Oxidative preparation of aromatic orthocarboxylates from aldehydes

Article abstract of DOI:10.1055/s-0029-1219793

Aromatic orthocarboxylates are oxidatively synthesized in good yields from hydroxyacetals derived from the corresponding aromatic aldehydes. In situ generation of hydroxyacetal and successive oxidation by DDQ provides a one-pot preparation of aromatic orthocarboxylates from aldehydes. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1219793

1190
LETTER
Oxidative Preparation of Aromatic Orthocarboxylates from Aldehydes
O
xidative Preparat
i
ionof
r
romati
o
O
rthocarbo
y
xylates uki Tanabe,b Xinyao He,a Prasath Kothandaraman,a Motoki Yamane*a
a
Division of Chemistry and Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang Technological University,
21 Nanyang Link, Singapore 637371, Singapore
Fax +6567911961; E-mail: yamane@ntu.edu.sg
Department of Chemistry, Graduate School of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8571, Japan
b
Received 1 February 2010
R2
R2
OH
R2
OH
[O]
Abstract: Aromatic orthocarboxylates are oxidatively synthesized
in good yields from hydroxyacetals derived from the corresponding
aromatic aldehydes. In situ generation of hydroxyacetal and succes-
sive oxidation by DDQ provides a one-pot preparation of aromatic
orthocarboxylates from aldehydes.
cat. H+
R2C(CH2OH)3
O
O
O
O
O
O
O
R1
O
H
R1
H
R1
R1
Key words: orthoester, oxidation, acetal, aldehyde, one-pot reac-
1
2
A
3
tion
Scheme 1
Table 1 Preparation of Hydroxy Acetal 2a
Due to their stability towards nucleophiles and strong
bases and ease of conversion into carboxylic acid deriva-
tives by acidic solvolysis, orthoesters have been paid
much attention as masked carboxylic acids and esters.1
Orthoesters are also important as a building block in or-
ganic synthesis in their own right.2 It had been difficult to
prepare orthoesters directly by reaction of carboxylic ac-
ids or esters with alcohols under acid catalysis, the condi-
tions commonly used in the equivalent acetal formation
from aldehydes or ketones.1 Since E. J. Corey and N. Raju
developed a practical synthetic method, involving Lewis
acid mediated rearrangement of oxetane esters,3 orthoe-
sters have been widely used in organic synthesis, especial-
ly in natural product synthesis.4 Improvements to this
oxetane ester method have been reported5 and other pre-
cursors such as nitriles,6 imidoesters,7 and orthoesters (for
orthoester exchange)8 have been used. Under these reac-
tion conditions, however, functional-group acceptability
is limited. Herein we report an oxidative preparation of bi-
cyclic aromatic orthocarboxylates from aldehydes.
Ph
O
OH
O
cat. TsOH⋅H2O
benzene, reflux
PhC(CH2OH)3
+
O
R
H
R
1
4
2
Entry
R
Product
2a
Yield (%)b,c
1
2
3
4
5
6
7
8
9
1a naphthalen-2-yl
1b 4-Me2NC6H4
1c 4-MeOC6H4
1d 4-MeC6H4
72
81
79
73
80
69
71
77
75
2b
2c
2d
1e Ph
2e
1f 4-BrC6H4
2f
1g 4-MeO2CC6H4
1h 2-phenylethen-1-yl
1i 2-phenylethyl
2g
2h
The conversion of an aldehyde into a bicyclic orthocar-
boxylate 3 was designed as depicted in Scheme 1,9 in
which the key intermediate, dialkoxy carbocation A, is
generated by an oxidation of hydroxyl acetal 2, which
would be easily prepared from aldehyde 1 and a triol un-
der acid-catalyzed azeotropic conditions.
2i
a Reaction conditions: aldehyde 1 (10 mmol), triol (12.5 mmol),
TsOH·H2O (0.2 mmol), benzene (40 mL), reflux.
b Isolated yield of a major diastereomer separated by column chroma-
tography and recrystallization (hexane–EtOAc).
c The relative stereochemistry of the major product was determined by
NOESY analysis.
Hydroxy acetals 2 were prepared from the corresponding
aldehydes and triol 410 in good yield as a mixture of dia-
stereoisomers in 10:1 to 7:1 ratio (Table 1). The major
isomers were isolated pure by silica gel column chroma-
tography (hexane–EtOAc = 4:1) followed by recrystalli-
zation (hexane–EtOAc).11
The oxidation of isolated hydroxyl acetals 2 was exam-
ined and various oxidants, such as N-bromosuccinimide
(NBS),12 cerium ammonium nitrate (CAN)13 and
14
Pd(OAc)2/O2 were tested. Finally, dichloro-5,6-dicy-
ano-1,4-benzoquinone (DDQ) was found to be suitable
for this purpose.15 The investigation of solvents and reac-
tion temperatures in the reactions of hydroxy acetal 2a
with DDQ is summarized in Table 2.
