Pd(II)-catalyzed asymmetric Wacker-type cyclization for the preparation of 2-vinylchroman derivatives with biphenyl tetraoxazoline ligands

Article abstract of DOI:10.1016/j.tet.2012.03.077

This article describes an efficient method for the preparation of chiral chroman derivatives by the Pd(II)-catalyzed asymmetric Wacker-type cyclization using a chelation-induced axially chiral tetraoxazoline ligand. Under the optimized conditions, up to 80% yield and up to 92% ee were obtained. This is the first example to utilize o-trisubstituted 3-butenylphenols as substrates in such transformation.

Full text of DOI:10.1016/j.tet.2012.03.077

Tetrahedron 68 (2012) 5209e5215
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Pd(II)-catalyzed asymmetric Wacker-type cyclization for the preparation
of 2-vinylchroman derivatives with biphenyl tetraoxazoline ligands
*
Qingchuan Liu, Ke Wen, Zhenfeng Zhang, Zhengxing Wu, Yong Jian Zhang, Wanbin Zhang
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
This article describes an efficient method for the preparation of chiral chroman derivatives by the Pd(II)-
catalyzed asymmetric Wacker-type cyclization using a chelation-induced axially chiral tetraoxazoline
ligand. Under the optimized conditions, up to 80% yield and up to 92% ee were obtained. This is the first
example to utilize o-trisubstituted 3-butenylphenols as substrates in such transformation.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 11 January 2012
Received in revised form 10 March 2012
Accepted 20 March 2012
Available online 28 March 2012
Keywords:
Chroman
Wacker-type cyclization
Palladium
Oxazoline ligand
Axial chirality
1. Introduction
excellent enantioselectivities (Scheme 1).7n In contrast to tradi-
tional axially chiral molecules, there is no axial chirality present in
In recent years, chiral chroman derivatives have attracted much
attention for their broad range of biological activities.1 For example,
siccanin has potent antifungal activity2 and rhododaurichromanic
acid A has effective activity as an anti-HIV agent.3 Vitamin E is
prevalent in nature as an antioxidant,4 nebivolol is widely used as
an anti-hypertensive agent,5 and conocurvone exhibits anti-HIV
activity via the prevention of cytopathic effects and replication of
HIV in human T-lymphoblastic cells.6
However, compared with extensive synthetic investigation,
which have been performed on structurally similar dihy-
drobenzofuran derivativies,7 only several syntheses concerning the
construction of dihydrobenzopyran (chroman) derivatives have
been reported.8e10 Very few of these reports concern catalytic
asymmetric syntheses involving allylic substitution1,9 and Wacker-
type cyclization.4e,10
We are interested in the development of Pd(II)-catalyzed
Wacker-type oxidative cyclization for the preparation of important
natural products and useful pharmaceutical intermediates in-
cluding oxygen-7neq and nitrogen-containing11 heterocycles. Re-
cently we developed an efficient catalytic asymmetric Wacker-type
cyclization using biphenyl tetraoxazoline ligands L. Several chiral
dihydrobenzofuran derivatives were prepared in good yields and
these ligands L because of their molecular symmetry. Yet, while the
biphenyl ligands chelated with one or two metal ions, only one of
the two diastereomers was produced. It is noteworthy that this
untraditional chelation-induced axially chiral complex system
could be applied to diverse range of substrates. Both o-tri-
substituted and o-tetrasubstituted allylphenols could be converted
to related products with excellent enantioselectivities. Encouraged
by these results, we applied this chelation-induced axially chiral
complex system to the asymmetric synthesis of chiral chroman
derivatives. There are currently only a few examples involving the
catalytic asymmetric synthesis of chiral chroman derivatives via
Wacker-type
cyclization
using
o-tetrasubstituted
3-
butenylphenols,10a o-disubstituted 3-butenylphenols,4e and o-
allylphenols10b as substrates. Herein we report the use of a new
type of o-trisubstituted 3-butenylphenol substrate for the prepa-
ration of 2-vinylchroman derivatives.
* Corresponding author. Tel./fax: þ86 021 54743265; e-mail address: wanbin@
Scheme 1. Wacker-type cyclization of o-allylphenols.
sjtu.edu.cn (W. Zhang).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.077

5210
Q. Liu et al. / Tetrahedron 68 (2012) 5209e5215
Table 2
2. Results and discussion
Condition optimization for the ring closure of oxazoline
Tempa
Catalystb
Time (d)
Yieldc (%)
2.1. Synthesis of ligands
Entry
R
1
2
3
4
5
6
7
Ph
Ph
rt
/
/
/
/
5
1
1
1
1
1
1
15
47
45
39
63
61
57
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Due to their molecular symmetry, we envisaged that the ligands
L could be synthesized readily following a reported procedure
(Scheme 2).7n The synthetic sequence involves oxidation of pyrene
to 2,20,6,60-tetracarboxy-1,10-biphenyl by NaIO4/RuCl312; followed
by oxazoline ring closure using a known process to afford the li-
gands L.13 However, this reported method provides unsatisfactory
yields of the desired product limiting the wide application of these
ligands.
i-Pr
t-Bu
Ph
i-Pr
t-Bu
DMAP
DMAP
DMAP
a
The temperature of step 2.3.
DMAP (25 mol %) was added in step 2.2.
Isolated yield.
b
c
Scheme 2. Synthesis of ligands L.
In order to improve the synthesis, we optimized the preparation
of ligands L. We were unable to obtain the high yields reported for
the oxidation of pyrene using the above conditions therefore we
studied the effect of catalyst, solvent, and temperature on this ox-
idation step (Table 1). Hydrated RuCl3 was used in the reaction as
the catalyst but it failed to provide an obvious increase in yield
compared to when using RuCl3 (entry 2 vs 1). Different mixed
solvent systems were also examined (entry 1, 3, 4). CCl4/MeCN/H2O
increased yields when compared to other mixed solvents (entry 4).
