Diversity-Oriented Synthesis of α-Functionalized Acylborons and Borylated Heteroarenes by Nucleophilic Ring Opening of α-Chloroepoxyboronates

Article abstract of DOI:10.1002/anie.201907349

The ring-opening reactions of N-methyliminodiacetyl (MIDA) α-chloroepoxyboronates with different nucleophiles allow the modular synthesis of a diverse array of organoboronates. These include seven types of α-functionalized acylboronates and seven types of

Full text of DOI:10.1002/anie.201907349

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Accepted Article
Title: Diversity-Oriented Synthesis of α-Functionalized Acylborons
and Borylated Heteroarenes via Nucleophilic Ring-Opening of α-
Chloroepoxyboronates
Authors: Honggen Wang, Dong-Hang Tan, Yuan-Hong Cai, Yao-Fu
Zeng, Wen-Xin Lv, Ling Yang, and Qingjiang Li
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201907349
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10.1002/anie.201907349
Angewandte Chemie International Edition
COMMUNICATION
Diversity-Oriented Synthesis of α-Functionalized Acylborons and
Borylated Heteroarenes via Nucleophilic Ring-Opening of -
Chloroepoxyboronates
Dong-Hang Tan, Yuan-Hong Cai, Yao-Fu Zeng, Wen-Xin Lv, Ling Yang, Qingjiang Li and Honggen
Wang*
Abstract:
The
ring-opening
reactions
of
MIDA
α-
diborylalkanes,[12] and copper(I)-catalyzed borylation of
aldehydes.[13] Remarkably, recent advances from the groups of
Perrin,[14] Ito and Bode[15] demonstrated the mild and concise
synthesis of acylborons by means of chemoselective oxidative
fragmentation of alkenyl N-methyliminodiacetyl (MIDA) boronates,
either via dihydroxylation/meta-periodate cleavage or direct
ozonolysis. Yet, the linear synthetic sequence involved may
greatly compromise the overall efficiency as well as the diversity
of the products. Herein, we report our realization of a divergent
acylboron synthesis via an unexpected nucleophilic ring-
opening/substitution reaction of MIDA α-chloroepoxyboronates
(Scheme 1b). The reaction allowed the efficient synthesis of a
wide variety of α-functionalized acylborons, some of which are
challenging targets by using alternative means. Moreover, by
reacting with dinucleophiles, several borylated heteroaromatics
were constructed in good efficiency.
chloroepoxyboronates with different nucleophiles allow the modular
synthesis of a diverse array of organoboronates. These include 7
types of α-functionalized acylboronates and 7 types of borylated
heteroarenes, some of which are difficult-to-access products using
alternative methods. The common synthons α-chloroepoxyboronates
could be viably synthesized via a two-step procedure from the
corresponding alkenyl MIDA boronates. Mild reaction conditions,
good functional group tolerance, and generally good efficiency were
observed. The utility of the products was also demonstrated.
There is a growing interest in the chemistry of acylborons.[1] Their
synthetic values, exemplified by their involvements in the
chemoselective amide formation,[2] synthesis of borylated
heterocycles[3] and -aminoboronic acids,[4] have rendered them
appealing targets in organic synthesis. Two classic approaches
toward acylboron preparation include the reaction of a boryl metal
species[5] with a carbonyl electrophile, and the reaction of an acyl
anion equivalent (generated under strong basic conditions) with
an electrophilic boryl reagent.[6] An elegant alternative to these
approaches is the Bode acylboron synthesis, wherein
a
electrophilic zwitterionic boronate reagent is used to react with
organometallic reagents to afford potassium acyltrifluroborates
(KATs).[7] Despite the great value, the harsh reaction conditions
associated with these methods eliminate their applicability in the
preparation of more functionalized or complex acylboron. Very
recently, Bode invented a new trifluoroborate iminium reagent
bearing a tin moiety which could undergo Stille coupling with aryl-
or vinylhalides to provide KATs.[8] By taking advantage of the
stability of sp3-B boronates, several conceptually new routes to
acylborons based on the late-stage functional group manipulation
of a boron-containing organic precursor were also developed
(Scheme 1a). In this regard, Yudin and Ito reported the oxidation
reaction of α-hydroxy boronates into acylboron-compounds. The
key α-hydroxy boronate intermediates were prepared via Barton
radical decarboxylation of MIDA α-borylcarboxylic acid,[9] ring-
opening of 2-boryl oxirane,[10] dihydroxylation of alkenyl
boronates,[11]
oxidation
of
unsymmetrical
geminal
Scheme 1. Synthesis of acylborons.
