AgF/TFA-promoted highly efficient synthesis of α-haloketones from haloalkynes

Article abstract of DOI:10.1016/j.tetlet.2014.01.027

A AgF/TFA-promoted highly efficient synthesis of a wide range of α-haloketones from haloalkynes is described. The reactions are conducted under convenient conditions and provide products in moderate to excellent yields, with broad substrate scope, including a variety of aromatic chloroalkynes and bromoalkynes.

Full text of DOI:10.1016/j.tetlet.2014.01.027

Tetrahedron Letters 55 (2014) 1373–1375
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
AgF/TFA-promoted highly efficient synthesis of a-haloketones
from haloalkynes
⇑
⇑
Zheng-Wang Chen , Dong-Nai Ye, Min Ye, Zhong-Gao Zhou, Shen-Huan Li, Liang-Xian Liu
Department of Chemistry & Chemical Engineering, Gannan Normal University, Ganzhou, Jiangxi 341000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A AgF/TFA-promoted highly efficient synthesis of a wide range of
a
-haloketones from haloalkynes is
Received 7 October 2013
Revised 29 December 2013
Accepted 8 January 2014
Available online 13 January 2014
described. The reactions are conducted under convenient conditions and provide products in moderate
to excellent yields, with broad substrate scope, including a variety of aromatic chloroalkynes and
bromoalkynes.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
a-Haloketone
Haloalkyne
Synthesis
Transition metal
a
-Haloketones are versatile building blocks for the synthesis of
Inspired by previous experiment observation,21 we first stud-
ied the reaction of phenylethynyl bromide (1a) with water in
acetic acid using AgBF4 as the catalyst, and the desired 2-bro-
mo-1-phenylethanone (2a) was obtained in 42% GC yield
(Table 1, entry 1). We next examined different commonly used
metal salts, they were ineffective compared with AgBF4 (Table 1,
entries 2–6). The solvent played an important role and trifluoro-
acetic acid is the solvent of choice for the reaction (Table 1,
entries 7–12). However, the control experiment results showed
that the bromoalkyne (1a) can be effectively converted to the
2-bromo-1-phenylethanone (2a) without addition of any transi-
tion metal (Table 1, entry 13), which implies that silver salt
promotes the reaction. Different silver species were also tested.
To our delight, AgF was superior to any other silver salts so
far tested and could afford the desired product with 92% GC
yield, and the side product was mainly benzoic acid (Table 1,
entries 14–18). The temperature was then examined, and 40 °C
was optimal for this reaction (Table 1, entry 19). After some
attempts, we considered that the optimized reaction conditions
are as follows: 1a (0.5 mmol), water (1 equiv) with TFA (1 mL)
and AgF (5 mol %) at 40 °C for 6 h (Table 1, entry 19).
With the success in finding the optimum reaction conditions
(Table 1, entry 19), the scope and the utility of this method with
other 1-haloalkynes under the standard conditions were then
investigated in detail. As summarized in Table 2, both electron-
rich and electron-deficient 1-haloalkynes afforded the corre-
sponding products in good to excellent yields (2b–x). Clearly,
the electronic effect played an important role, with electron-rich
substituents on the benzene ring affording the products in high-
er yields than the corresponding strong electron-withdrawing
biologically active heterocycle compounds1 and natural products.2
Over the past decades, direct conversion of carbonyl compounds
into
-Chlorination of ketones can be achieved using various reagents
such as molecular chlorine,3 sulfuryl chloride,4 P-toluenesulfonyl
chloride,5 N-chlorosuccinimide,6 copper chloride,7 and others.8
Bromination of ketones can be accomplished by using bromination
agents including molecular bromine,9 copper bromide,10 N-bromo-
succinimide,11 bromide/bromated couple,12 3-methylimidazolium
tribromide13 HBr14 and others.15 However, most of these methods
suffer from one or more disadvantages such as environmentally
hazardous halogen molecules, long reaction times, harsh reaction
conditions, cumbersome work-up procedures, and the formation
a-haloketones is a widely applied synthetic transformation.
a
a
-
of
a,a-dihalogenated products. Therefore, development of new
methodologies by using readily available materials and cheap re-
agents with high efficiency is still a field receiving undoubted cur-
rent attention.
