A convenient synthesis of tri- and tetramethylbenzaldehydes from readily available phenols

Article abstract of DOI:10.1055/s-0033-1340302

This letter describes a convenient synthesis of the six isomeric tri- and tetramethylbenzaldehydes, which are not readily available from major chemical suppliers. Formylation of readily available phenols via electrophilic aromatic substitution provides compounds containing the correct aromatic substitution pattern. ?Suzuki cross-coupling of the corresponding trifluoromethanesulfonates with methylboronic acid then provides the benzaldehydes as single isomers. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1340302

LETTER
▌381
lAetteCr onvenient Synthesis of Tri- and Tetramethylbenzaldehydes from Readily
Available Phenols
Polymethylbenzaldehyde Synthesis
Persis Dhankher, Tom D. Sheppard*
Department of Chemistry, University College London, 20 Gordon St, London, WC1H 0AJ, UK
E-mail: tom.sheppard@ucl.ac.uk
Received: 08.10.2013; Accepted after revision: 28.10.2013
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Abstract: This letter describes a convenient synthesis of the six iso-
meric tri- and tetramethylbenzaldehydes, which are not readily
available from major chemical suppliers. Formylation of readily
available phenols via electrophilic aromatic substitution provides
compounds containing the correct aromatic substitution pattern.
Suzuki cross-coupling of the corresponding trifluoromethanesulfo-
nates with methylboronic acid then provides the benzaldehydes as
single isomers.
H
H
H
H
H
H
1a
1d
1b
1e
1c
Key words: aldehydes, palladium, Suzuki, aromatic compounds,
formylation
1f
Substituted benzaldehydes are important starting materi- Figure 1 Tri- and tetramethylbenzaldehydes that are not readily
available commercially
als for use in a variety of chemical processes and they are
frequently employed in medicinal chemistry to introduce
substituted aryl groups into potential drug molecules. The
OH
OH
O
O
R1
R2
R1
R2
R1
R2
introduction of multiple methyl groups onto the benzene
ring can serve to alter the preferred three-dimensional
conformation of the aryl unit in the molecule, leading to
subtle changes in chemical and biological properties.1
There are 19 different benzaldehydes incorporating one or
more methyl substituents on the aromatic ring and 13 of
these compounds are available commercially in gram
quantities from major suppliers.2 The remaining com-
pounds 1a–f (Figure 1) are not available from major com-
mercial suppliers, so typically they must be synthesized
from more readily available aryl precursors. Aldehydes
1a–f have previously been synthesized by a variety of dif-
ferent routes including direct formylation of polymethyl-
ated benzenes,3 side-chain oxidation of polylmethylated
benzenes,4 Grignard reaction of an aryl bromide with a
suitable electrophile,5 partial reduction of carboxylic acid
derivatives,6 or degradation of bicyclic systems.7 In the
latter three cases the starting materials used are often as
complex to prepare as the target aldehyde itself. Whilst di-
rect formylation of a polymethylated benzene potentially
offers a very direct route, polymethyl benzenes are prone
to acid-catalyzed isomerization processes during the
harsh conditions often needed for electrophilic aromatic
substitution reactions.8 This can lead to complex mixtures
of regioisomeric products which can be extremely diffi-
cult to separate.
H
H
R4
R4
R4
R3
R3
R3
1a–f
R1–R4 = H, Me
Scheme 1 Proposed synthetic route to tri- and tetramethylbenzalde-
hydes
As part of an ongoing medicinal chemistry project, we re-
quired access to all of the 19 methylated benzaldehyde
isomers to explore a complex structure–activity relation-
ship. In order to prepare all of the six isomers shown in
Figure 1, we have developed a new synthetic route to en-
able all of these compounds to be prepared from cheap,
commercially available phenols.
We envisaged that the desired aldehydes could potentially
be synthesized by formylation of a phenol in an electro-
philic aromatic substitution reaction, followed by cross-
coupling of the phenol-derived sulfonate ester with meth-
ylboronic acid (Scheme 1). The phenol group would serve
to activate the aromatic ring towards electrophilic aromat-
ic substitution, preventing competing isomerization pro-
cesses, and direct the substitution reaction to provide the
desired product isomer. After isolation of the desired re-
gioisomer, the phenol can then be converted into a methyl
group via the corresponding trifluormethanesulfonate es-
ter. The phenols 2a–e required for the synthesis of alde-
hydes 1a–e are all commercially available. In the case of
aldehyde 1f, a suitable dihydroquinone precursor 2f con-
taining the required substitution pattern is commercially
available (vide infra).
