Water as a Hydride Source in Palladium-Catalyzed Enantioselective Reductive Heck Reactions

Article abstract of DOI:10.1002/anie.201700195

Pd-catalyzed intramolecular asymmetric carbopalladation of N-aryl acrylamides followed by reduction of C(sp³)-Pd intermediate using diboron–water as a hydride source afforded enantioenriched 3,3-disubstituted oxindoles in high yields and enantioselectivities. When heavy water was used as a deuterium donor in combination with bis(catecholato)diboron (Cat₂B₂), deuterium was incorporated into the products with high synthetic efficiency. The ligand determined both the enantioselectivity of the reaction and the reaction pathways, thereby affording either hydroarylation (reductive Heck) or carboborylation products.

Full text of DOI:10.1002/anie.201700195

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201700195
German Edition: DOI: 10.1002/ange.201700195
Synthetic Methods
Hot Paper
Water as a Hydride Source in Palladium-Catalyzed Enantioselective
Reductive Heck Reactions
Wangqing Kong, Qian Wang, and Jieping Zhu*
Abstract: Pd-catalyzed intramolecular asymmetric carbo-
palladation of N-aryl acrylamides followed by reduction of
C(sp3)-Pd intermediate using diboron–water as a hydride
source afforded enantioenriched 3,3-disubstituted oxindoles in
high yields and enantioselectivities. When heavy water was
used as a deuterium donor in combination with bis(catecho-
lato)diboron (Cat2B2), deuterium was incorporated into the
products with high synthetic efficiency. The ligand determined
both the enantioselectivity of the reaction and the reaction
pathways, thereby affording either hydroarylation (reductive
Heck) or carboborylation products.
S
ince its initial disclosure by Cacchi and co-workers,[1] the
palladium-catalyzed hydroarylation or reductive Heck reac-
tion between arylhalides (pseudohalides) and alkenes has
been well-exploited and used in natural product synthesis.[2,3]
However, in sharp contrast to the great progress recorded in
the field of asymmetric Heck reactions,[4] the development of
enantioselective reductive Heck reactions remains challeng-
ing[5] and highly enantioselective protocols have been devel-
oped only very recently by the groups of Buchwald,[6] Jia,[7]
Zhou,[8] de Vries, and Minnaard.[9] Tertiary amines (proton
sponge, N-methyl dicyclohexylamine), sodium formate, and
PhCOOH-iPr2NEt have been used as hydride donors in
combination with the palladium catalyst and chiral ligand.
Water is without doubt the most cost-efficient and
environmentally benign hydrogen/hydride source.[10] Very
recently, Stokes et al. discovered a diboron-assisted Pd-
catalyzed transfer hydrogenation of alkenes and alkynes
with water (H2O) as a hydride source at room temperature
(Scheme 1a).[11] Song and coworkers have subsequently
reported reduction of N-heteroaromatics with a similar
catalytic system,[12] while Prabhu et al. proposed that hydro-
gen (H2 gas) generated under these catalytic conditions was
responsible for the reduction of olefins.[13] Prompted by the
difficulties, which we encountered in using intramolecular
reductive Heck reaction for the construction of complex
natural products,[14] and our long-standing interests in the
development of domino enantioselective carbopalladation/
intermolecular nucleophilic trapping of the resulting
Scheme 1. Pd-catalyzed reductive Heck reaction.
C(sp3)-Pd complex for the synthesis of biologically relevant
heterocycles,[15] we became interested in developing an
enantioselective reductive cyclization of acetanilides 1 for
the synthesis of 3,3-disubstituted oxindoles 2. Herein, we
report that in the presence of a catalytic amount of Pd(OAc)2,
tBuPhOX (L1, Figure 1), and a stoichiometric amount of
tetrahydroxydiboron [B2(OH)4] and water, intramolecular
hydroarylation of acetanilides 1 occurred smoothly to afford 2
in excellent yields and high enantioselectivities (Scheme 1b).
We also document that the deuterated compounds are easily
accessible using the couple Cat2B2/D2O as a D atom donor.
