Aldehydes from Grignard reagents with formic acid

from moo
(format & minor edits by metanoid)
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These belong to a new thread as they have little to do with Sommelet reaction.

Here is Tetrahedron Letters, 21, 2869-2872 (1980) scanned and OCR'ed:

Fumie Sato, Kaoru Oguro, Hiroshi Watanabe, and Masao Sato
Department of Synthetic Organic Chemistry, Faculty of Engineering
Kyoto University, Kyoto, Japan

Summary: Grignard reagents react with formic acid in tetrahydrofuran to produce aldehydes in relatively good yields. Various aldehydes such as alkyl, aryl, allyl, benzyl and vinyl aldehydes were prepared from the corresponding Grignard reagents. The reaction with vinyl Grignard reagents proceeded with retention of configuration.

Many methods have been reported for the preparation of aldehydes by the reactions of Grignard reagents with masked formic acid or formal derivatives1. However, the reaction with formic acid itself, which is obviously the most direct approach, was reported to afford aldehydes only in very low yields2,3, and, therefore, has not been used for aldehyde synthesis.

Recently, a striking solvent effect of THF on Grignard reactions with acid chlorides was observed. In marked contrast to the reaction in ether, the reaction in THF gave ketones almost quantitatively. This finding prompted us to reinvestigate the reaction of Grignard reagents with formic acid in THF in expectation of production of aldehydes in better yields than in ether.

In the preliminary investigation, the reaction of two moles of hexylmagnesium bromide with a mole of formic acid in THF was carried out, and a satisfactory yield (72%) of heptanal was obtained. However, rather suprisingly, heptanal was found to be produced in a 55% yield even when ether was used as the solvent. The yield was lower than for the reaction in THF but not so low as previously reported2,3. Though the precise reason is not clear, we believe that insufficient drying of formic acid was responsible for the low yield of aldehydes in the previous investigations.

In view of the potential economy of this aldehyde synthesis in THF, we decided to carry out the reaction which gives the magnesium salt of formic acid by treatment with an equimolar amount of a readily available Grignard reagent such as ethylmagnesium bromide, and then to treat the magnesium salt with one mole of the desired Grignard reagent as shown in eqs 1 and 2.

(1)HCOOH + C2H5 MgBr ---> HCOOMgBr + C2H6

(2) HCOOMgBr + RMgBr ---> HCR(OMgBr)2 ---H2O --> RCHO

In a representative procedure, ethylmagnesium bromide in THF (0.84 M; 16 ml, 13.4 mmol) was added dropwise (20 min) to a solution of formic acid (0.45 ml, 11.9 mmol) in dry THF (15 ml) while stirring under argon at 0°C. Hexylmagnesium bromide (0.79 M; 10.5 ml, 8.3 mmol) was then added (10 min) to this solution, and the reaction mixture was stirred for 30 min at room temperature. The reaction mixture was decomposed with 2N HCl, extracted with ether, dried over Na2 SO4 , and then distilled under reduced pressure (62°C, 35 Torr) to afford heptanal (0.72 g, 75% yield).

The presumed intermediate (1) seemed stable under the reaction conditions and was converted to aldehyde only by hydrolysis, as the 1H NMR analysis of the reaction mixture in THF showed no peak due to formyl protons before hydrolysis, whereas the peak appeared after the addition of 2N HCl to the sample in the NMR tube.

As illustrated by the entries in Table 1, the method can be readily extended to various Grignard reagents such as alkyl, aryl, benzyl, allyl and vinyl Grignard reagents. The listed yields were obtained using the above procedure without optimization for each substrate. It can be seen that the yields were satisfactory in all cases except for secondary aliphatic Grignard reagents. The reaction with vinylic Grignard reagents followed by hydrolysis under neutral conditions (by addition of H2O)8 afforded an alpha,beta-unsaturated aldehyde with the same stereoconfiguration as the starting Grignard reagents, indicating that the reaction of vinylic Grignard reagents with formic acid proceeds with retention of configuration. Unfortunately, even if a Grignard reagent is prepared from a pure (E) or (Z)-1-alkenyl halide, it becomes a mixture of (E) and (Z)-1-alkenyl- magnesium halides9,10,11. Therefore, pure (E) and (Z)-2-alkenals could not be obtained directly. However, as (Z)-2-alkenal is easily isomerized to the stable (E)-isomer by acid, pure (E)-2-alkenal may be obtained easily by the present method. Thus, pure (E)-cinnamaldehyde was prepared from the Grignard reagent from either (E) or (Z)-beta-bromostyrene by hydrolysis with 2N HCl after the reaction. Most aldehyde syntheses by the reactions of Grignard reagents with formic acid derivatives in the literatures need the acidic hydrolysis step. Therefore, it seems difficult to prepare (Z)-2-alkenals by these methods. Therefore, it is important to note that the present aldehyde synthesis makes it possible to prepare (Z)-2-alkenals from (Z)-l-alkenylmagnesium halides from either (E) or (Z)-beta-bromostyrene by hydrolysis with 2N HCl after the reaction. Most aldehyde syntheses by the reactions of Grignard reagents with formic acid derivatives in the literatures need the acidic hydrolysis step. Therefore, it seems difficult to prepare (Z)-2-alkenals by these methods. Therefore, it is important to note that the present aldehyde synthesis makes it possible to prepare (Z)-2-alkenals from (Z)-l-alkenylmagnesium halides.

