A new method for the synthesis of bicyclic pyran acetals

Article abstract of DOI:10.1002/jhet.5570440638

(Chemical Equation Presented) cis-Fused bicyclic acetals were obtained from the unusual cyclization reaction between diols and dihydropyran. Furothiopyran, substituted pyranopyrans, and pyranooxepine and pyranobenzoxepine compounds were obtained with high diastereoselectivity and cis-diastereomers were obtained in high yields.

Full text of DOI:10.1002/jhet.5570440638

Nov-Dec 2007
A New Method For the Synthesis of Bicyclic Pyran Acetals
1493
Duygu Ergunes, Volkan Kumbaraci, Bekir Karliga, Naciye Talinli*
Istanbul Technical University, Faculty of Science and Letters, Department of Chemistry
TR-34469, Maslak, Istanbul, Turkey
Corresponding author. E-mail: talinlin@itu.edu.tr
Received June 21, 2006
OH
CH
H
PPTS (0,1 eq)
5 o
(
2
)
n
+
(CH2)n
2
C
O
O
O
OH
n= 0, 1, 2
H
cis-Fused bicyclic acetals were obtained from the unusual cyclization reaction between diols and
dihydropyran. Furothiopyran, substituted pyranopyrans, and pyranooxepine and pyranobenzoxepine
compounds were obtained with high diastereoselectivity and cis-diastereomers were obtained in high
yields.
J. Heterocyclic Chem., 44, 1493 (2007).
Because the protective groups play important roles in
elimination and recyclization to the oxonium ion, final
modern multi-step synthetic organic chemistry, in recent
years, numerous publications appeared on the selection of
the most suitable protecting group for hydroxy functions.
In our previous work, we reported selective o-benzylation
of primary hydroxy groups of di-and tri-hydroxy
compounds by using bis(acetylacetonato) copper as
catalyst [1]. We showed that bis (acetylacetonato) copper
is very efficient in promoting the benzylation of primary
aliphatic alcohols versus secondary aliphatic alcohols and
phenolic hydroxy groups.
step: formation of the compound (I).
Scheme I
R
OH
OH
OH
R
R
H
R
+
O
.
.
O
..
O
..
H
H
OH
R
R
It is known that another common way for the protection
of hydroxy groups is to form tetrahydropyranyl ether.
Diols in which two hydroxyl groups are far away from
each other can be protected as monotetrahydropyranyl
ethers in good yields [2]. However, in these reactions
formation rate of diprotection products is very low and the
reason is not clear. There is no report on the protection of
R
R
-
H O
2
O
HO
O
..
HO
R= COOCH
3
R
R
O
..
O
..
1
,2 and 1,3-diols with 3,4-dihydro-2H-pyran (DHP).
Therefore, we have been interested in ꢀ and ꢁ-hydroxy
alcohols with DHP because of the possibility of
Structure and the stereochemistry of the compound (I)
were elucidated by spectroscopic and chromatographic
experiments. Spectroscopic data showed that the reaction
was highly diastreoselective and formation of cis isomer
was exclusive. The structure was established by nmr
studies and compared with the similar studies done before
generating bicyclic acetalic products.
In order to investigate the type of the protection
products, we decided to begin with bishydroxymethyl-
dimethylmalonate which can be easily prepared
[
3,,7,8,9]. Coupling constant 3.6 Hz for the bridgehead
protons (dihedral angle of H4a and H8a is 52°)
demonstrated the formation of cis-fused bicyclic.
from
dimethylmalonate
and
formaldehyde.
Bishydroxymethyl- dimethylmalonate was reacted
with DHP in the presence of p-toluen sulfonic acid-
pyridin catalyst and surprisingly compound (I) was
obtained in up to 90 %. Probable reaction mechanism is
illustrated in Scheme I. First step is acetal formation by
addition of one of the hydroxyl group of the diol to the
dihydropyran in the usual way, second step: ring
opening of the dihydropyran moiety and generation of
an enol ether, third step: acid catalyzed water
According to the MM dekstop molecular mechanic
calculations, two pyran rings are in the chair conformation
(
Scheme II).
The acetalic proton is observed approximately at 4.6
ppm. This smaller value is not in accordance with the one
given before [3,5]. This difference is attributed to the
structure of the compound. Acetalic proton is shielded by
the carbonyl group and corresponding peak shifts to lower

