Silver-catalyzed formal [3+2]-cycloaddition of α-trifluoromethylated methyl isocyanides: a facile stereoselective synthesis of CF3-substituted heterocycles

Article abstract of DOI:10.1039/c6cc10124k

An Ag-catalyzed formal [3+2]-cycloaddition of α-trifluoromethylated methyl isocyanides with polar double bonds has been developed for the facile access to trifluoromethylated oxazolines, imidazolines and pyrrolines under mild conditions. The practicality of this chemistry is demonstrated by the gram-scale synthesis of oxazolines with excellent yields and facile transformations of the formed oxazolines to trifluoromethylated β-amino alcohols in quantitative yields.

Full text of DOI:10.1039/c6cc10124k

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Silver-Catalyzed Formal [3+2]-Cycloaddition of α-Trifluoromethylated Methyl Isocyanides:
Facile Stereoselective Synthesis of CF3-Substituted Heterocycles†
Xue Zhang,
‡
a,b Xin Wang, b Yuelei Gaob and Xianxiu Xu*a,b
‡
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
5
DOI: 10.1039/b000000x
trifluoromethylated compounds. However, to our knowledge,
40 although αꢀtrifluoromethylated methyl isocyanide (2,2,2ꢀ
trifluoroethyl isocyanide, Figure 1) was prepared more than 40
years ago,11 it was mainly used as a ligand in organometallic
chemistry,12 and only two examples of Ugiꢀtype multicomponent
reactions using αꢀtrifluoromethylated methyl isocyanides as
45 nucleophiles were reported to date.13 It is probably because the βꢀ
fluoride elimination of αꢀtrifluoromethylated carbanion hindered
the development of synthetic utilities of the CF3ꢀsubstituted
isocyanides as active methylene synthons .3c,14
A
Ag-catalyzed formal [3+2]-cycloaddition of α-
trifluoromethylated methyl isocyanides with polar double
bonds has been developed for the facile access to
trifluoromethylated oxazolines, imidazoline and pyrroline
10 under mild conditions. The practicality of this chemistry is
demonstrated by an excellent-yielding, gram-scale synthesis,
and facile transformations of the formed oxazolines to
trifluoromethylated β-amino alcohols in quantitative yields.
Because incorporation of fluorine atoms or fluoroalkylated
15 groups into organic molecules often leads to dramatic changes in
their
chemical,
physical
and
biological
properties,
trifluoromethylated heterocycles play a significant role in the
pharmaceutical chemistry, agrochemistry, and material science.1
While a number of synthetic methods for the construction of CF3ꢀ
20 substituted heterocycles relying on the direct trifluoromethylation
of heterocycles2 or the cyclization of CF3ꢀcontaining building
blocks3 have been reported, the development of facile and
practical synthetic approaches is still of great interest.
