Pyrrolidine-camphor derivative as an organocatalyst for asymmetic michael additions of α,α-disubstituted aldehydes to β-nitroalkenes: Construction of quaternary carbon-bearing aldehydes under solvent-free conditions

Article abstract of DOI:10.1002/adsc.200800771

A novel pyrrolidine-camphor organocatalyst 3 was designed, synthesized and proven to be an efficient catalyst for the asymmetric Michael reaction. Treatment of α,α-disubstituted aldehydes with β-nitroalkenes in the presence of 20 mol% organocatalyst 3 and

Full text of DOI:10.1002/adsc.200800771

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DOI: 10.1002/adsc.200800771
Pyrrolidine-Camphor Derivative as an Organocatalyst for
Asymmetic Michael Additions of a,a-Disubstituted Aldehydes
to b-Nitroalkenes: Construction of Quaternary Carbon-Bearing
Aldehydes under Solvent-Free Conditions
Chihliang Chang,a Ssu-Hsien Li,a Raju Jannapu Reddy,a and Kwunmin Chena,*
a
Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan 116, ROC
Fax : (+886)-2-2932-4249; e-mail: kchen@ntnu.edu.tw
Received: December 11, 2008; Revised: March 30, 2009; Published online: May 27, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800771.
Abstract: A novel pyrrolidine-camphor organocata-
lyst 3 was designed, synthesized and proven to be
an efficient catalyst for the asymmetric Michael re-
action. Treatment of a,a-disubstituted aldehydes
with b-nitroalkenes in the presence of 20 mol% or-
ganocatalyst 3 and 20 mol% benzoic acid under sol-
vent-free conditions provided the desired Michael
product possessing an all-carbon quaternary center
with high chemical yields (up to 99% yield) and
high levels of enantioselectivities (up to 95% ee).
and there has been only a few reports on the use of a,
a-disubstituted aldehydes.[7] The use of an a,a-disub-
stituted aldehyde donor should directly produce a Mi-
chael product with an all-carbon quaternary center.
Most recently, many research groups have inde-
pendently demonstrated that brine and water are
good reaction media for asymmetric Michael reac-
tions of aldehydes and ketones with nitroolefins.[8]
Performing organic reactions in aqueous medium is
one of the most fundamental and challenging goals
and considerable progress has been made in recent
years.[9] On the other hand, solvent-free condi-
Keywords: asymmetric catalysis; Michael reaction;
b-nitroalkenes; quaternary carbon centers; solvent-
free reaction
AHCTUNGTRENNUNG
tions,[5k,7a,10] have proved to be very effective in many
reaction types due to the intimacy of the reactants.
Recently, we have designed and synthesized camphor-
containing thiourea derivatives, as organocatalysts for
the asymmetric aldol reaction on water.[11] In continu-
ation of our research interest, we herein, report an
Remarkable advances have been realized in the use eco-friendly process for the direct asymmetric Mi-
of small privileged organic molecules to catalyze chael reaction of a,a-disubstituted aldehydes with b-
asymmetric reactions. The development of organoca- nitroalkene acceptors. The novel pyrrolidine-based
talysts in asymmetric reaction has attracted much at- camphor derivative serves as an efficient bifunctional
tention in recent years as organocatalysts are general- organocatalyst to catalyze the reaction and provide
ly non-toxic, highly efficient and selective, environ- Michael products possessing an all-carbon quaternary
mentally friendly, and stable under aerobic and aque- center under solvent-free conditions. High levels of
ous reaction conditions.[1,2] The Michael reaction is chemical yields and enantioselectivities were general-
one of the most efficient and powerful atom-econom- ly achieved (up to 99% chemical yield and 95% ee).
ic carbon-carbon bond forming reactions in organic
The design and synthesis of highly stereoselective,
chemistry[3] and, therefore, developing enantioselec- readily accessible and tunable catalysts are always de-
tive Michael reactions has been the focus of many or- sirable for asymmetric catalysis. In this direction, we
ganic chemists for decades.[4] Since the pioneering have developed an efficient synthesis of pyrrolidine-
works of organocatalysts, many methods have been camphor organocatalyst 3. We began with the known
developed for the direct asymmetric Michael addition Boc protected (S)-2-aminomethylpyrrolidine (1),[12]
of unmodified aldehydes/ketones with nitroalkenes to which was treated with ketopinic acid under standard
produce enantiomerically enriched nitroalkanes.[5] coupling conditions (HOBt, EDC and Et3N in
The synthesis of quaternary stereogenic centers is CH2Cl2) to give product 2 with an 84% yield
considered a challenging task in organic synthesis[6] (Scheme 1). Reduction of 2 using sodium borohydride
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Chihliang Chang et al.
