Highly stereoselective synthesis of cis-alkenyl pinacolboronates and potassium cis-alkenyltrifluoroborates via a hydroboration/protodeboronation approach

Article abstract of DOI:10.1021/jo801191v

(Chemical Equation Presented) A number of alkynyl pinacolboronates bearing various functional groups were synthesized according to literature methods. These were then stereoselectively reduced to the ds-alkenyl pinacolboronates via hydroboration with dicyclohexylborane followed by chemoselective protodeboronation using acetic acid. Treatment with potassium hydrogen fluoride smoothly converted these to the corresponding potassium organotrifluoroborates.

Full text of DOI:10.1021/jo801191v

SCHEME 1
Highly Stereoselective Synthesis of cis-Alkenyl
Pinacolboronates and Potassium
cis-Alkenyltrifluoroborates via a Hydroboration/
Protodeboronation Approach
Gary A. Molander* and Noel M. Ellis
Roy and Diana Vagelos Laboratories, Department of
Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104-6323
product synthesis, we sought to synthesize pinacolboronate 9b
en route to the corresponding trifluoroborate (Scheme 1).
Lindlar reduction,2a Peterson olefination,2b hydride-mediated
inversion,2c and rhodium-catalyzed hydroboration of the cor-
responding alkyne according to the method of Miyaura2d either
failed to give the product in synthetically useful yields or gave
highly sensitive dialkylboranes as products. We therefore sought
a general method for the production of cis-alkenylboron
reagents. Noting the large difference in reactivity between
pinacolboronates and dialkylboranes, we reasoned that a dif-
ferentially substituted 1,1-dibora reagent (Figure 1) might
undergo selective protodeboronation in the presence of 1 equiv
of an appropriate protonating agent.
Gratifyingly, hydroboration of 9a with 1 equiv of dicyclo-
hexylborane3 (prepared in advance and stored under an inert
atmosphere as the solid) in THF at room temperature led to a
homogeneous solution that was then treated with 1 equiv of
acetic acid. These unoptimized conditions led to isolation of
9b in 42% yield. Shortly thereafter, a careful search of the
literature revealed a similar reduction of 9-BBN-derived alky-
nylborinates, which also utilized dicyclohexylborane and acetic
acid.2e Although the substrate scope in that report was limited
to borinates containing simple alkyl groups, certain elements
of that procedure proved beneficial in our efforts to expand the
chemistry to more elaborate pinacolboronates. Specifically, the
use of AcOH at 0 °C, followed by treatment with several
equivalents of ethanolamine to scavenge unwanted boron side
products, greatly simplified the workup while giving the products
in both greater purity and yield. The alkenylboronate could be
isolated in nearly pure form by simple filtration over Celite.
Using this protocol, our initial substrate 9b was isolated in 57%
yield with complete stereoselectivity.
gmolandr@sas.upenn.edu
ReceiVed June 2, 2008
A number of alkynyl pinacolboronates bearing various
functional groups were synthesized according to literature
methods. These were then stereoselectively reduced to the
cis-alkenyl pinacolboronates via hydroboration with dicy-
clohexylborane followed by chemoselective protodeborona-
tion using acetic acid. Treatment with potassium hydrogen
fluoride smoothly converted these to the corresponding
potassium organotrifluoroborates.
The production of stereodefined alkenyl organometallics is a
goal of ever-increasing value in synthetic organic chemistry
owing to the ability of these organometallics to cross-couple
with little if any erosion in stereochemical purity. Although
numerous organometallic species take part in cross-coupling
reactions, boron-containing reagents are unique for the variety
of ways in which they can be synthesized, the relatively mild
conditions under which they cross-couple, their atom economy,
ease of handling, and low environmental impact.1 Alkenylboron
reagents are most commonly synthesized by hydroboration of
an appropriate terminal alkyne, and although this is a useful
and reliable method, it results in stereoselective production of
the trans-alkenylboron derivative. Access to cis-alkenylboron
derivatives is well precedented in the literature,2 and yet the
vast majority of examples to date possess a conspicuous dearth
of functional groups.
We next explored the scope of this hydroboration/protode-
boronation method using a wide range of alkynyl pinacolbor-
onates. These were synthesized in one step from the appropriate
alkynes and isopropoxy-1,3,2-dioxaborolane by following the
method of Brown et al.4 The results are summarized in Table
1. Trimethylsilyl, cyclohexyl, and phenyl-bearing substrates
underwent reduction to give their respective cis-boronates in
high yield (entries 1-3). It is noteworthy that the steric bulk of
the trimethylsilyl group had no negative impact on the rate at
which the solution became homogeneous, or on the yield of
the reaction. Only slightly lower in yield were the reactions of
As part of a growing program to create highly functionalized
organotrifluoroborates and apply them in the context of natural
(1) Molander, G. A.; Felix, L. A. J. Org. Chem. 2005, 70, 3950–3956, and
references cited therein.
(2) (a) Brown, H. C.; Srebnik, M.; Bhat, N. G. Tetrahedron Lett. 1988, 29,
2635–2638. (b) Matteson, D. S.; Majumdar, D. Organometallics 1983, 2, 230–
236. (c) Campbell, J. B., Jr.; Molander, G. A. J. Organomet. Chem. 1978, 156,
71–79, and references cited therein. (d) Miyaura, N.; Ohmura, T.; Yamamoto,
Y. J. Am. Chem. Soc. 2000, 122, 4990–4991. (e) Soderquist, J. A.; Rane, A. M.;
Matos, K.; Ramos, J. Tetrahedron Lett. 1995, 36, 6847–6850. (f) Srebnik, M.;
Deloux, L. J. Org. Chem. 1994, 59, 6871–6873.
(3) Abiko, A. Organic Syntheses; Wiley: New York, 2004; Collect Vol. X,
p 273.
(4) Brown, H. C.; Bhat, N. G.; Srebnik, M. Tetrahedron Lett. 1988, 29, 2631–
2634.
10.1021/jo801191v CCC: $40.75
Published on Web 08/06/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6841–6844 6841