50 Fig. 1 EWG substituted methyl isonitriles.
Since it was exploited by Schöllkopf and Gerhart in 1968,4
25 active methylene isocyanides have found wide applications in
organic synthesis.4ꢀ9 A number of electronꢀwithdrawing groups
(EWG) substituted methyl isocyanides have been prepared as
valuable synthons,5ꢀ10 such as isocyanoacetate,6 tosylmethyl
isocyanide (TosMIC),7 isocyanoacetamide,8 isocyanoacetonitrile9
30 and isocyanomethylphosphonate10 (Figure 1). Among them,
isocyanoacetate,6 TosMIC7 and isocyanoacetamide8 are notable
examples and have been shown to participate in various types of
transformations for the synthesis of diverse class of nitrogen
containing heterocycles and amino acid derivatives. In principle,
35 the strong electronꢀwithdrawing effect of the trifluoromethyl
group should make the αꢀtrifluoromethylated methyl isocyanides
to be the potential active αꢀacidic isocyanides, which are
promising synthons for the divergent synthesis of
Recently, Hu and coworkers reported the homocoupling15a and
crossꢀcoupling15b of gemꢀdifluoroalkenes via the radical reactions
of relative stable αꢀtrifluoromethylated benzylsilver intermediates,
generated by a AgFꢀmediated process (Scheme 1, top).16
55 Meanwhile, silver salts are powerful catalysts for the formal
[3+2]ꢀcycloaddition of isocyanoacetate.17 Therefore, we
envisioned that it could be possible to use αꢀtrifluoromethylated
methyl isocyanides as precursors for the generation of αꢀ
isocyanoꢀαꢀtrifluoromethylated carbanions catalyzed by silver
60 salts under basic conditions, thus allowing to expand the
synthetic application of αꢀacidic isocyanides to construction of
CF3ꢀsubstituted heterocycles. During the course of our study on
isonitrileꢀbased annulation,18 we herein reported a facile silverꢀ
catalyzed formal [3+2]ꢀcycloaddition of αꢀtrifluoromethylated
65 methyl isocyanides for the divergent synthesis of
trifluoromethylated heterocycles via the new, stable and versatile
aCollege of Chemistry, Chemical Engineering and Materials Science, Key
Laboratory of Molecular and Nano Probes, Ministry of Education,
Shandong Normal University, Jinan 250014, China.
Eꢀmail: xuxx677@sdnu.edu.cn
αꢀisocyanoꢀαꢀtrifluoromethylated carbanion, produced by
a
Ag2CO3ꢀcatalyzed process (Scheme 1, bottom). This study on αꢀ
trifluoromethylated carbanion chemistry represents the first
70 example for the efficient and practical synthesis of a wide range
of trifluoromethylated fiveꢀmembered nitrogenꢀcontaining
heterocycles from isocyanides,19 furthermore, it could provide a
facile protocol for the synthesis of useful trifluoromethylated βꢀ
aminoalcohol building blocks.20
bDepartment of Chemistry, Northeast Normal University, Changchun
130024, China.
†Electronic Supplementary Information (ESI) available: Experimental
details and spectral data for 3, 5, 7, 9 and 10 are included in the
supporting information. For ESI data see DOI: 10.1039/b000000x/
‡ Both authors contributed equally to this work.
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Table 1 Optimization of reaction conditionsa
ent.
cat.
b.
sol.
t.
y. (%)b,c
(x mol%)
(y mol%)
DBU (20)
K2CO3 (20)
tꢀBuOK
(h)
45
45
45
1
2
3
Ag2CO3 (10)
Ag2CO3 (10)
Ag2CO3 (10)
CH2Cl2
CH2Cl2
CH2Cl2
76 (1.6 : 1)
58 (1.3 : 1)
62 (1.4 : 1)
(20)
4
5
6
7
Ag2CO3 (10)
Ag2CO3 (10)
Ag2CO3 (10)
Ag2CO3 (5)
DBU (20)
DBU (20)
DBU (20)
DBU (10)
CH3CN
THF
toluene
toluene
16
82 (1.2 : 1)
2.5 82 (2.4 : 1)
2 94 (3.5 : 1)
2.5 93 (3.7 : 1)
(95)d
8
9
Ag2CO3 (2.5)
Ag2CO3 (5)
ꢀꢀꢀ
Ag2O (5)
AgOAc (5)
CuCl (5)
CuI (5)
DBU (5)
ꢀꢀꢀ
toluene
toluene
toluene
toluene
toluene
toluene
toluene
18
45
45
4
2
42
42
91 (3.6 : 1)
49 (2.5 : 1)
25 (2.5 : 1)
93 (3.5 : 1)
90 (3.1 : 1)
89 (2.7 : 1)
86 (2.6 : 1)
10
11
12
13
14
DBU (10)
DBU (10)
DBU (10)
DBU (10)
DBU (10)
aReaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), catalyst and base
in solvent (1.0 mL) at 15 oC. bYield was determined by 1H NMR
spectroscopy with CH2Br2 as internal standard. cd.r. was listed in the
parentheses and determined by 1H NMR spectroscopy. dIsolated Yields.
