Enantioselective synthesis of 1-vinyltetrahydroisoquinolines via Pd-catalyzed intramolecular asymmetric allylic amination reactions

Article abstract of DOI:10.1016/j.tet.2011.05.125

1-Vinyltetrahydroisoquinolines serve as versatile intermediates for the synthesis of a variety of naturally occurring isoquinoline alkaloids. 1-Vinyl-6,8-dimethoxytetrahydroisoquinoline 4 and 1-vinyl-5,6,7- trimethoxytetrahydroisoquinoline 6 with >90% ee by means of Pd-catalyzed intramolecular asymmetric allylic amination reactions, using MPN and BOP ligands, developed in our laboratory. The fine-tuning capability of the MPN and BOP ligands has played a significant role in the optimization of enantioselectivity. Interesting substituent effect as well as solvent effect on the product selectivity and enantioselectivity was observed. Plausible mechanisms are proposed, which can accommodate various findings, including the critical importance of the activation of the trifluoroamide moiety through its coordination to the Lewis acidic Pd²⁺ metal center.

Full text of DOI:10.1016/j.tet.2011.05.125

Tetrahedron 67 (2011) 6513e6523
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioselective synthesis of 1-vinyltetrahydroisoquinolines via Pd-catalyzed
intramolecular asymmetric allylic amination reactions
*
Chih-Wei Chien, Ce Shi, Chi-Feng Lin, Iwao Ojima
Department of Chemistry, Stony Brook UniversitydState University of New York, Stony Brook, NY 11794-3400, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 April 2011
Received in revised form 29 May 2011
Accepted 30 May 2011
Available online 2 June 2011
1-Vinyltetrahydroisoquinolines serve as versatile intermediates for the synthesis of a variety of naturally
occurring isoquinoline alkaloids. 1-Vinyl-6,8-dimethoxytetrahydroisoquinoline 4 and 1-vinyl-5,6,7-tri-
methoxytetrahydroisoquinoline 6 with >90% ee by means of Pd-catalyzed intramolecular asymmetric
allylic amination reactions, using MPN and BOP ligands, developed in our laboratory. The fine-tuning
capability of the MPN and BOP ligands has played a significant role in the optimization of enantiose-
lectivity. Interesting substituent effect as well as solvent effect on the product selectivity and enantio-
selectivity was observed. Plausible mechanisms are proposed, which can accommodate various findings,
including the critical importance of the activation of the trifluoroamide moiety through its coordination
to the Lewis acidic Pd2þ metal center.
Dedicated to Professor Satoshi Omura for
his outstanding contribution for the ad-
vancement of organic, natural products and
medicinal chemistry
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Tetrahydroisoquinoline
Asymmetric allylic amination
Palladium
Phosphoramidite ligand
Phosphonite ligand
1. Introduction
3,4-dihydroisoquinolines13,14 as well as 1-alkylidenetetrahyd-
roisoquinolines,15 and other transformations.16 In 2003, a Pd-
Development of efficient methods for the synthesis of C1-
substituted tetrahydroisoquinolines has attracted much interest
among synthetic organic chemists, mainly due to the interesting
pharmacological properties these alkaloids possess.1 Members of
this family (Fig. 1) have shown diverse activities,2 e.g., anti-
inflammatory properties,3,4 neuromuscular transmission blocking,5
anti-platelet aggregation activity,6 enzyme inhibitory activities for
catalyzed intramolecular asymmetric allylic amination (AAA) of
catalyzed by a Pd catalyst with a chiral P,N-ligand in the presence of
a
strong base was reported, which gave 6,7-dimethoxy-1-
vinyltetrahydroisoquinoline in a single step, introducing chirality
at the C1 position.17 Although high enantioselectivity (82e88% ee)
was realized under optimized conditions, the catalytic activity of
this system was insufficient since it required 12e23 days to reach
synthetically meaningful conversions.
acetylcholinesterase (AChE),7 and -glucosidase.8 Thus, in order to
a
study the biological and pharmacological activities of this class of
compounds, the efficient synthesis of these alkaloids in enantio-
merically pure form is of great importance.
Optically active C1-substituted tetrahydroisoquinolines has
been prepared through diastereoselective reactions for the in-
troduction of chirality at the C1 position. Other methods utilizing
enantioselective reactions to introduce the chirality at the C1 po-
sition have been developed in the past decade, e.g., enantioselective
PicteteSpengler reaction,9 alkylation, vinylation or cyanation of
3,4-dihydroisoquinolines,10e12 asymmetric hydrogenation of
In order to achieve excellent efficiency and enantioselectivity,
the selection of suitable chiral ligands for this process is essential.
We have been developing a library of novel enantiopure mono-
dentate phosphite,18 and phosphoramidite (MPN)19e22 ligands
based on axially chiral biphenols. These ligands can be readily
prepared and are fine-tunable for a variety of catalytic asymmetric
reactions, e.g., asymmetric hydrogenation,18 asymmetric hydro-
formylation,19 asymmetric conjugate additions to cycloalkenones
and nitroalkenes,19,20 and asymmetric allylic alkylation as well as
its application to the total synthesis of (þ)-
g
-lycorane.21,22
Since a couple of these chiral MPN ligands were found to be
extremely effective (up to 99.7% ee) in the Pd-catalyzed asymmetric
allylic alkylation mentioned above,21,22 we anticipated that this type
of ligands would be effective for this AAA process. Thus, we
* Corresponding author. Tel.: þ1 631 632 1339; fax: þ1 631 632 7942; e-mail
address: iojima@notes.cc.stonybrook.edu (I. Ojima).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.125

6514
C.-W. Chien et al. / Tetrahedron 67 (2011) 6513e6523
H
O
MeO
N
COCF3
MeO
OMe
H
Pd2(dba)3 / L*
solvent, temp.
O
OMe
OMe
MeO
MeO
N
N
∗
OMe
MeO
OMe
OCO2C2H3
COCF3
N
N
MeO
MeO
MeO
MeO
N
3
4
OMe
OMe
O
H
N
MeO
OMe
(-)- -methylthaicanine
O
Isopyruthaline
MeO
COCF3
MeO
MeO
Pd2(dba)3 / L*
solvent, temp.
∗
MeO
MeO
OCO2R
COCF3
MeO
MeO
N
5a
: R = Ph
5h: R = 4-FPh
5i:
6
MeO
N
5b: R = CH2CCl3
5c: R = CH2CF3
R = 4-ClPh
O
O
5j: R = 3-FPh
5k:
5d
: R = CH=CH2
R = F5Ph
: R = 4-NO2Ph
(S)-Sinactine
(S)-Crispine A
5e: R = C(Me)=CH2 5l
5f
: R = 4-MeOPh
5m: R = 2,6-Me2Ph
5n
5g: R = 4-MePh
: R = 2,6-iPr2Ph
8
20'
HO
OSO3Na
Scheme 2. AAA reactions of 3 and 5.
6
R2
R1
NaO3SO
H
17'
N
O
O
11b
14'
OH
1
3
N
H
R2
R2
OSO3Na
R1
1
(C11b-Hβ; R = Me, R2 = H)
Schulzeine A
R3
Schulzeine B (C11b-Hα; R1, R2 = H);
1
2
Schulzeine C
(C11b-Hβ; R , R = H)
O
O
O
O
P
N
P
N
Fig. 1. Selected naturally occurring C1-substituted tetrahydroisoquinolines.
R3
R2
R1
R2
employed chiral MPN ligands to this intramolecular AAA reaction of
1, which indeed gave 2 with excellent enantioselectivity (up to 96%
ee) and high catalyst activity under neutral conditions (Scheme 1).23
(S)-MPN-La: R1 = H
(R)-MPN-Lf: R2 = H, R3 = Ph
MPN-Lb
(S)-
(S)-
(S)-
: R1 = Me
: R1 = Br
: R1 = Ph
MPN-Lg
(S)-
(R)-
(R)-
: R2 = Me, R3 = Ph
MPN-Lc
MPN-Ld
: R = Ph, R3 = H
2
MPN-Lh
MPN-Li
: R2 = H, R3 = 2-Np
(S)-MPN-Le: R1 = t-Bu
(S)-MPN-Lj: R2 = H, R3 = 1-Np
MeO
Pd2(dba)3
L*
MeO
MeO
NHCOCF3
OCO2R'
N
*
CH2Cl2, r.t.
MeO
COCF3
2
R4
1
R5
up to 96% ee
Scheme 1. Highly efficient AAA reaction of 1.
OPPh2
OPPh2
OPAr2
OPAr2
We have also developed a library of novel chiral bidentate
bisphosphonite (BOP) ligands based on axially chiral biphenols and
successfully applied it to the intermolecular AAA reaction.24
Building upon the successful application of our MPN ligands
tothe enantioselective synthesis of 6,7-dimethoxy-1-vinyltetrahyd-
roisoquinoline 2 through Pd-catalyzed AAA reaction (Scheme 1), we
have expanded the scope of the AAA reaction to the enantioselective
synthesis of 6,8-dimethoxy-1-vinyltetrahydroisoquinoline 4 and
R5
R4
: R4 = H
BOP-La
(R)-BOP-Le: R5 = Ph, Ar = Ph
(R)-
(R)-
5
: R4 = Me
(R)-
: R = p-Tolyl, Ar = Ph
BOP-Lb
BOP-Lf
(R)-BOP-Lc: R4= Br
(R)-BOP-Ld: R4= Ph
: R5 = 3,5-m-Xylyl, Ar = Ph
BOP-Lg
(R)-
(R)-BOP-Lh: R5 = H, Ar = p-Tolyl
(R)-BOP-Li: R5 = H, Ar = 3,5-m-Xylyl
5,6,7-trimethoxy-1-vinyl>tetrahydroisoquinoline
6 (Scheme 2),
Fig. 2. Phosphoramidite (MPN) and bisphosphonite (BOP) ligands.
using MPN and BOP ligands (Fig. 2), which serve as versatile in-
termediates for the synthesis of naturally occurring alkaloids ex-
emplified in Fig. 1. We describe here unexpected substituent effects
of methoxy groups on the AAA reaction and interesting mechanistic
implications, besides the synthetic utility of the process.
iodinated side product was observed. The Sonogashira coupling
of 8 with propargyl alcohol proceeded rather slowly, but gave 9 in
high yield. Selective hydrogenation of 9 over P2eNi catalyst gave
cis-allylic alcohol 10 exclusively. Acylation of 10 with vinyl chloro-
formate gave allyl vinyl carbonate 3 in excellent yield.
