Hetero diacylation of 1,1-diborylalkanes: Practical synthesis of 1,3-diketones

Article abstract of DOI:10.1016/j.cclet.2019.12.016

An efficient protocol for the synthesis of asymmetric 1,3-diketones was reported through diacylation of 1,1-diborylalkanes using two different acyl sources. In this transformation, an enolate boron species was initially formed by introducing an acyl group

Full text of DOI:10.1016/j.cclet.2019.12.016

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Hetero diacylation of 1,1-diborylalkanes: Practical synthesis of
1,3-diketones
Liang-Hua Zou, Min Fan, Lu Wang, Chao Liu
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S1001-8417(19)30730-2
https://doi.org/10.1016/j.cclet.2019.12.016
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Chinese Chemical Letters
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Please cite this article as: Zou L-Hua, Fan M, Wang L, Liu C, Hetero diacylation of
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Hetero diacylation of 1,1-diborylalkanes: Practical synthesis of 1,3-diketones
Liang-Hua Zoua,*, Min Fana, Lu Wangb,*, Chao Liub,*
a Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Pharmaceutical Sciences, Jiangnan University, Wuxi
214122, China
b State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute of LICP, Lanzhou Institute of Chemical Physics (LICP),
Chinese Academy of Sciences, Lanzhou 730000, China

Chinese Chemical Letters
journal homepage: www.elsevier.com
Communication
Hetero diacylation of 1,1-diborylalkanes: Practical synthesis of 1,3-diketones
Liang-Hua Zou a,* zoulianghua@jiangnan.edu.cn, Min Fana,b, Lu Wangb,* wanglu@licp.cas.cn
, Chao Liub, chaoliu@licp.cas.cn
a Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122,
China
b State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute of LICP, Lanzhou Institute of Chemical Physics (LICP), Chinese
Academy of Sciences, Lanzhou 730000, China
 Corresponding author:
E-mail address:
 Corresponding author:
E-mail address:
 Corresponding author:
E-mail address:
Graphical Abstract
An efficient protocol for the synthesis of asymmetric 1,3-diketones was reported through diacylation of 1,1-diborylalkanes using
two different acyl sources. In this transformation, an enolate boron species was initially formed by introducing an acyl group,
then it was trapped by another acyl group to form 1,3-diketone. This method not only provided the gateway to obtain a series of
1,3-diketones, but also afforded an operationally simple and efficient access to pyrazoles and isoxazoles
ABSTRACT
An efficient protocol for the synthesis of asymmetric 1,3-diketones was reported through diacylation of 1,1-
diborylalkanes using two different acyl sources. In this transformation, an enolate boron species was
initially formed by introducing an acyl group, then it was trapped by another acyl group to form 1,3-
———
 Corresponding authors.
E-mail addresses: zoulianghua@jiangnan.edu.cn (L. Zou),wanglu@licp.cas.cn (L. Wang), chaoliu@licp.cas.cn (C. Liu)

2
diketone. This method not only provided the gateway to obtain a series of 1,3-diketones, but also afforded
an operationally simple and efficient access to pyrazoles and isoxazoles.
Keywords:1,1-Diborylalkanes,Diacylation,Enolate boron species,Boron-stabilized carbanion intermediates,1,3-Diketones
Pyrazoles
Article history:
Received
Received in revised form
Accepted
Available online
Many natural products containing 1,3-diketone moiety exhibit broad biological activities, such as antimicrobial, antiviral, and
antifungal activities [1]. They can also act as bidentate ligands in metal catalysis and luminescent materials [2, 3]. Besides, 1,3-
diketones are widely used as versatile synthons for the construction of various heterocycles [1, 4-6] or C–C bond formation [7-15].
Therefore, considerable efforts have recently been devoted to the synthesis of this useful scaffold [1, 4]. So far, several strategies have
been developed for the synthesis of 1,3-diketones, including (a) Enolate strategy (Scheme 1, Eq. a) [16-22], (b) Umpolung strategy
(Scheme 1, Eq. b) [23-25], and (c) carbonylation of ketones (Scheme 1, Eq. c) [26]. Despite these advances, there are still some
important challenges, such as the requirement of multistep preparation of precursors, the use of toxic or expensive reagents, and limited
substrate scope, that need to be addressed for the synthesis of 1,3-diketones. Hence, the development of new and efficient protocols in
which such challenges can be overcome are of great significance in synthetic organic chemistry.
Scheme 1. General approaches to 1,3-diketones.
1,1-Diborylalkanes, as a linkage with two binding sites, have attracted increasing attention due to their significant application in
mono- or difunctionalization and the fact that they can be employed as a good platform molecule for bifunctional transformation [27].
However, the difunctionalization of the two C–B bonds of 1,1-diborylalkanes is still underdeveloped [27]. Usually, this transformation
is realized through cross-coupling reactions under transition metal catalyzed conditions [28-35]. Furthermore, the 1,1-diborylalkanes
could be used in nucleophilic addition to carbonyl compounds for the synthesis of enolate boron species through the boron-stabilized
carbanion intermediates. These enolate boron species acted as nucleophiles, which could be further trapped by another electrophile to
build new chemical structures through the difunctionalization of 1,1-diborylalkanes [36]. Based on this concept, our group recently first
introduced carboxylic acid as an acyl synthon to form an enolate boron species, followed by trapping with various electrophiles to build
ketones [37]. We reasoned that 1,3-diketones could be formed when the enolate boron species were formed, in combination with the
insertion of another acyl source. Herein, we report an efficient protocol for the synthesis of asymmetric 1,3-diketones through
diacylation of 1,1-diborylalkanes using two different acyl sources (Scheme 1, Eq. d).

