Selective synthesis of 2-Aryl-2 H - And 4-Aryl-4 H -3,5-diformylpyrans from acetal with aromatic aldehydes catalyzed by lewis acids

Article abstract of DOI:10.1055/s-0030-1259681

A selective method for 2-aryl-2H- and 4-aryl-4H-3,5-diformylpyrans synthesis from 1,1,3,3-tetramethoxypropane and aromatic aldehydes was developed using an FeClcatalyst in MeOH-AcOH and an AlClcatalyst in DMA-AcOH. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1259681

LETTER
857
Selective Synthesis of 2-Aryl-2H- and 4-Aryl-4H-3,5-diformylpyrans from
Acetal with Aromatic Aldehydes Catalyzed by Lewis Acids
L
ewis AcidCataly
o
zedRegiose
r
lective
F
i
ormatio
h
nof PyranD
i
erivati
d
ves e Horikawa, Yasushi Obora,* Yasutaka Ishii*
Department of Chemistry and Materials Engineering, Faculty of Chemistry, Materials and Bioengineering and ORDIST, Kansai University,
Suita, Osaka 564-8680, Japan
Fax +81(6)63394026; E-mail: obora@kansai-u.ac.jp; E-mail: r091001@kansai-u.ac.jp
Received 21 January 2011
these diformylpyrans by simply switching the catalyst and
Abstract: A selective method for 2-aryl-2H- and 4-aryl-4H-3,5-di-
the solvent system in easily accessible substrates.
formylpyrans synthesis from 1,1,3,3-tetramethoxypropane and aro-
matic aldehydes was developed using an FeCl3 catalyst in MeOH–
AcOH and an AlCl3 catalyst in DMA–AcOH.
1,1,3,3-Tetramethoxypropane (1) with benzaldehyde (2a)
was chosen as the model substrate, and the reaction was
Key words: acetals, pyrans, aldehydes, Lewis acids, catalysis
carried out under various conditions (Table 1).
CHO
O
Pyrans are core structures in biologically active materials
and natural products.1,2 In particular, formylpyran is a key
fragment in pharmaceuticals such as antileishmanial
drugs.3 Despite the widespread use of the formyl function-
ality in synthetic chemistry, a limited number of works on
the synthesis of formylpyrans and their derivatives have
been reported.4 Shaabani and co-workers reported the
preparation of dialkyl 5-formyl-2H-pyran-2,3-dicarboxy-
lates by an intramolecular Wittig reaction.4a Perumal and
co-workers reported the preparation of 2-imino-2H-pyr-
ancarboxaldehydes by the reaction of b-keto amides with
a Vilsmeier reagent.4b
OMe OMe
OMe
Ar
MeO
CHO
3
1
Lewis acid (cat.)
+
+
ArCHO
2
OHC
Ar
O
CHO
4
Scheme 1
For example, reaction of 1 (1 mmol) with 2a (5 mmol) in
the presence of FeCl3⋅6H2O (0.1 mmol, 20 mol% based on
the amount of 1 used) in MeOH–AcOH (1 mL:2 mL) at
50 °C for 15 hours afforded 2-phenyl-2H-3,5-diformylpy-
ran (3a) in 75% yield along with 4-phenyl-4H-3,5-di-
formylpyran (4a) in only 2% yield (Table 1, entry 1). The
reaction was highly regioselective and afforded 3a almost
exclusively (the selectivity of 3a was 97%). The reaction
using FeCl3 gave similar results, and 4a was not detected
at all by GC analysis (entry 2). In this reaction, the use of
excess amount (5 equiv) of 2a was effective to achieve the
reaction in high yields. Thus, when 1 equivalent (1 mmol)
and 3 equivalents (3 mmol) of 2a were used toward 1, the
yield of 3a was decreased to 27% and 48%, respectively
(entries 3 and 4).
Although diformylpyrans are potentially far better build-
ing blocks in organic synthesis, less attention has been
paid to their preparation.5 For example, 4-phenyl-4H-3,5-
diformylpyran (4a) was prepared by oxidation of cyclo-
heptatrienylmalonaldehyde to benzylidenemalonalde-
hyde, followed by treatment with malonaldehyde.5a
However, the existing approach requires a multistep pro-
cess, and stoichiometric amounts of waste salts are
formed in the course of the reaction. The development of
a facile and one-step synthetic method for the synthesis of
2H- and 4H-diformylpyrans, using easily accessible sub-
strates, is therefore a highly desirable and challenging tar-
get.
