Stereoselective Synthesis of Trisubstituted Vinylboronates from Ketone Enolates Triggered by 1,3-Metalate Rearrangement of Lithium Enolates

Article abstract of DOI:10.1002/anie.201909235

An unprecedented stereoselective synthesis of trisubstituted vinylboronates is reported to proceed by direct borylation of lithium ketone enolates under transition-metal-free conditions. The stereospecific C?O borylation of lithium enolates was triggered by a carbonyl-induced 1,3-metalate rearrangement via a C-bound boron enolate. DFT calculations and control experiments revealed that the stereoselectivity is controlled by sterics. A variety of stereospecific trisubstituted vinylboronates, together with several tetrasubstituted vinylboronates, were conveniently synthesized with the newly developed methodology. Based on the transformation of stereospecific vinylboronate, a single isomer of Dienestrol was efficiently obtained.

Full text of DOI:10.1002/anie.201909235

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Accepted Article
Title: Stereoselective Synthesis of Trisubstituted Vinylboronates from
Ketone Enolates Triggered by 1,3-Metalate Rearrangement
Authors: Yue Hu, Wei Sun, Tao Zhang, Nuo Xu, Jianeng Xu, Yu Lan,
and Chao Liu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201909235
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10.1002/anie.201909235
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Stereoselective Synthesis of Trisubstituted Vinylboronates from
Ketone Enolates Triggered by 1,3-Metalate Rearrangement
Yue Hu,+ Wei Sun,+ Tao Zhang, Nuo Xu, Jianeng Xu, Yu Lan, and Chao Liu*
Abstract: An unprecedented stereoselective synthesis of
trisubstituted vinylboronates was reported from the direct borylation
of lithium ketone enolates under transition-metal-free conditions. The
stereospecific C-O borylation of lithium enolates was triggered by a
carbonyl-induced 1,3-metalate rearrangement through C-bound
boron enolate. DFT calculations and control experiments revealed
that the stereoselectivity was controlled by steric hindrance. A
variety of stereospecific trisubstituted vinylboronates, together with
several tetrasubstituted vinylboronates, were conveniently
synthesized with the newly developed methodology. Based on the
transformation of stereospecific vinylboronate, a single isomeric
Dienestrol was efficiently obtained. Previously, this compound could
only be synthesized as a mixture of stereoisomers.
substituted substrates (Scheme 1d).[9] Herein, we achieved an
unprecedented stereoselective synthesis of internal
trisubstituted vinylboronates via novel 1,3-metalate
rearrangement triggered transition-metal-free borylation of
ketone enolates (Scheme 1e). As a result, various stereospecific
trisubstituted vinylboronates were readily synthesized from
easily accessible lithium ketone enolates.
a
Organoboron compounds are powerful reagents in chemical
sciences. The introduction of boron into organic molecules has
deeply revolutionized the way of creating new chemical bonds
for precise chemical synthesis.[1] As an important class of
organoboron compounds, vinylboronates have been widely
applied as olefination reagents for the synthesis of various
alkenyl-containing compounds, such as their applications in the
powerful Zweifel olefination,[2] Suzuki-Miyaura coupling,[3] and
Petasis reaction.[4] Recently, the novel transformations of
vinylboron ate complexes further highlight the applications of
vinylboronates.[5] Although many elegant strategies have been
developed for the synthesis of vinylboronates, the
stereoselective synthesis of internal trisubstituted vinylboronates
is still limited.[6] The transition-metal-catalyzed hydroboration of
internal alkynes and carbo/hydro boration of allenes were the
major approaches to access stereospecific internal trisubstituted
vinylboronates, while they usually suffered from inherent
regioselectivity to give a mixture of regioisomers (Scheme 1a
and 1b).[7] The Pd-catalyzed dehydrogenative borylation of
internal styrenes was also an alternative approach, while very
few examples were presented (Scheme 1c).[8] Recently, the
boron-Wittig reaction of aldehydes provides a transition-metal-
free approach to access internal trisubstituted vinylboronates,
where high stereoselectivity could be achieved only with bulky
[*]
Dr. Y. Hu, W. Sun, N. Xu, J. Xu, 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)
Scheme 1. Strategies for the stereoselective synthesis of internal
trisubstituted vinylboronates.
