Stereoselective synthesis of tetrasubstituted alkenylboronates via 1,1-organodiboronates

Article abstract of DOI:10.1021/jo1003407

The stereoselective synthesis of tetrasubstituted alkenylboronates was established via the lithiation/nucleophilic addition reaction of 1,1-organodiboronates to carbonyl compounds. The present approach enables the facile and practical synthesis of tetrasu

Full text of DOI:10.1021/jo1003407

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We previously reported the easy access to air-stable
Stereoselective Synthesis of Tetrasubstituted
Alkenylboronates via 1,1-Organodiboronates
1,1-organodiboronates via Rh-catalyzed sequential hydro-
boration of 1-alkynes.4 The deprotonation reaction of the
R-C-H bond adjacent to the boronate moieties of 1a was
examined using lithium 2,2,6,6-tetramethylpiperazide (LTMP).
Kohei Endo,* Munenao Hirokami, and
Takanori Shibata*
TABLE 1. Variety of 1,1-Organodiboronates
Department of Chemistry and Biochemistry, School of
Advanced Science and Engineering, Waseda University,
Shinjuku, Tokyo 169-8555, Japan
kendo@aoni.waseda.jp; tshibata@waseda.jp
Received February 23, 2010
The stereoselective synthesis of tetrasubstituted alkenyl-
boronates was established via the lithiation/nucleophilic
addition reaction of 1,1-organodiboronates to carbonyl
compounds. The present approach enables the facile and
practical synthesis of tetrasubstituted olefins, which are use-
ful synthetic intermediates for further functionalizations.
The development of a practical and stereoselective synth-
esis of multisubstituted olefins is a promising study in
material and pharmaceutical chemistry. There are numerous
reports on the synthesis of multisubstituted olefins that can
readily undergo further functionalizations.1 However, it
is difficult to achieve the stereoselective synthesis of tetra-
substituted alkenylboronates via the well-known reactions
even though further C-C bond formation could yield
synthetically important tetrasubstituted olefins.2,3 In this
paper, we present a practical and facile synthesis of tetra-
substituted alkenylboronates via the nucleophilic addition of
1,1-organodiboronates to carbonyl compounds (Scheme 1,
Bpin = pinacolboryl).
aE/Z ratio was determined by NMR. The minor product was not
observed. The geometry was confirmed by NOESY analyses and the
conversion to literature known compounds.
The subsequent nucleophilic addition to acetophenone (2a)
afforded (E)-tetrasubstituted alkenylboronate 3a in high
yield (entry 1, Table 1).5 A precedent reported the lithiation
of bisborylmethane and the subsequent nucleophilic addi-
tion, which led to ketones or aldehydes via successive oxida-
tion. However, there have been no reports for the isolation of
SCHEME 1. Addition of 1a-g to Acetophenone 2a
(2) For recent examples, see: (a) Itami, K.; Kamei, T.; Yoshida, J. J. Am.
Chem. Soc. 2003, 125, 14670–14671. (b) Shimizu, M.; Nakamaki, C.;
Shimono, K.; Schelper, M.; Kurahashi, T.; Hiyama, T. J. Am. Chem. Soc.
2005, 127, 12506–12507. (c) Nishihara, Y.; Miyasaka, M.; Okamoto, M.;
Takahashi, H.; Inoue, E.; Tanemura, K.; Takagi, K. J. Am. Chem. Soc. 2007,
129, 12634–12635. (d) Takimoto, M.; Hou, Z. J. Am. Chem. Soc. 2009, 131,
18266–18268.
(1) (a) Denmark, S. E.; Amburgey, J. J. Am. Chem. Soc. 1993, 115, 10386–
10387. (b) Brown, S. D.; Armstrong, R. W. J. Am. Chem. Soc. 1996, 118,
6331–6332. (c) Organ, M. G.; Cooper, J. T.; Rogers, L. R.; Soleymanzadeh,
F.; Paul, T. J. Org. Chem. 2000, 65, 7959–7970. (d) Shi, Y.; Peterson, S. M.;
Haberaecker, W. W., III; Blum, S. A. J. Am. Chem. Soc. 2008, 130, 2168–
2169. (e) Konno, T.; Kinugawa, R.; Morigaki, A.; Ishihara, T. J. Org. Chem.
2009, 74, 8456–8459.
(3) (a) McMurry, J. E.; Fleming, M. P. J. Am. Chem. Soc. 1974, 96, 4708–
4709. (b) Mukaiyama, T.; Sato, T.; Hanna, J. Chem. Lett. 1973, 2, 1041–1044.
€
For other olefination reactions, see: (c) Furstner, A. Chem. Rev. 1999, 99,
991–1045. (d) Peterson, D. J. J. Org. Chem. 1968, 33, 780–784. (e) Tamao, K.;
Ishida, N.; Ito, Y.; Kumada, M. Org. Synth. 1990, 69, 96–105.
DOI: 10.1021/jo1003407
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Published on Web 04/15/2010
J. Org. Chem. 2010, 75, 3469–3472 3469
2010 American Chemical Society