SYNLETT 2014, 25, 0381–0384
Advanced online publication: 04.12.2013
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DOI: 10.1055/s-0033-1340302; Art ID: ST-2013-D0950-L
© Georg Thieme Verlag Stuttgart · New York

382
P. Dhankher, T. D. Sheppard
LETTER
The formylation of phenols 2a–e was carried out using di- With the desired triflates in hand, we then turned our at-
chloromethyl methyl ether and aluminium trichloride at tention to the proposed Suzuki cross-coupling with methyl-
room temperature (Scheme 2).9 Phenol 2a underwent for- boronic acid (Scheme 3 and Table 1). The cross-coupling
mylation in good yield to give aldehyde 3, which was con- of methylboronic acid with aryl triflates has previously
verted into triflate 4 under standard conditions. The been reported under a variety of conditions. We evaluated
formylation of phenol 2b under similar conditions gave a several protocols for the conversion of triflate 4 into alde-
mixture of isomeric aldehydes where the major product hyde 1a.16 With Pd(PPh3)4 as the catalyst, negligible con-
was the undesired para-substitution product. Neverthe- version into the desired product was observed using either
less, the isomers could readily be separated by chromatog- K2CO3 or K3PO4 as the base. Upon switching to PdCl2(dp-
raphy, and aldehyde 59 was subsequently converted into pf), however, excellent conversion into the desired prod-
aryl trifluoromethanesulfonate 6.10 Phenol 2c underwent uct 1a was observed.16d With optimized conditions for the
formylation in good yield to give aldehyde 711 which was Suzuki cross-coupling in hand we went on to complete the
in turn converted into triflate 8.12 The formylation of phe- synthesis of the aldehydes 1a–e (Table 1).
nol 2d gave a mixture of isomeric aldehydes 913 and 1014
which was converted into a mixture of the two corre-
OTf
sponding triflates 1113 and 12.14 This mixture of isomers
R1
R2
R5
R4
R1
R5
MeB(OH)2 (3 equiv)
PdCl2(dppf) (10 mol%)
is inconsequential as both triflates 11 and 12 will ultimate-
ly be converted into the same aldehyde 1d upon Suzuki
coupling with methylboronic acid. Phenol 2e provides no
regioselectivity issues in the aromatic substitution reac-
tion, and aldehyde 1315 and triflate 14 were synthesized
without difficulty.
R2
R4
K2CO3 (2 equiv)
THF–H2O (10:1)
reflux
R3
R3
R1, R2, R4 = H, Me
3 = H, Me, CHO
R5 = CHO, Me
1a–e
R
Scheme 3 Suzuki cross-coupling of trifluoromethanesulfonates with
methylboronic acid
OH
O
OH
O
OTf
b
a
H
H
Table 1 Suzuki Cross-Coupling Reactions
Entry
Trifluoromethanesulfonate Product
Yield (%)
2a
3
4
1
2
3
4
5
4
1a17
1b18
1c6a
1d19
1e3c
99
99
61
97
80
H
O
H
O
O
6
OTf
OH
OH
b
a
8
2b
5
6
11 and 12
O
14
H
H
b
a
OH
OH
OH
OTf
The remaining aldehyde 1f was synthesized from com-
mercially available dihydroquinone 2f via trifluorometh-
anesulfonate formation and cross-coupling to give ester
15 (Scheme 4).20 An unoptimized reduction–oxidation se-
quence then provided aldehyde 1f3a in moderate yield.
