Metal-free one-pot α-benzoxylation of benzylic alcohols with acids or aldehydes

Article abstract of DOI:10.1016/j.tetlet.2017.12.030

A metal-free strategy has been developed for α-benzoxylation of benzylic alcohols with acids or aldehydes. The reaction proceeds via sequential oxidation and α-benzoxylation in one pot. Importantly, the reactions are performed in metal-free condition and utilize cheap aqueous TBHP as an oxidant, affording α-benzoxy ketones in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2017.12.030

Accepted Manuscript
Metal-free one-pot α-benzoxylation of benzylic alcohols with acids or aldehydes
Yefu Zhu, Yong Zheng, Weibin Song, Bole Wei, Lijiang Xuan
PII:
S0040-4039(17)31523-X
https://doi.org/10.1016/j.tetlet.2017.12.030
TETL 49532
DOI:
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
28 September 2017
4 December 2017
8 December 2017
Please cite this article as: Zhu, Y., Zheng, Y., Song, W., Wei, B., Xuan, L., Metal-free one-pot α-benzoxylation of
benzylic alcohols with acids or aldehydes, Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.
2017.12.030
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Metal-free one-pot α-benzoxylation of benzylic alcohols with acids or aldehydes
Yefu Zhu, Yong Zheng, Weibin Song, Bole Wei and Lijiang Xuan*
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy
of Sciences, 501 Haike Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
*Corresponding Author. Tel/fax: +86 21 20231968.
E-mail address: ljxuan@simm.ac.cn.
Abstract:
A metal-free strategy has been developed for α-benzoxylation of benzylic alcohols with acids or
aldehydes. The reaction proceeds via sequential oxidation and α-benzoxylation in one pot.
Importantly, the reactions are performed in metal-free condition and utilize cheap aqueous TBHP
as an oxidant, affording α-benzoxy ketones in moderate to good yields.
Key words: nBu4NI, TBHP, α-benzoxy ketones, cross-dehydrogenative coupling
1

α-Benzoxyketones are widely represented among natural products (1-3),1a-1c and pharmaceutically
active molecules such as PI3Kαinhibitor (4),1d and TNF trimerization inhibitor (5) (Figure 1).1e As
a result, the search for efficient protocols for the synthesis of α-benzoxyketones has become
necessary.
Conventionally, the strategies toward α-benzoxy ketones, including the substitution of α-halo
carbonyl compounds,2 insertion reaction of α-diazoketones with alkaline carboxylates,3 and the
direct oxidative coupling of ketones with toxic heavy metal oxidants,4 suffer from drawbacks such
as harsh reaction conditions, low chemoselectivity and handling of toxic reagents. Consequently,
the development of novel and convenient protocols for α-benzoxy ketones from readily accessible
starting material under catalytic, metal-free, and chemoselective conditions is highly desirable.
In recent years, there has been great interest in the exploration and development of
−C, C−O, and C−N bonds 5,6
cross-dehydrogenative coupling (CDC) methods for C
.
Notably, the
combination of iodine catalysts and tert-butyl hydroperoxide (TBHP) as water-soluble co-oxidants,
has been increasingly explored due to the environmentally benign and inexpensive oxidation
reagents in place of expensive or toxic heavy metal oxidants.7
In 2011, Ishihara realized (hypo) iodite-catalyzed α-benzoxylation of carbonyl compounds with
carboxylic acids.8 Later, Cheng, Wang and Pan achieved nBu4NI-catalyzed α-benzoxylation of
ketones with alcohols, aldehydes, and terminal aryl alkenes, respectively.9-11 In 2016, Xu obtained
α-acyloxycarbonyl compounds from acetone and aromatic carboxylic acids using KI as a
catalyst.12 Most recently, Chen group also used CuCl2 as a catalyst to achieve α-acyloxylation
reaction with another cheap substrate N,N-dialkylamides and aromatic carboxylic acids.13 Despite
the significant advances made from traditional approaches, most of them utilized the ketones as a
precursor and some of the substrates are limited, which involved multi-steps synthesis or getting
limited kinds of products.
In continuation of our research on CDC reactions, we herein report an nBu4NI-catalyzed
benzoxylation of benzylic alcohols with readily available benzoic acids and benzaldehydes via
sequential oxidation and α-benzoxylation in one pot.14 Benzylic secondary alcohols are easily
prepared from the Grignard reaction of aryl bromides with aldehydes. The reactions are performed
in metal-free condition and use cheap aqueous TBHP as an oxidant, affording α-benzoxy ketones
in moderate to good yields.
2

