Palladium-catalyzed intramolecular reductive olefin hydrocarbonation: Benzylic hydrogen serving as a new hydrogen donor

Article abstract of DOI:10.1039/c7cc01423f

A palladium-catalyzed intramolecular hydrocarbonation of unactivated alkenes was achieved, in which toluene is used as a hydrogen donor for the first time. The radical transfer hydrogenation is designed and realized based on the Bond Dissociation Energy (

Full text of DOI:10.1039/c7cc01423f

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
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DOI: 10.1039/C7CC01423F
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Palladium-Catalyzed Intramolecular Reductive Olefin
Hydrocarbonation: Benzylic Hydrogen Playing as a New Hydrogen
Donor
Received 00th January 20xx,
Accepted 00th January 20xx
Xu Dong, Jie Cui, Jian Song, Ying Han, Qing Liu, Yunhui Dong and Hui Liu*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
palladium-catalyzed intramolecular hydrocarbonation of
unactivated alkenes was achieved, in which toluene is used as
hydrogen donor for the first time. The radical transfer
hydrogenation is designed and realized basing on the Bond
Dissociation Energy (BDE) value. Toluene derivate which is cheap,
readily available and easily handled, plays as a new hydrogen
donor in radical involved reactions, providing a novel and
promising perspective for future reductive reactions.
The clinical success of potential drug candidates shows
correlation with the carbon bond saturation as defined by
fraction sp3-hybridized carbon atoms in the molecule.1
Consequently, synthetic methods that enable the construction
of Csp3-Csp3 bonds could have a major effect on the new
pharmaceuticals discovery and development. Alkyl-alkyl
coupling reactions are among the most challenging of coupling
processes, due in part to the potential β-hydride elimination
from intermediates in the catalytic cycle.2 In the past decades,
substantial progress have been achieved in alkyl-alkyl coupling
reactions using unactivated alkyl halides electrophiles to
couple with alkyl lithium,3 alkyl Grignard,4 alkylznic reagents5
and alkylboron reagents6 which could be obtained from the
functionalization of olefins (Scheme 1, a and b).7 Obviously,
reductive olefin hydrocarbonation, in which to replace
alkylmetallic reagents by olefins coupling with alkyl
electrophiles, would present appealing advantages to
traditional cross-coupling reactions, such as less expensive
substrates, broader substrate availability and better functional
group compatibility (Scheme 1, c). However, radical-based
versions remain underestimated, probably owing to the
prejudice that radical intermediates are difficult to control.
Recently, several breakthroughs on catalytic hydrogen-
atom-transfer-triggered transformations are achieved to
Scheme 1 Transition-metal-catalyzed alkyl-alkyl construction with unactivated alkyl
electrophiles.
overcome the great synthetic challenges. Starting from the
pioneering work of Mukaiyama8 on hydrofunctionalization
reactions, hydrosilanes have been developed into a practical
and milder alternative hydride source in manganese, iron, and
cobalt catalyzed hydrogenation of alkenes, constructing
numerous carbon-heteroatom and carbon-carbon bonds.9 It is
worth noting that alkenes play the role of nuclephilic radical
equivalents or alkylmetallic equivalents in these
transformations, exhibiting a novel and promising
perspective.10 However, there are few examples reported on
the coupling reaction of unactivated alkyl halides and
unactivated alkenes. Very recently, Fu and Liu describe a Ni-
catalyzed intermolecular reductive olefin hydrocarbonation
between olefins and alkyl halides without using any
o rga no metalli c rea gent, i n w hi ch sil a ne D EMS
(Diethoxymethylsilane) is used as hydrogen source and
reductant (Scheme 2, a).11 Considering the mechanism, the key
unactivated carbon radical intermediate
I caught our
attentions. The traditional DEMS plays as the radical reductant
whose BDE is between 83.7-94.6 kcal.mol-1, providing the
unactivated Csp3-H bond whose BDE is between 95.5-106
kcal.mol-1.12 According to our previous work on the palladium
catalyzed radical reactions, a very similar carbon radical
intermediate IV should exist (Scheme 2, b). It is well known
that the benzylic hydrogen of toluene, whose BDE 88 kcal.mol-
1 is closed to the Si-H, is activated easily in the radical initiating
School of Chemical Engineering, Shandong University of Technology, 266 West
Xincun Road, Zibo, 255049, China.
E-mail: huiliu1030@sdut.edu.cn
† Electronic Supplementary Information (ESI) available: Experimental procedures,
compound characterization, and copies of 1H and 13C NMR spectra.
See DOI: 10.1039/x0xx00000x
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reductive product 2a was isolated in 18% (entry 1).
View Article Online
PdCl2(PPh3)2 did not improve the reaDcOtioI:n10.1o0b3v9/ioCu7CslCy0,14b2u3Ft
Pd(PPh3)4 could increase the yield to 32%, which implied the
ligand PPh3 might favor this transformation (entries 2 and 3).
