RE[N(SiMe3)2]3-Catalyzed Guanylation/Cyclization of Amino Acid Esters and Carbodiimides

Article abstract of DOI:10.1021/acs.joc.7b02550

The example of rare-earth metal-catalyzed guanylation/cyclization of amino acid esters and carbodiimides is well-established, forming 4(3H)-2-alkylaminoquinazolinones in 65-96% yields. The rare-earth metal amides RE[N(TMS)₂]₃ (RE = Y, Yb, Nd, Sm, La; TMS = SiMe₃) showed high activities, and La[N(TMS)₂]₃ performed best for a wide scope of the substrates.

Full text of DOI:10.1021/acs.joc.7b02550

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Article
RE[N(SiMe3)2]3-Catalyzed Guanylation/Cyclization
of Amino Acid Esters and Carbodiimides
Chengrong Lu, Chao Gong, Bei Zhao, Lijuan Hu, and Yingming Yao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02550 • Publication Date (Web): 16 Jan 2018
Downloaded from http://pubs.acs.org on January 16, 2018
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The Journal of Organic Chemistry
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RE[N(SiMe3)2]3-Catalyzed Guanylation/Cyclization of Amino Acid
Esters and Carbodiimides
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Chengrong Lu, Chao Gong, Bei Zhao*, Lijuan Hu, and Yingming Yao
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Sciꢀ
ence, Soochow University, Suzhou 215123, People’s Republic of China.
Email: zhaobei@suda.edu.cn
Supporting Information Placeholder
ABSTRACT: The example of rareꢀearth metalꢀcatalyzed guanylation/cyclization of amino acid esters and carbodiimides is wellꢀ
established, forming 4(3H)ꢀ2ꢀalkylamino quinazolinones in 65ꢀ96% yields. The rareꢀearth metal amides RE[N(TMS)2]3 (RE = Y,
Yb, Nd, Sm, La; TMS = SiMe3) showed high activities and La[N(TMS)2]3 performed best in a wide scope of the substrates.
bodiimides was used instead.10
Introduction
As we know, transition metal compounds especially rareꢀearth
metal complexes with diverse ligands have excellent activities
in the guanylation reaction.11 So it is a rational attempt to emꢀ
ploy the rareꢀearth metal complex in the guanylaꢀ
tion/cyclization of amino acid esters and carbodiimides. A
series of 4(3H)ꢀ2ꢀalkylamino quinazolinones in good to excelꢀ
lent yields were obtained using rareꢀearth metal amides
RE[N(TMS)2]3 as the catalysts.
NꢀHeterocyclic compounds quinazolinones are well noted for
their wide existence among natural products and more imꢀ
portantly for their potent biological and medicinal properties.1
Efficient synthetic methods of quinazolinones and their deꢀ
rivatives have attracted much attention for several years.
Treatment of 2ꢀhalobenzoic acid with guanidines2 yielded
quinazolinones in the presence of copper iodide. The transꢀ
formation found limited application due to the relative narrow
substrate scope and a large dosage of additives. Palladium and
Results and discussion
molybdenumꢀmediated
domino
cyclocarbonylaꢀ
In many cases, the reactivity of rareꢀearth metal complexes is
greatly influenced by ligand structure. The initial test was thus
started from the screening of rareꢀearth metal catalysts, while
the neat reaction of ethyl 2ꢀaminobenzoate 1a with N,N’ꢀ
diisopropyl carbodiimide 2a (iPrN=C=NiPr, simplified as DIC)
was examined as the model reaction. The results are summaꢀ
rized in Table 1. To our delight, all the rareꢀearth metal comꢀ
pounds we used, including trivalent ytterbium compounds
YbCl3, Yb(OAr)3 (Ar = 2,6ꢀtBu2C6H3), Yb[N(TMS)2]3, and
Yb[N(TMS)2]3(µꢀCl)Li(THF)3 successfully catalyze the
guanylation/cyclization of the model reaction in good yields
(55ꢀ70%) (Table 1, entries 1ꢀ4). Overall consideration of the
preparation procedure and the activities of the compounds, the
simple trivalent ytterbium amide Yb[N(TMS)2]3 was chosen as
the ideal catalyst. And the subsequent screening of reaction
tion/cyclizations were convenient methods for the synthesis of
2ꢀaminoquinazolinones, which avoided using gaseous CO.3
However, low reactant diversity was the disadvantage in some
cases. Aminolysis of isatoic anhydride, followed by reacting
with cyanamide,4 isocyanide,5 or isothiocyanate,6 produces
miscellaneous quinazolinones, which were I2/cumyl hydroperꢀ
oxideꢀmediate or catalyzed by Cu, Pd, or Co complexes. Only
one example was found to yield the target quinazolinones
from isatoic anhydride without any catalyst.7 Utilizing the azaꢀ
Wittig reaction of iminophosphorane with heterocumulene on
solid phase, for the synthesis of 2ꢀaminoꢀsubstituted 3Hꢀ
quinazolineꢀ4ꢀone usually began with isatoic anhydride as
well.8 Because of the commercially available or readily generꢀ
ated isatoic anhydride, which gave rise to differently substitutꢀ
ed quinazolinone skeletons, the strategies based on isatoic
anhydride were popular. However, the toxic reagents are usuꢀ
ally required, and generally long and tedious procedures lead
to unsatisfying overall yields in many cases. Recently, novel
pathways have been explored to construct quinazolinones
starting with amino acid ester and cyanamide, isothiocyanate,
or thiourea.9 Xi and Zhang developed a Znꢀcatalyzed tandem
guanylation/amidation of amino acid ester, in which carꢀ
o
temperature based on the ytterbium amide suggested 60 C
was optimal (Table 1, entries 3, and 5ꢀ6). Rare earth metal
amides of different metal centers were tested, which gave rise
to yields of ~60% (Table 1, entries 3 and 7ꢀ10).
Table 1 Screening of catalystsa
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Entry
Cat.
