Iron-catalyzed benzylic addition of 2-methyl azaarenes to substituted trifluoromethyl ketones

Article abstract of DOI:10.1080/00397911.2020.1867178

This paper demonstrated a new and economical methodology using Fe(ClO₄)₂·H₂O as a catalyst for the direct C(sp³)–H functionalization of 2-methyl azaarenes via addition to trifluoromethyl ketones. The use of Fe salts as a Lewis acid catalyst has shown great potential as an accessible, affordable, and effective catalyst for the reaction. Under mild, optimized conditions, an extensive range of 2-alkenylated azaarenes was produced with yields of up to 95%.

Full text of DOI:10.1080/00397911.2020.1867178

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Iron-catalyzed benzylic addition of 2-methyl
azaarenes to substituted trifluoromethyl ketones
Jiayu Alicia Lim & Yong-Chua Teo
To cite this article: Jiayu Alicia Lim & Yong-Chua Teo (2021) Iron-catalyzed benzylic addition
of 2-methyl azaarenes to substituted trifluoromethyl ketones, Synthetic Communications, 51:7,
1076-1084, DOI: 10.1080/00397911.2020.1867178
To link to this article: https://doi.org/10.1080/00397911.2020.1867178
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2021, VOL. 51, NO. 7, 1076–1084
https://doi.org/10.1080/00397911.2020.1867178
Iron-catalyzed benzylic addition of 2-methyl azaarenes to
substituted trifluoromethyl ketones
Jiayu Alicia Lim and Yong-Chua Teo
Natural Sciences and Science Education, National Institute of Education, Nanyang Technological
University, Singapore, Singapore
ABSTRACT
ARTICLE HISTORY
Received 2 November 2020
This paper demonstrated a new and economical methodology using
Fe(ClO4)2ꢀH2O as a catalyst for the direct C(sp3)–H functionalization
of 2-methyl azaarenes via addition to trifluoromethyl ketones. The
use of Fe salts as a Lewis acid catalyst has shown great potential as
an accessible, affordable, and effective catalyst for the reaction.
Under mild, optimized conditions, an extensive range of 2-alkeny-
lated azaarenes was produced with yields of up to 95%.
KEYWORDS
Benzylic addition; C–H
functionalization; iron-
catalyzed; quinalidine;
trifluoromethyl ketones
GRAPHICAL ABSTRACT
Fe(ClO4)2.H2O
O
(5 mol%)
OH
CF3
R1
R
+
R'
CF3
DMSO, 60 o
24 h
C
N
N
R'
up to 95 % yield
Introduction
Over the years, C–H functionalization has remained an area of great interest among the
synthetic community as it opens up a multitude of ground-breaking possibilities in
expediting organic synthesis routes. In isolation, the ubiquitous C–H bond is apolar and
inert[1] but initial developments in C–H functionalization strategies found organometal-
lic routes to be effective in activating C–H bonds.[2] Current research continues to be
focused on overcoming two of the main challenges of C–H functionalization—control-
ling site selectivity and enhancing catalytic efficiency.[3] It has been found that directing
groups not only trigger the cleavage of the C–H bond but nature and steric effect of the
directing group also play a key role in determining the regioselectivity of the product.[3]
The appeal of directed C–H functionalization lies in its potential to refine traditional
synthesis routes and serve as a more efficient and green alternative to cross-coupling
reactions,[4] which often involve multiple pre-preparation steps and require boron or
halide containing compounds. C–H functionalization also presents new schemes of logic
for the retrosynthesis of complex molecules.[5] Through these simplified transformation
routes, a new class of precursors can be employed for synthesis.[6]
CONTACT Yong-Chua Teo
yongchua.teo@nie.edu.sg
Natural Sciences and Science Education, National Institute
of Education, Nanyang Technological University, 1, Nanyang Walk, Singapore 637616, Singapore.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

