Highly stereoselective and practical synthesis of α-trichloromethyl amines and 2,2-dichloroaziridines from chloroform

Article abstract of DOI:10.1002/adsc.201100713

A highly stereoselective and practical synthesis of α-trichloromethyl amines by nucleophilic trichloromethylation of N-(tert-butylsulfinyl)imines with chloroform was achieved. The obtained α-trichloromethyl amines can be further transformed into chiral 2,2-dichloroaziridines through an intramolecular nucleophilic substitution methodology. 2,2-Dichloroaziridines can also be produced directly from chloroform and N-(tert-butylsulfinyl)imines through a one-pot procedure. Copyright

Full text of DOI:10.1002/adsc.201100713

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DOI: 10.1002/adsc.201100713
Highly Stereoselective and Practical Synthesis of a-Trichloro-
methyl Amines and 2,2-Dichloroaziridines from Chloroform
Ya Li,a,b,* Tao Zheng,a Wei Wang,a Wei Xu,c Yingchao Ma,a Sishi Zhang,a
Han Wang,a and Zhihua Suna,*
a
College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Road,
Shanghai 201620, Peopleꢀs Republic of China
Fax : (+86)-21-6779-1432; e-mail: ya.li@sues.edu.cn or sungaris@gmail.com
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
b
345 Lingling Road, Shanghai 200032, Peopleꢀs Republic of China
Department of Biology, Texas A&M University, College Station, Texas 77843, USA
c
Received: September 10, 2011; Published online: January 19, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100713.
Abstract: A highly stereoselective and practical
synthesis of a-trichloromethyl amines by nucleo-
philic trichloromethylation of N-(tert-butylsulfinyl)-
approach to incorporate trichloromethyl group(s) into
target compounds based on radical trichloromethyla-
tion strategy.[4a]
A
Compounds that contain the a-trichloromethyl
amine substructure are of great pharmacological in-
terest due to their biological activities.[5] It was be-
lieved that incorporation of an a-trichloromethyl
amine subunit can result in higher metabolism and
improved biological properties of a target drug candi-
date.[5] Besides, a-trichloromethyl amines are highly
valuable synthetic intermediates in organic synthesis,
and have frequently been employed as precursors for
the synthesis of a-amino acids,[6] 2,2-dichloroaziri-
dines,[7] a-mono- and a-dichloromethyl amines,[8] 3,3-
dichloropyrrolidines[9] along with trichloromethylated
heterocyclic compounds.[10] Not surprisingly, the syn-
thesis of a-trichloromethyl amines has drawn many
synthetic endeavors.[11,12] Some of the reagents used
a-trichloromethyl amines can be further trans-
formed into chiral 2,2-dichloroaziridines through an
intramolecular nucleophilic substitution methodolo-
gy. 2,2-Dichloroaziridines can also be produced di-
rectly from chloroform and N-(tert-butylsulfinyl)-
ACHTUNGTRENNUNGimines through a one-pot procedure.
Keywords: chloroform; dichloroaziridines; imines;
a-trichloromethyl amines; trichloromethyl substitu-
ents
Halogenation is a common structural feature of more previously include trichloroacetic acid,[11c,d] carbon
than 4000 naturally occurring compounds.[1] Halogen- tetrachloride,[11e] and trichloromethane (chloro-
ated natural products, especially those with trichloro- form).[11f,g] For example, the earliest reported method
methyl groups, such as the dysamides, barbamide, dys- for the preparation of a-trichloromethyl amines was
idin, sintokamides, and herbacic acid, have recently developed via the addition reaction between tri-
come to the focus of interest of organic and medicinal chloroacetic acid and imines. However, these reagents
chemists as well as biologists.[2] For the majority of suffer from disadvantages such as harsh reaction con-
chlorinated natural products, a biosynthetic pathway ditions, lack of generality, and/or low product yields.
involving an electrophilic or radical chlorination can Reactions of 2,2,2-trichloroethanimine derivatives
be proposed and remains a subject of intense study.[2,3] with nucleophiles can also provide a way to construct
While chlorinated natural products are attracting in- a-trichloromethyl amines.[12] However, the general
creasing attention as targets for chemical synthesis, and efficient asymmetric synthesis of a-trichlorometh-
the availability of synthetic methods for stereoselec- yl amines still remains a challenge. Recently, our re-
tive trichloromethylation is highly limited.[4] Very re- search group has described a highly stereoselective
cently, Zakarian and co-workers developed an elegant method for nuleophilic trichloromethylation of N-
diastereoselective ruthenium-catalyzed chloroalkyla- (tert-butylsulfinyl)imines with trimethyl(trichlorome-
tion of titanium enolates, which represents a viable thyl)silane (TMSCCl3).[13] However, TMSCCl3 is not
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Adv. Synth. Catal. 2012, 354, 308 – 312

