C3-symmetric proline-functionalized organocatalysts: Enantioselective michael addition reactions

Article abstract of DOI:10.1002/ejoc.201000569

C₃-Symmetric, tripodal catalyst 4 based on 1,3,5- triethylbenzene, which incorporates the features of a molecular receptor, is shown to catalyze Michael addition reactions ofcarbonyl compounds to β-nitrostyrenes in a high stereoselectivity (up to 99:1a dr and up to 98%ee). Copyright

Full text of DOI:10.1002/ejoc.201000569

FULL PAPER
DOI: 10.1002/ejoc.201000569
C3-Symmetric Proline-Functionalized Organocatalysts: Enantioselective
Michael Addition Reactions
Jarugu Narasimha Moorthy*[a] and Satyajit Saha[a]
Keywords: Asymmetric synthesis / Michael addition / Organocatalysis / Amino acids
C3-Symmetric, tripodal catalyst 4 based on 1,3,5-triethyl-
benzene, which incorporates the features of a molecular re-
ceptor, is shown to catalyze Michael addition reactions of
carbonyl compounds to β-nitrostyrenes in a high stereoselec-
tivity (up to 99:1dr and up to 98%ee).
standing this notion, there is growing interest in the exploi-
tation of C3 symmetry in chiral recognition, and recent re-
ports have sufficiently demonstrated utilization of C3 sym-
metry in the development of chiral catalysts as well as in
the design of receptors for molecular recognition.[4]
Introduction
The obvious advantage with catalysts of higher symmetry
in the realm of asymmetric synthesis is the reduction in
number of reaction pathways, which is expected to manifest
in higher selectivity.[1] However, C2 symmetry is more con-
In our research, we have been concerned with exploi-
spicuous in the design of catalysts in comparison to C3 sym- tation of sterics to control molecular order and otherwise
metry.[2] One of the reasons for this appears to be the skep- to develop functional organic materials.[5] We surmised that
ticism with which the use of C3 symmetry in catalyst design sterically favored geometries of 2,4,6-substituted 1,3,5-tri-
was regarded; initially, the argument put forward for the alkylbenzenes should be appealing for convenient exploi-
possible failure of C3-symmetric receptors in guest binding tation in the development of C3-symmetric catalysts for ap-
is that the steric requirements for possible diastereomeric plication in organocatalysis. Notably, 1,3,5-triethylbenzene
transition states would be the same or less distinguishable, has been exploited as a nice platform to develop receptor
leading to no or poor enantiodiscrimination.[3] Notwith- systems for a range of sensing applications.[6] We designed
Figure 1. Structures of proline-derived catalysts 1–7 examined for enantioselective Michael reactions.
the threefold proline-functionalized C3-symmetric 1,3,5-tri-
alkylbenzenes 1–4 (Figure 1) as organocatalysts with the ex-
pectation that the tethered pyrrolidine moieties based on
chiral proline would enclose a void space over the aromatic
[a] Department of Chemistry, Indian Institute of Technology,
Kanpur 208016, India
E-mail: moorthy@iitk.ac.in
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J. N. Moorthy, S. Saha
FULL PAPER
benzene platform within which enamine catalysis may be was treated with substituted amines to afford Boc-protected
carried out with high enantioselectivity. N-aryl--prolinamides, the deprotection of which under
Our premise was that whereas one of the tethered pro- standard conditions involving 20% TFA in DCM at 0 °C
lines would be utilized for enamine formation with a led to N-aryl--prolinamides 1, 2, and 7 in respectable over-
nucleophilic ketone, the N–H bonds of the other two all yields. Catalysts 3–6 were synthesized by reduction of
tethered prolines should in some way form hydrogen bonds the corresponding prolinamides with BH3·SMe2 in THF.
to the electrophile in a highly diastereoselective manner to
permit high enantioselectivity. We particularly chose nitro-
Enantioselective Michael Additions with Catalysts 1–7
olefins as electrophilic partners, as the oxygen atoms of the
nitro group may involve a maximum number of hydrogen
bonds with catalysts 1–4. Thus, we explored the latter in
mediating Michael additions of carbonyl compounds to
nitroalkenes enatioselectively. While our investigations were
in progress, Fujioka et al. reported an analogous 1,3,5-tri-
imidazoline C3-symmetric catalyst for Michael additions of
1,3-diketones to β-nitrostyrenes.[7] Herein, we show that the
C3-symmetric catalyst 4 catalyzes the Michael addition of a
variety of ketones to nitroolefins to afford conjugate ad-
dition products with high diastereo- and enantioselectivi-
ties.
