Stereoselective synthesis of α-(dichloromethyl)-amines, α-(chloromethyl)amines, and α-chloro-aziridines

Article abstract of DOI:10.1039/c4ra00471j

Protocols for the stereoselective synthesis of α-(dichloromethyl) amines, α-(chloromethyl)amines, and α-chloroaziridines are presented. Diastereoselective synthesis of α-(dichloromethyl)amines was achieved based on nucleophilic dichloromethylation of aromatic N-tert-butylsulfinyl aldimines with (dichloromethyl)trimethylsilane at a low reaction temperature. Slowly warming the reaction mixture up to room temperature gave α-chloro cis-aziridines. Additionally, with Bu₃SnH as the reductant, α-(dichloromethyl)amines were readily obtained from easily accessible α-(trichloromethyl)amines via mono-dechlorination. Over-reduction was successfully suppressed. Subsequent radical mono-dechlorination of the α-(dichloromethyl)amines gave the corresponding α-(chloromethyl)amines in good to excellent yields.

Full text of DOI:10.1039/c4ra00471j

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Stereoselective synthesis of a-(dichloromethyl)-
amines, a-(chloromethyl)amines, and a-chloro-
aziridines†
Cite this: RSC Adv., 2014, 4, 14254
*
Desheng Li, Ya Li, Zhiqiu Chen, Huaqi Shang, Hongsen Li and Xinfeng Ren
Protocols for the stereoselective synthesis of a-(dichloromethyl)amines, a-(chloromethyl)amines, and
a-chloroaziridines are presented. Diastereoselective synthesis of a-(dichloromethyl)amines was achieved
based on nucleophilic dichloromethylation of aromatic N-tert-butylsulfinyl aldimines with
(dichloromethyl)trimethylsilane at a low reaction temperature. Slowly warming the reaction mixture up to
room temperature gave a-chloro cis-aziridines. Additionally, with Bu3SnH as the reductant,
a-(dichloromethyl)amines were readily obtained from easily accessible a-(trichloromethyl)amines via
mono-dechlorination. Over-reduction was successfully suppressed. Subsequent radical mono-
dechlorination of the a-(dichloromethyl)amines gave the corresponding a-(chloromethyl)amines in good
to excellent yields.
Received 17th January 2014
Accepted 10th March 2014
DOI: 10.1039/c4ra00471j
www.rsc.org/advances
attracted a lot of attention over many years and remains a hot
subject of intense study.6,7 In this eld, the Kharash reaction
Introduction
has oen been employed to introduce a chlorinated methyl
group into some organic compounds.6 For example, Zakarian
and coworkers described an efficient ruthenium-catalyzed
radical chloroalkylation of titanium enolates, an approach for
stereoselective introduction of the trichloromethyl and
dichloromethyl groups.6a,b While existing methods have made it
possible to synthesize many functionalized chlorinated mole-
cules, developing more diverse methodologies that can incor-
porate chlorinated methyl groups into organic compounds is
certainly highly desirable.
a-Chloroaziridines, a valuable subclass of C-heteroatom-
substituted aziridines, are highly important intermediates in
the synthesis of many other aziridine derivatives and diverse
types of ring-opening products.8,9 Since the work of Deyrup and
co-workers on the synthesis of a-chloroaziridines was repor-
ted,10 the synthesis and reactivity of chloroaziridines has drawn
continuous attention. Though several synthetic strategies (such
as Darzens-type reactions of imines with dichloromethyl-con-
taining compounds,11 nitrene addition to vinyl chlorides,12 and
addition of acyl chlorides across 2H-azirines13) have been pub-
lished, the efficient synthesis of a-chloroaziridines remains a
challenge, and, to the best of our knowledge, the asymmetric
synthesis of a-chloroaziridines has not been disclosed.
More than 5000 natural products from both terrestrial and
marine origins have been discovered to contain covalently
bonded halogen substituent(s), predominantly chlorine.1 These
compounds are of great structural diversity, and exhibit a wide
variety of biological activities, including antibiotic, antitumor,
and analgesic activities.1 For example, vancomycin has been
used clinically as a drug to treat bacterial infections. From a
biological point of view, the halogen-containing structural
motif plays an important role in determining the selectivity and
affinity of the natural product's interaction with its biological
target.2 Structural and mechanistic investigations on natural
halogenating enzymes revealed that enzymatic introduction of
halogens during natural product assembly alters the product's
physical and electronic characteristics, thereby giving rise to its
specic biological activity.2,3 Therefore, halogenation has been a
popular tool to ne-tune a drug candidate's biological proper-
ties in modern drug discovery.4
Chlorinated methyl groups, including chloromethyl,
dichloromethyl, and trichloromethyl groups, are structural
features present in a lot of bioactive natural products (such as
barbamide and sintokamide A) and pharmaceuticals, such as
Nasonex and Lotemax.1,5 Developing methods for incorporation
of chlorinated methyl groups into organic compounds has
We have been interested in the synthesis and reactivity of
chlorinated amines. Recently, we found that trimethyl(tri-
chloromethyl)silane (TMSCCl3) and chloroform were excellent
trichloromethylating reagents towards Ellman's N-tert-butylsul-
nyl imines,14 which enables highly stereoselective synthesis of
a-(trichloromethyl)aminesviaanucleophilictrichloromethylation
strategy.15 Besides, the obtained a-(trichloromethyl)amines can be
Department of Chemistry and Chemical Engineering, Shanghai University of
Engineering Science, 333 Longteng Road, Shanghai, 201620, China. E-mail: ya.li@
sues.edu.cn
† Electronic supplementary information (ESI) available: Copies of the 1H and 13
C
NMR spectra of the new compounds. CCDC 976642. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c4ra00471j
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used as synthetic precursors to prepare enantiomerically pure into a reaction mixture of 2a and DCM in DMF, no desired
a,a-dichloroaziridines.16 In our continuous efforts in developing reaction took place, and the imine 2a was partially recovered
efficient synthesis of chlorinated amines, herein we present a (entry 1–2). The use of n-BuLi to deprotonate DCM at a
systematic study for stereoselective synthesis of a-(dichlor- temperature of ꢀ90 ꢁC followed by the addition of 2a only
omethyl)amines, a-(chloromethyl)amines, and a-chloroaziridines resulted in a complex reaction mixture (entry 3).
for the rst time.
We then turned our attention to commercially available
(dichloromethyl)trimethylsilane (TMSCCl2H) 4. It is noteworthy
that only scattered examples of direct dichloromethylation of
carbonyl compounds with TMSCCl2H have been described,22
while its dichloromethylation reaction towards imines has yet
not been investigated.23 Tetrabutylammonium triphenyldi-
uorosilicate (TBAT) was rst tried as the mediator, for TBAT
was reported to be quite efficient in the nucleophilic tri-
chloromethylation reaction between trimethyl(trichloromethyl)
silane (TMSCCl3) and N-tert-butylsulnyl aldimines.15a However,
Results and discussion
a-(Dichloromethyl)amines are frequently involved in the
synthesis of structurally diverse amines and aziridines.17
However, synthetic methods for the a-(dichloromethyl)amines
are very limited.18 Lithium aluminum hydride reduction of
a-(trichloromethyl)amines was employed to prepare the corre-
sponding a-(dichloromethyl)amines.18a,19 But this reaction
suffers from low yields and over-reduction, and byproducts
including amines with rearranged carbon skeletons and azir-
idines are also frequently found. Metal-mediated photolytic
radical addition of ethyl iodide to chiral dichloroacetaldehyde
N-acylhydrazones was reported to afford the target
compounds.20 However, the yields were very low, even when a
large excess of radical precursors was used (usually 10–20
equivalents compared to N-acylhydrazones). A general method
for the highly stereoselective synthesis of a-(dichloromethyl)
amines, and especially, the asymmetric synthesis of structurally
diverse a-(dichloromethyl)amines, is yet to be developed.
