Synthesis of isoindoles via 1,3-dipolar cycloaddition of α-azido carbonyl compounds onto intramolecular alkenes and their conversion into substituted aromatic hydrocarbons

Article abstract of DOI:10.1055/s-0030-1260221

α-Azido carbonyl compounds bearing a 2-alkenylaryl moiety in the α-position are found to be promising precursors in the synthesis of isoindoles via 1,3-dipolar cycloaddition of azides to alkenes. Applications of these isoindoles in the preparation of 1,2,3,4-tetrasubstituted naphthalene and 9,10-disubstituted anthracene derivatives were developed via [4+2]-cycloaddition reactions of isoindoles with dimethyl acetylenedicarboxylate and benzynes, respectively, followed by deaminative aromatization. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1260221

3552
PAPER
Synthesis of Isoindoles via 1,3-Dipolar Cycloaddition of a-Azido Carbonyl
Compounds onto Intramolecular Alkenes and Their Conversion into
Substituted Aromatic Hydrocarbons
S
ynthesis of Isoin
e
doles via
1
n
,3-Dipola
r
C
n
ycloadditiony Meng Kiat Tong, Benjamin Wei-Qiang Hui, Sze Hui Chua, Shunsuke Chiba*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
21 Nanyang Link, Singapore 637371, Singapore
Fax (+65) 6791 1961; E-mail: shunsuke@ntu.edu.sg
Received 19 July 2011; revised 18 August 2011
sulting triazolines7,8 would produce isoindoles 2 as shown
Abstract: a-Azido carbonyl compounds bearing a 2-alkenylaryl
in Scheme 1.
moiety in the a-position are found to be promising precursors in the
synthesis of isoindoles via 1,3-dipolar cycloaddition of azides to
R2
alkenes. Applications of these isoindoles in the preparation of
1,2,3,4-tetrasubstituted naphthalene and 9,10-disubstituted an-
thracene derivatives were developed via [4+2]-cycloaddition reac-
tions of isoindoles with dimethyl acetylenedicarboxylate and
benzynes, respectively, followed by deaminative aromatization.
R1
R1
R2
N
N
N
N
N
N
azide–alkene
cycloaddition
R3
R3
triazoline
Key words: isoindoles, organic azides, 1,3-dipolar cycloaddition,
1
aromatic hydrocarbons, benzynes
R1
R2
R1
R1
H
R2
R2
N2
NH
Isoindoles and their derivatives are attractive candidates
for organic light-emitting devices (OLEDs) due to their
highly fluorescent and electroluminescent properties,1
and they have been regarded as highly reactive substrates
in [4+2]-cycloadditions with various dienophiles for the
preparation of oligoacenes.2 One of the most common
synthetic methods for the preparation of isoindoles is the
reaction of phthalaldehyde and an amine in the presence
of reductants or nucleophiles.3 However, there remains a
need for the development of general and versatile routes
for the preparation of isoindoles, especially 1,3-disubsti-
tuted derivatives, with selective control of the substituents
using readily available building blocks.4
N
N
– N2
R3
isoindole 2
R3
R3
Scheme 1 Synthetic route to isoindoles
Treatment of aryl Grignard reagents or aryllithium species
prepared from 2-alkenylaryl bromides 3 with diethyl ox-
alate provided the corresponding a-keto esters, which
were then reduced with sodium cyanoborohydride to af-
ford a-hydroxy esters 4 (Table 1). a-Hydroxy ketone 4l
was prepared by conversion of 2-alkenylbenzaldehyde 5
into cyanohydrin trimethylsilyl ether 69 and subsequent
treatment of 6 with a Grignard reagent followed by acid
work-up of the resulting imine (Scheme 2). Alcohols 4
were converted into mesylates 7, which were reacted with
sodium azide in N,N-dimethylformamide to provide a-
azido carbonyl compounds 1 as shown in Scheme 3.
We have recently reported a methodology for the synthe-
sis of isoindole derivatives from a-azido carbonyl com-
pounds possessing a 2-alkenylaryl moiety at the a-
position via azide-alkene 1,3-dipolar cycloaddition.5 This
is a full account of this isoindole synthesis and its applica-
tion to the preparation of 1,2,3,4-tetrasubstituted naphtha-
lene and 9,10-disubstituted anthracene derivatives
through [4+2]-cycloaddition reactions of isoindoles with
electron-deficient alkynes and benzynes, respectively,
followed by deaminative aromatization.
TMSCN (1 equiv)
Et3N (0.1 equiv)
OTMS
CH2Cl2, 0 °C
CHO
CN
5
Among numerous diverse approaches to the synthesis of
azaheterocycles, 1,3-dipolar cycloaddition of azides to
alkenes6 have proven to be versatile methods for provid-
ing ready access to azaheterocycles. We envisaged that
the intramolecular azide-alkene cycloaddition reaction of
1 and subsequent elimination of dinitrogen from the re-
6
1) p-TolMgBr
Et2O, reflux
OH
2) 2 M aq HCl, r.t.
O
SYNTHESIS 2011, No. 21, pp 3552–3562
Advanced online publication: 14.09.2011
x
x.
x
x
.
2
0
1
1
4l 47%
DOI: 10.1055/s-0030-1260221; Art ID: Z70811SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Synthesis of a-hydroxy ketones 4l

PAPER
Synthesis of Isoindoles via 1,3-Dipolar Cycloaddition
3553
Table 1 Synthesis of a-Hydroxy Esters 4
Table 1 Synthesis of a-Hydroxy Esters 4 (continued)
R1
R2
method A
Mg, THF;
then (EtO2C)2
–78 °C
method A
R1
R2
R1
R2
R1
R2
Mg, THF;
then (EtO2C)2
–78 °C
R3
R3
R3
R3
O
O
method B
method B
BuLi, THF;
then (EtO2C)2
–78 °C
X
X
X
Br
X
Br
BuLi, THF;
then (EtO2C)2
–78 °C
CO2Et
CO2Et
3
3
R1
R2
R1
R2
NaBH3CN
NaBH3CN
R3
R3
OH
THF–H2O–AcOH
86% (2 steps)
OH
THF–H2O–AcOH
86% (2 steps)
X
X
CO2Et
CO2Et
4
4
Entry
Product
Method
Yielda (%)
(ratio Z/E)
Entry
Product
Method
Yielda (%)
(ratio Z/E)
4
1
A
86
70
OH
8
B
45
CO2Et
OH
4a
CO2Et
4h
2
3
A
B
OH
F
CO2Et
9
10
11
B
B
B
68
48
63
OH
CO2Et
4b
Ph
4i
Br
83 (2.4:1)
85 (3.5:1)b
OH
CO2Et
OH
CO2Et
4c
4-MeOC6H4
4j
4
5
B
B
OH
CO2Et
OH
N
4d
CO2Et
4k
a Isolated yields (2 steps) are noted above.
b Z- and E-isomers could be separated by flash column chromatogra-
phy and the Z-isomer was used for further transformations.
26
OH
CO2Et
R1
R2
R1
R2
4e
MsCl, Et3N
R3
R3
OH
OMs
CH2Cl2, 0 °C
X
X
6
7
B
B
45
45
COR4
COR4
OH
4
7 54–98%
CO2Et
R1
R2
4f
NaN3
R3
DMF, 0 °C
90%
N3
X
OH
COR4
1 71–90%
CO2Et
4g
Scheme 3 Synthesis of a-azido carbonyl compounds
Synthesis 2011, No. 21, 3552–3562 © Thieme Stuttgart · New York

3554
B. M. K.Tong et al.
PAPER
Table 2 Synthesis of Isoindoles (continued)
Next, isoindole formation via the intramolecular azide-
alkene cycloaddition was investigated. As expected, the
reaction proceeded smoothly by heating azide 1a in tolu-
ene (0.1 M concentration) at 100 °C to give isoindole 2a10
in good yield (entry 1).11 A variety of substituted isoin-
doles 2 were synthesized as shown in Table 2. Various
substituents were installed at C3 of the isoindoles 2b–h,
e.g. methyl, benzyl, and several cycloalkyl moieties as
well as a hexenyl group (entries 2–8). A fluoro or a bromo
group also could be introduced at C5 or C4 of the isoin-
dole ring of 2i,j, respectively (entries 9, 10). It is notewor-
thy that a heterocyclic framework such as 6H-pyrrolo[3,4-
b]pyridine 2k could be readily accessible using this meth-
od (entry 11). The reaction of azide 1l having a 4-methyl-
benzoyl group instead of ethoxycarbonyl also proceeded
smoothly to afford isoindole 2l in 85% yield (entry 12).
