Facile construction of highly functionalized 2-pyrrolines via FeCl 3-catalyzed reaction of aziridines with arylalkynes

Article abstract of DOI:10.1039/b910408a

A series of highly functionalized 2-pyrrolines have been constructed by using a novel FeCl₃-catalyzed reaction of aziridines with arylalkynes, in which an aryl-substituted alkenyl cation is involved.

Full text of DOI:10.1039/b910408a

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Facile construction of highly functionalized 2-pyrrolines via
FeCl3-catalyzed reaction of aziridines with arylalkynesw
Jinmin Fan, Linfeng Gao and Zhiyong Wang*
Received (in Cambridge, UK) 27th May 2009, Accepted 17th June 2009
First published as an Advance Article on the web 15th July 2009
DOI: 10.1039/b910408a
A
series of highly functionalized 2-pyrrolines have been
(Table 1, entries 1–3) and nitromethane was found to be the
best solvent.z When dichloromethane or dichloroethane was
employed as the solvent, an amount of unidentified product
was detected. Different Lewis acids including other iron salts
were also examined and we found that iron(III) chloride was the
best catalyst for this transformation (Table 1, entries 4–11).
To our delight, the reaction yield (GC) can be enhanced to
72% when lowered the reaction temperature to ꢀ20 1C
(Table 1, entries 12–13). In addition, phenylacetylene can
polymerize in acid conditions and a larger amount of phenyl-
acetylene may facilitate the reaction, which was confirmed in
entry 14, Table 1. Organophosphine catalysts have been
documented to catalyze the ring-opening reaction of aziridine.
However, using our system, no reaction happened using
FeCl3 with either organophosphine as co-catalyst (Table 1,
entries 15–16) nor using the organophosphine as the catalyst
alone (not presented in Table 1). Furthermore, Binol
phosphonic acid was also not effective under the same reaction
conditions (Table 1, entry 18).
constructed by using a novel FeCl3-catalyzed reaction of
aziridines with arylalkynes, in which an aryl-substituted alkenyl
cation is involved.
Nitrogen-containing five-membered heterocycles are common
structural scaffolds in natural products and pharmaceutical
agents. Interest in their chemistry continues unabated due to
their usefulness as biologically active agents as well as their
utility as key intermediates in the synthesis of numerous
natural products and medicinal reagents.1 Among nitrogen-
containing five-membered heterocycles, 2-pyrrolines are rather
unusual because of the enamine skeleton. Such characteristics
have made 2-pyrrolines significant synthetic targets and hence
they have continued to give chemists incentive in exploring
new methods for their construction.2 They have also received a
lot of attention as intermediates in the syntheses of biologically
active pyrroles and pyrrolidines3 via combinatorial techniques.
Aziridines are versatile building blocks and the regio- and
stereo-controlled ring opening reactions of aziridines with
nucleophiles constitute useful tools for the synthesis of many
nitrogen-containing biologically active molecules, and many
reagents have recently been developed to realize the opening of
the aziridine ring. However, the most often used reagents are
O-, S-, and N-nucleophiles.4 Only a few examples were
reported using carbon nucleophiles, such as allylsilanes,
enamines, Grignard reagents, organolithiums, Wittig reagents,
cuprates and malonates, in the ring-opening reaction of
aziridines.5 The ring opening reaction of aziridines with
functionalized alkynes via cleavage of the C–N bond still
remains unknown in the literature.6
After the optimization of the reaction conditions, we
examined the scope and the generality of the transformation.
First, we focused on the reactivity of different arylalkynes 2.
As shown in Table 2, a variety of arylalkynes with electron-
donating or electron-withdrawing groups were employed as
the reaction substrates and the reactions afforded the corres-
ponding 2-pyrroline products in moderate to high yields. The
presence of a weak electron-withdrawing substituent on
the arylalkyne appeared to have only a slight influence on
the reactivity (Table 2, 3b and 3d). However, a strong electron-
withdrawing substituent retarded the reaction and the desired
products 3f and 3g were not detected. On the other hand, a
strong electron-donating substituent on the arylalkyne favored
the reaction and the corresponding 2-pyrrolines were obtained
in high yields (Table 2, 3c, 3i and 3m)—perhaps due to a more
stable aryl-substituted alkenyl cation intermediate (see below).
