Synthesis and Applications of Unquaternized C-Bound Boron Enolates

Article abstract of DOI:10.1021/jacs.8b00614

A general and facile method to prepare unquaternized C-bound boron enolates by a ligand-controlled O-to-C isomerization is reported. Using this protocol, C-bound pinacolboron enolates have been isolated in pure form for the first time, and have been fully characterized by NMR spectroscopy and X-ray crystallography. In contrast to the general perception, such C-boron enolates are stable without coordinative saturation at the boron. Moreover, C-boron enolates present reactivities that are distinct from the O-boron enolates, and their applications in C-O and C-C bond formations are demonstrated.

Full text of DOI:10.1021/jacs.8b00614

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Communication
Synthesis and Applications of Un-quaternized C-bound Boron Enolates
Elvis Wang Hei Ng, Kam-Hung Low, and Pauline Chiu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b00614 • Publication Date (Web): 26 Feb 2018
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Synthesis and Applications of Un-quaternized C-bound Boron
Enolates
Elvis Wang Hei Ng, KamꢀHung Low‡ and Pauline Chiu*
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Department of Chemistry, and the State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam
Road, Hong Kong, P. R. China
Supporting Information Placeholder
ABSTRACT:
A general and facile method to prepare
unꢀquaternized Cꢀbound boron enolates by a ligandꢀcontrolled
OꢀtoꢀC isomerization is reported. Using this protocol, Cꢀbound
pinacolboron enolates have been isolated in pure form for the first
time, and have been fully characterized by NMR spectroscopy
and Xꢀray crystallography. In contrast to the general perception,
such Cꢀboron enolates are stable without coordinative saturation
at the boron. Moreover, Cꢀboron enolates present reactivities
that are distinct from the Oꢀboron enolates, and their applications
in C‒O and C‒C bond formations are demonstrated.
Figure 2. Representative examples of isolated Cꢀboron enolates
stabilized by boron quaternization.
Although there is
a generally perceived instability of
unꢀquarternized Cꢀboron enolates, recent computational studies
have indicated that the stability is highly dependent on the nature
of the carbonyl group and the boryl group.6 While Cꢀboron
enolates of aldehydes were predicted to be thermodynamically
unstable compared to their Oꢀbound isomers, Cꢀboron enolates of
esters with electron rich boryl group in particular, were predicted
to be stable even without boron quaternization or intramolecular
coordination. Nevertheless, this has yet to be experimentally
verified.
Boron enolates are wellꢀknown reactive intermediates that have
been prepared and used in numerous applications, particularly for
aldol reactions1 in total syntheses. Despite their wide use in
organic synthesis, the fact that there are two isomeric forms has
been largely disregarded (Fig. 1). In practice, the term “boron
enolate” has almost always been used in reference to the Oꢀbound
isomer (Oꢀboron enolate). The Cꢀbound isomer (Cꢀboron enolate,
or αꢀborylcarbonyl), on the other hand, has received much less
attention.2 Being potentially chiral and amphoteric, Cꢀboron
enolates could be expected to exhibit a reactivity profile different
from that of Oꢀboron enolates.
Two reports of Cꢀboron enolates without apparent boron
quaternization have appeared (Fig. 3).7 Abiko et al have reported
Cꢀboron enolates as a minor component in equilibrium with their
Oꢀboron enolates, in an enolboration of a hindered ester.
Marder’s group has also observed Cꢀboron enolates in a Pt
catalyzed diborylation reaction.
In this case, however,
stablization by intramolecular coordination between the βꢀboryl
group and the carbonyl oxygen cannot be ruled out,8 and later
commentary has suggested that it may be critical for stability.2
Therefore, it was still not clear whether unꢀquaternized Cꢀboron
enolates without extra stabilization by intramolecular coordination
can be thermodynamically favored over the Oꢀboron enolates.
Furthermore, neither of these Cꢀboron enolates had been isolated,
or explicitly engaged in further reactions.
