Chemoselective Trifluoroethylation Reactions of Quinazolinones and Identification of Photostability

Article abstract of DOI:10.1021/acs.joc.9b00470

Herein, we report chemoselective trifluoroethylation routes of unmasked 2-arylquinazolin-4(3H)-ones using mesityl(2,2,2-trifluoroethyl)iodonium triflate at room temperature. Homologous C-, O-, and N-functionalized subclasses are accessed in a straightforward manner with a wide substrate scope. These chemoselective branching events are driven by Pd-catalyzed ortho-selective C-H activation at the pendant aryl ring and base-promoted reactivity modulation of the amide group, leveraging the intrinsic directing capability and competing pronucleophilicity of the quinazolin-4(3H)-one framework. Furthermore, outstanding photostability of the quinazolin-4(3H)-one family associated with nonradiative decay is presented.

Full text of DOI:10.1021/acs.joc.9b00470

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Article
Chemoselective Trifluoroethylation Reactions of
Quinazolinones and Identification of Photostability
Saikat Maiti, Jaeshin Kim, Jae-Heon Park, Dongsik Nam, Jae Bin Lee, Ye-Jin Kim, Jung-Min Kee, Jeong
Kon Seo, Kyungjae Myung, Jan-Uwe Rohde, Wonyoung Choe, Oh-Hoon Kwon, and Sung You Hong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00470 • Publication Date (Web): 03 May 2019
Downloaded from http://pubs.acs.org on May 3, 2019
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Chemoselective Trifluoroethylation Reactions of Quinazolinones and
Identification of Photostability
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Saikat Maiti,†, Jaeshin Kim,† Jae-Heon Park,‡, Dongsik Nam,‡ Jae Bin Lee,† Ye-Jin Kim,‡,
⊥
∥
∥
Jung-Min Kee,‡ Jeong Kon Seo,§ Kyungjae Myung,⊥ Jan-Uwe Rohde,‡ Wonyoung Choe,‡ Oh-
Hoon Kwon,*,‡,∥ and Sung You Hong*,†
†School of Energy and Chemical Engineering, Ulsan National Institute of Science and Technology (UNIST), 50
UNIST-gil, Ulsan 44919, Republic of Korea
‡Department of Chemistry, UNIST, 50 UNIST-gil, Ulsan 44919, Republic of Korea
§UNIST Central Research Facilities, UNIST, 50 UNIST-gil, Ulsan 44919, Republic of Korea
⊥Center for Genomic Integrity (CGI), Institute for Basic Science (IBS), 50 UNIST-gil, Ulsan 44919, Republic of
Korea
∥Center for Soft and Living Matter, IBS, 50 UNIST-gil, Ulsan 44919, Republic of Korea
TOC Figure
Intrinsic DGs
O
R2
room temperature conditions
NH
+
OTf
I
Mes
Photostability
69 examples
CH2CF3
N
R1
up to 98% yield
CH2CF3
O
N
O
O
R2
R2
R2
CH2CF3
CH2CF3
NH
N
N
R1
N
N
R1
R1
No Protecting Group Chemistry
No Pre-Functionalization
ABSTRACT: Herein, we report chemoselective trifluoroethylation routes of unmasked 2-
arylquinazolin-4(3H)-ones using mesityl(2,2,2-trifluoroethyl)iodonium triflate at room temperature.
Homologous C-, O-, and N-functionalized subclasses are accessed in a straightforward manner with a
wide substrate scope. These chemoselective branching events are driven by Pd-catalyzed ortho-selective
C–H activation at the pendant aryl ring and base-promoted reactivity modulation of the amide group,
leveraging the intrinsic directing capability and competing pronucleophilicity of the quinazolin-4(3H)-one
framework. Furthermore, outstanding photostability of the quinazolin-4(3H)-one family associated with
nonradiative decay is presented.
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INTRODUCTION
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Chemoselective modifications of heterocycles constitute a central theme in synthetic methodology.1 The
incorporation of organofluorine entities profoundly affects the bioavailability, binding efficacy, and
metabolic profiles of lead compounds.2 In particular, the CH2CF3 moiety acts as an electron-withdrawing
bioisostere of ethoxy or ethyl groups, and the illustrated examples of 2,2,2-trifluoroethylated small
molecules having biological importance are shown in Scheme 1a.2,3 Orthogonal reaction manifolds,
protecting group-free operations, and late-stage functionalizations offer concise, complementary, and step
economic routes to create molecular diversity and expand chemical space.4 Given the difficulties in
achieving chemoselective profiles and broad functional-group tolerance, the development of switchable
trifluoroethylation methods to modify unactivated heterocycles remains a significant challenge.
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Scheme 1. Triply Chemoselective Trifluoroethylation
(a) Bioactive small molecules bearing trifluoroethyl moiety
NC
CF3
CF3
Cl
CF3
N
S
N
N
N
N
CF3
F3C
O
F
Androgen receptor modulator
Patent No. WO 2008042571
CF3
Quazepam (Doral)
Treatment of insomnia
O
O
O
CF3
O
NH
N
N
H
F
N
H
NH
N
N
N
F
O
O
F3C
Telcagepant (MK-0974)
CGRP receptor antagonist
Flecainide (Tambocor)
Antiarrhythmic agent
This work
(b)
Chemoselective branching modes
Late-stage modification of 2-arylquinazolin-4(3H)-one core
+
"CH2CF3
"
CH2CF3
Pd
O
O
N
O
M
+
R2
6
R2
"CH2CF3
"
5
R2
XLn
N
2
N
M
N
N
1
R1
R1
N
R1
Iminol form
C–O formation
Amide form
C–N formation
Cyclometalated form
C–C formation
Our working hypothesis: intrinsic DGs & competing pronucleophilicity
The prevalence of quinazolinone alkaloids in natural products and pharmaceuticals makes their
synthetic modifications appealing.5 The unmasked and unactivated quinazolin-4(3H)-one framework
possesses integral structural features with inherent directing group (DG) capability and amide-iminol
tautomerism, posing both challenges and opportunities for late-stage trifluoroethylations (Scheme 1b).
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Our strategy to modify quinazolin-4(3H)-one alkaloids has two notable features: (i) chemoselective
activation of competing pronucleophilic sites to accomplish C-, O-, and N-trifluoroethylations and (ii)
complete exclusion of protecting group chemistry and pre-functionalization.
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Although indisputable synthetic advances in individual electrophilic trifluoroethylations have recently
emerged,6–8 the switchable trifluoroethylations of heterocyclic scaffolds appear to be uncharted. The
critical task in the efficient construction of molecular complexity is to establish orthogonal reaction
manifolds, which obviate the need of multiple de novo operations.9 Although a number of important
chemoselective reactions are well-established,4c,4d the development of chemoselective reaction modes
suitable for late-stage modification remains a challenging mission owing to cross-reactivity
interference.9c As a part of our continued studies on reactivity-controlled direct modifications using
hypervalent iodine reagents,10 herein we disclose trifluoroethylations of 2-arylquinazolin-4(3H)-ones (1)
through reactivity discrimination (Scheme 1b): Pd-catalyzed direct site-selective C–H activation and
base-promoted routes facilitate late-stage trifluoroethylations with a wide scope. In addition, the
photostability of the parent and modified quinazolinone family is highlighted via steady-state and time-
resolved spectroscopic analyses.
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RESULTS AND DISCUSSION
We embarked on our C-trifluoroethylation approach through a stoichiometric model study, in which we
synthesized and isolated the tetrameric palladacycle (Scheme 2a; see experimental section). Single crystal
X-ray analysis of this complex corroborates that Lewis-basic heteroatoms within the quinazolin-4(3H)-
one framework served as intrinsic DGs for C–H activation.11 Among the various synthetic equivalents of
a CH2CF3 synthon, mesityl(2,2,2-trifluoroethyl)iodonium triflate (2) introduced by the Novak group was
selected due to its accessibility, bench stability, mildness, and versatile nucleofugality.8,12 The tetrameric
palladacycle and 2 in the presence of trifluoroacetic acid (TFA) provided the target product 2-(4-bromo-2-
(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (3i) in 67% isolated yield (Scheme 2a).
Intrigued by this result, we tested the feasibility of catalytic C-trifluoroethylation using 2-(p-
tolyl)quinazolin-4(3H)-one (1a), Pd(OAc)2 and 2. To our delight, the desired product 2-(4-methyl-2-
(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (3a) was isolated in 91% yield under the standard
conditions: 20 mol% Pd(OAc)2 and 20 equiv TFA in 1,2-dichloroethane (DCE) at room temperature (rt)
(see the Supporting Information, Section II, Table S1). On the basis of this experimental insight, we
postulate that the catalytic cycle (Scheme 2b) is initiated by a concerted metalation deprotonation (CMD)
pathway to give the putative intermediate A. The reaction conditions may favor the formation of a
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monomeric palladacycle over a dimeric or tetrameric one. Iodonium salt 2 transfers the trifluoroethyl
entity to generate a high-valent Pd(IV)–CH2CF3 intermediate B.8 Finally, reductive elimination (RE)
furnishes the respective product 3, while releasing a Pd(II)-species.12b,12c,12e Alternatively, the two-electron
oxidative CH2CF3 transfer and subsequent C–C bond forming RE may involve a dinuclear Pd(III)2
intermediate, as both mononuclear Pd(IV)13a,13b,13c and dinuclear Pd(III)2 complexes13d,13e have been
observed in Pd-catalyzed C–H functionalization with hypervalent iodine reagents.
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Scheme 2. C-Trifluoroethylation Approach
(a) Stoichiometric model study of C-trifluoroethylation
intrinsic DGs
5-membered palladacycle
Br
1/4
O
N
N
Pd
Pd
O
N
Pd
N
N
Br
O
N
N
Pd
O
N
Br
H2O
Mes
I
OTf
Br
X-ray
CH2CF3
Isolated and air-stable
tetrameric palladacycle
, 86%
2
(1.5 equiv)
O
N
TFA (20 equiv)
Pd(OAc)2 (1.0 equiv)
DCE, rt, air, 6 h
O
CH2CF3
DCE, rt,
air, 24 h
NH
NH
N
Br
1i
3i
, 69% (isolated yield)
Br
(b) Proposed catalytic cycle
O
R2
CH2CF3
NH
PdII
X2
1
2-Arylquinazolinone
N
R1
3
RE
CMD
2 HX
TFA
O
N
O
CH2CF3
R2
R2
PdII
Ln
PdIV
N
XLn
N
N
R1
R1
CH2CF3 Transfer
[O]
B
Intermediate
A
Intermediate
MesI
2
Iodonium salt
–
X– = AcO–, CF3CO2 , or TfO–.
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We accordingly explored the generality of catalytic C-trifluoroethylation using structurally diverse
substrates 1 (Scheme 3). Electron-rich substrates bearing alkyl substituents (Me, Et, iPr, and tBu)
smoothly underwent the reaction to afford 3a–3d in high yields. The structure of 3a was unambiguously
confirmed via single crystal X-ray analysis.11 Even substrate 2-(4-methoxyphenyl)quinazolin-4(3H)-one
(1f) was well tolerated; a reduced amount of TFA (10 equiv) was used to impede the concurrent ethereal
cleavage. The C-trifluoroethylation was found to tolerate electron-deficient substituents such as halogens
(1g–1k, 1p), nitro (1l), and trifluoromethyl (1m) groups in moderate-to-good yields. 3p was obtained as
the sole regioisomer, which may be attributed to steric hindrance between the bulky Br substituent and an
adjacent ligand of the Pd complex that would arise if the other ortho position were to be metalated.
Unfortunately, the nitrile bearing 1n did not react. Conversely, compound 3o bearing a biphenyl moiety
was isolated in 89% yield. A substituent in one of the ortho-positions (C2) of the pendant aryl ring was
found to have no deleterious effect as revealed by the formation of 3p and 3p. We also assessed the
impact of R2-substituents. Substrates bearing a halogen in different positions (1r–1u, 1w), a methoxy
(1q), or a methyl (1v) group were tolerated to afford the respective C2-products in moderate-to-good
yields. The reaction of disubstituted substrates (1x, 1y) gave their respective products in fair yields (72%
and 87%, respectively). The NO2-substituted 1z underwent the reaction furnishing the C2-product in 84%
yield. The C2-trifluoroethylation method appears to be selective for monofunctionalization, without
formation of any bis(trifluoroethylated) product even in the presence of an excess amount of 2 (see the
Supporting Information, Table S1).