2. Results and discussion
In a similar manner, 3,4,5-trimethoxy-2-(2-trifluoroacetamid-
oethyl)phenylallyl carbonates 5aen were prepared with some
modifications, as illustrated in Scheme 4. The nitro-aldol reaction of
commercially available 2,3,4-trimethoxybezaldehyde 11 gave (E)-
nitroalkene 12 exclusively. Nitroalkene 12 was reduced to amine 13
by LiAlH4, followed by reaction with trifluoroacetic anhydride to
give trifluoroacetamide 14. In order to introduce iodine at ortho to
the trifluoroacetamidoethyl group, bromination of 14 with NBS was
used to block the meta position, giving 15. The iodination of 15 by
N-iodosuccinimide (NIS) afforded 16 in 94% yield. The Sonogashira
coupling of 16 with propargyl alcohol took place selectively with
2.1. Preparation of allylic carbonate substrates
4,6-Dimethoxy-2-(2-trifluoroacetamidoethyl)phenylallyl car-
bonate
3 was prepared as illustrated in Scheme 3. 3,5-
Dimethoxyphenylethylamide 7 was obtained by the literature
procedure.25,26 The synthetic procedure from 7 to 3 largely fol-
lowed the protocol reported by us for the preparation of 1,23 which
was a modification of the Katsuki procedure.17 In the iodination
step, an iodine/silver sulfate combination was found to be more
efficient than ICl to give 8, although the formation of some bis-

C.-W. Chien et al. / Tetrahedron 67 (2011) 6513e6523
6515
H
N
H
N
high level of enantioselectivity as that observed in the reactions of
1.23 As Table 1 shows, the best result was 47% ee (entry 3) when (S)-
MPN-Lc (R1¼Br) was used as the chiral ligand. (S)-MPN-Ld (R¼Ph),
which achieved 95e96% ee in the AAA reaction of 1,23 gave only 29%
ee (entry 4). (S)-MPN-La (R1¼H) afforded (R)-(þ)-4 with 26% ee
(entry 1), which has the opposite configuration to that induced by
all other MPN ligands examined. The results appear to indicate that
the methoxy group at the C3 position of 3, which is ortho to the allyl
carbonate moiety, is responsible for the observed marked difference
in enantioselectivity for the AAA reaction of 1 and that of 3.
MeO
MeO
MeO
COCF3
MeO
MeO
COCF3
a
c
b
I
OMe
OMe
7
8
H
N
H
N
COCF3
OH
COCF3
OH
d
OMe
10
OMe
9
Table 1
H
N
COCF3
Efficacy of MPN ligands in the Pd-catalyzed AAA reaction of 3
OCO2CH=CH2
OMe
3
Scheme 3. Preparation of AAA substrate 1 Reagents and conditions: (a) Ag2SO4, I2,
EtOH, 0 ꢀC, 6 h, 88%; (b) Pd(PPh3)2Cl2, CuI, propargyl alcohol, i-Pr2NH, rt, 48 h, 83%; (c)
P2eNi, EtOH, H2 (1 atm), rt, 16 h, 97%; (d) ClCO2C2H3, pyridine, CH2Cl2, 0 ꢀC, 1.5 h, 93%.
Entrya
Ligand
Time (h)
Conv.b (%)
4 eec (%)
1
2
3
4
(S)-MPN-La
(S)-MPN-Lb
(S)-MPN-Lc
(S)-MPN-Ld
10
16
22
48
>95
>95
>95
>95
26 (R)
19 (S)
47 (S)
29 (S)
the iodide to give 17. Subsequent hydrogenation of 17 over P2eNi
not only reduced the triple bond, but also removed the bromine to
afford the corresponding (Z)-allylic alcohol 18. Finally, the (Z)-allylic
alcohol 18 was acylated with different chloroformates to give the
corresponding allylic carbonates 5aen.
a
Reaction was run with 3 (0.05 mmol), Pd2(dba)3 (1.25ꢁ10ꢂ4 mmol), and MPN-L
(7.50ꢁ10ꢂ4 mmol) in CH2Cl2 (1.0 mL) at room temperature.
b
Determined by 1H NMR.
Determined by chiral HPLC analysis (OD-H column, isopropanol/hexanes¼0.5/
c
OMe O
OMe
OMe
99.5), flow rate: 0.5 mL/min.
MeO
MeO
MeO
MeO
NO2
MeO
MeO
NH2
b
H
a
Since none of simple MPN ligands gave encouraging result, we
examined the efficacy of BOP ligands, (R)-BOP-Laei, in this AAA
reaction. Results are summarized in Table 2. The reactions pro-
ceeded very smoothly in DMF at room temperature and completed
in 1.5e8 h. Among the first four BOP ligands employed (BOP-Laed),
which bears H, Me, Br, and Ph groups at the 3,30 positions, BOP-Lc
(R4¼Br) gave the best result, i.e., 72% ee (entry 3). However, BOP-Le
(R5¼Ph and Ar¼Ph) achieved even better result, giving (S)-(þ)-4
with 79% ee (entry 5). Enantioselectivity was further increased to
84% ee and 88% ee by introducing 4-methylbenzyl (BOP-Lf) and
3,5-dimethylbenzyl (BOP-Lg) groups, respectively, in place of
benzyl group (entries 6 and 9). Introduction of p-tolyl (BOP-Lh) and
3,5-xylyl (BOP-Li) groups as Ar moiety, keeping methyl groups as
the 3,30 substituents, also improved the enantioselectivity to 72% ee
and 80% ee, respectively (entries 12 and 13), as compared to 68% ee
achieved by the parent ligand, BOP-Lb (entry 2).
11
12
13
OMe
OMe
H
H
N
MeO
MeO
N
COCF3
MeO
MeO
COCF3
d
c
e
g
Br
14
15
OMe
OMe
H
N
H
MeO
MeO
COCF3
OH
MeO
MeO
N COCF3
f
I
Br
Br
16
17
OMe
OMe
H
H
N
MeO
MeO
N
COCF3
OH
MeO
MeO
COCF3
OCO2R
h
Table 2
The Pd-catalyzed AAA reaction of 3 with BOP ligands
Entrya
Ligand
Temp (ꢀC)
Time (h)
Conv.b (%)
4 (S) eec (%)
18
5a-n
1
2
3
4
5
6
7
8
(R)-BOP-La
(R)-BOP-Lb
(R)-BOP-Lc
(R)-BOP-Ld
(R)-BOP-Le
(R)-BOP-Lf
(R)-BOP-Lf
(R)-BOP-Lf
(R)-BOP-Lg
(R)-BOP-Lg
(R)-BOP-Lg
(R)-BOP-Lh
(R)-BOP-Li
rt
rt
rt
rt
rt
rt
0
1.5
4
8
8
6
>95
>95
>95
>95
>95
>95
>95
<5
>95
>95
<5
>95
>95
35
68
72
68
79
84
88
nd
88
90
nd
72
80
Scheme 4. Preparation of carbonates 5aen. Reagents and conditions: (a) NH4OAc,
CH3NO2, 100 ꢀC, 1 h, 91%; (b) LiAlH4, THF, 65 ꢀC, 3 h; (c) (CF3CO)2O, NEt3, CH2Cl2, 0 ꢀC,
1.5 h, 65% for two steps; (d) NBS, CCl4, 60 ꢀC, 16 h, 92%; (e) NIS, CF3CO2H, CH3CN, reflux,
24 h, 94%; (f) Pd(PPh3)2Cl2, CuI, propargyl alcohol, i-Pr2NH, reflux, 18 h, 75%; (g) P2eNi,
EtOH, H2 (1 atm), rt, 40 h, 75%; (h) ClCO2R, pyridine, CH2Cl2, 0 ꢀC, 3 h, 71e99%.
8
24
48
8
24
48
8
2.2. AAA reaction of allylic carbonate 3
ꢂ25
9
rt
10
11
12
13
0
The Pd-catalyzed AAA reaction of 4,6-dimethoxyphenylallyl
carbonate 3 was first carried out using MPN ligands under the same
conditions as those employed in the reaction of 4,5-dimethox-
yphenylallyl carbonate 1,23 which gave excellent results (Scheme 1).
The reaction proceeded smoothly to give (S)-(þ)-tetrahy-
droisoquinoline 4 in excellent yield (Table 1). To our surprise,
however, the reactions using (S)-MPN-Laed did not give the same
ꢂ25
rt
rt
12
a
Reaction was run with 3 (0.05 mmol), Pd2(dba)3 (1.25ꢁ10ꢂ3 mmol) and BOP-L
(3.75ꢁ10ꢂ3 mmol) in DMF (1.0 mL).
b
See the captions in Table 1.
See the captions in Table 1.
c

6516
C.-W. Chien et al. / Tetrahedron 67 (2011) 6513e6523
Lowering the reaction temperature from room temperature to
ꢀC improved enantioselectivity to 88% ee (from 84% ee, entry 7)
for BOP-Lf and to 90% ee (from 88% ee, entry 9) for BOP-Lg.
However, at ꢂ25 ꢀC, the reaction was basically shut down (entries 8
and 11).
were employed to assess their effects on the AAA reaction, using
0
(S)-MPN-Le. As Table 3 shows (entries 6e12), there is a remarkable
solvent effect on this reaction. The reaction in acetonitrile gave
opposite enantiomer, (R)-(ꢂ)-6 with low enantiopurity (entry 8).
Also, the formation of side product 22a is enhanced in less polar or
non-polar solvents (entries 9e12). The results may imply a possible
involvement of hydrogen bonding somewhere in the mechanism.
Next, we examined the efficacy of newer MPN ligands, bearing
benzyl-type substituents, i.e., PhCH2, PhCMe2, Ph2CH, 2-NpCH2, and
1-NpCH2, at the 3,30 positions, MPN-Lfej in this reaction. Results are
summarized in Table 4. Reaction using (R)-MPN-Lf in CH2Cl2 at room
temperature gave 6 with 85% ee in 57% yield (entry 1). Introduction
of bulkier substituents, PhCMe2 (MPN-Lg), and Ph2CH (MPN-Lh) did
not improve the enantioselectivity (entries 2 and 3). However, the
use of 2-NpCH2 (MPN-Lh) or 1-NpCH2 (MPN-Lh) group in place of
benzyl group was beneficial to improve the yield of 6 (entries 4 and
5), and the reaction using (S)-MPN-Lj induced 85% ee, which was the
same as that by MPN-Lf, but yield of 6 was better (65%) (entry 5).
The reaction using (S)-MPN-Lj at 0 ꢀC improved enantioselectivity to
88% ee, but the side product formation increased as well (entry 6). In
a manner similar to the solvent effect observed for the reactions
using (S)-MPN-Le (see Table 3), the use of polar solvent, such as DMF
clearly improves the product selectivity to form 6, but enantiose-
lectivity was lowered (entry 8).
In the hope of minimizing the formation of side product 22, we
prepared various allylic carbonates 5ben and examined the effects
of the substituents on the product selectivity, using (S)-MPN-Lj as
the chiral ligand. Results are summarized in Table 5. When
electron-withdrawing substituents, i.e., CH2CCl3 (5b) and CH2CF3
(5c), were used, no or minimum amount of 22 was formed (entries
1 and 2). The use of vinyl ethers, CH]CH2 (5d) and C(Me)¼CH2
(5e), also eliminated the formation of 22 (entries 3 and 4). In these
four substrates, however, enantioselectivity was 66e79% ee.
Introduction of strongly electron-withdrawing or very bulky sub-
stituents, i.e., C6F5 (5k), 4-NO2C6H4 (5l), 2,6-Me2C6H3 (5m) and 2,6-
i-Pr2C6H3 (5n), effectively blocks the formation of 22 as well
(entries 10e13). It is noteworthy that allyl carbonates with strongly
electron-withdrawing group on the phenyl moiety almost shut
down the reaction (entries 10 and 11). The results imply that the
basicity of the leaving group, i.e., aryloxide ion, has a significant role
2.3. AAA reactions of allylic carbonates 5aen
The Pd-catalyzed AAA reaction of 3,4,5-trimethoxylphenylallyl
carbonate 5d was first carried out in DMF at room temperature,
using (R)-BOP-Lg ligand since this ligand gave the best result (90%
ee), so far, in the reaction of 3, as described above. However, again
to our surprise, the reaction gave (S)-(þ)-tetrahydroisoquinoline 6
with only 42% ee although the reaction was very fast, clean and
completed in 2 h. We also tried one of Trost’s representative
modular ‘DPPBA ligand’, (1R,2R)-N,N0-bis(20-diphenylphosphino-
benzoyl)-1,2-diaminocyclohexane,27 under the same conditions,
but the conversion was only 18% after 120 h and enantioselectivity
was 13% ee. Accordingly, we screened MPN ligands as well as sol-
vents for the reaction of 5a (R¼Ph), which achieved excellent re-
sults in the reaction of 1 (Scheme 1). Results are summarized in
Table 3. When the AAA reaction was run in DMF, using (S)-MPN-
Laee, it proceeded fast and completed in 4e7 h to give 6 in ex-
cellent yield (entries 1e3 and 6), except for (S)-MPN-Ld (entry 4).
