Convergent synthesis of the quinolone substructure of BILN 2061 via carbonylative sonogashira coupling/cyclization

Article abstract of DOI:10.1021/jo060556q

A convergent synthesis of quinolone 2 (key substructure of the protease inhibitor BILN 2061) was developed via palladium-catalyzed carbonylation of 2-iodo-5-methoxy-aniline (4) with thiazolylacetylene 5.

Full text of DOI:10.1021/jo060556q

In this Note we describe an alternative convergent synthesis
of 2 based on the palladium-catalyzed carbonylative Sonogashira
coupling4 of 2-iodo-5-methoxyaniline (4) with thiazolylacetylene
5 (Scheme 1). This approach may also provide a practical and
general access4 to polysubstituted quinolones related to structure
2.
Convergent Synthesis of the Quinolone
Substructure of BILN 2061 via Carbonylative
Sonogashira Coupling/Cyclization
Nizar Haddad,* Jonathan Tan, and Vittorio Farina
The synthesis of 4 from the commercially available 4-iodo-
3-nitroanisole is straightforward.5 Reduction of 4-iodo-3-ni-
troanisole with hydrazine hydrate leads to 4 in 79% isolated
yield 5a (Scheme 2). A 93% yield has recently been reported in
the reduction of 4-iodo-3-nitroanisole with hydrazine monohy-
drate in the presence of FeCl3.5b
The synthesis of thiazolylacetylene 5 was accomplished by
two different methods; the first one (Scheme 3) is based on the
preparation of iodothiazole 8 from 2-isopropylaminothiazoline-
4-one 6.6 Following Wiemer’s protocol7 for the synthesis of
vinyl iodides from ketones, thiazolyl phosphate 7 was prepared
from 6 in 83% yield, then it was converted without further
purification to the desired iodothiazole 8 upon treatment with
in situ generated TMSI. Sonogashira coupling8 with TMS-
acetylene provided the desired product 9 in quantitative yield.
Removal of the TMS protecting group9 was achieved in 98%
isolated yield upon treatment of 9 with K2CO3/MeOH, providing
the target substructure 5 ready for coupling with 4.
An alternative synthesis of 5 introduces the acetylene upon
coupling of lithiated TMS-acetylene to the previously reported10
N-methoxy-N-methylchloroacetamide 10 to provide 1111 in 93%
yield. Subsequently, 11 was converted, without further purifica-
tion, to thiazole 9 upon treatment with isopropyl thiourea in
54% isolated yield over two steps. Cleavage of the TMS
protecting group (K2CO3/MeOH) provided 5 in almost quantita-
tive yield (Scheme 4).
Palladium-catalyzed carbonylative Sonogashira/cyclization of
iodoanilines and iodophenols with terminal acetylenes has been
reported to provide selective formation of quinolones and
chromones, respectively, in high yields. On the basis of findings
by Torii and Kalinin,4 we expected that Et2NH (used as solvent)
should provide a good balance of basicity and steric hindrance
for carbonylative coupling/cyclization of iodoanisidine 4 with
thiazolylacetylene 5. We hoped to be able to minimize formation
of the corresponding amide 12 (Scheme 5) and promote
formation of a six- vs five-membered ring (sometimes observed
Department of Chemical DeVelopment, Boehringer Ingelheim
Pharmaceuticals Inc., 900 Ridgebury Rd., P.O. Box 368,
Ridgefield, Connecticut 06877-0368
nhaddad@rdg.boehringer-ingelheim.com
ReceiVed March 13, 2006
A convergent synthesis of quinolone 2 (key substructure of
the protease inhibitor BILN 2061) was developed via
palladium-catalyzed carbonylation of 2-iodo-5-methoxy-
aniline (4) with thiazolylacetylene 5.
