An oxidation of benzyl methyl ethers with NBS that selectively affords either aromatic aldehydes or aromatic methyl esters

Article abstract of DOI:10.1021/jo1004313

Either mono- or dibromination of benzyl methyl ethers can be achieved by controlling the amount of NBS and the temperature. Elimination of methyl bromide from the monobrominated intermediates produces aromatic aldehydes, whereas hydrolysis of the dibrominated intermediates affords aromatic methyl esters in good yields.

Full text of DOI:10.1021/jo1004313

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acid hydrolysis. Although the first aldehyde formation from
An Oxidation of Benzyl Methyl Ethers with NBS that
Selectively Affords Either Aromatic Aldehydes or
Aromatic Methyl Esters
benzyl methyl ether was reported by Markees in 1958,3 it has
not been widely applied due to its moderate yields and harsh
reaction conditions.4,5 Recently, a more efficient method has
been reported by Pradhan et al. utilizing an oxoammonium
salt.6 On the other hand, the oxidation of benzyl ethers to
yield esters was reported using either strong oxidizing agents
such as Cr(VI)-periodic acid,7 4-methoxy-TEMPO-cata-
lyzed sodium hypochlorite oxidation,8 or heavy metals such
as uranium hexafluoride.9 More recently, Strazzolini and
Runcio reported a facile method for the oxidation of benzyl
ethers to esters by concentrated nitric acid in dichlo-
romethane.10 Such conditions are incompatible with a
wide range of functional groups, and/or the reagents are
expensive.
Abdelrahman S. Mayhoub,† Arindam Talukdar, and
Mark Cushman*
Department of Medicinal Chemistry and Molecular
Pharmacology, School of Pharmacy and Pharmaceutical
Sciences, and the Purdue Center for Cancer Research,
Purdue University, West Lafayette, Indiana 47907. †On leave
from Faculty of Pharmacy, Al-Azhar University,
Cairo 11884, Egypt.
cushman@purdue.edu
This paper describes a method to selectively convert
benzyl methyl ethers to either aromatic aldehydes or aro-
matic methyl esters by reaction with either 1 or 2 equivalents
of NBS in carbon tetrachloride. The conversion of benzyl
methyl ethers to the corresponding methyl esters by NBS has
not been previously reported.
Received March 8, 2010
Initially, NBS oxidative cleavage of 2,6-dichlorobenzyl
methyl ether 1b in refluxing CCl4 was studied utilizing excess
NBS. The reaction mixture was illuminated by a normal 60-
W light bulb (Table 1, entry 5). The purification method was
optimized by extraction with dilute NaOH to remove the
unreacted NBS and the reaction byproducts (succinimide
and HBr). As reported, the corresponding aldehyde 2b was
obtained in low yield. Interestingly, the major product
was the corresponding methyl ester, which may be formed
through reaction of the dibromobenzyl intermediate 8 with
NaOH (Scheme 1). Next, the conditions for each oxidation
type were examined. To determine whether higher tempera-
tures are essential for bromide elimination and methyl ether
cleavage to produce the aldehyde, the reaction was con-
ducted at room temperature (entry 3). Interestingly, the only
isolable product was the methyl ester 3b, in excellent yield,
with no detectable aldehyde.
Either mono- or dibromination of benzyl methyl ethers
can be achieved by controlling the amount of NBS and
the temperature. Elimination of methyl bromide from the
monobrominated intermediates produces aromatic alde-
hydes, whereas hydrolysis of the dibrominated intermedi-
ates affords aromatic methyl esters in good yields.
The initial step in the proposed mechanism is formation of
a monobromo intermediate 4 (Scheme 1) that can either
break down, at higher temperature, into an aldehyde, or
undergo an immediate second free-radical bromination. The
relatively unstable dibromomethoxyl intermediate 8 may
react with 0.1 M NaOH to afford the corresponding ester
(Scheme 1). The reported3 moderate yields of aldehydes may
be due to the use of excess NBS, leading to formation of
dibromomethoxymethyl intermediates. These intermediates
may decompose at high reaction temperature. Unlike the
Chemical reactions that result in oxidation of benzyl ether
methylene carbons are important chemical transformations
because they often convert chemically stable functional
groups into reactive groups, including aldehydes1 and esters,2
that are widely used in organic synthesis.
Most studies on benzyl ether oxidation with NBS have
focused on cleavage to the corresponding aldehyde via
formation of N-benzylsuccinimide derivatives followed by
(3) Markees, D. G. J. Org. Chem. 1958, 23, 1490.
(4) Lovins, R. E.; Andrews, L. J.; Keef, R. M. J. Org. Chem. 1963, 28,
2847.
(5) Micheal, E. M.; Hangenah, J. A. Heterocycles 1987, 25, 117.
(6) Pradhan, P. P.; Bobbitt, J. M.; Bailey, W. F. J. Org. Chem. 2009, 74,
9524.
(1) (a) Feltenberger, J. B.; Hayashi, R.; Tang, Y.; Babiash, E. S. C.;
Hsung, R. P. Org. Lett. 2009, 11, 3666. (b) Rayabarapu, D. K.; Zhou, A.;
Jeon, K. O.; Samarakoon, T.; Rolfe, A.; Siddiqui, H.; Hanson, P. R.
Tetrahedron 2009, 65, 3180. (c) Batsomboon, P.; Phakhodee, W.; Ruchirawat,
S.; Ploypradith, P. J. Org. Chem. 2009, 74, 4009.
(2) (a) Chen, Y.; Cho, C.; Larock., R. C. Org. Lett. 2009, 11, 173.
(b) Martinez, C.; Alvarez, R.; Aurrecoechea, J. M. Org. Lett. 2009, 11, 1083.
(c) Iwai, T.; Fujihara, T.; Terao, J.; Tsuji, Y. J. Am. Chem. Soc. 2009, 131,
6668. (d) Mahboobi, S.; Dove, S.; Sellmer, A.; Winkler, M.; Eichhorn, E.;
Pongratz, H.; Ciossek, T.; Baer, T.; Maier, T.; Beckers, T. J. Med. Chem.
2009, 52, 2265.
(7) Zhang, S.; Xu, L.; Trudell, M. L. Synthesis 2005, 11, 1757.
(8) (a) Cho, S. N.; Park, C. H. Bull. Korean Chem. Soc. 1994, 15, 924.
(b) Cho, S. N.; Park, C. H. J. Korean Chem. Soc. 1995, 39, 657.
(9) Goosen, A.; McCleland, C. W.; Johnannes, P.; Vender, M. W.
S. Africa J. Chem. 1987, 40, 30.
(10) Strazzolini, P.; Runcio, A. Eur. J. Org. Chem. 2003, 2, 526.
DOI: 10.1021/jo1004313
r
Published on Web 04/07/2010
J. Org. Chem. 2010, 75, 3507–3510 3507
2010 American Chemical Society

