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2 September 2009

Tris(2,4,6-trimethoxyphenyl)phosphine (TTMPP): Efficient Catalysts for the Cyanosilylation and Cyanocarbonation of Aldehydes and Ketones

,
and
Department of Science Education, Faculty of Education, Ibaraki University, Ibaraki, 310-8512 Japan
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Author to whom correspondence should be addressed.
Molecules2009, 14(9), 3353-3359;https://doi.org/10.3390/molecules14093353
This article belongs to the Special Issue Organocatalysis
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Abstract

A variety of aldehydes and ketones were transformed to their corresponding cyanohydrin silyl ethers in good to excellent yields in the presence of 1-5 mol% of tris(2,4,6-trimethoxyphenyl)phosphine (TTMPP). Cyanohydrin carbonates were also readily prepared using 5-10 mol% of TTMPP as an organocatalyst.

Introduction

The addition of trimethylsilyl cyanide (TMSCN) to carbonyl compounds is one of the most popular strategies to afford cyanohydrins, which can be conveniently converted into various important polyfunctionalized building blocks for the synthesis of many natural products and bioactive molecules, including α-hydroxyl carbonyl compounds and β-amino alcohols [1,2,3,4,5,6,7]. Consequently, many catalytic systems, such as metal salts, organocatalysts, inorganic solid acids and bases, have been developed to enhance the efficiency of this transformation. Organophosphorous compounds have also been employed. Mukaiyama reported that Bu3P and Ph3P act as catalysts for the cyanosilylation with aldehydes [8]. Plumet [9,10] and Tian [11] independently reported that phosphonium salts-catalyzed cyanosilylation with aldehydes and ketones. Verkade’s base (cycloazaphosphine) also acts as a good catalyst in this reaction [12]. In search of other useful organophosphorous catalysts, we have now examined the use of a highly basic phosphine, tris(2,4,6-trimethoxyphenyl)phosphine (TTMPP), as a catalyst.
TTMPP is known to be a highly basic phosphine owing to its extensive methoxy-substitution [13]. Based on this property, some unique catalytic reactions have been reported [14,15,16,17,18,19]. We have also reported that TTMPP acts as a good Lewis base catalyst in the reaction with silylated nucleophiles via O-Si and C-Si bond activation [20,21,22,23,24,25]. Herein we wish to report an efficient catalytic cyanosiyliation of various aldehydes and ketones using TTMPP as a catalyst.

Results and Discussion

Initially, the reactions of different aldehydes with trimethylsilyl cyanide in the presence of 1 mol% of TTMPP in DMF at room temperature were examined. For both aromatics having an electron-donating or -withdrawing group and aliphatic aldehydes, the reaction proceeded quite smoothly and the desired products were obtained at high yield within 30 min (Table 1). The product was obtained in lower yield when other phosphines, such as Bu3P, Ph3P and TMPP were used instead of TTMPP (Table 1, entries 1 vs. 10-12). The reaction also smoothly proceeded in THF. However, the reactions performed in MeCN and toluene were inferior when compared to those in DMF and THF.
Table
Table 1. Cyanosilylation of various aldehydes.[a]
Table 1. Cyanosilylation of various aldehydes.[a]
Molecules 14 03353 i001
EntryPhosphinesAldehydesolventYield (%)
1TTMPPC6H5CHODMF98
24-CH3OC6H4CHO99
34-ClC6H4CHO95
44-NO2C6H4CHO98
5α-Naphthaldehyde92
6β-Naphthaldehyde90
7C8H17CHO95
8C6H5CH2CH2CHO92
9cyclo-C6H11CHO93
10TMPP[b]C6H5CHO45
11Ph3P30
12nBu3P68
13TTMPPTHF95
14CH3CN55
15toluene30
[a] Reactions were carried out on a 0.5 mmol scale with 1.2 equiv of TMSCN.[b] Tris(4-methoxyphenyl)phosphine.
Table
Table 2. TTMPP-Catalyzed cyanosilylation of various ketones.[a]
Table 2. TTMPP-Catalyzed cyanosilylation of various ketones.[a]
Molecules 14 03353 i002
EntryKetones (3)Temp (°C)Yield (%)
1 Molecules 14 03353 i004r.t.97
2[b], [c]99
395
493
598
690
793
894
976
10[d]r.t.trace
1150 °C97
1296
1395
[a] Reactions were carried out on a 0.5 mmol scale with 1.2 equiv of TMSCN.[b] 1 mol% of TTMPP was used. [c] Reaction time: 5 h. [d] Reaction time: 24 h.
Next, we investigated the scope of this TTMPP-catalyzed reaction of ketones (Table 2). In the case of aliphatic ketones, the reaction proceeded smoothly in the presence of 5 mol% of TTMPP in DMF at room temperature. Good results were obtained for both acyclic and cyclic ketones. This reaction also proceeded smoothly when 1 mol% of TTMPP was used. Only 1,2-addition products were observed for unsaturated ketones. On the other hand, for the typical aromatic ketone acetophenone, only a trace amount of the product was obtained at room temperature even after 24 h. Then, the reaction was carried out at the elevated temperature. The desired product was obtained in 95% yield at 50 °C in DMF within 1 h. Under the same conditions, a variety of aromatic ketones were transformed to their corresponding cyanohydrin silyl ethers in high yield.
Cyanocarbonation [26,27,28,29,30,31,32,33] of aldehydes and ketones with cyanoformate was also examined (Table 3). Cyanohydrin carbonates are configurationally stable and significantly less prone to hydrolysis than cyanohydrin trimethylsilyl ethers. We examined the scope of this TTMPP-catalyzed reaction of aldehydes and ketones using methyl cyanoformate. Good results were obtained for both aromatics having an electron-donating or -withdrawing group and aliphatic aldehydes in the presence of 5 mol% of TTMPP in THF at room temperature. The reaction also proceeded smoothly with various aliphatic ketones in the presence of 10 mol% TTMPP, but was unsuccessful with aromatic ketones under these conditions.
Table
Table 3. TTMPP-Catalyzed cyanocarbonation of aldehydes and ketone.[a]
Table 3. TTMPP-Catalyzed cyanocarbonation of aldehydes and ketone.[a]
Molecules 14 03353 i003
EntryCarbonyl Compound (3)Time (h)Yield (%)
C6H5CHO1 h98
24-CH3OC6H4CHO4 h85
34-ClC6H4CHO95
44-BrC6H4CHO98
54-NO2C6H4CHO88
6α-Naphthaldehyde1 h98
7β-Naphthaldehyde85
8C8H17CHO4 h87
9C6H5CH2CH2CHO92
10cyclo-C6H11CHO88
11[b]C6H13COCH320 h75
12[b]C6H5CH2CH2COCH385
13[b]C6H5COCH324 h5
14[b], [c]48 h10
[a] Reactions were carried out on a 0.5 mmol scale with 1.5 equiv of methyl cyanoformate; [b] 10 mol% of TTMPP was used; [c] At 50 °C.