Using imine 2a as a model substrate, we rstly examined its
dichloromethylation reaction with dichloromethane (DCM) 1
(Table 1, entry 1–3). DCM is readily available and its addition
reaction to aldehydes and ketones is well-known.21 When a
strong base, such as Lithium diisopropylamide (LDA) and
sodium hexamethyldisilazane (NaHMDS), was slowly added
Table 2 Synthesis of a-(dichloromethyl)amines 3 from 4 and imines 2
Products 3
Table 1 Survey of reaction conditions for the dichloromethylation of
aromatic imine 2a
Entry
X
Reaction conditions
Yielda (%)
drb
d
1
2
3
4
5
6
7
8
X ¼ H, 1
LDA, DMF, ꢀ40 ꢁ
C
0
0
—
0
0
0
7
35
49
90
—
d
X ¼ H, 1
NaHMDS, DMF, ꢀ40 ꢁ
C
—
d
d
X ¼ H, 1
n-BuLi, THF, ꢀ90 ꢁ
C
—
d
X ¼ TMS, 4
X ¼ TMS, 4
X ¼ TMS, 4
X ¼ TMS, 4
X ¼ TMS, 4
X ¼ TMS, 4
X ¼ TMS, 4
TBAT, THF, ꢀ70 ꢁ
TBAT, DMF, ꢀ40 ꢁ
i-Pr2NEt, DMF, rt
AcOK, DMF, ꢀ40 ꢁ
C
C
—
d
—
d
—
d
C
—
d
t-BuONa, DMF, ꢀ40 ꢁ
C
—
9
t-BuOK, THF, ꢀ70 ꢁ
C
C
98 : 2
98 : 2
10c
t-BuOK, THF, ꢀ70 ꢁ
Isolated yield. Determined by 1H NMR spectroscopy and HPLC
analysis on the crude product. The reactant ratio 2a : 4 : base ¼
a
b
c
a
Isolated yield. b dr determined by 1H NMR and LC-MC analysis on the
d
1 : 2.2 : 2.2. Not determined.
crude product.
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we were surprised to nd that TBAT was not effective at all; no the nucleophilic dichloromethylation of N-tert-butylsulnyl
desired product 3a was observed and compound 2a was recov- imines, slowly warming the reaction mixture up to room
ered almost completely (entry 4). Changing the solvent to more temperature exclusively afforded the corresponding a-chloro
polar DMF had no benecial effect on the reaction outcome cis-aziridine 5a in a very good yield and with a very high dia-
(entry 5). Oxygen- and nitrogen-based bases were also tried stereoselectivity (Scheme 1). These results indicated that the
(entry 6–10), and nally, strong bases, t-BuONa or t-BuOK, were reaction outcome between TMSCCl2H and N-tert-butylsulnyl
found to be quite efficient in promoting this reaction (entry 8–9). imines was controlled by the reaction temperature. Specically,
Optimization of the reactant ratio (2a : 4 : t-BuOK
¼
quenching the reaction at a low temperature provided the cor-
1.0 : 2.2 : 2.2) further increased the yield to 90% (entry 10). responding addition products 3, whereas allowing the reaction
Unlike TMSCCl3, reagent 4 is not moisture sensitive and can also mixture to slowly warm up to room temperature afforded the
be readily prepared from TMSCl and DCM in a single step,24 a-chloro cis-aziridines.
which provides signicant advantages for practical synthesis.
The scope and the results of the reaction are summarized in
With the optimized reaction conditions (entry 10), we Table 3. As shown, the aromatic imines were smoothly con-
examined the substrate scope of this dichloromethylation verted into the corresponding a-chloro cis-aziridines. Donating
reaction. As shown in Table 2, various aromatic, hetero- substituent on the aromatic ring gave better yields (Table 3, 5a
aromatic, and a,b-unsaturated imines reacted with 4 smoothly, and 5b), paralleling the reactivity of N-tert-butylsulnyl imines
giving the corresponding a-(dichloromethyl)amines in good to in the nucleophilic dichloromethylation (Table 2). The stereo-
excellent yields and with excellent diastereoselectivities. It selectivity is generally very high; in no case were we able to
seems that the electronical nature of the substituents on the isolate other minor diastereoisomers. Unlike N-sulnyl
aromatic ring has a signicant effect on the yield: aromatic a-iodoaziridine, the a-chloro cis-aziridines 5 are stable to silica
imines with electron-donating substituents (Table 2, 3a–3d), gel during column chromatography.25
such as methyl, isopropyl and methoxy group, give higher yields
The stereochemistry of a-chloroaziridines 5 was deduced
than those with electron-withdrawing substituents (3f–3h). For from the magnitude of the coupling constant between CHAr
imine 2h with a strong electron-withdrawing triuromethyl and CHCl protons (J ¼ 5.6 Hz),11c which revealed that the
group, a moderate yield of 53% was obtained (3h). Aliphatic substituents at the aziridine ring adapted a cis conguration.
imines derived from butyraldehyde or isobutyraldehyde Single-crystal X-ray analysis of 5c further conrmed the absolute
decomposed rapidly under the strong basic conditions probably conguration of compound 5 (see Fig. 1). Interestingly, X-ray
due to enolization. As a result, only a very small amount of crystallography study also revealed that, in the crystal, mole-
product was produced (less than 5%). The conguration of the cules are linked through halogen bonding between the chloro
addition products 3a–3k were assigned to be (Rs,S), based on a
similar nonchelation-controlled transition-state mode compa-
rable with that for the nucleophilic trichloromethylation of
N-tert-butylsulnyl imines.15
Table 3 Scope of the intramolecular substitution reaction to afford
a-chloro cis-aziridines 5
It was envisioned that the dichloromethylated sulnamide
anion species (the nitrogen-anion species of 3) generated from
the rst nucleophilic addition step could further attack the
electrophilic chloro-attached carbon atom, and a cascade
addition-intramolecular substitution reaction of imines with
TMSCCl2H may proceed. Thus it would provide a streamlined
synthesis of a-chloroaziridines.8 It is noteworthy that an elegant
diastereoselective synthesis of a-iodoaziridines was recently
reported by Bull and coworkers, starting from diiodomethane
and N-tert-butylsulnyl imines via a similar strategy.25
Products 5
Using imine 2a as the model compound, the possible
cascade reaction between compound 2a and 4 was examined at
different reaction conditions. Aer screening several reaction
parameters (including base, solvent, and temperature), we
found that, under otherwise identical reaction conditions for
a
b
Isolated yield. Where >94 : 6 stated, only the cis-diastereoisomer
could be observed by 1H NMR on the crude product. dr determined
c
by 1H NMR on the crude product.
Scheme 1 Synthesis of the a-chloroaziridine 5a.
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Scheme 2 Radical mono-dechlorination of a-(trichloromethyl)amine
6a.