Figure 1. Natural products and bioactive compounds containing α-benzoxy ketones motifs
Table 1. Optimization of reaction conditions.a, b
Entry
1
Catalyst
nBu4NI
nBu4NI
nBu4NI
nBu4NI
nBu4NI
nBu4NI
I2
Oxidant
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DTBP
O2
Solvent
MeCN
H2O
Yield (%)b
42
11
35
54
27
72
12
15
5
2
3
PhCl
4
DMSO
DCE
5
6
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
7
8
KI
9
NIS
10
11
12
13
14
15
16
17
NBS
0
trace
0
nBu4NI
nBu4NI
nBu4NI
nBu4NI
nBu4NI
none
H2O2
trace
0
mCPBA
K2S2O8
TBHP
none
0
0
0
nBu4NI
aConditions: 1aa (0.5 mmol), 2aa (1 mmol), catalyst (10 mol %), oxidant (5 equiv), solvent (2 ml),
100 °C, 12 h.
bIsolated yield.
TBHP = tert-butyl hydroperoxide. 70% water solution.
DTBP = di-t-butyl peroxide
3

The initial reaction was carried out by treating 1-phenylpropan-1-ol 1aa with benzoic acid 2aa in
the presence of 10 mol % nBu4NI and 5 equiv of TBHP in MeCN at 100°C for 12h (Table 1, entry
1). As expected, the desired product 3aa was obtained in 42 % yield. The screening of solvents
showed EtOAc was the best solvent (entry 6). Other solvents, such as H2O, PhCl, DMSO, and
DCE, proved to be less efficient than EtOAc (entries 2-5). The other iodine source catalysts, such
as I2, KI, NIS, failed to give any improvement (entries 7-9). Aside nBu4NI other halogen specie
such as NBS was completely unproductive (entry 10). TBHP as an oxidant was found to be
superior over the other oxidants screened, such as DTBP, O2, H2O2, mCPBA, and K2S2O8 (entries
11-14). Furthermore, the reaction did not proceed without the use of nBu4NI or TBHP (entries 16
and 17).
Table 2. α-Benzoxylation of benzylic alcohols with acids.a,b
4

aConditions: 1a (0.5 mmol), 2a (1 mmol), nBu4NI (10 mol %), aq. TBHP (5 equiv), EtOAc (2 ml),
100 °C, 12 h.
bIsolated yield.
cDMSO as solvent.
With the optimal conditions in hand, a number of benzoic acids were employed as
α-benzoxylation regents to react with 1-phenylpropan-1-ol (1aa) to afford α-benzoxylation
products, and the results are shown in Table 2. In general, the benzoic acids with ortho, para, and
meta electron-donating groups (Me, OMe, and t-Bu) (3ab, 3ac, 3ad, 3ah, 3ai, 3ak, and 3al)
produced the desired products in relatively higher yields than electron-withdrawing groups (Cl, Br,
F) substituted benzoic acids (3ae, 3af, 3am, 3an, and 3ao). Meanwhile, benzoic acids having
ortho-substituted groups afforded slightly poorer yields of the corresponding products possibly
due to their steric hindrance (3ak-3ap). The strong electron-withdrawing group (NO2) substituted
benzoic acid gave the products in lower yields (3ag, 3aj and 3ap). Next, the substituted
1-phenylpropan-1-ol was tested for this conversion. 1-Phenylpropan-1-ol with both electron-rich
(OMe and Me) and electron-deficient (F, Cl, Br) groups proceeded smoothly and afforded the
corresponding products in moderate to good yields (3ba-3bf). Besides 1-phenylpropan-1-ol, other
benzylic alcohols coupled with benzoic acid smoothly under the optimized conditions, giving the
desired products in moderate yields (3bg-3bi). Notably, NHPI could also be employed as a good
coupling partner for the reaction (3bj). What’s more, aliphatic acids could also be applied as good
substrates to get products in moderate yields (3bk, 3bl).
Considering wide application of aldehydes as aroyl surrogates in CDC reactions, we next tried
benzoxylation by treating 1-phenylpropan-1-ol 1aa with benzaldehyde. To our delight, using H2O
as solvent, the reaction proceeded smoothly between 1-phenyl-1-propanol (4a) and benzaldehyde
(5), giving the product (3aa) in 67% yield. A series of substituted benzaldehydes were examined
for this reaction (Table 3). Benzaldehydes bearing electron-rich (OMe, Me) and electron-deficient
groups (F, Cl, Br, and NO2) could react with 1-phenyl-1-propanol successfully generating the
corresponding products in moderate to good yields (Table 3). In addition, heteroaryl aldehyde,
such as 2-thiophenaldehyde, also underwent reaction to deliver the desired product in 66% yield
(3as). Significantly, besides 1-phenyl-1-propanol, 1-phenylpentan-1-ol (3bg) and 1-phenylethanol
(3bi) were also suitable for this transformation. Furthermore, aliphatic aldehydes were also
applied in this reaction to give the resultant products (3bm, 3bn) in appreciable amount.
Table 3. α-Benzoxylation of benzylic alcohols with aldehydes.a, b
5

