New opportunities for duff reaction

Article abstract of DOI:10.1007/s11178-005-0229-4

Reaction of 2,4-di-tert-butylphenol with urotropin in conditions of Duff reaction takes an abnormal route and instead of the expected di-tert-butylsalicylaldehyde provides a mixture of N-substituted 3,5-di-tert-butyl-2-hydroxybenzylamines and redox conjugate benzoxazines containing mostly 6,8-di-tert-butyl-3-(3,5-di-tert-butyl-2-hydroxybenzyl)-2H-3, 4-dihydrobenz[e][1,3]oxazine. A solvolysis of an individual benzoxazine in the system HO(CH₂)₂OH-H₂O-HCl affords di(3,5-di-tert-butyl-2-hydroxybenzyl)amine, and in AcOH 3,5-di-tert- butylsalicilaldehyde. A mechanism of Duff reaction was suggested involving the formation of a benzoxazine intermediate. 2005 Pleiades Publishing, Inc.

Full text of DOI:10.1007/s11178-005-0229-4

Russian Journal of Organic Chemistry, Vol. 41, No. 5, 2005, pp. 703-706. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 5, 2005,
pp. 718-721.
Original Russian Text Copyright Ó 2005 by Belostotskaya, Komissarova, Prokof’eva, Kurkovskaya, Vol’eva.
New Opportunities for Duff Reaction
I.S. Belostotskaya, N.L. Komissarova, T.I. Prokof’eva, L.N. Kurkovskaya, and V.B. Vol’eva
Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Moscow, 119991Russia
e-mail: komissarova@polymer.chph.ras.ru
Received June 1, 2004
Abstract—Reaction of 2,4-di-tert-butylphenol with urotropin in conditions of Duff reaction takes an abnormal
route and instead of the expected di-tert-butylsalicylaldehyde provides a mixture of N-substituted 3,5-di-tert-
butyl-2-hydroxybenzylamines and redox conjugate benzoxazines containing mostly 6,8-di-tert-butyl-3-(3,5-di-
tert-butyl-2-hydroxybenzyl)-2H-3,4-dihydrobenz[e][1,3]oxazine.A solvolysis of an individual benzoxazine in the
system HO(CH2)2OH–H2O–HCl affords di(3,5-di-tert-butyl-2-hydroxybenzyl)amine, and in AcOH 3,5-di-tert-
butylsalicilaldehyde. A mechanism of Duff reaction was suggested involving the formation of a benzoxazine
intermediate.
Duff reaction consisting in treating phenols with
urotropin at elevated temperature in ethylene glycol or
glycerol in the presence of H3BO3 underlies one of the
most convenient preparation methods for ortho-hydroxy-
substituted aromatic aldehydes [1]. Its mechanism and
the reason of the high regioselectivity are poorly under-
stood. Presumably the overall process involves a phenol
aminomethylation with iminomethane (CH2=NH) arising
through the thermal decomposition of the urotropin, the
oxidation of aminophenol with urotropin to give imine
followed by its hydrolysis[2].
In the course of the study of Duff reaction with 2,4-
di-tert-butylphenol (I) under standard conditions we found
that the expected 3,5-di-tert-butyl-2-hydroxybenzaldehyde
(II) was not a single or the main reaction product. Its
yield did not exceed 2%. The chromatographic analysis
of the reaction products revealed and afforded in a
preparative overall yield of around 80% two redox
conjugate couples of compounds: 2,4-(di-tert-butyl)-6-
dimethylaminomethylphenol (III), N-methyl-bis(3,5-di-
tert-butyl-2-hydroxybenzyl)amine (IV), and the cor-
responding substituted benzoxazines V and VI.
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1070-4280/05/4105-0703Ó2005 Pleiades Publishing, Inc.

