Asymmetric synthesis of 1-vinyltetrahydroisoquinoline through Pd-catalyzed intramolecular allylic amination

Article abstract of DOI:10.1016/j.tet.2007.04.097

Asymmetric synthesis of 6,7-dimethoxy-1-vinyltetrahydroisoquinolines through Pd-catalyzed intramolecular allylic amination of 3-(amidoethylphenyl)prop-2-enyl carbonates was studied, using a library of fine-tunable monodentate phosphoramidite ligands. Unde

Full text of DOI:10.1016/j.tet.2007.04.097

Tetrahedron 63 (2007) 8563–8570
Asymmetric synthesis of 1-vinyltetrahydroisoquinoline through
Pd-catalyzed intramolecular allylic amination
*
Ce Shi and Iwao Ojima
Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400, USA
Received 15 March 2007; revised 24 April 2007; accepted 27 April 2007
Available online 3 May 2007
Abstract—Asymmetric synthesis of 6,7-dimethoxy-1-vinyltetrahydroisoquinolines through Pd-catalyzed intramolecular allylic amination of
3-(amidoethylphenyl)prop-2-enyl carbonates was studied, using a library of fine-tunable monodentate phosphoramidite ligands. Under
optimized conditions, excellent enantiopurity (up to 96% ee) and 100% product selectivity were achieved. 1-Vinyltetrahydroquinoline
thus obtained is a highly versatile intermediate for the synthesis of various biologically active alkaloids of medicinal interest.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
workers, which was able to construct the heterocycle by
introducing the chirality at the C1 position simultaneously
in a single step (Scheme 1).22 The reaction led to a highly
versatile C1-substituted tetrahydroisoquinoline, which can
be easily transformed into various tetrahydroisoquinoline al-
kaloids. This could be a highly efficient approach if excellent
reaction rate and enantioselectivity were attained. The chiral
Pd catalyst system used in this process was, however, not
able to achieve high catalytic activity (12–23 days were
needed to reach synthetically meaningful conversions)
although very good enantioselectivity (82–88% ee under the
optimized conditions) was achieved.22 Accordingly, the
development of more efficient chiral Pd catalyst systems is
apparently necessary to make this process highly efficient
and synthetically useful.
C1-Substituted tetrahydroisoquinolines are abundantly
found in nature, especially in a variety of plants, soil, and ma-
rine microorganisms, and provide important synthetic targets
because of their pharmacological properties.1 Members of
this family have shown diverse activities,1 e.g., cytotoxicity,2
antagonist activity to D1 and NMDA receptors,3 analgesic
activity,4 pathogenesis of Parkinson’s disease,5 and enzyme
inhibitory activities for glucosidases6 and monoamine
oxidases.7 Thus, the synthesis of this class of compounds in
optically active forms is very important for the study of
their biological and pharmacological activities, hence has
attracted much interest in developing efficient methods and
methodologies among synthetic organic chemists.8,9
Traditionally, the synthesis of optically active C1-substituted
tetrahydroisoquinolines relied largely on the diastereoselec-
tive reactions to introduce the chirality at the C1 position.10
Several enantioselective catalytic approaches have recently
been developed for the introduction of chirality at the C1
position, e.g., enantioselective Pictet–Spengler reaction,11
enantioselective alkylation, vinylation, alkynylation or
cyanation of 3,4-dihydroisoquinolines,12–17 enantioselective
alkynylation of tetrahydroisoquinolines,18 asymmetric
hydrogenation of 3,4-dihydroisoquinolines19,20 as well as
1-alkylidenetetrahydroisoquinolines,21 etc.8
H
MeO
MeO
N
R
MeO
MeO
/
Pd L*
Solvent, Base
N
R
*
OR'
Scheme 1. Pd-catalyzed intramolecular allylic amination approach to
1-vinyltetrahydroisoquinolines.
In order to achieve high efficiency in the reaction rate and
enantioselectivity, the development of suitable chiral ligands
for this process is crucial. We have been developing a library
of novel enantiopure monodentate phosphoramidite and
phosphite ligands based on axially chiral biphenols, which
can be readily prepared and modified, for a variety of cata-
lytic asymmetric reactions.23 The salient feature of these
ligands is their fine-tuning capability through modification
of the R1, R2, and R3 groups (Fig. 1). High catalytic activity
and enantioselectivity have been achieved in various transi-
tion metal-catalyzed transformations, including asymmetric
In 2003, a Pd-catalyzed intramolecular asymmetric allylic
amination approach was reported by Katsuki and co-
Keywords: Asymmetric synthesis; Allylic amination; Palladium; Monoden-
tate phosphoramidite; Alkaloid; Tetrahydroisoquinoline.
* Corresponding author. Tel.: +1 631 632 7947; fax: +1 631 632 7942;
e-mail: iojima@notes.cc.sunysb.edu
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.04.097

8564
C. Shi, I. Ojima / Tetrahedron 63 (2007) 8563–8570
4
4
R1
R2
R1
R2
5, starting from commercially available 3,4-dimethoxyphe-
5
3
5
3
nylethylamine (1). For the preparation of 5a-1 and 5a-2
and 5b-1–5b-3, the amine moiety of 1 was converted to
tosylamide and trifluoroacetylamide first and then iodinated
to give 2a and 2b, respectively. Katsuki and co-workers used
HIO3/I2 for this iodination for the preparation of 2b (66%
yield). We used ICl in place of HIO3/I2 and obtained 2b in
95% yield. Sonogashira coupling of 2a and 2b with prop-
argyl alcohol gave 3a and 3b, which were subsequently
hydrogenated over P2–Ni to afford the corresponding Z-
alcohols 4a and 4b, respectively, in excellent overall yields.
The Z-allylic alcohols 4, thus obtained, were acylated with
chloroformates (Me, vinyl, and Ph) to give the carbonates
5a-1 and 5a-2 and 5b-1–5a-3 in excellent yields. Katsuki
and co-workers used (trifluoroacetylaminoethylphenyl)-
prop-2-enyl acetate and pivaloate, but we found that the in-
tramolecular allylic amination reaction using our ligands
proceeded much faster when the corresponding carbonates
were used in a preliminary feasibility study. Thus, we
employed only carbonates in this work. In addition, we used
tosyl besides trifluoroacetyl for the amide moiety. The tert-
butyl carbonate 5a-3 was prepared by using (t-Boc)2O in
the acylation of 4a. For the preparation of E-allylic carbon-
ate 5a-1-t, 2a was subjected to the Heck reaction with
methyl acrylate to give 6a, which was subsequently reduced
by DIBAL-H to afford E-allylic alcohol 4a-t. Then, 4a-t
was reacted with methyl chloroformate to give E-allylic
carbonate substrate 5a-1-t in high overall yield.
6
2
6
2
R3
R3
O
O
R3
O
O
1
1
P
O
P
N
1'
1'
2'
2'
6'
6'
R1
R2
R1
R2
5'
3'
3'
5'
4'
4'
Figure 1. Chiral biphenol-based phosphoramidite and phosphite ligands.
hydrogenation,24 asymmetric hydroformylation,23 asym-
metric conjugate additions to cycloalkenones and nitro-
alkenes,23,25 and asymmetric allylic alkylation as well as
its application to the total synthesis of (+)-g-lycorane.26,27
Since a couple of these chiral monodentate phosphoramidite
ligands were found to be extremely effective (up to 99.7%
ee) in the Pd-catalyzed asymmetric allylic alkylation, we
thought this type of ligands would be effective for the asym-
metric allylic amination process as well and optimization
could be done through systematic modifications through
library synthesis.