2c
2d
7
8
R1
R1
a
b
OH
OTf
R2
R2
O
OH
O
O
9 R1 = CHO, R2 = H
10 R1 = H, R2 = CHO
O
11 R1 = CHO, R2 = H
12 R1 = H, R2 = CHO
O
a, b
c, d
MeO
MeO
H
OH
H
H
b
a
2f
15
1f
OH
OH
OTf
Scheme 4 Reagents and conditions: a) Tf2O, Et3N, CH2Cl2, 98%; b)
MeB(OH)2, K2CO3, PdCl2(dppf), THF–H2O, reflux, 87%; c)
DIBAL-H, PhMe–Et2O, 63%; d) DMSO, COCl2, then Et3N, CH2Cl2,
18%.
2e
13
14
Scheme 2 Forymlation of starting phenols and subsequent conver-
sion into the corresponding aryl trifluoromethanesulfonates. Reagents
and conditions: a) Cl2CHOMe, AlCl3, CH2Cl2, r.t., 65% (3), 15% (5),
71% (7), 44% (9 and 10), 60% (13); b) Tf2O, Et3N, CH2Cl2, 64% (4),
34% (6), 53% (8), 95% (11 and 12), 46% (14).
In conclusion, we have developed a general synthetic
route to tri- or tetramethylbenzaldehydes from readily
available phenols. Electrophilic aromatic formylation21 of
a phenol provides access to compounds with the required
substitution pattern as single isomers. Conversion into the
Synlett 2014, 25, 381–384
© Georg Thieme Verlag Stuttgart · New York

LETTER
Polymethylbenzaldehyde Synthesis
383
corresponding triflate22 and Suzuki cross-coupling with
methylboronic acid23 furnishes the target tri- and tetra-
methylbenzaldehydes as single isomers.
(14) Mori, K.; Ichikawa, Y.; Kobayashi, M.; Shibata, Y.;
Yamanaka, M.; Akiyama, T. J. Am. Chem. Soc. 2013, 135,
3964.
(15) Kadam, S. H.; Paknikar, S. WO 2011128018 A1, 2011.
(16) (a) Zhou, X.; Tse, M. K.; Wan, T. S. M.; Chan, K. S. J. Org.
Chem. 1996, 61, 3590. (b) Enguehard, C.; Renou, J.-L.;
Collot, V.; Hervet, M.; Rault, S.; Gueiffier, A. J. Org. Chem.
2000, 65, 6572. (c) Gray, M.; Andrews, I. P.; Hook, D. F.;
Kitteringham, J.; Voyle, M. Tetrahedron Lett. 2000, 41,
6237. (d) Molander, G. A.; Yun, C.-S. Tetrahedron 2002,
58, 1465.
Acknowledgment
We would like to thank the University College London Drug Disco-
very PhD Program for supporting this work through the award of a
studentship (to P.D.) and Professor Neil Millar (UCL Pharmacolo-
gy) for helpful discussions.
(17) Matsubara, Y.; Takekuma, S.-I.; Yokoi, K.; Yamamoto, H.;
Nozoe, T. Chem. Lett. 1984, 13, 631.
(18) Sudali, A.; Rao, G. S. K. Indian J. Chem., Sect. B: Org.
Chem. Incl. Med. Chem. 1989, 28, 110.
(19) Lever, J. G.; Scrivens, W. A. EP 1036782 A1, 2000.
(20) Gokhale, A.; Schiess, P. Helv. Chim. Acta 1998, 81, 251.
(21) General Procedure for Formylation
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
experimental procedures and 1H and 13C NMR spectra for all com-
pounds.SunpIgfpi
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Aluminium trichloride (4.82 g, 36 mmol) was added to a
solution of phenol (33 mmol) in anhydrous CH2Cl2 (50 mL)
under argon, and the solution was stirred for 10 min.
Dichloromethyl methyl ether (3.3 mL, 36 mmol) was added
dropwise via a syringe pump (7.7 mL/h). The reaction was
left to stir for a further 10 min before cold H2O (200 mL) was
added slowly. After stirring for a further 10 min, the organic
layer was separated and washed with brine (100 mL) and
H2O (150 mL), dried over MgSO4, filtered, and concentrated
to give the aldehyde which was purified by column
chromatography.
References and Notes
(1) Brameld, K. A.; Kuhn, B.; Reuter, D. C.; Stahl, M. J. Chem.
Inf. Model. 2008, 48, 1.