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Scheme 1. Synthesis of camphor-containing pyrrolidine organocatalyst 3.
to provide the corresponding exo alcohol as a single single crystal X-ray structure analysis (see Supporting
diastereomer which was treated with TFA in CH2Cl2 Information).[13]
provided the desired organocatalyst 3 without inci-
As a model case, we explored the direct Michael
dent. The synthetic route of 3 is quite straightforward reaction of isobutyraldehyde (4a) with trans-b-nitro-
and can be scaled up to gram quantities (3.0 g). The styrene (5a) catalyzed by 3 on water or brine. A low
structure of organocatalyst 3 was fully characterized chemical yield was obtained when H2O was used as
1
by IR, H-, 13C NMR and HR-MS analyses and the the reaction medium with moderate enantioselectivity
absolute stereochemistry was further confirmed by a (Table 1, entry 1). Both the chemical yield and stereo-
Table 1. Optimization of enantioselective Michael addition of isobutyraldehyde (4a) to b-nitrostyrene (5a) catalyzed by 3.[a]
Entry
Cat. 3 [mol%]
Solvent
Additive[b]
T [oC]
t [days]
Yield[c] [%] of 6a
ee [%][d]
1
2
3
4
5
6
7
8
10
10
15
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
H2O
–
–
–
–
–
–
–
–
0
0
0
0
0
0
0
0
0
0
0
30
30
30
30
30
30
0
7.0
7.0
5.0
5.0
1.0
3.0
3.0
3.0
3.0
3.0
2.0
2.0
2.0
2.0
2.0
1.0
0.5
1.0
1.0
14
45
56
80
67
46
48
34
39
42
62
90
67
24
26
77
77
88
17
42
68
67
77
54
11
53
52
52
70
75
71
77
75
78
78
79
85
87
Brine
Brine
Brine
MeOH
i-PrOH
THF
CH2Cl2
CHCl3
Toluene
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
9
–
–
–
10
11
12
13
14
15
16
17
18
19
TsOH
AcOH
HCl
TFA
Citric acid
PhCO2H
PhCO2H
PhCO2H
À20
[a]
Unless otherwise specified, all reactions were carried out using isobutyraldehyde (4a, 0.80 mmol), trans-b-nitrostyrene
(5a, 0.20 mmol) and 10–20 mol% catalyst 3.
20 mol% of acid additive was added.
[b]
[c]
[d]
Isolated yield.
Determined by chiral HPLC analysis (see Supporting Information).
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Pyrrolidine-Camphor Derivative as an Organocatalyst for Asymmetic Michael Additions
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selectivity increased when brine was used as the reac- obtained when TsOH was used under the solvent-free
tion medium at 08C (Table 1, entry 2). The reactivity conditions at 308C (Table 1, entry 12). No significant
and enantioselectivity increased with increasing improvement was observed in terms of both reactivity
amount of catalyst loading (Table 1, entries 3 and 4). and selectivity when acetic acid was used as an addi-
At 08C the chemical yields and enantioselectivities tive (Table 1, entry 13). The use of HCl and TFA pro-
were not significantly improved in polar solvents like vided the desired Michael adduct with low chemical
MeOH, i-PrOH and THF (Table 1, entries 5–7). The yields (Table 1, entries 14 and 15). This may be due to
Michael product 6a was obtained, with poor results, the protonation of the amine catalyst decreasing the
when the reaction was carried out in CH2Cl2 and nucleophilicity and subsequently hampering the en-
CHCl3 for 3 days (Table 1, entries 8 and 9). Low amine formation. Significant reactivity and selectivity
chemical yield (41%) and good enantioselectivity were observed when the reaction was carried out with
(70% ee) were obtained when the reaction was car- 20 mol% citric acid at 308C under neat conditions
ried out in toluene at 08C (Table 1, entry 10). Only (Table 1, entry 16). The reactivity increased in the
traces amount of the product 6a was observed when presence of benzoic acid to give the desired product
we performed the reaction in DMSO, DMF, CH3CN 6a with 77% yield and 79% ee (Table 1, entry 17).