We describe here a successful application of these novel
phosphoramidite ligands to the Pd-catalyzed intramolecular
allylic amination reaction for the asymmetric synthesis of
1-vinyltetrahydroisoquinolines (Scheme 1), which have
been obtained in nearly quantitative yields and excellent
enantiopurity up to 96% ee.
2. Results and discussion
2.3. Pd-catalyzed intramolecular asymmetric allylic
amination of substrates 5
2.1. Monodentate phosphoramidite ligand library
The screening of the best chiral ligand among the small
library of monodentate phosphoramidite ligands, L1–L7,
shown in Figure 2 was conducted in two steps. First, we ex-
amined the effect of the amine moiety on the catalyst activity
and enantioselectivity, using 5a-1 as the substrate (Scheme
3). For this comparison, we used ligands L1a and L2–L7,
which do not have any susbtituents at the 3 and 30 positions
of the biphenyl moiety. The reactions were carried out in
CH2Cl2 using Pd2(dba)3 (2.5 mol %) and 3 equiv of a chiral
ligand/Pd at 0.05 M concentration of 5a-1 at room tempera-
ture (25 ꢀC). Results are summarized in Table 1.
A library of enantiopure monodentate phosphoramidite li-
gands consisting of various biphenol moieties and amine
moieties were prepared according to the procedures reported
previously by our laboratory23,24,27 (Fig. 2) and used for the
intramolecular allylic amination reactions.
2.2. Preparation of 3-(amidoethylphenyl)prop-2-enyl
carbonate substrates
A series of 3-(amidoethylphenyl)prop-2-enyl carbonates 5
were prepared, largely following the procedure reported by
Katsuki and co-workers for two substrates,22 with modifica-
tions. Scheme 2 illustrates the syntheses of these substrates
As Table 1 shows, all reactions completed within 5–12 h to
give the desired cyclization product 7a(R) in quantitative
R2
O
O
O
O
O
O
P
N
P N
P
N
N
Ph
O
O
P
N
(S)-L2
R2
(S)-L4
(S)-L3
(S)-L1a R2= H
(S)-L1b R2= Me
(S)-L1c R2= Br
(S)-L1d R2= Ph
(S)-L1e R2= t-Bu
Ph
Ph
Ph
Ph
Ph
Ph
O
P
O
O
O
P
P
N
N
O
O
(S)-L5
(S, S, S)-L7
(S, R, R)-L6
Figure 2. Library of enantiopure monodentate phosphoramidite ligands used in this study.

C. Shi, I. Ojima / Tetrahedron 63 (2007) 8563–8570
8565
R
NH
1)TFA2O or Ts-Cl (1.2 eq.)
NEt3 (2 eq.), CH2Cl2
2) ICl (1.1 eq.) CH2Cl2
OH
MeO
MeO
MeO
MeO
NH2
(1.2 eq.)
(PPh3)2PdCl2 (2 mol %),
CuI (1 mol %), HNEt2
I
1
2a R= Ts
93%
2b R= TFA 95%
R
NH
R
NH
R
MeO
MeO
MeO
NH
MeO
H2/P2-Ni
ClCO2R (1.1 eq.)
pyridine, 0 °C- rt
EtOH
MeO
OH
MeO
OCO2R'
OH
95%
94%
95%
93%
97%
R = Ts
5a-1
R' = Me
3a R= Ts
91%
4a R= Ts
95%
R = Ts
5a-2
5b-1
5b-2
5b-3
R' = vinyl
R' = Me
R' = vinyl
R' = Ph
3b R= TFA 94%
4b R= TFA 97%
R = TFA
R = TFA
R = TFA
Ts
NH
Ts
NH
(t-Boc)2O (2.0 eq.),
MeO
MeO
MeO
Bu4NI (0.1 eq.)
O
NaOH (4 eq.), DCM-H2O
92%
O
O
MeO
OH
4a
5a-3
H
N
H
N
Pd(OAc)2 (2.5 mol %),
P(o-Tol)3 (5 mol %)
MeO
MeO
Ts
OMe
MeO
Ts
DIBAL-H, THF
-78 °C- rt
88%
methyl acrylate (1.1 eq.)
NEt3 (2eq.), Toluene, reflux
MeO
I
2a
6a
O
93%
H
N
H
N
MeO
Ts
MeO
MeO
Ts
ClCO2Me (1.1 eq.)
pyridine, 0 °C- rt
MeO
OCO2Me
OH
96%
4a-t
5a-1-t
Scheme 2. Preparation of substrates 5.
Ts
NH
moiety (entry 6). However, ligand L7(S,S,S), which is a dia-
stereomer of L6(S,R,R), induces virtually no asymmetric in-
duction (entry 7). These results clearly indicate that L6 is
a matching pair and L7 mismatching pair. It is of interest
to note that ligand L7 was one of the better ligands in the
asymmetric allylic alkylation reaction for (+)-lycorane syn-
thesis, achieving 92.6% ee.26 The observed sharp contrast
indicates how different these two reaction systems are
even though both are asymmetric allylic substitution reac-
tions. After the first screening, we selected L1a bearing
a small dimethylamine moiety as our lead ligand in terms
of the catalyst activity and enantioselectivity.
Pd2(dba)3 (2.5 mol %)
L* (3 equiv./Pd)
MeO
MeO
MeO
MeO
N
*
Ts
CH2Cl2, 0.05M, rt
OCO2Me
5a-1
7a
Scheme 3. Intramolecular asymmetric allylic amination of 5a-1 for ligand
screening.
Table 1. Ligand screening: effect of the amine moiety
Entry
Ligand
Time (h)
Conv.a,b (%)
% eeb
1
2
3
4
5
6
7
L1a
L2
L3
L4
L5
L6
L7
5
5
7
7
7
100
100
100
100
100
100
100
45 (R)
25 (R)
42 (R)
0.5 (R)
13 (R)
45 (R)
0.1 (R)
Next, the effect of the substituent R2 at the 3 and 30 positions
of the biphenyl moiety on the catalytic activity and enantio-
selectivity was examined under the same reaction conditions
as those for the first ligand screening mentioned above.
Thus, ligands L1a–L1e were examined for their efficacy in
the formation of tetrahydroisoquinoline 7a. Results are
shown in Table 2. Apparently, the enantioselectivity in-
creases (45% eeꢁ74% ee) as the bulkiness of the substituent
at the 3 and 30 positions increases, i.e., H<Me<Br<Ph (en-
tries 1–4), but t-Bu is so bulky that it causes negative effect
(entry 5). However, the most dramatic effect of the 3,30-sub-
stituents is the direction of asymmetric induction, i.e., L1a
(R2¼H) induces R configuration in the product 7a, while
L1b (R2¼Me), L1c (R2¼Br), L1d (R2¼Ph), and L1e
(R2¼t-Bu) give 7a with S configuration. Thus, the substitu-
ent R2 at the 3 and 30 positions exert a significant influence
on the extent and direction of asymmetric induction, as an-
ticipated from our experience in the previous catalytic
12
12
Determined by 1H NMR.
