Organocatalytic asymmetric addition of thiols to trifluoromethylaldimine: An efficient approach to chiral trifluoromethylated N,S-acetals

Article abstract of DOI:10.1002/adsc.201200845

The first organocatalytic asymmetric addition of thiols to trifluoromethylaldimine for the construction of chiral trifluoromethylated N,S-acetals has been achieved in high yields (up to 99%) and excellent enantioselectivities (up to 95% ee) with 1 mol% of a bifunctional organocatalyst.

Full text of DOI:10.1002/adsc.201200845

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DOI: 10.1002/adsc.201200845
Organocatalytic Asymmetric Addition of Thiols to
Trifluoromethylaldimine: An Efficient Approach to Chiral
Trifluoromethylated N,S-Acetals
Xin Fang,a Qing-Hua Li,a Hai-Yan Tao,a and Chun-Jiang Wanga,b,*
a
College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, Peopleꢀs Republic of China
Fax : (+86)-27-6875-4067; e-mail: cjwang@whu.edu.cn
State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, Peopleꢀs Republic of China
b
Received: September 20, 2012; Revised: November 4, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200845.
Abstract: The first organocatalytic asymmetric ad-
dition of thiols to trifluoromethylaldimine for the
construction of chiral trifluoromethylated N,S-ace-
tals has been achieved in high yields (up to 99%)
and excellent enantioselectivities (up to 95% ee)
with 1 mol% of a bifunctional organocatalyst.
fusaperazine A (4) and (+)-11,11’-dideoxyverticillin
A (5) (Figure 1).[7] In sharp contrast to the well-docu-
mented approaches to access either trifluoromethylat-
ed compounds[1–3] or sulfur-containing compounds,[5,6]
the development of effective method for the catalytic
asymmetric construction of the trifluoromethylated
N,S-acetal motif still remains elusive.
Keywords: asymmetric catalysis; bifunctional orga-
Recently, Antilla and co-workers developed an ele-
gant organocatalyzed addition reaction of thiols to
highly active N-acylimines leading to the asymmetric
synthesis of chiral N,S-acetals in excellent yields and
enantioselectivities.[8] Most recently, we reported the
first asymmetric sulfa-Michael addition of thiols to tri-
fluoromethylated electron-deficient alkenes catalyzed
nocatalysts;
enantioselectivity;
N,S-acetals;
trifluoromethyl group
ACHTUNGTRENNUNG
Organofluorine compounds have attracted considera- by a bifunctional amine-thiourea, which serves as
ble attention in pharmaceutical, agrochemical and a generally efficient protocol for the direct construc-
material research as a result of the beneficial proper- tion of chiral building blocks bearing a unique tri-
ties brought by the fluorine atom.[1] Trifluoromethyl- fluoromethyl group and a sulfur atom at the stereo-
containing compounds are of great interest in various genic center.[9]
fields because of the high electronegativity and specif-
Encouraged by these achievements, we envisioned
ic properties. On the other hand, the introduction of that an acid-base bifunctional organocatalyst[10] could
a trifluoromethyl group in biologically active mole- efficiently enhance the nucleophilicity of the thiol and
cules has become an important strategy for increasing
the biological activity of a molecule, since the pres-
ence of the trifluoromethyl moiety may assist drug ab-
sorption, modify its tissue distribution, and signifi-
cantly change preferred molecular conformations.[2]
Among various trifluoromethyl-containing com-
pounds, trifluoromethylated amines are of primary
significance since these privileged chiral synthons
have high potential as core elements for the develop-
ment of related compounds leading to medicinal
agents[3] and exhibit interesting biological activity as
exemplified by compounds 1–3[4] shown in Figure 1.