and 1,4-dioxane (data not shown). Although good re- The enantioselectivity was further improved to 85%
sults were achieved in aqueous medium, the reaction ee when the reaction was carried out at 08C for 1 day
still suffered from the longer reaction time (5 days). (Table 1, entry 18). The reactivity dropped significant-
The reaction was completed in 2 days when it was car- ly when the reaction was carried out at À208C but re-
ried out under neat conditions at 08C. A reasonable tained the same level of stereoselectivity (Table 1,
chemical yield (62%) and good stereoselectivity (75% entry 19). Among the additives used, benzoic acid
ee) were observed (Table 1, entry 11).
turned out to be the most efficient. It is worth men-
Encouraged by these results, we then proceeded to tioning here that only 4 equivalents of isobutyralde-
optimize the catalysis conditions. The presence of a hyde were used as a donor to b-nitrostyrene for this
Brønsted acid could promote the formation of the en- catalytic process.[5a–e,g,h,k,n,o]
amine species, and thereby, improve both the reactivi-
With these optimal reaction conditions, we further
ty and selectivities. To test this, we then studied the examined a variety of nitroolefins (5a–l) with isobu-
additive effect of the Michael addition in the presence tyraldehyde (4a) to establish the general utility of this
of 20 mol% of various acid additives. High chemical asymmetric transformation (Table 2). All reactions
yield (90%) with good enantioselectivity (71%) were were performed under solvent-free conditions at 08C
Table 2. Substrate studies of the Michael addition of 4a to various b-nitroalkenes (5a–m) under solvent-free conditions at
08C.[a]
Entry
5
R
Product 6
Time [days]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
C6H5
6a
6b
6c
6d
6e
6f
6g
6h
6i
1.0
0.5
3.0
0.5
0.5
3.0
0.5
1.0
0.5
0.5
0.5
0.5
3.0
88
89
92
88
96
66
88
88
89
98
92
88
56
85
84
71
85
83
52
85
60
85
84
85
84
90
4-Me-C6H4
2-MeO-C6H4
3-MeO-C6H4
4-MeO-C6H4
2-CF3-C6H4
3-CF3-C6H4
2-Br-C6H4
3-Br-C6H4
4-Br-C6H4
3-Cl-C6H4
4-Cl-C6H4
PhCH2CH2
9
10
11
12
13[d]
5j
5k
5l
6j
6k
6l
5m
6m
[a]
Unless otherwise specified, all reactions were carried out using 4a (0.80 mmol) with various nitroalkenes 5a–m
(0.20 mmol) in the presence of 3 (20 mol%) and benzoic acid (20 mol%) under neat conditions.
Isolated yields.
Determined by chiral HPLC analysis (see Supporting Information).
The reaction was carried out at ambient temperature.
[b]
[c]
[d]
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Chihliang Chang et al.
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in the presence of 20 mol% of 3 and 20 mol% of ben- not yet been effectively utilized in the asymmetric Mi-
zoic acid. Various 3- or 4-substituted nitroalkenes re- chael addition.[7a,e] In this regard, the reaction of un-
acted well with 4a to provide the Michael products symmetrical a,a-disubstituted aldehydes (2-methylbut-
(6a, b, d, e and 6i–l) with 88–98% yields and 83–85% anal and 2-phenylpropionaldehyde) with nitroalkenes
enantioselectivities (Table 2, entries 1, 2, 4, 5, 7 and catalyzed by 3 was then studied. Unfortunately, no de-
9–12). In the case of 2-substituted nitroalkenes (5c, f sired product was isolated.[14]
and h) moderate enantioselectivities were observed
The substituted chiral, non-racemic pyrrolidines are
(Table 2, entries 3, 6 and 8). This may be due the common structural units found in many natural and
steric hindrance caused by the 2-substituent of the unnatural products that possess interesting and impor-
phenyl ring. In addition to aromatic nitroalkenes, an tant biological activities.[15] To demonstrate the utility
aliphatic nitroalkene such as (4-nitrobut-3-enyl)ben- of this methodology, Michael adduct 7a was trans-
zene (5m) was also a good Michael acceptor for this formed into a spiro-pyrrolidine derivative by means
catalytic system. The desired product (6m) was ob- of a one-step procedure (Scheme 2). Hydrogenation
tained with high enantioselectivity under the optimum of d-nitroaldehyde 7a in the presence of Pd/C fur-
reaction conditions (Table 2, entry 13).