Furthermore, the combination of Pd2(dba)3 and PPh3 greatly
promoted the yield to 62% (entry 4). Employment of some
proton donor additives, such as PhB(OH)2/B(OH)3/H2O, did not
give positive results (entries 5-7), indicating the proton did not
benefit this transformation. Then we evaluated a series of
ligands for this reaction (entries 8-10). To our delight, the using
of Ph2PCy increased the yield dramatically to 85%. The
screening of base showed that Cs2CO3 kept the top status
(entries 11-13). By decreasing the reaction temperature to 100
oC, the yield of 2a fell to 73%, indicating the temperature was
crucial to this transformation (entry 14). Further adjustment of
Ph2PCy offered no appreciable benefit (entries 15-16). On the
basis of these results, the optimal conditions were determined
to include Pd2(dba)3 combined with Ph2PCy and Cs2CO3 in
toluene at 130 °C (entry 8).
Scheme 2 Design plan basing on the bond dissociation energy (BDE).
conditions to generate the benzylic radical.13 However, almost
all the attentions are focusing on the further transformation of
benzylic radical, and the leaving hydrogen radical is totally
neglected. Based on the BDE value, the hydrogen radical
generated from toluene was potential to be used as a radical
reductant instead of Si-H derivates. Herein, we discovered a
new
Pd-catalyzed
intramolecular
reductive
olefin
With the conditions established above, we next evaluated
hydrocarbonation between unactivated alkenes and alkyl
halides, firstly using benzylic hydrogen as radical reductant
(Scheme 2, b).
the substrates scope (Table 2). Firstly, the R3 groups at
Table 2 Results of Pd-catalyzed hydrocarbonation of unactivated alkenesa
We initiated our investigation to test the hypothesis by
employing unactivated iodide 1a as substrate (Table 1). In the
beginning, we tried numerous reactions using Pd(OAc)2/dppf
which was reported to generated alkyl radical easily,14
however, only the iodide atom transfer radical cyclization
product was obtained. Encouragingly, with the combination of
o
PdCl2(dppf) and Cs2CO3 in toluene at 130 C, the desired cyclic
Table 1 Optimization of the reaction conditionsa
Entry
1c
Catalyst
PdCl2(dppf)
PdCl2(PPh3)2
Pd(PPh3)4
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Ligand
-
Base/Additive
Cs2CO3/-
Yield (%)b
18
2c
-
-
Cs2CO3/-
Cs2CO3/-
Cs2CO3/-
12
32
62
33
22
20
85
67
49
18
11
35
73
70
57
3c
4
5
6
7
8
9
10
11
12d
13
14e
15f
16g
PPh3
PPh3
PPh3
PPh3
Cs2CO3/PhB(OH)2
Cs2CO3/B(OH)3
Cs2CO3/H2O
Cs2CO3/-
Ph2PCy
Cy3P·HBF4
(3-OMe-Ph)3P
Ph2PCy
Ph2PCy
Ph2PCy
Ph2PCy
Ph2PCy
Ph2PCy
Cs2CO3/-
Cs2CO3/-
K2CO3/-
Et3N/-
Cy2NMe/-
Cs2CO3/-
Cs2CO3/-
Cs2CO3/-
a Reaction conditions: 1a (0.2 mmol), catalyst (5 mol%), ligand (30 mol%), additive
(0.6 mmol), Cs2CO3 (0.4 mmol), toluene (3 mL), nitrogen atmosphere, 24 h, 130 oC.
b Isolated yield. c Catalyst (10 mol%). d 1a was recovered in 63%. e 100 oC. f Ph2PCy
(20 mol%). g Ph2PCy (40 mol%).
a Reaction conditions: 1 (0.2 mmol), Pd2(dba)3 (0.01 mmol), Ph2PCy (0.06 mmol),
Cs2CO3 (0.4 mmol), toluene (3 mL), nitrogen atmosphere, 24 h, 130 oC. Isolated
yield. b Pd2(dba)3 (0.015 mmol), Ph2PCy (0.09 mmol).
2 | J. Name., 2012, 00, 1-3
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C4 position were investigated. Substrates bearing alkyl group
at C4 afforded the corresponding products in declining yields,
indicating steric hindrance of R3 may have a negative effect to
View Article Online
DOI: 10.1039/C7CC01423F
the transformation (2b-2d), however, aryl substituents at C4
only produced the 6-endo cyclization/Heck products.15
Additionally, the substrate 1q (R3 = H) gave an inseparable
mixture of reductive product 2q and Heck product 3q (for
details see SI, page S23). To our delight, the alkyl substitution
at the C5 position generated the desired products in very good
yields (2e and 2f), although it might undergo β-hydrogen
elimination from the intermediate IV easily (Scheme 2). The C1
position showed excellent compatibility with both alkyl and
aryl, providing the reductive products in good yields (2g-2j).