Now, we attempted to synthesize a-(dichloromethyl)amines
from a-(trichloromethyl)amines via mono-dechlorination.
Using compound 6a as a model substrate, several reductants
were examined. While NaBH4, LiAlH4 and Zn all resulted in the
decomposition of the starting material,28 Bu3SnH proved
successful in promoting the reaction.27f–h This reaction
proceeded in excellent selectivity under optimized reaction
conditions, consisting of only 1.05 equivalent of Bu3SnH and
catalytic amount of AIBN in toluene (Scheme 2). The corre-
sponding a-(dichloromethyl)amine 3a and a-(chloromethyl)
amine 7a were obtained in 91% and 4% yields, respectively,
indicating that over-reduction was suppressed under the
reported reaction conditions.
Using the optimal reaction conditions, the mono-dechlori-
nation of several a-(trichloromethyl)amines were further
investigated. As shown in Table 4, this reaction was applied to
both aromatic and aliphatic substrates, and the desired prod-
ucts were obtained in very good to excellent yields for all cases.
Remarkably, the chloro functional groups on the phenyl ring
Fig. 1 Determination of the configuration of the a-chloro cis-azir-
idines 5.
substituent and the sulnamide oxygen,26 forming chains
running along the b-axis direction (see the ESI†).
The high cis-selectivity for compound 5 can be explained by a
transition-state model, in which the Ar and N-sulnyl groups
are assumed to align in an anti conformation so as to avoid the
eclipsing interactions. The N-group and chloride are placed in
an antiperiplanar fashion and the other chloride is positioned
away from the N-sulnyl group. Thus, the intramolecular
cyclization would lead to the observed stereoselectivity as
shown in Fig. 2. A similar transition state was also reported for
the asymmetric synthesis of cis-iodoaziridines from diiodo-
methane and N-tosylimines.25
Our direct dichloromethylation protocol is the rst case of
efficient and stereoselective synthesis of a-(dichloromethyl)-
amines (Table 2), although this strategy has its own limitations.
It could not be applied to enolizable imines, so the corre-
sponding a-(dichloromethyl)amines and the subsequent azir- Table 4 Synthesis of 3 from a-(trichloromethyl)amines 6 via mono-
dechlorination
idine products could not be obtained. Therefore, an alternative
method to prepare structurally diverse a-(dichloromethyl)-
amines needs to be developed.
A lot of mono-dechlorination methods using trichloromethyl
derivatives as the starting materials have been investigated.27,28
For such reactions, the dechlorination activity is strongly
inuenced by the electronic and steric environment of the
substituents attached to the trichloromethyl group, and the
ability to suppress over-reduction is of critical importance in
achieving efficient chemoselective transformations.27 Recently,
catalyst Pt/C was used to enable precise reduction control of
trichloromethyl ketones to dichloromethyl derivatives, and the
amount of over-reduction product monochloromethyl ketone
could be minimized to around 5%.27a
Products 3
Fig. 2 The transition-state model for the formation of cis-chlor-
oaziridines 5.
a
Isolated yield.
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Scheme 4 A single-step synthesis of a-(chloromethyl)amine 7a from
compound 3a.
Scheme 3 Synthesis of aziridines 5 from the a-(dichloromethyl)-
amines 3.
were intact (3l), opening possibilities for further functionaliza-
tion. Thus, an alternative methodology was successfully devel-
oped for the synthesis of a-(dichloromethyl)amines.
The obtained a-(dichloromethyl)amines are useful precur-
sors for the synthesis of 2-chloro cis-aziridines, especially alkyl
group-substituted aziridines that were not accessible from
enolizable imines. Treatment of compounds 3m and 3n with
lithium hexamethyldisilazane (LiHMDS) in DMF at a low reac-
tion temperature gave the corresponding a-chloroaziridines 5g
and 5h in good yields and with very high diastereoselectivities
(>93 : 7), respectively (Scheme 3).
Encouraged by the success of the mono-dechlorination, we
further applied this method to synthesize a-(chloromethyl)-
amines, highly valuable synthetic intermediates for the prepa-
ration of a great number of bioactive molecules.29 Currently, the
most commonly used method involves the chlorination of
vicinal amino alcohols.30 However, the starting materials are of
limited access and the reaction conditions for chlorination is
very sensitive and restrictive. Another route to synthesize
Fig. 3 Stability of the chlorinated methyl radicals.
a-(chloromethyl)amines employs an asymmetric reduction of
N-protected a-chloroimines. Nevertheless, the type of substit-
uent at the aziridine ring has a signicant effect on the reaction
outcome; in some cases the starting material can be trans-
formed into the corresponding a-(chloromethyl)amines in a
selective way,31 whereas in many other cases reduction of
a-chloroimines affords mixtures of the a-(chloromethyl)amines,
aziridines, and dehalogenated amines.19,32 Development of
more general methods for the highly efficient synthesis of
structurally diverse a-(chloromethyl)amines is still highly
desirable.33
Using the same reaction conditions as shown in Table 4,
several a-(dichloromethyl)amines were smoothly converted into
the corresponding a-(chloromethyl)amines 7 in very good yields
(Table 5). The chloro substituent on the phenyl ring reaction is
well tolerated (7d) and the reaction is also applicable to both
aliphatic and aromatic a-(dichloromethyl)amines.
Table 5 Synthesis of a-(chloromethyl)amines 7 from the a-(dichlor-
omethyl)amines 3
To further explore the feasibility of a single-step synthesis of
a-(chloromethyl)amines
from
a-(trichloromethyl)amines,
compound 3a was investigated under the above reaction condi-
tions except that 2.1 equivalent of Bu3SnH was used. This reac-
tion proceeded smoothly, giving compound 7a in 77% yield
(Scheme 4). With the aforementioned experimental results for
the synthesis of a-(dichloromethyl)- and a-(chloromethyl)
amines, the order of the reactivity of the radical intermediates is
listed as follows (Fig. 3):
Products 7
Conclusion
Two highly efficient protocols for stereoselective synthesis of
structurally diverse a-(dichloromethyl)amines are presented: one
involves nucleophilic dichloromethylation of aromatic N-tert-
butylsulnyl aldimines with (dichloromethyl)-trimethylsilane
(TMSCCl2H), and the other employs a radical mono-dechlori-
nation strategy using easily accessible a-(trichloromethyl)amines
as the starting materials. Subsequent radical mono-dechlorina-
tion of the a-(dichloromethyl)amines gives the corresponding
a-(chloromethyl)amines in good to excellent yields. Additionally,
a
Isolated yield.
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the reaction outcome between N-tert-butylsulnyl aldimines and
TMSCCl2H is controlled by the reaction temperature: N-tert-
butylsulnyl aldimines undergoes the nucleophilic dichlor-
(Rs)-N-((S)-2,2-Dichloro-1-m-tolylethyl)-2-methylpropane-2-sul-
namide (3c). Light yellow solid (131 mg, 85%); mp 99.1–
100.4 ꢁC; [a]D25 ꢀ 31.9 (c ¼ 0.51 in CHCl3); IR (lm): vmax ¼ 3334,
2962, 1460, 1056, 889, 815, 734 cmꢀ1; 1H NMR (CDCl3) d 7.29 (d,
J ¼ 7.9 Hz, 1H), 7.19 (dd, J ¼ 12.4, 6.4 Hz, 3H), 6.01 (d, J ¼ 4.0 Hz,
1H), 4.82 (dd, J ¼ 6.7, 4.0 Hz, 1H), 4.05 (d, J ¼ 6.8 Hz, 1H), 2.38
(s, 3H), 1.29 (s, 9H); 13C NMR (CDCl3) d 138.4, 136.5, 129.7,
128.63, 128.56, 124.9, 75.7, 66.2, 57.2, 22.7, 21.5; MS (ESI) m/z:
308.1 [M + H]+; HRMS (ESI) m/z: [M + Na]+ calcd for
ꢁ
omethylation at a low reaction temperature of ꢀ70 C, whereas
allowing the reaction mixture to warm up to room temperature
affords 2-chloro cis-aziridines. Alternatively, 2-chloro cis-azir-
idines can be prepared from a-(dichloromethyl)amines based on
a classical intramolecular substitution reaction.
