Benzoyl peroxide (BPO)-promoted oxidative trifluoromethylation of tertiary amines with trimethyl(trifluoromethyl)silane

Article abstract of DOI:10.1039/c0cc01073a

The benzoyl peroxide (BPO)-promoted oxidative functionalization of tertiary amines under transition-metal-free reaction conditions was developed. Various 1-trifluoromethylated tetrahydroisoquinoline derivatives were prepared by employing this method. It c

Full text of DOI:10.1039/c0cc01073a

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Benzoyl peroxide (BPO)-promoted oxidative trifluoromethylation
of tertiary amines with trimethyl(trifluoromethyl)silanew
Lingling Chua and Feng-Ling Qing*ab
Received 22nd April 2010, Accepted 7th July 2010
DOI: 10.1039/c0cc01073a
The benzoyl peroxide (BPO)-promoted oxidative functionalization
of tertiary amines under transition-metal-free reaction
conditions was developed. Various 1-trifluoromethylated tetra-
hydroisoquinoline derivatives were prepared by employing this
method. It constitutes the first example of direct trifluoro-
methylation of tertiary amines.
As tetrahydroisoquinoline derivatives are important structural
features of pharmaceutical and natural products6 and synthetic
1-trifluoromethyl analogues of tetrahydroisoquinoline alkaloids
are of potential biological interest,7 we focused on the
direct oxidative trifluoromethylation of tetrahydroisoquinoline
derivatives. Prior to this work, the only way to construct the
1-trifluoromethyltetrahydroisoquinoline framework was via the
intramolecular Pictet–Spengler reaction.7 Recently, an effective
CuBr-catalyzed oxidative difluoromethylation of tertiary amine
with difluoroenol silyl ethers using tert-butyl hydroperoxide
(TBHP) as the oxidant was developed by our group.4q On the
basis of this work, we started the oxidative trifluoromethylation
of tertiary amine by treatment of 1,2,3,4-tetrahydroisoquinoline
1 with CF3TMS/KF in the presence of catalytic CuBr and
TBHP. Unfortunately, the desired product 1a was not observed
and only a trace amount of compound 1b was obtained [eq. (1)].
Compound 1b may be formed from the further oxidation of 1a.
Altering the relative amounts of reagents, solvents and reaction
temperature did not lead to improvement. Since CuBr/TBHP is
widely used for a-C–H activation of tertiary amines to produce
iminium ion intermediates,4 we speculated that the failure of
oxidative trifluoromethylation under these reaction conditions
was because: (1) the rate of formation of nucleophile CF3ꢀ from
CF3TMS/KF is not consistent with the rate of generation of the
iminium ions; (2) the ‘‘CF3Cu’’,8 which was in situ generated
from CF3TMS/KF/CuBr, does not react with the iminium
ion; (3) the Ruppert–Prakash reagent (CF3TMS) undergoes
decomposition under these reaction conditions. Thus, we turned
our attention to exploring other transition metal catalysts and
oxidants for this oxidative trifluoromethylation.
Amines bearing a trifluoromethyl group located at the a-position
are widely applicable in the synthesis of pharmaceuticals and
agrochemicals,1 because the strongly electron withdrawing
nature and large hydrophobic domain of the trifluoromethyl
group can dramatically influence the basicity and solubility of
amines, and thus modify the bioavailability and stability of
target drugs. As a result, trifluoromethylated amines have
attracted considerable attention as synthetic targets. Among
these synthetic methods, one of the most effective methods for
synthesizing such compounds is the nucleophilic trifluoro-
methylation of imines or their equivalents with trimethyl-
(trifluoromethyl)silane (Ruppert–Prakash reagent, CF3TMS).2
Recently, direct functionalization of tertiary amines in the
a-position has attracted much interest in organic chemistry and
the fine chemical industry, since the starting materials could be
used directly without prefunctionalization and thus the reaction
had the advantages of atom- and step-economy, high efficiency,
low cost and minimal environmental impact.3–5 Generally, direct
oxidative transformation at the a-position of tertiary amines is
performed in two steps: a-C–H activation of amine to produce
iminium ion intermediates and subsequent reaction with nucleo-
philes. Transition-metal catalysts3–5 or metal–oxo species3a–g are
required for the initial C–H activation. In the light of environ-
mental consciousness and safety concerns, the development of
new transition-metal-free functionalization of tertiary amines is
desirable. To date, various nucleophiles have been used to
capture the iminium ions.3–5 However, to the best of our
knowledge, the reaction of trifluoromethyl-based nucleophilic
reagent (CF3ꢀ) with in situ generated iminium ion, which
would be a direct route to trifluoromethylated amines, has
not been reported. We describe herein the first effective, atom-
and step-economical synthesis of trifluoromethylated amines
through benzoyl peroxide (BPO)-mediated trifluoromethylation
of tertiary amines with trimethyl(trifluoromethyl)silane under
transition-metal-free reaction conditions.
