2-Substituted-2,3-dihydro-1 H -quinolin-4-ones via acid-catalyzed tandem rupe rearrangement-donnelly-farrell ring closure of 2-(3′-hydroxypropynyl) anilines

Article abstract of DOI:10.1055/s-0030-1259309

A range of 2-substituted 2,3-dihydro-1H-quinolin-4-ones have been synthesized from anilines by a two-step process involving Sonogashira coupling with a propargyl alcohol then acid-catalyzed cyclization of the resulting 2-(3′-hydroxypropynyl)anilines. The cyclization reaction appears to proceed via regioselective rearrangement of the propargyl alcohol to an α,β-unsaturated ketone (Rupe rearrangement) and then 6-endo-trig ring closure (Donnelly-Farrell cyclization). The isolation of the α,β-unsaturated ketone intermediate in one example supports this pathway. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1259309

LETTER
241
2-Substituted-2,3-dihydro-1H-quinolin-4-ones via Acid-Catalyzed Tandem
Rupe Rearrangement–Donnelly–Farrell Ring Closure of 2-(3¢-Hydroxy-
propynyl)anilines
2
-Substituted-
e
o
d
-1
H
-quinoli
e
S
yn
r
thesis ica Pisaneschi,*a,b Jimmy J. P. Sejberg,b Cecile Blain,b Wang Hei Ng,b Eric O. Aboagye,a Alan C. Spivey*b
a
Comprehensive Cancer Imaging Centre, Imperial College London, Faculty of Medicine, Hammersmith Hospital Campus,
Du Cane Road, London, W12 0NN, UK
Department of Chemistry, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK
Fax +44(20)75945841; E-mail: f.pisaneschi@imperial.ac.uk; E-mail: a.c.spivey@imperial.ac.uk
b
Received 14 December 2010
Dedicated to Prof. Alberto Brandi on the occasion of his 60th birthday
Thus, following Pd/Cu-catalyzed coupling to yield alky-
nyl aniline 3a in 76% yield, attempted acid-catalyzed hy-
drolysis of the acetamide by heating in concentrated HCl–
H2O (1:1, v/v), was found to furnish dimethyl-2,3-dihy-
Abstract: A range of 2-substituted 2,3-dihydro-1H-quinolin-4-
ones have been synthesized from anilines by a two-step process in-
volving Sonogashira coupling with a propargyl alcohol then acid-
catalyzed cyclization of the resulting 2-(3¢-hydroxypropy-
nyl)anilines. The cyclization reaction appears to proceed via re- dro-1H-quinolin-4-one (4a) in 98% yield after basic
gioselective rearrangement of the propargyl alcohol to an a,b-
unsaturated ketone (Rupe rearrangement) and then 6-endo-trig ring
closure (Donnelly–Farrell cyclization). The isolation of the a,b-
unsaturated ketone intermediate in one example supports this path-
way.
workup and chromatographic purification (Scheme 2).
R4
R4
OH
R3
OH
R3
O
X
Key words: quinolinone, Sonogashira coupling, Rupe rearrange-
ment, cyclization, alkaloids, alkynes
2
b
R3
R4
a
NHR1
NHR1
R2
N
H
R2
R2
1 X = Br, I, OTf
1 = H, Ac
3
4
R
Quinolines and quinolinones constitute the core unit of
numerous alkaloids and synthetic compounds with inter-
esting pharmacological properties.1,2 2-Substituted 2,3-di-
hydro-1H-quinolin-4-ones have shown analgesic3 and
antimalarial4 activity and have attracted attention recently
as antimitotic antitumor agents.5,6 Interest in these com-
pounds led to a significant number of synthetic methods
being described in the literature for their preparation.7–16
However, the direct preparation of 2,3-dihydro-1H-quin-
olin-4-ones from readily available anilines has received
relatively little attention.9,13,16
Scheme 1 Synthesis of 2,3-dihydro-1H-quinolin-4-ones 3: (a)
Sonogashira coupling, (b) acid-catalyzed cyclization
OH
O
OH
OTf
2a
b
a
NHAc
NHAc
N
H
4a
1a
3a
Scheme 2 Synthesis of 2,2-dimethyl-2,3-dihydro-1H-quinolin-4-
one (4a). Reagents and conditions: (a) 2-methylbut-3-yn-2-ol (2a),
PdCl2(PPh3)2, CuI, Ph3P, pyridine, Et3N, 90 °C, 3 h (76%); (b) concd
HCl, H2O, 120 °C, 1.5 h (98%).