Figure 1. Comparison of the Oꢀbound and Cꢀbound isomers of
boron enolates.
However, to synthesize Cꢀboron enolates has been a challenge.
Traditionally, this has been attributed to their tendency towards
isomerization to the Oꢀboron enolates,3 thermodynamically driven
by the formation of a strong B‒O bond, and kinetically facilitated
by an empty p orbital on boron. Therefore, a major strategy to
generate Cꢀboron enolates has been to stabilize the boron by
quaternization (Fig. 2).2 This has led to elegant work culminating
in the successful preparation and isolation of a number of stable
Cꢀboron enolates4 whose carbonyl functionality can be chemically
manipulated, making them versatile precursors for the synthesis of
various borylated compounds.5
Figure 3. Cꢀboron enolates without boron quaternization.
There is also another challenge, namely the lack of control over
the O/C isomerization of boron enolates.9 All isomerizations
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reported toꢀdate were presumed to occur via uncatalyzed 1,3ꢀboryl
The scope of this OꢀtoꢀC isomerization is quite broad (Scheme
1). Primary, secondary and tertiary esters, as well as
α,αꢀdisubstituted and β,βꢀdisubstituted esters investigated were
cleanly and quantitatively converted to their corresponding
Cꢀboron enolates using this protocol, where the rate of the
isomerization decreases with increasing steric encumbrance.
Amides undergo OꢀtoꢀC isomerization even more readily than
esters, and do not even require particularly nucleophilic phosphine
to induce the isomerization. This can be attributed to the greater
resonance delocalization of amides compared to esters, resulting
in stabilization of the carbonyl group and therefore a higher
preference for Cꢀboron enolate formation.14 Consistent with this
trend, attempts to generate Cꢀboron enolates from Oꢀboron
enolates of ketones were unsuccessful.15
shifts.2, 3, 6b As a result, the formation of Oꢀ or Cꢀboron enolates
has been dependent largely on the substrate structure, and the
selective formation of Oꢀ and Cꢀboron enolates from the same
substrate has not yet been demonstrated.10
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Herein we report the facile preparation of unꢀquaternized
Cꢀboron enolates, via a copperꢀcatalyzed OꢀtoꢀC isomerization;
moreover, we also demonstrate their applications in organic
synthesis.
Catalyzed by copper hydride,11,12 and with pinacolborane as the
stoichiometric reductant, benzyl acrylate 1a was reduced as
expected to Oꢀboron enolate 2a. Upon the addition of a catalytic
amount of phosphine or NHC, we discovered that an OꢀtoꢀC
isomerization occurred to generate a new species, Cꢀboron enolate
3a (Scheme 1). The process was monitored by 1H NMR
spectroscopy, and both the Oꢀboron enolate 2a, and then the
Cꢀboron enolate 3a after isomerization, were characterized by in
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situ H and 13C NMR spectroscopy. The rate of the isomerization
correlated roughly with the nucleophilicity of the ligands, in the
following order of efficiency: IPr > (n-Bu)3P > (cꢀHex)3P >
PhMe2P > Ph2MeP ≈ (EtO)3P ≈ (t-Bu)3P > Ph3P ≈ none. In most
of our studies, the readily available and inexpensive (n-Bu)3P was
routinely used.
To ascertain the structure of the new species, the more volatile
Cꢀboron enolate, 3b, was synthesized and isolated in a pure state
by vacuum distillation. Although 3b is very moisture sensitive
and undergoes protodeboronation in minutes when exposed to air,
it is stable at room temperature under argon for weeks without
appreciable decomposition. The 1H and 11B NMR spectra of
Cꢀboron enolate 3b are consistent with the proposed structure.
Figure 4. Xꢀray crystallographic structure of Cꢀboron enolate 3c
(ORTEP representation, 50% probability ellipsoids).
