PIFA–BF3·OEt2 mediated intramolecular regioselective domino cyclization of ynamides: A novel method for the synthesis of tetrahydroisoquinoline-oxazol-2(3H)-ones

Article abstract of DOI:10.1016/j.bmc.2017.03.034

The transition metal-free intramolecular regioselective domino cyclization of N-Boc protected ynamides has been developed to provide the corresponding tetrahydroisoquinoline-oxazo-2(3H)-ones in moderate to good yields.

Full text of DOI:10.1016/j.bmc.2017.03.034

Accepted Manuscript
PIFA–BF3·OEt2 mediated intramolecular regioselective domino cyclization of
ynamides: A novel method for the synthesis of tetrahydroisoquinoline-oxa-
zol-2(3H)-ones
Winai Ieawsuwan, Somsak Ruchirawat
PII:
S0968-0896(16)31519-X
http://dx.doi.org/10.1016/j.bmc.2017.03.034
BMC 13632
DOI:
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 December 2016
9 March 2017
17 March 2017
Please cite this article as: Ieawsuwan, W., Ruchirawat, S., PIFA–BF3·OEt2 mediated intramolecular regioselective
domino cyclization of ynamides: A novel method for the synthesis of tetrahydroisoquinoline-oxazol-2(3H)-ones,
Bioorganic & Medicinal Chemistry (2017), doi: http://dx.doi.org/10.1016/j.bmc.2017.03.034
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Graphical Abstract
PIFA–BF3·OEt2 mediated intramolecular
regioselective domino cyclization of
ynamides: A novel method for the synthesis
of tetrahydroisoquinoline-oxazol-2(3H)-ones
Winai Ieawsuwan a,∗ and Somsak Ruchirawat a,b,c
a Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6 Road, Laksi,
Bangkok 10210, Thailand
b Chemical Biology Program, Chulabhorn Graduate Institute, 54 Kamphaeng Phet 6 Road, Laksi, Bangkok
10210, Thailand
c Center of Excellence on Environmental Health and Toxicology (EHT), Ministry of Education, 54 Kamphaeng
Phet 6 Road, Laksi, Bangkok 10210, Thailand

Bioorganic & Medicinal Chemistry
journal homepage: www.els evier.com
PIFA–BF3·OEt2 mediated intramolecular regioselective domino cyclization of
ynamides: A novel method for the synthesis of tetrahydroisoquinoline-oxazol-2(3H)-
ones
Winai Ieawsuwan a,∗ and Somsak Ruchirawat a,b,c
a Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6 Road, Laksi, Bangkok 10210, Thailand
b Chemical Biology Program, Chulabhorn Graduate Institute, 54 Kamphaeng Phet 6 Road, Laksi, Bangkok 10210, Thailand
c Center of Excellence on Environmental Health and Toxicology (EHT), Ministry of Education, 54 Kamphaeng Phet 6 Road, Laksi, Bangkok 10210, Thailand
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The transition metal-free intramolecular regioselective domino cyclization of N-Boc protected
ynamides has been developed to provide the corresponding tetrahydroisoquinoline-oxazo-2(3H)-
ones in moderate to good yields.
Available online
2017 Elsevier Ltd. All rights reserved.
Keywords:
Ynamide
Hypervalent iodine
Domino cyclization
Tetrahydroisoquinoline
Oxazol-2(3H)-one
1. Introduction
been developed toward the synthesis of substituted oxazol-2(3H)-
ones and most of them have relied on carbonyl condensation to
establish cyclic carbamate moiety.3 The new developments for
the synthesis of 3,5-disubstituted oxazol-2(3H)-ones recently
utilized Au(I)-,4 Pd(II)-,5 or Cu(I)-catalyzed6 cycloisomerizations
of ynamides7 bearing alkoxy carbamate as the nitrogen protecting
groups. These cycloisomerizations provide an efficient and rapid
access to 3,5-disubstituted oxazol-2(3H)-ones. Interestingly, Zhu
and co-worker described an elegant synthesis of various 3,4,5-
trisubstituted oxazol-2(3H)-one derivatives using the palladium-
catalyzed coupling of ynamides with aryl halides (Scheme 1a).8
Oxazol-2(3H)-ones are among the valuable building blocks in
organic synthesis;1 they have been found to exhibit potent
biological activities, such as antibacterial, antitumor,
cyclooxygenase-2 inhibitory, neuroleptic, and herbicidal
activities as shown in Figure 1.2 Various classical methods have
Moreover,
the
palladium-catalyzed
cycloisomerization-
halogenation reaction sequence of ynamides, developed by Zhu
and co-workers, resulted in a variety of 4-halo-oxazol-2(3H)-one
derivatives which further underwent Suzuki–Miyaura cross-
coupling reactions leading to a wide range of 3,4,5-trisubstituted
oxazol-2(3H)-one derivatives (Scheme 1b).9a In addition, the
transition metal-free iodocyclization of ynamides also provided
the corresponding 4-iodo-oxazol-2(3H)-ones by using NIS-
K2CO3
condition.9b
Alternatively,
the
intermolecular
iodoamination of terminal ynamides followed by palladium-
catalyzed Suzuki–Miyura cross-coupling/cyclization reaction was
an efficient synthetic strategy for the synthesis of 3,4,5-
trisubstituted oxazol-2(3H)-one derivatives (Scheme 1c).10
Although the new developments for the synthesis of
Figure 1. Biologically important molecules that contained the
oxazo-2(3H)-one skeleton.
———
∗ Corresponding author. E-mail: winai@cri.or.th

polysubstituted oxazol-2(3H)-one from ynamides have been
widely studied, but those reactions are only restricted to the
ynamides bearing an N-aryl or N-benzyl moiety. Thus, the
modifications and transformations for the new types of N-
substituted ynamides to prepare the valuable N-containing
cyclization of ynamides to afford the corresponding
tetrahydroisoquinoline-oxazol-2(3H)-ones in moderate to good
yields.
2. Results and discussion
heterocycles still remain
breakthroughs.
a
challenge awaiting new
The initial study was the synthesis of ynamide 3a via copper-
catalyzed
direct
cross-coupling
of
tert-butyl
3,4-
dimethoxyphenethylcarbamate and phenylethynyl bromide under
basic conditions.19 We found that the use of CuSO4·5H2O as a
catalyst4b,19c gave the desired ynamide 3a in a low yield of 10%
and homocoupling of phenylethynyl bromide was observed.
Increasing the amount of CuSO4·5H2O along with prolonging the
reaction time did not improve yield of ynamide 3a. The
alternative method using CuI as a catalyst19b in the presence of
KHMDS gave the ynamide 3a in only 10%. Interestingly, we
found that the addition rate of KHMDS solution was crucial for
this cross-coupling reaction, as adding the KHMDS solution
gradually over 3 hours via syringe pump furnished the desired
ynamide 3a in yields up to 75%.20 Since CuI method provided the
best yield of the ynamide 3a, this method was employed for the
preparation of various ynamides 3a-r in yields ranging from 15
to 98% (Table 1, entries 1-16).21
Recently, hypervalent iodine reagents have been vastly
applied in a number of significant transformations due to their
useful oxidizing properties, benign environmental character, ease
of handling, low toxicity, and commercial availability.11
[Bis(trifluoroacetoxy)iodo]benzene (BTI or PIFA) is one of the
most important hypervalent iodine reagents which has been
employed as a mild oxidant for many transformations, for
example,
intramolecular
oxidative
biaryl
coupling,12
intramolecular electrophilic aromatic amidation,13 intramolecular
alkene amidation,14 and intramolecular alkyne amidation.15 The
modes of activations of PIFA usually involve the activation of
electron-rich aromatic compounds, substituted alkenes or
alkynes. The activation properties of PIFA as an excellent
activator of alkynes moiety has prompted us to hypothesize that
the ynamide bearing 3,4-dimethoxyphenylethane and tert-
butyloxy carbamate moieties on the nitrogen atom could react
with PIFA in the presence of Lewis acid via cycloisomerization
to form a new C–O bond (Scheme 1d). The resulting oxazol-
2(3H)-one intermediate could then isomerize to the reactive N-
acyl iminium ion which further reacts with the electron-rich
aromatic ring via the Pictet–Spengler type reaction to establish a
new C–C bond regioselectively.16 This would be the first
example for the synthesis of such 3,4,5-trisubstituted oxazol-
2(3H)-one from the corresponding ynamide in a domino metal-
free fashion. Moreover, the desired product, which possesses a
tetrahydroisoquinoline core structure, could be biologically active
or provide opportunities for further transformations to other
With these ynamides in hand, we next investigated their
PIFA-mediated domino regioselective cyclization and the results
are shown in Table 2. We initially studied the reaction of the
ynamide 3a in the presence of PIFA (1.1 equiv) in CH2Cl2 at –78
°C to room temperature for 18 h; however, only the starting
material 3a was recovered (Table 2, entry 1). Surprisingly,
adding 1.2 equivalent of BF3·OEt2 to the reaction mixture of
Table 1.
Synthesis of ynamides 3 using CuI-catalyzed cross-coupling
reactions.
important
tetrahydroisoquinoline
core structures, such as the phthalide
derivatives.16a,17
The similar
tetrahydroisoquinoline-oxazol-2(3H)-one core structures have
also been obtained as the products from the oxidation of ethyl 1-
benzylidene tetrahydroisoqunoline carboxylate derivatives by
using stoichiometric amount of toxic Pb(OAc)4 with a very
limited substrate scope.18 Hence, we now report the new
development on PIFA mediated domino regioselective double
Entry Ar1
Ar2
R
3 (%)a
3a, 75
3b, 49
3c, 98
3d, 72
3e, 24
3f, 56
3g, 76
3h, 65
3i, 72
3j, 70
3k, 76
3l, 29
3m, 56
3n, 44
3o, 53
3p, 69
3q, 15
3r, 68
1
3,4-(MeO)2-C6H3
Ph
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Et
2
3,4-(MeO)2-C6H3
3,4-OCH2O-C6H3
o-MeO-C6H4
m-MeO-C6H4
p-MeO-C6H4
p-F-C6H4
3
4
5
6
7
8
3,4-OCH2O-C6H3
Ph
9
3,4-(MeO)2-C6H3
3,4-OCH2O-C6H3
o-MeO-C6H4
m-MeO-C6H4
p-MeO-C6H4
p-F-C6H4
10
11
12
13
14
15
16
17
18
3,4,5-(MeO)3-C6H2
Ph
3,4-(MeO)2-C6H3
Ph
Ph
3,4-(MeO)2-C6H3
Ph
a Isolated yield after column chromatography on silica.
Scheme 1. Cyclization of the N-alkynyl alkyloxycarbamate to
3,4,5-trisubstituted oxazol-2(3H)-ones.

