Tandem arylation and regioselective allylic etherification of 2,3-allenol: Via Pd/B cooperative catalysis

Article abstract of DOI:10.1039/c9ob01792e

An efficient method for the construction of arylated allylic ethers was developed via three-component tandem arylation and allylic etherification of 2,3-allenol with aryl iodides and alcohols. In the cooperative catalytic system of a palladium complex and triethylborane, the process allows rapid access to functionalized 1-arylvinylated 1,2-diol derivatives in good to high yields with complete branch-selectivities. The synthetic utility of the present process was demonstrated by the late-stage functionalization of a drug molecule, the gram-scale synthesis and the elaboration of the products.

Full text of DOI:10.1039/c9ob01792e

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Tandem arylation and regioselective allylic
etherification of 2,3-allenol via Pd/B cooperative
catalysis†
Cite this: DOI: 10.1039/c9ob01792e
Received 14th August 2019,
Accepted 20th August 2019
Hongfang Li,a,b Tao Li,b Yu Jen Hsueh,b Xue Wu,*a Feng Xu*c and
b
DOI: 10.1039/c9ob01792e
Yong Jian Zhang
*
rsc.li/obc
An efficient method for the construction of arylated allylic ethers transformation remains challenging. In general, the trans-
was developed via three-component tandem arylation and allylic formation provides linear products as the major products
etherification of 2,3-allenol with aryl iodides and alcohols. In the (Scheme 1). There is only one example reported by Ma and
cooperative catalytic system of a palladium complex and triethyl- Zhao for the three-component reaction of 2,3-allenols, aryl
borane, the process allows rapid access to functionalized 1-aryl- iodides and amines to afford branched allyl amines with high
vinylated 1,2-diol derivatives in good to high yields with complete regioselectivities.5 Therefore, the development of a new cata-
branch-selectivities. The synthetic utility of the present process lytic system for the tandem three-component reaction to
was demonstrated by the late-stage functionalization of a drug provide branch-selective products is highly desired.
molecule, the gram-scale synthesis and the elaboration of the
Pd-Catalyzed allylic etherification is one of the most power-
ful methods for the formation of C–O bonds.6 However, alco-
hols generally attack the less hindered position of the
π-allylpalladium intermediates in this transformation. The
construction of allylic ethers with branch-selectivity via Pd-
catalyzed allylic etherification remains elusive.7 Most recently,
we presented a highly branch-selective allylic etherification of
vinylethylene carbonates (VECs) with alcohols.8 With coopera-
tive catalysis by the palladium complex and boron reagent, the
process allowed rapid access to tertiary ethers with complete
regioselectivity. Inspired by these results, we envisioned that
the tandem arylation and allylic etherification of 2,3-allenol9
with aryl iodides and alcohols could be achieved with branch
selectivity with a palladium complex and a boron reagent as a
cooperative catalytic system.10 We hypothesize that the Pd-cata-
lyzed arylation of 2,3-allenol with aryl iodide could provide ary-
lated allylpalladium intermediate A, which reacts with the
boron reagent to afford boronate intermediate B. The inter-
mediate B could capture alcohol to furnish the key intermedi-
ate C. This species would subsequently undergo nucleophilic
addition regioselectively to give the desired branched product.
The borate could be released for the next catalytic cycle8,11
(Scheme 2). Herein we report the realization of this idea and
products.
The Pd-catalyzed cross-coupling of aryl halides or alkenyl
halides with alkenes known as the Heck reaction is one of the
most powerful methods for the C–C bond formation.1 As an
expanding process, the cross-coupling of aryl halides with
allenes could produce aryl-substituted π-allylpalladium inter-
mediates, which allows subsequent allylic substitution with
nucleophiles (Scheme 1). In 1984, Tsuji and Shimizu reported
for the first time the Pd-catalyzed tandem arylation and allylic
amination of allenes to afford arylated allylic amines in high
yields.2 In contrast with Pd-catalyzed allylic substitution, this
transformation could dispense with the preinstallation of the
leaving group for the allylic donors, and could form two
chemical bonds in one-pot operation. In this context, various
nucleophiles have been applied for this three-component
transformation to provide complex compounds with diverse
functionalities.3,4 However, the regioselective control of the
aKey Laboratory for Organism Resources of the Changbai Mountain and Functional
Molecules, Ministry of Education, and Department of Chemistry, College of Science,
Yanbian University, 977 Gongyuan Road, Yanji, Jilin 133002, P. R. China.