Endo et al.
JOCNote
the corresponding alkenyl boronates that are derived from
ketones.6 The reaction of 1,1-organodiboronates 1b-1f
and ketone 2a gave the corresponding (E)-products 3b-3f in
high to excellent yields (entries 2-6). The benzyloxy group
diminished the yield of product 3g albeit with almost perfect
stereoselectivity (entry 7).
TABLE 2. Variety of Ketones
SCHEME 2. Addition of 1e to Ketones 2a-l
Various types of carbonyl compounds were used for the
synthesis of multisubstituted alkenylboronates (Scheme 2,
Table 2). The reactions of symmetrical ketones such as
benzophenone (2b) and cyclohexanone (2c) afforded the
corresponding products 3h and 3i, respectively, in almost
quantitative yields (entries 1 and 2). The reaction of aromatic
ketones 2d-j gave the products 3j-p in good to excellent
yields with almost perfect stereoselectivities (entries 3-9).
The electronic effect of aryl ketones bearing an electron-
withdrawing or electron-donating substituent did not
change the stereoselectivity (entries 8 and 9). Aliphatic
ketones such as 3-methylbutan-2-one (2k) and 1-cyclohexy-
lethanone (2l) afforded the corresponding products 3q and
3r, respectively, in high to excellent yields with almost perfect
stereoselectivities (entries 10 and 11). The reaction of 1a with
2f afforded 3u in excellent yield and stereoselectivity
(Scheme 3). Therefore, the aryl group of ketones could
regulate the stereoselectivity in every case.
SCHEME 3. Addition of 1a to 2f
aE/Z ratio was determined by NMR analyses. The minor product was
not observed. The geometry was confirmed by NOESY analyses, the
conversion to literature known compounds, and X-ray diffraction analyses.
To verify the configuration of the isolated alkene products,
we converted some of them into known compounds.7,8 The
Suzuki-Miyaura cross-coupling reaction of 3a using a cata-
lytic amount of [Pd(Pt-Bu3)2] with iodobenzene gave the litera-
ture known compound 4a, the geometry of whose olefinic
moiety is (Z); therefore, the geometry of alkenylboronate 3a
should be (E) (Scheme 4). The use of 3e gave the literature
known compound 4e, the geometry of whose olefinic moiety is
(Z); therefore, the geometry of alkenylboronate 3e should be
(E). The cross-coupling reaction of 3k gave the literature
known compound 4k (Scheme 5). Moreover, the X-ray diffrac-
tion analysis of 3l clearly shows that (E)-product was obtained
(see, Supporting Information). Therefore, the stereochemistry
of these products could be confirmed.
The coordinating group in ketones on the boronate moiety
changed the stereoselectivities of products (Scheme 6). The
reaction of 2-methoxyacetophenone 2m gave the corres-
ponding product 3s, whose major stereoisomer had an
opposite geometry compared with those of products 3e
and 3j-p as shown in Table 2. The strongly coordinative
dimethylamino group of 2n obviously controlled the
stereoselectivity to give the corresponding (E)-product 3t
in moderate yield (entry 2). These results indicate that the
(4) Endo, K.; Hirokami, M.; Shibata, T. Synlett 2009, 1131–1135.
(5) For the optimization of reaction conditions, see Supporting Informa-
tion.
(6) The nucleophilic addition of lithium triborylmethide was reported:
(a) Castle, R. B.; Matteson, D. S. J. Organomet. Chem. 1969, 20, 19–28.
(b) Matteson, D. S.; Tripathy, P. B. J. Organomet. Chem. 1970, 21, 6–8.
(c) Matteson, D. S.; Tripathy, P. B. J. Organomet. Chem. 1974, 69, 53–62.
The nucleophilic addition of lithium bis(ethylenedioxyboryl)methide or bis-
(trimethylene-dioxyboryl)methide and subsequent oxidation was reported:
(d) Matteson, D. S.; Moody, R. J.; Jesthi, P. K. J. Am. Chem. Soc. 1975, 97,
5608–5609. (e) Matteson, D. S.; Moody, R. J. J. Am. Chem. Soc. 1977, 99,
3196–3197. (f) Matteson, D. S.; Moody, R. J. Organometallics 1982, 1,
20–28.
(7) For 4a: (a) Anderson, P. G. Tetrahedron Lett. 1994, 35, 2609–2610.
For 4e: (b) Joo, W.-C.; Hong, J.-H.; Choi, S.-B.; Son, H.-E. J. Organomet.
Chem. 1990, 391, 27–36. For 4k: (c) Tolbert, L. M.; Ali, M. Z. J. Org. Chem.
1985, 50, 3288–3295.
(8) (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 20,
3437–3440. Pd/P(t-Bu)3 is an excellent catalyst for Suzuki-Miyaura cross-
coupling reactions: (b) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc.
2000, 122, 4020–4028.
3470 J. Org. Chem. Vol. 75, No. 10, 2010

