Synthesis of Chiral 1,4-Benzodioxanes and Chromans by Enantioselective Palladium-Catalyzed Alkene Aryloxyarylation Reactions

Article abstract of DOI:10.1002/anie.201600379

A highly enantioselective alkene aryloxyarylation led to the high-yielding formation of a series of 1,4-benzodioxanes, 1,4-benzooxazines, and chromans containing quaternary stereocenters with excellent enantioselectivity. The sterically bulky and conformationally well defined chiral monophosphorus ligand L4 or L5 was responsible for the high reactivity and enantioselectivity of these transformations. The application of this method to the synthesis of the chiral chroman backbone of α-tocopherol was demonstrated. One P is plenty: A sterically bulky and conformationally well defined chiral monophosphorus ligand enabled the highly enantioselective synthesis of a series of Oheterocycles containing a quaternary stereocenter by alkene aryloxyarylation (see scheme; X=O, C, N). The application of this transformation to the synthesis of the chiral chroman backbone of α-tocopherol is demonstrated.

Full text of DOI:10.1002/anie.201600379

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International Edition: DOI: 10.1002/anie.201600379
German Edition: DOI: 10.1002/ange.201600379
Asymmetric Cyclization
Synthesis of Chiral 1,4-Benzodioxanes and Chromans by Enantio-
selective Palladium-Catalyzed Alkene Aryloxyarylation Reactions
Naifu Hu, Ke Li, Zheng Wang, and Wenjun Tang*
Abstract: A highly enantioselective alkene aryloxyarylation
led to the high-yielding formation of a series of 1,4-benzodiox-
anes, 1,4-benzooxazines, and chromans containing quaternary
stereocenters with excellent enantioselectivity. The sterically
bulky and conformationally well defined chiral monophos-
phorus ligand L4 or L5 was responsible for the high reactivity
and enantioselectivity of these transformations. The applica-
tion of this method to the synthesis of the chiral chroman
backbone of a-tocopherol was demonstrated.
significant attention over the years. In particular, several
excellent metal-catalyzed asymmetric transformations have
been developed, including an intramolecular Wacker-type
[10]
cyclization,[8] allylic substitution,[9] aryl C O coupling, and
À
[11]
À
allylic C H oxidation.
The palladium-catalyzed alkene
aryloxyarylation, involving the coupling of a phenol bearing
a pendant alkene with an aryl halide, offered facile access to
2-substituted chromans from readily available starting mate-
rials.[12–14] This alkene difunctionalization pioneered by Wolfe
and co-workers was best promoted by the use of a sterically
bulky monophosphorus ligand. However, in contrast to
several excellent examples of enantioselective alkene amino-
arylation and alkoxyarylation, an enantioselective variant of
alkene aryloxyarylation remains elusive.[15] We believed that
an asymmetric version of such transformation would not only
provide chiral chroman derivatives, but would also lead to the
formation of various chiral benzo-fused six-membered
oxygen heterocycles, such as 1,4-benzodioxanes and 1,4-
benzooxazines. Herein we report an enantioselective palla-
dium-catalyzed alkene aryloxyarylation that has led to
a series of chiral 1,4-benzodioxanes, chromans, and 1,4-
benzooxazines bearing quaternary stereocenters in excellent
yield with high enantioselectivity.
M
any bioactive natural products and drugs contain chiral
1,4-benzodioxane or chroman units (Scheme 1).[1] For exam-
ple, 1,4-benzodioxane lignans represented by silybin A[2] are
a group of natural products that exhibit a wide range of
interesting biological activities, such as hepatoprotective,
Over past several years, our research group has focused on
the development of efficient chiral monophosphorus ligands
for asymmetric catalysis. The success of those conformation-
ally well defined and sterically bulky P-stereogenic
Scheme 1. Natural products and drugs containing chiral 1,4-benzodiox-
ane and chroman moieties.
monophosphorus ligands based on
a dihydrobenzo[d]-
[1,3]oxaphosphole framework in various asymmetric
carbon–carbon bond-forming reactions[16] prompted us to
investigate the alkene aryloxyarylation between 2-((2-meth-
ylallyl)oxy)phenol (1a) and bromobenzene (2a). The reac-
tions were performed in toluene at 1108C under nitrogen for
18 h with NaOtBu as the base in the presence of [Pd2(dba)3]
(2 mol%) and a chiral ligand (4 mol%; Table 1, entries 1–8).
Previous studies by Wolfe and co-workers[14] on alkene
aryloxyarylation between aryl/alkenyl halides and 2-(but-3-
en-1-yl)phenols indicated the importance of a suitable mono-
phosphorus ligand for such reactions to proceed in high yield.
We were delighted that ligands L1–L5 were effective for the
formation of the desired 1,4-benzodioxane product 3aa.
Interestingly, the ligand structure played a significant role
on both reactivity and enantioselectivity.
The use of BI-DIME (L1) provided compound 3aa in low
yield with low enantioselectivity, and a major side product
was derived from an intermolecular Heck-type reaction
(Table 1, entry 1). Encouragingly, ligand L2 with a methyl
substituent at the 2-position effectively inhibited the forma-
tion of this side product and dramatically improved both the
yield (69%) and the enantioselectivity (45% ee; Table 1,
anticancer, and antioxidant activity. Doxazosin[3] is a selective
a1-adrenoceptor antagonist with a 1,4-benzodioxane moiety
that is used to treat high blood pressure and urinary retention
associated with benign prostatic hyperplasia. Englitazone[4] is
an antidiabetic agent with a chiral chroman structure. a-
