I2-catalyzed aerobic oxidative C(sp3)-H amination/C-N cleavage of tertiary amine: Synthesis of quinazolines and quinazolinones

Article abstract of DOI:10.1021/acs.joc.5b00474

An iodine-catalyzed oxidative C(sp³)-H amination/C-N cleavage of tertiary amines couducted under an oxygen atmosphere has been developed and affords a route to quinazolines and quinazolinones in good to excellent yields via a domino ring annulation. The method is metal-free, peroxide-free, and operationally simple to implement with a wide scope of substrates and represents a new avenue for multiple C-N bond formations.

Full text of DOI:10.1021/acs.joc.5b00474

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Article
I2-Catalyzed Aerobic Oxidative C(sp3)-H Amination/C-N Cleavage
of Tertiary Amine: Synthesis of Quinazolines and Quinazolinones
Yizhe Yan, Ying Xu, Bin Niu, Huifang Xie, and Yanqi Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00474 • Publication Date (Web): 05 May 2015
Downloaded from http://pubs.acs.org on May 6, 2015
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I2-Catalyzed Aerobic Oxidative C(sp3)-H Amination/C-N
Cleavage of Tertiary Amine: Synthesis of Quinazolines and
Quinazolinones
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Yizhe Yan†‡*, Ying Xu†, Bin Niu†, Huifang Xie† and Yanqi Liu†*
† School of Food and Biological Engineering, Zhengzhou University of Light Industry,
Zhengzhou, 450000, P. R. China.
‡ Henan Collaborative Innovation Center for Food Production and Safety, Zhengzhou, 450000, P. R. China.
Eꢀmail: yanyizhe@mail.ustc.edu.cn; liuyanqi@zzuli.edu.cn
ABSTRACT：An iodine-catalyzed oxidative C(sp3)-H amination/C-N cleavage of tertiary amines
couducted under oxygen atmosphere has been developed affording a rount to quinazolines and
quinazolinones in good to excellent yields via a domino ring annulation. The method is
metal-free, peroxide-free and operationally simple to implement with a wide variety of substrates
scope, and represents a new avenue for multiple C-N bond formations.
INTRODUCTION
Recently, transitionꢀmetalꢀfree intermolecular or intramolecular oxidative C(sp3)ꢀH
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aminations have emerged as important strategies for direct CꢀN bond formations because of
inexpensive, low toxicity, atom and step economical advantages.1 In 2011, hypervalent iodine
(III)ꢀmediated intermolecular oxidative C(sp3)ꢀH aminations were initially developed by
Chang and Muniz, respectively.2 Although the reactions avoided the use of metals,
stoichiometric iodobenzene was generated as a waste product and the substrates employed
remained limited to imides. More recently, we3 and others4 have developed iodine or
iodideꢀmediated intramolecular and intermolecular oxdative amination of activated C(sp3)ꢀH
bonds. However, excessive quantities of dangerous peroxide reagents were usually used as
oxidants, which limited their broad applications in organic synthesis. Thus, the development
of environmentally friendly catalytic systems for oxidative C(sp3)ꢀH amination remains
challenging.
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In contrast, tertiary amines serving as carbon source via CꢀN bond cleavage has emerged as
a useful strategy for CꢀC bond formations. For example, in 2009, Li reported an interesting
ironꢀcatalyzed synthesis of methyleneꢀbridged bisꢀ1,3ꢀdicarbonyl derivatives from
1,3ꢀdicarbonyl compounds using N,Nꢀdimethylaniline as a methylene donor.5a Subsequently,
Perumal reported a palladiumꢀcatalyzed alkylation of indole via aliphatic CꢀH bond activation
of tertiary amines followed by CꢀN bond cleavage (Scheme 1a).5b Meanwhile, Li also reported
a palladiumꢀcatalyzed oxidative coupling of trialkylamines with aryl iodides providing alkyl
aryl ketones, wherein the ketone carbonyl of the ketones was derived from the carbon atom of
trialkylamines.5c Recently, Li5d and Cheng5e also described a new route for C3ꢀformylation of
indole via copperꢀcatalyzed CꢀN bond cleavage using N,N,N’,N’ꢀtetramethylethylenediamine
(TMEDA) as a carbonyl sources, respectively. Very recently, metalꢀfree C3ꢀformylation of
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indoles have has been reported by Wang6a and Li6b using N,Nꢀdimethylaniline or TMEDA as
carbonyl sources (Scheme 1b). To the best of our knowledge, tertiary amines as a carbon
source for CꢀN bond formations hasve rarely been rarely reported.
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Scheme 1. New Strategies Using Tertiary Amines as Carbon Source
Quinazolines7 and quinazolinones8 are important structural units found in many natural
products and pharmaceuticals. Although several good results were achieved,3b,3c,9 the
development of more environmentally friendly methods remains highly desirable. As a
continuation of our ongoing study into the metalꢀfree synthesis of heterocycles,3 herein we
report
a novel and effcient synthesis of quinazolines and quinazolinones via an
iodineꢀcatalyzed tandem C(sp3)ꢀH amination, CꢀN cleavage and oxidative cyclization process
(Scheme 1c). The additional carbon atom of the heterocyclic ring originates from Nꢀmethyl
group of tertiary amine. Two CꢀN bonds were formed in a oneꢀpot reaction under metalꢀfree
conditions. Notably, molecular oxygen was used as a green and safe oxidant, avoiding the use
of peroxides, which could lead to explosion at high temperature.
RESULTS AND DISCUSSION
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Table 1. Optimization of Reaction Conditionsa
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entry
1
cat
NIS
NIS
NIS
I2
oxidant
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DTBP
H2O2
N source
NH3(aq)
none
yield(%)b
68
2
3c
n.d.
n.d.
