Retropinacol/Cross-pinacol Coupling Reactions - A Catalytic Access to 1,2-Unsymmetrical Diols

Summary

A novel account for the synthesis of unsymmetrical 1,2-diols based on a retropinacol/cross-pinacol coupling mechanism is described. Due to the catalytic execution of this reaction a considerable improvement compared to conventional cross-pinacol couplings is achieved.

Abstract

Unsymmetrical 1,2-diols are hardly accessible by reductive pinacol coupling processes. A successful execution of such a transformation is bound to a clear recognition and strict differentiation of two similar carbonyl compounds (aldehydes → secondary 1,2-diols or ketones → tertiary 1,2-diols). This fine-tuning is still a challenge and an unsolved problem for an organic chemist. There exist several reports on successful execution of this transformation but they cannot be generalized. Herein we describe a catalytic direct pinacol coupling process which proceeds via a retropinacol/cross-pinacol coupling sequence. Thus, unsymmetrical substituted 1,2-diols can be accessed with almost quantitative yields by means of an operationally simple performance under very mild conditions. Artificial techniques, such as syringe-pump techniques or delayed additions of reactants are not necessary. The procedure we describe provides a very rapid access to cross-pinacol products (1,2-diols, vicinal diols). A further extension of this new process, e.g. an enantioselective performance could provide a very useful tool for the synthesis of unsymmetrical chiral 1,2-diols.

Introduction

The pinacol coupling reaction is a general and commonly used method for the preparation of symmetrically vicinal diols (1,2-diols, pinacols). For comprehensive reviews in this field see references Hirao¹, Chatterjee and Joshi², Ladipo³, and Gansäuer and Bluhm⁴. In contrast to that, only a few reports were published to refer an efficient realization of cross-pinacol coupling reactions to yield the corresponding unsymmetrical 1,2-diols (titanium(IV) chloride/manganese⁵, samarium(II) iodide⁶, magnesium/trimethylchlorosilane⁷, vanadium(II)⁸, zirconium/tin⁹, and ytterbium¹⁰). Thus, the intermolecular cross-pinacol coupling reaction still remains a big challenge in organic chemistry, especially the catalytic execution of this transformation.

The formation of cross coupling products is kinetically disfavored under conditions of a classical pinacol coupling. To obtain sufficient amounts of the unsymmetrical product delayed addition of one carbonyl compound is possible. There exist a few examples which are developing this concept, but they are based on several specific experimental manipulations and hence cannot be generalized. In addition, the required excess of one carbonyl compound in these transformations resulted in a laborious separation of a complex product mixture¹¹. An alternative for this purpose is represented by the precomplexation of one reactant rendering equimolar amounts of an additional reagent necessary.

Various examples of a reversible pinacol reaction have been described¹². These lead to the consideration that such conditions might be an optimal starting point for the selective synthesis of cross coupling products. Since a low-valent metal as well as a reactive radical species is formed simultaneously in situ, unsymmetrical diols could be formed exclusively in the presence of a suitable carbonyl reactant. To the best of our knowledge such a method has not been reported before (Porta et al. described a comparable pinacol cleavage and subsequent coupling by the additional deployment of stoichiometric amounts of AIBN (2,2′-azo-bis-isobutyronitrile) to generate the required radicals)¹³.

Herein a protocol is visualized which provides a rapid and operationally simple access to unsymmetrical 1,2-diols. The unsymmetrical pinacol products are mostly accessible in excellent yields (>95%). Undesired symmetrically pinacol products are not observed. This new cross-pinacol methodology is based upon a retropinacol/cross-pinacol coupling sequence. It will be demonstrated in the following by representative reactions of benzopinacole (1,1,2,2-tetraphenyl-1,2-ethanediol, 1) with 2-ethylbutyraldehyde (in the aldehyde series) and with diethylketone (in the ketone series).

Protocol

1. Preparation of Titanium(IV) tert-butoxide/Triethylchlorosilane Solution

1. Dissolve 400 mg (400 μl) titanium(IV) tert-butoxide (1 mmol) in 10 ml of dry dichloromethane. Add 150 mg (170 μl) triethylchlorosilane (1 mmol) to this solution at RT. 1 ml of this dichloromethane-solution contains 0.1 mmol titanium(IV) tert-butoxide and 0.1 mmol triethylchlorosilane.

