Facile synthesis of tetrahydro-1 H-isoindolones via a sequential three-component copper-catalyzed coupling/propargyl-allenyl isomerization/[4 + 2] cyclization reaction

Article abstract of DOI:10.1021/ol102235t

An interesting sequential three-component copper-catalyzed coupling/propargyl-allenyl isomerization/[4 + 2] cyclization reaction, providing a facile synthesis of highly substituted tetrahydro-1H-isoindolones from conjugated vinylic alkynes, imines, and α,β-unsaturated enoic acid chlorides is reported. The most attractive feature of this transformation is that three stereogenic centers could be generated in one step with high diastereoselectivity.

Full text of DOI:10.1021/ol102235t

ORGANIC
LETTERS
2010
Vol. 12, No. 21
5048-5051
Facile Synthesis of
Tetrahydro-1H-isoindolones via a
Sequential Three-Component
Copper-Catalyzed Coupling/
Propargyl-Allenyl Isomerization/[4 + 2]
Cyclization Reaction
Jian Cao† and Xian Huang*,†,‡,§
Department of Chemistry, Zhejiang UniVersity (Xixi Campus),
Hangzhou 310028, People’s Republic of China, and State Key Laboratory of
Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, 354 Fenglin Lu, Shanghai 200032, People’s Republic of China
wululing@zju.edu.cn
Received September 18, 2010
ABSTRACT
An interesting sequential three-component copper-catalyzed coupling/propargyl-allenyl isomerization/[4 + 2] cyclization reaction, providing a
facile synthesis of highly substituted tetrahydro-1H-isoindolones from conjugated vinylic alkynes, imines, and r,ꢀ-unsaturated enoic acid
chlorides is reported. The most attractive feature of this transformation is that three stereogenic centers could be generated in one step with
high diastereoselectivity.
Multicomponent reactions (MCRs) have attracted consider-
able attention due to the fact that complex molecules can be
easily prepared from simple compounds in one reaction
sequence.1 Allenes show unique reactivity in organic syn-
thesis2 and many studies have been performed on their
preparation and reactivity.3 [4 + 2] cycloaddition of ene/
yne-allenes provides a convenient route for the construction
of complex ring systems.4 Mu¨ller et al. pioneered the
Sonogashira coupling/propargyl-allenyl isomerization reac-
tions for the synthesis of a variety of useful compounds
including chalcones, pyrazolines, pyrroles, fluorescent spi-
rocycles, and some other pharmaceutically interesting het-
(2) (a) Patai, S. The Chemistry of Ketenes, Allenes, and Related
Compounds; John Wiley & Sons: New York, 1980. (b) Schuster, H. F.;
Coppola, G. M. Allenes in Organic Synthesis; John Wiley & Sons: New
York, 1984. (c) Landor, S. R. The Chemistry of Allenes; Academic Press:
New York, 1982; Vols. 1-3. (d) Krause, N.; Hashmi, A. S. K. Modern
Allene Chemistry; Wiley-VCH: Weinheim, Germany, 2004; Vols. 1-2.
(3) (a) Ma, S. Chem. ReV. 2005, 105, 2829. (b) Ma, S. Acc. Chem. Res.
2003, 36, 701. (c) Ma, S. Acc. Chem. Res. 2009, 42, 1679. (d) Ma, S. Eur.
J. Org. Chem. 2004, 1175. (e) Ma, S. Aldrichimica Acta 2007, 40, 91. (f)
Marshall, J. A. Chem. ReV. 1996, 96, 31. (g) Yamamoto, Y.; Radhakrishnan,
U. Chem. Soc. ReV. 1999, 28, 199. (h) Zimmer, R.; Dinesh, C. U.; Nandanan,
E.; Khan, F. A. Chem. ReV. 2000, 100, 3067. (i) Marshall, J. Chem. ReV.
2000, 100, 3163.
† Zhejiang University.
‡ Chinese Academy of Sciences.
§ Prof. Huang passed away on March 6, 2010. He had been fully in charge
of this project. At this moment, Prof. Luling Wu is finishing all the projects
with the help from Prof. Shengming Ma.
