One-pot migration-formylation of benzyl aryl ethers under Duff reaction condition

Article abstract of DOI:10.1016/j.tetlet.2013.06.133

A one-pot migration-formylation of benzyl aryl ethers under Duff reaction condition is described. The reaction was performed with HMTA (hexamethylene tetramine) and TFA (trifluoroacetic acid). Under the optimal reaction conditions, a variety of Bn and PMB ethers underwent ortho rearrangement.

Full text of DOI:10.1016/j.tetlet.2013.06.133

Tetrahedron Letters 54 (2013) 4789–4792
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Tetrahedron Letters
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One-pot migration–formylation of benzyl aryl ethers under Duff
reaction condition
⇑
Subhash P. Chavan , Pradeep B. Lasonkar
Division of Organic Chemistry, CSIR-NCL (National Chemical Laboratory), Pune 411008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot migration–formylation of benzyl aryl ethers under Duff reaction condition is described. The
reaction was performed with HMTA (hexamethylene tetramine) and TFA (trifluoroacetic acid). Under
the optimal reaction conditions, a variety of Bn and PMB ethers underwent ortho rearrangement.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 15 May 2013
Revised 25 June 2013
Accepted 26 June 2013
Available online 4 July 2013
Keywords:
One-pot
ortho Rearrangement
Duff reaction
Hexamethylene tetramine
Benzyl aryl ethers
3,5-Disubstituted salicylaldehydes have been shown to possess
interesting pharmacological properties and find usage in interest-
ing environmental applications. They also have great significance
in synthetic organic chemistry, particularly in the area of asym-
metric synthesis as salen ligands, which are combination of amines
with 3,5-disubstituted salicylaldehyde.1 For example, several
asymmetric diiron complexes have been synthesized2 from substi-
tuted salicylaldehyde, and these complexes mimic the spectro-
scopic properties of purple acid phosphatase enzymes. The use of
bifunctional ligand systems is an attractive method of simulating
the reactivity of natural enzymes.3 They are also precursors to
Schiff-base macrocycles. Duff and Bills reported formylation of
phenolic compounds using hexamethylene tetramine,4 which
was later modified by Smith.5 The Duff protocol for formylation
of structurally and electronically demanding phenols has become
an important tool in the arsenal of synthetic chemists.6
We describe herein a facile one-pot migration–formylation,
when aryl benzyl ethers were subjected to Duff reaction condi-
tions. The rearrangement shown above in Scheme 1 was observed
when we subjected 1a (Table 1) for formylation under Duff reac-
tion condition, wherein 1a was found to undergo smooth ortho
rearrangement as well as formylation. The ortho rearrangement
was mediated by TFA7 followed by the formylation on the electron-
ically rich phenolic ring. To the best of our knowledge, there is no
report on ortho rearrangement and formylation in one pot.
O
OH
R
O
H
HMTA, TFA
80 °C
R
R=Br, CHO, tBu,
CH2COOCH3
Scheme 1. One-pot migration–formylation of benzyl aryl ethers.
To optimize the reaction conditions (Table 1), we replaced the
solvent TFA with other acids like acetic acid, methanesulfonic acid
and triflic acid wherein we found that in acetic acid starting mate-
rial was recovered and in comparatively more acidic condition like
triflic acid or methanesulfonic acid, starting material got decom-
posed. We also varied the formylating agent and performed the
reaction with paraformaldehyde and formalin but no product for-
mation was observed in the presence of TFA. The stoichiometry
of hexamethylene tetramine and also the amount of trifluoroacetic
acid used were also varied. We found that 2 equiv of hexamethyl-
ene tetramine and 3–4 mL of trifluoroacetic acid were needed per
mmol of the benzyl aryl ethers for optimal results.
Having established the protocol, scope and limitations studies
were conducted (Table 2). First, it was decided to examine the
effect of substitution on the phenolic ring. Compound 1a bearing
carbomethoxy methyl at para position to the phenolic group, was
found to undergo smooth ortho rearrangement and formylation
in 3 h with 70% yield after purification by column chromatography.
⇑
Corresponding author. Fax: +91 20 5892629.
E-mail address: sp.chavan@ncl.res.in (S.P. Chavan).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.133

