Diastereoconvergent negishi cross-coupling using functionalized cyclohexylzinc reagents

Article abstract of DOI:10.1021/ol403673e

Highly diastereoselective Pd-catalyzed cross-coupling reactions of functionalized 2-, 3-, and 4-substituted cyclohexylzinc reagents with aryl, heteroaryl, and alkenyl iodides have been performed under mild conditions. The use of Ruphos (2-dicyclohexylphos

Full text of DOI:10.1021/ol403673e

Letter
pubs.acs.org/OrgLett
Diastereoconvergent Negishi Cross-Coupling Using Functionalized
Cyclohexylzinc Reagents
Kohei Moriya and Paul Knochel*
Department Chemie, Ludwig-Maximilian-Universitat Munchen, Butenandtstrasse 5-13, 81377, Munchen, Germany
̈
̈
̈
S
* Supporting Information
ABSTRACT: Highly diastereoselective Pd-catalyzed cross-
coupling reactions of functionalized 2-, 3-, and 4-substituted
cyclohexylzinc reagents with aryl, heteroaryl, and alkenyl
iodides have been performed under mild conditions. The use
of Ruphos (2-dicyclohexylphosphino-2′,6′-diisopropoxy-
biphenyl) as a ligand as well as LiCl and N-ethylpyrrolidone
(NEP) as additives leads to especially high diastereoselectiv-
ities and displays good functional group tolerance. The
stereoselectivity can be explained by assuming that the intermediate palladium moiety occupies an equatorial position of the
cyclohexyl ring.
he performance of diastereoselective cross-coupling
Scheme 1. Pd-Catalyzed Diastereoconvergent Cross-
Couplings of a Functionalized Cyclohexylzinc Reagent
reactions on Csp centers1 is an important synthetic task
3
T
for an efficient setup of multiple stereocenters. Several
diastereoselective Pd-catalyzed reactions on cyclic systems
have been reported so far,2 and other transition metals such
as Ni,3 Fe,4 and Co5 have also been used.6 We have also
reported that cyclohexylzinc reagents with alkyl substituents at
2
3
positions 2, 3, and 4 undergo Pd-catalyzed Csp and Csp
coupling reactions in a diastereoconvergent way.2a,7 High
diastereoselectivities were usually obtained in these systems;
however, the presence of functional groups in the ring
substituents complicated such cross-couplings (lower yields
and diastereoselectivities). Herein, we report an improved
cross-coupling procedure allowing the use of various function-
alized cyclohexylzinc reagents. Such Pd-catalyzed Negishi cross-
coupling reactions with various aryl, heteroaryl, and alkenyl
iodides proceed in very high stereoselectivities and good yields.
Thus, ethyl 4-iodocyclohexylcarboxylate 1a was treated with
commercially available zinc dust (3 equiv) in THF to produce
the corresponding cyclohexylzinc reagent 2a (30 °C, 4 h; 82%
yield).8 The presence of an acidic proton at the α-position to
the ester group did not hamper the zinc insertion, and the
resulting zinc reagent 2a proved to be stable for several weeks
increased the yield to 76% (entry 3).14 The best results were
obtained by replacing SPhos with Ruphos (2-dicyclohexylphos-
phino-2′,6′-diisopropoxybiphenyl),11c and the thermodynami-
cally favored trans-product 3aa was obtained in 80% isolated
yield15 with a trans/cis ratio of 96:4 (entry 4).
This cross-coupling procedure using the cyclohexylzinc
reagent 2a was extended to various aryl iodides (Table 2,
entries 1−8). Sensitive functional groups such as a ketone
(entry 2), an aldehyde (entry 3), a nitro group (entry 4), and a
cyano group (entry 5) were tolerated under the reaction
conditions.
without significant decomposition at 25 °C.9 1H NMR and 13
C
In addition to electron-poor aryl iodides, an electron-rich aryl
iodide can also be used (entry 6). Moreover, meta- or ortho-
substituted aryl and heterocyclic iodides gave equally high
diastereoselectivities (entries 7−9). Furthermore, the 3-
substituted cyclohexylzinc reagent 2b produced the thermody-
namically favored cis-cross-coupling products (entries 10−13).
An aromatic chloride substituent (entry 12) and an enone
group (entry 13) are both compatible with the cross-coupling
conditions.
NMR spectroscopy of this zinc reagent 2a in THF-d8 indicated
that a trans/cis mixture of ca. 60:40 was produced (Scheme 1).
The cross-couplings of this zinc reagent (1.0 equiv) with
methyl 4-iodobenzoate10 (0.7 equiv) in the presence of various
Pd-catalysts were examined. Preliminary experiments showed
that the ligands of Buchwald11 were the most promising. Thus,
the use of SPhos (2-dicyclohexylphosphino-2′,6′-dimethoxy-
biphenyl)11b led to a moderate yield (41% yield) and
diastereoselectivity (dr = 85:15) at −25 °C12 (Table 1, entry
1). The addition of N-ethylpyrrolidone (NEP, 10 vol %)
improved the yield as well as the diastereoselectivity (65%
yield; dr = 92:8; entry 2).13 Further addition of LiCl (1.5 equiv)
Received: December 18, 2013
Published: January 15, 2014
© 2014 American Chemical Society
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Letter
Table 1. Effect of Ligands and Additives
Scheme 2. Diastereoconvergent Cross-Couplings of
Cyclohexylzinc Reagents with a Nitrogen Functional Group
a
b
c
d
entry
ligand
additive
yield
dr
1
2
3
SPhos
SPhos
SPhos
−
41%
65%
76%
85:15
92:8
92:8
NEP (10 vol %)
NEP (10 vol %)
LiCl (1.5 equiv)
NEP (10 vol %)
LiCl (1.5 equiv)
4