1
494
A New Method For the Synthesis of Bicyclic Pyran Acetals
Vol 44
Scheme II
diol, only the corresponding thiophenopyran (3) was
obtained in the higher yield than that of ethylene glycol.
cis-2-Buten-1,4-diol and 2,3-dihydroxymethylbenzene
were reacted with DHP and compound (4) and (5) yielded
respectively. Only cis diastereomers were obtained in all
reactions as common.
Table I
Products and the yields
Entry
Product
Yields %
2
2
ppm. Although J value of C7 protons is 11.2 Hz, J for
C2 protons is 9.6 Hz which is unusual for pyran rings.
This result is ascribed to the presence of methoxycarbonyl
groups at neighbouring carbon atom.
H
H
3
3
COOC
COOC
OH
OH
COOCH
COOCH
3
3
b
92
O
O
1
In one of the previous studies stereoelectronic control
in acetal formation was investigated and it is reported that
acetal formation is controlled by stereoelectronic effects
OH
OH
OH
SH
a,3
O
30
O
2
[
3]. During the formation of bicyclic and tricyclic acetals
at ambient temperature, first kinetically controlled cis
product is formed. To form thermodynamically controlled
trans product, intermediate of cis conformer should
undergo a conformational change in order to form a more
stable conformation of trans cyclic acetals (Scheme III).
a
S
70
O
3
OH
a
6
0
O
O
OH
Scheme III
4
OH
OH
O
O
a
OH
70
O
R
R
O
5
O
R
R
a : yields are given from GC analysis, b: yield of isolated product
cis isomer
Another starting material was pentaerythritol. From the
GC-MS analysis, it was observed that 3,3-bishydroxy-
methyl-pyranopyran formed in the yield of 10% but it
could not be separated from the mixture properly. So, its
spectroscopic data was not given in the experimental part.
O
OH
O
R
R
O
R
O
O
R
R
R
trans isomer
1
However, when the H nmr spectrum of the crude product
was investigated, two doublets at 3.5 and 3.1 ppm with
J=9.6 Hz were observed as seen before compound (I).
These doublets could not belong to any of other possible
acetalic products. This result supported the formation of
the bicyclic structure.
If conformational changes are restricted due to the
structural reasons cis isomer formations are favored. The
reason of the formation of cis and trans isomer mixtures
could be explained with easy twisting between acetal
conformers. In our case, two electron withdrawing
methoxycarbonyl groups restricted the twisting and also
All starting materials and products prepared with this
novel method are given in the Table 1.
activated -CH group for nucleophilic attack which is
2
In conclusion, we have described herein a simple
reaction pathway for the the synthesis of cis-fused
bicyclic acetals. Starting from easily accesible diols,
bicyclic acetals are obtained with high diastereo-
selectivity. In addition to its efficiency and simplicity,
this method provides opportunities to obtain interesting
target molecules using different substituted diols and
dihydropyrans.
followed by subsequent cyclization of enol ether.
In order to extend this method for the synthesis of
different type of bicyclic acetals, several diols were
reacted with DHP. Ethylene glycol gave furopyran (2) in
low yield. This compound was previously obtained from
hex-3-en-1,6-diol in good yield [3]. The spectroscopic
data of compound (2) is in accordance with the one
obtained before. When thioethylene glycol was used as

