Efficient syntheses of KDR kinase inhibitors using a Pd-catalyzed tandem C-N/suzuki coupling as the key step

Article abstract of DOI:10.1021/jo062228w

(Chemical Equation Presented) A family of four potent KDR kinase inhibitors containing an indol-2-yl quinolin-2-one structure was utilizing a Pd-catalyzed tandem C-N and C-C coupling sequence.

Full text of DOI:10.1021/jo062228w

Efficient Syntheses of KDR Kinase Inhibitors Using a Pd-Catalyzed
Tandem C-N/Suzuki Coupling as the Key Step
Yuan-Qing Fang, Robert Karisch, and Mark Lautens*
DaVenport Chemistry Laboratories, Department of Chemistry, UniVersity of Toronto, 80 St. George Street,
Toronto, Ontario M5S 3H6, Canada
mlautens@chem.utoronto.ca
ReceiVed October 26, 2006
A family of four potent KDR kinase inhibitors containing an indol-2-yl quinolin-2-one structure was
utilizing a Pd-catalyzed tandem C-N and C-C coupling sequence.
Introduction
Protein tyrosine kinases are an important family of enzymes
that catalyze phosphorylation of the OH group on selected
tryrosine residues using ATP. These enzymes are involved in
many important biological processes such as cellular signaling
pathways, regulation of key cell function, proliferation, dif-
ferentiation, anti-apoptotic signaling, and neutrile growth.1
Dysregulation of enzymes under pathological settings are
responsible for many diseases such as cancer, tumor growth,
pathological angiogenesis, and diabetes.2 KDR (kinase insert
domain-containing receptor) is one of the human tyrosine
kinases that has a high affinity for vascular endothelial growth
factor (VEGF) and is believed to be a primary mediator of
tumor-induced angiogenesis.3 Therefore, compounds which
inhibit or regulate the KDR kinase are of great interest as
potential therapeutic agents.
FIGURE 1. Indole-containing KRD kinase inhibitors.
quinolin-2-one structure (Figure 1).7 The inhibitors disclosed
by Merck differ in the substitution at the 5-position of the indole
ring (Figure 2). Compounds 2-4 have an O-linker between the
indole and the side chain, while compound 1 has a methylene-
linked piperazine moiety.
Most small molecule inhibitors bind to the active side of
tyrosine kinases via two key hydrogen bonds and other
secondary interactions by mimicking the adenine moiety of the
natural ligand ATP.4 Indoles5 are widely found in medicinal
agents and are considered “privileged scaffolds”. SUGEN (now
part of Pfizer) found an indolin-2-one as a pharmacophore for
potent KDR kinase inhibitors,6 and Merck recently reported a
class of potent KDR kinase inhibitors containing the indol-2-yl
FIGURE 2. Merck’s family of KDR kinase inhibitors.
(1) Krause, D. S.; Van Ettern, R. A. N. Engl. J. Med. 2005, 353, 172.
(2) (a) Zetter, B. R. Annu. ReV. Med. 1998, 49, 407. (b) Traxler, P. Expert
Opin. Ther. Targets 2003, 7, 215. (c) Glade-Bender, J.; Kandel, J. J.;
Yamashiro, D. J. Expert Opin. Biol. Ther. 2003, 3, 263.
(3) (a) Yancopoulos, G. D.; Davis, S.; Gale, N. W.; Rudge, J. S.;
Wiegand, S. J.; Holash, J. Nature 2000, 407, 242. (b) Carmeliet, P.; Jain,
R. K. Nature 2000, 407, 249.
Compound 1 has been advanced to clinical development for
cancer therapy; therefore, large quantities of the drug candidate
are required via chemical synthesis.7 Many different literature
(4) Morin, M. J. Oncogene 2000, 19, 6574.
(6) (a) Sun, L.; Tran, N.; Liang, C.; Tang, F.; Rice, A.; Schreck, R.;
Waltz, K.; Shawver, L. K.; McMahon, G.; Tang, C. J. Med. Chem. 1999,
42, 5120. (b) Shaheen, R. M.; Davis, D. W.; Liu, W.; Zebrowski, B. K.;
Wilson, M. R.; Bucana, C. D.; McConkey, D. J.; McMahon, G.; Ellis, L.
M. Cancer Res. 1999, 59, 5412.
(5) (a) Sundberg, R. J., Ed. Indoles; Academic Press: San Diego, 1996.
(b) Gribble, G. W. Perkin 1 2000, 1045. (c) Cacchi, S.; Fabrizi, G. Chem.