(2) All three methlybenzaldehydes and all six dimethyl-
benzaldehydes can be purchased from major commercial
suppliers; 2,4,5-trimethylbenzaldehyde, 2,3,6-trimethyl-
benzaldehyde, 2,3,5,6-tetramethylbenzaldehyde, and
pentamethylbenzaldehyde are also readily available.
(3) (a) Olah, G. A.; Kuhn, S. J. J. Am. Chem. Soc. 1960, 82,
2380. (b) Niedzielski, E. L.; Nord, F. F. J. Org. Chem. 1943,
8, 147. (c) Tanaka, M.; Fujiwara, M.; Ando, H. J. Org.
Chem. 1995, 60, 3846. (d) Smith, L. I.; Agre, C. L. J. Am.
Chem. Soc. 1938, 60, 648. (e) Fuson, R. C.; Southwick, P.
L.; Rowland, S. P. J. Am. Chem. Soc. 1944, 66, 1109.
(4) (a) Blackstock, D. J.; Fischer, A.; Richards, K. E.; Wright,
G. J. Aust. J. Chem. 1973, 26, 775. (b) Hunziker, E.; Myhre,
P. C.; Penton, J. R.; Zollinger, H. Helv. Chim. Acta 1975, 58,
230.
2-Hydroxy-3,5-dimethylbenzaldehyde (3)
Brown viscous oil; Rf = 0.97 (EtOAc–PE, 1:1). IR: νmax
=
3201, 2921, 1646, 1467, 1260 cm–1. 1H NMR (600 MHz,
CDCl3): δ = 11.09 (s, 1 H, OH), 9.81 (s, 1 H, CHO), 7.20 (br
s, 1 H, ArH), 7.15 (s, 1 H, ArH), 2.29 (s, 3 H, Me), 2.23 (s,
3 H, Me). 13C NMR (150 MHz, CDCl3): δ = 196.8 (CH),
158.0 (Cq), 139.1 (CH), 131.0 (CH), 128.6 (Cq), 126.6 (Cq),
119.9 (Cq), 20.3 (CH3), 15.1 (CH3). HRMS (EI): m/z calcd
for C9H10O2 [M]+: 150.0680; found: 150.0681.
(22) General Procedure for Trifluoromethanesulfonate
Synthesis
(5) (a) Smith, L. I.; Nichols, J. J. Org. Chem. 1941, 6, 489.
(b) Mannschreck, A.; Hartmann, E.; Buchner, H.; Andert, D.
Tetrahedron Lett. 1987, 28, 3479.
Triethylamine (4.04 g, 40 mmol) was added to a solution of
phenol (13 mmol) in anhydrous CH2Cl2 (13 mL) at –78 °C
under argon, and the solution stirred for 30 min.
Trifluoromethanesulfonic anhydride (2.5 mL, 15 mmol, 1.1
equiv) was added dropwise via a syringe pump (7.7 mL/h).
The reaction was left to stir for a further 2 h. The reaction
mixture was diluted with CH2Cl2 (15 mL) and washed with
sat. NaHCO3 (20 mL), brine (20 mL), and H2O (20 mL),
dried (MgSO4), filtered, and concentrated to give the
trifluoromethanesulfonate which was purified by column
chromatography.
(6) (a) Gaspar, P. P.; Hsu, J.-P.; Chari, S.; Jones, M. Jr.
Tetrahedron 1985, 41, 1479. (b) Benington, F.; Morin, R.
D.; Clark, L. C. Jr. J. Org. Chem. 1960, 25, 1542. (c) Smith,
D. G.; Smith, D. J. H. J. Chem. Soc., Chem. Commun. 1975,
459.
(7) Matsubara, Y.; Takekuma, S.-I.; Yokoi, K.; Yamamoto, H.;
Nozoe, T. Bull. Chem. Soc. Jpn. 1987, 60, 1415.
(8) (a) McCaulay, D. A.; Lien, A. P. J. Am. Chem. Soc. 1952,
74, 6246. (b) Allen, R. H. J. Am. Chem. Soc. 1960, 82, 4856.
(c) Olah, G. A.; Meyer, M. W.; Overchuk, N. A. J. Org.