BELOSTOTSKAYA et al.
704
The heating at higher temperature did not increase
reaction was reversible. The retroaminolmethylation is
probably one of the reasons of low yield of the
salicylaldehyde not exceeding usually 25–30%. The
complete conversion of phenol I at the use of 3–4-fold
urotropin excess is apparently due to the suppression of
the retroreaction.
the yield of aldehyde II, and below 100° the interaction
of phenol I resulted only in a formation of a molecular
complex with (CH2)6N4 in 1:1 ratio identical to that
arising at mixing equimolar amounts of phenol and
urotropin in an alcohol solution with subsequent removal
of the solvent. The transformations of the complex at
heating to 130–140°C furnished the same set of com-
pounds III– VI. This fact and also the character of
compounds III– VI where the nitrogen is linked to three
carbon atoms suggest that the urotropin decomposition
in the course of Duff reaction is not obligatory. The
reaction products arise in the direct reaction between
the phenol and the urotropin, and in the first stage of
reaction a molecular complex is formed. Theoretically
presumable is complexes formation with a stoichiometry
from 1:1 to 4:1. An important role in the stabilization of
their structure must play the hydrogen bonds between
phenol hydroxy groups and the nitrogen atoms of
urotropin. The formation of similar complexes from the
unsubstituted phenol and urotropin was established by
X-ray diffraction study [3]. The complexing makes
understandable the regioselectivity of the reaction and
facilitates the hydride shifts in the intermediates.
In the “normal” Duff reaction the presumed precursor
of the aldehyde is the imine originating from the
aminomethylphenol oxidation. In the event of phenol I
the oxidation products of aminomethylphenols III and
IV are benzoxazines V and VI. Thus the opportunity to
prepare aldehyde from phenol I by Duff procedure should
depend on the possibility to convert benzoxazines V and
VI into imines.
We previously established investigating the oxidation
of amine III with inorganic oxidants in various media
that benzoxazine V and aldehyde II formed in a neutral
(benzene) and acid (AcOH) media respectively [4]. It
was also observed that in AcOH a solvolytic conversion
of benzoxazine V into aldehyde II was possible. We
performed a conversion of benzoxazine VI into aldehyde
II by boiling in AcOH in the presence of urotropin.
Therewith the conversion occurred in AcOH without
urotropin at a considerably smaller rate.
Under standard conditions at a slight urotropin excess
(1:1.2) the prevailing product of the Duff reaction was
benzoxazine VI (yield 55%). On increasing the urotropin
excess to the three-fold level we obtained benzoxazine
VI in a 70% yield with a small amount of initial compound
I and traces of substances III–V as impurities. The
experimental results were independent of the presence
or absence of boric acid. The traces of III–V in the
reaction mixture suggest that they could have formed
intermediately and then transformed into benzoxazine VI.
Taking into account the data obtained it is presumable
that compounds like benzoxazines V and VI are common
intermedistes of the Duff reactuin, and the character of
the trial products is governed by the solvolytic stability of
the benzoxazine ring depending on the nature of the
medium. The “abnormal” Duff reaction found for phenol
I is apparently due to the stability of benzoxazine VI in
the neutral ethylene glycol. In reaction carried out in
AcOH the benzoxazine ring is able to open, and the
“normal” Duff reaction occurs furnishing aldehyde II,
and the intermediate formation of benzoxazine VI is
detected in the course of hte process by chromotography.
Actually, the authentic amine III heated with excess
urotropin transformed into benzoxazine VI. In the course
of reaction the formation of phenol I was detected
indicating that aminomethylation in the course of Duff
Noteworthy that formation of aldehyde II in AcOH
was inhibited by the presence of water: in 80% AcOH
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RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 5 2005

NEWOPPORTUNITIES FOR DUFF REACTION
705
the aldehyde yield decreased to 10%, and in 70%AcOH
Scheme 1.
the reaction was virtually stopped at the stage of
benzoxazine VI formation.Analogously in 85% HCOOH
the maximum (»5%) yield of benzoxazine VI was
obtained, and at higher water content alongside
benzoxazine VI also benzyl alcohol (VII) and traces of
dibenzylamine (VIII) were detected. Compounds VII
and VIII are solvolysis products of benzoxazine VI. This
fact was proved by heating a benzoxazine VI sample in
aqueous HCOOH or in ethylene glycol in the presence
of aqueous HCl (Scheme 1).
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[5].
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The solvent effect observed by an example of Duff
reaction with phenol I is apparently of general character
and is due to the possibility of alternative solvolytic
transformations of the benzoxazine intermediate. The key
point of these transformations is the opening of the
benzoxazine ring catalyzed by a proton affording
aminomethyl cation IX that may cleave with a loss of
a methylene unit (in the medium HCOOH–H2O) or may
undergo isomerization resulting from 1,3-hydride shift
giving iminium ion X (inAcOH), the direct precursor of
imine XI and aldehyde II (Scheme 2). Therefore the
urotropin role becomes understandable: it increases the
lifetime of ion IX and the possibility of its isomerization.
Ion X may be responsible for the appearance of side
products of Duff reaction methylated in the aromatic ring
9,,,
also to isolate it preparatively in reaction of equimolar
mixture phenol–urotropin in the presence of catalytic
quantity of AcOH under heating in a microwave oven.
Therefore the study of the “abnormal” Duff reaction
with phenol I provided a possibility to reveal details of
the reaction mechanism, and the stepwise performance
of the reaction with replacement of solvent extended its
synthetic opportunities. Therewith we succeeded to
increase the yield of the “normal” reaction product,
aldehyde II virtually to a quantitative value.
EXPERIMENTAL
1H NMR spectra were registered on a spectrometer
Bruker WH-250.
1
[5]. We succeeded to observe imine XI by H NMR
method when performing the reaction in AcOH, and
Scheme 2.
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RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 5 2005

