Metal-Free C-2-H Alkylation of Quinazolin-4-ones with Alkanes via Cross-Dehydrogenative Coupling

Article abstract of DOI:10.1021/acs.orglett.9b00638

A practically useful approach for the cross-dehydrogenative coupling of quinazolin-4-one with simple nonactivated alkanes is reported. The products were smoothly formed under mild reaction conditions, within short reaction time at ambient temperature. The formation of new Csp³-Csp² bonds occurred at the electron-poor C-2 position of quinazolin-4-one. The approach has the potential to be an important tool for the late-stage functionalization of advanced synthetic intermediates and may find many applications in medicinal chemistry.

Full text of DOI:10.1021/acs.orglett.9b00638

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Metal-Free C‑2‑H Alkylation of Quinazolin-4-ones with Alkanes via
Cross-Dehydrogenative Coupling
Shuai Mao,†,§,⊥ Kaixiu Luo,‡,⊥ Lu Wang,† Hong-Yi Zhao,† Andrea Shergalis,§ Minhang Xin,†
Nouri Neamati,*,§ Yi Jin,*,‡ and San-Qi Zhang*,†
†Department of Medicinal Chemistry, School of Pharmacy, Xi’an Jiaotong University, Xi’an 710061, China
‡Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical
Science and Technology, Yunnan University, Kunming 650091, P. R. China
§Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
S
* Supporting Information
ABSTRACT: A practically useful approach for the cross-dehydrogenative
coupling of quinazolin-4-one with simple nonactivated alkanes is reported.
The products were smoothly formed under mild reaction conditions, within
short reaction time at ambient temperature. The formation of new Csp3-Csp2
bonds occurred at the electron-poor C-2 position of quinazolin-4-one. The
approach has the potential to be an important tool for the late-stage
functionalization of advanced synthetic intermediates and may find many applications in medicinal chemistry.
s a significant subclass of quinazoline derivatives, 2-
alkylquinazolin-4-ones are widely found in bioactive
Scheme 1. Approaches to 2-Substituted Quinazolin-4-one
A
natural products, synthetic drugs, pharmaceuticals, and agro-
chemicals (Figure 1).1 Traditional strategies to synthesize the
Figure 1. Selected representatives of bioactive 2-alkylquinazolin-4-
ones.
molecules involve the acid/base-promoted condensation
reactions of aldehydes, esters, or carboxylic acids with amides
under harsh conditions (Scheme 1a, route 1).2 However,
despite of recent notable advance (Scheme 1a, routes 2 and
3),3 they generally suffer from one or more drawbacks such as
using expensive and toxic catalysts, needing complex
homogeneous catalytic systems or expensive feedstocks, the
presence of transition metals as trace impurities in the final
products, and unsuitability for the synthesis of 2-alkyl-
quinazolinones. Therefore, there is still a need for an efficient
and economical method to synthesize 2-alkylquinazolinones.
Directive late-stage modification of quinazolinones is of great
value and significance for rapid synthesis of selective 2-alkyl
quinazolin-4-ones under mild reaction conditions.4,5
Indeed, by the Minisci reaction, radical approaches have
been developed as a strategy to carry on alkylation of
quinazolinones, where an alkyl radical is coupled with a
quinazolinone under oxidizing and acidic conditions to
assemble the functionalized product (Scheme 1b). However,
the limitation of the method is that the functionalized alkyl
substrates such as carboxylic acids,6a,b halides,6c aldehydes,6d,e
boronic acids,6f,g organic peroxides,6h alkyltrifluoroborates,6i
and sulfinate salts6j,l are required as radical precursors. In
addition, an excess of the radical precursor, high temperature,
strong oxidant, stoichiometric amounts of expensive metal salts
or photocatalyst are required to obtain good yields.6h,i,7−9
Thus, development of efficient C-2 alkylation of quinazoli-
nones remains attractive to organic chemists. Recently, direct
methods of Csp3-C bonds by cross-dehydrogenative coupling
(CDC) have been developed as a versatile and efficient
technique for complex molecule syntheses.10 Alkylation of
quinazolinones is increasingly attractive as a C−C bond
formation methodology, offering a powerful alternative to
Received: February 20, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00638
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
standard cross coupling reactions. To the best of our
knowledge, C-2-H alkylation of quinazolin-4-ones with simple
alkanes via CDC reaction is rarely reported.11 Herein, we
report the selective formation of Csp3−Csp2 bonds by CDC of
simple unfunctionalized alkanes with quinazolin-4-ones under
mild reaction conditions.