R1
R2
R1
R2
R3
R3
NH
COR4
N3
toluene, 100 °C
COR4
1
2
Entry
Product
Yield (%)
Method Aa
Method Bb
6
7
–
70
NH
CO2Et
2f
Table 2 Synthesis of Isoindoles
R1
R2
–
54
NH
R1
R2
CO2Et
R3
R3
NH
COR4
N3
2g
toluene, 100 °C
COR4
1
2
82e
–
Entry
Product
Yield (%)
8
NH
Method Aa
Method Bb
CO2Et
2h
1
2
3
98
83
75
99c
NH
F
9
10
11
NH
–
–
–
82
57
61
CO2Et
2a
2b
CO2Et
2i
NH
Br
94
–
CO2Et
NH
CO2Et
Ph
2j
NH
CO2Et
NH
N
2c
CO2Et
4-MeOC6H4
2k
4
5
–
–
87d
NH
12
NH
85
–
CO2Et
2d
COp-Tol
2l
a Method A: azide 1, toluene (0.1 M), 100 °C, 3 h.
b Method B: 1. mesylate 7, NaN3 (1.2 equiv), DMF (0.3 M), 0 °C,
workup; 2. crude azide, toluene (0.1 M), 100 C, 3–5 h.
c A Z/E-mixture (5.4:1) of 1c was used as a starting material.
d Z-Isomer of 1d was used as the starting material.
87
NH
CO2Et
e E-Isomer of 1h was used as the starting material.
2e
Synthesis 2011, No. 21, 3552–3562 © Thieme Stuttgart · New York

PAPER
Synthesis of Isoindoles via 1,3-Dipolar Cycloaddition
3555
R1
Although isoindole derivatives have been utilized in
[4+2]-cycloaddition reactions with various dienophiles
for the synthesis of oligoacenes,2 the reactivity of 1,3-di-
substituted isoindoles in oligoacene synthesis has not
been explored extensively. Based on this background, we
investigated the reactivity of our 1,3-disubstituted isoin-
doles in the synthesis of substituted aromatic
hydrocarbons such as naphthalenes and anthracenes via
[4+2]-cycloaddition with alkynes and benzynes, respec-
tively, followed by an oxidative deamination-aromatiza-
tion sequence (Scheme 4).
R1
R2
R4
CO2Et
R4
R2
N
R3
N
R3
[4+2] cycloaddition
CO2Et
R1 R2
2
R3
deaminative aromatization
CO2Et
Scheme 4 Synthetic route to aromatic hydrocarbons
To prepare naphthalenes, reactions of isoindoles 2a with
alkynes were investigated (Scheme 5). It was found that
treatment of isoindole 2a with dimethyl acetylenedicar-
boxylate in toluene at 100 °C provided the corresponding
[4+2]-adduct, naphthalen-1,4-imine 8a in 98% yield.12
H
N
MeO2C
CO2Me
CO2Me
CO2Me
NH
toluene, 100 °C
17 h
CO2Et
8a 98%
CO2Et
It was expected that oxidation of the imine moiety of 8a
with peroxides could promote deaminative aromatization
with elimination of nitroxyl (NHO) from the putative N-
oxide. Treatment of naphthalen-1,4-imine with m-chlo-
roperoxybenzoic acid in the presence of sodium hydrogen
2a
Scheme 5 [4+2]-Cycloaddition with dimethyl acetylenedicarboxy-
late
carbonate provided naphthalene 9a in 96% yield (Table 3,
entry 1). Oxidation with Oxone® (potassium peroxy-
monosulfate) was sluggish, affording 9a in moderate yield
even after 70 hours (entry 2). Hydrogen peroxide showed
no reactivity at all toward the oxidative deamination (en-
try 3).
Table 3 Oxidative Deamination for Synthesis of Naphthalenesa
H
N+
–O
H
N
CO2Me
CO2Me
[O]
CO2Me
CO2Me
– HNO
CO2Et
CO2Et
Naphthalenes bearing an alkene tether such as 9h
(Table 4, entry 1) and a fluorine atom 9i (entry 2) could be
prepared via [4+2]-cycloaddition with dimethyl acety-
lenedicarboxylate followed by m-chloroperoxybenzoic
acid mediated deaminative aromatization of the resulting
1,4-imines 8 (Table 4).
CO2Et
9a
8a
Entry Oxidant
(equiv)
Additive
(equiv)
Conditions
Yielda
(%)
1
2
MCPBA (1.5) NaHCO3 (2) CH2Cl2, r.t., 14 h
96
58
We next examined the [4+2]-cycloaddition of isoindoles
with benzynes for the preparation of anthracene deriva-
tives. When 2-trimethylsilylphenyl triflate (11a)13 was
subjected to reaction with N–H isoindole 2a in the pres-
ence of cesium fluoride in acetonitrile, the desired N–H
Oxone (5)
–
MeOH–H2O (1:1),
50 °C, 70 h
3
H2O2 (1.5)
–
MeOH, 50 °C, 24 h
0
a Isolated yields.
Table 4 Synthesis of Naphthalenes
Entry
Isoindole
Iminea
Time (h)
Yieldc (%) Naphthalenesb
Time (h) Yieldc (%)
H
N
CO2Me
CO2Me
CO2Me
1
2h
24
51
94
26
20
70
69
CO2Et
CO2Me
CO2Et
8h
9h
H
N
F
CO2Me
F
CO2Me
CO2Me
2
2i
39
CO2Me
CO2Et
CO2Et
8i
9i
a 1,4-Imines 8 were prepared by treatment of the corresponding isoindoles 2 (DMAD, toluene, 100 °C).
b Naphthalenes 9 were synthesized by the reaction of 1,4-imines 8 (MCPBA, NaHCO3, CH2Cl2, r.t.).
c Isolated yields.
Synthesis 2011, No. 21, 3552–3562 © Thieme Stuttgart · New York

3556
B. M. K.Tong et al.
PAPER
anthracen-9,10-imine 12a was formed in only 47% yield thracen-9,10-imine 12a, resulting in oligomerization to
along with highly luminescent compounds as side prod- form a highly conjugated aromatic compound. To prevent
ucts (Table 5, entry 1). The 1H NMR analysis showed that such side reactions, the N–H moiety of 2a was protected
these side products contain large numbers of aromatic by methylation (LiH, MeI, DMF, 77%). The reaction of
protons, which may indicate that the generated benzyne N-methylisoindole 10a with benzyne generated from 2-
reacted with the N–H moiety of N–H isoindole 2a or an- trimethylsilylphenyl triflate (11a) and cesium fluoride af-
Table 5 [4+2]-Cycloaddition of Isoindoles with Benzynes
R
N
conditions
time
benzyne
precusors
11
+
N
R
(1.1 equiv)
CO2Et
CO2Et
2a R = H
12a R = H
13a R = Me
10a R = Me
Entry
1
R
H
Benzyne precursor
Conditions
Product
Yielda (%)
47b
Me3Si
CsF (1.5 equiv), MeCN, r.t., 72 h
12a
TfO
11a
11a
2
3
Me
Me
CsF (1.5 equiv), MeCN, r.t., 84 h
TBAT (2 equiv), THF, r.t., 6 h
13a
13a
89
99
11a
I
4
Me
n-BuLi (1.2 equiv), THF, –78 °C, 2 h
13a
49
TfO
11b
a Isolated yields.
b 10a was recovered in 51% yield.
Table 6 Synthesis of Aromatic Hydrocarbons
R
PhCH2N+Et3Cl–
(30 mol %)
benzyne
precusors
11
TBAT
(2 equiv)
aromatic
imine
13
N-Me
+
hydrocarbons
(1.1 equiv)
aq. NaOH–CHCl3, r.t.
THF, r.t.
14
CO2Et
10
Entry
Isoindole Benzyne precursor Iminea
Time (h) Yield (%) Aromatic hydrocarbona Time (h) Yield (%)
Me
Me3Si
N
1
10h
15
quant
5
48
TfO
CO2Et
11a
CO2Et
13h
14h
Me
N
F
F
2
3
10i
11a
24
98
23
14
66
CO2Et
CO2Et
13i
14i
Me
N
Me3Si
TfO
b
10a
5
–
69c
EtO2C
EtO2C
13ac
11c
14ac
a Isolated yields.
b 13ac was not characterized and further utilized for the next deaminative aromatization.
c 2-step yield from isoindole 10a.
