Synthesis of enantioenriched triarylmethanes by stereospecific cross-coupling reactions

Article abstract of DOI:10.1002/anie.201202527

Coupling with inversion: Chiral diarylmethanol derivatives undergo a stereospecific nickel-catalyzed cross-coupling reaction with aryl Grignard reagents (see scheme). The reaction proceeds with inversion of configuration and high enantiospecificity. The m

Full text of DOI:10.1002/anie.201202527

Angewandte
Chemie
DOI: 10.1002/anie.201202527
Cross-Coupling
Synthesis of Enantioenriched Triarylmethanes by Stereospecific Cross-
Coupling Reactions**
Buck L. H. Taylor, Michael R. Harris, and Elizabeth R. Jarvo*
Triarylmethanes are attractive targets because of their
applications in medicinal and materials chemistry.[1–7] For
example, several triarylmethanes have emerged as promising
pharmacological agents for treating cancer,[2] bacterial infec-
tion,[3] and diabetes (Scheme 1).[4] Triarylmethanes also have
applications as dye precursors,[5] photochromic agents,[6] and
reagents in material science.[7] The triarylmethine moiety can
also be found as a core structure in natural products such as
cassigarol B.[8] The classical approach to synthesize these
compounds relies on Friedel–Crafts reactions.[9–12] Despite
DPEphos provided triarylmethane 2 with low enantiospeci-
ficity (Table 1, entry 1).[19] All other ligands examined
resulted in unacceptably low conversion of starting material
1a (Table 1, entries 2–4).[20] The use of other catalysts,
including those based on palladium and copper, did not lead
to the desired reactivity.[21] We concluded that few catalysts
are able to undergo efficient oxidative addition with 1a. This
limitation restricts our ability to optimize the catalyst toward
reducing deleterious side reactions, which include racemiza-
tion of the putative alkylnickel intermediate[22] and formation
of products 3, which are derived from homocoupling.[23]
However, we considered that a substrate that was more
active toward oxidative addition would overcome this limi-
tation. We were encouraged to test this hypothesis because
the use of certain catalysts led to reactions with promising
À
recent advances using chiral Brønsted acids and directed C H
activation reactions,[13,14] the asymmetric synthesis of triaryl-
methanes remains challenging. We envisioned an approach
based on the stereospecific cross-coupling methodology
recently developed in our laboratory.[15,16] Herein we describe
the synthesis of enantioenriched triarylmethanes by cross-
coupling reactions of diarylmethanol derivatives, which are
easily prepared by a variety of asymmetric methods.[17]
Table 1: Effect of chelating leaving groups.
Entry Ether
R
Ligand
Yield 2 es 2
[%][a]
Yield 3
[%][b] [%][a]
1[c,d]
2[d]
(S)-1a
(Æ)-1a
(Æ)-1a
(S)-1a
DPEphos
rac-BINAP
dppf
56[e]
<2
3
33
–
–
18[e,f]
26
10
Me
3[d]
4[d]
dppb
14
93
<2
Scheme 1. Biologically relevant triarylmethanes.
5
(Æ)-1b
(Æ)-1c
DPEphos
DPEphos
<2
–
–
<2
At the outset, we found that direct application of our
previously reported method was unsatisfactory for triaryl-
methane synthesis.[18] The reaction of methyl ether 1a with an
aryl Grignard reagent in the presence of [Ni(cod)2] and
6[g]
67
16
7
(S)-1d
(S)-1d
(S)-1d
(S)-1d
(S)-1d
(Æ)-1d
(S)-1d
DPEphos
dppb
dpppent
dpph
dppo
MePh2P
Ph3P
69[e]
67
73
>95
84
12
46
93
>99
>99
>99
–
17[e,f]
3
<2
<2
<2
<2
5
8[d]
9[h]
[*] B. L. H. Taylor, M. R. Harris, Prof. E. R. Jarvo
Department of Chemistry, University of California, Irvine
Irvine, CA 92697 (USA)
10[h]
11[h]
12[h,i]
13[h,i]
E-mail: erjarvo@uci.edu
Homepage: http://chem.ps.uci.edu/~erjarvo/
90
94
[a] Determined by 1H NMR analysis using an internal standard
[**] This work was supported by the University of California Cancer
Research Coordinating Committee. B.L.H.T. thanks Allergan for
a Graduate Fellowship. M.R.H. thanks the University of California
for a Chancellor’s Fellowship and the Ford Family Foundation for
a Predoctoral Fellowship. We thank Frontier Scientific and Sigma–
Aldrich for the donation of chemicals. Dr. John Greaves is
acknowledged for mass spectrometry data. Dr. Joseph Ziller is
acknowledged for X-ray crystallography data.
