[3+2] Cycloaddition of masked o-benzoquinones with azomethine ylides

Article abstract of DOI:10.1055/s-0031-129043

A simple and efficient access to highly functionalized isoindolone derivatives via a [3+2] cycloaddition process between in situ generated azomethine ylides with various stable (isolable) masked o-benzoquinones is described. This approach allows a rapid and general synthesis of isoindolones with substituents to further manipulate and elaborate the structural complexity. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-129043

LETTER
▌1901
letter
[3+2] Cycloaddition of Masked o-Benzoquinones with Azomethine Ylides
Highly Substituted Isoindolone and Isoindoline Derivatives
Santhosh Kumar Chittimalla,* Rajesh Kuppusamy, Anjan Chakrabarti
AMRI Singapore Research Centre, 61 Science Park Road, #05-01, The Galen, Science Park III, Singapore 117525, Singapore
Fax +6563985511; E-mail: santhosh.chittimalla@amriglobal.com
Received: 02.05.2012; Accepted after revision: 18.06.2012
derivatives were utilized to label the terminal amino
groups in various biological objects.9d In addition, isoin-
doline compounds are known for their HSP-90
modulator9e and IKK2 inhibitory activities.9f Further-
Abstract: A simple and efficient access to highly functionalized
isoindolone derivatives via a [3+2] cycloaddition process between
in situ generated azomethine ylides with various stable (isolable)
masked o-benzoquinones is described. This approach allows a rapid
and general synthesis of isoindolones with substituents to further more, hypoglycemic mitiglinide,9g an octahydroisoindole
manipulate and elaborate the structural complexity.
derivative is used for the treatment of diabetes, and
tandospirone9h is used as an antidepressant.
Key words: masked o-benzoquinones, [3+2] cycloadditions, azo-
methine ylides, isoindolones, isoindolines
As shown in Scheme 1, MOB 2 has three reactive sites
namely C2=C3, C4=C5, and C1=O; thus, upon reaction
with 1,3-dipoles could provide products of type I, II,
and/or III, respectively. It is well-established that 1,3-di-
polar compounds of the azomethine ylide kind on reaction
with Michael acceptors provide products of type II. Con-
sequently pathway a could be ruled out.10
Masked o-benzoquinones (MOB) or orthoquinone mono-
ketals are extremely useful synthons in organic synthesis.1
Liao and co-workers have successfully demonstrated the
usefulness of MOB by employing them in inter- and intra-
molecular Diels–Alder reactions, hetero-Diels–Alder re-
actions to obtain functionally rich cycloadducts which in
turn were utilized as key intermediates for the synthesis of
natural products.2 Recently, several other research groups
have effectively exploited MOB chemistry for the synthe-
sis of natural products with unique structural frame-
works.3 However, MOB are known to be very reactive and
undergo spontaneous self-dimerization to provide Diels–
Alder dimers.1,4 During extensive studies on developing
synthetic strategies employing MOB chemistry, it was
found that a suitably substituted MOB can be stabilized
and could be isolated for further synthetic transforma-
tions.1b,5 MOB with its inherent multifunctional structure
is a versatile building block not only for Diels–Alder re-
actions but also for a repertoire of other reactions includ-
ing photorearrangements,6a Michael additions,6b 1,2-
additions,6c epoxidations,6d cyclopropanations,6e,f and the
construction of anthraquinones.6g Inspite of such undis-
puted synthetic value, to our knowledge MOB were sel-
dom utilized in 1,3-dipolar cycloadditions. Herein, we
report the results of this endeavor and provide preliminary
results on the reaction of isolable MOB 2 with azomethine
ylides 37 and 4.8
R
B
A
C
MeO
MeO
pathway a
O
C
A
B
type I
R
B
A
C
4
R
A
C
5
6
3
B
MeO
MeO
MeO
MeO
2
pathway b
1
O
O
type II
2
B
C
B
A
C
R
A
pathway c
MeO
MeO
type III
O
Scheme 1 Possible products in the reaction between MOB and a di-
polarophile
However, MOB is a dienone system where pathway b or
c could compete to provide products of type II or III, re-
spectively. Therefore, we commenced our study by
choosing 5,6,6-trimethoxy cyclohexa-2,4-dienone (2a) as
the model substrate to optimize the reaction conditions.
