Synthesis of 6-trifluoromethylindolo[1,2-c]quinazolines and related heterocycles using N-(2-iodophenyl)trifluoroacetimidoyl chlorides as starting material via C-H bond functionalization

Article abstract of DOI:10.1039/c0cc03197f

A mild, two-step reaction for the synthesis of 6-trifluoromethylindolo[1,2- c]quinazolines from readily available indoles and N-(2-iodophenyl) trifluoroacetimidoyl chlorides via addition-elimination/arylation is described. An array of aza-fused trifluoromethylated heterocycles can be easily assembled via Friedel-Crafts reaction/C-H bond activation by this methodology.

Full text of DOI:10.1039/c0cc03197f

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Synthesis of 6-trifluoromethylindolo[1,2-c]quinazolines and related
heterocycles using N-(2-iodophenyl)trifluoroacetimidoyl chlorides
as starting material via C–H bond functionalizationw
Jiangtao Zhu,a Haibo Xie,a Zixian Chen,ab Shan Lia and Yongming Wu*a
Received 12th August 2010, Accepted 28th October 2010
DOI: 10.1039/c0cc03197f
A mild, two-step reaction for the synthesis of 6-trifluoromethylin-
dolo[1,2-c]quinazolines from readily available indoles and N-(2-
iodophenyl)trifluoroacetimidoyl chlorides via addition–elimination/
arylation is described. An array of aza-fused trifluoromethylated
heterocycles can be easily assembled via Friedel–Crafts reaction/
C–H bond activation by this methodology.
Indole scaffolds are one of the most extensively studied class of
heterocyclic compounds, and have been increasingly attracting
attention as bioactive natural products and their pharmaceutical
implications.1 Moreover, fused indole derivatives such as
indolocarbazoles,2 indoloisoquinolines,3 indoloquinolines,4
Scheme 1 Methods for synthesis of indolo[1,2-c]quinazolines.
and indoloquinazolines5 display a number of interesting phar-
macological properties. Among them, indolo[1,2-c]quinazolines
show potent activity against bacterial and fungal strains.6 It’s a
of starting material or required multiple steps. Inspired by recent
advances in the direct arylation of pyrroles and indoles with
aryl halides,11,3a we designed another approach to construct
6-trifluoromethylindolo[1,2-c]quinazolines via palladium-catalyzed
intramolecular cyclization of 1-(N-arylimino)indole derivatives,
which can be easily assembled by reacting N-phenyltrifluoro-
acetimidoyl chlorides with indoles via the addition/elimination
process (route c, Scheme 1).
known fact that the trifluoromethyl group can dramatically
influence the properties of organic molecules, thereby increasing
their applicability as pharmaceuticals, agrochemicals, or build-
ing blocks for synthetic materials.7 Recently, our group has
focused on the syntheses of fluorinated heterocycles by using
N-phenyltrifluoroacetimidoyl halides as starting materials.8
Here, we report a straightforward procedure to synthesize
6-trifluoromethyl indolo[1,2-c]quinazolines via palladium-
catalyzed C–H functionalization of intermediary 1-(N-arylimi-
no)indoles complexes, which can be easily prepared by addition–
elimination reaction of N-phenyltrifluoroacetimidoyl chlorides
with indoles. This strategy can also lead to the formation of
other related trifluoromethylated heterocycles via Friedel–Crafts
reaction/C–H bond activation.
The cyclization precursor 2a was typically prepared from
reacting N-(2-iodophenyl)trifluoroacetimidoyl chloride 1a
with 3-methylindole by the addition/elimination process in
the presence of butyllithium in THF at ꢀ78 1C in good yield.
We subsequently investigated different palladium sources to
identify an optimum catalyst for intramolecular cyclization of
2a. We have studied palladium sources, such as PdCl2(PPh3)2,
Pd2dba3, Pd(PPh3)4, Pd(OAc)2/PPh3, and found that the
Pd(OAc)2/PPh3 system was a desirable catalyst for this
transformation. Optimization on the reaction was also
performed against various bases and reaction media, the
results were summarized in Table 1. It showed that the yields
were nearly quantitative when bases like KOAc, K3PO4 and
K2CO3 were used while Cs2CO3 only afforded the desired
product in moderate yield (entries 1, 5–7, Table 1). It was
found that DMF was the optimal solvent for this reaction,
while other solvents (DMSO, CH3CN, and toluene) resulted in
lower yields (entries 2–4, Table 1).
6-Methyl- and 6-benzylindolo[1,2-c]quinazolines were
synthesized by reacting acetyl and benzoyl chlorides with
2-(20-amino)phenylindole, which was obtained by Fisher indole
cyclization from the hydrazone of 2-aminophenyl ethyl ketone
and phenylhydrazine condensation (route a, Scheme 1).9
Trifluoro-methylated analogues were prepared by palladium-
catalyzed reaction of readily available bis(o-trifluoro-
acetimidophenyl)acetylene with aryl or vinyl halides, followed
by cyclization of the resultant derivatives (route b, Scheme 1).10
These reported methods suffered from either limited availability
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 345 Ling-Ling,
Road, Shanghai 200032, China. E-mail: ymwu@mail.sioc.ac.cn;