Initially, catalysts 1 and 2 were conjectured to be ideal
for binding the electrophilic nitroolefin through N–H···O
hydrogen bonds involving the amide hydrogen atoms. Thus,
triamide catalysts 1 and 2 were explored for their ability to
mediate Michael addition of cyclohexanone to β-nitro-
styrene under a variety of conditions (Table 1).
As revealed by the results in Table 1, the enantio-
selectivity was found to be frustratingly poor even with
some additives, whereas the reactions proceeded smoothly
to afford the Michael adducts in respectable yields and dia-
stereoselectivity. We thus reasoned that the tethered-prolin-
amides 1 and 2 are presumably locked conformationally by
intramolecular N–H···O hydrogen bonding as shown in
Figure 2a, leading to the observed reactivity that seemingly
occurs from the nitroolefin, which is not bound in the en-
closure over the benzene surface. This fact together with
Results and Discussion
Synthesis of Catalysts 1–7
Arylprolinamides 1, 2, and 7 (Figure 1) were synthesized our observation that organocatalytic Michael additions are
starting from Boc-protected -proline, which was treated generally promoted by 2-aminomethylpyrrolidine deriva-
with ethyl chloroformate in THF in the presence of Et3N tives and not as much with prolinamides[8] spurred us to
at 0 °C to afford the mixed anhydride (Scheme 1). The latter consider reduced analogs 3 and 4. We believed that the in-
Scheme 1.
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C3-Symmetric Proline-Functionalized Organocatalysts
Table 1. Screening of catalysts 1 and 2 for the enantioselective
Michael addition reaction of cyclohexanone to p-methoxy-β-nitro-
styrene in various solvents with different additives.[a]
Table 2. Screening of catalyst 4 in mediating the enantioselective
Michael addition of cyclohexanone to p-methoxy-β-nitrostyrene.[a]
Entry Solvent
Additive[b]
[10 mol-%]
Time Yield[c] dr[d]
ee[e]
[%]
Catalyst Solvent
Additive
[10 mol-%]
Time Yield[b] dr[c]
ee[d]
[%]
[h]
[%]
Ͼ90
Ͼ88
[h]
[%]
1
2
3
DMSO
DMF
THF
none
none
none
none
none
none
none
none
none
32
32
85:15
90:10
nd[f]
95:5
98:2
nd[f]
96:4
98:2
95:5
98:2
nd[f]
nd[f]
nd[f]
95:5
64
73
1[e]
1
DCM
DCM
DMF
dioxane
H2O
DCM
DCM
DCM
DMF
dioxane
H2O
–
30
16
16
18
18
28
15
15
15
16
16
20
90
90
88
86
92
60
87
90
85
90
92
56
88
92
98:2
98:2
95:5
96:4
95:5
98:2
98:2
95:5
96:4
96:4
95:5
96:4
95:5
24
25
22
26
18
38
22
20
22
34
36
32
28
36 slow
nd[f]
88
TFA
TFA
TFA
TFA
–
–
TFA
–
TFA
TFA
TFA
TFA
4
5
6
7
IPA
36
32
56
32
32
48
36
48
48
48
24
60
88
Ͻ15
88
67
65
1
DCM
toluene
CH3CN
brine
98
1
nd[f]
85
1
2[e]
2
8
93
85
90
9
NMP
DCM
brine
DCM
DCM
IPA
2
10
11
12
13
14
TFA
TFA
85
2
Ͻ30
slow
slow
85
nd[f]
nd[f]
nd[f]
87
2
p-TsOH
Mosher’s acid
DNBA
2
2
hexane
IPA
2
[a] The reactions were run with p-methoxy-β-nitrostyrene (0.3–
0.4 mmol) at 3Ϯ1 °C under identical conditions. [b] TFA = tri-
fluoroacetic acid; p-TsOH = p-toluenesulfonic acid; DNBA = 3,5-
dinitrobenzoic acid. [c] Based on p-methoxy-β-nitrostyrene. [d] The
syn/anti ratio was determined by 500 MHz H NMR spectroscopy.
