Prolylprolinol-catalyzed asymmetric michael addition of aliphatic aldehydes to nitroalkenes

Article abstract of DOI:10.1002/adsc.200900687

Several novel prolylprolinol catalysts have been designed and synthesized. This type of compound showed high catalytic efficiency on pro-moting the direct addition of unmodified aldehydes to nitroalkenes. Among the catalysts surveyed, the least bulky memb

Full text of DOI:10.1002/adsc.200900687

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DOI: 10.1002/adsc.200900687
Prolylprolinol-Catalyzed Asymmetric Michael Addition of
Aliphatic Aldehydes to Nitroalkenes
Dengfu Lu,a Yuefa Gong,a,* and Weizhou Wangb
a
School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, 1037 Luoyu Road,
Wuhan 430074, Peopleꢀs Republic of China
Fax : (+86)-27-8754-3632; e-mail: gongyf@mail.hust.edu.cn
College of Chemistry and Chemical Engineering, Luoyang Normal University, Luoyang 471022, Peopleꢀs Republic of
b
China
Received: October 1, 2009; Published online: February 19, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900687.
Abstract: Several novel prolylprolinol catalysts
have been designed and synthesized. This type of
compound showed high catalytic efficiency on pro-
moting the direct addition of unmodified aldehydes
to nitroalkenes. Among the catalysts surveyed, the
least bulky member (8d) exhibited the best perfor-
mance on both efficiency and stereoselectivity, pro-
viding the products with up to 97% ee value with
1.5–5 mol% catalyst loading. Additionally, compu-
tational studies of the transition state have been
conducted to explain the high diastereo- and enan-
tioselectivity.
also exhibited excellent diastereo- and enantioselec-
tivity on this reaction.[4o]
Keywords: aldehydes; bifunctional catalysts; Mi-
chael addition; nitroalkenes; organocatalysis
As a highly efficient and atom-economic reaction, the
Michael addition plays a prominent role in construct-
Compared with type A, bifunctional catalysis[6] is
ing carbon-carbon bonds in organic synthesis.[1] With deemed to be a more efficient mode for the conjugate
the current interest in stereochemistry, the organoca- addition of aldehydes to nitroalkenes since both the
talytic asymmetric Michael addition of various nucle- carbonyl and the nitro group could be activated si-
ophiles to electron-deficient olefins has attracted multaneously by enamine formation and hydrogen
much attention in recent decades.[2] Since the addition bonding.[7] The introduction of sulfonamide (catalyst
of aliphatic aldehydes to nitroalkenes[3] could gener- 4),[5o] amino alcohol,[5b] (thio)urea,[5c,j,l] camphor[5d] and
ate versatile synthetic building blocks, several l-pro- sulfamide[5a] moieties into amine catalysts as H-bond
line-derived catalysts have been developed and suc- donors has led to satisfactory results in the above re-
cessfully applied, which can be generally divided into
two types: a bulky type[4] and a bifunctional type,[5]
according to the activating modes (Figure 1). Pyrroli-
dine-morpholine 1 was the first catalyst reported by
Barbas IIIꢀs group for the Michael addition of un-
modified aldehydes to nitroalkenes.[4s] As the most
representative bulky type catalyst, diphenylprolinol
trimethylsilyl ether 3, described by Hayashiꢀs group,
Figure 1. Catalyst types for the reaction of aliphatic alde-
hydes with nitroalkenes.
644
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 644 – 650

Prolylprolinol-Catalyzed Asymmetric Michael Addition of Aliphatic Aldehydes to Nitroalkenes
action. In addition, 4-hydroxyprolylamide 5 and tri- reaction was carried out in dichloromethane at 08C
peptide H-d-Pro-Pro-Asp-NH2, reported by Palo- with 10 mol% of the catalyst together with benzoic
mo[5k] and Winnemers groups,[5f,g] respectively, showed acid as an additive, and the results are summarized in
excellent diastereo- and enantioselectivity on this re- Table 1. To our delight, the reaction mediated by
action.