aConditions: 1a (0.5 mmol), 4a (1 mmol), nBu4NI (10 mol %), aq. TBHP (5 equiv), H2O (2 ml),
100 °C, 12 h.
bIsolated yield.
To gain some insight into the mechanism of the reaction, the reactions were performed in the
presence of radical scavenger TEMPO (2 equiv), only trace of product 3aa was formed,
suggesting a possible radical pathway. When the reaction occured between perester (7) and
propiophenone (1a) in absence of TBHP, 3aa was obtained in 67% yield.
On the basis of our experimental observation and precedent reports, we have devised the
mechanistic pathway as depicted in Scheme 1. Initially, TBHP decomposes to generate t-butyl
peroxy radical with the assistant of iodine anion. Under nBu4NI and TBHP, benzaldehyde
generates acyl radical (I).15 Next, acyl radical forms t-butyl perester (II) under TBHP. Meanwhile,
acyl radical (I) gives benzoic acid cation (III) under TBHP and OH-. Next, t-butyl peroxy radical
abstracted α-H of the ketone to give α-carbonyl radical (IV). Then, the reaction between
theα-carbonyl radical (IV) and the t-butyl perester (II) gives the α-benzoxylation product3aa.
Alternatively, the α-carbonyl radical (IV) is oxidized to form a cation intermediate (V).16 Finally,
the reaction between cation intermediate (V) and carboxylic acid anion (III) affords the final
product 3aa.17
6

O
OH
n
Bu4NI
COOH
aq. TBHP
O
+
+
TEMPO
EtOAc
O
2aa
5aa
1aa
3aa
trace
O
OH
n
Bu4NI
CHO
aq. TBHP
O
TEMPO
H2O
O
1aa
3aa
trace
O
O
OH
t
OO -Bu
n
Bu4NI
+
O
EtOAc
O
67%
7
1aa
3aa
I-
TBHPH2
+
OH-
t
+
1/2 I2
+
-BuO
Ph-CHO
n
Bu4NI
TBHP
O
O
TBHP
OH-
TBHP
t
Ph COO-
Ph
OO -Bu
Ph
II
I
III
OH
O
TBHP
Ph
Ph
1a
TBHP
O
I-
Ph
IV
O
1/2 I2
Ph
+
V
O
O
O
+
Ph
Ph
t
OO -Bu
Ph
IV
Ph
II
Ph
O
O
Ph-COO-
O
+
+
3aa
V
III
Scheme 1. Proposed possible mechanism
In summary, we have demonstrated an nBu4NI-catalyzed α-benzoxylation of benzylic alcohols
with acids or aldehydes via sequential oxidation and α-benzoxylation in one pot, which avoids
multi-step synthesis and features water as solvent. Both reactions utilize environmentally benign
aqueous THBP as oxidant, show excellent functional group tolerance, and provide a convenient
access toward various types of α-benzoxy ketones.
Acknowledgements
We are grateful to the National Science & Technology Major Project “Key New Drug Creation
7

and Manufacturing Program” (NO.SIMM1601ZZ-03).
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Highlights
•
•
•
•
•
We synthesized α-benzoxylation of benzylic alcohols with acids or aldehydes.
The reaction proceeded via sequential oxidation and α-benzoxylation in one pot.
The reactions were performed in metal-free condition in moderate to good yields.
We utilized cheap aqueous TBHP as an oxidant.
Both aromatic acids or aldehydes and aliphatic acids or aldehydes can be applied in the
reaction.
.
9