Synthesis of chiral 1-substituted tetrahydroisoquinolines by the intramolecular 1,3-chirality transfer reaction catalyzed by Bi(OTf)3

Article abstract of DOI:10.1021/jo102452d

The intramolecular 1,3-chirality transfer reaction of chiral amino alcohols 1 with 99% ee was developed to construct chiral 1-substituted tetrahydroisoquinoline 2. Bi(OTf)₃ (10 mol %)-catalyzed cyclization of 1 (R = H) afforded (S)-1-(E)-propenyl tetrahydroisoquinoline 2 (R = H) in 83% yield with a ratio of 98:2. The stereochemistry at the newly formed chiral center was produced by a syn S_N2′-type process. In this reaction, the substituent on the benzene ring of 1 significantly affected the reactivities and selectivities. A plausible reaction mechanism was proposed.

Full text of DOI:10.1021/jo102452d

ARTICLE
pubs.acs.org/joc
Synthesis of Chiral 1-Substituted Tetrahydroisoquinolines by the
Intramolecular 1,3-Chirality Transfer Reaction Catalyzed by Bi(OTf)3
Nobuyuki Kawai,* Ryuzou Abe, Mika Matsuda, and Jun’ichi Uenishi
Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8412, Japan
S Supporting Information
b
ABSTRACT: The intramolecular 1,3-chirality transfer reaction of
chiral amino alcohols 1 with 99% ee was developed to construct
chiral 1-substituted tetrahydroisoquinoline 2. Bi(OTf)3 (10 mol
%)-catalyzed cyclization of 1 (R = H) afforded (S)-1-(E)-propenyl
tetrahydroisoquinoline 2 (R = H) in 83% yield with a ratio of 98:2.
The stereochemistry at the newly formed chiral center was pro-
duced by a syn SN20-type process. In this reaction, the substituent on
the benzene ring of 1 significantly affected the reactivities and
selectivities. A plausible reaction mechanism was proposed.
etrahydroisoquinolines, especially 1-substi-
1,2,3,4-Ttuted tetrahydroisoquinolines, are com-
pounds of great interest due to their biological and
pharmacological properties.1 For instance, 1-methyl- and 1-phenyl
tetrahydroisoquinoline are involved in the treatment of Parkinson’s
and other nervous disorders,1d and derivatives with methoxy or
hydroxy substituents at the 6 and/or 7 position comprise the widest
group of naturally occurring alkaloids.2 Preparation of these com-
pounds has received much attention, especially with regard to efforts
directed at asymmetric synthesis.3-10 The most important synthetic
methods are the Pictet-Spengler cyclization,4 the reduction of
1-substituted 3,4-dihydroisoquinolines,5 R-alkylation of chiral
formamidines,6 and organolithium additions to imines.7 These meth-
ods allow the synthesis of enantioenriched 1-substituted tetrahydroi-
soquinolines in two steps: cyclization and creation of a stereocenter,
although only the asymmetric Pictet-Spengler reaction creates the
stereogenic carbon at C-1 simultaneously with the ring closure.
Furthermore the alternative reported synthetic methods of enantioen-
riched 1-substituted tetrahydroisoquinolines in one step include
intramolecular aminoselenation with chiral selenium compounds,8
asymmetric allylic amination catalyzed by Pd(0) complex,9 and an
enantioselective aza-Michael reaction.10 These methods still need
improvement with regard to the selectivity of chiral induction.
Direct amino substitution of alcohols has emerged as an
attractive area of research because this approach is considered more
efficient.11,12 Although there are many catalysts for direct allylic ami-
nations or amino substitutions of allylic alcohols reported in the
literature, only a few reports involve chiral transfer with a chiral
secondary allylic alcohol as a substrate.12e,12g,13 In several examples,
the racemic amine and amide were afforded by passing through the
cationic intermediate, except for a few reports13 dealing with PdCl2-
(CH3CN)2 or [P(t-Bu)2o-biphenyl]AuCl-AgSbF6 as a catalyst.
Since strict stereocontrol ring formation is desired, we have
designed a new stereocontrolled synthesis of 1-substituted
tetrahydroisoquinoline by an intramolecular SN20-type reaction,
in which the attack of an amino nucleophile onto the prochiral
carbon of olefin in an exo-trig fashion results in the formation of a
tetrahydroisoquinoline ring. Stereoselective 1,3-chirality transfer
might be expected in either a syn-SN20- or anti-SN20-type process
intramolecularly. Recently, we have found and communicated
Scheme 1. Bi(OTf)3-Catalyzed Cyclization via 1,3-Chirality Transfer
Received: December 15, 2010
Published: February 28, 2011
r
2011 American Chemical Society
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Scheme 2. Synthesis of the Precursors
Table 1. Optimization of Reaction Conditions
that Bi(OTf)3 is an efficient catalyst in the stereoselective cyclization
of substrate possessing a chiral allylic alcohol 1a conjugated with a
benzene ring to afford the (S)-1-(E)-propenyl tetrahydroisoquino-
line 2a in 83% yield with a ratio of 98:2.14 (Scheme 1) The absolute
configuration of 2a was determined to be S by conversion to known
compound 3,15 followed by a comparison of the specific rotation on
the sign. In our previous communication, we have a few examples.
The reactions were then studied in more depth, and we report herein
a detailed study of the Bi(OTf)3-catalyzed intramolecular 1,3-
chirality transfer reaction with a broad scope. In particular, the effect
of the substituent on the benzene ring of 1 was examined in the
reaction to establish it as an efficient methodology for the synthetic
application of naturally occurring alkaloids.
entry
X
temp (°C)
time (h)
yield (%)
ratio (S:R)a
1
Cl
-15
-15
-15
0
0.5
2
85
0
82:18
2
Br
3
OTf
OTf
OTf
OTf
OTf
0.5
0.1
12
83
82
64
63
49
98:2
94:6
96:4
96:4
96:4
4
’ RESULTS AND DISCUSSION
5
-50
-15
-15
6b
7b,c
0.5
Preparation of Cyclization Precursors. Scheme 2 shows the
synthesis of the cyclization precursor 1a as a general synthesis.
The chiral allylic alcohol moiety has been introduced by the
Suzuki coupling reaction of 5a16 and boronate 6.17 We began the
synthesis from 2-(o-bromophenyl)acetonitrile 4a18 prepared
from benzyl bromide by cyanation in DMSO. Reduction of the
nitrile with NaBH4 and a catalytic amount of NiCl2 in MeOH
followed by protection of the resultant amine with Boc2O gave 5a
in 89% yield. The (E)-alkenyl boronate 6 was prepared by
hydroboration of the chiral alkyne 919 with pinacolborane in
89% yield. (E)-Trisubstituted alkenylboronate 7 and (Z)-alkenyl
boronate 820 were also prepared. The homologation of 9 with BuLi
and MeI, followed by the hydroboration, gave 7 in 88% yield in 2
steps. The treatment of 9 with BuLi and 2-isopropoxy-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane followed by the hydrozirconation
of the resultant alkynylboronate gave 8 in 50% yield in 2 steps. The
cross-coupling reaction of 5a and 6 proceeded in the presence of
0.5
a Determined by HPLC. b In the absence of MS-4 Å. c H2O (30 mol %)
was added before the addition of the solution of 1a.
5 mol % of PdCl2(dppf) as a catalyst and NaHCO3 in aqueous
solution and produced 10a in 86% yield. Deprotection of 10a with
TBAF in THF afforded the alcohol 1a in 95% yield.
Bi-Catalyzed Cyclizations. The effect of the counteranion
was examined in Bi(III)-catalyzed cyclization of 1a in Table 1. In the
presence of MS-4 Å, BiCl3 completed the reaction at -15 °C in 30
min to afford 2a in 85% yield with a ratio of 82:18 (entry 1). By
contrast, the softer bromide counteranion did not promote the
reaction at -15 °C (entry 2). In entry 3, Bi(OTf)3 proved to be the
most efficient catalyst in the high 1,3-chiraity transfer. The tempera-
ture effect was examined in the Bi(OTf)3-catalyzed cyclization. At
0 °C, the reaction was completed within 5 min to afford 2a in 82%
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Table 2. Substituent Effect on the Amino Group
yield along with a slight loss of selectivity (94:6) (entry 4). The
reaction took much longer at -50 °C, leading to a lower yield of 2a,
and no significant increase in the selectivity was observed in entry 5.
The addition of MS-4 Å was very important to complete the reaction
and obtain 2a in high yield by comparison of entries 3 and 6. In entry
7, the addition of 30 mol % of H2O in Bi(OTf)3 to generate TfOH
resulted in a low yield of 2a.
Under the optimized conditions, the scope of the reaction with
respect to the amide substrate was examined with catalyst (Table 2).
The methyl and benzyl carbamate were less reactive for the
cyclization than the Boc group, and the cyclized products 2b and
2c were obtained in 65% and 67% yield with ratios of 90:10 and
89:11, respectively. When the sulfonamide with a nitro substituent, a
nosyl group, was used, the reaction was completed within 30 min,
and the corresponding product 2d was obtained in 91% yield with a
70:30 ratio. Neither the PMB amine nor the pivaloyl amide cyclized
at all, and starting materials were recovered.
Several precursors that were substituted at the para position
relative to the alkenyl substituent on the benzene ring were used
in the Bi(OTf)3-catalyzed cyclization under the following con-
ditions: 10 mol % of Bi(OTf)3 with MS-4 Å in DCM at -15 or
-20 °C. The cyclizations proceeded smoothly, within 5 min, and
the methyl substituent 2e and chloro substituent 2f were
obtained in 71% and 88% yields, respectively, with high 1,3-
chirality transfer (Table 3). The 2g substituted with a methoxy
group, which is a more electron-donating group than a methyl
group, was obtained in quantitative yield. However, non-1,3-
chirality transfer was observed. The cyclization of hydroxy-
substituted 1h was promoted by Bi(OTf)3 and resulted in no
selectivity. In contrast, the reaction of the methoxy substituent at
the meta position relative to the alkenyl substituent on the
benzene ring was completed at -15 °C in 2.3 h, and 2i was
obtained in 82% yield with high 1,3-chirality transfer (95:5). The
cyclizations of the m-chloro substituent required 2 days at 0 °C to
go to completion to give 2j in 68% yield with a ratio of 93:7.
These results indicate that a mesomeric effect enhanced the
reactivity and selectivity. The methyl substituent at the ortho
position relative to the alkenyl substituent on the benzene ring
was examined. However, the reaction did not take place at
-15 °C, requiring warming to room temperature, and 2k was
obtained in 74% yield with a significant loss of selectivity (77:23).
The substituent effect on the allylic alcohol was examined with 1l
at -15 °C, and the corresponding product 2l possessing a quaternary
carbon was obtained in 60% yield with a ratio of 74:26.
Further studies were designed to test the effects of substitution
on the allylic alcohol moiety and to clarify the reaction mechan-
ism (Scheme 3). When cis-olefin 1m was subjected to the
reaction conditions, the reaction was far more sluggish, even
after 1 day at room temperature with 50 mol % of Bi(OTf)3,
giving only low yield of ent-2a with a ratio of 29:71. Surprisingly,
on the acetate 1n, the cyclization did not take place at -15 °C
within 0.5 h. When the reaction was performed at 0 °C, the
corresponding product 1a was obtained in 91% yield with a ratio
of 64:36. It is noteworthy that the hydroxy group of allylic alcohol
plays an important role in the cyclization.
Mechanism of the Cyclization. The stereochemical out-
come of the Bi(III)-catalyzed amination of the 1 is characteristic
of a concerted SN20-type substitution.21 On the basis of the
results, BiBr3, a soft Lewis acid, did not catalyze the reaction due
to the low stability of the carbonyl complexes. In contrast, BiCl3
and especially Bi(OTf)3, in which the Lewis acidity of bismuth is
amplified by three strong electron-withdrawing groups, are
strong and relative hard, effective Lewis acids. Therefore, the
mechanism for the intramolecular Bi(III)-catalyzed amination of
allyl alcohols involving π-activation of the allylic CdC bond was
found to be at odds with the high oxophilicity of Bi(OTf)3.
Rather, a mechanism involving σ-activation of the hydroxyl
group appears to be more in line with the pronounced σ-acidity
of the cationic Bi(III) complexes. Thus, as shown in Figure 1, the
coordination of Bi(OTf)3 with the hydroxy group of allyl alcohol
followed by elimination of TfOH formed the complex II. Bi of
the complex II coordinates the carbonyl group of Boc to
determine the face selectivity, followed by syn SN20-type cycliza-
tion to afford 2a along with Bi(OH)(OTf)2. Finally, Bi(OTf)3
would be regenerated from TfOH and Bi(OH)(OTf)2 by the
assistance of MS-4 Å.