The anticipated reaction between azomethine ylide and
MOB would provide highly substituted isoindolones.
Compounds with an isoindole core are viewed as privi-
leged structures in medicinal chemistry.9 For example, it
was reported that compounds with an isoindole moiety
were employed for the treatment of neurobehavioral dis-
orders,9c as local anesthetics9a and were also known for
their high contraceptive activity.9a Moreover, isoindole
At the outset, a mixture of sarcosine, paraformaldehyde,
and MOB 2a in toluene was refluxed for six hours in the
presence of MgSO4. To our delight, adduct 5a was ob-
tained as the only product in 76% yield via [3+2] cycload-
dition of MOB 2a with transiently generated azomethine
ylide 3 (Scheme 2, Table 1, entry 1). Further optimization
revealed that yield of cycloaddition product 5a could be
improved to 89% by conducting the reaction in a sealed
tube under the same reaction conditions (Table 1, entry 2).
SYNLETT 2012, 23, 1901–1906
Advanced online publication: 16.07.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-129043; Art ID: ST-2012-B0383-L
© Georg Thieme Verlag Stuttgart · New York

1902
S. K. Chittimalla et al.
LETTER
R1
R1
methine ylide 3 to provide the isoindolone 5d in 89%
yield.
R2
R2
PhI(OAc)2
MeOH, 0 °C
MeO
MeO
Table 1 Reaction of MOB with in situ Generated Azomethine Ylide
100%
conversion
MeO
3a
OH
O
2
1a R1 = H, R2 = OMe
1b R1 = H, R2 = Me
1c R1 = H, R2 = ketal
1d R1 = H, R2 = Br
1e R2 = H, R1 = ketal
Entry MOB
Reaction Product/Yield
time (h)
Yield
(%)
MeO
MeO
MeO
b
N
Me
1f
R
2 = H, R1 = t-Bu
MeO
MeO
1g R2 = H, R1 = Ph
1h R2 = H, R1 = Br
MeO
O
R1
O
R2
1b
2
2a
2a
6
6
5a
5a
76
89
a
NH
MeO
MeO
O
ketal:
O
O
N
Me
8
MeO
MeO
MeO
MeO
O
O
3
2b
16
5b
62
33
Me
R1
R1
N
R2
R1
R2
N
Me
MeO
N
Me
N Me
+
+
R2
MeO
MeO
MeO
OH
MeO
MeO
O
OH
7b
O
5
6
7
R
Me
Tos
N
MeO
MeO
N
C
R
H2C
CH2
3
4
N
Me
O
MeO
MeO
Scheme 2 Synthesis of isolable MOB 2 from 2-methoxyphenols 1
and their reactions with in situ generated azomethine ylides 3 and 4.
Reagents and conditions: (a) sarcosine (2.5 equiv), (CH2O)n (6.0
equiv), toluene, reflux (in situ generation of azomethine ylide 3); (b)
TOSMIC, KOt-Bu, THF (in situ generation of azomethine ylide 4).
O
O
O
R =
4c
2c
16
5c
56
24
89
R
With these conditions in hand, the scope of the MOB part-
ner was explored. All the MOB utilized in the present
study are prepared by the treatment of a methanolic solu-
tion of commercially available (for 1a and 1h) or readily
accessible phenols 1 with diacetoxyiodobenzene at 0 °C
to room temperature for 30 minutes. High yields (up to
98%) of pure MOB 2 were achieved after column chro-
matographic purification (Scheme 2).11 Accordingly,
MOB 2b and 2c were utilized in this reaction. The reac-
tions of MOB 2b and 2c with azomethine ylide 3 were
sluggish and needed 16 hours reaction time for their com-
plete consumption. The desired cycloadducts 5b and 5c
were obtained in moderate yields (ca. 60%), in addition
corresponding aromatized products 7b and 7c were pro-
duced in 33% and 24% yields, respectively. Besides,
MOB 2c provided 14% of the other isomer 6c (Figure 1).
