An efficient synthesis of 2,6-disubstituted 2,3-dihydro-4 h -pyran-4-ones via sonogashira coupling of p -toluenethiol esters

Article abstract of DOI:10.1055/s-0029-1219794

An efficient strategy for the synthesis of 2,6-disubstituted 2,3-dihydro-4H-pyran-4-ones has been developed, which relied on Sonogashira coupling of alkynes and p-toluenethiol esters and AgOTf-promoted 6-endo-dig cyclization of the derived -hydroxy ynones

Full text of DOI:10.1055/s-0029-1219794

LETTER
1239
An Efficient Synthesis of 2,6-Disubstituted 2,3-Dihydro-4H-pyran-4-ones via
Sonogashira Coupling of p-Toluenethiol Esters
S
ynthesis of 2,6-D
a
isubstituted
r
2,3-Dih
u
ydro-4
H
-pyr
h
an-4-ones iko Fuwa,* Seiji Matsukida, Makoto Sasaki
Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan
Fax +81(22)7178896; E-mail: hfuwa@bios.tohoku.ac.jp
Received 15 February 2010
R2
R1
OPG
O
R1
OPG
SR
Abstract: An efficient strategy for the synthesis of 2,6-disubstitut-
ed 2,3-dihydro-4H-pyran-4-ones has been developed, which relied
on Sonogashira coupling of alkynes and p-toluenethiol esters and
AgOTf-promoted 6-endo-dig cyclization of the derived b-hydroxy
ynones.
R2
Sonogashira
coupling
O
Key words: palladium, cross-coupling, cyclization, heterocycles,
dihydropyrans
R1
OH
R1
O
O
R2
6-endo-dig
cyclization
R2
deprotect
O
Thiol esters serve as a stable and easy-to-handle surrogate
for acid chlorides in palladium-catalyzed reactions.1
Fukuyama and co-workers reported a mild and efficient
reduction of ethanethiol esters with triethylsilane in the
presence of Pd/C, which constitutes the prototype of
palladium-catalyzed reactions of thiol esters.2 Subse-
quently, they also reported that coupling of ethanethiol es-
ters with organozinc reagents3 or terminal alkynes4 under
palladium catalysis is also feasible, which allows for effi-
cient synthesis of unsymmetrical ketones. Meanwhile,
Liebeskind et al. have described palladium-catalyzed cou-
pling of p-toluenethiol esters with organotin5 or orga-
noboron reagents,6 which also provides access to
unsymmetrical ketones.
Scheme 1 Our strategy for the synthesis of 2,6-disubstituted 2,3-di-
hydro-4H-pyran-4-ones
gave ynone 3 in 39% yield (entry 1). Prolonged reaction
time was necessary for consumption of 1a, during which
time 1,4-addition of ethanethiol to the product ynone 3
was observed as a side reaction. To improve the product
yield, we screened a variety of reaction conditions. We
found that p-toluenethiol ester 1b displays better reactivi-
ty than 1a; reaction of 1b and 2 under the same conditions
for 4 hours gave 3 in an improved 73% yield (entry 2).
Benzenethiol ester 1c and p-nitrobenzenethiol ester 1d
proved to be less efficient than 1b (entries 3 and 4). We
preferred to use p-toluenethiol esters in the following ex-
periments not only because of their good reactivity profile
but also because of easy handling of crystalline p-tolu-
enethiol. We found Pd2(dba)3·CHCl3 to be the optimal
source of palladium for the present reaction (entries 5 and
6). When a mixture of 1b and 2 was reacted in the pres-
ence of a Pd2(dba)3·CHCl3/(2-furyl)3P catalyst system and
CuI in DMF–Et3N (5:1) at 50 °C for 4.5 hours, the desired
ynone 3 was isolated in 77% yield (entry 5). Although
longer reaction time (22 h) was necessary, the reaction
proceeded even at room temperature to give 3 in a compa-
rable yield of 80% (entry 6).