(PhSiMe3). [b] Enantiospecificity (es)=eeproduct/eestarting material ꢀ100%.
Determined by SFC chromatography using a chiral stationary phase.
[c] 408C. [d] 5 mol% [Ni(cod)2], 10 mol% ligand. [e] Yield after chro-
matography. [f] Dimer 3 was isolated as a mixture of racemic and meso
stereoisomers. [g] Enantiomers of (Æ)-1c are not separable by SFC
chromatography using a chiral stationary phase. [h] [Ni(acac)2] substi-
tuted for [Ni(cod)2]. [i] 40 mol% ligand. acac=acetylacetonate,
cod=1,5-cyclooctadiene, Nap=2-naphthyl, definitions of ligands are
given in Ref. [24].
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201202527.
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Table 2: Scope of Cross-Coupling Reaction.
enantiospecificity, albeit the products were obtained in low
yield (Table 1, entry 4).[24]
We considered activating the ether to accelerate the
oxidative addition step, thus leading to reactions that could be
promoted with a broad range of catalysts. We were attracted
to the use of a directing group to increase the reaction rate,[25]
as certain nickel-catalyzed cross-coupling reactions benefit
from a strategically positioned functional group on the
substrate.[26,27] For example, the presence of pendant carbox-
ylates accelerate transmetalation of nickel thiolates during
the cross-coupling of thioethers with arylzinc reagents.[28] We
postulated that coordination of the ether to a magnesium
Entry
1
Product
Ar3
Yield S.M.[b] Prod.[b] es[c]
[%][a] ee [%] ee [%] [%]
N/
A
98
99
98
Ph
82
86
N/A
N/A
2
p-MeC6H4
p-MeOC6H4 88
p-
(Me2N)C6H4
p-FC6H4
m-
93
93
93
91
92
91
3[d]
4
68
5[e,f]
6[e]
92
77
93
93
91
90
98
97
À
Lewis acid would accelerate cleavage of the benzylic C O
bond (Scheme 2).[29] We designed ethers that contain pendant
Lewis bases capable of magnesium-ion chelation. Impor-
tantly, this strategy would provide traceless activation of the
substrate, as the directing group is excised during the reaction
and is thus not present in the product.
MeOC6H4
7
97
83
93
93
92
87
99
94
8[e,g]
9[e,f]
85
56
81
81
74
69
92
85
10[e,f,g]
All data are averages of two experiments. [a] Yield after chromatography.
[b] Determined by SFC chromatography using a chiral stationary phase.
[c] Enantiospecificity (es)=eeproduct/eestarting material ꢀ100%. [d] dpph was
used in place of dppo. [e] [Ni(cod)2] was used in place of [Ni(acac)2].
[f] Reaction run for 72 h. [g] Reaction run at 408C. N/A=not applicable,
Prod.=product, S.M.=starting material.
À
Scheme 2. Design of a chelating leaving group to activate C O bonds
toward oxidative addition
We were pleased to find that substrates 1c and 1d, which
contain pendant dimethylamino and methoxy groups, respec-
tively, were converted into product in improved yield
compared to non-chelating substrate 1a (Table 1, entries 6–
7). In the presence of a range of ligands and either [Ni(cod)2]
or [Ni(acac)2], methoxyethyl ether 1d gave a high yield of
product 2 and was therefore selected for further study. As
found above, the use of DPEphos resulted in a reaction of low
enantiospecificity and gave significant quantities of dimer 3
(Table 1, entry 7). However, the use of ligands in the
bis(diphenylphosphino)alkane series gave reactions of very
high enantiospecificity (Table 1, entries 8–11);[30] the use of
the catalyst derived from [Ni(acac)2] and dpph led to
complete conversion of 1d into triarylmethane 2 with no
detectable products derived from homocoupling (Table 1,
entry 10). Triphenylphosphine was also an effective ligand for
the cross-coupling reaction, although the enantiospecificity of
the reaction is slightly lower (Table 1, entry 13). Bis(diphe-
nylphosphino)alkanes were therefore selected as ligands for
subsequent studies.
