Pd-Catalyzed Regioselective Decarboxylative/C-H α-Alkoxyalkenylation of Heterocycles Using α-Carboxyvinylethers

Article abstract of DOI:10.1021/acscatal.7b01330

A direct introduction of vinyl ethers into C-H bond of heterocycles is reported. For this purpose, decarboxylative direct C-H cross-coupling of 1,3-diazoles with α-carboxyvinyl ethers as coupling partners was achieved under Pd(0)/Cu(I) cooperative catalysis to produce various α-heteroarylated vinylethers. This methodology was applied to the innovative production of heteroarylated enolizable ketones and naturally occurring bis-oxa(thia)zoles.

Full text of DOI:10.1021/acscatal.7b01330

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Letter
Pd-Catalyzed Regioselective Decarboxylative / C-H #-
Alkoxyalkenylation of Heterocycles using #-Carboxyvinylethers
Jean-Baptiste E.Y. Rouchet, Mahmoud Hachem, Cedric Schneider, and Christophe Hoarau
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b01330 • Publication Date (Web): 12 Jul 2017
Downloaded from http://pubs.acs.org on July 12, 2017
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Pd-Catalyzed Regioselective Decarboxylative / C−H
α-Alkoxyalkenylation of Heterocycles using α-
Carboxyvinylethers
Jean-Baptiste E. Y. Rouchet, Mahmoud Hachem, Cédric Schneider, Christophe Hoarau*
Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA (UMR 6014), 76000 Rouen,
France
Keywords: α-Alkoxyalkenylation, Enol ether, C-H Functionalization, Azoles, Decarboxylative
cross-coupling, Pd-catalysis, α-Carboxyvinylethers
Abstract: A direct introduction of vinyl ethers into C−H bond of heterocycles is reported. For
this purpose, decarboxylative direct C−H cross-coupling of 1,3-diazoles with α-carboxyvinyl
ethers as coupling partners was achieved under Pd(0)/Cu(I) cooperative catalysis to produce
various α-heteroarylated vinylethers. This methodology was applied to the innovative production
of heteroarylated enolizable ketones and naturally-occurring bis-oxa(thia)zoles.
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Vinyl ethers are found in many natural products and biologically active molecules. They
represent one of the most reactive and synthetically-valuable class of hetero-substituted alkenes
for the synthesis of complex organic molecules. Employed as masked-ketones and activated
alkenes, vinyl ethers might be involved in number of chemical transformations such as
hydrolysis, reduction, cycloaddition reactions, Heck and related cross-coupling reactions to
produce poly-functionalized ketones, alcohols, heterocycles and alkenes.[1-2]In particular, the,
transition-metal catalyzed heteroarylation of enol ethers has drawn lot of attention. The Heck
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reaction of non- prefunctionalized vinyl ethers with halides is currently the most step-economical
[3,4]
developed strategy.
However, this reaction is fraught with difficulties associated with
selectivity issues (α/β and Z/E). Therefore, others traditional cross-coupling approaches have
been considered using pre-metalated vinyl ethers in order to control the regio- and the
stereochemistry (Figure 1).[2,5] In this context, straightforward, atom-economic, and
environmentally benign method for direct heteroarylation of vinyl ethers with a full control of
the E/Z stereochemistry and α/β regiochemistry are highly demanded.