E-mail: wuxue@ybu.edu.cn
bSchool of Chemistry and Chemical Engineering, and Shanghai Key Laboratory of
Electrical Insulation and Thermal Aging, Shanghai Jiao Tong32 University, 800
Dongchuan Road, Shanghai 200240, P. R. China. E-mail: yjian@sjtu.edu.cn
cShanghai Jiao Tong University Affiliated Sixth People’s Hospital South Campus,
6600 Nanfeng Hwy, Shanghai 201400, P. R. China. E-mail: xuf@smu.edu.cn
†Electronic supplementary information (ESI) available: Detailed experimental
procedures; characterization data of all of the new compounds; copies of 1H and
13C NMR spectra of the products. See DOI: 10.1039/c9ob01792e
Scheme 1 Pd-Catalyzed tandem arylation and allylic substitution of
allenes.
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when the reaction was carried out using different mono-phos-
phine ligands. When the reaction was carried out with biden-
tate phosphine ligands (for details, see the ESI†), we found
that the reaction with DPPF as the ligand proceeded smoothly
to afford allylic ether 4aa in 64% yield with complete regio-
selectivity (entry 4). Finally, we tried to further screen the reac-
tion solvent with DPPF as a ligand and K2CO3 as a base at
80 °C (entries 6–13). The reaction in THF showed the best
result, affording allylic ether 4aa in 75% yield with complete
regioselectivity (entry 8). As a control experiment, when the
reaction was carried out without BEt3, the desired allylic ether
4aa could not be obtained (entry 12). This result implied that
the boron reagent plays an important role not only in control-
ling the regioselectivity, but also in improving the nucleophili-
city of alcohols. The reaction with bromobenzene under other-
wise identical conditions also proceeded (entry 13), but the
yield decreased obviously. The asymmetric variant of the three-
component transformation was also examined by using chiral
ligands. However, only poor enantioselectivities were observed
by using various chiral phosphorus ligands (see the ESI†).
With the optimal conditions in hand (Table 1, entry 8),
the reaction scope was evaluated firstly by the reaction of
2,3-allenol 1 and iodobenzene (2a) with various alcohols
(Table 2). The reaction with benzyl alcohol with an electron-
donating group revealed better efficiency than that with an
electron-withdrawing group. The reactions with 1-naphthyl-
methyl alcohol and 2-furanylmethyl alcohol proceeded
smoothly to give the corresponding allylic ethers 4ad and 4ae
in good yields. Simple ethanol, cyclohexylmethyl alcohol and
2-phenylethyl alcohol were also suitable for the reaction to give
the corresponding allylic ethers 4af–4ah in moderate to good
yields. Significantly, various alkenyl moieties could be intro-
duced to give the corresponding allyl ethers 4ai–4al with good
efficiencies. In addition, various functional groups such as
keto-, cyano- and chloro-groups could also be installed under
the reaction conditions to afford the corresponding allylic
ethers 4am–4ao in moderate yields. Unfortunately, tandem ary-
lation and allylic hydroxylation with water did not occur under
the reaction conditions.
Scheme 2 Tandem arylation and regioselective allylic etherification of
2,3-allenol via Pd/B cooperative catalysis.
present the tandem arylation and regioselective allylic etherifi-
cation of 2,3-allenol with aryl iodides and alcohols in the coop-
erative catalytic system of a palladium complex and a boron
reagent, a practical and efficient approach which allows rapid
access to valuable 1-arylvinylated 1,2-diol derivatives in accep-
tably high yields with complete regioselectivities.
In the preliminary study, buta-2,3-dien-1-ol (1), iodo-
benzene (2a) and benzyl alcohol (3a) were chosen as standard
reaction partners (Table 1). We firstly carried out the reaction
in the presence of Pd2(dba)3·CHCl3 (2.5 mol%), triphenyl-
phosphine (10 mol%), BEt3 (5 mol%), and K2CO3 (2 equiv.) in
1,2-dichloroethane (DCE) at 80 °C for 12 h (Table 1). To our
delight, the reaction proceeded to give the desired allylic ether
4aa with complete regioselectivity, albeit the yield was moder-
ate (46%, entry 1). With these conditions in hand, we next
screened different ligands. The yield did not improve further
Table 1 Condition optimizationsa
Entry
Ligand
Solvent
Yieldb (%)
Next, the generality of the protocol was evaluated by the
reaction of 2,3-allenol 1 and 4-methoxylbenzyl alcohol (3b)
with different aryl iodides (Table 3). A variety of aryl iodides,
bearing groups with different electronic and steric properties
on the aryl group, were tolerated under the reaction conditions
to afford the corresponding arylated allylic ethers 4cb–4lb in
moderate to high yields with complete regioselectivities. The
aryl iodides with electron-donating groups showed better
efficiency than those with electron-withdrawing groups.