91
NH3(aq)
NH3(aq)
NH3(aq)
NH4HCO3
NH4OAc
NH4Cl
4
5
nBu4NI
I2
45
6
74
7
I2
91
8
I2
97
9
I2
NH4Cl
65
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15d
16e
I2
NH4Cl
96
I2
K2S2O8
Air
NH4Cl
trace
80
I2
NH4Cl
I2
O2 (1atm)
N2
NH4Cl
NH4Cl
97
I2
25
I2
O2
NH4Cl
36
I2
O2
NH4Cl
86
a
Reaction conditions: 1a (0.2 mmol), 2a (TMEDA, 0.4 mmol), N source (0.4 mmol), catalyst
b
(0.04 mmol), oxidant (0.8 mmol), DMSO (1 mL), 120 °C, 20 h.
Isolated yield; n.d.= not
detected. No TMEDA. Solventꢀfree and 10 equiv of TMEDA was used. e 10 mol% of
c
d
iodine.
Initially, we began our study with the reaction of 2ꢀaminobenzophenone (1a, 0.2 mmol),
TMEDA (2a, 2.0 equiv), ammonia (2.0 equiv), tertꢀbutyl hydroperoxide (TBHP, 70% in
water, 4.0 equiv) as the oxidant and NIS (20 mol%) as the catalyst. When the reaction mixture
was heated in 1 mL of DMSO at 120 °C for 20 h, 4ꢀphenylquinazoline (3a) was obtained in
68% isolated yield by flash column chromatography (Table 1, entry 1). Expectedly, in the
absence of ammonia or TMEDA, no desired product 3a was detected, which indicated that
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ammonia may be the nitrogen source of the product and TMEDA is the carbon source of the
product (Table 1, entries 2 and 3). Then when various iodine reagents were used as the
catalyst, molecular iodine gave the best result with a yield of 91% (Table 1, entries 4 and 5).
Subsequently, when various nitrogen sources such as NH4HCO3, NH4OAc and NH4Cl were
examined, NH4Cl gave the the highest yield (97%) of all (Table 1, entries 6ꢀ8). Examination
of various peroxides, such as diꢀtertꢀbutylperoxide (DTBP), H2O2 (30% in water) and K2S2O8,
didn’t obtain better results (Table 1, entries 9ꢀ11). Notably, 3a was also obtained in 80% yield
under air without additional oxidants (Table 1, entry 12). When oxygen (1atm) was employed
as the oxidant, the reaction would efficiently give 3a in 97% yield (Table 1, entry 13).
However, only 25% of 3a was obtained under nitrogen atmosphere, which indicated that
molecular oxygen is essential for this reaction (Table 1, entry 14). When the reaction was
carried out under solventꢀfree conditions with 10 equiv. of TMEDA being used, 3a was
isolated in only 36% yield (Table 1, entry 15), and reducing the loading of iodine to 10%
decreased the yield of 3a to 86% (Table 1, entry 16). Thus, an optimal set of conditions are
determined as described in entry 13.
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Under the optimal reaction conditions, various Nꢀmethylamines 2b-2g were employed as
the carbon source for the synthesis of quinazolines (Table 2). Firstly, when various tertiary
amines such as 1ꢀmethylpiperidine (2b), 4ꢀmethylmorpholine (2c) and N,Nꢀdimethylaniline
(2d) were used instead of TMEDA, all the reaction gave the desired product 3a, and 2d gave
higher yield than 2b and 2c. In addition, using secondary amines such as Nꢀmethylaniline
(2e), Nꢀmethylbenzylamine (2f) and N,N’ꢀdimethylethylenediamine (2g) as carbon sources,
the reaction also would generate 3a in moderate yield, wtih 2e affording higher yield than 2f
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and 2g. These results clearly show that the reactivity of aromatic amines was greater than that
of aliphatic amines, and the reactivity of tertiary amines was also greater than that of
secondary amines. That was probably associated with the difference in the stablity of iminium
iodide intermediate in the reaction pathway.
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Table 2. The Substrate Scope of Various Aminesa
a
Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), NH4Cl (0.4 mmol), I2 (0.04 mmol),
DMSO (1 mL), O2 (1 atm), 120 °C, 20 h. b Isolated yield.
Subsequently, we investigated the substrate scope of orthoꢀcarbonylꢀsubstituted anilines
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under the optimized reaction conditions (Table 3). Firstly, when R1 was an aromatic
substituent, the substrates 1a-1h could give the corresponding products 3a-3h in excellent
yields regardless of the electronꢀwithdrawing (F, Cl or Br) or electronꢀdonating groups (Me)
on the phenyl ring.
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Table 3. The Substrate Scope of Ortho-carbonyl anilinesa
a
Reaction conditions: 1 (0.2 mmol), 2a (TMEDA, 0.4 mmol), NH4Cl (0.4 mmol), I2 (0.04
b
c
mmol), DMSO (1 mL), O2 (1 atm), 120 °C, 20 h.
mixture.
1i was recovered. Unknown complex
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However, none of the desired product 3i was obtained with 1i bearing 2,4,6ꢀtrimethyl
substituents on the phenyl ring as substrate because of the steric effect. When R1 was a
2ꢀnaphthyl substituent, product 3j was obtained in a 99% isolated yield. In contrast, when R1
was an aliphatic substituent, substrates 1k-1q could give the corresponding products 3k-3q in
lower yields except of 1n. Obviously, the reactivity of tertiary alkyl substituents was greater
than that of secondary and primary alkyl substituent. Finally, when Cl, Br and NO2 groups
were introduced into 5ꢀposition of 2ꢀaminobenzophenone, the desired products 3r-3t were
obtained in excellent yields. Notably, carbonꢀhalogen bonds of the substrates remained intact
during all the reactions, providing an additional handle for further derivatization. In order to
investigate the practicability of this method, a synthesis of 3a could be scalable from 0.2
mmol to 10 mmol with a 90% yield, which indicated that this method could be widely applied
in organic synthesis.
