Highly stereoselective synthesis of (Z)-3-methoxy-1-methyleneisoindoles via DMAP catalyzed cyclization of methyl 2-alkynylbenzimidates

Article abstract of DOI:10.1016/j.tet.2019.04.036

A DMAP (4-dimethylaminopyridine) catalyzed cyclization of methyl 2-alkynylbenzimidates has been developed, which affords 3-methoxy-1-methyleneisoindoles with excellent Z-stereoselectivity under mild and transition-metal-free conditions. The (Z)-3-methoxy-

Full text of DOI:10.1016/j.tet.2019.04.036

Accepted Manuscript
Highly stereoselective synthesis of (Z)-3-methoxy-1-methyleneisoindoles via DMAP
catalyzed cyclization of methyl 2-alkynylbenzimidates
Tuanli Yao, Xiujuan Liang, Zhen Guo, Dong Yang
PII:
S0040-4020(19)30448-X
https://doi.org/10.1016/j.tet.2019.04.036
TET 30281
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 20 March 2019
Accepted Date: 15 April 2019
Please cite this article as: Yao T, Liang X, Guo Z, Yang D, Highly stereoselective synthesis of (Z)-3-
methoxy-1-methyleneisoindoles via DMAP catalyzed cyclization of methyl 2-alkynylbenzimidates,
Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.04.036.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Highly Stereoselective Synthesis of (Z)-3-Methoxy-1-methyleneisoindoles via
DMAP Catalyzed Cyclization of Methyl 2-Alkynylbenzimidates
Tuanli Yao a, b, *, Xiujuan Liang a, Zhen Guo a, and Dong Yang a
aCollege of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology,
Xi’an, 710021, China.
bShaaxi Key Laboratory of Chemical Additives for Industry, Shaanxi University of Science and Tec
hnology, Xi’an, 710021, China.
Email: yaotuanli@sust.edu.cn
Abstract: A DMAP (4-dimethylaminopyridine) catalyzed cyclization of methyl 2-
alkynylbenzimidates has been developed, which affords 3-methoxy-1-methyleneisoindoles with
excellent Z-stereoselectivity under mild and transition-metal-free conditions. The (Z)-3-
methoxy-1-methyleneisoindole products can be converted to corresponding 3-amino-1-
methyleneisoindoles, 3-methoxy-isoindoles, 3-methyleneisoindolinones and isoindolinones
with high efficiency.
Key words: cyclization; metal-free; 2-alkynylbenzimidates; 3-methoxy-1-methyleneisoindoles
1. Introduction
Intramolecular cyclization of alkynes containing proximate nucleophilic centers represents
one of the most efficient methods to synthesize heterocyclic molecules [1]. Intramolecular
hydroamination of alkynes using nitrogen-containing internal nucleophiles such as imines [2]
and amides [3], has been well explored. These cyclizations were achieved in the presence of
excess base, or catalysts such as transition metal or base. However, imidates, which are more
nucleophilic and chemoselective than amides, were underdeveloped. The cyclization of in situ
generated imidates from 2-alkynylbenzonitriles has been investigated, in which excess
methoxide or ethoxide was applied [4]. Recently, synthesis of 2-alkoxyisoquinolines [5] and 3-
methoxy-1-methylene-1H-isoindoles [6] via transition-metal-catalyzed cyclization of 2-
alkynylbenzimidates have been reported (Scheme 1). To date, no transition-metal-free
cyclization of 2-alkynylbenzimidates using base as the catalyst which fulfils the requirements of
green chemistry, has been reported.

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Our research interest in intramolecular cyclization of alkynes [7] promoted us to investigate
base mediated cyclization of methyl 2-alkynylbenzimidates, Herein, we report the successful
DMAP catalyzed cyclization of methyl 2-alkynylbenzimidates which shows much improved
regioselectivity comparing with corresponding silver catalyzed cyclization and preferentially
forms (Z)-3-methoxy-1-methyleneisoindoles with excellent stereoselectivity.
Scheme 1. Intramolecular cyclization of 2-alkynylbenzimidates
2. Results and discussion
We initiated our investigation by examing the reaction of methyl 2-
(phenylethynyl)benzimidate (1a) in MeCN. In the presence of 3.0 equiv of K2CO3, a mixture of 1-
benzylidene-3-methoxyisoindole (2a) and 1-methoxy-3-phenylisoquinoline (2a') was obtained
in a 55% total yield with a moderate 3.3:1 regioselectivity (5-exo-dig vs 6-endo-dig) (Table 1,
entry 1). The reaction shows excellent stereoselectivity (Z-5-exo vs E-5-exo) and only the Z-
isomer of 2a was obtained. Encouraged by this promising result, we first investigated the effect
of bases on the reaction. A little bit lower yield and similar regioselectivity were obtained when
using Na2CO3 as the base (Table 1, entry 2). However, using Cs2CO3 as the base only provided 8%
of the cyclized products (Table 1, entry 3). A weaker base such as NaOAc led to better
regioselectivity, albeit in a lower 45% yield (Table 1, entry 4). Interestingly, t-BuOK which was
successfully applied in the cyclization of o-alkynylbenzamides, did not provide any cyclization
product (Table 1, entry 5). When pyridine was employed, a lower yield was observed with a

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similar regioselectivity (Table 1, entry 6). 4-Dimethylaminopyridine (DMAP) which is a stronger
base than pyridine, afforded a better 61% yield with similar regioselectivity (Table 1, entry 7).
Using protic solvents which can readily protonate alkenyl anion intermediates generated in the
cyclization, dramatically improved the regioselectivity (Table 1. entries 9-12) and iPrOH
outperformed in both yield and regioselectivity. The yield and selectivity can be further
improved by employing catalytic 15 mol % of DMAP (Table 1, entry 13). In the absence of DMAP,
a much lower 51% yield of 2a was obtained and 15% of 1a was recovered under otherwise
same conditions (Table 1, entry 14). In addition, prolonging reaction time would not make the
reaction complete. The optimized conditions were thus selected on the basis of these results.
Table 1. Optimization of reactiona
Entry Solvent
Base
Yield (%)b
Ratio (2a : 2a’)
3.3 : 1
55
49
8
1
2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeOH
EtOH
K2CO3 (3.0 eq.)
Na2CO3 (3.0 eq.)
Cs2CO3 (3.0 eq.)
NaOAc (3.0 eq.)
t-BuOK (3.0 eq.)
pyridine (1.0 eq.)
DMAP (1.0 eq.)
DMAP (1.0 eq.)
DMAP (1.0 eq.)
DMAP (1.0 eq.)
DMAP (1.0 eq.)
DMAP (0.15 eq.)
-
4.0 : 1
4.3 : 1
3
45
4.8 : 1
4
5
0
39
61
50
61
72
71
75
51
3.2 : 1
4.0 : 1
7.8 : 1
8.4 : 1
8.0 : 1
7.5 : 1
10 : 1
6 : 1
6
7
9
10
11
12
13
14c
iPrOH
tBuOH
iPrOH
iPrOH
aReaction conditions: 1a (0.2 mmol), base, solvent (1.5 mL), 70 °C, 24 h, air. bIsolated yield. c15%
of 1a was recovered.
With the optimized conditions in hand (Table 1, entry 13), the scope of this cyclization
was examined (Table 2). This DMAP-catalyzed cyclization was found to be completely

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stereoselective and only Z-isomer of
2
was obtained in all cases. When phenyl on the
remote end of the alkyne moiety was substituted with a strong electron-withdrawing-
group on the para position, only the desired products 2b-e were isolated (Table 2,
entries 2-5). An electron-donating para methoxy substitution led to an incomplete
reaction because the carbon–carbon triple bond is not sufficiently polarized and
produced isomers 2g and 2g′ in 36% and 16% yields, respectively (Table 2, entry 7).
Phenyl and phenyl substituted with a halide or an alkyl group afforded the desired 1-
methylene-3-methoxyisoindoles 2a, 2f, 2h and 2i in 60-68% yields and 0-8% yields of the
isomeric 1-methoxyisoquinolines (Table 2, entries 1, 6, 8 and 9). All these results are
consistent with an intramolecular anion cyclization mechanism [9]. Alkyl and alkenyl
substituted alkynes afforded 1-methoxyisoquinolines 2j
′ and 2k′ as the major
products (Table 2, entries 10 and 11). The effect of substitution on the aromatic ring
bearing imidate group has also been examined. Halide, alkyl, methoxy and CF3 group are
all well tolerated (Table 1, entries 12-18). The existing of a substitution on the 6-positon
of methyl 2-alkynylbenzimidate enhanced the selectivity and afforded predominantly 2p
(Table 2. entry 16). Methyl 2-naphthimidate 1s produced isomers 2s and 2s
′ in 57%
and 15% yields, respectively, favoring the desired product 2s (Table 2. entry 19). The
structure of 2s was confirmed by single-crystal X-ray diffraction [10]. It is worth noting
that, although the isomeric 1-methoxy isoquinolines were isolated as undesired
products in this chemistry, they are still medicinally important hetereocycles.
Table 2. DMAP-catalyzed cyclization of methyl 2-alkynylbenzimidatesa
Entry
Product (s)
% Isolated Yield(s)

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R
1
2
H
2a
2b
2c
2d
2e
2f
2a’
2b’
2c’
2d’
2e’
2f’
68+7
74+0
66+0
62+0
48+0
60+8
36+16
63+5
63+0
p-CO2Et
o-CO2Me
p-CF3
p-CN
3
4
5
6
p-F
7b
8c
9d
p-OMe
o-Me
o-i-Pr
2g
2h
2i
2g’
2h’
2i’
10e
2j
2j’
21+45
11
2k
2k’
24+58
12
2l
2l’
52+0
OMe
Me
N
13
Ph
2m
2m’
54+7
R