Having established optimal reaction conditions, we exam-
ined the scope of the reaction with respect to the aryl
Grignard reagent (Table 2). In general, the reaction of
substrates containing extended aromatic moieties proceed
with very high enantiospecificity. Although the use of
2-methoxyethyl ether 1d led to optimal yields of product,
methyl ether 1a underwent cross-coupling with a variety of
Grignard reagents with high enantiospecificity and gave
products in slightly lower yields.[31] For the majority of
Grignard reagents examined, dppo was found to be the
optimal ligand, although when para-methoxyphenylmagne-
sium bromide is used, dpph was the best ligand (Table 2,
entry 3). Whereas the use many of the Grignard reagents
work well in the presence of [Ni(acac)2], some gave better
yields when [Ni(cod)2] was used (Table 2, entries 5 and 6);
[Ni(cod)2] had a more general scope with respect to the
Grignard reagent. We were pleased to find that the presence
of a dimethylamino group was tolerated (Table 2, entry 4);
thiophene and benzothiophene-based Grignard reagents
were also tolerated (Table 2, entries 7 and 8). A phenan-
threne-derived substrate also underwent cross-coupling,
although the reaction was relatively slow, presumably owing
to steric congestion in the product (Table 2, entries 9 and 10).
Nevertheless, the reactions were highly enantiospecific,
including the reaction where 2-naphthylmagnesium bromide
was used as the Grignard reagent, although mild heating was
required for this reaction to proceed.[32]
The cross-coupling reaction proceeds with inversion of
configuration at the methine carbon. The absolute configu-
ration of the alcohol (S)-4 was determined by comparison of
the measured optical rotation to
a literature value
(Scheme 3).[33] After alkylation of (S)-4 and cross-coupling
of the resulting ether with 2-thienylmagnesium bromide, the
configuration of the product, triarylmethane 5, was deter-
mined to be R by X-ray crystallographic analysis.[34] This
stereochemical outcome is consistent with an oxidative
addition that occurs with inversion of configuration.[35]
To demonstrate the utility of the cross-coupling method,
we synthesized an enantioenriched biologically active triaryl-
methane (Scheme 4). Racemic triarylmethane 8, an analogue
2
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which are easily synthesized by the asymmetric arylation of
aldehydes. A variety of aryl Grignard reagents can be used in
the cross-coupling reaction, which proceed with high enan-
tiospecificity. The method was applied to the asymmetric
synthesis of an anti-breast-cancer agent. Studies to further
expand the scope of this reaction and elucidate the mecha-
nism are underway.
Experimental Section
Representative procedure for cross-coupling reactions (Table 2,
entry 1): In
a
glovebox, nickel(II) acetylacetonate (5.1 mg,
0.020 mmol, 0.10 equiv), 1,8-bis(diphenylphosphino)octane (19 mg,
0.040 mmol, 0.20 equiv), and PhMe (1.6 mL) were added to a 7 mL
vial. The reaction mixture was stirred for 10 min and ether (Æ)-1d
(58 mg, 0.20 mmol, 1.0 equiv) was added. The vial was removed from
the glovebox and phenylmagnesium bromide (0.20 mL, 0.40 mmol,
2.0m in Et2O, 2.0 equiv) was added dropwise. The reaction mixture
was stirred for 48 h before quenching with 2-propanol (1.5 mL). The
solution was eluted through a plug of silica and concentrated in vacuo.
The residue was purified by flash column chromatography through
silica gel (0–3% Et2O/pentane) to afford 2-benzhydrylnaphthalene as
a white solid. First run: 50.3 mg (86%). Second run: 46.1 mg (79%).
Scheme 3. Determination of the stereochemistry associated with the
cross-coupling reaction. For the X-ray structure of (R)-5, thermal
ellipsoids are shown at 50% probability. DMF=N,N-dimethylforma-
mide.
Received: April 1, 2012
Published online: && &&, &&&&
Keywords: cross-coupling · Grignard reagents · nickel ·
.
stereospecific reactions · triarylmethanes
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of tamoxifen, was reported to have anti-breast-cancer activity
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cancer cells; promising activity in vivo was also demon-
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tion and alkylation of 7 gave the target triarylmethane 8. This
approach is highly modular: a variety of aryl Grignard
reagents can be used in the cross-coupling reaction and
a variety of aminoalkyl groups can be appended in the last
step to afford a library of enantioenriched analogues of 8.
