Synthesis of 7-(E)-alkenyl-4-amino-3-quinolinecarbonitriles via Pd-mediated Heck, Stille, and Suzuki reactions

Article abstract of DOI:10.1016/j.tet.2008.10.063

A regio- and stereoselective synthesis of 7-(E)-alkenyl-4-amino-3-quinolinecarbonitriles via Pd-mediated coupling reactions was developed. The comparison and optimization of stereoselectivity of the Heck, Stille, and Suzuki reactions of 7-bromo or 7-trifl

Full text of DOI:10.1016/j.tet.2008.10.063

Tetrahedron 65 (2009) 57–61
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Synthesis of 7-(E)-alkenyl-4-amino-3-quinolinecarbonitriles via Pd-mediated
Heck, Stille, and Suzuki reactions
*
Yanong D. Wang , Minu Dutia, M. Brawner Floyd, Amar S. Prashad, Dan Berger, Melissa Lin
Chemical and Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A regio- and stereoselective synthesis of 7-(E)-alkenyl-4-amino-3-quinolinecarbonitriles via Pd-medi-
ated coupling reactions was developed. The comparison and optimization of stereoselectivity of the
Heck, Stille, and Suzuki reactions of 7-bromo or 7-triflate-3-quinolinecarbonitrile are described. Com-
pound 7 and 10 were potent inhibitors of Src kinase and Raf/Mek activity, respectively.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 8 October 2008
Accepted 21 October 2008
Available online 25 October 2008
1. Introduction
alkenes (Heck reaction13,14) or alkene equivalents, such as vinyl-
stannane (Stille reaction15,16) or vinylboron compounds (Suzuki
Protein tyrosine kinases (PTKs) are key enzymes in signal
transduction pathways regulating a number of cellular functions
such as cell growth and differentiation. Kinase over-expression or
mutations are often associated with various diseases. Small mole-
cule inhibitors of protein kinases have shown great therapeutic
potential for treatment of diverse disease states, especially cancer.1–4
Miscellaneous scaffolds have been used as templates for de-
velopment of kinase inhibitors, for example, 4-anilino-3-quinoli-
necarbonitrile, a privileged kinase scaffold discovered at Wyeth.5,6
It was observed that variation of substituents on the 4-anilino
group of 3-quinolinecarbonitrile had a major impact on the kinase
specificity. SKI-606 (1)7–9 (Fig. 1), currently in clinical trials as an
anti-cancer agent, is a potent inhibitor of Src kinase. We have also
reported the potent inhibition of Mek kinase by the 7-alkoxy-4-
anilino-3-quinolinecarbonitrile (2).10 In order to further probe the
SAR of 3-quinolinecarbonitriles as kinase inhibitors, compounds
possessing an (E)-alkenyl group at the C-7 position of 3-quinoli-
necarbonitrile scaffold, exemplified by structure 3, were therefore
designed as potential Src or Mek inhibitors.
reaction17,18).
We envisioned that 7-(E)-alkenyl-3-quinolinecarbonitrile (3)
could be effectively assembled via the coupling reaction of
a 7-bromo (or triflate)-3-quinolinecarbonitrile intermediate (A)
and an alkenyl building block (B, C or D) (Fig. 1).
2.1. Heck reaction
As depicted in Scheme 1, 1-(but-3-enyl)-4-methylpiperazine (5)
was prepared by treatment of 4-bromobut-1-ene with N-methyl-
piperazine.19 Under typical Heck conditions, the coupling reaction
of 7-triflate-3-quinolinecarbonitrile (6)20 with 5 gave a mixture of
E/Z isomers of 7 along with a double bond migration by-product (8)
as an inseparable 70:15:15 (E-7/Z-7/8) mixture as determined by
LC–NMR. The predominant E-7 product is obtained by an addition–
elimination mechanism, in which the
b-hydride elimination is
stereoselective and occurs in a syn manner.14,21 The formation of
double bond isomerization product (Z-7) and double bond migra-
tion product (8) is likely due to a reversible b-hydride elimination
process and a sluggish dissociation step of the olefin from the
Pd(II)-H species.22 Similar results were reported on unsymmetrical
non-functionalized alkenes.23,24 The coupling of 9 and 5 provided
a 35% yield of products 10 (EþZ) and 11 in an analogous ratio of
80:10:10 (E-10/Z-10/11).