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14
15
H
2n
2n’
2o’
47+12
61+0
CO2Me 2o
16f
2p
2p’
50+0
R
17
18
H
2q
2q’
2r’
72+8
72+0
CO2Et 2r
19
2s
2s’
57+15
b
aReaction conditions: 1 (0.2 mmol), DMAP (0.15 eq.), iPrOH (1.5 mL), 70 °C, 24 h. 18% of SM
recovered. c12% of SM recovered. d11% of SM recovered. e90 °C. f37% of SM recovered.
Comparing with silver catalyzed cyclization of methyl 2-alkynylbenzimidates, DMAP catalyzed
cyclization showed much improved regioselectivity favoring 5-exo-dig in all the cases. Although
the same trend is followed by these two conditions in most cases, it should be noted that when
phenyl on the remote end of the alkyne moiety has an ortho substitution, 6-endo-dig cyclization
is disfavored in DAMP catalyzed cyclization because of the steric hindrance during cyclization,
which led to formation of 2h and 2i as the major products (Table 2, entries 8 and 9). This is a

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notable contrast to transition-metal-catalyzed cyclization of 2-alkynyl-benzimidates, in which 1-
alkoxyisoquinoline 2h’ and 2i′ were the major products (Scheme 2) [7d].
Scheme 2. Comparison of DMPA catalyzed cyclization with silver-catalyzed cyclization
The proposed mechanism for the DMAP catalyzed cyclization of methyl 2-
alkynylbenzimidates is shown in Scheme 3. The benzimidate N-H was first deprotonated
by DMAP to form imidate nitranion
I. A 5-exo-dig and 6-endo-dig cyclization onto the
triple bond could generate carboanion intermediate II and III, which could be
protonated by DMAP·H+ to afford product
catalyst DMAP.
2 and 2' and simultaneously regenerate the
Scheme 3. Proposed mechanism

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To demonstrated the synthetic utility of the present method, the DMAP catalyzed cyclization
was amenable to scale-up to gram quantities, which proceeded with same efficiency as the
milligram-scale reaction (Scheme 4).
Scheme 4. Gram-scale synthesis of 2b
The versatility of this cyclization chemistry was further demonstrated by elaboration of the 1-
methylene-3-methoxyisoindole products 2. 3-Amino-1-methyleneisoindoles 3 were prepared by
reacting 2 with various amines such as primary amine, secondary amine and aniline (Scheme 5).
3-Methoxyisoindoles 4 were prepared by Pd/C-catalyzed hydrogenation. Demethylation of 2
afforded 3-methyleneisoindolin-1-ones 5, which can be converted to 3-benzylisoindolin-1-ones
6 by Pd/C hydrogenation (Scheme 6).
Scheme 5. Preparation of 3-amino-1-methyleneisoindoles (3)a and 1-benzyl-3-
methoxyisoindoles (4)b.

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aReaction conditions: 2a (0.2 mmol) and amine (1.2 mmol) in MeOH (0.4 mL) at 50 °C for 24h.
bReaction conditions: 2 (0.5 mmol), Pd/C (10 mol %) and H2 (1 atm) in MeOH (15 mL) at RT for 12h.
cAmine (12 mmol) in iPrOH (1 mL) at 100 °C for 24h. d14% of SM was recovered.
Scheme 6. Preparation of 3-methyleneisoindolin-1-ones (5)a and 3-benzylisoindolin-1-ones (6)b.
aReaction conditions: 2 (0.5 mmol), TsOH (7.5 mmol) and NaBr (30 mmol) in MeOH (70 mL) at 50 °C for
2h.
bReaction conditions: 5 (0.3 mmol), H2 (1 atm) and Pd/C (10 mol %) in MeOH (10 mL) at RT for 7h
.
3. Conclusions
In summary, we have developed an efficient, regio- and stereoselective synthesis of
1-methylene-3-methoxyisoindoles via DMAP-catalyzed cyclization of methyl 2-alkynyl-
benzimidates. This method features mild reaction conditions, excellent Z-
stereoselectivity, scalability and good functional group compatibility. Comparing with
silver catalyzed cyclization of methyl 2-alkynylbenzimidates, DMAP catalyzed cyclization
showed much improved regioselectivity favoring 5-exo-dig in all the cases. The 3-methoxy-1-
methyleneisoindole products can be efficiently converted to corresponding 3-

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methyleneisoindolin-1-ones, isoindolin-1-ones, 3-methoxyisoindoles and 3-amino-1-
methylene-isoindoles.
4. Experimental
4.1 General information
NMR spectra were recorded on a Bruker AM 400 or 600 MHz spectrometer and calibrated
using residual undeuterated solvent as an internal reference (CDCl3 (1H): δ = 7.26 ppm; CDCl3
(13C): δ = 77.16 ppm; DMSO-d6 (1H): 2.50 ppm; DMSO-d6 (13C): 39.52 ppm). HPLC/MS analysis
was carried out with gradient elution (5% CH3CN to 100% CH3CN) on an Agilent 1200 RRLC with
a photodiode array UV detector and an Agilent 6224 TOF mass spectrometer (also used to
produce high resolution mass spectra). Melting points were determined on a Stanford Research
Systems OptiMelt apparatus. The infrared (IR) spectra were acquired as thin films using a
universal ATR sampling accessory on a Bruker Vertex 80 FT-IR spectrometer and the absorption
frequencies are reported in cm-1. Flash chromatography separations were carried out using
silica gel columns. The new compounds were characterized by 1H NMR,13C NMR, HRMS, and IR.
The structure of known compounds were further confirmed by comparing their 1H NMR and 13C
NMR data with those of literature. All reagents and solvents were used as received from
commercial
sources
without
further
purification.
2-((4-
(Trifluoromethyl)phenyl)ethynyl)benzamide [11], 2-(cyclohex-1-en-1-ylethynyl) benzamide [12],
1b [7d], 1c [7d], 1g [7d], 1f[7d], 1g[7d], 1h[7d], 1i[7d], 1n[7d], and 1p[7d] were prepared
according to literature procedure.
4.2. Synthesis of 2-bromo-5-(trifluoromethyl)benzamide.
A solution of 2-bromo-5-(trifluoromethyl)benzoic acid (2.67 g, 10.0 mmol, 1.0 equiv) in
thionyl chloride (10 mL) was refluxed for 3h. After cooling down to room temperature, excess
thionyl chloride was removed under reduced pressure. Aqueous ammonia (25 wt %, 10 mL) was
added drop-wise and the reaction was stirred for 16h at room temperature. The precipitate was
collected by filtration, washed with water and dried under air to afford desired product as a

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white solid (2.63 g, 98%): m.p.: 163-164 °C. 1H NMR (600 MHz, DMSO) δ 8.06 (s, 1H), 7.90 (d, J =
8.3 Hz, 1H), 7.78 (s, 1H), 7.75 – 7.66 (m, 2H). 13C{1H} NMR (151 MHz, DMSO) δ 167.8, 140.3,
134.0, 128.2 (q, J = 32.2 Hz), 127.2 (d, J = 3.3 Hz), 125.1 (q, J = 3.7 Hz), 123.7 (d, J = 272.7 Hz),
123.5 (d, J = 1.4 Hz). IR (neat) 3354, 1721, 1499, 1123 cm-1. HRMS (ESI-TOF) m/z: [M+Na] + calcd
for C8H5BrF3NNaO 289.9399; found 289.9394.
4.3. General procedure for the synthesis of 2-alkynylbenzamides.
To a solution of 2-halobenzamide (2.0 mmol, 1.0 equiv) in MeCN (13 mL) were added
PdCl2(PPh3)2 (0.05 equiv), terminal alkyne (1.2 equiv.), and Et3N (3.0 equiv.). The resulting
mixture was stirred at 80 °C under argon. The progress of the reaction was monitored by TLC
analysis to establish completion. After cooling to room temperature, the reaction was diluted
with ethyl acetate (30 mL), washed with water (30 mL) and brine (30 mL). The organic phase
was dried (anhydrous MgSO4) and concentrated under reduced pressure. The residue was
purified by column chromatography (Silica Gel, petroleum ether / ethyl acetate).
4.3.1. 2-((4-Cyanophenyl)ethynyl)benzamide [13]. This product was obtained as a yellow solid
1
(0.399 g, 81%): m.p.: 172-173 °C. H NMR (400 MHz, CDCl3) δ 8.00 – 7.96 (m, 1H), 7.67 – 7.57
(m, 5H), 7.52 – 7.47 (m, 2H), 6.91 (s, 1H), 6.25 (s, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 168.6,
135.9, 133.9, 132.4, 132.3, 131.2, 130.0, 129.8, 127.3, 119.5, 118.5, 112.6, 93.5, 91.8. IR (neat)
3297, 3183, 3051, 2223, 1647, 1499 cm-1. HRMS (ESI-TOF) m/z: [M+H] + calcd for C16H11N2O
247.0866; found 247.0866.
4.3.2. 2-(Hex-1-yn-1-yl)benzamide. This product was obtained as a yellow solid (0.334 g, 83%)
and the spectral data were consistent with literature [14]. 1H NMR (400 MHz, CDCl3) δ 8.14 –
8.08 (m, 1H), 7.67 (s, 1H), 7.50 – 7.45 (m, 1H), 7.42 – 7.33 (m, 2H), 5.78 (s, 1H), 2.48 (t, J = 7.1
Hz, 2H), 1.65 – 1.56 (m, 2H), 1.52 – 1.41 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H).
4.3.3. 2-Fluoro-6-(phenylethynyl)benzamide. This product was obtained as a pale yellow solid
(0.391 g, 72%): m.p. 136-138 °C. 1H NMR (400 MHz, CDCl3) δ 7.52 – 7.46 (m, 2H), 7.39 – 7.26 (m,
5H), 7.11 – 7.03 (m, 1H), 6.62 (s, 1H), 6.11 (s, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 166.0, 159.5
(d, J = 251.5 Hz), 132.0, 131.2 (d, J = 10.1 Hz), 129.1, 128.8 (d, J = 3.0 Hz), 128.6, 126.3 (d, J =

