Thermal Retro-Aldol Reaction Using Fluorous Ether F-626 as a Reaction Medium

Abstract

A high-boiling, fluorous-organic hybrid ether, F-626, was tested for use in thermal retro-aldol reactions and found to be an excellent reaction medium in view of the ease of separation from the product by fluorous/organic biphasic treatment. The recovered F-626 can be readily reused for subsequent runs.

The emergence of new solvents in synthesis has stimulated renewed interest in traditional organic synthesis normally based on conventional organic solvents. [¹] [²] We are interested in the use of F-626 (Figure  [¹] ), which is a fluorous-organic hybrid ether that was originally developed by Kao Corporation, [³] as a solvent for green organic synthesis. [4] The unique characteristics of F-626 include its good potential use as a substitute for organic solvents, and its thermomorphic nature when treated with organic substrates and reagents. [5] Despite its relatively high boiling point (214 ˚C/760 mmHg), F-626 is nevertheless easily recoverable by fluorous/organic biphasic treatment. We previously reported on the use of F-626 as a solvent in a variety of synthetic reactions, such as the Vilsmeyer formylation reaction, [4a] the Wolff-Kishner reduction, [4a] the Diels-Alder reaction, [4a] fluorous tin hydride based radical reactions, [4a] and the Mizoroki-Heck reaction. [4b]

The thermal retro-aldol reaction is a well-known reaction that is thought to proceed through a concerted mechanism. [6] [7] The retro-aldol products can be used as useful synthetic intermediates to prepare analogues of natural products or for structure confirmation. [7] Typically, the reaction is carried out in a sealed tube because the use of high-boiling organic solvents often requires cumbersome procedures to separate them from the products. In this work, we report that F-626 is an excellent reaction medium for thermal retro-aldol reactions that is easily separable from the products.

We examined the thermally induced retro-aldol reaction using 2-hydroxymethyl-1-phenyl-1-hexanone (1a) as a model compound. The results are summarized in Table  [¹] . Heating 1a at 200 ˚C for four hours without solvent gave a 75:25 mixture of the desired product 1-phenyl-1-hexanone (2a) and 2-methylene ketone 3a, which is formed as a by-product through dehydration, in 47% total yield (entry 1). The use of the ionic liquid [bmim]NTf₂ as a solvent under similar conditions gave an even worse result: a 50:50 mixture of 2a and 3a (entry 2). We found that F-626 worked quite well for the thermal retro-aldol reaction. Whereas the fluorous ether solvent, F-626, does not dissolve 1a at room temperature, upon heating, one layer resulted (Figure  [²] ). After cooling, biphasic workup using acetonitrile and FC-72 (perfluorohexanes), followed by purification using silica gel chromatography, gave a 98% combined yield of 2a and 3a in a ratio of 95:5 (entry 3). For this retro-aldol reaction, heating to 200 ˚C is critical, since lowering the temperature to 180 ˚C resulted in a sluggish reaction (entry 4).

Table 1 Thermal Retro-Aldol Reaction and Reaction Media^a

Entry	Solvent	Temp (˚C)	Yield (%)b	2a/3a ratioc
1	neat	200	47	75:25
2	[bmim]NTf2 (0.5 mL)	200	65d	50:50
3	F-626 (4 mL)	200	98	95:5
4	F-626 (4 mL)	180	36d	89:11
a Reaction was carried out on 0.5 mmol scale for 4 h. b Isolated yields after silica gel chromatography. c Determined by ¹H NMR analysis of the crude reaction mixture. d NMR yield.

We then examined the thermal retro-aldol reaction of several aldol compounds using F-626 as reaction medium. The results are summarized in Table  [²] . With the exception of p-hydroxyl-substituted phenone derivative 1d, retro-­aldol products were obtained with high selectivity in preference to the dehydration products. In the case of 1d, the acidic proton arising from the phenol portion, may catalyze the dehydration reaction (entry 5); consistent with this rationale, the corresponding p-methoxy substrate 1e gave the retro-aldol product 2e with high selectivity (entry 6). Aldol substrate 1f, having a secondary alcohol moiety, underwent the retro-aldol reaction in a shorter reaction time (entry 7). Aliphatic α-hydroxymethyl ketone also worked well to give a good yield of ketone 2g (entry 8).

