Palladium-catalyzed stereoselective synthesis of 3-(aminomethylene)- oxindoles

Article abstract of DOI:10.1016/j.tetlet.2011.04.071

An efficient palladium-catalyzed protocol for the stereoselective synthesis of 3-(aminoarylmethylene)-oxindoles has been developed. In this approach, Ugi-4-component reaction adducts were used as starting materials for carbopalladative cyclization-Buchwal

Full text of DOI:10.1016/j.tetlet.2011.04.071

Tetrahedron Letters 52 (2011) 3329–3332
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Tetrahedron Letters
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Palladium-catalyzed stereoselective synthesis of 3-(aminomethylene)-oxindoles
Morteza Bararjanian a, Saeedeh Hosseinzadeh a, Saeed Balalaie a, , Hamid Reza Bijanzadeh b, Eckardt Wolf c
⇑
a Peptide Chemistry Research Center, K.N. Toosi University of Technology, PO Box 15875-4416, Tehran, Iran
b Department of Chemistry, Tarbiat Modares University, PO Box 141115-175, Tehran, Iran
c Tofigh Daru Res. & Eng. Co., 61st St. km 18 Karaj Highway, Tehran 37515-375, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 February 2011
Revised 4 April 2011
Accepted 18 April 2011
Available online 24 April 2011
An efficient palladium-catalyzed protocol for the stereoselective synthesis of 3-(aminoarylmethylene)-
oxindoles has been developed. In this approach, Ugi-4-component reaction adducts were used as starting
materials for carbopalladative cyclization–Buchwald reaction sequences.
Ó 2011 Published by Elsevier Ltd.
Dedicated to Professor Ali Seyyedi Isfahani
on the occasion of his 75th birthday.
Keywords:
Carbopalladative cyclization
Buchwald reaction
3-(Aminoarylmethylene)-oxindoles
Active acetylenic compounds
Stereoselective synthesis
The design of new sequencing MCRs (multi-component reac-
tions) with subsequent transformations, including, for example,
cyclization, and formation of new functional groups is a very useful
procedure for developing molecular architectures.1 Meanwhile, the
sequencing of MCRs is a promising synthetic strategy for generat-
ing collections of molecules by DOS (Diversity Oriented Synthesis).
This is an emerging field involving the synthesis of combinatorial
libraries of diverse small molecules for biological screening.2
Oxindoles are an important class of heterocycles which are of-
ten found in bioactive molecules as the key substructure.3 Substi-
tuted 3-methylene-oxindoles which contain a heteroatom in the
exocyclic alkene also play important roles within the class of func-
tionalized oxindoles, for example, (Z)-3-(aminomethylene)-oxin-
doles have been identified as protein kinase inhibitors,4 and
include examples such as BIBF 1120,5 GW8510,6 and GW491619,7
and the recently identified Aurora B inhibitor, hesperadin8 (Fig. 1).
Furthermore, 3-(aminomethylene)-oxindoles are versatile pre-
cursors for further synthetic manipulations and have been em-
ployed widely in total syntheses of natural products, and for the
preparation of novel nonnatural compounds.9 There are several ap-
proaches for the synthesis of 3-(aminomethylene)-oxindoles,
mates or sulfonamides;11 (c) reaction of 3-chloroalkylidene-oxin-
doles with amines;12 (d) sequential carbonylation of 2-alkynyl-
anilines in the presence of CuCl2;13 (e) cyclization of 2-alkynyl iso-
cyanates in the presence of FeCl3 followed by nucleophilic addition
under microwave irradiation.14
Although a number of methods are available for the synthesis of
these oxindoles, the reported methods have some drawbacks,
including lack of generality, limited functional group tolerance,
lengthy synthetic sequences, and harsh reaction conditions. The
need for the development of a stereoselective and diversity oriented
approach for the synthesis of these compounds is of interest and a
considerable challenge for organic chemists. Our previous research
to develop novel reactions15 combined with the biological activities
of various 3-(aminoarylmethylene)-oxindoles has prompted us to
develop sequential reactions to access these heterocycles.
A retrosynthetic analysis suggested the formation of an exocy-
clic double bond in 3-(aminoarylmethylene)-oxindoles via ring-
closure of N-substituted 2-alkynylamides I (resulting from the
Ugi-4-component reaction of an aldehyde 1, a 2-haloaniline 2, a
propiolic acid 3, and an isocyanide 4), through a carbopalladative
cyclization–Buchwald reaction16 using a Pd-catalyst (Scheme 1).