We recently reported that the FeCl3·6H2O-catalyzed
cross-cyclodimerization of acetals, such as 3,3-diethoxy-
propionate with active methylene compounds, leads to
coumalates as the major products.6 During the course of
this study, we describe here a novel selective synthetic
method for 2-aryl-2H-3,5- and 4-aryl-4H-3,5-diformyl-
pyrans from 1,1,3,3-tetramethoxypropane and aromatic
aldehydes using a Lewis acid catalyst (Scheme 1). This
reaction provides a selective method for the synthesis of
The catalytic activity and the selectivity of this reaction
were markedly influenced by the choice of Lewis acid; it
was found that FeCl3⋅6H2O was the best catalyst for regio-
selective formation of 3a (entry 1). Reactions using other
selected Lewis acids such as CeCl3⋅7H2O, YbCl3⋅6H2O,
and ScCl3⋅6H2O resulted in a decrease in the yields of 3a
(entries 5–7). The reaction was also affected by the sol-
vent employed, and the best result with regard to selective
formation of 3a was obtained in a mixed solvent of MeOH
(1 mL) and AcOH (2 mL). Here, AcOH would play an im-
portant role in the efficient generation of 1,3-diformylpro-
pane (A, vide infra) by acid-assisted hydrolysis of 1.6,7
SYNLETT 2011, No. 6, pp 0857–0861
x
x.
x
x.
2
0
1
1
Advanced online publication: 22.02.2011
DOI: 10.1055/s-0030-1259681; Art ID: U00611ST
© Georg Thieme Verlag Stuttgart · New York

858
N. Horikawa et al.
LETTER
reaction using AlCl3⋅6H2O as the catalyst, under the same
conditions as in entry 1, was lower than that of the reac-
tion using FeCl3⋅6H2O as the catalyst (entry 10). In addi-
tion, a divergent inverse regiochemistry was apparent and
4-phenyl-4H-3,5-diformylpyran (4a) was obtained as the
major isomer (entry 10).
Table 1 Lewis Acid Catalyzed Coupling of 1,1,3,3-Tetramethoxy-
propane (1) with Benzaldehyde (2a) under Various Conditionsa
CHO
O
OMe OMe
OMe
Ph
CHO
MeO
1
3a
Further screening of the reaction revealed that selection of
appropriate solvents enhances the reactivity and selectiv-
ity of the AlCl3⋅6H2O-catalyzed reaction. The reaction of
1 with 2a in a mixed solvent of N,N-dimethylacetamide
(DMA) and AcOH (1:2) gave the highest yield and selec-
tivity for 4a (entry 12). The solvent effect was investigat-
ed by examining the reaction in several selected solvents
combined with AcOH (entries 12–15). The use of N,N-
dimethylformamide (DMF) gave a comparable result to
that obtained with DMA, but other solvents, for example,
dimethyl sulfoxide (DMSO) and 1,3-dimethyl-2-imidazo-
lidinone (DMI), gave low yields of 4a with low regiose-
lectivities (entries 13–15). As mentioned above, the use of
AcOH as solvent is crucial to achieve the reaction. For ex-
ample, in the reaction using only DMA as the solvent, 1
was not completely converted, and the yield of 4a was
only 2% (entry 17). Furthermore, the reaction in the ab-
sence of DMA resulted in complete conversion of 1, but
no desired products 3a and 4a were obtained (entry 18).
These results indicate that both AcOH and a coordinating
solvent like DMA are necessary to achieve the
AlCl3⋅6H2O-catalyzed reaction.
Lewis acid (cat.)
Solvent
+
+
OHC
Ph
PhCHO
2a
O
CHO
4a
Entry Lewis acid
Solvent
(mL)
Yield of Yield of
3a (%)b 4a (%)b
1
FeCl3·6H2O
FeCl3
MeOH (1)–AcOH (2)
MeOH (1)–AcOH (2)
MeOH (1)–AcOH (2)
MeOH (1)–AcOH (2)
75 (69)
70
27
48
29
33
46
n.d.
