Alkylamino-Directed One-Pot Reaction of N-Alkyl Anilines with CO, Amines and Aldehydes Leading to 2,3-Dihydroquinazolin-4(1H)-ones

Article abstract of DOI:10.1002/adsc.201801267

An economical and efficient approach to pharmaceutically and biologically significant 2,3-dihydroquinazolin-4(1H)-ones has been disclosed. The one-pot multicomponent reaction was performed through a palladium-catalyzed ortho-selective oxidative carbonylat

Full text of DOI:10.1002/adsc.201801267

Title: Embedded Alkylamino-Directed One-Pot Reaction of N-Alkyl
Anilines with CO, Amines and Aldehydes Leading to 2,3-
Dihydroquinazolin-4(1H)-ones
Authors: xiaopeng zhang, Zhengwei Li, Qianqian Ding, Xiaochuan Li,
Xuesen Fan, and Guisheng Zhang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801267
Link to VoR: http://dx.doi.org/10.1002/adsc.201801267

10.1002/adsc.201801267
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Alkylamino-Directed One-Pot Reaction of N-Alkyl Anilines
with CO, Amines and Aldehydes Leading to 2,3-
Dihydroquinazolin-4(1H)-ones
Xiaopeng Zhang,* Zhengwei Li, Qianqian Ding, Xiaochuan Li, Xuesen Fan, and
Guisheng Zhang*
Henan Key Laboratory of Organic Functional Molecules and Drug Innovation, Collaborative Innovation Center of
Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions,
Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007,
China
Tel/Fax: (+86) 373-3325250; E-mail: zhangxiaopengv@sina.com; E-mail: zgs@htu.cn.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. An economical and efficient approach to
pharmaceutically and biologically significant 2,3-
dihydroquinazolin-4(1H)-ones has been disclosed. The one-
pot multicomponent reaction was performed through a
palladium-catalyzed ortho-selective oxidative
carbonylation of N-substituted anilines with CO and
primary amines, and subsequent condensation with
aldehydes in MeCN by using alkylamino as the directing
group, KI/AcOH as the additives, and Cu(OAc)2 as the
oxidant. This intriguing straightforward method features
embedded directing strategy, simple starting materials, mild
conditions, high atom/step economic economy, broad
substrate scope and good product diversity.
H
HN
Cl
N
N
O
N
H2NO2S
N
O
Metolazone
Evodiamine
(anti-cancer/antitumor/inflammatory/
obesity/cardiovascular diseases/
microbial/Alzheimer's disease agents)
(anti-hypertensive, saluretic, diuretic,
treatment of severe refractory
congestive cardiac failure)
Figure 1. Representative examples of clinically significant
DHQA medications.
a. Cyclocondensation of o-aminobenzamides with aldehydes
Keywords: C-H activation; 2,3-dihydroquinazolin-4(1H)-
ones; embedded directing group; N-alkyl anilines;
palladium
R1
R1
N
NH
R4
R3
O
R2
R2
H
+
R3
R4
H
N
N
O
O
b. Cyclization of o-nitrobenzamides/o-azidobenzamides with carbonyl compounds
H
2,3-Dihydroquinazolin-4(1H)-ones (DHQAs) are an
important class of nitrogen-containing heterocycles
with a wide range of pharmaceutical and biological
activities such as anticancer,[1] antitumor,[1b,2]
NX
N
R4
R5/H
R3
O
R2
R2
H
+
N
N
R3
R4
R5/H
O
O
X= O2 or N2
antihypertensive,[3]
antibacterial,[5]
anti-inflammatory,[4]
antipsychotic,[3b]
c. Cyclocondensation of isatoic anhydrides, primary amines and aldehydes
antifungal,[6]
R1
N
R1
N
antihistaminic,[7] antiviral,[8] anti-Plasmodium,[9]
O
R4
R3
O
R3NH2
R2
R2
+
+
diuretic,[1b,3a,10]
vasodilating,[11]
analgesic,[4c]
O
R4
H
N
anthelmintic[12] effects and cathepsins B & H,[13]
cholinesterases,[14] coagulation factor Xa,[15] HIV-1
reverse transcriptase,[16] inosine 5’-monophosphate
dehydrogenase,[17] protein kinase C-θ,[18] transient
receptor potential melastatin 219 inhibition. For
example, evodiamine[2a,4a,20] and metolazone[10b,21] are
typical representatives of clinically significant DHQA
medications (Figure 1).