Determined by HPLC using Chiralpak AD-RH, CH3CN/H2O.
a
b
yield based on the 1H NMR and HPLC analyses. It is worthy
of note that this catalyst/reaction system does not require any
additional base, e.g., Cs2CO3, K2CO3, and Na2CO3, which is
22
essential for Katsuki’s catalyst/reaction system in CH2Cl2.
It is clear from the results shown in Table 1 that bulkier the
amine moiety becomes, slower the reaction. Also, bulkier
amine moieties give lower enantioselectivity as exemplified
by the use of L4 bearing a diisopropylamine moiety (entry
4). Only exception for this general observation is ligand
L6(S,R,R), which bears a bulky bis(1-phenylethyl)amine

8566
C. Shi, I. Ojima / Tetrahedron 63 (2007) 8563–8570
Table 2. Ligand screening: effect of the substituent R2
E olefin geometry, 5a-1-t, gives 7a with opposite configura-
tion (R) (entry 4), but the enantiopurity of the product (71%
ee) is only slightly lower than 7a(S) obtained in the reaction
of 5a-1 with Z olefin geometry (entry 1). The results indicate
that the sense of enantioface selection by the chiral catalyst
is the same in these two cases, leading to the formation of the
two enantiomers of 7a. In contrast to the 5a series, the reac-
tions of the 5b series (R¼CF3CO) are highly sensitive to the
carbonate substituent R0 (entries 5–7). The introduction of
a vinyl- or a phenyl-carbonate to the 5b series substantially
increases the enantioselectivity of the reaction, and tetra-
hydroisoquinoline 7b with 95% ee (S) is obtained with the
phenyl-carbonate substrate 5b-3 (entry 7). It is also notewor-
thy that a marked difference is observed between 5a-2 (46%
ee) and 5b-2 (89% ee), which have the same vinyl-carbonate
moiety but differs in the amide moiety, i.e., N-Ts versus
N-CF3CO (entries 2 and 6).
Entry
Ligand
Time (h)
Conv.a,b (%)
% eeb
1
2
3
4
5
L1a (R2¼H)
L1b (R2¼Me)
L1c (R2¼Br)
L1d (R2¼Ph)
L1e (R2¼t-Bu)
5
7
10
10
16
100
100
100
100
100
45 (R)
48 (S)
59 (S)
74 (S)
23 (S)
Determined by 1H NMR.
a
b
Determined by HPLC using Chiralpak AD-RH, CH3CN/H2O.
asymmetric transformations using this type of ligands.23–27
After two-step ligand screenings, we selected L1d (R2¼
Ph) as the ligand of choice for the intramolecular asymmet-
ric allylic amination of the substrates of this type.
Although the enantioselectivity attained by L1d was only
74% ee in the reaction of 5a-1, we hypothesized that much
higher enantioselectivity could be achieved through modifi-
cation of the substrate structure. In fact, as described below,
excellent enantioselectivity (95% ee) has been, indeed,
achieved through substrate structure modifications. As de-
scribed above, we have prepared six substrates bearing an
N-tosyl moiety (5a) and an N-trifluoroacetyl moiety (5b)
as well as methyl, vinyl, tert-butyl, and phenyl in the carbon-
ate moiety. In addition to the six substrates bearing a Z olefin
moiety, a substrate with E olefin geometry, 5a-1-t, was also
prepared and examined. The reactions were run under the
same conditions as those used for the screening of the
ligands described above, using L1d as the chiral ligand
(Scheme 4). Results are summarized in Table 3.
Finally, the effects of the reaction variables, i.e., reaction
temperature and concentration, on the reaction rate and
enantioselectivity were examined with the optimized ligand
and substrate combination using L1d as the chiral ligand and
5b-3 as the substrate (Scheme 5). As Table 4 shows, the sub-
strate concentration only affects reaction rate, as anticipated.
The enantioselectivity increases slightly when the reaction is
run at a lower temperature (ꢂ25 ꢀC) (entry 5, 96% ee). How-
ever, the enantioselectivity clearly drops when the reaction is
carried out at 50 ꢀC (entry 6, 84% ee). Thus, the reaction at
room temperature (25 ꢀC) and 0.5 M concentration appears
to be near optimal, which is synthetically very convenient.
O
CF3
NH
MeO
MeO
Pd2(dba)3 (2.5 mol %)
MeO
MeO
R
NH
L1d (3 equiv./Pd)
Pd2(dba)3 (2.5 mol %)
N
CF3
MeO
MeO
MeO
MeO
CH2Cl2
L1d (3 equiv./Pd)
OCO2Ph
O
N
R
CH2Cl2, 0.05M, rt
*
OCO2R'
5b-3
7b (S)
5a, 5b
7a, 7b
Scheme 5. Highly efficient catalytic asymmetric synthesis of tetrahydroiso-
quinoline 7b.
Scheme 4. Reactions of 5a and 5b using L1d as the chiral ligand.
As Table 3 shows, the bulkiness of the carbonate substituent
R0 does not have much influence on the reaction in the 5a
series of substrates (R¼Ts) although t-Bu-carbonate 5a-3
gives a slightly better enantioselectivity (77% ee) and slower
reaction rate (entry 3) than Me-carbonate 5a-1 (entry 1). The
introduction of a vinyl group to the carbonate moiety accel-
erates the reaction, but lowers enantioselectivity (entry 2).
The geometry of the olefin moiety is critical for the direction
of asymmetric induction, i.e., the substrate bearing an
3. Experimental
3.1. General method and material
1H and 13C NMR spectra were measured on a Varian Inova-
300 NMR or a Varian Inova-400 NMR spectrometer in a deu-
terated solvent. The enantiomeric excess was determined by
HPLC: Waters M45 system with Waters 484 detector using
Table 3. Reactions of 5a and 5b using L1d as the chiral ligand
Table 4. Effects of reaction temperature and concentration
Entry Substrate
R
R0
Olefin
geometry
Time (h) Conv.a,b % eeb
(%)
Entry Concn (M) Temp (ꢀC) Time (h) Conv.a,b (%) % eeb
1
2
3
4
0.01
0.05
0.5
0.05
0.05
0.05
25
25
25
0
14
7
6
10
14
5
100
100
100c
100
100
100
95 (S)
95 (S)
94 (S)
95 (S)
96 (S)
84 (S)
1
2
3
4
5
6
7
5a-1
5a-2
5a-3
5a-1-t
5b-1
5b-2
5b-3
Ts
Ts
Ts
Ts
Me
Z
Z
Z
E
Z
Z
Z
10
5
100
100
100
100
100
100
100
74 (S)
46 (S)
77 (S)
71 (R)
79 (S)
89 (S)
95 (S)
Vinyl
t-Bu
Me
18
10
10
7
5
ꢂ25
6d
50
CF3CO Me
CF3CO Vinyl
CF3CO Ph
Determined by 1H NMR.
Determined by HPLC using Chiralcel OD-H, hexanes/i-PrOH.
Isolated yield of 87% (100% product selectivity) in 1.0 mmol scale reac-
tion.
