A convenient and practical approach to α-diketones via reactions of internal aryl alkynes with N-iodosuccinimide/water

Article abstract of DOI:10.1055/s-2008-1067240

A convenient and practical approach to α-diketones via reactions of alkynes with N-iodosuccinimides/water at 70°C has been developed. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067240

PAPER
2879
A Convenient and Practical Approach to a-Diketones via Reactions of Internal
Aryl Alkynes with N-Iodosuccinimide/Water
C
a
onvenient and Practic
i
al
A
pp
n
roach to
a
-D
g
iketones yu Niu,a Hua Fu,*a Yuyang Jiang,a,b Yufen Zhaoa
b
Fax +86(10)62781695; E-mail: fuhua@mail.tsinghua.edu.cn
Received 17 April 2008; revised 22 May 2008
of bromine over chlorine. Extending this logic, we be-
lieved that NIS could thus be a better halogenation reagent
than either NCS or NBS, so we attempted the reaction of
diphenylacetylene with NIS in a acetonitrile–water mix-
ture at 70 °C for 10 hours. Surprisingly, a 62% yield of
benzil was obtained, with all the diiodoketone trans-
formed into the a-diketone (entry 6). When iodine was
used, the benzil was only obtained in 19% yield under the
same conditions (entry 7). After optimizing the condi-
tions, the oxidation of the internal alkynes to a-diketones
was found to proceed best with NIS/water as the oxidant
and acetonitrile as the solvent at 70 °C.
Abstract: A convenient and practical approach to a-diketones via
reactions of alkynes with N-iodosuccinimides/water at 70 °C has
been developed.
Key words: a-diketones, alkynes, N-iodosuccinimide, convenient
and practical, water
A convenient and efficient approach to a-diketones is
highly desirable because such compounds are versatile
building blocks for a variety of chemical transformations1
such as the preparation of biologically active heterocyclic
compounds,2 photoinitiators3 and chiral alcohols.4 Al-
though several methods have been reported for synthesis
of a-diketones,5 the oxidation of properly substituted in-
ternal alkynes is the most straightforward process. Previ-
ous oxidation methods include the use of potassium
permanganate,6 DMSO7 or ozonolysis, or are peroxidant-
based,8 transition-metal-catalyzed9 or acid-promoted.10
Practical applications of these methods is limited, howev-
er, since many are neither environmentally benign nor op-
eratively efficient and involve hazardous transition-
metals, high temperatures or cryogenic reaction condi-
tions. Herein, we report a more convenient, practical and
environmentally friendly one-pot method for the synthe-
sis of a-diketones via reaction of internal alkynes with N-
iodosuccinimide (NIS) and water.
Table 1 Reactions of Diphenylacetylene and Water with N-Halo-
succinimides or Iodine: Optimization of Conditionsa
O
X
Ph
O
Ph
O
O
X
MeCN–H2O
10 h
+
Ph
Ph
+
N
X
Ph
Ph
1a
3ax
2a
O
Entry NXS
Solvent
Temp
Yield of Yield of
(°C)
r.t.
r.t.
r.t.
70
2a (%)b 3ax (%)b
1
2
3
4
5
6
7
NCS
NBS
NIS
NCS
NBS
NIS
I2
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
trace
trace
20
18
17
0
Initially, we chose diphenylacetylene and N-halosuccin-
imides (NCS, NBS, NIS) or I2 as model substrates with
which to optimize the reaction conditions in an acetoni-
trile–water mixture (10:1 v/v). Room temperature reac-
tions with NCS and NBS for 10 hours provided
dichloroketone (3aCl) and dibromoketone (3aBr) in 18%
and 17% yields, respectively, but no a-diketone product
(benzil) was found (Table 1, entries 1 and 2). NIS gave
only a-diketone product under the same conditions (entry
3). When the reaction temperature was increased to 70 °C,
yields of dihaloketones (3aCl and 3aBr) significantly in-
creased, and benzil was observed (see entries 4 and 5). We
reasoned that the use of NBS provided more benzil than
NCS because the a-diketone was formed through hydro-
lysis of the dihaloketones due to the better leaving power
11
51
23
0
70
29
70
62
70
19
0
a Reaction conditions: diphenylacetylene (0.25 mmol), N-halosuccin-
imide or I2 (0.5 mmol), MeCN (2 mL), H2O (0.2 mL).
b Isolated yield.
