Investigation on the reactions of o-hydroxybenzyl alcohols with vinyl ethers under acidic and/or thermal conditions

Article abstract of DOI:10.1002/jhet.74

The reaction of vinyl ethers with o-hydroxybenzyl alcohols under different reaction conditions was investigated. The aim of this attempt was to find out whether the protection reactions or the hetero Diels-Alder reaction of quinone methide in situ generat

Full text of DOI:10.1002/jhet.74

226
Investigation on the Reactions of o-Hydroxybenzyl Alcohols with
Vinyl Ethers Under Acidic and/or Thermal Conditions
Vol 46
Volkan Kumbaraci, Duygu Ergunes, Melike Midilli,
Seckin Begen, and Naciye Talinli*
Faculty of Science and Letters, Department of Chemistry, Istanbul Technical University,
TR-34469, Maslak, Istanbul, Turkey
*E-mail: talinlin@itu.edu.tr
Received June 23, 2008
DOI 10.1002/jhet.74
Published online 13 April 2009 in Wiley InterScience (www.interscience.wiley.com).
The reaction of vinyl ethers with o-hydroxybenzyl alcohols under different reaction conditions was
investigated. The aim of this attempt was to find out whether the protection reactions or the hetero
Diels–Alder reaction of quinone methide in situ generated from o-hydroxybenzyl alcohol is more likely
to occur. o-hydroxybenzyl alcohols can give hetero Diels–Alder reactions with dihydro-2H-pyran at
high temperatures but only when used with acid catalysts. At room temperature, even in the presence of
acid catalyst, reactions yielded regular protection products. However, butyl vinyl ether and 4-methoxy-
3-butenone could not give intermolecular cycloaddition reactions under the acidic conditions, because
both decomposed to the new products with acids. Hetero-Diels–Alder products obtained only under ther-
mal conditions but in low yields.
J. Heterocyclic Chem., 46, 226 (2009).
INTRODUCTION
tivity from the reaction of 1,2- and 1,3-diols and DHP
[3] (Scheme 1). In reactions carried out at 25ꢀC using
pyridine-p-toluene sulfonic acid (PPTS) as the catalyst,
the first step is acetal formation by the addition of one
of the hydroxyl groups of the diol to DHP in the usual
way, the second step is ring opening of the DHP moiety
and the generation of an enol ether, and the third step is
water elimination and recyclization to the oxonium ion.
In particular, fused pyranobenzoxepine (I) was
obtained from the o-hydroxymethylbenzyl alcohol
(Fig. 1).
Protective groups play important roles in modern mul-
tistep synthetic organic chemistry and numerous publica-
tions on the selection of more suitable protecting groups
for hydroxyl functions have appeared in recent years.
In our previous study, we reported selective o-benzy-
lation of primary hydroxyl groups of di-and tri-hydroxyl
compounds by using bis(acetylacetonato) copper as a
catalyst [1].
Another well-known method for the protection of
hydroxy groups is forming tetrahydropyranyl ether by
reaction with 3,4-dihydro-2H-pyran (DHP). By using
this method, diols, in which two hydroxyl groups are far
away from each other can be protected in good yields.
Hence, the main products are monotetrahydropyranyl
ethers [2]. In these reactions, the reason for the low
yield of the diprotection products is not well
understood.
Formation of bicyclic acetals under catalytic condi-
tions from aliphatic dihydroxy compounds leads us to
investigate the reactions of aromatic dihydroxy com-
pounds with DHP. We have chosen o-hydroxybenzyl
alcohol as the diol because it has either two types of
OH groups for protection reactions or it is the precursor
of the quinone methide intermediate [4–6].
The aim of this study is to compare whether the
protection reactions are more likely, or the hetero
However, we have recently demonstrated that bicyclic
acetals can readily be obtained with high diastereoselec-
C
V
2009 HeteroCorporation

March 2009
Investigation on the Reactions of o-Hydroxybenzyl Alcohols with Vinyl Ethers
Under Acidic and/or Thermal Conditions
227
Scheme 1
Scheme 2
Diels–Alder reaction of quinone methide in situ gener-
ated from o-hydroxybenzyl alcohol is more likely to
occur.