ð1Þ
After screening of a number of reaction conditions, we were
delighted to find that the desired product 1a and the
corresponding oxidative product 1b were generated in 18%
yield (determined by 19F NMR) by using diethyl azodicarboxylate
(DEAD) as an oxidant in the absence of transition metal
catalyst. To improve this transformation, different oxidants
were further tested. Benzoyl peroxide (BPO) was found as the
best oxidant (Table 1, entries 1–5). Switching the solvent to
dichloromethane (DCM), the yield of the desired product 1a
and 1b was increased to 84%. Other solvents such as CH3CN,
1,2-dimethoxyethane (DME), 1,2-dichloroethane (DCE),
tetrahydrofuran (THF) and N,N-dimethylformamide (DMF)
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry, 345 Lingling Lu, Shanghai 200032, China.
E-mail: flq@mail.sioc.ac.cn; Fax: +86-21-64166128;
Tel: +86-21-54925187
b College of Chemistry, Chemical Engineering and Biotechnology,
Donghua University, 2999 North Renmin Lu, Shanghai 201620,
China
w Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/c0cc01073a
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 6285–6287 6285

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Table 1 Oxidative trifluoromethylation of tetrahydroisoquinoline 1a
less reactive (13–15). The presence of Cl, Br and allyl groups in
the products is very useful for further synthetic transformation
(5a, 11a, 14a). It is apparent that the increasing electron
density on the N-aromatic ring resulted in high selectivities
(high ratio of products a/b) while it had a slight impact on the
yields (3, 7). Furthermore, 2-phenyl-2,3,4,9-tetrahydro-1H-
pyrido[3,4-b]indole underwent the oxidative trifluoromethyl-
ation and the somewhat lower yield might be imputable to the
presence of unprotected amine (16).
Entry
Oxidant
Solvent
Yield (%)b (1a : 1b)
1
2
3
4
5
6
7
8
9
10
DEAD
NBS
AIBN
DDQ
BPO
BPO
BPO
BPO
BPO
BPO
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DME
18 (3.5 : 1)
35 (8.2 : 1)
8 (2.1 : 1)
—
72 (3.7 : 1)
44 (3.0 : 1)
64 (4.2 : 1)
68 (1.5 : 1)
52 (3.5 : 1)
84 (3.4 : 1) (82c)
Considering that the presence of trace transition metal
impurities may play a catalytic role in this transformation,
all reagents were purified extensively before use. Furthermore,
quantitative elemental analysis of BPO by ICP-AES (inductively
coupled plasma-atomic emission spectrometry) showed that
the concentration of all transition metals in the BPO employed
in our experiments is less than 0.50 ppm, and thus the
possibility of transition metal catalysis of this oxidative
trifluoromethylation could be excluded.
DCE
THF (reflux)
DMF
DCM (reflux)
a
The reaction was carried out with 0.2 mmol of 1, 0.6 mmol
of CF3TMS, 0.6 mmol of KF, 0.3 mmol of BPO in DCM (0.25 M).
b
The ratio of 1a/1b and yield were determined by 19F NMR using
c
benzotrifluoride as an internal standard. Isolated yield.
The detailed mechanism remains to be elucidated. However,
it is reasonable to assume that the reaction proceeds through a
radical intermediate on the basis of the previous literature.9,10
The radical intermediate A was probably formed by hydrogen
transfer via either of two different pathways. Electron transfer
from intermediate A gave iminium intermediate B. Thꢀe
subsequent nucleophilic capture of intermediate B by CF3
afforded the desired product (Scheme 1).
were also suitable for this oxidative trifluoromethylation albeit
giving moderate yields (entries 5–9). It should be noted that 1a
and 1b were not easily separated by flash chromatography. To
simplify the purification, hydrogenation of a mixture of 1a and
1b in the presence of Pd/C gave a single product 1a.