O
O
d. Cyclocondensation of o-aminobenzonitriles with carbonyl compounds
H
N
R4
NH2
CN
O
R2
R5/H
R2
+
NH
R4
R5/H
O
Scheme 1. Previous synthetic approaches to DHQAs.
Due to their immense and important biological
activities, the synthesis of DHQAs has attracted
considerable interests. Among the established
1
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10.1002/adsc.201801267
Advanced Synthesis & Catalysis
synthetic protocols, the typical procedures involve
cyclocondensation of o-amino-benzamides (usually
obtained by ammonolysis of isatoic anhydride) with
aldehydes (Scheme 1a),[3a,22] reductive cyclization of
o-nitrobenzamides or o-azidobenzamides with
of N-alkyl anilines was used as an embedded
directing group (DG) to trigger the ortho-selective C-
H functionalization reactions.
Embedded Directing Group
carbonyl
compounds
(Scheme
1b),[23]
R1
R1
cyclocondensation of isatoic anhydrides, primary
amines (or ammonium salts) and aldehydes (Scheme
1c),[2b,5a,22a,24] and cyclocondensation of o-
aminobenzonitriles with carbonyl compounds
(Scheme 1d).[25] Despite the above advances, however,
one major drawback associated with all the above
approaches is that the N1-containing starting materials
applied in these protocols are usually complex, costly,
and lack structural diversity. In addition, these
synthetic strategies also suffer from certain
limitations such as harsh reaction conditions, lengthy
steps, tedious procedures for preparation of catalysts
and tedious work-up conditions. Moreover, most of
the efforts mainly focus on the development of
various catalytic systems at present, no report has
N
R4
R3
NH
O
Pd(OAc)2
R2
+
+ +
R3 NH2
CO
R2
R4
H
N
H
O
Scheme 3. Embedded alkylamino-directed Pa-catalyzed
reaction to DHQAs.
During the past decades, the direct transformation
of inert C-H bonds into carbon-carbon and carbon-
heteroatom bonds via transition-metal-catalyzed
activation & functionalization under the influence of
the given DG has emerged as a powerful and valuable
tool to simplify the synthesis of complex molecules
dramatically.[26] However, the DGs applied in this
strategy are usually difficult to be integrated into the
desired products, thereby, result in additional
synthetic steps being often required to both install the
DGs into the starting materials and remove them after
C-H functionalization. Compared to the traditional
DGs, so called embedded DGs, which can be
integrated into the corresponding products, show
unparalleled superiority.
Recently, Guan’s, Lei’s and our groups have found
that N-alkyl anilines can be used for the Pd-catalyzed
ortho-selective C-H carbonylation with CO for the
synthesis of isatoic anhydrides, o-aminobenzoates,
and o-aminobenzamides (Scheme 4).[27] Based on
these studies, we envision that alkylamino group may
be used as embedded DG to synthesize DHQAs
(Scheme 3).
been
found
on
the
synthesis
of
2,3-
dihydroquinazolin-4(1H)-ones by employing simple,
cheap and readily available starting materials from
the source. An intriguing question is whether simple
N-substituted anilines, CO, amines and aldehydes can
be used as the substrates for straightforward
construction of DHQAs (Scheme 2), which, to the
best of our knowledge, has not been explored to date.
This proposed protocol would provide an entirely
new facile, practical and efficient approach to such
compounds with high atom/step economy if it works.
However, there are at least three big challenges
should be addressed: 1) There should be enough
energy (using appropriate catalytic system) to
activate CO under mild conditions; 2) The ortho-
selective C-H carbonylation of N-substituted anilines
with CO should be controlled; 3) The reaction system
should avoid the formation of 1,3-dialkylureas via
transition metal-catalyzed oxidative carbonylation of
amines under the necessary oxidative reaction
conditions.