Nov-Dec 2007
A New Method For the Synthesis of Bicyclic Pyran Acetals
1495
EXPERIMENTAL
(ddd, 1-H , J= 9.3,8.2, 6.4), 2.68 (ddd, 1-H ,J=8.2, 8.1,6.4),
ax
eq
1
3
1
.81-1.50 (m, 7H, ring protons);
C nmr (CDCl3, proton
decoupled): ꢀ 99.9, 69.4,62.4,30.8, 25.6, 24.8, 19.6; ms m/z 144
All general chemicals and starting materials purchased from
commercial sources, except 2,2-dihydroxymethyl-dimethyl-
malonate. IR spectra were recorded on a Jasco FT-IR 5300
spectrometer using neat compounds as films between NaCl cells
or crystalline compound as KBr disks. H and C NMR spectra
were run with Bruker 250 MHz spectrometer and reported as
ppm relative to TMS. GC-MS spectra were obtained on Thermo
Finnigan Trace DSQ instrument using ZB-5MS capillary
column. The products were purified by column chromatography
on neutral silicagel 60 (0,040-0,063 mm) from Merck,
Darmstadt.
+
(
M ),103, 101, 89, 85, 61, 60, 41. Anal. Calcd. For C H OS : C,
7 12
5
8.29; H, 8.39. Found: C, 58.74; H, 8.51
aS,5aR-Tetrahydropyrano[2,3-b]-2H-5,5a, 9a-tetrahydro-
oxepine (4). This compound was obtained as a colorless oil after
purification with column chromatogrphy by using ethyl
acetate/hexane (20/80) as the eluent, ir (NaCl cell): 1614 (C=C),
9
1
13
-1
1
1
201 (O-C-O) cm ; H nmr (CDCl ): ꢀ 5.57-5.53 ( m, 2H,
3
olefinic H ), 4.52 (d, 1H, ,H-9a, J=2.9), 4.11(dd, 1H, 2-H ,J=
ax
1
1
.
4
,
2
.
9
)
,
4
.
0
4
(
d
d
,
1
H
,
2
-
H
J
=
1
0
.
9
,
7
.
8
)
,
3
.
7
8
(
t
d
,
1
H
,
8
-
H
,
e
q
,
e
q
J=10.7, 3.6), 3.4 (ddd, 1H, 8-H J=11.3, 6.8, 4.7), 1.74-1.44 (m,
ax
1
3
7
1
H, ring protons); C nmr (CDCl3, proton decoupled): ꢀ
Synthesis of 2,2-Bishydroxymethyl-dimethylmalonate. The
solution of 13.2 g (0.10 mole) dimethylmalonate in 100 ml
dioxane was cooled to 4-5° and 33 g of 20% formaldehyde
solution (0.22 mol) was added. pH was adjusted to 8 with
triethylamine and stirred at this temperature for 20 minutes.
Then the solution was allowed to warm to room temperature and
stirred for 2 hours. The solution was diluted with water and
product was extracted with dichloromethane, dried and the
solvent was evaporated. The residue was crystallized from
dichloromethane/hexane (1/1), yield 13.6g ( 72%), mp 78-79°; ir
28.4, 126.8, 100.2, 63.8, 62.0, 55.4, 31.2, 26.1, 19.9, ms (CI):
+
m/z 155 (M ), 101, 85, 67, 57. Anal. Calcd. For C H O : C,
9
14
2
7
0.10; H, 9.15. Found: C, 70.38; H, 9.38.
1aS,7aR-Tetrahydropyrano[2,3-b]-4,5-dihydro-1H-2-
1
benzoxepine (5). This compound was purified by column
chromatography using ethyl acetate/ hexane (20/80) as the
1
eluent and gained as a colorless oil, H nmr (CDCl ): ꢀ 7.33-
3
7
1
.16 (m, 4H, ar), 4.86 ( d, 1H, 2-Hax(eq), J= 11.7), 4.82( d, 1H, H-
1a, J=3.5), 4.54 (d, 1H, 2-Heq(ax) J= 11.7), 3.85 ( td, 1H, H-10ax
-
1
J=11.4, 3.6, ), 3.54 ( dt, 1H, H-10eq, J=11.3, 6.9, 3.5), 3.4 (m, 2H,
(
potassium bromide): 3433 (OH), 1732 (CO) cm ; 1H nmr
1
3
H-5), 1.8-1.4 (m, 5H, pyran ring protons); C nmr (CDCl3,
(
CDCl ): ꢀ 4.12 ( s, 4H, CH ), 3.79 (s, 6H, CH ), 2.94 (s, 2H,
3
2
3
proton decoupled): ꢀ 138.4, 137.8, 128.4, 127.6, 127.4, 125.6,
OH); ms: m/z 175, 145, 113, 85, 67, 59.
+
9
1
7
8.2, 72.0, 63.8, 36.0, 32.2, 26.1, 19.9; ms: m/z 204 (M ), 143,
General Procedure for the Reaction of Diols with 3,4-
Dihydro-2H-Pyran. 1,5 mmol of Dihydropyran was added to
the solution of diol compound (1 mmol) in methylene chloride
21, 120, 93, 85, 77, 67. Anal. Calcd. For C H O : C, 76.44; H,
1
3
16
2
.90. Found: C, 76.64; H, 7.61.
(
8
10 ml) containing PPTS (0,1 mol). The solution was stirred for
hours at 25 ºC, then washed with half-saturated brine in order
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to remove the catalyst. The solvent is removed and the product
was purified by an appropriate method.
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3
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[
pyran (1). This compound was crystallized from acetone/water
mixture (1/1), mp 83°C; ir (potassium bromide): 1741 (CO),
[
-
1 1
1
3
3
3
226 (OCO) cm ; H nmr (CDCl ): ꢀ 4.6 ( d, 1H, acetalic H, J=
3
.6 Hz), 4.2 ( d, 1H, H-2 eq, J= 9.6), 3.8 ( d, 1H, H-2 , J=9.7),
.75 ( ddd, 1H, H-7 , J= 11.1, 7.2, 2.3), 3.72 (s, 6H, OCH ),
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ax
eq
3
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ax
1
3
C nmr (CDCl , proton decoupled): ꢀ 169.04, 99.7, 65.8, 63.6,
3
+
5
9.3, 52.4, 30.4, 25.4, 19.9, 18.9 ; ms: m/z. 258 (M ), 245, 193,
[
6] Yadav, J. S.; Reddy, B.V.S.; Madhuri, Ch.; Sabitha, G.;
1
45, 113, 85. Anal. Calcd. For C H O : C, 55.81; H, 7.02.
12
18
6
Jagannadh, B.; Kumar, S.K.; Kunwar, A.C. Tetrahedron Lett. 2001, 42,
381.
Found: C, 56.14; H, 7.31
6
4
aR,7aS-Perhydrothiopheno[2,3-b]pyran (3). This compound
[
7] Alonso, F.; Lorenzo, E.; Mendelez, J.; Yus, M. Tetrahedron
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was purified by column chromatography, using (20/ 80) ethyl
2
1
acetate/ hexane as the eluent and obtained as a colorless oil, H
[
nmr(CDCl ): ꢀ 4.62 (d, 1H, acetalic H, J=3.6), 3.84 (ddd, 1H, H-
3
2ax, J=11.2, 6.5, 3.6), 3.52 ( dt, 1H, H-2 , J=11.2, J=6.5), 2.72
eq