Reaction was performed in a sealed tube.
a
b
c
7
Determined by 1H NMR.
a
b
Determined by HPLC; for N-Ts products 7a: Chiralpak AD-RH, CH3CN/
H2O; for N-TFA products 7b: Chiralcel OD-H, hexanes/i-PrOH.
d

C. Shi, I. Ojima / Tetrahedron 63 (2007) 8563–8570
8567
Chiralcel OD-H column (hexanes/i-PrOH¼98:2, 0.5 mL/
min) or a Shimadzu LC-2010A HPLC system using a Chiral-
pak AD-RH column (CH3CN/H2O¼50:50, 0.5 mL/min).
Melting points were measured on a Thomas Hoover Capil-
lary melting point apparatus. Optical rotations were mea-
sured on a Perkin–Elmer Model 241 polarimeter. TLC was
performed on Merck DC-alufolien with Kieselgel 60F254
and flash chromatography was carried out on silica gel 60
(Silicyle; 40–63 mm particle size). High-resolution mass
spectrometric analyses were carried out at the Mass Spec-
trometry Laboratory, University of Illinois Urbana-Cham-
paign, Urbana, IL. All solvents were purified using the
Solvent Purification System 400-4 from Innovative Technol-
ogy, Inc. All chemicals were purchased from Aldrich and
Acros Chemical Co. unless otherwise noted. Tris(dibenzyl-
ideneacetone)dipalladium(0) was purchased from Strem
Chemicals Inc. All reactions were carried out under nitrogen
or argon atmosphere.
0 ꢀC for 1 h. Reaction was quenched by addition of water
at the same temperature and the layers were separated.
The aqueous phase was extracted with CH2Cl2 three times,
and combined organic layer was washed with brine, dried
over MgSO4, filtered, and concentrated to afford N-trifluoro-
acetyl-1 as a pale yellow solid. Mp 82.0–83.0 ꢀC; 1H NMR
(300 MHz, CDCl3) d 2.83 (t, J¼6.7 Hz, 2H), 3.60 (q, J¼
6.7 Hz, 2H), 3.87 (s, 6H), 6.27 (br, 1H), 6.69 (d, J¼1.7 Hz,
1H), 6.73 (dd, J¼1.7 Hz, 8.1 Hz, 1H), 6.83 (d, J¼8.1 Hz,
1H). The product was used in the next step without further
purification.
To a well-stirred solution of N-trifluoroacetyl-1 in CH2Cl2
(10 mL), 1 M ICl in CH2Cl2 (6.1 mL) was added dropwise
at room temperature. The reaction mixture was stirred at
room temperature until TLC had indicated the complete con-
version of the starting material. The reaction was quenched
by addition of saturated Na2SO3 solution. The aqueous layer
was extracted three times with CH2Cl2. The combined or-
ganic layer was washed with water and brine, and dried
over MgSO4. The crude product was obtained after filtration
and evaporation of the solvent. Recrystallization of the crude
product from MeOH afforded 2b as a white solid (2.1 g, 95%
3.2. Monodentate phosphoramidite ligands
Chiral ligands L1a–e, L4–L7 were prepared according to
the procedures previously reported by our laboratory.23,27
Two new phosphoramidite ligands, L2 and L3, were
obtained using the same method as that reported for the
preparation of L4 and L5.27
1
yield). Mp 124.5–125.5 ꢀC; H NMR (300 MHz, CDCl3)
d 2.97 (t, J¼7.2 Hz, 2H), 3.61 (q, J¼6.6 Hz, 2H), 3.84 (s,
3H), 3.86 (s, 3H), 6.37 (br s, 1H), 6.69 (s, 1H), 7.24 (1H,
s); 13C NMR (75 MHz, CDCl3) d 38.9, 40.0, 55.8, 56.1,
87.9, 112.6, 115.7 (q, J¼286 Hz), 121.8, 132.6, 148.5, 149.6,
157.3 (q, J¼36 Hz); HRMS (ESI) calcd for C12H14NO3F3I
[M+H]+ 403.9971, found 403.9981 (D¼2.5 ppm).
3.2.1. O,O0-(S)-(5,50,6,60-Tetramethyl-1,10-biphenyl-2,20-
diyl)-N-benzyl-N-methylphosphoramidite (L2). White
solid; 75% yield; mp 106.5–108 ꢀC; [a]D22 242.9 (c 0.40,
1
CHCl3); H NMR (300 MHz, CDCl3) d 1.93 (s, 3H), 1.96
(s, 3H), 2.17 (d, J¼6.0 Hz, 3H), 2.20 (s, 3H), 2.23 (s, 3H),
3.80 (dd, J¼12.6 Hz, 15 Hz, 1H), 4.21 (dd, J¼8.7 Hz,
15.7 Hz, 1H), 6.70 (d, J¼7.8 Hz, 1H), 6.95–7.28 (m, 8H);
13C NMR (75 MHz, CDCl3) d 17.4 (d, J¼3.8 Hz), 20.2 (d,
J¼2.9 Hz), 32.1 (d, J¼10.3 Hz), 53.1 (d, J¼31.6 Hz),
118.5 (d, J¼20.0 Hz), 127.1, 128.3 (d, J¼13.7 Hz), 129.7,
132.3, 133.4, 136.7 (d, J¼54.1 Hz), 138.6 (d, J¼3.7 Hz),
148.4 (d, J¼4.3 Hz), 149.1; 31P NMR (121.5 Hz, CDCl3)
d 141.9; HRMS (EI) calcd for C24H26NO2P [M]+
391.1701, found 391.1703 (D¼0.5 ppm).
3.2.2. O,O0-(S)-(5,50,6,60-Tetramethyl-1,10-biphenyl-2,20-
diyl)-N,N-diethylphosphoramidite (L3). White solid;
85% yield; mp 123–124 ꢀC; [a]D22 213.9 (c 0.38, CH2Cl2);
1H NMR (300 MHz, CDCl3) d 1.02 (t, J¼6.9 Hz, 6H), 1.98
(s, 3H), 2.04 (s, 3H), 2.29 (s, 6H), 2.76–2.84 (m, 2H),
2.93–3.02 (m, 2H), 6.83 (d, J¼8.1 Hz, 1H), 6.99 (d,
J¼8.1 Hz, 1H), 7.06 (d, J¼8.1 Hz, 1H), 7.13 (d, J¼8.1 Hz,
1H); 13C NMR (75 MHz, CDCl3) d 14.6 (d, J¼2.3 Hz),
17.3 (d, J¼6.3 Hz), 20.1, 38.0 (d, J¼21.6 Hz), 118.0, 118.5
(d. J¼2.3 Hz), 129.2, 129.4 (d, J¼13.4 Hz), 148.8 (d,
J¼4.0 Hz), 149.3; 31P NMR (121.5 MHz, CDCl3) d 144.1;
HRMS (EI) calcd for C20H26NO2P [M]+ 343.1701, found
343.1701 (D¼0 ppm).