RMgBr RCHO Yield %
C6H13MgBr C6H13CHO 75
C8 H17 MgBr C8 H17 MgBrCHO 70
C3 H7 CH(CH3 )MgBr C3 H7 CH(CH3 )CHO 38
BrMg-(CH2)4-MgBr OHC-(CH2)4-CHO 55
C6H5MgBr C6H5CHO 81
E/Z = 15/85
E/Z = 65/35
E/Z = 16/84
E/Z == 65/35

E/Z = 89/ll
E/Z = 87/13

References and Notes

1 For a recent review, see C.A. Buehler and D.E. Pearson, "Survey of Organic Syntheses" vol
2 N.D. Zeiinsky, Chem. Ztg., 28, 303 (1904).
3 J. Houben, Chem. Ztg., 29, 667 (1905).
4 L.I. Smith and J. Nichols, J. Org. Chem., 6, 489 (1941).
5 F. Sato, M. Inoue, K. Oguro. and M. Sato, Tetrahedron Lett., 4303 (1979).
6 Formic acid dried over boric acid anhydride by the method of Schlesinger and Martin was
7 H.I. Schlesinger and A.W. Martin, J. Amer. Chem. Soc., 36, 1590 (1914).
8 Instead of 2N HC1, H2O was used for hydrolysis in the case of vinylic Grignard reagents;
9 B. Mechin and N. Naulet, J. Organometal. Chem., 39, 229 (1972).
10 T. Yoshino and Y. Manabe. J. Amer. Chem. Soc., 85, 2860 (1963). T. Yoshino, Y. Manabe, and Y. Kikuchi, J. Amer. Chem. Soc., 86, 4670 (1964).
11 G.J. Martin and M.L. Martin, Bull. Soc. Chem., 1636 (1966).
12 R.A. Raphael and F. Sondheimer, J. Chem. Soc., 2693 (1951).

I also found this.

Tetrahedron Letters, 25, 1843-1844 (1984):

FORMYLATION OF ORGANOMETALLIC COMPOUNDS WITH LITHIUM (OR SODIUM) FORMATE. PART I. A FACILE SYNTHESIS OF ALDEHYDES FROM GRIGNARD REAGENT M. Bogavac, L. Arsenijevic, S. Pavlov and V. Arsenijevic Department of Organic Chemistry, Faculty of Pharmacy Belgrade, Yugoslavia Summary: Grignard reagent reacts with lithium (or sodium) formate in boiling THF giving the corresponding aldehydes in good yields. This reaction can be carried out at room temperature as well, but stirring of the reaction mixture for two or three days is required.

Aldehydes can be obtained by the reaction of Grignard reagent with a variety of compounds1 and, recently, with several N-formyl amines2-4. Some of this formamides give the aldehydes free of secondary alcohol by-product. It has been also shown that aldehydes can, be prepared in good yields by the reaction of scrupulously anhydrous formic acid with two moles of Grignard reagent, provided the reaction is carried out in THF solution5. The earlier described synthesis of aldehydes from formic acid [or copper(II) formate] and Grignard reagents, on account of low yields, was of no preparative value6,7.

In this paper we have investigated the possibility of avoiding the use of formic acid (the drying of this acid is a rather tedious process) and have found that the formylation of Grignard reagent with lithium or sodium formate is very convenient, one pot procedure, and gives aldehydes without secondary alcohol as by-product ; also, in this reaction only one mole of Grignard reagent is used and the transfer of the reagent to the dropping funnel is unnecessary. These salts are commercially available or may be easily prepared in the laboratory.