[e] Based on chiral HPLC analyses for the major syn diastereomer.
[a] The reactions in all solvents were run with p-methoxy-β-nitro-
styrene (0.3–0.4 mmol) at 3Ϯ1 °C under identical conditions by
employing the catalyst (20 mol-%), unless mentioned otherwise.
[b] Based on p-methoxy-β-nitrostyrene. [c] The syn/anti ratio was
determined by 500 MHz H NMR spectroscopy. [d] Based on chi-
ral HPLC analyses for the major syn diastereomer. [e] 10 mol-%
1
1
[f] Not determined.
was employed.
creased entropy of the pyrrolidines introduced through the
The enantioselective Michael addition of cyclohexanone
CH2–NH–CH2 tether might allow the appropriate transi- to p-methoxy-β-nitrostyrene under these conditions was ex-
tion-state geometries for Michael additions to be adopted amined uniformly for amide catalysts 1, 2, and 7 and for
rather easily. Thus, catalyst 4 in which the ethyl groups sup- aminomethylpyrrolidine derivatives 3, 5, and 6. C1- and C2-
posedly ensure all the tethered aminomethylpyrrolidines to Symmetric aminomethylpyrrolidine functionalized 1,3,5-tri-
be syn[9] was screened for mediating the Michael addition ethylbenzenes 5 and 6 and C2-symmetric amide derivative
of cyclohexanone to p-methoxy-β-nitrostyrene at ca. 3 °C 7 were synthesized and examined for their enantiocatalytic
under various conditions shown in Table 2; a perusal of the behavior in regulating the Michael addition reaction of cy-
results shows that the reaction proceeds well in dichloro- clohexanone to p-methoxy-β-nitrostyrene to establish the
methane with a very high stereoselectivity (Table 2, En- influence of enclosure inherent to the C3-symmetric cata-
try 5).
lysts (i.e., 3 and 4) vis-à-vis C1- and C2-symmetric catalysts
Figure 2. (a) Possible N–H···O H-bond mediated conformational locking in amide catalyst 2, and (b) plausible transition-state geometry
for Michael addition with catalyst 4.
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J. N. Moorthy, S. Saha
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(i.e., 5 and 6). In Table 3 are consolidated the results of the Table 4. Results of the enantioselective Michael reaction by using
C3-symmetric tripodal catalyst 4.[a]
Michael addition reactions between cyclohexanone and p-
methoxy-β-nitrostyrene for catalysts 1–7 under uniform re-
action conditions at 10 mol-% catalyst loading.
Table 3. Screening of catalyst 4 in mediating the enantioselective
Michael addition of cyclohexanone to p-methoxy-β-nitrostyrene.[a]
Entry Catalyst
Time
[h]
Yield[b]
[%]
dr[c]
ee[d]
[%]
1
2
3
4
5
6
7
1
2
38
38
32
32
64
42
42
84
82
82
88
45
88
86
96:4
96:4
95:5
98:2
96:4
96:4
97:3
32
34
86
98
78
90
34
3
4
5[e]
6[e]
7[e]
[a] The reactions were run with p-methoxy-β-nitrostyrene (0.3–
0.4 mmol) at 3Ϯ1 °C under identical conditions. [b] Based on p-
methoxy-β-nitrostyrene. [c] The syn/anti ratio was determined by
500 MHz 1H NMR spectroscopy. [d] Based on chiral HPLC analy-
ses for the major syn diastereomer. [e] No perceptible difference in
stereochemistry was observed when the catalyst loading was in-
creased to 30 mol-% for 5 and 15 mol-% for 6 and 7.
