Palladium-catalyzed asymmetric reductive Heck reaction of aryl halides

Article abstract of DOI:10.1002/anie.201501712

Asymmetric reductive Heck reaction of aryl halides is realized in high stereoselectivity. Hydrogen-bond donors, trialkylammonium salts in a glycol solvent, were used to promote halide dissociation from neutral arylpalladium complexes to access cationic, stereoselective pathways.

Full text of DOI:10.1002/anie.201501712

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201501712
German Edition: DOI: 10.1002/ange.201501712
Asymmetric Catalysis
Palladium-Catalyzed Asymmetric Reductive Heck Reaction of Aryl
Halides**
Guizhou Yue, Kaining Lei, Hajime Hirao, and Jianrong (Steve) Zhou*
Abstract: Asymmetric reductive Heck reaction of aryl halides
is realized in high stereoselectivity. Hydrogen-bond donors,
trialkylammonium salts in a glycol solvent, were used to
promote halide dissociation from neutral arylpalladium com-
plexes to access cationic, stereoselective pathways.
I
n the 1980s, Cacchi et al. reported that aryl halides reacted
with enones and enals to form conjugate adducts in the
presence of palladium catalysts.[1] Alkyl amines and formates
were the hydride source in the process.[2] Typically, neutral or
anionic aryl–Pd complexes were used and electron-poor
olefins and styrene were preferred olefin substrates for
insertion.[3] As a common feature, the key aryl–Pd species
were coordinatively saturated by ligands (phosphines, N-
heterocyclic carbenes, halides, and acetates). This saturation
successfully helps to out-compete undesirable b-hydride
elimination processes.[4] This reaction was used in racemic
syntheses of drug candidates, and for many years an
enantioselective version was unavailable.[5] In comparison,
metal-catalyzed conjugate additions using Cu,[6] Rh,[7] or Pd[8]
catalysts also afforded the same sets of conjugate adducts, but
they needed to use organometallic reagents, the latter often
being made from aryl halides.[9]
Scheme 1. Comparison of two reductive Heck reactions. DMF=N,N-
dimethylformamide, Tf=trifluoromethanesulfonyl.
Previously, Buchwald et al. initiated the study of asym-
metric reductive Heck reactions using aryl triflates and
nonaflates, and intramolecular insertion into enones gave
moderate ee values in most examples (Scheme 1a).[10] Herein,
we report reductive Heck reaction of aryl halides to provide
3-arylindanones in high ee values (Scheme 1b). These chiral
compounds are used in the synthesis of indatraline (antide-
pressant), tefludazine (antipsychotic), and tolterodine for the
treatment of urinary disorders.[11] Today, a dozen asymmetric
methods are available to access chiral indanones,[12] but
a general method to access 3-arylindanones is still lacking.[13]
Asymmetric 1,4-addition of organometallic reagents to
indenone is often out-competed by 1,2-addition.[14]
Initially, we used (E)-o-bromochalcone in a model study,
and it was easily prepared from an aldol condensation of
a methyl ketone and benzaldehyde (Table 1). After many
trials, we found that spiro-di(1,1’-indanyl)bisphosphine (SDP)
afforded excellent ee values (entries 1–3). The SDP ligands
were pioneered by Qi-Lin Zhou and have found widespread
applications in asymmetric metal catalysis.[15] BINAP, DM-
SEGPHOS, and Xyl-MeO-BIPHEP gave 35–77% ee
(entries 4–9). Bisphosphine oxides and phosphine oxazolines
(Pfaltz’s PHOX) were found to be catalytically inactive
(entries 10–12).
A 1:3 molar combination of benzoic acid and iPr2NEt
were used to form an alkylammonium salt in situ during
reaction. The latter was used to ionize the arylpalladium
halide by hydrogen bonding, in a glycol solvent (Table 2). The
excess alkylamine was needed for formation of palladium
hydride and regeneration of the active catalyst. When benzoic
acid was omitted, both the yield and ee value decreased
significantly (Table 2, entry 1).
[*] Dr. G. Yue, K. Lei, Prof. Dr. H. Hirao, Prof. Dr. J. Zhou
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University
Singapore 637371 (Singapore)
E-mail: jrzhou@ntu.edu.sg
Dr. G. Yue
College of Science, Sichuan Agricultural University
Ya’an, Sichuan, 625014 (China)
[**] We thank the Singapore Ministry of Education Academic Research
Fund (MOE2013-T2-2-057 and MOE2014-T1-001-021) for financial
support, and the Chinese Scholarship Council for financial support
to G.Y. Dr. Rakesh Ganguly and Dr. Yongxin Li conducted X-ray
diffraction analysis of one product. KL and GYcontributed equally to
experiments in this work.