Highly Stereoselective and Practical Synthesis of a-Trichloromethyl Amines and 2,2-Dichloroaziridines
commercially available and its storage requires mois- form (only 1.4 equiv.), and THF as solvent at a low re-
ture-free conditions.[14]
action temperature proved to be quite efficient, and
2,2-Dichloroaziridine represents an important com- the desired product a-trichloromethyl amine 3a can
pound from synthetic, mechanistic, and medicinal be obtained in 92% yield with a diastereoselectivity
points of view.[15] The presence of heteroatoms on the of up to 95:5.
ring has been observed to affect the reactivity of the
Eventually, the above conditions were applied to a
aziridines in such a way that in many cases com- wide array of structurally diverse imines as summar-
pounds can be transformed into other aziridine deriv- ized in Table 1. A variety of structurally diverse (R)-
atives, whereas in other cases the ring undergoes (tert-butylsulfinyl)aldimines
reacted
with
the
cleavage affording diverse types of interesting prod- trichloromethyl anion (generated in situ from chloro-
AHCTUNGTRENNUNG
ucts. From a biological point of view, they serve as form 1 and NaHMDS) to give the corresponding a-
precursors for the synthesis of biologically active com- trichloromethyl amines in good to excellent yields
pounds such as indolinones,[15b] analogues of natural and with very high diastereoselectivities. Remarkably,
alkaloids such as isoquinolinones[15c] and isoquino- the reactions were carried out under strong basic con-
ACHTUNGTRENNUNG
lines,[15d] and amidines.[15e] Currently, the most ditions but were still amenable to sulfinylimines bear-
common method for the synthesis of 2,2-dichloroaziri- ing a-hydrogen atom(s) (see entries 13 and 14,
dines comprises dichlorocarbene-imine addition.[16] Table 1), which is in sharp contrast to our reported
An intramolecular SN2 type reaction from a-trichloro- trimethyl
methyl amines has also been used to construct 2,2- chloromethylation reactions of chiral sulfinylimines
dichloro
aziridines.[7a,17] To the best of our knowledge, with TMSCCl3 were very sensitive to base [for exam-
however, owing to the severe limitations of existing ple, tetrabutylammonium triphenyldifluorosilicate
(trichloromethyl)silane chemistry.[13] Tri-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
methods, the asymmetric synthesis of 2,2-dichloroazir- (TBAT), and CsF], and sulfinylimines bearing a-hy-
idines has never been reported. As part of our con- drogen atom(s) usually gave lower yields. It is also
tinuing effort in selective trichloromethylation reac- worthy to point out that, for imine 2e containing a
tions, we wish to disclose the highly stereoselective strong electron-withdrawing nitro group, this reaction
and practical trichloromethylation reaction using could proceed smoothly and gave the expected prod-
chloroform and Ellmanꢀs N-(tert-butanesulfinyl)i- uct 3e in high yield (81%), while trichloromethylation
mines[18] which has enabled us to efficiently synthesize of 2e with TMSCCl3 failed. In view of the generality
enantiomerically pure 2,2-dichloroaziridines through of this reaction, the ready availability of chloroform,
a simple intramolecular nucleophilic substitution pro- as well as the high diastereoselectivities and good to
tocol.
excellent yields, our herein reported highly diastereo-
Chloroform (1) has long been known to be a highly selective trichloromethylation method represents a
efficient dichlorocarbene reagent.[19] In contrast, its great advantage compared to the old ones.[11,12,13] The
use as a nucleophilic trichloromethylation reagent has absolute configuration of sulfinamides 3 (except 3e
received less attention although its addition to car- and 3k) were determined to be (Rs, S) by comparison
bonyl compounds has been well documented.[20] As to of the NMR spectra with our earlier reported data
its use for the preparation of a-trichloromethyl (see the Supporting Information for details),[13] which
amines, only two reports dealing with its addition indicates that the stereochemistry of the nucleophilic
with imines have appeared in the literature.[11f,g] addition was also not chelation controlled. The con-
Taking the reasonable thermal stability and nucleo- figurations of 3e and 3k were assigned by analogy.
À
philicity of trichloromethyl anion into account, we en-
With the expectation that the C Cl bond could be
