Stereoselective Synthesis of Trisubstituted Alkenylboron Reagents by Boron-Wittig Reaction of Ketones

Article abstract of DOI:10.1021/acs.orglett.9b01663

Application of the boron-Wittig reaction to ketone electrophiles provides a straightforward route to trisubstituted alkenylboronic esters. With either a pentamethyldiethylenetriamine or trimethyl-1,4,7-triazacyclononane additive, the olefination can occur

Full text of DOI:10.1021/acs.orglett.9b01663

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Stereoselective Synthesis of Trisubstituted Alkenylboron Reagents
by Boron-Wittig Reaction of Ketones
Sheila Namirembe, Chenpeng Gao, Ryan P. Wexler, and James P. Morken*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S
* Supporting Information
ABSTRACT: Application of the boron-Wittig reaction to ketone electro-
philes provides a straightforward route to trisubstituted alkenylboronic esters.
With either a pentamethyldiethylenetriamine or trimethyl-1,4,7-triazacyclo-
nonane additive, the olefination can occur with very high levels of
stereocontrol and in good chemical yield.
n the 1970s, Pelter1 and Matteson2 developed a boron-
Wittig reaction that accomplishes homologation of
Table 1. Effect of Amine Additives on Stereoselection in
Boron-Wittig Reaction of Methyl Isopropyl Ketone
I
aldehydes via the intermediacy of alkenylboron intermediates.
Whereas Pelter employed geminal bis(trialkylboranes), Matte-
son employed geminal bis(ethylene glycolboronates). In both
cases, the reactivity of the alkenylboron intermediate was
sufficiently high as to render isolation of the organoboron
impractical. Recently, we have investigated the boron-Wittig
reaction between aldehydes and geminal bis(pinacolboronates)
as a route to easily isolable disubstituted alkenylboronate
products.3 In the context of an ongoing natural products
synthesis project, we required access to a stereodefined
trisubstituted alkenylboronate and considered that the boron-
Wittig reaction of ketone electrophiles might provide an
efficient inroad (Scheme 1). Of note, recent experiments by
a
b
entry
reagent
additive (equiv)
3 (%)
E/Z
1
2
3
4
5
6
7
8
1
2
1
1
1
1
1
1
none
none
50
54
54
62
63
50
63
60
60:40
75:25
78:22
90:10
94:6
78:22
93:7
79:21
TMEDA (1.5)
PMDTA (1.2)
PMDTA (1.5)
HMTETA (1.5)
TMTAN (1.5)
Me6TREN (1.5)
a
b
1
Isolated yield of purified product. E/Z ratios determined by H
Scheme 1. Site-Selective Functionalization of 1,2-
Bis(boronates)
NMR of unpurified reaction mixture.
Pattison4 as well as Shibata and Endo5 probed the boron-
Wittig reaction of ketones, but in the former case the
intermediate alkenylboronates were not isolated, and in the
latter case the authors focused on the construction of
tetrasubstituted alkenylboroantes.6 In this paper, we demon-
strate that, for a number of ketones, an efficient and highly
stereoselective boron-Wittig reaction to construct trisubtituted
alkenylboronates can be accomplished and we show that the
stereoselectivity can be significantly affected by the use of
amine additives, with triamine derivatives being particularly
effective.
as an olefination reagent, the E isomer of product was formed
in a 60:40 E/Z ratio and in 50% yield. Notably, when the
lithiated geminal bis(boronate) was prepared by in situ
deprotonation of CH2(Bpin)2 with LiTMP (giving complex
2), the olefination occurred with improved stereoselectivity
(75:25 E/Z) and in comparable yield. This result suggested
that the presence of amine additives should have an impact on
reaction stereoselectivity of the boron-Wittig reaction, and this
feature was probed more thoroughly. Of relevance to this
hypothesis, studies by Matteson showed that addition of amine
additives could enhance reaction efficiency in boron-Wittig
Our preliminary studies probed the reactivity of methyl
isopropyl ketone in the boron-Wittig reaction. As depicted in
Table 1, when pure lithiated geminal bis(boronate) 1,
conveniently prepared as described by Cho,7 was employed
Received: May 10, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01663
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reactions.2a In this case, while use of amine-free reagent 1 in
conjunction with TMEDA resulted in a slight increase in
stereocontrol during the boron-Wittig reaction (entry 3), use
of the 1.2 equiv of triamine compound PMDTA resulted in a
marked improvement in stereoselection (entry 4), which could
be improved even more by use of 1.5 equiv of reagent (94:6 E/
Z, entry 5). Of note, use of another triamine ligand (TMTAN,
entry 5) also afforded enhanced selectivity while two
tetraamine additives provided only moderate results (entries
6, 8).
