Efficient synthesis of sterically hindered arenes bearing acyclic secondary alkyl groups by suzuki-miyaura cross-couplings

Article abstract of DOI:10.1002/anie.201411518

Bulky P,P-O ligands were designed to inhibit isomerization and reduction side reactions during the cross coupling between sterically hindered aryl halides and alkylboronic acids. Suzuki-Miyaura cross-couplings between di-ortho-substituted aryl bromides and acyclic secondary alkylboronic acids have been achieved with high yields. The method has also enabled the preparation of ortho-alkoxy di-ortho-substituted arenes bearing isopropyl groups in excellent yields. The utility of the synthetic method has been demonstrated in a late-stage modification of estrone and in the application to a new synthetic route toward gossypol. No side reaction: The shown bulky P,P-O ligands (right) successfully inhibit isomerization and reduction side reactions of the cross-coupling of sterically hindered substrates such as di-ortho-substituted aryl bromides with acyclic secondary alkylboronic acids. The method also allows the preparation of ortho-alkoxy di-ortho-substituted isopropyl arenes in excellent yields.

Full text of DOI:10.1002/anie.201411518

Angewandte
Chemie
DOI: 10.1002/anie.201411518
Cross-Coupling
Efficient Synthesis of Sterically Hindered Arenes Bearing Acyclic
Secondary Alkyl Groups by Suzuki–Miyaura Cross-Couplings**
Chengxi Li, Tianyu Chen, Bowen Li, Guolan Xiao, and Wenjun Tang*
=
Abstract: Bulky P,P O ligands were designed to inhibit
isomerization and reduction side reactions during the cross
coupling between sterically hindered aryl halides and alkyl-
boronic acids. Suzuki–Miyaura cross-couplings between di-
ortho-substituted aryl bromides and acyclic secondary alkyl-
boronic acids have been achieved with high yields. The method
has also enabled the preparation of ortho-alkoxy di-ortho-
substituted arenes bearing isopropyl groups in excellent yields.
The utility of the synthetic method has been demonstrated in
a late-stage modification of estrone and in the application to
a new synthetic route toward gossypol.
T
he cross-coupling of aryl halides with alkyl substrates[1–5]
has become an important method for the formation of
substituted aryls and complements the traditional Friedel–
Crafts alkylation. In particular, aryl–alkyl Suzuki–Miyaura
cross-couplings are increasingly employed in the total syn-
thesis of complex natural products and drug molecules.[1i]
Despite their growing synthetic relevance, aryl–alkyl
Suzuki–Miyaura cross-couplings are often complicated by
reduction and/or isomerization side reactions as a result of the
presence of b-hydrogen atoms in the alkyl group.[3a] These
issues become severe in cross-couplings between sterically
hindered aryl halides and acyclic secondary alkylboronic
acids, as isomerization and reduction products D and E often
become the major products (Scheme 1). The high-yielding
synthesis of di-ortho-substituted arenes bearing acyclic sec-
ondary alkyl groups is thus particularly challenging by cross-
coupling reactions. Buchwald[3g] reported a high-yielding
method for an aryl–isopropyl Negishi cross-coupling that
was used in the highly selective transformation of a series of
mono-ortho-substituted halides. Organ et al.[3l] reported high
selectivities in aryl–isopropyl Negishi cross-coupling of non-
hindered substrates by employing a palladium catalyst with
a bulky N-heterocyclic carbene (NHC) ligand. Excellent
selectivity was reported by Biscoe and co-workers[3r] in the
aryl–isopropyl Stille cross-coupling and Suzuki–Miyaura
cross-coupling[3s] of nonhindered substrates. Feringa et al.[3t]
Scheme 1. Reduction and isomerization in Suzuki–Miyaura cross-cou-
plings of sterically hindered aryl halides and acyclic secondary alkylbor-
onic acids.