On the basis of the concept mentioned earlier, we
reacted o-hydroxybenzyl alcohol with DHP in the pres-
ence of PPTS at the reflux temperature of toluene. The
reaction produced cis-fused pyrano[2,3-b]benzopyran
(III) and self-reaction products of DHP (IX) (Scheme
3). However, the yield was lower than that of Baldwin’s
method. The regular mono protection product (V) was
also obtained in low yield. Diprotection products were
not detected.
RESULTS AND DISCUSSION
Quinone methides are generally produced under ther-
mal, photolytic, or catalytic conditions. In past years, o-
hydroxybenzaldehydes have been preferred for genera-
tion of quinone methides under catalytic conditions [7–
9]. Treatment of salicylaldehydes with 3,4-DHP in the
presence of metal triflates resulted in pyrano[2,3-b]ben-
zopyrans. For the reactions carried out under thermal
conditions different precursors were used; while Ohwada
and coworkers [10] used 4H-1,2-benzoxazines as precur-
sor, Baldwin and coworkers [11] proposed a new
method for o-quinone methide generation from o-meth-
yleneacetoxy-phenols. They investigated the reactions of
o-acetyloxymethyl phenol (2-hydroxybenzyl acetate)
with dienophiles (including DHP) under thermal condi-
tions (Scheme 2). Bray reported the generation and het-
ero-Diels–Alder reaction of an o-quinone methide using
iPrMgCl under mild, anionic conditions [11]. Reactions
of another precursor o-hydroxybenzyl alcohol and open-
chain enol ethers under thermal conditions was investi-
gated by Pochini and coworkers [12].
The structure and the stereochemistry of compound
(III) was elucidated by spectroscopic and chromato-
graphic data and the results were compared with former
results [7–9]. Spectroscopic data showed that the reac-
tion was highly diastereoselective, and the coupling con-
stant, J ¼ 2.6 Hz for the bridgehead protons proved the
formation of the cis-fused bicyclic structure.
However, when the reaction was performed in toluene
without catalyst, a desired pyranobenzopyran formed in
very low yield, in contrast to Baldwin’s result. Mono
protection product V was observed as main product and
Scheme 3
Under photolytic conditions o-hydroxybenzyl alcohol
and DHP also produced benzopyranopyran derivatives
[13] (Scheme 2).
However, there are no reports on the reaction of o-
hydroxybenzyl alcohol with DHP under both catalytic
and thermal conditions. Therefore, in this study, we
have investigated the reaction products of DHP and o-
hydroxybenzyl alcohol, both with acid catalysts and
under thermal conditions.
Figure 1. Reaction product of DHP and o-hydroxymethylbenzyl
alcohol.
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228
V. Kumbaraci, D. Ergunes, M. Midilli, S. Begen, and N. Talinli
Vol 46
Table 1
Reaction conditions and products with yields.
Subs
Catalyst
Solvent
Temp. (ꢀC)
Products and yields (%)a
I
I
PPTS
Amb. 15
PPTS
Amb. 15
–
PPTS
Amb. 15
PPTS
PPTS
CH2Cl2
CH2Cl2
Toluene
Toluene
Toluene
CH2Cl2
CH2Cl2
CH3Cl
25
25
V (75) VII (7)b
V (62) VII (10)b
III (35) IX (50) V (6)
III (15) IX (75)
I
I
110
110
110
25
25
62
110
110c
110
I
V (30) III (10)
II
II
II
II
II
II
VI (80) VIII (5)b
VI (70) VIII (9)b
VI (60) VIII (6)b IX (10)
IV (36) IX (52)
Toluene
Toluene
Toluene
PPTS
Amb. 15
IV (40) IX (50) VI (4)
IV (15) IX (75)
a Not isolated.
b Reaction was performed with Dean–Stark apparatus.
c Yields are from GC analysis.
the rest of the reaction mixture was mainly unreacted o-
hydroxybenzyl alcohol.
