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Angewandte
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tively inhibited isomerization and reduction side reactions
and enabled the formation of cross-coupling products
between di-ortho-substituted aryl halides with acyclic secon-
dary alkylboronic acids in high yields. The method has also
allowed the preparation of ortho-alkoxy di-ortho-substituted
isopropyl arenes in excellent yields by cross-couplings. Its
synthetic utility has been successfully demonstrated in the
late-stage modification of estrone and the application to
a new synthetic route toward gossypol.
It is well-known that ligands can exert significant influ-
ence on reactivity and selectivity of transition-metal-cata-
lyzed cross-couplings.[7] We hypothesized that the design of
a bulky P,P O ligand[8] could be beneficial for the coupling of
=
aryl halides with acyclic secondary alkylboronic acids under
the following conditions (Scheme 3): 1) The hemilabile coor-
=
Scheme 3. Design of bulky P,P O ligands for the Suzuki–Miyaura
coupling of sterically hindered aryl halides with acyclic secondary
alkylboronic acids.
Scheme 4. Cross-coupling between 2-bromo-1,3,5-trimethylbenzene (1)
and isopropylboronic acid (2): ligand study.
dination[7d] of the P O group can block an empty coordina-
=
tion site at the palladium center, but does not lower the
required rates of transmetallation and reductive elimination
in the cross-coupling of sterically hindered aryl halides with
alkylboronic acids. 2) The formation of a five-membered
palladacycle from the ligand can ensure this hemilabile
the ligand. The formation of 3 was not observed when the
monophosphorus ligand PCy3 was employed. Significant
isomerization and reduction occurred when S-Phos, X-Phos,
P(tBu)3, BI-DIME,[10] or AntPhos[11] were employed as the
ligand. Among them, BI-DIME showed slightly better
selectivity and 3 was formed in 59% yield. Although the
screened monophosphorus ligands did not provide satisfac-
=
coordination. 3) The P,P O ligand should be sufficiently
bulky to promote facile reductive elimination,[9] and effec-
tively block other open coordination sites around the Pd
center to inhibit b-hydride elimination, isomerization, and
=
tory yields, the newly developed P,P O ligands L1–3 were
highly efficient. Excitingly, the use of ligand L1 resulted in the
formation of 3 in more than 70% yield. The use of the
=
reduction. 4) A well-defined and tunable P,P O ligand
=
skeleton should help to shape the required structure system-
conformationally more rigid P,P O ligand L2 gave 3 in over
atically. Toward this end, we designed a bis(di-tert-butylphos-
80% yield. An excellent yield (92%) was achieved when L3
was employed and the side products 4 and 5 were both formed
in only 4% yield, thus providing one of the highest
selectivities in cross-couplings between di-ortho-substituted
aryl halides and aliphatic secondary alkyl substrates to date.
Next, a series of mono- or di-ortho-substituted aryl
bromides were cross-coupled with acyclic primary or secon-
dary alkyl substrates in excellent yields and selectivities
through the Suzuki–Miyaura cross-coupling with L3 as the
ligand (Table 1). High yields (90–99%) were achieved for
=
phinyl)methane monooxide (L1) and three bulky P,P O
ligands (L2–4) on the basis of a 2,3-dihydrobenzo[d]-
[1,3]oxaphosphole framework developed in our laboratory.[10]
It is noteworthy that all these ligands can be prepared in five
steps in gram quantities.
The Suzuki–Miyaura cross-coupling between 2-bromo-
1,3,5-trimethylbenzene (1) and isopropylboronic acid (2) was
studied (Scheme 4). Various commercially available phos-
phorus ligands were also tested for comparison. The reactions
were performed in toluene under nitrogen atmosphere at
1008C for 12 h in the presence of 0.5 mol% [{Pd-
(cinnamyl)Cl}2] and 2 mol% ligand with K3PO4·H2O
(3 equiv) as the base. As shown in Scheme 4, different
phosphorus ligands provided very different results. Diphos-
phines, such as BINAP and DPPF, gave the isomerization
product 4 and the reduction product 5 as the major products,
with little formation of the desired product 3. A low
conversion and selectivity was also observed with PPh3 as
a
range of mono-ortho-substituted isopropyl arenes
(entries 1–9). The ortho substituents were not limited to
methyl, ethyl, and isopropyl groups. Functional groups such as
methoxy, nitro, cyano, quinoline, and pyridine moieties were
well tolerated. A series of di-ortho-substituted arenes bearing
acyclic primary or secondary alkyl groups and various
substituents and functionalities were successfully formed in
high yields and selectivities (entries 12–26). Functional
groups, such as methoxy, cyano, carbonyl, and amino groups
2
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
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