Synthesis of Isoindoles from Intramolecular Condensation of Benzyl Azides with α-Aryldiazoesters

Article abstract of DOI:10.1021/acs.joc.8b03180

Rh-catalyzed intramolecular condensation of the benzyl azides with α-aryldiazoesters was explored. The reaction proceeded through the nucleophilic attack of the organic azide onto a rhodium carbenoid, while releasing nitrogen gas, affording the α-imino es

Full text of DOI:10.1021/acs.joc.8b03180

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Note
Synthesis of Isoindoles from Intramolecular
Condensation of Benzyl Azides with #-Aryldiazoesters
Jing Zhu, Rui Li, Yan Su, and Peiming Gu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03180 • Publication Date (Web): 21 Mar 2019
Downloaded from http://pubs.acs.org on March 21, 2019
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Synthesis of Isoindoles from Intramolecular Condensation of Benzyl
Azides with α-Aryldiazoesters
8
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Jing Zhu, Rui Li, Yan Su, Peiming Gu*
Department of Chemistry, Ningxia University, Yinchuan 750021, China
Phone: +86(951)206-2274
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Fax: +86(951)206-2323
E-mail: gupm@nxu.edu.cn
Tables of contents
CO2R3
N2
CO2R3
R2
Rh2(oct)4 (1 mol %)
R1
R1
N H
R2
13 examples, yield up to 99%
N3
Abstract
Rh-catalyzed intramolecular condensation of the benzyl azides with α-aryldiazoesters was explored.
The reaction proceeded through the nucleophilic attack of the organic azide onto a rhodium
carbenoid while releasing nitrogen gas, affording the α-imino esters as the primary product.
Tautomerization of the imino esters efficiently gave thirteen desired isoindoles with good to
excellent yields.
The isoindoles and their derivatives are very reactive compounds, and they have been widely
applied in multi-disciplinary research fields. For examples, the isoindoles are employed as synthetic
building blocks for tetracenes,1 and also they are embedded in the material chemistry.2 Due to their
important usage, quite a few synthetic methods towards the isoindoles have been reported.3,4 The
organic azides are very powerful materials for synthesizing aza-cycles compounds, however it was
less involved in isoindoles chemistry, and only Chiba’s group had reported an intramolecular 1,3-
dipolar cycloaddition of azides onto alkenes for synthesis of isoindoles.4c In this paper, we will
report the Rh-catalyzed intramolecular condensation of benzyl azides with α-aryldiazoesters for
addressing the isoindoles.
The rhodium(II) catalyzed interception of the diazo compounds with organic azides was initially
reported by Wee and co-workers, and two unexpected imines were observed during their exploration
of the C-H insertion with indoline diazoamides.5 Then the conversion was confirmed by Lecourt
and Micouin,6 and further explored in our group7 and Doyle group,8 demonstrating its excellent
efficiency in synthesis of α-imine esters. We envisioned that the isoindole 2a could be accessed with
the interception reaction of 1a, featuring an azidomethyl moiety attached on the ortho-position of
the α-aryldiazoester (Scheme 1). The rhodium catalyst would promote the formation of carbenoid I
from the diazo compound, then the azide would attack on to the rhodium complex with the
nucleophilic inner nitrogen atom, resulting in an intermediate II. Rhodium-carbon bond cleavage
and nitrogen extrusion of intermediate II would give the α-imino ester III, which would rapidly
proceed via a tautomerization process for producing the desired isoindole 2.
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CO2R3
NH
N2
N3
interception of carbenoids
CO2R3
R2
with organic azides
R1
R1
R2
1
2
7
8
9
Rh cat
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CO2R3
N
Rh
Rh
CO2R3
N N2
CO2R3
N N2
R1
R1
R1
R2
R2
R2
I
II
III
Scheme 1. Designed process for synthesis of isoindoles
With the above vision in mind, the first substrate 1a was prepared from the commercially
available 3-isochromanone 3a (Scheme 2). Treatment of 3a with HBr gas in EtOH at 50oC for 5 h
gave the corresponding ethyl 2-(2-(bromomethyl)phenyl)acetate as a sole product according to
Vincent’s procedure,9 then azidation of the corresponding bromide with sodium azide in DMF
delivered the benzyl azide 4a with 95% yield for two steps. Further Regitz diazo transfer reaction10
of 4a with 4-acetamidobenzenesulfonyl azide (p-ABSA) in the presence of DBU gave the desired
substrate 1a11 with 88 % yield.
N2
O
1) HBr, EtOH
p-ABSA, DBU
CO2Et
CO2Et
O
2) NaN3
95% for two steps
88%
N3
N3
3a
4a
1a
Scheme 2. Synthesis of substrate1a.
The substrate 1a was a bit sensitive to the natural light, and it should be kept in dark place.
Otherwise, trace isoindole 2a could be observed if the sample was exposed to natural light for
several days. The rhodium(II) salts5,6,7a and copper salts7b,7c had been employed as the
catalysts for the interception reaction, therefore, Cu(OTf)2, CuPF6(MeCN)4, Rh2(OAc)4 and
Rh2(oct)4 were selected for promoting the reaction of 1a. All the experiments were performed with
0.2 mmol of 1a in the presence of 1 mol % of copper salts or rhodium salts in dichloromethane at
room temperature (entries 1-4, Table 1). To our delight, the known isoindole 2a12 could be observed
with each case. Rh2(oct)4 was demonstrated as the best catalyst, and the isoindole 2a was isolated
in 97% yield. It should be noted that the isoindole was regarded as a potentially instable substance,
therefore purification of the isoindoles by flash column chromatography should be quickly finished.
Otherwise, the yield would be reduced. Further evaluation of the solvents did not improve the yield
(entries 4-7, Table 1), and the halogenated hydrocarbon solvents seemed to be more suitable for the
conversion. The conversion failed to give isoindole 2a if the reaction of 1a was carried without
catalyst in DCM at room temperature (entry 8, Table 1) or at refluxing DCM (entry 9, Table 1).
Themolysis of the substrate 1a in refluxing DCE (at about 80 ºC) for 17 h could be successful, where
the isoindole 2a was produced with only 56% yield (entry 10, Table 1).
Table 1. Optimization reaction conditions for synthesis of isoindole 2aa.
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N2
CO2Et
NH
Metal catalyst
CO2Et
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7
1a
2a
N3
8
9
Entry
Catalyst
Solvent
DCM
DCM
DCM
CH2Cl2
DCE
Time (h)
Yield (%)b
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1
2
Cu(OTf)2
18
4
31
62
74
97
64
38
82
-
CuPF6(MeCN)4
Rh2(OAc)4
Rh2(oct)4
3
12
4
4
5
Rh2(oct)4
10
24
4
6
Rh2(oct)4
THF
7
Rh2(oct)4
CHCl3
DCM
DCM
DCE
8
no catalyst
no catalyst
no catalyst
48
12
17
9c
10d
trace
56
a) Reaction of 1a (0.2 mmol) with metal catalyst (0.002 mmol) in the solvent (2.0 mL) for the above
mentioned time; b) Isolated yield; c) At refluxing DCM; d) At refluxing DCE.
Then the scope of substrates was examined with Rh2(oct)4, and the results were summarized in
Table 2. As disclosed, isoindoles are very reactive compounds, especially in solution.3 Therefore,
the handling time for the isoindoles and their stability would affect the isolated yields. All the azides
1 examined here could be converted into the corresponding isoindoles 2 with good to excellent
yields, and generally the isoindole was observed as the sole product from the NMR of the each crude
reaction mixture (entries 1-4 and entries 7-13, Table 2), which demonstrated the powerful efficiency
of reaction. All the isoindoles were purified as soon as possible, then the yield difference should be
mainly due to the stability of the products during the purification process. The reaction of azide 1a
(0.4 mmol) was re-examined in CH2Cl2, and 2a was isolated in 92% yield (entry 1, Table 2). It was
reported that stabilization of the isoindoles could be accessed by introduction of electron
withdrawing groups,3 which would be beneficial to good isolated yield. Isoindoles 2b and 2c, both
attaching a bromo substituent, were obtained with excellent isolated yields from the substrates 1b
and 1c, and the reaction time was 3 h and 6 h, respectively (entries 2 and 3, Table 2). The reaction
of 4-CF3 substrate 2d for 5 h afforded the isoindole 1d with 82% yield. Though the isoindole 1e
with a cyano group was supposed to be more stable, but the substrate 2e was less reactive, which
might be due to the long-distance л-л conjugation between the cyano group and the diazo group. It
took 20 h for the substrate 2e to be consumed, where the long reaction time led to the reduced yield
(entry 5, Table 2). The electron donating substituents at the aryl ring were supposed to be negative
for the stability, and the reactions of the substrates with a methyl or a methoxyl group in 2 h to 7 h
gave the isoindoles in 75%-88% yields. It should be noted that there was still a bit of azide 1f left
when the reaction was stopped at 4 h. If the reaction was prolonged to 16 h, the 2f was produced
with only 66% yield, and excessive reaction of the isoindole might be proceeded. The 2f had been
isolated with 98% yield when the substrate was employed as 0.29 mmol, where all the material 1f
was consumed. The azide 1k bearing an additional phenyl group at the benzylic carbon were
converted into a 1,3-disubstituted isoindole 2k with 88% yield, and 2k could be produced with 99%
yield when 0.8 mmol of 1k was applied for the conversion (entry 11, Table 2), where the structure
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assignment was supported by an X-ray crystallographic structure determination. Also, the reaction
of azide 1l with a methyl group at the benzylic carbon gave 2l with 74% yield, and the yield
difference between 2k and 2l might be due to the conjugated system (entry 11 vs entry 12, Table 2).
