Arylation of α-pivaloxyl ketones with arylboronic reagents via Ni-catalyzed sp3 C-O activation

Article abstract of DOI:10.1039/c1cc11193k

A Suzuki-Miyaura coupling of α-pivaloxyl ketones via Ni-catalyzed sp³ C-O activation to produce α-aryl ketones is developed. This study offers a convenient method to construct α-arylation products from readily available α-hydroxyl carbonyl compounds.

Full text of DOI:10.1039/c1cc11193k

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COMMUNICATION
Arylation of a-pivaloxyl ketones with arylboronic reagents via
Ni-catalyzed sp3 C–O activationw
Kun Huang,a Gang Li,b Wei-Ping Huang,a Da-Gang Yua and Zhang-Jie Shi*ac
Received 28th February 2011, Accepted 28th April 2011
DOI: 10.1039/c1cc11193k
A
Suzuki–Miyaura coupling of a-pivaloxyl ketones via
via sp3 C–O activation of carboxylates is still unknown. Here-
in, we demonstrate the first successful example of Suzuki–
Miyaura coupling of a-pivaloxyl ketones via Ni-catalyzed sp3
C–O activation.
Ni-catalyzed sp3 C–O activation to produce a-aryl ketones is
developed. This study offers a convenient method to construct
a-arylation products from readily available a-hydroxyl carbonyl
compounds.
To explore the possibility of the Suzuki–Miyaura coupling
via sp3 C–O activation, a-pivaloxyl acetophenone 1a was
selected as a model substrate for optimization due to its easy
preparation from commercially available 2-hydroxyaceto-
phenone (Table S1w). To our delight, when the pivalate 1a
and phenylboronic acid 2a were reacted in toluene in the
presence of Ni(PCy3)2Cl2 as a catalyst and NaOtBu as a base,
the desired cross-coupling product 4aa was obtained in a 24%
GC yield, accompanied by both the reduced and hydrolyzed
by-products (entry 1). Further investigation indicated that
KOtBu and NaH acting as bases (entries 2 and 4) showed
partial reactivity, while other inorganic and organic bases were
not beneficial for this transformation (entries 2–8). In fact, the
amount of base (NaOtBu) was also critical. Both increasing and
decreasing the amount of base dramatically diminished the
efficiency. Solvents also played an important role (entries 12–18).
Although moderate yields were obtained with toluene or
DMF as the solvent (entries 12 and 14), the intensive surveys
indicated that a mixture of toluene/DMF in a 1 : 1 ratio was
better and the desired product was obtained in 65% yield in
40 min (entry 17). The screening of various ratios of toluene
and DMF showed that the isolated yield increased to 81%
when a 2 : 1 ratio of toluene to DMF was employed as a mixed
solvent (entry 19). Further investigation implied that an
decrease in the amount of boronic acid led to a lower yield.
The reaction time was also vital for this transformation, and
either lengthening or shortening the time decreased the yield.
It is interesting to note that phenylboroxine 3a also displayed
good reactivity and the desired product was afforded in 71%
isolated yield (entry 22).
