The reaction of terminal alkynes with PhI(OAc)2: a convenient procedure for the preparation of α-acyloxy ketones

Article abstract of DOI:10.1016/j.tetlet.2009.07.081

Treatment of terminal alkynes with PhI(OAc)₂ in different acids at 70 °C provided the corresponding α-acyloxy ketones in good to excellent yields. A plausible mechanism has been proposed based on the experimental results.

Full text of DOI:10.1016/j.tetlet.2009.07.081

Tetrahedron Letters 50 (2009) 5578–5581
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The reaction of terminal alkynes with PhI(OAc)2: a convenient procedure for
the preparation of
a-acyloxy ketones
*
Dong-Liang Mo, Li-Xin Dai, Xue-Long Hou
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of terminal alkynes with PhI(OAc)2 in different acids at 70 °C provided the corresponding a-
acyloxy ketones in good to excellent yields. A plausible mechanism has been proposed based on the
experimental results.
Received 23 June 2009
Revised 13 July 2009
Accepted 14 July 2009
Available online 19 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
a
-Acetoxy ketones are one class of important intermediates in
65% yield. Almost the same yield was obtained when the reaction
proceeded under aerobic conditions.
organic synthesis. They are easily transformed into a-hydroxy ke-
tones, which are found in a variety of biologically interesting nat-
palladacycle 3
O
ural products.1 To date many procedures have been developed to
PhI(OAc)2
Ph
OAc
+
O
prepare
a-acetoxy ketones, such as the acetolysis of a-bromo ke-
Ph
DCE, 60 °C
tones,2 the anodic oxidation of enol acetates in acetic acid,3 the
4a
1a
2
Cu-catalyzed insertion reaction of a-diazo ketones with carboxylic
acids,4 the oxidation of ketones with lead tetraacetate,5 the oxida-
tion of ketones with manganese(III) acetate in acetic acid,6 and lead
tetraacetate oxidation of trimethylsilyl enol ethers.7 However they
suffered from the low yields and environmental problem. Some
other oxidants were also used in the transformation of ketones into
ð1Þ
OAc
Pd
PPh2
a
-acetoxy ketones.8,9 On the other hand, hypervalent iodine re-
palladacycle 3
agents have attracted much attention of synthetic chemists in re-
cent years because of their interesting activity, ready availability,
and easy handling.10,11 Oxidation of terminal alkynes to ketones
in the presence of hypervalent iodine compounds has been docu-
mented,12 However, few reports were given on the direct transfor-
Based on the above results, the influence of the reaction param-
eters on the reaction was investigated (Table 1). Screening of sol-
vents showed that -acetoxy ketone 4a was obtained in 65%,
a
53%, or 66% yield, respectively, when the reaction proceeded in
dichloroethane (DCE), MeCN, or MeOH (entries 1, 6, and 8) while
lower yields of desired product were isolated if CHCl3, toluene,
THF, DME and DMF were used as solvent (entries 2–5 and 7). When
acetic acid was the solvent the yield of product 4a increased to 87%
(entry 9), while it decreased to 78% and 80%, respectively, when
2 equiv of water or AcOK was added (entries 14 and 15). No desired
product 4a was separated if KI and I2 were used as additives (not
shown in Table 1). We also studied the influence of the tempera-
ture on the reaction. Poor yield of 4a was obtained when the reac-
tion was carried out at room temperature (entry 10) while the
yields were 85% and 76% if the reaction ran at 100 °C and 120 °C,
respectively (entries 12 and 13).
mation of alkynes to
a
-acetoxy ketones.13,14a During our studies on
the reaction using palladacycles as catalyst,15 we found that
a
-
acetoxy ketones were produced when the terminal alkynes reacted
with iodosobenzene diacetate. Herein, we would like to report this
convenient procedure for preparing a-acetoxy ketones by the reac-
tion of terminal alkynes with hypervalent iodine compounds as
oxidant.
Initially we studied the reaction of phenylacetylene 1a with
oxabicyclic alkene 2 using palladacycle 3 as catalyst in the pres-
ence of PhI(OAc)2 in dichloroethane (DCE) at 60 °C under argon.