ynamide 3a and PIFA in CH2Cl2 at –78 °C at which the reaction
was kept for 4 h gave full conversion and oxazol-2(3H)-one 4a
was isolated in 40% yield along with oxazolidine-2,4-dione 5a
and the corresponding imide 6a in the ratio of 3:1:3, respectively
(Table 2, entry 2). Increasing the equivalents of BF3·OEt2 to 1.5
and 2.0 at –78 °C could lower the amount of oxazolidine-2,4-
dione 5a, but the desired oxazol-2(3H)-one 4a product was
isolated in 33 and 43% yield, respectively (Table 2, entries 3-4).
These results indicated that oxazolidine-2,4-dione 5a could be
derived from the key intermediate of this domino reaction and
oxazol-2(3H)-one 4a might easily decompose under strongly
acidic conditions. In addition, the formation of imide 6a has been
investigated previously to occur by an acid-catalyzed hydration
of the ynamide derivatives.22 Thus, 4 Å molecular sieve was
added in order to minimize the amount of moisture in the
reaction mixture; consequently, the ratio of oxazol-2(3H)-one 4a
to imide 6a improved to 8:3 (Table 2, entry 5). Finally, the effect
of the temperature was examined. We found that the yield of the
corresponding oxazol-2(3H)-one 4a increased up to 59%, while
the reaction was performed at –96 °C for 3 h, most likely to be
due to the slower rate of decomposition of oxazol-2(3H)-one 4a
at this temperature than at higher ones (Table 2, entry 6).
Additionally, other solvents, such as chloroform, 1,2-
dichloroethane, acetonitrile, toluene, Et2O and acetone, were also
examined but all gave unsatisfied results.23
substitution pattern of the aryl ring C. The 3,4-dimethoxyphenyl
substituent on the ring C produced the low yield of oxazol-2(3H)-
ones 4b and 4p perhaps due to the relatively facile decomposition
under strongly acidic conditions (Table 3, entries 2 and 16). On
the other hand, ynamides with 3,4-methylenedioxyphenyl, ortho-
methoxyphenyl, or meta-methoxyphenyl as the aryl ring C all
gave the corresponding products 4c-e and 4j-l in yields ranging
from 41 to 72% (Table 3, entries 3-5 and 10-12). However, the
ynamides with para-methoxyphenyl as the aryl ring C provided
the corresponding oxazol-2(3H)-ones 4f and 4m in 31-39% yield
plausibly due to their more labile nature under strongly acidic
conditions (Table 3, entries 6 and 13). The electron withdrawing
group effect on aryl ring C was also investigated and we found
that ynamides 3g and 3n with para-fluorophenyl as the aryl ring
C gave the corresponding products 4g and 4n in 36-38% yield
(Table 3, entries 7 and 14).
Further studies were carried out in order to investigate and
propose a reaction mechanism which can account for the
observed experimental results. We anticipated that the C–O bond
formation might rapidly occur first and the subsequent
intramolecular electrophilic addition from the electron-rich
aromatic ring could then take place. During the optimization
reaction condition, we found that ynamide 3a was completely
consumed within 10 minutes after addition of BF3·OEt2 (1.2
equiv) to provide 4a and 5a in the ratio of 1:1. On the other hand,
when the ynamide 3r bearing an ethyloxy carbamate moiety was
then evaluated under the similar optimized condition, the reaction
did not provide any product (Scheme 2a). Moreover, ynamide 3q,
bearing phenyl groups both at the terminal alkyl and alkyne
moieties, under our optimized condition provided only the
The optimal condition (Table 2, entry 6) was then employed for
converting various ynamides 3b-p to the corresponding products
to establish the scope and generality of this novel method as
shown in Table 3. From the yields, it could be clearly seen that,
for the similar aryl group (Ar2) on ring C, the ynamides with 3,4-
dimethoxyphenyl as the aryl ring A provided the corresponding
oxazol-2(3H)-ones in slightly higher yields than those containing
a 3,4-methylenedioxyphenyl as the ring A (Table 3, entries 1-14).
The presence of an additional electron-donating methoxy group
as the 3,4,5-trimethoxyphenyl group on ring A of the ynamides
3o and 3p, when compared with 3a and 3b, lowered the yields of
the products 4o and 4p dramatically to be in the range of 20-22%
(Table 3, entries 13-14). Nevertheless, the principal effect for the
production of oxazol-2(3H)-ones apparently depended on the
Table 3.
PIFA–BF3·OEt2 mediated intramolecular regioselective
domino cyclization of ynamides 3.
Entry Ynamide
R
Ar2
4 (%)a
4a, 59
4b, 19
4c, 41
4d, 69
4e, 72
4f, 31
4g, 36
4h, 44
4i, 56
4j, 50
4k, 62
4l, 51
4m, 39
4n, 38
4o, 20
4p, 22
Table 2.
Optimization of reaction conditions.
1
3a
3b
3c
3d
3e
3f
R1 = R2 = MeO, R3 = H
Ph
2b
3b
4
3,4-(MeO)2-C6H3
3,4-OCH2O-C6H3
o-MeO-C6H4
m-MeO-C6H4
p-MeO-C6H4
p-F-C6H4
5
6
7
3g
3h
3i
Entry BF3·OEt2 (equiv) Temp (°C) Time (h) Ratio 4a:5a:6aa 4a (%)b
8
R1–R2 = OCH2O, R3 = H Ph
1
-
–78 to rt
–78
18
4
-
nrc
40
33
43
38
59
9
3,4-(MeO)2-C6H3
2
1.2
1.5
2.0
2.0
2.0
3:1:3
16:1:28
21:1:20
8:1:3
8:1:2
10
11
12
13
14
15b
16
3j
3,4-OCH2O-C6H3
o-MeO-C6H4
m-MeO-C6H4
p-MeO-C6H4
p-F-C6H4
3
–78
3
3k
3l
4
–78
3
5d
6d
–78
3
3m
3n
3o
3p
–96
3
a Ratio was detemined by integration of the 1H NMR of the crude product.
b Isolated yield after preparative thin-layer chromatography.
c nr = no reaction.
R1 = R2 = R3 = MeO
Ph
3,4-(MeO)2-C6H3
a Isolated yield after preparative thin-layer chromatography.
b The reaction was carried out for 30 min.
d 4 Å molecular sieve was added.

formation of the key intermediate N-acyl iminium ion C which
can be readily attacked by nucleophiles. In path A, the Pictet-
Spengler type reaction occurs when Ar1 is an electron-rich
aromatic, activated by the second equivalent of BF3·OEt2,
thereby creating a new C–C bond of cation D. The subsequent
rearomatization of cation D followed by elimination of a proton
of N-acyl iminium ion E leads to the formation of the desired
oxazol-2(3H)-ones 4. In path B, in case when the N-acyl iminium
ion C did not react with the aromatic Ar1, water could act as a
nucleophile instead and attack at the reactive center of N-acyl
iminium ion C after aqueous work up, thus leading to the cation
F. Tautomerism of cation F leads to the corresponding
oxazolidine-2,4-dione 5. It is noteworthy that because
oxazolidine-2,4-dione 5 was always observed as a byproduct in
different ratios with the oxazol-2(3H)-one 4, the second
cyclization of C to D (path A) could be relatively slower than the
generation of C.
Scheme 2. Experiments for mechanistic study.
oxazolidine-2,4-dione 5b in 61% yield as the product (Scheme
2b). These results suggested that the first cyclization took place
rapidly under our standard condition and tert-butyl carbamate
functional group plays an important role for the 5-endo-dig ring
closure. The C–O bond cleavage property of the tert-butyl group
under Lewis acid condition in comparison with that of the ethyl
carbamate might account for the different results. Thus, once the
N-acyl iminium ion was formed, an appropriate nucleophile, such
as the electron-rich aromatic rings, would attack at the reactive
center. On the other hand, ynamide 3q without electron-rich
aromatic rings provided the corresponding oxazolidine-2,4-dione
5b as the major product. In addition, oxazolidine-2,4-dione 5a
should be considered as a precursor of N-acyl iminium ion
intermediate for Pictet-Spengler cyclization under Lewis acid
condition. However, treatment of 5a in the presence of 2
equivalents of BF3·OEt2 under optimized reaction condition
resulted in no reaction (Scheme 2c).
3. Conclusion
In summary, we have developed a novel method for the
synthesis of tetrahydroisoquinoline-oxazol-2(3H)-ones based on
the intramolecular regioselective domino cyclization of
ynamides. This transition metal-free process allows for the rapid
production of tetrahydroisoquinoline-oxazol-2(3H)-one building
blocks useful for the synthesis of new bioactive products. Further
studies on the application of hypervalent iodine mediated
reactions of ynamides and the derived products are being
conducted and will be reported in due course.
4. Experimental
4.1. General information
Based on both experimental evidences and the reported
literatures, we propose a plausible mechanism for the formation
of oxazol-2(3H)-one 4 and oxazolidine-2,4-dione 5 as shown in
Scheme 3. The activation of the triple bond of ynamide by PIFA
leads to the formation of the iodonium intermediate A.15c,f
Subsequently, an intramolecular regioselective 5-endo-dig ring
closure of intermediate A occurs upon its reaction with the first
equivalent of BF3·OEt2 thereby generating the tert-butyl cation
and trifluoroacetate anion, leading to the enamine B. The
enamine-iminium tautomerism of intermediate B results in the
Unless otherwise noted, reactions were run in oven-dried
round-bottomed flasks. Toluene was purified by the solvent
purification system. Dichloromethane was dried over CaH2,
distilled under argon atmosphere, and kept over 4 Å molecular
sieve prior to use. PIFA, as received from the suppliers, was
dried under vacuum at room temperature for 48 h and kept in
argon-filled glove box. All other compounds were used as
received from the suppliers. The crude reaction mixtures were
concentrated by a rotary evaporator that removed organic
solvents under reduced pressure. Column chromatography was
performed using silica gel 60 [particle size 60-200 µm (70-230
mesh ASTM) or 40-63 µm (230-400 mesh ASTM)]. Preparative
thin-layer chromatography was performed using silica gel 60
PF254
.
Analytical thin-layer chromatography (TLC) was
performed with silica gel 60 F254 aluminum sheets. Nuclear
magnetic resonance (NMR) spectra were recorded either on a
Bruker AVIII-300 (1H: 300 MHz, 13C: 75 MHz) or a Bruker
AVIII-HD-400 (1H: 400 MHz, 13C: 100 MHz) using
deuterochloroform as solvents with tetramethylsilane as an
internal standard. Chemical shifts for 1H NMR spectra were
reported in parts per million (ppm, δ) downfield from
tetramethylsilane. Splitting patterns are described as singlet (s),
doublet (d), triplet (t), quartet (q), multiplet (m), broad (br),
doublet of doublet (dd) and doublet of doublet of doublet (ddd).
Infrared spectra were recorded on a Perkin Elmer Spectrum One
FT-IR Spectrophotometer using the universal attenuated total
reflectance (ATR) technique and were reported in wavenumbers
(cm−1). Low resolution mass spectra were determined using a
Thermo Scientific DSQ II single quadrupole GC/MS with
FOCUS GC. High resolution mass spectra (HRMS) were
obtained using time-of-flight (TOF) via atmospheric pressure
chemical ionization (APCI) or electrospray ionization (ESI) on
Bruker MicroTOF spectrometer. Melting points were determined
Scheme 3. Proposed mechanism for the formation of oxazol-
2(3H)-one 4 and oxazolidine-2,4-dione 5.

