General and efficient protocol for formylation of aromatic and heterocyclic phenols

Article abstract of DOI:10.1055/s-0032-1317500

A convenient, general procedure for formylation of diverse range of phenols with the Duff protocol has been developed. The procedure gives dialdehydes when possible. Georg Thieme Verlag KG Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317500

PAPER
▌3683
pGapeerneral and Efficient Protocol for Formylation of Aromatic and Heterocyclic
Phenols
Duff Formylation of Phenols
Kamil Skonieczny,a Georgios Charalambidis,b Mariusz Tasior,a Maciej Krzeszewski,c Ayfer Kalkan-Burat,a
Athanassios G. Coutsolelos,*b Daniel T. Gryko*a,c
a
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
Fax +48(22)6326681; E-mail: dtgryko@icho.edu.pl
b
Chemistry Department, University of Crete, Voutes Campus, P.O. Box 2208, 71003 Heraklion, Crete, Greece
E-mail: coutsole@chemistry.uoc.gr
c
Warsaw University of Technology, Faculty of Chemistry, Noakowskiego 3, 00-664 Warsaw, Poland
Received: 03.08.2012; Accepted after revision: 02.10.2012
literature12 followed by optimization of such parameters
Abstract: A convenient, general procedure for formylation of di-
as temperature, time, and concentration of reagents, led us
verse range of phenols with the Duff protocol has been developed.
to the following protocol: a) phenol (10 mmol), TFA (7–
8 mL), HMTA (20 mmol), 70 °C, 72 h, then 100 °C, 4 h;
b) aq HCl, 100 °C, 1 h. Using this protocol we obtained
dialdehyde 16 in 44% yield directly from the reaction
The procedure gives dialdehydes when possible.
Key words: aldehydes, arenes, electrophilic aromatic substitution,
heterocycles, phenols
mixture, without the need for any purification. The
strength of the Duff reaction is well illustrated by direct
Aromatic aldehydes are one of the most important classes
comparison with the synthesis of aldehyde 16 published
of reagents used in organic synthesis. Over the last de-
by Richter and Lash,13 that required three steps and multi-
cades many methods allowing direct formylation of aro-
ple chromatography.
matic rings have been developed with Vilsmeier–Haack,1
Gattermann–Koch,2 and Reimer–Tiemann3 reactions be-
ing the most recognized, and few more that are less
known.4 All these well-established protocols suffer, how-
ever, from the same drawback: they allow only monosub-
stitution as a result of aromatic ring deactivation; and for
many applications further formylation is needed, which
involves tedious, multistep synthesis. Nevertheless, there
are several reports on a successful multiple formylation in
a single step using the Duff reaction. Diformylated phe-
nols obtained in this process have been used as precursors
for the synthesis of various drugs,5 sensors,6 receptors,7
and protein inhibitors.8 The Duff reaction, developed in
the 1930s9 and then modified by Smith,10 requires the use
of hexamethylenetetramine (HMTA) in strongly acidic
media. As a consequence of its mechanism, involving a
series of equilibrium reactions, with iminium ion interme-
diates that do not deactivate aromatic ring, a polysubstitu-
tion is achievable.11 A survey of the literature reveals that
various procedures, sometimes differing quite significant-
ly, were proposed for diformylation of phenols. Recogniz-
ing the enormous utility of the Duff reaction, we set
ourselves the goal to establish one universal procedure,
which could be subsequently used for a broad range of de-
manding, aromatic substrates.
Having a good procedure in hand, scope and limitations
studies were conducted. First, it was decided to examine
other monosubstituted resorcinols 2–4. 4-Ethylresorcinol
(2), 4-hexylresorcinol (3), and 2-nitroresorcinol (4) were
successfully transformed into the corresponding dialde-
hydes 17–19 (Table 1). Strongly electron-withdrawing,
nitro substituent in position 2 of resorcinol did not hamper
the reaction outcome. Encouraged by these results the use
of 4,6-disubstituted resorcinols 5 and 6 was considered.