Haloalkynes are one kind of the most important intermediates
and versatile building blocks.16 Several mild and convenient meth-
ods have been developed and thus have increased the attractive-
ness of this class of compounds in organic synthesis.17,18
Recently, we and others have reported the nucleophilic addition
reaction of haloalkynes.19 As part of our continuing project in the
functionalization of haloalkynes, here we wish to report a novel
AgF/TFA promoted highly efficient synthesis of
a-chloroketones
or
a
-bromoketones from haloalkynes.20
⇑
Corresponding authors. Tel.: +86 797 8393536; fax: +86 797 8393670.
E-mail address: chenzwang@126.com (Z.-W. Chen).
0040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2014.01.027

1374
Z.-W. Chen et al. / Tetrahedron Letters 55 (2014) 1373–1375
Table 1
Table 2
Preparation of various
Optimization of reaction conditions for the synthesis of
a
-haloketonesa
a
-haloketones from haloalkynesa,b
O
O
AgF (5 mol %)
X
metal salt
Br
R
Br
X
R
TFA, H2O (1 equiv.)
solvent, H2O
1
2
1a
2a
O
O
O
Entry
Metal salt
Solv.
Temp
Yieldb (%)
Br
Br
Br
Br
1
2
3
4
5
6
7
8
AgBF4
FeCl3
CuI
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
Ac2O
MeOH
Dioxane
Acetone
Toluene
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
70
70
70
70
70
70
70
60
80
50
80
70
70
70
70
70
70
70
40
rt
42
30
n.p.
5
15
19
15
13
n.p.
30
2a, 91%
2b, 95%
2c, 94%
(86%)[c]
HAuCl4
RuCl3
RhCl3
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
—
Ag2CO3
AgNO3
AgOAc
AgOTf
AgF
O
O
O
Br
Br
Br
9
2d, 95%
2e, 85%
10
11
12
13
14
15
16
17
18
19
20
2f, 65%
11
90
81
O
O
O
Br
Br
86
57
70
72
O
2i, 76%
2g, 86%
2h, 83%
92
94 (91)
80
O
O
O
AgF
AgF
Br
Br
Br
Br
Br
Br
Br
Br
Br
a
Reactions were carried out using 1a (0.5 mmol), water (1.0 equiv), solvent,
F
F
Cl
Br
(1.0 mL) and metal salt (5 mol %) for 6 h.
2j, 87%
O
2k, 81%
O
2l, 88%
O
b
Determined by GC. The number in parentheses is isolated yield.
Br
groups (2b–x). Substitution at the 2-position of the aromatic
ring slightly lowered the yields (2j, 2k, 2s and 2t). The reaction
conditions were compatible with alkyl, alkyloxy, aryl, fluoro,
chloro, bromo, nitro, cyano, and trifluoromethyl groups (2b–x).
It should be pointed out that the carbon–halogen bonds were
well tolerated and the products containing halogen were affor-
ded smoothly. Especially the aryl bromides and chlorides could
be further functionalized (2l–o and 2x). The substrates with
strong electron-withdrawing groups required prolonged reaction
time to afford good yields (2p–r and 2u). In addition to bro-
moalkynes, chloroalkynes were also shown to be highly effec-
tive substrates for the transformation; the corresponding
Br
Cl
2n, 73%
2o, 65%
2m, 84%
O
O
O
Br
NO2
NO2
2p, 77% 16 h
CN
2q, 75% 16 h
2r, 66% 16h
O
O
O
Br
Cl
CF3
CF3
F3C
CF3
2s, 82%
2t, 61%
products
(2v–x).
a-chloroketones can be obtained in high yields as well
2u, 78% 16 h
O
O
O
Cl
Cl
Possible mechanisms were proposed and outlined in Scheme 1
on the basis of the previous reports and our observation.21,22
First, the alkenyl cation intermediate A was generated by the
electrophilic addition of proton, followed by nucleophilic attack
of trifluoroacetic anion to produce enol trifluoroacetate B, which
subsequently underwent successive hydrolysis and keto–enol
Cl
2v, 81%
2w, 90%
2x, 88%
c10 mmol scale of the reaction.