2. Results and discussion
The Pd-mediated arylations of alkenes, including Heck, Stille,
and Suzuki reactions, have received a great deal of attention in the
last two decades and have been applied to the synthesis of a wide
range of biologically interesting compounds.11,12 These reactions
can be broadly defined as the Pd-catalyzed coupling of organic
electrophiles (such as alkenyl or aryl (sp2) halides or triflates) with
2.2. Stille reaction
The unsatisfactory product mixtures obtained by the Heck re-
actions of 6 and 925prompted us to investigate the alternative Stille
coupling reaction. The Pd-mediated Stille reaction has been widely
used for the synthesis of complex molecules, due to typically mild
reaction conditions, the tolerance of functional groups, and the ease
* Corresponding author. Tel.: þ1 845 602 5253; fax: þ1 845 602 5561.
E-mail address: wangd@wyeth.com (Y.D. Wang).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.063

58
Y.D. Wang et al. / Tetrahedron 65 (2009) 57–61
Cl
Cl
Cl
S
N
N
HN
OMe
HN
MeO
O
CN
MeO
O
CN
N
N
N
N
N
N
1, SKI-606
2
N
N
B
N
R2
R2
+
or
SnBu3
O
HN
N
HN
R1
CN
3
C
R1
X
CN
N
N
or
N
7
N
1
B
O
N
N
3
A
D
Figure 1.
N
N-Me-piperazine/K2CO3/
18-crown ether/CH3CN, reflux
32%
N
Br
5
4
Cl
Cl
Cl
Cl
Cl
Cl
HN
N
OMe
HN
N
OMe
HN
N
OMe
5/Pd(OAc)2/PPh3/
MeO
CN
6
7
MeO
CN
NaHCO3, DMF, 70 °C
MeO
TfO
CN
+
50%
N
N
N
N
6
7 (E+Z)
8
Cl
Cl
Cl
S
N
N
S
N
S
N
N
N
HN
N
HN
HN
5/Pd(OAc)2/PPh3/
+
CN
CN
CN
6
NaHCO3, DMF
35%
N
N
N
Br
N
7
N
N
9
10 (E+Z)
11
35% (10:1)
Scheme 1.
of preparation of vinylstannanes. Hydrostannation of but-3-yn-1-ol
readily provided (E)-vinylstannane (13)26 as the major product,
along with a minor product of (Z)-vinylstannane (14) (Scheme 2).
Separation of the isomers was achieved by column chromatogra-
phy. Tosylation of 13 followed by amination with N-methylpiper-
azine afforded vinylstannane 16.
The Stille coupling reaction between 6 and 16 produced 7-(E)-
alkenyl-3-quinolinecarbonitrile 7 in 65% yield with an E/Z ratio of
98.0:2.0 as determined by HPLC and 1H NMR. Using the same
procedure, reaction of 9 and 16 afforded 10 in 58% yield, with an
equal E/Z ratio of 98.0:2.0. Double bond migration products were
not observed in this reaction. It is known in the literature27 that the
Stille coupling reaction is stereospecific, where the E/Z ratio of
product is typically correlated with the E/Z ratio of vinylstannane.
Thus, we postulated that 2% of the Z-isomer observed in these
coupling reaction was likely due to the contamination by the
Z-isomer of vinylstannane. Nonetheless, this methodology repre-
sented a significant improvement over the Heck reaction as
a means of providing our target compounds with excellent
stereoselectivity.
