Stereoselective synthesis of C-sulfonylated aziridines from halomethyl phenyl sulfone and N-tert-butanesulfinyl imines

Article abstract of DOI:10.1039/c3ra44174a

A highly efficient and stereoselective synthesis of C-sulfonylated aziridines is developed by using a one-step aza-Darzens reaction. When sodium bis(trimethylsilyl)amide (NaHMDS) was used as the base, bromomethyl phenyl sulfone reacted with N-tert-butanesulfinyl imines to afford the 2-sulfonylated aziridine products in very good yields and with stereoselectivities up to 50:1. The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c3ra44174a

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Stereoselective synthesis of C-sulfonylated
aziridines from halomethyl phenyl sulfone and
Cite this: RSC Adv., 2014, 4, 969
N-tert-butanesulfinyl imines†
Received 6th August 2013
Accepted 4th November 2013
*
*
Ya Li, Haiji Huang, Zhen Wang, Fan Yang, Desheng Li, Bo Qin and Xinfeng Ren
DOI: 10.1039/c3ra44174a
www.rsc.org/advances
A highly efficient and stereoselective synthesis of C-sulfonylated Therefore, the synthesis of C-sulfonylated aziridines have drawn
aziridines is developed by using a one-step aza-Darzens reaction. a lot of endeavors.6,8 A method reported by Carlier and
When sodium bis(trimethylsilyl)amide (NaHMDS) was used as the base, coworkers used a cascade Michael addition–intramolecular
bromomethyl phenyl sulfone reacted with N-tert-butanesulfinyl substitution reaction between 1-bromoalkene sulfones and
imines to afford the 2-sulfonylated aziridine products in very good primary amines.8a Deprotonation of N-Bus (Bus ¼ tert-butyl-
yields and with stereoselectivities up to 50 : 1.
sulfonyl)-protected terminal aziridines to generate an aziridinyl
anion followed by trapping with benzenesulfonyl uoride could
also access the target compounds.8c,8d However, both methods
are only limited to specic compounds. Addition of chlor-
omethyl phenyl sulfone to N-aryl imines for the synthesis of
C-sulfonylated aziridines was also developed; however, the
substrates were limited only to aryl imines, and the N-aryl
protecting group in the substrate makes it difficult to further
functionalize the nitrogen atom.7b
As to the asymmetric synthesis of C-sulfonylated aziridines,
it has proven challenging and only a few examples have been
reported.9 Recently, Bew and coworkers developed an expedient
synthesis of C-sulfonylated aziridines from O-acylated (S)-
N-(a-methylbenzyl)-N-(2-(phenylsulfonyl)ethyl)-hydroxylamine,
based on an intramolecular ring-closure strategy.9a Good yield
and moderate stereoselectivity was obtained. However, the
O-acylated reactant is not easily accessible and its preparation
requires a several-step synthesis starting from (S)–N-(a-methyl-
benzyl)hydroxylamine, which will limit its practical use. The
reaction between N-hydroxy-N-phenylpivalamide and vinyl-
sulfonylbenzene catalyzed by chiral quaternary salts also affor-
ded the C-sulfonylated aziridine product.9b However, this
reaction suffers from low yields and poor enatioselectivities.