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Particularly, the direct C(sp3)–H functionalization[7] of azaarenes is of great interest
due to the prevalence of the moiety in various natural products and pharmaceuticals,
such as the drug Montelukast, alkaloid natural products[8] (ꢁ)-Angustrureine and
(ꢁ)-Galipeine as well as the fluorescent probe Quinaldine Red.[9] Through strategies
such as late-stage functionalization,[10] there is great potential to speed up synthesis
processes of such medicinal products as well as discover new effective drugs.
The C(sp3)–H bond in the methyl group of methyl azaarenes has been successfully
functionalized via addition to a variety of carbonyl compounds, such as the alde-
hydes,[11] isatins,[12] and a-oxoesters.[13]
Ketones generally have lower reactivity than aldehydes because they have an add-
itional electron-donating group, which not only reduces their partial positive charge on
the carbonyl carbon but also contributes to steric hindrance. These factors make it chal-
lenging for ketones to undergo nucleophilic addition compared to aldehydes. As a strat-
egy to overcome this problem, Shaikh[14] reported that an electron-withdrawing CF3
moiety adjacent to the reactive carbonyl carbon site was effective in activating the
ketonic carbon, allowing for direct benzylic addition. The reaction was conducted in the
presence of excess methylazaarenes at a temperature of up to 110 ꢂC using the lanthan-
ide salt Yb(OTf)3 as a catalyst for the addition reaction. However, the drawbacks of the
reaction were the use of expensive rare metal catalysts and the rather high-temperature
requirement. In this context, we have reported a practical and convenient strategy for
the benzylic addition of azaarenes to trifluoromethyl ketone using InCl3 under mild
conditions.[15] Based on this precedent, we observed that the reaction can also be cata-
lyzed by a 10 mol% FeCl3 catalyst in THF at 60 ꢂC (Table 1, entry 1). Iron salts are
inexpensive, relatively less toxic, and as a consequence more environmentally benign in
comparison to other transition metals. Fe(OAc)2 has previously been used as a Lewis
acid catalyst in several C(sp3)–H functionalization reactions, including the addition of
methyl azaarenes to a-oxoesters[13] and to aldimines.[16] Moreover, the application of Fe
salts as Lewis acid for C–H functionalization[17] still remains limited. Encouraged with
this initial result, we decided to venture into broadening the scope for the benzylic add-
ition of azaarenes to trifluoromethyl ketone using Fe salts as catalysts which have yet to
be reported.
Results and discussion
In our initial study, quinalidine 1 and 2,2,2-trifluoroacetophenone 2 were used as model
substrates for the C–H functionalization reaction. The reaction was carried out using
2,2,2-trifluoroacetophenone (1 equiv.), Quinaldine (2.5 equiv.), Fe salt (10 mol%) in
0.5 mL THF at 60 ꢂC for 24 h. The results are shown in Table 1.
In the first stage, the catalytic efficiency of eight iron salts was tested and compared.
Fe(ClO4)2ꢀH2O was found to be the most effective catalyst, giving the alkenylated prod-
uct the highest yield of 93% (Table 1, entry 8). FeCl3, FeBr3, Fe(OAc)2 also gave the
alkenylated product in good yield, ranging from 84% to 90% (entries 1, 2, and 7). The
remaining Fe salts were not effective, giving moderate to poor yields of the product
(entries 3–6).

