Mohammad G.
Dekamin
*,
Zahra
Karimi
and
Mehdi
Farahmand
Pharmaceutical and Biologically-Active Compounds Research Laboratory, Department of Chemistry, Iran University of Science and Technology, Tehran 16846-13114, Iran. E-mail: mdekamin@iust.ac.ir; Fax: +98-21-7322 7703
First published on 20th March 2012
In contrast to tetrabutylammonium hydroxide, its tetraethylammonium counterpart reacts with N-hydroxyphthalimide to afford tetraethylammonium 2-(N-hydroxycarbamoyl)benzoate (TEAHCB) rather than tetraethylammonium phthalimide-N-oxyl (TEAPINO). TEAHCB contains at the same time benzoate and hydroxycarbamoyl functionalities in a proper geometry to activate reaction components as Lewis basic and Lewis acidic centers, respectively. TEAHCB was found to be able to efficiently catalyze very rapid cyanosilylation of a wide variety of carbonyl compounds at 0.15 mol% catalyst loading under solvent-free conditions at room temperature as a simple and readily available bifunctional organocatalyst.
On the other hand, hydrocyanation and cyanosilylation of carbonyl compounds are among the most important strategies for C–C bond-forming reactions in organic synthesis. The adduct products provide versatile intermediates such as cyanohydrins and cyanohydrin trialkylsilyl ethers, respectively. In particular, cyanohydrin trimethylsilyl ethers are industrially valuable and important intermediates for the synthesis of α-hydroxy acids and esters, α-amino acids, acyloins, vicinal diols, β-amino alcohols and other biologically active compounds.6,9 For instance, cyanosilylation is the key step in the manufacture of (+)-biotin,10a Ditropan or its analogues,10b and insecticides such as cypermethrin and fluvalinate.11a Cyanohydrin trialkylsilyl ethers are generally prepared by the addition of trimethylsilyl cyanide (TMSCN), a safe and easily handled reagent compared to HCN, NaCN or KCN,6,9 to carbonyl compounds in the presence of Lewis acids,11 Lewis bases10a,12 and double activating9b,13 or bifunctional10b,14 catalytic systems. Therefore, a large body of work has been devoted to the development of cyanohydrin trimethylsilyl ethers synthesis. However, many of these protocols often involve heavy or expensive transition metal catalysts, poor yield of the products or prolonged reaction times, inert atmosphere or anhydrous solvents, the use of hygroscopic catalysts and tedious work-up procedures.10–14
Traditional Lewis acid catalytic systems promote cyanosilylation through direct complexation of the metal species to both the carbonyl group of aldehydes or ketones and the cyano group of TMSCN.9,11 On the other hand, Lewis basic catalysts including the majority of organocatalytic systems often react with the silicon atom of TMSCN to produce more reactive hypercoordinated silicon intermediates.12a,15–21 Hence, a few Lewis acid organocatalytic systems have been introduced for cyanosilylation of carbonyl compounds. Although catalysts such as N-iodosuccinimide22 or different alkyl triphenylphosphonium containing soft halide ions including iodide or bromide23 have been introduced in recent years, the use of a hydrogen bond donor moiety is more feasible and practical in organocatalysis. Interestingly, hydrogen bonding has demonstrated significant effects on the catalytic activity of bifunctional organocatalysts.6,24–27 The use of different thio-urea derivatives,6,24 tetramethyl guanidine,25 alkali-metal salts of α-aminoacids26 and tetraethylammonium 2-(carbamoyl)benzoate27 has proved the influence of hydrogen bonding on the catalytic activity of bifunctional organocatalysts for cyanosilylation of carbonyl compounds.
In continuation of our interest to develop more efficient organocatalysts for cyanosilylation of carbonyl compounds,16c,18b–d,19a,27 we wish herein to report our recent findings on the improved and smooth addition of TMSCN to carbonyl compounds using tetraethylammonium 2-(N-hydroxycarbamoyl)benzoate (TEAHCB, 1), as a new bifunctional organocatalyst, under solvent-free conditions (Scheme 1).
![]() | ||
Scheme 1 Cyanosilylation of carbonyl compounds using tetraethylammonium 2-(N-hydroxycarbamoyl)benzoate (TEAHCB, 1). |
![]() | ||
Scheme 2 Different phthalimide-N-oxyl salts 4 produced by the reaction of NHPI (2) with TBAOH or alkali metal hydroxides 3a–d. |
Interestingly, in our previous research, we found that tetraethylammonium hydroxide (TEAOH, 3e) reacts with the carbonyl groups of imide functionality of the phthalimide instead of the more acidic N−H proton to afford tetraethylammonium 2-(carbamoyl)benzoate (TEACB) as a bifunctional organocatalyst.27 In our hands, TEACB demonstrated higher catalytic activity in both cyanosilylation of carbonyl compounds and cyclotrimerization of isocyanates compared to the PINO nucleophile 4 in the typical catalytic systems.27,30 Hence, we decided to investigate the reactivity of TEAOH toward NHPI (2). It was found that although the imide moiety in the structure of 2 survived through the reaction with 3a–d,18b,c the situation is completely altered in the reaction with 3e to afford TEAHCB (1) as a new bifunctional organocatalyst (Scheme 3).