When this reaction was carried out with catalyst,
none of the corresponding acetalic structures were found
in the reaction mixture, instead the sole product (90%)
was compound XII which resulted from the reaction of
o-hydroxybenzyl alcohol and acetaldehyde produced
from the decomposition of butyl vinyl ether in acidic
medium. Compound XII was synthesized [14] before,
from o-hydroxybenzyl alcohol and acetaldehyde dime-
thylacetal with 42% yield. There are several studies on
the decomposition of vinyl ethers yielding acetaldehyde
[15,16]. As seen in Scheme 4, similar to DHP, vinyl
butyl ether afforded the desired acetalic structure
with yield lower than that of the regular protection
product.
Furthermore, the reaction of 3-bromo-2-hydroxy-
methyl phenol with DHP under similar reaction condi-
tions resulted in the corresponding pyranobenzopyran
(IV).
To investigate the effect of reaction conditions on
product types and their distribution, reactions were
repeated at different temperatures, using different sol-
vents and catalysts. Results of these studies are tabulated
in Table 1.
The catalysts are PPTS and the strong acidic ion
exchange resin Amberlyst-15. The reason for choosing
Amberlyst-15 was to investigate the influence of acid
structure on diastereoselectivity, but no change on ste-
reoselectivity was observed. Increasing the reaction time
did not effect the reaction yield or type of products. At
room temperature, the expected protection products
were obtained. As the reaction temperature was
increased to 62ꢀC self-reaction products of DHP began
to form.
The reaction of 4-methoxy-3-butenone with o-hydrox-
ybenzyl alcohol was also performed with and without
catalyst. In the presence of catalyst mainly two products
were obtained; compounds XIII (80%) and XIV (10%).
Compound XIII resulted from o-hydroxybenzyl alcohol
and 3-oxo-butanal formed in situ from the transforma-
tion of 4-methoxy-3-butenone [17] (Scheme 5).
After determination of the appropriate reaction condi-
tions for the formation of quinone methides, we worked
on similar reactions of open-chain enol ethers. In this
attempt, the aim was to compare the type of products
with the products produced before. Butyl vinyl ether
was chosen as open-chain enol ether. The reaction of
butyl vinyl ether with o-hydroxybenzyl alcohol in tolu-
ene without catalyst resulted, mainly in two products; a
corresponding 2-butoxychroman X (10%) and a usual
addition compound XI (50%) (Scheme 4). The ratio of
two products was determined by GC analysis of the
crude product. 2-Butoxychroman has been recently pro-
duced by Ohwada and coworkers [10] under thermal
conditions from 4H-1,2-benzoxazines, and also by Bray
[11] from o-hydroxybenzyl acetate.
Formation of compound XIV can be explained with
the cyclization reaction of 4-methoxy-3-butenone in
acidic medium as described previously [18]. When the
reaction was performed without catalyst, the main prod-
uct was again compound XIII (50%). However,
Scheme 4
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Investigation on the Reactions of o-Hydroxybenzyl Alcohols with Vinyl Ethers
Under Acidic and/or Thermal Conditions
229
Scheme 5
solvent, the crude products were purified by column chroma-
tography using ethyl acetate/hexane as the eluent.
General procedure B (without catalyst). Vinyl ether com-
pound (2 mmol) was added dropwise to the solution of I (1
mmol) in toluene (30 mL) and the solution was stirred for 24
h under reflux conditions. Then the solvent was evaporated
and the crude product was purified by column chromatography
using ethyl acetate/hexane as the eluent.
Crude products
(EtOAc/hexane)
III, IX
5/95
5/95
15/85
10/90
IV, IX
V, VII
X, XI
1
compound XV was also detected from GC-MS and H
NMR analysis with a yield of 20%. This compound is
formed through the [4 þ 2] cycloaddition reaction of
quinone methide to 4-methoxy-3-butenone. Desktop mo-
lecular modeling calculations indicated that substituents
existing in diaxial positions are more favorable struc-
tures for compound XV. NMR studies also supports the
MM2 calculations, because the coupling constant for
acetalic and methine protons is J ¼ 2.8.