A general method for the highly stereoselective synthesis of
C-sulfonylated aziridines, and, especially, the asymmetric
synthesis of C-sulfonylated di- and tri-substituted aziridines, is
still highly desirable. Herein we report a highly stereoselective
synthesis of C-phenylsulfonylated aziridines via a one-step aza-
Darzens reaction of halomethyl phenyl sulfone with Ellman’s
N-tert-butanesulnyl imines.10
As the smallest saturated nitrogen-containing heterocyclic
compound, aziridine has been receiving considerable attention
since its rst synthesis at the end of 19th century.1 Due to the
intrinsically high reactivity of these three-membered heterocy-
cles, aziridines are being used extensively in the synthesis of a
wide variety of bioactive nitrogen-containing compounds.1,2
C-heteroatom-substituted aziridines, i.e., aziridines with the
heteroatom substituent (such as halo atom, sulfonyl, alkoxy,
nitro, and phosphoryl) directly bonded to the carbon atom(s) of
the three-membered ring, represent a valuable subclass of
aziridines.3 Owing to the existence of the heteroatom substitu-
ents, this kind of aziridines possess unique chemical reactiv-
ities,3 and they have been used for the synthesis of many other
aziridine derivatives and diverse types of ring-opening
products.3,4
The sulfonyl group is well-known for imparting biological
activity to a lot of natural and unnatural products.5 Therefore,
the C-sulfonylated aziridine is of great structural and synthetic
interests. Taking advantage of the basis that the aziridines can
undergo regioselective ring-opening reactions3,4 and sulfones
can be used for versatile synthetic transformations,6 the C-sul-
fonylated aziridines are valuable synthetic intermediates in the
preparation of bioactive nitrogen-containing molecules.7
Department of Chemistry and Chemical Engineering, Shanghai University of
Engineering Science, 333 Longteng Road, Shanghai 201620, China. E-mail: ya.li@
sues.edu.cn; renxf@sues.edu.cn; Fax: +86-21-67791214; Tel: +86-21-67791220
† Electronic supplementary information (ESI) available: Experimental details,
characterization data, and copies of the 1H and 13C NMR spectra of the new
compounds. CCDC 938808 (for 4a), 966482 (for 6). For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c3ra44174a
Firstly, chloromethyl phenyl sulfone 1 was chosen as the
nucleophile.11 Using imine 2a as the model compound, the aza-
Darzens reaction between compound 1 and imine 2a was
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Table 2 Scope of the reaction
examined at different reaction conditions. Into an equimolar
mixture of sulfone 1 and imine 2a in THF at ꢀ70 ꢁC was slowly
added a THF solution of LiHMDS (Table 1, entry 1). The reaction
mixture was kept at ꢀ70 C for 0.5 h and then quenched with
ꢁ
1 N HCl. A complex mixture of the addition products between
(phenylsulfonyl)bromomethyl anion and compound 2a and
aziridine stereoisomers was obtained according to HPLC-MS
analysis. Surprisingly, when DMF was used as the solvent, this
reaction proceeded smoothly and the target product 4a‡ was
obtained at 68% yield and with 7 : 1 stereoselectivity (entry 2).
Further optimization using different base and solvent was tried
and no improvement was observed (entry 3, Table 1). Given the
fact that the bromide ion was a better leaving group, commer-
cially available bromomethylsulfone 3 was used as the nucleo-
phile. Fortunately, its reaction with imine 2a afforded the
product 4a at a better yield and a higher stereoselectivity (entry
4–6). Aer a quick survey of the reactant ratio, the product was
obtained at a yield up to 83% and with a diastereoselectivity up
to 50 : 1 (entry 6).
With the optimized reaction conditions in hand (Table 1,
entry 6), the scope and limitation of this method was examined.
As shown in Table 2, this reaction can be applied to aromatic
and aliphatic imines, both with good stereoselectivities.
Aromatic imines with electron-withdrawing substituents, such
as chloro or the triuoromethyl group (Table 2, entry 2–4), can
oen deliver the target products at better yields and with higher
stereoselectivities, compared to those with electron-donating
substituents (entry 7–9). However, the ortho-chloro substituent
resulted in a comparably lower yield of 55% (entry 5), which
indicates that steric hindrance may exert an effect on this
reaction. Heteroaromatic imines, 2-furyl- and 2-pyridyl imines,
were also tried. However, the desired products were not
obtained, possibly due to the labile nature of the resultant
products under specied reaction conditions. For enolizable
aliphatic imines, although the reaction was carried out under
strong basic conditions, this reaction proceeded smoothly
Entry Product
Yield of 4a 4/other diastereomersb
1
2
3
4
5
6
7
8
4a, R ¼ C6H5
83%
67%
75%
77%
55%
76%
61%
50 : 1
4.8 : 1
43 : 1
4b, R ¼ p-Cl-C6H4
4c, R ¼ 3,4-ClC6H3
4d, R ¼ m-CF3-C6H4
4e, R ¼ o-Cl-C6H4
4f, R ¼ 4-Br-C6H4
4g, R ¼ p-MeO-C6H4
32 : 1
5.5 : 1
6.0 : 1
3.3 : 1
7.0 : 1
8.4 : 1
5.0 : 1
40 : 1
4h, R ¼ p-(CH3)2C-C6H4 63%
9
4i, R ¼ m-CH3-C6H4
4j, R ¼ 2-naphthyl
4k, R ¼ styryl
62%
66%
65%
53%
54%
10
11
12
13
4l, R ¼ isopropyl
4m, R ¼ isobutyl
7.8 : 1.1 : 1
24 : 1
a
b
Isolated yield. Determined by HPLC-MS analysis of the crude
product.
