Integrated catalytic C-H transformations for one-pot synthesis of 1-arylisoindoles from isoindolines via palladium-catalyzed dehydrogenation followed by C-H arylation

Article abstract of DOI:10.1021/ol2001232

A one-pot conversion of isoindolines to 1-arylisoindoles was established from palladium-catalyzed cascade C-H transformations, that is, the dehydrogenation of isoindolines to give isoindoles, with subsequent C-H arylation of the isoindoles.(Figure Presented)

Full text of DOI:10.1021/ol2001232

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1238–1241
Integrated Catalytic C-H Transformations
for One-Pot Synthesis of 1-Arylisoindoles
from Isoindolines via Palladium-Catalyzed
Dehydrogenation Followed by C-H
Arylation
Toshimichi Ohmura,* Akihito Kijima, and Michinori Suginome*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of
Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
ohmura@sbchem.kyoto-u.ac.jp; suginome@sbchem.kyoto-u.ac.jp
Received January 14, 2011
ABSTRACT
A one-pot conversion of isoindolines to 1-arylisoindoles was established from palladium-catalyzed cascade C-H transformations, that is, the
dehydrogenation of isoindolines to give isoindoles, with subsequent C-H arylation of the isoindoles.
Organic compounds containing an aryl-heteroaryl con-
jugated π-system have received much interest across a wide
range of research fields, including organic synthesis, medic-
inal chemistry, and materials sciences.1 Among the various
efficient synthetic methods for these compounds, transition-
metal-catalyzed C-H arylation of heteroaromatic com-
pounds has become an important synthetic method.2,3 This
method has an advantage over transition metal-catalyzed
cross-coupling reactions,4 in that the use of halogenated or
metalated aromatic starting materials can be avoided. To
make the strategy based on C-H arylation more useful and
practical, its application to a cascade catalytic process, in
(3) For examples on catalytic C-H arylation of pyrroles, indoles,
and indolizines, see: (a) Akita, Y.; Itagaki, Y.; Takizawa, S.; Ohta, A.
Chem. Pharm. Bull. 1989, 37, 1477. (b) Filippini, L.; Gusmeroli, M.;
Riva, R. Tetrahedron Lett. 1992, 33, 1755. (c) Park, C.-H.; Ryabova, V.;
Seregin, I. V.; Sromek, A. W.; Gevorgyan, V. Org. Lett. 2004, 6, 1159. (d)
Lane, B. S.; Sames, D. Org. Lett. 2004, 6, 2897. (e) Rieth, R. D.;
Mankad, N. P.; Calimano, E.; Sadighi, J. P. Org. Lett. 2004, 6, 3981.
(f) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127,
8050. (g) Joucla, L.; Putey, A.; Joseph, B. Tetrahedron Lett. 2005, 46,
ꢀ
(1) For examples, see: (a) Liegault, B.; Lapointe, D.; Caron, L.;
Vlassova, A.; Fagnou, K. J. Org. Chem. 2009, 74, 1826. (b) Campeau,
L.-C.; Stuart, D. R.; Leclerc, J.-P.; Bertrand-Laperle, M.; Villemure, E.;
Sun, H.-Y.; Lasserre, S.; Guimond, N.; Lecavallier, M.; Fagnou, K.
ꢀ
8177. (h) Toure, B. B.; Lane, B. S.; Sames, D. Org. Lett. 2006, 10, 1979.
ꢀ
J. Am. Chem. Soc. 2009, 131, 3291. (c) Liegault, B.; Petrov, I.; Gorelsky,
(i) Wang, X.; Gribkov, D. V.; Sames, D. J. Org. Chem. 2007, 72, 1476. (j)
Roger, J.; Doucet, H. Adv. Synth. Catal. 2009, 351, 1977. (k) Gryko,
D. T.; Vakuliuk, O.; Gryko, D.; Koszarna, B. J. Org. Chem. 2009, 74,
S. I.; Fagnou, K. J. Org. Chem. 2010, 75, 1047. (d) Jafarpour, F.;
Rahiminejadan, S.; Hazrati, H. J. Org. Chem. 2010, 75, 3109.
