Organocatalyst Efficiency in the α-Aminoxylation and α-Hydrazination of Carbonyl Derivatives in Aqueous Media or in a Ball-Mill

Article abstract of DOI:10.1002/ejoc.201601357

Pyrrolidine-derived organocatalysts have been tested in two types of α-heterofunctionalization reactions in aqueous media or under solvent-free ball-milling conditions. The best results in terms of both activity and enantioselectivity were obtained with O

Full text of DOI:10.1002/ejoc.201601357

A Journal of
Accepted Article
Title: Organocatalyst efficiency in α-aminoxylation and α-hydrazination
of carbonyl derivatives in aqueous media and ball-mill
Authors: Radovan Sebesta, Eva Veverkova, and Viktoria Modrocka
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Organocatalyst efficiency in α-aminoxylation and α-hydrazination
of carbonyl derivatives in aqueous media and ball-mill
Eva Veverková,[a] Viktória Modrocká,[a] and Radovan Šebesta*[a]
Abstract: Pyrrolidine-derived organocatalysts were tested in two
types of α-heterofunctionalization reactions in aqueous media or
under solvent-free ball-milling conditions. The best results in terms
both activity and enantioselectivity were obtained with O-silylated 4-
hydroxyproline derivatives in the α-aminoxylation reaction between n-
butyraldehyde and nitrosobenzene (83% yield for water, 86% yield for
ball milling and ee > 99%). Very good yield (82%) and excellent optical
purity (ee > 99%) were also achieved in the α-hydrazination reaction
of 3-phenylpropanal with dibenzyl azodicarboxylate using the ball-
milling technique.
important chiral building blocks such as 1,2-diols or α-amino
acids.[11b]
In the first published reports, (S)-proline was described as an
efficient catalyst both in α-aminoxylation,[12] and α-amination.[13]
Other proline-derived as well as catalysts of different structural
types proved useful for these reactions too.[14] Proline-catalyzed
reactions were carried out in traditional, polar organic solvents
such as acetonitrile, dimethylformamide, dimethylsulfoxide, or
chlorinated solvents. The use of these solvents contributes to the
increase of the amount of organic waste. Since water is the most
environmentally friendly solvent, Chua et al. developed highly
enantioselective (S)-thiaproline catalyzed α-aminoxylation of
aldehydes performed in the presence of this solvent and
tetrabutylammonium bromide.[15] The respective α-aminoxy
alcohols were obtained in good to high yields (74–88%) and great
enantioselectivities (93–>99%). Another environmentally friendly
alternative is conducting stereoselective reactions under solvent-
free conditions, using ball milling techniques. To the best of our
knowledge, there are no reports of α-aminoxylation or α-
hydrazination reactions of carbonyl compounds performed by ball
milling technique.
Introduction
Enantioselective organocatalysis has become one of the pillars of
asymmetric catalysis.[1] It served in the synthesis of many
biologically relevant chiral molecules.[2] Rising environmental
awareness prompted research of green chemistry aspects within
organocatalysis as well. Stereoselective organocatalytic reactions
have been performed under a variety of less common, and
potentially more environmentally friendly, experimental
conditions.[3] Water and other aqueous media proved viable
alternatives to organic solvents.[4] Furthermore, solvent-free
conditions are intensively studied for organocatalytic reactions.[5]
Bolm and co-workers performed pioneering studies on utilization
of ball-milling technique in asymmetric organocatalytic aldol
reaction and anhydride opening.[6] Juaristi has shown that
peptide-based organocatalyst are effective in promoting aldol
reactions under ball-milling conditions.[7] Prolinamides are also
useful for aldol reactions under solvent-free conditions.[8] Michael
additions were successfully performed under solvent-free
conditions too.[9] Lamaty has shown that asymmetric phase-
transfer catalyzed alkylations of Schiff Bases work well under ball-
milling conditions.[10]
In this context, we decided to investigate typical α-aminoxylaton
and α-hydrazination reactions of carbonyl compounds using a
series of proline and 4-hydroxyproline derivatives as catalysts in
an aqueous medium as well as under solvent-free conditions in a
ball mill.
