Ate complexes of secondary boronic esters as chiral organometallic-type nucleophiles for asymmetric synthesis

Article abstract of DOI:10.1021/ja2077813

The addition of an aryllithium reagent to a secondary boronic ester leads to an intermediate boron-ate complex that behaves as a chiral nucleophile, reacting with a broad range of electrophiles with inversion of stereochemistry. Depending on the electrophile, the C-B bond can be converted into C-I, C-Br, C-Cl, C-N, C-O, and C-C, all with very high levels of stereocontrol. This discovery now adds a new, readily available, configurationally stable, chiral organometallic-type reagent to the arsenal of methods for use in asymmetric organic synthesis.

Full text of DOI:10.1021/ja2077813

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pubs.acs.org/JACS
Ate Complexes of Secondary Boronic Esters as Chiral
Organometallic-Type Nucleophiles for Asymmetric Synthesis
Robin Larouche-Gauthier, Tim G. Elford, and Varinder K. Aggarwal*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, United Kingdom
S Supporting Information
b
ABSTRACT: The addition of an aryllithium reagent to a
secondary boronic ester leads to an intermediate boron-ate
complex that behaves as a chiral nucleophile, reacting with a
broad range of electrophiles with inversion of stereochem-
istry. Depending on the electrophile, the CÀB bond can be
Figure 1. Formation of a reactive boron-ate complex and its potential
reaction with electrophiles.
converted into CÀI, CÀBr, CÀCl, CÀN, CÀO, and CÀC,
all with very high levels of stereocontrol. This discovery now
adds a new, readily available, configurationally stable, chiral
organometallic-type reagent to the arsenal of methods for
use in asymmetric organic synthesis.
Scheme 1. Initial Investigations of the Reactivity of Boron-
Ate Complexes
he field of organic synthesis usually involves the union of
T
nucleophiles with electrophiles.1 However, while the devel-
opment of complex chiral electrophiles has progressed signifi-
cantly, the parallel development of chiral nucleophiles and in
particular chiral organometallic reagents (without α-hetero-
atoms) has been considerably slower. Hoffmann2 showed that
chiral Grignard reagents could be obtained using the sulfoxideÀ
Mg exchange reaction of halosulfoxides. Knochel3 developed a
method for converting organoboranes or catechol boronic esters
into configurationally stable organozinc reagents. In both cases,
the preparation of the organometallic was either somewhat
limited in scope or rather cumbersome to perform in practice.
More recently, Knochel has shown that configurationally labile
organozinc reagents can be employed in highly diastereoselective
synthesis.4 In this paper, we report the discovery that secondary
boronic esters can be converted into reactive nucleophiles by the
addition of an aryllithium reagent and that the resulting boron-
ate complexes react with a broad range of electrophiles with
inversion of stereochemistry.
of configuration after activation with an alcoholic base.8 In our
design strategy, we chose to form a boron-ate complex directly
from a boronic ester, initially with an electron-rich aryllithium,
not only to provide further enhancement of its nucleophilicity
but also to help stabilize the aryl boronic ester byproduct
(Figure 1). In order to preserve the boron-ate complex, we
needed a diol with a clamlike tendency to remain on boron and
not dissociate, so we selected a simple pinacol (pin) ester.