10 mol% of 8a was completed within 3 h, providing
After the golden rush of organocatalysis, “low load- addition product 12a in a yield of 93%, syn:anti ratio
ing”, “simple”, “reusable” and “scalable” have of 89:11, and 88% ee (Table 1, entry 2), while diphe-
become the new keywords in modern catalyst nylprolinol 2 showed very low catalytic activity
design.[8] Although several great catalysts have been (Table 1, entry 1). Fortunately, the catalyst loading
documented, high catalyst loading (10–20 mol%) and can be reduced to 3 mol% without erosion of the dia-
a large excess of aldehyde (up to 10 equiv.) were gen- stereo- and enantioselectivity, although a prolonged
erally required, hence it still remains a challenge to time was required (Table 1, entries 3 and 4). In turn,
develop novel catalysts for the asymmetric addition of several solvents were examined (Table 1, entries 5–8).
aldehydes to nitroalkenes with low catalyst loading.
We noticed that diphenylprolinol 2, one of the most
Table 1. Optimization of catalytic asymmetric conjugation
typical bifunctional organocatalysts[9], showed quite
low activity in the addition of aldehydes compared to
its silyl ether 3.[4n] As suggested by Jørgensen et al.,
its low catalyst turnover was ascribed to the formation
of relatively stable and unreactive hemiaminal species
between diphenylprolinol and aldehyde.[10] Based on
this viewpoint, we envisioned that the formation of
hemiaminal would be prevented when the amino and
hydroxy groups are far enough from each other, thus
we chose prolylprolinol as a backbone to develop a
new class of catalysts. The novel prolylprolinol com-
pounds were easily prepared in three steps as illus-
trated in Scheme 1. The key intermediate N-(N-Cbz-
prolyl)proline methyl ester 6 formed by condensation
of Cbz-l-proline and l-proline methyl ester can be
easily converted into different alcohols 7a–d, and the
desired prolylprolinol compounds 8a–d can be ob-
tained after the deprotection of the Cbz group.
additions of propanal to nitrostyrene.[a]
Entry Catalyst
(mol%)
Solvent Time Yield
dr[c] ee[d]
To get initial information on our hypothesis, the
catalytic activity of the compound 8a was firstly eval-
uated in the model reaction of propanal with nitro-
styrene in comparison with diphenylprolinol 2. The
[h]
[%][b]
[%]
1
2
3
4
5
6
7
8
2 (20)
CH2Cl2 72
CH2Cl2 2.5
<5
93
92
92
91
80
90
<20
93
94
nd
nd
8a (10)
8a (5)
89:11 88
84:16 87
87:13 88
85:15 87
88:12 86
92:8 91
CH2Cl2
8
8a (3)[e]
8a (3)[e]
8a (3)[e]
8a (3)[e]
8a (3)[e]
9 (10)
CH2Cl2 20
CHCl3 24
hexane 36
toluene 64
THF
72
nd
nd
9
CH2Cl2 1.5
CH2Cl2 2.5
CH2Cl2 24
CH2Cl2 24
CH2Cl2 20
CH2Cl2 20
75:25 36
88:12 57
95:5 92
85:15 89
94:6 93
87:13 82
10
11
12
13
14
10 (10)
8b (3)[e]
8c (3)[e]
8d (3)[e]
11 (3)[e]
93
92
94
92
[a]
Unless otherwise specified, all reactions were carried out
using propaldehyde (0.6 mmol), nitrostyrene
(0.20 mmol), x mol% catalyst and the equivalent amount
of benzoic acid in 1 mL indicated solvent at 08C.
Isolated yield.
[b]
[c]
1
Scheme 1. Synthetic routes to prolylprolinols 8a–d. Reagents
and conditions: a) DCC, CH2Cl2, 08C, 2 h, 97%; b) for 7a–c:
RMgBr, THF, À158C, 4–6 h, 25–64%; for 7d: NaBH4/LiCl,
THF, À58C, 2 h, 82%; c) 10% Pd/C, H2, MeOH, 4 h, 85%.
Determined by H NMR spectroscopy of the crude prod-
ucts.