48
8
2
n.d.
1
2
3c
4d
5
FeCl3·6H2O
FeCl3·6H2O
2
CeCl3·7H2O MeOH (1)–AcOH (2)
YbCl3·6H2O MeOH (1)–AcOH (2)
4
6
4
7
ScCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
AlCl3·6H2O
AlCl3
MeOH (1)–AcOH (2)
MeOH (3)
4
8
n.d.
n.d.
21
29
52 (43)
41
22
30
17
2
9
AcOH (3)
As Lewis acid, protic acid such as p-toluenesulfonic acid
was ineffective to afford 3a and 4a in only 2% and 9%
yields, respectively, under the conditions of entry 1.
10
MeOH (1)–AcOH (2)
MeOH (1)–AcOH (2)
DMA (1)–AcOH (2)
DMF (1)–AcOH (2)
DMSO (1)–AcOH (2)
DMI (1)–AcOH (2)
DMA (1)–AcOH (2)
DMA (3)
11
12
13
14
15
16
17
18
19
8
The substrate scope was then investigated under the opti-
mized conditions for the formation of 3, using
FeCl3⋅6H2O as the catalyst in a MeOH–AcOH solvent
system, as shown in Table 1, entry 1. The results are listed
in Table 2. The reactions of 1 with a variety of aromatic
aldehydes 2a–i afforded the corresponding 2-aryl-2H-3,5-
diformylpyrans 3a–i in moderate to excellent yields with
high regioselectivities (Table 2). Among the aldehydes 2
examined in this study, aromatic aldehydes having elec-
tron-withdrawing groups gave higher yields of 3 than did
aromatic aldehydes having electron-donating groups (en-
tries 1–7). When 2-naphthaldehyde (2h) was used, 2-
naphthyl-2H-3,5-diformylpyran (3h) was obtained exclu-
sively, in 78% isolated yield (entry 8). The reaction with
trans-cinnamaldehyde (2i) was sluggish and gave the cor-
responding diformylpyran (3i) in low yield (10%;
Table 2, entry 9). The use of aliphatic aldehyde such as
2,2-dimethylpropionaldehyde did not induce diformylpy-
ran derivatives at all.
AlCl3·6H2O
AlCl3·6H2O
AlCl3·6H2O
AlCl3·6H2O
AlCl3
5
6
12
19
2
AlCl3·6H2O
AlCl3·6H2O
FeCl3·6H2O
n.d.
3
AcOH (3)
3
DMA (1)–AcOH (2)
10
9
a Conditions: 1 (1 mmol) was allowed to react 2a with (5 mmol) in the
presence of Lewis acid (0.1 mmol) in solvent at 50 °C for 15 h.
b GC yields based on 1 used. The numbers in parentheses show iso-
lated yields.
c Compound 2a (1 mmol) was used.
d Compound 2a (3 mmol) was used.
Indeed, the reaction in the absence of AcOH did not pro- We then examined the reaction of 1 with 2 using
duce any 3a (entry 8). In this reaction, the use of MeOH AlCl3⋅6H2O in DMA–AcOH, as shown in Table 1, entry
as a cosolvent with AcOH gave a higher yield of 3a (entry 10. The results are listed in Table 3. Various aromatic al-
1 vs. entry 9).
dehydes 2a–i were reacted with 1 to afford the corre-
sponding 4-aryl-4H-3,5-diformylpyrans 4 in moderate to
good yields with high regioselectivities (Table 3). The re-
giochemistry of the products, that is, 2-aryl-2H-3,5-di-
It is noteworthy that changing the Lewis acid not only had
a significant impact on the reactivity, but also affected the
selectivity between 3a and 4a. Thus, the reactivity of the
Synlett 2011, No. 6, 857–861 © Thieme Stuttgart · New York

LETTER
Lewis Acid Catalyzed Regioselective Formation of Pyran Derivatives
859
Table 2 FeCl3⋅6H2O-Catalyzed Synthesis of 2-Aryl-2H-3,5-di-
formylpyrans 3 from 1 and Aromatic Aldehydes 2a
Table 3 AlCl3⋅6H2O-Catalyzed Synthesis of 4-Aryl-4H-3,5-di-
formylpyrans 4 from 1 with Aromatic Aldehydes 2a
OMe OMe
OMe OMe
OHC
O
AlCl3⋅6H2O (cat.)
