Rapid and Efficient Synthesis of 1H-Indol-2-yl-1H-quinolin-2-ones

Article abstract of DOI:10.1021/ol035541i

(Equation Presented) A concise and efficient synthesis of the novel indol-2-yl-1H-quinolin-2-one ring system found in the potent and selective KDR kinase inhibitors 1-3 is presented.

Full text of DOI:10.1021/ol035541i

ORGANIC
LETTERS
2003
Vol. 5, No. 21
3975-3978
Rapid and Efficient Synthesis of
1H-Indol-2-yl-1H-quinolin-2-ones
Jeffrey T. Kuethe,* Audrey Wong, and Ian W. Davies
Department of Process Research, Merck & Co., Inc., P.O. Box 2000,
Rahway, New Jersey 07065
jeffrey_kuethe@merck.com
Received August 14, 2003
ABSTRACT
A concise and efficient synthesis of the novel indol-2-yl-1H-quinolin-2-one ring system found in the potent and selective KDR kinase inhibitors
1−3 is presented.
Tyrosine kinases are a class of enzymes that are believed to
play a critical role in the signal transduction of a number of
cellular functions and have contributed to a wide range of
diseases.1 The kinase insert domain receptor (KDR) is a
tyrosine kinase that has a high affinity for vascular endo-
thelial growth factor (VEGF) and is thought to be a primary
mediator of tumor-induced angiogenesis.2 Inhibition of the
KDR receptor may be useful for the prevention and treatment
of tumor-induced angiogenesis. Recently, a number of potent
and selective KDR inhibitors such as 1-3 have been
Conventional approaches to 2-aryl indoles typically rely
upon cross coupling of 2-indolyl halides, boronic acids, or
identified for the potential use in a range of cancer
indications.3-5 In this letter, we describe a rapid and efficient
stannanes and silanes.6 Although effective methods are
synthesis of the 1H-indolyl-2-yl-1H-quinolin-2-one ring
available for the preparation of 2-indolyl boronic acids and
system, the key pharmacophore present in compounds 1-3.
silanes,7 the major limitation with most of these approaches
are the additional steps needed for the preparation of the
coupling partners to enter the palladium-catalyzed reaction.
While a number of other classical methods (e.g., Fisher,
Madelung, Bischler, Reissert, Nenitzescu, and Leimgruber-
Batcho)8 have been successfully employed for the synthesis
(1) (a) Carmeliet, P.; Jain, R. K. Nature 2000, 407, 249. (b) Folkman, J.
Nature Med. 1995, 1, 27. (c) Zetter, B. R. Annu. ReV. Med. 1998, 49, 407.
(d) Folkman, J. N. Engl. J. Med. 1995, 333, 1757. (e) Traxler, P. Expert
Opin. Ther. Targets 2003, 7, 215 and references therein.
(2) (a) Veikkola, T.; Karkkainen, M.; Claesson-Welsh, L.; Alitalo, K.
Cancer Res. 2000, 60, 203. (b) Thomas, K. A. J. Biol. Chem. 1996, 271,
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(3) Fraley, M. E.; Antanavage, J.; Arrington, K. L.; Ciecko, P. A.;
Coll, K. E.; Gribbs, J. B.; Hambaugh, S. R.; Hartman, G. D.; Heimbrook,
D. C.; Hoffman, W. F.; Hungate, R. W.; Kohl, N. E.; Mao, X.; McFall, R.
C.; Rands, E.; Rickert, K.; Sepp-Lorenzino, L.; Shipman, J. M.; Tebben,
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American Chemical Society, Boston, MA, Sept 2002; Abstract MEDI-
221.
(4) (a) DeFeo-Jones, D.; Helmbrook, D. C.; Jones, R. E. US Patent
US2002/0041880 A1, 2000. (b) Fraley, M. E.; Arrington, K. L.; Bilodeau,
M. T.; Hartman, G. A.; Hoffman, W. F.; Kim, Y.; Hungate, R. W. US
Patent 6,306,874 B1, 2001.
(5) Fraley, M. E.; Hoffman, W. F.; Arrington, K. L.; Hungate, R. W.;
Hartman, G. D.; McFall, R. C.; Coll, K. E.; Richert, K.; Thomas, K. A.;
McGaughey, G. B. Curr. Med. Chem. 2003, in press.
10.1021/ol035541i CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/25/2003