C
13H19Cl2NOSNa 330.0457; found 330.0465.
(Rs)-N-((S)-2,2-Dichloro-1-(4-methoxyphenyl)ethyl)-2-methyl-
Experimental
General methods
propane-2-sulnamide (3d). Light yellow solid (156 mg, 96%);
mp 80.8–81.7 ꢁC; [a]D25 ꢀ 20.6 (c ¼ 0.60 in CHCl3); IR (lm): vmax
All commercial reagents and solvents were used directly as
purchased without further purication. THF was distilled from
sodium/benzophenone. N,N-Dimethylformamide was distilled
from CaH2. Flash chromatography was performed on silica gel
with petroleum ether (PE)–EtOAc as the eluent. Melting points
were uncorrected. Optical rotations were measured with a
sodium lamp. 1H NMR spectra were recorded at 400 MHz.
Decoupled13C NMR spectrawere recordedat 100MHz. Chemical
shis (d) are reported in parts per million (ppm) and referenced
to the residual solvent peak, and J values are given in hertz (Hz).
¼ 3401, 3112, 2923, 1513, 1246, 1026, 786 cmꢀ1
;
1H NMR
(CDCl3) d 7.34 (d, J ¼ 8.7 Hz, 2H), 6.92 (d, J ¼ 8.8 Hz, 2H), 6.01 (d,
J ¼ 3.9 Hz, 1H), 4.82 (dd, J ¼ 6.5, 3.9 Hz, 1H), 4.01 (d, J ¼ 6.5 Hz,
1H), 3.81 (s, 3H), 1.28 (s, 9H); 13C NMR (CDCl3) d 156.0, 129.3,
128.4, 114.0, 75.7, 65.4, 57.1, 55.3, 22.6; MS (ESI) m/z: 324.1 [M +
H]+; HRMS (ESI) m/z: [M + Na]+ calcd for C13H19Cl2NO2SNa
346.0406; found 346.0415.
(Rs)-N-((S)-2,2-Dichloro-1-phenylethyl)-2-methylpropane-2-sul-
namide (3e). Light yellow solid (127 mg, 86%); mp 62.1–
62.6 ꢁC; [a]D25 ꢀ 27.3 (c ¼ 0.55 in CHCl3); IR (lm): vmax ¼ 3479,
1
3991, 3119, 1455, 1028, 921, 739, 699 cmꢀ1; H NMR (CDCl3) d
General procedure for the synthesis of a-(dichloromethyl)-
amine 3a from TMSCHCl2 4 and (R)-N-tert-butanesulnyl
imine 2a
t-BuOK (123 mg, 1.1 mmol) in THF (2 mL) was added dropwise (ESI) m/z: 294.0 [M + H]+; HRMS (ESI) m/z: [M + Na]+ calcd for
7.40 (dt, J ¼ 7.4, 4.6 Hz, 5H), 6.04 (d, J ¼ 3.8 Hz, 1H), 4.87 (dd, J ¼
6.9, 3.8 Hz, 1H), 4.09 (d, J ¼ 6.7 Hz, 1H), 1.29 (s, 9H); 13C NMR
(CDCl3) d 136.4, 129.0, 128.7, 128.0, 75.5, 66.0, 57.2, 22.7; MS
to a mixture of imine 2a (112 mg, 0.5 mmol) and TMSCHCl2 4
(173 mg, 1.1 mmol) in THF (2.0 mL) at ꢀ70 ꢁC. The reaction
C
12H17Cl2NOSNa 316.0300; found 316.0306.
(Rs)-N-((S)-2,2-Dichloro-1-(4-chlorophenyl)ethyl)-2-methyl-
mixture was stirred over 0.5 h. Then 1 N HCl (10 mL) was added propane-2-sulnamide (3f). Light yellow solid (108 mg, 66%);
at ꢀ70 ꢁC, and the quenched reaction mixture was extracted mp 84.8–85.4 ꢁC; [a]2D5 ꢀ 13.4 (c ¼ 0.60 in CHCl3); IR (lm): vmax
three times with ethyl acetate (20 ML ꢂ 3). The combined ¼ 3389, 3120, 1490, 1092, 1015, 919, 767 cmꢀ1; 1H NMR (CDCl3)
organic layer was dried over anhydrous Na2SO4. Evaporation of d 7.37 (s, 4H), 6.01 (d, J ¼ 3.8 Hz, 1H), 4.85 (dd, J ¼ 7.1, 3.8 Hz,
the solvent afforded the crude product, which was subjected to 1H), 4.06 (d, J ¼ 7.0 Hz, 1H), 1.28 (s, 9H); 13C NMR (CDCl3) d
ash chromatography to give pure a-(dichloromethyl)amine 3a. 135.0, 134.7, 129.5, 128.8, 75.1, 65.1, 57.3, 22.6; MS (ESI) m/z:
(Rs)-N-((S)-2,2-Dichloro-1-p-tolylethyl)-2-methylpropane-2-sul- 328.0 [M + H]+; HRMS (ESI) m/z: [M + Na]+ calcd for
ꢁ
namide (3a). Colorless solid (139 mg, 90%); mp 72.1–73.8 C;
[a]2D5 ꢀ20.5 (c ¼ 0.51 in CHCl3); IR (lm): vmax ¼ 3388, 3103, 1456,
C
12H16Cl3NOSNa 349.9910; found 349.9923.
(Rs)-N-((S)-2,2-Dichloro-1-(2-chlorophenyl)ethyl)-2-methyl-
1028, 925, 741 cmꢀ1; 1H NMR (CDCl3) d 7.30 (d, J ¼ 8.1 Hz, 2H), propane-2-sulnamide (3g). Light yellow solid (115 mg, 70%);
7.20 (d, J ¼ 8.0 Hz, 2H), 6.02 (d, J ¼ 3.9 Hz, 1H), 4.83 (dd, J ¼ 6.7, mp 88.5–90.2 ꢁC; [a]D25 ꢀ 35.4 (c ¼ 0.52 in CHCl3); IR (lm): vmax
3.9 Hz, 1H), 4.06 (d, J ¼ 6.7 Hz, 1H), 2.35 (s, 3H), 1.28 (s, 9H); 13
C
¼ 3152, 2962, 1470, 1042, 905, 747 cmꢀ1; 1H NMR (CDCl3) d 7.48
NMR (CDCl3) d 138.9, 133.4, 129.4, 127.9, 75.6, 65.8, 57.1, 22.7, (dd, J ¼ 7.4, 2.0 Hz, 1H), 7.40 (dd, J ¼ 7.5, 1.7 Hz, 1H), 7.36–7.29
21.1; MS (ESI) m/z: 307.9 [M + H]+; HRMS (ESI) m/z: [M + Na]+ (m, 2H), 6.11 (d, J ¼ 3.7 Hz, 1H), 5.28 (dd, J ¼ 9.4, 3.7 Hz, 1H),
calcd for C13H19Cl2NOSNa 330.0457; found 330.0471.