showed an efficient aryl–isopropyl Kumada coupling method
that was also applicable to the reaction of several di-ortho-
substituted aryl halides with Q-Phos as the ligand. In contrast,
significant isomerization and low yields were observed in
aryl–isopropyl Suzuki–Miyaura couplings of ortho-substi-
tuted aryl halides in particular.[3d] High yields and selectivities
remained to be achieved for the Suzuki–Miyaura coupling
between di-ortho-substituted aryl halides and acyclic secon-
dary alkylboronic acids. An efficient method for the coupling
of ortho-alkoxy di-ortho-substituted aryl halides with isopro-
pylboronic acids is not available that might be applicable to
the synthesis of biologically interesting natural products[6]
(Scheme 2). We herein present the design and development
=
of bulky P,P O ligands L3 and L4 and their efficient
utilization in aryl–alkyl cross-couplings. These ligands effec-
[*] C. Li, T. Chen, B. Li, G. Xiao, Prof. Dr. W. Tang
State Key Laboratory of Bio-organic and Natural Products Chemis-
try, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences
345 Ling Ling Rd, Shanghai 200032 (China)
E-mail: tangwenjun@sioc.ac.cn
[**] We are grateful to NSFC-21432007, 21272254, STCSM-13J1410900,
the “Thousand Plan” Youth program, and Mettler Toledo for ReactIR
Instrument.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201411518.
Scheme 2. Biologically interesting natural products with sterically hin-
dered isopropyl aryl moieties.
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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-
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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
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Table 1: Cross-coupling of sterically hindered aryl halides and acyclic
secondary alkylboronic acids.
serve as an important method for the synthesis of isopropyl
arene natural products. However, excellent yields (> 90%)
and selectivities have not yet been achieved. We reasoned
that the coordinating ability of the ortho-alkoxy group to the
palladium catalyst led to a slower rate of reductive elimi-
nation, allowing the formation of isomerization and reduction
side products. Indeed, the coupling between 1-bromo-2-
methoxynaphathalene and isopropylboronic acid with L2
provided the isopropyl arene in only 16% yield with a 0.2:1
ratio of iPr/nPr substituents (Table 2, entry 1). Encouragingly,
Table 2: Cross-couplings between sterically hindered ortho-alkoxy di-
ortho-substituted aryl halides and isopropylboronic acids.
[a] Reaction conditions, unless otherwise specified: aryl bromide
(0.25 mmol), 1.5 equiv of isopropylboronic acid (2), 0.5 mol% [{Pd-
(cinnamyl)Cl}2], 2 mol% of L4, 3.0 equiv of K3PO4·H2O, toluene, 1008C,
12 h. [b] Yields of isolated iPr–Ar. [c] iPr/nPr ratios were determined by
HPLC on a C18 reverse-phase column or by 1H NMR spectroscopy. [d] L2
was employed as the ligand. [e] L3 was employed as the ligand.
use of the bulkier ligand L3 led the desired product in an
improved yield (51%) with a 1.3:1 ratio of iPr/nPr substitu-
ents (entry 2). Excitingly, the cross-coupling with ligand L4
led to the desired coupling product with a 31/1 ratio of iPr/nPr
products, providing the ortho-alkoxy di-ortho-substituted
isopropyl arenes in the best yield achieved to date by cross-
coupling (94%, entry 3). Thus, a series of ortho-alkoxy di-
ortho-substituted isopropyl arenes were efficiently synthe-
sized in excellent yields and selectivities. Functionalities such
as ketone, aldehyde, nitrile, and ester moieties were well
tolerated (entries 4–10). According to a kinetic study moni-
tored by React-IR, the coupling of 4-bromo-3,5-dimethoxy-
benzaldehyde (entry 9) proceeded completely within 4 h at
a Pd catalyst loading of 0.5 mol%.[12]
In order to investigate the remarkable efficiency of L3/L4-
mediated cross-couplings toward sterically hindered isopro-
pyl arenes, both [Pd(L3)Cl2] and [Pd(L4)Cl2] complexes were
prepared with [(COD)PdCl2] as the Pd source.[12] Notably,
both Pd complexes were applicable as catalysts for the cross-
couplings. The X-ray structures[13] showed the steric bulk and
[a] Reaction conditions, unless otherwise specified: aryl bromide
(0.25 mmol), 1.5 equiv of isopropylboronic acid (2), 0.5 mol% [Pd-
(cinnamyl)Cl]2, 2 mol% of L3, 3.0 equiv of K3PO4·H2O, toluene, 1008C,
12 h. [b] Yields of isolated iPr–Ar. [c] iPr/nPr ratios were determined by
HPLC on a C18 reverse-phase column or by 1H NMR spectroscopy.
