[Fe(F20TPP)Cl] catalyzed intramolecular C-N bond formation for alkaloid synthesis using aryl azides as nitrogen source

Article abstract of DOI:10.1039/c0cc01825b

The syntheses of alkaloids including indoles, indolines, tetrahydroquinolines, dihydroquinazolinones and quinazolinones have been accomplished in moderate to excellent yields via [Fe(F₂₀TPP)Cl] catalyzed intramolecular C-N bond formation using aryl azides as nitrogen source.

Full text of DOI:10.1039/c0cc01825b

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[Fe(F20TPP)Cl] catalyzed intramolecular C–N bond formation
for alkaloid synthesis using aryl azides as nitrogen sourcew
Yungen Liu, Jinhu Wei and Chi-Ming Che*
Received 10th June 2010, Accepted 23rd July 2010
DOI: 10.1039/c0cc01825b
The syntheses of alkaloids including indoles, indolines, tetra-
hydroquinolines, dihydroquinazolinones and quinazolinones have
been accomplished in moderate to excellent yields via
[Fe(F20TPP)Cl] catalyzed intramolecular C–N bond formation
Scheme 1 Indole formation catalyzed by [Fe(F20TPP)Cl].
using aryl azides as nitrogen source.
Transition metal mediated nitrene insertion into sp2 and sp3
C–H bonds is an appealing methodology for C–N bond
formation,1 and a number of metal catalysts such as those of
Mn, Ru, Co, Cu, Ag and Au have been reported to display
potent activity toward this type of C–N bond formation
reactions.2,3 An important development in this endeavour is
the introduction of dirhodium(II, II) complexes as catalysts.4
However, due to the low natural abundance of rhodium on earth,
there is a surge of interest to develop inexpensive and biocompa-
tible metal complexes as alternatives to dirhodium(II, II) catalysts.
Alkaloids are a family of nitrogen atom containing natural
products with active pharmaceutical properties.5 Nitrene
transfer and insertion reactions for the formation of C–N
bonds can be used for preparing alkaloids. For example, Du
Bois and co-workers reported the synthesis of (À)-tetrodotoxin
through intramolecular nitrene insertion into C–H bonds
catalyzed by dirhodium(II, II) complex.4a Driver and co-workers
reported the preparation of indole and indoline compounds
using rhodium and iridium complexes as catalysts.6 Recently,
there has been a growing interest in developing iron catalysts
for the construction of C–N bonds.7
are comparable to those reported by Driver wherein
dirhodium(II, II) catalyst was employed.6a On the other hand,
the indole moiety can also be formed by insertion of aryl
nitrene into the a-position of cinnamates (Table 1). With
[Fe(F20TPP)Cl] as catalyst, all of the ortho-azido-cinnamates
3
gave the corresponding indoles 2 in 86–91% yields
(7 examples) and with complete azide consumption.
Next, the syntheses of indolines 8, 10 and tetrahydroquinolines
9, 11 via direct amination of saturated benzylic C–H bonds
were studied (Table 2). With [Fe(F20TPP)Cl] as catalyst, all of
these four substrates 4a, 4b and 5a, 5b gave the corresponding
indolines 8 and tetrahydroquinolines 9 in good yields and with
complete azide consumption (Table 2, entries 1–4). However,
when compounds 6a and 6b were used as the substrates,
2-phenyl indoles 12a and 12b were obtained (entries 5, 6).
Even after protection of the OH group by methylation,
compound 6c still gave 2-phenyl indole (12a) as the major
product (entry 7). Compound 6d gave 3-methoxy indoline 10d
(cis : trans = 1 : 0.58) in 75% yield with complete azide
consumption (entry 8). Interestingly, the OH group in compounds
7a–7d could tolerate the reaction conditions and 2-phenyl-3-
hydroxy tetrahydroquinolines 11a–11d were obtained in good
yields with moderate diastereoselectivities (entries 9–12).
The syntheses of dihydroquinazolinones 14 (63–83% yields)
were achieved from ortho-azidobenzamide derivatives 13 via
direct amination of saturated C–H bonds (Table 3). With
[Fe(F20TPP)Cl] as catalyst, amination of benzylic C–H bonds
of dibenzyl amine 13a and isoindoline 13b gave the corresponding
dihydroquinazolinones 14a and 14b in good yields (Table 3,
entries 1, 2). Amination of tetrahydroisoquinoline 13c
(Table 3, entry 3) gave 14c in moderate yield and quinazolinone
15c was detected as a minor product. Importantly, the
intramolecular amination at the 21 C–H bonds of piperidine
13d, pyrrolidine 13e, and diethyl amine 13f have been
accomplished to give dihydroquinazolinones 14d–f in moderate
yields with quinazolinones 15d–f as the minor products,
respectively (Table 3, entries 4–6). Even the insertion at 11
C–H bonds of dimethylamine 13g could proceed to give 14g in
moderate yield with 15g as a minor product (Table 3, entry 7).
