Structure and reactivity of boron-ate complexes derived from primary and secondary boronic esters

Article abstract of DOI:10.1021/acs.orglett.5b00918

Boron-ate complexes derived from primary and secondary boronic esters and aryllithiums have been isolated, and the kinetics of their reactions with carbenium ions studied. The second-order rate constants have been used to derive nucleophilicity parameters for the boron-ate complexes, revealing that nucleophilicity increased with (i) electron-donating aromatics on boron, (ii) neopentyl glycol over pinacol boronic esters, and (iii) 12-crown-4 ether.

Full text of DOI:10.1021/acs.orglett.5b00918

Letter
pubs.acs.org/OrgLett
Structure and Reactivity of Boron-Ate Complexes Derived from
Primary and Secondary Boronic Esters
Kathryn Feeney,† Guillaume Berionni,‡ Herbert Mayr,*,‡ and Varinder K. Aggarwal*,†
†Department of Chemistry, University of Bristol, Cantock’s Close, Bristol, BS8 1TS, U.K.
‡Department Chemie, Ludwig-Maximilians-Universitat Munchen, Butenandtstr. 5-13, 81377 Munchen, Germany
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S
* Supporting Information
ABSTRACT: Boron-ate complexes derived from primary and
secondary boronic esters and aryllithiums have been isolated, and
the kinetics of their reactions with carbenium ions studied. The
second-order rate constants have been used to derive nucleophil-
icity parameters for the boron-ate complexes, revealing that
nucleophilicity increased with (i) electron-donating aromatics on
boron, (ii) neopentyl glycol over pinacol boronic esters, and (iii)
12-crown-4 ether.
hiral organoboron compounds are widely employed in
Casymmetric synthesis since they can be transformed into a
variety of functional groups, often with complete stereo-
specificity. The transformations are usually initiated by addition
of a nucleophile to the electrophilic boron atom followed by a
stereospecific 1,2-migration.1 We recently reported an alter-
native mode of reactivity that further increases the synthetic
utility of these valuable intermediates. We found that normally
electrophilic boronic esters 1 could be rendered nucleophilic
through addition of an aryllithium leading to the formation of
boron-ate complexes (BACs 2) and that such intermediates
reacted with a range of electrophiles 3 to give different products
depending on the substitution of the aromatic ring (Scheme
1).2 With para-electron-donating or electron-withdrawing
substituents on the aryl lithium, adducts 4 were obtained
with inversion of configuration,2 while use of meta-electron-
donating substituents led to reactions on the aromatic ring
ultimately leading to aryl coupled products.3 To establish
further the use of these reagents in synthesis we wanted to gain
a deeper understanding of their reactivity and so applied the
well-established benzhydrylium method to quantify their
nucleophilic reactivity.4 Herein, we describe how the
nucleophilicity of alkyl and benzyl BACs is influenced by the
nature of the aryllithium, the diol ester, and the structure of the
organic component, in comparison with aryl and heteroaryl
BACs.5−7
A range of boron-ate complexes (BACs) 2a−l bearing
different aryl groups, diol esters, and carbon substituents were
prepared by addition of an aryllithium [PhLi, p-CF3C6H4Li, or
(m-CF3)2C6H3Li] to a solution of boronic ester 1 in Et2O
(Scheme 1). Crystallization at rt gave a range of analytically
pure primary and secondary BACs 2a−l in moderate to good
yields, as white air-sensitive solids (Figure 1), all of which
exhibited a singlet at δ ≈ +5 ppm in the 11B NMR spectrum.
Scheme 1. Formation of Lithium Boron-Ate Complexes
(BACs) 2 by Treatment of Boronic Esters 1 with
Aryllithiums and Subsequent Reactions with an Electrophile
2,3
E+
Figure 1. Lithium BACs 2a−l derived from the corresponding pinacol
and neopentyl glycol boronic esters 1. Yields after recrystallization in
Et2O.
Received: March 30, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00918
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Table 1. Structures, Absorption Maxima λmax, and
Electrophilicity Parameters E for Benzhydrylium Ions 3a−d
Used as Reference Electrophiles4
To elucidate the relationship between structures and
reactivities of 2a−l, we studied the kinetics of their reactions
with benzhydrylium ions 3a−d (Table 1). These have been
used as reference electrophiles for the construction of
comprehensive reactivity scales covering a reactivity range of
more than 30 orders of magnitude4 and have recently also been
used for quantifying the nucleophilicities of various organo-
boron derivatives.5−7 Carbenium ions 3a−d were reacted with
representative BACs, and the products were fully characterized
(Scheme 2).8
Figure 2. Exponential decay of the absorbance of benzhydrylium 3b
(7.8 × 10−6 M) in the presence of 25 equiv of the BAC 2d−Li+ (1.98
× 10−4 M) in CH3CN (kobs = 7.11 × 10−1 s−1). Inset: Determination
of the second-order rate constant, k2, from the dependence of kobs on
the concentration of 2d−Li+ (k2 = 3.61 × 103 M−1 s−1).