(Hetero)Arylation of acyclic enol ethers
by Heck reaction
-(Hetero)Arylation of acyclic enol ethers
by cross coupling approaches
[Pd]
[Pd]
HetAr
M
HetAr
OR1
HetAr
+
HetAr
+
OR1
OR1
X
X
OR1
M = ZnCl, B(OR)2, BF3K, SnR3
X = OTf, I, Br
This work: decarboxylative C-H coupling of heterocycles with -carboxyvinyl ethers
OR2
2
R1
R1
OR2
N
Y
Stereo- and regioselective reaction
First C-H heteroarylation of enol ethers
Z
N
CO2H
Z
H
Y
[Pd/Cu]
Figure 1. Pd-catalyzed heteroarylation of enol ethers
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Faced with the necessity to do ‘better with less’, the direct C−H functionalization of
heterocycles has emerged as powerful and complementary approach avoiding the generation of
metalated heteroarenes, sometimes air-moisture sensitive and unstable.[6] Since the past decades,
explosive achievements have been made in direct C-C bonds formation including arylation,
alkenylation, alkylation, carbonylation and acylation. As a complementary approach to
dramatically increase the functional diversity, the direct C−H introduction of valuable functions,
which offers several options for chemical-modulation and/or reactivity, is of great synthetic
interest. While remarkable advances have been made in direct C−H alkenylation of
heterocycles,[7] the transition-metal catalyzed direct C−H α-alkoxyalkenylation of heterocycles
with vinyl ethers has not been reported so far.[8] In line with our ongoing interest in the direct
introduction of hetero-substituted alkenes into C−H bond of heterocycles,[9] and knowing that
carboxylic acids are regarded as potential air-stable and easy to handle masked catalytic
organometallic building blocks by transition-metal-mediated extrusion of CO2,[10-13] we turned
our attention to the α-alkoxylated acrylic acids (2) as coupling partners for palladium-catalyzed
hetero-substituted alkenylation of heterocycles (Figure 1). Herein, Pd(0)-catalyzed and Cu(I)-
mediated decarboxylative / C−H α-alkoxyalkenylation of (hetero)arenes using challenging α-
alkoxylated acrylic acids (2) is reported. This methodology gives access to stereocontrolled gem-
heteroarylated vinyl ethers, and offers a rational and step-economical route to attractive
polysubstituted heteroarylated enol ethers. As an application, the decarboxylative / C−H α-
alkoxyalkenylation reaction was applied to afford a novel and convenient entry point into α,β-
enolizable α-ketoazole structures[14] and biologically active C2-C4’ linked azoles.[15]
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Table 1. Decarboxylative coupling: Reaction optimization
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Solvent/DMSO
(8/3)/[Conc.]
Yield
[%]a,b
Entry
[Pd]
Ligand
[Additive]
Ratio 2A/1a
1
2
Pd(OAc)2
Pd(OAc)2
PdBr2
dcpe
dcpe
dcpe
dcpe
dppe
dppe
dppe
dppe
dcpe
dppe
--
CuCO3•Cu(OH)2
CuCO3•Cu(OH)2
CuCO3•Cu(OH)2
CuCO3•Cu(OH)2
CuCO3•Cu(OH)2
Cu2O
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
2/1
1,4-Diox./0.2M
DMAc/0.2M
DMAc/0.2M
DMAc/ 0.2M
DMAc/ 0.2M
DMAc/ 0.2M
DMAc/ 0.2M
DMAc/ 0.2M
DMAc/0.2M
DMAc/0.1M
DMAc/0.1M
n.r.
23
34
41
62
55
29
29
78
96
n.r.
3
4
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
--
5
6
7
Cu(OAc)2
8
Ag2CO3
9
CuCO3•Cu(OH)2
CuCO3•Cu(OH)2
CuCO3•Cu(OH)2
10
11
2/1
2/1
aReaction conditions: [Pd] (10 mol%), ligand (20 mol%), 1a (0.1 mmol), (Z)-2a (0.2 mmol),
b
CuCO3•Cu(OH)2 (3.5 equiv), solvent/DMSO (8:3), MS 4Å, 140 °C, 12 h. Yield based on isolated
product after flash chromatography. 1,4-Diox = 1,4-Dioxane. n.r. = no reaction
We first established reaction conditions to operate the decarboxylative C−H coupling of
1,3,4-oxadiazole 1a with β-arylated α-methoxyacrylic acid 2A prepared as pure (Z)-isomer
through an aldol reaction followed by a dehydroxylation and hydrolysis of the resulting ester[16]
(Table 1). We observed that the heteroarylated enol ether 3Aa was not produced using strictly
the Greaney’s conditions.[11a] However, by switching the 1,4-dioxane/DMSO mixture of solvents
for DMAc/DMSO, the reaction occurred leading to the expected enol ether 3Aa in 23% yield.
