Synthesis of indolo[1,2-c]quinazolines from 2-alkynylaniline derivatives through Pd-catalyzed indole formation/cyclization with N,N-dimethylformamide dimethyl acetal

Article abstract of DOI:10.3762/bjoc.14.218

An efficient strategy for the synthesis of 6-unsubstituted indolo[1,2-c]quinazolines is described. The Pd-catalyzed reaction of o-(oaminophenylethynyl) trifluoroacetanilides with Ar-B(OH)2 afforded 2-(o-aminophenyl)-3-arylindoles, that were converted to 1

Full text of DOI:10.3762/bjoc.14.218

Synthesis of indolo[1,2-c]quinazolines from 2-alkynylaniline
derivatives through Pd-catalyzed indole formation/cyclization
with N,N-dimethylformamide dimethyl acetal
Antonio Arcadi1, Sandro Cacchi2, Giancarlo Fabrizi2, Francesca Ghirga3,
Antonella Goggiamani2, Antonia Iazzetti*2 and Fabio Marinelli*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 2411–2417.
1Dipartimento di Scienze Fisiche e Chimiche, Università di L’Aquila,
Via Vetoio, 671010 Coppito (AQ), Italy, 2Dipartimento di Chimica e
Tecnologie del Farmaco, Sapienza, Università di Roma, P.le A. Moro
5, 00185, Rome, Italy and 3Center for Life Nano Science@Sapienza,
Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome,
Italy
doi:10.3762/bjoc.14.218
Received: 18 April 2018
Accepted: 31 August 2018
Published: 14 September 2018
Associate Editor: J. Aubé
Email:
Antonia Iazzetti* - antonia.iazzetti@uniroma1.it; Fabio Marinelli* -
fabio.marinelli@univaq.it
© 2018 Arcadi et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
arylboronic acids; DMFDMA; indoles; indoloquinazolines;
quinazolines
Abstract
An efficient strategy for the synthesis of 6-unsubstituted indolo[1,2-c]quinazolines is described. The Pd-catalyzed reaction of o-(o-
aminophenylethynyl) trifluoroacetanilides with Ar–B(OH)2 afforded 2-(o-aminophenyl)-3-arylindoles, that were converted to
12-arylindolo[1,2-c]quinazolines by adding dimethylformamide dimethyl acetal (DMFDMA) to the reaction mixture after extrac-
tive work-up. This reaction outcome is different from the previously reported Pd-catalyzed sequential reaction of the same sub-
strates with Ar–I, Ar–Br and ArN2+BF4−, that afforded 12-arylindolo[1,2-c]quinazolin-6(5H)-ones. Moreover, 12-unsubstituted
indolo[1,2-c]quinazolines can be obtained both by reacting 2-(o-aminophenyl)indoles with DMFDMA or by sequential Pd-cata-
lyzed reaction of o-(o-aminophenylethynyl)aniline with DMFDMA.
Introduction
Indoloquinazoline derivatives constitute an important class of aim to discover novel drug candidates [5-8]. In particular,
compounds which exhibit a wide range of biological activities libraries of 6-substituted indolo[1,2-c]quinazolines were synthe-
[1-4]. Then, extensive searches aimed at discovering pharmaco- sized and exhibited good antimicrobial as well as notable anti-
logically active compounds encouraged the synthesis of some fungal activities [9-11]. Since the isolation of hinckdentine A,
new products containing the indolequinazoline nucleus with the an unusual marine alkaloid from the bryozoan Hincksinoflustra
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denticulata collected off the eastern coast of Tasmania [12,13], followed by cyclization to 3 and elimination of trifluoroacetic
indolo[1,2-c]quinazolines related to hinckdentine A received in- acid (Scheme 1). Later, a procedure that allows the introduction
creasing attention as a source of new and useful pharmaceuti- of a variety of substituents other than CF3 in the 6-position
cals. One well-established approach is based on the elaboration (without the substituent in the 12-position) was reported by
of a preformed indole ring, for example through cyclocondensa- Wang and co-workers [22]. More recently, we showed that the
tion of 2-(o-aminophenyl)indoles with 2-cyanobenzothiazoles Pd-catalyzed reaction of o-(o-aminophenylethynyl) trifluoro-
[14], aldehydes [9] and formic acid [15,16], or reactions of acetanilides 5 with aryl halides and aryldiazonium salts led to
2-(2-bromoaryl)-1H-indoles with aldehydes and aqueous the formation of 12-arylindolo[1,2-c]quinazolin-6(5H)-ones 8 in
ammonia [17] or with amino acids [18]. An alternative ap- moderate to excellent yields (Scheme 2a) [23]. Very likely,
proach to indoloquinazolines is represented by sequential proce- under these reaction conditions, the palladium-catalyzed reac-
dures that use 2-alkynylaniline derivatives as starting materials, tion of 5 gave intermediates 6; then, cyclization to 7 followed
via their conversion to 2-(o-aminophenyl)indole derivatives fol- by elimination of trifluoromethane afforded products 8.
lowed by further cyclization [19-22]. Our interest in this field
led to the development of an original approach to 6-trifluoro- Since the unique molecular skeleton of hinckdentine A is
methyl-12-aryl(vinyl)indolo[1,2-c]quinazolines 4 through constituted of a 6-unsubstituted indolo[1,2-c]quinazoline
sequential Pd-catalyzed reactions of bis(o-trifluoroacetamido- nucleus [12,13], we planned to modify our previous procedures
phenyl)acetylene (1) with aryl or vinyl halides and triflates fol- to address the 6-unsubstituted-12-arylindolo[1,2-c]quinazolines
lowed by cyclization reactions (Scheme 1) [19].
