Anionic, in situ generation of formaldehyde: A very useful and versatile tool in synthesis

Article abstract of DOI:10.1021/ol070145b

(Chemical Equation Presented) A very simple, safe and powerful method for the in situ generation of formaldehyde at low temperature in anhydrous conditions is described. This new tool avoids the use of gaseous formaldehyde and is suitable for basic carbon nucleophiles which cannot be generated in aqueous reaction media. Various substrates, including organolithium reagents and enolates, underwent smooth hydroxymethylation showing the versatility of this process. A Wittig reaction was also carried out in high yield.

Full text of DOI:10.1021/ol070145b

ORGANIC
LETTERS
2007
Vol. 9, No. 6
1165-1167
Anionic, in Situ Generation of
Formaldehyde: A Very Useful and
Versatile Tool in Synthesis
Geoffrey Deguest, Laurent Bischoff,* Corinne Fruit, and Francis Marsais
Laboratoire de Chimie Organique Fine et He´te´rocyclique, CNRS UMR 6014,
IRCOF-INSA Rouen, B.P. 08, 76131 Mont-Saint-Aignan, France
laurent.bischoff@insa-rouen.fr
Received January 19, 2007
ABSTRACT
A very simple, safe and powerful method for the in situ generation of formaldehyde at low temperature in anhydrous conditions is described.
This new tool avoids the use of gaseous formaldehyde and is suitable for basic carbon nucleophiles which cannot be generated in aqueous
reaction media. Various substrates, including organolithium reagents and enolates, underwent smooth hydroxymethylation showing the versatility
of this process. A Wittig reaction was also carried out in high yield.
Formaldehyde is a widespread reagent in chemistry, though
its availability as a pure material is very limited. Except
aqueous solutions (“formalin”), in which the aldehyde is
predominantly under its hydrate structure, formaldehyde is
generally generated from its poorly reactive polymeric
precursors (i.e., trioxane or polyoxomethylene). Both oxida-
tive synthesis from methanol1 and depolymerisation2 can be
performed one pot or in a separate vessel. Thermal cracking
however produces self-reactive and highly toxic gaseous
formaldehyde.
would afford a large choice of leaving groups with a possible
modulation of their stabilities as anionic species. Mechanistic
considerations led us to choose X among acids X-H
exhibiting pKa values presumably lower than their alcohol
X-CH2OH precursors. Favoring cleavage of X-CH2O- with
concomitant release of formaldehyde would be effective only
if the leaving group X- is more stable than the alcoolate
(Scheme 1). For this purpose, we focused our attention
We wish to report herein an extremely simple, safe and
very versatile method for the in situ generation of anhydrous
formaldehyde in organic solvents. This method proceeds
under basic conditions, allowing subsequent hydroxymeth-
ylation of carbanionic structures such as organometallics or
enolates.
Scheme 1. Alkaline Generation of Formaldehyde
Structures such as X-CH2OH are stable, provided that X
has a restrained leaving group ability. Nitrogen moieties
(1) For an in situ formaldehyde production process from methanol, see:
Shreiber, E.H.; Roberts, G.W. Chem. Ind. 2001, 82, 391.
(2) Numerous examples account for the use of gaseous formaldehyde.
For a recent device for continuous production by trioxane cracking, see:
Kachi, H.; He, F.; Sakamoto, K. Chem. Express 1990, 5, 701.
toward benzotriazolylmethanol Bt-CH2-OH 1, a com-
mercially available reagent developed by Katritzky’s group,3
10.1021/ol070145b CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/20/2007