In summary, we have developed a nickel-catalyzed cross-
coupling reaction for the synthesis of enantioenriched triaryl-
methanes. The substrates are diarylmethanol derivatives,
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[23] Homocoupling has been previously observed in palladium-
catalyzed cross-coupling reactions of benzylic electrophiles; see
Ref. [11b].
[24] Abbreviations:
binaphthyl,
BINAP = 2,2’-bis(diphenylphosphanyl)-1,1’-
dppb = 1,4-bis(diphenylphosphino)butane;
dpppent = 1,5-bis(diphenylphosphino)pentane; dpph = 1,6-bis
(diphenylphosphino)hexane; dppo = 1,8-bis(diphenylphosphi-
no)octane; dppf = 1,1’-bis(diphenylphosphino)ferrocene; DPE-
phos = bis(2-diphenylphosphinophenyl)ether.
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[30] dpppent has been used in the palladium-catalyzed cross-coupling
of benzylic carbonates with arylboronic acids; see Ref. [11a].
[31] For example, methyl ether 1a reacts with meta-methoxyphenyl-
magnesium bromide under the reaction conditions in Table 2,
entry 6, to provide cross-coupling product in 63% yield and
99% es. See the Supporting Information for additional exam-
ples.
[14] In
a creative approach, prochiral triarylmethanes can be
desymmetrized in a pyridine-directed enantioselective palla-
À
dium-catalyzed C H bond activation: B.-F. Shi, N. Maugel, Y.-H.
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[18] The results vary depending on the identity of the aryl Grignard
reagent. For a detailed comparison of cross-coupling reactions of
methyl ethers with those of methoxyethyl ethers when using
dppo and PPh3, see the Supporting Information, Table SI-1.
[32] The product in Table 2, entry 10 was isolated as a mixture of
rotamers, as determined by 1H NMR and 13C NMR spectroscopy
and mass spectrometry data. However, convergence of the
[19] Enantiospecificity
(es) = eeproduct/eestarting material ꢁ 100%;
see
1
a) S. E. Denmark, T. Vogler, Chem. Eur. J. 2009, 15, 11737;
b) S. E. Denmark, M. T. Burk, A. J. Hoover, J. Am. Chem. Soc.
2010, 132, 1232.
rotamers was not observed in a variable-temperature H NMR
experiment. See the Supporting Information for details.
[33] F. Tjosaas, T. Anthonsen, E. E. Jacobsen, ARKIVOC 2008, (6),
81.
[34] CCDC 881153 ((R)-5) contains the supplementary crystallo-
graphic 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.
[35] Reductive elimination at nickel catalysts occurs with retention of
configuration: J. E. Bꢂckvall, O. S. Andell, Organometallics
1986, 5, 2350.
[20] Approximately 30 phosphine ligands were examined and the use
of the majority resulted in no reaction. For example, starting
material 1a was recovered in > 90% when the following ligands
were used: xantphos (4,5-bis(diphenylphosphino)-9,9-dimethyl-
xanthene), dppe (1,4-bis(diphenylphosphino)ethane), biphep
(2,2’-bis(diphenylphosphino)-1,1’-biphenyl), tBu3P, and Cy3P,
and davephos (2-dicyclohexylphosphino-2’-(N,N-dimethylami-
no)biphenyl).
[21] See the Supporting Information for details.
[22] In the absence of nickel and ligand, no reaction occurs. The cause
of decreased enantiospecificity is currently under investigation.
[36] In the absence of nickel and ligand, the reaction of 6 with
p-MeOC6H4MgBr (3 equiv) gives triarylmethane 7 in 30% yield
and 23% ee (29% es).
À
We hypothesize that reversible homolyis of the Ni C bond is
4
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Cross-Coupling
B. L. H. Taylor, M. R. Harris,
E. R. Jarvo*
&&&& — &&&&
Synthesis of Enantioenriched
Triarylmethanes by Stereospecific Cross-
Coupling Reactions
Coupling with inversion: Chiral diarylme-
thanol derivatives undergo a stereospe-
cific nickel-catalyzed cross-coupling
reaction with aryl Grignard reagents (see
scheme). The reaction proceeds with
inversion of configuration and high
enantiospecificity. The method has been
applied to the asymmetric synthesis of
a triarylmethane-based anti-cancer com-
pound.
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These are not the final page numbers!