Synthesis of cis-2,6-tetrahydropyran-4-one via diastereoselectively intramolecular cyclization of β-hydroxy allyl ketone

Article abstract of DOI:10.1016/j.tet.2012.02.076

A series of cis-2,6-tetrahydropyran-4-ones was synthesized from the intramolecular cyclization reaction of β-hydroxy allyl ketones in the presence of Me₃SiOTf as catalyst. The β-hydroxy allyl ketone was prepared from allylation reaction with β-hydroxynitrile without protection of hydroxy functionality under the Barbier-type reaction condition.

Full text of DOI:10.1016/j.tet.2012.02.076

Tetrahedron 68 (2012) 3915e3919
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Synthesis of cis-2,6-tetrahydropyran-4-one via diastereoselectively
intramolecular cyclization of b-hydroxy allyl ketone
*
Adam Shih-Yuan Lee , Li-Shin Lin, Yu-Ting Chang
Department of Chemistry, Tamkang University, New Taipei 251, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of cis-2,6-tetrahydropyran-4-ones was synthesized from the intramolecular cyclization reaction
Received 29 November 2011
Received in revised form 21 February 2012
Accepted 28 February 2012
Available online 16 March 2012
of
b-hydroxy allyl ketones in the presence of Me3SiOTf as catalyst. The b-hydroxy allyl ketone was
prepared from allylation reaction with
under the Barbier-type reaction condition.
b
-hydroxynitrile without protection of hydroxy functionality
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
O
OH
OH
O
Tetrahydropyrans bearing substituents at the 2- and/or 6-
positions on the ring are often observed in a large number of bi-
ologically important natural products, which exhibit interesting
biological properties such as phorboxazole,1 zampanolide,2 laso-
nolide,3 ratjadone,4 leucascandrolide,5 swinholides,6 misakinol
ides,7 sorangicin A,8 scytophycins,9 and laulimalide.10 Tetrahydrop
yran-4-ones usually employed as important synthetic intermed
iates for natural product synthesis. Over the years much effort has
been directed toward the development of new strategies for their
synthesis.11e17 Continuing interest in the development of synthetic
methodology of tetrahydropyranone synthesis provided the im-
petus to initiate a project designed to develop a new and more
expedient route to the formation of tetrahydropyranone rings. Our
group reported a Barbier-type reaction of allyl bromide with nitrile
could generate allyl ketone at room temperature18 and an intra-
molecular cyclization of homoallyl alcohol to tetrahydrofuran was
CN
R
R
R
O
CH3
Scheme 1.
phenylpropanenitrile 1 (1.0 equiv), zinc powder (4.0 equiv), and
allyl bromide (2.0 equiv) in anhydrous THF was added AlCl3
(0.6 equiv) at 0 ꢀC and stirred at room temperature for 2 h and the
expected product 2 (42%) was obtained with 35% recovery of
starting material (Scheme 2). An exothermic phenomenon was
observed when AlCl3 was introduced to the reaction mixture. It
should be noted that the slow addition of AlCl3 decreased the for-
mation yield of product 2. We also observed that increment of allyl
bromide to 2.5 equiv did improve the product yield. Thus, we
rearranged the introducing amount of allyl bromide in consequent
steps, 0.5 equiv of allyl bromide was added to the reaction mixture
after 1 h stirring at room temperature, and the yield of 2 was
dramatically increased to 80%. The less acidic quenching process
afforded in the presence of
was attracted to the formation of
may be achieved by reaction of -hydroxynitrile with allyl bromide
L
-proline as a promoter.19 Our attention
-hydroxy allyl ketone, which
b
b
under the Barbier-type reaction condition and then this b-hydroxy
allyl ketone undergo intramolecular cyclization (6-endo-trig)20
OH
OH
O
0oC-rt, THF;
aq. HCl
would generate the desired tetrahydropyran-4-one (Scheme 1).21,22
Br
CN
+
Ph
Ph
2
1
2. Results and discussion
42% + S.M. (35%)
54%
*
*
*
*
Zn/AlCl3 (4/0.6), 2.0 Allyl-Br, rt, 2h; 2M HCl
Zn/AlCl3 (4/0.6), 2.5 Allyl-Br, rt, 2h; 2M HCl
3-Hydroxy-3-phenylpropanenitrile 1 was initially chosen as the
investigating substrate. Treatment of 1 with allyl bromide in the
presence of a Lewis acid AlCl3 should generate
b-hydroxy allyl ke-
Zn/AlCl3 (4/0.6), 2.0 Allyl-Br,rt,1 h; 0.5 Allyl-Br, 1h; 2M HCl
80%
84%
tone product 2. To reaction mixture of 3-hydroxy-3-
a
Zn/AlCl3 (4/0.6), 2.0 Allyl-Br,rt,1 h; 0.5 Allyl-Br, 1h; 0.5M HCl
Scheme 2. Optimization of allylation to nitrile.
* Corresponding author. Tel.: þ886 2 2621 5656x2543; fax: þ886 2 26222 3830.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.02.076

3916
A.S.-Y. Lee et al. / Tetrahedron 68 (2012) 3915e3919
O
O
also improved the yield of product 2. It is interesting to note that
protection of hydroxy group was not necessary under this Barbier-
type reaction condition.