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Scheme 3. Substrate Scope of the C-Trifluoroethylationa
O
O
R2
R2
Pd(OAc)2 (20 mol%)
TFA (20 equiv)
CH2CF3
NH
OTf
NH
I
Mes
+
CH2CF3
DCE, rt
air, 24 h
standard conditions
N
N
R1
R1
1
2
3
(1.0 equiv)
(1.5 equiv)
O
O
(R1 = Et), 82%
(R1 = iPr), 84%
(R1 = tBu), 87%
(R1 = H), 86%
3b
3c
3d
3e
CH2CF3
CH2CF3
NH
NH
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N
N
3a
, 91%
1 mmol scale: 90%
R1
Me
X-ray
O
N
O
O
CH2CF3
NH
CH2CF3
CH2CF3
NH
NH
F
N
N
(R1 = F), 70%
R1
3g
b
3f
, 63%
(R1 = Cl), 69% (77%)
(R1 = Br), 69% (92%)
(R1 = I), 85%
3k
, 44%
(59%)
OMe
3h
3i
F
O
3j
CH2CF3
O
NH
CH2CF3
O
NH
N
CH2CF3
NH
N
R1
(R1 = NO2), 61%
3l
3m
N
(R1 = CF3), 54%
(R1 = CN), 0%
O
3p
, 64%
3o
, 89%
Br
Ph
3n
R2
O
O
CH2CF3
CH2CF3
CH2CF3
NH
NH
NH
N
N
N
F
Me
, 83%
Me
(R2 = OMe), 36%c (49%)c
(R2 = F), 87%
(R2 = Cl), 60%
3q
3r
3p'
3p''
, 62%
3s
O
Me
O
O
R2
CH2CF3
CH2CF3
CH2CF3
NH
NH
NH
N
F
N
Cl
N
(R2 = F), 78%
(R2 = Br), 90%
(R2 = Me), 56%
3t
3x
, 72%
3w
, 48%
3u
3v
O
N
O
CH2CF3
Me
Me
NH
CH2CF3
NH
N
NO2
3z
3y
, 87%
, 84%
aReaction conditions: 1 (1.0 equiv), 2 (1.5 equiv), Pd(OAc)2 (20 mol%), TFA (20 equiv), DCE, rt, 24 h, isolated
yields. bTFA (10 equiv). cTFA (5.0 equiv). Isolated yields based on the recovered starting materials are given in
parentheses.
Next, we pursued switchable O- and N-trifluoroethylation modes of 1a by leveraging the subtle
differences in competing pronucleophilicity (Table 1). 1a and 2 were subjected to metal-free and rt
conditions. In the absence of base, the reaction preferentially occurred at the O-center to deliver 4a in 49%
yield (entry 1). Through base and solvent screening (entries 2–7; see also the Supporting Information,
Section II), the optimized yield (93%) of 4a was achieved using K2CO3 (1 equiv) in MeCN along with the
minor N-isomer 5a. Solid-phase reaction led to decrease in chemoselectivity, ~2.5:1 mixture of 4a and 5a
in 92% yield (entry 8). The N-trifluoroethylated 5a culminated in 89% yield, when 2.0 equiv of LiOtBu
was used as a moderately strong base (entry 10). Dry toluene under an N2 atmosphere was essential,
because the isomeric ratio significantly changed under routine conditions (entries 9 and 10). The need for
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inert conditions is likely due to the moisture-sensitivity of the base. A reduced amount of LiOtBu (1.0
equiv) diminished the yield of 5a (entry 11). LiMHDS (entry 12) also resulted in the preferential
formation of N-isomer 5a over O-isomer 4a. This reactivity preference is presumably attributed to the
amide-iminol tautomerism of the quinazolinone scaffold. Whereas mild bases lead to the putative iminol
form, relatively stronger bases allow the direct lithiation at the N-center. However, pathways involving
[2,3]-rearrangement of T-shaped O–I or N–I intermediates14 or a 4-coordinate I(III)-intermediate15 cannot
be ruled out.
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Table 1. Optimization of Reaction Conditionsa
CH2CF3
O
O
O
CH2CF3
NH
N
2
(1.5 equiv)
N
+
N
N
base, solvent
rt, 12 h
N
4a
1a
5a
Me
Me
Me
(0.127 mmol, 1.0 equiv)
O-isomer
N-isomer
yield (%)b
4a
base (equiv) and
entry
solvent conditions
5a
trace
trace
trace
trace
trace
trace
6
1
2
MeCN
49
81
89
82
70
75
93
66
41
10
22
10
Na2CO3 (2.0), MeCN
3
K2CO3 (2.0), MeCN
4
Li2CO3 (2.0), MeCN
5
K2CO3 (2.0), DCE
6
K2CO3 (2.0), DCM
7
K2CO3 (1.0), MeCN
8
K2CO3 (2.0), solvent-freec
LiOtBu (2.0), toluene, air
LiOtBu (2.0), dry toluene, N2
LiOtBu (1.0), dry toluene, N2
LiMHDS (2.0), dry toluene, N2
26
9
49
10
11
12
89
69
88
b
c
aReaction conditions: 1a (1.0 equiv), 2 (1.5 equiv), base, rt, 12 h. Isolated yield. Grinding with a mortar and
pestle. DCM = dichloromethane, LiMHDS = lithium hexamethyldisilamide.
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Scheme 4. Substrate Scope of the O-Trifluoroethylationa
7
8
9
CH2CF3
O
R2
O
R2
OTf
NH
K2CO3 (1.0 equiv)
N
I
Mes
+
R1
CH2CF3
N
1
MeCN, rt
air, 12 h
N
4
R1
10
11
12
13
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2
(1.0 equiv)
(1.5 equiv)
(R1 = Me), 93%
4a
CH2CF3
CH2CF3
O
1 mmol scale: 93%
O
N
(R1 = Et), 87%
(R1 = iPr), 97%
(R1 = tBu), 93%
4b
N
N
N
4c
4d
R1
4e
, 88%
X-ray
O
CH2CF3
CH2CF3
CH2CF3
(R1 = F), 93%
(R1 = Cl), 89%b
(R1 = Br), 75%
(R1 = I), 68%
4g
4h
4i
O
O
N
N
N
N
F
N
N
4j
R1
4k
OMe
, 95%
O
4f
, 92%
F
CH2CF3
CH2CF3
CH2CF3
O
O
N
(R1 = NO2), 84%
4l
N
N
N
N
(R1 = CF3), 95%
4m
N
(R1 = CN), 91%
4n
4p
, 86%
R1
4o
, 77%
Ph
Br
CH2CF3
CH2CF3
CH2CF3
R2
O
N
O
N
O
R2
Me
N
N
N
N
(R2 = F), 88%
(R2 = Cl), 83%b
(R2 = F), 98%
(R2 = Br), 88%
4v
, 80%
b
4r
4t
4s
4u
CH2CF3
CH2CF3
CH2CF3
O
N
O
O
Me
Me
N
N
N
N
F
N
NO2
4z
b
4w
4y
, 78%
, 86%
, 61%
aReaction conditions: 1 (1.0 equiv), 2 (1.5 equiv), K2CO3 (1.0 equiv), MeCN, rt, 12 h, isolated yields. b1 (1.0 equiv),
2 (2.0 equiv), K2CO3 (1.5 equiv), MeCN, rt, 12 h, isolated yields.
Following the success in establishing the O- and N-functionalization sets, we evaluated the versatility
of O-trifluoroethylation on various substrates 1 (Scheme 4). A marginal effect of the electronic properties
of R1-substituents within the 2-phenyl ring was observed, yielding the O-products in moderate-to-high
yields. Electron-deficient NO2 (1l), CF3 (1m), and CN (1n) substituents were well-tolerated and exhibited
good yields. R2-bearing substrates (1r–1w, 1y) were shown to provide the O-products in good-to-high
yields. The NO2-substituted substrate 1z afforded its corresponding O-product in 61% yield. Subsequently,
we evaluated the substrate scope of the alternative N-trifluoroethylation (Scheme 5). The reactions were
performed under inert conditions. A wide range of substituents were compatible with standard conditions.
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Electron-rich substrates afforded the corresponding N-isomers (5a–5f, 5o) more efficiently and in higher
yields than those of the electron-deficient species (5g–5k, 5m, 5n, 5p, 5r, 5w, 5w’), due to the strong
nucleophilic character.
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In place of the iodonium salt 2, we further evaluated the feasibility of 1,1,1-trifluoro-2-iodoethane
(CF3CH2I) in base-promoted O- and N-trifluoroethylations. Quinazolinone 1g (0.125 mmol) was treated
with CF3CH2I (1.5 equiv) and K2CO3 (1.0 equiv) in MeCN (1.5 mL) under ambient conditions. However,
even after 20 h, no O-trifluoroethylated product (4g) was detected giving the remaining starting material.
Similarly, when we treated 1g (0.083 mmol) with CF3CH2I (1.5 equiv) in presence of LiOtBu (2.0 equiv)
in dry toluene (1.5 mL), no N-trifluoroethylation occured. These results indicate that the switchable
reaction modes are not solely controlled by basicity, but also governed by the suitable electrophilic
character of the trifluoroethylating reagent. The stronger electrophilicity of hypervalent iodine(III) reagent
2 over CF3CH2I allowed more effective and readily tunable reaction modes.
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Scheme 5. Substrate Scope of the N-Trifluoroethylationa
O
O
R2
R2
CH2CF3
N
NH
OTf
LiOtBu (2.0 equiv)
I
Mes
+
R1
CH2CF3
N
N
R1
Dry toluene, rt
N2, 12 h
1
2
5
(1.0 equiv)
(1.5 equiv)
(R1 = Me), 89%
O
N
5a
O
CH2CF3
1 mmol scale: 86%
N
CH2CF3
(R1 = Et), 89%
(R1 = iPr), 90%
(R1 = tBu), 91%
(R1 = H), 82%
N
N
5b
5c
N
5d
5e
OMe
X-ray
5f
, 61%
R1
5d
of
O
N
O
O
N
(R1 = F), 75%
(R1 = Cl), 76%
CH2CF3
5g
5h
5i
CH2CF3
CH2CF3
N
F
N
(R1 = Br), 84%
(R1 = I), 67%
N
5j
R1
R1
(R1 = CF3), 74%
(R1 = CN), 43%
5m
5n
5k
, 57%
F
R2
O
F
O
N
O
O
CH2CF3
CH2CF3
CH2CF3
CH2CF3
N
N
N
N
N
F
N
N
Ph
(R2 = H), 60%
5w
5o
, 76%
5p
, 61%
5r
, 70%
Br
2
5w'
(R = Me), 71%
aReaction conditions: 1 (1.0 equiv), 2 (1.5 equiv), LiOtBu (2.0 equiv) , dry toluene, rt, 12 h, isolated yields.
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Regarding the identity of the products, single crystal X-ray analyses of 4e and 5d unambiguously
confirmed their molecular structures.11 In addition, the CH2CF3 signals of the O- and N-isomers in their
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respective F NMR spectra (377 MHz, CDCl3) revealed distinct chemical shift signatures at about -73
1
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and -68 ppm, respectively. As revealed by the H and C NMR spectra, the CH2CF3 signals of the O-
isomers appeared downfield-shifted compared to those of the N-isomers due to the stronger inductive
character.
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Figure 1. Photophysical studies of quinazolinones. a) Biologically important quinazolinones and b) their
photophysics with schematic energy diagrams.
Considering the biological importance of quinazolinone alkaloids (Figure 1a),5 the chemoselective
incorporation of trifluoroethyl moiety can profoundly affect their pharmaceutical aspects by modifying
the lipophilicity, chemical and metabolic stabilities.2,3 Over the last few decades, the importance of
photochemical inertness of bio-active molecules, pharmaceutical drugs, and biomaterials has been
recognized, which is closely linked to their efficacy and/or safety.16 For example, the DNA bases reveal
an exceptionally high photostability under photoexcitation conditions. This largely allows organisms in
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Nature to avoid photo-triggered mutagenesis.17 In addition, securing the photostability of pharmaceutical
drugs is important to avoid adverse effects (e.g., production of phototoxic metabolites) or reduced shelf-
life associated with photodegradation (Figure 1b).16,17 Yet, in the context of the
photophysical/photochemical properties of parent and modified quinazolinone alkaloids, their ultrashort
excited-state lifetimes and high photostability have not been disclosed.
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Figure 2. Representative photophysics in MeCN. a) Steady-state electronic absorption and emission spectra. b) fs-
Resolved fluorescence measured at 380 nm. The compounds are given in each panel. Excitation wavelength was set
at 320 nm to induce the lowest electronic transition. Fluorescence quantum yields and lifetime constants are also
given in each corresponding panel. Dotted lines in the panel (a) correspond to the wavelength region of Raman
scatter from MeCN after subtracting the signals from the solvent.
In this regard, we investigated the photophysics of compounds 1a, 3a, 4a, and 5a by measuring static
electronic spectra as well as femtosecond (fs)-resolved fluorescence kinetic profiles in a series of solvents
(the spectra in Figure 2 were recorded in MeCN; see also the Supporting Information, Section III, Figures
S1–S3 recorded in CHCl3, n-hexane, and MeOH, respectively). The compounds were found to barely
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emit with the quantum yields of 0.6–3.1  10-4. This originated from the ultrashort lifetimes of the excited
states on the timescales of mainly several hundreds fs. The ultrashort-lived nature of the excited states of
the parent quinazolinone and trifluoroethylated structural subclasses indicates an exceptionally high
photostability. It is noteworthy that this characteristic feature is comparable to the nucleobases, whose
excited states with ring puckering can be mixed/crossed and connected to the ground state by the
occurrence of conical intersections; this mediates facile internal conversion on comparable timescales.17
For 1a and 3a, the prototropic tautomers can coexist. This may cause the observation of multiple lifetime
components. However, this is not the case here based on the fact that the lifetimes and their fractions for
both 1a and 3a match well those of 5a, which constitutes only the amide tautomer (Table S4). It follows
that the main tautomer of 1a and 3a at rt is the amide form, showing ultrafast relaxation via the conical
intersections among multiple electronic states as in the case of 5a (Figure 1b, case I).