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17.2 Hz), 123.3 (d, J = 5.1 Hz), 122.6, 116.3 (d, J = 22.2 Hz), 94.8, 86.0 (d, J = 4.0 Hz). IR (neat)
3841, 2210, 1650, 1493 cm-1. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C15H10FNNaO 262.0639;
found 262.0639.
4.3.4. 5-Methyl-2-(phenylethynyl)benzamide. This product was obtained as a yellow solid
(0.419 g, 89%) and the spectral data were consistent with literature [11]. 1H NMR (400 MHz,
CDCl3) δ 7.94 (s, 1H), 7.54 – 7.44 (m, 4H), 7.37 (d, J = 2.4 Hz, 2H), 7.36 (s, 1H), 7.28 (d, J = 7.7 Hz,
1H), 5.88 (s, 1H), 2.40 (s, 3H).
4.3.5. Methyl 2-((2-carbamoyl-4,5-dimethoxyphenyl)ethynyl)benzoate. This product was
1
obtained as a pale yellow solid (0.658 g, 97%): m.p.: 148-151 °C. H NMR (400 MHz, CDCl3) δ
8.41 (s, 1H), 7.90 (d, J = 7.4 Hz, 1H), 7.68 (s, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H),
7.29 (t, J = 7.6 Hz, 1H), 6.96 (s, 1H), 6.47 (s, 1H), 3.851 (s, 3H), 3.845 (s, 3H), 3.81 (s, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 167.2, 166.1, 150.7, 149.5, 134.5, 132.1, 130.6, 130.3, 128.4, 127.5,
123.3, 115.6, 113.1, 113.0, 93.4, 92.9, 56.1, 56.0, 52.4; IR (neat) 3825, 2925, 2847, 2374, 1723,
1657, 1591, 1514 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C19H18NO5 340.1179; found
340.1180.
4.3.5. 2-(Phenylethynyl)-5-(trifluoromethyl)benzamide. This product was obtained as a white
1
solid (0.463 g, 80%): m.p.: 136-138 °C. H NMR (600 MHz, CDCl3) δ 8.38 (s, 1H), 7.75 – 7.66 (m,
2H), 7.57 – 7.50 (m, 2H), 7.46 (s, 1H), 7.43 – 7.31 (m, 3H), 6.85 (s, 1H); 13C{1H} NMR (151 MHz,
CDCl3) δ 135.5, 134.2, 131.9, 130.9 (q, J = 33.0 Hz), 130.0, 128.9, 127.7 (q, J = 3.6 Hz), 127.6,
124.0, 123.6(q, J = 272.9 Hz), 121.5, 98.5, 86.6 (one carbon missing due to overlap); IR (neat)
3378, 2220, 1650, 1615, 1496, 1120 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H11F3NO
290.0787; found 290.0790.
4.3.6. Ethyl 4-((2-carbamoyl-4-(trifluoromethyl)phenyl)ethynyl)-benzoate. This product was
1
obtained as a white solid (0.412 g, 57%): m.p.: 155-156 °C. H NMR (600 MHz, CDCl3) δ 8.31 (s,
1H), 8.03 (d, J = 8.3 Hz, 2H), 7.75 – 7.68 (m, 2H), 7.58 (d, J = 8.3 Hz, 2H), 7.24 (s, 1H), 6.84 (s, 1H),
4.37 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 167.3, 165.9,
136.1, 134.3, 131.8, 131.4, 131.3 (d, J = 33.2 Hz), 129.9, 127.7 (d, J = 3.3 Hz), 127.4 (q, J = 3.6

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Hz), 126.0, 123.55 (d, J = 272.9 Hz), 123.53, 97.1, 88.9, 61.6, 14.5; IR (neat) 3368, 2985, 2216,
1722, 1646, 1612, 1445, 1123 cm-1. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C19H15F3NO3
362.0999; found 362.1000.
4.3.7. 1-(Phenylethynyl)-2-naphthamide. This product was obtained as a white solid (0.532 g,
1
98%): m.p. 170-171 °C; H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 8.1 Hz, 1H), 8.10 (d, J = 8.7 Hz,
1H), 7.89 (t, J = 7.9 Hz, 2H), 7.71 – 7.54 (m, 4H), 7.50 (s, 1H), 7.46 – 7.38 (m, 3H), 6.22 (s, 1H).
13C{1H} NMR (101 MHz, CDCl3) δ 169.2, 134.4, 133.9, 133.3, 131.8, 129.6, 129.2, 128.9, 128.5,
128.2, 127.8, 127.5, 126.2, 122.4, 118.5, 102.0, 85.9; IR (neat) 3362, 3050, 2913, 1792cm-1;
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C19H14NO 272.1070; found 272.1069.
4.4. General Procedure for the Synthesis of methyl 2-alkynylbenzimidates 1.
To a solution of 2-alkynylbenzamide (0.5 mmol, 1.0 equiv) in CH2Cl2 (6 mL) at 0°C, was added
trimethyloxonium tetrafluoroborate (1.5 equiv.). The reaction mixture was warmed up to room
temperature and stirred overnight. The completed reaction was quenched with methanol (1.5
mL) and concentrated under reduced pressure. The residue was purification by column
chromatography (deactivated Silica Gel, DCM/MeOH) to afford methyl 2-alkynylbenzimidates 1.
4.4.1. Methyl 2-((4-(trifluoromethyl)phenyl)ethynyl)benzimidate (1d). This product was
obtained as a yellow oil (0.107 g, 70%): 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 7.77 – 7.71 (m,
1H), 7.66 - 7.57 (m, 5H), 7.42 – 7.38 (m, 2H), 3.94 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.2,
134.9, 133.9, 132.1, 130.7 (d, J = 32.3 Hz), 130.2, 129.2, 128.3, 126.5, 125.6 (q, J = 3.8 Hz), 124.0
(d, J = 273.7 Hz), 120.6, 93.9, 89.6, 53.7; IR (neat) 3037, 2940, 2308 1440 cm-1; HRMS (ESI-TOF)
m/z: [M+H]+ calcd for C17H13F3NO 304.0944; found 304.0945.
4.4.2. Methyl 2-((4-cyanophenyl)ethynyl)benzimidate (1e). This product was obtained as a
yellow oil (0.096 g, 74%): 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.1 Hz, 1H), 7.68 – 7.56 (m,
5H), 7.51 – 7.37 (m, 2H), 4.04 (s, 3H). This compound is not stable enough to obtain 13C{1H}
NMR; IR (neat) 2929, 2677, 2219 1535, 1385 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C17H13N2O 261.1022; found 261.1023.

ACCEPTED MANUSCRIPT
4.4.3. Methyl 2-(cyclohex-1-en-1-ylethynyl)benzimidate (1j). This product was obtained as a
1
yellow oil (0.073 g, 61%): H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 7.72 (d, J = 7.3 Hz, 1H), 7.46
(d, J = 7.2 Hz, 1H), 7.36 – 7.25 (m, 2H), 6.26 (t, J = 6.0 Hz, 1H), 3.89 (s, 3H), 2.32 – 2.17 (m, 2H),
2.17 – 2.06 (m, 2H), 1.70 – 1.53 (m, 4H); 13C{1H} NMR (101 MHz, CDCl3) δ 166.7, 136.8, 133.6,
133.3, 130.0, 128.1, 128.0 121.8, 120.5, 98.0, 84.9, 53.5, 29.0, 26.0, 22.4, 21.6; IR (neat) 2932,
2858, 2198, 1544, 1436 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H18NO 240.1383; found
240.1382.
4.4.4. Methyl 2-(hex-1-yn-1-yl)benzimidate (1k). This product was obtained as a yellow oil
(0.080 g, 74%): 1H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 7.74 – 7.69 (m, 1H), 7.49 – 7.43 (m, 1H),
7.34 – 7.25 (m, 2H), 3.89 (s, 3H), 2.45 (t, J = 7.1 Hz, 2H), 1.66 – 1.55 (m, 2H), 1.51 – 1.40 (m, 2H),
0.92 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 166.9, 134.1 133.5, 123.0, 128.0, 127.8,
122.1, 97.7, 78.8, 53.4, 30.8, 22.3, 19.6, 13.8; IR (neat) 3454, 3337, 2934, 2867, 2225, 1573,
1486 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C12H16NO 216.1383; found 216.1384.
4.4.5. Methyl 2-fluoro-6-(phenylethynyl)benzimidate (1l). This product was obtained as a yellow
oil (0.084 g, 67%): 1H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 7.52 – 7.46 (m, 2H), 7.38 – 7.30 (m,
5H), 7.10 – 7.04 (m, 1H),3.96 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 164.9, 159.0 (d, J = 251.5
Hz), 131.9, 130.8 (d, J = 9.1 Hz), 129.1, 128.6, 128.3 (d, J = 4.0 Hz), 125.9 (d, J = 17.2 Hz), 123.4
(d, J = 3 Hz), 122.6, 116.3 (d, J = 22.2 Hz), 94.5, 86.0 (d, J = 4.0 Hz), 53.9; IR (neat) 2947, 2849,
2214, 1607, 1566, 1493 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H13FNO 254.0976; found
254.0976.
4.4.6. Methyl 5-methyl-2-(phenylethynyl)benzimidate (1m). This product was obtained as a
1
yellow oil (0.085 g, 68%): H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 7.57 (s, 1H), 7.56 – 7.52 (m,
2H), 7.49 (d, J = 7.9 Hz, 1H), 7.36 – 7.31 (m, 3H), 7.23 – 7.17 (m, 1H), 3.93 (s, 3H), 2.37 (s, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 167.1, 138.9, 134.0, 133.7, 131.8, 130.9, 128.9, 128.8, 128.6,
122.9, 118.3, 95.0, 87.5, 53.6, 21.6; IR (neat) 3293, 3038, 2309, 1502, 1543 cm-1; HRMS (ESI-
TOF) m/z: [M+H]+ calcd for C17H16NO 250.1226; found 250.1228.

