Difunctionalization of ketones: Via gem -bis(boronates) to synthesize quaternary carbon with high selectivity

Article abstract of DOI:10.1039/c8cc07781a

All-carbon quaternary centres are significant and prevalent structural frameworks but their preparation routes are rare and challenging, especially methods with common substrates. Herein, we report a convenient process to construct all-carbon quaternary c

Full text of DOI:10.1039/c8cc07781a

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Difunctionalization of ketones via
gem-bis(boronates) to synthesize quaternary
carbon with high selectivity†
Cite this: Chem. Commun., 2018,
54, 13375
Received 28th September 2018,
Accepted 5th November 2018
Purui Zheng, Yujie Zhai, Xiaoming Zhao * and Tao XU
*
DOI: 10.1039/c8cc07781a
rsc.li/chemcomm
All-carbon quaternary centres are significant and prevalent structural
frameworks but their preparation routes are rare and challenging,
especially methods with common substrates. Herein, we report a
convenient process to construct all-carbon quaternary centres from
ketones via the diborylation process and Suzuki–Miyaura cross-
coupling reaction. This methodology, which simultaneously introduces
two different kinds of electrophilic structures, exhibits a large substrate
scope and high functional group tolerance. The reaction products with
aldehyde and allylic groups have proved to be versatile synthons to
prepare complex molecules crucial for natural product synthesis.
Scheme 1 The construction of quaternary carbon from tertiary boronates or
precursors.
The facile generation of tertiary boronates faces many issues.
The formation of all-carbon quaternary centres, a widespread Recently, transition-metal catalyzed hydroboration reaction of
structural pattern in biologically active molecules and natural olefin has provided an efficient route to form boronic substrates.
products, is still a challenge for synthetic chemists.1 The However, it generally takes place in an anti-Markovnikov way to
Suzuki–Miyaura cross-coupling reaction, as one of the powerful give boronates on the less substituted site of the trisubstituted
methods to construct carbon–carbon bonds, has also been alkenes.7 As a result, some other pathways were developed to
applied in the formation of quaternary carbon centres. This access tertiary boronic esters, but their application is limited.8
reaction commonly relies on tertiary electrophiles rather than Herein, we address a transformation of gem-bis(boronate) com-
tertiary boronic esters, since they are easier to synthesize.2 Even pounds with different electrophiles through a tertiary boronate
so, there are only a few examples of the Suzuki–Miyaura intermediate to concurrently construct two kinds of carbon–
reaction with tertiary electrophiles.3 This is connected to their carbon bonds with high selectivity, which provides an efficient
low ability to oxidatively add to metal complexes, and further- and useful protocol to difunctionalize ketones (Scheme 2).
more, these formed alkyl–metal complexes readily undergo
Ketones are ubiquitous and abundant starting materials
b-hydride elimination. As such, some other methods were which play an important role as in organic synthesis. Traditionally,
developed to form quaternary carbon centres.4 Allylic secondary carbonyls react with nucleophiles, such as Grignard reagents, to
boronic esters can be employed to be utilized as tertiary form the tertiary alcohol products. As a consequence, it would be
boronate precursors (eqn (1), Scheme 1).5 In addition, Aggarwal
and co-workers have impressively described the enantioselective
lithiation–borylation procedure to give tertiary alcohols upon oxida-
tion or other carbon–carbon coupled products (eqn (2), Scheme 1).6
Nevertheless, to develop a method with common substrates is still
of high demand.
Shanghai Key Laboratory of Chemical Assessment and Sustainability,
School of Chemical Science and Engineering, Tongji University, 1239 Siping Road,
Shanghai, 200092, P. R. China. E-mail: taoxu@tongji.edu.cn,
xmzhao08@mail.tongji.edu.cn
Scheme 2 Difunctionalization of ketones with a-boron aldehyde inter-
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
mediates.
c8cc07781a
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Table 1 The optimization of reaction conditionsa
attractive to access the quaternary carbon centres by successively
reacting different electrophiles with gem-bis(boronates) that can be
easily obtained from carbonyls via an umpolung (Scheme 2).9
However, this reaction has a low chemoselectivity, which can
be circumvented by stepwise introduction of the respective
electrophile.10 Occasionally, the substitution stops after the first
step, leaving behind a monoboronate species.11 Given this recent
success of this approach, we considered introducing aldehyde
groups into the diboron species to give a-boron aldehydes, in
which the aldehyde functionality helps in activating the second
boronate by C/O isomerization, then subsequently facilitates the
second substitution.