a-Aryl carbonyl compounds have an important structural
motif, which exist widely in pharmaceutical and natural
compounds with diverse biological activities.1 Its importance
has stimulated the development of practical synthetic routes to
build up such a structural unit.2 In the last several decades,
two excellent methods have been developed to synthesize
a-aryl carbonyl compounds.3 On one hand, Buchwald and
Hartwig independently developed the Pd-catalyzed a-arylation
of ketones, esters, and amides using aryl halides as the
electrophiles.4 On the other hand, Fu and other groups
achieved the same goal by using an alternative arylation
strategy, which employs a-halo carbonyl compounds as the
electrophiles and organometallic reagents as the nucleophiles.5
Meanwhile, Suzuki–Miyaura coupling has been well developed
and is now one of the most useful tools for constructing C–C
bonds in both the laboratory and industry due to the ready
availability, low toxicity and high functional group tolerance
of organoboronic reagents.6 Recently, tremendous progress
has also been made for cross-coupling reactions via transition
metal-catalyzed C–O activation.7 Among these investigations,
the cleavage of sp2 C–O bonds in aryl methyl ethers, aryl
pivalates and carbamates has been a main focus.8 In contrast,
research into sp3 C–O activation has slightly lagged behind. In
this regard, transition metal-catalyzed transformations of the
relatively active sp3 C–O bonds in allyl/benzyl ethers and
esters have been thoroughly studied.9 Kambe, Fu and Dong
have developed the coupling of alkyl tosylates and ethers,
respectively.10 To our knowledge, direct a-arylation of ketones
Under the optimized conditions, different leaving groups of
2-hydroxyacetophenone were examined. As shown in Table 1,
the acetate 1b was not a good substrate and only a trace amount
of product was observed with a large amount of hydrolyzed
by-product (entry 1). In comparison, the corresponding
carbonate (1c), carbamate (1d) and benzoate (1e) provided a
small amount of products together with the unreacted starting
materials during the same period (entries 2–4). The free
hydroxyl acetophenone did not give any product (entry 5).
Methyl ether and silyl ether also exhibited much lower reactivities
a Beijing National Laboratory of Molecular Sciences (BNLMS) and
Key Laboratory of Bioorganic Chemistry and Molecular Engineering
of Ministry of Education, College of Chemistry and Green Chemistry
Center, Peking University, Beijing 100871, China
b Department of Chemistry, Nanyang Normal University, NanYang,
Hunan, 473061, China
c State Key Laboratory of Applied Organic Chemistry, Lanzhou
University, Lanzhou 730000, China. E-mail: zshi@pku.edu.cnc;
Fax: +86-10-62751708; Tel: +86-10-62760890
w Electronic supplementary information (ESI) available: See DOI:
10.1039/c1cc11193k
c
7224 Chem. Commun., 2011, 47, 7224–7226
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Table 1 The cross-coupling reaction of different derivatives of
2-hydroxylacetophenonea
active sites for the further orthogonal transformations to produce
highly functionalized derivatives (entries 4, 5 and 8–12).
Next, we concentrated our attention on exploring different
aryl ketone derivatives (Table 3). Indeed, most of the pivalates
gave good to excellent yields. The electronic nature of the
aromatic substituents at the o-, m- or p- positions did not affect
the efficacy. As shown in Table 3, regardless of whether the
substrates were electron-rich or electron-deficient, all of them
showed good to high efficacy. Moreover, oxygen-containing
groups, such as BnO (4va), as well as MOMO (4wa) were
compatible with this arylation although some of them
showed great reactivities in previously developed cross-coupling
reactions.8 These groups offer a chance for further functional-
izations to construct C–C and C–X bonds.8 In addition, the
C–F bond was also compatible for further transformation
(4ta).11 Notably, an aliphatic ketone (4sa) was also a suitable
substrate and the desired product was obtained in a moderate
yield under the optimized conditions. A lower yield of 4xa was
obtained due to the hydrolysis of ethyl benzoate under the
reaction conditions. Since aryl pivalates are also suitable for
Suzuki–Miyaura cross-coupling,8c,e we tested the substrate 4ya
to differentiate between the reactivity of the aryl pivalate and
a-aliphatic pivalate. To our delight, the coupling occurred
chemoselectively at the a-position of the ketone, leaving the
aryl pivalate untouched. Thus, it is possible to carry out
sequential coupling reactions of different pivalate groups
in the same molecule under the same conditions. This observa-
tion also offered a method to program the cross-couplings
to construct complicated molecules from simple starting
materials.
Entry
R
GC yield (%)b
1
2
3
4
5
6
7
8
Ac (1b)
trace
11
26
8
n.p.
9
Boc (1c)
CONEt2 (1d)
COPh (1e)
H (1f)
TBS (1g)
CH3 (1h)
Ph (1i)
15
64c
a
All the reactions were carried out on the scale of 0.25 mmol of 1.