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Table 4. The Substrate Scope of 2-Aminobenzamidesa
a Reaction conditions: 4 (0.2 mmol), 2a (TMEDA, 0.4 mmol), I2 (0.04 mmol), DMSO (1 mL),
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O2 (1 atm), 120 °C, 20 h.
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We next expected to utilize this novel approach for the synthesis of quinazolinones (Table
4). To our delight, the reaction of 2ꢀaminoꢀNꢀphenylbenzamide (4a) with TMEDA under
standard conditions gave the desired 3ꢀphenylquinazolinꢀ4(3H)ꢀone (5a) in 78% isolated
yield. Similarly, 2ꢀaminoꢀNꢀalkylbenzamide 4b-4e also afforded the corresponding products
5b-5e in moderate (48%ꢀ62%) yield. Unfortunately, none of the desired product 5f was
formed when 2ꢀaminobenzamide (4f) was used as substrate.
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To gain insight into the mechanistic aspects of the reaction, several control experiments
were carried out (Scheme 2). Firstly, radical trapping experiments were carried out where it
was observed that the reaction was not inhibited at all in the presence of
2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy (TEMPO) as a radical scavenger (Scheme 2a). This
observation implied that the reaction might not proceed viaundergo a radical pathway, which
is in contrast to our previous work.3aꢀ3c According to Li’s report,5a HCHO was possibly
generated as the an intermediate. However, when the reaction was completed, the mixture was
still exhibited a brown color due to the presence of iodine. The presence of HCHO could not
be detected by the Nash test on the basis of a color change.
Scheme 2. Control Experiments and 15N-labeling Experiment
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I2 (20 mol%)
O2 (balloon)
TEMPO (1 equiv)
1a
(a)
(b)
2a
+
3a
NH4Cl (2 equiv)
DMSO
120°C, 20 h
99%
H2
C
H
C
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I2 (20 mol%)
O2 (balloon)
Ac
Ac
Ac
Ac
O
O
+
2a
+
NH4Cl (2 equiv)
DMSO
120°C, 20 h
N
H
N
7a, n.d.
7b, n.d.
6
Ph
I2 (20 mol%)
O2 (balloon)
15NH4Cl (2 equiv)
DMSO
N15
(c)
1a
+
2a
CH
N
120°C, 20 h
15N-3a, 99%
Scheme 3. A Proposed Mechanism
A similar reaction was performed by replacing 1a with 6 under standard conditions (Scheme
2b). Neither Nash product 7a nor its oxidation product 7b were detected, indicating an
absence of intermediate HCHO. Moreover, a 15Nꢀlabeling experiment was also carried out,
affording 15N-3a in 99% yield, which unambiguously established that the nitrogen atom of
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quinazolines was derived from NH4Cl, rather than TMEDA (Scheme 2c).
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On the basis of results described above and previous reports,3,5, 6, 10a plausible mechanism is
proposed for the formation of the quinazolines (Scheme 3). Initially, the reaction of TMEDA
with iodine gives an aminium iodide A, and then generates an iminium iodide B by removing
one molecular HI.11 Subsequently, nucleophilic addition of 1a to B provides an intermediate
C by removal of another molecular HI. The intermediate D could be formed via an elimination
of C. Then through nucleophilic addition of ammonia, D is transformed into an addition
intermediate E. Finally, 3a is obtained via a tandem condensationꢀoxidation process of E.
Notably, two molecular HI generated in situ, are oxidized by oxygen to regenerate iodine to
complete the I2/Iꢀ catalytic cycle.
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CONCLUSIONS
We have developed an iodineꢀcatalyzed aerobic domino reaction for the synthesis of
quinazolines and quinazolinones. Two CꢀN bonds are formed in a oneꢀpot process via
CꢀH/CꢀN cleavage. The additional carbon atom of heterocycles originates from Nꢀmethyl
moiety of TMEDA. This novel approach is 1) metalꢀfree; 2) peroxideꢀfree; 3) operationally
simple; 4) a broad substrate scope which distinguishes it from other known quinazoline and
quinazolinone syntheses. Further studies are ongoing to expand the synthetic utility of this
versatile catalytic system.
EXPERIMENTAL SECTION
Unless otherwise indicated, all commercial reagents and solvents were used without additional
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purification. Chemical shifts (in ppm) of 1HꢀNMR spectra were referenced to tetramethylsilane (δ
= 0 ppm) in CDCl3 as an internal standard. 13CꢀNMR spectra were calibrated with CDCl3 (δ =
7
8
9
77.00 ppm). HRMS (EI) was recorded on a TOF mass analyzer
.
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Preparation of Substrates
Substrates 1a, 1r, 1t, 2 and 4f are commercially available. Other substrates 1 and 4 were
prepared using previously reported literature procedures.4g, 12
Synthesis of 4a12
Isatoic anhydride (815 mg, 5 mmol) was dissolved in EtOH (10 mL) with aniline (916 ꢁL, 5
mmol) and I2 (127 mg, 0.5 mmol). The mixture was stirred under reflux overnight. After cooling,
the reaction mixture was concentrated in vacuo, diluted with EtOAc, washed with saturated aq
Na2S2O3, washed with brine and dried over anhydrous Na2SO4. The organic phase was
concentrated in vacuum and purified by chromatographic column on silica gel, giving
2ꢀaminoꢀNꢀphenylbenzamide (4a) as a light yellow solid (742 mg, 70% yield).
Synthesis of 4b-4e12
Isatoic anhydride (815 mg, 5 mmol) in DMF was treated with benzylamine (547 ꢁL, 5 mmol) at
50ꢀ60 °C for 1 h. After the completion, the mixture was washed with H2O and extracted with
EtOAc. The organic layer was dried over anhydrous Na2SO4, concentrated in vacuum under
reduced pressure and purified by chromatographic column on silica gel, giving 2ꢀaminoꢀNꢀ
(phenylmethyl)ꢀBenzamide (4b) as a white solid (1.1 g, 98 % yield)..