The formation of aromatized products 7b and 7c can be
presumed to be produced from the initially generated cy-
cloadducts 5b and 5c, respectively.12 Under the optimized
reaction conditions, bromo-substituted MOB 2d13 partici-
pated in the cycloaddition with the in situ generated azo-
N
Me
MeO
OH
7c
Br
Br
N
Me
MeO
MeO
MeO
MeO
O
O
R
5
2d
6
5d
R
O
MeO
MeO
O
N
Me
MeO
MeO
O
Me
Me
R =
O
6d
2e
7
5e
54
Synlett 2012, 23, 1901–1906
© Georg Thieme Verlag Stuttgart · New York

LETTER
Highly Substituted Isoindolone and Isoindoline Derivatives
1903
Table 1 Reaction of MOB with in situ Generated Azomethine Ylide
3a (continued)
Me
Me
O
N
N
O
O
Entry MOB
Reaction Product/Yield
time (h)
Yield
(%)
O
MeO
MeO
MeO
MeO
R
O
O
6c 14%
6e 3%
N
Me
Figure 1 Other isomers obtained in the reaction between MOB 2c and
2e with azomethine ylide 3
MeO
OH
7e
38
to note that in the cycloaddition reaction disubstituted
double bond was preferred over the trisubstituted perhaps
due to the steric factors. Electron-donating substitutions
like OMe and Br at 5-position of MOB 2a and 2d, respec-
tively, activate the C2=C3 double bond by conjugation to-
wards the cycloaddition. Hence these reactions were
completed in shorter reaction times (ca. 6 h). For MOB 2b
and 2c longer reaction times (ca. 16 h) were required for
complete consumption of these MOB. As the reaction
time increased, the formed isoindolines were prone to aro-
matization which is evident from the formation of isoin-
dolines 7b and 7c. Substitutions at the 4-position of MOB
2f–h are not effecting/activating the C2=C3 double bond
and, moreover, are in close proximity (steric affect) to the
reacting center. This might be the reason for the observed
increase in reaction time to 16 hours in these cases. Con-
sequently, both increase in reaction time along with the
steric influence due to the presence of substitutions at 4-
position facilitated easy aromatization to furnish com-
pounds 7f–h. Thus, the factors influencing the aromatiza-
tion are a cumulative effect of reaction time, steric and
electronic factors. As of now it is unclear why only the ke-
tal-substituted MOB provided the cycloadducts of type 6c
and 6e. We believe that the cycloadducts 5a–e can be eas-
ily transformed to the corresponding aromatized com-
pounds (isoindolines).14 MOB 2 with R1 = R2 = H are
known for their self-dimerization2b quite easily and are
not isolable due to which such substrates were not utilized
in this study.
R
O
R
MeO
MeO
N
Me
MeO
OH
Me
Me
R =
Me
7
8
9
2f
16
16
16
7f
87
60
85
Ph
Ph
N
Me
MeO
MeO
MeO
O
OH
Br
2g
7g
Br
N
Me
MeO
MeO
MeO
O
OH
2h
7h
a Reaction conditions: MOB (1.0 equiv), sarcosine (5.0 equiv), para-
formaldehyde (10.0 equiv), MgSO4 (3.0 equiv) were refluxed in dry
MeCN in a sealed tube.
b Reaction was conducted under conventional reflux (using reflux
condensor) and argon atmosphere.
Next, we investigated the possibility of utilizing MOB 2
in the reaction with TOSMIC 4. MOB 2a obtained after
the oxidation of 2,3-dimethoxy phenol (1a) was as such
utilized for the next transformation without column chro-
matographic purification. Thus obtained MOB 2a and
TOSMIC were taken in dry THF to which KOt-Bu in dry
THF was added dropwise and stirred at room temperature
for three hours. To this reaction mixture water was added
and extracted with ethylacetate (three times). All organic
fractions were combined and concentrated under reduced
pressure followed by column chromatography to provide
the desired product 8a in only 35% yield along with 25%
of unreacted MOB 2a. No better result was generated
upon increasing the equivalents of KOt-Bu or TOSMIC.