R2
N
O
CO
Pd(OAc)2
R1
R1
R1
isatoic anhydrides
o-aminobenzoates
o-aminobenzamides
O
O
R2
R2
NH
NH
3
CO,
R
OH
R1
Pd(OAc)2
O
R3
H
O
R2
NH
3
CO,
R
NH2
Scheme 2. Retrosynthetic analysis of DHQAs.
H
Pd(OAc)2
N
R3
O
Because of the above challenges, such
straightforward route to DHQAs under mild
condition has not been realized, although it would
substantially broaden bioactive DHQAs library.
Herein, we demonstrate the first example of a
straightforward method for synthesis of DHQAs
through a Pd-catalyzed one-pot reaction of simple N-
alkyl anilines, CO, amines and aldehydes (Scheme 3).
This reaction successfully combines Pd-catalyzed
ortho-selective C-H carbonylation, amidation and
cycloaminoacetal formation. The alkylamino group
Scheme 4. Pd-catalyzed ortho-selective C-H carbonylation
of N-alkyl anilines.
We began our study by testing the Pa-catalyzed
oxidative carbonylation of N-methylaniline 1a with
CO (bubble), aniline 2a, and benzaldehyde 3a. The
results were summarized in Table 1. To our delight,
o
when the reaction conducted at 70 C in MeCN with
KI/HCl as the additive and Cu(OAc)2 as the oxidant
2
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10.1002/adsc.201801267
Advanced Synthesis & Catalysis
for 8 h, the desired product 1-methyl-2,3-diphenyl-
DHQA (4-1a) could be obtained in 23% yield (entry
1) together with a certain amount of 1,3-diphenylurea
and 1-methyl-1,3-diphenylurea and a small amount of
reaction failed to proceed in the absence of KI or
AcOH, indicating that both KI and AcOH were
indispensable during this transformation (entries 6
and 7). Next, the effect of the common solvents such
as MeCN, toluene, 1,4-dioxane, DMF, and DMSO on
the reaction was examined (entries 5, 8-11) and the
results showed that MeCN worked most effectively
(entry 5), followed by DMF (entry 10). Finally, we
explored the oxidant performance among Cu(OAc)2,
O2, Cu(OAc)2/O2, CuCl2, and CuBr2 (entries 5, 12-
15). Compared with the inferior efficacy of O2 (entry
12), Cu(OAc)2 gave the best result (entry 5), the
combination of Cu(OAc)2/O2 failed to further
increase the product yield (entry 13), while CuCl2 and
CuBr2 didn’t work at all. Scale-up experiment could
afford the target product 4-1a in 36% yield under the
optimized reaction conditions (See SI, page S2).
N-methyl
isatoic
anhydride
and
2-
(methylamino)benzoic acid as by-products. Single
crystals of 4-1a were obtained by slow evaporation of
the ethanol solution at room temperature. The Oak
Ridge Thermal Ellipsoid Plot (ORTEP) drawing of 4-
1a is given in Figure 2.[28] Further screening of the
acid additive among FeCl3, TsOH, citric acid, and
AcOH revealed that AcOH emerged as the most
effective acid additive (entries 2-5). However, the
Table 2. Scope of amines.[a]
CO (bubble)
Pd(OAc)2 (5% mol)
CHO
N
NH
+
R3 NH2
+
N
Cu(OAc)2 (2 equiv)
KI, AcOH, MeCN
70 oC, 8 h
R3
O
1a
2
3a
4
N
N
N
N
N
N
O
O
O
Figure 2. X-ray crystal structure of 4-1a. The level set for
thermal ellipsoids of all non-hydrogen atoms is 30%.