Fortunately, the yield of 2l could be improved to 85% if the reaction was performed in CHCl3. Then
the methyl α-aryldiazoester 1m was also successfully converted into the isoindole 2m with 87%
yield (entry 13, Table 2).
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Table 2. Conversion of azide 1 to isoindole 2a.
CO2R3
N2
CO2R3
R2
Rh2(oct)4 (1 mol %)
R1
R1
N H
R2
1
2
N3
entry
Azide1
Time (h)
4
Isoindole 2
Yield (%)b
N2
CO2Et
NH
CO2Et
1
2
3
4
5
6
92
93
90
82
70c
N3
1a
N2
2a
CO2Et
Br
CO2Et
Br
NH
3
6
N3
1b
N2
2b
2c
2d
2e
2f
CO2Et
NH
CO2Et
Br
Br
N3
1c
N2
N3
CO2Et
NH
CO2Et
CO2Et
CO2Et
CO2Et
F3C
5
F3C
1d
N2
CO2Et
NH
NC
20
NC
N3
1e
N2
CO2Et
NH
Me
16
4
66
75d
98e
Me
N3
4
1f
N2
CO2Et
NH
Me
7
8
2
4
86
88
Me
N3
1g
2g
N2
CO2Et
NH
MeO
CO2Et
MeO
N3
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1h
2h
2i
N2
N3
CO2Et
NH
CO2Et
MeO
9
4
7
82%c
80%
MeO
1i
N2
CO2Et
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CO2Et
NH
10
11
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13
OMe N3
OMe
1j
N2
2j
CO2Et
CO2Et
Ph
NH
3
4
88
99f
Ph
N3
1k
N2
2k
CO2Et
CO2Et
NH
8
74
85g
Me
Me
N3
10
1l
N2
2l
CO2Me
CO2Me
Me
NH
17
87
Me
N3
1m
2m
a) Reaction of azide 1 (0.4 mmol) with Rh2(oct)4 (3 mg, 0.004 mmol) in CH2Cl2 (4.0 mL) for the above
mentioned time; b) isolated yield; c) 0.2 mmol azide 1 was employed; d) a bit of azide 1f was left; e) 0.29
mmol azide 1f was employed; f) 0.8 mmol azide 1 was employed; g) reaction in CHCl3.
In summary, a synthetic method toward isoindoles has been designed and developed, and the
intramolecular interception of benzyl azides with α-aryldiazoesters is practical and efficient,
affording thirteen isoindoles with good to excellent yields.
EXPERIMENTAL SECTION
All the reagents were purchased from Acros, Sigma-Aldrich, Alfa-Aesar, Aladdin, Accela or Adamas,
and they were used as received. All the solvents were distilled using the classic method before use.
The reactions were monitored by thin layer chromatography (TLC) on 2.5*10 cm, 250 μm analytical
plates coated with silica gel 60 F254, and they were purchased from Qingdao Haiyang Chemical
Co. Ltd. The thin layer chromatography plates were visualized by exposure to the ultraviolet light
(UV, 254 nm) or Phosphomolybdic acid. Purification of the synthetic compounds by the flash
column chromatography employed the neutral Silica gel (200-300 mesh or 300-400 mesh), which
were purchased from Qingdao Haiyang Chemical Co. Ltd. The NMR spectra were recorded on a
Bruker 400 MHz spectrometer, and the tetramethylsilane (δ = 0 and δ = 7.26 for CDCl3, δ = 0 and
δ = 2.05 for acetone-d6, δ = 0 and δ = 2.50 for DMSO-d6) was used as an internal standard for 1H
NMR (400MHz) and CDCl3 (δ = 77.16), acetone-d6 (δ = 29.84), DMSO-d6(δ = 39.92) for 13C
NMR(100 MHz), and the 13C NMR were plus APT [methyl and methine (down), methylene and
quaternary carbon (up)]. The IR spectra were recorded on a Perkein Elmer with potassium bromide
crystal optic rectangle. High-resolution mass spectra (HRMS) were measured on a LTQ Orbitrap
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XL Domain35A (Thermo Fisher) spectrometer, and the electro spray ionization (ESI) was used as
the ion source. The isoindole 4a had been previously prepared by Mathias’s procedure13. And azides
4b-4m were prepared according to the method that our previously reported procedure7, and
isochromanones 3a was purchased from Accela. The lactone 3b was prepared from the known
dicarboxylic acid.14 The lactones 3c and 3h were prepared from the known dicarboxylic acids.15 The
lactone 3e was prepared from the known dicarboxylic acid.16 The lactones 3f and 3g were prepared
from the known dicarboxylic acids.17 The lactone 3i was prepared from the known dicarboxylic
acid.18 The lactones 3k and 3l were prepared from the known dicarboxylic acids.19 And the
isoindoles 2a, 2k and 2l had been previously prepared by SatoshiItoa’s procedure12. All the reaction
of the benzyl azides with α-aryldiazoesters were carried out in dry reaction vessels or flasks under
a positive pressure of nitrogen or argon.
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6-bromoisochroman-3-one(3b). To a stirred solution of the known 4-bromo-2-(2-methoxy-2-
.
oxoethyl) benzoic acid14 (3.10 g, 11.4 mmol) in THF (36.0 ml) was added 2.0 M BH3 Me2S (6.3 ml,
12.6 mmol), and the mixture was heated to 40ºC for 4 h. Then it was cooled to room temperature
and 4.0 M HCl (30 ml) was added to quench the reaction. The mixture was extracted with ethyl
acetate (20 mL × 3), and washed with brine (20 mL). The organic phase was dried over anhydrous
Na2SO4 and concentrated. The residue was purified by flash chromatography to give the lactone 3b
as a white solid (1.80 g, 70% yield), known compound20(a); Rf = 0.62 (Et2O/0.5 M aqueous
1
NaH2PO4/HOAc/PE = 0.9/0.09/0.01/1); H NMR (CDCl3, 400 MHz) δ 7.45 (d, J = 8.0 Hz, 1H),
7.40 (s, 1 H), 7.14 (d, J = 8.0 Hz, 1H), 5.27 (s, 2H),3.70 (s, 2H); 13C{1H} NMR (CDCl3, 100 MHz,
plus APT) δ (up) 169.9, 133.3, 130.7, 122.8, 69.7, 35.9, δ (down) 130.7, 130.2, 126.5.
7-bromoisochroman-3-one(3c). The lactone 3c (2.03 g) was prepared from the known 5-bromo-
2-(2-methoxy-2-oxoethyl)benzoic acid15 (3.22 g, 11.8 mmol) by the procedure for the preparation
of lactone 3b, and the yield was 76%, known compound20(a), Rf = 0.44 (EtOAC/PE = 1/1); 1H NMR
(CDCl3, 400 MHz) δ 7.47 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.11 (d, J = 8.0 Hz, 1H), 5.27 (s, 2H),
3.66 (s, 2H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up) 170.0, 133.6, 130.0, 121.1, 69.3,
35.8, δ (down) 131.9, 128.8, 127.9.
7-(trifluoromethyl)-1H-isochromen-3(4H)-one(3d). The lactone 3d (1.81 g) was prepared from
the known 2-(carboxymethyl)-5-(trifluoromethyl)benzoic acid14 (2.87 g, 11.6 mmol) by the
procedure for the preparation of lactone 3b, and the yield was 72%, Mp: 158-159 ºC, Rf = 0.63
(EtOAC/PE = 1/1); 1H NMR (CDCl3, 400 MHz) δ 7.63 (d, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7. 37 (d,
J = 8.0 Hz, 1H), 5.37 (s, 2H), 3.79 (s, 2H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up)
169.6, 135.2, 132.5, 130.1 (q, JCF = 33 Hz), 123.8 (q, JCF = 270 Hz), 69.6, 36.2, δ (down) 127.8,
125.9 (q, JCF = 3 Hz), 121.9 (q, JCF = 3 Hz). IR (film) 1734 cm-1; HRMS (ESI-TOF) m/z [M + Na]+
calcd for C10H7F3O2Na 239.0290, found 239.0290.
3-oxoisochromane-7-carbonitrile(3e). The lactone 3e (705.0 mg) was prepared from the known
5-cyano-2-(2-methoxy-2-oxoethyl)benzoic acid16 (1.23 g, 5.6 mmol) by the procedure for the
preparation of lactone 3b, and the yield was 72%, Mp:147-149 ºC, Rf = 0.26 (Et2O/0.5 M aqueous
NaH2PO4/HOAc/PE = 2.7/0.27/0.03/1); 1H NMR (CDCl3, 400 MHz) δ 7.68 (dd, J = 8.0 Hz and 1.6
Hz, 1H), 7.59 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 5.36 (s, 2 H), 3.81 (s, 2H); 13C{1H} NMR (CDCl3,
100 MHz, plus APT) δ (up) 169.3, 136.5, 133.0, 118.1, 111.5, 69.1, 36.3, δ (down) 132.7, 128.4,
128.2. IR (film) 1737 cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C10H7NO2Na 196.0369,
found 196.0369.