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Interestingly, the excited-state lifetime of iminol-based/O-trifluoroethylated 4a is significantly
elongated to several tens of picosecond (ps) timescale with a slight increase in the quantum yield (Figure
S1, chloroform). The longer lifetime by O-substitution has been previously reported by Ashwood et al.
through the time-resolved study of O-methylguanine.17e The raised energy barrier of iminol-based O-
substitution is attributed to the retarded vibrational relaxation. Accordingly, in the less viscous n-hexane,
the decay was observed to accelerate with the time constant of 14 ps. In MeOH and MeCN, the
contribution of this slow component to the relaxation of photoexcited 4a becomes significantly smaller
compared to new faster components having the time constants of 1 and 10 ps (Figure 2 and Figure S3; see
also Table S4). The emergence of the new components can be understood if we consider the role of the
charge-transferred (CT) state as a mediating state for efficient relaxation to the ground state in this system.
In the polar solvents, this CT state can be stabilized such that the conical intersection to the CT state
becomes accessible, e.g., in 1 ps, and finally relaxes to the ground state in 10 ps (Figure 1b, case II).
CONCLUSION
In summary, we have developed chemoselective trifluoroethylation methods to afford C-, O-, and N-
functionalized quinazolinone subclasses at room temperature. The inherent directing capability and
competing pronucleophilicity of the unmasked and unactivated quinazolin-4(3H)-one framework were
leveraged with a Pd catalyst or bases in the presence of mesityl(2,2,2-trifluoroethyl)iodonium triflate.
Based on a stoichiometric model study with an isolated tetrameric palladacycle, the Pd-catalyzed site-
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selective direct C–H trifluoroethylation was established. The switchable N- and O-reactivity modes were
accomplished through the base-promoted reactions, and the synthetically suitable electrophilic character
of the iodonium salt over CF3CH2I was disclosed. In addition, the inherent high photostability of parent
and modified quinazolinones was inferred from the ultrashort fluorescence lifetimes and low quantum
yields. We envision that the chromophoric scaffold of the quinazolinone family will be beneficial for the
design of pharmaceutics for which photodegradation needs to be minimized.
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EXPERIMENTAL SECTION
Instrumentation and Chemicals. All reagents were purchased from standard suppliers (Sigma-
Aldrich, Alfa Aesar, or TCI) and were used without further purification. Flash column chromatography
was performed using Merck silica gel 60 (mesh 230-400). Analytic thin layer chromatography (TLC) was
performed on Merck Silica Gel F254 plates (0.25 mm). H, broadband proton-decoupled 13C, and 19F
1
NMR spectra were recorded on a Bruker Avance III HD 400 MHz instrument. The chemical shift values
19
are reported in parts per million (ppm) with respect to residual solvent signals. F NMR chemical shift
values are calibrated to ,,-trifluorotoluene ( = -62.61 ppm, CDCl3).18 Data are given as follows:
chemical shift in ppm (δ), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, brs = broad singlet,
m = multiplet), coupling constant (J, Hz), and integration. High-resolution mass spectra (HRMS) were
performed on a Thermo Scientific Q Exactive Plus Hybrid Quadrupole-Orbitrap mass spectrometer or on
a JEOL AccuTOF LC-Plus 4G+ DART coupled to a DART-SVP ion source (Ionsense Inc.). FTIR spectra
in attenuated total reflectance (ATR) mode were recorded on a Shimadzu IRTracer-100 and reported in
wave number (cm-1). Melting points of the compounds were measured by using a digital melting point
apparatus (KRUSS, Germany). Experimental details of for steady-state and time-resolved spectroscopic
methods can be found in the Supporting Information (Section III). Crystal structures of tetrameric
palladacycle, 3a, 5d, and 4e were solved by the direct method and refined by full-matrix least-squares
calculations using the SHELXTL program package (Supporting Information, Section IV). Thermal
ellipsoid plots were drawn at the 50% probability level.
Materials. Preparation of mesityl(2,2,2-trifluoroethyl)iodonium trifluoromethanesulfonate 2:
Iodonium salt 2 was prepared according to the previously reported literature procedure.
(Step 1)19 To a reaction mixture of trifluoroacetic anhydride (TFAA, 18 mL, 130 mmol) and
trifluoroacetic acid (TFA, 155 µL, 2.0 mmol, 10 mol%) was added H2O2 (2.0 mL, 50 wt. % aq. solution,
35 mmol) in a dropwise manner at 0 C. After stirring for 5 min, CF3CH2I (2.0 mL, 20 mmol) was added.
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Thereafter, the reaction mixture was warmed to rt. After 20 h, it was concentrated in vacuo and the
residue was recrystallized to furnish the intermediate, (2,2,2-trifluoroethyl)-λ3-iodanediyl bis(2,2,2-
trifluoroacetate) (3.5 g, 8.0 mmol, 40% yield). It was directly used for the next step.
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(Step 2)8a To the intermediate in DCM (15 mL) were added mesitylene (1.7 mL, 12 mmol) and triflic
acid (TfOH, 0.71 mL, 8.0 mmol, in a dropwise manner) at 0 C. After 24 h at 0 C, the reaction mixture
was concentrated in vacuo. A white precipitate was formed by the addition of Et2O (30 mL). The target
product 2 was obtained through filtration, rinsing (Et2O), and then recrystallization (Et2O/conc. MeOH).
White solid (2.9 g, 6.1 mmol, 76% yield). 1H NMR (400 MHz, CDCl3) δ = 6.89 (s, 2H), 4.71 (q, J = 8 Hz,
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2H), 2.43 (s, 6H), 2.24 (s, 3H); C NMR (100 MHz, CDCl3) δ = 141.9, 137.4, 128.0, 118.5 (q, J = 318
Hz), 104.3, 68.7 (q, J = 39 Hz), 29.6, 20.7.
Preparation of 2-arylquinazolin-4(3H)-ones (1)5:
R1-substituted 2-arylquinazoline-4(3H)-ones (1) were prepared based on the previously reported
literature procedure using anthranilamide and corresponding benzaldehyde derivatives.5c Anthranilamide
(1.0 equiv) and benzaldehyde derivative (1.2 equiv) were dissolved in DMSO. Then, the reaction mixture
was stirred at 100 C. After completion of the reaction, the mixture was cooled to rt. The precipitate was
formed by addition of water, and collected by filtration. Recrystallization in ethanol afforded the target
compound 1. * 1a,5c 1b,5g 1c,5g 1d,5g 1e,5c 1f,5c 1g,5h 1h,5c 1i,5g 1j,5i 1k,5j 1l,5k 1m,5l 1n,5g 1o,5m 1p,5m 1p’,5q
and 1p’’5g were previously reported in the literature.
R2-substituted 2-arylquinazoline-4(3H)-ones (1) were prepared based on the previously reported
literature procedure using 2-halobenzoic acids and benzamidine hydrochloride.5e Into a two-neck round-
bottom flask were added substituted 2-halobenzoic acid (1.0 equiv) and benzamidine hydrochloride (1.5
equiv) in DMF. The reaction flask was evacuated, back-filled with nitrogen several times, and then
vigorously stirred for 10 min. Cs2CO3 (2.0 equiv) was added to the reaction mixture. After 15 min, CuI
(20 mol%) was subsequently added and stirred at rt for 12 h under a nitrogen atmosphere. After
completion of the reaction, the reaction mixture was filtered. The solvent residue was concentrated in
vacuo, and the residue was purified by flash column chromatography to yield the target compound 1. *
1q,5n 1r,5o 1s,5p 1t,5p 1u,5p 1v,5p 1w,5o 1x,10b 1y,10b 1z,10b and 1w’10b were previously reported in the
literature.
1
Data of Starting Materials (all the compounds 1 were previously reported. Thus H NMR data are
provided)
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2-(p-Tolyl)quinazolin-4(3H)-one (1a).5c White solid (2.39 g, 74%); H NMR (400 MHz, DMSO-d6) δ
= 12.46 (s, 1H), 8.15 (d, J = 8 Hz, 1H), 8.10 (d, J = 8 Hz, 1H), 7.83 (t, J = 8 Hz, 1H), 7.73 (d, J = 8 Hz,
1H), 7.51 (t, J = 8 Hz, 1H), 7.36 (d, J = 8 Hz, 2H), 2.39 (s, 3H).
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2-(4-Ethylphenyl)quinazolin-4(3H)-one (1b).5g White solid (421 mg, 56%); H NMR (400 MHz,
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DMSO-d6) δ = 12.47 (s, 1H), 8.16 – 8.11 (m, 3H), 7.83 (t, J = 8 Hz, 1H), 7.73 (d, J = 8 Hz, 1H), 7.51 (t, J
= 8 Hz, 1H), 7.39 (d, J = 8 Hz, 2H), 2.69 (q, J = 8 Hz, 2H), 1.22 (t, J = 8 Hz, 3H).
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2-(4-Isopropylphenyl)quinazolin-4(3H)-one (1c).5g White solid (343 mg, 61%); H NMR (400 MHz,
DMSO-d6) δ = 12.47 (s, 1H), 8.16 – 8.11 (m, 3 H), 7.83 (t, J = 8 Hz, 1H), 7.73 (d, J = 8 Hz, 1H), 7.51 (t,
J = 8 Hz, 1H), 7.42 (d, J = 8 Hz, 2H), 3.00 (sept, J = 8 Hz, 1H), 1.24 (d, J = 8 Hz, 6H).
2-(4-(tert-Butyl)phenyl)quinazolin-4(3H)-one (1d).5g White solid (411 mg, 70%); 1H NMR (400 MHz,
DMSO-d6) δ = 12.48 (s, 1H), 8.16 – 8.12 (m, 3H), 7.83 (t, J = 8 Hz, 1H), 7.73 (d, J = 8 Hz, 1H), 7.56 (d, J
= 8 Hz, 2H), 7.51 (t, J = 8 Hz, 1H), 1.32 (s, 9H).
2-Phenylquinazolin-4(3H)-one (1e).5c White solid (576 mg, 48%); 1H NMR (400 MHz, DMSO-d6) δ =
12.55 (s, 1H), 8.20 – 8.15 (m, 3H), 7.87 – 7.83 (m, 1H), 7.75 (d, J = 8 Hz, 1H), 7.60 – 7.51 (m, 4H).
1
2-(4-Methoxyphenyl)quinazolin-4(3H)-one (1f).5c White solid (289 mg, 52%); H NMR (400 MHz,
DMSO-d6) δ = 12.41 (s, 1H), 8.19 (d, J = 8 Hz, 2H), 8.13 (d, J = 8 Hz, 1H), 7.81 (t, J = 8 Hz, 1H), 7.70 (d,
J = 8 Hz, 1H), 7.48 (t, J = 8 Hz, 1H), 7.09 (d, J = 8 Hz, 2H), 3.85 (s, 3H).
1
2-(4-Fluorophenyl)quinazolin-4(3H)-one (1g).5h White solid (388 mg, 44%); H NMR (400 MHz,
DMSO-d6) δ = 12.57 (s, 1H), 8.27 – 8.23 (m, 2H), 8.15 (d, J = 8 Hz, 1H), 7.84 (t, J = 8 Hz, 1H), 7.74 (d, J
= 8 Hz, 1H), 7.52 (t, J = 8 Hz, 1H), 7.40 (t, J = 8 Hz, 2H).
1
2-(4-Chlorophenyl)quinazolin-4(3H)-one (1h).5c White solid (430 mg, 38%); H NMR (400 MHz,
DMSO-d6) δ = 12.75 (s, 1H), 8.34 (d, J = 8 Hz, 2H), 8.17 (d, J = 8 Hz, 1H), 8.04 (d, J = 8 Hz, 2H), 7.87 (t,
J = 8 Hz, 1H), 7.78 (d, J = 8 Hz, 1H), 7.57 (t, J = 8 Hz, 1H).
1
2-(4-Bromophenyl)quinazolin-4(3H)-one (1i).5g White solid (521 mg, 53%); H NMR (400 MHz,
DMSO-d6) δ = 12.61 (s, 1H), 8.17 – 8.11 (m, 3H), 7.85 (t, J = 8 Hz, 1H), 7.78 – 7.73 (m, 3H), 7.54 (t, 1H).
1
2-(4-Iodophenyl)quinazolin-4(3H)-one (1j).5i White solid (676 mg, 68%); H NMR (400 MHz,
DMSO-d6) δ = 12.59 (s, 1H), 8.15 (d, J = 8 Hz, 1H), 7.98 – 7.92 (m, 4H), 7.84 (t, J = 8 Hz, 1H), 7.74 (d, J
= 8 Hz, 1H), 7.53 (t, J = 8 Hz, 1H).
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2-(3,5-Difluorophenyl)quinazolin-4(3H)-one (1k).5j White solid (209 mg, 37%); H NMR (400 MHz,
DMSO-d6) δ = 12.65 (s, 1H), 8.17 (d, J = 8 Hz, 1H), 7.96 – 7.85 (m, 3H), 7.78 (d, J = 8 Hz, 1H), 7.59 –
7.51 (m, 2H).
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2-(4-Nitrophenyl)quinazolin-4(3H)-one (1l).5k Yellow solid (281 mg, 19%); H NMR (400 MHz,
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DMSO-d6) δ = 12.83 (s, 1H), 8.43 – 8.37 (m, 4H), 8.19 (d, J = 8 Hz, 1H), 7.88 (t, J = 8 Hz, 1H), 7.80 (d, J
= 8 Hz, 1H), 7.58 (t, J = 8 Hz, 1H).
