Tandem reaction strategy of the Passerini/Wittig reaction based on the in situ capture of isocyanides: One-pot synthesis of heterocycles

Article abstract of DOI:10.1016/j.tet.2019.03.057

This paper reports the tandem reaction strategy of the Passerini/Wittig reaction based on the in situ capture of isocyanides. According to this strategy, plenty of isocyanides have been synthesized, which is immediately used for the tandem reaction of Passerini/Wittig reaction in one pot. Compared to the previous work, this strategy avoids the separation, purification, and storage of isocyanides, which prominently solves the problems of isocyanide-based multicomponent reaction such as: (a) The environmentally unfriendly (strong foul odor), (a) the labile of Isocyanides, (c) high toxicity of isocyanides. In the meantime, in order to expand the application scope of our strategy, 1H-isochromenes and 3H-2-benzoxepin-1-ones have also been synthesized, which undergoes four-step transformations in one-pot. In addition, a relatively credible reaction mechanism has also been proposed, based on a series of control experiments. Furthermore, preliminary testing was performed on biological activity of some obtained compounds; These results showed that the synthesized compounds exhibited certain activity over P. digitatum and P. italicum. 2019 Elsevier Science. All rights reserved.

Full text of DOI:10.1016/j.tet.2019.03.057

Accepted Manuscript
Tandem reaction strategy of the Passerini/Wittig reaction based on the in situ capture
of isocyanides: One-pot synthesis of heterocycles
Ming-Guo Liu, Na Liu, Wen-Heng Xu, Long Wang
PII:
S0040-4020(19)30386-2
https://doi.org/10.1016/j.tet.2019.03.057
TET 30243
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 January 2019
Revised Date: 27 March 2019
Accepted Date: 29 March 2019
Please cite this article as: Liu M-G, Liu N, Xu W-H, Wang L, Tandem reaction strategy of the Passerini/
Wittig reaction based on the in situ capture of isocyanides: One-pot synthesis of heterocycles,
Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.03.057.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Leave this area blank for abstract info.
Tandem Reaction Strategy of the Passerini/Wittig
Reaction Based on the in Situ Capture of
Isocyanides: One-Pot Synthesis of Heterocycles
Ming-Guo Liu, Na Liu, Wen-Heng Xu, Long Wang*
Key laboratory of inorganic nonmetallic crystalline and energy conversion materials, College of Materials and
Chemical Engineering, China Three Gorges University, Yichang, Hubei 443002, China.

ACCEPTED MANUSCRIPT
Tetrahedron
1
TETRAHEDRON
Pergamon
Tandem Reaction Strategy of the Passerini/Wittig Reaction Based
on the in Situ Capture of Isocyanides: One-Pot Synthesis of
Heterocycles
Ming-Guo Liu, Na Liu, Wen-Heng Xu, Long Wang*
Key laboratory of inorganic nonmetallic crystalline and energy conversion materials, College of Materials and Chemical Engineering,
China Three Gorges University, Yichang, Hubei 443002, China.
Abstract—This paper reports the tandem reaction strategy of the Passerini/Wittig reaction based on the in situ capture of isocyanides.
According to this strategy, plenty of isocyanides have been synthesized, which is immediately used for the tandem reaction of
Passerini/Wittig reaction in one pot. Compared to the previous work, this strategy avoids the separation, purification, and storage of
isocyanides, which prominently solves the problems of isocyanide-based multicomponent reaction such as: (a) The environmentally
unfriendly (strong foul odor), (a) the labile of Isocyanides, (c) high toxicity of isocyanides. In the meantime, in order to expand the
application scope of our strategy, 1H-isochromenes and 3H-2-benzoxepin-1-ones have also been synthesized, which undergoes four-step
transformations in one-pot. In addition, a relatively credible reaction mechanism has also been proposed, based on a series of control
experiments. Furthermore, preliminary testing was performed on biological activity of some obtained compounds; These results showed
that the synthesized compounds exhibited certain activity over P. digitatum and P. italicum. © 2019 Elsevier Science. All rights reserved
Keywords: Isocyanides; in situ capture; tandem reaction; heterocycles
a) Passerini reaction
R3
O
H
1
2
3
N
R -NC
R -COOH
R -CHO
R2
R1
1
. Introduction
O
O
b) Passerini/post-modification tandem reaction
In recent years, people have attached increasing
importance to isocyanide-based reactions, and a series of
X
1
2
3
R -NC
R -COOH
R -CHO
1
O
R
c) This work: in-situ capture of isocyanides based on Passerini/Wittig reaction
original symbolic achievements have been reported in
2
PR3Br
succession. Isocyanide-based multicomponent reactions
R2
O
O
have got extensive concern in the field of organic synthesis
due to its high reaction efficiency, wide range of substrates,
and the avoidance of intermediate separation losses and
or
OH
R3 COCHO or COOH
C
PPh3, C2Cl6, r.t.
H
R1 NC
R1 NHCHO
O
R
NEt(i-Pr)2, CH2Cl2
3
tedious processes. The Passerini reaction is a one pot
environmentally friendly
non-toxic isocyanides chemistry
undecomposed of isocyanides
one-pot synthesis heterocycles
three-component reaction for preparation of α-acyloxy
acidamide involving aldehyde and ketone, carboxylic acid
and isocyanide(Scheme 1a). Lots of diverse compounds in
complex structures are synthesized directly and efficiently
from simple and readily available materials through
advance protection or reservation of functional group on a
certain component and the linkage with postmodification
Scheme 1. The tandem reaction strategy of Passerini/Wittig
reaction based on the in situ capture of isocyanides.
In recent, a new strategy, via based on the in situ capture
of isocyanides, has been reported in succession. According
to this strategy, the in situ generation of isocyanides from
its precursor could solve some problems such as separation,
purification, the smell of exposure, decomposition.This
may dramatically overcome the drawbacks of isocyanide
4
reaction(Scheme 1b). This tandem reaction which based
on the Passerini reaction and its postmodification reaction
has, which exhibits a series of excellent achievements in
5
6
succession. However, this cascade reactions is barely used
chemistry. For example, Parsons et al. reported
in production practices at present, because: 1) The
environmentally unfriendly (strong foul odor), 2) the labile
of Isocyanides, and 3) high toxicity of isocyanides.
multicomponent cascade reaction based on the in situ
capture of isocyanides in 2005. This strategy was
developed to prepare isocyanides in situ through the ring
6a
opening of epoxide. In 2009, Kaim et al. reported the Ugi
reaction based on the in situ capture of isocyanides. This
strategy prepared isocyanides in situ from benzyl chloride,
6b-6d
silver cyanide and potassium cyanide.