Temperature also plays an important role in the oxidation reaction.
When the reaction temperature was increased from 40 ꢀC to 60 ꢀC,
the yield markedly improved from 52% to 71% (entry 5 vs 4),
however continual elevation of the temperature resulted in re-
duced yield because of purification issues (entry 6). In the second
step (one-pot process) we explored the effect of the temperature
and catalyst on the reaction to give ligands L from 2,20,6,60-tetra-
carboxy-1,10-biphenyl (Table 2). Throughout our investigation we
found that increasing the temperature of step 2.3 (Scheme 2) to
reflux greatly reduced the reaction time and improved the yield of
the product (entries 1, 2). The addition of a catalytic amount of
DMAP to steps 2.2 and 2.3 also improved the reaction yield (entries
5e7 vs 2e4). Finally, we prepared the ligands L with different
substituents of Ph, i-Pr, and t-Bu in yields of 63%, 61%, and 57%,
respectively.
Scheme 3. Reagents and conditions: (1) (CH2O)n, anhydrous MgCl2, triethylamine,
MeCN, reflux; (2) acetone, NaOH aqueous solution, rt; (3) H2 (1 atm), Pd/C, ethyl
acetate, rt; (4) ethyltriphenylphosphonium bromide, t-BuOK, toluene, rt.
8 h. Following purification, intermediate 4 was obtained.14 1 mol/L
NaOH aqueous solution was added slowly to a solution of 4 in ac-
etone at room temperature and the solution was stirred overnight.
After treatment with
1 mol/L hydrochloric acid and re-
crystallization, a colorless solid 5 was obtained. Hydrogenation of 5
with 5% Pd/C in ethyl acetate for 6 h gave a pale yellow oil 6. To
a solution of ethyltriphenylphosphonium bromide in toluene was
added t-BuOK at 0 ꢀC. After stirring for 2 h at room temperature,
a solution of 6 in toluene was slowly added to the solution men-
tioned above at 0 ꢀC. Following stirring of the mixture overnight at
room temperature and subsequent purification, substrate 1 was
obtained. This method allowed for the preparation of a diverse
range of substrates using readily available phenols bearing different
substituents.
2.3. Asymmetric catalytic Wacker-type cyclization
In order to test the catalytic activity and enantioselectivity of
this chelation-induced axially chiral Pd(II) complex in Wacker-type
cyclization using the o-trisubstituted 3-butenylphenol substrates,
substrate 1a lacking any substituents on the phenyl group was
selected as the model substrate (Table 3). The reaction was cata-
lyzed by 20 mol % Pd(II)eL complex generated in situ by mixing
Pd(OAc)2 with the tetraoxazoline ligand L (1:1 molar ratio), in the
presence of 4 equiv of p-benzoquinone in methanol at 60 ꢀC for
1 day. As shown in Table 3, the catalytic efficiency was largely de-
pendent on the substituents on the oxazoline rings. The ligand with
phenyl-substituted tetraoxazoline L1 showed remarkably higher
catalytic activity and enantioselectivity compared with ligands L2
and L3. No reaction occurred with the t-Bu-substituted tetraox-
azoline ligand L3.
Table 1
Condition optimization for the oxidization of pyrenea
Entry
Catalyst
Solvent
Temp (ꢀC)
Yieldb (%)
1
2
3
4
5
6
RuCl3
RuCl3$3H2O
RuCl3
RuCl3
RuCl3
CH2Cl2/MeCN/H2O
CH2Cl2/MeCN/H2O
EtOAc/MeCN/H2O
CCl4/MeCN/H2O
CCl4/MeCN/H2O
CCl4/MeCN/H2O
40
40
40
40
60
Reflux
25
27
23
52
71
61
RuCl3
a
The reactions were catalyzed by 4 mol % Ru(III) in the presence of 9.3 equiv of
NaIO4 using a mixed solvent in the ratio of 3/3/5.
b
Isolated yield.
We subsequently carried out optimizations on the Wacker-type
cyclization reaction of 1a with ligand L1 (Table 4). We discovered
that the types of anions and solvents used played an important role
in the catalyst system. The Pd(II) complexes formed from Pd(OAc)2
and Pd(OCOCF3)2 exhibit similar catalytic efficiencies (entries 1, 2).
However, the yield decreases sharply with the Pd(II) complexes
bearing bromide anions (entry 3). The Pd(OCOCF3)2/L catalytic
2.2. Synthesis of substrates
With the ligands L in hand, we prepared a series of unreported
o-trisubstituted 3-butenylphenols substrates for the Wacker-type
cyclization (Scheme 3). To a solution of phenol 3, anhydrous
MgCl2, and paraformaldehyde in MeCN was added triethylamine
and the reaction mixture was heated under reflux conditions for
ꢀ
system (2:1 Pd/L) failed to give better results (entry 4). 4 A

Q. Liu et al. / Tetrahedron 68 (2012) 5209e5215
5211
Table 3
both acetone and acetonitrile were found to be efficient solvents in
consideration of their effect on yield and enantioselectivity (entries
9, 10). Good enantioselectivity was obtained when using DMF,
however the yield was low (entry 11). Ethanol, toluene, THF, and
DCM were also examined but no ideal results were obtained (en-
tries 12e15).
Wacker-type cyclization reaction of 1a with different ligandsa
With the optimized reaction conditions in hand, we applied this
methodology to a series of o-trisubstituted 3-butenylphenols
mentioned above. The corresponding chiral chroman derivatives
were obtained as expected (Table 5). As shown in Table 5, good
catalytic activity and enantioselectivities were achieved regardless
of the steric or electronic properties of the phenyl group on the
substrates. For substrate 1a lacking any substituent groups on the
phenyl ring, 87% ee was obtained (entry 1). The pure olefin isomers
were obtained using preparative HPLC with chiral OD columns and
the configuration of each product was confirmed via two di-
mensional NMR (NOESY). Compound 1a was used as a representa-
tive molecule to explore the effect of Z and E olefins on the outcome
of the reaction. Up to 92% ee was obtained with the E olefin (entry
2). As these kinds of substrates are a mixture of olefin isomers and
are difficult to separate, the other compounds (1beh) were studied
using the E/Z mixtures in their respective ratios. For the substrates
in the order of 1b, 1c, and 1d with methyl substituents at a different
position of the phenyl group, the enantioselectivities increased
while the yields decreased (entries 4e6). More sterically hindered
i-Pr substituted substrate 1e afforded comparable results (entry 7).