of 2-subsitituted indoles, each has their limitations due to
either construction of the starting materials or harsh reaction
conditions, which may interfere with other sensitive func-
tionalities often located within the target molecule. Therefore,
mild synthetic methods that provide rapid assembly of the
indole ring and tolerate a wide range of functional groups
continue to offer significant advantages. Reactions leading
to increasing molecular complexity are important synthetic
tools, and it was envisioned that the reductive cyclization9
of a suitably substituted ortho-nitrostyrene would be an
attractive method for the construction of the indol-2-yl-1H-
quinolin-2-ones.
Scheme 1. Synthesis of KDR Kinase Inhibitor 1
Our first goal was the development of an efficient synthesis
of the ortho-nitrostyrene, and our approach was inspired by
the unique versatility of nitrobenzenes due to their ability to
serve as both nucleophilic and electrophilic partners.10
Addition of trimethylsilylmethylmagnesium chloride to a
solution of 911 in THF at -15 °C followed by oxidation of
the resulting nitronate intermediate with DDQ12 gave addition
compound 10 in 81% yield (Scheme 1). Alternatively, the
oxidation could be carried out with p-chloranil and gave 10
in 79% yield. Oxidation with aqueous iodine13 greatly
simplified the workup and gave 10 in 83% yield. Treatment
of a mixture of 10 and aldehyde 6a with catalytic TBAF
furnished the desired alcohol 11 in 87% isolated yield.14
However, it was more convenient to use 11 without purifica-
tion and convert it to styrene 12 by reaction with TFAA in
isopropyl acetate. Upon elimination with DBU, the trans-
nitro styrene 12 was obtained in 81% isolated yield by direct
crystallization from the reaction mixture.
With the key nitrostyrene in hand, the reductive cycliza-
tion of 12 was verified by the classic Cadogan/Sundberg
conditions using refluxing P(OEt)3 to give indole 13 in
76% yield.15 Alternatively, palladium-catalyzed reductive
cyclization of 12 using carbon monoxide as the terminal
reductant, i.e., the So¨derberg conditions [6 mol % Pd(OAc)2,
24 mol % PPh3,CO (6 atm), 70 °C] gave 13 in 94% isolated
yield.16 The quinolinone functionality was unmasked by
hydrolysis of chloroquinoline 13 in a 1:1 mixture of refluxing
AcOH/H2O5 and gave 1, which crystallized from the reaction
mixture in analytically pure form in 91% yield.
While optimizing the reaction of 10 with aldehyde 6a, we
discovered an interesting side reaction (Scheme 2). The
expected alcohol 11 was the primary reaction product (85%);
however, compound 14 was identified as the major byproduct
(10%) together with a small quantity of protiodesilylation
byproduct 1514 (3%). Presumably, 14 arises by addition of
the carbanion to the 4-position of 6a in Michael-type fashion
giving intermediate 16. Protonation of 16 then leads to 14.
Interestingly, upon aging of 14 for >3 h in either CDCl3 or
CD2Cl2, compound 14 decomposes to give a mixture of
aldehyde 6a, peroxide 17, aldehyde 18, and alcohol 19. We
speculate that retroaddition of 14 would give the nitro-
stabilized anion (pKa ) 25).17 Subsequent reaction with
molecular oxygen occurs to give 17. Compounds 18 and 19
most likely are derived from the known decomposition
pathways of 17.18
(6) (a) Johnson, C. N.; Stemp, G.; Anand, N.; Stephen, S. C.; Gallagher,
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references therein.
The synthesis of tertiary amine analogues 2 and 3 began
with ethers 20a19 and 20b (Scheme 3). Addition of trimeth-
(11) Horstmann, H.; Andrews, P.; Goennert, R. Eur. J. Med. Chem. Chim.
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(12) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Todesco, P. E. J. Org. Chem.
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(13) Oxidation of nitronates with iodine has previously been reported to
occur in low yield (∼20%). RajanBabu, T. V.; Reddy, G. S.; Fukunaga, T.
J. Am. Chem. Soc. 1985, 107, 5473.
(14) Bartoli, G.; Bosco, M.; Caretti, D.; Dalpozzo, R.; Todesco, R. E. J.
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3976
Org. Lett., Vol. 5, No. 21, 2003