SYNLETT 2010, No. 8, pp 1190–1192
Advanced online publication: 31.03.2010
DOI: 10.1055/s-0029-1219793; Art ID: D03010ST
x
x.
x
x.
2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

LETTER
Oxidative Preparation of Aromatic Orthocarboxylates
1191
Table 3 Preparation of Orthoester from Hydroxy Acetala
Particularly in halogenated solvents, the desired orthoe-
ster 3a was obtained along with oxidative hydrolysis
product 5. Increasing the reaction temperature resulted in
the orthoester 3a being obtained in higher yield (entries 3–
7). Finally, oxidation in refluxing 1,2-dichloroethane in
the presence of 4 Å molecular sieves gave orthoester 3a in
94% yield (entry 7).
Ph
Ph
OH
DDQ, 4 Å MS
DCE, reflux
O
O
O
O
O
Ar
2a–g
Ar
3a–g
Table 2 Optimization of Oxidative Preparation of Orthoester 3aa
Entry Hydroxy acetal 2
DDQb Time (h)Orthoester
Ar
3
Yield (%)
94
Ph
Ph
OH
Ph
OH
OH
1
2c
3
4
5
6
7
8
naphthalen-2-yl
4-Me2NC6H4
4-MeOC6H4
4-MeC6H4
Ph
2a
2b 1.2
2c 1.2
2d 2.0
1.2
5
3a
DDQ
+
O
O
O
O
O
O
O
0.5
7
3b 93
3c 92
3d 78
Ar
Ar
Ar
Ar = naphthalen-2-yl
2a
3a
5
20
7
Entry Solvent Temp (bp)b
Time Yield of Yield Yield of
(h) 3a (%) of 5 (%)2a (%)c
2e
2f
10.0
3e
3f
79
89
14
1
toluene r.t.
20
14
0
0
30
0
58
88
21
7
4-BrC6H4
10.0
10.0
11
10
0.2
2
MeCN r.t.
4-MeO2CC6H4
2g
3g
3
CH2Cl2 r.t.
10 20
CH2Cl2 reflux (40 °C) 8 62
41
24
14
12
6
2-phenylethen-1-yl 2h 1.2
3h 93
a Reaction conditions: hydroxyl acetal 2 (0.2 mmol), DDQ (0.24–2.0
mmol), 4 Å MS (100 mg), DCE (5 mL).
4
5
CCl4
CCl4
DCE
reflux (77 °C) 12 72
0
b Numbers show the molar amounts of DDQ.
c Reaction was performed at r.t.
6d
7d
reflux (77 °C)
reflux (84 °C)
4
5
87
94
0
0
Table 4 One-Pot Preparation of Aromatic Orthocarboxylate from
a Reaction conditions: hydroxyl acetal 2a (0.2 mmol), DDQ (0.24
mmol), solvent (5 mL).
Aldehydea
Ph
b Boiling point of the solvent.
PhC(CH2OH)3
c Numbers in parentheses show recovery of the starting material 2a.
d 4 Å MS added (100 mg/0.2 mmol of 2a).
O
cat. TsOH⋅H2O, DDQ
O
O
O
DCE–benzene (1:1)
Ar
H
Ar
Subsequently, the transformation of various hydroxyace-
tals of aromatic aldehydes was examined under the above
optimized reaction conditions (Table 2). In the case of
electron-rich aromatic acetals, the reactions proceeded
smoothly, and the desired orthoesters were obtained in
high yield (entries 2–4). Notably, hydroxyl acetal 2b, hav-
ing a p-dimethylaminophenyl group, was consumed rap-
idly at room temperature to give orthoester 3b in 93%
yield (entry 2). On the other hand, electron-deficient ace-
tals 2e and 2f required longer reaction times and gave low-
er yields of orthoesters 3. Even in such cases, high yields
were achieved by using excess of DDQ (entries 5 and 6).
Hydroxyacetal 2g, having a p-MeO2C group, however,
was not easily oxidized even by excess of DDQ and re-
sulted in only a 14% yield of orthoester 3g (entry 7). The
process was not restricted to aryl aldehydes; hydroxy ace-
tal 2h, derived from an alkenyl aldehyde, was found to be
efficiently converted into the corresponding a,b-unsatur-
ated orthoester 3h (entry 8).