4c-4e was synthesized according to the procedure for 4b.
General Procedure for the Synthesis of Quinazolines and Quinazolinones
Substrate 1 (0.2 mmol), I2 (11.6 mg, 20 mol%), NH4Cl (21.4 mg, 0.4 mmol), Nꢀmethylamines 2
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(0.4 mmol) and DMSO (1.0 mL) were successively added to a 10 mL of thick wall pressure
reaction tube with threeꢀway valve. After oxygen displacement, the mixture was stirred using
oxygen balloon at 120 °C as monitored by TLC. The solution was then cooled to r.t., diluted with
EtOAc (5 mL), washed with brine. The aqueous layers was extracted with EtOAc (3x10 mL), the
combined organic layers were dried over Na2SO4, filtered, and evaporated under vaccum. The
residue was purified bycolumn chromatography on silica gel (petroleum ether : ethyl acetate = 3:1)
to afford the desired quinazolines 3.
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Experimental procedure for quinazolinones 5 was similar to the procedure for 3 without adding
NH4Cl.
Characterization Data for the Products
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4-phenylquinazoline (3a)3b: Yield 97% (40 mg). Light yellow solid. m.p. 95–97 ºC. H NMR
(400 MHz, CDCl3) δ (ppm) 9.39 (s, 1 H, N=CHꢀN or 2ꢀArꢀH), 8.13 (d, J = 8.8 Hz, 2 H, 5,8ꢀArꢀH),
7.95ꢀ7.90 (m, 1 H, 7ꢀArꢀH), 7.82ꢀ7.76 (m, 2 H, 2’,6’ꢀPhꢀH), 7.64ꢀ7.56 (m, 4 H, 6ꢀArꢀH and
3’,4’,5’ꢀPhꢀH). 13C NMR (100 MHz, CDCl3) δ (ppm) 168.5 (C=N), 154.5 (N=CHꢀN), 150.9 (C),
137.0 (C), 133.7 (CH), 130.1 (CH), 129.9 (CH), 128.8 (CH), 128.6 (CH), 127.7 (CH), 127.1 (CH),
123.1 (C).
4-(4-fluorophenyl)quinazoline (3b)3b: Yield 98% (43.9 mg). Light yellow solid. m.p. 91–93 ºC.
1H NMR (400 MHz, CDCl3) δ (ppm) 9.37 (s, 1 H, N=CHꢀN), 8.13 (dd, J1 = 13.2 Hz, J2 = 8.4 Hz,
2 H, 5,8ꢀArꢀH), 7.96ꢀ7.91 (m, 1 H, 7ꢀArꢀH), 7.83ꢀ7.79 (m, 2 H, 2’,6’ꢀPhꢀH), 7.67ꢀ7.62 (m, 1 H,
6ꢀArꢀH), 7.31ꢀ7.26 (m, 2 H, 3’,5’ꢀPhꢀH). 13C NMR (100 MHz, CDCl3) δ (ppm) 167.3 (C=N),
164.0 (d, JCꢀF = 249.3 Hz, CꢀF), 154.5 (N=CHꢀN), 151.0 (C), 133.8 (CH), 133.2 (d, JCꢀF = 3.1 Hz,
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C), 132.0 (d, JCꢀF = 8.6 Hz, CH), 128.9 (CH), 127.9 (CH), 126.7 (CH), 123.0 (C), 115.8 (d, JCꢀF
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21.7 Hz, CH).
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4-(4-chlorophenyl)quinazoline (3c)3b: Yield 96% (46.1 mg). Light yellow solid. m.p. 116–118 ºC.
1H NMR (400 MHz, CDCl3) δ(ppm) 9.38 (s, 1 H, N=CHꢀN), 8.14ꢀ8.07 (m, 2 H, 5,8ꢀArꢀH),
7.96ꢀ7.91 (m, 1 H, 7ꢀArꢀH), 7.79ꢀ7.71 (m , 2 H, 2’.6’ꢀPhꢀH), 7.66ꢀ7.62 (m, 1 H, 6ꢀArꢀH),
7.58ꢀ7.55 (m, 2 H, 3’,5’ꢀPhꢀH). 13C NMR (100 MHz, CDCl3) δ (ppm) 167.1 (C=N), 154.6
(N=CHꢀN), 151.1 (C), 136.4 (CꢀCl), 135.5 (C), 133.8 (CH), 131.3 (CH), 129.0 (CH), 128.9 (CH),
127.9 (CH), 126.6 (CH), 122.9(C).
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4-(4-bromophenyl)quinazoline (3d)3b: Yield 95% (54 mg). Light yellow solid. m.p. 152–154 ºC.
1H NMR (400 MHz, CDCl3) δ (ppm) 9.38 (s, 1 H, N=CHꢀN), 8.16ꢀ8.07 (m, 2 H, 5,8ꢀArꢀH),
7.96ꢀ7.91 (m, 1 H, 7ꢀArꢀH), 7.75ꢀ7.61 (m, 5 H, 6ꢀArꢀH and PhꢀH). 13C NMR (100 MHz, CDCl3) δ
(ppm) 167.2 (C=N), 154.5 (N=CHꢀN), 151.1 (C), 135.9 (C), 133.9 (CH), 131.9 (CH), 131.5 (CH),
129.0 (CH), 128.0 (CH), 126.6 (CH), 124.8 (CꢀBr), 122.9 (C).