Here, we report a general and straightforward approach to
2,3-dihydro-1H-quinolin-4-ones 4 via a two-step process
which starts from readily available 2-(pseudo)halogenat-
ed anilines 1. The process involves Sonogashira coupling
with a propargylic alcohol 2,17,18 followed by a Brønsted
acid catalyzed cyclization of the resulting 2-(3¢-hydroxy-
propynyl)anilines 3 to give quinolin-4-ones 4 (Scheme 1).
2-Methylbut-3-yn-2-ol (2a, R3 = R4 = Me) has been used
widely as a readily available, cheap, nonvolatile protected
form of acetylene (cf. e.g., TMS-acetylene) which is un-
masked via thermolysis in the presence of base with evo-
lution of acetone.19,20 It was in the context of the use of
this reagent as a partner for Sonogashira coupling with 2-
trifloxy-N-acetylaniline (1a) that we serendipitously dis-
covered the facile cyclization process described herein.
To determine the scope of this ring closure, we investigat-
ed the synthesis and acid-catalyzed cyclization of a range
of 2-(3¢-hydroxypropynyl)anilines.
A series of Sonogashira coupling reactions were carried
out between 2-methylbut-3-yn-2-ol (2a) and 2-trifloxy-
and 2-bromo-N-acetylanilines 1a–d and 2-bromo- and 2-
iodoanilines (1e,f) using standard conditions involving
Pd(II)/Cu(I) pre-catalysts.21 The 2-trifloxy-N-acetyl-
anilines were synthesized from the corresponding 2-hy-
droxyanilines by N-acetylation (Ac2O in AcOH) then O-
triflation (Tf2O, pyridine in CH2Cl2). Moderate to good
SYNLETT 2011, No. 2, pp 0241–0244
x
x.
x
x.
2
0
1
1
Advanced online publication: 10.01.2011
DOI: 10.1055/s-0030-1259309; Art ID: G34610ST
© Georg Thieme Verlag Stuttgart · New York

242
F. Pisaneschi et al.
LETTER
Table 1 Sonogashira Coupling To Give 2-Alkynylanilines 328
Table 2 Acid-Catalyzed Ring Closure of 2-Alkynylanilines 3 To
Give 2,3-Dihydro-1H-quinolin-4-ones 429
OH
OH
X
PdCl2(PPh3)2
CuI, Ph3P
OH
O
+
py, Et3N, 90 °C
NHR1
NHR1
i) concd HCl, H2O
R2
R2
NHR1
ii) K2CO3
R2
N
R2
1a–f
2
3a–f
H
R1
R2
Time (h) Yield (%)
3a–f
4a–e
Entry
X
76 (1a → 3a)a
57 (1b → 3b)
43 (1c → 3c)
67 (1d → 3d)
42 (1e → 3e)
63 (1f → 3f)
Entry
R1
Ac
Ac
Ac
Ac
H
R2
Time (h) Yield (%)
1
2
3
4
5
6
OTf
OTf
OTf
Br
Ac
Ac
Ac
Ac
H
H
3
1
2
3
4
5
6
H
1
98 (3a → 4a)a
5-Cl
5-Me
4-F3CO
4-F3C
H
1.5
2
5-Cl
5-Me
1.5
4
68 (3b → 4b)
70 (3c → 4c)
60 (3d → 4d)
35 (3e → 4e)
70 (3f → 4a)
3
4-F3CO
8
Br
3
4-F3C
H
4
I
H
3
H
1.5
a As described in the text (Scheme 2).
a As described in the text (Scheme 2).
yields were obtained for all these Sonogashira coupling
reactions (Table 1).22,28
then 6-endo-trig Michael-type ring closure to give quino-
lin-4-one 4f (Scheme 3).
The ring-closure reactions of these 2-alkynylanilines 3 to
give the quinolin-4-ones 4 were performed in all cases by
heating at 120 °C in concentrated HCl–H2O (1:1, v/v) fol-
lowed by basic workup, as for the initial example de-
scribed above (Table 2).29
The acid-catalyzed rearrangement of propargylic alcohols
to a,b-unsaturated ketones (cf. 3f → II) is known as a
Rupe rearrangement23 and may proceed as indicated in
Scheme 3 or via an allenyl intermediate with assistance
from the 2-amino group.24 The cyclization of 2-aminoch-
alcones to 2-aryl-2,3-dihydro-1H-quinolin-4-ones (cf. II
→ 4f) is also well documented25 and the acid-catalyzed
variant is sometimes referred to as a Donnelly–Farrell cy-
clization.11,12 However, our tandem Rupe rearrangement–
Donnelly–Farrell cyclization to give quinolin-4-ones is
new and potentially provides access to a wider variety of
eventual C2 substituents than have been accessible from
chalcones.
