Stereoselective cross-coupling reaction of 1,1-diboryl-1-alkenes with electrophiles: A highly stereocontrolled approach to 1,1,2-triaryl-1-alkenes

Article abstract of DOI:10.1021/ja054484g

Palladium-catalyzed cross-coupling reaction of 1,1-diboryl-1-alkenes with aryl and alkenyl iodides was found to proceed stereoselectively, giving rise to the corresponding mono-coupled product as a single diastereomer with E-configuration. Second coupling of the initial product with another aryl iodide affords diverse triarylalkenes in their stereochemically pure form. This highly stereoselective approach for triarylalkenes allows one to synthesize both diastereomers in one pot from 1,1-diboryl-1-alkenes. Copyright

Full text of DOI:10.1021/ja054484g

Published on Web 08/17/2005
Stereoselective Cross-Coupling Reaction of 1,1-Diboryl-1-alkenes with
Electrophiles: A Highly Stereocontrolled Approach to 1,1,2-Triaryl-1-alkenes
Masaki Shimizu,* Chihiro Nakamaki, Katsuhiro Shimono, Michael Schelper, Takuya Kurahashi, and
Tamejiro Hiyama
Department of Material Chemistry, Graduate School of Engineering, Kyoto UniVersity, Kyoto UniVersity Katsura,
Nishikyo-ku, Kyoto 615-8510, Japan
Received July 7, 2005; E-mail: shimizu@npc05.kuic.kyoto-u.ac.jp
Scheme 1. Stereocontrolled Approach to 1,1,2-Triaryl-1-alkenes 4
Based on Sequential Cross-Coupling Reaction of 1,1-Diborylated
Alkenes 2 (Bpin is pinacolatoboryl)
Triarylated alkenes (TAA) constitute an important class of
nonsteroidal antiestrogens, as exemplified by tamoxifen, which is
currently used clinically for breast cancer treatment.1 Since anti-
estrogenic activity of TAA depends on configuration of the double
bond, stereocontrolled synthesis of TAA gains much interest for
exploration and improvement of TAA-based pharmaceuticals.2
Stepwise and 2-fold cross-coupling reaction of 1,1-dimetalated-
1-alkenes R1R2CdCM1M2 (1, R1 * R2)3 with electrophiles provides
a promising approach for stereoselective synthesis of such unsym-
metrical tetrasubstituted alkenes as TAA.4 Both diastereomers can
be prepared simply by reversing the order of employed electrophiles,
and furthermore, the whole transformation could be effected in a
one-pot procedure. When M1 and M2 in 1 are different, stereocontrol
of tetrasubstituted ethenes relies definitely on stereoselective
preparation of 1. Accordingly, structural variation in 1 is quite
limited.5 On the other hand, preparation of 1 (M1 ) M2) is much
more easily achieved to provide a broader scope of starting gem-
dimetalated alkenes 1. The intrinsic issue in the use of 1 (M1 )
M2) for the coupling reaction is whether the first coupling takes
place stereoselectively or not. Although gem-dizincio and -distannyl
reagents 1 leading to stereodefined nonarylated and diarylated
alkenes, respectively, have a few precedents,6 to our best knowledge,
there is no example of the present approach applied to TAA. In
this communication, we report a solution for the synthetic problem.
Namely, palladium-catalyzed cross-coupling reaction of 1,1-diboryl-
1-alkenes 2 with Ar2-I proceeds stereoselectively to give mono-
coupled product 3 with R and Ar2 being cis as a single diastereomer
(Scheme 1). Further coupling reaction of 3 with another iodide
Ar3-I allows us to establish a stereocontrolled approach to a diverse
kind of TAA 4.7 The whole transformation is applicable to facile
synthesis of both (Z)- and (E)-tamoxifen and can be carried out
sequentially in one pot, if desired.
Diboryl reagents 2 were readily prepared by gem-diborylation
of 1,1-dibromo-1-alkenes with bis(pinacolato)diboron8 or ketone
addition of tris(pinacolato)borylmethyllithium.9 At first, when 2a
(Ar1 ) Ph; R ) Et) was treated with p-F-C6H4-I in the presence
of Pd2dba3 (5 mol %)/P(t-Bu)3 (20 mol %) and 3 M KOH aqueous
solution in THF at room temperature, coupling product 3b was
isolated in 86% yield as a sole diastereomer (Table 1, entry 2).