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J. A. LIM AND Y.-C. TEO
Table 1. Optimization studies of Fe-catalyzed C–H functionalization of Quinaldine and 2,2,2-
Trifluoroacetophenonea.
Entry
[Fe] source
Solvent
Yieldb (%)
90[14]
86
1
2
FeCl3
FeBr3
THF
THF
3
4
5
6
Fe(acac)3
THF
THF
THF
THF
Trace
57
Trace
62
Fe2(C2O4)3 ꢀ 6H2O
Fe2O3
Fe(acac)2
7
Fe(OAc)2
THF
87
8
9
Fe(ClO4)2ꢀH2O
Fe(ClO4)2ꢀH2O
Fe(ClO4)2ꢀH2O
Fe(ClO4)2ꢀH2O
Fe(ClO4)2ꢀH2O
Fe(ClO4)2ꢀH2O
Fe(ClO4)2ꢀH2O
Fe(ClO4)2ꢀH2O
Fe(ClO4)2ꢀH2O
Fe(ClO4)2ꢀH2O
Fe(ClO4)2ꢀH2O
Fe(ClO4)2ꢀH2O
Fe(ClO4)2ꢀH2O
THF
93
89
91
72
70
97
95
60
Dioxane
t-BuOH
DCE
DCM
DMSO
DMF
Toluene
Water
DMSO
DMSO
DMSO
DMSO
10
11
12
13
14
15
16
17
18
19
20
89
95c
87d
28e
93f
aGeneral reaction conditions: Quinaldine (2.5 equiv.), 2,2,2-trifluoroacetophenone (0.5 mmol), [Fe salt] (10 mol%), solvent
(0.5 mL), 60 ꢂC, 24 h.
bIsolated yield after column chromatography
cFe(ClO4)2ꢀH2O (5.0 mol%).
dFe(ClO4)2ꢀH2O (5 mol%), 40 ꢂC.
eFe(ClO4)2ꢀH2O (5 mol%), R.T.
fFe(ClO4)2ꢀH2O (5 mol%) with Quinaldine (1.5 equiv.).
Proceeding to the second stage with Fe(ClO4)2ꢀH2O as the chosen catalyst, a variety
of solvents were screened. Polar aprotic solvent DMSO afforded the alkenylated product
in the highest yield of 97% (entry 13). Similarly, other polar aprotic solvents such as
DMF, THF, Dioxane, DCE and DCM worked well with good yields ranging from 70%
to 95% (entries 8, 9, 11, 12, and 14). A representative polar protic solvent, t-BuOH, was
also explored which gave an excellent yield of 91% yield (entry 10). It is remarkable to
highlight that the reaction can also proceed well using water as the sole solvent which
afforded the product with an excellent yield of 89% (entry 16). The only solvent that
performed relatively poorly was toluene, a non-polar solvent, which afforded a yield of
only 60%, perhaps suggesting the importance of a polar medium for the reagents to dis-
solve and the reaction to proceed.
The next stage involved the reduction of Fe(ClO4)2ꢀH2O catalyst loading from
10 mol% to 5 mol%, an important step in ensuring maximum cost-effectiveness. It was
noted that even at 5 mol% Fe(ClO4)2ꢀH2O catalyst loading, the yield was still excellent
at 95% (entry 17).
Finally, it was found that lowering the reaction temperature from 60 ꢂC to 40 ꢂC and
ambient room temperature caused the yield to be significantly compromised, with it
decreasing from 95% to 87% and 28%, respectively (entries 17–19). On the other hand,