TABLE 1. Hydroboration/Protodeboronation of Alkynyl
Pinacolboronates Bearing Various Functional Groupsa
FIGURE 1. 1,1-Dibora intermediate.
substrates bearing trifluoromethylphenyl, n-alkyl, tert-butyl-
dimethylsilyloxy, and difluorophenyl groups (entries 4-7). As
stated above, proline derivative 9b was obtained in a syntheti-
cally useful yet somewhat attenuated yield. This is not entirely
surprising given the acid-sensitive nature of the tert-butoxyl-
carbonyl group.
Certain functionalized substrates proved problematic with the
reduction sequence employed. The first of these was ethyne 10a
(entry 10). Given the success of the trimethylsilyl substrate 1a
in the reaction, we presume that the problem was steric and
not electronic. The strain induced by the increased steric bulk
of the triisopropylsilyl group likely led to competitive protode-
boronation of the otherwise stable pinacolboron moiety cis to
it, in the process yielding byproducts that were inseparable by
chromatographic methods or bulb-to-bulb distillation.
Nitro substitution in substrate 11 was also poorly tolerated
(entry 11). The Brown procedure4 failed in this case to provide
the pinacolboronate without several accompanying impurities.
Nevertheless, the semipure material was subjected to our
optimized hydroboration/protodeboronation sequence. Unfor-
tunately a complex mixture of products was obtained, most
likely from competitive reduction of the nitro functional group.
Likewise, the Brown method was unable to provide nitrile-
containing substrate 12 in a highly pure form. Somewhat
surprisingly, the hydroboration of crude 12 in Et2O failed to
give a homogeneous solution. Even when 2 equiv of dicyclo-
hexylborane were employed, compound 12 failed to hydrobo-
rate, and only decomposition products were recovered upon
treatment with AcOH followed by the usual workup (entry 12).
11B NMR confirmed this lack of reactivity in Et2O. Unexpect-
edly, 11B NMR experiments in THF indicated complete hy-
droboration. Addition of AcOH according to the established
protocol nevertheless gave a complex mixture of products in
THF as well. Identical results were observed with the alkynyl
pinacolboronate (13) arising from hex-5-ynenitrile (entry 13).
Given the sensitive nature of alkynyl pinacolboronates to
protodeboronation, we sought to advance our initial findings
into an operationally simple, one-pot multistep procedure for
the in situ generation and use of the alkynyl pinacol boronates.
Early attempts to carry out this procedure by reacting the lithium
acetylide with isopropoxy-1,3,2-dioxaborolane according to the
method of Brown,4 followed by anhydrous HCl quench and
cannulation onto solid dicyclohexylborane failed to give suc-
cessful hydroboration, even when a sacrificial equivalent of
dicyclohexylborane was added to quench the in situ generated
isopropanol. The discovery that pinacolborane itself could also
serve as the requisite source of boron in the reaction was
unexpected, but not unwelcome, and to the best of our
knowledge unprecedented (Scheme 2). More surprising still was
the discovery that the borohydride (14) resulting from reaction
of pinacolborane with the lithium acetylide was stable in Et2O
for prolonged periods, even at room temperature, as confirmed
a All reactions were carried out on 2 mmol scale in Et2O (4 mL),
using 1:1 starting material/borane. AcOH (2.2 equiv) was added at 0 °C,
then ethanolamine at 0 °C and the mixture was warmed to rt. b The
product was isolated as a 90:10 mixture of cis/trans isomers. c The
alkynyl pinacolboronate was not stable, necessitating that it be carried
through without characterization. d The product was isolated with 10%
of protodeboronation byproduct, which were inseparable by chromatogra-
phy or distillation. e Decomposition.
by 11B NMR. HCl quench then produced only hydrogen gas as
a byproduct, allowing clean hydroboration with dicyclohexyl-
borane.
Unfortunately, it was subsequently discovered that the LiCl
produced in the third step led to competitive protodeboronation
6842 J. Org. Chem. Vol. 73, No. 17, 2008