2-(4-(Trifluoromethyl)phenyl)quinazolin-4(3H)-one (1m).5l White solid (372 mg, 49%); 1H NMR (400
MHz, DMSO-d6) δ = 12.75 (s, 1H), 8.37 (d, J = 8 Hz, 2H), 8.18 (d, J = 8 Hz, 1H), 7.93 (d, J = 8 Hz, 2H),
7.87 (t, J = 8 Hz, 1H), 7.78 (d, J = 8 Hz, 1H), 7.57 (t, J = 8 Hz, 1H).
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4-(4-Oxo-3,4-dihydroquinazolin-2-yl)benzonitrile (1n).5g White solid (348 mg, 40%); H NMR (400
MHz, DMSO-d6) δ = 12.61 (s, 1H), 8.21 (d, J = 8 Hz, 2H), 8.16 (d, J = 8 Hz, 1H), 7.85 (t, J = 8 Hz, 1H),
7.75 (d, J = 8 Hz, 1H), 7.63 (d, J = 8 Hz, 2H), 7.54 (t, J = 8 Hz, 1H).
2-([1,1'-Biphenyl]-4-yl)quinazolin-4(3H)-one (1o).5m White solid (526 mg, 49%); 1H NMR (400 MHz,
DMSO-d6) δ = 12.59 (s, 1H), 8.31 (d, J = 8 Hz, 2H), 8.17 (d, J = 8 Hz, 1H), 7.88 – 7.83 (m, 3H), 7.79 –
7.75 (m, 3H), 7.55 – 7.50 (m, 3H), 7.43 (t, J = 8 Hz, 1H).
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2-(3-Bromophenyl)quinazolin-4(3H)-one (1p).5m White solid (1.15 g, 52%); H NMR (400 MHz,
DMSO-d6) δ = 12.62 (s, 1H), 8.38 (s, 1H), 8.20 – 8.15 (m, 2H), 7.86 – 7.80 (m, 1H), 7.79 – 7.76 (m, 2H),
7.57 – 7.50 (m, 2H).
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2-(2,4-Dimethylphenyl)quinazolin-4(3H)-one (1p’).5q White solid (1.4 g, 76%); H NMR (400 MHz,
CDCl3) δ = 9.85 (s, 1H), 8.29 (d, J = 8 Hz, 1H), 7.80 – 7.78 (m, 2H), 7.53 – 7.47 (m, 1H), 7.45 (s, 1H),
7.15 (d, J = 8 Hz, 2H), 2.51 (s, 3H), 2.40 (s, 3H).
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2-(2-Fluorophenyl)quinazolin-4(3H)-one (1p’’).5g White solid (1.1 g, 62%); H NMR (400 MHz,
CDCl3) δ = 10.01 (s, 1H), 8.36 (t, J = 8 Hz, 1H), 8.30 (d, J = 8 Hz, 1H), 7.82 – 7.77 (m, 2H), 7.56 – 7.49
(m, 2H), 7.36 (t, J = 8 Hz, 1H), 7.24 – 7.21 (m, 1H).
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5-Methoxy-2-phenylquinazolin-4(3H)-one (1q).5n White solid (201 mg, 5%); H NMR (400 MHz,
DMSO-d6) δ = 12.20 (s, 1H), 8.17 (d, J = 8 Hz, 2H), 7.71 (t, J = 8 Hz, 1H), 7.58 – 7.51 (m, 3H), 7.26 (d, J
= 8 Hz, 1H), 7.02 (d, J = 8 Hz, 1H), 3.89 (s, 3H).
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5-Fluoro-2-phenylquinazolin-4(3H)-one (1r).5o White solid (430 mg, 24%); H NMR (400 MHz,
DMSO-d6) δ = 12.55 (s, 1H), 8.19 – 8.16 (m, 2H), 7.83 – 7.78 (m, 1H), 7.61 – 7.53 (m, 4H), 7.28 – 7.23
(m, 1H).
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5-Chloro-2-phenylquinazolin-4(3H)-one (1s).5p White solid (282 mg, 16%); H NMR (400 MHz,
DMSO-d6) δ = 12.55 (s, 1H), 8.19 – 8.16 (m, 2H), 7.77 – 7.67 (m, 1H), 7.61 – 7.59 (m, 1H), 7.57 – 7.51
(m, 4H).
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6-Fluoro-2-phenylquinazolin-4(3H)-one (1t).5p White solid (1.24 g, 71%); H NMR (400 MHz,
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DMSO-d6) δ = 12.67 (s, 1H), 8.17 (d, J = 8 Hz, 2H), 7.85 – 7.81 (m, 2H), 7.76 – 7.71 (m, 1H), 7.60 –
7.53(m, 3H).
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6-Bromo-2-phenylquinazolin-4(3H)-one (1u).5p White solid (528 mg, 43%); H NMR (400 MHz,
DMSO-d6) δ = 12.73 (s, 1H), 8.23 (s, 1H), 8.19 – 8.16 (m, 2H), 7.99 (d, J = 8 Hz, 1H), 7.70 (d, J = 8 Hz,
1H), 7.61 – 7.54 (m, 3H).
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6-Methyl-2-phenylquinazolin-4(3H)-one (1v).5p White solid (976 mg, 30%); H NMR (400 MHz,
DMSO-d6) δ = 12.46 (s, 1H), 8.17 (d, J = 8 Hz, 2H), 7.96 (s, 1H), 7.66 (d, J = 8 Hz, 2H), 7.58 – 7.52 (m,
3H), 2.46 (s, 3H).
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7-Fluoro-2-phenylquinazolin-4(3H)-one (1w).5o White solid (780 mg, 44%); H NMR (400 MHz,
DMSO-d6) δ = 12.62 (s, 1H), 8.21 – 8.15 (m, 3H), 7.61 – 7.47 (m, 4H), 7.38 – 7.33 (m, 1H).
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7-Chloro-5-methyl-2-phenylquinazolin-4(3H)-one (1x).10b White solid (933 mg, 57%); H NMR (400
MHz, DMSO-d6) δ = 12.45 (s, 1H), 8.18 – 8.15 (m, 2H), 7.61 – 7.53 (m, 4H), 7.36 (s, 1H), 2.80 (s, 3H).
6,7-Dimethyl-2-phenylquinazolin-4(3H)-one (1y).10b White solid (582 mg, 32%); 1H NMR (400 MHz,
DMSO-d6) δ = 12.37 (s, 1H), 8.16 (d, J = 8 Hz, 2H), 7.91 (s, 1H), 7.58 – 7.52 (m, 4H), 2.39 (s, 3H), 2.37
(s, 3H).
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8-Nitro-2-phenylquinazolin-4(3H)-one (1z).10b Yellowish solid (228 mg, 12%); H NMR (400 MHz,
DMSO-d6) δ = 12.95 (s, 1H), 8.38 (d, J = 8 Hz, 1H), 8.31 (d, J = 8 Hz, 1H), 8.16 (d, J = 8 Hz, 2H), 7.67
– 7.55 (m, 4H).
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7-Fuoro-5-methyl-2-phenylquinazolin-4(3H)-one (1w').10b White solid (844 mg, 53%); H NMR (400
MHz, DMSO-d6) δ = 12.39 (s, 1H), 8.16 (d, J = 8 Hz, 2H), 7.60 – 7.52 (m, 3H), 7.29 (d, J = 8 Hz, 1H),
7.16 (d, J = 8 Hz, 1H), 2.81 (s, 3H).
Stoichiometric Model Study of C-Trifluoroethylation.
Synthesis of the tetrameric palladacycle and its C-trifluoroethylation: An oven-dried 10 mL round-
bottom flask was charged with 2-(4-bromophenyl)quinazolin-4(3H)-one 1i (86 mg, 0.29 mmol) and
Pd(OAc)2 (64 mg, 0.29 mmol, 1.0 equiv). This mixture was dissolved in 1,2-dichloroethane (DCE, 5 mL),
and stirred at rt for 6 h. Then the mixture was filtered, and the residue was washed with hexane to give the
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desired tetrameric palladacycle as a yellow solid (103 mg, 0.062 mmol (0.25 mmol: tetrameric form),
86%). 1H NMR (400 MHz, DMSO-d6) δ = 8.09 (d, J = 8 Hz, 1H), 7.86 – 7.79 (m, 3H), 7.71 (s, 1H), 7.49
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(d, J = 8 Hz, 2H); C{1H} NMR (100 MHz, DMSO-d6) δ = 164.8, 134.3, 134.2, 133.8, 133.7, 133.6,
128.7, 128.6, 128.2, 126.3, 126.2, 125.8, 123.2, 120.4; ATR-FTIR (cm-1): 1682, 1651, 1579, 1471, 1381,
1195, 1159, 1080. Single crystals were obtained from hexane/acetone through the vapour diffusion
method, and the compound was characterized by X-ray crystallography (see the Supporting Information,
Section IV).
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To an oven-dried 10 mL round-bottom flask charged with the tetrameric palladacycle (30 mg, 0.018
mmol, (0.072 mmol: tetrameric form)) and 2 (53 mg, 0.11 mmol) were added DCE (2 mL) and TFA (115
µL, 1.48 mmol). The reaction mixture was stirred at rt for 24 h. After completion of the reaction, the
solvent was removed in vacuo and the residue was purified by flash column chromatography (15–20%
ethyl acetate (EA) in hexane) to give 3i (19 mg, 0.050 mmol, 69%) as a white solid.
Representative
Procedure
for
the
Synthesis
of
2-(4-Methyl-2-(2,2,2-
trifluoroethyl)phenyl)quinazolin-4(3H)-one (3a).
An oven-dried 10 mL round-bottom flask was charged with 2-(p-tolyl)quinazolin-4(3H)-one 1a (60
mg, 0.25 mmol), 2 (182 mg, 0.38 mmol) and Pd(OAc)2 (11 mg, 0.050 mmol). To this mixture were added
DCE (5 mL) and TFA (396 µL, 5.0 mmol), and the reaction mixture was stirred at rt. The progress of the
reaction was monitored by TLC (20% EA in hexane). After the completion of reaction, the resulting
solution was diluted with dichloromethane and filtered through Celite. The reaction mixture was
concentrated in vacuo and the crude residue was purified by flash column chromatography (10–15% EA
in hexane) to give 3a (73.5 mg, 0.23 mmol, 91%) as a white solid.
(1 mmol-scale) An oven-dried 25 mL round-bottom flask was charged with 2-(p-tolyl)quinazolin-
4(3H)-one 1a (236 mg, 1.0 mmol), 2 (717 mg, 1.5 mmol) and Pd(OAc)2 (45 mg, 0.20 mmol). To this
mixture were added DCE (15 mL) and TFA (1.55 mL, 20 mmol), and the reaction mixture was stirred at
rt. The progress of the reaction was monitored by TLC (20% EA in hexane). After the completion of
reaction, the resulting solution was diluted with dichloromethane and filtered through Celite. The reaction
mixture was concentrated in vacuo and the crude residue was purified by flash column chromatography
(10–15% EA in hexane) to give 3a (286 mg, 0.90 mmol, 90%) as a white solid.
Representative Procedure for the Synthesis of 2-(p-Tolyl)-4-(2,2,2-trifluoroethoxy)quinazoline
(4a).
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An oven-dried 10 mL round-bottom flask was charged with 1a (60 mg, 0.25 mmol), 2 (182 mg, 0.38
mmol) and K2CO3 (35 mg, 0.25 mmol). To this mixture were added MeCN (5 mL) and the system stirred
at rt. The progress of the reaction was monitored by TLC (10% EA in hexane). After the completion of
reaction, the solvents were evaporated to dryness and the crude residue was purified by flash column
chromatography (2–5% EA in hexane) to give 4a (75 mg, 0.24 mmol, 93%) as a white solid.
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(1 mmol-scale) An oven-dried 25 mL round-bottom flask was charged with 1a (236 mg, 1.0 mmol), 2
(717 mg, 1.5 mmol) and K2CO3 (138 mg, 1.0 mmol). To this mixture were added MeCN (15 mL) and the
system stirred at rt. The progress of the reaction was monitored by TLC (10% EA in hexane). After the
completion of reaction, the solvents were evaporated to dryness and the crude residue was purified by
flash column chromatography (2–5% EA in hexane) to give 4a (295 mg, 0.93 mmol, 93%) as a white
solid.
Representative Procedure for the Synthesis of 2-(p-Tolyl)-3-(2,2,2-trifluoroethyl)quinazolin-
4(3H)-one (5a).
An oven-dried Schlenk tube was charged with 1a (60 mg, 0.25 mmol), 2 (182 mg, 0.38 mmol) and
LiOtBu (41 mg, 0.51 mmol). The tube was evacuated and purged with N2 repeatedly three times. To this
mixture was added degassed dry toluene (5 mL). After 12 h, the mixture was concentrated in vacuo and
purified by flash column chromatography (8–10% EA in hexane) to give 5a (72 mg, 0.23 mmol, 89%) as
a colourless semi-solid.
(1 mmol-scale) An oven-dried Schlenk tube was charged with 1a (236 mg, 1.0 mmol), 2 (717 mg, 1.5
mmol) and LiOtBu (160 mg, 2.0 mmol). The tube was evacuated and purged with N2 repeatedly three
times. To this mixture was added degassed dry toluene (15 mL). After 12 h, the mixture was concentrated
in vacuo and purified by flash column chromatography (8–10% EA in hexane) to give 5a (274 mg, 0.86
mmol, 86%) as a colourless semi-solid.
Characterization Data.
