"On water": Efficient iron-catalyzed cycloaddition of aziridines with heterocumulenes

Article abstract of DOI:10.1002/anie.201207746

In suspension: The reaction of aziridines with heterocumulenes in the presence of Fe(NO₃)₃×9 H₂O in aqueous suspension provides access to functionalized five-membered heterocycles in good to high yields. This protocol has a wide substrate scope, is simple, and uses a nontoxic and cheap catalyst. Copyright

Full text of DOI:10.1002/anie.201207746

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DOI: 10.1002/anie.201207746
Synthetic Methods
“On Water”: Efficient Iron-Catalyzed Cycloaddition of Aziridines with
Heterocumulenes**
Mani Sengoden and Tharmalingam Punniyamurthy*
Table 1: Optimization of the reaction conditions.[a]
The use of water as a reaction medium for organic synthesis
has attracted much interest in recent years,[1–3] because water
is the most abundant liquid on the planet, cheap, readily
available, nontoxic, and nonflammable. The [3+2] cycloaddi-
tion reaction of aziridines with heterocumulenes provides
Entry
Catalyst
Solvent
T [8C]
t [h]
Conversion
a powerful tool to access a wide range of functionalized five-
membered heterocycles that exhibit interesting biological and
medicinal properties.[4] Thus, the cycloaddition of aziridines
with carbodiimides,[5] isocyanates,[5–8] and isothiocya-
nates[5,7,9–11] has been studied employing Pd,[5] Ni,[6] HBF4,[7]
Mg–MeOH,[8] PBu3,[9] NaI[10] or Ph4SbBr[11]-based systems as
either the catalyst or stoichiometric reagent. These reactions
are effective in an organic medium and generally involve an
inert atmosphere. In continuation of our studies on hetero-
cycle synthesis,[13] we wish to herein report the first example of
iron(III)-catalyzed cycloaddition of aziridines with hetero-
cumulenes that takes place in aqueous suspension at moder-
ate temperature. The protocol is simple and utilizes environ-
mentally benign nontoxic and cheap iron(III) salt as the
catalyst[14] and water as a reaction medium in air.
Firstly, the optimization of the reaction conditions was
carried out by using phenyl isoselenocyanate (1a) and 1-
isopropyl-2-phenylaziridine (2a) as model substrates in the
presence of Fe(NO3)3·9H2O (10 mol%) and water as the
solvent at various temperatures (Table 1). Gratifyingly, the
reaction proceeded to afford selectively the target iminoazo-
selenolidine[12] 3a after five hours in 80% conversion at room
temperature when the suspension of the soluble
Fe(NO3)3·9H2O and the insoluble substrates 1a and 2a in
water was stirred (Table 1, entry 1). Increase of the reaction
temperature to 608C led to completion of the process in one
hour with 100% conversion (Table 1, entry 3). In a set of
iron(III) salts screened, Fe(NO3)3·9H2O, Fe2(SO4)3·5H2O,
FeCl3·6H2O, and [Fe(acac)3], all were active, and the former
afforded the best results (Table 1, entries 5–8). The effect of
an organic medium, such as toluene, CH2Cl2, and (CH2Cl)2,
was examined, but no reaction was observed, and the starting
material was recovered intact (Table 1, entries 9–11). Low-
ering the amount of the iron(III) catalyst (5 mol%) or the
3a [%][b]
1
2
3
4
5
6
7
8
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
FeCl3·6H2O
Fe2(SO4)3·5H2O
[Fe(acac)3]
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
–
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
toluene
CH2Cl2
(CH2Cl)2
H2O
25
40
60
60
60
60
60
60
60
40
60
60
5
3
1
2
1
1
1
1
1
1
1
8
80
87
100
82[c]
91[d]
87
58
47
n.d.
n.d.
n.d.
12
9
10
11
12
[a] Isoselenocyanate 1a (0.5 mmol), aziridine 2a (0.6 mmol),
Fe(NO3)3·9H2O (10 mol%) and solvent (1 mL) were stirred in air.
[b] Determined by 400 MHz 1H NMR spectroscopy. [c] 5 mol% of
catalyst used. [d] 1 equiv of aziridine 2a used. n.d.=not detected;
acac=acetylacetonate.
quantity of the aziridine (1 equiv) led to the formation of 3a
in less than 91% conversion (Table 1, entries 4 and 5).
Control experiments confirmed that without the iron(III)
catalyst the reaction produced 3a after eight hours in 12%
conversion (Table 1, entry 12).