4.41 (d, J ¼ 9.3 Hz, 1H), 1.30 (s, 9H); 13C NMR (CDCl3) d 134.7,
(Rs)-N-((S)-2,2-Dichloro-1-(4-isopropylphenyl)ethyl)-2-methyl- 132.7, 130.1, 129.9, 129.6, 127.2, 74.7, 64.1, 57.6, 22.6; MS (ESI)
propane-2-sulnamide (3b). Light yellow solid (158 mg, 94%); m/z: 328.0 [M + H]+; HRMS (ESI) m/z: [M + H]+ calcd for
mp 80.2–81.6 ꢁC; [a]D25 ꢀ 22.2 (c ¼ 0.56 in CHCl3); IR (lm): vmax
C
12H17Cl3NOS 328.0091; found 328.0098.
(Rs)-N-((S)-2,2-Dichloro-1-(3-(triuoromethyl)phenyl)ethyl)-
¼ 3434, 2959, 1464, 1389, 1046, 851, 757 cmꢀ1; 1H NMR (CDCl3)
d 7.33 (d, J ¼ 8.2 Hz, 2H), 7.24 (d, J ¼ 8.2 Hz, 2H), 6.01 (d, J ¼ 3.8 2-methylpropane-2-sulnamide (3h). White solid (96 mg, 53%);
Hz, 1H), 4.84 (dd, J ¼ 6.8, 3.8 Hz, 1H), 4.03 (d, J ¼ 6.7 Hz, 1H), mp 65.3–67.4 ꢁC; [a]D25 ꢀ 17.2 (c ¼ 0.63 in CHCl3); IR (lm): vmax
¼
2.92 (dd, J ¼ 13.8, 6.9 Hz, 1H), 1.29 (s, 9H), 1.25 (s, 3H), 1.24 (s, 3274, 2922, 1456, 1056, 883, 726, 697 cmꢀ1; H NMR (CDCl3) d
3H); 13C NMR (CDCl3) d 149.7, 133.8, 127.8, 126.8, 75.7, 66.0, 7.66 (d, J ¼ 9.1 Hz, 3H), 7.55 (t, J ¼ 7.6 Hz, 1H), 6.05 (d, J ¼ 3.7 Hz,
57.1, 33.8, 23.8, 22.7; MS (ESI) m/z: 335.9 [M + H]+; HRMS (ESI) 1H), 4.94 (dd, J ¼ 7.2, 3.7 Hz, 1H), 4.13 (d, J ¼ 7.1 Hz, 1H), 1.29 (s,
m/z: [M + Na]+ calcd for C15H23Cl2NOSNa 358.0770; found 9H); 13C NMR (CDCl3) d 137.2, 131.7, 129.2, 125.91, 125.87,
1
358.0775.
125.06, 125.02, 74.7, 64.1, 57.6, 22.6; MS (ESI) m/z: 362.0 [M + H]+;
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HRMS (ESI) m/z: [M + Na]+ calcd for C13H16Cl2F3NOSNa IR (lm): vmax ¼ 2923, 1477, 1293, 1082, 948, 810, 698 cmꢀ1; 1H
384.0174; found 384.0182.
NMR (CDCl3) d 7.29–7.15 (m, 4H), 4.55 (d, J ¼ 5.6 Hz, 1H), 3.90
(Rs)-N-((S)-2,2-Dichloro-1-(naphthalen-1-yl)ethyl)-2-methyl- (d, J ¼ 5.6 Hz, 1H), 2.37 (s, 3H), 1.20 (s, 9H); 13C NMR (CDCl3) d
propane-2-sulnamide (3i). Light yellow solid (139 mg, 81%); 137.9, 131.4, 129.5, 129.4, 128.1, 125.9, 57.6, 53.3, 37.6, 22.6,
mp 67.3–68.4 ꢁC; [a]D25 ꢀ 73.3 (c ¼ 0.60 in CHCl3); IR (lm): vmax 21.5; MS (ESI) m/z: 294.1 [M + Na]+; HRMS (ESI) m/z: [M + H]+
¼ 3306, 2953, 2924, 1455, 1064, 858, 773 cmꢀ1; 1H NMR (CDCl3) calcd for C13H19ClNOS 272.0870; found 272.0880.
d 7.98 (d, J ¼ 8.5 Hz, 1H), 7.90 (dd, J ¼ 13.8, 8.2 Hz, 2H), 7.66–
(Rs,2R,3S)-1-(tert-Butylsulnyl)-2-chloro-3-phenylaziridine (5c).
25
ꢁ
7.59 (m, 2H), 7.53 (ddd, J ¼ 9.5, 5.3, 2.2 Hz, 2H), 6.22 (d, J ¼ 4.2 Light yellow solid (85 mg, 66%); mp 71.1–71.8 C; [a]D + 54.4
Hz, 1H), 5.67 (dd, J ¼ 7.4, 4.2 Hz, 1H), 4.46 (d, J ¼ 7.3 Hz, 1H), (c ¼ 0.51 in CHCl3); IR (lm): vmax ¼ 2917, 1450, 1285, 1078, 918,
1.29 (s, 9H); 13C NMR (CDCl3) d 133.9, 132.3, 130.5, 129.5, 129.4, 699 cmꢀ1; 1H NMR (CDCl3) d 7.39 (ddd, J ¼ 7.3, 4.2, 1.5 Hz, 5H),
127.1, 125.9, 125.8, 125.1, 121.9, 75.7, 62.6, 57.3, 22.7; MS (ESI) 4.57 (d, J ¼ 5.6 Hz, 1H), 3.93 (d, J ¼ 5.6 Hz, 1H), 1.20 (s, 9H); 13
C
m/z: 343.9 [M + H]+; HRMS (ESI) m/z: [M + Na]+ calcd for NMR (CDCl3) d 131.4, 128.8, 128.5, 128.2, 57.6, 53.3, 37.5, 22.5;
C
16H19Cl2NOSNa 366.0457; found 366.0466.
(Rs)-N-((S,E)-1,1-Dichloro-4-phenylbut-3-en-2-yl)-2-methyl- for C12H16ClNOSNa 280.0533; found 280.0535.