DMA, AcOH
ArCH2O
+
MeO
OMe
MeO
OMe
Ar
1
2
1
CHO
FeCl3⋅6H2O (cat.)
O
CHO
+
MeOH, AcOH
4
ArCHO
Ar
2
CHO
3
Entry Aldehyde 2
Yield of product 3
Selectivity
(%)b
of 3/4c
Entry Aldehyde 2
Yield of product 3
Selectivity
OHC
(%)b
of 3/4c
O
H
CHO
O
O
CHO
R
R
H
1
2
3
4
5
6
7
2a R = H
4a 43
1:10
CHO
R
R
d
2b R = Me
4b 34
4c 40
4d 60
4e 73
4f 66
4g 80
–
1
2
3
4
5
6
7
2a R = H
3a 69
38:1
27:1
15:1
25:1
12:1
10:1
7:1
2c R = OMe
2d R = Cl
1:7
2b R = Me
2c R = OMe
2d R = Cl
3b 56
3c 35
3d 62
3e 57
3f 65
3g 85
1:16
1:70
2e R = CN
2f R = CHO
2g R = CF3
d
–
2e R = CN
2f R = CHO
2g R = CF3
1:53
1:22
OHC
O
O
H
8
9
CHO
O
O
CHO
d
H
8
9
–
2h
4h 51
CHO
OHC
O
O
2h
3h 78
d
–
Ph
CHO
Ph
H
O
O
CHO
2i
6:1
4i 34
Ph
Ph
H
a Conditions: 1 (1 mmol) was allowed to react with 2 (5 mmol) in the
presence of AlCl3·6H2O (0.1 mmol) in DMA–AcOH (1 mL:2 mL) at
50 °C for 15 h.
CHO
2i
3i 10
a Conditions: 1 (1 mmol) was allowed to react with 2 (5 mmol) in the
presence of FeCl3·6H2O (0.1 mmol) in MeOH–AcOH (1 mL:2 mL) at
50 °C for 15 h.
b Isolated yields of 4 as pure form.
c Determined by GC.
d Compound 4 was obtained exclusively, and compound 3 was not de-
tected by GC.
b Isolated yields of 3 as pure form.
c Determined by GC.
d Compound 3 was obtained exclusively, and compound 4 was not de-
tected by GC.
When FeCl3⋅6H2O is used as the catalyst, an enolate gen-
erated from A reacts with B through 1,2-addition to the
C=O group of B to afford C. Intramolecular cyclization
then gives 3 as the product (path a, Scheme 2). In contrast,
when the reaction is performed with an AlCl3⋅6H2O cata-
lyst in AcOH–DMA, the enolate generated from A reacts
with B by 1,4-addition (Michael-type addition), prior to
the 1,2-addition to the C=O group, giving the intermediate
D. Intramolecular cyclization affords 4 as the product
(path b, Scheme 2).
formylpyrans 3 or 4-aryl-4H-3,5-diformylpyrans 4, could
therefore be changed by choosing a suitable catalyst/sol-
vent system.
The detailed mechanism of this reaction has not yet been
fully confirmed at this moment, but a plausible reaction
mechanism for the transformation of 1 with 2 into 3 and 4
is shown in Scheme 2.
The reaction is thought to initiate the acid-assisted hydrol-
ysis of 1 to the intermediate 1,3-diformylpropane (A).6–8
Subsequently, an aldol-type condensation of A with 2, un-
der the influence of a Lewis acid (FeCl3⋅6H2O or
AlCl3⋅6H2O), affords the a,b-unsaturated aldehydes B.9
Heathcock and co-workers published a detailed discus-
sion of 1,2- vs. 1,4-addition of a,b-unsaturated alde-
hydes.10 They reported that a,b-unsaturated aldehydes
precede 1,2-addition.11 In contrast, the alternative Michael-
type reaction of a,b-unsaturated aldehydes has conven-
Synlett 2011, No. 6, 857–861 © Thieme Stuttgart · New York