(1) (a) Wasilke, J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem.
ReV. 2005, 105, 1001. (b) Lee, J. M.; Na, Y.; Han, H.; Chang, S. Chem.
Soc. ReV. 2004, 33, 302. (c) Montgomery, J. Acc. Chem. Res. 2000, 33,
467. (d) Ikeda, S. I. Acc. Chem. Res. 2000, 33, 511. (e) Tietze, L. F. Chem.
ReV. 1996, 96, 115. (f) Bunce, R. A. Tetrahedron 1995, 51, 13103.
10.1021/ol102235t  2010 American Chemical Society
Published on Web 10/06/2010

erocycles.5 Previously, we also established a series of
sequential reactions wherein an allene intermediate, generated
in situ, would undergo [4 + 2] cycloaddition reaction under
mild conditions, providing an efficient synthesis of structur-
ally complex polycycles with 2,3-dihydrofuran units,6 struc-
turally diverse fused dihydroisobenzofuran derivatives,7 and
polysubstituted pyridines and isoquinolines.8
The hydroisoindolone core is present in both synthetic and
naturally occurring compounds that exert a wide range of
pharmacological activities.9 For example, naturally occurring
fungal metabolites such as cytotoxic cytochalasin B10 and
recently discovered anti-HIV cytochalasin L-696,47411 both
contain the hydroisoindolone skeleton (Figure 1).
the intermediate N-(alk-4-en-2-ynyl)alk-2-enamides 4 which
would be generated from copper-catalyzed coupling of
vinylalkynes 1, imines 2, and R,ꢀ-unsaturated enoic acid
chlorides 3,13 may undergo subsequent propargyl-allenyl
isomerization reaction in the presence of a base leading to
the vinylallenes 5. An intramolecular [4 + 2] cycloaddition
may then proceed to furnish the highly substituted tetrahydro-
1H-isoindolones 6 (Scheme 1). Thus, by our strategy, three
Scheme 1
Figure 1. Several hydroisoindolone derivatives reported as biologi-
cally active compounds and pharmaceutical products.
new carbon-carbon bonds and one carbon-nitrogen bond
could be formed in a single stroke with the efficient assembly
of two rings from readily available starting materials.
Furthermore, because of the rigidity of the intermediate
vinylallenes 5, this intramolecular [4 + 2] cyclization was
anticipated to lead to polycycle 6 in a highly diastereose-
lective manner.14
While numerous methods have been reported for the
synthesis of isoindolone derivatives, they are generally
limited with respect to stereoselectivity and the types and
locations of substituents. In our continuous efforts to design
sequential reactions via allene intermediates,12 we report here
a sequential three-component copper-catalyzed coupling/
propargyl-allenyl isomerization/[4 + 2] cyclization reaction:
We initiated our study by attempting the reaction of 1a,
2a, and 3a (1.2:1:1.2) (Scheme 2). After being stirred at room
(4) (a) Ma, S.; Lu, P.; Lu, L.; Hou, H.; Wei, J.; He, Q.; Gu, Z.; Jiang,
X.; Jin, X. Angew. Chem., Int. Ed. 2005, 44, 5275. (b) Jiang, X.; Kong,
W.; Chen, J.; Ma, S. Org. Biomol. Chem. 2008, 6, 3606. (c) Padwa, A.;
Meske, M.; Murphree, S. S.; Watterson, S. H.; Ni, Z. J. Am. Chem. Soc.
1995, 117, 7071. (d) Wender, P. A.; Jenkins, T. E.; Suzuki, S. J. Am. Chem.
Soc. 1995, 117, 1843. (e) Padwa, A.; Filipkowski, M. A.; Meske, M.;
Watterson, S. H.; Ni, Z. J. Am. Chem. Soc. 1993, 115, 3776. (f) Kanematsu,
K.; Sugimoto, N.; Kawaoka, M.; Yeo, S.; Shiro, M. Tetrahedron Lett. 1991,
32, 1351.