In 2013, Kim et

ACCEPTED MANUSCRIPT
2
Tetrahedron
al. reported an integrated microfluid-based Passerini
6e
reaction. According to this strategy, isocyanides were
produced in situ within an integrated microfluidic system.
In 2015, Domling et al. reported the attainment of a
multicomponent reaction based on the in situ capture of
isocyanides with formamide, ketone, aldehyde and other
o
b
Entry
1
2
Solvent
THF
THF
Base
NaOH
K CO3
2
T[ C]
5a[%]
NR
13
6
f
60
60
oxygenated compounds as precursors.
3
4
5
6
7
8
9
10
11
THF
THF
THF
MeOH
Toluene
NEt3
NEt(i-Pr)2
DABCO
NEt(i-Pr)2
NEt(i-Pr)2
NEt(i-Pr)2
60
60
60
60
60
60
110
r.t.
110
110
16
23
11
NR
51
12
61
trace
NR
NR
The Wittig reaction is an all-important reaction for
preparation of carbon-carbon double bonds by the reaction
of phosphorus ylide and reactive carbonyl. This reaction is
characterized by simplicity of operation, mild conditions,
7
fewer side reactions, and high yield, etc. The Wittig
CH Cl2
reaction can be used to prepare five-member, six-member,
2
8
seven-member and macrocyclic heterocyclic compounds.
Toluene
NEt(i-Pr)
NEt(i-Pr)
--
2
2
The tandem reactions of isocyanide-based multicomponent
reaction and the Wittig reaction has been extensively used
Toluene
Toluene
Toluene
9
c
for organic synthesis, pharmaceutical synthesis, etc.
12
NEt(i-Pr)2
a
Conditions: 1a (1 mmol), PPh (1.5 mmol), C Cl (1.5
3
2
6
Isochromenes are very important category of compounds
that exhibit favorable biological activities. Additionally,
isochromenes are basic skeletons for some natural products,
sensors and biological active compounds. Thus, their
mmol), CH Cl (10 ml), base (3.0 mmol), air, 3a (1.1
2 2
mmol), 4a (1.1 mmol) and then solvent (10 ml), base
b
c
(
1.1mmol). Yields based on 1a. C Cl was replaced with
2 6
I .
2
1
0
synthesis methods have received certain attention. To the
best of our knowledge, however, no tandem reaction of in
situ capture of isocyanides based Passerini/Wittig reaction
The reaction substrate was expanded under the optimal
reaction conditions. It was found that the reaction exhibited
good universality for various substrates while the electronic
effects and steric effects of substrate functional groups did
not significantly affect the reaction(Scheme 2). Various
substituted phenyl carboxylic acids and aromatic
heterocyclic carboxylic acids can be transformed into target
compounds with good yields. Meanwhile, target
compounds can also be obtained with relatively moderate
yields for aliphatic carboxylic acids, such as formic acid
and acetic acid. The yield of 46-65% is the total yield of the
four-steps transformations, which was count on amide 1,
11
has been reported so far. Based on our previous studies,
we developed a tandem reaction strategy based on the in
situ capture of isocyanides of the Passerini/Wittig reaction
and a series of 1H-Isochromene and 3H-2-benzoxepin-1-
ones were synthesized by using the tandem-reaction.
2
. Results and Discussion
According to the literatures, we found that amide 1a was
while the yield of 68-89% was based on phosphonium salt
easily prepared from cyclohexanone and formamide with
[11a]
3
in the literature,
which was very different from this
[6f]
high yield. Therefore, amide 1a, phosphonium salts 3a
and parachlorobenzoic acid 4a were used as model
substrates to explore the reaction conditions.First, target
manuscript.
o
compound 5a was not obtained at 60 C by using THF and
NaOH as the solvent and base, respectively. To our surprise,
target compound 5a was obtained with a yield of 13% only
needed to change the base from NaOH to K CO to K CO .
2
3
2
3
Further optimization of the base showed that the yield was
3% when the base was diisopropylethylamine. Afterward,
2
the solvent was optimized, and it was found that the yield
was 51% when the solvent was changed to toluene.
However, the reaction could not be carried out when the
solvent was changed from THF to methanol. The reaction
temperature was further screened and it was found that
increasing the temperature was beneficial to the reaction.
o
Therefore, 110 C was found to be the most suitable
temperature for the reaction. It is also important to note that
the reaction cannot occur without base. However, when
C Cl was substituted by I , no target compound 4a was
2
6
2
1
2
obtained.
a
Table 1. Optimization of the reaction conditions.

ACCEPTED MANUSCRIPT
Tetrahedron
3
Cl
Cl
O
O
O
O
N
H
O
N
H
O
N
H
5a, 61%
5b, 61%
5c, 62%
NO2
O
O
O
O
N
H
O
N
H
O
N
H
5d, 59%
5e, 65%
5f, 53%
I
O
O
O
O
O
N
H
O
N
H
O
N
H
5
h, 60%
Scheme 3. Preparation of 3H‑ 2-benzoxepin-1-ones 8 by
5
g, 51%
5i, 51%
the tandem reaction.
Cl
O
O
O
O
N
H
j, 55%
O
N
O
N
H
After expanding the reaction substrate, we probed into
the reaction mechanism by condition control experiments.
The isocyanide 2c was obtained from amide 1c with the
yield of 93% under the action of C Cl , PPh and NEt(i-Pr)
2
H
5
5k, 46%
5l, 56%
NO2
S
2
6
3
(
Scheme 4a). The Passerini reaction between isocyanide 2c,
phosphonium salts 6c and 4-chlorophenylglyoxal 7c in
CH Cl at room temperature afforded intermediate 9c with
the yield of 98% (Scheme 4b). Under the action of NEt(i-
Pr) , intermediate 9c generated target compound 8c with
O
O
F
O
O
N
H
O
N
H
O
N
2
2
H
5
m, 51%
5n, 53%
5o, 57%
Scheme 2. Preparation of 1H-isochromenes 5 by the
tandem reaction. Condotions: 1 (1 mmol), PPh3 (1.5
2
a
7
9% yield (Scheme 4c). The isocyanide 2c reacted with
phosphonium salt 6c and 4-chlorophenylglyoxal 7c in
CH Cl at room temperature, providing target compound 8c
mmol), C Cl (1.5 mmol), CH Cl (10 ml), NEt(i-Pr) (3.0
2
6
2
2
2
2
2
mmol), air, r.t., 3 (1.1 mmol), 4 (1.1 mmol) and then
toluene (10 ml), NEt(i-Pr) (1.2 mmol), 110 C. Yields
based on 1.
o
b
at a yield of 77% (Scheme 4d). However, it should be noted
that no target compound was obtained when no additional
2
NEt(i-Pr) was added into the last step of the tandem
2
reaction (Scheme 4e).
