Oxidative heck arylation for the stereoselective synthesis of tetrasubstituted olefins using nitroxides as oxidants

Article abstract of DOI:10.1002/anie.201108211

One, two, and three! Nitroxides and dioxygen serve as oxidants in highly stereoselective oxidative Pd-catalyzed Heck arylations in which aryl boronic acids are used to synthesize triarylalkyl-substituted olefins. The reactions occur under very mild conditions at room temperature. As an example, the threefold sequential arylation of methyl acrylate is the crucial step in the stereoselective synthesis of Z-Tamoxifen.

Full text of DOI:10.1002/anie.201108211

Angewandte
Chemie
DOI: 10.1002/anie.201108211
Oxidative Olefin Arylation
Oxidative Heck Arylation for the Stereoselective Synthesis of
Tetrasubstituted Olefins Using Nitroxides as Oxidants**
Zhiheng He, Sylvia Kirchberg, Roland Frçhlich, and Armido Studer*
The Heck arylation belongs to the most important methods
a solution of 1 with PhB(OH)2, KF, [Pd(acac)2] (5 mol%), and
À
for C C bond formation and has therefore found widespread
TEMPO in propionic acid was stirred at room temperature,
product 2a was obtained with excellent diastereoselectivity
(E only) in 96% yield [Eq. (2)]. Double phenylation, which is
a problem when Pd(OAc)2 is used as the catalyst, was not
application in organic synthesis.[1] Various halides or pseudo
halides are readily cross-coupled with olefins under Pd
catalysis. In contrast, the oxidative Heck reaction using aryl
boronic acids in combination with an external oxidant and
a Pd catalyst has been less intensively investigated.[2,3]
Oxidative Heck-type coupling is strongly influenced by the
olefin substituents and therefore lacks generality. In partic-
ular the synthesis of highly substituted olefins using this
approach is not established. The regio- and stereoselective
synthesis of highly substituted olefins is very challenging.[4]
Herein we describe the mild and highly stereoselective
À
sequential oxidative Pd-catalyzed C H arylation of alkenes
for the synthesis of alkyltriarylethenes.
Our approach was based on the fact that substituents at
the olefin strongly influence the regio- and stereoselectivity of
the oxidative Heck coupling.[2] The goal was to develop an
iterative threefold Heck sequence starting from methyl
acrylate (1) [Eq. (1)]. The ester substituent is readily reduced
observed.[7] Under these mild conditions, other aryl boronic
acids bearing electron-rich and also electron-poor substitu-
ents reacted with complete diastereoselectivity (E only,
2b–d).
The best yields for the introduction of the second aryl group
were achieved upon reacting 2 with an arylboronic acid, KF,
4-HO-TEMPO, and Pd(OAc)2 in propionic acid at room
temperature (Table 1).[8a] With [Pd(acac)2] under otherwise
identical conditions only moderate yields were obtained.
The nature of the arylboronic acid influenced the
reactivity and selectivity. The highest selectivity was achieved
with the electron-poor CF3-substituted congener (> 98:2, see
3b), whereas with 4-MeC6H4B(OH)2 (27:1, 3a) and 4-
MeOC6H4B(OH)2 (10:1, 3c) lower selectivities resulted.
Encouraged by these results we decided to test also non-
acrylate-based disubstituted olefins and found that stilbene
and its derivatives reacted efficiently. In these reactions we
used pivalic acid/THF (5:1) as the solvent mixture.[8b]
Excellent yields and good selectivities were obtained in the
reaction of trans-stilbene with meta- and para-substituted aryl
boronic acids (3e–h). However, the yield dropped signifi-
cantly for the ortho-tolyl derivative, probably for steric
reasons (3i). We unambiguously assigned the relative config-
uration of 3e by X-ray analysis (Figure 1).[9] The stereochem-
ical outcome of the reaction agreed with that expected for an
oxidative Heck-type coupling.[2] Other compounds were
assigned by analogy. The unsymmetrical trans-phenyl-o-
tolylethene reacted with with PhB(OH)2 in good regioselec-
to the hydroxymethyl group to adjust the reactivity of the
intermediate olefins. Moreover, the allylic OH group can be
further chemically modified to vary the fourth substituent.