Scheme 2
(5) (a) Braun, R. U.; Ansorge, M.; Mu¨ller, T. J. J. Chem.sEur. J. 2006,
12, 9081. (b) Braun, R. U.; Zeitler, K.; Mu¨ller, T. J. J. Org. Lett. 2001, 3,
3297. (c) D’Souza, D. M.; Kiel, A.; Herten, D. P.; Mu¨ller, T. J. J.
Chem.sEur. J. 2008, 14, 529. (d) Braun, R. U.; Zeitler, K.; Mu¨ller, T. J. J.
Org. Lett. 2000, 2, 4181. (e) D’Souza, D. M.; Rominger, F.; Mu¨ller, T. J. J.
Angew. Chem., Int. Ed. 2005, 44, 153. (f) D’Souza, D. M.; Rominger, F.;
Mu¨ller, T. J. J. Chem. Commun. 2006, 4096.
temperature for 1 h in the presence of CuI and Et3N, the
reaction gave N-(alk-4-en-2-ynyl)alk-2-enamide 4a in 85%
yield and no vinylallene or Diels-Alder product was
detected.
Subsequently, different bases were tested to promote the
propargyl-to-allenyl isomerization and [4 + 2] cycloaddition
reaction (Table 1). Weak bases such as triethylamine or
K2CO3 could not trigger the reaction, while a stronger
(6) Shen, R.; Huang, X. Org. Lett. 2008, 10, 3283.
(7) Shen, R.; Huang, X.; Chen, L. AdV. Synth. Catal. 2008, 350, 2865.
(8) Sha, F.; Huang, X. Angew. Chem., Int. Ed. 2009, 48, 3458.
(9) (a) Jiang, J.; Devita, R. J.; Kumar, S.; Mills, S. G.; Tschirret-Guth,
R. A. Int. Patent WO 2007002457, 2007. (b) Kuethe, J. T.; Yin, J.; Huffman,
M. A.; Journet, M. Int. Patent WO 2007008564, 2007. (c) Rudd, J. A.;
Ngan, M. P.; Wai, M. K. Eur. J. Pharmacol. 1999, 366, 243. (d) Walling,
E. A.; Drafft, G. A.; Ware, B. R. Arch. Biochem. Biophys. 1988, 264, 321.
(10) (a) Haidle, A. M.; Myers, A. G. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 12048. (b) Thilly, W. G.; Liber, H. L.; Wogan, G. N. Front. Biol.
1978, 46, 53.
(13) Black, D. A.; Arndtsen, B. A. Org. Lett. 2004, 6, 1107.
(14) (a) Deutsch, E. A.; Snider, B. B. J. Org. Chem. 1982, 47, 2682.
(b) Deutsch, E. A.; Snider, B. B. Tetrahedron Lett. 1983, 24, 3701. (c)
Keck, G. E.; Kachensky, D. F. J. Org. Chem. 1986, 51, 2487. (d) Gibbs,
R. A.; Bartels, K.; Lee, R. W. K.; Okamura, W. H. J. Am. Chem. Soc.
1989, 111, 3717. (e) Curtin, M. L.; Okamura, W. H. J. Org. Chem. 1990,
55, 5278. (f) Krause, N. Liebigs Ann. Chem. 1993, 521.
(11) Linghan, R. B.; Hsu, A.; Silverman, K. C.; Bills, G. F.;
Dombrowski, A.; Goldman, M. E.; Darke, P. L.; Huang, L.; Koch, G.;
Ondeyka, J. G.; Goetz, M. A. J. Antibiot. 1992, 45, 686.
(12) (a) Shen, R.; Zhu, S.; Huang, X. J. Org. Chem. 2009, 74, 4118.
(b) Huang, X.; Zhu, S.; Shen, R. AdV. Synth. Catal. 2009, 351, 3118. (c)
Shen, R.; Chen, L.; Huang, X. AdV. Synth. Catal. 2009, 351, 2833.