The 1,2-metalate rearrangement by a nucleophilic group shift
from the boron center to an adjacent electrophilic center has
E-mail: chaoliu@licp.cas.cn
been demonstrated as one of the classic transformations in
T. Zhang, Prof. Dr. Y. Lan
5-6, 10]
organoboron chemistry.[2,
Our group recently has been
School of Chemistry and Chemical Engineering, Chongqing
University, Chongqing 400030 (P. R. China)
College of Chemistry and Molecular Engineering, Zhengzhou
University, Zhengzhou 450001 (P. R. China)
focusing on the borylative transformation of carbonyl compounds
with 1,2-metalate rearrangements as the essential step.[11] The
key for metalate rearrangements is to find a way to build up the
tetracoordinated boronates bearing both a proper migratory
nucleophilic group and a proper electrophilic center. Enolates,
as the central reactive form of carbonyl compounds, have been
widely utilized as carbonyl-containing carbon-nucleophiles in
many organic syntheses.[12] We envisioned that the reaction
W. Sun, N. Xu
University of Chinese Academy of Sciences
Beijing 100049 (P. R. China)
[+]
Yue Hu and Wei Sun contributed equally to this work
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201909235
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between an enolate anion En-1 and the diboron reagent B2pin2
might afford a tetracoordinated boron enolate O-I (Scheme 1e).
Structurally, the O-bound boron enolate O-I can isomerize to its
C-bound form C-I.[12] In the case of C-I, the carbonyl group
would locate at the -position of the tetracoordinated boron
center. The polar carbonyl group (C=O) has been shown to
induce 1,2-metalate rearrangement of acylborons to generate -
oxyboronates.[13] On the other hand, the bulky available
amphoteric B2pin2 has been used as a tri-coordinated boron
bearing a migratable boryl (Bpin) group.[14] Therefore, it was
reasonable to propose that the following novel carbonyl-induced
1,3-metalate rearrangement of C-bound boron enolate C-I could
occur to generate -oxylboronate II (Scheme 1e). It is known
that -oxylboron unit is facile to occur boron-Wittig elimination.[9,
result, R1 and R2 were stereoselective at the Z-position in the
final product.
15]
Therefore, the sequential B-O elimination of II’ would release
the desired vinylboronates 2.
Scheme 2. Initial studies on the stereoselective borylation of lithium ketone
enolate.
To validate our hypothesis in Scheme 1e, the lithium enolate
En-1a, generated from the deprotonation of 1-(4-
fluorophenyl)butan-1-one (1a) with LDA, was used as the model
substrate (Scheme 2). Heating the reaction mixture of En-1a
o
and B2pin2 (1.2 equiv) at 130 C for 12 h indeed afforded the
desired alkenylboronic ester 2a in 50% yield (Scheme 2, eq. 1).
Addition of Mg(OMe)2 (1.0 equiv) increased the yield of 2a to
79%. We speculated that Mg(OMe)2 was most likely to activate
carbonyl group to increase its polarity so as to enhance the
migration step. These reactions were highly selective to give the
Z-isomer as the major product (Z:E > 99:1) and the solid
structure of Z-2a was unambiguously confirmed by single crystal
X-ray diffraction. The reaction could be easily scaled up to 10
mmol without loss of reactivity and 2.18 g (79%, Z:E > 99:1) of
2a was isolated (eq. 1). When En-1a was prepared from the
activation of its corresponding silyl enol ether TMS-En-1a (Z:E >
99:1) with MeLi,[16] the borylation with B2pin2 proceeded well in
the absence of Mg(OMe)2 to give 2a in 71% yield. Moreover, a
different Z/E ratio of the starting silyl enol ether TMS-En-1a (Z:E
= 80:20) also selectively afforded Z-isomer of 2a in 78% yield.
