Synthesis of functionalized vinyl boronates via ruthenium-catalyzed olefin cross-metathesis and subsequent conversion to vinyl halides

Article abstract of DOI:10.1021/jo0345345

Functionalized vinyl pinacol boronates suitable for Suzuki cross-coupling reactions are synthesized using ruthenium-catalyzed olefin cross-metathesis of 1-propenyl pinacol boronate and various alkenes, including functionalized and 1,1-disubstituted alkenes. The resultant boronate cross products are stereoselectively transformed into predominantly Z-vinyl bromides and E-vinyl iodides. The vinyl bromides may be synthesized in a two-step, one-pot synthesis from a variety of olefins, resulting in a Z-selective formal vinyl bromide cross-metathesis reaction.

Full text of DOI:10.1021/jo0345345

Olefin cross-metathesis has become a viable synthetic
strategy for the generation of highly functionalized
alkenes,9,10 due to the development of ruthenium cata-
lysts such as 111 and 2.12 Cross-metathesis offers an
Syn th esis of F u n ction a lized Vin yl
Bor on a tes via Ru th en iu m -Ca ta lyzed Olefin
Cr oss-Meta th esis a n d Su bsequ en t
Con ver sion to Vin yl Ha lid es
Christie Morrill and Robert H. Grubbs*
Arnold and Mabel Beckman Laboratory of Chemical
Synthesis, Division of Chemistry and Chemical Engineering,
California Institute of Technology, Pasadena, California
91125
attractive alternative to alkyne hydroboration for vinyl
boronate synthesis. Alkenes are more easily prepared and
have low reactivity as compared to alkynes, and the
number of commercially available alkenes far exceeds
that of terminal alkynes. We have previously reported
the first cross-metathesis of pinacol vinyl boronate 5 and
an aliphatic terminal olefin,13 and Danishefsky has
successfully applied this methodology to the synthesis of
Suzuki macrocyclization precursors.14 In this paper, we
report the development of a new, synthetically more
accessible boronate cross partner and the extension of
vinyl boronate cross-metathesis to functionalized and 1,1-
disubstituted olefins. The boronate cross products can be
converted stereoselectively into either E- or Z-vinyl
halides.
rhg@caltech.edu
Received April 25, 2003
Abstr a ct: Functionalized vinyl pinacol boronates suitable
for Suzuki cross-coupling reactions are synthesized using
ruthenium-catalyzed olefin cross-metathesis of 1-propenyl
pinacol boronate and various alkenes, including function-
alized and 1,1-disubstituted alkenes. The resultant boronate
cross products are stereoselectively transformed into pre-
dominantly Z-vinyl bromides and E-vinyl iodides. The vinyl
bromides may be synthesized in a two-step, one-pot synthe-
sis from a variety of olefins, resulting in a Z-selective formal
vinyl bromide cross-metathesis reaction.
Scheme 1 illustrates our synthesis of the boronate cross
partners.15 We could not isolate boronic acid 3 due to its
rapid polymerization upon concentration,16 but 3 could
be directly converted into 5. Boronic acid 4 is also prone
to polymerization, but it is more stable than 3.17 In our
synthesis of 4, we were able to isolate a white, air-stable
solid in 10-20% yield by recrystallization from benzene.
This product appeared by NMR to be 4.18 Compound 4
could also be esterified in situ to form 6. Both 4 and 6
were variable mixtures of E- and Z-isomers. Compounds
5 and 6 were purified using silica gel chromatography,
Vinyl boronic acids and esters are versatile intermedi-
ates in organic synthesis.1 The boronate moiety can be
converted into hydrogen,1c an aldehyde or ketone,1c,2
a
halide,3 an amine,2 or an alkyl group.4 Most notably,
1-alkenylboron compounds are excellent components in
Suzuki cross-coupling reactions.5 Alkyne hydroboration
is usually employed to prepare vinyl boron reagents.1c,6
This protocol can deliver high yields of products under
mild conditions. However, terminal alkynes often require
several steps to prepare, and their inherent reactivity can
be problematic.7 In addition, â,â-disubstituted vinyl
boronates cannot be synthesized by alkyne hydrobora-
tion.8
(9) For recent reviews of olefin metathesis, see: (a) Trnka, T. M.;
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29. (b) Kotha, S.;
Sreenivasachary, N. Indian J . Chem., Sect. B 2001, 40, 763-780.
