Base-Promoted Synthesis of 2-Aryl Quinazolines from 2

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Base-Promoted Synthesis of 2-Aryl Quinazolines from 2-Aminobenzylamines in Water Tanmay Chatterjee, Dong In Kim, and Eun Jin Cho J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00327 • Publication Date (Web): 12 Apr 2018 Downloaded from http://pubs.acs.org on April 13, 2018

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The Journal of Organic Chemistry

Base-Promoted Synthesis of 2-Aryl Quinazolines from 2Aminobenzylamines in Water Tanmay Chatterjee,a Dong In Kim,b and Eun Jin Cho*,b a

Department of Chemistry

Birla Institute of Technology & Science, Pilani, Hyderabad Campus Jawahar Nagar, Shameerpet Mandal, Hyderabad, Telangana 500078, India. b

Department of Chemistry, Chung-Ang University

84 Heukseok-ro, Dongjak-gu, Seoul 06974, Republic of Korea. *E-mail: [email protected]

Abstract

A transition-metal free procedure for the synthesis of a highly valuable class of heteroaromatics, quinazolines, was developed by using easily available 2-aminobenzylamines and α,α,α-trihalotoluenes. The transformation proceeded smoothly in the presence of only sodium hydroxide and molecular oxygen in water at 100 °C, furnishing a variety of 2-aryl quinazolines. The crystallization process of the crude reaction mixture for the purification of the

solid

products circumvents

huge

solvent

consuming

work-up

and

column

chromatographic techniques, which make the overall process more sustainable and economical.

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Introduction

The interest of organic chemists in developing green methodologies for the synthesis of useful organic molecules has continued to increase.1 A reaction is considered ideal if it proceeds in a green reaction medium in the presence of benign reagents without the use of hazardous organic solvents, metal complexes and reagents, and also produces minimum or benign waste.1 The metal-free approach in organic synthesis is always more economical and is preferred over metal-mediated/catalyzed reactions that suffer from disadvantages such as the high cost of metal complexes and the possibility of toxic metal contamination in the final product; the latter restricts the use of such products in biological applications as pharmaceuticals. Hence, a huge number of metal-free synthetic methodologies has been developed over the past decades and the number continues to increase.2

Quinazoline is one of the highly valuable classes of fused heteroaromatics that is prevalent in numerous bioactive natural products, alkaloids, and life-saving synthetic pharmaceuticals. This scaffold is associated with anticancer, antituberculosis, antihypertensive, anticonvulsant, antibacterial, anti-inflammatory, and antimalarial properties (Figure 1).3


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Figure 1. Examples of pharmaceuticals having the quinazoline core structure.

Because of their great importance, a wide variety of synthetic methodologies4−18 have been developed for the synthesis of quinazolines, including copper-catalyzed Ullman-type coupling followed by oxidation of o-bromobenzylamines or o-bromobenzyl (pseudo)halides with amides or amidines [Scheme 1(A)]5 and the oxidative cyclization of arylamidines6 with one carbon synthons,6a aldehyde equivalents,6b,6c,6d or functionalized alkynes6d [Scheme 1(B)]. Quinazolines can also be generated by the reaction of benzimidates with dioxazolones,7 and the reaction of o-aminoaryl- or o-haloaryl carbonyl equivalents such as aldehydes, ketones, imines, and methanols with amines8 or amide equivalents such as nitriles,9 or ammonia equivalents in the presence of carbon sources such as aldehydes10 and DMA11 [Scheme 1(C)]. These species can also be produced by condensation of oaminobenzylamines with carbonyl equivalents such as aldehydes,12 ketones,13 alcohols,14 carboxylic acids,15 nitriles,16 or imine equivalents such as benzylamines17 or CO/ArBr18 [Scheme 1(D)]. Despite the significant advancements, many of these methods suffer from one or several drawbacks such as harsh reaction conditions and the use of hazardous and/or expensive transition metal complexes, ligands, additives, base, oxidants, and solvents, which can lead to the production of hazardous waste and metal contamination of the final product.4−18 Hence the development of greener synthetic methodologies for the synthesis of ACS Paragon Plus Environment


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quinazolines is still desirable. As a part of our continuing interest in the synthesis of valuable heteroaromatics,19 herein, we develop a sustainable methodology for the synthesis of 2-aryl quinazolines from easily available o-aminobenzylamines and α,α,α-trihalotoluenes20 by using only sodium hydroxide and molecular oxygen in water in the absence of any transition metal complex, ligand, chemical oxidant, or additive [Scheme 1(E)].