10. We wish to report here that, under suitable reaction condi-
tions, substrates 5 can be easily converted into target products
The reaction, which tolerates a variety of important functional 10 (Scheme 2b). Moreover, 12-unsubstituted analogues 13 are
groups, likely involves the formation of the indole intermedi- also available from 5 or from o-(o-aminophenylethynyl)anilines
ates 2 (through aminopalladation/reductive elimination) [20,21] 15 (see below).
Scheme 1: Synthesis of 6-trifluoromethyl-12-aryl(vinyl)indolo[1,2-c]quinazolines 4.
Scheme 2: Present and previously reported reactions starting from 5. DMFDMA: dimethylformamide dimethyl acetal.
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Results and Discussion
DMF at 100 °C to obtain indoloquinazolines 10. The results of
We have previously reported that arylboronic acids 12 can be this procedure, starting from a variety of o-(o-aminophenyl-
used in place of aryl halides in the Pd-catalyzed synthesis of ethynyl)trifluoroacetanilides 5 and arylboronic acids 12, are
indoles through aminopalladation/reductive elimination reac- summarized in Table 1.
tion from 2-alkynyltrifluoroacetanilides [24]. This reaction is
carried out in MeOH at 60 °C in the presence of K3PO4 under In some cases, 12-unsubstituted indolo[1,2-c]quinazoline deriv-
an oxygen atmosphere. We then decided to react substrate 5 atives 13 were also obtained as byproducts. Electron-rich aryl-
under these reaction conditions, in order to ascertain if the pres- boronic acids worked quite well (Table 1, entries 1, 3, and 4).
ence of methanol and base would result in the cleavage of the However, an attempt to carry out the reaction under air, instead
trifluoroacetylamide group after the formation of the indole of under O2 atmosphere, resulted in a loss of efficiency
ring, affording 2-(1H-indolo-2-yl)benzenamine derivatives 9 (Table 1, entry 2). Good results were also observed with
instead of products 8. We were pleased to observe the forma- phenyl- and 1-naphthylboronic acids (Table 1, entries 5 and 6).
tion of 9a in good yields when 5 was reacted with 4-methoxy- Electron-poor arylboronic acids proved to be effective (Table 1,
phenylboronic acid. A minor amount of product 11a (likely entries 7–10), and only (4-chlorophenyl)boronic acid gave a
deriving from a transamidation reaction [25] of initially formed moderate yield of product (Table 1, entry 10).
intermediate 6a) was also isolated. Then, 9a was treated with
dimethylformamide dimethyl acetal (DMFDMA) as a source of Products substituted in the indole and quinazoline frameworks
an electrophilic one-carbon unit at the formate oxidation level were also obtained (Table 1, entries 12–16). It is worth noting
[26,27], affording 12-arylindolo[1,2-c]quinazoline 10a in good that the reaction tolerates a -Br substituent (Table 1, entries 8
yield (Scheme 3).
and 16) which may serve as a useful handle for increasing mo-
lecular complexity through cross-coupling reactions. Only in
Based on this result, we tested an approach to target products 10 the case of two ortho-substituents on the aryl residue of the
avoiding the isolation of intermediates 9. After some boronic acid the reaction afforded the target product 10p in low
experimentation, we found that the best results were obtained yield (Table 1, entry 17), and 12-unsubstituted derivative 13p as
from the following procedure: 1) Pd-catalyzed reaction of 5 the major product.
with ArB(OH)2/K3PO4 in MeOH at 60 °C; 2) heating of the
reaction mixture at 100 °C to allow complete hydrolysis of by- Then, with the aim of obtaining 12-unsubstituted indoloquina-
products 11; 3) after extractive work-up, treatment of the crude zolines 13 selectively, we tested the use of DMFDMA for the
reaction mixture with an excess of DMFDMA (5 equiv) [28] in cyclization of 2-(o-aminophenyl)indoles 14. This reaction re-
Scheme 3: Two-step synthesis of 12-arylindolo[1,2-c]quinazoline 10a.