As shown in Table 2, when the reaction was performed on
a range of substrates, the corresponding a-diketones were
obtained in various yields. Diarylacetylenes showed high-
er reaction activity than monoarylacetylenes, and the in-
ternal alkynes containing electron-donating groups
provided higher yields than those containing electron-
withdrawing groups. For example, the yields of the corre-
sponding a-diketones gradually decreased using sub-
strates bearing increasingly electron-withdrawing groups
SYNTHESIS 2008, No. 18, pp 2879–2882
x
x.
x
x
.
2
0
0
8
Advanced online publication: 22.08.2008
DOI: 10.1055/s-2008-1067240; Art ID: F09108SS
© Georg Thieme Verlag Stuttgart · New York

2880
M. Niu et al.
PAPER
Table 2 Oxidation of Internal Alkynes with NIS/H2O to a-Diketonesa
Entry
1
1
2
Yield (%)b
62
O
O
1a
2a
O
Cl
Cl
2
3
4
60
56
29
O
1b
2b
O
Br
O
Br
1c
2c
O
O2N
O2N
O
1d
2d
Et
O
5
66
Et
O
1e
2e
O
MeO
MeO
6
7
8
65
63
54
O
1f
2f
O
Me
Me
O
1g
2g
O
H2N
BocHN
O
1h
2h
O
9
53
O
1i
2i
O
MeO
MeO
(CH2)5Me
10
11
52
37
(CH2)5Me
O
1j
2j
O
Et
Et
O
1k
2k
a Reaction conditions: internal alkyne (0.25 mmol), NIS (0.5 mmol), MeCN (2 mL), H2O (0.2 mL), 70 °C, 10 h.
b Isolated yield.
Synthesis 2008, No. 18, 2879–2882 © Thieme Stuttgart · New York

PAPER
Convenient and Practical Approach to a-Diketones
2881
ether) (for compound 2h, a small amount of EtOAc was used to ad-
just polarity of solvent) to provide the pure a-diketone.
O
I
I
R1
R1
O
R2
+
R1
R2
B
N
I
1,2-Diphenylethane-1,2-dione (2a)9c
Light-yellow solid; mp 93–94 °C.
1H NMR (300 MHz, CDCl3): d = 7.96–7.99 (m, 4 H), 7.63–7.69 (m,
2 H), 7.48–7.54 (m, 4 H).
H+
OH
R2
O
C
O
N
H2O
–
A
13C NMR (75 MHz, CDCl3): d = 194.5, 134.8, 133.0, 129.9, 129.0.
MS (EI): m/z [M+] = 210.3.
I
I
I
H
R1
R1
O
O
R2
R2
R1
NIS
E
1-(4-Chlorophenyl)-2-phenylethane-1,2-dione (2b)9c
Light-yellow solid; mp 75–76 °C.
R2
O
D O
H2O
HI
2
1H NMR (300 MHz, CDCl3): d = 7.91–7.98 (m, 4 H), 7.65–7.70 (m,
1 H), 7.48–7.55 (m, 4 H).
Scheme 1 Possible mechanism of a-diketone formation via reaction
of alkynes with NIS/H2O.
13C NMR (75 MHz, CDCl3): d = 193.9, 193.0, 141.6, 135.1, 132.7,
on the aryl ring (entries 1–4), while introduction of elec-
tron-donating groups on aryl ring could improve the
yields of the a-diketones (see entries 5–7). Compound 1h,
131.3, 131.2, 129.9, 129.4, 129.1.
MS (EI): m/z [M+] = 244.2.
containing a Boc-protected amine, yielded the free amino 1-(2-Bromophenyl)-2-phenylethane-1,2-dione (2c)14
Light-yellow solid; mp 40–41 °C.
1H NMR (300 MHz, CDCl3): d = 8.06–8.08 (m, 2 H), 7.80–7.83 (m,
1 H), 7.44–7.69 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 194.1, 191.4, 136.0, 134.5, 134.3,
133.7, 132.7, 132.5, 130.3, 128.9, 127.8, 121.8.
MS (EI): m/z [M+] = 288.2, 290.3.
a-diketone; presumably the Boc group was cleaved by HI
generated during the reaction of the internal alkynes with
NIS and water.
According to our experimental results and the reported lit-
erature,11 a possible reaction mechanism for the conver-
sion of internal alkynes into a-diketones under the action
of NIS and water, is shown in Scheme 1. Reaction of NIS
with internal alkyne first provides B, leaving a succin-
imide anion A. Nucleophilic attack of water on B leads to
an ortho-iodohydroxyl alkene intermediate C, whose
isomerization gives the a -iodoketone D. Iodination of D
produces the dibromoketone E (in fact, dichloroketone
(3aCl) and diiodoketone (3aBr) were obtained as shown
in Table 1), whose hydrolysis provides the target product
2.
