Stereoselective Syntheses of Highly Functionalized Imidazolidines and Oxazolidines via Ring-Opening Cyclization of Activated Aziridines and Epoxides with Amines and Aldehydes

Article abstract of DOI:10.1021/acs.joc.9b02278

A mild one-pot stereospecific synthetic route to highly functionalized imidazolidines and oxazolidines via S_N2-type ring-opening of the corresponding activated aziridines and epoxides with amines followed by p-toluenesulfonic acid (PTSA)-catalyzed intramolecular cyclization with aldehydes has been developed. The methodology tolerates a variety of functional groups and furnishes the desired products in high yields (up to 92%) with excellent stereoselectivities (de, ee > 99%). Interestingly, imidazolidines were formed as the cis-isomers, whereas oxazolidines were produced as trans-isomers exclusively.

Full text of DOI:10.1021/acs.joc.9b02278

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Article
Stereoselective Syntheses of Highly Functionalized Imidazolidines
and Oxazolidines via Ring-Opening-Cyclization of Activated
Aziridines and Epoxides with Amines and Aldehydes
Saima Tarannum, Sahid Sk, Subhomoy Das, Imtiyaz Ahmad Wani, and Manas K. Ghorai
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02278 • Publication Date (Web): 29 Nov 2019
Downloaded from pubs.acs.org on November 29, 2019
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Stereoselective Syntheses of Highly Functionalized Imidazolidines
and Oxazolidines via Ring-Opening-Cyclization of Activated
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Aziridines and Epoxides with Amines and Aldehydes
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Saima Tarannum, Sahid Sk, Subhomoy Das, Imtiyaz Ahmad Wani and Manas K. Ghorai*
Department of Chemistry, Indian Institute of Technology, 208016 Kanpur, Uttar Pradesh, India
Abstract
A mild one-pot stereospecific synthetic route to highly functionalized imidazolidines and
oxazolidines via SN2‐type ring‐opening of the corresponding activated aziridines and epoxides
with amines followed by PTSA catalyzed intramolecular cyclization with aldehydes has been
developed. The methodology tolerates a variety of functional groups and furnishes the desired
products in high yields (up to 92%) with excellent stereoselectivities (de, ee >99%).
Interestingly, imidazolidines were formed as the cis-isomers whereas oxazolidines were
produced as trans-isomers exclusively.
Introduction
Imidazolidine and Oxazolidine frameworks are widely found in a number of bioactive
compounds, natural products and pharmaceuticals (Figure 1).1,2 For example, chaetominine
inhibits the growth of K562 human leukemia and SW1116 colon cancer cells (IC50s = 20 and 28
nM, respectively).1b Alchorneine is known to work as a potential spasmolytic agent in dogs,1c
whereas, cyanogramide effectively reverses the adriamycin induced resistance of K562/A02 and
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Figure 1. Biologically Active Imidazolidine and Oxazolidine scaffolds
MCF-7/Adr cells.1e Quinocarcin exhibits potent cytotoxic activity against P388 leukemia in vivo
and good antimicrobial activity against both Gram-negative and Gram-positive bacteria,2a and
cyanocycline A shows broad spectrum antimicrobial and antitumor activity.2c These structural
motifs are used as versatile building blocks in bio-organic chemistry as well as, synthetic
reagents, namely, auxiliaries, catalysts etc.3,4 Moreover imidazolidines are easily transformed
into imidazoles which are core structures in many significant biomolecules.5
The general synthetic strategy for the preparation of imidazolidine and oxazolidine derivatives
involves condensation of aldehydes, ketones or oxo-compounds with 1,2-diamines and 1,2-
amino alcohols, respectively.6,4b Other synthetic methodologies for these two structural scaffolds
include (3+2) formal cycloaddition,7 1,3-dipolar azomethine ylide-imine (AYI) cycloaddition,8
tandem nucleophilic addition-cycloaddition,9 C(sp3)-H functionalization,10 aza-Wacker reaction
etc.11 Interestingly, in recent years, the cycloaddition reaction of activated aziridines with
different reacting partners, namely, cyclic N-sulfonyl imines,7a oxime ethers,7b glycine esters,7c
aldehydes7g,h and N-alkylanilines10a etc. has been studied for the production of imidazolidines
and oxazolidines. However, many of them apply environmentally hazardous metal salts to
catalyze the process along with costly ligands. Considering the unique structural features and
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biological activities of these two moieties, despite the advancement in the above mentioned
areas,7-11 a metal-free cost-effective synthetic strategy leading to the formation of highly
functionalized diastereo- and enantiopure imidazolidines and oxazolidines from easily accessible
starting materials is still highly desirable. Aziridines12 and epoxides13 are valuable building
blocks in organic synthesis and nucleophilic ring-opening products obtained from these two
small rings are often employed as important intermediates for the synthesis of bioactive nitrogen-
and oxygen-containing heterocycles. Earlier, we reported the synthesis of imidazolines via
Cu(OTf)2-mediated [3+2] cycloaddition reaction of activated aziridines with nitriles.14 However,
the non-racemic imidazolines were obtained with reduced enantioselectivity. In continuation of
our investigation on SN2-type ring-opening transformations of aziridines and epoxides with
amine nucleophiles,15 we have developed a simple strategy for the syntheses of diastereo- and
enantiopure highly substituted imidazolidines and oxazolidines via stereoselective SN2-type ring-
opening of aziridines and epoxides, respectively, with various amine nucleophiles followed by
condensation with aldehydes under one-pot conditions. Herein, we wish to report our results in
detail.
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Results and Discussion
Our study began with the reaction of activated aziridine (1a, 1.1 equiv) with aniline (2a, 1.0
equiv) under neat and catalyst free condition. The reaction went efficiently via SN2-type
regioselective ring opening of 1a by amine producing the ring-opening product 3a in 92% yield
in 2 h.15b 3a was then reacted with benzaldehyde (4a, 1.0 equiv) in the presence of 50 mol % of
BF3.OEt2 catalyst in refluxing THF for 6 h to provide the desired imidazolidine derivative (5a) as
a single diastereomer in 42% yield (Scheme 1). Spectroscopic data confirmed the structure of 3a
and 5a which was further supported by single crystal X-ray analysis.16 The diastereoselective
formation of 5a raised our interest to increase the efficiency of our two-step protocol in terms of
yield and pot-economy. We screened different Lewis acids, additives, and solvents to increase
the yield of the cyclization step in a one-pot protocol. When the ring-opening product was
reacted with 4a in the presence of BF3·OEt2 (100 mol %) in refluxing THF in a one-pot fashion,
the imidazolidine derivative 5a was obtained in 48% yield (entry 2, Table 1). Addition of 1.0
equiv of MgSO4 keeping the conditions intact did not increase the yield much (entry 3).
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Scheme 1. Ring-Opening-Cyclization of 2-Phenyl-N-tosylaziridine (1a) with Aniline (2a)
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and benzaldehyde (4a)
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When Cu(OTf)2 was used as the Lewis acid in the cyclization step, the yield of 5a eroded further
(entry 4). However, use of Lewis acids namely, FeCl3 and Sc(OTf)3, in refluxing THF, improved
the yield to some extent (entry 5,6). Since the yield of 5a was found to increase slightly using
Lewis acid catalysts, couple of Brønsted acids namely, benzoic acid and PTSA, were examined
in THF and DCE, respectively (entry 7–9). Improved yield was observed when PTSA (50 mol
%) was used as the acid catalyst in DCE solvent (entry 9). Using PTSA (50 mol %) and MgSO4
as the additive, 5a was obtained with the maximum yield (entry 10).12h The best result was
obtained using 20 mol % of PTSA and 100 mol % of MgSO4 in DCE at 65 °C to afford 5a in
overall 84% yield (entry 11). All the results are described in Table 1.
Table 1. Optimization Studies for One-Pot Synthesis of Imidazolidine (5a)a
entry
reaction conditionsb
5a
(%)c
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BF3·OEt2 (50 mol %), THF, reflux, 10 h
BF3·OEt2 (100 mol %), THF, reflux, 10 h
BF3·OEt2 (100 mol %), MgSO4 (100 mol %), THF, reflux, 8 h
Cu(OTf)2 (50 mol %), THF, reflux, 10 h
FeCl3 (50 mol %), THF, reflux, 8 h
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Sc(OTf)3 (50 mol %), THF, reflux, 8 h
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PhCO2H (100 mol %), THF, reflux, 6 h
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PTSA (50 mol %), THF, reflux, 6 h
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PTSA (50 mol %), DCE, 65 °C, 6 h
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PTSA (50 mol %), MgSO4 (100 mol %), DCE, 65 °C, 6 h
PTSA (20 mol %), MgSO4 (100 mol %), DCE, 65 °C, 6 h
PTSA (20 mol %), MgSO4 (100 mol %), toluene, 65 °C, 8 h
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aUnless otherwise mentioned, 0.55 mmol of 1a, 0.50 mmol of 2a, 0.50 mmol of
b
4a were reacted. Reaction conditions were screened for the cyclization step
only. cYield of the isolated product.