Methyl acrylate (1) is a well-established olefin for Heck
coupling with aryl boronic acids. Various oxidants have been
used to conduct that reaction.[2] After some experimentation
we found that the 2,2,6,6-tetramethylpiperidine-N-oxyl rad-
ical (TEMPO)[5,6] is a suitable oxidant for this reaction. When
[*] Z. He, Dr. S. Kirchberg, Dr. R. Frçhlich, Prof. Dr. A. Studer
Organisch-Chemisches Institut
Westfꢀlische Wilhelms-Universitꢀt
Corrensstrasse 40, 48149, Mꢁnster (Germany)
E-mail: studer@uni-muenster.de
=
tivity for steric reasons (9:1, 3l), and PhCH CHC6F5 deliv-
ered only one regioisomer 3j, probably for electronic reasons.
As expected, when the electronic difference of the aryl
substituents was not that pronounced (see, for example, 4-
[**] This work was financially supported by the Chinese Scholarship
Council (stipend to Z.H.). We thank Dr. Peter Nesvadba, BASF
Basel, for a gift of nitroxide 8 and Benjamin Vonhçren for
conducting some experiments.
=
CH3OC6H4CH CHC6H4-4-CF3), the regioselectivity was
lower (3:1, 3k). With respect to the yield, the reaction was
generally more efficient for electron-rich olefins. Excellent
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201108211.
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À
Table 1: Pd-catalyzed C H bond arylation of trans-disubstituted olefins
(X=H, OH).
Table 2: Oxidative phenylation of 4a.
R1
R2
Aryl
Yield [%] Prod.
3/3’
Ph
Ph
Ph
CO2Me
CO2Me
CO2Me
CO2Me
Ph
Ph
Ph
Ph
Ph
4-CH3C6H4
4-CF3C6H4
82[a,b]
67[a,b]
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
27:1[c]
>98:2[c]
10:1[c]
4-CH3OC6H4 41[a,b]
4-CH3C6H4
Ph
87[a,b]
99[d]
20:1[c]
Ph
Ph
Ph
Ph
Ph
Ph
4-CH3C6H4
25:1[e]
4-CH3OC6H4 91[d]
24:1[e]
Entry Oxidant
Solvent
T [8C] Yield [%][a]
5a/5a’[b]
4-FC6H4
3-CH3C6H4
2-CH3C6H4
Ph
84[d]
89[d]
35[d]
38[d]
52[d]
68[d]
69[d]
15:1[e]
24:1[e]
1
2
3
4
5
6
7
8
TEMPO
TEMPO
TEMPO
4-HO-TEMPO
4-AcNH-TEMPO EtCO2H
6
7
8
EtCO2H
EtCO2H
MeCO2H
EtCO2H
RT
50
50
47
54
28
37
31
51
46
68
9:1
6:1
14:1[e]
C6F5
>99:1[f]
>98:2[c,g]
9:1[f]
2.4:1
2.7:1
2.3:1
40:1
35:1
39:1
41:1
–
–
–
33:1
43:1
4-CH3OC6H4 4-CF3C6H4 4-CH3C6H4
Ph
Me
Me
Me
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
2-CH3C6H4 Ph
Ph
Ph
Ph
Ph
>99:1[e,h]
>99:1[e,h]
>99:1[e,h]
EtCO2H
EtCO2H
EtCO2H
EtCO2H
EtCO2H
EtCO2H
EtCO2H
EtCO2H
EtCO2H
4-CH3OC6H4 74[d]
4-ClC6H4
62[d]
9
8
77[c]
n.r.[d]
trace
trace
5
[a] Yield of isolated product; HO-TEMPO was used. [b] In propionic acid.
[c] Selectivity was determined by 1H NMR analysis. [d] Yield of isolated
product; TEMPO was used. [e] Selectivity was determined by GC
analysis. [f] Ratio of regioisomers. [g] Other regioisomer: 17% (Z/
E>98:2). [h] Other regioisomer not identified.
10
11
12
13
14
Cu(OAc)2
benzoquinone
PhI(OAc)2
AgOAc
O2 (1 atm)
79[e]
[a] Yield of isolated product. [b] Selectivity was determined by 1H NMR
analysis. [c] With 4 equiv PhB(OH)2, 4 equiv KF, and 4 equiv 8.