3.3.2. 1-Iodo-4,5-dimethoxy-2-[2-(4-methylbenzenesulfo-
nylamino)ethyl]benzene (2a). This compound was synthe-
sized in the same manner as that described for 2b. White
solid; 93% isolated yield; mp 125–127 ꢀC; 1H NMR
(300 MHz, CDCl3) d 2.41 (s, 3H), 2.84 (t, J¼6.9 Hz, 2H),
3.18 (q, J¼4.8 Hz, 2H), 3.80 (s, 3H), 3.81 (s, 3H), 4.70 (br
s, 1H), 6.67 (s, 1H), 7.13 (s, 1H), 7.27 (d, J¼8.1 Hz, 2H),
7.70 (d, J¼8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d 21.5, 40.2, 43.0, 55.9, 56.1, 87.9, 112.9, 121.7, 127.0,
129.6, 132.8, 136.9, 143.4, 148.3, 149.4; HRMS (ESI) calcd
for C17H21INO4S [M+H]+ 462.0236, found 462.0245
(D¼1.9 ppm).
3.3.3. 3-{4,5-Dimethoxy-2-[2-(trifluoroacetylamino)-
ethyl]phenyl}prop-2-ynol (3b). A mixture of 2b (403 mg,
1 mmol), Pd(PPh3)2Cl2 (14 mg, 0.02 mmol), and CuI
(1.9 mg, 0.01 mmol) was placed in a 50 mL round-bottomed
flask. After purging the flask with nitrogen, diethylamine
(5 mL) was added to the mixture, and the solution was
stirred for 20 min. Propargyl alcohol (68 mg, 1.2 mmol)
was added to the reaction mixture via a syringe. The reaction
mixture was stirred at room temperature until TLC indicated
the completion of the reaction. Then, saturated ammonium
chloride solution was added to quench the reaction. The
aqueous layer was extracted with EtOAc three times. The
combined organic layer was dried over MgSO4. Crude prod-
uct was obtained after filtration and evaporation of the sol-
vent. Further purification by flash column chromatography
on silica gel (hexanes/EtOAc¼5:1–1:1) afforded 3b as
3.3. Synthesis of substrates 5a-1–5a-3 and 5b-1–5b-3
3.3.1. 1-Iodo-4,5-dimethoxy-2-[2-(trifluoroacetylami-
no)ethyl]benzene (2b). To a stirred solution of homovera-
trylamine (1) (1 g, 5.5 mmol) and NEt3 (1.2 g, 11 mmol)
in CH2Cl2 (8 mL) was added slowly trifluoroacetic anhy-
dride (1.4 g, 6.6 mmol) at 0 ꢀC. The mixture was stirred at
1
a white solid (311 mg, 94% yield). Mp 117.5–119 ꢀC; H
NMR (300 MHz, CDCl3) d 2.99 (t, J¼7.2 Hz, 2H), 3.02
(br s, 1H), 3.59 (q, J¼7.2 Hz, 2H), 3.83 (s, 3H), 3.85 (s,

8568
C. Shi, I. Ojima / Tetrahedron 63 (2007) 8563–8570
3H), 4.49 (s, 2H), 6.56 (br s, 1H), 6.89 (s, 1H), 6.98 (br s,
1H); 13C NMR (75 MHz, CDCl3) d 33.5, 40.7, 51.4, 55.9,
55.9, 83.6, 90.3, 112.1, 114.4, 114.6, 115.9 (q, J¼280 Hz),
133.0, 147.6, 149.6, 157.5 (q, J¼36 Hz); HRMS (ESI) calcd
for C15H17NO4F3 [M+H]+ 332.1110, found 332.1116
(D¼1.8 ppm).
147.6, 148.8; HRMS (ESI) calcd for C20H24NO4S
[MꢂOH]+ 374.1426, found 374.1425 (D¼ꢂ0.3 ppm).
3.3.7. (E)-3-{4,5-Dimethoxy-2-[2-(4-methylbenzenesulfo-
nylamino)ethyl]phenyl}prop-2-enol (4a-t). Compound 2a
(461 mg, 1.0 mmol) was added to a solution of Pd(OAc)2
(5.6 mg,
0.0025 mmol)
and
P(o-tol)3
(15.2 mg,
3.3.4. 3-{4,5-Dimethoxy-2-[2-(4-methylbenzenesulfonyl-
amino)ethyl]phenyl}prop-2-ynol (3a). This compound
was synthesized in the same manner as that described for
0.0050 mmol), and NEt3 (202 mg, 2.0 mmol) in toluene
(10 mL). Then, methyl acrylate (95 mg, 1.1 mmol) was
added to this mixture via a syringe. The reaction mixture
was heated to reflux until TLC indicated the disappearance
of the starting material, and was cooled to room temperature.
After filtration through a pad of Celite, the filtrate was con-
centrated in vacuo and redissolved in CH2Cl2, washed with
2 N HCl, saturated NaHCO3, and brine. The organic layer
was dried over MgSO4. Crude product was obtained after
filtration and evaporation of the solvent. Further purification
by flash column chromatography on silica gel (hexane/
EtOAc¼8:1–3:1) afforded methyl (E)-3-{4,5-dimethoxy-2-
[2-(4-methylbenzenesulfonyl)ethyl]phenyl}propenoate (6a)
as a white solid (388 mg, 93% isolated yield). Mp 149–
1
3b. White solid; 91% isolated yield; mp 126–128 ꢀC; H
NMR (300 MHz, CDCl3) d 2.41 (s, 3H), 2.95 (t, J¼6.9 Hz,
2H), 3.23 (q, J¼6.1 Hz, 2H), 3.83 (s, 3H), 3.85 (s, 3H),
4.50 (s, 2H), 4.63 (t, J¼6.1 Hz, 1H), 6.56 (s, 1H), 6.89 (s,
1H), 7.25 (d, J¼8.4 Hz, 2H), 7.68 (d, J¼8.4 Hz, 2H); 13C
NMR (75 MHz, CDCl3) d 21.4, 34.8, 43.9, 51.4, 55.8,
55.9, 83.7, 90.5, 112.1, 114.2, 114.6, 126.9, 129.6, 133.5,
136.9, 143.3, 147.4, 149.5; MS (ES) cacld for
C20H22NO4S [MꢂOH]+ 372.1, found 372.1; HRMS (ESI)
calcd for C20H22NO4S [MꢂOH]+ 372.1270, found
372.1268 (D¼ꢂ0.5 ppm).
1
150 ꢀC; H NMR (300 MHz, CDCl3) d 2.41 (s, 3H), 2.92
3.3.5. (Z)-3-{4,5-Dimethoxy-2-[2-(trifluoroacetylami-
no)ethyl]phenyl}prop-2-enol (4b). P2–Ni catalyst was gen-
erated in situ following the standard procedure by adding
NaBH4 (1.0 mg, 0.02 mmol) to a suspension of Ni(OAc)2
(3.0 mg, 0.01 mmol) in EtOH (2 mL) at room temperature
under an nitrogen atmosphere with stirring. After 30 min,
neat ethylenediamine (1.64 mL, 0.024 mmol) was introduced
to the reaction mixture. After stirring the catalyst solution for
10 min, 3b (165 mg, 0.5 mmol) in ethanol (5 mL) was added.
The nitrogen atmosphere was then replaced by hydrogen.