It is surprising that
a-acetoxy acetophenone 4a was obtained in
40% yield (Eq. 1). Controlled experiment revealed that palladacycle
was not essential for the reaction. Indeed, when PhI(OAc)2 was
Under the optimized conditions, the scope of the substrates was
examined (Table 2).16 It can be seen that both aryl acetylenes and
aliphatic terminal alkynes are suitable substrates in the reaction,
used as the only oxidant,
a-acetoxy ketone was also produced in
affording the corresponding
a-acetoxy ketones in moderate to
excellent yields. Aryl acetylenes with methyl or trifluoromethyl
* Corresponding author.
group at the 4-position of benzene ring gave excellent yields of
E-mail address: xlhou@mail.sioc.ac.cn (X.-L. Hou).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.081

D.-L. Mo et al. / Tetrahedron Letters 50 (2009) 5578–5581
5579
Table 1
Table 2 (continued)
Optimization of the reaction conditionsa
Entry
8
Substrate, 1
Product
4
Yieldb
(%)
O
PhI(OAc)2
solvent, additive
Ph
OAc
Ph
O
1a
4a
h
93
OAc
Entry
Solvent
Temperature (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
DCE
60
60
60
60
60
60
60
60
60
25
70
100
120
60
65
26
26
16
29
53
19
66c
87
9
89
85
76
78d
80e
CHCl3
Toluene
THF
DME
CH3CN
DMF
MeOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
O
9
10
11
12
i
77
OAc
O
O
O
O
O
OAc
j
51c
41c
45c
—
O
EtO2C
EtO2C
OAc
O
k
l
EtO2
C
60
CO2Et
a
Reaction conditions: phenylacetylene 1a (0.6 mmol), PhI(OAc)2 (1.0 mmol),
solvent (1.5 mL). Reaction time: 12 h.
b
Isolated yields.
O
c
Ph
OAc
13% of
a
-methoxy ketone 6 as well as 6% of 7 was also separated.
H2O (2.0 equiv) was added.
AcOK (2.0 equiv) was added.
O
Ph
d
e
13
—
m
a
Reaction conditions: acetylene 1 (0.6 mmol), PhI(OAc)2 (1.0 mmol), solvent
Table 2
The scope of the terminal alkynes in the reactiona,16
(1.5 mL). Reaction time: 12 h.
b
Isolated yields.
PhI(OAc)2 (2.0 mmol), reaction time: 24 h.
O
c
PhI(OAc)2
R1
OAc
R1
HOAc, 70°C
4
1
products (entries 2 and 3) while those with substituent at the 2-
position of benzene ring afforded acetoxy ketones in lower yield
maybe due to the steric hindrance (entries 4 and 5). Substituted
naphthyl acetylene 1f also provided product 4f in high yield (entry
6). Reaction of aliphatic terminal alkynes furnished products in
excellent yields (entries 7 and 8), except tert-butyl acetylene 1i,
which gave a little bit lower yield of acetoxy ketone 4i (entry 9)
which may also be due to the steric hindrance. However, alkyne
1m with internal triple bond failed to afford oxidized product (en-
try 13). Interestingly, 1j and 1k with two terminal acetylenic bonds
are also suitable substrates, PhI(OAc)2 reacted with one triple bond
Entry
1
Substrate, 1
Product
4
a
Yieldb
(%)
O
OAc
89
90
94
81
64
85
95
O
OAc
2
3
4
5
6
7
b
c
d
e
f
specifically, providing a-acetoxy ketones with one triple bond in-
O
tact (entries 10 and 11). Moreover, the reaction showed tolerance
toward the carbon–carbon double bond. Reaction of 1,6-enyne 1l
furnished allyl ether 4l in 45% yield (entry 12).
The reaction also proceeded if other carboxylic acids were used.