4-2c, 60%
4-2d, 48%
4-2b, 68%
N
N
N
N
N
N
Cl
Table 1. Optimization of reaction conditions.[a]
O
O
O
Cl
4-2f, 51%
4-2g, 58%
4-2e, 46%
CO (bubble)
CHO
NH2
N
O
Pd(OAc)2 (5 mol %)
NH
+
+
N
N
N
N
N
N
N
additive, solvent, oxidant
70 oC, 8 h
O
1a
2a
3a
4-1a
O
O
F
Br
Cl
4-2i, 71%
4-2j, 69%
4-2h, 65%
entry additive
solvent
oxidant
Yield(%)[b]
N
N
N
N
N
N
1
KI/HCl
MeCN
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
23
0
OMe
2
KI/FeCl3
KI/TsOH
MeCN
MeCN
O
O
O
3
0
MeO
4-2l, 70%
4-2m, 73%
4-2k, 74%
4
KI/citric acid MeCN
0
5
KI/AcOH
KI
MeCN
MeCN
MeCN
Toluene
78
0
N
N
N
N
N
N
6
S
7
AcOH
0
Bn
O
O
N
8
KI/AcOH
KI/AcOH
KI/AcOH
KI/AcOH
KI/AcOH
KI/AcOH
KI/AcOH
KI/AcOH
15
44
63
42
28
O
OMe
4-2o, 56%
4-2p, 47%
4-2n, 76%
9
1,4-dioxane Cu(OAc)2
10
11
12
13
14
DMF
Cu(OAc)2
Cu(OAc)2
O2
N
N
O
DMSO
MeCN
MeCN
MeCN
MeCN
Cu(OAc)2/O2 78
CuCl2
CuBr2
0
0
15
[a]
4-2q, 36%
Reaction conditions: 1a (1.0 mmol), 2a (3.0 mmol), 3a
[a]
Reaction conditions: 1a (1.0 mmol), 2 (3.0 mmol), 3a
(1.5 mmol), KI (0.2 mmol), AcOH (5 mL), MeCN (10.0
mL), the mixture of 2 and AcOH were added dropwise.
(1.5 mmol), additive (KI: 0.2 mmol, liquid acid: 5.0 mL,
solid acid: 1.0 mmol), solvent (10.0 mL), oxidant (solid
oxidant 2.0 mmol, O2 bubble), the mixture of 2a and acid
were added dropwise. [b] Isolated yield.
[b]
Isolated yield.
3
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10.1002/adsc.201801267
Advanced Synthesis & Catalysis
With the optimized reaction conditions in hand, we
increased amount of byproduct 1,3-dibenzylurea
compared with the case of aniline, revealing that the
competitive self carbonylation enhanced to some
extent due to its high reactivity. Finally,
heteroaromatic amine thiazol-2-amine and polycyclic
aromatic amine naphthalen-1-amine were also
evaluated in this transformation to give the desired
products 4-2p and 4-2q in 47% and 36% yields,
respectively; the high steric hindrance of naphthalen-
1-amine may be responsible for the low yield of the
corresponding product 4-2q.
first turned our attention to investigate the generality
of this transformation. The scope of amines (2b-q)
was firstly examined. As shown in Table 2, both
aliphatic amines and aromatic amines could be well
tolerated with this protocol, affording the desired
products mostly in moderate to good yields (4-2b-q).
Steric effects seemed to have a certain impact on the
transformation; the greater the steric hindrance of the
amines was, the slightly lower the reactivity they
became. Although the product yields obtained from
the aromatic amines bearing the electron-donating
groups (4-2k-n) were a little higher than those
bearing the electron-withdrawing group (4-2f-j), their
difference was not obvious, indicating that this
transformation was not very sensitive to the
electronic effects of the amines. When benzylamine
was applied in this reaction, the desired product 4-2o
was obtained in 56% yield accompanied by an
Next, we evaluated the scope of aldehydes (3b-r)
and the results were summarized in Table 3.
Generally, aliphatic aldehydes worked less
effectively than the aromatic ones. Higher volatility
and/or steric hindrance may be accounted for the
unsatisfactory performance of the aliphatic aldehydes
(4-3b-f). Satisfyingly, however, aromatic aldehydes
could be well tolerated with the transformation,
affording the desired products in very high yields (4-
3g-r). Although the type and position of the
substituents on the benzene ring of the aromatic
aldehydes seemed to have a certain impact on this
reaction, it didn't make much difference.