The E-stereochemistry of 3b was determined by X-ray analysis of
its single crystal.10 Thus, the coupling reaction was found to take
place selectively with the boryl moiety cis to the ethyl group. The
scope of the stereoselective cross-coupling reaction is summarized
in Table 1. Perfect discrimination of two geminal boryl groups in
2a-2c (R ) Et) is general regardless of a substituent at the para-
position of Ar1 and Ar2 (entries 1-11 except for 9). The ortho-
methyl group in Ar2 also did not influence the stereoselectivity
(entry 9). In addition to 2a-2c, coupling reaction of 2d-2g bearing
Me, i-Pr, t-Bu, or CF3 as R also proceeded stereoselectively to give
Table 1. Stereoselective Cross-Coupling Reaction of 2 with
Ar2-Ia
entry
2
R
Ar1
Ar2
3b
yield (%)c
1
2
3
4
5
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b Et
2c Et
2d Me
2d Me
2d Me
Et
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
3a
3b
3c
83
86
75
74
61
60
55
87
78
67
66
69
66
70
68
71
54
39
72
Et
Et
Et
Et
Et
Et
Et
Et
p-F-C6H4
p-CF3-C6H4
p-EtO2C-C6H4 3d
p-H2N-C6H4
p-MeO-C6H4
p-RO-C6H4
p-Me-C6H4
o-Me-C6H4
p-F-C6H4
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
6
7d
8
9
10
11
12
13
14
15
16
17
18
19
p-Me-C6H4
p-CF3-C6H4 p-F-C6H4
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
p-CF3-C6H4
p-MeO-C6H4
p-CF3-C6H4
p-MeO-C6H4
p-CF3-C6H4
p-MeO-C6H4
C6H5
2e
2e
2f
2f
2g
i-Pr
i-Pr
t-Bu C6H5
t-Bu C6H5
CF3
C6H5
a Reaction conditions: 1 (0.1 mmol), Ar2-I (0.1 mmol), Pd2dba3 (5.0
µmol), P(t-Bu)3 (0.02 mmol), 3 M KOH aq. (0.1 mmol), THF (1 mL), rt.
b Obtained as a single diastereomer. c Isolated yield. d R: (CH2)2NMe2
3l-3s as a single diastereomer with the same stereochemical
outcome,11 although 2f reacted slower than others and gave 3q and
3r in lower yields.
At present, the reason the two boryl groups in 2 are completely
discriminated is unclear, although the step to be considered appears
to be a transmetalation process of the reaction.12 Considering A
values of Me (1.74 kcal/mol), Et (1.79), i-Pr (2.21), CF3 (2.4-
2.5), t-Bu (4.7; 4.9), and Ph (2.8) groups,13 the stereochemical
outcome cannot be explained simply by steric effect. For example,
2f having a t-Bu undergoes the carbon-carbon bond formation at
the cis position of the t-Bu group that is bulkier than a Ph group.
With stereodefined 3 in hand, we carried out the second cross-
coupling reaction with another aryl iodide Ar3-I. The reaction
proceeded smoothly in the presence of Pd[P(t-Bu)3]2 (5 mol %), 3
M NaOH aqueous solution upon heating at 60 °C to afford 4 as a
single stereoisomer. The results are summarized in Table 2. Both
diastereomers of 4 can be prepared from 2 simply by changing the
order of aryl iodides employed. Thus, stereochemically pure (Z)-
9
12506
J. AM. CHEM. SOC. 2005, 127, 12506-12507
10.1021/ja054484g CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Synthesis of 4 from 3 (Ar1 ) Ph, R ) Et) with Ar3-Ia
Acknowledgment. This work was supported by Grants-in-Aid
for COE Research on Elements Science, No. 12CE2005, and
Creative Scientific Research, No. 16GS0209, from the Ministry of
Education, Culture, Sports, Science, and Technology, Japan. We
thank Dr. Kenji Yoza, Bruker AXS Japan, for his assistance of
X-ray crystallographic analysis.
entry
3
Ar3
4b
yield (%)c
1
2
3
4
5
6
3a
3b
3f
3f
3g
3h
p-Me2N(CH2)2O-C6H4
p-MeO-C6H4
p-CF3-C6H4
p-Me-C6H4
C6H5
4a
4b
4c
4d
4e
4f
59
75
78
89
75
89
C6H5
Supporting Information Available: Experimental procedures and
analytical and spectroscopic data of new compounds (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
a Reaction conditions: 1 (0.1 mmol), Ar3-I (0.1 mmol), Pd[P(t-Bu)3]2
(5.0 µmol), 3 M NaOH aq. (0.1 mmol), THF (1 mL), 60 °C. b Obtained as
a single diastereomer. c Isolated yield.
