Formylation of phenols using formamidine acetate

Article abstract of DOI:10.1039/c6ob02727j

We report a new method to formylate phenol derivatives using formamidine acetate and acetic anhydride. This general-purpose transformation is a significant improvement over many other methods and does not require high temperatures or the addition of strong acid or base. Mono-, di-, and tri-formylated product can be obtained, depending on the substrate and conditions used.

Full text of DOI:10.1039/c6ob02727j

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Formylation of phenols using formamidine
acetate†
Cite this: DOI: 10.1039/c6ob02727j
S. Hessam M. Mehr,a Hannah Depmeier,a,b Katsuya Fukuyama,c
Received 25th November 2016,
Accepted 14th December 2016
Mahboobeh Maghamia and Mark J. MacLachlan*a
DOI: 10.1039/c6ob02727j
www.rsc.org/obc
We report a new method to formylate phenol derivatives using Gattermann reaction, but the toxic reagent and harsh con-
formamidine acetate and acetic anhydride. This general-purpose ditions required make the Gattermann reaction impractical.
transformation is a significant improvement over many other Furthermore, the familiar Reimer–Tiemann reaction15,16 often
methods and does not require high temperatures or the addition yields large amounts of non-aromatic, ring-expanded, and
of strong acid or base. Mono-, di-, and tri-formylated product can polymeric side products, resulting in poor yield of formylated
be obtained, depending on the substrate and conditions used.
product.17 Finally, the otherwise efficient preparation of salicyl-
aldehydes from phenols and paraformaldehyde reported by
Casnati et al.,18 Casiraghi et al.19 and Skattebøl20 has not
proven effective in introducing more than one formyl group on
an aromatic ring.
Aromatic aldehydes are convenient building blocks in syn-
thetic and materials chemistry as well as for pharmaceuticals
and biological systems. They are highly valued as inter-
mediates in chemistry, thanks to their excellent reactivity
toward nucleophiles and redox reagents.1,2 The facile acti-
vation of aldehydes has enabled many of their applications,
such as their use in self-assembled macrocycles3–7 and
covalent organic frameworks (COFs).8–14 This versatility comes
at a price, however, as their preparation is often complicated
by the fragile nature of the aldehyde product.
The above limitation is particularly troubling in the trans-
formation of phenols to salicylaldehydes, where oxidation reac-
tions often lead to substrate degradation. Further, syntheses
based on metalation require protection and deprotection
of the hydroxyl groups. Hence, direct formylation of phenols
is often only possible through electrophilic aromatic
substitution.
State-of-the-art formylation methods rely on iminium
species as a stable equivalent to formyl electrophiles. Best
known among these is the Vilsmeier–Haack reaction,21,22
where a chloroiminium intermediate acts as formylating
agent, Scheme 1a. The deactivating, positively-charged
iminium intermediate, e.g. 2, produced in this reaction limits
its ability to produce multiple formylations in a single step.23
Substrate deactivation, along with the use of highly reactive
POCl3/SOCl2 reagent, can also result in the formation of chlori-
nated side-products.24–26
The Duff reaction,27–30 Scheme 1b, mitigates the de-
activating effect of iminium substituents by initially introdu-
cing them as aminomethyl groups that are subsequently
Whereas ketone analogues of salicylaldehydes are easily
prepared using Friedel–Crafts acylation, the same method-
ology cannot be used in the case of aldehydes since formyl
halides and the putative formylium ion, HCO+, both decom-
pose with the formation of carbon monoxide. This instability
can be overcome by using HCN as a CO surrogate, as in the
aDepartment of Chemistry, University of British Columbia, 2036 Main Mall,
Vancouver, BC V6T 1Z1, Canada. E-mail: mmaclach@chem.ubc.ca
bDepartment of Pharmaceutical Chemistry, Technische Hochschule Köln,
CHEMPARK, Kaiser-Wilhelm-Allee, 51368 Leverkusen, Germany