While deuterium-labeled compounds are useful in mechanis-
tic studies of organic transformations and drug metabolism,[16]
deuterium is now a validated component of the medicinal
chemistry repertoire in searching for active and safe pharma-
ceuticals.[17]
To realize the aforementioned conceptually simple yet
appealing transformation, the enantioselectivity of the
carbopalladation step must be addressed, but several com-
petitive reaction pathways must also be avoided, such as:
1) formation of borylated oxindole 3 (in fact, carboborylation
of alkenes is known[18] and conversion of 1 to 3 has been
reported);[19] 2) direct Miyaura-borylation of arylhalide
(pseudohalide) 4 and its cross-coupling with the starting
material 1;[20] 3) direct reduction of the double bond to 5
according to Stokes et al. (Scheme 1a).[11]
[*] Dr. W. Kong, Dr. Q. Wang, Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Products
Institute of Chemical Sciences and Engineering
ꢀcole Polytechnique Fꢁdꢁrale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@eplf.ch
2-(2-(4-Fluorophenyl)-N-methylacrylamido)phenyl tri-
fluoromethanesulfonate (1a) was chosen as a model substrate
to evaluate the feasibility of our approach. In accordance with
the report by Eycken et al.,[19] heating a solution of 1a and
Pin2B2 in acetonitrile/water (MeCN/H2O, v/v = 20/1) at 1008C
in the presence of PdCl2(MeCN)2 (0.1 equiv), PPh3
(0.2 equiv), and 1,4-diazabicyclo[2.2.2]octane (DABCO,
2.0 equiv) afforded carboborylation product 3a (R1 = Me,
Homepage: http://lspn.epfl.ch
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201700195.
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R2 = 4-FC6H4) in 75% yield (entry 1, Table 1). To our delight,
using (S)-tBuPHOX (L1; Figure 1)[21] as a ligand switched the
reaction pathway completely, affording 2a exclusively in 65%
yield with excellent enantioselectivity (e.r. 97/3, entry 2,
respectively), but in diminished yields (entries 4–5, Table 1).
The influence of the diboron reagents on the reaction
outcome was subsequently probed (entries 6–7, Table 1) and
tetrahydroxydiboron was found to reach an optimum, afford-
ing 2a in 90% yield with an e.r. of
93:7.[22] Carrying out the reaction at
Table 1: Optimization of the reaction conditions.
808C and with 2 equiv of H2O
slightly increased the enantioselec-
tivity to 95:5 (entries 8–9, Table 1).
Strikingly, using the electron-defi-
cient PHOX-type ligand (S)-L2
Entry
Ligand
Diboron
Base
Solvent
T [8C]
Yield 2a [%][c]
e.r.[d]
(Figure 1) shut the reaction down
completely (entry 10, Table 1).
Other bidentate ligands such as
BINAP (L3; Figure 1) and SEG-
PHOS (L4; Figure 1) gave inferior
results (entries 11–12, Table 1). No
reaction was observed when elec-
tron-rich and conformationally
rigid bisphospholane L5 and mono-
dentate phosphoramidite ligand L6
were used (entries 13–14, Table 1;
Figure 1). Further screening of the
solvents and Pd sources (entries 15–
19, Table 1) did not improve the
yield or the enantioselectivity of the
reaction. Finally, optimum condi-
tions were defined as follows:
1[b]
2[b]
3[b]
4[b]
5[b]
6[b]
7[b]
8[b]
9
10
11
12
13
14
15
16
17
18[f]
19[g]
PPh3
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L1
L1
L1
L1
L1
B2Pin2
B2Pin2
B2Pin2
B2Pin2
B2Pin2
DABCO
DABCO
DIPEA
TMG
DBU
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
toluene
THF
100
100
100
100
100
100
100
80
80
80
80
80
80
80
80
80
80
80
80
75 (3a)
65
trace
40[e]
45
60
90
88
90
N.R.
70
42
N.R.
N.R.
46
N.D.