(2) For recent reviews on catalytic C-H arylation of heteroaromatic
compounds, see: (a) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200. (b)
Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (c)
Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173. (d) Bellina,
F.; Rossi, R. Tetrahedron 2009, 65, 10269. (e) Roger, J.; Gottumukkala,
A. L.; Doucet, H. ChemCatChem 2010, 2, 20.
ꢀ
9517. (l) Roy, D.; Mom, S.; Beauperin, M.; Doucet, H.; Hierso, J.-C.
Angew. Chem., Int. Ed. 2010, 49, 6650. See also refs 1a and 1d.
(4) (a) de Meijere, A., Diederich, F., Eds; Metal-Catalyzed Cross-
Coupling Reactions; Wiley-VCH: Weinheim, 2004. (b) Li, J. J., Gribble,
G. W., Eds. Palladium in Heterocyclic Chemistry, 2nd ed.; Elsevier: Oxford,
2007.
r
10.1021/ol2001232
Published on Web 01/28/2011
2011 American Chemical Society

Table 1. Optimization of Reaction Conditions for Palladium-
Catalyzed One-Pot Dehydrogenation/C-H Phenylation of 1aa
Scheme 1. Concept for Synthesis of Isoindoles with Carbon
Functional Group Based on Catalytic C-H Transformations
yield
yield of
entry
catalyst
Pd(dba)2
Pd(dba)2/DPPF
Pd(dba)2/2PPh3
Pd(dba)2/2SPhos
Pd(dba)2/2PCy3
Pd(dba)2/
additive
of 2a (%)b base 5a (%)b
1
2
3
4
5
6
-
-
-
-
-
-
56
10
11
62
60
59
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
0
4
2
9
61
69
which two or more C-H transformations are achieved by a
single catalyst, is highly attractive.5
Our recent interest has been directed to the development of
a new concept for the synthesis of isoindole derivatives
utilizing catalytic C-H transformations (Scheme 1).6,7 To
avoid isolation of the air-sensitive isoindoles that are sub-
jected to functionalization,8 we particularly focused on cas-
cade transformations starting from isoindolines, which are
easy to handle and are easily available via several synthetic
methods.9 In this regard, we have established a palladium-
catalyzed conversion of isoindolines to 1-boryl- and 1,3-
diborylisoindoles via sequential dehydrogenation and C-H
borylation.10 Herein, we describe the conversion of isoindo-
lines to 1-arylated isoindoles via integrated catalytic C-H
transformations. The dehydrogenation of isoindolines and
the C-H arylation of the isoindoles was achieved in one-pot
using a single palladium catalyst.
2P(t-Bu)3
7
8
9
10
11
12
13
14
Pd[P(t-Bu)3]2
Pd[P(t-Bu)3]2
Pd[P(t-Bu)3]2
Pd[P(t-Bu)3]2
Pd[P(t-Bu)3]2
Pd[P(t-Bu)3]2
Pd[P(t-Bu)3]2
Pd[P(t-Bu)3]2
Me2Sc
55
58
68
92e
-
-
-
-
-
NaOH
NaOH
NaOH
NaOH 98 (97)f
K2CO3
K3PO4
KOAc
KF
NaOH
NaOH
27
48
73
norbornened
t-BuCHdCH2
cyclohexened
cyclohexened
cyclohexened
cyclohexened
cyclohexened
cyclohexened
cyclohexened
d
0
29
3
0
15g Pd[P(t-Bu)3]2
16i Pd[P(t-Bu)3]2
42h
59h
-
a Pd complex (0.010 mmol), additive, and 1a (0.20 mmol) were
reacted in 1,4-dioxane (0.3 mL) at 110 °C for 14 h. 3a (0.60 mmol) and
base (0.80 mmol) were then added to the mixture and the resulting mixture
was stirred at 110 °C for 24 h. b GC yield based on 1a. c 2.0 μmol. d 1.0 mmol.
e Average of entries 10-16. f Isolated yield based on 1a in 0.4 mmol scale
reaction. g Bromobenzene was used instead of 3a. h Cyclohexenylbenzenes,
products via Heck reaction of cyclohexene with aryl halide, were formed as
side products. i Iodobenzene was used instead of 3a.
