Branched Arylalkenes from Cinnamates: Selectivity Inversion in Heck Reactions by Carboxylates as Deciduous Directing Groups

Article abstract of DOI:10.1002/anie.201605744

A decarboxylative Mizoroki–Heck coupling of aryl halides with cinnamic acids has been developed in which the carboxylate group directs the arylation into its β-position before being tracelessly removed through protodecarboxylation. In the presence of a copper/palladium catalyst, both electron-rich and electron-deficient aryl bromides and chlorides bearing numerous functionalities were successfully coupled with broadly available cinnamates, with selective formation of 1,1-disubstituted alkenes. This reaction concept, in which the carboxylate acts as a deciduous directing group, ideally complements traditional 1,2-selective Heck reactions of styrenes.

Full text of DOI:10.1002/anie.201605744

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Communications
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International Edition: DOI: 10.1002/anie.201605744
German Edition: DOI: 10.1002/ange.201605744
Cross-Coupling
Branched Arylalkenes from Cinnamates: Selectivity Inversion in Heck
Reactions by Carboxylates as Deciduous Directing Groups
Jie Tang, Dagmar Hackenberger, and Lukas J. Goossen*
Abstract: A decarboxylative Mizoroki–Heck coupling of aryl
halides with cinnamic acids has been developed in which the
carboxylate group directs the arylation into its b-position
before being tracelessly removed through protodecarboxyla-
tion. In the presence of a copper/palladium catalyst, both
electron-rich and electron-deficient aryl bromides and chlor-
ides bearing numerous functionalities were successfully cou-
pled with broadly available cinnamates, with selective forma-
tion of 1,1-disubstituted alkenes. This reaction concept, in
which the carboxylate acts as a deciduous directing group,
ideally complements traditional 1,2-selective Heck reactions of
styrenes.
Scheme 1. Synthesis of substituted alkenes.
1,1-Disubstituted alkenes are prevalent in natural[1] and
synthetic products[2] with a wide spectrum of applications.
Traditional syntheses of this substructure, such as Wittig or
Peterson olefinations,[3] arylations of alkynes,[4] olefin meta-
thesis,[5] and transition-metal-catalyzed cross-coupling reac-
tions of preformed a-metalated vinylarenes[6] or 2-alkenyl
electrophiles,[7] are limited in scope, waste-intensive, and/or
require multistep syntheses of starting materials.
1,1-diarylalkenes might be accomplished by an added copper
or silver decarboxylation catalyst [Eq. (3)]. However, this
attractive approach seemed to be out of reach, because the
same catalyst combination is known to effectively promote
a decarboxylative cross-coupling with formation of 1,2-diaryl-
alkenes [Eq. (2)].[17]
The utility of carboxylates as directing groups that are
The selective synthesis of 1,1-diarylalkenes from widely
available aryl (pseudo)halides by Heck-type reactions would
be a welcome alternative.[8] However, electronic and steric
factors usually determine the regiochemical outcome of the
carbopalladation for simple hydrocarbons,[9–12] so that 1,2-
diarylalkenes are obtained from styrenes [Scheme 1,
Eq. (1)].[13] Only in very few cases has this selectivity been
successfully shifted towards the 1,1-diarylakenes: Zou et al.
reported that aryl triflates react with selected styrenes with
formation of 1,1-diarylakenes when using a urotropine base
and the exceptionally bulky 1,1’-bis[di(1-naphthyl)phosphi-
no]ferrocene (dnpf) ligand.[14]
As a result of the wealth of methods for their preparation,
cinnamic acids are more widely available in greater structural
diversity than styrenes, and are, thus, more attractive starting
materials.[15] In Heck coupling reactions with aryl halides, the
carboxylate group should direct the carbopalladation into its
b-position,[16] thereby leading to the intermediate formation
of diarylacrylic acids. Their in situ conversion into the desired
tracelessly cleavable in situ has been demonstrated for
[18]
example, for C H hydroxylations, amidations,[19] (hydro)-
À
arylations,[20] and alkoxylations.[21] Ideally, the carboxylate will
act as a deciduous rather than a removable directing group,
staying in place for only just as long as it is required to direct
the metal catalyst into the a-position, but is destabilized by
the newly formed bond to an extent that it is shed directly
afterwards.