The best result in DMF (64% ee) was obtained with (S)-MPN-Le
(entry 6). Since the reaction in DMF using (S)-MPN-Ld, was slow,
for some reason, we ran the reaction in CH2Cl2 with all other re-
action variables intact. Then, the reaction was very fast and gave 6
with 78% ee (entry 5). However, the yield of 6 was reduced to 58%
with the unexpected formation of allyl phenyl ether 22a (R¼Ph) as
the side product. This side product 22a should have been formed by
the attack of a phenoxide ion, which was generated upon formation
of p-allylic Pd intermediate 20a, on the p-allyl system (Scheme 5).
The formation of 22a is conceptually possible if the intramolecular
attack of the trifluoroamide is slow. Nevertheless, we never ob-
served such a side product in the reactions of 1 and 3.28 Therefore,
this result strongly suggests that there must be some unique reason
for the slow nucleophilic cyclization for 20a, which allows the
phenoxide ion to compete.
Table 3
in the formation of p-allylic Pd complex 20 (see Scheme 5). Other
Screening of MPN ligands for the AAA reaction of 5a
allyl carbonates, bearing 4-MeO (5f), 4-Me (5g), 4-F (5h), 4-Cl (5i)
and 3-F (5j) on the phenyl moiety, led to 83e89% ee, but with
modest to substantial formation of 22 (entries 5e9).
We examined the effects of additives on the product selectivity
and enantioselectivity in the AAA reactions of several allylic car-
bonate substrates in CH2Cl2. As mentioned above, there seemed to
be a possible involvement of hydrogen bonding when the reaction
was run in non-polar solvents. Accordingly, we added tert-butanol,
trifluoroethanol (TFE), and hexafluoroisopropanol (HFIPA). Results
are shown in Table 6.
Entrya Ligand
Solvent
(S)-MPN-La DMF
(S)-MPN-Lb DMF
Time (h) Conv.b (%) 6b (%) 6 (S) eec (%)
1
2
7
7
>95
>95
>95
>95
>95
>95
>95
91
98
98
94
97
58
93
90
77
55
31
29
24
24 (þ)
23 (þ)
46 (þ)
68 (þ)
78 (þ)
64 (þ)
64 (þ)
17 (ꢂ) (R)
62 (þ)
40 (þ)
15 (þ)
29 (þ)
3
4
5
6
7
8
9
(S)-MPN-Lc DMF
(S)-MPN-Ld DMF
(S)-MPN-Ld CH2Cl2
(S)-MPN-Le DMF
(S)-MPN-Le NMP
(S)-MPN-Le CH3CN
(S)-MPN-Le THF
4
70
3
7
4
The reaction of 5a in CH2Cl2 with 1% (v/v) t-BuOH did not im-
prove the selectivities (entry 1). In contrast, the addition of 1% (v/v)
TFE to the reaction of 5a increased the enantioselectivity to 91% ee
(from 85% ee in pure CH2Cl2: see Table 4), giving 6 in 66% yield
(entry 2), where in the only side product was 22a. However, when
5% (v/v) TFE was used, the yield of 6 was dramatically reduced to
only 13% (94% ee) and two side products, i.e., 22a (39%) and 22c
(R¼CF3CH2, 48%), were formed (entry 3). When 1% (v/v) HFIPA was
70
4
4
4
4
>95
>95
>95
>95
10
11
12
(S)-MPN-Le (CH2Cl)2
(S)-MPN-Le CH2Cl2
(S)-MPN-Le Toluene
a
Reaction was run with 5a (0.05 mmol), Pd2(dba)3 (1.25ꢁ10ꢂ3 mmol), and MPN-
added, the formation of
a mixture of 22a (33%) and 22o
L (7.50ꢁ10ꢂ3 mmol) in DMF (1.0 mL).
b
The conversion and product yield were determined by 1H NMR.
Determined by chiral HPLC (OD-H column, eluent: isopropanol/hexanes¼1.2/
(R¼(CF3)2CH, 67%) was observed (entry 4).
c
In the reaction of 5d, the addition of 1% (v/v) TFE improved the
enantiopurity of 6 to 85% ee (from 76% ee in pure CH2Cl2: see Table
4) with 88% product selectivity (entry 6). The addition of 0.5% (v/v)
TFE, however, did not have appreciable effects (entry 5). With 1% (v/
v) HFIPA, the reaction was slowed down and the exclusive
98.8), flow rate: 1 mL/min.
Since the choice of solvent showed marked effects on the re-
action process and enantioselectivity, several different solvents

C.-W. Chien et al. / Tetrahedron 67 (2011) 6513e6523
6517
OMe
MeO
H
N
MeO
COCF3
OCO2R
MeO
MeO
L*2Pd(0)
N
MeO
*
COCF3
MeO
5a-n
6
MeO
H
N
MeO
MeO
MeO
MeO
COCF3
OCO2R
N
*
COCF3
L*2Pd(0)
19
21
L*2Pd(0)
+
MeO
MeO
H
N
CO2
H
N
MeO
MeO
-OR
COCF3
OR
MeO
MeO
COCF3
PdL*2
20
22
Scheme 5. Proposed mechanism for the intramolecular AAA reaction of 5.
Table 6
Table 4
Pd-catalyzed AAA reaction of 5a with MPN-Lfej
Effects of additives on the AAA reaction of 5 using (S)-MPN-Lj in CH2Cl2
Entrya Carbonate Additive Time (h) Conv.b (%) 6b (%) 6 (S) eec (%)
Entrya
Ligand
Solvent
Time (h)
Conv.b (%)
6b (%)
6 eec (%)
1
2
3
4
5
6
7
8
5a
5a
5a
5a
5d
5d
5d
5d
5e
5e
5e
5m
% t-BuOH
1% TFE
5% TFE
1% HFIPA
0.5% TFE
1% TFE
1% HFIPA
1% t-BuOH
1% t-BuOH
1% TFE
2
2
24
2
2
2
48
2
2
2
2
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
66d
66d
13e
0f
82 (þ)
91 (þ)
94 (þ)
nd
76 (þ)
85 (þ)
nd
79 (þ)
74 (þ)
87 (þ)
91 (þ)
86 (þ)
1
2
3
4
5
6d
7
8
(R)-MPN-Lf
(S)-MPN-Lg
(R)-MPN-Lh
(R)-MPN-Li
(S)-MPN-Lj
(S)-MPN-Lj
(S)-MPN-Lj
(S)-MPN-Lj
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
DMF
4
2
96
2
2
2
>95
>95
>95
>95
>95
>95
>95
>95
57
76
71
67
65
59
67
98
85 (ꢂ)
35 (þ)
35 (ꢂ)
78 (ꢂ)
85 (þ)
88 (þ)
83 (þ)
69 (þ)
97d
88d
0g
2
7
100
100
91d
81d
88d
9
a
See the captions in Table 3.
See the captions in Table 3.
See the captions in Table 3.
Reaction was run at 0 ꢀC.
10
11
12
b
c
1.5% TFE
1% TFE
2
d
a
Reaction was run with 5 (0.05 mmol), Pd2(dba)3 (1.25ꢁ10ꢂ3 mmol), and (S)-
MPN-Lj (7.50ꢁ10ꢂ3 mmol) in CH2Cl2 (1.0 mL) at room temperature. The amount of
an additive (%) is by volume.
b
Table 5
Pd-catalyzed AAA reaction of 5ben using (S)-MPN-Lj
See the captions in Table 3.
See the captions in Table 3.
Compound 22c was formed as the side product.
A mixure of 22a and 22c was formed as side products.
c
d
Entrya
Carbonate
Time (h)
Conv.b (%)
6b (%)
6 (S) eec (%)
e
f
1
2
3
4
5
6
7
8
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
2
2
2
2
2
2
2
2
2
>95
>95
>95
>95
>95
>95
>95
>95
>95
<5
100
98
100
100
57
60
46
33
28
66 (þ)
69 (þ)
76 (þ)
79 (þ)
85 (þ)
83 (þ)
87 (þ)
87 (þ)
89 (þ)
nd
A mixture of 22a (33%) and 22o (R¼(CF3)2CH, 67%) was formed.
g
Compound 22o was formed exclusively.
(see Table 5, entries 4 and 12 for comparison). The reaction of 5e
with 1.5% (v/v) TFE gave 6 in 81% yield and 91% ee (entry 11), which
is practically the best result so far.
9
10
11
12
13
120
120
2
100
100
98
2.4. Mechanism of intramolecular AAA reaction
<5
>95
>95
nd
70 (þ)
2
100
71 (þ)
The findings obtained from the solvent effects, allylic carbonate
structures, and effects of protic additives, provide the following
mechanistic implications (Scheme 6): (i) The CF3CONHCH2 moiety
a
Reaction was run with 5 (0.05 mmol), Pd2(dba)3 (1.25ꢁ10ꢂ3 mmol), and (S)-
MPN-Lj (7.50ꢁ10ꢂ3 mmol) in CH2Cl2 (1.0 mL) at room temperature.
b
See the captions in Table 3.
See the captions in Table 3.
in p
-allylic intermediate 20 (200 for substrates 1, 3, and 5 in general)
c
needs to be ionized without an extra base to undergo nucleophilic
allylic substitution reaction; (ii) The ROꢂ counter anion in 200 acts
as the base to deprotonate the CF3CONHCH2 moiety, but the ba-
sicity of ROꢂ anion is not sufficient to do the task without the ac-
tivation of the amide moiety; (iii) The Pd2þ acts as a Lewis acid to
activate the CF3CONHCH2 moiety so that ROꢂ anion can abstract
a proton from this moiety, and produce a neutral ROH (or its tau-
tomer), which is an inert nucleophile under the reaction
formation of side product 22o was observed (entry 7). The addition
of tert-butanol slightly improved the enantioselectivity to 79% ee
without affecting reaction rate and product selectivity (entry 8).
The addition of 1% (v/v) TFE to the reactions of 5e and 5m was
beneficial, giving 6 with 87% ee (entry 10) and 86% ee (entry 12),
respectively, with only a little decrease in the product selectivity

6518
C.-W. Chien et al. / Tetrahedron 67 (2011) 6513e6523
conditions; (iv) The CeN bond formation can take place through
either reductive elimination (path a) or nucleophilic attack of the
amide anion (path b); (v) In a non-polar solvent, there is a plausible
hydrogen bonding between the oxygen of the MeO group at C5 and
amide hydrogen (see 20-HB), which is counterproductive for the
activation of the amide group through coordination to Pd2þ metal
center; (vi) While the ionization of the amide group is slowed
down, ROꢂ counter anion exclusively attacks the less hindered
either reductive elimination of 20D (n¼3) or the nucleophilic attack
of the amide nitrogen anion from the Pd metal side in accordance
with the principle of least motion, i.e., not through normal anti-
periplanar trajectory. This makes a lot of sense since this is an
intramolecular process and the activation of the amide moiety
through its coordination to the Lewis acidic Pd2þ metal center to
generate amide nitrogen anion as the nucleophile (see Scheme 6).
terminal carbon of the
p-allylic Pd complex (20F) to form 22.