4-(3,5-difluorophenyl)quinazoline (3e)3b: Yield 97% (47 mg). Light yellow solid. m.p. 100–102
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ºC. H NMR (400 MHz, CDCl3) δ (ppm) 9.39 (s, 1 H, N=CHꢀN), 8.15 (d, J = 8.4 Hz, 1 H,
8ꢀArꢀH), 8.11ꢀ8.07 (m, 1 H, 5ꢀArꢀH), 7.98ꢀ7.93 (m, 1 H, 7ꢀArꢀH), 7.69ꢀ7.64 (m, 1 H, 6ꢀArꢀH),
7.36ꢀ7.30 (m, 2 H, 2’,6’ꢀPhꢀH), 7.07ꢀ7.00 (m, 1 H, 4’ꢀPhꢀH). 13C NMR (100 MHz, CDCl3) δ (ppm)
165.7 (t, JCꢀF = 2.6 Hz, C=N), 164.2 (dd, JCꢀF1 = 249.1 Hz, JCꢀF2 = 12.4 Hz, CꢀF1 and CꢀF2), 154.5
(N=CHꢀN), 151.2(C), 140.1 (t, JCꢀF = 9.2 Hz, C), 134.1 (CH), 129.2 (CH), 128.3 (CH), 126.1 (CH),
122.6 (C), 113.1 (dd, JCꢀF1 = 18.9 Hz, JCꢀF2 = 7.5 Hz, CHꢀCF1 and CHꢀCF2), 105.4 (t, JCꢀF = 25.0
Hz, CF1ꢀCHꢀCF2).
4-(3-chlorophenyl)quinazoline (3f)3b: Yield 96% (46.1 mg). Light yellow solid. m.p. 81–83 ºC.
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1H NMR (400 MHz, CDCl3) δ (ppm) 9.38 (s, 1 H, N=CHꢀN), 8.14 (d, J = 8.4 Hz, 1 H, 8ꢀArꢀH),
8.10ꢀ8.07 (m, 1 H, 5ꢀArꢀH), 7.97ꢀ7.91 (m, 1 H, 7ꢀArꢀH), 7.79 (t, J = 1.6 Hz, 1 H, 6ꢀArꢀH),
7.68ꢀ7.62 (m, 2 H, 2’,6’ꢀPhꢀH), 7.58ꢀ7.49 (m, 2 H, 4’,5’ꢀPhꢀH). 13C NMR (100 MHz, CDCl3) δ
(ppm) 166.8 (C=N), 154.5 (N=CHꢀN), 151.1 (C), 138.8 (CꢀCl), 134.7 (C), 133.9 (CH), 130.1
(CH), 129.88 (CH), 129.86 (CH), 129.0 (CH), 128.1 (CH), 128.0 (CH), 126.5 (CH), 122.9 (C).
4-(p-tolyl)quinazoline (3g)3b: Yield 98% (43.1 mg). Light yellow solid. m.p. 32–34 ºC. 1H NMR
(400 MHz, CDCl3) δ (ppm) 9.37 (s, 1 H, N=CHꢀN), 8.18ꢀ8.09 (m, 2 H, 5,8ꢀArꢀH), 7.93ꢀ7.88 (m, 1
H, 7ꢀArꢀH), 7.70 (dd, J1 =6.4 Hz, J2 = 1.6 Hz, 2 H, 2’,6’ꢀPhꢀH), 7.63ꢀ7.58 (m, 1 H, 6ꢀArꢀH), 7.39
(d, J = 8.0 Hz, 2 H, 3’,5’ꢀPhꢀH), 2.48 (s, 3 H, CH3). 13C NMR (100 MHz, CDCl3) δ (ppm) 168.4
(C=N), 154.7 (N=CHꢀN), 151.1 (C), 140.3 (C), 134.3 (C), 133.6 (CH), 130.0 (CH), 129.3 (CH),
128.9 (CH), 127.6 (CH), 127.2 (CH), 123.2 (C), 21.4 (CH3).
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4-(m-tolyl)quinazoline (3h)3b: Yield 96% (42.3 mg). Yellow oil. H NMR (400 MHz, CDCl3) δ
(ppm) 9.38 (s, 1 H, N=CHꢀN), 8.15ꢀ8.09 (m, 2 H, 5,8ꢀArꢀH), 7.93ꢀ7.88 (m, 1 H, 7ꢀArꢀH),
7.62ꢀ7.54 (m, 3 H, 6ꢀArꢀH and 2’,6’ꢀPhꢀH), 7.45 (t, J = 7.6 Hz, 1 H, 5’ꢀPhꢀH), 7.39 (d, J = 7.6 Hz,
1 H, 4’ꢀPhꢀH), 2.48 (s, 3 H, CH3). 13C NMR (100 MHz, CDCl3) δ (ppm) 168.5 (C=N), 154.6
(N=CHꢀN), 151.0 (C), 138.5 (C), 137.0 (C), 133.6 (CH), 130.7 (CH), 130.4 (CH), 128.8 (CH),
128.3 (CH), 127.6 (CH), 127.14 (CH), 127.08 (CH), 123.2 (C), 21.4 (CH3).
4-(naphthalen-2-yl)quinazoline (3j)3b: Yield 99% (50.7 mg). Yellow solid. m.p. 133–135 ºC. 1H
NMR (400 MHz, CDCl3) δ (ppm) 9.43 (s, 1 H, N=CHꢀN), 8.26 (d, J = 1.6 Hz, 1 H, 1’ꢀNapꢀH),
8.21ꢀ8.13 (m, 2 H, 5,8ꢀArꢀH ), 8.03 (d, J = 8.8 Hz, 1 H, 7ꢀArꢀH), 7.96ꢀ7.87 (m, 4 H,
3’4’,5’,8’ꢀNapꢀH), 7.62ꢀ7.54 (m, 3 H, 6ꢀArꢀH and 6’,7’ꢀNapꢀH). 13C NMR (100 MHz, CDCl3) δ
(ppm) 168.3 (C=N), 154.6 (N=CHꢀN), 151.1 (C), 134.4 (C), 133.9 (C), 133.7, 132.8 (C), 130.2
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(CH), 128.9 (CH), 128.6 (CH), 128.4 (CH), 127.8 (CH), 127.3 (CH), 127.1 (CH), 126.8 (CH),
126.7 (CH), 123.3 (C).
