Highly stereoselective trichloromethylation of N-(tert-Butylsulfinyl) aldimines: Facile synthesis of chiral α-trichloromethylamines

Article abstract of DOI:10.1002/ejoc.201001495

The first highly stereoselective and facile synthesis ofα- trichloromethylamines is described by using a nucleophilic trichloromethylation strategy. With tetrabutylammonium triphenyldifluorosilicate (TBAT) as the mediator, the trichloromethyl anion (CCl

Full text of DOI:10.1002/ejoc.201001495

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201001495
Highly Stereoselective Trichloromethylation of N-(tert-Butylsulfinyl)aldimines:
Facile Synthesis of Chiral α-Trichloromethylamines
Ya Li,*[a] Yunlv Cao,[a] Jiaying Gu,[a] Wei Wang,[a] Han Wang,[a] Tao Zheng,[a] and
Zhihua Sun*[a,b]
Keywords: Sulfur / Amines / Nucleophilic addition / Diastereoselectivity / Trichloromethylation
The first highly stereoselective and facile synthesis of
α-trichloromethylamines is described by using a nucleophilic
trichloromethylation strategy. With tetrabutylammonium tri-
phenyldifluorosilicate (TBAT) as the mediator, the tri-
chloromethyl anion (CCl3–) from TMSCCl3 can be transferred
to N-(tert-butylsulfinyl)aldimines in excellent yields and with
high diastereoselectivity (Ն99:1dr).
roethylidene)benzenesulfonamide with pyrrole or pyrazole
afforded the expected addition products.[11a,12] However,
these methods suffer from low yields and lack generality.
More recently, Abbaspour Tehrani reported a facial synthe-
sis of α,β-unsaturated α-trichloromethylamines by Lewis
acid promoted Petasis-type reaction of 2,2,2-trichloroethan-
imines with styryl- or phenylethynyltrifluoroborates.[13] As
to the asymmetric synthesis of α-trichloromethylamines,
only two examples have been disclosed: one was using the
addition reaction between in situ generated N-acyl-N-
(2,2,2-trichloroethylidene)amines and the cyclic enamine
(S)-1-(cyclohexenyl)-2-(methoxymethyl)pyrrolidene,[14] and
the other involved ring opening of 3-trichloromethyl β-sul-
tam by using alcohols or amines to afford β-trichloromethyl
β-amino sulfonates or sulfonamides.[2c] To the best of our
knowledge, there is no general method available for the
highly stereoselective synthesis of α-trichloromethylamines
by using a direct trichloromethylation strategy, and the ge-
neral and efficient asymmetric synthesis of α-trichlorome-
thylamines still remains an unexplored research area. As
part of our continuing efforts in the development of ef-
ficient methodologies for the synthesis of chiral α-(haloge-
nated methyl)amines,[15] herein we report the first stereose-
lective synthesis of α-trichloromethylamines by using read-
ily accessible trimethyl(trichloromethyl)silane (TMSCCl3,
1).
Introduction
The trichloromethyl unit is a structural feature present in
a vast number of bioactive natural products and pharma-
ceutical drugs, and it was found to be the key component
for potent activity and low toxicity in some cases.[1] In this
context, α-trichloromethylamines are attracting enormous
recent attention in the field of medicinal chemistry as well
as synthetic chemistry.[2] It was believed that incorporation
of the α-trichloromethylamine subunit can result in higher
metabolism and improved biological properties of a target
drug candidate.[2a,2b] Moreover, the α-trichloromethylamine
subunit is highly valuable synthetic intermediate in organic
synthesis, which has frequently served as a precursor for the
synthesis of α-amino acids,[3] 2,2-dichloroaziridines,[4] α-di-
and monochloromethylamines,[5] 3,3-dichloropyrrolidines,[6]
along with trichloromethylated heterocyclic compounds.[7]
Despite its importance for applications related to life sci-
ences, the synthesis of α-trichloromethylamines has not
been well explored. The few known methods are mainly
based on the use of a trichloromethyl anion equivalent
–
(“CCl3 ”), including trichloroacetic acid,[8] trichlorometh-
ane,[9] carbon tetrachloride,[10] or 2,2,2-trichloroethanimine
derivatives[11] as precursors. The earliest reported method
for the preparation of α-trichloromethylamines involved the
addition reaction between trichloroacetic acid and im-
ines.[8a,8b] Friedel–Crafts-type reaction of N-(2,2,2-trichlo-
[a] College of Chemistry and Chemical Engineering, Shanghai
University of Engineering Science
Results and Discussion
333 Longteng Road, Shanghai 201620, China
Fax: +86-21-67791432
In previous reports, TMSCCl3 (1) turned out to be an
especially useful trichloromethylating reagent for carbonyl
compounds,[16] commonly accomplished under various
fluoride (F–) sources [tris(diethylamino)sulfonium difluo-
romethylsilicate (TASF), potassium fluoride (KF), and tet-
rabutylammonium fluoride (TBAF)] or weak Lewis bases
E-mail: ya.li@sues.edu.cn
sungaris@gmail.com
[b] State Laboratory of Drug Research, Shanghai Institute of
Materia Medica, Chinese Academy of Sciences
Shanghai 201620, China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001495.
676
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 676–679

