Efficient Synthesis of α-Chloroketones Catalyzed by Fluorous Hydrazine-1,2-Bis(Carbothioate) Organocatalyst

Article abstract of DOI:10.1007/s10562-015-1676-3

A novel and recoverable fluorous hydrazine-carbothioate organocatalyst was prepared. It could catalyze α-chlorination of alkyl ketones with N-chlorosuccinimide as chlorine source under mild reaction conditions. The reaction afforded the corresponding α-ch

Full text of DOI:10.1007/s10562-015-1676-3

Catal Lett (2016) 146:570–574
DOI 10.1007/s10562-015-1676-3
Efficient Synthesis of a-Chloroketones Catalyzed by Fluorous
Hydrazine-1,2-Bis(Carbothioate) Organocatalyst
Yi-Wei Zhu1 Yi-Xin Shi1
•
Received: 27 October 2015 / Accepted: 5 December 2015 / Published online: 31 December 2015
Ó Springer Science+Business Media New York 2015
Abstract A novel and recoverable fluorous hydrazine-
carbothioate organocatalyst was prepared. It could catalyze
a-chlorination of alkyl ketones with N-chlorosuccinimide
as chlorine source under mild reaction conditions. The
reaction afforded the corresponding a-chlorinated carbonyl
compounds with excellent yields at rapid reaction speed.
1 Introduction
a-Chlorocarbonyl [1–11] compounds have attracted con-
siderable attention from organic and medicinal chemists,
primarily because they display a wide range of physiological
activities and precursors of biologically active drugs
(Scheme 1). Such benefits have created lots of synthetic
interest in chlorination catalysis including the innovative use
of Lewis acids, amberlyst, transitional metal complexes and
inorganic reagents. Currently, there is also much interest in
organocatalysts [7, 16–23] due to their low toxicity, opera-
tional simplicity, efficiency, and good stereoselectivity
compared to traditional metal-based catalysts. Inspired by
flourous tag idea, [12–15] herein, our group applied the new
fluorous hydrazine-1,2-bis(carbothioate) C1 and hydrazine-
1,2-dicarboxylate C2 (Scheme 2) to the a-chlorination
reaction of alkyl ketones with N-chlorosuccinimide (NCS) as
chlorine source [24–30]. We found the fluorous hydrazine-
1,2-bis(carbothioate) demonstrated superior catalytic activ-
ity and efficiency, and the reactions proceeded smoothly at
the presence of the organic fluorous catalyst to afford the
desired products in excellent yields. Moreover, the fluorous
catalyst C1 could be easily recovered by fluorous solid-phase
extraction (F-SPE) without using environmentally harmful
perfluorous solvents.
Graphical Abstract
Keywords Fluorous organocatalyst Á
N-chlorosuccinimide Á a-Chlorination Á
Fluorous solid-phase extraction (F-SPE)
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-015-1676-3) contains supplementary
material, which is available to authorized users.
2 Results and Discussion
The fluorous hydrazine-1,2-bis(carbothioate) C1 and
hydrazine-1,2-dicarboxylate C2 were synthesized as shown
in Scheme 3. 2-Perfluorohexyl ethanol II was treated with
1,10-(thio)carbonyl diimidazole I at room temperature.
Quenching with water and extraction with petroleum ether
provided the crude product III, after purification in a
& Yi-Wei Zhu
yiwei.zhu@ahpu.edu.cn
1
School of Biology and Chemical Engineering, Anhui
Polytechnic University, 8 Middle Beijing Road,
Wuhu 24100, Anhui, People’s Republic of China
123

