Selective 1,2-dihalogenation and oxy-1,1-dihalogenation of alkynes by N-halosuccinimides

Article abstract of DOI:10.1016/j.tetlet.2011.06.047

1,2-Dihalogenation and oxy-1,1-dihalogenation of alkynes by N-halosuccinimides can be selectively realized through using different reaction conditions. α,β-Dihalo alkenes were obtained exclusively using THF as solvent without using any catalyst, while α,α

Full text of DOI:10.1016/j.tetlet.2011.06.047

Tetrahedron Letters 52 (2011) 4320–4323
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Tetrahedron Letters
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Selective 1,2-dihalogenation and oxy-1,1-dihalogenation of alkynes
by N-halosuccinimides
⇑
Jinhua Liu, Wenjuan Li, Chao Wang, Yao Li, Zhiping Li
Department of Chemistry, Renmin University of China, Beijing 100872, China
a r t i c l e i n f o
a b s t r a c t
Article history:
1,2-Dihalogenation and oxy-1,1-dihalogenation of alkynes by N-halosuccinimides can be selectively real-
Received 19 April 2011
Revised 4 June 2011
Accepted 10 June 2011
Available online 17 June 2011
ized through using different reaction conditions.
as solvent without using any catalyst, while -dihalo ketones were synthesized using a mixed solvent
of THF and H2O in the presence of FeCl3Á6H2O. Terminal aromatic alkynes are smoothly transformed into
-dihalo ketones on water without a catalyst.
a,b-Dihalo alkenes were obtained exclusively using THF
a,a
a,a
Ó 2011 Elsevier Ltd. All rights reserved.
Halogenated organic compounds are important synthetic inter-
mediates due to their feasible transformation into a variety of func-
tional molecules. The reactions of unsaturated carbon–carbon
bonds with halogens are widely used for the preparation of haloge-
nated products.1 For example, the electrophilic addition of bromine
FeCl3Á6H2O catalyst (entries 7–9). Additionally, CuCl2Á2H2O, CuBr2,
and Cu(OTf)2 were also examined under the standard reaction con-
ditions (entries 10–12). However, Cu(II)-catalyzed reactions show
no obvious differences from the case of no catalyst (entry 6). These
results indicated that FeCl3Á6H2O plays a key role for the selective
formation of 4a.
to alkynes is a classic method for the synthesis
a,b-dibromo al-
kenes.2 However, bromine is hazardous and volatile, which heavily
limits its applications in synthetic processes. Alternatively, N-halo-
succinimides (NXS) are currently used as mild sources of halogen
in synthetic chemistry due to their easy handling. Although the
Under the established reaction conditions, the scopes of the
reactions were investigated (Tables 2 and 3). A variety of a,b-diha-
lo alkenes 3 were obtained by the reactions of alkynes with NBS
and NCS (Table 2).7 Recently, Shao and Shi reported an efficient
dibromination of terminal aromatic alkynes by the combination
of NBS and lithium bromide in THF.8 In the case of phenylacetylene
1d, (E)-(1,2-dibromovinyl)benzene 3d was selectively obtained,
implying that an ionic bromination mechanism could be opera-
tive.1 In contrast, E- and Z-isomers 3d were formed under our con-
ditions (entry 4). This result indicated that the present 1,2-
dihalogenation more likely undergoes through a radical mecha-
nism (Scheme 1).9 NIS failed to give the corresponding diiodoalk-
enes 3. We hypothesized that the elimination of vinyl radical A
to alkyne 1 would be much faster than the abstraction of the sec-
ond iodine atom from NIS. It should be noted that trans-dihalo
products were formed in some cases because the stabilities of vinyl
radicals A are affected by the substituent of alkynes.10
transformation of alkynes with NXS to
presence of nucleophilic solvents has been extensively investi-
gated,3 surprisingly,
,b-dihalogenation of alkynes has virtually
a,a-dihalo ketones in the
a
been untouched.4 Additionally, in the cases of oxy-1,1-dihalogen-
ation of alkynes by NXS, the scopes of the substrates are still lim-
ited and Bronsted acid catalysts had to be used for less reactive
alkynes.5 Therefore, further studies of the reactions of alkynes with
NXS under different reaction conditions to give different products
are highly welcome. Herein we report our efforts on selective
dihalogenation of alkynes to achieve selective syntheses of
halo ketones and ,b-dihalo alkenes through simply adding or not
adding FeCl3Á6H2O catalyst.