Enantiomerically enriched sulfur-containing com-
pounds also exhibit important applications in many
areas of chemistry and biology.[5] Chiral N,S-acetals
Figure 1. Examples of biologically important molecules con-
are common structural motifs present in numerous
biologically important natural products,[6] such as the acetal motifs.
taining privileged trifluoromethylamine and chiral N,S-
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Table 1. Screening of reaction conditions for the addition of
benzyl mercaptan 2a to trifluoromethylated aldimine 1a cat-
alyzed by bifunctional organocatalysts.[a]
Scheme 1. Asymmetric addition of thiols to trifluoromethy-
laldimines.
simultaneously activate the trifluoromethylated
aldimACHTUNGTRENNUNGine through hydrogen bonding interactions with
the imino group, and thereby realize the challenging
target of trifluoromethylated N,S-acetals with high
enantioselectivity (Scheme 1). Herein, we would like
to document a highly enantioselective addition of
thiols to trifluoromethyl aldimine catalyzed by a bi-
functional squaramide-based organocatalyst with as
low as to 1 mol% catalyst loading, providing trifluoro-
methylated N,S-acetals in high yields and excellent
enantioselectivities.
We began our investigation by examining the cata-
lytic asymmetric addition of benzyl mercaptan 2a to
trifluoromethylated aldimine 1a in dichloromethane
at room temperature with bifunctional organocata-
lysts derived from 1,2-diaminocyclohexane or Cincho-
na alkaloids (Figure 2).[11] To our delight, this addition
reaction proceed efficiently in less than 30 min with
the commonly used bifunctional amine-thioureas af-
fording the expected adducts in high yields albeit with
moderate enantioselectivities (50–77% ee) (Table 1,
entries 1–5). To further improve the enantioselectivity,
[a]
All reactions were carried out with 0.20 mmol of 1a,
0.24 mmol of 2a in 0.5 mL of solvent. PMP=p-methoxy-
phenyl.
Isolated yield.
Determined by HPLC analysis.
Carried out in PhMe within 20 h.
Carried out at 08C.
[b]
[c]
[d]
[e]
we turned our attention toward the use of chiral 1,2-
diaminocyclohexane and Cinchona alkaloids-derived
squaramides as the H-bonding motif[12] since they had
been demonstrated to be efficient for a variety of
asymmetric transformations.[13] Gratifyingly, a signifi-
cant increase of enantioselectivity was achieved when
cinchonidine-derived squaramide catalyst V was em-
ployed as the bifunctional catalyst (entry 7). Chiral
BINOL-derived phosphoric acids VI-a and VI-b,
which exhibited excellent results in the addition reac-
tion of thiols to highly active N-acylimines,[8] were
also tested in this transformation. However, a much
lower catalytic activity was observed together with
a relatively poor enantiomeric excess (entries 8 and
9). Subsequent screening of solvents showed that the
reaction media had a significant effect on the enantio-
selectivity. Less polar solvents such as DCM, toluene,
and ether were superior to polar and protic solvents
(entries 7 and 10–13), and DCM gave the best results
in terms of the yield and the enantioselectivity. Re-
ducing the reaction temperature to 08C has no effect
on the yield, but a slightly decrease on the enantiose-
lectivity (entry 14). Remarkably, high yield and enan-
tioselectivity and fast reaction rate were maintained
Figure 2. Structures of the screened bifunctional organocata-
lysts.
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Organocatalytic Asymmetric Addition of Thiols to Trifluoromethylaldimine
Table 2. Asymmetric addition of various thiols 2 to fluori-
nated aldimines 1 with organocatalyst V.[a]
tries 7, 9 and 13). Noticeably, for alkyl thiol 2j with
the longer carbon chain n-C12H25, high reactivity and
enantioselectivity were still maintained at the similar
level (entry 10). Secondary thiols either with an acy-
clic isopropyl group or with cyclic groups such as cy-
clohexyl and cyclopentyl were also tested, and excel-
lent enantioselectivity and reaction rate were ob-
served for each case (entries 6, 11 and 12). The consis-
tently excellent enantioselectivity obtained with the
tertiary tert-butyl thiol 2h is noteworthy (entry 8), as
such a sterically hindered tertiary thiol was shown to
be a relatively challenging nucleophile in previous
studies,[13h] although a longer reaction time was need
to maintain the high yield. Chlorodifluoromethylated
aldimine 1b and bromodifluoromethylated aldimine
1c also worked well affording the expected adducts in
high yields with good enantioselectivities (entries 16
and 17). Aromatic thiol 2p also exhibited high reactiv-
ity in this reaction affording a good yield albeit with
a moderate enantioselectivity[14] (entry 18).
