Synthesis of Secondary and Tertiary Alkyl Boronic Esters by gem-Carboborylation: Carbonyl Compounds as Bis(electrophile) Equivalents

Article abstract of DOI:10.1002/anie.201804684

An unprecedent gem-carboborylation of aldehydes and ketones provides access to various secondary and tertiary alkyl boronic esters. The addition of B₂pin₂ to a carbonyl compound generates α-oxyl-substituted alkyl boron species. Organ

Full text of DOI:10.1002/anie.201804684

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Title: Access to Secondary and Tertiary Alkyl Boronic Esters via gem-
Carboborylation using Carbonyl as Bis(electrophile) Equivalent
Authors: Dunfa Shi, Lu Wang, Chungu Xia, and Chao Liu
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10.1002/anie.201804684
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Access to Secondary and Tertiary Alkyl Boronic Esters via gem-
Carboborylation using Carbonyl as Bis(electrophile) Equivalent
Dunfa Shi, Lu Wang, Chungu Xia and Chao Liu*
Abstract: An unprecedent gem-carboborylation of aldehydes and
ketones was demonstrated. Various secondary and tertiary alkyl
boronic esters were conveniently obtained. The addition of B2pin2 to
carbonyls provides -oxyl containing alkylborons. Organolithiums
and Grignard reagents were applied as the C-nucleophiles for the
1,2-metallate rearrangement process. Organolithiums could be
generated from C-H lithiation or halogen/lithium exchanges. Utilizing
chiral ligand generated chiral alkyl boronic ester, demonstrating the
catalyst-controlled enantioselectivity for this transformation.
complexes also showed powerful ability for the synthesis of
secondary and tertiary alkyl boronic esters (Scheme 1c).[5]
However, either vinylboronic esters or vinyl lithium reagents are
not easily accessible. Since the initial discovery by Sadighi, the
1,2-addition of B2pin2 to aldehydes and ketones have been
demonstrated as a practical method for the synthesis of -oxyl
boronates.[6] The use of the -oxyl as a leaving group with a
carbon nucleophile will directly achieve the synthesis of
secondary and tertiary alkyl boronic esters from aldehydes and
ketones. Such hypothesis will exhibit that carbonyls can be used
as bis(electrophile) equivalents to react with one B-nucleophile
and one C-nucleophile to achieve a gem-carboborylation. The
wide availability of B2pin2 and aldehydes/ketones makes this
strategy appealing. Herein, we demonstrated our recent
progress on this unprecedented gem-carboborylation of
aldehydes and ketones for the synthesis of secondary and
tertiary alkyl boronic esters, in which carbonyls were used as
bis(electrophile) equivalents (Scheme 1d).
Alkyl boronic esters are of increasing importance to many fields
across chemical science, not only due to the versatile
transformation of their C-B bonds but also because of their
applications in medicinal chemistry.[1] However, the preparation
of alkyl boronic esters is still unable to meet their rapid growing
demands. Especially, the synthesis of secondary and tertiary
alkyl boronic esters still remains great challenges to date. Many
efforts have been devoted to their syntheses through the
borylation of alkenes, alkyl (pseudo)halides, etc.[2] Since the
poineering research by Matteson and Mah, the 1,2-metalate
rearrangement of -leaving group containing tetracoordinated
boron chemistry has been developed as a versatile strategy for
the synthesis of alkyl boronic esters.[3] The essence for such
strategy is to find a proper way to build up those -leaving group
containing tetracoordinated boron species. In the classic
Matteson homologations, the -halo boronic esters were not
easily accessible. One feasible approach is the reaction of a pre-
prepared organoboronic ester with dihalomethyl lithium reagent
(R2 = H, Scheme 1a).[3a] However, any other gem-dihalo
organolithium (R2 ≠ H) are uneasy to access. As a result, only
secondary alkyl boronic esters can be facilely obtained via this
approach. Recently, the lithiation/borylation approach has been
developed as a versatile method for the synthesis of various
secondary and tertiary alkyl boronic esters.[4] This approach
generally started with the formation of carbamates or benzoates
from alcohols, followed by lithiation to afford an -leaving group
(O-type) containing lithium reagent. Consequently, the resulted
lithium reagent reacted with a pre-prepared organoboronic ester
to give the key tetracoordinated boron species (Scheme 1b).
Obviously, the formation of carbamates or benzoates from
alcohols and the pre-prepared organoboronic esters requires
extra synthetic procedures. The recently developed electrophile-
induced 1,2-metalate rearrangement of vinylboron ate
Scheme 1. Strategies for the synthesis of secondary and tertiary alkyl boronic
esters via 1,2-metalate rearrangement.
