Novel approach to 3,4-dihydro-2(1H)-quinolinone derivatives via cyclopropane ring expansion

Article abstract of DOI:10.1021/ol802669r

N-(1'-Alkoxy)cyclopropyl-2-haloanilines are transformed to 3,4-dihydro-2(¹H)-quinolinones via palladium-catalyzed cyclopropane ring expansion. The reaction tolerates a variety of functional groups such as ester, nitrile, ether, and ketone group

Full text of DOI:10.1021/ol802669r

ORGANIC
LETTERS
2009
Vol. 11, No. 5
1043-1045
Novel Approach to
3,4-Dihydro-2(1H)-quinolinone Derivatives
via Cyclopropane Ring Expansion
Takayuki Tsuritani,* Yuhei Yamamoto, Masashi Kawasaki, and Toshiaki Mase
Process Research, PreClinical Department, Banyu Pharmaceutical Co. Ltd., 3 Okubo,
Tsukuba, Ibaraki 300-2611, Japan
takayuki_tsuritani@merck.com
Received November 19, 2008
ABSTRACT
N-(1′-Alkoxy)cyclopropyl-2-haloanilines are transformed to 3,4-dihydro-2(1H)-quinolinones via palladium-catalyzed cyclopropane ring expansion.
The reaction tolerates a variety of functional groups such as ester, nitrile, ether, and ketone groups.
The benzo-fused lactam skeleton is an important element in
a number of pharmacologically and biologically active
compounds. The 3,4-dihydro-2(1H)-quinolinone scaffold is
one important member of this class, and its derivatives are
found in many natural products and drug candidates.1 3,4-
Dihydro-2(1H)-quinolinones are classically synthesized via
electrophilic aromatic substitution reactions, such as the
Friedel-Crafts reaction,2a Beckmann rearrangement of in-
danone oxime,2b and cyclization of nitrenium ion;2c,d how-
ever, these methods require a stoichiometric amount of metal
salt. Moreover, the reactions with electron deficient substrates
in general give unsatisfactory results. Recently, various
reports of efficient catalytic systems for the preparation of
3,4-dihydro-2(1H)-quinolinones have been published.3
During the course of our study we found that 2-methoxy-
3,4-dihydroquinoline (2a) was formed as a byproduct when
N-(1′-methoxy)cyclopropyl-2-iodoaniline (1a) was subjected
to Larock indole synthesis conditions (Scheme 1).4,5 This
Scheme 1. Larock Indole Synthesis against
N-(1′-Methoxy)cyclopropyl-2-iodoaniline
(1) (a) Chen, M.-H.; Fitzgerald, P.; Singh, S. B.; O’Neill, E. A.;
Schwartz, C. D.; Thompson, C. M.; O’Keefe, S. J.; Zaller, D. M.; Doherty,
J. B. Bioorg. Med. Chem. Lett. 2008, 18, 2222. (b) Singer, J. M.; Barr,
B. M.; Coughenour, L. L.; Gregory, T. F.; Walters, M. A. Bioorg. Med.
Chem. Lett. 2005, 15, 4560. (c) Oshiro, Y.; Sakurai, Y.; Sato, S.; Kurahashi,
N.; Tanaka, T.; Kikuchi, T.; Tottori, K.; Uwahodo, Y.; Miwa, T.; Nishi, T.
J. Med. Chem. 2000, 43, 177. (d) Zhao, H.; Thurkauf, A.; Braun, J.;
Brodbeck, R.; Kieltyka, A. Bioorg. Med. Chem. Lett. 2000, 10, 2119. (e)
Tamura, Y. S.; Goldman, A. E.; Bergum, W. P.; Semple, E. J. Bioorg.
Med. Chem. Let. 1999, 9, 2573.
result prompted us to examine this palladium-catalyzed
cyclopropane ring expansion reaction. The 3,4-dihydroquino-
(2) (a) Beck, J. R.; Kwok, R.; Booher, R. N.; Brown, A. C.; Patterson,
L. E.; Pranc, P.; Rockey, B.; Pohland, A. J. Am. Chem. Soc. 1968, 90,
4706. (b) Torisawa, Y.; Nishi, T.; Minamikawa, J. Bioorg. Med. Chem.
Lett. 2007, 17, 448. (c) Kikugawa, Y.; Nagashima, A.; Sakamoto, T.;
Miyazawa, E.; Shiiya, M. J. Org. Chem. 2003, 68, 6739. (d) Cherest, M.;
Lusinchi, X. Tetrahedron Lett. 1989, 30, 715.
(3) (a) Fujita, K.; Takahashi, Y.; Owaki, M.; Yamamoto, K.; Yamaguchi,
R. Org. Lett. 2004, 6, 2785. (b) Yang, B. H.; Buchwald, S. L. Org. Lett.
1999, 1, 35. (c) Wolfe, J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron
1996, 52, 7525. (d) Ali, B. E.; Okuro, K.; Vasapollo, G.; Alper, H. J. Am.
Chem. Soc. 1996, 118, 4264. (e) Jones, K.; Wilkinson, J.; Ewin, R.
Tetrahedron Lett. 1994, 35, 7673
.
10.1021/ol802669r CCC: $40.75
Published on Web 02/04/2009
2009 American Chemical Society