ACCEPTED MANUSCRIPT
4.4.7. Methyl 2-((2-(imino(methoxy)methyl)-4,5-dimethoxyphen-yl)ethynyl) benzoate (1o). This
1
product was obtained as a yellow oil (0.076 g, 45%) and 56% of SM was recovered. H NMR
(400 MHz, CDCl3) δ 7.94 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.32
(t, J = 7.6 Hz, 1H), 7.28 (s, 1H), 7.05 (s, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 3.87 (s, 6H); 13C{1H} NMR
(101 MHz, CDCl3) δ 166.3, 166.0, 150.3, 149.2, 134.2, 132.0, 131.2, 130.7, 128.4, 126.0, 123.3,
115.9, 114.5, 110.9, 93.7, 92.0, 56.13, 56.10, 54.2, 52.5; IR (neat) 3433, 3326, 2925, 2854, 2202,
1721, 1590, 1450 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C20H20NO5 354.1336; found
354.1340.
4.4.8. Methyl 2-(phenylethynyl)-5-(trifluoromethyl)benzimidate (1q). This product was obtained
1
as a yellow oil (0.071 g, 47%): H NMR (600 MHz, CDCl3) δ 8.03 (s, 1H), 7.71 (d, J = 8.1 Hz, 1H),
7.63 (d, J = 8.1 Hz, 1H), 7.58-7.55 (m, 2H), 7.39-7.34 (m, 3H), 3.97 (s, 3H); 13C{1H} NMR (151
MHz, CDCl3) δ 165.7, 134.4, 134.2, 132.1, 130.4 (q, J = 33.1 Hz), 129.7, 128.8, 126.7 (q, J = 3.5
Hz), 125.5 (q, J = 3.3 Hz), 125.1, 123.7 (q, J = 272.6 Hz), 122.0, 98.4, 86.2, 54.0; IR (neat) 3480,
2949, 2215, 1645, 1610, 1496, 1129 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H13F3NO
304.0944; found 304.0947.
4.4.9. Ethyl 4-((2-(imino(methoxy)methyl)-4-(trifluoromethyl)phen-yl)ethynyl)benzoate (1r).
1
This product was obtained as a yellow oil (0.079 g, 42%): H NMR (600 MHz, CDCl3) δ 8.05 –
8.01 (m, 3H), 7.73 (d, J = 8.1 Hz, 1H), 7.65 (dd, J = 8.1, 0.8 Hz, 1H), 7.61 (d, J = 8.3 Hz, 2H), 4.37
(q, J = 7.1 Hz, 2H), 3.98 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 166.0,
165.7, 134.8, 134.4, 131.9, 131.2, 130.9 (q, J = 33.7 Hz), 129.8, 126.8(q, J = 3.6 Hz), 126.4, 125.6
(q, J = 3.8 Hz), 124.5, 124.1 (q, J = 272.6 Hz), 97.1, 88.6, 61.5, 54.1, 14.5; IR (neat) 3668, 3337,
2941, 2214, 1720, 1645, 1606, 1442, 1127 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C20H17F3NO3 376.1155; found 376.1156.
4.4.10. Methyl 1-(phenylethynyl)-2-naphthimidate (1s). This product was obtained as a light
green oil (0.096 g, 67%): 1H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 8.3 Hz, 1H), 7.88 – 7.76 (m, 3H),
7.71 – 7.53 (m, 4H), 7.44 – 7.36 (m, 3H), 4.05 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 168.1,
133.8, 133.5, 132.9, 131.9, 129.3, 128.8, 128.7, 128.3, 127.9, 127.7, 127.3, 124.7, 122.8, 119.5,

ACCEPTED MANUSCRIPT
101.6, 85.3, 54.3; IR (neat) 3058, 2929, 2582, 2204, 1642, 1437 cm-1; HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C20H16NO 286.1226; found 286.1227.
4.5. General Procedure for the Cyclization of Methyl 2-alkynylbenzimidates.
A solution of compound 1 (0.2 mmol, 1.0 equiv) and 4-dimethylaminopyridine (15 mol %) in
isopropanol (1.5 mL) was heated at 70 °C for 24h. After cooling to room temperature, the
reaction mixture was diluted with brine (20 mL), and extracted with EtOAc (20 mL x 2). The
combined organic layers were dried with anhydrous MgSO4, filtered and concentrated under
reduced pressure. The residue was purified by column chromatography (Silica Gel, petroleum
ether/EtOAc).
4.5.1. (Z)-1-Benzylidene-3-methoxy-1H-isoindole (2a). This product was obtained as a white
solid (0.032 g, 68%): m.p. 93-94 °C; (lit. [7d] 94-96 °C). The spectral data are consistent with
1
literature [7d]. H NMR (400 MHz, CDCl3) δ 8.25 – 8.19 (m, 2H), 7.76 (d, J = 7.6 Hz, 1H), 7.59 –
7.54 (m, 1H), 7.47 – 7.38 (m, 3H), 7.35 (td, J = 7.4, 0.8 Hz, 1H), 7.32 – 7.26 (m, 1H), 6.90 (s, 1H),
4.27 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 173.4, 145.5, 143.2, 136.3, 131.4, 130.2, 129.5,
128.7, 128.3, 127.7, 120.4, 120.0, 119.7, 56.4.
4.5.2. 1-Methoxy-3-phenylisoquinoline (2a’). This product was obtained as a white solid (0.0033
g, 7%): m.p. 41-42 °C; (lit. [7d] 41-42 °C). The spectral data are consistent with literature [7d]. 1H
NMR (400 MHz, CDCl3) δ 8.23 (d, J = 8.2 Hz, 1H), 8.17 (d, J = 7.4 Hz, 2H), 7.77 (d, J = 8.2 Hz, 1H),
7.68 (s, 1H), 7.66 – 7.60 (m, 1H), 7.53 – 7.44 (m, 3H), 7.38 (t, J = 7.3 Hz, 1H), 4.23 (s, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 160.7, 148.1, 139.7, 139.0, 130.7, 128.8, 128.6, 126.9, 126.8, 126.6,
124.4, 119.2, 110.6, 53.8.
4.5.3. Ethyl (Z)-4-((3-methoxy-1H-isoindol-1-ylidene)methyl)benzo-ate (2b). This product was
obtained as a white solid (0.0468 g, 74%): m.p. 92-93 °C; (lit. [7d] 94-96 °C). The spectral data
are consistent with literature [7d]. 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.4 Hz, 2H), 8.06 (d, J
= 8.4 Hz, 2H), 7.73 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 7.4 Hz, 1H), 7.44 (td, J = 7.5, 0.9 Hz, 1H), 7.36 (t,
J = 7.4 Hz, 1H), 6.87 (s, 1H), 4.37 (q, J = 7.1 Hz, 2H), 4.26 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H); 13C{1H}

ACCEPTED MANUSCRIPT
NMR (101 MHz, CDCl3) δ 174.1, 166.7, 147.4, 143.0, 140.8, 131.0, 130.5, 129.8, 129.4, 128.2,
120.6, 119.9, 118.5, 61.1, 56.6, 14.6 (one carbon missing due to overlap).
4.5.4. Methyl (Z)-2-((3-methoxy-1H-isoindol-1-ylidene)methyl)be-nzoate (2c). This product was
obtained as a yellow solid (0.0384 g, 66%): m.p. 67-69 °C; (lit. [7d] 65-66 °C). The spectral data
are consistent with literature [7d]. 1H NMR (400 MHz, CDCl3) δ 8.73 (d, J = 7.9 Hz, 1H), 7.94 (dd,
J = 7.9, 1.2 Hz, 1H), 7.85 – 7.80 (m, 2H), 7.60 – 7.52 (m, 2H), 7.45 (td, J = 7.5, 1.0 Hz, 1H), 7.38 –
7.30 (m, 2H), 4.22 (s, 3H), 3.90 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 174.0, 168.3, 146.6,
143.2, 136.8, 133.5, 131.8, 130.7, 130.4, 130.2, 129.7, 128.0, 127.5, 120.3, 120.2, 117.6, 56.4,
52.3.
4.5.5. (Z)-3-Methoxy-1-(4-(trifluoromethyl)benzylidene)-1H-isoindole (2d). This product was
obtained as a white solid (0.037 g, 62%): m.p. 117-119 °C; 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J
= 8.1 Hz, 2H), 7.74 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 7.4 Hz, 1H), 7.46 (t, J =
7.3 Hz, 1H), 7.37 (t, J = 7.3 Hz, 1H), 6.86 (s, 1H), 4.26 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
174.3, 147.5, 142.9, 139.8, 131.3, 130.5, 129.9, 129.4 (q, J = 32.4 Hz), 128.3, 125.5 (q, J = 3.7 Hz),
124.5 (q, J = 272.7 Hz), 120.6, 120.0, 117.9, 56.6; IR (neat) 3046, 2918, 1577, 1445 cm-1; HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C17H13F3NO 304.0944; found 304.0944.
4.5.6. (Z)-4-((3-Methoxy-1H-isoindol-1-ylidene)methyl)benzo-nitrile (2e). This product was
obtained as a white solid (0.025 g, 48%): m.p. 152-153 °C; 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J
= 6.9 Hz, 2H), 7.72 (d, J = 7.5 Hz, 1H), 7.64 (d, J = 7.2 Hz, 2H), 7.56 (d, J = 7.5 Hz, 1H), 7.46 (t, J =
7.4 Hz, 1H), 7.38 (t, J = 7.4 Hz, 1H), 6.80 (s, 1H), 4.26 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
174.6, 148.4, 142.7, 140.9, 132.3, 131.4, 130.6, 130.0, 128.6, 120.8 120.0, 119.5, 117.3, 110.7,
56.7; IR (neat) 2941, 1643, 1596, 1534 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H13N2O
261.1022; found 261.1024.
4.5.7. (Z)-1-(4-Fluorobenzylidene)-3-methoxy-1H-isoindole (2f). This product was obtained as a
white solid (0.0294 g, 58%): m.p. 89-90 °C; (lit. [7d] 88-89 °C). The spectral data are consistent
1
with literature [7d]. H NMR (400 MHz, CDCl3) δ 8.24 – 8.18 (m, 2H), 7.73 (d, J = 7.6 Hz, 1H),
7.55 (d, J = 7.5 Hz, 1H), 7.44 (td, J = 7.5, 1.0 Hz, 1H), 7.35 (td, J = 7.4, 0.8 Hz, 1H), 7.11 – 7.05 (m,