When we used the above optimized conditions for the reaction of
the phenylacetylene 1a (1.0 equiv), PhI(OAc)2 (2.0 equiv), and dif-
OAc
F3C
F3C
O
O
OAc
OAc
ferent acids (8.0 equiv) in DCE, the corresponding
tones were obtained in good yields (Eq. 2).
a-acyloxy ke-
CF3
PhI(OAc)2
RCOOH
(8 equiv)
O
Ph
OCOR
5a-d
CF3
Ph
DCE, 70°C
O
1a
ð2Þ
OAc
5a-d
51%
82%
56%
69%
R
MeO
H
Et
Bu
Ph
MeO
Based on the observations made by us and the others,14a a plau-
sible mechanism could be proposed (Scheme 1). Reaction of the
terminal alkyne with PhI(OAc)2 forms the alkynyliodonium salts
O
g
OAc

5580
D.-L. Mo et al. / Tetrahedron Letters 50 (2009) 5578–5581
The reaction also proceeded by using catalytic amount of iodo-
R
OAc
Ph
benzene in the presence of 3-chloroperoxybenzoic acid and
BF3ꢁEt2O and water in acetic acid at 30 °C, affording 4a in 40% yield
after 3 days (Eq. 6).18
PhI(OAc)2
HOAc
HOAc
R
I
R
AcO
I
Ph
H
OAc
Int-A
Int-B
PhI (0.1 equiv)
R
H
mCPBA (2 equiv)
BF3 Et2O (3 equiv), H2O (5 equiv)
R
H
R
H
O
H
.
ð6Þ
OAc
Ph
AcO
IPh
OAc
O
IPh
Int-E
Ph
AcO
I OAc
AcOH, 30°C, 3 days
Ac2O
Ph
40% yield
4a
1a
Int-C
Int-D
In summary, we have developed an efficient protocol for the
preparation of -acyloxy ketones by the reaction of terminal al-
kynes with PhI(OAc)2. The yields are good to excellent. A plausible
mechanism was proposed. Further investigations on the reaction
and its applications in organic synthesis are in progress.
H
H
AcO-
R
AcOH
R
a
OAc
I
Ph
OAc
Int-F
O
O
4
Scheme 1. A possible mechanism.
Acknowledgments
This work was financially supported by the Major Basic
Research Development Program (2006CB806100), National Natural
Science Foundation of China (20532050, 20672130, and
20821002), Chinese Academy of Sciences, and Science and Tech-
nology Commission of Shanghai Municipality.
Int-A. Then a Michael-type addition of AcOH to the alkynyliodoni-
um salt provides Int-B. Proton-transfer of Int-B affords (b-acetox-
yalkeny1) phenyliodonium acetate Int-C, which is converted to
Int-D. Attack of AcOꢀ on Int-D provided Int-E. Acidolysis of Int-E
yields alkyliodonium salts Int-F. Substitution of the phenyliodoni-
um group by AcOꢀ gives -acetoxy ketones 4.14a
a
Supplementary data
To have a better understanding of the mechanism, the reaction
was carried out in DCE/D2O (3:1) instead of in AcOH (Eq. 3).
Acetoxy ketone D-4a was obtained in 72% yield with D/H ratio of
99:1 at -position of carbonyl group. Controlled experiment
showed that no D/H exchange took place if -acetoxy ketone 4a
a-
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.07.081.
a
a
was exposed to the reaction conditions (Eq. 4). These results pro-
vided the experimental support for the formation of the intermedi-
ate Int-A and the intermolecular trapping of Int-E by the proton of
solvent.
References and notes
1. (a) For reference about esters as hydroxy functional groups, see: Green, T. W.;
Wuts, P. G. M. Protective Groups in Organic Synthesis; Wiley: New York, 1991;
(b) Noyori, R.; Kitamura, M.. In Modem Synthetic Methods; Scheffold, R., Ed.;
Springer: Heidelberg, 1989; Vol. 5, (c) Kaila, N.; Janz, K.; DeBernardo, S.; Bedard,
P. W.; Camphausen, R. T.; Tam, S.; Tsao, D. H. H. J. Med. Chem. 2007, 50, 21.
2. (a) Rather, J. B.; Reid, E. E. J. Am. Chem. Soc. 1919, 41, 75; (b) Ruggli, P.; Knecht, K.
Helv. Chim. Acta 1944, 27, 1108.