These results demonstrated a stereoselective process for this
enolate borylation (Scheme 2, eq. 2). Obviously, according to
the hypothesis in Scheme 1e, the migrative addition of boryl to
carbonyl group determined the stereostructure of the final
product 2, as the migrative addition tended to give II with R1 and
R2 at the trans-position to avoid the steric hindrance. Then, a
single bond rotation was required to generate II’ from II. As a
Scheme 3. Stereoselective synthesis of trisubstituted alkenylboronic esters
from lithium enolates. Reaction condition: see details in SI for the generation
of En-1 (0.5 mmol). B2pin2 (0.6 mmol), Mg(OMe)2 (0.5 mmol), DME or toluene
(1.5 mL), 130 oC, 12 h; Isolated yield; The ratio of Z/E was determined by 1H
NMR analysis. aB2pin2 (1.0 mmol). b150 oC, 12 h. cThe ratio of Z/E was
determined by GC analysis. dNo Mg(OMe)2 was added. eMg(OEt)2 (0.55 mmol)
was used instead of Mg(OMe)2, 160 oC, 24 h.
Then, various lithium ketone enolates were smoothly
converted to their corresponding stereospecific trisubstituted
vinylboronates (Scheme 3). As described above, the borylation
of internal alkynes has been demonstrated as the major
processes for the stereoselective synthesis of internal
trisubstituted vinylboronates,[6] but the inherent regioselectivity
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was depended on the discrimination of R1 and R2 in the alkyne
substrates (Scheme 1a). With this method, the borylative site
can be exclusively controlled by the C-O bond of lithium enolate.
For example, the isomeric 1,2-diaryl enolates En-1b and En-1b’
selectively gave their corresponding 2b and 2b’ in good yields
with excellent stereoselectivity, respectively. To our knowledge,
there is no other method to access these single Z-isomers in
pure form.[17] A variety of other lithium ketone enolates were
tested. The distinct substituents on the aromatic ring of the
substrates demonstrated that electronic properties showed trivial
influence on the reactivity (2c-2l). For instance, substrates
bearing electron-donating groups (1c, 1l) and electron-
withdrawing groups (1f) were all tolerated under the current
conditions, although only moderate yield was obtained when
CF3-substituted ketone was applied as the substrates. C-Cl (1d)
and C-Br (1e) functionalities were also well tolerated, providing
the possibility for further functionalizations. Delightfully, thienyl-
derived heterocycle was also suitable for this transformation to
provide the desired product 2g in 47% yield. In this case, a
relatively low stereoselectivity of 2g was observed. The steric-
hindered substrates with alkyl group at the β-position of the
carbonyl moiety were also applicable to the present
transformation, affording the corresponding products in
moderate to good yields (2m-2p). The site of the C-O bond in
these enolates could be at both -position and -position of aryl
group to generate their corresponding -aryl and -aryl
alkenylboronic esters 2q and 2r. Apart from lithium enolates
derived from aromatic ketones, those enolates derived from
aliphatic ketones could also be applied as substrates. Substrate
En-1s was successfully transformed into the desired
alkenylboronic ester 2s in moderate yield, and the enolate of β-
tetralone (En-1u) delivered 2u in 45% yield. For the enolates of
simple acyclic aliphatic ketone (En-1t) and cycloheptanone (En-
1v), their corresponding alkenylboronic esters 2t and 2v were
obtained in 81% and 40% yields, respectively. Aldehyde
enolates have rarely been used in organic synthesis, as they
were extremely reactive to result in undesirable side reactions.[12]
To our delight, the generation of lithium aldehyde enolates from
the activation of their silyl enols with MeLi was suitable for this
En-1ab and En-1ac also proceeded well to afford the
corresponding 2ab and 2ac in good yields. In the case of 2ac, a
74:26 of Z:E ratio was obtained.
The reaction between diazo ketones and trialkylboranes was
an important method for the generation of boron enolates.[18]
One example was applied to demonstrate the applicability of the
corresponding enolate in this transformation (Scheme 5, eq. 1).