Scheme 2. Substrate scope of various acyl chlorides. Reaction conditions: (i) 1a (0.375 mmol), 2a (0.25 mmol), CH3Li (0.625 mmol), THF (2.0
mL), -30 oC, 5 min then 100 oC, 8 h; (ii) ArCOCl (0.375 mmol), 100 oC, 10 h. Isolated yields of compound 3 were based on carboxylic acid.
In our previous report, we developed a dual functionalization of α-monoboryl carbanions through deoxygenative enolization with
carboxylic acids [37], in which the α-monoboryl carbanions was formed using CH3Li to activate 1,1-diborylalkane, followed by
addition to carboxylic acids, and then a new enolate boron specie was formed and trapped by another acyl source to afford 1,3-
diketones. In this report, the substrate scope was extensively explored under the optimized reaction conditions. In the meanwhile, the
application of 1,3-diketones was investigated to synthesize poly-substituted pyrazoles and isoxazoles. Firstly, in order to explore the
generality of the reaction, a broad range of aromatic acyl chlorides were investigated under the optimized conditions and the results are
summarized in Scheme 2. At first, product 3aa was obtained in 74% yield. Substrates bearing electron-donating groups –Me and –OMe
were also successfully employed in the reaction, providing the corresponding products 3ab and 3ac in 62% and 59% yields,
respectively. For the substrates containing electron-withdrawing group –CF3, and halogen –F, and –Br, the reaction also afforded
products 3ad-3af in good yields (52%, 59% and 54% yields, respectively). Next, the reaction was turned to other substrates with
substituents ortho-Cl and meta-Br affording products 3ag and 3ah in 62% and 64% yields, respectively. Furthermore, the substrate
bearing 2-naphthyl group also reacted well under the standard conditions, affording product 3ai in 68% yield. Two heterocycle acyl
chlorides were further investigated in the reaction, producing products 3aj and 3ak in 63% and 52% yields, respectively.
Scheme 3. Substrate scope of various carboxylic acids and gem-diborylalkanes. Reaction conditions: (i) 1 (0.375 mmol), 2 (0.25 mmol), CH3Li
o
o
o
(0.625 mmol), THF (2.0 mL), -30 C, 5 min then 100 C, 8 h; (ii) p-OMeC6H4COCl or p-FC6H4COCl (0.375 mmol), 100 C, 10 h. Isolated
yields of compound 3 were based on carboxylic acids.
In order to further explore the scope of the reaction, a series of carboxylic acids were investigated and the results are summarized in
Scheme 3. Functional groups, such as p-Me, p-OMe, p-NMe2 and p-F, were well tolerated, providing the corresponding products 3al-
3ao in good yields. Furthermore, the substrate bearing naphthyl group was also successfully employed in the reaction, affording product
3ap in 78% yield. Next, several other 1,1-diborylalkanes were then tested. These 1,1-diborylalkanes were easily accessed by our

development on the gem-diborylation of aldehydes, ketones and carboxylic esters [38-40]. Benzoic acid was applied as the coupling
partner, and 4-fluorobenzoyl chloride was used as the electrophilic trapping reagents to demonstrate the advantage of this method for
the synthesis of various α-substituted 1,3-diketones. These alkyl and benzyl substituted 1,1-diborylalkanes were suitable for this
transformation, affording the desired products in moderate to good yields (3aq, 3ar, 3as).
Having successfully developed an efficient method for the preparation of 1,3-diketones, we turned our focus on the utility of these
compounds to access heterocyclic scaffolds [35, 41-43]. A series of 1,3-diketones were reacted with hydrazine hydrate to produce
trisubstituted pyrazoles and the results are summarized in Scheme 4. Generally, almost all the tested examples provided the
corresponding products 4aa-4ah in excellent yields. According to literature report, fast tautomerism of the 1H-pyrazoles generally occurred
in CDCl3 solution [44-46]. Therefore, no isomers were observed for those products and those products were presented in one form.
Furthermore, phenylhydrazine was also successfully employed to react with 3aa, affording terasubstituted pyrazole 5aa in 78% yield
(Scheme 5, Eq. a). In the meanwhile, condensation of 3aa with hydroxylamine led to the formation of the corresponding isoxazole 6aa
in 89% yield in the presence of iodine (Scheme 5, Eq. b).
Scheme 4. The synthesis of trisubstituted pyrazoles. Reaction conditions: 3 (0.25 mmol), N2H4·H2O (0.5 mmol), EtOH (2.0 mL), 100 oC, 10 h.
Yields based on isolated products.
Scheme 5. The condensation of 1,3-diketones with phenylhydrazine and hydroxylamine. Reaction conditions: 3aa (0.25 mmol), PhNNH2 or
NH2OH·HCl (0.5 mmol), I2 (0.05 mmol), EtOH (2.0 mL), 80 oC, 10 h. Yields were obtained by isolating the pure products.
In conclusion, we developed a new method to synthesize various 1,3-diketones via the cross-coupling of 1,1-diborylalkanes and two
different acyl sources. In the process, the inert carboxylic acids could be directly transformed to 1,3-diketones and many functional
groups were well tolerated. Furthermore, these 1,3-diketones have been successfully employed to construct pyrazoles and isoxazoles.
Ongoing research, including further mechanistic details and expanding the substrate scope, are currently underway.
Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
Acknowledgments
This work was supported by the National Natural Science Foundation of China (Nos. 91745110, 21673261, 21603245, 21703265,
21872156, 21802150, 21773210, and 21603190), Natural Science Foundation of Jiangsu Province (Nos. BK20190002, BK20181194,
and BK20180247). Support from the Young Elite Scientist Sponsorship Program by CAST (No. YESS20170217), the Youth
Innovation Promotion Association CAS (No. 2018458) was also acknowledged.

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