Key words fluoroalkylated compounds - oxindole - asymmetric - Mannich addition
The δ-amino-α,β-unsaturated carbonyl compounds represent an important class of units
in modern organic and medicinal chemistry.[1 ] They are useful building blocks for the synthesis of various pharmaceuticals and
biologically active natural products.[2 ] It is well known that fluorine-containing compounds are considered as the extraordinarily
promising drug candidates because the introduction of fluorine atom or fluorine-containing
groups into organic compounds often significantly improves the chemical, physical,
and biological properties of the parent compound.[3 ]
[4 ] Especially, the fluoroalkyl-substituted molecules, such as trifluoromethylated and
difluoromethylated compounds, have attracted increasing attention.[5 ] Thus, the incorporation of fluoroalkyl into δ-amino-α,β-unsaturated carbonyl compounds
will provide novel fluorinated moieties, which might be applied in various research
fields. Among them, δ-amino-δ-fluoroalkyl-α,β-unsaturated carbonyl compounds are particularly
interesting, because the neighboring electron-withdrawing fluoroalkyl groups would
change the basicity of imine groups, thus affecting their bioactivities. Normally,
these compounds were prepared by vinylogous Mannich reactions.[6 ] In 1992, Tsukamoto and Kitazume reported the Lewis acid promoted reaction of fluorinated
N ,O -acetal with trimethylsilyloxyfuran (Scheme [1, a ]).[7 ] The Lewis acid catalyzed vinylogous Mannich addition of trimethylsilyloxyfuran to
fluorinated aldimines was disclosed by Crousse and co-workers in 2004 (Scheme [1, a ]).[8 ] Shi’s group realized the first enantioselective vinylogous Mannich reaction of fluorinated
aldimines bearing a chiral auxiliary [(S )-1-phenylethyl group] and siloxyfurans under the catalytic environment of silver
acetate and axially chiral phosphine-oxazoline ligand (Scheme [1, b ]).[9 ] Very recently, we developed a tunable and highly regio- and diastereoselective addition
reaction of acyclic silyl dienolates to α-fluoroalkyl sulfinylimines, in which the
Lewis acid TMSOTf was a critical parameter in the control of γ-site regioselectivity
(Scheme [1, c ]).[10 ] All the previous works need silylated substrates as the nucleophiles. From the point
of atom and step economy, it is worthy to investigate the addition reactions directly
using α,β-unsaturated carbonyl compounds as the nucleophiles. In light of the important
pharmaceutical implications of the privileged structural motif oxindole,[11 ] herein we report a regio- and diastereoselective vinylogous Mannich addition of
3-alkenyl-2-oxindoles to α-fluoroalkyl aldimines to afford various chiral α-alkylidene-δ-amino-δ-fluoroalkyl
oxindoles (Scheme [1, d ]).
Scheme 1 Synthesis of δ-amino-α,β-unsaturated carbonyl compounds by vinylogous Mannich reactions
Initially, the reaction conditions were optimized using (SS
)-N -tert -butanesulfinyl-3,3,3-trifluoroacetaldimine (1a )[12 ] and N -Boc-protected 3-alkylidene-2-oxindole 2a
[13 ] as the model substrates (Table [1 ]). Treatment of the substrates with TMSOTf and Et3 N gave only a silylated intermediate of 2a .[13d ] The desired product 3a was not obtained (Table [1 ], entry 1). In view of the better nucleophilic properties of the metallic enolate
intermediate in comparison to silyl enolate, LDA was chosen as the base. To our delight,
the addition reaction happened in the presence of LDA, and 3a was obtained in moderate yield, with virtually complete γ-site selectivity (>99:1
γ/α) and good diastereoselectivity (94:6 dr, Z /E = 8:1; Table [1 ], entry 2). Considering the fact that the addition of Lewis acid might improve the
yield and diastereoselectivity because of its coordination with sulfinylimine substrate,[14 ] different Lewis acids were then investigated. Among the three typical Lewis acids,
Ti(Oi -Pr)4 , AlMe3 , and BF3 ·OEt2 , Ti(Oi -Pr)4 showed the highest efficiency and sharply increased the yield of 3a from 60% to 98% (Table [1 ], entries 3–5). When the base was changed from LDA to KHMDS, 3a was obtained in similar yield with much higher Z /E ratio (Table [1 ], entry 6). Finally, different solvents including toluene, Et2 O, and hexane were screened (Table [1 ], entries 7–9). However, no better result was obtained.