The following are readily evident from Table 3: (i) C3-
Symmmetric amide-based catalysts 1 and 2 lead to poor ee
values. (ii) C1-Symmetric catalyst 5 does not lead to high
enantioselectivity under catalyst loading (30 mol-%) that is
comparable to that of 4; indeed, C2-symmetric catalyst 6
also does not afford the Michael adduct in an optical purity
comparable to that obtained with catalyst 4. (iii) One ob-
serves a gradual increase in the ee value on going from C1-
to C2- to C3-symmetric catalyst 4 (Table 3, Entries 4, 5, and
7). These results amply attest to the fact that the enclosure
formed by the tethered aminomethylpyrrolidines in C3-sym-
metric catalyst 4 contributes to better enantioselectivity.
[a] The reactions in all cases were run with β-nitrostyrene deriva-
tives (0.3–0.4 mmol) at 3Ϯ1 °C under identical conditions.
[b] Based on the β-nitrostyrene derivative. [c] The syn/anti ratio was
determined by 500 MHz H NMR spectroscopy. [d] Based on chi-
ral HPLC analyses of the major syn diastereomer.
1
Supposedly, the CH2–NH–CH2 tether also permits the suit- (Table 4, Entries 1–16); whereas a high diastereoselectivity
able transition-state geometry to be adopted rather easily, was observed for electron-rich nitroolefins (syn/anti up to
as was presupposed. In Figure 2b is shown the plausible 99:1), marginally less selectivity was observed for electron-
geometry for binding of the nitroolefin and the ketone that deficient olefins (up to 94:6; Table 4, Entries 8, 9, 12, and
accounts for the observed enantioselectivity.
13). In the same vein, low enantioselectivity (ca. 88%) was
Buoyed by the results with catalyst 4, we investigated the observed for electron-poor nitroolefins in contrast to their
enantioselective Michael addition of cyclic as well as acyclic electron-rich counterparts (ca. 97–98%). Rather attenuated
ketones and 1,3-diketones to a variety of conjugated ni- enantioselectivity was observed for nitroolefins substituted
troolefins (Table 4); the nitroolefins were both aliphatic as with aliphatic groups such as cyclohexyl and isobutyl (ca.
well as aromatic, and the latter were varied in terms of elec- 86–90%ee; Table 4, Entries 15 and 16). For conjugate ad-
tron-poor/rich attributes.
dition of cyclopentanone to β-nitrostyrenes substituted
Under a catalytic loading of 10 mol-% in dichlorometh- with electron-rich and poor substituents, both diastereo-
ane at Ϯ3 °C, the reactions went to completion in 20–42 h. and enantioselectivities were found to be significantly less
As shown in Table 3, the diastereoselectivity was found to as compared to those for cyclohexanone (Table 4, En-
be very high for the addition of cyclohexanone to a variety tries 17–19). Whereas virtually no diastereodiscrimination
of nitroolefins, with the syn diastereomer predominating was observed for the addition of acyclic propanaldehyde
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C3-Symmetric Proline-Functionalized Organocatalysts
ene, 1,3-bis(aminomethyl)-5-methyl-2,4,6-triethylbenzene, and 1-
(aminomethyl)-2,3,6-triethylbenzene, were prepared by following
the literature-reported procedures.
and benzoylacetone, a 1,3-diketone, to p-methoxy-β-nitro-
styrene, notable enantioselectivity was found for the syn
diastereomer. The Michael addition of both acetone and
acetylacetone to both electron-rich and poor nitrostyrene
led to the corresponding products in respectable yields with
ee values in the range 75–80% (Table 4, Entries 22–27). The
relatively poor stereoselectivities for acyclic aldehyde and
ketones should be traceable to the considerable flexibility
of the tether, which otherwise is also an advantage for stabi-
lizing the appropriate geometries of the transition states, as
mentioned earlier. However, it is the tradeoff between the
size/shape and the flexibility of the tether that is apparently
crucial for best results, as observed for the addition of cy-
clohexanone to a variety of nitroolefins. The results uncov-
ered herein compellingly signify the influence of C3-sym-
metric tripodal catalysts as applied to the Michael reaction,
which is one of the most important C–C bond-forming re-
actions.[10] The addition of carbon-centered nucleophiles to
nitroolefins that leads to functionalized products with mul-
tiple stereogenic centers is of tremendous importance in
view of the fact that the nitro functionality can be easily
transformed into a broad spectrum of optically enriched
intermediates.[11] A wide variety of catalysts has been devel-
oped for this particular reaction based on readily available
chiral amines,[12,13] due to the fact that the reaction affords
enantiomerically enriched products with two contiguous
stereocenters in a single step. Despite excellent results with
diverse catalysts, the design and development of new and
novel chiral organocatalysts is an enduring effort in the pur-
suit of enantiomerically pure compounds in organic synthe-
sis.