Meanwhile, in order to further expand the application
scope of our strategy, we also synthesized the known 3H-2-
Benzoxepin-1-ones by using this strategy. 3H-2-
Benzoxepin-1-ones are also an important category of
heterocycles which serves as the basic skeleton of some
1
3
important bioactive molecules and sensors. Therefore, a
series of 3H-2-benzoxepin-1-ones were synthesized using
the “one-pot” method based on the tandem-reaction
strategy of Passerini/Wittig reaction based on the in-situ
capture of isocyanides(Scheme 3). It was found that the
reaction exhibited good universality for substrate: Various
substrate were favorably converted into products even
when
butylformamide was used as substrate. The yield of 57-
1% also is the total yield of the four-steps transformations,
which is based on amide 1. However, no target compound
h and 8i were obtained when N-phenylformamide was
used as substrate.
N-primary-alkylformamide
such
as
N-n-
7
8

ACCEPTED MANUSCRIPT
4
Tetrahedron
Scheme 6. The synthesis of 3-(4-chlorophenyl)-N-
cyclohexyl-1H-isochromene-1-carboxamide in large scale.
At the same time, we also tested the bactericidal
activity of some synthetic compounds against Fusarium
graminearum, Magnaporthe oryzae, Penicillium digitatum,
Penicillium italicum, and Rhizoctonia solani with
triadmefon as the positive control (Table 2). The test
showed that the compounds had antibacterial activity
against P. digitatum and P. italicum. The compound 8c
exhibited an inhibition ratio of ≤ 81% against P. digitatum,
≤
79% against P. italicum, which was close to the inhibition
ratio of positive control agent Triadmefon. According to
the summary of the inhibition ratio and the structure-
activity relationship of the compound, the antibacterial
activity is higher when the substituent contains chlorine and
nitro substituent groups, such as 5d and 8c.
Scheme 4. Control experiments and mechanism
investigation.
On the base of the results of the controlled experiment,
Table 2. Fungicidal activities of compounds against five
kinds of fungus.
we proposed a possible reaction mechanism(Scheme 5).
First, hexachloroethane reacted with triphenylphosphine to
produced phosphonium salt 10; then phosphonium salt 10
Inhibition rate /(%)
P.
P.
F.
M.
oryzae
R.
solani
removed H O from amide 1 to get isocyanide 2 in situ;
Compd.
2
digitatum italicum
graminearum
Phosphonium salt 6 and phenylglyoxal 7 captured
isocyanide 2 produced intermediate 9 through Passerini
reaction; A molecule of HBr was removed by NEt(i-Pr)2
from intermediate 9 to get phosphine ylide 11; Phosphine
ylide 11 generated the target compound 8 through
intramolecular Wittig reaction in the heating condition.
5a
45
37
11
26
21
5
5
b
c
21
56
63
35
0
38
33
21
81
35
42
95
22
45
61
29
15
35
26
0
79
28
33
91
0
0
0
36
0
0
0
15
20
0
0
0
0
0
42
0
13
55
27
55
14
0
15
21
17
66
21
55
81
5d
5
5
g
j
R3
5k
0
0
COOH
8
a
R1 NHCHO Cl HNEt(i-Pr)2
PPh3Br
6
O
O
C2Cl6
O
1
H
8b
8c
8e
8f
11
48
19
11
72
N
PPh3
Cl2PPh3
R1
NC
R1
O
10
2
H2O
R3
COCHO
7
NEt(i-Pr)2
9
PPh3Br
NEt(i-Pr)2
triadmefon
Br HNEt(i-Pr)2
R1
O
3
.Conclusion
HN R1
O
O
O
NH
R3
O
heat
O
In summary, a novel tandem reaction strategy of the
Passerini/Wittig reaction based on the in situ capture of
isocyanides has been reported and two types of compounds
have been synthesized by using the strategy. This strategy
avoids the separation, purification, and storage of
isocyanides, which prominently solves the problems of
isocyanide-based multicomponent reaction such as: 1) The
environmentally unfriendly (strong foul odor), 2) the labile
of Isocyanides, 3) high toxicity of isocyanides. A series of
O
8
OPPh3
PPh3
11
R3
Scheme 5. The proposed possible mechanism.
In addition, we conducted a scale-up test to determine
the applicability of this strategy we developed. 5.74g of 5a
was synthesized with high yield through this tandem
reaction (Scheme 6).
1
H-isochromenes and 3H-2-benzoxepin-1-ones are
synthesized by using the one-pot process. Meanwhile,
preliminary testing was performed on biological activity of
some compounds; the test showed that the synthesized
compounds exhibited certain activity against P. digitatum
and P. italicum. Furthermore, we proposed a possible

ACCEPTED MANUSCRIPT
Tetrahedron
5
1
1a
1
mechanism of the present reaction through verification
based on a series of experiments under controlled
conditions.
lit 126–127 °C; H NMR (CDCl , 600 MHz) δ (ppm)
3
7.66 (d, J = 8.4 Hz, 2H, Ar-H), 7.39 (t, J = 7.8 Hz, 3H, Ar-
H), 7.30-7.23 (m, 2H, Ar-H), 7.10 (d, J = 7.2 Hz, 1H, Ar-
H), 6.48 (s, 1H, =CH), 6.28 (s, 1H, NH), 5.49 (s, 1H, CH),
.33 (s, 9H, 3CH ); C NMR (CDCl , 150 MHz) δ (ppm)
67.7, 149.9, 134.9, 132.0, 129.9, 128.8, 128.7, 127.4,
26.6, 125.9, 125.1, 124.2, 124.0, 101.5, 77.9, 51.3, 28.6.
13
1
1
1
3
3
4
. Experimental
4
.1 General
1
4.2.4 N-(tert-butyl)-3-(4-nitrophenyl)-1H-isochromene-1-
All the obtained products were characterized H NMR
1
3
carboxamide (5d). White solid, yield 59%, mp 166–167 °C,
spectra and C NMR spectra (400 MHz or 600 MHz).
