Synthesis of vinyl boronates from aldehydes by a practical boron-Wittig reaction

Article abstract of DOI:10.1021/acs.orglett.5b00480

A highly stereoselective boron-Wittig reaction between stable and readily accessible 1,1-bis(pinacolboronates) and aldehydes furnishes a variety of synthetically useful di- and trisubstituted vinyl boronate esters.

Full text of DOI:10.1021/acs.orglett.5b00480

Letter
pubs.acs.org/OrgLett
Synthesis of Vinyl Boronates from Aldehydes by a Practical Boron−
Wittig Reaction
John R. Coombs,† Liang Zhang,† and James P. Morken*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S
* Supporting Information
ABSTRACT: A highly stereoselective boron-Wittig reaction
between stable and readily accessible 1,1-bis(pinacolboronates)
and aldehydes furnishes a variety of synthetically useful di- and
trisubstituted vinyl boronate esters.
was developed, and employing alkylation reactions developed
by Matteson, construction of substituted derivatives is
straightforward.10 Considering the above-mentioned impor-
tance of vinyl boronates in organic synthesis, it was considered
that a boron−Wittig reaction employing geminal bis-
(pinacolboronates) might be strategically useful. In this
connection, the boron−Wittig reaction was pioneered by
Pelter and Matteson in the 1970s employing alkylboranes and
geminal bis(boronates), respectively.10−12 Most related to the
present research, Matteson and co-workers examined the
reaction between ethylene glycol-derived bis(boryl)methane 1
and a variety of carbonyl electrophiles (Scheme 1, eq 1). While
the one-pot boron−Wittig reaction/oxidation procedure to
provide aldehyde homologation products was extensively
studied, the reaction lacked practicality for two reasons:
preparation of 1 is not straightforward, and the intermediate
ethylene glycol-derived vinyl boronates were hydrolytically
sensitive. Moreover, other than a singular example of a reaction
between substituted 1,1-bis(boronate) esters and aldehydes,11c
use of the boron−Wittig reaction to provide trisubstituted vinyl
boronates has not been investigated.13 Herein, we report a
highly stereoselective boron−Wittig reaction between stable
and readily accessible 1,1-bis(pinacolboronates) and aldehydes
to furnish a variety of synthetically useful di- and trisubstituted
vinyl boronate esters (Scheme 1, eq 2). Importantly, the overall
transformation represents a transition-metal-free alternative to
alkyne hydroboration reactions.
inyl boronic esters are broadly useful functional motifs in
1
Vorganic synthesis.
While they possess high chemical
stability, they also participate in a variety of transformations
including Suzuki−Miyaura couplings,2 Chan−Lam couplings,3
Petasis reactions,4 and Hayashi−Miyaura conjugate additions,5
among other transformations. While there is an abundance of
reports regarding the synthesis of substituted vinyl boronates
from alkynes and alkenes, access to these species from alternate,
easily accessible, and readily available starting materials is
lacking.6 As evidenced in the Kishi synthesis of palytoxin,
selective and high-yielding preparation of vinyl boronates
directly from aldehydes can solve particularly challenging
synthesis problems.7 Lastly, highly regio- and stereoselective
syntheses of trisubstituted and 1,1-disubstituted vinyl boronates
remains a significant challenge.6i,8
Recent efforts in our laboratory have addressed the
preparation and utility of geminal bis(boronates) in organic
synthesis.9 In this context, a scalable preparation of bis(boryl)-
methane 2 (see Scheme 1 for structure) from dibromomethane
Scheme 1. Previous Example and Current Goals for the
Boron−Wittig Reaction
Initial studies focused on the synthesis of trans-vinyl
boronate esters and utilized nonsubstituted bis(pinacolato)-
boryl methane 2 and lithium tetramethyl piperidide (LiTMP)
as the base (Scheme 2). After deprotonation of 2 at 0 °C for 5
min, the mixture was cooled to −78 °C, the aldehyde added,
and the reaction mixture allowed to stir 4 h before being
allowed to warm to room temperature. The reaction was then
concentrated under reduced pressure and the derived vinyl
boronate isolated. As depicted in Scheme 2, high yields and
Received: February 14, 2015
Published: March 23, 2015
© 2015 American Chemical Society
1708
DOI: 10.1021/acs.orglett.5b00480
Org. Lett. 2015, 17, 1708−1711

Organic Letters
Letter
a
Scheme 2. Synthesis of trans-Vinylboronates via the Boron−
Scheme 3. Synthesis of 1,1-Disubstituted Vinylboronates
a
Wittig Reaction
a
Results are an average of two experiments. Isolated yields are
provided.