BILN 2061 has recently been reported as the first Hepatitis
C virus (HCV) NS3 protease inhibitor that shows antiviral
effects in infected humans.1 A discovery synthesis of the drug
was recently reported.2 The thiazole moiety of the quinoline
substructure was constructed through several transformations
including an Arndt-Eistert reaction, which employs the unsafe
reagent diazomethane (Scheme 1). As part of our studies on a
scalable synthesis of BILN 2061, we became interested in
devising a convergent approach to the quinolone subunit 2. A
preliminary scalable synthesis of 2 has recently been developed
in our group, and it is based on the cyclization of aryl amide 3
(Scheme 1).3
(1) (a) Reiser, M.; Hinrichsen, H.; Benhamou, Y.; Sentjens, R.; Wede-
meyer, H.; Calleja, L.; Forns, X.; Croenlein, J.; Yong, C.; Nehmiz, G.;
Steinmann, G. Hepatology 2003, 38 (Suppl. 1), 221A. (b) Lamarre, D.;
Anderson, P. C.; Bailey, M.; Beaulieu, P.; Bolger, G.; Bonneau, P.; Boes,
M.; Cameron, D. R.; Cartier, M.; Cordingley, M. G.; Faucher, A.-M.;
Goudreau, N.; Kawai, S. H.; Kukolj, G.; Lagace, L.; LaPlante, S. R.; Narjes,
H.; Poupart, M.-A.; Rancourt, J.; Sentjens, R. E.; St. George, R.; Simoneau,
B.; Steinmann, G.; Thibeault, D.; Tsantrizos, Y. S.; Weldon, S. M.; Yong,
C.-L.; Llina´s-Brunet, M. Nature 2003, 426, 186. (c) Benhamou, Y.;
Hinrichsen, H.; Sentjens, R.; Reiser, M.; Manns, M. P.; Forns, X.; Avendano,
C.; Croenlein, J.; Nehmiz, G.; Steinmann, G. Hepatology 2002, 36, 304A,
Abstract 563. (d) Hinrichsen, H.; Benhamou, Y.; Reiser, M.; Sentjens, R.;
Wedemeyer, H.; Calleja, J. L.; Forns, X.; Croenlein, J.; Nehmiz, G.;
Steinmann, G. Hepatology 2002, 36, 297A, Abstract 866.
(2) (a) Faucher, A.-M.; Bailey, M. D.; Beaulieu, P. L.; Brochu, C.;
Duceppe, J.-S.; Ferland, J.-M.; Ghiro, E.; Gorys, V.; Halmos, T.; Kawai,
S. H.; Poirier, M.; Simoneau, B.; Tsantrizos, Y. S.; Llina´s-Brunet, M. Org.
Lett. 2004, 6, 2901-2904. (b) Yee, N. K.; Farina, V.; Houpis, I. N.; Haddad,
N.; Frutos, R. P.; Gallou, F.; Wang, X.-J.; Wei. X.; Simpson, R. D.; Feng,
X.; Fuchs, V.; Xu, Y.; Tan, J.; Zhang, L.; Xu, J.; Smith-Keenan, L. L.;
Vitous, J.; Ridges, M. D.; Spinelli, E. M.; Johnson, M. J. Org. Chem.
Submitted for publication.
(4) (a) Torii, S.; Okumoto, H.; Xu, L.; Sadakane, M.; Shostakovsky, M.
V.; Ponomaryov, A. B.; Kalinin, V. N. Tetrahedron 1993, 49, 6773 and
references therein. (b) Kalinin, V. N.; Shostakovsky, M. V.; Ponomaryov,
A. B. Tetrahedron Lett. 1992, 33, 373.
(5) (a) Han, B. H.; Shin, D, H.; Cho, S. Y. Tetrahedron Lett. 1985, 26,
6233. (b) Ma, C.; Liu, X.; Li, X.; Flippen-Anderson, J.; Yu, S.; Cook, J.
M. J. Org. Chem. 2001, 66, 4525. (c) Jia, Y.; Zhu, J. Synlett 2005, 2469.
(d) For reduction of similar structures under hydrazine-free conditions see:
Andersen, A.; Wang, S.; Thompson, R. D.; Neumeyer, J. L. J. Heterocycl.
Chem. 1997, 34, 1633.
(6) Akerblom, E. Acta Chem. Scand. 1967, 21, 843.
(7) Lee, K.; Wiemer, D. F. Tetrahedron Lett. 1993, 34, 2433.
(8) (a) Sonogashira, K.; Tohda, Y.; Hagiwara, N. Tetrahedron Lett. 1975,
16, 4467. (b) Shin, K.; Ogasawara, K. Synlett 1995, 859.
(9) (a) Reference 8b. (b) Wender, P. A.; McKinney, J. A.; Mukai, C. J.
Am. Chem. Soc. 1990, 112, 5369. (c) Suffert, J. Tetrahedron Lett. 1990,
31, 7437.
(3) For scalable synthesis of quinolone 2 from 3 see: Frutos, R. P.;
Haddad, N.; Houpis, I.; Johnson, M.; Smith-Keenan, L. L.; Fuchs, V.; Yee,
N. K.; Farina, V.; Faucher, A.-M.; Brochu, C.; Hache´, B.; Duceppe, J.-S.;
Beaulieu, P. Synthesis. In press.
