Aziridines are an elite class of compounds present in various natural products and
have been useful intermediates as well as building blocks in organic synthesis.[
1
] In terms of synthetic transformations, the utility of aziridines derives from their
selective ring-opening reactions with various nucleophiles, which often form the basis
for more complex target syntheses, especially N-containing compounds.[2 ]
[3 ] γ-Butyrolactams (pyrrolidin-2-ones) are a class of versatile core structures present
in various natural products such as isocynamatrine[
4a,b
] and clausenamide[
4c–f
] and are also important intermediates in the synthesis of a variety of nitrogenated
heterocycles with interesting biological activities (Figure [1 ]).[4 ]
[5 ]
[6 ]
[7 ]
[8 ]
Due to their versatile applications in organic and medicinal chemistry, the development
of new synthetic routes for the preparation of pyrrolidin-2-ones is an important endeavor
and has been well documented in the literature.[10 ]
[11 ]
[12 ]
[13 ]
[14 ]
[15 ]
[16 ]
[17 ]
[18 ]
[19 ]
[20 ]
[21 ] However, most of the reactions suffer from one or more disadvantages, such as expensive
reagents, long reaction times, low yields, tedious workup, and, most importantly,
none of these methods cater a direct process for the synthesis of 3-(N-substituted)aminopyrrolidin-2-ones
and tend to be lengthy and cumbersome if the lactam contains any sort of substitution.
Recently, Ghorai et al. have reported the synthesis of pyrrolidin-2-one via a nucleophilic
ring opening with a methylene group[
22a
] in addition to other literature reports on the synthesis of 4-(N-substituted)aminopyrroildin-2-ones.[
22b,c
] Very recently, we have reported the synthesis of 3-mercapto-pyrrolidin-2-one starting
via ring opening of aziridines with masked mercaptoacid.[
22d
] To date, there is no report on the direct synthesis of 3-aminopyrrolidin-2-ones.
Figure 1 Pyrrolidin-2-one ring-containing natural products and pharmaceutical molecules
Ionic liquids (IL) have attracted much attention as environmentally friendly reaction
media,[23 ]
[24 ]
[25 ] catalysts,[
26–28
] and reagents[
29,30
] and are also easy to recycle.[29 ]
[30 ] Moreover, the synthesis of amides is important in many areas of chemistry, including
peptide, polymer, and complex molecule synthesis.[
31
] Inspired by these valid points and keeping the synthetic and pharmacological importance
of the amide group in mind we turned our attention to utilize masked amino acids as
substrates viz. 2-phenyl-1,3-oxazolan-5-one, which can introduce an amide group at
the α position into γ-lactam, which is the target molecule in the present investigation.
In this Letter, we report a new molecular-iodine-catalyzed one-pot atom efficient
method for the preparation of 3-(N-substituted)aminopyrrolidin-2-ones 3 in a single step using [bmim]OH as a green reaction promoter. This one-pot synthetic
protocol is highly atom efficient as there is no byproduct formation and involves
novel utilization of the masked amino acid 2-phenyl-1,3-oxazolan-5-one (1 ) with terminal aziridines 2 affording 3-(N-substituted)aminopyrrolidin-2-ones 3 in high yield and excellent diastereoselectivity, in favor of the cis isomer (Scheme [1 ]). Furthermore, the present synthesis of 3-(N-substituted)amino functionalized γ-lactam
3 is an outcome of our quest for developing new synthetic routes employing green chemistry
protocols.[
32
]
Scheme 1 One-pot aminoacetylation of aziridines 2 in ionic liquid [bmim]OH
In a preliminary experimentation, a controlled reaction was carried out using 2-phenyl-1,3-oxazolan-5-one
(1 ) and aziridine 2a (Ar = Ph) in [bmim]OH but the reaction did not afford the desired γ-lactam 3a (Table [1 ], entry 1) even after 48 hours, rather conversion of tosylaziridines 2a into the corresponding amine 4a was observed (Scheme [2 ]). Then, we turned our attention to use molecular iodine as catalyst in conjunction
with different room-temperature ionic liquid (RTIL). For this purpose, 2-phenyl-1,3-oxazolan-5-one
(1 ) and aziridine 2a (R = Ph) were chosen as model substrates for the synthesis of representative compound
3a (Table [1 ]) wherein molecular iodine evidenced its catalytic efficacy in conjunction with RTIL,
affording 3a in excellent yield (Table [1 ], entry 1). A variety of RTIL were screened for the present reaction and amongst
[bmim]BF4 , [bmim]OH, [bmim]PF6 , and [bmim]Br, [bmim]OH was found to be the most effective RTIL for the conversion
of the tosyl aziridine 2a to the corresponding γ-lactam 3a (Table [1 ], entries 2–4).