a,a-di-
a
In the course of our studies on iron-catalyzed oxidative trans-
formation of C–H bond,6 (E)-1,2-dibromooct-1-ene 3a and 1,1-
dibromooctan-2-one 4a were obtained (Table 1, entry 1). Keeping
the importance of the halogenated compounds in mind, we further
investigated the selectivity of this transformation (Table 1). 3a was
exclusively formed in the absence of iron catalyst using THF as a
solvent (entries 2–5). On the other hand, 4a was formed in 18%
yield together with 3a when H2O was used as a co-solvent (entry
6). Importantly, 4a was obtained as the major product and the for-
mation of 3a was suppressed significantly in the presence of
Halogenation of ketones presents one of efficient methods for
the synthesis of
and mono-halogenation of ketones are still problems that have
not been solved.11 In our studies,
-dibromo ketones 4 were
a,a-dihalo ketones. However, the regioselectivity
a,a
selectively synthesized by the reactions of alkynes with NBS in
the presence of iron catalyst (Table 3).12 Realizing this reaction will
provide a new entry to this class of compounds using easily ob-
tained alkynes and cheap catalyst. Therefore, we further studied
the scope of this reaction. Terminal alkynes provided selective
oxy-1,1-dibromination product in good yields (entries 1–3). Either
symmetric or unsymmetric alkynes also gave the corresponding
products 4d–4g selectively (entries 4–7). Interestingly, the Mark-
⇑
Corresponding author.
E-mail address: zhipingli@ruc.edu.cn (Z. Li).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.047

J. Liu et al. / Tetrahedron Letters 52 (2011) 4320–4323
4321
Table 1
Table 2
Syntheses of
Optimization of the reaction conditionsa
a
,b-dihalo alkenes 3a
O
O
O
cat. FeCl3.6H2O
THF-H2O
X
R2
X
Br
Br
R1
R2
+
N
Br
+
+
N X
Hex
Hex
R1
°
C, 1 h
THF, 80
Hex
Br
Br
80
°C, 1 h
1a
2a
3a
4a
1
2
O
O
3
Entry 2a
Catalyst
(mol %)
THF
(mL)
H2O
(mL)
3ab
(%)
4ab
(%)
Entry
1
1
2
3
Yieldb (%)
76(64)
(equiv)
Hex
Br
1
1
FeCl3Á6H2O (5)
1
1
2
2
2
2
2
2
2
2
2
2
—
—
—
—
—
1
1
1
1
1
25
50
57
76
81
60
16
6
3
—
—
—
1a
NBS 2a
2
3
4
5
6
7
8
2
2
3
4
3
3
4
4
4
4
4
—
—
—
—
Hex
Br
Br
3a
C10H21
1b
2
3
4
2a
66(59)
75(67)
79(72)c
—
C10H21
Br
3b
—
18
50
61
80
28
20
27
FeCl3Á6H2O (5)
FeCl3Á6H2O (5)
FeCl3Á6H2O (5)
Br
Ph
Ph
2a
2a
9c
10c
11c
12c
6
Ph
1c
CuCl2Á2H2O (5)
58
60
58
Br
3c
CuBr2 (5)
1
1
Br
Cu(OTf)2 (5)
1d
a
Ph
Br
3d
Conditions: 1a (0.5 mmol), 80 °C, 1 h, under N2.
b
Reported yields were based on 1a and determined by 1H NMR using an internal
Br
Me
standard.
c
Three hours.