Table 2 F-626-Mediated Retro-Aldol Reaction^a

Entry	Substrate	Time (h)	Product		Yield (%)b (ratio 2/3)c
1 2d	1a	4 4	2a	3a	98 (95:5) 97 (94:6)
3	1b	4	2b	3b	70 (86:14)
4	1c	4	2c	3c	75 (93:7)
5	1d	4	2d	3d	60 (50:50)
6	1e	5	2e	3e	84 (94:6)
7	1f	2	2a	-	84 (>99:1)
8	1g	4	2g	3g	79 (98:2)
a The reaction was performed with 1 (0.5 mmol) and F-626 (4 mL) at 200 ˚C b Isolated yield after silica gel column chromatography. c Determined by ¹H NMR analysis. d Recovered F-626 was used.

The workup procedure [4a] is outlined in Scheme  [¹] . [8] Thus, treatment of 1a with F-626 at room temperature gave two layers that became homogeneous upon heating. After cooling, the product 2a was extracted into acetonitrile (4 mL) and the resulting acetonitrile layer was separated and washed with FC-72 (2 mL) to extract the remaining F-626. The FC-72 solution was combined with the separated F-626. After evaporation, 98% of F-626 was recovered that was essentially clean as judged by NMR analysis; recovered F-626 could be used for subsequent experiments without reducing the yield of 2a (Table  [²] , entry 2).

We previously reported on a ruthenium hydride-catalyzed reaction that gave α-hydroxymethyl ketones as principal products. [9] [¹0] [¹¹] The combined procedures - the ruthenium hydride-catalyzed reaction and the thermal retro-aldol ­reaction - would give a new protocol for the synthesis of ketones. As outlined in Scheme  [²] , one-pot synthesis of ­6-undecanone (2g) and 1-phenyl-1-hexanone (2a) was ­attained starting from 2-hexene-1-ol [¹²] or benzyl alcohol, respectively, upon reaction with 2-hexenal.

In summary, thermal retro-aldol reactions can be successfully carried out using the high-boiling fluorous-organic hybrid solvent, F-626, as a reaction medium in which both separation of the product and recycling of the solvent are easy to carry out. The procedure was successfully combined with RuH-catalyzed coupling reactions to give aldol-type products in a one-pot procedure that can be used for the synthesis of ketones.

Acknowledgment

T.F. and I.R. acknowledge JSPS and MEXT Japan for funding. We appreciate the generous gift of F-626 from the Kao Corporation.

References and Notes

• 1a Green Reaction Media in Organic Synthesis   Mikami K. Blackwell Publishing; Oxford: 2005. 
• 1b Green Separation Processes: Fundamentals and Applications   Afonso CAM. Crespo JG. Wiley-VCH; Weinheim: 2005. 
• For reviews on fluorous chemistry, see:
• 2a Handbook of Fluorous Chemistry   Gladysz JA. Curran DP. Horváth IT. Wiley-VCH; Weinheim: 2004. 
• 2b For a thematic issue on fluorous chemistry, see: Gladysz JA. Curran DP. Tetrahedron   2002.  58:  p.3823 
  Search in Google Scholar
• 2c Ryu I. Matsubara H. Emnet C. Gladysz JA. Takeuchi S. Nakamura Y. Curran DP. In Green Reaction Media in Organic Synthesis   Mikami K. Blackwell Publishing; Oxford: 2005.  p.59 
• 2d Matsubara H. Ryu I. In Green Separation Processes: Fundamentals and Applications   Afonso CAM. Crespo JG. Wiley-VCH; Weinheim: 2005.  p.219 
• 3a Fujii Y, Tamura E, Yano S, and Furugaki H. inventors; US Patent  6,060,626. 
• 3b Fujii Y. Furugaki H. Yano S. Kita K. Chem. Lett.  2000,  926 
• 3c Fujii Y. Furugaki H. Tamura E. Yano S. Kita K. Bull. Chem. Soc. Jpn.  2005,  78:  456 
  Search in Google Scholar
• 4a Matsubara H. Yasuda S. Sugiyama H. Ryu I. Fujii Y. Kita K. Tetrahedron  2002,  58:  4071 
  Search in Google Scholar
• 4b Fukuyama T. Arai M. Matsubara H. Ryu I. J. Org. Chem.  2004,  69:  8105 
  Search in Google Scholar
• 5 Chu Q. Yu MS. Curran DP. Tetrahedron  2007,  63:  9890 
  CrossrefSearch in Google Scholar
• 6a Smith GG. Yates BL. J. Org. Chem.  1965,  30:  2067 
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• 6b Yates BL. Quijano J. J. Org. Chem.  1969,  34:  2506 
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• 6c Westley JW. Evans RH. Pruess DL. Stempel A. Chem. Soc. D.  1970,  1467 
• 6d Yates BL. Ramirez A. Velasquez O. J. Org. Chem.  1971,  36:  3579 
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• 6e Ireland RE. Anderson RC. Badoud R. Fitzsimmons BJ. McGarvey GJ. Thaisrivongs S. Wilcox CS. J. Am. Chem. Soc.  1983,  105:  1988 
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• 6f Yoshioka M. Arai M. Nishizawa K. Hasegawa T. J. Chem. Soc., Chem. Commun.  1990,  374 
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• 7b Oikawa H. Oikawa M. Ichihara A. Ubukata M. Isono K. Biosci., Biotechnol., Biochem.  1994,  58:  1933 
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• 7d Kocienski PJ. Brown RCD. Pommier A. Procter M. Schmidt B. J. Chem. Soc., Perkin Trans. 1  1998,  9 
• 7e Horita K. Nagato S. Oikawa Y. Yonemitsu O. Chem. Pharm. Bull.  1989,  37:  1726 
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• 7f Wells JL. Bordner J. Bowles P. McFarland JW. J. Med. Chem.  1988,  31:  274 
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• 9 Doi T. Fukuyama T. Minamino S. Husson G. Ryu I. Chem. Commun.  2006,  1875 
  Crossref
• 10 Doi T. Fukuyama T. Minamino S. Ryu I. Synlett  2006,  3013 
  Thieme Connect
• 11 Denichoux A. Fukuyama T. Doi T. Horiguchi J. Ryu I. Org. Lett.  2010,  12:  1 
  CrossrefSearch in Google Scholar