2. Pinacol-reaction of Tetraphenyl-1,2-ethanediol (1) with 2-Ethylbutyraldehyde

1. Solve 366 mg of tetraphenyl-1,2-ethanediol (1, 1 mmol) and 300 mg (370 μl) of freshly distilled 2-ethylbutyraldehyde (3 mmol) in 3 ml dry dichloromethane.
2. Add 0.5 ml of the separately prepared titanium(IV) tert-butoxide/triethylchlorosilane solution (0.05 mmol).
3. Stir the resulting mixture at RT in a sealed reaction tube.
4. Confirm the reaction is completed by thin layer chromatography (eluent: hexane/acetone - 9/1) on silica gel TLC plates (60 F254). The end of reaction is reached at the time when tetraphenyl-1,2-ethanediol 1 can no longer be detected (∼12 hr). The Rf-value of the product is 0.3 ¹⁴.
5. Dilute the resulting reaction mixture with 50 ml of dichloromethane.
6. Wash the diluted reaction mixture successively by 20 ml saturated aqueous ammonium chloride and sodium hydrogen carbonate solution in a separatory funnel.
7. Isolate the organic layer by a separatory funnel. 
8. Dry the organic layer by stirring over dry magnesium sulfate.
9. Filtrate the suspension by a fluted paper filter and collect the filtrates.
10. Remove dichloromethane from the filtrate in vacuo at 40 °C using a rotary evaporator (10-30 mmHg). Evaporation of solvents will require 20 min.
11. Purify the remaining residue by flash column chromatography through a column of silica gel (0.035-0.070 mm, ACROS) with a gradient of hexane/acetone (starting from 19:1 and going down to 16:4) to acquire 280 mg of 1,2-diol 2f (0.99 mmol).
12. Confirm the identity of the 1,2-diol 2f by ¹H nuclear magnetic resonance spectroscopy (NMR) using CDCl₃ as solvent. For a 300 MHz NMR spectrometer, the ¹H NMR spectrum of the diol is as follows: δ =0.78 (t, 3H, J = 7.4 Hz), 0.87 (t, 3H, J = 7.3 Hz), 1.18-1.40 (m, 4H), 1.75-1.81 (m, 1H), 1.91 (s, 1H, OH), 3.12 (s, 1H, OH), 4.68 (d, 1H, J = 1.2 Hz), 7.19-7.37 (m, 6H), 7.44-7.46 (m, 2H), 7.61-7.63 (m, 2H).

3. Pinacol-reaction of Tetraphenyl-1,2-ethanediol (1) with Diethyl Ketone

1. Solve 366 mg of tetraphenyl-1,2-ethanediol (1,1 mmol) and 345 mg (423 μl) of diethyl ketone (4 mmol) in 3 ml dry dichloromethane.
2. Add 1 ml of the separately prepared titanium(IV) tert-butoxide/triethylchloro-silane solution (0.1 mmol). 
3. Stir the resulting mixture at RT in a sealed reaction tube.
4. Confirm the reaction is complete by thin layer chromatography (eluent: hexane/acetone, 9:1) on silica gel TLC plates (60 F254). The end of reaction is reached at the time, when tetraphenyl-1,2-ethanediol 1 cannot be detected (∼12 hr). The Rf of the product is 0.3 ¹⁴. 
5. Dilute the resulting reaction mixture with 50 ml of dichloromethane.
6. Wash the diluted reaction mixture successively by 20 ml saturated aqueous ammonium chloride and sodium carbonate solution in a separatory funnel.
7. Isolate the organic layer by a separatory funnel.
8. Dry the organic layer by stirring over dry magnesium sulfate.
9. Filtrate the suspension by a fluted paper filter and collect the filtrates. 
10. Remove dichloromethane in vacuo at 40 °C using a rotary evaporator (10-30 mmHg). Evaporation of volatile constituents will require 30 min.
11. Purify the remaining residue by flash column chromatography through a column of silica gel (0.035-0.070 mm, ACROS) with a gradient of hexane/acetone (starting from 19:1 and going down to 16:4) to acquire 250 mg of 1,2-diol 4f (0.93 mmol).
12. Confirm the identity of the product by ¹H nuclear magnetic resonance spectroscopy (NMR) using CDCl₃ as solvent. For a 300 MHz NMR spectrometer, the ¹H NMR spectrum of the diol 4f is as follows: δ = 0.92 (t, 6H, J = 7.6 Hz), 1.78 (m, 4H), 2.03 (s, 1H, OH), 2.83 (s, 1H, OH), 7.26-7.35 (m, 6H), 7.69-7.71 (m, 4H).

Results

In reactions of tetraphenyl-1,2-ethanediol 1 and acetone in the presence of catalytic amounts of titanium(IV)-alkoxides we observed the formation of 1,1-diphenyl-1,2-diol 4a and at the same time the formation of benzophenone 3 (Scheme 1). The corresponding symmetrical 1,2-diol formed by a competitive pinacol coupling of acetone was not detected. However, to obtain quantitative conversions extremely long and unacceptable reaction times were required under...

Discussion

An overall decrease in reaction times and higher yields is observed by deployment of electron-rich carbonyl compounds (compare entry 3 with 17, Table 1 or entry 19 with 13, Table 2). In addition, in reactions of ketones with bulky substituents a decrease in yields is observed under comparable conditions (compare entry 12 with 11, Table 2).

Although a wide range of carbonyl compounds can be applied in this novel pro...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
1,2-Dichloromethane	Sigma-Aldrich	319929
Titanium(IV) tert-butoxide	VWR International	200014-852
2-Ethylbutyraldehyde	Sigma-Aldrich	110094
Benzopinacol	Aldrich	B9807
Triethylchlorosilane	Aldrich	235067
Hexane, certified ACS	Fisher Scientific	H29220
Acetone, certified ACS	ACROS	42324
Ammonium chloride	ACROS	19997
Sodium hydrogen carbonate	ACROS	12336
Magnesium sulfate	ACROS	41348
Silica gel 60 F254 TLC plates	VWR International	1,057,140,001
Silica gel, 0.035-0.070 for flash-chromatography	ACROS	240360300