OH
O
O
0.05 M
+
Ph
Ph
CH3
Ph
To understand the scope of this new reaction, various
hydroxynitriles were studied as the substrates for prepration of
hydroxy allyl ketones and the results are shown in Table 1.
b
b
-
-
Reaction condition
Yield (cis / trans)
*
0.5 BF3.OEt2, THF, rt, 120h
Low yield
*
*
*
1.0 BF3.OEt2, THF, rt., 24h
0.1 ZnCl2, THF, rt., 33h
0.1 SnCl2, THF, rt., 58h
48% (71 / 29)
NR (SM)
Table 1
Synthesis of
b-hydroxy allyl ketones
NR (SM)
OH
OH
O
Zn/AlCl3 (4/0.6), 0 oC-rt., 1h;
Br
CN
*
*
0.1 MgBr2, THF, rt., 58h
0.1 BCl3, THF, rt., 42h
0.1 BBr3, THF, rt., 11h
+
NR (SM)
R
0.5 Allyl-Br, rt., 1h
R
Complicate
Entry
1
R
Yield
*
*
*
Complicate
53% (100/ 0)
53% (100/ 0)
57%
59%
0.1 Me3SiOTf, THF, rt., 18h
0.2 Me3SiOTf, THF, rt., 18h
+
+
+
13%
21%
17%
2
3
4
*
0.5 Me3SiOTf, THF, rt., 18h
43% (100/ 0)
84%
67%
Scheme 3.
Intramolecular cyclization reaction, in general, was reacted at
low concentration circumstance. In order to decreasing the using
amount of solvent, we investigated the higher reaction concen-
tration for this intramolecular cyclization reaction and the results
are shown in Scheme 4. The experimental results showed that 2.5%
introducing amount of Me3SiOTf to reacting substance 1-hydroxy-
1-phenylhex-5-en-3-one afforded the nearly yield of tetrahy-
dropyran-4-one at higher reaction concentration (0.1 M).
F
5
56%
Br
Br
6
7
67%
72%
O
O
O
OH
O
O
Me3SiOTf
THF, rt.
+
Ph
Ph
8
9
72%
51%
Ph
O
CH3
S
Yield (cis only)
+ Dehydration product
*
*
*
0.1 Me3SiOTf, THF, rt., 18h
0.02M
0.05M
0.05M
51%
+
+
+
16%
13%
8%
O
0.1 Me3SiOTf, THF, rt., 18h
0.05 Me3SiOTf, THF, rt., 18h
53%
48%
As shown in Table 1, reactions using aliphatic b-hydroxynitriles
(entries 1 and 2), electron-poor (entries 4e6) or electron-rich
(entry 7) benzanitriles, or heteroaromatic nitriles (entries 8 and
*
*
0.05 Me3SiOTf, THF, rt., 18h
0.025 Me3SiOTf, THF, rt., 18h
0.1M
0.1M
51%
52%
+
+
18%
16%
9) gave the desired
b
-hydroxy allyl ketones in reasonable to good
-hy-
Scheme 4.
yields. Aliphatic -hydroxynitrile (entry 2) having another
b
b
drogen next to hydroxyl functionality also proceeded clean reaction
under standard reaction condition.
A series of b-hydroxy allyl ketones was investigated under this
b
-Hydroxy allyl ketones were successfully prepared by the
Barbier-type reaction conditions. Therefore, the intramolecular
cyclizations of -hydroxy allyl ketones for generating the desired
Me3SiOTf-catalyzed intramolecular cyclization and the results are
shown in Table 2.
b
As shown in Table 2, reactions using aliphatic allyl ketones
(entries 1 and 2) and electron-poor (entries 4e6) aromatic allyl
ketones gave the desired cyclization products in reasonable to
moderate yields. The product yield of using electron-rich (entry 7)
aromatic allyl ketone was obtained much lower than those of using
electron-poor aromatic allyl ketones. Only the dehydrated with
isomerized product was obtained for heteroaromatic allyl ketones
(entries 8 and 9) under the reaction condition. We propose the
dehydration process may be faster than isomerization process that
causes the unsuccessfully intramolecular cyclization process. Thus,
tetrahydropyran-4-one were further investigated. 1-Hydroxy-1-
phenylhex-5-en-3-one (Table 1, entry 3) was chosen as the in-
vestigating substrate for intramolecular cyclization reaction (6-
endo-trig). Treatment of 1-hydroxy-1-phenylhex-5-en-3-one with
Lewis acid BF3$OEt2 in THF and the mixture was stirred at room
temperature for 24 h generated the expected tetrahydropyran-4-
one product in 48% yield with diastereoselectivity (cis/trans¼71/
29). Other Lewis acids also were investigated and Me3SiOTf was
observed as the best choice of catalyst for this intramolecular cy-
clization reaction (Scheme 3). A reaction mixture of 1-hydroxy-1-
phenylhex-5-en-3-one (1.0 mmol) and Me3SiOTf (0.1 mmol) in
THF (20 mL) was stirred at room temperature for 18 h and the
expected 2,6-disubstituted tetrahydropyran-4-one was obtained as
the only cis-stereoisomer and the dehydration product also was
obtained with 13% yield. Increasing the amount of Me3SiOTf did not
improved the yield of tetrahydropyran-4-one but the slightly in-
creased the yield of dehydration product.
we prepared the isomerized
b-hydroxy-a,b-unsaturated ketone
and then investigated this compound under the reaction condi-
tion.23 The expected heteroaromatic substituted tetrahydropyran-
4-ones were obtained under the reaction condition (Scheme 5).