and N-hydroxymethyl phtalimide 2.4 Both have comparable
pKa values around 8.35 and were expected to exhibit similar
reactivities. We propose this mechanism rather than a
nucleophilic attack at the deprotonated reagent on the basis
of the electrophilic trapping of phtalimide generated in this
way4 and on the observation that only benzotriazole or
phtalimide could be recovered from the crude materials. Both
reagents are generally involved in reactions providing the
C-O bond cleavage, (e.g., amino or amidomethylation
reactions).3 The straight cleavage of the N-C bond remains,
in our knowledge, unexplored for synthetic uses of formal-
dehyde itself.
Initial experiments were aimed at screening the reactivity
of BtCH2OH toward alkyllithium models. Starting with a
2-fold excess of n-hexyllithium or 2-pyridyllithium, treatment
of BtCH2OH led to hydroxymethylation products with
respectively 32% and 40% yields. Those yields were
calculated from the amount of organometallic reagent, which
is half-consumed during the deprotonation step. A similar
yield was obtained with phenethylmagnesium chloride at
room temperature, leading to phenylpropanol with a 33%
yield.
Figure 2. Simultaneous generation of nucleophile and formalde-
hyde.
of view, the use of LDA allowed easy diisopropylamine
removal by evaporation from the crude material. Further-
more, simple workup with water avoided the reprotonation
of benzotriazole or phtalimide lithium salt, the latter being
discarded in aqueous extracts.
This procedure was first successfully applied to pyridines
substituted with an ortho-directing group, such as 2-bro-
mopyridine6 or tertiary nicotinamides7 (Table 1, entries 1
and 2), providing a straightforward access to hydroxy-
methylated pyridines, which are more classically synthesized
by a two step formylation-reduction sequence.8
In order to avoid unnecessary consumption of the nucleo-
philic organolithium reagent during the deprotonation step,
lithium tetramethylpiperidide 3 (LiTMP) was added (Figure
1). We found that a combination of LiTMP and BtCH2OH
Table 1. Examining the Scope of Hydroxymethylation
Reactions under Conditions of Figure 2, i.e., 3 LiTMP/2
BtCH2OH
Figure 1. Optimizing molar ratio of reagent.
(2 molar equiv of each) gave a better yield for this reaction.
These encouraging results led us to explore the possibility
to use a single base to generate both the nucleophilic species
and formaldehyde. This method should be particularly
adapted for compounds that cannot undergo deprotonation
in aqueous conditions, such as precursors of unstabilised
enolates or heteroaromatic anions.
As depicted in Figure 2, the simultaneous formation of
the anionic nucleophile and X-CH2O- was carried out. Two
molar equivalents of BtCH2OH or N-hydroxymethylphtal-
imide and a 3-fold excess of an amide base, either LiTMP
or lithium diisopropylamide (LDA), afforded very clean
hydroxymethylation reactions within 1 h at -78 °C in
anhydrous THF. Decreasing the amount of BtCH2OH and
base resulted in lower yields. From an experimental point
(3) For an exhaustive review on this reagent, see Katritzky, A. R.; Manju,
K.; Singh, S. K.; Meher, N. K. Tetrahedron 2005, 61, 2555 and references
cited therein.
(4) Cul, A.; Chihab-Eddine, A.; Pesquet, A.; Marchalin, S.; Daich, A. J.
Heterocycl. Chem. 2003, 40, 499.
b
a N-hydroxymethylphtalimide was used instead of BtCH2OH; depro-
c
tonation with LDA instead of LiTMP; deprotonation with t-BuOK.
(5) Reboud-Ravaux, M. J. Am. Chem. Soc. 1980, 102, 1039.
1166
Org. Lett., Vol. 9, No. 6, 2007

Application of this optimized procedure to a selection of
widely used enolates gave promising results (entries 3-7).
Interestingly, the trapping of formaldehyde by the enolate
afforded the corresponding alcoolate without any possibility
of subsequent reprotonation.
and the phosphorus ylide were generated in situ and the
desired alkene was isolated with a good yield (Figure 3).
Indeed, no side-reaction, such as dehydration or double
hydroxymethylation was observed, except for entry 4. In this
case, R-tetralone is highly enolizable and we suspected the
formation of a dianionic species after the first hydroxy-
methylation. Interestingly, for this example the use of
potassium t-butoxide instead of a hindered amide base
afforded clean double hydroxymethylation (entry 5). Sub-
strates yielding strongly basic anions, generated from phe-
nylmethyl sulfone, picoline, or phenylacetylene (entries
8-10) were also studied to enhance the scope of the
hydroxymethylation reaction. These conditions led to the
same smooth and clean reaction, though with lower yields,
presumably due to equilibrated deprotonations. It is worth
noting, that the hydroxymethylation of a dithiane (entry 11),
affords a simple access to a R-hydroxyketone synthon.
Similarly, indole lithium salt could be used as a nitrogen
nucleophile, thus allowing its N-hydroxymethyl-
ation.
Figure 3. Wittig olefination with in situ-generated formaldehyde.
This makes our method a convenient tool for a reversed
synthesis of those alkenes, since the latter are generally
prepared from the aromatic aldehyde and methylene ylide.
As a conclusion, we have developed a highly efficient and
extremely simple, safe, and cheap method for the straight-
forward introduction of an unprotected hydroxymethyl group
onto carbon nucleophiles, and further uses of formaldehyde
such as N-hydroxymethylation or Wittig olefination. This
method advantageously avoids not only the use of poorly
reactive formaldehyde polymers, but also the risks inherent
to thermal generation of hazardous gaseous formaldehyde,
or the use of toxic chloromethyl ethers which would require
a subsequent deprotection step. Such procedure is of high
interest for the introduction of hydroxymethyl group onto
strongly basic anionic species and it is therefore a very
convenient tool in synthesis.
As far as the choice of the X group was concerned, similar
yields were obtained when BtCH2OH was replaced with
N-hydroxymethylphtalimide, as illustrated by representative
examples (Table 1, entries 3, 4 and 8). Both reagents exhibit
comparable behavior in this reaction.
Acknowledgment. G.D. is grateful to the MENESR for
a grant. Dr. Christian Montalbetti (Evotec, U.K.) is gratefully
acknowledged for fruitful discussions.
Further extension of this methodology was applied to a
Wittig olefination. Under our conditions, both formaldehyde
(6) (a) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew.
Chem., Int. Ed. 2004, 43, 2206. (b) Mongin, F.; Queguiner, G. Tetrahedron
2001, 57, 4059.
(7) (a) Epsztajn, J.; Brzezinski, J. Z.; Jo´zwiak, A. J. Chem. Res., Synop.
1986, 18, 18. (b) Deguest, G.; Devineau, A.; Bischoff, L.; Fruit, C.; Marsais,
F. Org. Lett. 2006, 8, 5889.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(8) Srinivasan, J. M.; Burks, H. E.; Smith, C. R.; Viswanathan, R.;
Johnston, J. N. Synthesis 2005, 2, 330.
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