Table 1. Optimization of the Pd(0)-Catalyzed Cyclopropane
Ring-Expansion Reaction of 1ba
Table 2. Synthesis of Substituted 3,4-Dihydro-2(1H)-
quinolinonesa
entry
Pd (x)
ligand (y)
PPh3 (12)
base
yield [%]b
1
2
3
4
5
6
Pd(OAc)2 (5)
Pd2(dba)3 (1.5)
Pd(OAc)-P(biphenyl)(t-Bu)2 (3.0)
Pd2(dba)3 (1.5)
Pd2(dba)3 (1.5)
Pd2(dba)3 (1.5)
Pd2(dba)3 (1.5)
Pd2(dba)3 (1.5)
Pd2(dba)3 (1.5)
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
t-BuOK
K2CO3
K2CO3
14
11
39
82
22
93
0
PPh3 (7.5)
X-Phos (7.5)
BIPHEP (3.8)
X-Phos (7.5)
X-Phos (7.5)
X-Phos (7.5)
X-Phos (7.5)
7
8c
42
7
9d
a Reaction was conducted under nitrogen atmosphere on 1.0 mmol scale.
b Yield was determined by HPLC. c Reaction was conducted at 60 °C.
d Reaction was conducted at 40 °C.
line 2a was thought to be obtained through an intramolecular
reaction of 1a, and hence when the reaction was conducted
in the absence of the alkyne, 2-methoxy-3,4-dihydroquinoline
(2a) was obtained in a better yield. Herein we report a novel
synthesis of 3,4-dihydro-2(1H)-quinolinones from N-(1′-
alkoxy)cyclopropyl-2-haloanilines. N-(1′-Alkoxy)cyclopro-
pyl-2-haloanilines were readily synthesized from the corre-
sponding 2-haloanilines with (1-ethoxycyclopropoxy)-
trimethylsilane according to Yoshida’s procedure.6
When we applied this protocol to the corresponding bromo
derivative 1b instead of iodide 1a, the desired compound
2a was obtained in only 14% yield (Table 1, entry 1). To
improve the yield, the reaction conditions were extensively
examined. The results are summarized in Table 1. It was
found that the choice of palladium ligand was quite
important. The use of the electron-rich biphenyl-based
phosphine ligands7 delivered the desired compound 2a in
good yield (Table 1, entries 3 and 4). Especially, when the
more sterically demanding ligand, X-Phos, was employed,
a significant improvement was achieved.8 The use of K2CO3
as base led to the best result (Table 1, entry 4 vs 6) while
t-BuOK gave no desired compound (Table 1, entry 7). A
lower reaction temperature resulted in a lower yield (Table
1, entries 8 and 9). When the reaction was performed in
toluene or dioxane as a solvent instead of DMF under the
optimized conditions, the conversion became lower (10%
conversion in toluene and 35% conversion in dioxane).
a Reaction was conducted under a nitrogen atmosphere on 1.0 mmol
scale. b Yield of the isolated product. c Reaction was quenched with 1N
HCl instead of H2O. d Average yield for 2 experiments.
With optimized reaction conditions in hand, we next
examined the scope and limitations of this reaction. The
results are summarized in Table 2. Chloroaniline derivatives
also furnished the desired cyclized products in moderate yield
although the corresponding bromo- and iodoaniline deriva-
tives gave better yields with a shorter reaction period (Table
2, entries 4, 13, and 16). In some cases, the 2-alkoxy-3,4-
dihydroquinoline 2 was partially hydrolyzed during aqueous
workup operations, and 3,4-dihydro-2(1H)-quinolinone 3 was
obtained as byproduct (Table 2, entry 5). Though this
hydrolysis was suppressed when the substrate bearing the
more sterically demanding group, such as isopropyl, was
employed, the conversion was lower (Table 2, compare
entries 5, 7, and 8).9 Therefore, we decided to conduct the
hydrolysis of the 2-alkoxy-3,4-dihydroquinolines before the
extraction. The reaction tolerated a variety of functional
groups, such as ester (Table 2, entries 5-8), nitrile (Table
2, entry 10), ether (Table 2, entries 12 and 13), and ketone
(Table 2, entry 18) groups. The substrate bearing a NO2
(4) Tsuritani, T.; Strotman, N. A.; Yamamoto, Y.; Kawasaki, M.;
Yasuda, N.; Mase, T. Org. Lett. 2008, 10, 1653.
(5) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689.
(6) Yoshida, Y.; Umezu, K.; Hamada, Y.; Atsumi, N.; Tabuchi, F. Synlett
2003, 2139.
(7) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapers, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653.
(8) We also examined other biphenyl-based phosphine ligands, such as
S-Phos, Ru-Phos, and Dm-Phos with the reaction of 1k; however, better
results were not obtained (Table 2, entry 13).
(9) About 10% of 3,4-dihydro-2(1H)-quinolinone was generated when
the reaction of 1j or 1p was quenched with water.
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Org. Lett., Vol. 11, No. 5, 2009