Unfortunately, the reaction conditions were not suitable for
the reaction with 2-iodotoluene. Both 1- and 2-naphthyl
groups could be installed to give the allylic ethers in good
yields. The iodides with heteroaromatic moieties were also
suitable substrates for the reaction, providing the corres-
ponding allylic ethers 4ob–4qb in good to high yields.
1
2
3
4
5
6
7
8
PPh3
PCy3
DCE
DCE
DCE
DCE
46
43
30
64
42
70
47
75
68
Trace
35
NR
38
DPPB
DPPF
BINAP
DPPF
DPPF
DPPF
DPPF
DPPF
DPPF
DPPF
DPPF
DCE
Benzene
Toluene
THF
MTBE
Dioxane
CH3CN
THF
9
10
11
12c
13d
THF
a Reaction conditions: Pd2(dba)3·CHCl3 (2.5 mol%), ligand (10 mol%
for mono-phosphines, 5 mol% for bidentate ligands), BEt3 (5 mol%),
base (0.4 mmol), 1 (0.2 mmol), 2a (0.24 mmol), 3a (0.24 mmol),
solvent (2.0 mL), at 80 °C for 12 h. b Yields are of isolated materials.
c The reaction was carried out without BEt3 under otherwise identical
conditions. d The reaction was carried out with bromobenzene instead
of iodobenzene. DCE = 1,2-dichloroethane; THF = tetrahydrofuran;
MTBE = methyl tert-butyl ether.
To demonstrate the synthetic utility of the present tandem
arylation and allylic etherification protocols, the late-stage
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Table 2 Tandem arylation and allylic etherification of 2,3-allenol 1 with
iodobenzene (2a) and different alcoholsa
Table 3 Tandem arylation and allylic etherification of 2,3-allenol 1 with
different aryl iodides 2 and 4-methoxylbenzyl alcohol (3b)a
a Reaction conditions: Pd2(dba)3·CHCl3 (2.5 mol%), DPPF (5 mol%),
BEt3 (5 mol%), K2CO3 (0.4 mmol), 1 (0.2 mmol), 2a (0.24 mmol), 3
(0.24 mmol), THF (2.0 mL), 12 h. Yields are of isolated materials.
a Reaction conditions: Pd2(dba)3·CHCl3 (2.5 mol%), DPPF (5 mol%),
BEt3 (5 mol%), K2CO3 (0.4 mmol), 1 (0.2 mmol), 2 (0.24 mmol), 3b
(0.24 mmol), THF (2.0 mL), 12 h. Yields are of isolated materials.
functionalization of a drug molecule (Scheme 3), the gram-
scale transformation and the elaboration of the products of
allylic ethers (Scheme 4) have been investigated. The late-stage
functionalization of perphenazine,12 an antipsychotic drug,
could be achieved by the three-component tandem reaction of
2,3-allenol 1, iodobenzene (2a) and perphenazine to afford
allylic ether 5 in 78% yield. The tandem reaction of 2,3-allenol
1 with iodobenzene (2a) and benzyl alcohol (3a) on a 7.0 mmol
scale under the optimal conditions proceeded smoothly to
afford allylic ether 4aa in 59% yield (1.05 g). The reduction of
4aa proceeded well in the presence of palladium hydroxide to
produce diol 6 in 92% yield, albeit poor diastereoselectivity
(4 : 5 dr) was observed. Dihydrofuran 7 could be obtained in a
high yield by the ring-closing metathesis of 4ai in the presence
of the Hoveyda-Grubbs’ II catalyst.
Scheme 3 Late-stage functionalization of perphenazine.
In conclusion, we have developed an efficient method for
the construction of arylated allylic ethers via three-component
tandem arylation and allylic etherification of 2,3-allenol with
aryl iodides and alcohols. In the cooperative catalytic system of
a palladium complex and triethylborane, the process allows
rapid access to functionalized 1-arylvinylated 1,2-diol deriva-
tives in good to high yields with complete branch-selectivities. Scheme 4 Gram-scale transformation and elaboration of allylic ethers.
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The synthetic utility of the present process was demonstrated
by the late-stage functionalization of a drug molecule, the
gram-scale synthesis and the elaboration of the products.
Further investigation of this three-component tandem aryla-
tion and regioselective allylic substitution with other nucleo-
philes is currently underway in our laboratory and will be
reported in due course.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21572130 and 21871179), the Innovation
Fund from the Joint Research Center for Precision Medicine
set up by Shanghai Jiao Tong University and Affiliated Sixth
People’s Hospital South Campus (IFPM2017B008). We thank
the Instrumental Analysis Center of Shanghai Jiao Tong
University for HRMS analysis.
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