Indole[1,2-c]quinazolines by palladium-catalyzed cyclization of bis(o-trifluoroacetamidophenyl) acetylene with aryl and vinyl halides or triflates

Article abstract of DOI:10.1055/s-2001-17458

6-Trifluoromethyl-12-aryl(vinyl)indolo[1,2-c]quinazolines are prepared in high yield through the palladium-catalyzed reaction of readily available bis (o-trifluoroacetamidophenyl)acetylene with aryl or vinyl halides and triflates, followed by cyclization

Full text of DOI:10.1055/s-2001-17458

LETTER
1605
Indole[1,2-c]quinazolines by Palladium-Catalyzed Cyclization of Bis(o-
trifluoroacetamidophenyl) acetylene with Aryl and Vinyl Halides or Triflates
a
b
c
b
b
P
A
d-Catalyze
d
Synt
n
hesis of
I
ndo
t
le[1,2-
o
c
]quinazoline
n
s
io Arcadi, Sandro Cacchi,* Alberto Cassetta, Giancarlo Fabrizi, Luca M. Parisi
a
Dipartimento di Chimica, Ing. Chimica e Materiali, Via Vetoio, 67100 L’Aquila, Italy
b
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Università “La Sapienza”, P.le A. Moro 5,
0185 Roma, Italy
0
Fax +39(6)49912780; E-mail: sandro.cacchi@uniroma1.it
c
Institute of Structural Chemistry - CNR Trieste, XRD1 beamline - Elettra Trieste
Received 22 June 2001
We report that reaction of bis(o-trifluoroacetamidophe-
nyl)acetylene 1 with aryl or vinyl halides and triflates 2,
in the presence of a palladium catalyst, provides a
Abstract: 6-Trifluoromethyl-12-aryl(vinyl)indolo[1,2-c]quinazo-
lines are prepared in high yield through the palladium-catalyzed re-
action
of
readily
available
bis(o-trifluoroacetamido-
straightforward approach to functionalized indolo[1,2-
phenyl)acetylene with aryl or vinyl halides and triflates, followed
by cyclization of the resultant derivatives. The reaction, which tol- c]quinazolines 3 (Scheme 2).8
,9
erates a variety of important functional groups, probably involves
The starting alkyne required for our approach was readily
the formation of a 3-aryl-2-(o-trifluoroacetamidophenyl)indole in-
termediate, followed by its cyclization to the indolequinazoline
product. Formation of the indoloquinazoline nucleus has been un-
ambiguously determined via X-ray analysis.
prepared through palladium-catalyzed coupling of o-trif-
7
luoroacetamidophenyl iodide with o-ethynylaniline, fol-
lowed by reaction of the resultant coupling product with
trifluoroacetic anhydride.10
Key words: indoloquinazolines, cyclization, palladium, catalysis,
alkynes
F3COCHN
R
Our reaction of o-alkynyltrifluoroacetanilides with aryl
and vinyl halides or triflates has been proved to be a ver-
satile tool for the construction of functionalized indole
rings from terminal and internal alkynes. By employing
this methodology, a variety of 2-unsubstituted 3-arylin-
Pd cat
+
RX
NHCOCF3
N
N
R = aryl, vinyl
X = I, Br, OTf
F3C
1
2
doles, 2,3-disubstituted indoles and 2-substituted 3-
1
2
3
3
allylindoles have been prepared. When the reaction is
carried out under an atmosphere of carbon monoxide, 2- Scheme 2
substituted 3-acylindoles can be obtained in good yields.4
Adaptation of the methodology to a solid-supported
The palladium-catalyzed reaction of 1 with p-iodoanisole
was chosen as the model system when we started our in-
vestigation of this cyclization chemistry. Pd(PPh ) and
5
synthesis and applications to the synthesis of biologically
4
,6
active molecules have also been reported. More recent-
ly, the methodology has been extended to develop a new
route to indolo[3,2-c]quinolines through a one-pot pro-
cess involving the reaction of o-(o-aminophenyl)trifluoro-
acetanilide with aryl iodides, in the presence of carbon
monoxide, followed by the cyclization of the resultant 3-
acylindole derivative (Scheme 1).
3
4
K CO , successfully employed in our previous synthesis
2
3
7
7
of indolo[3,2-c]quinolines, were selected as the precata-
lyst species and the base, respectively. The reaction
proved to be strongly influenced by the nature of the sol-
vent, as shown by the results summarized in Table 1.