2-(4-Methyl-2-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (3a). Rf = 0.4 (hexane:EA, 4:1);
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white solid (73.5 mg, 91%); mp 221−223 °C; F NMR (377 MHz, CDCl3) δ = -65.1 (t, J = 12 Hz); H
NMR (400 MHz, CDCl3) δ = 10.88 (s, 1H), 8.25 (d, J = 8 Hz, 1H), 7.82 – 7.75 (m, 2H), 7.60 (d, J = 8 Hz,
1H), 7.51 (t, J = 8 Hz, 1H), 7.34 (d, J = 8 Hz, 1H), 7.31 (s, 1H), 4.00 (q, J = 12 Hz, 2H), 2.45 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ = 163.2, 152.7, 148.8, 141.3, 135.0, 133.6, 131.7, 129.6 (q, J = 3
Hz), 129.5, 129.2, 127.8, 127.2, 126.5, 125.9 (q, J = 275 Hz), 120.8, 36.4 (q, J = 30 Hz), 21.5; ATR-FTIR
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(cm-1): 1666, 1612, 1597, 1469, 1344, 1257, 1124, 1076; HRMS (ESI+) m/z [M+H]+ calcd for
C17H14F3N2O 319.1053; found 319.1053.
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2-(4-Ethyl-2-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (3b). Rf = 0.4 (hexane:EA, 4:1); white
solid (54 mg, 82%); mp 219−220 °C; 19F NMR (377 MHz, CDCl3) δ = -65.1 (t, J = 12 Hz); 1H NMR (400
MHz, CDCl3) δ = 10.09 (s, 1H), 8.29 (d, J = 8 Hz, 1H), 7.81 (t, J = 8 Hz, 1H), 7.76 (d, J = 8 Hz, 1H),
7.57 (d, J = 8 Hz, 1H), 7.53 (t, J = 8 Hz, 1H), 7.36 (d J = 8 Hz, 1H), 7.33 (s, 1H), 4.01 (q, J = 12 Hz, 2H),
2.75 (q, J = 8 Hz, 2H), 1.29 (t, J = 8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ = 162.8, 152.6, 148.7,
147.7, 135.1, 132.7, 132.0, 129.6 (q, J = 3 Hz), 129.1, 128.4, 127.9, 127.3, 126.6, 125.7 (q, J = 240 Hz),
120.9, 36.5 (q, J = 29 Hz), 28.8, 15.4; ATR-FTIR (cm-1): 1670, 1610, 1598, 1465, 1352, 1309, 1251,
1134, 1082, 948; HRMS (ESI+) m/z [M+H]+ calcd for C18H16F3N2O 333.1209; found 333.1208.
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2-(4-Isopropyl-2-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (3c). Rf = 0.4 (hexane:EA, 4:1);
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white solid (69 mg, 84%); mp 208−210 °C; F NMR (377 MHz, CDCl3) δ = -65.2 (t, J = 12 Hz); H
NMR (400 MHz, CDCl3) δ = 10.04 (s, 1H), 8.29 (d, J = 8 Hz, 1H), 7.81 (t, J = 8 Hz, 1H), 7.75 (d, J = 8
Hz, 1H), 7.57 (d, J = 8 Hz, 1H), 7.52 (t, J = 8 Hz, 1H), 7.38 (d, J = 8 Hz, 1H), 7.35 (s, 1H), 4.02 (q, J =
12 Hz, 2H), 3.00 (sept, J = 8, 4 Hz, 1H), 1.31 (s, 3H), 1.30 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ =
162.6, 152.5, 152.2, 148.7, 135.0, 132.1, 131.4, 129.6 (q, J = 3 Hz), 129.0, 127.9, 127.3, 127.0, 126.6,
125.9 (q, J = 275 Hz), 120.9, 36.6 (q, J = 29 Hz), 34.1, 23.8; ATR-FTIR (cm-1): 1668, 1610, 1598, 1471,
1354, 1305, 1255, 1138, 1078, 1055; HRMS (ESI+) m/z [M+H]+ calcd for C19H18F3N2O 347.1366; found
347.1364.
2-(4-(Tert-butyl)-2-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (3d). Rf = 0.4 (hexane:EA, 4:1);
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white solid (69 mg, 87%); mp 208−209 °C; F NMR (377 MHz, CDCl3) δ = -65.2 (t, J = 12 Hz); H
NMR (400 MHz, CDCl3) δ = 10.11 (s, 1H), 8.28 (d, J = 8 Hz, 1H), 7.81 (t, J = 8 Hz, 1H), 7.75 (d, J = 8
13
Hz, 1H), 7.59 – 7.52 (m, 3H), 7.50 (s, 1H), 4.02 (q, J = 12 Hz, 2H), 1.38 (s, 9H); C{1H} NMR (100
MHz, CDCl3) δ = 162.9, 154.5, 152.6, 148.8, 135.0, 131.7, 130.2, 129.3 (q, J = 2 Hz), 128.8, 127.9,
127.3, 126.6, 125.9 (q, J = 276 Hz), 125.8, 120.9, 36.7 (q, J = 29 Hz), 35.0, 31.2; ATR-FTIR (cm-1):
1670, 1610, 1599, 1564, 1467, 1355, 1284, 1255, 1120, 1085; HRMS (ESI+) m/z [M+H]+ calcd for
C20H20F3N2O 361.1522; found 361.1521.
2-(2-(2,2,2-Trifluoroethyl)phenyl)quinazolin-4(3H)-one (3e). Rf = 0.4 (hexane:EA, 4:1); white solid
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(47 mg, 86%); mp 202−203 °C; F NMR (377 MHz, CDCl3) δ = -65.1 (t, J = 12 Hz); H NMR (400
MHz, CDCl3) δ = 10.89 (s, 1H), 8.26 (d, J = 8Hz, 1H), 7.84 – 7.76 (m, 2H), 7.71 – 7.69 (m, 1H), 7.57 –
7.50 (m, 4H), 4.02 (q, J = 12 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ = 163.2, 152.6, 148.7, 135.1,
134.6, 132.9, 130.9, 129.7 (q, J = 2 Hz), 129.3, 128.9, 127.9, 127.4, 126.6, 125.9 (q, J = 275 Hz), 120.9,
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36.5 (q, J = 30 Hz); ATR-FTIR (cm-1): 1676, 1606, 1595, 1469, 1357, 1257, 1134, 1072; HRMS (ESI+)
m/z [M+H]+ calcd for C16H12F3N2O: 305.0896; found 305.0896.
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2-(4-Methoxy-2-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (3f). Rf = 0.30 (hexane:EA, 4:1);
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white solid (42 mg, 63%); mp 224−225 °C; F NMR (377 MHz, CDCl3) δ = -64.9 (t, J = 12 Hz); H
NMR (400 MHz, CDCl3) δ = 10.77 (s, 1H), 8.26 (d, J = 8 Hz, 1H), 7.82 – 7.74 (m, 2H), 7.65 (d, J = 12
Hz, 1H), 7.51 (t, J = 8 Hz, 1H), 7.05 (t, J = 8 Hz, 1H), 7.03 (s, 1H), 4.05 (q, J = 12 Hz, 2H), 3.90 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ = 163.4, 161.3, 152.5, 148.9, 135.0, 131.7 (q, J = 3 Hz), 130.9,
127.8, 127.1, 126.9, 126.5, 125.9 (q, J = 276 Hz) 120.7, 118.8, 113.7, 55.6, 36.7 (q, J = 30 Hz); ATR-
FTIR (cm-1): 1674, 1608, 1570, 1465, 1355, 1253, 1240, 1132, 1085, 1072; HRMS (ESI+) m/z [M+H]+
calcd for C17H14F3N2O2 335.1002; found 335.1002.
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2-(4-Fluoro-2-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (3g). Rf = 0.40 (hexane:EA, 4:1);
white solid (52 mg, 70%); mp 228−229 °C; 19F NMR (377 MHz, CDCl3) δ = -66.0 (t, J = 12 Hz), -108.2
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– -102.3 (m); H NMR (400 MHz, CDCl3) δ = 10.71 (s, 1H), 8.28 (d, J = 8 Hz, 1H), 7.83 (t, J = 8 Hz,
1H), 7.77 (d, J = 8 Hz, 1H), 7.71 (dd, J = 8 Hz, 1H), 7.55 (t, J = 8 Hz, 1H), 7.29 – 7.24 (m, 2H), 4.03 (q, J
= 12 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ = 164.9, 163.2, 162.4, 151.7, 148.6, 135.2, 132.6 (q, J
= 5 Hz), 131.4 (d, J = 9 Hz), 130.8 (d, J = 3 Hz), 127.7 (d, J = 28 Hz), 126.6, 125.5 (d, J = 276 Hz),
120.8, 119.9 (d, J = 22 Hz), 116.0 (d, J = 21 Hz), 36.6 (q, J = 30 Hz); ATR-FTIR (cm-1): 1674, 1585,
1469, 1354, 1298, 1255, 1220, 1145, 1076; HRMS (ESI+) m/z [M+H]+ calcd for C16H11F4N2O: 323.0802;
found 323.0802.
2-(4-Chloro-2-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (3h). Rf = 0.40 (hexane:EA, 4:1);
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white solid (49 mg, 69%); mp 237−238 °C; F NMR (377 MHz, CDCl3) δ = -65.0 (t, J = 12 Hz); H
NMR (400 MHz, CDCl3) δ = 11.15 (s, 1H), 8.27 (d, J = 8 Hz, 1H), 7.83 (t, J = 8 Hz, 1H), 7.77 (d, J = 8
Hz, 1H), 7.69 (d, J = 12 Hz, 1H), 7.58 – 7.53 (m, 3H), 4.03 (q, J = 12 Hz, 2 H); 13C{1H} NMR (100 MHz,
CDCl3) δ = 163.4, 151.6, 148.6, 137.1, 135.3, 132.9, 132.9, 131.7 (q, J = 3 Hz), 130.7, 129.1, 127.9,
127.7, 126.6, 125.6 (q, J = 275 Hz), 120.8, 36.4 (q, J = 30 Hz); ATR-FTIR (cm-1): 1676, 1606, 1568,
1469, 1377, 1298, 1246, 1138, 1091; HRMS (ESI+) m/z [M+H]+ calcd for C16H11ClF3N2O: 339.0507;
found 339.0506.
2-(4-Bromo-2-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (3i). Rf = 0.40 (hexane:EA, 4:1);
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white solid (48 mg, 69%); mp 237−238 °C; F NMR (377 MHz, CDCl3) δ = -65.0 (t, J = 12 Hz); H
NMR (400 MHz, CDCl3) δ = 10.80 (s, 1H), 8.28 (d, J = 8 Hz, 1H), 7.84 – 7.81 (m, 1H), 7.76 (s, 1H), 7.72
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– 7.69 (m, 2H), 7.60 – 7.54 (m, 2H), 4.02 (q, J = 12 Hz, 2H); C{1H} NMR (100 MHz, CDCl3) δ =
163.2, 151.6, 148.5, 135.8, 135.3, 133.4, 132.1, 131.8 (q, J = 3 Hz), 130.7, 127.9, 127.7, 126.6, 125.6 (q,
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J = 276 Hz), 125.3, 120.8, 36.3 (q, J = 30 Hz); ATR-FTIR (cm-1): 1678, 1606, 1566, 1469, 1375, 1300,
1244, 1138, 1091; HRMS (ESI+) m/z [M+H]+ calcd for C16H11BrF3N2O: 383.0001; found 383.0001.
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2-(4-Iodo-2-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (3j). Rf = 0.45 (hexane:EA, 4:1); white
solid (44 mg, 85%); mp 226−227 °C; 19F NMR (377 MHz, CDCl3) δ = -65.0 (t, J = 12 Hz); 1H NMR (400
MHz, CDCl3) δ = 11.12 (s, 1H), 8.26 (d, J = 8 Hz, 1H), 7.92 – 7.81 (m, 3H), 7.76 (d, J = 8 Hz, 1H), 7.56
(t, J = 8 Hz, 1H), 7.46 (d, J = 12 Hz, 1H), 4.00 (q, J = 12 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ =
163.4, 151.8, 148.6, 141.7, 138.0, 135.3, 134.0, 131.7 (q, J = 3 Hz), 130.7, 127.9, 127.7, 126.6, 125.6 (q,
J = 276 Hz),120.8, 97.3, 36.1 (q, J = 30 Hz); ATR-FTIR (cm-1): 1680, 1597, 1546, 1477, 1363, 1282,
1246, 1136, 1070; HRMS (ESI+) m/z [M+H]+ calcd for C16H11F3IN2O: 430.9863; found 430.9863.
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2-(3,5-Difluoro-2-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (3k). Rf = 0.35 (hexane:EA, 4:1);
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white solid (29 mg, 44%); mp 233−235 °C; F NMR (377 MHz, CDCl3) δ = -65.6 (m), -107.4 – -107.5
(m), -107.7 – -107.8 (m); 1H NMR (400 MHz, CDCl3) δ = 11.48 (s, 1H), 8.29 (d, J = 8 Hz, 1H), 7.87 (t, J
= 8 Hz, 1H), 7.78 (d, J = 8 Hz, 1H), 7.58 (t, J = 8 Hz, 1H), 7.38 (d, J = 8 Hz, 1H), 7.11 (d, J = 8 Hz, 1H),
4.15 (q, J = 12 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ = 163.5, 162.7 (d, J = 265 Hz), 162.6 (d, J =
237 Hz), 150.5 (t, J = 3 Hz), 148.4, 137.1 (q, J = 4 Hz), 135.4, 128.0 (d, J = 7 Hz), 126.7, 125.4 (q, J =
276 Hz), 120.9, 114.0 (d, J = 20 Hz), 113.2 (dd, J1 = J2 = 24 Hz), 106.6 (d, J = 24 Hz), 106.3 (d, J = 24
Hz), 37.0 (q, J = 31 Hz); ATR-FTIR (cm-1): 1674, 1608, 1506, 1467, 1373, 1336, 1247, 1126, 1089;
HRMS (ESI+) m/z [M+H]+ calcd for C16H10F5N2O 341.0708; found 341.0708.