XII
XIII, XIV
XIII þ XV
30/70
30/70
20/70/10 (ether/hexane/methanol)
3,4,4a-10a-Tetrahydro-2H,5H-pyrano[2,3-b]chromene
1
(III). Colorless oil. H NMR (DMSO-d6) d: 7.09 (d, J ¼ 8.4,
1H, Ar-H6), 7.04 (t, J ¼ 7.6, 1H, Ar-H8), 6.86 (t, J ¼ 7.4, 1H,
Ar-H7), 6.78 (d, J ¼ 8.2, 1H, Ar-H9), 5.28 (d, J ¼ 2.4, 1H,
H10a), 3.85 (td, J ¼ 11.9, J ¼ 8.1, 1H, H2ax), 3.61 (dt, J ¼
11.4, J ¼ 8.2, 1H, H2eq), 2.86 (dd, J ¼ 16.6, J ¼ 6.8, 1H,
H5ax), 2.64 (dd, J ¼ 16.6, J ¼ 5.6, 1H, H5eq), 2.08 (m, 1H,
H4a), 1.8–1.53 (m, 4H, 1H, H3,4); 13C NMR (DMSO-d6) d:
152.7, 129.5, 127.3, 120.7, 120.4, 115.9, 96.2, 62.4, 31.1, 27.8,
24.0, 22.8; ms: m/z: 190 (Mþ), 131(58), 84 (55), 83 (100), 55
(30).
These results indicated that o-hydroxybenzyl alcohols
can give hetero Diels–Alder reactions with DHP at high
temperatures but only when used with acid catalysts. At
room temperature, even in the presence of acid catalyst,
reactions yielded regular protection products. However,
butyl vinyl ether and 4-methoxy-3-butenone could not
give intermolecular cycloaddition reactions under the
acidic conditions, because both decomposed to the new
products with acids. Hetero-Diels–Alder products were
obtained only under thermal conditions but in low
yields.
7-Bromo-3,4,4a-10a-tetrahydro-2H,5H-pyrano[2,3-b]chro-
mene (IV). Yellowish oil. IR: 3054, 2949, 1607, 1484, 1421,
1265, 1078, 909, 756, 739, 705 cmꢁ1 1H NMR (CDCl3): d
;
7.18 (d, J ¼ 8.6, 1H, Ar-H8), 7.14 (s,1H, Ar-H6), 6.74 (d, J ¼
8.6, 1H, Ar-H9), 5.31 (d, J ¼ 2.6, 1H, H10a), 3.98 (td, J ¼
12.2, J ¼ 6.1, 1H, H2ax), 3.71 (dt, J ¼ 11.8, J ¼ 4.8, 1H,
H2eq), 2.90 (dd, J ¼ 16.7, J ¼ 5.9, 1H, H5ax), 2.60 (dd, J ¼
16.7, J ¼ 4.9, 1H, H5eq), 2.16 (m, 1H, 1H, H4a), 1.81–1.61 (m,
4H, H3,4); 13C NMR (CDCl3): d 152.1, 131.8, 130.3, 122.1,
118.2, 112.7, 96.7, 62.6, 31.4, 28.7, 24.0, 23.4; ms: m/z: 270
(M þ 2), 268 (Mþ), 209 (15), 84 (100), 83 (85), 55 (40).
2-[(Tetrahydro-2H-pyran-2-yloxy)methyl]phenol (V). Yellowish
EXPERIMENTAL
All general chemicals and starting materials purchased from
commercial sources, except PPTS. IR spectra were recorded
on a Jasco FTIR 5300 spectrometer using neat compounds as
films between NaCl cells. 1H and 13C NMR spectra were run
with Bruker 250 MHz spectrometer and reported as ppm rela-
tive to TMS. GC-MS spectra were obtained on Thermo Finni-
gan Trace DSQ instrument using ZB-5MS capillary column.
The products were purified by column chromatography on neu-
tral silicagel 60 (0.040–0.063 mm) from Merck, Darmstadt.