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10.1021/jo062228w CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/25/2007
J. Org. Chem. 2007, 72, 1341-1346
1341

Fang et al.
SCHEME 1. Merck’s Process Routes toward KDR Inhibitor 1
SCHEME 2. Novel Indole Synthesis via a Pd-Catalyzed Tandem C-N/Suzuki Coupling
SCHEME 3. Key Retrosynthetic Step for the Core of
Merck’s KDR Inhibitors
methods (Scheme 1) have been used for the synthesis of 1,
including: (1) a Fisher indole reaction from hydrazone 5, (2)
reductive condensation of nitroketone 6, (3) nitrene C-H
insertion cyclization via reduction of 7, (4) Pd-catalyzed
cyclization of imime 8, and (5) Suzuki coupling of boronic acid
9 and aryl bromide 10. Among these methods, reductive
cyclization from either 6 or 7 have been the most efficient routes
from readily available starting materials. The convergent Suzuki
coupling between 9 and 10 also proved to be successful for the
preparation of kilogram quantities of product 1. The overall
yields range from 50 to 60% over six to seven steps.
Recently, we have developed a new general and efficient route
to indoles via a Pd- or Cu-catalyzed tandem cross-coupling using
a gem-dihalovinylaniline.8 In particular, Pd-catalyzed tandem
C-N and Suzuki coupling allows for the formation of a large
range of 2-substituted indoles from a gem-dihalovinylaniline
and commercially available boronic acids (Scheme 2).8a Here,
we report the syntheses of KDR inhibitors 1-4 to highlight
our methodology and its generality and efficiency.
is known to readily hydrolyze upon treatment with strong acid
to give the indole-quinolinone core.7a We have developed
efficient protocols for the synthesis of 12 from corresponding
nitrobenzaldehyde 14. Boronic acid 13 could be obtained from
directed ortholithiation of 2-methoxyquinoline (15). A model
reaction between substrate 12 and boronic acid 13 using a
catalytic amount of Pd(OAc)2 (3 mol %) and S-Phos (6 mol
%) in the presence of K3PO4‚H2O in toluene at 100 °C gave
the desired product 11 in 75% yield.
Results and Discussion
The retrosynthetic plan is straightforward for the construction
of the indole-quinolinone core (Scheme 3). A tandem coupling
gem-dibromovinylaniline 12 and 2-methoxyquinolin-3-ylboronic
acid (13) would give the indole-methoxyquinoline 11, which
Initially, a one-pot, two-step procedure through gem-dibro-
moolefination9 followed by Sn(II) reduction was used for the
synthesis of gem-dibromovinyl substrate 18 from nitrobenzal-
dehyde 16 in good yield (Scheme 4).8a However, considering
SnCl2‚H2O as a reductant generates large amounts of waste (six
electrons requires a minimum of 3 equiv of this reagent), we
sought a better method for reduction such as catalytic hydro-
genation. The presence of an alkene and two halogens poses a
(7) (a) Kuethe, J. T.; Wong, A.; Qu, C.; Smitrovich, J.; Davies, I. W.;
Hughes, D. L. J. Org. Chem. 2005, 70, 2555. (b) Payack, J. F.; Vazquez,
E.; Matty, L.; Kress, M. H.; McNamara, J. J. Org. Chem. 2005, 70, 175.
(c) Wong, A.; Kuethe, J. T.; Davies, I. W.; Hughes, D. L. J. Org. Chem.
2004, 69, 7761. (d) Davies, I. W.; Smitrovich, J. H.; Qu, C. (Merck & Co.,
Inc., U.S.A.) PCT Int. Appl. WO 2005000804, 2005. (e) Karki, S. B.;
Deshpande, S. R.; Thompson, K. C.; Payne, A. H.; Gandek, T. P. (Merck
& Co. Inc. U.S.A.). PCT Int. Appl. WO 2004087651, 2004. (f) Kuethe, J.
T.; Wong, A.; Davies, I. W. Org. Lett. 2003, 5, 3975. (g) Fraley, M. E.;
Arrington, K. L.; Buser, C. A.; Ciecko, P. A.; Coll, K. E.; Fernandes, C.;
Hartman, G. D.; Hoffman, W. F.; Lynch, J. J.; McFall, R. C.; Rickert, K.;
Singh, R.; Smith, S.; Thomas, K. A.; Wong, B. K. Bioorg. Med. Chem.
Lett. 2004, 14, 351.