T (oC) Yield (%)b
6
7
8
9
1
YbCl3
80
80
80
58
57
66
55
52
67
61
68
59
65
2
(2,6ꢀtBu2C6H3O)3Yb
Yb[N(TMS)2]3
3
10
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60
4
Yb[N(TMS)2]3(µꢀCl)Li(THF)3 80
Figure 1 (a) In situ 1H NMR spectrum of the model reaction
with the molar ratio of 2a to 1a 2: 1; (b) the 1H NMR specꢀ
trum of major product 3aa; (c) the 1H NMR spectrum of byꢀ
product 4.
5
Yb[N(TMS)2]3
Yb[N(TMS)2]3
La[N(TMS)2]3
Nd[N(TMS)2]3
Sm[N(TMS)2]3
Y[N(TMS)2]3
40
60
60
60
60
60
6
7
Subsequently, a routine screening of the reaction conditions,
including the central metals of rareꢀearth metal amides, cataꢀ
lyst loading, temperature, solvent, and reaction time was asꢀ
sessed with the 1:2 molar ratio of 1a to 2a. The results showed
us that with the increasing of metal ion radius (Yb ~ Y< Gd <
Sm < Nd < La), the yields of 4(3H)ꢀ2ꢀisopropylamino
quinazolinone 3aa increased from 40% to 84% (Table 2, enꢀ
tries 1ꢀ6). Raising the temperature is beneficial to the reaction
(Table 2, entries 1 and 7ꢀ9), whereas the solvent has a negative
effect on the reaction (Table 2, entries 9ꢀ12). Reaction time
and the amount of catalyst cannot be reduced on the premise of
ensuring the yield (Table 2, entries 9 and 13ꢀ17). As a result,
the reaction should be performed better in the presence of 5
mol% La[N(TMS)2]3 at 100 oC for 24 h without solvent.
8
9
10
aConditions: 1 mmol of 2ꢀaminobenzoates, 1 mmol of DIC.
bIsolated yields.
Since the yields stayed around 60% and a certain amount of
reactant 1a was always observed by TLC detection after the
reaction was quenched, while DIC was fully consumed, apꢀ
parently some other reaction occurred to DIC. It was conjecꢀ
tured that ethanol released during the cyclization may conꢀ
sume the reactant DIC. To verify the hypothesis, the reaction
of ethanol with DIC in 1:1 molar ratio was conducted in the
presence of lanthanum amide La[N(TMS)2]3, and the byprodꢀ
uct isourea 4 was isolated in 75% yield (Scheme 1). Meanꢀ
Table 2 Screening of the optimal conditions a
1
while, in CDCl3, the in situ H NMR spectrum of the model
reaction (Figure 1(a)) catalyzed by La[N(TMS)2]3 was carried
out for 24 h, which showed the main reaction occurred (Figure
1(b)), together with the addition of ethanol with DIC (Figure
1(c)), when the molar ratio of DIC 2a to ethyl 2ꢀ
aminobenzoate 1a was 2:1. Thus, molecular sieves and anhyꢀ
drous calcium dichloride were deliberately added to remove
ethanol in the catalytic system, respectively. However, the
strategy had no significant effects on the outcomes of the exꢀ
periments, for the yields of 3ꢀisopropylꢀ2ꢀ(isopropylamino)ꢀ
quinazolinꢀ4(3H)ꢀone 3aa were still unsatisfying, varied from
56ꢀ66% (SI, Table S1). Nevertheless, when the molar ratio of
2a to 1a increased to 2:1, the yields of the product dramaticalꢀ
ly increased up to 96% (Table 2, entry 9). Thus, our hypotheꢀ
sis about the side reaction of ethanol addition to the carꢀ
bodiimide was confirmed, and it happened to be reported by
Tamm and Eisen recently, using actinide complexes as cataꢀ
lysts.12
Entry
Cat.
Catalyst Solvent
loading
(mol%)
T
(oC)
Time Yield
(h)
(%)b
1
La[N(TMS)2]3
Nd[N(TMS)2]3
Sm[N(TMS)2]3
Gd[N(TMS)2]3
Y[N(TMS)2]3
Yb[N(TMS)2]3
La[N(TMS)2]3
La[N(TMS)2]3
La[N(TMS)2]3
La[N(TMS)2]3
La[N(TMS)2]3
5
5
5
5
5
5
5
5
5
5
5
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
60
60
60
60
60
60
40
80
100
24
24
24
24
24
24
24
24
24
24
24
84
81
74
65
42
40
78
86
96
40
36
2
3
4
5
6
7
8
9
10
11
Toluene 100
1,4ꢀ
100
Dioxane
12
13
La[N(TMS)2]3
La[N(TMS)2]3
5
5
DMSO
ꢀ
100
100
24
6
43
76
Scheme 1 The addition reaction of ethanol with DIC
2
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La[N(TMS)2]3
La[N(TMS)2]3
La[N(TMS)2]3
La[N(TMS)2]3
5
ꢀ
ꢀ
ꢀ
ꢀ
100
100
100
100
12
18
24
24
80
85
55
20
An ester group effect of 2ꢀaminobenzoates has also been studꢀ
t
1
2
3
4
ied. The esters bearing bulky leaving groups, such as Bu and
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5
nBu, turned out to be outstanding substrates and the products
3aa were obtained in 94% and 93% (Table 3, entries 5 and 6).
Consideration of the practicability, environmental friendliness
and potential production cost, ethyl 2ꢀaminobenzoates were
still recommended.
2.5
1
aConditions: 1 mmol of 2ꢀaminobenzoates, 2 mmol of DIC.
bIsolated yields.
5
6
7
8
Table 3 The influence of different alkoxy groups of estersa
The evaluation of the substrate scope under optimal conditions
was summarized in Scheme 2. The electronic effect of the
substituents of the esters has great effect on the outcomes.