Results and Discussion
Aminoxylation
In the first part of our work, we examined the reaction between n-
butyraldehyde (1) and nitrosobenzene (2) catalyzed by catalysts
C1-C8 (Figure 1, Scheme 1). We have chosen the substrate 1
because α-aminoxylation of n-butyraldehyde represents one of
the key steps in the stereoselective synthesis of an antiepileptic
agent levetiracetam.[16] The selection of catalysts was affected by
our good experience with a catalyst efficiency of these type of
proline and 4-hydroxyproline derivatives in Michael addition,[9a]
and Mannich reaction carried out in aqueous media.[17]
α-Functionalizations of carbonyl compounds belong to the most
important methods for the stereoselective formation of C-O, or C-
N
bond respectively.[11] α-Aminoxylation and α-amination
reactions present a valuable route for the synthesis of biologically
active compounds because they lead to the generation of
[a]
E. Veverková, V. Modrocká, R. Šebesta
Department of organic chemistry, Faculty of Natural Sciences
Comenius University in Bratislava
Mlynska dolina, Ilkovicova 6, 84215 Bratislava, Slovakia
E-mail: radovan.sebesta@fns.uniba.sk, web:
www.radovansebesta.com
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201601357
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Table 1. Enantioselective α-aminoxylation in aqueous conditions.[a]
Entry
Ratio
1a:2
Catalyst
(mol-%)
Time
(min)
Yield of
(%)[d]
3
ee
(%)[e]
1
2
3
4
5
6
7
8
9
1.2 : 1
3 : 1
3 : 1
3 : 1
3 : 1
3 : 1
3 : 1
3 : 1
3 : 1
C1 (20)
C1 (20)
C1 (20)
C1 (10)
C2 (10)
C3 (20)
C3 (10)
C4 (20)
C5 (10)
30[b]
15[c]
10
6
-
72
78
83
65
66
77
85
37
> 99
> 99
> 99
> 99
> 99
> 99
> 99
> 99
5
10
Figure 1.
45
In an initial experiment, we used nearly equimolar amounts of
starting compounds and 20 mol-% of catalyst C1. The reaction
was carried out in a large excess of water. Inspired by Zhong and
45
50
co-workers,[15]
which
applied
two
equivalents
of
210
tetrabutylammonium bromide in α-aminoxylation reactions
proceeding in water, we also used corresponding amounts of this
phase-transfer catalyst. The complete consumption of
nitrosobenzene was indicated by a color change of the reaction
mixture from green to yellow. However, we obtained only very
small quantity of product 3 after 30 min (Table 1, entry1). This
prompted us to change the ratio of aldehyde/nitrosobenzene to
3:1 and decrease the amount of water. Under these conditions,
the reaction time was reduced in half, and the product 3 was
isolated in synthetically interesting yield 72% with excellent
enantioselectivity (> 99% ee) (Table 1, entry 2). Then we tried to
exclude the tetrabutylammonium bromide from the reaction
mixture. Surprisingly, even shorter reaction time 5 min was
sufficient for complete conversion. Yields and enantioselectivity
remained high even if catalyst loading was decreased to 10 mol-%
(Table 1, entries 3, 4).
[a] The reaction of nitrosobenzene (0.3 mmol), butanal (0.9 mmol), and
organocatalyst (0.03 mmol) was performed in water (1 mL).
performed with tetrabutylammonium bromide (2 equiv.) in excess of water (5
mL); [c] Reaction performed with tetrabutylammonium bromide (2 equiv). [d] Yield
of isolated product; [e] Determined by enantioselective HPLC.