[d]
[e]
Determined by chiral-phase HPLC on Chiralcel OD-H.
5 mol% benzoic acid were added.
Adv. Synth. Catal. 2010, 352, 644 – 650
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645

Dengfu Lu et al.
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Dichloromethane was still the most appropriate one helpful to fix their location in the transition state,
in terms of both reactivity and stereoselectivity. while playing a weak role in activating nitrostyrene.
Encouraged by these preliminary results, further The less bulky R group favored the formation of an
modification of the catalyst structure was carried out H-bond, thus leading to better enantioselectivity. Be-
to improve the stereoselectivity. The effect of carbon- sides, a more acidic hydroxy group was also beneficial
yl group of 8a was firstly taken into consideration. for the formation of an H-bond, so 8b also showed an
For this purpose, the corresponding reduced product excellent performance (95:5 dr, 92% ee; Table 1,
9 was prepared and tested. In this case, a rather low entry 11). Considering synthetic accessibility and
diastereo- and enantioselectivity (75:25 dr and 36% atomic economy, 8d was chosen for further investiga-
ee) were observed though the catalytic activity was tions.
comparable to 8a (Table 1, entry 9). This might sug-
Next, various acid and base additives were exam-
gest that the rigidity of the Pro-Pro scaffold is vital to ined and the results are listed in Table 2. The reaction
achieve high stereoselectivity. Next, the (S,R)-prolyl- were finished after 8 h with 75% ee when no additive
prolinol 10, a diastereomer of 8a, was prepared and was used. Apparently, acid additives with appropriate
used for assessing the effect of the configuration of pKa values enhanced both the reactivity and enantio-
the prolinol moiety. As a consequence, a marked de- selectivity (Table 2, entries 2–5). However, addition of
crease in enantioselectivity was observed, indicating a strong acid such as 3,5-dinitrobenzoic acid or TFA
the obvious configuration mismatch (Table 1, caused detrimental effects on the reaction (entries 6
entry 10). Further efforts were made to investigate and 8). Moreover, addition of l-(+)-tartaric acid did
the impact of R groups for catalysts 8a–d. Unexpect- not lead to any obvious synergy or mismatch (Table 2,
edly, bulky groups were not necessary to improve the entry 9). The presence of an equivalent of water
diastereo- and enantioselectivity. Among the four cat- showed slight effects on the reaction rate and enantio-
alysts surveyed, the least bulky one 8d provided the selectivity (Table 2, entry 10). In contrast, base addi-
best results (94:6 dr, 93% ee, Table 1, entry 13). Cata- tives, like DABCO, DIPEA, DMAP and imidazole,
lyst 11, which bears no hydroxy group, was also effec- caused a significant decline in conversions and stereo-
tive albeit providing inferior enantioselectivity selectivities (Table 2, entries 11–14). When benzoic
(Table 1, entry 14). According to the above observa- acid served as additive, the loading of 8d could be fur-
tions, we speculated that the formation of an H-bond ther reduced to 1.5 mol% (Table 2, entry 15).
between the hydroxy and the nitro group would be
Table 2. Effect of additives on the reaction[a]
.
Entry
Additive[b]
Time [h]
Conversion [%][c]
dr[d]
ee[e] [%]
1
2
3
4
5
6
7
8
None
PhCOOH
8
3
4
4
5
24
3
24
8
8
>99
>99
>99
>99
>99
<50
>99
<30
>99
>99
>99
>99
>99
>99
90[i]
91:9
93:7
75
88
85
87
84
n.d.
76
n.d.
80
81
79
59
64
72
88
4-MeO-C6H4COOH
4-F-C6H4COOH
4-NO2-C6H4COOH
3,5-di-NO2-C6H3COOH
CH3COOH
CF3COOH
tartaric acid
H2O
DABCO
DIPEA
DMAP
imidazole
89:11
90:10
89:11
n.d.[f]
92:8
n.d.[f]
96:4
9
10[g]
11
12
13
14
15[h]
94:6
5
86:14
76:24
63:37
82:18
91:9
10
12
10
36
PhCOOH
[a]
Unless otherwise specified, all reactions were carried out using propanal (0.6 mmol), nitrostyrene (0.20 mmol) and
3 mol% 8d at room temperature.