-OR
H
N
H
N
-OR
+
CF3
CF3
(MeO)n
(MeO)n
+
O
Pd
L*2
O
Pd
L*2
20'A
20'B
HOR
N
O
CF3
a
N
b
CF3
(MeO)n
(MeO)n
a
O
Pd
Pd
L*2
L*2
20'D
20'C
b
21'
(MeO)n
CF3
N
O
Pd
L*2
20'E
COCF3
Scheme 7. Proposed mechanism for the kinetic resolution.
H
N
Me
OMe
O
MeO
MeO
NHCOCF3
-OR
MeO
3. Conclusions
22
X
MeO
As described above, we have successfully synthesized 1-vinyl-
6,8-dimethoxytetrahydroisoquinoline 4 and 1-vinyl-5,6,7-trimetho-
xytetrahydroisoquinoline 6 with >90% ee by means of Pd-catalyzed
intramolecular AAA reactions, using MPN and BOP ligands, de-
veloped in our laboratory. The 1-vinlyltetrahydroisoquinolines thus
obtained serve as versatile intermediates for the synthesis of a va-
riety of naturally occurring isoquinoline alkaloids. For the optimi-
zation of enantioselectivity, the fine-tuning capability of the MPN
and BOP ligands has played a significant role. Plausible mechanisms
of the reactions that can accommodate the results obtained have
been proposed. The solvent effects have revealed the critical im-
portance of the activation of the trifluoroamide moiety through its
coordination to the Lewis acidic Pd2þ metal center. In the AAA re-
action of 5, a kinetic resolution appears to have taken place to enrich
enantioselectivity. The facts that BOP ligands gave the best results in
the AAA reaction of 3, while MPN ligands served best in the reaction
of 5, may indicate the need for more flexibility to accommodate the
coordination of trifluoroamide moiety of 5 bearing a sterically de-
manding methoxy group at the C3 position, which can easily be
achieved by non-chelating MPN ligands.
PdL*2
L*2Pd
20-HB
20A
20F
Scheme 6. Proposed mechanism for the formation of 210 and 22.
These mechanistic implications nicely explain the unique fea-
ture of the AAA reaction of 5 as compared to those of 1 and 3,
wherein the formation of side product 22 was observed only in the
reaction of 5 that bears a MeO group at the C5 position.
There is another intriguing mechanistic implication from the
observed inverse correlation between enantioselectivity and
product selectivity, including the effect of 1% (v/v) TFE as an addi-
tive. The results strongly imply that there is a kinetic resolution in
the transformation of 20 to 21 and/or 22 (Scheme 5), and the minor
diastereomer of 20 reacts preferentially with ROꢂ anion to enrich
the major diastereomer of 20, which leads to higher enantiose-
lectivity in the formation of desirable product 6.
To obtain insights into the kinetic resolution implied, we carried
out molecular modeling of the two diastereomeric key in-
termediates, 20C-pro-S and 20C-pro-R, bearing (S)-MNP-Ld as the
chiral ligand, using the Spartan Program. For simplicity, we used
p-
4. Experimental section
allylic Pd complexes bearing a covalent OePd2þ bond with an
imidate structure (20C) for this modeling study (Scheme 7). The
semi-empirical energy calculation (PM3) using the Spartan pro-
gram indicated that 20C-pro-S is more favorable than 20C-pro-R by
31 kJ/mol, which is consistent with the observed formation of (S)-
(þ)-6, and also explains the selective elimination of 20F arising
from 20C-pro-R through reaction with ROꢂ anion to form 22.
However, it should be noted that this molecular mechanics calcu-
lation has revealed that (S)-21 (i.e., (S)-6 as well) is formed through
4.1. General methods and materials
1H and 13C NMR spectra were measured on a Varian Inova-300
NMR or a Varian Inova-400 NMR spectrometer in a deuterated
solvent. The enantiomeric excess was determined by HPLC: Shi-
madzu LC-2010A HPLC system using a Chiralcel OD-H column
(hexanes/i-PrOH¼98.8/1.2, 1.0 mL/min). Melting points were
measured on a Thomas Hoover Capillary melting point apparatus

C.-W. Chien et al. / Tetrahedron 67 (2011) 6513e6523
6519
and are uncorrected. Specific optical rotations were measured on
a PerkineElmer Model 241 polarimeter. TLC was performed on
Merck DC-alufolien with Kieselgel 60F254 and flash chromatogra-
temperature under nitrogen with stirring. After 30 min, neat ethyl-
enediamine (1.64 L, 0.024 mmol) was introduced to the reaction
m
mixture. After stirring the catalyst solution for 10 min, 9 (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 analysis indicated the completion of the reaction. The re-
action was quenched by addition of water. The aqueous layer was
extracted with EtOAc (10 mLꢁ3). The combined organic layer was
washed with saturated NaHCO3 solution and brine, and dried over
anhydrous MgSO4. Crude product was obtained after filtration and
evaporation of the solvent. Further purification by flash column
chromatography on silica gel (hexanes/EtOAc¼3/1/1/1) afforded
10 (161 mg, 97% yield) as a colorless oil: 1H NMR (300 MHz, CDCl3)
phy was carried out on silica gel 60 (Silicyle; 40e63 mm particle
size). High-resolution mass spectrometric analyses were carried
out at the Mass Spectrometry Laboratory, University of Illinois
Urbana-Champaign, Urbana, IL. All reactions were carried out un-
der nitrogen atmosphere.
All solvents were purified using the Solvent Purification System
400-4 from Innovative Technology, Inc. All chemicals were pur-
chased from Aldrich and Acros Chemical Co. unless otherwise
noted. Tris(dibenzylideneacetone) dipalladium(0) was purchased
from Strem Chemicals, Inc. Chiral biphenols, chiral phosphor-
amidite ligands, MPN-Laee, and chiral diphosphonite ligands
BOP-Laei were prepared according to the procedure previously
reported by our laboratory.23,24 (1R,2R)-(þ)-N,N0-Bis(20-diphenyl-
phosphinobenzoyl)-1,2-diaminocyclohexane was purchased from
Acros Organics.
d
2.18 (br s, 1H), 2.83 (t, J¼6.9 Hz, 2H), 3.52 (q, J¼6.6 Hz, 2H), 3.77 (s,
3H), 3.79 (s, 3H), 3.95 (d, J¼6.6 Hz, 2H), 6.03 (dt, J¼6.9, 11.1 Hz, 1H),
6.31 (d, J¼11.1 Hz, 1H), 6.33 (d, J¼2.4 Hz, 1H), 6.39 (d, J¼2.4 Hz, 1H),
6.80 (br s,1H); 13C NMR (75 MHz, CDCl3)
d 32.8, 39.7, 55.3, 55.7, 60.1,
97.3, 105.9, 115.8 (q, J¼286 Hz), 117.2, 124.5, 133.1, 137.9, 157.3 (q,
J¼37 Hz), 157.7, 160.0; HRMS (ESI) calcd for C15H17NO3F3 [MꢂOH]þ
4.2. Synthesis of substrates 3 and 5aen
316.1161, found 316.1172 (
D
¼þ3.5 ppm).
4.2.1. 1-Iodo-4,6-dimethoxy-2-[2-(trifluoroacetylamino)ethyl]-ben-
zene (8). To a suspension of 3,5-dimethoxyphenylethylamide 725,26
(277 mg, 1.00 mmol) and Ag2SO4 (936 mg, 3.00 mmol) in 10 mL
EtOH at 0 ꢀC, was added a solution of I2 (280 mg, 1.10 mmol) in
30 mL EtOH dropwise over 30 min. The mixture was stirred at the
same temperature for another 6 h. TLC analysis indicated full
conversion of the starting material and formation of mono-
iodinated product 8 as well as bis-iodinated product. The mixture
was then filtrated through a pad of Celite and the filtrate was
concentrated to afford a crude product. Flash chromatography of
the crude produce on silica gel (hexanes/EtOAc¼10/1/5/1) gave
pure mono-iodinated product 8 (355 mg, 88% yield) as a white
4.2.4. Ethenyl
(Z)-3-{4,6-dimethoxy-2-[2-(trifluoroacetylamino)-
ethyl]phenyl}prop-2-enyl carbonate (3). To a solution of 10 (166 mg,
0.5 mmol) and pyridine (1.0 mL) in CH2Cl2 (10 mL) was added
slowly vinyl 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 (10 mLꢁ4). Combined organic layer
was washed with water, brine and dried over anhydrous MgSO4.
Crude product was obtained after filtration and evaporation of the
solvent. Further purification by flash column chromatography on
silica gel (hexanes/EtOAc¼3/1) afforded 3 (187 mg, 93% yield) as
a white solid: mp 65e67 ꢀC; 1H NMR (300 MHz, CDCl3)
d 2.87 (t,
solid: mp 126e128 ꢀC; 1H NMR (300 MHz, CDCl3)
d
3.07 (t, J¼6.9 Hz,
J¼6.9 Hz, 2H), 3.53 (q, J¼6.9 Hz, 2H), 3.77 (s, 3H), 3.79 (s, 3H), 4.56
(m, 3H), 4.88 (dd, J¼2.1, 13.8 Hz, 1H), 5.91 (dt, J¼6.3, 11.1 Hz, 1H),
6.30 (d, J¼2.1 Hz, 1H), 6.39 (d, J¼2.7 Hz, 1H), 6.45 (d, J¼11.4 Hz, 1H),
6.71 (br s, 1H), 6.95 (dd, J¼6.3, 14.1 Hz, 1H); 13C NMR (75 MHz,
2H), 3.62 (q, J¼6.9 Hz, 2H), 3.78 (s, 3H), 3.80 (s, 3H), 6.33 (d,
J¼2.7 Hz, 1H), 6.41 (d, J¼2.7 Hz, 1H), 6.47 (br s, 1H); 13C NMR
(75 MHz, CDCl3)
d 39.6, 39.7, 55.4, 56.5, 81.5, 97.6, 106.8, 115.8 (q,
J¼286 Hz), 142.3, 157.0 (q, J¼36 Hz), 161.1; HRMS (EI) calcd for
CDCl3) d 32.6, 39.3, 55.3, 55.5, 66.4, 97.3, 98.0, 106.2, 115.8 (q,
C12H13O3NIF3 [M]þ 402.9893, found 402.9892 (
D
¼ꢂ0.1 ppm).
