NBS/DBU mediated one-pot synthesis of α-acyloxyketones from benzylic secondary alcohols and carboxylic acids

Article abstract of DOI:10.1039/c6ob02173e

A simple and efficient one-pot NBS/DBU-mediated method has been developed for the synthesis of α-acyloxyketones from various benzylic secondary alcohols and carboxylic acids. Through this methodology, a series of α-acyloxyketones could be obtained in good to excellent yields under mild conditions. Importantly, this new reaction avoids the direct usage of toxic metal catalysts or potentially dangerous peroxide oxidants.

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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DOI: 10.1039/C6OB02173E
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NBS/DBU mediated one-pot synthesis of α-acyloxyketones from benzylic
secondary alcohols and carboxylic acids†
Minghui Zhu, Wei Wei*, Daoshan Yang, Hong Cui, Huanhuan Cui, Xuejun Sun, Hua Wang*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5 DOI: 10.1039/b000000x
A simple and efficient one-pot NBS/DBU-mediated method
has been developed for the synthesis of α-acyloxyketones from
various benzylic secondary alcohols and carboxylic acids.
Through this methodology, a series of α-acyloxyketones could
10 be obtained in good to excellent yields under mild conditions.
Importantly, this new reaction avoids the direct usage of toxic
metal catalysts or potentially dangerous peroxide oxidants.
α-Acyloxy carbonyl compounds represent the basic building
blocks in synthetic organic chemistry, which are the important
15 structural motifs existing widely in
a large number of
pharmaceuticals and biologically active compounds.1 The
installation of acyloxy substituents at the carbonyl α-position is a
longstanding goal in organic synthesis and a number of methods
have been thereby developed. Traditionally, α-acyloxy carbonyl
20 compounds can be prepared by the substitution of α-halo
carbonyl compounds2/ insertion of α-diazoketones3 with alkaline
carboxylates and the coupling reaction of ketones with toxic
heavy metal oxidants such as Pb(OAc)4, Mn(OAc)3, and
Tl(OAc)3.4 Recently, hypervalent iodine compounds as effective
25 oxidants to promote acyloxylation reaction have been reported.5-8
For example, the direct oxidative coupling of ketones with
carboxylic acids using a hypervalent iodine catalyst in the
presence of an excess amount of m-CPBA5 or peracetic acid6 as a
co-oxidant, and TBAI-catalyzed the intra- and intermolecular
30 oxidative couplings of carbonyl compounds with carboxylic
acids7/benzylic alcohols8/ toluene derivatives9 using H2O2 or
TBHP as a co-oxidant were presented (eqns (1-3)). Alternative
50 dangerous peroxide oxidants, toxic metal catalysts, or low yields.
Therefore, the development of mild, efficient, metal- and
peroxide-free methods to access α-acyloxy carbonyl compounds
is still highly desirable in synthetic and pharmaceutical chemistry.
As part of our continuous interest in the metal-free synthetic
55 transformations,16 herein, we report a simple NBS/DBU-mediated
one-pot protocol for the synthesis of α-acyloxyketones via α-
acyloxylation reaction of benzylic secondary alcohols with
various carboxylic acids (eqn (7)). The present method provides a
methods
including
the
using
N-methyl-O-
benzoylhydroxylamine,10 benzoyl peroxide11 aldehydes,12 and
35 alkenes13 (eqn (4)) as a carboxylic acid source, iodine-catalyzed
oxo-acyloxylation of alkenes (eqn (5)),14 and pybox–Cu(II)
complex catalyzed synthesis of α-acyloxy carbonyl compounds
from ketones (eqn (6))15 have also been developed. However,
most of these well-established protocols may suffer from some
40 certain disadvantages such as use of a large excess of ketone
motifs, harsh reaction conditions, an excess amount of potentially
simple and highly efficient approach to
a variety of α-
60 acyloxyketones in good to excellent yields under the metal and
peroxide-free conditions.
a
The Key Laboratory of Life-Organic Analysis and Key Laboratory of
Initially, the 1-phenylpropan-1-ol 1a and benzoic acid 2a
were used as model substrates to determine the optimized
reaction conditions (Table 1). Various organic and inorganic
65 bases were firstly investigated when the model reactions were
Pharmaceutical Intermediates and Analysis of Natural Medicine, School
of Chemistry and Chemical Engineering, Qufu Normal University, Qufu
45 273165,
Shandong,
huawang_qfnu@126.com
China.
