Catalyst-free tandem halogenation/semipinacol rearrangement of allyl alcohols with sodium halide in water

Article abstract of DOI:10.1039/c8gc00478a

An economical, convenient and eco-friendly procedure for the one-pot synthesis of β-haloketones with an α-quaternary carbon center via the tandem halogenation/semipinacol rearrangement of allyl alcohols with NaX (X = Cl, Br, I) in H₂O under ope

Full text of DOI:10.1039/c8gc00478a

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A
convenient procedure for the synthesis of β-haloketones via the tandem
halogenation/semipinacol rearrangement of allyl alcohols with NaX.

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Catalyst-free Tandem Halogenation/Semipinacol Rearrangement
of Allyl Alcohols with Sodium Halide in Water
Zhixuan Zenga, Xudong Xuna, Liwu Huanga, Jiecheng Xua, Gongming Zhua, Guofeng Lib, Wangsheng
Sun*b, Liang Hong*a, Rui Wang*b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An economical, convenient and eco-friendly procedure for the with electrophilic halogen resource was also reported by other
one-pot synthesis of β-haloketones with a α-quaternary carbon researchers10. It is worth mentioning that the group of Martín-
center via the tandem halogenation/semipinacol rearrangement Matute11
reported
the
Ir-catalyzed
redox
of allyl alcohols with NaX (X= Cl, Br, I) in H2O under open-air isomerization/halogenation of allylic alcohols. It showed
conditions has been demonstrated. The catalyst-free process transition metal catalysis may also play a vital role in this field.
affords various halogenated products in moderate to excellent A breakthrough in this field inducing enantioselectivity on the
yields (up to 98%). The features of this procedure include catalyst- final products with organocatalysts was developed by Tu12. The
free, aqueous medium, low-cost sodium halide, open to air, group
reported
bromination/semipinacol rearrangement of allylic alcohols by
using (DHQD)2PYDZ and NBS for the construction of chiral
a
wonderful
enantioselective
excellent yield and gram scalable preparation.
β
-
bromoketones with excellent yields and ee value. Afterwards
many great works were reported in the organocatalytic
，
Introduction
asymmetric synthesis of β
-haloketones.13
Attentions on the green and sustainable chemistry have driven
chemists to adopt environmentally benign reactions and
conditions. One of the important influential factors in a
reaction is solvent effect, and the organic solvents are widely
used in the organic synthesis, but many of them are harmful to
the ecosystems or human body1. Thus, organic reactions in
water2 have drawn increasing attention of researchers3.
However, these methods suffered some disadvantages
including expensive electrophilic halogenation reagents or
catalysts, usage of great amounts of toxic or volatile organic
solvents, large excess of additives like strong base or acid,
obnoxious smelling reagents, stirring under an inert
atmosphere and symmetric
substrates. Therefore, a more economical, convenient and
eco-friendly procedure for the construction of -haloketones is
α,α-diaryl or dialkyl allylic alcohols
Organohalogen compounds4 such as
especially containing an all-carbon -quaternary carbon
β-haloketones,
β
α
center, have showed important synthetic utility5 and
bioactivity6, especially in the context of total synthesis7. Thus,
great efforts have been made in the construction of these
ketones by chemists in the past years. Among these methods,
reactions involving semipinacol rearrangement8 showed to be
a valuable strategy. The general process involves allyl alcohols
substrates, electrophilic halogenating reagents in organic
still in great demand. What’s more, to the best of our
knowledge, there exists no example of tandem
halogenation/semipinacol rearrangement of allyl alcohol in
water, and nucleophilic14 halogenation reagent for the
construction of
β-haloketones by semipinacol rearrangement
of allyl alcohol was few reported.
solvent with catalysts and/or additive to obtain the
β-
haloketones (Scheme 1, route a). For instance, in 1973,
Johnson9 reported allyl alcohols reacted with t-BuOCl to give
β
-chloroketones via semipinacol rearrangement. Such strategy
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Table 1 Optimization of the reaction conditions.a