For substrates with a 4-OMe and 4-Ph group on the phenyl ring (1f
and 1g, respectively) only moderate ee values were obtained (en-
tries 8, 9). The substrate 1h with a 4-Cl substituent also provided
good enantioselectivity of 87% ee (entry 10).
Entry
Ligand
Time (d)
Yield (%)
ee (%)b
1
2
3
L1
L2
L3
1
1
1
67
35
/
85
32
/
a
The reactions were catalyzed by 20 mol % Pd(II)eL complex generated in situ by
mixing Pd(OAc)2 with tetraoxazoline L (1:1 molar ratio) in the presence of 4 equiv of
p-benzoquinone in methanol at 60 ꢀC for 1 day. The substrate 1a was a 1.8:1 mixture
of olefin isomers. The absolute configuration of 2a was confirmed according to
specific rotation compared to relative Ref. 9a.
b
Determined by the HPLC using chiral OD-H column.
Table 4
Condition optimization of the Wacker-type cyclization reaction of 1a with ligand L1a
Entry
Pd(II)
Solvent
Yield (%)
ee (%)b
1
2
3
Pd(OAc)2
Pd(OCOCF3)2
PdBr2
Methanol
Methanol
Methanol
Methanol
Methanol
Methanol
Methanol
Methanol
Acetone
Acetonitrile
DMF
67
69
30
40
89
85
Trace
/
58
61
32
42
28
10
/
85
87
73
83
73
20
/
4c
5d
6e
7f
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Table 5
Substrate scopea,b
8g
9
/
87
73
81
49
25
3
10
11
12
13
14
15
Ethanol
Toluene
THF
Entry
Substrate
The ratio (Z/E)
Yield (%)
ee (%)
DCM
/
1
2
3
4
5
6
7
8
9
1a (R¼H)
1.8:1
E
Z
3.3:1
4.4:1
3.1:1
2.3:1
4.7:1
1.7:1
1.9:1
69
68
70
80
73
72
75
68
75
65
87
92
84
75
80
85
84
61
70
87
a
The reactions were catalyzed by 20% Pd(II)eL1 complex generated in situ by
mixing Pd(II) with tetraoxazoline L1 (1:1 molar ratio) in the presence of 4 equiv of p-
benzoquinone at 60 ꢀC for 1 day. The substrate 1a was a 1.8:1 mixture of olefin
isomers. The absolute configuration of 2a was confirmed according to specific ro-
tation compared to relative Ref. 9a.
1a (R¼H)
1a (R¼H)
1b (R¼4-Me)
1c(R¼5-Me)
1d (R¼6-Me)
1e (R¼4-i-Pr)
1f (R¼4-OMe)
1g (R¼4-Ph)
1h (R¼4-Cl)
b
Determined by the HPLC using chiral OD-H column.
c
Pd(OCOCF3)2/L1¼2/1.
d
ꢀ
Molecular sieves (4 A) were added.
e
The oxidant is O2.
10
f
The temperature of the reaction is 50 ꢀC for 2 day.
a
g
The temperature of the reaction is 40 ꢀC for 2 day.
The reactions were catalyzed by 20 mol % Pd(OCOCF3)2eL1 complex generated
in situ by mixing Pd(OCOCF3)2 with tetraoxazoline L1 (1:1 molar ratio) in the
presence of 4 equiv of p-benzoquinone in methanol at 60 ꢀC for 1 day. The substrates
were mixtures of olefin isomers. The absolute configuration of the 2beh was de-
duced by similarity to 2a.
b
molecular sieves were also used. Interestingly, although the ee
value decreased, an improvement in yield was observed (entry 5).
When oxygen was applied to the reaction as an oxidant in place of
p-benzoquinone, significantly lower enantioselectivity was ob-
served (entry 6). The effect of temperature on the reaction was also
examined (entries 2, 7, 8). In consideration of the decomposition of
the p-benzoquinone at high temperatures, the temperature of the
reaction was not raised above 60 ꢀC. When the reaction tempera-
ture was reduced to 50 ꢀC, the reaction became sluggish and only
trace amounts of product were obtained. When the reaction tem-
perature was decreased to 40 ꢀC no reaction occurred.
Determined by the HPLC using chiral OD-H column.
A plausible mechanism for the asymmetric reaction is shown in
Scheme 4.7aeg,l First, Pd(OCOCF3)2 and the ligand form the Pd(II)
catalyst A. The substrate then reacts with A to form the six-
membered Pd(II) intermediate B. Subsequently, the product and
Pd(II) hydride species C were obtained from B. In the presence of p-
benzoquinone, Pd(0) intermediate D was obtained. In this step, p-
benzoquinone promotes reductive elimination from the Pd(II) hy-
dride species C,15 and the coordination of the resulting Pd(0) to p-
benzoquinone enhances the stability of the Pd(0) species to avoid
its precipitation.15e,g Finally, the Pd(II) catalyst A is regenerated
with p-benzoquinone as the terminal oxidant.