of the quinoline moiety, the electron-rich 2-methoxy-3-
quinoline carboxaldehyde 6b20 was used. Treatment of a 1:1
mixture of crude 21a and 6b with catalytic TBAF furnished
alcohol 22a in 84% yield. In similar fashion, alcohol 22b
was formed in 96% yield. There was no evidence of the
formation of 1,4-dihydroquinoline products of type 14.
Conversion of crude 22a and 22b to styrenes 23a and 23b,
respectively, was effected by reaction with TFAA followed
by elimination of the trifluoroacetate with DBU at 60 °C,
which afforded nitrostyrenes 23a (65%) and 23b (74%).
There was no detectable amount of the corresponding cis-
styrene in the crude reaction mixture. Reductive cyclization
of 23a in refluxing P(OEt)3 gave indole 24a in 63% yield.
On the other hand, catalytic reductive cyclization with 6 mol
% Pd(OAc)2 and 24 mol % PPh3 in an atmosphere of CO
(60 psi) at 70 °C gave 24a in 88% yield. Reductive
cyclization of 23b gave indole 24b in 57% yield for the
Sundberg conditions and 92% yield for the So¨derberg
catalytic conditions. Deprotection of 24a,b was accomplished
with HCl and afforded 2 and 3, respectively, in near
quantitative yield.
Scheme 2. Oxidative Decomposition Pathway for 14
The pyridone analogues 27 and 28 were accessed in a
similar manner by starting with silyl compound 21c14 and
21
aldehydes 25 and 26
(Figure 1). Catalytic reductive
ylsilylmethylmagnesium chloride to a THF solution of either
20a or 20b at -15 °C followed by oxidation with aqueous
iodine solution gave silyl compounds 21a and 21b in 84 and
81% yields, respectively. To eliminate any unwanted side
reactions between the anion of 21a or 21b and the 4-position
Scheme 3. Synthesis of KDR Kinase Inhibitors 2 and 3
Figure 1. Preparation of pyridone derivatives 27 and 28.
cyclization using Pd(OAc)2/PPh3/CO of these isomeric
styrenes gave the corresponding indoles, which were hydro-
lyzed in a one-pot procedure by the direct addition of aqueous
HCl to provide pyridones 27 (83%) and 28 (82%).
In conclusion, we have demonstrated an efficient and rapid
means of constructing highly functionalized o-nitrostyrenes
from 4-nitrophenol in four synthetic steps with only one
isolation. Catalytic reductive cyclization with Pd(OAc)2/PPh3/
CO provides the desired 1H-indolyl-2-yl-quinolines in excel-
lent yield. The desired quinone functionality of the potent
KDR kinase inhibitor 1-3 was unmasked from either the
chloroquinoline or methoxyquinoline by simple hydrolysis.
The overall sequence as described does not require the use
(19) Chabrien, P.; Najor, H.; Giudicelli, R. Bull. Soc. Chim. Fr. 1955,
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Org. Lett., Vol. 5, No. 21, 2003
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of chromatography. We are currently exploring alternative
routes to the novel 1H-indolyl-2-yl-1H-quinolin-2-one ring
system.
Supporting Information Available: Experimental details
and characterization data of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank Dr. Peter G. Dormer for
valuable NMR assistance and Dr. Jacqueline Smitrovich, for
helpful discussion.
OL035541I
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