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Interestingly, the enol ether 3aA was only isolated as pure (Z)-isomer (Table 1, entries 1 and 2)
and the stereochemistry was confirmed by single crystal X-ray structure determination.[17a,b]
After an additional screening of palladium sources and phosphine ligands,[17c] enol ether 3aA
was isolated in a fair 62% yield using Pd(acac)2 catalyst and dppe as ligand. However, the use of
other copper sources or silver carbonate as oxidants was detrimental (Table 1, entries 6-8)
leading predominantly to protodecarboxylative side product 4 (Figure 2). Full conversion of
1,3,4-oxadiazole 1a as well as quantitative production of (Z)-3aA were finally reached by
reacting 2 equivalents of α-methoxyacrylic acid (Z)-2A along with reducing of the (Z)-3aA
concentration from 0.2 to 0.1 M (Table 1, entries 9-10). When lowering the amount of [Pd]-
charge (from 10 to 5 mol%) and removing the molecular sieve, the efficiency of the Pd(0)-
catalyzed and Cu(I)-mediated decarboxylative process is significantly affected.[17c] Moreover the
decarboxylative coupling failed without palladium and ligand[18] (Table 1, Entry 11).
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With the optimized conditions in hands, we turned our attention to the scope and
limitations of the Pd-catalyzed and Cu-mediated decarboxylative C−H alkenylation
methodology. We first performed the C-2 alkenylation of 1,3,4-oxadiazoles 1a-g with a broad
panel of substituted β-arylated α-methoxyacrylic acids 2A-I. Overall, the cross-coupling was
successfully achieved whatever the electronic effect and the position of substituents on both
aromatic units of coupling partners 1 and 2 affording α-methoxyoxadiazolylalkenes (Z)-3 in fair
to excellent yields (Scheme 1). The β−heteroarylated α-methoxyacrylic acid 2G led also to the
desired product (Z)-3aG in 54% isolated yield. We were pleased to find that alkyl groups on both
coupling partners 1 and 2 are also tolerated under our optimized experimental conditions. The
corresponding 1,2-trisubstituted methoxylated alkenes (Z)-3aH and (Z)-3fA were obtained in
moderate to good yields. Interestingly, the methodology remains efficient with α-benzyloxy- and
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α-phenoxyacrylic acids (Z)-2J-K leading to corresponding enol ethers (Z)-3aJ and (Z)-3aK in
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moderate 45-62% isolated yields.
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Scheme 1. Scope of decarboxylative / direct C−H α-methoxyalkenylation of 1,3,4-oxadiazoles
with various α–alkoxyacrylic acids 2A-K
We next sought to investigate the scope of heterocycles (Scheme 2). Interestingly,
electronically different heterocycles displayed a good reactivity with α-methoxyacrylic acids (Z)-
2A-I. The α-phenoxy and α-benzyloxy (Z)-2J-K also proved to be reactive by switching the
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palladium source Pd(acac)2 to PdCl2 to provide a broad set of heteroarylated enol ethers (Z)-9-
11in fair to excellent yields (Scheme 2).
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Scheme 2. Scope of decarboxylative / direct C-H alkenylation of azoles using various α–
alkoxyacrylic acids 2A-L as coupling partners. [a] dcpe instead of dppe. [b] Addition of CuI (10
mol%).
The decarboxylative / C−H α-alkoxyalkenylation of variously substituted benzoxazoles 5a-c as
well as oxazole derivatives, such as 5-arylated oxazoles 6a-c and 5-arylated ethyl oxazole-4-
carboxylates 7a-d, were successfully achieved using either dppe or dcpe ligands to produce the
heteroarylated enol ethers 9-11 in 50-73% yields while limiting the main homocoupling side
reaction. α–Phenoxy and benzyloxyalkoxyacrylic acids 2J-K were also reactive with
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(benzo)oxazole derivatives 5-7 leading to the corresponding heteroarylated enol ethers 9-11J-K
in moderate 35% to good 75% isolated yields. To complete the scope of heterocycles, we found
that the cross-coupling of α-methoxyacrylic acid (Z)-2A with less acidic benzothiazole 8a under
the optimized protocol provided the heteroarylated 12aA in only 25% isolated yield. However,
the reaction could be improved by using CuI as additive. Indeed, this latter is supposed to
facilitate the catalytic metalation key-step of less-acidic and more-electron-rich 1,3-diazoles, such
as thiazole and imidazole, through the formation of [Cu]-heterocycle pre-complex in order to
increase the C2-H acidity.[19, 20] In that case, the benzothiazolyl enol ether 12aA, as well as two
additional benzothiazolyl enol ethers 12bA and 12aD, have been produced in 49% and 65%
isolated yields (Scheme 2).