TABLE 2. Conversion of cis-Alkenyl Pinacolboronates to the
SCHEME 2
Corresponding Trifluoroboratesa
of the pinacolboron moiety upon addition of acetic acid. These
problems were quite easily solved via cannula filtration of the
heterogeneous solution of alkynyl pinacolboronate before adding
it to the hydroborating reagent. A single example, however, was
explored as the method gave a moderate yield and proved no
easier to implement than our optimized two-step procedure.
In general, optimized conditions for the hydroboration/
protodeboronation sequence led to products of greater than 95%
purity, frequently without the need for column chromatography.
Even greater levels of purity could be obtained via conversion
of the pinacol esters to the corresponding potassium organo-
trifluoroborates, using saturated aqueous potassium hydrogen
fluoride according to published methods.1 The tetracoordinate
potassium organotrifluoroborates have several advantages over
traditional tricoordinate organoboron reagents. In addition to
being highly tractable crystalline solids, they are stable toward
numerous oxidative and nucleophilic/basic reagents that show
little or no tolerance of boronic acids and boronate esters.5 A
representative sampling of cis-pinacolboronates were therefore
selected for conversion to the corresponding trifluoroborates.
The results are summarized in Table 2. All compounds subjected
to treatment with potassium hydrogen fluoride gave good to
excellent isolated yields. These were conveniently isolated by
precipitation from acetone with use of Et2O or hexane at room
temperature. During long-term storage on the bench, the alkenyl
pinacolboronates were observed to change color and decompose
with a concomitant increase in pinacol-containing impurities
a All reactions were carried out using 2 mmol of organotrifluoroborate
in MeOH (0.5 M) and 10 mmol of KHF2 (∼4.5 M).
1
by H NMR. The trifluoroborates underwent no such changes.
Furthermore, as already stated, conversion to the potassium
trifluoroborate was generally accompanied by an increase in
purity according to H NMR spectroscopy.
dicyclohexylborane (356 mg, 2.0 mmol) were weighed out together
under inert atmosphere. Et2O (4 mL) was then added at rt, and the
reaction was stirred for 30 min. The reaction was then cooled to 0
°C, and neat glacial acetic acid (0.126 mL, 2.2 mmol) was added.
After stirring for 10 min, ethanolamine (0.266 mL, 4.4 mmol) was
added and the reaction was brought to rt. Dilution with hexanes
was followed by filtration over a silica plug to afford 3b in 83%
yield as a clear viscous oil with greater than 95% purity (382 mg,
1
In summary, we have developed a mild and general method
for the synthesis of cis-alkenyl pinacolboronates and potassium
organotrifluoroborates, beginning with the corresponding ter-
minal alkynes. Substrates bearing branched alkyl, n-alkyl, silyl,
silyloxy, aryl, and carbamate functional groups were all well
tolerated. Nitriles and nitro groups, however, led to complex
mixtures of products. Conversion to the corresponding potassium
trifluoroborates was uneventful and high yielding in all cases
studied. In addition, we have developed a facile, multistep
procedure that produces the cis-pinacolboronate directly from
the alkyne without the need to isolate the intermediate alkynyl
pinacolboronate. The reaction proceeds via the intermediacy of
a hitherto unreported borohydride. Studies toward the use of
cis-alkenyl trifluoroborates for stereospecific coupling in natural
product synthesis are ongoing in our laboratories.
1
1.66 mmol). H NMR (500 MHz, CDCl3) δ7.54 (d, J ) 7.15 Hz,
2H), 7.33-7.18 (m, 4H), 5.59 (d, J ) 14.9 Hz, 1H), 1.29 (s, 12H);
13C NMR (125.8 MHz, CDCl3) δ 148.1, 138.6, 128.6, 128.0, 127.9,
83.5, 24.8. The spectral data were in agreement with those reported
in the literature.2e
General Procedure for the Conversion of cis-Alkenyl Pinacol-
boronates to the Corresponding Potassium Trifluoroborates:
Preparation of (Z)-2-(Phenyl)ethenyltrifluoroborate (3c). After
dissolving compound 3b (460 mg, 2.0 mmol) in MeOH (4 mL) at
rt, a saturated aqueous solution of potassium hydrogen fluoride
(∼4.5 M, 2.22 mL) was added dropwise and the reaction was
allowed to stir at rt for 2 h. The solvent was then removed in vacuo
to afford a mixture of solids that was dried under high vacuum
(>0.5 Torr) overnight. Extraction of the solid mixture with acetone
(3 × 10 mL), followed by Bu¨chner funnel filtration (3×) afforded
a solution of the product in acetone. This solution was then reduced
in vacuo to afford a concentrated acetone solution of the product
(∼2 mL). After addition of Et2O (∼30 mL) and Bu¨chner funnel
filtration of the precipitate, the product was obtained in 62% yield
(260 mg, 1.24 mmol) as a white crystalline solid. Mp >250 °C. 1H
NMR (500 MHz, acetone-d6) δ 7.63 (d, J ) 7.3 Hz, 2H), 7.15 (d,
Experimental Section
General Procedure for the Hydroboration/Protodeboronation
of Alkynyl Pinacolboronates: Preparation of (Z)-4,4,5,5-Tetra-
methyl-2-styryl-1,3,2-dioxaborolane (3b). 4,4,5,5-Tetramethyl-2-
(phenylethynyl)-1,3,2-dioxaborolane (456 mg, 2.0 mmol) and
(5) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275–286.
J. Org. Chem. Vol. 73, No. 17, 2008 6843