It is well known that 2,3-dihydro-4H-pyran-4-one deriva-
tives are the versatile intermediates for the synthesis of
functionalized tetrahydropyrans and spiroacetals. Several
methods, such as hetero-Diels–Alder reaction,7 palladi-
um-catalyzed oxidative cyclization of b-hydroxy enones,8
and intramolecular oxa-conjugate cyclization of b-hy-
droxy ynones,9 have been reported for the synthesis of
2,3-dihydro-4H-pyran-4-one derivatives, although prepa-
ration of suitable precursors for these reactions is difficult
in some cases.8b Herein, we report a new strategy for the
synthesis of 2,6-disubstituted 2,3-dihydro-4H-pyran-4-
ones, which relied on Sonogashira coupling of readily ac-
cessible terminal alkynes and p-toluenethiol esters and 6-
endo-dig cyclization of the derived b-hydroxy ynones, as
summarized in Scheme 1.
Various combinations of terminal alkynes and p-tolu-
enethiol esters were tolerated under the optimized condi-
tions to deliver the corresponding ynone in 73–82% yield
(Table 2).10
We initially examined palladium-catalyzed coupling of
thiol esters 1a–d and alkyne 2 as a model case (Table 1).
Coupling of ethanethiol ester 1a and 2 (2 equiv) under the
conditions reported by Fukuyama et al.4 [PdCl2(dppf), (2-
furyl)3P, CuI] in DMF–Et3N (5:1) at 50 °C for 22 hours
For each ynone, the MPM group was removed by treat-
ment with DDQ to give the respective b-hydroxy ynone in
85–100% yield (Table 3). We found that b-hydroxy
ynones thus obtained underwent smooth 6-endo-dig cy-
clization upon exposure to AgOTf9a,b in CH2Cl2 at room
temperature, leading to 2,6-disubstituted 2,3-dihydro-4H-
pyran-4-one derivatives in excellent yields (94–100%).11
This 6-endo-dig cyclization could be performed either un-
der catalytic or stoichiometric conditions without affect-
SYNLETT 2010, No. 8, pp 1239–1242
x
x.
x
x.
2
0
1
0
Advanced online publication: 23.03.2010
DOI: 10.1055/s-0029-1219794; Art ID: U01010ST
© Georg Thieme Verlag Stuttgart · New York

1240
H. Fuwa et al.
LETTER
Table 2 Synthesis of Various Ynones
Table 1 Optimization of Reaction Conditions
Pd2(dba)3⋅CHCl3 (0.05 equiv)
(2-furyl)3P (0.4 equiv)
CuI (1.7 equiv)
3 OMPM
R1
OMPM
R1
OMPM
R2
BnO
BnO
2 (2.0 equiv)
DMF–Et3N (5:1), 50 °C
OMPM
OMPM
SR
S
R2
A or B
CuI (1.7 equiv)
DMF–Et3N (5:1)
50 °C
(1.5–2.0 equiv)
OMPM
3
5 R2 = n-Bu
O
O
10–16
Me
6 R2 = CH2CH2CH2OTBDPS
O
3
1b R1 = CH2CH2CH2OBn
4 R1 = cyclohexyl
7 R2 = Ph
O
1a R = Et
A PdCl2(dppf) (0.1 equiv), (2-furyl)3P (0.25 equiv)
1b R = 4-MeC6H4 B Pd2(dba)3⋅CHCl3 (0.05 equiv), (2-furyl)3P (0.4 equiv)
8 R
2 = cyclohexyl
9 R2 = CMe2CH2OBn
1c R = Ph
1d R = 4-O2NC6H4
Entry Thiol Alkyne Product
ester
(yield, %)
Entry
Thiol ester 1
Catalyst system
Yield (%)
1
2
3
4
5
6a
1a
1b
1c
1d
1b
1b
A
A
A
A
B
B
39
73
70
65
77
80
BnO
OMPM
O
1a
1b
5
6
Me
10 80%
BnO
OMPM
O
2b
1b
OTBDPS
a The reaction was performed at r.t.
ing the product yield (entry 2), but the reaction proceeded
faster under the latter conditions; the reaction completed
within 3.4 hours under the stoichiometric conditions,
while it took 9.5 hours to complete under the catalytic
conditions.