In order to elucidate the role of other solvents in lieu of RTIL as reaction medium,
various solvents were used under the present reaction conditions. The results validate
our premise that the reaction would not only be faster but also result in higher yield
using RTIL as compared to other conventional solvents (Table [1 ], entries 2, 5–9). Interestingly, yield of the target compound 3a is poor using polar aprotic solvents (Table [1 ], entries 8 and 9). Thus, RTIL [bmim]OH stands out as the choice, with its fast conversion
and quantitative yield in conjunction with molecular iodine, as an inexpensive and
versatile catalyst in the present envisaged synthetic protocol. The optimum catalyst
loading for molecular iodine was found to be 10 mol%. When the amount of catalyst
decreased from 10 mol% to 5 mol% relative to the substrates, the yield of product
3a was reduced (Table [2 ], entries 2 and 10). However, the use of 15 mol% of the catalyst showed the same
yield, and the same time was required (Table [1 ], entries 2 and 11). It was noted that a higher reaction temperature (up to 60 °C)
instead of room temperature had no appreciable effect on the yield.
Next, in order to investigate the substrate scope for the general validity of the
present investigation, a variety of tosyl aziridines 2 were used under the optimized reaction conditions, and different 3-(N-substituted)aminopyrrolidin-2-ones
3 were synthesized. The yields were consistently good (Table [2 ]), and the highest yield was 96% (Table [2 ], entry 3). Thus, the present optimized synthesis is accomplished by stirring a mixture
of 2-phenyl-1,3-oxazolan-5-one (1 ), aziridine 2 , and molecular iodine in [bmim]OH at room temperature for 5–6 hours.[
33
]
Scheme 2 Reaction of masked amino acid 1 and aziridines 2 in [bmim]OH
Table 1 Optimization of Reaction Conditions for the Formation of 3a
a
Entry
RTIL/solvent
I2 (mol%)
Time (h)b
Yield (%)c
1
[bmim]OH
–
48
–
2
[bmim]OH
10
5
94
3
[bmim]PF6
10
10
86
4
[bmim]Br
10
10
88
5
1,4-dioxane
10
17
74
6
MeCN
10
15
78
7
CH2 Cl2
10
18
75
8
DMF
10
16
41
9
DMSO
10
16
46
10
[bmim]OH
5
5
88
11
[bmim]OH
15
5
94
a Reaction conditions: 1 (2 mmol), 2a (2 mmol), I2 (0.2 mmol), [bmim]OH (5 mL).
b Stirring time at r.t.
c Yield of isolated and purified product 3a .
Isolation and purification by recrystallization afforded the target compound 3 in 85–96% yield with 96–98% diastereoselectivity (Table [2 ]) in favor of the cis isomer. Product 3 was extracted with EtOAc leaving the [bmim]OH behind, which can be recycled easily
for further use without loss of efficiency (Table [3 ]). The diastereomeric ratios in the crude isolates were checked by 1 H NMR spectroscopy to note any alteration of these ratios during subsequent purification.
The crude isolates of 3 were found to be a diastereomeric mixture containing 96–98% of the cis isomer.