Mayhoub et al.
JOCNote
TABLE 1. Benzyl Methyl Ether Oxidation Reactions
SCHEME 1. Postulated Reaction Pathways
SCHEME 2. Benzyl Methyl Ether Oxidation Reactions
With respect to the proposed reaction mechanism, the
optimal NBS stoichiometry is informative. In the case of
aldehyde formation, using 1.0 equivalent of NBS afforded a
slightly better yield than reported.3 In the case of ester
formation, 2.0 equivalents of NBS are necessary for optimal
yield. Using more than the optimal NBS equivalent(s) re-
sulted in lower yields.
With the optimal conditions identified, the full scope of the
methodology was investigated. A range of benzyl methyl
ethers were subjected to both reaction conditions (Scheme 2).
Unsubstituted phenyl as well as ortho-, para-, and meta-substi-
tuted derivatives were utilized (Table 1, entries 1, 2, and 6-23).
The same trends were observed. The modified reported condi-
tions (1 equivalent of NBS/reflux) afforded aldehydes in
moderate yields (Table 1, entries 2, 4, 7, and 9), while our
new method (2 equivalents of NBS/room temperature) af-
forded esters in high yields (Table 1, entries 1, 3, 6, and 8).
In the case of electron-deficient aromatic rings, the oxi-
dative ester formation proceeded smoothly in a shorter
aAdded portionwise.
reported N-benzylsuccinimide intermediates3 obtained by
conducting the reaction at high temperature, dibromo-
methoxymethyl intermediates are hypothesized to be formed
under very mild conditions.
3508 J. Org. Chem. Vol. 75, No. 10, 2010

