3A. Results and Discussions
3.3 Borax as an Efficient Metal-Free Catalyst for Hetero-Michael Reactions
Chapter 3 52
Table 3.2.6. B(OH)3 (20mol%) catalyzed conjugate addition of thiols to α,β–unsaturated compounds in MeOH at room temperature
O O
S S
H SH
n
n O S Boric acid (20 mol% )
+
Schem e 3.2.3
Entry HS SH
n Olefins Solvent Product Time
(min) Yield (%) 1 n=2
O H2O 50a 5 75
2 n=3
O H2O 51a 5 85
3 n=2
O MeOH 50a 4 75
4 n=3
O MeOH 51a 4 78
5 n=2
O EtOH 50a 4 71
6 n=3
O EtOH 51a 4 76
3.3 Borax as an Efficient Metal-Free Catalyst for Hetero-Michael
Chapter 3 53
each case with the best performance being in water containing 10 mol% of the catalyst.
Accordingly, all the reactions discussed herein after were conducted with this combination.
Table 3.3.1. The Michael addition of thiophenol with methyl acrylate under different reaction conditions
Entry Borax(mol%) Solvent Time (min) Yield (%)
1 0 H2O 5 5
2 20 H2O 5 95
3 10 H2O 5 95
4 1 H2O 5 40
5 10 MeOH 5 30
6 10 CH3CN 5 64
7 10 (CH3)2CO 5 70
8 10 AcOEt 5 70
A variety of electron deficient olefins such as methylacrylate, acrylonitile, acrylamide, cyclohexanone and methyl methacrylate underwent facile 1,4 addition with a wide range of thiols catalyzed by borax (10 mol%) in water at room temperature to afford the corresponding β-adducts in high to very high yields (Table 3.3.2). Unsaturated ketones, nitriles, amides, aldehydes and esters reacted readily with both aliphatic and aromatic thiols to provide the corresponding Michael adducts (entries 1-20, Table 3.3.2). The reactions were clean. The borax-water system worked also very well for α- and β-substituted Michael acceptors at ambient temperatures. It was found that with methyl being either at α- or β-position, the protocol gave good yields (entries 12-15, Table 3.3.2) in 5-10 min, while with phenyl at β-position took longer reaction times (1.5-3 h, entries 23-25, Table 3.3.2). Acceptors like carvone and pulegone reacted readily with aliphatic thiols (entries 21 and 22, Table 3.3.2). Notably, the present protocol worked well for the conjugate addition of cysteine to acrylamide (entry 11, Table 3.3.2) giving 88% isolated yield of the adduct.
This reaction is relevant in the context of alkylation of cysteine in proteins with acrylamide under mildly aqueous alkaline conditions and is considered to be useful for cysteine identification during protein sequencing.76,77
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Table 3.3.2. Borax catalysed Michael addition of thiols to olefins in water at room temperature
Entry Thiol Olefin Product Time
min(h) Yield (%)a
1 SH CO2Me 31a 5 95, 97b
2 SH
MeO
CO2Me 32a 5 92
3 SH
O2N
CO2Me 33a 5 92
4 C2H5SH CO2Me 34a 5 89
5 C12H25SH CO
2Me 35a (3) 75
6 SH CN 36a 5 94
7 C2H5SH CN 52a 5 87
8 C12H25SH CN 38a (2.5) 72
9 SH CONH
2 39a 5 93, 96b
10 C4H9SH CONH2 40a 5 87
11 HS COOH
NH2
CONH2 53a 30 88
12 SH
CO2Me
41a 5 88
13 C4H9SH
CO2Me
42a 5 82
14 SH CHO 44a 10 85
15 SH CO
2Me 54a 10 86
16 SH
O 45a 5 92
17 SH
MeO
O 46a 5 90
Chapter 3 55
18 SH
O2N
O 47a 5 88
19 C2H5SH
O 48a 5 90
20 C12H25SH
O 49a (2.5) 70
21 C2H5SH
O H
55a (3) 85
22 C2H5SH
O
H 56a (3) 82
23 C2H5SH
Ph Ph
O 57a (1.5) 89
24 SH
Ph Ph
O 58a (3) 75
25 SH
Ph Me
O 59a (2) 80
a Isolated Yield,
b Yield on 7 g scale
The borax catalyzed Michael addition in water is applicable also to dithiols without any difficulty, as shown in Scheme 3.3.2.
HS SH
O
S S
O O
n n = 2, 3
+ Borax (20 mol%) rt, water/ 84-94%
Scheme 3.3.2 n
The reactions proceeded with alacrity giving bis-adducts in very good yields (Table 3.3.3).
Such reactions are expected to be useful in the designed synthesis of organo-sulfur polymers,
supramolecular architectures and macromolecules. Incidentally, H2N-CO-CH2-CH2-S-CH2-CH2-S-CH2-CH2-CO-NH2 obtained from the reaction of 1,3 propanedithiol and two equivalents of acrylamide (entry 2, Table 3.3.3) is an interesting
compound,22,23 the preparation of which does not seem to be available in open literature. Two Japanese patents22,23 reported the use of the compound as a photographic development accelerator TH-482_03612207
Chapter 3 56
and a constituent of color photographic developer. This was used also in lithographic plate processing solution.
Table 3.3.3 Borax catalysed Michael addition of dithiols to olefins in water at room temperature
Entry HS SH
n Olefins Product Time
(min) Yield (%)a
1 n=2 CONH2 60a 15 92
2 n=3 CONH
2 61a 15 94
3 n=2
O 50a 15 84
4 n=3
O 51a 20 87
5 n=2 CO2Me 62a 15 86
6 n=2 CO
2Me 63a 20 85
a Isolated Yields
The borax-water protocol is applicable to aza-Michael reactions as well. A variety of α,β-unsaturated compounds underwent 1,4 addition with a wide range of aliphatic amines in the presence of 10 mol% of borax at ambient temperatures to afford the corresponding β-amino compounds in high yields. Some representative examples are set out in Table 3.3.4. An internal comparison of the results of thiol additions with those of amine additions under similar experimental conditions shows that the former are more facile than the latter. Indeed, this observation is in agreement with the result of an earlier kinetic studies.78 Based on kinetic data it was predicted that –SH groups are many times more reactive than amines in aqueous alkaline solution.
Table 3.3.4. Borax catalyzed Michael addition of amines to olefins in water at room temperature
Entry Amine Olefin Product Time(h)/
Yield(%)a
1 NH CO2Me 1a 3/86
2 O NH CO2Me 4a 3/92
Chapter 3 57
3 NH
2 CO2Me 5a 2/89
4
Bu nBu HN
n CO2Me 3a 2/92
5 NH CN 13a 2/90
6 NH
2 CN 25a 1.5/86
7
Bu n-Bu HN
n- CN 24a 2/92
8 NH2
MeO
CO2Me 64a 8/25
9
H2N OPh
O CO2Me 65a 8/0
a Isolated Yields
Finally, recyclability of the catalyst was examined through a series of reactions with thiophenol and methyl acrylate using aqueous phase containing borax. The reaction continued giving good results from second through the fifth cycles with the yields being 95, 94, 92 and 90%, respectively. However, the yield was reduced to 80% at the sixth cycle. This is explained by attrition and leaching of the catalyst. Important is also to note that the borax-water protocol can be applied to a relatively larger scale (7 g) of operation giving very good yields (Table 3.3.4, entries 1 and 9).
A comparison of the present results with those of the corresponding boric acid catalyzed aza- and thia-Michael reactions, as presented under Section 3.2, suggests that under similar experimental conditions borax appear to be either as good as or slightly better than boric acid in catalyzing the chosen reactions.
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