Onthebasisofourrecentdevelopmentsonpost-functionalization
ofmulti-componentreaction(MCR)sequences, wedesignedaproce-
dure for the efficient conversion of Ugi-4MCR intermediates I into 3-
(aminoarylmethylene)-oxindoles as shown in Scheme 2. Palladium/
phosphine-catalyzed cyclization of N-substituted-2-alkynylamides
I with secondary amines produces the 3-(aminoarylmethylene)-
including: (a) syn-aminopalladation of a,b-acetylenic amides using
phthalimide in the presence of palladium acetate and PhI(OAc)2;10
(b) cyclization of 2-alkynyl aryl isocyanates with amides, carba-
⇑
Corresponding author.
E-mail address: Balalaie@kntu.ac.ir (S. Balalaie).
0040-4039/$ - see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2011.04.071

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M. Bararjanian et al. / Tetrahedron Letters 52 (2011) 3329–3332
O
O
S
H
N
O
N
N
N
N
O
N
N
NH
O
S
NH
O
NH
O
NH
O
H
N
N
N
Et
S
MeO
N
H
O
O
N
H
N
H
N
H
O
BIBF 1120
GW8510
GW491619
hesperdin
Figure 1. Oxindole-based kinase inhibitors.
oxindoles via sequential carbopalladative cyclization–Buchwald
reactions.
(2 mmol, 2 equiv), tri(2-furyl)phosphine (0.1 mmol, 0.1 equiv),
Pd(OAc)2 (0.05 mmol, 0.05 equiv), and Cs2CO3 (2 mmol, 2 equiv)
in toluene (20 mL) under reflux for 12 h, yielded 80% of the desired
product (6a) (Table 1). Gratifyingly, we found that this transforma-
tion was general for compound I derived from a wide range of
benzaldehydes, isocyanides, and secondary amines providing an
easy access to highly substituted 3-(aminoarylmethylene)-2-oxin-
doles 6a-k with Z-configuration (Table 1).
The Ugi reaction has several advantages such as wide scope,
high variability (four diversity points), generates multifunctional
adducts, and allows the possibility to carry out subsequent trans-
formations. Several post-transformations on Ugi products have
been reported, such as cyclocondensation,17 radical cyclization,18
SNAr,19 SN2,20 and SN20 reactions21 and metathesis reactions.22
In all cases various cyclic scaffolds were obtained. The combina-
tion of rich and diverse palladium-catalyzed chemistry with the Ugi
reactionhasalsobeeninvestigated.23 Anumberofmedicinallyactive
heterocycles were synthesized using the Heck reaction, N-arylation,
C-arylation of a benzylic carbon, C–H functionalization, the Suzuki–
Miyaura reaction and Sonogashira coupling, on properly functional-
izedUgiadducts.24 In mostcases, theefficiencyofthese reactionsde-
pends on the type of functionality in the Ugi-products. In the present
approach, N-substituted 2-alkynylamides I were synthesized via the
four-component reaction of benzaldehydes 1, 2-iodoaniline (2),
phenylpropiolicacid(3)andisocyanides4.15a Thereactionofsecond-
ary amines with N-substituted-2-alkynylamides I catalyzed by
Pd(OAc)2 in the presence of Cs2CO3 led to the formation of 3-(amino-
arylmethylene)-oxindoles. The results are summarized in Table 1.
Optimization of the reaction conditions was carried out for the
synthesis of compound 6a as a model substrate. The Ugi-4MCR prod-
uct Ia from the reaction of benzaldehyde (1a), 2-iodoaniline (2), phe-
nylpropiolic acid (3) and cyclohexylisocyanide (4a) in MeOH, was
chosento screen thedomino carbopalladative cyclization–Buchwald
coupling reaction. Pd(OAc)2 as the catalyst precursor, several bases
and phosphine ligands were examined to establish standard reac-
tion conditions for the addition of morpholine. K2CO3, Cs2CO3 and
Et3N were used under identical conditions and the best results were
obtained using Cs2CO3. Whereas PPh3 as the ligand led to low yields,
the reaction with tri(2-furyl)phosphine and racemic-BINAP gave the
desired product in good yield. Tri(2-furyl)phosphine was chosen as
the preferred ligand due to it being more cost-effective.