A representative chiral secondary boronic ester, 2, was pre-
pared by lithiationÀborylation of primary 2,4,6-triisopropyl-
benzoate 1 (Scheme 1).9 We were delighted to find that
treatment of boronic ester 2 with p-MeOC6H4Li (3a) followed
by I2 gave the corresponding secondary alkyl iodide 4 in high
yield and with almost complete inversion of stereochemistry
(Scheme 1). The enantiospecificity (e.s.) of the reaction ([ee of
product/ee of starting material] Â 100%) was 97%.10 Interest-
ingly, the intermediate boron-ate complex bearing two different
carbon substituents reacted exclusively with the secondary alkyl
substituent in preference to the aryl substituent, a feature
The limited progress in the development of enantioenriched
chiral organometallics stems from the need to satisfy three
fundamental requirements simultaneously: (i) ease of synthesis,
(ii) configurational stability, and (iii) reactivity. The creation of
chiral organometallics is especially challenging because these
requirements are usually mutually exclusive. We believed that the
choice of metal was critical, and elected boron since the first two
requirements were easily met with chiral secondary boronic
esters.5 However, reactivity was a major issue, as boronic esters
are stable, isolable compounds that are unreactive toward
electrophiles. We reasoned that the corresponding boron-ate
complexes should be more reactive. Indeed, some limited success
had been reported in the reactions of benzyl trifluoroborate salts6
and sp/sp2 trifluoroborate salts7 with specific electrophiles, but
their scope was rather limited. In addition, secondary alkyl
boranes have been halogenated with predominantly inversion
Received: August 17, 2011
Published: September 22, 2011
r
2011 American Chemical Society
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Table 2. Investigation into the Scope of Possible
Electrophilesa
Figure 2. Possible reaction pathways of boron-ate complexes with
electrophiles.
Table 1. Effect of Electron-Donating and -Withdrawing
Substituents on the Enantioselectivity
observed with all of the electrophiles explored. In contrast, in
reactions of related boron-ate complexes with metal salts,
exclusive transfer of the aryl group and not the secondary alkyl
group to the electrophilic metal is consistently observed.11
However, the high stereoselectivity observed with I2 was not
general for other electrophiles. For example, reaction with
diisopropyl azodicarboxylate (DIAD) gave hydrazine 5 in high
yield but in virtually racemic form (Scheme 1). We presumed
that in this case, the reaction occurred predominantly through a
single-electron transfer (SET) pathway (Figure 2),2b,12 leading
to the racemic product, whereas the reaction with I2 occurred
predominantly via a polar (two-electron) pathway, leading to the
enantioenriched product. On this basis, we reasoned that the
balance between the two pathways should be tunable through
variation of the nature of the aryl group on boron. An electron-
deficient aromatic group on boron should make the boron-ate
complex less nucleophilic, but we expected the SET process to be
slowed more than the polar process because removing an
electron from the CÀB bond of the boron-ate complex should
be considerably harder.
a All of the boronic esters had e.r. > 95:5. See the Supporting Information
for full details. b Electrophile was added at 0 °C. c Electrophile was added
as a solution in acetonitrile. d Separation of the enantiomers of the chloro
analogue of 2 was not possible, but the 4-MeO derivative was separable.
e Electrophile was added as a solution in acetonitrile at À40 °C.
f Electrophile was added as a solution in propionitrile with 12-crown-
4. g Electrophile was added as a solution in propionitrile at À78 °C with
12-crown-4. h The intermediate TMP-protected alcohol was directly
converted to the secondary alcohol. The reported yield is for the
two steps. i Yield was calculated by 1H NMR analysis using an internal
standard because of product volatility.
A range of aryllithiums were therefore explored in the reaction
with DIAD, and we indeed found that the e.s. steadily increased
with increasing electron-withdrawing capacity of the aromatic
ring, with the maximum stereoselectivity being observed with
3,5-(CF3)2C6H3Li (3b) (Table 1). Pentafluorophenyllithium
was not effective in this process.
Reactions of several boron-ate complexes derived from both
aryllithium reagents 3a and 3b were tested with a broad range of
electrophiles (Table 2). N-iodosuccinimide (NIS) gave essen-
tially complete enantiospecificity with both aryllithium reagents
(entry 2), while N-bromosuccinimide (NBS) gave complete
selectivity only with aryllithium 3b (entry 3). For chlorination,
we found that trichloroisocyanuric acid (TCCA) was superior to
N-chlorosuccinimide (which was unreactive) and that once again
higher selectivity was found with aryllithium 3b than with
aryllithium 3a (entry 4).13 Performing the reaction at À40 °C
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Table 3. Investigation into the Scope of Boronic Estersa
event, the reaction with tropylium tetrafluoroborate gave the
desired adduct without any racemization with both aryllithium
reagents3aand 3b (entry 10). Eschenmoser’s salt and a diazonium
salt were also suitable electrophiles, furnishing the corresponding
amine and azo products with complete enantiospecificity (entries 11
and 12). The latter two electrophiles did not react with secondary
dialkylboronic esters, demonstrating the increased reactivity of the
benzylic substrate. The reaction with TCCA also occurred with
essentially complete enantiospecificity (entry 13).