ACCEPTED MANUSCRIPT
2H), 6.85 (s, 1H), 4.25 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 173.5, 162.7 (d, J = 250.5 Hz),
145.0, 143.1, 133.1 (d, J = 8.0 Hz), 132.6 (d, J = 3.3 Hz), 130.2, 129.6, 127.8, 120.5, 119.6, 118.7,
115.7 (d, J = 21.6 Hz), 56.4.
4.5.8. 3-(4-Fluorophenyl)-1-methoxyisoquinoline (2f’). This product was obtained as a white
solid (0.004 g, 8%): m.p. 79-81 °C; (lit. [7d] 81-83 °C). The spectral data are consistent with
literature [7d]. 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.3 Hz, 1H), 8.17 – 8.09 (m, 2H), 7.75 (d, J
= 8.1 Hz, 1H), 7.67 – 7.58 (m, 2H), 7.52 – 7.45 (m, 1H), 7.19 – 7.10 (m, 2H), 4.22 (s, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ163.4 (d, J = 248.6 Hz), 160.7, 147.1, 139.0, 135.8, 130.8, 128.6, 128.5,
126.7 (d, J = 11.2 Hz), 124.4, 119.0, 115.7 (d, J = 21.5 Hz), 110.3, 53.8.
4.5.9. (Z)-3-methoxy-1-(4-methoxybenzylidene)-1H-isoindole (2g). This product was obtained as
a yellow solid (0.0193 g, 36%) and 18% of SM was recovered. m.p. 142-143 °C (lit. [7d] 143-145
°C). The spectral data are consistent with literature [7d]. 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J =
8.8 Hz, 2H), 7.73 (d, J = 7.7 Hz, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.42 (td, J = 7.6, 0.9 Hz, 1H), 7.32 (t, J
= 7.1 Hz, 1H), 6.94 (d, J = 8.9 Hz, 2H), 6.87 (s, 1H), 4.25 (s, 3H), 3.84 (s, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 172.7, 159.9, 143.6, 143.3, 132.9, 129.9, 129.3, 127.3, 120.3, 119.9, 119.5, 114.3,
56.3, 55.5 (one carbon missing due to overlap).
4.5.10. 1-Methoxy-3-(4-methoxyphenyl)isoquinoline (2g’). This product was obtained as a white
solid (0.0083 g, 16%): m.p. 56-58 °C; (lit. [7d] 58-59 °C). The spectral data are consistent with
literature [7d]. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.2 Hz, 1H), 8.14 – 8.05 (m, 2H), 7.73 (d, J
= 8.2 Hz, 1H), 7.61 (dd, J = 7.0, 1.2 Hz, 1H), 7.58 (s, 1H), 7.48 – 7.42 (m, 1H), 7.09 – 6.93 (m, 2H),
4.22 (s, 3H), 3.86 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 160.5, 160.2, 147.8, 139.2, 132.4,
130.7, 128.1, 126.6, 126.2, 124.3, 118.8, 114.2, 109.4, 55.6, 53.8.
4.5.11. (Z)-3-Methoxy-1-(2-methylbenzylidene)-1H-isoindole (2h). This product was obtained as
a white solid (0.032 g, 64%) and 12% of SM was recovered. m.p. 73-74 °C (lit. [7d] 70-71 °C). The
1
spectral data are consistent with literature [7d]. H NMR (400 MHz, CDCl3) δ 8.75 (d, J = 7.8 Hz,
1H), 7.80 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.46 (td, J = 7.5, 1.0 Hz, 1H), 7.37 (td, J = 7.4,
0.7 Hz, 1H), 7.34 – 7.28 (m, 1H), 7.23 – 7.19 (m, 2H), 7.16 (s, 1H), 4.26 (s, 3H), 2.52 (s, 3H);

ACCEPTED MANUSCRIPT
13C{1H} NMR (101 MHz, CDCl3) δ 173.5, 145.4, 143.2, 137.6, 134.5, 132.2, 130.4, 130.2, 129.4,
128.2, 127.7, 126.3, 120.3, 119.7, 117.0, 56.4, 20.5.
4.5.12. 1-Methoxy-3-(o-tolyl)isoquinoline (2h’). This product was obtained as colorless oil
(0.0030 g, 6%). The spectral data are consistent with literature [7d]. 1H NMR (400 MHz, CDCl3) δ
8.26 (d, J = 8.2 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.70 – 7.61 (m, 1H), 7.57 – 7.49 (m, 2H), 7.32 (s,
1H), 7.31 – 7.27 (m, 3H), 4.15 (s, 3H), 2.49 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 160.1, 151.0,
140.7, 138.7, 136.7, 131.1, 130.7, 130.1, 128.1, 126.63, 126.60, 126.0, 124.3, 118.6, 114.6, 54.0,
21.2.
4.5.13. (Z)-1-(2-Isopropylbenzylidene)-3-methoxy-1H-isoindole (2i). This product was obtained
as a white solid (0.0349 g, 63%) and 11% of SM was recovered. The spectral data are consistent
with literature [7d]. 1H NMR (400 MHz, CDCl3) δ 8.61 (dd, J = 6.3, 2.9 Hz, 1H), 7.81 (d, J = 7.6 Hz,
1H), 7.57 (d, J = 7.5 Hz, 1H), 7.46 (t, J = 7.4 Hz, 1H), 7.38 (d, J = 7.4 Hz, 1H), 7.36 – 7.26 (m, 4H),
4.24 (s, 3H), 3.47 (hept, J = 6.8 Hz, 1H), 1.33 (s, 3H), 1.31 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3)
δ 173.5, 147.9, 145.6, 143.3, 133.3, 132.7, 130.3, 129.4, 128.5, 127.7, 125.9, 125.1, 120.3,
119.6, 117.0, 56.4, 29.7, 23.9.
4.5.14. (Z)-1-(Cyclohex-1-en-1-ylmethylene)-3-methoxy-1H-isoindole (2j). This product was
obtained as a yellow oil (0.010 g, 21%): 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 7.6 Hz, 1H), 7.51
(d, J = 7.5 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.29 (t, J = 7.4 Hz, 1H), 6.54 (s, 1H), 6.30 (t, J = 4.4 Hz,
1H), 4.16 (s, 3H), 2.86 – 2.82 (m, 2H), 2.34 – 2.19 (m, 2H), 1.78 – 1.69 (m, 2H), 1.78 – 1.69 (m,
2H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.4, 143.4, 142.6, 137.1, 135.9, 129.8, 128.9, 127.1,
124.4, 120.0, 119.4, 56.0, 28.5, 27.1, 23.2, 22.3; IR (neat) 2937, 2862, 1583, 1442 cm-1 HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C16H18NO 240.1383; found 240.1384.
4.5.15. 3-(Cyclohex-1-en-1-yl)-1-methoxyisoquinoline (2j’). This product was obtained as a
yellow oil (0.021 g, 45%): 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 8.1 Hz,
1H), 7.57 (t, J = 7.5 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.18 – 7.11 (m, 2H), 4.14 (s, 3H), 2.59 – 2.48
(m, 2H), 2.34 – 2.30 (m, 2H), 1.89 – 1.77 (m, 2H), 1.76 – 1.65 (m, 2H); 13C{1H} NMR (101 MHz,
CDCl3) δ 159.7, 149.0, 139.0, 135.5, 130.5, 127.9, 126.7, 126.0, 124.3, 119.1, 108.6, 53.5, 26.2,

ACCEPTED MANUSCRIPT
25.9, 23.1, 22.6; IR (neat) 2929, 2858, 1627, 1578, 1498, 1453, 832 cm-1; HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C16H18NO 240.1383; found 240.1384.
4.5.16. (Z)-3-Methoxy-1-pentylidene-1H-isoindole (2k). This product was obtained as a yellow
oil (0.0103 g, 24%): 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7.5 Hz, 1H), 7.50 (d, J = 7.4 Hz, 1H),
7.39 (t, J = 7.4 Hz, 1H), 7.31 (t, J = 7.3 Hz, 1H), 6.18 (t, J = 7.6 Hz, 1H), 4.16 (s, 3H), 2.73 (q, J = 7.5
Hz, 2H), 1.55 – 1.50 (m, 2H), 1.47 – 1.37 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 171.5, 146.0, 141.8, 131.1, 129.3, 127.3, 125.3, 120.1, 119.4, 56.0, 31.9, 27.8, 22.7,
14.2; IR (neat) 2929, 2859, 1669, 1502, 1449 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C14H18NO 216.1383; found 216.1385.
4.5.17. 3-Butyl-1-methoxyisoquinoline (2k’). This product was obtained as a yellow oil (0.025 g,
1
58%) The spectral data were consistent with literature [15]. H NMR (400 MHz, CDCl3) δ 8.15
(d, J = 8.3 Hz, 1H), 7.64 – 7.53 (m, 2H), 7.41 (t, J = 7.5 Hz, 1H), 6.99 (s, 1H), 4.09 (s, 3H), 2.75 (t, J
= 7.5 Hz, 2H), 1.81–1.69 (m, 2H), 1.45 – 1.33 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 160.4, 153.2, 138.8, 130.3, 125.8, 125.7, 124.2, 118.3, 111.9, 53.7, 37.8, 31.7,
22.7, 14.3; IR (neat) 2932, 2860, 1597, 1498 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C14H18NO 216.1383; found 216.1386.
4.5.18. (Z)-1-Benzylidene-4-fluoro-3-methoxy-1H-isoindole (2l). This product was obtained as a
white solid (0.026 g, 52%): m.p. 93-95 °C; 1H NMR (400 MHz, CDCl3) δ 8.22 – 8.17 (m, 2H), 7.56
– 7.50 (m, 1H), 7.45 – 7.35 (m, 3H), 7.31 (t, J = 7.4 Hz, 1H), 6.99 (t, J = 8.7 Hz, 1H), 6.91 (s, 1H),
4.28 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.9, 156.4 (d, J = 256.5 Hz), 146.7 (d, J = 3.0 Hz),
144.8, 135.9, 131.5, 131.4, 128.7, 128.7, 121.5, 117.2 (d, J = 15 Hz), 115.7 (d, J = 3.0 Hz), 114.6
(d, J = 20.2 Hz), 56.8; IR (neat) 3022, 2924, 2852, 1473, 1443 cm-1; HRMS (ESI-TOF) m/z: [M+H]+
calcd for C16H13FNO 254.0976; found 254.0977.
4.5.19. (Z)-1-Benzylidene-3-methoxy-5-methyl-1H-isoindole (2m). This product was obtained as
a white solid (0.028 g, 54%): m.p. 78-81 °C; 1H NMR (400 MHz, CDCl3) δ 8.25 – 8.18 (m, 2H) 7.63
(d, J = 7.8 Hz, 1H), 7.41 (t, J = 7.7 Hz, 2H), 7.36 (s, 1H), 7.31 – 7.25 (m, 2H), 6.84 (s, 1H), 4.26 (s,
3H), 2.44 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 173.3, 145.4, 140.8, 137.9, 136.4, 131.2,