Chem. 1964, 29, 2313. (d) Guisnet, M.; Gnep, N. S.; Morin,
S. Microporous Mesoporous Mater. 2000, 35, 47.
(e) Hoefnagel, A. J.; van Bekkum, H. Catal. Lett. 2003, 85,
7.
(9) Konakahara, T.; Kiran, Y. B.; Okuno, Y.; Ikeda, R.; Sakai,
N. Tetrahedron Lett. 2010, 51, 2335.
(10) Chasset, S.; Chevreuil, F.; Ledoussal, B.; Le Strat, F.;
Benarous, R. WO 2012140243 A1, 2012.
(11) Boldron, C.; Gamez, P.; Tooke, M. D.; Spek, L. A.; Reedijk,
J. Angew. Chem. Int. Ed. 2005, 44, 3585.
(12) Chappell, M. D.; Conner, S. E.; Gonzalez, V. I. C.; Lamar, J.
E.; Li, J.; Moyers, J. S.; Owens, R. A.; Tripp, A. E.; Zhu, G.
WO 2005118542 A1, 2005.
2-Formyl-4,6-dimethylphenyl trifluoromethane-
sulfonate (4)
Yellow viscous oil; Rf = 0.91 (EtOAc–PE, 1:1). IR: νmax
=
2883, 1701, 1598, 1407, 1207, 1136 cm–1. 1H NMR (600
MHz, CDCl3): δ = 10.19 (s, 1 H, CHO), 7.62 (d, 1 H, J = 2.0
Hz, ArH), 7.38 (d, 1 H, J = 2.0 Hz ArH), 2.42 (s, 3 H, Me),
2.40 (s, 3 H, Me). 13C NMR (150 MHz, CDCl3: δ = 187.4
(CH), 145.9 (Cq), 139.1 (Cq), 138.8 (CH), 132.5 (Cq), 129.2
(Cq), 128.5 (CH), 118.4 (q, J = 321 Hz, Cq), 20.9 (CH3), 16.5
(CH3). HRMS (EI): m/z calcd for C10H9F3O4S [M]+:
282.0174; found: 282.0174.
(23) General Procedure for Suzuki Cross-Coupling
K2CO3 (397 mg, 3 mmol) and PdCl2(dppf)·CH2Cl2 (116 mg,
10 mol%) were added to a solution of aryl trifluoromethane-
sulfonate (1 mmol) in THF (25 mL) which was left to stir for
5 min. H2O (HPLC grade, 1.25 mL) was added, followed by
methylboronic acid (255 mg, 4 mmol). The reaction was
heated at reflux overnight. EtOAc (7 mL) was added, and the
(13) Winn, M.; Reilly, E. B.; Liu, G.; Huth, J. R.; Jae, H-S.;
Freeman, J.; Pei, Z.; Zhili, X.; Lynch, J.; Kester, J.; von
Geldern, T. W.; Leitza, S.; DeVries, P.; Dickinson, R.;
Mussatto, D.; Okasinki, G. F. J. Med. Chem. 2001, 44, 4393.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 381–384

384
P. Dhankher, T. D. Sheppard
LETTER
organic layer was separated and washed with H2O (2 × 10
mL), dried over MgSO4, filtered, and concentrated to give
the aldehyde which was purified by column
chromatography.
1 H, CHO), 7.46 (s, 1 H, ArH), 7.20 (s, 1 H, ArH), 2.52 (s, 3
H, Me), 2.33 (s, 3 H, Me), 2.30 (s, 3 H, Me). 13C NMR (150
MHz, CDCl3): δ = 193.5 (CH), 138.3 (Cq), 136.4 (CH),
136.3 (Cq), 135.4 (Cq), 134.3 (Cq), 130.1 (CH), 21.2 (CH3),
20.2 (CH3), 14.3 (CH3). HRMS (EI): m/z calcd for C10H12O
[M]+: 148.0888; found: 148.0876.
2,3,5-Trimethylbenzaldehyde (1a)
Brown oil; Rf = 0.82 (EtOAc–PE, 1:1). IR: νmax = 2923,
1692, 1478 cm–1. 1H NMR (600 MHz, CDCl3): δ = 10.28 (s,
Synlett 2014, 25, 381–384
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