Synthesis 2011, No. 21, 3552–3562 © Thieme Stuttgart · New York

PAPER
Synthesis of Isoindoles via 1,3-Dipolar Cycloaddition
3557
FT-IR spectrophotometer. HRMS were obtained with a Q-Tof Pre-
mier LC HR mass spectrometer. X-ray crystallographic analyses
were performed on a Bruker X8 APEX X-ray diffractometer. Melt-
ing points are uncorrected and were recorded on a Buchi B-54 melt-
ing point apparatus. Flash column chromatographs were performed
using Silicycle 60 silica gel and distilled eluting solvents. Toluene
was obtained from an Innovative Technology PS-400-5 Solvent Pu-
rification System. EtOH was distilled from Na under N2 and stored
over MS 4A. THF and Et2O, when used as solvents for the reac-
tions, were distilled from Na and benzophenone under N2. DMF
was distilled from CaH2 under N2 and stored over MS 4A. Benzyne
precursors 11a,17 11b,18 and 11c19 were prepared according to the
literature procedures. Tetrabutylammonium difluorotriphenylsili-
cate (TBAT) was purchased from Sigma-Aldrich, Pte. Ltd. For the
synthesis of alcohols 4 and azides 1, see Supporting Information.
Me
N
MCPBA (1.5 equiv)
NaHCO3 (2 equiv)
CH2Cl2, r.t.
24 h
CO2Et
CO2Et
14a 45%
13a
PhCH2N+Et3Cl– (30 mol%)
13a
14a 81%
aq NaOH–CHCl3, r.t.
1.5 h
Scheme 6 Deaminative aromatization
forded the desired anthracen-9,10-imine 13a in 89%
yield, however, a long reaction time (84 h) was required
(entry 2). It was found that the use of tetrabutylammonium
difluorotriphenylsilicate (TBAT)14 instead of cesium fluo-
ride reduces the reaction time to six hours and improves
Ethyl 3-Isopropyl-2H-isoindole-1-carboxylate (2a); Typical
Procedure from Azides
A soln of azide 1a (105 mg, 0.404 mmol) in toluene (4 mL) was
stirred at 100 °C for 3 h. The mixture was cooled to r.t., the solvent
the yield of 13a to 99% (entry 3). Utilization of 2-io- was removed in vacuo, and the resulting crude mixture was purified
by flash column chromatography (hexane–EtOAc, 85:15) to give
formation of 13a in moderate yield (entry 4).15
isoindole 2a (92 mg, 0.397 mmol, 98%).
dophenyl triflate (11b) with n-butyllithium resulted in the
To obtain anthracenes, deaminative aromatization of an-
thracen-9,10-imine 13a was investigated (Scheme 6). Al-
though oxidation with m-chloroperoxybenzoic acid,
which is the optimized conditions for naphthalen-1,4-
imines (see Table 3), resulted in the formation of the cor-
responding anthracene 14a in moderate yield, the reaction
with dichlorocarbene generated in situ from aqueous sodi-
um hydroxide and chloroform in the presence of a phase-
Ethyl 3-Isopropyl-2H-isoindole-1-carboxylate (2a); Typical
Procedure by a Two-Step Reaction from Mesylates 7
To an ice cold soln of 7a (83 mg, 0.27 mmol) in DMF (1 mL) main-
tained at 0 °C was added NaN3 (27 mg, 0.41 mmol), and the mixture
was stirred at the same temperature for 1 h. The mixture was then
diluted with H2O and extracted with Et2O (2 ×). The combined or-
ganic extracts were then washed with water, brine, and dried
(MgSO4). After removal of solvent in vacuo, the crude material was
then dissolved in toluene (2.8 mL) and heated at 100 °C for 3 h. On
transfer catalyst afforded anthracene 14a in 81% yield removal of the solvent in vacuo, the crude residue was subjected to
within 1.5 hours.16
flash column chromatography (hexane–EtOAc, 85:15) to afford 2a
(51 mg, 0.221 mmol, 83% from 7a).
By employing this two-step sequence, 10-hexenylan-
thracenes 14h as well as 3-fluoroanthracenes 14i could be
Colorless crystals; mp 140–142 °C.
IR (KBr): 3422, 3043, 2974, 1651, 1503, 1454, 1366, 1327, 1263,
accessed in good yields (Table 6, entries 1 and 2). This
1098, 1063 cm–1.
method allowed the construction of the benzo[f]tet-
1H NMR (400 MHz, CDCl3): d = 1.45 (t, J = 7.1 Hz, 3 H), 1.46 (d,
raphene framework 14ac (entry 3) by using 9,10-phenan-
J = 7.0 Hz, 6 H), 3.53 (sept, J = 7.0 Hz, 1 H), 4.45 (q, J = 7.1 Hz, 2
thryne derived from 11c.
H), 7.06 (dd, J = 7.0, 8.0 Hz, 1 H), 7.27 (dd, J = 7.0, 8.5 Hz, 1 H),
In summary, we have disclosed a concise and versatile
method for the synthesis of substituted isoindoles from a-
azido carbonyl compounds bearing a 2-alkenylaryl moi-
ety in the a-position via 1,3-dipolar azide-alkene cycload-
dition. Application of these isoindoles in the preparation
of 1,2,3,4-tetrasubstituted naphthalene and 9,10-disubsti-
tuted anthracene derivatives was developed via [4+2]-cy-
7.68 (d, J = 8.5 Hz, 1 H), 8.03 (d, J = 8.0 Hz, 1 H), 10.3 (br, 1 H).
13C NMR (100 MHz, C6D6): d = 15.1, 22.5, 27.6, 60.4, 109.9, 121.4,
121.8, 122.0, 123.5, 126.5, 129.4, 138.0 (br), 163.1 (br).
HRMS (ESI): m/z [M + H]+ calcd for C14H18NO2: 232.1338; found:
232.1339.
Ethyl 3-Methyl-2H-isoindole-1-carboxylate (2b)
cloaddition reactions of isoindoles with dimethyl Off-white crystals; yield: 94% from 1b, 75% from 7b (2 steps); mp
173–176 °C.
acetylenedicarboxylate and benzynes, respectively, fol-
lowed by deaminative aromatization.
IR (KBr): 3420, 3053, 2982, 1647, 1506, 1460, 1362, 1339, 1287,
1088, 1032 cm–1.
1H NMR (400 MHz, C6D6): d = 1.18 (t, J = 7.3 Hz, 3 H), 2.27 (s, 3
H), 4.26 (q, J = 7.3 Hz, 2 H), 7.02 (dd, J = 6.9, 8.2 Hz, 1 H), 7.28
(dd, J = 6.9, 8.2 Hz, 1 H), 7.47 (d, J = 8.2 Hz, 1 H), 8.33 (d, J = 8.2
Hz, 1 H), 11.79 (br, 1 H).
13C NMR (100 MHz, C6D6): d = 11.2, 15.1, 60.3, 110.0, 121.0,
121.67, 121.74, 125.3, 126.4, 128.3, 129.4, 163.4 (br).
1H NMR spectra were measured on Bruker Avance 300, 400, or 500
MHz and Jeol ECA 400 MHz spectrometers in CDCl3 [internal
standard: CHCl3 (for 1H, d = 7.26)], CD2Cl2 [internal standard:
CH2Cl2 (for H, d = 5.32)], C6D6 [internal standard: C6H6 (for H,
d = 7.16)], or DMSO-d6 [internal standard: DMSO (for 1H,
d = 2.50)]. 13C NMR spectra were measured on Bruker Avance 300,
400, or 500 MHz and Jeol ECA 400 MHz spectrometers in CDCl3
[internal standard: CDCl3 (for 13C, d = 77.0)], CD2Cl2 [internal stan-
dard: CH2Cl2 (for 13C, d = 54.0)], C6D6 [internal standard: C6H6 (for
13C, d = 128.4)], or DMSO-d6 [internal standard: DMSO (for 13C,
d = 39.5)]. IR spectra were recorded on a Shimadzu IR Prestige-21
1
1
HRMS (ESI): m/z [M + H]+ calcd for C12H14NO2: 204.1025; found:
204.1026.
Ethyl 3-Benzyl-2H-isoindole-1-carboxylate (2c)
Light-pink needles; yield: 99% from 7c (2 steps); mp 197–199 °C.
Synthesis 2011, No. 21, 3552–3562 © Thieme Stuttgart · New York

3558
B. M. K.Tong et al.
PAPER
IR (KBr): 3412, 3019, 2978, 1657, 1504, 1464, 1333, 1261, 1084
cm–1.
1H NMR (400 MHz, CD2Cl2): d = 1.39 (t, J = 7.3 Hz, 3 H), 4.36 (q,
J = 7.3 Hz, 2 H), 4.44 (s, 2 H), 7.03 (dd, J = 7.3, 8.2 Hz, 1 H), 7.20
(m, 6 H), 7.60 (d, J = 8.2 Hz, 1 H), 8.01 (d, J = 8.7 Hz, 1 H), 11.09
(br, 1 H).
13C NMR (100 MHz, CD2Cl2): d = 15.0, 33.0, 60.6, 110.1, 120.8,
121.1, 122.0, 124.4, 126.2, 127.3, 128.4 (br), 129.1, 129.3, 130.0
(br), 138.7, 162.5 (br).