The generalization of the strategy was made by the reaction of a variety of aldehydes 4a–h with
the ring-opening product 3a under optimized conditions (Table 2). Aldehydes with electron
donating group (−CH3) and withdrawing groups (−Cl and –NO2) did not affect the reaction
producing imidazolidines 5b−d in 78−88% yields as single diastereomers (entries 2−4). To
evaluate the steric effect on the course of cyclization of the ring-opening product with aldehydes,
we carried out the one-pot cyclization with m-bromobenzaldehyde (4e) and o-tolualdehyde (4f).
The corresponding imidazolidine derivatives 5e,f were isolated from the reaction mixture in high
yields as single diastereomers (entries 5,6). When 3a was reacted with 2-naphthaldehyde (4g) in
one pot fashion, the corresponding product 5g was obtained in 85% yield with excellent de (entry
7). Next, we explored hetaryl aldehydes under the optimized conditions. When 1a was treated
with 2a in neat condition followed by addition of hetaryl aldehydes (4h,i) in presence of catalytic
amount of PTSA and equimolar amount of MgSO4 in DCE at 65 °C, the corresponding
imidazolidine derivatives (5h,i) were obtained in high yields with excellent diastereoselectivities
(entries 8,9). To evaluate the prospect of an alkyl aldehyde under similar reaction conditions,
next, the ring-opening cyclization reaction was performed with propanal (4j), and to our great
pleasure, the desired product 5j was obtained in 80% yield as a single diastereomer (entry 10).
All the results are summarized in Table 2.
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Table 2. One-Pot Stepwise Synthesis of Imidazolidines (5a–j)a
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entry
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aldehyde (4)
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yield (%)b
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aUnless otherwise noted, 0.55 mmol of 1a, 0.50 mmol of 2a, 0.50 mmol of 4a–j, 0.10 mmol
of PTSA and 0.50 mmol of MgSO4 were reacted. bYields of isolated products.
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mixture.
The strategy was further explored with several racemic 2-aryl-N-tosylaziridines 1b–e under
optimized reaction conditions (Table 3). The ring-opening reaction of aziridine (1b) possessing
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electron-donating aryl group with aniline (2a) followed by cyclization with 4-nitrobenzaldehyde
(4d) yielded imidazolidine derivative 5k in 85% yield as a single diastereomer (entry 1).
Similarly, 2-aryl-N-tosylaziridines with electron withdrawing halide groups in the phenyl ring
(1c–e) underwent smooth transformation with 2a and 4d to yield imidazolidines 5l–n in high
yields with excellent diastereoselectivities (entries 2–4). All the results are described in Table 3.
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Table 3. One-Pot Synthesis of Imidazolidines (5k–n) from Activated Aziridinesa
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aziridine (1)
imidazolidine (5)
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aUnless otherwise noted, 0.55 mmol of 1b–e, 0.50 mmol of 2a, 0.50 mmol of 4d, 0.10 mmol
of PTSA and 0.50 mmol of MgSO4 were reacted. bYields of isolated products.
cDiastereomeric ratios have been determined by H NMR analysis of the crude reaction
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mixture.
To generalize the methodology further, the ring-opening of aziridine 1a was carried out with
different aryl amines (2b–e) possessing both electron rich and deficient aryl groups (Table 4).
The ring-opening of 1a went efficiently with aryl amines, 2b,c, followed by condensation with
aldehyde 4d to yield imidazolidines, 5o and 5p, respectively, in high yields with excellent
diastereoselectivities (entries 1,2). Even with electron withdrawing aryl amines (2d,e), the ring-
opening of 1a followed by cyclization with 4d underwent successfully to yield imidazolidines,
5q and 5r, respectively, in good yields as single diastereomers (entries 3,4). Unfortunately, the
ring-opening products of aziridine 1a with ortho- and meta-substituted anilines did not yield
imidazolidine derivatives when cyclization was carried out in the presence of aldehydes. Next,
the formation of imidazolidine was explored with alkyl amine, namely, isopropyl amine (2f), and
as expected, 5s was isolated from the reaction mixture in high yield with excellent
diastereoselectivity (entry 5). All the results are described in Table 4.
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Table 4. One-Pot Synthesis of Imidazolidines (5o–s) from Amines (2b–f)a
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entry
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amine (2)
imidazolidine (5)
yield (%)b
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of PTSA and 0.50 mmol of MgSO4 were reacted. bYields of isolated products.
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mixture.
Next, we studied the electronic effect of different arylsulfonyl groups (Table 5). Initially 1f was
treated with 2a for 2 h followed by 4d under optimized conditions. The reaction went smoothly
and the imidazolidine derivative 5t was formed in 87% yield as a single diastereomer (entry 1).
Then, electron-donating (1g) and electron withdrawing (1h) groups were also examined as N-
arylsulfonyl groups and in all the cases the formation of imidazolidine derivatives (5u,v) were
observed in high yields with excellent diastereoselectivities (de >99%) (entries 2,3). All results
are shown in Table 5.
Table 5. One-Pot Synthesis of Imidazolidines (5t–v) from 2-phenyl-N-sulfonylaziridines
(1f–h)a
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entry 2-phenyl-N-PG-aziridine (1)
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1f: PG = phenylsulfonyl
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1g: PG = (4-(tert-butyl)phenyl)sulfonyl
1h: PG = (4-fluorophenyl)sulfonyl
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aUnless otherwise noted, 0.55 mmol of 1f–h, 0.50 mmol of 2a, 0.50 mmol of 4d, 0.10 mmol
of PTSA and 0.50 mmol of MgSO4 were reacted. bYields of isolated products.
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cDiastereomeric ratios have been determined by H NMR analysis of the crude reaction
mixture.
To assess the efficiency of our developed protocol for one-pot ring-opening of aziridines with
amines followed by cyclization with aldehydes, a gram-scale reaction was performed with
aziridine 1a, aniline (2a) and aldehyde 4d under optimized reaction conditions. The effectiveness
of the small-scale reaction was found to be similar upon scale-up producing 5d in 82% yield
(Scheme 2).
Scheme 2. Gram-scale Synthesis of Imidazolidine (5d)
To expand the scope of the methodology, next, we explored 2-phenyloxirane (6a) for the ring-
opening-cyclization reaction under optimized conditions (Table 6). When the ring-opening
product obtained from the reaction between 6a and 2a was condensed with 4a in one-pot
conditions, the oxazolidine derivative 7a was produced efficiently in 88% yield as a single
diastereomer (entry 1). The successful formation of oxazolidine derivatives 7b,c were also
observed from electron withdrawing aromatic aldehydes, namely, 4-nitrobenzaldehyde (4d) and
2-chlorobenzadehyde (4k), respectively, in high yields with excellent stereoselectivities (entries
2,3). When, the ring-opening product was treated with disubstituted aldehyde, 2-bromo-5-
methoxybenzaldehyde (4l), to our pleasure, the corresponding oxazolidine derivative 7d was
obtained with excellent yield and diastereoselectivity (entry 4). The relative 2,4-trans
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stereochemistry of 7 was determined by NOESY experiment of 7a.16 All the results are detailed
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in Table 6.
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Table 6. One-Pot Synthesis of Oxazolidines (7a–d) from 2-phenyl oxirane (6a), Aniline (2a)
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and Aldehydes (4)a
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entry
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aldehyde (4)
oxazolidine (7)
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aUnless otherwise noted, 0.55 mmol of 6a, 0.50 mmol of 2a, 0.50 mmol of 4, 0.10 mmol of
PTSA and 0.50 mmol of MgSO4 were reacted. bYields of isolated products. cDiastereomeric
ratios have been determined by 1H NMR analysis of the crude reaction mixture.
The synthetic potential of the methodology was further demonstrated by the formation of non-
racemic imidazolidine derivatives starting from enantiopure activated N-tosylaziridine (S)-1a,
aryl amines 2 and aryl aldehydes 4 (Table 7). When (S)-1a was reacted with 2a,d the ring-
opening products upon treatment with benzaldehyde (4a) and p-nitrobenzaldehyde (4d) produced
imidazolidine derivatives (S)-5a,d and (S)-5q, respectively, in high yields with excellent
diastereo- and enantioselectivities (entries 1–3). The absolute configuration of 5 was determined
as (2S,4S) based on the crystal structure of 5a.16 All results are shown in Table 7.
Table 7. One-Pot Asymmetric Synthesis of Imidazolidines (2S,4S)-5 from 2-phenyl-N-
tosylaziridines (S)-1a, Aryl Amines (2) and Aryl Aldehydes (4)a
entry aziridine aryl amine aldehyde
(S)-1a (2) (4)
imidazolidine (5)
yield
(%)b
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aUnless otherwise noted, 0.55 mmol of (S)-1a, 0.50 mmol of 2, 0.50 mmol of 4, 0.10 mmol of
b
c
PTSA and 0.50 mmol of MgSO4 were reacted. Yields of isolated products. Diastereomeric
ratios have been determined by 1H NMR analysis of the crude reaction mixture.