2,2,2-trifluoroethanol (TFE) as the solvent. In addition, we
tested different additives. Changing the additive from TMSN3
to NaN3 resulted in increased yield to 48% (entry 6). The use
of other sources of azide or iodine did not lead to formation of
the product (entries 7−8). Next, we examined the influence of
various oxidants (entries 9−17). The use of Koser’s reagent
(PhI(OH)OTs) or (bis(trifluoroacetoxy)iodo)-
pentafluorobenzene (entries 10 and 11) provided lower yield
of 3a than PhI(OCOCF3)2 (entry 9). Other oxidizing agents,
such as IBX, PhI(OAc)2, DMP, Na2S2O8, DTBP, TEMPO, t-
BuOOH, and m-CPBA, did not initiate the transformation.
With the optimized oxidant and additive, we investigated the
relative ratio of reactants (entries 18−19). We also observed
that the conversion remained incomplete, even though the
reaction time was prolonged. To overcome this problem, we
intended to add PIFA and NaN3 in small batches. When a total
of three equivalents of PhI(O2CCF3)2 and NaN3 was added
with a 0.5 equiv batch-mode every 0.5 h, the isolated yield
reached 79% (entries 18−19).
After obtaining the optimized reaction conditions (Table 1,
entry 18), we explored the scope of this hypervalent iodine-
mediated cross-dehydrogenative coupling of quinazolin-
4(3H)-one with cyclopentane. First of all, the variation in
the cycloalkane part of the reaction was studied. The reaction
was found to work well with a range of cycloalkanes of various
ring sizes. Cyclopentane reacted to give the corresponding
product 2a in 79% yield (Scheme 2). Similarly, cyclohexane,
cycloheptane, and cyclooctane also underwent smooth
coupling to form products 2c, 2d, and 2e in 67%, 68%, and
71% yields, respectively. After studying the scope of alkanes in
cross-coupling, we turned our attention toward substituted
quinazolin-4(3H)-one. Substrates bearing either an electron-
withdrawing group (3e−3l) or electron-donating (3m and 3n)
space on C5-, C6-, or C7-positions of the quinazoline rings all
reacted smoothly to afford the desired products in good to
excellent yields. Quinazolin-4(3H)-one substituted with
various functional groups, such as Me, OMe, F, Cl, Br, I,
and NO2, at C6- or C7-positions were well-tolerated in the
reaction system and provided the possibility for further
functionalization of the polysubstituted quinazolin-4(3H)-
one, enabling these products to be used as core structures
for drug. Additionally, substrates bearing either two electron-
donating or electron-withdrawing groups on C6-, and C7-
positions of the quinazoline rings all reacted smoothly to afford
the desired products in good yields (3o−3t). We examined the
efficiency of inhibition of human A549 cells in vitro and found
that the inhibition rate increased with increasing cycloalkane
size, and compound 3t caused >80% inhibition at 10 μM
(Supporting Information). It is noteworthy that compound 3t
was obtained in 67% yield from a large-scale reaction (5 mmol
of 1t). To further investigate the functional group tolerance,
next, we investigated N3-substituted quinazolin-4-ones as
starting materials.