2.3. Suzuki reaction
To avoid the necessityof a tedious chromatographic separation of
(E) and (Z)-isomers in the Stille protocol, we embarked on an in-
vestigation of the Suzuki reaction. As an effective tool for C–C bond
formation, the Suzuki reaction has also been used extensively be-
cause vinylboronic esters (acids) can be prepared with high regio-
and stereoselectivity under relatively mild reaction conditions. We
have previously described28 an efficient stereoselective synthesis of
(E)-vinylboronic esters via a Zr-mediated hydroboration of alkynes.
Thus, aminoalkyne (17)29 was converted to (E)-vinylboronic ester
(19) (<1% of Z isomer as determined by 1H NMR) (Scheme 3), which
can be used for the next step without further purification.
Reaction conditions, including solvents, Pd catalysts, reaction
temperature, and time, were examined in order to optimize this
chemistry. We have found that compounds 7 and 10 can be prepared
in a one-pot protocol inwhich vinylboronic ester 19 was generated in
situ. It is noteworthy that a particular solvent system (toluene/eth-
anol/water, 10:1:1) is crucial in this coupling reaction to accommo-
date the solubility requirement of all substrates and reagents and to

Y.D. Wang et al. / Tetrahedron 65 (2009) 57–61
59
HSnBu3/AIBN/, 90 °C
57%
SnBu3
+
HO
HO
HO
SnBu3
12
13 (E)
14 (Z)
TsCl/
2,6-lutidine,
rt, 20h
65%
SnBu3
TsO
15
N-Me-piperazine/
THF, 45 °C, 2h
quant.
yield
SnBu3
N
N
16
6/Pd(PPh3)4/NMP
100 °C, 2h
9/Pd(PPh3)4/NMP
100 °C, 2h
Cl
Cl
Cl
S
N
N
HN
CN
OMe
HN
CN
MeO
N
N
N
N
N
N
10, 53%, 98.0:2.0 (E/Z)
7, 65%, 98.0:2.0 (E/Z)
Scheme 2.
ensure complete conversion. Under the optimal coupling reaction
conditions (Pd(PPh3)4/NaHCO3/toluene/EtOH/H2O, 90 ꢀC, 4 h), cou-
pling of 6 and 19 provided the target product (7) in 76% yield. Like-
wise, compound 10 was obtained from 9 and 19 in 63% yield. In both
cases, only trace amount of Z-isomer (<1%) was observed.
reaction conditions, 7-(E)-alkenyl-3-quinoline-carbonitriles (7 and 10)
were prepared efficiently with excellent regio- and stereoselectivity.
3. Experimental
3.1. General
2.4. Biological activity of 7 and 10
Melting points were determined in open capillary tubes on a Mel-
temp melting point apparatus and are uncorrected. 1H NMR spectra
were recorded on a NT-300 WB spectrometer. Electrospray (ES) mass
spectra were recorded on a Microma Platform mass spectrometer. Flash
chromatography was performed with Baker 40 mM silica gel. Reactions
were generally carried out under an inert atmosphere of nitrogen.
In a Lance format Src enzymatic assay,30 compound 7 had an
IC50 value of 2.1 nM. It was also found that 7 inhibited cell growth
in a Src-dependent cell proliferation assay30 with an IC50 of 58 nM.
Compound 10 was a potent inhibitor of Raf/Mek activity, having an
IC50 of 19 nM in an enzymatic assay31 and an IC50 of 14 nM in
a Lovo cellular assay.31 A full account of their biological activities
and SAR will be disclosed in a separate report.