(8) (a) Fang, Y.-Q.; Lautens, M. Org. Lett. 2005, 7, 3549. (b) Yuen, J.;
Fang, Y.-Q.; Lautens, M. Org. Lett. 2006, 8, 653. (c) Fayol, A.; Fang, Y.-
Q.; Lautens, M. Org. Lett. 2006, 8, 4203. (d) Lautens, M.; Alberico, D.;
Bressy, C.; Fang, Y-Q.; Mariampillai, B.; Wilhelm, T. Pure. Appl. Chem.
2006, 78, 351.
(9) (a) Ramiraz, F.; Desal, N. B.; McKelvie, N. J. Am. Chem. Soc. 1962,
84, 1745. (b) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769.
1342 J. Org. Chem., Vol. 72, No. 4, 2007

Syntheses of KDR Kinase Inhibitors
SCHEME 4
SCHEME 5
SCHEME 6. Synthesis of KDR Kinase Inhibitor 1
significant challenge for the selective reduction. While most
traditional heterogeneous catalysts such as Pd/C were inefficient,
1% vanadium-doped platinum on carbon (abbreviated as 1%
Pd-C[V], supplied by Degussa) proved to be extremely
selective.10 A two-step procedure using Ramirez olefination9a
with CBr4/PPh3 led to efficient formation of the gem-dibro-
moolefin 17, which upon catalytic hydrogenation using 1%
Pt-C[V] catalyst gave the aniline substrate 18 in quantitative
yield.
The synthesis of the quinoline boronic acid 13 started from
commercially available 2-chloroquinoline, which reacted with
sodium methoxide in methanol to give the desired 2-methoxy-
quinoline (15) in excellent yield.11 Upon treatment of 15 with
LDA in the presence of triisopropyl borate in THF, boronic
acid 13 was obtained in excellent yield as a white crystalline
solid (Scheme 5).
conditions. When a gram-scale coupling was performed, the
solid product 19 was obtained by recrystallization, although the
yield was slightly lower (80%).
Reduction of the ester 19 using LiAH4 at -10 °C gave the
desired benzyl alcohol in good yield. Low temperature was
required to prevent formation of the over-reduced product 24.
TPAP/NMO12 was found to be the optimal oxidant to convert
the benzyl alcohol into aldehyde 20 using only 2 mol % catalyst
loading. A reductive amination of the aldehyde 20 and N-
mesylpiperizine (21) successfully afforded the benzylpiperizine
22. The KDR kinase inhibitor 1 was obtained as its hydrochlo-
ride salt in excellent yield under hydrolytic conditions.
Our indole synthesis approach was also successfully applied
to the remaining KDR inhibitors (2-4) starting from com-
mercially available 5-hydroxy-2-nitrobenzaldehyde (25) (Scheme
7). Alkylation of phenol 25 with either 2-methoxyethyl iodide
(27a) or N-2-chloroethylpiperidine hydrochloride (27b) in the
presence of K2CO3 in DMF afforded products 26a or 26b in
good yield. Alkylation with alkyl chloride 27c, however, was
less efficient. Subjecting aldehydes 26 (a or b or c) to the
Ramirez olefination, followed by catalytic hydrogenation using
1% Pd-C[V] gave aniline substrates 29 (a or b or c) in good
The Pd-catalyzed tandem C-N/C-C coupling of 18 with 13
proceeded smoothly in the presence of K3PO4‚H2O in 86% yield
(Scheme 6). Excess 13 (1.5 equiv) was required to compensate
for a parasitic processes such as protodeboration leading to 15
and homocoupling product leading to diquinoline 23 under these
(10) Strem catalogue (2004-2006) no. 78-1512.
(11) Lister, T.; Prager, R. H.; Tsaconas, M.; Wilkinson, K. L. Aust. J.
Chem. 2003, 56, 913.
(12) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem.
Soc., Chem. Commun. 1987, 1625.
J. Org. Chem, Vol. 72, No. 4, 2007 1343

Fang et al.
SCHEME 7
and 1% Pt-C[V] (365 mg) in MeOH (30 mL) was hydrogenated
under 1 atm of H2 (balloon) for 8 h until all the starting material
was consumed. The catalyst was removed by filtration, and the
solvent was removed under vacuum to afford the product as an
analytically pure sample without chromatographic purification (3.35
yield. The tandem coupling reactions using gem-dibromovinyl-
aniline substrates 29 (a or b or c) with boronic acid 13 furnished
the indole 30 (a or b or c), albeit in lower yield than 19. Upon
hydrolysis, the desired KDR inhibitors 2-4 were obtained in
excellent yields.