Following our effort for the construction of a broad range of
substituted quinazolines as potential inhibitors of kinases,12,13
and in connection to our continued interest in developing
efficient metal-free functionalization strategies,14 herein we
decided to investigate the use of hypervalent iodine reagents
for the direct alkylation of quinazolin-4-ones with unfunction-
alized alkanes. Initially, we evaluated various reaction
conditions for the direct coupling of quinazolin-4-one (1a)
with cyclopentane (2a). To our delight, when we used Kita’s
methods,15 the cross-coupling occurred in the presence of
(bis(trifluoroacetoxy)iodo)benzene (PIFA) and trimethylsilyl
azide (TMSN3) at ambient temperature in 1,1,1,3,3,3-
hexafluoro-2-propanol ((CF3)2CHOH) to product 3a with a
yield of 21% (Table 1, entry 1). However, product 3a was not
formed in the absence of either PhI(OCOCF3)2 or NaN3. A
variety of polar and nonpolar solvents were then employed
(entries 1−5). The best yield (36% of 3a) was achieved with
a
Table 1. Optimization of Reaction Conditions
additive
(equiv)
yield
b
entry oxidant (equiv)
solvent
t (h)
(%)
1
2
3
4
5
6
7
PIFA (2)
PIFA (2)
PIFA (2)
PIFA (2)
PIFA (2)
PIFA (2)
PIFA (2)
TMSN3 (2)
TMSN3 (2)
TMSN3 (2)
TMSN3 (2)
TMSN3 (2)
NaN3 (2)
HFIP
CH2Cl2
TFE
CH3CN
toluene
TFE
8 h
8 h
8 h
8 h
8 h
3 h
8 h
21
15
36
n.d.
n.d.
48
c
(nBu)4NN3
(2)
TFE
n.d.
8
9
10
PIFA (2)
PIFA (2)
PhI(OH)OTs
(2)
I2 (2)
NaN3 (2)
NaN3 (2)
TFE
TFE
TFE
8 h
3 h
3 h
n.d.
46
24
d
11
12
13
14
15
16
17
18
19
F5−PIFA (2)
IBX (2)
PhI(OAc)2 (2)
DMP (2)
Na2S2O8 (2)
DTBP (2)
TEMPO (2)
PIFA (3)
NaN3 (2)
NaN3 (2)
NaN3 (2)
NaN3 (2)
NaN3 (2)
NaN3 (2)
NaN3 (2)
NaN3 (3)
NaN3 (4)
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
3 h
41
12 h
12 h
12 h
12 h
12 h
12 h
3 h
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
79
e
e
PIFA (4)
5 h
80
Gratifyingly, a range of aryl- and alkylquinazolin-4(3H)-ones
1u−1y was found to be suitable substrates and underwent the
C−H cycloalkylation to give 3u−3y with good efficiencies.
However, in the cases of 4-quinazolinamine derivatives 1z,
a
Reaction conditions: Unless otherwise noted, the reaction was
carried out with 1a (0.2 mmol), 2a (1.0 mmol), oxidant (0.4 mmol),
additive (0.4 mmol) in solvent (4 mL) under air atmosphere at
1
messy results were observed based on H NMR of the crude
b
c
ambient temperature. Isolated yields. 34% of quinazolin-4-ones was
mixture (3z). Linear alkanes, such as n-hexane and isopentane,
were also suitable substrates and afforded the corresponding
products in moderate yields (3aa, 62% and 3ab, 72%). C2-
substitued product 3aa was formed along with C3-substitued
analog in the ratio of 4:1 when n-hexane was the substrate.
d
e
recovered. Under argon (1 atm) atmosphere. Oxidant and additive
were added in batches of 0.5 equiv in 0.5 h in tervals. PIFA=
[Bis(trifluoroacetoxy)iodo] benzene, TEMPO = (2,2,6,6-Tetrame-
thylpiperidin-1-yl) oxyl, PIDA = (Diacetoxyiodo)benzene, DTBP =
tert-Butyl peroxide, IBX= 2-iodoxybenzoic acid.