The Z-configuration of the products was confirmed using 1H
NMR spectroscopy with a diagnostic signal for the Z-isomer ob-
served at d 5.56–5.64 (H-4 of the oxindole). This unusual high-field
shift is related to the aromatic ring current of the phenyl ring. For
an indication of the stereoselectivity of this reaction, the chemical
shifts of the H-4 proton were compared with those of the reported
analogues.14 NOE experiments on compound 6g further confirmed
the structure as the Z-isomer.
According to known palladium chemistry, the domino carbopal-
ladative cyclization–Buchwald reaction can be categorized as fol-
lows: (1) oxidative addition of haloarene I to Pd(0); (2) insertion
of palladium on the alkyne moiety (carbopalladation); (3) nucleo-
philic addition of the secondary amine; (4) reductive elimination to
afford the 3-(aminoarylmethylene)-oxindoles 6a–k with regenera-
tion of the Pd(0) species.
In conclusion, an efficient approach for the stereoselective syn-
thesis of (Z)-3-(aminoarylmethylene)-oxindoles has been devel-
oped via palladium-catalyzed Ugi-carbopalladative cyclization–
Buchwald reaction sequences. Overall these reactions accomplish
both intramolecular C–C bond formation and intermolecular C–N
bond formation across a carbon–carbon triple bond in a regioselec-
tive fashion. High bond forming efficiency (BFE), good yields, and
stereoselective syntheses of 3-(aminoarylmethylene)-oxindoles
via diversity oriented synthesis (DOS) have been established.
General procedure for the synthesis of 3-(aminoarylmethylene)-
oxindoles 6a–k: 2-Iodoaniline (2) (219 mg, 1 mmol), benzaldehyde
1 (1 mmol), and MeOH (5 mL) were stirred for 30 min. Then,
phenyl propiolic acid (3) (146 mg, 1 mmol) and, after 15 min, iso-
cyanide 4 (1 mmol) were added, and the mixture stirred at ambi-
ent temperature for 24 h. The progress of the reaction was
We were pleased to find that under the optimized conditions
reaction of N-[(cyclohexylcarbamoyl) (phenyl)methyl]-N-(2-iodo-
phenyl)-3-phenylpropionamide (Ia) (1 mmol), morpholine (5a)
R2
3
R4
R2
R2
HO
O
N
R5
X
X
C
N
R3
O
O
H
N
N
N
NH2
4
R3
H
2
R1
R3
N
O
H
R1
O
O
I
R1
1
Scheme 1. Retrosynthetic pathway for the synthesis of 3-(aminoarylmethylene)-oxindoles.

M. Bararjanian et al. / Tetrahedron Letters 52 (2011) 3329–3332
3331
3
R2
N
X
5 mol% Pd(OAc)2
n
HO
O
I
10 mol% P(2-furyl)3
I
MeOH
O
C
N R
O
H
N
rt , 24 h
2 eq Cs2CO3 , toluene, reflux, 12 h
NH
N
N
R
NH2
4
H
R1
R3
N
Ar
O
H
2
O
X
n
O
Ar
5
6 a-k
I
1
Scheme 2. Stereoselective synthesis of (Z)-3-(aminoarylmethylene)-oxindoles through sequential reactions.
Table 1
Synthesis of (Z)-3-(aminoarylmethylene)-oxindoles via Ugi-carbopalladative cyclization–Buchwald reaction sequences
Ph
H4
N
X
5 mol% Pd(OAc)2
I
NH2
n
O
H
10 mol% P(2-furyl)3
MeOH
C
N R
I
+
+
+
O
2 eq Cs2CO3, toluene, reflux, 12 h
Ar
H
rt , 24 h
N
HO
O
N
R
1
2
4
3
NH
Ar
6a-k
X
n
O
5
Product
Ar
R
X
n
Yielda (%)
6a
6b
6c
6d
6e
6f
6g
6h
6i
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-NC–C6H4
4-Me2N–C6H4
4-MeC6H4
Cyb
Cy
O
CH2
N–CH2CH2OH
N–Me
O
CH2
CH2
O
O
O
2
2
2
2
2
2
1
2
2
2
2
80
78
70
85
83
80
76
63
84
77
82
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Bn
Cy
Cy
Cy
6j
6k
4-MeOC6H4
O
a
Isolated yield.
