One-pot synthesis of 1H-isochromenes and 1,2-dihydroisoquinolines by a sequential isocyanide-based multicomponent/Wittig reaction

Article abstract of DOI:10.1039/c5ob02405f

A one-pot synthesis of 1H-isochromenes and 1,2-dihydroisoquinolines by a I-MCR/Wittig sequence was developed. The reaction of phosphonium salt 5, an acid, an amine (or without), and an isocyanide gave the 1H-isochromenes 7 or 1,2-dihydroisoquinolines 9 in

Full text of DOI:10.1039/c5ob02405f

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One-Pot Synthesis of 1H-Isochromenes and 1,2-Dihydroisoquinolines by
a Sequential Isocyanide-based Multicomponent/Wittig Reaction
Long Wang,a,b ZhiꢀRong Guan,a and MingꢀWu Dinga,*
aKey Laboratory of Pesticide & Chemical Biology of Ministry of Education, Central China Normal
University, Wuhan 430079, P. R. China
bCollege of Materials and Chemical Engineering, China Three Gorges University, Yichang, Hubei
443002, P. R. China.
Eꢀmail: mwding@mail.ccnu.edu.cn
ABSTRACT: A oneꢀpot synthesis of 1Hꢀisochromenes and 1,2ꢀdihydroisoquinolines by a
IꢀMCR/Wittig sequence was developed. The reaction of phosphonium salt 5, acid, amine (or without),
and isocyanide gave the 1Hꢀisochromenes 7 or 1,2ꢀdihydroisoquinolines 9 in good yields by a
sequential Passerini or Ugi condensation and intramolecular Wittig reaction in the presence of K2CO3.
Key words: 1Hꢀisochromene; isoquinoline; Ugi reaction; Passerini reaction; intramolecular Wittig
reaction; isocyanide
Introduction
1HꢀIsochromene unit represents a useful structural motif found in natural products and biologically
active compounds. Some natural products containing 1Hꢀisochromene can be found in bacteria, fungi
and higher plants. Recently reported natural products include banchromene,1 indigotide A,2 kalafungin3
and some of their derivatives were found to show good antitumor activities.4 The methods described for
the preparation of 1Hꢀisochromenes either involves tandem nucleophilic addition and cyclization of the
2ꢀ(1ꢀalkynyl)arylaldehydes catalyzed by various late transition metal complexes involving Au,5 Pd,6
10
Cu,7 Ag,8 or In,9 or cyclization of 2ꢀ(1ꢀalkynyl)arylethanols in the presence of I2 or Au complexes,11
or intramolecular Heck12 and Wittig reaction.13 1,2ꢀDihydroisoquinolines also play an important role in
the field of medicinal chemistry due to their excellent pharmacological potential. Some

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1,2ꢀdihydroisoquinoline derivatives have been used as good βꢀsecretase (BACEꢀ1) inhibitors,14
ATPꢀcompetitive inhibitors of the nodꢀlike receptor protein (NLRP1) inflammasome,15 brain specific
and shelfꢀstable monoamine oxidase (MAO) inhibitors,16 antibacterial agents17 and novel carriers for
specific delivery of drugs to the brain.18 The reported synthetic methods for 1,2ꢀdihydroisoquinolines
include tandem nucleophilic addition and cyclization of the 2ꢀ(1ꢀalkynyl)arylaldehydes and amine
catalyzed by Ag, Cu or Au complexes,19 Yb(OTf)3,20 CoCl2,21 I2,22 or no catalyst,23
pseudoꢀthreeꢀcomponent reactions of arynes with Nꢀaryl imines,24 cyclization of
2ꢀ(1ꢀalkynyl)arylethylamines in the presence of Au complexes,11 and platinumꢀcatalyzed sequential
rearrangement of amides and aminocyclization.25 Consequently, new and convenient synthetic method
to 1Hꢀisochromenes and 1,2ꢀdihydroisoquinolines would provide a valuable tool to synthetic organic
and pharmaceutical chemists.
The isocyanide based multicomponent reactions (IꢀMCRs), mainly Ugi and Passerini reaction, have
become a useful synthetic tool in organic and medicinal chemistry for rapid preparation of organic
molecules.26 The sequences of Ugi and Passerini reactions, followed by postꢀcondensation
transformations, constitute extremely powerful methods for the preparation of complex molecules,
especially heterocyclic compounds with diverse structures.27ꢀ33 For example, a postꢀUgi and
BuchwaldꢀHartwig/Michael reaction was utilized successifully to prepare functionalized
spiro[indolineꢀ3,2′ꢀpyrrole]ꢀ2,5′ꢀdiones in moderate to good yields.27 3ꢀHydroxyisoquinolines were also
obtained by sequential Ugi/reductive Heck cyclization.28 The sequence of IꢀMCRs/Horner reaction has
been used in preparation of butenolides, pyrrolidinones and pyridines under mild reaction condition.32
We
have
recently
reported
an
efficient
synthesis
of
multisubstituted
2,3ꢀdihydroꢀ1Hꢀ2ꢀbenzazepinꢀ1ꢀones and 3Hꢀ2ꢀbenzoxepinꢀ1ꢀones by an IꢀMCR/Wittig sequence
starting from phosphonium salt precursors (using as acid component in the IꢀMCR).33 Continuing our
interests in synthesis of various heterocycles via multicomponent reaction,34 herein we wish to report a
new efficient synthesis of 1Hꢀisochromenes and 1,2ꢀdihydroisoquinolines by an IꢀMCR/Wittig
sequence starting from phosphonium salt precursors, which were used as aldehyde components in the
IꢀMCR.
Results and Discussion