[b]
Reaction
In the second part, we investigated the asymmetric α-
aminoxylation of n-butyraldehyde with nitrosobenzene under ball-
milling conditions. Because of both nitrosobenzene, as well as all
tested catalysts, are solids, we assumed that the reaction would
be suitable for ball-milling conditions. The presence of a liquid
component, n-butanal, in the reaction mixture did not precludes
use of the ball-milling technique. We have previously found that a
liquid diarylprolinol silyl ether catalyst can be successfully
employed under ball-milling conditions.[9a] Lamaty even described
a positive effect of a small amount of a solvent in the reaction
mixture and termed it as liquid assisted milling.[18] In an initial
experiment, the 20 mol-% of catalyst C1 with a combination of
reactants in ratio n-butyraldehyde/nitrosobenzene 3:1 was ball-
milled for 5 min. After this time, we observed complete
consumption of nitrosobenzene and the product 3 was isolated in
86% yield. We were pleased to observe that ball-milling conditions
have no negative effect on enantioselectivity of the reaction, as
the enantiomeric purity of compound 3 remained excellent (> 99%
ee) (Table 2, entry 1). Next, we investigated the effect of catalyst
loading on the reaction. Interestingly, decreasing the amount the
catalyst to 10 mol-% gave similar results to those obtained with
20 mol-% (Table 2, entry 2). However, when the amount of
catalyst was lowered to just 1 mol-%, we observed the only trace
of product in the reaction mixture (Table 2, entry 3). Hence, the
amount 10 mol-% we considered as optimal catalyst loading for
testing other catalysts. The catalysts C3 and C4 also afforded
very good yields and enantioselectivities, but the reaction time
had to be prolonged to 10 min (Table 2, entries 7, 9). We have
also performed a control experiment using dry stirring of the
reaction mixture instead of ball milling (Table 2, entry 8). In
otherwise identical conditions, dry stirring afforded product 3 in
Scheme 1.
With optimal reaction conditions in hands, we screened another
pyrrolidine derivatives as catalysts for the α-aminoxylation
reaction of n-butyraldehyde (1). The O-alkylated catalyst C2
afforded comparable outcome in comparison with catalyst C1. On
the other hand, the reaction with O-acylated catalysts C3 and C4
required significantly longer reaction time for reaching complete
conversion (Table 1, entries 5- 8). The poor yield with N-
arylsulfonyl proline amide C5, which worked very well in our
previous study on Mannich reaction in the presence of water, was
probably caused by relatively long reaction time vs. lower stability
of product (Table 1, entry 9). It is notable that the
enantioselectivity was very high in all cases.
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10.1002/ejoc.201601357
European Journal of Organic Chemistry
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only 6%. Similarly to the reaction in water, the catalyst C5
performed poorly also under ball milling conditions (Table 2,
entries 10). Simple proline (C7) and 4-hydroxyproline (C8)
appeared not suitable catalysts for the aminoxylation under ball
milling conditions (Table 2, entries 11 and 12).
Under the optimal reaction conditions (ball-milling, catalyst C1),
we have tested two other aldehydes in this reaction. The reaction
between of 3-methylbutanal (1b) and nitrosobenzene afforded
product 3b in good yield, but with low enantiomeric excess (Table
2, entry 13). On the other hand, 3-phenylpropanal (1c) afforded
the corresponding product 3c in good yield with excellent
enantiomeric purity (Table 2, entry 14).
Hydrazination
After the successful application of aqueous media or solvent free
ball-milling condition in the enantioselective α-aminoxylation
reaction, we further extended the scope of these methods for an
enantioselective α-hydrazination. We decided to examine the
reaction of 3-phenylpropionaldehyde (4a) with dibenzyl
azodicarboxylate (5a). The initial addition product of this reaction
was reduced with NaBH4 to the corresponding aminoalcohol 6.