4,6-Dichlororesorcinol (5) smoothly afforded monoalde-
hyde 12. Interestingly, 4,6-di-tert-butylresorcinol (6)
gave in addition to the expected aldehyde 13 also the dial-
dehyde 20 as an unexpected product of ipso-substitution,
that to the best of our knowledge, was not reported so far
for this reaction.
Subsequently, attention was turned to structurally and
electronically demanding phenols. Sashidhara and co-
workers found that subjecting 8-hydroxyquinoline to the
Duff reaction results in the formation of 7-methylamino-
methylene-8-oxo-7,8-dihydroquinoline-5-carbaldehyde
instead of the expected dialdehyde.14 This result was ratio-
nalized based upon existence of strong intramolecular hy-
drogen bond. To our delight, the formylation of the
corresponding N-oxide 7 smoothly afforded dialdehyde
21 as the only isolable product (Table 1). It is worth men-
tioning that the synthesis of the analogous aldehyde was
successfully accomplished by Fiedler using multistep ap-
proach.15 Also two regioisomeric hydroxybenzofurans16 8
and 9 were successfully diformylated under optimized
conditions to give the previously unknown aldehydes 22
and 23. Monoformylation of identical hydroxybenzofuran
was recently reported by Dubonosov.17 Interestingly, al-
We decided to employ the transformation of 2-methylres-
orcinol (1) into dialdehyde 16 as a model reaction. Brief
examination of various conditions used so far in the
SYNTHESIS 2012, 44, 3683–3687
Advanced online publication: 24.10.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1317500; Art ID: SS-2012-Z0640-OP
© Georg Thieme Verlag Stuttgart · New York

3684
K. Skonieczny et al.
PAPER
Table 1 Duff Formylation of Phenols
OH
OH
OH
1. HMTA, TFA
2. HClaq
OHC
+
OHC
CHO
R
R
R
Phenol
Monoaldehyde
Yield (%)
–
Dialdehyde
Yield (%)
44
OHC
CHO
OH
1
–
–
16
HO
OH
OH
HO
Et
CHO
Et
2
3
4
5
6
–
–
–
–
–
17
18
19
–
55
42
40
–
HO
OH
HO
CHO
n-Hex
CHO
n-Hex
–
–
HO
OH
HO
OH
CHO
OHC
HO
CHO
OH
–
–
HO
OH
NO2
NO2
Cl
Cl
Cl
Cl
12
13
68
22
–
HO
t-Bu
HO
OH
t-Bu
OH
HO
OH
CHO
CHO
t-Bu
CHO
OH
t-Bu
t-Bu
20
27
HO
HO
OH
CHO
CHO
7
–
–
–
–
21
59
N
O
OHC
HO
N
O
OH
HO
OH
CHO
Ph
Ph
8
9
–
–
–
–
22
23
29
15
Ph
Ph
Ph
Ph
O
O
OHC
OHC
Ph
Ph
O
HO
O
HO
CHO
n-Hex
n-Hex
10
11
14
15
35
18
–
–
–
–
–
HO
O
O
HO
O
O
CHO
CO2Et
CO2Et
N
N
–
OHC
OH
OH
Synthesis 2012, 44, 3683–3687
© Georg Thieme Verlag Stuttgart · New York

PAPER
Duff Formylation of Phenols
3685
HRMS (EI): m/z calcd for C10H10O4 [M+•]: 194.0579; found:
194.0588.
though simple hydroxyl-coumarins proved to be trouble-
some substrates in the Duff reaction, formylation of
benzo[c]coumarin 10 smoothly afforded aldehyde 14 in
35% yield. Finally complex heterocyclic phenol 11 pos-
sessing indolizine skeleton was formylated to afford alde-
hyde 15 as the only regioisomer.
Anal. Calcd for C10H10O4: C, 61.85; H, 5.19. Found: C, 61.79; H,
5.12.