Next, the scope of this BPO-promoted oxidative trifluoro-
methylation was investigated by treatment of different tetra-
hydroisoquinoline derivatives under the aforementioned
optimized reaction conditions. As shown in Table 2, the
oxidative trifluoromethylation of all the substrates proceeded
smoothly to give the corresponding products in 35–89%
yields. In general, both N-aryl-substituted and N-alkyl
substituted tetrahydroisoquinolines underwent the reaction.
However, N-alkyl-substituted tetrahydroisoquinolines proved
We also examined the BPO-promoted direct functionalization
of tetrahydroisoquinoline 1 with other nucelophiles. The
results are depicted in Fig. 1. Indole, nitromethane, and
TMSCN all afforded the desired oxidative products 1c–1e in
moderate and high yields respectively, while a catalytic
amount of CuBr was needed in the reaction of 1 with
phenylacetylene, in which the participation of CuBr in the
generation of iminium ion could not be excluded. It was
Table 2 Trifluoromethylation of tetrahydroisoquinolinesa
a
Reaction conditions: amine (0.5 mmol), CF3TMS (1.5 mmol), KF (1.5 mmol), BPO (0.75 mmol), DCM (2 mL), reflux, 5–10 h. The data in
b
parentheses are the ratio of two products a/b, which determined by 19F NMR. Isolated yield after chromatography. Isolated yield of product a
d
after hydrogenation. The NO2 group was transformed to the NH2 group in the course of reduction by Pd/C.
c
c
6286 Chem. Commun., 2010, 46, 6285–6287
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N. Komiya and H. Terai, Angew. Chem., Int. Ed., 2005, 44,
6931; (c) S.-I. Murahashi, N. Komiya, H. Terai and T. Nakae,
J. Am. Chem. Soc., 2003, 125, 15312; (d) S.-I. Murahashi, Angew.
Chem., Int. Ed. Engl., 1995, 34, 2443; (e) S.-I. Murahashi, T. Saito,
T. Naota, H. Kumobayashi and S. Akutagawa, Tetrahedron Lett.,
1991, 32, 5991; (f) S.-I. Murahashi, T. Naota, T. Kuwabara,
T. Saito, H. Kumobayashi and S. Akutagawa, J. Am. Chem.
Soc., 1990, 112, 7820; (g) S.-I. Murahashi, T. Naota and
K. Yonemura, J. Am. Chem. Soc., 1988, 110, 8256;
(h) N. Chatani, T. Asaumi, S. Yorimitsu, T. I keda, F. Kakiuchi
and S. Murai, J. Am. Chem. Soc., 2001, 123, 10935; (i) S. J. Pastine,
D. V. Gribkov and D. Sames, J. Am. Chem. Soc., 2006, 128,
14220.
Scheme 1 The proposed mechanism of oxidative trifluoromethylation.
4 Copper-catalyzed oxidative transformation of tertiary amines, see:
(a) Z. Li and C.-J. Li, J. Am. Chem. Soc., 2004, 126, 11810;
(b) Z. Li and C.-J. Li, Org. Lett., 2004, 6, 4997; (c) Z. Li and
C.-J. Li, Eur. J. Org. Chem., 2005, 3173; (d) Z. Li and C.-J. Li,
J. Am. Chem. Soc., 2005, 127, 6968; (e) Z. Li and C.-J. Li, J. Am.
Chem. Soc., 2005, 127, 3672; (f) Z. Li, D. S. Bohle and C.-J. Li,
Proc. Natl. Acad. Sci. U. S. A., 2006, 103, 8928; (g) Z. Li and
C.-J. Li, J. Am. Chem. Soc., 2006, 128, 56; (h) Z. Li and C.-J. Li,
J. Am. Chem. Soc., 2006, 128, 11810; (i) Y. Zhang, Z. Li and
C.-J. Li, J. Am. Chem. Soc., 2006, 128, 4242; (j) O. Basle and
C.-J. Li, Green Chem., 2007, 9, 1047; (k) O. Basle and C.-J. Li, Org.
Lett., 2008, 10, 3661; (l) L. Zhao and C.-J. Li, Angew. Chem., Int.