The reaction of 2-methylisoindoline (1a) was initially
examined in 1,4-dioxane at 110 °C in the presence of
phosphine-free Pd(dba)2 (5 mol %), which was found to
be effective for the dehydrogenation/C-H borylation se-
quence in a previous study (entry 1, Table 1).10,11 Dehydro-
genation of 1a took place efficiently to give 2-methylisoin-
dole (2a) in 56% yield after 14 h. Chlorobenzene (3a, 3equiv)
and NaOH (4 equiv) were then added to the reaction mix-
ture, and the resulting solution was stirred at 110 °C for 24 h.
However, no phenylated products were observed under these
reaction conditions. We tested several phosphorus ligands to
find a catalyst for C-H arylation while maintaining the
catalyst activity for dehydrogenation (entries 2-6). We
found that palladium catalysts generated in situ from Pd-
(dba)2 with PCy3 or P(t-Bu)3 (Pd/P = 1/2) were effective for
both dehydrogenation and C-H phenylation (entries 5
and 6). The phenylation took place at both the C1 and C3
positions of 2a to afford double-phenylated 5a in 61-69%
yields. The formation of monophenylated 4a was observed
during the course of the reaction, indicating that 5a was
formed via a stepwise double C-H phenylation of 2a.12 It is
important to note that 3a and NaOH were required to be
€
(5) (a) Muller, T. J. J., Ed. Metal Catalyzed Cascade Reactions;
Springer: Berlin, 2006. For general statement of reaction integration, see:
(b) Suga, S.; Yamada, D.; Yoshida, J. Chem. Lett. 2010, 39, 404.
(6) For reviews on isoindole, see: (a) Jones, G. B.; Chapman, B. J. In
Comprehensive Heterocyclic Chemistry II, Katrizky, A. R.; Rees, C. W.;
Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol 2, p 1. (b) Donohoe,
T. J. In Science of Synthesis; Thomas, E. J., Ed.; Georg Thieme Verlag;
Stuttgart, 2000; Vol 10, p 653.
(7) For examples on transition-metal-catalyzed synthesis of isoindoles,
ꢀ
ꢀ
see: (a) Sole, D.; Vallverdu, L.; Solans, X.; Font-Bardıa, M.; Bonjoch, J.
J. Am. Chem. Soc. 2003, 125, 1587. (b) Kadzimirsz, D.; Hildebrandt, D.;
Merz, K.; Dyker, G. Chem. Commun. 2006, 661. (c) Ding, Q.; Ye, Y.; Fan,
R.; Wu, J. J. Org. Chem. 2007, 72, 5439. (d) Heugebaert, T. S. A.; Stevens,
C. V. Org. Lett. 2009, 11, 5018. (e) Sole, D.; Serrano, O. Org. Biomol. Chem.
2009, 3382. (f) Shimizu, H.; Igarashi, T.; Murakami, M. Bull. Korean Chem.
ꢀ
ꢀ
Soc. 2010, 31, 1461. (g) Sole, D.; Serrano, O. J. Org. Chem. 2010, 75, 6267.
(8) Ahmed, M.; Kricka, L. J.; Vernon, J. M. J. Chem. Soc., Perkin 1
1975, 71.
(9) For examples, see: (a) Sakuragi, A.; Shirai, N.; Sato, Y.; Kurono,
Y.; Hatano, K. J. Org. Chem. 1994, 59, 148. (b) Ebden, M. R.; Simpkins,
N. S.; Fox, D. N. A. Tetrahedron 1998, 54, 12923. (c) Hou, D.-R.; Hsieh,
Y.-D.; Hsieh, Y.-W. Tetrahedron Lett. 2005, 46, 5927. (d) Yamamoto,
Y.; Saigoku, T.; Nishiyama, H.; Ohgai, T.; Itoh, K. Org. Biomol. Chem.