Synthesis of Chiral α-Trichloromethylamines
[potassium
carbonate
(K2CO3),
sodium
formate Table 1. Survey of the reaction conditions.
(HCOONa), and so on]. It was observed that the tri-
–
chloromethyl anion (CCl3 ), generated in situ from 1 and a
base showed both higher thermal stability and better nu-
cleophilicity in comparison to trichloromethyllithium
(CCl3Li).[17] Although its addition reaction to carbonyl
compounds has been extensively explored, only one report
dealing with its addition to imines has appeared in the lit-
erature (trichloromethylation of salicylaldimines through
initial formation of an intramolecular boron complex fol-
lowed by interaction with TMSCCl3 gave the tri-
chloromethylated adducts in only 34% yield).[18] We envi-
sioned that the reactions between TMSCCl3 and chiral im-
ines, such as widely used N-(tert-butylsulfinyl)aldimines,
would provide an excellent approach to obtain chiral α-tri-
chloromethylamines by taking advantage of the reasonable
Entry Fluoride source Solvent
(equiv.)
T
[°C]
dr[a]
Yield
[%][b]
1
2
3
4
5
CsF (1.1)
CsF (1.1)
CsF (1.1)
TBAT (0.5)
TBAT (1.0)
TBAT (1.0)
TBAT (1.0)
DMF
THF
diglyme
THF
THF
THF
–20
–20
–20
–20
–20
–60
–60
82:18
80:20
85:15
99:1
99:1
99:1
30
67
50
52
71
83
94
6
7[c]
THF
99:1
[a] Determined by 1H NMR spectroscopy and HPLC analysis of
the crude product. [b] Isolated yield (3a + 3aЈ). [c] 1.5 equiv. of
TMSCCl3 was used.
–
stability of the CCl3 anion and its the high electrophilic
properties and the powerful chiral directing ability of N-
(tert-butylsulfinyl)aldimines. With these in mind, first we
Eventually, the above conditions were applied to a wide
tried the diastereoselective nucleophilic trichloromethyl- array of structurally diverse imines as summarized in
ation of (R)-(tert-butylsulfinyl)aldimine 2a with reagent 1. Table 2. A remarkable feature of this reaction is that it can
When compound 1 (1.1 equiv., in THF) was added to a be applied to non-enolizable, enolizable, aromatic, and het-
solution of aldimine 2a (1 equiv.) and CsF (0.5 equiv.) in erocyclic imines alike. High diastereoselectivity was ob-
THF at 0 °C, a facial addition reaction occurred, and corre- served in each case, and good to excellent yields were ob-
sponding products 3a + 3aЈ can be obtained in 35% yield tained with non-enolizable imines (Table 2, Entries 1–10)
(Scheme 1). More interestingly, analysis of the crude reac- and with imines that bear only one α-hydrogen atom
1
tion mixture and the obtained product by H NMR spec- (Table 2, Entry 11). Note that the electronic withdrawing/
troscopy showed that the reaction proceeded diastereoselec- donating nature of the substituent on the aromatic ring had
tively with 4:1dr.
an undetectable effect on both the yield and diastereoselec-
tivity. However, relatively lower yields (35%) were obtained
in the case of imine 2l, which bears two α-hydrogen atoms
(Table 2, entry 12). Careful TLC analysis revealed that im-
ine 2l disappeared shortly after the reaction was performed
and indicates a labile enolization of 2l under such basic con-
ditions. On the other hand, relatively lower diastereoselec-
tivities were obtained for all entries when CsF was used
as the fluoride source (Table 2, values in parentheses). The
fluoride difference upon diastereoselectivities appears to be
Scheme 1. Trichloromethylation of 2a by using CsF as the media-
tor.
Encouraged by the above results, we then carried out a due to the steric bulk of tetrabutylammonium counterion,
series of experiments to improve both the yield and dia- which played an important role in the trichloromethyl
stereoselectivity. Aldimine 2a was used as a model com- transfer process.[19]
pound, and the reaction conditions were carefully tuned as
The absolute configuration of sulfinamide 3a was deter-
shown in Table 1. It is apparent that the reaction was signif- mined by single-crystal X-ray analysis (Figure 1a), and was
icantly influenced by the fluoride source, the reaction sol- consistent with our prediction based on a commonly used
vent, and the reaction temperature. Using CsF as the fluo- nonchelation-controlled transition-state mode to give the
ride source, and less polar to polar solvents, such as di- Cram products (Figure 1b), in which the tert-butyl group
glyme, THF, and DMF, expected product 2a can only be adopts the antiperiplanar arrangement with respect to the
obtained in 30–67% yield (Table 1, Entries 1–3). After sev- C=N bond.[15,20] However, recent studies indicated that,
eral trials, we found that the combination of THF and mainly due to the contribution of intramolecular hydrogen
TBAT (tetrabutylammonium triphenyldifluorosilicate) bonding of the oxygen with the imine hydrogen, the sulfinyl
could give better yield and excellent diastereoselectivity oxygen in a s-cis arrangement with respect to the C=N
(Table 1, Entries 4–7). It is worthy to note that 1.0 equiv. of bond is the most stable conformation for the N-(phenylsulf-
–
TBAT is used to ensure complete conversion of reagent 2a. inyl)imine.[21] The approach of the nucleophile (CCl3 ) to
Also, temperature is important and a lower temperature is this conformation would also lead to the observed stereose-
helpful for higher yield (Table 1, Entries 5 and 6). The best lectivity as shown in Figure 1c. We tentatively assume that
yield and diastereoselectivity were reached with 1.5 equiv. one or both transition-state modes are involved in this tri-
of TMSCCl3 and 1.0 equiv. of TBAT in THF solution at chloromethylation reaction. The configurations of 3b–l
–60 °C (Table 1, Entry 7).
were assigned by analogy.
Eur. J. Org. Chem. 2011, 676–679
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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677

