Stereoselective synthesis of (E)-(trisubstituted alkenyl)borinic esters: Stereochemistry reversed by ligand in the palladium-catalyzed reaction of alkynylborates with aryl halides

Article abstract of DOI:10.1021/ol902278q

"Chemical Equation Presented" The palladium-catalyzed reaction of alkynylborates with aryl halides stereoselectively gave (E)-(trisubstituted alkenyl)-9-BBNs, in which two different aryl groups were installed trans to each other.

Full text of DOI:10.1021/ol902278q

ORGANIC
LETTERS
2009
Vol. 11, No. 23
5434-5437
Stereoselective Synthesis of
(E)-(Trisubstituted alkenyl)borinic Esters:
Stereochemistry Reversed by Ligand in
the Palladium-Catalyzed Reaction of
Alkynylborates with Aryl Halides
Naoki Ishida, Yasuhiro Shimamoto, and Masahiro Murakami*
Department of Synthetic Chemistry and Biological Chemistry, Kyoto UniVersity,
Katsura, Kyoto 615-8510, Japan
murakami@sbchem.kyoto-u.ac.jp
Received October 2, 2009
ABSTRACT
The palladium-catalyzed reaction of alkynylborates with aryl halides stereoselectively gave (E)-(trisubstituted alkenyl)-9-BBNs, in which two
different aryl groups were installed trans to each other.
Organoboron compounds are stable and easily handled
organometallics with well understood reactivities, rendering
them indispensable synthetic reagents for carbon-carbon
bond formation.1 In addition, organoboron compounds have
found increasing applications in the fields of pharmaceutical
chemistry2 and materials science.3 Therefore, the develop-
ment of efficient methods to prepare them is of even higher
demand than ever.
alcohols.4 However, the selective preparation of both stere-
oisomers of (trisubstituted alkenyl)(diorganyl)boranes re-
mains a significant challenge.5,6 We have reported that
alkynyl(triaryl)borates (aryl ) Ar1) react with aryl halides
(Ar2-X) in the presence of a palladium catalyst to afford
(trisubstituted alkenyl)(diaryl)boranes, in which the two aryl
groups (Ar1 and Ar2) are incorporated cis to each other across
the resulting carbon-carbon double bond.7 Considering the
potential utility of these compounds, we embarked on
the development of a complementary synthetic method for
the (E)-isomers. In this Letter, we describe the stereoselective
synthesis of (E)-(trisubstituted alkenyl)-9-BBNs by a pal-
Well established preparative methods exist for the syn-
thesis of (monosubstituted alkenyl)(diorganyl)boranes such
that these compounds have been widely applied for the
synthesis of unsaturated organic compounds like allylic
(4) Salvi, L.; Jeon, S.-J.; Fisher, E. L.; Carroll, P. J.; Walsh, P. J. J. Am.
Chem. Soc. 2007, 129, 16119, and references cited therein.
(1) Suzuki, A.; Brown, H. C. Organic Synthesis Via Boranes; Aldrich:
Milwaukee, WI, 2003; Vol. 3.
(5) For stereoselective synthesis of (trisubstituted alkenyl)(dialkyl)bo-
ranes via addition of X-BR2 (X ) halogen and thiolate) to alkynes, see: (a)
Suzuki, A. Pure. Appl. Chem. 1986, 58, 629. (b) Ishiyama, T.; Nishijima,
(2) (a) Rock, F. L.; Mao, W.; Yaremchuk, A.; Tukalo, M.; Cre´pin, T.;
Zhou, H.; Zhang, Y.-K.; Hernandez, V.; Akama, T.; Baker, S. J.; Plattner,
J. J.; Shapiro, L.; Martinis, S. A.; Benkovic, S. J.; Cusack, S.; Alley, M. R. K.
Science 2007, 316, 1759. (b) Zhu, Y.; Zhao, X.; Zhu, X.; Wu, G.; Li, W.;
Ma, Y.; Yuan, Y.; Yang, J.; Hu, Y.; Ai, L.; Gao, Q. Z. J. Med. Chem.
2009, 52, 4192.
K.; Miyaura, N.; Suzuki, A. J. Am. Chem. Soc. 1993, 115, 7219
(6) For a review of the reactions of alkynyltriorganylborate with
electrophiles, giving (trisubstituted alkenyl)(diorganyl)boranes, see: Negishi,
.
E. J. Organomet. Chem. 1976, 108, 281
.
(3) (a) Entwistle, C. D.; Marder, T. B. Chem. Mater. 2004, 16, 4574.
(b) Yamaguchi, S.; Wakamiya, A. Pure Appl. Chem. 2006, 78, 1413. (c)
Ja¨kle, F. Coord. Chem. ReV. 2006, 250, 1107.
(7) (a) Ishida, N.; Miura, T.; Murakami, M. Chem Commun. 2007, 4381.
See also: (b) Ishida, N.; Narumi, M.; Murakami, M. Org. Lett. 2008, 10,
1279.
10.1021/ol902278q CCC: $40.75
Published on Web 10/30/2009
 2009 American Chemical Society