The reaction mixture was stirred until TLC indicated the
completion of the reaction. The reaction was quenched by ad-
dition of water. The aqueous layer was extracted with EtOAc
three times. The combined organic layer was washed with
saturated NaHCO3 solution and brine. After dried over
MgSO4, crude product was obtained after filtration and evap-
oration of the solvent. Further purification by flash column
chromatography on silica gel (hexanes/EtOAc¼3:1–1:1) af-
forded 4b as a colorless oil (161 mg, 97% yield). 1H NMR
(300 MHz, CDCl3) d 2.19 (br s, 1H), 2.83 (t, J¼6.9 Hz,
2H), 3.52 (q, J¼6.6 Hz, 2H), 3.83 (s, 3H), 3.84 (s, 3H),
4.23 (dd, J¼1.5 Hz, 6.9 Hz, 2H), 5.90 (dt, J¼6.9 Hz,
11.4 Hz, 1H), 6.62 (d, J¼11.4 Hz, 1H), 6.64 (s, 1H), 6.66
(s, 1H), 6.81 (br s, 1H); 13C NMR (75 MHz, CDCl3)
d 32.2, 40.2, 55.9, 56.0, 59.2, 112.8, 113.1, 115.8 (q,
J¼286 Hz), 127.8, 128.1, 129.6, 131.3, 147.4, 148.4, 157.3
(q, J¼37 Hz); HRMS (ESI) calcd for C15H18NO4F3Na
[M+Na]+ 356.1086, found 356.1088 (D¼0.6 ppm).
(t, J¼6.9 Hz, 2H), 3.14 (q, J¼6.6 Hz, 2H), 3.80 (s, 3H), 3.88
(s, 6H), 4.41 (t, J¼6.0 Hz, 1H), 6.23 (d, J¼15.9 Hz, 1H), 6.64
(s, 1H), 7.00 (s, 1H), 7.27 (d, J¼5.1 Hz, 2H), 7.68 (d, J¼
5.1 Hz, 2H), 7.79 (d, J¼15.9 Hz, 1H); 13C NMR (75 MHz,
CDCl3) d 21.5, 33.0, 44.2, 51.7, 55.9, 56.0, 108.9, 113.1,
117.1, 125.2, 127.0, 129.6, 131.3, 136.9, 140.9, 143.4,
148.1, 150.9, 167.4; HRMS (ESI) calcd for C21H26NO6S
[M+H]+ 420.1481, found 420.1477 (D¼ꢂ1.0 ppm).
To a solution of 6a (210 mg, 0.5 mmol) in toluene at ꢂ78 ꢀC,
was added dropwise 1 M DIBAL-H (2.0 mL) in hexanes.
The mixture was kept at ꢂ78 ꢀC for 1 h, warmed up to
room temperature and kept for 3 h. The reaction was
quenched by MeOH (0.5 mL), followed by the addition of
saturated Rochelle0s salt solution. The aqueous layer was ex-
tracted three times with CH2Cl2. The combined organic
layer was washed with brine and dried over MgSO4. Crude
product was obtained after filtration and evaporation of the
solvent. Further purification by flash column chromato-
graphy on silica gel (CH2Cl2/MeOH¼95:5) afforded 4a-t
as a colorless oil (172 mg, 88% yield). 1H NMR
(300 MHz, CDCl3) d 2.39 (s, 3H), 2.83 (t, J¼7.2 Hz, 2H),
3.11 (q, J¼6.9 Hz, 2H), 3.82 (s, 3H), 3.86 (s, 3H), 4.30
(dd, J¼1.2 Hz, 5.6 Hz, 2H), 4.81 (t, J¼6.3 Hz, 1H), 6.13
(dt, J¼5.6 Hz, 15.6 Hz, 1H), 6.53 (s, 1H), 6.76 (dt,
J¼1.2 Hz, 15.6 Hz, 1H), 6.93 (s, 1H), 7.24 (d, J¼6.6 Hz,
2H), 7.67 (d, J¼6.6 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d 21.4, 33.2, 44.1, 55.9, 63.6, 109.2, 112.8, 126.9, 127.9,
128.0, 128.4, 129.5, 129.6, 137.0, 143.4, 148.0, 148.7;
HRMS (ESI) calcd for C20H25NO5SNa [M+Na]+
414.1351, found 414.1342 (D¼ꢂ2.2 ppm).
3.3.6. 3-{4,5-Dimethoxy-2-[2-(4-methylbenzenesulfonyl-
amino)ethyl]phenyl}prop-2-enol (4a). This compound was
synthesized in the same manner as that described for 4b.
White solid; 95% isolated yield; mp 104–106 ꢀC; 1H NMR
(300 MHz, CDCl3) d 1.94 (s, 1H), 2.41 (s, 3H), 2.73 (t,
J¼6.2 Hz, 2H), 3.14 (q, J¼6.0 Hz, 2H), 3.82 (s, 3H), 3.84
(s, 3H), 4.23 (dd, J¼1.2 Hz, 6.9 Hz, 2H), 4.64 (t, J¼
6.0 Hz, 1H), 5.90 (dt, J¼6.9 Hz, 8.9 Hz, 1H), 6.53 (d,
J¼8.9 Hz, 1H), 6.57 (s, 1H), 6.60 (s, 1H), 7.25 (d, J¼
8.1 Hz, 2H), 7.64 (d, J¼8.1 Hz, 2H); 13C NMR (75 MHz,
CDCl3) d 21.8, 33.1, 44.1, 56.2, 56.3, 59.6, 112.9, 113.4,
127.3, 128.3, 128.7, 129.9, 130.1, 132.1, 137.1, 143.7,
3.3.8. Methyl (Z)-3-{4,5-dimethoxy-2-[2-(trifluoroacetyl-
amino)ethyl]phenyl}prop-2-enyl carbonate (5b-1). To
a solution of 4b (166 mg, 0.5 mmol) and pyridine (1.0 mL)
in CH2Cl2 (10 mL) was added slowly methyl chloroformate
(52 mg, 0.55 mmol) in 3 mL CH2Cl2 (3 mL) at 0 ꢀC. After
stirring the mixture at 0 ꢀC for 3 h, the reaction was quenched
by saturated CuSO4, and aqueous phase was extracted with
diethyl ether four times. Combined organic layer was washed
with water and brine, and dried over MgSO4. Crude product

C. Shi, I. Ojima / Tetrahedron 63 (2007) 8563–8570
8569
was obtained after filtration and evaporation of the solvent.
Further purification by flash column chromatography on sil-
ica gel (hexanes/EtOAc¼3:1) afforded 5b-1 as a white solid
(185 mg, 95% yield). Mp 76.5–77.5 ꢀC; 1H NMR (300 MHz,
CDCl3) d 2.93 (t, J¼6.6 Hz, 2H), 3.58 (q, J¼6.6 Hz, 2H),
3.78 (s, 3H), 3.92 (s, 6H), 4.83 (dd, J¼1.2 Hz, 6.6 Hz, 2H),
5.91 (dt, J¼6.6 Hz, 11.4 Hz, 1H), 6.69 (s, 1H), 6.71 (s, 1H),
6.84 (d, J¼11.4 Hz, 1H), 6.85 (br s, 1H); 13C NMR (75 MHz,
CDCl3) d 32.0, 39.8, 54.8, 55.8, 56.0, 64.4, 113.1, 115.8 (q,
J¼286 Hz), 125.7, 126.9, 128.4, 132.7, 147.3, 148.7, 155.8,
157.3 (q, J¼37 Hz); HRMS (ESI) calcd for C17H20NO6F3Na
[M+Na]+ 414.1140, found 414.1156 (D¼3.9 ppm).