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4-(tert-butyl)quinazoline (3k)3b: Yield 85% (31.6 mg). Yellow oil. 1H NMR (400 MHz, CDCl3) δ
(ppm) 9.23 (s, 1 H, N=CHꢀN), 8.47 (dd, J1 = 8.8 Hz, J2 = 0.8 Hz, 1 H, 8ꢀArꢀH), 8.07 (dd, J1 = 8.8
Hz, J2 = 0.8 Hz, 1 H, 5ꢀArꢀH), 7.85ꢀ7.80 (m, 1 H, 7ꢀArꢀH), 7.61ꢀ7.56 (m, 1 H, 6ꢀArꢀH), 1.66 (s, 9
H, 3CH3). 13C NMR (100 MHz, CDCl3) δ (ppm) 176.8 (C=N), 153.7 (N=CHꢀN), 151.0 (C), 132.4
(CH), 130.1 (CH), 126.5 (CH), 126.2 (CH), 123.1 (C), 40.0 (C), 30.7 (CH3).
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4-isopropylquinazoline (3l)3b: Yield 82% (28.2 mg). Yellow oil. H NMR (400 MHz, CDCl3) δ
(ppm) 9.23 (s, 1 H, N=CHꢀN), 8.18 (d, J = 8.4 Hz, 1 H, 8ꢀArꢀH), 8.05 (d, J = 8.4 Hz, 1 H, 5ꢀArꢀH),
7.90ꢀ7.85 (m, 1 H, 7ꢀArꢀH), 7.66ꢀ7.61 (m, 1 H, 6ꢀArꢀH), 3.94 (h, J = 6.8 Hz, 1 H, CH), 1.45 (d, J
= 6.8 Hz, 6 H, 2CH3). 13C NMR (100 MHz, CDCl3) δ (ppm) 175.8 (C=N), 154.7 (N=CHꢀN),
150.0 (C), 133.2 (CH), 129.3 (CH), 127.3 (CH), 124.1 (CH), 123.1 (C), 30.9 (CH), 21.7 (CH3).
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4-cyclopentylquinazoline (3m,)3b: Yield 71% (27.7 mg).Yellow oil. H NMR (400 MHz, CDCl3)
δ (ppm) 9.23 (s, 1 H, N=CHꢀN), 8.21 (d, J = 8.4 Hz, 1 H, 8ꢀArꢀH), 8.04 (d, J = 8.4 Hz, 1 H,
5ꢀArꢀH), 7.90ꢀ7.65 (m, 2 H, 6,7ꢀArꢀH), 4.05ꢀ4.00 (m, 1 H, CH), 2.22ꢀ2.10 (m, 4 H, 2CH2),
1.94ꢀ1.91 (m, 2 H, CH2), 1.80ꢀ1.78 (m, 2 H, 2CH2). 13C NMR (100 MHz, CDCl3) δ (ppm) 174.7
(C=N), 154.7 (N=CHꢀN), 149.8 (C), 133.3 (CH), 129.1 (CH), 128.3 (CH), 127.3 (CH), 124.6 (C),
42.4 (CH), 32.7 (CH2), 26.2 (CH2).
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4-butylquinazoline (3o): Yield 35% (13 mg). Yellow oil. H NMR (400 MHz, CDCl3) δ (ppm)
9.22 (s, 1 H, N=CHꢀN), 8.15 (d, J = 8.4 Hz, 1 H, 8ꢀArꢀH), 8.04 (d, J = 8.4 Hz, 1 H, 5ꢀArꢀH),
7.91ꢀ7.86 (m, 1 H, 7ꢀArꢀH), 7.67ꢀ7.64 (m, 1 H, 6ꢀArꢀH), 3.29 (t, J = 8.0 Hz, 2 H, CH2), 1.91ꢀ1.85
(m, 2 H, CH2), 1.54ꢀ1.48 (m, 2 H, CH2), 1.00 (t, J = 7.6 Hz, 3 H, CH3). 13C NMR (100 MHz,
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CDCl3) δ (ppm) 171.8 (C=N), 154.6 (N=CHꢀN), 149.9 (C), 133.5 (CH), 129.2 (CH), 127.5 (CH),
124.7 (CH), 124.0 (C), 34.4 (CH2), 31.1 (CH2), 22.9 (CH2), 13.9 (CH3). HRMS (EI) m/z calc.
C12H14N2: 186.1157, found: 186.1145.
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4-hexadecylquinazoline (3p):Yield 25% (17.7 mg). Yellow solid. m.p. 48–50 ºC. 1H NMR (400
MHz, CDCl3) δ (ppm) 9.22 (s, 1 H, N=CHꢀN), 8.14 (dd, J1 = 8.4 Hz, J2 = 0.8 Hz, 1 H, 8ꢀArꢀH),
8.04 (d, J = 8.8 Hz, 1 H, 5ꢀArꢀH), 7.91ꢀ7.86 (m, 1 H, 7ꢀArꢀH), 7.66ꢀ7.62 (m, 1 H, 6ꢀArꢀH), 3.27 (t,
J = 8.0 Hz, 2 H, CH2), 1.91ꢀ1.86 (m, 2 H, CH2), 1.50ꢀ1.45 (m, 2 H, CH2), 1.41ꢀ1.35 (m, 2 H, CH2),
1.35ꢀ1.24 (m, 22 H, ꢀ(CH2)11ꢀ), 0.88 (t, J = 6.8 Hz, 3 H, CH3). 13C NMR (100 MHz, CDCl3) δ
(ppm) 171.8 (C=N), 154.6 (N=CHꢀN), 149.9 (C), 133.5 (CH), 129.2 (CH), 127.4 (CH), 124.7
(CH), 124.0 (CH), 34.7 (CH2), 31.9 (CH2), 29.74 (CH2), 29.67 (CH2), 29.63 (CH2), 29.60 (CH2),
29.5 (CH2), 29.4 (CH2), 29.3 (CH2), 29.1 (CH2), 22.7 (CH2), 14.1 (CH3). HRMS (EI) m/z calc.