nished the products 3-phenyl-spiro-pyrrolidine N-
We then selected cyclopentanecarboxaldehyde (4b) oxide (8) and 1-hydroxy-3-phenyl-spiro-pyrrolidine
as another donor to react with both electron-rich and (9) in high yields. Then, the 3-phenyl-spiro-pyrrolidine
electron-deficient aromatic nitroalkenes (5a–l). These N-oxide (8) was further subject to NaBH4 reduction
reactions proceeded smoothly and the corresponding in EtOH to afford spiro-product 9 in excellent yield
Michael products (7a–l) were obtained with excellent (Scheme 2).
yields (80–99%) and high levels of enantioselectivity
In summary, we have developed an efficient synthe-
(up to 94%) (Table 3, entries 1–12). Again, the Mi- sis of a novel pyrrolidine-derived organocatalyst 3
chael reaction proceeded smoothly with aliphatic ni- which comprises a structurally rigid camphor scaffold.
troalkenes. High chemical yield (85%) and excellent We have also demonstrated a practical application of
enantioselectivity (95% ee) were observed when (4- organocatalyst 3 for Michael additions of a,a-disub-
nitrobut-3-enyl)benzene (5m) was used (Table 3, stituted aldehydes to b-nitrostyrenes to produce qua-
entry 13). In the case of a heteroaromatic nitroalkene ternary carbon-containing products with high to ex-
the corresponding Michael adduct (7n) was obtained cellent chemical yields and high levels of enantiose-
with high enantioselectivity (Table 3, entry 14). The lectivities under solvent-free conditions. This repre-
use of unsymmetrical a,a-disubsituted aldehydes have sents an alternative, attractive method for asymmetric
Table 3. Generality of the Michael addition of 4b to various b-nitroalkenes (5a–n) under solvent-free condition at 08C.[a]
Entry
5
R
Product 7
Time [days]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
C6H5
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
1.0
1.0
0.5
0.5
0.5
3.0
1.5
1.0
0.5
1.0
0.5
1.0
1.0
1.0
95
95
99
99
94
80
90
85
84
86
87
97
85
95
93
93
81
92
88
77
94
80
92
92
92
92
95
89
4-Me-C6H4
2-MeO-C6H4
3-MeO-C6H4
4-MeO-C6H4
2-CF3-C6H4
3-CF3-C6H4
2-Br-C6H4
3-Br-C6H4
4-Br-C6H4
3-Cl-C6H4
4-Cl-C6H4
PhCH2CH2
2-thienyl
9
10
11
12
13
14
[a]
All reactions were carried out using 4b (0.80 mmol) with various nitroalkenes 5a–n (0.20 mmol) in the presence of 3
(20 mol%) and benzoic acid (20 mol%) under neat conditions at 08C.
Isolated yields.
[b]
[c]
Determined by chiral HPLC analysis (see Supporting Information).
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Pyrrolidine-Camphor Derivative as an Organocatalyst for Asymmetic Michael Additions
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Scheme 2. Synthesis of spiro-pyrrolidines 8 and 9.
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Massi, Angew. Chem. 2008, 120, 4716–4739; Angew.
Chem. Int. Ed. 2008, 47, 4638–4660.
Michael additions. Further studies of the newly devel-
oped catalyst in organocatalysis are currently under-
way.
[2] Special issues on organocatalysis, see: a) Chem. Rev.
2007, 107, no. 12; b) Acc. Chem. Res. 2004, 37, no. 8;
c) Adv. Synth. Catal. 2004, 346, 9–10; d) P. I. Dalko,
Enantioselective Organoctalysis, Wiley-VCH, Wein-
heim, 2007; e) A. Berkessel, H. Grçger, Asymmetric
Organocatalysis: From Biomimetic Concepts to Appli-
cations in Asymmetric Synthesis Wiley-VCH, Wein-
heim, 2005.
Experimental Section
General Procedure for the Asymmetric Michael
Reaction
The a,a-disubstituted aldehyde (4a or 4b) (0.80 mmol) was
added to a mixture of catalyst 3 (13.6 mg, 0.04 mmol), ben-
zoic acid (4.9 mg, 0.04 mmol) and corresponding nitroalkene
(0.20 mmol). The reaction mixture was stirred at 08C for the
requisite times as indicated in Table 1, Table 2 and Table 3.
