Transition metal-free trifluoromethylation of n-Allylamides with sodium Trifluoromethanesulfinate: Synthesis of Trifluoromethyl-containing oxazolines

Article abstract of DOI:10.1002/adsc.201400144

A transition metal-free method for the trifluoromethylation of N-allylamides has been developed, and the corresponding trifluoromethylcontaining oxazolines were prepared in moderate to good yields. The protocol uses readily available substituted N-allylamides as the starting materials, inexpensive and easily stored sodium trifluoro- ACHTUNGTRENUNGmethanesulfinate as the trifluoromethyl source, iodobenzene diacetate as the oxidant, and the procedure involves sequential intermolecular trifluoromethylation of alkenes with sodium trifluoro- ACHTUNGTRENUNGmethanesulfinate and intramolecular cyclization. This is the first example to prepare CF3-containing oxazolines. Therefore, the present method should afford an efficient and practical strategy for synthesis of other CF3-containing cyclic compounds.

Full text of DOI:10.1002/adsc.201400144

UPDATES
DOI: 10.1002/adsc.201400144
Transition Metal-Free Trifluoromethylation of N-Allylamides with
Sodium Trifluoromethanesulfinate: Synthesis of Trifluoromethyl-
Containing Oxazolines
Jipan Yu,a Haijun Yang,a and Hua Fua,*
a
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of
Chemistry, Tsinghua University, Beijing 100084, Peopleꢀs Republic of China
Fax : (+86)-10-6278-1695; e-mail: fuhua@mail.tsinghua.edu.cn
Received: February 7, 2014; Revised: August 1, 2014; Published online: November 5, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400144.
Abstract: A transition metal-free method for the
trifluoromethylation of N-allylamides has been de-
veloped, and the corresponding trifluoromethyl-
containing oxazolines were prepared in moderate to
good yields. The protocol uses readily available sub-
stituted N-allylamides as the starting materials, in-
expensive and easily stored sodium trifluoro-
able N-allylamides to oxazoles is an attractive alterna-
tive to traditional processes,[4] and the use of transi-
tion metals such as Au,[5] Pd,[6] Ag,[7] Cu,[8] and Mo[9]
greatly promotes the synthesis of various oxazole de-
rivatives. On the other hand, the CF3-containing mol-
ecules exhibit unique properties including elevated
electronegativity, hydrophobicity, metabolic stability,
and bioavailability, so they often find use in pharma-
ceuticals, agrochemicals and functional materials.[10,11]
Recently, the introduction of the trifluoromethyl
group to various organic molecules has attracted wide
attention,[12] and there has been great progress in
transition metal-mediated or catalyzed functionaliza-
tions of alkenes.[13] Inspiringly, the methods for transi-
tion metal-free trifluoromethylation have recently
been developed. Baran and co-workers have reported
ACHTUNGTRENNUNGmethanesulfinate as the trifluoromethyl source,
iodobenzene diacetate as the oxidant, and the pro-
cedure involves sequential intermolecular trifluoro-
methylation of alkenes with sodium trifluoro-
ACHTUNGTRENNUNGmethanesulfinate and intramolecular cyclization.
This is the first example to prepare CF3-containing
oxazolines. Therefore, the present method should
afford an efficient and practical strategy for synthe-
sis of other CF3-containing cyclic compounds.
À
an efficient transition metal-free C H trifluoromethy-
lation of heterocycles,[14] and Nicewiczꢀs group has de-
veloped a novel transition metal-free hydrotrifluoro-
methylation of alkenes with N-Me-9-mesitylacridini-
um as a photoredox catalyst.[15] Nevado and co-work-
ers have explored a transition metal-free aryltrifluoro-
methylation of activated alkenes with Togni’s
reagent.[16] We have developed an efficient transition
metal-free trifluoromethylation and arylation of al-
kenes to yield 3-(trifluoromethyl)-indolin-2-one deriv-
Keywords: difunctionalization; oxazoles; sodium
trifluoromethanesulfinate; transition metal-free
procedure; trifluoromethylation
Introduction
The oxazole motif is an important nitrogen heterocy- atives with sodium trifluoromethanesulfinate.[17] To
cle that widely occurs in many natural products, as the best of our knowledge, the synthesis of CF3-con-
well as biologically and pharmaceutically active mole- taining oxazole derivatives has not been reported thus
cules.[1] Furthermore, 2,5-substituted oxazoles are far. Herein, we report an efficient transition metal-
useful building blocks and intermediates in organic free trifluoromethylation of N-allylamides leading to
synthesis.[2] The traditional methods for the synthesis CF3-containing oxazole derivatives by using inexpen-
of oxazoles mainly include both dehydration of an sive, readily available and easily stored sodium tri-
amido alcohol and condensation of a nitrile with an fluoromethanesulfinate (Langloisꢀs reagent[18]) as the
amino alcohol.[3] However, they usually need extend- trifluoromethyl source.
