Regio- and stereoselective synthesis of highly functionalized vinyl ethers via coiodination of acetylenic ketones

Article abstract of DOI:10.1016/j.tetlet.2013.12.084

A Cu(OTf)₂-catalyzed highly regio- and stereoselective coiodination of acetylenic ketones was reported, providing a mild and convenient method for the synthesis of (Z)-β-carbonyl-β-iodoenol ethers in good yields.

Full text of DOI:10.1016/j.tetlet.2013.12.084

Tetrahedron Letters 55 (2014) 1065–1067
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regio- and stereoselective synthesis of highly functionalized vinyl
ethers via coiodination of acetylenic ketones
⇑
Meihua Xie , Jitan Zhang, Peng Ning, Zhannan Zhang, Xing Liu, Linbo Wang
Key Laboratory of Functional Molecular Solids (Ministry of Education), Anhui Key Laboratory of Molecular Based Materials, College of Chemistry and Materials Science, Anhui
Normal University, Wuhu 241000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A Cu(OTf)2-catalyzed highly regio- and stereoselective coiodination of acetylenic ketones was reported,
Received 1 October 2013
Revised 11 December 2013
Accepted 24 December 2013
Available online 3 January 2014
providing a mild and convenient method for the synthesis of (Z)-b-carbonyl-b-iodoenol ethers in good
yields.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Acetylenic ketone
Alcohol
Coiodination reaction
Vinyl ether
Table 1
Polysubstituted alkenes are ubiquitous in many natural
products and materials and serve as potential intermediates in
organic synthesis. Therefore, regio- and stereoselective construc-
tion of polysubstituted alkenes is in high demand in organic chem-
istry.1 Polysubstituted vinyl ethers, members of polysubstituted
alkenes, are important structural units in drugs such as Nileprost2
and have been used in various reactions such as cycloaddition,
cyclopropanation, isoxazoline synthesis, and cross aldol reactions.3
However, synthesis of vinyl ether is challenging because direct
O-alkylation of enolates is not generally viable and vinylation of
alcohols is limited to special cases.4 Therefore, vinyl ether is gener-
ally synthesized by indirect methods, including acid- or metal-
catalyzed vinyl ether exchange,5 base-catalyzed isomerization of
allyl ethers,6 modification of existing vinyl ethers,7 and coupling
of alcohols with vinyl halides8 or vinyl boronates.9 However, these
processes have some limitations such as the need for strong bases,
strong acids, noble metals, and limited substrate substitution.
Stereoselective synthesis of vinyl ethers directly from the intermo-
lecular reaction of an alcohol and an alkyne under mild conditions
remains a difficult task.10
Optimization of the reaction conditions
CH3
I2-PhI(OAc)2
(1.0 equiv)
O
O
CH3OH
+
(20 mol%)
solvent (2 mL)
catalyst
I
CH3O
3a
CH3
1a
2a
Entry
Solvent
Catalyst
T (°C)
Time (h)
Yielda (%)
1b
2b
3
4
5
6
7
8
9
10
11
12
13
14
15c
16d
CH3CN
CH3CN
CH3CN
CH3CN
THF
Toluene
CH2Cl2
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
—
25
25
25
25
25
25
25
25
40
Reflux
40
40
40
40
40
40
24
24
24
24
24
24
24
24
3
NR
NR
43
NR
Trace
47
32
67
74
71
0
Cu(OTf)2
Cu(OTf)2
—
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CuI
CuCN
CuBr
CuCl2
Cu(OTf)2
Cu(OTf)2
3
24
24
24
24
3
On the other hand, vinyl halides are important compounds in
the synthesis of various natural products, pharmaceuticals, and
polymers due to their extensive applications in numerous transfor-
mations such as halogen-metal exchange reactions and transition-
metal-catalyzed cross-coupling reactions.11 Cohalogenation, the
0
10
50
75
61
3
a
b
c
Isolated yield based on 1a.
No PhI(OAc)2 was added.
30 mol % Cu(OTf)2 was used.
10 mol % Cu(OTf)2 was used.
⇑
Corresponding author. Tel.: +86 0553 3869310; fax: +86 0553 3883517.
