Angewandte
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Chemie
Table 1: Asymmetric alkene aryloxyarylation of 2-((2-methylallyl)oxy)-
phenol (1a) and bromobenzene (2a).
provided a diminished yield (72%; Table 1, entry 15), and no
formation of 3aa was observed when an organic base, such as
triethylamine or DABCO, was employed.
We then investigated the substrate scope of this enantio-
selective alkene aryloxyarylation. A series of 1,4-benzodiox-
anes 3ab–al containing a quaternary stereocenter were
formed in good yield with high enantioselectivity
(Scheme 2). Various para-, meta-, and ortho-substituted aryl
bromides (substrates 2a–g) were applicable, and the corre-
sponding chiral 1,4-benzodioxanes were obtained in 78–83%
yield with 84–95% ee. The use of alkenyl bromide 2h also
provided the desired cyclization product 3ah with 89% ee,
albeit in low yield (25%). Both 1- and 2-naphthyl bromide
could also be employed to form 3ai and 3aj, respectively.
Heteroaryl bromides, such as 2k and 2l, were fully tolerated
and converted into the corresponding 1,4-benzodioxanes 3ak
and 3al containing heterocyclic moieties in high yield with
excellent enantioselectivity. The substituent at the quaternary
stereocenter was not limited to a methyl group; a 1,4-
benzodioxane 3ba with an ethyl substituent at the stereocen-
ter was also formed with 94% ee in 70% yield. Besides 1,4-
benzodioxanes, a 1,4-benzooxazine product 3ca was also
formed with 92% ee in 60% yield. A chroman product 3da
with a quaternary stereocenter was synthesized with 82% ee
in 80% yield, and a related chroman product 3ea with
a phenyl substituent at the stereocenter was prepared with
good enantioselectivity (81% ee), albeit in low yield (20%).
The key chiral chroman structure of englitazone,[4] 3 fa, was
successfully prepared in 88% ee, although a relatively low
yield (35%) was observed. A reaction of 2-allylphenol (1g)
provided the benzofuran compound 3ga in 60% yield with
15% ee, thus indicating that the chiral palladium catalyst was
more selective for the preparation of benzo-fused six-
Entry[a] L*
Solvent Base
T
Yield ee
[8C] [%][b] [%][c]
1
2
L1
L2
toluene NaOtBu 110 22
12
45
50
77
60
–
toluene NaOtBu 110 69
toluene NaOtBu 110 56
toluene NaOtBu 110 88
toluene NaOtBu 110 90
toluene NaOtBu 110
toluene NaOtBu 110
3
L3
4
L4
5
L5
6
7
(S)-MonoPhos
(S)-BINAP
–
–
–
–
–
8
(S,S)-Me-Duphos toluene NaOtBu 110
9
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
dioxane NaOtBu 110 60
75
77
25
80
86
93
92
92
–
10
11
12
13
14
15
16
17
18
CPME
DMF
c-C6H12
C6F6
NaOtBu 110 45
NaOtBu 110 10
NaOtBu 110 82
NaOtBu 110 88
C6F6
C6F6
C6F6
C6F6
NaOtBu
K2CO3
NaOH
TEA
60 88
60 72
60 83
60
60
–
–
C6F6
DABCO
–
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), [Pd2(dba)3]
(0.004 mmol, 2 mol%), ligand (0.008 mmol, 4 mol%), base (0.4 mmol),
solvent (1 mL), nitrogen atmosphere, 18 h. The absolute configuration of
the products was assigned by analogy according to the absolute
configuration of 3 fa and 5b. [b] Yields of the isolated product. [c] The
ee value was determined by HPLC on a Chiralcel OJ-H column.
CPME=cyclopentyl methyl ether, DABCO=1,4-diazabicyclo[2.2.2]-
octane, dba=dibenzylideneacetone, DMF=N,N-dimethylformamide,
TEA=triethylamine.
membered oxygen heterocycles.
A gram-scale reaction
between 1a and 4-bromo-1,1’-biphenyl (2b) was conducted,
and the desired cyclization product 3ab was isolated in 75%
yield with 91% ee, thus demonstrating the practicality of this
method.
The high enantioselectivities and yields observed in the
formation of 1,4-benzodioxanes, a 1,4-benzooxazine, and
chromans prompted us to investigate the reaction mechanism.
The reaction between 2-((2-methylallyl)oxy)phenol (1a) and
bromobenzene (2a) with a scalemic composition of L4
showed a good linear relationship of the ee values of the
ligand and product 3aa, thus indicating that this transforma-
tion is catalyzed by a palladium catalyst with a single chiral
monophosphorus ligand L4. Further analysis of the reaction
between 2-(but-3-en-1-yl)phenol (1 f) and bromobenzene
(2a) revealed the formation of 3 fa as well as two main side
products SP1 and SP2 (Scheme 3). Presumably, the reaction
proceeded via a Heck intermediate INT, followed by two
more Heck processes to form SP1 or an alkene aryloxyar-
ylation to form SP2. Thus, it was reasonable that an improved
yield was observed for the synthesis of 3da bearing a quater-
nary stereocenter, in which case the Heck process was
inhibited effectively owing to the more hindered nature of
its 1,1-disubstituted olefin moiety.
entry 2). The low aryl structure of the monophosphorus
ligand was also influential. AntPhos (L3) provided the
product in much higher yield and enantioselectivity than BI-
DIME (Table 1, entry 3). In particular, both L4 and L5 with
substituents at the 2-position provided 3aa in excellent yield
(88 and 90%; Table 1, entries 4 and 5). Good enantioselec-
tivity (77% ee) was observed with L4 (Table 1, entry 4). For
comparison, some commercially available chiral mono- or
diphosphines, such as monophos, BINAP, and Me-Duphos,
were ineffective, thus demonstrating the importance of
a sterically bulky monophosphorus ligand in this transforma-
tion (Table 1, entries 6–8). We thus chose L4 as the ligand for
further optimization. Screening of the solvent (Table 1,
entries 9–13) showed that hexafluorobenzene with an
inverted quadrupole moment further enhanced the enantio-
selectivity to 86% ee (Table 1, entry 13). We found that the
reaction took place even at 608C to give the desired product
3aa in 88% yield with 93% ee (Table 1, entry 14). A strong
base was required for this reaction: Potassium carbonate
On the basis of the studies by Wolfe and co-workers[17] as
well as our own observation, a catalytic cycle for the synthesis
Angew. Chem. Int. Ed. 2016, 55, 5044 –5048
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5045