Mechanism
A plausible mechanism for the formation of imidazolidines and oxazolidines is depicted in
Scheme 3. Based on our observations, we believe that the ring opening reactions of activated
aziridines and epoxides proceed via a regioselective SN2-type pathway as described by us
earlier.15b Amine nucleophile 2a attacks the aziridine 1a at the benzylic position to produce the
corresponding ring opening product 3a, which in the presence of acid-catalyst PTSA and
additive MgSO4, forms the corresponding iminium ion 8a when reacted with 4a. Subsequently,
intramolecular nucleophilic attack by the tosyl amide on iminium ion probably through the
cationic intermediate 8a' occurs in such a way that it leads to the more favorable TS 8c where the
electronic 1,4-π-π stacking interaction outweighs the steric repulsion arising out of the
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Scheme 3. Plausible Mechanism
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interaction between the ortho-hydrogens of aromatic ring at C-2 and methylene hydrogen at C-5
of the ring to produce the 2,4-cis diastereomer 5a of imidazolidine derivatives as the only
product. The formation of the other isomer 5a' was not observed from the less stable TS 8b
probably due to strong steric hinderance between three syn-aromatic rings. On the contrary, in
the case of epoxide 6a, the intramolecular attack of the hydroxyl group on the cationic
intermediate 10a' leads to the stable species 10b where aromatic rings at the 2,4-position of
oxazolidine rings are anti to each other producing the major 2,4-trans diastereomer 7a.16 The
formation of 2,4-cis diastereomer 7a' through the TS 10c was not observed probably due to a
destabilizing steric repulsion between ortho-hydrogens of C-2 aromatic ring and one of the C-5
methylene hydrogens in oxazolidine rings.
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Conclusion
In summary, we have described an efficient and straightforward protocol for the synthesis of
imidazolidines and oxazolidines starting from cheap and readily available starting materials via
regioselective ring‐opening of activated aziridines and epoxides with different amine
nucleophiles and a subsequent condensation with aldehydes under one-pot reaction condition.
The prominent features of this environmentally benign methodology are mild reaction
conditions, devoid of any metal-based Lewis acid, operational simplicity, wide substrate scope,
high yields of the products, and excellent stereoselectivities (de, ee >99%). We believe that the
described strategy would be very useful in organic synthesis.
Experimental Section
General Procedures. The analytical thin layer chromatography (TLC) was carried out for
monitoring the progress of the reactions using silica gel 60 F254 precoated plates. Visualizations
of the spots were accomplished with a UV lamp or I2 stain. Active Aluminium oxide was used
for flash column chromatographic purification using a combination of distilled ethyl acetate and
petroleum ether as the eluent. Unless otherwise mentioned, all the reactions were carried out in
oven-dried glassware under an atmosphere of nitrogen or argon using anhydrous solvents. Where
appropriate, the solvents and all of the reagents were purified prior to use following the
guidelines of Armarego and Chai.17 The monosubstituted N-tosylaziridines (1a–e)18 and N-
arylsulfonylaziridines (1f–h)19 were prepared by following earlier reports. All the commercial
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reagents were used as received without further purification unless otherwise mentioned. Proton
nuclear magnetic resonance (1H NMR) spectra were recorded at 400 MHz and 500 MHz. The
chemical shifts were recorded in parts per million (ppm, δ) using tetramethylsilane (δ 0.00) as
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the internal standard. Splitting patterns of the H NMR are mentioned as singlet (s), doublet (d),
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doublet of doublets (dd), triplet (t), multiplet (m) etc. Proton-decoupled carbon nuclear magnetic
resonance (13C{1H} NMR) spectra were recorded at 100 MHz and 125 MHz. HRMS were
obtained using (ESI) mass spectrometer (TOF). KBr pellets were used for IR spectra of solid
compounds. The melting point measurements were made using a hot stage apparatus and are
reported as uncorrected. The enantiomeric excess (ee) was determined by chiral HPLC with
Chiralpak AD-H and Lux 5u Cellulose-2 (detection at 254 nm) using hexane and isopropanol as
the mobile phase and a UV/VIS detector. Optical rotations were measured using a 6.0 mL cell
with a 1.0 dm path length and are reported as [α]25D (c in g per 100 mL solvent) at 25 °C.
General procedure for ring-opening of aziridines/oxiranes with amines followed by
cyclization with aldehydes. A clean and dried double neck round-bottom flask under argon
charged with aziridine/oxirane (0.55 mmol, 1.1 equiv) and (aromatic/alkyl) amine (0.50 mmol,
1.0 equiv) was allowed to stir at rt for 2 h. The formation of ring opening product was monitored
by TLC. After complete consumption of amine, aldehyde (0.50 mmol, 1.0 equiv) dissolved in
(2.0 mL) of DCE, PTSA (0.10 mmol, 0.2 equiv), MgSO4 (0.50 mmol, 1.0 equiv) were added to
this reaction mixture containing ring opening product and then again stirred at 65 °C in the oil
bath for appropriate time. The formation of cyclized product and the progress of reaction was
monitored by TLC. After completion, the aqueous layer was extracted with diethyl ether (3 ×
10.0 mL), dried over anhydrous Na2SO4 followed by concentration under reduced pressure. The
crude concentrate was purified by flash column chromatography on silica gel (230−400 mesh)
using diethyl ether in petroleum ether as the eluent to afford the corresponding pure
imidazolidine/oxazolidine product.
(2S,4S)-2,3,4-triphenyl-1-tosylimidazolidine (5a). The general method described above was
followed when aziridine (S)-1a (150.3 mg, 0.55 mmol) was reacted with aniline 2a (45 µL, 0.50
mmol) at room temperature for 2 h followed by addition of benzaldehyde 4a (51 µL, 0.50 mmol)
along with PTSA (17.2 mg, 0.10 mmol) and MgSO4 (60.2 mg, 0.50 mmol) in DCE at 65 °C for 6
h to afford (2S,4S)-5a (190.9 mg, 0.42 mmol) as a white solid in 84% yield. Rf 0.55 (20%
diethyl ether in petroleum ether); MP 177–179 °C; [α]25D +56.0 (c 0.2 in CH2Cl2) for a >99% ee
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sample. Optical purity was determined by chiral HPLC analysis (Lux 5u Cellulose-2 column),
hexane–isopropanol, 95:5; flow rate = 1.0 mL/min; tR 1: 27.4 min (minor), tR 2: 13.9 min
(major); IR ṽmax (KBr, cm-1) 3060, 3028, 2943, 2873, 1597, 1500, 1449, 1349, 1334, 1306, 1232,
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1212, 1165, 1119, 1088, 1060, 1029, 992, 960, 929, 860, 816, 749, 696, 671; H NMR (CDCl3,
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500 MHz) δ 2.29 (s, 3H), 3.23 (dd, 1H, J = 13.4, 10.5 Hz), 3.90 (dd, 1H, J = 10.4, 7.2 Hz), 4.29
(dd, 1H, J = 13.4, 7.1 Hz), 6.25 (d, 2H, J = 8.0 Hz), 6.38 (s, 1H), 6.75 (t, 1H, J = 7.3 Hz), 6.98
(d, 2H, J = 8.0 Hz), 7.05 (dd, 2H, J = 8.8, 7.3 Hz), 7.20–7.27 (m, 5H), 7.36–7.39 (m, 1H), 7.41–
13
7.44 (m, 2H), 7.60 (d, 2H, J = 8.3 Hz), 7.74 (d, 2H, J = 7.7 Hz); C{1H} NMR (CDCl3, 125
MHz) δ 21.4, 54.1, 63.1, 80.3, 113.2, 118.7, 126.2, 127.2, 127.5, 127.8, 128.5, 128.6, 128.7,
128.9, 129.8, 134.8, 139.3, 139.7, 144.4, 147.2; HRMS (ESI-TOF) calcd for C28H27N2O2S
(M+H)+ 455.1793, found 455.1798.
3,4-diphenyl-2-(p-tolyl)-1-tosylimidazolidine (5b). The general method described above was
followed when aziridine 1a (150.3 mg, 0.55 mmol) was reacted with aniline 2a (45 µL, 0.50
mmol) at room temperature for 2 h followed by addition of 4-methylbenzaldehyde 4b (59 µL,
0.50 mmol) along with PTSA (17.2 mg, 0.10 mmol) and MgSO4 (60.2 mg, 0.50 mmol) in DCE
at 65 °C for 6 h to afford 5b (201.5 mg, 0.43 mmol) as a white solid in 86% yield. Rf 0.66 (20%
diethyl ether in petroleum ether); MP 189–191 °C; IR ṽmax (KBr, cm-1) 3028, 2938, 2886, 1598,
1500, 1450, 1403, 1348, 1306, 1234, 1165, 1120, 1088, 1063, 1013, 960, 891, 869, 817, 750,
671; 1H NMR (CDCl3, 500 MHz) δ 2.28 (s, 3H), 2.38 (s, 3H), 3.23 (dd, 1H, J = 13.4, 10.6 Hz),
3.88 (dd, 1H, J = 10.4, 7.1 Hz), 4.26 (dd, 1H, J = 13.4, 7.0 Hz), 6.23 (d, 2H, J = 8.0 Hz), 6.34 (s,
1H), 6.74 (t, 1H, J = 7.3 Hz), 6.97 (d, 2H, J = 8.0 Hz), 7.03 (t, 2H, J = 7.3 Hz), 7.18–7.26 (m,
13
7H), 7.60 (t, 4H, J = 8.3 Hz); C{1H} NMR (CDCl3, 125 MHz) δ 21.1, 21.4, 54.1, 63.0, 80.3,
113.2, 118.6, 126.3, 127.1, 127.4, 127.7, 128.7, 128.8, 129.3, 129.7, 134.9, 136.7, 138.3, 139.3,
144.3, 147.2; HRMS (ESI-TOF) calcd for C29H29N2O2S (M+H)+ 469.1950, found 469.1958.