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The phosphonium salt precursors 5 were prepared according to standard protocols (Scheme 1).35
Protection of aldehydes 1 with Ac2O in acidic condition gave compounds 2. Bromination of 2 with the
NBS led to its 2ꢀbromomethyl derivatives 3, which were deprotected to give
2ꢀbromomethylbenzaldehydes 4. Reaction of 4 with triphenylphosphine or diphenylmethylphosphine
produced the corresponding phosphonium salt precursors 5.
OAc
OAc
CH2Br
OAc
OAc
CHO
CH3
Ac2O
NBS
H2SO4
88-92%
78-81%
X
X
X
CH3
1
2
3
CHO
CHO
Ph2PR
HCl
74-83%
85-87%
X
CH2P+Ph2R Br-
X
CH2Br
4
5
5a: X=H, R=Ph
5b: X=H, R=Me
5c: X=Cl, R=Me
Scheme 1. Preparation of phosphonium salt precursors 5
The phosphonium salts 5a-b, benzoic acid and tꢀbutylisocyanide were selected initially as the
Passerini reactants (Scheme 2). When the above three components were stirred in CH2Cl2 at room
temperature for 48 h, the Passerini product 6a was often obtained as semiꢀsolid or oil with high
hydroscopic property which was difficult to be purified. So after washed by ether/petroleum ether (V/V
= 1:1), the crude phosphonium salt 6a was used directly without further purification for intramolecular
Wittig reaction. The R group, solvent and base utilized had notable effect on this reaction. We firstly
investigated the intramolecular Wittig reaction of diphenylmethyl phosphonium salt 5b (R = Me). As
the solid K2CO3 was used as base at 60 °C, low to moderate yields of the product 7a were obtained
when THF or methanol were used as solvents (15ꢀ45%, Table 1, entry 1ꢀ2). But when toluene was
utilized as solvent, the best yield was reached (86%, Table 1, entry 3) at 110 °C. Utilizing the more
basic NaOH resulted in lower yield of the product (24%, Table 1, entry 4). Moderate yields were
obtained in case that NEt3 was used in methanol or toluene (45ꢀ56%, Table 1, entry 5ꢀ6). The
intramolecular Wittig reaction of triphenyl phosphonium salt 5a (R = Ph) gave low yields in both
K2CO3/toluene and NEt3/MeOH system (17ꢀ23%, Table 1, entry 7ꢀ8), which implied the low reactivity
of triphenyl phosphonium salt in intramolecular Wittig reaction.

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H
N
O
O
Ph
CHO
CH2Cl2
r.t.
PhCOOH
+
O
t-BuNC
CH2P+Ph2R Br-
CH2P+Ph2R Br-
6a
5a-b
H
N
O
Base
O
Solvent
Ph
7a
Scheme 2. Optimization of the reaction condition
Table 1. Screening reactions conditions for intramolecular Wittig reaction
Yieldc
entry
R
solvent
Conditiona
Baseb
(%)
45
1
2
3
4
5
6
7
8
Me
Me
THF
60 °C /2 h
60 °C /2 h
K2CO3
K2CO3
K2CO3
NaOH
NEt3
MeOH
toluene
toluene
MeOH
toluene
toluene
MeOH
15
Me
Me
Me
Me
Ph
110 °C /2 h
110 °C /1 h
60 °C /12 h
110 °C /2 h
110 °C /2 h
60 °C /12 h
86
24
63
42
23
17
NEt3
K2CO3
NEt3
Ph
aCondition for Ugi reaction: CH2Cl2, r.t., 48 hr;
bTwo equiv. of the base was used. c Isolated yields.
With the optimized condition, various phosphonium salts 5b-c (R = Me), acids and isocyanides were
employed for the reaction (Scheme 3). All of the reactions were carried out smoothly to give the
corresponding 1Hꢀisochromenes 7 in toluene at reflux temperature, and good yields were obtained with
various substituents on the reactants (Table 2). Various acids can be used in above oneꢀpot cyclization
to prepare 1Hꢀisochromenes 7. As indicated in Table 2, good yields (7aꢀ7d and 7kꢀ7o, 81ꢀ89%, Table 2)
were obtained as R1 are aromatic groups regardless of the electroꢀdonating or electroꢀwithdrawing
substituents on the benzene ring. Relative lower yields (7eꢀ7j, 7p-q, 68ꢀ78%, Table 2) were resulted
when R1 are alkyl, 2ꢀfuryl, 2ꢀthiophenyl or oꢀsubstituted aromatic groups.

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R2HN
O
R1
CHO
CH2P+Ph2Me Br-
R1COOH
R2NC
CH2Cl2
r.t.
+
O
O
X
X
CH2P+Ph2Me Br-
6
5b-c
R2HN
O
K2CO3 (s)
toluene
reflux
O
X
R1
7
Scheme 3. Preparation of 1Hꢀisochromenes 7
Table 2. Preparation of 1Hꢀisochromenes 7a
X
R1
R2
Yieldb (%)
7a
7b
H
H
Ph
tꢀBu
tꢀBu
86
83
4ꢀCH3C6H4
7c
7d
7e
7f
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
4ꢀNO2C6H4
4ꢀClC6H4
2ꢀCH3C6H4
2ꢀFC6H4
2ꢀIC6H4
CH3
tꢀBu
tꢀBu
87
89
76
78
73
76
71
77
82
85
81
84
82
68
tꢀBu
tꢀBu
7g
7h
7i
tꢀBu
tꢀBu
H
tꢀBu
7j
ClCH2
tꢀBu
c
c
c
c
7k
7l
Ph
cꢀC6H11
cꢀC6H11
4ꢀClC6H4
7m
7n
7o
7p
4ꢀCH3C6H4 cꢀC6H11
4ꢀNO2C6H4 cꢀC6H11
Ph
tꢀBu
tꢀBu
O
7q
H
tꢀBu
70
S
aReaction condition: i) CH2Cl2, r.t., 48 hr; ii) toluene, K2CO3 (s), 110 °C, 1ꢀ3 h.
bIsolated yields based on phosphonium 5b-c. ccyclohexyl.
The Ugi reactions of phosphonium salts 5b-c, acids, amines and isocyanides also took place to give
phosphonium intermediates 8. In the presence of K2CO3/toluene system, 1,2ꢀdihydroisoquinolines 9
were obtained in moderate yields (45ꢀ57%, 9aꢀ9o, Table 3) via intramolecular Wittig reaction of 8