11 80%
BnO
OMPM
O
Ph
3a
4a
5b
6b
7a
1b
1b
1b
4
7
8
9
6
7
In conclusion, we have developed an efficient method for
the synthesis of 2,6-disubstituted 2,3-dihydro-4H-pyran-
4-one derivatives. We have found that efficiency of Sono-
gashira coupling of terminal alkynes and thiol esters could
be significantly enhanced by the use of p-toluenethiol es-
ters as an electrophilic component, affording the corre-
sponding b-alkoxy ynones in good yields. AgOTf-
promoted cyclization of the derived b-hydroxy ynones
furnished 2,6-disubstituted 2,3-dihydro-4H-pyran-4-ones
in excellent yields. Application of the present method to
the synthesis of natural products is currently under inves-
tigation.
12 82%
BnO
OMPM
O
13 75%
BnO
MPM
Me Me
O
OBn
O
Acknowledgment
14 82%
15 80%
16 73%
This work was supported in part by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science
and Technology (MEXT), Japan.
OMPM
O
OTBDPS
References and Notes
(1) For reviews, see: (a) Fukuyama, T.; Tokuyama, H.
Aldrichimica Acta 2004, 37, 87. (b) Prokopcová, H.; Kappe,
C. O. Angew. Chem. Int. Ed. 2009, 48, 2276.
OMPM
O
Ph
(2) Fukuyama, T.; Kin, S.-C.; Li, L. J. Am. Chem. Soc. 1990,
4
112, 7050.
(3) (a) Tokuyama, H.; Yokoshima, S.; Yamashita, T.;
Fukuyama, T. Tetrahedron Lett. 1998, 39, 3189.
(b) Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Lin,
S.-C.; Li, L.; Fukuyama, T. J. Braz. Chem. Soc. 1998, 9, 381.
a Conditions: 2.0 equiv of alkyne were used.
b Conditions: 1.5 equiv of alkyne were used.
Synlett 2010, No. 8, 1239–1242 © Thieme Stuttgart · New York

LETTER
Synthesis of 2,6-Disubstituted 2,3-Dihydro-4H-pyran-4-ones
1241
(4) Tokuyama, H.; Miyazaki, T.; Yokoshima, S.; Fukuyama, T.
Synlett 2003, 1512.
Table 3 Synthesis of Various 2,6-Disubstituted 2,3-Dihydro-4H-
pyran-4-ones
(5) (a) Wittenberg, R.; Srogl, J.; Egi, M.; Liebeskind, L. S. Org.
Lett. 2003, 5, 3033. (b) Li, H.; Yang, H.; Liebeskind, L. S.
Org. Lett. 2008, 10, 4375.
R1
O
R2
R1
OMPM
R2
1. DDQ, pH 7 buffer
CH2Cl2, r.t.
(6) (a) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122,
11260. (b) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett.
2000, 2, 3229.
(7) For example, see: (a) Danishefsky, S.; Kerwin, J. F. Jr.;
Kobayashi, S. J. Am. Chem. Soc. 1982, 104, 358. (b) Keck,
G. E.; Li, X.-Y.; Krichnamurthy, D. J. Org. Chem. 1995, 60,
5998.
(8) (a) Reiter, M.; Ropp, S.; Gouverneur, V. Org. Lett. 2004, 6,
91. (b) Reiter, M.; Turner, H.; Mills-Webb, R.; Gouverneur,
V. J. Org. Chem. 2005, 70, 8478.
2. AgOTf, CH2Cl2, r.t.
O
O
17–23
10–16
Entry Ynone Product
Yield Yield
step 1 step 2
(%)
(%)
BnO
O
O
(9) For example, see: (a) Wang, C.; Forsyth, C. J. Org. Lett.