Ed., 2008, 47, 7075; (m) C.-J. Li, Acc. Chem. Res., 2009, 42, 335;
(n) X.-L. Xu and X.-N. Li, Org. Lett., 2009, 11, 1027;
(o) Y.-M. Shen, M. Li, S.-Z. Wang, T.-G. Zhan, Z. Tan and
C.-C. Guo, Chem. Commun., 2009, 953; (p) Y. Zhang, H. Fu,
Y. Jiang and Y.-F. Zhao, Org. Lett., 2007, 9, 3813; (q) L. Chu,
X. Zhang and F.-L. Qing, Org. Lett., 2009, 11, 2197; (r) L. Huang,
X. Zhang and Y. Zhang, Org. Lett., 2009, 11, 3730;
(s) D. Sureshkumar, A. Sud and M. Klussmann, Synlett, 2009,
1558.
5 For other metal-catalyzed a-C–H activation of tertiary amines, see:
(a) R. B. Wilson Jr. and R. M. Laine, J. Am. Chem. Soc., 1985, 107,
361; (b) B. DeBoef, S. J. Pastine and D. Sames, J. Am. Chem. Soc.,
2004, 126, 6556; (c) A. J. Catino, J. M. Nichols, B. J. Nettles and
M. P. Doyle, J. Am. Chem. Soc., 2006, 128, 5648; (d) Z. Li, R. Yu
and H. Li, Angew. Chem., Int. Ed., 2008, 47, 7497; (e) C. M. Rao
Volla and P. Vogel, Org. Lett., 2009, 11, 1701; (f) W. Han and
A. R. Ofial, Chem. Commun., 2009, 5024.
6 For representative recent reviews, see: (a) K. W. Bentley, Nat.
Prod. Rep., 2005, 22, 249; (b) K. W. Bentley, Nat. Prod. Rep., 2006,
23, 444.
7 (a) A. S. Golubev, N. D. Chkanikov, M. Yu. Antipin, Yu.
T. Struchkov, A. F. Kolomiets and A. V. Fokin, Izv. Akad. Nauk,
Ser. Khim., 1992, 1831; (Chem. Abs., 1993, 118, 101); (b) P. Bravo,
M. Crucianelli, A. Farina, S. V. Meille, A. Volonterio and
M. Zanda, Eur. J. Org. Chem., 1998, 435; (c) V. M. Muzalevskiy,
V. G. Nenajdenko, A. V. Shastin, E. S. Balenkova and G. Haufe,
Tetrahedron, 2009, 65, 7553.
8 (a) D. M. Wiemers and D. J. Burton, J. Am. Chem. Soc., 1986, 108,
832; (b) H. Urata and T. Fuchikami, Tetrahedron Lett., 1991, 32,
91; (c) Z.-Y. Long, J.-X. Duan, Y.-B. Lin, C.-Y. Guo and
Q.-Y. Chen, J. Fluorine Chem., 1996, 78, 177; (d) B. R. Langlois
and N. Roques, J. Fluorine Chem., 2007, 128, 1318; (e) F. Cottet
and M. Schlosser, Eur. J. Org. Chem., 2002, 327; (f) G. G.
Dubinina, H. Furutachi and D. A. Vicic, J. Am. Chem. Soc.,
2008, 130, 8600; (g) G. G. Dubinina, J. Ogikubo and D. A. Vicic,
Organometallics, 2008, 27, 6233; (h) M. Oishi, H. Kondo and
H. Amii, Chem. Commun., 2009, 1909.
9 (a) L. Horner and H. Junkermann, Justus Liebigs Ann. Chem.,
1955, 591, 53; (b) L. Horner and W. Kirmse, Justus Liebigs Ann.
Chem., 1955, 597, 48; (c) J. Lalevee, X. Allonas, J. P. Fouassier and
K. U. Ingold, J. Org. Chem., 2008, 73, 6489.
10 (a) S. Murata, M. Miura and M. Nomura, J. Chem. Soc., Chem.
Commun., 1989, 116; (b) S. Murata, K. Teramoto, M. Miura and
M. Nomura, Bull. Chem. Soc. Jpn., 1993, 66, 1297.
Fig. 1 Oxidative functionalization of 1 with various nucleophiles.