Scheme 1. Strategies for the Synthesis of Quinazolines

Previous work (A)

Cu-cat. additive, base

Y

X

R1

+

2

NH2

R Br X = NH2; Y = O X = Br, OTs; Y = NH

N

R1

O2, solvent

N

R2

(B) one carbon synthon

NH

R1

2

N H or

R

R2

N

R CHO

R3

Y

O

R3 R2

R1

= R4CHO, (HCHO) n, RCH2OH, R

4

or Nitrogen and carbon sources

TIPS R5

Pd, Rh, Co, Cu-cat. or organocatalyst ligand, additive

O

N O or R CH2NH2

+ X

X = H; Y = NH X = NH2; Y = O X = I, Br; Y = O

R2

N

one carbon = DMSO, DMF, DMA, NMP, TMEDA synthon R4CHO

(C)

N

R1

oxidant, base solvent

4

HN

R1

or

+

R5

Cu-cat. or Lewis acid ligand, additive

N

R1

oxidant, base solvent

R2

N

NH R4CH2NH2 = R4CH2NH2, RCH2OH, RCN,

R NH2 [Nitrogen sources] = NH3, NH4Cl, NH4OAc, NaN3 [Carbon sources] = ArCHO, ArCH2NH2, DMA

(D) R

NH2

1

NH2

R2R3C=O or + R2CH=NH or CO + ArBr

Pd, Ir, Pt, Fe, Cu-cat. or photocatalyst and/or oxidant ligand, additive base, solvent

N

R1

R2

N

R2R3C=O = R2CHO, R2COR3, R2CH2OH, R2COOH, R2CN etc. R2CH=NH = R2CH2NH2 This work (E) NH2

R1

NH2

+ R2

CX3 NaOH O2 , H2 O

N

R1 N

X = Br, Cl


+ NaX R2

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Results and Discussion

The investigation was commenced by reacting 2-aminobenzylamine (1a) with α,α,αtribromotoluene (2a) in the presence of 4 equiv of 1,4-diazabicyclo[2.2.2]octane (DABCO) in 0.2 M MeCN at 80 °C under molecular oxygen atmosphere. Gratifyingly, 52% of the desired 2-phenylquinazoline (3aa) was formed, along with 25% of 2-phenyl-3,4-dihydroquinazoline (3aa′) (Table 1, entry 1). Controlled experiments confirmed that base, molecular oxygen, and heat were essential for the transformation (Table 1, entries 2−4). The use of various tertiary amine bases such as quinuclidine, NMM, DMAP, TEA, TMEDA, and DBU did not improve the yield of 3aa (Table 1, entry 1 vs. entries 5−10). The reactant concentration was also optimized. When the reactant concentration was increased to 1 M, the yield of 3aa increased (Table 1, entry 1 vs. entries 11−13), which may be due to higher rate of intermolecular substitution at higher concentration. The reaction temperature was optimized to 100 °C (Table 1, entry 12 vs. entries 14−16). Various solvents such as DMF, DMSO, dioxane, toluene, and H2O were found to be less efficient than MeCN (Table 1, entry 15 vs. entries 18−22), but the use of an inorganic base, K2CO3, instead of DABCO in water was found to be more effective (Table 1, entry 22 vs. entry 23). Various inorganic bases (Cs2CO3, NaOH, and KOH) were also employed using water as the solvent, among which NaOH was found to be most effective (Table 1, entry 23 vs. entries 24−26). The stoichiometry of the base (NaOH) was optimized to 3 equivalents (Table 1, entry 25 vs. entry 27). The use of 1.5 equiv of 2a did not improve the result (Table 1, entry 27 vs. entry 28). Similar results were achieved when 2a was chosen as the limiting reagent in the presence of 1.2 equiv of 1a (Table 1, entry 27 vs. entry 29). Thus, two different reaction conditions were considered optimal for the corresponding organic transformation, one using DABCO as the base in MeCN (Table 1, entry 15; condition A) and the other using NaOH as the base in water (Table 1, entry 27;

condition B). Under both the optimized reaction conditions A and B, α,α,α-trichlorotoluene



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was found to be slightly less reactive compared to α,α,α-tribromotoluene (Table 1, entries 15 vs 30 and 27 vs 31). Being more environmentally benign and economical, condition B was generally employed to explore the substrate scope by using NaOH as one of the least expensive bases that also generates a benign salt (NaBr or NaCl) as the side product.