J¼286 Hz), 116.0, 126.7, 127.2, 138.2, 142.3, 152.9, 157.3 (q, J¼37 Hz),
157.8, 160.3; HRMS (ESI) calcd for C15H17NO3F3 [M-OCO2C2H3]þ
4.2.2. 3-{4,6-Dimethoxy-2-[2-(trifluoroacetylamino)ethyl]phenyl}
prop-2-ynol (9). A mixture of 8 (403 mg, 1.00 mmol), Pd(Ph3)2Cl2
(21 mg, 0.025 mmol), and CuI (9.5 mg, 0.05 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 analysis indicated the completion of
the reaction (48 h). Then, saturated ammonium chloride solution
(5 mL) was added to quench the reaction. The aqueous layer was
extracted with EtOAc (15 mLꢁ3). The combined organic layer was
dried over anhydrous MgSO4. Crude product was obtained after
filtration and evaporation of the solvent. Further purification of the
crude product by flash column chromatography on silica gel (hex-
anes/EtOAc¼5/1/1/1) afforded 9 as a white solid (275 mg, 83%
316.1161, found 316.1157 (
D
¼ꢂ1.3 ppm).
4.2.5. N-[2-(2,3,4-Trimethoxyphenyl)ethyl]-2,2,2-trifluoroacetamide
(14). A mixture of 2,3,4-trimethoxybenzaldehyde (11) (2.55 g,
13.0 mmol), ammonium acetate (1.10 g, 14.3 mmol) in nitromethane
(65 mL) was stirred for 1 h at 100 ꢀC. The reaction mixture was cooled
to room temperature, treated with water (50 mL) to quench the re-
action, and extracted with ether (60 mLꢁ3). The combined organic
layer was washed with brine (50 mL) and dried over anhydrous
MgSO4. The solvent was removed in vacuo and the residue recrys-
tallized from EtOH to give 12 (2.82 g, 91% yield) as a pale yellow solid:
mp 77.0e77.5 ꢀC; 1H NMR (400 MHz, CDCl3)
d 3.87 (s, 3H), 3.92 (s,
3H), 3.99 (s, 3H), 6.72 (d, J¼8.8 Hz,1H), 7.20 (d, J¼8.8 Hz,1H), 7.77 (d,
J¼13.6 Hz, 1H), 8.08 (d, J¼13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
56.2, 60.9, 61.2, 107.7, 117.1, 126.5, 135.2, 142.5, 154.3, 157.3.
yield): mp 121.5e123 ꢀC; 1H NMR (300 MHz, CDCl3)
d
2.99 (t,
To a solution of LiAlH4 (3.23 g, 85.1 mmol) in THF (25 mL) was
J¼6.9 Hz, 2H), 3.15 (br s,1H), 3.59 (q, J¼6.9 Hz, 2H), 3.79 (s, 3H), 3.83
added a solution of 12 (5.09 g, 21.3 mmol) in THF (175 mL) slowly at
0 ꢀC. The reaction mixture was heated to 65 ꢀC and stirred for 3 h.
The reaction was then quenched by 20% KOH. The resulting slurry
was filtered through Celite pad and the filtrate was concentrated in
vacuo. The residue was extracted with ether (30 mLꢁ3) and the
combined organic layer was washed with brine (20 mL), dried over
anhydrous MgSO4, and filtered. The filtrate was concentrated in
vacuo to give 2-(2,3,4-trimethoxyphenyl)ethylamine (13) (3.44 g,
16.3 mmol) as a yellow liquid, which was directly used in the next
amidation step without further purification.
(s, 3H), 4.54 (s, 2H), 6.33 (br s, 2H), 7.09 (br s,1H); 13C NMR (75 MHz,
CDCl3)
J¼286 Hz),142.9,157.5 (q, J¼36 Hz),160.9,161.6; HRMS (EI) calcd for
C15H16NO4F3 [M]þ 331.1031, found 331.1034 (
¼þ0.3 ppm).
d 34.3, 40.4, 51.7, 55.4, 79.8, 94.7, 96.9, 104.3, 106.1, 115.9 (q,
D
4.2.3. (Z)-3-{4,6-Dimethoxyl-2-[2-(trifluoroacetylamino)ethyl]-phe-
nyl}prop-2-enol (10). P2eNi catalystwas generated in situ following
the standard procedure29 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

6520
C.-W. Chien et al. / Tetrahedron 67 (2011) 6513e6523
To a stirred solution of 13 (3.44 g, 16.3 mmol) and NEt3 (4.12 g,
same manner as that described for 8: 75% yield; yellow solid; mp
83.0e85.0 ꢀC; 1H NMR (400 MHz, CDCl3)
2.41 (br s, 1H), 2.83 (t,
40.7 mmol) in CH2Cl2 (96 mL) was added dropwise trifluoro-
acetic anhydride (3.45 mL, 24.4 mmol) at 0 ꢀC with stirring. The
mixture was stirred at 0 ꢀC for 1 h. Reaction was quenched by the
addition of water at the same temperature, and the layers were
separated. The aqueous layer was extracted with CH2Cl2
(30 mLꢁ3), and combined organic layer was washed with brine
(30 mL) and dried over anhydrous MgSO4. After concentrated in
vacuo, crude product was purified by column chromatography on
silica gel (hexanes/EtOAc¼4/1) to give 14 (4.24 g, 65% in two
d
J¼6.4 Hz, 2H), 3.43 (q, J¼6.0 Hz, 2H), 3.81 (s, 3H), 3.83 (s, 3H), 3.89
(s, 3H), 4.18 (d, J¼6.8 Hz, 2H), 5.94 (dt, J¼6.8, 11.6 Hz, 1H), 6.46 (s,
1H), 6.56 (d, J¼11.6 Hz, 1H), 7.24 (br s, 1H); 13C NMR (100 MHz,
CDCl3)
d
25.3, 40.3, 56.0 59.0, 60.6, 60.9, 109.5, 115.8 (q, J¼286 Hz),
121.7, 129.1, 131.5, 132.4, 141.3, 151.6, 151.9, 157.4 (q, J¼36 Hz); HRMS
(ESI) calcd for C16H20F3NO5Na [MþNa]þ 386.1191, found 386.1192
(D
¼þ0.3 ppm).
Carbonates 5a to 5n were synthesized in the same manner as
steps) as a yellow oil: 1H NMR (400 MHz, CDCl3)
d
2.78 (t,
that described for 3.
J¼6.8 Hz, 2H), 3.45 (q, J¼6.4 Hz, 2H), 3.78 (s, 3H), 3.80 (s, 3H),
3.86 (s, 3H), 6.58 (d, J¼8.4 Hz, 1H), 6.78 (d, J¼8.4 Hz, 1H), 7.49 (br
4.2.10. Phenyl (Z)-3-{3,4,5-trimethoxy-2-[2-(trifluoroacetylamino)
ethyl]phenyl}prop-2-enyl carbonate (5a). Yield 90%; yellow oil; 1H
s, 1H); 13C NMR (100 MHz, CDCl3)
d 28.8, 41.2, 55.7, 60.4, 60.7,
107.6, 115.7 (q, J¼286 Hz), 123.7, 124.3, 142.0, 151.4, 152.7, 157.1 (q,
NMR (400 MHz, CDCl3)
d
2.85 (t, J¼6.4 Hz, 2H), 3.43 (q, J¼6.0 Hz,
J¼36 Hz); HRMS (ESI) calcd for C13H17F3NO4 [MþH]þ 308.1110,
2H), 3.84 (s, 3H), 3.85 (s, 3H), 3.91 (s, 3H), 4.84 (d, J¼7.2 Hz, 2H),
6.00 (dt, J¼7.2, 11.6 Hz, 1H), 6.54 (s, 1H), 6.79 (d, J¼11.6 Hz, 1H),
7.14e7.55 (m, 4H), 7.35e7.39 (m, 2H); 13C NMR (100 MHz, CDCl3)
found 308.1103 (
D
¼ꢂ2.3 ppm).
4.2.6. N-[2-(5-Bromo-2,3,4-trimethoxyphenyl)ethyl]-2,2,2-
trifluoroacetamide (15). N-Bromosuccinimide (NBS) (5.15 g,
28.93 mmol) was added to a solution of 14 (5.93 g, 19.29 mmol) in
CCl4 (50 mL). The mixture was stirred at 60 ꢀC for 16 h and then
cooled to room temperature. Water (50 mL) was added to the re-
action mixture and extracted with CH2Cl2 (3ꢁ60 mL). The com-
bined organic layer was washed with saturated Na2SO3 (50 mL) and
brine (50 mL) and dried over anhydrous MgSO4. After concentrated
in vacuo, crude product was purified by column chromatography
on silica gel (hexanes/EtOAc¼4/1) to give 15 (6.86 g, 92%) as a white
d
25.3, 40.4, 56.0, 60.6, 61.0, 65.0, 109.2, 115.8 (q, J¼286 Hz), 120.9,
122.2, 125.9, 126.0, 129.4, 129.5, 130.5, 133.0, 141.8, 151.0, 151.8,
152.1,153.6,157.3 (q, J¼37 Hz); HRMS (ESI) calcd for C23H24F3NO7Na
[MþNa]þ 506.1403, found 506.1402 (
¼ꢂ0.2 ppm).
D
4.2.11. 2,2,2-Trichloroethyl (Z)-3-{3,4,5-trimethoxy-2-[2-(trifluoro-
acetylamino)ethyl]phenyl}prop-2-enyl carbonate (5b). Yield 71%;
yellow oil; 1H NMR (400 MHz, CDCl3)
d
2.85 (t, J¼6.0 Hz, 2H), 3.43
(q, J¼6.4 Hz, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 3.93 (s, 3H), 4.76 (s, 2H),
4.81 (d, J¼7.2 Hz, 2H), 5.96 (dt, J¼7.2, 11.6 Hz, 1H), 6.54 (s, 1H), 6.78
solid: mp 62.5e64.0 ꢀC; 1H NMR (400 MHz, CDCl3)
d
2.81 (t,
J¼6.8 Hz, 2H), 3.49 (q, J¼6.4 Hz, 2H), 3.87 (s, 3H), 3.88 (s, 3H), 3.89
(s, 3H), 7.07 (s, 1H), 7.19 (br s, 1H); 13C NMR (100 MHz, CDCl3)
28.9,
(d, J¼11.6 Hz, 1H), 7.12 (br s, 1H); 13C NMR (100 MHz, CDCl3)
d 25.3,
40.4, 56.0, 60.6, 60.9, 65.3, 76.7, 94.3, 109.1, 115.8 (q, J¼286 Hz),
122.1, 125.6, 130.4, 133.2, 141.7, 151.7, 152.1, 153.8, 157.2 (q, J¼36 Hz);
HRMS (ESI) calcd for C19H21Cl3F3NO7Na [MþNa]þ 560.0233, found
d
41.1, 60.8, 60.9, 61.0, 111.7, 115.8 (q, J¼287 Hz), 127.9, 128.3, 147.4,
150.4, 151.2, 157.2 (q, J¼37 Hz); HRMS (ESI) C13H16BrF3NO4 [MþH]þ
560.0237 (
D¼þ0.7 ppm).
386.0215, found 386.0215 (
D¼0.0 ppm).