3.2. Heck reaction: compounds 6, 7, 10
In summary, we present here a synthesis of 7-(E)-alkenyl-3-quino-
linecarbonitriles using Pd-mediated coupling reactions. We have eval-
uated the stereoselectivity of Heck, Stille, and Suzuki coupling reactions
of two 7-Br (or OTf)-3-quinolinecarbonitriles. Under the optimized
3.2.1. 1-(But-3-enyl)-4-methylpiperazine (5)
A mixture of N-methylpiperazine (2.0 g, 20 mmol), 4-bromobut-
1-ene (4) (3.24 g, 24 mmol), 18-crown ether (0.26 g, 1 mmol), and
O
B
Cp2ZrHCl
N
O
O
neat
O
N
+
BH
N
N
19
18
17
9/Pd(PPh3)4/NaHCO3/
tol-EtOH-H2O (10:1:1),
90 °C, 4h
6/Pd(PPh3)4/NaHCO3/
tol-EtOH-H2O (10:1:1),
90 °C, 4h
Cl
Cl
Cl
S
N
N
HN
OMe
HN
N
MeO
CN
CN
N
N
N
N
N
10, 63%, 99.5:0.5 (E/Z)
7, 76%, 99.5:0.5 (E/Z)
Scheme 3.

60
Y.D. Wang et al. / Tetrahedron 65 (2009) 57–61
potassium carbonate (4.2 g, 30 mmol) in acetonitrile (20 mL) was
heated at reflux overnight. The resulting mixture was filtered
through a pad of silica gel and the filtrate was concentrated, which
turned into a mixture of oil and solid. The mixture was filtered and
washed with hexane. The filtrate was concentrated to provide 1.0 g
3.3. Stille reaction: compounds 7, 10, 13–16
3.3.1. (E)-1-(Tri-n-butylstannyl)-1-buten-4-ol (13)
A stirred mixture of 3-butyn-1-ol (12) (3.50 g, 50 mmol) and
AIBN (0.25 g, 1.5 mmol), contained in a round-bottomed flask
equipped with a reflux condenser, was purged with N2 at 25 ꢀC and
treated with tri-n-butyltin hydride (20.2 ml, 75 mmol). The mix-
ture was slowly heated to 90 ꢀC and the resulting vigorous exo-
thermic reaction was moderated by removal of the heating bath
and reflux of the butynol. After the initial reaction, the solution was
stirred at 100 ꢀC for 18 h. The solution was cooled and the crude
product was subjected to chromatography on silica gel with a 3–
20% gradient of EtOAc in hexane. After elution of a small amount of
Z-isomer (13), the E-isomer (14) was obtained as a colorless oil
(10.3 g, 57%). The 1H NMR spectrum was identical to that
reported.24
of 5 (32%) as an oil. 1H NMR (
d, DMSO-d6): 5.79 (m, 1H), 5.04 (dd,
J¼26, 2.2 Hz, 1H), 4.98 (dd, J¼22, 2.1 Hz, 1H), 3.33 (s, 3H), 2.50 (t,
J¼2.0 Hz, 3H), 2.33 (m, 8H), 2.19 (m, 2H).
3.2.2. Method A: 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-
methoxy-7-[4-(4-methylpiperazin-1-yl)but-1-enylquino-
line-3-carbonitrile (E-7/Z-7/8)
To a mixture of NaHCO3 (19 mg, 0.23 mmol), PPh3 (8.0 mg,
0.029 mmol), and Pd(OAc)2 (4.0 mg, 0.019 mmol) were added 5
(36 mg, 0.23 mmol) and 6 (100 mg, 0.19 mmol) in DMF (2.0 mL) via
syringe. The reaction mixture was heated at 70 ꢀC for 15 h and
partitioned between EtOAc and aqueous NH4Cl. The combined or-
ganics were dried over anhydrous Na2SO4, concentrated, and pu-
rified by column chromatography to give 50 mg yellow solid (50%)
of E-7/Z-7/8 as an inseparable mixture; mp 208 ꢀC. The mixture of
E-7/Z-7/8 was analyzed by LC–NMR.