Reaction conditions:
(5 mol %) for 6 h.
a
1 (0.5 mmol), TFA (1.0 mL), water (1 equiv) and AgF
tautomerism to generate
a-haloketones 2. When the silver salt
b
Isolated yield.
was added in the system, it can activate the triple bond of the
haloalkyne 1, and help to form the intermediate A in the first
step.
CF3COO-
OCOCF3
H2O/H+
O
H+
R
In conclusion, we have presented a general and facile method
R
X
R
X
for the synthesis of
be easily prepared from terminal alkynes or aldehydes.23 The
AgF/TFA-promoted reaction tolerated variety of functional
a
-haloketones from 1-haloalkynes, which can
X
R
X
B
A
2
1
a
Scheme 1. Possible reaction mechanism.
groups. The proposed mechanism indicates that enol trifluoroace-
tate may be the intermediate in this transformation. It may be
noted that this method is eco-friendly and economical, because
the solvent TFA is easy to be recycled by distilling operation with
medium boiling point (72.4 °C). Further utilization of this proce-
dure and understanding the mechanism will continue in our
laboratory.
Acknowledgements
The authors thank the NSFC (21202023 and 21162001), NSF of
Jiangxi Province (20114BAB213006) for financial support.

Z.-W. Chen et al. / Tetrahedron Letters 55 (2014) 1373–1375
1375
15. For some selective examples, see: (a) Kavala, V.; Naik, S.; Patel, B. K. J. Org.
Chem. 2005, 70, 4267–4271; (b) Macharla, A. K.; Nappunni, R. C.; Marri, M. R.;
Peraka, S.; Nama, N. Tetrahedron Lett. 2012, 53, 191–195; (c) Lee, J. C.; Park, J. Y.;
Yoon, S. Y.; Bae, Y. H.; Lee, S. J. Tetrahedron Lett. 2004, 45, 191–193; (d) Bekaert,
A.; Provot, O.; Rasolojaona, O.; Alami, M.; Brion, J. D. Tetrahedron Lett. 2005, 46,
4187–4191; (e) Prakash, G. K. S.; Ismail, R.; Garcia, J.; Panja, C.; Rasul, G.;
Mathew, T.; Olah, G. A. Tetrahedron Lett. 2011, 52, 1217–1221; (f) Khan, A. T.;
Ali, M. A.; Goswami, P.; Choudhury, L. H. J. Org. Chem. 2006, 71, 8961–8963; (g)
Kim, E.-H.; Koo, B.-S.; Song, C.-E.; Lee, K.-J. Synth. Commun. 2001, 31, 3627–
3632.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
01.027.
References and notes
16. For selective examples for the application of haloalkynes, please see: (a)
Seregin, I. V.; Ryabova, V.; Gevorgyan, V. J. Am. Chem. Soc. 2007, 129, 7742–
7743; (b) Trofimov, A.; Chernyak, N.; Gevorgyan, V. J. Am. Chem. Soc. 2008, 130,
13538–13539; (c) Besselièvre, F.; Piguel, S. Angew. Chem., Int. Ed. 2009, 48,
9553–9556; (d) Dudnik, A. S.; Gevorgyan, V. Angew. Chem., Int. Ed. 2010, 49,
2096–2098; (e) Usanov, D. L.; Yamamoto, H. J. Am. Chem. Soc. 2011, 133, 1286–
1289; (f) Ano, Y.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2011, 133, 12984–
12986; (g) Li, Y.; Liu, X.; Jiang, H.; Feng, Z. Angew. Chem., Int. Ed. 2010, 49, 3338–
3341; (h) Li, Y.; Liu, X.; Jiang, H.; Liu, B.; Chen, Z.; Zhou, P. Angew. Chem., Int. Ed.
2011, 50, 6341–6345; (i) Frederick, M. O.; Mulder, J. A.; Tracey, M. R.; Hsung, R.
