The palladium-catalyzed transfer hydrogenation/heterocyclization of β- (2-aminophenyl)-α,β-ynones. An approach to 2-aryl- and 2-vinylquinolines

Article abstract of DOI:10.1055/s-1999-2629

The palladium-catalyzed transfer hydrogenation/cyclization of readily available β-(o-aminophenyl)-α,β-ynones I affords 2-aryl- and 2- vinylquinolines 3 in good yield.

Full text of DOI:10.1055/s-1999-2629

LETTER
401
The Palladium-Catalyzed Transfer Hydrogenation/Heterocyclization of b-(2-
Aminophenyl)-a,b-ynones. An Approach to 2-Aryl- and 2-Vinylquinolines
Sandro Cacchi,*a Giancarlo Fabrizi,a Fabio Marinelli*b
a Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Università “La Sapienza”, P.le A. Moro 5,
00185 Roma, Italy
b Dipartimento di Chimica, Ing. Chimica e Materiali, Via Vetoio, 67100 L’Aquila, Italy
Fax + 39 (6) 4991.2780; E-mail: cacchi@uniroma1.it
Received 28 December 1998
Abstract. The palladium-catalyzed transfer hydrogenation/cycliza-
tion of readily available b-(o-aminophenyl)-a,b-ynones 1 affords 2-
aryl- and 2-vinylquinolines 3 in good yield.
Key words: quinolines, transfer hydrogenation, palladium cataly-
sis, cyclization, alkynes
The quinoline nucleus is prevalent in a variety of biologi-
cally active compounds. In particular, the 2-substituted
quinoline subunit is present in some naturally occurring
substances1 and in a new and structurally simple class of
peptidoleukotriene LTD4 antagonists, developed recently
as very promising antiasthmatic therapeutics.2 One of
these compounds has also been shown to inhibit the plate-
let-activating factor (PAF) synthesis.3
Numerous approaches to the construction of the quinoline
skeleton have been reported4 and palladium-mediated
syntheses have drawn considerable interest in recent
years. Palladium catalysis in this area has been applied to
the hydroarylation(hydrovinylation)/cyclization of 3,3-di-
ethoxy-1-(o-acetamidophenyl)-1-propyne with aryl and
vinyl halides;5 to the reaction of o-iodoanilides with sub-
stituted alkenes followed by a cyclization step;6a-d to the
coupling/oxidation/cyclization of o-iodoanilides with
acetylenic carbinols;7 and the carbonylative coupling/con-
jugate addition/cyclization of o-ethynylanilines with aryl
iodides.8
Scheme 1
Herein we report that the palladium-catalyzed transfer
hydrogenation9,10/ cyclization of readily available b-(o-
aminophenyl)-a,b-ynones 1 may provide a promising,
new approach to 2-aryl- and 2-vinylquinolines 3 (Scheme
1).
Aryl a,b-ynones, 1a-h, have been synthesized through the
carbonylative coupling of o-trimethylsilylethynylaniline
7a11 and aryl iodides (Scheme 2a). The preparations have
been carried out in the presence of PdCl2, a bidentate
phosphine ligand and n-Bu4NF, under a balloon of carbon
monoxide, according to our standard conditions (Scheme
2a).12 Our results are summarized in Table 1.
Scheme 2
This procedure gave good results with aryl iodides bear-
ing electron-donating substituents (Table 1, entries 1 and
2). However, in the presence of electron-withdrawing
substituents, the corresponding a,b-ynones were obtained
in low yield. The competitive non-carbonylative coupling
leading to 9 was found to be a significant side reaction or
the main reaction pathway (Table 1, entries 4 and 9).
Changing phosphine ligands to evaluate their possible in-
fluence on the reaction outcome proved unsatisfactory.
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402
S. Cacchi et al.
LETTER
MeOH (58 mL/mmol) at 70 °C; procedure C, 5.5 mol %
of dppf, 3.8 equiv of HCOOH, 3 equiv of Et3N, 5 mol %
Pd(OAc)217 at 70 °C.
Using these procedures, a variety of a,b-ynones 1 have
been successfully converted into 2-substituted quinolines
as summarized in Table 2. Heterogeneous conditions
(procedure B) have been found to give 3 in good yield.
However, significant amounts of overreduction deriva-
tives, the tetrahydroquinolines 6, have been sometimes
isolated. No attempts have been made to establish whether
6 is generated via transfer hydrogenation of 310j and/or cy-
clization of saturated intermediates 4 followed by reduc-
tion of the resultant 3,4-dihydro quinolines 5. Higher
product selectivity has been observed under homoge-
neous conditions, though quinoline products have been
often isolated in lower yield. With vinyl a,b-ynones the
employment of procedure B may lead to the formation of
quinoline derivatives containing a saturated 2-substituent.
