Synthesis of Alkenyl Boronates from Epoxides with Di-[B(pin)]-methane via Pd-Catalyzed Dehydroboration

Article abstract of DOI:10.1021/acs.orglett.7b03853

A practical and broadly applicable catalytic method for the synthesis of (E)-alkenylborons is presented. Reactions are promoted by [Pd(Cl)(η³-C₃H₅)]₂ and proceed by the dehydroboration of cyclic borates. Through

Full text of DOI:10.1021/acs.orglett.7b03853

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Alkenyl Boronates from Epoxides with Di-[B(pin)]-
methane via Pd-Catalyzed Dehydroboration
Stephanie A. Murray, Eugenia C. M. Luc, and Simon J. Meek*
Department of Chemistry, The University of North Carolina, Chapel Hill, North Carolina 27599-3290, United States
S
* Supporting Information
ABSTRACT: A practical and broadly applicable catalytic
method for the synthesis of (E)-alkenylborons is presented.
Reactions are promoted by [Pd(Cl)(η3-C3H5)]2 and proceed
by the dehydroboration of cyclic borates. Through the use of
epoxides and readily available di-B(pin)-methane (pin =
pinacolato), a range of allylic alcohol-containing alkenyl boronates, including those that contain a tertiary alcohol, may be
prepared in up to 75% yield and >20:1 E/Z.
connection to research associated with the development of 1,1-
lkenylboronic acid pinacol esters are versatile molecules for
1
Aorganic synthesis. As such, a variety of methods have been diborons as useful reagents for stereoselective synthesis, we
became interested in the use of epoxides as electrophilic coupling
partners, which represent charge-separated synthons (vs carbon-
yls). As a result, the addition of [(pin)B]2C(H)Li to an epoxide
leads to 1,3-disposed alkoxide and B(pin) moieties incapable of
eliminating (e.g., B) and ready to participate in further
reactions.10 We hypothesized that the loss of H−B(pin) from
B would provide a simple strategy for the synthesis of alkenyl
boronates bearing an allylic alcohol with stereochemistry arising
from the chiral epoxide. Such a process could be accomplished by
the use of palladium catalysis to effect a formal dehydroboration,
via a transmetalation and β-hydride elimination sequence of
events. Newhouse and co-workers reported a related efficient
dehydrogenation strategy that employs a Pd salt and an allyl
oxidant for the synthesis of α,β-unsaturated amides, esters, and
nitriles via zinc enolates (eq 1).11 In this regard, we decided to see
if a similar approach could be applied to the dehydroboration of
intermediates such as B for the preparation of alkenylborons.
developed for their preparation; these include alkene cross-
metathesis,2,3 alkyne hydroboration,4 alkyne reduction,5 cross-
coupling,6 and alkene C−H borylation.7 Of considerable value
are protocols that in tandem efficiently form stereodefined
alkenylborons as well as establishing allylic functionality.8
In addition to the former methods, the boron-Wittig reaction
represents an efficient metal-free process for the stereoselective
generation of alkenyl boronates by the coupling of aldehydes or
ketones with readily available 1,1-diborylalkanes (Scheme 1).9
For example, addition of [(pin)B]2C(H)Li (1) to an aldehyde
results in 1,2-positioned alkoxide and B(pin) groups (e.g., A),
which undergo elimination via the loss of (pin)BOLi. In
Scheme 1. Synthesis of Alkenyl Boronates with
Diborylmethane
Herein, we report the stereoselective alkenylation of epoxides
by a coupling/dehydroboration method that simultaneously
generates a stereodefined allylic alcohol and (E)-alkenyl boronic
ester. The overall transformation represents the direct
alkenylation of an epoxide, equivalent to a stereoselective
aldehyde alkenylation.
We initiated our studies with the coupling of (R)-styrene oxide
2 and 1 (Table 1). Subjecting epoxide 2 to [(pin)B]2C(H)Li in
THF at 22 °C for 1 h, followed by treatment with 2.5 mol % of
Received: December 9, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03853
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
a b
,
Table 1. Reaction Optimization
Scheme 2. Alkenyl Boron Synthesis Epoxide Scope
b
b
entry
Pd catalyst
temp °C
conv (%); 3/4
E/Z
1
2
3
4
5
6
7
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
Pd(Ph3)4
20
40
60
60
60
60
60
60
60
<5; −
42; >98:2
63; >98:2
59; <2:98
76; <2:98
46; <2:98
63; <2:98
62; >98:2
60; >98:2
>20:1
>20:1
PdCl2(dppb)
PdCl2(dppf)
Pd(dba)2, binap
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
c
8
d
>20:1
>20:1
9
a
b
Reactions performed under N2 atm. Values determined by analysis
of 400 or 600 MHz 1H NMR spectra of unpurified mixtures with DMF
as internal standard. Reaction run at [0.16 M]. Reaction run at [0.05
M].