But when the same reaction was repeated with a column
purified MOB 2a, the yield was dramatically improved to
73%. Subsequently, column purified MOB 2b and 2c
were subjected to standard reaction conditions to provide
c Isoindolone 6c was also isolated in 14% yield.
d Isoindolone 6e was also isolated in 3% yield.
Subsequently, we turned our attention to the 4-substituted
MOB 2e–h. Thus, MOB 2e provided cycloadduct 5e in
54% and aromatized product 7e in 38% along with 3% of
isoindolone 6e under the standard reaction conditions
(Figure 1). MOB 2f (t-Bu), 2g (4-Ph), 2h (4-Br) bearing
different substitutions at the 4-position exclusively fur-
nished the aromatized isoindoline products 7f (87%), 7g
(60%), and 7h (85%), respectively. As a result, MOB 2f–
h provided a straightforward route for the synthesis of
isoindolines 7f–h bearing multifunctional groups with an
opportunity to further elaborate the structures.
Noticeably, MOB with different substitutions on the ring
were all compatible under the standard conditions either
producing the isoindolone and/or isoindoline derivatives
in very good total yields. At this juncture, it is important
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1901–1906

1904
S. K. Chittimalla et al.
LETTER
Table 2 Reaction of MOB with TOSMIC (Azomethine Ylide 4)a
the desired products 8b and 8c in 78% and 60% yield, re-
spectively. Next, it was decided to utilize MOB 2e,g,h in
the reaction, which have a substitution at the 4-position.
Contrary to our expectation, none of the expected prod-
ucts 8e, 8g, or 8h could be isolated; however, TLC analy-
sis of the corresponding reaction mixture indicated
complete consumption of the respective MOB substrate.
Entry
MOB
Product/Yield
Yield (%)
MeO
MeO
MeO
NH
MeO
MeO
MeO
O
O
The absence of a positive result was inconclusive in these
cases; the reason being the 1H NMR of the crude reaction
mixture with MOB 2e as starting material has shown the
peaks corresponding to the product 8e. At this stage, we
attribute the failure of isolation of the isoindolone prod-
uct(s) 8e, 8g, or 8h to their instability which might be air-
and light-sensitive.15 Thus, another approach that would
reduce such uncertainties was desired. It was decided to in
situ trap the free NH produced during the reaction. Conse-
quently, in the modified reaction procedure, after the com-
plete consumption of MOB 2e as indicated by TLC
analysis, 1.5 equivalents of KOt-Bu were added to the re-
action mixture along with the dropwise addition of ben-
zylbromide. The reaction mixture was allowed to stir at
room temperature for another two hours. Gratifyingly,
this procedure provided compound 9e in 30% yield as the
only product. Increasing the reaction temperature to 50 °C
or performing the reaction at reflux in an attempt to im-
prove the yield of the adduct 9e failed. However, the yield
of compound 9e could be improved to 63% (Table 2, entry
9) by conducting the initial cycloaddition reaction at 0 °C
for five hours followed by the addition of KOt-Bu (1.0
equiv) and benzylbromide (3.0 equiv) at the same temper-
ature and allowing the reaction mixture to stir at room
temperature for eight hours.
1b
2
2a
2a
8a
8a
35
73
NH
MeO
MeO
MeO
MeO
O
O
O
3
2b
8b
78
R
MeO
MeO
R
NH
MeO
MeO
O
O
R =
O
4
2c
8c
60
R
R
NH
MeO
MeO
MeO
MeO
O
O
O
R =
In summary, we have successfully presented the [3+2] cy-
cloaddition reactions of azomethine ylides 3 and 4 with
readily available MOB 2, which furnished the highly sub-
stituted isoindoline structures 5–9 in good yields. The
products described in this study are densely functional-
ized and are versatile building blocks for the synthesis of
more complex molecules. In general, excellent site selec-
tivities were observed where the disubstituted double
bond preferentially reacted over the trisubstituted double
bond. Further investigations to broaden the scope of this
methodology with the hope of accessing intermediates for
biologically important products are in progress.