C24H38N2: 354.3035, found: 354.3027.
6-chloroquinazoline (3q)3b: Yield 32% (10.5 mg). Light yellow solid. m.p. 140–142 ºC. 1H NMR
(400 MHz, CDCl3) δ (ppm) 9.37 (s, 1 H, 4ꢀArꢀH), 9.35 (s, 1 H, 2ꢀArꢀH), 8.02 (d, J = 8.8 Hz, 1 H,
8ꢀArꢀH), 7.94 (d, J = 2.0 Hz, 1 H, 5ꢀArꢀH), 7.87 (dd, J1 = 8.8 Hz, J2 = 2.0 Hz, 1 H, 7ꢀArꢀH). 13
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NMR (100 MHz, CDCl3) δ (ppm) 159.3 (CH=N), 155.5 (N=CHꢀN), 148.5 (C), 135.2 (CH), 133.7
(CꢀCl), 130.3 (CH), 125.8 (CH), 125.6 (C).
6-chloro-4-phenylquinazoline (3r)3b: Yield 98% (47 mg). Light yellow solid. m.p. 134–136 ºC.
1H NMR (400 MHz, CDCl3) δ (ppm) 9.38 (s, 1 H, N=CHꢀN), 8.11 (d, J = 2.0 Hz, 1 H, 5ꢀArꢀH),
8.08 (d, J = 9.2 Hz, 1 H, 8ꢀArꢀH), 7.85 (dd, J1 = 9.2 Hz, J2 = 2.4 Hz, 1 H, 7ꢀArꢀH), 7.79ꢀ7.74 (m, 2
H, 2’,6’ꢀPhꢀH), 7.63ꢀ7.58 (m, 3 H, 3’,4’,5’ꢀPhꢀH). 13C NMR (100 MHz, CDCl3) δ (ppm) 167.7
(C=N), 154.8 (N=CHꢀN), 149.5 (C), 136.5 (C), 134.7 (CH), 133.5 (CꢀCl), 130.6 (CH), 130.4 (CH)
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129.8 (CH), 128.8 (CH), 125.8 (CH), 123.7 (C).
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6-bromo-4-phenylquinazoline (3s)3b: Yield 96% (54.5 mg). Light yellow solid. m.p. 144–146 ºC.
1H NMR (400 MHz, CDCl3) δ (ppm) 9.39 (s, 1 H, N=CHꢀN), 8.28 (d, J = 1.2 Hz, 1 H, 5ꢀArꢀH),
8.00ꢀ7.96 (m, 2 H, 7,8ꢀArꢀH), 7.79ꢀ7.74 (m, 2 H, 2’,6’ꢀPhꢀH), 7.63ꢀ7.58 (m, 3 H, 3’,4’,5’ꢀPhꢀH).
13C NMR (100 MHz, CDCl3) δ (ppm) 167.6 (C=N), 154.8 (N=CHꢀN), 149.7 (C), 137.3 (CH),
136.5 (C), 130.7 (CH), 130.4 (CH), 129.9 (CH), 129.2 (CH), 128.9 (CH), 124.2 (C), 121.6 (CꢀBr).
6-nitro-4-phenylquinazoline (3t)3b: Yield 82% (41.2 mg). Light yellow solid. m.p. 130–132 ºC.
1H NMR (400 MHz, CDCl3) δ (ppm) 9.52 (s, 1 H, N=CHꢀN), 9.08 (d, J = 2.4 Hz, 1 H, 5ꢀArꢀH),
8.67 (dd, J1 = 9.2 Hz, J2 = 2.8 Hz, 1 H, 7ꢀArꢀH), 8.27 (d, J = 9.2 Hz, 1 H, 8ꢀArꢀH), 7.84ꢀ7.81 (m, 2
H, 2’,6’ꢀPhꢀH), 7.68ꢀ7.62 (m, 3 H, 3’,4’,5’ꢀPhꢀH). 13C NMR (100 MHz, CDCl3) δ (ppm) 170.5
(C=N), 157.2 (N=CHꢀN), 153.4 (C), 146.0 (CꢀNO2), 135.8 (C), 131.07 (CH), 131.05 (CH), 130.1
(CH), 129.1 (CH), 127.0 (CH), 124.1 (CH), 122.0 (C).
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3-phenylquinazolin-4(3H)-one (5a)13: Yield 78% (34.6 mg).Yellow solid. m.p. 138–140 ºC. H
NMR (400 MHz, CDCl3) δ (ppm) 8.38ꢀ8.35 (m, 1H, 5ꢀArꢀH), 8.15 (s, 1H, N=CHꢀN), 7.83ꢀ7.76
(m, 2H, 7,8ꢀArꢀH), 7.58ꢀ7.42 (m, 6H, 6ꢀArꢀH and PhꢀH). 13C NMR (100 MHz, CDCl3) δ (ppm)
160.7 (C=O), 147.8 (C), 146.0 (N=CHꢀN), 137.4 (C), 134.6 (CH), 129.6 (CH), 129.1 (CH), 127.6
(CH), 127.5 (CH), 127.2 (CH), 127.0 (CH), 122.4 (C).
3-benzylquinazolin-4(3H)-one (5b)13: Yield 62% (29.3 mg). Light yellow solid. m.p. 120–121 ºC.