No coordination between Bi and the carbonyl group led to ent-
2a via an anti SN20-type process with a ratio similar to that of 2a.
The possibility that Bi(OTf)3 coordinates function of both the
hydroxy group and the carbonyl group at the same time for a
concerted mechanism based on the crystalline structure of a
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Table 3. Scope and limitation
nonahydrate of Bi(OTf)322 established by Dubac cannot be ruled
out. The Bi atom has a negative charge in the complex I and
cannot coordinate with the carbonyl group of Boc.23 The
coordination ability of the oxygen atom of the carbonyl group
with Bi atom can be considered as the nucleophilicity of those of
carbamates from the results in Table 2. The tBu ester (Boc) has
nucleophilicity higher than that of Bn ester (Cbz) and methy-
l ester (methyl carbamate).24
Scheme 3. Cyclizations of (Z) Isomer and the Acetate Deri-
vative
A possible mechanism can be proposed for the observed poor
1,3-chirality transfer in the cyclizations of 1k-1n in Figure 2.
The steric hindrance between the methyl group (or the benzylic
proton) and the vinyl proton in possible two conformations A
(and B) prevented the coordination between Bi and the carbonyl
group in the cyclizations of 1k (and 1l). In the same way, the
cyclization of the (Z)-isomer 1m has been attributed to the
strong steric hindrance between the allylic proton and the
benzylic proton (or the aromatic proton). (C) In the cyclization
of the acetate 1n, the 14-membered chelating complex D was
assumed to be formed on the basis of the reduced reactivity and
selectivity.25 The low stereocontrolled cyclization via syn and anti
attack has been attributed to the flexibility of the 14-membered
chelating complex.
A plausible mechanism can be proposed for the observed poor
1,3-chirality transfer in the cyclization of 1g (Scheme 4). There
could be a cascade of electrons, moving from the methoxy
substituent to the coordinated hydroxy group with Bi(OTf)3.
This would cause an elimination of the hydroxy group and lead to
no stereoselective ring closure.
natural product synthesis, additional reaction conditions of 1g
were examined, as shown in Table 4. In entries 1 and 2, the
effects of reaction temperature were examined. At -40 °C, the
reaction completed after 45 min and the product 2g was
obtained in 96% yield with a ratio of 75:25 (entry 1). A further
decrease to -78 °C resulted in no improvement in the
selectivity (entry 2). Toluene was used as a solvent in entry 3,
and cyclization of 1g at -40 °C proceeded to give 2g in 34%
yield with a ratio of 70:30. When the 10 mol % of pyridine
(entry 4) was added in the mixtures of catalyst and MS-4 Å in
DCM followed by addition of the solution of 1g in DCM, the
product 2g was obtained in 81% yield with ratios of 75:25.25
Synthesis of the Chiral Oxygen-Substituted Tetrahydro-
hydroisoquinoline at the 6 Position. For the application to
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Figure 1. Plausible mechanism of the cyclization.
Figure 2. Consideration of the selectivity on the transition states A (on 1k), B (on 1l), C (on 1m), and D (on 1n).
Scheme 4. Rationalization for the Enhancement of the Reactivity and Selectivity by p-Methoxy Substituent
Next, the effects of the counterion were examined. With 10 mol
% of BiCl3, the cyclization proceeded at -40 °C to afford 2g in
56% yield with nonchiral transfer in entry 5. The combination
of Bi(OTf)3 and KPF6 resulted in a nonimprovement in chiral
transfer with 56% yield in entry 6.
Although high 1,3-chirality transfer was not achieved, the focus
was to establish a methodology for the synthesis of oxygen-
substituted 1-propenyl tetrahydroisoquinoline at the 6 position
in a suitable optically pure form. Pivaloyl ester 1i was chosen as a
possible solution to the present substitution problem. A few
comments concerning the choice of this particular pivaloyl ester
are in order. First, the ester substituent is electron-withdrawing.
Second, the bulky t-Bu group may minimize the potential of the
oxygen lone pairs of the carbonyl group for chelation with Bi.
Finally, the ester is suitable as a protective group of phenol
derivative for the synthetic applications.
Removal of a methyl group of 4g26 with BBr3 in DCM followed
by esterification of the resultant phenol gave 4o in 84% yield in 2
steps (Scheme 5), After 3 general steps [(1) reduction of nitrile and
protection; (2) Suzuki coupling; (3) desilylation] were conducted,
the precursor 1o was prepared in 60% yield in 3 steps. With the
precursor 1o in hand, the cyclization reaction was examined.
Although Bi-catalyzed cyclization of 1o proceeded to completion
at -15 °C much slower than that of 1g, high 1,3-chirality transfer
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was achieved. After 7 h, the ester 2o wasobtainedin81% yieldwitha
ratio of 93:7.
(350 mL) were added (Boc)2O (15.6 g, 71.6 mmol), NiCl2 6H2O (941
3
mg, 3.93 mmol), and NaBH4 (7.0 g, 189 mmol) at 0 °C. The reaction
mixture was stirred at room temperature for 1.5 h and treated with Et2NH
(4.3 mL, 71.6 mmol). The mixture was stirred for 0.5 h and evaporated. To
the residue were added EtOAc and saturated aqueous NH4Cl, the aqueous
layer was extracted with EtOAc 3 times, and the combined organic extracts
were washed with brine, driedover MgSO4, and evaporated. Purification of
the residue by column chromatography on silica gel or distillation gave 5.
Yields: 5a (89%), 5b (68%) ClCO2Me was added instead of Boc2O, 5c
(65%) CbzCl was added instead of Boc2O, 5d (65%) o-nitrobenzensulfo-
nyl chloride was added instead of Boc2O, 5e (80%), 5f (69%), 5g (61%),
5h (60%), 5i (58%), 5j (61%), 5k (68%), 5o (73%).
’ CONCLUSION
We have described Bi(OTf)3-catalyzed chiral synthesis of
1-substituted tetrahydroisoquinolines from chiral amino allyl
alcohol via a 1,3-chirality transfer process. The stereochemistry at
the newly formed chiral center is produced by a syn SN20-type process.
In this reaction, the substituent on the benzene ring of 1 significantly
affected the reactivities and selectivities. The precursor substituted
with a methoxy group at the para position relative to the alkenyl
substituent on the benzene ring gave the corresponding 2g in 99%
yield with a loss of chirality transfer on the Bi(OTf)3-catalyzed cycliza-
tion under the optimized conditions. The replacement of a methoxy
group with a pivaloyl ester achieved high 1,3-chirality transfer in the
reaction to afford the oxygen-substituted tetrahydrohydroisoquino-
line derivatives, which are observed in natural products and biologi-
cally important products. The reaction mechanism has been pro-
posed to be an attractive interaction based on the intermediary Bi
complex coordination of the hydroxy group and the carbonyl group.
The cyanide 4 was prepared from the corresponding bromide by
cyanation in the literature.17 4a,17 4e,27 4f,28 4g,26 4h,29 4i,30 4j,31 and
4k32 had been reported previously.
Compounds 5a,16 5b,33 and 5c34 had been reported previously, and
their identities were confirmed by comparison of their spectroscopic
data with the reported data. Characterization data for the new com-
pounds 5d, 5e, 5f, 5g, 5h, 5i, 5j, 5k, and 5o are shown below.
N-Nosyl-N-[2-(2-bromophenyl)ethyl]amine (5d). Colorless oil,
1
Rf = 0.32 (20% EtOAc in hexane); H NMR (500 MHz, CDCl3) δ
7.45 (d, J = 8.0 Hz, 1H), 7.20-7.09 (m, 8H), 5.00 (s, 2H), 4.78-4.72 (m,
1H), 3.41-3.37 (m, 2H), 2.89 (t, J = 7.0 Hz, 1H), 2.73 (t, J = 7.0 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 136.8, 133.8, 133.5, 133.0, 132.8, 131.2,
131.0, 128.7, 127.7, 126.3, 125.4, 124.4, 43.2, 36.5; IR (neat, cm-1) 3019,
2927, 1541, 1416, 1360, 1215, 1168, 1074; MS m/z 385 (M þ Hþ); HRMS
(CI) calcd for C14H14BrN2O4S m/z 384.9857, found: 384.9865.
’ EXPERIMENTAL SECTION
Synthesis of the Precursor
Reduction of Nitrile and the Protection of the Resultant
Amine. To a stirred solution of cyanide 4 (35.7 mmol) in MeOH
N-Boc-N-[2-(2-bromo-5-methyl-phenyl)ethyl]amine (5e). White
solid, Rf = 0.46 (20% EtOAc in hexane); mp 71-72 °C; H NMR
Table 4. Cyclization of 1g under Several Conditions
1
(CDCl3, 500 MHz) δ 7.40 (d, J = 8.1 Hz, 1H), 7.04 (s, 1H), 6.90 (d, J =
8.1 Hz, 1H), 4.59 (brs, 1H), 3.39-3.35 (m, 2H), 2.92-2.28 (m, 2H),
2.28 (s, 3H), 1.44 (s, 9H); 13C NMR (CDCl3, 125 MHz) δ 155.8, 137.9,
137.4, 132.5, 131.8, 128.9, 121.1, 79.2, 40.3, 36.2, 28.4, 20.8; IR (KBr,
cm-1) 3359, 2989, 1685, 1526, 1465, 1394, 1366, 1278, 1250, 1167,
1025; MS m/z 313 (Mþ); HRMS (EI) calcd for C14H20BrNO2 m/z
313.0677, found 313.0685. Anal. Calcd for C14H20BrNO2: C, 53.51; H,
6.42; N, 4.46. Found: C, 53.41; H, 6.43; N, 4.34.
entry
additivea
pyridine
temp (°C)
time (h)
yield (%)
ratio (S:R)b
N-Boc-N-[2-(2-bromo-5-chloro-phenyl)ethyl]amine (5f). White
1
solid, Rf = 0.51 (20% EtOAc in hexane); mp 70-71 °C; H NMR
1
-40
-78
-40
-20
-40
-15
0.8
0.1
4
96
40
34
81
56
56
75:25
74:26
70:30
75:25
56:44
71:29
(CDCl3, 500 MHz) δ 7.46 (d, J = 8.5 Hz, 1H), 7.21 (d, J = 2.5 Hz, 1H),
7.07 (dd, J = 8.5, 2.5 Hz, 1H), 4.59 (br, 1H), 3.38 (td, J = 6.5, 6.5 Hz, 2H),
2.92 (t, J = 6.5 Hz, 2 H), 1.43 (s, 9H); 13C NMR (CDCl3, 125 MHz) δ
155.8, 140.2, 133.9, 133.3, 130.9, 128.2, 122.4, 79.4, 39.9, 36.3, 28.3; IR
(KBr, cm-1) 3583, 3019, 2400, 1709, 1508, 1464, 1367, 1216, 1168, 1100,
1030; MS m/z 333 (Mþ); HRMS (EI) calcd for C13H17BrClNO2 m/z
333.0131, found 333.0135. Anal. Calcd for C13H17BrClNO2: C, 46.66; H,
5.12; N, 4.19. Found: C, 46.39; H, 4.95; N, 4.01.
2
3c
4
0.5
1.2
5d
6
e
KPF6
2.5
c
a 10 mol %. b Determined by HPLC. Toluene was used as a solvent.
d BiCl3 was used. e Bi(OTf)2PF6 was formed in situ.12e
Scheme 5. Preparation of Pivaloyl Ester 1o and the Cyclization
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N-Boc-N-[2-(2-bromo-5-methoxy-phenyl)ethyl]amine (5g). White
solid, Rf = 0.32 (20% EtOAc in hexane); mp 88-90 °C; H NMR
with EtOAc 3 times. The combined organic extracts were washed with brine
and dried over MgSO4. Evaporation of the solvent and purification of the
residue by column chromatography using hexane/EtOAc (9:1) as the
eluent gave 4o (5.01 g, 99%). Colorless solid. Rf = 0.32 (20% EtOAc in
hexane); mp 70-71 °C; 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J = 8.7
Hz, 1H), 7.26 (d, J = 2.7 Hz, 1H), 6.96 (dd, J = 8.7, 2.7 Hz, 1H), 3.83 (s,
1H), 1.36 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 176.6, 150.8, 133.8,
131.0, 123.3, 123.0, 119.6, 116.5, 39.2, 27.0, 24.9; IR (neat, cm-1) 2976
2936, 2874, 2253, 1806, 1754, 1713, 1604, 1578, 1470, 1366, 1271, 1157,
1113, 1028; MS m/z 295 (Mþ); HRMS (EI) calcd for C13H14BrNO2 m/z
295.0207, found 295.0205. Anal. Calcd for C13H14BrNO2: C, 52.72; H,
4.76; N, 4.73. Found: C, 52.49; H, 4.69; N, 4.50.