1
3
Entry Ar
Time (h) Orthoester
3
Yield (%)
1
naphthalen-2-yl
4-Me2NC6H4
1a
1b
1c
1d
20
10c
24
24
20
24
24
3a
3b
3c
3d
92
92
90
87
2b
3
4-MeOC6H4
4-MeC6H4
4
5b
6
2-phenylethen-1-yl 1h
3hc 92
2-furyl
1j
3j
88
91
7
2-thienyl
1k
3k
a Reaction conditions: aldehyde 1 (0.5 mmol), triol (0.55 mmol),
DDQ (0.55 mmol), TsOH·H2O (0.055mmol) with Soxhlet filled with
4 Å MS.
b DDQ was added after the confirmation of complete consumption of
aldehyde.
We then attempted one-pot preparation of orthoesters
from aldehydes without isolation of the intermediate hy-
droxyl acetals (Table 4). When naphthalenecarbaldehyde
1a was treated with triol 4 and catalytic amount of tolu-
enesulfonic acid hydrate (TsOH·H2O) in the presence of
c The reaction time after the addition of DDQ.
1.2 molar amounts of DDQ and heated at reflux tempera-
ture in a dichloromethane–benzene (1:1) mixed solvent,
Synlett 2010, No. 8, 1190–1192 © Thieme Stuttgart · New York

1192
H. Tanabe et al.
LETTER
orthoester 3a was obtained in 92% yield (entry 1). How-
ever, p-dimethylaminobenzaldehyde (1b) and cinnamal-
dehyde (1h) were found to be easily oxidized by DDQ
before the acetalization and gave complex mixtures.
When DDQ was added after the complete acetalyzation of
these aldehydes, the desired orthoesters 3b and 3h were
obtained in good yields (entries 2 and 5). This methodol-
ogy is applicable for the preparation of heteroaromatic or-
thocarboxylates (entries 6 and 7).
References and Notes
(1) For reviews, see: (a) Greene, T. W.; Wuts, P. G. M.
Protective Groups in Organic Synthesis, 3rd ed.; Wiley:
New York, 1999, 437. (b) DeWolfe, R. H. Carboxylic Ortho
Acid Derivatives; Academic Press: New York, 1970.
(c) DeWolfe, R. H. Synthesis 1974, 153. (d) Pindur, U.;
Müller, J.; Flo, C.; Witzel, H. Chem. Soc. Rev. 1987, 16, 75.
(2) Wipf, P.; Tsuchimoto, T.; Takahashi, T. Pure Appl. Chem.
1999, 71, 415.
(3) Corey, E. J.; Raju, N. Tetrahedron Lett. 1983, 24, 5571.
(4) (a) Liao, S.-G.; Chen, H.-D.; Yue, J.-M. Chem. Rev. 2009,
109, 1092. (b) Stanoeva, E.; He, W.; De Kimpe, N. Bioorg.
Med. Chem. 2005, 13, 17. (c) Corey, E. J.; Kang, M.; Desai,
M. C.; Ghosh, A. K.; Houpis, I. N. J. Am. Chem. Soc. 1988,
110, 649.
(5) (a) Wipf, P.; Aslan, D. C. J. Org. Chem. 2001, 66, 337.
(b) Wipf, P.; Xu, W.; Kim, H.; Takahashi, H. Tetrahedron
1997, 53, 16575. (c) Wipf, P.; Xu, W. J. Org. Chem. 1993,
58, 5880.
(6) (a) McElvain, S. M.; Nelson, J. W. J. Am. Chem. Soc. 1942,
64, 1825. (b) Shevchenko, V. I.; Koval, A. A. Zh. Obshch.
Khim. 1968, 38, 22.
Additionally, orthoesters were expected to be prepared
from the corresponding alcohols if the alcohols were oxi-
dized to aldehyde by DDQ. As DDQ is used to deprotect
p-methoxybenzyl (PMB) ethers,16 we attempted the con-
version of p-methoxybenzyl alcohol to the orthoester
(Scheme 2). When p-methoxybenzyl alcohol was treated
with triol 4, DDQ, and a catalytic amount of TsOH·H2O in
a mixed solvent of 1,2-dichloroethane and benzene (1:1),
the corresponding orthoester 2c was obtained in 89%
yield.
(7) (a) McElvain, S. M.; Nelson, J. W. J. Am. Chem. Soc. 1942,
64, 1825. (b) McElvain, S. M. J. Am. Chem. Soc. 1950, 72,
1661. (c) McElvain, S. M.; Schroeder, J. P. J. Am. Chem.