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scaling down the amount of quinaldine substrate used in excess from 2.5 equiv. to 1.5
equiv. did not drastically affect the yield, with 93% yield still being afforded at the end
of the reaction (entry 20).
Therefore, the overall optimized conditions for the C–H functionalization reaction
between Quinaldine and 2,2,2-Trifluoroacetophenone were decided to be
Fe(ClO4)2ꢀH2O (5 mol%) in DMSO at 60 ꢂC, with 1.5 equiv. of Quinaldine in excess.
These conditions afforded an excellent yield of 93% (entry 20).
With the above optimized conditions at hand, a range of trifluoromethyl ketones was
then reacted with quinaldine to test the generality of the system. The results are
reported in Table 2.
In this study, a series of Br-, Cl- and F-substituted trifluoroacetophenones were
reacted with quinalidine under the optimized conditions to broaden the reaction
scope. Although all the reactions afforded reasonably good yields from 73% to 95%
(Table 2, entries 1–5), there appeared to be a corresponding trend between the pos-
ition of the electron-withdrawing halogen substituent on the aromatic ring and the
resultant yield. Specifically, the para position was most favorable—moving the Br
substituent from ortho to meta to para position on the aromatic ring resulted in the
yield increasing from 73% to 87% to 95%, respectively (Table 2, entries 1–3).
Similarly, the Cl substituent in the para position of the aromatic ring gave an excel-
lent yield of 91% (Table 2, entry 4). Only the F substituent in the para position did
not have the same effect on the reaction, with a comparably lower yield of 74%
(Table 2, entry 5). The favourability of the para position may suggest that steric hin-
drance near the reactive carbonyl carbon may impede the reaction. Having two F
substituents at the meta and para positions of the aromatic ring of trifluoroacetophe-
none did however raise the yield to 85% (Table 2, entry 6), which may indicate that
the presence of an additional electronegative F atom was able to further activate the
carbonyl carbon toward nucleophilic attack. This effect is further corroborated
by the reaction using the next substrate, trifluoroacetophenone with an electron-with-
drawing CF3 substituent at the para position of the aromatic ring, which gave an
excellent yield of 92% (Table 2, entry 7).
The scope of substrates was expanded to trifluoromethyl ketones with substituents
of different electronic properties (Table 2, entries 8–12). The electron-donating 3-
phenyl substituent (Table 2, entry 8) appeared to stabilize instead of activating the
carbonyl carbon, and thus the yield was significantly lower than before at 63%. The
yield was slightly raised to 68% (Table 2, entry 9) with a conjugated phenyl sub-
stituent (Table 2, entry 9), whereby the compound was pre-synthesized[14] and then
further reacted with quinaldine. Comparing the reactions using ethyl 4,4,4-trifluoroa-
cetoacetate (Table 2, entry 10) and ethyl 3,3,3-trifluoropyruvate (Table 2, entry 11),
the electron-withdrawing effect of the C¼O bond of the ester group was stronger in
the latter due to its proximity to the reactive carbonyl carbon, thus activating the
carbonyl carbon to a greater extent. Thus, the latter had a higher yield of 60%
(Table 2, entry 11) compared to the former with a yield of 50% (Table 2, entry 10).
It is also interesting to note that the substrate with an electrophilic thiophene sub-
stituent directly bonded to the reactive carbonyl carbon produced an excellent yield
of 94% (Table 2, entry 12).

1080
J. A. LIM AND Y.-C. TEO
Table 2. C–H functionalization of quinaldine with a range of trifluoromethyl ketones catalyzed by
Fe(ClO4)2ꢀH2O in DMSOa.
Entry
1
R
Product
3a
Yield[b] (%)
93
2
73
3b
3
4
87
95
3c
3d
5
6
91
74
85
3e
3f
7
8
3g
92
3h
9
63
68
3i
3j
10
11
12
13
50
60
94
3k
3l
3m
aGeneral reaction conditions: Quinalidine (1.5 equiv.), trifluromethyl ketone (0.5 mmol), Fe(ClO4)2ꢀH2O (5 mol%), DMSO
(0.5 mL), 60 ꢂC, 24 h.
bIsolated yield after column chromatography.

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Table 3. C–H functionalization of a range of 2-methyl azaarenes with 2,2,2-trifluoroacetophenone
catalyzed by Fe(ClO4)2ꢀH2O in DMSOa.
Entry
Amine
Product
Yield[b](%)
4a
41
1
2
4b
4c
50
30
3
4
4d
71
5
6
7
8
4e
4F
4g
4h
44
42
82
38
9
4i
95
aGeneral reaction conditions: 2-Methylazaarene (1.5 equiv.), 2,2,2-trifluoroacetophenone (0.5 mmol), Fe(ClO4)2ꢀH2O
(5 mol%), DMSO (0.5 mL), 60 ꢂC, 24 h.
bIsolated yield after column chromatography.
Under the same optimized conditions, a range of 2-methyl azaarenes was then
reacted with 2,2,2-trifluoroacetophenone to further broaden the substrate scope of the
catalytic system. The resulting experimental yields are reported in Table 3.
In this section, several Br-, Cl- and F-substituted quinalidines (Table 3, entries 1–6).
were reacted with 2,2,2-trifluoroacetophenone, with the halogen atom bonded to differ-
ent positions on the aromatic ring. Across the board, the C6 and C7 positions were
found to be less favorable than the C4 position, resulting in low yields ranging from