For example, subjection of 1j to the ammonium formate-
Pd/C system produced 2-cyclooctylquinoline18 in high
yield (Scheme 3).
For example, the sterically encumbered electron-donating
ligand tris(2,4,6-trimethoxyphenyl)phosphine (ttmpp) did
not consistently give the highest yields (Table 1, entries 6
and 10) and the use of 1,3-bis(diphenylphosphino)pro-
pane (dppp) was found to afford reaction mixtures similar
to those obtained with 1,1’-bis(diphenyl phosphino)fer-
rocene (dppf) (Table 1, compare entry 4 with entry 5). A
simple solution to the problem was found by decreasing
the concentration of the alkyne component and aryl iodide
from 0.14-0.17 M and 0.21-0.25 M, respectively, to 0.06
M and 0.09 M. Under these conditions - that increased the
concentration of carbon monoxide in the reaction - a re-
markable increase of the yield of 1 as well as of the 1:9 ra-
tio was observed (Table 1, compare entry 4 with entry 7,
entry 5 with entry 8 and entry 9 with entry 11). It has been
reported elsewhere13 that the concentration of the reagents
plays an important role in determining the regioselectivity
of the carbonylative coupling of iodophenol with nor-
bornene.
The vinyl a,b-ynones 1i and 1j have been prepared from
2-ethynylaniline 7b and the corresponding vinyl triflates
in 48 and 58% yield, respectively, in the presence of
Pd(OAc)2, dppp and triethylamine, under a balloon of car-
bon monoxide (Scheme 2b), as described in the litera-
ture.14
Three basic procedures have been developed for the pal-
ladium-catalyzed transfer hydrogenation/cyclization step:
procedure A, 3.8 equiv of HCOOH, 5 equiv of n-Bu3N, 4
mol % Pd(OAc)2(PPh3)215 in DMF (8 mL/mmol) at 70 °C;
procedure B, 3 equiv of HCOONH4, 10 mol % Pd/C16 in
Synlett 1999, No. 4, 401–404 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
The Palladium-Catalyzed Transfer Hydrogenation/Heterocyclization of b-(2-Aminophenyl)-a,b-ynones
403
Scheme 3
Scheme 5
The utilization of a,b-ynones 1 as precursors of dia-
rylquinolines through our hydroarylation/cyclization
methodology19 has been briefly explored (Scheme 4).
However, the reaction of 1a with m-iodotoluene, used as
model system, resulted in the formation of a mixture of re-
gioisomeric quinolines (Table 3, entries 1 and 2). The em-
ployment of conditions reported20 to favor the role of
coordinating effects in directing the carbopalladation step
gave rise to increased regioselectivity, with the main
product arising from the adduct bearing the palladium
fragment close to the o-aminophenyl substituent. Howev-
er, hydroarylation derivatives were isolated in poor yield
from a complex reaction mixture we have not further an-
alyzed (Table 3, entry 3).
In conclusion, the palladium-catalyzed transfer hydrogen-
ation/ cyclization approach of 2-aryl and 2-vinylquino-
lines described here may provide a useful entry into this
class of compounds. It appears to be quite simple, can tol-
erate a wide range of functional groups and allows the
preparation of numerous quinoline derivatives from readi-
ly available building blocks under mild conditions.
Acknowledgement
Work carried out in the framework of the National Project "Stereo-
selezione in Sintesi Organica. Metodologie ed Applicazioni" sup-
ported by the Ministero dell'Università e della Ricerca Scientifica e
Tecnologica, Rome, and by the University “La Sapienza”, Rome.
The authors are also greatly indebted to Dr. Luciana Turchetto of
the Istituto Superiore di Sanità for obtaining the mass spectra of new
products.
References and Notes
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Scheme 4
(5) Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L.; Pace, P. Tetra-
hedron 1996, 52, 10225.
Interestingly, when the N-trifluoroacetyl derivative 12
was subjected to m-iodotoluene in the presence of
Pd(OAc)2 and HCOOK to assess the possible influence of
the amino group of 1 on the regiochemistry of the carbo-
palladation step, no quinoline derivative was formed. The
main reaction product (42% yield) was in this case the 4-
alkylidenebenzoxazine 13 (Scheme 5), most probably
generated through the oxypalladation/reductive elimina-
tion tandem mechanism.21 The Z stereochemistry of 13
was assumed on the grounds of previously described het-
eropalladation/reductive elimination tandem reactions of
alkynes with organopalladium complexes.22
(6) (a) Cacchi, S.; Palmieri, G. Tetrahedron 1983, 39, 3373;
(b) Larock, R.C.; Babu, S. Tetrahedron Lett. 1987, 28, 5291;
(c) Larock, R.C.; Kuo, M.Y. Tetrahedron Lett. 1991, 32, 569;
(d) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Pace, P.