70
–
97:3
–
95:5
96:4
93:7
93:7
95:5
95:5
–
73.5:26.5
46.5:23.5
–
–
95:5
–
Cat2B2
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
B2(OH)4
B2(OH)4
B2(OH)4
B2(OH)4
B2(OH)4
B2(OH)4
B2(OH)4
B2(OH)4
B2(OH)4
B2(OH)4
B2(OH)4
B2(OH)4
B2(OH)4
DMF
MeCN
MeCN
55:45
94.5:5.5
95:5
87
88
PdCl2(MeCN)2/L1
as
catalyst,
[a] Reaction conditions: 1a (0.1 mmol), PdCl2(MeCN)2 (0.1 equiv), ligand (0.2 equiv), base (4.0 equiv),
diboron (2.0 equiv), H2O (2.0 equiv), solvent (2.0 mL, 0.05m) in a sealed tube at 808C for 14 h; [b] H2O
(6.0 equiv) was used; [c] yields of isolated products; [d] determined by chiral supercritical fluid
chromatography; [e] compound 3a was isolated in 27% yield; [f] with Pd(OAc)2; [g] with Pd2(dba)3
(dba=bis(dibenzylideneacetone)). Key: B2Pin2 =bis(pinacolato)diboron,
Cat2B2 =bis(catecolato)diboron, DABCO=1,4-diazabicyclo[2.2.2]octane, DBU=1,8-diazabicyclo-
[5,4,0]undec-7-ene, TMG=1,1,3,3-tetramethylguanidine, MeCN=acetonitrile, THF=tetrahydrofuran,
DMF=N,N-dimethylformamide, N.R.=no reaction, N.D.=none detected.
DABCO as base, and the couple
B2(OH)4/H2O as a hydride donor in
MeCN at 808C (entry 9, Table 1).
With the optimum conditions in
hand (entry 9, Table 1), the general-
ity of the asymmetric reductive
Heck reaction was subsequently
investigated (Scheme 2). The Ca
aromatic substituent bearing an
electron donating or withdrawing group located at different
positions (ortho, meta, para) were well-tolerated to afford
3-methyl 3-aryl substituted oxindoles (2a–2h) in high yields
with excellent enantioselectivities. Alkyl substituents at the
Ca position, including those functionalized with CH2OMe
and CH2NBnTs, were compatible leading to the correspond-
ing oxindoles (2i–2k) in good yields with slightly diminished
e.r. values. Notably, in the case of benzyl substituted
acetanilide 1j, the alternative process involving Heck/intra-
molecular CH-functionalization leading to spirooxindole did
not take place.[23] The reductive Heck reaction of N-benzyl
acetanilide 1l proceeded efficiently to provide 2l in 86%
yield with an e.r. of 95.5:4.5. As the N-benzyl is readily
removed, it constitutes a route to N-unsubstituted oxindoles.
Finally, the effect of substituents on the benzene ring of the
aniline moiety was investigated. Once again, the electronic
effect remained minimal and the desired products
2m–s bearing different substituents (Me, Ph, OMe, Cl, F)
were obtained in good yields with high enantioselectivities.
The reaction was successfully applied to the synthesis of
6,7-benzoxindole 2t (86%, e.r. 96.5:3.5) and 4,5-benzoxindole
Figure 1. Structures of ligands.
Table 1). The structure of the base was found to play an
important role in the selective conversion of 1a to 2a. Thus,
replacing DABCO with Hꢀnigꢁs base (N,N-diisopropylethyl-
amine or DIPEA), a widely used hydride source in reductive
Heck reactions (entry 3, Table 1), produced only a trace
amount of 2a. Using other bases such as TMG and DBU
afforded 2a with high enantioselectivities (95:5 and 96:4,
2
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due to the H-D exchange between D2O and tetrahydroxydi-
boron. In line with this assumption, replacement of B2(OH)4
with Cat2B2 furnished 2a-D in 68% yield with 95:5 e.r. and
92% D-incorporation. This result clearly demonstrates that
H2O is the hydride source of this reaction. Using 1a as
a substrate and Cat2B2/H2O or Cat2B2/D2O as a hydride
donor, a side-by-side kinetic experiment monitored by
19F NMR spectroscopy provided a kinetic isotope effect
(KIE) value of 1.8. This value indicated that H atom transfer
might not be the turnover-limiting step in the reductive Heck
process.[25] Finally, resubmitting boronate 3b (R1 = Me, R2 =
Ph) to our standard reaction conditions led to recovery of the
starting material, suggesting that protonolysis of 3b is not
responsible for the formation of 2.