Br
5
6
1e
1f
2a
2a
89(76)d
93(85)e
ovnikov-type product 4h was obtained when ethyl propiolate 1m
was applied under the standard conditions (entry 8), which shows
a different regioselectivity compared with protonic acid-catalyzed
Me
3e
Br
O2N
reactions.13 Furthermore,
a,a-dichloro and a,a-diiodo ketones
Br
were also synthesized by applying NCS and NIS under the standard
conditions (entries 9–11).
For terminal aromatic alkynes, oxy-1,1-dibromination products
414 were obtained efficiently using only water as solvent (Ta-
ble 4).15 The reaction of 1d with NBS led to a quantitative yield
of 4l (entry 1). Substituted aromatic alkynes also led to the desired
products on water in good yields (entries 2–4). Although 1-butyl-
4-ethynylbenzene 1q is not a good substrate for this transforma-
tion due to its low solubility in water (entry 5), the desired product
4p was obtained in good yield under our established iron-catalyzed
conditions, Method B (entry 6). Similarly, the efficiency of chlorina-
tion could be improved by iron catalyst (entries 8 and 10). 2,2-Diio-
O2N
Br
3f
Pr
Pr
Pr
Br
1g
1h
1i
7
8
9
2a
2a
2a
62(48)
92(79)
99(89)
Pr
Br
3g
Me
Ph
Ph
Me
Et
O
Ph
Br
Br
Et
3h
Ph
Br
Br 3i
O
do-1-phenylethanone 4s could be synthesized,16 albeit in
a
Me
Ph
moderate isolated yield due to the decomposition of the separation
process (entry 11).
10
2a
90(84)f
Me
1j
Ph
Cl
Br
3j
In summary, we have developed selective methods for the
synthesis of a,b-dihalo alkenes and a,a-dihalo ketones by the reac-
11
12
1a
1d
NCS 2b
84(50)
82(65)
Hex
Cl
Cl
3k
tions of alkynes with N-halosuccinimides. Both 1,2-dihalogenation
and oxy-1,1-dihalogenation of alkynes by N-halosuccinimides can
be selectively achieved under different mild reaction conditions.
2b
Ph
Cl 3l
a
Acknowledgments
Conditions: 1 (0.5 mmol), 2 (1.5 mmol), 80 °C, 1 h, under N2.
NMR yields were based on 1 and determined by NMR using an internal stan-
b
dard; isolated yields were given in parentheses.
Financial support by the National Science Foundation of China
(20832002 and 21072223), the Fundamental Research Funds for
the Central Universities, and the Research Funds of Renmin Univer-
sity of China (10XNL017) is gratefully acknowledged. We thank
Zhi-Xiang Yu in Peking University for helpful discussion.
c
The ratio of E/Z was 4:1.
The ratio of E/Z was 1.6:1.
The ratio of E/Z was 2:1.
d
e
f
The ratio of E/Z was 2:1.
2. (a) Goehring, R. R. In Encyclopaedia of reagents for organic synthesis; Paquette, L.
A., Ed.; John Wiley & Sons: New York, 1995; 1, pp 679–680; (b)The merck index;
Budavari, S., O’Neil, M. J., Smith, A., Heckelman, P. E., Kinneary, J. F., Eds., twelfth
ed.; Merck: Rahway, 1996.
3. (a) Hiegel, G. A.; Bayne, C. D.; Ridley, B. Synth. Commum. 2003, 33, 1997–2002;
(b) Karlov, S. S.; Shutov, P. L.; Churakov, A. V.; Lorberth, J.; Zaitseva, G. S. J.
Organomet. Chem. 2001, 627, 1–5; (c) Reed, S. F., Jr. J. Org. Chem. 1965, 30, 2195–
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.06.047.
References and notes
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J. Liu et al. / Tetrahedron Letters 52 (2011) 4320–4323
Table 3
Syntheses of
Table 4
a,
a
-halo ketones 4a
The reactions of terminal aromatic alkynes with 2a
O
O
.