ACCEPTED MANUSCRIPT
130.6, 130.5, 128.7, 128.1, 120.7, 119.5, 119.4, 56.3, 21.7; IR (neat) 3022, 2923, 2852, 1473,
1443 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H16NO 250.1226; found 250.1227.
4.5.20. 1-Methoxy-7-methyl-3-phenylisoquinoline (2m’). This product was obtained as a white
solid (0.004 g, 7%): m.p. 77-79 °C; 1H NMR (400 MHz, CDCl3) δ 8.17 – 8.13 (m, 2H), 8.01 (s, 1H),
7.68 (d, J = 8.3 Hz, 1H), 7.64 (s, 1H), 7.49 – 7.43 (m, 3H), 7.38 – 7.33 (m, 1H), 4.22 (s, 3H), 2.51 (s,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ 160.2, 147.1, 139.8, 137.1, 136.6, 132.8, 128.8, 128.4,
126.7, 123.4, 119.2, 110.5, 53.7, 22.0 (one carbon missing due to overlap); IR (neat) 3026, 2924,
2856, 1574, 1452 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H16NO 250.1226; found
250.1228.
4.5.21. (Z)-1-Benzylidene-3,5,6-trimethoxy-1H-isoindole (2n). This product was obtained as a
yellow solid (0.0277 g, 47%): m.p. 144-146 °C; (lit.7d 140-143 °C). The spectral data are
consistent with literature [7d]. 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 7.4 Hz, 2H), 7.38 (t, J =
7.7 Hz, 2H), 7.29 – 7.25 (m, 1H), 7.22 (s, 1H), 7.01 (s, 1H), 6.76 (s, 1H), 4.24 (s, 3H), 3.99 (s, 3H),
3.92 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 173.3, 151.4, 149.8, 145.6, 136.9, 136.4, 131.2,
128.7, 128.1, 123.1, 119.2, 102.5, 56.40, 56.38, 56.35(one carbon missing due to overlap).
4.5.22. 1,6,7-Trimethoxy-3-phenylisoquinoline (2n’). This product was obtained as a white solid
(0.0069 g, 12%): m.p. 169-171 °C; (lit. [7d] 170-171 °C). The spectral data are consistent with
literature [7d]. 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 7.3 Hz, 2H), 7.57 (s, 1H), 7.49 (s, 1H), 7.45
(t, J = 7.6 Hz, 2H), 7.35 (t, J = 7.3 Hz, 1H), 7.06 (s, 1H), 4.21 (s, 3H), 4.01 (s, 3H), 4.00 (s, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 159.6, 153.1, 149.7, 146.9, 139.9, 135.3, 128.8, 128.2, 126.6,
113.8, 109.9, 105.7, 103.1, 56.3, 56.2, 53.7.
4.5.23. Methyl (Z)-2-((3,5,6-trimethoxy-1H-isoindol-1-ylidene)meth-yl)benzoate (2o). This
1
product was obtained as a yellow solid (0.042 g, 60%): m.p. 131-132 °C; H NMR (400 MHz,
CDCl3) δ 8.68 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.71 (s, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.30
(t, J = 7.6 Hz, 1H), 7.27 (s, 1H), 6.99 (s, 1H), 4.18 (s, 3H), 3.99 (s, 3H), 3.92 (s, 3H), 3.89 (s, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 173.9, 168.3, 151.4, 150.0, 146.7, 137.1, 136.8, 133.6, 131.8,
130.6, 129.8, 127.3, 123.3, 116.8, 102.9, 102.3, 56.5, 56.4, 52.3 (one carbon missing due to

ACCEPTED MANUSCRIPT
overlap); IR (neat) 3001, 2947, 2838, 1716, 1597 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C20H20NO5 354.1336; found 354.1338.
4.5.24. (Z)-1-Benzylidene-3,4,5-trimethoxy-1H-isoindole (2p). This product was obtained as a
yellow solid (0.030 g, 50%) and 37% of SM was recovered. m.p. 114-116 °C (lit. [7d] 116-118 °C).
The spectral data are consistent with literature [7d]. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.5
Hz, 2H), 7.45 – 7.34 (m, 3H), 7.26 (d, J = 7.4 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.75 (s, 1H), 4.27 (s,
3H), 3.96 (s, 3H), 3.90 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.1, 152.8, 144.8, 144.0, 137.6,
136.5, 131.0, 128.6, 128.0, 123.2, 118.6, 115.3, 115.0, 62.4, 57.0, 56.8.
4.5.25. (Z)-1-Benzylidene-3-methoxy-5-(trifluoromethyl)-1H-isoindole (2q). This product was
obtained as a white solid (0.044 g, 72%): m.p. 75-77 °C; 1H NMR (600 MHz, CDCl3) δ 8.22 (d, J =
7.5 Hz, 2H), 7.84 - 7.80 (m, 2H), 7.68 (d, J = 8.2 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H), 7.33 (t, J = 7.4 Hz,
1H), 6.96 (s, 1H), 4.27 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 172.2, 146.1, 144.3, 135.7, 131.7,
130.3, 129.9 (q, J = 32.8 Hz), 129.0, 128.8, 126.4 (q, J = 3.3 Hz), 124.4 (q, J = 272.4 Hz), 122.4,
120.0, 117.8 (q, J = 3.9 Hz), 56.7; IR (neat) 3026, 2924, 1684, 1595, 1450, 1123 cm-1; HRMS (ESI-
TOF) m/z: [M+H]+ calcd for C17H13F3NO 304.0944; found 304.0952.
4.5.26. 1-Methoxy-3-phenyl-7-(trifluoromethyl)isoquinoline (2q’). This product was obtained as
a yellow oil (0.005 g, 8%): 1H NMR (600 MHz, CDCl3) δ 8.53 (s, 1H), 8.19 – 8.13 (m, 2H), 7.86 (d, J
= 8.6 Hz, 1H), 7.79 (dd, J = 8.5, 1.6 Hz, 1H), 7.70 (s, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.41 (t, J = 7.3 Hz,
1H), 4.25 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 161.0, 150.5, 140.6, 139.0, 129.20 (q, J =
312.7 Hz), 129.21, 128.9, 128.1, 127.8, 127.0, 126.5 (q, J = 3.8 Hz), 122.6 (q, J = 4.2 Hz), 118.1,
110.0, 54.1; IR (neat) 2924, 2854, 1639, 1580, 1497, 1122 cm-1; HRMS (ESI-TOF) m/z: [M+H]+
calcd for C17H13F3NO 304.0944; found 304.0953.
4.5.27. Ethyl (Z)-4-((3-methoxy-5-(trifluoromethyl)-1H-isoindol-1-ylidene)methyl)benzoate (2r).
1
This product was obtained as a white solid (0.054 g, 72%): m.p. 112-113 °C; H NMR (600 MHz,
CDCl3) δ 8.24 (d, J = 8.4 Hz, 2H), 8.06 (d, J = 8.4 Hz, 2H), 7.82 - 7.78 (m, 2H), 7.68 (d, J = 7.8 Hz,
1H), 6.92 (s, 1H), 4.38 (q, J = 7.1 Hz, 2H), 4.26 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (151
MHz, CDCl3) δ 172.7, 166.4, 145.9, 145.6, 139.8, 131.2, 130.4, 130.2 (d, J = 33.2 Hz), 130.0,