The electron demand of substituents on the aryl ring ap-
peared to have no significant effect on the cyclization pro-
cess. The yields ranged from 60–98% with the exception
of the 4-trifluoromethyl derivative 3e which was obtained
in just 35% yield. Both the aniline 1e and the 2-alkynyla-
niline 3e leading to this product were observed to have
low thermal stability; probably explaining the reduced
yields in this sequence. The acetamide is not critical for
successful cyclization as the free aniline 3f cyclized effi-
ciently, albeit in reduced yield relative to its acetamide an-
alogue 3a (cf. entries 1 and 6, Table 2).
For the cyclization of the N-acetyl compounds 3a–d, ace-
tamide hydrolysis, at least in the case of the 4-trifluo-
romethoxy-substituted substrate 3d occurs in situ
immediately prior to ring closure as evidenced by our iso-
lation after four hours of an approximately 1:1 mixture of
the expected quinolin-4-one 4d and the N-acetyl-a,b-
unsaturated ketone 5 (Scheme 4).
We envisage that the cyclization, in the case of the free
aniline 3f, probably proceeds via regioselective hydra-
tive–dehydrative rearrangement of the alkyne moiety,
possibly via aldol I, to give a,b-unsaturated ketone II,
When compound 5 was resubjected to the same conditions
for additional four hours, complete conversion into quin-
olin-4-one 4d was achieved. Direct conversion of anilide
3d into quinolin-4-one 4d required eight hours (Table 2,
entry 5, 60% yield).
OH
+
OH
OH2
H2O, H+
NH2
H2O
NH2
3f
I
With the aim to further widen the scope of this new ap-
proach, we investigated the introduction of different
groups at C2 of the quinolin-4-one ring. Thus, we synthe-
sized 2-ethynylaniline 6 from 2-iodoaniline (1f) by Sono-
gashira coupling with trimethylsilylacetylene then
protonolysis of the trimethylsilyl group. Deprotonation of
this terminal alkyne (BuLi) and quenching with benzalde-
hyde gave propargyl alcohol 3g (R2 = H, R3 = Ph) in 26%
+OH
O
H+
N
H2
N
H
4f
II
Scheme 3 Proposed mechanism for the acid-catalyzed cyclization
Synlett 2011, No. 2, 241–244 © Thieme Stuttgart · New York

LETTER
2-Substituted-2,3-dihydro-1H-quinolin-4-one Synthesis
243
OH
O
O
F3CO
F3CO
F3CO
H+, 4 h
+
N
NHAc
1:1
NHAc
H
4d
5
3d
H+, 4 h
Scheme 4 Isolation of a,b-unsaturated ketone intermediate 5 during a cyclization reaction to give quinolin-4-one 4d
unoptimized yield. Reaction with acetophenone required
transmetalation to the organocerate (CeCl3)26,27 to sup-
press enolization but gave propargyl alcohol 3h (R2 = Me,
R3 = Ph) in 60% yield (Scheme 5).
References and Notes
(1) Michael, J. P. Nat. Prod. Rep. 2008, 25, 166.
(2) Sable, D.; Murakawa, G. J. Dis. Mon. 2004, 50, 381.
(3) Atwal, M. S.; Bauer, L.; Dixit, S. N.; Gearien, J. E.; Morris,
R. W. J. Med. Chem. 1965, 8, 566.
(4) LaMontagne, M. P.; Blumbergs, P.; Smith, D. C. J. Med.
Chem. 1989, 32, 1728.
(5) Xia, Y.; Yang, Z.-Y.; Xia, P.; Bastow, K. F.; Tachibana, Y.;
Kuo, S.-C.; Hamel, E.; Hackl, T.; Lee, K.-H. J. Med. Chem.
1998, 41, 1155.
R1
O
I
c
a
R2
R3
N
H
NH2
NH2
(6) Zhang, S.-X.; Feng, J.; Kuo, S.-C.; Brossi, A.; Hamel, E.;
Tropsha, A.; Lee, K.-H. J. Med. Chem. 2000, 43, 167.
(7) Ahmed, N.; van Lier, J. E. Tetrahedron Lett. 2006, 47, 2725.
(8) Gong, Y.; Kato, K. J. Fluorine Chem. 2004, 125, 767.
(9) Nemoto, T.; Fukuda, T.; Hamada, Y. Tetrahedron Lett.