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(Scheme 4). Different acids and primary amines may be utilized in above oneꢀpot cyclization to prepare
1,2ꢀdihydroisoquinolines 9. The moderate yields may be due to the low reactivity of the amide group
for intramolecular Wittig reaction. As indicated in Table 3, the cyclized products can be obtained when
R1 are H and aromatic groups and R3 are aromatic groups. The reactions failed to produce
1,2ꢀdihydroisoquinolines 9 as aliphatic amines (R3 = alkyl group, 9pꢀ9r, Table 3) were utilized.
R2HN
O
R1
R1COOH
CHO
CH2P+Ph2Me Br-
MeOH
r.t.
R2NC
+
N
O
R3
R3NH2
X
CH2P+Ph2Me Br-
X
8
5b-c
R2HN
O
N
K2CO3 (s)
R3
R1
toluene
reflux
X
9
Scheme 4. Preparation of 1,2ꢀdihydroisoquinolines 9
Table 3. Preparation of 1,2ꢀdihydroisoquinolines 9a
X
R1
R2
R3
Yieldb (%)
9a
9b
H
H
Ph
Ph
tꢀBu
tꢀBu
Ph
56
57
4ꢀClC6H4
9c
9d
9e
9f
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
Ph
tꢀBu
tꢀBu
tꢀBu
tꢀBu
tꢀBu
tꢀBu
tꢀBu
4ꢀCH3C6H4
4ꢀClC6H4
2ꢀCH3C6H4
3ꢀClC6H4
4ꢀClC6H4
4ꢀClC6H4
4ꢀClC6H4
4ꢀClC6H4
4ꢀClC6H4
4ꢀEtOC6H4
4ꢀClC6H4
4ꢀClC6H4
4ꢀClC6H4
nꢀPr
51
54
45
47
50
55
48
50
51
54
53
45
49
0
4ꢀCH3C6H4
Ph
Ph
9g
9h
9i
4ꢀNO2C6H4
4ꢀClC6H4
4ꢀCF3C6H4
9j
4ꢀCH3OC6H4 tꢀBu
9k
9l
3ꢀNO2C6H4
Ph
tꢀBu
tꢀBu
9m
9n
9o
9p
9q
9r
H
tꢀBu
c
c
Ph
cꢀC6H11
tꢀBu
4ꢀClC6H4
4ꢀClC6H4
4ꢀClC6H4
4ꢀClC6H4
nꢀBu
cꢀC6H11
nꢀBu
iꢀPr
0
tꢀBu
0

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aReaction condition: i) MeOH, r.t., 48 hr; ii) toluene, K2CO3 (s), 110 °C, 2ꢀ4 h.
bIsolated yields based on phosphonium 5b-c. ccyclohexyl.
Conclusions
In conclusion, the IꢀMCR/Wittig sequence starting from phosphonium salt precursors for preparing
1Hꢀisochromenes and 1,2ꢀdihydroisoquinolines is reported. The method was adapted to the synthesis of
various multisubstituted 1Hꢀisochromenes and 1,2ꢀdihydroisoquinolines in oneꢀpot fashion under mild
reaction condition, which makes it useful in synthetic and medicinal chemistry.
Experimental Section
General
All reactions were performed in roundꢀbottom flasks under an atmosphere of air. Unless otherwise noted,
materials were purchased from commercial suppliers and used without further purification. Dichloromethane
was used after distillation. Toluene was distilled from Na, and stored over 4A molecular sieves. Column
chromatography purifications were performed under “flash” conditions using 400ꢀ630 mesh silica gel.
Analytical thinꢀlayer chromatography (TLC) was carried out on silica gel 60 F254 plates, which were
visualized by exposure to ultraviolet light. Melting points were uncorrected. HRMS were measured on
Angilent 6224 TOF LC/MS spectrometer. NMR were recorded in CDCl3 on a Varian Mercury 400 or 600
spectrometer and resonances relative to TMS. Data are reported as follows: chemical shift, multiplicity (s =
single, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (Hz) and integration. 13C NMR
spectra were recorded on Varian Mercury 400/600 (100/150 MHz) with complete proton decoupling
spectrophotometers (CDCl3: 77.0 ppm).
General Procedure for the Preparation of 1H-Isochromenes 7
A mixture of phosphonium salt 5b-c31 (1 mmol), acid (1 mmol) and isocyanide (1 mmol) was stirred in
methylene dichloride (5 mL) at room temperature for 48 h, and then the solvent was evaporated under
reduced pressure. The residue was washed with ether/petroleum ether (10 mL, V/V = 1:1). The solid
K2CO3 (0.27 g, 2 mmol) with toluene (5 mL) was added to the reaction system and the reaction mixture
was stirred at 110 °C for 1ꢀ3 h. The solvent was removed under reduced pressure and the residue was
purified by flash chromatography on silica gel (ether/petroleum ether = 1 : 4, V/V) to give 7.

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N-(tert-butyl)-3-phenyl-1H-isochromene-1-carboxamide (7a). Light yellow solid (yield 0.264 g,
86%), mp 87ꢀ89 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.74 (d, J = 7.8 Hz, 2H, ArꢀH), 7.44ꢀ7.23 (m,
6H, ArꢀH), 7.12 (d, J = 7.2 Hz, 1H, ArꢀH), 6.52 (s, 1H, =CH), 6.38 (s, 1H, NH), 5.52 (s, 1H, CH), 1.34
(s, 9H, 3CH3); 13C NMR (CDCl3, 150 MHz) δ (ppm) 167.9, 150.9, 133.5, 130.2, 129.1, 128.6, 128.5,
127.1, 126.7, 125.1, 124.7, 124.6, 124.1, 123.9, 102.1, 77.9, 51.3, 29.1, 28.6, 28.0. HRMS Calculated
for [C20H21NO2+H]+: 308.1651, Found: 308.1643.
N-(tert-butyl)-3-(p-tolyl)-1H-isochromene-1-carboxamide (7b). Light yellow solid (yield 0.267 g,
83%), mp 86ꢀ87 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.62 (d, J = 8.4 Hz, 2H, ArꢀH), 7.39 (d, J =
7.2 Hz, 1H, ArꢀH), 7.27ꢀ7.20 (m, 4H, ArꢀH), 7.08 (d, J = 7.8 Hz, 1H, ArꢀH), 6.45 (s, 1H, =CH), 6.39 (s,
1H, NH), 5.48 (s, 1H, CH), 2.37 (s, 3H, CH3), 1.32 (s, 9H, 3CH3); 13C NMR (CDCl3, 150 MHz) δ (ppm)
167.9, 151.0, 139.2, 130.7, 130.3, 129.3, 129.2, 128.6, 126.8, 126.5, 125.1, 124.6, 123.7, 101.3, 77.8,
51.2, 28.6, 21.3. HRMS Calculated for [C21H23NO2+H]+: 322.1807, Found: 322.1801.
N-(tert-butyl)-3-(4-nitrophenyl)-1H-isochromene-1-carboxamide (7c). Yellow solid (yield 0.305 g,
87%), mp 167ꢀ168 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.26 (d, J = 8.4 Hz, 2H, ArꢀH), 7.89 (d, J
= 9.0 Hz, 2H, ArꢀH), 7.43ꢀ7.27 (m, 3H, ArꢀH), 7.18 (d, J = 6.6 Hz, 1H, ArꢀH), 6.70 (s, 1H, =CH), 6.23
(s, 1H, NH), 5.55 (s, 1H, CH), 1.36 (s, 9H, 3CH3); 13C NMR (CDCl3, 150 MHz) δ (ppm) 167.3, 148.7,
147.5, 139.5, 129.3, 129.0, 128.4, 126.9, 125.1, 125.0, 124.9, 128.8, 123.9, 123.8, 105.7, 77.9, 51.4,
28.6. HRMS Calculated for [C20H20N2O2+H]+: 353.1501, Found: 353.1492.
N-(tert-butyl)-3-(4-chlorophenyl)-1H-isochromene-1-carboxamide (7d). White solid (yield 0.304 g,
89%), mp 126ꢀ127 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.66 (d, J = 9.0 Hz, 2H, ArꢀH), 7.40ꢀ7.23
(m, 5H, ArꢀH), 7.11 (d, J = 7.2 Hz, 1H, ArꢀH), 6.48 (s, 1H, =CH), 6.28 (s, 1H, NH), 5.49 (s, 1H, CH),
1.33 (s, 9H, 3CH3); 13C NMR (CDCl3, 150 MHz) δ (ppm) 167.7, 149.9, 134.9, 132.0, 129.9, 128.8,
128.7, 128.6, 127.4, 126.6, 125.9, 125.1, 124.0, 102.5, 77.9, 51.3, 28.6. HRMS Calculated for
[C20H20ClNO2+H]+: 342.1261, Found: 342.1253.
N-(tert-butyl)-3-(o-tolyl)-1H-isochromene-1-carboxamide (7e). Light yellow oil (yield 0.243 g,
1
76%); H NMR (CDCl3, 600 MHz) δ (ppm) 7.45 (t, J = 7.8 Hz, 2H, ArꢀH), 7.31ꢀ7.26 (m, 5H, ArꢀH),
7.10 (d, J = 5.4 Hz, 1H, ArꢀH), 6.34 (s, 1H, NH), 6.12 (s, 1H, =CH), 5.49 (s, 1H, CH), 2.47 (s, 3H,
CH3), 1.36 (s, 9H, 3CH3); 13C NMR (CDCl3, 150 MHz) δ (ppm) 167.7, 153.5, 136.7, 134.5, 130.9,
130.7, 128.9, 128.8, 127.2, 126.3, 125.9, 125.8, 124.5, 123.9, 106.3, 78.0, 51.3, 28.7, 20.9. HRMS
Calculated for [C21H23NO2+H]+: 322.1807, Found: 322.1796.