(10) Tillyer, R.; Frey, L. F.; Tschaen, D. M.; Dolling, U. H. Synlett 1996,
225.
(11) For an alternative synthesis of compound 11 see: Livingston, R.;
Cox, L. R.; Odermatt, S.; Diederich, F. HelV. Chim. Acta 2002, 85, 3052.
10.1021/jo060556q CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/20/2006
J. Org. Chem. 2006, 71, 5031-5034
5031

SCHEME 1. (a) Reported Discovery Approach and (b1, b2) Convergent Approaches
SCHEME 2
SCHEME 3
quinolone 2 in 71% assay yield with 3.8% of amide 12 and no
detectable amount of 15. The structure of 2 was confirmed by
1
comparison of its H NMR, 13C NMR, and LCMS data to an
authentic sample that was prepared by cyclization of amide 3
(Scheme 1, b1)3.
A slightly improved yield was consistently obtained when
PdCl2(dppf) was used as catalyst. High conversion with low
yield of quinolone 2 was obtained when Pd(OAc)2 was used as
catalyst (entry 3); in fact amide 12 was obtained as the major
product under these conditions. Recent interest in the application
of palladium-thiourea-dppp complex in carbonylative Sono-
gashira under mild conditions and its application in the synthesis
of flavones12 led us to examine these catalytic conditions for
the formation quinolone 2 (entry 4). The results after 24 h at
50 °C indicate 50% conversion with less than 20% yield along
with the formation of 10% of amide 12. The reaction with PdCl2-
(dppf) was also run at lower temperature and CO pressure (entry
5): interestingly, complete conversion was detected after 24 h
providing quinolone 2 in 60% yield, although higher levels of
amide 12 were detected.
On the basis of the above data, we used PdCl2(dppf) as
catalyst in Et2NH at 120 °C under 250 psi of CO, and obtained
the desired quinolone 2 in 70% isolated yield. Amide 12 was
detected in 2.9% as the major side-product in the reaction
mixture, with no detectable amount of 15. LCMS data indicated
the presence of intermediates 13 and 14 at levels below 0.5%.
In summary, a convergent synthesis of 2, the quinolone
substructure of BILN 2061, was developed by applying Pd-
catalyzed carbonylative annulation as the key step in the
sequence. The synthesis of thiazoleacetylene 5 and the carbo-
nylative Sonogashira/cyclization step may provide general access
to structurally related quinolones.
SCHEME 4. Alternative Synthesis of 5
Experimental Section
2-Iodo-5-methoxyaniline (4). A two-necked 100-mL flask,
equipped with condenser, was charged with 4-iodo-3-nitroanisole
(2.79 g, 10.0 mmol), graphite (3 g), and absolute ethanol (30 mL)
under N2 atmosphere. Hydrazine monohydrate (0.97 mL, 20.0
mmol) was added at 25 °C then the mixture was heated to reflux
for 8 h. The reaction mixture was cooled to room temperature and
filtered through Celite. The solvent was removed under reduced
pressure and the product was purified by flash chromatography (40
g silica, EtOAc:Hex gradient from 1:8 to 1:1, respectively) to
in related protocols4,12) by selective 6-endo-cyclization, by
routing reactive intermediate 13 through intermediate 14, and
therefore direct the ring-closure to provide, regioselectively, the
desired quinolone 2.
Several reaction conditions for the coupling/cyclization
sequence were examined and the key results are summarized
in Table 1. The typical conditions (entry 1) provided the desired
(12) Miao, H.; Yang, Z. Org. Lett. 2000, 2, 1765.
5032 J. Org. Chem., Vol. 71, No. 13, 2006

SCHEME 5. Formation of Quinolone 2
TABLE 1. Catalysts Effect on the Carbonylative Sonogashira
Coupling/Cyclization
column chromatography (hexanes:EtOAc, 2:1, Rf 0.6) to give 3.5
g of 8 in 55% yield. 1H NMR (400 MHz, CDCl3): δ 6.56 (s, 1H),
5.24 (br s, 1H), 3.63 (m, 1H), 1.29 (d, J ) 6.4, 6H). 13C NMR
(100 MHz, CDCl3): δ 169.6, 109.8, 90.0, 49.1, 22.7; HRMS (APCI)
calcd for [M + H]+ C6H10IN2S 268.9609, found 268.9615.