LC–NMR was performed on a Bruker AVANCE 600 MHz spec-
trometer equipped with a 4 mm i.d. flow probe with an active
volume of 120 ml. All LC–NMR experiments were conducted using
loop storage mode. Proton NMR spectra were acquired using a 1D
NOESYPRESAT sequence to achieve solvent suppression. HPLC
analysis was performed on an Agilent Model 1100 HPLC system
equipped with an autosampler, binary pump, and a variable
wavelength detector monitoring at 254 nm. Chromatographic
3.3.2. (3E)-4-(Tri-n-butylstannyl)but-3-enyl 4-methylbenzene-
sulfonate (15)
To a stirred solution of 14 (5.42 g, 15 mmol) in 30 ml of 2,6-
lutidine was added tosyl chloride (8.58 g, 45 mmol) while main-
taining 25 ꢀC. After 20 h the excess tosyl chloride was decomposed
by the addition of 30 ml of water and 5 ml of pyridine while cooling
to maintain 25 ꢀC. The resulting mixture was partitioned with DCM
and diluted aqueous NaHCO3. The organic layer was washed with
water, dried, and concentrated at <35 ꢀC, finally distilled at
0.5 mm/Hg, to give 15 (5.0 g, 65%) as an oil. 1H NMR (
d, DMSO-d6):
7.76 (d, J¼8.3 Hz, 2H), 7.47 (d, J¼8.3 Hz, 2H), 5.93 (d, J¼18.8 Hz, 1H),
5.78 (dt, J¼18.8, 5.9 Hz, 1H), 4.06 (t, J¼6.5 Hz, 2H), 2.42 (s, 3H), 2.35
(m, 2H), 1.41 (m, 6H), 1.25 (m, 6H), 0.85 (m, 15H).
separation was carried out using a 5
column under isocratic conditions consisting of 87% D2O and 13%
m
m 4.6ꢁ150 mm XTerra RP18
acetonitrile-d3 with 0.02% TFA buffer.
3.3.3. 1-Methyl-4-[(3E)-4-(tri-n-butylstannyl)but-3-
enyl]piperazine (16)
1H NMR of E-7 (
d
, DMSO-d6): 9.81 (br s, 1H), 8.40 (s, 1H), 7.95–
7.66 (m, 3H), 7.33 (br s, 1H), 6.82 (d, J¼16 Hz, 1H), 6.59 (m, 1H), 3.97
A solution of 14 (1.55 g, 3.0 mmol), 1-methylpiperazine (1.33 ml,
12 mmol), and 3.0 ml of THF was stirred for 24 h at 25 ꢀC and 45 ꢀC
for 2 h. The solution was concentrated to dryness under vacuum,
and the residue was partitioned with 1:1 hexane/Et2O and diluted
aqueous NaHCO3. The organic layer was washed with water, dried,
and concentrated at <30 ꢀC to give 16 as an amber oil (quantitative
yield), which was used in the next step without purification.
(s, 3H), 3.87 (s, 3H), 3.49 (m, 2H), 2.50–2.30 (m, 10H), 2.18 (s, 3H).
1H NMR of Z-7 (
d, DMSO-d6): 9.81 (s, 1H), 8.41 (s, 1H), 7.88 (s,
1H), 7.85 (s,1H), 7.75 (s,1H), 7.35 (s,1H), 6.61 (d, J¼11.8 Hz,1H), 5.91
(dt, J¼11.8, 6.4 Hz, 1H), 3.96 (s, 3H), 3.86 (s, 3H), 2.45 (m, 2H), 2.42
(m, 2H), 2.34 (br, 8H), 2.16 (s, 3H).
1H NMR of 8 (
d, DMSO-d6): 9.81 (s, 1H), 8.42 (s, 1H), 7.85 (s, 1H),
7.75 (s, 1H), 7.67 (s, 1H), 7.35 (s, 1H), 5.80 (dt, J¼15.6, 6.7 Hz, 1H),
5.52 (dt, J¼15.6, 6.7 Hz 1H), 3.96 (s, 3H), 3.86 (s, 3H), 3.48 (d,
J¼6.7 Hz, 2H), 2.92 (d, J¼6.7 Hz, 2H), 2.34 (br, 8H), 2.16 (s, 3H).