Previously Xiao et al. reported that alkylammonium salts
or a glycol solvent facilitated halide dissociation in regiose-
lective Heck reactions.[16] We found that both R3NH+ salts
and glycol were needed in our study of the asymmetric Heck
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201501712.
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Table 1: The effect of chiral bisphosphines (GC conversion and cali-
Table 3: Effect of solvents on the model reductive Heck reaction.
brated GC yield).
Entry Solvent
Dielectric
constant
Conv.
[%][a]
Yield
[%][a]
ee
Cationic
[%][b] pathway
1
ethylene
glycol
EtOH
iPrOH
THF
acetone
DMA
DMF
37
100
87
97
yes
2
3
4
5
6
7
25
18
8
21
38
37
35
55
100
70
100
100
30
38
72
54
76
78
99
95
0
11
5
yes
yes
no
no
no
86
mainly
[a] Determined by GC. [b] Determined by HPLC on a chiral stationary
phase. DMA=dimethylacetamide, THF=tetrahydrofuran.
Entry
Chiral ligands
Conv. [%][a]
Yield [%][a]
ee [%][b]
of the aryl–Br bond was not significant. Trialkylamines were
the hydride source (entries 8–10), as previously reported by
others.[10a,20] When NaOAc was used as the base, the glycol
was the plausible hydride source (entry 11).[21]
1
2
3
4
5
6
7
8
(R)-SDP
(R)-Tol-SDP
(R)-Xyl-SDP
(R)-BINAP
(R)-DM-Segphos
(R)-DTBM-Segphos
(R)-MeO-BIPHEP
(R)-iPr-MeO-BIPHEP
(R)-Xyl-MeO-BIPHEP
(R)-BINAP(O)
(R)-Xyl-SDP(O)
(R)-iPr-PHOX
100
100
100
50
75
0
25
100
65
0
93
87
43
35
68
0
20
78
61
0
97
97
69
À60
À54
–
À71
À81
À77
–
The glycol solvent was also important to stabilize the
bromide anion (Table 3, entry 1).[22] The reaction became
much slower in both ethanol and isopropanol (entries 2 and
3). In THF, toluene, and acetone, almost 0% ee was observed.
Thus, in these solvents, olefin insertion into the neutral
palladium complex took place, and was non-stereoselective.
A dramatic disparity was found between DMF (86% ee) and
DMA (5% ee; entries 6 and 7).[23] The difference cannot be
explained by high solvent polarity[24] or strong solvation of
metal cations. The formyl hydrogen atom of DMF was
reported to participate in hydrogen bonding between DMF
molecules.[25] Thus, DMF may serve as the hydrogen-bond
donor in this case, while DMA cannot.[26]
9
10
11
12
0
0
0
0
–
–
[a] Determined by GC. [b] Determined by HPLC on a chiral stationary
phase. dba=dibenzylideneacetone.
Table 2: Optimization of reaction conditions for the model reductive
Heck reaction.
In examination of the scope of the asymmetric cyclization
(Scheme 2), we chose to use Tol-SDP because it performed
better than the parent SDP in cyclization of most substrates.
Both electron-donating and electron-withdrawing groups can
be present on b-aryl rings of chalcones. Thiophene, furan, and
indole were compatible with the palladium catalysis. A b-
cyclohexyl group can also be present. A b-cyclopropyl group
led to 54% ee while other alkyl groups led to even lower
selectivity.
Single-crystal X-ray diffraction of a product containing
ferrocene unequivocally established the 3S configuration
(Scheme 3a). For a chalcone carrying an a-methyl group,
asymmetric cyclization gave the trans isomer as the major
product, which is both the kinetically and thermodynamically
favored product (Scheme 3b). When ortho-chlorochalcone
was tested, the reaction did not proceed at 1008C because of
the difficult oxidative addition. At 1308C, 85% ee was
observed (Scheme 3c).
3-Arylindanones can be transformed into many chiral
compounds (Scheme 4), which are not straightforward to
make from other reactions: hydrogenolysis over Pd/C,
reduction to a cis-alcohol with NaBH4, Baeyer–Villiger
oxidation oxidized to a lactone, and palladium-catalyzed a-
arylation with good trans selectivity.[27] No ee erosion was
observed on biarylmethine centers. Furthermore, cis-3-
phenyl-1-indanol was readily substituted with either a thio-
phene ring[28] or an allyl group by trans addition to an indanyl
cation.