[d] n.r.=no reaction. [e] With 4 equiv PhB(OH)2 and 4 equiv KF.
temperature in the presence of KF and TEMPO, phenylation
occurred in 47% yield with good stereoselectivity (9:1;
Table 2, entry 1). Selectivity was determined by 1H NMR
analysis and the relative configuration was determined
unambiguously by X-ray analysis of the major isomer 5a
(see Figure 1).[9] Yield was improved by increasing the
temperature at the expense of lower selectivity (Table 2,
entry 2). The reaction was less efficient in acetic acid (Table 2,
entry 3). Replacing TEMPO with 4-HO-TEMPO or 4-
AcNH-TEMPO led to lower yields (Table 2, entries 4 and
5). Surprisingly, the selectivity dropped, indicating that the
reduced nitroxide formed during reoxidation of the Pd0
species likely ligates the Pd metal which can influence the
stereochemical outcome of the b-H elimination step. Along
this line, the sterically highly hindered nitroxides 6[10] and 7[11]
provided the arylation product with excellent selectivity
(Table 2, entries 6 and 7). Interestingly, nitroxide 8,[12] which
is between TEMPO and 6 in size, afforded a better yield while
the very high selectivity was maintained (Table 2, entries 8
and 9). Such subtle steric effects of the nitroxide on transition-
metal-catalyzed oxidative couplings are unprecedented.
Importantly, 8 was readily recovered in 76–82% (see the
Supporting Information). Other oxidants such as Cu(OAc)2,
benzoquinone, PhI(OAc)2, and AgOAc did not work well
(Table 2, entries 10–13). Surprisingly, O2 (balloon, 1 atm),
which was not an efficient oxidant for the first two arylations,
Figure 1. Molecular structures of 3e (left) and 5a (right).
regio and trans/cis selectivity were also obtained in the
arylation of trans-methyl-b-styrene, which can be obtained
from 2a by reduction and deoxygenation (3m–o).
Oxidative arylation occurred stereospecifically, as docu-
mented by the transformation of cis-stilbene to the isomeric
arylation products. Thus, reaction with 4-MeC6H4B(OH)2
under our standard conditions afforded tolyl stilbene 3e’ in
72% yield as a 13:1 mixture of isomers (3e’/3e). By analogy,
alkenes 3 f’ (61%, ratio 12:1) and 3g’ (55%, ratio 8:1) were
obtained as major isomers upon reaction of cis-stilbene with
4-MeOC6H4B(OH)2 and 4-FC6H4B(OH)2, respectively.
We then focused on the highly challenging arylation of the
À
C H group in trisubstituted olefins. Electron-poor b,b-diaryl-
acrylates were not reactive enough to undergo oxidative Heck
coupling. The ester moiety was reduced and arylation was
optimized with allyl alcohol 4a and PhB(OH)2 to provide 5a
and 5a’ (Table 2). Oxidants and solvents were systematically
varied. With 2 equiv of PhB(OH)2 in propionic acid at room
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Table 3: Scope of the third arylation.
ation of methyl acrylate (1) with 4-(2-
dimethylaminoethoxy)phenylboronic acid using [Pd-
(acac)2] as the catalyst afforded 9 in high yield and
complete E selectivity. Renewed Pd-catalyzed oxi-
dative arylation with PhB(OH)2 provided 10 in
quantitative yield and high Z selectivity. DIBALH
reduction gave allyl alcohol 11 (86%) ready for the
third arylation. As expected based on our model
studies, arylation of this electron-rich system 11 (Z/
E = 22:1) could be conducted with nitroxide 8 as an
oxidant, and 12 was obtained in 54% yield with
excellent stereospecificity. It is important to note
that O2-mediated phenylation of 11 did not deliver
product 12, showing the importance of the nitroxide
for this difficult arylation. Oxidation,[15] Wittig meth-
enylation, and hydrogenation under slightly modi-
fied literature conditions[14a] eventually afforded Z-
Tamoxifen.[16]
In summary, we have documented the potential
of the nitroxide-mediated Pd-catalyzed oxidative
Heck arylation for the stereoselective synthesis of
tetrasubstituted triarylated olefins. The reactions
presented mostly occurred in good yields and high
stereoselectivities under mild conditions. Impor-
tantly, we have shown that the nature of the oxidant
strongly influences the oxidative Heck reaction. Our
results show that in future studies on nitroxide-
R1
R2
R3
Aryl
Prod. Yield [%][a]
5/5’[b]
20:1
CH2OH Ph
CH2OH Ph
CH2OH Ph
CH2OH Ph
CH2OH Ph
CH2OH Ph
CH2OH Ph
CH2OH 4-CH3C6H4 Ph
CH2OH 4-CH3C6H4 Ph
CH2OH 4-CF3C6H4 Ph
CH2OH 4-CF3C6H4 Ph
CH2OH Ph
CH2OH Ph
CH2OH Ph
CH2OH Ph
Me
Et
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CF3C6H4
4-CH3OC6H4
3-CH3C6H4
2-CH3C6H4
3-FC6H4
4-PhC6H4
Ph
5b
5c
5d
5e
5 f
5g
5h
5i
79[c]
54[c]
45[c]
77[c]
32[c]
51[c]
57[c]
45[c]
67[d]
71[c]
57[d]
19[c]
78[d]
57[c]
49[d]
70[c]
64[c]
6[c]
29:1
24:1
34:1
27:1
34:1
17:1
17:1
13:1
30:1
30:1
>98:2
>98:2
>98:2
>98:2
–
Ph
Ph
Ph
5i
5j
5j
4-CH3OC6H4 Ph
4-CH3OC6H4 Ph
4-CF3C6H4
5k
5k
5l
Ph
Ph
Ph
Ph
Ph
4-CF3C6H4
5l
Ph
Ph
Ph
Ph
Ph
Ph
5m
5n
5o
–
–
iPr
[a] Yield of isolated product. [b] Selectivity was determined by 1H NMR analysis.