ed reaction times and elevated temperatures, and the
dehydration method requires stoichiometric amounts
of dehydrating agent in which the product purification
is tedious. The oxidative cyclization of readily avail-
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Table 1. Optimization of conditions on trifluoromethylation of 4-methyl-N-(2-phenylallyl)benzamide (1b) with CF3SO2Na
leading to 2-5-phenyl-2-para-tolyl-5-(2,2,2-trifluoroethyl)-4,5-dihydrooxazole (2b).[a]
Entry
Cat.
Oxidant
Solvent
Temp. [oC]
Yield [%][b]
1
2
3
4
5
6
7
8
–
–
–
–
–
–
–
–
m-CPBA
t-BuOOH
PhI(OAc)2
K2S2O8
DCE
DCE
DCE
DCE
90
90
90
90
90
90
90
90
90
60
90
90
90
90
trace
28
72
trace
0
68
19
57
54
58
53
40
54
–
DCE
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
CH2Cl2
toluene
MeCN
EtOAc
DCE
DCE
DCE
DCE
DCE
9
–
–
CuI
Pd(OAc)2
FeCl3
NiCl2
10
11
12
13
14
63
[a]
Reaction conditions: 4-methyl-N-(2-phenylallyl)benzamide (1b) (0.2 mmol), CF3SO2Na (0.5 mmol), oxidant (0.5 mmol),
catalyst (0.02 mmol), solvent (2 mL), temperature (60 or 908C), reaction time (24 h) under nitrogen atmosphere.
Isolated yield.
[b]
Results and Discussion
a lower yield due to steric hindrance of the ortho-
methyl (entry 4). The substrates with R2 =aryl or hy-
As shown in Table 1, our search for optimized reac- drogen provided higher yields than 1t with R2 =
tion conditions began by treating 4-methyl-N-(2-phe- methyl (entry 20), and 1u with an internal alkene
nylallyl)benzamide (1b) with CF3SO2Na in the pres- gave 41% yield (entry 21). A lower temperature and
ence of different oxidants in dichloroethane (DCE) at longer time were required for 1v containing R1 =
908C under a nitrogen atmosphere (entries 1–4), and methyl (entry 22). The trifluoromethylation leading to
PhI(OAc)2 gave the highest yield (entry 3). No target CF3-containing oxazolines (2) could tolerate various
product was observed in the absence of oxidant functional groups including C F bond (entry 7), C Cl
(entry 5). Other solvents were attempted (entries 6– bond (entries 8 and 15), C Br bond (entry 9), nitro
9), and 1,2-dichloroethane (DCE) provided the best (entries 10 and 11), nitrogen heterocycles (entries 12
result (compare entries 3, 6–9). When the tempera- and 18) and oxygen heterocycle (entries 13 and 19) in
ture was decreased to 608C, the yield was reduced the substrates.
À
À
À
(entry 10). Four common catalysts were added to the
Inspired by the results above, we prepared spirocy-
reaction system, and the reactivity was obviously de- clic compound 2w by using the present method. As
creased (entries 11–14). The results showed that the shown in Scheme 1, 3,4-dihydronaphthalen-1(2H)-one
transition metals did not catalyze this reaction (on the (3) underwent the three-step reaction (addition of
contrary, they inhibited the reactivity of the substrates), TMSCN to ketone, reduction and formation of am-
so the transition metal-free trifluoromethylation of N- monium) to provide (1,2-dihydronaphthalen-4-yl)me-
allylamides is suitable under following conditions: thanamine hydrochloride (4) in 31% total yield, and
PhI(OAc)2 as the oxidant, DCE as the solvent at then reaction of 4 with 4-methylbenzoyl chloride in
908C under a nitrogen atmosphere.
the presence of triethylamine gave 1w in 80% yield.