ladium-catalyzed reaction of alkynylborates with aryl halides,
in which the two different aryl groups are installed trans to
each other.
Alkynylborate 1a was readily prepared by the reaction of
Ph-9-BBN with but-1-ynyllithium in THF,8 and subsequent
cation exchange with tetramethylammonium chloride in
methanol (Scheme 1). The borate 1a is obtained as a white
the corresponding triphenylborate.7a Although we at-
tempted to isolate the produced triorganoborane 3a, it
failed because 3a was prone to decompose in air. Instead,
3a was immediately hydrolyzed with acetic acid9 to give
the alkene (Z)-4a (E/Z ) 3/97, entry 1). The E/Z ratio
changed in favor of the (E)-isomer as the steric bulkiness
of the monodentate phosphine increased (entries 2-4).
Surprisingly, the stereochemical preference was reversed
for the (E)-isomer (E/Z ) 92/8) when bidentate ligand
DPEPhos having a large bite angle was used (entry 5).
Finally, it was found that XANTPhos, possessing an even
larger bite angle, exclusively gave (E)-4a in 73% yield
(entry 6).
Scheme 1.
Preparation of Alkynylborate 1aa
Thus, the stereochemistry of the product depended strongly
on the phosphine ligand employed. A proposed mechanism
for the trans-addition reaction is shown in Scheme 2: (i)
a Reagents and conditions: (a) THF, -78 °C to rt, 1 h. (b) Me4NCl,
MeOH, rt, 5 min.
Scheme 2. Proposed Mechanism
precipitate of high purity, stable to air and moisture, and
therefore, storable without any decomposition for several
months.
Alkynylborate 1a thus derived from Ph-9-BBN is
preferred over the corresponding alkynyltriarylborate as
the starting substance from a synthetic point of view. It
was subjected to the palladium-catalyzed reaction with
4-bromoanisole in the presence of various phosphine
ligands (Table 1). When tri(o-tolyl)phosphine was em-
Table 1. Ligand Screeninga
oxidative addition of 4-bromoanisole (2a) to palladium(0)
gives arylpalladium bromide A, (ii) arylpalladium species
A is coordinated by alkynylborate 1a to form intermediate
B, (iii) carbopalladation across the carbon-carbon triple bond
occurs in a cis fashion to provide alkenylpalladium C, and
(iv) a phenyl group on boron migrates to the R-carbon with
inversion of stereochemistry,10,11 resulting in the formation
of trans-addition product 3a with regeneration of the
palladium(0).12
entry
ligand
yield of 4a/ %b E/Z of 4ab
The ligand-dependent reaction pathway of the phenyl
migration is explained as follows. Tri(o-tolyl)phosphine is
relatively less stereodemanding and, when located around
the palladium center, provides enough space for the phenyl
group on boron to undergo 1,3-migration to palladium
(Scheme 4). On the other hand, a bulky bidentate ligand
XANTPhos likely disfavors the 1,3-phenyl migration from
boron to palladium. Instead, the direct 1,2-migration of the
phenyl group from boron onto the R-carbon dominates,10
giving trans-addition product. Tri(tert-butyl)phosphine and
Buchwald-type ligands, which are intermediates between
tri(o-tolyl)phosphine and XANTPhos in sterics, may permit
both of these pathways, resulting in a mixture of E/Z isomers.
Next, we tried to isolate the addition product in the form
of an alkenylborane, which was applicable to subsequent
synthetic transformations rather than losing a carbon-boron
linkage by hydrolysis. When the reaction mixture was
directly subjected to a migrative oxidation reaction with
1
2
3
4
5
6
P(o-tol)3
P(t-Bu)3
1-[(t-Bu)2P](biphenyl)
2-[(t-Bu)2P](1,1′-binaphthyl)
DPEPhos
69
47
18
21
24
73
3/97
17/83
28/72
67/33
92/8
XANTPhos
>99/1
a Reaction conditions: 1.0 equiv of 1a, 1.05 equiv of 2a, 2.5 mol % of
[PdCl(π-allyl)]2, 6 mol % of ligand, toluene, 70 °C, 30 min; then AcOH,
rt, 3 h. b Determined by GC analysis.
ployed as the ligand, the phenyl group on boron underwent
1,3-migration onto the palladium in preference to the
bridgehead sp3 carbons of the 9-BBN moiety, and the (Z)-
isomer was stereoselectively formed, as with the case of
(8) Whiteley, C. G. S. Afr. J. Chem. 1982, 35, 9.
(9) The protonolysis of alkenylboranes with acetic acid proceeds in a
stereospecific fashion: Brown, H. C.; Zweifel, G. J. Am. Chem. Soc. 1959,
81, 1512.
Org. Lett., Vol. 11, No. 23, 2009
5435