As described, the generated three-coordinated-boron enolate
treated with MeLi further generated B-En-1q. This activation
made the enolate anion easy to react with B2pin2 to afford the
desired alkenylboronic ester 2q in 39% yield. Very recently, we
have developed an approach to generate boron enolates directly
from carboxylic acid and 1,1-diborylalkanes.[19] Thus, an enolate
B-En-1ad, derived from the reaction between benzoic acid and
1,1-diborylethane, was applied to react with B2pin2, and the
desired 2ad was obtained in 44% yield (Scheme 5, eq. 2).
Scheme 5. Borylation of ketone enolates from different precursors.
As hypothesized in Scheme 1e, the interaction between
enolate anion and B2pin2 initially generated a tetracoordinated-
boron enolate with an equilibrium between O-bound O-I and C-
bound C-I forms. Moreover, the interaction may promote B2pin2
to offer a nucleophilic boryl group.[20] The sequential 1,3-
metalate rearrangement was crucial for boryl addition to the
carbonyl group. The NMR experiments were first carried out and
exhibited that the lithium enolate was in O-bound form. After its
interaction with B2pin2, the generated boron enolate was also in
O-bound form with the observation of Z/E isomers in equilibrium
at room temperature (See detailed NMR in SI), although several
quaternized boron enolates have shown to be C-bound.[21] The
DFT calculations also showed an easy isomerization between
the O-bound and C-bound boron enolate with an energy barrier
of 14.4 kcal/mol (with lithium butyrophenone enolate En-1d and
B2pin2 as the model). The subsequent 1,3-boryl shift in the C-
bound enolate to attack its carbonyl group could occur through
two possible conformations, the Erythro-migration and the
Threo-migration (Figure 1). According to the DFT calculations,
the overall activation free energy of the Erythro-migration was
31.0 kcal/mol, which was 3.1 kcal/mol lower than that of Threo-
migration (34.1 kcal/mol). Obviously, the Erythro-migration (7-ts-
borylative
transformation.
The
corresponding
terminal
vinylboronates 2w and 2x were obtained in 65% and 54% yields,
respectively.
ery) resulted in
a small steric interaction between the
pseudoaxial C1-Ph and C2-H. In contrast, the Threo-migration
(7-ts-thr) would result in a repulsion between the pseudoaxial
C1-Ph and C2-Et. Therefore, the Erythro-migration was
kinetically favored, which thus led to the formation of Z-
alkenylboron through an easy B-O elimination of the -oxylboron
unit (Scheme 1e, II’). On the contrary, the Threo-migration would
lead to E-alkenylboron. A value of Z:E = 98:2, predicted by the
DFT calculation based on the energy difference of 7-ts-ery and
7-ts-thr, was in agreement with the experimental result. The free
energy profiles revealed that the steric hindrance controlled the
stereoselectivity. Moreover, the 1,3-boryl shift to attack the
Scheme 4. Synthesis of tetrasubstituted alkenylboronic esters via borylation of
lithium ketone enolates. Reaction condition: aB2pin2 (1.2 equiv) was used.
bB2cat2 (4.0 equiv) was used instead of B2pin2, no Mg(OMe)2 was added, 150
oC, 24 h, pinacol and Et3N were needed for work-up after the completion of the
reaction. cThe ratio of Z/E was determined by 1H NMR analysis.
Furthermore, using tetrasubstituted lithium enolates, various
tetrasubstituted vinylboronic esters were also synthesized under
this transition-metal-free condition (Scheme 4). Several
representative lithium enolates, such as the enolates of
cyclobutyl, cyclopentyl and cyclohexyl phenylketones, afforded
their alkenylboronic esters in high yields (2y, 2z and 2aa),
respectively. The enolates of acyclic substituent phenylketone
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10.1002/anie.201909235
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carbonyl group was the rate-determining step in the overall
transformation.[22]
The synthetic versatility of the present reaction was further
investigated through the transformation of these stereospecific
vinylboronates (Scheme 7). The homo-coupling of 2a was
achieved in the presence of a catalytic amount of PdCl2,
affording conjugated diene (E,E)-homo-2a in high yield with
excellent stereoselectivity. Dienestrol is an approved API, which
has been used in treatment of menopausal symptoms and
prostate cancer. The traditional methods usually provided a
mixture of stereoisomers. To our delight, based on this
stereospecific synthesis of trisubstituted vinylboronates, a highly
efficient protocol for the synthesis of single isomeric Dienestrol
from the homo-coupling of 2c followed by demethylation was
disclosed (Scheme 7a).[23] Moreover, the stereoselective access
to trisubstituted alkenes could be realized by using two different
protocols from the same starting material 2h, providing E-2h-cc1
and Z-2h-cc1 in 98% and 65% yields in excellent
stereoselectivity, respectively (Scheme 7b). Furthermore,
To further demonstrate the steric hindrance on controlling the
stereoselectivity, an aldehyde enolate En-1ae was subjected to
the reaction conditions, in which the small C1-H group was
presented. The desired vinylboronic ester 2ae was obtained in
54% yield with a low stereoselectivity (Z:E = 58:42) (Scheme 6,
eq. 1). Meanwhile, the lithium enolate of 4-heptanone En-1af
(C1-Pr and C2-Et) gave the desired vinylboronic ester 2af in
60% yield with a high Z-selectivity (Z:E = 97:3) (Scheme 6, eq.