The absolute configuration of the trifluoromethylat-
ed N,S-acetal 3c was determined unambiguously to be
R
by
a
single X-ray crystallographic analysis
(Figure 3).[15] Those of other adducts were tentatively
proposed on the basis of these results.
To examine the mechanism for this addition reac-
tion, we carried out NMR studies of the substrate–
catalyst combination. Mixing an equal amount of 1a
with catalyst V in CDCl3 resulted in no significant
change of the resonances (1H NMR and 19F NMR
analysis), which indicates that the non-covalent inter-
actions of them are probably very weak.[16] A similar
phenomenon has been noticed by Jacobsen for the
Strecker reaction.[17] Nearly racemic adduct 3a was
obtained when methanol was employed as reaction
[a]
All reactions were carried out with 0.20 mmol of 1,
0.24 mmol of 2 in 0.5 mL of DCM.
Yield of the isolated products 3 after chromatographic
purification.
Determined by HPLC analysis.
Reaction time: 48 h.
Reaction time: 10 min.
[b]
[c]
[d]
[e]
even when the reaction was performed with as low as solvent, since solvation of methanol to the imino
1 mol% of catalyst loading (entry 16). group of 1a might disturb the hydrogen bonding inter-
With the optimal reaction conditions in hand, an action between V and 1a. The same experiment was
array of thiols was tested to investigate the generality also studied for a mixture of thiol 2a and V, and the
of this reaction, and the results are summarized in 1H NMR spectrum revealed that 2a is deprotonated
Table 2. Substituted benzyl thiols bearing electron- by the tertiary amine of the catalyst.[16] Based on the
rich, electron-neutral, or electron-deficient groups on above experimental results and the absolute configu-
the aromatic ring reacted smoothly with trifluorome-
thylated aldimine 1a to afford the expected adducts
(3a–3c) with high yields and excellent enantioselectiv-
ities (91–94%) (Table 2, entries 1–3). Heteroaromatic
furfuryl mercaptan 2o also work well in this transfor-
mation leading to the corresponding adduct in 90%
ee (entry 15). To further probe the steric effects of
substituent on this catalytic system, various alkyl
thiols with branched and sterically bulky substituents
were employed. Primary alkyl thiols with n-alkyl sub-
stituents such as ethyl, n-propyl, and 2-phenylethyl
group all have afforded high yields and excellent
enantioselectivities (entries 4, 5 and 14). Allyl thiol
2m was also a viable nucleophile as were the
branched isobutyl thiol 2g and isoamyl thiol 2i (en- Figure 3. X-ray crystallographic structure of (R)-3c.
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Acknowledgements
This work is supported by the 973 Program (2011CB808600),
the National Natural Science Foundation of China
(20972117, 21172176), NCET-10-0649, IRT1030, the Funda-
mental Research Funds for the Central Universities, and
Large-scale Instrument And Equipment Sharing Foundation
of Wuhan University. We thank Prof. Hua Li in Wuhan Uni-
versity for solving the crystal structure.
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6 Organocatalytic Asymmetric Addition of Thiols to
Trifluoromethylaldimine: An Efficient Approach to Chiral
Trifluoromethylated N,S-Acetals
Adv. Synth. Catal. 2013, 355, 1 – 6
Xin Fang, Qing-Hua Li, Hai-Yan Tao, Chun-Jiang Wang*
6
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