MS (ESI) m/z: 280.1 [M + Na]+; HRMS (ESI) m/z: [M + Na]+ calcd
propane-2-sulnamide (3j). Light yellow solid (128 mg, 80%);
mp 112.4–114.2 C; [a]D ꢀ16.7 (c ¼ 0.55 in CHCl3); IR (lm): aziridine (5d). White solid (109 mg, 71%); mp 121.2–121.9 C;
(Rs,2R,3S)-1-(tert-Butylsulnyl)-2-chloro-3-(naphthalen-1-yl)-
25
ꢁ
ꢁ
vmax ¼ 3092, 2986, 1449, 1058, 969, 780, 751 cmꢀ1
;
1H NMR [a]D25 + 45.3 (c ¼ 0.60 in CHCl3); IR (lm): vmax ¼ 2974, 1463,
(CDCl3) d 7.43 (d, J ¼ 7.5 Hz, 2H), 7.36–7.27 (m, 3H), 6.85 (d, J ¼ 1286, 1059, 927, 770, 722 cmꢀ1; H NMR (CDCl3) d 8.16 (d, J ¼
1
15.9 Hz, 1H), 6.33 (dd, J ¼ 15.9, 6.6 Hz, 1H), 5.87 (d, J ¼ 3.0 Hz, 8.2 Hz, 1H), 7.89 (dd, J ¼ 18.6, 7.9 Hz, 2H), 7.56 (ddd, J ¼ 21.1,
1H), 4.47–4.43 (m, 1H), 3.76 (d, J ¼ 7.7 Hz, 1H), 1.29 (s, 9H); 13
C
12.0, 7.2 Hz, 4H), 4.79 (d, J ¼ 5.5 Hz, 1H), 4.62 (d, J ¼ 5.5 Hz, 1H),
NMR (CDCl3) d 136.1, 135.7, 128.6, 128.5, 126.9, 123.6, 75.6, 1.29 (s, 9H); 13C NMR (CDCl3) d 133.4, 132.4, 128.9, 127.3, 126.7,
64.9, 57.1, 22.6; MS (ESI) m/z: 319.9 [M + H]+; HRMS (ESI) m/z: 126.2, 126.1, 124.9, 122.7, 57.7, 53.5, 35.7, 22.5; MS (ESI) m/z:
[M + Na]+ calcd for C14H19Cl2NOSNa 342.0457; found 342.0458. 307.9 [M + H]+; HRMS (ESI) m/z: [M + H]+ calcd for C16H19ClNOS
(Rs)-N-((S)-2,2-Dichloro-1-(furan-2-yl)ethyl)-2-methylpropane- 308.0870; found 308.0878.
2-sulnamide (3k). Oil (102 mg, 72%); [a]2D5 + 2.8 (c ¼ 0.52 in
(Rs,2R,3S)-1-(tert-Butylsulnyl)-2-chloro-3-(2-chlorophenyl)-
CHCl3); IR (lm): vmax ¼ 3400, 2988, 2929, 1624, 1171, 1030, aziridine (5e). Light yellow oil (89 mg, 61%); [a]2D5 ꢀ 36.9 (c ¼
690 cmꢀ1; 1H NMR (CDCl3) d 7.42 (d, J ¼ 1.1 Hz, 1H), 6.55 (d, J ¼ 0.53 in CHCl3); 1H NMR (CDCl3) d 7.44–7.41 (m, 2H), 7.33–7.29
3.3 Hz, 1H), 6.39 (dd, J ¼ 3.3, 1.8 Hz, 1H), 6.13 (d, J ¼ 3.4 Hz, (m, 2H), 4.66 (d, J ¼ 5.6 Hz, 1H), 4.32 (d, J ¼ 5.6 Hz, 1H), 1.24 (s,
1H), 4.88 (dd, J ¼ 9.0, 3.4 Hz, 1H), 4.02 (d, J ¼ 8.9 Hz, 1H), 1.31 9H); 13C NMR (CDCl3) d 135.2, 129.8, 129.7, 129.6, 129.5, 126.4,
(s, 9H); 13C NMR (CDCl3) d 149.8, 143.1, 110.8, 109.9, 73.9, 62.1, 57.7, 52.9, 35.9, 22.5; MS (ESI) m/z: 314.0 [M + Na]+; HRMS (ESI)
57.5, 22.7; MS (ESI) m/z: 306 [M + Na]+; HRMS (ESI) m/z: [M + m/z: [M + Na]+ calcd for C12H15Cl2NOSNa 314.0144; found
Na]+ calcd for C10H15Cl2NO2SNa 306.0093; found 306.0091.
314.0143.
(Rs,2R,3S)-1-(tert-Butylsulnyl)-2-chloro-3-(4-chlorophenyl)-
aziridine (5f). Light yellow oil (75 mg, 51%); [a]2D5 + 88.1 (c ¼ 0.56
in CHCl3); IR (lm): vmax ¼ 2925, 1491, 1289, 1085, 861, 743
General procedure for the synthesis of 2-chloro cis-aziridine
5a from TMSCHCl2 4 and (R)-N-tert-butanesulnyl imine 2a
1
cmꢀ1; H NMR (CDCl3) d 7.36 (s, 4H), 4.56 (d, J ¼ 5.6 Hz, 1H),
t-BuOK (123 mg, 1.1 mmol) in THF (2 mL) was added to a 3.89 (d, J ¼ 5.6 Hz, 1H), 1.19 (s, 9H); 13C NMR (CDCl3) d 129.8,
reaction mixture of imine 2a (112 mg, 0.5 mmol) and TMSCHCl2 129.5, 129.4, 126.3, 57.7, 52.9, 36.9, 22.5; MS (ESI) m/z: 314.0 [M
4 (173 mg, 1.1 mmol) in THF (2.0 mL) at ꢀ70 C. The reaction + Na]+; HRMS (ESI) m/z: [M + Na]+ calcd for C12H15Cl2NOSNa
ꢁ
mixture was stirred for 0.5 h at this temperature and then was 314.0144; found 314.0157.
warmed up to room temperature over 1.0 h. The reaction was
quenched by 1.0 N HCl (10 mL) and the quenched reaction
General procedure for the synthesis of a-(dichloromethyl)-
mixture was extracted three times with ethyl acetate (20 ML ꢂ
amine 3l from a-(trichloromethyl)amine
3). The combined organic layer was dried over anhydrous
Na2SO4. Evaporation of the solvent afforded the crude product, Bu3SnH (153 mg, 0.525 mmol) and catalytic AIBN (5 mg) in
which was subjected to ash chromatography to give pure toluene (1 mL) was added slowly to a solution of a-(tri-
2-chloro cis-aziridine 5a.
chloromethyl)amine 6l (199 mg, 0.5 mmol) in toluene (2 mL) at
(Rs,2R,3S)-1-(tert-Butylsulnyl)-2-chloro-3-p-tolylaziridine (5a). 90 ꢁC. The reaction mixture was stirred for 3 h and then cooled
Light yellow oil (114 mg, 84%); [a]2D5 + 69.6 (c ¼ 0.59 in CHCl3); to room temperature. Half saturated KF–H2O (10 mL) was
IR (lm): vmax ¼ 2924, 1459, 1290, 1086, 927, 707 cmꢀ1; 1H NMR added to the reaction mixture. Aer ltration of the precipitate,
(CDCl3) d 7.31 (d, J ¼ 8.1 Hz, 2H), 7.20 (d, J ¼ 7.9 Hz, 2H), 4.56 (d, the reaction mixture was extracted three times with ethyl acetate
J ¼ 5.6 Hz, 1H), 3.90 (d, J ¼ 5.5 Hz, 1H), 2.37 (s, 3H), 1.20 (s, 9H); (20 ML ꢂ 3). The combined organic layers were dried over
13C NMR (CDCl3) d 138.4, 128.9, 128.7, 128.5, 57.6, 53.4, 37.5, anhydrous Na2SO4. Evaporation of the solvent afforded the
22.6, 21.2; MS (ESI) m/z: 294.1 [M + Na]+; HRMS (ESI) m/z: [M + crude product, which was subjected to ash chromatography to
H]+ calcd for C13H19ClNOS 272.0870; found 272.0875.
give pure a-(dichloromethyl)amine 3l.