on Electrothermal 9100 melting point apparatus and reported
without correction.
tert-Butyl 3,4-dimethoxyphenethylcarbamate (563 mg, 2.00
mmol), 5-(bromoethynyl)benzo[d][1,3]dioxole (900 mg, 4.00
mmol), CuI (76.0 mg, 0.40 mmol), 1,10-phenanthroline (79.3
mg, 0.44 mmol) in toluene (5 mL) and KHMDS (0.50 M in
toluene, 8.00 mL, 4.00 mmol) were employed. After usual
workup, the crude product was purified by column
chromatography (SiO2, hexane:EtOAc; 20:1 to 5:1 + 1% Et3N as
eluent) to obtain 3c (832 mg, 98%) as a pale yellow oil. 1H NMR
(300 MHz, CDCl3) δ: 6.90 (br.d, J = 7.6 Hz, 1H), 6.86-6.70 (m,
5H), 5.96 (s, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 3.70 (t, J = 7.3 Hz,
2H), 2.94 (t, J = 7.3 Hz, 2H), 1.46 (br.s, 9H) ppm; 13C NMR (75
MHz, CDCl3) δ: 153.9, 148.9, 147.7, 147.3, 147.1, 130.7, 125.2,
120.9, 116.8, 112.2, 111.3, 111.2, 108.3, 101.1, 82.3, 82.0, 70.3,
55.9, 55.8, 50.5, 33.8, 27.9 ppm; IR (neat): νmax = 2935, 2247,
1717, 1592, 1515, 1493, 1447, 1388, 1368, 1305, 1261, 1236,
1154, 1032, 935, 853, 809, 763 cm-1; EI-MS: m/z (relative
intensity) = 425 (2, M+), 369 (99), 341 (15), 310 (16), 293 (9),
279 (8), 205 (30), 174 (17), 167 (19), 165 (55), 164 (69), 151
(57), 149 (100), 121 (11), 107 (13), 71 (26); TOF-HRMS calcd
for C24H27NO6Na (M + Na)+ 448.1731, found 448.1730.
4.2. General procedure for the synthesis of ynamide 3.
A 50 mL 2-neck round bottom flask equipped with a
condenser and a septum was charged with tert-butyl 3,4-
dimethoxyphenethylcarbamate, (bromoethynyl)benzene (1.5
equiv), CuI (0.2 equiv), 1,10-phenanthroline (0.22 equiv) under
argon atmosphere. Subsequently, toluene was added and the
reaction mixture was stirred at 90 °C for 5 minute. A solution of
KHMDS (1.2 equiv) was slowly added to the reaction mixture
using syringe pump over 3 h. The resulting dark-brown solution
was stirred at 90 °C for 18 h and cooled to room temperature.
The reaction mixture was quenched with the mixture of conc.
ammonium hydroxide/brine (1:1), stirred at room temperature for
30 min, and extracted with EtOAc. The combined organic layers
were dried over anh. Na2SO4 and concentrated in vacuo.
4.2.1. tert-Butyl 3,4-
dimethoxyphenethyl(phenylethynyl)carbamate
(3a)
4.2.4. tert-Butyl 3,4-dimethoxyphenethyl((2-
methoxyphenyl)ethynyl)carbamate (3d)
tert-Butyl 3,4-dimethoxyphenethylcarbamate (1.27 g, 4.50
mmol), (bromoethynyl)benzene (1.22 g, 6.75 mmol), CuI (171
mg, 0.90 mmol), 1,10-phenanthroline (178 mg, 0.99 mmol) and
KHMDS (0.45 M in toluene, 12.0 mL, 5.40 mmol) were
employed. After usual workup, the crude product was purified by
column chromatography (SiO2, hexane:EtOAc; 20:1 to 5:1 + 1%
Et3N as eluent) to obtain 3a (1.28 g, 75%) as a pale yellow oil. 1H
NMR (300 MHz, CDCl3) δ: 7.43-7.34 (m, 2H), 7.34-7.21 (m,
3H), 6.85-6.73 (m, 3H), 3.87 (s, 3H), 3.85 (s, 3H), 3.72 (t, J = 7.5
Hz, 2H), 2.96 (t, J = 7.5 Hz, 2H), 1.46 (br.s, 9H) ppm; 13C NMR
(75 MHz, CDCl3) δ: 153.8, 148.9, 147.7, 130.7, 128.2, 127.1,
123.7, 120.9, 112.2, 111.4, 83.8, 82.3, 70.7, 55.9, 55.8, 50.4,
33.8, 27.9 ppm; IR (neat): νmax = 2973, 2934, 2242, 1716, 1592,
1515, 1454, 1393, 1368, 1305, 1261, 1238, 1143, 1029, 853, 806,
754 cm-1; EI-MS: m/z (relative intensity) = 381 (0.1, M+), 325
(17), 266 (13), 165 (51), 152 (22), 151 (26), 150 (13), 130 (16),
57 (100); TOF-HRMS calcd. for C23H28NO4 (M + H)+ 382.2013,
found 382.2018.
tert-Butyl 3,4-dimethoxyphenethylcarbamate (422 mg, 1.50
mmol), 1-(bromoethynyl)-2-methoxybenzene (633 mg, 3.00
mmol), CuI (57.0 mg, 0.30 mmol), 1,10-phenanthroline (59.5
mg, 0.33 mmol) in toluene (5 mL) and KHMDS (0.48 M in
toluene, 4.10 mL, 1.95 mmol) were employed. After usual
workup, the crude product was purified by column
chromatography (SiO2, hexane:EtOAc; 40:1 to 4:1 + 1% Et3N as
eluent) to obtain 3d (442 mg, 72%) as a pale yellow oil. 1H NMR
(300 MHz, CDCl3) δ: 7.30 (br.d, J = 7.1 Hz, 1H), 7.27-7.19 (m,
1H), 6.93-6.77 (m, 5H), 3.87 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H),
3.74 (t, J = 7.5 Hz, 2H), 3.00 (t, J = 7.5 Hz, 2H), 1.47 (br.s, 9H)
ppm; 13C NMR (75 MHz, CDCl3) δ: 159.2, 153.7, 148.8, 147.6,
132.3, 130.9, 128.4, 120.9, 120.3, 113.0, 112.2, 111.3, 110.6,
87.5, 82.1, 67.2, 55.8, 55.7, 55.6, 50.3, 33.6, 27.9 ppm; IR (neat):
νmax = 2967, 2936, 2245, 1712, 1592, 1514, 1463, 1391, 1366,
1236, 1156, 1027, 852, 807, 754 cm-1; EI-MS: m/z (relative
intensity) = 411 (0.3, M+), 355 (31), 354 (33), 296 (19), 280 (11),
164 (100), 160 (13), 151 (43), 121 (5); TOF-HRMS calcd for
C24H29NO5Na (M + Na)+ 434.1938, found 434.1936.
4.2.2. tert-Butyl 3,4-dimethoxyphenethyl((3,4-
dimethoxyphenyl)ethynyl)carbamate (3b)
tert-Butyl 3,4-dimethoxyphenethylcarbamate (111 mg, 0.50
mmol), 4-(bromoethynyl)-1,2-dimethoxybenzene (157 mg, 0.65
mmol), CuI (19.0 mg, 0.10 mmol), 1,10-phenanthroline (22.5
mg, 0.13 mmol) in toluene (3 mL) and KHMDS (0.50 M in
toluene, 1.30 mL, 0.65 mmol) were employed. After usual
workup, the crude product was purified by preparative thin-layer
chromatography (SiO2, hexane:EtOAc; 4:1 + 1% Et3N as eluent)
4.2.5. tert-Butyl 3,4-dimethoxyphenethyl((3-
methoxyphenyl)ethynyl)carbamate (3e)
tert-Butyl 3,4-dimethoxyphenethylcarbamate (422 mg, 1.50
mmol), 1-(bromoethynyl)-3-methoxybenzene (633 mg, 3.00
mmol), CuI (57.0 mg, 0.30 mmol), 1,10-phenanthroline (59.5
mg, 0.33 mmol) in toluene (5 mL) and KHMDS (0.48 M in
toluene, 4.10 mL, 1.95 mmol) were employed. After usual
workup, the crude product was purified by column
chromatography (SiO2, hexane:EtOAc; 20:1 to 5:1 + 1% Et3N as
eluent) to obtain 3e (147 mg, 24%) as a pale yellow oil. 1H NMR
(300 MHz, CDCl3) δ:7.20 (dd, J = 8.0, 7.9 Hz, 1H), 6.97 (br.d, J
= 7.4 Hz, 1H), 6.91 (br.s, 1H), 6.84-6.75 (m, 4H), 3.87 (s, 3H),
3.83 (s, 3H), 3.78 (s, 3H), 3.72 (t, J = 7.4 Hz, 2H), 2.96 (t, J = 7.4
Hz, 2H), 1.46 (br.s, 9H) ppm; 13C NMR (75 MHz, CDCl3) δ:
159.2, 153.6, 148.8, 147.6, 130.6, 129.1, 124.6, 123.1, 120.8,
115.7, 113.3, 112.1, 111.3, 83.6, 82.2, 70.6, 55.75, 55.65, 55.0,
50.3, 33.7, 27.8 ppm; IR (neat): νmax = 2977, 2937, 2245, 1718,
1598, 1516, 1453, 1390, 1368, 1236, 1155, 1029, 850, 763, 687
cm-1; EI-MS: m/z (relative intensity) = 411 (0.2, M+), 354 (47),
296 (24), 165 (100), 164 (16), 152 (30), 150 (18); TOF-HRMS
calcd for C24H29NO5Na (M + Na)+ 434.1938, found 434.1947.
1
to obtain 3b (107 mg, 49%) as a pale yellow oil. H NMR (300
MHz, CDCl3) δ: 7.00 (br.d, J = 8.6 Hz, 1H), 6.90 (br.s, 1H),
6.84-6.77 (m, 4H), 3.89 (s, 3H), 3.88 (s, 3H), 3.87 (s, 3H), 3.85
(s, 3H), 3.71 (t, J = 7.4 Hz, 2H), 2.96 (t, J = 7.4 Hz, 2H), 1.47
(br.s, 9H) ppm; 13C NMR (75 MHz, CDCl3) δ: 153.8, 148.79,
148.76, 148.5, 147.6, 130.7, 124.2, 120.9, 115.7, 114.1, 112.1,
111.3, 111.0, 82.2, 82.1, 70.2, 55.81, 55.77, 55.76, 55.71, 50.5,
33.8, 27.9 ppm; IR (neat): νmax = 2935, 2837, 2245, 1715, 1596,
1577, 1509, 1463, 1416, 1387, 1305, 1253, 1238, 1136, 1024,
851, 806, 762 cm-1; EI-MS: m/z (relative intensity) = 441 (0.3,
M+), 385 (19), 279 (12), 221 (37), 178 (25), 164 (59), 150 (14),
149 (80), 97 (49), 85 (33), 83 (38), 71 (73), 69 (100); TOF-
HRMS calcd. for C25H31NO6Na (M + Na)+ 464.2044, found
464.2048.
4.2.3. tert-Butyl (benzo[d][1, 3]dioxol-5-
ylethynyl)(3,4-dimethoxyphenethyl)carbamate
(3c)
4.2.6. tert-Butyl 3,4-dimethoxyphenethyl((4-
methoxyphenyl)ethynyl)carbamate (3f)