Experimental

General

All reactions were performed under an argon atmosphere using oven-dried glassware. Flash column chromatography was performed using silica gel Wakogel C-200. Preparative thin-layer chromatography was carried out on silica gel Wakogel B-5F. Dehydrate DMF, THF, toluene and CH3CN were purchased from Wako Chemical. Other commercially available reagents were used as received without further purification. 1H NMR and 13C NMR spectra were recorded on a JEOL JMN-GS400 spectrometer (399.65 MHz for 1H and 100.40 MHz for 13C).

General Procedure for the TTMPP-Catalyzed Cyanosilylation of Aldehydes and Ketones

To a solution of TTMPP (0.05 mmol) in DMF (1 mL) was added aldehyde or ketone (0.5 mmol) and trimethylsilyl cyanide (0.60 mmol) at room temperature. After stirring for 30 min, the resultant mixture was quenched with water. The mixture was extracted with EtOAc and organic layer was washed with brine and dried over anhydrous Na2SO4, and evaporated. The crude mixture was purified by column chromatography on silica gel (EtOAc-hexane = 1:10) to give the corresponding product. The products are all known compounds identified by their spectroscopic data and comparison with literature values [8,9,10,11,12,34]. The purity of the product was confirmed by 1H NMR analysis.

General Procedure for the TTMPP-Catalyzed Cyanocarbonation of Aldehydes

To a solution of TTMPP (0.05 mmol) in THF (1 mL) was added aldehyde (0.5 mmol) and methyl cyanoformate (0.75 mmol) at room temperature. After stirring for 30 min, the resultant mixture was quenched with water. The mixture was extracted with Et2O and organic layer was washed with brine and dried over anhydrous Na2SO4, and evaporated. The crude mixture was purified by column chromatography on silica gel (EtOAc-hexane = 1:3) to give the corresponding product. The products are all known compounds identified by their spectroscopic data and comparison with literature values [27,28,29,30,31,32,33]. The purity of the product was confirmed by 1H NMR analysis.
α-(Trimethylsilyloxy)phenylacetonitrile: 1H-NMR (400 MHz, CDCl3) δ 0.21 (s, 9H), 5.45 (s, 1H), 7.35 – 7.50 (m, 5H); 13C NMR (100 MHz, CDCl3) δ −0.3, 63.4, 119.1, 126.0, 128.4, 129.0, 136.0.
2-Trimethylsilyloxy-2-phenylpropanenitrile: 1H-NMR (400 MHz, CDCl3) δ 0.17 (s, 9H), 1.85 (s, 3H), 7.35 – 7.56 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 1.0, 33.5, 71.5, 121.3, 124.8, 128.4, 141.9.
α-(Methoxycarboxy)phenylacetonitrile: 1H-NMR (400 MHz, CDCl3) δ 3.87 (s, 3H), 6.28 (s, 1H), 7.39 – 7.55 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 55.9, 66.6, 115.6, 127.8, 129.1, 130.6, 131.1, 153.9.