Chemical shifts were reported in parts per million (ppm, δ)
downfield from tetramethylsilane. Proton coupling patterns
are described as singlet (s), doublet (d), triplet (t), multiplet
11a
1
lit 167–168 °C; H NMR (CDCl , 600 MHz) δ (ppm)
3
8
.26 (d, J = 8.4 Hz, 2H, Ar-H), 7.89 (d, J = 8.4 Hz, 2H, Ar-
H), 7.42 (d, J = 7.2 Hz, 1H, Ar-H), 7.39-7.28 (m, 2H, Ar-
H), 7.18 (d, J = 6.6 Hz, 1H, Ar-H), 6.70 (s, 1H, =CH), 6.23
(
m);
13
(
s, 1H, NH), 5.55 (s, 1H, CH), 1.36 (s, 9H, 3CH3);
C
NMR (CDCl , 150 MHz) δ (ppm) 167.3, 148.7, 147.5,
3
4
4
.2 Typical procedure for the synthesis of 5
.2.1 3-(4-chlorophenyl)-N-cyclohexyl-1H-isochromene-1-
1
39.5, 129.3, 129.0, 128.4, 126.9, 125.1, 125.0, 124.9,
24.8, 123.9, 123.8, 105.7, 77.9, 51.4, 28.6.
1
carboxamide (5a)
A mixture of PPh (378 mg,1.5 mmol) and C Cl (355 mg,
4.2.5
N-(tert-butyl)-3-(p-tolyl)-1H-isochromene-1-
3
2
6
1
.5 mmol) in CH Cl (10 mL) was stirred at room
carboxamide (5e). White solid, yield 65%, mp 84–86 °C,
2 2
11a
1
temperature under air condition for 1 h. Subsequently,
lit 86–87 °C; H NMR (CDCl , 600 MHz) δ (ppm) 7.62
3
NEt(i-Pr) (387 mg, 3 mmol) and 1a (127 mg, 1 mmol)
(d, J = 7.8 Hz, 2H, Ar-H), 7.39 (t, J = 7.2 Hz, 1H, Ar-H),
7.27-7.19 (m, 4H, Ar-H), 7.08 (d, J = 7.2 Hz, 1H, Ar-H),
6.45 (s, 1H, =CH), 6.39 (s, 1H, NH), 5.48 (s, 1H, CH), 2.37
2
were added. The mixture was stirred for 2 h and then 3a
(
439 mg, 1.1 mmol) and 4a (172 mg, 1.1 mmol) were
13
added and stirred for another 12 h. After the reaction was
completed, the solvent of CH Cl (10 mL) was changed to
(s, 3H, CH ), 1.32 (s, 9H, 3CH ); C NMR (CDCl , 150
3 3 3
2
2
MHz) δ (ppm) 168.0, 151.0, 139.2, 130.7, 130.3, 129.2,
128.6, 126.8, 126.5, 125.2, 124.5, 123.9, 101.3, 77.8, 51.2,
28.6, 21.3.
toluene (10 mL) and NEt(i-Pr) (142 mg, 1.1 mmol) was
2
o
added and stirred at 110 C for another 2 h. After removing
the solvent under reduced pressure, the resulting crude was
purified by column chromatography with petroleum
ether/ethyl acetate (10:1, v/v) as eluent to give 5a. White
4.2.6
N-(tert-butyl)-3-(o-tolyl)-1H-isochromene-1-
11a
carboxamide (5f). Light yellow oil, yield 53%, lit light
yellow oil; H NMR (CDCl , 600 MHz) δ (ppm) 7.45 (t, J
= 5.4 Hz, 2H, Ar-H), 7.33-7.21 (m, 5H, Ar-H), 7.10 (d, J =
5.4 Hz, 1H, Ar-H), 6.34 (s, 1H, =CH), 6.12 (s, 1H, NH),
5.48 (s, 1H, CH), 2.50 (s, 3H, CH ), 1.36 (s, 9H, 3CH ); C
NMR (CDCl , 150 MHz) δ (ppm) 167.7, 153.5, 136.7,
134.5, 130.9, 130.7, 128.9, 128.8, 128.6, 127.2, 126.3,
125.8, 124.6, 123.9, 106.3, 77.9, 51.3, 28.7, 20.9.
1
1a
1
1
solid, yield 65%, mp 194–196 °C, lit 196–197 °C; H
3
NMR (CDCl , 600 MHz) δ (ppm) 7.66 (d, J = 8.4 Hz, 2H,
3
Ar-H), 7.39 (t, J = 8.4 Hz, 3H, Ar-H), 7.28-7.22 (m, 2H,
Ar-H), 7.11 (d, J = 7.2 Hz, 1H, Ar-H), 6.48 (s, 1H, =CH),
1
3
3
3
6
7
.30 (d, J = 7.2Hz, 1H, NH), 5.59 (s, 1H, CH), 3.85 (d, J =
3
.8 Hz, 1H, CH), 1.93 (d, J = 9.6 Hz, 1H, 0.5 CH ), 1.80 (t,
2
J = 9.6 Hz, 1H, 0.5 CH ), 1.64 (d, J = 9.6 Hz, 1H, 0.5 CH ),
2
2
1
1
.57 (t, J =9.6 Hz, 2H, CH ), 1.40-1.27 (m, 2H, CH ), 1.23-
2 2
13
.11 (m, 2H, CH ), 1.09-1.01 (m, 1H, 0.5 CH ); C NMR
4.2.7 N-(tert-butyl)-3-(2-iodophenyl)-1H-isochromene-1-
2
2
(
CDCl , 150 MHz) δ (ppm) 167.5, 150.1, 134.9, 131.9,
carboxamide (5g). White solid, yield 51%, mp 74–76 °C,
3
11a
1
1
1
30.0, 128.9, 128.7, 127.4, 126.4, 125.9, 125.1, 124.2,
02.4, 77.9, 47.8, 32.7, 25.3, 24.5.