J = 7.3 Hz, 2 H), 7.02 (dd, J = 7.3, 7.8 Hz, 1 H), 7.20 (dd, J = 7.3,
8.7 Hz, 1 H), 7.70 (d, J = 7.8 Hz, 1 H), 7.95 (d, J = 8.7 Hz, 1 H),
10.25 (br, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 7.9, 8.2, 14.7, 58.9, 107.7,
120.3, 120.4, 120.6, 122.9, 125.2, 127.9, 133.2, 160.5.
HRMS (ESI): m/z [M + H]+ calcd for C14H16NO2: 230.1181; found:
230.1176.
Ethyl 3-(Hex-5-enyl)-2H-isoindole-1-carboxylate (2h)
Orange solid; yield: 82% from 1h; mp 93–94 °C.
IR (KBr): 3418, 3356, 3233, 1645, 1539, 1504, 999, 917 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C18H18NO2: 280.1338; found:
280.1337.
1H NMR (300 MHz, CDCl3): d = 1.48 (t, J = 7.2 Hz, 3 H), 1.43–1.50
(m, 2 H), 1.75–1.85 (m, 2 H), 2.03–2.11 (m, 2 H), 3.06 (t, J = 7.5
Hz, 2 H), 4.47 (q, J = 7.2 Hz, 2 H), 4.09–5.01 (m, 2 H), 5.75 (ddt,
J = 6.7, 10.3, 17.0 Hz, 1 H), 7.04–7.09 (m, 1 H), 7.24–7.29 (m, 1 H),
7.63 (d, J = 8.7 Hz, 1 H), 8.03 (d, J = 8.7 Hz, 1 H), 11.21 (br, 1 H).
Ethyl 3-(4-Methoxybenzyl)-2H-isoindole-1-carboxylate (2d)
White flakes; yield: 87% from 7d (2 steps); mp 170–172 °C.
IR (KBr): 3410, 3048, 2936, 1649, 1510, 1464, 1429, 1246, 1032
cm–1.
1H NMR (400 MHz, CDCl3): d = 1.40 (t, J = 7.3 Hz, 3 H), 3.76 (s,
3 H), 4.34 (s, 2 H), 4.37 (q, J = 7.3 Hz, 2 H), 6.80 (d, J = 8.2 Hz, 2
H), 7.04 (dd, J = 7.3, 7.8 Hz, 1 H), 7.13 (d, J = 8.2 Hz, 2 H), 7.24–
7.28 (m, 1 H), 7.58 (d, J = 7.8 Hz, 1 H), 8.01 (d, J = 8.7 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 14.7, 30.5, 55.0, 59.0, 108.1,
113.8, 115.6, 120.1, 120.7, 123.0, 125.1, 127.7, 129.3, 130.6, 131.2,
157.7, 160.7.
13C NMR (75 MHz, CDCl3): d = 14.9, 26.4, 28.8, 29.7, 33.6, 60.1,
109.0, 114.8, 120.5, 120.9, 121.1, 124.0, 125.9, 128.4, 133.2, 138.5,
163.1.
HRMS (EI): m/z [M + H]+ calcd for C17H22NO2: 272.1651; found:
272.1643.
Ethyl 5-Fluoro-3-isopropyl-2H-isoindole-1-carboxylate (2i)
Light-yellow crystals; yield: 82% from 7i (2 steps); mp 191–193 °C.
HRMS (ESI): m/z [M + H]+ calcd for C19H20NO3: 310.1443; found:
310.1436.
IR (KBr): 3421, 3044, 2972, 1663, 1537, 1450, 1368, 1327, 1258,
1182, 1057 cm–1.
Ethyl 3-Cyclohexyl-2H-isoindole-1-carboxylate (2e)
White crystals; yield: 87% from 7e (2 steps); mp 145–147 °C.
1H NMR (400 MHz, CDCl3): d = 1.44–1.48 (m, 9 H), 3.42 (sept,
J = 6.8 Hz, 1 H), 4.43 (q, J = 6.8 Hz, 2 H), 7.03 (ddd, J = 2.1, 9.0,
JHF = 9.0 Hz, 1 H), 7.23 (dd, J = 2.1, JHF = 10.0 Hz, 1 H), 8.00 (dd,
J = 5.0, JHF = 9.0 Hz, 1 H), 10.58 (br, 1 H).
IR (KBr): 3424, 3040, 2932, 1659, 1520, 1460, 1261, 1080, 1036
cm–1.
1H NMR (400 MHz, CDCl3): d = 1.40–1.45 (m, 3 H), 1.46 (t, J = 6.8
Hz, 3 H), 1.60–2.06 (m, 7 H), 3.14–3.16 (m, 1 H), 4.42 (q, J = 6.8
Hz, 2 H), 7.04 (dd, J = 7.8, 8.2 Hz, 1 H), 7.26 (dd, J = 7.8, 8.7 Hz,
1 H), 7.68 (d, J = 8.7 Hz, 1 H), 8.02 (d, J = 8.8 Hz, 1 H), 10.56 (br,
1 H).
13C NMR (100 MHz, CDCl3): d = 14.7, 25.9, 26.5, 32.7, 36.7, 59.9,
108.7, 120.5, 120.7, 120.9, 122.4, 125.7, 127.7 (br), 136.1 (br),
162.2 (br).
13C NMR (100 MHz, CDCl3): d = 14.7, 22.1, 26.7, 60.1, 102.9 (d,
J = 22.9 Hz), 109.2, 116.7 (d, J = 27.7 Hz), 121.5 (d, J = 9.5 Hz),
122.8 (d, J = 9.5 Hz), 125.1 (br), 135.7 (br), 157.0 (d, J = 237.6 Hz),
161.9 (br).
HRMS (ESI): m/z [M + H]+ calcd for C14H17NO2F: 250.1243;
found: 250.1245.
Ethyl 4-Bromo-3-methyl-2H-isoindole-1-carboxylate (2j)
Light-blue fibers; yield: 57% from 7j (2 steps); mp 214–216 °C.
HRMS (ESI): m/z [M + H]+ calcd for C17H22NO2: 272.1651; found:
272.1646.
IR (KBr): 3227, 3067, 2978, 1661, 1526, 1501, 1470, 1441, 1292,
1096 cm–1.
Ethyl 3-Cyclobutyl-2H-isoindole-1-carboxylate (2f)
White solid; yield : 70% from 7f (2 steps); mp 111–113 °C.
1H NMR (300 MHz, DMSO-d6): d = 1.35 (t, J = 7.2 Hz, 3 H), 2.81
(s, 3 H), 4.31 (q, J = 7.2 Hz, 2 H), 7.00 (dd, J = 7.1, 8.4 Hz, 1 H),
7.20 (d, J = 7.1 Hz, 1 H), 7.91 (d, J = 8.4 Hz, 1 H), 13.30 (br, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 13.5, 14.6, 59.3, 108.3, 115.2,
119.8, 121.2, 124.5, 125.6, 127.8, 129.3, 160.3.
HRMS (ESI): m/z [M + H]+ calcd for C12H13NO279Br: 282.0130;
found: 282.0130.
IR (KBr): 3420, 3020, 2943, 1647, 1503, 1460, 1312, 1265, 1099,
1038 cm–1.
1H NMR (300 MHz, C6D6): d = 1.14 (t, J = 7.1 Hz, 3 H), 1.57–1.70
(m, 1 H), 1.72–1.81 (m, 1 H), 2.03–2.10 (m, 2 H), 2.15–2.32 (m, 2
H), 3.60–3.75 (m, 1 H), 4.39 (q, J = 7.1 Hz, 2 H), 7.07 (dd, J = 6.8,
8.2 Hz, 1 H), 7.33 (dd, J = 6.8, 8.7 Hz, 1 H), 7.67 (d, J = 8.7 Hz, 1
H), 8.45 (d, J = 8.2 Hz, 1 H), 11.63 (br, 1 H).
13C NMR (100 MHz, C6D6): d = 15.1, 19.4, 29.8, 33.5, 60.4, 110.1,
121.4, 121.8, 121.9, 124.1, 126.5, 129.4, 135.3 (br), 163.2 (br).
Ethyl 5-Isopropyl-6H-pyrrolo[3,4-b]pyridine-7-carboxylate
(2k)
White fibers; yield: 61% from 7k (2 steps); mp 173–175 °C.
HRMS (ESI): m/z [M + H]+ calcd for C15H18NO2: 244.1338; found:
244.1334.