The effect of solvent on the oxidative cyclization reaction was
also examined (Table 4, entries 9e15). Compared with methanol,

5212
Q. Liu et al. / Tetrahedron 68 (2012) 5209e5215
To a solution of 2,20,6,60-tetracarboxy-1,10-biphenyl (3.5 g,
10.6 mmol) and DMF (2 drops) in CH2Cl2 (50 ml) was added another
solution of SOCl2 (16 ml, 0.22 mol) in CH2Cl2 (30 ml) at 0 ꢀC. After
stirring for 3 h at room temperature, the reaction mixture was
heated under reflux conditions for 8 h. After removal of the solvent
and excess SOCl2, the residue was dissolved in CH2Cl2 (40 ml). The
mixture was added to a solution of 2-amino-2-phenylethanol
(6.5 g, 47.6 mmol), DMAP (305 mg, 2.5 mmol), and triethylamine
(8.0 ml, 60.4 mmol) in CH2Cl2 (50 ml). After stirring the mixture for
20 h at room temperature, additional triethylamine (17.5 ml,
132.1 mmol) and MsCl (4.1 ml, 52.5 mmol) were added to the
mixture at 0 ꢀC, and the reaction mixture was heated under reflux
conditions overnight (w18 h). The mixture was diluted with
CH2Cl2, washed with brine, and dried over Na2SO4. After removal of
the solvent, the residue was purified by flash column chromatog-
raphy to give the yellowish ligand L1 (4.9 g, 63% yield). 1H NMR
(400 MHz, CDCl3):
d
8.09 (d, J¼8.0 Hz, 4H), 7.47 (d, J¼8.0 Hz, 2H),
7.27e7.21 (m, 12H), 7.11 (dd, J¼1.6, 8.0 Hz, 8H), 5.18 (dd, J¼8.4,
10.4 Hz, 4H), 4.40 (dd, J¼8.4, 10.4 Hz, 4H), 3.91 (t, J¼8.4 Hz, 4H).
4.2.1.2. 2,20,6,60-Tetra[(40S)-isopropyloxazolin-20-yl]-1,10-biphenyl
(L2). Compound L2 was prepared from 2,20,6,60-tetracarboxy-1,10-
biphenyl using a similar procedure to that of L1 (3.9 g, 61% yield). 1H
Scheme 4. Possible mechanism for the Pd(II)-catalyzed Wacker-type cyclization.
3. Conclusion
NMR (400 MHz, CDCl3):
d
7.89 (d, J¼8.0 Hz, 4H), 7.34 (d, J¼7.6 Hz,
2H), 3.98 (t, J¼7.6 Hz, 4H), 3.76 (dd, J¼8.0, 14.8 Hz, 4H), 3.70 (dd,
J¼8.0, 15.6 Hz, 4H), 1.52e1.60 (m, 4H), 0.76 (d, J¼6.8 Hz, 12H), 0.73
(d, J¼6.4 Hz, 12H).
In summary, we have applied our chelation-induced axially
chiral palladium complex system to construct chiral chroman de-
rivatives. The reaction result is dependent on the Pd(II) salt, re-
action temperature, solvent, substituent groups, and especially the
ligand. Under the optimized conditions, good catalytic activity and
enantioselectivities were achieved, regardless of the steric or
electronic properties of the phenyl group on the substrates. Both (E)
and (Z) isomers of these kinds of substrates afforded high enan-
tioselectivities, especially for (E) isomers, with enantioselectivity of
up to 92% ee being obtained.
4.2.1.3. 2,20,6,60-Tetra[(40S)-tert-butyloxazolin-20-yl]-1,10-biphenyl
(L3). Compound L3 was prepared from 2,20,6,60-tetracarboxy-1,10-
biphenyl using a similar procedure to that of L1 (4.0 g, 57% yield). 1H
NMR (400 MHz, CDCl3):
2H), 3.92 (dd, J¼12.0, 13.2 Hz, 4H), 3.74e3.68 (m, 8H), 0.67 (s, 36H).
d
7.92 (d, J¼8.0 Hz, 4H), 7.31 (d, J¼8.0 Hz,
4.2.2. Preparation of the substrates 1.
4.2.2.1. 2-[(3-Methyl)-3-pentenyl]phenol (1a). NaOH (1 mol/L)
aqueous solution (60 ml, 60 mmol) was added slowly to a solution
of 4a (6 ml, 57.5 mmol) in acetone (40 ml) and the mixture was
stirred at room temperature for 14 h. 1 mol/L hydrochloric acid
(80 ml, 80 mmol) was added and the solution was filtered. The
filtration residue was recrystallized from petroleum ether/ethyl
acetate to give the white intermediate 5a (7.4 g, 79% yield). Hy-
drogenation of 5a with a hydrogen balloon using 5% Pd/C (1.4 g) in
ethyl acetate (80 ml) for 6 h followed by filtration and purification
by flash column chromatography, gave a pale yellow oil 6a (7.3 g,
97% yield). To a solution of ethyltriphenylphosphonium bromide
(37.4 g, 0.1 mol) in toluene (100 ml), t-BuOK (11.3 g, 0.1 mol) was
added at 0 ꢀC. After stirring for 2 h at room temperature, a solution
of 6a in toluene (20 ml) was slowly added to the red solution
mentioned above at 0 ꢀC. The mixture was stirred overnight at room
temperature, and quenched by the addition of saturated NH4Cl so-
lution. The mixture was extracted with Et2O and the combined or-
ganic layers were washed with brine and dried over Na2SO4. After
removal of the solvent, the residue was purified by flash column
chromatography to give the substrate 1a8c (5.3 g, 68% yield). 1H NMR
(data for 1.8:1 mixture of olefin isomers based on the relative in-
4. Experimental section
4.1. General
All air- and moisture-sensitive manipulations were carried out
with standard Schlenk techniques under nitrogen. Methanol, eth-
anol, acetone, MeCN, DMF, THF, toluene, and dichloromethane were
dried according to published procedures. The commercially avail-
able reagents were used without further purification. TLC was run
on 2ꢁ5 cm silica plate. Column chromatography was run on silica
gel (200e300 mesh). 1H NMR (400 MHz) spectra and 13C NMR
(100 MHz) spectra were obtained on a Varian MERCURY plus-400
spectrometer. HRMS was performed on a Micromass LCT TM at
the Instrumental Analysis Center of Shanghai Jiao Tong University.