Scheme 2
.
Plausible Reaction Mechanism
Scheme 3. Reaction with Diaminoacetal 5
37% yield along with 7 and 8 in 28% yield (Scheme 3).
This transformation can be explained by the cyclopropane
ring expansion of 5 followed by palladium-catalyzed in-
tramolecular N-arylation.12 The formation of N-aryl-2,3-
dihydro-1H-benzoimidazole 9, which would be generated by
palladium-catalyzed intramolecular N-arylation of 1,1-di-
anilinocyclopropane 5, was not observed.
In conclusion, we have developed a novel synthetic method
for the construction of 3,4-dihydro-2(1H)-quinolinones via
cyclopropane ring expansion. This method is also applicable
to synthesize 5,6-dihydrobenzimidazo[1,2-a]quinoline. Fur-
ther studies to expand this chemistry and provide deeper
insight into the mechanism are currently under investigation
in our laboratory.
substituent gave no desired compound while the substrate
was consumed completely (Table 2, entry 17).
A plausible reaction mechanism is shown in Scheme 2.
The oxidative addition of aryl halide 1b to palladium(0) I
followed by intramolecular ligand exchange would give the
four-membered azapalladacycle III.10 Then, palladium rear-
rangement accompanied with cyclopropane ring opening
furnishes the energetically favorable seven-membered aza-
palladacycle IV.11 Finally, reductive elimination produces
2-methoxy-3,4-dihydroquinoline (2a), and the regeneration
of the reactive palladium(0) species I. The formation of
N-aryl-R,ꢀ-unsaturated imidate 4, which would be generated
by ꢀ-hydride elimination from the palladacycle IV, was not
observed.
Acknowledgment. We thank Dr. Yasuda N., Merck &
Co. Inc., for his helpful advice and Dr. Ohsawa H., Merck
& Co. Inc., for HRMS measurements.
Interestingly, when 1,1-dianilinocyclopropane 5 was em-
ployed instead of N-(1′-alkoxy)cyclopropyl-2-haloanilines 1,
5,6-dihydrobenzimidazo[1,2-a]quinoline 6 was obtained in
Supporting Information Available: Detailed experimen-
tal procedures and characterization data of each compound.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(10) (a) Watanabe, T.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2008,
10, 1759. (b) Sole´, D.; Serrano, O. Angew. Chem., Int. Ed. 2007, 46, 7270.
(c) Sole´, D.; Vallverdu´, L.; Solans, X.; Font-Bardia, M.; Bonjock, J. J. Am.
Chem. Soc. 2003, 125, 1587.
(11) This rearrangement is considered to be a heteroanalogue of a
cyclopropylcarbinylpalladium to homoallylpalladium sigma complex trans-
formation. For cyclopropylmethylpalladium to homoallylpalladium rear-
rangements, see: (a) Zhao, L.; de Meijere, A. AdV. Synth. Catal. 2006, 248,
2484. (b) Nu¨ske, H.; Bra¨se, S.; Kozhushkov, S. I.; Noltemeyer, M.; Es-
Sayed, M.; de Meijere, A. Chem.-Eur. J. 2002, 8, 2350.
OL802669R
(12) A similar type of this palladium-catalyzed intramolecular N-arylation
was reported by Junjappa: Venkatesh, C.; Sundaram, G. S. M.; Ha, H.;
Junjappa, H. J. Org. Chem. 2006, 71, 1280.
Org. Lett., Vol. 11, No. 5, 2009
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