In summary, we have successfully demonstrated our newly
developed indole synthesis methodology in the preparation of
a family of KDR kinase inhibitors, which have potential use in
cancer therapy. KDR kinase inhibitor 1 was obtained in an
overall 63% yield in seven linear steps, while KDR inhibitors
2-4 were obtained in an overall yield of 20-42% over five
steps. This method is readily adapted to synthesize many more
analogues of KDR kinase inhibitors.
1
g, 100%). H NMR was identical to the one-pot procedure using
SnCl2‚2H2O as the reducing agent: Rf ) 0.20 (20% EtOAc in
hexanes); mp 112-113 °C; IR (neat, cm-1) 3476, 3368, 3244, 2950,
1
1698, 1623, 1502, 1437, 1289, 1243, 1198, 1149, 1106. H NMR
(400 MHz, CDCl3) δ 7.97 (1H, d, J ) 1.8 Hz), 7.84 (1H, dd, J )
8.5, 1.9 Hz), 7.29 (1H, s), 6.98 (1H, d, J ) 8.4 Hz), 4.14 (2H, br),
3.86 (3H, s); 13C NMR (75 MHz, CDCl3) δ 167.0, 147.9, 133.2,
131.8, 131.7, 120.8, 120.0, 114.9, 94.8, 52.0; HRMS (EI) calcd
for C10H9NO2Br2 ([M]+) 332.9000, found 332.9004.
2-Methoxy-3-quinolin-3-ylboronic Acid (13). To a solution of
2-methoxyquinoline11 (10.0 g, 62.8 mmol) and triisiopropyl borate
(17.86 g, 95.1 mmol) in THF (140 mL) at -78 °C was added a
solution of LDA (75.4 mmol, prepared from i-Pr2NH and n-BuLi).
The mixture was stirred at -78 °C for 4 h and slowly warmed to
rt overnight. The reaction was quenched with saturated NH4Cl (68
mL) and acidified to pH ) 5 with 3 M HCl. Organic solvents (THF
and hexanes) were evaporated under vacuum, and boronic acid was
precipitated as a white solid. The resulting mixture was filtered
through a Buchner funnel, and the solid was washed thoroughly
with H2O to afford the boronic acid 13 after dried under high
vacuum (12.11 g, 95%): 1H NMR (400 MHz, CDCl3) δ 8.64 (1H,
s), 7.85 (1H, d, J ) 8.3 Hz), 7.80 (1H, d J ) 7.9 Hz), 7.68 (1H,
dd, J ) 14.1, 1.1 Hz), 7.41 (1H, J ) 7.5 Hz), 5.91 (2H, s, br), 4.18
(3H, s); 13C NMR (100 MHz, CDCl3) δ 164.9, 149.8, 148.1, 131.1,
128.6, 127.4, 125.5, 124.7, 53.9; HRMS (EI) calcd for C10H10BNO3
([M]+) 203.0754, found 203.0758.
Experimental Section
Preparation of Methyl 3-(2,2-dibromovinyl)-4-nitrobenzoate
(17). To a solution of methyl 3-formyl-4-nitrobenzoate (3.14 g, 15
mmol) and CBr4 (5.48 g, 16.5 mmol) in DCM (50 mL) was added
dropwise PPh3 (7.86 g, 30 mmol) solution in DCM (50 mL) at 0
°C. After addition, the mixture was stirred for 1 h and warmed to
rt. The solution was filtered through a short silica gel column,
eluting with 20% EtOAc/hexanes. The solvent was evaporated, and
the residue was purified by chromatography with 10-20% EtOAc/
hexanes to afford the product as a slightly yellow solid (5.23 g,
95.5%): 1H NMR (400 MHz, CDCl3) δ 8.27 (1H, t, J ) 0.8 Hz),
8.19-8.13 (2H, m), 7.76 (1H, s), 3.99 (3H, s); 13C NMR (100 MHz,
CDCl3) δ 164.9, 149.4, 134.7, 133.2, 133.1, 131.7, 130.6, 125.2,
94.9, 53.2; HRMS (EI) calcd for C10H8NO4Br2 ([M]+) 363.8820,
found 363.8823.