4.2. Procedures and analytical data
4.2.1. Preparation of the ligands L.
4.2.1.1. 2,20,6,60-Tetra[(40S)-phenyloxazolin-20-yl]-1,10-biphenyl
(L1). To a solution of pyrene (3.0 g, 0.015 mol) in MeCN (60 ml), CCl4
(60 ml), and water (100 ml) was added NaIO4 (30 g, 0.14 mol) and
anhydrous RuCl3 (0.12 g, 0.0006 mol). After stirring for 0.5 h, the
reaction mixture was heated to 60 ꢀC overnight (w18 h). Solvent was
evaporated under reduced pressure and the residue was washed
with water (30 ml) and CH2Cl2 (30 ml) to give a white solid. Acetone
(30 ml) was added and the mixture was filtered. The acetone was
evaporated under reduced pressure and the resulting yellow residue
was dissolved in MeOH. CH2Cl2 was added to precipitate a white
solid, which was filtered to give the product 2,20,6,60-tetracarboxy-
1,10-biphenyl as a colorless solid (3.5 g, 86% yield).
tegration of peaks at
d 1.93 and 1.85; 400 MHz, CDCl3): d 7.36e7.19
(m, 2H), 7.36e7.19 (m, 2H), 7.08e7.02 (m, 1H), 7.08e7.02 (m, 1H),
6.90 (d, J¼8.1 Hz, 1H), 6.90 (d, J¼8.1 Hz, 1H), 5.57 (m, 1H), 5.55 (m,
1H), 5.52e5.43 (m, 1H), 5.52e5.43 (m, 1H), 2.95e2.88 (m, 2H),
2.95e2.88 (m, 2H), 2.59e2.55 (m, 2H), 2.55e2.51 (m, 2H), 1.94e1.92
(m, 3H), 1.86e1.84 (m, 3H), 1.73e1.69 (m, 3H), 1.68e1.63 (m, 3H).
We confirmed the configuration of each isomer of 1a (ratio of
1.8:1) according to two dimensional NMR (NOESY) (Scheme 5).
From Scheme 5, we can find that the minor isomer shows HeH
interactions between the alkenyl H (
d
¼5.52e5.43) and the allyl H

Q. Liu et al. / Tetrahedron 68 (2012) 5209e5215
5213
(
d
¼2.55e2.51), while the major isomer lacks these interactions. The
Pd/C (500 mg) for 6 h and filtration by kieselguhr gave a pale yellow
oil 6b. To a solution of ethyltriphenylphosphonium bromide (14.5 g,
38.9 mmol) in toluene (60 ml), t-BuOK (4.4 g, 38.9 mmol) was
added at 0 ꢀC. The mixture was stirred for 2 h at room temperature
and a solution of 6b in toluene (10 ml) was slowly added to the
blood red solution mentioned above at 0 ꢀC. The mixture was
stirred overnight at room temperature, then quenched by the ad-
dition of saturated NH4Cl solution. The mixture was extracted with
Et2O and the combined organic layers were washed with brine and
dried over Na2SO4. After removal of the solvent, the residue was
purified by flash column chromatography to give the substrate
1b (1.8 g, 45% yield). 1H NMR (data for 3.3:1 mixture of olefin
minor isomer is therefore E configuration and the major one is Z
configuration.
isomers based on the relative integration of peaks at
d 1.76 and
1.70; 400 MHz, CDCl3): 7.00e6.86 (m, 2H), 7.00e6.86 (m, 2H),
d
6.70e6.65 (m,1H), 6.70e6.65 (m,1H), 5.34e5.25 (m,1H), 5.34e5.25
(m, 1H), 5.00e4.59 (m, 1H), 5.00e4.59 (m, 1H), 2.71e2.56 (m, 2H),
2.71e2.56 (m, 2H), 2.39e2.24 (m, 2H), 2.39e2.24 (m, 2H), 2.28 (s,
3H), 2.28 (s, 3H),1.80e1.74 (m, 3H),1.72e1.68 (m, 3H),1.62e1.51 (m,
3H), 1.62e1.51 (m, 3H); 13C NMR (100 MHz, CDCl3):
d 151.5, 136.1,
131.1, 131.0, 130.2, 127.8, 127.7, 127.6, 120.2, 119.2, 115.4, 115.2, 40.2,
32.2, 29.4, 28.9, 23.9, 20.8, 16.2, 13.7, 13.4; HRMS (ESI) calcd for
C13H17O [MꢂH]ꢂ: 189.1279, found 189.1274.
4.2.2.3. 5-Methyl-2-[(3-methyl)-3-pentenyl]phenol
(1c). Compound 1c was prepared from 3c by a similar procedure
with 1b (1.60 g, overall 35% yield). 1H NMR (data for 4.4:1 mixture
of olefin isomers based on the relative integration of peaks at
d 1.58
and 1.51; 400 MHz, CDCl3): 7.02e6.94 (m, 1H), 7.02e6.94 (m, 1H),
d
6.71e6.63 (m, 1H), 6.71e6.63 (m, 1H), 6.59 (s, 1H), 6.59 (s, 1H),
5.31e5.22 (m, 1H), 5.31e5.22 (m, 1H), 4.76 (s, 1H), 4.72 (s, 1H),
2.69e2.61 (m, 2H), 2.69e2.61 (m, 2H), 2.34e2.21 (m, 2H),
2.34e2.21 (m, 2H), 2.28 (s, 3H), 2.28 (s, 3H), 1.68e1.62 (m, 3H),
1.60e1.56 (m, 3H), 1.53e1.49 (m, 3H); 13C NMR (100 MHz, CDCl3):
d
153.6, 137.4, 136.1, 130.3, 130.1, 125.5, 121.7, 120.1, 119.2, 116.2, 40.1,
32.2, 29.0, 28.5, 23.8, 21.2, 16.7, 13.6, 13.4; HRMS (ESI) calcd for
C13H17O [MꢂH]ꢂ: 189.1279, found 189.1267.