[d] Ligand L4 was employed.
were compatible with the reaction, which thus provides
advantages over the corresponding Negishi and Kumada aryl–
alkyl cross-couplings.[3] Various acyclic primary or secondary
alkylboronic acids were also successfully employed to form
the corresponding alkyl arenes in high yields and selectivities
(entries 11–13 and 24–26).
The aryl–isopropyl cross-coupling of ortho-alkoxy di-
ortho-substituted arenes with isopropylboronic acids may
=
chelating nature through both P and P O coordination in the
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Scheme 6. Synthesis of gossypol intermediate 13 by employing the
aryl–alkyl cross-coupling strategy. a) AcOH, DCM, RT, 82%;
b) 1. Et3SiH, PBr3, DCM; 2. NBS, THF; 3. Tf2O, Et3N, DCM; 50%
(3 steps); c) iPrB(OH)2, [Pd(cinnamyl)Cl]2 (0.5 mol%), L4 (2 mol%),
86%, (iPr/nPr=9.6:1); d) Pd/C, H2, Et3N, MeOH, 99%.
Figure 1. X-ray structure of [Pd(L3)Cl2] and [Pd(L4)Cl2]. A,B) front and
top view of [Pd(L3)Cl2]; C,D) front and top view of [Pd(L4)Cl2];
E) Model of Pd(L3/L4)Ar(iPr) during the reductive elimination step
(hydrogen atoms and a dichloromethane molecule were omitted for
clarity).
bromination and triflate formation provided 11 in 50%
overall yield in three steps. Cross-coupling of 11 with
isopropylboronic acid with Pd-L4 as the catalyst provided
compound 12 in 86% yield with a 9.6:1 ratio of iPr/nPr
substitution. Removal of the triflate group in 12 using Pd/C/
H2 provided compound 13, a key intermediate in the synthesis
of gossypol,[16] in 99% yield.
=
solid state (Figure 1). We considered that the hemilabile P O
coordination contributes to the steric bulk at the right rear
side of the Pd center and also allows a fast reductive
elimination. Both L3 and L4 effectively block coordination
from the top and front left sides of the palladium center and
leave limited space for b-hydrogen elimination and isomer-
ization pathways. In comparison, L4 is even bulkier than L3
because of its dimethylamino moiety, which further facilitates
the reductive elimination[9,14] and allows the synthesis of
ortho-alkoxy di-ortho-substituted isopropyl arenes with excel-
lent selectivities and yields. Coordination between the
dimethylamino group of L4 and the palladium center was
not observed.
=
In summary, we have designed and developed bulky P,P
O ligands that successfully inhibit the isomerization and
reduction side reactions in Suzuki–Miyaura cross-couplings
between sterically hindered aryl halides and alkylboronic
acids. Ligands L3 and l4 have enabled Suzuki–Miyaura cross-
couplings between di-ortho-substituted aryl bromides and
acyclic secondary alkylboronic acids to the corresponding
products in high yields. The method has also enabled the
preparation of ortho-alkoxy di-ortho-substituted isopropyl
arenes in excellent yields by cross-couplings. Its synthetic
utility has been demonstrated in a late-stage modification of
estrone and the application to a new synthetic route toward
gossypol. Further development of efficient aryl–alkyl or
alkyl–alkyl cross-couplings are currently ongoing in our
group and progress will be reported in due course.