2006, 47, 4365.
6 R1 = H
3 R1 = CR2R3OH
O
1f
7
b
R2
R3
Scheme
5 Reagents and conditions: (a) i. TMS-acetylene,
PdCl2(PPh3)2, CuI, PPh3, i-Pr2NH, toluene, r.t., 16 h; ii. KOH,
MeOH–H2O, r.t., 3 h (38%); (b) n-BuLi, THF, –5 °C to r.t. (6 → 3g,
R2 = H, R3 = Ph, 26%) or n-BuLi, CeCl3, THF, –5 °C to r.t. (6 → 3h,
R2 = Me, R3 = Ph, 60%); (c) concd HCl, H2O, 120 °C, 1.5 h (7a,
R2 = H, R3 = Ph, 50%; 7b, R2 = Me, R3 = Ph, 26%).
(10) Shintani, R.; Yamagami, T.; Kimura, T.; Hayashi, T. Org.
Lett. 2005, 7, 5317.
(11) Donnelly, J. A.; Farrell, D. F. Tetrahedron 1990, 46, 885.
(12) Donnelly, J. A.; Farrell, D. F. J. Org. Chem. 1990, 55, 1757.
(13) Grigg, R.; Liu, A.; Shaw, D.; Suganthan, S.; Woodall, D. E.;
Yoganathan, G. Tetrahedron Lett. 2000, 41, 7125.
(14) Kundu, N. G.; Mahanty, J. S.; Das, P.; Das, B. Tetrahedron
Lett. 1993, 34, 1625.
(15) Clarke, I. P.; Meth-Cohn, O. ARKIVOC 2000, (iii), 372.
(16) Majumdar, K. C.; Taher, A.; Ponra, S. Synlett 2010, 735.
(17) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467.
(18) Chinchilla, R.; Nájera, C. Chem. Rev. 2007, 107, 874.
(19) Ames, D. E.; Bull, D.; Takundwa, C. Synthesis 1981, 364.
(20) Mal’kina, A. G.; Brandsma, L.; Vasilevsky, S. F.; Trofimov,
B. A. Synthesis 1996, 589.
(21) Melissaria, A. P.; Litt, M. H. J. Org. Chem. 1992, 57, 6998.
(22) Although we did not explore this, it is also possible to
synthesize 2-alkynylanilines directly from anilines by C–H
activation at the 2-position, see: Tobisu, M.; Ano, Y.;
Chatani, N. Org. Lett. 2009, 9, 3250.
After heating at 120 °C in concd HCl–H2O (1:1, v/v) as
previously, we were very pleased to observe that quinolin-
4-ones 7a (R2 = H, R3 = Ph) and 7b (R2 = Me, R3 = Ph)
were obtained in 50% and 26% yields, respectively. No
attempt was made to optimize these yields but it is appar-
ent that the process is applicable to the synthesis of quin-
olin-4-ones with alternative substitution patterns at C2.
In conclusion, we have reported a straightforward method
for the preparation of 2-substituted-2,3-dihydro-1H-quin-
olin-4-ones by acid-catalyzed cyclization of 2-(3¢-hydrox-
ypropynyl)anilines. These substrates can be prepared
from readily available 2-bromo-, 2-iodo-, and 2-trifloxy-
anilines or N-acetylanilines via Sonogashira coupling,
making the route attractive for accessing this class of het-
erocycle which is found in many biologically active sub-
stances. For the free aniline substrates ring closure is
postulated to comprise Rupe rearrangement–Donnelly–
Farrell cyclization whereas for the N-acetylanilines it
comprises Rupe rearrangement–acetamide hydrolysis–
Donnelly–Farrell cyclization.
(23) Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 429.
(24) Jacubert, M.; Provot, O.; Peyrat, J.-F.; Hamze, A.; Brion,
J.-D.; Alami, M. Tetrahedron 2010, 66, 3775.
(25) Muthukrishnana, M.; Mujahida, M.; Punitharasua, V.;
Dnyaneshwara, D. A. Synth. Commun. 2010, 40, 1391.
(26) Lord, M. D.; Negri, J. T.; Paquette, L. A. J. Org. Chem.
1995, 60, 191.
(27) Liu, H. J.; Shia, K. S.; Shang, X.; Zhu, B. Y. Tetrahedron
1999, 55, 3803.
Supporting Information for this article comprising full expe-
rimental details and spectroscopic data is available online at http://
www.thieme-connect.com/ejournals/toc/synlett.