When using 5ꢀsubstituted ethyl 2ꢀaminobenzoates bearing
electronꢀwithdrawing groups (Fꢀ, Clꢀ, Brꢀ, Iꢀ, pyridinyl), the
stronger the electron withdrawing abilities of the groups were,
the lower the yields were (Scheme 2, 3baꢀ3fa). Electron donatꢀ
ing groups (OMeꢀ, Meꢀ and naphthyl) also lead to a slight drop
in yields (Scheme 2, 3gaꢀ3ja). Excellent yields of the products
were obtained by using different carbodiimides, including
symmetrical or unsymmetrical carbodiimides (Scheme 2, 3abꢀ
3ag’). It is worth mentioning that when using unsymmetrical
carbodiimides with aromatic and aliphatic substituents in difꢀ
ferent side, meanwhile the aliphatic substituent in the form of
NCH2R, a pair of cyclization isomers were obtained (Scheme 2,
3ad and 3ad’, 3ag and 3ag’). Compared with the reported
spectra of the same compounds in previous work, 8c the major
products were 3ad and 3ag, respectively. Furthermore, imino
acid esters also gave out the corresponding product 3kb in
91% yield.
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Entry
R
Yield(%)b
1
2
3
4
5
6
Me
Et
68
85
73
83
93
94
Bn
iPr
nBu
tBu
aConditions: 1 mmol of 2ꢀaminobenzoates, 2 mmol of DIC.
bIsolated yields.
Based on the mechanism raised by Zhang10 and the evidence
from the H NMR experiment mentioned above, we proposed
1
the possible mechanism of the current transformation, shown
in Scheme 3. The aminolysis of rareꢀearth metal amide
RE[N(TMS)2]3 with ethyl 2ꢀaminobenzoate would gernerate
intermediate A. Coordination of carbodiimide DIC to A
/intramolecular insertion might provide intermediate C. Intraꢀ
molecular nucleophilic amidation in C should occur to release
3aa and yield intermediate D at the same time. Finally, interꢀ
mediate D underwent proton exchange with another molecule
of ethyl 2ꢀaminobenzoate to regenerate the active species A,
while a molecule of ethanol was released. The byproduct ethaꢀ
nol was captured by DIC to yield isourea 4 under the same
condition. In the case of unsymmetrical carbodiimides, when
forming intermediate B, it is tend to form the structure of B-1
rather than the structure B-2, since the electron cloud density
of the N atom bearing the aromatic ring was somewhat greater
than the other side, which leads to more powerful nucleophilic
attack to the carbonyl carbon in the ester group (Scheme 4).
COOEt
Scheme 2 Substrate scope
O
N
O
N
O
N
O
N
F
Cl
Br
N
N
N
N
NH
NH
NH
NH
3ca, 76%
3ba, 66%
3da, 82%
3aa, 96%
O
N
O
N
O
N
N
O
N
N
I
O
N
N
NH
N
NH
NH
NH
Tol
3ga, 86%
3fa, 80%
3ha, 83%
3ea, 86%
O
O
N
N
O
N
N
O
N
C N
Ph
H
N
NH2
N
N
N
C
RE
RE[N(TMS)2]3
N
NH
NH
NH
Tol
N
NH
Ph
N
O
H
N
OEt
HN(TMS)2
A
RE
3ac, 95%
3ia, 87%
3ab, 98%
3ja, 97%
O
OEt
B
O
O
O
O
Ph
Bn
Ph
Ph
N
O
N
N
N
DIC
RE[N(TMS)2]3
EtOH
N
NH
tBu
N
N
N
NH
Bn
N
NH
Ph
N
NH
Cy
H
4
3ad
3ad'
COOEt
NH2
65(32)%
3ae, 90%
3af, 92%
N
O
O
O
RE OEt
N
nBu
Ph
N
N
D
N
O
N
Ph
RE
N
N
NH
nBu
N
NH
Ph
N
OEt
O
Ph
C
66(31)%
3ag
3ag'
3kb, 91%
N
N
NH
3
3aa
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Ethyl 2-amino-5-chlorobenzoate (1c). 1H NMR (400 MHz,
Scheme 3 Possible catalytic mechanism.
CDCl3): δ 7.83 (d, J = 2.5 Hz, 1H, ArH), 7.20 (dd, J = 8.8, 2.5 Hz,
1H, ArH), 6.60 (d, J = 8.8 Hz, 1H, ArH), 5.73 (s, 2H, NH2), 4.33
(q, J = 7.1 Hz, 2H, CH2), 1.39 (t, J = 7.1 Hz, 3H, CH3) ppm.
1
2
3
4
5
6
7
Ethyl 2-amino-5-bromobenzoate (1d). 1H NMR (400 MHz,
CDCl3): δ 7.97 (d, J = 2.4 Hz, 1H, ArH), 7.32 (dd, J = 8.8, 2.4 Hz,
1H, ArH), 6.57 (t, J = 7.5 Hz, 1H, ArH), 5.76 (s, 2H, NH2), 4.33
(q, J = 7.1 Hz, 2H, CH2), 1.39 (t, J = 7.1 Hz, 3H, CH3) ppm.
8
9
Scheme 4 Possible intermediate.
Ethyl 2-amino-5-iodobenzoate (1e). 1H NMR (400 MHz,
CDCl3): δ 8.05 (d, J = 2.2 Hz, 1H, ArH), 7.38 (dd, J = 8.7, 2.2 Hz,
1H, ArH), 6.36 (d, J = 8.7 Hz, 1H, ArH), 5.69 (s, 2H, NH2), 4.24
(qd, J = 7.1, 3.4 Hz, 2H, CH2), 1.30 (t, J = 7.1 Hz, 3H, CH3) ppm.