6-methylisochroman-3-one(3f). The 3f (413.0 mg) was prepared from the known 2-
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((methoxycarbonyl) methyl)-4-methylbenzoic acid17(1.33 g, 6.3 mmol) by the procedure for the
preparation of lactone 3b, and the yield was 40%, known compound,20(a) Rf = 0.37(EtOAC/PE =
1/3); 1H NMR (CDCl3, 400 MHz) δ 7.09-7.15 (m, 2H), 7.04 (s, 1H), 5.28 (s, 2H), 3.67 (s, 2H), 2.37
(s, 3H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up) 171.0, 138.8, 131.0, 128.7, 70.1, 36.3,
δ (down) 128.0, 127.7, 124.6, 21.3.
7-methylisochroman-3-one(3g). The 3g (614.0 mg) was prepared from the known 2-(2-
methoxy-2-oxoethyl)-5-methylbenzoic acid16 (1.22 g, 5.8 mmol) by the procedure for the
preparation of lactone 3b, and the yield was 65%, known compound20(b), Rf = 0.36(EtOAC/PE =
1/3); 1H NMR (acetone-d6, 400 MHz) δ 7.15-7.20 (m, 3H), 5.31 (s, 2H), 3.70 (s, 2H), 2.33 (s, 3H);
13C{1H} NMR (acetone-d6, 100 MHz, plus APT) δ (up) 170.3, 136.6, 132.5, 129.0, 69.4, 35.4, δ
(down) 128.9, 126.6, 125.2, 20.1.
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6-methoxyisochroman-3-one(3h). The 3h (430.0 mg) was prepared from the known 4-methoxy-
2-(2-methoxy-2-oxoethyl) benzoic acid15 (2.00 g, 8.9 mmol) by the procedure for the preparation of
3b, and the yield was 27%, known compound 20(c), Rf = 0.46 (EtOAC/PE = 1/2); 1H NMR (CDCl3,
400 MHz) δ 7.16 (d, J = 8.0 Hz, 1H), 6.82 (dd, J = 8.0 Hz and 2.4 Hz, 1H), 6.76 (d, J = 2.4 Hz, 1
H), 5.27 (s, 2 H), 3.82 (s, 3 H), 3.69 (s, 2 H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up)
170.9, 160.2, 132.7, 123.8, 69.9, 36.7, δ (down) 126.0, 112.9, 112.7, 55.6.
7-methoxy-1H-isochromen-3(4H)-one(3i). The 3i (697.0 mg) was prepared from the known 2-
(carboxymethyl)-5-methoxybenzoic acid15 (1.87 g, 8.9 mmol) by the procedure for the preparation
of 3b, and the yield was 44%, known compound 18, Rf = 0.48 (EtOAC/PE = 1/2); 1H NMR (CDCl3,
400 MHz) δ 7.13 (d, J = 8.4 Hz, 1H), 6.87 (dd, J = 8.4 Hz and 2.8 Hz, 1H), 6.79 (d, J = 2.8 Hz, 1
H), 5.27 (s, 2 H), 3.82 (s, 3 H), 3.65 (s, 2 H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up)
171.0, 158.9, 132.7, 122.6, 70.1, 35.3, δ (down) 128.1, 114.2, 110.4, 55.5.
8-methoxy-1H-isochromen-3(4H)-one(3j). The 3j (539.0 mg) was prepared from the known 2-
(carboxymethyl)-6-methoxybenzoic acid15 (1.81 g, 8.6 mmol) by the procedure for the preparation
of 3b, and the yield was 35%, Rf = 0.47 (EtOAC/PE = 1/2); 1H NMR (CDCl3, 400 MHz) δ 7.28 (t,
J = 8.4 Hz, 1H), 6.80 (t, J = 8.4 Hz, 2H), 5.40 (s, 2 H), 3.85 (s, 3 H), 3.67 (s, 2 H); 13C{1H} NMR
(CDCl3, 100 MHz, plus APT) δ (up) 170.9, 155.2, 132.4, 119.7, 65.4, 35.7, δ (down) 129.8, 119.2,
109.1, 55.6. IR (film) 1750 cm-1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C10H11O3 179.0703,
found 179.0701.
1-phenylisochroman-3-one(3k). To a stirred solution of known 2-(2-benzoylphenyl) acetic
acid18(1.20 g, 5.0 mmol) in EtOH (4 ml) was added NaBH4 (209.0 mg 5.5 mmol) in small portion,
o
and the reaction temperature was controlled bellow 10 C. The mixture was warmed to room
temperature for 8 h, and the EtOH was removed under vacumn. Then 10% aqueous HCl (2 ml) was
added, and the mixture was extracted with CH2Cl2 (2 mL× 3), washed by water (3 mL), dried over
anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography to give the
lactone 3k (1.20 g, 92% yield) as a pale-yellow solid, known compound 20(d), Rf = 0.71 (EtOAC/PE
= 1/1); 1H NMR (CDCl3, 400 MHz) δ 7.23-7.46 (m, 8 H), 6.96 (d, J = 7.6 Hz, 1 H), 6.39 (s, 1 H),
3.74 (d, J = 18.0 Hz, 1H), 3.63 (d, J = 18.0 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT)
δ (up) 170.7, 137.0, 134.7, 131.1, 36.6, δ (down) 129.1, 129.0, 128.9 (2), 127.6 (2), 127.4 (2), 126.1,
82.2.
1-methylisochroman-3-one(3l). The lactone 3l (844.0 mg) was prepared from the known 2-(2-
acetylphenyl) acetic acid18 (1.00 g, 5.6 mmol) by the procedure for the preparation of lactone 3h,
and the yield was 93%, known compound 20(d), Rf = 0.33 (EtOAC/PE = 1/3); 1H NMR (CDCl3, 400
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MHz) δ 7.20-7.36 (m, 4H), 5.48 (q, J = 6.8 Hz, 1H), 3.74 (d, J = 18.4 Hz, 1H), 3.68 (d, J = 18.4
Hz, 1H), 1.76 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up) 170.8, 135.8,
130.7, 36.2, δ (down) 128.6, 127.5, 127.1, 123.6, 76.4, 19.1.
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ethyl 2-(2-(azidomethyl)phenyl)acetate(4a). To a stirred solution of 3-isochromanone 3a (1.80
g, 12.1 mmol) in dry EtOH (30 mL) was introduced HBr gas for 5 h, then EtOH was evaporated to
afford the ethyl 2-(2-(bromomethyl) phenyl)acetate (3.05 g) as a brown oil. Then the crude ethyl 2-
(2-(bromomethyl) phenyl) acetate was dissolved in DMF (40 ml), and NaN3 (1.50 g, 23.0 mmol)
was added into the mixture. The mixture was kept at 70 ºC for 40 min, then it was partitioned
between EtOAc (15 mL) and H2O (10 mL). The organic phase was separated and the aqueous phase
was extracted with EtOAc (30 mL × 2). The combined organic phase was washed with water (30
ml × 4), dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash
chromatography to give the azide 4a as a yellow oil (2.53 g, 95% yield from 3a), known compound13,
1H NMR (CDCl3, 400 MHz) δ 7.28-7.36 (m, 4H), 4.42 (s, 2H), 4.15 (q, J = 7.2 Hz, 2H), 3.71 (s,
2H), 1.25 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up) 171.3, 134.1,
133.4, 61.2, 53.0, 38.7, δ (down) 131.3, 130.1, 129.0, 127.9, 14.3.
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ethyl 2-(2-(azidomethyl)-5-bromophenyl)acetate(4b). The azide 4b (1.46 g) was prepared from
3b (1.80 g, 7.9 mmol) by the procedure for the preparation of azide 4a, and the yield was 97%, Rf
= 0.52 (EtOAC/PE = 1/6); 1H NMR (CDCl3, 400 MHz) δ 7.43 (d, J = 2.0 Hz, 1H), 7.39 (dd, J =
8.4 Hz and 2.0 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 4.34 (s, 2H), 4.13 (q, J = 7.2 Hz, 2H), 3.64 (s,
2H), 1.23 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up) 170.3, 135.2,
133.1, 122.4, 61.2, 52.0, 38.0, δ (down) 133.9, 130.6, 131.2, 14.0. IR (film) 2102, 1733 cm-1; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C11H12BrN3O2Na 320.0005, found 320.0003.
ethyl 2-(2-(azidomethyl)-4-bromophenyl)acetate(4c). The azide 4c (1.43 g) was prepared from
3c (1.98 g, 8.7 mmol) by the procedure for the preparation of azide 4a, and the yield was 59%, Rf =
0.37 (EtOAC/PE = 1/7); 1H NMR (CDCl3, 400 MHz) δ 7.48 (d, J = 2.0 Hz, 1H), 7.44 (dd, J = 8.0
Hz and 2.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 4.38 (s, 2H), 4.14 (q, J = 7.2 Hz, 2H), 3.64 (s, 2H),
1.24 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up) 170.6, 136.3, 132.1,
121.5, 61.3, 52.3, 38.1, δ (down) 132.8, 132.5, 131.8, 14.2. IR (film) 2102, 1732 cm-1; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C11H12BrN3O2Na 320.0005, found 320.0004.