(28) General Procedure for the Sonogashira Couplings with
2-Methylbut-3-yn-2-ol (2a)
The iodo-, bromo-, or triflate-substituted aniline was
dissolved in Et3N–pyridine (1:1, 0.1 M), and nitrogen was
bubbled through for 10 min at r.t. 2-Methylbut-3-yn-2-ol (2a
1.5 equiv) was added, and the solution was stirred for 10 min
with nitrogen bubbling through. CuI (0.05 equiv), Ph3P (0.5
equiv), and (PPh3)2PdCl2 (0.05 equiv) were then added, and
the resulting suspension was heated at 90 °C for 1.5–3 h (see
Table 1). The reaction mixture was cooled to r.t. and
quenched with a sat. solution of NaCl. The mixture was then
Acknowledgment
The MRC and CRUK (Grant C2536/A7602) are thanked for grant
support (J.J.P.S., F.P.). We are grateful also to the Nuffield Found-
ation and the EU Erasmus program for provision of project support
(W.H.N., C.B.).
Synlett 2011, No. 2, 241–244 © Thieme Stuttgart · New York

244
F. Pisaneschi et al.
LETTER
extracted twice with EtOAc, and the combined organic
phases were dried over MgSO4, filtered, and concentrated in
vacuo. The desired products were purified by flash
chromatography.
N-[2-(3-Hydroxy-3-methylbut-1-ynyl)phenyl]acetamide
(3a)
Colorless oil (76% yield). ESI-HRMS: m/z calcd for
C13H15NO2Na: 240.1000; found: 240.1001 (D = 0.4 ppm).
ESI-MS: m/z (%) = 240 (95) [MNa+], 200(100). 1H NMR
(400 MHz, CDCl3): d = 8.29 (d, J = 8.3 Hz, 1 H, 6-H), 7.81
(br s, 1 H, NH), 7.31 (dd, J = 7.7, 1.3 Hz, 1 H, 3-H), 7.26 (td,
J = 8.3, 1.5 Hz, 1 H, 5-H), 6.96 (t, J = 7.4 Hz, 4-H), 2.15 (s,
3 H, CH3CONH), 1.61 [s, 6 H, C(CH3)2OH]. 13C NMR (101
MHz, CDCl3): d = 168.4 (s, CO), 138.9 (s, Ar), 131.5 (d, Ar),
129.7 (d, Ar), 123.4 (d, Ar), 119.4 (d, Ar), 111.4 (s, Ar),
101.5 (s, 2 C, C≡), 65.7 [s, C(CH3)2OH], 31.5 [q, 2 C,
C(CH3)2OH], 24.8 (q, CH3CO). IR: nmax = 3360, 2924, 2853,
2400, 1662, 1523, 1447 cm–1.
HCl–H2O (1:1, v/v; 0.1 M) and heated at 120 °C for 1.5–8 h
(see Table 2). The reaction mixture was then concentrated in
vacuo. Water was then added followed by K2CO3 up to
pH = 11. The mixture was extracted twice with EtOAc, and
the combined organic phases were dried over MgSO4,
filtered, and concentrated in vacuo. Final quinolinones were
purified by flash chromatography.
2,2-Dimethyl-2,3-dihydro-1H-quinolin-4-one (4a)
Yellow oil (70% yield). ESI-HRMS: m/z calcd for
C11H14NO: 176.1075; found: 176.1071 (D = –2.3 ppm). ESI-
MS: m/z (%) = 176 (78) [MH+], 120 (100). 1H NMR (400
MHz, CDCl3): d = 7.83 (dd, J = 7.9, 1.4 Hz, 1 H, Ar), 7.35–
7.27 (m, 1 H, Ar), 6.71 (m, 1 H, Ar), 6.63 (d, J = 8.2 Hz, 1
H, Ar), 4.18 (s, 1 H, NH), 2.61 (s, 2 H, 3-H), 1.35 [s, 6 H,
NC(CH3)2]. 13C NMR (100 MHz, CDCl3): d = 194.0 (s, CO),
149.8 (s, Ar), 135.4 (d, Ar), 127.2 (d, Ar), 118.1 (d, Ar),
117.5 (d, Ar), 115.8 (s, Ar), 53.6 (s, 2-C), 50.6 (t, 3-C), 27.7
(q, 2 C, CH3). IR: nmax = 3333, 2924, 2853, 1659, 1613, 1481
cm–1.
(29) General Procedure for the Acid-Catalyzed Cyclization
Sonogashira coupling product 3a–h was dissolved in concd
Synlett 2011, No. 2, 241–244 © Thieme Stuttgart · New York

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