Despite the importance of trisubstituted vinyl boronates,
production of these motifs by methods such as internal alkyne
hydroboration can suffer from low regioselectivity.6c,14
Furthermore, methods for the trans-selective construction of
trisubstituted vinyl boronates are limited.15 To address these
challenges, we considered the boron−Wittig reaction between
geminal bis(boronates) and aldehydes. In a preliminary
experiment, pinacol-derived geminal bis(boronate) 21 was
deprotonated at 0 °C with LiTMP in THF and then treated
with n-hexanal. After 4 h of reaction at −78 °C, the derived Z
trisubstituted vinyl boronate 24 was produced in high yield and
in a synthetically useful diastereomer ratio (Scheme 4). While
a
See text for details. Reaction employed 1.2 equiv of 2, 1.2 equiv of
LiTMP, and 1 equiv of aldehyde. Results are an average of two
experiments. Yield represents isolated yield after purification by silica
gel chromatography. Reaction performed at 0 °C to room
temperature for 1.5 h.
b
Scheme 4. Development of Boron−Wittig Conditions with
1,1-Bis(boronates) and Aldehydes
excellent levels of stereoselectivity were obtained with linear
aldehydes (3 and 4) as well as those containing α-branches (5−
7). Importantly, high levels of stereoselectivity could still be
obtained even if the deprotonation and carbonyl addition were
conducted at 0 °C and warmed to room temperature, thereby
allowing shorter reaction times (4 and 12). Synthetically
challenging dienyl and enynyl boronate esters (8−14) could
also be obtained in high yield and stereoselectivity by
employing corresponding unsaturated aldehydes.
While it might be considered that construction of 1,1-
disubstituted vinyl boronates could arise from the boron−
Wittig reaction of substituted geminal bis(boronates) with
formaldehyde, in practice this transformation was only
moderately effective. Thus, reaction of lithiated bis(boronates)
with formaldehyde (generated by treatment of paraformalde-
hyde with catalytic toluenesulfonic acid) for 4 h at −78 °C
provided moderate yields of the derived vinyl boronate (see the
Supporting Information). As an alternative, it was found that
reaction of lithiated geminal bis(boronates) with diiodo-
methane for 2 h at 60 °C provided efficient access to 1,1-
disubstituted vinyl boronates. In this transformation, it is
assumed that the lithiated bis(boronate) first undergoes
alkylation with CH2I2 ,and subsequent to nucleophilic
substitution, B−I elimination results in formation of the
product alkene. In this manner, vinyl boronate 15 was afforded
in high yield from diiodomethane and the corresponding
substituted geminal bis(boronate) (Scheme 3). Additionally, α-
branched vinyl boronate 16 was also furnished in good yield. Of
note, this strategy provides an attractive complement to allene
protoborylation and alkyne hydrometalation/borylation se-
quences.6i,8d,f,g
addition of Lewis acids or use of alternate solvents did not alter
selectivity in a useful manner (see the Supporting Information
for this data), the use of alternate boronic esters was observed
to alter stereoselection dramatically. With the neopentylglyco-
lato (npg) derivative, the trisubstituted vinyl boronate was
produced in a 77:23 Z/E ratio, while the dimethylpentanedio-
lato (dmpd) derivative furnished the E isomer selectively
(27:73 Z/E).