Scheme 2 Vinylogous Mannich addition of 3-alkenyl-2-oxindoles to α-fluoroalkyl aldimines
With the optimized conditions in hand, the substrate scope of direct asymmetric vinylogous
Mannich (AVM) reaction was surveyed.[15 ]
[16 ] The results are summarized in Scheme [2 ]. Firstly, 3-alkylidene-2-oxindoles 2a –d bearing diverse nitrogen protecting groups, Boc, Moc, Bn, and Me, reacted smoothly
with 1a under identical conditions, affording the corresponding products 3a –d in moderate to good yields and excellent stereoselectivities. Additionally, the reaction
conditions displayed good compatibility with the substituent pattern on the phenyl
ring of the 2-oxindole. The substrates 2e –g , bearing electron-donating and electron-withdrawing groups, can be efficiently transformed
to the corresponding products in excellent yields and stereoselectivities. Subsequently,
the patterns of R3 in 3-alkylidene-2-oxindole 2h –j having aromatic groups were tested as the substrates. The reactions proceeded well
affording products 3h –j in good yields and diastereoselectivities, although the Z /E ratios were comparably low. It was noteworthy that this protocol could be applied
to difluoromethylated sulfinylimine 1b . The corresponding difluoromethylated products 3k –n were conveniently obtained under the optimal reaction conditions. The 3-(propan-2-ylidene)benzofuran-2(3H )-one 2o
[17 ] was also a suitable substrate for this reaction to furnish the product 3o in modest yield and good stereoselectivity.
The absolute configuration of these α-alkylidene-δ-amino-δ-fluoroalkyl oxindoles 3 was confirmed by X-ray crystallographic analysis of compounds 3d (Figure [1 ]).[18 ] Normally, a nonchelated transition-state model was involved in the addition reaction
of nucleophiles to fluorinated sulfinylimines.[12 ] The stereochemical outcome observed in the present study could also be explained
by the nonchelated transition-state model, in which the sulfinyl oxygen coordinates
to Ti(Oi -Pr)4 and sterically shields the Re face of the imine. Thus, the Si attack from metallic enolate intermediates would produce adducts 3 with (C
S
,S
S
)-configurations. The high Z /E ratios in compound 3 might be caused by the cyclic structure of nucleophilic enolate intermediates.[19 ] The accurate reaction mechanism still needs further investigation.
Table 1 Optimization of Reaction Conditionsa
Entry
Base
Lewis acid
Solvent
Temp (°C)
Yield (%)b
Z /E
b
drb
1c
Et3 N
TMSOTf
CH2 Cl2
0 to r.t.
0
–
2
LDA
–
THF
–78
60
8:1
94:6
3
LDA
Ti(Oi -Pr)4
THF
–78
98
6:1
94:6
4
LDA
AlMe3
THF
–78
58
12:1
92:8
5
LDA
BF3 ·OEt2
THF
–78
70
7:1
95:5
6
KHMDS
Ti(Oi -Pr)4
THF
–78
97
16:1
93:7
7
KHMDS
Ti(Oi -Pr)4
toluene
–78
87
12:1
93:7
8
KHMDS
Ti(Oi -Pr)4
Et2 O
–78
41
2:1
94:6
9
KHMDS
Ti(Oi -Pr)4
hexane
–78
18
–
a Reactions were carried out using 1a (0.3 mmol), 2a (0.36 mmol, 1.2 equiv), base (0.36 mmol, 1.2 equiv), and Lewis acid (0.33 mmol, 1.1
equiv) in dry solvent (2.5 mL) for 12 h.
b Ratios and yields were determined by 19 F NMR spectroscopy of the crude reaction mixture using benzotrifluoride as an internal
standard.
c Base (0.33 mmol, 1.1 equiv) and Lewis acid (0.36 mmol, 1.2 equiv).
Figure 1 X-ray crystal structure of 3d and proposed transition-state model
It should be mentioned that the N -tert -butylsulfinyl group can serve not only as an efficient chiral auxiliary, but also
as an amine protecting group.[20 ] It could be readily cleaved under mild acidic conditions. After deprotection, the
trifluoromethylated free amines 4 can be easily obtained in high yield (Scheme [3 ]).
Scheme 3 Conversion of 3d into the free primary amine 4
In summary, we have demonstrated a practical and efficient approach to synthesize
α-alkylidene-δ-amino-δ-fluoroalkyl oxindoles via a regio- and stereoselective vinylogous
Mannich-type reaction of fluorinated N -tert -butanesulfinyl aldimines with 3-alkenyl-2-oxindoles. This protocol displayed broad
substrate scope, good functional-group compatibility, and satisfactory stereocontrol.
Further applications of this method for the preparation of new fluorinated bioactive
molecules are in progress.