5-Hexyl-2,4-dihydroxyisophthalaldehyde (18)
Following the general procedure, 4-hexylresorcinol (3; 1.00 g, 5.1
mmol) was treated with HMTA (1.44 g, 10.3 mmol) in TFA (6 mL).
The precipitated crystals were filtered and recrystallized from EtOH
to afford a light orange crystalline solid; yield: 0.54 g (42%); mp
60–61 °C.
In conclusion, we have developed an efficient and versa-
tile protocol for diformylation of phenols. Less reactive
starting materials usually participate in this reaction, but
monosubstitution dominates. This procedure, in many
cases, allows isolation of the desired product by simple
filtration, without chromatography and helps to avoid an-
noying multistep syntheses, as was shown by comparison
with literature data. This facile procedure opens the way
for a variety of complex aldehydes to be used in materials
or medicinal chemistry.
1H NMR (500 MHz, CDCl3): δ = 0.89 (s, 3 H), 1.32 (q, J = 4.5 Hz,
6 H), 1.58 (t, J = 7.5 Hz, 2 H), 2.57 (t, J = 7.5 Hz, 2 H), 7.47 (s, 1
H), 9.69 (s, 1 H), 10.39 (s, 1 H), 12.39 (s, 1 H), 12.95 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 14.1, 22.6, 28.3, 29.0, 29.1, 31.6,
108.8, 112.8, 123.6, 140.6, 165.6, 167.8, 193.6, 194.4.
HRMS (EI): m/z calcd for C14H18O4 [M+•]: 250.1205; found:
250.1199.
4,6-Dihydroxy-5-nitroisophthalaldehyde (19)
All chemicals were used as received, unless otherwise noted. Re-
agent grade solvents (CH2Cl2, hexane, toluene) were distilled prior
use. All reported NMR spectra were recorded on 400 or 500 MHz
spectrometer unless otherwise noted. Chemical shifts (δ ppm) were
determined with TMS as the internal reference; J values are given
in Hz. Chromatography was performed on silica gel (Kieselgel 60,
200–400 mesh). Mass spectra were obtained via EI MS. Phenol 11
was prepared as described in literature.18
Following the general procedure, 2-nitroresorcinol (4; 1.00 g, 6.5
mmol) was treated with HMTA (2.34 g, 16.7 mmol) in TFA (6 mL).
The precipitated crystals were filtered, washed with H2O (40 mL)
and recrystallized from EtOH to afford 19 as a yellow crystalline
solid; yield: 0.54 g (40%); mp 195–196 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.20 (s, 1 H), 9.79 (br s, 2 H),
9.98 (s, 2 H).
13C NMR (125 MHz, DMSO-d6): δ = 116.2, 131.6, 136.9, 158.9,
191.0, 191.0.
Duff Formylation of Phenols; General Procedure
To the phenolic substrate (1 equiv) dissolved in a minimum amount
of TFA (7–8 mL for 10 mmol of phenol) was added HMTA (2
equiv) under argon atmosphere. Addition of the HMTA was done
slowly as the reaction was very exothermic. The solution was stirred
at 70 C for 72 h and then at 100 °C for another 4 h. Subsequently,
aq HCl (10%, ~10 mL for 10 mmol of phenol) was added and the
reaction mixture was kept at 100 °C for 1 h. The whole suspension
was cooled down to r.t. and left overnight without stirring. In most
cases, the formation of a precipitate was observed, which was fil-
tered, washed extensively with H2O, and dried overnight under high
vacuum (Table 1).
HRMS (EI): m/z calcd for C8H5NO6 [M+•]: 211.0117; found:
211.0110.
3,5-Dichloro-2,6-dihydroxybenzaldehyde (12)
Following the general procedure, 4,6-dichlororesorcinol (5; 12.14
g, 68 mmol) was treated with HMTA (9.52 g, 68 mmol) in TFA (64
mL). The precipitated crystals were filtered and washed extensively
with H2O. After 12 h, the supernatant was filtrated one more time
giving a second portion of the product. The yellow crystals obtained
were dried overnight under vacuum; yield: 9.65 g (68%); mp 168–
169 °C.