Entry Change of conditions
Conv. [%][a] Yield [%][a] ee [%][b]
1
no BzOH
100
100
100
36
80
91
45
38
55
51
93
94
88
73
55
91
97
58
74
76
80
96
95
93
96
2
3
AcOH instead of BzOH
CF3CO2H
4
AgOTf instead of BzOH 100
5
Ag2CO3
90
100
100
100
100
100
100
6
ZnCl2
7
ZnBr2
8
proton sponge as base
9
Et3N
10
11
DABCO
NaOAc
[a] Determined by GC. [b] Determined by HPLC on a chiral stationary
phase. DABCO=1,4-diazobicyclo[2.2.2]octane.
reaction of aryl halides.[17] In our DFT studies, hydrogen
bonding of trialkylammonium NH and alcoholic ROH with
a halide ion not only lowered the barrier, but also stabilized
the ionized products.[18] Silver salts were commonly believed
to remove halide ions from neutral aryl palladium halides
with ease in Heck reactions.[19] However, AgOTf and Ag2CO3
led to poor results (Table 2, entries 4 and 5). They probably
caused oxidation of phosphines. In comparison, redox-inac-
tive zinc salts gave around 80% ee (entries 6 and 7). In
entries 1–7 where there was a problem of material balance,
and a complex mixture of unidentifiable byproducts were
seen in the GC analysis. The simple byproduct from reduction
2
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Scheme 4. Transformation of chiral 3-phenylindane without loss in the
ee values.
Scheme 2. Reductive Heck reaction of ortho-bromochalcones. Yields
are those of isolated products (0.5 mmol scale).
Figure 1. Transition structure TS-R (left) and lower-energy transition
structure TS-S (right) for aryl insertion in cationic [(R)-Tol-SDP](o-
chalconyl)palladium(II). The ligand Tol-SDP is in space-filling model
and other atoms of the complex are shown as ball-and-stick model.
Pd blue, P orange, O red, and C (of chalcone) green.
conclusions were drawn: a) The energy gap of two transition
states was calculated to be 4.6 kcalmolÀ1, which is consistent
with observed 97% ee at 90–1008C. b) The main pathway that
proceeds via TS-S gives the major S-configured product and
its insertion barrier is around 17 kcalmolÀ1. c) No severe van
der Waals contact was identified in either of the two TSs, so
a simple model of steric repulsion seems implausible. d) A
close examination of TS-S revealed that the ketone oxygen
atom (highlighted in red) was close to a hydrogen atom of a P-
À
tolyl ring. The C H···O distance is 2.2 ꢀ and the bond angle
À
of C-H-O is 1528. They fall into the prescribed range for C
H···O weak hydrogen bonds,[29] and provides stabilization of
around 0.5–4 kcalmolÀ1.[30] This kind of attractive interaction
was absent in TS-R. Recently, the use of aryl CH···O
hydrogen bonding and other weak attractive forces have
emerged in asymmetric metal catalysis.[31]
In summary, we report a reductive Heck reaction process
which uses aryl halides directly to afford 3-arylindanones in
high ee values. As a key reaction design, alkylammonium salts
and glycol were used as hydrogen-bond donors to help halide
dissociation under mild reaction conditions. Alkylammonium
salts are routinely formed from alkylamines in asymmetric
Heck reactions[32] and they may act as halide abstractors in
polar solvents in, for example, Overmanꢁs Heck cycliza-
tions.[33]
Scheme 3. Reductive Heck reaction of other chalcone derivatives
(yields of isolated products) and ORTEP of (S)-3-ferrocenyl-1-indanone
with 50% probability of thermal ellipsoids.[34]
We then conducted DFT calculations on the stereo-
determining step of aryl insertion using a cationic complex
[(R)-Tol-SDP](o-chalconyl)palladium(II) (Figure 1). Several
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Keywords: asymmetric catalysis · hydrogen bonding · olefins ·
palladium · synthetic methods
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Received: February 23, 2015
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Asymmetric Catalysis
G. Yue, K. Lei, H. Hirao,
J. Zhou*
&&&& — &&&&
Palladium-Catalyzed Asymmetric
Reductive Heck Reaction of Aryl Halides
Hydrogen-bond donors promote halide
dissociation from neutral arylpalladium
halides to access an enantioselective
cationic pathway. The use of trialkylam-
monium salts in a glycol solvent enables
asymmetric reductive Heck reaction of
aryl halides in high stereoselectivity.
6
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!