Table 2. Study of the Influence of 12-Crown-4 Ether on the
Reaction Rates of BACs 2a and 2e with Benzhydrylium Ion
3b in CH3CN at 20 °C
Scheme 2. Products 4 from the Reaction of BACs 2 with
Benzhydrylium Tetrafluoroborates 3b−d (For Details and
Yields, see Supporting Information)
a
Only approximate value 50%.
For kinetic analysis, these reactions were performed under
pseudo-first-order conditions with at least a 10-fold excess of
BACs 2a−l and were monitored at λmax of benzhydrylium ions
3b−d (Table 1) by using a conventional or a stopped-flow
spectrophotometer. Fitting of a monoexponential function to
the observed decays of the absorbance values of 3b−d gave the
kobs values, which were plotted against the boron-ate
concentrations, giving straight lines with slopes equal to the
second-order rate constant, k2 (see Figure 2 and Tables 2 and
3). This behavior was observed for all systems reported in this
letter, indicating the stabilities of the boron-ate complexes
under these conditions.
We initially investigated the effect of the nature of the
counterion, Li+, on the rate by using 12-crown-4 as an additive.
As illustrated in Table 2, a 2.5- and 3-fold increase of reactivity
of BACs 2a and 2e, respectively, was observed when using 1
equiv of 12-crown4 ether, showing that Li+ has a small effect on
the nucleophilic reactivities of the boron-ate complexes. It is
believed the 12-crown-4 sequesters the lithium cation of the
BAC 2,9 preventing the Li+ from binding to the diol oxygen
atoms and thus slightly enhancing the reactivity of the C−B
bond. This finding is consistent with our recent observations
showing that the counterions of heteroaryl BACs have a
negligible effect on their reactivity.5
boron was found to greatly reduce the reactivity of the BACs.
Thus, in reaction with the benzhydrylium ion 3b, 2f [Ar = (m-
CF3)2-C6H3] was found to be 7 times less reactive than 2d [Ar
= p-CF3−C6H4] and 61 times less reactive than 2b [Ar = Ph]
(from comparison of k2 values). The same trend was apparent
with the primary boron-ates 2a, 2c, and 2e. BACs with
electron-donating aryl substituents were too labile to be
isolated; however, the p-OMe-Ar (attached to B) substituted
analogue of 2b was synthesized in solution and found to have a
rate constant of 3 × 103 M−1 s−1, approximately 1000-times
more reactive toward the benzhydrylium ion 3d than the bis(m-
CF3)-substituted BAC 2f (k2 = 2.16 M−1 s−1). Thus, the
substituents on the aryl moieties were found to have a much
more pronounced effect on nucleophilicity in the benzyl series
than for the recently reported thienyl BACs, where the
difference in reactivity between the p-OMe and bis(m-CF3)
BACs was found to be 30-fold.5
The effect of the diol ligand attached to boron on reactivity
was also explored. The neopentyl derivative 2g was found to
react with benzhydryliums 3b−d on average 100 times faster
than the pinacol analogue, 2d (Table 3). This effect is weaker
than that found for heteroaryl BACs, where the neopentyl
derivatives were on average 104 times more reactive than the
pinacol derivatives.5 The activating effect of the neopentyl
glycol ester ligand compared to the pinacol ester, although less
pronounced in the benzyl series, is a general effect and may
have important practical implications, as it should enable
coupling with a broader set of electrophiles.5,10 The higher
reactivity of neopentyl glycol esters over pinacol boronic esters
is thought to be due to their reduced steric hindrance.5
We then investigated the effect of the aryl group on the
nucleophilicities of the BACs. As shown in Table 3, rate
constants k2 for the reaction of BACs with benzhydrylium
cations 3b−d were used to obtain nucleophilicity parameters N
and susceptibility parameters sN, according to eq 1. Increasing
the electron-withdrawing character of the aryl unit attached to
B
DOI: 10.1021/acs.orglett.5b00918
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Table 3. Second-Order Rate Constants k2 for the Reactions
of Lithium BACs 2 with Ar2CH+BF4− 3b−d in CH3CN at 20
°C and Resulting Nucleophile-Specific Parameters N and sN
of BACs 2a−j
Figure 3. Effect of carbon substitution on the rate constant, k2, in
reaction of BACs 2 with carbenium ion 3b (20 °C in CH3CN).
thought to be due to its small size. These rate constants are in
line with our previous work, where secondary benzylic boron-
ate complexes were found to be more reactive than their
secondary alkyl analogues.2a Cyclopropyl boron-ate 2i was
found to be more nucleophilic than the isopropyl boron-ate 2h
(krel = 6.5), demonstrating the combined effects of the
electronic effects of the cyclopropyl ring and reduced steric
hindrance.
