Copper-catalyzed oxidative trifluoromethylation of benzylic sp3 C-H bond adjacent to nitrogen in amines

Article abstract of DOI:10.1016/j.tetlet.2011.02.038

Copper-catalyzed trifluoromethylation via oxidative sp³ C-H activation at the α-position of nitrogen in tetrahydroisoquinoline derivatives using DDQ and Ruppert-Prakash reagent has been successfully achieved. The reaction of various amines gave

Full text of DOI:10.1016/j.tetlet.2011.02.038

Tetrahedron Letters 52 (2011) 1898–1900
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Tetrahedron Letters
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Copper-catalyzed oxidative trifluoromethylation of benzylic sp3 C–H bond
adjacent to nitrogen in amines
Hiromasa Mitsudera a,b, Chao-Jun Li a,
⇑
a Department of Chemistry and FQRNT Center for Green Chemistry and Catalysis, McGill University, 801 Sherbrooke Street West, Montreal, Quebec, Canada H3A 2K6
b Agric. Chem. Res. Lab., Sumitomo Chem. Co., Ltd, 4-2-1 Takatsukasa, Takarazuka, Hyogo 665, Japan
a r t i c l e i n f o
a b s t r a c t
Copper-catalyzed trifluoromethylation via oxidative sp3 C–H activation at the
tetrahydroisoquinoline derivatives using DDQ and Ruppert–Prakash reagent has been successfully
achieved. The reaction of various amines gave the corresponding trifluoromethylated products in
15–90% yields under mild conditions.
a-position of nitrogen in
Article history:
Received 3 February 2011
Accepted 8 February 2011
Available online 17 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
C–H functionalization
Copper-catalyzed
Fluorination
Oxidative coupling
Heterocycle
Fluorinated moieties such as the trifluoromethyl group can dra-
matically influence the polarity, solubility, chemical reactivity, and
intermolecular interactions of an entire molecule.1a–c Amines tri-
cat. CuI
N
N
rt, DDQ, DMF
Ruppert-Prakash reagent
R
R
X
X
fluoromethylated at the a-position of nitrogen are important inter-
H
CF3
mediates for pharmaceuticals, agrochemicals, and organic
materials.1d–g One of the general methods to obtain trifluoro-
methyl containing amines is based on the addition of a CF3 group
on to imine double bonds by using, for example, the Ruppert–Prak-
ash reagent (trifluoromethyltrimethylsilane, CF3TMS).2 Although
Figure 1. Copper-catalyzed trifluoromethylation of C–H bond.
To begin our study, the substrate and oxidant reported by our
group earlier4 were selected as the initial trial (Table 1, entry 1).
Unfortunately, the desired product was not observed and most of
the starting materials were recovered without change. We contem-
plated that CF3TMS was most likely decomposed by the reaction
with oxidants under these reaction conditions. It is important to
note that during the process of our investigations, Qing and
these methods have provided
a-trifluoro-methylated amine deriv-
atives effectively,3 a more direct and simpler synthetic method
such as the direct trifluoro-methylation of the a-position of nitro-
gen via sp3 C–H activation is still highly attractive.
In our own studies, we recently reported various cross-dehy-
drogenative-coupling reactions between various nucleophiles and
sp3 C–H bonds via the in situ generation of iminium intermediates
by using an oxidizing reagent.4 Highly efficient arylation5 and
phosphinylation6 of sp3 C–H bonds are also possible. We specu-
lated the possibility of a direct catalytic conversion of the sp3
co-workers reported
a direct trifluoromethylation of tertiary
amines with benzoyl peroxide using CF3TMS in methylene chloride
under refluxing conditions.7 However, the reaction conditions
provided over-oxidized byproducts and required an additional
reduction step to obtain the desired products. Furthermore, it
cannot be modified for asymmetric synthesis readily. In addition,
transition metal catalyzed trifluoromethylation of imine and imin-
ium (proposed intermediates in our investigation) has not been
reported to the best of our knowledge.
In order to find conditions that will selectively oxidize the
amine while at the same time will not destroy CF3TMS, different
oxidants were further tested and we found that the reaction with
DDQ8 as an oxidant gave the desired compound in moderate yield
(Table 1, entry 2).
C–H bond at the
a-position of amines into trifluoromethylated
products by using CF3TMS, amenable for potential asymmetric syn-
thesis to generate optically active trifluoromethylated derivatives.
Herein, we wish to report a highly efficient copper-catalyzed triflu-
oromethylation via oxidative sp3 C–H activation at the
a-position
of nitrogen in tetrahydroisoquinoline derivatives using DDQ and
CF3TMS under very mild conditions (Fig. 1).
⇑
Corresponding author. Tel.: +1 514 398 8457; fax: +1 514 398 3797.