3. Shono, T.; Matsumura, Y.; Nakagawa, Y. J. Am. Chem. Soc. 1975, 97, 6144.
4. Shinada, T.; Kawakami, T.; Sakai, H.; Takada, I.; Ohfune, Y. Tetrahedron Lett.
1998, 39, 3757.
O
PhI(OAc)2
OAc
Ph
Ph
DCE/D2O = 3:1
70°C
yield = 72%
ð3Þ
D
D-4a
D:H = 99:1
D
1a
O
O
5. Cavill, G. W. K.; Solomon, D. H. J. Chem. Soc. 1955, 4426.
6. Demir, A. S.; Camkerten, N.; Akgun, H.; Tanyeli, C.; Mahasneh, A. S.; Watt, D. S.
Synth. Commun. 1990, 20, 2279.
PhI(OAc)2
OAc
D(H)
OAc
Ph
Ph
DCE/D2O = 3:1
70°C
(H)D
ð4Þ
7. Rubottom, G. M.; Gruber, J. M.; Kincaid, K. Synth. Commun. 1976, 6, 59.
8. Ochiai, M.; Takeuchi, Y.; Katayama, T.; Sueda, T.; Miyamoto, K. J. Am. Chem. Soc.
2005, 127, 12244.
9. Sheng, J. M.; Li, X. L.; Tang, M. F.; Gao, B. T.; Huang, G. S. Synthesis 2007, 8, 1165.
10. Some reviews of hypervalent iodine reagents: (a) Dohi, T.; Kita, Y. Chem.
Commun. 2009, 2073; (b) Uyanik, M.; Ishihara, K. Chem. Commun. 2009, 2086;
(c) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299; (d) Ciufolini, M. A.;
Braun, N. A.; Canesi, S.; Ousmer, M.; Chang, J.; Chai, D. Synthesis 2007, 24, 3759;
(e) Wirth, T. Angew. Chem., Int. Ed. 2005, 44, 3656; (f) Zhdankin, V. V.; Stang, P. J.
Chem. Rev. 2002, 102, 2523.
11. Some examples of hypervalent iodine in organic synthesis: (a) Mendelsohn, B.
A.; Lee, S.; Kim, S.; Teyssier, F.; Aulakh, V. S.; Ciufolini, M. A. Org. Lett. 2009, 11,
1539; (b) Fan, R. H.; Li, W. X.; Pu, D. M.; Zhang, L. Org. Lett. 2009, 11, 1425; (c)
Jiang, M.; Shi, M. Tetrahedron 2009, 65, 798; (d) Fan, R. H.; Ye, Y.; Li, W. X.;
Wang, L. F. Adv. Synth. Catal. 2008, 350, 2488; (e) Fan, R. H.; Pu, D. M.; Gan, J. H.;
Wang, B. Tetrahedron Lett. 2008, 49, 492; (f) Yusubov, M. S.; Funk, T. V.; Chi, K.
W.; Cha, E. H.; Kim, G. H.; Kirschning, A.; Zhdankin, V. V. J. Org. Chem. 2008, 73,
295; (g) Richardson, R. D.; Desaize, M.; Wirth, T. Chem. Eur. J. 2007, 13, 6745;
(h) Fan, R. H.; Pu, D. M.; Wen, F. Q.; Wu, J. J. Org. Chem. 2007, 72, 8994; (i) Yu, L.;
Chen, B.; Huang, X. Tetrahedron Lett. 2007, 48, 925; (j) Richardson, R. D.; Wirth,
T. Angew. Chem., Int. Ed. 2006, 45, 4402; (k) Yusubov, M. S.; Wirth, T. Org. Lett.
2005, 7, 519; (l) Moriarty, R. M. J. Org. Chem. 2005, 70, 2893; (m) Ou, W.; Chen,
Z. C. Synth. Commun. 1999, 29, 4443; (n) Wirth, T.; Hirt, U. H. Synthesis 1999, 8,
1271; (o) Kirschning, A. Eur. J. Org. Chem. 1998, 11, 2267; (p) Kirschning, A. J.
Org. Chem. 1995, 60, 1228.