[*]
D.-H. Tan, Y.-H. Cai, Y, Y.-F Zeng, W.-X Lv, L. Yang, Prof. Q. Li,
Prof. H. Wang
Guangdong Key Laboratory of Chiral Molecule and Drug Discovery,
School of Pharmaceutical Sciences, Sun Yat-sen University,
Guangzhou 510006, China
Our inspiration for this design was drawn from the rearrangement
reaction of α-haloepoxysilanes, disclosed by Utimoto and Oshima
two decades ago.[16] Upon the treatment of various metal halides,
α-haloepoxysilanes were converted into valuable α-
haloacylsilane products (Scheme 1c). We thus questioned the
amenability of α-chloroepoxyboronates in similar rearrangement
reactions. The use of different nucleophiles or dinucleophiles may
result in a facile and divergent synthesis of organoborons. We
recently disclosed a stereoselective chlorination of alkenyl MIDA
boronates.[17] The chemoselective epoxidation of the α-
E-mail: wanghg3@mail.sysu.edu.cn
Prof. H. Wang
State Key Laboratory for Chemistry and Molecular Engineering of
Medicinal Resources, School of Chemistry and Pharmaceutical
Sciences of Guangxi Normal University, Guilin 541004, China
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201907349
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COMMUNICATION
chloroalkenyl boronates with m-CPBA provided a reliable route to
MIDA α-chloroepoxyboronates as typically bench-stable solid.
Nevertheless, previous studies by Yudin,[18] Burke[19] and
Gevorgyan[20] indicated the 1,2-boryl migration might be a
competing side reaction (Scheme 1d).
reaction, giving the α-iodo acylboron products in good yields.
Interestingly, this type of products are intriguing synthons but
have not been synthesized according to literature survey.
The success of ring-opening reaction using external iodide
nucleophile encouraged us to explore the feasibility of using α-
chloroepoxyboronate as a platform molecule in the modular
synthesis of more complex -functionalized acylborons.
Treatment of 1a with indole in HFIP at slightly elevated
temperature (50 oC) effected a C-C bond formation to provide the
corresponding -indolyl acylboronate (4) in 73% yield. The C2- or
N-substituted indole was also applicable (5, 6). Further, after the
first rearrangement reaction of aryl -chloroepoxyboronate in
HFIP, the heteroatom-centered nucleophile, including anilines
and sodium mercaptobenzothiazole was introduced and the
reaction gave the -amino (7-9) or -sulfur acylboronates (10) in
good efficiency. It should be pointed out that -amino
acylboronates are important synthons in chemoselective peptide
ligation. KSCN was also effective nucleophile to provide the -
thiocyano acylboronate (10). In this case, the evaporation of HFIP
solvent before the substitution reaction ensured a higher yield. In
another vein, the use of potassium benzoate as a nucleophile in
the presence of 18-crown-6 led to the formation of -oxygen
acylboronate (12a). Interestingly, upon prolonging the reaction
time, 12a was cleanly isomerized to -carbonyl boronate 12b in
good yield.[9] "The interaction between the * orbital of the
carbonyl group and the C–B orbital[23] and/or the conjugation of
the carbonyl with the aryl moiety in 12b may provide a
thermodynamic driving force to this process. The scope of the
reaction was not limited to aryl -chloroepoxyboronates, alkyl
substituted substrates were also applicable in these reaction, as
represented by the effective bromination (14) and thiocyanation
(15) reaction. It should be noted that the majority of these -
functionalized acylboronates were new synthons in spite of their
great synthetic potential.