To switch the reaction of cinnamic acids with aryl halides
from a decarboxylative coupling pathway to the desired Heck
pathway, with the carboxylate acting as a deciduous directing
group, it is critical to identify a catalyst system that
a) promotes the carbopalladation of cinnamic acids with
unprecedented efficiency and b) efficiently mediates the
decarboxylation of diarylacrylic acids, but c) does not pro-
mote the decarboxylation of cinnamates, thus blocking
decarboxylative cross-coupling (Scheme 2).
Prerequisite (a) already represented a substantial hurdle
because the reactivity of the electron-rich cinnamate salts
formed under the basic conditions of a Heck process is low.
The Nꢀjera and Fujiwara research groups found that cinnamic
acids gave unsatisfactory yields (42%) even under optimized
conditions, whereas the corresponding alkyl cinnamates
reacted quantitatively.[22] However, these literature results
demonstrate that both oxidative addition and carbopallada-
tion should take place at temperatures below those required
for most decarboxylative coupling reactions.
[*] J. Tang, D. Hackenberger, Prof. Dr. L. J. Goossen
FB Chemie-Organische Chemie
Technische Universitꢀt Kaiserslautern
Erwin-Schrçdinger-Strasse, Geb. 54
67663 Kaiserslautern (Germany)
E-mail: goossen@chemie.uni-kl.de
Homepage: http://www.chemie.uni-kl.de/goossen
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201605744.
To probe whether prerequisites (b) and (c) could be
fulfilled, we performed decarboxylation studies, and were
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Table 1: Optimization of the reaction conditions.[a]
Entry
[Pd]
Ligand
[M]
Yield [%]
3aa
4aa
5aa
1[b]
2[b]
3[b]
4[b,c]
5[b]
6[d]
7
8
9
10
11
12
13
14
15
16
17
18
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
PdCl2
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
Cy3P
(p-tol)3P
BINAP
Johnphos
(o-tol)3P
(o-tol)3P
(o-tol)3P
(o-tol)3P
(o-tol)3P
(o-tol)3P
(o-tol)3P
(o-tol)3P
(o-tol)3P
(o-tol)3P
(o-tol)3P
(o-tol)3P
(o-tol)3P
–
–
4
2
6
5
12
23
40
<1
<1
9
10
4
12
<1
12
7
12
12
14
13
11
8
13
12
14
12
10
10
11
7
CuBr
Sc(OTf)3
–
Ag2CO3
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuCl
Cu2O
CuBr
CuBr
6
28
73
76
76
78
77
92
83
82
86
88
90
75
25
42
88
43
<1
6
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
Scheme 2. Mechanistic outline for the envisioned process.
delighted to find that an additional aryl group strongly
activates the substrates towards CO2 extrusion. Thus, b-
tolylcinnamic acid underwent almost quantitative protode-
carboxylation at 1308C in the presence of a Cu2O catalyst,
whereas under the same conditions, cinnamic acid showed
< 5% conversion after 16 h (see Table S1 in the Supporting
Information).