1-(4-Nitrophenyl)-2-phenylethane-1,2-dione (2d)9c
Light-yellow solid; mp 139–140 °C.
1H NMR (300 MHz, CDCl3): d = 8.36 (d, J = 8.9 Hz, 2 H), 8.17 (d,
J = 8.9 Hz, 2 H), 7.98–8.01 (m, 2 H), 7.69–7.74 (m, 1 H), 7.55 (t,
J = 7.9 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 192.8, 192.1, 151.2, 137.3, 135.4,
132.4, 130.9, 130.0, 129.2, 124.1.
MS (EI): m/z [M+] = 255.4.
1-(2-Ethylphenyl)-2-phenylethane-1,2-dione (2e)15
Light-yellow oil.
1H NMR (300 MHz, CDCl3): d = 7.23–7.99 (m, 9 H), 3.10 (q,
J = 7.6 Hz, 2 H), 1.30 (t, J = 7.6 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 196.7, 194.7, 147.5, 134.6, 133.9,
133.2, 131.5, 131.0, 130.0, 129.0, 125.9, 27.4, 15.4.
MS (EI): m/z [M+] = 238.1.
In summary, we have developed a convenient, practical
and environmentally friendly method for the synthesis of
a-diketones. The protocol uses NIS and water as the oxi-
dant, acetonitrile as the solvent, and oxidation of the inter-
nal alkynes was performed at 70 °C. The direct
functionalization of a-diketones by this inexpensive sys-
tem (NIS/H2O) is of practical importance.
1-(4-Methoxyphenyl)-2-phenylethane-1,2-dione (2f)9c
Light-yellow solid; mp 60–61 °C.
1H NMR (300 MHz, CDCl3): d = 7.93–7.98 (m, 4 H), 7.61–7.67 (m,
1 H), 7.49 (t, J = 7.5 Hz, 2 H), 6.97 (m, 2 H), 3.88 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 194.8, 193.1, 164.9, 134.7, 133.2,
132.3, 129.8, 128.9, 126.1, 114.3, 55.6.
MS (EI): m/z [M+] = 240.2.
All reactions were performed under air. Unless otherwise noted, all
reagents were purchased from commercial sources and used with-
out further purification. Substituted alkynes are prepared via Sono-
gashira coupling.12 N-Iodosuccinimide was prepared according to
the reported procedure.13 NMR measurments were recorded with
TMS or solvent resonance as the internal standard (1H NMR: TMS
at d = 0.00 ppm, CDCl3 at d = 7.26 ppm; 13C NMR: CDCl3 at d =
77.0 ppm).
1-Phenyl-2-(p-tolyl)ethane-1,2-dione (2g)9c
Light-yellow oil.
1H NMR (300 MHz, CDCl3): d = 7.96 (d, J = 8.2 Hz, 2 H), 7.86 (d,
J = 7.9 Hz, 2 H), 7.61–7.67 (m, 1 H), 7.49 (t, J = 7.2 Hz, 2 H), 7.29
(d, J = 7.9 Hz, 2 H), 2.43 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 194.7, 194.3, 146.2, 134.7, 133.1,
130.6, 129.9, 129.8, 129.7, 128.9, 21.9.
MS (EI): m/z [M+] = 224.3.
Synthesis of a-Diketones; General Procedure
Solid NIS (0.5 mmol, 113 mg) was added to a flask charged with in-
ternal alkyne (0.25 mmol) in MeCN (2 mL) and H2O (0.2 mL). The
solution was stirred at 70 °C for 10 h then the resulting solution was
cooled to r.t. and CHCl3 (10 mL) and aq Na2S2O3 (1 M, 10 mL) were
added. The separated organic phase was dried over anhydrous
Na2SO4 and concentrated under rotary evaporation, and the residue
was purified by column chromatography on silica gel (petroleum
Synthesis 2008, No. 18, 2879–2882 © Thieme Stuttgart · New York

2882
M. Niu et al.
PAPER
1-(4-Aminophenyl)-2-phenylethane-1,2-dione (2h)16
Yellow solid; mp 125–126 °C.
References
(1) (a) Babudri, F.; Fiandanese, V.; Marchese, G.; Punzi, A.
Tetrahedron Lett. 1995, 40, 7305; and references therein.