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Conclusion
In summary, a rareꢀearth metal amide catalyzed guanylaꢀ
tion/cyclization of amino acid esters and carbodiimides is an
ideal method for the synthesis of 3ꢀalkylꢀ4(3H)ꢀ2ꢀalkylamino
quinazolinones, which is the first utility of rareꢀearth metal
complexes in this field. The readily available catalyst
Ln[N(TMS)2]3 exhibits broad substituent tolerance, mild conꢀ
ditions, and provides 3ꢀalkylꢀ4(3H)ꢀ2ꢀalkylamino quinazoliꢀ
nones in good to excellent yields. The plausible mechanism of
the guanylation/cyclization transformation is described in deꢀ
tail. Furthermore, a competitive reaction, the addition of alcoꢀ
hols with carbodiimides was observed in the process, which
was also catalyzed by RE[N(TMS)2]3. Extensive studies are
now in progress in our laboratory.
Ethyl 2-amino-5-methoxybenzoate (1g). 1H NMR (400 MHz,
CDCl3): δ 7.36 (d, J = 3.0 Hz, 1H, ArH), 6.93 (dd, J = 8.9, 3.0 Hz,
1H, ArH), 6.61 (d, J = 8.9 Hz, 1H, ArH), 5.42 (s, 2H, NH2), 4.33
(q, J = 7.1 Hz, 2H, CH2), 3.75 (s, 3H, OCH3), 1.38 (t, J = 7.1 Hz,
3H, CH3) ppm.
Ethyl 2-amino-5-methylbenzoate (1h). 1H NMR (400 MHz,
CDCl3): δ 7.67 (s, 1H, ArH), 7.09 (dd, J = 8.3, 1.9 Hz, 1H, ArH),
6.59 (d, J = 8.3 Hz, 1H, ArH), 5.53 (s, 2H, NH), 4.33 (q, J = 7.1
Hz, 2H, CH2), 2.24 (s, 3H, ArCH3), 1.39 (t, J = 7.1 Hz, 3H, CH3)
ppm.
1
Ethyl 3-amino-2-naphthoate (1i). H NMR (400 MHz, CDCl3):
δ 8.50 (s, 1H, ArH), 7.72 (d, J = 8.3 Hz, 1H, ArH), 7.53 (d, J =
8.3 Hz, 1H, ArH), 7.46 – 7.34 (m, 1H, ArH), 7.23 – 7.13 (m, 1H,
ArH), 6.97 (s, 1H, ArH), 5.58 (s, 2H, NH2), 4.42 (q, J = 7.1 Hz,
2H, CH2), 1.45 (t, J = 7.1 Hz, 3H, CH3) ppm.
Experimental section
General Procedures. All manipulations and reactions were
conducted under a purified argon atmosphere using standard
Schlenk or glovebox techniques. Solvents were degassed and
distilled from sodium benzophenone ketyl under argon prior to
use. All commercial available chemicals, including liquid
amino acid esters and carbodiimides, were dried with CaH2
and distilled in a vacuum or at atmospheric pressure prior to
use. Amino acid esters, other than 1a, 1f, 1j and 1k (bought
from J&K Chemical), were prepared. Unsymmetrical carꢀ
bodiimides 2b-2g were synthesized following the previous
work.13 Rareꢀearth metal catalysts YbCl3,14 (2,6ꢀ
tBu2C6H3ArO)3Yb,15 Yb[N(TMS)2]3,16 and Yb[N(TMS)2]3(µꢀ
Typical procedure for the preparation of carbodiimides
In a typical procedure, corresponding isothiocyanates and amines
were ground manually in a mortar in a 1:1 stoichiometric ratio for
15ꢀ20 minutes. After that, the solid product was scraped off the
walls of the mortar affording thiourea quantitatively. To a soluꢀ
tion of iodine (20.0 mmol) and triphenylphosphine (20 mmol) in
CH2Cl2 (80 mL), a solution of 16.7 mmol thiourea and triethylaꢀ
mine (41.4 mmol) in CH2Cl2 (80 mL) was added and the mixture
was stirred under ultrasonic. According to the TLC test, the reacꢀ
tion was quenched after appropriate time. The crude mixture was
concentrated under reduced pressure, then purified by column
chromatography using hexane as the elution to give the carꢀ
bodiimide.
17
Cl)Li(THF)3 were prepared according to literature methods,
respectively. NMR spectra were recorded using a Brukerꢀ400
MHz spectrometer at room temperature. High Resolution
Mass (HRMS) spectra were obtained using Bruker ESIꢀTOF.
Characteristic data of carbodiimides:
Typical procedure for the preparation of amino acid esters:
1
Diphenylmethanediimine (2b). H NMR (400 MHz, CDCl3): δ
Thionyl chloride (23.52 mmol) was added dropwise to a solution
of 2ꢀaminoꢀ5ꢀchlorobenzoic acid (19.6 mmol) in 50 mL ethanol in
ice bath. The mixture was heated to reflux for 18 h, then neutralꢀ
ized by adding saturated aqueous NaHCO3. The mixture was
extracted with ethyl acetate for three times, the organic layer was
collected and dried over anhydrous Na2SO4, filtered. After solvent
evaporation under reduced pressure, the crude mixture was puriꢀ
fied by flash column chromatography to give the product 1c as a
paleꢀyellow solid (1.6 g, 70 %).
7.42ꢀ 7.30 (m, 4H, ArH), 7.27ꢀ7.17 (m, 6H, ArH) ppm.
1
Di-p-tolylmethanediimine (2c). H NMR (400 MHz, CDCl3): δ
7.12 (dd, J = 20.7, 8.2 Hz, 8H, ArH), 2.35 (s, 6H, CH3) ppm.
N-Benzyl-N-phenylmethanediimine (2d). 1H NMR (400 MHz,
CDCl3): δ 7.37 (d, J = 4.4 Hz, 4H, ArH), 7.30 (dt, J = 8.8, 4.3 Hz,
1H, ArH), 7.24 (t, J = 7.8 Hz, 2H, ArH), 7.09 (t, J = 7.4 Hz, 1H,
ArH), 6.99 (d, J = 7.5 Hz, 2H, ArH), 4.56 (s, 2H, CH2) ppm.