5
8e
8g
0
O
2e
6
7
2g R = Ph
2h R = Br
0
0
8h
R
N
Bn
MeO
MeO
O
8c
9d
2e
2e
9e
9e
30
63
a Reaction conditions: MOB (1.0 equiv), TOSMIC (1.3 equiv), KOt-
Bu (2.0 equiv), THF, r.t., 3 h.
General Procedure for the Preparation of MOB
To a solution of 2-methoxyphenol (1.0 mmol) in anhyd MeOH (6.0
mL) was added DAIB (1.2 mmol) at r.t. After stirring for 20 min,
MeOH was evaporated, and flash column was performed using
EtOAc and hexanes as eluent to obtain the corresponding MOB.
b Unpurified MOB 2a was utilized.
c After step a, to the crude reaction mixture was added KOt-Bu (1.5
equiv), BnBr (1.8 equiv), and stirred for 2 h.
d After step a at 0 °C for 5 h, to the crude reaction mixture at 0 °C was
added KOt-Bu (1.0 equiv), BnBr (3.0 equiv), and stirred for 8 h at r.t.
Typical Experimental Procedure for the Synthesis of Isoin-
doline 5a
To solution of 2a (185 mg, 1.0 mmol), sarcosine (180 mg, 2.00
mmol), paraformaldehyde (180 mg, 6.00 mmol) in toluene was add-
ed MgSO4 (360 mg, 3.00 mmol). The reaction mixture was allowed
to reflux in a sealed tube. After the completion of reaction, the sol-
vent was evaporated in vacuo, and the residue was chromato-
graphed over silica gel by using hexanes–EtOAc as eluent to give
isoindoline 5a in 89% yield.
Synlett 2012, 23, 1901–1906
© Georg Thieme Verlag Stuttgart · New York

LETTER
Highly Substituted Isoindolone and Isoindoline Derivatives
1905
Isoindoline 5a
(C), 96.9 (CH), 114.7 (C), 117.3 (CH), 121.5 (C), 123.3 (CH), 153.1
(C), 188.7 (C).
1H NMR (300 MHz, CDCl3): δ = 2.05–2.13 (m, 1 H), 2.34 (s, 3 H),
2.76–2.82 (m, 1 H), 2.86–2.91 (m, 2 H), 3.31 (s, 3 H), 3.33–3.38 (m,
2 H), 3.47 (s, 3 H), 3.61 (s, 3 H), 4.91 (d, J = 2.1 Hz, 1 H). 13C NMR
(100 MHz, CDCl3): δ = 37.5 (CH), 41.9 (CH3), 46.2 (CH), 50.9
(CH3), 51.5 (CH3), 54.9 (CH2), 55.2 (CH3), 62.7 (CH2), 98.3 (C),
102.7 (CH), 151.7 (C), 202.2 (C).
Isoindoline 8b
1H NMR (400 MHz, CDCl3): δ = 1.90 (s, 3 H), 3.27 (s, 6 H), 6.56–
6.58 (m, 2 H), 6.44–6.45 (m, 1 H), 8.76 (br s, 1 H). 13C NMR (100
MHz, CDCl3): δ = 16.8 (CH3), 51.1 (2 × CH3), 114.3 (CH), 119.6
(C), 121.3 (CH), 122.1 (CH), 123.1 (2 × C), 135.7 (C), 190.6 (C).
Isoindoline 5b
1H NMR (400 MHz, CDCl3): δ = 1.78 (dd, J = 1.2, 2.4 Hz, 3 H),
2.23 (dd, J = 6.0, 8.4 Hz, 1 H), 2.32 (s, 3 H), 2.63 (app dd, J = 8.4,
9.6 Hz, 1 H), 2.72–2.76 (m, 1 H), 2.90 (dd, J = 5.2, 9.6 Hz, 1 H),
3.25 (s, 3 H), 3.32–3.39 (m, 2 H), 3.40 (s, 3 H), 5.70–5.73 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 18.9 (CH3), 40.9 (CH), 41.9
(CH3), 46.2 (CH), 49.7 (CH3), 50.8 (CH3), 55.2 (CH2), 61.9 (CH2),
99.6 (C), 133.3 (CH), 136.0 (C), 204.0 (C).
