Lewis acid-catalyzed Csp3-H functionalization of methyl azaarenes with α-trifluoromethyl carbonyl compounds

Article abstract of DOI:10.1016/j.tetlet.2012.12.013

A Lewis acid promoted Csp³-H bond functionalization of methyl azaarenes with α-trifluoromethylated carbonyl compounds is described. Catalytic amounts of Yb(OTf)₃ provided a straightforward access to the corresponding trifluoromethylated alcohols in excellent yields up to 94% under mild reaction conditions.

Full text of DOI:10.1016/j.tetlet.2012.12.013

Tetrahedron Letters 54 (2013) 695–698
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Tetrahedron Letters
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Lewis acid-catalyzed Csp3–H functionalization of methyl azaarenes with
a-trifluoromethyl carbonyl compounds
⇑
Vincent B. Graves, Abid Shaikh
Department of Chemistry, Georgia Southern University, Statesboro, GA 30460-8064, USA
a r t i c l e i n f o
a b s t r a c t
A Lewis acid promoted Csp3–H bond functionalization of methyl azaarenes with
carbonyl compounds is described. Catalytic amounts of Yb(OTf)3 provided a straightforward access to
the corresponding trifluoromethylated alcohols in excellent yields up to 94% under mild reaction
conditions.
a-trifluoromethylated
Article history:
Received 26 October 2012
Revised 3 December 2012
Accepted 5 December 2012
Available online 12 December 2012
Published by Elsevier Ltd.
Keywords:
Azaarenes
C–H functionalization
Trifluoromethyl ketone
Catalysis
Lewis acid
Introduction
fluoromethyl hydroxy compounds have recently been investigated
for their anti-fibrillogenesis properties in Alzheimer’s disease.11
Csp2-H functionalization using transition metal catalysts proved
a valuable tool in C–C bond formation.1 In contrast; Csp3–H func-
tionalization of alkyl group directly attached to aromatic ring is
less explored. A few known methods involve the use of Pd and
Cu based catalysts for the C–H activation of substituted azines
and azarenes.2 Recent investigations demonstrated the role of Le-
wis acid catalysts in Csp3–H functionalization of 2-methylazaa-
Results and discussion
Continuing our interest in the synthesis of trifluoromethylated
alcohols, herein, we report a simple protocol for Lewis acid pro-
moted addition of substituted 2-methylquinoline and 2-methyl-
pyridine with
a-trifluoromethyl carbonyl compounds, producing
renes with
and azodicarboxylates.6 However, the coupling of 2-methylazaa-
renes with -trifluoromethylated carbonyl compounds to provide
a
,b-unsaturated carbonyls,3 aldimines,4 carbonyls,5
corresponding trifluoromethyl alcohols. In order to validate this
idea, quinaldine 1 and ethyl 3,3,3-trifluoropyruvate 2a were cho-
sen as model substrates and were screened in the presence of var-
ious Lewis acid as well as Brønsted acid catalysts. The optimization
studies are summarized in Table 1.
a
trifluoromethylated tertiary alcohols has not yet been explored.
Our investigations revealed the Lewis acid-catalyzed C–H function-
alization of 2-alkylazaarene with
a-trifluoromethylated carbonyl
Initial trials with Sc(OTf)3 and AgOTf (Table 1, entries 1 and 2)
did not provide the expected product at all. Cu(OAc)2 under various
solvents, molar ratios, and temperature conditions promoted the
reaction only up to a 45% conversion (Table 1, entries 3–5). In con-
trast, the results using Yb(OTf)3 were inspiring. The conversion
jumped to 94% with only 5 mol % of catalyst at relatively lower
reaction temperature of 90 °C (Table 1, entry 6). Increasing the cat-
alyst amount to 10 mol % did not affect the conversion; on the
other hand increasing temperature to 110 °C gave a lower conver-
sion of 88% (Table 1, entries 7 and 8). Trials with Brønsted acid such
as TfOH (10 mol %) also promoted the reaction with 84% conver-
sion, although a higher temperature of 120 °C was required
(Table 1, entries 9–11). CF3COOH (Table 1, entry 12) and PTSA (Ta-
ble 1, entry 13) were also examined but the conversion was not
satisfactory.
compounds can be achieved under mild reaction conditions.
Design and synthesis of fluorine-based drugs have gained sig-
nificant attention7 and numerous studies proved the role of fluo-
rine atom in facilitating drug delivery and improving binding to
the target sites.8 Currently, more than 20% of the top selling drugs
have at least one fluorine atom in them. Trifluoromethylated (–CF3)
compounds are particularly interesting due to their strong electron
withdrawing effect that can create exceptional properties.9 Various
independent studies have also shown the presence of CF3-group is
essential for the biological activity of many compounds.10 Also, tri-
⇑
Corresponding author. Tel.: +1 912 478 0973; fax: +1 912 478 0699.
E-mail address: malnu@georgiasouthern.edu (A. Shaikh).
0040-4039/$ - see front matter Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2012.12.013