This compound can serve as a chiral intermediate in the synthesis
of an aminopeptidase inhibitor bestatin.[19] Firstly, we had found
the optimal ratio of reactants. As follows from Table 3, a two-fold
excess of parent aldehyde 4a was enough for obtaining a high
yield of aminoalcohol 6a (Table 2, cf. entries 1, 2 and 4, 5). Further
increase of ratio 4a:5a had no positive effect on the yield of
product 6a (Table 2, entries 3 and 6). Similarly, with α-
aminoxylation mentioned above, the catalyst C2 was very
competent also for amination reaction (Table 2, entries 7 and 8).
Scheme 2.
Table 2. Enantioselective α-aminoxylation under solvent-free conditions.[a]
Entry
R
Ratio
1:2
Catalyst
(mol-%)
Time
(min)
Yield of
3 (%)[b]
ee
(%)[c]
Scheme 3.
1
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
iPr
Bn
3 : 1
3 : 1
3 : 1
1,5 : 1
1,2 : 1
3 : 1
3 : 1
3 : 1
3 : 1
3 : 1
3 : 1
3 : 1
3 : 1
3 : 1
C1 (20)
C1 (10)
C1 (1)
5
86 (3a)
76 (3a)
< 5 (3a)
46 (3a)
< 5 (3a)
70 (3a)
77 (3a)
6[d] (3a)
80 (3a)
< 5 (3a)
9 (3a)
> 99
Based on our previous study of Mannich reaction,[17] we used
NaHCO3 as a base additive in these experiments. We also
realized some experiments without NaHCO3 to ascertain the
influence of base on this amination reaction. As follow from Table
3 (entries 9 vs. 10), the yield of 6a was unchanged, but
enantioselectivity decreased from 96 to 54 % when 10 mol-%
NaHCO3 was used in water media. We assume that the base
promoted undesired background reaction. On the other hand, the
yield increased twice and enantioselectivity stayed excellent in
present of the base under ball-milling conditions. (Table 2, entries
12, 13). As it follows from these results, the base is not suitable
for above-described hydrazination reaction catalyzed by C3 in
aqueous media. We assumed, that while the base caused
undesired background in water media, solid NaHCO3 improves
mechanical abrasion under ball-milling conditions. Therefore, all
ball-milling experiments were performed using 10 mol-% of
NaHCO3.
Control experiments under dry stirring conditions were also
performed (Table 3, entries 11 and 14). Under these conditions,
the corresponding product 6a was isolated in considerably lower
yields than under both aqueous as well as ball-milling conditions.
Sulfonamides C5 and especially C6 afforded product 6a with high
enantioselectivity (96 - >99 % ee), but the yields were rather low
both under aqueous as well as ball milling conditions (Table 2,
entries 14 - 16). Also (S)-proline (C7) and 4-hydroxyproline C8 as
a catalyst for α-hydrazination under ball-milling conditions were
not very efficient. Using (S)-proline, we obtained product 6a in
40% yield, in the case of 4-hydroxyproline C8 we observed only
2
5
> 99
3
5
-
4
C1 (10)
C1 (10)
C2 (10)
C3 (10)
C3 (10)
C4 (10)
C5 (10)
C7 (10)
C8 (10)
C1 (10)
C1 (10)
5
-
5
5
-
6
5
> 99
7
10
10
10
30
5
> 99
8
-
9
> 99
10
11
12
13
14
-
-
5
12 (3a)
78 (3b)
84 (3c)
-
5
28
97
5
[a]
The reaction of nitrosobenzene (0.3 mmol), butanal (0.9 mmol), and
organocatalyst (0.03 mmol) was was ball-milled at a frequency of 20 Hz. [b] Yield
of isolated product;
experiment performed under conventional stirring at room temperature in
solvent-free conditions.
[c]
[d]
Determined by enantioselective HPLC.
Control
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10.1002/ejoc.201601357
European Journal of Organic Chemistry
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traces of product in the reaction mixture. These results were
similar to those observed in the study of aminoxylation.