Fax: +86 21-64166128
The scope and limitation of the palladium-catalyzed
cyclization reaction was explored by employing various
indoles and N-aryltrifluoroacetimidoyl chlorides 1 containing
a wide range of functional groups. N-Aryltrifluoroacetimidoyl
b Department of Chemistry, Huazhong University of Science and
Technology, Wuhan, Hubei 430074, China
chlorides
1 containing both electron-withdrawing and
w Electronic supplementary information (ESI) available: Full
experimental procedures and data. CCDC 784283 (3i) and 784284
(4c). For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c0cc03197f
electron-donating groups were suitable substrates and gave
the corresponding products in excellent yields (entries 5–11,
Table 2). Electron-rich indoles showed better reactivity and
c
1512 Chem. Commun., 2011, 47, 1512–1514
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Table 1 Optimization of reaction conditionsa
Scheme 2 Formation of an expanded seven-membered ring.
Entry
Base
Solvent
Time
Yieldb (%)
to completion. However, only a trace amount of the desired
product 3a was detected when N-(2-chlorophenyl)trifluoro-
acetimidoyl chloride was used, even under prolonged heating
at the above temperature. The polycyclic products 3 were fully
characterized by 1H and 13C NMR methods and mass spectro-
scopic data. The structure of product 3i was further confirmed
by X-ray crystallographic analysis.w
When the 2-position of the indole moiety was blocked by a
methyl or phenyl group, an expanded seven-membered fused
ring product 4 was obtained in excellent yields at 140 1C
(Scheme 2). The structure of 4c was unambiguously
confirmed by X-ray analysis.w The formation of the seven-
membered ring via palladium-catalyzed direct arylation is
uncommon hence rarely reported.13
1
2
3
4
5
6
7
KOAc
KOAc
KOAc
KOAc
K2CO3
K3PO4
Cs2CO3
DMF
15 min
15 min
3 h
100 (96)
87
74
34
97
DMSO
CH3CN
toluene
DMF
DMF
DMF
3 h
15 min
15 min
15 min
100
60
a
Conditions: 2a (0.3 mmol), Pd(OAc)2 (5 mol%), PPh3 (10 mol%),
b
base (200 mol%), solvent (2 mL), 100 1C. The yield was determined
by 19F NMR; isolated yield in parentheses.
Table 2 Synthesis of various 6-trifluoromethylindolo[1,2-c]quinazolinesa
The reaction was then successfully extended to pyrrole and
pyrazole, affording pyrrolo[1,2-c]quinazoline 3t and pyrazolo-
[1,5-c]quinazoline 3u in good yields (eqn (1), Scheme 3). We also
explored N-(2-iodophenyl)trifluoroacetimidoyl chlorides with
indoles, pyrrole and benzene via Friedel–Crafts reaction to
acquire the corresponding intermediate for the direct arylation.
By this methodology, some other related trifluoromethylated
heterocycles, such as pyrrolo[1,2-a]quinoxaline 5a (eqn (2),
Scheme 3), indolo[3,2-c]quinolines 6a and 6b (eqn (3),
Scheme 3), and 6-(trifluoromethyl)phenanthridine 7a (eqn (4),
Scheme 3), were obtained in moderate to good yields.
Entry
R1
R2
R3
Yieldc (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
9-Me
H
H
H
H
H
H
H
H
3-OMe
2-Me
2-Me
2-F
2-Cl
2-CF3
2-NO2
H
H
H
H
H
H
H
3b/86
3c/88
3d/90
3e/92
3f/97
3g/87
3h/97
3i/75
3j/86
3k/96
3l/67
3m/88
3n/92
3o/67
3p/58
3q/54
3r/38
3s/50
Ph
Et
Pr
Me
H
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
In conclusion, we have developed an efficient two-step reac-
tion for the synthesis of substituted 6-trifluoromethylindolo
[1,2-c]quinazolines from N-(2-iodophenyl)trifluoroacetimidoyl
chlorides and indoles via addition–elimination and subsequent
palladium-catalyzed arylation. When the 2-position of indole
was blocked by substitutions, a seven-membered ring was
formed instead. The applicability of the methodology has been
9
10
11b
12b
13
14
15
16b
17b
18b
H
H
10-OMe
8-Me
11-Cl
9-F
9-Cl
10-NO2
10-Br
a
Conditions: 2 (0.3 mmol), Pd(OAc)2 (5 mol%), PPh3 (10 mol%),
b
KOAc (200 mol%), DMF (2 mL), 15 min, 100 1C. The reaction
temperature was elevated to 140 1C. Yields of isolated products.
c
furnished the desired products in good yields (entries 12 and
13, Table 2). In agreement to previous reports,12 the reaction
of other electron-deficient indoles gave the indolo[1,2-
c]quinazolines in moderate yields, which was in accordance
with the mechanism of the electrophilic aromatic substitution
at the palladium center (SEAr) (entries 14–18, Table 2). Other
halide substitutions (e.g., Cl, Br) survived under our optimal
reaction conditions, providing a useful handle for further
cross-coupling reactions (entries 9, 14, 16, and 18, Table 2).
3-Substituted indoles (e.g., 3-ethyl, 3-phenyl and 3-propyl)
could be effectively converted to the corresponding products
(entries 2–4, Table 2). N-(2-Bromophenyl)trifluoroacetimidoyl
chloride afforded product 3a in 78% yield although an elevated
temperature of 140 1C was needed in order to drive the reaction
Scheme 3 Synthesis of other related trifluoromethylated heterocycles.
Chem. Commun., 2011, 47, 1512–1514 1513
c
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This work was supported by the National Science
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