The lack of boron quaternization in these Cꢀboron enolates
confers reactivity to their C‒B bonds that distinguishes them from
other known, quaternized Cꢀboron enolates (Fig. 2), whose boryl
groups are protected and therefore unreactive. Although Cꢀboron
enolates 3 are quite prone to protodeboronation because of the
lability of the enolate, the C‒B bond can be transformed in situ to
a C−O bond by an anhydrous oxidation (Scheme 2). In the event,
treatment of 3a with trimethylamine Nꢀoxide16 resulted in ~ 40%
yield of 4a,17 but employing N,Nꢀdimethylaniline Nꢀoxide18 with a
better amine leaving group successfully oxidized a range of
Cꢀboron enolates to afford αꢀhydroxyesters 4a, 4k-o in very good
yields (Scheme 2).
The 11B NMR signal at
BPin moiety (cf. nꢀBuBPin,
of an ateꢀtype boron complex. This is corroborated by the
carbonyl group resonating at
174.9 ppm in the 13C NMR
spectrum, diagnostic of a typical ester carbonyl without strong
coordination (cf. methyl propionate, 173.9 ppm). Finally, the
absence of any stabilization by quaternization is unequivocally
confirmed by Xꢀray crystallographic analysis of 3c (Fig. 4),13
δ
32.5 ppm was typical of a tricoordinate
37 ppm) and inconsistent with that
δ
δ
δ
a
particularly crystalline Cꢀboron enolate derived from
4ꢀacryloylmorpholine. The planarity of the boron centre, together
with the observation that the carbonyl oxygen and the BPin
moiety were actually diametrically opposed, showed that these
Cꢀboron enolates are indeed stable even without stabilization by
extra coordination. We rationalized that the diminished Lewis
acidity of BPin (compared to BR2) invited less electron donation
from the enolate oxygen to the boron centre and resulted in less
preference for the Oꢀbound isomer.6a
Scheme 2. Oxidation of C-boron enolates 3
Scheme 1. Generation of C-boron enolates 3
Furthermore, sequencing an asymmetric reduction using chiral
phosphineꢀligated copper hydride to generate the Oꢀboron enolate
enantioselectively,19 a diastereoselective OꢀtoꢀC isomerization,
and finally a stereospecific oxidation using N,Nꢀdimethylaniline
Nꢀoxide − converted 1p and 1q to alcohols 4p and 4q bearing two
new stereogenic centers, with good diastereoselectivities and in
high ee (Scheme 3).20,21 Notably, the oxidation of Cꢀboron enolate
3q demonstrates the selective functionalization of the two
secondary ꢀBPin groups. Alternatively, the use of an excess of the
amine oxide and extended reaction time oxidized 3q in one step to
the chiral diol-4q.
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3r, which did not undergo the Claisen rearrangement, but rather,
provided lactate 4r in excellent yield upon further oxidation.
Scheme 3. Asymmetric reduction, diastereoselective
isomerization and stereospecific oxidation sequence.
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Scheme 5. Manipulation of reaction conditions to control
the formation of O-boron enolate and C-boron enolate.
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The synthetic potential of unꢀquaternized Cꢀboron enolates is
further demonstrated by enabling C−C bond formation from the
C−B bond via a Suzuki−Miyaura cross coupling under anhydrous
conditions (Scheme 4).22 Our studies found that the phosphines
used to induce OꢀtoꢀC isomerization were detrimental to the
subsequent palladiumꢀcatalyzed coupling. But by employing IPr,
which can be used at as low as 1 mol % to induce the
isomerization, Cꢀboron enolate 3d thus obtained was successfully
Although it appears at first glance that free phosphine or free
NHC could be directly promoting the isomerization, this is in fact
not the case. When (IPr)Cu(OAc)2 − a wellꢀcharacterized and
robust copper complex that does not dissociate and release
unligated NHC − was used to generate the copper hydride catalyst
in the reaction,26 a very fast OꢀtoꢀC isomerization of 2f to 3f still
occurred, even at a catalyst loading level as low as 0.5 mol%.17
This led us to surmise that NHC or nucleophilic phosphines may
not be promoting the isomerization directly as nucleophilic
catalysts, but rather as ligands to copper, which has always been
present in the reaction as a result of the reduction conditions.
coupled with various aryl bromides, catalyzed by
a
palladiumꢀcataCXium A complex, to afford 5a-p in good yields.