To survey the utility of the boron−Wittig reaction for the
construction of trisubstituted vinyl boronates, a number of
linear and α-branched aldehydes were reacted with geminal
bis(boronates) 21 or 23. As observed in Scheme 5,
trisubstituted vinyl boronates are furnished in moderate to
high diastereoselectivity and good yield. Of note, both the cis-
and the trans-isomers of trisubstituted vinyl boronate 27/28
can be afforded in moderate stereoselectivity simply by varying
the ligand on the boron. Cyclohexyl- and tert-butyl-substituted
1709
DOI: 10.1021/acs.orglett.5b00480
Org. Lett. 2015, 17, 1708−1711

Organic Letters
Letter
Scheme 5. Scope of Boron−Wittig Reaction for
Scheme 6. Gram-Scale Synthesis of Vinyl Boronates
a
Trisubstituted Vinyl Boronates
In conclusion, a boron−Wittig reaction that employs readily
available geminal bis(boronates) has been described. The
overall transformation represents a simple and efficient method
for the synthesis of synthetically challenging vinyl boronates
that are often less accessible by other routes. Furthermore, the
described method is transition-metal free, utilizes readily
available or easily accessible starting materials, and is therefore
appealing for large-scale operations.
a
Results are an average of two experiments. Yield represents isolated
ASSOCIATED CONTENT
* Supporting Information
■
of purified material.
S
Experimental procedures, full spectroscopic data for new
compounds, and chiral separations. This material is available
free of charge via the Internet at http://pubs.acs.org.
pinacol-derived geminal bis(boronates) produce sterically
hindered vinyl boronates with high stereoselectivity (33 and
34). Notably, these products would be difficult to access via
alternative methods. Also of note, a synthetically challenging Z-
trisubstituted dienylboronate was accessed in excellent yield
and good selectivity through the reaction of an α,β-unsaturated
aldehyde (35). Further, enantiomerically enriched tris-
(boronates)16 can be converted to bis(boronates) with
complete conservation of enantiomeric purity and in excellent
diastereoselectivity (31). Lastly, a trend emerges and should be
noted: the E isomer is favored when either large boronate
substituents (R1) or large aldehyde substituents (R2) are
employed (29, 31, 33, 34, 36, and 37), and this selectivity can
be enhanced with the dmpd ligand (30). In contrast, when both
a small aldehyde (i.e., linear alkyl R2) and a small boronate are
employed, the Z product stereochemistry is favored (24, 35).
Although stereoselectivity is only moderate for construction of
some trisubstituted vinyl boronates, the lack of regioselectivity
that can plague other methods is avoided through the boron−
Wittig reaction. For example, through appropriate reagent
choice, the boron−Wittig reaction provides access to both
regioisomers 36 and 37 in high yield and with excellent
diastereoselectivity.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: morken@bc.edu.
Author Contributions
†J.R.C. and L.Z. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by grants from the National Institutes
of Health (GM 059417). J.R.C. was supported by a LaMattina
Graduate Fellowship.
REFERENCES
■
(1) (a) Ramachandran, P. V.; Brown, H. C. Recent Advances in
Borane Chemistry. In Organoboranes for Synthesis; ACS Symposium
Series 783; American Chemical Society: Washington, DC, 2001.
(b) Matteson, D. S. Tetrahedron 1989, 45, 1859. (c) Brown, H. C.;
Campbell, J. B., Jr. Aldrichimica Acta 1981, 14, 3. (d) Hall, D. G., Ed.
Boronic Acids: Preparation, Applications in Organic Synthesis and
Medicine, 2nd ed.; Wiley-VCH: Weinheim, 2011.
Considering that the boron−Wittig reaction employs
commercially available and easily accessible reagents and does
not require the use of expensive transition metals, large-scale
operations are likely to be of interest. To study this feature, 1,2-
disubstituted (38), trisubstituted (36), and 1,1-disubstituted
(15) vinyl boronates were targeted (Scheme 6), and it was
found that they can be accessed efficiently in high yields, even
on a gram scale.