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N-(tert-butyl)-3-(2-fluorophenyl)-1H-isochromene-1-carboxamide (7f). Light yellow solid (yield
0.253 g, 78%), mp 87ꢀ88 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.72 (t, J = 7.2 Hz, 1H, ArꢀH), 7.41
(d, J = 7.2 Hz, 1H, ArꢀH), 7.33ꢀ7.12 (m, 6H, ArꢀH), 6.64 (s, 1H, =CH), 6.46 (s, 1H, NH), 5.51 (s, 1H,
CH), 1.35 (s, 9H, 3CH3); 13C NMR (CDCl3, 150 MHz) δ (ppm) 167.8, 160.9, 159.3, 146.3, 130.2, 129.9,
128.7, 127.9, 127.5, 126.6, 125.1, 124.5, 124.4, 121.9, 116.3, 107.4, 77.7, 51.3, 28.6. HRMS
Calculated for [C20H20FNO2+H]+: 326.1556, Found: 326.1548.
N-(tert-butyl)-3-(2-iodophenyl)-1H-isochromene-1-carboxamide (7g). White solid (yield 0.316 g,
73%), mp 73ꢀ75 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.94 (d, J = 8.4 Hz, 1H, ArꢀH), 7.53ꢀ7.08 (m,
7H, ArꢀH), 6.47 (s, 1H, NH), 6.17 (s, 1H, =CH), 5.64 (s, 1H, CH), 1.41 (s, 9H, 3CH3); 13C NMR
(CDCl3, 100 MHz) δ (ppm) 167.3, 153.6, 140.1, 139.7, 130.5, 130.4, 130.3, 128.5, 128.1, 127.7, 126.4,
124.1, 124.0, 107.1, 96.4, 78.0, 51.4, 28.7. HRMS Calculated for [C20H20INO2+H]+: 434.0617, Found:
434.0601.
N-(tert-butyl)-3-methyl-1H-isochromene-1-carboxamide (7h). Light yellow oil (yield 0.187 g, 76%);
1H NMR (CDCl3, 600 MHz) δ (ppm) 7.32 (d, J = 7.8 Hz, 1H, ArꢀH), 7.23ꢀ7.14 (m, 2H, ArꢀH), 6.92 (d,
J = 7.8 Hz, 1H, ArꢀH), 6.29 (s, 1H, NH), 5.70 (s, 1H, =CH), 5.32 (s, 1H, CH), 1.99 (s, 3H, CH3), 1.39
(s, 9H, 3CH3); 13C NMR (CDCl3, 150 MHz) δ (ppm) 168.1, 151.9, 130.4, 128.6, 126.3, 125.4, 124.9,
122.6, 102.7, 77.7, 51.2, 28.6, 19.6. HRMS Calculated for [C15H19NO2+H]+: 246.1494, Found:
246.1485.
N-(tert-butyl)-1H-isochromene-1-carboxamide (7i). Light yellow solid (yield 0.163 g, 71%), mp
1
58ꢀ60 °C; H NMR (CDCl3, 600 MHz) δ (ppm) 7.36 (d, J = 7.2 Hz, 1H, ArꢀH), 7.24ꢀ7.18 (m, 2H,
ArꢀH), 6.96 (d, J = 7.2 Hz, 1H, ArꢀH), 6.56 (d, J = 6.0 Hz, 1H, =CH), 6.31 (s, 1H, NH), 5.86 (d, J = 6.0
Hz, 1H, =CH), 5.34 (s, 1H, CH), 1.38 (s, 9H, 3CH3); 13C NMR (CDCl3, 150 MHz) δ (ppm) 167.6,
142.9, 128.7, 128.4, 127.1, 126.4, 124.9, 123.2, 106.5, 76.9, 51.1, 28.5. HRMS Calculated for
[C14H17NO2+H]+: 232.1338, Found: 232.1329.
N-(tert-butyl)-3-(chloromethyl)-1H-isochromene-1-carboxamide (7j). White solid (yield 0.216 g,
77%), mp 124ꢀ125 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.36 (d, J = 6.0 Hz, 1H, ArꢀH), 7.24ꢀ6.95
(m, 3H, ArꢀH), 6.85 (s, 1H, NH), 5.91 (s, 1H, =CH), 5.53 (s, 1H, CH), 4.24 (d, J = 12.0 Hz, 1H,
1/2ClCH2), 4.14 (d, J = 12.0 Hz, 1H, 1/2ClCH2), 1.36 (s, 9H, 3CH3); 13C NMR (CDCl3, 150 MHz) δ
(ppm) 167.9, 147.8, 128.7, 127.8, 127.7, 126.9, 126.0, 123.9, 105.0, 77.6, 51.8, 44.3, 28.7. HRMS
Calculated for [C15H18ClNO2+H]+: 280.1104, Found: 280.1093.

