Iron-catalysed C-3 functionalisation of indolizines via C-H bond cleavage

Article abstract of DOI:10.3184/174751912X13383077583357

The synthesis of 3,3'-(arylmethylene)diindolizine with a FeCl₃ .6H₂O catalyst has been achieved with excellent efficiency at room temperature. Various indolizines were prepared by the reaction with either aromatic or aliphatic aldehydes to produce di- or triheteroarylmethanes.

Full text of DOI:10.3184/174751912X13383077583357

JOURNAL OF CHEMICAL RESEARCH 2012
RESEARCH PAPER 441
AUGUST, 441–443
Iron-catalysed C-3 functionalisation of indolizines via C–H bond cleavage
Xu Shao-hong
Department of Chemistry and Chemical Engineering; Xinxiang University; Xinxiang 453003, P. R. China
The synthesis of 3,3’-(arylmethylene)diindolizine with a FeCl3.6H2O catalyst has been achieved with excellent effi-
ciency at room temperature. Various indolizines were prepared by the reaction with either aromatic or aliphatic
aldehydes to produce di- or triheteroarylmethanes.
Keywords: indolizine, C-3 functionalisation, benzylation, iron-catalysed synthesis
Transition metal-catalysed C–C bond formation reactions
involving C–H bond activation1–5 are distinquished from the
traditional transition metal-catalysed reactions by fewer steps
and less wastage. The older methods need prefunctionalisation
of both reaction partners. These transformations exhibit even
more advantages for arylation, alkenylation, alkynylation and
alkylation of heteroaromatics, because some important types
of heteroaryl organometallic compounds have proven chal-
lenging to synthesise and may even be insufficiently stable to
participate in cross-coupling processes. The regioselective
conversion of C–H to C–C bonds would result in shortening of
synthetic schemes by allowing the use of readily available
starting materials.6–11
Indolizines are interesting structures in a wide variety of
natural products with useful biological activities11–16 and phar-
maceutical properties.17–22 The functionalisation of indolizines
have attracted considerable interest in the past and metal-
catalysed direct functionalisation of indolizines has been
explored recently.17–29
Triaryl- and triheteroarylmethanes have attracted much
attention from organic chemists and many such compounds
have found widespread applications in synthetic, medicinal,
and industrial chemistry.30–32 Triarylmethanes can be synthe-
sised by a number of methods, but most of them are multi-step
processes and require harsh conditions, while Friedel–Crafts
arene alkylation is a major technique in the formation of new
arene-alkane C–C bonds.33–38 Bis-indolylalkanes obtained by
the condensation of indoles with aromatic or aliphatic alde-
hydes requires the use of several Brønsted and Lewis acids.39–41
In the quest to develop a mild and practical protocol for the
synthesis of triaryl-/triheteroarylmethanes, we speculated that
iron(III) catalyst, which has recently been shown to catalyse
a variety of C–C/C–N bond forming reactions,42–47 might be
ideal for effecting the condensation of aldehydes and activated
arenes.
and 7). However, AlCl3 was a much more effective catalyst and
FeCl3 gave the best results at room temperature (Table 1,
entries 8 and 9). The transformation completed under 60 °C
in 2h in 96 % isolated yield (Table 1, entry 10). Otherwise,
CH3CN performed better than other apolar aprotic solvents
(CCl4, THF, Et2O) and aprotic polar solvents (DMF, DMSO)
(Table 1, entries 11–18). Furthermore, this transformation was
very practical as it does not need the use of bases or ligands
and the rigorous exclusion of air/moisture was not required.
These optimised conditions have been applied successfully
for the condensation of a variety of indolizines with aldehydes.
The results are summarised in Table 2. They showed that both
electron-withdrawing and electron-donating substituents had
no significant effect on the yields (Table 2, entries 1–3). The
presence of a substituent on the ortho-position of aromatic
aldehydes did not cause any decrease in the reaction yields
(Table 2, entry 4). In the case of aliphatic aldehydes such as
n-butyraldehyde, the reaction proceeded satisfactory in com-
parison with aromatic aldehydes (Table 2, entry 5). Attempts
to use other indolizine derivatives in the reaction with benzal-
dehyde were mostly successful. Methyl, ethyl and n-butyl
indolizine-1-carboxylate were all compatible with the catalyst
system (Table 2, entries 6–8).
Table 1 Optimisation of reaction conditionsa
Entry
Catalyst
Solvent
Yield/%b
We investigated the electrophilic substitution reaction of
indolizines with aldehydes in the presence of a catalytic
amount of iron(III) chloride at room temperature to form tri-
heteroarylmethane derivatives, the preparation of which
usually requires multi-step processes and harsh conditions.
1
2
FeCl2.4H2O
FeBr2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
CHCl3
CCl4
0
0
3
FeSO4
0
4
Fe(acac)2
Fe2O3
0
0
5
6
CuCl2.2H2O
Cu(OAc)2.H2O
FeCl3.6H2O
AlCl3
30c
22c
92
81
96c
46
51
60
39
38
23
16
17
Results and discussion
7
The preliminary results that illustrate the efficiency and versa-
tility of FeCl3-promoted indolizines’ condensation with alde-
hydes to afford triheteroarylmethanes-3,3′-(phenylmethylene)
diiindolizine-1-carbonitrile are described in this work.
The formation of a 1,1-bis-indolizine-methane product was
not observed in the presence of FeCl2, FeBr2, FeSO4, Fe(acac)2
and Fe2O3 (Table 1, entries 1–5). Comparable yields were
obtained when CuCl2.2H2O and Cu(OAc)2.H2O were used as
catalysts under 60 °C for 2 h in CH3CN (Table 1, entries 6
8
9
10
11
12
13
14
15
16
17
18
FeCl3.6H2O
FeCl3
FeCl3
FeCl3
FeCl3
THF
FeCl3
Et2O
FeCl3
EtOAc
DMF
FeCl3
FeCl3
DMSO
a Reaction conditions: indolizine-1-carbonitrile (0.4 mmol),
benzaldehyde (0.2 mmol), catalyst (0.01 mmol), solvent (2 mL),
RT, 2 h. b Isolated yield. c Performed at 60 °C for 2 h.
* Correspondent. E-mail: shaohong_xu@126.com