4.2.12. 2,2,2-Trifluoroethyl (Z)-3-{3,4,5-trimethoxy-2-[2-(trifluoro-
acetylamino)ethyl]phenyl}prop-2-enyl carbonate (5c). Yield 74%;
4.2.7. N-[2-(5-Bromo-6-iodo-2,3,4-trimethoxyphenyl)ethyl]-2,2,2-
trifluoroacetamide (16). N-Iodosuccinimide (NIS) (6.41 g,
28.50 mmol) was added to a solution of 15 (7.34 g, 19.00 mmol) in
CH3CN (75 mL). To this mixture was added trifluoroacetic acid
(2.12 mL, 28.50 mmol) dropwise. The mixture was refluxed for 24 h
and then cooled to room temperature. Water (50 mL) was added to
the reaction mixture, and CH3CN was removed under reduced
pressure. The residue was extracted with CH2Cl2 (3ꢁ60 mL) and the
combined organic layer was washed with saturated Na2SO3 (50 mL)
and water (50 mL), and dried over anhydrous MgSO4. After con-
centrated in vacuo, crude product was purified by column chro-
matography on silica gel (hexanes/EtOAc¼4/1) to give 16 (9.11 g,
94%) as a off-white solid: mp 75.0e77.0 ꢀC; 1H NMR (400 MHz,
yellow oil; 1H NMR (400 MHz, CDCl3)
d
2.84 (t, J¼6.0 Hz, 2H), 3.42
(q, J¼6.8 Hz, 2H), 3.84 (s, 3H), 3.86 (s, 3H), 3.93 (s, 3H), 4.50 (q,
J¼8.4 Hz, 2H), 4.79 (dd, J¼1.2, 6.8 Hz, 2H), 5.94 (dt, J¼6.8 Hz,
11.6 Hz, 1H), 6.51 (s, 1H), 6.78 (d, J¼11.6 Hz, 1H), 7.11 (br s, 1H); 13C
NMR (100 MHz, CDCl3)
d 25.3, 40.6, 56.1, 60.7, 61.0, 63.5 (q,
J¼37 Hz), 65.5, 109.2, 115.8 (q, J¼286 Hz), 122.2, 122.5 (q,
J¼276 Hz), 125.6, 130.4, 133.4, 141.9, 151.8, 152.2, 153.9, 157.3 (q,
J¼36 Hz); HRMS (ESI) calcd for C19H21F6NO7Na [MþNa]þ 512.1120,
found 512.1122 (
D¼þ0.4 ppm).
4.2.13. Ethenyl (Z)-3-{3,4,5-trimethoxy-2-[2-(trifluoroacetylamino)
ethyl]phenyl}prop-2-enyl carbonate (5d). Yield 90%; yellow oil; 1H
CDCl3):
d
3.23 (t, J¼6.4 Hz, 2H), 3.54 (q, J¼6.8 Hz, 2H), 3.88 (m, 6H),
NMR (400 MHz, CDCl3)
d
2.84 (t, J¼6.4 Hz, 2H), 3.43 (q, J¼6.4 Hz,
3.92 (s, 3H), 6.96 (br s, 1H); 13C NMR (100 MHz, CDCl3)
d
35.8, 38.7,
2H), 3.85 (s, 3H), 3.86 (s, 3H), 3.93 (s, 3H), 4.59 (dd, J¼2.0, 6.4 Hz,
1H), 4.78 (dd, J¼1.6, 7.2 Hz, 2H), 4.92 (dd, J¼2.4, 14.0 Hz, 1H), 5.94
(dt, J¼7.2, 11.2 Hz, 1H), 6.53 (s, 1H), 6.76 (dd, J¼0.4, 7.2 Hz, 1H), 7.04
(dd, J¼6.0, 13.6 Hz, 1H), 7.14 (br s, 1H); 13C NMR (100 MHz, CDCl3)
60.8, 61.0, 61.2, 101.7, 115.8 (q, J¼286 Hz), 121.9, 132.4, 147.3, 150.9,
151.0, 157.3 (q, J¼37 Hz); HRMS (ESI) calcd for C13H15BrF3INO4
[MþH]þ 511.9181, found 511.9185 (
¼þ0.8 ppm).
D
d
25.3, 40.5, 56.1, 60.7, 61.0, 64.9, 98.0, 109.2, 115.8 (q, J¼286 Hz),
4.2.8. 3-{2-Bromo-3,4,5-trimethoxy-6-[2-(trifluoroacetylamino)-
ethyl]phenyl}prop-2-ynol (17). Arylpropynol 17 was synthesized in
the same manner as that described for 9: 75% yield; brown solid;
122.2, 125.8, 130.5, 133.0, 141.8, 142.6, 151.8, 152.2, 152.6, 157.3 (q,
J¼37 Hz); HRMS (ESI) calcd for C19H22F3NO7Na [MþNa]þ 456.1246,
found 456.1249 (
D¼þ0.7 ppm).
mp 88.5e90.5 ꢀC; 1H NMR (400 MHz, CDCl3)
d
3.09 (t, J¼7.2 Hz, 2H),
3.53 (q, J¼6.4 Hz, 2H), 3.86 (s, 3H), 3.89 (s, 3H), 3.91 (s, 3H), 4.55 (s,
2H), 7.12 (br s, 1H); 13C NMR (100 MHz, CDCl3)
28.3, 40.1, 51.5 60.9,
4.2.14. 1-Methylethenyl (Z)-3-{3,4,5-trimethoxy-2-[2-(trifluoroace-
tylamino)ethyl]phenyl}prop-2-enyl carbonate (5e). Yield 91%; yel-
d
61.0, 61.2, 81.8, 96.0, 115.8 (q, J¼286 Hz), 116.0, 120.7, 130.6, 147.8,
low oil; 1H NMR (400 MHz, CDCl3)
d
1.95 (s, 3H), 2.85 (t, J¼6.0 Hz,
150.6, 151.2, 157.6 (q, J¼36 Hz); HRMS (ESI) calcd for C16H18BrF3NO5
2H), 3.43 (q, J¼6.8 Hz, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 3.92 (s, 3H),
[MþH]þ 440.0320, found 440.0316 (
¼ꢂ0.9 ppm).
D
4.69e4.79 (m, 4H), 5.95 (dt, J¼6.8, 11.6 Hz, 1H), 6.52 (s, 1H), 6.75 (d,
J¼11.6 Hz,1H), 7.14 (br s,1H); 13C NMR (100 MHz, CDCl3)
d 19.1, 25.3,
4.2.9. (Z)-3-{3,4,5-Trimethoxy-2-[2-(trifluoroacetylamino)ethyl]-
phenyl}prop-2-enol (18). Arylpropenol 18 was synthesized in the
40.5, 56.1, 60.7, 61.0, 64.6, 101.9, 109.2, 115.9 (q, J¼287 Hz), 122.2,
126.2, 130.6, 132.7,141.8, 151.8,152.1,152.8,152.9,157.3 (q, J¼37 Hz);

C.-W. Chien et al. / Tetrahedron 67 (2011) 6513e6523
6521
HRMS (ESI) calcd for C20H24F3NO7Na [MþNa]þ 470.1403, found
(q, J¼6.4 Hz, 2H), 3.84 (s, 3H), 3.86 (s, 3H), 3.92 (s, 3H), 4.90 (dd,
J¼1.2, 7.2 Hz, 2H), 5.99 (dt, J¼7.2, 11.6 Hz, 1H), 6.52 (s, 1H), 6.85 (d,
470.1398 (
D¼ꢂ1.1 ppm).
J¼11.6 Hz, 1H), 7.14 (br s, 1H); 13C NMR (100 MHz, CDCl3)
d 25.4,
4.2.15. 4-Methoxyphenyl (Z)-3-{3,4,5-trimethoxy-2-[2-(trifluoroace-
tylamino)ethyl]phenyl}prop-2-enyl carbonate (5f). Yield 95%; yellow
40.4, 56.0, 60.7, 61.0, 66.8, 109.0, 115.8 (q, J¼286 Hz), 122.3, 124.7,
125.6 (m), 130.2, 134.2, 136.6 (m), 138.5 (m), 139.1 (m), 140.0 (m),
141.1 (m), 141.9, 142.5 (m), 151.2, 151.9, 152.2, 157.3 (q, J¼36 Hz);
LCeMS (ESI) calcd for C23H19F8NO7 [M]þ 573.1, found 591.0
[MþNH4]þ.
oil; 1H NMR (400 MHz, CDCl3)
d
2.86 (t, J¼6.4 Hz, 2H), 3.43 (q,
J¼6.8 Hz, 2H), 3.79 (s, 3H), 3.84 (s, 3H), 3.86 (s, 3H), 3.92 (s, 3H), 4.83
(dd, J¼1.2, 7.2 Hz, 2H), 6.00 (dt, J¼7.2, 11.6 Hz, 1H), 6.54 (s, 1H), 6.78
(d, J¼11.6 Hz, 1H), 6.87 (d, J¼9.2 Hz, 2H), 7.06 (d, J¼9.2 Hz, 2H) 7.11
(br s, 1H); 13C NMR (100 MHz, CDCl3)
d
25.3, 40.5, 55.6, 56.1, 60.7,
4.2.21. 4-Nitrophenyl (Z)-3-{3,4,5-trimethoxy-2-[2-(trifluoro-acety-
lamino)ethyl]phenyl}prop-2-enyl carbonate (5l). Yield 80%; yellow
61.0, 64.9, 109.3, 114.5, 115.9 (q, J¼281 Hz), 121.8, 122.2, 126.1, 130.6,
132.9, 141.8, 144.7, 151.8, 152.2, 154.0, 157.3 (q, J¼34 Hz), 157.5;
HRMS (ESI) calcd for C24H26F3NO8Na [MþNa]þ 536.1508, found
oil; 1H NMR (400 MHz, CDCl3)
d
2.85 (t, J¼6.4 Hz, 2H), 3.43 (q,
J¼6.4 Hz, 2H), 3.84 (s, 3H), 3.85 (s, 3H), 3.92 (s, 3H), 4.87 (dd, J¼1.2,
6.8 Hz, 2H), 5.99 (dt, J¼6.8, 11.2 Hz, 1H), 6.52 (s, 1H), 6.82 (d,
J¼11.2 Hz, 1H), 7.15 (br s, 1H), 7.36 (d, J¼9.2 Hz, 2H), 8.25 (d,
536.1509 (
D
¼þ0.2 ppm).
4.2.16. 4-Methylphenyl (Z)-3-{3,4,5-trimethoxy-2-[2-(trifluoro-ace-
tylamino)ethyl]phenyl}prop-2-enyl carbonate (5g). Yield 92%; yel-
J¼9.2 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 25.3, 40.5, 56.1, 60.7,
61.0, 65.6, 109.4, 115.8 (q, J¼287 Hz), 121.7, 122.2, 125.3, 125.4, 130.4,
133.4, 141.8, 145.4, 151.8, 152.2, 152.4, 155.4, 157.3 (q, J¼36 Hz);
HRMS (ESI) calcd for C23H23F3N2O9Na [MþNa]þ 551.1253, found
low oil; 1H NMR (400 MHz, CDCl3)
d
2.33 (s, 3H), 2.85 (t, J¼6.4 Hz,
2H), 3.43 (q, J¼6.0 Hz, 2H), 3.84 (s, 3H), 3.86 (s, 3H), 3.92 (s, 3H),
4.83 (d, J¼6.8 Hz, 2H), 6.00 (dt, J¼6.8, 11.6 Hz, 1H), 6.54 (s, 1H), 6.78
(d, J¼11.6 Hz, 1H), 7.02 (d, J¼8.4 Hz, 2H), 7.15e7.17 (m, 3H); 13C NMR
551.1248 (D¼ꢂ0.9 ppm).