lit 73–75 °C; H NMR (CDCl , 600 MHz) δ (ppm) 7.94
3
(d, J = 8.4 Hz, 1H, Ar-H), 7.52 (d, J = 7.2 Hz, 1H, Ar-H),
7
.47 (d, J = 7.2 Hz, 1H, Ar-H), 7.40 (t, J = 7.8 Hz, 1H, Ar-
4
.2.2
N-cyclohexyl-3-(p-tolyl)-1H-isochromene-1-
H), 7.31-7.26 (m, 2H, Ar-H), 7.13-7.07 (m, 2H, Ar-H),
6.47 (s, 1H, =CH), 6.17 (s, 1H, NH), 5.64 (s, 1H, CH), 1.41
(s, 9H, 3CH ); C NMR (CDCl , 150 MHz) δ (ppm) 167.1,
153.6, 140.1, 139.7, 130.5, 130.4, 130.3, 128.6, 128.5,
128.1, 127.7, 126.4, 124.1, 123.9, 106.6, 96.2, 78.0, 51.3,
28.5.
carboxamide (5b). White solid, yield 61%, mp 167–169 °C,
lit 168–169 °C; H NMR (CDCl , 600 MHz) δ (ppm)
7
H), 7.28-7.20 (m, 4H, Ar-H), 7.10 (d, J = 7.2 Hz, 1H, Ar-
H), 6.46 (s, 1H, =CH), 6.41 (d, J = 7.2Hz, 1H, NH), 5.59 (s,
1
1a
1
13
3
3
3
.63 (d, J = 7.8 Hz, 2H, Ar-H), 7.41 (d, J = 7.2 Hz, 1H, Ar-
1
9
1
1
H, CH), 3.85 (s, 1H, CH), 2.40 (s, 3H, CH ), 1.95 (d, J =
.0 Hz, 1H, 0.5 CH ), 1.81 (d, J = 7.2 Hz, 1H, 0.5 CH ),
.65-1.57 (m, 3H, CH , 0.5 CH ), 1.38-1.28 (m, 2H, CH ),
.20-1.11 (m, 2H, CH ), 1.07-1.03 (m, 1H, 0.5 CH );
3
2
2
4.2.8
N-cyclohexyl-3-phenyl-1H-isochromene-1-
2
2
2
carboxamide (5h). White solid, yield 60%, mp 144–145 °C,
lit 144–146 °C; H NMR (CDCl , 600 MHz) δ (ppm)
7.73 (d, J = 7.2 Hz, 2H, Ar-H), 7.45-7.35 (m, 4H, Ar-H),
7.29-7.21 (m, 2H, Ar-H), 7.10 (d, J = 7.2 Hz, 1H, Ar-H),
6.50 (s, 1H, =CH), 6.40 (d, J = 7.2 Hz, 1H, NH), 5.60 (s,
1
3
11a
1
C
2
2
3
NMR (CDCl , 150 MHz) δ (ppm) 167.9, 151.2, 139.4,
3
1
1
30.7, 130.5, 129.3, 128.7, 127.0, 126.4, 125.0, 124.7,
23.9, 101.2, 77.8, 47.9, 32.7, 25.4, 24.5, 21.4.
1
H, CH), 3.86 (s, J = 8.4 Hz, 1H,H, CH), 1.96-1.78 (m, 2H,
4
.2.3 N-(tert-butyl)-3-(4-chlorophenyl)-1H-isochromene-1-
CH ), 1.66-1.51 (m, 3H, 1.5 CH ), 1.39-1.11 (m, 5H, 2.5
CH ); C NMR (CDCl , 150 MHz) δ (ppm) 167.7, 151.0,
2 3
2
2
13
carboxamide (5c). White solid, yield 62%, mp 124–125 °C,

ACCEPTED MANUSCRIPT
6
Tetrahedron
1
1
33.4, 130.3, 129.1, 128.7, 128.6, 127.1, 126.4, 125.0,
24.7, 124.1, 101.0, 77.8, 47.8, 32.7, 25.3, 24.4.
128.7, 127.9, 126.9, 126.4, 126.1, 125.7, 124.3, 123.8,
101.2, 77.8, 51.4, 28.6.
4
.2.9
N-(tert-butyl)-3-(furan-2-yl)-1H-isochromene-1-
4.2.15 N-(tert-butyl)-3-(2-fluorophenyl)-1H-isochromene-
carboxamide (5i). White solid, yield 51%, mp 96–97 °C,
1-carboxamide (5o). White solid, yield 57%, mp 88–89 °C,
1
1a
1
11a
1
lit 98–99 °C; H NMR (CDCl , 600 MHz) δ (ppm) 7.49–
lit 87–88 °C; H NMR (CDCl , 600 MHz) δ (ppm) 7.72
3
3
7
.05 (m, 5H, Ar–H), 6.63–6.46 (m, 2H, Ar–H), 6.45 (s, 1H,
(t, J = 7.2 Hz, 1H, Ar-H), 7.41 (d, J = 7.2 Hz, 1H, Ar-H),
7.36-7.18 (m, 4H, Ar-H), 7.12 (d, J = 7.2 Hz, 2H, Ar-H),
6.64 (s, 1H, =CH), 6.46 (s, 1H, NH), 5.51 (s, 1H, CH), 1.35
NH), 6.42 (s, 1H,=CH), 5.46 (s, 1H, CH), 1.33 (s, 9H,
1
3
3
1
1
CH3); C NMR (CDCl , 150 MHz) δ (ppm) 167.7, 148.6,
3
13
43.3, 143.1, 129.3, 128.7, 127.1, 126.7, 125.9, 124.1,
11.5, 108.0, 101.3, 77.5, 51.3, 28.5.
(s, 9H, 3CH ); C NMR (CDCl , 150 MHz) δ (ppm) 167.8,
3
3
160.9, 159.3, 146.3, 130.2, 129.9, 128.7, 127.9, 127.5,
26.6, 125.2, 124.5, 124.4, 121.9, 116.3, 107.4, 77.7, 51.3,
1
4
.2.10
N-(tert-butyl)-3-methyl-1H-isochromene-1-
28.6.
11a
carboxamide (5j). Light yellow oil, yield 55%, lit light
yellow oil; H NMR (CDCl , 600 MHz) δ (ppm) 7.32 (d, J
1
3
4.3 Typical procedure for the synthesis of 8
=
7.2 Hz, 1H, Ar-H), 7.21 (t, J = 7.2 Hz, 1H, Ar-H), 7.16 (d,
J = 7.2 Hz, 1H, Ar-H), 6.92 (d, J = 7.2 Hz, 1H, Ar-H), 6.29
4.3.1
4-(4-chlorophenyl)-N-cyclohexyl-1-oxo-1,3-
(
3
s, 1H, NH), 5.70 (s, 1H, =CH), 5.32 (s, 1H, CH), 1.99 (s,
dihydrobenzo[c]oxepine-3-carboxamide (8a).
