Palladium-Catalyzed Cross-Coupling of gem-Bis(boronates) with Aryl Halides: An Alternative to Access Quaternary α-Aryl Aldehydes

Article abstract of DOI:10.1021/acs.orglett.8b03560

The compounds with a quaternary α-aryl aldehyde skeleton are important units in organic chemistry. Previously, the aryl group and carbonyl group are introduced in a stepwise manner. Herein, a novel route is developed to construct the quaternary α-aryl aldehydes with gem-bis(boronates) as precursors, in which the two groups are installed simultaneously. The gem-bis(boronates) are readily available from ketones; as a result, this methodology provides a more general strategy to produce the quaternary α-aryl aldehydes with broad scopes and synthetic convenience.

Full text of DOI:10.1021/acs.orglett.8b03560

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed Cross-Coupling of gem-Bis(boronates) with
Aryl Halides: An Alternative To Access Quaternary α‑Aryl Aldehydes
Purui Zheng, Yujie Zhai, Xiaoming Zhao,* and Tao XU*
Shanghai Key Laboratory of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji
University, 1239 Siping Road, Shanghai, 200092, P. R. of China
S
* Supporting Information
ABSTRACT: The compounds with a quaternary α-aryl aldehyde skeleton
are important units in organic chemistry. Previously, the aryl group and
carbonyl group are introduced in a stepwise manner. Herein, a novel route
is developed to construct the quaternary α-aryl aldehydes with gem-
bis(boronates) as precursors, in which the two groups are installed
simultaneously. The gem-bis(boronates) are readily available from ketones; as a result, this methodology provides a more
general strategy to produce the quaternary α-aryl aldehydes with broad scopes and synthetic convenience.
Scheme 1. Routes To Access the Quaternary α-Aryl
Aldehyde
he α-aryl carbonyl framework has been a versatile
Tprecursor to construct complex structures which are
widespread in natural products, bioactive molecules, and
material compounds (Figure 1).1 Numerous methods were
developed to access the α-aryl carbonyl derivatives, including
α-aryl esters, amides, and ketones.2 However, there were few
routes to afford α-aryl aldehyde, due to the competing aldol
condensation process under basic media. Recently, some
methodologies with transition-metal catalysis3 or organo-
catalysis4 were utilized to obtain these α-aryl aldehyde
products. However, they usually focused on the process to
afford the tertiary α-aryl aldehyde skeletons. The synthesis of
quaternary α-aryl aldehydes remains scarce and is still in high
demand.
To gain the quaternary α-aryl aldehydes, traditionally α-aryl
acetic esters or α-aryl acetonitriles were employed. After
repetitive nucleophilic alkylation with different alkyl halides
and reductive process, the quaternary α-aryl aldehydes are
obtained in several steps (Scheme 1, eq 1).5 Considering the
limited available structure of starting materials when it comes
to multifunctional groups, especially for some substituents that
are sensitive to reductant, such as ester or cyanide in other
sites, more steps in fact were involved to finish the
requirement. To facilitate the routes, methods with the help
of transition-metals were developed.6 For instance, the
Buchwald group reported the palladium-catalyzed α-arylation
of aldehyde with aryl halides but still only limited α-tertiary
aldehydes were tested (Scheme 1, eq 2).7 In addition, both of
these methods need to install the aryl group or aldehyde (or its
precursor) to the substrates in advance. Herein, we report a
new transformation of gem-bis(boronates) compounds that
were easily obtained from ketones to access the quaternary α-
aryl aldehyde products, which introduce the aryl and carbonyl
groups simultaneously in the process (Scheme 1, eq 3).
