The Bu4NI-catalyzed alfa-acyloxylation of ketones with benzylic alcohols

Article abstract of DOI:10.1039/c4cc01652a

The Bu₄NI-catalyzed reaction of ketones with benzylic alcohols was achieved, leading to alfa-acyloxycarbonyl compounds in moderate to good yields. This metal-free procedure featured the employment of facilely and commercially available starting materials and TBHP as a clean oxidant with high atom economy. This journal is the Partner Organisations 2014.

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The Bu4NI-catalyzed alfa-acyloxylation of ketones with benzylic alcohols
Songjin Guo,a Jin-Tao Yu,a Qiang Dai,a Haitao Yanga and Jiang Cheng*,a,b
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
acyloxylation product was obtained in 66% yield (Table 1, entry
50 2); while KI delivered the alfaꢀacyloxyketone in 12% yield
(Table 1, entry 3). CuI and FeCl2 were totally ineffective for this
transformation. Other oxidants, such as K2S2O8, diꢀtertꢀbutyl
peroxide (DTBP) and H2O2 resulted in no product (Table 1,
entries 6ꢀ8). The yield was further increased to 74 % (12 h) and
55 84 % (24 h) in PhCN, respectively (Table 1, entry 10). Using
MeCN, a 67% yield was obtained (Table 1, entry 11). However,
the reaction did not run in THF and DCE (Table 1, entries 9 and
12). No product was detected in the absence of either Bu4NI or
TBHP (Table 1, entries 13 and 14).
5
The Bu4NI-catalyzed reaction of ketones with benzylic
alcohols was achieved, leading to alfa-acyloxycarbonyl
compounds in moderate to good yields. This metal-free
procedure featured with the employing of facilely and
commercially available starting materials and TBHP as a
10 clean oxidant with high atom economy.
alfaꢀAcyloxylation of carbonyl compound is an important
transformation because the formed alfaꢀacyloxyketones are useful
building blocks1 and can facilely transform into alfaꢀhydroxy
ketones as structural subunit in a variety of biologically active
15 natural products.2 Traditionally, this molecular is prepared by the
reaction between the derivatives of ketones and carboxylic acids
to avoid the using of heavy metal oxidants.3 For example, alfaꢀ
acyloxylation was achieved by the reaction of alfaꢀhalocarbonyl
compounds with carboxylates.4 In 1998, Ohfune reported the
20 copperꢀcatalyzed insertion of alfaꢀdiazoketones into carboxylic
acids to give alfaꢀacyloxyketones.5 The chiral amineꢀcatalyzed
alfaꢀoxybenzoylation with benzoyl peroxide has also been
described.6 In 2005, Tomkinson developed a general protocol for
the alfaꢀacyloxylation of carbonyl compound by NꢀmethylꢀOꢀ
25 benzoylhydroxylamine.7 However, among all the aforementioned
transformations, further functionalization in either the ketones or
carboxylic acids motifs is required to fulfill the alfaꢀacyloxylation,
which is time consumed and decreases the atom economy. On the
contrary, the rutheniumꢀcatalyzed addition of carboxylic acids to
30 propargyl alcohols was an atom economical pathway leading to
alfaꢀacyloxyketones.8 An elegant example on the (hypo)ioditeꢀ
catalyzed direct alfaꢀoxyacylation of carbonyl compounds with
carboxylic acids was demonstrated by Ishihara.9 Miyamoto
reported the iodobenzeneꢀcatalyzed alfaꢀacetoxylation of ketones
35 via in situ generation of hypervalent (diacyloxyiodo)benzenes
using mꢀchloroperbenzoic acid.10 From the functional group
transformation point of view, the development of such a reaction
using surrogate of carboxylic acids is necessary.
60 Table 1. Selected results of screening the optimal conditions.
O
OH
O
Ph
+
Ph
O
Ph
1a
Ph
O
2a
3aa
Entry
1
2
3
4
5
6
7
Catalyst
I2
Bu4NI
KI
Oxidant
TBHP
TBHP
TBHP
TBHP
TBHP
K2S2O8
DTBP
H2O2
TBHP
TBHP
TBHP
TBHP
TBHP
ꢀꢀ
Solvent
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
THF
PhCN
MeCN
DCE
PhCN
PhCN
Yield(%)a
<1
66(71)b
12
CuI
<1
<1
<1
<5
<1
<1
FeCl2
Bu4NI
Bu4NI
Bu4NI
Bu4NI
Bu4NI
Bu4NI
Bu4NI
ꢀꢀ
8
9
10
11
12
13
14
74(84)b(73)b,c
67(75)b
<1
<1
<1
Bu4NI
a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst (0.2 equiv),
oxidant (6 equiv), air, 90 oC, 12 h, sealed tube, solvent (2 mL). b 24 h. c 70
oC.