A mixture of PPh (378 mg,1.5 mmol) and C Cl (355 mg,
1
3
H, CH ), 1.39 (s, 9H, 3CH ); C NMR (CDCl , 150 MHz)
3 3 3
3
2
6
δ (ppm) 168.1, 151.9, 130.4, 128.6, 126.3, 125.4, 124.9,
1
.5 mmol) in CH Cl2 (10 mL) was stirred at room
2
1
22.6, 102.7, 77.7, 51.2, 28.6, 19.6.
temperature under air condition for 1 h. Subsequently,
NEt(i-Pr) (387 mg, 3 mmol) and 1a (127 mg, 1 mmol)
were added. The mixture was stirred for 2 h and then 6a
2
4
.2.11 N-(tert-butyl)-3-(chloromethyl)-1H-isochromene-1-
carboxamide (5k). White solid, yield 46%, mp 122–124 °C,
lit 124–125 °C; H NMR (CDCl , 600 MHz) δ (ppm)
7
7
(
525 mg, 1.1 mmol) and 7a (185 mg, 1.1 mmol) were
1
1a
1
3
added and stirred for another 12 h. After the reaction was
completed, the solvent of CH Cl (10 mL) was changed to
.36 (d, J = 6.0 Hz, 1H, Ar-H), 7.26-7.18 (m, 2H, Ar-H),
.00-6.92 (m, 1H, Ar-H), 6.86 (s, 1H, NH), 5.91 (s, 1H,
2
2
toluene (10 mL) and NEt(i-Pr) (142 mg, 1.1 mmol) was
2
o
=
CH), 5.53 (s, 1H, CH), 4.29-4.10 (m, 2H, CH ), 1.37 (s,
2
added and stirred at 110 C for another 3 h. After removing
1
3
9
1
5
H, 3CH3); C NMR (CDCl , 150 MHz) δ (ppm) 167.9,
3
the solvent under reduced pressure, the resulting crude was
purified by column chromatography with petroleum
ether/ethyl acetate (10:1, v/v) as eluent to give 8a. White
47.8, 128.7, 128.0, 127.8, 126.9, 126.0, 124.1, 105.0, 77.6,
1.8, 44.3 28.7.
11b
1
solid, yield 69%, mp 206–207 °C, lit 209–212 °C; H
4
.2.12 N-(tert-butyl)-1H-isochromene-1-carboxamide (5l).
NMR (CDCl , 600 MHz) δ (ppm) 7.92 (d, J = 7.8 Hz, 1H,
3
1
1a
1
White solid, yield 56%, mp 55–56 °C, lit 58–60 °C; H
NMR (CDCl , 600 MHz) δ (ppm) 7.36 (d, J = 7.2 Hz, 1H,
Ar-H), 7.58 (t, J = 7.2 Hz, 1H, Ar-H), 7.45-7.38 (m, 2H,
Ar-H), 7.34 (d, J = 8.4 Hz, 1H, Ar-H), 7.29 (d, J = 8.4 Hz,
3
Ar-H), 7.23-7.17 (m, 2H, Ar-H), 6.96 (d, J = 7.2 Hz, 1H,
Ar-H), 6.57 (d, J = 6.0 Hz, 1H, =CH), 6.31 (s, 1H, NH),
5
9
1
5
2
H, Ar-H), 7.24 (d, J = 7.8 Hz, 2H, Ar-H), 6.08 (s, 1H,
CH), 5.62 (d, J = 7.2 Hz, 1H, NH), 3.78-3.66 (m, 1H, CH),
.86 (d, J = 6.6 Hz, 1H, =CH)), 5.34 (s, 1H, CH), 1.38 (s,
1
.88-1.60 (m, 5H, 2.5CH ), 1.45-0.82 (m, 5H, 2.5CH );
2 2
1
3
1
3
H, 3CH3); C NMR (CDCl , 150 MHz) δ (ppm) 167.7,
3
CNMR (CDCl , 150 MHz) δ (ppm) 168.5, 164.8, 139.4,
3
43.0, 128.8, 128.6, 127.2, 126.5, 125.0, 123.3, 106.6, 77.3,
1.2, 28.7.
1
1
2
35.7, 134.3, 134.0, 132.9, 132.6, 132.3, 131.1, 129.8,
29.5, 128.6, 128.4, 127.4, 127.3, 74.5, 48.6, 32.7, 25.2,
4.7.
4
.2.13 N-cyclohexyl-3-(4-nitrophenyl)-1H-isochromene-1-
carboxamide (5m). White solid, yield 51%, mp 205–207 °C,
4
.3.2
N-cyclohexyl-1-oxo-4-(p-tolyl)-1,3-
1
1a
1
lit 207–208 °C; H NMR (CDCl , 600 MHz) δ (ppm)
3
dihydrobenzo[c]oxepine-3-carboxamide (8b). White solid,
11b 1
8
.30 (q, J = 8.4 Hz, 2H, Ar-H), 7.91 (q, J = 8.4 Hz, 2H, Ar-
yield 63%, mp 125–127 °C, lit 128–130 °C; H NMR
CDCl , 600 MHz) δ (ppm) 7.97 (d, J = 7.8 Hz, 1H, Ar-H),
H), 7.52-7.40 (m, 1H, Ar-H), 7.38-7.28 (m, 2H, Ar-H),
(
7
7
3
7
6
3
.24-7.16 (m, 1H, Ar-H), 6.71 (t, J = 7.2 Hz, 1H, =C-H),
.24 (d, J = 9.6 Hz, 1H, NH), 5.67 (t, J = 7.2 Hz, 1H, CH),
.58 (d, J = 7.8 Hz, 2H, Ar-H), 7.48-7.40 (m, 2H, Ar-H),
.28 (d, J = 8.4 Hz, 2H, Ar-H), 7.13 (d, J = 8.4 Hz, 2H, Ar-
.88 (d, J = 10.2 Hz, 1H, CH), 2.04-1.06 (m, 10H, 5CH2);
H), 6.04 (s, 1H, CH), 5.39 (d, J = 6.0 Hz, 1H, NH), 3.67 (d,
J = 9.0 Hz, 1H, CH), 2.31 (s, 3H, CH ), 1.96-1.77 (m, 2H,
CH ), 1.54 (d, J = 6.6 Hz, 3H, 1.5CH ), 1.22-0.93 (m, 5H,
2
1
1
1
3
C NMR (CDCl , 150 MHz) δ (ppm) 167.2, 148.9, 147.6,
3
3
1
1
39.5, 129.4, 129.0, 128.5, 126.7, 125.2, 125.0, 124.8,
23.9, 105.7, 77.9, 48.1, 32.8, 25.3, 24.5.