The reaction mechanism was proposed that
b-hydroxy allyl
ketone, which is firstly isomerized in situ to -hydroxy-a,b
b
-un-
saturated ketone and then followed by the intramolecular Michael
addition reaction to its corresponding tetrahydropyran-4-one. The

A.S.-Y. Lee et al. / Tetrahedron 68 (2012) 3915e3919
3917
Table 2
Intramolecular cyclization reactions of
b-hydroxy allyl ketones
O
0.1M
OH
O
O
2.5% Me3SiOTf,
THF, r.t.
+
R
R
R
O
CH3
Entry
1
R
Time (h)
Yield
33%
14
18
Fig. 1. Proposed transition state of diastereoselectively intramolecular cyclization.
2
3
4
61%
52%
48%
80% yield. Tetrahydro-3,6-dimethyl-2-phenylpyran-4-one 4a and
4b was not separated and theirs diastereomeric ratio was de-
termined by comparison of 1H NMR spectral analysis (4a:4b¼81
16
23
þ
þ
16%
9%
:19) of the authentic compounds.24 It is interesting to note that
a-
methyl allyl ketone 5 was cyclized to 2-substituted tetrahydro-5,6-
dimethylpyran-4-one with single stereoisomer and all-cis-2,5,6-
diastereomer was observed.
F
5
20
48%
þ
þ
12%
12%
Br
Br
6
7
22
14
58%
6%
O
O
8
9
23
21
Only 1,4-Dienyl-3-ketone
S
Only 1,4-Dieny1-3-ketone
O
Scheme 6.
The spiro-compound also may be generated by intramolecular
cyclization of tertiary-hydroxy allyl ketone, which was prepared
O
0.05-0.1M
from allylation reaction of
b-hydroxynitrile with ketone. Thus,
OH
O
O
2.5% Me3SiOTf,
THF, r.t., 16h
CH3
compound 7 was synthesized and investigated under the intra-
molecular cyclization reaction condition and spiro-tetrahy-
dropyran-4-one 8 was afforded with 60% yield (Scheme 7).
+
R
R
CH3
R
O
CH3
R
Yield
O
33% cis + 6% trans
24% cis + 14% trans
5% cis + 5% trans
+
+
+
17%
31%
41%
O
S
O
Scheme 7.
Scheme 5.
3. Conclusion
diastereoselectivity may be explained by the cyclization of
b-hy-
In conclusion, the
allylation reaction of
droxy functionality under the Barbier-type reaction condition. The
cis-2,6-tetrahydropyran-4-one was synthesized from the intra-
b
-hydroxy allyl ketone was prepared from
droxy- -unsaturated ketone to the corresponding tetrahy-
a,b
b-hydroxynitrile without protection of hy-
dropyran-4-one via a chair-like transition state (Fig. 1). The possible
stereochemical outcomes for the generation of cis-2,6-disubs
tituted tetrahydropyran-4-one by intramolecular cyclization of
b-
molecular cyclization reaction of
b-hydroxy allyl ketones in the
hydroxy- -unsaturated ketone are proposed and explained for
a,b
presence of Me3SiOTf as catalyst. The polysubstituted tetrahy-
dropyran-4-one and spiro-compound also may be generated by
this intramolecular cyclization reaction.
a thermodynamically control reaction whereas the bulky sub-
stituents (R and CH3) occupy the equatorial positions to avoid the
1,3-diaxial repulsive interaction.24
In order to expand the scope of this intramolecular cyclization
reaction,
a
-substituted allyl ketones were synthesized and in-
4. Experimental
4.1. General
vestigated for synthesis of polysubstituted tetrahydropyran-4-
one16 (Scheme 6). 1-Hydroxy-2-methyl-1-phenylhex-5-en-3-one
3 was synthesized (anti/syn ratio was not determined) and it was
cyclized under the reaction condition and a mixture of tetrahydro-
3,6-dimethyl-2-phenylpyran-4-one 4a and 4b was obtained with
All reagents were purchased from Aldrich and Riedel-deHaen
and all were used directly without further purification. The 1H

3918
A.S.-Y. Lee et al. / Tetrahedron 68 (2012) 3915e3919
NMR (proton nuclear magnetic resonance) spectra were recorded
at 300 MHz (Bruker-AC300P) with deuteriochloroform (CDCl3,
Aldrich 99.8 atom% D) as the solvent and the internal standard. The
13C NMR (carbon nuclear magnetic resonance) spectra were
recorded at 75.5 MHz (Bruker-AC300P) with CDCl3 as the solvent
and the internal standard. Chemical shifts are reported in parts per
million and resonance patterns are reported with the notations of
either s (singlet), d (doublet), t (triplet), q (quartet), or m (multi-
plet). Coupling constant (J) are reported in hertz (Hz).