Scheme 3.
Synthesis of Borinic Estersa b
,
a Reaction conditions: 1.0 equiv of alkynylborate 1, 1.05 equiv of aryl halide 2, 1 mol % of (xantphos)PdCl(π-allyl), toluene, 70 °C, 30 min; then 1.5
equiv of Me3NO, DCM, rt, 2 h. Isolated yields were shown. The major isomers shown in the table were observed with >95/5 ratio by NMR analysis. The
stereochemistries of 5g and 5m were determined by NOE analysis and those of other borinic esters 5 were assumed by analogy. b Aryl iodide was used.
trimethylamine-N-oxide, (trisubstituted alkenyl)borinic ester
5a in which the bridgehead sp3 carbon migrated onto oxygen
was obtained stereoselectively.13 The resulting borinic ester
(E)-5a was stable enough to be isolated by column chroma-
tography on silica gel and could be stored without any
decomposition for a longer period of time than 1 month. Most
importantly, this reagent could be employed for subsequent
carbon-carbon bond forming reactions (vide infra).
scope of the aryl group on boron was also broad; electron-
rich (5g and 5n) and -deficient (5f) phenyl and thienyl (5l)
groups successfully participated in the migration reaction.
Scheme 4. 1,3-Migration of Aryl Group
A wide variety of borinic esters were synthesized with
use of the palladium/XANTPhos system followed by mi-
grative oxidation with trimethylamine-N-oxide (Scheme 3).
Aryl halides having either an electron-donating or an
electron-withdrawing substituent gave the corresponding
borinic esters in good yields (5a and 5b). Phthalimide (5c),
chloro (5f, 5j, and 5l), and ester (5i) groups remained intact
under the reaction conditions. A sterically demanding aryl
iodide was also reactive (5d). In addition to the substituted
phenyl groups, 2- and 3-bromothiophene afforded the desired
product in good yield (5e and 5h). Primary alkyl (5a to 5g,
5l, and 5m), secondary alkyl (5h to 5k), and aryl (5n) groups
can be used as the substituent of the alkynyl moiety. The
Finally, we applied this reaction to the synthesis of both
isomers of Tamoxifen (Scheme 5), which has been in clinical
5436
Org. Lett., Vol. 11, No. 23, 2009