ethyl 2-(2-(azidomethyl)-4-(trifluoromethyl)phenyl)acetate(4d). The azide 4d (597.0 mg) was
prepared from 3d (900.0 mg, 4.2 mmol) by the procedure for the preparation of azide 4a, and the
yield was 50%, Rf = 0.72 (EtOAC/PE = 1/3); 1H NMR (CDCl3, 400 MHz) δ 7.60 (s, 1H), 7.58 (d, J
= 8.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 4.49 (s, 2H), 4.17 (q, J = 7.2 Hz, 2H), 3.76 (s, 2H), 1.26 (t,
J = 7.2 Hz, 3 H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up) 170.4, 137.2, 135.3, 130.2 (q,
J
CF = 33 Hz), 123.93 (q, JCF = 270 Hz), 61.6, 52.5, 38.5, δ (down) 131.8, 126.4 (q, JCF = 3 Hz),
125.7 (q, JCF = 3 Hz), 14.2. IR (film) 2102, 1734 cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C12H12F3N3O2Na 310.0774, found 310.0775.
ethyl 2-(2-(azidomethyl)-4-cyanophenyl)acetate(4e). The azide 4e (175.0 mg) was prepared
from 3e (326.0 mg, 1.2 mmol) by the procedure for the preparation of azide 4a, and the yield was
62%, Rf = 0.42(EtOAC/PE = 1/3); 1H NMR (CDCl3, 400 MHz) δ 7.66 (s, 1H), 7.62 (d, J = 8.0 Hz,
1H), 7.42 (d, J = 8.0 Hz, 1H), 4.48 (s, 2H), 4.17 (q, J = 7.2 Hz, 2H), 3.76 (s, 2H), 1.26 (t, J = 7.2
Hz, 3 H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up) 170.0, 138.4, 135.9, 118.3, 111.9,
61.7, 52.1, 38.7, δ (down) 132.8, 132.3, 132.1, 14.2. IR (film) 2100, 1732 cm-1; HRMS (ESI-TOF)
m/z [M + Na]+ calcd for C12H12N4O2Na 267.0853, found 267.0851.
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ethyl 2-(2-(azidomethyl)-5-methylphenyl)acetate(4f). The azide 4f (465.0 mg) was prepared
from 3f (413.0 mg, 2.5 mmol) by the procedure for the preparation of azide 4a, and the yield was
78%, Rf = 0.60 (EtOAC/PE = 1/5); 1H NMR (CDCl3, 400 MHz) δ 7.20 (d, J = 7.6 Hz, 1H), 7.10-
7.12 (m, 2H), 4.37 (s, 2H), 4.15 (q, J = 7.2 Hz, 2H), 3.67 (s, 2H), 2.35 (s, 3H), 1.26 (t, J = 7.2 Hz,
3H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up) 171.3, 138.8, 133.1, 130.9, 61.1, 52.6,
38.5, δ (down) 132.0, 130.1, 128.4, 21.1, 14.2. IR (film) 2096, 1733 cm-1; HRMS (ESI-TOF) m/z
[M + Na]+ calcd for C12H15N3O2Na 256.1057, found 256.1054.
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ethyl 2-(2-(azidomethyl)-4-methylphenyl)acetate(4g). The azide 4g (700.0 mg) was prepared
from 3g (610.0 mg, 3.8 mmol) by the procedure for the preparation of azide 4a, and the yield was
80%, Rf = 0.53 (EtOAC/PE = 1/10); 1H NMR (CDCl3, 400 MHz) δ 7.13-7.20 (m, 3H), 4.38 (s, 2H),
4.14 (q, J = 7.2 Hz, 2H), 3.67 (s, 2H), 2.36 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (CDCl3,
100 MHz, plus APT) δ (up) 171.5, 137.6, 133.8, 130.2, 61.2, 53.0, 38.3, δ (down) 131.2, 130.8,
129.7, 21.2, 14.3. IR (film) 2098, 1733 cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C12H15N3O2Na 256.1057, found 256.1055.
ethyl 2-(2-(azidomethyl)-5-methoxyphenyl)acetate(4h).The azide 4h(200.0 mg) was prepared
from 3h (430.0 mg, 2.4 mmol) by the procedure for the preparation of azide 4a, and the yield was
32%, Rf = 0.72 (EtOAC/PE = 1/2); 1H NMR (CDCl3, 400 MHz) δ 7.21 (d, J = 8.4 Hz, 1H), 6.85 (d,
J = 2.4 Hz, 1H), 6.80 (dd, J = 8.4 Hz and 2.4 Hz, 1H), 4.33 (s, 2H), 4.14 (q, J = 7.2 Hz, 2H), 3.79
(s, 3H), 3.67 (s, 2H), 1.24 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up)
171.0, 159.8, 134.8, 126.0, 61.1, 52.4, 38.7, δ (down) 131.5, 116.9, 112.6, 55.3, 14.1. IR (film) 2097,
1732 cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C12H15N3O3Na 272.1006, found 272.1004.
ethyl 2-(2-(azidomethyl)-4-methoxyphenyl)acetate(4i). The azide 4i (238.0 mg) was prepared
from 3i (348.0 mg, 1.9 mmol) by the procedure for the preparation of azide 4a, and the yield was
49%, Rf = 0.72 (EtOAC/PE = 1/5); 1H NMR (CDCl3, 400 MHz) δ 7.19 (d, J = 8.4 Hz, 1H), 6.87 (d,
J = 2.4 Hz, 1H), 6.83 (dd, J = 8.4 Hz and 2.4 Hz, 1H), 4.37 (s, 2H), 4.12 (q, J = 7.2 Hz, 2H), 3.78
(s, 3H), 3.62 (s, 2H), 1.23 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up)
171.4, 158.9, 135.2, 125.0, 61.0, 52.8, 37.7, δ (down) 132.2, 115.4, 113.7, 55.3, 14.1. IR (film) 2100,
1733 cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C12H15N3O3Na 272.1006, found 272.1000.
ethyl 2-(2-(azidomethyl)-3-methoxyphenyl)acetate(4j). The azide 4j (369.0 mg) was prepared
from 3j (539.0 mg, 3.0 mmol) by the procedure for the preparation of azide 4a, and the yield was
49%, Rf = 0.70 (EtOAC/PE = 1/5); 1H NMR (CDCl3, 400 MHz) δ 7.23 (d, J = 8.0 Hz, 1H), 6.85 (t,
J = 8.0 Hz, 2H), 4.43 (s, 2H), 4.10 (q, J = 7.2 Hz, 2H), 3.82 (s, 3H), 3.65 (s, 2H), 1.21 (t, J = 7.2
Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up) 171.2, 158.5, 135.3, 122.8, 61.2, 45.4,
38.8, δ (down) 129.8, 123.2, 109.9, 55.8, 14.2. IR (film) 2097, 1735 cm-1; HRMS (ESI-TOF) m/z
[M + Na]+ calcd for C12H15N3O3Na 272.1006, found 272.0996.
ethyl 2-(2-(azido(phenyl)methyl)phenyl)acetate(4k). The azide 4k (485.0 mg) was prepared
from 3k (998.0 mg, 4.5 mmol) by the procedure for the preparation of azide 4a, and the yield was
40%, Rf = 0.28 (EtOAC/PE = 1/5); 1H NMR (CDCl3, 400 MHz) δ 7.38-7.42 (m, 1H), 7.24-7.34 (m,
8H), 6.00 (s, 1H), 4.03 (q, J = 7.2 Hz, 2H), 3.58 (s, 2H), 1.17 (t, J = 7.2 Hz, 3H); 13C{1H} NMR
(CDCl3, 100 MHz, plus APT) δ (up) 171.0, 138.8, 137.8, 132.4, 61.0, 38.7, δ (down) 131.5, 128.7
(2), 128.5, 128.4, 128.1, 127.8, 127.5 (2), 65.3, 14.1. IR (film) 2098, 1732 cm-1; HRMS (ESI-TOF)
m/z [M + Na]+ calcd for C17H17N3O2Na 318.1213, found 318.1213.
ethyl 2-(2-(1-azidoethyl)phenyl)acetate(4l). The azide 4l (983.0 mg) was prepared from 3l
(844.0 mg, 5.2 mmol) by the procedure for the preparation of azide 4a, and the yield was 81%, Rf =
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0.68 (EtOAC/PE = 1/3); 1H NMR (CDCl3, 400 MHz) δ 7.42 (d, J = 7.6 Hz, 1H), 7.22-7.32 (m, 3H),
4.91 (q, J = 6.8 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.73 (d, J = 15.6 Hz, 1H), 3.63 (d, J = 15.6 Hz,
1H), 1.53 (d, J = 6.8 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT)
δ (up) 171.3, 139.5, 131.9, 61.3, 38.7, δ (down) 131.3, 128.3, 128.2, 126.5, 57.2, 21.1, 14.3. IR (film)
2103, 1733 cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C12H15N3O2Na 256.1057, found
256.1054.