Next, the scope of the procedure was studied for the
reactions of the substituted isoselenocyanates (Table 2). A
series of substrates 1a–l having both the electron-withdrawing
and -donating groups on the phenyl ring readily reacted with
aziridine 2a to give the target products in one hour with good
to high yields.[12] For example, aryl isoselenocyanates con-
taining 2-methoxy, 3-methyl, 4-chloro, 4-iodo, 4-methoxy, 4-
methyl, and 4-nitro substituents on the phenyl ring reacted to
the target products 3b–h in 61–90% yield. Recrystallization
of 3b in hexane gave crystals, the structure of which was
confirmed by single-crystal X-ray analysis (Figure 1). Aryl
isoselenocyanate bearing 3,4-dimethyl substituents on the
phenyl ring proceeded to give 3i in 93% yield. Naphthyl 1j
and fluorene 1k isoselenocyanates underwent reactions to
afford 3j and 3k in 85% and 75% yield, respectively. A
similar result was observed with cyclohexyl isoselenocyanate
1l affording 3l in 72% yield.
[*] M. Sengoden, Prof. T. Punniyamurthy
Department of Chemistry
Indian Institute of Technology Guwahati
Guwahati-781039 (India)
E-mail: tpunni@iitg.ernet.in
[**] We thank Department of Science and Technology, New Delhi and
Council of Scientific and Industrial Research, New Delhi for financial
Support.
The reactions of a series of aziridines were further studied
with phenyl isoselenocyanate (Table 3). As above, the reac-
tions took place efficiently to afford the target molecules in
good to high yield. For example, aryl aziridines 2b–o having
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201207746.
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Table 2: Reaction of substituted isoselenocyanates with aziridine.[a]
Table 3: Reaction of substituted aziridines with isoselenocyanate.[a]
Entry
Isoselenocyanates
R
Product (Yield [%])[b]
Entry
Aziridine
R
R’
Product
(Yield [%])[b]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
1i
Ph
3a (88)
3b (90)
3c (85)
3d (86)
3e (89)
3 f (82)
3g (79)
3h (61)
3i (93)
3j (85)
3k (75)
3l (72)
2-MeOC6H4
3-MeC6H4
4-ClC6H4
1
2
3
4
2b
2c
2d
2e
2 f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
H
Bn
nBu
cyclohexyl
Ph
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
Bz
Boc
Ph
Ph
Ph
Ph
3m (81)
3n (75)
3o (91)
3p (79)
3q (61)
3r (78)
3s (66)
3t (74)
3u (86)
3v (71)
3w (88)
3x (82)
3y (87)
3z (71)
3aa n.d.
3ab n.d.
4-IC6H4
4-MeOC6H4
4-MeC6H4
4-NO2C6H4
3,4-Me2C6H3
1-naphthyl
2-fluorene
cyclohexyl
5
Ph
6[c]
7
2-ClC6H4
3-NO2C6H4
4-BrC6H4
4-ClC6H4
4-FC6H4
4-MeOC6H4
4-MeC6H4
3,4-Me2C6H3
(-C6H4-4-CH2)2N(iPr)
Ph
9
8
9
10
11
12
1j
1k
1l
10
11
12
13
14
15
16
[a] Reaction conditions: Isoselenocyanate 1a–l (0.5 mmol), aziridine 2a
(0.6 mmol), Fe(NO3)3·9H2O (10 mol%) and water (1 mL) were stirred at
608C for 1 h in air. [b] Yield of isolated product.
Ph
[a] Reaction conditions: Aziridine 2b–q, isoselenocyanate 1a
(0.5 mmol), Fe(NO3)3·9H2O (10 mol%), and water (1 mL) were stirred
at 608C for one hour in air. [b] Yield of isolated product. [c] Reaction
time: 2.5 h. n.d.=not detected.
provide the target molecules 7–9 in 65–79% yields. Isothio-
cyanates 6 exhibited greater reactivity compared to carbodii-
mides 4 and isocyanates 5. These observed results suggest that
the procedure affords a general method for the cycloaddition
of aziridines with heterocumulenes to give the target hetero-
cycles in good to high yield.
To investigate if the protocol can be applied to a larger
scale, the reaction of 1b with 2a was examined on gram scale
(Scheme 1). As above, the reaction readily proceeded to
afford 3b in 91% yield. This result clearly suggests that the
Figure 1. ORTEP diagram of ((Z)-N-(3-isopropyl-5-phenyl-1,3-selenazo-
lidin-2-ylidene)-2-methoxybenzenamine (3b). Thermal ellipsoids are
drawn at a 40% probability level. Hydrogen atoms have been omitted
for clarity.[15]
unsubstituted, benzyl, n-butyl, cyclohexyl, and phenyl sub-
stituents on the nitrogen atom gave the target iminoazosele-
nolidines 3m–q in 61–91% yields. Moreover, both the
substrates bearing electron-donating and -withdrawing
groups on the phenyl ring of the aziridines were compatible,
and the cycloaddition products were obtained in high yields.