442 JOURNAL OF CHEMICAL RESEARCH 2012
Table 2 The reaction of aldehydes with various indolizinesa
Experimental
Starting materials were purchased from common commercial sources
and solvents were all purified and dried according to standard meth-
ods prior to use. Column chromatography was carried out on SiO2
(300–400 mesh). 1H NMR spectra were recorded with a Bruker
400 MHz spectrometer using TMS as internal standard. 13C NMR
spectra were recorded at 100 MHz using TMS as internal standard.
The multiplicities are reported as follows: singlet (s), doublet (d),
doublet of doublets (dd), multiplet (m). Mass spectroscopy data were
collected with HRMS-EI and HRMS-ESI instrument.
Entry
1
Indolizine
Aldehydes
Products
Yield
/% b
Synthesis of triheteroarylmethane
A mixture of indolizines (0.4 mmol), aldehydes (0.2 mmol), FeCl3
(5 mol%), in CH3CN (2 mL) was stirred at room temperature for 2 h.
Afterward, the mixture was filtered through a pad of Celite. The
solvent was evaporated under reduced pressure, and the residue was
subjected to flash column chromatography to obtain the desired
product.
91
3,3'-((4-Methoxyphenyl)methylene)diindolizine-1-carbonitrile (T 2-1):
Purification by column chromatography (silica gel, ethyl acetate/
petroleum ether = 1/3, v/v) gave a white solid; m.p. 257–259 °C.
1H NMR (400 MHz, CDCl3, TMS) δ 7.63–7.69 (m, 4 H), 7.11 (t,
J = 8.0 Hz, 2 H), 7.06 (d, J = 7.6 Hz, 2 H), 7.00 (d, J = 8.0 Hz, 2 H),
2
3
95
98
6.73 (t, J = 8.0 Hz, 2 H), 6.35 (s, 2 H), 5.69 (s, 1 H), 3.81 (s, 3 H). 13
C
NMR (100 MHz, CDCl3) δ 159.5, 138.8, 129.4, 127.8, 123.7, 122.4,
118.2, 117.2, 116.6, 114.8, 113.3, 81.4, 55.3, 40.3. HRMS (EI) Calcd
for C26H18N4O (M+) 402.1481; found 402.1490.
3,3'-(Phenylmethylene)diindolizine-1-carbonitrile (T 2-2) Purifica-
tion by column chromatography (silica gel, ethyl acetate/petroleum
1
ether = 1/3, v/v) gave a white solid; m.p. 249–250 °C. H NMR
(400 MHz, CDCl3, TMS) δ 7.68 (t, J = 7.2 Hz, 4 H), 7.37 (t, J =
7.2 Hz, 3 H), 7.17 (t, J = 7.2 Hz, 2 H), 7.11–7.12 (m, 2 H), 6.74 (t, J =
7.2 Hz, 2 H), 6.34 (s, 2 H), 5.80 (s, 1 H). 13C NMR (100 MHz, CDCl3)
δ 138.8, 136.1, 129.4, 128.5, 128.4, 123.7, 123.4, 122.4, 118.1, 117.3,
116.5, 113.4, 81.4, 41.0. HRMS (EI) Calcd for C25H16N4 (M+)
372.1375; found 372.1380.
3,3'-((4-Chlorophenyl)methylene)diindolizine-1-carbonitrile (T 2-3):
Purification by column chromatography (silica gel, ethyl acetate/
petroleum ether = 1/3, v/v) afforded as a white solid; m.p. 260–
262 °C. 1H NMR (400 MHz, CDCl3, TMS) δ 7.69 (d, J = 9.2 Hz, 2 H),
7.65 (d, J = 8.4 Hz, 2 H), 7.38 (t, J = 8.4 Hz, 2 H), 7.10–7.16 (m, 4 H),
6.76 (t, J = 8.4 Hz, 2 H), 6.35 (s, 2 H), 5.77 (s, 1 H). 13C NMR
(100 MHz, CDCl3) δ 138.9, 134.7, 134.4, 129.8, 129.7, 123.6, 122.8,
122.6, 118.2, 117.3, 116.4, 113.5, 81.6, 40.4. HRMS (EI) Calcd for
C25H15ClN4 (M+) 406.0985; found 406.0989.
3,3′-(Thiophen-2-ylmethylene)diindolizine-1-carbonitrile (T 2-4):