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V. B. Graves, A. Shaikh / Tetrahedron Letters 54 (2013) 695–698
Table 1
Evaluation of various Lewis acid and Brønsted acid catalystsa
O
catalyst
F3C
OH
O
OEt
F3C
OEt
conditions
N
N
O
1
2a
3a
Entry
Catalyst (mol %)
Solvent
Temp (°C)
Time (h)
Conv.b (%)
1
2
3
4
5
6
7
8
Sc(OTf)3 (10)
AgOTf (10)
Cu(OAc)2 (5)
Cu(OAc)2 (5)
Cu(OAc)2 (10)
Yb(OTf)3 (5)
Yb(OTf)3 (10)
Yb(OTf)3 (5)
TfOH (5)
TfOH (10)
TfOH (10)
CF3COOH (10)
PTSA (10)
THF
THF
THF
80
80
80
110
110
90
90
110
90
24
24
24
12
12
12
12
12
12
12
12
12
12
0
0
21
40
45
94
94
88
79
82
84
25
51
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
9
10
11
12
13
90
110
110
110
a
Reaction conditions: quinaldine 1 (0.70 mmol), ethyl trifluoropyruvate 2a (0.35 mmol), catalyst (5–10 mol %).
Determined by GCMS.
b
Table 2
Substrate scope of 2-methyl azaarenesa
O
F3C
OH
OEt
OEt
F3C
N
Yb(OTf)3 (5 mol%)
3a-i
or
O
O
Dioxane
90-110 oC
12 h
2a
N
or
O
F3C OH
Azaarene
O
O
OEt
N
F3C
OEt
4a-i
2b
Entry
1
Azaarene
Reactant
Product
T (°C)
Yieldb (%)
2a
2b
3b
4b
90
110
89
91
N
N
N
2a
2b
3c
4c
90
110
94
70
2
3
4
5
2a
2b
3d
4d
90
110
91
87
2a
2b
3a
4a
90
110
78
83
N
2a
2b
3e
4e
90
110
86
91
N
N
N
2a
2b
3f
4f
90
110
94
93
Br
F
6
7
2a
2b
3g
4g
90
110
88
79
2a
2b
3h
4h
90
110
81
72
8
9
N
Cl
2a
2b
3i
4i
90
110
85
87
N
a
Reaction conditions: quinaldine 1 (0.70 mmol), ethyl trifluoropyruvate 2a and ethyl trifluoroacetoacetate 2b (0.35 mmol), Yb(OTf)3 (5 mol %), dioxane (2 mL).
Isolated yields after flash chromatography.
b

V. B. Graves, A. Shaikh / Tetrahedron Letters 54 (2013) 695–698
697
O
HO
2b
2a
F3C
CF3
OH
O
OEt
Yb(OTf)3
Dioxane
Yb(OTf)3
Dioxane
N
N
N
OEt
110 oC/12h
90 oC/12h
5b, 61%, dr 9:10
5a, 55%, dr 9:10
2b
2a
N
O
N
N
Yb(OTf)3
Dioxane
Yb(OTf)3
Dioxane
OEt
OEt
110 oC/12h
90 oC/12h
CF3 O
6b, 88%
HO CF3
HO
6a, 91%
Figure 1. Yb(OTf)3 promoted Csp3–H functionalization of 2-ethyl pyridine and 1-methyl isoquinoline with 2a and 2b.
Table 3
Scope of methyl azaarenes with various trifluoromethyl ketones
O
HO
Yb(OTf)3 (5 mol%)
CF3
R
Azaarene
CH3
Azaarene
F3C
R
Dioxane
110 oC / 12 h
ketone
7a-9d
Entry
1
Azaarene
R
Product
Yielda (%)
CH3CH2-
7a
79
90
N
2
3
7b
7c
88
4
5
6
7d
8a
8b
93
83
94
S
CH3CH2-
N
7
8c
91
8
8d
9a
9b
89
83
94
S
CH3CH2-
9
N
10
11
12
9c
91
89
9d
S
a
Isolated yields after flash chromatography.
The substrate scope of this reaction was investigated by treating
(78–94%) and no by-product formation was observed. Based on
the excellent results obtained in case of 2a, a similar sequence of
substrates was tried with ethyl trifluoroacetoacetate 2b. After opti-
mizing the reaction conditions, it was observed that a slight in-
various substituted 2-methyl pyridines and 2-methyl quinolines
with ethyl trifluoropyruvate (2a). The results are summarized in
Table 2. All the reactions proceeded in good to excellent yields