1
(CDCl3, 400 MHz) δ 7.41 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 2.8 Hz, 1H),
6.66 (dd, J = 8.8, 2.8 Hz, 1H), 4.61 (brs, 1H), 3.77 (s, 3H), 3.30-3.45
(m, 2H), 2.90 (t, J = 7.0 Hz, 2H), 1.43 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 158.9, 155.8, 139.3, 133.3, 116.4, 115.0, 114.0, 79.3, 55.4, 40.2,
36.6, 28.4; IR (KBr, cm-1) 3335, 2971, 1686, 1543, 1477, 1244, 1172;
MS m/z; 329 (Mþ); HRMS (EI) calcd for C14H20BrNO3 m/z
329.0626, found 329.0624. Anal. Calcd for C14H20BrNO3: C, 50.92;
H, 6.10; N, 4.24. Found: C, 51.21; H, 6.11; N, 4.39.
N-Boc-N-[2-(2-bromo-5-hydroxy-phenyl)ethyl]amine (5h). White
1
solid, Rf = 0.15 (20% EtOAc in hexane); mp 83-85 °C; H NMR
(CDCl3, 400 MHz) δ 7.33 (d, J = 8.6 Hz, 1H), 6.78 (s, 1H), 6.63 (dd, J =
8.6, 2.6 Hz, 1H), 4.77 (brs, 1H), 3.39-3.34 (m, 2H), 2.86-2.83 (m,
2H), 1.43 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 156.4, 155.9, 139.0,
133.5, 117.8, 115.7, 114.2, 79.9, 40.2, 36.3, 28.4; IR (KBr, cm-1) 3332,
2977, 2932, 1681, 1593, 1575, 1517, 1472, 1394, 1367, 1290, 1246, 1165,
1056; MS m/z; 315 (Mþ); HRMS (EI) calcd for C13H18BrNO3 m/z
315.0469, found 315.0466. Anal. Calcd for C13H18BrNO3: C, 49.38; H,
5.74; N, 4.43. Found: C, 49.66; H, 5.94; N, 4.52.
N-Boc-N-[2-(2-bromo-4-methoxy-phenyl)ethyl]amine (5i). Colorless
oil, Rf = 0.32 (20% EtOAc in hexane); 1H NMR (500 MHz, CDCl3) δ 7.12
(d, J = 8.4 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.80 (dd, J = 8.4, 2.4 Hz, 1H),
4.58 (brs, 1H), 3.78 (s, 3H), 3.35 (td, J= 6.7, 6.7 Hz, 2H), 2.88 (t, J=6.7Hz,
2H), 1.43 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 158.7, 155.9, 131.3,
124.6, 118.0, 113.6, 113.6, 79.2, 55.5, 40.5, 35.4, 28.4; IR (neat, cm-1) 3361,
2976, 1705, 1605, 1567, 1495, 1455, 1441, 1391, 1365, 1340, 1245, 1172,
1038; MS m/z 329 (Mþ); HRMS (EI) calcd for C14H20BrNO3 m/z
329.0626, found 329.0621.
(2S)-(E)-2-(tert-Butyldimethylsilyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)but-3-ene (6). In sealed tube, to the solution of 9 (5.58
g, 30.3 mmol) in THF (4 mL) was added fresh pinacolborolane (4.87 mL,
33.3 mmol) at room temperature. The mixture was stirred at 130 °C for 1
day. The resulting mixture was treated with satd NH4Cl aq and extracted
with EtOAc 3 times. The combined organic extracts were washed with brine
and dried over MgSO4. Concentration and purification of the residue by
column chromatography using hexane/EtOAc (17:3) as the eluent gave 6
(8.41 g, 89%). Colorless oil, [R]20D 3.19 (c 0.95, CHCl3). Other than optical
rotation, the physical properties of (þ)-6 matched those reported for (()-6
in the literature.17
(2S)-(E)-2-(tert-Butyldimethylsilyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)pent-3-ene (7). To the solution of 9 (1.2 g, 6.5
mmol) in THF (30 mL) was added 1.58 M solution of BuLi in hexane
(4.7 mL, 7.5 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 min
and treated with MeI (1.2 mL, 19.7 mmol). The reaction mixture was
stirred at room temperature for 1 h and quenched with satd NH4Cl aq.
The aqueous layer was extracted with Et2O, and the organic extract was
washed with H2O and brine, dried over MgSO4, and concentrated in
vaccuo. The crude product was conducted to the next hydroboration
reaction, the same procedure as for 6, without further purification. After
workup, purification of the residue by column chromatography using
hexane/EtOAc (40:1) as an eluent gave 7 (1.86 g, 88%). Colorless oil,
Rf = 0.63 (10% Et2O in hexane); [R]20D -9.1 (c 0.97, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 6.25 (1H, dd, J = 8.0, 1.5 Hz), 4.65 (1H, d, J = 8.0,
6.5 Hz), 1.67 (3H, d, J = 1.5 Hz), 1.26 (6H, s), 1.25 (6H, s), 1.17 (3H, d,
J = 6.5 Hz), 0.87 (9H, s), 0.03 (3H, s), 0.01 (3H, s); 13C NMR (125
MHz, CDCl3) δ 150.4, 139.5, 137.9, 83.2, 65.6, 25.9, 24.9, 24.5, 23.5,
18.2, 13.9, -4.5, -4.7; IR (neat, cm-1) 3433, 1637, 1215, 1140, 754;
MS (EIþ) m/z 326 (Mþ). HRMS calcd for C17H35BO3Si (Mþ) m/z
326.2448, found 326.2446.
(2S)-(Z)-2-(tert-Butyldimethylsilyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)but-3-ene (8). To the solution of 9 (258 mg, 1.4
mmol) in Et2O (1.4 mL) was added 1.58 M solution of BuLi in hexane (0.8
mL, 1.4 mmol) at -78 °C. The mixture was stirred at -78 °C for 30 min
and treated with the solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-
dioxaborane (265 mg, 1.4 mmol) in Et2O. The reaction mixture was stirred
at -78 °C for 4.5 h and quenched with 1 N HCl aq. The aqueous layer was
extracted with Et2O, and the organic extract was washed with brine, dried
over MgSO4, and concentrated in vaccuo. The crude product was
conducted to the next reaction without further purification.
To the solution of Cp2ZrCl(H) (376 mg, 1.46 mmol) in THF (2.4
mL) was added the solution of the crude product in THF (2.4 mL). The
reaction mixture was stirred for 1 h and treated with dist H2O (1 mL).
The mixture was stirred for 10 h and concentrated in vaccuo. The residue
was extracted with Et2O, and the organic extract was washed with brine,
dried, concentrated. Purification of the residue by column chromatog-
raphy on silica gel using hexane/EtOAc (40:1) as an eluent gave 8 (225
mg, 50%). Colorless oil, Rf = 0.71 (10% Et2O in hexane); [R]20D 40.5 (c
0.27, CHCl3). Other than optical rotation, the physical properties of
(þ)-8 matched those reported for (()-8 in the literature.20
N-Boc-N-[2-(2-bromo-4-chloro-phenyl)ethyl]amine (5j). White
solid, Rf = 0.5 (20% EtOAc in hexane); mp 36-38 °C; 1H NMR
(CDCl3, 500 MHz) δ 7.55 (d, J = 2.0 Hz, 1H), 7.22 (dd, J = 8.1, 2.0 Hz,
1H), 7.15 (d, J = 8.1 Hz, 1H), 4.59 (brs, 1H), 3.40-3.25 (m, 2H), 2.95-
2.85 (m, 2H), 1.42 (s, 9H); 13C NMR (CDCl3, 125 MHz) δ 155.8,
137.0, 132.9, 132.4, 131.6, 127.7, 124.8, 79.3, 40.1, 35.8, 28.4; IR (KBr, cm-1
)
3454, 3018, 2979, 2933, 2400, 1708, 1507, 1471, 1392, 1367, 1216, 1168,
1103, 1038; MS m/z333 (Mþ);HRMS(EI) calcdforC13H17BrClNO2 m/z
333.0131, found 333.0135. Anal. Calcd for C13H17BrClNO2: C, 46.66; H,
5.12; N, 4.19. Found: C, 46.39; H, 4.95; N, 4.01.
N-Boc-N-[2-(2-bromo-3-methyl-phenyl)ethyl]amine (5k). White
1
solid, Rf = 0.5 (20% EtOAc in hexane); mp 77-78 °C; H NMR (500
MHz, CDCl3) δ7.13 (dd, J= 7.5, 7.5 Hz, 1H), 7.11 (d, J= 7.5 Hz, 1H), 7.05
(d, J = 7.5 Hz, 1H), 4.59 (brs, 1H), 3.40-3.39 (m, 2H), 2.99-2.97 (m,
2H), 2.42 (s, 3H), 1.43 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 155.9,
138.8, 138.7, 129.1, 128.4, 127.3, 126.9, 79.2, 40.2, 37.1, 28.4, 24.0; IR
(CHCl3, cm-1) 3453, 3017, 2979, 1708, 1509, 1392, 1366, 1216, 1169,
1025; MS m/z 313 (Mþ); HRMS (EI) calcd for C14H20BrNO2 m/z
313.0677, found 313.0685. Anal. Calcd for C14H20BrNO2: C, 53.51; H,
6.42; N, 4.46. Found: C, 53.60; H, 6.40; N, 4.42.
N-Boc-N-[2-(2-bromo-5-pivaroyloxy-phenyl)ethyl]amine (5o). White
solid, Rf = 0.45 (20% EtOAc in hexane); mp 110-111 °C; 1H NMR (500
MHz, CDCl3) δ 7.52 (d, J = 8.5 Hz, 1H), 6.93 (s, 1H), 6.83 (d, J = 8.5 Hz,
1H), 4.63 (s, 1H), 3.38-3.36 (m, 2H), 3.00-2.90 (m, 2H), 1.43 (s, 9H),
1.34 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 176.7, 155.8, 150.3, 139.7,
133.4, 124.0, 121.4, 120.7, 79.3, 40.0, 39.1, 36.3, 28.4, 27.1; IR (CHCl3,
cm-1) 2977, 1749, 1703, 1508, 1469, 1366, 1269, 1157, 1119, 1025; MS
m/z 399 (Mþ); HRMS (EI) calcd for C18H25BrNO4 m/z 399.1045, found
399.1049. Anal. Calcd for C18H26BrNO4: C, 54.01; H, 6.55; N, 3.50. Found:
C, 53.87; H, 6.77; N, 3.35.
4-Bromo-3-(cyanomethyl)phenyl Pivalate (4o). To a stirred solution
of cyanide 4h (3.62 g, 17 mmol) in DCM (250 mL) were added pyridine
(4.95 mL, 61.2 mmol) and pivaloyl chloride (4.95 mL, 61.2 mmol) at 0 °C.
The mixture was stirred at room temperature for 1 day. The resulting
mixture was treated with satd NH4Cl aq. The aqueous layer was extracted
2108
dx.doi.org/10.1021/jo102452d |J. Org. Chem. 2011, 76, 2102–2114

The Journal of Organic Chemistry
ARTICLE
Suzuki Cross-Coupling. To the mixture of 5 (2.24 mmol),
NaHCO3 (933 mg, 11 mmol), and 6 (2.9 mmol) in 1,4-dioxane (30
mL) and H2O (12 mL) was added PdCl2(dppf) (91.5 mg, 0.11 mmol).
The reaction mixture was stirred at 80 °C for 2 h and quenched with
H2O. The aqueous layer was extracted with EtOAc, and the organic
extract was washed with brine, dried over MgSO4, and concentrated in
vaccuo. Purification by column chromatography on silica gel using 5%
EtOAc in hexane as an eluent gave 10. Yields: 10a (86%), 10b (84%),
10c (75%), 10d (64%), 10e (76%), 10f (67%), 10g (78%), 10h (68%),
10i (78%), 10j (84%), 10k (53%), 10l (87%),35 10m,36 10o (84%).
(3S)-(E)-N-Boc-N-[2-[2-(3-tert-butyldimethylsilyloxy-1-butenyl)phenyl]-
3H), 1.44 (s, 9H), 1.30 (d, J = 5.6 Hz, 3H), 0.93 (s, 9H), 0.10 (s, 3H),
0.09 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 155.8, 137.1, 136.0, 135.8,
133.4, 130.8, 127.6, 126.2, 124.8, 79.0, 69.4, 41.2, 33.3, 28.4, 25.9, 24.7,
21.0, 18.3, -4.6, -4.7; IR (neat, cm-1) 3361, 2929, 2857, 1708, 1613,
1504, 1462, 1390, 1365, 1252, 1173, 1077; MS m/z 419 (Mþ); HRMS
(EI) calcd for C24H41NO3Si m/z 419.2856, found 419.2860.