The expected increase in the radical (SET) pathway and
therefore erosion of the e.s. did not materialize with these benzylic
substrates; in fact, the exact opposite was observed. We presume
that the π system of the aromatic ring must enhance the polar
(2eÀ) pathway to a greater extent than the radical (1eÀ) pathway.
The most dramatic effect of the nature of aryllithium reagent 3
on the enantiospecificity of the reaction was observed in the
amination of the benzylic boronic ester using DBAD (entry 14):
with electron-rich p-MeOC6H4Li (3a), racemic hydrazine was
obtained, whereas with electron-deficient 3,5-(CF3)2C6H3Li
(3b), the hydrazine was formed with 98% e.s.
In order to determine the scope of this chemistry, we briefly
explored reactions of more hindered and more functionalized
boronic esters, predominantly with TCCA (Table 3).13 We were
pleased to see that not only the ethyl analogue 6 but also the
considerably more hindered isobutyl analogue 7 could be used,
furnishing the corresponding chloride with high e.s. (entries 1
and 2). Chlorination of the similarly hindered benzylic boronic
ester 8 also occurred with good enantiospecificity (entry 3).
While chlorination using TCCA was not compatible with the
pendant alkene on boronic ester 9, alkylation with tropylium
tetrafluoroborate occurred uneventfully to furnish the desired
adduct with good selectivity (entry 4). Esters are common
functional groups in organic synthesis, so it was important to find
out whether aryllithium 3b would show sufficient chemoselectivity
and react with the hindered pinacol boronic ester rather than a
carboxylic ester.18 Chlorination of boronic ester 10 was therefore
tested, and the product was obtained in high yield with complete
enantiospecificity (entry 5), thus indicating a very high level of
chemoselectivity. Finally, we have shown that boronic esters
bearing an azide (11, entry 6) or a silylether (12, entry 7) are
also tolerated, thus demonstrating the relatively broad functional
group compatibility of this chemistry.
The reactions of chiral organometallic reagents (Grignard re-
agents, organolithiums, organozincs) with electrophiles usually
occur with retention of configuration.2c,19 In contrast, it was
reported that Stille-type cross-coupling of benzylic stannanes20
and halosilanes21 occurs with inversion. Sporadic examples of
Suzuki-type cross-coupling of secondary boronic esters have also
been reported. Crudden22 reported reactions of benzylic boronic
esters that occurred with retention of configuration, and Suginome23
extended this protocol to include α-(acylamino)benzylic boronic
esters. More recently, Molander reported the coupling of β-amido
secondary alkyl trifluoroborates.24 In the latter two cases, the
reactions occurred with inversion of stereochemistry. The closest
examples to the current work involve the halogenation of boron-ate
complexes derived from chiral boranes which occurred with
inversion.8 The SE2 reactions that we have described also occur
with inversion, presumably because of the steric hindrance of the
boron-ate complex (Figure 2); its bulk prevents the electrophile
from approaching from the same side as boron, so the reactions
occur with inversion. The fact that the SE2 reactions must occur with
a All of the boronic esters had e.r. > 96:4. See the Supporting Information
1
for full details. Ar = 4-MeOC6H4. b Yield was calculated by H NMR
analysis using an internal standard. The product was prone to decom-
position on silica gel. c Electrophile was added at À40 °C with 12-crown-
4 and then warmed to room temperature.
with aryllithium 3b led to essentially complete enantiospecificity
(entry 5). As indicated above, reaction with DIAD employing
aryllithium 3b led to high e.s. (entry 6), and through further
optimization of the conditions14 and switching to dibenzyl
azodicarboxylate (DBAD), we obtained considerably higher
selectivity (entry 7). This one-pot transformation of a secondary
boronic ester into an amino functionality is a significant advance
over current methods.15
The oxidation of a boronic ester to an alcohol with retention of
configuration is the archetypal transformation of organoboron
intermediates. With a suitable electrophilic oxidant, we expected
that this fundamental transformation could be made to occur
with inversion of stereochemistry using our novel protocol.