IR (KBr): 3414, 3048, 2974, 1651, 1537, 1476, 1314, 1098, 1069,
1026 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.45 (t, J = 7.4 Hz, 3 H), 1.46 (d,
J = 6.9 Hz, 6 H), 3.48 (sept, J = 6.9 Hz, 1 H), 4.54 (q, J = 7.4 Hz, 2
H), 6.97 (dd, J = 4.1, 8.5 Hz, 1 H), 8.03 (dd, J = 1.4, 8.5 Hz, 1 H),
8.74 (dd, J = 1.4, 4.1 Hz, 1 H), 10.27 (br, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.9, 22.2, 27.1, 60.7, 108.9,
115.5, 116.5, 129.4, 134.8, 141.7, 151.8, 161.8.
Ethyl 3-Cyclopropyl-2H-isoindole-1-carboxylate (2g)
Colorless prisms; yield: 54% from 7g (2 steps); mp 146–148 °C.
IR (KBr): 3420, 3054, 2979, 1647, 1504, 1466, 1319, 1265, 1103,
1057 cm–1.
1H NMR (400 MHz, CD2Cl2): d = 0.93–0.97 (m, 2 H), 1.07–1.12
(m, 2 H), 1.39 (t, J = 7.3 Hz, 3 H), 2.21–2.26 (m, 1 H), 4.35 (q,
Synthesis 2011, No. 21, 3552–3562 © Thieme Stuttgart · New York

PAPER
Synthesis of Isoindoles via 1,3-Dipolar Cycloaddition
3559
HRMS (ESI): m/z [M + H]+ calcd for C13H17N2O2: 233.1290; found:
233.1286.
13C NMR (75 MHz, CDCl3): d = 14.2, 18.0, 18.8, 25.1, 52.5, 62.2,
83.6 (8), 83.7 (1), 110.6 (d, JC-F = 24.8 Hz), 111.4 (d, JC-F = 22.5
Hz), 123.6 (d, JC-F = 9.0), 142.1, 151.2 (d, JC-F = 8.3 Hz), 155.2,
156.2, 161.1 (d, JC-F = 245.3 Hz), 162.9, 164.9, 167.4.
(3-Isopropyl-2H-isoindol-1-yl)(p-tolyl)methanone (2l)
Bright-yellow crystals; yield: 85% from 1h; mp 209–210 °C.
HRMS (EI): m/z [M + H]+ calcd for C20H23NO6F: 392.1509; found:
IR (KBr): 3406, 3048, 2972, 1580, 1554, 1528, 1449, 1331, 1302,
1107 cm–1.
392.1506.
1-Ethyl 2,3-Dimethyl 4-Isopropylnaphthalene-1,2,3-tricarboxy-
late (9a); Typical Procedure
1H NMR (400 MHz, CDCl3): d = 1.48 (d, J = 7.3 Hz, 6 H), 2.47 (s,
3 H), 3.58 (sept, J = 7.3 Hz, 1 H), 7.05 (dd, J = 7.3, 7.8 Hz, 1 H),
7.13 (dd, J = 7.3, 8.2 Hz, 1 H), 7.28–7.36 (m, 3 H), 7.67–7.78 (m, 3
H), 11.44 (br, 1 H).
13C NMR (100 MHz, CDCl3): d = 21.6, 22.0, 26.8, 119.7, 120.4,
120.8, 121.3, 123.8, 126.5, 128.8, 128.9, 129.2, 137.6, 141.3, 141.4,
182.8.
To a soln of naphthalen-1,4-imine 8a (147.7 mg, 0.396 mmol) and
NaHCO3 (68 mg) in CH2Cl2 (4 mL) was added MCPBA (107 mg,
0.621 mmol) at r.t. The mixture was stirred under a N2 atmosphere
at this temperature for 19 h. Sat. aq Na2S2O3 soln (20 mL) was add-
ed to quench the reaction and the mixture was extracted with Et2O
(3 ×). The combined organic layers were washed with 0.1 M aq
NaOH soln, followed by brine, and dried (MgSO4). Removal of sol-
vent under reduced pressure gave a crude residue that was purified
by column chromatography (hexane–EtOAc, 8:2) to give 9a (135.7
mg, 0.379 mmol, 96%) as a yellow solid; mp 87.0–88.4 °C.
HRMS (ESI): m/z [M + H]+ calcd for C19H20NO: 278.1545; found:
278.1544.
1-Ethyl 2,3-Dimethyl 4-Isopropylnaphthalen-1,4-imine-1,2,3-
tricarboxylate (8a); Typical Procedure
To a soln of 2a (231 mg, 1.02 mmol) in toluene (10 mL) at r.t. was
added DMAD (0.15 mL, 1.22 mmol). The mixture was stirred under
an N2 atmosphere at 100 °C for 17 h. Removal of the solvent under
reduced pressure followed by column chromatography (hexane–
EtOAc, 8:2) gave 8a (374 mg, 1.00 mmol; 98% as a yellow oil.
IR (KBr): 2984, 2953, 2901, 1732, 1389, 1369, 1200, 1182, 1148
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.41 (t, J = 7.2 Hz, 3 H), 1.58 (d,
J = 7.2 Hz, 6 H), 3.65 (br, 1 H), 3.90 (s, 3 H), 3.93 (s, 3 H), 4.48 (q,
J = 7.2 Hz, 2 H), 7.58–7.66 (m, 2 H), 8.02–8.05 (m, 1 H), 8.36–8.39
(m, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.2, 22.3, 32.4, 52.7, 53.0, 62.2,
125.7, 126.2, 127.2, 128.0 (4), 128.0 (4), 128.1, 129.5, 130.3, 132.4,
132.6, 144.5, 167.1, 168.0, 169.8.
IR (KBr): 3019, 2970, 2955, 2940, 1734, 1719, 1373, 1180, 1146,
1126, 1026, 756, 667 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.14 (d, J = 6.9 Hz, 6 H), 1.40 (t,
J = 7.2 Hz, 3 H), 3.03 (sept, J = 6.9 Hz, 1 H), 3.41 (br, 1 H), 3.71 (s,
3 H), 3.77 (s, 3 H), 4.41 (dq, J = 7.2, 10.8 Hz, 2 H), 7.03–7.11 (m,
2 H), 7.29–7.32 (m, 1 H), 7.69–7.72 (m, 1 H).
HRMS (EI): m/z [M + H]+ calcd for C20H23O6: 359.1495; found:
359.1481.
13C NMR (75 MHz, CDCl3): d = 14.2, 18.1, 18.9, 25.0, 52.3, 62.0,
77.0, 83.6, 121.5, 122.5, 125.5, 125.8, 146.7, 148.2, 154.8, 156.4,
163.0, 164.9, 167.6.
HRMS (EI): m/z [M + H]+ calcd for C20H24NO6: 374.1604; found:
374.1601.
1-Ethyl 2,3-Dimethyl 4-(Hex-5-enyl)naphthalene-1,2,3-tricar-
boxylate (9h)
Pale yellow oil; yield: 70% from 8h.
IR (KBr): 3022, 1732, 1639, 1616, 1574, 1506, 1439, 982, 912
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.41 (t, J = 7.2 Hz, 3 H), 1.54–1.62
(m, 2 H), 1.68–1.79 (m, 2 H), 2.09–2.16 (m, 2 H), 3.07–3.13 (m, 2
H), 3.90 (s, 3 H), 3.93 (s, 3 H), 4.49 (d, J = 7.2 Hz, 2 H), 4.95–5.07
(m, 2 H), 5.82 (ddt, J = 6.7, 10.3, 17.1 Hz, 1 H), 7.61–7.71 (m, 2 H),
8.02–8.05 (m, 1 H), 8.11–8.15 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.3, 29.5, 30.5, 30.9, 33.6, 52.8,
53.1, 62.3, 114.9, 125.2, 125.9, 127.0, 128.9, 129.3, 129.9, 132.9,
138.7, 140.3, 167.1, 168.1, 169.2.
1-Ethyl 2,3-Dimethyl 4-(Hex-5-enyl)naphthalen-1,4-imine-
1,2,3-tricarboxylate (8h)
Yellow oil; yield: 51% from 2h.
IR (KBr): 2978, 2951, 2936, 2857, 1717, 1630, 991, 912 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.39 (t, J = 7.2 Hz, 3 H), 1.51–1.54
(m, 4 H), 2.07–2.17 (m, 2 H), 2.22–2.23 (m, 1 H), 2.40–2.48 (m, 1
H), 3.72 (s, 3 H), 3.76 (s, 3 H), 4.41 (dq, J = 7.2, 10.8 Hz, 2 H),
4.94–5.05 (m, 2 H), 5.81 (ddt, J = 6.7, 10.3, 17.0 Hz, 1 H), 7.04–
7.11 (m, 2 H), 7.26–7.29 (m, 1 H), 7.69–7.72 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.3, 24.5, 27.4, 29.4, 33.6, 52.4,
52.5, 62.1, 77.4, 78.7, 114.9, 120.6, 122.6, 125.9, 126.1, 138.6,
146.1, 149.0, 154.3, 156.1, 163.2, 164.6, 167.6.