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methyl 2-(2-(1-azidoethyl)phenyl)acetate(4m). To a stirred solution of ethyl 2-(2-(1-azidoethyl)
phenyl)acetate 4m (337.0 mg, 1.4 mmol) in THF/H2O (1:1, 5.0 ml) was added LiOH.H2O (14.4
mmol). The mixture was heated to 70°C for 12 h, then it was cooled to room temperature and
acidified with aqueous HCl (2.0 M) to pH = 1−2. The mixture was extracted with ethyl acetate (4
mL×3), and washed by brine, dried over anhydrous Na2SO4, and concentrated. The residue was
purified by flash chromatography to give the corresponding 2-(2-(1-azidoethyl) phenyl) acetic acid
(290.0 mg) as a colorless oil. The sample was dissolved in MeOH (5 ml), and AcCl (0.2 ml, 2.0
o
mmol) was added at 0 C. The reaction mixture was kept for 5 h, then MeOH was removed. The
residue was purified by flash chromatography to give the azide 4m (260.0 mg, 70% yield) as a
colorless oil, Rf = 0.44 (EtOAC/PE = 1/6); 1H NMR (CDCl3, 400 MHz) δ 7.24-7.46 (m, 4H), 4.90
(q, J = 6.8 Hz, 1H), 3.73 (q, J = 16.0 Hz, 2H), 3.70 (s, 3H), 1.53 (d, J = 6.8 Hz, 3H); 13C{1H} NMR
(CDCl3, 100 MHz, plus APT) δ (up) 171.7, 139.6, 131.8, 38.6, δ (down) 131.3, 128.4, 128.3, 126.6,
57.3, 52.4, 21.1. IR (film) 2104, 1738 cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C11H13N3O2Na 242.0900, found 242.0903.
ethyl 2-(2-(azidomethyl)phenyl)-2-diazoacetate(1a). To a stirred solution of 4a (1.00 g, 4.6
mmol) in CH3CN (15 ml) under nitrogen atmosphere was added DBU (1.04 g, 6.8 mmol). 30 min
later, the p-ABSA (1.63 g, 6.8 mmol) was added into the mixture. The reaction was kept for an
additional 18 h, then CH3CN was removed. The residue was purified by flash chromatography to
afford 1a (1.00 g, 90% yield) as a yellow oil, Rf = 0.61 (EtOAC/PE = 1/4); 1H NMR (CDCl3, 400
MHz) δ 7.36-7.46 (m, 4H), 4.40 (s, 2H), 4.29 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H); 13C{1H}
NMR (CDCl3, 100 MHz, plus APT) δ (up) 165.7, 135.8, 124.6, 61.4, 52.9, δ (down) 131.2, 129.7,
129.5, 128.8, 14.5. IR (film) 2096, 1704 cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C11H11N5O2Na 268.0805, found 268.0810.
ethyl 2-(2-(azidomethyl)-5-bromophenyl)-2-diazoacetate(1b). The 1b (358.0 mg) was
prepared from 4b (434.0 mg, 1.5 mmol) by the procedure for the preparation of 1a, and the yield
1
was 76%, Rf = 0.59 (EtOAC/PE = 1/7); H NMR (CDCl3, 400 MHz) δ 7.57 (d, J = 2.0 Hz, 1H),
7.52 (dd, J = 8.4 Hz and 2.0 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 4.37 (s, 2H), 4.30 (q, J = 7.2 Hz,
2H), 1.32 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up) 165.2, 134.7,
126.6, 122.4, 61.7, 52.4, δ (down) 133.8, 132.5, 131.2, 14.6. IR (film) 2094, 1694 cm-1; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C11H10BrN5O2Na 345.9910, found 345.9913.
ethyl 2-(2-(azidomethyl)-4-bromophenyl)-2-diazoacetate(1c). The 1c (473.0 mg) was
prepared from 4c (403.0 mg, 1.4 mmol) by the procedure for the preparation of 1a, and the yield
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was 92%, Rf = 0.43 (EtOAC/PE = 1/7); H NMR (CDCl3, 400 MHz) δ 7.63 (d, J = 2.0 Hz, 1H),
7.52 (dd, J = 8.4 Hz and 2.0 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 4.40 (s, 2H), 4.14 (q, J = 7.2 Hz,
2H), 1.32 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up) 160.1, 137.9,
123.7, 123.5, 61.7, 52.4, δ (down) 132.6, 132.5, 132.0, 14.6. IR (film) 2091, 1695 cm-1; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C11H10BrN5O2Na 345.9910, found 345.9919.
ethyl 2-(2-(azidomethyl)-4-trifluoromethyl)-2-diazoacetate(1d). The 1d (597.0 mg) was
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prepared from 4d (597.0 mg, 2.1 mmol) by the procedure for the preparation of 1a, and the yield
was 93%, Rf = 0.68 (EtOAC/PE = 1/3); 1H NMR (CDCl3, 400 MHz) δ 7.74 (s, 1H), 7.63 (dd, J =
8.4 Hz and 1.6 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 4.49 (s, 2H), 4.32 (q, J = 7.2 Hz, 2H), 1.33 (t, J
= 7.2 Hz, 3 H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up) 165.0, 136.5, 131.3 (q, JCF
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33 Hz), 128.5, 123.7 (q, JCF = 270 Hz), 61.8, 52.5, δ (down) 131.2, 126.4 (q, JCF = 3 Hz), 125.5 (q,
JCF = 3 Hz), 14.4. IR (film) 2095, 1699 cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C12H10F3N5O2Na 336.0679, found 336.0676.
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ethyl 2-(2-(azidomethyl)-4-cyanophenyl)-2-diazoacetate(1e). The 1e (109.0 mg) was prepared
from 4e (175.0 mg, 0.7 mmol) by the procedure for the preparation of 1a, and the yield was 56%,
Rf = 0.46 (EtOAC/PE = 1/3); 1H NMR (acetone-d6, 400 MHz) δ 7.93-7.96 (m, 1H), 7.83 (dd, J =
8.4 Hz and 1.6 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 4.67 (s, 2H), 4.29 (q, J = 7.2 Hz, 2H), 1.29 (t, J
= 7.2 Hz, 3H); 13C{1H} NMR (acetone-d6, 100 MHz, plus APT) δ (up) 164.2, 136.9, 130.2, 117.8,
112.0, 61.2, 51.6, δ (down) 132.8, 131.7, 131.4, 13.8. IR (film) 2092, 1694 cm-1; HRMS (ESI-TOF)
m/z [M + Na]+ calcd for C12H10N6O2Na 293.0757, found 293.0757.
ethyl 2-(2-(azidomethyl)-5-methylphenyl)-2-diazoacetate(1f). The 1f (467.0 mg) was prepared
from 4f (465.0 mg, 2.0 mmol) by the procedure for the preparation of 1a, and the yield was 90%,
Rf = 0.70 (EtOAC/PE = 1/5); 1H NMR (acetone-d6, 400 MHz) δ 7.42 (d, J = 8.0 Hz, 1H), 7.36 (s,
1H), 7.27 (d, J = 8.0 Hz, 1H), 4.47 (s, 2H), 4.26 (q, J = 7.2 Hz, 2H), 2.42 (s, 3H), 1.27 (t, J = 7.2
Hz, 3H); 13C{1H} NMR (acetone-d6, 100 MHz, plus APT) δ (up) 165.1, 138.7, 133.0, 124.8, 60.9,
52.2, δ (down) 131.8, 130.0, 129.9, 20.0, 13.9. IR (film) 2090, 1697 cm-1; HRMS (ESI-TOF) m/z
[M + Na]+ calcd for C12H13N5O2Na 282.0962, found 282.0961.
ethyl 2-(2-(azidomethyl)-4-methylphenyl)-2-diazoacetate(1g). The 1g (506.0 mg) was
prepared from 4g (600.0 mg, 2.6 mmol) by the procedure for the preparation of 1a, and the yield
was 76%, Rf = 0.30 (EtOAC/PE = 1/10); 1H NMR (DMSO-d6, 400 MHz) δ 7.24-7.42 (m, 3H), 4.45
(s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 2.35 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (DMSO-d6,
100 MHz, plus APT) δ (up) 165.7, 139.7, 135.9, 121.7, 61.4, 52.3, δ (down) 132.0, 130.9, 129.8,
21.2, 14.7. IR (film) 2090, 1698 cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C12H13N5O2Na
282.0962, found 282.0959.
ethyl 2-(2-(azidomethyl)-5-methoxyphenyl)-2-diazoacetate(1h). The 1h (216.0 mg) was
prepared from 4h (200.0 mg, 0.80 mmol) by the procedure for the preparation of 1a, and the yield
was 98%, Rf = 0.72 (EtOAC/PE = 1/2); 1H NMR (DMSO-d6, 400 MHz) δ 7.44 (d, J = 8.8 Hz, 1H),
7.12 (d, J = 2.8 Hz, 1H), 7.03 (dd, J = 8.8 Hz and 2.8 Hz, 1H), 4.40 (s, 2H), 4.22 (q, J = 7.2 Hz,
2H), 3.78 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (DMSO-d6, 100 MHz, plus APT) δ (up)
165.4, 159.6, 127.8, 126.1, 61.4, 52.0, δ (down) 132.1, 117.2, 115.3, 55.8, 14.7. IR (film) 2087,
1692 cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C12H13N5O3Na 298.0911, found 298.0912.