visioned that the reactions between chloroform and substituted by the amino nucleophile, we carried out
N-(tert-butanesulfinyl)imines would proceed. With the intramolecular cyclization reaction of 3 in order
this in mind, first we examined the trichloromethyla- to get 2,2-dichloroaziridines 4, an important class of
tion reaction between chloroform (1) and imine 2a aziridines. By using compound 3a as a model com-
under different reaction conditions (Scheme 1). After pound, we examined the intramolecular substitution
screening several papameters (e.g., solvent, base, and reaction under appropriate conditions. We found that
temperature), a reaction system comprising sodium the reaction was significantly influenced by the reac-
bis(trimethylsilyl)amide (NaHMDS) as base, chloro- tion solvent. When the reactions were carried out in
THF, CH2Cl2, or toluene as solvent, and different
bases (such as NaHMDS, LiHMDS, NaH, and pyri-
dine) were applied, no expected product 4a was
formed. However, when polar solvents such as DMF
and NMP were used as the solvents, the reaction pro-
ceeded smoothly under strong basic conditions and
the corresponding 2,2-dichloroaziridine 4a can be ob-
tained. After several trials, we found that the combi-
Scheme 1. Trichloromethylation of imine 2a using chloro-
form.
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Ya Li et al.
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Table 1. Trichloromethylation of N-(tert-butylsulfinyl)aldi-
mines 2 using HCCl3.
nation of DMF and NaHMDS at low reaction temper-
ature (À408C) could give better results (yield: 76%).
Eventually, we chose the optimized reaction condi-
tions to study the scope of the reaction and the results
are summarized in Table 2. As shown, both electron-
Table 2. Synthesis of 2,2-dichloroaziridines 4 from com-
pounds 3.
rich and electron-deficient a-trichloromethyl amines
were smoothly converted into the 2,2-dichloroaziri-
dine products. Generally, good yields can usually be
obtained for a-trichloromethyl amines with electron-
donating or moderate electron-withdrawing substitu-
ents. The reaction of 3e also gave the expected prod-
uct 4e, albeit in lower yield (45%).
To further explore the feasibility of a one-pot syn-
thesis of 2,2-dichloroaziridines from chloroform,
imine 2a was subjected to the above reaction condi-
tions for making 2,2-dichloroaziridine 4a. Indeed, this
reaction occurred and the corresponding product
formed with 96:4 diastereoselectivity, furnishing 4a in
75% yield (Scheme 2).
In conclusion, we have successfully developed a
highly stereoselective and practical synthesis of a-tri-
chloromethyl amines and 2,2-dichloroaziridines from
chloroform. Nucleophilic trichloromethylation of N-
(tert-butylsulfinyl)aldimines with chloroform affords
[a]
Yields of isolated pure material.
Diastereomeric ratios were determined by H NMR and
HPLC-mass spectroscopy on the crude reaction mixture.
For more details, see the Supporting Information.
[b]
1
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Highly Stereoselective and Practical Synthesis of a-Trichloromethyl Amines and 2,2-Dichloroaziridines
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diastereoselectivities. The obtained a-trichloromethyl
amines can be further transformed into chiral 2,2-di-
chloroaziridines through an intramolecular nucleo-
philic substitution methodology. It was also found
that 2,2-dichloroaziridines can be produced directly
from chloroform and N-(tert-butylsulfinyl)aldimines
through a one-pot procedure.
Experimental Section
General Procedure for Trichloromethylation of
Imines using HCCl3 (1)
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Acknowledgements
Support of our work by the National Natural Science Foun-
dation of China (21102089), Research Innovation Program
of Shanghai Municipal Education Commission (12YZ155),
the Special Scientific Foundation for Outstanding Young
Teachers in Shanghai Higher Education Institutions
(gjd10003), Key Laboratory of Organofluorine Chemistry
(Chinese Academy of Sciences), Disciplines Construction
Projects of Colleges and Universities in Shanghai (Innovation
Team Building Projects of Pharmaceutical Engineering) (No.
11K18B), Innovation Program of University Students in
Shanghai University of Engineering Science (cx1104011), and
Start-up Funding of Shanghai University of Engineering Sci-
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