4.2.2.4. 6-Methyl-2-[(3-methyl)-3-pentenyl]phenol
(1d). Compound 1d was prepared from 3d by a similar procedure
with 1b (640 mg, overall 14% yield). 1H NMR (data for 3.1:1 mixture
of olefin isomers based on the relative integration of peaks at
d 1.62
and 1.54; 400 MHz, CDCl3): 7.03e6.97 (m, 2H), 7.03e6.97 (m, 2H),
d
6.83e6.77 (m, 1H), 6.83e6.77 (m, 1H), 5.34e5.25 (m, 1H),
5.34e5.25 (m, 1H), 4.78e4.62 (m, 1H), 4.78e4.62 (m, 1H),
2.75e2.59 (m, 2H), 2.75e2.59 (m, 2H), 2.39e2.21 (m, 2H),
2.39e2.21 (m, 2H), 2.27 (s, 3H), 2.27 (s, 3H), 1.78e1.63 (m, 3H),
1.78e1.63 (m, 3H), 1.63e1.52 (m, 3H), 1.63e1.52 (m, 3H); 13C NMR
(100 MHz, CDCl3):
d 152.4, 152.3, 136.3, 136.2, 129.1, 129.0, 128.5,
128.4, 128.2, 123.8, 123.7, 120.9, 120.8, 120.5, 119.4, 40.3, 32.4, 29.7,
Scheme 5. The two dimensional NMR (NOESY) spectra of 1a (Z/E¼1.8:1).
29.2, 24.1, 16.3, 16.3, 13.9, 13.6; HRMS (ESI) calcd for C13H17
O
[MꢂH]ꢂ: 189.1279, found 189.1274.
4.2.2.2. 4-Methyl-2-[(3-methyl)-3-pentenyl]phenol (1b). To a so-
lution of phenol 3b (2.6 g, 24.0 mmol), anhydrous MgCl2 (3.5 g,
36.8 mmol), and paraformaldehyde (5.0 g, 166.5 mmol) in MeCN
(100 ml) was added triethylamine (12.8 ml, 91.8 mmol). The re-
action mixture was heated under reflux conditions for 8 h.
Hydrochloric acid (5%) was added and the mixture extracted with
ether and dried over Na2SO4. Solvent was evaporated under re-
duced pressure and the residue was purified by flash column
chromatography to give the intermediate 4b (2.8 g, 86% yield).
1 mol/L NaOH aqueous solution (23 ml, 23 mmol) was added slowly
to a solution of 4b (2.8 g, 20.6 mmol) in acetone (15 ml) and the
mixture was stirred at room temperature for 14 h. Hydrochloric
acid (1 mol/L, 30 ml, 30 mmol) was added and a light yellow de-
position was obtained. The solution was filtered and the filtration
residue 5b was dissolved in ethyl acetate. Hydrogenation using 5%
4.2.2.5. 4-Isopropyl-2-[(3-methyl)-3-pentenyl]phenol
(1e). Compound 1e was prepared from 3e by a similar procedure
with 1b (1.6 g, overall 31% yield). 1H NMR (data for 2.3:1 mixture of
olefin isomers based on the relative integration of peaks at
d 1.74
and 1.68; 400 MHz, CDCl3): 6.97e6.91 (m, 2H), 6.97e6.91 (m, 2H),
d
6.71e6.67 (m, 1H), 6.71e6.67 (m, 1H), 5.31e5.22 (m, 1H), 5.31e5.22
(m, 1H), 4.65e4.53 (m, 1H), 4.65e4.53 (m, 1H), 2.89e2.77 (m, 1H),
2.89e2.77 (m, 1H), 2.71e2.56 (m, 2H), 2.71e2.56 (m, 2H),
2.36e2.34 (m, 2H), 2.36e2.34 (m, 2H), 1.76e1.73 (m, 3H), 1.69e1.67
(m, 3H), 1.61e1.57 (m, 3H), 1.52e1.47 (m, 3H), 1.24e1.20 (m, 6H),
1.24e1.20 (m, 6H); 13C NMR (100 MHz, CDCl3):
d
151.7, 141.5, 136.0,
128.5, 128.4, 124.9, 120.2, 119.2, 115.3, 115.2, 40.1, 33.6, 32.1, 29.5,
28.9, 24.5, 23.8, 16.2, 13.6, 13.4; HRMS (ESI) calcd for C15H21
O
[MꢂH]ꢂ: 217.1592, found 217.1581.

5214
Q. Liu et al. / Tetrahedron 68 (2012) 5209e5215
4.2.2.6. 4-Methoxy-2-[(3-methyl)-3-pentenyl]phenol
4.2.3.3. 2,7-Dimethyl-2-vinylchroman (2c). Colorless oil. 1H
NMR (400 MHz, CDCl3):
(d, J¼7.6 Hz, 1H), 5.86 (dd, J¼10.8, 17.6 Hz, 1H), 5.18 (dd, J¼1.2,
17.2 Hz, 1H), 5.07 (dd, J¼1.2, 10.8 Hz, 1H), 2.68e2.64 (m, 2H), 2.28
(s, 3H), 1.94e1.77 (m, 2H), 1.42 (s, 3H); 13C NMR (100 MHz, CDCl3):
(1f). Compound 1f was prepared from 3f by a similar procedure
with 1b (1.2 g, overall 24% yield). 1H NMR (data for 4.7:1 mixture
of olefin isomers based on the relative integration of peaks at
d
6.91 (d, J¼8.0 Hz, 1H), 6.70 (s, 1H), 6.65
d
2.32 and 2.26; 400 MHz, CDCl3): d 6.72e6.67 (m, 2H), 6.72e6.67
(m, 2H), 6.65e6.60 (m, 1H), 6.65e6.60 (m, 1H), 5.31e5.23 (m, 1H),
5.31e5.23 (m, 1H), 4.51e4.44 (m, 1H), 4.51e4.44 (m, 1H), 3.76 (s,
3H), 3.75 (s, 3H), 2.69e2.62 (m, 2H), 2.69e2.62 (m, 2H), 2.33 (t,
J¼8.1 Hz, 2H), 2.26 (t, J¼8.2 Hz, 2H), 1.74e1.72 (m, 3H), 1.68e1.66
(m, 3H), 1.60e1.56 (m, 3H), 1.52e1.47 (m, 3H); 13C NMR (100 MHz,
d 154.0, 141.6, 137.4, 129.3, 120.9, 118.5, 117.4, 114.0, 76.8, 32.0, 27.3,
22.4, 21.3; HRMS (EI) calcd for C13H16O [M]þ: 188.1201, found
188.1199.