860
N. Horikawa et al.
LETTER
LA
OMe OMe
OMe
O
O
O
O
O
Lewis acid
ArCHO
+
MeO
H
H
Ar
H
H
H
2
1
A
LA
O
O
CHO
CHO
O
O
O
H
H
LA = FeCl3⋅6H2O
– LA
Ar
H
Ar
Ar
path a
– H2O
– H2O
CHO
B
CHO
C
CHO
3
LA
O
O
O
H
OHC
Ar
OHC
Ar
O
OH
H
O
– H2O
H
LA = AlCl3⋅6H2O
– LA
Ar
H
path b
– H2O
CHO
CHO
CHO
B
4
D
Scheme 2 Plausible reaction mechanism
m/z (%) = 214 (26) [M]+, 186 (100), 129 (66), 128 (38), 115 (20).
HRMS (EI): m/z calcd for C13H10O3 [M]+ 214.0630; found:
214.0636.
tionally been performed in protic solvents in the presence
of a base, which assisted conversion of the nucleophile to
its enolate form.10,12 The regiochemistry of the a,b-unsat-
urated aldehydes is influenced by the solvent, the counte-
rion, and the electronic nature of the enolate.8 The role of
DMA is as yet unclear, but a basic solvent such as DMA
would accelerate the enol-forming step from A in the re-
action, which predominates Michael-type addition as
shown in path b, Scheme 2.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science and Tech-
nology, Japan, the High-Tech Research Center Project for Private
Universities (2005–2009), and the Strategic Project to Support the
Formation of Research Bases at Private Universities (2009–2014),
with a matching fund subsidy from the Ministry of Education, Cul-
ture, Sports, Science and Technology.
In conclusion, we reported the synthesis of 2-aryl-2H- and
4-aryl-4H-3,5-diformylpyrans from 1,1,3,3-tetramethox-
ypropane with various aromatic aldehydes. The present
reaction provides a facile and efficient synthetic method
using easily accessible starting materials. Furthermore,
the selective formation of 2-aryl-2H-3,5-diformylpyrans
and 4-aryl-4H-3,5-diformylpyrans was achieved simply
by tuning the catalyst/solvent system. Further studies of
the scope and synthetic applications of the reaction, and a
detailed elucidation of the reaction mechanism, are cur-
rently being performed.
References and Notes
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A Typical Reaction Procedure for the Preparation of Com-
pound 3a (Table 1, Entry 1)
A mixture of FeCl3⋅6H2O (27 mg, 0.1 mmol, 20 mol%), 1 (164 mg,
1 mmol), and 2a (531 mg, 5 mmol) in MeOH (1 mL) and AcOH (5
mL) was stirred at 50 °C for 15 h under air (1 atm). The conversions
and yields of products were estimated from peak areas based on an
internal standard using GC, and the product 3a was obtained in 75%
yield. The reaction mixture was neutralized by 5% aq NaHCO3 and
was extracted with EtOAc (30 mL). The organic layer was evapo-
rated under reduced pressure to remove unreacted 2a. The product
3a was isolated by column chromatography (230–400 mesh silica
gel, n-hexane–EtOAc = 3:1) in 69% yield (74 mg). White solid (mp
110–112 °C). 1H NMR: d = 9.59 (s, 1 H, CHO), 9.39 (s, 1 H, CHO),
7.55–7.57 (m, 2 H, CH), 7.39 (s, 5 H, Ph), 6.48 (s, 1 H, CH). 13
C
NMR: d = 189.68 (CHO), 185.70 (CHO), 166.80 (OCH), 137.00
(C), 133.20 (CH), 129.87 (CH), 128.96 (CH), 128.42 (C), 127.35
(CH), 117.15 (C), 79.02 (CH). IR (neat): 3033, 2859, 1684, 1641,
1563, 1409, 1306, 1193, 1127, 897, 750, 696 cm–1. GC-MS (EI):
Synlett 2011, No. 6, 857–861 © Thieme Stuttgart · New York

LETTER
Lewis Acid Catalyzed Regioselective Formation of Pyran Derivatives
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