Cy = cyclohexyl.
b
monitored by TLC (eluent: hexane/EtOAc, 5:1). Upon completion,
the mixture was diluted with saturated NaHCO3 solution (30 mL)
and extracted with EtOAc (3 ꢀ 20 mL). The combined organic
phase was dried over Na2SO4 and the solvent removed under re-
duced pressure. The crude Ugi adduct was added to a flask contain-
ing toluene (20 mL), Pd(OAc)2 (11 mg, 0.05 equiv), Cs2CO3 (652 mg,
2 mmol), tri(2-furyl)phosphine (23 mg, 0.1 equiv) and the second-
ary amine (2 mmol). The resulting mixture was heated at reflux for
12 h. After cooling, the mixture was washed with brine (2 ꢀ 30 mL)
and the organic phase collected. The organic layer was dried over
Na2SO4, filtered and concentrated in vacuo. Purification by column
chromatography on silica gel (hexane/EtOAc) gave products 6a–k
in 63–85% yield.
J = 7.8 Hz, HAr), 6.31 (s, 1H, CH), 6.53 (m, 1H, HAr), 6.64 (d, 1H,
J = 6.5 Hz, NH), 6.81 (m, 2H, HAr), 7.25–7.55 (m, 10H, HAr); 13C
NMR (125 MHz, CDCl3): d 24.5, 24.6, 25.5, 32.7, 32.8, 48.4, 52.8,
59.2, 67.6, 97.9, 109.8, 119.0, 120.5, 122.7, 126.6, 127.6, 127.8,
128.4, 129.5, 129.6, 130.3, 130.6, 131.2, 135.2, 135.6, 137.0,
161.6, 165.0, 167.8; mass: HR-MS (ESI) calcd for C33H36N3O3
[M+1]+ 522.27516, found 522.27512.
N-Cyclohexyl-2-{(Z)-2-oxo-3-[phenyl(piperidin-1-yl)methylene]
oxindolin-1-yl}-2-phenylacetamide (6b) 0.405 g, 78%; mp: 273 °C
(decomposed); IR (KBr, cmꢁ1): 3263, 2930, 1683, 1635, 1560; 1H
NMR (500 MHz, CDCl3): d 1.12–2.00 (m, 16H, Hcyclohexyl and HPiper-
idyl), 3.45–3.64 (m, 4H, 2CH2, CH2N), 3.86–3.92 (m, 1H, Hcyclohexyl),
5.63 (d, 1H, J = 7.7 Hz, H4, HAr), 6.33 (s, 1H, CH), 6.53 (t, 1H,
J = 7.5 Hz, HAr), 6.78 (d, 1H, J = 7.5 Hz, HAr), 6.82 (t, 1H, J = 7.7 Hz,
N-Cyclohexyl-2-{(Z)-3-[morpholino(phenyl)methylene]-oxin-
dolin-1-yl}-2-phenylacetamide (6a) 0.416 g, 80%; mp: 206 °C
(decomposed); IR (KBr, cmꢁ1): 3277, 2934, 1687, 1637, 1555; 1H
NMR (500 MHz, CDCl3): d 1.12–1.93 (m, 10H, Hcyclohexyl), 3.60 (br
s, 4H, CH2O), 3.86–3.90 (m, 5H, CH2N and Hcyclohexyl), 5.63 (d, 1H,
H
Ar), 6.88 (br s, 1H, NH), 7.23–7.60 (m, 10H, HAr); 13C NMR
(125 MHz, CDCl3): d 23.8, 24.5, 24.6, 25.6, 27.4, 32.7, 48.3, 53.1,
59.3, 97.1, 109.5, 118.7, 120.4, 122.1, 127.0, 127.4, 127.7, 128.3,
129.2, 129.3, 130.2, 130.5, 131.0, 135.9, 136.0, 136.6, 162.8,

3332
M. Bararjanian et al. / Tetrahedron Letters 52 (2011) 3329–3332
165.0, 168.1; mass: HR-MS (ESI) calcd for C34H38N3O2 [M+1]+
520.29589, found 520.29585.
9. Trost, B. M.; Brennan, M. K. Synthesis 2009, 3003–3025.
10. Tang, S.; Peng, P.; Pi, S. F.; Liang, Y.; Wang, N.-X.; Li, J. H. Org. Lett. 2008, 10,
1179–1182.
11. Miura, T.; Toyoshima, T.; Takahashi, Y.; Murakami, M. Org. Lett. 2009, 11, 2141–
2143.
12. (a) Beccalli, E. M.; Marchesini, A.; Pilati, T. Tetrahedron 1994, 50, 12697–12712;
(b) Beccalli, E. M.; Marchesini, A. Tetrahedron 1995, 51, 2353–2362.
13. Tang, S.; Yu, Q. F.; Peng, P.; Li, J. H.; Zhong, P.; Tang, R. Y. Org. Lett. 2007, 9,
3413–3416.