Isoindoline 9e
1H NMR (400 MHz, CDCl3): δ = 0.78 (s, 3 H), 1.24 (s, 3 H), 3.38
(s, 6 H), 3.66 (ABq, J = 10.8 Hz, 4 H), 5.01 (s, 2 H), 5.13 (d, J = 0.8
Hz, 1 H), 6.05 (d, J = 0.8 Hz, 1 H), 6.79 (d, J = 2.0 Hz, 1 H), 7.18–
7.21 (m, 2 H), 7.29–7.36 (m, 4 H). 13C NMR (100 MHz, CDCl3):
δ = 21.8 (CH3), 23.2 (CH3), 30.3 (C), 50.6 (2 × CH3), 54.1 (CH2),
77.5 (2 × CH2), 94.8 (C), 100.7 (CH), 119.2 (CH), 120.4 (C), 124.2
(CH), 125.2 (CH), 127.8 (2 × CH), 128.4 (CH), 129.0 (2 × CH),
133.2 (2 × C), 135.4 (C), 188.3 (C).
Isoindoline 5e
1H NMR (300 MHz, CDCl3): δ = 0.74 (s, 3 H), 1.19 (s, 3 H), 2.06
(t, J = 9.6 Hz, 1 H), 2.36 (s, 3 H), 2.78 (dd, J = 6.6, 9.6 Hz, 1 H),
3.02 (app dd, J = 9.6, 9.6 Hz, 1 H), 3.11–3.17 (m, 1 H), 3.29 (s, 3
H), 3.40 (s, 3 H), 3.43–3.49 (m, 2 H), 3.52–3.64 (m, 4 H), 4.76 (s, 1
H), 6.06 (br s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 21.8 (CH3),
23.1 (CH3), 30.2 (C), 42.1 (CH3), 42.8 (CH), 46.9 (CH), 50.0 (CH3),
50.3 (CH3), 54.6 (CH2), 60.5 (CH2), 77.3 (CH2), 77.5 (CH2), 96.4
(C), 101.0 (CH), 125.7 (CH), 143.2 (C), 203.7 (C).
References and Notes
(1) (a) Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. Rev.
2004, 104, 1383. (b) Liao, C.-C.; Peddinti, R. K. Acc. Chem.
Res. 2002, 35, 856. (c) Singh, V. Acc. Chem. Res. 1999, 32,
324.
(2) (a) Hsu, D.-S.; Chou, Y.-Y.; Tung, Y.-S.; Liao, C.-C. Chem.
Eur. J. 2010, 16, 3121. (b) Lu, P.-H.; Yang, C.-S.; Devendar,
B.; Liao, C.-C. Org. Lett. 2010, 12, 2642. (c) Kao, T.-C.;
Chuang, G. J.; Liao, C.-C. Angew. Chem. Int. Ed. 2008, 47,
7325. (d) Liao, C.-C. Pure Appl. Chem. 2005, 77, 1221.
(3) (a) Sacher, J. R.; Weinreb, S. M. Tetrahedron 2011, 67,
10203. (b) Mehta, G.; Maity, P. Tetrahedron Lett. 2011, 52,
1749. (c) Kobayashi, S.; Suzuki, T. Org. Lett. 2010, 12,
2920. (d) Cook, S. P.; Polara, A.; Danishefsky, S. J. J. Am.
Chem. Soc. 2006, 128, 16440.
Isoindoline 6e
1H NMR (400 MHz, CDCl3): δ = 0.74 (s, 3 H), 1.20 (s, 3 H), 2.29
(s, 3 H), 2.41 (d, J = 9.6 Hz, 1 H), 2.48 (t, J = 9.6 Hz, 1 H), 2.71 (t,
J = 9.6 Hz, 1 H), 3.11 (s, 3 H), 3.27–3.29 (m, 1 H), 3.31 (s, 3 H),
3.33–3.45 (m, 2 H), 3.52 (d, J = 11.2 Hz, 1 H), 3.61 (dd, J = 2.8,
10.8 Hz, 1 H), 3.75 (dd, J = 2.8, 10.8 Hz, 1 H), 4.64 (s, 1 H), 5.99
(d, J = 10.4 Hz, 1 H), 6.73 (dd, J = 1.2, 10.4 Hz, 1 H). 13C NMR (75
MHz, CDCl3): δ = 21.7 (CH3), 23.0 (CH3), 30.4 (C), 42.2 (CH3),
44.1 (CH), 48.4 (CH3), 50.2 (CH3), 52.7 (C), 55.6 (CH2), 61.6
(CH2), 77.8 (2 × CH2), 97.7 (C), 102.3 (CH), 125.5 (CH), 151.3
(CH), 193.0 (C).