The cross coupling reaction, as well as the oxidation, has also
been performed using isolated Cꢀboron enolate 3b,17 which
confirmed that the Suzuki coupling indeed proceeded via the
To further examine the involvement of copper in the mechanism
of isomerization, Oꢀboron enolate 2i was generated by an
alternative route in the absence of copper (Scheme 6).27 Whereas
the treatment of 2i thus generated with P(nꢀBu)3 alone did not see
any OꢀtoꢀC isomerization, the introduction of [(Ph3P)CuH]6 and
P(nꢀBu)3 induced isomerization to 3i, indicating that copper does
play a key role in the isomerization. These observations allude to
a mechanism that involves a metal, in contrast to previous
proposals and calculations that explored uncatalyzed, direct
1,3ꢀboryl shifts to account for Cꢀboron enolate formation.6b,7b
Cꢀboron enolate, and not via the Oꢀboron enolate in
CurtinꢀHammett scenario.
a
Scheme 4. Suzuki-Miyaura Coupling of C-boron enolates 3
Scheme 6. O-to-C isomerization of O-boron enolate 2i
Our observations, taken together with literature reports that
pinacol boronic esters undergo B → Cu transmetallation in the
presence of copper,28 led us to hypothesize that the isomerization
proceeds via the intermediacy of copper enolates. Presumably, in
the presence of copper, boron enolates can undergo a B → Cu
transmetallation to form the corresponding copper enolates, where
they equilibrate via O/C as well as E/Z isomerizations.29
Phosphines or NHC presumably act as ligands on copper to
modify the relative stabilities of Oꢀbound and Cꢀbound copper
enolates, and thereby affect the isomerization efficiency.30 In fact,
E/Z isomerization of Oꢀboron enolates was invariably observed
alongside the OꢀtoꢀC isomerization, and the E/Z isomerization
was also promoted by the presence of phosphines. Mechanistic
studies are currently underway in our laboratory to elucidate more
details of this isomerization mechanism.
The reactivity of the unꢀquaternized Cꢀboron enolate is also
notably distinct from that of Oꢀboron enolate. For example, an
aldol reaction occurred for Oꢀboron enolate 2d with an
aldehyde,23 but did not occur for its Cꢀboron enolate counterpart,
3d.17 Moreover, whereas Cꢀboron enolates 3 underwent oxidation
and cross coupling reactions as shown in Schemes 2 and 4, under
the same conditions, Oꢀboron enolates 2 provided little or none of
the C‒O, C‒C coupled products.17
In fact, by a judicious choice of reaction conditions, the extent
of OꢀtoꢀC isomerization of the boron enolates can be controlled,
allowing the reactivity of either the Oꢀbound or Cꢀbound isomer
to be exploited as desired (Scheme 5). In the absence of additional
phosphine, reductively generated Oꢀboron enolate 2r
spontaneously underwent Irelandꢀtype Claisen rearrangement24 to
afford carboxylic acid 6 in good yield.25 On the other hand, by
introducing 10 mol % of (nꢀBu)3P to promote the isomerization,
the reaction was intercepted to form exclusively Cꢀboron enolate
In summary, we have described a general synthesis of
unꢀquaternized Cꢀboron enolates by a copperꢀcatalyzed OꢀtoꢀC
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(8) For reports of intramolecular coordination between carbonyl
isomerization of the corresponding boron enolates, and the
synthetic applications of these Cꢀboron enolates have been
demonstrated in subsequent C‒O and C‒C bond forming reactions.