(b) De Kimpe, N.; Stanoeva, E.; Boeykens, M. Synthesis
1994, 427; and references therein.
1H NMR (300 MHz, CDCl3): d = 7.46–7.98 (m, 7 H), 6.64 (d,
J = 8.6 Hz, 2 H), 4.25 (br s, 2 H).
13C NMR (75 MHz, CDCl3): d = 195.5, 192.7, 152.9, 134.5, 133.4,
132.6, 129.9, 128.8, 123.1, 113.9.
(2) (a) Barta, T. E.; Stealey, M. A.; Collins, P. W.; Weier, R. M.
Bioorg. Med. Chem. Lett. 1998, 8, 3443. (b) Zhao, Z. J.;
Wisnoski, D. D.; Wolkenberg, S. E.; Leister, W. H.; Wang,
Y.; Lindsley, C. W. Tetrahedron Lett. 2004, 45, 4873.
(c) Held, I.; Xu, S. J.; Zipse, H. Synthesis 2007, 1185.
(d) Rong, F.; Chow, S.; Yan, S. Q.; Larson, G.; Hong, Z.;
Wu, J. Bioorg. Med. Chem. Lett. 2007, 17, 1663.
(3) (a) Bibaut-Renauld, C.; Burget, D.; Fouassier, J. P.; Varelas,
C. G.; Thomatos, J.; Tsagaropoulos, G.; Ryrfors, L. O.;
Karlsson, O. J. J. Polym. Sci., Part A: Polym. Chem. 2002,
40, 3171. (b) Ams, M. R.; Wilcox, C. S. J. Am. Chem. Soc.
2007, 129, 3966.
MS (EI): m/z [M+] = 225.4.
1-Naphthyl-2-phenylethane-1,2-dione (2i)17
Light-yellow oil.
1H NMR (300 MHz, CDCl3): d = 9.30 (d, J = 8.6 Hz, 1 H), 7.89–
8.13 (m, 5 H), 7.45–7.77 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 197.1, 194.6, 135.9, 135.1, 134.7,
134.1, 133.3, 130.9, 129.9, 129.4, 129.0, 128.8, 128.6, 127.1, 125.9,
124.4.
MS (EI): m/z [M+] = 260.1.
(4) (a) Casey, C. P.; Guan, H. J. Am. Chem. Soc. 2007, 129,
5816. (b) Procuranti, B.; Connon, S. J. Chem. Commun.
2007, 14, 1421.
1-(4-Methoxyphenyl)octane-1,2-dione (2j)
Light-yellow oil.
1H NMR (300 MHz, CDCl3): d = 7.96 (d, J = 8.9 Hz, 2 H), 6.95 (d,
J = 8.9 Hz, 2 H), 3.88 (s, 3 H), 2.85 (t, J = 7.5 Hz, 2 H), 1.63–1.73
(m, 2 H), 1.26–1.41 (m, 6 H), 0.88 (t, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 204.0, 191.2, 164.7, 132.6, 124.9,
114.2, 55.5, 38.8, 31.5, 28.8, 22.9, 22.4, 13.9.
MS (EI): m/z [M+] = 248.3.
(5) (a) Naoki, K.; Nasuo, U. Bull. Chem. Soc. Jpn. 2001, 74,
755. (b) Katritzky, A. R.; Zhang, D. Z.; Kirichenko, K.
J. Org. Chem. 2005, 70, 3271; and references therein.
(6) (a) Srinvasan, N. S.; Lee, D. G. J. Org. Chem. 1979, 44,
1574. (b) Lee, D. G.; Chang, V. S. Synthesis 1978, 6, 462.
(7) (a) Wolfe, S.; Pilgrim, W. R.; Garrad, T. F.; Chamberlain, P.
Can. J. Chem. 1971, 49, 1099. (b) Yusybov, M. S.;
Filimonov, V. D. Synthesis 1991, 131. (c) Chi, K. W.;
Yusubov, M. S.; Filimonov, V. D. Synth. Commun. 1994, 24,
2119. (d) Foster, E. J.; Babuin, J.; Nguyen, N.; Williams, V.
E. Chem. Commun. 2004, 18, 2052.
1-Phenylbutane-1,2-dione (2k)18
Light-yellow oil.
1H NMR (300 MHz, CDCl3): d = 7.98 (d, J = 7.2 Hz, 2 H), 7.64 (t,
J = 7.2 Hz, 1 H), 7.49 (t, J = 7.9 Hz, 2 H), 2.91 (q, J = 7.2 Hz, 2 H),
1.20 (t, J = 7.2 Hz, 3 H).