2-(4-Nitro-2-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (3l). Rf = 0.30 (hexane:EA, 7:3); white
solid (23 mg, 61%); mp 246−248 °C; 19F NMR (377 MHz, CDCl3) δ = -64.9 (t, J = 12 Hz); 1H NMR (400
MHz, CDCl3) δ = 11.04 (s, 1H), 8.45 – 8.42 (m, 2H), 8.30 (d, J = 8 Hz, 1H), 7.93 (d, J = 8 Hz, 1H), 7.88
(t, J = 8 Hz, 1H), 7.80 (d, J = 8 Hz, 1H), 7.61 (t, J = 8 Hz, 1H), 4.15 (q, J = 12 Hz, 2H); 13C{1H} NMR
(100 MHz, DMSO-d6) δ = 161.7, 151.9, 148.1, 148.0, 140.3, 134.7, 132.0, 131.5 (q, J = 3 Hz), 127.5,
127.4, 126.8, 125.9 (q, J = 276 Hz), 125.8, 123.2, 121.2, 34.8 (q, J = 29 Hz); ATR-FTIR (cm-1): 1678,
1599, 1523, 1469, 1344, 1294, 1246, 1130, 1089; HRMS (ESI+) m/z [M+H]+ calcd for C16H11F3N3O3:
350.0747; found 350.0747.
2-(2-(2,2,2-Trifluoroethyl)-4-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (3m). Rf
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(hexane:EA, 7:3); white solid (49 mg, 54%); mp 230−232 °C; F NMR (377 MHz, CDCl3) δ = -63.0, -
65.1 (t, J = 12 Hz); 1H NMR (400 MHz, CDCl3) δ = 11.42 (s, 1H), 8.25 (d, J = 8 Hz, 1H), 7.90 – 7.78 (m,
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4H), 7.79 (s, 1H), 7.58 (t, J = 8 Hz, 1H), 4.1 (q, J = 30 Hz, 2H); C{1H} NMR (100 MHz, CDCl3) δ =
163.5, 151.3, 148.5, 137.8, 135.4, 132.9 (q, J = 33 Hz), 131.0 (q, J = 3 Hz), 130.2, 129.6 (q, J = 3 Hz),
128.0, 127.9, 126.6, 125.9 (q, J = 203 Hz), 125.8 (q, J = 4 Hz), 123.1 (q, J = 199 Hz), 120.9, 36.6 (q, J =
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30 Hz); ATR-FTIR (cm-1): 1680, 1602, 1446, 1344, 1325, 1247, 1138, 1120, 1070; HRMS (ESI+) m/z
[M+H]+ calcd for C17H11F6N2O: 373.0770; found 373.0770.
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2-(3-(2,2,2-Trifluoroethyl)-[1,1'-biphenyl]-4-yl)quinazolin-4(3H)-one (3o). Rf = 0.35 (hexane:EA,
4:1); white solid (61 mg, 89%); mp 212−214 °C; 19F NMR (377 MHz, CDCl3) δ = -65.0 (t, J = 12 Hz); 1H
NMR (400 MHz, CDCl3) δ = 10.05 (s, 1H), 8.32 (d, J = 8 Hz, 1H), 7.85 – 7.72 (m, 5H), 7.67 – 7.64 (m,
2H), 7.55 – 7.51 (m, 3H), 7.49 – 7.44 (m, 1H), 4.11 (q, J = 12 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3)
δ = 162.7, 152.2, 148.7, 144.0, 139.4, 135.1, 133.2, 131.7, 130.2 (q, J = 3 Hz), 129.5, 129.2, 128.5, 127.9,
127.6. 127.5, 127.4, 126.6, 125.9 (q, J = 275 Hz), 121.0, 36.6 (q, J = 30 Hz); ATR-FTIR (cm-1): 1647,
1600, 1554, 1471, 1440, 1361, 1292, 1263, 1136, 1082; HRMS (ESI+) m/z [M+H]+ calcd for
C22H16F3N2O 381.1209; found 381.1206.
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2-(5-Bromo-2-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (3p). Rf = 0.40 (hexane:EA, 4:1);
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white solid (45 mg, 64%); mp 239−240 °C; F NMR (377 MHz, CDCl3) δ = -65.0 (t, J = 12 Hz); H
NMR (400 MHz, CDCl3) δ = 11.13 (s, 1H), 8.38 (d, J = 8 Hz, 1H), 7.94 (s, 1H), 7.84 (t, J = 8 Hz, 1H),
7.78 (d, J = 8 Hz, 1H), 7.70 (dd, J = 8, 2 Hz, 1H), 7.57 (t, J = 8 Hz, 1H), 7.40 (d, J = 8 Hz, 1H), 4.01 (q, J
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= 11 Hz, 2H); C{1H} NMR (100 MHz, CDCl3) δ = 163.4, 151.1, 148.5, 136.1, 135.3, 134.3, 134.0,
132.6, 128.8 (q, J = 3 Hz), 127.9, 127.8, 126.8, 125.5 (q, J = 276 Hz), 122.9, 120.9, 36.2 (q, J = 29 Hz);
ATR-FTIR (cm-1): 1676, 1608, 1585, 1469, 1373, 1278, 1246, 1128, 1085; HRMS (ESI+) m/z [M+H]+
calcd for C16H11BrF3N2O 383.0001; found 383.0001.
2-(2,4-Dimethyl-6-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (3p’). Rf = 0.45 (hexane:EA,
4:1); white solid (65 mg, 83%); mp 212−214 °C; 19F NMR (377 MHz, CDCl3) δ = -64.9 (t, J = 12 Hz); 1H
NMR (400 MHz, CDCl3) δ = 9.83 (s, 1H), 8.26 (d, J = 8 Hz, 1H), 7.84 – 7.76 (m, 2H), 7.54 (t, J = 8 Hz,
1H), 7.13 (s, 2H), 3.44 (q, J = 12 Hz, 2H), 2.39 (s, 3H), 2.27 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
= 162.2, 152.6, 148.8, 140.5, 136.8, 135.1, 132.3, 131.5, 129.9, 128.6 (q, J = 3 Hz), 127.9, 127.5, 126.7,
125.6 (q, J = 275 Hz), 121.1, 36.9 (q, J = 30 Hz), 21.38, 19.88; ATR-FTIR (cm-1): 1667, 1609, 1449,
1302, 1256, 1136, 1089; HRMS (ESI+) m/z [M+H]+ calcd for C18H16F3N2O 333.1209; found 333.1209.
2-(2-Fluoro-6-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (3p’’). Rf = 0.40 (hexane:EA, 4:1);
white solid (48 mg, 62%); mp 174−176 °C; 19F NMR (377 MHz, CDCl3) δ = -65.2 (t, J = 12 Hz), -113.3
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– -113.34 (m); H NMR (400 MHz, CDCl3) δ = 9.95 (s, 1H), 8.29 (d, J = 8 Hz, 1H), 7.83 (t, J = 8 Hz,
1H), 7.77 (d, J = 8 Hz, 1H), 7.58 – 7.51 (m, 2H), 7.32 (d, J = 8 Hz, 1H), 7.27 – 7.23 (m, 1H), 3.82 (q, J =
8 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ = 162.0, 160.6 (d, J = 248 Hz), 148.6, 147.8, 135.1, 132.3
(d, J = 9 Hz), 131.9 (q, J = 3 Hz), 128.2 (d, J = 3 Hz), 127.9 (d, J = 5 Hz), 126.8, 124.5 (q, J = 275 Hz),
124.0, 123.1 (d, J = 15 Hz), 121.4, 116.4 (d, J = 22 Hz), 36.4 (q, J = 28 Hz); ATR-FTIR (cm-1): 1670,
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1602, 1465, 1305, 1256, 1141, 1082; HRMS (ESI+) m/z [M+H]+ calcd for C16H11F4N2O 323.0802; found
323.0804.
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5-Methoxy-2-(2-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (3q). Rf = 0.40 (hexane:EA, 7:3);
white solid (19 mg, 36%) (49% based on recovered starting materials using 5.0 equiv TFA); mp 191−192
°C; 19F NMR (377 MHz, CDCl3) δ = -65.2 (t, J = 12 Hz); 1H NMR (400 MHz, CDCl3) δ = 9.22 (s, 1H),
7.70 (t, J = 8 Hz, 1H), 7.60 – 7.48 (m, 4H), 7.34 (d, J = 12 Hz, 1H), 6.96 (d, J = 8Hz, 1H), 4.03 (s, 3H),
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3.98 (q, J = 12 Hz, 2H); C{1H} NMR (100 MHz, CDCl3) δ = 160.7, 160.4, 152.8, 151.1, 135.4, 134.4,
133.0, 131.1, 129.6 (q, J = 3 Hz), 129.0, 128.7,121.5 (q, J = 274 Hz), 120.1, 110.9, 108.7, 56.6, 36.5 (q, J
= 29 Hz); ATR-FTIR (cm-1): 1668, 1602, 1568, 1471, 1367, 1307, 1259, 1130, 1105, 1082; HRMS
(ESI+) m/z [M+H]+ calcd for C17H14F3N2O2 335.1002; found 335.1002.
5-Fluoro-2-(2-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (3r). Rf = 0.40 (hexane:EA, 4:1);
white solid (56 mg, 87%); mp 222−224 °C; 19F NMR (377 MHz, CDCl3) δ = -65.1 (t, J = 12 Hz), -109.7
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– -109.8 (m); H NMR (400 MHz, CDCl3) δ = 10.50 (s, 1H), 7.77 – 7.71 (m, 2H), 7.57 – 7.55 (m, 4H),
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7.17 (t, J = 8 Hz, 1H), 4.02 (q, J = 8 Hz, 2H); C{1H} NMR (100 MHz, CDCl3) δ = 161.5 (d, J = 260
Hz), 153.5, 150.6, 135.5, 135.4, 133.9, 133.1, 131.3, 129.7 (q, JC,F = 3 Hz), 129.2, 129.1, 127.2, 125.8 (q,
J = 275 Hz), 123.8 (d, J = 5 Hz), 114.1 (d, J = 20 Hz), 36.5 (q, J = 29 Hz); ATR-FTIR (cm-1): 1668, 1614,
1469, 1425, 1361, 1249, 1130, 1091; HRMS (ESI+) m/z [M+H]+ calcd for C16H11F4N2O: 323.0802; found
323.0802.
5-Chloro-2-(2-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (3s). Rf = 0.40 (hexane:EA, 4:1);
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white solid (41 mg, 60%); mp 235−237 °C; F NMR (377 MHz, CDCl3) δ = -65.1 (t, J = 12 Hz); H
NMR (400 MHz, CDCl3) δ = 10.33 (s, 1H), 7.73 – 7.63 (m, 3H), 7.58 – 7.50 (m, 4H), 4.01 (q, J = 12 Hz,
2H); 13C{1H} NMR (100 MHz, CDCl3) δ = 161.2, 153.2, 151.1, 134.5, 133.9, 133.1, 131.3, 130.1, 129.7
(q, J = 3 Hz), 129.3, 129.2, 129.1, 127.2, 125.8 (q, J = 274 Hz), 118.2, 36.6 (q, J = 29 Hz); ATR-FTIR
(cm-1): 1664, 1597, 1460, 1369, 1301, 1249, 1120, 1091, 1070; HRMS (ESI+) m/z [M+H]+ calcd for
C16H11ClF3N2O: 339.0507; found 339.0504.
6-Fluoro-2-(2-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (3t). Rf = 0.35 (hexane:EA, 4:1);
white solid (59 mg, 78%); mp 210−212 °C; 19F NMR (377 MHz, CDCl3) δ = -65.2 (t, J = 12 Hz), -111.7
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– -111. 8 (m); H NMR (400 MHz, CDCl3) δ = 11.08 (s, 1H), 7.84 (dd, J1 = 4 Hz, J2 = 4 Hz, 1H), 7.78
(dd, J1 = 4 Hz, J2 = 4 Hz, 1H), 7.71 – 7.69 (m, 1H), 7.58 – 7.51 (m, 4H), 4.00 (q, J = 12 Hz, 2H); 13C{1H}
NMR (100 MHz, CDCl3) δ = 162.7 (d, J = 3 Hz), 161.2 (d, J = 248 Hz), 152.0 (d, J = 2 Hz), 145.4 (d, J =
2 Hz), 134.3, 132.9, 131.1, 130.3 (d, J = 8 Hz), 129.6 (q, J = 3 Hz), 129.4, 128.9, 125.8 (q, J = 276 Hz),
123.7 (d, J = 24 Hz), 122.1 (d, J = 9 Hz), 111.5 (d, J = 23 Hz), 36.5 (q, J = 29 Hz); ATR-FTIR (cm-1):
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1676, 1612, 1479, 1379, 1259, 1199, 1122, 1093; HRMS (ESI+) m/z [M+H]+ calcd for C16H11F4N2O:
323.0802; found 323.0802.