(4) (a) Chittimalla, S. K.; Shiao, H.-Y.; Liao, C.-C. Org.
Biomol. Chem. 2006, 4, 2267. (b) Liao, C.-C.; Chu, C.-S.;
Lee, T.-H.; Rao, P. D.; Ko, S.; Song, L.-D.; Hsiao, H.-C.
J. Org. Chem. 1999, 64, 4102.
Isoindoline 7b
1H NMR (400 MHz, CDCl3): δ = 2.25 (s, 3 H), 2.56 (s, 3 H), 3.73
(5) (a) Lai, C.-H.; Shen, Y.-L.; Wang, M.-N.; Rao, N. S. K.;
Liao, C.-C. J. Org. Chem. 2002, 67, 6493. (b) Yen, C.-F.;
Peddinti, R. K.; Liao, C.-C. Org. Lett. 2000, 2, 2909.
(6) (a) Liao, C.-C.; Wei, C.-P. Tetrahedron Lett. 1991, 32, 4553.
(b) Hsieh, M.-F.; Rao, P. D.; Liao, C.-C. Chem. Commun.
1999, 1441. (c) Hou, H.-F.; Peddinti, R. K.; Liao, C.-C. Org.
Lett. 2002, 4, 2477. (d) Runcie, K. A.; Taylor, R. J. K. Org.
Lett. 2001, 3, 3237. (e) McKillop, A.; Perry, D. H.; Edwards,
M.; Antus, S.; Farkas, L.; Nogradi, M.; Taylor, E. C. J. Org.
Chem. 1976, 41, 282. (f) Banwell, M. G.; Collis, M. P.
J. Chem. Soc., Chem. Commun. 1991, 1343. (g) Mitchell,
A. S.; Russell, R. A. Tetrahedron 1997, 53, 4387.
(7) (a) Tsuge, O.; Kanemasa, S.; Ohe, M.; Takenaka, S. Bull.
Chem. Soc. Jpn. 1987, 60, 4079. (b) Joucla, M.; Martier, J.
J. Chem. Soc., Chem. Commun. 1985, 1566.
(8) (a) Smith, N. D.; Huang, D.; Cosford, N. D. P. Org. Lett.
2002, 4, 3537. (b) Airaksinen, A. J.; Ahlgren, M.;
(s, 3 H), 3.82–3.84 (m, 2 H), 3.88–3.91 (m, 2 H), 6.52 (s, 1 H). 13
C
NMR (100 MHz, CDCl3): δ = 15.9 (CH3), 42.5 (CH3), 58.1 (CH2),
60.5 (CH3), 60.9 (CH2), 115.4 (CH), 124.6 (C), 129.4 (C), 137.2
(C), 143.7 (C), 144.5 (C).
Isoindoline 7e
1H NMR (300 MHz, CDCl3): δ = 0.78 (s, 3 H), 1.27 (s, 3 H), 2.56
(s, 3 H), 3.66 (ABq, J = 10.8 Hz, 4 H), 3.83 (s, 3 H), 3.89 (br s, 2 H),
3.98 (br s, 2 H), 4.84 (br s, 1 H), 5.28 (s, 1 H), 6.89 (s, 1 H). 13C
NMR (75 MHz, CDCl3): δ = 21.9 (CH3), 23.2 (CH3), 30.2 (C), 42.7
(CH3), 56.2 (CH3), 57.7 (CH2), 59.7 (CH2), 77.6 (2 × CH2), 100.7
(CH), 107.5 (CH), 123.6 (C), 126.5 (C), 132.1 (C), 140.9 (C), 145.8
(C).