RuPhos
80%
96:4
a
SPhos = 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl; Ruphos
b
= 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl. NEP = N-
ethylpyrrolidone. Isolated yield of the trans-diastereomer. dr (trans/
cis) determined by capillary GC and H NMR analysis.
c
d
1
Table 2. Scope of Pd-Catalyzed Diastereoconvergent Cross-
Couplings of Substituted Cyclohexylzinc Reagents with Aryl
Iodides
Table 3. Scope of Pd-Catalyzed Diastereoconvergent Cross-
Couplings of Substituted Cyclohexylzinc Reagents with Aryl
Iodides
a
b
Isolated yield of the trans-diastereomer. dr (trans/cis) determined by
1
capillary GC and H NMR analysis.
(dr = 99:1). Similarly, in the case of the 3-amino substituted
cyclohexylzinc reagent 2d prepared from the corresponding
cyclohexyl iodide 1d (40 °C, 8 h; 75% yield) the cis-1,3-
disubstituted cyclohexane 3da was obtained in 84% yield and
excellent diastereoselectivity (dr =99:1). Also, cyclohexylzinc
reagents with nitrogen-containing functional groups such as an
amide (2e, entry 1, Table 3) or a benzylamine substituent (2f,
entry 2) underwent the cross-couplings with excellent
diastereoselectivity (dr =99:1). In the case of cyclohexylzinc
reagents bearing an OTBS group (2g, entry 3) or TBS group
(2h, entry 4), the cross-coupling reaction proceeded well,
leading to the expected products 3ga and 3ha in 70−75% yield
and dr = >97:3. A cyclohexylzinc reagent bearing a terminal
a
b
Isolated yield of the major diastereomer. dr (major/minor)
c
1
determined by capillary GC and H NMR analysis. This reaction
was performed at −10 °C for 144 h. This reaction was performed at
−10 °C for 48 h.
d
Cyclohexylzinc reagents bearing other functional groups
were subjected to the cross-coupling reaction (Scheme 2 and
Table 3). Thus, the 4-amino substituted cyclohexylzinc reagent
2c prepared from the corresponding cyclohexyl iodide 1c (30
°C, 20 h; 84% yield) underwent a smooth cross-coupling with
methyl 4-iodobenzoate affording the trans-1,4-disubstituted
cyclohexane 3ca in 78% yield and excellent diastereoselectivity
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Letter
alkynyl group9 was readily prepared and led to the cross-
coupling product 3ia in 59% yield with modest diastereose-
lectivity (dr = 88:12). The reduced selectivity may be a
consequence of the lower bulkiness of the alkynyl group.16
Furthermore, cross-coupling reactions using 2-substituted
cyclohexylzinc reagents17 were examined (Scheme 3). Thus,
trans-cross-coupling product 6 will be obtained through the
usual retentive reductive elimination.2g,21,22,24 Again we
propose that the mixture of cis- and trans-cyclohexylzinc
reagents 7 are converted in a convergent way to the
thermodynamically more stable cis-Pd-intermediate 8 bearing
the PdAr group in an equatorial position. The cis-cross-coupling
product 9 will be formed via retentive reductive elimina-
tion.2g,21,22,24
In summary, we have developed stereoconvergent cross-
coupling reactions of various functionalized cyclohexylzinc
reagents, which can be prepared by direct insertion of zinc dust
to the corresponding cyclohexyl iodides. The stereoselectivity is
excellent for a 3- or 4-substituted cyclohexyl ring system and is
also applicable for some 2-substituted zinc reagents. Our
method provides a range of 1,2-, 1,3-, and 1,4-substituted
cyclohexane derivatives stereoselectively. Further extensions are
currently underway in our laboratories.
Scheme 3. Diastereoconvergent Cross-Coupling Reaction of
1,2-Substituted Cyclohexylzinc Reagents
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedure, characterization of the compounds,
and spectroscopic data. This material is available free of charge
via the Internet at http://pubs.acs.org.
cyclohexylzinc reagent 2j (trans/cis = ca. 70:30)18 was treated
with methyl 4-iodobenzoate under similar conditions to form
the cross-coupling product 3ja in excellent diastereoselectivity.
However, this behavior is not general and may be complicated,
especially in ring closure reactions. We have prepared the
diiodide 1k by standard methods.19 Its treatment with zinc dust
in THF selectively provided the alkylzinc derivative 2k (30 °C,
7 h; 84% yield) as a mixture of diastereomers. The addition of a
Pd-catalyst led to a ring closure reaction, furnishing the tricyclic
product 3k in 48% yield as a 1:1 mixture of diastereomers.
A tentative mechanism20 can be suggested for explaining the
observed diastereoselectivity in this cross-coupling reaction
(Scheme 4). In the case of 4-substituted cyclohexylzinc
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: Paul.Knochel@cup.uni-muenchen.de.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The research leading to these results has received funding from
Forschungsgemeinschaft (SFB749, B2). We also thank BASF
SE (Ludwigshafen), and Rockwood Lithium GmbH (Hoechst)
for the generous gift of chemicals. We thank Dr. Tobias Thaler
and Dr. Stephanie Seel (LMU, Munchen ,2010) for their
valuable discussions. K.M. thanks DAAD for a scholarship.
̈
Scheme 4. Tentative Mechanism for the
Diastereoconvergent Cross-Couplings
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