Conclusions

In conclusion, we demonstrated that TTMPP catalyzes cyanosilylation reactions using TMSCN. TTMPP effectively activated the C-Si bond of TMSCN, and the reaction proceeded smoothly to afford the corresponding products. This reaction can be applied to wide variety of aldehydes and ketones. Cyanohydrin carbonates could also be readily prepared with methyl cyanoformate using 5-10 mol% of TTMPP as catalyst.

References

  1. Evans, D.A.; Truesdale, L.K. Carbonyl insertion reactions of silicon pseudohalides: catalysis. Tetrahedron Lett. 1973, 4929–4932. [Google Scholar]
  2. Evans, D.A.; Carroll, G.L.; Truesdale, L.K. Synthetic applications of trimethylsilyl cyanide. An efficient synthesis of aminomethyl alcohols. J. Org. Chem. 1974, 39, 914–917. [Google Scholar] [CrossRef]
  3. North, M. Catalytic, asymmetric cyanohydrin formation. Synlett 1993, 807–820. [Google Scholar] [CrossRef]
  4. Gregory, J.H. Cyanohydrins in nature and the laboratory: Biology, preparations, and synthetic applications. Chem. Rev. 1999, 99, 3649–3682. [Google Scholar] [CrossRef]
  5. North, M. Synthesis and applications of non-racemic cyanohydrins. Tetrahedron: Asymmetry 2003, 14, 147–176. [Google Scholar] [CrossRef]
  6. Brunel, J.-M.; Holmes, I.P. Chemically catalyzed asymmetric cyanohydrin syntheses. Angew. Chem. Int. Ed. 2004, 43, 2752–2778. [Google Scholar] [CrossRef]
  7. Khan, N.H.; Kureshy, R.I.; Abdi, S.H.R.; Agrawal, S.; Jasra, R. Metal catalyzed asymmetric cyanation reactions. Cood. Chem. Rev. 2008, 252, 593–623. [Google Scholar] [CrossRef]
  8. Kobayashi, S.; Tsuchiya, Y.; Mukaiyama, T. A facile sythesis of cyanohydrin trimethylsilyl ethers by the addition reaction of trimethylsilyl cyanide with aldehydes under basic condition. Chem. Lett. 1991, 537–540. [Google Scholar]
  9. Córdoba, R.; Plumet, J. Methyltriphenylphosphonium iodide catalyzes the addition of trimethylsilyl cyanide to aldehydes. Tetrahedron Lett. 2003, 44, 6157–6159. [Google Scholar] [CrossRef]
  10. Amurrio, I.; Córdoba, R.; Csákÿ, A.G.; Plumet, J. Tetrabutylammonium cyanide catalyzes the addition of TMSCN to aldehydes and ketones. Tetrahedron 2004, 60, 10521–10524. [Google Scholar] [CrossRef]
  11. Wang, X.; Tian, S.-K. Catalytic cyanosilylation of ketones with simple phosphonium salt. Tetrahedron Lett. 2007, 48, 6010–6013. [Google Scholar] [CrossRef]
  12. Fetterly, B.; Verkade, J.G. P(RNCH2CH2)N: Efficient catalysis for the cyanosilylation of aldehydes and ketones. Tetrahedron Lett. 2005, 46, 8061–8066. [Google Scholar] [CrossRef]
  13. Wada, M.; Higashizaki, S. A highly basic triphenylphosphine, [2,4,6-(MeO)3C6H2]3P. J. Chem. Soc. Chem. Commun. 1984, 482–483. [Google Scholar] [CrossRef]
  14. Yoshimoto, K.; Kawabata, H.; Nakamichi, N.; Hayashi, M. Tris(2,4,6-trimethoxyphenyl)-phosphine (TTMPP): A novel catalyst for selective deacetylation. Chem. Lett. 2001, 30, 934–935. [Google Scholar]
  15. Kawabata, H.; Hayashi, M. Lewis base-catalyzed transformation of α,β-unsaturated aldehydes to saturated carboxylic acids, esters, and amides. Tetrahedron Lett. 2002, 43, 5645–5647. [Google Scholar] [CrossRef]
  16. Weeden, J.A.; Chisfolm, J.D. Phosphine-catalyzed nitroaldol reactions. Tetrahedron Lett. 2006, 47, 9313–9316. [Google Scholar] [CrossRef]
  17. Hirata, N.; Hayashi, M. Nitroaldol reaction catalyzed by tris(2,4,6-trimethoxyphenyl)phosphine (TTMPP). Synth. Commun. 2007, 37, 1653–1657. [Google Scholar] [CrossRef]
  18. Chuprakov, S.; Malyshev, D.A.; Trofimov, A.; Gevorgyan, V. Sila Morita-Baylis-Hillman reaction of cyclopropenes. J. Am. Chem. Soc. 2007, 129, 14868–14869. [Google Scholar] [CrossRef]
