Triflic acid-catalyzed C sp3 - H functionalization of 2-methyl azaarenes with a α-trifluoromethyl imino ester

Article abstract of DOI:10.1016/j.tetlet.2014.08.061

A Br?nsted acid promoted C_sp³-H functionalization of 2-alkyl azaarenes with α-trifluoromethylated imino ester is described. A catalytic amount of triflic acid provided straightforward access to the corresponding trifluoromethylated amino esters via concomitant in situ one step N-alkyl deprotection. On further hydrolysis of ester, synthesis of quinoline derived unnatural trifluoromethylated amino acids has been achieved in a short and efficient manner.

Full text of DOI:10.1016/j.tetlet.2014.08.061

Tetrahedron Letters 55 (2014) 5572–5575
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Triflic acid-catalyzed Csp3 —H functionalization of 2-methyl azaarenes
with a
a-trifluoromethyl imino ester
⇑
Mark Blocker, Supriya Immaneni, Abid Shaikh
Department of Chemistry, Georgia Southern University, 521 College of Education Drive, Statesboro, GA 30460-8064, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A Brønsted acid promoted Csp3 —H functionalization of 2-alkyl azaarenes with
a-trifluoromethylated
Received 24 July 2014
Revised 8 August 2014
Accepted 13 August 2014
Available online 19 August 2014
imino ester is described. A catalytic amount of triflic acid provided straightforward access to the corre-
sponding trifluoromethylated amino esters via concomitant in situ one step N-alkyl deprotection. On fur-
ther hydrolysis of ester, synthesis of quinoline derived unnatural trifluoromethylated amino acids has
been achieved in a short and efficient manner.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Azaarenes
C–H functionalization
Trifluoromethyl imino ester
Triflic acid
Brønsted acid
Introduction
which is a very important feature for drug delivery.10 The increased
lipophilicity, and superior metabolic stability compared to those of
Csp3 —H functionalization using transition metal catalysts is a
valuable tool in C–C bond formation.1 Recent investigations dem-
onstrated the role of Lewis acid catalysts in Csp3 —H functionaliza-
the methyl analogues, often account for an improved activity pro-
file.11 The different medicinal applications of fluorinated organic
molecules are widespread. Some of the most well-known drugs
are ProzacÒ (anti-depressant), DiflucanÒ (anti-fungal agent), Caso-
dexÒ (anti-cancer agent) and Desflurane (inhalation anesthetic).12
Recent applications of organofluorine compounds include, poten-
tial therapeutics for HIV, cancer and Alzheimer’s disease.13 Accord-
ingly, the synthesis of these molecules is in great demand and the
search for new biologically active fluorinated compounds is in the
forefront of organic and medicinal chemistry research. Fluorine-
tion of 2-methylazaarenes with
a
,b-unsaturated carbonyls,2
aldimines,3 carbonyls,4 and azodicarboxylates.5 Our recent investi-
gations revealed the effectiveness of a transition metal-based
Lewis acid catalyst Yb(OTf)3 in C–H functionalization of 2-alkylaz-
aarene with
a-trifluoromethylated carbonyl compounds under
mild reaction conditions.6 In contrast, Brønsted acid catalyzed
Csp3 —H functionalization of 2-methyl azaarenes has not been fully
explored and only a few reports are documented in the literature.7
Thus, the development of Brønsted acid catalyzed synthetic meth-
ods for Csp3 —H functionalization is highly desirable. The use of
Brønsted acids as catalysts has various advantages, they are inex-
pensive, readily available and do not involve residual metal con-
tamination as compared to metal-based Lewis acid catalysts.
Organofluorine chemistry has received extensive attention
especially in the pharmaceutical industry and in materials science
due to the unique properties of fluorinated compounds.8 Trifluo-
romethylated compounds are of particular interest as the strong
electron-withdrawing effect of CF3 group contributes to a number
of biologically important molecular properties.9 For example, it
results in a significant increase in lipophilicity of the molecule,
containing amino acids in particular,
a-trifluoromethyl amino
acids are of special interest.14 Incorporation of a C–F bond on
amino acids results in conformationally and proteolytically stable
peptides with enhanced lipophilicity.15 The modified amino acids
possess different properties and reactivity resulting from an
increase in the electronegativity of the trifluoromethyl group.16
They can be used as peptidomimetics and therapeutic agents and
thus are interesting subjects in current medical investigations.17
As a part of our ongoing research in the development of
Brønsted acid catalyzed Csp3 —H functionalization of 2-methyl azaa-
renes that are pre-functionalized with a trifluoromethyl group,18
herein, we disclose a new efficient approach for the synthesis of
a wide variety of quinoline derived
Triflic acid (TfOH) promoted the Csp3 —H functionalization of
methyl azaarenes with -trifluoromethyl imino ester to provide
the corresponding -trifluoromethyl amino esters in good yields.
a-trifluoromethyl amino esters.
a
⇑
Corresponding author. Tel.: +1 912 478 0973; fax: +1 912 478 0699.
E-mail address: malnu@georgiasouthern.edu (A. Shaikh).
a
http://dx.doi.org/10.1016/j.tetlet.2014.08.061
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