1H NMR (400 MHz, CDCl3) δ (ppm) 8.33 (dd, J1 = 8.0 Hz, J2 = 0.8 Hz, 1H, 5ꢀArꢀH), 8.18 (s, 1H,
N=CHꢀN), 7.79ꢀ7.71 (m, 2H, 7,8ꢀArꢀH), 7.54ꢀ7.49 (m, 1H, 6ꢀArꢀH), 7.38ꢀ7.26 (m, 5H, PhꢀH),
5.21 (s, 2H, CH2). 13C NMR (100 MHz, CDCl3) δ (ppm) 160.9 (C=O), 147.6 (C), 146.4
(N=CHꢀN), 135.6 (C), 134.3 (CH), 129.0 (CH), 128.3 (CH), 128.0 (CH), 127.4 (CH), 127.2 (CH),
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3-butyl-quinazolin-4(3H)-one (5c)14: Yield 55% (22.2 mg). Light yellow solid. 71–73 ºC H
NMR (400 MHz, CDCl3) δ (ppm) 8.32 (dd, J1 = 8.0 Hz, J2 = 0.8 Hz, 1H, 5ꢀArꢀH), 8.09 (s, 1H,
N=CHꢀN), 7.79ꢀ7.71 (m, 2H, 7,8ꢀArꢀH), 7.54ꢀ7.28 (m, 1H, 6ꢀArꢀH), 4.02 (t, J = 7.4 Hz, 2H, CH2),
1.83ꢀ1.75 (m, 2H, CH2), 1.46ꢀ1.39 (m, 2H, CH2), 0.98 (t, J = 7.4 Hz, 3H, CH3). 13C NMR (100
MHz, CDCl3) δ (ppm) 160.9 (C=O), 147.6 (C), 146.7 (N=CHꢀN), 134.2 (CH), 127.3 (CH), 127.1
(CH), 126.7 (CH), 122.0 (C), 46.9 (CH2), 31.4 (CH2)., 19.8 (CH2)., 13.6 (CH3)..
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3-isopropylquinazolin-4(3H)-one (5d)13: Yield 56% (21 mg). Yellow solid. 91–93 ºC 1H NMR
(400MHz, CDCl3) δ (ppm) 8.32 (dd, J1 = 8.0 Hz, J2 = 0.8 Hz, 1H, 5ꢀArꢀH), 8.13 (s, 1H, N=CHꢀN),
7.78ꢀ7.69 (m, 2H, 7,8ꢀArꢀH), 7.53ꢀ7.48 (m, 1H, 6ꢀArꢀH), 5.20 (h, J = 6.8 Hz, 1H, CH), 1.50 (d, J
= 6.8 Hz, 6H, 2CH3). 13C NMR (100 MHz, CDCl3) δ (ppm) 160.6 (C=O), 147.5 (C), 143.5
(N=CHꢀN), 134.1 (CH), 127.2 (CH), 127.1 (CH), 126.8 (CH), 121.9 (C), 46.0 (CH), 22.0 (CH3).
3-(tert-butyl)quinazolin-4(3H)-one (5e)13: Yield 48% (19.4 mg). Light yellow solid. 66–68 ºC. 1H
NMR (400MHz, CDCl3) δ (ppm) 8.43 (s, 1H, N=CHꢀN), 8.30 (d, J = 8.0 Hz, 1H, 5ꢀArꢀH),
7.76ꢀ7.74 (m, 2H, 7,8ꢀArꢀH), 7.53ꢀ7.49 (m, 1H, 6ꢀArꢀH), 1.78 (s, 9H, 3CH3). 13C NMR (100 MHz,
CDCl3) δ (ppm) 161.9 (C=O), 147.1 (C), 144.0 (N=CHꢀN), 133.9 (CH), 126.9 (CH), 126.64 (CH),
126.62 (CH), 123.0 (C), 60.8 (C), 28.6 (CH3).
15N-labeling Experiment
15NꢀAmmounium chloride (15N, 99%, No. NLMꢀ467ꢀ1) was purchased from Cambridge Isotope
Laboratories, Inc without further purification.
Substrate 1 (0.2 mmol), I2 (11.6 mg, 20 mol%), 15NH4Cl (21.8 mg, 0.4 mmol), TMEDA (60 ꢁL,
0.4 mmol) and DMSO (1.0 mL) were successively added to a 10 mL of reaction tube with
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threeꢀway valve. After oxygen displacement, the mixture was stirred using oxygen balloon at
120 °C as monitored by TLC. The solution was then cooled to r.t., diluted with EtOAc (5 mL),
washed with brine. The aqueous layers was extracted with EtOAc (3x10 mL), the combined
organic layers were dried over Na2SO4, filtered, and evaporated under vaccum. The residue was
purified bycolumn chromatography on silica gel (petroleum ether : ethyl acetate = 3:1) to afford
the desired product 15N-3a (41mg, 99% yield).
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3-15N-4-phenylquinazoline (15N-3a): Light yellow solid. m.p. 85–87 ºC. H NMR (400 MHz,
CDCl3) δ (ppm) 9.39 (d, J = 14.8 Hz, 1H, N=CHꢀ15N), 8.16ꢀ8.12 (m, 2 H, 5,8ꢀArꢀH), 7.95ꢀ7.90 (m,
1 H, 7ꢀArꢀH), 7.82ꢀ7.76 (m, 2 H, 2’,6’ꢀPhꢀH), 7.64ꢀ7.57 (m, 4 H, 6ꢀArꢀH and 3’,4’,5’ꢀPhꢀH). 13
C
NMR (100 MHz, CDCl3) δ (ppm) 168.4 (C=N), 154.4 (d, J = 4.3 Hz, N=CHꢀ15N), 150.9 (d, J =
3.1 Hz, C), 136.9 (d, J = 7.1 Hz, C), 133.7 (CH), 130.1 (CH), 129.9 (d, J = 1.7 Hz, CH), 128.7
(CH), 128.6 (CH), 127.7 (CH), 127.1 (CH), 123.1 (d, J = 1.4 Hz, C). HRMS (EI) m/z calc.
C14H10N15N: 207.0814, found: 207.0804.
ASSOCIATED CONTENT
Supporting Information Available. 1H ,13C NMR and HRMS spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENT
We are grateful to the National Natural Science Foundation of China (21376228), Science and
Technology Research Key Project of Department of Education of Henan Province
(15A150005) and the Doctoral Research Foundation of Zhengzhou University of Light
Industry (2014BSJJ032).
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