(3S)-(E)-N-Boc-N-[2-[2-(3-tert-butyldimethylsilyloxy-1-butenyl)-5-chlo-
rophenyl]ethyl]amine (10f). Colorless oil. Rf = 0.31 (10% EtOAc in hex-
ane); [R]D22 -17.9 (c1.0, CHCl3);1HNMR(CDCl3, 500 MHz) δ7.36 (d,
J = 8.2 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H), 7.12 (s, 1H), 6.72 (d, J = 15.6 Hz,
1H), 6.09 (dd, J = 15.6, 5.5 Hz, 1H), 4.53 (br, 1H), 4.48 (dq, J = 6.0, 6.0 Hz,
1H), 3.30-3.29 (m, 2H), 2.84-2.83 (m, 2H), 1.44 (s, 9H), 1.30 (d, J = 5.5
Hz, 3H), 0.93 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H); 13C NMR (CDCl3, 100
MHz) δ 155.7, 138.0, 137.3, 134.8, 132.8, 129.8, 127.6, 126.9, 123.9, 79.3,
69.1, 40.9, 33.3, 28.4, 25.8, 24.5, 18.2, -4.6, -4.7; IR (neat, cm-1) 3361,
2956, 2929, 2857, 1707, 1594, 1507, 1479, 1391, 1366, 1252, 1172, 1094; MS
m/z 439 (Mþ); HRMS (EI) calcd for C23H38NO3Si m/z 439.2309, found:
439.2318.
(3S)-(E)-N-Boc-N-[2-[2-(3-tert-butyldimethylsilyloxy-1-butenyl)-5-me-
thoxyphenyl]ethyl]amine (10g). Colorless oil. Rf = 0.30 (10% EtOAc in
hexane); [R]22D -2.0 (c 1.0, C6H6); 1H NMR (400 MHz, C6D6) δ 7.38
(d, J = 8.4 Hz, 1H), 6.92 (d, J = 15.6 Hz, 1H), 6.68 (dd, J = 8.4, 2.8 Hz, 1H),
6.66 (d, J = 2.8 Hz, 1H), 6.06 (dd, J= 15.6, 6.0 Hz, 1H), 4.47 (dq, J= 6.4, 6.0
Hz, 1H), 4.12 (brs, 1H), 3.34 (s, 3H), 3.21-3.18 (m, 2H), 2.75-2.68 (m,
2H), 1.43 (s, 9H), 1.33 (d, J = 6.4 Hz, 3H), 1.03 (s, 9H), 0.15 (s, 3H), 0.14
(s, 3H); 13C NMR (100 MHz, C6D6) δ 160.2, 156.3, 138.9, 135.5, 129.8,
128.9, 126.1, 116.2, 113.6, 79.1, 70.8, 55.4, 42.3, 34.9, 29.1, 26.7, 25.7,
19.0, -5.2, -5.5; IR (neat, cm-1) 3367, 2930, 1713, 1607, 1501, 1390,
1365, 1255, 1171, 1096; MS m/z 435 (Mþ); HRMS (EI) calcd for
C24H41NO4Si m/z 435.2805, found: 435.2797.
(3S)-(E)-N-Boc-N-[2-[2-(3-tert-butyldimethylsilyloxy-1-butenyl)-5-hy-
droxyphenyl]ethyl]amine (10h). Colorless oil. Rf = 0.18 (20% EtOAc in
hexane); [R]22D -20.8 (c 0.67, CHCl3); 1H NMR (CDCl3, 500 MHz) δ
7.72 (dd, J = 8.5, 2.0 Hz, 1H), 7.31 (d, J= 8.5Hz, 1H), 6.82 (s, 1H), 6.66 (s,
1H),6.65 (d, J= 15.5 Hz, 1H), 5.98 (dd, J= 15.5, 5.5 Hz, 1H), 4.66 (s, 1H),
4.46 (qd, J = 6.5, 5.5 Hz, 1H), 3.35-3.22 (m, 2H), 2.82-2.71 (m, 2H),
1.44 (s, 9H), 1.29 (d, J = 6.5 Hz, 3H), 0.92 (s, 9H), 0.09 (s, 3H), 0.08 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 156.2, 155.7, 137.6, 134.6,
127.6, 124.6, 116.5, 114.2, 79.6, 69.5, 60.5, 41.2, 33.4, 28.4, 25.9, 24.7,
18.3, -4.6, -4.7; IR (neat, cm-1) 3352, 2955, 2930, 2885, 2857, 1682,
1607, 1577, 1504, 1461, 1393, 1367, 1252, 1165, 1095; MS m/z 421 (Mþ);
HRMS (EI) calcd for C23H39NO4Si m/z 421.2648, found 421.2655.
(3S)-(E)-N-Boc-N-[2-[2-[3-(tert-butyldimethylsilyloxy)but-1-enyl]-4-
methoxyphenyl]ethyl]amine (10i). Colorlessoil. Rf = 0.30(10% EtOAc
in hexane); [R]22D -22.2 (c 1.0, CHCl3); 1H NMR (CDCl3, 500 MHz)
δ 7.05 (d, J = 8.2 Hz, 1H), 6.98 (d, J = 2.5 Hz, 1H), 6.75 (dd, J = 8.2, 2.5
Hz, 1H), 6.74 (d, J = 15.6 Hz, 1H), 6.11 (dd, J = 15.6, 5.3 Hz, 1H), 4.49
(dt, J = 6.4, 5.3 Hz, 1H), 4.49 (br, 1H), 3.81 (s, 3H), 3.29-3.27 (m, 2H),
2.81-2.80 (m, 2H), 1.43 (s, 9H), 1.31 (d, J = 6.4 Hz, 3H), 0.93 (s, 9H),
0.10 (s, 3H), 0.09 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 158.4, 155.8,
137.3, 136.8, 131.1, 128.6, 125.0, 113.0, 111.4, 79.1, 69.2, 55.3, 41.4, 32.6,
28.4, 25.9, 24.6, 18.3, -4.6, -4.7; IR (neat, cm -1) 3374, 2930, 2857,
1712, 1606, 1573, 1497, 1390, 1365, 1251, 1168, 1044 ; MS m/z 435 (Mþ);
HRMS (EI) calcd for C24H41NO4Si m/z 435.2805, found: 435.2802.
(3S)-(E)-N-Boc-N-[2-[2-[3-(tert-butyldimethylsilyloxy)but-1-enyl]-4-
chlorophenyl]ethyl]amine (10j). Colorless oil. Rf = 0.30 (10% EtOAc
in hexane); [R]22D -63.1 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3)
δ 7.41 (s, 1H), 7.14 (d, J = 7.0 Hz, 1H), 7.06 (d, J = 7.0 Hz, 1H), 6.73 (d,
J = 15.0 Hz, 1H), 6.13 (dd, J = 15.0, 4.5 Hz, 1H), 4.49 (brs, 1H), 3.34-
3.20 (m, 2H), 2.88-2.75 (m, 2H), 1.43 (s, 9H), 1.30 (d, J = 5.5 Hz, 3H),
0.93 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
155.7, 138.0, 138.0, 134.7, 132.5, 131.4, 127.2, 126.1, 123.8, 79.3, 69.0,
41.0, 32.9, 28.4, 25.9, 24.5, 18.3, -4.7, -4.7; IR (neat, cm-1) 3359, 2955,
2929, 2857, 1706, 1507, 1480, 1390, 1365, 1251, 1170, 1089; MS m/z
ethyl]amine (10a). Colorless oil, Rf = 0.38 (10% EtOAc in hexane);
1
[R]20 -19.3 (c 1.10, CHCl3); H NMR (300 MHz, CDCl3) δ 7.46
D
(1H, dd, J = 7.2, 2.4 Hz), 7.25- 7.15 (2H, m), 7.10 (1H, dd, J = 6.4, 2.4 Hz),
6.80 (1H, d, J = 15.6 Hz), 6.13 (1H, dd, J = 15.6, 5.1 Hz), 5.58 (1H, s), 4.51
(1H, qdd, J = 6.4, 5.1, 1.3 Hz), 3.48-3.41 (2H, m), 2.89 (2H, t, J = 6.8 Hz),
1.31 (3H, d, J=6.4Hz), 1.14(9H, s), 0.94(9H, s), 0.11(3H, s), 0.09(3H, s);
13C NMR (125 MHz, CDCl3) δ 155.8, 136.8, 136.3, 136.2, 130.0, 127.4,
126.8, 126.3, 124.9, 79.1, 69.3, 41.1, 33.4, 28.4, 25.9, 24.6, 18.3, -4.6, -4.7; IR
(neat, cm-1) 3454, 2930, 1707, 1507, 908, 732; MS (EIþ) m/z 405 (Mþ);
HRMS calcd for C23H39NO3Si (Mþ) m/z 405.2699, found 405.2703.
(3S)-(E)-N-Methoxycarbonyl-N-[2-[2-(3-tert-butyldimethylsilyloxy-
1-butenyl)phenyl]ethyl]amine (10b). Colorless oil, Rf = 0.65 (30%
EtOAc in hexane); [R]20D -22.0 (c 0.67, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 7.45 (1H, dd, J = 6.7, 1.8 Hz), 7.22-7.17 (2H, m), 7.13 (1H,
d, J = 6.7 Hz), 6.78 (1H, d, J = 15.3 Hz), 6.12 (1H, dd, J = 15.3, 5.5 Hz),
4.67 (1H, s), 4.50 (1H, qd, J = 6.1, 5.5 Hz), 3.66 (3H, s), 3.40-3.37 (2H,
m), 2.87-2.89 (2H, m), 1.31 (3H, d, J = 6.1 Hz), 0.93 (9H, s), 0.11 (3H,
s), 0.09 (3H, s); 13C NMR (125 MHz, CDCl3) δ 156.9, 136.9, 136.3,
136.0, 130.0, 127.4, 126.9, 126.3, 124.8, 69.3, 52.0, 41.6, 33.5, 25.9, 24.6,
18.3, -4.6, -4.7; IR (neat, cm-1) 3451, 1711, 1516, 910, 733; MS
(CIþ) m/z 364 (M þ Hþ); HRMS calcd for C20H34NO3Si (M þ Hþ)
m/z 364.2308, found 364.2300.
(3S)-(E)-N-Cbz-N-[2-[2-(3-tert-butyldimethylsilyloxy-1-butenyl)-
phenyl]ethyl]amine (10c). Colorless oil, Rf = 0.63 (20% EtOAc in
hexane); [R]20 -81.3 (c 0.06, CHCl3); 1H NMR (500 MHz,
D
CDCl3) δ 7.40 (1H, d, J = 7.3 Hz), 7.36-7.32 (5H, m), 7.22-7.16
(2H, m), 7.11 (1H, d, J = 7.1 Hz), 6.78 (1H, d, J = 15.3 Hz), 6.11 (1H,
dd, J = 15.3, 5.5 Hz), 5.10 (2H, s), 4.74 (1H, bs), 4.49 (1H, d, J = 6.1,
5.5 Hz), 3.41-3.40 (2H, m), 2.90 (2H, bs), 1.30 (3H, d, J = 6.1 Hz),
0.93 (9H, s), 0.10 (3H, s), 0.08 (3H, s); 13C NMR (125 MHz, CDCl3)
δ 156.3, 136.91, 136.9, 136.3, 135.9, 130.0, 128.51, 128.5, 128.1,
127.4, 126.9, 126.4, 124.8, 69.3, 66.6, 41.6, 33.4, 25.9, 24.6, 18.3,
-4.6, -4.7; IR (neat, cm-1) 3423, 1646, 1518, 1145, 967, 752; MS
(CIþ) m/z 440 (M þ Hþ); HRMS calcd for C26H38NO3Si (M þ Hþ)
m/z 440.2621, found 440.2629.
(3S)-(E)-N-Nosyl-N-[2-[2-(3-tert-butyldimethylsilyloxy-1-butenyl)phenyl]-
ethyl]amine (10d). Colorless oil, Rf = 0.40 (30% EtOAc in hexane);
[R]20D -10.5 (c 0.19, CHCl3); 1H NMR (500 MHz, CDCl3) δ 8.08-8.06
(1H, m), 7.82 (1H, dd, J= 6.1, 3.7 Hz), 7.70 (2H, dd, J= 5.5, 3.7 Hz), 7.37 (1H,
d, J = 7.3 Hz), 7.18-7.10 (2H, m), 7.04 (1H, d, J = 6.7 Hz), 6.69 (1H, d, J =
15.3Hz),6.06(1H, dd,J= 15.3, 4.9 Hz), 5.32 (1H, s), 4.46 (1H, qd, J= 6.7, 4.9
Hz), 3.33-3.29 (2H, m), 2.91-2.94 (2H, m), 1.27 (3H, d, J = 6.7 Hz), 0.92
(9H, s), 0.09 (3H, s), 0.07 (3H, s); 13C NMR (125 MHz, CDCl3) δ 147.8,
137.3, 136.3, 134.5, 133.8, 133.4, 132.8, 130.9, 130.0, 127.5, 127.3, 126.5, 125.4,
124.4, 69.1, 44.2, 33.6, 25.8, 24.6, 18.2, -4.6, -4.7; IR (neat, cm-1) 3434, 2956,
2253, 1640, 1543, 1362, 1169, 907, 732. MS (EIþ) m/z 490 (Mþ); HRMS
calcd for C24H34N2O5SSi (M þ) m/z 490.1957, found 490.1965.