4.2.9. tert-Butyl (2-(benzo[d][1,3]dioxol-5-
yl)ethyl)((3,4-
dimethoxyphenyl)ethynyl)carbamate (3i)
tert-butyl 3,4-dimethoxyphenethylcarbamate (281 mg, 1.00
mmol), 1-(bromoethynyl)-4-methoxybenzene (422 mg, 2.00
mmol), CuI (38.1 mg, 0.20 mmol), 1,10-phenanthroline (39.6
mg, 0.22 mmol) in toluene (4 mL) and KHMDS (0.45 M in
toluene, 2.70 mL, 1.20 mmol) were employed. After usual
workup, the crude product was purified by column
chromatography (SiO2, hexane:EtOAc; 30:1 to 5:1 + 1% Et3N as
eluent) to obtain 3f (232 mg, 56%) as a pale yellow oil. 1H NMR
(300 MHz, CDCl3) δ: 7.33 (br. d, J = 8.3 Hz, 2H), 6.84 (d, J =
8.6 Hz, 2H), 6.82-6.77 (m, 3H), 3.87 (s, 3H), 3.85 (s, 3H), 3.81
(s, 3H), 3.70 (t, J = 7.5 Hz, 2H), 2.95 (t, J = 7.5 Hz, 2H), 1.46
(br.s, 9H) ppm; 13C NMR (75 MHz, CDCl3) δ: 158.8, 153.7,
148.7, 147.5, 132.3, 130.6, 120.8, 115.5, 113.7, 112.1, 111.2,
82.0, 81.9, 70.0, 55.7, 55.6, 55.0, 50.3, 33.6, 27.7 ppm; IR (neat):
νmax = 2936, 2835, 2244, 1717, 1607, 1515, 1457, 1393, 1368,
1285, 1245, 1157, 1030, 833 cm-1; EI-MS: m/z (relative intensity)
= 411(0.3, M+), 355 (43), 327 (14), 296 (13), 165 (100), 160 (32),
151 (39); TOF-HRMS calcd for C24H29NO5Na (M + Na)+
434.1938, found 434.1936.
tert-Butyl (2-(benzo[d][1,3]dioxol-5-yl)ethyl)carbamate (531
mg, 2.00 mmol), 4-(bromoethynyl)-1,2-dimethoxybenzene (964
mg, 4.00 mmol), CuI (76.2 mg, 0.40 mmol), 1,10-phenanthroline
(79.3 mg, 0.44 mmol) in toluene (5 mL) and KHMDS (0.50 M in
toluene, 6.00 mL, 3.00 mmol) were employed. After usual
workup, the crude product was purified by column
chromatography (SiO2, hexane:EtOAc; 15:1 to 10:1 + 1% Et3N
1
as eluent) to obtain 3i (616 mg, 72%) as a pale yellow oil. H
NMR (300 MHz, CDCl3) δ: 7.00 (br.d, J = 9.1 Hz, 1H), 6.90 (s,
1H), 6.82-6.67 (m, 4H), 5.89 (s, 2H), 3.87 (s, 6H), 3.68 (t, J = 7.1
Hz, 2H), 2.92 (t, J = 7.1 Hz, 2H), 1.47 (br.s, 9H) ppm; 13C NMR
(75 MHz, CDCl3) δ: 153.8, 148.7, 148.5, 147.5, 146.1, 131.9,
124.2, 121.8, 115.7, 114.1, 110.9, 109.3, 108.2, 100.7, 82.2, 82.0,
70.1, 55.9, 55.8, 50.6, 33.9, 27.9 ppm; IR (neat): νmax = 2925,
2247, 1716, 1596, 1515, 1490, 1443, 1390, 1365, 1245, 1140,
1027, 937, 854, 809, 763 cm-1; EI-MS: m/z (relative intensity) =
425 (6, M+), 370 (22), 369 (100), 368 (23), 343 (17), 341 (27),
325 (14), 322 (30), 221 (31), 207 (11), 190 (35), 178 (26), 165
(14), 151 (41), 149 (71), 148 (46), 135 (83), 119 (19), 91 (32);
TOF-HRMS calcd. for C24H27NO6Na (M + Na)+ 448.1731, found
448.1726.
4.2.7. tert-Butyl 3,4-dimethoxyphenethyl((4-
fluorophenyl)ethynyl)carbamate (3g)
tert-Butyl 3,4-dimethoxyphenethylcarbamate (281 mg, 1.00
mmol), 1-(bromoethynyl)-4-fluorobenzene (299 mg, 1.50 mmol),
CuI (38.0 mg, 0.20 mmol), 1,10-phenanthroline (40.0 mg, 0.22
mmol) in toluene (4 mL) and KHMDS (0.45 M in toluene, 3.30
mL, 1.50 mmol) were employed. After usual workup, the crude
product was purified by column chromatography (SiO2,
hexane:EtOAc; 10:1 to 7:1 + 1% Et3N as eluent) to obtain 3g
(305 mg, 76%) as a pale yellow oil. 1H-NMR (400 MHz, CDCl3)
δ: 7.34 (br.s, 2H), 6.99 (dd, J = 8.8, 8.7 Hz, 2H), 6.80 (s, 1H),
6.79 (d, J = 9.4 Hz, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 3.71 (t, J =
7.4 Hz, 2H), 2.95 (t, J = 7.4 Hz, 2H), 1.48 (br.s, 9H) ppm; 13C-
NMR (100 MHz, CDCl3) δ: 161.9 (d, J = 248.0 Hz), 153.74,
148.8, 147.7, 132.5, 130.6, 120.9, 119.7, 115.4 (d, J = 22.0 Hz),
112.1, 111.3, 83.3, 82.4, 69.6, 55.9, 55.8, 50.3, 33.8, 27.9 ppm;
IR (neat): νmax = 2977, 2936, 2245, 1718, 1600, 1511, 1455,
1393, 1368, 1307, 1289, 1261, 1236, 1151, 1029, 941, 835, 812,
761 cm-1; EI-MS: m/z (relative intensity) = 399 (0.1, M+), 343
(24), 342 (10), 284 (15), 165 (54), 152 (23), 151 (14), 148 (17),
57 (100); TOF-HRMS calcd. for C23H26FNO4Na (M + Na)+
422.1738, found 422.1744.
4.2.10. tert-Butyl (2-(benzo[d][1, 3]dioxol-5-
yl)ethyl)(benzo[d][1, 3]dioxol-5-
ylethynyl)carbamate (3j)
tert-Butyl (2-(benzo[d][1,3]dioxol-5-yl)ethyl)carbamate (265
mg, 1.00 mmol), 5-(bromoethynyl)benzo[d][1,3]dioxole (450
mg, 2.00 mmol), CuI (38.1 mg, 0.20 mmol), 1,10-phenanthroline
(39.6 mg, 0.22 mmol) in toluene (4 mL) and KHMDS (0.40 M in
toluene, 3.00 mL, 1.20 mmol) were employed. After usual
workup, the crude product was purified by column
chromatography (SiO2, hexane:CH2Cl2; 4:1 to 1:1 + 1% Et3N as
eluent) to obtain 3j (286 mg, 70%) as a pale yellow oil. 1H NMR
(300 MHz, CDCl3) δ: 6.90 (d, J = 7.3 Hz, 1H), 6.83 (s, 1H), 6.78-
6.66 (m, 4H), 5.96 (s, 2H), 5.91 (s, 2H), 3.66 (t, J = 7.3 Hz, 2H),
2.91 (t, J = 7.3 Hz, 2H), 1.47 (br.s, 9H) ppm; 13C NMR (75 MHz,
CDCl3) δ: 153.7, 147.5, 147.2, 147.0, 146.0, 131.8, 125.2, 121.7,
116.7, 111.1, 109.2, 108.2, 108.1, 101.0, 100.6, 82.1, 81.9, 70.2,
50.6, 33.8, 27.8 ppm; IR (neat): νmax = 2978, 2894, 2249, 1717,
1504, 1491, 1456, 1388, 1369, 1305, 1246, 1154, 1039, 936, 855,
809 cm-1; EI-MS: m/z (relative intensity) = 409 (1, M+), 353 (25),
325 (5), 295 (5), 279 (8), 221 (10), 174 (14), 167 (28), 149 (100),
135 (21), 113 (15), 111 (16), 99 (12), 97 (26), 85 (22), 83 (23),
71 (47), 69 (39); TOF-HRMS calcd. for C23H23NO6Na (M + Na)+
432.1418, found 432.1425.
4.2.8. tert-Butyl (2-(benzo[d][1,3]dioxol-5-
yl)ethyl)(phenylethynyl)carbamate (3h)
tert-Butyl (2-(benzo[d][1,3]dioxol-5-yl)ethyl)carbamate (531
mg, 2.00 mmol), (bromoethynyl)benzene (724 mg, 4.00 mmol),
CuI (76.2 mg, 0.40 mmol), 1,10-phenanthroline (79.3 mg, 0.44
mmol) in toluene (5 mL) and KHMDS (0.48 M in toluene, 5.00
mL, 2.40 mmol) were employed. After usual workup, the crude
product was purified by column chromatography (SiO2,
hexane:EtOAc; 100:1 to 20:1 + 1% Et3N as eluent) to obtain 3h
(475 mg, 65%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3)
δ: 7.43-7.33 (m, 2H), 7.33-7.23 (m, 3H), 6.79-6.68 (m, 3H), 5.91
(s, 2H), 3.69 (t, J = 7.4 Hz, 2H), 2.93 (t, J = 7.4 Hz, 2H), 1.48
(br.s, 9H) ppm; 13C NMR (75 MHz, CDCl3) δ: 153.8, 147.6,
146.2, 131.9, 130.7, 128.2, 127.1, 123.6, 121.9, 109.4, 108.3,
4.2.11. tert-Butyl (2-(benzo[d][1, 3]dioxol-5-
yl)ethyl)((2-methoxyphenyl)ethynyl)carbamate
(3k)
tert-Butyl (2-(benzo[d][1,3]dioxol-5-yl)ethyl)carbamate (398
mg, 1.50 mmol), 1-(bromoethynyl)-2-methoxybenzene (633 mg,
3.00 mmol), CuI (57.1 mg, 0.30 mmol), 1,10-phenanthroline
(59.5 mg, 0.33 mmol) in toluene (5 mL) and KHMDS (0.48 M in
toluene, 4.10 mL, 1.95 mmol) were employed. After usual
workup, the crude product was purified by column
chromatography (SiO2, hexane:CH2Cl2; 2:1 to 1:1 + 1% Et3N as
eluent) to obtain 3k (450 mg, 76%) as a pale yellow oil. 1H NMR
(300 MHz, CDCl3) δ: 7.34 (br.d, J = 6.7 Hz, 1H), 7.21 (dd, J =
8.7, 7.3 Hz, 1H), 6.89 (d, J = 7.5 Hz, 1H), 6.85 (d, J = 8.0 Hz,
1H), 6.78 (s, 1H), 6.73 (s, 2H), 5.87 (s, 2H), 3.86 (s, 3H), 3.71 (t,
100.8, 83.8, 82.4, 70.8, 50.6, 34.0, 28.0 ppm; IR (neat): νmax
=
2978, 2933, 2887, 2242, 1717, 1503, 1490, 1443, 1393, 1368,
1306, 1245, 1147, 1039, 930, 856, 809, 754 cm-1; EI-MS: m/z
(relative intensity) = 365 (1, M+), 309 (82), 281 (10), 265 (12),
239 (10), 235 (14), 206 (5), 149 (100), 136 (57), 135 (62), 130
(42), 119 (26), 91 (42), 77 (23); TOF-HRMS calcd. for
C22H23NO4Na (M + Na)+ 388.1519, found 388.1519.
J = 7.4 Hz, 2H), 2.97 (t, J = 7.4 Hz, 2H), 1.47 (br.s, 9H) ppm; 13
C
NMR (75 MHz, CDCl3) δ: 159.2, 153.6, 147.5, 146.0, 132.2,
132.0, 128.3, 121.8, 120.3, 112.9, 110.5, 109.3, 108.1, 100.6,
87.4, 82.1, 67.2, 55.6, 50.5, 33.7, 27.8 ppm; IR (neat): νmax
=