Characteristic data of amino acid esters:
N-Cyclohexyl-N-phenylmethanediimine (2e). 1H NMR (400
MHz, CDCl3): δ 7.33 – 7.18 (m, 2H, ArH), 7.16 – 7.03 (m, 3H,
ArH), 3.56 – 3.34 (m, 1H, CH), 2.07 – 1.90 (m, 2H, CH2), 1.82 –
1.70 (m, 2H, CH2), 1.61 – 1.41 (m, 3H, CH2), 1.40 – 1.21 (m, 3H,
CH2) ppm.
Ethyl 2-amino-5-fluorobenzoate (1b). 1H NMR (400 MHz,
CDCl3): δ 7.54 (dd, J = 9.7, 3.1 Hz, 1H, ArH), 7.01 (ddd, J = 9.0,
7.7, 3.1 Hz, 1H, ArH), 6.60 (dd, J = 9.0, 4.5 Hz, 1H, ArH), 5.58
(s, 2H, NH2), 4.32 (q, J = 7.1 Hz, 2H, CH2), 1.37 (t, J = 7.1 Hz,
3H, CH3) ppm.
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N-tert-Butyl-N-phenylmethanediimine (2f). 1H NMR (400
MHz, CDCl3): δ 7.31 – 7.22 (m, 2H, ArH), 7.15 – 7.04 (m, 3H,
ArH), 1.39 (s, 9H, CH3) ppm.
= 7.2 Hz, 6H, CH3), 1.28 (d, J = 6.4 Hz, 6H, CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ 162.0, 149.3, 148.6, 142.6, 135.8, 126.9,
119.6, 84.7, 43.9, 23.0, 20.3 ppm. HRMS (ESIꢀTOF) m/z:
[M+H]+ calcd for C14H19IN3O 372.0567; Found 372.0558. M.p.:
120.5ꢀ121.7 oC.
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N-Butyl-N-phenylmethanediimine (2g). 1H NMR (400 MHz,
CDCl3): δ 7.39 – 7.18 (m, 2H, ArH), 7.12 – 7.00 (m, 3H, ArH),
3.40 (t, J = 6.8 Hz, 2H, CH2), 1.78 – 1.54 (m, 2H, CH2), 1.51 –
1.33 (m, 2H, CH2), 0.94 (t, J = 7.4 Hz, 3H, CH3) ppm.
3-Isopropyl-2-(isopropylamino)pyrido[2,3-d]pyrimidin-4(3H)-
one (3fa). Colorless solid, Yied: 80 %; 1H NMR (400 MHz,
CDCl3): δ 8.69 (dd, J = 4.6, 2.1 Hz, 1H, ArH), 8.35 (dd, J = 7.8,
2.1 Hz, 1H, ArH), 7.04 (dd, J = 7.8, 4.6 Hz, 1H, ArH), 5.41 (s,
1H, NH), 4.68 (d, J = 6.6 Hz, 1H, CH), 4.63 – 4.52 (m, 1H, CH),
1.54 (d, J = 7.2 Hz, 6H, CH3), 1.31 (d, J = 6.5 Hz, 6H, CH3) ppm.
13C NMR (100 MHz, CDCl3): δ 163.5, 159.0, 156.0, 151.3, 136.9,
118.3, 112.3, 44.1, 23.1, 20.4 ppm. HRMS (ESIꢀTOF) m/z:
[M+H]+ calcd for C13H19N4O 247.1553; Found 247.1545. M.p.:
185.9ꢀ187.1 oC.
Typical procedure for the guanylation/cyclization of amino
acid esters and carbodiimides
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A 5 mL Schlenk tube under dried argon was charged with
Yb[N(TMS)2]3 (0.05 mmol), ethyl 2ꢀaminobenzoate (1.00 mmol)
and a stirring bar. After the catalyst was dissolved, DIC (2.00
mmol) was added into the tube. The mixture was stirred at 100 oC
for 24 h, diluted with ethyl acetate, and then the crude mixture
was purified by column chromatography with ethyl acetate/ petroꢀ
leum ether (1:20) to give the desired product as a colorless solid.
3-Isopropyl-2-(isopropylamino)-6-methoxyquinazolin-4(3H)-
one (3ga). Colorless solid, Yield: 86 %; 1H NMR (400 MHz,
CDCl3): δ 7.42 (d, J = 2.9 Hz, 1H, ArH), 7.25 – 7.17 (m, 1H,
ArH), 7.11 (dd, J = 8.9, 3.0 Hz, 1H, ArH), 5.38 (s, 1H, NH), 4.27
(dq, J = 12.9, 6.5 Hz, 1H, CH), 4.22 – 4.13 (m, 1H, CH), 3.78 (s,
3H, OCH3), 1.49 (d, J = 7.2 Hz, 6H, CH3), 1.23 (d, J = 6.4 Hz,
6H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 163.3, 155.4,
148.0, 143.9, 126.4, 124.8, 117.9, 106.6, 55.9, 43.8, 23.1, 20.5
ppm. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C15H22N3O2
276.1707; Found 276.1700. M.p.: 123.9ꢀ124.8 oC.
Characteristic data of quinazolin-4(3H)-ones:
3-Isopropyl-2-(isopropylamino)quinazolin-4(3H)-one
(3aa).
1
Colorless solid, Yield: 96 %; H NMR (400 MHz, CDCl3): δ 8.08
(dd, J = 8.0, 1.3 Hz, 1H, ArH), 7.59 – 7.48 (m, 1H, ArH), 7.31 (d,
J = 8.1 Hz, 1H, ArH), 7.16 – 7.01 (m, 1H, ArH), 5.48 (s, 1H,
NH), 4.40 (dd, J = 11.2, 5.1 Hz, 2H, CH), 1.55 (d, J = 7.2 Hz, 6H,
CH3), 1.31 (d, J = 6.2 Hz, 6H, CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ 163.4, 149.2, 149.1, 134.2, 127.3, 124.7, 122.4, 117.7,
43.8, 23.1, 20.5 ppm. HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for
C14H19N3ONa 268.1420; Found 268.1435. M.p.: 79.8ꢀ80.1 oC.