Plots of log k2 for these reactions vs the electrophilicity
parameters E of 3b−d (Table 1) were linear (Figure 4),
Figure 4. Correlation of the second-order rate constants k2 (Table 3)
for the reactions of lithium BACs 2 with benzhydrylium tetrafluor-
oborates 3 in CH3CN toward the electrophilicity parameters E of 3
from Table 1.
indicating the applicability of eq 1 for determining the
nucleophilicity parameters N and the susceptibility parameters
sN of the boron-ates 2a−j (Table 3). The sN values, which
correspond to the slopes of these correlations, are in the narrow
range 0.6 < sN < 0.8 (Figure 4 shows almost parallel lines),
indicating that the relative reactivities of the BACs 2 depend
little on the reactivity of the reference electrophile. As the sN
values are similar to those of borylated π-systems, the N values
can be used for a direct comparison of the nucleophilic
reactivities of these different classes of compounds (Figure 5).
a
Nucleophilicity parameter N and susceptibility parameter sN, as
b
defined in eq 1. The decays were not strictly monoexponential, and
c
the k2 values were not used for determining N and sN. As observed by
1H NMR spectroscopy, decomposition of the BAC in CH3CN at 20
°C was faster than its reaction with 3d, preventing the measurement of
the k2 value. Second part of a biexponential decay. sN was estimated.
d
e
The effect of the substitution pattern of the sp3 carbon
attached to boron was then analyzed by comparing the second-
order rate constants, k2, of the reactions of the p-CF3 BACs
with 3b (Figure 3). This comparison revealed a remarkable
trend in reactivity due to substitution at the ipso position: in the
benzylic series, phenylmethyl boron-ate 2d was found to be 12
times more reactive than the benzylic analogue 2c, despite its
increase in steric hindrance. Thus, electronic activation,
presumably through hyperconjugation from the methyl C−H
bonds, outweighs the steric effects.
In contrast, isopropyl boron-ate complex 2h was found to be
8 times less reactive than the primary BAC 2j demonstrating
the opposite effect of the addition of a methyl group at the ipso
carbon atom on the nucleophilic reactivity of the BAC in the
alkyl series. The surprisingly high reactivity of ethyl BAC 2j is
log k2(20 °C) = sN(N + E)
(1)
Figure 5 illustrates the nucleophilicity parameters N
(susceptibility parameters sN in parentheses) of these novel
BACs, benchmarked against a range of other C-centered
nucleophiles. The retarding effect of trifluoromethyl groups on
the nucleophilic reactivities of phenethyl- and benzyl-
substituted boron-ate complexes 2a−f is shown. The greater
nucleophilicity of phenethyl BACs in comparison to their
benzyl analogues is also apparent, as well as the superior
nucleophilicity of neopentyl BAC 2g (N = 11.29) compared to
its pinacol analogue 2d (N = 8.56). It can be seen that these
C
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and reactivity of these boron-ates has allowed us to optimize
the nucleophilicity of the complexes. Work is ongoing to
harness this nucleophilicity with other families of electrophiles
such as imines and aldehydes.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, and spectroscopic data for all new
compounds. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b00918.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: V.Aggarwal@bristol.ac.uk
*E-mail: Herbert.Mayr@cup.uni-muenchen.de
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank EPSRC and the Bristol 105 Chemical Synthesis DTC
for studentship support (EP/G036764/1). This collaboration
was supported by COST STSM (CM0905) and the Deutsche
Forschungsgemeinschaft (SFB749/B1). We thank Dr. A. R.
Ofial, E. Follet, V. Morozova (Munich) and Dr. D. Leonori, Dr.
E. Myers (Bristol) for helpful discussions and Dr. S.
Stephenson (Munich) for assistance with NMR.
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■
Figure 5. Comparison of nucleophilicity parameters N (susceptibility
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3
Csp nucleophiles are slightly more nucleophilic than the
corresponding 5-methylthienyl BACs, where the electrophilic
2
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secondary benzyl and alkyl boron-ate complexes. This is the
first time N parameters have been measured for sp3-centered C
nucleophiles. A preliminary study showed that the lithium
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to the boron atom, and the substitution of the sp3 carbon. The
diol used has a major effect with neopentyl glycol being 100-
fold more reactive than pinacol. The nature of the aryl group
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substituent, with the nucleophilicity parameters following the
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secondary alkyl. The reactivities of these BACs were found to
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and furyl BACs; this is the first direct comparison between the
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1
(8) H NMR analysis of the crude product mixtures indicated that
products 4a−e (Scheme 2) were accompanied by minor quantities
(∼5−10%) of diarylmethanes Ar2CH2 formed by hydride transfer of
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reactivity also accounts for why electron-rich aromatic boron-
ate complexes sometimes react at the sp3 carbon atom and
sometimes at the aromatic ring depending on the substitution
pattern of the aromatic ring.3 Thus, the boron-ate complexes
studied in this report have been shown to be powerful
nucleophiles, and the relationship found between the structure
3
2
́
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M.; Jankowski, P.; Sporzynski, A.; Urban
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DOI: 10.1021/acs.orglett.5b00918
Org. Lett. XXXX, XXX, XXX−XXX