E-mail address: xiemh@mail.ahnu.edu.cn (M. Xie).
d
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.084

1066
M. Xie et al. / Tetrahedron Letters 55 (2014) 1065–1067
Table 2
Cu(OTf)2
R3OH
PhI
Coiodination of acetylenic ketonesa
O
+ I2
AcOI
PhI(OAc)2
I2-PhI(OAc)2
Cu(OTf)2 (20 mol%)
R1
R2
O
-TfOH
R1
C
R3OH
+
O
C
R2
(R3O)CuIIII(OTf)
A
R3O
I
40 o
C
R1
1
2
3
R2
Entry
1 (R1, R2)
2 (R3)
Yieldb (%)
AcOI
R3OH
1
2
3
4
5
6
7
8
C6H5, p-CH3C6H4
C6H5, C6H5
C6H5, C6H5
C6H5, p-CH3OC6H4
C6H5, p-CH3OC6H4
p-CH3C6H4, p-CH3OC6H4
C6H5, p-CH3OC6H4
C6H5, 3,4-(CH3O)2C6H3
p-CH3C6H4, p-CH3OC6H4
C6H5, p-ClC6H4
C6H5, p-ClC6H4
C6H5, p-ClC6H4
C6H5, p-NO2C6H4
C6H5, p-NO2C6H4
C6H5, p-NO2C6H4
C6H5, o-BrC6H4
CH3
CH3
(CH3)2CH
CH3
CH3CH2
CH3CH2
(CH3)2CH
(CH3)2CH
(CH3)2CH
CH3
CH3CH2
(CH3)2CH
CH3
74 (3a)
72 (3b)
61 (3c)
88 (3d)
78 (3e)
80 (3f)
67 (3g)
62 (3h)
74 (3i)
71 (3j)
62 (3k)
58 (3l)
32 (3m)
29 (3n)
20 (3o)
65 (3p)
42 (3q)
R1
OR3
TfO CuIII
I
CuI(OTf)
R2
B
O
O
R2
R1
O
R1
R2
9
R3O
I
10
11
12
13
14
15
16
17
3
R3O
CuIII OTf
I
C
CH3CH2
(CH3)2CH
CH3
Scheme 1. A tentative mechanism for the coiodination of acetylenic ketones.
C6H5, 2-furyl
(CH3)2CH
ketone 1a was subjected to 20 equiv of methanol and 1.0 equiv
of I2 in 2 mL of acetonitrile at 25 °C for 24 h, even in the pres-
ence of 20 mol % Cu(OTf)2 (Table 1, entries 1 and 2). Given that
iodination of unsaturated carbon–carbon bond is a considerably
slow reaction because of the low electrophilicity of iodine, and
PhI(OAc)2 is a widely used oxidizing reagent to activate iodide,16
we added PhI(OAc)2 to the reaction system. Gratifyingly, the
target product 3a was isolated in 43% yield when I2-PhI(OAc)2
was used as iodinating reagent (Table 1, entry 3), while no prod-
uct formation was detected in the absence of Cu(OTf)2 (Table 1,
entry 4). Only trace of 3a was detected using THF as the solvent
(Table 1, entry 5). Modest yields were obtained when the
reaction was performed in toluene or CH2Cl2 (Table 1, entries
6 and 7). The yield of 3a was improved to 67% when 2 mL of
CH3OH was used as both reactant and solvent (Table 1, entry
8). The yield of 3a was further improved to 74% after raising
the reaction temperature to 40 °C (Table 1, entry 9). Increasing
the reaction temperature to reflux resulted in a slightly lower
yield of 3a (Table 1, entry 10). The use of some other copper
catalysts gave inferior results (Table 1, entries 11–14). An
increase in the amount of Cu(OTf)2 has no apparent effect on
the yield while a reduced amount was detrimental to the yield
of 3a (Table 1, entries 15 and 16). Based on these experimental
results, we defined 20 mol % Cu(OTf)2, 1.0 equiv I2-PhI(OAc)2, and
2 mL of CH3OH at 40 °C as the optimum reaction conditions for
the transformation.
a
Reaction conditions: acetylenic ketone (0.25 mmol), I2 (0.25 mmol), PhI(OAc)2
(0.25 mmol), Cu(OTf)2 (0.05 mmol), and alcohol (2 mL) at 40 °C for 3 h under air
atmosphere.
b
Isolated yield based on 1.
simultaneous introduction of a halogen atom and a suitable nucle-
ophile across carbon–carbon multiple bonds, is a useful reaction
that rapidly generates halohydrocarbons.12 Jiang and co-workers
reported the synthesis of trisubstituted b-haloenol acetates by
cohalogenation of terminal alkynes.13 Yanada and co-workers re-
ported the synthesis of tetrasubstituted enol esters by coiodination
of internal alkynes with carboxylic acid, while the use of alcohol in-
stead of carboxylic acid failed to produce the desired vinyl ether.14
To the best of our knowledge, direct synthesis of vinyl ether con-
taining halogen by intermolecular cohalogenation of alkynes has
not been reported. Recently, we have been interested in the regio-
and stereoselective synthesis of multisubstituted alkenes from
alkynes.15 In continuation of our research interest in this field,
we wish to report herein the regio- and stereoselective synthesis
of highly functionalized vinyl ethers through coiodination of acety-
lenic ketones.