Scheme 1 Generation of trifluoromethylated alkyl silver intermediates.
Initially, the [3 + 2]ꢀcycloaddition of 3ꢀnaphthaldehyde 1a
and 1ꢀmethylꢀ4ꢀ(2,2,2ꢀtrifluoroꢀ1ꢀisocyanoethyl)benzene 2a was
employed to optimize the reaction conditions. It was found that,
catalyzed by Ag2CO3 (10 mol %) and in the presence of DBU
(DBU = 1,8ꢀdiazabicyclo[5.4.0]ꢀundecꢀ7ꢀene, 20 mol %) in
dichloromethane at 15 oC for 45 h, the desired
trifluoromethylated oxazoline 3aa was obtained in 76% yield
40 Table 2 Scope of aldehydes 1a
5
10 with low diasteroselectivity (Table 1, entry 1). K2CO3 and tꢀ
BuOK afforded lower product yield and diasteroselectivity (Table
1, entries 2 and 3). A survey of solvents identified toluene as the
most suitable media, the reaction was completed in 2 h and the
oxazoline 3aa was obtained in 94% yield with good
15 diasteroselectivity (d.r. = 3.5 : 1) (Table 1, entries 4ꢀ6).
Decreasing the catalyst loading to 5 mol% and the amount of
DBU to 10 mol% gave similar results (Table 1, entries 7 and 8).
In the absence of Ag2CO3 or DBU, the reaction became very slow
(Table 1, entries 9 and 10). For comparison, Ag2O (entry 11),
20 AgOAc (entry 12), CuCl (entry 13), and CuI (entry 14) were less
effective catalysts than Ag2CO3.
With the optimal conditions in hand (Table 1, entry 7), the
reaction of viable aldehydes 1 with isocyanide 2a was examined;
the results summarized in Table 2 revealed that the scope of the
25 aldehyde turned out to be very general. Besides 3ꢀnaphthaldehyde
1a, a wide range of substituted aryl aldehydes 1bꢀm reacted with
isocyanide 2a to give the trifluoromethylated oxazolines 3aa-ma
mostly in excellent yields and good diasteroselectivity. Compared
with the electronꢀdeficient and ꢀneutral aryl aldehydes 1a-g, the
30 reaction of electronꢀrich ones 1h, 1i and 1k is slower. Heteroaryl
aldehydes 1n-p also afforded the oxazolines 3na-pa in excellent
yields. Ethyl glyoxylate 1q and cinnamaldehyde 1r also delivered
the corresponding [3+2]ꢀcycloaddition products in high yields,
albeit with lower diasteroselectivity. The reactions of alkyl
35 aldehydes 1s and 1t with isocyande 2a gave good product yields
and with moderate diasteroselectivity. In addition, the practicality
aReaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), catalyst and base in
solvent (2.0 mL) at 15 oC; isolated yields. b1.5 g 3pa was obtained.
cAg2CO3 (10 mol%), DBU (20 mol%).
of this [3+2]ꢀcycloadddtion demonstrated by the excellentꢀ
yielding, gramꢀscale synthesis of 3pa under very mild reaction
45 conditions. The two diastereomers of 3pa could be isolated by
flash column, and the relative configuration of the trifluoromethyl
2
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oxazole 3pa was assigned by NOSEY spectrum analysis and the
structure of the minor isomer 3pa2 was unambiguously
αꢀsilver isocyanide III.22 Then, the nucleophilic addition of
intermediate II or III on the aldehyde 1 takes place to form
confirmed by singleꢀcrystal Xꢀray analysis.21 The stereochemical 30 intermediate IV, followed by cyclization to give oxazoline silver
structures of the rest of the products 3 were assigned by analogy
with their NMR spectra.