HRMS (EI): m/z [M + H]+ calcd for C23H27O6: 399.1808; found:
399.1792.
1-Ethyl 2,3-Dimethyl 6-Fluoro 4-Isopropylnaphthalene-1,2,3-
tricarboxylate (9i)
Yellow solid; yield: 69% from 8i; mp 73.5–75.1 °C.
HRMS (EI): m/z [M + H]+ calcd for C23H28NO6: 414.1917; found:
414.1918.
IR (KBr): 2982, 2953, 1730, 1441, 1416, 1369, 1346, 1180, 1140
cm–1.
1H NMR (400 MHz, CDCl3): d = 1.42 (t, J = 7.2 Hz, 3 H), 1.58 (d,
J = 8.0 Hz, 6 H), 3.58 (br, 1 H), 3.94 (s, 3 H), 3.96 (s, 3 H), 4.49 (q,
J = 7.2 Hz, 2 H), 7.42 (m, 1 H), 7.99 (dd, JH-F = 11.6, JH-H = 2.4 Hz,
1 H), 8.08 (dd, JH-F = 9.4, JH-H = 5.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.2, 22.0, 32.4, 52.8, 53.1, 62.3,
110.4 (d, JC-F = 21.4 Hz), 118.5 (d, JC-F = 25.1 Hz), 125.3, 127.2,
130.0 (d, JC-F = 9.5 Hz), 130.5, 132.4, 134.0 (d, JC-F = 9.1 Hz),
143.7 (d, JC-F = 5.8 Hz), 161.6 (d, JC-F = 248.5 Hz), 166.9, 167.7,
169.5.
1-Ethyl 2,3-Dimethyl 6-Fluoro-4-isopropylnaphthalen-1,4-
imine-1,2,3-tricarboxylate (8i)
White solid; yield: 94% from 2i; mp 120.5–120.8 °C.
IR (KBr): 3455, 3439, 3418, 2974, 2955, 1715, 1607, 1468, 1452,
1435, 1373, 1196, 1123 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.13 (dd, J = 3.6, 6.9 Hz, 6 H),
1.40 (t, J = 7.2 Hz, 3 H), 2.97 (sept, J = 6.9 Hz, 1 H), 3.41 (br, 1 H),
3.72 (s, 3 H), 3.78 (s, 3 H), 4.41 (dq, J = 7.2, 10.5 Hz, 2 H), 6.69–
6.76 (m, 1 H), 7.03 (dd, JH-F = 7.8 Hz, JH-H = 2.1 Hz, 1 H), 7.63 (dd,
JH-F = 7.8 Hz, JH-H = 2.1 Hz, 1 H).
Synthesis 2011, No. 21, 3552–3562 © Thieme Stuttgart · New York

3560
B. M. K.Tong et al.
PAPER
HRMS (ESI): m/z [M + H]+ calcd for C20H22O6: 377.1400; found:
was purified by flash column chromatography (hexane–EtOAc,
377.1403.
8:2) to afford 13a (220.4 mg, 0.686 mmol, 99%) as a colorless oil.
IR (KBr): 3441, 3418, 2978, 2936, 1748, 1732, 1663, 1647, 1636,
1389, 1369, 1198, 1150 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.42–1.54 (br, 6 H), 1.44 (t, J = 7.2
Hz, 3 H), 2.20 (s, 3 H), 2.82 (sept, J = 6.9 Hz, 1 H), 4.66 (br, 2 H),
6.98 (br, 4 H), 7.34 (br, 3 H), 7.61 (br, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.6, 18.9, 26.3, 32.3, 61.6, 79.6,
81.4, 119.6, 121.0, 123.8, 125.4, 125.9, 148.5, 168.4.
Ethyl 3-Isopropyl-2-methyl-2H-isoindole-1-carboxylate (10a);
Typical Procedure
To an ice-cold soln of N–H isoindole 2a (99.4 mg, 0.429 mmol) and
MeI (32.2 mL, 0.515 mmol) in DMF (4.3 mL) was added LiH (18.8
mg, 2.374 mmol). The mixture was stirred under a N2 atmosphere
at r.t. for 17 h. H2O was slowly added and the mixture was extracted
using EtOAc (3 ×). The combined organic layers were washed with
brine and dried (MgSO4). Removal of the solvent under reduced
pressure gave the crude residue, which was purified by flash column
chromatography (hexane–EtOAc, 8:2) to give 10a (81.1 mg, 0.331
mmol, 77%) as a pale-brown solid; mp 51.8–53.6 °C.
HRMS (ESI): m/z [M + H]+ calcd for C21H24NO2: 322.1807; found:
322.1798.
Compound 13ac was not characterized and utilized for further
deaminative aromatization.
IR (KBr): 3262, 2967, 2955, 2916, 2875, 2849, 1748, 1362, 1130,
1111, 1072, 1026, 1005, 758 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.46 (t, J = 7.2 Hz, 3 H), 1.52 (d,
J = 7.2 Hz, 6 H), 3.54 (sept, J = 7.2 Hz, 1 H), 4.26 (s, 3 H), 4.41 (q,
J = 7.2 Hz, 2 H), 6.99–7.04 (m, 1 H), 7.11–7.24 (m, 1 H), 7.78 (d,
J = 8.7 Hz, 1 H), 8.12 (d, J = 8.7 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.8, 21.9, 26.3, 33.9, 59.4, 110.0,
120.5, 120.7, 121.3, 121.4, 125.1, 129.5, 138.7, 162.3.
HRMS (EI): m/z [M + H]+ calcd for C15H20NO2: 246.1494; found:
246.1493.
Ethyl 9-Isopropylanthrathen-9,10-imine-10-carboxylate (12a)
Brown solid; yield: 47% from N–H isoindole 2a with 11a in the
presence of CsF; mp 136.6–138.2 °C.
IR (KBr): 3456, 3437, 3416, 3399, 3381, 1738, 1715, 1694, 1643,
1607, 1387, 1371, 1184, 1169, 1150 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.29 (d, J = 6.9 Hz, 6 H), 1.45 (t,
J = 7.2 Hz, 3 H), 3.10 (sept, J = 6.9 Hz, 1 H), 3.43 (br, 1 H), 4.51 (q,
J = 7.2 Hz, 2 H), 6.90–7.00 (m, 4 H), 7.18 (d, J = 6.6 Hz, 2 H), 7.41
(d, J = 6.9 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 14.6, 18.4, 25.1, 61.8, 74.8, 78.4,
Ethyl 3-(Hex-5-enyl)-2-methyl-2H-isoindole-1-carboxylate
(10h)
Brown oil; yield: 87% from 2h.
IR (KBr): 2978, 2932, 2859, 1674, 1416, 1217, 1107, 912 cm–1.
120.2. 121.0, 125.2, 125.9, 150.4, 150.7, 169.1.
HRMS (EI): m/z [M + H]+ calcd for C20H22NO2: 308.1651; found:
308.1649.
1H NMR (300 MHz, CDCl3): d = 1.47 (t, J = 7.2 Hz, 3 H), 1.47–1.55
(m, 2 H), 1.62–1.72 (m, 2 H), 2.06–2.13 (m, 2 H), 3.02 (t, J = 7.6
Hz, 2 H), 4.20 (s, 3 H), 4.41 (q, J = 7.2 Hz, 2 H), 4.94–5.03 (m, 2
H), 5.77 (ddt, J = 6.8, 10.2, 17.0 Hz, 1 H), 7.02–7.07 (m, 1 H), 7.21–
7.24 (m, 1 H), 7.57 (d, J = 8.4 Hz, 1 H), 8.08 (d, J = 8.4 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.9, 24.7, 29.0, 33.6, 34.2, 59.6,
110.5, 115.1, 119.6, 121.1, 121.2, 123.1, 125.7, 129.0, 134.2, 138.5,
162.4.
Ethyl 9-(Hex-5-enyl)-N-methylanthracen-9,10-imine-10-car-
boxylate (13h)
Pale yellow oil; yield: quant from 10h.
IR (KBr): 2978, 2938, 1732, 995, 912 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.48 (t, J = 7.1 Hz, 3 H), 1.63 (br,
5 H), 2.16 (br, 5 H), 2.59 (br, 1 H), 4.57 (br, 2 H), 4.96–5.09 (m, 2
H), 5.87 (ddt, J = 6.7, 10.3, 17.0 Hz, 1 H), 7.00–7.02 (m, 4 H), 7.13–
7.16 (m, 2 H), 7.39–7.41 (m, 1 H), 7.62–7.65 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.7, 23.4, 25.1, 30.0, 31.2, 33.8,
61.7, 79.8, 114.8, 119.9, 123.7, 125.7, 126.4, 128.1, 130.3, 135.2,
139.0, 168.4.