3.3.4. Method B: 4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]
phenyl}amino)-7-[(1E)-4-(4-methylpiperazin-1-yl)but-1-
enyl]quinoline-3-carbonitrile (10)
3.2.3. 4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]
phenyl}amino)-7-[4-(4-methylpiperazin-1-yl)but-1-enyl]
quinoline-3-carbonitrile (E-10/Z-10/11)
A N2-purged mixture of 7-bromo-4-{3-chloro-4-[(1-methyl-1H-
imidazol-2-yl)sulfanyl]anilino}-3-quinolinecarbonitrile (9) (377 mg,
0.80 mmol), 16 (0.50 g, 1.12 mmol), and 4.0 ml of NMP were treated
with Pd(Ph3P)4 (92 mg, 0.08 mmol). The mixture was stirred at
100 ꢀC for 1 h, treated with an additional portion of Pd(Ph3P)4
(30 mg, 0.025 mmol), stirred at 110 ꢀC for1 h, cooled, andpartitioned
with DCM and diluted aqueous NaHCO3. The organic layer was
washed with water, dried, and concentrated. The residue was stirred
in 5:1 Et2O/hexane and the resulting solid was collected by filtration.
The crude product was purified by flash column chromatography
(eluting with EtOAc/MeOH/TEA) to give a solid, which was stirred in
MeOH, filtered, and dried to give 251 mg (58%) of 10 as an off-white
solid; mp 225 ꢀC. MS (ESI) m/z 544.2 (Mþ1)þ1. Anal. Calcd for
C29H30ClN7S: C, 64.01; H, 5.56; N, 18.02. Found: C, 64.01; H, 5.52; N,
17.68.
Following the procedure used to prepare 7/8 (method A), E-10/
Z-10/11 was obtained from 9 and 5 as a pale yellow solid (35%); mp
218 ꢀC.
1H NMR of E-10 (
d, DMSO-d6): 9.86 (s, 1H), 8.59 (s, 1H), 8.30 (d,
J¼8.7 Hz, 1H), 7.80 (s, 1H), 7.79 (d, J¼8.7 Hz, 1H), 7.54 (d, J¼1.1 Hz, 1H),
7.44 (s, 1H), 7.16 (d, J¼1.1 Hz, 1H), 7.15 (m, 1H), 6.64 (m, 2H), 6.54 (d,
J¼8.6 Hz, 1H), 3.61 (s, 3H), 2.37 (m, 12H), 2.15 (s, 3H). Anal. Calcd for
C29H30ClN7S: C, 64.01;H, 5.56; N,18.02. Found: C, 64.01; H, 5.52; N,17.68.
1H NMR of Z-10 (
d, DMSO-d6): 9.90 (s, 1H), 8.62 (s, 1H), 8.37 (d,
J¼8.6 Hz, 1H), 7.91 (s, 1H), 7.61 (d, J¼8.6 Hz, 1H), 7.55 (d, J¼1.0 Hz,
1H), 7.46 (s, 1H), 7.17 (d, J¼8.7 Hz, 1H), 7.16 (s, 1H), 6.65 (d,
J¼11.5 Hz, 1H), 6.54 (d, J¼8.7 Hz, 1H), 5.91(dt, J¼11.5, 6.9 Hz, 1H),
3.60 (s, 3H), 2.55 (m, 2H), 2.52 (m, 2H), 2.35 (br, 8H), 2.15 (s, 3H).
1H NMR of 11 (
d
, DMSO-d6): 9.90 (s, 1H), 8.62 (s, 1H), 8.34 (d,
3.3.5. 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[4-
(4-methylpiperazin-1-yl)but-1-enyl]quinoline-3-carbonitrile (7)
Following the procedure used to prepare 10 (Method B), 7 was
obtained from 6 and 16 as an off-white solid (65%); mp 148–150 ꢀC.
MS (ESl) m/z 526.1. Anal. Calcd for C27H29Cl2N5O2$0.6H2O: C, 60.36;
H, 5.67; N, 13.04. Found: C, 60.04; H, 5.69; N, 12.83.