2005, 3, 1768. (e) Hou, D.-R.; Wang, M.-S.; Chung, M.-W.; Hsieh, Y.-D.;
Tsai, H.-H. G. J. Org. Chem. 2007, 72, 9231.
(10) Ohmura, T.; Kijima, A.; Suginome, M. J. Am. Chem. Soc. 2009,
131, 6070.
(11) For limited example on palladium-catalyzed dehydrogenation
of isoindoline to give isoindole, see: Grigg, R.; Somasunderam, A.;
Sridharan, V.; Keep, A. Synlett 2009, 97. See also ref 7g.
(12) All attempts for selective synthesis of 4a from 1a failed because
reactivity of 2a and 4a in the C-H phenylation was similar under the
palladium-catalyzed conditions.
Org. Lett., Vol. 13, No. 5, 2011
1239

added after the first dehydrogenation step, as the addition of
these reagents to the initial reaction mixture resulted in low
conversion of 1a. It should also be noted that use of electron-
rich and sterically bulky trialkylphosphines is critical for the
one-pot, two-step conversion. Slower dehydrogenation was
observed in the reactions with Pd/DPPF and Pd/PPh3
catalysts (entries 2 and 3), whereas a palladium complex
bearing SPhos (2-dicyclohexylphosphino-20,60-dimethoxy-1,
10-biphenyl) was effective for dehydrogenation, but was
inefficient for C-H phenylation (entry 4).
Table 2. Palladium-Catalyzed One-Pot Dehydrogenation/C-H
Phenylation of Isoindolines 1a
Several additives were examined with Pd[P(t-Bu)3]2
catalyst to improve the reaction (entries 7-10). The addi-
tion of a catalytic amount of Me2S (1 mol %), which was
found to be effective for the synthesis of 1-borylisoindoles
via dehydrogenation/C-H borylation of isoindolines,10 did
not result in a significant improvement in dehydrogenation
with an inefficient C-H arylation (entry 7). In contrast,
effective dehydrogenation took place on addition of an
alkene as a hydrogen acceptor (entries 8-10). Finally, we
found that an efficient conversion of 1a to 2a was achieved
in the presence of cyclohexene (5 equiv), leading to the
formation of the final product 5a in high yield (entry 10).
The second step (C-H phenylation) was also optimized
(entries 10-14). The C-H phenylation proceeded effi-
ciently with use of NaOH as a base (entry 10), whereas
other bases such as K2CO3, K3PO4, KOAc, and KF gave
poor results (entries 11-14). Bromo- and iodobenzene could
also be employed in the C-H phenylation of 2a, although
the yields of 5a were lower than that obtained using chloro-
benzene (3a), because of the competing Heck reaction with
the remnant cyclohexene (entries 15 and 16).
The optimized reaction conditions were then employed
for the dehydrogenation/C-H phenylation of various iso-
indolines 1 (Table 2). Although dehydrogenation of N-Et-,
N-i-Pr-, and N-t-Bu-substituted isoindolines 1b-dtook place
smoothly to give the corresponding isoindoles 2b-d in high
yields, the C-H phenylation was sensitive to the steric
bulkiness of the alkyl groups (entries 1-3). Selective forma-
tion of 5b was achieved in the reaction of N-Et-substituted 2b
(entry 1), whereas the phenylation of N-i-Pr-substituted 2c
resulted in a slow formation of a mixture of mono- and
double-phenylated products (entry 2). A much more sluggish
phenylation was observed in the reaction of N-t-Bu-substi-
tuted 2d (entry 3). N-Me-substituted isoindolines 1e-i were
then subjected to the sequential reaction (entries 4-8).