Org. Lett., Vol. 12, No. 21, 2010
5049

reaction probably because of the effect of byproduct
Et3NH+Cl- in the coupling reaction. Then we carried out
the reaction using various vinylalkynes 1, imines 2, and R,ꢀ-
unsaturated enoic acid chlorides 3. As indicated in Table 2,
the reactions proceeded smoothly to afford the corresponding
tetrahydro-1H-isoindolones 6 in moderate to good yields. R1
and R2 in vinylalkynes 1 can be H, alkyl, and aryl group
(Table 2, entries 1, 2, 7, and 8). Various C-aryl/heteroaryl-
and N-alkyl/aryl-substituted imines were also successful
(entries 1 and 3-6). Similar alkyl and aryl diversity can be
incorporated with the R,ꢀ-unsaturated enoic acid chloride
(entries 1, 9, and 10).
Table 1. Base Effect on the Propargyl-Allenyl Isomerization
and Diels-Alder Reactiona
entry
base
time (h)
yield of 6a
1
2
3
4
5
6
7
Et3N (1.2 equiv)
K2CO3 (1.2 equiv)
t-BuOK (1.2 equiv)
t-BuOK (0.1 equiv)
DBU (1.2 equiv)
DBN (1.2 equiv)
DBU (0.1 equiv)
12
12
NR
NR
This approach is not limited to the isolated CdN bond of
imines. The CdN bond in nitrogen-containing aromatic
heterocycles such as quinoline and isoquinoline can also be
employed in this reaction. As shown in Scheme 3, the one-
0.5
0.5
0.5
0.5
0.5
unidentified mixture
unidentified mixture
91
88
93
a The reaction was carried out with 4a (0.28 mmol) in MeCN (1 mL)
at rt.
Scheme 3
base such as t-BuOK gave an unidentified mixture. DBU
(1,8-diazabicyclo[5.4.0]undec-7-ene) and DBN (1,5-dia-
zabicyclo[4.3.0]non-5-ene) proved to be suitable options,
however, and gave 6a as the sole product in good yields at
room temperature. Further study showed that a catalytic
amount of DBU was sufficient to promote this reaction.
We then tried to combine these two steps into a one-pot
reaction, without the isolation of N-(alk-4-en-2-ynyl)alk-2-
enamide 4a. When the copper-catalyzed coupling reaction
was complete, DBU was added to the reaction mixture, and
after 12 h the tetrahydro-1H-isoindolone 6a was obtained in
80% overall yield. It should be noted that 3.0 equiv of DBU
was required to promote the propargyl-allenyl isomerization
pot reaction of quinoline or isoquinoline, vinylalkyne 1b,
and R,ꢀ-unsaturated enoic acid chlorides 3a and 3c gave
Table 2. Synthesis of Tetrahydro-1H-isoindolones 6a
1
2
3
entry
R1
R2
R3
R4
R5
R6
yield of 6 (%)
1
2
3
4
5
6
7
8
9
10
-(CH2)3- (1a)
Ph
Ph
p-tol (2a)
p-tol (2a)
Bn (2b)
p-MeOC6H4 (2c)
n-Pr (2d)
allyl (2e)
p-MeOC6H4 (2c)
Bn (2b)
Bn (2b)
Me
Me
Me
Me
Me
Me
Me
Me
Ph
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3b)
Ph (3c)
80 (6a)
84 (6b)
92 (6c)
78 (6d)
81 (6e)
55 (6f)
74 (6g)
73 (6h)
58 (6i)
41 (6j)
-(CH2)4- (1b)
-(CH2)4- (1b)
-(CH2)4- (1b)
-(CH2)4- (1b)
-(CH2)4- (1b)
p-MeOC6H4
p-tol
R-furyl
p-ClC6H4
p-tol
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
H
Ph (1c)
H (1d)
p-MeOC6H4
-(CH2)4- (1b)
-(CH2)4- (1b)
Bn (2b)
Me
a Unless otherwise specified, the reaction was carried out with 1 (1.2 equiv), 2 (1.0 equiv), 3 (1.2 equiv), CuI (0.1 equiv), and Et3N (1.5 equiv) in MeCN
at rt for 1 h and then with DBU (3.0 equiv) for 8-12 h.