14. Cantagrel, G.; de Carné-Carnavalet, B.; Meyer, C.; Cossy, J. Org. Lett. 2009, 11,
4262–4265.
15. (a) Bararjanian, M.; Balalaie, S.; Rominger, F.; Movassagh, B.; Bijanzadeh, H. R. J.
Org. Chem. 2010, 75, 2806–2812; (b) Bararjanian, M.; Balalaie, S.; Movassagh,
B.; Bijanzadeh, H. R. Tetrahedron Lett. 2010, 51, 3277–3279.
Acknowledgments
S.B.andM.B.gratefullyacknowledgetheAlexandervonHumboldt
foundation for research fellowships. We are grateful to Professor R.
Gleiterforhelpfuldiscussions.WeexpressourgratitudetoMr.M.Jali-
levand, managing director of Kimia Exir Company for donation of
chemicals and financial support.
16. (a) D’Souza, D. M.; Müller, T. J. J. Chem. Soc. Rev. 2007, 36, 1095–1108; (b)
D’Souza, D. M.; Muschelknautz, C.; Rominger, F.; Müller, T. J. J. Org. Lett. 2010,
12, 3364–3367; (c) Schönhaber, J.; Frank, W.; Müller, T. J. J. Org. Lett. 2010, 12,
4122–4125.
17. (a) Nixey, T.; Tempest, P.; Hulme, C. Tetrahedron Lett. 2002, 43, 1637–1639; (b)
Marcaccini, S.; Pepino, R.; Pozo, M. C.; Basurto, S.; Garcia-Valverde, M.; Torroba,
T. Tetrahedron Lett. 2004, 45, 3999–4001; (c) Corres, N.; Delgado, J. J.; Garcia-
Valverde, M.; Marcaccini, S.; Rodriguez, T.; Rojo, J.; Torroba, T. Tetrahedron
2008, 64, 2225–2232.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.04.071.
References and notes
18. (a) El Kaim, L.; Grimaud, L.; Miranda, L. D.; Vieu, E. Tetrahedron Lett. 2006, 47,
8259–8261; (b) El Kaim, L.; Grimaud, L.; Vieu, E. Org. Lett. 2007, 9, 4171–4173.
19. (a) Cristau, P.; Vors, J. P.; Zhu, J. Org. Lett. 2001, 3, 4079–4082; (b) Tempest, P.;
Ma, V.; Kelly, M. G.; Jones, W.; Hulme, C. Tetrahedron Lett. 2001, 42, 4963–4968;
(c) Cristau, P.; Vors, J. P.; Zhu, J. Tetrahedron 2003, 59, 7859–7870; (d) Spatz, J.
H.; Umkehrer, M.; Kalinski, C.; Ross, G.; Burdack, C.; Kolb, J.; Bach, T.
Tetrahedron Lett. 2007, 48, 8060–8064.
20. (a) Ugi, I.; Schmid, T. J. Prakt. Chem. 1997, 339, 652–655; (b) Umkehrer, M.;
Kolb, J.; Burdack, C.; Ross, G.; Hiller, W. Tetrahedron Lett. 2004, 45, 6421–6424;
(c) Neo, A. G.; Delgado, J.; Marcaccini, C. S.; Marcos, C. F. Tetrahedron Lett. 2005,
46, 23–26; (d) Golebiowski, A.; Klopfenstein, S. R.; Shao, X.; Chen, J. J.; Colson,
A. O.; Grieb, A. L.; Russell, A. F. Org. Lett. 2000, 2, 2615–2617; (e) de Greef, M.;
Abeln, S.; Belkasmi, K.; Dömling, A.; Orru, R. V. A.; Wessjohann, L. A. Synthesis
2006, 3997–4004; (f) Xing, X.; Wu, J.; Feng, G.; Dai, W. M. Tetrahedron 2006, 62,
6774–6781; (g) Banfi, L.; Riva, R.; Basso, A. Synlett 2010, 23–41.
21. Banfi, L.; Basso, A.; Cerulli, V.; Guanti, G.; Riva, R. J. Org. Chem. 2008, 73, 1608–
1611.
22. Dietrich, S. A.; Banfi, L.; Basso, A.; Damonte, G.; Guanti, G.; Riva, R. Org. Biomol.
Chem. 2005, 3, 97–106.
23. (a) Tsuji, J. Palladium Reagents and Catalysts; Wiley-VCH: Chichester, 2004;
(b)Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich, F., Eds.;
Wiley-VCH: Weinheim, 2004.