Methyl, methoxy, and trifluoromethyl groups on the benzene
ring did not affect the reactivity in either the dehydrogenation
or the C-H phenylation, giving double phenylated products
5e-h in high yields. The second C-H phenylation of 2i
proceeded smoothly, despite the presence of the sterically
demanding 4-methyl group (entry 8).
yield of
yield of 4
entry
R1
R2
R3
R4
Et
i-Pr
t-Bu
Me
Me
Me
Me
Me
2 (%)b
and 5 (%)c
1
H
H
H
Me
MeO
F3C
Me
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
Me
1b
1c
1d
1e
1f
1g
1h
1i
96 (2b)
99 (2c)
99 (2d)
91 (2e)
92 (2f)
97 (2g)
88 (2h)
92 (2i)
82 (5b)
66e (4c), 13e (5c)
32f (4d), 0f (5d)
84 (5e)
2d
3
4
5
6
7
92 (5f)
99 (5g)
85 (5h)
81 (5i)
8
a Pd[P(t-Bu)3]2 (0.020 mmol), cyclohexene (2.0 mmol), and 1 (0.40
mmol) were reacted in 1,4-dioxane (0.6 mL) at 110 °C for 14 h. 3a (1.2
mmol) and NaOH (1.6 mmol) were then added to the mixture and the
resulting mixture was stirred at 110 °C for 24 h. b Determined by 1H NMR
and GC. c Isolated yield based on 1. d 3a (5 equiv) and NaOH (5 equiv) were
used. e 1H NMR yield after 48 h. f 1H NMR yield after 71 h.
Electron-rich aryl chlorides 3b and 3c, as well as electron-
deficient 3d, reacted with 4a to give 5j-lin high yields (entries
2-4), although the reaction of sterically demanding 3e with
4a was slow, resulting in the formation of 5m in a moderate
yield (entry 5). 3-Chloropyridine (3f) successfully took part
in the C-H arylation, yielding 5n in good yield (entry 6). The
C-H phenylation of 4-methoxyphenyl-substituted isoindole
2k and 4-trifluoromethylphenyl-substituted 2l gave the cor-
responding 1,3-diarylisoindoles 5k and 5l, respectively, in
good yields (entries 7 and 8). 1,2-Dimethylisoindole (2m) was
more reactive than 4a, 2k, and 2l in the C-H arylation,
leading to a reaction with sterically demanding 3e to give 5q
in high yield (entry 11). However, the reaction of 2m with the
more hindered 3h was slow under the conditions used (entry
12). An application of the dehydrogenation/C-H arylation
sequence is demonstrated in the reaction with 1,4-dichloro-
benzene (3i), which led to an efficient synthesis of phenylene-
linked isoindole 5s (Scheme 2).
Isoindoles have attracted much interest in applications
such as fluorescent and electroluminescent materials13,14
(13) For study on utilization of isoindoles as fluorescent and electro-
luminescent materials, see: (a) Zweig, A.; Metzler, G.; Maurer, A.;
Roberts, B. G. J. Am. Chem. Soc. 1967, 89, 4091. (b) Ding, Y.; Hay,
A. S. J. Pom. Sci. Part A: Polym. Chem. 1999, 37, 3293. (c) 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. (d) 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. (e) Jiao, L.;
Yu, C.; Lin, M.; Wu, Y.; Cong, K.; Meng, T.; Wang, Y.; Hao, E. J. Org.
Chem. 2010, 75, 6035.
2-Methylisoindolines 1j-m bearing a substituent at the
C1 position were then subjected to the reactions with various
aryl chlorides 3 (1.5 equiv) (Table 3). Dehydrogenation of
1-aryl-2-methylisoindolines 1j-l and 1,2-dimethylisoindo-
line (1m) took place cleanly under the optimized conditions
to give the corresponding isoindoles 4a and 2k-m in high
yields (entries 1-12). Isoindole 4a underwent subsequent
C-H phenylation with 3a to afford 5a in 97% yield (entry 1).
(14) Photophysical properties of 1-arylated isoindoles obtained in
this study are summarized in Supporting Information.