2978, 2937, 2244, 1717, 1491, 1444, 1392, 1369, 1308, 1246,
1151, 1010, 932, 752 cm-1; EI-MS: m/z (relative intensity) = 395
(0.44, M+), 339 (64), 338 (26), 264 (6), 160 (38), 149 (100), 135
(18), 123 (11), 119 (32), 91 (28), 57 (63); TOF-HRMS calcd. for
C23H25NO5Na (M + Na)+ 418.1625, found 418.1634.
Hz, 2H), 1.47 (br.s, 9H) ppm; 13C-NMR (100 MHz, CDCl3) δ:
161.8 (d, J = 248.1 Hz), 153.7, 147.6, 146.1, 132.5, 131.8, 121.9,
119.6, 115.4 (d, J = 22.0 Hz), 109.3, 108.3, 100.8, 83.2, 82.4,
69.6, 50.5, 34.0, 27.9 ppm; IR (neat): νmax = 2980, 2933, 2246,
1717, 1601, 1510, 1490, 1444, 1393, 1368, 1307, 1293, 1246,
1227, 1149, 1039, 930, 834, 811, 760 cm-1; EI-MS: m/z (relative
intensity) = 383 (0.4, M+), 327 (38), 326 (12), 283 (6), 257 (5),
253 (6), 178 (8), 149 (50), 148 (32), 136 (25), 135 (14), 119 (10),
91 (13), 57 (100); TOF-HRMS calcd. for C22H22FNO4Na (M +
Na)+ 406.1425, found 406.1424.
4.2.12. tert-Butyl (2-(benzo[d][1,3]dioxol-5-
yl)ethyl)((3-methoxyphenyl)ethynyl)carbamate
(3l)
tert-Butyl (2-(benzo[d][1,3]dioxol-5-yl)ethyl)carbamate (398
mg, 1.50 mmol), 1-(bromoethynyl)-3-methoxybenzene (633 mg,
3.00 mmol), CuI (57.1 mg, 0.30 mmol), 1,10-phenanthroline
(59.5 mg, 0.33 mmol) in toluene (5 mL) and KHMDS (0.48 M in
toluene, 4.10 mL, 1.95 mmol) were employed. After usual
workup, the crude product was purified by column
chromatography (SiO2, hexane:EtOAc; 40:1 to 20:1 + 1% Et3N
4.2.15. tert-Butyl (phenylethynyl)(3,4,5-
trimethoxyphenethyl)carbamate (3o)
tert-Butyl 3,4,5-trimethoxyphenethylcarbamate (623 mg, 2.00
mmol), (bromoethynyl)benzene (724 mg, 4.00 mmol), CuI (76.2
mg, 0.40 mmol), 1,10-phenanthroline (79.3 mg, 0.44 mmol) in
toluene (5 mL) and KHMDS (0.48 M in toluene, 5.00 mL, 2.40
mmol) were employed. After usual workup, the crude product
was purified by column chromatography (SiO2, hexane:EtOAc;
20:1 to 5:1 + 1% Et3N as eluent) to obtain 3o (432 mg, 53%) as a
1
as eluent) to obtain 3l (173 mg, 29%) as a pale yellow oil. H
NMR (300 MHz, CDCl3) δ: 7.20 (dd, J = 8.0, 7.9 Hz, 1H), 6.97
(br.d, J = 7.5 Hz, 1H), 6.90 (br.s, 1H), 6.81 (ddd, J = 8.3, 2.6, 0.9
Hz, 1H), 6.77-6.67 (m, 3H), 5.90 (s, 2H), 3.80 (s, 3H), 3.69 (t, J
= 7.4 Hz, 2H), 2.92 (t, J = 7.4 Hz, 2H), 1.48 (br.s, 9H) ppm; 13
C
1
pale yellow oil. H NMR (300 MHz, CDCl3) δ: 7.41-7.34 (m,
NMR (75 MHz, CDCl3) δ: 159.2, 153.6, 147.5, 146.1, 131.8,
129.1, 124.6, 123.2, 121.8, 115.7, 113.4, 109.3, 108.2, 100.7,
2H), 7.34-7.24 (m, 3H), 6.48 (s, 2H), 3.85 (s, 6H), 3.81 (s, 3H),
3.74 (t, J = 7.3 Hz, 2H), 2.96 (t, J = 7.3 Hz, 2H), 1.48 (br.s, 9H)
ppm; 13C NMR (75 MHz, CDCl3) δ: 153.4, 152.9, 136.3, 133.5,
130.4, 127.9, 126.9, 123.3, 105.6, 83.4, 82.0, 70.6, 60.3, 55.7,
49.7, 34.2, 27.6 ppm; IR (neat): νmax = 2937, 2242, 1717, 1590,
1508, 1457, 1393, 1368, 1239, 1126, 1011, 825, 755 cm-1; EI-
MS: m/z (relative intensity) = 411 (0.1, M+), 355 (20), 296 (6),
195 (97), 181 (40), 165 (11), 148 (10), 130 (26), 121 (12), 103
(14), 91 (16), 77 (12), 57 (100); TOF-HRMS calcd. for
C24H30NO5 (M + H)+ 412.2119, found 412.2109.
83.6, 82.3, 70.6, 55.1, 50.5, 33.9, 27.8 ppm; IR (neat): νmax
=
2978, 2937, 2245, 1717, 1598, 1574, 1490, 1445, 1389, 1368,
1293, 1246, 1153, 1039, 935, 851, 808, 780 cm-1; EI-MS: m/z
(relative intensity) = 395 (1, M+), 339 (67), 311 (10), 295 (12),
269 (8), 265 (9), 160 (44), 149 (100), 136 (31), 119 (13), 91 (13);
TOF-HRMS calcd. for C23H26NO5 (M + H)+ 396.1806, found
396.1809.
4.2.13. tert-Butyl (2-(benzo[d][1,3]dioxol-5-
yl)ethyl)((4-methoxyphenyl)ethynyl)carbamate
(3m)
4.2.16. tert-Butyl ((3,4-
dimethoxyphenyl)ethynyl)(3,4,5-
trimethoxyphenethyl)carbamate (3p)
tert-Butyl (2-(benzo[d][1,3]dioxol-5-yl)ethyl)carbamate (398
mg, 1.50 mmol), 1-(bromoethynyl)-4-methoxybenzene (633 mg,
3.00 mmol), CuI (57.1 mg, 0.30 mmol), 1,10-phenanthroline
(59.5 mg, 0.33 mmol) in toluene (5 mL) and KHMDS (0.48 M in
toluene, 3.80 mL, 1.80 mmol) were employed. After usual
workup, the crude product was purified by column
chromatography (SiO2, hexane:EtOAc; 20:1 to 15:1 + 1% Et3N
tert-Butyl 3,4,5-trimethoxyphenethylcarbamate (623 mg, 2.00
mmol), 4-(bromoethynyl)-1,2-dimethoxybenzene (964 mg, 4.00
mmol), CuI (76.2 mg, 0.40 mmol), 1,10-phenanthroline (79.3
mg, 0.44 mmol) in toluene (5 mL) and KHMDS (0.48 M in
toluene, 5.00 mL, 2.40 mmol) were employed. After usual
workup, the crude product was purified by column
chromatography (SiO2, hexane:EtOAc; 10:1 to 3:1 + 1% Et3N as
eluent) to obtain 3p (651 mg, 69%) as a pale yellow oil. 1H NMR
(300 MHz, CDCl3) δ: 7.00 (br.d, J = 8.0 Hz, 1H), 6.91 (s, 1H),
6.80 (d, J = 8.3 Hz, 1H), 6.48 (s, 2H), 3.88 (s, 6H), 3.85 (s, 6H),
3.81 (s, 3H), 3.73 (t, J = 7.1 Hz, 2H), 2.95 (t, J = 7.1 Hz, 2H),
1.47 (br.s, 9H) ppm; 13C NMR (75 MHz, CDCl3) δ: 153.4, 152.7,
148.5, 148.2, 136.2, 133.5, 123.9, 115.3, 113.8, 110.7, 105.5,
81.8, 81.7, 70.0, 60.2, 55.5, 55.4, 49.8, 34.1, 27.5 ppm; IR (neat):
νmax = 2937, 2838, 2247, 1716, 1590, 1513, 1457, 1417, 1386,
1368, 1305, 1239, 1153, 1127, 1024, 852, 810, 762 cm-1; EI-MS:
m/z (relative intensity) = 471 (0.03, M+), 415 (73), 221 (56), 206
(9), 194 (100), 181 (40), 179 (41), 165 (16), 151 (10), 137 (9),
107 (6), 91 (8), 77 (8); TOF-HRMS calcd. for C26H33NO7Na (M
+ Na)+ 494.2149, found 494.2137.
1
as eluent) to obtain 3m (333 mg, 56%) as a pale yellow oil. H
NMR (300 MHz, CDCl3) δ: 7.33 (dd, J = 8.3 Hz, 2H), 6.83 (d, J
= 8.9 Hz, 2H), 6.77-6.67 (m, 3H), 5.90 (s, 2H), 3.80 (s, 3H), 6.67
(t, J = 7.4 Hz, 2H), 2.91 (t, J = 7.4 Hz, 2H), 1.47 (br.s, 9H) ppm;
13C NMR (75 MHz, CDCl3) δ: 159.0, 153.9, 147.6, 146.1, 132.5,
132.0, 121.9, 115.7, 113.8, 109.4, 108.3, 100.8, 82.2, 70.2, 55.2,
50.6, 34.0, 28.0 ppm; IR (neat): νmax = 2977, 2932, 2244, 1717,
1607, 1514, 1490, 1444, 1393, 1368, 1308, 1286, 1245, 1154,
1037, 935, 831, 810 cm-1; EI-MS: m/z (relative intensity) = 395
(1, M+), 339 (59), 311 (18), 295 (12), 265 (5), 191 (4), 160 (41),
149 (100), 135 (36), 119 (26), 91 (25); TOF-HRMS calcd. for
C23H25NO5Na (M + Na)+ 418.1625, found 418.1625.
4.2.14. tert-Butyl (2-(benzo[d][1,3]dioxol-5-
yl)ethyl)((4-fluorophenyl)ethynyl)carbamate (3n)
4.2.17. tert-Butyl
phenethyl(phenylethynyl)carbamate (3q)
tert-Butyl (2-(benzo[d][1,3]dioxol-5-yl)ethyl)carbamate (106
mg, 0.40 mmol), 1-(bromoethynyl)-4-fluorobenzene (119 mg,
0.60 mmol), CuI (15.0 mg, 0.08 mmol), 1,10-phenanthroline
(16.0 mg, 0.09 mmol) in toluene (2 mL) and KHMDS (0.45 M in
toluene, 1.30 mL, 0.60 mmol) were employed. After usual
workup, the crude product was purified by column
chromatography (SiO2, hexane:EtOAc; 30:1 + 1% Et3N as
tert-Butyl phenethylcarbamate (443 mg, 2.00 mmol),
(bromoethynyl)benzene (543 mg, 3.00 mmol), CuI (76.2 mg,
0.40 mmol), 1,10-phenanthroline (79.3 mg, 0.44 mmol) in
toluene (5 mL) and KHMDS (0.48 M in toluene, 3.80 mL, 1.80
mmol) were employed. After usual workup, the crude product
was purified by column chromatography (SiO2, hexane:EtOAc;
100:0 to 30:1 + 1% Et3N as eluent) to obtain 3q (94.4 mg, 15%)
as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ: 7.33-7.10 (m,
10H), 3.66 (t, J = 7.5 Hz, 2H), 2.94 (t, J = 7.5 Hz, 2H), 1.39 (s,
1
eluent) to obtain 3n (67.0 mg, 44%) as a pale yellow oil. H-
NMR (400 MHz, CDCl3) δ: 7.34 (br.s, 2H), 6.99 (dd, J = 8.8, 8.7
Hz, 2H), 6.75 (d, J = 7.7 Hz, 1H), 6.74 (s, 1H), 6.70 (d, J = 7.8
Hz, 2H), 5.90 (s, 2H), 3.68 (t, J = 7.3 Hz, 2H), 2.91 (t, J = 7.3