1H NMR (500 MHz, CDCl3): δ = 7.55 (s, 1 H), 9.21 (br s, 2 H),
10.35 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 110.4, 111.7, 136.3, 155.3, 193.4.
HRMS (EI): m/z calcd for C7H4Cl2O3 [M+•]: 205.9537; found:
4,6-Dihydroxy-5-methylisophthalaldehyde (16)
Following the general procedure, 2-methylresorcinol (1; 10.00 g, 80
mmol) was treated with HMTA (29.00 g, 207 mmol) in TFA (70
mL); yield: 6.4 g (44%); white crystalline solid; mp 182–183 °C
(Lit.19 mp 185–185.5 °C).
205.9528.
1H NMR (400 MHz, CDCl3): δ = 2.13 (s, 3 H), 7.71 (s, 1 H), 9.78
(s, 2 H), 12.03 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 26.56, 113.4, 115.0, 140.0, 166.2,
Anal. Calcd for C7H4Cl2O3: C, 40.61; H, 1.95. Found: C, 40.51; H,
1.91.
194.2.
3,5-Di-tert-butyl-2,6-dihydroxybenzaldehyde (13) and 5-(tert-
Butyl)-2,4-dihydroxyisophthalaldehyde (20)
HRMS (EI): m/z calcd for C9H8O4 [M+•]: 180.0423; found:
180.0417.
Following the general procedure, 4,6-di-tert-butylresorcinol (6;
1.00 g, 4.5 mmol) was treated with HMTA (1.63 g, 11.6 mmol) in
TFA (6 mL). The solid obtained contained two products 13 and 20,
which were separated by column chromatography on silica gel us-
ing CH2Cl2–hexanes (2:1) as eluent.
5-Ethyl-2,4-dihydroxyisophthalaldehyde (17)
Following the general procedure, 4-ethylresorcinol (2; 1.00 g, 7.2
mmol) was treated with HMTA (2.03 g, 14.5 mmol) in TFA (5 mL).
After stirring at r.t. overnight, the formation of a precipitate was ob-
served at the bottom of the flask. The solvents were poured out and
the remaining solid was dissolved in CH2Cl2 (75 mL). The organic
layer was washed with H2O (2 × 10 mL), dried (Na2SO4), and evap-
orated; yield: 0.78 g (55%); white crystalline solid; mp 71–74 °C.
13
Yield: 0.25 g (22%); yellow crystalline solid; mp 123–124 °C.
1H NMR (400 MHz, DMSO-d6): δ = 1.34 (s, 18 H), 7.34 (s, 1 H),
10.21 (s, 1 H), 11.26 (s, 2 H).
1H NMR (300 MHz, CDCl3): δ = 1.22 (d, J = 7.5 Hz, 3 H), 2.62 (q,
J = 7.5 Hz, 2 H), 7.49 (s, 1 H), 9.70 (s, 1 H), 10.39 (s, 1 H), 12.39
(s, 1 H), 12.96 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 30.22, 34.71, 113.19, 127.77,
134.14, 158.85, 196.64.
HRMS (ESI): m/z calcd for C15H22O3 [M + H]+: 251.1647; found:
251.1648.
13C NMR (75 MHz, CDCl3): δ = 13.6, 21.6, 108.9, 113.0, 125.0,
140.0, 165.8, 167.9, 193.9, 194.6.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3683–3687

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K. Skonieczny et al.
PAPER
Anal. Calcd for C15H22O3: C, 71.97; H, 8.86. Found: C, 71.75; H,
8.90.
4-Formyl-2-hexyl-3-hydroxy-6H-dibenzo[b,d]pyran-6-one (14)
Following the general procedure, benzo[c]coumarin 10 (0.53 g, 1.8
mmol) was treated with HMTA (0.70 g, 5.0 mmol) in TFA (10 mL).
CH2Cl2 (10 mL) was added to the crude reaction mixture and phases
were separated. The aqueous phase was extracted with CH2Cl2 (10
mL) and the organic layers were combined, and dried (Na2SO4).