(2) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147. (c) Lennox, A. J.;
Lloyd-Jones, G. C. Chem. Soc. Rev. 2014, 43, 412.
(3) (a) Shade, R. E.; Hyde, A. M.; Olsen, J.-C.; Merlic, C. A. J. Am.
Chem. Soc. 2010, 132, 1202. (b) Winternheimer, D. J.; Merlic, C. A.
Org. Lett. 2010, 12, 2508.
1710
DOI: 10.1021/acs.orglett.5b00480
Org. Lett. 2015, 17, 1708−1711

Organic Letters
Letter
(4) (a) Candeias, N. R.; Montalbano, F.; Cal, P. M. S. D.; Gois, P. M.
P. Chem. Rev. 2010, 110, 6169. (b) de Graaff, C.; Ruijter, E.; Orru, R.
V. A. Chem. Soc. Rev. 2012, 41, 3969.
(16) Coombs, J. R.; Zhang, L.; Morken, J. P. J. Am. Chem. Soc. 2014,
136, 16140.
(5) (a) Takaya, Y.; Ogasawara, M.; Hayashi, T. Tetrahedron Lett.
1998, 39, 8479. (b) Takaya, Y.; Senda, T.; Kurushima, H.; Ogasawara,
M.; Hayashi, T. Tetrahedron: Asymmetry 1999, 10, 4047.
(6) Selected references to the synthesis of trans-vinyl boronates from
terminal alkynes: (a) Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc.
1975, 97, 5249. (b) Lane, C. F.; Kabalka, G. W. Tetrahedron 1976, 32,
981. (c) Tucker, C. E.; Davidson, J.; Knochel, P. J. Org. Chem. 1992,
57, 3482. (d) Pereira, S.; Srebnik, M. Organometallics 1995, 14, 3127.
cis-vinyl boronates from terminal alkynes: (e) Ohmura, T.; Yamamoto,
Y.; Miyaura, N. J. Am. Chem. Soc. 2000, 122, 4990. (f) Molander, G. A.;
Ellis, N. M. J. Org. Chem. 2008, 73, 6841. (g) Mirzayans, P. M.;
Pouwer, R. H.; Williams, C. M.; Bernhardt, P. V. Tetrahedron 2009, 65,
8297. (h) Gunanathan, C.; Holscher, M.; Pan, F.; Leitner, W. J. Am.
̈
Chem. Soc. 2012, 134, 14349. (i) Jang, H.; Zhugralin, A. R.; Lee, Y.;
Hoveyda, A. H. J. Am. Chem. Soc. 2011, 133, 7859. (j) Yoshida, H.;
Kageyuki, I.; Takaki, K. Org. Lett. 2014, 16, 3512. (k) Barbeyron, R.;
Benedetti, E.; Cossy, J.; Vasseur, J. J.; Arseniyadis, S.; Smietana, M.
Tetrahedron 2014, 70, 8431. From alkenes: (l) Blackwell, H. E.;
O’Leary, D. J.; Chatterjee, A. K.; Washenfelder, R. A.; Bussmann, D.
A.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 58. (m) Morrill, C.;
Grubbs, R. H. J. Org. Chem. 2003, 68, 6031. (n) Morrill, C.; Funk, T.
W.; Grubbs, R. H. Tetrahedron Lett. 2004, 45, 7733. (o) Funk, T. W.;
Efskind, J.; Grubbs, R. H. Org. Lett. 2005, 7, 187. (p) McNulty, L.;
Kohlbacher, K.; Borin, K.; Dodd, B.; Bishop, J.; Fuller, L.; Wright, Z. J.
Org. Chem. 2010, 75, 6001. (q) Hemelaere, R.; Carreaux, F.; Carboni,
B. J. Org. Chem. 2013, 78, 6786. (r) Kiesewetter, E. T.; O’Brien, R. V.;
Yu, E. C.; Meek, S. J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc.