Mayhoub et al.
JOCNote
SCHEME 3. Thiazolyl Methyl Ether Oxidation Reactions
SCHEME 4. Conversion of 1e to 3e
time (entries 18-21). In contrast, an electron-rich system
afforded only the aldehyde (entries 16 and 17).
Based on these findings, the details of the reaction me-
chanism outlined in Scheme 1 may be considered. There are
two possible pathways following the first bromination step.
First, the aldehyde-formation pathway includes elimination
of bromide anion to form the resonance-stabilized benzylic
carbocation intermediate 5 T 6. The liberated bromide anion
may then attack the intermediate 5 T 6 leading to cleavage of
the C-O bond to yield the corresponding aldehyde. The
other possibility for the monobromo derivative 4, when the
reaction is performed at room temperature, is to undergo a
second free-radical bromination to form a dibromobenzyl
intermediate 8 that decomposes in the presence of hydroxide
to afford the esters (Scheme 1).
TABLE 2. Thiazolyl Methyl Ether Oxidation Reactions
reaction conditions
starting
material
NBS
(equiv)
time
(h)
temp
(°C)
yield
(%)
entry
product
This mechanism is supported by the fact that certain
electron-withdrawing groups (e.g., p-NO2) on the aromatic
ring completely disfavor aldehyde formation, presumably by
increasing the energy of the cationic intermediate 5 T 6
(Scheme 1). On the other hand, a m-NO2 group, which would
have less of an effect on the energy of the proposed carboca-
tion intermediate 5 T 6, afforded either aldehyde or ester
products as determined by the reaction conditions (Table 1,
entries 22 and 23). Moreover, it was expected that selective
aldehyde and/or ester formation could be performed by
controlling the reaction conditions involving bis(methoxy-
methyl)benzene (1e, Scheme 4). It was expected that com-
pounds 16, 17, 18, and 3e might be obtained by treatment of
1e with 1, 2, 3, and 4 equivalents of NBS, respectively, and
controlling the temperature. Instead, the only isolable pro-
duct was the diester 3e under all reaction conditions (Table 1,
entries 10-15). The only observed difference was the yield.
In the first case (Table 1, entry 10), instead of all of the
starting material reacting with NBS (1 equivalent) to form 1
equivalent of monobromo intermediate 11 that could de-
compose to afford the aldehyde 16 (1 equivalent), approxi-
mately 20% of the starting material reacted to form the
tetrabromo intermediate 13 that decomposed into the diester
3e (0.2 equivalents), and 75% of the starting material was
recovered. Similarly, approximately 40% of the starting
material reacted when 2 equivalents NBS was used
(Table 1, entry 11), and 60% was reacted when 3 equivalents
of NBS were used with 40% of starting material being recov-
ered (Table 1, entry 13). It was assumed that the aldehyde 17
could be obtained by enhancing the cleavage step of the
1
2
3
4
5
6
1j
1j
1k
1k
1l
1
2
1
2
1
2
1
24
1
24
1
reflux
rt
reflux
rt
reflux
rt
2g
3i
2h
3j
2i
3k
74
79
55
71
57
65
1l
24
bis(monobromo) intermediate 12 (Scheme 4), and therefore,
the reaction was conducting using 2 equivalents of NBS at
reflux (Table 1, entry 12). Instead, such reaction conditions also
furnished the diester 3e in a lower yield (Table 1, entry 12) in
comparison with running the reaction at room temperature
(Table 1, entry 11). Next, when 4 equivalents of NBS were
added to the reaction mixture in portions, at a rate of 1
equivalent every 3 h, the diester 3e was obtained in an excellent
yield (Table 1, entry 15). Evidently, once bromination starts, all
of the brominated intermediates 11, 12, and 15 are rapidly
brominated until the tetrabrominated intermediate 13 is
formed and all of the available NBS is consumed.
Encouraged by the mild conditions and high yields of this
reaction, the same reaction conditions were investigated
on more complicated structures utilizing several phenyl-
thiazoles (Scheme 3). The corresponding aldehydes and
esters were obtained selectively in good yields (Table 2,
entries 1-6).
In conclusion, a method was developed to generate alde-
hydes and esters in good yields under mild conditions using
an inexpensive and commercially available reagent. Regulat-
ing the NBS/ether ratio and temperature controlled forma-
tion of aldehydes vs methyl esters. The advantages of this
J. Org. Chem. Vol. 75, No. 10, 2010 3509