(Rs,2R,3S)-1-(tert-Butylsulnyl)-2-chloro-3-m-tolylaziridine (5b).
(Rs)-N-((S)-2,2-Dichloro-1-(2,4-dichlorophenyl)ethyl)-2-meth-
Light yellow oil (126 mg, 93%); [a]2D5 + 155.9 (c ¼ 0.95 in CHCl3); ylpropane-2-sulnamide (3l). White solid (176 mg, 97%); mp
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112.6–113.6 ꢁC; [a]D25 ꢀ14.2 (c ¼ 0.57 in CHCl3); IR (lm): vmax
¼
[M ꢀ 56]+; HRMS (EI) m/z: [M ꢀ 56]+ calcd for C5H10ClNOS
1
3121, 2868, 1478, 1038, 903, 797 cmꢀ1; H NMR (CDCl3) d 7.43 167.0172; found 167.0170.
(dd, J ¼ 5.2, 3.0 Hz, 2H), 7.33 (dd, J ¼ 8.5, 1.9 Hz, 1H), 6.07 (d, J ¼
3.6 Hz, 1H), 5.24 (dd, J ¼ 9.4, 3.6 Hz, 1H), 4.37 (d, J ¼ 9.4 Hz,
1H), 1.30 (s, 9H); 13C NMR (CDCl3) d 135.5, 133.4, 133.3, 130.7,
129.7, 127.5, 74.3, 63.5, 57.6, 22.6; MS (ESI) m/z: 361.8 [M + H]+;
General procedure for the synthesis of a-(chloromethyl)amine
7a from a-(dichloromethyl)amine 3a
HRMS (ESI) m/z: [M + H]+ calcd for C12H16Cl4NOS 361.9701; Bu3SnH (153 mg, 0.525 mmol) and catalytic AIBN (5 mg) in
found 361.9712.
toluene (1 mL) was added to a solution of a-(dichloromethyl)
ꢁ
(Rs)-N-((S)-1,1-Dichloro-3-methylbutan-2-yl)-2-methylpropane- amine 3a (112 mg, 0.5 mmol) in toluene (2 mL) at 90 C. The
2-sulnamide (3m). White solid (113 mg, 87%); mp 54.8–56.5 reaction mixture was stirred over 3 h and then cooled to room
ꢁC; [a]D25 ꢀ 23.1 (c ¼ 0.52 in CHCl3); IR (lm): vmax ¼ 3466, 3111, temperature. Half saturated KF–H2O (10 mL) was added to the
2965, 1474, 1015, 922, 749 cmꢀ1; 1H NMR (CDCl3) d 5.91 (d, J ¼ reaction mixture. Aer ltration of the precipitate, the reaction
2.3 Hz, 1H), 3.42 (d, J ¼ 8.1 Hz, 1H), 3.33 (td, J ¼ 7.9, 2.3 Hz, 1H), mixture was extracted three times with ethyl acetate (20 ML ꢂ
1.92 (dd, J ¼ 14.0, 6.9 Hz, 1H), 1.31 (s, 9H), 1.13 (d, J ¼ 6.8 Hz, 3). The combined organic layers were dried over anhydrous
3H), 1.07 (d, J ¼ 6.7 Hz, 3H); 13C NMR (CDCl3) d 75.8, 69.7, 57.4, Na2SO4. Evaporation of the solvent afforded the crude product,
31.8, 23.1, 19.9, 19.4; MS (ESI) m/z: 260.0 [M + H]+; HRMS (ESI) which was subjected to ash chromatography to give pure
m/z: [M + Na]+ calcd for C9H19Cl2NOSNa 282.0457; found a-(chloromethyl)amine 7a.
282.0466.
(Rs)-N-((S)-2-Chloro-1-p-tolylethyl)-2-methylpropane-2-sulna-
(Rs)-N-((S)-1,1-Dichloropentan-2-yl)-2-methylpropane-2-sul- mide (7a). Oil (125 mg, 91%); [a]2D5 ꢀ 21.4 (c ¼ 0.50 in CHCl3); IR
namide (3n). White solid (105 mg, 81%); mp 121.7–122.3 ꢁC; (lm): vmax ¼ 3404, 3118, 2922, 1456, 1027, 940, 734 cmꢀ1; H
1
[a]2D5 ꢀ 54.8 (c ¼ 1.00 in CHCl3); IR (lm): vmax ¼ 3138, 2960, NMR (CDCl3) d 7.28 (s, 1H), 7.26 (s, 1H), 7.19 (d, J ¼ 7.9 Hz, 2H),
2864, 1361, 1053, 899, 772 cmꢀ1; 1H NMR (CDCl3) d 5.77 (d, J ¼ 4.64 (dd, J ¼ 10.5, 5.7 Hz, 1H), 3.83 (dd, J ¼ 5.9, 2.3 Hz, 2H), 3.76
2.7 Hz, 1H), 3.63 (tdd, J ¼ 7.7, 4.7, 2.7 Hz, 1H), 3.38 (d, J ¼ 7.6 (d, J ¼ 4.1 Hz, 1H), 2.35 (s, 3H), 1.24 (s, 9H); 13C NMR (CDCl3) d
Hz, 1H), 1.84–1.76 (m, 1H), 1.64 (dddd, J ¼ 10.2, 7.4, 4.9, 3.4 Hz, 138.4, 136.0, 129.5, 127.2, 59.4, 56.4, 48.4, 22.6, 21.1; MS (ESI) m/
2H), 1.49–1.39 (m, 1H), 1.27 (s, 9H), 0.98 (t, J ¼ 7.2 Hz, 3H); 13
C
z: 274.0 [M + H]+; HRMS (ESI) m/z: [M + H]+ calcd for
13H21ClNOS 274.1027; found 274.1026.
NMR (CDCl3) d 76.5, 63.8, 56.9, 34.4, 22.8, 18.9, 13.7; MS (EI) m/
z: 259 [M]+; HRMS (EI) m/z: [M]+ calcd for C9H19Cl2NOS
259.0564; found 259.0563.
C
(Rs)-N-((S)-2-Chloro-1-phenylethyl)-2-methylpropane-2-sulna-
mide (7b). Oil (113 mg, 87%); [a]2D5 ꢀ34.0 (c ¼ 0.53 in CHCl3); IR
1
(lm): vmax ¼ 3229, 1455, 1051, 924, 720, 697 cmꢀ1; H NMR
(CDCl3) d 7.42–7.34 (m, 5H), 4.71 (dd, J ¼ 10.4, 5.7 Hz, 1H), 3.88
(d, J ¼ 5.9 Hz, 2H), 3.78 (d, J ¼ 4.0 Hz, 1H), 1.27 (s, 9H); 13C NMR
(CDCl3) d 139.0, 128.9, 128.6, 127.3, 59.6, 56.5, 48.4, 22.6; MS
General procedure for the synthesis of 2-chloro cis-aziridine
5g from a-(dichloromethyl)amine 3m
LiHMDS (0.5 mmol, 1.0 mol Lꢀ1 in THF) was added to a solution (ESI) m/z: 260.0 [M + H]+; HRMS (ESI) m/z: [M + H]+ calcd for
of a-(dichloromethyl)amine 3m (147 mg, 0.5 mmol) in DMF (1.5
mL) at ꢀ40 ꢁC. The reaction mixture was stirred at this
C
12H19ClNOS 260.0870; found 260.0878.