Drying agent was filtered, and the supernatant was evaporated with
silica gel (10 g). Chromatography (SiO2, CH2Cl2) afforded 14 as a
colorless solid; yield: 204 mg (35%); Rf = 0.58 (CH2Cl2); mp 115–
117 °C.
1H NMR (500 MHz, CDCl3): δ = 0.92 (t, J = 7.1 Hz, 3 H), 1.36 (m,
4 H), 1.43 (m, 2 H), 1.69 (quint, J = 7.3 Hz, 2 H), 2.74 (t, J = 7.8 Hz,
2 H), 7.57 (dt, J = 7.8, 1.0 Hz, 1 H), 7.86 (dt, J = 8.1, 1.4 Hz, 1 H),
8.02 (m, 2 H), 8.39 (dd, J = 8.0, 1.4 Hz, 1 H), 10.67 (s, 1 H), 12.47
(s, 1 H).
20
Yield: 0.27 g (27%); white crystalline solid; mp 109–110 °C.
1H NMR (500 MHz, CDCl3): δ = 1.40 (s, 9 H), 7.59 (s, 1 H), 9.70
(s, 1 H), 10.40 (s, 1 H), 12.39 (s, 1 H), 13.50 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 29.2, 34.3, 109.1, 112.4, 130.6,
138.3, 165.7, 169.2, 194.0, 194.7.
HRMS (ESI): m/z calcd for C12H13O4 [M – H]–: 221.0814; found:
221.0815.
Anal. Calcd for C12H13O4: C, 64.85; H, 6.35. Found: C, 64.72; H,
6.40.
5,7-Diformyl-8-hydroxyquinoline 1-Oxide (21)
13C NMR (125 MHz, CDCl3): δ = 14.1, 22.6, 29.1, 29.3, 29.4, 31.7,
108.6, 108.7, 119.7, 121.0, 128.2, 128.5, 130.6, 130.8, 134.5, 135.3,
151.4, 159.9, 162.6, 193.8.
HRMS (ESI): m/z calcd for C20H20O4 + Na [M + Na]+: 347.1254,
found: 347.1253.
Following the general procedure, 8-hydroxyquinoline 1-oxide (7;
1.00 g, 6.2 mmol) was treated with HMTA (2.25 g, 16.1 mmol) in
TFA (7 mL). The precipitated crystals were filtered, washed with
H2O (40 mL), and recrystallized from EtOH to afford 21 as a yellow
crystalline solid; yield: 0.79 g (59%); mp 205–206 °C (EtOH).
1H NMR (500 MHz, DMSO-d6): δ = 7.95 (dd, J = 8.5, 6.5 Hz, 1 H),
8.46 (s, 1 H), 8.87 (dd, J = 6.0, 1.0 Hz, 1 H), 9.40 (dd, J = 9.0, 1.0
Hz, 1 H), 10.11 (s, 1 H), 10.43 (s, 1 H), 19.63 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 118.7, 119.5, 127.1, 129.2,
129.4, 132.3, 136.9, 138.4, 165.8, 186.8, 192.0.
HRMS (EI): m/z calcd for C11H7NO4 [M+•]: 217.0375; found:
217.0371.
Ethyl 4-Formyl-3-hydroxypyrido[1,2-a]indole-10-carboxylate
(15)
Following the general procedure, ethyl 3-hydroxypyrido[1,2-a]in-
dole-10-carboxylate (11; 1.00 g, 3.9 mmol) was treated with HMTA
(1.42 g, 10.1 mmol) in TFA (10 mL). The solid obtained was puri-
fied by column chromatography on silica gel using toluene and
toluene–acetone (99:1) as eluent; yield: 0.2 g (18%); orange crystal-
line solid; mp 172–173 °C.
Anal. Calcd for C11H7NO4: C, 60.83; H, 3.25; N, 6.45. Found: C,
60.68; H, 3.08; N, 6.49.