Firstly, the reaction of 3-phenyl-1-p-tolylprop-2-yn-1-one (1a)
and methanol was investigated. The results are summarized in
Table 1. It was found that no reaction happened when acetylenic
Figure 1. The molecular structures of compounds 3a and 3e.

M. Xie et al. / Tetrahedron Letters 55 (2014) 1065–1067
1067
Using the optimized reaction conditions in Table 1, entry 9,
Supplementary data
the scope of this reaction was then studied. As shown in Table 2,
the coiodination reactions of differently substituted acetylenic
ketones proceeded smoothly and the desired products were gen-
erally obtained in good yields. Alcohols could be methanol, etha-
nol, or isopropanol. R1 in acetylenic ketones could be a phenyl or
tolyl group. R2 in acetylenic ketones could be phenyl (Table 2, en-
tries 2 and 3), electron-rich phenyl (Table 2, entries 1, 4–9), elec-
tron-poor phenyl (Table 2, entries 10–16), or 2-furyl groups
(Table 2, entry 17). It is noted that the reactions were compli-
cated and the desired products 3 were obtained in low yields
when R2 is p-NO2-substituted phenyl group (Table 2, entries
13–15). Unfortunately, no desired product was isolated when
R1 or R2 was an alkyl group.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
12.084.
References and notes
1. For reviews, see: (a) Oger, C.; Balas, L.; Durand, T.; Galano, J. M. Chem. Rev. 2013,
113, 1313; (b) McDonald, R. I.; Liu, G. S.; Stahl, S. S. Chem. Rev. 2011, 111, 2981;
(c) Flynn, A. B.; Ogilvie, W. W. Chem. Rev. 2007, 107, 4698.
2. (a) Herrmann, M.; Böhlendorf, B.; Irschik, H.; Reichenbach, H.; Höfle, G. Angew.
Chem., Int. Ed. 1998, 37, 1253; (b) Takahashi, A.; Kirio, Y.; Sodeoka, M.; Sasai, H.;
Shibasaki, M. J. Am. Chem. Soc. 1989, 111, 643. and references cited therein.
3. (a) Krompiec, S.; Bujak, P.; Szczepankiewicz, W. Tetrahedron Lett. 2008, 49,
6071; (b) Harmata, M.; Lee, D. R.; Barnes, C. L. Org. Lett. 2005, 7, 1881; (c)
Kawano, Y.; Fujisawa, H.; Mukaiyama, T. Chem. Lett. 2005, 34, 614; (d) Davies,
H. M. L.; Hu, B. H. J. Org. Chem. 1992, 57, 3186.
4. (a) Seo, S. Y.; Yu, X. H.; Marks, T. J. J. Am. Chem. Soc. 2009, 131, 263; (b) Arimitsu,
S.; Jacobsen, J. M.; Hammond, G. B. J. Org. Chem. 2008, 73, 2886; (c) Ramana, C.
V.; Mallik, R.; Gonnade, R. G.; Gurjar, M. K. Tetrahedron Lett. 2006, 47, 3649.
5. (a) Nakamura, A.; Tokunaga, M. Tetrahedron Lett. 2008, 49, 3729; (b) Bosch, M.;
Schlaf, M. J. Org. Chem. 2003, 68, 5225; (c) Okimoto, Y.; Sakaguchi, S.; Ishii, Y. J.
Am. Chem. Soc. 2002, 124, 1590.
The regio- and stereochemistry of the functionalized vinyl
ethers was determined based on the X-ray diffraction analysis of
compounds 3a and 3e (Fig. 1). The molecular structures show that
the double bonds in 3a and 3e are in Z-configuration, and the alk-
oxyl group is attached to the b-carbon of the carbonyl group and
the iodine atom is attached to the
a-carbon, which suggests that
the coiodination of acetylenic ketones worked in a syn-fashion.
Based on previous researches16a and the above experimental re-
sults, a tentative mechanism for the copper-catalyzed coiodination
of acetylenic ketones is shown in Scheme 1. First, I2 could be read-
6. (a) Su, C. C.; Williard, P. G. Org. Lett. 2010, 12, 5378; (b) Duval, E.; Zoltobroda,
G.; Langlois, Y. Tetrahedron Lett. 2000, 41, 337.