Table 3. Enantioselective α-hydrazination under aqueous and ball-milling
conditions.[a]
Entry
Catalyst
Ratio
4a : 5a
Method[b]
Time
(h)
Yield of
6a (%)[c]
ee
(%)[d]
1
C1
C1
C1
C1
C1
C1
C2
C2
C3
C3
C3
C3
C3
C3
C4
C5
C5
C6
C7
C8
1 : 1
2 : 1
3 : 1
1 : 1
2 : 1
3 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
A
1
36
65
64
32
82
79
61
78
58
58
32
34
67
16
52
11
28
24
40
<5
>99
>99
>99
>99
>99
>99
>99
>99
96
2
A
1
Scheme 4.
3
A
1
4
B[e]
B[e]
B[e]
A
0.2
0.2
0.2
1
Both aminoxylation as well as hydrazination proceed through
enamine activation. For explanation of the stereochemical course
of these reactions, one can apply Houk-List model for proline-
catalyzed aldol reactions.[20] Similar model has been invoked also
by Cordova for proline-catalyzed aminoxylation of carbonyl
compounds.[21] By applying these findings, carboxylic function of
the silyloxyproline-type catalysts that we have used in our study
can act as a directing group for the electrophile, in this instance
nitro compound or azodicarboxylate. In both cases, enamine
react via its Re-face and the corresponding product with (R)-
configuration is obtained (Scheme 5). Absolute configurations of
obtained products were assigned by comparison of signs of
optical rotations with literature values (see Supporting
information).
5
6
7
8
B
0.2
4
9
A
10
11
12
13
14
15
16
17
18
19
20
A[e]
C
2
54
8
-
B
1
64
B[e]
C[e]
B[e]
A
0.5
0.5
0.2
17
0.5
17
0.5
0.5
>99
-
96
98
B[e]
A
94
99
B[e]
B[e]
80
-
[a]
All reactions were performed with 3-phenylpropanal (1.0 mmol), dibenzyl
[b]
Scheme 5.
azodikarboxylate (0.5 mmol), catalyst (0.05 mmol).
Method A: aqueous
conditions in brine (1 mL); method B: ball-milling at a frequency of 20 Hz; [c] Yield
of isolated product; [d] Determined by enantioselective HPLC; with additive
[e]
10 mol-% NaHCO3.
Conclusions
Using the optimal ball-milling conditions, we have also
investigated the hydrazination reaction of aldehyde 4b with
azodicarboxylate 5a and aldehyde 4b with azodikarboxylate 5b
(Scheme 4). Alcohol 6b was isolated with high enantiomeric purity
(85% ee) but only medium yield 54%. Somewhat lower yield was
probably caused by volatility of the starting aldehyde, propanal
(4b). On the other hand, 3-phenylpropionaldehyde (4a) reacted
with diisopropyl azodicarboxylate (5b) affording alcohol 6c in
good yield and enantioselectivity.
From the pyrrolidine derivatives screened, O-silylated-derived 4-
hydroxyprolines C1 and C2 were the most-effective for both α-
aminoxylation and α-hydrazination reaction.
The corresponding products were obtained in high yields and with
excellent enantioselectivities by using aqueous as well as ball-
milling conditions. The synthetically more valuable method seems
to be ball-milling technique due to its considerably shorter reaction
times, solvent-free conditions and easier work up.
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chromatography (SiO2, AcOEt/hexane 1:3) afforded compound 6 as a
colorless oil.
Experimental Section
General Information
Catalysts C1–C6 were prepared according to literature procedures (C1,[22]
C2,[23] C3-C4,[24] C5,[25] C6[17]). Catalysts C7 and C8 were purchased from
Sigma-Aldrich. For compounds characterization data, see supporting
information.
Acknowledgements
This publication is the result of the project implementation:
26240120025 supported by the R&DOP funded by the European
Regional Development Fund.