698
V. B. Graves, A. Shaikh / Tetrahedron Letters 54 (2013) 695–698
LA
Lewis acid
CF3
R
N
N
H
N
AL
1
O
F3C OH
F3C
O LA
N
R
N
R
3a
Figure 2. Proposed hypothesis on Lewis acid promoted Csp3–H functionalization of methyl azaarenes.
crease in reaction temperature (110 °C) was necessary due to the
fact that 2b is comparatively less electrophilic than 2a. In all the
cases, reactions provided good to excellent yields (70–93%). An
important observation worth mentioning is that the reactions with
halogenated azaarenes (Table 2, entries 6–8) provided the ex-
pected products without the loss of halogens.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
12.013.
The reactivity of 2-ethyl pyridine and 1-methyl isoquinoline
was also investigated (Fig. 1). The reaction of 2-ethyl pyridine with
2a and 2b provided the expected product 5a and 5b as a mixture of
diastereomers in 55% and 61% yields, respectively. 1-Methyl iso-
quinoline with 2a and 2b proceeded exclusively at the Csp3–H po-
sition and provided the addition products in excellent yields.
To investigate the generality of this method, furthermore, the
substrate scope with regard to various trifluoromethyl ketones
was examined. The first set of reactions was carried out with quin-
References and notes
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a
-trifluoromethylated ketones to afford the corresponding Csp3–
H functionalized products 8a–9d in yields ranging from 83% to
94%. The results are summarized in Table 3.
Lewis acid promoted Csp3–H activation of 2-methyl azaarenes
occurs under the proton-transfer condition.3a Coordination of a Le-
wis acid significantly increases the acidity of Csp3–H bond that
leads to the cleavage of C–H bond to generate a metal enamide
species. The addition of metal enamide to the electrophilic car-
bonyl carbon would afford a metal enolate intermediate, which
on further protonation would give the expected product. We envi-
sion that the coordination of metal with carbonyl oxygen would
also promote the reaction by facilitating the attack on electron
deficient carbon. The hypothesis is shown in Figure 2.
In conclusion, we have developed an efficient and simple proto-
col for the Csp3–H functionalization of 2-alkyl azaarenes with
a-
trifluoromethyl carbonyl compounds.12 Yb(OTf)3 promoted the
reaction to provide the corresponding trifluoromethyl hydroxy
compounds in good to excellent yields. In all the cases, exclusively
only one product was observed which eliminates the possibility of
the formation of Friedel–Crafts alkylation product. The products
were obtained as a racemic mixture and our current efforts are di-
rected toward developing enantioselective synthesis.
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(b) Sood, A.; Abid, M.; Hailemichael, S.; Foster, M.; Torok, B.; Torok, M. Bioorg.
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12. General procedure: Quinaldine
1
(100 mg, 0.70 mmol) and ethyl
trifluoropyruvate 2a (47 L, 0.35 mol) were placed in a screw cap pressure
l
tube along with 2 mL of 1,4-dioxane. Ytterbium triflate (21 mg, 5 mol %) was
added with constant stirring. The closed tube was then stirred at 90 °C for 12 h.
Inert reaction atmosphere is not necessary. After the reaction was completed,
as indicated by TLC, the resulting reaction mixture was directly subjected to
column chromatography (hexane/ethyl acetate 90:10–80:20) to get a white
solid with 78% isolated yield.
Acknowledgments
Financial support provided by Georgia Southern University and
Faculty Research Grant (FRC-GSU) to A.S. is gratefully
acknowledged.