4790
S. P. Chavan, P. B. Lasonkar / Tetrahedron Letters 54 (2013) 4789–4792
Table 1
comparatively lower yield and took longer time for the consump-
Optimization of reaction conditions
tion of starting material. Secondly, it was decided to examine the
effect of substitution on the migrating benzyl ring. Accordingly,
when we subjected compound 1g bearing para methoxybenzyl
ether (Table 2, entry 7) to the optimal reaction conditions, it also
underwent ortho rearrangement and formylation on both the rings
to afford compound 2g. Analysis of the 1H NMR of 2g showed the
presence of two formyl groups in the molecule. After careful exam-
ination of NMR it was concluded that the migrating para-methoxy-
benzyl ring also gets formylated. When we subjected compound 1i
bearing para nitrobenzyl ether (Table 2, entry 9) to study the effect
of the electron withdrawing group on the benzyl ring under the
similar reaction conditions, we found that the benzyl group gets
deprotected leading to the formation of para nitrobenzyl alcohol.
We believe that the migration–formylation proceeds via the
reaction pathway illustrated in Scheme 2. Under acidic condition,
the benzyloxy group gets protonated to form free phenol and ben-
zyl cation. The benzyl cation thus generated is concomitantly cap-
tured by phenol in a Friedel–Crafts fashion to form 2-benzyl
phenol.8 This mechanism is in good agreement with that proposed
by Seoane and Sagrera.9 Addition of phenol to imine, which was
generated in situ from HMTA and TFA, preferentially undergoes
electrophilic substitution reaction at the ortho-position of –OH, in
a Mannich fashion, followed by hydrolysis to provide the alde-
hyde.4–6 The reaction follows this pathway was further proven by
carrying out a set of reactions as described below.
O
OH
O
Conditions
H
Table 1
1c
2c
Entrya
Solventb
Formylating agent
Time (h)/temp (°C)
Yieldc
1
2
3
4
5
6
7
AcOH
TFA
TFA
HMTA
HMTA
HMTA
HMTA
HMTA
Paraformaldehyde
Formalin
8/80
8/80
3/80
1.5/80
1/80
10/80
10/80
00d
51
74
CF3SO3H
CH3SO3H
TFA
00e
00e
00f
00f
TFA
a
Reactions (entries 1–5) were carried out with 2 equiv of HMTA except entry 2
where 1 equiv was used.
b
3–4 mL of solvents were used for 1 mmol of substrate.
c
Isolated yield.
Starting material recovered.
d
e
Starting material decomposed.
From GC and 1H NMR.
f
We then varied the substitution at 4-position to the phenolic group
with electronically rich as well as electronically demanding func-
tional groups. We observed that compounds with Bu and bromo
groups at para position to the phenolic group (1c, 1d) also under-
went facile migration–formylation whereas the electron with-
drawing group such as formyl at para position 1e gave
t
As shown in Scheme 3, we treated 1d with TFA at 80 °C and
found that it smoothly underwent ortho-rearrangement to furnish
phenol 3.8,9 Under similar reaction conditions 2-(benzyloxy)-5-
bromobenzaldehyde 4 resulted in only debenzylated product 510
Table 2
Scope of substitution on phenyl and benzyl rings
Entry
Substratea
Time (h)
Product
OH
Yieldb (%)
O
O
O
O
1
3
70
O
O
2a
1a
1b
O
O
OH
O
Br
2
3.5
61
Br
O
O
2b
O
O
OH
O
3
4
5
3
5
6
74
59
52
1c
2c
OH
O
O
O
1d
Br
2d
Br
O
OH
1e
2e
O
O

S. P. Chavan, P. B. Lasonkar / Tetrahedron Letters 54 (2013) 4789–4792
4791
Table 2 (continued)
Entry
Substratea
Time (h)
Product
Yieldb (%)
OH
O
6
7
4
68
55
1f
2f
O
OH
O
O
O
O
O
O
3.5
1g
2g
Br
O
NO2
8
3
52
O
1i
O
1h
O
O
OH
Br
O
OH
O
9
6
00c
NO2
O
O
2h
O
a
Benzyl aryl ethers were prepared by treating corresponding phenols with the appropriate benzyl bromide in DMF under basic condition (K2CO3).
b
c
Isolated yield.
Debenzylated product observed, confirmed by 1H NMR.
instead of 6. Further proof for the mechanism was deduced, when
1f, where one of the ortho positions is already blocked by the
methyl group (Table 1, entry 6), was subjected to optimal reaction
conditions. It underwent ortho-rearrangement and para formyla-
tion, which was confirmed by 1H NMR spectroscopy. This may be
contrasted with the result obtained when 1d was subjected to Duff
reaction conditions as described earlier which led to the formation
of compound 2f which clearly gives credence to the hypothesis
that ortho-rearrangment precedes the formylation.
In summary, a novel one-pot synthetic route to access substi-
tuted salicylaldehyde from benzyl aryl ether involving migration
of the benzyl group and formylation in moderate to good yields
has been developed.11 We are currently exploring the application
of this methodology for the synthesis of natural and non-natural
products which will be reported in due course.
H
H
O
R
O
R
O
R
TFA
OH
O
OH
i) HMTA,
TFA
H
ii) H3O
R
R
Scheme 2. Plausible reaction mechanism.
Acknowledgments
OH
P.L. thanks CSIR, New Delhi, India, for a fellowship. We thank Dr.
U.R. Kalkote and Dr. H.B. Borate for helpful discussion.
TFA
O
80 °C, 1 h, 76%
Br
Supplementary data
3
1d
Br
Supplementary data associated with this article can be found, in
theonlineversion, at http://dx.doi.org/10.1016/j.tetlet.2013.06.133.
O
OH
Br
O
OH
O
O
References and notes
TFA
H
H
H
80 °C, 2 h, 70%
1. For usage of 3,5-disubstituted salicylaldehydes, please see: (a) Larrow, J. F.;
Jacobsen, E. N. Top. Organomet. Chem. 2004, 6, 123; (b) Cozzi, P. G. Chem. Soc.
Rev. 2004, 410; (c) Oleinika, I. I.; Kochneva, A. I.; Oleinika, I. V.; Ivanchevb, S. S.;
Tolstikova, G. A. Russ. J. Org. Chem. 2008, 44, 927.
2. Lambert, E.; Chabut, B.; Chardon-Noblat, S.; Deronzier, A.; Chottard, G. V.;
Bousseksou, A.; Tuchagues, J.-P.; Laugier, J.; Bardet, J.; Bardet, M.; Latour, J.-M. J.
Am. Chem. Soc. 1997, 119, 9424.
Br
6
Br
5
4
Not observed
Scheme 3. Evidence for mechanism.