Moreover, the alkenyl halides also proved to be efficient
reactants in the transformation.
gem-Bis(boronate) substrates that can be obtained from
aldehydes or ketones have powerful potential to transfer to
other compounds. For instance, the Shibata and Morken
groups reported the coupling reaction of gem-bis(boronates)
with aryl halides to give the benzyl boronates.8 In 2014, the
coupling reactions of gem-bis(boronates) with alkenyl halide to
give allylic boronates and with 1,1-dibromoalkene to give
Received: November 7, 2018
Figure 1. Selected drug compounds with α-aryl carbonyl framework.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03560
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Optimization Conditions
Scheme 4. Scopes with Respect to the gem-Bis(boronates)
Substrates
a
a
The reactions were conducted on 0.1 mmol scale. For the details on
the experimental procedure, see Supporting Information. Yields were
1
determined by H NMR with CH2Br2 as an internal standard.
a
Scheme 3. Scopes with Respect to the Aryl Substrates
a
The reactions were conducted on 0.2 mmol scale under the
optimized condition in Scheme 2 with L4 as ligand at 60 °C. Isolated
yields were given.
carboxylic acids, respectively.12 In the meantime, we also
reported a methodology to introduce the aldehyde and allylic
group to this type of substrate to construct a quaternary carbon
center, which provides a protocol for difunctionalization of
ketones.13 In this letter, we report the transformation of gem-
bis(boronates) to access the α-aryl aldehyde substrate by the
strategy we developed in the previous work.
We commenced this study with compound 1a and 4-
iodotoluene (2a) as the model substrates under the previous
conditions (Scheme 2). However, no desired product was
found with PPh3 (L1) as the ligand. Likewise, the reaction with
trimethoxylphosphine (L2) or 1,2-bis(diphenylphosphino)-
benzene (L3) did not give any product. It was to our delight
to find a 51% yield of the desired product in the presence of
tri-tert-butylphosphine tetrafluoroborate (L4) as the ligand.
The yield could be improved to 87% when the reaction was
conducted at 60 °C and an 84% yield at 85 °C. Another
phosphine ligand, such as Xanphos (L5), only gave trace
product while the nitrogen ligands were not useful in these
conditions. Additionally, control experiments showed that the
catalyst, ligand, and the preactive reagent (n-BuLi)14 were all
crucial to the transformation (for more details, see Supporting
Information).
a
The reactions were conducted on 0.2 mmol scale under the
optimized conditions in Scheme 2 with L4 as ligand at 60 °C. Isolated
b
yields were given. The reaction was conducted on 1 mmol scale.
c
The reaction was conducted at 85 °C
allenes were reported.9 In addition, the alkylation of gem-
bis(boronates) to afford alkylboronic esters was achieved with
or without metal catalysis.10 Meanwhile, other transformations
of gem-bis(boronates) also drew attention.11 Very recently, the
Pattison and Liu groups developed methods to introduce the
ketone group by reacting gem-bis(boronates) with esters and
With the optimal conditions in hands, we turned our
attention to the generality of this palladium-catalyzed trans-
formation of gem-bis(boronates). As shown in Scheme 3, the
yield of 3a did not experience a significant change on the 1
mmol scale. Aryl iodides with different substituents were
employed in this transformation, and moderate to high yields
B
DOI: 10.1021/acs.orglett.8b03560
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Organic Letters
Letter
a
Scheme 5. Scopes with Respect to the Alkenyl Substrates
Scheme 7. Proposed Catalytic Cycle
Then we studied the scope of substrates with respect to the
gem-bis(boronate) compounds (Scheme 4). It was worth
mentioning that both the acyclic (4a−4d) and cyclic (4e−4i)
bis(boronate) substrates can proceed smoothly to give the
corresponding products in moderate to good yields. The gem-
bis(boronates) bearing ether (4b), CF3 (4c), fluorine (4d),
ketal (4h), or amine (4i) can be tolerant in the transformation.
Meanwhile, as mentioned in Scheme 3, the aryl partners with
substituted sulfur ether (4a), ester (4f), ether (4h), and
heterocycle (4g) groups could smoothly generate the
corresponding products under these conditions.
a
The reactions were conducted on 0.2 mmol scale under the
optimized condition in Scheme 2 with L4 as ligand at 60 °C. Isolated
yields were given. For 5g and 5h, Ar′ = p-ClPh.
2
Besides, another type of Csp -halide substratealkenyl
bromide substrateswere also studied in this transforma-
tion.15 From Scheme 5, it can be found that the alkenyl
bromide substrates with a variety of functional groups, either
an electron-donating or electron-withdrawing group, could
afford the corresponding products in good to high yields. In
addition to ether (5a, 5b), chloride (5g, 5h), CF3 (5c),
thiophene (5e), and ketal (5i) groups, further study on the
substituents showed benzodioxan (5d), nitro (5f), and sulfuryl
(5i) groups can also survive in the process.