Table 1. Optimization of Reaction Conditionsa

NH2 NH2 1a entry

X

CX3 +

base

N

solvent, O2 X = Br, Cl temp., 16 h 2a

N

N

3aa

solvent (conc) temp. (o C)

base (equiv)

NH

+

3aa' yield b

variation 3aa

3aa'

52 trace 0 0 48 41 31 6

25 63 0 83 22 17 20 0

1 2 3 4 5 6 7 8

Br DABCO (4) Br DABCO (4) Br Br DABCO (4) Br Quinuclidine (4) Br NMM (4) Br DMAP (4) Br TEA (4)

MeCN (0.2 M) MeCN (0.2 M) MeCN (0.2 M) MeCN (0.2 M) MeCN (0.2 M) MeCN (0.2 M) MeCN (0.2 M) MeCN (0.2 M)

9 10

Br Br

TMEDA (4) DBU (4)

MeCN (0.2 M) MeCN (0.2 M)

80 80

-

8 trace

0 0

11 12 13

Br Br Br

DABCO (4) DABCO (4) DABCO (4)

MeCN (0.5 M) MeCN (1 M) MeCN (2 M)

80 80 80

-

60 70 62

12 9 0

80 25 (r.t.) 80 80 argon atmosphere c 80 80 80 80 -

14

Br

DABCO (4)

MeCN (1 M)

90

-

75

0

15

Br

DABCO (4)

MeCN (1 M)

100

-

78

0

16

Br

DABCO (4)

MeCN (1 M)

110

-

74

0

17

Br

DABCO (3)

MeCN (1 M)

100

-

72

0

18

Br

DABCO (4)

DMF (1 M)

100

-

52

trace

19

Br

DABCO (4)

DMSO (1 M)

100

-

50

trace

20 21

Br Br

DABCO (4) DABCO (4)

100 100

-

10 trace

43 trace

22 23

Br Br

100 100

-

45 65

0 0

24 25 26 27 28 29d 30 31

Br Br Br Br Br Br Cl Cl

DABCO (4) K2CO3 (4) Cs2CO3 (4)

Dioxane (1 M) toluene (1 M) H2O (1 M) H2O (1 M) H2O (1 M) H2O (1 M) H2O (1 M) H2O (1 M) H2O (1 M) H2O (1 M) MeCN (1 M) H2O (1 M)

100 100 100 100 100 100 100 100

1.5 equiv 2a

48 74 70 73 73 72 65 63

0 0 0 0 0 0 0 0

NaOH (4) KOH (4) NaOH (3) NaOH (3) NaOH (3) DABCO (4) NaOH (3)


-

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a

Reaction conditions: 1a (0.1 mmol) and 2a (0.12 mmol) were used unless and otherwise

stated. bYield was determined by 1H NMR spectrometry of crude reaction mixture using bromoform as an internal standard. cMolecular oxygen was removed by repeated vacuumfreeze-thaw cycles. d1a (0.12 mmol) and 2a (0.1 mmol) were used.

The substrate scope of the reaction was explored under both optimized conditions A and B (Table 2). First, the scope of the reaction with respect to 2-aminobenzylamines was explored. 2-Aminoarylamines substituted with both electron-donating groups (Me and OMe) and electron-withdrawing groups (Br, Cl, F, OCF3, CN, and NO2) were successfully reacted with

α,α,α-tribromotoluene or α,α,α-trichlorotoluene to furnish the corresponding 2-aryl quinazoline derivatives in moderate to high yields (Table 2, 3aa–3ma). The scope of the reaction was then evaluated with respect to α,α,α-trihalotoluenes. α,α,α-Trihalotoluenes substituted with electron-donating and -withdrawing groups reacted smoothly with 1a (Table 2, 3ab–3af). The scale-up experiment (gram-scale reaction of 1a with 2a under condition B) was found to be straightforward, producing 50% of 3aa (Table 2, 3aa). The attempted reaction of 2-aminobenzyl alcohol (4a) with 2a under condition B to furnish 2-phenyl-4Hbenzo[d][1,3]oxazine (5aa) did not proceed, possibly due to the lower nucleophilicity of alcohols compared to amines [Scheme S1(A), see Supporting Information]. The aliphatic trichloride, 1,1,1-trichloro-2-methylpropan-2-ol also did not participate in the reaction with

1a [Scheme S1(B), SI].