2). These results further confirmed that the steric hinderance
controlled the stereoselectivity and the repulsion between C1-Pr
and C2-Et groups was enough to result in
stereoselectivity.
a
high
vinylboronate
2a
was
successfully
transformed
to
cyclopropylboronate 2a-cp in 78% yield in a stereospecific
manner (d.r. > 99:1) under the condition of ZnEt2/CH2I2.
Meanwhile, in the presence of NaOH/I2, 2a was smoothly
converted to stereospecific vinyl iodide 2h-l, which was believed
to be useful building block for further transformations (Scheme
7c).
Figure 1. Newman projections of Erythro-migration and Threo-migration.
In summary, a stereoselective synthesis of trisubstituted
vinylboronates from the transition-metal-free borylation of lithium
ketone enolates has been successfully developed. Carbonyl-
induced 1,3-metalate rearrangement through C-bound boron
enolate was demonstrated to enable the stereospecific C-O
borylation of lithium enolates. DFT calculations and control
experiments revealed that the steric hindrance predominantly
controlled the stereoselectivity. A variety of stereospecific tri-
substituted vinylboronates and several tetrasubstituted
vinylboronates were easily obtained. With the stereospecific
Scheme 6. Steric effects on the borylation of lithium aldehyde enolate and
aliphatic ketone enolate
vinylboronates,
a
Pd-catalyzed homo-coupling efficiently
afforded a single isomeric Dienestrol. Moreover, this enolate
borylation process could diversify into stereospecific tri-
substituted olefins, vinyl iodide and cyclopropylboronate
derivatives.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (Grant no. 91745110, 21673261, 21603245,
21633013, 21703265, 21872156, 21802150, 21822303 and
21772020), Natural Science Foundation of Jiangsu Province
(Grant no. BK20181194, BK20180247). Support from the Young
Elite Scientist Sponsorship Program by CAST (YESS20170217),
the Youth Innovation Promotion Association CAS (2018458)
were also acknowledged.
Keywords: Borylation • Vinylboronates • Lithium Enolate •
Metalate Rearrangement • Stereospecific Synthesis
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COMMUNICATION
COMMUNICATION
Yue Hu, Wei Sun, Tao Zhang, Nuo Xu,
Jianeng Xu, Yu Lan, and Chao Liu*
Page No. – Page No.
Stereoselective Synthesis of
Trisubstituted Vinylboronates from
Ketone Enolates Triggered by 1,3-
Metalate Rearrangement
1 to 3: An unprecedented stereoselective synthesis of trisubstituted vinylboronates
from the transition-metal-free borylation of lithium ketone enolates was developed.
Carbonyl-induced 1,3-metalate rearrangement through C-bound boron enolate was
demonstrated to trigger the stereospecific C-O borylation of lithium enolates. DFT
calculation and control experiment reveal that the steric hindrance controlled the
stereoselectivity. A variety of stereospecific trisubstituted vinylboronates and
several tetrasubstituted vinylboronates were easily obtained. Based on the
transformation of stereospecific vinylboronates, a single isomeric Dienestrol was
efficiently obtained.
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