(100 MHz, CDCl3)
d
20.8, 25.3, 40.5, 56.0, 60.6, 61.0, 64.9,109.2,115.8
4.2.22. 2,6-Dimethylphenyl (Z)-3-{3,4,5-trimethoxy-2-[2-(trifluoro-
acetylamino)ethyl]phenyl}prop-2-enyl carbonate (5m). Yield 99%;
(q, J¼287 Hz), 120.6, 122.2, 126.0, 129.9, 130.6, 132.9, 135.8, 141.8,
148.9, 151.8, 152.1, 153.8, 157.3 (q, J¼36 Hz); HRMS (ESI) calcd for
yellow oil; 1H NMR (400 MHz, CDCl3)
d
2.19 (s, 6H), 2.86 (t, J¼6.4 Hz,
C24H26F3NO7Na [MþNa]þ 520.1559, found 520.1564 (
D¼þ1.0 ppm).
2H), 3.43 (q, J¼6.4 Hz, 2H), 3.83 (s, 3H), 3.86 (s, 3H), 3.92 (s, 3H),
4.85 (dd, J¼1.2, 6.8 Hz, 2H), 6.00 (dt, J¼6.8, 11.2 Hz, 1H), 6.53 (s, 1H),
6.79 (d, J¼11.2 Hz, 1H), 7.05e7.07 (m, 3H), 7.10 (br s, 1H); 13C NMR
4.2.17. 4-Fluorophenyl (Z)-3-{3,4,5-trimethoxy-2-[2-(trifluoro-ace-
tylamino)ethyl]phenyl}prop-2-enyl carbonate (5h). Yield 91%; yel-
(100 MHz, CDCl3) d 15.8, 25.2, 40.3, 55.9, 60.5, 60.8, 65.0, 109.1,115.7
low oil; 1H NMR (400 MHz, CDCl3)
d
2.85 (t, J¼6.4 Hz, 2H), 3.42 (q,
(q, J¼286 Hz), 122.2, 125.9, 126.0, 128.6, 129.9, 130.4, 132.9, 141.7,
J¼6.4 Hz, 2H), 3.83 (s, 3H), 3.85 (s, 3H), 3.91 (s, 3H), 4.83 (dd, J¼1.2,
6.8 Hz, 2H), 5.98 (dt, J¼6.8, 11.6 Hz, 1H), 6.53 (s, 1H), 6.79 (d,
J¼11.6 Hz, 1H), 7.02e7.06 (m, 2H), 7.09e7.13 (m, 2H), 7.17 (br s, 1H);
148.2, 151.7, 152.0, 152.8, 157.2 (q, J¼36 Hz); HRMS (ESI) calcd for
C25H28F3NO7Na [MþNa]þ 534.1716, found 534.1718 (
¼þ0.4 ppm).
D
13C NMR (100 MHz, CDCl3)
d
25.3, 40.4, 56.0, 60.6, 61.0, 65.1, 109.2,
4.2.23. 2,6-Diisopropylphenyl (Z)-3-{3,4,5-trimethoxy-2-[2-(trifluo-
roacetylamino)ethyl]phenyl}prop-2-enyl carbonate (5n). Yield 72%;
115.8 (q, J¼286 Hz), 116.1 (d, J¼24 Hz), 122.2, 122.4 (d, J¼8 Hz),
125.8, 130.5, 133.0, 141.8, 146.9 (d, J¼3 Hz), 151.8, 152.1, 153.6, 157.3
(q, J¼37 Hz), 160.3 (d, J¼244 Hz); HRMS (ESI) calcd for
yellow oil; 1H NMR (400 MHz, CDCl3)
d
1.21 (d, J¼6.8 Hz,12H), 2.86 (t,
J¼6.4 Hz, 2H), 3.01 (, J¼6.8 Hz, 2H) 3.43 (q, J¼6.0 Hz, 2H), 3.82 (s, 3H),
3.86 (s, 3H), 3.92 (s, 3H), 4.86 (dd, J¼1.2, 7.2 Hz, 2H), 6.00 (dt, J¼7.2,
11.2 Hz,1H), 6.57 (s,1H), 6.80 (d, J¼11.2 Hz,1H), 7.14e7.24 (m, 4H); 13C
C23H23F4NO7Na [MþNa]þ 524.1308, found 524.1311 (
¼þ0.6 ppm).
D
4.2.18. 4-Chlorophenyl (Z)-3-{3,4,5-trimethoxy-2-[2-(trifluoro-ace-
tylamino)ethyl]phenyl}prop-2-enyl carbonate (5i). Yield 94%; yellow
NMR (100 MHz, CDCl3) d 23.2, 25.3, 27.3, 40.4, 56.0, 60.6, 60.9, 65.1,
109.1, 115.8 (q, J¼287 Hz),122.2,124.0,126.1,126.8,130.5,132.8,140.3,
oil; 1H NMR (400 MHz, CDCl3)
d
2.85 (t, J¼6.0 Hz, 2H), 3.42 (q,
141.7,145.7,151.8,152.1,153.7,157.3 (q, J¼36 Hz); HRMS (ESI) calcd for
J¼6.4 Hz, 2H), 3.84 (s, 3H), 3.85 (s, 3H), 3.92 (s, 3H), 4.83 (dd, J¼1.2,
7.2 Hz, 2H), 5.98 (dt, J¼7.2, 11.6 Hz, 1H), 6.53 (s, 1H), 6.79 (d,
J¼11.6 Hz, 1H), 7.10 (d, J¼8.8 Hz, 2H), 7.16 (br s, 1H), 7.33 (d,
C29H36F3NO7Na [MþNa]þ 590.2342, found 590.2346 (
¼þ0.7 ppm).
D
4.3. Intramolecular asymmetric allylic amination
J¼8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 25.3, 40.5, 56.1, 60.6,
61.0, 65.2, 109.2, 115.8 (q, J¼286 Hz), 122.2, 122.3, 125.7, 129.5, 130.5,
131.5,133.1,141.8, 149.5,151.8,152.1,153.3,157.3 (q, J¼36 Hz); HRMS
(ESI) calcd for C23H23ClF3NO7Na [MþNa]þ 540.1013, found 540.1012
4.3.1. (S)-(þ)-1-Ethenyl-3,5-dihydro-6,8-dimethoxy-2-trifluro-ace-
tyl-1,2,3,4-tetrahydroisoquinoline (4). A solution of (R)-BOP-Lg
(2.8 mg, 0.0033 mmol) and Pd2(dba)3 (1.0 mg, 0.0011 mmol) in DMF
(0.5 mL) was added to a 5 mL round-bottomed flask with a stirring
bar under N2. The mixture was stirred at room temperature until the
color of the solution turned to light yellow from purple, and cooled
down to 0 ꢀC. Then, 3 (20 mg, 0.05 mmol) in DMF (0.5 mL) was
added to the catalyst solution via a syringe. The mixture was stirred
at 0 ꢀC until TLC analysis indicated the completion of the reaction
(24 h). The reaction mixture was passed through a short pad of silica
gel using hexanes/EtOAc (12/1/8/1) as the eluent. The filtrate was
then concentrated and subject to HPLC analysis, using a Chiralcel
(D
¼ꢂ0.2 ppm).
4.2.19. 3-Fluorophenyl (Z)-3-{3,4,5-trimethoxy-2-[2-(trifluoro-ace-
tylamino)ethyl]phenyl}prop-2-enyl carbonate (5j). Yield 82%; yellow
oil; 1H NMR (400 MHz, CDCl3)
d
2.84 (t, J¼6.4 Hz, 2H), 3.41 (q,
J¼6.0 Hz, 2H), 3.83 (s, 3H), 3.84 (s, 3H), 3.90 (s, 3H), 4.83 (dd, J¼0.8,
7.2 Hz, 2H), 5.97 (dt, J¼7.2, 11.6 Hz, 1H), 6.53 (s, 1H), 6.79 (d,
J¼11.6 Hz, 1H), 6.91e6.96 (m, 3H), 7.21 (br s, 1H), 7.28e7.34 (m, 1H);
13C NMR (100 MHz, CDCl3)
d 25.3, 40.4, 56.0, 60.6, 60.9, 65.2, 109.0
(d, J¼23 Hz), 109.1, 113.0 (d, J¼21 Hz), 115.8 (q, J¼287 Hz), 116.6 (q,
J¼3 Hz), 122.2, 125.6, 130.2 (d, J¼9 Hz), 130.4, 133.1, 141.8, 151.7 (d,
J¼11 Hz), 151.8, 152.1, 153.0, 157.2 (q, J¼36 Hz), 162.7 (d, J¼247 Hz);
HRMS (ESI) calcd for C23H23F4NO7Na [MþNa]þ 524.1308, found
OD-H column (hexanes/i-PrOH¼99.5/0.5, 0.5 mL/min). Product 4
23
was isolated in quantitative yield as colorless oil: 90% ee; [a]
D
þ159.7 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) (a mixture of two
rotamers in 2:1 ratio) d 2.75e2.83 (m, 1H), 2.92e3.02 (m, 1H), [3.30
524.1305 (
D¼ꢂ0.6 ppm).
(td, J¼4.8, 12.0 Hz, 0.33H)], 3.63 (td, J¼4.8, 12.0, 0.67H)], 3.80 (s, 3H),
3.81 (s, 3H), [3.92e3.97 (m, 0.67H), 4.37e4.43 (m, 0.33H)],
4.88e4.94 (m, 1H), 5.18e5.23 (m, 1H), [5.74e5.75 (m, 0.33H),
6.16e6.17 (m, 0.67H)], 5.90e5.99 (m, 1H), [6.26e6.27 (m, 0.67H),
6.28e6.29 (m, 0.33H)], 6.35 (d, J¼2.0 Hz, 1H); 13C NMR (100 MHz,
4.2.20. Pentafluorophenyl (Z)-3-{3,4,5-trimethoxy-2-[2-(trifluoroa-
cetylamino)ethyl]phenyl}prop-2-enyl carbonate (5k). Yield 89%;
yellow oil; 1H NMR (400 MHz, CDCl3)
d
2.85 (t, J¼6.4 Hz, 2H), 3.42

6522
C.-W. Chien et al. / Tetrahedron 67 (2011) 6513e6523
CDCl3) (a mixture of two rotamers) (major)
d
29.5, 39.9, 51.5, 55.5,
of (S)-3,30-Dibenzyl-5,50,6,60-tetramethyl-1,10-biphenyl-2,20-diol24
55.6, 97.1, 104.3, 115.1, 116.8 (q, J¼287 Hz), 135.2, 135.4, 135.9, 156.0
(0.42 g, 1.00 mmol) in toluene (5 mL) was added hexamethyl-
phosphorous triamide (248 mg, 1.50 mmol) under nitrogen. The
resulting mixture was stirred at 80 ꢀC for 17 h. The solvent was
evaporated under reduced pressure to afford a gel-like product,
which was further purified by column chromatography on silica gel
(pretreated with 1% NEt3 in hexanes) using hexanes/EtOAc (19/1) as
(q, J¼36 Hz), 157.6, 160.1 (minor)
d
28.0, 38.0, 53.4, 55.5, 55.6, 97.0,
104.6, 115.0, 116.8 (q, J¼287 Hz), 135.1, 135.9, 136.1, 156.0 (q,
J¼36 Hz), 157.0, 160.3; HRMS (ESIþ) calcd for C15H17NO3F3 [MþH]þ
316.1161, found 316.1153 (
D¼ꢂ2.5 ppm).