giving the corresponding aziridine products in moderate yields
(Table 2, 53% and 54% yield for 4l and 4m, respectively). Among
all the four possible aziridine products, only two aziridine dia-
stereomers were detected by HPLC-MS for all entries except
entry 4l. Besides, all the aziridine products listed in Table 2 can
be easily puried from the crude reaction mixtures by ash
column chromatography.
The absolute conguration of sulnamide 4a was deter-
mined by single-crystal X-ray analysis (Fig. 1), and the
congurations of others were assigned by analogy. The high cis-
selectivity for compound 4 can be explained by a six-membered
chairlike transition state, in which the metal coordinates with
one of the oxygen of the sulfonyl group and the sulnyl imine
nitrogen atom. The sulnyl imine is assumed to adopt the s-cis
conformation in the transition state, as indicated by recent
Table 1 Survey of reaction conditions
4a/other
diastereomers
Entry
Reaction conditionsb
Yield of 4aa
1
2
3
4
5
6c
1, LiHMDS, THF, ꢀ70 ꢁ
C
C
Trace
68%
23%
78%
45%
83%
Nd
1, LiHMDS, DMF, ꢀ50 ꢁ
7 : 1
1, LiHMDS, toluene, ꢀ70 ꢁ
C
Nd
3, LiHMDS, THF, ꢀ70 ꢁ
C
50 : 1
Nd
50 : 1
3, NaHMDS, DMF, ꢀ50 ꢁC
3, NaHMDS, THF, ꢀ70 ꢁ
C
a
b
Isolated yield. Determined by HPLC-MS analysis of the crude
product. c The molar ratio 2a : 3:base ¼ 1.0 : 1.2 : 1.2. d Not determined.
Fig. 1 X-ray crystal structure of 4a.
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studies that the sulnyl oxygen in a s-cis arrangement with
N-Sulfonyl activation is oen desired because aziridines with
respect to the C]N bond is the most stable conformation for N-sulfonyl activation oen afford superior reactivity and regio-
the N-(phenylsulnyl) imine.12 Thus, the approach of the specicity.3,4 Therefore, introduction this activating group
nucleophile to the less hindered face of the imine would lead to by oxidation of compound 4 with MCPBA was attempted.
the observed stereoselectivity as shown in Fig. 2. A similar This oxidation reaction proceeded smoothly and the corre-
transition state was also reported for the asymmetric synthesis sponding oxidation products 7a§ and 7b were obtained in 87%
of aziridine 2-phosphonates from diethyl iodomethylphospho- and 85% yields, respectively (Scheme 3). Efforts were also tried
nate and enantiopure sulnimines.3c
to remove the tert-butyl sulnyl group under acidic (such as
Next, several sulnylketimines were investigated, and they HCl in methanol, or TFA in acetone)10 or strong basic (such as
all reacted smoothly under the same reaction conditions. As CH3MgBr in THF)3b conditions. However, the substrate 4a
shown in Scheme 1, the electronic withdrawing/donating decomposed gradually under the above specied reaction
nature of the substituent on the aromatic ring has little effect on conditions.
this reaction, and very good yield was obtained for each case
To further explore the chemical reactivity of the C-sulfony-
(Scheme 1). However, when ketimine 5d derived from aceto- lated aziridine motif, compound 7b was investigated under
phenone was subjected to the reported reaction conditions, no typical Suzuki cross-coupling reaction conditions (Scheme 4).
desired product was obtained, which may be due to its low This reaction proceeded smoothly, giving the corresponding
reactivity and enolization.