2
2
13
.5CH ); CNMR (CDCl , 150 MHz) δ (ppm) 168.8, 164.4,
39.6, 138.2, 136.9, 133.4, 132.6, 132.4, 132.3, 131.3,
29.9, 129.4, 129.3, 125.8, 75.0, 48.5, 32.3, 25.3, 24.6, 21.0.
2
3
4
.2.14 N-(tert-butyl)-3-(thiophen-2-yl)-1H-isochromene-1-
carboxamide (5n). White solid, yield 53%, mp 105–108 °C,
1
1a
1
lit 107–108 °C; H NMR (CDCl , 600 MHz) δ (ppm)
3
4.3.3
N-(tert-butyl)-4-(4-chlorophenyl)-1-oxo-1,3-
7
=
.42-7.03 (m, 7H, Ar-H), 6.46 (s, 1H, NH), 6.38 (s, 1H,
CH), 5.50 (s, 1H, CH), 1.35 (s, 9H, 3CH3); C NMR
dihydrobenzo[c]oxepine-3-carboxamide (8c). White solid,
yield 71%, mp 160–162 °C, lit 163–164 °C; H NMR
(CDCl , 600 MHz) δ (ppm) 7.96 (d, J = 7.8 Hz, 1H, Ar-H),
13
11b
1
(
CDCl , 150 MHz) δ (ppm) 167.7, 146.5, 137.8, 129.7,
3
3

ACCEPTED MANUSCRIPT
Tetrahedron
7
7
7
.58 (t, J = 7.2 Hz, 1H, Ar-H), 7.48-7.42 (m, 2H, Ar-H),
.38 (d, J = 7.8 Hz, 1H, Ar-H), 7.33 (d, J = 8.4 Hz, 2H, Ar-
triphenylphosphonium bromide (9c).
A mixture of isocyanide 2c (125 mg, 1.5 mmol),
phosphonium salts 6c (477 mg, 1.0 mmol) and 4-
chlorophenylglyoxal 7c (218 mg, 1.3 mmol) in CH Cl (10
H), 7.29 (d, J = 8.4 Hz, 2H, Ar-H), 6.02 (s, 1H, CH), 5.38
1
3
(
s, 1H, NH), 1.22 (s, 9H, 3CH3); C NMR (CDCl , 150
3
2
2
MHz) δ (ppm) 168.4, 165.1, 140.2, 135.2, 134.3, 133.9,
mL) was stirred at room temperature under air condition for
24 h. After the reaction was completed, the solvent was
removed under reduced pressure, the resulting crude was
washed with petroleum ether/diethyl ether (2:1, v/v) to give
1
5
33.0, 132.5, 132.2, 130.9, 129.7, 129.3, 128.4, 127.4, 74.5,
1.7, 28.3.
1
1b
4
.3.4
N-(tert-butyl)-1-oxo-4-(p-tolyl)-1,3-
8a. Light yellow solid, yield 98%, mp 175–178 °C, lit
1
dihydrobenzo[c]oxepine-3-carboxamide (8d). White solid,
178–179 °C; H NMR (DMSO, 600 MHz) δ (ppm) 8.36 (s,
1H, N-H), 8.02 (d, J = 8.4 Hz, 2H, Ar-H), 7.95 (d, J = 7.8
Hz, 1H, Ar-H), 7.87 (t, J = 7.2 Hz, 3H, Ar-H), 7.77-7.53 (m,
15H, Ar-H), 7.34-7.06 (m, 2H, Ar-H), 6.27 (s, 1H, CH),
1
1b
1
yield 66%, mp 136–137 °C, lit 136–138 °C; H NMR
(
CDCl , 600 MHz) δ (ppm) 7.98 (d, J = 9.0 Hz, 1H, Ar-H),
3
7
.62-7.54 (m, 2H, Ar-H), 7.49-7.40 (m, 2H, Ar-H), 7.29 (d,
1
3
J = 9.0 Hz, 2H, Ar-H), 7.16 (d, J = 9.0 Hz, 2H, Ar-H), 5.99
5.66-5.43 (m, 2H, CH ), 1.22 (s, 9H, 3CH ); CNMR
2
3
(
s, 1H, CH), 5.25 (s, 1H, NH), 2.33 (s, 3H, CH ), 1.14 (s,
(DMSO, 100 MHz) δ (ppm) 189.6, 164.7, 162.1, 139.0,
135.0, 133.9, 133.8, 133.5, 132.3, 132.2, 132.1, 131.8,
130.5, 130.1, 130.0, 129.8, 129.7, 129.2, 129.1, 128.9,
128.8, 128.1, 125.2, 117.8, 116.9, 77.6, 51.1, 28.0, 26.8,
26.3.
3
1
3
9
1
1
2
H, 3CH3); C NMR (CDCl , 150 MHz) δ (ppm) 168.8,
3
64.4, 140.4, 138.2, 136.7, 133.5, 133.3, 132.7, 132.4,
32.3, 131.2, 129.9, 129.4, 129.3, 125.8, 75.0, 51.6, 28.2,
1.0.
4
.3.5
4-(4-bromophenyl)-N-cyclohexyl-1-oxo-1,3-
dihydrobenzo[c]oxepine-3-carboxamide (8e). White solid,
yield 57%, mp 220–223 °C, lit 222–224 °C; H NMR
Acknowledgements
1
1b
1
(
7
7
CDCl , 600 MHz) δ (ppm) 7.93 (d, J = 7.8 Hz, 1H, Ar-H),
.55 (t, J = 7.2 Hz, 1H, Ar-H), 7.45-7.38 (m, 4H, Ar-H),
.35 (d, J = 8.4 Hz, 1H, Ar-H), 7.23 (d, J = 8.4 Hz, 2H, Ar-
We gratefully acknowledge financial support of this
work by the National Natural Science Foundation of China
(No. 21602123)
3
H), 6.06 (s, 1H, CH), 5.57 (d, J = 7.2 Hz, 1H, NH), 3.71 (d,
J = 8.4 Hz, 1H, CH), 1.86 (d, J = 9.0 Hz, 1H, 0.5CH2),
1
1
.75-1.55 (m, 4H, 2CH ), 1.39-1.26 (m, 2H, CH ), 1.19-
References
2
2
1
3
.04 (m, 2H, CH ), 0.98-0.86 (m, 1H, 0.5CH ); CNMR
2
2
(
1
1
CDCl , 150 MHz) δ (ppm) 168.5, 164.8, 139.4, 135.9,
34.8, 132.9, 132.6, 132.3, 131.5, 131.1, 129.8, 129.5,
27.6, 122.2, 74.5, 48.8, 32.6, 25.3, 24.7.