4.3.2. (S)-(þ)-1-Ethenyl-2-trifluoroacetyl-5,6,7-trimethoxy-1,2,3,4-
tetrahydroisoquinoline (6). Reactions were run in the same manner
as that for 3, but using MPN ligands and several different solvents
with and without additives, as well as running the reaction at room
temperature. The result using 5a, (S)-MPN-Lj in CH2Cl2 with 1%
(v/v) TFE is shown as a typical example:
the eluent to give (R)-MPN-Lf (0.32 g, 65%) as a white solid: mp
22
110.0e112.0 ꢀC; [
a]
ꢂ176.2 (c 0.5, CH2Cl2); 1H NMR (400 MHz,
D
CDCl3)
d 1.94 (s, 3H), 2.01 (s, 3H), 2.22 (s, 3H), 2.23 (s, 3H), 2.52 (s,
3H), 2.55 (s, 3H), 3.70 (d, J¼15.2 Hz, 1H), 4.17 (m, 1H), 6.86 (s, 1H),
6.91 (s, 1H), 7.28 (m, 10H); 31P NMR (121.5 MHz, CDCl3)
140.8;
HRMS (EI) calcd for C24H26NO2P [M]þ 391.1701, found 391.1703
d
Compound 6: 99% yield; yellow oil; 91% ee; [
a
]
D
23 þ134.6 (c 1.0,
(D
¼þ0.5 ppm).
CH2Cl2); 1H NMR (400 MHz, CDCl3) (a 79:21 mixture of two
Other new MPN ligands were synthesized in the same manner
rotamers)
d
2.69e2.87 (m, 2H), [3.16 (td, J¼4.8, 14.0 Hz, 0.21H), 3.45
as that for (R)-MPN-Lf, using the corresponding arylmagnesium
bromides.
(td, J¼4.8, 14.0 Hz, 0.79H)], 3.80 (s, 3H), 3.83 (s, 3H), 3.84 (s, 3H),
[3.99e4.04 (m, 0.79H), 4.45e4.50 (m, 0.21H)], 5.02e5.15 (m, 1H),
5.26e5.29 (m, 1H), [5.40e5.41 (m, 0.21H), 5.88e6.02 (m, 1.79H)],
[6.38 (s, 0.21H), 6.41 (s, 0.79H)]; 13C NMR (100 MHz, CDCl3) (a 79:21
4.4.2. O,O0-(S)-[3,30-Bis(dimethylphenylmethyl)-5,50,6,60-tetra-
methyl-1,10-biphenyl-2,20-diyl]-N,N-dimethylphosphoramidite [(S)-
mixture of two rotamers) (major)
106.5, 116.4 (q, J¼286 Hz), 118.4, 119.6, 128.2, 135.3, 141.0, 150.8,
21.7, 37.3, 55.5, 55.9, 57.8, 60.3,
d
23.3, 39.6, 55.5, 55.9, 60.4, 60.7,
MPN-Lg]. Yield 69%; white solid; mp 157e159 ꢀC; [
a]
20 þ225.4 (c
D
0.6, CH2Cl2); 1H NMR (300 MHz, CDCl3)
d 1.55 (s, 3H), 1.62 (s, 3H),
152.3, 155.5 (q, J¼36 Hz) (minor)
d
1.65 (s, 3H), 1.66 (s, 3H), 1.72 (s, 3H), 1.80 (s, 3H), 1.85 (s, 3H), 2.12 (br
106.2, 116.5 (q, J¼286 Hz), 118.3, 120.3, 128.0, 136.3, 141.3, 151.1,
s, 3H), 2.16 (s, 3H), 2.29 (s, 3H), 6.83 (s, 1H), 7.08e7.26 (m, 10H), 7.29
152.1, 155.5 (q, J¼36 Hz); HRMS (ESIþ) calcd for C16H18F3NO4 [M]þ
(s, 1H); 31P NMR (121.5 MHz, CDCl3)
d
142.7; HRMS (EI) calcd for
345.1188, found 346.1264 (
D
¼ꢂ0.6 ppm).
C36H42NO2P [M]þ 551.2953, found 551.2934 (
D¼ꢂ1.9 ppm).
This reaction was accompanied by the formation of side product
22. The characterization data of 22a and 22c are shown below.
4.4.3. O,O0-(R)-[3,30-Bis(diphenylmethyl)-5,50,6,60-tetramethyl-1,10-bi-
phenyl-2,20-diyl]-N,N-dimethylphosphoramidite [(R)-MPN-Lh]. Yield
4.3.3. 1-[(Z)-3-Phenoxyprop-1-enyl]-2-[2-(trifluoroacetylamino)-
ethyl]-2,3,4-trimethoxybenzene (22a). White solid; mp 100.0e102.0
65%; colorless oil; [
a
]
20 ꢂ177.8 (c 0.5, CH2Cl2); 1H NMR (300 MHz,
D
CDCl3)
d
1.89 (s, 3H), 2.00 (s, 3H), 2.16 (s, 3H), 2.19 (s, 3H), 2.33 (s, 3H),
ꢀC; 1H NMR (400 MHz, CDCl3)
d
2.89 (t, J¼6.0 Hz, 2H), 3.40 (q,
2.36 (s, 3H), 5.75 (s, 1H), 5.95 (s, 1H), 6.74 (d, J¼6.6 Hz, 2H), 6.98 (d,
J¼6.0 Hz, 2H), 3.85 (s, 3H), 3.89 (s, 3H), 3.91 (s, 3H), 4.73 (dd, J¼1.2,
5.6 Hz, 2H), 6.24 (dt, J¼5.6, 15.6 Hz, 1H), 6.83 (s, 1H), 6.87 (d,
J¼15.6 Hz, 1H), 6.96e6.99 (m, 3H), 7.06 (br s, 1H), 7.29e7.33 (m,
J¼6.9 Hz, 2H), 7.13e7.33 (m, 18H); 31P NMR (121.5 MHz, CDCl3)
d
142.1; HRMS (EI) calcd for C44H42NO2P [M]þ 647.2953, found
647.2969 (D¼þ1.7 ppm).
2H); 13C NMR (100 MHz, CDCl3)
d 24.4, 41.0, 56.0, 60.7, 61.0, 68.2,
105.9, 106.0, 114.8, 115.8 (q, J¼286 Hz), 121.0, 121.7, 127.2, 129.5,
4.4.4. O,O0-(R)-[3,30-Bis(naphthalen-2-ylmethyl)-5,50,6,60-tetra-
methyl-1,10-biphenyl-2,20-diyl]-N,N-dimethylphosphoramidite [(R)-
131.7, 141.9, 151.5, 152.5, 157.3 (q, J¼36 Hz), 158.4; HRMS (ESI) calcd
for C22H24F3NO5 [M]þ 439.1607, found 462.1498 (
D¼ꢂ1.3 ppm).
MPN-Li]. Yield 63%; colorless oil; [
a
]
20 ꢂ490.9 (c 0.5, CH2Cl2); 1H
D
NMR (300 MHz, CDCl3)
d
1.93 (s, 3H), 2.00 (s, 3H), 2.18 (s, 3H), 2.19
4.3.4. 1-[(Z)-3-(2,2,2-Trifluoroethoxy)prop-1-enyl]-2-[2-(tri-
fluoroacetylamino)ethyl]-2,3,4-trimethoxybenzene (22c). Pale yel-
(s, 3H), 2.53 (s, 3H), 2.56 (s, 3H), 3.83 (d, J¼15.6 Hz, 1H), 4.22 (d,
J¼15.6 Hz, 1H), 4.29 (d, J¼15.6 Hz, 1H), 4.36 (d, J¼15.6 Hz, 1H), 6.86
(s, 1H), 6.90 (s, 1H), 7.39e7.46 (m, 6H), 7.69e7.83 (m, 8H); 31P NMR
low oil; 1H NMR (400 MHz, CDCl3)
d
2.93 (t, J¼6.4 Hz, 2H), 3.45 (q,
J¼6.0 Hz, 2H), 3.85e3.92 (m, 11H), 4.31 (dd, J¼0.8, 6.4 Hz, 2H), 6.10
(dt, J¼6.4, 15.6 Hz, 1H), 6.81 (s, 1H), 6.81 (d, J¼15.6 Hz, 1H), 7.08 (br
(121.5 MHz, CDCl3)
595.2640, found 595.2659 (
d
140.5; HRMS (EI) calcd for C40H38NO2P [M]þ
D
¼þ1.9 ppm).
s, 1H); 13C NMR (100 MHz, CDCl3)
d 24.5, 41.0, 56.0, 60.7, 61.0, 67.4
(q, J¼34 Hz), 72.7, 105.9, 115.8 (q, J¼286 Hz), 121.8, 124.0 (q,
J¼278 Hz), 126.9, 130.2, 131.4, 142.1, 151.5, 152.6, 157.3 (q, J¼36 Hz);
HRMS (ESI) calcd for C18H21F6NO5Na [MþNa]þ 468.1222, found
4.4.5. O,O0-(S)-[3,30-Bis(naphthalen-1-ylmethyl)-5,50,6,60-tetra-
methyl-1,10-biphenyl-2,20-diyl]-N,N-dimethylphosphoramidite [(S)-
MPN-Lj]. Yield 92%; colorless oil; [
NMR (300 MHz, CDCl3) d 1.95 (s, 3H), 2.02 (s, 3H), 2.13 (s, 3H), 2.14
a
]
20 þ389.5 (c 0.5, CH2Cl2); 1H
D
468.1226 (
D¼þ0.9 ppm).
(s, 3H), 2.60 (s, 3H), 2.62 (s, 3H), 4.06 (d, J¼15.9 Hz, 1H), 4.56 (d,
J¼15.9 Hz, 1H), 4.62 (d, J¼15.9 Hz, 1H), 4.79 (d, J¼15.9 Hz, 1H), 6.74
(d, J¼8.1 Hz, 2H), 7.38e7.52 (m, 8H), 7.77e7.92 (m, 4H), 8.07e8.15
4.3.5. 1-[(Z)-3-(1,1,1,3,3,3-Hexafluoroprop-2-yloxy)prop-1-enyl]-2-
[2-(trifluoroacetylamino)ethyl]-2,3,4-trimethoxybenzene (22o). Pale
yellow oil; 1H NMR (400 MHz, CDCl3)
d
2.93 (t, J¼6.4 Hz, 2H), 3.44
(m, 2H); 31P NMR (121.5 MHz, CDCl3)
d 140.4; HRMS (EI) calcd for
(q, J¼6.4 Hz, 2H), 3.86 (s, 3H), 3.88 (s, 3H), 3.92 (s, 3H), 4.22 (septet,
J¼6.0 Hz, 1H), 4.51 (d, J¼6.6 Hz, 2H), 6.10 (dt, J¼6.6, 15.6 Hz, 1H),
6.80 (s, 1H), 6.87 (d, J¼15.6 Hz, 1H), 7.04 (br s, 1H); 13C NMR
C40H38NO2P [M]þ 595.2640, found 595.2623 (
D¼ꢂ1.7 ppm).
Acknowledgements
(100 MHz, CDCl3)
d 24.6, 40.9, 56.0, 60.7, 61.0, 70.7, 74.9e75.9 (m),
106.0, 115.8 (q, J¼287 Hz), 121.6 (q, J¼282 Hz), 122.0, 125.4, 130.9,
This research was supported by a grant from the National Sci-
ence Foundation (CHE-0809315).
132.4, 142.4, 151.6, 152.6, 157.4 (q, J¼36 Hz); HRMS (ESI) calcd for
C19H20F9NO5Na [MþNa]þ 536.1095, found 536.1098 (
¼þ0.6 ppm).
D
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6523
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