To demonstrate the synthetic utility of this method, the
coupling of sterically hindered aryl bromides with isopropyl
substrates was employed in a late-stage modification of
estrone (Scheme 5). Bromide 6[15] was readily synthesized
Received: November 28, 2014
Published online: && &&, &&&&
Keywords: aryl–alkyl cross-coupling · boronic acids ·
.
isopropyl arenes · ligand design · reductive elimination
Scheme 5. Synthesis of 4-isopropyl-substituted estrone 7.
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and isopropylboronic acid with Pd-L4 as the catalyst provided
the 4-isopropyl-substituted isolated estrone derivative 7 in
87% yield on a 1-gram scale, thus demonstrating the
applicability of this method.
The cross-coupling was further applied in a new synthetic
route toward gossypol, a male antifertility agent and PAF
antagonist (Scheme 6).[16] A Diels–Alder reaction between
diene 8 and dimethoxyquinone 9 provided benzoquinone 10
in 82% yield. Reduction of 10 using HSiEt3/PBr3, followed by
4
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[12] See the Supporting Information for details.
[13] CCDC 1026685 ([Pd(L3)Cl2]), 1036101 ([Pd(L4)Cl2]), and
1029789 (11) contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
[14] Conjugation between the Me2N group and the phenyl ring in L4
was not observed in the crystal structure. In this case, the Me2N
group might serve as an electron-withdrawing group, as men-
tioned by Buchwald in reference [3h], thus further facilitating
the reductive elimination.
[4] Examples of nickel-catalyzed aryl—alkyl couplings: a) K.
Tamao, Y. Kiso, K. Sumitani, M. Kumada, J. Am. Chem. Soc.
1972, 94, 9268; b) L. Melzig, A. Gavyushin, P. Knochel, Org.
Lett. 2007, 9, 5529; c) V. B. Phapale, M. Guisꢁn-ceinos, E.
BuÇuel, D. J. Cꢁrdenas, Chem. Eur. J. 2009, 15, 12681; d) A.
Joshi-Pangu, M. Ganesh, M. R. Biscoe, Org. Lett. 2011, 13, 1218.
[5] Examples of other metal-catalyzed aryl–alkyl coupling: iron,
a) G. Cahiez, S. Marquais, Tetrahedron Lett. 1996, 37, 1773; b) G.
Cahiez, H. Avedissian, Synthesis 1998, 1199; c) A. Fꢂrstner, A.
Leitner, M. Mendez, H. Krause, J. Am. Chem. Soc. 2002, 124,
13856; Cobalt, d) G. Cahiez, H. Avedissian, Tetrahedron Lett.
1998, 39, 6159.
[15] E. Schwenk, C. G. Castle, E. Joachim, J. Org. Chem. 1963, 28,
136.
[16] a) A. I. Meyers, J. J. Willemsen, Chem. Commun. 1997, 1573;
b) K. Dodou, R. J. Anderson, W. J. Lough, D. A. P. Small, M. D.
Shelley, P. W. Groundwater, Bioorg. Med. Chem. 2005, 13, 4228;
c) J. Wei, D. L. V. Jagt, R. E. Royer, L. M. Deck, Tetrahedron
Lett. 2010, 51, 5757; d) L. Li, Y. Liu, Q. Wang, Eur. J. Org. Chem.
2013, 8014.
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Cross-Coupling
C. Li, T. Chen, B. Li, G. Xiao,
W. Tang*
&&& — &&&
Efficient Synthesis of Sterically Hindered
Arenes Bearing Acyclic Secondary Alkyl
Groups by Suzuki–Miyaura Cross-
Couplings
=
No side reaction: The shown bulky P,P O
tuted aryl bromides with acyclic secon-
dary alkylboronic acids. The method also
allows the preparation of ortho-alkoxy di-
ortho-substituted isopropyl arenes in
excellent yields.
ligands (right) successfully inhibit iso-
merization and reduction side reactions
of the cross-coupling of sterically hin-
dered substrates such as di-ortho-substi-
6
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!