(3S)-(E)-N-Boc-[2-[2-(3-tert-butyldimethylsilyloxy-1-butenyl)-5-me-
thylphenyl]ethyl]amine (10e). Colorless oil. Rf = 0.30 (10% EtOAc in
hexane); [R]22D -26.5 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz)
δ 7.35 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.96 (s, 1H), 6.74 (d,
J = 15.6 Hz, 1H), 6.07 (dd, J = 15.6, 5.2 Hz, 1H), 4.53 (br, 1H), 4.48(dqd,
J = 6.4, 6.4, 1.2 Hz, 1H), 3.32-3.30 (m, 2H), 2.84-2.83 (m, 2H), 2.31 (s,
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ARTICLE
439 (Mþ); HRMS (EI) calcd for C23H38ClNO3Si m/z 439.2309, found
439.2314.
d, J = 15.3 Hz), 6.15 (1H, dd, J = 15.3, 5.5 Hz), 4.89 (1H, s), 4.52 (1H, qd,
J = 6.7, 5.5 Hz), 3.66 (3H, s), 3.30-3.35 (2H, m), 2.89 (2H, t, J = 7.3 Hz),
1.37 (3H, d, J = 6.7 Hz); 13C-NMR (125 MHz, CDCl3) δ 157.1, 136.5,
136.5, 136.1, 130.0, 127.6, 127.0, 126.4, 126.4, 68.6, 52.2, 41.8, 34.3, 23.2;
IR (neat, cm-1) 3441, 1696, 1524, 1260, 908, 730; MS (EIþ) m/z 249
(Mþ); HRMS calcd for C14H19NO3 (Mþ) m/z 249.1365, found
249.1371.
(3S)-(E)-N-Cbz-N-[2-[2-(3-hydroxy-1-butenyl)phenyl]ethyl]amine
(1c). Colorless solid. Rf = 0.17 (30% EtOAc in hexane); mp 41-
42 °C; [R]20D 0.86 (c 0.78, CHCl3); 1H NMR (500 MHz, CDCl3) δ
7.43 (1H, dd, J = 6.7, 1.8 Hz), 7.37-7.31 (5H, m), 7.23-7.17 (2H, m),
7.14-7.09 (1H, m), 6.93 (1H, d, J = 15.9 Hz), 6.15 (1H, dd, J = 15.9,
5.5 Hz), 5.10 (2H, s), 5.00 (1H, bs), 4.52 (1H, qd, J = 6.7, 5.5 Hz),
3.40-3.29 (2H, m), 2.91-2.88 (2H, m), 1.37 (3H, d, J = 6.7 Hz); 13C
NMR (125 MHz, CDCl3) δ 156.4, 136.5, 136.4, 136.3, 135.9, 129.8,
128.51, 128.1, 127.5, 127.0, 126.4, 126.2, 68.5, 66.7, 41.7, 34.2, 23.2; IR
(neat, cm-1) 3419, 1646, 1524, 1250, 1139; MS (EIþ) m/z 325 (M þ);
HRMS calcd for C20H23NO3 (Mþ) m/z 325.1678, found 325.1681.
Anal. Calcd for C20H23NO3: C, 73.82; H, 7.12; N, 4.30. Found: C,
73.96; H, 7.07; N, 4.38.
(3S)-(E)-N-Boc-N-[2-[2-[3-(tert-butyldimethylsilyloxy)but-1-enyl]-3-
methylphenyl]ethyl]amine (10k). Colorless oil. Rf = 0.30 (10% EtOAc
in hexane); [R]22D -19.0 (c 0.26, CHCl3); 1H NMR(300MHz, CDCl3)
δ 7.09 (dd, J = 7.3, 6.1 Hz, 1H), 7.07 (d, J = 6.1 Hz, 1H), 7.03 (d, J = 7.3
Hz, 1H), 6.51 (d, J = 16.5 Hz, 1H), 5.70 (dd, J = 16.5, 5.115 Hz, 1H),
4.51-4.47 (m, 2H), 3.31-3.30 (m, 2H), 2.83-2.80 (m, 2H), 2.28
(s, 3H), 1.43 (s, 9H), 1.32 (d, J = 6.1 Hz, 3H), 0.93 (s, 9H), 0.12 (s,
3H), 0.11 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 155.8, 140.0, 139.3,
136.8, 136.4, 128.3, 127.2, 126.6, 124.8, 77.2, 69.3, 41.0, 33.8, 28.4,
25.9, 24.7, 21.1, 18.3, -4.7, -4.8; IR (neat, cm-1) 3369, 2928, 2857,
2360, 1707, 1507, 1462, 1391, 1365, 1252, 1172, 1081, 1003; MS m/z
419 (Mþ); HRMS (EI) calcd for C24H41N3OSi m/z 419.2856, found
419.2851.
(4S)-(E)-N-Boc-N-[2-[2-(4-tert-butyldimethylsilyloxy-2-pentenyl)phe-
nyl]ethyl]amine (10l). Colorless oil. Rf = 0.25 (10% EtOAc in hexane);
[R]20D -12.6 (c 0.26, CHCl3); 1H NMR (270 MHz, CDCl3) δ 7.19-
7.14 (3H, m), 7.04 (1H, m), 5.33 (1H, dq, J = 8.2, 1.2 Hz), 4.67 (1H, dq,
J =8.2, 6.3Hz), 4.50 (1H, bs), 3.34-3.31 (2H, m), 2.77 (2H, t, J =7.0 Hz),
1.93(3H, d, J=1.2 Hz), 1.42 (9H, s), 1.27 (3H, d, J=6.3Hz), 0.90(9H, s),
0.10 (3H, s), 0.09 (3H, s); 13C NMR (125 MHz, CDCl3) δ 155.7, 145.1,
135.6, 135.4, 133.7, 129.5, 128.5, 126.9, 126.3, 79.1, 66.0, 41.5, 33.1, 28.4,
25.9, 24.4, 19.1, 18.2, -4.5, -4.6; IR (neat, cm-1) 3453, 1642, 1508, 903,
725; MS(EIþ) m/z419 (Mþ);HRMScalcdfor C24H41NO3Si (Mþ) m/z
419.2856, found 419.2851.
(3S)-(E)-N-Boc-N-[2-[2-[3-(tert-butyldimethylsilyloxy)but-1-enyl]-5-
pivaroyloxyphenyl]ethyl]amine (10o). Colorless oil. Rf = 0.30 (10%
EtOAc in hexane); [R]22D -17.4 (c 1.0, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 7.43 (d, J = 8.0 Hz, 1H), 6.90 (dd, J = 8.0, 2.5 Hz, 1H), 6.83 (d,
J = 2.5 Hz, 1H), 6.73 (d, J = 15.5 Hz, 1H), 6.29 (dd, J = 15.5, 5.5 Hz, 1H),
4.55 (br, 1H), 4.48 (dq, J = 6.5, 5.5 Hz, 1H), 3.31-3.28 (m, 2H), 2.86-
2.85 (m, 2H), 1.44 (s, 9H), 1.35 (s, 9H), 1.30 (d, J = 6.5 Hz, 3H), 0.93 (s,
9H), 0.10 (s, 3H), 0.08 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 177.0,
155.8, 150.2, 137.5, 136.9, 133.9, 127.3, 124.3, 122.7, 119.9, 77.2, 69.3,
40.9, 39.0, 33.3, 28.4, 27.1, 25.9, 24.6, 18.3, -4.6, -4.7; IR (neat, cm-1):
3401, 2973, 2931, 2857, 1753, 1713, 1605, 1508, 1393, 1366, 1250, 1157,
1121; MS m/z 505 (Mþ); HRMS (EI) calcd for C28H47NO5Si m/z
505.3223, found 505.3229.
Desilylation of TBS Ether. To the solution of 10 (10 mmol) was
added a 1.0 M solution of TBAF (11 mL, 11 mmol) in THF. The
reaction mixture was stirred and treated with H2O. The aqueous layer
was extracted with EtOAc, and the organic extract was washed with
brine, dried over MgSO4, and concentrated in vaccuo. Purification by
column chromatography on silica gel gave 1. Yields: 1a (95%), 1b
(80%), 1c (81%), 1d (96%), 1e (91%), 1f (98%), 1g (92%), 1h (90%),
1i (99%), 1j (91%), 1k (95%), 1l (95%), 1m (39% in 2steps), 1o (97%).
(3S)-(E)-N-Boc-N-[2-[2-(3-hydroxy-1-butenyl)phenyl]ethyl]amine
(3S)-(E)-N-Nosyl-N-[2-[2-(3-hydroxy-1-butenyl)phenyl]ethyl]amine
(1d). Colorless oil. Rf = 0.07 (30% EtOAc in hexane); [R]20D 3.3 (c 0.2,
1
CHCl3); H NMR (500 MHz, CDCl3) δ 8.11-8.09 (1H, m), 7.84-
7.81 (1H, m), 7.72-7.70 (2H, m), 7.40 (1H, d, J = 7.3 Hz), 7.20-7.14
(2H, m), 7.06 (1H, d, J = 7.3 Hz), 6.81 (1H, d, J = 15.3 Hz), 6.13 (1H, dd,
J = 15.3, 6.1 Hz), 5.43 (1H, t, J = 6.1 Hz), 4.51 (1H, qd, J = 6.7, 6.1 Hz),
3.32-3.28 (2H, m), 2.90- 3.00 (2H, m), 1.37 (3H, d, J = 6.7 Hz); 13C
NMR (125 MHz, CDCl3) δ 147.8, 136.6, 136.2, 134.9, 133.9, 133.4,
132.9, 130.8, 129.9, 127.8, 127.4, 126.6, 126.1, 125.4, 68.8, 44.5, 33.9,
23.4; IR (neat, cm-1) 3358, 2971, 1639, 1539, 1362, 1162, 730; MS
(FAB) m/z 399 (M þ Naþ); HRMS calcd for C18H20N2O5SNa (M þ
Naþ) m/z 399.0991, found 399.0987.
(3S)-(E)-N-Boc-N-[2-[2-(3-hydroxybut-1-enyl)-5-methylphenyl]-
ethyl]amine (1e). Colorless solid. Rf = 0.17 (30% EtOAc in hexane); mp
60-62 °C; [R] 22D 20.7 (c 1.0, CHCl3); 1H NMR (CDCl3, 500 MHz) δ
7.33 (d, J = 7.5 Hz, 1H), 7.02 (d, J = 7.5 Hz, 1H), 6.94 (s, 1H), 6.90 (d, J =
15.5 Hz, 1H), 6.10 (dd, J = 15.5, 5.5 Hz, 1H), 4.73 (br, 1H), 4.55-4.48 (m,
1H), 3.26-3.24 (m, 2H), 2.84-2.82 (m, 3H), 2.31 (s, 3H), 1.44 (s, 9H),
1.36 (d, J = 6.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 156.0, 137.2,
136.1, 135.6, 133.6, 130.6, 127.6, 126.3, 79.5, 77.2, 68.6, 41.4, 34.4, 28.4, 23.2,
21.0; IR (neat, cm-1) 3357, 2975, 2930, 1693, 1613, 1515, 1455, 1392, 1366,
1252, 1171, 1056; MS (EIþ) m/z 306 (Mþ); HRMS calcd for C18H28NO3
(Mþ) m/z 306.2069, found 306.2061. Anal. Calcd for C18H 28NO3: C,
70.79; H, 8.91; N, 4.59. Found: C, 71.08; H, 9.18; N, 4.43.
(3S)-(E)-N-Boc-N-[2-[5-chloro-2-(3-hydroxybut-1-enyl)-phenyl]ethyl]-
amine (1f). White solid. Rf = 0.17 (30% EtOAc in hexane); mp 84-86 °C;
[R]22D þ19.8 (c 1.0, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.34 (d, J =
8.1 Hz, 1H), 7.16 (dd, J = 8.1, 1.8 Hz, 1H), 7.10 (d, J = 1.8 Hz, 1H), 6.88 (d,
J = 15.6 Hz, 1H), 6.12 (dd, J = 15.6, 5.2 Hz, 1H), 4.78 (brs, 1H), 4.51 (brs,
1H), 3.24-3.22 (m, 2H), 3.05 (brs, 1H), 2.82 (t, J = 7.0 Hz, 2H), 1.43 (s,
9H), 1.36 (d, J = 5.2 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 156.0,
138.0, 137.0, 135.1, 132.8, 130.0, 127.7, 127.0, 125.2, 79.7, 68.3, 41.0, 34.4,
28.4, 23.1; IR (KBr, cm-1) 3855, 3753, 3651, 3366, 2975, 1686, 1534, 1459,
1367, 1274, 1173; MS m/z325 (Mþ);HRMS(EI) calcdforC17H24ClNO3
m/z325.1445, found 325.1436. Anal. Calcd for C17H24ClNO3: C, 62.67; H,
7.42; N, 4.30. Found: C, 62.95; H, 7.42; N, 4.34.