We first investigated the rearrangement reaction of phenyl-
substituted MIDA α-chloroepoxyboronate. As expected, a number
of Lewis acids were effective to promote the desired reaction as
reported in rearrangement reaction of α-haloepoxysilanes.[21]
However, a better 82% yield was obtained under the additive-free
conditions when the polar and acidic hexafluoroisopropanol
(HFIP) [22] was used as solvent at room temperature (Scheme 1).
Interestingly, no 1,2-boryl migration side product was observed.
The scope of this synthesis was then explored with a series of
substituted aryl α-chloroepoxyboronates. Some valuable
functional groups such as fluoro (2b-d), chloro (2e-f), bromo (2g),
trifluoromethyl (2h) and cyano (2i) were well tolerated to afford
the corresponding acylboronates in generally moderate to good
yields. For substrates bearing electron-withdrawing substituents,
a higher reaction temperature was beneficial for reactivity.
Scheme 2. Conversion of α-chloroepoxyboronates to -halo acylborons. [a] rt.
1.5 h. [b] rt, 9 h. [c] 70 oC, overnight. [d] 50 oC, overnight.
The subjection of alkyl substituted MIDA α-chloroepoxyboronates
in the above reaction conditions failed to give the products in
satisfactory yields. We reasoned that a carbon cation might be
formed in the reaction mechanism (SN1 substitution) and the
instability of secondary carbon cation may account for the low
reactivity. However, the use of NaI as nucleophile in DCM resulted
in a clean SN2 nucleophilic ring-opening/chloride elimination
Scheme 3. Synthesis of -functionalized acylborons. Reaction conditions: [a]
1a, indole, HFIP, rt, 1.5 h. [b] 1a, HFIP, 1.5 h; then amine, CH3CN, rt, overnight.
[c] 1a, HFIP, 1.5 h; then indoline, CH3CN, rt, 3 h. [d] 1a, HFIP, 1.5 h; then sodium
mercaptobenzothiazole, CH3CN, rt, 3h. [e] 1a, HFIP, 1.5 h; then KSCN, CH3CN,
rt, 2h. [f] 1a, HFIP, 1.5 h; then PhCOOK, 18-crown-6, CH3CN, 0.5 h. [g] 1a, HFIP,
1.5 h; then PhCOOK, 18-crown-6, CH3CN, overnight. [h] 1a, NaBr, CH3CN, 70
oC, 24 h. [i]1r, NaBr, CH3CN, 90 oC, overnight. [j] 1r, KSCN, CH3CN, 50 oC,
overnight. For more details, see SI.
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10.1002/anie.201907349
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Boron-containing heteroarenes are of great value due to the
versatility of C-B bond to be involved in diverse chemical bonds
formation,[24] thereby facilitating the quick assemblies of
heteroaromatics-based molecular library.[25] The 2-boryl
heteroarenes, however, are typically unstable,[26] which precludes
their practical utilization. The engagements of -haloketones as
dielectrophiles in heterocycle synthesis encouraged us to
examine the synthetic potential of α-chloroepoxyboronates in
downstream transformations leading to borylated heterocycles,
particularly those among the privileged scaffolds in medicinal
chemistry.[27] As a matter of fact, Yudin pioneered the use of -
bromo acylboronates and oxalyl boronates, both prepared via
Scheme 4. Synthesis of borylated heterocycles. Reaction conditions: [a] 1, thiobenzamide, CH3CN, 100 oC, 8h. [b] 1, HFIP; then thiobenzamide, CH3CN, rt, 9 h. [c]
1, o-phenylenediamine, CH3CN, air, 70 oC, 8 h. [d] 1, HFIP; then o-phenylenediamine, CH3CN, air, 50 oC, overnight. [e] 1, NaI; dinucleophiles, CH3CN, 50 oC, 20 h.