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6-Bromo-2-(2-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (3u). Rf = 0.35 (hexane:EA, 4:1);
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white solid (58 mg, 90%); mp 206−208 °C; F NMR (377 MHz, CDCl3) δ = -65.2 (t, J = 12 Hz); H
NMR (400 MHz, CDCl3) δ = 10.79 (s, 1H), 8.36 (s, 1H), 7.89 (dd, J1 = J2 = 4 Hz, 1H), 7.69 – 7.63 (m,
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2H), 7.59 – 7.51 (m, 3H), 4.00 (q, J = 12 Hz, 2H); C{1H} NMR (100 MHz, CDCl3) δ = 162.0, 153.0,
147.5, 138.3, 134.2, 133.2, 131.3, 129.7, 129.6 (q, J = 3 Hz), 129.2, 129.1, 129.0, 125.9 (q, J = 275 Hz),
122.2, 121.0, 36.5 (q, J = 30 Hz); ATR-FTIR (cm-1): 1674, 1602, 1471, 1361, 1282, 1246, 1134, 1068;
HRMS (ESI+) m/z [M+H]+ calcd for C16H11BrF3N2O 383.0001; found 383.0001.
6-Methyl-2-(2-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (3v). Rf = 0.45 (hexane:EA, 4:1);
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white solid (42 mg, 56%); mp 231−233 °C; F NMR (377 MHz, CDCl3) δ = -65.2 (t, J = 12 Hz); H
NMR (400 MHz, CDCl3) δ = 9.97 (s, 1H), 8.09 (s, 1H), 7.68 – 7.62 (m, 3H), 7.55 – 7.50 (m, 3H), 3.99 (q,
J = 12 Hz, 2H), 2.52 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ = 162.7, 151.5, 146.6, 137.9, 136.6,
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134.8, 132.9, 130.9, 129.6 (q, J = 3 Hz), 129.0, 128.9, 127.7, 126.0, 125.8 (q, J = 275 Hz), 120.7, 36.5 (q,
J = 30 Hz), 21.5; ATR-FTIR (cm-1): 1668, 1610, 1593, 1489, 1357, 1251, 1134, 1078; HRMS (ESI+)
m/z [M+H]+ calcd for C17H14F3N2O 319.1053; found 319.1051.
7-Fluoro-2-(2-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (3w). Rf = 0.45 (hexane:EA, 4:1);
white solid (42 mg, 48%); mp 218−220 °C; 19F NMR (377 MHz, CDCl3) δ = -65.2 (t, J = 12 Hz), -102.1
(m); 1H NMR (400 MHz, CDCl3) δ = 10.43 (s, 1H), 8.28 (dd, J1 = 8 Hz, J2 = 8 Hz, 1H), 7.67 – 7.65 (m,
1H), 7.56 – 7.53 (m, 3H), 7.42 (dd, J1 = 4 Hz, J2 = 4 Hz, 1H), 7.27 – 7.22 (m, 1H), 4.00 (q, J = 12 Hz,
2H); 13C{1H} NMR (100 MHz, CDCl3) δ = 168.3, 165.7, 162.3, 153.9, 150.9 (d, J = 13 Hz), 134.3, 133.0,
131.2, 129.7 (q, J = 3 Hz), 129.7 (d, J = 10 Hz), 129.1 (d, J = 22 Hz), 125.8 (q, J = 275 Hz), 117.6, 116.2
(d, J = 23 Hz), 113.3 (d, J = 21 Hz), 36.5 (q, J = 29 Hz); ATR-FTIR (cm-1): 1678, 1608, 1573, 1448,
1359, 1261, 1132, 1078; HRMS (ESI+) m/z [M+H]+ calcd for C16H11F4N2O: 323.0802; found 323.0800.
7-Chloro-5-methyl-2-(2-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (3x). Rf = 0.45 (hexane:EA,
4:1); white solid (33 mg, 72%); mp 248−250 °C; 19F NMR (377 MHz, CDCl3) δ = -65.2 (t, J = 12 Hz); 1H
NMR (400 MHz, CDCl3) δ = 10.77 (s, 1H), 7.71 – 7.69 (m, 1H), 7.59 – 7.49 (m, 3H), 7.24 (s, 1H), 4.01
(q, J = 12 Hz, 2H), 2.78 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ = 163.5, 153.5, 151.3, 143.2, 140.1,
134.0, 132.9, 131.1, 130.0, 129.7 (q, J = 3 Hz), 129.2, 128.8, 125.8 (q, J = 275 Hz), 125.5, 117.8, 36.5 (q,
J = 30 Hz), 22.7; ATR-FTIR (cm-1): 1666, 1589, 1508, 1442, 1352, 1259, 1128, 1066; HRMS (ESI+) m/z
[M+H]+ calcd for C17H13ClF3N2O: 353.0663; found 353.0661.
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6,7-Dimethyl-2-(2-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (3y). Rf = 0.45 (hexane:EA, 4:1);
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white solid (51 mg, 87%); mp 249−251 °C; F NMR (377 MHz, CDCl3) δ = -65.2 (t, J = 12 Hz); H
NMR (400 MHz, CDCl3) δ = 10.21 (s, 1H), 8.02 (s, 1H), 7.65 – 7.63 (m, 1H), 7.54 – 7.50 (m, 4H), 4.00
(q, J = 12 Hz, 2H), 2.43 (s, 3H), 2.42 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ = 162.4, 151.5, 147.0,
145.5, 137.3, 134.9, 132.9, 130.9, 129.6 (q, J = 2 Hz), 129.0, 128.9, 128.1, 126.4, 125.8 (q, J = 275 Hz),
118.7, 36.4 (q, J = 30 Hz), 20.6, 19.9; ATR-FTIR (cm-1): 1666, 1610, 1593, 1469, 1365, 1303, 1251,
1132, 1085; HRMS (ESI+) m/z [M+H]+ calcd for C18H16F3N2O: 333.1209; found 333.1209.
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8-Nitro-2-(2-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (3z). Rf = 0.40 (hexane:EA, 7:3); white
solid (51 mg, 84%); mp 264−266 °C; 19F NMR (377 MHz, CDCl3) δ = -65.4 (t, J = 8 Hz); 1H NMR (400
MHz, CDCl3) δ = 9.66 (s, 1H), 8.52 (d, J = 8 Hz, 1H), 8.15 (d, J = 8 Hz, 1H), 7.64 – 7.54 (m, 5H), 4.2 (q,
J = 12 Hz, 2H); 13C{1H} NMR (100 MHz, DMSO-d6) δ = 160.7, 156.1, 146.4, 140.1, 133.4, 132.7, 131.0,
130.5, 129.7, 129.4 (q, J = 3 Hz), 128.4, 128.3, 126.4, 126.3 (q, J = 276 Hz), 122.4, 34.7 (q, J = 29 Hz);
ATR-FTIR (cm-1): 1668, 1610, 1521, 1435, 1354, 1303, 1257, 1141, 1068; HRMS (ESI+) m/z [M+H]+
calcd for C16H11F3N3O3: 350.0747; found 350.0747.
2-(p-Tolyl)-4-(2,2,2-trifluoroethoxy)quinazoline (4a). Rf = 0.70 (hexane:EA, 9:1); white solid (75 mg,
93%); mp 137−138 °C; 19F NMR (377 MHz, CDCl3) δ = -73.3 (t, J = 8 Hz); 1H NMR (400 MHz, CDCl3)
δ = 8.44 (d, J = 8 Hz, 2H), 8.20 (d, J = 8 Hz, 1H), 8.02 (d, J = 8 Hz, 1H), 7.87 (t, J = 8 Hz, 1H), 7.56 (d, J
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= 8 Hz, 1H), 7.32 (d, J = 8 Hz, 2H), 5.12 (q, J = 8 Hz, 2H), 2.45 (s, 3H); C{1H} NMR (100 MHz,
CDCl3) δ = 165.1, 159.7, 152.4, 141.3, 134.8, 134.3, 129.4, 128.5, 128.1, 126.9, 123.5 (q, J = 276 Hz),
123.4, 114.5, 62.7 (q, J = 37 Hz), 21.6; ATR-FTIR (cm-1): 1624, 1573, 1494, 1454, 1423, 1350, 1278,
1165, 1091; HRMS (ESI+) m/z [M+H]+ calcd for C17H14F3N2O 319.1053; found 319.1053.
2-(4-Ethylphenyl)-4-(2,2,2-trifluoroethoxy)quinazoline (4b). Rf = 0.70 (hexane:EA, 9:1); white solid
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(57.9 mg, 87%); mp 112−114 °C; F NMR (377 MHz, CDCl3) δ = -73.3 (t, J = 8 Hz); H NMR (400
MHz, CDCl3) δ = 8.46 (d, J = 8 Hz, 2H), 8.20 (d, J = 8 Hz, 1H), 8.02 (d, J = 8 Hz, 1H), 7.87 (t, J = 8 Hz,
1H), 7.56 (t, J = 8 Hz, 1H), 7.35 (d, J = 8 Hz, 2H), 5.13 (q, J = 8 Hz, 2H), 2.75 (q, J = 8 Hz, 2H), 1.30 (t,
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J = 8 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ = 165.0, 159.6, 152.4, 147.5, 135.1, 134.2, 128.6,
128.2, 128.1, 126.9, 123.6 (q, J = 275 Hz), 123.3, 114.5, 62.7 (q, J = 36 Hz), 29.0, 15.5; ATR-FTIR (cm-
1): 1624, 1579, 1558, 1494, 1421, 1352, 1267, 1165, 1091; HRMS (ESI+) m/z [M+H]+ calcd for
C18H16F3N2O 333.1209; found 333.1209.
2-(4-Isopropylphenyl)-4-(2,2,2-trifluoroethoxy)quinazoline (4c). Rf = 0.70 (hexane:EA, 9:1); white
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solid (64 mg, 97%); mp 94−96 °C; F NMR (377 MHz, CDCl3) δ = -73.3 (t, J = 8 Hz); H NMR (400
MHz, CDCl3) δ = 8.47 (d, J = 8 Hz, 2H), 8.19 (d, J = 8 Hz, 1H), 8.02 (d, J = 8 Hz, 1H), 7.86 (t, J = 8 Hz,
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1H), 7.55 (t, J = 8 Hz, 1H), 7.38 (d, J = 8 Hz, 2H), 5.11 (q, J = 8 Hz, 2H), 3.01 (sept, J = 8 Hz, 1H), 1.32
(d, J = 8 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ = 165.0, 159.7, 152.4, 152.1, 135.3, 134.2, 128.6,
128.1, 126.9, 126.8, 123.6 (q, J = 275 Hz), 123.3, 114.5, 62.6 (q, J = 37 Hz), 34.2, 24.0; ATR-FTIR (cm-
1): 1622, 1585, 1556, 1492, 1417, 1348, 1273, 1163, 1089; HRMS (ESI+) m/z [M+H]+ calcd for
C19H18F3N2O 347.1366; found 347.1366.
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2-(4-(Tert-butyl)phenyl)-4-(2,2,2-trifluoroethoxy)quinazoline (4d). Rf = 0.70 (hexane:EA, 9:1); white
solid (60 mg, 93%); mp 108−110 °C; 19F NMR (377 MHz, CDCl3) δ = -73.3 (t, J = 8 Hz); 1H NMR (400
MHz, CDCl3) δ = 8.47 (d, J = 8 Hz, 2H), 8.20 (d, J = 8 Hz, 1H), 8.02 (d, J = 8 Hz, 1H), 7.86 (t, J = 8 Hz,
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1H), 7.57 – 7.53 (m, 3H), 5.11 (q, J = 8 Hz, 2H), 1.40 (s, 9H); C{1H} NMR (100 MHz, CDCl3) δ =
165.0, 159.6, 154.3, 152.4, 134.9, 134.2, 128.3, 128.2, 126.9, 125.6, 123.6 (q, J = 276 Hz), 123.3, 114.5,
62.6 (q, J = 6 Hz), 35.0, 31.4; ATR-FTIR (cm-1): 1625, 1577, 1494, 1419, 1350, 1267, 1168, 1109, 1089;
HRMS (ESI+) m/z [M+H]+ calcd for C20H20F3N2O 361.1522; found 361.1522.
2-Phenyl-4-(2,2,2-trifluoroethoxy)quinazoline (4e). Rf = 0.70 (hexane:EA, 9:1); white solid (48 mg,
88%); mp 123−124 °C; 19F NMR (377 MHz, CDCl3) δ = -73.3 (t, J = 8 Hz); 1H NMR (400 MHz, CDCl3)
δ = 8.57 – 8.54 (m, 2H), 8.22 (d, J = 8 Hz, 1H), 8.04 (d, J = 8 Hz, 1H), 7.88 (t, J = 4 Hz, 1H), 7.60 – 7.56
(m, 1H), 7.54 – 7.51 (m, 3H), 5.14 (q, J = 8 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ = 165.2, 159.6,
152.4, 137.5, 134.3, 131.0, 128.6, 128.5, 128.2, 127.2, 123.5 (q, J = 275 Hz), 114.6, 62.7 (q, J = 36 Hz);
ATR-FTIR (cm-1): 1620, 1575, 1498, 1419, 1352, 1263, 1163, 1118, 1091; HRMS (ESI+) m/z [M+H]+
calcd for C16H12F3N2O: 305.0896; found 305.0896.