P.; Huang, J.; Kurtz, K. C. M.; Shen, L.; Douglas, C. J. J. Am. Chem. Soc. 2003, 125,
2368–2369; (j) Peng, J.; Shang, G.; Chen, C.; Miao, Z.; Li, B. J. Org. Chem. 2013,
78, 1242–1248.
17. For representative preparation of haloalkynes from terminal alkynes, please
see: (a) Verboom, W.; Westmijze, H.; De Noten, L. J.; Vermeer, P.; Bos, H. J. T.
Synthesis 1979, 296–297; (b) Hofmeister, H.; Annen, K.; Laurent, H.; Wiechert,
R. Angew. Chem., Int. Ed. Engl. 1984, 23, 727–729; (c) Sasson, Y.; Webster, O. W.
J. Chem. Soc., Chem. Commun. 1992, 1200–1201; (d) Abele, E.; Rubina, K.; Abele,
R.; Gaukhman, A.; Lukevics, E. J. Chem. Res. (S) 1998, 618–619; (e) Abele, E.;
Fleisher, M.; Rubina, K.; Abele, R.; Lukevics, E. J. Mol. Catal. A: Chem. 2001, 165,
121–126.
18. For representative preparation of haloalkynes from aldehydes, please see: (a)
Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769–3772; (b) Ramirez, F.;
Desai, N. B.; McKelvie, N. J. Am. Chem. Soc. 1962, 84, 1745–1747; (c) Shen, W.;
Wang, L. J. Org. Chem. 1999, 64, 8873–8879; (d) Okutani, M.; Mori, Y. J. Org.
Chem. 2009, 74, 442–444.
19. For some selective examples, see: (a) Chen, Z.; Jiang, H.; Li, Y.; Qi, C. Chem.
Commun. 2010, 8049–8051; (b) Chary, B. C.; Kim, S.; Shin, D.; Lee, P. H. Chem.
Commun. 2011, 7851–7853; (c) Wang, S.; Li, P.; Yu, L.; Wang, L. Org. Lett. 2011,
13, 5968–5971; (d) Yamagishi, M.; Okazaki, J.; Nishigai, K.; Hata, T.; Urabe, H.
Org. Lett. 2012, 14, 34–37. and reference cited therein.
1. For a review, see: Erian, A. W.; Sherif, S. M.; Gaber, H. M. Molecules 2003, 8,
793–865.
2. De Kimpe, N.; Verhé, R. In The Chemistry of
a-Haloketones, a-Haloaldehydes and
a
-Haloimines; Patai, S., Ed.; Wiley: Chichester, UK, 1988; pp 1–119.
3. Aston, J. G.; Newkirk, J. D.; Jenkins, D. M.; Dorsky, J. Org. Synth. Coll. III 1955,
538.
4. Wyman, D. P.; Kaufman, P. R. J. Org. Chem. 1964, 29, 1956–1960.
5. Brummond, K. M.; Gesenberg, K. D. Tetrahedron Lett. 1999, 40, 2231–2234.
6. For selective examples, see: (a) Lee, J. C.; Bae, Y. H.; Chang, S.-K. Bull. Korean
Chem. Soc. 2003, 24, 407–408; (b) Salama, T. A.; Novák, Z. Tetrahedron Lett.
2011, 52, 4026–4029; (c) Pravst, I.; Zupan, M.; Stavber, S. Tetrahedron 2008, 64,
5191–5199.
7. Kosower, E. M.; Cole, W. J.; Wu, G.-S.; Cardy, D. E.; Meisters, G. J. Org. Chem.
1963, 28, 630–633.
8. For selective examples, see: (a) Podgorsek, A.; Jurisch, M.; Stavber, S.; Zupan,
M.; Iskra, J.; Gladysz, J. A. J. Org. Chem. 2009, 74, 3133–3140; (b) Xu, Z.; Zhang,
D.; Zou, X. Synth. Commun. 2006, 36, 255–258; (c) Lee, J. C.; Park, H. J. Synth.