ACCEPTED MANUSCRIPT
129.7, 126.5 (q, J = 3.3 Hz), 124.1 (q, J = 272.4 Hz), 120.6, 120.0, 117.7 (q, J = 3.8 Hz), 61.0, 56.6,
14.4; IR (neat) 2926, 2856, 1716, 1641, 1600, 1545, 1483, 1112 cm-1; HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C20H17F3NO3 376.1155; found 376.1155.
4.5.28. (Z)-1-Benzylidene-3-methoxy-1H-benzo[e]isoindole (2s). This product was obtained as a
light green solid (0.033 g, 57%): m.p. 163-164 °C; 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 8.5 Hz,
1H), 8.33 (d, J = 7.5 Hz, 2H), 7.94 (d, J = 8.1 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.67 – 7.60 (m, 2H),
7.59 (s, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 4.29 (s, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 173.0, 147.7, 138.5, 136.9, 135.1, 132.3, 130.1, 129.4, 129.3,
128.7, 128.6, 127.8, 126.6, 126.4, 124.1, 117.9, 56.2 (one carbon missing due to overlap); IR
(neat) 3053, 2925, 2856, 1584, 1448 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C20H16NO
286.1226; found 286.1232.
4.5.29. 4-Methoxy-2-phenylbenzo[f]isoquinoline (2s’). This product was obtained as a white
1
solid (0.0085 g, 15%): m.p. 133-135 °C; H NMR (400 MHz, CDCl3) δ 8.76 – 8.67 (m, 1H), 8.48 (s,
1H), 8.28 – 8.21 (m, 2H), 8.16 (d, J = 9.0 Hz, 1H), 7.95 – 7.88 (m, 1H), 7.78 (d, J = 9.0 Hz, 1H),
7.72 – 7.65 (m, 2H), 7.55 – 7.49 (m, 2H), 7.45 – 7.39 (m, 1H), 4.26 (s, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 161.0, 149.8, 140.0, 137.7, 134.1, 129.1, 129.0, 128.9, 128.8, 128.4, 127.3, 127.1,
127.0, 123.7, 121.3, 116.2, 106.4, 54.0; IR (neat) 2924, 2852, 1482 cm-1; HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C20H16NO 286.1226; found 286.1230.
4.6. General Procedure for the Synthesis of 3-Amino-1-methyleneisoindoles (3).
A solution of compound 2a (0.2 mmol, 1.0 equiv) and amine (1.2 mmol, 6.0 equiv.) in MeOH
(0.4 mL) was heated at 50 °C for 24 h. After cooling to room temperature, the reaction mixture
was diluted with saturated NaHCO3 (20 mL), and extracted with EtOAc (20 mL x 2). The
combined organic layers were dried with anhydrous MgSO4, filtered and concentrated. The
residue was purified by column chromatography (Silica Gel, petroleum ether/EtOAc) to afford
compound 3a.
4.6.1. (Z)-1-Benzylidene-3-(pyrrolidin-1-yl)-1H-isoindole (3a). This product was obtained as a
yellow solid (0.046 g, 84%): m.p. 212-213 °C; (lit. [16] 210-212 °C). The spectral data were

ACCEPTED MANUSCRIPT
1
consistent with literature [16]. H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 7.6 Hz, 2H), 7.78 (d, J =
7.6 Hz, 1H), 7.70 (d, J = 7.7 Hz, 1H), 7.42 – 7.33 (m, 3H), 7.30 (t, J = 7.5 Hz, 1H), 7.19 (t, J = 7.3 Hz,
1H), 6.59 (s, 1H), 3.99 (br, 4H), 2.06 (br, 4H); 13C{1H} NMR (101 MHz, CDCl3) δ 163.9, 148.1,
145.0, 137.7, 132.0, 130.5, 128.7, 128.5, 127.1, 126.7, 122.4, 120.0, 112.6, 50.0, 48.4, 26.7,
24.5; IR (neat) 3041, 2917, 2862 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C19H19N2 275.1543;
found 275.1543.
4.6.2. (Z)-1-Benzylidene-N-phenyl-1H-isoindol-3-amine (3b). This product was obtained as a
1
yellow oil (0.053 g, 89%): H NMR (400 MHz, DMSO) δ 10.02 (s, 1H), 8.28 (d, J = 7.6 Hz, 2H),
8.23– 8.14 (m, 3H), 8.00 (d, J = 7.3 Hz, 1H), 7.58 – 7.40 (m, 6H), 7.28 (t, J = 7.4 Hz, 1H), 7.10 (t, J
= 7.3 Hz, 1H), 6.99 (s, 1H); 13C{1H} NMR (101 MHz, DMSO) δ 161.0, 148.2, 141.5, 140.5, 136.9,
132.5, 130.2, 129.0, 128.8, 128.4, 127.3, 127.2, 122.6, 120.3, 119.8, 119.3, 115.3; IR (neat)
3281, 3053, 2953, 1597, 1493, 1447 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C21H17N2
297.1386; found 297.1386.
4.6.3. (Z)-1-Benzylidene-N-(4-methoxyphenyl)-1H-isoindol-3-amine (3c). This product was
1
obtained as a yellow oil (0.0653 g, 100%): H NMR (400 MHz, DMSO) δ 9.98 (s, 1H), 8.27 (d, J =
7.6 Hz, 2H), 8.20 – 8.10 (m, 3H), 7.96 (d, J = 7.1 Hz, 1H), 7.57 – 7.38 (m, 4H), 7.27 (t, J = 7.3 Hz,
1H), 7.06 (d, J = 8.9 Hz, 2H), 6.93 (s, 1H), 3.80 (s, 3H); 13C{1H} NMR (101 MHz, DMSO) δ 160.7,
154.9, 141.5, 137.0, 133.6, 132.4, 130.1, 129.0, 128.4, 127.3, 127.0, 120.7, 120.3, 119.7, 114.3,
114.1, 55.2 (one carbon missing due to overlap); IR (neat) 3298, 3040, 2920, 1511 cm-1; HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C22H19N2O 327.1492; found 327.1492.
4.6.4. (Z)-2-((1-Benzylidene-1H-isoindol-3-yl)amino)ethan-1-ol (3d). 2-Aminoethan-1-ol (12
mmol) in isopropanol (1 mL) at 100 °C was applied. This product was obtained as a pale yellow
solid (0.0354 g, 67%): m.p. 170-172 °C; 1H NMR (400 MHz, DMSO) δ 8.25 (s, 1H), 8.21 (d, J = 7.5
Hz, 2H), 7.93 – 7.84 (m, 2H), 7.46 (t, J = 7.0 Hz, 1H), 7.42 – 7.33 (m, 3H), 7.19 (t, J = 7.3 Hz, 1H),
6.70 (s, 1H), 5.12 (s, 1H), 3.78 – 3.73 (m, 2H), 3.73 – 3.66 (m, 2H); 13C{1H} NMR (101 MHz,
DMSO) δ 164.9, 148.5, 142.9, 137.5, 131.7, 130.0, 128.9, 128.2, 127.2, 126.4, 120.1, 119.5,
111.7, 59.8, 45.1; IR (neat) 3660, 3298, 3046, 2919, 2855, 1518, 1571 cm-1; HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C17H17N2O 265.1335; found 265.1336.

ACCEPTED MANUSCRIPT
4.6.5. (Z)-N-Benzyl-1-benzylidene-1H-isoindol-3-amine (3e). Phenylmethanamine (12 mmol) in
isopropanol (1 mL) at 100 °C was applied. This product was obtained as a light green solid
(0.046 g, 74%): m.p. 113-116 °C; 1H NMR (400 MHz, DMSO) δ 8.68 (t, J = 5.8 Hz, 1H), 8.23 (d, J =
7.5 Hz, 2H), 7.91 – 7.86 (m, 2H), 7.52 – 7.44 (m, 3H), 7.42 – 7.31 (m, 5H), 7.26 (t, J = 7.3 Hz, 1H),
7.18 (t, J = 7.3 Hz, 1H), 6.71 (s, 1H), 4.83 (d, J = 5.8 Hz, 2H); 13C{1H} NMR (101 MHz, DMSO) δ
164.6, 148.7, 143.1, 139.6, 137.4, 131.7, 130.1, 128.8, 128.3, 128.1, 127.8, 127.1, 127.0, 126.4,
119.9, 119.5, 112.1, 45.7; IR (neat) 3268, 3058, 2924, 1670, 1453 cm-1; HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C22H19N2 311.1543; found 311.1541.
4.7. General Procedure for the Synthesis of 3-Methoxyisoindoles (4).
Compound 2 (0.5 mmol, 1.0 equiv) and Pd/C (5 wt %, 0.106 g, 0.05 mmol, 0.1 equiv.) were
added to MeOH (15 mL). H2 gas (1 atm) was introduced using a balloon and the reaction
mixture was stirred at room temperature for 12 h. The reaction mixture was filtered and
concentrated under reduced pressure. The residue was purified by column chromatography
(Silica Gel, petroleum ether/EtOAc) to afford compound 4.
4.7.1. Benzyl-3-methoxy-1H-isoindole (4a). This product was obtained as a yellow oil (0.086 g,
1
72%): H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.0 Hz, 1H), 7.39 – 7.28 (m, 4H), 7.28 – 7.24 (m,
3H), 7.00 (d, J = 7.3 Hz, 1H), 4.97 (dd, J = 8.5, 5.8 Hz, 1H), 4.12 (s, 3H), 3.46 (dd, J = 13.4, 5.8 Hz,
1H), 2.80 (dd, J = 13.4, 8.5 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 169.6, 153.2, 138.4, 132.8,
129.8, 128.8, 128.2, 127.4, 126.5, 122.9, 120.7, 69.5, 55.4, 40.1; IR (neat) 2938, 2856, 1622,
1581, 1445 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H16NO 238.1226; found 238.1226.
4.7.2. 3-Methoxy-1-(4-(trifluoromethyl)benzyl)-1H-isoindole (4b). This product was obtained as
a yellow oil (0.101 g, 66%): 1H NMR (400 MHz, CDCl3) δ 7.53 – 7.42 (m, 3H), 7.35 – 7.25 (m, 4H),
7.20 – 7.03 (m, 1H), 4.91 (br, 1H), 4.05 (s, 3H), 3.29 (dd, J = 13.5, 6.1 Hz, 1H), 3.00 (dd, J = 13.5,
7.4 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 169.9, 152.8, 142.4, 132.9, 130.2, 129.2, 128.8 (d, J
= 32.3 Hz), 127.8, 125.1 (q, J = 3.7 Hz), 124.5 (d, J = 273.0 Hz), 122.6, 120.9, 69.0, 55.5, 39.8; IR
(neat) 2926, 2855, 1625, 1602, 1577 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H15F3NO
306.1100; found 306.1101.