D-4a
4a
D:H = 1:99
When the reaction was carried out in MeOH,
a-methoxy ketone 6
and methoxy enolate 7 were afforded in 13% and 6% yields, respec-
tively, in addition to the formation of -acetoxy ketone 4a in 66%
a
yield (Eq. 5). These results gave the evidence to support the pres-
ence of the intermediate Int-F.
O
OAc
Ph
4a
66%
PhI(OAc)2
+
ð5Þ
Ph
OAc
6%
O
MeOH, 70°C
OMe
1a
OMe
Ph
Ph
+
6
7
13%
When the reaction proceeded in AcOH by using the oxidant
PhI = NTs instead of PhI(OAc)2, product 4a was obtained in 76%
yield. However, when the reaction was performed in MeOH or
CH3CN, no desired products were detected by 1H NMR. Evidently,
PhI = NTs could first be converted PhI(OAc)2 in acetic acid which
12. (a) Merkushev, E. B.; Karpitakaya, L. G.; Novosel’taeva, G. I. Dokl. Akad. Nauk.
SSSR 1979, 245, 607; (b) Vasil’eva, V. P.; Khalfina, I. L.; Karpitskaya, L. G.;
Merkuahev, E. B. Zh. Org. Khim. 1987, 23, 2225.
13.
a-Aetoxy ketone was obtained in 4% yield in the reaction of alkyne with HClO4
as byproduct: Montheard, J. P.; Camps, M.; Chatzopoulos, M.; Yahia, M. O. A.;
Guilluy, R.; Deruaz, D. J. Chem. Res. (Syn) 1983, 9, 224.
then reacted with the substrates to form a
-acetoxy ketones.17

D.-L. Mo et al. / Tetrahedron Letters 50 (2009) 5578–5581
5581
14. (a) Ochiai, M.; Kunishima, M.; Fuji, K.; Nagao, Y. J. Org. Chem. 1989, 54, 4038; (b)
Stang, P. J.; Arif, A. M.; Crittell, C. M. Angew. Chem., Int. Ed. Engl. 1990, 29, 287;
(c) Kitamura, T.; Kotani, M.; Fujiwara, Y. Synthesis 1998, 1416.
washed with NaHCO3 solution (5 mL ꢂ 2), and dried with anhydrous
Na2SO4. Then, the solvent was removed and the residue was purified by
flash chromatography on silica gel using PE/EtOAc (5:1) as eluent to give
product 4a. Oil, 95 mg (89% yield). 1H NMR (400 MHz, CDCl3): d 2.22 (s,
3H), 5.34 (s, 2H), 7.45–7.49 (m, 2H), 7.57–7.61 (m, 1H), 7.89 (d, J = 7.6 Hz,
2H); 13C NMR (100 MHz, CDCl3): 20.42, 65.91, 127.61, 128.73, 133.77,
134.03, 170.30, 192.06; MS (EI) m/z (rel): 178 (1, M+), 161 (3), 136 (1), 105
(100), 91 (3), 77 (37), 51 (12), 43 (19).
15. Zhang, T.-K.; Mo, D.-L.; Dai, L.-X.; Hou, X.-L. Org. Lett. 2008, 10, 3689.
16. Representative procedure for the preparation of
phenylacetylene 1a and PhI(OAc)2: In Schlenk tube, phenylacetylene 1a
(66 L, 0.6 mmol) was added to a stirring mixture of PhI(OAc)2 (322 mg,
a-acetoxy ketones by
a
l
1.0 mmol), and acetic acid (1.5 mL) under atmosphere of air. The mixture
was stirred at 70 °C for 12 h for the completion of the reaction (monitored
by TLC). The solution was diluted with dichloromethane (5 mL) and water
(5 mL) was added. The aqueous solution was extracted with
dichloromethane (5 mL ꢂ 3) and the combined organic layers were
17. When PhI = NTs was stirred at 70 °C in acetic acid for 5 h, PhI(OAc)2 and TsNH2
were obtained in 88% yield.
18. If the reaction was performed at 70 °C, no desired product was detected in the
crude reaction mixture by 1H NMR.