General Procedure for the Preparation of Catalysts 1–7: To a two-
necked, round-bottomed flask containing Boc--proline (10.08 g,
48.1 mmol) in dry THF (60 mL) was added triethylamine (4.86 g,
48.1 mmol) under a N2 atmosphere. The resultant solution was co-
oled to 0 °C. Subsequently, ethyl chloroformate (5.22 g, 48.1 mmol)
was introduced dropwise over a period of 45 min. After the solu-
tion was stirred at this temperature for 1 h, 1,3,5-tris(aminome-
thyl)-2,4,6-triethylbenzene (2.0 g, 8.0 mmol) was added under a N2
atmosphere in small portions. The reaction mixture was stirred at
0 °C for 1 h, at room temperature for 2 h, and heated at reflux for
48 h; the reaction was continually monitored by TLC analyses. At
the end of the reaction, as judged by TLC analysis, the reaction
mixture was cooled to room temperature and filtered. The filtrate
was concentrated to afford the crude product, which was further
purified by silica-gel column chromatography. For deprotection of
the above Boc-protected prolinamide derivative, the substrate was
dissolved in dry DCM (40 mL) and cooled to 0 °C. TFA (12 mL)
was slowly added to this solution at 0 °C, which was then stirred
for 3 h at room temperature. The reaction mixture was evaporated
in vacuo and washed thoroughly with petroleum ether. The oil was
dissolved in a minimum amount of water and basified with
NH4OH, extracted with chloroform, washed thoroughly with
water, dried with anhydrous Na2SO4, and concentrated to yield the
pure carboxamide.
General Procedure for the Reduction of N-Arylprolinamides: The
pure prolinamide available from the above reaction (2.52 g,
4.6 mmol) was dissolved in anhydrous THF (30 mL) and cooled to
0 °C. To the solution was added BH3·SMe2 (2.12 g, 28 mmol)
slowly with vigorous stirring. Later, the reaction mixture was
heated at reflux for 7 h, cooled, and carefully acidified with 10%
HCl. The contents were further heated at reflux for 6 h. The reac-
tion mixture was then cooled to 0 °C and basified with 2  NaOH
solution, and the solvent was removed in vacuo. The organic matter
was extracted with DCM, washed with water, dried, and concen-
trated to obtain the pure amine in respectable yield.
Conclusions
We have designed and synthesized C3-symmetric tripodal
organocatalysts with receptor features based on 1,3,5-trialk-
ylbenzenes for application in enantioselective reactions.
From a systematic investigation that entailed modification
of the catalyst structure in light of the observed selectivities
with catalysts 1 and 2, the catalyst 4 that enjoys conforma-
tional flexibility was designed and shown to be effective for
highly diastereo- and enantioselective Michael additions of
carbonyl compounds to β-nitrostyrenes. To account for the
high stereoselectivities observed with organocatalyst 4 for
Michael additions, the transition state structure involving
1: Yield 86%; m.p. 102–104 °C. [α]2D5 = –35.26 (c = 0.2, DCM). IR
(KBr): ν = 1530, 1642, 2866, 2964, 3297 cm–1. 1H NMR (500 MHz,
˜
CDCl3): δ = 1.66–1.72 (m, 6 H), 1.87–1.94 (m, 3 H), 2.10–2.18 (m,
3 H), 2.30 (s, 9 H), 2.77–2.88 (m, 3 H), 2.93–2.99 (m, 3 H), 3.79
(dd, J = 5.3, 6.2 Hz, 3 H), 4.38–4.46 (m, 6 H), 7.57 (br. s, 3 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 16.0, 26.0, 30.7, 38.6, 47.1,
60.3, 133.0, 137.0, 174.4 ppm. HRMS (ESI+): calcd. for
C27H42N6O3 [M + H]+ 499.3396; found 499.3384.