O
O
cat. FeCl3 6H2O
Method A
Method B
R2
Br
X
(5 mol %)
R1
Ar
R1
R2
Ar
+
N
X
+
N X
THF-H2O
80 oC, 3 h
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1
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4
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Entry
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1
4
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Entry
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3
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80(65)
O
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Br
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A
A
98(91)
72(65)
Ph
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Bu
O
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3
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2a
2a
2a
2a
2a
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87(68)
72(65)
75(57)
74(66)
69(66)
77(69)
57(49)
55(35)
(72)
Bu
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2
Cl
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1n
1o
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Cl
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Br
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1e
1h
Br
O
Br
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3
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A
A
68(63)
82(74)
O
O
O
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F
Pr
Br
4
F
MeO
Bu
4n
Br
Br
Br
Br
4d
MeO
Bu
Br
Me
Br
5
Ph
Ph
Ph
1p
Br
4o
4e
5
6
A
B
34
87(81)
O
Br
Et
Br
6
1i
1q
Br
4f
4p
Ph
Cl
7
8
A
B
62(52)
90(86)
O
Cl
Cl
7
1d
1n
1d
1l
Ph
Br
4g
Cl
O
4q
EtOOC
O
9
10
A
B
51
85(81)
1m
Br
8
Cl
EtOOC
Br
Cl
4h
Cl
O
Cl
4r
9
1a
1h
1a
Hex
O
Cl
4i
I
11
A
67(43)
Ph
O
I
4s
Me
Cl
10
Ph
a
Method A: 1 (0.5 mmol), 2 (1.1 mmol), H2O (1.0 mL), 80 °C, 3 h, under N2;
Cl
4j
Method B: 1 (0.5 mmol), 2 (2.0 mmol), H2O (1.0 mL), THF (2.0 mL), FeCl3Á6H2O
O
(0.025 mmol), 80 °C, 3 h, under N2.
b
I
NMR yields were based on 1 and determined by NMR using an internal stan-
dard; isolated yields were given in parentheses.
11
NIS 2c
74(49)
Hex
I
4k
a
Conditions: 1 (0.5 mmol), 2a (2 mmol), FeCl3Á6H2O (0.025 mmol), 80 °C, 3 h,
under N2.
O
O
b
NMR yields were based on 1 and determined by NMR using an internal stan-
dard; isolated yields were given in parentheses.
N
X
c
N
X
50 °C.
R2
X
X
R2
X
O
O
R1
R2
R1
R1
O
O
1
A
3
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N
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7. The representative procedure for synthesis of 3a: To a mixture of 1-octyne 1a
(0.5 mmol) and N-bromosuccinimide 2a (1.5 mmol) was added
tetrahydrofuran (THF, 2.0 mL) under nitrogen at room temperature. The
reaction temperature was raised to 80 °C for 1 h. The reaction temperature
O
O
Scheme 1. A tentative mechanism for the formation of 3.
was cooled to room temperature. The resulting reaction solution was
evaporated in vacuo to afford the crude product. NMR yield was determined
by 1H NMR using dibromomethane as an internal standard. Solvent was
evaporated, and the residue was purified by flash column chromatography on
silica gel with petroleum ether as an eluent. The fraction with a Rf = 0.9

J. Liu et al. / Tetrahedron Letters 52 (2011) 4320–4323
4323
(petroleum ether) was collected to give the desired product 3a. 1H NMR (ppm)
d 6.40 (s, 1H), 2.60 (t, J = 7.6 Hz, 2H), 1.61–1.54 (m, 2H), 1.36–1.31 (m, 6H), 0.90
(t, J = 6.8 Hz, 3H); 13C NMR (ppm) d 127.0, 102.1, 36.9, 31.5, 28.0, 27.0, 22.5,
14.0.
column chromatography on silica gel with ethyl acetate/petroleum ether
(1:200) as an eluent. The fraction with a Rf = 0.6 (ethyl acetate/petroleum
ether = 1:10) was collected to give the desired product 4a. 1H NMR (ppm) d
5.80 (s, 1H), 2.92 (t, J = 7.3 Hz, 2H), 1.72–1.65 (m, 2H), 1.38–1.31 (m, 6H), 0.89
(t, J = 6.8 Hz, 3H); 13C NMR (ppm) d 196.9, 42.9, 34.8, 31.4, 28.5, 24.2, 22.4, 13.9.