E-mail address: cj.li@mcgill.ca (C.-J. Li).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.038

H. Mitsudera, C.-J. Li / Tetrahedron Letters 52 (2011) 1898–1900
1899
Table 1
Table 2
Optimization of reaction conditionsa
Copper-catalyzed trifluoromethylation of aminesa
catalyst
oxidant
10 mol%CuI
3 equiv CF3TMS/KF
1.3 equiv DDQ
CF3TMS/KF
N
N
N
Ph
R
N
Ph
DMF
temp., 18h
DMF
R
CF3
CF3
rt,18h
1
2
1a
2a
Entry Oxidant (equiv) Catalyst (mol%) KFc (equiv) Temp Yieldb (%)
Entry
R
Product
Yieldb (%)
1
2
3
4
5
6
7
8
Ph-
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
––
––
––
85 (81)
67 (65)
62 (57)
73 (73)
76 (69)
63(58)
49 (41)
60 (46)
15 (11)
52 (40)
55 (48)
32(––)
NDc
1
2
3
4
5
6
7
8
TBHP(2.0)
DDQ (2.0)
DDQ (1.0)
DDQ (2.0)
DDQ (1.3)
DDQ (1.3)
DDQ (1.3)
DDQ (1.3)
DDQ (1.3)
DDQ (1.3)
DDQ (1.3)
DDQ (1.3)
DDQ (1.3)
DDQ (1.3)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (5)
CuI (10)
CuI (20)
CuBr (10)
CuCl (10)
CuOTf (10)
CuI (10)
CuI (10)
CuI (10)
None
2
2
2
3
3
3
3
3
3
3
4
3
0d
3
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
rt
nd (73)
52
72 (4)
77
90
87
84
72
68
68
2-MeOC6H4–
3-MeOC6H4–
4-MeOC6H4–
4-BrC6H4–
4-ClC6H4–
4-CF3C6H4–
1-Naphthyl-
2-Pyridyl-
Bn-
9
9
10
11
12
13
14
15
10
11
12
13
14
2-Pyridylmethyl-
86
85
46
0
Allyl-
Piv-
Boc-
H-
rt
rt
NDc
ND
a
Reactions were carried out on a 0.15 mmol scale in DMF (0.5 mL) under argon
with oxidant, CF3TMS/KF and catalyst.
Reported yields were based on 1a and determined by NMR methods using an
internal standard. Recoveries are given in parentheses.
a
Reactions were carried out on a 0.15 mmol scale in DMF (0.5 mL) under argon
b
with CF3TMS/KF as oxidant and catalyst.
Reported yields were based on 1 and determined by 1H NMR methods using an
b
c
internal standard. Isolated yields are given in parentheses.
Same amount of CF3TMS was added in the reaction.
3 equiv of CF3TMS was added in the reaction.
c
d
Starting materials were recovered.
In order to improve the yield, the reaction was conducted by
changing the reaction parameters, such as catalyst, solvent, and
reactant ratio. The reaction with 3.0 equiv of CF3TMS/KF, 1.3 equiv
of DDQ, together with 5–10 mol% of CuI as the catalyst stirred in
DMF under an argon atmosphere at 70 °C overnight gave the
desired product 2a in high yield (Table 1, entries 5 and 6). It is
important to note that, in these cases, the over oxidized byproduct
as reported by Qing and co-workers was not detected by 1H NMR.
We then carried out further examinations to know more details
about the reaction: in the absence of KF, product 1a was observed
in moderate yield under the above conditions (Table 1, entry 13);
and no product was detected in the absence of CuI (Table 1, entry
14). The reaction proceeded equally well at room temperature
(Table 1, entry 12), which is very important for potential asymmet-
ric synthesis.
N
DDQ
R
1
2
DDHQ
Cu CF3
Cu
X
B
C
A
TMS-F + KX
Cl
CF3TMS + KF
Cl
X = I or DDHQ
=
DDHQ
HO
O
Next, the scope of our reaction was investigated by the treat-
ment of various amines under the aforementioned optimized
reaction conditions (Table 2).
NC
CN
Scheme 1. Plausible mechanism for the trifluoromethylation.
Both 2-aryl-substituted and 2-alkyl-substituted tetrahydroiso-
quinolines were effective substrates for the oxidative trifluorome-
thylation reaction. The reaction with 2-benzyl, 2-pyridylmethyl,
and 2-allyl tetrahydroisoquinolines gave 1-trifluoromethylated
tetrahydroisoquinolines regioselectively (Table 2, entries 10–12).
In the case of the 4-trifluoromethylphenyl group, the yield de-
creased possibly due to the increased oxidative potential of the
corresponding amine derivative caused by the electron-withdraw-
ing trifluoromethyl group. Consistent with this hypothesis, sub-
strates bearing even stronger electron-withdrawing groups, such
as 2-acyl and alkoxycarbonyl group did not react at all with DDQ
at room temperature (Table 2, entries 13 and 14).