Synlett 1996, 568.
(7) Kundu, N.; Mahanty, J.S.; Das, P.; Das, B. Tetrahedron Lett.
1993, 34, 1625; Mahanty, J.S.; De, M.; Das, P.; Kundu, N. Te-
trahedron 1997, 53, 13397.
(8) Torii, S.; Xu, L.H.; Sadakane, M.; Okumoto, H. Synlett 1992,
513.
(9) For reviews, see: Ram, S.; Ehrenkaufer, R.E. Synthesis 1988,
91; Johnstone, R.A.W.; Wilby, A.H.; Entwistle, I.D. Chem.
Rev. 1985, 85, 129.
Synlett 1999, No. 4, 401–404 ISSN 0936-5214 © Thieme Stuttgart · New York

404
S. Cacchi et al.
LETTER
(10) For a recent reference, see for example: a) Rajagopal, S.; Spa-
tola, A.F. J. Org. Chem. 1995, 60, 1347; b) Dragovich, P.S.;
Prins, T.J.; Zhou, R. J. Org. Chem. 1995, 60, 4922; c) Satake,
A.; Shimizu, I.; Yamamoto, A. Synlett 1995, 64; d) Rao,
H.S.P.; Reddy, K.S. Tetrahedron Lett. 1994, 35, 171; e) Tani,
K.; Ono, N.; Okamoto, S.; Sato, F. J. Chem. Soc., Chem. Com-
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Am. Chem. Soc. 1993, 115, 152; g) Alper, H.; Vasapollo, G.
Tetrahedron Lett. 1992, 33, 7477; h) Arcadi, A.; Bernocchi,
E.; Cacchi, S.; Marinelli, F. Synlett 1991, 27; i) Wiener, H.;
Blum, J.; Sasson, Y. J. Org. Chem. 1991, 56, 4481; j) Balc-
zewsky, P.; Joule, J.A. Synth. Commun. 1990, 20, 2815.
(11) Compound 7a was prepared in 88% isolated yield upon reac-
tion of o-iodoaniline (5.4 g, 24.6 mmol) with trimethylsilyl-
acetylene (4.15 mL, 29.6 mmol) in the presence of diethylami-
ne (4 mL), Pd(PPh3)4 (0.071 g, 0.06 mmol) and CuI (0.023 g,
0.12 mmol) in DMF (2 mL) at room temperature under a ni-
trogen atmosphere overnight.
(d, J = 8.8 Hz, 2H), 3.84 (s, 3H); 13C NMR (CDCl3) d 160.7,
156.8, 148.2, 136.6, 132.1, 129.5, 129.4, 128.8, 127.4, 126.8,
125.8,118.5, 114.1, 55.3; MS m/e (relative intensity) 235 (M+,
100), 220 (37), 192 (34).
(17) A typical preparation according to procedure C is as follows:
to a stirred solution of 1f (0.140g, 0.53 mmol) in DMF (3 mL)
were added, in this order, triethylamine (0.3 mL, 2.13 mmol),
Pd(OAc)2 (0.006g, 0.027 mmol), dppf ( 0.016g, 0.029 mmol)
and formic acid (0.076 mL, 2.02 mmol). The reaction mixture
was stirred at 70 °C for 3 h, then cooled and extracted (0.1 M
HCl, EtOAc). The combined organic layers were dried
(Na2SO4) and evaporated. The residue was purified by chro-
matography (silica gel 40-60 mm, n-hexane/EtOAc 90/10) to
give 0.101 g of 3f (77% yield): mp 138-139 °C; IR (KBr)
1730, 1610 cm-1; 1H NMR (CDCl3) d 8.30-8.18 (m, 4H), 8.11
(d, J = 8.4 Hz, 2H), 7.91 (d, J = 8 Hz, 1H), 7.87-7.71 (m, 2H),
7.60-7.52 (m, 1H), 2.65 (s, 3H); 13C NMR (CDCl3) d 197.9,
155.8, 148.0, 143.5, 137.4, 137.2, 130.0, 129.7, 128.8, 127.7,
127.5, 127.4, 126.9, 119.0, 26.8; MS m/e (relative intensity)
247 (M+, 59), 232 (100), 204 (60).
(12) Arcadi, A.; Cacchi, S.; Marinelli, F.; Pace, P.; Sanzi, G. Syn-
lett 1995, 823. Anhydrous THF and Et3N were used. Commer-
cially available 1 M solution of n-Bu4NF in THF was dried
over 4 Å molecular sieves.
(13) Moinet, C.; Fiaud, J.C. Synlett 1997, 97.
(14) Ciattini, P.G.; Morera, E.; Ortar, G. Tetrahedron Lett. 1991,
32, 6449.