Satisfactorily, heteroaromatic aldehydes such as
Table 3. Scope of aldehydes.[a]
CO (bubble)
Pd(OAc)2 (5% mol)
NH2
N
R4
NH
+
+
R4 CHO
N
Cu(OAc)2 (2 equiv)
KI, AcOH, MeCN
70 oC, 8 h
O
thiophene-3-carbaldehyde
(3p)
and
3-
1a
2a
3
4
pyridinealdehyde (3q) together with polycyclic 1-
naphthaldehyde (3r) could work effectively,
affording the desired products in yield of 84%, 76%,
and 72%, respectively.
N
N
N
N
N
N
O
O
O
Subsequently, this protocol was surveyed with a
variety of N-substituted anilines (1a-l) to further
demonstrate its generality (Table 4). We were pleased
to find that the reaction could proceed smoothly with
N-methyl/ethyl aniline, affording the desired 4-1a and
4-1b in 78% and 71% yield, respectively. However,
the product yields decreased accordingly with the
increase of the N-substituents bulk (4-1c, 4-1d, 4-1e),
indicating that this transformation was very sensitive
to steric hindrance to the embedded DGs, which also
was confirmed by the different performance of N-
substituted anilines bearing ortho-, meta-, and para-
substituents at the benzene ring during this
transformation (4-1f~4-1k). No obvious difference
was observed in product yields when the
transformation performed with the N-substituted
anilines containing electron-donating methyl
substituent and those containing weak electron-
withdrawing chlorine substituent at the benzene ring,
respectively (4-1f vs 4-1i, 4-1g vs 4-1j, 41-h vs 4-1k),
however, when the N-substituted anilines bearing
strong electron-withdrawing group such as –NO2 and
–CN were applied in this protocol, no desired product
could be obtained (4-1l, 4-1m). The reaction failed to
give the desired product when aniline was applied
instead of N-substituted aniline owing to the self
carbonylation of aniline to afford 1,3-diphenylurea
was predominated under the current conditions (4-1n).
Further extension of this transformation to cyclic N-
4-3c, 50%
4-3d, 44%
4-3b, 56%
N
Bn
N
N
N
N
O
N
O
O
4-3f, 52%
4-3g, 80%
4-3e, 35%
OMe
MeO
N
N
N
N
N
N
OMe
O
O
O
4-3i, 78%
Cl
4-3j, 86%
4-3h, 76%
F
N
N
N
N
N
N
Cl
O
O
O
4-3l, 76%
4-3m, 78%
4-3k, 72%
Br
Cl
S
N
N
N
N
N
N
O
O
O
4-3o, 74%
4-3p, 84%
4-3n, 79%
N
N
O
N
N
N
O
4-3r, 72%
4-3q, 76%
[a]
Reaction conditions: 1a (1.0 mmol), 2a (3.0 mmol), 3
substituted
anilines
such
as
1,2,3,4-
(1.5 mmol), KI (0.2 mmol), AcOH (5 mL), MeCN (10.0
mL), the mixture of 2a and AcOH were added dropwise. [b]
Isolated yield.
tetrahydroquinoline (1o) and indoline (1p) revealed
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801267
Advanced Synthesis & Catalysis
Experimental Section
that the former could tolerate this protocol, while the
latter failed to work in this system.
