, W.; Gum, A. Chem. Eng. Technol.
2005, 28, 871.
(17) For comparison, the reaction between ketone 1a, formaldehyde (2a),
and aniline (3a), catalyzed by 10 mol % of (S)-proline, was performed using
MW irradiation without simultaneous cooling (15 W, 2.5 h; see also Table
2, entry 5). Under these conditions, the maximum temperature reached was
89 °C, and the product was obtained in just 53% yield, having an ee of
91%. (The temperature profile is included in Supporting Information).
(18) Reactions in oil bath were performed in the 10 mL glass vessels
used in the MW-assisted experiments.
(19) Analogous observations have also been made in other organocatalytic
Mannich-type reactions. Kappe, C. O.; Barbieri, V. Personal communication.
(20) For an excellent discussion on MW effects in organic synthesis,
see: Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199.
(21) (a) Masamune, T.; Takasugi, M.; Suginome, H.; Yokoyama, M. J.
Org. Chem. 1964, 29, 681. (b) Modak, A. S.; Sahasrabudhe, S. D. Indian
J. Chem., Sect. B 1984, 23, 980.
2890 J. Org. Chem., Vol. 71, No. 7, 2006