Subsequently, the scope of this [3+2]ꢀcycloaddition was
evaluated with respect to some selected trifluoromethylated
intermediate V. Finally, protonation occurs to afford the product
3 with regeneration of the catalysts, silver and DBU, for the next
catalytic cycle (Scheme 2). Last year, Ma and coworkers reported
5
a
copperꢀtriggered threeꢀcomponent reaction of CF3CHN2,
isocyanides 2; results are summarized in Table 3. The reaction 35 nitriles, and aldehydes for the diastereoselective synthesis of CF3ꢀ
tolerates isocyanides 2 bearing various R groups, such as phenyl
substituted oxazolines.23 In their reaction, an analogue formal
[3+2]ꢀcycloaddtion of copper stablized trifluoromethylated
ammonium ylide intermediate with aldehydes is proposed.
Next, the divergent synthesis of trifluoromethylated fiveꢀ
10 (2b), paraꢀ (2c–f), metaꢀ (2g), and orthoꢀ substituted (2h) aryl,
hetereoaryl (2i), and alkyl group (2j). The reactions of
isocyanides 2 with electronꢀdeficient (2d–f) and ꢀneutral aryl
groups (2b and 2g) are faster than the ones with electronꢀrich aryl 40 membered heterocycles was investigated from the formal [3+2]ꢀ
groups (2c and 2h). To our delight, alkyl substituted isocyanide
15 2j also gave the products 3aj and 3cj in excellent yields when the
catalyst loading was increased to 30 mol%.
cycloadditon of isocyanide 2a with polar double bonds (Scheme
3). Under the standard conditions for aldehydes (Table 1, entry
7), the cycloaddition of 2a with ketone 4 gave the oxazoline 5
with two adjacent tetrasubstituted tertiary carbon center in
45 excellent yield. When the imine 6 and acrylonitrile 8 were used,
the trifluoromethylated imidazoline 724 and pyrroline 9 were
obtained in 95% and 60% yields, respectively.
Table 3 Scope of trifluoromethlated isocyanides 2a
aReaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), catalyst and base in
solvent (2.0 mL) at 15 oC; isolated yields. Ag2CO3 (10 mol%), DBU (20
b
mol%). cAg2CO3 (30 mol%), DBU (60 mol%).
Scheme 3 Synthesis of CF3ꢀsubstituted heterocycles.
50
To test the synthetic utility of the present synthetic protocol,
the transformation of the oxazole to βꢀamino alcohol was
performed. As shown in Scheme 4, the hydrolysis of oxazoles
3pa1 and 3pa2 under acidic conditions provide the βꢀ
trifluoromethylated βꢀamino alcohol 10a and 10b in quantitative
20
On the basis of our above observations (Table 1ꢀ3) and
literature precedent on the silverꢀcatalyzed formal [3+2]ꢀ
cyclization of isocyanoacetate,17 a plausible catalytic cycle is
proposed (Scheme 2). The reaction starts with the formation of a
complex I from silver and isocyanide 2, deprotonation by DBU to
55 yields, respectively.
25 produce carbanion silver intermediate II or its tautomer
Scheme 4 Transformation of oxazolines to βꢀtrifluoromethylated building
blocks.
Finally, the synthesis of the chiral trifluoromethylated
60 oxzolines was also investigated by the asymmetric version of this
[3+2]ꢀcycloadditions (Scheme 5). Preliminary attempts revealed
that 3ah was obtained in 88% combined yield in the presence of
Dixon’s ligand,17a although the diastereoselectivity is moderate
(dr = 2.7 : 1), the enantioselectivity of both diasteroisomers is
65 high (enantiomeric excess is 83% and 93%, respectively). Under
the identical conditons, oxzoline 3aa was obtained in 98%
combined yield (dr = 2.5 : 1) with moderate but promising 61%
and 72% ee of two diasteroisomers, respectively (see the
Supporting Information for details).
Scheme 2 Plausible catalytic cycle for oxazoline formation.
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trifluoromethylated methyl isocyanides with polar double bonds
has been developed for the expeditious synthesis of various
trifluoromethylated heterocycles, such as oxazolines, imidazoline
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stable and versatile complex of αꢀisocyanoꢀαꢀtrifluoromethylated
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4
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