General procedure for the synthesis of 2,3-
dihydroquin-azolin-4(1H)-ones
Table 4. Scope of N-substituted anilines.[a]
N-Substitutedaniline (1.0 mmol), aldehyde (1.5 mmol),
Pd(OAc)2 (0.05 mmol), Cu(OAc)2 (2.0 mmol), KI (0.2
mmol) and CH3CN (10 mL) were charged in a 50 mL
three-necked round-bottom flask equipped with a stir bar
and a condenser. The mixture of AcOH (5 mL) and a
primary amine (3.0 mmol) was added into a constant
pressure dropping funnel, which was then connected with
one neck of the flask. Another neck was equipped with a
T-branch pipe connected with a CO balloon. The flask was
then evacuated and back-filled with CO three times,
R1
R1
NH2
CHO
CO (bubble)
Pd(OAc)2 (5% mol)
N
NH
+
+
R2
R2
Cu(OAc)2 (2 equiv)
KI, AcOH, MeCN
70 oC, 8 h
N
O
1
2a
3a
4
N
N
N
O
N
N
N
followed by stirring at 70 oC for
8
h
with
O
O
continuous bubble of CO and slow dripping of AcOH and
the primary amine. Then the reaction mixture was cooled
to room temperature and the CO balloon was removed. A
small amount of black powder of suspected metallic Cu
and Pd could be detected in the reaction mixture according
to the XPS study (See SI, page S2-S3). Subsequently,
saturated NaCl solution (30 mL) was added into the flask
and the mixture was extracted with EtOAc (3×10 mL). The
combined organic layers were dried over anhydrous
Na2SO4 and then evaporated in vacuo. The residue was
purified by column chromatography on silica gel to afford
the corresponding 2,3-dihydroquin-azolin-4(1H)-ones 4
with petroleum ether/ethyl acetate (15:1) as the eluent.
4-1b, 71%
4-1c, 35%
4-1a, 78%
Ph
N
Bn
N
N
N
N
N
O
O
O
4-1e, 0
4-1f, 0
4-1d, 22%
Cl
N
N
N
N
N
N
O
O
O
4-1h, 64%
4-1i, 0
4-1g, 56%
Acknowledgements
N
N
N
N
Cl
N
N
We are grateful for the financial support from the National
Natural Science Foundation of China (No. 21772033, U1604285),
PCSIRT (IRT1061), the 111 Project (D17007) and Program for
Innovative Research Team in Science and Technology in
University of Henan Province (No. 15IRTSTHN003).
Cl
O2N
O
O
O
4-1k, 56%
4-1l, 0
4-1j, 54%
H
N
N
N
N
N
N
NC
References
O
O
O
4-1n, 0
4-1o, 31%
4-1m, 0
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N
N
O
4-1p, 0
[a]
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Reaction conditions: 1 (1.0 mmol), 2a (3.0 mmol), 3a
(1.5 mmol), KI (0.2 mmol), AcOH (5 mL), MeCN (10.0
mL), the mixture of 2a and AcOH were added dropwise. [b]
Isolated yield.
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In summary, an economical and efficient relay
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DHQAs through
[4] a) H. Yu, H.-W. Jin, W.-Z. Gong, Z.-L. Wang, H.-P.
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a
palladium-catalyzed ortho-
selective C-H functionalization of N-substituted
anilines with CO, amines and aldehydes based on the
embedded directing strategy. This embedded
alkylamino-directed carbonylation reaction tolerates a
wide range of functional groups and is a reliable
method for the rapid elaboration of simple substrates
into various substituted DHQAs, which are important
potential biologically active molecules. The mild
conditions, use of simple and readily available
substrates, and multi-component one-pot reaction
manner make this transformation very green and
practical.
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10.1002/adsc.201801267
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6
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10.1002/adsc.201801267
Advanced Synthesis & Catalysis
COMMUNICATION
Alkylamino-Directed One-Pot Reaction of N-Alkyl
Anilines with CO, Amines and Aldehydes Leading
to 2,3-Dihydroquinazolin-4(1H)-ones
R1
R1
CO(bubble)
N
R4
R3
NH
O
Pd(OAc)2, Cu(OAc)2
R2
+ +
R3 NH2
R2
R4
H
N
KI, AcOH, MeCN
70 oC, 8 h
H
Adv. Synth. Catal. Year, Volume, Page – Page
O
49 examples, up to 86% yield
simple raw materials and low cost
one-pot manner and mild conditions
high atom economy and step economy
Xiaopeng Zhang,* Zhengwei Li, Qianqian Ding,
Xiaochuan Li, Xuesen Fan, and Guisheng Zhang*
broad substrate scope and good product diversity
7
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