Notably, under condition B the process generated NaX (X = Br, Cl) as the only side product that remained in the aqueous phase and could be easily removed from the crude reaction mixture through washing. In addition, all the products were solid, except for 3ae. Therefore, crystallization could be attempted in order to isolate and purify the solid products to make the overall process more sustainable by avoiding a huge solvent consuming work-up and column



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chromatographic steps. To our delight, the yields of 3ba, 3fa, 3ga, 3ja, and 3ab (Table 2) obtained through crystallization of the crude reaction mixture were similar to that obtained through work-up followed by silica gel column chromatography.

Table 2. Substrate Scopea,b

NH2

R1

DABCO (4 equiv), MeCN (1 M) (Condition A) CX3 or NaOH (3 equiv), H2O (1 M) R1 (Condition B)

+ R2

NH2 1

2 X = Br and Cl

Me

3ba: 64% (X = Br, A) 58% (X = Br, B) 55%d (X = Br, B) 43% (X = Cl, B) Br

N

N

3ca: 62% (X = Br, A) 60% (X = Br, B)

Cl

N

N

N

N

3da: 65% (X = Br, B)

N

3ea: 60% (X = Br, A) 61% (X = Br, B) 45% (X = Cl, B) Cl

N

N

N

Cl

N

N

MeO

R2

3

N

N 3aa: 75% (X = Br, A) 70% (X = Br, B) 61% (X = Cl, B) 50%c (X = Cl, B)

N

O2, 100 oC, 16 - 24 h

Me

N

N

3fa: 67% (X = Br, A) 62% (X = Br, B) 60%d (X = Br, B) F N N

N Cl

3ga: 70% (X = Br, A) 64% (X = Br, B) 59%d (X = Br, B) F3CO

3ha: 69% (X = Br, A) 79% (X = Br, B) 52% (X = Cl, B)

O2N

N

N

3ia: 75% (X = Br, B)

N

N

N

N

CN 3ja: 78% (X = Br, A) 81% (X = Br, B) 77%d (X = Br, B) 60% (X = Cl, B) O 2N

3ka: 55% (X = Br, B)

3la: 61% (X = Br, B)

N

N

N

N

N Br

N

Me 3ab: 76% (X = Br, A) 71% (X = Br, B) 70%d (X = Br, B)

3ma: 61% (X = Br, A) 64% (X = Br, B)

N

N

N

Br 3ac: 65% (X = Br, A) 66% (X = Br, B)

N

Cl N

N

Cl 3ad: 68% (X = Cl, B)

F 3ae: 58% (X = Br, B)

3af: 71% (X = Br, A) 61% (X = Cl, B)


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a

c

Reaction conditions: 1 (0.3 mmol), 2 (0.36 mmol). bYield of isolated products is reported.

Gram-scale synthesis: 1a (7 mmol), 2a (8.4 mmol); dYield of products obtained through

crystallization of crude mixture.

To shed light on the reaction mechanism, we performed a series of controlled experiments including a kinetic isotopic effect (KIE) experiment. When the reaction of 1a with 2a was performed in the presence of DABCO in MeCN (condition A) at room temperature under argon atmosphere, only 2-phenyl-3,4-dihydroquinazoline (3aa′) was formed in 60% yield [Scheme 2(A)]. 3aa′ was isolated and subjected to several reaction conditions. When 3aa′ was heated in MeCN or H2O at 100 °C under molecular oxygen atmosphere, it was fully converted to 3aa (based on the remaining 3aa′ detected by 1H NMR analysis of the crude reaction mixture), which revealed that 3aa′ was the intermediate of the reaction [Scheme 2(B)]. However, under argon atmosphere, 3aa′ was not converted to 3aa, which confirms the role of molecular oxygen as an oxidant for the oxidation of 3aa′ to 3aa [Scheme 2(C)]. Interestingly, when 3aa′ was heated in MeCN or H2O at 70 °C under molecular oxygen atmosphere, a trace amount of 3aa was formed, which revealed that high temperature (over 70 °C) is required for the oxidation of 3aa′ to 3aa [Scheme 2(D)].