1. For some examples, see: (a) L. Reguera, Y. Mendez, A. R.
3
Humpierre, O. Valdes and D. G. Rivera, Acc. Chem. Res.,
2
018, 51, 1475; (b) M. Giustiniano, A. Basso, V. Mercalli, A.
Massarotti, E. Novellino, G. C. Tron and J. P. Zhu, Chem.
Soc. Rev., 2017, 46, 1295; (c) B. R. Song and B. Xu, Chem.
Soc. Rev., 2017, 46, 1103; (d) V. Marti-Centelles, M. D.
Pandev, M. I. Burguete and S. V. Luis, Chem. Rev., 2015, 115,
4
.3.6
4-(4-bromophenyl)-N-(tert-butyl)-1-oxo-1,3-
dihydrobenzo[c]oxepine-3-carboxamide (8f). White solid,
1
1b
1
yield 66%, mp 146–148 °C, lit 149–151 °C; H NMR
CDCl , 600 MHz) δ (ppm) 7.94 (d, J = 7.2 Hz, 1H, Ar-H),
8
736; (e) B. Zhang and A. Studer, Chem. Soc. Rev., 2015, 44,
3505; (f) A. L. Odom and T. J. McDaniel, Acc. Chem. Res.,
015, 48, 2822; (g) A. Dӧmling, W. Wang and K. Wang,
(
7
7
3
.56 (t, J = 7.8 Hz, 1H, Ar-H), 7.46-7.39 (m, 4H, Ar-H),
.35 (d, J = 7.2 Hz, 1H, Ar-H), 7.25 (d, J = 8.4 Hz, 2H, Ar-
2
Chem. Rev., 2012, 112, 3083; (h) M. M. Heravi, V. Zadsirjan,
M. Dehghani and T. Ahmadi, Tetrahedron, 2018, 74, 3391; (i)
M. M. Heravi and N. Nazari, Curr. Org. Chem., 2017, 21,
H), 6.00 (s, 1H, CH), 5.48 (s, 1H, NH), 1.23 (s, 9H, 3CH );
3
1
3
C NMR (CDCl , 150 MHz) δ (ppm) 168.5, 165.0, 140.1,
3
1
440; (j) S. Sadjadi, M. M. Heravi and N. Nazari, RSC Adv.,
1
1
35.5, 134.9, 133.0, 132.6, 132.3, 131.5, 131.0, 129.7,
29.5, 127.6, 122.2, 74.5, 51.8, 28.3.
2
016, 6, 53203.
2
.
For some examples, see: (a) H. Na and T. S. Teets, J. Am.
Chem. Soc., 2018, 140, 6353; (b) Y. Katsuma, N. Tsukahara,
L. L. Wu, Z. Y. Lin and M. Yamashita, Angew. Chem. Int.
Ed., 2018, 57, 6109; (c) Q. Y. Wan, W. P. To, C. Yang and C.
M. Che, Angew. Chem. Int. Ed., 2018, 57, 3089; (d) S. J.
Tereniak and S. S. Stahl, J. Am. Chem. Soc., 2017, 139,
14533; (e) S. Okumura, F. Z. Sun, N. Ishida and M.
Murakami, J. Am. Chem. Soc., 2017, 139, 12414; (f) C. C.
Mokhtarzadeh, C. E. Moore, A. L. Rheingold and J. S.
Figueroa, Angew. Chem. Int. Ed., 2017, 56, 10894; (g) X. Liu,
C. Manzur, N. Novoa, S. Celedón, D. Carrillo, J.-R. Hamon.
Coord. Chem. Rev., 2018, 357, 144-172; (h) S. V. Chepyshev,
J. A. Lujan-Montelongo, A. Chao and F. F. Fleming, Angew.
Chem. Int. Ed., 2017, 56, 4310; (i) X. H. Hong, Q. T. Tan, B.
X. Liu and B. Xu, Angew. Chem. Int. Ed., 2017, 56, 3961; (j)
L. A. Buldt, X. W. Guo, A. Prescimone and O. S. Wenger,
Angew. Chem. Int. Ed., 2016, 55, 11247; (k) W. Q. Kong, Q.
Wang and J. P. Zhu, Angew. Chem. Int. Ed., 2016, 55, 9714;
4
.3.7
4-(4-bromophenyl)-N-butyl-1-oxo-1,3-
dihydrobenzo[c]oxepine-3-carboxamide (8g). White solid,
1
1b
1
yield 68%, mp 175–176 °C, lit 176–178 °C; H NMR
CDCl , 600 MHz) δ (ppm) 8.04 (d, J = 7.8 Hz, 1H, Ar-H),
(
7
7
3
.64 (t, J = 7.2 Hz, 1H, Ar-H), 7.55-7.45 (m, 3H, Ar-H),
.41 (d, J = 7.8 Hz, 1H, Ar-H), 7.27 (d, J = 8.4 Hz, 2H, Ar-
H), 7.00 (s, 1H, =CH), 6.90 (s, 1H, NH), 5.31 (s, 1H, CH),
.40-3.30 (m, 2H, CH ), 1.50-1.35 (m, 2H, CH ), 1.33-1.16
3
(
(
1
1
2
2
1
3
m, 2H, CH ), 0.90 (d, J = 7.8 Hz, 3H, CH ); C NMR
2
3
CDCl , 100 MHz) δ (ppm) 167.9, 165.7, 141.5, 136.6,
3
35.0, 134.1, 132.9, 132.4, 131.5, 129.6, 129.5, 128.9,
28.7, 122.5, 75.4, 39.0, 31.3, 19.9, 13.6.
4
4
.4 Typical procedure for the synthesis of 9c
.3.1
(2-(((1-(tert-butylamino)-3-(4-chlorophenyl)-1,3-
dioxopropan-2-yl)oxy)carbonyl)benzyl)

ACCEPTED MANUSCRIPT
8
Tetrahedron
(
l) D. Noda, A. Tahara, Y. Sunada and H. Nagashima, J. Am.
Karanam, G. M. Reddy, Y. L. Tsai and W. W. Lin, Angew.
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