Endo et al.
JOCNote
SCHEME 4. Suzuki-Miyaura Cross-Coupling of 3a and 3e
SCHEME 5. Suzuki-Miyaura Cross-Coupling of 3k
SCHEME 6. Addition of 1e to Ketones 2m and 2n
FIGURE 1. Plausible mechanism for stereoselectivity.
lithiated diboronates to ketones.10,11 The intramolecular
coordination of the oxygen atom in the pinacolboryl group
on the lithium atom is feasible.12 syn-Elimination through
LiO-C-C-Bpin affords the corresponding product 3. To
identify their stereoselectivities, DFT computations of OLi-1
and OLi-2 at the B3LYP/6-31G* level of theory were
performed for the geometry optimizations.13 Surprisingly,
the optimized geometries, opt-OLi-1 and opt-OLi-2, show
that path A could predominate via OLi-1 or OLi-2. The
difference in the relative energies, which include the zero-
point vibrational energies (ZPEs), is not very large between
opt-OLi-1 and opt-OLi-2. Since the dihedral angle of LiO-
C-C-B2pin is less than 20° in opt-OLi-1 and opt-OLi-2,
SCHEME 7. Synthesis of Tamoxifen Derivative (Z)-5
(10) The syn-elimination after homologation of organoboronic acid
pinacol ester using lithiated epoxides gave the tetrasubstituted olefin in
excellent stereoselectivity: (a) Shimizu, M.; Fujimoto, T.; Minezaki, H.;
Hata, T.; Hiyama, T. J. Am. Chem. Soc. 2001, 123, 6947–6948. (b) Shimizu,
M.; Fujimoto, T.; Liu, X.; Minezaki, H.; Hata, T.; Hiyama, T. Tetrahedron
2003, 59, 9811–9823. The steric influence of mono-boron compounds and
aldehydes or ketones realized the stereoselective synthesis of di- or tri-
substituted olefins. The rationale of stereoselectivity was described in detail:
(c) Pelter, A.; Buss, D.; Colclough, E.; Singaram, B. Tetrahedron 1993, 49,
7077–7103. (d) Pelter, A. Pure Appl. Chem. 1994, 66, 223–233. (e)
Kawashima, T.; Yamashita, N.; Okazaki, R. J. Am. Chem. Soc. 1995, 117,
6142–6143. (f) Sakai, M.; Saito, S.; Kanai, G.; Suzuki, A.; Miyaura, N.
Tetrahedron 1996, 52, 915–924.
(11) The in situ trapping of lithium alkoxide did not proceed at -78 and
0 °C before syn-elimination in our case. Vedrenne, E.; Wallner, O. A.; Vitale,
M.; Schmidt, F.; Aggarwal, V. K. Org. Lett. 2009, 11, 165–168.
(12) The intramolecular coordination of heteroatom to lithium center has
been described in the nucleophilic addition of 1,1-disilylmethane to carbonyl
compounds: Itami, K.; Nokami, T.; Yoshida, J.-i. Org. Lett. 2000, 2, 1299–
1302.
stereoselectivity of syn-elimination could be controlled by
means of the coordination on boron.
Finally, we examined the two-step synthesis of tamoxifen
derivative 5 from 1e (Scheme 7). Although a biological
activity of 5 higher than that of tamoxifen has been reported,
the stereoselective synthesis of 5 had not been established
previously.9 A precedent for the stereoselective synthesis of
tamoxifen derivatives was not suitable for the synthesis of
tetrasubstituted olefins bearing asymmetrical alkyl groups.
The cross-coupling reaction of 3j and ArI afforded the
desired product 5 in 76% yield as a sole stereoisomer. The
present synthetic route could be complementary to the pre-
vious syntheses of various types of tamoxifen congeners
bearing triaryl substituents.2
A plausible mechanism could be expressed as shown in
Figure 1. Typical models for lithium alkoxide intermediates,
OLi-1 and OLi-2, are shown after nucleophilic addition of
(13) The DFT computational calculations were performed using the
Spartan’08 suite for Mac (Wave function, Inc.). Zero-point vibrational
energies (ZPEs) were calculated for all structures, and the geometry was
verified as true minima using frequency analysis. The B3LYP/6-31G* and
the B3LYP/6-31þG* level gave almost similar results; thus, the results using
the B3LYP/6-31G* are shown. No coordination of the oxygen atom in the
pinacolboryl group on the lithium atom gave the same optimized geometries
at the expense of calculating time.
(9) Meegan, M. J.; Hughes, R. B.; Lloyd, D. G.; Williams, D. C.; Zisterer,
D. M. J. Med. Chem. 2001, 44, 1072–1084.
J. Org. Chem. Vol. 75, No. 10, 2010 3471