Typical procedure for the α-aminoxylation of butanal to
nitrosobenzene in aqueous medium. The mixture of nitrosobenzene
(32.1 mg, 0.3 mmol) and butanal (81 μL, 0.9 mmol) in water (1 mL) was
stirred for 5 min at 0 °C. The catalyst (0.03 mmol) was then added and the
reaction mixture was stirred at room temperature until the green solution
turned yellow. Then, EtOH (10 mL) and NaBH4 (57 mg) was added, and
the reaction mixture was stirred for another 10 min at room temperature.
The reaction mixture was diluted with water (20 mL) and extracted with
CH2Cl2 (3 x 20 mL). The combined organic extracts were dried (Na2SO4)
and concentrated under vacuum after filtration. Purification of the residue
by column chromatography (SiO2, AcOEt/hexane 1:5 – 1:3) afforded
compound 3 as a colorless oil.
Keywords: asymmetric synthesis • organocatalysis • α-
aminoxylation • α-amination • ball-milling
[1]
[2]
P. I. Dalko, Comprehensive Enantioselective Organocatalysis: Catalysts,
Reactions, and Applications, Wiley-VCH, Weinheim, 2013.
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Cabrera, Chem. Soc. Rev. 2013, 42, 774-793; c) R. Marcia de Figueiredo,
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5409; c) A. Bruckmann, A. Krebs, C. Bolm, Green Chem. 2008, 10, 1131-
1141.
Typical procedure for the α-aminoxylation of butanal to
nitrosobenzene under solvent-free conditions. The mixture of
nitrosobenzene (32.1 mg, 0.3 mmol) butanal (81 μL, 0.9 mmol), the
catalyst (0.03 mmol) and one drop of water was ball-milled at 20 Hz. The
reaction time is specified in Table 2. Then, the reaction mixture was
dissolved in EtOH (10 mL) and NaBH4 (57 mg) was added. After 10 min
stirring, the reaction mixture was diluted with water (20 mL) and extracted
with CH2Cl2 (3 x 20 mL). The combined organic extracts were dried
(Na2SO4) and concentrated in vacuo after filtration. Purification of the
residue by column chromatography (SiO2, AcOEt/hexane 1:5 – 1:3)
afforded compound 3 as a colorless oil.
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Vizcaíno-Milla, J. M. Sansano, C. Nájera, B. Fiser, E. Gõmez-Bengoa,
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Typical procedure for the α-hydrazination reaction of 3-
phenylpropanal with dibenzyl azodicarboxylate in water (Method A)
The mixture 3-phenylpropanal (134 mg, 1.0 mmol), dibenzyl
azodikarboxylate (149 mg, 0.5 mmol), catalyst (0.05 mmol) was stirred at
room temperature in brine (1 mL) until yellow color of azodicarboxylate
disappeared. Then, the reaction mixture was diluted with water (50 mL),
extracted with AcOEt (2 x 20 mL) and dried (Na2SO4). Volatiles was
removed by evaporation under vacuum, and the residue was diluted with
mixture ethanol/acetonitrile (9:1, 10 mL) and NaBH4 (40 mg) was added.
The reaction mixture was stirred for 10 min. Then aqueous NH4Cl solution
(50 mL) was added and organic ratio was extracted with EtOAc (2x50 mL).
The combined extracts were dried (Na2SO4) and concentrated in vacuo
after filtration. Purification of the residue by column chromatography (SiO2,
AcOEt/hexane 1:3) afforded compound 6 as a colorless oil.
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10.1002/ejoc.201601357
European Journal of Organic Chemistry
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Entry for the Table of Contents
Layout 1:
FULL PAPER
Application of aqueous media and
solvent-free conditions have been
assessed for asymmetric
organocatalytic α-aminoxylation and
hydrazination of aldehydes. Both sets
of conditions considerably sped up
these reactions, while keeping high
enantioselectivity.
Asymmetric organocatalysis
E. Veverková, V. Modrocká, R. Šebesta*
Page No. – Page No.
Organocatalyst efficiency in α-
aminoxylation and α-hydrazination of
carbonyl derivatives in aqueous
media and ball-mill
*one or two words that highlight the emphasis of the paper or the field of the study
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