65
After the establishment of the optimal reaction condition, the
scope of benzylic alcohols was studied, as shown in Figure 1. As
expected, all substrates ran smoothly under the standard
procedure. The reaction were tolerant to the electronic nature of
70 the benzylic alcohols as both electronꢀwithdrawing and donating
substituted substrates worked well to deliver the alfaꢀ
acyloxylation products in good to excellent yields. Chloro and
bromo groups survived well under this procedure, which was
suitable for potentially further functionalization (3ca and 3da).
75 Moreover, the steric hindrance had little effect on this
transformation, as evidenced by the high yields of 3ha and 3ia.
Importantly, the heteroꢀaryl methanols were also good reaction
Recently, the combination of Bu4NI and tertꢀbutyl
40 hydroperoxide (TBHP) has been well documented in the CꢀO11
and CꢀN12 bond formation reaction. Herein, we report the
employment of TBHP in TBAIꢀcatalyzed alfaꢀoxyacylation of
ketones by benzylic alcohols leading to alfaꢀacyloxyketones.
We started our study by using the model reaction shown in
45 Table 1: benzylic alcohol (0.2 mmol), propiophenone (0.4 mmol),
I2 (0.2 equiv) and TBHP (70% aqueous, 6 equiv) in EtOAc (2
mL). However, no reaction took place after heating the mixture at
o
90 C for 12 h. To our delight, replacing I2 with Bu4NI, the alfaꢀ
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partners in this transformation. For example, pyridinꢀ2ꢀ 35 Secondly, heating the combination of 2ꢀiodoꢀ1ꢀphenylpropanꢀ1ꢀ
ylmethanol provided 3ja in 55% yield. Notably, the scope of
alcohol was not limited to benzylic alcohols since the aliphatic
primary alcohols also worked to some extent under the standard
procedure. For example, isobutyl alcohol provided the desired
one with benzylic alcohol produced the alfaꢀoxybenzoylation
product in 12% yield under the standard reaction (Scheme 1, eq
2). In addition, ketones are prone to take place the oxidative alfaꢀ
hydroxylation in the presence of hypervalent iodine.13 However,
5
product 3ka in 48% yield and 51% yield of 3la was obtained for 40 under the standard procedure, no reaction took place between
(E)ꢀcinnamicalcohol.
benzylic alcohol and 2ꢀhydroxyꢀ1ꢀphenylpropanꢀ1ꢀone (Scheme
1, eq 2). These results ruled out the possibility of 2ꢀhydroxyꢀ1ꢀ
phenylpropanꢀ1ꢀone and 2ꢀiodoꢀ1ꢀphenylpropanꢀ1ꢀone as the
intermediates for this transformation. Thirdly, as shown in Table
45 1, the replacement of TBAI with I2 inhibited the reaction.
Moreover, the reaction of carboxylic acid with 2ꢀiodoꢀ1ꢀ
phenylpropanꢀ1ꢀone resulted in 44% yield (Scheme 1, eq 3). Thus,
Figure 1. Scope of benzylic alcohola
O
Bu4NI (20 mol %), tBuOOH (6 equiv)
OH
O
+
Ph
PhCN, 90 o
C
R
O
R
Ph
3
1
2a
O
O
R = 4-Cl, 3ca, 77%
R = 4- Br, 3da, 71%
R = 4-F, 3ea, 81%
a
mechanism like MacMillan’s procedure involving the
O
Ph
Ph
Ph
sequential alfaꢀhalogenation of ketone and SN2 reactions of the
50 formed alfaꢀiodo ketone attacked by carboxylic anion is ruled
out.14 Finally, both benzoic acid and tertꢀbutyl perester was
detected in the absence of ketone under the standard procedure.
The reaction of benzoic acid with ketone under the standard
procedure provided the product in 92% yield (Scheme 1, eq 3).