J ) 7.5 Hz, 2H), 7.03 (t, J ) 7.2 Hz, 1H), 6.55 (br s, 1H),
5.64-5.72 (m, 1H); 13C NMR (125.8 MHz, acetone-d6) δ 141.5,
135.5 (q, J ) 5.8 Hz), 128.6 (q, J ) 2.9 Hz), 127.2, 125.1; 19F
NMR (471 MHz, acetone-d6) δ -136.62; 11B NMR (128.37 MHz,
acetone-d6) δ 2.01; IR (KBr) 2930, 1635, 1467 cm-1; HRMS (ESI)
calcd for C8H7BF3 171.0593, found 171.0588.
to stir for an additional 30 min after reaching homogeneity, at which
point it was cooled to 0 °C. AcOH and ethanolamine were added
according to the standard procedure. The reaction was then filtered
over a plug of silica to afford 3b in 52% yield as a clear viscous
oil with greater than 95% purity (239 mg, 1.04 mmol). Spectral
data were identical with those of previously isolated material.
General Procedure for the One-Pot Conversion of Alkynyl
Pinacolboronates to cis-Alkenyl Pinacolboronates: In Situ Genera-
tion of Lithium 4,4,5,5-Tetramethyl-2-(phenylethynyl)-1,3,2-diox-
aborolan-2-ide (14). Phenylacetylene (0.22 mL, 2 mmol) was
dissolved in Et2O (2 mL) and cooled to -78 °C. n-BuLi (2 mmol)
was then added dropwise, and the resulting lithium acetylide
solution was stirred for 30 min at -78 °C. A solution of 4,4,5,5-
tetramethyl-1,3,2-dioxaborolane in Et2O (2 mL) was then added,
and after stirring at -78 °C for 10 min the solution of borohydride
14 was allowed to warm to a temperature at which it could be stirred
freely. After 5 min of stirring, anhydrous HCl (4.0 M in dioxane,
2 mmol) was added dropwise, and the heterogeneous solution was
allowed to warm to rt. Schlenk filtration over Celite was carried
out directly onto solid dicyclohexylborane (356 mg, 2 mmol), and
the filter was washed with Et2O (2 mL). The reaction was allowed
Acknowledgment. This work was generously supported by
the National Institutes of Health (GM035249). We gratefully
acknowledge the research group of Professor Patrick Walsh
(University of Pennsylvania) for a number of insights and Dr.
Rakesh Kohli (University of Pennsylvania) for obtaining high
resolution mass spectra of new compounds.
Supporting Information Available: Experimental proce-
dures, spectral characterization, and copies of 1H, 13C, 11B, and
19F NMR spectra for all compounds prepared by the method
described. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO801191V
6844 J. Org. Chem. Vol. 73, No. 17, 2008