When 1,2-diphenylethyne was used, the annulation still
produced the corresponding 2-pyrroline product 3e but with
a slightly lower yield (Table 2, 3e). For different aziridines 1,
the presence of an electron-withdrawing substituent on the
benzene ring of the aziridine showed a slight influence on the
Recently, iron as an abundant, economical and environ-
mentally friendly metal has shown increasing promise as a
catalyst in many organic syntheses.7 As part of a program
directed toward the development of iron-catalyzed reactions for
the synthesis of biologically active heterocyclic compounds,8 we
present herein a novel protocol for the construction of highly
functionalized 2-pyrrolines via FeCl3-catalyzed reaction of
aziridines and arylalkynes (Scheme 1).
In our initial studies, 2-phenyl-1-tosylaziridine (1a) was
treated with phenylacetylene (2a) in the presence of FeCl3
Hefei National Laboratory for Physical Science at Microscale,
Joint- Lab of Green Synthetic Chemistry and Department of
Chemistry, University of Science and Technology of China, Hefei,
230026, P. R. China. E-mail: zwang3@ustc.edu.cn;
Fax: (+86) 551-360-3185; Tel: (+86) 551-360-3185
w Electronic Supplementary Information (ESI) available: Synthesis of
substrates, characterization data and NMR spectra of all products.
See DOI: 10.1039/910408a
Scheme 1 FeCl3-catalyzed reaction of aziridines with arylalkynes.
Chem. Commun., 2009, 5021–5023 | 5021
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Table 1 Optimization of the reaction conditionsa
trisubstituted 2-pyrroline 3j as diastereomers, albeit with low
diastereoselectivity (syn :anti = 15 : 2). The 2-methyl-2-phenyl-
1-tosylaziridine also gave the corresponding 2-pyrrolines
3l and 3m in good yields, incorporating quaternary carbons
into the 2-pyrrolines.
Subsequently, we set out to study the transformation of
2-pyrrolines into the important building blocks, g-amino
ketones.9 After optimization of the reaction conditions, we
achieved a one-pot protocol for synthesis of g-amino ketones
with good yields under mild conditions (Table 3). As can be
seen, various aziridines and arylalkynes can be readily
transformed to the desired g-amino ketones.
To clarify the mechanism of this process, we examined the
reaction of aziridines without the activated tosyl group
[Scheme 2, eqn (1)]. No desired product was detected when
unactivated aziridines 1f or 1g were employed in the reaction
with phenylacetylene. Aziridine 1h was also examined under
the optimized conditions shown in Scheme 2, eqn (2).
However, No reaction occurred and 93% of starting material
was recovered. Furthermore, the reaction turned out to be
messy when alkyl alkyne 2h was employed in the reaction of
aziridine 1a and only a trace amount of desired product 3p was
detected by 1H NMR spectroscopy of the crude mixture
[Scheme 2, eqn (3)].
Entry Catalyst
Solvent
T/1C t/h
Yield (%)b
1d
2d
3d
4
FeCl3
FeCl3
FeCl3
FeCl3
CH3NO2 rt
CH3NO2 rt
DCE
0.25 46
2
2
12
15
rt
CH3NO2 rt
CH3NO2 rt
CH3NO2 rt
CH3NO2 rt
CH3NO2 rt
CH3NO2 rt
CH3NO2 rt
CH3NO2 rt
CH3NO2
CH3NO2 ꢀ20
CH3NO2 ꢀ20
CH3NO2 ꢀ20
CH3NO2 ꢀ20
CH3NO2 ꢀ20
0.25 61
0.25 33
0.5
2
5
6
7
8
Zr(OTf)4
Fe(NO3)3ꢂ9H2O
FeCl2ꢂ4H2O
Fe(OTf)3
CuCl2ꢂ2H2O
Fe2(SO4)3ꢂ5H2O
Fe(acac)3
FeCl3
FeCl3
FeCl3
FeCl3 + Ph3P
FeCl3+ DPPEg
—
Tracec
36
6
9
0
9
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
10
11
12
13
14e
15e
16e
17e
Tracec
0
67
72
77(71f)
0
0
0
0
18e
CH3NO2 ꢀ20
4
0
Based on the results above, a plausible mechanism is
proposed in Scheme 3. Aziridine 1a is activated by FeCl3 to
form a zwitterionic intermediate A, which is then attacked by
the phenylacetylene to generate an aryl-substituted alkenyl
cation B. An intramolecular cyclization gives the desired
product 3a and regenerates the iron catalyst.
a
Reaction conditions: aziridine 1a (0.5 mmol), phenylacetylene 2a
b
(1.0 mmol), dry solvent (2.0 ml), N2. GC yield with internal
standard. Determined by 1H NMR spectroscopy of the crude
c
d
mixture. Wet solvents. Phenylacetylene 2a (1.5 mmol). Isolated
e
f
g
yield in the parenthesis. 1,2-bis(diphenylphosphino)ethane.