Reaction conditions: 1 (0.5 mmol), BPO (0.75 mmol), nucleophile
(1.5 mmol), DCM (2 mL), reflux, 5–10 h. 20 mmol% CuBr was added
in the reaction of 1 with phenylacetylene.
noteworthy that only the desired products were produced in
the oxidative functionalization of tetrahydroisoquinolines
with these nucleophiles and no corresponding further oxidative
products generated compared to the reactions of oxidative
trifluoromethylation, indicating the unique characteristics of
the trifluoromethyl group.
In summary, the first oxidative transformation of tertiary
amines promoted by benzoyl peroxide (BPO) without transition
metal was developed.11 Various 1-trifluoromethylated tetra-
hydroisoquinoline derivatives were prepared by employing
this method. It constituted the first example of direct trifluoro-
methylation of tertiary amines.
Notes and references
1 (a) W. R. Dolbier, J. Fluorine Chem., 2005, 126, 157;
(b) A. Sutherland and C. L. Willis, Nat. Prod. Rep., 2000, 17,
621; (c) N. C. Yoder and K. Kumar, Chem. Soc. Rev., 2002, 31,
335; (d) X. L. Qiu, W. D. Meng and F. L. Qing, Tetrahedron, 2004,
60, 6711; (e) K. L. Kirk, J. Fluorine Chem., 2006, 127, 1013;
(f) M. Sani, A. Volonterio and M. Zanda, ChemMedChem, 2007,
2, 1693; (g) S. Leger, C. I. Bayly, W. C. Black, S. Desmarais,
J. P. Falgueyret, F. Masse, M. D. Percival and J. F. Truchon,
Bioorg. Med. Chem. Lett., 2007, 17, 4328; (h) R. Smits,
C. D. Cadicamoo, K. Burger and B. Koksch, Chem. Soc. Rev.,
2008, 37, 1727; (i) W. K. Hagmann, J. Med. Chem., 2008, 51, 4359;
(j) P. D. O’Shea, C. Y. Chen, D. Gauvreau, F. Gosselin,
G. Hughes, C. Nadeau and R. P. Volante, J. Org. Chem., 2009,
74, 1605.
2 (a) D. W. Nelson, R. A. Easley and B. N. V. Pintea, Tetrahedron
Lett., 1999, 40, 25; (b) J. C. Blazejewski, E. Anselmi and
M. P. Wilmshurst, Tetrahedron Lett., 1999, 40, 5475;
(c) D. W. Nelson, J. Owens and D. Hiraldo, J. Org. Chem.,
2001, 66, 2572; (d) G. K. S. Prakash, M. Mandal and
G. A. Olah, Angew. Chem., Int. Ed., 2001, 40, 589; (e) G. K. S.
Prakash, M. Mandal and G. A. Olah, Org. Lett., 2001, 3, 2847;
(f) G. K. S. Prakash and M. Mandal, J. Am. Chem. Soc., 2002, 124,
6538; (g) W. Xu and W. R. Dolbier, Jr., J. Org. Chem., 2005, 70,
4741; (h) A. D. Dilman, D. E. Arkhipov, V. V. Levin, B. A. A.
Korlyukov, M. I. Struchkova and V. A. Tartakovsky, J. Org.
Chem., 2008, 73, 5643; (i) H. Kawai, A. Kusuda, S. Nakamura,
M. Shiro and N. Shibata, Angew. Chem., Int. Ed., 2009, 48, 6324;
(j) A. Huang, H. Q. Liu, W. Massefski and E. Saiah, Synlett, 2009,
2518; (k) R. T. Gritsenko, V. V. Levin, A. D. Dilman,
P. A. Belyakov, M. I. Struchkova and V. A. Tartakovsky,
Tetrahedron Lett., 2009, 50, 2994 and references therein.
11 Only two papers described the a-C–H activation of amines without
transition metal: (a) A. S. K. Tsang and M. H. Todd,
Tetrahedron Lett., 2009, 50, 1199; (b) X. Z. Shu, X. F. Xia,
Y. F. Yang, K. G. Ji, X. Y. Liu and Y. M. Liang, J. Org. Chem.,
2009, 74, 7464.
3 Ru-catalyzed oxidative transformation of tertiary amines, see:
(a) S.-I. Murahashi, T. Nakae, H. Terai and N. Komiya,
J. Am. Chem. Soc., 2008, 130, 11005; (b) S.-I. Murahashi,
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 6285–6287 6287