cCenter for Liberal Arts, Meiji Gakuin University, Yokohama 244-8539, Japan
†Electronic supplementary information (ESI) available: Detailed formylation
procedure, purification steps and full characterization of products. See DOI:
10.1039/c6ob02727j
Scheme 1 Vilsmeier–Haack (a) and Duff (b) formylation of phloro-
glucinol, 1.
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Table 1 Formamidine acetate–acetic anhydride formylation of various
phenols
oxidized to iminiums through hydride transfer under the con-
ditions of the reaction. Although this reaction is effective for
many substrates, formation of polymeric side-products compli-
cates its application to highly reactive substrates like phloro-
glucinol, 1. Thus, state-of-the-art procedures to formylate 1
require a large excess of expensive CF3CO2H, and give a low
yield of 15%.
In our recent work to find an improved preparation of 2,4,6-
triformylphloroglucinol (TFP), a molecule that has proven
useful for liquid crystals,31 COFs,32,33 and other materials,34–39
we found that a method originally proposed for the formylation
of anilines40 can bring about efficient formylation of phenols,
Scheme 2. This method uses acetic anhydride and formamidine
acetate, 3, which is commercially available and easily prepared
from triethyl orthoformate.41 We have since optimized the reac-
tion conditions to effect the multiple formylation of a variety of
phenols in high yield and under mild conditions.
Compared to the iminium substituents encountered in
Vilsmeier intermediates, the CH(NHAc)2 groups in intermedi-
ate 4 are less deactivating, explaining the improved access to
compounds with multiple formyl groups using this method.
Except for acetic acid, which is produced as a byproduct,
strong acids and bases are avoided, allowing the use of sensi-
tive substrates.
Table 1 describes the formylation of a number of phenol
derivatives using the present method. In exploring the scope
of this reaction, we used it in challenging aldehyde syntheses,
some inspired by our previous experience with Schiff-base pre-
cursors. For instance, the state-of-the-art procedures for com-
pounds 8 and 9 use the Duff reaction and give poor yields
(22% and 10%, respectively).42–44 Similarly, the preparation of
11 was previously accomplished in a four-step synthesis involv-
ing protection and deprotection of the OH groups.45
F.A.a
equiv.
Ac2O
equiv.
Yield
(%)
Product
Solvent
Temp.
Duration
5
8
4
4
5
5
4
8
8
16
8
8
10
10
8
16
16
Dioxaneb
THF
THF
100 °C
85 °Cc
55 °C
45 °C
95 °C
95 °C
95 °C
95 °C
48 h
24 h
24 h
24 h
72 h
48 h
48 h
48 h
69
82
80
51
51
76
52
89
6
7d
8
THF
9
Dioxaneb
Dioxaneb
Dioxaneb
Dioxaneb
10
11
12
We attempted the formylation of 1,3-dimethoxybenzene
and 1,3,5-trimethoxybenzene under similar conditions to
those used for the preparation of 6 and 8 but found that these
substrates were substantially less reactive. Thus, the presence
of the hydroxyl group seems to be essential for facile formyla-
tion. Moreover, formylation occurred in the ortho position rela-
tive to the hydroxyls for all substrates—no p-formyl products
were observed.
a Formamidine acetate. b 1,4-Dioxane. c Reaction carried out above
boiling point pf solvent in a bomb. d Yield of 7 using the Duff pro-
cedure is 44%.46
In summary, formylation reactions using formamidine
acetate and acetic anhydride address some of the main short-
comings of the Vilsmeier and Duff procedures. Namely, harsh
conditions and deactivating iminium intermediates are
avoided, enabling efficient multiple formylation without the
complication of side reactions. The efficiency of the present
route makes it the method of choice for the preparation of a
wide variety of formylated phenols, as demonstrated with
several interesting examples here. We anticipate that this
method of formylation will be of considerable use for chemists.
We thank NSERC for funding this research (Discovery
Grant).
Notes and references
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Scheme 2 Formylation of
acetate and acetic anhydride.
a phenol derivative using formamidine
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