(10) For a review of cross-metathesis, see: Chatterjee, A. K.; Choi,
T.-L.; Sanders, D. P.; Grubbs, R. H. J . Am. Chem. Soc. 2003, in press.
(11) Schwab, P.; Grubbs, R. H.; Ziller, J . W. J . Am. Chem. Soc. 1996,
118, 100-110.
(1) (a) Ramachandran, P. V.; Brown, H. C. Recent Advances in
Borane Chemistry. Organoboranes for Synthesis; ACS Symposium
Series 783; American Chemical Society: Washington, DC, 2001; pp
1-15. (b) Matteson, D. S. Tetrahedron 1989, 45, 1859-1885. (c) Brown,
H. C.; Campbell, J . B., J r. Aldrichim. Acta 1981, 14, 3-11.
(2) Rangaishenvi, M. V.; Singaram, B.; Brown, H. C. J . Org. Chem.
1991, 56, 3286-3294.
(3) (a) Brown, H. C.; Hamaoka, T.; Ravindran, N. J . Am. Chem. Soc.
1973, 95, 5786-5788. (b) Brown, H. C.; Hamaoka, T.; Ravindran, N.
J . Am. Chem. Soc. 1973, 95, 6456-6457.
(4) (a) Brown, H. C.; Bhat, N. G. J . Org. Chem. 1988, 53, 6009-
6013. (b) Brown, H. C.; Basavaiah, D.; Kulkarni, S. U.; Bhat, N. G.;
Vara Prasad, J . N. V. J . Org. Chem. 1988, 53, 239-246.
(5) (a) Miyaura, N. Organoboron Compounds. Top. Cur. Chem. 2002,
219, 11-59. (b) Suzuki, A. J . Organomet. Chem. 1999, 576, 147-168.
(c) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483.
(6) Beletskaya. I.; Pelter, A. Tetrahedron 1997, 53, 4957-5026.
(7) Eymery, F.; Iorga, B.; Savignac, P. Synthesis 2000, 2, 185-213.
(8) â,â-Disubstituted vinyl boronates can be synthesized using
haloboration. For examples, see: (a) Suzuki, A. Pure Appl. Chem. 1986,
58, 629-638. (b) Satoh, Y.; Serizawa, H.; Miyaura, N.; Hara, S.; Suzuki,
A. Tetrahedron Lett. 1988, 29, 1811-1814.
(12) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953-956.
(13) Blackwell, H. E.; O’Leary, D. J .; Chatterjee, A. K.; Washen-
felder, R. A.; Bussmann, D. A.; Grubbs, R. H. J . Am. Chem. Soc. 2000,
122, 58-71.
(14) Njardarson, J . T.; Biswas, K.; Danishefsky, S. J . J . Chem. Soc.,
Chem. Commun. 2002, 23, 2759-2761.
(15) Matteson, D. S. J . Am. Chem. Soc. 1960, 82, 4228-4233.
(16) Kerins, F.; O’Shea, D. F. J . Org. Chem. 2002, 67, 4968-4971.
(17) Braun, J .; Normant, H. Bull. Soc. Chim. Fr. 1966, 8, 2557-
2564.
(18) The material that we isolated is a mixture of 4, its correspond-
ing cyclic trimer, and probably small amounts of higher oligomers. The
predominant species as detected by GC/MS is the cyclic trimer. In
addition, the boronic acids in this mixture may be partially hydrated.
Attempts to remove any excess water (using vacuum) from 4 after
recrystallization resulted only in decomposition. However, the solid
obtained after recrystallization was already of adequate purity to
participate in cross-metathesis reactions, which work for both the
monomeric and the trimeric versions of 4.
10.1021/jo0345345 CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/26/2003
J . Org. Chem. 2003, 68, 6031-6034
6031

TABLE 1. Vin yl Bor on a te Cr oss-Meta th esisa
a
b
(1 equiv cross partner) 5 mol % 2, 0.2 M in CH2Cl2, reflux. 0.2-0.4 mmol scale. 1.0 equiv, unless otherwise indicated. c Determined
by 1H NMR. 2.0 equiv. e E/Z ) 1:16. f 2.5 equiv.
d
SCHEME 1
successful cross-metathesis reactions using an alkenyl
boronic acid (i.e., 4). Although reactions with 4 are highly
E-selective, the resultant low isolated yields, due in part
to the high polarity and cyclic trimerization16 of the cross
products, made pinacol boronic esters 5 and 6 more
favorable reagents. While use of 5 and 6 affords cross-
metathesis products in similar yields and E/Z selectivity
(Table 1, entries 3 and 4), the ability to prepare 6 in
higher yield and greater ease than 5 led us to primarily
use 6 in further studies.