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N-cyclohexyl-3-phenyl-1H-isochromene-1-carboxamide (7k). White solid (yield 0.273 g, 82%), mp
1
144ꢀ146 °C; H NMR (CDCl3, 600 MHz) δ (ppm) 7.74 (d, J = 7.2 Hz, 2H, ArꢀH), 7.43ꢀ7.21 (m, 6H,
ArꢀH), 7.11 (d, J = 7.2 Hz, 1H, ArꢀH), 6.50 (s, 1H, =CH), 6.41 (d, J = 7.2 Hz, 1H, NH), 5.60 (s, 1H,
CH), 3.88ꢀ3.84 (m, 1H, NCH), 1.93ꢀ1.05 (m, 10H, 5CH2); 13C NMR (CDCl3, 150 MHz) δ (ppm) 167.7,
151.0, 133.4, 130.3, 129.1, 128.6, 128.5, 127.1, 126.4, 125.0, 124.7, 124.1, 102.0, 77.8, 47.8, 32.7, 25.3,
24.4. HRMS Calculated for [C22H23NO2+H]+: 334.1807, Found: 334.1800.
3-(4-chlorophenyl)-N-cyclohexyl-1H-isochromene-1-carboxamide (7l). White solid (yield 0.312 g,
85%), mp 196ꢀ197 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.66 (d, J = 8.4 Hz, 2H, ArꢀH), 7.41ꢀ7.23
(m, 5H, ArꢀH), 7.11 (d, J = 7.2 Hz, 1H, ArꢀH), 6.48 (s, 1H, =CH), 6.30 (d, J = 7.2 Hz, 1H, NH), 5.59 (s,
1H, CH), 3.88ꢀ3.83 (m, 1H, NCH), 1.92ꢀ1.06 (m, 10H, 5CH2); 13C NMR (CDCl3, 150 MHz) δ (ppm)
167.5, 150.1, 134.9, 131.9, 130.0, 128.9, 128.7, 127.4, 126.4, 126.0, 124.9, 124.0, 102.4, 77.7, 47.8,
32.7, 25.3, 24.5. HRMS Calculated for [C22H22ClNO2+H]+: 368.1417, Found: 368.1406.
N-cyclohexyl-3-(p-tolyl)-1H-isochromene-1-carboxamide (7m). White solid (yield 0.281 g, 81%),
mp 168ꢀ169 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.63 (d, J = 7.8 Hz, 2H, ArꢀH), 7.41 (d, J = 7.2
Hz, 1H, ArꢀH), 7.29ꢀ7.21 (m, 4H, ArꢀH), 7.10 (d, J = 7.8 Hz, 1H, ArꢀH), 6.46 (s, 1H, =CH), 6.41 (d, J =
7.2 Hz, 1H, NH), 5.59 (s, 1H, CH), 3.88ꢀ3.83 (m, 1H, NCH), 2.40 (s, 3H, CH3), 1.94ꢀ1.06 (m, 10H,
2CH2); 13C NMR (CDCl3, 150 MHz) δ (ppm) 167.9, 151.2, 139.4, 130.7, 130.5, 129.3, 128.7, 127.0,
126.4, 125.0, 124.7, 123.9, 101.2, 77.8, 47.9, 32.7, 25.4, 24.5, 21.4. HRMS Calculated for
[C23H25NO2+H]+: 348.1964, Found: 348.1957.
N-cyclohexyl-3-(4-nitrophenyl)-1H-isochromene-1-carboxamide (7n). White solid (yield 0.318 g,
84%), mp 207ꢀ208 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.29 (t, J = 8.4 Hz, 2H, ArꢀH), 7.91 (q, J =
8.4 Hz, 2H, ArꢀH), 7.46ꢀ7.18 (m, 4H, ArꢀH), 6.70 (t, J = 7.8 Hz, 1H, =CH), 6.24 (t, J = 9.0 Hz, 1H,
NH), 5.67 (t, J = 7.8 Hz, 1H, CH), 3.89ꢀ3.85 (m, 1H, NCH), 1.96ꢀ1.07 (m, 10H, 5CH2); 13C NMR
(CDCl3, 150 MHz) δ (ppm) 167.2, 148.9, 147.6, 139.5, 129.4, 129.0, 128.5, 126.7, 125.2, 125.0, 124.8,
123.9, 105.7, 77.9, 48.1, 32.8, 25.3, 24.5. HRMS Calculated for [C22H22N2O4+H]+: 379.1658, Found:
379.1648.
N-(tert-butyl)-6-chloro-3-phenyl-1H-isochromene-1-carboxamide (7o)
White solid (yield 0.281 g, 82%), mp 113ꢀ115 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.73 (d, J = 7.8
Hz, 2H, ArꢀH), 7.43ꢀ7.11 (m, 6H, ArꢀH), 6.51 (s, 1H, =CH), 6.37 (s, 1H, NH), 5.50 (s, 1H, CH), 1.33 (s,
9H, 3CH3); 13C NMR (CDCl3, 150 MHz) δ (ppm) 167.9, 150.9, 133.5, 130.2, 129.2, 128.6, 128.5,