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Table 1: Synthesis of 12-arylindolo[1,2-c]quinazolines 10.a
Entry
R1
R2
5
Ar
Time (h)b
10 (% yield)c
13 (% yield)c
1
2
3
4
5
6
7
8
9
10
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
4-MeO-C6H4-
4-MeO-C6H4-
4-Me-C6H4-
2-Me-C6H4-
phenyl
3, 16, 16
24, 18, 16
5, 16, 16
5, 16, 16
24, 8, 12
2, 16, 2
10a (76)
10a (49)d
10b (61)
10j (56)
10c (75)
10d (60)
10e (69)
10f (60)
10g (59)
10h (52)
–
–
–
13j (11)
–
1-naphthyl
–
4-CF3-C6H4-
4-Br-C6H4-
4-MeO2C-C6H4-
4-Cl-C6H4-
4, 7, 16
–
2, 16, 6
–
3, 28, 2
–
6, 16, 3
13h (12)
11
H
H
5a
18, 16, 2
10i (65)
13i (12)
12
13
Me
Me
H
H
5b
5b
4-MeO-C6H4-
phenyl
18, 6, 1
24, 5, 4
10k (63)
10l (72)
13k (5)
–
14
Me
H
5b
1, 16, 8
10m (76)
–
15
16
Me
H
COOMe 5c
4-MeO-C6H4-
4-Br-C6H4-
5, 16, 3
10n (60)
10o (58)
–
–
Me
5d
6, 16, 1.5
17
H
H
5a
24, 24, 8
10p (12)
13p (38)
aReactions were carried out at 60 °C on 0.345 mmol scale using 1.0 equiv of 5, 2.0 equiv of 13, 0.05 equiv of Pd(OAc)2, 0.05 equiv of dppp and
2 equiv of K3PO4 in MeOH (2 mL) under an atmosphere of O2; then 100 °C; work-up; then 5 equiv of DMFDMA in DMF (2 mL), 100 °C. bNumbers
refer to the 1st, 2nd and 3rd step, respectively. cIsolated yields. dCarried out under air atmosphere.
quired only a slight excess of DMFDMA (1.2 equiv), and was previously demonstrated that the selective formation of 16
afforded derivatives 13 as sole products in high yields occurs under these conditions [31]) followed by the hydrolysis
(Table 2).
of the COCF3 group of the crude product (Scheme 4).
As described in Supporting Information File 1, indoles 14a–c Moreover, the palladium-catalyzed reaction of 15a in the pres-
(R1 = R3, R2 = H) were obtained by cyclization of the corre- ence of DMFDMA led directly to the formation of quinazoline
sponding o-(o-aminophenylethynyl)anilines 15a–c with 13a in 71% yield through a sequential process (Scheme 5a).
PdCl2(MeCN)2 [29,30]. Indoles 14d,e (R1 ≠ R3) could not be
obtained in such way (due to the lack of selectivity between the The selective formation of products 13 from 15 (and also from
two different NH2 groups in the hydroamination reaction), and 3-unsubstituted indoles 14) is not trivial, since the previously
were obtained by cyclization of the corresponding o-(o-amino- reported gold-catalyzed reaction of 15a with aldehydes as elec-
phenylethynyl) trifluoroacetanilides 5 with PdCl2(MeCN)2 (it trophiles resulted in the divergent formation of 11H-indolo[3,2-
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Table 2: Synthesis of 12-unsubstituted indolo[1,2-c]-quinazolines 13.a
Entry
R1
R2
R3
14
Time (h)
13 (% yield)b
1
2
3
4
5
H
H
H
14a
14b
14c
14d
14e
5
13a (86)
13b (87)
13c (81)
13d (95)
13e (73)
Me
H
Me
24
6
COOMe
H
H
COOMe
Me
H
25
24
Me
Me
H
aReactions were carried out at 100 °C on 0.481 mmol scale using 1.2 equiv of DMFDMA in DMF (2 mL). bIsolated yields.
Scheme 4: Synthesis of indoles 14.
c]quinolines 17 (Scheme 5b) [32] through functionalization of
C-3 position of the indole ring instead of N-1.
The sequential reaction shown in Scheme 5, path a, probably
occurs through cyclization of 15a to indole 14a, followed by the
reaction with DMFDMA; however, an alternative path in which
one amino group interact with DMFDMA to give a formami-
dine intermediate [27] before cyclization cannot be ruled out.
Conclusion
We have reported here an efficient procedure for the prepara-
Scheme 5: Sequential preparation of 13a from 15a.
tion of 12-arylindolo[1,2-c]quinazolines 10 from o-(o-amino-
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12.Blackman, A. J.; Hambley, T. W.; Picker, K.; Taylor, W. C.;
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indoles 14, or from o-(o-aminophenylethynyl)aniline 15a, selec-
tive formation of 12-unsubstituted[1,2-c]quinazolines 13 was
accomplished, without competitive formation of products
derived from C-3 functionalization at the indole moiety.
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Supporting Information File 1
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of NMR spectra.
[https://www.beilstein-journals.org/bjoc/content/
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We gratefully acknowledge the University of L’Aquila and the
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Sapienza, University of Rome, for financial support.
ORCID® iDs
Antonio Arcadi - https://orcid.org/0000-0001-9053-648X
Francesca Ghirga - https://orcid.org/0000-0002-5591-5190
Antonia Iazzetti - https://orcid.org/0000-0002-7792-774X
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doi:10.1002/1099-0690(200208)2002:16<2671::AID-EJOC2671>3.0.C
O;2-X
See for a review.
22.Xu, M.; Xu, K.; Wang, S.; Yao, Z.-J. Tetrahedron Lett. 2013, 54,
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