(300 MHz, CDCl3) d 2.86 (t, J¼6.9 Hz, 2H), 3.51 (q,
J¼6.3 Hz, 2H), 3.85 (s, 6H), 4.57 (dd, J¼2.1 Hz, 6.0 Hz,
1H), 4.84 (dd, J¼1.2 Hz, 6.9 Hz, 2H), 4.90 (dd, J¼2.1 Hz,
13.8 Hz, 1H), 5.87 (dt, J¼6.9 Hz, 11.4 Hz, 1H), 6.64 (s,
1H), 6.65 (s, 1H), 6.65 (br s, 1H), 6.81 (d, J¼11.4 Hz,
1H), 6.98 (dd, J¼6.0 Hz, 13.8 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 32.0, 39.9, 55.9, 56.0, 64.9, 98.2,
113.1, 115.9 (q, J¼286 Hz), 125.1, 126.8, 128.4, 133.2,
142.4, 147.4, 148.8, 152.8, 157.3 (q, J¼37 Hz); HRMS
(ESI) calcd for C18H20NO6F3Na [M+Na]+ 426.1140, found
426.1148 (D¼1.9 ppm).
3.3.13. Phenyl (Z)-3-{4,5-dimethoxy-2-[2-(trifluoroacetyl-
amino)ethyl]phenyl}prop-2-enyl carbonate (5b-3). Color-
less oil; 97% isolated yield; H NMR (300 MHz, CDCl3)
Other carbonates, 5a-1, 5a-2, 5b-2, 5b-3, and 5a-1-t, were
synthesized in the same manner as that described for 5b-1.
1
d 2.92 (t, J¼6.6 Hz, 2H), 3.54 (q, J¼6.6 Hz, 2H), 3.90 (s,
3H), 3.92 (s, 3H), 4.94 (dd, J¼1.2 Hz, 6.9 Hz, 2H), 5.99
(dt, J¼6.9 Hz, 11.4 Hz, 1H), 6.70 (s, 1H), 6.72 (s, 1H),
6.80 (br s, 1H), 6.90 (d, J¼11.4 Hz, 1H), 7.14 (m, 2H),
7.30 (m, 1H), 7.43 (m, 2H); 13C NMR (75 MHz, CDCl3)
d 31.9, 39.8, 55.8, 55.9, 65.0, 113.0, 115.6 (q, J¼286 Hz),
120.8, 125.0, 126.1, 126.7, 128.5, 129.4, 133.3, 147.2,
148.6, 150.8, 153.8, 157.2 (q, J¼37 Hz); HRMS (ESI) calcd
for C22H22NO6F3Na [M+Na]+ 476.1297, found 476.1313
(D¼3.4 ppm).
3.3.9. Methyl (Z)-3-{4,5-dimethoxy-2-[2-(4-methylbenz-
enesulfonylamino)ethyl]phenyl}prop-2-enyl carbonate
1
(5a-1). White solid; 95% isolated yield; mp 49–50 ꢀC; H
NMR (300 MHz, CDCl3) d 2.41 (s, 3H), 2.75 (t, J¼6.2 Hz,
2H), 3.17 (q, J¼6.0 Hz, 2H), 3.76 (s, 3H), 3.84 (s, 6H),
4.26 (dd, J¼1.2 Hz, 6.9 Hz, 2H), 4.61 (t, J¼6.0 Hz, 1H),
5.93 (dt, J¼6.9 Hz, 8.9 Hz, 1H), 6.55 (d, J¼8.9 Hz, 1H),
6.57 (s, 1H), 6.64 (s, 1H), 7.27 (d, J¼8.1 Hz, 2H), 7.64 (d,
J¼8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 21.8, 33.6,
43.8, 55.2, 56.2, 56.3, 64.8, 113.1, 113.2, 125.8, 127.3,
127.4, 128.9, 129.9, 132.9, 137.4, 143.6, 147.6, 149.0,
156.0; HRMS (ESI) calcd for C22H27NO7SNa [M+Na]+
472.1406, found 472.1395 (D¼ꢂ2.3 ppm).
3.3.14. tert-Butyl (Z)-3-{4,5-dimethoxy-2-[2-(4-methyl-
benzenesulfonylamino)ethyl]phenyl}-prop-2-enyl car-
bonate (5a-3). To a solution of 4a (195 mg, 0.5 mmol), (t-
Boc)2O (133 mg, 1 mmol), and Bu4NI (18 mg, 0.05 mmol)
in CH2Cl2 (5.0 mL) was added dropwise 1 mL 2 M NaOH
aqueous solution (1.0 mL) at 0 ꢀC. After addition, the mix-
ture was stirred overnight. The reaction was quenched by ad-
dition of water. The aqueous layer was separated and
extracted with CH2Cl2 three times. The combined organic
layer was washed with brine and dried over MgSO4. Crude
product was obtained after filtration and evaporation of the
solvent. Further purification by flash column chromato-
graphy on silica gel (hexanes/EtOAc¼2:1) afforded 5a-3
as a colorless oil (225 mg, 92%). 1H NMR (300 MHz,
CDCl3) d 1.46 (s, 9H), 2.41 (s, 3H), 2.72 (t, J¼7.2 Hz,
2H), 3.15 (q, J¼7.2 Hz, 2H), 3.83 (s, 6H), 4.53 (t,
J¼6.0 Hz, 1H), 4.59 (dd, J¼1.5 Hz, 6.9 Hz, 2H), 5.79 (dt,
J¼6.9 Hz, 11.4 Hz, 1H), 6.60 (s, 1H), 6.62 (d, J¼11.4 Hz,
1H), 6.64 (s, 1H), 7.27 (d, J¼6.3 Hz, 2H), 7.68 (d,
J¼6.6 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 21.5, 27.7,
33.3, 43.4, 55.9, 63.5, 83.3, 112.7, 112.9, 125.9, 127.0,
127.2, 128.5, 129.6, 132.0, 137.1, 143.3, 147.3, 148.5,
153.3; HRMS (ESI) calcd for C25H33NO7SNa [M+H]+
514.1875, found 514.1878 (D¼0.6 ppm).
3.3.10. Ethenyl (Z)-3-{4,5-dimethoxy-2-[2-(4-methylbenz-
enesulfonylamino)ethyl]phenyl}prop-2-enyl carbonate
1
(5a-2). White solid; 94% isolated yield; mp 68–70 ꢀC; H
NMR (300 MHz, CDCl3) d 2.41 (s, 3H), 2.72 (t, J¼7.2 Hz,
2H), 3.10 (q, J¼7.2 Hz, 2H), 3.83 (s, 6H), 4.57 (dd,
J¼1.2 Hz, 6.0 Hz, 1H), 4.64 (t, J¼5.7 Hz, 1H), 4.71 (dd,
J¼1.2 Hz, 6.6 Hz, 2H), 4.91 (dd, J¼1.2 Hz, 11.1 Hz, 1H),
5.81 (dt, J¼6.9 Hz, 14.4 Hz, 1H), 6.62 (s, 2H), 6.69 (d,
J¼14.4 Hz, 1H), 7.04 (dd, J¼6.0 Hz, 11.1 Hz, 1H), 7.27
(d, J¼6.3 Hz, 2H), 7.68 (d, J¼6.6 Hz, 2H); 13C NMR
(75 MHz, CDCl3) d 21.4, 33.3, 43.4, 55.9, 64.9, 97.9,
112.7, 112.9, 124.9, 126.9, 127.0, 128.6, 129.6, 133.2,
137.0, 142.6, 143.3, 147.4, 148.7, 152.6; HRMS (ESI) calcd
for C23H28NO7S [M+H]+ 462.1586, found 462.1583
(D¼ꢂ0.6 ppm).