ThiazoleTMS-acetylene (9): (a) From 4-iodo-2-isopropylami-
nothiazoline (8): To a solution of 8 (75.0 mg, 0.28 mmol) and
TMS-acetylene (0.12 mL, 0.84 mmol) in Et3N (3 mL) were added
PdCl2(PPh3)2 (19.7 mg, 0.028 mmol) and CuI (5.4 mg, 0.028 mmol)
then the mixture was stirred under Ar atmosphere at reflux for 2 h.
The reaction mixture was cooled to room temperature, diluted with
MTBE (10 mL), then washed with brine. The organic fraction was
concentrated under reduced pressure then the product was purified
by column chromatography (Hex:EtOAc 4:1) to give 65.3 mg of
the desired product 9 in 98% yield.
time,
h
amide yield,b
entry
1
catalyst
conditions
12,a %
%
PdCl2(PPh3)2
6
6
250 psi CO, 120 °C
in Et2NH
250 psi CO, 120 °C
in Et2NH
250 psi CO, 120 °C
in Et2NH
50 psi CO, 50 °C,
DBU in Et2NH
50 psi CO, 50 °C
in Et2NH
3.8
71
2
3
4
5
PdCl2(dppf)
Pd(OAc)2
2.9
68.3
10.4
5.3
73c
25
6
PdCl2(PPh3)2,
thiourea-dppp,
PdCl2(dppf)
24
24
<20
60
a Area % at 256 nm relative to quinolone 2. b Yield was determined by
HPLC quantitative assay. c 70% Isolated yield after column chromatography.
(b) From N-methoxy-N-methylchloroacetamide (10): To a
cold (-20 °C) solution of TMS-acetylene in toluene (5 mL) was
added LHMDS (8.0 mL, 1 M in THF, 8 mmol) dropwise over 2
min keeping T < -5 °C. The mixture was stirred at 0 °C for 30
min, then transferred to the cold (-10 °C) reaction mixture that
contains amide 10 (1.0 g, 7.2 mmol) in toluene (10 mL) at a rate
that kept T < -5 °C. The resulting mixture was stirred for 20 min
at -5 °C then 1.5 h at room temperature, quenched by slow addition
to cold 1 N HCl (5 mL) under N2, then stirred for 5 min. The
organic fraction was separated and washed with brine, then dried
over Na2SO4. Evaporation of the solvents under reduced pressure
provided crude 11 (1.17 g, 93% yield) which was used for next
1
provide 1.97 g of the desired product in 79% isolated yield. H
NMR (400 MHz, CDCl3) δ 7.46 (d, J ) 8.7 Hz, 1H), 6.29 (d, J )
2.8 Hz, 1H), 6.11 (dd, J ) 2.8, 8.7 Hz, 1H), 4.02 (s, 2H), 3.72 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 161.0, 147.7, 138.9, 106.6,
100.0, 73.5, 55.1; NMR data are in full agreement with the
published data for this compound in ref 5b.
4-Iodo-2-isopropylaminothiazoline (8). In a three-necked 500-
mL flask, equipped with mechanical stirrer, N2 inlet, and addition
funnel, KHMDS (0.5 M in toluene, 96 mL, 48.0 mmol) was added
to a cold (-20 °C) mixture of 2-isopropylaminothiazoline-4-one
(5.09 g, 32.2 mmol) in dry THF (200 mL). The mixture was stirred
for 20 min then diphenylchlorophosphate (10.0 mL, 48.3 mmol)
was added at this temperature followed by stirring at 0 °C for an
additional 90 min. The reaction mixture was then treated with 1.8
M NH4OH (70 mL), and the product was extracted with MTBE
(200 mL), dried over Na2SO4, then concentrated under reduced
pressure to provide 10.43 g of the labile intermediate 2-isopropyl-
aminothiazoline-4-diphenyl phosphate (7) in 83% yield. The product
1
step without further purification. H NMR (400 MHz, CDCl3): δ
4.23 (s, 2H), 0.26 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 178.1,
103.1, 99.1, 49.4, -1.0; NMR data are in full agreement with the
published data in ref 11.
A solution of crude R-chloroketone 11 (1.17 g, 6.7 mmol) and
isopropylthiourea (0.792 g, 6.7 mmol) in THF (14 mL) was stirred
at room temperature for 16 h. Water (10 mL) and MTBE (20 mL)
were added, the organic fraction was separated, and the aqueous
was washed with 2 × 6 mL of TBME. The combined organics
were washed with brine, dried over Na2SO4, concentrated, and
purified by flash chromatography (Hex:EtOAc 10:1, respectively)
to give 0.86 g of pure product 9 in 54% isolated yield over the two
1
was used for the next step without further purification. H NMR
(400 MHz, CDCl3): δ 7.32 (m, 5H), 7.26 (m, 5H), 5.97 (s, 1H),
5.07 (br s, 1H), 3.61 (m, 1H), 1.24 (d, J ) 6.4, 6H).