After the nitroalkene had been consumed as shown by TLC
analysis, the reaction mixture was subject to flash column
chromatography on silica gel (ethyl acetate/hexanes: 1:10)
to afford the pure Michael product.
[3] P. Perlmutter, Conjugate Addition Reactions in Organic
Synthesis, Pergamon, Oxford, 1992.
[4] For reviews of organocatalytic asymmetric conjugate
addition reactions, see: a) K. Tomioka, Y. Nagaoka, M.
Yamaguchi, in: Comprehensive Asymmetric Catalysis,
Vol. III, chap. 31.1 and 31.2 (Eds.: E. N. Jacobsen, A.
Pfaltz, H. Yamamoto), Springer, New York, 1999; b) S.
Sulzer-Mosse, A. Alexakis, Chem. Commun. 2007,
3123–3135; c) J. L. Vicario, D. Badia, L. Carrillo, Syn-
thesis 2007, 2065–2092; d) S. B. Tsogoeva, Eur. J. Org.
Chem. 2007, 1701–1716; e) O. M. Berner, L. Tedeschi,
D. Enders, Eur. J. Org. Chem. 2002, 1877–1894; f) N.
Krause, A. Hoffmann-Roder, Synthesis 2001, 171–196;
g) M. P. Sibi, S. Manyem, Tetrahedron 2000, 56, 8033–
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[5] Asymmetric Michael additions of aldehydes and ke-
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Martin, Org. Lett. 2001, 3, 2423–2425; b) J. M. Betan-
cort, C. F. Barbas III, Org. Lett. 2001, 3, 3737–3740;
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3614; d) T. Ishii, S. Fujioka, Y. Sekiguchi, H. Kotsuki, J.
Am. Chem. Soc. 2004, 126, 9558–9559; e) Y. Hayashi,
H. Gotoh, T. Hayashi, M. Shoji, Angew. Chem. 2005,
117, 4284–4287; Angew. Chem. Int. Ed. 2005, 44, 4212–
4215; f) Y. Xu, W. Zou, H. Sunden, I. Ibrahem, A. Cor-
dova, Adv. Synth. Catal. 2006, 348, 418–424; g) S. Luo,
X. Mi, L. Zhang, S. Liu, H. Xu, J.-P. Cheng, Angew.
Chem. 2006, 118, 3165–3169; Angew. Chem. Int. Ed.
2006, 45, 3093–3097; h) C. Palomo, S. Vera, A. Mielgo,
E. Gomez-Bengoa, Angew. Chem. 2006, 118, 6130–
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Mosse, M. Laars, K. Kriis, T. Kanger, A. Alexakis, Org.
Lett. 2006, 8, 2559–2562; j) S. V. Pansare, K. Pandya, J.
Am. Chem. Soc. 2006, 128, 9624–9625; k) C.-L. Cao,
M.-C. Ye, X.-L. Sun, Y. Tang, Org. Lett. 2006, 8, 2901–
2904; l) E. Reyes, J. L. Vicario, D. Badia, L. Carrillo,
Org. Lett. 2006, 8, 6135–6138; m) Y. Xu, A. Cordova,
Chem. Commun. 2006, 460–462; n) T. Mandal, C.-G.
2,2-Dimethyl-4-nitro-3-phenyl-butanal (6a): 1H NMR
(400 MHz, CDCl3): d=9.49 (s, 1H), 7.34–7.29 (m, 1H),
7.28–7.22 (m, 2H), 7.22–7.15 (m, 2H), 4.85 (dd, J=13.1 and
11.3 Hz, 1H), 4.69 (dd, J=13.1 and 4.2 Hz, 1H), 3.78 (dd,
J=11.3 and 4.2 Hz, 1H), 1.12 (s, 3H), 0.96 (s, 3H);
13C NMR (100 MHz, CDCl3): d=204.1, 135.3, 128.9, 128.5,
127.9, 76.1, 48.2, 48.0, 21.4, 18.6. The enantiomeric excess
was determined by chiral HPLC analysis using a Chiralcel
OD-H column (i-PrOH/hexanes: 20/80, flow rate:
0.8 mLminÀ1, l=254 nm): tR =13.6 min (major), 18.5 min
(minor).
Acknowledgements
We thank the National Science Council of the Republic of
China (NSC 96–2113M-003-005-MY3) for financial support
for this work. We are grateful to the Academic Paper Editing
Clinic at NTNU, and the National Center for High-Perfor-
mance Computing for providing us with computer time and
facilities.
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