[c] With O2 (balloon, 1 atm). [d] With nitroxide 8 (4 equiv).
performed well and 5a was isolated in 79% yield with
excellent selectivity (43:1; Table 2, entry 14).
mediated oxidative coupling reactions, nitroxides other than
the typically used TEMPO should be included. Furthermore,
we applied our arylation methodology to the synthesis of Z-
Tamoxifen. Protecting groups were not necessary for the
synthesis of this pharmacologically important olefin.
Under optimized conditions we tested the scope of the
third arylation using either O2 or 8 as oxidants (Table 3).[13]
Under O2 atmosphere the para- and meta-substituted phenyl-
boronic acids reacted with good to very good yields and high
selectivities to provide the corresponding tetrasubstituted
olefins (see 5b–e,g,h). A significantly reduced yield was
obtained for the o-tolyl derivative (5 f), for steric reasons. We
found that the aryl group in trans position to the H atom
influenced the reaction outcome. With the more electron-rich
p-tolyl derivative, the yield decreased using the O2 protocol
and 5i was isolated in 45%. Replacing O2 with 8 led to an
increase of the yield (67%). However, for the electron-poor
trans-4-CF3C6H4 congener, the O2 setup provided a better
result (5j). A similar and even more pronounced trend was
observed when R3 was varied. Oxidative phenylation of the
electron-rich 4-CH3OC6H4 derivative with O2 provided 5k in
only 19% yield, whereas with 8, 5k was isolated in 78% yield
with excellent selectivity. The electron-poor 4-CF3C6H4
derivative afforded 5l in 57% using O2, and the nitroxide
protocol delivered 5l in 49% yield. Hence, for electron-rich
olefins, the reaction was better using 8 as oxidant and the third
arylation of electron-poorer olefins is better conducted with
O2.
Scheme 1. Synthesis of Z-Tamoxifen: a) 4-(2-dimethylaminoethoxy)phe-
nylboronic acid (2 equiv), TEMPO (2 equiv), KF (2 equiv), [Pd(acac)2]
(5 mol%), EtCO2H, RT, 24 h; b) PhB(OH)2 (4 equiv), HO-TEMPO
(2 equiv), KF (4 equiv), Pd(OAc)2 (5 mol%), EtCO2H, RT, 24 h;
c) DIBALH, THF; d) PhB(OH)2 (4 equiv), 8 (4 equiv), KF (4 equiv),
Pd(OAc)2 (10 mol%), EtCO2H, 408C, 24 h; e) tetrapropylammonium
perruthenate (5 mol%), NMO (2 equiv), RT, 0.5 h (80%, E/Z=18:1);
f) NaH, Ph3PCH3Br, THF, reflux, 4 h (85%, Z/E=13:1); g) H2, Pd/C,
EtOAc, RT, 2 h (95%, Z/E=13:1).
We were pleased to find that the final arylation was not
restricted to bisarylated allyl alcohols as substrates. The OH
group was not necessary as shown by the successful prepa-
ration of 5m (R1 = Me) and 5n (R1 = Et). However, with the
bulkier iPr congener, the yield dropped to 6% (see 5o).
Finally, we applied our oxidative Heck sequence to the
synthesis of Z-Tamoxifen (Scheme 1).[4a–c,f,14] Oxidative aryl-
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Studer, Angew. Chem. 2008, 120, 9690; Angew. Chem. Int. Ed.
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Received: November 22, 2011
Revised: January 4, 2012
Published online: March 1, 2012
À
Keywords: alkenes · boronic acids · C H arylation · palladium ·
.
TEMPO
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[9] CCDC 853228 (3e) and CCDC 853229 (5a) contain the supple-
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Angew. Chem. Int. Ed. 2012, 51, 3699 –3702