Though a-boron aldehydes or esters were synthesized, they relied
on very special boron structures consisting of chelating groups to
stabilize the structure.12 In general, this method has no downstream
synthetic application besides protodeboronation.13 Recently,
Pattison and co-workers reported a tertiary a-boron ketone
as an intermediate, which was produced from deprotonated
gem-bis(boronates) reacting with esters under metal-free con-
ditions, but just introducing the same electrophilic reagent for
Entry
Changes from the standard conditions
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
Standard conditions (LG = OCOOMe)
No pre-active reagent (nBuLi)
89
0
MeLi, NaOtBu, LiOtBu as pre-active reagent
LG = Cl, Br, OBz, OTs
4/0/0
76/70/88/80
0/0
HCOOnBu, HCOOBn as solvent
THF/DMF (v/v 10/1) as solvent
Bipyridine, Phen, dppe as ligand
NiBr2(dme), CuI, Fe(OAc)2 as catalyst
No Pd(OAc)2 or no PPh3
18
44/16/60
0/0/0
0/30
Pd(OAc)2 (5 mol%), PPh3 (12 mol%)
80
a
The reaction was conducted on a 0.1 mmol scale. For details on the
b
experimental procedure, see the ESI. The yield was determined by
1H NMR with CH2Br2 as an internal standard. Phen = 1,10-phenanthroline.
dppe = 1,2-bis(diphenylphosphino)ethane. dme = 1,2-dimethoxyethane.
We next explored the scope of this transformation with a
both substitutions.14 The Liu and Xia group reported a reaction variety of allylic substrates under the optimized reaction
of diborylalkane with acid compounds to introduce the ketone
group without any catalyst but only three examples on the
Table 2 The scopes with respect to the allylic substratesa
quaternary carbon construction.15 Furthermore, as a versatile
group, the aldehyde group cannot be successfully imbedded
through these methods. To the best of our knowledge, tertiary
a-boron aldehydes are still little studied in either synthesis
or application. The homologation of ketones to introduce an
aldehyde group with a boron-Wittig reaction after oxidation was
reported; however, it only gave compounds with a tertiary
carbon.16 Therefore, this strategy provides a convenient protocol
to construct all-carbon quaternary centres with an aldehyde group.
Initial investigations of this process focused on compound 1a
that was easily prepared from 4-phenylbutan-2-one to react with
allylic substrates as electrophiles (E2) and DMF as an aldehyde
group donor (E1). To facilitate the reaction, the organoboronate 1a
was first lithiated in situ by mixing 1a with nBuLi in THF
(for details, see the ESI†).17 The reaction with allyl methyl
carbonate 2a proceeded smoothly with Pd(OAc)2/PPh3 as catalyst
at room temperature to give the corresponding product 3a in 89%
NMR yield (entry 1, Table 1). No product or very little was detected
in the absence of nBuLi or with other bases, such as MeLi, NaOtBu
or LiOtBu (entries 2 and 3, Table 1). Changing the leaving group to
Cl, Br, OBz, and OTs decreased the yields (entry 4, Table 1).
Different from that previously reported, the use of the esters butyl-
and benzylformate showed no product (entry 5, Table 1). The
mixed solvent THF/DMF (v/v 10/1) reduced the reactivity; only 18%
of the product was observed (entry 6, Table 1). Altering the ligands
on the metal complex did not impede the product formation;
however, a decrease in reactivity could be detected (entry 7, Table 1).
The reaction was much less effective with other metal catalysts, for
instance, NiBr2(dme), CuI or Fe(OAc)2 (entry 8, Table 1). Also, no
product was found in the absence of catalyst but a moderate
yield was given without any ligand (entry 9, Table 1).18 In
addition, the reaction could well take place at a low loading
a
The reaction was conducted on a 0.2 mmol scale under the standard
b
conditions in Table 1. Isolated yields and l-/b-ratios were given. Utilizing
Br as a leaving group. The 2r/1a ratio was 3/1.
c
of catalyst (entry 10, Table 1).