2: Yield 90%; m.p. 72–74 °C. [α]2D5 = –49.31(c = 0.2, DCM). IR
(KBr): ν = 1501, 1658, 2871, 2965, 3320 cm–1. 1H NMR (500 MHz,
˜
attack of the enamine derived from the carbonyl com- CDCl3): δ = 1.17 (t, J = 7.6 Hz, 9 H), 1.63–1.72 (m, 6 H), 1.90–
2.02 (m, 3 H), 2.13–2.18 (m, 3 H), 2.59–2.73 (m, 6 H), 2.77–2.82
(m, 3 H), 2.92–2.97 (m, 3 H), 3.74 (dd, J = 5.7, 8.9 Hz, 3 H), 4.38
(dd, J = 4.5, 14.3 Hz, 3 H), 4.47 (dd, J = 2.9, 12.5 Hz, 3 H), 7.45
(br. s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 16.4, 23.0,
26.2, 30.7, 37.7, 47.2, 60.5, 132.2, 144.1, 174.8 ppm. HRMS (ESI+):
calcd. for C30H48N6O3 [M + H]+ 541.3866; found 541.3867.
pounds is presumed to attack the β-nitrostyrene that is
bound through N–H···O hydrogen bonds in the cavity
enclosed by the CH2–NH–CH2 tethers over the benzene
surface. Thus, the results reported herein with the tripodal
catalysts based on 1,3,5-triethylbenzene exemplify a new ap-
proach for organocatalysis in general.
3: Yield 78%; gummy liquid. [α]2D5 = +9.09 (c = 0.2, DCM). IR
(KBr): ν = 1265, 2875, 2966, 3420 cm–1. 1H NMR (500 MHz,
˜
CDCl3): δ = 1.31–1.37 (m, 6 H), 1.61–1.75 (m, 3 H), 1.81–1.93 (m,
3 H), 2.41 (s, 9 H), 2.61–2.72 (m, 6 H), 2.81–2.93 (m, 6 H), 3.16–
3.24 (m, 3 H), 3.74 (d, J = 5.8 Hz, 6 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 15.5, 25.4, 29.4, 29.6, 46.2, 48.7, 55.0, 58.2.135.0 ppm.
Experimental Section
The required substituted amines, viz., 1,3,5-tris(aminomethyl)-
2,4,6-trimethylbenzene, 1,3,5-tris(aminomethyl)-2,4,6-triethylbenz-
Eur. J. Org. Chem. 2010, 6359–6365
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6363

J. N. Moorthy, S. Saha
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HRMS (ESI+): calcd. for C27H48N6 [M + H]+ 457.4018; found
457.4018.
Acknowledgments
J. N. M. is thankful to Department of Science and Technology
(DST), New Delhi for generous financial support. S. S. is grateful
to Council of Scientific and Industrial Research (CSIR), New Delhi
for a Senior Research Fellowship.
4: Yield 78%; gummy liquid. [α]2D5 = +13.9 (c = 0.2, DCM). IR
1
(KBr): ν = 2869, 2960, 3307 cm–1. H NMR (500 MHz, CDCl ): δ
˜
3
= 1.21 (t, J = 6.5 Hz, 9 H), 1.32–1.39 (m, 6 H), 1.65–1.79 (m, 3
H), 1.82–1.89 (m, 3 H), 2.08 (br. s, 3 H), 2.64–2.96 (m, 18 H), 3.16–
3.23 (m, 3 H), 3.69 (s, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ
= 17.0, 22.9, 25.2, 29.4, 46.1, 47.8, 54.6, 58.7, 134.1, 142.2 ppm.
HRMS (ESI+): calcd. for C30H54N6 [M + H]+ 541.3866; found
541.3867.