Mayhoub et al.
JOCNote
newly developed methodology include no restrictions on
humidity conditions required and no heavy metal used.
Physical and spectral data of compounds 3i and 2g as
representative examples for synthesized esters and aldehydes
are shown below.
Dimethyl 2-(4-Chlorophenyl)thiazole-4,5-dicarboxylate (3i):
yellow solid (79%); mp 72-73 °C; 1H NMR (CDCl3) δ 7.90 (d, J
= 8.4 Hz, 2 H), 7.43 (d, J = 8.4 Hz, 2 H), 4.00 (s, 3 H), 3.94 (s, 3
H); 13C NMR (CDCl3) δ 169.8, 160.3, 151.6, 137.7, 130.4, 129.3,
128.1, 53.1, 53.0; MS (m/z, rel intensity) 336 (MNaþ, 36.7), 334
(MNaþ, 100); HRMS (ESI) m/z MNaþ 333.9921, calcd for
C13H10ClNO4SNa 333.9917.
Experimental Section
General Procedure for Preparation of Esters. The methyl ether
(1 mmol) and NBS (356 mg, 2 mmol) were added to CCl4
(10 mL). The reaction mixture was stirred at room temperature
for 3-24 h and illuminated by a 60-W light bulb. The light
source was placed 10 cm away from the flask. The solvent was
removed under reduced pressure. An aq NaOH solution (0.1 M,
3 mL) was added to the residue, the mixture was stirred for
15-30 s at room temperature, and then EtOAc (10 mL) was
added. The organic layer was separated, dried over anhydrous
MgSO4, and removed under reduced pressure. The crude
products were 92-98% pure. For further purification, the
obtained oil/solid was subjected to chromatography. The reac-
tion worked properly with crystallized NBS, not with the crude
form.
General Procedure for Preparation of Aldehydes. The methyl
ether (1 mmol) and NBS (178 mg, 1 mmol) were added to CCl4
(15 mL). The reaction mixture was heated at reflux for 1 h and
was illuminated by a 60-W light bulb. The light source was
placed 10 cm away from the flask. The solvent was removed
under reduced pressure. The obtained mass was partitioned
between EtOAc (10 mL) and NaOH (0.1 M NaOH, 5 mL). The
organic layer was separated, dried over anhydrous MgSO4, and
removed under reduced pressure. The obtained oil/solid could
then be purified by making a sodium bisulfite addition com-
pound or by chromatography. The reaction worked properly
with crystallized NBS, not with the crude form.
Methyl 2-(4-Chlorophenyl)-4-formylthiazole-5-carboxylate
1
(2g): white solid (74%); mp 139-140 °C; H NMR (CDCl3) δ
10.61 (s, 1 H), 7.96 (d, J = 8.7 Hz, 2 H), 7.45 (d, J = 8.7 Hz, 2 H),
3.99 (s, 3 H); 13C NMR (CDCl3) δ 184.8, 169.8, 160.4, 155.7,
138.1, 135.3, 130.1, 129.3, 128.4, 53.3; MS (m/z, rel intensity)
284 (MHþ, 36.7), 282 (MHþ, 100); HRMS (ESI) m/z MHþ
281.9987, calcd for C12H9ClNO3S 281.9992.
Acknowledgment. This work was sponsored by the NIH/
NIAID Regional Center of Excellence for Biodefense and
Emerging Infectious Diseases Research (RCE) Program.
Support is gratefully acknowledged from the Region V
“Great Lakes” RCE (NIH award 1-U54-AI-057153). This
research was also supported by a fellowship to A.S.M. from
the Egyptian government.
Supporting Information Available: Preparation of methyl
ethers, characterization data, and copies of NMR spectra for all
new and known compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
3510 J. Org. Chem. Vol. 75, No. 10, 2010