E-mail:
weiweiqfnu@163.com;
† Electronic Supplementary Information (ESI) available: Experimental
details. See DOI: 10.1039/b000000x/
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Table 1 Optimization of the reaction conditionsa
Table 2 Results for NBS/DBU mediated synthesis of α-acyloxyketones
from various benzylic secondary alcohols and carboxylic acidsab,
Entry
1
2
3
4
5
6
7
8
Base
Solvent
THF
THF
THF
THF
THF
THF
DME
1,4-dioxane
DCE
DMF
CH3CN
H2O
Toluene
EtOH
DMSO
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
Yield (%)b
K2CO3
Na2CO3
NaOH
Et3N
0
0
0
32
74
93
50
99
76
71
18
19
0
DABCO
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
--
9
10
11
12
13
14
15
16
17
18
19
0
0
0c
93d
0
DBU
0e
a
Reaction conditions: 1) 1a (0.25 mmol), 2a (0.375 mmol), NBS (0.5
5 mDioalz),ab1ihc;yc2l)oB[5a.s4e.0(]0u.n5dmecm-7o-le)n,es;oDlvMenEt :(21,m2-LD)i,m6e0t°hCo,xyaeirt,h2anhe., DDBCUE:: 11,,28--
b
f
Dichloroethane; Isolated yields based on 1a. c 25oC. d 80oC. without of
NBS.
performed in the presence of NBS at 60oC for 1h. Among a range
of bases examined, organic base DBU (1,8-diazabicycloundec-7-
10 ene) was found to be the best one to promote this transformation,
while inorganic bases such as K2CO3, Na2CO3 and NaOH did not
lead to the formation of the desired product 3aa (Table 1, entries
1-6). Further optimization of solvents suggested that 1,4-dioxane
was the best reaction medium (Table 1, entry 8). In contrast,
15 when the reaction was performed in CH3CN or H2O, the desired
product 3aa was isolated in low yield (Table 1, entries 11 and 12).
The reaction did not occur in toluene, EtOH, or DMSO (Table 1,
entries 13-15). Moreover, no conversion was observed when the
reaction was performed at room temperature (Table 1, entry 16).
20 The optimized reaction temperature is 60oC, and a higher
temperature (80oC) led to the slightly lower yield (93%) (Table 1,
entries 8 and 17). Additionally, no product was detected when the
reaction was conducted in the absence of DBU or NBS (Table 1,
entries 18 and 19).
25 With the optimized conditions in hand, we next explored the
scope and generality of this reaction using various alcohols and
carboxylic acids. As shown in Table 2, in general, benzylic
secondary alcohol derivatives with both electron-donating and
electron-withdrawing substituents on the aromatic ring could be
30 successfully transformed into the desired products in moderate to
excellent yields (3aa-3ha). Furthermore, long chain alkyl
substituted benzylic secondary alcohols did not hinder the
reaction, affording the corresponding products in good yields (3ia
and 3ja). Moreover, 1-(naphthalen-1-yl)ethanol and cyclic
35 secondary alcohol such as 1,2,3,4-tetrahydronaphthalen-1-ol and
2,3-dihydro-1H-inden-1-ol were also discovered to be suitable
40
a
Reaction conditions: 1) 1 (0.25 mmol), 2 (0.375 mmol), NBS (0.5
b
mmol), 1,4-dioxane (2 mL), 60°C, air, 1h; 2) DBU (0.5 mmol), 2 h.