5050
Org. Lett., Vol. 12, No. 21, 2010

fused polycycles 6k-m under the same conditions as those
employed with normal imines.
All products were afforded as single stereoisomers and
the stereochemistry was revealed by X-ray diffraction of 6g,15
6l,16 and 6m17 (Figure 2).
pargyl-allenyl isomerization/[4 + 2] cyclization reaction,
affording bicyclic tetrahydro-1H-isoindolones from readily
available vinylalkynes, imines, and R,ꢀ-unsaturated enoic
acid chlorides efficiently. Furthermore, the CdN bond in
heteroaromatic compounds such as quinoline and isoquino-
line can also be employed in this sequential one-step reaction
affording fused polycycles incorporating three adjacent
stereocenters with excellent diastereoselectivity. Further
explorations in this area are currently underway.
In conclusion, we have realized a highly diastereoselective
sequential three-component copper-catalyzed coupling/pro-
Acknowledgment. We are grateful to the National Natural
Science Foundation of China (Project Nos. 20732005 and
20872127), the National Basic Research Program of China
(973 Program, 2009CB825300), and the Fundamental Re-
search Funds for the Central Universities for financial
support.
Supporting Information Available: Spectroscopic data
for 4a, and 6a-m, X-ray crystal data for 6g, 6l, and 6m,
and detailed experimental procedures. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL102235T
(15) Crystal data for 6g: C29H27NO2, MW ) 421.52, triclinic, space
j
group P1, final R indices [I > 2σ(I)], R1 ) 0.0385, wR2 ) 0.0954; R indices
(all data), R1 ) 0.0587, wR2 ) 0.0998; a ) 10.1023(4) Å, b ) 10.2563(6)
Å, c ) 12.5612(6) Å, R ) 78.656(4)°, ꢀ ) 74.978(4)°, γ ) 68.060(5)°, V
) 1158.71(10) Å3, T ) 293(2) K, Z ) 2, reflections collected/unique 7635/
4067 (Rint ) 0.0149), number of observations [I > 2σ(I)] 2749, parameters
292. Supplementary crystallographic data have been deposited at the
Cambridge Crystallographic Data Centre, CCDC 793327.
(16) Crystal data for 6l: C21H21NO, MW ) 303.39, monoclinic, space
group P2(1)/n, final R indices [I > 2σ(I)], R1 ) 0.0507, wR2 ) 0.1128; R
indices (all data), R1 ) 0.0689, wR2 ) 0.1214; a ) 11.5025(12) Å, b )
9.3758(10) Å, c ) 15.0540(16) Å, R ) 90°, ꢀ ) 101.188(2)°, γ ) 90°, V
) 1592.6(3) Å3, T ) 293(2) K, Z ) 4, reflections collected/unique 8873/
3299 (Rint ) 0.0337), number of observations [I > 2σ(I)] 2405, parameters
210. Supplementary crystallographic data have been deposited at the
Cambridge Crystallographic Data Centre, CCDC 793326.
(17) Crystal data for 6m: C27H25NO, MW ) 379.48, triclinic, space
j
group P1, final R indices [I > 2σ(I)], R1 ) 0.0399, wR2 ) 0.0835; R indices
(all data), R1 ) 0.0943, wR2 ) 0.0948; a ) 9.0955(10) Å, b ) 11.2163(14)
Å, c ) 11.8083(15) Å, R ) 113.640(12)°, ꢀ ) 108.357(11)°, γ )
96.114(10)°, V ) 1009.2(2) Å3, T ) 293(2) K, Z ) 2, reflections collected/
unique 7886/3670 (Rint ) 0.0320), number of observations [I > 2σ(I)] 1893,
parameters 263. Supplementary crystallographic data have been deposited
at the Cambridge Crystallographic Data Centre, CCDC 793328.
Figure 2. ORTEP representations of 6g, 6l, and 6m.
Org. Lett., Vol. 12, No. 21, 2010
5051