(4-chlorophenyl)-3,4-diphenyl-1-tosylimidazolidine (5c). The general method described above
was followed when aziridine 1a (150.3 mg, 0.55 mmol) was reacted with aniline 2a (45 µL, 0.50
mmol) at room temperature for 2 h followed by addition of 4-chlorobenzaldehyde 4c (70.2 mg,
0.50 mmol) along with PTSA (17.2 mg, 0.10 mmol) and MgSO4 (60.2 mg, 0.50 mmol) in DCE
at 65 °C for 6 h to afford 5c (190.7 mg, 0.39 mmol) as a white solid in 78% yield. Rf 0.65 (20%
diethyl ether in petroleum ether); MP 134–136 °C; IR ṽmax (KBr, cm-1) 2924, 1597, 1500, 1451,
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1350, 1165, 1089, 1009, 960, 806, 750, 720, 694, 669; 1H NMR (CDCl3, 500 MHz) δ 2.29 (s,
3H), 3.20 (dd, 1H, J = 13.5, 10.5 Hz), 3.88 (dd, 1H, J = 10.4, 7.1 Hz), 4.28 (dd, 1H, J = 13.3, 7.4
Hz), 6.23 (d, 2H, J = 8.1 Hz), 6.32 (s, 1H), 6.76 (t, 1H, J = 7.3 Hz), 6.99 (d, 2H, J = 8.0 Hz),
7.05 (dd, 2H, J = 8.8, 7.5 Hz), 7.16–7.18 (m, 2H), 7.20–7.25 (m, 2H), 7.26–7.28 (m, 1H), 7.40
13
(d, 2H, J = 8.6 Hz), 7.59 (d, 2H, J = 8.3 Hz), 7.67 (d, 2H, J = 8.2 Hz); C{1H} NMR (CDCl3,
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125 MHz) δ 21.5, 54.1, 63.2, 79.9, 113.2, 119.0, 126.2, 127.5, 127.9, 128.7, 128.8, 129.0, 129.8,
134.5, 134.6, 138.3, 139.1, 144.5, 147.0; HRMS (ESI-TOF) calcd for C28H26ClN2O2S (M+H)+
489.1404, found 489.1409.
(2S,4S)-2-(4-nitrophenyl)-3,4-diphenyl-1-tosylimidazolidine (5d). The general method
described above was followed when aziridine (S)-1a (150.3 mg, 0.55 mmol) was reacted with
aniline 2a (45 µL, 0.50 mmol) at room temperature for 2 h followed by addition of 4-
nitrobenzaldehyde 4d (75.5 mg, 0.50 mmol) along with PTSA (17.2 mg, 0.10 mmol) and MgSO4
(60.2 mg, 0.50 mmol) in DCE at 65 °C for 6 h to afford (2S,4S)-5d (219.8 mg, 0.44 mmol) as a
white solid in 88% yield. Gram-scale synthesis of 5d was achieved when aziridine 1a (1.2 g, 4.4
mmol) was reacted with aniline 2a (0.36 mL, 4.0 mmol) at room temperature for 2 h followed by
addition of 4-nitrobenzaldehyde 4d (0.6 g, 4.0 mmol) along with PTSA (0.138 g, 0.80 mmol)
and MgSO4 (0.48 g, 4.0 mmol) in DCE at 65 °C for 6 h to afford 5d (1.64 g, 3.28 mmol) as a
white solid in 82% yield. Rf 0.60 (20% diethyl ether in petroleum ether); MP 174–176 °C; [α]25
D
+48.0 (c 0.35 in CH2Cl2) for a >99% ee sample. Optical purity was determined by chiral HPLC
analysis (Lux 5u Cellulose-2 column), hexane–isopropanol, 95:5; flow rate = 1.0 mL/min; tR 1:
78.5 min (minor), tR 2: 88.0 min (major); IR ṽmax (KBr, cm-1) 3462, 3030, 2923, 2853, 1738,
1642, 1598, 1521, 1502, 1455, 1408, 1348, 1263, 1236, 1165, 1108, 1089, 1046, 1010, 898, 861,
816, 750, 676; 1H NMR (CDCl3, 400 MHz) δ 2.30 (s, 3H), 3.17 (dd, 1H, J = 13.4, 10.4 Hz), 3.90
(dd, 1H, J = 10.4, 7.3 Hz), 4.30–4.35 (m, 1H), 6.23 (d, 2H, J = 8.0 Hz), 6.40 (s, 1H), 6.81 (t, 1H,
J = 7.3 Hz), 7.01 (d, 2H, J = 8.0 Hz), 7.08 (dd, 2H, J = 8.6, 7.3 Hz), 7.15–7.17 (m, 2H), 7.22–
7.30 (m, 3H), 7.62 (d, 2H, J = 8.6 Hz), 7.94 (d, 2H, J = 8.5 Hz), 8.29 (d, 2H, J = 8.6 Hz);
13C{1H} NMR (CDCl3, 125 MHz) δ 21.5, 54.2, 63.3, 79.8, 113.2, 119.4, 123.9, 126.0, 127.4,
128.1, 128.3, 128.9, 129.1, 129.9, 134.3, 138.7, 144.8, 146.8, 147.0, 148.2; HRMS (ESI-TOF)
calcd for C28H26N3O4S (M+H)+ 500.1644, found 500.1641.
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2-(3-bromophenyl)-3,4-diphenyl-1-tosylimidazolidine (5e). The general method described above
was followed when aziridine 1a (150.3 mg, 0.55 mmol) was reacted with aniline 2a (45 µL, 0.50
mmol) at room temperature for 2 h followed by addition of 3-bromobenzaldehyde 4e (58 µL,
0.50 mmol) along with PTSA (17.2 mg, 0.10 mmol) and MgSO4 (60.2 mg, 0.50 mmol) in DCE
at 65 °C for 6 h to afford 5e (202.2 mg, 0.38 mmol) as a white solid in 76% yield. Rf 0.64 (20%
diethyl ether in petroleum ether); MP 160–162 °C; IR ṽmax (KBr, cm-1) 3030, 2923, 2853, 1599,
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1504, 1455, 1351, 1305, 1263, 1161, 1093, 1071, 1029, 894, 848, 813, 749, 666; H NMR
(CDCl3, 400 MHz) δ 2.37 (s, 3H), 3.84 (dd, 1H, J = 11.0, 2.4 Hz), 4.12 (dd, 1H, J = 11.0, 7.9
Hz), 5.21 (dd, 1H, J = 7.9, 2.4 Hz), 6.35 (d, 2H, J = 7.9 Hz), 6.48 (s, 1H), 6.61 (t, 1H, J = 7.3
Hz), 6.93-7.00 (m, 4H), 7.06-7.17 (m, 6H), 7.25–7.28 (m, 1H), 7.36 (d, 1H, J = 7.9 Hz), 7.39-
13
7.41 (m, 3H); C{1H} NMR (CDCl3, 100 MHz) δ 21.6, 53.7, 61.5, 115.3, 118.3, 122.9, 126.0,
126.2, 127.1, 127.3, 128.8, 129.0, 129.7, 130.2, 130.4, 131.7, 135.9, 140.3, 141.2, 142.4, 143.6;
HRMS (ESI-TOF) calcd for C28H26BrN2O2S (M+H)+ 533.0898, found 533.0891.
3,4-diphenyl-2-(o-tolyl)-1-tosylimidazolidine (5f). The general method described above was
followed when aziridine 1a (150.3 mg, 0.55 mmol) was reacted with aniline 2a (45 µL, 0.50
mmol) at room temperature for 2 h followed by addition of 2-methylbenzaldehyde 4f (58 µL,
0.50 mmol) along with PTSA (17.2 mg, 0.10 mmol) and MgSO4 (60.2 mg, 0.50 mmol) in DCE
at 65 °C for 6 h to afford 5f (163.9 mg, 0.35 mmol) as a white solid in 70% yield. Rf 0.72 (10%
diethyl ether in petroleum ether); MP 138–140 °C; IR ṽmax (KBr, cm-1) 2925, 2854, 1598, 1501,
1463, 1351, 1213, 1164, 1089, 1034, 956, 936, 887, 814, 749, 672; 1H NMR (CDCl3, 500 MHz)
δ 2.31 (s, 3H), 2.77 (s, 3H), 3.49 (dd, 1H, J = 12.6, 10.3 Hz), 4.18 (dd, 1H, J = 10.3, 6.9 Hz),
4.35 (dd, 1H, J = 12.6, 6.9 Hz), 6.21 (d, 2H, J = 8.0 Hz), 6.48 (s, 1H), 6.75 (t, 1H, J = 7.4 Hz),
7.01–7.08 (m, 5H), 7.21–7.26 (m, 6H), 7.29–7.33 (m, 2H), 7.52 (m, 2H); 13C{1H} NMR (CDCl3,
125 MHz) δ 21.4, 22.7, 53.4, 61.6, 78.7, 114.4, 119.2, 126.1, 126.3, 127.5, 127.6, 127.9, 128.6,
128.7, 128.9, 129.7, 131.2, 131.5, 131.7, 137.2, 138.0, 139.3, 147.9; HRMS (ESI-TOF) calcd for
C29H29N2O2S (M+H)+ 469.1950, found 469.1945.