M. Blocker et al. / Tetrahedron Letters 55 (2014) 5572–5575
5573
Table 1
Optimization of reaction conditions using various Lewis acid and Brønsted acid catalystsa
Ph
CH3
CF3
N
1a
H2N
CF3
O
Catalyst
HN
CH3
OEt
OEt
Conditions
N
N
N
Ph
OEt
4a
O
3
Racemic Mixture
F3C
O
2
Entry
Catalyst (mol %)
Solvent
Temp. (°C)
Time (h)
Conv.b (%)
1
2
3
4
5
6
7
8
AgOTf (10)
Cu(OTf)2 (5)
Cu(OAc)2 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (20)
TfOH (10)
TfOH (10)
TfOH (20)
TfOH (20)
THF
80
24
12
12
12
12
12
24
12
12
12
12
12
0
0
0
0
Toluene
Toluene
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Toluene
Toluene
110
110
100
100
100
110
100
80
0
74c
72c
85c
60c
34c
0
9
10
11
12
AcOH (20)
TsOH (20)
TFA (20)
110
110
110
0
a
b
c
Reaction conditions: Ethyl trifluoro imino ester 2 (50 mg, 0.18 mmol), azaarene 1a (0.36 mmol), catalyst (5–20 mol %).
Determined by 19F NMR using limiting reagent ethyl trifluoro imino ester 2 as a reference.
Exclusively 4a product formation was observed.
desired transformation. One-pot deprotection of the N-alkyl group
provided the amino esters 4a–h. All of the reactions were carried
out in a screw-cap pressure tube under argon.
With the optimized conditions in hand, the substrate scope of
this reaction was investigated by treating various substituted 2-
Results and discussion
Continuing with our interest in the development of catalytic
direct Mannich reactions, we investigated the Brønsted acid-cata-
lyzed reaction between 2-methyl azaarenes and a-trifluoro-methyl
imino ester. Although Lewis acid catalysis could be achieved, the
reactions turned out to be sluggish and no product formation
was observed. We decided to investigate a strategy based on the
methyl quinolines 1a–h with
a-trifluoromethyl imino ester 2.
The results are summarized in Fig. 1. All the reactions proceeded
in good yields ranging from 60% to 80% and no by-product forma-
tion was observed. Relatively higher yields were obtained when
quinoline bearing electron-donating groups such as methyl 4b
and ethoxy 4d were used. On the other hand, the presence of an
electron-withdrawing group such as halogens proved detrimental
and resulted in lower yields of 4c, 4e, and 4f. An important obser-
vation worth mentioning is that the reactions with halogenated
azaarenes provided the expected products without the loss of hal-
ogens. In all cases, the expected N-alkyl intermediate was not
observed and free amine products were obtained. Reaction of 1-
methyl isoquinoline 1h with ester 2 also proceeded exclusively
at the Csp3 —H position; followed by in situ deprotection of the N-
alkyl group which provided the expected product 4h in 79% yield.
(See Fig. 2)
Based on the excellent results obtained in case of methyl quin-
olines 1a–h, a similar transformation was tried with 2-alkyl pyri-
dines 5a–e with imino ester 2. 2-Methyl pyridine 5a provided
the corresponding Csp3 —H functionalization 6a in 69% yield. 2,3-
dimethyl pyridine 5b, 2,4-diemthyl pyridine 5c, and 2,6-dimethyl
pyridine 5d provided only C-2 functionalized products 6b–d,
respectively. The reactivity of 2-ethyl pyridine with 2 provided
the expected product 6e as a mixture of diastereomers in 55% yield.
In order to extend this approach, the synthesis of unusual fluo-
rine containing amino acid was carried out using the base pro-
moted hydrolysis of ester 4d. Corresponding trifluoromethyl
amino acid 7d was obtained as a white solid in 88% yield using
aq NaOH within 2 h of reaction time. (See Fig. 3)
activation of both nucleophilic and electrophilic sites via
a
Brønsted acid utilizing the fact that the equilibrium between 2-
methylquinoline and its enamine counterpart bearing an exocyclic
double bond can be easily shifted.19 In order to test the idea, 2-
methylquinoline 1a was initially chosen as an alkyl-azaarene
model substrate and imino ester 2 as a reagent. Imino ester 2
was prepared following a literature method20 from ethyl trifluoro-
pyruvate and a-methyl benzylamine to obtain 94% yield within 4 h
of reaction time. Preliminary studies revealed that high tempera-
ture (100 °C) and a closed reaction vessel promote the best condi-
tions for this transformation.
Initial trials to activate the Csp3 —H for the new C–C bond forma-
tion between 1a and 2 with Lewis acid catalysts AgOTf and
Cu(OTf)2 (Table 1, entries 1 and 2) did not provide the expected
product 4a or the intermediate 3. Cu(OAc)2 and Yb(OTf)3 also failed
to promote the reaction utilizing different solvents and various cat-
alyst stoichiometries (Table 1, entries 3–5). After meeting with no
success with Lewis acid catalysts, we began our investigations
using Brønsted acid catalyst. The initial trial with triflic acid (TfOH)
catalyzed the reaction at 100 °C to provide the product in 74% yield
(Table 1, entry 6). Further increasing the temperature to 110 °C did
not improve the product yield (Table 1, entry 7). On the other hand,
increasing the catalyst concentration from 10 mol % to 20 mol %
significantly increased the conversion to 85% at 100 °C (Table 1,
entry 8). Trials with other Brønsted acids such as AcOH
(20 mol %) also promoted the reaction albeit with lower conversion
(Table 1, entry 10). Rather surprisingly, TsOH and CF3COOH
(Table 1, entries 11 and 12) did not provide the desired prod-
uct. Deprotection of the N-benzyl group in the presence of
Brønsted acids such as acetic acid and trifluoroacetic acid is
reported in the literature21 that could be complimenting the
Mechanistically, Brønsted acid promoted Csp3 —H activation of
2-methyl azaarenes occurs under proton-transfer conditions. 2-
Methyl azaarene, the representative example 2-methyl quinoline
1a, gets protonated at the nitrogen center, which significantly
increases the acidity of Csp3 —H bond that triggers the cleavage of