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Scheme 3. Synthesis of biologically active structures. Reaction conditions: i) X = O, AgSbF6 (1
eq), CH2Cl2, -20 °C, 12 h; ii) X = S, CaCO3 (1 eq), EtOH, reflux, 6 h.
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To illustrate the potential usefulness of this novel regio- and stereo-controlled access to
heteroarylated enol ethers, two synthetic applications were investigated (Scheme 3). To date and
to the best of our knowledge, while the palladium-catalyzed direct C-H aroylation of 1,3-diazoles
have been already reported,[21-23] the direct production of valuable 2-(2-oxoxalkyl)-1,3-
diazoles[24] through direct C2-H functionalization of 1,3-diazoles remain highly challenging. In
this context, the first application of this methodology was directed towards the challenging
synthesis of α,β-enolizable α-keto-1,3-diazoles which are immediately available by adding a
deprotection step of the enol ether function. Selected as inhibitors of fatty acid amide
hydrolase,[14] the heteroarylated ketones 13 and 14 were produced by treatment of methylated
enol ethers (Z)-3aA and benzylated (Z)-11cJ with BBr3 and BCl3 respectively, according to the
nature of the enol ether.[25, 26] As an additional application, the α,β-enolizable α-ketoazoles 14
was used as a building block for the synthesis of naturally-occurring C2-C4’ linked bis-
oxa(thia)zole.[15] In particular, the α,β-enolizable α-ketoazole 14 was used both to prepare the C2-
C4’ linked bis-oxazole 16 applying the Blümlein-Lewis reaction[27] and the C2-C4’ linked
oxazole-thiazole 17 via the Hantzsch’s condensation.[28]
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To gain insight into the mechanism, we carried out several control experiments (Scheme
4). First, the decarboxylative cross-coupling was executed with cesium (Z)-α-methoxycinnamate
salt 18 (Scheme 4, eq 1). Interestingly, the addition of CuBr used as electrophile to generate the
methoxycinnamate copper salt was required to generate the desired product (Z)-3aA in good
yield. Moreover, under stoichiometric amount of Pd(acac)2 and dppe as ligand, no cross-coupling
product was obtained. Importantly, the Heck coupling reaction of cesium (Z)-α-
methoxycinnamate salt 18 with phenyl bromide followed by CuBr-mediated
protodecarboxylation[29] led to the exclusive production of the β-diphenylated vinyl ether 19
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(Scheme 4, eq 2).[17c] Therefore, the oxidative Heck-type / protodecarboxylative sequence for the
synthesis of (Z)-3aA can be discarded. All these data highlighted the importance of
CuCO3•Cu(OH)2 both in the oxidation step of Pd(0) to Pd(II) and in the crucial generation of
copper carboxylate intermediate that may lead to the generation of alkenyl copper intermediate
(II) through the ipso-decarboxylative cupratation process. (Figure 2)
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Scheme 4. Additional experiments for mechanism study
(1) Role of [Cu] in the decarboxylative step
Pd(acac)2 (10 mol%)
dppe (20 mol%)
CuCO3 Cu(OH)2 (3.5 eq.), MS 4Å
N
DMAc/DMSO (8/3), 140 °C, 12 h
OMe
N
O
Ph
Without CuBr, 14%
CuBr (1.0 eq.), 68%
CsO2C
MeO
(Z)-3aA
N
N
+
O
Ph
Pd(acac)2 (1 eq.)
dppe (1 eq.), MS 4Å
DMAc/DMSO (8/3), 140 °C, 12 h
1a (1 eq.)
(Z)-18, (2 eq.)
N
OMe
N
O
Ph
(Z)-3aA
(2) Heck reaction followed by protodecarboxylative process
CuBr / TMEDA (10mol%)
Pd(OAc) (3 mol%)
140 °C, 16 h, DMPU
Br
CsO2C
MeO
+
MeO
58%
(Z)-18
19
(3) In situ protodecarboxylation then Fujiwara-Moritani reaction:
Pd(acac)2 (10 mol%)
N
OMe
N
dppe (20 mol%), 1a (1 eq.)