Endo et al.
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mized geometries did not show the predominant rotation
from 3t-OLi-1 and 3t-OLi-2. The inhibition of the coordina-
tion of the LiO moiety on the B2pin suggests that syn-
elimination through LiO-C-C-B1pin would probably
give 3t.
In conclusion, we demonstrated the easy and practical
approach to the stereocontrolled synthesis of the tetrasub-
stituted alkenylboronates in high to excellent yields. The
almost complete stereoselectivity is a characteristic feature of
the reactions presented in this paper. The stereoselectivity
can be determined by NMR analyses, Pd-catalyzed cross-
coupling reactions of alkenylboronates, X-ray diffraction
analyses, and computational studies of the optimized geo-
metries of intermediates. These results can serve as expedi-
ents for the synthesis of multisubstituted alkenylboronates,
which are useful and powerful synthetic intermediates used
in organic chemistry.
Experimental Section
To a solution of 1a (84.6 mg, 0.3 mmol) in THF (0.5 mL) at
0 °C was added LTMP (0.3 mmol, 0.4 M in THF). After 5 min,
ketone 2a (24 mg, 0.2 mmol) was added at 0 °C. The reaction
mixture was stirred at room temperature for 1 h and filtered
through a pad of silica gel with ether (50 mL). Concentration
and purification by silica gel column chlomatography (EtOAc/
hexane = 1:30) gave the product 3a in 48.5 mg, 94% yield: white
solid; mp 63 °C; 1H NMR (CDCl3, 400 MHz) δ 7.29-7.15 (m,
5H), 2.04 (d, J = 1.1 Hz, 3H), 1.84 (d, J = 1.1 Hz, 3H), 1.07 (s,
12H); 13C NMR (CDCl3, 100 MHz) δ 147.4, 146.3, 127.7, 127.6,
126.5, 82.9, 24.5, 20.2, 17.1; 11B NMR (CDCl3, 128 MHz) δ 31.1;
IR (KBr, cm-1) 2979, 1620, 1373, 1300, 1124, 862, 771, 685;
HRMS (FAB, positive) m/z calcd for C16H23BO2 258.1791,
found 258.1805.
FIGURE 2. Intramolecular coordination on a boron atom.
syn-elimination could take place. The addition to aryl ketones
induces the rotation in path A; the steric bulkiness of R1 and
R2 did not change the stereolselectivity. Therefore, the steric
influence of aryl ketones is unclear. The addition to aliphatic
ketones 2k induces the rotation in path A; the steric influence
of aliphatic ketones seems essential. Although the exact dri-
ving force of stereoselectivity is unclear, the present DFT
calculations support the experimental results.
The inversion of stereoselectivity using 2n obviously
indicates the coordination of the nitrogen atom on the
boron atom in the pinacolboryl group (B2pin). The coordi-
nation on the boron atom inhibits the syn-elimination
through LiO-C-C-B2pin. The DFT computations using
the B3LYP/6-31G* level of theory could give the opti-
mized geometries, opt-3t-OLi-1 and opt-3t-OLi-2, including
the coordination of the nitrogen atom on the boron atom
in the pinacolboryl group (Figure 2). However, these opti-
Acknowledgment. This work was financially supported by
Grant-in-Aid for Young Scientists (B) (No. 21750108) from
the Japan Society for the Promotion of Science and Waseda
University Grant for Special Research Project. K.E. thanks
the Society of Synthetic Organic Chemistry, Japan for a
Teijin Pharma Award.
Supporting Information Available: General procedure,
physical properties and NMR spectra of new compounds, and
DFT calculations. This material is available free of charge via
the Internet at http://pubs.acs.org.
3472 J. Org. Chem. Vol. 75, No. 10, 2010