The highest yield and reaction rate were obtained in DM-
SO. Consequently, the following reaction conditions were
usually employed when the reaction was extended to in-
H2N
1
. ArI, CO, Pd(PPh
CO , MeCN, 50 °C
. MeOH:H O 95:5, K CO
0 °C
3
)
4
,
Ar
clude other aryl and vinyl halides or triflates: Pd(PPh ) ,
K
2
3
N
3 4
1
1
2
2
2
3
,
K CO , DMSO, 50 °C. Our preparative results are sum-
2 3
8
marized in Table 2.
NHCOCF3
N
H
The reaction gives good results with neutral, electron-rich
and electron-poor aryl halides as well as with various vi-
nyl bromides and triflates. p-Bromoacetophenone re-
quires a higher reaction temperature (Table 2, entry 8).
Steric hindrance close to the oxidative addition site ap-
pears to hamper the reaction to some extent (Table 2,
compare entry 6 with entry 7).
Scheme 1
Synlett 2001, No. 10, 28 09 2001. Article Identifier:
437-210X,E;2001,0,10,1605,1607,ftx,en;G12901st.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
1
©
As to the mechanism, the reaction might proceed via the
aminopalladation-reductive elimination domino pathway

1
606
A. Arcadi et al.
LETTER
Table 1 Solvent Effect in the Palladium-Catalyzed Reaction of
Bis(o-trifluoroacetamidophenyl)acetylene 1 with p-Iodoanisole.a
Table 2 Preparation of Indolo[1,2-c]quinazolines 3 from Bis(o-tri-
fluoroacetamido phenyl)acetylene 1 and Aryl or Vinyl Halides and
Triflates 2.a
Entry
Solvent
THF
Time [h]
24c
Yield [%] of 3ab
Entry Aryl or vinyl halide and triflate 2 Time [h] Yield [%]
1
2
3
4
5
60
27
56
40
40
92
b
of 3
Dioxane
MeCN
DMF
24c
1
2
3
4
5
6
7
8
9
0
p-MeO-C H -I
1.5
2
92
97
86
74
72
69
22
90c
90
75
a
b
c
d
e
f
6
4
24c
p-MeCO-C H -I
6
4
24c
p-MeCOO-C H -I
2
6
4
DMA
24c
p-F-C H -I
2
6
4
6
DMSO
1.5d
PhI
p-Me-C H -I
4
a
-2
Reactions were conducted at 7.5 10 M starting substrate in anhyd
4
6
4
solvents (5 mL) at 50 °C using the following molar ratios: 1:p-
iodoanisole:Pd(PPh ) :K CO = 1:1:0.05:5.
3
4
2
3
o-Me-C H -I
4
g
h
i
6
4
b
c
Yields refer to single runs and are given for isolated products.
After this time, TLC indicated that the starting alkyne was still
p-MeCO-C H -Br
5
6
4
present into the reaction mixture.
d
PhCH = CHBrd
2
After this time, TLC indicated completion of the reaction.
1
1
2
j
I
COOEt
COOEt
(
as other reactions of this type),1–7 followed by cyclization
1
2
4
2
68
87
k
l
of the resultant 3-arylindole derivative 4 to give the tetra-
cyclic derivative 5 that subsequently affords the indole-
quinazoline product via elimination of trifluoroacetic
acid. Formation of 4 through the alternative reaction path-
way involving (1) carbopalladation of the carbon-carbon
triple bond, (2) isomerization of the resultant cis -vi-
nylpalladium adduct to the trans -vinylpalladium ad-
I
1
COMe
1
5
TfO
Ph
duct, (3) formation of a six-membered ring nitrogen-
containing palladacycle intermediate via nucleophilic at-
tack of nitrogen to palladium, and (4) subsequent regener-
ation of the palladium(0) catalyst through reductive
elimination cannot be a priori ruled out (Scheme 3).
1
1
3
4
2
2
85
86
m
n
OTf
EtOOC
OTf
1
5
1
1
95
91
o
RPdX
OTf
PdR
COOMe
NHCOCF3
Pd(0)
16
OTf
p
1
+ 2
-
HX
N
NH
NHCOCF3
O
F3C
O
Ph
F3C
O
-
Pd(0)
R
a
-2
Unless otherwise stated, reactions were conducted at 7.5 10 M
in starting substrate in anhyd DMSO (5 mL) at 50 °C using the fol-
lowing molar ratios: 1:2:Pd(PPh ) :K CO = 1:1:0.05:5.