Scheme 6. Derivatives of α-Aryl Aldehyde (CDI = N,N′-
Carbonyldiimidazole)
The quaternary α-aryl substrate 3a obtained by this method
was used to demonstrate the synthetic utility of this
methodology (Scheme 6). The aldehyde structure was readily
converted to primary alcohol 6a after reduction. The amine 6b
was given in high yield through imine formation and LiAlH4
reductive processes. Meanwhile, the alkenyl group can be also
introduced by a Witting reaction to produce compound 6c. In
addition, the product 3a can be smoothly transformed to
quaternary benzyl nitrile substrate 6d in excellent yield.
A proposed catalytic cycle to determine the mechanism was
addressed in Scheme 7 based on the experiments and previous
work. The lithium salt A was obtained under the n-BuLi
condition, which could react with DMF to give the α-boron
aldehyde B. The present equilibrium between C-bond B and
O-bond boron isomer B′ facilitated the transmetalation with
the ArPd(L)I complex. After transformation from intermediate
C′ to C, the product was produced with reductive elimination
as well as the regeneration of the palladium catalyst.
were obtained to furnish the corresponding products. The
compounds with a substituent in the ortho, meta, or para
position can smoothly give the quaternary α-aryl aldehydes. A
variety of functional groups such as alkyl (3a), chloride (3c),
fluorine (3h), CF3 (3i), ether (3d, 3g), ester (3c), and cyanide
(3f) groups were all well-tolerated in this reaction. Hetero-
cycles, such as thiophene (3k) and N-methylpyrazole (3l),
were also successfully introduced to the α-position of
aldehydes. Notably, strong base- or reductant-sensitive func-
tional groups, such as ester and cyanide in the aryl partners,
can survive under these conditions, albeit using n-BuLi in this
process.
In conclusion, we reported a convenient route to synthesize
the quaternary α-aryl aldehyde substrate by palladium-
catalyzed transformation of gem-bis(boronates), which is very
easily obtained from ketones. Compared with previous
methods, this methodology could introduce the two functional
C
DOI: 10.1021/acs.orglett.8b03560
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03560.
■
S
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Description of additional data; procedures and charac-
terization data for all compounds (PDF)
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: taoxu@tongji.edu.cn.
*E-mail: xmzhao08@mail.tongji.edu.cn.
ORCID
(11) (a) Murray, S. A.; Liang, M. Z.; Meek, S. J. J. Am. Chem. Soc.
2017, 139, 14061. (b) Miura, T.; Nakahashi, J.; Zhou, W.; Shiratori,
Y.; Stewart, S. G.; Murakami, M. J. Am. Chem. Soc. 2017, 139, 10903.
(c) Miura, T.; Nakahashi, J.; Murakami, M. Angew. Chem., Int. Ed.
2017, 56, 6989. (d) Wang, L.; Zhang, T.; Sun, W.; He, Z.; Xia, C.;
Lan, Y.; Liu, C. J. Am. Chem. Soc. 2017, 139, 5257. (e) Hwang, C.; Jo,
W.; Cho, S. H. Chem. Commun. 2017, 53, 7573. (f) Lee, Y.; Baek, S.
-y.; Park, J.; Kim, S.-T.; Tussupbayev, S.; Kim, J.; Baik, M.-H.; Cho, S.
H. J. Am. Chem. Soc. 2017, 139, 976.
Xiaoming Zhao: 0000-0002-1447-128X
Tao XU: 0000-0002-4228-4895
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the “Thousand Talents Plan” Youth Program (No.
13802350017), Shanghai Pujiang Talents Program (No.
13802360072), and Tongji University for the financial support.
(12) (a) Iacono, C. E.; Stephens, T. C.; Rajan, T. S.; Pattison, G. J.
Am. Chem. Soc. 2018, 140, 2036. (b) Sun, W.; Wang, L.; Xia, C.; Liu,
C. Angew. Chem., Int. Ed. 2018, 57, 5501.
(13) Zheng, P.; Zhai, Y.; Zhao, X.; XU, T. Chem. Commun. 2018, 54,
13375.
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DOI: 10.1021/acs.orglett.8b03560
Org. Lett. XXXX, XXX, XXX−XXX