3-Isopropyl-2-(isopropylamino)-6-methylquinazolin-4(3H)-
one (3ha). Colorless solid, Yield: 83 %; 1H NMR (400 MHz,
CDCl3): δ 7.88 (s, 1H, ArH), 7.37 (dd, J = 8.3, 1.9 Hz, 1H, ArH),
7.29 – 7.19 (m, 1H, ArH), 5.48 (s, 1H, NH), 4.48 – 4.23 (m, 2H,
CH), 2.38 (s, 3H, ArCH3), 1.55 (d, J = 7.2 Hz, 6H, CH3), 1.31 (d,
J = 6.3 Hz, 6H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 163.4,
148.7, 147.1, 135.7, 132.1, 126.6, 124.6, 117.5, 43.8, 23.1, 21.1,
20.5 ppm. HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for
C15H21N3ONa 282.1577; Found 282.1591. M.p.: 134.8ꢀ136.3 oC.
6-Fluoro-3-isopropyl-2-(isopropylamino)quinazolin-4(3H)-one
1
(3ba). Colorless solid, Yield: 66 %; H NMR (400 MHz, CDCl3):
δ 7.61 (dd, J = 8.8, 2.8 Hz, 1H, ArH), 7.29 – 7.06 (m, 2H, ArH),
5.30 (s, 1H, NH), 4.36 (d, J = 6.8 Hz, 1H, CH), 4.26 (dq, J = 13.1,
6.5 Hz, 1H, CH), 1.46 (d, J = 7.2 Hz, 6H, CH3), 1.21 (d, J = 6.4
Hz, 6H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 162.7, 162.6,
159.4, 157.0, 148.6, 145.8, 126.7, 126.6, 122.7, 122.4, 118.2,
118.1, 111.6, 111.3, 43.8, 22.9, 20.2 ppm. 19F NMR (376.5 MHz,
CDCl3): δ ꢀ120.07 ppm. HRMS (ESIꢀTOF) m/z: [M+H]+calcd for
C14H19FN3O 264.1507; Found 264.1499. M.p.: 80.9ꢀ81.6 oC.
3-Isopropyl-2-(isopropylamino)benzoquinazolin-4(3H)-one
1
(3ia). Yellow solid, Yield: 87 %; H NMR (400 MHz, CDCl3):
δ8.63 (s, 1H, ArH), 7.83 (d, J = 8.3 Hz, 1H, ArH), 7.72 (d, J = 8.4
Hz, 1H, ArH), 7.67 (s, 1H, ArH), 7.41 – 7.35 (m, 1H, ArH), 7.25
(t, J = 7.2 Hz, 1H, ArH), 5.38 (s, 1H, NH), 4.48 – 4.21 (m, 2H,
CH), 1.50 (d, J = 7.2 Hz, 6H, CH3), 1.26 (d, J = 6.2 Hz, 6H, CH3)
ppm. 13C NMR (100 MHz, CDCl3): δ 163.8, 148.2, 144.5, 137.6,
129.6, 129.5, 128.7, 128.0, 127.2, 124.3, 120.4, 118.6, 43.8, 23.1,
20.7 ppm. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C18H22N3O
296.1757; Found 296.1750. M.p.: 134.6ꢀ136.1 oC.
6-Chloro-3-isopropyl-2-(isopropylamino)quinazolin-4(3H)-
one (3ca). Colorless solid, Yield: 76 %; 1H NMR (400 MHz,
CDCl3): δ 8.03 (d, J = 2.4 Hz, 1H, ArH), 7.46 (dd, J = 8.7, 2.5 Hz,
1H, ArH), 7.30 – 7.20 (m, 1H, ArH), 5.43 (s, 1H, NH), 4.51 –
4.29 (m, 2H, CH), 1.55 (d, J = 7.2 Hz, 6H, CH3), 1.31 (d, J = 6.2
Hz, 6H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 162.4, 149.2,
147.8, 134.5, 127.5, 126.5, 126.4, 118.6, 43.9, 23.1, 20.4 ppm.
HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for C14H18ClN3ONa
302.1031; Found 302.1028. M.p.: 119.4ꢀ120.8 oC.
3-Isopropyl-2-(isopropylamino)-8-methylquinazolin-4(3H)-
one (3ja). Yellow solid, Yield: 97 %; 1H NMR (400 MHz,
CDCl3): δ7.87 (dd, J = 8.0, 0.7 Hz, 1H, ArH), 7.34 (d, J = 7.1 Hz,
1H, ArH), 6.96 (t, J = 7.6 Hz, 1H, ArH), 5.36 (s, 1H, NH), 4.30
(dq, J = 12.9, 6.4 Hz, 2H, CH), 2.39 (s, 3H, CH3), 1.48 (d, J = 7.2
Hz, 6H, CH3), 1.27 (d, J = 6.4 Hz, 6H, CH3) ppm. 13C NMR (100
MHz, CDCl3): δ 163.6, 148.1, 134.2, 132.7, 124.6, 121.8, 117.3,
44.0, 22.6, 20.2, 17.1 ppm. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd
for C15H21N3O 260.1757; Found 260.1754. M.p.: 127.2ꢀ128.2 oC.
6-Bromo-3-isopropyl-2-(isopropylamino)quinazolin-4(3H)-one
1
(3da). Colorless solid, Yield: 82 %; H NMR (400 MHz, CDCl3):
δ 8.18 (d, J = 2.1 Hz, 1H, ArH), 7.58 (dd, J = 8.7, 2.3 Hz, 1H,
ArH), 7.18 (d, J = 8.7 Hz, 1H, ArH), 5.43 (s, 1H, NH), 4.51 –
4.26 (m, 2H, CH), 1.54 (d, J = 7.2 Hz, 6H, CH3), 1.30 (d, J = 6.3
Hz, 6H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 162.2, 149.3,
148.1, 137.2, 129.6, 126.7, 119.1, 114.8, 43.9, 23.0, 20.4 ppm.
HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for C14H18BrN3ONa
346.0525; Found 346.0541. M.p.: 129.5ꢀ130.8 oC.
3-Phenyl-2-(phenylamino)quinazolin-4(3H)-one
(3ab).
1
Colorless solid, Yield: 98 %; H NMR (400 MHz, CDCl3): δ 8.15
(dd, J = 7.9, 1.0 Hz, 1H, ArH), 7.68 – 7.55 (m, 4H, ArH), 7.53 –
7.45 (m, 3H, ArH), 7.42 – 7.35 (m, 2H, ArH), 7.28 (t, J = 7.9 Hz,
2H, ArH), 7.25 – 7.19 (m, 1H, ArH), 7.06 (t, J = 7.4 Hz, 1H,
ArH), 5.95 (s, 1H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ
162.5, 148.6, 146.4, 137.9, 134.8, 134.6, 130.9, 130.3, 129.1,
6-Iodo-3-isopropyl-2-(isopropylamino)quinazolin-4(3H)-one
1
(3ea). Colorless solid, Yield: 86 %; H NMR (400 MHz, CDCl3):
δ 8.36 (d, J = 2.1 Hz, 1H, ArH), 7.73 (dd, J = 8.6, 2.2 Hz, 1H,
ArH), 7.04 (d, J = 8.6 Hz, 1H, ArH), 5.38 (s, 1H, NH), 4.47 (d, J
= 6.7 Hz, 1H, CH), 4.35 (dq, J = 13.1, 6.5 Hz, 1H, CH), 1.52 (d, J
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129.0, 127.2, 125.7, 124.1, 123.7, 120.9, 118.5 ppm. HRMS (ESIꢀ
125.1, 122.7, 117.8, 41.7, 31.5, 20.19, 14.0 ppm. HRMS (ESIꢀ
TOF) m/z: [M+H]+ calcd for C18H20N3O 294.1601; Found
294.1606. M.p.: 137.6ꢀ138.9 oC
TOF) m/z: [M+Na]+ calcd for C20H15N3ONa 336.1107; Found
336.1125. M.p.: 140.0ꢀ141.4 oC.
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3-(p-Tolyl)-2-(p-tolylamino)quinazolin-4(3H)-one
(3ac).
3-Butyl-2-(phenylamino)quinazolin-4(3H)-one
(3ag’).
1
1
Colorless solid, Yield: 95 %; H NMR (400 MHz, CDCl3): δ 8.04
(dd, J = 7.9, 1.0 Hz, 1H, ArH), 7.56 – 7.45 (m, 1H, ArH), 7.37 (d,
J = 8.1 Hz, 1H, ArH), 7.27 (dd, J = 8.1, 3.9 Hz, 4H, ArH), 7.17 –
7.06 (m, 3H, ArH), 6.98 (d, J = 8.2 Hz, 2H, ArH), 5.86 (s, 1H,
NH), 2.33 (s, 3H, CH3), 2.19 (s, 3H, CH3) ppm. 13C NMR (100
MHz, CDCl3): δ 162.7, 148.7, 146.8, 140.4, 135.3, 134.6, 133.7,
131.8, 131.5, 129.4, 128.7, 127.2, 125.6, 123.4, 121.2, 118.4,
21.4, 20.9 ppm. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for
C22H20N3O 342.1601; Found 342.1592. M.p.: 145.4ꢀ146.8 oC.
Colorless liquid, Yield: 31 %; H NMR (400 MHz, CDCl3): δ
8.04 (dd, J = 8.0, 1.0 Hz, 1H, ArH), 7.46 (t, J = 7.4 Hz, 1H, ArH),
7.40 – 7.21 (m, 4H, ArH), 7.16 – 7.00 (m, 3H, ArH), 4.21 – 4.07
(m, 2H, CH2), 1.81 – 1.60 (m, 2H, CH2), 1.45 – 1.34 (m, 2H,
CH2), 0.92 (t, J = 7.3 Hz, 3H, CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ 162.4, 134.5, 129.6, 127.7, 124.1, 123.4, 122.0, 41.6,
30.1, 20.5, 14.0 ppm. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for
C18H20N3O 294.1601; Found 294.1608.
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2-Phenyl-3-(phenylimino)hexahydroimidazo[1,5-a]pyridin-
1(5H)-one (3kb). Colorless solid, Yield: 91 %; 1H NMR (400
MHz, CDCl3): δ 7.32 (d, J = 7.1 Hz, 3H, ArH), 7.25 (d, J = 5.4
Hz, 2H, ArH), 7.10 (t, J = 7.4 Hz, 2H, ArH), 6.84 (t, J = 7.2 Hz,
1H, ArH), 6.76 (d, J = 7.5 Hz, 2H, ArH), 3.88 (dd, J = 11.4, 3.5
Hz, 1H, CH2), 3.72 – 3.47 (m, 1H, CH2), 2.69 (t, J = 12.4 Hz, 1H,
CH), 2.24 (d, J = 12.9 Hz, 1H, CH2), 1.95 (d, J = 10.6 Hz, 1H,
CH2), 1.58 – 1.40 (m, 3H, CH2), 1.29 – 1.22 (m, 1H, CH2) ppm.
13C NMR (100 MHz, CDCl3): δ 147.7, 143.7, 133.1, 128.9, 128.7,
128.1, 127.8, 121.9, 121.8, 59.3, 43.0, 28.4, 25.0, 23.0 ppm.
HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C19H20N3O 306.1601;
Found 306.1605. M.p.: 131.8ꢀ132.3 oC.
2-(Benzylamino)-3-phenylquinazolin-4(3H)-one
(3ad).