(Rs)-N-((S)-2-Chloro-1-(naphthalen-1-yl)ethyl)-2-methylpropane-
temperature over 0.5 h. Then half saturated NH4Cl–H2O (10 mL) 2-sulnamide (7c). Light yellow oil (95 mg, 61%); [a]2D5 ꢀ 80.5 (c
was added at ꢀ40 ꢁC. The quenched reaction mixture was ¼ 0.54 in CHCl3); IR (lm): vmax ¼ 3201, 2923, 1464, 1364, 1050,
extracted three times with ethyl acetate (20 ML ꢂ 3). The 798 cmꢀ1; 1H NMR (CDCl3) d 8.12 (d, J ¼ 8.5 Hz, 1H), 7.88 (dd, J
combined organic layer was dried over anhydrous Na2SO4. ¼ 15.1, 8.1 Hz, 2H), 7.64–7.50 (m, 4H), 5.50 (dd, J ¼ 10.0, 5.5 Hz,
Evaporation of the solvent afforded the crude product, which 1H), 4.12–4.03 (m, 3H), 1.22 (s, 9H); 13C NMR (CDCl3) d 134.0,
was subjected to ash chromatography to give pure 2-chloro cis- 133.8, 130.6, 129.3, 129.2, 126.8, 125.9, 125.1, 125.0, 122.5, 56.4,
aziridine 5g.
55.2, 48.1, 22.6; MS (ESI) m/z: 310.0 [M + H]+; HRMS (ESI) m/z:
(Rs,2R,3S)-1-(tert-Butylsulnyl)-2-chloro-3-isopropylaziridine [M + Na]+ calcd for C16H20ClNOSNa 332.0846; found 332.0855.
(5g). Oil (92 mg, 82%); [a]D25 ꢀ 57.7 (c ¼ 0.55 in CHCl3); IR (lm):
(Rs)-N-((S)-2-Chloro-1-(2,4-dichlorophenyl)ethyl)-2-meth-
vmax ¼ 2923, 2852, 1464, 1081, 964, 683 cmꢀ1; 1H NMR (CDCl3) d ylpropane-2-sulnamide (7d). White solid (136 mg, 83%); mp
25
ꢁ
4.36 (d, J ¼ 5.7 Hz, 1H), 2.55 (dd, J ¼ 8.9, 5.7 Hz, 1H), 1.97–1.88 91.0–91.8 C; [a]D ꢀ 9.2 (c ¼ 0.52 in CHCl3); IR (lm): vmax
¼
(m, 1H), 1.28 (s, 9H), 1.14 (d, J ¼ 6.8 Hz, 3H), 1.08 (d, J ¼ 6.8 Hz, 3431, 3123, 2958, 1589, 1470, 1095, 1014, 936, 782 cmꢀ1
;
1H
3H); 13C NMR (CDCl3) d 57.0, 54.2, 43.1, 27.4, 22.3, 20.4, 19.7; NMR (CDCl3) d 7.45–7.40 (m, 2H), 7.31 (dd, J ¼ 8.4, 2.1 Hz, 1H),
MS (EI) m/z: 223 [M]+; HRMS (EI) m/z: [M]+ calcd for C9H18ClNOS 5.13 (dt, J ¼ 6.8, 4.9 Hz, 1H), 4.11 (d, J ¼ 6.9 Hz, 1H), 3.94 (dd, J ¼
223.0798; found 223.0795.
11.4, 4.7 Hz, 1H), 3.85 (dd, J ¼ 11.4, 5.1 Hz, 1H), 1.23 (s, 9H); 13
C
(Rs,2R,3S)-1-(tert-Butylsulnyl)-2-chloro-3-propylaziridine (5h). NMR (CDCl3) d 130.3, 129.7, 127.3, 113.8, 110.0, 56.9, 55.3, 47.8,
White solid (100 mg, 89%), mp 64.6–66.6 ꢁC; [a]D25 ꢀ 155.8 (c ¼ 22.5; MS (ESI) m/z: 327.9 [M + H]+; HRMS (ESI) m/z: [M + Na]+
0.61, CHCl3); IR (lm): vmax ¼ 2961, 1476, 1291, 1086, 923, 757, calcd for C12H16Cl3NOSNa 349.9910; found 349.9913.
716 cmꢀ1; 1H NMR (CDCl3) d 4.36 (d, J ¼ 5.5 Hz, 1H), 2.82 (ddd,
(Rs)-N-((S)-2-Chloro-1-(furan-2-yl)ethyl)-2-methylpropane-2-
J ¼ 9.3, 5.5, 3.8 Hz, 1H), 1.85–1.77 (m, 1H), 1.71–1.63 (m, 1H), sulnamide (7e). Light yellow oil (94 mg, 75%); [a]2D5 ꢀ 2.3 (c ¼
1.58–1.50 (m, 2H), 1.26 (s, 9H), 1.02 (t, J ¼ 7.3 Hz, 3H); 13C NMR 0.54 in CHCl3); IR (lm): vmax ¼ 3174, 2961, 1677, 1459, 1012,
(CDCl3) d 66.3, 57.0, 52.9, 35.4, 29.1, 19.8, 13.9; MS (EI) m/z: 167 740 cmꢀ1; 1H NMR (CDCl3) d 7.40 (d, J ¼ 1.2 Hz, 1H), 6.45 (d, J ¼
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3.3 Hz, 1H), 6.36 (dd, J ¼ 3.2, 1.8 Hz, 1H), 4.72 (dd, J ¼ 12.5, 5.9
Hz, 1H), 3.88 (dd, J ¼ 5.6, 0.9 Hz, 2H), 3.81 (d, J ¼ 7.0 Hz, 1H),
1.25 (s, 9H); 13C NMR (CDCl3) d 151.5, 142.7, 110.6, 108.7, 56.7,
55.0, 46.8, 22.5; MS (ESI) m/z: 249.9 [M + H]+; HRMS (ESI) m/z:
[M + H]+ calcd for C10H17ClNO2S 250.0663; found 250.0673.
(Rs)-N-((S)-1-Chloro-3-methylbutan-2-yl)-2-methylpropane-2-
sulnamide (7f). White solid (96 mg, 85%); mp 63.9–64.8 ꢁC;
[a]2D5 ꢀ 62.8 (c ¼ 0.51 in CHCl3); IR (lm): vmax ¼ 3195, 2958,
1439, 1049, 892, 735 cmꢀ1; 1H NMR (CDCl3) d 3.66–3.57 (m, 2H),
3.35 (d, J ¼ 6.2 Hz, 1H), 3.26 (ddd, J ¼ 11.4, 6.4, 5.0 Hz, 1H), 2.05
(dq, J ¼ 13.5, 6.8 Hz, 1H), 1.24 (s, 9H), 1.03 (d, J ¼ 6.8 Hz, 6H);
13C NMR (CDCl3) d 62.6, 56.2, 47.4, 30.2, 22.6, 19.1, 18.5; MS
(ESI) m/z: 226.0 [M + H]+; HRMS (ESI) m/z: [M + H]+ calcd for
C9H21ClNOS 226.1027; found 226.1037.
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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 (cs1304007), is gratefully acknowledged. We thank
Yingzhou Li (Nanyang Technological University, Singapore) for
helpful discussions.
Notes and references
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