NaI (8.94 g, 60 mmol) was added to the solution of crude
phosphate 7 (7.7 g, 19.9 mmol) in dry acetonitrile (70 mL). The
mixture was cooled to 0 °C followed by dropwise addition of TMS
chloride (7.57 mL, 60 mmol). The reaction mixture was stirred at
room temperature for 90 min, then quenched by addition of a
saturated solution of NaHCO3 (30 mL). CH2Cl2 (70 mL) was added,
and the aqueous fraction was separated and extracted with CH2Cl2
(70 mL). The combined organics were dried over Na2SO4, then
concentrated under reduced pressure. The product was purified by
1
steps. H NMR (400 MHz, CDCl3): δ 6.50 (s, 1H), 6.18 (br d,
1H), 3.39 (m, 1H), 1.05 (d, J ) 6.5, 6H), 0.05 (s, 9H). 13C NMR
(100 MHz, CDCl3): δ 168.7, 133.3, 111.9, 99.8, 93.5, 48.6, 22.9,
0.00; HRMS (APCI) Calcd for [M + H]+ C11H19N2SSi 239.1038,
found 239.1045.
4-Ethynyl-2-isopropylaminothiazoline (5). Alkyne 9 (1.0 g, 4.2
mmol) was dissolved in MeOH (30 mL), then cooled to 0 °C. K2-
CO3 (0.62 g, 4.5 mmol) was added and stirring was continued at 0
J. Org. Chem, Vol. 71, No. 13, 2006 5033

°C for an additional 1.5 h. The reaction was diluted with EtOAc
(20 mL) and water (20 mL) and the aqueous fraction was washed
with EtOAc, then the organics were combined, washed with brine,
dried, and concentrated under reduced pressure to give 0.68 g of
water provided 0.88 g of pure product in 70% isolated yield. Mp
245-247 °C. H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H),
1
7.95 (d, J ) 8.9 Hz, 1H), 7.76 (d, J ) 7.6 Hz, 1H), 7.50 (s, 1H),
7.28 (d, J ) 2.3 Hz, 1H), 6.89 (dd, J ) 2.3, 8.9 Hz, 1H), 6.52 (d,
J ) 1.6 Hz, 1H), 3.98 (m, 1H), 3.87 (s, 3H), 1.22 (d, J ) 6.5 Hz,
6H). 13C NMR (100 MHz, DMSO-d6) δ 176.6, 167.6, 161.9, 144.0,
143.4, 141.8, 126.4, 119.5, 113.0, 106.6, 105.6, 99.6, 55.4, 46.2,
22.3; HRMS (APCI) calcd for C16H18N3O2S 316.1114, found
316.1108. Analytical data are in full agreement with those of the
authentic compound from ref 3.
1
the desired product in >97% yield. H NMR (400 MHz, CDCl3):
δ 6.70 (s, 1H), 5.5 (br s, 1H), 3.82 (m, 1H), 3.05 (s, 1H), 1.25 (d,
J ) 6.4, 6H). 13C NMR (100 MHz, CDCl3): δ 167.9, 132.2, 112.2,
78.7, 76.1, 48.0, 22.8; HRMS (APCI) calcd for [M + H]+ C8H11N2S
167.0643, found 167.0641.
2-(2-Isopropylaminothiazol-4-yl)-7-methoxy-4a,8a-dihydro-
1H-quinolin-4-one (2). 2-Iodo-5-methoxyaniline (224.15 mg, 0.9
mmol) and thiazoleacetylene 5 (200.00 mg, 1.2 mmol) were stirred
in Et2NH (3 mL) in the presence of PdCl2(dppf) (10.0 mg, 0.014
mmol) at 120 °C under 250 psi of CO for 6 h. The reaction was
cooled to room temperature, then diluted with MeOH (20 mL).
Water (40 mL) was added dropwise at room temperature in 20 min
to precipitate the product, which after filtration and drying provided
1.2 g of crude product of 73% purity. Recrystallization from MeOH/
Supporting Information Available: 1H NMR of 7; 1H and 13
C
NMR spectra for compounds 2, 4, 5, 8, 9, 11, and an authentic
sample 2. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO060556Q
5034 J. Org. Chem., Vol. 71, No. 13, 2006