Further applications of these species in organic synthesis are
anticipated. We envisage that this unusual OꢀtoꢀC isomerization
could occur in other reaction contexts (e.g. conjugate borylation)
where similar Oꢀboron enolates have been implicated as
intermediates.
oxgyen and a βꢀBPin group, see: (a) Lee, J. C. H.; McDonald, R.; Hall, D.
G. Nat. Chem. 2011, 3, 894; (b) Ohmura, T.; Awano, T.; Suginome, M. J.
Am. Chem. Soc. 2010, 132, 13191.
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(9) For examples of the analogous OꢀtoꢀC isomerization of silyl
enolates, see: (a) Kim, Y.; Chang, S. Angew. Chem. Int. Ed. 2016, 55, 218;
(b) Heydari, A.; Alijanianzadeh, R. Chem. Lett. 2003, 32, 226.
(10) Marder has reported that the ligand on the Pt catalyst has some
effect on the selectivity between Oꢀ vs Cꢀboron enolate formation (see ref
7b). However, a followꢀup computational study by the same group
considered an uncatalyzed 1,3ꢀboryl shift as the isomerization mechanism
(see ref 6b), which did not account for the ligand effect. Despite the
insights from these works, controlled formation of either isomer from the
same substrate with high selectivity remained to be demonstrated.
(11) Copper hydride can be preꢀformed, or generated in situ from
copper(II) acetate and pinacolborane: Lee, D.ꢀW.; Yun, J. Tetrahedron
Lett. 2005, 46, 2037.
ASSOCIATED CONTENT
Supporting Information
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The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures and spectra (PDF)
Crystallographic data of 3c (CIF)
(12) For reviews of copper hydride catalyzed reactions, see: (a)
Deutsch, C.; Krause, N.; Lipshutz, B. H. Chem. Rev. 2008, 108, 2916; (b)
Daeuble, J. F.; Stryker, J. M.; Chiu, P.; Ng, W. H. In Hexa-ꢀ-hydro-
AUTHOR INFORMATION
hexakis(triphenylphosphine)hexacopper, Encyclopedia of Reagents for
Organic Synthesis; John Wiley & Sons, Ltd: New York, 2001.
(13) CCDC 1553753 contains the crystallographic data for compound
3c. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(14) Larson, G. L.; Cruz de Maldonado, V.; Fuentes, L. M.; Torres, L.
E. J. Org. Chem. 1988, 53, 633.
Corresponding Author
pchiu@hku.hk
Author Contributions
‡ Author responsible for Xꢀray diffraction analysis.
(15) OꢀBoron enolates were successfully generated from the reduction
of methyl vinyl ketone and chalcone, but introduction of phosphine or IPr
did not lead to any observable OꢀtoꢀC isomerization.
(16) (a) Soderquist, J. A.; Najafi, M. R. J. Org. Chem. 1986, 51, 1330;
(b) Kabalka, G. W. J. Organomet. Chem. 1977, 125, 273.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
(17) See Supplementary Information for details.
(18) Zhu, C.; Wang, R.; Falck, J. R. Org. Lett. 2012, 14, 3494.
(19) (a) Lipshutz, B. H.; Servesko, J. M.; Taft, B. R. J. Am. Chem. Soc.
2004, 126, 8352; (b) Ding, J.; Hall, D. G. Tetrahedron 2012, 68, 3428.
(20) Alcohol 4q is not stable for isolation and was therefore protected
as the TBS ether TBS-4q before isolation.
We thank Kong Ching Wong for preliminary experiments. We
also acknowledge the UGC Research Grants Council of Hong
Kong SAR, P. R. China for a GRF grant (Project No. HKU
17302415), the State Key Laboratory of Synthetic Chemistry, and
UGC funding administered by HKU for supporting the
electrospray ionization quadrupole TOF mass spectrometry
facilities for Interdisciplinary Research in Chemical Science.