Typical Experimental Procedure for the Synthesis of Isoin-
doline 8a
To a solution of 2a (185 mg, 1.0 mmol) and TOSMIC (255 mg, 1.3
mmol) in dry THF (6.0 mL) was added KOt-Bu (225 mg, 2.0 mmol)
at r.t. The reaction mixture was allowed to stir at r.t. until the disap-
pearance of MOB 2a as indicated by TLC analysis. Solvent was
evaporated, sat. aq NH4Cl was added to the residue and extracted
with EtOAc (3×). Organic layers were dried over Na2SO4, filtered,
the solvent evaporated, and the residue was chromatographed over
silica gel using CH2Cl2–MeOH as eluent to give isoindoline 8a in
73% yield.
Vepsalainen, J. J. Org. Chem. 2002, 67, 5019. (c) van
Leusen, A. M.; Siderius, H.; Hoogenboom, B. E.; van
Leusen, D. Tetrahedron Lett. 1972, 52, 5337.
(9) (a) Pokholenko, A. A.; Voitenka, Z. V.; Kovtunenko, V. A.
Russ. Chem. Rev. 2004, 73, 771. (b) Marinicheva, G. E.;
Gubina, T. I. Chem. Heterocycl. Compd. 2004, 40, 1517.
(c) Kovacs, B.; Pinegar, L. A. US 20090318520 A1, 2009.
(d) Concha-Herrera, V.; Vivo-Truyols, G.; Torres-Lapasio,
J. R.; Garcia-Alvarez-Coque, M. C. Anal. Chim. Acta 2004,
518, 191. (e) Williams, B. J.; Williams, M.; Frederickson,
M. US 20110098290 A1, 28.04.2011. (f) Jin, Q. WO
2010102968 A1, 16.09.2010. (g) Liu, J.; Yang, Y.; Ji, R.
Isoindoline 8a
1H NMR (300 MHz, CDCl3): δ = 3.37 (s, 6 H), 3.78 (s, 3 H), 5.86
(s, 1 H), 6.54–6.61 (m, 1 H), 7.40–7.47 (m, 1 H), 8.62 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 51.9 (2 × CH3), 55.5 (CH3), 95.8
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1901–1906

1906
S. K. Chittimalla et al.
LETTER
Helv. Chim. Acta 2004, 87, 1935. (h) Ishizumi, K.; Kojima,
A.; Antoku, F. Chem. Pharm. Bull. 1991, 39, 2288.
(14) For example, when compound 5d was treated with 4 N HCl
in dioxane for 1 h furnished compound 7d (after NH4OH
wash) in quantitative yield (Scheme 3).
(10) (a) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. Rev. 2006,
106, 4484. (b) Najera, C.; Sangano, J. M. Curr. Org. Chem.
2003, 7, 1105. (c) Gothelf, K. V.; Jørgensen, K. A. Chem.
Rev. 1998, 98, 863. (d) Huisgen, R. J. Org. Chem. 1976, 41,
403. (e) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2,
565.
(11) Chittimalla, S. K.; Liao, C.-C. Tetrahedron 2003, 59, 4039.
(12) For example, when column purified compound 5c was
subjected to the standard reaction conditions [sarcosine (1.0
equiv), paraformaldehyde (2.0 equiv), MgSO4(1.5 equiv) in
THF at reflux temperature for 12 h] aromatized product 7c
was isolated in 40% yield as expected along with 10%
unreacted starting material (remaining was a complex
mixture by 1H NMR analysis with no indication for the
formation of other possible cycloaddition products).
(13) Lin, K.-C.; Chittimalla, S. K.; Peddinti, R. K.; Liao, C.-C.
J. Chin. Chem. Soc. Taipei 2004, 51, 1037.
4 N HCl
dioxane
Br
Br
N
Me
N Me
MeO
r.t., 1 h
MeO
MeO
O
OH
7d
quantitative
5d
Scheme 3
(15) (a) Ohmura, T.; Kijima, A.; Suginome, M. Org. Lett. 2011,
13, 1238. (b) Ahmed, M.; Kricka, L. J.; Vernon, J. M.
J. Chem. Soc., Perkin Trans. 1 1975, 71.
Synlett 2012, 23, 1901–1906
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