References
Scheme 2. One-Pot Synthesis of (Z)-Tamoxifena
(1) (a) Magarian, R. A.; Overacre, L. B.; Singh, S.; Meyer, K. L. Curr. Med.
Chem. 1994, 1, 61. (b) Wiseman, H. Tamoxifen: Molecular Basis of Use
in Cancer Treatment and PreVention; Wiley: Chichester, U.K., 1994. (c)
Jordan, V. C. J. Med. Chem. 2003, 46, 883. (d) Jordan, V. C. J. Med.
Chem. 2003, 46, 1081.
(2) Miller, R. B.; Al-Hassan, M. I. J. Org. Chem. 1985, 50, 2121. (b)
Studemann, T.; Knochel, P. Angew. Chem., Int. Ed. Engl. 1997, 36, 93.
(c) Zhou, C.; Emrich, D. E.; Larock, R. C. Org. Lett. 2003, 5, 1579. (d)
Tessier, P. E.; Penwell, A. J.; Souza, F. E. S.; Fallis, A. G. Org. Lett.
2003, 5, 2989. (e) Zhou, C.; Larock, R. C. J. Org. Chem. 2005, 70, 3765.
(f) Zhou, C.; Larock, R. C. J. Org. Chem. 2005, 70, 3765.
(3) Review on preparation and reactions of 1,1-dimetalated 1-alkenes: (a)
Marek, I. Chem. ReV. 2000, 100, 2887. See also review on recent chemistry
on bisborylated compounds: (b) Dembitsky, V. M.; Ali, H. A.; Srebnik,
M. Appl. Organomet. Chem. 2003, 17, 327.
a Reagents and conditions: (a) 2a (1.0 equiv), Ph-I (1.0 equiv), Pd2dba3
(5 mol %), P(t-Bu)3 (20 mol %), 3 M KOH aqueous solution, dioxane, rt,
2 h; (b) Me2N(CH2)2O-C6H4-I (1.0 equiv), 100 °C, 22 h.
Scheme 3. Cross-Coupling Reaction of 2a with Alkenyl Halides
Leading to Polysubstituted 1,3-Dienes and [3]Dendralenea
(4) Sequential cross-coupling of 1,1-dihalo-1-alkenes is well-documented as
an efficient synthesis of trisubstituted alkenes. (a) Sugihara, T. In
Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi,
E.-i., Ed.; John Wiley & Sons: New York, 2002; Vol. 1, p 649. (b) Minato,
A.; Suzuki, K.; Tamao, K. J. Am. Chem. Soc. 1987, 109, 1257. (c) Roush,
W. R.; Brown, B. B.; Drozda, S. E. Tetrahedron Lett. 1988, 29, 3541. (d)
Zeng, X.; Qian, M.; Hu, Q.; Negishi, E.-i. Angew. Chem., Int. Ed. 2004,
43, 2259.
(5) Itami and Yoshida reported Cu-catalyzed carbomagnezation of alkynyl-
(2-pyridyl)silane generated stereodefined 1-magnesio-1-silyl-1-alkenes,
which underwent Pd-catalyzed cross-coupling reactions, at first, as a
Grignard reagent and then, after transmetalation of silicon to boron, as a
boron reagent, giving rise to diverse tamoxifen-type alkenes stereoselec-
tively. (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.
(6) Zn: (a) Creton, I.; Marek, I.; Normant, J. F. Synthesis 1996, 1499. (b)
Negishi, E.-i.; Sawada, H.; Tour, J. M.; Wei, Y. J. Org. Chem. 1988, 53,
913. Sn: (c) Quayle, P.; Wang, J.; Xu, J.; Urch, C. J. Tetrahedron Lett.
1998, 39, 485. See also: (d) Duboudin, J. G.; Jousseaume, B. J.
Organomet. Chem. 1979, 168, 1. (e) Creton, I.; Marek, I.; Normant, J. F.
Tetrahedron Lett. 1999, 40, 1899.