The substitution pattern at C2 position was also explored, and
the results showed that phenyl, benzyl and sterically hindered
isopropyl substitutions did not affect the transformation (2k
-
Scheme 4 Preliminary mechanism exploration.
2n). Moreover, the bicyclic compound 2o could also be
obtained in 65% yield and no d.r. was obtained from the H
1
NMR. To further investigate the substrate scope of this
strategy, we employed 4-nitrophenylsulfonyl as the N-protect
group, and the desired product 2p was obtained smoothly in
67% yield.
To examine the transformation in the presence of
stoichiometric hydrogen donor, substrate 1a was subjected to
the standard conditions with 3.0 equivalents of toluene in
trifluorotoluene (Scheme 3). To our delight, this procedure
also yielded the target motifs in 41% yield.
Further examination of solvents bearing benzylic hydrogen
was also carried out (Table 3). The expected reductive
transformation performed perfectly in xylene mixture and
mesitylene, 2a was obtained in good yields (entry 1 and 2). To
our delight, the ethylbenzene could also work as the hydrogen
donor and afforded 2a successfully (entry 3), steric hindrance
and lower activity of benzylic position might be responsible for
the relatively declining yield.
In order to obtain direct evidence for the source of
hydrogen abstraction, we performed this transformation in
toluene-D8 (Scheme 4, a). The deuterated product 2a-D-I was
isolated in 77% yield with 96% deuterium. Apparently, the
observation of deuterated ratio supports that the hydrogen
atom is totally derived from toluene. A competition deuterium
kinetic isotope effect (KIE) study was carried out by employing
a mixture of toluene and tolene-D8. The deuterated product
2a-D-II was isolated in 81% with 22% deuterium, revealing a
KIE of 3.5 (Scheme 4, b). The observations show clearly that
the activity of benzylic hydrogen is higher compared with
benzylic deuterium, which can account for the longer reaction
time in eq a, Scheme 4. These results also indicated a rate-
determining step might be involved in the hydrogen
abstracting from toluene.
In addition, the 1,2-diphenylethane
(5) was isolated
successfully from the standard reaction system (for data see
SI). In order to verify 1,2-diphenylethane was the byproduct of
this reaction, we performed this reaction in the absent of
substrate (Scheme 4, c). As expected, no compound
5 was
detected. This outcome revealed that 1,2-diphenylethane
existed as a result of the reductive transformation.
Based on the preliminary investigations and prior works of
other groups16, we propose the following palladium-radical
involved mechanism for this reductive olefin hydrocarbonation
Scheme 3 Studies with stoichiometric PhMe for the reductive strategy.
Table 3 Texting experiments of solvent bearing benzylic hydrogena
(Scheme 5). Alkyl radical
Pd(0), which then adds to the alkene moiety to deliver a 5-exo
cyclization intermediate . Then the intermediate abstracted
6 could be generated from 1a and
7
7
H atom directly from the benzylic moiety of PhCH3 to deliver
the reduction product 2a, accompanied with the release of
benzyl radical
offers another benzyl radical 8’ in the course of regenerating
the Pd(0) catalyst. Finally, the 1,2-diphenylethane ( ) was
afforded by coupling of two benzyl radical groups to terminate
this conversion. Alternatively, both and 8’ could occur self-
coupling to yield 1,2-diphenylethane (
8. Simultaneously, palladium iodine species 9
Entry
Hydrogen Donor
xylene
mesitylene
ethylbenzene
Yield (%)b
1
2
3
79
68
49
5
8
a Reaction conditions: 1 (0.2 mmol), Pd2(dba)3 (0.01 mmol), Ph2PCy (0.06 mmol),
Cs2CO3 (0.4 mmol), solvent (hydrogen donor) (3 mL), nitrogen atmosphere, 24 h,
130 oC. b Isolated yield.
5
).
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In conclusion, we have developed a novel intramolecular
hydrocarbonation of unactivated alkenes with unactivated
alkyl iodides. The low-cost, readily available and safety toluene
is employed as the hydrogen donor in radical reactions for the
first time. Moreover, more solvents bearing benzylic hydrogen,
such as xylene, mesitylene and ethylbenzene could serve as
hydrogen-donating uneventfully. This new discovery provides
us a promising perspective for future reductive reactions. The
preliminary mechanistic hypothesis was established. Basing on
the KIE investigation, the rate-determining step was proposed
to be the hydrogen abstraction from toluene. Further efforts
towards examining mechanistic possibilities and broader
applications using toluene as reductant are currently
underway.
We thank the National Natural Science Foundation of China
(21302057 and 21405095), the Young Talents Joint Fund of
Shandong Province (ZR2015JL005), and Special Funding for
Postdoctoral Innovation Project of Shandong Province
(201501002). We are grateful to the support from Zibo Positive
Additive Co., Ltd.
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