Entry
[O]
Sol.
T (oC)
Atm.
Yieldb(%)
1
2
PIDA
H2O
RTc
RT
RT
RT
RT
RT
40
50
40
40
40
40
40
40
40
40
N2
75
O2 in Air
tBuO2H
H2O2
H2O
Air
N2
NRd
NR
NR
NR
75
3
4
H2O
H2O
N2
5
6
7
K2S2O8
PIDA
H2O
N2
H2O
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
PIDA
H2O
89
8
PIDA
H2O
89
9
PIDA
THF
trace
70
10
11
12
13
14
15f
16g
PIDA
DCM
MeCN
MeOH
PhMe
H20
PIDA
63
PIDA
73
Scheme 1 Synthesis of
β
-haloketones from allyl alcohols.
PIDA
66
70
86
PIDAe
PIDA
H2O
Driven by our previous work on the halogenation of aryl
compounds,15 we envisaged that sodium halide/oxidant
combination may induce the semipinacol rearrangement of
allyl alcohol. And considering the solubility of sodium halide in
the reaction process, water may be a good choice.
PIDA
H2O
80
a Unless otherwise noted, the reaction was carried out on o.1 mmol scale in 1 mL
b
solvent with the ratio of 1a /[O]/NaBr = 1.0: 2.0: 4.0 under N2 or air for 24h.
Isolated yield. c Room temperature. d No reaction. e 1.0 equiv PIDA. f KBr was used
a bromide source. g CuBr was used a bromide source.
Herein, we reported such a synthesis of
α-quaternary
carbon center β-haloketones via tandem halogenation
semipinacol rearrangement of allyl alcohols with sodium halide
and PIDA in water without any catalyst.
/
With the aforementioned results in hand, we explored
whether NaCl or NaI would procced smoothly in the process.
Fortunately, the prospective products were obtained in 78%
and 81%, respectively
(Table 2). Encouraged by the
satisfactory results, we next subjected other symmetric α,α-
diaryl allylic alcohols (1b-d) under the optimized conditions. All
Results and discussion
Allyl alcohol 1a as a model substrate was used in our
beginning investigation. 1a with NaBr and PIDA in 1mL water
was stirred at room temperature under N2, to our great
delight, the reaction could procced smoothly to give the
the substrates with either electron-deficient or electron-rich
aryl groups performed well and give the desired β-haloketones
3ba-3dc) in moderate to excellent yields. Moreover, when
(
cyclic allylic alcohol 1e was tested, it showed excellent
desired
β-haloketone 3ab in 75 % yield (Table 1, entry 1).
tolerance to the process to afford the halogenated products
Then several other oxidants were tested in the process,
unfortunately, none of them could promote the reaction
(Table 1, entries 2-5). To investigate the effect of the reaction
atmosphere, the process was performed under the air, and the
air almost had no effect on the reaction (Table 1, entry 6).
Then we attempted to increase the yield by raising the
3ea
,
3eb and 3ec in 95%, 98% and 94%, respectively). For
-diaryl allylic alcohol 1f, it performed well
unsymmetrical
α,α
for chlorination and bromination to give 3fa and 3fb in good
yields of 83% and 88%, while the iodization gave a complex
mixture. Similarly, for substrates 1h and 1i, the brominating
products 3hb and 3ib were obtained with 65% and 54% yields,
respectively. However, the chlorinating and iodinating
products of 1h and 1i were two kinds of rearrangement
products. Another kind unsymmetrical allylic alcohol 1g with
an aryl and an alkyl substituent, the desired products 3gb and
3gc with exclusive migration of aryl group, was obtained in
89% and 77% yields, respectively. And the non-terminal olefin
1j went smoothly in the bromination to give 3jb with 85%
yield, but complex mixture in the chlorination and no reaction
in the iodization were observed. In addition, the Et-group
substitutional allylic alcohol 1k performed well in the standard
temperature to 40
℃, gratifyingly, the yield could improve to
89 % (Table 1, entry 7). However, the yield was kept when
further raising the temperature (Table 1, entry 8). Evaluation
of the solvent effect was subsequently carried out, all the
tested solvent failed to increase the yield (Table 1, entries 9-
13). The main disadvantages of this procedure is related with
the use of an external oxidant PIDA in a two-fold excess. When
the amount of PIDA was reduced to 1.0 equiv., the yield was
reduced greatly from 89% to 70% (Table 1, entry 7 vs entry
14). In order to rich the bromide source of the reaction, we
also tried other bromides like KBr or CuBr. The reaction went
smoothly to deliver the product in 86% and 80% yield
respectively.