c
d
[Pd(Cl)(η3-C3H5)]2 and allyl chloride as the oxidant, resulted in
<5% conversion to desired alkenyl boronate 3 (entry 1). It was
found, however, that increasing the temperature to 40 and 60 °C
(entries 2 and 3) facilitates the reaction, affording the desired
product in 42 and 63% yield, respectively, as the (E)-alkene
isomer (>20:1).12 Other palladium sources such as Pd(PPh3)4
(entry 4), PdCl2(dppb) (entry 5), PdCl2(dppf) (entry 6), and
PdCl2(binap) were found to be ineffective and only afforded
significant amounts of the O-allyl product 4.
With optimal conditions in hand, we next set out to explore the
reaction scope. As illustrated in Scheme 2, the alkenyl boronate
synthesis is general for a wide variety of epoxides. Trans-
formations proceed in the presence of 2.5 mol % of [Pd(Cl)(η3-
C3H5)]2 and allyl chloride (3 equiv) in THF at 60 °C for 24 h.
Various aryl-substituted epoxides can be effectively converted
through the alkenylation process into the corresponding alkenyl
boronates (3a−e) in good yields (45−67% yield) and stereo-
selectivity (>20:1 E/Z). Notably, it was found that there is no
loss in enantiopurity in the formation of 3a when (R)-styrene
oxide (99:1 er) is employed. The transformation is also effective
for the preparation of alkyl-substituted alkenyl boronic esters.
Under standard conditions, a wide variety of terminal alkyl
epoxides, including those that contain methyl, cyclohexyl,
phenyl, and TBS-ether functionality, can be converted efficiently
and stereoselectively into (E)-alkenyl boronic esters 3f−3j in
61−71% isolated yield. It was found that the epoxide alkenylation
reaction is amenable to gram-scale preparation of alkenyl boronic
esters, as demonstrated by the preparation of 1.14 g of
enantioenriched allylic alcohol 3h under standard conditions.
Unsubstituted and volatile ethylene oxide can also be employed
in the catalytic dehydroboration process to furnish allylic alcohol
3k as a single alkene isomer, albeit in diminished 23% yield.
Alkenyl boronates derived from 1,1-disubstituted epoxides are
formed equally effectively. Such examples include isobutylene
oxide and α-methylstyrene oxide derived alkenyl boronates 3l
and 3m generated in 75 and 67% isolated yield, respectively.
Furthermore, the reaction is tolerant of existing stereocenters as
tertiary alcohol 3n is formed in a 53% yield and >20:1 E/Z.
Internal six-membered 1,2-disubstituted epoxides perform
equally well for the stereoselective synthesis of trisubstituted
alkenylborons. Under standard conditions in Scheme 2,
[(pin)B]2C(H)Li (1) opens the ring of the cyclohexene oxide
a
b
Reactions performed under N2 atm. Yield represents isolated yield
of purified material and is an average of two experiments.
as well as sterically hindered limonene oxide, and subsequent Pd-
catalyzed dehydroboration furnishes 3o and 3p in 50 and 34%
yield (>20:1 E/Z). This is in contrast to the reaction with
cyclopentene oxide (3r), which does not undergo ring opening
with carbanion 1.
The alkenylation process was also found to work well with
more complex progesterone- and androsterone-derived 1,1-
disubstituted epoxides (Figure 1). For example, following
epoxide opening at 45 °C with 1 (1.5 equiv), 4 and 5 are
efficiently generated in 47 and 67% yield, respectively. As
previously noted in our bis-electrophile couplings with 1,10
modification of the 1,1-diboron fragment with additional groups
Figure 1. Alkenylation of steroid-derived epoxides.
B
DOI: 10.1021/acs.orglett.7b03853
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(e.g., [(pin)B]2C(H)Me) is not tolerated in the dehydrobora-
tion.
The robustness of the alkenylboron protocol was found to
extend to variations in both the cyclic ether and nucleophile
components, such as oxetane 6 and borylsilyl methane 8
(Scheme 3). First, it was found that parent oxetane (6) can be
to be a problem, further studies to understand the details of this
process are ongoing.
The (E)-alkenyl boronate allylic alcohols generated through
the described protocol can be functionalized in a variety of ways.