4.2.3.4. 2,8-Dimethyl-2-vinylchroman (2d). Colorless oil. 1H
CDCl3):
d
153.7, 148.0, 147.9, 136.0, 135.9, 130.2, 120.3, 119.2, 116.3,
NMR (400 MHz, CDCl3):
d
6.97 (dd, J¼2.0 Hz, 8.0 Hz, 1H), 6.88 (s,
116.2, 116.1, 112.0, 56.1, 40.0, 32.0, 29.5, 29.1, 23.8, 16.2, 13.7, 13.4.
HRMS (ESI) calcd for C13H17O2 [MꢂH]ꢂ: 206.1307, found
206.1233.
1H), 6.79 (d, J¼8.4 Hz, 1H), 5.87 (dd, J¼10.8, 17.2 Hz, 1H), 5.19 (dd,
J¼1.2, 16.8 Hz, 1H), 5.07 (dd, J¼1.2, 10.8 Hz, 1H), 2.86e2.77 (m, 1H),
2.76e2.62 (m, 2H), 1.96e1.79 (m, 2H), 1.42 (s, 3H), 1.21 (d, J¼6.8 Hz,
6H); 13C NMR (100 MHz, CDCl3):
d 152.3, 141.9, 128.6, 127.1, 126.0,
4. 2. 2. 7. 4-Phenyl-2-[(3-methyl)-3-pentenyl]phenol
(1g). Compound 1g was prepared from 3g by a similar procedure
with 1b (1.1 g, overall 18% yield). 1H NMR (data for 1.7:1 mixture of
120.9, 119.4, 113.6, 76.9, 32.1, 27.7, 23.0, 16.5; HRMS (EI) calcd for
C13H16O [M]þ: 188.1201, found 188.1204.
olefin isomers based on the relative integration of peaks at
d
1.76
4.2.3.5. 6-Isopropyl-2-methyl-2-vinylchroman (2e). Colorless oil.
and 1.70; 400 MHz, CDCl3): 7.57e7.27 (m, 7H), 7.57e7.27 (m, 7H),
d
1H NMR (400 MHz, CDCl3):
d
6.97 (dd, J¼2.0, 8.0 Hz, 1H), 6.88 (s,
6.83 (d, J¼7.6 Hz, 1H), 6.83 (d, J¼7.6 Hz, 1H), 5.34e5.25 (m, 1H),
5.34e5.25 (m, 1H), 5.00e4.80 (m, 1H), 5.00e4.80 (m, 1H),
2.80e2.64 (m, 2H), 2.80e2.64 (m, 2H), 2.41e2.29 (m, 2H),
2.41e2.29 (m, 2H), 1.78e1.75 (m, 3H), 1.71e1.68 (m, 3H), 1.62e1.58
1H), 6.79 (d, J¼8.4 Hz, 1H), 5.87 (dd, J¼10.8, 17.2 Hz, 1H), 5.19 (dd,
J¼1.2, 16.8 Hz, 1H), 5.07 (dd, J¼1.2, 10.8 Hz, 1H), 2.86e2.77 (m, 1H),
2.76e2.62 (m, 2H), 1.96e1.79 (m, 2H), 1.42 (s, 3H), 1.21 (d, J¼6.8 Hz,
6H); 13C NMR (100 MHz, CDCl3):
d 152.2, 141.8, 140.3, 127.2, 125.5,
(m, 3H), 1.54e1.49 (m, 3H); 13C NMR (100 MHz, CDCl3):
d
153.5,
121.0, 116.7, 114.0, 76.7, 33.4, 32.1, 27.3, 24.5, 22.9; HRMS (EI) calcd
153.4, 141.3, 135.9, 134.2, 129.4, 129.3, 128.9, 127.0, 126.8, 126.1,
126.0,125.9,120.4,119.4,115.9,115.8, 40.1, 32.1, 29.5, 29.0, 23.9,16.2,
13.7, 13.5; HRMS (ESI) calcd for C18H19O [MꢂH]ꢂ: 251.1436, found
251.1434.
for C15H20O [M]þ: 216.1514, found 216.1513.
4.2.3.6. 6-Methoxy-2-methyl-2-vinylchroman (2f).1 Colorless oil.
1H NMR (400 MHz, CDCl3):
d
6.79 (d, J¼8.9 Hz, 1H), 6.71e6.67 (m,
1H), 6.58 (d, J¼6.4 Hz, 1H), 5.85 (dd, J¼11.2, 17.6 Hz, 1H), 5.17 (dd,
J¼1.6, 17.6 Hz, 1H), 5.06 (dd, J¼1.2, 10.4 Hz, 1H), 3.74 (s, 3H),
2.71e2.66 (m, 2H), 1.93e1.77 (m, 2H), 1.42 (s, 3H); HRMS (EI) calcd
for C13H16O2 [M]þ: 204.1150, found 204.1148.