PdBr2
Pd(TFA)2
Pd(dba)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
–
These preliminary experiments served to define a starting
point for the rational development of a catalyst. We chose the
reaction of potassium cinnamate 1a with 4-bromotoluene
(2a) as a model to systematically investigate the influence of
Heck and decarboxylation catalysts on the reaction outcome
under various conditions (Table 1). Subjecting substrates 1a
and 2a to classical Mizoroki–Heck conditions (Table 1,
entry 1) led to only low conversion being observed, mostly
to the non-decarboxylated Heck product 4aa, along with
decarboxylative cross-coupling product 5aa. However, when
copper(I) bromide was added, the selectivity for the branched
product 4aa increased sharply, which indicates that the soft
Lewis acid CuBr promotes the carbometalation step more
strongly than the decarboxylation (entry 2). The addition of
Lewis acids, such as Sc(OTf)3, facilitated the Heck coupling
reaction even more strongly, but the selectivity was lower
(entries 2 and 3). This finding suggests that the role of the
copper is mainly that of a soft Lewis acid. Lower yields were
observed starting from preformed copper cinnamate, which
speaks against the intermediacy of these compounds in the
transformation (entry 4). In the presence of Ag2CO3, 5aa was
formed as the main product (entry 5). Increasing the temper-
ature led to preferential formation of decarboxylated product
3aa over 4aa, without reducing the selectivity for the
branched over the linear product 5aa (entries 6 and 7).
Systematic variation of the phosphine ligand revealed that
the moderately electron-donating, sterically demanding
ligand tri-o-tolylphosphine was most effective and gave
greater than 10:1 selectivity for 3aa at full conversion
(entries 8–12). Pd(acac)2 was found to be the optimal Pd
precursor (entries 13–16). Among the Cu sources, copper
halides and CuBr, in particular, were most effective
(entries 17 and 18). A solvent mixture of NMP and quinoline
gave the best results (entries 19 and 20).
19[e]
20[f]
21[g]
22[g]
23[g]
24
CuBr/KOAc
CuBr/K2CO3
CuBr/K2CO3
–
12
15
<1
16
<1
25
CuBr
<1
[a] Reaction conditions: 1a (0.60 mmol), 2a (0.5 mmol), [M] (10 mol%),
1,10-phenanthroline (10 mol%), [Pd] (2 mol%), P ligand (5 mol%),
3 mL solvent (NMP/quinoline (1:1)), 1708C, 16 h. Yields were deter-
mined by GC analysis after esterification with MeI using n-tetradecane as
an internal standard. For abbreviations see Ref. [23]. [b] 1308C.
[c] Copper cinnamate was used instead of 1a. [d] 1508C. [e] In NMP.
[f] In NMP/mesitylene (1:1). [g] Starting from cinnamic acid.
confirmed that neither the Pd nor the Cu catalyst alone are
able to mediate this transformation (entries 24 and 25).
We next investigated the scope of the optimized proce-
dure (2 mol% Pd(acac)2, 5 mol% (o-tol)3P, 5 mol% Cu2O,
10 mol% 1,10-phenanthroline, NMP/ quinoline (1:1), 1708C,
16 h) with regard to the a,b-unsaturated carboxylic acids.
Both electron-rich and electron-poor cinnamic acids
reacted smoothly with 4-bromotoluene (2a; Table 2).
Common functionalities, such as halo, ester, ether, carbonyl,
and even nitro and amino groups, were tolerated. The
reaction also proceeded well with heterocyclic and alkyl-
substituted allylic acids.
The reaction is also widely applicable with regard to the
electrophilic coupling partner (Table 3). ortho-, meta-, and
para-substituted aryl bromides bearing sensitive functional-
ities including ether, ester, carbonyl, thioether, and tertiary
amino groups were successfully converted. Besides aryl
bromides, alkenyl and heteroaryl bromides were successfully
converted, although in somewhat lower yields. Changing the
ligand to XPhos led to less expensive, but also less reactive,
aryl chlorides also being converted in high yields.
The addition of potassium acetate is required when
starting directly from cinnamic acid, whereas stronger bases
retard the reaction (entries 21–23). Control experiments
2
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Table 2: Scope with regard to the carboxylates.[a]
Table 3: Scope with regard to the electrophiles.[a]
[a] Reaction conditions: 1 (1.20 mmol), 2a (1.00 mmol), CuBr
(10 mol%), 1,10-phenanthroline (10 mol%), Pd(acac)2 (2 mol%),
(o-tol)3P (5 mol%), 3 mL of solvent (NMP/quinoline (1:1)), 1708C, 16 h.