(s, eOH, 1H), 5.10e5.21 (m, 3H), 5.92 (m, 1H), 6.98e7.04 (m, 2H),
7.26e7.32 (m, 2H); 13C NMR:
48.3, 50.6, 69.1, 115.1, 115.4, 119.4,
127.2,127.3,129.7,138.5,138.6, 208.7; HRMS m/z 208.0897 (calcd for
C12H13FO2, 208.0900); MS m/z 123 (33),125 (base),149 (5),167 (28).
d
4.3.5. 1-(4-Bromophenyl)-1-hydroxyhex-5-en-3-one (Table 1, entry
5). 1H NMR:
d
2.82e2.84 (m, 2H), 3.20 (d, J¼7.1 Hz, 2H), 5.12e5.24
(m, 3H), 5.75 (m, 1H), 7.24 (dd, J¼1.7, 6.7 Hz, 2H), 7.48 (dd, J¼1.9,
6.6 Hz, 2H); 13C NMR:
48.1, 50.4, 68.9, 119.3, 121.1, 127.2, 129.5,
d
131.3, 141.8, 208.3; HRMS m/z 268.0099 (calcd for C12H13BrO2,
268.0099); MS m/z 157 (13), 185 (base), 187 (83), 227 (23), 229 (21).
4.2. General procedure for synthesis of
from -hydroxynitrile
b-hydroxy allyl ketone
b
4.3.6. 1-(3-Bromophenyl)-1-hydroxyhex-5-en-3-one (Table 1, entry
Aluminum trichloride (0.6 mmol) was added at once to a solu-
tion of zinc powder (4.0 mmol), -hydroxynitrile (1.0 mmol), and
6). 1H NMR:
d
2.76e2.85 (m, H2, 2H), 3.20 (d, J¼6.9 Hz, 2H),
b
5.11e5.24 (m, 3H), 5.90 (m, 1H), 7.18e7.28 (m, 2H), 7.41 (d, J¼7.5 Hz,
allylic bromide (1.5 mmol) in anhydrous THF (5 mL) at 0 ꢀC (ice-
water bath).20 The reaction mixture was warmed to room tem-
perature and then stirred at room temperature for an hour. Another
0.5 mmol of allylic bromide was added to the reaction mixture and
stirred at room temperature for an hour. After the reaction was
completed (monitored by TLC), aqueous HCl (2 M, 5 mL) was added
to the reaction mixture and stirred at room temperature for 5 min.
The reaction mixture was passed through a short silica gel column
and the organic solvent was removed directly under reduced
pressure. Further purification is achieved on a flash chromatograph
with silica gel and ethyl acetate/hexane as eluant.
1H), 7.54 (d, J¼6.8 Hz, 1H); 13C NMR:
d 48.1, 50.4, 68.8, 119.3, 122.4,
124.1, 128.6, 129.5, 129.6, 130.4, 145.1, 208.3; HRMS m/z 268.0103
(calcd for C12H13BrO2, 268.0099); MS m/z 155 (10), 157 (21), 183
(48), 185 (base), 225 (7), 227 (20), 251 (12), 253 (11), 270 (15).
4.3.7. 1-(Benzo[d][1,3]dioxol-6-yl)-1-hydroxyhex-5-en-3-one (Table
1, entry 7). 1H NMR:
d
2.80e2.85 (m, 2H), 3.20 (dd, J¼1.2, 7.3 Hz,
2H), 5.12e5.18 (m, 3H), 5.89e5.94 (m, 2H), 6.75e6.80 (m, 2H), 6.87
(d, J¼1.1 Hz, 1H); 13C NMR:
d 48.2, 50.7, 69.5, 100.9, 106.2, 108.0,
118.9, 119.2, 129.8, 136.9, 146.8, 147.6, 208.6; HRMS m/z 234.0889
(calcd for C13H14O4, 234.0892); MS m/z 121 (16), 149 (base), 150
(50), 151 (85), 175 (8), 193 (80), 216 (5).
4.3. General procedure for synthesis of cis-2,6-disubstituted
tetrahydropyran-4-one from
b
-hydroxy allyl ketone
4.3.8. 1-Hydroxy-1-(thiophen-2-yl)hex-5-en-3-one (Table 1, entry
8). 1H NMR:
d
2.91e3.08 (m, 2H), 3.22 (d, J¼6.8 Hz, 2H), 5.14e5.24
Trimethylsilyl triflate (0.025 mmol) was added to a solution of
b
-
(m, 2H), 5.41 (m, 1H), 5.91 (m, 1H), 6.94e6.97 (m, 2H), 7.24 (d,
hydroxy allyl ketone (1.0 mmol) in anhydrous THF (10 mL) at room
temperature and the reaction mixture was stirred at room tem-
perature for an appropriate time. After the reaction was completed
(monitored by TLC), H2O (2 M, 10 mL) ant extracted with ether
(2ꢁ20 mL). The combined organic layer was washed with Brine
(10 mL), and then dried with MgSO4. The organic solvent was re-
moved directly under reduced pressure and further purification is
achieved on a flash chromatograph with silica gel and ethyl acetate/
hexane as eluant.