1H NMR (500 MHz, CDCl3): δ = 1.49 (t, J = 7.0 Hz, 3 H), 4.46 (q,
J = 7.1 Hz, 2 H), 6.77–6.81 (m, 1 H), 7.07 (d, J = 9.1 Hz, 1 H), 7.14–
7.19 (m, 1 H), 8.35 (d, J = 7.3 Hz, 1 H), 8.40 (dd, J = 9.4, 1.1 Hz, 1
H), 8.60 (d, J = 9.0 Hz, 1 H), 10.84 (s, 1 H), 12.49 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 14.6, 59.8, 97.1, 108.7, 112.9,
116.8, 121.4, 122.2, 124.8, 127.0, 127.4, 133.0, 139.9, 162.1, 164.9,
189.8.
5-Hydroxy-2,3-diphenylbenzofuran-4,7-dicarbaldehyde (22)
Following the general procedure, 2,3-diphenylbenzofuran-5-ol (8;
1.00 g, 3.5 mmol) was treated with HMTA (1.26 g, 9.0 mmol) in
TFA (7 mL). The solid obtained was purified by column chroma-
tography on silica gel using CH2Cl2 and CH2Cl2–MeOH (99:1) as
eluent; yield: 0.35 g (29%); yellow crystalline solid; mp 202–
203 °C.
1H NMR (500 MHz, CDCl3): δ = 7.28–7.37 (m, 3 H), 7.44–7.48 (m,
2 H), 7.51–7.59 (m, 5 H), 8.25 (s, 1 H), 9.56 (s, 1 H), 10.56 (s, 1 H),
12.70 (s, 1 H).
HRMS (EI): m/z calcd for C16H13NO4 [M+•]: 283.0845; found:
283.0833.
Anal. Calcd for C16H13NO4: C, 67.84; H, 4.63; N, 4.94. Found: C,
67.64; H, 4.62; N, 4.98.
13C NMR (125 MHz, CDCl3): δ = 113.1, 117.5, 117.7, 120.9, 127.3,
128.7, 129.0, 129.3, 129.9, 130.0, 130.2, 133.1, 136.8, 147.3, 158.0,
163.4, 188.0, 193.5.
HRMS (EI): m/z calcd for C22H14O4 [M+•]; 342.0892; found:
342.0880.
Acknowledgment
D.T.G., K.S., and M.T. would like to thank Foundation for Polish
Science (Grant number TEAM/2009-4/3). A.G.C. and G.Ch. thank
European Commission FP7 REGPOT-2008-1, Project BIOSOLE-
NUTI No 229927, Heraklitos grant from Ministry of Education and
GSRT.
Anal. Calcd for C22H14O4: C, 77.18; H, 4.12. Found: C, 76.96; H,
4.13.
6-Hydroxy-2,3-diphenyl-1-benzofuran-5,7-dicarbaldehyde (23)
Following the general procedure, phenol 9 (0.80 g, 2.8 mmol) was
treated with HMTA (1.00 g, 7.2 mmol) in TFA (10 mL). The result-
ing oil was initially recrystallized (CH2Cl2–hexanes), followed by
chromatography (SiO2, CH2Cl2) to afford pure aldehyde 23 as or-
ange crystals; yield: 144 mg (15%); mp 160–163 °C; Rf = 0.51
(CHCl3).
1H NMR (500 MHz, CDCl3): δ = 7.37 (m, 3 H), 7.49 (m, 3 H), 7.53
(m, 2 H), 7.68 (m, 2 H), 8.14 (s, 1 H), 10.37 (br s, 1 H), 10.72 (s, 1
H), 12.09 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 107.7, 117.4, 120.1, 124.3, 126.8
(2 signals), 128.5 (2 signals), 128.7 (2 signals), 129.2 (2 signals),
129.4 (2 signals), 129.6 (2 signals), 130.8, 152.2, 157.6, 163.2,
190.1 (2 signals).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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Synthesis 2012, 44, 3683–3687
© Georg Thieme Verlag Stuttgart · New York

PAPER
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