3.3.11. Methyl (E)-3-{4,5-dimethoxy-2-[2-(4-methylbenz-
enesulfonylamino)ethyl]phenyl}prop-2-enyl carbonate
(5a-1-t). Colorless oil; 96% isolated yield; 1H NMR
(300 MHz, CDCl3) d 2.41 (s, 3H), 2.82 (t, J¼6.9 Hz, 2H),
3.12 (q, J¼6.9 Hz, 2H), 3.80 (s, 3H), 3.83 (s, 3H), 3.86 (s,
3H), 4.58 (t, J¼6.3 Hz, 1H), 4.75 (dd, J¼1.2 Hz, 6.6 Hz,
2H), 6.03 (dt, J¼6.6 Hz, 15.3 Hz, 1H), 6.55 (s, 1H), 6.78
(d, J¼15.3 Hz, 1H), 6.90 (s, 1H), 7.26 (d, J¼8.1 Hz, 2H),
7.67 (d, J¼8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d 21.5, 33.1, 43.9, 54.8, 55.9, 68.6, 109.1, 112.8, 122.8,
127.0, 127.4, 128.3, 129.6, 132.0, 137.0, 143.3, 148.0,
149.2, 155.6; HRMS (ESI) calcd for C22H27NO7SNa
[M+Na]+ 472.1406, found 472.1397 (D¼ꢂ1.9 ppm).
3.4. Intramolecular asymmetric allylic amination
3.4.1. 1-Ethenyl-2-trifluoroacetyl-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (7b).
A solution of ligand
L1d (3.5 mg, 0.0075 mmol) and Pd2(dba)3 (1.2 mg,
0.00125 mmol) in CH2Cl2 (0.5 mL) was added to a 5 mL
round-bottomed flask with a stirring bar under N2. The solu-
tion was stirred at room temperature until the color of the
solution turned to light yellow from purple. Then, 5b-3
(23 mg, 0.05 mmol) in CH2Cl2 (0.5 mL) was added to the
catalyst solution via a syringe. The mixture was stirred at
room temperature until TLC indicated completion of the
3.3.12. Ethenyl (Z)-3-{4,5-dimethoxy-2-[2-(trifluoroace-
tylamino)ethyl]phenyl}prop-2-enyl carbonate (5b-2).
1
White solid; 93% isolated yield; mp 59–60.5 ꢀC; H NMR

8570
C. Shi, I. Ojima / Tetrahedron 63 (2007) 8563–8570
reaction. The reaction mixture was passed through a short
pad of silica gel using hexanes/EtOAc (10:1–6:1) as the elu-
ent. The filtrate was then concentrated and subject to HPLC
analysis, using a Chiralcel OD-H column (hexanes/i-PrOH¼
98:2, 0.5 mL/min), which indicated that the enantiopurity of
the product 7b was 95% ee with 100% conversion and prod-
uct selectivity. The product 7b was isolated as colorless oil
as a mixture of two rotamers in 75:25 ratio (determined by
References and notes
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1
1H NMR at 25 ꢀC). [a]2D3 169.7 (c 0.40, CHCl3); H NMR
(400 MHz, CDCl3) d 2.68–2.78 (m, 1H), 2.91–3.01 (m,
1H), 3.01–3.28 (m, 0.25H), 3.50–3.58 (m, 0.75H), 3.83 (s,
2.25H), 2.854 (s, 2.25H), 3.85 (s, 0.75H), 3.86 (s, 0.75H),
3.99–4.04 (m, 0.75H), 4.47–4.52 (m, 0.25H), 5.01–5.17 (m,
1H), 5.29–5.33 (m, 1H), 5.43–5.45(m, 0.25H), 5.91–6.07 (m,
1.75H), 6.59 (s, 0.75H), 6.61 (s, 0.75H), 6.55 (s, 0.25H), 6.63
(s, 0.25H); 13C NMR (100 MHz, CDCl3) Major: d 28.9, 40.2,
55.8, 56.1, 56.2, 110.9, 111.3, 116.8 (q, J¼287 Hz), 118.9,
125.0, 125.5, 135.9, 148.1, 148.6, 155.9 (q, J¼26 Hz);
Minor: d 27.5, 38.0, 56.2, 56.3, 58.1, 110.5, 111.7, 116.8
(q, J¼287 Hz), 118.7, 124.7, 126.3, 136.8, 148.0, 148.9,
156.0 (q, J¼26 Hz); HRMS (ESI) calcd for C15H17NO3F3
[M+H]+ 316.1161, found 316.1164 (D¼0.9 ppm).
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3.4.2. 1-Ethenyl-2-(4-methylbenzenesulfonyl)-6,7-di-
methoxy-1,2,3,4-tetrahydroisoquinoline (7a). This com-
pound was obtained in the same manner as that described
for 7b. White solid; 87% isolated yield; 74% ee (Chiralpak
AD-RH; CH3CN/H2O¼50:50, 0.5 mL/min); mp 137–
138 ꢀC; [a]D23 67 (c 0.03, CHCl3); 1H NMR (300 MHz,
CDCl3) d 2.37 (s, 3H), 2.47–2.52 (m, 1H), 2.63–2.75 (m,
1H), 3.25–3.35 (m, 1H), 3.81 (s, 3H), 3.83 (s, 3H), 3.87–
3.88 (m, 1H), 5.05 (dt, J¼1.5 Hz, 17.1 Hz, 1H), 5.17 (dt,
J¼1.5 Hz, 10.2 Hz, 1H), 5.46 (d, J¼5.4 Hz, 1H), 5.90
(ddd, J¼5.4 Hz, 10.2 Hz, 17.1 Hz, 1H), 6.64 (s, 1H), 6.52 (s,
1H), 7.19 (d, J¼6.3 Hz, 2H), 7.66 (d, J¼6.3 Hz, 2H); 13C
NMR (75 MHz, CDCl3) d 21.4, 27.2, 39.1, 55.8, 55.9,
57.7, 110.4, 111.3, 117.6, 125.4, 125.6, 127.1, 129.4,
137.3, 137.9, 143.0, 147.4, 148.0; HRMS (ESI) calcd
for C20H24NO4S [M+H]+ 374.1426, found 374.1436
(D¼2.7 ppm).
Acknowledgements
23. Hua, Z.; Vassar, V.; Choi, H.; Ojima, I. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5411–5416.
This work was supported by a grant from the National Sci-
ence Foundation. Generous support from Mitsubishi Chem-
ical Corporation is also gratefully acknowledged. The
authors thank Stephen Chaterpaul and Kimberly Odynocki
for technical assistance.
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2006, 17, 642–657.