![]() | ||
Scheme 3 Unusual reaction pathway of 2 and 3e to produce TEAHCB (1). |
At first, a mixture of 4-chlorobenzaldehyde (5a) and TMSCN was treated with 0.3 mol% of TEAHCB (1) under solvent-free conditions at room temperature (Table 1). It was found that the cyanide addition occurred almost instantaneously to afford the desired trimethylsilylated cyanohydrin 6a with 99% conversion in 5 min (entry 1). By employing lower catalyst loading, 0.15 mol%, the desired product was obtained in quantitative yield. Furthermore, the reaction was studied on a 10 mmol scale, and we were delighted to find that only a minute amount of 1 (0.08 mol%) was required to catalyze the cyanosilylation of 5a at room temperature (entries 2 and 3). It is obvious that the best result in terms of turnover number (TON) and turnover frequency (TOF) could be achieved using 0.15 mol% catalyst loading of 1 (entry 2). On the other hand, no reaction was observed in the absence of 1 under similar reaction conditions (entry 4). Therefore, the lower catalyst loading required for this transformation compared to many organocatalytic systems having oxygen as their sole nucleophilic site18 and even TEACB27 demonstrates the simultaneous role of benzoate functionality of catalyst 1 and hydrogen bonding formed by its N-hydroxycarbamoyl moiety in a proper geometry in activating both TMSCN and carbonyl group for smooth cyanosilylation of diverse carbonyl compounds (Scheme 4, Table 2). It is expected that nucleophilic attack from the benzoate functionality of catalyst 1 on TMSCN produces pentavalent silicon intermediate 7 as the first reaction intermediate. The high reactivity of the pentavalent or hexavalent silicon intermediates to promote many organic transformations mediated by silicon reagents is well known.9c,12a,27,31 Therefore, the cyanide transfer from the pentavalent silicon atom to the activated carbonyl group by hydrogen bonding in complex 8 forms intermediate 9. Subsequent decomposition of pentavalent intermediate 9 gives product 6 and regenerates catalyst 1.
Entry | Catalyst | Mol% | Time/min | Conversionb (%) | TONc | TOFd/h−1 |
---|---|---|---|---|---|---|
a TMSCN (3 mmol) was added to a mixture of 4-chlorobenzaldehyde (5a, 2.5 mmol) and TEAHCB (1) under solvent-free conditions at room temperature except for entry 3 where the reaction was performed on a 10 mmol scale. b Determined by GC analysis. c Turnover number. d Turnover frequency. e Tetraethylammonium 2-(carbamoyl)benzoate as catalyst.27 | ||||||
1 | TEAHCB (1) | 0.3 | 5 | 100 | 333 | 4000 |
2 | TEAHCB (1) | 0.15 | 8 | 100 | 667 | 5000 |
3 | TEAHCB (1) | 0.08 | 25 | 99 | 990 | 2376 |
4 | — | — | 120 | 0 | — | — |
5 | TEACBe | 0.5 | 15 | 98 | 196 | 784 |
![]() | ||
Scheme 4 Plausible mechanism for cyanosilylation of carbonyl compounds 5 catalyzed by TEAHCB (1). |
Entry | Carbonyl compound (5) | Time (min) | Product (6)b | Conversion (%)c | Ref. |
---|---|---|---|---|---|
a TMSCN (3 mmol) was added to a mixture of carbonyl compound 5 (2.5 mmol) and TEAHCB 1 (1.1 mg) under solvent-free conditions at room temperature. b All products are known and were well-characterized by IR and NMR spectral data as compared with those obtained from authentic samples or reported in the literature.6,11,12,16,19,20 c Determined by GC analysis. | |||||
1 |
![]() |
8 |
![]() |
100 | 11g |
2 |
![]() |
10 |
![]() |
100 | 11h |
3 |
![]() |
2 |
![]() |
100 | 11h |
4 |
![]() |
5 |
![]() |
97 | 11n |
5 |
![]() |
3 |
![]() |
99 | 16b |
6 |
![]() |
10 |
![]() |
100 | 20a |
7 |
![]() |
15 |
![]() |
97 | 11g |
8 |
![]() |
15 |
![]() |
100 | 11g |
9 |
![]() |
20 |
![]() |
99 | 11h |
10 |
![]() |
15 |
![]() |
99 | 11g |
11 |
![]() |
15 |
![]() |
100 | 11m |
12 |
![]() |
15 |
![]() |
99 | 11g |
13 |
![]() |
15 |
![]() |
98 | 20a |
14 |
![]() |
15 |
![]() |
100 | 11g |
15 |
![]() |
20 |
![]() |
98 | 11m |
16 |
![]() |
20 |
![]() |
95 | 12b |
17 |
![]() |
20 |
![]() |
96 | 20a |
18 |
![]() |
25 |
![]() |
90 | 20a |
19 |
![]() |
20 |
![]() |
100 | 20a |
20 |
![]() |
30 |
![]() |
70 | 20a |
21 |
![]() |
30 |
![]() |
92 | 6d |
22 |
![]() |
30 |
![]() |
95 | 19a |
Encouraged by these results, other carbonyl compounds were subjected to cyanosilylation under optimal reaction conditions (TEAHCB 0.15 mol%, 1.2 equiv. of TMSCN, room temperature, solvent-free conditions). Table 2 shows that aromatic, heterocyclic and aliphatic aldehydes or ketones 5 have been effectively converted to the corresponding products 6. The reactions proceed very cleanly at room temperature under mild conditions. After completion of the reaction (monitored by TLC), the catalyst could be easily separated from the reaction mixture by aqueous extraction. Therefore, a simple work-up affords the desired products without any chromatographic purification. In general, the reaction conditions are very mild and high to quantitative yields of the products could be obtained within very short reaction time.