  19. Trofimov, A.; Gevorgyan, V. Sila-Morita-Baylis-Hillman reaction of arylvinyl ketones: overcoming the dimerization problem. Org. Lett. 2009, 11, 253–255. [Google Scholar] [CrossRef]
  20. Matsukawa, S.; Okano, N.; Imamoto, T. Phosphine catalyzed aldol reaction between ketene silyl acetals and aldehydes: nucleophilic O–Si and C–Si bond cleavage by phosphines. Tetrahedron Lett. 2000, 41, 103–107. [Google Scholar] [CrossRef]
  21. Matsukawa, S.; Obu, K. TTMPP catalyzed one-pot silyl ketene acetal-imine condensation route to β-lactams. Chem. Lett. 2004, 33, 1626–1627. [Google Scholar] [CrossRef]
  22. Matsukawa, S.; Kitazaki, E. Catalytic cyanomethylation of carbonyl compounds and imines with highly basic phosphine Tetrahedron Lett. 2008, 49, 2982–2984. [Google Scholar]
  23. Matsukawa, S.; Saijo, M. TTMPP-catalyzed trifluoromethylation of carbonyl compounds and imines with trifluoromethylsilane. Tetrahedron Lett. 2008, 49, 4855–4857. [Google Scholar]
  24. Matsukawa, S.; Sekine, I. TTMPP-catalyzed addition of alkynes using trimethylsilylacetylenes. Synth. Commun. 2009, 39, 1718–1721. [Google Scholar] [CrossRef]
  25. Matsukawa, S.; Tsukamoto, K. TTMPP: An efficient organocatalyst in the ring-opening of aziridines with silylated nucleophiles. Org. Biomol. Chem. 2009, 7, 3792–3796. [Google Scholar] [CrossRef]
  26. Belokon’, Y.N.; Clegg, W.; Harrington, R.W.; Ishibashi, E.; Nomura, H.; North, M. Enantioselective and Diastereoselective Syntheses of Cyanohydrin Carbonates. Tetrahedron 2007, 63, 9724–9740. [Google Scholar]
  27. Tian, S.-K.; Deng, Li. Enantioselective cyanocarbonation of ketones with chiral base. Tetrahedron 2006, 62, 11320–11330. [Google Scholar] [CrossRef]
  28. Scholl, M.; Lim, C.-K.; Fu, G.C. Convenient and efficient conversion of aldehydes to acylated cyanohydrins using tributyltin cyanide as a catalyst. J. Org. Chem. 1995, 60, 6229–6231. [Google Scholar] [CrossRef]
  29. Okimoto, M.; Chiba, T. A convenient and improved method for the preparation of cyanohydrin esters from acyl cyanides and aldehydes. Synthesis 1996, 1188–1190. [Google Scholar] [CrossRef]
  30. Tian, S.-K.; Deng, Li. A highly enantioselective chiral Lewis base-catalyzed asymmetric cyanation of ketones. J. Am. Chem. Soc. 2001, 123, 6195–6196. [Google Scholar] [CrossRef]
  31. Tian, J.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. An asymmetric cyanation reaction and sequential asymmetric cyanation-nitroaldol reaction using a [YLi3{tris(binaphthoxide)}] single catalyst component: Catalyst tuning with achiral additives. Angew. Chem. Int. Ed. 2002, 41, 3636–3638. [Google Scholar] [CrossRef]
  32. Iwanami, K.; Hinakubo, Y.; Oriyama, T. Catalyst-free DMSO-promoted synthesis of cyanohydrin carbonates from aldehydes. Tetrahedron Lett. 2005, 46, 5881–5883. [Google Scholar] [CrossRef]
  33. Chinchilla, R.; Nájera, R.; Ortega, F.J. Enantioselective cyanoformylation of aldehydes using a recyclable dimeric cinchonidine ammonium salt as an organocatalyst. Tetrahedron: Asymmetry 2008, 19, 265–268. [Google Scholar] [CrossRef]
  34. Prakash, G.K.S.; Vaghoo, H.; Panja, C.; Surampudi, V.; Kultyshev, R.; Mathew, T.; Olah, G. A. Effect of carbonates/phosphates as nucleophilic catalysts in dimethylformamide for efficient cyanosilylation of aldehydes and ketones. Proc. Natl. Acad. Sci. USA 2007, 104, 3026–3030. [Google Scholar]
  • Sample Availability: Samples of the compounds of interest are available from the authors.

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