4. 2. 2. 8. 4-Chloro-2-[(3-methyl)-3-pentenyl]phenol
(1h). Compound 1h was prepared from 3h by a similar procedure
with 1b (450 mg, overall 9% yield). 1H NMR (data for 1.9:1 mixture
of olefin isomers based on the relative integration of peaks at
d 1.72
and 1.66; 400 MHz, CDCl3): 7.10e6.99 (m, 2H), 7.10e6.99 (m, 2H),
d
4.2.3.7. 6-Phenyl-2-methyl-2-vinylchroman (2g). Colorless oil.
6.68 (d, J¼8.4 Hz, 1H), 6.68 (d, J¼8.4 Hz, 1H), 5.31e5.22 (m, 1H),
5.31e5.22 (m, 1H), 2.68e2.53 (m, 2H), 2.68e2.53 (m, 2H),
2.34e2.21 (m, 2H), 2.34e2.21 (m, 2H), 1.74e1.71 (m, 3H), 1.67e1.65
(m, 3H), 1.60e1.56 (m, 3H), 1.51e1.47 (m, 3H); 13C NMR (100 MHz,
1H NMR (400 MHz, CDCl3):
d
7.56e7.25 (m, 7H), 6.93 (d, J¼8.8 Hz,
1H), 5.88 (dd, J¼10.8, 18.0 Hz, 1H), 5.21 (dd, J¼1.2, 17.2 Hz, 1H), 5.10
(dd, J¼1.2, 10.4 Hz, 1H), 2.79e2.72 (m, 2H), 2.00e1.81 (m, 2H), 1.46
(s, 3H); 13C NMR (100 MHz, CDCl3):
d 153.9,141.4,141.3,128.8, 128.2,
CDCl3):
d
152.6, 152.4, 135.6, 130.8, 130.2, 130.1, 127.2, 126.9, 125.5,
126.9, 126.7, 126.3, 121.7, 117.3, 114.2, 77.2, 32.0, 27.4, 22.9; HRMS
120.6, 119.6, 116.7, 39.7, 31.7, 29.2, 28.6, 23.8, 16.1, 13.6, 13.4; HRMS
(EI) calcd for C18H18O [M]þ: 250.1358, found 250.1352.
(ESI) calcd for C12H14ClO [MꢂH]ꢂ: 209.0733, found 209.0718.
4.2.3.8. 6-Chloro-2-methyl-2-vinylchroman (2h). Colorless oil.
4.2.3. General procedure for Pd(II)-catalyzed asymmetric oxidative
cyclization. In the nitrogen atmosphere, 20 mol % of the catalyst
Pd(OCOCF3)2 and 20 mol % of ligand L1 were stirred in 2 ml MeOH
to coordinate for 0.5 h at room temperature. Then 4 equiv of p-
benzoquinone was added to the mixture. At last, the substrate 1
dissolved in 4 ml MeOH was added to the solution mentioned
above for 24 h at 60 ꢀC. After removal of the solvent, the residue was
purified by flash column chromatography to afford the products 2.
1H NMR (400 MHz, CDCl3):
d
7.07e6.99 (m, 2H), 6.79 (d, J¼8.8 Hz,
1H), 5.82 (dd, J¼10.8, 17.2 Hz, 1H), 5.14 (dd, J¼1.2, 17.2 Hz, 1H), 5.07
(dd, J¼1.2,10.4 Hz,1H), 2.70e2.63 (m, 2H),1.95e1.75 (m, 2H),1.42(s,
3H); 13C NMR (100 MHz, CDCl3):
d 152.9, 141.0, 129.1, 127.5, 124.6,
123.2, 118.3, 113.4, 31.5, 27.4, 22.7; HRMS (EI) calcd for C12H13ClO
[M]þ: 208.0655, found 208.0656.
Acknowledgements
4.2.3.1. 2-Methyl-2-vinylchroman (2a).8c,9a Colorless oil. ½a 2D0
ꢃ
ꢂ19 (c 0.55, CHCl3, ee¼83%); 1H NMR (400 MHz, CDCl3):
d
7.10 (t,
This work was supported by the National Nature Science
Foundation of China (09JC1407800), Science and Technology
Commission of Shanghai Municipality (20972095 and 21172143)
and Nippon Chemical Industrial Co., Ltd. We thank Professor T.
Imamoto and Dr. M. Sugiya for helpful discussions and the In-
strumental Analysis Center of Shanghai Jiao Tong University for
HRMS analysis.
J¼7.5 Hz, 1H), 7.02 (d, J¼7.5 Hz, 1H), 6.86 (d, J¼7.5 Hz, 1H), 6.82 (m,
1H), 5.85 (dd, J¼10.5, 17.0 Hz, 1H), 5.18 (dd, J¼1.0, 17.5 Hz, 1H), 5.06
(dd, J¼1.0, 11.0 Hz, 1H), 2.78e2.64 (m, 2H), 1.96e1.79 (m, 2H), 1.43
(s, 3H).
4.2.3.2. 2,6-Dimethyl-2-vinylchroman (2b). Colorless oil. 1H
NMR (400 MHz, CDCl3):
d
6.91 (d, J¼7.5 Hz, 1H), 6.84 (s, 1H), 6.76 (d,
J¼8.4 Hz, 1H), 5.85 (dd, J¼10.4, 17.2 Hz, 1H), 5.18 (dd, J¼1.2, 17.2 Hz,
1H), 5.06 (dd, J¼1.2, 10.8 Hz, 1H), 2.74e2.59 (m, 2H), 2.25 (s, 3H),
Supplementary data
1.95e1.77 (m, 2H), 1.42 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 152.0,
141.6, 129.9, 129.1, 128.2, 121.2, 116.8, 114.1, 76.7, 32.0, 27.4, 22.7,
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.03.077.
20.7; HRMS (EI) calcd for C13H16O [M]þ: 188.1201, found 188.1200.

Q. Liu et al. / Tetrahedron 68 (2012) 5209e5215
5215
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