9H) ppm; 13C NMR (75 MHz, CDCl3) δ: 153.7, 152.1, 138.2,
130.8, 129.0, 128.5, 128.2, 127.1, 126.5, 83.8, 82.3, 80.9, 50.4,
34.3, 27.93, 27.85 ppm; IR (neat): νmax = 2979, 2933, 2244, 1720,
1455, 1393, 1368, 1307, 1248, 1150, 753, 691 cm-1; EI-MS: m/z
(relative intensity) = 321 (8, M+), 265 (19), 264 (15), 221 (44),
220 (10), 130 (50), 105 (100), 91 (8), 79 (9), 77 (7), 57 (73);
TOF-HRMS calcd. for C21H23NO2Na (M + Na)+ 344.1621, found
344.1628.
3-(3,4-Dimethoxyphenethyl)-5-phenyloxazolidine-2,4-dione
1
(5a): (20 mg, 11%) as a yellow viscos oil. H NMR (300 MHz,
CDCl3) δ: 7.42-7.33 (m, 3H), 7.21-7.13 (m, 2H), 6.75-6.66 (m,
3H), 5.62 (s, 1H), 3.85 (s, 3H), 3.98-3.76 (m, 2H), 3.80 (s, 3H),
2.99 (t, J = 7.3 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ:
170.8, 154.8, 148.6, 147.6, 131.3, 129.4, 128.8, 128.6, 125.9,
120.6, 111.6, 110.9, 79.8, 55.4, 40.6, 32.1 ppm; IR (neat): νmax
=
2939, 1815, 1736, 1592, 1515, 1443, 1411, 1366, 1263, 1237,
1149, 1105, 1026, 808, 761, 734, 699 cm-1; EI-MS: m/z (relative
intensity) = 341 (28, M+), 165 (12), 164 (100), 151 (64), 149
(33), 135 (4), 121 (5), 105 (10), 91 (10), 84 (14), 77 (10); TOF-
HRMS calcd. for C19H19NO5Na (M + Na)+ 364.1155, found
364.1168.
4.2.18. Ethyl 3,4-
dimethoxyphenethyl(phenylethynyl)carbamate
(3r)
Ethyl 3,4-dimethoxyphenethylcarbamate (253 mg, 1.00
mmol), (bromoethynyl)benzene (362 mg, 2.00 mmol), CuI (38.1
mg, 0.20 mmol), 1,10-phenanthroline (39.6 mg, 0.22 mmol) in
toluene (5 mL) and KHMDS (0.48 M in toluene, 3.20 mL, 1.50
mmol) were employed. After usual workup, the crude product
was purified by column chromatography (SiO2, hexane:EtOAc;
10:1 to 5:1 + 1% Et3N as eluent) to obtain 3r (241 mg, 68%) as a
tert-Butyl
3,4-dimethoxyphenethyl(2-
phenylacetyl)carbamate (6a): (11 mg, 5%) as a colorless oil. 1H
NMR (300 MHz, CDCl3) δ: 7.36-7.18 (m, 5H), 6.78 (d, J = 8.6
Hz, 1H), 6.74-6.66 (m, 2H), 4.22 (s, 2H), 3.88 (t, J = 7.7 Hz, 2H),
3.85 (s, 3H), 3.82 (s, 3H), 2.76 (t, J = 7.7 Hz, 2H), 1.48 (s, 9H)
ppm; 13C-NMR (75 MHz, CDCl3) δ: 174.0, 153.0, 148.9, 147.6,
135.1, 131.4, 129.5, 128.3, 126.7, 120.8, 112.2, 111.3, 83.0, 55.9,
55.8, 46.5, 44.5, 34.5, 27.9 ppm; IR (neat): νmax = 2975, 2934,
1731, 1688, 1515, 1455, 1359, 1262, 1236, 1143, 1030, 852, 772
cm-1; EI-MS: m/z (relative intensity) = 399 (4, M+), 299 (2), 180
(3), 165 (13), 164 (100), 151 (22), 149 (7), 91 (19), 77 (3); TOF-
HRMS calcd. for C23H29NO5Na (M + Na)+ 422.1938, found
422.1937.
1
pale yellow oil. H NMR (300 MHz, CDCl3) δ: 7.43-7.36 (m,
2H), 7.35-7.25 (m, 3H), 6.84-6.76 (m, 3H), 4.22 (q, J = 7.0 Hz,
2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.78 (t, J = 7.5 Hz, 2H), 2.98 (t, J
= 7.5 Hz, 2H), 1.30 (t, J = 7.0 Hz, 3H) ppm; 13C NMR (75 MHz,
CDCl3) δ: 155.1, 148.9, 147.7, 131.1, 130.5, 128.2, 127.5, 123.3,
120.9, 112.1, 111.3, 83.0, 70.8, 63.1, 55.9, 55.8, 51.2, 33.7, 14.3
ppm; IR (neat): νmax = 2982, 2936, 2835, 2243, 1719, 1592, 1515,
1464, 1443, 1403, 1373, 1261, 1236, 1141, 1105, 1027, 805, 755,
692 cm-1; EI-MS: m/z (relative intensity) = 353 (36, M+), 352
(100), 325 (28), 324 (38), 297 (22), 280 (7), 165 (29), 164 (72),
151 (60), 150 (13), 149 (13), 130 (22), 117 (29), 105 (13), 103
(14), 91 (8); TOF-HRMS calcd. for C21H24NO4 (M + H)+
354.1699, found 354.1706.
4.3.2. 1-(3,4-Dimethoxyphenyl)-8,9-dimethoxy-
5,6-dihydro-3H-oxazolo[4,3-a]isoquinolin-3-one
(4b)
Ynamide 3b (44.2 mg, 0.10 mmol), PIFA (47.3 mg, 0.11
mmol), 4 Å molecular sieve (200 mg) and BF3·OEt2 (25 µL, 0.20
mmol) in dry CH2Cl2 (3 mL) were employed. The reaction was
4.3. General procedure for PIFA-BF3·OEt2 mediated domino
cyclization.
−96 °C for 30 min. After usual workup, the crude
carried out at
product was purified by preparative thin-layer chromatography
A 25 mL round bottom flask was charged with ynamide 3,
PIFA (1.1 equiv) and 4 Å molecular sieve in dry CH2Cl2 at room
temperature under argon atmosphere. Then the reaction mixture
(SiO2, hexane:EtOAc; 1:1 + 1% Et3N as eluent) to obtain 4b (7.3
1
mg, 19%) as a pale yellow solid (m.p. 89-93 °C). H NMR (300
MHz, CDCl3) δ: 7.28 (dd, J = 8.4, 2.0 Hz, 1H), 7.18 (s, 1H), 7.16
(d, J = 2.0 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.75 (s, 1H), 3.93
(s, 3H), 3.92 (s, 3H), 3.87 (s, 3H), 3.83 (t, J = 6.2 Hz, 2H), 3.66
(s, 3H), 3.01 (t, J = 6.2 Hz, 2H) ppm; 13C-NMR (75 MHz,
CDCl3) δ: 153.5, 149.5, 149.5, 149.1, 148.0, 133.2, 126.4, 121.2,
119.7, 118.4, 117.1, 111.5, 111.0, 110.0, 107.2, 56.03, 55.99,
38.5, 29.0 ppm; IR (neat): νmax = 2935, 2839, 1753, 1594, 1511,
1464, 1379, 1321, 1263, 1133, 1097, 1023, 858 cm-1; EI-MS: m/z
(relative intensity) = 383 (31, M+), 355 (21), 327 (36), 326 (42),
324 (100), 312 (87), 296 (24), 249 (22), 204 (16), 178 (93), 165
(99), 161 (38), 149 (64), 137 (24), 123 (95), 111 (32), 105 (38),
97 (44), 83 (48), 71 (44), 69 (47); TOF-HRMS calcd. for
C21H21NO6Na (M + Na)+ 406.1261, found 406.1252.
−96 °C using a MeOH/liquid N
was cooled to
2 bath, followed by
addition of BF3·OEt2 (2.0 equiv). The reaction mixture was
stirred at −96 °C for 3 h, quenched with sat. NaHCO3 (5 mL) at
−96 °C, and allowed to warm up to room temperature. The
organic layer was separated and the aqueous layer was extracted
with CH2Cl2. The combined organic layers were dried over anh.
Na2SO4 and concentrated in vacuo.
4.3.1. 8,9-Dimethoxy-1-phenyl-5,6-dihydro-3H-
oxazolo[4,3-a]isoquinolin-3-one (4a)
Ynamide 3a (202 mg, 0.53 mmol), PIFA (251 mg, 0.58
mmol), 4 Å molecular sieve (500 mg) and BF3·OEt2 (131 µL,
1.06 mmol) in dry CH2Cl2 (5 mL) were employed. After usual
workup, the crude product was purified by column
chromatography (SiO2, hexane:EtOAc; 4:1 to 1:1 + 1% Et3N as
eluent) to obtain 4a (101 mg, 59%) as a white solid (m.p. 148-
149 °C). 1H NMR (300 MHz, CDCl3) δ: 7.68 (d, J = 6.9 Hz, 2H),
7.45-7.30 (m, 3H), 7.16 (s, 1H), 6.76 (s, 1H), 3.91 (s, 3H), 3.82
(t, J = 6.2 Hz, 2H), 3.64 (s, 3H), 3.01 (t, J = 6.2 Hz, 2H) ppm;
13C NMR (75 MHz, CDCl3) δ: 153.4, 149.4, 147.8, 133.0, 128.6,
128.5, 126.52, 126.49, 119.2, 116.7, 111.3, 107.0, 55.9, 55.7,
38.3, 28.9 ppm; IR (neat): νmax = 2938, 1757, 1515, 1381, 1265,
1214, 1100, 1048, 750, 700 cm-1; EI-MS: m/z (relative intensity)
= 323 (100, M+), 294 (12), 267 (26), 266 (35), 264 (15), 236 (5),
178 (11), 161 (7), 149 (19), 111 (8), 105 (30), 97 (13), 77 (36),
69 (29), 57 (31); TOF-HRMS calcd. for C19H18NO4 (M + H)+
324.1230, found 324.1238.
4.3.3. 1-(Benzo[d][1,3]dioxol-5-yl)-8,9-dimethoxy-
5,6-dihydro-3H-oxazolo[4,3-a]isoquinolin-3-one
(4c)
Ynamide 3c (42.6 mg, 0.10 mmol), PIFA (47.3 mg, 0.11
mmol), 4 Å molecular sieve (200 mg) and BF3·OEt2 (25 µL, 0.20
mmol) in dry CH2Cl2 (3 mL) were employed. The reaction was
−96 °C for 30 min. After usual workup, the crude
carried out at
product was purified by preparative thin-layer chromatography
(SiO2, hexane:EtOAc; 1:1 + 1% Et3N as eluent) to obtain 4c
1
(15.1 mg, 41%) as a pale yellow solid (m.p. 171-174 °C). H
NMR (300 MHz, CDCl3) δ: 7.22-7.10 (m, 2H), 7.16 (s, 1H), 6.84
(d, J = 8.1 Hz, 1H), 6.74 (s, 1H), 6.01 (s, 2H), 3.91 (s, 3H), 3.82
(t, J = 6.2 Hz, 2H), 3.68 (s, 3H), 3.00 (t, J = 6.2 Hz, 2H) ppm;
13C-NMR (75 MHz, CDCl3) δ: 153.4, 149.4, 148.02, 147.98,
133.0, 126.4, 122.4, 121.0, 118.5, 116.9, 111.4, 108.5, 107.3,

107.2, 101.4, 56.0, 55.9, 38.5, 29.0 ppm; IR (neat): νmax = 2932,
2905, 1753, 1610, 1514, 1489, 1381, 1271, 1237, 1213, 1095,
1034, 925 cm-1; EI-MS: m/z (relative intensity) = 367 (100, M+),
360 (8), 352 (8), 311 (25), 310 (34), 249 (14), 204 (9), 178 (9),
149 (37), 135 (12), 112 (21), 97 (11), 83 (15); TOF-HRMS calcd.
for C20H17NO6Na (M + Na)+ 390.0948, found 390.0944.
HRMS calcd. for C20H19NO5Na (M + Na)+ 376.1155, found
376.1161.
4.3.7. 1-(4-fluorophenyl)-8,9-dimethoxy-5,6-
dihydro-3H-oxazolo[4,3-a]isoquinolin-3-one (4g)
Ynamide 3g (60.0 mg, 0.15 mmol), PIFA (71.0 mg, 0.17
mmol), 4 Å molecular sieve (200 mg) and BF3·OEt2 (38 µL, 0.30
mmol) in dry CH2Cl2 (2 mL) were employed. After usual
workup, the crude product was purified by preparative thin-layer
chromatography (SiO2, hexane:EtOAc; 3:2 + 1% Et3N as eluent)
to obtain 4g (18.2 mg, 36%) as a pale yellow solid (m.p. 59-61
4.3.4. 8,9-Dimethoxy-1-(2-methoxyphenyl)-5,6-
dihydro-3H-oxazolo[4,3-a]isoquinolin-3-one (4d)
Ynamide 3d (80.8 mg, 0.20 mmol), PIFA (92.9 mg, 0.22
mmol), 4 Å molecular sieve (200 mg) and BF3·OEt2 (50 µL, 0.40
mmol) in dry CH2Cl2 (3 mL) were employed. After usual
workup, the crude product was purified by preparative thin-layer
chromatography (SiO2, hexane:EtOAc; 1:1 + 1% Et3N as eluent)
to obtain 4d (47.6 mg, 69%) as a white solid (m.p. 163-165 °C).
1H NMR (300 MHz, CDCl3) δ: 7.51 (dd, J = 7.6, 1.6 Hz, 1H),
7.41 (ddd, J = 7.6, 7.6, 1.7 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H),
7.00 (d, J = 8.5 Hz, 1H), 6.72 (s, 1H), 6.63 (s, 1H), 3.89 (s, 3H),
3.87 (t, J = 6.4 Hz, 2H), 3.75 (s, 3H), 3.51 (s, 3H), 3.03 (t, J = 6.4
Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ: 157.4, 154.0, 149.0,
147.6, 131.3, 131.0, 129.6, 125.4, 120.5, 120.4, 117.4, 117.2,
111.2, 110.9, 107.7, 55.9, 55.5, 55.4, 38.3, 28.5 ppm; IR (neat):
νmax = 2938, 2840, 1748, 1598, 1515, 1490, 1463, 1433, 1262,
1248, 1212, 1168, 1094, 1051, 1021, 863, 789, 751 cm-1; EI-MS:
m/z (relative intensity) = 353 (100, M+), 338 (6), 310 (8), 296
(10), 294 (39), 135 (23); TOF-HRMS calcd. for C20H20NO5 (M +
H)+ 354.1336, found 354.1341.
1
°C). H-NMR (400 MHz, CDCl3) δ: 7.66 (dd, J = 8.9, 5.3 Hz,
2H), 7.12 (dd, J = 8.7, 8.6 Hz, 2H), 7.07 (s, 1H), 6.76 (s, 1H),
3.92 (s, 3H), 3.83 (t, J = 6.2 Hz, 2H), 3.66 (s, 3H), 3.02 (t, J = 6.2
Hz, 2H) ppm; 13C-NMR (100 MHz, CDCl3) δ: 162.7 (d, J =
249.8 Hz), 153.4, 149.6, 148.0, 132.2, 128.7 (d, J = 8.2 Hz),
126.6, 124.8 (d, J = 3.6 Hz), 119.2, 116.6, 115.8 (d, J = 21.9 Hz),
111.5, 106.9, 56.0, 55.9, 38.4, 29.0 ppm; IR (neat): νmax = 2929,
2848, 1751, 1610, 1516, 1505, 1465, 1380, 1262, 1228, 1213,
1169, 1159, 1090, 1042, 1013, 839, 805, 785, 749 cm-1; EI-MS:
m/z (relative intensity) = 341 (100, M+), 312 (10), 285 (23), 284
(28), 282 (24), 221 (9), 178 (20), 167 (6), 161 (9), 149 (16), 127
(17), 123 (27), 111 (9), 97 (13), 83 (14), 81 (15), 71 (19), 69
(22); TOF-HRMS calcd. for C19H16FNO4Na (M + Na)+ 364.0956,
found 364.0948.
4.3.8. 1-Phenyl-5,6-dihydro-3H-[1,3]dioxolo[4,5-
g]oxazolo[4,3-a]isoquinolin-3-one (4h)
4.3.5. 8,9-Dimethoxy-1-(3-methoxyphenyl)-5,6-
dihydro-3H-oxazolo[4,3-a]isoquinolin-3-one (4e)
Ynamide 3h (200 mg, 0.55 mmol), PIFA (259 mg, 0.60
mmol), 4 Å molecular sieve (200 mg) and BF3·OEt2 (135 µL,
1.10 mmol) in dry CH2Cl2 (5 mL) were employed. After usual
workup, the crude product was purified by column
chromatography (SiO2, hexane:EtOAc; 5:1 to 2:1 + 1% Et3N as
eluent) to obtain 4h (74.4 mg, 44%) as a pale yellow solid (m.p.
Ynamide 3e (91.1 mg, 0.22 mmol), PIFA (105 mg, 0.24
mmol), 4 Å molecular sieve (200 mg) and BF3·OEt2 (56 µL, 0.44
mmol) in dry CH2Cl2 (3 mL) were employed. After usual
workup, the crude product was purified by preparative thin-layer
chromatography (SiO2, hexane:EtOAc; 1:1 + 1% Et3N as eluent)
to obtain 4e (56.8 mg, 72%) as a white solid (m.p. 156-158 °C).
1H NMR (300 MHz, CDCl3) δ: 7.35-7.26 (m, 2H), 7.25-7.19 (m,
2H), 6.89 (ddd, J = 6.9, 2.4, 2.4 Hz, 1H), 6.76 (s, 1H), 3.92 (s,
3H), 3.83 (t, J = 6.2 Hz, 2H), 3.82 (s, 3H), 3.67 (s, 3H), 3.01 (t, J
= 6.2 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ: 159.8, 153.4,
149.6, 147.9, 133.0, 129.7, 129.5, 126.6, 119.4, 118.8, 116.8,
114.8, 111.7, 111.4, 107.4, 56.0, 55.8, 55.3, 38.4, 29.0 ppm; IR
(neat): νmax = 2939, 2839, 1751, 1604, 1575, 1513, 1464, 1427,
1378, 1267, 1239, 1210, 1101, 1035, 862, 783, 749 cm-1; EI-MS:
m/z (relative intensity) = 353 (100, M+), 338 (7), 324 (6), 296
(20), 282 (17), 135 (10), 107 (5); TOF-HRMS calcd. for
C20H20NO5 (M + H)+ 354.1336, found 354.1344.
1
187-189 °C). H NMR (300 MHz, CDCl3) δ: 7.66-7.59 (m, 2H),
7.46-7.32 (m, 3H), 7.08 (s, 1H), 6.74 (s, 1H), 5.96 (s, 2H), 3.80
(t, J = 6.2 Hz, 2H), 2.98 (t, J = 6.2 Hz, 2H) ppm; 13C NMR (75
MHz, CDCl3) δ: 153.4, 148.2, 146.8, 133.6, 128.8, 128.7, 128.3,
128.1, 126.7, 119.2, 118.0, 109.0, 104.4, 101.4, 38.4, 29.6 ppm;
IR (neat): νmax = 2922, 1749, 1502, 1480, 1447, 1383, 1254,
1161, 1037, 933, 866, 735, 694 cm-1; EI-MS: m/z (relative
intensity) = 307 (100, M+), 278 (23), 250 (61), 221 (7), 149 (17),
139 (8), 116 (9), 105 (38), 102 (8), 89 (9), 77 (45); TOF-HRMS
calcd. for C18H13NO4Na (M + Na)+ 330.0737, found 330.0743.
4.3.9. 1-(3,4-Dimethoxyphenyl)-5,6-dihydro-3H-
[1,3]dioxolo[4,5-g]oxazolo[4,3-a]isoquinolin-3-
one (4i)
4.3.6. 8,9-Dimethoxy-1-(4-methoxyphenyl)-5,6-
dihydro-3H-oxazolo[4,3-a]isoquinolin-3-one (4f)
Ynamide 3i (50.5 mg, 0.12 mmol), PIFA (56.2 mg, 0.13
mmol), 4 Å molecular sieve (200 mg) and BF3·OEt2 (30 µL, 0.24
mmol) in dry CH2Cl2 (3 mL) were employed. After usual
workup, the crude product was purified by preparative thin-layer
chromatography (SiO2, hexane:EtOAc; 2:1 + 1% Et3N as eluent)
to obtain 4i (24.6 mg, 56%) as a pale yellow solid (m.p. 134-136
Ynamide 3f (41.2 mg, 0.10 mmol), PIFA (47.3 mg, 0.11
mmol), 4 Å molecular sieve (200 mg) and BF3·OEt2 (25 µL, 0.20
mmol) in dry CH2Cl2 (3 mL) were employed. After usual
workup, the crude product was purified by preparative thin-layer
chromatography (SiO2, hexane:EtOAc; 2:1 + 1% Et3N as eluent)
to obtain 4f (11.0 mg, 31%) as a white solid (m.p. 164-167 °C).
1H NMR (300 MHz, CDCl3) δ: 7.61 (d, J = 8.8 Hz, 2H), 7.13 (s,
1H), 6.95 (d, J = 8.8 Hz, 2H), 6.74 (s, 1H), 3.91 (s, 3H), 3.85 (s,
3H), 3.83 (t, J = 6.2 Hz, 2H), 3.65 (s, 3H), 3.00 (t, J = 6.2 Hz,
2H) ppm; 13C NMR (75 MHz, CDCl3) δ: 160.0, 153.6, 149.3,
148.0, 133.2, 128.4, 126.2, 121.0, 118.2, 117.2, 114.1, 111.4,
107.0, 56.0, 55.9, 55.4, 38.5, 29.0 ppm; IR (neat): νmax = 2936,
2840, 1749, 1608, 1506, 1464, 1381, 1296, 1250, 1231, 1212,
1170, 1093, 1025, 834, 791, 749, 733 cm-1; EI-MS: m/z (relative
intensity) = 353 (100, M+), 338 (12), 324 (6), 297 (16), 296 (20),
294 (21), 282 (12), 266 (6), 176 (4), 135 (55), 107 (4); TOF-
1
°C). H NMR (300 MHz, CDCl3) δ: 7.22 (dd, J = 8.3, 2.0 Hz,
1H), 7.21 (s, 1H), 7.20 (d, J = 2.0 Hz, 1H), 6.90 (d, J = 8.3 Hz,
1H), 6.74 (s, 1H), 5.96 (s, 2H), 3.93 (s, 3H), 3.88 (s, 3H), 3.80 (t,
J = 6.2 Hz, 2H), 2.98 (t, J = 6.2 Hz, 2H) ppm; 13C NMR (75
MHz, CDCl3) δ: 153.3, 149.5, 149.1, 148.0, 146.8, 133.7, 127.9,
120.9, 119.7, 118.3, 118.2, 111.3, 109.9, 109.0, 104.3, 101.4,
56.0, 55.9, 38.4, 29.6 ppm; IR (neat): νmax = 2926, 1752, 1516,
1483, 1415, 1385, 1262, 1228, 1175, 1144, 1034, 929, 857, 749
cm-1; EI-MS: m/z (relative intensity) = 367 (0.5, M+), 287 (9),
285 (26), 232 (13), 230 (20), 208 (100), 195 (41), 180 (17), 167
(18), 139 (10), 118 (9), 97 (9), 77 (13); TOF-HRMS calcd. for
C20H17NO6Na (M + Na)+ 390.0948, found 390.0949.