Amination at the 31 C–H bonds of isopropylamine 13h
proceeded smoothly to give the product 14h in 71% yield
(Table 3, entry 8).
In recent work, we found that [Fe(F20TPP)Cl] (H2F20TPP =
meso-tetrakis(pentafluorophenyl)porphyrin) is an effective
catalyst for aziridination of alkenes, sulfimidation of both alkyl
and aryl sulfides, allylic amination of a-methyl styrenes and
amination of saturated C–H bonds using sulfonyl and aryl
azides as the nitrogen source.8 Herein we report that
[Fe(F20TPP)Cl] is an effective catalyst for preparing alkaloids
including indoles, indolines, tetrahydroquinolines, dihydro-
quinazolinones and quinazolinones via intramolecular amination
of sp2 and sp3 C–H bonds with aryl azides as the nitrogen source.
At the outset, indole formation was selected as the model
reaction (Scheme 1). With [Fe(F20TPP)Cl] as catalyst,
substituted methyl a-azido-cinnamates 1 including the ones
with electron-withdrawing or electron-donating substituents
gave indoles 2 in 85–95% yields (9 examples, see the Supporting
Information) and with complete azide consumption. The results
Department of Chemistry and Open Laboratory of Chemical Biology
of the Institute of Molecular Technology for Drug Discovery and
Synthesis, The University of Hong Kong, Pokfulam Road, Hong
Kong, China. E-mail: cmche@hku.hk; Fax: 852 2857 1586
w Electronic supplementary information (ESI) available: Experimental
procedures and compound characterization data. See DOI: 10.1039/
c0cc01825b
The amination of sp2 C–H bonds catalyzed by
[Fe(F20TPP)Cl] (Scheme 1 and Table 1) possibly involves
c
6926 Chem. Commun., 2010, 46, 6926–6928
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Table 1 Indole formation catalyzed by [Fe(F20TPP)Cl]a
Table 2 Indoline and tetrahydroquinoline formation catalyzed by
[Fe(F20TPP)Cl]a
Entry Substrate
Product
Time/h Yield (%)b
Entry
1
Substrate
Product
Time/h
14
Yield (%)b
80
1
16
18
18
24
24
24
24
86
89
88
89
91
90
89
2
3
4
5
6
2
14
82
3
4
5
14
14
15
79
81
74
6
7
8
15
18
18
78
7
a
All reactions were performed with 0.20 mmol azide, 0.004 mmol
[Fe(F20TPP)Cl], and 60 mg 4 A molecular sieves in 1 mL of anhydrous
76
b
ClCH2CH2Cl under N2. Isolated yield.
75c
iron-nitrene/imido intermediates and might proceed through
mechanisms analogous to those proposed by Driver and
co-workers for dirhodium-catalyzed analogues.6a,b For
[Fe(F20TPP)Cl] catalyzed amination of sp3 C–H bonds
(Tables 2 and 3), a hydrogen atom abstraction mechanism3m,9
is proposed (Scheme 2, using substrate 6d as an example).
Firstly, [Fe(F20TPP)Cl] catalyzes the decomposition of aryl
azide to give an iron-nitrene/imido complex A.10 Then, a
9
16
16
18
20
72d
79e
75f
73g
10
11
benzyl radical intermediate
B could be generated by
an intramolecular hydrogen atom abstraction pathway.
Formation of the C–N bond is accomplished after the
proposed benzyl radical intermediate undergoes collapse and
rotation/collapse processes to give a mixture of cis- and
trans-isomer 10d (cis : trans = 1 : 0.58). In addition, a mixture
of cis- and trans-10a was isolated in a ratio of B1 : 1 in the
course of the reaction when 6a was employed as the substrate
(Scheme 3). But compound 10a is unstable and is converted to
12a under the reaction conditions.
12
a
All reactions were performed with 0.20 mmol azide, 0.004 mmol
[Fe(F20TPP)Cl], and 60 mg 4 A molecular sieves in 1 mL of anhydrous
b
ClCH2CH2Cl under N2. Isolated yield. cis : trans = 1 : 0.58. dr =
c
d
In summary, the commercially-available and air-stable
[Fe(F20TPP)Cl] complex is an effective catalyst for preparing
indoles, indolines, tetrahydroquinolines, dihydroquinazoli-
nones and quinazolinones via intramolecular amination of
sp2 and sp3 C–H bonds with aryl azides as the nitrogen source.
This work was supported by the Hong Kong Research
Grants Council (HKU 7007/08 and HKU/CRF/01/08), and
e
1 : 0.38. dr = 1 : 0.24. dr = 1 : 0.29. dr=1 : 0.35.
f
g
the Areas of Excellence Scheme established under the Uni-
versity Grants Committee of the Hong Kong Special Admin-
istrative Region, China (AoE 10/01P).
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 6926–6928 6927

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Table
3 Dihydroquinazolinone and quinazolinone formation
catalyzed by [Fe(F20TPP)Cl]a
Scheme 3 Formation of 2-phenylindolin-3-ol (10a).
Notes and references
Entry Substrate
Time/h 14 (yield %)b
15 (yield %)b
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Scheme 2 Possible pathway of C–N bond formation.
6928 Chem. Commun., 2010, 46, 6926–6928
c
This journal is The Royal Society of Chemistry 2010