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126.7, 125.1, 124.7, 124.6, 124.1, 102.1, 77.9, 51.3, 28.6. HRMS Calculated for [C20H20ClNO2+H]+:
342.1255, Found: 342.1261.
N-(tert-butyl)-3-(furan-2-yl)-1H-isochromene-1-carboxamide (7p)
White solid (yield 0.202 g, 68%), mp 98ꢀ99 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.47ꢀ7.09 (m, 5H,
ArꢀH), 6.66ꢀ6.49 (m, 2H, ArꢀH), 6.45 (s, 1H, NH), 6.42 (s, 1H, =CH), 5.46 (s, 1H, CH), 1.33 (s, 9H,
3CH3); 13C NMR (CDCl3, 150 MHz) δ (ppm) 167.7, 148.6, 143.3, 143.1, 129.3, 128.7, 127.1, 126.7,
125.9, 124.1, 111.5, 108.0, 101.3, 77.5, 51.3, 28.5. HRMS Calculated for [C18H19NO3+H]+: 298.1438,
Found: 298.1438.
N-(tert-butyl)-3-(thiophen-2-yl)-1H-isochromene-1-carboxamide (7q)
White solid (yield 0.220 g, 70%), mp 107ꢀ108 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.39ꢀ7.07 (m,
7H, ArꢀH), 6.45 (s, 1H, NH), 6.37 (s, 1H, =CH), 5.48 (s, 1H, CH), 1.33 (s, 9H, 3CH3); 13C NMR
(CDCl3, 150 MHz) δ (ppm) 167.6, 146.4, 137.8, 129.6, 128.7, 127.8, 126.9, 126.4, 126.0, 125.7, 124.2,
123.8, 101.1, 77.8, 51.3, 28.5. HRMS Calculated for [C18H19NO2S+H]+: 314.1209, Found: 314.1209.
General Procedure for the Preparation of 1,2-dihydroisoquinolines 9
A mixture of phosphonium salt 5b-c (1 mmol), amine (1 mmol), acid (1 mmol) and isocyanide (1 mmol)
was stirred in methanol (5 mL) at room temperature for 48 h, and then the solvent was evaporated
under reduced pressure. The residue was washed with ether/petroleum ether (10 mL, V/V = 1:1). The
solid K2CO3 (0.27 g, 2 mmol) with toluene (5 mL) was added to the reaction system and the reaction
mixture was stirred at 110 °C for 2ꢀ4 h. The solvent was removed under reduced pressure and the
residue was purified by flash chromatography on silica gel (ether/petroleum ether = 1 : 2, V/V) to give
9.
N-(tert-butyl)-2,3-diphenyl-1,2-dihydroisoquinoline-1-carboxamide (9a). Light yellow solid (yield
1
0.214 g, 56%), mp 189ꢀ191 °C; H NMR (CDCl3, 600 MHz) δ (ppm) 7.55 (d, J = 7.8 Hz, 2H, ArꢀH),
7.31ꢀ6.88 (m, 12H, ArꢀH), 6.57 (s, 1H, =CH), 6.42 (s, 1H, NH), 5.33 (s, 1H, CH), 1.26 (s, 9H, 3CH3);
13C NMR (CDCl3, 150 MHz) δ (ppm) 170.3, 146.9, 140.4, 136.5, 131.2, 128.7, 128.6, 128.5, 128.4,
128.1, 127.9, 127.1, 127.0, 124.2, 122.6, 122.4, 111.6, 69.0, 51.3, 28.6; HRMS Calculated for
[C26H26N2O+H]+: 383.2123, Found: 383.2118.
N-(tert-butyl)-2-(4-chlorophenyl)-3-phenyl-1,2-dihydroisoquinoline-1-carboxamide (9b). White
solid (yield 0.237 g, 57%), mp 188ꢀ190 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.53 (d, J = 7.8 Hz,

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2H, ArꢀH), 7.33ꢀ7.23 (m, 7H, ArꢀH), 7.06 (d, J = 8.4 Hz, 2H, ArꢀH), 6.93 (d, J = 8.4 Hz, 2H, ArꢀH),
6.54 (s, 1H, =CH), 6.14 (s, 1H, NH), 5.27 (s, 1H, CH), 1.23 (s, 9H, 3CH3); 13C NMR (CDCl3, 150
MHz) δ (ppm) 170.0, 145.5, 140.4, 136.2, 131.3, 128.7, 128.5, 128.4, 127.8, 127.6, 127.4, 127.2, 127.1,
124.4, 123.8, 123.6, 111.5, 68.8, 51.3, 28.4; HRMS Calculated for [C26H25ClN2O+H]+: 417.1734,
Found: 417.1716.
N-(tert-butyl)-3-phenyl-2-(p-tolyl)-1,2-dihydroisoquinoline-1-carboxamide (9c). White solid (yield
1
0.212 g, 51%), mp 141ꢀ143 °C; H NMR (CDCl3, 600 MHz) δ (ppm) 7.55 (d, J = 7.8 Hz, 2H, ArꢀH),
7.29ꢀ7.21 (m, 7H, ArꢀH), 6.91 (d, J = 8.4 Hz, 2H, ArꢀH), 6.86 (d, J = 8.4 Hz, 2H, ArꢀH), 6.55 (s, 1H,
=CH), 6.51 (s, 1H, NH), 5.27 (s, 1H, CH), 2.18 (s, 3H, CH3), 1.26 (s, 9H, 3CH3); 13C NMR (CDCl3,
150 MHz) δ (ppm) 170.4, 144.6, 140.5, 136.7, 132.4, 131.2, 129.4, 129.2, 128.4, 127.9, 127.8, 127.1,
127.0, 124.1, 122.6, 122.5, 111.1, 69.3, 51.2, 28.5, 20.6; HRMS Calculated for [C27H28N2O+Na]+:
419.2099, Found: 419.2091.
N-(tert-butyl)-2-(4-chlorophenyl)-3-(p-tolyl)-1,2-dihydroisoquinoline-1-carboxamide (9d). White
solid (yield 0.243 g, 54%), mp 213ꢀ215 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.41 (d, J = 7.8 Hz,
2H, ArꢀH), 7.32ꢀ7.20 (m, 4H, ArꢀH), 7.09 (d, J = 7.8 Hz, 2H, ArꢀH), 7.06 (d, J = 8.4 Hz, 2H, ArꢀH),
6.92 (d, J = 8.4 Hz, 2H, ArꢀH), 6.51 (s, 1H, =CH), 6.20 (s, 1H, NH), 5.26 (s, 1H, CH), 2.30 (s, 3H,
CH3), 1.23 (s, 9H, 3CH3); 13C NMR (CDCl3, 150 MHz) δ (ppm) 170.1, 145.6, 140.3, 138.3, 133.4,
131.3, 129.4, 129.2, 128.7, 128.5, 127.7, 127.6, 127.1, 127.0, 123.8, 123.6, 111.0, 68.9, 51.3, 28.6,
21.1; HRMS Calculated for [C27H27ClN2O+Na]+: 453.1710, Found: 453.1706.
N-(tert-butyl)-3-phenyl-2-(o-tolyl)-1,2-dihydroisoquinoline-1-carboxamide (9e). White solid (yield
1
0.178 g, 45%), mp 207ꢀ209 °C; H NMR (CDCl3, 600 MHz) δ (ppm) 7.78ꢀ6.61 (m, 14H, ArꢀH and
=CH), 6.60 (s, 0.30H, NH), 6.21 (s, 0.70H, NH), 5.08 (s, 0.30H, CH), 4.87 (s, 0.70H, CH), 2.65 (s, 2H,
CH3), 1.76 (s, 1H, CH3), 1.27 (s, 9H, 3CH3); 13C NMR (CDCl3, 150 MHz) δ (ppm) 169.6, 145.5, 141.9,
136.5, 132.3, 131.7, 131.0, 128.7, 128.6, 128.5, 128.4, 128.2, 128.1, 128.0, 127.9, 127.8, 126.2, 126.1,
113.2, 68.0, 51.2, 28.6, 18.9; HRMS Calculated for [C27H28N2O+H]+: 397.2280, Found: 397.2276.
N-(tert-butyl)-2-(3-chlorophenyl)-3-phenyl-1,2-dihydroisoquinoline-1-carboxamide (9f). Light
yellow solid (yield 0.195 g, 47%), mp 56ꢀ58 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.55 (d, J = 7.8
Hz, 2H, ArꢀH), 7.32ꢀ7.24 (m, 7H, ArꢀH), 7.05 (s, 1H, ArꢀH), 6.99ꢀ6.81 (m, 3H, ArꢀH), 6.58 (s, 1H,
=CH), 6.12 (s, 1H, NH), 5.30 (s, 1H, CH), 1.23 (s, 9H, 3CH3); 13C NMR (CDCl3, 150 MHz) δ (ppm)
169.8, 148.1, 140.3, 136.1, 134.3, 131.2, 128.7, 128.5, 128.3, 127.9, 127.7, 127.4, 127.2, 127.1, 124.7,