HRMS (EI): m/z [M + H]+ calcd for C18H24NO2: 286.1807; found:
286.1803.
Ethyl 5-Fluoro-3-isopropyl-2-methyl-2H-isoindole-1-carboxy-
late (10i)
White solid; yield: 85% from 2i; mp 87.4–88.0 °C.
HRMS (ESI): m/z [M + H]+ calcd for C24H28NO2: 362.2120; found:
362.2126.
IR (KBr): 2976, 2934, 2907, 2874, 1673, 1632, 1416, 1398, 1386,
1171 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.46 (t, J = 7.2 Hz, 3 H), 1.49 (d,
J = 7.2 Hz, 6 H), 3.48 (sept, J = 7.2 Hz, 1 H), 4.24 (s, 3 H), 4.40 (q,
J = 7.2 Hz, 2 H), 6.97–7.04 (m, 1 H), 7.35 (dd, JH-F = 10.5 Hz,
JH-H = 2.1 Hz, 1 H), 8.10 (dd, JH-F = 9.6 Hz, JH-H = 5.4 Hz, 1 H).
10-Ethyl 2-Fluoro-9-isopropyl-N-methylanthracen-9,10-imine-
10-carboxylate (13i)
Colorless oil; yield: 98% from 10i.
IR (KBr): 2978, 2936, 2903, 1748, 1732, 1601, 1472, 1445, 1389,
1371, 1198, 1148 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.45 (br t, J = 7.2 Hz, 9 H), 2.20
(m, 3 H), 2.78 (sept, J = 6.9 Hz, 1 H), 4.52 (br, 2 H), 6.65 (br, 1 H),
7.02 (br, 3 H), 7.37 (br, 2 H), 7.61 (br, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.7, 18.8, 26.3, 32.3, 61.8, 79.2,
81.5, 111.3 (d,, JC-F = 22.7 Hz), 112.7, 120.5 (d, JC-F = 113.6 Hz),
124.2, 125.7, 126.0, 128.1, 130.3, 135.2, 148.0, 151.3, 161.0 (d,
JC-F = 243.8 Hz), 168.8.
13C NMR (75 MHz, CDCl3): d = 14.9, 21.9, 26.7, 34.1, 59.7, 103.4
(d, JC-F = 22.5 Hz), 110.6, 116.0 (d, JC-F = 27.0 Hz), 120.6 (d, JC-F
=
10.5 Hz), 123.5 (d, JC-F = 9.0 Hz), 126.6, 137.9 (d, JC-F = 7.5 Hz),
157.9 (d, JC-F = 237.0 Hz), 162.1.
HRMS (EI): m/z [M + H]+ calcd for C15H19NO2F: 264.1400; found:
264.1401.
HRMS (ESI): m/z [M + H]+ calcd for C21H23NO2F: 340.1713;
found: 340.1707.
Ethyl 9-Isopropyl-N-methylanthracen-9,10-imine-10-carboxy-
late (13a); Typical Procedure
To a soln of isoindole 10a (169.9 mg, 0.693 mmol) and TBAT
(748.7 mg, 1.387 mmol) in THF (7 mL) was added dropwise 2-(tri-
methylsilyl)phenyl triflate (185 mL, 0.762 mmol) at r.t. The mixture
was stirred under a N2 atmosphere at this temperature for 6 h. Sol-
vent was removed under pressure and the resulting crude mixture
Ethyl 10-Isopropylanthracene-9-carboxylate (14a); Typical
Procedure
To a soln of anthracen-9,10-imine 13a (82.4 mg, 0.236 mmol) and
PhCH2N+Et3Cl– (18.9 mg, 0.083 mmol) in CHCl3 (3 mL) was added
Synthesis 2011, No. 21, 3552–3562 © Thieme Stuttgart · New York

PAPER
Synthesis of Isoindoles via 1,3-Dipolar Cycloaddition
3561
50% aq NaOH (0.6 mL). The mixture stirred at r.t. under a N2 atmo-
sphere for 1.5 h before 3 M aq HCl (10 mL) was added to quench
the reaction. The organic layer was extracted with EtOAc (3 ×) and
the combined extracts were washed with water and brine, and dried
(MgSO4). Removal of the solvent under reduced pressure gave the
crude mixture which was subjected to flash column chromatogra-
phy (hexane–EtOAc, 9:1) to yield 14a (60.2 mg, 0.206 mmol, 81%)
as yellow crystals; mp 114.0–114.9 °C.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
This work was supported by funding from Nanyang Technological
University, Singapore Ministry of Education, and Science & Engi-
neering Research Council (A*STAR grant No. 082 101 0019). We
thank Dr. Yongxin Li (Division of Chemistry and Biological Che-
mistry, School of Physical and Mathematical Sciences, Nanyang
Technological University) for assistance in X-ray crystallographic
analysis.
IR (KBr): 2984, 2965, 2936, 1715, 1372, 1175, 1152, 1026 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.52 (t, J = 7.2 Hz, 3 H), 1.75 (d,
J = 7.2 Hz, 6 H), 4.59 (sept, J = 7.2 Hz, 1 H), 4.67 (q, J = 7.2 Hz, 2
H), 7.41–7.51 (m, 4 H), 7.96–8.00 (m, 2 H), 8.47–8.50 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 14.6, 23.1, 28.8, 61.9, 125.1, 125.5,
126.1, 126.2, 128.3, 128.4, 129.0, 143.6, 170.5.
References
HRMS (EI): m/z [M + H]+ calcd for C20H21O2: 293.1542; found:
(1) (a) Mori, S.; Nagata, M.; Nakahata, Y.; Yasuta, K.; Goto, R.;
Kimura, M.; Taya, M. J. Am. Chem. Soc. 2010, 132, 4054.
(b) Varotto, A.; Nam, C.-Y.; Radivojevic, I.; Tome, J. P. C.;
Cavaleiro, J. A. S.; Black, C. T.; Drain, C. M. J. Am. Chem.
Soc. 2010, 132, 2552. (c) Mi, B.-X.; Wang, P.-F.; Liu,
M.-W.; Kwong, H.-L.; Wong, N.-B.; Lee, C.-S.; Lee, S.-T.
Chem. Mater. 2003, 15, 3148. (d) Ding, Y.; Hay, A. S.
J. Polym. Sci. Part A: Polym. Chem. 1999, 37, 3293.
(e) Gauvin, S.; Santerre, F.; Dodelet, J. P.; Ding, Y.; Hlil, A.
R.; Hay, A. S.; Anderson, J.; Armstrong, N. R.; Gorjanc, T.
C.; D’Iorio, M. Thin Solid Films 1999, 353, 218.
293.1529.
Ethyl 10-(Hex-5-enyl)anthracene-9-carboxylate (14h)
Pale yellow oil; yield: 48% from 13h.
IR (KBr): 3069, 1717, 1639, 1562, 1523, 991, 910 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.53 (t, J = 7.2 Hz, 3 H), 1.63–1.73
(m, 2 H), 1.78–1.88 (m, 2 H), 2.15–2.22 (m, 2 H), 3.60–3.66 (m, 2
H), 4.67 (q, J = 7.2 Hz, 2 H), 4.95–5.08 (m, 2 H), 5.84 (ddt, J = 6.7,
10.2, 17.0 Hz, 1 H), 7.49–7.55 (m, 4 H), 7.97–8.03 (m, 2 H), 8.26–
8.31 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 14.7, 28.3, 29.7, 31.0, 33.9, 61.9,
114.9, 125.0, 125.7, 126.0, 126.5, 127.7, 128.2, 129.1, 138.4, 138.9,
170.4.
(f) Matuszewski, B. K.; Givens, R. S.; Srinivasachar, K.;
Carlson, R. G.; Higuchi, T. Anal. Chem. 1987, 59, 1102.
(g) Zweig, A.; Metzler, G.; Maurer, A.; Roberts, B. G. J. Am.
Chem. Soc. 1967, 89, 4091.
HRMS (EI): m/z [M + H]+ calcd for C23H25O2: 333.1855; found:
333.1854.
(2) (a) Duan, S.; Sinha-Mahapatra, D. K.; Herndon, J. W. Org.
Lett. 2008, 10, 1541. (b) Chen, Y.-L.; Lee, M.-H.; Wong,
W.-Y.; Lee, A. W. M. Synlett 2006, 2510. (c) Chen, Z.;
Müller, P.; Swager, T. M. Org. Lett. 2006, 8, 273.
Ethyl 2-Fluoro-9-isopropylanthracene-10-carboxylate (14i)
Pale yellow solid; yield: 66% from 13i; mp 74.6–76.0 °C.