Table 2 One-Pot Synthesis of 3-(N-Substituted)aminopyrrolidin-2-ones 3
Entry
Aziridine
2
Ar
Time
(h)a,b
Product
3
Yield
(%)c,d
cis /
trans
e
1
2a
Ph
5
3a
94
96:4
2
2b
4-MeOC6 H4
5
3b
89
96:4
3
2c
4-O2 NC6 H4
5
3c
96
98:2
4
2d
4-BrC6 H4
5
3d
93
96:4
5
2e
4-ClC6 H4
5
3e
92
98:2
6
2f
3-ClC6 H4
5
3f
95
98:2
7
2g
4-MeC6 H4
6
3g
88
97:3
8
2h
4-AcC6 H4
6
3h
91
97:3
9
2i
4-FC6 H4
5
3i
85
96:4
10
2j
3-MeC6 H4
6
3j
91
97:3
11
2k
3-BrC6 H4
5
3k
94
98:2
12
2l
1-naphthyl
5
3l
89
98:2
a Reaction conditions: 1 (2 mmol), 2a (2 mmol), I2 (0.2 mmol), [bmim]OH (5 mL).
b Stirring time at r.t.
c Yield of isolated and purified product.
d All compounds gave C, H, and N analyses ± 0.39% and satisfactory spectral (IR, 1 H NMR, 13 C NMR] and MS (EI) data.
e As determined by 1 H NMR spectroscopy of the crude products.
On the basis of 1 H NMR spectroscopy and the literature precedent,[
34
] the cis stereochemistry was conclusively assigned to 3 , as their coupling constants (J
5H,4Ha = 7.0–7.6 Hz, J
5H,4Hb = 6.3–6.7 Hz) was lower than that for the minor trans isomer (J
5H,4Ha = 10.5–10.8 Hz, J
5H,4Hb = 11.5–11.9 Hz). Furthermore, the assigned cis stereochemistry of lactams 3 was also established by NOE observations (Figure [2 ]). For example, 7.8% NOE was observed by between 5-H and 4-Ha ; 8.1% between 3-H and 4-Ha of product 3a . This indicates that 3-H, 4-Ha , and 5-H are located on the same face of the molecule, that is, cis to one another.
The formation of 3-(N-substituted)aminopyrrolidin-2-ones 3 can be rationalized by nucleophilic attack of the methylene carbon (C-4) of the masked
amino acid 1 to the less substituted carbon of tosyl aziridine 2 regioselectively, followed by protonation of aziridine nitrogen leading to the intermediate
4 (Scheme [3 ]). The adduct 4 undergoes intramolecular nucleophilic attack of the nitrogen atom of the NHTs group
at the carbonyl carbon (C-5) of the 1,3-oxazolan-5-one moiety to yield the target
compounds 3 (Scheme [3 ]). This conclusion is based on the observation that the representative intermediate
compounds 4a (Ar = Ph), 4e (Ar = 4-ClC6 H4 ), and 4i (Ar = 4-FC6 H4 ) could be isolated in 41–49% yield, these could be converted into the corresponding
lactams 3a , 3e , and 3i in quantitative yields.[
35
]
Presumably, in the ring-transformation step, iodine plays a key role in the reaction
by polarizing the carbonyl group of the substrate 1 , thereby enhancing the electrophilicity of the carbonyl carbon, which facilitates
the nucleophilic attack of the NHTs of aziridine 2 . Usually, the electronic factor favors the aziridine ring opening by a nucleophilic
attack at the benzylic carbon. However, when the steric factor predominates over the
electronic factor, the nucleophile prefers to attack at the terminal carbon rather
than the benzylic carbon.[
36
] Here, presumably due to bulky nature of the attacking nucleophile, the steric factor
predominates over the electronic effect to afford products 3 .
Scheme 3 Plausible mechanism for the formation of 3-(N-substituted)aminopyrrolidin-2-ones 3
Table 3 Recyclability of [bmim]OH in the Synthesis of 3a
Run
1
2
3
4
5
Yield (%)
96
96
95
95
92
Figure 2 NOE observations of pyrrolidin-2-ones 3
In conclusion, we have documented an original and practical regio- and diastereoselective
route to synthetically and pharmaceutically important 3-(N-substituted)aminopyrrolidin-2-ones
via nucleophilic aziridine ring opening with a novel substrate viz. 2-phenyl-1,3-oxazolan-5-one.
The efficacy of the reaction lies in its high yield, no byproduct formation, ambient
temperature, and recyclability of the ionoc liquid [bmim]OH. Thus, this simple methodology
would be a practical alternative to the existing procedures for the production of
this kind of fine chemicals to cater to the need of academia as well as of industry.