On the basis of the aforementioned results, a possible
catalytic cycle is proposed (Scheme 4). Oxidative addition of
tBuPHOX ligated Pd0 to aryl triflate 1, followed by intra-
Scheme 2. Scope of the enantioselective reductive Heck reaction.
2u (89%, e.r. 95:5). Upon recrystallization, oxindole 2u was
obtained in 80% yield with an e.r. of 99.5:0.5. The absolute
configuration of 2u was determined to be 3S by X-ray
crystallographic analysis and that of all other oxindoles was
assigned accordingly.[24] It is remarkable that a domino
cyclization of diene 1v proceeded smoothly to afford
spirooxindole 2v in good yield, albeit with moderate enan-
tioselectivity. Finally, arylchloride was compatible under
these conditions (2e, 2p).
Control experiments were performed to gain insight on
the mechanism of this transformation (Scheme 3). Treatment
of 1a in the absence of either H2O or diboron under otherwise
standard conditions failed to produce compound 2a, suggest-
ing that both reagents play a critical role in this trans-
formation. Performing the reductive Heck reaction of 1a
using the couple D2O-B2(OH)4 afforded 2a with only 52%
deuterium incorporation. The low D-incorporation was likely
Scheme 4. Possible reaction mechanism.
molecular carbopalladation, would afford the cationic C(sp3)-
PdII intermediate A, which is subsequently converted to a PdII
hydroxo complex B.[26] Transmetalation of B with the diboron
reagent would provide alkyl-PdII-boron complex C, which
would furnish intermediate D upon reaction with a molecule
of H2O. 1,4-D migration by s-bond metathesis from D
furnishes alkyl-PdII-D species E with release of B(OR)2(OD).
Finally, reductive elimination from E would deliver the
desired product 2 with concurrent regeneration of Pd0L*
catalyst.
Treatment of 1a using HCOONa as a hydride donor
under our standard conditions afforded 2a in 75% yield with
an e.r. of 85:15 (for details, see the Supporting Information).
This experiment further illustrated the difficulties associated
with the development of this type of domino process. In fact,
although the reduction is not involved in the stereocenter-
generating step, the presence of a nucleophile (HCOONa)
might modify the coordination sphere of the metal center,
hence the enantioselectivity of the carbopalladation step.[15]
An important advantage of the present method is the easy
access to D-labeled compounds. Thus, using D2O as a D atom
donor in combination with Cat2B2 under otherwise standard
Scheme 3. Control experiments.
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enantioselectivities with a high level of D-incorporation
(Scheme 5). These compounds would be difficult to access
by applying other reductive Heck conditions.
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In conclusion, we developed the first Pd-catalyzed asym-
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a hydride donor. A series of enantioenriched oxindoles
bearing a C3-quaternary stereocenter were obtained in
excellent yields with high enantioselectivities. The CH2D
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Acknowledgements
Financial support from EPFL (Switzerland) and the Swiss
National Science Foundation (SNSF) is gratefully acknowl-
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Conflict of interest
The authors declare no conflict of interest.
Keywords: asymmetric synthesis · deuterium labeling ·
hydride donors · oxindoles · reductive Heck reactions
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Manuscript received: January 8, 2017
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Synthetic Methods
W. Kong, Q. Wang,
J. Zhu*
&&&& — &&&&
Water as a Hydride Source in Palladium-
Catalyzed Enantioselective Reductive
Heck Reactions
Water as a reductant? Intramolecular
asymmetric carbopalladation of N-aryl
acrylamides, followed by reduction of
C(sp3)-Pd intermediate using water as
a hydride source, afforded 3,3-disubsti-
tuted oxindoles in high yields and enan-
tioselectivities. Enantioenriched oxin-
doles bearing a CH2D substituent were
accessible using D2O as a reductant.
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!