Purification by column chromatography (silica gel, ethyl acetate/
petroleum ether = 1/3, v/v) gave a white solid; m.p. 213–215 °C.
1H NMR (400 MHz, CDCl3, TMS) δ 7.66–7.72 (m, 4 H), 7.32 (d,
J = 7.6 Hz, 2 H), 7.13 (t, J = 8.0 Hz, 2 H), 7.00 (t, J = 8.0 Hz, 1 H),
6.74–6.80 (m, 3 H), 6.51 (s, 2 H), 6.07 (s, 1 H). 13C NMR (100 MHz,
CDCl3) δ 139.1, 138.8, 127.4, 127.1, 126.3, 123.6, 123.1, 122.6,
118.3, 117.0, 116.5, 113.5, 81.5, 36.1. HRMS (EI) Calcd for C23H14N4S
(M+) 378.0939; found 378.0930.
4
5
96
93
6
7
8
94
78
71
3,3′-(Butane-1,1-diyl)diindolizine-1-carbonitrile (T 2-5): Purifica-
tion by column chromatography (silica gel, ethyl acetate/petroleum
1
ether = 1/3, v/v) gave a white solid; m.p. 187–189 °C. H NMR
a Reaction conditions: Indolizines (0.4 mmol), aldehydes
(0.2 mmol), FeCl3.6H2O (0.01 mmol),CH3CN (2 mL), RT, 2h.
b Isolated yield.
(400 MHz, CDCl3, TMS) δ 7.80 (d, J = 7.2 Hz, 2 H), 7.63 (d, J =
7.2 Hz, 2 H), 7.07 (t, J = 7.6 Hz, 2 H), 6.89 (s, 2 H), 6.75 (t, J =
6.8 Hz, 2 H), 4.54 (t, J = 7.2 Hz, 1 H), 2.20–2.26 (m, 2 H), 1.44–1.49
(m, 2 H), 1.01 (t, J = 7.6 Hz, 3 H). 13C NMR (100 MHz, CDCl3) δ
138.6, 124.0, 123.3, 122.1, 118.2, 116.7, 115.4, 113.4, 81.2, 34.6,
33.6, 20.8, 13.9. HRMS (EI) Calcd for C22H18N4 (M+) 338.1531; found
338.1528.
Conclusion
In conclusion, we report our results concerning the study of
indolizines’ C-3 functionalisation involving C–H activation
afford a diversity of C-3 substitution by benzylation. We
have introduced a well-precedented electrophilic substitution
reaction of indolizines with aldehydes in the presence of a
catalytic amount of FeCl3.6H2O under mild conditions to afford
triheteroarylmethane derivatives. As part of the continuing
exploration of new chemistry of the indolizine ring, this
reaction has potential applications in organic syntheses and
industrial processes.
Dimethyl 3,3'-(phenylmethylene)diindolizine-1-carboxylate (T 2-6):
Purification by column chromatography (silica gel, ethyl acetate/
petroleum ether = 1/3, v/v) gave a white solid; m.p. 211–212 °C.
1
(lit:48 210–211 °C) H NMR (400 MHz, CDCl3, TMS) δ 8.27 (d,
J = 8.0 Hz, 2 H), 7.64 (d, J = 7.6 Hz, 2 H), 7.34–7.36 (m, 3 H), 7.19
(d, J = 7.6 Hz, 2 H), 7.09 (t, J = 8.0 Hz, 2 H), 6.67 (t, J = 6.8 Hz, 2 H),
6.63 (s, 2 H), 5.72 (s, 1 H), 3.82 (s, 6 H). 13C NMR (100 MHz, CDCl3)
δ 165.2, 137.1, 136.7, 129.2, 128.6, 128.0, 123.3, 123.2, 122.2, 120.0,
116.8, 112.8, 103.0, 50.9, 41.3. HRMS (EI) Calcd for C27H22N2O4
(M+) 438.1580; found 438.1587.

JOURNAL OF CHEMICAL RESEARCH 2012 443
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petroleum ether = 1/3, v/v) gave a yellow solid; m.p. 176–177 °C.
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J = 7.2 Hz, 2 H), 7.34–7.35 (m, 3 H), 7.18–7.20 (m, 2 H), 7.06–7.10
(m, 2 H), 6.64–6.67 (m, 4 H), 5.72 (s, 2 H), 4.29–4.33 (m, 2 H), 1.35
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