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2-(naphthalen-2-yl)-3,4-diphenyl-1-tosylimidazolidine (5g). The general method described
above was followed when aziridine 1a (150.3 mg, 0.55 mmol) 5e was reacted with aniline 2a (45
µL, 0.50 mmol) at room temperature for 2 h followed by addition of 2-naphthaldehyde 4g (78.1
mg, 0.50 mmol) along with PTSA (17.2 mg, 0.10 mmol) and MgSO4 (60.2 mg, 0.50 mmol) in
DCE at 65 °C for 6 h to afford 5g (214.4 mg, 0.42 mmol) as a white solid in 85% yield. Rf 0.44
(20% diethyl ether in petroleum ether); MP 179–181 °C; IR ṽmax (KBr, cm-1) 2923, 2853, 1598,
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1500, 1454, 1349, 1213, 1163, 1089, 1019, 959, 813, 749, 694, 672; H NMR (CDCl3, 500
MHz) δ 2.29 (s, 3H), 3.28 (dd, 1H, J = 13.5, 10.5 Hz), 3.95 (dd, 1H, J = 10.4, 7.2 Hz), 4.32 (dd,
1H, J = 13.4, 7.1 Hz), 6.31 (d, 2H, J = 8.0 Hz), 6.53 (s, 1H), 6.77 (t, 1H, J = 7.3 Hz), 6.98 (d, 2H,
J = 8.0 Hz), 7.06 (dd, 2H, J = 8.6, 7.3 Hz), 7.20–7.26 (m, 5H), 7.50–7.52 (m, 2H), 7.62 (d, 2H, J
= 8.0 Hz), 7.84–7.93 (m, 4H), 8.16 (s, 1H); 13C{1H} NMR (CDCl3, 125 MHz) δ 21.8, 54.5, 63.5,
81.0, 113.7, 119.2, 125.4, 126.2, 126.67, 126.69, 126.8, 127.87, 127.91, 128.0, 128.2, 128.7,
129.0, 129.1, 129.3, 130.1, 133.5, 133.8, 139.6; HRMS (ESI-TOF) calcd for C32H29N2O2S
(M+H)+ 505.1950, found 505.1958.
2-(furan-2-yl)-3,4-diphenyl-1-tosylimidazolidine (5h). The general method described above was
followed when aziridine 1a (150.3 mg, 0.55 mmol) was reacted with aniline 2a (45 µL, 0.50
mmol) at room temperature for 2 h followed by addition of 2-furaldehyde 4h (41 µL, 0.50 mmol)
along with PTSA (17.2 mg, 0.10 mmol) and MgSO4 (60.2 mg, 0.50 mmol) in DCE at 65 °C for 6
h to afford 5h (166.7 mg, 0.37 mmol) as a white solid in 75% yield. Rf 0.76 (20% diethyl ether
in petroleum ether); MP 133–135 °C; IR ṽmax (KBr, cm-1) 2922, 2852, 1598, 1501, 1454, 1350,
1236, 1163, 1090, 1013, 956, 813, 747, 669; 1H NMR (CDCl3, 500 MHz) δ 2.31 (s, 3H), 3.48
(dd, 1H, J = 12.8, 10.0 Hz), 4.06 (dd, 1H, J = 9.7, 7.1 Hz), 4.31 (dd, 1H, J = 12.6, 7.2 Hz), 6.35-
6.38 (m, 4H), 6.58 (d, 1H, J = 6.3 Hz), 6.75 (t, 1H, J = 7.3 Hz), 7.03–7.08 (m, 4H), 7.22–7.24
13
(m, 4H), 7.28–7.29 (m, 1H), 7.42 (d, 1H, J = 1.0 Hz), 7.57 (d, 2H, J = 8.3 Hz); C{1H} NMR
(CDCl3, 125 MHz) δ 21.8, 54.7, 62.8, 75.0, 109.1, 110.8, 113.6, 119.2, 126.4, 127.8, 128.2,
129.1, 129.3, 130.1, 135.1, 139.7, 143.6, 144.6, 146.3, 152.7; HRMS (ESI-TOF) calcd for
C26H25N2O3S (M+H)+ 445.1586, found 445.1581.
3,4-diphenyl-2-(thiophen-2-yl)-1-tosylimidazolidine (5i). The general method described above
was followed when aziridine 1a (150.3 mg, 0.55 mmol) was reacted with aniline 2a (45 µL, 0.50
mmol) at room temperature for 2 h followed by addition of 2-thiophenecarboxaldehyde 4i (46
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µL, 0.50 mmol) along with PTSA (17.2 mg, 0.10 mmol) and MgSO4 (60.2 mg, 0.50 mmol) in
DCE at 65 °C for 6 h to afford 5i (165.8 mg, 0.36 mmol) as a white solid in 72% yield. Rf 0.72
(20% diethyl ether in petroleum ether); MP 162–164 °C; IR ṽmax (KBr, cm-1) 2918, 2850, 1598,
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8
9
1
1500, 1453, 1351, 1163, 1089, 957, 813, 751, 700, 670; H NMR (CDCl3, 400 MHz) δ 2.29 (s,
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3H), 3.36 (dd, 1H, J = 12.8, 10.4 Hz), 3.99 (dd, 1H, J = 10.3, 7.3 Hz), 4.26–4.31 (m, 1H), 6.34
(d, 2H, J = 7.9 Hz), 6.54 (s, 1H), 6.75 (t, 1H, J = 7.3 Hz), 7.00–7.07 (m, 5H), 7.21–7.32 (m, 7H),
7.57 (d, 2H, J = 7.9 Hz); 13C{1H} NMR (CDCl3, 125 MHz) δ 21.5, 53.9, 63.2, 77.6, 113.6,
119.1, 121.6, 126.1, 126.2, 127.38, 127.43, 127.8, 128.75, 128.84, 128.9, 129.8, 134.8, 137.6,
138.9, 145.2; HRMS (ESI-TOF) calcd for C26H25N2O2S2 (M+H)+ 461.1357, found 461.1351.
2-ethyl-3,4-diphenyl-1-tosylimidazolidine (5j). The general method described above was
followed when aziridine 1a (150.3 mg, 0.55 mmol) was reacted with aniline 2a (45 µL, 0.50
mmol) at room temperature for 2 h followed by addition of propanal 4j (36 µL, 0.50 mmol)
along with PTSA (17.2 mg, 0.10 mmol) and MgSO4 (60.2 mg, 0.50 mmol) in DCE at 65 °C for 6
h to afford 5j (162.6 mg, 0.40 mmol) as a white solid in 80% yield. Rf 0.62 (20% diethyl ether in
petroleum ether); MP 139–141 °C; IR ṽmax (KBr, cm-1) 3028, 2966, 2928, 1597, 1502, 1453,
1
1350, 1305, 1234, 1212, 1163, 1122, 1090, 1040, 1028, 990, 937, 851, 814, 748, 673; H NMR
(CDCl3, 500 MHz) δ 1.21 (t, 3H, J = 7.4 Hz), 1.82–1.90 (m, 1H), 1.97–2.04 (m, 1H), 2.24 (s,
3H), 3.36 (dd, 1H, J = 13.6, 9.9 Hz), 3.65–3.68 (m, 1H), 4.30 (dd, 1H, J = 13.7, 7.7 Hz), 5.33
(dd, 1H, J = 9.8, 3.9 Hz), 6.14 (d, 2H, J = 8.0 Hz), 6.68 (t, 1H, J = 7.3 Hz), 6.92 (d, 2H, J = 8.2
Hz), 7.02–7.05 (m, 2H), 7.12 (d, 2H, J = 7.0 Hz), 7.20–7.28 (m, 3H), 7.56 (d, 2H, J = 8.3 Hz);
13C{1H} NMR (CDCl3, 125 MHz) δ 10.4. 21.7, 29.6, 54.3, 62.0, 80.1, 112.4, 118.1, 125.9, 127.7,
128.0, 129.1, 129.3, 130.0, 134.8, 140.5, 144.5, 146.1; HRMS (ESI-TOF) calcd for C24H27N2O2S
(M+H)+ 407.1793, found 407.1790.