J¼3.3 Hz, 1H); 13C NMR:
d 48.0, 50.4, 66.0, 119.1, 123.3, 124.4, 126.4,
129.7, 144.6, 207.9; HRMS m/z 196.0560 (calcd for C10H12O2S,
196.0558); MS m/z 112 (33), 113 (55), 126 (base), 137 (8), 163 (10),
168 (12).
4.3.9. 1-(Furan-2-yl)-1-hydroxyhex-5-en-3-one (Table 1, entry
9). 1H NMR:
d
2.87e3.13 (m, 2H), 3.23 (d, J¼7.2 Hz, 2H), 5.13e5.24
(m, 3H), 5.91 (m, 1H), 6.26 (d, J¼3.4 Hz, 1H), 6.33 (m, 1H), 7.36 (d,
J¼2.1 Hz, 1H); 13C NMR:
d 46.8, 48.1, 63.3, 106.0, 110.1, 119.2, 129.6,
141.8, 154.9, 207.9; HRMS m/z 180.0786 (calcd for C10H12O3,
180.0786); MS m/z 110 (base), 111 (16), 137 (10), 139 (42), 155 (10).
4.3.1. (E)-6-Hydroxyundeca-1,7-dien-4-one (Table 1, entry 1). 1H
NMR:
d
0.89 (t, J¼7.4 Hz, 3H), 1.32e1.42 (m, 2H), 1.90e2.03 (m, 2H),
2.38 (s, eOH, 1H), 2.66 (d, J¼6.5 Hz, 2H), 3.20 (d, J¼7.0 Hz, 2H), 4.52
(m, 1H), 5.12e5.22 (m, 2H), 5.46 (m, 1H), 5.69 (m, 1H), 5.90 (m, 1H);
4.3.10. Tetrahydro-2-methyl-6-(pent-1-enyl)pyran-4-one (Table 2,
entry 1). 1H NMR:
d
0.87 (t, J¼7.4 Hz, 3H), 1.32 (d, J¼6.1 Hz, 3H),
1.35e1.42 (m, 2H), 1.97e2.04 (m, 2H), 2.17e2.36 (m, 4H), 3.75 (m,
1H), 4.03 (m, 1H), 5.51 (m, 1H), 5.70 (m, 1H); 13C NMR:
13.9, 22.0,
13C NMR:
d 13.6, 22.2, 34.2, 48.5, 48.9, 68.6,119.3,129.9,130.8,132.3,
208.9; HRMS m/z 182.1302 (calcd for C11H18O2, 182.1307); MS m/z
d
109 (58), 124 (50), 136 (97), 154 (base).
22.1, 34.2, 47.6, 49.2, 73.0, 77.5, 129.2, 133.5, 206.9; HRMS m/z
182.1311 (calcd for C11H18O2,182.1307); MS m/z 110 (7),111 (18),126
(91), 139 (base), 180 (30), 181 (58); IR: (neat) 2961 (w), 2932 (w),
2872 (w) 2361 (w), 1721 (C]O, s), 1050 (m), 967 (m).
4.3.2. 1-Cyclohexyl-1-hydroxyhex-5-en-3-one (Table 2, entry 2). 1H
NMR:
3.04 (dd, J¼1.3, 7.1 Hz, 2H), 3.18 (s, OH, 1H), 3.61 (t, J¼6.7 Hz, 1H),
4.96 (m, 1H), 5.78e5.69 (m, 2H); 13C NMR:
25.7, 26.0, 27.7, 28.4,
d
0.70e1.11 (m, 6H), 1.44e1.58 (m, 4H), 2.39 (d, J¼6.7 Hz, 2H),
d
4.3.11. 2-Cyclohexyl-tetrahydro-6-methylpyran-4-one (Table 2, entry
31.1, 42.8, 45.7, 48.0, 71.2, 118.3, 130.0, 209.2; HRMS m/z 197.1542
(calcd for C12H21O2, 197.1539 [MþH]þ); MS m/z 136 (57), 137 (62),
154 (base), 179 (93), 195 (22).
2). 1H NMR:
d 0.95e1.15 (m, 2H), 1.19e1.27 (m, 3H), 1.30 (d,
J¼6.1 Hz, 3H), 1.50 (m, 1H), 1.64e1.77 (m, 4H), 1.96 (m, 1H),
2.20e2.26 (m, 2H), 2.32e2.39 (m, 2H), 3.30 (m, 1H), 3.70 (m, 1H);
13C NMR:
d 22.0, 25.9, 26.0, 26.4, 28.2, 28.9, 43.1, 44.9, 49.6, 73.2,
4.3.3. 1-Hydroxy-1-phenylhex-5-en-3-one (Table 1, entry
3). 1H NMR:
2.73e2.92 (m, 2H), 3.17 (d, J¼6.9 Hz, 2H), 5.09e5.20
(m, 3H), 5.87 (m,1H), 7.24e7.35 (m, 5H); 13C NMR:
48.2, 50.6, 69.6,
2
and
81.2, 208.3; HRMS m/z 196.1468 (calcd for C12H20O2, 196.1463); MS
m/z 112 (36), 113 (base), 137 (3), 152 (5), 178 (4); IR (neat) 2925 (s),
2852 (m), 1720 (C]O, s), 1272 (m), 1063 (w).
d
d
119.1, 125.5, 127.4, 128.3, 129.7, 142.8, 208.5; HRMS m/z 190.0998
(calcd for C12H14O2, 190.0994); MS m/z 105 (81), 107 (base), 120
(25), 149 (26), 162 (12).