Methyl 4-Amino-3-(2,2-dibromovinyl)benzoate (18). A mixture
of methyl 3-(2,2-dibromovinyl)-4-nitrobenzoate (3.65 g, 10 mml)
Methyl 2-(2-Methoxyquinolin-3-yl)-1H-indole-5-carboxylate
(19). To a 5 mL round-bottomed flask was charged 18 (0.1675 g,
1344 J. Org. Chem., Vol. 72, No. 4, 2007

Syntheses of KDR Kinase Inhibitors
0.5 mmol), 13 (0.1523 g, 0.75 mmol), Pd(OAc)2 (3.4 mg, 0.015
mmol), S-Phos (12.3 mg, 0.03 mmol), and K3PO4‚H2O (0.58 g,
2.5 mmol). The solid mixture was purged with argon for 10 min
followed by addition of toluene (2.5 mL). The resulting mixture
was stirred at rt for 2 min and heated at 100 °C for 1.5 h. The
mixture was diluted with EtOAc (10 mL) and H2O, and the organic
phase was separated and dried over Na2SO4. The crude material
was chromatographed with 20% EtOAc/hexanes to afford the
product as a white solid (0.143 g, 86%): 1H NMR (300 MHz,
DMSO) δ 11.89 (1H, s), 8.74 (1H, s), 8.31 (1H, s), 7.94 (1H, d, J
) 7.2 Hz), 7.84 - 7.77 (2H, m), 7.70 (1H, dd, J ) 7.0, 1.3 Hz),
7.56 (1H, d, J ) 8.5 Hz), 7.50 (1H, dd, J ) 6.9, 1.2 Hz), 7.32 (1H,
d, J ) 1.3 Hz), 4.18 (3H, s), 3.86 (3H, s); 13C NMR (100 MHz,
DMSO) δ 167.2, 158.3, 144.7, 139.4, 135.5, 134.2, 130.0, 127.8,
127.7, 126.4, 124.9, 124.8, 123.0, 122.9, 120.9, 116.5, 111.4, 104.7,
53.8, 51.7; HRMS (EI) calcd for C20H16N2O3 ([M]+) 332.1161,
found 332.1161.
[2-(2-Methoxyquinolin-3-yl)-1H-indol-5-yl]-methanol. To a
suspension of the methyl ester 19 (0.543 g, 1.63 mmol) in dry Et2O
(15 mL) at -15 °C was added LiAlH4 (0.312 g, 8.2 mmol) in two
portions under argon. The mixture was vigorously stirred under 0
°C for 5 h and then was quenched with NH4Cl (10 mL). The mixture
was extracted with EtOAc until no product was observed in the
aqueous phase. The solution was washed with brine and dried over
Na2SO4. The crude material was chromatographed with 50% EtOAc
in hexanes to afford the product as a slightly yellow solid (0.471
g, 95%): 1H NMR (400 MHz, CDCl3) δ 9.66 (1H, s, br), 8.43
(1H, s), 8.43 (1H, s), 7.85 (1H, d, J ) 8.3 Hz), 7.76 (1H, dd, J )
7.9, 1.3 Hz), 7.63-7.59 (2H, m), 7.44-7.39 (2H, m), 7.22 (1H,
dd, J ) 8.3, 1.5 Hz), 7.04 (1H, dd, J ) 2.2, 0.9 Hz), 4.79 (2H, d,
J ) 5.7 Hz), 4.31 (3H, s), 1.58 (1H, t, J ) 5.7 Hz); 13C NMR (100
MHz, DMSO) δ 158.3, 145.4, 136.2, 135.4, 134.3, 133.1, 129.8,
128.4, 127.7, 127.2, 125.7, 125.0, 122.7, 119.5, 116.7, 111.6, 101.4,
66.5, 54.2; HRMS (ESI) calcd for C19H17N2O2 ([M + H]+)
305.1284, found 305.1281.
54.2, 52.4, 46.2, 34.2; HRMS (ESI) calcd for C24H27N4O3S ([M +
H]+) 451.1798, found 451.1799.