2013, 135, 6026.
(7) Armstrong, R. W.; Beau, J.-M.; Cheon, S. H.; Christ, W. J.;
Fujioka, H.; Ham, W.-H.; Hawkins, L. D.; Jin, H.; Kang, S. H.; Kishi,
Y.; Martinelli, M. J.; McWhorter, W. W., Jr.; Mizuno, M.; Nakata, M.;
Stutz, A. E.; Talamas, F. X.; Taniguchi, M.; Tino, J. A.; Ueda, K.;
Uenishi, J.; White, J. B.; Yonaga, M. J. Am. Chem. Soc. 1989, 111, 7525.
(8) (a) Takahashi, K.; Ishiyama, T.; Miyaura, N. J. Organomet. Chem.
2001, 47, 625. (b) Takagi, J.; Takahashi, K.; Ishiyama, T.; Miyaura, N.
J. Am. Chem. Soc. 2002, 124, 8001. (c) Moran, W. J.; Morken, J. P. Org.
Lett. 2006, 8, 2413. (d) Gao, F.; Hoveyda, A. H. J. Am. Chem. Soc.
2010, 132, 10961. (e) Meng, F.; Jung, B.; Haeffner, F.; Hoveyda, A. H.
Org. Lett. 2013, 15, 1414. (f) Guan, W.; Michael, A. K.; McIntosh, M.
L.; Koren-Selfridge, L.; Scott, J. P.; Clark, T. B. J. Org. Chem. 2014, 79,
7199. (g) Jang, H.; Jung, B.; Hoveyda, A. H. Org. Lett. 2014, 16, 4658.
(9) (a) Sun, C.; Potter, B.; Morken, J. P. J. Am. Chem. Soc. 2014, 136,
6534. (b) Hong, K.; Liu, X.; Morken, J. P. J. Am. Chem. Soc. 2014, 136,
10581. (c) Potter, B.; Szymaniak, A. A.; Edelstein, E. K.; Morken, J. P.
J. Am. Chem. Soc. 2014, 136, 17918.
(10) Matteson, D. S.; Moody, R. J. Organometallics 1982, 1, 20.
(11) (a) Matteson, D. S.; Moody, R. J.; Jesthi, P. K. J. Am. Chem. Soc.
1975, 97, 5608. (b) Matteson, D. S.; Jesthi, P. K. J. Organomet. Chem.
1976, 110, 25. (c) Matteson, D. S.; Moody, R. J. J. Am. Chem. Soc.
1977, 99, 3196. (d) Pelter, A.; Buss, D.; Colclough, E.; Singaram, B.
Tetrahedron 1993, 49, 7077.
(12) For chromium-promoted coversion of aldehydes to vinyl
boronates, see: Takai, K.; Shinomiya, N.; Kaihara, H.; Yoshida, N.;
Moriwake, T.; Utimoto, K. Synlett 1995, 963.
(13) The stereoselective synthesis of tetrasubstituted alkenyl
boronates from phenyl ketones was reported. However, reactions of
aldehydes were not investigated: (a) Endo, K.; Hirokami, M.; Shibata,
T. J. Org. Chem. 2010, 75, 3469. (b) Endo, K.; Sakamoto, A.; Ohkubo,
T.; Shibata, T. Chem. Lett. 2011, 40, 1440.
(14) (a) Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc. 1972, 94, 4370.
(b) He, X.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 1696.
(c) Konno, T.; Chae, J.; Tanaka, T.; Ishihara, T.; Yamanaka, H. Chem.
Commun. 2004, 690. (d) Semba, K.; Fujihara, T.; Terao, J.; Tsuji, Y.
Chem.Eur. J. 2012, 18, 4179.
(15) Sundararaju, B.; Furstner, A. Angew. Chem., Int. Ed. 2013, 52,
̈
14050.
1711
DOI: 10.1021/acs.orglett.5b00480
Org. Lett. 2015, 17, 1708−1711