ethyl 2-(2-(azidomethyl)-4-methoxyphenyl)-2-diazoacetate(1i). The 1i (172.0 mg) was
prepared from 4i (238.0 mg, 0.9 mmol) by the procedure for the preparation of 1a, and the yield
was 66%, Rf = 0.71 (EtOAC/PE = 1/5); 1H NMR (DMSO-d6, 400 MHz) δ 7.45 (d, J = 8.4 Hz, 1H),
7.10 (d, J = 2.8 Hz, 1H), 7.02 (dd, J = 8.4 Hz and 2.8 Hz, 1H), 4.45 (s, 2H), 4.20 (q, J = 7.2 Hz,
2H), 3.80 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (DMSO-d6, 100 MHz) δ 165.8, 160.5,
138.0, 133.8, 116.3, 115.9, 114.5, 61.3, 55.8, 52.3, 14.8. IR (film) 2087, 1692 cm-1; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C12H13N5O3Na 298.0911, found 298.0913.
ethyl 2-(2-(azidomethyl)-3-methoxyphenyl)-2-diazoacetate(1j). The 1j (195.0 mg) was
prepared from 4j (200.0 mg, 0.8 mmol) by the procedure for the preparation of 1a, and the yield
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was 89%, Rf = 0.68 (EtOAC/PE = 1/5); 1H NMR (CDCl3, 400 MHz) δ 7.36 (t, J = 8.0 Hz, 1H), 7.04
(d, J = 8.0 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 4.43 (s, 2H), 4.29 (q, J = 7.2 Hz, 2H), 3.87 (s, 3H),
1.30 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up) 165.9, 158.8, 127.0,
124.0, 61.4, 47.1, δ (down) 130.0, 123.4, 111.3, 55.8, 14.5. IR (film) 2091, 1699 cm-1; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C12H13N5O3Na 298.0911, found 298.0911.
ethyl 2-(2-(azido(phenyl)methyl)phenyl)-2-diazoacetate(1k). The 1k (368.0 mg) was prepared
from 4k (414.0 mg, 1.4 mmol) by the procedure for the preparation of 1a, and the yield was 82%,
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Rf = 0.44 (EtOAC/PE = 1/4); H NMR (DMSO-d6, 400 MHz) δ 7.22-7.60 (m, 9H), 6.14 (s, 1H),
4.12 (t, J = 6.8 Hz, 2H), 1.15 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (DMSO-d6, 100 MHz, plus APT)
δ (up) 165.58, 140.73, 139.01, 123.98, 61.39, δ (down) 133.3, 130.7, 129.2, 129.1 (2), 128.6 (2),
127.5 (2), 65.3, 14.8. IR (film) 2094, 1694 cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C17H15N5O2Na 344.1118, found 344.1118.
ethyl 2-(2-(1-azidoethyl)phenyl)-2-diazoacetate(1l). The 1l (450.0 mg) was prepared from 4l
(646.0 mg, 2.8 mmol) by the procedure for the preparation of 1a, and the yield was 63%, Rf = 0.44
(EtOAC/PE = 1/6); 1H NMR (CDCl3, 400 MHz) δ 7.54 (d, J = 7.6 Hz, 1H), 7.36-7.50 (m, 3H), 4.81
(q, J = 6.8 Hz, 1H), 4.29 (q, J = 7.2 Hz, 2H), 1.53 (d, J = 6.8 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H);
13C{1H} NMR (CDCl3, 100 MHz, plusAPT) δ (up) 161.0, 141.7, 123.9, 61.6, δ (down) 131.7, 130.3,
128.8, 127.1, 58.0, 21.3, 14.6. IR (film) 2090, 1699 cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd
for C12H13N5O2Na 282.0962, found 282.0961.
methyl 2-(2-(1-azidoethyl)phenyl)-2-diazoacetate(1m). The 1m (233.0 mg) was prepared from
4m (260.0 mg, 1.2 mmol) by the procedure for the preparation of 1a, and the yield was 80%, Rf =
0.46 (EtOAC/PE = 1/6); 1H NMR (CDCl3, 400 MHz) δ 7.24-7.46 (m, 4H), 4.81 (q, J = 6.8 Hz, 1H),
3.83 (s, 3H), 1.53 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up) 171.1,
141.8, 120.8, δ (down) 131.7, 130.4, 128.8, 127.2, 58.0, 52.5, 21.3. IR (film) 2092, 1698 cm-1;
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C11H11N5O2Na 268.0805, found 268.0804.
ethyl 2H-isoindole-1-carboxylate(2a). To a stirred solution of Rh2(oct)4 (3.0 mg, 0.004 mmol)
in DCM (4 ml) was added 1a (100.0 mg, 0.40 mmol), and the mixture was keep for 4 h. Then the
mixture was concentrated and the residue was purified by flash chromatography to give the
isoindole 2a (73.0 mg, 97% yield from 1a) as a white soild, Mp:120-122 ºC, Rf = 0.28 (EtOAC/PE
= 1/4); 1H NMR (DMSO-d6, 400 MHz) δ 13.28 (s, 1H), 7.96 (d, J = 8.8, 1H), 7.64-7.71 (m, 2H),
7.19-7.23 (m, 1H), 7.02-7.06 (m, 1H), 4.33 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H); 13C{1H}
NMR (DMSO-d6, 100 MHz, plus APT) δ (up) 161.1, 127.4, 125.6, 110.7, 59.7, δ (down) 125.3,
121.8, 121.7, 120.5, 117.6, 14.8. IR (film) 3195, 1645 cm-1; HRMS (ESI-TOF) m/z [M + H]+ calcd
for C11H12NO2 190.0863, found 190.0862.
ethyl 6-bromo-2H-isoindole-1-carboxylate(2b). The 2b (100.0 mg) was prepared from 1b
(130.0 mg, 0.40 mmol) by the procedure for the preparation of 2a, and the yield was 93%, Mp:140-
141 ºC, Rf = 0.25 (EtOAC/PE = 1/3); 1H NMR (DMSO-d6, 400 MHz) δ 13.50 (s, 1H), 8.11 (s, 1H),
7.71 (s, 1H), 7.69 (d, J = 8.8, 1H), 7.14 (dd, J = 8.8 Hz and 2.0 Hz, 1H), 4.34 (q, J = 7.2 Hz, 2H),
1.36 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (DMSO-d6, 100 MHz, plus APT) δ (up) 160.8, 128.1, 123.9,
119.1, 110.5, 60.0, δ (down) 124.8, 124.3, 122.4, 118.5, 15.0. IR (film) 3231, 1666 cm-1; HRMS
(ESI-TOF) m/z [M + H]+ calcd for C11H11BrNO2 267.9968, found 267.9977.
ethyl 5-bromo-2H-isoindole-1-carboxylate(2c). The 2c (96.5 mg) was prepared from 1c (130.0
mg, 0.40 mmol) by the procedure for the preparation of 2a, and the yield was 90%, Mp:141-142 ºC,
Rf = 0.25 (EtOAC/PE = 1/3); 1H NMR (CDCl3, 400 MHz) δ 11.15 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H),
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7.82 (s, 1H), 7.43 (s, 1H), 7.31 (d, J = 8.8 Hz, 1H), 4.47 (q, J = 7.2 Hz, 2H), 1.47 (t, J = 7.2 Hz,
3H); 13C{1H} NMR (DMSO-d6, 100 MHz, plus APT) δ (up) 160.9, 126.5, 125.4, 114.6, 111.4, 60.0,
δ (down) 128.2, 123.9, 122.7, 117.2, 15.0. IR (film) 3225, 1665 cm-1; HRMS (ESI-TOF) m/z [M +
H]+ calcd for C11H11BrNO2 267.9968, found 267.9963.
ethyl 5-(trifluoromethyl)-2H-isoindole-1-carboxylate(2d). The 2d (84.0 mg) was prepared
from 1d (125.0 mg, 0.40 mmol) by the procedure for the preparation of 2a, and the yield was 82%,
Mp:171-172 ºC, Rf = 0.44 (EtOAC/PE = 1/3); 1H NMR (DMSO-d6, 400 MHz) δ 13.75 (s, 1H), 8.17
(s, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.88 (s, 1H), 7.39 (dd, J = 8.8 Hz and 1.6 Hz, 1H), 4.36 (q, J =
7.2 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (DMSO-d6, 100 MHz, plus APT) δ (up) 160.9,
127.6, 125.5 (q, JCF = 270 Hz), 123.8, 122.3 (q, JCF = 33 Hz), 111.7, 61.3, δ (down) 122.0, 120.7 (q,
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J
CF = 5Hz), 120.4 (q, JCF = 3Hz), 120.0, 15.0. IR (film) 3221, 1685 cm-1; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C12H11F3NO2 258.0736, found 258.0734.
ethyl 5-cyano-2H-isoindole-1-carboxylate(2e). The 2e (34.0 mg) was prepared from 1e (54.0
mg, 0.20 mmol) by the procedure for the preparation of 2a, and the yield was 72%, Mp:178-180 ºC,
Rf = 0.21 (EtOAC/PE = 1/2); 1H NMR (DMSO-d6, 400 MHz) δ 13.90 (s, 1H), 8.36 (s, 1H), 8.07 (d,
J = 8.8 Hz, 1H), 7.90 (s, 1H), 7.41 (d, J = 8.8 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 1.37 (t, J = 7.2 Hz,
3H); 13C{1H} NMR (DMSO-d6, 100 MHz, plus APT) δ (up) 160.8, 127.1, 124.1, 120.6, 112.1,
130.9, 60.3, δ (down) 130.0, 125.3, 121.9, 120.2, 14.9. IR (film) 3216, 1678 cm-1; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C12H10N2O2Na 237.0635, found 237.0633.
ethyl 6-methyl-2H-isoindole-1-carboxylate(2f). The 2f (53.0 mg) was prepared from 1f (104.0
mg, 0.40 mmol) for 16 h by the procedure for the preparation of 2a, and the yield was 66%. Further,
the 2f (60.0 mg) could be produced from 1f (104.0 mg, 0.40 mmol) for 4 h, and the yield was 75%.