Efficient Synthesis of a-Chloroketones Catalyzed by Fluorous Hydrazine-1,2-Bis(Carbothioate)…
571
EtOAc, MeCN and THF gave moderate to good yields
ranging from 62 to 99 % as illustrated in Table 1, entries
7–10. We hoped that the examination of alternative sol-
vents would speed up the reaction, but protic polar
methanol proved to be the best solvent. This can be
explained by further hydrogen bonding of methanol with
fluorous hydrazine-1,2-bis(carbothioate) to give even
stronger hydrogen bonds. After an extensive screening of
the reaction parameters, the best yield was obtained in
MeOH at 25 °C catalyzed by C1 (5 mol%) (Table 1, entry
4).
Anti-infective agent
Selective estrogen receptor
Scheme 1 Examples of biologically active drugs with a-chlorocar-
bonyl group
The substrate scope of the reaction under the optimal
conditions described above was explored next (Table 2).
The methoxy derivative 1c and 1d were slower than 1b
(Table 2, entry 1–3). The more acidic structures like 1,3-
diketones and b-ketoesters were also studied. The
chloronations of 1e and 1f was very fast and afforded good
yields (Table 2, entry 4, 5). The b-ketoester derivatives 1g,
1h and 1i afforded excellent yields within just 10 min
(Table 2, entry 6–8). The most reactive ketones 1j and
1 k could only afford dichloride in a very short time
(Table 2, entry 9 and 10), when we added the loading of
NCS, we got pretty good yield of the dichloride
compounds.
Scheme 2 Fluorous hydrazine-1,2-bis(carbothioate) C1 and hydra-
zine-1,2-dicarboxylate C2
column, compound III reacted with hydrazine monohy-
drochloride and triethylamine. The fluorous hydrazine (C1,
C2) was isolated as white powder.
We also performed the catalyst-recovery experiments
using model reaction. After completion of the reaction, the
mixture was concentrated and then loaded onto a Fluo-
roFlashs silica gel cartridge for F-SPE. It was found that
the catalyst could be recovered in high yield (87–91 %)
with excellent purity (99 %). The recycling reactions using
the recovered catalyst were conducted 3 times as shown in
Scheme 4 and the model reaction could still afford 85 %
yield after 3 times recovery of the fluorous catalyst
(Scheme 4).
The a-chlorination of 1-indanone 1a was chosen as
model reaction. To optimize the reaction conditions, vari-
ous parameters including catalyst, solvents and catalyst
loadings were investigated. The non-catalyzed a-chlorina-
tion of 1-indanone was a slow reaction (Table 1, entry 1).
The inclusion of catalyst C1 gave a dramatic increase in
the reaction rate (Table 1, entry 2), and it was a more
efficient catalytic structure compared to catalyst C2
(Table 1, entry 3). When we investigated the catalyst
loadings, together considered the economical efficiency,
the optimal reaction catalyst loading was set to C1 5 mol%
(Table 1, entry 3–5). When the usage of NCS was
1.2 mmol, the molecular ratio of 2a:3a was much higher
than that of 2.0 mmol. Different solvents such as CH2Cl2,
The mechanism of this reaction was not very clear. One
explanation was that NCS by means of hydrogen bonding
could act as a precursor for the formation of Cl?, which in
turn could behave as a Lewis acid in the reaction medium
and accelerate the a-chlorination by adding the quantity of
electrophile in the reaction (Fig. 1).
Scheme 3 Preparation of
fluorous hydrazine-1,2-
bis(carbothioate) C1 and
hydrazine-1,2-dicarboxylate C2
123