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conditions (representative examples are summarized in Table 2).19
In general, the allylic substrates with either aryl substitutes (3b–3o)
or alkyl groups (3p–3v) reacted smoothly to give the corresponding
products in high yields and good linear/branched (l-/b-) selectivity.
It is reasonable that the substituent at the ortho position could give
a better l-/b- ratio than that at the para or meta position (3c–3e).
Halide functionalities are well tolerated under these conditions
(3f–3h). The compounds bearing the CF3 and ether groups
remained unchanged (3i–3l). Importantly, heterocyclic structures
consisting of furan and thiophene were also suitable substrates
(3m, 3n). The allylic substrates with substituents in the b-position Scheme 3 Synthesis of compound 8.
afforded products with acceptable yields (3p, 3q). It is worthwhile
to mention that although nBuLi is present in this reaction, strongly
ester (4j), and OBn (4l) groups smoothly generated the corres-
ponding products under these conditions.
base-sensitive functional groups, such as esters and carbonyls,
were converted as part of the allylic substrate (3q, 3r). Moreover,
other functional groups including alkenes, OBn and imines were
also successfully coupled (3s, 3t, 3u). Furthermore, it was shown
that the aliphatic secondary allylic substrate also had good
l-/b-selectivity (3v).
Then the substrate scope was further extended to a series of
substituted ketone compounds (Table 3). To our delight, both
the acyclic (4a–4g) and cyclic (4h–4l) ketone substrates can be
converted to the corresponding products in moderate to good
yields. In addition, for the ketones including the heterocyclic
compounds (4k, 4l), the aldehyde and alkene functional groups
could also be efficiently introduced at the carbonyl carbon site
with this method. With regard to different substituents, it is
worthwhile to mention the high functional group tolerance of
this reaction. The substrates bearing aryl halide (4a, 4b), CF3
(4c), ether (4d, 4k), imine (4f, 4l), heterocycle (4g), ketal (4j),
To further illustrate the utility of this transformation, the
method was applied for the formal synthesis of (Æ)-acorone and
isoacorone (Scheme 3). Compound 8 is an important precursor
to access these natural products.20 Despite its previously reported
synthesis, a more efficient synthetic pathway was developed using
this protocol. Compound 6 could be conveniently obtained from
commercial substrate 5. After the Wacker reaction and Aldol
condensation, compound 8 could be obtained in only four steps
with a high yield.
In an effort to provide insight into the reaction mechanism,
some control experiments were conducted (Scheme 4). In the
absence of an allylic substrate, compound 9 was believed to be
produced from the isomerization of tertiary a-boron aldehyde,
which was corroborated by the boron signal at 23.8 ppm in a
11B NMR spectrum.21 The chemical shift was consistent with
the literature reported on the O-bond BPin isomer of esters.22
The product was formed after adding an allylic substrate and
catalyst to the above reaction. Compound 9 was quenched with
D2O to generate product 10 (97% D) accompanied by the
vanishing of the signal at 23.8 ppm and the emergence of a signal
at 5.2 ppm that corresponds to the PinB(OD)À anion. Compound
10 could not give product 3a under the standard conditions. If the
reaction was conducted with THF as a solvent, compound 11 was
detected. This substrate also did not proceed to give the quaternary
product 3a. These control experiments proved that the tertiary
a-boron aldehyde intermediate provides a vital significance to this
transformation (for more details, see the ESI†).
Table 3 The scope with respect to ketonesa
a
The reaction was conducted on a 0.2 mmol scale under the standard
b
conditions in Table 1. Isolated yields and l-/b-ratios were given. Utilizing
Br as a leaving group. The ratio of the E/Z isomer was 10/1.
c
Scheme 4 The mechanistic study.
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In summary, herein we report a convenient methodology to
difunctionalize ketone compounds through gem-bis(boronates),
which introduces two significant transformable functional groups
simultaneously. This method exhibits a wide substrate scope and
high functional group tolerance. The synthetic utility of this
method was further demonstrated through producing the inter-
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Mechanistic investigations suggest that the tertiary a-boron
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The authors acknowledge Dr Gerald Bauer for polishing
the manuscript and helpful discussion. We acknowledge the
‘‘Thousand Talents Plan’’ Youth Program (No. 13802350017)
and Tongji University for the financial support.
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Conflicts of interest
The authors declare no competing financial interest.
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