Soc. 1949, 71, 40. (d) McElvain, S. M.; Stevens, C. L. J. Am.
Chem. Soc. 1946, 68, 1917.
(8) (a) Arbusov, A. A.; Yuldasheva, E. K. Dokl. Akad. Nauk
SSSR 1950, 70, 231. (b) Stetter, H.; Reske, E. Chem. Ber.
1970, 103, 639. (c) Hebky, J. Collect. Czech. Chem.
Commun. 1948, 13, 442.
PhC(CH2OH)3
cat. TsOH⋅H2O, DDQ
DCE–benzene (1:1), 20 h
OH
MeO
Ph
Ph
O
OH
O
O
O
O
O
Ar
H
(9) Electrochemocal oxidation of acetals is reported, see:
Scheeren, J. W.; Goossens, H. J. M.; Top, W. H. Synthesis
1978, 283.
(10) Rockendorf, N.; Sperling, O.; Lindhorst, K. Aust. J. Chem.
2002, 55, 87.
Ar
89%
Ar
Ar = 4-MeOC6H4
Scheme 2
(11) We separated the diastereomers for the purpose of structural
analysis of the major stereoisomers. This separation is surely
unnecessary for the subsequent step.
(12) Pieck, J. C.; Kuch, F.; Grolle, F.; Linne, U.; Carell, T. J. Am.
Chem. Soc. 2006, 128, 1404.
In conclusion, a convenient method to prepare aromatic
orthocarboxylates has been developed starting from alde-
hydes as their precursors.
(13) (a) Classon, B.; Garegg, P. J.; Samuelsson, B. Acta Chem.
Scand. Ser. B 1984, 38, 419. (b) Johansson, R.; Samuelsson,
B. J. Chem. Soc., Perkin Trans. 1 1984, 2371. (c) Georg, G.
I.; Mashava, P. M.; Akgün, E.; Milstead, M. W. Tetrahedron
Lett. 1991, 32, 3151. (d) Wang, Y.; Babirad, S. A.; Kishi, Y.
J. Org. Chem. 1992, 57, 468.
General Procedure for the One-Pot Preparation of Orthocar-
boxylic Ester 3
To a 30 mL three-neck round-bottom flask equipped with a Soxhlet
condenser containing 4 Å MS, a solution of aldehyde (0.5 mmol),
triol (0.55 mmol), and PTSA·H2O (0.055 mmol) in a mixture of
DCE (5 mL) and benzene (5 mL) was added. After heating for the
period described in the text, the reaction mixture was filtered though
Celite. The volatile materials were removed under reduced pressure
and the crude material purified by column chromatography on Flo-
risil (hexane–EtOAc = 2:1).
(14) Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. J. Org.
Chem. 1999, 64, 6750.
(15) (a) Findlay, J. W. A.; Turner, A. B. J. Chem. Soc. 1971, 23.
(b) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.;
Yonemitsu, O. Tetrahedron 1986, 42, 3021. (c) Tanaka, T.;
Oikawa, Y.; Hamada, T.; Yonemitsu, O. Tetrahedron Lett.
1986, 27, 3651. (d) Oikawa, Y.; Tanaka, T.; Horita, K.;
Yonemitsu, O. Tetrahedron Lett. 1984, 25, 5397.
(e) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron
Lett. 1982, 23, 885.
1-(Naphthalen-2-yl)-4-phenyl-2,6,7-trioxabicyclo [2.2.2]octane
(3a)
1H NMR (400 MHz, CDCl3): d = 4.55 (6 H, s), 7.20–7.22 (2 H, m),
7.33–7.34 (1 H, m), 7.37–7.41 (2 H, m), 7.46–7.50 (2 H, m), 7.76–
7.78 (1 H, m), 7.82–7.89 (3 H, m), 8.19 (1 H, s). 13C NMR (100
MHz, CDCl3): d = 37.0, 72.2, 108.2, 123.2, 125.1, 125.2, 126.0,
126.4, 127.5, 127.9, 128.0, 128.6, 129.1, 132.7, 133.6, 134.4, 135.8.
IR (ZnSe): 3054, 1326, 1268, 1132, 1022, 970, 900, 858, 694 cm–1.
Anal. Calcd (%) for C21H18O3: C, 79.22; H, 5.70. Found: C, 79.11;
H, 5.82.
(16) PMB ethers are known to be oxidized by DDQ to afford
acetals in the presence of alcohols, see: Ito, Y.; Ohnishi, Y.;
Ogawa, T.; Nakahara, Y. Synlett 1998, 1102.
Synlett 2010, No. 8, 1190–1192 © Thieme Stuttgart · New York

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