Zirconocene-mediated highly regio- and stereoselective synthesis of multisubstituted olefins starting from 1-alkynylboronates

Article abstract of DOI:10.1021/ja075234y

Multisubstituted olefins are efficiently prepared by the zirconocene-mediated regio- and stereoselective coupling between 1-alkynylboronates and ethylene, followed by sequential transformation in moderate to high yields. The proper combination of substrates and reaction conditions is important for high yields. The synthesis of various tetrasubstituted alkenes in a regio- and stereocontrolled manner is described. This methodology has been applied to the synthesis of (Z)-tamoxifen in a concise, regio- and stereoselective manner. This multicomponent coupling strategy involves the characteristics of 1-alkynylboronates toward high selectivities followed by palladium(0)-mediated cross-coupling with aryl halides. Copyright

Full text of DOI:10.1021/ja075234y

Published on Web 10/02/2007
Zirconocene-Mediated Highly Regio- and Stereoselective Synthesis of
Multisubstituted Olefins Starting from 1-Alkynylboronates
Yasushi Nishihara,* Mitsuru Miyasaka, Masanori Okamoto, Hideki Takahashi, Eiji Inoue,
Kenki Tanemura, and Kentaro Takagi
DiVision of Chemistry and Biochemistry, Graduate School of Natural Science and Technology, Okayama UniVersity,
3-1-1 Tsushimanaka, Okayama 700-8530, Japan
Received July 13, 2007; E-mail: ynishiha@cc.okayama-u.ac.jp
Table 1. Synthesis of Trisubstituted Ethenes 3 via
Stereocontrolled Suzuki-Miyaura Cross-Coupling Reactions of
Alkenylboronates 2 with Aryl Iodidesa
Because the expeditious, regio- and stereoselective synthesis of
multisubstituted olefins is one of the most challenging subjects in
synthetic organic chemistry,1 efficient multicomponent couplings
of this type are of interest and hold a potential for diversity-oriented
syntheses.2-4 Although it is known that various alkynes are
oxidatively coupled on the low-valent zirconium,5 the complete
regiocontrolled formation of zirconacycles is difficult when unsym-
metrical alkynes are employed. We also studied the zirconacyclo-
pentene formation using unsymmetrical diarylethynes,6 but complete
regioselectivity is not observed.7 Trimethylsilyl group (Me3Si-) can
selectively occupy at the R-position of zirconacycles,8 but the further
transformation is rather limited. The pioneering work of Srebnik
demonstrated the preparation of highly functionalized vinylbor-
onates by hydrozirconation of 1-alkynylboronates9 with Schwartz’s
reagent (Cp2ZrHCl).10 One assumes that the reaction of 1-alkynyl-
boronates with Takahashi’s reagent (Cp2ZrCl2/2EtMgBr)11 would
be useful because the resulting boron-containing zirconacyclo-
pentenes can be converted into various compounds by the subse-
quent transformation. Herein, we report a versatile procedure for
the regioselective formation of zirconacyclopentenes from 1-alky-
nylboronates and successive transformation to give regio- and
stereocontrolled tri- and tetrasubstituted olefins (eq 1; Bpin is
pinacolatoboryl).
run
2
Ar1
Ar2
3
% yieldb
1
2a
C6H5
4-MeO-C6H4
4-CF3-C6H4
2-Me-C6H4
4-NH2-C6H4
4-F-C6H4
4-EtOCO-C6H4
2-pyridyl
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
81
83
83
80
55
82
79
86
92
58
56
94
85
85
72
85
75
2
3
4
5
6
7
8
4-NC-C6H4
4-NO2-C6H4
2-HO-C6H4
4-MeCO-C6H4
1-naphthyl
2-thienyl
9
10
11
12
13
14
15
16
17
2b
2c
4-MeO-C6H4
4-CF3-C6H4
C6H5
4-CF3-C6H4
C6H5
4-MeO-C6H4
a The reactions were carried out at room temperature for 12 h by using
2 (2 mmol), aryl iodides (2.2 mmol), KOH (6.0 mmol), Pd(dba)2 (10 mol
b
%), and P(t-Bu)3 (20 mol %) in THF (20 mL). Isolated yield.