4.3.12. Tetrahydro-2-methyl-6-phenylpyran-4-one (Table 2, entry
3). 1H NMR:
d
1.42 (d, J¼6.2 Hz, 3H), 2.33e2.64 (m, 4H), 3.93 (m,
1H), 4.65 (dd, J¼3.9, 10.5 Hz, 1H), 7.28e7.39 (m, 5H); 13C NMR:
4.3.4. 1-(4-Fluorophenyl)-1-hydroxyhex-5-en-3-one (Table 1, entry
d 21.9, 46.0, 48.1, 73.3, 76.6, 78.4, 125.5, 126.5, 127.8, 128.4, 140.7,
4). 1H NMR:
d
2.73e2.90 (m, 2H), 3.18 (d, J¼6.4 Hz, 2H), 3.41
206.3; HRMS: m/z 190.0993 (base)(calcd for C12H14O2, 190.0994);

A.S.-Y. Lee et al. / Tetrahedron 68 (2012) 3915e3919
3919
MS m/z 105 (60), 107 (33), 171 (3), 172 (4), 190 (base); IR (neat) 2975
(w), 2865 (w), 2360 (w), 1716 (C]O, s), 1056 (m), 697 (s).
1.5 Hz, 1H), 2.51 (d, J¼6.2 Hz, 1H), 2.54 (d, J¼3.3 Hz, 1H), 2.58e2.65
(m, 2H), 3.40 (d, J¼5.8 Hz,1H), 2.86e3.93 (m, 2H), 4.17 (d, J¼10.3 Hz,
1H), 4.81 (d, J¼2.8 Hz, 1H), 7.24e7.42 (m, 10H); HRMS m/z 204.1153
(calcd for C13H16O2, 204.1150); MS m/z 107 (42), 115 (15), 117 (28),
118 (17), 162 (70), 203 (5), 204 (base); IR (neat) 2974 (w), 2933 (w),
2879 (w), 1712 (C]O, s), 1022 (m), 699 (s).
4.3.13. 2-(4-Fluorophenyl)-tetrahydro-6-methylpyran-4-one (Table
2, entry 4). 1H NMR:
d
1.41 (d, J¼6.0 Hz, 3H), 2.31e2.62 (m, 4H),
3.91 (m, 1H), 4.63 (dd, J¼3.4, 10.9 Hz, 1H), 7.02e7.10 (m, 2H),
7.32e7.38 (m, 2H); 13C NMR:
22.1, 49.2, 49.3, 73.7, 78.1, 115.4,
d
115.6,127.4,127.5,136.6,164.1, 206.4; HRMS m/z 208.0903 (calcd for
C12H13FO2, 208.0900); MS m/z 122 (65), 123 (base), 124 (32), 125
(44), 149 (18), 190 (10); IR (neat) 2976 (w), 1715 (C]O, s), 1607 (w),
1510 (s), 1221 (s), 825 (s).
4.3.20. 2-Cyclohexyl-tetrahydro-5,6-dimethylpyran-4-one (Scheme
6, 6a). 1H NMR:
d
0.95 (d, J¼6.7 Hz, 3H), 0.98e1.25 (m, 6H), 1.31
(d, J¼6.0 Hz, 3H), 1.48 (m, 1H), 1.71e1.74 (m, 4H), 1.94 (m, 1H),
2.15e2.41 (m, 3H), 3.26 (m, 1H); 13C NMR: 9.3, 20.4, 25.9, 26.0, 26.4,
28.2, 28.9, 43.1, 45.2, 51.9, 79.0, 81.5, 209.5; HRMS m/z 210.1616
(calcd for C13H22O2, 210.1620); MS m/z 109 (39), 127 (56), 137 (15),
166 (base), 167 (15); IR (neat) 2925 (m), 2853 (w), 1714 (C]O, s),
14,450 (w), 1160 (w), 1092 (w), 891 (w).
4.3.14. 2-(4-Bromophenyl)-tetrahydro-6-methylpyran-4-one (Table
2, entry 5). 1H NMR:
d
1.41 (d, J¼6.1 Hz, 3H), 2.62e2.31 (m, 4H),
3.97e3.86 (m, 1H), 4.61 (dd, J¼3.1, 11.1 Hz, 1H), 7.23e7.27 (m, 2H),
7.50 (dd, J¼6.7, 1.8 Hz, 2H); 13C NMR:
d 21.9, 48.9, 49.0, 73.4, 77.7,
127.2, 128.3, 131.5, 139.7, 205.9; HRMS m/z 268.0103 (calcd for
C12H13BrO2, 268.0099); MS m/z 155 (13),157 (15),183 (73),184 (85),
185 (base), 270 (78); IR (neat) 2974 (w), 1716 (C]O, s), 1488 (m),
1066 (s), 1010 (s), 814 (s).