Purity of compounds was proved by GC analysis (column:
HP-1, 30m, 50 100ꢀC, 20ꢀC/min to 290ꢀC, 50 290ꢀC).
1
oil. H NMR (CDCl3): d 8.6 (broad s, 1H, OH), 7.20 (d, J ¼
7.8, 1H, Ar), 7.01–6.84 (m, 2H, Ar), 6.82 (d, J ¼ 8.1, 1H,
Ar), 4.90 (d, J ¼ 12.1, 1H, benzylic H), 4.71 (t, J ¼ 2.7, 1H,
acetalic H), 4.64 (d, J ¼ 12.2, 1H, benzylic H), 3.99–3.90 (m,
1H, OCH2), 3.63–3.56 (m, 1H, OCH2), 1.82–1.25 (m, 6H, py-
ran ring H); 13C NMR (CDCl3): d 204.1, 152.6 128.0, 124.9,
121.3, 120.6, 116.72, 96.4, 66.5, 48.3, 31.17; ms: m/z: 208
(Mþ), 124 (83), 108 (90), 85 (100), 77 (60).
Preparation of PPTS. 0.15 mol of pyridine was added to
0.003 mol of p-toluenesulfonic acid and the mixture was
stirred at room temperature for 20 min. After evaporation of
pyridine, the product was crystallized from acetone.
General procedure A (with catalyst). Vinyl ether com-
pound (2 mmol) was added dropwise to a stirred solution of I
or III (1 mmol) and PPTS (0.1 mmol) in toluene (30 mL). The
mixture was stirred at reflux temperature for 24 h in a Dean
Stark apparatus. Then the solution was washed with half-satu-
rated brine to remove the catalyst. After the evaporation of
2-Butoxychroman (X). Colorless oil. IR: 3054, 2949, 1607,
1484, 1421, 1265, 1078, 909, 756, 739, 705 cmꢁ1 1H NMR
;
(CDCl3): d 7.01–6.79 (m, 4H, Ar), 5.23 (d, J ¼ 2.8, 1H, ace-
talic H), 3.84 (dt, J ¼ 9.6, J ¼ 7.1, J ¼ 3.6, 1H, benzylic
Ha(e)), 3.56 (dt, J ¼ 10.2, J ¼ 6.7, J ¼ 3.1, 1H, benzylic
He(a)), 2.95 (td, J ¼ 11.2, J ¼ 6.2, J ¼ 4.7, 1H, OCH2), 2.60
(dt, J ¼ 16.3, J ¼ 3. 7, 1H, OCH2), 2.16–1.87 (m, 2H,1H,
ring CH2), 1.59–1.47 (m, 2H, CH2), 1.36–1.22 (m, 2H, CH2),
0.86 (t, J ¼ 3.6, 3H,CH3); 13C NMR (CDCl3): d 152.3, 129.2,
127.2, 122.7, 120.5,116.9, 112.7, 97.1, 67.9, 31.7, 26.6, 20.6,
Journal of Heterocyclic Chemistry
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V. Kumbaraci, D. Ergunes, M. Midilli, S. Begen, and N. Talinli
Vol 46
19.22, 13.7; ms: m/z: 206.28 (Mþ), 132 (72), 131 (100), 107
(38), 77 (32).
2-Methyl-4H-benzo[d][1,3]dioxine (XII). Orange liquid, IR:
[2] Nishiguci, T.; Fujisaki, S.; Kuroda, M.; Kajisak, S.; Saitoh,
S. J Org Chem 1998, 63, 8183.
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3047, 2959, 2872, 1588, 1480, 1406, 1271, 1230, 1112 cmꢁ1
.
1H NMR (CDCl3): d 7.01–684 (m, 4H, Ar), 5.19 (t, J ¼ 5.2,
1H, acetalic H), 5.01(d, J ¼ 14.6, 1H, CH2), 4.82 (d, J ¼
14.6, 1H, CH2), 1.58 (d, J ¼ 4.9, 3H, CH3); 13C NMR
(CDCl3): d 152.8, 127.6, 125.0, 120.9, 120.6, 116.7, 98.0,
66.3, 20.5; ms: m/z: 150.0 (Mþ),105 (65), 78 (100).