(18) 2-Cyclooctylquinoline: mp oil; 1H NMR (CDCl3) d 8.06 (d, J
= 8.5 Hz, 2H), 7.75 (dd, J = 7.9, 1.3 Hz, 1H), 7.66 (td, J = 7.0,
1.3 Hz, 1H), 7.46 (td, J = 7.4, 1.1 Hz, 1H), 7.28 (d, J = 8.5 Hz,
1H), 3.17 (m, 1 H), 2.15-1.6 (m, 14H); 13C NMR (CDCl3) d
147.7, 136.4, 129.3, 129.1, 127.5, 126.9, 125.6, 120.1, 118.2,
47.7, 33.5, 26.7, 26.5, 26.2; MS m/e (relative intensity) 239
(M+, 30), 182 (50), 156 (100).
(19) Cacchi, S.; Fabrizi, G.; Moro, L.; Pace, P. Synlett 1997, 1367;
Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L; Pace, P. Tetra-
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481; Arcadi, A.; Bernocchi, E.; Burini, A.; Cacchi, S.; Mari-
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(15) A typical preparation according to procedure A is as follows:
to a stirred solution of 1b (0.208g, 0.88 mmol) in DMF (3 mL)
were added, in this order, n-Bu3N (1.05 mL, 4.42 mmol),
Pd(OAc)2(PPh3)2 (0.026g, 0.035 mmol) and formic acid
(0.127 mL, 3.36 mmol). The reaction mixture was stirred at 70
°C for 4.5 h, then cooled and extracted (0.1 M HCl, EtOAc).
The combined organic layers were dried (Na2SO4) and evapo-
rated. The residue was purified by chromatography eluting
with a n-hexane/EtOAc (95/5 v/v) mixture to give 0.136 g of
3b (70 % yield): mp 38-40 °C; IR (KBr) 1610 cm -1; 1H NMR
(CDCl3) d 8.20 (d, J = 8 Hz, 2H), 8.01(bs, 1H), 7.94-7.68 (m,
4H), 7.55-7.45 (m, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.30-7.25 (m,
1H), 2.46 (s, 3H); 13C NMR (CDCl3) d 157.5, 147.9, 138.6,
137.0, 130.3, 129.8, 129.4, 128.7, 128.3, 127.4, 126.3, 124.8,
119.0, 21.6; MS m/e (relative intensity) 239 (M+, 100), 208
(22), 132 (41).
(16) A typical preparation according to procedure B is as follows:
to a stirred solution of 1a (0.200g, 0.80 mmol) in MeOH (45
mL) were added, in this order, 10% Pd/C (0.085 g, 0.080
mmol) and ammonium formate (0.150 g, 2.39 mmol). The re-
action mixture was stirred under N2 at 70 °C for 2 h. Then, it
was cooled and filtered. The filtrate was extracted (0.5 M
NaHCO3, EtOAc). The combined organic layers were dried
(Na2SO4) and evaporated. The residue was purified by chro-
matography eluting with a n-hexane/EtOAc (99/1 v/v) mix-
ture to give 0.038 g of 6a (20% yield) and 0.126 g of 3a (67%
yield).
(20) Hay, L.A.; Koenig, T.M.; Ginah, F.O.; Copp, J.D.; Mitchell,
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Org. Chem. 1998, 63, 1001; Cacchi, S.; Fabrizi, G.; Moro, L.
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747; Cacchi, S. Fabrizi, G.; Moro, L. Tetrahedron Lett. 1998,
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5081; Arcadi, A. Synlett 1997, 941-943; Arcadi, A.; Anacar-
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3129.
6a: mp 61-63 °C; IR (KBr) 3380, 1600 cm -1; 1H NMR
(CDCl3) d 7.30 (d, J = 8.8 Hz, 2H), 7.02-6.96 (m, 2H), 6.87 (d,
J = 8.8 Hz, 2H), 6.67-6.59 (m, 1H), 6.50 (d, J = 8.5 Hz, 1H),
4.36 (dd, J = 9.2, 3.5 Hz, 1H), 3.79 (s, 3H), 2.90-2.65 (m, 2H),
2.09-1.90 (m, 2H); 13C NMR (CDCl3) d 158.9, 144.8, 136.8,
129.3, 127.6, 126.8, 120.8, 117.1, 113.93,113.86, 55.7, 55.3,
31.1, 26.5; MS m/e (relative intensity) 239 (M+, 100), 208
(22), 132 (41).
3a: mp 123-124 °C; IR (KBr): 1600 cm-1; 1H NMR (CDCl3) d
8.15-8.06 (m, 4H), 7.81-7.64 (m, 3H), 7.51-7.42 (m, 1H), 7.02
Synlett 1999, No. 4, 401–404 ISSN 0936-5214 © Thieme Stuttgart · New York