Scheme 2. Controlled Experiments for Mechanistic Studies



To check the involvement of radical intermediates in the reaction, the model reaction of 1a with 2a was performed under condition B in the presence of radical quenchers such as TEMPO and 1,4-dinitrobenzene and was found to be unaffected, indicating the noninvolvement of radicals during the full course of the reaction (Scheme S2, SI).

Further, a kinetic isotopic effect (KIE) experiment was carried out by subjecting 2a to a 1:1 mixture of 1a and 1a-D2 under condition B and molecular oxygen atmosphere at 100 °C for 4 h (Scheme 3). The relative rate constant (kH/kD) of 3aa versus 3aa-D, determined by 1

H-NMR analysis of the isolated products, was 6.67, which revealed that the oxidation of 2-

phenyl-3,4-dihydroquinazoline (3aa′) to 2-phenyl quinazoline (3aa) is the rate-determining step of the reaction.21

Scheme 3. Kinetic Isotopic Effect (KIE) Experiment


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Based on the results of the above experiments, we proposed a reaction mechanism as outlined below (Scheme 4). The base-promoted intermolecular substitution of 2a by 1a produced A, which upon base-mediated intramolecular substitution followed by elimination furnished the key intermediate 2-phenyl-3,4-dihydroquinazoline (3aa′). Finally, 3aa′ was oxidized to 3aa by molecular oxygen as the rate-determining step.

Scheme 4. Proposed Reaction Mechanism

In conclusion, we developed a sustainable synthetic procedure for the synthesis of valuable 2aryl quinazolines by using easily available 2-aminobenzylamines and α,α,α-trihalotoluene in aqueous sodium hydroxide solution at 100 °C. This methodology possesses several advantages, such as a transition-metal-free protocol, the use of cheap sodium hydroxide as a base, use of water and molecular oxygen as a green and renewable solvent and oxidant, respectively, and isolation/purification of the solid products through crystallization of the crude reaction mixture, which circumvents huge solvent consuming work-up and column chromatographic techniques. These features make the overall process more sustainable and



economical. A wide variety of 2-aryl quinazolines was synthesized by the procedure and scale-up of the experiment to the gram-scale was also found to be straightforward. Based on the controlled experiments and kinetic isotopic effect experiments, base-promoted intermolecular substitution followed by intramolecular substitution (cyclization), elimination, and oxidation by molecular oxygen is proposed for the synthesis of quinazolines through the intermediacy of 3,4-dihydroquinazolines, where the oxidation step was found to be the ratedetermining step. We believe that this simple synthetic methodology will find useful application for the synthesis of valuable quinazolines in an economical and sustainable manner.

EXPERIMENTAL SECTION

General Reagent Information

All reagents and solvents including DABCO and NaOH were purchased from Sigma-Aldrich, Alfa Aesar, TCI chemical companies. Flash column chromatography was performed using Merck silica gel 60 (70-230 mesh).

General Analytical Information

The 2-aminobenzylamine derivatives and quinazoline products were characterized by 1H, 13C NMR, and FT-IR spectroscopy. NMR spectra were recorded on a Bruker 600 MHz instrument (600 MHz for 1H NMR and 151 MHz for 13C NMR). Copies of 1H and 13C NMR spectra can be found at the end of the Supporting Information. 1H NMR experiments are reported in units, parts per million (ppm), and were measured relative to residual chloroform


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(7.26 ppm) in the deuterated solvent.