2-(4-nitrophenyl)-3-phenyl-4-(m-tolyl)-1-tosylimidazolidine (5k). The general method described
above was followed when aziridine 1b (158.0 mg, 0.55 mmol) was reacted with aniline 2a (45
µL, 0.50 mmol) at room temperature for 2 h followed by addition of 4-nitrobenzaldehyde 4d
(75.5 mg, 0.50 mmol) along with PTSA (17.2 mg, 0.10 mmol) and MgSO4 (60.2 mg, 0.50 mmol)
in DCE at 65 °C for 6 h to afford 5k (218.3 mg, 0.42 mmol) as a white solid in 85% yield. Rf
0.67 (20% diethyl ether in petroleum ether); MP 164–166 °C; IR ṽmax (KBr, cm-1) 3042, 2924,
2855, 1598, 1524, 1502, 1455, 1408, 1349, 1232, 1201, 1164, 1108, 1090, 1012, 992, 963, 893,
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868, 824, 751, 696, 676; H NMR (CDCl3, 500 MHz) δ 2.27 (s, 3H), 2.29 (s, 3H), 3.15 (dd, 1H,
J = 13.6, 10.6 Hz), 3.85 (dd, 1H, J = 10.4, 7.1 Hz), 4.27–4.31 (m, 1H), 6.22 (d, 2H, J = 8.0 Hz),
6.38 (s, 1H), 6.80 (t, 1H, J = 7.3 Hz), 6.92–6.95 (m, 2H), 6.99–7.08 (m, 5H), 7.13–7.16 (m, 1H),
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7
8
9
13
7.60 (d, 2H, J = 8.3 Hz), 7.92 (d, 2H, J = 8.6 Hz), 8.27 (d, 2H, J = 8.7 Hz); C{1H} NMR
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(CDCl3, 125 MHz) δ 21.8, 54.7, 63.7, 80.1, 113.5, 119.7, 123.3, 124.2, 127.0, 127.8, 128.7,
129.2, 129.29, 129.34, 130.3, 134.7, 139.1, 139.2, 145.2, 147.2, 147.4, 148.6; HRMS (ESI-TOF)
calcd for C29H28N3O4S (M+H)+ 514.1801, found 514.1806.
4-(4-chlorophenyl)-2-(4-nitrophenyl)-3-phenyl-1-tosylimidazolidine (5l). The general method
described above was followed when aziridine 1c (169.2 mg, 0.55 mmol) was reacted with aniline
2a (45 µL, 0.50 mmol) at room temperature for 2 h followed by addition of 4-nitrobenzaldehyde
4d (75.5 mg, 0.50 mmol) along with PTSA (17.2 mg, 0.10 mmol) and MgSO4 (60.2 mg, 0.50
mmol) in DCE at 65 °C for 6 h to afford 5l (218.9 mg, 0.41 mmol) as a white solid in 82% yield.
Rf 0.52 (20% diethyl ether in petroleum ether), MP 190–192 °C, IR ṽmax (KBr, cm-1) 3064, 2925,
2855, 1598, 1522, 1502, 1493, 1455, 1349, 1264, 1233, 1200, 1165, 1090, 1013, 993, 961, 899,
847, 741, 667; 1H NMR (CDCl3, 400 MHz) δ 2.30 (s, 3H), 3.13 (dd, 1H, J = 13.4, 10.4 Hz), 3.89
(dd, 1H, J = 10.4, 6.7 Hz), 4.31 (dd, 1H, J = 13.4, 6.7 Hz), 6.21 (d, 2H, J = 7.9 Hz), 6.39 (s, 1H),
6.83 (t, 1H, J = 7.3 Hz), 7.01 (d, 2H, J = 7.9 Hz), 7.07–7.11 (m, 4H), 7.24–7.25 (m, 2H), 7.61 (d,
2H, J = 8.6 Hz), 7.91 (d, 2H, J = 8.6 Hz), 8.29 (d, 2H, J = 8.6 Hz); 13C{1H} NMR (CDCl3, 125
MHz) 21.5, 54.1, 62.8, 79.8, 113.3, 119.7, 123.9, 127.4, 127.5, 128.2, 129.1, 129.3, 130.0, 133.9,
134.3, 137.3, 144.9, 146.6, 146.8, 148.3; HRMS (ESI-TOF) calcd for C28H25ClN3O4S (M+H)+
534.1254, found 534.1258.
(4-bromophenyl)-2-(4-nitrophenyl)-3-phenyl-1-tosylimidazolidine (5m). The general method
described above was followed when aziridine 1d (193.7 mg, 0.55 mmol) was reacted with
aniline 2a (45 µL, 0.50 mmol) at room temperature for 2 h followed by addition of 4-
nitrobenzaldehyde 4d (75.5 mg, 0.50 mmol) along with PTSA (17.2 mg, 0.10 mmol) and MgSO4
(60.2 mg, 0.50 mmol) in DCE at 65 °C for 6 h to afford 5m (228.5 mg, 0.39 mmol) as a white
solid in 79% yield. Rf 0.54 (20% diethyl ether in petroleum ether); MP 203–205 °C; IR ṽmax
(KBr, cm-1) 2923, 1598, 1522, 1501, 1409, 1349, 1232, 1199, 1165, 1089, 1010, 961, 899, 862,
1
820, 751, 693, 678; H NMR (CDCl3, 400 MHz) δ 2.30 (s, 3H), 3.13 (dd, 1H, J = 13.4, 10.4
Hz), 3.87 (dd, 1H, J = 10.4, 6.7 Hz), 4.29–4.34 (m, 1H), 6.20 (d, 2H, J = 8.0 Hz), 6.39 (s, 1H),
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6.83 (t, 1H, J = 7.3 Hz), 7.00–7.11 (m, 6H), 7.41 (d, 2H, J = 8.6 Hz), 7.60 (d, 2H, J = 7.9 Hz),
13
7.90 (d, 2H, J = 9.2 Hz), 8.29 (d, 2H, J = 9.2 Hz); C{1H} NMR (CDCl3, 100 MHz) δ 21.6,
54.1, 62.9, 79.9, 113.3, 119.8, 122.0, 124.0, 127.5, 127.8, 128.3, 129.2, 130.1, 132.4, 134.3,
137.9, 145.1, 146.6, 146.9, 148.3; HRMS (ESI-TOF) calcd for C28H25BrN3O4S (M+H)+
578.0749, found 578.0748.
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4-(3-fluorophenyl)-2-(4-nitrophenyl)-3-phenyl-1-tosylimidazolidine (5n). The general method
described above was followed when aziridine 1e (160.2 mg, 0.55 mmol) was reacted with aniline
2a (45 µL, 0.50 mmol) at room temperature for 2 h followed by addition of 4-nitrobenzaldehyde
4d (75.5 mg, 0.50 mmol) along with PTSA (17.2 mg, 0.10 mmol) and MgSO4 (60.2 mg, 0.50
mmol) in DCE at 65 °C for 6 h to afford 5n (196.6 mg, 0.38 mmol) as a white solid in 76%
yield. Rf 0.78 (20% diethyl ether in petroleum ether); MP 169–171 °C; IR ṽmax (KBr, cm-1) 2923,
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2852, 1598, 1523, 1501, 1453, 1348, 1201, 1164, 1089, 1010, 957, 895, 809, 750, 693, 675; H
NMR (CDCl3, 500 MHz) δ 2.30 (s, 3H), 3.15 (dd, 1H, J = 13.6, 10.4 Hz), 3.88 (dd, 1H, J = 10.3,
7.1 Hz), 4.29–4.33 (m, 1H), 6.21 (d, 2H, J = 8.0 Hz), 6.39 (s, 1H), 6.81–6.87 (m, 2H), 6.90–6.95
(m, 2H), 7.01 (d, 2H, J = 8.0 Hz), 7.07–7.10 (m, 2H), 7.23–7.27 (m, 1H), 7.60 (d, 2H, J = 8.1
Hz), 7.91 (d, 2H, J = 8.4 Hz), 8.29 (d, 2H, J = 8.7 Hz); 13C{1H} NMR (CDCl3, 125 MHz) δ 21.5,
2
2
54.0, 63.0, 79.8, 113.1 (d, JC−F = 22.7 Hz), 113.2, 115.1 (d, JC−F = 20.3 Hz), 119.7, 121.6,
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4
124.0, 127.4, 128.2, 129.1, 130.0, 130.8 (d, JC−F = 8.3 Hz), 134.2, 141.5 (d, JC−F = 7.2 Hz),
1
145.0, 146.6, 146.8, 148.3, 163.1 (d, JC−F = 245.6 Hz); HRMS (ESI-TOF) calcd for
C28H25FN3O4S (M+H)+ 518.1550, found 518.1551.
2-(4-nitrophenyl)-4-phenyl-3-(p-tolyl)-1-tosylimidazolidine (5o). The general method described
above was followed when aziridine 1a (150.3 mg, 0.55 mmol) and p-toluidine 2b (53.5 mg, 0.50
mmol) dissolved in 1.0 mL of DCE was stirred at room temperature for 2 h followed by addition
of 4-nitrobenzaldehyde 4d (75.5 mg, 0.50 mmol) along with PTSA (17.2 mg, 0.10 mmol) and
MgSO4 (60.2 mg, 0.50 mmol) in DCE at 65 °C for 6 h to afford 5o (218.3 mg, 0.42 mmol) as a
white solid in 85% yield. Rf 0.58 (20% diethyl ether in petroleum ether); MP 172–174 °C; IR
ṽmax (KBr, cm-1) 2922, 1598, 1518, 1453, 1348, 1200, 1164, 1089, 1010, 962, 898, 861, 804,
741, 699, 676; 1H NMR (CDCl3, 400 MHz) δ 2.23 (s, 3H), 2.31 (s, 3H), 3.16 (dd, 1H, J = 13.4,
10.4 Hz), 3.91 (dd, 1H, J = 10.4, 6.7 Hz), 4.29 (dd, 1H, J = 13.4, 6.7 Hz), 6.14 (d, 2H, J = 8.6
Hz), 6.34 (s, 1H), 6.88 (d, 2H, J = 8.6 Hz), 7.03 (d, 2H, J = 8.6 Hz), 7.15–7.17 (m, 2H), 7.21–
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7.30 (m, 3H), 7.62 (d, 2H, J = 7.9 Hz), 7.93 (d, 2H, J = 8.6 Hz), 8.28 (d, 2H, J = 9.2 Hz);
13C{1H} NMR (CDCl3, 100 MHz) δ 20.4, 21.6, 54.3, 63.5, 80.1, 113.4, 124.0, 126.1, 127.6,
128.1, 128.5, 128.8, 129.1, 129.5, 130.0, 134.5, 138.9, 144.7, 144.9, 147.4, 148.2; HRMS (ESI-
TOF) calcd for C29H28N3O4S (M+H)+ 514.1801, found 514.1803.