4.3.10. 1-(Benzo[d][1,3]dioxol-5-yl)-5,6-dihydro-
3H-[1,3]dioxolo[4, 5-g]oxazolo[4,3-a]isoquinolin-
3-one (4j)
4.3.13. 1-(4-Methoxyphenyl)-5,6-dihydro-3H-
[1,3]dioxolo[4,5-g]oxazolo[4,3-a]isoquinolin-3-
one (4m)
Ynamide 3j (26.6 mg, 0.07 mmol), PIFA (30.7 mg, 0.07
mmol), 4 Å molecular sieve (200 mg) and BF3·OEt2 (16 µL, 0.13
mmol) in dry CH2Cl2 (2 mL) were employed. After usual
workup, the crude product was purified by preparative thin-layer
chromatography (SiO2, hexane:EtOAc; 2:1 + 1% Et3N as eluent)
to obtain 4j (11.4 mg, 50%) as a pale yellow solid (m.p. 203-206
Ynamide 3m (110 mg, 0.28 mmol), PIFA (131 mg, 0.30
mmol), 4 Å molecular sieve (200 mg) and BF3·OEt2 (70 µL, 0.55
mmol) in dry CH2Cl2 (4 mL) were employed. After usual
workup, the crude product was purified by preparative thin-layer
chromatography (SiO2, hexane:EtOAc; 2:1 + 1% Et3N as eluent)
to obtain 4m (36.3 mg, 39%) as a white solid (m.p. 164-167 °C).
1H NMR (300 MHz, CDCl3) δ: 7.54 (d, J = 8.9 Hz, 2H), 7.03 (s,
1H), 6.94 (d, J = 8.9 Hz, 2H), 6.72 (s, 1H), 5.95 (s, 2H), 3.85 (s,
3H), 3.79 (t, J = 6.2 Hz, 2H), 2.97 (t, J = 6.2 Hz, 2H) ppm; 13C
NMR (75 MHz, CDCl3) δ: 160.0, 153.4, 148.0, 146.8, 133.7,
128.5, 127.7, 120.7, 118.3, 118.2, 114.3, 108.9, 104.2, 101.3,
55.3, 38.4, 29.5 ppm; IR (neat): νmax = 2902, 2841, 1750, 1665,
1598, 1503, 1481, 1385, 1295, 1249, 1174, 1033, 933, 834 cm-1;
EI-MS: m/z (relative intensity) = 337 (100, M+), 322 (7), 308
(12), 281 (17), 280 (27), 266 (8), 135 (48), 107 (5); TOF-HRMS
calcd. for C19H16NO5 (M + H)+ 338.1023, found 338.1015.
1
°C). H NMR (300 MHz, CDCl3) δ: 7.12 (dd, J = 8.1, 1.7 Hz,
1H), 7.05 (s, 2H), 6.85 (d, J = 8.1 Hz, 1H), 6.73 (s, 1H), 6.02 (s,
2H), 5.96 (s, 2H), 3.79 (t, J = 6.2 Hz, 2H), 2.96 (t, J = 6.2 Hz,
2H) ppm; 13C NMR (75 MHz, CDCl3) δ: 153.3, 148.2, 148.1,
148.0, 146.8, 133.4, 127.9, 122.1, 121.4, 118.5, 118.1, 109.0,
108.8, 107.5, 104.4, 101.43, 101.38, 38.4, 29.6 ppm; IR (neat):
νmax = 2923, 1748, 1502, 1480, 1443, 1384, 1258, 1229, 1095,
1069, 1031, 926, 858, 813, 748 cm-1; EI-MS: m/z (relative
intensity) = 351 (100, M+), 322 (17), 295 (54), 294 (62), 265
(18), 176 (16), 161 (22), 149 (67), 147 (12), 133 (10), 121 (29),
89 (13); TOF-HRMS calcd. for C19H13NO6Na (M + Na)+
374.0635, found 374.0645.
4.3.14. 1-(4-fluorophenyl)-5,6-dihydro-3H-
[1,3]dioxolo[4,5-g]oxazolo[4,3-a]isoquinolin-3-
one (4n)
4.3.11. 1-(2-Methoxyphenyl)-5,6-dihydro-3H-
[1,3]dioxolo[4,5-g]oxazolo[4,3-a]isoquinolin-3-
one (4k)
Ynamide 3n (63.0 mg, 0.16 mmol), PIFA (78.0 mg, 0.18
mmol), 4 Å molecular sieve (200 mg) and BF3·OEt2 (41 µL, 1.06
mmol) in dry CH2Cl2 (2 mL) were employed. After usual
workup, the crude product was purified by preparative thin-layer
chromatography (SiO2, hexane:EtOAc; 3:1 + 1% Et3N as eluent)
to obtain 4n (20.4 mg, 38%) as a white solid (m.p. 163-166 °C).
1H-NMR (400 MHz, CDCl3) δ: 7.60 (dd, J = 8.8, 5.3 Hz, 2H),
7.12 (dd, J = 8.6, 8.6 Hz, 2H), 7.00 (s, 1H), 6.75 (s, 1H), 5.97 (s,
2H), 3.80 (t, J = 6.2 Hz, 2H), 2.98 (t, J = 6.2 Hz, 2H) ppm; 13C-
NMR (100 MHz, CDCl3) δ: 162.7 (d, J = 249.7 Hz), 153.2,
148.3, 146.9, 132.6, 128.8 (d, J = 8.3 Hz), 128.1, 124.5 (d, J =
3.5 Hz), 119.1, 117.8, 116.0 (d, J = 22.0 Hz), 109.1, 104.1, 101.4,
38.4, 29.5 ppm; IR (neat): νmax = 2919, 2856, 1752, 1602, 1509,
1481, 1386, 1254, 1230, 1159, 1069, 1037, 934, 839, 820, 749
cm-1; EI-MS: m/z (relative intensity) = 325 (100, M+), 296 (26),
295 (20), 269 (35), 268 (55), 239 (13), 221 (39), 207 (11), 178
(51), 167 (13), 161 (24), 149 (49), 127 (18), 123 (46), 111 (19),
97 (26), 83 (28), 73 (28), 71 (42), 69 (27); TOF-HRMS calcd. for
C18H12FNO4Na (M + Na)+ 348.0643, found 348.0635.
Ynamide 3k (99.0 mg, 0.25 mmol), PIFA (118 mg, 0.28
mmol), 4 Å molecular sieve (200 mg) and BF3·OEt2 (63 µL, 0.50
mmol) in dry CH2Cl2 (3 mL) were employed. After usual
workup, the crude product was purified by preparative thin-layer
chromatography (SiO2, hexane:EtOAc; 1:1 + 1% Et3N as eluent)
to obtain 4k (52.5 mg, 62%) as a white solid (m.p. 186-188 °C).
1H NMR (300 MHz, CDCl3) δ: 7.47 (dd, J = 7.6, 1.8 Hz, 1H),
7.41 (dd, J = 8.2, 1.8 Hz, 1H), 7.05 (dd, J = 7.5, 1.0 Hz, 1H),
6.99 (d, J = 8.7 Hz, 1H), 6.70 (s, 1H), 6.56 (s, 1H), 5.91 (s, 2H),
3.84 (t, J = 6.3 Hz, 2H), 3.76 (s, 3H), 3.00 (t, J = 6.3 Hz, 2H)
ppm; 13C NMR (75 MHz, CDCl3) δ: 157.2, 153.8, 147.6, 146.5,
131.1, 131.0, 130.0, 127.0, 120.8, 120.4, 118.5, 117.3, 111.4,
108.4, 104.9, 101.1, 55.3, 38.2, 29.1 ppm; IR (neat): νmax = 2967,
2916, 1738, 1494, 1465, 1435, 1384, 1285, 1252, 1030, 1020,
934, 882, 763, 750, 741 cm-1; EI-MS: m/z (relative intensity) =
337 (100, M+), 308 (5), 280 (14), 278 (47), 178 (13), 149 (7), 135
(35), 123 (8); TOF-HRMS calcd. for C19H16NO5 (M + H)+
338.1023, found 338.1027.
4.3.15. 8,9, 10-Trimethoxy-1-phenyl-5,6-dihydro-
3H-oxazolo[4,3-a]isoquinolin-3-one (4o)
4.3.12. 1-(3-Methoxyphenyl)-5,6-dihydro-3H-
[1,3]dioxolo[4,5-g]oxazolo[4,3-a]isoquinolin-3-
one (4l)
Ynamide 3o (41.2 mg, 0.10 mmol), PIFA (47.3 mg, 0.11
mmol), 4 Å molecular sieve (200 mg) and BF3·OEt2 (25 µL, 0.20
mmol) in dry CH2Cl2 (3 mL) were employed. The reaction was
Ynamide 3l (93.0 mg, 0.24 mmol), PIFA (111 mg, 0.25
mmol), 4 Å molecular sieve (200 mg) and BF3·OEt2 (59 µL, 0.47
mmol) in dry CH2Cl2 (3 mL) were employed. After usual
workup, the crude product was purified by preparative thin-layer
chromatography (SiO2, hexane:EtOAc; 2:1 + 1% Et3N as eluent)
to obtain 4l (40.8 mg, 51%) as a white solid (m.p. 171-176 °C).
1H NMR (300 MHz, CDCl3) δ: 7.31 (dd, J = 8.0, 7.7 Hz, 1H),
7.22 (d, J = 7.7 Hz, 1H), 7.15 (d, J = 2.3 Hz, 1H), 7.14 (s, 1H),
6.90 (dd, J = 8.1, 2.5 Hz, 1H), 6.73 (s, 1H), 5.96 (s, 2H), 3.81 (s,
3H), 3.79 (t, J = 6.2 Hz, 2H), 2.97 (t, J = 6.2 Hz, 2H) ppm; 13C
NMR (75 MHz, CDCl3) δ: 159.7, 153.2, 148.2, 146.8, 133.4,
129.8, 129.4, 128.2, 119.4, 118.9, 117.9, 115.0, 111.6, 108.9,
104.5, 101.4, 55.3, 38.3, 29.5 ppm; IR (neat): νmax = 2904, 1751,
1598, 1575, 1477, 1429, 1384, 1288, 1260, 1228, 1168, 1034,
926, 864, 792, 749 cm-1; EI-MS: m/z (relative intensity) = 337
(100, M+), 308 (12), 281 (14), 280 (34), 278 (16), 266 (22), 149
(10), 135 (19), 123 (8), 107 (12); TOF-HRMS calcd. for
C19H16NO5 (M + H)+ 338.1023, found 338.1015.
−96 °C for 30 min. After usual workup, the crude
carried out at
product was purified by preparative thin-layer chromatography
(SiO2, hexane:EtOAc; 2:1 + 1% Et3N as eluent) to obtain 4o (7.0
1
mg, 20%) as a white solid (m.p. 81-83 °C). H NMR (300 MHz,
CDCl3) δ: 7.42-7.36 (m, 2H), 7.36-7.28 (m, 3H), 6.62 (s, 1H),
3.92 (s, 3H), 3.82 (s, 3H), 3.79 (t, J = 6.0 Hz, 2H), 3.34 (s, 3H),
2.98 (t, J = 6.0 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ:
154.0, 153.8, 150.7, 141.1, 135.9, 131.0, 129.8, 128.0, 127.3,
127.1, 115.8, 112.1, 107.2, 61.2, 60.0, 56.2, 38.7, 30.7 ppm; IR
(neat): νmax = 2937, 2842, 1752, 1597, 1516, 1464, 1419, 1377,
1240, 1198, 1128, 1024 cm-1; EI-MS: m/z (relative intensity) =
353 (100, M+), 296 (12), 294 (16), 282 (17), 219 (30), 194 (11),
178 (25), 164 (72), 151 (26), 149 (13), 105 (36); TOF-HRMS
calcd. for C20H19NO5Na (M + Na)+ 376.1155, found 376.1163.
4.3.16. 1-(3,4-Dimethoxyphenyl)-8,9, 10-
trimethoxy-5,6-dihydro-3H-oxazolo[4,3-
a]isoquinolin-3-one (4p)