(21) (R)ꢀTolBINAP served to promote the isomerization in this case
and no additional phosphine was needed to convert 2q to 3q.
(22) (a) Doucet, H. Eur. J. Org. Chem. 2008, 2008, 2013; (b) Crudden,
C. M.; Glasspoole, B. W.; Lata, C. J. Chem. Commun. 2009, 6704; (c)
Wang, C.ꢀY.; Derosa, J.; Biscoe, M. R. Chem. Sci. 2015, 6, 5105.
(23) (a) Lee, K.ꢀs.; Hoveyda, A. H. J. Am. Chem. Soc. 2010, 132, 2898;
(b) Kim, H.; Yun, J. Adv. Synth. Catal. 2010, 352, 1881; (c) Lipshutz, B.
H.; Papa, P. Angew. Chem. Int. Ed. 2002, 41, 4580; (d) Hoffmann, R. W.;
Ditrich, K.; Fröch, S. Liebigs Ann. Chem. 1987, 977; (e) Gennari, C.;
Colombo, L.; Poli, G. Tetrahedron Lett. 1984, 25, 2279
(24) (a) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc.
1976, 98, 2868; (b) Ireland, R. E.; Wipf, P.; Armstrong, J. D. J. Org.
Chem. 1991, 56, 650; (c) Corey, E. J.; Lee, D. H. J. Am. Chem. Soc. 1991,
113, 4026
(25) (a) Miller, S. P.; Morken, J. P. Org. Lett. 2002, 4, 2743; (b) Wong,
K. C.; Ng, E.; Wong, W.ꢀT.; Chiu, P. Chem. Eur. J. 2016, 22, 3709.
(26) Yun, J.; Kim, D.; Yun, H. Chem. Commun. 2005, 5181.
(27) (a) Adams, M. R.; Tien, C.ꢀH.; Huchenski, B. S. N.; Ferguson, M.
J.; Speed, A. W. H. Angew. Chem. Int. Ed. 2017, 56, 6268; (b) Chong, C.
C.; Rao, B.; Kinjo, R. ACS Catal. 2017, 7, 5814.
(28) For examples of BPin to Cu transmetallation, see: (a) Deng, J. Z.;
Paone, D. V.; Ginnetti, A. T.; Kurihara, H.; Dreher, S. D.; Weissman, S.
A.; Stauffer, S. R.; Burgey, C. S. Org. Lett. 2009, 11, 345; (b) Kim, J.;
Park, S.; Park, J.; Cho, S. H. Angew. Chem. Int. Ed. 2016, 55, 1498; (c)
Lin, L.; Yamamoto, K.; Mitsunuma, H.; Kanzaki, Y.; Matsunaga, S.;
Kanai, M. J. Am. Chem. Soc. 2015, 137, 15418; (d) Park, J.; Lee, Y.; Kim,
J.; Cho, S. H. Org. Lett. 2016, 18, 1210; (e) Shi, Y.; Hoveyda, A. H.
Angew. Chem. Int. Ed. 2016, 55, 3455; (f) Wei, X.ꢀF.; Shimizu, Y.; Kanai,
M. ACS. Cent. Sci. 2016, 2, 21; (g) Zhang, Z.ꢀQ.; Zhang, B.; Lu, X.; Liu,
J.ꢀH.; Lu, X.ꢀY.; Xiao, B.; Fu, Y. Org. Lett. 2016, 18, 952.
(29) Plotzitzka, J.; Kleeberg, C. Organometallics 2014, 33, 6915.
(30) We cannot exclude the possibility that copper may be acting as a
Lewis acid in the isomerization mechanism, but this seems inconsistent
with the reactivity trend that electronꢀrich ligands were more effective
than electron poor ones. For an example of Lewis acidꢀcatalyzed
borylative shift, see: van der Mei, F. W.; Miyamoto, H.; Silverio, D. L.;
Hoveyda, A. H. Angew. Chem. Int. Ed. 2016, 55, 4701.
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