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122.6, 122.2, 120.7, 112.1, 68.8, 51.4, 28.4; HRMS Calculated for [C26H25ClN2O+H]+: 417.1734,
Found: 417.1722.
N-(tert-butyl)-2-(4-chlorophenyl)-3-(4-nitrophenyl)-1,2-dihydroisoquinoline-1-carboxamide (9g).
1
Yellow solid (yield 0.241 g, 50%), mp 271ꢀ273 °C; H NMR (CDCl3, 600 MHz) δ (ppm) 8.13 (d, J =
8.4 Hz, 2H, ArꢀH), 7.74 (d, J = 8.4 Hz, 2H, ArꢀH), 7.40ꢀ7.22 (m, 4H, ArꢀH), 7.08 (d, J = 9.0 Hz, 2H,
ArꢀH), 6.95 (d, J = 8.4 Hz, 2H, ArꢀH), 6.61 (s, 1H, =CH), 5.61 (s, 1H, NH), 5.30 (s, 1H, CH), 1.21 (s,
9H, 3CH3); 13C NMR (CDCl3, 150 MHz) δ (ppm) 169.7, 147.2, 144.8, 143.1, 139.1, 131.0, 129.0,
128.8, 128.3, 128.1, 127.6, 125.2, 123.9, 123.8, 123.7, 123.5, 113.6, 68.2, 51.5, 28.6; HRMS
Calculated for [C26H24ClN3O3+Na]+: 484.1404, Found: 484.1400.
N-(tert-butyl)-2,3-bis(4-chlorophenyl)-1,2-dihydroisoquinoline-1-carboxamide (9h). White solid
1
(yield 0.248 g, 55%), mp 179ꢀ181 °C; H NMR (CDCl3, 600 MHz) δ (ppm) 7.49 (d, J = 7.8 Hz, 2H,
ArꢀH), 7.33ꢀ7.20 (m, 6H, ArꢀH), 7.06 (d, J = 8.4 Hz, 2H, ArꢀH), 6.93 (d, J = 8.4 Hz, 2H, ArꢀH), 6.49 (s,
1H, =CH), 5.86 (s, 1H, NH), 5.27 (s, 1H, CH), 1.21 (s, 1H, 3CH3); 13C NMR (CDCl3, 150 MHz) δ
(ppm) 169.9, 145.1, 139.7, 134.9, 134.0, 131.3, 128.8, 128.7, 128.6, 128.0, 127.5, 127.2, 124.6, 123.8,
123.7, 111.5, 68.6, 51.4, 28.5; HRMS Calculated for [C26H24Cl2N2O+H]+: 451.1344, Found: 451.1336.
N-(tert-butyl)-2-(4-chlorophenyl)-3-(4-(trifluoromethyl)phenyl)-1,2-dihydroisoquinoline-1-carbox
1
amide (9i). Light yellow solid (yield 0.232 g, 48%), mp 108ꢀ110 °C; H NMR (CDCl3, 600 MHz) δ
(ppm) 7.67 (d, J = 7.8 Hz, 2H, ArꢀH), 7.53 (d, J = 7.8 Hz, 2H, ArꢀH), 7.35ꢀ7.22 (m, 4H, ArꢀH), 7.08 (d,
J = 8.4 Hz, 2H, ArꢀH), 6.94 (d, J = 7.2 Hz, 2H, ArꢀH), 6.56 (s, 1H, =CH), 5.79 (s, 1H, NH), 5.29 (s, 1H,
CH), 1.22 (s, 9H, 3CH3); 13C NMR (CDCl3, 150 MHz) δ (ppm) 169.9, 145.0, 140.0, 139.6, 131.1,
130.1, 129.9, 128.9, 128.7, 128.6, 128.2, 127.6, 127.4, 127.2, 125.5, 125.0, 124.8, 123.8, 123.6, 123.0,
112.5, 68.6, 51.5, 28.4; HRMS Calculated for [C27H24ClF3N2O+H]+: 485.1608, Found: 485.1597.
N-(tert-butyl)-2-(4-chlorophenyl)-3-(p-tolyl)-1,2-dihydroisoquinoline-1-carboxamide (9j). Light
1
yellow solid (yield 0.223 g, 50%), mp 139ꢀ141 °C; H NMR (CDCl3, 600 MHz) δ (ppm) 7.46 (d, J =
8.4 Hz, 2H, ArꢀH), 7.31ꢀ7.20 (m, 4H, ArꢀH), 7.06 (d, J = 9.0 Hz, 2H, ArꢀH), 6.92 (d, J = 9.0 Hz, 2H,
ArꢀH), 6.81 (d, J = 9.0 Hz, 2H, ArꢀH), 6.46 (s, 1H, =CH), 6.13 (s, 1H, NH), 5.25 (s, 1H, CH), 3.77 (s,
3H, OCH3), 1.23 (s, 9H, 3CH3); 13C NMR (CDCl3, 150 MHz) δ (ppm) 170.1, 159.6, 145.6, 140.2,
131.6, 128.7, 128.6, 128.5, 127.7, 127.6, 127.4, 124.2, 123.9, 123.7, 114.0, 113.9, 110.2, 68.9, 55.3,
51.3; 28.5. HRMS Calculated for [C27H27ClN2O2+H]+: 447.1839, Found: 447.1833.
N-(tert-butyl)-2-(4-chlorophenyl)-3-(3-nitrophenyl)-1,2-dihydroisoquinoline-1-carboxamide (9k).