In conclusion, we have developed a novel protocol for
convenient and effective construction of functionalized
2-pyrrolines from readily available substrates under mild
Table 2 Reaction of substituted aziridines 1 with arylalkynes 2ab
conditions. The use of
a simple iron salt as catalyst
renders the protocol suitable for large-scale synthesis,
providing a valuable route to assemble biologically active
molecules.
Table 3 Reaction of aziridines 1 with arylalkynes 2 to synthesis of
g-amino ketones 4 in one-pot protocola
Entry
R1
R2
R3
Product
Yield (%)b
a
Reaction conditions: aziridine 1 (0.5 mmol), arylalkyne 2 (1.5 mmol),
b
1
2
3
4
5
6
H
H
4-Br
4-Br
3-Cl
H
H
H
H
H
H
Me
H
OMe
H
OMe
H
OMe
4a
4b
4c
4d
4e
4f
66
79
64
71
60
60
FeCl3 (0.05 mmol), CH3NO2 (2.0 ml), ꢀ20 1C, 0.5 h, N2. Yield of
isolated product. 2 h. syn : anti = 15 : 2 was determined by 1H
NMR spectroscopy.
c
d
a
Aziridine 1 (0.5 mmol), arylalkyne 2 ( 1.5 mmol), FeCl3 (0.05 mmol),
CH3NO2 (2.0 ml), ꢀ20 1C, 0.5 h, N2, then 5 mmol H2O, rt, 12 h.
annulation (Table 2, 3a, 3h and 3k). 2-Aryl-3-alkyl-substituted
aziridines also participate effectively in the reaction, with
anti-2-(4-methoxyphenyl)-3-methyl-1-tosylaziridine 1j giving
b
Yield of isolated product.
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46.4, 21.7; IR (liquid film, cmꢀ1): v = 3063, 3030, 1598, 1493, 1354,
1165, 1091, 1028, 910, 698; HRMS(EI-TOF) calc. C23H21NO2S (M+):
375.1293. Found: 375.1290.
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Scheme 2 Additional experiments.
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Scheme 3 A plausible mechanism for the reaction of aziridines and
arylalkynes.
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This work was supported by the National Natural Science
Foundation of China (20628202 and 90813008).
Notes and references
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¨
z Representative procedure for FeCl3-catalyzed construction of
functionalized 2-pyrrolines: FeCl3 (8.1 mg, 0.05 mmol) and aziridine
1a (137.0 mg, 0.5 mmol) were loaded into a 10 ml oven-dried flask and
the system put under vacuum and charged with N2 three times. The
system was cooled to ꢀ20 1C and a solution of alkyne 2a (153.0 mg,
1.5 mmol) in freshly distilled CH3NO2 (2.0 mL) was added using a
syringe over 20 min. The resulting mixture was maintained at ꢀ20 1C
for another 10 min, then the solvent was evaporated under reduced
pressure. The residue was purified by column chromatography on
silica gel using PE : EtOAc : Et3N (10 : 1 : 0.03, v/v/v) as eluent to give
2-pyrroline 3a as a light yellow oil (133.0 mg, 71%). 1H NMR (CDCl3,
300 MHz, ppm): d = 7.63–7.60 (m, 2 H), 7.50 (d, J = 8.1 Hz, 2 H),
7.40–7.38 (m, 3 H), 7.23 (d, J = 8.1 Hz, 2 H), 7.17–7.15 (m, 3 H),
6.86–6.83 (m, 2 H), 5.43 (d, J = 2.7 Hz , 1 H), 4.45 (dd, J = 12.3,
9.9 Hz 1 H), 3.83 (dd, J = 12.3, 8.1 Hz, 1 H), 3.71-3.64 (m, 1 H), 2.44
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