3-[5-(4-Methanesulfonylpiperazin-1-ylmethyl)-1H-indol-2-yl]-
1H-quinolin-2-one Hydrochloride (1). The literature procedure7c
for the hydrolysis of the 2-methoxyquinoline was followed: A
mixture of 22 (0.225 g, 0.5 mmol) and concd HCl (0.6 mL) in
MeOH (4 mL) was heated under reflux (6 h) and stirred at rt
overnight. The resulting suspension was filtered and washed with
small portion of MeOH to afford the product as a yellow solid
(0.225, 95%): 1H NMR (400 MHz, DMSO-d6) δ 12.21 (1H, s),
11.83 (1H, s), 11.05 (1H, s), 8.61 (1H, s), 7.79 (1H, s), 7.74 (1H,
d, J ) 7.5 Hz), 7.60 (1H, d, J ) 8.3 Hz), 7.54 (1H, ddd, J ) 7.7,
7.7, 1.5 Hz), 7.40 (2H, d, J ) 9.0 Hz), 7.35 (1H, d, J ) 7.5 Hz),
7.26 (1H, ddd, J ) 7.5, 7.5, 1.1 Hz), 4.42 (2H, d, J ) 4.2 Hz),
3.71 (2H, d, J ) 12.7 Hz), 3.40 (2H, J ) 12.0 Hz), 3.26 (2H, t, J
) 11.9 Hz), 3.14 (2H, t, J ) 11.8 Hz), 2.99 (3H, s); 13C NMR
(100 MHz, CDCl3) δ 160.6, 137.7, 137.0, 134.9, 130.5, 128.0,
128.0, 125.0, 123.8, 122.5, 122.2, 120.0, 119.4, 115.1, 112.1, 102.4,
59.7, 49.9, 42.4, 35.2; HRMS (EI) calcd for C23H25N4O3S ([M +
H]+) 437.1641, found 437.1641.
5-(2-Methoxyethoxy)-2-nitrobenzaldehyde (26a). A 10-mL
round-bottomed flask was charged with 5-hydroxy-2-nitroben-
zaldhyde (0.668 g, 4 mmol) and K2CO3 (1.11 g, 8 mmol). After
the mixture was purged with argon for 5 min, anhydrous DMF (3
mL) and 2-iodoethyl methyl ether (1.02 g, 6 mmol) were added,
and the resulting mixture was heated at 75 °C overnight (12 h).
The mixture was poured into 1 M NaOH (5 mL), extracted with
Et2O (3 × 20 mL), washed with NaHCO3 (10 mL), H2O (10 mL),
and brine (10 mL), and dried over MgSO4. The crude material was
purified using silica gel column chromatography (33% EtOAc in
hexanes) to afford the product 26a as a slight yellow solid (0.881
g, 98%): mp 74-75 °C; IR (neat, cm-1): 2898, 1693, 1586, 1511,
1334, 1282, 1248, 1030; 1H NMR (400 MHz, CDCl3) δ 10.49 (1H,
s), 8.16 (1H, d, J ) 9.2 Hz), 7.36 (1H, d, J ) 2.9 Hz), 7.20 (1H,
dd, J ) 9.1, 3.0 Hz), 4.28-4.26 (2H, m), 3.81-3.78 (2H, m),
3.46 (3H, s); 13C NMR (100 MHz, CDCl3) δ 188.6, 163.4, 142.4,
134.4, 127.4, 119.3, 113.9, 70.6, 68.7, 59.4; HRMS (EI) calcd for
C10H12NO5 ([M + H]+) 226.0715, found 226.0715.
2-(2,2-Dibromovinyl)-4-(2-methoxyethoxy)-1-nitrobenzene (28a).
To a solution of the aldehyde 26a (0.122 g, 0.5 mmol) and
CBr4 (0.250 g, 0.75 mmol) in DCM (3 mL) was added a solu-
tion of PPh3 (0.393 g, 1.5 mmol) in DCM (1 mL) at 0 °C. The
mixture was stirred for 30 min, warmed to rt, and quenched with
NaHCO3 (5 mL). The resulting mixture was extracted with Et2O
(15 mL) and EtOAc (15 mL). The organic layer was washed with
brine and dried over MgSO4. The crude material was purified by
flash chromatography to afford 28a as a slightly yellow solid
(0.1553 g, 80%): mp 97-98 °C; IR (neat, cm-1) 2911, 1582, 1509,
1332, 1243, 1126, 1078; 1H NMR (400 MHz, CDCl3) δ 8.17 (1H,
d, J ) 9.0 Hz), 7.79 (1H, d, J ) 0.6 Hz), 7.04 (1H, dd, J ) 1.8,
0.6 Hz), 7.01 (1H, dd, J ) 9.2, 1.8 Hz), 4.24-4.22 (2H, m), 3.80-
3.78 (2H, m), 3.47 (3H, s); 13C NMR (100 MHz, CDCl3) δ 162.8,
140.1, 134.9, 134.1, 127.7, 117.0, 115.3, 92.8, 70.8, 68.5, 59.5;
HRMS (EI) calcd for C11H11NO4Br2 ([M]+) 378.9055, found
378.9076.
2-(2-Methoxyquinolin-3-yl)-1H-indole-5-carbaldehyde (20).