For example, the substrates having 2-chloro, 3-nitro, 4-bromo,
4-chloro, 4-fluoro, 4-methoxy, and 4-methyl substituents on
the phenyl ring reacted to the target molecules 3r–x in 66–
88% yields. Aryl aziridine 2n having 3,4-dimethyl substitu-
ents on the phenyl ring underwent reaction with 87% yield. A
similar result was observed with aziridine 2o giving the target
molecule 3z in 71% yield. Under these conditions, N-
benzoyl-2-phenyl aziridine (2p) proceeded in an intramolec-
ular cyclization to afford 4,5-dihydro-2,5-diphenyloxazole
(10) in 78% yield as sole product (see the Supporting
Information), whereas the aziridine 2q underwent decom-
position and no cycloaddition product was obtained.
Table 4: Reaction of heterocumulene with isoselenocyanate.[a]
Entry Heterocumulene
X
R
R’
t [h] Product
(Yield [%])[b]
1
2
3
4
5
6
7
8
9
4a
4b
4a
5a
5b
5c
6a
6b
6c
6d
N
N
N
O
O
O
S
S
S
S
Ph
4-ClC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
2
3
7a (79)
7b (75)
4-Me
H
4-MeO
4-Me
4-Cl
4-MeO
4-Me
3,5-Me2
1.5 7c (68)
3.5 8a (65)
3
5
1
1
1
1
8b (71)
8c (67)
9a (76)
9b (78)
9c (71)
9d (74)
10
Ph
Finally, to reveal the generality of the protocol, the
reactions of aziridines 2 with carbodiimides 4, isocyanates 5,
and isothiocyanates 6 were studied as representative exam-
ples (Table 4). The reactions occurred efficiently at 808C to
[a] Reaction condition: Heterocumulene 4–6 (0.5 mmol), aziridine 2
(0.6 mmol), Fe(NO3)3·9H2O (10 mol%) and water (1 mL) were stirred at
808C. [b] Yield of isolated product.
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monitored by TLC using ethyl acetate and hexane. The reaction
mixture was then cooled to room temperature and extracted with
diethyl ether (3 ꢀ 10 mL). The organic layer was washed with water
(5 mL). Drying (Na2SO4) and evaporation of the solvent gave
a residue that was purified by silica gel column chromatography
using hexane and ethyl acetate (19:1) as eluent.
Scheme 1.
Received: September 25, 2012
Revised: October 30, 2012
Published online: November 20, 2012
protocol may be used for the gram-scale synthesis of the
target heterocycles.
The proposed catalytic cycle is shown in Scheme 2. Iron
salts are soluble in water, while the aziridines and hetero-
cumulenes float on the surface of water as either oil or
Keywords: aziridine · cycloaddition · heterocumulene · iron ·
water
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Scheme 2. Proposed catalytic cycle.
a mixture of oil and solid. The resulting suspension proceeds
to react on stirring to give the target molecules as water-
insoluble oil or solid. These results suggest that the reaction
may take place on the water–oil interface. Furthermore, (S)-
2a reacted with 1b to give optically active 3b, thus suggesting
that the reaction may not involve a carbocation intermediate
(Scheme 3, see the Supporting Information). Thus, chelation
of the iron species with nitrogen of the aziridines may lead to
the formation of the intermediate a (see Scheme 2) that could
cyclize to complete the catalytic cycle giving the target
products.
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Scheme 3.
In summary, an efficient, simple, and general route for the
[3+2] cycloaddition reaction of aziridines with heterocumu-
lenes on water has been described using iron(III) catalysis in
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environmental points of view to access the target heterocycles
in good to high yields.
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Experimental Section
General procedure for the cycloaddition reaction of aziridines with
heterocumulenes: A mixture of heterocumulene (0.5 mmol), aziri-
dine 2 (0.6 mmol), Fe(NO3)3·9H2O (0.05 mmol), and water (1 mL)
was stirred at 60–808C for 1–5 h. The progress of reaction was
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Angewandte
Chemie
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[15] CCDC-899302 (3b) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
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Angew. Chem. Int. Ed. 2013, 52, 572 –575
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