4.3.21. Tetrahydro-5,6-dimethyl-2-phenylpyran-4-one (Scheme 6,
6b). 1H NMR:
d
1.07 (d, J¼6.7 Hz, 3H),1.45 (d, J¼6.2 Hz, 3H), 2.37 (m,
1H), 2.63e2.69 (m, 2H), 3.7 (m, 1H), 4.66 (dd, J¼6.3, 8.0 Hz, 1H),
7.28e7.40 (m, 5H); 13C NMR:
9.3, 20.5, 49.6, 51.6, 78.9, 79.3, 125.6,
d
127.9, 128.5, 140.9, 207.9; HRMS m/z 204.1150 (calcd for C13H16O2,
204.1150); MS m/z 104 (base),107 (54),118 (25),160 (32), 186 (3); IR
(neat) 2975 (w), 1714 (C]O, s), 1453 (w), 1069 (m), 756 (m), 698 (s).
4.3.15. 2-(3-Bromophenyl)-tetrahydro-6-methylpyran-4-one (Table
2, entry 6). 1H NMR:
d
1.42 (d, J¼6.3 Hz, 3H), 2.31e2.62 (m, 4H),
3.91 (m, 1H), 4.62 (dd, J¼3.0, 11.3 Hz, 1H), 7.25 (m, 1H), 7.44 (m, 1H),
7.57 (d, J¼1.7 Hz, 1H); 13C NMR: 22.1, 49.1, 49.2, 73.7, 77.8, 122.8,
124.2, 128.8, 130.2, 131.1,143.1, 206.0; HRMS m/z 268.0103 (calcd for
C12H13BrO2, 268.0099); MS m/z 103 (25),155 (14),157 (16),182 (68),
184 (base), 270 (80); IR: (neat) 2975 (w), 2861 (w), 1715 (C]O, s),
1061 (m), 781 (m), 691 (m).
4.3.22. Spiro-tetrahydropyran-4-one (Scheme 7, 8). 1H NMR:
(d, J¼5.9 Hz, 3H), 1.38e1.51 (m, 6H), 1.68e1.76 (m, 4H), 2.15e2.32
(m, 4H), 3.95e2.89 (m, 1H); 13C NMR:
21.2, 21.7, 22.5, 25.4, 31.9,
d 1.28
d
39.5, 49.3, 52.2, 65.7, 75.9, 208.3; HRMS m/z 182.1304 (calcd for
C11H18O2, 182.1307); MS m/z 105 (12), 126 (63), 139 (73), 142 (22),
141 (17), 149 (100), 182 (base). IR: (neat) 2930 (m), 2859 (w), 1717
(C]O, s), 1274 (m), 999 (m), 850 (w).
4.3.16. 2-(Benzo[d][1,3]dioxol-5-yl)-tetrahydro-6-methylpyran-4-
one (Table 2, entry 7). 1H NMR:
d
1.40 (d, J¼6.1 Hz, 3H), 2.30e2.55
(m, 4H), 3.90 (m, 1H), 4.56 (dd, J¼5.2, 9.1 Hz, 1H), 5.95 (s, 2H),
Acknowledgements
6.77e6.84 (m, 2H), 6.91 (d, J¼1.3 Hz, 1H); 13C NMR:
d 22.2, 49.3,
49.4, 73.6, 78.6, 101.1, 106.5, 108.3, 119.3, 134.8, 147.4, 148.0, 206.7;
HRMS m/z 234.0888 (calcd for C13H14O4, 234.0892); MS m/z 121 (7),
149 (56), 150 (98), 234 (base); IR (neat) 2974 (w), 2899 (w), 2361
(w), 1716 (C]O, s), 1239 (s), 1036 (s), 810 (m).
We thank the National Science Council in Taiwan (NSC 98-2119-
M-032-002-MY3) and Tamkang University for financial support.
References and notes
4.3.17. Tetrahydro-2-methyl-6-(thiophen-2-yl)pyran-4-one
(cis/
trans¼1/1) (Table 2, entry 8). 1H NMR:
d
1.27 (d, J¼6.0 Hz, 3H), 1.40
1. Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995, 117, 8126.
2. Tanaka, J.; Higa, T. Tetrahedron Lett. 1996, 37, 5535.
3. Horton, P. A.; Koehn, F. E.; Longley, R. E.; McConnell, O. J. J. Am. Chem. Soc. 1994,
116, 6015.
4. Schummer, D.; Gerth, K.; Reichenbach, H.; Hofle, G. Liebigs Ann. Chem.
1995, 685.