13. Markovnikov-type product refers to the compound where the electrophile
(Br+) is on the carbon which is to the carbonyl group. Heasley, V. L.; Buczala, D.
M.; Chappell, A. E.; Hill, D. J.; Whisenand, J. M.; Shellhamer, D. F. J. Org. Chem.
2002, 67, 2183–2187.
8. Shao, L.-X.; Shi, M. Synlett 2006, 1269–1271.
9. (a) Skell, P. S.; Tlumak, R. L.; Seshadri, S. J. Am. Chem. Soc. 1983, 105, 5125–5131;
(b) Buckles, R. E.; Johnson, R. C.; Probst, W. J. J. Org. Chem. 1957, 22, 55–59.
10. (a) Clark, A. J.; Filik, R. P. In Organic Reaction Mechanisms; Knipe, A. C., Watts, W.
E., Eds.; John Wiley & Sons Ltd, 1997; pp 99–137. Chapter 3; (b) Melandri, D.;
Montevecchi, P. C.; Navachia, M. L. Tetrahedron 1999, 55, 12227–12236.
11. (a) Podgorsek, A.; Jurisch, M.; Stavber, S.; Zupan, M.; Iskra, J.; Gladysz, J. A. J.
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12. The representative procedure for synthesis of 4a: To a mixture of 1-octyne 1a
(0.5 mmol), N-bromosuccinimide 2a (2.0 mmol), and FeCl3Á6H2O (0.025 mmol)
was added water (1.0 mL) and tetrahydrofuran (THF, 2.0 mL) under nitrogen at
room temperature. The reaction temperature was raised to 80 °C for 3 h. The
temperature of the reaction was cooled to room temperature. The resulting
reaction solution was quenched with 2 mL of saturated NaHCO3 and extracted
with 15 mL of ether for three times. The extract was dried over MgSO4. The
resulting reaction solution was directly filtered through a pad of silica by ethyl
acetate. The solvent was evaporated in vacuo to afford the crude product. NMR
yield was determined by 1H NMR using dibromomethane as an internal
standard. Solvent was evaporated, and the residue was purified by flash
14. Masuda, H.; Takase, K.; Nishio, M.; Hasegawa, A.; Nishiyama, Y.; Ishi, Y. J. Org.
Chem. 1994, 59, 5550–5555.
15. The representative procedure for synthesis of 4i: To a mixture of phenylacetylene
1d (0.5 mmol) and N-bromosuccinimide 2a (1.1 mmol) was added water
(1.0 mL) under nitrogen at room temperature. The reaction temperature was
raised to 80 °C for 3 h. The temperature of the reaction was cooled to room
temperature. The resulting reaction solution was extracted with 15 mL of ether
for three times. The extract was dried over MgSO4. The solvent was evaporated
in vacuo to afford the crude product. NMR yield was determined by 1H NMR
using dibromomethane as an internal standard. Solvent was evaporated, and
the residue was purified by flash column chromatography on silica gel with
ethyl acetate/petroleum ether (1:200) as an eluent. The fraction with a Rf = 0.6
(ethyl acetate/petroleum ether = 1:10) was collected to give the desired
product 4i. 1H NMR (ppm) d 8.12–8.09 (m, 2H), 7.66 (t, J = 7.4 Hz, 1H), 7.53
(t, J = 7.4 Hz, 2H), 6.75 (s, 1H); 13C NMR (ppm) d 185.9, 134.4, 130.8, 129.6,
128.9, 39.7.
16. Mono-iodo ketones were prepared by the reactions of alkynes with
a
combination of 2-iodoxybenzoic acid and I2: Yadav, J. S.; Reddy, B. V. S.;
Singh, A. P.; Basak, A. K. Tetrahedron Lett. 2008, 49, 5880–5882.