Hydrocinnamaldehyde (1aa) was initially applied to test the
hypothesis shown in Scheme 1d. With ICyCuCl (ICy = 1,3-
dicyclohexylimidazol-2-ylidene) as the catalyst, the addition of
B2pin2 to 1aa can easily occur to give -OBpin alkyl boronic
ester 1aa-I which contains one C-Bpin and one O-Bpin.[6a] Then,
MeLi was added as the model C-nucleophile. Two experiments
were first carried out by using one or two equivalents of MeLi,
respectively. MeLi was added at -30 oC and the reaction
[a]
D. Shi, Dr. L. Wang, Prof. C. Xia, Prof. Dr. C. Liu
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, P. R. China
E-mail: chaoliu@licp.cas.cn
o
mixtures were then heated at 80 C for 6 hours. As a result, the
[b]
D. Shi
University of Chinese Academy of Sciences
Beijing, 100049 (China)
experiment with one equivalent of MeLi afforded 30% of the
desired 2aa, while two equivalents of MeLi only afforded trace
amount of 2aa. It has been demonstrated that the energy
difference between the interaction of C-nucleophile with C-Bpin
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201804684
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and with O-Bpin is small.[7] Therefore, adding MeLi to 1aa-I will
have two possibilities to form C-B-Me or O-B-Me moiety (as
shown in 1aa-II). The formation of O-B-Me will obviously reduce
the leaving ability of OBpin group. Those results suggested that
1) one equivalent of MeLi would not exclusively form C-B-Me to
keep the OBpin as the leaving group; 2) two equivalents of MeLi
would fully convert 1aa-I to 1aa-II,[6f] while the formation of O-B-
Me in 1aa-II blocked the 1,2-migration, as a result to decrease
the yield of 2aa.
The key to solve this problem is to find a way to make the -
oxyl of 1aa-II a better leaving group under the reaction condition.
Very recently, acyl chloride has been applied by Aggarwal and
coworkers to increase the leaving ability of amino group.[8]
Inspired by this report, some acyl chlorides were tested in this
transformation to increase the leaving ability of -oxyl group in
1aa-II (Scheme 2). To our delight, the use of benzoyl chloride
remarkably increased the yield of 2aa to 85%. Benzyl
chloroformate gave 84% yield. Both phenyl chloroformate
(ClCOOPh) and methyl chloroformate (ClCOOMe) afforded
almost quantitative yields of the desired 2aa. It was observed
that a slight amount of diphenyl carbonate was generated in the
reaction with ClCOOPh, which made the separation of the
desired product troublesome, thus, ClCOOMe was finally used
for further studies.
Scheme 3. Access to secondary alkyl boronic esters via gem-carboborylation
of aldehydes with B2pin2 and MeLi as the nucleophiles. Reaction conditions: 1)
1 (0.50 mmol), B2pin2 (0.55 mmol), ICyCuCl (5 mol%), NaOtBu (10 mol%),
toluene (2.0 mL), 80 oC, 4 h, 2) MeLi (1.1 mmol), -30 oC, 3 min, 3) ClCOOMe
(0.60 mmol), 80 oC, 6 h. Yields based on isolated products; [a] Determined by
NMR analysis; [b] n.d.= not determined; [c] Determined by GC-MS analysis.
When ketones were applied in this transformation, various
tertiary alkyl boronic esters were easily obtained (Scheme 4). As
demonstrated by the Clark group, the addition of B2pin2 to
ketones is relatively sluggish than that of aldehydes.[6c]
Therefore, a prolonged reaction time is required to complete this
addition step. Aromatic ketones such as acetophenone and
propiophenone gave benzylic tertiary alkyl boronic esters in
moderate to good yields (2ba-2bd). Aliphatic ketones afforded
their corresponding tertiary alkyl boronic esters in good yields
(2be-2bi). Aromatic C-F, C-Cl and C-OMe were well tolerated
(2be-2bg). Moreover, the reaction temperature of the last
o
substitution step was raised to 100 C, which benefited to the
completion of the reaction. In these transformations, -OBpin
alkyl boronic esters were initially generated for the following
homologative carbonation. A free -OH alkyl boronic ester 2bh-
OH derived from benzylacetone was also tested and it was
successfully methylated with MeLi by using ClCOOMe as a
promotor and the desired 2bh was obtained in 70% yield (See
details in supporting information), illustrating that the free -OH
alkyl boronic ester was competent in the homologation step
under this esterification condition with ClCOOMe.
Scheme 2. Initial investigation on gem-carboborylation of aldehyde. [a] The
yield was determined by NMR analysis with CH2Br2 as the standard. [b] Yield
of isolated product.