5. D’Ambrosio, M.; Guerriero, A.; Debitus, C.; Pietra, F. Helv. Chim. Acta 1996, 79, 51.
6. Carmely, S.; Kashman, Y. Tetrahedron Lett. 1985, 26, 511.
7. Tanaka, J.; Higa, T.; Kobayashi, M.; Kitagawa, I. Chem. Pharm. Bull. 1990, 38, 2967.
8. Jansen, R.; Wray, V.; Irschik, H.; Reichenbach, H.; Hofle, G. Tetrahedron Lett.
1985, 26, 6031.
(d, J¼6.0 Hz, 3H), 2.27e2.48 (m, 4H), 2.69e2.72 (m, 2H), 2.89e2.91
(m, 2H), 3.90e4.03 (m, 2H), 4.89 (dd, J¼5.3, 9.1 Hz, 1H), 5.54 (t,
J¼4.9 Hz, 1H), 6.91e6.99 (m, 4H), 7.29e7.33 (m, 2H); 13C NMR:
d
21.2, 22.0, 45.2, 48.9, 49.1, 67.6, 70.9, 73.5, 74.5, 124.1, 125.4, 126.3,
126.4, 126.6, 143.7, 205.9, 206.3; HRMS m/z 196.0560 (calcd for
C10H12O2S, 196.0558); MS m/z 112 (32), 113 (54), 126 (base), 137 (5),
163 (10), 168 (14); IR: (neat) 2974 (w), 1717 (C]O, s), 1585 (s), 1442
(w), 1043 (m), 700 (s).
9. Moore, R. E.; Patterson, G. M. L.; Mynderse, J. S.; Barchi, J., Jr. Pure Appl. Chem.
1986, 58, 263.
10. Ishibashi, M.; Moore, R. E.; Patterson, G. M. L.; Xu, C.; Clardy, J. J. Org. Chem.
1986, 51, 5300.
11. Baker-Glenn, C.; Hodnett, N.; Reiter, M.; Ropp, S.; Ancliff, R.; Gouverneur, V. J.
4.3.18. 2-(Furan-2-yl)-tetrahydro-6-methylpyran-4-one
(cis/
trans¼6/4) (Table 2, entry 9). 1H NMR:
1.27 (d, J¼6.4 Hz, 3H), 1.38
d
(d, J¼5.9 Hz, 3H), 2.30e2.89 (m, 8H), 3.87e3.92 (m, 2H), 4.70 (dd,
J¼2.5, 12.1 Hz, 1H), 5.35 (dd, J¼6.9, 2.6 Hz, 1H), 6.27e6.37 (m, 4H),
Am. Chem. Soc. 2005, 127, 1481.
12. Kawai, N.; Lagrange, J.-M.; Ohmi, M.; Uenishi, J. J. Org. Chem. 2006, 71, 4530.
13. Reddy, U. C.; Raju, B. R.; Kumar, E. K. P.; Saikia, A. K. J. Org. Chem. 2008, 73, 1628.
14. Piccialli, V. Synthesis 2007, 2585.
7.40e7.42 (m, 2H); 13C NMR:
d 21.6, 22.0, 43.1, 45.1, 49.1, 49.2, 67.8,
68.9, 71.9, 73.4, 107.7, 109.9, 110.2, 110.3, 142.9, 143.0, 206.0; HRMS
m/z 180.0785 (calcd for C10H12O3, 180.0786); MS m/z 110 (27), 121
(13), 122 (23), 136 (8), 138 (11), 152 (18), 180 (base); IR (neat) 2975
(w), 2360 (w), 1715 (C]O, s), 1344 (m), 1015 (m), 741 (s).
15. Wong, M.-K.; Chung, N.-W.; He, L.; Yang, D. J. Am. Chem. Soc. 2003, 125, 158.
16. Dalgard, J. E.; Rychnovsky, S. D. J. Am. Chem. Soc. 2004, 126, 15662.
17. Liu, H.; Wan, S.; Floreancig, P. E. J. Org. Chem. 2005, 70, 3814.
18. Lee, A. S.-Y.; Lin, L.-S. Tetrahedron Lett. 2000, 41, 8803.
19. Lee, A. S.-Y.; Tsao, K.-W.; Chang, Y.-T.; Chu, S.-F. Tetrahedron Lett. 2007, 48, 6790.
20. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
21. Lee, A. S.-Y.; Wang, S.-H.; Chang, Y.-T.; Chu, S.-F. Synlett 2003, 2359.
22. Lee, A. S.-Y.; Lin, M.-C.; Lin, C.-C.; Chang, Y.-T. J. Chin. Chem. Soc. 2010, 57, 795.
23. Yadav, L. D. S.; Singh, S.; Rai, V. K. Synlett 2010, 240.
24. Reiter, M.; Turner, H.; Gouverneur, V. Chem. Eur. J. 2006, 12, 7190.
4.3.19. Tetrahydro-3,6-dimethyl-2-phenylpyran-4-one (Scheme 6,
4aþ4b). 1H NMR: (CDCl3)
0.80 (d, J¼6.6 Hz, 3H), 0.89 (d, J¼7.3 Hz,
d
3H), 1.37 (d, J¼6.0 Hz, 3H), 1.43 (d, J¼6.3 Hz, 3H), 2.32 (dt, J¼15.0,