BELOSTOTSKAYA et al.
706
Molecular complex of phenol I with urotropin.
added 0.46 g (1 mmol) of benzoxazine VI was heated
for 30 min at 130°C. On cooling the reaction mixture the
separated crystals of hydrochloride were filtered off,
washed with water, and dried; mp of amine VIII hydro-
chloride 231–232°C. To the hydrochloride obtained was
added dropwise at intermittent shaking under a layer of
ether a water solution of KOH. On evaporation of ether
we obtained 0.36 g (81%) of amine VIII, mp 153–154°C.
1H NMR spectrum (CDCl3), d, ppm (J, Hz): 1.29 s (18H,
t-Bu), 1.43 s (18H, t-Bu), 3.92 s (4H, CH2), 6.95 d (2H,
Ph, J 2.5), 7.25 d (2H, Ph, J 2.5). Found, %: C 79.00;
H 9.96. C30H47NO2. Calculated %: C 79.35; H 10.40.
In 20 ml of EtOH 0.41 g (2 mmol) of phenol I and 0.28
g (2 mmol) of urotropin was heated for 1 h. On evaporating
the solvent the precipitated crystals were recrystallized
from hexane, mp 82–83°C. 1H NMR spectrum CDCl3),
d, ppm (J, Hz): 1.29 s (9H, t-Bu), 1.41 s (9H, t-Bu),
4.73 s (12H, CH2), 6.56 d (1H, Ph, J 8.4), 7.07 d.d
(1H, Ph, 8.4, J 2.6), 7.29 d (1H, Ph, J 2.6).
Benzoxazine (VI) from 2,4-di-tert-butyl-6-di-
methylaminomethylphenol (III). A mixture of 0.9 g
(3.5 mmol) of amine III and 1 g (7 mmol) of urotropin
was heated in 50 ml of ethylene glycol for 45 min at
140–150°C. On cooling the reaction mixture was poured
in water, the reaction products were extracted into ether,
the extract was dried over MgSO4. On evaporating the
solvent to the oily residue methanol was added, and
crystals precipitated [6]. We obtained 0.6 g of benzoxazine
VI, yield 87%.
The study was carried out under the financial support
of the Russian Foundation for Basic Research (grant
no. 02-04-49452).
REFERENCES
1. Duff, J. and Bills, E., J. Chem. Soc., 1941, p. 547.
2. Komissarova, N.L., Belostotskaya, I.S., Shubina, O.V.,
Grishina, E.A., and Ershov, V.V., Zh. Org. Khim., 1992,
vol. 28, p. 188.
3. Knop, A. and Sheib, V., Fenol’nye smoly i materialy na ikh
osnove (Phenolic Resins and Matherials Based on Them),
Moscow: Khimiya, 1983, p. 68.
4. Belostotskaya, I.S., Vol’eva, V.B., Komissarova, N.L.,
Dekaprilevich, M.O., Khrustalev, V.N., Karmilov, A.Yu.,
Ershov, V.V., Izv. Akad. Nauk, Ser. Khim., 1997, p. 1328.
5. Duff, J. and Furness, V., J. Chem. Soc., 1951, p. 1512.
6. Komissarova, N.L., Belostotskaya, I.S., Shubina, O.V.,
Ershov, V.V., Voznesenskii, V.N., and Chervin, I.I., Izv. Akad.
Nauk SSSR, Ser. Khim., 1988, p. 2186.
7. Dokukina, M.A., Vol’eva, V.B., Belostotskaya, I.S.,
Komissarova, N.L., Karmilov, A.Yu., and Ershov, V.V., Izv.
Akad. Nauk, Ser. Khim., 1992, p. 2380.
Reaction of phenol I with urotropin. a. In a glacial
and in diluted acetic acid. A mixture 0.4 g (2 mmol) of
phenol I and 0.5 g (4 mmol) of urotropin was heated for
1 h in 50 ml of glacial ACOH. After treating the reaction
mixture with water, extraction of products with ether, and
evaporating the extract we obtained 0.33 g (67%) of
aldehyde II [7]. The heating of the mixture with the same
composition in 70% ACOH afforded 0.48 g (94%) of
benzoxazine VI.
b. In formic acid. Amixture 0.4 g (2 mmol) of phenol
I and 0.5 g (4 mmol) of urotropin was heated for 1 h in
50 ml of 85% formic acid. The precipitated crystals were
filtered off to obtain 0.44 g (95%) of benzoxazine VI.
Di(3,5-di-tert-butyl-2-hydroxybenzyl)-amine
(VIII). In ethylene glycol with 5 ml of hydrochloric acid
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 5 2005