Addition of 1-alkynylboronate 1a to Takahashi’s reagent gener-
ated in situ smoothly produced zirconacyclopentene which, upon
hydrolysis, afforded (Z)-4,4,5,5-tetramethyl-2-(2-phenyl-1-buten-
1-yl)-1,3,2-dioxaborolane (2a) in 50% GC yield with excellent
regio- and stereoselectivities (vide infra). However, the reaction
was always accompanied by the dihydrogenated starting material,10c
as a byproduct, indicating that some of the zirconacyclopentenes
release the ethylene part to form the zirconacyclopropenes. To
improve the yield of 2a, we adapted the procedure to prepare the
parent zirconacyclopentane (Cp2ZrC4H8) by introduction of atmo-
spheric ethylene gas in situ to Negishi’s reagent (Cp2ZrCl2/2nBuLi).
This compound is reported to react cleanly with various alkynes.12
Accordingly, new classes of alkenylboronates 2a-c were obtained
exclusively in good to high yields by hydrolysis of the formed
zirconacyclopentenes A (eq 2). The regioselectivity of 2 was
with substituted aromatic iodides across 2a (runs 1-13). It is
noteworthy that the regiochemistry can be readily reversed by inter-
converting the functionality on the aryl group (Ar1) in alkynylbo-
ronates 1 and the aryl iodide (Ar2). Accordingly, 1-alkynylboronates,
2b as well as 2c, successfully reacted with iodobenzene to produce
the desired products 3n (run 14) and 3p (run 16), respectively.
Respectively, they are regioisomers of 3a and 3b. Furthermore,
the present coupling reaction of 2a was extended to the reaction
with an alkyl iodide,14 giving rise to [(1Z)-1-ethyl-1-octenyl]benzene
(4) in 44% yield with excellent Z-selectivity (eq 3).15
1
determined by H NMR spectra. The presence of a highly shifted
singlet in the double bond region (5.38-5.53 ppm) is indicative
that the hydrogen atom located gemenal to the boron functionality.10c
On the other hand, the 11B NMR chemical shift in the region (29.8-
30.1 ppm) is appropriate to vinylboronates.
With stereodefined 2a-c in hand, we performed the Suzuki-
Miyaura cross-coupling13 with various aryl iodides Ar2-I. The results
are summarized in Table 1. The reaction was general and proceeded
Reagents and conditions: 2a (2.4 mmol), nC6H13-I (2.0 mmol), Ni(cod)2
(4 mol %), bathophenanthroline (8 mol %), KOtBu (3.2 mmol), 2-butanol
(12 mL), 60 °C, 5 h, 44%.
9
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J. AM. CHEM. SOC. 2007, 129, 12634-12635
10.1021/ja075234y CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Regio- and Stereocontrolled Synthesis of the
cyclopentenes followed by Cu/Pd cross-coupling and Suzuki-
Miyaura coupling with various aryl iodides. Further studies to
disclose the factors for the regioselectivity and to expand this
approach to a general stereocontrolled synthesis of π-conjugated
molecules will be the subjects of forthcoming papers.
Boron-Containing Tetrasubstituted Olefinsa
Acknowledgment. The authors gratefully thank Prof. Tamotsu
Takahashi for a generous gift of Cp2ZrCl2 and Prof. Hiroshi
Nakazawa and Dr. Masumi Itazaki at Osaka City University for
measurements of elemental analyses. This work was supported by
a Grant-in-Aid for Scientific Research on Priority Areas “Advanced
Molecular Transformations of Carbon Resources” from the Ministry
of Education, Culture, Sports, Science and Technology, Japan. Y.N.
also acknowledges Astellas Foundation for Research on Medicinal
Resources, Saneyoshi Scholarship Foundation, and the Japan
Securities Scholarship Foundation.