The detailed mechanism for the reaction remains to be
elucidated. On the basis of the previous literature of the copper
catalyzed trifluoromethylation9 and the oxidation of tetrahydro-
isoquinolines with DDQ,8 oxidation of N-substituted tetrahydro-
isoquinoline with DDQ generates dihydroquinoline salt A as the
first step. Next, trifluoromethylcopper B, generated by the reac-
tion of CuI and CF3TMS/KF, undergoes nucleophilic addition to
give the desired products and copper salt C. The generated C
would be reused to form CF3Cu B in the nucleophilic step again
(Scheme 1.)
In summary, a copper-catalyzed trifluoromethylation of sp3
C–H bonds adjacent to a nitrogen atom was developed. The reac-
tion of various tetrahydroisoquinoline derivatives gave the corre-
sponding trifluoromethylated products in 15–90% yields under
very mild conditions. The scope, applications, mechanism, and
asymmetric version of this reaction are under investigation.
Experimental procedure: Compounds 2a, 2b, 2d, 2f, 2g, 2j, and 2l
are known compounds and their 1H NMR, 19F NMR, and 13C NMR
spectra are consistent with the literature.7
To a mixture of CuI (3.0 mg, 0.015 mmol), 2-phenyl-1,2,3,4-tet-
rahydroisoquinoline (36.4 mg, 0.15 mmol), potassium fluoride
(26.1 mg, 0.45 mmol), and 0.3 mL DMF were added. Then trifluo-
romethyltrimethylsilane (66 lL, 0.45 mmol) was dropped into
the mixture under argon at room temperature. The resulting mix-
ture was stirred for 15 min. Then DDQ (0.2 mL, 1.0 M in DMF,

1900
H. Mitsudera, C.-J. Li / Tetrahedron Letters 52 (2011) 1898–1900
Yagupolskii, Y. L.; Tyrra, W.; Naumann, D.; Fischer, H. T. M.; Scherer, H. J.
Fluorine Chem. 2008, 129, 14.
4. (a) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 11810; (b) Li, Z.; Li, C.-J. J. Am. Chem.
Soc. 2005, 127, 6968; (c) Basle, O.; Li, C.-J. Green Chem. 2007, 9, 1047; (d) Li, C. J.
Acc. Chem. Res. 2009, 42, 335.
5. Basle, O.; Li, C.-J. Org. Lett. 2008, 10, 3661.
6. Baslé, O.; Li, C.-J. Chem. Commun. 2009, 4124.
7. Chu, L.; Qing, F.-L. Chem. Commun. 2010, 46, 6285.
8. Tsang, A. S.-K.; Todd, M. H. T. Tetrahedron Lett. 2009, 50, 1199.
9. Oishi, M.; Kondo, H.; Amii, H. Chem. Commun. 2009, 1909.
0.2 mmol) was dropped into the mixture over 5 min under argon at
room temperature. The resulting mixture was stirred at the same
temperature for 15 min. The resulting suspension was diluted with
hexane/ethyl acetate (3/1) solution and then saturated sodium
hydrogen carbonate aqueous solution was dropped into the reac-
tion mixture. After the organic layer was separated, the water layer
was extracted twice with hexane/ethyl acetate (3/1) solution. The
combined organic layer was washed twice with water and dried
with sodium sulfate. The resulting solution was filtered through
a short silica gel in a pipette eluting with hexane/ethyl acetate
(3/1). Solvent was evaporated and the residue was purified by flash
column chromatography on silica gel with hexane as eluent to give
the desired product.10
10. Characterization
of
unknown
compounds.
2-(3-Methoxyphenyl)-1-
(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline 2c: 1H NMR (300 MHz, CDCl3,
293 K, TMS): d ppm 7.34–7.19 (m, 5H), 6.59 (dd, J = 2.4 Hz, J = 8.1 Hz, 1H), 6.53
(t, J = 2.4 Hz, 1H), 6.42 (dd, J = 2.4 Hz, J = 8.1 Hz, 1H), 5.14 (q, J = 7.8 Hz, 1H),
3.82 (s, 3H), 3.83–3.75 (m, 1H), 3.55–3.47 (m, 1H), 3.07–3.02 (m, 2H). 19F NMR
(282 MHz, CDCl3): d ppm À71.5 (d, J = 7.9 Hz, 3F). 13C NMR (75 MHz, CDCl3,
293 K, TMS): d ppm 160.7, 150.7, 136.8, 130.0, 128.8 (t, J = 1.7 Hz), 128.7, 128.5,
127.9, 107.3 (d, J = 1.1 Hz), 103.5, 101.4, 60.7 (q, J = 26.5 Hz), 55.3, 43.6, 27.4 (d,
J = 1.1 Hz). HRMS ESI (m/z): [M+H]+ calcd for C17H17ONF3, 308.12568; found,
308.12536. 2-(4-Bromophenyl)-1-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline
2e: 1H NMR (300 MHz, CDCl3, 293 K, TMS): d ppm 7.38–7.23 (m, 6H), 6.83
(d, J = 9.0 Hz, 2H), 5.06 (q, J = 8.1 Hz, 1H), 3.80–3.73 (m, 1H), 3.48–3.40 (m, 1H),
3.09–3.01 (m, 2H). 19F NMR (282 MHz, CDCl3): d ppm À71.6 (d, J = 7.6 Hz, 3F).