(7) Palladium-catalyzed cross-coupling reaction of 1-aryl-1,2-diboryl-1-alkenes
with aryl iodides was reported to produce triarylalkenes as a mixture of
regioisomers. (a) Brown, S. D.; Armstrong, R. W. J. Am. Chem. Soc.
1996, 118, 6331. (b) Brown, S. D.; Armstrong, R. W. J. Org. Chem. 1997,
62, 7076.
(8) (a) Hata, T.; Kitagawa, H.; Masai, H.; Kurahashi, T.; Shimizu, M.; Hiyama,
T. Angew. Chem., Int. Ed. 2001, 40, 790. (b) Kurahashi, T.; Hata, T.;
Masai, H.; Kitagawa, H.; Shimizu, M.; Hiyama, T. Tetrahedron 2002,
58, 6381.
a Reagents and conditions: (a) (E)-PhHCdC(H)I, Pd(PPh3)4 (5 mol %),
3 M KOH aq., THF, rt, 73% yield (2E4E:2E4Z ) 98:2); (b) (Z)-
PhHCdC(H)Br, Pd(PPh3)4 (5 mol %), 3 M KOH aq., THF, 40 °C, 72%
yield (2Z4E:2Z4Z ) 96:4); (c) (E)-HexHCdC(H)I, PdCl2(dppf) (5 mol %),
3 M KOH aq., DME, 40 °C, 81% yield; (d) Ph-I, PdCl2(dppf) (5 mol %),
3 M KOH aq., THF, 60 °C, 81% yield.
and (E)-tamoxifen (4a and 4e) were synthesized, respectively, as
listed in entries 1 and 5.
Moreover, the whole transformation can be carried out sequen-
tially in one pot. A facile synthesis of (Z)-tamoxifen (4a) from 2a
is demonstrated in Scheme 2.
Furthermore, the present stereocontrol in the coupling reaction
of 2 was extended to the reactions with alkenyl iodides and
bromides, giving rise to 3-borylated 1,3-dienes 5 and 6 in good
yields with high E-selectivity (Scheme 3).14 Boronates 5 and 6 can
serve as versatile precursors of polysubstituted 1,3-dienes. For
example, stereocontrolled [3]dendralene 715 and triphenylated 1,3-
diene 8 were easily obtained in good yields by successive
Pd-catalyzed coupling reactions with alkenyl and aryl iodides,
respectively.
(9) (a) Matteson, D. S.; Tripathy, P. B. J. Organomet. Chem. 1970, 21, P6.
(b) Matteson, D. S.; Tripathy, P. B. J. Organomet. Chem. 1974, 69, 53.
(10) See Supporting Information.
(11) Stereochemistries of 3j, 3k, 3n, 3o, and 3r were also determined by X-ray
analysis. See Supporting Information. E-Configuration of 3s was assigned
by comparison of the spectral data with those of (Z)-3s. Liu, X.; Shimizu,
M.; Hiyama, T. Angew. Chem., Int. Ed. 2004, 43, 879.
(12) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (b) Miyaura, N.
Cross-Coupling Reaction: A Practical Guide; Springer-Verlag: Berlin,
2002; Vol. 219, p 11. (c) Miyaura, N. J. Organomet. Chem. 2002, 653,
54. A reviewer suggested the possibility of an equilibration of 3. In view
that (Z)-3 reportedly reacts with aryl iodides under similar conditions
without their isomerization to (E)-3 (ref 5), we consider such equilibration
may be excluded.
(13) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic
Compounds; John Wiley and Sons: New York, 1994; p 695.
(14) Stereochemistry of 5 and 6 was determined by NOE experiments.
In summary, we have demonstrated stereoselective cross-coupling
reaction of 1,1-diboryl-1-alkenes with aryl iodides to afford the
corresponding (E)-alkenylboronates as single diastereomers. In
conjunction with the subsequent coupling of the boronates, this
approach provides an efficient and completely stereocontrolled
access to TAA, including tamoxifen. In addition, this method is
applicable to stereoselective preparation of polysubstituted 1,3-
dienes. Further studies are in progress to disclose the factors for
the stereoselection and to expand this approach to a general
stereocontrolled synthesis of π-conjugated molecules.
(15) Shimizu, M.; Tanaka, K.; Kurahashi, T.; Shimono, K.; Hiyama, T. Chem.
Lett. 2004, 33, 1066.
JA054484G
9
J. AM. CHEM. SOC. VOL. 127, NO. 36, 2005 12507