Boronate cross-metathesis is moderately to highly
E-selective and is compatible with a variety of functional
groups. As shown in Table 1, styrenes, allylsilanes, and
protected alcohols and amines undergo efficient meta-
thesis. Additionally, 1,1-disubstituted olefins are excel-
lent cross partners, and their metathesis results in
products (e.g., 13a and 13b) that cannot be prepared by
but 6 was isolated in significantly higher yields (80%)
relative to 5 (60%).
The results of the cross-metathesis reaction between
vinyl boron reagents 4, 5, or 6 and various olefins are
summarized in Table 1.19 Entries 1 and 2 show the first
(19) Efficient vinyl boronate cross-metathesis can also be achieved
with use of catalyst 1 when unhindered aliphatic terminal olefins are
used, as we have previously reported (ref 13).
6032 J . Org. Chem., Vol. 68, No. 15, 2003

TABLE 2. In Situ Vin yl Bor on a te
Cr oss-Meta th esis/Br om in a tion a
TABLE 3. Iod in a tion of Vin yl P in a col Bor on a tesa
a
I2 (2 equiv), NaOH (3 equiv), THF, rt; 0.4 mmol scale.
Determined by 1H NMR.
b
cases the isolated yields of the vinyl halides were greater
than the isolated yields of the corresponding vinyl
boronate cross product, which provides a way to curb the
purification losses that are encountered with some vinyl
boronate cross products.
a
(1) (1 equiv cross partner) 5 mol % 2, 0.2 M in CH2Cl2, reflux;
(2) (1 equiv boronate) Br2 (2 equiv), 0 °C; NaOMe (2 equiv), MeOH,
b
0 °C; 0.2-0.4 mmol scale, unless otherwise indicated. 2.0 equiv,
unless otherwise indicated. c Determined by 1H NMR. 2.0 mmol
d
scale. f 2.5 equiv.
We were unable to obtain high yields of the vinyl iodide
product using one-pot cross-metathesis/iodination reac-
tions (I2, NaOH). However, vinyl iodides are obtained in
high isolated yields when purified vinyl boronates are
used as starting materials (Table 3). The olefin stereo-
chemistry of the starting vinyl boronate is retained
during these reactions.3a
alkyne hydroboration. High levels of E-selectivity are
achieved by using either styrenes or olefins that have
secondary or tertiary allylic substitution.
Monitoring the boronate cross-metathesis reactions by
1H NMR (CD2Cl2 solvent) reveals that nearly all of the
terminal olefin cross partner is transformed into the
desired cross product.20 For example, we observed 86%
conversion of 15 to the desired cross product 16.21 The
lower isolated yield of 16 (i.e., 61%) indicates that some
decomposition occurs during purification by column chro-
matography. This example is typical of the lower-yielding
reactions reported in Table 1.
Vinyl halides, like vinyl boronates, are valuable com-
ponents in Suzuki cross-coupling reactions. In addition,
they have been designated as one of the most important
building blocks of transition-metal-catalyzed syntheses
in general.22 The inability to synthesize alkenyl halides
using olefin cross-metathesis has been a long-standing
problem.23 However, the ability to prepare vinyl bor-
onates using cross-metathesis provides a unique route
to vinyl halides, which employs the halogenation proce-
dures reported by Brown3 to stereoselectively convert the
vinyl boronate cross-metathesis products into vinyl bro-
mides and iodides.
The reaction of iodine with a vinyl boronate compound
is more sensitive to steric bulk on the boron atom than
that of bromine. Brown observed that iodinations were
unsuccessful using boronate catechol esters and had to
hydrolyze them prior to iodination, whereas brominations
readily occurred for both the boronic acids and their
catechol esters.3 In addition, pinacol boronate esters have
been reported to resist reaction with iodine.26 In our
studies, we observed little or no iodination using Brown’s
conditions (ether, 0 °C) and had to employ a more polar
solvent and a higher temperature (THF, room tempera-
ture) to observe high product yields. It is possible that
the sensitivity of the iodination reactions to solvent
polarity contributed to the inefficiency of the one-pot
cross-metathesis/iodination reactions, as these reactions
had to be carried out in either CH2Cl2 or a CH2Cl2/THF
mixed solvent system in order to allow efficient perfor-
mance of the metathesis reaction.