13C NMR (75 MHz, CDCl3, 293 K, TMS): d ppm 148.3, 136.6, 132.0, 128.8 (d,
J = 4.4 Hz), 128.5, 126.5, 116.0, 111.2, 60.4 (q, J = 30.4 Hz), 43.7, 27.4. HRMS ESI
(m/z): [M+H]+ calcd for C16H14BrNF3, 356.02567; found, 356.02592. 2-(1-
Naphthyl)-1-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline 2h: 1H NMR
(300 MHz, CDCl3, 293 K, TMS): d ppm 8.35–8.31 (m, 1H), 7.89–7.86 (m, 1H),
7.63 (d, J = 8.1 Hz, 1H), 7.57–7.46 (m, 3H), 7.40–7.24 (m, 4H), 7.02 (br s, 1H),
4.99 (q, J = 8.4 Hz, 1H), 3.87 (br s, 1H), 3.44–3.40 (m, 1H), 2.82 (br s, 2H). 19F
NMR (282 MHz, CDCl3): d ppm À72.5 (br s, 3F). 13C NMR (75.4 MHz, CDCl3,
293 K, TMS): d ppm 148.3, 137.3, 134.9, 129.3, 128.7 (q, J = 2.2 Hz), 128.4,
126.3, 126.2, 126.1, 125.7, 125.0, 123.8, 119.8, 113.1, 62.3(q, J = 28.7 Hz), 47.2,
26.2. HRMS ESI (m/z): [M+H]+ calcd for C20H17NF3, 328.13076; found,
328.13126. 2-(2-Pyridyl)-1-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline 2i:
1H NMR (300 MHz, CDCl3, 293 K, TMS): d ppm 8.23 (d, J = 3.6 Hz, 1H), 7.52 (t,
J = 6.6 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.33–7.22 (m, 3H), 6.71 (d, J = 7.8 Hz,
1H), 6.67 (t, J = 5.1 Hz, 1H), 6.46 (q, J = 8.4 Hz, 1H), 3.87–3.81 (m, 1H), 3.78–3.70
(m, 1H), 3.18–3.09 (m, 1H), 5.05–2.56 (m, 1H). 19F NMR (282 MHz, CDCl3): d
ppm À71.6 (d, J = 8.8 Hz, 3F). 13C NMR (75.4 MHz, CDCl3, 293 K, TMS): d ppm
157.7, 147.6, 137.8, 136.6, 129.2, 129.1, 129.0, 128.6, 128.5, 127.8, 126.4,
124.0, 113.8, 106.5, 54.6 (q, J = 30.4 Hz), 41.5, 27.5 (d, J = 1.1 Hz). HRMS ESI
(m/z): [M+H]+ calcd for C15H14N2F3, 279.11036; found, 279.10998. 2-(2-
Pyridylmethyl)-1-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline 2k: 1H NMR
(300 MHz, CDCl3, 293 K, TMS): d ppm 8.52 (d, J = 4.5 Hz, 1H), 7.74–7.68 (m,
1H), 7.59 (d, J = 7.8 Hz, 1H), 7.31–7.16 (m, 5H), 4.36 (q, J = 8.1 Hz, 1H), 4.14 (s,
2H), 3.31–3.23 (m, 1H), 2.87–2.85 (m, 2H), 2.79–2.73 (m, 1H). 19F NMR
(282 MHz, CDCl3): d ppm À73.2 (s, 3F). 13C NMR (75.4 MHz, CDCl3, 293 K,
TMS): d ppm 159.1, 148.9, 137.3, 136.9, 129.5 (d, J = 2.2 Hz), 128.6, 128.3,
128.2, 126.1, 122.6, 122.3, 62.8(d, J = 27.6 Hz), 62.5, 46.3, 27.3. HRMS ESI (m/z):
[M+H]+ calcd for C16H16N2F3, 293.12601; found, 293.12555.
Acknowledgments
We are grateful to the Canada Research Chair (Tier I) foundation
(to C.-J. Li), NSERC, FRQNT and McGill University for support of our
research.
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