(1a). Colorless solid. Rf = 0.12 (30% EtOAc in hexane); mp 60-62 °C;
1
[R]22 þ20.7 (c 1.0, CHCl3); H NMR (CDCl3, 500 MHz) δ 7.44
D
(dd, J = 6.6 2.4 Hz, 1H), 7.20-7.12 (m, 2H), 7.11 (dd, J = 6.6, 2.4 Hz,
1H), 6.95 (d, J = 15.9 Hz, 1H), 6.16 (dd, J = 15.9, 5.5 Hz, 1H), 5.80 (s,
1H), 4.54 (qd, J = 6.2, 5.5 Hz, 1H), 3.43-3.35 (m, 2H), 2.95-2.80 (m,
2H), 1.27 (s, 1H), 1.38 (d, J = 6.2 Hz, 3H), 1.16 (s, 9H); 13C NMR
(CDCl3, 125 MHz) δ 155.9, 136.4, 136.2, 129.8, 127.4, 126.915,
126.913, 126.42, 79.5, 68.5, 41.3, 34.5, 28.4, 23.3; IR (neat, cm-1
)
3357, 2975, 2930, 1693, 1613, 1515, 1455, 1392, 1366, 1252, 1171,
1056; MS m/z 306 (Mþ); HRMS (EI) calcd for C18H28NO3 m/z
306.2069, found 306.2061. Anal. Calcd for C18H28NO3: C, 70.79; H,
8.91; N, 4.59. Found: C, 71.08; H, 9.18; N, 4.43.
(3S)-(E)-N-Methoxycarbonyl-N-[2-[2-(3-hydroxy-1-butenyl)phenyl]-
ethyl]amine (1b). Colorless oil. Rf = 0.10 (30% EtOAc in hexane);
[R]D22 27.3 (c 0.91, CHCl3); 1H-NMR (500 MHz, CDCl3) δ 7.43 (1H,
d, J = 6.7 Hz), 7.17-7.22 (2H, m), 7.12 (1H, dd, J = 8.5, 1.8 Hz), 6.92 (1H,
(3S)-(E)-N-Boc-N-[2-[2-(3-hydroxybut-1-enyl)-5-methoxyphenyl]-
ethyl]amine (1g). White solid. Rf = 0.17 (30% EtOAc in hexane); mp
97-98 °C; [R]22D þ21.0 (c 1.0, C6H6); 1H NMR (400 MHz, C6D6) δ
7.33 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 15.6 Hz, 1H), 6.68 (dd, J = 8.4, 2.8
Hz, 1H), 6.65 (d, J = 2.8 Hz, 1H), 6.07 (dd, J = 15.6, 5.6Hz, 1H), 4.51 (td,
J = 5.6 Hz, 1H), 4.40-4.47 (m, 1H), 3.36 (s, 3H), 3.15-3.08 (m, 2H),
2.68-2.64 (m, 2H), 1.39 (s, 9H), 1.38 (d, J = 5.6 Hz, 3H); 13C NMR
(125 MHz, C6D6) δ 160.2, 156.8, 138.8, 136.1, 130.3, 128.5, 126.5, 116.3,
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ARTICLE
113.3, 79.6, 69.2, 55.4, 42.3, 35.6, 29.1, 24.4; IR (KBr, cm-1) 3378, 2972,
1686, 1535, 1366, 1281, 1162; MS m/z 321 (Mþ); HRMS (EI) calcd for
C18H27NO4 m/z 321.1940, found 321.1944. Anal. Calcd for C18H27NO4:
C, 67.27; H, 8.47; N, 4.36. Found: C, 67.53; H, 8.33; N, 4.33.
NMR (125 MHz, CDCl3) δ 155.9, 137.3, 136.8, 136.2, 129.9, 129.8, 128.0,
127.5, 126.2, 79.6, 63.7, 40.9, 34.3, 28.3, 23.2; IR (neat, cm-1) 3420, 1732,
1652; MS (FAB) m/z 292 (Mþ); HRMS calcd for C17H26NO3 (M þ Hþ)
m/z 292.1913, found 292.1910.
(3S)-(E)-N-Boc-N-[2-[2-(3-hydroxybut-1-enyl)-5-hydroxyphenyl]-
ethyl]amine (1h). White solid. Rf = 0.30 (50% EtOAc in hexane); mp
98-100 °C; [R]22D þ17.9 (c 1.0, CHCl3); 1H NMR(300 MHz, CDCl3)
δ 7.25 (d, J = 8.2 Hz, 1H), 6.77 (d, J = 15.7 Hz, 1H), 6.69 (d, J = 8.2 Hz,
1H), 6.61 (s, 1H), 5.99 (dd, J= 15.7, 6.2 Hz, 1H), 4.83 (brs, 1H), 4.53-4.38
(m, 1H), 3.32-3.15 (m, 2H), 2.80-2.70 (m, 2H), 1.42 (s, 9H), 1.36 (d, J =
6.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 156.3, 155.9, 137.7, 133.8,
128.2, 127.7, 126.3, 116.5, 114.2, 79.8, 68.9, 41.2, 34.1, 28.4, 23.2; IR (KBr,
cm-1) 3352, 3018, 2978, 1692, 1607, 1577, 1504, 1455, 1394, 1367, 1251,
1215, 1164, 1096; MS m/z 307 (Mþ); HRMS (EI) calcd for C17H25NO4
m/z 307.1783, found 307.1791. Anal. Calcd for C17H25NO4: C, 66.43; H,
8.20; N, 4.56. Found: C, 66.71; H, 8.00; N, 4.58.
(3S)-(E)-N-Boc-N-[2-[2-(3-hydroxybut-1-enyl)-4-methoxyphenyl]-
ethyl]amine (1i). Colorless oil. Rf = 0.17 (30% EtOAc in hexane);
[R]22D þ11.7 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.03 (d,
J = 8.4 Hz, 1H), 6.96 (d, J = 1.7 Hz, 1H), 6.92 (d, J = 15.7 Hz, 1H), 6.75
(dd, J = 8.4 Hz, 1H), 6.14 (dd, J = 15.7, 5.5 Hz, 1H), 4.69 (br, 1H), 4.52
(br, 1H), 3.81 (s, 3H), 3.22-3.21 (m, 2H), 2.80 (br, 1H), 2.82-2.79
(m, 2H), 1.44 (s, 9H), 1.38 (d, J = 5.5 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 158.5, 156.0, 137.6, 136.6, 130.8, 128.6, 126.4, 113.2, 111.5,
79.5, 68.5, 55.3, 41.6, 33.8, 28.4, 23.2; IR (neat, cm-1) 3362, 2974,
1693, 1606, 1496, 1365, 1252, 1166, 1040; MS m/z 321 (Mþ); HRMS
(EI) calcd for C18H27NO4 m/z 321.1940, found 321.1947.
(3S)-(E)-N-Boc-N-[2-[4-chloro-2-(3-hydroxybut-1-enyl)-phenyl]-
ethyl]amine (1j). Colorless oil. Rf = 0.17 (30% EtOAc in hexane);
[R]22D þ11.0 (c 0.84, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.40 (s,
1H), 7.14 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 15.5
Hz, 1H), 6.16 (dd, J = 15.5, 5.0 Hz, 1H), 4.70 (brs, 1H), 4.53 (brs, 1H),
3.25-3.18 (m, 2H), 2.88 (brs, 1H), 2.84-2.82 (m, 2H), 1.44 (s, 9H),
1.37 (d, J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 156.0, 138.3,
137.7, 134.6, 132.6, 131.1, 127.3, 126.3, 125.2, 79.7, 68.3, 41.2, 34.1, 28.4,
23.1; IR (neat, cm-1) 3376, 2976, 2931, 1686, 1593, 1523, 1481, 1392,
1366, 1250, 1167, 1054; MS m/z 325 (Mþ); HRMS (EI) calcd for
C17H24ClNO3 m/z 325.1445, found 325.1451.
(3S)-(E)-N-Boc-N-[2-[2-(3-hydroxybut-1-enyl)-3-methylphenyl]ethyl]-
amine (1k). Colorless oil. Rf = 0.17 (30% EtOAc in hexane); [R]22D -3.3
(c 0.54, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.08 (dd, J = 6.3, 6.3 Hz,
1H), 7.06 (dd, J = 6.3, 2.1 Hz, 1H), 6.99 (dd, J = 6.3, 2.1 Hz, 1H), 6.62 (d,
J = 16.2 Hz, 1H), 5.80 (dd, J = 16.2, 6.8 Hz, 1H), 4.82 (brs, 1H), 4.51 (dq,
J = 6.8, 6.3 Hz, 1H), 3.83 (brs, 1H), 3.19 (dd, J = 8.7, 7.2 Hz, 2H), 2.91-
2.74 (m, 2H), 2.26 (s, 3H), 1.44 (s, 9H), 1.38 (d, J = 6.3 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 156.1, 139.8, 137.4, 136.5, 136.3, 128.3, 127.2,
126.8, 126.2, 79.7, 68.8, 41.3, 35.4, 28.4, 22.9, 20.6; IR (neat, cm-1) 3350,
2974, 1691, 1519, 1365, 1252, 1171; MS m/z 305 (Mþ); HRMS (EI) calcd
for C18H27NO3 m/z 305.1991, found 305.1986.
(3S)-(E)-N-Boc-N-[2-[2-(3-acetoxy-1-butenyl)phenyl]ethyl]amine
(1n). To a solution of 1a (12.0 mg, 41 μmol) in pyridine (0.5 mL) was
added Ac2O (7.8 μL, 82 μmol). The resultant mixture was stirred at room
temperature for 1 h, and DMAP (0.5 mg, 4.1μmol) was added. After stirring
for 20 min, the solution was concentrated. Purification of the residue by thin
layer chromatography on silica gel eluted with 70% EtOAc in hexane gave
1n (12.4 mg, 90%) as a colorless oil. Rf = 0.58 (20% EtOAc in hexane);
[R]20D -59.6 (c 0.97, CHCl3); 1H NMR (270 MHz, CDCl3) δ 7.46-7.42
(1H, m), 7.24-7.13 (3H, m), 6.89 (1H, d, J= 15.6 Hz), 6.04 (1H, dd, J= 15.6,
6.9 Hz), 5.51 (1H, dq, J = 6.9, 6.5 Hz), 3.33-3.26 (2 H, m), 2.89-2.84 (2H,
m), 2.08 (3H, s), 1.43 (9H, s), 1.42 (3H, d, J = 6.5 Hz), 7.13-7.24 (3H, m),
7.42 (1H, m); 13C NMR (125 MHz, CDCl3) δ 170.4, 155.8, 136.6, 135.6,
131.0, 130.0, 129.2, 128.0, 126.8, 126.3, 79.1, 71.3, 41.2, 33.6, 28.4, 21.4, 20.4;
IR (neat, cm-1) 3450, 1707, 1646, 1508, 1215, 754, 669; MS (EIþ) m/z 333
(Mþ); HRMS calcd for C19H27NO4 m/z 333.1940, found 333.1944.
(3S)-(E)-N-Boc-N-[2-[2-(3-hydroxybut-1-enyl)-5-pivaroyloxy-phenyl]-
ethyl]amine (1o). White crystal, Rf = 0.20 (30% EtOAc in hexane); mp
90-93 °C; [R]22D þ14.8 (c 0.1, CHCl3); 1H NMR (500 MHz, CDCl3) δ
7.40 (d, J = 8.4 Hz, 1H), 6.89 (dd, J = 8.4, 2.3 Hz, 1H), 6.88 (d, J = 15.5 Hz,
1H), 6.82 (d, J = 2.3 Hz, 1H), 6.10 (dd, J = 15.5, 6.4 Hz, 1H), 4.80 (brs,
1H), 4.54-4.45 (m, 1H), 3.27-3.20 (m, 2H), 3.20 (brs, 1H), 2.88-2.80
(m, 2H), 1.43 (s, 9H), 1.35 (d, J = 6.4 Hz, 3H), 1.34 (s, 9H); 13C NMR
(125 MHz, CDCl3) δ 177.0, 156.0, 150.2, 137.5, 136.6, 134.1, 127.4, 125.6,
122.5, 119.9, 79.5, 68.4, 41.1, 39.0, 34.4, 28.4, 27.1, 23.2; IR (neat, cm-1
)
3452, 2978, 2933, 2874, 1745, 1698, 1605, 1511, 1458, 1395, 1367, 1276,
1242, 1216, 1157, 1124, 1056, 1030; MS m/z391 (Mþ);HRMS(EI) calcd
for C22H33NO5 m/z 391.2358, found 391.2352. Anal. Calcd for
C22H33NO5: C, 67.49; H, 8.50; N, 3.58. Found: C, 67.28; H, 8.33; N, 3.50.