a
i
Reagents and conditions: (a) PrOH (0.8 equiv), CuCl (1.0 equiv),
Supporting Information Available: Details of all experimental
procedures and spectroscopic data of new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
Pd(PPh3)4 (10 mol %), the corresponding aryl iodide (1.0 equiv), THF,
room temp, 1 h; (b) ethyl vinyl ether (1.5 equiv), 50 °C, 20 h, then CuCl
(1.0 equiv), DMPU (1.5 equiv), Pd(PPh3)4 (10 mol %), iodobenzene (1.1
equiv), THF, 50 °C, 3 h; (c) allyloxytrimethylsilane (1.5 equiv), 50 °C, 20
h, then CuCl (1.0 equiv), DMPU (1.5 equiv), Pd(PPh3)4 (10 mol %),
iodobenzene (1.1 equiv), THF, 50 °C, 3 h; (d) homoallyl bromide (1.5
equiv), 50 °C, 20 h, then CuCl (1.0 equiv), DMPU (1.5 equiv), Pd(PPh3)4(10
mol %), iodobenzene (1.1 equiv), THF, 50 °C, 3 h.
References
(1) (a) Denmark, S. E.; Amburgey, J. J. Am. Chem. Soc. 1993, 115, 10386.
(b) Brown, S. D.; Armstrong, R. W. J. Am. Chem. Soc. 1996, 118, 6331.
(c) Organ, M. G.; Cooper, J. T.; Rogers, L. R.; Soleymanzadeh, F.; Paul,
T. J. Org. Chem. 2000, 65, 7959.
(2) (a) Itami, K.; Kamei, T.; Yoshida, J.-i. J. Am. Chem. Soc. 2003, 125,
14670. (b) Kamei, T.; Itami, K.; Yoshida, J.-i. AdV. Synth. Catal. 2004,
346, 1824.
(3) Zhou, C.; Larock, R. C. J. Org. Chem. 2005, 70, 3765.
(4) Shimizu, M.; Nakamaki, C.; Shimono, K.; Schelper, M.; Kurahashi, T.;
Hiyama, T. J. Am. Chem. Soc. 2005, 127, 12506.
(5) Takahashi, T.; Kotora, M.; Hara, R.; Xi, Z. Bull. Chem. Soc. Jpn. 1999,
72, 2591.
(6) Tilley reported that unsymmetrical but tetra- or pentafluorophenyl sub-
stituted diarylethynes resulted in regioselective couplings to zirconacy-
clopentadienes owing to the effects of electron-withdrawing perfluoroaryl
groups, see: Johnson, S. A.; Liu, F.-Q.; Suh, M. C.; Zuercher, S.; Haufe,
M.; Mao, S. S. H.; Tilley, T. D. J. Am. Chem. Soc. 2003, 125, 4199.
(7) See Supporting Information.
(8) (a) Buchwald, S. L.; Nielsen, R. B. J. Am. Chem. Soc. 1989, 111, 2870.
(b) Hara, R.; Xi, Z.; Kotora, M.; Xi, C.; Takahashi, T. Chem. Lett. 1996,
1003.
Before hydrolysis, zirconacyclopentene A formed in situ can
serve as versatile precursors of tetrasubstituted olefins bearing the
boron functionalities. For example, as shown in Scheme 1,
stereocontrolled formation of 5a-c were easily accomplished by
sequential one-pot Pd-catalyzed coupling reactions with various aryl
iodides. Again, the stereochemistry of 5a-c can be confirmed by
comparison of the spectroscopic data with those of the reported
authentic compounds of stereochemistry verified by X-ray analyses.4
Substitution of the ethylene moiety of zirconacyclopentene A (Ar1
) C6H5) with the corresponding unsaturated organic molecules
afforded zirconacyclopentenes B, which further reacted with
iodobenzene under similar conditions to afford 6, 7, and 8.16
(9) Recent papers for synthetic utility of 1-alkynylboronates, see: (a)
Yamamoto, Y.; Ishii, J.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc. 2004,
126, 3712. (b) Nishihara, Y.; Okamoto, M.; Inoue, Y.; Miyazaki, M.;
Miyasaka, M.; Takagi, K. Tetrahedron Lett. 2005, 46, 8661. (c) Suginome,
M.; Shirakura, M.; Yamamoto, A. J. Am. Chem. Soc. 2006, 128, 14438.