In addition, the 2f (58.0 mg) had been prepared from 1f (75.0 mg, 0.29 mmol) for 4 h, and the yield
was 98%. Mp:115-116 ºC, Rf = 0.23 (EtOAC/PE = 1/5); 1H NMR (DMSO-d6, 400 MHz) δ 13.10
(s, 1H), 7.73 (s, 1H), 7.59 (d, J = 8.8 Hz, 2H), 6.89 (dd, J = 8.8 Hz and 1.2 Hz, 1H), 4.32 (q, J =
7.2 Hz, 2H), 2.39 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (DMSO-d6, 100 MHz, plus APT)
δ (up) 161.2, 134.4, 128.1, 124.3, 110.0, 59.6, δ (down) 124.5, 121.6, 119.1, 117.7, 22.4, 15.1. IR
(film) 3237, 1657 cm-1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C12H14NO2 204.1019, found
204.1016.
ethyl 5-methyl-2H-isoindole-1-carboxylate(2g). The 2g (70.0 mg) was prepared from 1g (104.0
mg, 0.40 mmol) by the procedure for the preparation of 2a, and the yield was 86%, Mp:147-148 ºC,
Rf = 0.44 (EtOAC/PE = 1/5); 1H NMR (DMSO-d6, 400 MHz) δ 13.14 (s, 1H), 7.86 (d, J = 8.8 Hz,
1H), 7.52 (d, J = 3.6 Hz, 1H), 7.43 (s, 1H), 7.06 (dd, J = 8.8 Hz and 3.6 Hz, 1H), 4.31 (q, J = 7.2
Hz, 2H), 2.34 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (DMSO-d6, 100 MHz, plus APT) δ
(up) 161.1, 130.4, 126.1 (2), 110.6, 59.6, δ (down) 128.0, 120.3, 120.1, 116.7, 21.8, 15.1. IR (film)
3215, 1646 cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C12H13NO2Na 226.0839, found
226.0832.
ethyl 6-methoxy-2H-isoindole-1-carboxylate(2h). The 2h (77.0 mg) was prepared from 1h
(110.0 mg, 0.40 mmol) by the procedure for the preparation of 2a, and the yield was 88%, Mp:150-
151 ºC, Rf = 0.46 (EtOAC/PE = 1/2);1H NMR (DMSO-d6, 400 MHz) δ 12.94 (s, 1H), 7.52-7.62 (m,
2H), 7.28 (s, 1H), 6.71 (d, J = 8.8 Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H), 3.80 (s, 3H), 1.36 (t, J = 7.2
Hz, 3H); 13C{1H} NMR (DMSO-d6, 100 MHz, plus APT) δ (up) 161.2, 157.9, 128.8, 121.5, 110.1,
59.5, δ (down) 123.3, 118.2, 116.0, 98.0, 55.2, 15.1. IR (film) 3207, 1649 cm-1; HRMS (ESI-TOF)
m/z [M + H]+ calcd for C12H14NO3 220.0968, found 220.0969.
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ethyl 5-methoxy-2H-isoindole-1-carboxylate(2i). The 2i (36.0 mg) was prepared from 1i (55.0
mg, 0.20 mmol) by the procedure for the preparation of 2a, and the yield was 82%, Mp:121-122 ºC,
Rf = 0.50 (EtOAC/PE = 1/2); 1H NMR (DMSO-d6, 400 MHz) δ 13.05 (s, 1H), 7.85 (d, J = 9.2 Hz,
1H), 7.48 (d, J = 3.2 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.89 (dd, J = 9.2 Hz and 2.4 Hz, 1H), 4.31
(q, J = 7.2 Hz, 2H), 3.76 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (DMSO-d6, 100 MHz,
plus APT) δ (up) 161.0, 154.9, 125.9, 123.5, 110.9, 59.7, δ (down) 121.8, 119.5, 116.2, 98.75, 55.5,
15.0. IR (film) 3239, 1667 cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C12H13NO3Na 242.0788,
found 242.0786.
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ethyl 4-methoxy-2H-isoindole-1-carboxylate(2j). The 2j (70.0 mg) was prepared from 1j
(110.0 mg, 0.40 mmol) by the procedure for the preparation of 2a, and the yield was 80%, Mp:117-
118 ºC, Rf = 0.51 (EtOAC/PE = 1/2); 1H NMR (DMSO-d6, 400 MHz) δ 13.16 (s, 1H), 7.54 (d, J =
3.2 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 6.89 (d, J = 7.2 Hz, 1H), 4.31 (q, J
= 7.2 Hz, 2H), 3.88 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (DMSO-d6, 100 MHz, plus
APT) δ (up) 161.2, 154.0, 129.1, 118.8, 111.3, 59.7, δ (down) 126.5, 115.2, 112.9, 99.3, 55.3, 15.0.
IR (film) 3235, 1660 cm-1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C12H14NO3 220.0968, found
220.0968.
ethyl 3-phenyl-2H-isoindole-1-carboxylate(2k). The 2k (94.0 mg) was prepared from 1k (129.0
mg, 0.40 mmol) for 3 h by the procedure for the preparation of 2a, and the yield was 88%. Further,
the 2k (210.0 mg) could be prepared from 1k (258.0 mg, 0.80 mmol) for 4 h, and the yield was 99%.
Mp:142-143 ºC, Rf = 0.41 (EtOAC/PE = 1/4);1H NMR (DMSO-d6, 400 MHz) δ 13.45 (s, 1H), 8.06
(d, J = 8.8 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 7.6 Hz, 2H), 7.53 (t, J = 8.0 Hz, 2H), 7.41
(t, J = 7.2 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H), 1.39
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(t, J = 7.2 Hz, 3H); C{1H} NMR (DMSO-d6, 100 MHz, plus APT) δ (up) 161.2, 131.4, 129.3,
129.1, 123.1, 111.4, 59.9, δ (down) 129.3 (2), 128.5 (2), 128.2, 125.7, 123.0, 121.2, 121.0, 15.1. IR
(film) 2925, 1660 cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C17H15NO2Na 288.0995, found
288.0991.
ethyl 3-methyl-2H-isoindole-1-carboxylate(2l). The 2l (69.0 mg) was prepared from 1l (104.0
mg, 0.40 mmol) for 10 h by the procedure for the preparation of 2a, and the yield was 85% where
the solution was CHCl3. Further, the 2l (60.0 mg) could be produced from 1l (104.0 mg, 0.40 mmol)
for 8 h, and the yield was 74% where the solution was CH2Cl2. Rf = 0.31 (EtOAC/PE = 1/4); 1H
NMR (DMSO-d6, 400 MHz) δ 13.05 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H),
7.20 (t, J = 7.6 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 4.30 (q, J = 7.2 Hz, 2H), 2.58 (s, 3H), 1.35 (t, J =
7.2 Hz, 3H); 13C{1H} NMR (DMSO-d6, 100 MHz, plus APT) δ (up) 161.1, 127.9, 123.9 (2), 108.2,
59.3, δ (down) 125.6, 121.0, 120.7, 120.4, 15.1, 11.2. IR (film) 3231, 1666 cm-1; HRMS (ESI-TOF)
m/z [M + H]+ calcd for C12H14NO2 204.1019, found 204.1013.
methyl 3-methyl-2H-isoindole-1-carboxylate(2m). The 2m (66.0 mg) was prepared from 1m
(98.0 mg, 0.40 mmol) by the procedure for the preparation of 2a, and the yield was 87%, Mp:186-
187 ºC, Rf = 0.29 (EtOAC/PE = 1/4); 1H NMR (DMSO-d6, 400 MHz) δ 13.10 (s, 1H), 7.89 (d, J =
8.8 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.20 (t, J = 7.2 Hz, 1H), 6.99 (t, J = 7.2 Hz, 1H), 3.82 (s, 3H),
2.58 (s, 3H); 13C{1H} NMR (DMSO-d6, 100 MHz, plus APT) δ (up) 161.3, 128.1, 123.9 (2), 107.9,
δ (down) 125.7, 121.1, 120.7, 120.3, 51.0, 11.2. IR (film) 3226, 1640 cm-1; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C11H12NO2 190.0863, found 190.0858.