use for cancer treatment.14,15 The reaction of 1a with
bromobenzene with the palladium/tri(o-tolyl)phosphine cata-
lyst followed by oxidation with trimethylamine-N-oxide gave
borinic ester (Z)-5o (71% yield, E/Z ) 7/93). On the other
hand, the corresponding (E)-isomer was stereoselectively
obtained in 83% yield (E/Z ) >95/5) when the reaction of
1a with bromobenzene was carried out with the palladium/
XANTPhos calatyst, the loading of which could be decreased
even to 0.1 mol %. The Suzuki-Miyaura coupling reaction
of each stereoisomer of 5o with 1-bromo-4-[2-(N,N-dim-
ethylamino)ethoxy]benzene (2b) afforded Tamoxifen (6) with
retention of each stereochemistry. Thus, the present study
made it possible to synthesize either stereoisomer of tetra-
substituted olefins16 starting from the same substances by
choice of the appropriate ligand.
Scheme 5. Synthesis of Tamoxifensa
In summary, we have developed a new catalyst system
for the palladium-catalyzed reaction of alkynylborates with
aryl halides, which produces (E)-(trisubstituted alkenyl)bo-
ranes stereoselectively. With both stereoisomers being avail-
(10) For substitutive 1,2-migration from boron to the R-carbon with
inversion of stereochemistry, see: Ko¨brich, G.; Merkle, H. R. Angew. Chem.,
Int. Ed. 1967, 6, 74
.
(11) Inversion of the stereochemistry was also observed in the palladium-
catalyzed cross-coupling reaction of 2-bromo-1,3-dienes with organozinc
reagents: Zeng, X.; Hu, Q.; Qian, M.; Negishi, E. J. Am. Chem. Soc. 2003,
a Reagents and conditions: (a) 1 mol % of (o-tol)3PPdCl(π-allyl), toluene,
70 °C, 30 min; then 1.5 equiv of Me3NO, DCM, rt, 2 h. (b) 0.1 mol % of
(xantphos)PdCl(π-allyl), toluene, 70 °C, 5 h; then 1.5 equiv of Me3NO,
DCM, rt, 5 h. (c) 1.05 equiv of 4-BrC6H4[O(CH2)2NMe2] (2b), 2.5 mol %
of Pd(OAc)2, 5 mol % of SPhos, K3PO4, THF, 60 °C, 12 h for (E)-5o, 24 h
for (Z)-5o.
125, 13636
.
(12) An alternative mechanism is conceivable; the arylpalladium bromide
A acts as an electrophile to place the palladium on the carbon ꢀ to boron
and induces migration of a phenyl group on boron to the R-carbon. A similar
mechanism has been assumed for analogous reactions of alkynylborates
with alkyl halides, most of which lacked in stereoselectivity. The high
stereoselectivity obtained in the present reaction led us to favor the
mechanism proposed in the text.
able, the reinforced palladium-catalyzed reaction of alky-
nylborates serves as an authentic method for the synthesis
of (trisubstituted alkenyl)boron compounds.
(13) Soderquist, J. A.; Najafi, M. R. J. Am. Chem. Soc. 1986, 51, 1330
(14) Wiseman, H. Tamoxifen: Molecular Basis of Use in Cancer
Treatment and PreVention; Wiley: Chichester, U.K., 1994
.
.
(15) For representative Tamoxifen syntheses, see: (a) Millar, R. B.; Al-
Hassan, M. I. J. Org. Chem. 1985, 50, 2121. (b) Potter, G. A.; McCague,
R. J. Org. Chem. 1990, 55, 6184. (c) Brown, S. D.; Armstrong, R. W. J.
Org. Chem. 1997, 62, 7076. (d) Studemann, T.; Knochel, P. Angew. Chem.,
Int. Ed. 1997, 36, 93. (e) Tessier, P. E.; Penwell, A. J.; Souza, F. E. S.;
Fallis, A. G. Org. Lett. 2003, 5, 2989. (f) Itami, K.; Kamei, T.; Yoshida,
J.-i. J. Am. Chem. Soc. 2003, 125, 14670. (g) Shimizu, M.; Nakamaki, C.;
Shimono, K.; Schelper, M.; Kurahashi, T.; Hiyama, T. J. Am. Chem. Soc.
2005, 127, 12506. (h) Nishihara, Y.; Miyasaka, M.; Okamoto, M.;
Takahashi, H.; Inoue, E.; Tanemura, K.; Takagi, K. J. Am. Chem. Soc. 2007,
Acknowledgment. This work was supported by a Grant-
in-Aid for Science Research on Priority Areas (No. 19027032,
Synergy of Elements) from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
Supporting Information Available: Experimental details
and selected spectral data for new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
129, 12634
.
(16) (a) Itami, K.; Mineno, M.; Muraoka, N.; Yoshida, J. J. Am. Chem.
Soc. 2004, 126, 11778. (b) Flynn, A. B.; Ogilvie, W. W. Chem. ReV. 2007,
107, 4698
.
OL902278Q
Org. Lett., Vol. 11, No. 23, 2009
5437