(10) (a) Zheng, B.; Srebnik, M. J. Organomet. Chem. 1994, 474, 49. (b) Deloux,
L.; Skrzypczak-Jankun, E.; Cheesman, B. V.; Sabat, M.; Srebnik, M. J.
Am. Chem. Soc. 1994, 116, 10302. (c) Deloux, L.; Srebnik, M. J. Org.
Chem. 1994, 59, 6871. (d) Zheng, B.; Srebnik, M. J. Org. Chem. 1995,
60, 3278. (e) Deloux, L.; Srebnik, M. J. Org. Chem. 1995, 60, 3276. (f)
Pereira, S.; Srebnik, M. J. Org. Chem. 1995, 60, 4316. (g) Pereira, S.;
Srebnik, M. Organometallics 1995, 14, 3127. (h) Desurmont, G.; Klein,
R.; Uhlenbrock, S.; Laloe¨, E.; Deloux, L.; Giolando, D. M.; Kim, Y. W.;
Pereira, S.; Srebnik, S. Organometallics 1996, 15, 3323. (i) Deloux, L.;
Srebnik, M. Tetrahedron Lett. 1996, 37, 2735. (j) Quntar, A. A. A.;
Srebnik, M. Org. Lett. 2004, 6, 4243.
An additional motivation for this study is our interest in
developing an efficient route to (Z)-tamoxifen, which has been
widely used for the treatment of breast cancer at all stages.
Tamoxifen’s anti-estrogen biological activity resides entirely in the
Z-isomer. Although there are a number of stereoselective syntheses
of (Z)-tamoxifen,2,4,17 either they are not regio- and stereoselective
or they involve multistep procedures employing starting materials
that are not readily available. Our route to (Z)-tamoxifen involves
a multicomponent reaction of readily available 5a (from 2a,
(11) (a) Takahashi, T.; Nitto, Y.; Seki, T.; Saburi, M.; Negishi, E. Chem. Lett.
1990, 2259. (b) Takahashi, T.; Seki, T.; Nitto, Y.; Saburi, M.; Rousset,
C. J.; Negishi, E. J. Am. Chem. Soc. 1991, 113, 6266.
(12) (a) Takahashi, T.; Xi, Z.; Rousset, C. J.; Suzuki, N. Chem. Lett. 1993,
1001. (b) Xi, Z.; Hara, R.; Takahashi, T. J. Org. Chem. 1995, 60, 4444.
(13) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(14) Gonzalez-Bobes, F.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 5360.
(15) Z-Configuration of 4 was assigned by comparison of the spectral data
with those of (E)-4. Shi, J.-c.; Negishi, E.-i. J. Organomet. Chem. 2003,
687, 518.
(16) Hara, R.; Nishihara, Y.; Landre´, P. D.; Takahashi, T. Tetrahedron Lett.
1997, 38, 447 and references cited therein.
i
ethylene, PrOH, iodobenzene), and N-[2-(4-iodophenoxy)ethyl]-
N,N-dimethylamine (eq 4). It is noteworthy that the reaction is
(17) For some 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. Engl. 1997, 36, 93. (e) Tessier, P. E.; Penwell, A. J.; Souza, F. E.
S.; Fallis, A. G. Org. Lett. 2003, 5, 2989.
highly regioselective (possibly >99:1), since the crude tamoxifen
1
obtained is around 99% pure according to H NMR spectrum.
In summary, we have developed a versatile direct synthesis of
multisubstituted olefins by a regioselective formation of zircona-
JA075234Y
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