[4] Chiba, K.; Hirano, T.; Kitano, Y.; Tada, M. Chem Commun
1999, 8, 691.
[5] Katada, T.; Eguchi, S.; Esaki, T.; Sasaki, T. J Chem Soc
Perkin Trans I 1984, 1, 2649.
[6] van De Water, R. W.; Pettus, T. R. R. Tetrahedron 2002,
58, 5367.
1-(4H-Benzo[d][1,3]dioxin-2-yl)propan-2-one (XIII). Yellowish
oil, IR: 3047, 2916, 2865, 1718, 1588, 1489, 1271, 1231,
[7] Yadav, J. S.; Reddy, B. V. S.; Aruna, M.; Venugopal, C.;
Ramalingam, T.; Kumar, S. K.; Kunwar, A. C. J Chem Soc Perkin
Trans I 2002, 2, 165.
1
1124, 910 cmꢁ1; H NMR (CDCl3): d 7.17–6.81 (m, 4H, Ar),
5.43 (t, J ¼ 5.1, 1H, acetalic H), 5.01 (d, J ¼ 4.6, 1H, ben-
zylic Ha(e)), 4.81(d, J ¼ 4.5, 1H, benzylic He(a)), 2.97 (d, J ¼
5.1, 2H, CH2), 2.25 (s, 3H, CH3); 13C NMR (CDCl3): d 204.1,
152.61 128.02, 124.91, 121.34, 120.64, 116.72, 96.42,
66.50, 48.34, 31.17; ms: m/z: 192 (Mþ), 174 (42), 106 (99), 78
(100).
[8] Yadav, J. S.; Reddy, B. V. S.; Madhuri, Ch.; Sabitha, G.;
Jagannadh, B.; Kumar, S. K.; Kunwar, A. C. Tetrahedron Lett 2001,
42, 6381.
[9] Yadav, J. S.; Reddy, B. V. S.; Chandrsiah, L.; Jagannadh,
B.; Kumar, K. S.; Kunwar, A. C. Tetrahedron Lett 2002, 43, 4527.
[10] Sugimoto, H.; Nakamura, S.; Ohwada, T. Adv Synth Catal
2007, 349, 669.
1,3,5,-Triacetylbenzene (XIV). White crystals (mp
¼
163ꢀC). 1H NMR (CDCl3): d 8.69 (s, 3H, Ar), 2.7 (s, 9H,
CH3); EI-MS: m/z: 204 (Mþ), 189 (100), 161 (32), 43 (53).
trans-2-Methoxy-3-acetylchroman (XV). Yellowish oil, IR:
[11] (a) Rodriguez, R.; Adlington, R. M.; Moses, J. E.; Cowley,
A.; Baldwin, J. E. Org Lett 2004, 6, 3617; (b) Bray, C. D. Org Bio-
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3050, 2880, 1715, 1489, 1217, 1183, 1018, 755 cmꢁ1 1H
;
[12] Arduini, A.; Pochini, A.; Ungaro, R.; Domiano, P. J Chem
Soc Perkin Trans I 1986, 8, 1391.
NMR (CDCl3): d 7.15–6.83 (m, 4H, Ar), 5.20 (d, J ¼ 2.9, 1H,
acetalic H), 3.54 (s, 3H, O-methyl), 3.09–2.91 (m, 3H, ben-
zylic and methine H), 2.25 (s, 3H, CH3); 13C NMR (250 MHz,
CDCl3): d 205.6, 152.6, 128.91, 127.60, 124.90, 121.20,
116.90, 99.64, 58.2, 49.78, 30.75, 24.78; ms: m/z: 206 (Mþ),
174 (24), 132 (26), 130 (100), 43 (24). Anal. Calcd for
C12H14O3: C, 69.88; H, 6.84. Found: C, 69.62, H, 6.95.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet