Synthesis of indolo[2,3-b]quinolines by palladium-catalyzed annulation of unsaturated isothioureas

Article abstract of DOI:10.1246/cl.2009.772

Treatment of l-(2-alkynyl)phenyl-3-aryl-2-methylisothioureas with 5 mol% [Pd(η³-C₃H₅)C1]₂ in the presence of CuTC (copper thiophenecarboxylate) and Cs₂CO₃ at 130 °C provided a wide range of

Full text of DOI:10.1246/cl.2009.772

772
Chemistry Letters Vol.38, No.8 (2009)
Synthesis of Indolo[2,3-b]quinolines by Palladium-catalyzed Annulation
of Unsaturated Isothioureas
Hiroshi Takeda, Takayuki Ishida, and Yoshiji TakemotoÃ
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501
(Received May 25, 2009; CL-090512; E-mail: takemoto@pharm.kyoto-u.ac.jp)
Me
N
Treatment of 1-(2-alkynyl)phenyl-3-aryl-2-methylisothio-
2
1
Cl
N
ureas with 5 mol % [Pd(ꢀ3-C3H5)Cl]2 in the presence of CuTC
(copper thiophenecarboxylate) and Cs2CO3 at 130 ꢀC provided
a wide range of 6-N-alkylated indolo[2,3-b]quinolines in good
yields.
3
4
N
5
Cl
N
Me
Br
N
N
6
H
cryptotackieine
perophoramidine
Cyclic amidines are important structural motifs that are fre-
quently involved in natural products and biologically active
molecules.1 Cryptotackieine and perophoramidine (Figure 1)
are representative indoloquinoline alkaloids.2 A series of indo-
lo[2,3-b]quinolines would be promising candidates as cytotoxic
DNA intercalators and topoisomerase II inhibitors.2
Figure 1. Natural products bearing indolo[2,3-b]quinolines.
R1
R1
R1
Pd
N
X
"Pd"
R2
N
R2
N
N
N
N
R2
Ph
Various synthetic methods have been developed to construct
these target molecules. Most of these methods rely on the nucleo-
philic addition of amines to nitriles, amides, or their equivalents
such as imidoyl chlorides, imidates, and thioimidates,3 as well as
the thermal cyclization of enyne-carbodiimides.4 Recently, cas-
cade radical annulations of benzotriazoles,2c,5 O-phenyl oxime
ethers,6 and alkynyl N-arylthioureas7 have been described as al-
ternative methods. In contrast, few transition metal catalyzed re-
actions have been reported for the synthesis of indoloquinolines.
Therefore, we investigated efficient synthetic methods for these
target molecules by using a Pd0-catalyzed amidination reaction.
Liebeskind pioneered the use of such amidinyl metal com-
plexes as 2A in the synthesis of protected aryl amidines from iso-
thiourea and arylboronic acids.8,9 Furthermore, we have already
reported the Pd-catalyzed cyanoamidation of unsaturated carba-
moyl cyanide to afford various oxindoles.10 Based on these re-
sults, we selected methyl sulfide as a leaving group (X) of iso-
thiourea 1 and explored the Pd-catalyzed reaction of 1 in the
presence of CuTC (Scheme 1). We report here that the Pd-cata-
lyzed intramolecular amidination of readily available alkynyl-
isothioureas 1 provides a direct route to 6-N-alkylindolo[2,3-
b]quinolines 3.11
We initially examined the Pd-catalyzed reaction of 1,2-di-
methylisothiourea 1a, which was readily prepared by the reac-
tion of thiourea with MeI, under various conditions (Table 1).
Although the reaction did not proceed without palladium cata-
lyst, treatment of 1a with [Pd(ꢀ3-C3H5)Cl]2 (5 mol %) and (2-
furyl)3P (40 mol %) in the presence of CuTC (1 equiv) and
Cs2CO3 (2 equiv) at 130 ꢀC provided the desired tetracyclic ad-
duct 3a in 43% yield, with no contamination by alkenyl sulfide
4 (Entry 1). After several optimization studies, we found that
the use of somewhat bulky bidentate phosphine ligands such
as dppb and dppf improved the chemical yield up to 74%
(Entries 2–6). In addition, the same reaction with a catalytic
Ph
Ph
X
Pd
X
2A
2B
1 (X = SMe)
R1
R1
X
or
N
N
R2
N
N
R2
Ph
3
4
Scheme 1. Transition-metal-catalyzed amidination.
Table 1. Survey of annulation conditionsa
Bu
Bu
[Pd(η3-C3H5)Cl]2
ligand, "Cu"
Me
Cs2CO3
N
N
N
xylene, 130 °C
Ph
Me
RS
N
3a
1a: R = Me, 1b: R = Bn
Entry
R
Ligand (equiv)
‘‘Cu’’ (equiv)
Yield/%b
1
2
3
4
5
6
7
8
9
10
Me (2-furyl)3P (0.4)
Me (p-tolyl)3P (0.4)
Me (o-tolyl)3P (0.4)
CuTC (1.0)
CuTC (1.1)
CuTC (1.1)
CuTC (1.1)
CuTC (1.1)
CuTC (1.1)
CuTC (0.3)
43
54
17
50
74
69
51
37
64
17
Me
Me
Me
Me
Me
Bn
BINAP (0.3)
dppb (0.3)
dppf (0.3)
dppf (0.3)
dppb (0.3)
dppb (0.3)
dppb (0.3)
.
CuBr SMe2 (1.5)
CuTC (1.1)
—
Bn
aAll reactions were carried out with 5 mol % of [Pd(ꢀ3-
C3H5)Cl]2 and 2 equiv of Cs2CO3. Isolated yield.
b
After having established optimal reaction conditions, we
next explored the scope and limitation of the substrates. As
shown in Table 2, a wide array of 1,2-dimethylisothioureas
1c–1j can be cyclized to the corresponding indoloquinolines
3c–3j in yields of 33 to 76%. Importantly, a variety of elec-
.
amount of CuTC or with 1.5 equiv of CuBr SMe2 resulted in
a lower yield (Entries 7 and 8). The use of benzylisothiourea
1b had only marginal effects on the reaction rate and yield
(Entries 9 and 10).
Copyright Ó 2009 The Chemical Society of Japan

Chemistry Letters Vol.38, No.8 (2009)
773
ly, nucleophilic attack of the aryl group12 to the PdII complex
and reductive elimination of the resulting palladium complex af-
ford the tetracyclic product 3.
In conclusion, we demonstrated that the Pd-catalyzed annu-
lation of 1,2-dialkylisothioureas proceeded efficently to give 6-
N-alkylindoloquinolines in good yields. This method supple-
ments the known pericyclic and electrocyclic routes to these
compounds.
Table 2. Scope and limitation of substrates
R1
R1
Y
[Pd(η3-C3H5)Cl]2
(5 mol %)
X
Z
CuTC (1.1 equiv)
Me
N
N
N
Cs2CO3, dppb
xylene, 130 °C
Ar
Me
MeS
N
1c-j
3c-j
Entry
1 (R1) Ar
Time/h
24
Product
Yield/%
67
This work was supported in part by a Grant-in-Aid for
Scientific Research (B) (Y.T.) and ‘‘Targeted Proteins Research
Program’’ from the Ministry of Education, Culture, Sports,
Science and Technology of Japan.
Me
3c
(X = Me
1
2
3
4
5
6
7
8
1c (Bu)
1d (Bu)
1e (Bu)
1f (Bu)
1g (Bu)
1h (Bu)
1i (Bu)
1j (Ph)
Y = Z = H)
References and Notes
1
OMe
NMe2
Cl
3d
(X = OMe
Y = Z = H)
19
3
59
50
76
33
45
76a
76
`
L. Verotta, T. Pilati, M. Tato, E. Elisabetsky, T. A. Amador, D. S. Nunes,
J. Nat. Prod. 1998, 61, 392; S. A. Morris, R. J. Andersen, Tetrahedron
1990, 46, 715; R. Miura, K. Matsui, K. Hirotsu, A. Shimada, M. Takatsu,
S. Otani, J. Chem. Soc., Chem. Commun. 1973, 703; S. von Johne, D.
3e
Groger, M. Hesse, Helv. Chim. Acta 1971, 54, 826.
¨
(X = NMe2
Y = Z = H)
2
a) M. H. M. Sharaf, P. L. Schiff, Jr., A. N. Tackie, C. H. Phoebe, Jr.,
G. E. Martin, J. Heterocycl. Chem. 1996, 33, 239. b) K. Cimanga,
T. De Bruyne, L. Pieters, M. Claeys, A. Vlietinck, Tetrahedron Lett.
´
1996, 37, 1703. c) W. Peczynska-Czoch, F. Pognan, Ł. Kaczmarek, J.
´
Boratynski, J. Med. Chem. 1994, 37, 3503. d) S. M. Verbitski, C. L.
3f
(X = Cl
Y = Z = H)
24
6.5
5
Mayne, R. A. Davis, G. P. Concepcion, C. M. Ireland, J. Org. Chem.
2002, 67, 7124.
3
4
Recent example: M.-P. Heck, S. P. Vincent, B. W. Murray, F. Bellamy,
C.-H. Wong, C. Mioskowski, J. Am. Chem. Soc. 2004, 126, 1971.
M. Schmittel, J.-P. Steffen, B. Engels, C. Lennartz, M. Hanrath, Angew.
Chem., Int. Ed. 1998, 37, 2371; M. Schmittel, J.-P. Steffen, D.
CN
3g
(X = CN
Y = Z = H)
´
Rodrıguez, B. Engelen, E. Neumann, M. E. Cinar, J. Org. Chem.
Me
2008, 73, 3005; C. Shi, Q. Zhang, K. K. Wang, J. Org. Chem. 1999,
64, 925; X. Lu, J. L. Petersen, K. K. Wang, J. Org. Chem. 2002, 67,
5412; T. H. M. Jonckers, S. van Miert, K. Cimanga, C. Bailly, P. Colson,
3h
(X = H
Y = Z = Me)
`
M.-C. De Pauw-Gillet, H. van den Heuvel, M. Claeys, F. Lemiere, E. L.
Me
Esmans, J. Rozenski, L. Quirijnen, L. Maes, R. Dommisse, G. L. F.
`
3ia (Z = OMe,
X = Y = H)
3ib (Y = OMe,
X = Z = H
Lemiere, A. Vlietinck, L. Pieters, J. Med. Chem. 2002, 45, 3497.
´
A. Marsili, Tetrahedron 1968, 24, 4981; Ł. Kaczmarek, W. Peczynska-
10
24
5
OMe
´
Czoch, J. Osiadacz, M. Mordarski, W. A. Sokalski, J. Boratynski, E.
´
Marcinkowska, H. Glazman-Kusnierczyk, C. Radzikowski, Bioorg.
Med. Chem. 1999, 7, 2457; A. R. Katritzky, T.-B. Huang, M. V.
Voronkov, P. J. Steel, J. Org. Chem. 2000, 65, 8069; J. Bergman, R.
Ph
3j
(X = Y = Z = H)
˚
Engqvist, C. Stalhandske, H. Wallberg, Tetrahedron 2003, 59, 1033;
P. Vera-Luque, R. Alajarin, J. Alvarez-Builla, J. J. Vaquero, Org. Lett.
2006, 8, 415.
aTotal yield (3ia:3ib = 58:42).
6
F. Portela-Cubillo, B. A. Surgenor, R. A. Aitken, J. C. Walton, J. Org.
Chem. 2008, 73, 8124; F. Portela-Cubillo, J. S. Scott, J. C. Walton,
J. Org. Chem. 2008, 73, 5558.
tron-rich aryl groups on the aryl ring (Ar) promoted this process.
Functional groups, such as ether, amine, chloride, and cyanide,
were tolerated (Entries 1–5). However, substrates bearing an
electron-withdrawing group tended to decrease the chemical
yields (Entry 5). Indeed, the reaction of isothiourea bearing a
3,5-bis(trifluoromethyl)phenyl group gave no cyclized adduct.
The N-arylisothioureas 1h and 1i with substituents in the meta
position similarly underwent annulation, and gave the desired
products in respective yields of 45 and 76% (Entries 6 and 7).
In the latter case, two regioisomers 3ia and 3ib were obtained
in a ratio of 58/42. With regard to the substituent (R1) on the
alkynyl group, both alkyl and phenyl groups were tolerated
under these conditions (Entry 8).
7
8
W. Du, D. P. Curran, Org. Lett. 2003, 5, 1765.
C. L. Kusturin, L. S. Liebeskind, W. L. Neumann, Org. Lett. 2002, 4,
983.
9
R. Hua, H. Takeda, S. Onozawa, Y. Abe, M. Tanaka, J. Am. Chem. Soc.
2001, 123, 2899; M. Toyofuku, S. Fujiwara, T. Shin-ike, H. Kuniyasu,
N. Kambe, J. Am. Chem. Soc. 2008, 130, 10504; M. Toyofuku, S.
Fujiwara, T. Shin-ike, H. Kuniyasu, N. Kambe, J. Am. Chem. Soc.
2005, 127, 9706.
10 Y. Kobayashi, H. Kamisaki, R. Yanada, Y. Takemoto, Org. Lett. 2006,
8, 2711; Y. Kobayashi, H. Kamisaki, H. Takeda, Y. Yasui, R. Yanada,
Y. Takemoto, Tetrahedron 2007, 63, 2978; Y. Yasui, H. Kamisaki, Y.
Takemoto, Org. Lett. 2008, 10, 3303.
11 Y.-L. Chen, H.-M. Hung, C.-M. Lu, K.-C. Li, C.-C. Tzeng, Bioorg. Med.
Chem. 2004, 12, 6539.
The reaction proceeds through oxidative addition of the
MeS–C bond to palladium(0),8,9 followed by ligand exchange
with CuTC, which promotes insertion to the internal alkyne, to
give the alkenylpalladium complex 2B (Scheme 1). Subsequent-
12 A. E. Shilov, G. B. Shul’pin, Chem. Rev. 1997, 97, 2879; D. Garcia-
Cuadrado, P. de Mendoza, A. A. C. Braga, F. Maseras, A. M.
Echavarren, J. Am. Chem. Soc. 2007, 129, 6880.
Published on the web (Advance View) June 27, 2009; doi:10.1246/cl.2009.772