4792
S. P. Chavan, P. B. Lasonkar / Tetrahedron Letters 54 (2013) 4789–4792
3. (a) Murthy, N. N.; Mahroof-Tahir, M.; Karlin, K. D. J. Am. Chem. Soc. 1993, 115,
10404; (b) Gobel, M. W. Angew. Chem., Int. Ed. Engl. 1994, 33, 1141; (c) Young,
M. J.; Chin, J. J. Am. Chem. Soc. 1995, 117, 10577; (d) Kodera, M.; Shimakoshi, H.;
Kano, K. Chem. Commun. 1996, 1737.
Chikate, R. C.; Patwardhan, N.; Patil, S. Catal. Commun. 2007, 8, 139; (e) Luzzio,
F. A.; Chen, J. J. Org. Chem. 2009, 74, 5629.
9. Sagrera, G.; Seoane, G. Synthesis 2009, 24, 4190.
10. Fletcher, S.; Gunnung, P. Tetrahedron Lett. 2008, 49, 4817.
4. For formylation of aromatic compounds see: (a) Duff, J. C.; Bills, E. J. J. Chem. Soc.
1932, 1987; (b) Duff, J. C.; Bills, E. J. J. Chem. Soc. 1934, 1305; (c) Duff, J. C.; Bills,
E. J. J. Chem. Soc. 1941, 547; (d) Duff, J. C.; Bills, E. J. J. Chem. Soc. 1945, 276.
5. Smith, W. E. J. Org. Chem. 1972, 37, 3972.
6. Skonieczny, K.; Charalambidis, G.; Tasior, M.; Krzeszewski, M.; Kalkan-Burat,
A.; Coutsolelos, A. G.; Gryko, D. T. Synthesis 2012, 44, 3683. and ref. cited
therein.
7. For TFA mediated rearrangement, please see: (a) Svanholm, U.; Parker, V. D. J.
Chem. Soc., Chem. Commun. 1972, 645; (b) Svanholm, U.; Parker, V. D. J. Chem.
Soc., Perkin Trans. 2 1974, 169; (c) Harwood, L. M. J. Chem. Soc., Chem. Commun.
1982, 1120; (d) Geetha, N.; Kuppusamy Balasubramanian, K. Tetrahedron Lett.
1998, 39, 1417.
8. For acid/Lewis acid catalyzed rearrangements, please see: (a) Tarbell, D. S.;
Petropoulos, J. C. J. Am. Chem. Soc. 1952, 74, 244; (b) Goldberg, F. W.; Magnus,
P.; Turnbull, R. Org. Lett. 2005, 7, 4531; (c) Petchmanee, T.; Ploypradith, P.;
Ruchirawat, S. J. Org. Chem. 2006, 71, 2892; (d) Bhure, M. H.; Rode, C. V.;
11. Typical experimental procedure: Benzyl aryl ether 1d (500 mg, 1.91 mmol,
1.0 equiv) was dissolved in TFA (7 mL) under N2, and hexamethylenetetramine
(536 mg, 3.83 mmol, 2.0 equiv) was added in one portion. The solution was
stirred at 80 °C for 5 h and cooled to room temperature. Then, aq HCl (10%,
7 mL) was added and the reaction mixture was heated at 90 °C for additional
1 h. The mixture was then cooled to room temperature. The product was
extracted with ethyl acetate (2 Â 10 mL). The combined organic extracts were
washed with brine (10 mL), dried (anhydrous Na2SO4) and the solvent was
removed in vacuo. The residue was purified by column chromatography (silica
gel) using pet. Ether/ethyl acetate (9:1) to provide pure product 2d in 59% yield
(330 mg, yellow solid, mp 87–89 °C). 1H NMR (400 MHz, CDCl3 + CCl4): d 3.99
(s, 2H), 7.21–7.34 (m, 5H), 7.40 (d, J = 2.7 Hz, 1H), 7.53 (d, J = 2.7 Hz, 1H), 9.82
(s, 1H), 11.2 (s, 1H); 13C NMR (100 MHz, CDCl3 + CCl4): d 34.7, 111.2, 121.4,
126.5, 128.6 (2C), 128.9 (2C), 132.9, 133.6, 138.8, 139.7, 158.5, 195.3; IR (CHCl3,
cmÀ1): mmax 2917, 2849, 1658, 1433, 1274, 1163; HRMS m/z: Calcd for
C14H12O2Br À291.0015, observed À291.0017.