To a mixture of the alcohol (0.266 g, 0.874 mmol), NMO (0.151
g, 1.31 mmol), and 4 Å molecular sieves (0.3 g) was added dry
DCM (8.5 mL), and the resulting mixture was stirred at rt for 10
min before addition of TPAP (6.1 mg, 0.00175 mmol). The reaction
mixture was stirred at rt for 24 h, quenched by addition of Na2SO3
(10 mL), and diluted with HOAc (20 mL). The organic phase was
separated, washed with brine, and dried over Na2SO4. The crude
material after removal of solvent was chromatographed with 25%
EtOAc/hexnaes to afford a slightly yellow solid (0.241 g, 91%):
1
mp 202-203 °C; H NMR (400 MHz, CDCl3) δ 10.06 (1H, s),
9.96 (1H, br), 8.52 (1H, s), 8.20 (1H, d, J ) 0.7 Hz), 7.88 (1H, d,
J ) 8.3 Hz), 7.83-7.79 (2H, m), 7.66 (1H, ddd, J ) 7.9, 7.0, 1.5
Hz), 7.55 (1H, d, J ) 8.1 Hz), 7.45 (1H, ddd, J ) 7.9, 7.9, 1.5
Hz), 7.22 (1H, dd, J ) 2.2, 0.9 Hz), 4.32 (3H, s); 13C NMR (75
MHz, CDCl3) δ 192.7, 158.1, 145.7, 139.9, 136.0, 135.8, 130.3,
130.2, 128.1, 127.8, 127.2, 125.9, 125.5, 125.2, 123.0, 115.9, 112.0,
102.7, 54.3; HRMS (ESI) calcd for C19H15N2O2 ([M + H]+)
303.1128, found 303.1130.
3-[5-(4-Methanesulfonylpiperazin-1-ylmethyl)-1H-indol-2-yl]-
2-methoxyquinoline (22). To a mixture of the aldehyde 20 (75.6
mg, 0.248 mmol), 1-methanesulfonylpiperazine (41 mg, 0.25
mmol), and 4 Å molecular sieves (0.1 g) was added DCM (5 mL),
followed by NaHB(OAc)3 (79.5 mg, 0.375 mmol). The resulting
mixture was stirred at rt for 24 h. The mixture was filtered through
a Celite pad and washed with EtOAc. The residue after removal of
solvent was chromatographed with 100% EtOAc to afford a slightly
yellow solid (0.1035 g, 93%): 1H NMR (400 MHz, CDCl3) δ 9.65
(1H, s), 8.43 (1H, s), 7.86 (1H, d, J ) 8.3 Hz), 7.77 (1H, d, J )
7.9 Hz), 7.61 (1H, t, J ) 7.6 Hz), 7.54 (1H, s), 7.43-7.40 (2H,
m), 7.17 (1H, d, J ) 8.3 Hz), 7.03 (1H, s), 4.27 (3H, s), 3.64 (2H,
s), 3.24 (4H, br), 2.75 (3H, s), 2.59 (4H, br); 13C NMR (75 MHz,
CDCl3) δ 158.4, 145.5, 136.0, 135.4, 134.2, 129.8, 129.2, 128.3,
127.6, 127.2, 125.6, 125.0, 124.3, 121.2, 116.8, 111.3, 101.3, 63.4,
2-(2,2-Dibromovinyl)-4-(2-methoxyethoxy)phenylamine (29a).
A mixture of the nitrobenzene (0.155 g, 0.41 mmol) and 1% Pt-C
[V] (15 mg) in MeOH (5 mL) was hydrogenated at 50 psi for 15
h using a Parr hydrogenator. After removal of the catalyst through
filtration, solvent was evaporated, and the residue was purified by
flash chromatography with 20% f 25% EtOAc in hexanes to afford
29a as a colorless oil (0.118 g, 79%): IR (neat, cm-1) 3439, 3357,
1
2924, 2880, 1609, 1497, 1259, 1228, 1124. H NMR (500 MHz,
CDCl3) δ 7.33 (1H, t, J ) 0.6 Hz), 6.94 (1H, d, J ) 2.9 Hz), 6.81
(1H, ddd, J ) 8.7, 2.9, 0.5 Hz), 6.65 (1H, d, J ) 8.7 Hz), 4.07-
4.05 (2H, m), 3.73-3.71 (2H, m), 3.46 (2H, br), 3.45 (3H, s); 13
C
NMR (125 MHz, CDCl3) δ 151.5, 137.8, 134.0, 122.7, 117.4, 114.9,
92.7, 71.3, 68.2, 59.3; HRMS calcd for C11H14NO2Br2 ([M + H]+)
349.9385, found 349.9375.