7. (a) Schranck, J.; Wu, X. F.; Neumann, H.; Beller, M. Chem. Eur. J. 2012, 18, 4827;
(b) Guarda, E. A.; Marzari, M. R. B.; Frizzo, C. P.; Guarda, P. M.; Zanatta, N.;
Bonacorso, H. G.; Martins, M. A. P. Tetrahedron Lett. 2012, 53, 170; (c)
Winternheimer, D. J.; Shade, R. E.; Merlic, C. A. Synthesis 2010, 2497.
8. Nordmann, G.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 4978.
9. Shade, R. E.; Hyde, A. M.; Olsen, J. C.; Merlic, C. A. J. Am. Chem. Soc. 2010, 132,
1202.
10. (a) Dang, Y. F.; Qu, S. L.; Wang, Z. X.; Wang, X. T. Organometallics 2013, 32,
2804; (b) Kondo, M.; Kochi, T.; Kakiuchi, F. J. Am. Chem. Soc. 2011, 133, 32; (c)
Breuer, K.; Teles, J. H.; Demuth, D.; Hibst, H.; Schäfer, A.; Brode, S.; Domgörgen,
H. Angew. Chem., Int. Ed. 1999, 38, 1401.
11. (a) Wen, Y. M.; Jiang, H. F. Tetrahedron Lett. 2013, 54, 4034; (b) Chelucci, G.
Chem. Rev. 2012, 112, 1344; (c) Lin, Y. Y.; Wang, Y. J.; Lin, C. H.; Cheng, J. H.; Lee,
C. F. J. Org. Chem. 2012, 77, 6100; (d) Greenaway, R. L.; Campbell, C. D.;
Chapman, H. A.; Anderson, E. A. Adv. Synth. Catal. 2012, 354, 3187; (e)
Boukouvalas, J.; Loach, R. P. J. Org. Chem. 2008, 73, 8109.
12. (a) Gottam, H.; Vinod, T. K. J. Org. Chem. 2011, 76, 974; (b) Stavber, S.; Jareb, M.;
Zupan, M. Synthesis 2008, 1487.
13. Chen, Z. W.; Li, J. H.; Jiang, H. F.; Zhu, S. F.; Li, Y. B.; Qi, C. R. Org. Lett. 2010, 12,
3262.
14. Okamoto, N.; Miwa, Y.; Minami, H.; Takeda, K.; Yanada, R. J. Org. Chem. 2011,
76, 9133.
15. (a) Xie, M. H.; Feng, C. Y.; Zhang, J. T.; Liu, C. Q.; Fang, K.; Shu, G. Y.; Zuo, W. S. J.
Organomet. Chem. 2011, 696, 3397; (b) Xie, M. H.; Lin, G. F.; Zhang, J. H.; Li, M.;
Feng, C. Y. J. Organomet. Chem. 2010, 695, 882; (c) Xie, M. H.; Wang, J. L.; Gu, X.
X.; Sun, Y.; Wang, S. W. Org. Lett. 2006, 8, 431.
12a
ily converted into acetyl hypoiodite via oxidation by PhI(OAc)2.
In the presence of an alcohol, acetyl hypoiodite would oxidize
Cu(OTf)2 to an Cu(III) intermediate A.17 This highly electrophilic
Cu(III) species then coordinated to the acetylenic ketone and the
Cu–OR would insert into the C–C triple bond to give the interme-
diate C, which would undergo reductive elimination to deliver
the products 3 and release the copper catalyst.
In summary, we have demonstrated a mild and convenient
method for the regio- and stereoselective synthesis of functional-
ized vinyl ethers. Given the versatility of functional groups like
C–C double bond, iodo, and carbonyl contained in the product,
we believe that the current method would be of high potential
utility in organic synthesis.
Acknowledgments
The authors are grateful to the National Natural Science
Foundation of China (Nos. 21272004 and 20772001) for financial
support of this work. We are also grateful to Prof. Jiping Hu,
Prof. Gaosheng Yang, Dr. Zhuo Chai and Mr. Xiaolong Mo for their
helpful assistance.
16. (a) Fan, R. H.; Li, W. X.; Pu, D. M.; Zhang, L. Org. Lett. 2009, 11, 1425; (b)
Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299.
17. (a) Seayad, J.; Seayad, A. M.; Chai, C. L. L. Org. Lett. 2010, 12, 1412; (b) Li, W. X.;
Gan, J. H.; Fan, R. H. Tetrahedron Lett. 2010, 51, 4275.