J¼8.8 Hz, 1H), 7.75 (s, 1H), 7.55 (d, J¼1.0 Hz, 1H), 7.51 (d, J¼8.8 Hz,
1H), 7.46 (s, 1H), 7.17 (d, J¼8.7 Hz, 1H), 7.16 (s, 1H), 6.54 (d, J¼8.7 Hz,
1H), 5.80 (dt J¼15.6, 6.6 Hz, 1H), 5.57(dt, J¼15.6, 6.6 Hz, 1H), 3.61 (s,
3H), 3.57 (d, J¼6.6 Hz, 2H), 2.92 (d, J¼6.6 Hz, 2H), 2.35 (br, 8H), 2.15
(s, 3H).

Y.D. Wang et al. / Tetrahedron 65 (2009) 57–61
61
3.4. Suzuki reaction: compounds 7, 10
for biological evaluation of compound 7, and Dr. Robert Mallon
and Dr. Donald Wojciechowicz for biological evaluation of
compound 10. We also thank Drs. Diane Boschelli, Dennis
Powell, Allan Wissner, and Tarek Mansour for their support of
this work.
3.4.1. Method C: 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-
methoxy-7-[(1E)-4-(4-methylpiperazin-1-yl)but-1-enyl]
quinoline-3-carbonitrile (7)
To a mixture of 1-but-3-ynyl-4-methyl-piperazine (17) (1.85 g,
14.4 mmol) and 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (18)
(1.46 g, 9.6 mmol) was added bis(cyclopentadienyl)-zirconium
chloride hydride (124 mg, 0.48 mmol). The resulting mixture was
stirred at room temperature for 24 h and was diluted with toluene/
ethanol/water (80 mL/8 mL/8 mL). Compound 6 (2.50 g, 4.70 mmol),
K2CO3 (1.99 g, 14.4 mmol), and Pd(PPh3)4 (285 mg, 0.238 mmol)
were added. The reaction mixture was heated at 90 ꢀC for 4 h and
partitioned between saturated aqueous NaHCO3 and CH2Cl2. The
combined organics were dried over anhydrous Na2SO4, concen-
trated, and purified by silica gel flash column chromatography (10:1
CH2Cl2/MeOH) to give 1.92 g (75%) of 7 as an off-white solid; mp
References and notes
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142–143 ꢀC. MS (ESl) m/z 526.1; 1H NMR (
d, DMSO-d6): 9.81 (br s,
7. Golas, J. M.; Lucas, J.; Etienne, C.; Golas, J.; Discafani, C.; Sridhar, L.; Boghaert, E.;
Arndt, K.; Ye, F.; Boschelli, D. H.; Li, F.; Titsch, C.; Huselton, C.; Chaudhary, I.;
Boschelli, F. Cancer Res. 2005, 65, 5358.
1H), 8.40 (s, 1H), 7.95–7.66 (m, 3H), 7.33 (br s, 1H), 6.82 (d, J¼16 Hz,
1H), 6.59 (m, 1H), 3.97 (s, 3H), 3.87 (s, 3H), 3.49 (m, 2H), 2.50–2.30
8. Golas, J. M.; Arndt, K.; Etienne, C.; Lucas, J.; Nardin, D.; Gibbons, J.; Frost, P.;
Ye, F.; Boschelli, D. H.; Boschelli, F. Cancer Res. 2003, 62, 375.
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M. B.; Zhang, N.; Torres, N.; Levin, J.; Du, X.; Wojciechowicz, D.; Discafani, C.;
Kohler, C.; Kim, S. C.; Feldberg, L. R.; Collins, K.; Mallon, R. Bioorg. Med. Chem.
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18. Bellina, F.; Carpita, R. R. Synthesis 2004, 2419.
19. Schmidt, A. M.; Eilbracht, P. J. Org. Chem. 2005, 70, 5528.
20. Berger, D.; Dutia, M.; Powell, D.; Wissner, A.; DeMorin, F.; Raifeld, Y.; Weber, J.;
Boschelli, F. Bioorg. Med. Chem. Lett. 2002, 12, 2989.