5574
M. Blocker et al. / Tetrahedron Letters 55 (2014) 5572–5575
CH3
1. NaOH (2 eqv.)
H2O / EtOH
TfOH
EtO
EtO
Cl
H2N
CF3
O
H2N
F3C NH3
OH
CF3
O
(20 mol%)
50 oC / 2 h
N
Ph
OEt
Azaarene
OEt
Azaarene
CH3
OEt
N
N
1,4-Dioxane
100 oC / 12 h
F3C
2. HCl
1a-h
O
O
4d
7d, 88%
4a-h
2
Figure 3. Base promoted hydrolysis of ester 4d to obtain trifluoromethyl amino
acid 7d.
H3C
EtO
Br
H2N
H2N
CF3
CF3
OEt
OEt
N
N
O
O
4b
, 83%
4a, 81%
TfOH
(HA)
-HA
N
H
CF3
N
H
N
9
F
N
COOEt
H2N
H2N
CF3
O
H
CF3
1a
8
A
OEt
OEt
Ph
CH3
N
N
2
O
4d, 80%
4c, 74%
Ph
CH3
CF3
H2N
CF3
O
H2N
N
CF3
OEt
H2N
N
CF3
OEt
HN
OEt
OEt
N
N
4a
Cl
O
3
O
O
4f, 78%
4e, 65%
Figure 4. Working hypothesis of Brønsted acid promoted Csp3 —H functionalization
of methyl azaarenes with -trifluoro imino ester.
a
N
O
H2N
CF3
O
OEt
and also promoted the in situ N-alkyl deprotection to provide the
corresponding trifluoromethyl amino esters in good yields. In all
the cases, exclusively only one product was observed. To broaden
the scope of this methodology, amino ester product was converted
to the corresponding trifluoromethylated amino acid. In all cases,
the products were obtained as a racemic mixture and our current
efforts are directed toward developing an enantioselective synthe-
sis for these compounds.
OEt
N
H2N CF3
4g, 61%
4h, 79%
Figure 1. Brønsted acid promoted Csp3 —H functionalization of methyl azaarenes
with -trifluoro imino ester. Reaction conditions: Ethyl trifluoro imino ester 2
(50 mg, 0.18 mmol), azaarene 1a–h (0.36 mmol), TfOH (20 mol %), 1,4-dioxane
(2 mL) at 100 °C, 12 h. Isolated yields after flash chromatography.
a
Acknowledgments
CH3
TfOH
H2N
CF3
O
(20 mol%)
N
Ph
OEt
R2
R2
Financial support provided by Georgia Southern University,
College Office of Undergraduate Research (COUR) award to M.B.
and National Science Foundation, USA (DMR 1229292) is gratefully
acknowledged.
OEt
R1
1,4-Dioxane
100 oC / 12 h
N
N
F3C
R1
5a-e
O
6a-e
2
R1 = H, CH3
R2 = H, 3-CH3, 4-CH3, 6-CH3
Supplementary data
H2N
CF3
O
H2N
CF3
OEt
H2N
CF3
OEt
Supplementary data (Experimental procedure and full
characterization (1H, 13C, 19F NMR and MS data) for all compounds)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2014.08.061.
OEt
N
N
N
O
O
6a
, 69%
6b, 73%
6c, 73%
H2N
H2N
CF3
CF3
O
References and notes
OEt
OEt
N
N
O
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azaarenes with
(50 mg, 0.18 mmol) and 2-methyl quinoline 1a (49
in a screw-cap pressure tube along with 2 mL 1,4-dioxane. The mixture was
flushed with argon and stirred for 2 min at room temperature. Triflic acid (4 L,
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-trifluoromethyl imino ester: Ethyl trifluoro imino ester
2
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l
L, 0.36 mol) were placed
l
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20 mol %) was added with constant stirring. The closed tube was stirred at
100 °C for 12 h. After the reaction was completed, as indicated by TLC and 19F
NMR, the resulting reaction mixture was directly subjected to column
chromatography (hexane/ethyl acetate 90:10 to 50:50) to obtain a white
solid in 81% isolated yield.