Site-Selective Mono-Oxidation of 1,2-Bis(boronates)

Article abstract of DOI:10.1021/acs.orglett.9b01204

Site-selective oxidation of vicinal bis(boronates) is accomplished through the use of trimethylamine N-oxide in 1-butanol solvent. The reaction occurs with good efficiency and selectivity across a range of substrates, providing 2-hydro-1-boronic esters which are shown to be versatile intermediates in the synthesis of chiral building blocks.

Full text of DOI:10.1021/acs.orglett.9b01204

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Site-Selective Mono-Oxidation of 1,2-Bis(boronates)
Lu Yan and James P. Morken*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S
* Supporting Information
ABSTRACT: Site-selective oxidation of vicinal bis(boronates) is
accomplished through the use of trimethylamine N-oxide in 1-butanol
solvent. The reaction occurs with good efficiency and selectivity across a
range of substrates, providing 2-hydro-1-boronic esters which are shown
to be versatile intermediates in the synthesis of chiral building blocks.
atalytic enantioselective diboration is a valuable tool for
transforming inexpensive, abundant alkenes into a variety
primary-selective C−C bond-forming reactions mentioned
above, the oxidation reaction is secondary-selective and
provides a versatile new motif for construction of difunctional
molecules.
We considered that selectivity in oxidation of 1,2-bis-
(boronates) could arise from one of two different manifolds.
First, we considered that if coordination of the oxidant to
boron was sensitive to steric effects and the subsequent 1,2-
boron shift were facile, then selectivity for the primary site
might be observed; such an outcome might be expected with a
hindered, highly reactive oxidant (Scheme 2, eq 1).
C
of functionalized chiral products.11 Over the past several years,
our group has introduced efficient and stereoselective alkene
diboration reactions that are catalyzed by chiral rhodium1a,b or
platinum1c,d complexes and most recently has developed a
carbohydrate-catalyzed asymmetric process.1f,g In addition to
these reports, Nishiyama2 has advanced a Rh(phebox)-
catalyzed enantioselective process, and Hoveyda3 has provided
routes to enantiomerically enriched vicinal bis(boronates) by
catalytic alkyne double hydroboration and by a three-
component reaction involving vinylboron compounds. While
the products of alkene diboration readily undergo stereo-
retentive oxidation to furnish vicinal diols, particularly useful
strategies emerge when site selective monofunctionalization of
1,2-bis(boronates) can be conducted (Scheme 1): the
Scheme 2. Prospective Selectivity Paradigms in Vicinal
Diboronate Oxidation Reactions
Scheme 1. Site-Selective Functionalization of 1,2-
Bis(boronates)
Alternatively, if 1,2-boronate rearrangement is the rate-limiting
step and coordination of the oxidant to boron is reversible,
then the more substituted electron-rich carbon may migrate
preferentially, providing selectivity as depicted in eq 2. With
this mechanistic framework as a guiding principle, a series of
oxidants and reaction conditions were analyzed for either
primary-selective or secondary-selective oxidation.
organoboron motif that remains after a selective mono-
functionalization reaction can be transformed separately, such
that the overall process can give rise to a broad array of useful
motifs. So far, only two site-selective transformations of
nonfunctionalized4 1,2-bis(boronates) have been developed,
one involving regioselective Suzuki−Miyaura coupling5 and
the other involving homologation with chiral lithiated
carbamates.6 In this report, we show that with appropriate
reaction conditions, oxidation of 1,2-bis(boronates) can be
accomplished with excellent site selectivity. Unlike the
To gain a baseline understanding of selectivity with
peroxyanions,7 1,2-bis(boronic) 1 (Table 1) was treated with
a 1:1 mixture of potassium hydride and tert-butyl hydro-
1
peroxide for 1 h and analyzed by H NMR. This reaction
proceeded to 65% conversion, providing mono-oxidation
Received: April 5, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01204
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Survey of Oxidants in Selective Oxidation of 1,2-
Bis(boronates)
Table 2. Impact of Solvent and Reaction Conditions on
Oxidation of 1,2-Bis(boronates) with Amine Oxides
a
b
a
b
b
entry
oxidant
equiv
solvent
conv (%)
5
(%)
entry
oxidant
% conv
2
(%)
10
3
(%)
52
1
2
3
4
5
6
7
8
9
TMANO
TMANO
TMANO
TMANO
TMANO
TBANO
TBANO
NMO
1.5
1.5
1.5
1.5
1.5
1.5
2.0
1.5
2.0
THF
DMF
72
80
68
67
65
49
82
54
92
41
1
2
3
4
5
6
KH/tBuOOH
mCPBA
(t-BuO)2
(BzO)2
pyridine N-oxide
Me3NO
65
62
<5
<5
<5
65
36
40
32
44
42
64
46
70
<5
43
CHCl3
toluene
n-BuOH
n-BuOH
n-BuOH
n-BuOH
n-BuOH
42
23
a
1
Conversion determined by H NMR versus an internal standard.
Percent yield determined after purification by silica gel chromatog-
b
NMO
raphy.
a
1
Conversion determined by H NMR versus an internal standard.
Percent yield determined after purification by silica gel chromatog-
b
product 2 together with the product resulting from over
oxidation (3); the mono alcohol product arising from
oxidation of the primary organoboronic ester was not detected.
As depicted in Table 1, other oxidants were examined in the
oxidation. m-Chloroperbenzoic acid afforded overoxidized
product 3 exclusively (entry 2). The neutral peroxides di-
tert-butyl peroxide and dibenzoyl peroxide were unreactive
even at elevated temperatures. Lastly, amine N-oxides were