(8) (a) McDonald, R. N.; Schwab, P. A. J. Am. Chem. Soc. 1964,
86, 4866. (b) Aronovitch, C.; Tal, D.; Mazur, Y.
Tetrahedron Lett. 1982, 23, 3623.
(9) (a) Sheats, W. B.; Olli, L. K.; Stout, R.; Lundeen, J. T.;
Justus, R.; Nigh, W. G. J. Org. Chem. 1979, 44, 4075.
(b) Che, C. M.; Yu, W. Y.; Chan, P. M.; Cheng, W. C.; Peng,
S. M.; Lau, K. C.; Li, W. K. J. Am. Chem. Soc. 2000, 122,
11380. (c) Giraud, A.; Provot, O.; Peyrat, J.-F.; Alami, M.;
Brion, J.-D. Tetrahedron 2006, 62, 7667. (d) Tummatorn,
J.; Khorphueng, P.; Petsom, A.; Muangsin, N.; Chaichitc,
N.; Roengsumran, S. Tetrahedron 2007, 63, 11878.
(10) (a) Dayan, S.; Ben-David, I.; Rozen, S. J. Org. Chem. 2000,
65, 8816. (b) Wan, Z. H.; Jones, C. D.; Mitchell, D.; Pu, J.
Y.; Zhang, T. Y. J. Org. Chem. 2006, 71, 826.
13C NMR (75 MHz, CDCl3): d = 203.8, 192.5, 134.5, 132.0, 130.1,
128.8, 32.1, 6.8.
MS (EI): m/z [M+] = 162.4.
2,2-Dibromo-2-phenylacetophenone (3aBr)19
Light-yellow solid; mp 108–109 °C.
1H NMR (300 MHz, CDCl3): d = 7.72–7.75 (m, 2 H), 7.63–7.67 (m,
2 H), 7.24–7.46 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 186.2, 140.9, 133.1, 131.4, 130.8,
129.7, 128.9, 128.0, 126.7, 69.5.
(11) (a) Reed, S. F. Jr. J. Org. Chem. 1965, 30, 2195.
(b) Heasley, V. L.; Shellhamer, D. F.; Chappell, A. E.; Cox,
J. M.; Hill, D. J.; McGovern, S. L.; Eden, C. C. J. Org.
Chem. 1998, 63, 4433.
2,2-Dichloro-2-phenylacetophenone (3aCl)20
Light-yellow solid; mp 65–66 °C.
1H NMR (300 MHz, CDCl3): d = 7.77–7.80 (m, 2 H), 7.64–7.69 (m,
2 H), 7.27–7.49 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 186.7, 139.5, 133.2, 131.8, 131.1,
129.8, 128.9, 128.1, 126.0, 89.9.
(12) Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N.
Synthesis 1980, 627.
(13) Chaikovskii, V. K.; Skorokhodov, V. I.; Filimonov, V. D.
Russ. J. Org. Chem. 2001, 37, 1572.
(14) Tiecco, M.; Testaferri, L.; Tingoli, M.; Chianelli, D.;
Bartoli, D. J. Org. Chem. 1991, 56, 4529.
(15) Noh, T.; Choi, K.; Kwon, H.; Chang, D. J.; Park, B. S. Bull.
Korean Chem. Soc. 1999, 20, 539.
(16) Yi, X. B.; Wu, G. S.; Lu, F. C. Chin. J. Polym. Sci. 2002, 20,
219.
(17) Yamamori, T.; Adachi, I. Tetrahedron Lett. 1980, 21, 1747.
(18) Chang, C. L.; Kumar, M. P.; Liu, R. S. J. Org. Chem. 2004,
69, 2793.
(19) Correia, J. J. Org. Chem. 1992, 57, 4555.
(20) Nobrega, J. A.; Goncalves, S. M. C.; Peppe, C. Synth.
Commun. 2002, 32, 3711.
Acknowledgment
This work was supported by the National Natural Science Founda-
tion of China (Grant No. 20672065), Chinese 863 Project (Grant
No. 2007AA02Z160), Programs for New Century Excellent Talents
in University (NCET-05-0062) and Changjiang Scholars and inno-
vative Research Team in University (PCSIRT) (No. IRT0404) in
China and the Key Subject Foundation from Beijing Department of
Education (XK100030514).
Synthesis 2008, No. 18, 2879–2882 © Thieme Stuttgart · New York