R
3
4
2
3
b
Yields refer to single runs and are given for isolated products. All
N
N
new products had satisfactory elemental analysis and their spectra
were consistent with the postulated structures.
NHCOCF3
N
F3C
O
F3C
c
COCF3
OH
At 100 °C.
5
4
d
Employed as a commercially available E/Z mixture. However,
only the indolo[1,2-c]quinazoline derivative containing the E styryl
fragment was isolated.
-
CF3COOH
R
N
N
F3C
3
Scheme 3
Synlett 2001, No. 10, 1605–1607 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Pd-Catalyzed Synthesis of Indole[1,2-c]quinazolines
1607
To sum up, we have demonstrated that the palladium-cat-
alyzed reaction of readily available bis(o-trifluoroaceta-
midophenyl)acetylene with aryl or vinyl halides and
triflates provides a straightforward new route to the con-
struction of the indolo[1,2-c]quinazoline skeleton. The
methodology can tolerate many important functional
groups and should allow for easy access to a wide variety
of substituted derivatives of this class of compounds.
mmol) was added. The mixture was stirred at 50 °C for 2 h.
After cooling, the reaction mixture was diluted with ethyl
acetate, washed with water, dried over Na SO , and
2
4
concentrated under vacuum. The residue was
chromatographed on silica gel eluting with n-hexane/ethyl
acetate (95/5 v/v) to afford 0.140 g (86%) of 4-(6-trifluoro-
methylindolo[1,2-c]quinazolin-12-yl)-benzoic acid ethyl
-
1
ester 3c: mp 149-150 °C; IR (KBr) 2982, 1710 cm ;
1
H NMR = 8.26 (d, J = 8.1 Hz, 2 H), 8.19 (bs, 1 H), 7.84
(
d, J = 8.1 Hz, 2 H), 7.71-7.35 (m, 7 H), 7.25 (t, J = 6.8 Hz,
1
H),), 4.47 (q, J = 6.8 Hz, 2 H),), 1.46 (t, J = 6.8 Hz, 3 H);
C NMR = 166.5, 139.1, 137.1, 130.9, 130.5, 130.4,
30.3, 129.9, 129.3, 129.1, 129.0, 124.6, 124.1, 123.6,
21.9, 119.4, 119.1 (q, J = 275.2 Hz), 114.5 (q, J = 7.7 Hz),
1
3
Acknowledgment
1
1
1
3
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. Financial support of this research by the Uni-
versity „La Sapienza“, Rome, and by the Consiglio Nazionale delle
Ricerche (CNR) is also gratefully acknowledged.
+
13.9, 61.3, 14.5; MS m/z (relative intensity) 434 (M , 85),
89(100). Anal. Calcd for C H N F O : C, 69.12; N, 6.45
2
5
17
2
3
2
H, 3.94. Found: C, 69.20; N, 6.48 H, 3.92.
The structure of 3c was unambiguously confirmed by X-ray
analysis. Crystallographic Structure Solution: crystals of 3c
were obtained by slow evaporation of a chloroform solution.
Room temperature crystallographic data were collected, by
means of a MarResearch 345 Imaging Plate, at the XRD1
synchrotron beamline at Elettra. Wavelength was set to 0.75
Å by means of a double crystal Si (1 1 1)monochromator.
Two different data collection were carried out in order to
collect good high resolution data and to avoid saturation of
the intense low resolution reflections. A grand total of 720
degrees of oscillation were acquired. Raw data were
indexed, integrated and then scaled together by using HKL
References and Notes
(
(
(
(
(
(
(
(
1) Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L.; Pace, P.
Synlett 1997, 1363.
2) Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett. 1992,
3
3, 3915.
3) Cacchi, S.; Fabrizi, G.; Pace, P. J. Org. Chem. 1998, 63,
001.
1
4) Arcadi, A.; Cacchi, S.; Carnicelli, V.; Marinelli, F.
Tetrahedron 1994, 50, 437.
5) Collini, M. D.; Ellingboe, J. W. Tetrahedron Lett. 1997, 38,
1
2
package. The crystal system was found monoclinic with a
unit cell: a = 18.130(4), b = 4.7260(10), c = 24.668(6),
= 103.13(2), after the inspection of systematic absences
the space group was found P 21/a. Data were merged
together giving 4734 unique reflections, the Rmerge was
0.031. The structure solution was solved by direct methods,
7963.