55 Even in the absence of TBHP, tertꢀbutyl perester reacted with
O
O
R
R = 4- NO2, 3fa, 65%
R = 4- OCOPh, 3ga, 61%
R = 2-Me, 3ha, 68%
O
O
R = H, 3aa, 84%
R = 4-MeO, 3ba, 80%b
3ia, 88%
O
O
O
Ph
Ph
Ph
O
O
i-Pr
O
O
N
O
O
3ja, 55%
3ka, 48%c
3la, 51%d
10
ketone to produce the alfaꢀoxybenzoylation product in
comparable 74% yield (Scheme 1, eq 4).
a
a
Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), Bu4NI (0.2 equiv),
o
b
TBHP (70% aqueous, 6 equiv), PhCN (2 mL), air, 90 C, 24 h. 2a (0.6
mmol), 36 h. c DMSO (1 mL), 48 h. d DMSO (1 mL).
Scheme 1. Preliminary mechanism study
15
Next, the substrates scope and limitation of ketones were
studied, as shown in Figure 2. 1ꢀPhenylbutanꢀ1ꢀone ran smoothly
under the standard procedure, providing the alfaꢀacyloxylation
product 3ac in 72% yield. 1ꢀ(Thiophenꢀ2ꢀyl)propanꢀ1ꢀone
provided the desired product 3ad in 67% yield. Notably, aliphatic
20 ketones was also suitable partnerfor this transformation. For
example, cyclohexanone provided the product 3ae in 34% yield.
Figure 2. Scope of ketonea
60
Based on these experimental results, two proposed
mechanisms are illustrated in Scheme 2. Firstly, the oxidation of
TBAI by TBHP produces [Bu4N]+[IOn]ꢀ (n = 1 or 2).15 Then, the
65 alfaꢀH of ketone was abstracted by [Bu4N]+[IO]nꢀ to produce the
alfaꢀcarbonyl radical 4.16 Meanwhile, in the presence of TBHP,
benzylic alcohol is oxidized to benzoyl radical,17a,17b which
subsequently converts to the tertꢀbutyl perester.17c Then the
reaction between the alfaꢀcarbonyl radical 4 and the tertꢀbutyl
70 perester delivers the final alfaꢀacyloxylation product (Path B,
Scheme 2). This step was confirmed by eq 4 in Scheme 1.
Alternatively, similar with Yu’s and Zhu’s procedures, the
formed radical is believed to be oxidized by [Bu4N]+[IOn]ꢀ (n = 1
or 2) to form a cation intermediate 5.11c,12f In this case, although
75 the formed cation possessing a positive charge next to a carbonyl
seems not stable, some examples involving such an alfaꢀcarbonyl
cation species were well documented.18 Finally, the reaction
between the cation intermediate 5 and carboxylic anion19
produces the target molecular (Path A, Scheme 2). At the current
80 stage, none of the two possible pathways can be thoroughly ruled
out.
a
Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), Bu4NI (0.2 equiv),
25 TBHP (70% aqueous, 6 equiv), PhCN (2 mL), air, 90 oC. Ketone (5
equiv), 48 h.
b
To improve the practicability of this reaction, a 10 mmol scale
reaction was conducted and 3aa was isolated in a comparable
30 85% yield.
More experiments were conducted to gain some insights into
this reaction. Firstly, adding 50 mol% of TEMPO decreased the
yield of the model process (table 1) to 63%, indicating a radical
pathway may be involved in this transformation (Scheme 1, eq 1).
2
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In conclusion, we have developed a TBAIꢀcatalyzed alfaꢀ
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Scheme 2. Proposed mechanism
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We thank the National Natural Science Foundation of China
(no. 21272028, 21202013), “Innovation & Entrepreneurship
Talents” Introduction Plan of Jiangsu Province, the Natural
Science Foundation of Zhejiang Province (no. R4110294),
80
15 Jiangsu Key Laboratory of Advanced Catalytic Materials &
Technology and State Key Laboratory of Coordination
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School of Petrochemical Engineering, Jiangsu Key Laboratory of
90
20
Advanced Catalytic Materials and Technology, Changzhou University,
Changzhou 213164, P. R. China; E-mail: jiangcheng@cczu.edu.cn
b
State Key Laboratory of Coordination Chemistry, Nanjing University,
Nanjing 210093, P. R. China
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† Electronic Supplementary Information (ESI) available: See
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