2-(4-Methoxyphenyl)-4-(2,2,2-trifluoroethoxy)quinazoline (4f). Rf = 0.50 (hexane:EA, 9:1); white solid
(61 mg, 92%); mp 125−127 °C; 19F NMR (377 MHz, CDCl3) δ = -73.3 (t, J = 8 Hz); 1H NMR (400 MHz,
CDCl3) δ = 8.50 (d, J = 8 Hz, 2H), 8.17 (d, J = 8 Hz, 1H), 7.98 (d, J = 8 Hz), 7.84 (t, J = 8 Hz, 1H), 7.53
(t, J = 8 Hz, 1H), 7.02 (d, J = 8 Hz, 2H), 5.10 (q, J = 8 Hz, 2H), 3.90 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ = 165.0, 162.1, 159.3, 152.5, 134.2, 130.2, 127.9, 126.6, 123.6 (q, J = 275 Hz), 123.4, 114.3,
113.9, 62.6 (q, J = 36 Hz), 55.5; ATR-FTIR (cm-1): 1622, 1579, 1517, 1456, 1354, 1251, 1159, 1159,
1091; HRMS (ESI+) m/z [M+H]+ calcd for C17H14F3N2O2 335.1002; found 335.1002.
2-(4-Fluorophenyl)-4-(2,2,2-trifluoroethoxy)quinazoline (4g). Rf = 0.70 (hexane:EA, 9:1); white solid
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(44 mg, 93%); mp 131−133 °C; F NMR (377 MHz, CDCl3) δ = -73.3 (t, J = 8 Hz), -110.02 – -110.10
(m); 1H NMR (400 MHz, CDCl3) δ = 8.58 – 8.54 (m, 2H), 8.21 (d, J = 8 Hz, 1H), 8.01 (d, J = 8 Hz, 1H),
7.88 (t, J = 8 Hz, 1H), 7.58 (t, J = 8 Hz, 1H), 7.21 – 7.17 (m, 2H), 5.11 (q, J = 8 Hz, 2H); 13C{1H} NMR
(100 MHz, CDCl3) δ = 165.2, 164.9 (d, J = 248 Hz), 158.6, 152.3, 134.4, 133.7 (d, J = 3 Hz), 130.7 (d, J
= 9 Hz), 128.1, 127.2, 123.5 (q, J = 276 Hz), 123.4, 115.6 (d, J = 21 Hz), 114.5, 62.6 (q, J = 36 Hz);
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ATR-FTIR (cm-1): 1622, 1577, 1514, 1498, 1404, 1348, 1276, 1163, 1089; HRMS (ESI+) m/z [M+H]+
calcd for C16H11F4N2O: 323.0802; found 323.0799.
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2-(4-Chlorophenyl)-4-(2,2,2-trifluoroethoxy)quinazoline (4h). Rf = 0.70 (hexane:EA, 9:1); white solid
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(58.9 mg, 89%); mp 128−130 °C; F NMR (377 MHz, CDCl3) δ = - 73.3 (t, J = 8 Hz); H NMR (400
MHz, CDCl3) δ = 8.50 (d, J = 8 Hz, 2H), 8.22 (d, J = 8 Hz, 1H), 8.02 (d, J = 8 Hz, 1H), 7.89 (t, J = 8 Hz,
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1H), 7.60 (t, J = 8 Hz, 1H), 7.49 (d, J = 8 Hz, 2H), 5.1 (q, J = 8 Hz, 2H); C{1H} NMR (100 MHz,
CDCl3) δ = 165.2, 158.4, 152.2, 137.1, 136.0, 134.4, 129.8, 128.8, 128.2, 127.3, 123.5 (q, J = 276 Hz),
123.4, 114.5, 62.8 (q, J = 36 Hz); ATR-FTIR (cm-1): 1624, 1585, 1575, 1498, 1421, 1402, 1267, 1159,
1091; HRMS (ESI+) m/z [M+H]+ calcd for C16H11ClF3N2O: 339.0507; found 339.0507.
2-(4-Bromophenyl)-4-(2,2,2-trifluoroethoxy)quinazoline (4i). Rf = 0.70 (hexane:EA, 9:1); white solid
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(47.5 mg, 75%); mp 124−125 °C; F NMR (377 MHz, CDCl3) δ = -73.3 (t, J = 8 Hz); H NMR (400
MHz, CDCl3) δ = 8.43 (d, J = 8 Hz, 2H), 8.22 (d, J = 8 Hz, 1H), 8.02 (d, J = 8 Hz, 1H), 7.65 (d, J = 8 Hz,
2H), 7.60 (t, J = 8 Hz, 1H), 5.11 (q, J = 8 Hz, 2H); C{1H} NMR (100 MHz, CDCl3) δ = 165.2, 158.5,
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152.2, 136.4, 134.5, 131.8, 130.1, 128.2, 127.4, 125.7, 123.5 (q, J = 276 Hz), 123.4, 114.6, 62.8 (q, J = 36
Hz); ATR-FTIR (cm-1): 1622, 1573, 1556, 1496, 1400, 1348, 1271, 1161, 1089; HRMS (ESI+) m/z
[M+H]+ calcd for C16H11BrF3N2O: 383.0001; found 383.0001.
2-(4-Iodophenyl)-4-(2,2,2-trifluoroethoxy)quinazoline (4j). Rf = 0.70 (hexane:EA, 9:1); white solid
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(38.2 mg, 68%); mp 133−135 °C; F NMR (377 MHz, CDCl3) δ = -73.3 (t, J = 8 Hz); H NMR (400
MHz, CDCl3) δ = 8.24 (d, J = 8 Hz, 2H), 8.18 (d, J = 8 Hz, 1H), 7.88 – 7.82 (m, 3H), 7.57 (t, J = 8 Hz,
1H), 5.07 (q, J = 8 Hz, 2H); C{1H} NMR (100 MHz, CDCl3) δ = 165.1, 158.6, 152.2, 137.8, 137.0,
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134.4, 130.1, 128.2, 127.4, 123.5 (q, J = 276 Hz), 123.4, 114.6, 98.0, 62.8 (q, J = 36 Hz); ATR-FTIR (cm-
1): 1622, 1581, 1494, 1419, 1348, 1261, 1182, 1155, 1085; HRMS (ESI+): m/z [M+H]+ calcd for
C16H11F3IN2O: 430.9863, found 430.9850.
2-(3,5-Difluorophenyl)-4-(2,2,2-trifluoroethoxy)quinazoline (4k). Rf = 0.70 (hexane:EA, 9:1); white
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solid (62.8 mg, 95%); mp 138−139 °C; F NMR (377 MHz, CDCl3) δ = -73.3 (t, J = 8 Hz), -109.7 – -
109.8 (m); 1H NMR (400 MHz, CDCl3) δ = 8.18 (d, J = 8 Hz, 1H), 8.03 – 7.98 (m, 3H), 7.90 – 7.86 (m,
1H), 7.61 – 7.57 (m, 1H), 6.94 – 6.89 (m, 1H), 5.06 (q, J = 8 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3)
δ = 165.3, 164.5 (d, J = 12 Hz), 162.1 (d, J = 12 Hz), 157.1 (t, J = 4 Hz), 152.0, 141.0 (t, J = 10 Hz),
134.6, 128.3, 127.8, 123.5 (q, J = 276 Hz), 123.4, 114.8, 111.2 (d, J = 26 Hz), 111.1 (d, J = 12 Hz), 106.0
(t, J = 26 Hz), 62.9 (q, J = 36 Hz); ATR-FTIR (cm-1): 1629, 1598, 1564, 1494, 1421, 1355, 1269, 1168,
1111, 1080, 1024; HRMS (ESI+) m/z [M+H]+ calcd for C16H10F5N2O: 341.0708; found: 341.0704.
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2-(4-Nitrophenyl)-4-(2,2,2-trifluoroethoxy)quinazoline (4l). Rf = 0.60 (hexane:EA, 9:1); white solid
(66 mg, 84%); mp 166−167 °C; 19F NMR (377 MHz, CDCl3) δ = -73.3 (t, J = 8 Hz); 1H NMR (400 MHz,
CDCl3) δ = 8.72 (d, J = 8 Hz, 2H), 8.35 (d, J = 8 Hz, 2H), 8.26 (d, J = 8 Hz, 1H), 8.07 (d, J = 8 Hz, 1H),
7.94 (t, J = 8 Hz, 1H), 7.66 (t, J = 8 Hz, 1H), 5.14 (q, J = 8 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ
= 165.5, 157.2, 152.1, 149.4, 143.3, 134.8, 129.3, 128.5, 128.2, 123.8, 123.5, 123.4 (q, J = 276 Hz),
114.8, 63.0 (q, J = 36 Hz); ATR-FTIR (cm-1): 1622, 1575, 1519, 1423, 1344, 1271, 1178, 1155, 1122,
1089; HRMS (ESI+) m/z [M+H]+ calcd for C16H11F3N3O3: 350.0747; found 350.0747.
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4-(2,2,2-Trifluoroethoxy)-2-(4-(trifluoromethyl)phenyl)quinazoline (4m). Rf = 0.70 (hexane:EA, 9:1);
white solid (58 mg, 95%); mp 146−147 °C; 19F NMR (377 MHz, CDCl3) δ = -62.7, -73.3 (t, J = 8 Hz); 1H
NMR (400 MHz, CDCl3) δ = 8.67 (d, J = 8 Hz, 2H), 8.24 (d, J = 8 Hz, 1H), 8.06 (d, J = 8 Hz, 1H), 7.94 –
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7.90 (m, 1H), 7.77 (d, J = 8 Hz, 2H), 7.65 – 7.61 (m, 1H), 5.13 (q, J = 8 Hz, 2H); C{1H} NMR (100
MHz, CDCl3) δ = 165.3, 158.1, 152.2, 140.8, 134.6, 132.9 (q, J = 32 Hz), 128.8, 128.4, 127.8, 125.6 (q, J
= 4 Hz), 123.5, 123.4 (q, J = 275 Hz), 122.9, 114.8, 62.9 (q, J = 37 Hz); ATR-FTIR (cm-1): 1624, 1577,
1558, 1494, 1423, 1321, 1267, 1161, 1116, 1091, 1064; HRMS (ESI+) m/z [M+H]+ calcd for
C17H11F6N2O: 373.0770; found 373.0770.
4-(4-(2,2,2-Trifluoroethoxy)quinazolin-2-yl)benzonitrile (4n). Rf = 0.70 (hexane:EA, 9:1); white solid
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(60.9 mg, 91%); mp 174−176 °C; F NMR (377 MHz, CDCl3) δ = -73.3 (t, J = 8 Hz); H NMR (400
MHz, CDCl3) δ = 8.68 (t, J = 12 Hz, 2H), 8.25 (d, J = 8 Hz, 1H), 8.06 (d, J = 8 Hz, 1H), 7.93 (t, J = 8 Hz,
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1H), 7.81 (d, J = 8 Hz, 2H), 7.65 (t, J = 8 Hz, 1H), 5.13 (q, J = 8 Hz, 2H); C{1H} NMR (100 MHz,
CDCl3) δ = 165.3, 157.4, 152.0, 141.5, 134.7, 132.3, 128.9, 128.4, 128.0, 123.5, 123.4 (q, J = 275 Hz),
118.8, 114.8, 114.1, 62.9 (q, J = 37 Hz); ATR-FTIR (cm-1): 2227, 1618, 1573, 1492, 1425, 1352, 1282,
1259, 1165, 1091; HRMS (ESI+) m/z [M+H]+ calcd for C17H11F3N3O: 330.0849; found 330.0849.
2-([1,1'-Biphenyl]-4-yl)-4-(2,2,2-trifluoroethoxy)quinazoline (4o). Rf = 0.70 (hexane:EA, 9:1); white
solid (49 mg, 77%); mp 132−134 °C; 19F NMR (377 MHz, CDCl3) δ = -73.3 (t, J = 8 Hz); 1H NMR (400
MHz, CDCl3) δ = 8.63 (d, J = 8 Hz, 2H), 8.22 (d, J = 8 Hz, 1H), 8.05 (d, J = 8 Hz, 1H), 7.91 – 7.87 (m,
1H), 7.76 (d, J = 8 Hz, 2H), 7.70 (d, J = 8 Hz, 2H), 7.61 – 7.57 (m, 1H), 7.49 (t, J = 8 Hz, 2H), 7.41 –
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7.38 (m, 1H), 5.15 (q, J = 8 Hz, 2H); C{1H} NMR (100 MHz, CDCl3) δ = 165.1, 159.3, 152.4, 143.6,
140.7, 136.5, 134.3, 129.1, 129.0, 128.2, 127.8, 127.4, 127.3, 126.6, 123.6 (q, J = 276 Hz), 123.4, 114.6,
62.7 (q, J = 36 Hz); ATR-FTIR (cm-1): 1622, 1577, 1552, 1492, 1419, 1400, 1350, 1269, 1170, 1141,
1089; HRMS (ESI+) m/z [M+H]+ calcd for C22H16F3N2O 381.1209; found 381.1209.
2-(3-Bromophenyl)-4-(2,2,2-trifluoroethoxy)quinazoline (4p). Rf = 0.70 (hexane:EA, 9:1); white solid
(54 mg, 86%); mp 140−142 °C; 19F NMR (377 MHz, CDCl3) δ = -73.3 (t, J = 8 Hz); 1H NMR (400 MHz,
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