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REINVESTIGATION OF THE GRIGNARD REACTIONS WITH FORMIC ACID.
A CONVENIENT METHOD FOR PREPARATION OF ALDEHYDES

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 yields^2,3, 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 reported^2,3. 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 + C₂H₅MgBr  --->  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 Na₂SO₄, 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 halides^9,10,11. 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.

TABLE 1
-------------------------------------------------------
RMgBr			RCHO			Yield %
-------------------------------------------------------
C6H13MgBr		C6H13CHO		75
C8H17MgBr		C8H17MgBrCHO		70
C3H7CH(CH3)MgBr		C3H7CH(CH3)CHO		38
BrMg-(CH2)4-MgBr	OHC-(CH2)4-CHO		55
C6H5MgBr		C6H5CHO			81
C6H5CH2MgBr		C6H5CH2CHO		61
C3H7-CH=CH-CH2MgBr	C3H7-CH(CHO)-CH=CH2	50
C4H9-CH=CH-MgBr		C4H9-CH=CH-CHO
	E/Z = 15/85		E/Z = 16/84	60
	E/Z = 65/35		E/Z == 65/35	58
C6H5-CH=CH-MgBr		C6H5-CH=CH-CHO
	E/Z = 89/ll	E/Z = 87/13		67
-------------------------------------------------------

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).

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I also found this. Tetrahedron Letters, 25, 1843-1844 (1984):

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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
amines^2-4. 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 value^6-7.
        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 %
					HCOOLi	HCOONa
--------------------------------------------------------------
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-Naphthaldehyd	78	
8.	C6H5CH=CHMgBr	C6H5CH=CHCHO	72
--------------------------------------------------------------
*)Prepared according to H. Normant8.

References
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).

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