condition, the 3ka, 3kb and 3kc were achieved in 82%, 94%
and 65% yield, respectively. In generally, as can be seen from
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our investigation, the bromination/semipinacol rearrangement
The synthetic potential and utility of this process was further
usually gave better yield than the corresponding chlorination demonstrated through several transformations by the product
or iodination.
3ab
sodium azide could achieve the product
Similarly, when treated with 4-methylthiophenol, it could
generate the product with 88% yield. In addition, it also
(
Scheme 3). The substitution of the bromine atom with
4
in 75% yield.
Table 2 Synthesis of β-haloketones from 1 and sodium halide.a
6
could be reduced by NaBH4 to give alcohol 5 in 95 % yield.
O
O
O
X
X
X
F
Cl
F
Cl
X = Cl, 3ca, 74%
X = Br, , 70%
3cb
X = I, 3cc, 47%
X = Cl, 3aa, 78%
X = Br, 3ab, 89%
X = I, 3ac, 81%
X = Cl, 3ba, 83%
X = Br, 3bb, 87%
X = I, 3bc, 79%
Scheme 3 Transformations of the product.
O
O
F
X
X
X
Next, we tentatively speculated a mechanism similar to
those reported in the literature (Scheme 4).13b,13g The allylic
alcohol 1a would react with the active PhI(X)2 which is formed
from the PhI(OAc)2 and sodium halide to give the halonium ion
H3C
F
O
CH3
X = Cl,3ea, 95%
X = Br, 3eb, 98%
X = I, 3ec, 94%
X = Cl, 3da, 74%
X = Br, 3db, 80%
X = I, 3dc, 32%
X = Cl, 3fa, 83%
X = Br, 3fb, 88%
X =I, complex mixture
intermediate
A with the concomitant 1,2-migration of the
migrating group. Subsequently, the formation of the
haloketone is accompanied by deprotonation.
β-
O
O
O
X
X
X
tBu
CF3
CF3
X = Cl, complex mixture
X = Br, 3gb, 89%
X = I, 3gc, 77%
X = Br, 3hb, 65%
X = Cl or I, two kinds of
rearrangement products
X = Br, 3ib, 54%
X = Cl or I, two kinds of
rearrangement products
O
O
Scheme 4 The proposed mechanism.
X
X
Experimental
X = Cl, 3ka, 82%
X = Br, 3kb, 94%
X = I, 3kc, 65%
X = Cl, complex mixture
X = Br, 3jb, 85%
X = I, no reaction
General procedure for the synthesis of β-haloketones 3
aReaction condition: Allyl alcohol 1 (0.1 mmol, 1.0 equiv), PIDA (0.2 mmol, 2.0
equiv), NaX (0.4 mmol, 4.0 equiv), water (1 mL), 40oC, under air. b Isolated yield.
To a 10 mL round-bottom flask equipped with a magnetic
stirrer bar, were added (0.1 mmol, 1.0 equiv), PIDA (0.2
1
mmol, 2.0 equiv) and NaBr (0.4 mmol, 4.0 equiv). Then water
(1 mL) was added, and the mixture was then stirred at 40oC.
To test the practicality of this strategy, a gram-scale reaction
was employed (Scheme 2). The target product 3ab could be
obtained in 88% yield (89%, 0.1 mmol).
Then the reaction was monitored by TLC and till
1 was
consumed up. Afterwards, the reaction mixture was cooled
down, quenched with saturated NaHCO3 (10 mL), followed by
extraction with ethyl acetate (3 x 5 mL) and washed with brine,
dried over Na2SO4, filtered and then concentrated in vacuum.
The residue was then purified by column chromatography on
silica gel (PE/EA, ~300 mL) to afford the desired product 3.
Scheme 2 Gram-scale reaction.
Conclusions
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D’hooghe, N. D. Kimpe, Chem. Rev., 2011, 111, 3268; (f) Z. L.
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In summary, we have described a low-cost, simple and efficient
approach for the construction of β-haloketones containing a α-
quaternary carbon center via the halogenation/semipinacol
rearrangement of allyl alcohols with NaX (X= Cl, Br, I) in H2O under
open to air without any catalyst or additive. The process afforded
the desired β-haloketones in moderate to excellent yields with
several advantages including: (1) catalyst- and additive-free; (2)
aqueous medium; (3) low cost; (4) open to air. In addition, the
synthetic utility of the method could be demonstrated by the gram-
scale reaction and multifarious transformations of the product.
.
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We are grateful for financial support from the NSFC
(21572278, 21502079), the Program for Chang-Jiang Scholars
and Innovative Research Team in University (IRT_15R27), the
Fundamental Research Funds for the Central Universities
(lzujbky-2017-k11), Guangdong Natural Science Funds for
Distinguished Young Scholars (2017A030306017), and the
Pearl River S&T Nova Program of Guangzhou (201710010160).
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