J. Org. Chem, Vol. 72, No. 4, 2007 1345

Fang et al.
2-Methoxy-3-[5-(2-methoxyethoxy)-1H-indol-2-yl]quinoline
(30a). A 10 mL round-bottomed flask was charged with substrate
29a (0.118 g, 0.323 mmol), boronic acid 13 (0.098 g, 0.48 mmol),
and K3PO4‚H2O. After the flask was purged with argon for 10 min,
a solution of Pd(OAc)2 (2.3 mg, 0.01 mmol) and S-Phos (8.2 mg,
0.02 mmol) in PhMe (1.5 mL) was cannulated into the reaction
mixture. After heating to 100 °C for 1.5 h, the reaction was
quenched by addition of NaHCO3, extracted with EtOAc (3 × 10
mL), and dried over Na2SO4. The crude material was purified by
flash chromatography using 25% EtOAc in hexanes to afford 30a
as a slightly yellow oil (0.0831 g, 74%): IR (neat, cm-1) 3454,
50% EtOAc in hexanes (column length 5 cm) to afford the product
as a yellow solid (41 mg, 95%): 1H NMR (400 MHz, DMSO-d6)
δ 12.15 (1H, s), 11.43 (1H, s), 8.51 (1H, s), 7.73 (1H, d, J ) 7.9
Hz), 7.51 (1H, d, J ) 7.8 Hz), 7.42 (1H, d, J ) 9.0 Hz), 7.37 (1H,
d, J ) 8.1 Hz), 7.24 (1H, t, J ) 7.5 Hz), 7.22 (1H, s), 7.05 (1H,
d, J ) 2.2 Hz), 6.77 (1H, dd, J ) 8.5, 2.1 Hz), 4.09 (2H, t, J ) 4.5
Hz), 3.68 (2H, t, J ) 4.5 Hz), 3.33 (3H, s); 13C NMR (100 MHz,
CDCl3) δ 160.6, 152.7, 137.5, 134.1, 133.7, 131.9, 130.0, 128.2,
127.7, 122.5, 122.3, 119.5, 114.9, 112.9, 112.5, 102.3, 101.7, 101.7,
70.7, 67.2, 58.2; HRMS (ESI) calcd for C20H19N2O3 ([M + H]+)
335.1390, found 335.1390.
1
3389, 2924, 1622, 1476, 1451, 1398, 1213, 1194, 1120; H NMR
(400 MHz, CDCl3) δ 9.53 (1H, br), 8.38 (1H, s), 7.84 (1H, d, J )
8.3 Hz), 7.73 (1H, dd, J ) 8.0, 1.2 Hz), 7.59 (1H, ddd, J ) 8.2,
7.0, 1.5 Hz), 7.39 (1H, ddd, J ) 7.9, 7.0, 1.1 Hz), 7.32 (1H, d, J
) 8.8 Hz), 7.11 (1H, d, J ) 2.4 Hz), 6.97 (1H, dd, J ) 2.2, 0.9
Hz), 6.93 (1H, dd, J ) 8.8, 2.4 Hz), 4.24 (3H, s), 4.19-4.17 (2H,
m), 3.80-3.77 (2H, m), 3.47 (3H, s); 13C NMR (100 MHz, CDCl3)
δ 158.3, 153.8, 145.3, 135.1, 134.3, 132.1, 129.6, 128.7, 127.6,
127.1, 125.7, 124.9, 116.9, 114.0, 112.1, 103.2, 101.2, 71.5, 68.2,
59.4, 54.2; HRMS calcd for C21H21N2O3 ([M + H]+) 349.1546,
found 349.1540.
3-[5-(2-Methoxyethoxy)-1H-indol-2-yl]-1H-quinolin-2-one (4).
A mixture of 30a (45 mg, 0.129 mmol) and HCl (3 mL, 3 M) was
heated at 90 °C overnight. Solid K2CO3 was carefully added to the
mixture until the pH > 7, and the resulting mixture was filtered.
The solid collected was purified by flash chromatography using
Acknowledgment. This work is supported by NSERC
(Canada), Merck Frosst, and the University of Toronto. Y.-Q.F.
thanks the Ontario Government and the University of Toronto
for financial support in the form of postgraduate scholarships
(OGS). R.K. thanks NSERC for a summer undergraduate
research scholarship. We thank Degussa for donation of Pt
catalysts.
Supporting Information Available: Experimental procedure
and characterization data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO062228W
1346 J. Org. Chem., Vol. 72, No. 4, 2007