[f] 1, HFIP; then dinucleophiles, CH3CN, 70 oC, 1 h; TEA, rt, 1h. [g] 1, HFIP; then dinucleophiles, CH3CN, 70 oC, 8 h; Amberlite IRA-67, 40 oC, 1h. [h] 1a,
phenylhydrazine, CH3CN, rt, 2 h. [i] 1, NaBr, DCM, 90 oC; then malononitrile, Et2NH, CH3CN, rt, 3 h. [j] 1, HFIP; then malononitrile, Et2NH, CH3CN, rt, 0.5 h. For
more details, see SI.
multi-step procedures, in the preparation of several types of
borylated heteroaromatics.[3a,10] We found that thiobenzamide and
o-phenylenediamine could react directly with alkyl -
chloroepoxyboronates under additive-free conditions to deliver
the corresponding borylated 5-alkyl thiazoles (16a-d) and
borylated 3-alkyl quinoxalines (17a-d), respectively. The aryl α-
chloroepoxyboronates were also applicable, but the
rearrangement reaction to form an -chloro acylboronate
intermediate in HFIP prior to the addition of external
dinucleophiles led to higher yields with one single separation
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might serve as the oxidant for aromatization for the synthesis of
quinoxalines. Similarly, the telescoped synthesis of borylated
imidazo[1,2-a]pyridines
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(18a-g),
borylated
imidazo[1,2-
substitution/condensation methodology with phenylhydrazine
resulted in a formation of borylated 1,2-dihydro-1,2-diazete
product (20). And the reaction of malononitrile successfully
delivered the 2-borylated furans (21a-f) in moderate to high yields.
In all these cases, complete regioselectivity was observed and the
obtained 2-MIDA boryl heteroarenes are air-stable as indicated
previously.[3,4,23] To the best of our knowledge, 2-boryl derivatives
of imidazo[1,2-b]pyridazine (19a) and 1,2-dihydro-1,2-diazete (20)
have not been reported in the literature.
[3]
[4]
The synthetic value of the products was also explored. When
reacting MIDA acylboronate 8 with benzyl azide,[2a] the amide
ligation product 22 could be obtained (eq 1). On the other hand,
the borylated thiazole 16e was subjected to Suzuki-Miyaura
coupling under our previously reported conditions,[17] leading to
synthesis of a fully-substituted thiazole 23 in 82% yield (eq 2).
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In conclusion, the bench-stable α-chloroepoxyboronates
served as intriguing synthons toward the modular synthesis of a
wide variety of synthetically important organoborons. These
include 7 types of -functionlized acylboronates and 7 types of
borylated heteroarenes, some of which are difficult-to-access
products using alternative methods. All the products reported
could be isolated in chemically pure form and are bench-stable
solids, which ease them synthetic applications. Mild reaction
conditions, generally good yields, and exclusive regioselectivity
were observed. Synthetic applications to amide ligation reaction
and cross-coupling reactions were demonstrated.
[10]
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Financial supports from the Key Project of Chinese National
Programs for Fundamental Research and Development
(2016YFA0602900), the Local Innovative and Research Teams
Project of Guangdong Pearl River Talents Program
(2017BT01Y093) are gratefully acknowledged.
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Previously, we observed a vertical alignment of the C-B(MIDA) bond
with respect to the carbonyl C=O bond in the crystal structures of a
fluorinated α-boryl ketone compound (CCDC 1450162), which might be
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details, see: W.-X. Lv, Y.-F. Zeng, Q. Li, Y. Chen, D.-H. Tan, L. Yang,
H. Wang, Angew. Chem. Int. Ed. 2016, 55, 10069.
Keywords: acylboronate
•
borylated heteroarene
•
-
chloroepoxyboronate • rearrangement • ring-opening
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10.1002/anie.201907349
Angewandte Chemie International Edition
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D.-H. Tan, Y.-H. Cai, Y, Y.-F Zeng, W.-X
Lv, L. Yang, Q. Li, H. Wang*
Page No. – Page No.
Diversity-Oriented Synthesis of α-
Functionalized
Borylated
Acylborons
Heteroarenes
and
via
Text for Table of Contents
Nucleophilic Ring-Opening of -
Chloroepoxyboronates
The nucleophilic ring-opening reactions of N-methyliminodiacetyl (MIDA) -chloroepoxyboronates, a new synthon prepared via
a two-step procedure from alkenyl MIDA boronates, lead to the facile synthesis of 7 types of α-functionalized acylboronates and
7 types of borylated heteroarenes in a divergent manner. Some of the products are difficult-to-access by using alternative
methods. Mild and simple reaction conditions, good functional group tolerance, and generally good efficiency were observed.
The utility of the products was also demonstrated.
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