GC yield with the use of n-dodecane as an internal standard.
Isolated yield.
b
c
(entries 6 and 7). It should be noted that phenyl ether offered
the product in a 64% isolated yield (1i), while leaving the
phenyl etheral sp2 C–O untouched (entry 8).
Moreover, various boronic acids and arylboroxines were
surveyed (Table 2). Initially, different aryl boronic acids were
employed under the standard conditions, but only some of
them were efficient (entries 1–6). From the obtained results,
both their steric hindrance and electronic properties dramati-
cally affected the efficacy. Fortunately, further investigation
indicated that the corresponding arylboroxines of electron rich
and sterically hindered boronic acids showed promising reac-
tivities (entries 7–14), thus offering a valuable complementary
method. Notably, disubstituted boroxines were also suitable
substrates for this transformation (entries 11 and 13). It is of
great importance to note that various functional groups, for
example, MeO and F, survived well, providing the potential
Table 3 Cross-coupling of 1 with phenylboronic acid 2aa,b
Table 2 Cross-coupling of different arylboronic acids derivatives
with 1aa
Entry
Ar (2 or 3)
5 (%)b
1
2
3
4
5
6
7
8
Ph (2a)
4aa (81)
4ab (75)
4ac (67)
4ad (76)
4ae (68)
4af (71)
4ag (67)
4ah (55)
4ai (61)
4aj (64)
4ak (68)
4al (61)
4am (74)
4an (66)
p-MeC6H4 (2b)
m-MeC6H4 (2c)
p-FC6H4 (2d)
m-FC6H4 (2e)
p-ButC6H4 (2f)
p-PhC6H4 (3g)
o-MeC6H4 (3h)
p-MeOC6H4 (3i)
m-MeOC6H4 (3j)
3-Me-4-F-C6H3 (3k)
o-FC6H4 (3l)
9
10
11
12
13
14
3,5-DiMe-C6H3 (3m)
1-naphthyl (3n)
a
All the reactions were carried out on the scale of 0.25 mmol of 1a.
A 40 min reaction time was required for boronic acids and 60 min for
a
All the reactions were carried out on the scale of 0.25 mmol of 1.
Isolated yield.
b
boroxines. Isolated yield.
b
c
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Notes and references
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Scheme 1 The catalytic cycle of the cross-coupling between pivalates
1 and aryl boronic reagents 2 or 3 via Ni catalysis.
The proposed catalytic cycle of this arylation is shown in
Scheme 1. Under the reaction conditions, the precatalyst Ni(II)
was reduced to Ni(0) in the presence of organoboronic
reagents and base. Pivalate 1 oxidatively added to the in situ
generated Ni(0) species to form the alkyl-Ni(II) intermediate 5,
which is in equilibrium with enolate 6. After the transmetalla-
tion with arylboronic reagents 2 or 3, probably through a
6-membered transition state 7 or 8, the aryl alkyl Ni(II) species
10 was generated. Although the equilibrium existed to form
the relatively stable Ni-enolate 11, the formation of the
thermodynamically more stable arylated product 4 was highly
preferred to complete the catalytic cycle with regeneration of
the Ni-catalyst.
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In conclusion, we have developed the first Suzuki–Miyaura
coupling of a-pivaloxyl ketones via nickel-catalyzed sp3 C–O
activation. This development offers a new strategy for the
construction of a-arylation products. The studies here exhibit
broad applicability for fundamental studies to understand new
reactivities of different carboxylates. Further investigations to
expand the substrate scope and apply such chemistry in
synthesis are underway.
Support of this work by NSFC (No. 20821062, 20832002,
20925207, 21072010) and the ‘‘973’’ Project from the MOST of
China (2009CB825300) is gratefully acknowledged.
c
7226 Chem. Commun., 2011, 47, 7224–7226
This journal is The Royal Society of Chemistry 2011