Alkaline salts of formic acid are very slightly soluble in THF, but on heating, they react with Grignard reagent whereby the latter is added to the formate carbonyl group. If the reaction is carried out in ether, the yields are considerably lower, even after refluxing the reaction mixture for three days. If a mixture of ether and THF (1:2) is applied, the yields are approximately the same as those obtained in THF, but a longer heating is required ; this is significant in cases when it is more convenient to prepare Grignard reagent in ethereal than in THF solution.

Representative procedure: to 0.192 mole of Grignard reagent (prepared from 4.8 g of magnesium, 37.4 g of 2-bromoanisol and 200 ml of THF), 11.5 g (0.22 mole) of lithium formate is added and the reaction mixture is heated with boiling in a nitrogen atmosphere until an almost clear solution is obtained (about 2 h), the major part of THF is removed by distillation, 100 ml of ether and about 0.1 g of hydroquinone are added to the residue, and the reaction mixture is decomposed with dilute HCl (cooled to 0°). 2-Methoxybenzaldehyde is isolated in usual way and distilled under nitrogen: bp 114°C/17 mmHg, mp 36-7°C. The yield is 23 g (85%).

Entry RMgBr(Cl)8 R-CHO Yield %
1. C6H5MgBr C6H5CHO 85 79
2. C6H5MgCl* C6H5CHO 80 72
3. o-CH3OC6H4MgBr o-CH3OC6H4CHO 85 76
4. (CH3)2CHMgCl (CH3)2CHCHO 80 75
5. p-BrC6H4MgBr p-BrC6H4CHO 83 69
6. C6H5CH2MgCl C6H5CH2CHO 79
7. 1-Naphthyl-MgBr 1-Naphthaldehyde 78
* Prepared according to H. Normant8.


1 R.S. Brinkmeyer, E.W. Collington, A.I. Meyers, Org. Synth., 54, 42 (1974) and references therein.
2 D. Comins, A.I. Meyers, Synthesis, 403 (1978).
5 G.A. Olah, M. Arvanaghi, Angew. Chem., 93, (1981), 925.
4 W. Amaratunga, M.I. Erechet, Tetrahedron Lett., 24, 1143 (1983).
5 F. Sato, M. Inoue, K. Oguro, M. Sato, Tetrahedron Lett., 21, 2869 (1980).
6 N.D. Zelinsky, Chem. Ztg., 28, 303 (1904).
7 J. Houben, Chem. Ztg., 29, 667 (1905).
8 H. Normant, Bull. Soc. Chim. Fr., 728 (1957).

This one from hermanroempp (format & minor edits by metanoid)


To a solution of 5.47g (119 mmol) of anhydrous formic acid in 150 ml anhydrous THF under an atmosphere of nitrogen a solution of ethylmagnesium bromide, prepared from 14.6 g (134 mmol) ethyl bromide and 3.26g (134 mmol) magnesium turnings in 160 ml THF, is added during the course of 2h with constant stirring at 0-2°C. At the same temperature then a solution of n-heptylmagnesium bromide, prepared from 14.9g (82.2 mmol) and 2.02g (83.2 mmol) magnesium turnings in 110 ml THF is added with stirring during the course of 1h. The solution is stirred for another 2h at room temperature.

The batch is then hydrolysed by adding 100 ml of 2M HCl and extracted by shaking with 400 ml Et2O (in a sep funnel). The organic phase is washed with saturated NaCl solution and then dried over Na2SO4. The solvent is removed under a weak vacuum and the remaining oil is purified by fractional distillation.

Yield 7.45g (70 % of the theory) of octanal, b.p.(13 Torr) = 62-65°C, nD20 = 1.4207

Note: Anhydrous formic acid is obtained by drying over anhydrous copper sulfate and distillation of the pre-dried acid, b.p.(760 Torr)= 100-101°C.

Aldehyde synthesis by addition of a Grignard compound R-MgX to the magnesium bromide salt of formic acid (generated from formic acid + ethylmagnesium bromide) and subsequent hydrolysis. The use of THF as solvent is essential for this kind of synthesis.

[Translated from:
Tietze-Eicher: "Reaktionen und Synthesen im organisch-chemischen Praktikum", p. 93, 1981, Thieme-Verlag, Stuttgart; New York]

Italics hermanroempp's