With the optimal conditions in hand, various aldehydes were
first tested in this gem-carboborylation protocol with B2pin2 and
MeLi as the nucleophiles to access secondary alkyl boronic
esters (Scheme 3). Simple aliphatic aldehydes afforded their
corresponding secondary alkyl boronic esters in good yields
(2ab-2ag). Functional groups, such as OMe, SMe, alkenyl and
aromatic CF3, were well tolerated (2ah-2ak). Aliphatic aldehydes,
which contains aromatic groups (including furyl), were also
tested and good to excellent yields were obtained (2ak-2ao).
Aromatic aldehydes gave their corresponding secondary
benzylic boronic esters in good yields (2ap-2as).
Scheme 4. Access to tertiary alkyl boronic esters via gem-carboborylation of
ketones with B2pin2 and MeLi as the nucleophiles. Reaction conditions: 1) 1
(0.50 mmol), B2pin2 (0.55 mmol), ICyCuCl (5 mol%), NaOtBu (10 mol%),
toluene (2.0 mL), 80 oC, 22 h, 2) MeLi (1.3 mmol), -30 oC, 3 min, 3) ClCOOMe
(0.80 mmol), 100 oC, 6 h. Yields based on isolated products; [a] -OH alkyl
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boronic ester 2bh-OH derived from benzylacetone was directly used for
methylation.
Next, this protocol also allowed the application of various C-
nucleophiles to form C-C bonds to give various secondary and
tertiary alkyl boronic esters. First, commercially available
organolithiums and Grignard reagents were tested (Scheme 5).
Nabumetone and anisic aldehyde were selected as the tentative
n
carbonyl compounds. With nabumetone as the substrate, BuLi,
sBuLi and iBuLi afforded their corresponding tertiary alkyl boronic
esters in good yields (2ca, 2da, 2ea). Whilst, primary (EtMgBr)
and secondary (CpMgCl, Cp = cyclopentyl) alkyl Grignard
reagents afforded good yields of the desired tertiary alkyl
boronic esters (2fa, 2ga). With anisic aldehyde as the substrate,
PhMgCl, BnMgCl and BuMgCl gave the desired secondary
benzylic boronic esters in moderate to good yields (2ha, 2ia,
2ja).
t
Scheme 6. gem-Carboborylation with organolithiums obtained via C-H
lithiation and halogen/lithium exchange.
Secondary and tertiary alkyl boronic esters are closely related
to enantioselective synthesis.[2b, 9] The enantioselectivity of those
classic Matteson homologations are usually substrate-control
with the embeddedness of a chiral auxiliary in the diol moiety of
the boronic ester. Those lithiation/borylation approaches are
reagent-control with the addition of stoichiometric amounts of
chiral amines.[4] Catalyst-controlled enantioselectivity is an
appealing strategy for the synthesis of chiral alkyl boronic
esters.[2b] Unsaturated double bonds are ideal prochiral moieties
in organic transformations. The recent development of
enantioselective nucleophilic addition of B2pin2 to aldehydes and
ketones by the Ito group provided us an opportunity to achieve a
catalyst-controlled enantioselective gem-carboborylation of
6h]
carbonyls.[6g,
Aldehyde 1aa and ketone 1bh were used to
Scheme 5. Substrate scope of organometal reagents. Reaction conditions: 1)
1 (0.50 mmol), B2pin2 (0.55 mmol), ICyCuCl (5 mol%), NaOtBu (10 mol%),
toluene (2.0 mL), 80 oC, 22 h, 2) MeLi (1.3 mmol), -30 oC, 3 min, 3) ClCOOMe
(0.80 mmol), 100 oC, 6 h. Yields based on isolated products; [a] 1) reaction
verify this hypothesis (Scheme 7). When (R)-DTBM-SEGPHOS
was used as the chiral ligand and MeLi as the C-nucleophile, the
desired (S)-2aa was obtained with a 91% ee value in 45% yield.
When (S)-DTBM-SEGPHOS was used, the desired (R)-2aa was
obtained with a 91% ee value in 46% yield (Scheme 7, eq. 1).
Moreover, Applying Ito’s asymmetric 1,2-borylation of ketones[6g]
in this transformation successfully resulted in asymmetric tertiary
alkyl boronic ester (Scheme 7, eq. 2). These results elucidated
that the enantioselectivity of the product was controlled by the
catalyst. Furthermore, according to the report by the Ito group,
(R)-DTBM-SEGPHOS afforded S-isomer of the addition product
-oxyl alkylboronic ester.[6h] The obtained (S)-configuration of
2aa is consistent with the inversion process of 1,2-metallate
rearrangement, verifying the mechanistic insight of our initial
proposal of this transformation in Scheme 1d.
time:
4
h, 2) R3-M (1.1 mmol), 3) ClCOOMe (0.60 mmol), 80 oC; [b]
Determined by NMR analysis.