1
Colorless solid, Yield: 65 %; H NMR (400 MHz, CDCl3): δ 8.11
(d, J = 7.8 Hz, 1H, ArH), 7.58 (t, J = 7.6 Hz, 1H, ArH), 7.51 (t, J
= 7.4 Hz, 2H, ArH), 7.44 (t, J = 7.6 Hz, 2H, ArH), 7.31 – 7.24 (m,
4H, ArH), 7.22 (d, J = 6.9 Hz, 3H, ArH), 7.15 (t, J = 7.5 Hz, 1H,
ArH), 4.63 (d, J = 5.5 Hz, 2H, CH2), 4.43 (s, 1H, NH) ppm. 13C
NMR (100 MHz, CDCl3): δ 162.7, 149.5, 149.4, 138.5, 134.7,
130.7, 130.0, 128.9, 128.7, 127.5, 127.4, 127.3, 125.1, 122.8,
117.8 ppm. HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for
C21H17N3ONa 350.1264; Found 350.1279. M.p.: 136.3ꢀ137.7 oC.
3-Benzyl-2-(phenylamino)quinazolin-4(3H)-one
(3ad’).
1
Colorless solid, Yield: 32 %; H NMR (400 MHz, DMSOꢀd6): δ
8.69 (s, 1H, NH), 8.03 (dd, J = 7.9, 1.1 Hz, 1H, ArH), 7.69 – 7.62
(m, 1H, ArH), 7.57 (d, J = 7.7 Hz, 2H, ArH), 7.32 (td, J = 7.8, 4.0
Hz, 6H, ArH), 7.28 – 7.21 (m, 3H, ArH), 7.07 (t, J = 7.3 Hz, 1H,
ArH), 5.61 (s, 2H, CH2) ppm. 13C NMR (100 MHz, DMSOꢀd6): δ
162.0, 148.2, 147.9, 139.1, 136.4, 134.5, 128.6, 128.4, 127.2,
126.7, 126.5, 123.5, 122.5, 117.2 ppm. HRMS (ESIꢀTOF) m/z:
[M+H]+ calcd for C21H17N3OH 328.1444; Found 328.1434. M.p.:
176.8ꢀ178.3 oC.
Characteristic data of isourea 4:
Ethyl -N,N'-diisopropylcarbamimidate (4). Colorless oil, Yield:
1
60%; H NMR (400 MHz, CDCl3): δ 4.03 (q, J = 7.0 Hz, 2H,
CH2), 3.73 (br, 1H, CH), 3.37 (br, 1H, NH), 3.12 (br, 1H, CH),
1.20 (t, J = 8.2 Hz, 3H, CH2CH3), 1.07 (s, 12H, CH(CH3)2) ppm.
13C NMR (100 MHz, CDCl3): δ 150.9, 59.7, 45.1, 42.4, 23.2,
22.9, 13.4 ppm.
ASSOCIATED CONTENT
Supporting Information
2-(Cyclohexylamino)-3-phenylquinazolin-4(3H)-one
(3ae).
1
Colorless solid, Yield: 90 %; H NMR (400 MHz, CDCl3): δ 8.12
(dd, J = 7.9, 1.1 Hz, 1H, ArH), 7.60 (dd, J = 11.6, 4.7 Hz, 3H,
ArH), 7.53 (t, J = 7.3 Hz, 1H, ArH), 7.42 (d, J = 8.2 Hz, 1H,
ArH), 7.30 (d, J = 7.3 Hz, 2H, ArH), 7.15 (t, J = 7.5 Hz, 1H,
ArH), 4.07 – 3.96 (m, 1H, CH), 3.89 (d, J = 7.6 Hz, 1H, NH),
2.11 – 1.85 (m, 2H, CH2), 1.57 (d, J = 9.6 Hz, 3H, CH2), 1.49 –
1.31 (m, 2H, CH2), 1.20 – 1.11 (m, 1H, CH2), 1.11 – 0.94 (m, 2H,
CH2) ppm. 13C NMR (100 MHz, CDCl3): δ 162.9, 149.9, 148.9,
135.0, 134.7, 130.7, 130.0, 129.0, 127.4, 125.1, 122.5, 117.7,
50.0, 33.0, 25.7, 24.7 ppm. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd
for C20H22N3O 320.1757; Found 320.1762. M.p.: 121.1ꢀ122.2 oC.
The Supporting Information is available free of charge on the
ACS Publications website.
Table S1, and 1H NMR and 13C NMR spectra of compounds
3aaꢀ3ia and 4
AUTHOR INFORMATION
Corresponding Author
* Fax: +86ꢀ512ꢀ65880305; Tel: +86ꢀ512ꢀ65880305.
ACKNOWLEDGMENT
2-(tert-Butylamino)-3-phenylquinazolin-4(3H)-one
(3af).
1
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (Grant No. 21572151) and
PAPD.
Colorless solid, Yield: 92 %; H NMR (400 MHz, CDCl3): δ 8.18
(d, J = 7.9 Hz, 1H, ArH), 7.69 – 7.61 (m, 3H, ArH), 7.58 (t, J =
7.4 Hz, 1H, ArH), 7.49 (d, J = 8.2 Hz, 1H, ArH), 7.37 – 7.30 (m,
2H, ArH), 7.21 (t, J = 7.5 Hz, 1H, ArH), 3.96 (s, 1H, NH), 1.45
(s, 9H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 163.0, 149.5,
148.2, 135.4, 134.6, 130.7, 129.9, 129.0, 127.3, 125.4, 122.5,
117.7, 52.6, 29.2 ppm. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for
C18H20N3O 294.1601; Found 294.1602. M.p.: 148.0ꢀ149.0 oC.
REFERENCES
[1] For selected reviews, see: (a) Gulevich, A. V.; Dudnik, A. S.;
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1
solid, Yield: 66 %; H NMR (400 MHz, CDCl3): δ 8.12 (dd, J =
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