After exploration of various oxidants and reaction optimization,
we found that 2,2,6,6-tetramethylpiperidine-1-oxoammonium
tetrafluoroborate16 was an effective electrophilic oxidant, and
following cleavage of the NÀO bond, the secondary alcohol was
obtained in 70% e.s. with predominantly inversion of stereochemi-
stry (entry 8). Reaction with tropylium tetrafluoroborate was
also successful and again furnished the adduct with essentially
complete enantiospecificity (inversion) even with electron-rich
aryllithium 3a (entry 9).
Benzylic boronic esters were also explored. These were
expected to be much more reactive but also considerably more
prone to SET processes because of the increased stability of an
intermediate benzylic radical. Indeed, while there are a few
examples of benzylic organometallic reagents bearing neighbor-
ing chelating substituents to hold and lock the stereochemistry of
the metal, racemization results without such groups.17 In the
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inversion also accounts for the observed chemoselective reaction of
the alkyl over the aryl substituent; the aryl substituent cannot invert.
In conclusion, we have discovered a surprisingly simple
approach for the creation of a new class of enantioenriched,
chiral organometallics that simultaneously satisfies the three
fundamental requirements of ease of synthesis, configurational
stability, and reactivity: the addition of an aryllithium to a
secondary pinacol boronic ester. The subsequent boron-ate
complex that is generated behaves like a new class of organome-
tallic reagents that react with a broad range of electrophiles, all
with inversion of configuration. Depending on the nature of the
electrophile, some of the reactions are complicated by competing
SET processes, which result in a diminution of the enantiospe-
cificity. This is often a dominant feature of many conventional
chiral organometallic reagents but one that was only occasionally
observed with the boron-ate complexes. Furthermore, and unlike
other organometallic reagents, we have the capacity to tune the
reactivity of the boron-ate complex by varying the aryl group to
minimize competing SET processes, thereby leading to an
enhancement in the enantiospecificity.
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’ ASSOCIATED CONTENT
S
Supporting Information. Details of mechanistic studies
b
(12) For examples of SET processes involving boron-ate
complexes, see: (a) Schuster, G. B. Pure Appl. Chem. 1990, 62, 1565.
(b) Sorin, G.; Mallorquin, R. M.; Contie, Y.; Baralle, A.; Malacria, M.;
Goddard, J.-P.; Fensterbank, L. Angew. Chem., Int. Ed. 2010, 49, 8721.
See the Supporting Information for more details.
demonstrating the competing radical pathway in the amination
process, experimental procedures, and analytical data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) For the reactions with TCCA, aryllithium 3b was generated by
transmetalation of aryl tributylstannane with n-BuLi rather than from the
corresponding bromide. When the aryl bromide was employed, small
amounts of secondary alkyl bromides were formed, presumably via BrCl,
which was generated as follows:
’ AUTHOR INFORMATION
Corresponding Author
v.aggarwal@bristol.ac.uk
’ ACKNOWLEDGMENT
We thank the EPSRC and the European Research Council
(FP7/2007-2013, ERC Grant 246785) for financial support.
V.K.A. thanks the Royal Society for a Wolfson Research Merit
Award and the EPSRC for a Senior Research Fellowship. R.L.-G.
thanks the FQRNT (Quꢀebec) for a postdoctoral fellowship. We
thank Inochem-Frontier Scientific for the generous donation of
boronic acids and boronic esters.
(14) 12-Crown-4 was added to enhance the reactivity of the ate
complex. We believe that by complexing lithium, the crown ether should
inhibit coordination of the metal to the oxygen of the boronic ester,
which would otherwise promote ring opening to a borinic ester and
thereby lead to lower reactivity.
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