2006, 8, 2997. (b) Nicolaou, K. C.; Frederick, M. O.;
Burtoloso, A. C. B.; Denton, R. M.; Rivas, F.; Cole, K. P.;
Aversa, R. J.; Gibe, R.; Umezawa, T.; Suzuki, T. J. Am.
Chem. Soc. 2008, 130, 7466. (c) Schuler, M.; Silva, F.;
Bobbio, C.; Tessier, A.; Gouverneur, V. Angew. Chem. Int.
Ed. 2008, 47, 7927.
(10) Typical Procedure for Sonogashira Coupling of p-
Toluenethiol Esters and Terminal Alkynes (Table 2,
Entry 1)
Me
1
2
3
4
5
6
7
10
11
12
13
14
15
16
85
96a
17
BnO
O
O
98a
98b
OTBDPS
92
90
To a solution of Pd2(dba)3·CHCl3 (13.2 mg, 0.0128 mmol),
CuI (82.7 mg, 0.434 mmol), and (2-furyl)3P (23.7 mg, 0.102
mmol) in degassed DMF (1.1 mL) was added a solution of
1b (118.7 mg, 0.2555 mmol) in degassed DMF (1.1 mL), 1-
hexyne (0.059 mL, 0.51 mmol), and Et3N (0.430 mL). The
resultant mixture was stirred at 50 °C for 4.4 h. After being
cooled to r.t., the reaction mixture was diluted with H2O and
extracted with Et2O. The organic layer was washed with
brine, dried over MgSO4, filtered, and concentrated under
reduced pressure. Purification of the residue by flash
chromatography on silica gel (5–10% EtOAc–hexanes)
gave ynone 10 (86.7 mg, 80%) as a yellow oil.
18
BnO
O
O
Ph
97a
100a
98a
98b
94a
19
BnO
O
O
Spectroscopic Data for Ynone 10
100
IR (film): 2930, 2210, 1670, 1513, 1455, 1247, 1095, 698
cm–1. 1H NMR (500 MHz, CDCl3): d = 7.32 –7.26 (m, 5 H),
7.21 (d, J = 8.0 Hz, 2 H), 6.83 (d, J = 8.5 Hz, 2 H), 4.47–4.37
(m, 4 H), 4.00 (m, 1 H), 3.77 (s, 3 H), 3.44 (t, J = 5.0 Hz, 2
H), 2.86 (dd, J = 7.5, 7.0 Hz, 1 H), 2.63 (dd, J = 5.0, 4.5 Hz,
1 H), 2.36–2.29 (m, 2 H), 1.74–1.60 (m, 4 H), 1.58–1.50 (m,
2 H), 1.49–1.36 (m, 2 H), 0.89 (t, J = 7.5 Hz, 3 H). 13C NMR
(125 MHz, CDCl3): d = 186.1, 159.1, 138.4, 130.4, 129.3 (2
C), 128.3 (2 C), 127.5 (2 C), 127.4, 113.6 (2 C), 94.9, 81.2,
74.7, 72.8, 71.1, 70.1, 55.2, 50.6, 31.0, 29.6, 25.4, 21.9, 18.6,
13.4. ESI-HRMS: m/z calcd for C27H34NaO4 [M + Na]+:
445.2349; found: 445.2365.