No benzoin condensation or desilylation by-products were observed. Acid-sensitive aldehydes such as furfural (5j), thiophene-2-carbaldehyde (5k) and cinnamaldehyde (5l) produced the desired cyanohydrin trimethylsilyl ethers rather than products of polymerization or Michael addition in quantitative yields (Table 2, entries 10–12). This may indicate that the catalytic system selectively activates the carbonyl function and keeps the double bonds of these acid sensitive substrates intact.27 As shown in Table 2, electronic effects and the nature of the substituents on the aromatic ring showed relatively strong effects on the required reaction time for the complete conversion of aldehydes. As a consequence of proposed bifunctional organocatalysis, substrates containing electron-withdrawing groups (entries 1 and 3–5) react much faster than ones bearing electron-donating groups (entries 7–11). This can be interpreted by considering that the cyanide transfer from the pentavalent silicon atom in complex 8 is the slowest step of the reaction mechanism (Scheme 4). However, 4-bromobenzaldehyde (5b) did not demonstrate any substantial substituent effect and its reaction required similar reaction time to benzaldehyde (5f). On the other hand, 4-methoxybenzaldehyde (5h) required shorter reaction time compared to 2-methoxybenzaldehyde (5i) due to proximity of the methoxy group to the carbonyl group in 5i which impedes hydrogen bonding between the catalyst and the carbonyl moiety of the substrate. Furthermore, due to the steric bulk, ketones such as cyclohexanone (5q), acetophenone (5r), benzophenone (5t), and their derivatives required longer reaction times than aldehydes (entries 16–22).11d,f The reaction of acyclic and cyclic aliphatic carbonyl compounds also afforded the corresponding products in very good yields in longer time compared to aromatic and heterocyclic carbonyl compounds (entries 13–17). Finally, this new catalytic system is far superior in terms of low catalyst loading and shorter reaction time as compared to other protocols for the addition of TMSCN to ketones (entries 16–22).11d,f,k,16,17,27
The comparison of the present method with respect to the catalyst loading, required reaction time, and simplicity of performance with those reported in the literature reveals that a practical and very fast method for the cyanosilylation of carbonyl compounds has been established using TEAHCB as a new bifunctional organocatalyst with unique geometry. To illustrate the efficiency of the present method, Table 3 is shown to compare our results with some of organocatalytic protocols reported in the literature recently.
Entry | Substrate | Method [equivalent of TMSCN/ TOF (h−1)] | ||||
---|---|---|---|---|---|---|
1a | 220c![]() |
317a![]() |
419b![]() |
527![]() |
||
a Solvent-free conditions. b THF as solvent. c CH2Cl2 as solvent. | ||||||
1 | Benzaldehyde | 1.2/4000 | — | 1.2/97.0 | 2/0.62 | 1.2/552.0 |
2 | 4-Chlorobenzaldehyde | 1.2/5000 | 1.1/8.0 | 1.2/39.6 | - | 1.2/784.0 |
3 | 4-Methoxylbenzaldehyde | 1.2/2667 | 1.1/27.6 | 1.2/32.7 | 2/0.15 | 1.2/446.4 |
4 | Cinnamaldehyde | 1.2/2640 | 1.1/30.0 | — | — | 1.2/258.7 |
5 | 3-Phenylpropanal | 1.2/2613 | — | 1.2/32.7 | — | 1.2/198.0 |
6 | 4-Nitroacetophenone | 1.2/2000 | — | — | — | 1.2/99.0 |
Footnote |
† Electronic supplementary information (ESI) available: 1H NMR and 13C NMR spectra for TEAHCB (1) and 1H NMR for selected products 6a and 6s. See DOI: 10.1039/c2cy20037f |
This journal is © The Royal Society of Chemistry 2012 |