1240
Org. Lett., Vol. 13, No. 5, 2011

Table 3. Palladium-Catalyzed One-Pot Dehydrogenation/C-H Arylation of 1-Substituted Isoindolinesa
entry
1
yield of 2 or 4a (%)b
ArCl
3a (Ar = Ph)
yield of 5 (%)c
1
1j (R5 = Ph)
99d (4a)
- (4a)
- (4a)
- (4a)
- (4a)
- (4a)
99 (2k)
99 (2l)
93i (2m)
- (2m)
- (2m)
- (2m)
97 (5a)
93 (5j)
2
1j
3b (Ar = 4-MeC6H4)
3c (Ar = 4-MeOC6H4)
3d (Ar = 4-F3CC6H4)
3e (Ar = 2-MeC6H4)
3f (Ar = 3-pyridyl)
3a
3e
4f
5
1j
77 (5k)
85 (5l)
48g (5m)
74g (5n)
66 (5k)
71 (5l)
1j
1j
6h
1j
7
1k (R5 = 4-MeOC6H4)
8
1l (R5 = 4-F3CC6H4)
3a
9
1m (R5 = Me)
3a
90 (5o)
97 (5p)
86 (5q)
25j (5r)
10
11
12
1m
1m
1m
3g (Ar = 3-MeC6H4)
3e
3h (Ar = 2,6-Me2C6H3)
a Pd[P(t-Bu)3]2 (0.020 mmol), cyclohexene (2.0 mmol), and 1 (0.40 mmol) were reacted in 1,4-dioxane (0.6 mL) at 110 °C for 14 h. 3 (0.60 mmol) and
NaOH (0.80 mmol) were then added to the mixture and the resulting mixture was stirred at 110 °C for 24 h. b Determined by 1H NMR and GC. c Isolated
yield based on 1. d Average of entries 1-6. e 3c (0.80 mmol) was used. f 3d (0.80 mmol) was used. g Yield after 48 h. h 3f (1.0 mmol) and NaOH (1.0 mmol)
were used. i Average of entries 9-12. j 1H NMR yield after 72 h.
Scheme 2. Synthesis of Phenylene-Linked Isoindole 5s
Scheme 3. Synthesis of 5,12-Diphenylnaphthacene (8) Utilizing
Isoindole 5a
as well as synthetic intermediates.15 A synthetic applica-
tion of the arylated isoindoles is demonstrated by the
Diels-Alder reaction of 5a with naphthalyne, which was
generated in situ from 2,3-dibromonaphthalene (6) with
n-butyllithium (Scheme 3).16 The reaction proceeded
cleanly to give amine 7 in a high yield. Amine 7 served as
a useful precursor of 5,12-diphenyltetracene (8),17 which
afforded 8 in a good yield on treatment with mCPBA.18
In conclusion, we have established an efficient route to
1-aryl-substituted isoindoles via the palladium-catalyzed
dehydrogenation of isoindolines and subsequent C-H
arylation of the resulting isoindoles. The synthesis of dehy-
drogenation products in high yields is achieved by the addi-
tion of cyclohexene as a hydrogen acceptor. A wide range of
aryl chlorides is applicable to the C-H arylation. Further
development of the isoindole synthetic method based on the
dehydrogenation/C-H functionalization is now being un-
dertaken in this laboratory.
(15) For examples of Diels-Alder reaction of isoindoles, see: (a)
Chen, Y.-L.; Lee, M.-H.; Wong, W.-Y.; Lee, A. W. M. Synlett 2006,
2510. (b) Duan, S.; Sinha-Mahapatra, D. K.; Herndon, J. W. Org. Lett.
2008, 10, 1541.
(16) For related tetracene synthesis utilizing 1,3-unsubstituted iso-
indoles, see: (a) LeHoullier, C. S.; Gribble, G. W. J. Org. Chem. 1983, 48,
€
2364. (b) Chen, Z.; Muller, P.; Swager, T. M. Org. Lett. 2006, 8, 273.
(17) For another route to 8, see: Zhou, L.; Nakajima, K.; Kanno, K.;
Takahashi, T. Tetrahedron Lett. 2009, 50, 2722.
(18) Gribble, G. W.; Allen, R. W.; Anderson, P. S.; Christy, M. E.;
Colton, C. D. Tetrahedron Lett. 1976, 17, 3673.
Supporting Information Available. Experimental details
and characterization data of the products. This material is
available free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 5, 2011
1241