B
DOI: 10.1021/acs.orglett.9b00638
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Substrate Scope for Alkylation of Quinazolin-4-
ones
Scheme 3. Control Experiments for Mechanistic Study
a b
,
Scheme 4. Plausible Mechanistic Pathway
ligand exchange of trifluoroacetate for azide to form the highly
reactive PhI(N3)2 A,17 which decomposes into PhI and the
azidyl radical B. The azide radical B abstracts a hydrogen atom
from alkane to generate the alkyl radical C and hydrazoic
acid.18 The alkyl radical C attacks the protonated quinazolin-4-
one at the most electrophilic C2 position to generate a radical
cation D. Subsequently, hydrogen-atom transfer (HAT)
followed by deprotonation gives the final product 3a.19
In conclusion, a highly selective direct oxidative transition-
metal-free protocol for cross-coupling of quinazolin-4-ones
with simple nonfunctionalized alkanes was developed. This
methodology provides a simple and feasible method to
predictably functionalize unactivated Csp3-H bonds with
biologically important quinazolin-4-ones under mild con-
ditions. The protocol features a highly efficient synthetic
process, wide substrate scope, and high functional-group
tolerance. Because of the importance of quinazolinone scaffold
in medicinal chemistry, the method can be easily used for the
modular synthesis of bioactive quinazolin-4-one libraries.
Detailed mechanical research and study of antitumor activity
are currently underway.
a
Scope of alkanes in cross-dehydrogenative coupling. Reaction
conditions: quinazolin-4-ones 1 (0.2 mmol), alkane (10 equiv),
PhI(O2CCF3)2 (3 equiv), and NaN3 (3 equiv) in TFE (4 mL) at rt.
b
Isolated yield.
Likewise, alkylation at the 3° site over the 2° site was more
preferred (C2/C3 > 99:1) for the branched isopentane.
However, heterocyclic alkanes, such as 1,4-dioxane and
piperidine, were inert under these conditions (3ac and 3ad).
After exploring the scope of the cross-dehydrogenative
coupling of quinazolin-4-ones and alkanes, we turned our
attention to explore the mechanism of the coupling. A radical-
trapping experiment was carried out. The radical trapping
reagent TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) was
introduced into the standard reaction system (Scheme 3, eq
1). As expected, the reaction was totally suppressed with
formation of only the TEMPO−cyclohexane adduct 4a
(detected by HRMS analysis, see page 6 in the Supporting
Information). This fact clearly points to the involvement of
radicals in the reaction. In addition, a control experiment
without the use of alkane resulted in no products (Scheme 3,
eq 2). These results indicate that the alkane is first initiated
relative to the quinazoline. Subsequently, we used our
substrates in methods reported for generating azidyl radicals,16
and we remain detected desired product (3b), albeit at a lower
yield (Scheme 3, eq 3). This experiment shows that the
process is also initiated by azidyl radicals. On the basis of these
facts, a possible radical-chain mechanism is proposed in
Scheme 4. At first, PhI(O2CCF3)2 reacts with NaN3 through
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00638.
Methods, procedures, optimization of reaction con-
ditions, antitumor activity research, synthesis of 3t,
control experiments, compound characterization, spec-
tral data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: neamati@umich.edu.
*E-mail: jinyi@ynu.edu.cn.
*E-mail: sqzhang@xjtu.edu.cn.
C
DOI: 10.1021/acs.orglett.9b00638
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
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Shuai Mao: 0000-0003-0856-8007
Andrea Shergalis: 0000-0002-1155-1583
Minhang Xin: 0000-0002-5827-9580
Yi Jin: 0000-0003-1348-2486
Author Contributions
⊥S.M. and K.L. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank the financial support from the National Nature
Science Foundation of China (21602169, 81803490, and
21662044), The China Postdoctoral Science Foundation
(2016M592775), and Xi’an Jiaotong University New Lecturer
plan (334100038).
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DOI: 10.1021/acs.orglett.9b00638
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