24. (a) Erb, W.; Neuville, L.; Zhu, J. J. Org. Chem. 2009, 74, 3109–3115. and
references cited therein; (b) Bonnaterre, F.; Bois-Choussy, M.; Zhu, J. Org. Lett.
2006, 8, 4351–4354; (c) Salcedo, A.; Neuville, L.; Zhu, J. J. Org. Chem. 2008, 73,
3600–3603; (d) Bonnaterre, F.; Bois-Choussy, M.; Zhu, J. Beilstein J. Org. Chem.
2008, 1–11; (e) Kalinski, C.; Umkehrer, M.; Ross, G.; Kolb, J.; Burdack, C.;
Hillerb, W. Tetrahedron Lett. 2006, 47, 3423–3426; (f) Kalinski, C.; Umkehrer,
M.; Schmidt, J.; Ross, G.; Kolb, J.; Burdack, C.; Hillerb, W.; Hoffmann, S. D.
Tetrahedron Lett. 2006, 47, 4683–4686.
1. (a) Dömling, A. In Multicomponent Reactions; Zhu, J., Bienaymé, H., Eds.; Wiley-
VCH: Weinheim, 2005; pp 76–95; (b) Tietze, L. F. Chem. Rev. 1996, 96, 115–136;
(c) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in Organic Synthesis;
Wiley-VCH: Weinheim, 2006. pp 542-565; (d) Tietze, L. F. In Stimulating
Concepts in Chemistry; Shibasaki, M., Stoddart, J. F., Eds.; Wiley-VCH: Weinheim,
2000; pp 39–64; (e) Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168;
(g) Dömling, A. Chem. Rev. 2006, 106, 17–89.
2. (a) Isambert, N.; Lavilla, R. Chem. Eur. J. 2008, 14, 8444–8454; (b) Arndtsen, B. A.
Chem. Eur. J. 2009, 15, 302–313; (c) Sunderhaus, J. D.; Martin, S. F. Chem. Eur. J.
2009, 15, 1300–1308.
3. (a) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209–2218; (b) Galliford, C.
V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748–8758.
4. (a) Treu, M.; Guertler, U.; Karner, T.; Kraemer, O.; Quant, J. J.; Zahn, S. K. WO
200815 2013 A1, Chem. Abstr. 2009, 150, 55987y.; (b) Treu, M.; Mantoulidis, A.;
Tontsch-Grunt, U. WO2007122219 A1, Chem. Abstr. 2007, 147, 502230v.; (c)
Heckel, A.; Roth, G. R.; Joerg, K.; Hoerer, S.; Uphues, I. US20050203104 A1,
Chem. Abstr. 2005, 143, 306172f.; (d) Burgdorf, L. T.; Bruge, D.; Greiner, H.;
Kordowicz, M.; Sirrenberg, C.; Zenke, F. (Merck Patent) WO2006131186 A1,
Chem. Abstr. 2006, 146, 62590j.
5. (a) Hilberg, F.; Roth, G. J.; Krssak, M.; Kautschitsch, S.; Sommergruber, W.;
Grunt, U. T.; Chesa, P. G.; Bader, G.; Zoephel, A.; Quant, J.; Heckel, A.; Rettig, W.
R. Cancer Res. 2008, 68, 4774–4782; (b) Roth, G. J.; Heckel, A.; Colbatzky, F.;
Handschuh, S.; Kley, J.; Lehmann-Lintz, T.; Lotz, R.; Tontsch-Grunt, U.; Walter,
R.; Hilberg, F. J. Med. Chem. 2009, 52, 4466–4480.
6. Johnson, K.; Liu, L.; Majdzadeh, N.; Chavez, C.; Chin, P. C.; Morrison, B.; Wang,
L.; Park, J.; Chugh, P.; Chen, H. -M.; D’Mello, S. R. J. Neurochem. 2005, 93, 538.
7. Eberwein, D. J.; Harrington, L.; Griffin, R.; Tadepalli, S.; Knick, V.; Phillips, K.;
Dickerson, S.; Davies, S. Proc. Am. Assoc. Cancer Res. 2002, 43. abstract 1611.
8. Hauf, S.; Cole, R. W.; LaTerra, S.; Zimmer, C.; Schnapp, G.; Walter, R.; Heckel, A.;
van Meel, J.; Rieder, C. L.; Peters, J. M. J. Cell Biol. 2003, 161, 281.