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3-(4-(tert-butyl)phenyl)-2-(4-nitrophenyl)-4-phenyl-1-tosylimidazolidine (5p). The general
method described above was followed when aziridine 1a (150.3 mg, 0.55 mmol) was reacted
with 4-tert-butylaniline 2c (79 µL, 0.50 mmol) at room temperature for 2 h followed by addition
of 4-nitrobenzaldehyde 4d (75.5 mg, 0.50 mmol) along with PTSA (17.2 mg, 0.10 mmol) and
MgSO4 (60.2 mg, 0.50 mmol) in DCE at 65 °C for 6 h to afford 5p (227.8 mg, 0.41 mmol) as a
white solid in 82% yield. Rf 0.70 (20% diethyl ether in petroleum ether); MP 185–187 °C; IR
ṽmax (KBr, cm-1) 3036, 2960, 2866, 1709, 1606, 1519, 1493, 1455, 1393, 1348, 1320, 1268,
1232, 1198, 1164, 1107, 1089, 1059, 1011, 963, 898, 861, 814, 754, 700, 676; 1H NMR (CDCl3,
500 MHz) δ 1.26 (s, 9H), 2.28 (s, 3H), 3.16 (dd, 1H, J = 13.6, 10.6 Hz), 3.89 (dd, 1H, J = 10.4,
7.1 Hz), 4.29–4.33 (m, 1H), 6.16 (d, 2H, J = 8.9 Hz), 6.36 (s, 1H), 6.94 (d, 2H, J = 8.0 Hz), 7.08
(m, 2H), 7.14-7.16 (m, 2H), 7.22–7.28 (m, 3H), 7.59 (d, 2H, J = 8.3 Hz), 7.93 (d, 2H, J = 8.4
13
Hz), 8.27 (d, 2H, J = 8.7 Hz); C{1H} NMR (CDCl3, 125 MHz) δ 21.9, 31.8, 34.2, 54.7, 64.0,
80.2, 113.2, 124.2, 126.0, 126.4, 127.8, 128.4, 128.7, 129.4, 130.1, 134.7, 139.4, 142.5, 145.0,
145.1, 147.6; HRMS (ESI-TOF) calcd for C32H34N3O4S (M+H)+ 556.2270, found 556.2270.
(2S,4S)-3-(4-fluorophenyl)-2-(4-nitrophenyl)-4-phenyl-1-tosylimidazolidine (5q). The general
method described above was followed when aziridine (S)-1a (150.3 mg, 0.55 mmol) was reacted
with 4-fluoroaniline 2d (47 µL, 0.50 mmol) at room temperature for 2 h followed by addition of
4-nitrobenzaldehyde 4d (75.5 mg, 0.50 mmol) along with PTSA (17.2 mg, 0.10 mmol) and
MgSO4 (60.2 mg, 0.50 mmol) in DCE at 65 °C for 6 h to afford (2S,4S)-5q (204.4 mg, 0.39
mmol) as a white solid in 79% yield. Rf 0.75 (20% diethyl ether in petroleum ether); MP 163–
165 °C; [α]25D +76.0 (c 0.5 in CH2Cl2) for a >99% ee sample. Optical purity was determined by
chiral HPLC analysis (Chiralpak AD-H column), hexane–isopropanol, 98:2; flow rate = 1.0
mL/min; tR 1: 71.9 min (minor), tR 2: 58.6 min (major); IR ṽmax (KBr, cm-1) 3057, 2925, 2854,
1598, 1522, 1508, 1453, 1407, 1348, 1266, 1233, 1210, 1199, 1164, 1108, 1089, 1059, 1009,
962, 897, 862, 817, 760, 699, 676; 1H NMR (CDCl3, 400 MHz) δ 2.33 (s, 3H), 3.16 (dd, 1H, J =
13.4, 10.4 Hz), 3.87 (dd, 1H, J = 10.4, 7.3 Hz), 4.27–4.32 (m, 1H), 6.16 (dd, 2H, J = 9.1, 4.2
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Hz), 6.29 (s, 1H), 6.77 (t, 2H, J = 8.5 Hz), 7.06–7.16 (m, 4H), 7.06 (d, 2H, J = 8.5 Hz), 7.16 (d,
2H, J = 7.9 Hz), 7.22–7.30 (m, 3H), 7.62 (d, 2H, J = 8.5 Hz), 7.91 (d, 2H, J = 8.5 Hz), 8.28 (d,
2H, J = 8.5 Hz); 13C{1H} NMR (CDCl3, 125 MHz) δ 21.6, 54.4, 63.9, 80.3, 114.4 (d, 3JC−F = 8.3
7
8
9
2
4
Hz), 115.6 (d, JC−F = 28.6 Hz), 124.0, 126.1, 127.7, 128.4 (d, JC−F = 4.8 Hz), 129.3, 130.1,
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134.5, 138.4, 143.3, 145.1, 147.0, 148.3, 156.9 (d, JC−F = 255.8 Hz); HRMS (ESI-TOF) calcd
for C28H25FN3O4S (M+H)+ 518.1550, found 518.1557.
3-(4-chlorophenyl)-2-(4-nitrophenyl)-4-phenyl-1-tosylimidazolidine (5r). The general method
described above was followed when aziridine 1a (150.3 mg, 0.55 mmol) and 4-chloroaniline 2e
(63.7 mg, 0.50 mmol) dissolved in 1.0 mL of DCE was stirred at room temperature for 2 h
followed by addition of 4-nitrobenzaldehyde 4d (75.5 mg, 0.50 mmol) along with PTSA (17.2
mg, 0.10 mmol) and MgSO4 (60.2 mg, 0.50 mmol) in DCE at 65 °C for 6 h to afford 5r (202.9
mg, 0.38 mmol) as a white solid in 76% yield. Rf 0.62 (20% diethyl ether in petroleum ether);
MP 194–196 °C; IR ṽmax (KBr, cm-1) 3064, 2925, 1597, 1523, 1495, 1453, 1408, 1348, 1265,
1233, 1200, 1165, 1089, 1058, 1008, 961, 897, 861, 845, 812, 754, 699, 676; 1H NMR (CDCl3,
400 MHz) δ 2.32 (s, 3H), 3.16 (dd, 1H, J = 13.4, 10.4 Hz), 3.87 (dd, 1H, J = 10.4, 7.3 Hz), 4.30–
4.35 (m, 1H), 6.15 (d, 2H, J = 8.5 Hz), 6.30 (s, 1H), 7.00–7.07 (m, 4H), 7.12 (d, 2H, J = 7.9 Hz),
7.22–7.30 (m, 3H), 7.62 (d, 2H, J = 7.9 Hz), 7.89 (d, 2H, J = 8.5 Hz), 8.27 (d, 2H, J = 8.5 Hz);
13C{1H} NMR (CDCl3, 100 MHz) δ 21.6, 54.3, 63.7, 79.9, 114.4, 124.0, 124.6, 126.0, 127.6,
128.3, 128.4, 128.9, 129.3, 130.1, 134.3, 138.3, 145.2, 145.5, 146.5, 148.3; HRMS (ESI-TOF)
calcd for C28H25ClN3O4S (M+H)+ 534.1254, found 534.1256.
3-isopropyl-2-(4-nitrophenyl)-4-phenyl-1-tosylimidazolidine (5s). The general method described
above was followed when aziridine 1a (150.3 mg, 0.55 mmol) was reacted with isopropylamine
2f (40 µL, 0.50 mmol) at room temperature for 2 h followed by addition of 4-nitrobenzaldehyde
4d (75.5 mg, 0.50 mmol) along with PTSA (17.2 mg, 0.10 mmol) and MgSO4 (60.2 mg, 0.50
mmol) in DCE at 65 °C for 6 h to afford 5s (174.5 mg, 0.37 mmol) as a white solid in 75% yield.