Bi(OTf)3-Catalyzed Cyclization. To the mixture of Bi(OTf)3
(10.4 mg, 16 μmol) and MS-4 Å (94 mg) in DCM (1.6 mL) was added
the solution of 1 (0.16 mmol) in DCM (1.4 mL) at -15 °C. The
reaction mixture was stirred and quenched with satd NaHCO3 aq, the
aqueous layer was extracted with EtOAc, and the organic extract was
washed with brine, dried over MgSO4, and concentrated in vaccuo.
Purification of the residue by column chromatography on SiO2 gave 2.
Yields: 2a (83%) from 1a, 2b (65%), 2c (67%), 2d (91%), 2e (71%), 2f
(88%), 2g (99%), 2h (86%), 2i (82%), 2j (68%), 2k (74%), 2l (60%), 2a
(91%) from 1n, 2o (81%).
Determination of ee by HPLC:
2a: (Daicel Chiralcel AD-H, n-hexane/ isopropanol = 95/5, flow rate
0.5 mL/min, T = 20 °C, 254 nm): tR = 9.7 min (minor), tS = 12.5 min
(major)
2b: (Daicel Chiralcel OD-H, n-hexane/ isopropanol = 90/10, flow
rate 0.5 mL/min, T = 20 °C, 254 nm): tS = 10.5 min (major), tR = 14.5
min (minor),
(3S)-(E)-N-Boc-N-[2-[2-(3-hydroxy-1-pentenyl)phenyl]ethyl]amine
(1l). Colorless oil. Rf = 0.17 (30% EtOAc in hexane); [R]20D 6.9 (c 1.54,
CHCl3); H NMR (500 MHz, CDCl3) δ 7.19-7.14 (3H, m), 7.10-
2c: (Daicel Chiralcel OD-H, n-hexane/ isopropanol = 90/10, flow
rate 0.5 mL/min, T = 20 °C, 254 nm): tS = 11.9 min (major), tR = 15.7
min (minor)
1
7.09 (1H, m), 5.42 (1H, d, J = 8.5 Hz), 4.79-4.75 (2H, m), 3.32-3.29
(1H, m), 3.15-3.11 (1H, m), 2.82-2.76 (2H, m), 2.02 (3H, s), 1.43
(9H, s), 1.32 (3H, d, J = 6.7 Hz); 13C NMR (125 MHz, CDCl3) δ 156.1,
145.2, 135.8, 135.3, 134.3, 129.8, 126.9, 126.4, 79.7, 64.3, 42.3, 34.7, 28.4,
23.0, 19.1; IR (neat, cm-1) 3419, 1687, 1519, 1171; MS (EIþ) m/z 305
(Mþ); HRMS calcd for C18H27NO3 m/z 305.1991, found 305.1999.
(3S)-(Z)-N-Boc-N-[2-[2-(3-hydroxy-1-butenyl)phenyl]ethyl]amine
(1m). Colorless oil. Rf = 0.16 (30% EtOAc in hexane); [R]20D -72.5 (c
0.13, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.16-7.21 (3H, m), 7.09
(1H, d, J = 6.7 Hz), 6.56 (1H, d, J = 11.0 Hz), 5.79 (1H, t, J = 10.4 Hz),
4.58-4.51 (2H, m), 3.47-3.41 (1H, m), 3.26-3.18 (1H, m), 2.90-2.87
(1H, m), 2.70-2.66 (1H, m), 1.36 (9H, s), 1.32 (3H, d, J = 5.5 Hz); 13C
2d: (Daicel Chiralcel OD-H, n-hexane/ isopropanol = 90/10, flow
rate 0.5 mL/min, T = 20 °C, 254 nm): tS = 35.6 min (major), tR = 47.9
min (minor)
2e: (Daicel Chiralcel AD-H, n-hexane/ isopropanol = 95/5, flow rate
0.3 mL/min, T = 20 °C, 254 nm): tR = 17.8 min (minor), tS = 27.3 min
(major)
2f: (Daicel Chiralcel AD-H, n-hexane/ isopropanol = 95/5, flow rate
0.3 mL/min, T = 20 °C, 254 nm): tR = 15.4 min (minor), tS = 20.2 min
(major)
2g: (Daicel Chiralcel AD-H, n-hexane/ isopropanol = 95/5, flow rate
0.5 mL/min, T = 20 °C, 254 nm): tR = 11.0 min (minor), tS = 17.0 min
(major)
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2h: (Daicel Chiralcel AD-H, n-hexane/ isopropanol = 95/5, flow rate
0.5 mL/min, T = 20 °C, 254 nm): tR = 39.1 min (minor), tS = 55.9 min
(major)
20.9, 17.6; IR (neat, cm-1) 2973, 2928, 1695, 1415, 1364, 1335, 1290, 1253,
1234, 1167, 1133, 1097, 1040; MS m/z; 287 (Mþ); HRMS (EI) calcd for
C18H25NO2 m/z 287.1878, found 287.1885.
2i: (Daicel Chiralcel AD-H, n-hexane/ isopropanol = 95/5, flow rate
0.5 mL/min, T = 20 °C, 254 nm): tR = 13.5 min (minor), tS = 17.1 min
(major)
2j: (Daicel Chiralcel AD-H, n-hexane/ isopropanol = 98.8/1.3, flow
rate 0.5 mL/min, T = 20 °C, 254 nm): tR = 18.4 min (minor), tS = 21.0
min (major)
2k: (Daicel Chiralcel OD-H, n-hexane/ isopropanol = 99/1, flow rate
1.0 mL/min, T = 20 °C, 254 nm): tS = 4.6 min (major), tR = 6.3 min
(minor),
2l: (Daicel Chiralcel AD-H, n-hexane/ isopropanol = 95/5, flow rate
0.5 mL/min, T = 20 °C, 254 nm): tR = 13.4 min (minor), tS = 16.6 min
(major)
(1S)-(E)-N-Boc-6-chloro-1-(1-propenyl)-tetrahydroisoquinoline
(2f). Colorless oil. Rf = 0.63 (20% EtOAc in hexane); [R]22D þ117 (c 0.3,
CHCl3);1HNMR(CDCl3, 500MHz) δ7.14 (dd, J= 8.2, 2.1 Hz, 1H), 7.13
(s, 1H), 7.03(d, J= 8.2 Hz, 1H), 5.56 (dd, J= 15.4, 5.2 Hz, 1H), 5.47 (dq, J=
15.4, 6.1 Hz, 1H), 5.65-5.30 (m, 1H), 4.10 (brs, 1H), 3.14 (brs, 1H), 2.90-
2.83 (m, 1H), 2.70-2.65 (m, 1H), 1.68 (d, J = 6.1 Hz, 3H), 1.48 (s, 9H);
13C NMR (CDCl3, 125 MHz) δ 154.5, 136.6, 134.3, 132.0, 130.5, 129.4,
128.6, 127.7, 126.1, 79.9, 55.7, 37.1, 28.7, 28.5, 17.6; IR (neat, cm-1) 3019,
1684, 1420, 1366, 1216, 1162; MS m/z; 307 (Mþ); HRMS (EI) calcd for
C17H22ClNO2 m/z 307.1339, found 307.1336.
(1S)-(E)-N-Boc-6-methoxy-1-(1-propenyl)-tetrahydroisoquinoline
(2g). Colorless oil. Rf = 0.63 (20% EtOAc in hexane); [R]22D þ62.0 (c 0.4,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.02 (d, J = 8.4 Hz, 1H), 6.75 (dd,
J = 8.4, 2.4 Hz, 1H), 6.65 (d, J = 2.4 Hz, 1H), 5.58 (dd, J = 14.6, 5.3 Hz, 1H),
5.48 (dq, J = 14.6, 6.1 Hz, 1H), 5.45 (brs, 1H), 4.12 (brs, 1H), 3.78 (s, 3H),
3.17 (brs, 1H), 2.95-2.80 (m, 1H), 2.68 (dt, J = 16.0, 3.5 Hz, 1H), 1.68 (d,
J = 6.1 Hz, 3H), 1.48 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 158.0, 154.6,
135.8, 131.1, 128.9, 128.0, 126.7, 113.1, 112.3, 79.5, 55.9, 55.1, 37.2, 29.1,
28.4, 17.5; IR (CHCl3, cm-1) 2974, 2932, 2836, 1694, 1612, 1581, 1503,
1454, 1416, 1364, 1335, 1287, 1239, 1164, 1121, 1096, 1040; MS m/z 303
(Mþ); HRMS (EI) calcd for C18H25NO3 m/z 303.1834, found 303.1841.
(1S)-(E)-N-Boc-6-hydroxy-1-(1-propenyl)-tetrahydroisoquinoline
2o: (Daicel Chiralcel AD-H, n-hexane/ isopropanol = 95/5, flow rate
0.5 mL/min, T = 20 °C, 254 nm): tR = 9.7 min (minor), tS = 11.7 min
(major)
(1S)-(E)-N-Boc-1-(1-propenyl)-tetrahydroisoquinoline (2a). Colorless
solid. Rf = 0.63 (20% EtOAc in hexane); mp 41-42 °C; [R]20D 151.9 (c
0.95, CHCl3);. 1H NMR (500 MHz, CDCl3) δ 7.19-7.11 (4H, m), 5.62-
5.47 (3H, m), 4.12 (1H, brs), 3.20 (1H, brs), 2.94-2.85 (1H, m), 2.75-
2.70 (1H, m), 1.68 (3H, d, J = 6.1 Hz), 1.48 (9H, s); 13C NMR (125 MHz,
CDCl3) δ 154.6, 135.8, 134.6, 130.9, 128.8, 127.9, 127.0, 126.4, 125.9, 79.6,
56.5, 37.6, 28.8, 28.5, 17.6; IR (neat, cm-1) 2977, 2250, 1682, 1164, 909,
735; MS (EIþ) m/z 273 (Mþ); HRMS calcd for C17H23NO2 (Mþ) m/z
273.1729, found 273.1720. Anal. Calcd for C17H23NO2: C, 74.69; H, 8.48;
N, 5.12. Found: C, 74.95; H, 8.30; N, 5.13.
(2h). Colorless oil. Rf = 0.23 (20% EtOAc in hexane); [R]22 -0.31
D
(c 0.42, CHCl3); 1H NMR (500 MHz, CDCl3) δ 6.87 (d, J = 8.3 Hz, 1H),
6.60 (brd, J = 8.3 Hz, 1H), 6.53 (d, J = 2.0 Hz, 1H), 5.53-5.23 (m, 3H),
4.0 (brs, 1H), 3.08 (brs, 1H), 2.78-2.70 (m, 1H), 2.55 (dt, J = 15.8,
4.1 Hz, 1H), 1.60 (d, J = 6.2 Hz, 3H), 1.41 (s, 9H); 13C NMR (125 MHz,
CDCl3) δ 154.9, 154.4, 136.2, 131.1, 129.2, 127.8, 127.0, 115.0, 113.6, 80.0,
56.3, 37.5, 29.0, 28.6, 17.7; IR (CHCl3, cm-1) 3399, 1650, 1427, 1161; MS
m/z 290 (M þ H)þ; HRMS (CI) calcd for C17H24NO3 m/z 290.1756,
found 290.1764.
(1S)-(E)-Methyl-1-(1-propenyl)-3,4-dihydroisoquinoline-2(1H)-car-
boxylate (2b). Colorless oil. Rf = 0.63 (20% EtOAc in hexane); [R]20
D
137.4 (c 0.46, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.19-7.10 (4H,
m), 5.64-5.52 (3H, m), 4.10 (1H, bs), 3.74 (3H, s), 3.28 (1H, bs),
2.96-2.91 (1H, m), 2.75-2.71 (1H, m), 1.68 (3H, d, J = 5.8 Hz); 13
C
NMR (125 MHz, CDCl3) δ 155.9, 135.6, 134.4, 130.7, 128.8, 127.9,
127.5, 126.6, 126.0, 56.2, 52.6, 38.2, 28.6, 17.6; IR (neat, cm-1) 3588,
2952, 1702, 1534, 1446, 1122, 963, 765. MS (EIþ) m/z 231 (Mþ);
HRMS calcd for C14H17NO2 (Mþ) m/z 231.1259, found 231.1253.