Yields of isolated products.
The new decarboxylative Heck process was successfully
combined with a traditional Heck reaction into a convenient
one-pot synthesis of unsymmetrically substituted 1,1-diaryl-
alkenes from two different aryl bromides and methyl acrylate.
In the first step, a cinnamate salt was synthesized from the
corresponding aryl bromide and methyl acrylate by a Mizor-
oki–Heck reaction followed by hydrolysis of the methyl
cinnamate. Subsequently, without solvent change or isolation
of intermediates, a decarboxylative Heck coupling reaction
furnishes the 1,1-diarylethylene in 62% yield (Scheme 3).
A series of experiments was performed to shed more light
on the reaction mechanism (see the Supporting Information).
The reaction occurred smoothly in the presence of the radical
scavenger 2,2,6,6-tetramethylpiperidinyloxyl (TEMPO), thus
suggesting that neither coupling nor decarboxylation proceed
through a radical pathway.[24] The reaction of styrene with 4-
bromotoluene (2a) yielded the linear product 4aa with high
selectivity, which rules out a reaction pathway involving
protodecarboxylation followed by a Heck reaction. When the
reaction was performed with the deuterium-labeled starting
material potassium (E)-3-(3,4-dimethoxyphenyl)-2-prope-
noate-3-d (D-1d), only 20% of the deuterium was incorpo-
rated in the original position of the carboxylate group. This
[a] Reaction conditions: 1a (1.20 mmol), 2 (1.00 mmol), CuBr
(10 mol%), 1,10-phenanthroline (10 mol%), Pd(acac)2 (2 mol%),
(o-tol)3P (5 mol%), 3 mL of solvent (NMP/quinoline (1:1)), 1708C, 16 h.
Yields of isolated products. [b] 1a (0.60 mmol), 2 (0.5 mmol), CuBr
(10 mol%), 1,10-phenanthroline (10 mol%), Pd(acac)2 (2 mol%),
XPhos (5 mol%), 3 mL of solvent (NMP/quinoline (1:1)), 1708C, 16 h.
Yields of isolated products. FG=functional group.
indicates that the Heck coupling and decarboxylation steps
occur in a separate rather than concerted fashion.
In conclusion, the decarboxylative Heck reaction dis-
closed herein opens up a convenient route to the synthesis of
unsymmetrical 1,1-disubstituted alkenes from widely avail-
able precursors. Key advantages are the good regiochemical
control, which is complementary to that of traditional Heck
reactions, the use of cinnamates as the source of the vinyl
group, and the excellent functional group tolerance. In this
À
process, the carboxylate controls the regiochemistry of C C
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acrylate.
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We thank the DFG (SFB/TRR88 “3MET”), the Chinese
Scholarship Council (fellowship to J.T.), and the Stipendien-
stiftung Rheinland-Pfalz (fellowship to D.H.) for financial
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Keywords: alkenes · carboxylic acids · copper · Heck reaction ·
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[23] phen = 1,10-phenanthroline; acac = acetylacetonate; BINAP =
2,2’-bis(diphenylphosphino)-1,1’-binaphthyl;
Johnphos = (2-
biphenyl)di-tert-butylphosphine; TFA = trifluoroacetate; dba =
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Received: June 14, 2016
Published online: && &&, &&&&
4
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Communications
Cross-Coupling
J. Tang, D. Hackenberger,
L. J. Goossen*
&&&& — &&&&
Branched Arylalkenes from Cinnamates:
Selectivity Inversion in Heck Reactions by
Carboxylates as Deciduous Directing
Groups
Directors cut: A palladium/copper-cata-
lyzed Mizoroki–Heck coupling of aryl
halides with cinnamic acids has been
developed in which the carboxylate group
directs the arylation into its b-position
before being tracelessly removed through
protodecarboxylation. 1,1-Disubstituted
alkenes are selectively obtained in this
transformation, which ideally comple-
ments traditional 1,2-selective Heck
reactions of styrenes.
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!