Tocopherol[5] is the most significant member of the vitamin E
family, which features a key chroman ring containing
a quaternary stereocenter. The asymmetric synthesis of
chiral 1,4-benzodioxanes[6] and chromans[7] has thus gained
[*] N. Hu, K. Li, Prof. Dr. W. Tang
State Key Laboratory of Bio-organic and Natural Products Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Ling Ling Rd, Shanghai 200032 (China)
E-mail: tangwenjun@sioc.ac.cn
Dr. Z. Wang
Innovation Center China, AstraZeneca Global R&D (China)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201600379.
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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
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Scheme 3. Formation of the main side products SP1 and SP2 in the
synthesis of chroman 3 fa.
Scheme 2. Enantioselective palladium-catalyzed alkene aryloxyarylation
reactions. Unless otherwise specified, all reactions were performed at
608C under nitrogen for 18 h with 1 (0.2 mmol), 2 (0.4 mmol),
[Pd2(dba)3] (0.004 mmol, 2 mol%), L4 (0.008 mmol, 4 mol%), and
NaOtBu (0.4 mmol) in C6F6 (1 mL). Product ee values were determined
by HPLC on a chiral stationary phase. The absolute configuration of
3 fa was determined by comparing its optical rotation with reported
data,[4] and that of the other products was assigned by analogy.
[a] Product 3ab was isolated from a gram-scale reaction in 75% yield
with 91% ee. [b] A mixture of cis- and trans-b-bromostyrene was
employed (cis/trans 16:84). [c] L5 was used as the ligand, and
cyclohexane was used as the solvent. [d] L5 was used as the ligand,
and toluene was used as the solvent. The reactions were performed at
1108C. [e] Product 3ga was synthesized from the substrates 2-(2-
methylallyl)phenol (1g) and 2a.
Figure 1. Proposed catalytic cycle and stereochemical model.
oxopalladation[18] could give Pd complex IV. Reductive
elimination of complex IV forms the product 3aa and
regenerates the Pd0 species I to complete the catalytic cycle.
The stereochemical outcome is presumably determined at the
syn-oxopalladation step. DFT calculations[19] of the Pd species
III revealed two major conformers IIIA and IIIB for syn-
oxopalladation. The conformer IIIB is apparently sterically
congested between the phenyl group of the substrate 1a and
the tert-butyl group of L4, whereas in the energetically more
favorable conformer IIIA, 1a is coordinated away from the
tert-butyl group of L4, thus leading to the cyclization product
3aa with the observed configuration. The anthracenyl moiety,
the tert-butyl group, and the substituent at the 2-position of L4
all contribute to this well-defined stereochemical process.
of the chiral 1,4-benzodioxane 3aa is proposed in Figure 1.
Oxidative addition of the Pd0 species I by PhBr (2a) leads to
the formation of PdII complex II. With NaOtBu as the base,
ligand exchange between the bromide group and the substrate
1a takes place to form the Pd complex III, which could either
lead to the formation of Heck-type products, or a syn-
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structure[7] (Scheme 4). When compound 4[8c–e] was treated
with bromobenzene in the presence of a Pd–ent-L5 catalyst,
compound 5a was obtained with 60% ee in 65% yield.
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Scheme 4. Synthesis of the chiral chroman unit of a-tocopherol.
Similarly, the reaction between compound 4 and (E)-(2-
bromovinyl)benzene formed the desired product 5b with
53% ee in 60% yield. The conversion of 5b into a-tocopherol
should be possible through oxidative cleavage of the alkene to
afford the corresponding known aldehyde, which has pre-
viously been transformed into the natural product.[8c]
In summary, we have developed a highly enantioselective
alkene aryloxyarylation that has led to the formation of
a series of 1,4-benzodioxanes, a 1,4-benzooxazine, and chro-
mans containing quaternary stereocenters with high enantio-
selectivity in good yield. The chiral monophosphorus ligands
L4 and L5 were responsible for the excellent reactivity and
enantioselectivity of these transformations. The application of
this method to the synthesis of the chiral chroman core
structure of a-tocopherol was also demonstrated. The stereo-
chemical model gained from this study will certainly be
helpful for the design of better catalytic systems and the
further expansion of the scope and synthetic utility of this
transformation. Studies along these lines are ongoing.
Acknowledgements
We are grateful to the NSFC (21432007, 21272254, 21572246)
and the “Thousand Plan” Youth Program.
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Keywords: asymmetric catalysis · 1,4-benzodioxanes ·
1,4-benzooxazines · chromans ·
P-stereogenic phosphorus ligands
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[18] Related syn-oxopalladation or syn-aminopalladation steps have
been frequently documented; see Refs. [13a,15b,c] and: R. M.
Fornwald, J. A. Fritz, J. P. Wolfe, Chem. Eur. J. 2014, 20, 8782. An
anti-oxopalladation is less likely in this case.
[19] DFT calculations were performed with the Gaussian03 package,
and the geometries were optimized with UB3LYP and a standard
basis set of 3-21G for all atoms. Multiple conformational
searches resulted in only two major conformers, IIIA and IIIB,
suitable for syn-oxopalladation. Conformer IIIA is 10.12 kcal
molÀ1 lower in energy than conformer IIIB.
Received: January 13, 2016
Revised: February 3, 2016
Published online: March 15, 2016
5048 www.angewandte.org
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Angew. Chem. Int. Ed. 2016, 55, 5044 –5048