After getting the optimum reaction conditions, we Finally, trifluoromethylation of 1w with CF3SO2Na
investigated the scope for the trifluoromethylation of under the standard conditions afforded the target
N-allylamides (1) with CF3SO2Na leading to CF3-con- product (2w) in 43% yield.
taining oxazole derivatives. As shown in Table 2, the
We attempted the synthesis of chiral oxazolines
tested substrates provided moderate to good yields. containing CF3 groups. As shown in Scheme 2, tri-
For substituents on the Ar of N-allylamides (1), those fluoromethylation of (R)-N-(1-phenylallyl)benzamide
substrates containing electron-donating groups with CF3SO2Na was performed under the standard
showed slightly higher reactivity than those with elec- conditions, a pair of diastereoisomers of 2x and 2x’
tron-withdrawing groups, and substrate 1d gave
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Transition Metal-Free Trifluoromethylation of N-Allylamides
Table 2. Trifluoromethylation of N-allylamides (1) with CF3SO2Na leading to CF3-containing oxazolines (2).[a]
[a]
Reaction conditions: N-allylamide (1) (0.2 mmol), CF3SO2Na (0.5 mmol), PhI(OAc)2 (0.5 mmol), DCE (2 mL), tempera-
ture (908C), reaction time (24 h) under nitrogen atmosphere.
Isolated yield.
Temperature (408C), reaction time (72 h).
[b]
[c]
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Jipan Yu et al.
Scheme 1. Synthesis of compound 2w by using the present method.
fore, the present method is effective for the scaled-up
synthesis of CF3-containing oxazolines.
We explored the possible reaction mechanism for
the transition metal-free trifluoromethylation of N-al-
lylamides. As shown in Scheme 4, the radical scaveng-
er, 2.5 equiv. of 2,2,6,6-tetramethylpiperidinyl-1-oxyl
(TEMPO), was added to the reaction system of
4-methyl-N-(2-phenylallyl)benzamide
(1b)
and
CF3SO2Na, and the mixture was treated under the
standard conditions. No target product was found,
and the result showed that the reaction could involve
a free radical intermediate process. Further, TEMPO-
CF3 at 19F NMR À55 ppm was not observed by
Scheme 2. Synthesis of chiral oxazolines 2x and 2x’.
(dr=4:1) was observed, and pure products 2x and 2x’ 19F NMR, which implied that other free radicals
were obtained after isolation by a preparative TLC.
rather than CCF3 occurred at the beginning of the pro-
A scale-up experiment was investigated by using cess.[19] Therefore, a possible mechanism for the tran-
the trifluoromethylation of 1b as an example sition metal-free trifluoromethylation of N-allyla-
(Scheme 3). Reaction of 10 mmol (2.51 g) of 1b with mides is proposed in Scheme 5 according to the re-
25 mmol (4.90 g) of CF3SO2Na under the standard sults above and the previous references.[19,20] First, re-
conditions provided 2b in 55% yield (1.76 g). There- action of PhI(OAc)2 with CF3SO2Na provides I or II
leaving NaOAc, and desorption of I or II gives free
radicals III and IV or V under the conditions of heat-
ing.[19] Treatment of IV or V with N-allylamide (1) af-
fords VI freeing SO2 and PhI, and intramolecular cy-
AHCTUNGTREGcNNUN lization of VI in the presence of III yields the target
product (2) freeing AcOH.
Conclusions
We have developed a simple, efficient and practical
transition metal-free trifluoromethylation of N-allyl-
AHCTUNGTRENNUNG
Scheme 3. Synthesis of 2b on a gram scale under the stan-
dard conditions.
ACHTUNGTRENNUNG
Scheme 4. Treatment of 4-methyl-N-(2-phenylallyl)benzamide (1b) with CF3SO2Na in the presence of TEMPO under the
standard conditions.
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Transition Metal-Free Trifluoromethylation of N-Allylamides
Scheme 5. Possible mechanism for the trifluoromethylation of N-allylamides with CF3SO2Na.