5 mol% additive were employed.
Conversion estimated by TLC analysis.
Determined by H NMR spectroscopy of the crude products.
Determined by chiral-phase HPLC on Chiralcel OD-H.
Not determined.
One equivalent of H2O was added.
With 1.5 mol% 8d.
Isolated yield.
[b]
[c]
[d]
[e]
[f]
1
[g]
[h]
[i]
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Adv. Synth. Catal. 2010, 352, 644 – 650

Prolylprolinol-Catalyzed Asymmetric Michael Addition of Aliphatic Aldehydes to Nitroalkenes
Under the above optimized conditions, the Michael tivities (77–88% ee) after 36–60 h (Table 3, entries 1–
addition reactions of other aliphatic aldehydes with 4). The reaction of isovaleraldehyde proceeded more
nitrostyrene were investigated in the presence of slowly than that of unbranched aldehydes due to the
1.5 mol% of 8d at room temperature. As shown in hindrance of the isopropyl group, so 3 mol% of 8d
Table 3, the corresponding adducts 12a–12f were af- was employed (Table 3, entry 5). The less reactive iso-
forded in high yields (71–90%) with good stereoselec- butyraldehyde was also tolerated in the presence of
Table 3. Addition reaction between aldehydes and nitroalkenes catalyzed by 8d.[a]
Entry
1
Product
8d [%]
Temperature [oC]
Time [h]
Yield [%][b]
dr[c]
ee[d] [%]
1.5
5
r.t.
À20
36
36
90
88
91:9
96:4
88
96
2
1.5
5
r.t.
À20
40
36
87
92
94:6
98:2
83
93
3
4
5
1.5
5
r.t.
À20
48
48
85
83
92:8
99:1
78
93
1.5
5
r.t.
À20
60
48
83
84
96:4
99:1
77
93
3
5
r.t.
À20
60
60
82
78
97:3
99:1
82
93
6
7
10[e]
r.t.
60
36
71
97
–
80
93
5
À20
99:1
8
5
5
5
5
5
À20
À20
À20
À20
À20
24
20
35
12
28
98
96
94
99
94
98:2
98:2
99:1
98:2
99:1
93
95
92
95
95
9
10
11
12
13
14
5
5
À20
À20
60
40
96
96
97:3
98:2
93
81
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Dengfu Lu et al.
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Table 3. (Continued)
Entry
Product
8d [%]
Temperature [oC]
Time [h]
36
Yield [%][b]
93
dr[c]
ee[d] [%]
15
5
À20
95:5
91:9
98:2
92
16
5
5
À20
À20
60
24
75
95
97
96
17[f]
[a]
Unless otherwise specified, all reactions were carried out on 0.2 mmol scale using x mol% 8d and 5 mol% benzoic acid.
[b]
[c]
[d]
[e]
[f]
Isolated yield.
1
Determined by H NMR spectroscopy of the crude products.
Determined by chiral-phase HPLC.
10 mol% benzoic acid were added.
Reaction carried out on a 10-mmol scale.
10 mol% of 8d, furnishing a moderate yield of 12f method can be found elsewhere.[13] As shown in
with good enantioselectivity (Table 3, entry 6). A sig- Figure 2, TS1, which leads to the formation of the
nificant improvement in the diastereo- and enantiose- major product observed experimentally, is found to
À
lectivity was achieved when the reactions were carried be much more stable than TS2. Evidently, the O
out at lower temperature. The diastereoselectivity was
raised up to more than 99:1 and enantioselectivity up
to 96% ee at À208C. In these cases, 5 mol% of 8d was
added to shorten the reaction time. As in previous re-
ports, the reaction selectively afforded the syn isomer
with the (R,S) absolute configuration.[6n]
Then the reactions of a variety of b-arylnitroal-
kenes with butyraldehyde were further examined. Ad-
dition products 12g–n were obtained in excellent
yields with high diastereo- and enantioselectivities.