(m, 10H), 2.18 (s, 3H); 13C NMR (
d, DMSO-d6): 154.93, 153.95, 150.15,
149.63,142.99,137.06,133.89,132.55,129.72,125.28,123.88,122.68,
120.06, 118.36, 116.84, 113.13, 101.71, 88.32, 57.29, 56.28, 54.72,
54.72, 52.51, 52.51, 45.70, 30.69, 24.93. Anal. Calcd for
C27H29Cl2N5O2$1.7H2O: C, 58.21; H, 5.84; N, 12.57. Found: C, 58.48;
H, 5.47; N, 12.30.
3.4.2. 4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}-
amino)-7-[(1E)-4-(4-methylpiperazin-1-yl)but-1-enyl]quinoline-3-
carbonitrile (10)
Following the procedure used to prepare 7 (Method C), 10 was
obtained from 9 as an off-white solid (63%). MS (ESI) m/z 544.2
(Mþ1)þ1
; d, DMSO-d6): 9.86 (s, 1H), 8.59 (s, 1H), 8.30 (d,
1H NMR (
J¼8.7 Hz, 1H), 7.80 (s, 1H), 7.79 (d, J¼8.7 Hz, 1H), 7.54 (d, J¼1.1 Hz,
1H), 7.44 (s, 1H), 7.16 (d, J¼1.1 Hz, 1H), 7.15 (m, 1H), 6.64 (m, 2H),
6.54 (d, J¼8.6 Hz, 1H), 3.61 (s, 3H), 2.37 (m, 12H), 2.15 (s, 3H); 13C
21. Heck, R. F. J. Am. Chem. Soc. 1969, 91, 6707.
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24. Mabic, S.; Vaysse, L.; Benezra, C.; Lepoittevin, J. Synthesis 2006, 7, 1127.
25. Boschelli, D. H.; Wang, Y.; Boschelli, F. C.; Berger, D. M.; Zhang, N.; Powell,
D. W.; Ye, F.; Yamashita, A.; Demorin, F. F.; Wu, B.; Tsou, H.; Overbeek-
Klumpers, E. G.; Wissner, A. U.S. Patent 6,521,618.
NMR (d, DMSO-d6): 152.77, 150.13, 140.95, 134.49, 132.80, 130.21,
129.90, 129.90, 129.76, 129.30, 127.92, 125.55, 125.55, 125.36,
124.08, 123.97, 123.33, 123.10, 118.37, 116.79, 88.95, 56.84, 54.11,
54.11, 51.77, 51.77, 44.94, 33.25, 29.98. Anal. Calcd for
C29H30ClN7S$0.2H2O: C, 63.59; H, 5.59; N, 17.90. Found: C, 63.46; H,
5.57; N, 17.84.
26. Pilli, R. A.; de Andrade, C. K. Z.; Souto, C. R. O.; de Meijere, A. J. Org. Chem. 1998,
63, 7811.
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28. Wang, Y. D.; Kimball, G.; Prashad, S. A.; Wang, Y. Tetrahedron Lett. 2005, 8777.
29. Vaillancourt, V. A.; Staley, S.; Huang, A.; Nugent, R. A.; Chen, K.; Nair, S. K.;
Nieman, J. A.; Strohbach, J. W. PCT Int. Appl. WO 2002002558, 2002.
30. Boschelli, D. H.; Wang, Y. D.; Johnson, S.; Wu, B.; Ye, F.; Barrios Sosa, A. C.; Golas,
J. M.; Boschelli, F. J. Med. Chem. 2004, 47, 1599.
31. Berger, D. M.; Dutia, M.; Powell, D.; Floyd, M. B.; Torres, N.; Mallon, R.; Woj-
ciechowicz, D.; Kim, S.; Feldberg, L.; Collins, K.; Chaudhary, I. Bioorg. Med. Chem.
2008, 16, 9202.
Acknowledgements
We thank the members of the Wyeth Discovery Analytical
Chemistry Department for the spectral data and elemental
analyses. We thank Mrs. Jennifer Golas and Dr. Frank Boschelli