Isolated yields based on 1. c 2) DBU (0.5 mmol), 4h.
substrates, which delivered the desired products in 70%-92%
45 yields (3ka-3ma). The scope of the present transformation was
further expanded to a variety of carboxylic acids. In addition to
2
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benzoic acid 2a, a series of substituted benzoic acids containing
either electron-rich or electron-deficient groups were all
compatible with this process to give the corresponding products
in excellent yields (3ab-3an). Notably, various functional
5 substituents including halogen, methoxyl, and nitro group could
be tolerated in this procedure, thus providing the chances for
further modification of these products. As expected, alkyl acids
such as 3-phenylpropanoic acid 2o, propionic acid 2p, acetic acid
2q, but-2-ynoic acid 2r, and but-2-enoic acid 2s were also
10 suitable for this reaction, and the desired products (3ao-3as) were
obtained in moderate to good yields.
To obtain some insights into this reaction, several control
experiments were carried out (eqns. (8-10)). Initially, when the α-
bromo ketone 6a with benzoic acid 2a was performed in the
15 presence of DBU, the desired product 3aa was isolated in 75%
yield (eqn 8). Furthermore, when the reaction of 1-phenylpropan-
1-ol 1a with N-bromosuccinimide (NBS) was performed in the
absence of acid and DBU, α-bromo ketone 6a was obtained in
87% yield (eqn 9 (a)). Nevertheless, when the reaction of alcohol
20 1a with Br2 was performed in 1,4-dioxane at 60oC, none of α-
bromo ketone 6a was detected (eqn 9 (b)). Moreover, the
reactions of propiophenone 5a with Br2 and NBS were also
investigated. As shown in eqn (10), when the reaction of
propiophenone with Br2 was performed in 1,4-dioxane at 60oC, α-
25 bromo ketone 6a was isolated in 74% yield (eqn 10 (a)), however,
the direct treatment of propiophenone 5a with NBS only gave a
trace amount of α-bromo ketone 6a (eqn 10 (b)). The above
On the basis of the above results and referring to previous
50 reports,18,19 a tentative reaction pathway was proposed in Scheme
1. Initially NBS may react with alcohol 1 to form hypobromite
intermediate 4, which will be further transformed to give ketone
along with the generation of HBr. Subsequently, the interaction
of NBS with HBr would lead to the formation of Br2.19 Next, α-
55 bromination of ketone 5 with Br2 gave the key intermediate α-
bromo ketone 6. Finally, the nucleophilic substitution of α-bromo
ketone 6 by acid 2 in the presence of base would produce the
desired product 3.
results indicated that α-bromo ketone should be
a key
intermediate, which was formed through sequential alcohol
30 oxidation and α-bromination of ketone in the present reaction
system. It should be noted that the desired product 3aa would be
obtained in 62% yield when the reaction of propiophenone 5a
with benzoic acid 2a was performed under the standard
conditions (eqn 11). The formation of product 3aa should be
35 caused by acid promoted the α-bromination of ketone with NBS
leading to α-bromo ketone 6a,17 which further reacted with
benzoic acid 2a to give the product 3aa in the presence of DBU.
In addition, when the reaction of 1-phenylpropan-1-ol 1a with N-
bromosuccinimide (NBS) was conducted in the absence of acid
40 and DBU under N2, α-bromo ketone 6a was still isolated in 78%
yield, suggesting that dioxygen is not key oxidant to promote the
formation of intermediate α-bromo ketone 6 (eqn 12).
60
Scheme 1. Tentative reaction pathway
In conclusion, a simple and efficient one-pot synthesis method
has been developed for the construction of α-acyloxyketones via
the NBS/DBU mediated α-acyloxylation reaction of benzylic
secondary alcohols and carboxylic acids under mild conditions.
65 Through this methodology, various α-acyloxyketones could be
conveniently and efficiently obtained in good to excellent yields
from readily-available starting materials. The present protocol
avoids the direct usage of toxic metal catalysts or potentially
dangerous peroxide oxidants, which is expected to expand the
70 potential applications of α-acyloxyketones in the pharmaceutical
and synthetic chemistry.
This work was supported by the National Natural Science
Foundation of China (No. 21302109, 21302110, 21375075, and
21675099), the Natural Science Foundation of Shandong
45
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DOI: 10.1039/C6OB02173E
A simple and efficient NBS/DBUꢀmediated oneꢀpot procedure has been developed for the
synthesis of αꢀacyloxyketones from benzylic secondary alcohols and carboxylic acids