To learn about the substrate scope and practical
implementation of the amine-modified boron-Wittig reaction,
we investigated the reaction of isopropyl methyl ketone
further. Rather than employing pure lithiated geminal diboron
reagent 1, we investigated whether use of in situ deprotonation
with LiTMP, followed by addition of the amine additive
PMDTA, could still furnish the alkenylboronate in high
selectivity and yield. After some optimization, it was found that
isomerically enriched product (91:9 E/Z) could be obtained
and that, with 2 equiv of reagent, consistently high isolated
yields were also observed. As depicted in Figure 1, alkenyl
Figure 2. Boron-Wittig reaction of aryl ketones in the presence of
PMDTA and TMTAN additives. Isolated yields are of purified
material and represent an average of two experiments. Stereoisomer
1
ratio determined by H NMR analysis.
none increased from 82:18 to 99:1 E/Z. Comparably high
levels of E stereoselection were observed with other aryl and
heteroaryl methyl ketones, and even a less encumbered dialkyl
ketone could now furnish the E isomer (6) albeit with only
moderate stereoselectivity.
The level and sense of stereoselectivity in the boron-Wittig
reaction may be rationalized by the mechanism proposal put
forward in Scheme 2. We consider that addition of the geminal
Figure 1. Conversion of aliphatic ketones to alkenylboronates by the
boron-Wittig reaction. Isolated yields are of purified material and
represent an average of two experiments. Stereoisomer ratio
Scheme 2. Proposed Origin of Stereoselectivity in the
Boron-Wittig Reaction of Ketones
1
determined by H NMR analysis.
boronate 3 was obtained in 80% yield under these conditions.
Examination of other substrates revealed that ketones bearing
an α-substituent generally reacted in high levels of stereo-
control (products 5, 7−9) whereas ketones lacking such a
steric bias between the two carbonyl substituents provided
only moderate levels of stereoselection and, remarkably,
favored the Z isomer of alkenylboronate (4, 6).
Examination of aryl alkyl ketone substrates with PMDTA as
the amine additive showed that selectivity could remain high
so long as the alkyl group retains an α branch (Figure 2,
method a). For instance, phenyl tert-butyl ketone furnished the
alkenylboronate 12 in excellent yield and stereoselectivity.
Similar observations were made for compounds 13−15.
Notably, acetophenone furnished the E isomer in lower
stereoselection. Given the expected utility of alkenylboronates
that derive from boron-Wittig reaction of aryl methyl ketone
substrates, we reinvestigated acetopheone but with TMTAN as
the amine additive. In these experiments, it was found that
optimal results were obtained with 0.5 equiv of TMTAN
additive. As shown in Figure 2 (method b), with the addition
of TMTAN, the stereoselectivity for olefination of acetophe-
bis(boronate) carbanion to the ketone may proceed as shown
in Scheme 2 where, in line with a model put forward by
Bassindale and Taylor,8 the smallest group on the nucleophile
(H) would lie between the carbonyl substituents. This addition
mode would furnish A as the immediate addition product. We
consider that if O−B elimination is rapid (faster than bond
rotation), then reaction through B giving the E alkene should
be favored, as it minimizes steric interactions with the
nonreacting B(pin) group. In contrast, if elimination is slow,
bond rotation may allow conversion of A to C where the small
B
DOI: 10.1021/acs.orglett.9b01663
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
H atom is sited proximal to the large Li(triamine) group;
elimination would then give the Z alkene. In connection to
this, studies by Reich show that PMDTA and TMTAN convert
dimeric Li enolates into monomeric complexes, with TMTAN
being much more effective.9 During the boron-Wittig reaction,
we suspect that the intermediacy of dimeric alkoxides may
serve to stabilize the addition product and thereby allow path
C to operate, whereas with TMTAN rapid elimination through
B occurs thus furnishing a greater proportion of the E product.
Further computational experiments to study the details of this
working model are in progress and will be described separately.
Practical aspects of the boron-Wittig reaction of ketones
were examined as depicted in Scheme 3. First, it was
ACKNOWLEDGMENTS
The authors acknowledge the NIH for funding (NIGMS GM-
R35-127140).
■
REFERENCES
■
(1) Pelter, A.; Buss, D.; Colclough, E.; Singaram, B. Hindered
Organoboron Groups in Organic Chemistry. 23. The Interactions of
Dimesitylboron Stabilised Carbanions with Aromatic Ketones and
Aldehydes to Give Alkenes. Tetrahedron 1993, 49, 7077.