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J. A. LIM AND Y.-C. TEO
30% to 50% (Table 3, entries 1, 2, 3, 5, and 6). Only the Cl atom in the C4 position
gave a good yield of 71% (Table 3, entry 4). Between the C6 and C7 positions, both the
Cl- and F-substituted quinaldines afforded better yields at the C6 position. The effect of
electron-donating substituents on the quinoline was also investigated. Interestingly, at
the same C6 position, a weakly donating methyl substituent gave a much higher yield
of 82% (Table 3, entry 7) compared to 38% when a strongly donating OMe substituent
was used (Table 3, entry 8). In addition, 1-methyl isoquinoline, an isomer of 2-methyl-
quinoline (Quinaldine), was just as effective as its counterpart, bringing in an excellent
yield of 95% (Table 3, entry 9), suggesting the feasibility of reaction using other substi-
tuted 1-methyl isoquinolines. Other monocyclic azaarenes, such as 2-methylpyridine
and 2,6 lutidine, provided negligible returns in yield. Similarly, quinolines with substitu-
ents at the C8 position and 2-methylquinoxaline produced trace amounts of
the product.
Experimental
General procedure
0.75 mmol of quinalidine (1.5 equiv.), 0.5 mmol 2,2,2-trifluoroacetophenone (1.0 equiv.),
0.025 mmol of Fe(ClO4)2ꢀH2O (5 mol%), and 0.5 mL of DMSO were added to an 8-mL
reaction vial containing a magnetic stir bar and a screw cap was fitted to it. The reac-
tion vial was immersed in a preheated 60 ꢂC oil bath and the mixture was stirred in a
closed system for 24 h. After 24 h, the heterogeneous mixture was cooled to room tem-
perature and dichloromethane was added into the vial to dilute the mixture. Using vac-
uum filtration, the mixture was then filtered through a pad of Celite. The vial was
washed with 5 ꢃ 8 mL of dichloromethane and the washings from each time were fil-
tered through the Celite as well. Anhydrous Na2SO4 was added to the collected filtrate
to remove any water from the organic extracts and the solvent was then removed by
rotary evaporation under reduced pressure. Thereafter, the crude product was purified
by silica-gel flash column chromatography (hexane:ethyl acetate) to afford the intended
1
addition product. The identity and purity of the product were confirmed by H NMR,
13C spectroscopic analysis, and elemental analysis.
1,1,1-Trifluoro-2-phenyl-3-(quinolin-2-yl)propan-2-ol (3a)
White solid (93%, 148.9 mg); mp 104.2–104.6 ꢂC
1H NMR (400 MHz, CDCl3): d 3.68 (d, J ¼ 14.8 Hz, 1H), 3.79 (d, J ¼ 14.8 Hz, 1H),
7.22–7.31 (m, 4H), 7.49–7.53 (m, 1H), 7.68–7.76 (m, 4H), 7.97 (d, J ¼ 8.4 Hz, 1H), 8.07
(d, J ¼ 8.4 Hz, 1H), 8.48 (bs, 1H)
13C NMR (100 MHz, CD3OD): d 42.3, 78.7 (q, J ¼ 30.0 Hz), 122.8 (overlapping q sig-
nal), 124.2, 125.6 (overlapping q signal), 127.8, 128.2, 128.4, 129.0, 129.1, 129.2, 129.4,
131.2, 138.3, 139.2, 147.8, 159.1
Analytical Calculated for C18H14F3NO: C, 68.13; H, 4.45; N, 4.41. Found: C, 68.28; H,
4.51; N, 4.49.
All spectral data correspond to those given in the literature.[14,15]

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Conclusion
In summary, a new Fe catalytic system has been successfully developed for the C–H
functionalization of 2-methylazaarenes via addition to trifluoromethyl ketones. The
yields obtained for the benzylic addition of quinaldine to substituted trifluoromethyl
ketones were comparable to those obtained using the indium catalytic system. The
affordability and sustainability of Fe salts as catalysts pose a great advantage and the
exploration of trifluoromethyl ketones is a significant step toward widening the scope of
substrates to be used for future research.
Supporting Information: Full experimental detail, 1H and 13C NMR spectra, and
elemental analysis. This material can be found via the “Supplementary Content” section
of this article’s webpage.
Funding
The present work was financially supported by the National Institute of Education, Nanyang
Technological University [RI 5/17 TYC].
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