Brominations (Br2, NaOMe) can be performed in situ
with the cross-metathesis reaction, resulting in a one-
pot vinyl bromide synthesis (Table 2).24,25 In agreement
with Brown’s observations,3b the olefin stereochemistry
of the vinyl boronate is always inverted, resulting in
predominantly Z-vinyl bromides. Surprisingly, in several
In summary, we have generated both functionalized
and â,â-disubstituted vinyl boronates using ruthenium-
catalyzed olefin cross-metathesis of 1-propenyl pinacol
boronate 6, which is readily synthesized from com-
mercially available reagents in significantly higher yield
than its vinyl analogue 5. We halogenated the boronate
cross products to form predominantly Z-vinyl bromides
and E-vinyl iodides. Thus, the components of Suzuki and
numerous other metal-catalyzed coupling reactions were
constructed out of alkenes. Brominations can be carried
out in one-pot with the cross-metathesis reaction, result-
ing in the first examples of effective Z-vinyl bromide
synthesis via olefin cross-metathesis.
(20) Using excess cross partner rather than excess boronate did not
significantly affect the amount of cross product formed.
(21) Conversions were calculated relative to an anisole internal
standard.
(22) Tsuji, J . Reactions of Organic Halides and Pseudohalides.
Transition Metal Reagents and Catalysts: Innovations in Organic
Synthesis; Wiley: New York, 2000; pp 27-108.
(23) Grubbs group, unpublished results.
(24) Excess boronate is utilized in order to minimize the formation
of homodimers, which form dibrominated side products.
(25) For ease of purification, it was sometimes advantageous to use
5 rather than 6, as methylated side products were sometimes observed
with 6.
(26) Stewart, S. K.; Whiting, A. Tetrahedron Lett. 1995, 36, 3929-
3932.
J . Org. Chem, Vol. 68, No. 15, 2003 6033

purified 4 was obtained by recrystallization from benzene. 1H
NMR (300 MHz, CD3CN, ppm): (cyclic trimer, E-isomer) δ 6.49
(3H, dq, J ) 17.7, 6.0 Hz), 5.37 (3H, dq, J ) 17.6, 1.7 Hz), 1.80
(9H, dd, J ) 6.6, 1.8 Hz) 13C NMR (300 MHz, CD3CN, ppm):
(cyclic trimer, E-isomer) δ 147.8, 22.1. HRMS (EI): calcd for
C9H15B3O3 204.1300, found 204.1301.
Exp er im en ta l Section
Gen er a l P r oced u r e for Cr oss-Meta th esis of Com p ou n d s
4, 5, or 6. A solution of catalyst 2 (5 mol % relative to the cross
partner) and dry dichloromethane (cross partner ) 0.2 M) was
added via cannula to a flame-dried, round-bottomed flask
equipped with a reflux condenser and kept under slight argon
pressure. The olefin cross partner and either 4, 5, or 6 were
added to the flask via syringe. The brick red solution was
refluxed for roughly 12 h. The mixture was then concentrated
in vacuo, and the product(s) were purified by silica gel chroma-
tography.
4,4,5,5-Tetr a m eth yl-2-vin yl[1,3,2]d ioxa bor ola n e (5). The
same procedure described above, only using vinylmagnesium
bromide, was followed. After the ether extractions, the organic
layer was dried with sodium sulfate, and the solution was
concentrated in vacuo but was not allowed to become completely
concentrated (which would lead to decomposition of the acid
intermediate). The solution was added to a flask containing 50
mL of diethyl ether and 5 g of activated 4 Å molecular sieves. A
7 g portion of pinacol (59 mmol) was added, and the solution
was allowed to stir (under argon flow) at room temperature for
about 12 h, at which point the solution was passed through a
filter and concentrated in vacuo using a weak-vaccuum rotovap
(as 5 is somewhat volatile). The crude product was purified using
column chromatography (9:1 pentane/diethyl ether). 1H NMR
(300 MHz, CDCl3, ppm): δ 6.0 (3H, m), 1.29 (12H, s). 13C NMR
(300 MHz, CDCl3, ppm): δ 137.1, 83.5, 25.1. HRMS (EI): calcd
for C8H15BO2 154.1165, found 154.1165.
4,4,5,5-Tetr a m eth yl-2-p r op en yl[1,3,2]d ioxa bor ola n e (6).