General procedure for retro-aldol reactions using F-626: α-Hydroxymethyl ketone 1a (0.5 mmol, 104.7 mg) and F-626 (4 mL, 5.64 g) were placed in a 5 mL two-necked round-bottom flask, and heated at 200 ˚C for 4 h under nitrogen. After cooling to room temperature, the reaction mixture was poured into a separation funnel, and MeCN (4 mL) was added. The MeCN layer was separated, and extracted with FC-72 (6 × 0.33 mL). The combined fluorous layers were evaporated to give F-626 (5.53 g, 98%). The crude reaction mixture obtained from the MeCN layer was purified by silica gel chromatography (hexane-EtOAc, 98:2) to give a mixture of 2a and 3a (87.6 mg; 2a/3a = 95:5)

To a 5 mL two-necked flask, RuHCl(CO)(PPh₃)₃ (0.05 mmol, 48.1 mg), benzene (3 mL) and 2-hexene-1-ol (1 mmol, 101.1 mg) were added, and the resulting mixture was heated at 80 ˚C for 10 h under nitrogen. After cooling to room temperature, the solvent was removed under reduced pressure, F-626 (4 mL) was added and the mixture was heated at 200 ˚C for 4 h. Biphasic workup using MeCN and FC-72, followed by purification using silica gel chroma-­tography (hexane-EtOAc, 98:2) gave a mixture of 2g and 3g (51 mg; 2g/3g = 96:4)