Rf 0.44 (20% diethyl ether in petroleum ether); MP 110–112 °C; IR ṽmax (KBr, cm-1) 2923, 2851,
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1599, 1521, 1494, 1456, 1346, 1162, 1092, 1013, 854, 823, 756, 740, 700, 672; H NMR
(CDCl3, 500 MHz) δ 0.96 (d, 3H, J = 6.4), 1.02 (d, 3H, J = 6.4), 2.36 (s, 3H), 2.54–2.60 (m, 1H),
3.05–3.08 (m, 1H), 3.15–3.18 (m, 1H), 4.88–4.91 (m, 1H), 5.55 (s, 1H), 7.12 (d, 2H, J = 8.0 Hz),
7.21–7.29 (m, 5H), 7.45 (d, 2H, J = 8.3 Hz), 7.68 (d, 2H, J = 7.9 Hz), 8.11 (d, 2H, J = 8.7 Hz);
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13C{1H} NMR (CDCl3, 125 MHz) δ 17.9, 21.8, 22.7, 48.6, 54.0, 62.0, 80.3, 123.6, 127.5, 127.9,
128.0, 128.1, 128.8, 129.7, 129.8, 135.9, 140.5, 144.3, 148.1, 148.3; HRMS (ESI-TOF) calcd for
C25H28N3O4S (M+H)+ 466.1801, found 466.1801.
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2-(4-nitrophenyl)-3,4-diphenyl-1-(phenylsulfonyl)imidazolidine (5t). The general method
described above was followed when aziridine 1f (142.6 mg, 0.55 mmol) was reacted with aniline
2a (45 µL, 0.50 mmol) at room temperature for 2 h followed by addition of 4-nitrobenzaldehyde
4d (75.5 mg, 0.50 mmol) along with PTSA (17.2 mg, 0.10 mmol) and MgSO4 (60.2 mg, 0.50
mmol) in DCE at 65 °C for 6 h to afford 5t (211.2 mg, 0.43 mmol) as a white solid in 87% yield.
Rf 0.57 (20% diethyl ether in petroleum ether); MP 144–146 °C; IR ṽmax (KBr, cm-1) 3064, 2926,
2855, 1600, 1524, 1447, 1408, 1349, 1233, 1200, 1168, 1090, 1011, 963, 898, 861, 823, 749,
699; 1H NMR (CDCl3, 500 MHz) δ 3.18 (dd, 1H, J = 13.6, 10.6 Hz), 3.83 (dd, 1H, J = 10.3, 7.0
Hz), 4.26–4.30 (m, 1H), 6.23 (d, 2H, J = 8.0 Hz), 6.44 (s, 1H), 6.80 (t, 1H, J = 7.3), 7.05–7.15
(m, 4H), 7.21–7.29 (m, 5H), 7.47 (t, 1H, J = 7.6), 7.73 (d, 2H, J = 7.3 Hz), 7.93 (d, 2H, J = 8.3
Hz), 8.28 (d, 2H, J = 8.9 Hz); 13C{1H} NMR (CDCl3, 125 MHz) δ 54.6, 63.8, 80.2, 113.7, 119.9,
124.3, 126.4, 127.9, 128.5, 128.7, 129.5, 129.8, 134.1, 137.9, 139.0, 147.1, 147.3, 148.6; HRMS
(ESI-TOF) calcd for C27H24N3O4S (M+H)+ 486.1488, found 486.1485
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1-((4-(tert-butyl)phenyl)sulfonyl)-2-(4-nitrophenyl)-3,4-diphenylimidazolidine
(5u).
The
general method described above was followed when aziridine 1g (173.5 mg, 0.55 mmol) was
reacted with aniline 2a (45 µL, 0.50 mmol) at room temperature for 2 h followed by addition of
4-nitrobenzaldehyde 4d (75.5 mg, 0.50 mmol) along with PTSA (17.2 mg, 0.10 mmol) and
MgSO4 (60.2 mg, 0.50 mmol) in DCE at 65 °C for 6 h to afford 5u (249.1 mg, 0.46 mmol) as a
white solid in 92% yield. Rf 0.50 (20% diethyl ether in petroleum ether); MP 184–186 °C; IR
ṽmax (KBr, cm-1) 2963, 2927, 1597, 1524, 1502, 1455, 1401, 1348, 1233, 1199, 1168, 1112,
1086, 1010, 964, 898, 861, 757, 699; 1H NMR (CDCl3, 500 MHz) δ 1.25 (s, 9H), 3.15–3.19 (m,
1H), 3.71–3.74 (m, 1H), 4.27–4.31 (m, 1H), 6.19 (d, 2H, J = 7.8 Hz), 6.43 (s, 1H), 6.78-6.81 (m,
1H), 7.05-7.13 (m, 4H), 7.22-7.28 (m, 5H), 7.64 (d, 2H, J = 8.0 Hz), 7.93 (d, 2H, J = 8.3 Hz),
8.28 (d, 2H, J = 8.3 Hz); 13C{1H} NMR (CDCl3, 125 MHz) δ 31.3, 35.5, 54.7, 63.8, 80.0, 113.6,
119.7, 124.2, 126.3, 126.7, 127.7, 128.4, 128.7, 129.5, 134.6, 139.2, 147.2, 147.3, 148.6, 158.2;
HRMS (ESI-TOF) calcd for C31H32N3O4S (M+H)+ 542.2114, found 542.2119.
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1-((4-fluorophenyl)sulfonyl)-2-(4-nitrophenyl)-3,4-diphenylimidazolidine (5v). The general
method described above was followed when aziridine 1h (152.5 mg, 0.55 mmol) was reacted
with aniline 2a (45 µL, 0.50 mmol) at room temperature for 2 h followed by addition of 4-
nitrobenzaldehyde 4d (75.5 mg, 0.50 mmol) along with PTSA (17.2 mg, 0.10 mmol) and MgSO4
(60.2 mg, 0.50 mmol) in DCE at 65 °C for 6 h to afford 5v (226.6 mg, 0.45 mmol) as a white
solid in 90% yield. Rf 0.54 (20% diethyl ether in petroleum ether); MP 90–92 °C; IR ṽmax (KBr,
cm-1) 3064, 2927, 1593, 1523, 1501, 1493, 1454, 1405, 1349, 1294, 1237, 1212, 1200, 1170,
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1155, 1088, 1076, 1010, 961, 898, 862, 822, 751, 697; H NMR (CDCl3, 500 MHz) δ 3.20 (dd,
1H, J = 13.6, 10.6 Hz), 3.91 (dd, 1H, J = 10.3, 7.1 Hz), 4.28–4.32 (m, 1H), 6.27 (d, 2H, J = 8.0
Hz), 6.42 (s, 1H), 6.81–6.84 (m, 1H), 6.88–6.92 (m, 2H), 7.09–7.16 (m, 4H), 7.22–7.30 (m, 3H),
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7.73–7.76 (m, 2H), 7.93 (d, 2H, J = 8.4 Hz), 8.29 (d, 2H, J = 8.7 Hz); C{1H} NMR (CDCl3,
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125 MHz) δ 54.5, 63.8, 80.2, 113.5, 117.0 (d, JC−F = 22.7 Hz), 120.1, 124.3, 126.4, 128.58,
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128.63, 129.5 (d, JC−F = 8.3 Hz), 130.6, 130.7, 133.9 (d, JC−F = 2.7 Hz), 138.8, 147.0, 147.1,
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148.6, 166.1 (d, JC−F = 255.8 Hz); HRMS (ESI-TOF) calcd for C27H23FN3O4S (M+H)+
504.1393, found 504.1390.
2,3,4-triphenyloxazolidine (7a). The general method described above was followed when 2-
phenyloxirane 6a (0.06 mL, 0.55 mmol) was reacted with aniline 2a (45 µL, 0.50 mmol) at room
temperature for 2 h followed by addition of benzaldehyde 4a (51 µL, 0.50 mmol) along with
PTSA (17.2 mg, 0.10 mmol) and MgSO4 (60.2 mg, 0.50 mmol) in DCE at 65 °C for 6 h to afford
7a (117.5 mg, 0.39 mmol) as a thick liquid in 78% yield. Rf 0.80 (20% diethyl ether in petroleum
ether); IR ṽmax (neat, cm-1) 3062, 3029, 2924, 2868, 1599, 1503, 1453, 1363, 1342, 1287, 1211,
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1157, 1098, 1076, 1028, 964, 918, 880, 841, 807, 751, 698; H NMR (CDCl3, 500 MHz) δ 3.91
(dd, 1H, J = 8.6, 6.9 Hz), 4.43 (dd, 1H, J = 13.5, 6.9 Hz), 4.86 (t, 1H, J = 6.8 Hz), 6.05 (s, 1H),
6.56 (d, 2H, J = 7.9 Hz), 6.77 (t, 1H, J = 7.3 Hz), 7.12 (dd, 2H, J = 8.6, 7.3 Hz), 7.27–7.44 (m,
6H), 7.51 (d, 2H, J = 7.3 Hz), 7.68 (d, 2H, J = 7.2 Hz); 13C{1H} NMR (CDCl3, 125 MHz) δ 65.2,
73.6, 94.8, 114.6, 119.0, 126.9, 127.6, 128.0, 129.0, 129.15, 129.22, 129.3, 140.4, 141.1, 147.2;
HRMS (ESI-TOF) calcd for C21H20NO (M+H)+ 302.1545, found 302.1547.
2-(4-nitrophenyl)-3,4-diphenyloxazolidine (7b). The general method described above was
followed when 2-phenyloxirane 6a (0.06 mL, 0.55 mmol) was reacted with aniline 2a (45 µL,
0.50 mmol) at room temperature for 2 h followed by addition of 4-nitrobenzaldehyde 4d (75.5
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