CuCO3 (3.5 eq), MS 4Å
DMAc/DMSO (8/3), 140 °C
CuCO3 (3.5 eq.)
DMAc/DMSO (8/3)
140 °C, 12 h
H
O
Ph
(Z)-2B
OMe
OMe
MeO
(Z)-3aA
4
no product by crude NMR
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This latter may be facilitated by the electron-withdrawing inductive effect of the methoxy group
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30]
since we noted that the decarboxylative cross-coupling of 1,3,4-oxadiazole 1a with cinnamic
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acid failed under the optimized conditions.[13, 17c] We then investigated the cross-coupling of the
protodecarboxylative enol ether 4 with 1a under optimal experimental conditions (Scheme 4, eq
3).[31] The reaction failed precluding a two-steps mechanism involving initially a
protodecarboxylation followed by a Fujiwara-Moritani oxidative Heck-type coupling. Finally,
the effect of radical scavenger was examined, and 2,2,6,6-tetramethylpiperidine 1-oxyl
(TEMPO) did not inhibit the reaction.[17b] Thus a radical process is unlikely involved.
Figure 2. Proposed catalytic pathways.
Based on previous reports [10-12] and our control experiments, a plausible reaction pathway is
delineated in Figure 2. The success of this coupling depends on the interception of the generated
alkenyl copper intermediate (II) produced by copper-catalyzed extrusion of CO2, and the C-2-
palladated heterocycle (I) through a transmetalation step. The generation of the C-2-palladated
key-intermediate (I) is highly dependent both on the intrinsic acidity and nucleophilicity of C2-H
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site of 1,3-(oxa)diazoles and may be considered according to two pathways, (i) the catalytic
palladation of heterocycles with Pd(OAc)2 through base-assisted concerted[34] or none-concerted
(carbanionic-type) process,[35] or (ii) the transmetalation of the in situ generated heteroarylcopper
intermediate (III) to Pd(OAc)2.[19] Base on our experimental observations, we presume that most
acidic oxazole derivatives are appropriate for direct palladation with or without [Cu]-
assistance.[19e] By contrast, the use of CuI as additive for the success of the coupling with
benzothiazoles indicates a copper-assisted pre-activation of the heterocycle leading probably to
the generation of benzothiazolylcopper intermediate III.[19-20]
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In conclusion, we have reported a practical, straightforward, and unprecedented regio-
and stereoselective direct introduction of enol ethers onto C−H bonds of heterocycles by
decarboxylative/ direct C−H alkenylation of various azoles under palladium catalysis using α-
carboxyenol ether as new hetero-substituted alkenylating agent. This procedure offer a rational
and step-economical route to attractive regio- and stereocontrolled 1,2-polyheteroarylated enol
ethers in moderate to good yield. Moreover, this methodology constitutes a novel and convenient
entry point into the synthesis of α,β-enolizable α-ketoazoles and C2-C4’ linked bis-azoles.
AUTHOR INFORMATION
Corresponding Author
christophe.hoarau@insa-rouen.fr
ACKNOWLEDGMENT
This work has been partially supported by INSA Rouen, Rouen University, CNRS, EFRD,
European INTERREG IV A France (Channel) and Labex SynOrg (ANR-11-LABX-0029). We
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also thank the CRIHAN for software optimization and kind technical support. We thank also Dr.
M. Sanselme for X-ray structure determination.
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Supporting information: Experimental procedures, characterization data, details on the X-ray
analyses of compound (Z)-3aA, and 1H and 13C NMR spectra for compounds.
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Centre and allocated the deposition number: CCDC 1545339. c) For complete details concerning
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[31] Exemples of cascade protodecarboxylation/Fujiwara-Moritani reaction: a) Myers, A.;
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[32] We confirmed that α-carboxyenol ether 2 underwent smooth decarboxylation when treated
with stoichiometric amount of copper carbonate in the absence of palladium under optimized
conditions producing 1,2-substituted enol ether 4 in 60% yield.
[33] It is noteworthy that the cesium α-alkoxyvinylcarboxylate at 140 °C in DMAc/DMSO is not
subjected to a protodecarboxylative process.
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