Electron-withdrawing groups on the benzene ring ac-
celerated the reaction significantly. For instance, the
reaction of 4-trifluoromethylnitrostyrene with butyral-
dehyde was complete after 12 h, giving the adduct
12k in almost quantitative yield (Table 3, entry 11),
whereas the reaction of 3,4-methylenedioxynitrostyr-
ene needed nearly 60 h (Table 3, entry 13). Further
experiments demonstrated that b-alkylnitroalkenes
are also excellent Michael acceptors (Table 3, en-
tries 15 and 16).
Enlargement of the reaction scale was also tried.
The addition of butyraldehyde to 4-chloronitrostyrene
was carried out on a 10-mmol scale at À208C mediat-
ed by 5 mol% of 8d, affording 12i in 95% yield with-
out any decline in diastereo- and enantioselectivity
(Table 3, entry 17). Moreover, the catalyst was easily
recovered by a simple aqueous acid/base work-up
after the reaction was finished and can be reused.[11]
To better understand the high diastereo- and enan-
tioselectivity, the model reaction between propanal
and notrostyrene catalyzed by 8d was studied by DFT
calculations at the BHandH/6-311++G
(d,p) level.[12]
The reliability of the BHandH/6-311++GACHTNUGTRNE(NUG d,p) with the relative free energies. All distances are in ꢂ.
Figure 2. The calculated transition structures of the reaction
between propanal and nitrostyrene catalyzed by 8d along
AHCTUNGTRENNUNG
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Adv. Synth. Catal. 2010, 352, 644 – 650

Prolylprolinol-Catalyzed Asymmetric Michael Addition of Aliphatic Aldehydes to Nitroalkenes
À
4660; b) D. W. C. MacMillan, Nature 2008, 455, 304–
H···O and the C H···O hydrogen bonds help to dis-
criminate between the two possible transition-state
models TS1 and TS2 by 4.96 kcalmolÀ1 and the short-
308; c) A. Erkkila, I. Majander, P. M. Pihko, Chem.
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Chem. Rev. 2007, 107, 5471–5569; e) Enantioselective
Organocatalysis, (Ed.: P. I. Dalko), Wiley-VCH, Wein-
heim, 2007.
À
er O H···O hydrogen bond indicates its dominant
role. The involvement of the C H group, even though
À
it is a minor role, to fix the location of nitrostyrene in
the transition states also explains why the simplest
catalyst 8d with no bulky group on the prolinol
moiety exhibited the highest diastereo- and enantiose-
lectivity.
In summary, we have developed a novel bifunction-
al prolylprolinol catalyst 8d for the asymmetric conju-
gate addition of aliphatic aldehydes to nitroalkenes.
This catalyst exhibited rather high catalytic efficiency
and good to excellent levels of stereoselectivity. Due
to its synthetic simplicity and recoverability, we be-
lieve 8d is an ideal candidate for laboratory- or large-
scale preparations. Further applications of the catalyst
are being studied in our laboratory.
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Experimental Section
General Procedure
To a solution of the corresponding nitroalkene (0.2 mmol,
1.0 equiv.) in 1 mL of dichloromethane, 5 mol% of catalyst
and 5 mol% of benzoic acid were added, the mixture was
stirred at the indicated temperature for 20 min, then freshly
distilled aldehyde (0.6 mmol, 3.0 equiv.) was added. The re-
sulting solution was stirred at the same temperature for 12–
60 h. Then it was quenched with 1M HCl (1 mL), and ex-
tracted with ethyl acetate (3ꢃ1 mL). The combined organic
layers were dried over Na2SO4, concentrated under reduced
pressure and purified over silica gel by flash column chro-
matography to afford the corresponding Michael adducts
12a–p.
[5] For selected publications on bifunctional catalysts in
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Acknowledgements
This work was supported by National Natural Science Foun-
dation of China (20572028, 20872041). The Center of Analy-
sis and Testing of Huazhong University of Science and Tech-
nology is acknowledged for the characterization of new com-
pounds.
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