(1S)-(E)-N-Cbz-1-(1-propenyl)-tetrahydroisoquinoline (2c). Colorless
oil. Rf = 0.63 (20% EtOAc in hexane); [R]20D 102.4 (c 0.96, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 7.37-7.30 (5H, m), 7.19-7.11 (4H, m),
5.62-5.57 (3H, m), 5.19-5.13 (2H, m), 4.20-4.00 (1H, m), 3.30-3.27
(1H, m), 2.95-2.91 (1H, m), 2.79-2.70 (1H, m), 1.66 (3H, d, J = 9.7 Hz);
13C NMR (100 MHz, CDCl3) δ 155.2, 136.8, 135.4, 134.3, 130.5, 128.7,
128.4, 128.2, 127.9, 127.8, 127.5, 126.6, 126.0, 67.0, 56.3, 38.2, 28.6, 17.6; IR
(neat, cm-1) 3433, 2086, 1643; MS (EIþ) m/z 307 (Mþ); HRMS calcd for
C20H21NO2 (Mþ) m/z 307.1576, found 307.1572.
(1S)-(E)-N-Boc-7-methoxy-1-(1-propenyl)-tetrahydroisoquinoline
(2i). Colorless solid. Rf = 0.64 (20% EtOAc in hexane); mp 87-88 °C;
[R]22D þ129.7 (c 0.315, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.03 (d,
J = 8.4 Hz, 1H), 6.74 (dd, J = 8.4, 2.6 Hz, 1H), 6.65 (d, J = 2.6 Hz, 1H), 5.59
(dd, J = 15.0, 5.3 Hz, 1H), 5.52 (dq, J = 15.0, 6.0 Hz, 1H), 5.55-5.30 (m,
1H), 4.20-3.95 (m, 1H), 3.78 (s, 3H), 3.25-3.05 (m, 1H), 2.90-2.88 (m,
1H), 2.65 (dt, J = 15.7, 3.6 Hz, 1H), 1.68 (d, J = 6.0 Hz, 3H), 1.48 (s, 9H);
13C NMR (125 MHz, CDCl3) δ 157.7, 154.7, 137.0, 130.7, 130.0, 127.2,
126.8, 112.8, 79.6, 56.7, 55.3, 37.6, 28.5, 28.0, 17.6; IR (neat, cm-1) 3595,
3006, 2977, 2933, 1686, 1613, 1580, 1504, 1454, 1420, 1365, 1318, 1250,
1168, 1123, 1099, 1040 cm-1; MS m/z 303 (Mþ); HRMS calcd for
C18H25NO3 m/z 303.1834, found 303.1840. Anal. Calcd for C18H25NO3:
C, 71.26; H, 8.31; N, 4.62. Found: C, 70.95; H, 8.46; N, 4.5.
(1S)-(E)-N-Boc-7-chloro-1-(1-propenyl)-tetrahydroisoquinoline
(2j). Colorless oil. Rf = 0.64 (20% EtOAc in hexane); [R]22D þ148.1 (c
0.64, CHCl3);1H NMR (500 MHz, CDCl3) δ7.12 (d, J= 8.1 Hz, 1H), 7.10
(s, 1H), 7.04 (d, J = 8.1 Hz, 1H), 5.59-5.48 (m, 1H), 5.55-5.51 (m, 1H),
5.55-5.35 (m, 1H), 4.12 (brs, 1H), 3.13 (brs, 1H), 2.88-2.81 (m, 1H),
2.69-2.66 (m, 1H), 1.70 (d, J = 5.2 Hz, 3H), 1.48 (s, 9H); 13C NMR (125
MHz, CDCl3) δ 154.5, 137.7, 133.1, 131.5, 130.2, 130.1, 127.9, 127.8, 126.7,
79.9, 55.7, 37.4, 28.5, 28.3, 17.6; IR (neat, cm-1) 2975, 2930, 1696, 1600,
1486, 1454, 1416, 1365, 1339, 1312, 1290, 1247, 1233, 1192, 1128, 1100,
1041; MS m/z 307 (Mþ); HRMS (EI) calcd for C17H22ClNO2 m/z
307.1339, found 307.1333.
(1S)-(E)-N-Nosyl-1-(1-propenyl)-tetrahydroisoquinoline (2d). Colorless
oil. Rf = 0.33 (30% EtOAc in hexane); [R]20D 128.1 (c 0.13, CHCl3); 1H
NMR (500 MHz, CDCl3) δ 8.04-7.97 (1H, m), 7.70-7.59 (3H, m),
7.20-7.17 (2H, m), 7.11-7.05 (2H, m), 5.61-5.57 (1H, m), 5.50 (1H, d,
J = 6.7 Hz), 5.43-5.37 (1H, m), 4.04-3.96 (1H, m), 3.51-3.46 (1H, m),
2.92-2.87 (1H, m), 2.78-2.71 (1H, m), 1.58 (3H, d, J = 6.7); 13C NMR
(125 MHz, CDCl3) δ 147.9, 134.3, 134.2, 133.2, 131.5, 130.7, 130.0, 129.6,
129.0, 128.3, 127.9, 127.0, 126.1, 124.1, 58.2, 39.8, 28.4, 17.6; IR (neat, cm-1
)
3499, 1664, 1541, 1371, 1163, 966, 755; MS (EIþ) m/z 358 (Mþ); HRMS
calcd for C18H18N2O4S (Mþ) m/z 358.0987, found 358.0982.
(1S)-(E)-N-Boc-6-methyl-1-(1-propenyl)-tetrahydroisoquinoline
(2e). Colorless oil. Rf = 0.63 (20% EtOAc in hexane); [R]22D þ126.4 (c
0.6, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.01 (s, 1H), 7.00 (s, 1H),
6.95 (s, 1H), 5.59 (dd, J = 15.0, 5.1 Hz, 1H), 5.50 (dq, J = 15.0, 6.1 Hz, 1H),
5.55-5.35 (m, 1H), 4.20-3.90 (m, 1H), 3.30-3.10 (m, 1H), 2.95-2.80
(m, 1H), 2.65-2.73 (m, 1H), 2.31 (s, 3H), 1.68 (d, J = 6.1 Hz, 3H), 1.49 (s,
9H); 13C NMR (CDCl3, 125 MHz) δ 154.67, 136.02, 134.48, 132.86,
131.02, 129.27, 127.70, 126.80, 126.77, 79.55, 56.26, 37.41, 28.75, 28.48,
(1S)-(E)-N-Boc-8-methyl-1-(1-propenyl)-tetrahydroisoquinoline
(2k). Colorless oil. Rf = 0.75 (30% EtOAc in hexane); [R]22D þ140.0
(c 0.4, CHCl3); 1H NMR (500 MHz, CDCl3); the compound exists as a
mixture (1.12:1) of carbamate rotamers; signals corresponding to the
majorrotamer: δ 7.10 (d, J = 13.5 Hz, 1H), 7.01 (dd, J = 13.5, 7.5 Hz, 1H),
6.97 (d, J = 13.5 Hz, 1H), 5.75 (brs, 1H), 5.25 (dq, J = 13.0, 7.0 Hz, 1H),
2112
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ARTICLE
3.81-3.72 (m, 1H), 3.45-3.25 (m, 1H), 2.95-2.72 (m, 2H), 2.26 (s,
3H), 1.65 (brd, J = 7.0 Hz, 3H), 1.49 (s, 9H); representative signals
corresponding to the minor rotamer:δ 7.09 (d, J = 13.5Hz, 1H), 7.01 (dd,
J = 13.5, 7.5 Hz, 1H), 6.97 (d, J = 13.5 Hz, 1H), 5.60-5.50 (m, 1H), 5.25
(dq, J = 13.0, 7.0 Hz, 1H), 3.98-3.90 (m, 1H), 3.45-3.25 (m, 1H),
2.95-2.72 (m, 2H), 2.24 (s, 3H), 1.65 (brd, J = 7.0 Hz, 3H), 1.48 (s, 9H);
13C NMR (125 MHz, CDCl3) signals corresponding to both rotamer: δ
154.8, 154.7, 135.4, 134.8, 134.7, 135.0, 134.3, 129.5, 129.3, 128.1, 127.8,
127.6, 126.6, 126.5, 126.2, 79.7, 79.5, 53.7, 52.6, 38.9, 37.5, 28.7, 28.6, 28.5,
19.00, 18.99, 17.6; IR(CHCl3, cm-1) 3019, 2360, 2340, 1684, 1216, 1164,
1117; MS m/z 287 (Mþ); HRMS (EI) calcd for C18H25NO2 m/z
287.1885, found 287.1881.
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(d) Nishikata, T.; Lipshutz, B. H. Org. Lett. 2009, 11, 2377–2379. (e)
Shue, Y.-J.; Yang, S.-C.; Lai, H.-C. Tetrahedron Lett. 2003, 44, 1481–
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(1S)-(E)-N-Boc-1-(1-methyl-1-propenyl)-tetrahydroisoquinoline
(2l). Colorless oil. Rf = 0.75 (30% EtOAc in hexane); [R]20D 13.7 (c 0.71,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.20-7.15 (2H, m), 7.06-7.12
(2H, m), 5.67 (1H, d, J = 15.9 Hz), 5.57-5.48 (1H, m), 3.78-3.64 (2H,
m), 2.85-2.82 (2H, m), 1.75 (3H, s), 1.72-1.71 (3H, m), 1.47 (9H, s); 13
C
NMR (125 MHz, CDCl3) δ 155.6, 142.3, 138.2, 135.0, 128.2, 128.0, 126.2,
125.8, 121.6, 79.8, 61.5, 41.2, 30.4, 28.5, 26.8, 17.7; IR (neat, cm-1) 2979,
1671, 1166, 912, 742; MS (EIþ) m/z 287 (Mþ); HRMS calcd for
C18H25NO2 (Mþ) m/z 287.1885, found 287.1877.
(1S)-(E)-N-Boc-6-pivaroyloxy-1-(1-propenyl)-tetrahydroisoquinoline
(2o). Colorless oil. Rf = 0.64 (20% EtOAc in hexane); [R]22D þ125 (c 0.3,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.10 (d, J = 8.3 Hz, 1H), 6.86 (dd,
J = 8.3, 2.3 Hz, 1H), 6.82 (d, J = 2.3 Hz, 1H), 5.56 (dd, J = 15.4, 5.2 Hz, 1H),
5.48 (dq, J = 15.4, 6.1 Hz, 1H), 5.51-5.42 (m, 1H), 4.12 (brs, 1H),
3.15 (brs, 1H), 2.93-2.83 (m, 1H), 2.71-2.67 (m, 1H), 1.67 (d, J = 6.1 Hz,
3H), 1.48 (s, 9H), 1.34 (s, 9H); 13C NMR (CDCl3, 125 MHz) δ 177.2,
154.6, 149.4, 136.1, 133.2, 130.7, 129.0, 127.4, 121.4, 119.2, 79.8, 56.2,
39.0, 37.3, 28.8, 28.5, 27.1, 17.6; IR (neat, cm-1) 3017, 2977, 1747, 1685,
1478, 1420, 1366, 1337, 1280, 1217, 1148, 1118, 1030; MS (EIþ) m/z
373 (Mþ); HRMS calcd for C22H31NO4 (Mþ) m/z 373.2253, found
373.2246.
(12) For other recent examples of direct substitution of allylic
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Yadav, J. S.; Subba Reddy, B. V.; Srinivasa Rao, T.; Krishna, B. B. M.;
Narayana Kumar, G. G. K. S. Chem. Lett. 2007, 36, 1472–1473. (d)
Shirakawa, S.; Shimizu, S. Synlett 2008, 1539–1542. (e) Qin, H.;
Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed.
2007, 46, 409–413. (f) Kothandaraman, P.; Foo, S. J.; Chan, P. W. H. J.
Org. Chem. 2009, 74, 5947–5952. (g) Wang, G.-W.; Shen, Y.-B.; Wu, X.-
L. Eur. J. Org. Chem. 2008, 4367–4371. (h) Yang, H.; Fang, L.; Zhang,
M.; Zhu, C. Eur. J. Org. Chem. 2009, 666–672.
’ ASSOCIATED CONTENT
Supporting Information. Copies of the H and/or 13C
1
S
b
NMR spectra for compounds 1a-1o, 2a-2l, 2o, 4o, 5d-5k, 5o,
7, 10a-10l, and 10o. This material is available free of charge via
the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*kawai@mb.kyoto-phu.ac.jp
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37.
’ ACKNOWLEDGMENT
Research (no. 22790023 and 21590030) from the Ministry of
Education, Culture, Sports, Science and Technology (MEXT),
and Japan Society for the Promotion of Science (JSPS).
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was conducted to the next reaction.
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