The examples shown in Scheme 4 are illustrative: (1) The
Scheme 4. Utility of Alkenyl Boronic Ester Products
Scheme 3. Additional Substrate Variation
unprotected allylic alcohol 3h undergoes palladium-catalyzed
cross-coupling in the presence of 3 mol % of Pd(PPh3)4, Cs2CO3,
and aryl or alkenyl bromides in toluene for 8 h to afford the 1,3-
diene 10 and alkenylpyridine 11 in 65 and 59% yields,
respectively. (2) The hydroxyl moiety can also be used to direct
vinylboron functionalization.15 For example, subjection of
alkenyl boronic ester 3h to Simmons−Smith cyclopropanation
conditions reported by Shi [Et2Zn (5 equiv), CH2I2 (5 equiv),
CF3CH2OH, 22 °C, 18 h]16 results in an alcohol-directed
cyclopropanation to furnish cyclopropyl boronic ester 12 in 65%
yield and >20:1 dr.
In summary, we have developed a practical and robust Pd-
catalyzed method for the stereoselective synthesis of (E)-
alkenylborons via a coupling/dehydroboration of readily
accessible chiral epoxides. Transformations proceed efficiently
to furnish di- and trisubstituted alkenyl boronates in good yield
and >20:1 E/Z selectivity. Further investigations of stereo-
selective 1,1-diboron coupling processes are ongoing.
a
b
NMR yield. Deprotonation of 8 with LTMP (THF, 0 °C, 30 min)
proceeds to 65% conversion (see Supporting Information for
details).14
ring-opened, albeit less efficiently compared to an epoxide, by
carbanion 1 to form the corresponding six-membered ring
chelate that is reactive enough to undergo C−B(pin) trans-
metalation to Pd and subsequent β-hydride elimination. In this
regard, under standard conditions, 1 equiv of 6 affords
homoallylic alcohol 7 in 20% NMR yield (>20:1 E/Z). Notably,
the use of excess oxetane (5 equiv), compared to 1, in order to
assist ring opening did not lead to an increase in reaction
efficiency or yield. Second, we hypothesized that exchanging one
of the B(pin) groups in 1 with SiMe3 to the corresponding mixed
B/Si reagent 813 would enable the stereoselective generation of
(E)-alkenylsilanes, providing C−B(pin) transmetalation occurs
faster than the alternative 1,4-Brook rearrangement. Deproto-
nation of 8 with LTMP (THF, 0 °C, 30 min) and sequential
treatment with 2 followed by catalytic Pd and allyl chloride
results in the formation of 9 in 20% yield (>20:1 E/Z) and 23% of
product derived from epoxide opening. Notably, while the
reaction is low yielding, the vinylsilane is the only observable
alkenylation product (>98:2 Si/B), indicating that loss of the
B(pin) unit is kinetically faster than the corresponding
dehydrosilylation.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03853.
Experimental procedures and spectral and analytical data
for all products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sjmeek@unc.edu.
ORCID
To gain insight into the low conversion to 9, 1H NMR analysis
of the epoxide opening step was investigated (Scheme 3).
Treatment of 8 with LTMP followed by 2 results in 59%
conversion to cyclic borates C/D in 1.7:1 dr in addition to 32%
unreacted 2. Of note, the ratio of A/B did not change with
temperature. Attempts to follow the reaction after the addition of
5 mol % of Pd and allyl chloride resulted in a complex mixture,
where the amounts of both diastereoisomers C and D decrease,
vinylsilane begins to form, but a number unidentifiable
resonances are present. While epoxide opening does not seem
Simon J. Meek: 0000-0001-7537-9420
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the National Institutes of
Health (R01GM116987, 3R01GM116987-01S1) and the
University of North Carolina at Chapel Hill. AllyChem is
acknowledged for donations of B2(pin)2.
C
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REFERENCES
■
(1) Hall, D. G. Boronic Acids: Preparation and Applications in Organic
Synthesis and Medicine; Wiley-VCH: Weinheim, 2011.
(2) Overview of catalytic olefin metathesis: (a) Hoveyda, A. H.;
Zhugralin, A. R. Nature 2007, 450, 243. Recent review on catalytic CM:
(b) Prunet, J.; Grimaud, L. In Metathesis in Natural Product Synthesis:
Strategies, Substrates and Catalysts; Cossy, J., Arseniyadis, S., Meyer, C.,
Eds; Wiley-VCH: Weinheim, 2010; p 287.
(3) (a) Morrill, C.; Grubbs, R. H. J. Org. Chem. 2003, 68, 6031−6034.
(b) 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, 6026−6029.
(4) For recent reviews, see: (a) Barbeyron, R.; Benedetti, E.; Cossy, J.;
Vasseur, J.-J.; Arseniyadis, S.; Smietana, M. Tetrahedron 2014, 70, 8431−
8452. (b) Yoshida, H. ACS Catal. 2016, 6, 1799−1811.