(2) (a) Matteson, D. S.; Moody, R. J. Deprotonation of 1, 1-
Diboronic Esters and Reactions of the Carbanions with Alkyl Halides
and Carbonyl Compounds. Organometallics 1982, 1, 20. (b) Matteson,
D. S.; Moody, R. J.; Jesthi, P. K. Reaction of Aldehydes and Ketones
with a Boron-Substituted Carbanion, Bis(ethylenedioxyboryl) Me-
thide. Simple Aldehyde Homologation. J. Am. Chem. Soc. 1975, 97,
5608. (c) Matteson, D. S.; Jesthi, P. K. Lithium Bis-
(ethylenedioxyboryl) Methide and its Reactions with Carbonyl
Compounds and with the Chlorotriphenyl Derivatives of Germanium,
Tin and Lead. J. Organomet. Chem. 1976, 110, 25. (d) Matteson, D.
S.; Moody, R. J. Carbanions from Deprotonation of Gem-Diboronic
Esters. J. Am. Chem. Soc. 1977, 99, 3196.
Scheme 3. Practical Aspects of the Boron-Wittig Reaction of
Ketones
(3) Coombs, J. R.; Zhang, L.; Morken, J. P. Synthesis of Vinyl
Boronates from Aldehydes by a Practical Boron−Wittig Reaction.
Org. Lett. 2015, 17, 1708.
(4) Stephens, T. C.; Pattison, G. Transition-Metal-Free Homo-
logative Cross-Coupling of Aldehydes and Ketones with Geminal Bis
(boron) Compounds. Org. Lett. 2017, 19, 3498.
(5) (a) Endo, K.; Hirokami, M.; Shibata, T. Stereoselective Synthesis
of Tetrasubstituted Alkenylboronates via 1, 1-Organodiboronates. J.
Org. Chem. 2010, 75, 3469. (b) Endo, K.; Sakamoto, A.; Ohkubo, T.;
Shibata, T. Stereoselective Synthesis of Allylsilanes Bearing Tetrasub-
stituted Olefin via 2,2-Diborylethylsilane. Chem. Lett. 2011, 40, 1440.
(6) For application of the boron-Wittig reaction to the construction
determined that the reaction can be conducted on a
preparatively useful scale: a reaction employing 3 mmol of
acetophenone as substrate provided the alkenyl boronate
product 8 in comparable yield and stereoselectivity as reactions
conducted on a smaller scale. With respect to the synthesis
target mentioned in the introduction, we require access to
stereodefined β,γ-unsaturated amides. It was found that
employing the pinacol alkenyl boronates produced by the
boron-Wittig reaction in Suzuki−Miyaura cross-coupling with
an α-bromoamide provides a simple route to these compounds
with preservation of the alkene geometry.
In conclusion, we have developed a modified boron-Wittig
reaction that applies to ketone substrates and furnishes
trisubstituted alkenyl boronic esters as the reaction product.
This process provides direct access to many of these important
motifs in an efficient and stereoselective fashion.
́
of alkenylsilylboronates, see: La Cascia, E.; Cuenca, A. B.; Fernandez,
E. Opportune gem-Silylborylation of Carbonyl Compounds: A
Modular and Stereocontrolled Entry to Tetrasubstituted Olefins.
Chem. - Eur. J. 2016, 22, 18737.
(7) Lee, Y.; Park, J.; Cho, S. H. Generation and Application of
(Diborylmethyl)zinc(II) Species: Access to Enantioenriched gem-
Diborylalkanes by an Asymmetric Allylic Substitution. Angew. Chem.,
Int. Ed. 2018, 57, 12930.
(8) Bassindale, A. R.; Ellis, R. J.; Lau, J. C.-Y.; Taylor, P. G. The
Prediction of the Stereochemical Outcome of Reactions Between
Prochiral Carbanions and Prochiral Carbonyl Compounds in the
Absence of Chelation Control. J. Chem. Soc., Chem. Commun. 1986,
98.
(9) (a) Kolonko, K. J.; Biddle, M. M.; Guzei, I. A.; Reich, H. J.
Solution Structures of Lithium Enolates of Cyclopentanone, Cyclo-
hexanone, Acetophenones, and Benzyl Ketones. Triple Ions and
Higher Lithiate Complexes. J. Am. Chem. Soc. 2009, 131, 11525.
(b) Kolonko, K. J.; Guzei, I. A.; Reich, H. J. Structure and Dynamics
of α-Aryl Amide and Ketone Enolates: THF, PMDTA, TMTAN,
HMPA, and Crypt-Solvated Lithium Enolates, and Comparison with
Phosphazenium Analogues. J. Org. Chem. 2010, 75, 6163.
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.9b01663.
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.
C
DOI: 10.1021/acs.orglett.9b01663
Org. Lett. XXXX, XXX, XXX−XXX