examined, and it was found that whereas pyridine N-oxide is
unreactive (entry 5), the more electron-rich reagent trimethyl-
amine N-oxide (TMANO), a compound known to be effective
in organoborane oxidations,8 provided 75% conversion with
the mono-oxidation product being the predominant reaction
product (entry 6). Subsequent experiments with TMANO
(not shown) revealed that compound 2 was formed with >95%
enantiospecificity when enantiomerically enriched 1 was
employed as substrate. For this reason, amine N-oxides were
selected as a class of reagents for further study.
raphy.
and reaction conditions were then examined, with 2 equiv of
N-methylmorpholine N-oxide (NMO) furnishing the highest
overall isolated yield (entry 9, Table 2).
With effective reaction conditions developed, alkenes
bearing a number of functional groups were examined in the
tandem carbohydrate-catalyzed enantioselective diboration/
mono-oxidation sequence. As shown in Table 3, aliphatic
alkenes underwent the cascade reaction well, providing good
yields and enantioselectivity (compounds 5−8). Allyl benzenes
Table 3. Substrate Survey in Tandem Diboration/Mono-
Oxidation
To develop reaction sequences that employ alkenes as the
substrate for a cascade diboration/mono-oxidation sequence,
we investigated direct introduction of amine N-oxides to
reaction mixtures obtained from carbohydrate-catalyzed
diboration (Table 2). In these experiments, it was found to
be most convenient to treat the crude cascade reaction product
with pinacol such that boronic ester exchange would provide a
chromatographically stable pinacolato boronate as the isolable
product. As shown in Table 2, when the amount of TMANO
was increased, the extent of reaction increased from 65%
(Table 1, entry 6) to 72%; however, the isolated yield of
mono-oxidation product remained the same (Table 2, entry 1).
The presence of significant amounts of overoxidation product
suggested that the mono-oxidation product 5 (or its derived
borate ester) may be more reactive toward TMANO than the
bis(boronate) 4. Reasoning that enhanced reactivity of the
mono-oxidation product might be due to intramolecular Lewis
acid activation of the remaining boronic ester by the newly
formed borate ester motif, we considered other reaction media
that might alter such interactions. While DMF, toluene, and
chloroformsolvents that are not expected to significantly
interrupt internal chelationdid not alter the reaction
outcome, when 1-butanol was employed as the reaction
solvent, the isolated yield became much more reflective of the
extent of conversion, suggesting overoxidation was less
problematic. With 1-butanol as solvent, other amine N-oxides
a
1
Conversion determined by H NMR versus an internal standard.
b
Percent yield determined after purification by silica gel chromatog-
c
raphy. This experiment employed Cs2CO3 catalysis in place of TBS-
DHG/DBU, and therefore, the product is racemic.
B
DOI: 10.1021/acs.orglett.9b01204
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
also underwent smooth transformation to the β-hydroxybor-
onate (compounds 9, 10), as did compounds with a protected
hydroxyl groups (entries 11, 12, 14, and 15). Of consequence
with respect to synthetic utility, alkenes bearing adjacent pre-
existing stereogenic centers underwent the reaction with
product stereochemistry arising from near-complete catalyst
control (compounds 14, 15). As shown with compounds 16
and 17, terminal alkenes can undergo carbohydrate-catalyzed
alkene diboration selectively in the presence of internal
alkenes. With internal alkenes, mono-oxidation can be
accomplished, and as shown by compound 19, the benzylic
carbon migrates in preference to a secondary alkyl group.
Lastly, it was found that the two-step reaction sequence can be
performed on a preparatively useful scale with only minor
modification (see the Supporting Information) and deliver
comparable product yield (compound 5: 65% yield for 1 mmol
scale reaction).
Procedures, characterization, and spectral and chromato-
graphic data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: morken@bc.edu.
ORCID
James P. Morken: 0000-0002-9123-9791
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge the NIH for funding (NIGMS GM-
R35-127140). L.Y. is the recipient of a LaMattina Graduate
Fellowship.
To demonstrate the synthetic utility of the β-hydroxyl
boronic ester, several tandem enantioselective diboration/
mono-oxidation products were subjected to alcohol protection,
forming either a silyl ether or a methoxymethyl ether. As
shown in eq 3, after hydroxyl protection the primary boronic
ester can be transformed into a Boc-protected amine (20)
using a method developed in our laboratory.9 Conversion of
terminal alkenes to enantiomerically enriched 1,2-amino
alcohols represents a useful method to synthesize unnatural
amino alcohols. It was also found that the boronic ester can
undergo homologation when treated with conditions devel-
oped by Matteson (for ease of isolation, the boronate was
oxidized to alcohol, eq 4).10 Lastly, by employing an approach
developed by Aggarwal (eq 5), the pinacol boronate can be
replaced with a bromine atom.11
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■
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01204.
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DOI: 10.1021/acs.orglett.9b01204
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Letter
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DOI: 10.1021/acs.orglett.9b01204
Org. Lett. XXXX, XXX, XXX−XXX