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1
Yellow solid (yield 0.236 g, 51%), mp 139ꢀ141 °C; H NMR (CDCl3, 600 MHz) δ (ppm) 8.48 (s, 1H,
ArꢀH), 8.09 (d, J = 8.4 Hz, 1H, ArꢀH), 7.86 (d, J = 7.8 Hz, 1H, ArꢀH), 7.43ꢀ7.22 (m, 5H, ArꢀH), 7.08 (d,
J = 8.4 Hz, 2H, ArꢀH), 6.96 (d, J = 8.4 Hz, 2H, ArꢀH), 6.61 (s, 1H, =CH), 5.72 (s, 1H, NH), 5.29 (s, 1H,
CH), 1.22 (s, 9H, 3CH3); 13C NMR (CDCl3, 150 MHz) δ (ppm) 169.7, 148.4, 144.7, 138.9, 138.4,
133.7, 131.0, 129.6, 128.9, 128.8, 128.4, 127.6, 127.5, 127.2, 125.1, 123.9, 123.0, 121.7, 112.8, 68.5,
51.5, 28.5; HRMS Calculated for [C26H24ClN3O3+H]+: 462.1584, Found: 462.1574.
N-(tert-butyl)-2-(4-ethoxyphenyl)-3-phenyl-1,2-dihydroisoquinoline-1-carboxamide (9l). Light
yellow solid (yield 0.231 g, 54%), mp 139ꢀ141 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.55 (d, J =
7.2 Hz, 2H, ArꢀH), 7.30ꢀ7.20 (m, 7H, ArꢀH), 6.90 (d, J = 8.4 Hz, 2H, ArꢀH), 6.64 (d, J = 8.4 Hz, 2H,
ArꢀH), 6.53 (s, 1H, NH), 6.52 (s, 1H, =CH), 5.21 (s, 1H, CH), 3.88 (q, J = 6.6 Hz, 2H, OCH2), 1.32 (t,
J = 6.6 Hz, 3H, CH3), 1.26 (s, 9H, 3CH3); 13C NMR (CDCl3, 150 MHz) δ (ppm) 170.5, 154.9, 140.8,
140.5, 136.7, 131.3, 128.3, 128.0, 127.8, 127.5, 127.2, 127.1, 124.2, 124.1, 114.6, 114.5, 110.6, 69.7,
63.5, 51.2, 28.7, 14.8; HRMS Calculated for [C28H30N2O2+H]+: 427.2386, Found: 427.2388.
N-(tert-butyl)-2-(4-chlorophenyl)-1,2-dihydroisoquinoline-1-carboxamide (9m). Light yellow solid
(yield 0.191 g, 53%), mp 155ꢀ157 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.31ꢀ6.99 (m, 8H, ArꢀH),
6.66 (d, J = 7.2 Hz, 1H, =CH), 5.97 (s, 1H, NH), 5.85 (d, J = 7.8 Hz, 1H, =CH), 5.24 (s, 1H, CH), 1.22
(s, 9H, 3CH3); 13C NMR (CDCl3, 150 MHz) δ (ppm) 170.0, 143.7, 130.1, 129.4, 129.2, 128.0, 127.2,
126.7, 126.6, 126.5, 124.1, 117.8, 117.6, 105.1, 65.3, 51.4, 28.4; HRMS Calculated for
[C20H21ClN2O+Na]+: 363.1240, Found: 363.1249.
2-(4-chlorophenyl)-N-cyclohexyl-3-phenyl-1,2-dihydroisoquinoline-1-carboxamide (9n). Light
1
yellow solid (yield 0.200 g, 45%), mp 174ꢀ176 °C; H NMR (CDCl3, 600 MHz) δ (ppm) 7.54 (d, J =
7.2 Hz, 2H, ArꢀH), 7.32ꢀ7.23 (m, 7H, ArꢀH), 7.05 (d, J = 8.4 Hz, 2H, ArꢀH), 6.93 (d, J = 8.4 Hz, 2H,
ArꢀH), 6.48 (s, 1H, =CH), 5.98 (d, J = 6.6 Hz, 1H, NH), 5.35 (s, 1H, CH), 3.74ꢀ3.72 (m, 1H, NCH),
1.77ꢀ0.95 (m, 10H, 5CH2); 13C NMR (CDCl3, 150 MHz) δ (ppm) 170.0, 145.4, 140.9, 136.3, 131.6,
128.7, 128.6, 128.5, 127.8, 127.5, 127.4, 127.3, 124.6, 123.9, 123.8, 111.1, 68.3, 48.2, 32.8, 25.3, 24.3;
HRMS Calculated for [C28H27ClN2O+H]+: 443.1890, Found: 443.1884.
2,3-bis(4-chlorophenyl)-N-(tert-butyl)-6-chloro-1,2-dihydroisoquinoline-1-carboxamide (9o)
White solid (yield 0.237 g, 49%), mp 165ꢀ167 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.40 (d, J = 7.8
Hz, 2H, ArꢀH), 7.19ꢀ6.83 (m, 9H, ArꢀH), 6.40 (s, 1H, =CH), 5.77 (s, 1H, NH), 5.18 (s, 1H, CH), 1.13 (s,
9H, 3CH3); 13C NMR (CDCl3, 150 MHz) δ (ppm) 169.9, 145.1, 139.8, 134.9, 134.0, 131.3, 128.8,

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128.7, 128.6, 128.5, 128.0, 127.5, 127.4, 124.7, 123.8, 123.7, 111.3, 68.6, 51.4, 28.5; HRMS Calculated
for [C26H23Cl3N2O+H]+: 485.0949, Found: 485.0947.
Acknowledgments
We gratefully acknowledge financial support of this work by the National Natural Science Foundation
of China (No. 21572075 and 21172085).
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Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Central China Normal University, Wuhan, 430079, P. R.
China. Fax: (+86)-27-67862041; Tel: (+86)-27-67867958; E-mail: mwding@mail.ccnu.edu.cn
† Electronic Supplementary Information (ESI) available: [NMR spectra of 7a–q and 9a–o.]. See
DOI: 10.1039/b000000x/

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One-Pot Synthesis of 1H-Isochromenes and 1,2-Dihydroisoquinolines by a Sequential
Isocyanide-based Multicomponent/Wittig Reaction
Long Wang, Zhi-Rong Guan, and Ming-Wu Ding*
A new sequential isocyanide-based multicomponent/Wittig reaction was developed to construct
1H-isochromene and 1,2-dihydroisoquinoline derivatives.
CONHR2
CHO
IMCR/Wittig
Y
one-pot
X
CH2P+Ph2Me Br-
X
R1
Y = O, NR3
32 examples
45-89% overall yields