References and Notes

• 1a Green Reaction Media in Organic Synthesis   Mikami K. Blackwell Publishing; Oxford: 2005. 
• 1b Green Separation Processes: Fundamentals and Applications   Afonso CAM. Crespo JG. Wiley-VCH; Weinheim: 2005. 
• For reviews on fluorous chemistry, see:
• 2a Handbook of Fluorous Chemistry   Gladysz JA. Curran DP. Horváth IT. Wiley-VCH; Weinheim: 2004. 
• 2b For a thematic issue on fluorous chemistry, see: Gladysz JA. Curran DP. Tetrahedron   2002.  58:  p.3823 
  Search in Google Scholar
• 2c Ryu I. Matsubara H. Emnet C. Gladysz JA. Takeuchi S. Nakamura Y. Curran DP. In Green Reaction Media in Organic Synthesis   Mikami K. Blackwell Publishing; Oxford: 2005.  p.59 
• 2d Matsubara H. Ryu I. In Green Separation Processes: Fundamentals and Applications   Afonso CAM. Crespo JG. Wiley-VCH; Weinheim: 2005.  p.219 
• 3a Fujii Y, Tamura E, Yano S, and Furugaki H. inventors; US Patent  6,060,626. 
• 3b Fujii Y. Furugaki H. Yano S. Kita K. Chem. Lett.  2000,  926 
• 3c Fujii Y. Furugaki H. Tamura E. Yano S. Kita K. Bull. Chem. Soc. Jpn.  2005,  78:  456 
  Search in Google Scholar
• 4a Matsubara H. Yasuda S. Sugiyama H. Ryu I. Fujii Y. Kita K. Tetrahedron  2002,  58:  4071 
  Search in Google Scholar
• 4b Fukuyama T. Arai M. Matsubara H. Ryu I. J. Org. Chem.  2004,  69:  8105 
  Search in Google Scholar
• 5 Chu Q. Yu MS. Curran DP. Tetrahedron  2007,  63:  9890 
  CrossrefSearch in Google Scholar
• 6a Smith GG. Yates BL. J. Org. Chem.  1965,  30:  2067 
  Search in Google Scholar
• 6b Yates BL. Quijano J. J. Org. Chem.  1969,  34:  2506 
  Search in Google Scholar
• 6c Westley JW. Evans RH. Pruess DL. Stempel A. Chem. Soc. D.  1970,  1467 
• 6d Yates BL. Ramirez A. Velasquez O. J. Org. Chem.  1971,  36:  3579 
  Search in Google Scholar
• 6e Ireland RE. Anderson RC. Badoud R. Fitzsimmons BJ. McGarvey GJ. Thaisrivongs S. Wilcox CS. J. Am. Chem. Soc.  1983,  105:  1988 
  Search in Google Scholar
• 6f Yoshioka M. Arai M. Nishizawa K. Hasegawa T. J. Chem. Soc., Chem. Commun.  1990,  374 
• 7a Granberg KL. Edvinsson KM. Nilsson K. Tetrahedron Lett.  1999,  40:  755 
  Search in Google Scholar
• 7b Oikawa H. Oikawa M. Ichihara A. Ubukata M. Isono K. Biosci., Biotechnol., Biochem.  1994,  58:  1933 
  Search in Google Scholar
• 7c Oikawa M. Ueno T. Oikawa H. Ichihara A. J. Org. Chem.  1995,  60:  5048 
  Search in Google Scholar
• 7d Kocienski PJ. Brown RCD. Pommier A. Procter M. Schmidt B. J. Chem. Soc., Perkin Trans. 1  1998,  9 
• 7e Horita K. Nagato S. Oikawa Y. Yonemitsu O. Chem. Pharm. Bull.  1989,  37:  1726 
  Search in Google Scholar
• 7f Wells JL. Bordner J. Bowles P. McFarland JW. J. Med. Chem.  1988,  31:  274 
  Search in Google Scholar
• 9 Doi T. Fukuyama T. Minamino S. Husson G. Ryu I. Chem. Commun.  2006,  1875 
  Crossref
• 10 Doi T. Fukuyama T. Minamino S. Ryu I. Synlett  2006,  3013 
  Thieme Connect
• 11 Denichoux A. Fukuyama T. Doi T. Horiguchi J. Ryu I. Org. Lett.  2010,  12:  1 
  CrossrefSearch in Google Scholar

General procedure for retro-aldol reactions using F-626: α-Hydroxymethyl ketone 1a (0.5 mmol, 104.7 mg) and F-626 (4 mL, 5.64 g) were placed in a 5 mL two-necked round-bottom flask, and heated at 200 ˚C for 4 h under nitrogen. After cooling to room temperature, the reaction mixture was poured into a separation funnel, and MeCN (4 mL) was added. The MeCN layer was separated, and extracted with FC-72 (6 × 0.33 mL). The combined fluorous layers were evaporated to give F-626 (5.53 g, 98%). The crude reaction mixture obtained from the MeCN layer was purified by silica gel chromatography (hexane-EtOAc, 98:2) to give a mixture of 2a and 3a (87.6 mg; 2a/3a = 95:5)

To a 5 mL two-necked flask, RuHCl(CO)(PPh₃)₃ (0.05 mmol, 48.1 mg), benzene (3 mL) and 2-hexene-1-ol (1 mmol, 101.1 mg) were added, and the resulting mixture was heated at 80 ˚C for 10 h under nitrogen. After cooling to room temperature, the solvent was removed under reduced pressure, F-626 (4 mL) was added and the mixture was heated at 200 ˚C for 4 h. Biphasic workup using MeCN and FC-72, followed by purification using silica gel chroma-­tography (hexane-EtOAc, 98:2) gave a mixture of 2g and 3g (51 mg; 2g/3g = 96:4)