Commun. 2006, 36, 777–780; (d) Lee, J. G.; Park, I. S.; Seo, J. W. Bull. Korean
Chem. Soc. 1995, 16, 349–355; (e) Guy, A.; Lemaire, M.; Guette, J.-P. Synthesis
1982, 1018–1020.
9. For selective examples, see: (a) Curran, D. P.; Chang, C. T. J. Org. Chem. 1989, 54,
3140–3157; (b) Karimi, S.; Grohmann, K. G. J. Org. Chem. 1995, 60, 554–559; (c)
Attanasi, O. A.; Berretta, S.; Favi, G.; Filippone, G. P.; Mele, G.; Moscatelli, G.;
Saladino, R. Org. Lett. 2006, 8, 4291–4293; (d) Choi, H. Y.; Chi, D. Y. Org. Lett.
2003, 5, 411–414; (e) Julian, P. L.; Karpel, W. J. J. Am. Chem. Soc. 1950, 72, 362–
366.
10. (a) King, L. C.; Osturm, G. K. J. Org. Chem. 1964, 29, 3459–3461; (b) Shi, X.; Dai,
L. J. Org. Chem. 1993, 58, 4596–4598.
11. For some selective examples, see: (a) Tanemura, K.; Suzuki, T.; Nishida, Y.;
Satsumabayashi, K.; Horaguchi, T. Chem. Commun. 2004, 470–471; (b) Arbuj, S.
S.; Waghmode, S. B.; Ramaswamy, A. V. Tetrahedron Lett. 2007, 48, 1411–1415;
(c) Das, B.; Venkateswarlu, K.; Mahender, G.; Mahender, I. Tetrahedron Lett.
2005, 46, 3041–3044; (d) Meshram, H. M.; Reddy, P. N.; Sadashiv, K.; Yadav, J.
S. Tetrahedron Lett. 2005, 46, 623–626; (e) Yang, D.; Yan, Y. L.; Lui, B. J. Org.
Chem. 2002, 67, 7429–7431; (f) Meshram, H. M.; Reddy, P. N.; Vishnu, P.;
Sadashiv, K.; Yadav, J. S. Tetrahedron Lett. 2006, 47, 991–995.
12. Adimurthy, S.; Ghosh, S.; Patoliya, P. U.; Ramachandraiah, G.; Agrawal, M.;
Gandhi, M. R.; Upadhyay, S. C.; Ghosh, P. K.; Ranu, B. C. Green Chem. 2008, 10,
232–237.
20. (a) Xie, L.; Wu, Y.; Yi, W.; Zhu, L.; Xiang, J.; He, W. J. Org. Chem. 2013, 78, 9190–
9195; (b) Park, J.; Yeon, J.; Lee, P. H.; Lee, K. Tetrahedron Lett. 2013, 54, 4414–
4417.
21. Chen, Z.; Li, J.; Jiang, H.; Zhu, S.; Li, Y.; Qi, C. Org. Lett. 2010, 12, 3262–3265.
22. (a) Casado, R.; Contel, M.; Laguna, M.; Romero, P.; Sanz, S. J. Am. Chem. Soc.
2003, 125, 11925–11935; (b) Kanemitsu, H.; Uehara, K.; Fukuzumi, S.; Ogo, S. J.
Am. Chem. Soc. 2008, 130, 17141–17147; (c) Ogo, S.; Uehara, K.; Abura, T.;
Watanabe, Y.; Fukuzumi, S. J. Am. Chem. Soc. 2004, 126, 16520–16527.
23. Typical experimental procedure:
A mixture of haloalkyne (0.5 mmol), AgF
13. Chiappe, C.; Leandri, E.; Pieraccini, D. Chem. Commun. 2004, 2536–2537.
14. (a) Podgoršek, A.; Stavber, S.; Zupan, M.; Iskra, J. Green Chem. 2007, 9, 1212–
1218; (b) Zhang, G.; Liu, R.; Xu, Q.; Ma, L.; Liang, X. Adv. Synth. Catal. 2006, 348,
862–866.
(5 mol %) and water (1 equiv) in TFA (1 mL) was stirred at 40 °C for 6 h, after
which TFA was distilled out for reuse. The residue was separated by column
chromatography to give the pure sample.