ACCEPTED MANUSCRIPT
4.7.3. 1-Benzyl-4-fluoro-3-methoxy-1H-isoindole (4c). This product was obtained as a yellow oil
(0.109 g, 85%): 1H NMR (400 MHz, CDCl3) δ 7.37 – 7.20 (m, 6H), 7.00 (t, J = 8.8 Hz, 1H), 6.81 (d, J
= 7.5 Hz, 1H), 4.98 (dd, J = 7.8, 6.2 Hz, 1H), 4.13 (s, 3H), 3.41 (dd, J = 13.5, 5.8 Hz, 1H), 2.86 (dd, J
= 13.5, 8.2 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.3 (d, J = 3.6 Hz), 156.9, 156.4 (d, J =
54.7 Hz), 137.85, 131.0 (d, J = 6.8 Hz), 129.79, 128.23, 126.63, 120.1 (d, J = 14.8 Hz), 118.9 (d, J =
3.7 Hz), 114.6 (d, J = 19.9 Hz), 69.8, 55.8, 39.9; IR (neat) 3028, 2946, 1611, 1453 cm-1; HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C16H15FNO 256.1132; found 256.1133.
4.7.4. 1-Benzyl-3,5,6-trimethoxy-1H-isoindole (4d). This product was obtained as a red oil
1
(0.103 g, 69%) and 14% of SM was recovered. H NMR (400 MHz, CDCl3) δ 7.35 – 7.28 (m, 3H),
7.28 – 7.25 (m, 2H), 6.98 (s, 1H), 6.26 (s, 1H), 4.83 (dd, J = 9.4, 5.6 Hz, 1H), 4.09 (s, 3H), 3.90 (s,
3H), 3.70 (s, 3H), 3.53 (dd, J = 13.2, 5.6 Hz, 1H), 2.59 (dd, J = 13.2, 9.4 Hz, 1H); 13C{1H} NMR (101
MHz, CDCl3) δ 169.6, 150.4, 149.2, 146.8, 138.7, 130.1, 128.3, 126.7, 125.0, 106.0, 102.7, 69.2,
56.2, 56.0, 55.5, 40.5; IR (neat) 2941, 2845, 1573, 1499 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd
for C18H20NO3 298.1438; found 298.1438.
4.7.5. Methyl 2-((3,5,6-trimethoxy-1H-isoindol-1-yl)methyl)benzoa-te (4e). This product was
obtained as a pink solid (0.124 g, 70%): m.p. 116-118 °C; 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J =
7.7 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.33 – 7.26 (m, 2H), 6.96 (s, 1H), 6.48 (s, 1H), 4.87 (br, 1H),
4.08 (s, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.76 (s, 3H), 3.45 (br, 1H), 3.35 (dd, J = 12.9, 7.4 Hz, 1H);
13C{1H} NMR (101 MHz, CDCl3) δ 169.4, 168.2, 150.6, 149.1, 147.0, 140.8, 133.1, 131.8, 130.9,
130.4, 126.7, 124.8, 105.8, 102.7, 68.9, 56.2, 56.1, 55.5, 52.1, 38.9; IR (neat) 2926, 2850, 1718,
1574, 1498 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C20H22NO5 356.1492; found 356.1494.
4.8. General Procedure for the Synthesis of 3-Methylene-isoindolin-1-ones 5.
Compound 2 (0.5 mmol, 1.0 equiv), TsOH (7.5 mmol, 15 equiv) and NaBr (30 mmol, 60 equiv)
were added to MeOH (7 mL). The suspension was heated at 50 °C for 2h. After cooling to room
temperature, the reaction mixture was diluted with saturated NaHCO3 (30 mL) and extracted
with EtOAc (30 mL x 2). The combined organic layers were dried (anhydrous MgSO4), filtered

ACCEPTED MANUSCRIPT
and concentrated. The residue was purified by column chromatography (Silica Gel, petroleum
ether/EtOAc) to afford compound 5.
4.8.1. (Z)-3-Benzylideneisoindolin-1-one (5a). This product was obtained as a light green solid
(0.073 g, 66%): m.p. 182-184 °C; (lit. [17] 182-183 °C). The spectral data were consistent with
literature [17]. 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 7.8
Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.53 – 7.37 (m, 5H), 7.29 (t, J = 7.1 Hz, 1H), 6.53 (s, 1H); 13C{1H}
NMR (101 MHz, CDCl3) δ 169.4, 138.4, 135.1, 133.2, 132.4, 129.39, 129.36, 128.7, 127.9, 123.7,
120.0, 106.2 (one carbon missing due to overlap); IR (neat) 3860, 2922, 1704, 1455 cm-1;
HRMS(ESI-TOF) m/z: [M+H]+ calcd for C15H12NO 222.0913; found 222.0916.
4.8.2. (Z)-3-Benzylidene-7-fluoroisoindolin-1-one (5b). This product was obtained as a white
solid (0.092 g, 77%): m.p. 245-246 °C; 1H NMR (400 MHz, DMSO) δ 10.80 (s, 1H), 7.92 (d, J = 7.7
Hz, 1H), 7.77 – 7.68 (m, 1H), 7.64 (d, J = 7.4 Hz, 2H), 7.42 (t, J = 7.7 Hz, 2H), 7.36 – 7.26 (m, 2H),
6.84 (s, 1H); 13C{1H} NMR (101 MHz, DMSO) δ 166.3, 158.2 (d, J = 258.6 Hz), 141.9 (d, J = 2.9 Hz),
134.9 (d, J = 8.1 Hz), 134.5, 131.9, 129.3 (d, J = 34.1 Hz), 127.9, 117.0 (d, J = 3.5 Hz), 116.1 (d, J =
19.2 Hz), 115.2 (d, J = 14.2 Hz), 107.7, 79.3; IR (neat) 3213, 3050, 1702, 1488 cm-1; HRMS (ESI-
TOF) m/z: [M+H]+ calcd for C15H11FNO 240.0819; found 240.0819.
4.8.3. (Z)-3-Benzylidene-5,6-dimethoxyisoindolin-1-one (5c) [18]. This product was obtained as
a pale pink solid (0.141 g, 100%): m.p. 194-196 °C; 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.44
– 7.35 (m, 4H), 7.31 – 7.24 (m, 2H), 7.16 (s, 1H), 6.39 (s, 1H), 4.00 (s, 3H), 3.93 (s, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 169.4, 153.5, 151.1, 135.3, 133.4, 132.3, 129.3, 128.5, 127.6, 121.7,
105.2, 104.8, 101.7, 56.5, 56.4; IR (neat) 3196, 3058, 2946, 1601, 1491 cm-1; HRMS (ESI-TOF)
m/z: [M+H]+ calcd for C17H16NO3 282.1125; found 282.1124.
4.8.4. (Z)-3-(4-(Trifluoromethyl)benzylidene)isoindolin-1-one (5d). This product was obtained as
a white solid (0.120 g, 83%): m.p. 250-252 °C; (lit. [17] 249-250 °C). The spectral data were
1
consistent with literature [17]. H NMR (400 MHz, DMSO) δ 10.88 (s, 1H), 8.08 (d, J = 7.7 Hz,
1H), 7.85 – 7.75 (m, 3H), 7.75 – 7.69 (m, 3H), 7.59 (t, J = 7.4 Hz, 1H), 6.83 (s, 1H); 13C{1H} NMR
(101 MHz, DMSO) δ 169.2, 138.8, 138.5, 134.6, 132.5, 129.7, 129.5, 128.4, 127.0 (d, J = 31.9 Hz),

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125.4 (q, J = 3.6 Hz), 124.3 (d, J = 273.0 Hz), 122.8, 120.7, 104.0; IR (neat) 2957, 2922, 2850,
1704 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H11FNO 290.0787; found 290.0785.
4.8.5. Ethyl (Z)-4-((3-oxoisoindolin-1-ylidene)methyl)benzoate (5e). This product was obtained
as a white solid (0.116 g, 79%): m.p. 212-213 °C; 1H NMR (400 MHz, DMSO) δ 10.85 (s, 1H), 8.07
(d, J = 7.8 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.80 – 7.68 (m, 4H), 7.58 (t, J = 7.4 Hz, 1H), 6.81 (s,
1H), 4.31 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO) δ 169.2,
165.5, 139.4, 138.6, 134.4, 132.5, 129.6, 129.4, 129.1, 128.3, 127.9, 122.8, 120.6, 104.5, 60.7,
14.2; IR (neat) 3049, 1838, 1596, 1515, 1465 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C18H16NO3 294.1125; found 294.1128.
4.9. General Procedure for the Synthesis of 3-Benzylisoindolin-1-ones 6.
Compound 5 (0.3 mmol,1.0 equiv) and Pd/C (5 wt %, 0.064 g, 0.03 mmol, 0.1 equiv.) were
added to MeOH (10 mL), H2 gas (1 atm) was introduced using a balloon and the reaction
mixture was stirred at room temperature for 7 h. The reaction mixture was filtered and
concentrated under reduced pressure. The residue was purified by column chromatography
(Silica Gel, petroleum ether/EtOAc) to afford compound 6.
4.9.1. 3-Benzylisoindolin-1-one (6a). This product was obtained as a white solid (0.054 g, 81%):
m.p. 135-137 °C; m.p. 131-133 °C; (lit. [19] 129.7-131.3 °C). The spectral data were consistent
1
with literature [19]. H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 7.4 Hz, 1H), 7.51 (t, J = 7.4 Hz, 1H),
7.44 (t, J = 7.4 Hz, 1H), 7.32 – 7.25 (m, 4H), 7.23 – 7.13 (m, 3H), 4.80 (dd, J = 8.0, 5.8 Hz, 1H),
3.16 (dd, J = 13.5, 4.4 Hz, 1H), 2.86 (dd, J = 13.4, 8.5 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ
170.8, 147.0, 137.0, 132.1, 131.9, 129.5, 128.9, 128.5, 127.3, 124.0, 122.9, 58.2, 41.4; IR (neat)
3231, 3061, 2921, 1610, 1462 cm-1; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C15H13NNaO
246.0889; found 246.0888.
4.9.2. 3-Benzyl-7-fluoroisoindolin-1-one (6b). This product was obtained as a white solid (0.054
1
g, 74%): m.p. 156-157 °C; H NMR (400 MHz, CDCl3) δ 7.58 – 7.49 (m, 1H), 7.40 – 7.28 (m, 3H),
7.27 – 7.19 (m, 2H), 7.17 – 7.03 (m, 2H), 4.86 (br, 1H), 3.18 (dd, J = 13.5, 5.8 Hz, 1H), 2.99 (dd, J
= 13.5, 7.9 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.9, 159.3 (d, J = 261.2 Hz), 149.8 (d, J =