Huerta, J. M.; López, M.; Segarra, V.; Ryder, H.; Palacios, J. M. J.
Med. Chem. 2000, 43, 214.
Ynamide 3p (47.2 mg, 0.10 mmol), PIFA (47.3 mg, 0.11
mmol), 4 Å molecular sieve (200 mg) and BF3·OEt2 (25 µL, 0.20
mmol) in dry CH2Cl2 (3 mL) were employed. After usual
workup, the crude product was purified by preparative thin-layer
chromatography (SiO2, hexane:EtOAc; 1:1 + 1% Et3N as eluent)
to obtain 4p (13.9 mg, 22%) as a pale yellow solid (m.p. 56-57
3. (a) Aichaoui, H.; Jacques, H.; Poupaert, J. H.; Lesieur, D.;
Hénichart, J.-P. Tetrahedron 1991, 47, 6649; (b) Hamad, M. O.;
Kiptoo, P. K.; Stinchcomb, A. L.; Crooks, P. A. Bioorg. Med.
Chem. 2006, 14, 7051; (c) Savarimuthu, S. A.; Thomas, S. A.;
Prakash, D. G.; Gandh, T. ChemistrySelect 2016, 1, 2035.
4. (a) Hashmi, A. S. K.; Salathé, R.; Frey, W. Synlett 2007, 1763; (b)
Istrate, F. M.; Buzas, A. K.; Jurberg, I. D.; Odabachian, Y.;
Gagosz, F. Org. Lett. 2008, 10, 925.
1
°C). H NMR (300 MHz, CDCl3) δ: 6.98 (dd, J = 8.3, 2.0 Hz,
1H), 6.94 (d, J = 2.0 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 6.62 (s,
1H), 3.92 (s, 6H), 3.83 (s, 3H), 3.82 (s, 3H), 3.79 (t, J = 6.0 Hz,
2H), 3.38 (s, 3H), 2.98 (t, J = 6.0 Hz, 2H) ppm; 13C NMR (75
MHz, CDCl3) δ: 153.8, 150.6, 149.0, 147.9, 141.2, 136.0, 131.0,
122.6, 120.2, 114.9, 112.3, 110.6, 110.1, 107.3, 61.2, 60.2, 56.1,
55.9, 38.7, 30.8 ppm; IR (neat): νmax = 2936, 2840, 1750, 1599,
1514, 1464, 1416, 1376, 1320, 1256, 1240, 1173, 1125, 1107,
1063, 1025, 981, 810, 764, 749 cm-1; EI-MS: m/z (relative
intensity) = 413 (98, M+), 398 (12), 368 (7), 356 (12), 354 (14),
342 (19), 311 (11), 219 (23), 207 (28), 194 (28), 178 (24), 167
(27), 165 (100), 149 (50), 137 (31), 127 (25), 111 (27), 97 (44),
85 (31), 83 (40), 71 (58), 69 (70), 57 (79); TOF-HRMS calcd. for
C22H24NO7 (M + H)+ 414.1547, found 414.1541.
5. Lu, Z.; Xu, X.; Yang, Z.; Kong, L.; Zhu, G. Tetrahedron Lett.
2012, 53, 3433.
6. Lu, Z.; Yang, Z.; Cui, W.; Zhu, G. Chem. Lett. 2012, 41, 636.
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Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2010,
110, 5064; (b) Evano, G.; Coste, A.; Jouvin, K. Angew. Chem. Int.
Ed. 2010, 49, 2840; (c) Evano, G.; Jouvin, K.; Coste, A. Synthesis
2013, 45, 17; (d) Wang, X.-N.; Yeom, H.-S.; Fang, L.-C.; He, S.;
Ma, Z.-X.; Kedrowski, B. L.; Hsung, R. P. Acc. Chem. Res. 2014,
47, 560.
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2012, 77, 9871.
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Chem. 2015, 80, 3480; (b) Huang, H.; Zhu, X.; He, G.; Liu, Q.;
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4.3.17. 3-Phenethyl-5-phenyloxazolidine-2,4-
dione (5b)
11. For recent reviews, see: (a) Zhdankin, V. V. ARKIVOC 2009, 1;
(b) Tellitu, I.; Domínguez, E. Synlett 2012, 23, 2165; (c) Kita, Y.;
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Antonchick, A. P. Synlett 2015, 26, 1785; (e) Arnold, A. M.;
Ulmer, A.; Gulder, T. Chem. Eur. J. 2016, 22, 8728; (f) Wang, L.;
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P.; Vita, M. V.; Waser, J. Angew. Chem., Int. Ed. 2016, 55, 4436;
(h) Yoshimura, A.; Zhdankin, V. V. Chem. Rev. 2016, 116, 3328;
(i) Dohi, T.; Kita, Y. Curr. Org. Chem. 2016, 20, 580.
Ynamide 3q (64.3 mg, 0.20 mmol), PIFA (94.6 mg, 0.22
mmol), 4 Å molecular sieve (200 mg) and BF3·OEt2 (30 µL, 0.24
mmol) in dry CH2Cl2 (3 mL) were employed. After usual
workup, the crude product was purified by column
chromatography (SiO2, hexane:EtOAc; 50:1 to 10:1 + 1% Et3N
1
as eluent) to obtain 5b (34.2 mg, 61%) as a yellow oil. H NMR
(300 MHz, CDCl3) δ: 7.42-7.34 (m, 3H), 7.30-7.15 (m, 7H), 5.62
(s, 1H), 3.96-3.77 (m, 2H), 3.02 (t, J = 7.4 Hz, 2H) ppm; 13C
NMR (75 MHz, CDCl3) δ: 171.0, 155.0, 136.7, 131.4, 129.7,
129.0, 128.9, 128.7, 127.0, 126.1, 80.1, 41.2, 33.1 ppm; IR
(neat): νmax = 3031, 2947, 1816, 1738, 1442, 1412, 1338, 1146,
1106, 1010, 760, 698 cm-1; EI-MS: m/z (relative intensity) =
281(0.4, M+), 279 (7), 227 (5), 183 (4), 167 (17), 150 (11), 149
(100), 129 (6), 113 (6), 104 (8), 97 (9), 85 (11), 83 (14), 73 (13),
71 (24), 69 (21), 60 (10), 57 (37); TOF-HRMS calcd. for
C17H15NO3Na (M + Na)+ 304.0944, found 304.0946.
12. (a) Kita, Y.; Yakura, T.; Tohma, H.; Kikuchi, K.; Tamura, Y.
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Morioka, H.; Takizawa, S.; Arisawa, M.; Kita, Y. Tetrahedron
2001, 57, 345; (i) Moreno, I.; Tellitu, I.; SanMartín, R.;
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Tetrahedron Lett. 2002, 43, 9241; (l) Hamamoto, H.; Anilkumar,
G.; Tohma, H.; Kita, Y. Chem. Eur. J. 2002, 8 , 5377; (m)
Hamamoto, H.; Anilkumar, G.; Tohma, H.; Kita, Y. Chem.
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Hamamoto, H.; Shiozaki, Y.; Nambu, H.; Hata, K.; Tohma, H.;
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Acknowledgments
We are deeply appreciative of generous financial support from
the Thailand Research Fund (TRF; TRG5780054 for W.I.),
Chulabhorn Research Institute and Mahidol University.
Appendix A. Supplementary data
Supplementary data related to this article can be found at
http://
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20. For screening of copper salts and bases, see: supplementary
information.
21. It is noteworthy that ynamides 3a-3r were unstable on silica gel,
thus the mixture of 1% Et3N in eluent must be used for
chromatography.
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23. For screening of solvents, see: supplementary information.