6) Saulnier, M. G.; Frennesson, D. B.; Deshpande, M. S.; Vyas,
D. M. Tetrahedron Lett. 1995, 36, 7841.
7) Cacchi, S.; Fabrizi, G.; Pace, P.; Marinelli, F. Synlett 1999,
1
3
620.
using the SIR92 program. All the non H atoms of the
molecule were clearly identified. Refinement of the
8) For a recent references on the chemistry of indolo[1,2-
c]quinazolines, see: (a) Billimoria, A. D.; Cava, M. P. J.
Org. Chem. 1994, 59, 6777. (b) Merour, J.-Y.; Savelon, L.
Heterocycles 1991, 32, 849. (c) Molina, P.; Alajarin, M.;
Vidal, A. Tetrahedron 1990, 46, 1063.
2
structure, based on F , was then carried out by using
1
4
SHELX97 refinement program. The final anisotropic
refinement cycle (289 parameters)gave R1 = 0.0483 [for I >
2 (I)] and wR2 = 0.1469.
(
9) For a review on indolo[1,2-c]quinazolines, see:Billimoria,
X-ray data were deposited at the Cambridge Crystallo-
graphic Data Centre, deposition number: CCDC 167173.
(12) For processing of X-ray diffraction data collected in
oscillation mode,see: Otwinowski, Z.; Minor, W. Methods in
Enzymology: Macromolecular Crystallography, Part A,
Vol. 276; Carter C. W. Jr., Sweets R. M., Academic Press:
New York, 1997, 307–326.
A. D.; Cava, M. P. Heterocycles 1996, 42, 453.
(
10) Bis(o-trifluoroacetamidophenyl)acetylene 1 was prepared as
follows: to a solution of o-(o-aminophenylethynyl)trifluoro-
7
acetanilide (1.0 g, 3.29 mmol) in THF (10 mL) trifluoro-
acetic anhydride (0.929 mL, 6.58 mmol) was added
dropwise at 0 °C. The solution was stirred at room
temperature for 2 h. Then, n-hexane (50 mL) was added and
the resulting suspension was filtered to give 1 in quantitative
(13) Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.
J. Appl. Cryst. 1993, 26, 343.
-
1 1
yield: mp: 262-263 °C; IR (KBr) 3329, 1710 cm ; NMR
(14) Seldrick, G. M. Acta Cryst. 1990, A46, 467.
(15) For a reference on palladium-catalyzed overall trans
additions to acetylenic compounds, see: (a) Arcadi, A.;
Cacchi, S.; Fabrizi, G.; Marinelli, F.; Pace, P. Eur. J. Org.
Chem. 1999, 3305. (b) Cacchi, S.; Fabrizi, G.; Marinelli, F.;
Moro, L.; Pace, P. Tetrahedron 1996, 52, 10225. (c) Ji, J.;
Wang, Z.; Lu, X. Organometallics 1996, 15, 2821.
(d) Gibbs, R. A.; Krishnan, U.; Dolence, J. M.; Poulter, C. D.
J. Org. Chem. 1995, 60 , 7821. (e) de Vaal, P.; Dedieu, A. J.
Organomet. Chem. 1994, 478, 121. (f) Dyker, G.; Kellner,
A. Tetrahedron Lett. 1994, 35, 7633. (g) Zargarian, D.;
Alper, H. Organometallics 1991, 10, 2914.
1
3
(
DMSO-d ): = 10.60 (bs, 2 H), 7.71-7.42 (m, 8 H); C
6
NMR (DMSO-d ): = 155.1 (q, J = 37.0 Hz), 135.7, 132.2,
6
1
29.8, 127.6, 126.7, 119.4, 116.0 (q, J = 288.5 Hz), 90.4;
+
MS m/z (relative intensity) 400 (M , 66), 331(11), 286 (50),
34 (100). Anal. Calcd for C H N F O : C, 54.01; N, 7.00
2
1
8
10
2
6
2
H, 2.52. Found: C, 54.09; N, 7.02; H, 2.51.
(
11) A typical procedure is as follows (Table 2, entry 3): to a
solution of bis(o-trifluoroacetamidophenyl)acetylene 1
(0.150 g, 0.375 mmol), 4-carbethoxyphenyl iodide (0.075
mL, 0.450 mmol) and K CO (0.256 g, 1.875 mmol) in
2
3
DMSO (5 mL) under argon, Pd(PPh ) (0.022 g, 0.019
3
4
Synlett 2001, No. 10, 1605–1607 ISSN 0936-5214 © Thieme Stuttgart · New York