A procedure identical to that described for compound 5 was
followed, with less concern over decomposition of the boronic acid
intermediate upon concentration. 1H NMR (300 MHz, CDCl3,
ppm): (E-isomer) δ 6.65 (1H, dq, J ) 17.9, 6.5 Hz), 5.46 (1H,
dq, J ) 18.2, 1.7 Hz), 1.85 (3H, dd, J ) 6.6, 1.8 Hz), 1.27 (12H,
s); (Z-isomer) δ 6.5 (1H, m), 5.35 (1H, dq, J ) 13.8, 1.5 Hz), 1.98
(3H, dd, J ) 7.1, 1.7 Hz), 1.28 (12H, s). 13C NMR (300 MHz,
CDCl3, ppm): (E-isomer) δ 149.8, 83.2, 25.1, 22.1; (Z-isomer) δ
149.8, 83.0, 25.2, 18.9. HRMS (EI): calcd for C9H17BO2 168.1322,
found 168.1321.
Gen er a l P r oced u r e for On e-P ot Cr oss-Meta th esis/Br o-
m in a tion of Com p ou n d s 5 or 6. After completion of the cross-
metathesis reaction (carried out as described above), the reaction
vessel was placed in an ice bath, and bromine (2 equiv relative
to 5 or 6) was added dropwise via syringe. The reaction was
allowed to stir at 0 °C for 30 min, after which time a solution of
2 equiv (relative to 5 or 6) sodium methoxide (roughly 0.6 M in
anhydrous methanol) was added via syringe. The solution was
allowed to stir at 0 °C for 30 min, after which time aqueous
sodium thiosulfate was added. The aqueous layer was extracted
three times with dichloromethane. The organic layer was dried
with magnesium sulfate, filtered, and concentrated in vacuo, and
the product(s) were purified by silica gel chromatography.
Gen er a l P r oced u r e for Iod in a tion of Vin yl P in a col
Bor on a tes. The boronate and reagent-grade THF (boronate )
0.4 M) were added via syringe to a round-bottomed flask
equipped with an addition funnel and kept under slight argon
pressure. A solution of (3 equiv) sodium hydroxide (3 M in
deionized water) was added via syringe, and the solution was
stirred vigorously at room temperature for about 10 min. A
solution of iodine (2 equiv, 0.2 M in THF) was added dropwise
(via addition funnel) to the reaction mixture, waiting for the red-
orange color of the reaction to turn to yellow before adding more
iodine solution. As the reaction progressed, the red-orange color
disappeared more slowly, and by the end of the reaction, it did
not go away at all. Reaction times were, on average, about 2 h.
At the end of the reaction, aqueous sodium thiosulfate was
added, and the aqueous layer was extracted three times with
diethyl ether. The organic layer was dried with magnesium
sulfate, filtered, and concentrated in vacuo, and the product(s)
were purified by silica gel chromatography.
Ack n ow led gm en t. We thank the National Insti-
tutes of Health for financial support and Brian J . Kwan
for synthesizing compounds 18 and 20. We also thank
Daniel P. Sanders, Dr. Steven D. Goldberg, Dr. Brian
T. Connell, Dr. Arnab K. Chatterjee, and Dr. J ennifer
A. Love for helpful suggestions and insight.
1-P r op en ylbor on ic Acid (4). A 4.5 mL (40 mmol) portion
of trimethyl borate and 10 mL of diethyl ether were added via
syringe to a flame-dried, round-bottomed flask kept under slight
argon pressure. The flask was placed in a dry ice/acetone bath,
and 100 mL of 1-propenylmagnesium bromide (0.5 M in THF,
50 mmol) was added dropwise, over about 30 min, to the solution
using an addition funnel. After all the Grignard reagent had
been added, the reaction was allowed to stir for 1 h at -78 °C,
at which point the reaction was placed in an ice bath and 70
mL 30% aqueous HCl was added. After being stirred for 30 min,
the solution was warmed to room temperature and extracted
three times with 100 mL diethyl ether. The organic portion was
dried with sodium sulfate and concentrated in vacuo, and
Noted Ad d ed a fter ASAP P ostin g. In the version
posted ASAP on J une 26, 2003, this paper was incorrectly
formatted as an article. It was correctly formatted as a
note in the version posted on J uly 7, 2003.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal methods and characterization data (1H and 13C NMR,
HRMS) for compounds 7-14, 16, 17, 19, and 21-30. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O0345345
6034 J . Org. Chem., Vol. 68, No. 15, 2003