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5: Yield 76%; gummy liquid. [α]2D7 = –61.5 (c = 0.1, DCM). IR
(KBr): ν = 1265, 2875, 2966, 3420 cm–1. 1H NMR (500 MHz,
˜
CDCl3): δ = 1.15–1.28 (m, 9 H), 1.35–1.43 (m, 2 H), 1.68–1.78 (m,
1 H), 1.85–1.91 (m, 1 H), 2.27 (br. s, 1 H), 2,54–2.58 (m, 2 H),
2.64–2.77 (m, 4 H), 2.89–2.96 (m, 2 H), 3.27–3.34 (m, 1 H), 3.73
(d, J = 5.4 Hz, 2 H), 6.87 (s, 2 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 15.5, 15.8, 23.7, 26.7, 28.6, 29.4, 31.6, 47.7, 55.2, 56.1,
143.7, 144.2, 144.8, 145.1 ppm. HRMS (ESI+): calcd. for C18H30N2
[M + H]+ 275.2487; found 275.2487.
6: Yield 80%; gummy liquid. [α]2D7 = –51.23 (c = 0.2, DCM). IR
(KBr): ν = 1265, 2870, 2963, 3318 cm–1. 1H NMR (500 MHz,
˜
CDCl3): δ = 1.15 (t, J = 7.2 Hz, 6 H), 1.21 (t, J = 7.2 Hz, 3 H),
1.33–1.40 (m, 4 H), 1.66–1.80 (m, 2 H), 1.83–1.90 (m, 2 H), 2.25
(s, 3 H), 2.67–2.80 (m, 10 H), 2.82–2.96 (m, 4 H), 3.19–3.25 (m, 2
H), 3.70 (d, J = 3.8 Hz, 4 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 15.1, 15.1, 17.1, 22.8, 23.2, 25.1, 29.3, 46.1, 47.9, 54.7, 58.5,
132.3, 133.6, 140.0, 141.2 ppm. HRMS (ESI+): calcd. for C25H44N4
[M + H]+ 401.3644; found 401.3644.
7: Yield 88%; m.p. 68–70 °C. [α]2D7 = –20.2 (c = 0.1, DCM). IR
(KBr): ν = 1450, 1502, 1657, 2869, 2964, 3309 cm–1. 1H NMR
˜
(500 MHz, CDCl3): δ = 1.13–1.16 (m, 9 H), 1.64–1.70 (m, 4 H),
1.89–1.96 (m, 2 H), 2.10–2.18 (m, 2 H), 2.29 (s, 3 H), 2.60–2.70 (m,
6 H), 2.76–2.79 (m, 2 H), 2.90–2.94 (m, 2 H), 3.73 (dd, J = 5.3,
9.1 Hz, 2 H), 4.38 (dd, J = 4.2, 14.3 Hz, 2 H), 4.44 (dd, J = 4.6,
14.1 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 14.8, 15.1,
16.6, 22.9, 23.3, 26.1, 30.7, 37.9, 47.2, 60.5, 131.2, 132.9, 141.1,
142.7, 174.8 ppm. HRMS (ESI+): calcd. for C25H40N4O2 [M +
H]+ 429.3229; found 429.3233.
Typical Procedure for the Enantioselective Michael Reaction using
Catalyst 4: A mixture of the catalyst (0.023 g, 0.048 mmol) and
ketone (0.50 g, 4.8 mmol) in DCM was stirred at room temperature
for 45 min. Subsequently the temperature was cooled to 3 °C and
p-methoxy-β-nitrostyrene (0.09 g, 0.5 mmol) was introduced. The
reaction mixture was stirred at 3 °C until the reaction was judged to
be complete based on TLC analysis. Upon completion, the reaction
mixture was purified rapidly by passing through a short pad of
neutral silica gel column. The crude product before silica gel
chromatography was submitted to 1H NMR spectroscopic analysis
to determine the diastereomeric ratio. The product after SiO2
chromatography was analyzed by HPLC to determine the enantio-
meric as well as the diastereomeric ratios. The syn and anti dia-
stereomers of the Michael addition products were readily distin-
guished by 1H NMR spectroscopy by the diagnostic chemical shifts
of the –CHAr-proton (see the Supporting Information for the
chemical shift data).
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1
cle): Details of synthesis, copies of the H and 13C NMR spectra
of catalysts 1–7, 1H NMR diagnostic chemical shift data for syn
and anti Michael addition products, and HPLC profiles for all re-
sults in Table 4.
6364
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: April 23, 2010
Published Online: October 1, 2010
Eur. J. Org. Chem. 2010, 6359–6365
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6365