Besides, organolithiums could also be obtained via C-H
lithiation or halogen/lithium exchange. It will greatly enlarge the
scope of nucleophiles for this gem-carboborylation process.
Selected examples were presented in Scheme 6. The in situ C-
H lithiated thiophene was subjected to the reaction with
nabumetone, as a result, the desired tertiary alkyl boronic ester
2ka was obtained in 45% yield (Scheme 6a). The
halogen/lithium exchange of aryl bromides with butyllithium was
applied to react with anisic aldehyde. The corresponding diaryl
methylboronic esters were obtained in moderate yields (Scheme
6b, 2la, 2ma).
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This work was supported by the NNSFC (91745110, 21673261,
21603245, 21633013 and 21703265) and a Start-up funding
from LICP. Support from the Young Elite Scientist Sponsorship
Program by CAST, CAS Interdisciplinary Innovation Team, the
Key Program of CAS (QYZDJ-SSW-SLH051), the Youth
Innovation Promotion Association CAS (2018458) and the ‘Light
of West China’ Program were also acknowledged.
Keywords: gem-Carboborylation • Alkyl Boronic Esters •
Bis(electrophile) Equivalent • 1,2-Metallate Rearrangement •
Catalyst-Control Enantioselectivity
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Scheme 7. Catalyst-controlled enantioselectivity.
To probe the insightful information of this transformation, in
situ IR spectroscopy technique was applied to monitor the
reaction course of 1aa-I with MeLi and ClCOOMe (Scheme 8,
See 3D spectra in SI). Upon the addition of MeLi, the specific
absorbance of 1aa-I at 1324 cm-1 disappeared immediately,
a
new peak at 1291 cm-1 appeared. This
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phenomenon indicated an immediate interaction of MeLi with
1aa-I to generate 1aa-II. As ClCOOMe was added, this peak
gradually shifted to 1309 cm-1. Meanwhile, the specific
absorbance of ClCOOMe at 1786 cm-1 gradually decreased and
the specific absorbance of 1aa-III at 1708 cm-1 appeared. When
heating the mixture at 80 C, the peaks at 1786 cm-1 and 1708
o
cm-1 immediately decreased together with an observation of a
strong and broad absorbance at 1647 cm-1. At the same time,
suspension was observed in the reaction mixture. By
comparison with its standard IR spectrum, the 1647 cm-1 was
assigned to be the absorbance of LiOCOOMe. These
observations indicated that high temperature was beneficial to
both the acylation of -oxyl group of 1aa-I with ClCOOMe and
the 1,2-metalate rearrangement of 1aa-III to afford the desired
product 2aa and LiOCOOMe.
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Scheme 8. Reaction course monitored by in situ IR
In summary, we have demonstrated a gem-carboborylation of
aldehydes and ketones using carbonyl group as bis(electrophile)
equivalent to synthesize various secondary and tertiary alkyl
boronic esters. The 1,2-addition of B2pin2 to carbonyls provides
-oxyl alkylboronates. Organolithiums and Grignard reagents
were applied as the C-nucleophiles for the 1,2-metallate
rearrangement process. ClCOOMe was used to increase the
leaving ability of -oxyl group. Catalytic amount of chiral ligand
could promote to form chiral alkyl boronic ester, which supported
the catalyst-controlled enantioselectivity for this transformation.
[7]
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Acknowledgements
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10.1002/anie.201804684
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COMMUNICATION
COMMUNICATION
Dunfa Shi, Lu Wang, Chungu Xia, and
Chao Liu*
Page No. – Page No.
Access to Secondary and Tertiary
Alkyl Boronic Esters via gem-
Carboborylation using Carbonyl as
Bis(electrophile) Equivalent
One Stone Two Birds: gem-Carboborylation of aldehydes and ketones using
carbonyl group as bis(electrophile) equivalent was demonstrated. Various
secondary and tertiary alkyl boronic esters were conveniently obtained. The
addition of B2pin2 to carbonyls provides -leaving group containing alkylboronates.
Organolithiums and Grignard reagents were applied as the C-nucleophiles for the
1,2-metallate rearrangement process. Organolithiums could be generated from C-H
lithiation or halogen/lithium exchanges. Utilizing chiral ligand generates enantiopure
alkyl boronic ester, demonstrating the catalyst-controlled stereoselectivity for this
transformation.
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