(d) LeHoullier, C. S.; Gribble, G. W. J. Org. Chem. 1983,
48, 2364. (e) Kricka, L. J.; Vernon, J. M. J. Chem. Soc.,
Perkin Trans. 1 1973, 766. (f) Kricka, L. J.; Vernon, J. M.
J. Chem. Soc., Chem. Commun. 1971, 942.
IR (KBr): 2980, 2963, 2934, 1722, 1373, 1275, 1211, 1171, 1144
cm–1.
1H NMR (400 MHz, CDCl3): d = 1.52 (t, J = 7.2 Hz, 3 H), 1.73 (d,
J = 7.2 Hz, 6 H), 4.49 (br, 1 H), 4.67 (q, J = 7.2 Hz, 2 H), 7.33 (ddd,
J = 4.4, 6.8, 10.4 Hz, 1 H), 7.46–7.52 (m, 2 H), 7.97–8.07 (m, 3 H),
8.44–8.45 (br, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.6, 22.8, 29.0, 62.1, 108.1 (br),
117.9 (d, JC-F = 27.4 Hz), 125.7, 126.1, 126.3, 127.9 (br), 128.7 (d,
JC-F = 1.7 Hz), 128.9 (d, JC-F = 9.1 Hz), 129.4 (d, JC-F = 8.2 Hz),
129.5, 142.7 (d, JC-F = 7.8 Hz), 159.8 (d, JC-F = 243.8 Hz), 170.2.
(3) (a) Watanabe, Y.; Shim, S. C.; Uchida, H.; Mitsudo, T.;
Takegami, Y. Tetrahedron 1979, 35, 1433. (b) Simons, S.
S. Jr.; Johnson, D. F. J. Chem. Soc., Chem. Commun. 1977,
374. (c) Bonnett, R.; Brown, R. F. C. J. Chem. Soc., Chem.
Commun. 1972, 393.
(4) For recent reports on isoindole formation by other methods,
see: (a) Kitamura, M.; Moriyasu, Y.; Okauchi, T. Synlett
2011, 643. (b) Solé, D.; Serrano, O. J. Org. Chem. 2010, 75,
6267. (c) Ohmura, T.; Kijima, A.; Suginome, M. J. Am.
Chem. Soc. 2009, 131, 6070. (d) Heugebaert, T. S. A.;
Stevens, C. V. Org. Lett. 2009, 11, 5018. (e) Solé, D.;
Serrano, O. Org. Biomol. Chem. 2009, 7, 3382. (f) Yeom,
H.-S.; Lee, J.-E.; Shin, S. Angew. Chem. Int. Ed. 2008, 47,
7040. (g) Kadzimirsz, D.; Hildebrandt, D.; Merz, K.; Dyker,
G. Chem. Commun. 2006, 661. (h) Murashima, T.; Tamai,
R.; Nishi, K.; Nomura, K.; Fujita, K.; Uno, H.; Ono, N.
J. Chem. Soc., Perkin Trans. 1 2000, 995. (i) Dialer, H.;
Polborn, K.; Beck, W. J. Organomet. Chem. 1999, 589, 21.
(5) Hui, B. W.-Q.; Chiba, S. Org. Lett. 2009, 11, 729.
(6) (a) Nair, V.; Suja, T. D. Tetrahedron 2007, 63, 12247.
(b) Padwa, A. In 1,3-Dipolar Cycloaddition Chemistry, Vol.
2; Padwa, A., Ed.; Wiley-Interscience: New York, 1984,
316. (c) Feldman, K. S.; Iyer, M. R.; López, C. S.; Faza, O.
N. J. Org. Chem. 2008, 73, 5090. (d) Zhou, Y.; Murphy, P.
V. Org. Lett. 2008, 10, 3777. (e) Kim, S.; Lee, Y. M.; Lee,
J.; Lee, T.; Fu, Y.; Song, Y.; Cho, J.; Kim, D. J. Org. Chem.
2007, 72, 4886. (f) Huang, X.; Shen, R.; Zhang, T. J. Org.
Chem. 2007, 72, 1534. (g) Feldman, K. S.; Iyer, M. R.;
HRMS (ESI): m/z [M + H]+ calcd for C20H20O2F: 311.1447; found:
311.1446.
Ethyl 14-Isopropylbenzo[f]tetraphene-9-carboxylate (14ac)
Yellow solid; yield: 69% from 10a (2 steps); mp 136.7–137.4 °C.
IR (KBr): 3017, 2982, 1713, 1506, 1227, 1120 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.29 (t, J = 7.2 Hz, 3 H), 1.78 (d,
J = 7.2 Hz, 6 H), 4.49 (q, J = 7.2 Hz, 2 H), 4.58 (sept, J = 7.2 Hz, 1
H), 7.44–7.49 (m, 2 H), 7.54–7.59 (m, 4 H), 8.05–8.06 (m, 1 H),
8.14–8.17 (m, 2 H), 8.36–8.40 (m, 2 H), 8.57–8.59 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 13.9, 24.5, 32.6, 62.0, 123.5,
123.8, 124.6, 125.2, 126.2, 126.3, 126.4 (overlap), 127.2, 127.5,
128.0, 128.1, 128.8, 129.7, 129.9, 130.2, 130.4, 131.3 (overlap),
131.4(0), 131.4(3), 142.5, 171.8.
HRMS (EI): m/z [M + H]+ calcd for C28H25O2: 393.1855; found:
393.1852.
Synthesis 2011, No. 21, 3552–3562 © Thieme Stuttgart · New York

3562
B. M. K.Tong et al.
PAPER
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/conts/retrieving.html.
(11) The introduction of a carbonyl moiety at C1 in isoindoles is
indispensable for this isoindole formation. For an example,
the reaction of 2¢-vinylbenzyl azide under same reaction
conditions gave a complex mixture without the desired
isoindoles.
Hester, D. K. II Org. Lett. 2006, 8, 3113. (h) Feldman, K.
S.; Iyer, M. R. J. Am. Chem. Soc. 2005, 127, 4590.
(i) Hassner, A.; Amarasekara, A. S.; Andisik, D. J. Org.
Chem. 1988, 53, 27. (j) Liu, J.-M.; Young, J.-J.; Li, Y.-J.;
Sha, C.-K. J. Org. Chem. 1986, 51, 1120. (k) Sundberg, R.
J.; Pearce, B. C. J. Org. Chem. 1982, 47, 725. (l) Smith, P.
A. S.; Chou, S. P. J. Org. Chem. 1981, 46, 3970; and
references therein.
(12) (a) Solé, D.; Serrano, O. Org. Biomol. Chem. 2009, 7, 3382.
(b) Kadzimirsz, D.; Hildebrandt, D.; Merz, K.; Dyker, G.
Chem. Commun. 2006, 661.
(7) For reports on the mechanism of the elimination of
dinitrogen from triazoline intermediates with heterolytic
cleavage of the N–N bond; see: (a) Shea, K. J.; Kim, J.-S.
J. Am. Chem. Soc. 1992, 114, 4846. (b) Wladkowski, B. D.;
Smith, R. H. Jr.; Michejda, C. J. J. Am. Chem. Soc. 1991,
113, 7893; and references therein.
(13) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett.
1983, 1211.
(14) Pilcher, A. S.; Ammon, H. L.; DeShong, P. J. Am. Chem.
Soc. 1995, 117, 5166.
(8) A radical pathway via homolytic cleavage of the N–N bond
of triazoline intermediates is also proposed, for examples,
see references 6c, 6g, 6h, and: Broeckx, W.; Overbergh, N.;
Samyn, C.; Smets, G.; L’abbé, G. Tetrahedron 1971, 27,
3527.
(15) Matsumoto, T.; Hosoya, T.; Katsuki, M.; Suzuki, K.
Tetrahedron Lett. 1991, 32, 6735.
(16) Gribble, G. W.; Allen, R. W.; LeHoullier, C. S.; Eaton, J. T.;
Easton, N. R. J.; Slayton, R. I.; Sibi, M. P. J. Org. Chem.
1981, 46, 1025.
(9) Kobayashi, S.; Tsuchiya, Y.; Mukaiyama, T. Chem. Lett.
1991, 537.
(10) The structure of 2a was secured by X-ray crystallographic
analysis (see Supporting Information). CCDC-710407
contains the supplementary crystallographic data for
compound 2a. These data can be obtained free of charge
(17) Peña, D.; Cobas, A.; Pérez, D.; Guitián, E. Synthesis 2002,
1454.
(18) Ganta, A.; Snowden, T. S. Synlett 2007, 2227.
(19) Peña, D.; Pérez, D.; Guitiám, E.; Castedo, L. J. Org. Chem.
2000, 65, 6944.
Synthesis 2011, No. 21, 3552–3562 © Thieme Stuttgart · New York