Selectivie C–N bond cleavage is very useful in the preparation
of valuable synthetic intermediates. When compound 4a was
treated with BF3$OEt2 in CH2Cl2 solvent, the carbon-skeleton
rearranged product 6 was obtained in 61% yield (Scheme 2).13
The formation of enamines via ring-opening of aziridines is
important both in terms of aziridine chemistry and the appli-
cations of enamines in organic synthesis.14 The structure of
compound 6 was determined by single-crystal X-ray analysis
(Fig. 3).
Fig. 3 X-ray crystal structure of 6.
Fig. 2 Transition state for the formation of 4.
Scheme 3 Oxidation of compound 4a to the N-sulfonylated 7.
Scheme 1 Synthesis of tri-substituted aziridines 5.
Scheme 2 C–N Bond cleavage of aziridine 4a.
Scheme 4 Suzuki coupling reaction of compound 7b.
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coupling product 8 in good yield, which indicates the tolerance
of the chemical functionalities to the reaction conditions.
In conclusion, a highly stereoselective and efficient synthesis
of 2-sulfonylated aziridines via a one-step aza-Darzens reaction
was developed. Reaction of (R)-(N-tert-butylsulnyl)aldimines
with bromomethyl phenyl sulfone affords the corresponding
aziridines products at very good yields and with high stereo-
selectivities (up to 50 : 1). This method can be applied to both
aromatic and aliphatic imines. The synthetic applications of C-
sulfonylated aziridines are under further investigation in our lab.
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Acknowledgements
Support of our work by the National Natural Science Foundation
of China (21102089), Innovation Program of Shanghai Munic-
ipal Education Commission (12YZ155), and Innovation
Program of University Students in Shanghai Higher Education
Institutions (cs1204001), is gratefully acknowledged.
Notes and references
‡ Typical experimental procedure for the synthesis of 2-sulfonylated cis-aziridine
4a: NaHMDS (1.2 equiv, 1.2 mmol, 1.0 mol Lꢀ1 in THF) was added to a mixture of
the imine 2a (1.0 mmol) and bromomethyl phenyl sulfone (1.2 equiv, 1.2 mmol) in
THF (3.0 mL) at ꢀ70 ꢁC. Reaction mixture was stirred over 0.5 h. Then half
saturated NH4Cl–H2O (10 mL) was added at ꢀ70 ꢁC and the quenched reaction
mixture was extracted three times with ethyl acetate (20 mL ꢂ 3). The combined
organic layers were dried over anhydrous MgSO4. Evaporation of the solvent
afforded the crude product, which was subject to ash chromatography to give
pure aziridine 4a (302 mg, 83%). Compound 4a: white solid, mp 122.7–128.6 ꢁC
(from ethyl acetate/hexane); [a]2D5 ꢀ 7.0 (c 1.06 in CHCl3); IR (lm, nmax/cmꢀ1):
1448, 1333, 1157, 1081, 741, 690; 1H NMR (400 MHz, CDCl3) d 7.64–7.56 (m, 1H),
7.54–7.49 (m, 2H), 7.46–7.38 (m, 4H), 7.37–7.30 (m, 3H), 4.00 (d, J ¼ 6.5 Hz, 1H),
3.64 (d, J ¼ 6.5 Hz, 1H), 1.26 (s, 9H); 13C NMR (100 MHz, CDCl3) d 138.4, 134.0,
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+
§ Typical experimental procedure for oxidation of compound 4a to N-sulfonylated
product 7a: compound 4a (364 mg, 1 mmol) was dissolved in 5 mL dichloro-
methane, then 1.2 mmol MCPBA was added at 0 ꢁC. The reaction mixture was
stirred at 0 ꢁC for 4 h and was then 2 N Na2CO3 (4 mL) was added. The reaction
mixture was extracted three times with ethyl acetate (20 mL ꢂ 3). The combined
organic layers were dried over anhydrous MgSO4. Evaporation of the solvent
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/
cmꢀ1): 1449, 1324, 1160, 1128, 765, 713; 1H NMR (400 MHz, CDCl3) d 7.65–7.57 (m,
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