Y. Li, Y. Cao, J. Gu, W. Wang, H. Wang, T. Zheng, Z. Sun
SHORT COMMUNICATION
Table 2. Trichloromethylation of N-(tert-butylsulfinyl)aldimines 2
by using TMSCCl3 (1).
Figure 1. The X-ray crystal structure of 3a (a) and depiction of its
stereoselective formation (b, c).
The tBuS(O) group can be easily removed following re-
ported procedures without affecting the trichloromethyl
group.[20] For instance, compound 3a was subject to acid-
catalyzed alcoholysis with HCl/MeOH to afford α-tri-
chloromethyl 2-benzenemethanamine 4 in near-quantitative
yield (Scheme 2). To ensure that there was no racemization
during the deprotection process, we converted amine salt 4
into benzamide derivative 5. The optical purity of 5
(99%ee), determined by chiral HPLC, indicated that the
above deprotection procedure was reliable for the prepara-
tion of enantiomerically pure α-trichloromethylamines.
Scheme 2. Conversion of 3a into amine salt 4 and benzamide deriv-
ative 5.
[a] Yield of isolated pure material. [b] The dr values in parentheses
are those obtained with CsF as the fluoride source. [c] Determined
by 1H NMR spectroscopy and HPLC analysis of the crude reaction
mixture. For more details, see the Supporting Information.
Conclusions
In summary, we have successfully developed the first
highly stereoselective and facile synthesis of α-trichlorome-
thylamines by using a straightforward trichloromethylation
strategy. Trichloromethylation of (R)-(N-tert-butylsulfinyl)-
In 2001 Prakash, Olah, and co-workers reported an ele- aldimines with trimethyl(trichloromethyl)silane (TMSCCl3)
gant diastereoselective nucleophilic trifluoromethylation of affords the corresponding products in excellent yields and
N-(tert-butylsulfinyl)imines using the Ruppert–Prakash rea- with high diastereoselectivity (Ն99%dr). Facile and conve-
gent (TMSCF3).[19a] Compared to the trifluoromethyl anion nient deprotection of the tert-butylsulfinyl group gives the
–
(CF3 ) (generated from TMSCF3 in the presence of a fluo- target trichloromethylamines in quantitative yield without
–
ride activator), the trichloromethyl anion (CCl3 ) showed affecting the trichloromethyl group. The synthetic applica-
similar reactivity: both of which worked better for non-en- tions of α-trichloromethylamines are still under investiga-
olizable imines than enolizable ones.
tion in our lab.
678
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Eur. J. Org. Chem. 2011, 676–679

Synthesis of Chiral α-Trichloromethylamines
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Experimental Section
[6]
General Procedure for the Trichloromethylation of Imines by using
TMSCCl3 (1): TMSCCl3 (1; 1.5 equiv., 1.5 mmol) in THF (3 mL)
was added to a mixture of imine 2 (1 mmol) and TBAT (1 equiv.,
1 mmol) in THF (8 mL) at –60 °C. The reaction mixture was stirred
for 1 h. Then, a half-saturated NH4Cl/H2O solution (2 mL) was
added at low temperature, and the quenched reaction mixture was
extracted with ethyl acetate (3ϫ). The combined organic layers
were dried with anhydrous MgSO4. Evaporation of the solvent af-
forded the crude product, which was subjected to flash chromatog-
raphy to give the corresponding sulfonamide 3.
[7]
[8]
[9]
CCDC-784869 (for 3a) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[10]
[11]
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, characterization data, and copies of the
1H and 13C NMR spectra of the new compounds.
Acknowledgments
[12]
[13]
Financial support by Shanghai University of Engineering Science
and State Laboratory of Drug Research (CAS) are gratefully ac-
knowledged.
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Received: November 6, 2010
Published Online: December 17, 2010
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