(5) (a) Brown, H. C.; Srebnik, M.; Bhat, N. G. Tetrahedron Lett. 1988,
29, 2635−2638. (b) Srebnik, M.; Deloux, L. J. Org. Chem. 1994, 59,
6871−6873. (c) Soderquist, J. A.; Rane, A. M.; Matos, K.; Ramos, J.
Tetrahedron Lett. 1995, 36, 6847−6850. (d) Molander, G. A.; Ellis, N.
M. J. Org. Chem. 2008, 73, 6841−6844.
(6) (a) Takahashi, K.; Takagi, J.; Ishiyama, T.; Miyaura, N. Chem. Lett.
2000, 29, 126−127. (b) Takagi, J.; Takahashi, K.; Ishiyama, T.; Miyaura,
N. J. Am. Chem. Soc. 2002, 124, 8001−8006.
(7) (a) Coapes, R. B.; Souza, F. E. S.; Thomas, R. L.; Hall, J. J.; Marder,
T. B. Chem. Commun. 2003, 614−615. (b) Olsson, V. J.; Szabo,
Angew. Chem., Int. Ed. 2007, 46, 6891−6893. (c) Selander, N.; Willy, B.;
Szabo, K. J. Angew. Chem., Int. Ed. 2010, 49, 4051−4053. (d) Kondoh,
́
K. J.
́
A.; Jamison, T. F. Chem. Commun. 2010, 46, 907. (e) Takaya, J.; Kirai,
N.; Iwasawa, N. J. Am. Chem. Soc. 2011, 133, 12980−12983. (f) Kirai, N.;
Iguchi, S.; Ito, T.; Takaya, J.; Iwasawa, N. Bull. Chem. Soc. Jpn. 2013, 86,
784−799.
(8) For representative examples, see: (a) Li, H.; Carroll, P. J.; Walsh, P.
J. J. Am. Chem. Soc. 2008, 130, 3521−3531. (b) Hussain, M. M.; Li, H.;
Hussain, N.; Urena, M.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2009,
̃
131, 6516−6524. (c) Hussain, N.; Hussain, M. M.; Ziauddin, M.;
Triyawatanyu, P.; Walsh, P. J. Org. Lett. 2011, 13, 6464−6467.
́
(d) Hernandez-Toribio, J.; Hussain, M. M.; Cheng, K.; Carroll, P. J.;
Walsh, P. J. Org. Lett. 2011, 13, 6094−6097.
(9) (a) Matteson, D. S.; Moody, R. J. Organometallics 1982, 1, 20−28.
(b) Matteson, D. S.; Moody, R. J.; Jesthi, P. K. J. Am. Chem. Soc. 1975,
97, 5608−5609. (c) Matteson, D. S.; Jesthi, P. K. J. Organomet. Chem.
1976, 110, 25−37. (d) Matteson, D. S.; Moody, R. J. J. Am. Chem. Soc.
1977, 99, 3196−3197. (e) Pelter, A.; Buss, D.; Colclough, E.; Singaram,
B. Tetrahedron 1993, 49, 7077. (f) Endo, K.; Hirokami, M.; Shibata, T. J.
Org. Chem. 2010, 75, 3469−3472. (g) Endo, K.; Sakamoto, A.; Ohkubo,
T.; Shibata, T. Chem. Lett. 2011, 40, 1440−1442. (h) Coombs, J. R.;
Zhang, L.; Morken, J. P. Org. Lett. 2015, 17, 1708−1711. (i) Stephens, T.
C.; Pattison, G. Org. Lett. 2017, 19, 3498−3501.
(10) Murray, S. A.; Liang, M. Z.; Meek, S. J. J. Am. Chem. Soc. 2017,
139, 14061−14064.
(11) (a) Chen, Y.; Romaire, J. P.; Newhouse, T. R. J. Am. Chem. Soc.
2015, 137, 5875−5878. (b) Chen, Y.; Turlik, A.; Newhouse, T. R. J. Am.
Chem. Soc. 2016, 138, 1166−1169.
(12) Allyl acetate can be used in place of allyl chloride but results in
slightly lower efficiency; for example, 2.5 mol % of [Pd(Cl)(η3-C3H5)]2
and allyl acetate (3 equiv) afford 54% conversion.
(13) Matteson, D. S.; Majumdar, D. Organometallics 1983, 2, 230−236.
(14) The use of TMEDA/LTMP to improve deprotonation efficiency
as reported by Matteson12 results in <2% conversion to 9.
(15) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93,
1307−1370.
(16) (a) Lorenz, J. C.; Long, J.; Yang, Z.; Xue, S.; Xie, Y.; Shi, Y. J. Org.
Chem. 2004, 69, 327. (b) See ref 8b.
D
DOI: 10.1021/acs.orglett.7b03853
Org. Lett. XXXX, XXX, XXX−XXX