ACKNOWLEDGMENT
This work was supported by the National Natural Science Foundation of China (No 21662027),
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SUPPORTING INFORMATION
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The Supporting Information (copies of NMR spectra for the key compounds and X-ray
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crystallographic data for 4a) is available free of charge on the ACS Publications website
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References
1. (a) Chen, Z.; Müller, P.; Swager, T. M. Syntheses of Soluble, π-Stacking Tetracene
Derivatives.Org. Lett. 2006, 8 (2), 273. (b) Hsu, D.-T.; Lin, C.-H. Synthesis of Benzo[c] and
Naphtho[c]heterocycle Diesters and Dinitriles via Homoelongation. J. Org. Chem. 2009, 74
(23), 9180–9187.
2. Application in material chemistry, see: (a) Sole, D.; Vallverdu, L.; Solans, X.; Font-Bardia,
M.; Bonjoch, J. Intramolecular Pd-Mediated Processes of Amino-Tethered Aryl Halides and
Ketones:ꢀ Insight into the Ketone α-Arylation and Carbonyl-Addition Dichotomy. A New
Class of Four-Membered Azapalladacycles. J. Am. Chem. Soc. 2003, 125 (6), 1587–1594.
(b) Howard-Jones, A. R.; Walsh, C. T. Nonenzymatic Oxidative Steps Accompanying Action
of the Cytochrome P450 Enzymes StaP and RebP in the Biosynthesis of Staurosporine and
Rebeccamycin. J. Am. Chem. Soc. 2007, 129 (36), 11016–11017. (c) Neumann, C. S.; Walsh,
C. T. Biosynthesis of (-)-(1S,2R)-Allocoronamic Acyl Thioester by an FeII-Dependent
Halogenase and a Cyclopropane-Forming Flavoprotein. J. Am. Chem. Soc. 2008, 130 (43),
14022–14023. (d) Shiraki, T.; Morikawa, M.-A.; Kimizuka, N. Amplification of Molecular
Information through Self-Assembly: Nanofibers Formed from Amino Acids and Cyanine
Dyes by Extended Molecular Pairin. Angew. Chem. Int. Ed. 2008, 47 (1), 106–108.
3. For a review on the synthesis of isoindoles, see: Heugebaert, T. S. A.; Roman, B. I.; Stevens,
C.V. Synthesis of isoindoles and related iso-condensed heteroaromatic pyrroles. Chem. Soc.
Rev. 2012, 41, 5626–5640.
4. For several representative method, see: (a) Yeom, H.-S.; Lee, J.-E.; Shin, S. Gold-Catalyzed
Waste-Free Generation and Reaction of Azomethine Ylides: Internal Redox/Dipolar
Cycloaddition Cascade. Angew. Chem. Int. Ed. 2008, 47, 7040–7043. (b) Ohmura, T.; Kijima,
A.; Suginome, M. Synthesis of 1-Borylisoindoles via Palladium-Catalyzed
Dehydrogenation/C−H Borylation of Isoindolines. J. Am. Chem. Soc. 2009, 131, 6070–6071.
(c) Hui, B. W.-Q.; Chiba, S. Orthogonal Synthesis of Isoindole and Isoquinoline Derivatives
from Organic Azides. Org. Lett. 2009, 11, 729–732.
5. Wee, A. G. H.; Slobodian, J. Metal-Catalyzed Reaction of Indoline Diazoamides Possessing
a C-2 CH2X Substituent:ꢀ Site-Selectivity, Diastereoselectivity, and Chemoselectivity. J. Org.
Chem. 1996, 61, 2897−2900.
6. Blond, A.; Moumné, R.; Bégis, G.; Pasco, M.; Lecourt, T.; Micouin, L. Rhodium(II)
carbene-mediated modification of 2-deoxystreptamine surrogates. Tetrahedron Lett. 2011,
52, 3201−3203.
7. (a) Gu, P.; Wu, X.-P.; Su, Y.; Li, X.-Q.; Xue, P.; Li, R. Rhodium-Catalyzed Intermolecular
Reaction of Alkyl Azides with Diazo(aryl)acetates. Synlett. 2014, 25, 535−538. (b) Wu, X.-
P.; Su, Y.; Gu, P. Catalytic Enantioselective Desymmetrization of 1,3-Diazido-2-propanol
via Intramolecular Interception of Alkyl Azides with Diazo(aryl)acetates. Org. Lett. 2014,
16, 5339−5341. (c) Qiao, J.-B.; Zhao, Y.-M.; Gu, P. Asymmetric Intramolecular
Desymmetrization of meso-α,α′-Diazido Alcohols with Aryldiazoacetates: Assembly of
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The Journal of Organic Chemistry
Page 16 of 16
1
2
3
4
5
6
7
8
9
Chiral C3 Fragments with Three Continuous Stereocenters. Org. Lett. 2016, 18, 1984−1987
8. Mandler, M. D.; Truong, P. M.; Zavalij, P. Y.; Doyle, M. P. Catalytic Conversion of
Diazocarbonyl Compounds to Imines: Applications to the Synthesis of
Tetrahydropyrimidines and β-Lactams. Org. Lett. 2014, 16, 740−743.
9. For synthesis of 4a, see: Philippe, N.; Levacher, V.; Dupas, G.; Que´guiner, G.; Bourguignon,
J. Diastereoselective Protonation of Lactam Enolates Derived from (R)-Phenylglycinol. A
Novel Asymmetric Route to 4-Phenyl-1,2,3,4-tetrahydroisoquinolines. Org. Lett. 2000, 2
(15), 2185-2187.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
10. Regitz diazo transfer reaction, see: Regitz, M. New Methods of Preparative Organic
Chemistry. Transfer of Diazo Groups. Angew. Chem. Int. Ed. 1967, 6, 733-749.
11. Caution: the azides are suggested to be potentially explosive compounds, special precautions
must be taken in its handling. From the TGA and DSC experiments, the azide 1a was found
to be decomposed at about 80 oC.
12. isoindole 2a, a known compound, see: Ito, S.; Akaki, M.; Shinozaki, Y.; Iwabe, Y.; Furuya,
M.; Tobata, M.; Roppong, M.; Sato, T.; Itoh, N.; Oba, T. Efficient synthesis of isoindoles
using supercritical carbon dioxide. Tetrahedron Lett. 2017, 58 (13), 1338-1342.
13. Hanna, A.; Heidi, D.; Georges, V.; Gunnar, L.; Anders, K.; Mathias, H. Ligands to the (IRAP)
/AT4 receptor encompassing a 4-hydroxydiphenylmethane scaffold replacing Tyr2. Bioorg.
Med. Chem. 2008, 16 (14), 6924-6935.
14. Trost, B. M.; Kalnmals, C. A. Sulfones as Synthetic Linchpins: Transition-Metal-Free sp3–
sp2and sp2–sp2 Cross-Couplings Between Geminal Bis(sulfones) and Organolithium
Compounds. Chem. –Eur. J. 2018, 24 (36), 9066-9074.
15. Kilikli, A. A.; Dengiz, C.; Özcan, S.; Balci, M. Synthesis of Indolin-2-one, Isoindolin-1-one,
and Indole Derivatives from Homophthalic Acid. Synthesis. 2011, (22), 3697-3705.
16. Borsche, W.; Diacont, K.; Hanau, H. Über 5-Carboxyhomophthalsaure, 6-Nitro-phthalid und
6-Nitro-phthalimidin. Ber. Dtsch. Chem. Ges. 1934, 67B, 675-86.
17. Peter A. S. S.; Robert O. K. Cyclization of Isothiocyanates as a Route to Phthalic and
Homophthalic Acid Derivatives. J. Org. Chem. 1964, 29 (8), 2261-2265.
18. Kanapure, S. P.; Das, K. G.; Bhawal, B. M. An Improved Synthesis of 7-
Methoxyisochroman-3-one: A Synthon for Generation of o-Quinodimethanes. Synth.
Commun. 1984, 14 (13), 1205-1211.
19. Martin, S.; Peter, J. W. Light-Induced Decarboxylation of (o-Acylphenyl)acetic Acids. Org.
Lett. 2002, 4 (3), 379-382.
20. (a) Li, T.-T.; Xiang,C.-B.; Zhang, B.-J.; Yan, J. Hypervalent Iodine Catalyzed Cyclization of
Aryl–Substituted Alkanoic Acids. Helv. Chim. Acta. 2014, 97 (6), 854-860. (b) Zhang, B.-J.;
Han, L.-Q.; Li, T.-T.; Yan, J.; Yang, Z.-P. Ammonium Iodide–Promoted Cyclization of Aryl-
Substituted Carboxylic Acids. Synth. Commun. 2014, 44 (11), 1608-1613. (c) Brancaccio,
G.; Larizza, A.; Lettieri, G.; Monforte, P. 2-(Arylmethyl)arylacetic acids as potential
antiinflammatory agents. J. Med. Chem. 1981, 24 (8), 998-1000. (d) Shigehisa, H.; Hayashi,
M.; Ohkawa, H.; Suzuki, T.; Okayasu, H.; Mukai, M.; Yamazaki, A.; Kawai, R.; Kikuchi,
H.; Satoh, Y.; Fukuyama, A.; Hiroya, K. Catalytic Synthesis of Saturated Oxygen
Heterocycles by Hydrofunctionalization of Unactivated Olefins: Unprotected and Protected
Strategies. J. Am. Chem. Soc. 2016, 138 (33), 10597-10604.
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