572
Y. Zhu, Y. Shi
Table 1 a-Chlorination of 1-indanonea
Entry
Solvent
Catalyst (mol%)
Time (h)
Yieldb (%)
Molecular ratio, 2a:3ac
1
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
THF
–
96
1
99
99
48
98
92
97
62
99
99
67
95:5
2
C1 (10)
C2 (10)
C1 (5)
C1 (2)
C1 (5)
C1 (5)
C1 (5)
C1 (5)
C1 (5)
92:8
3
1
85:15
91:9
4
1
5
6d
1
90:10
72:28
94:6
1
7
48
24
8
8
MeCN
EtOAc
CH2Cl2
95:5
9
93:7
10
a
48
88:12
1a 1 mmol, NCS 1.2 mmol, solvent 3 mL
GC yield based on 1a (internal standard method)
GC-MS
b
c
d
NCS 2.0 mmol
quenched with brine (60 mL) and extracted with ether
(3 9 40 mL). The organic layers were combined and loaded
onto the fluorous silica gel, eluted it with 80 % methanol then
with ether to give the fluorous compounds. Purification in
standard gel if necessary, gave O,O-bis(3,3,4,4,5,5,6,6,7,7,
8,8,8-tridecafluorooctyl) hydrazine-1,2-bis(carbothioate)
3 Experimental
3.1 General Remarks
1H NMR, 13C NMR and 19F NMR spectra were charac-
terized with a Bruker Advance RX500 spectrometer. The
GC data was recorded on Agilent 7890a. All chemicals
were reagent grade and used as purchased without further
purifications. All the a-chloroketones products are known
compounds and were identified by comparing of their
physical and spectra data with those reported in literature.
1
C1 (2.363 g, 56 %) as a white solid; H NMR (500 MHz,
CD3OD): d 4.83–4.76 (m, 4H), 2.78–2.60 (m, 4H); 13C NMR
(125 MHz, CD3OD): d 194.2 (b), 122.7-111.1 (m), 65.3 (t),
32.8 (b); 19F NMR: d -82.5 (6F), -114.5 (4F), -122.9
(4F), -123.9 (4F), -124.6 (4F), -127.4 (4F); MS (ESI?)
m/z 843.00 (M-H).
3.2 Procedure for the Preparation of Fluorous
Hydrazine-1,2-Bis(Carbothioate) C1
3.3 Typical Procedure for Fluorous Hydrazine-1,2-
Bis(Carbothioate) C1 Catalyzed a-Chlorination
of Variety of Ketones
3,3,4,4,5,5,6,6,7,7,8,8,8-Tridecafluoro-1-octanol II (3.641
g, 10 mmol) was slowly added to a solution of di(1H-imi-
dazol-1-yl)methanethione I (1.958 g, 11 mmol) in dry CH2
Cl2. After stirring for 12 h at room temperature, the crude
reaction mixture was quenched with water and then extracted
with petroleumether (3 9 50 mL). The solventwas removed
under reduced pressure and the residue was dried under high
vacuum. The crude O-3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluo-
rooctyl 1H-imidazole-1-carbothioate III was taken up in
THF (50 mL) and hydrazine monohydrochloride (0.342 g,
5 mmol) and triethylamine (2.529 g, 25 mmol) were added
at room temperature. After 7 days, the reaction mixture was
Fluorous hydrazine-1,2-bis(carbothioate) C1 (0.042 g,
0.05 mmol) with NCS (0.013 g, 1.2 mmol) was added in
MeOH (3 mL) was stirred at 25 °C for 10 min. Then
ketone 1 (1 mmol) was added and the resulting mixture
was stirred at 25 °C for 1 h. After the reaction completed,
the mixture was concentrated and then loaded onto a Flu-
oroFlashÒ silica gel cartridge (5 g), eluted by 80 %
methanol at first for non-fluorous components. Then dried
over Na2SO4 and evaporated for GC analysis. Ether was
123

Efficient Synthesis of a-Chloroketones Catalyzed by Fluorous Hydrazine-1,2-Bis(Carbothioate)…
Table 2 C1 catalyzed a-chlorination of variety of ketonesa
573
Entry
1
Ketone
Reaction time (min)
20
Chloride/yieldc (%)
99
1b
2b
2
3
40
40
99
1c
2c
99
1d
1e
2d
4
5
15
98
2e
5
99
1f
2f
6
7
10
10
99
1g
2g
99
99
1h
1i
2h
2i
8
9
10
20
41
80b
3j
1j
123

574
Y. Zhu, Y. Shi
Table 2 continued
Entry
Ketone
Reaction time (min)
20
Chloride/yieldc (%)
10
44
82b
1k
3k
a
Ketone 1 mmol, NCS 1.2 mmol, C1 5 mol% solvent 3 mL
NCS 2.0 mmol
b
c
GC yield based on 1 (internal standard method)
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`
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Acknowledgments This work was supported by the Key Project of
Anhui Provincial Education Department (KJ2014A014) and Startup
Fund from AHPU (2014YQQ011).
123