20
BnO
Me Me
O
O
OBn
96
21
22
23
(11) Typical Procedure for Deprotection and AgOTf-
Promoted 6-endo-dig Cyclization of b-Alkoxy Ynone
(Table 3, Entry 1)
O
O
OTBDPS
88
To a solution of ynone 10 (79.4 mg, 0.188 mmol) in CH2Cl2–
pH 7 buffer (10:1, v/v, 1.9 mL) cooled to 0 °C was added
DDQ (48.4 mg, 0.207 mmol), and the resultant mixture was
stirred at r.t. for 1 h. The reaction was quenched with sat. aq
NaHCO3 solution. The whole mixture was filtered through a
pad of Celite, and the filtrate was extracted with EtOAc. The
organic layer was washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure.
Purification of the residue by flash chromatography on silica
gel (10–30% EtOAc–hexanes) gave a b-hydroxy ynone
(48.5 mg, 85%) as a yellow oil.
O
O
Ph
88
a Cyclization was performed using AgOTf (1.1 equiv) in CH2Cl2 at r.t.
b Cyclization was performed using AgOTf (0.1 equiv) in CH2Cl2 at r.t.
Spectroscopic Data for b-Hydroxy Ynone
IR (film): 3427, 2930, 2862, 2210, 1669, 1455, 1362, 1160,
1097 cm–1. 1H NMR (500 MHz, CDCl3): d = 7.33–7.25 (m,
Synlett 2010, No. 8, 1239–1242 © Thieme Stuttgart · New York

1242
H. Fuwa et al.
LETTER
5 H), 4.49 (s, 2 H), 4.12 (m, 1 H), 3.49 (t, J = 6.5 Hz, 2 H),
3.06 (br, 1 H), 2.69 (d, J = 6.0 Hz, 2 H), 2.35 (t, J = 7.5 Hz,
2 H), 1.79–1.67 (m, 2 H), 1.63–1.49 (m, 4 H), 1.45–1.37 (m,
2 H), 0.90 (t, J = 7.5 Hz, 3 H). 13C NMR (125 MHz, CDCl3):
d = 187.5, 138.2, 128.4 ( 2 C), 127.6 (2 C), 127.5, 95.5, 81.0,
72.9, 70.1, 67.3, 52.3, 33.5, 29.6, 25.9, 21.9, 18.6, 13.4. ESI-
HRMS: m/z calcd for C19H26NaO3 [M + Na]+: 325.1774;
found: 325.1770.
To a solution of the above b-hydroxy ynone (38.0 mg, 0.126
mmol) in CH2Cl2 (12.6 mL) was added AgOTf (35.5 mg,
0.138 mmol), and the resultant mixture was stirred at r.t. for
3.2 h under exclusion of light. The reaction mixture was
diluted with EtOAc and washed with brine. The organic
layer was dried over Na2SO4, filtered, and concentrated
under reduced pressure. Purification of the residue by flash
chromatography on silica gel (30% EtOAc–hexanes) gave
2,3-dihydro-4H-pyran-4-one 17 (36.5 mg, 96%) as a yellow
oil.
Spectroscopic Data for 2,3-Dihydro-4H-pyran-4-one 17
IR (film): 2955, 1666, 1604, 1398, 1099, 737 cm–1. 1H NMR
(500 MHz, CDCl3): d = 7.35–7.26 (m, 5 H), 5.29 (s, 1 H),
4.49 (s, 2 H), 4.31 (m, 1 H), 3.50 (t, J = 5.0 Hz, 2 H), 2.43–
2.30 (m, 2 H), 2.25–2.15 (m, 2 H), 1.89–1.68 (m, 4 H), 1.53–
1.46 (m, 2 H), 1.35–1.28 (m, 2 H), 0.89 (t, J = 7.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 193.4, 177.9, 138.33,
128.4 (2 C), 127.6 (2 C), 104.1, 104.0, 78.9, 73.0, 69.6, 41.0,
34.5, 31.3, 28.4, 25.3, 22.1, 13.7. ESI-HRMS: m/z calcd for
C19H27O3 [M + H]+: 303.1955; found: 303.1965.
Synlett 2010, No. 8, 1239–1242 © Thieme Stuttgart · New York

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