5-(4-Chlorophenyl)-2-phenyl-5-(2,2,2-trifluoroethyl)-4,5-
and easily stored CF3SO2Na as the trifluoromethyl
source, PhI(OAc)2 as the oxidant, and no transition
metal, ligand and additive were required. The proce-
dure avoided contamination of transition metals to
the products, and it is economical and environment
friendly chemistry. The reactions comprise intermo-
lecular trifluoromethylation of alkenes and intramo-
dihydrooxazole (2o): Eluent: petroleum ether/ethyl acetate
1
(3:1); isolated yield: 48 mg (71%); colorless film. H NMR
(400 MHz, CDCl3): d=8.04 (d, J=7.7 Hz, 2H), 7.53 (t, J=
7.0 Hz, 1H), 7.46 (t, J=7.5 Hz, 2H), 7.38–7.33 (m, 4H), 4.36
(d, J=14.9 Hz, 1H), 4.18 (d, J=14.8 Hz, 1H), 2.88 (dq, J=
11.1 Hz, J=10.0 Hz, 2ꢂ1H); 13C NMR (100 MHz, CDCl3):
d=162.9, 141.0, 134.0, 132.0, 129.0, 128.6, 128.4, 127.1, 126.0,
lecular cyclization, and the corresponding CF3-con- 124.8 (q, J=278.6 Hz), 84.4, 68.4, 44.3 (q, J=27.3 Hz);
19F NMR (376 MHz, CDCl3): d=À62.19 (s, 3F); ESI-MS:
taining oxazolines were obtained in moderate to good
yields. This is the first example to prepare CF3-con-
taining oxazole derivatives via difunctionalization of
alkenes. We believe that the present strategy will find
wide application in the synthesis of other CF3-contain-
ing cyclic compounds.
m/z=340.5 [M+H]+.
2-(Furan-2-yl)-5-(2,2,2-trifluoroethyl)-4,5-dihydrooxazole
(2s): Eluent: petroleum ether/ethyl acetate (5:1); isolated
yield: 30 mg (68%); colorless film. 1H NMR (400 MHz,
CDCl3): d=7.60 (d, J=3.3 Hz, 1H), 7.47 (d, J=4.9 Hz, 1H),
7.10–7.07 (m, 1H), 5.01–4.93 (m, 1H), 4.25 (dd, J=14.8 Hz,
J=9.9 Hz, 1H), 3.78 (dd, J=14.8 Hz, J=7.1 Hz, 1H), 2.71–
2.62 (m, 1H), 2.47–2.38 (m, 1H); 13C NMR (100 MHz,
CDCl3): d=159.4, 130.6, 130.2, 129.6, 127.6, 125.2 (q, J=
277.0 Hz), 73.6, 60.3, 39.3 (q, J=28.1 Hz); 19F NMR
Experimental Section
(376 MHz, CDCl3): d=À62.30 (s, 3F); ESI-MS: m/z=220.2
[M+H]+.
General Procedure for the Synthesis of Compounds
2a–w
A 25-mL Schlenk tube was charged with a magnetic stirrer
and 1,2-dichloroethane (2.0 mL). Substituted N-allylamide
(1) (0.2 mmol), CF3SO2Na (0.5 mmol, 78 mg), PhI(OAc)2
Acknowledgements
The authors wish to thank the National Natural Science
Foundation of China (Grant Nos. 21172128, 21372139 and
21221062), and the Ministry of Science and Technology of
China (Grant No. 2012CB722605) for financial support.
(0.5 mmol, 160 mg) were added to the tube under a nitrogen
atmosphere. The tube was sealed, and the mixture was
stirred at 908C for 24 h under a nitrogen atmosphere. The
resulting mixture was cooled to room temperature, the sol-
vent was removed by a rotary evaporator, and the residue
was purified by column chromatography on silica gel using
petroleum ether/ethyl acetate as eluent to give the desired
target product.
References
Three representative examples are shown below.
2,5-Diphenyl-5-(2,2,2-trifluoroethyl)-4,5-dihydrooxazole
(2a): Eluent: petroleum ether/ethyl acetate (5:1); isolated
yield: 38 mg (63%); colorless film. 1H NMR (400 MHz,
CDCl3): d=8.05 (d, J=7.2 Hz, 2H), 7.52 (t, J=7.3 Hz, 1H),
7.46 (t, J=7.5 Hz, 2H), 7.41–7.36 (m, 4H), 7.33–7.30 (m,
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27.3 Hz); 19F NMR (376 MHz, CDCl3): d=À65.87 (s, 3F);
ESI-MS: m/z=306.6 [M+H]+.
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