13

C NMR spectra are reported in ppm relative to

deuterochloroform (77.23 ppm) and all were obtained with 1H decoupling. Coupling constants were reported in Hz. FT-IR spectra were recorded on a Nicolet iS 10 ThermoFisher FT-IR spectrometer. Reactions were monitored by 1H-NMR of the crude reaction mixture using bromoform as the internal standard and products were detected by GC-MS using the Agilent GC 7890B/5977A inert MSD with Triple-Axis Detector. Mass spectral data of all unknown compounds were obtained from the Korea Basic Science Institute (Daegu) on a Jeol JMS 700 high resolution mass spectrometer. A quadrupole mass analyzer was used for HRMS measurements. Melting points of unknown compounds were recorded on a Stuart SMP30 apparatus.

Representative experimental procedure; Synthesis of 2-amino-5-methylbenzylamine (1b): An oven-dried 100 mL round bottom flask equipped with a magnetic stir bar was charged with 2-amino-5-methylbenzonitrile (5 mmol, 0.66 g) in dry tetrahydrofuran (10 mL) under argon atmosphere. To the solution of benzonitrile at 0 ℃ and under an argon atmosphere was slowly added borane (1.0 M in THF) in drops. The solution was stirred for 10 min at 0 ℃ and further 24 h at room temperature. The reaction progress was monitored by TLC and gas chromatography. The reaction mixture was quenched by addition of ethanol. HCl (2.0 M in diethyl ether) was added to resulting solution for salt formation. Precipitated salts were filtered with diethyl ether and then treated with excess of aqueous solution of ammonia. The resulting suspension was extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (MC/methanol = 10/1) to give 2-amino-5methylbenzylamine (2.95 mmol, 0.40 g) in 59 % yield.



Representative experimental procedure; Synthesis of α,α,α-tribromotoluene (2a): To an oven-dried two neck 100 mL round bottom flask equipped with a magnetic stir bar and a reflux condenser were flame dried and charged with aluminum bromide (2 mmol, 0.53 g), trimethylsilyl bromide (28 mmol, 4.29 g), α,α,α-trifluorotoluene (10 mmol, 1.46 g) under argon atmosphere. The reaction mixture was placed in the oil bath and heated at 80 °C. The reaction progress was monitored by TLC and gas chromatography. After completion of the reaction (about 20 h), the flask was cooled to room temperature and the reaction mixture was diluted with dichloromethane and water. The aqueous phase was further extracted with dichloromethane. The combined organic layers were dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (hexane/EtOAc = 30/1) to give α,α,α-tribromotoluene (9.6 mmol, 3.12g) in 96% yield.

Representative experimental procedure; Synthesis of 2-phenylquinazolines (3aa): A resealable tube equipped with a magnetic stir bar was charged with 2-amino benzylamine, 1a (37 mg, 0.3 mmol, 1.0 equiv.) and α,α,α-tribromotoluene, 2a (118 mg, 0.36 mmol, 1.2 equiv.). Then, for Condition A, DABCO (118 mg, 1.2 mmol, 4 equiv.) and MeCN (0.3 mL, 1M) and for Condition B, NaOH (40 mg, 0.93 mmol, 3.1 equiv; considering 93% purity of the reagent) and H2O (0.3 mL, 1 M) was added to the reaction mixture. Next, molecular oxygen was bubbled through the reaction mixture for 10 min and the reaction tube was completely sealed. The sealed tube was then heated in an oil bath at 100 oC for the required period of time. The reaction progress was monitored by TLC. After completion of reaction, the mixture was allowed to come to room temperature and diluted with ethyl acetate (EA) followed by washing with water. Under Condition B, the sludge was washed several times with ethyl acetate before its disposal to the environment. The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2) with hexane/EA to furnish the pure 2-phenylquinazolines,


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3aa (46 mg, 75%; Condition A and 43mg, 70%; Condition B), and the remaining 2a was recovered. The same procedure was followed for all the reactions mentioned in Table 2.

For crystallization technique, after the completion of reaction, the solid product was filtered and washed several times with water and dried by using blotting paper. Then the crude solid compound was crystallized from either hot hexane or hexane/ethyl acetate mixture.

Analytic Data of 2-Aminobenzylamines (1b-1m)

2-Amino-5-methylbenzylamine (1b):22 white solid (401 mg, 59%); 1H NMR (600 MHz,

CDCl3) δ 6.90 (d, J = 8.1 Hz, 1H), 6.88 (s, 1H), 6.60 (d, J = 8.1 Hz, 1H), 3.86 (s, 2H) 2.24 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 143.8, 129.9, 128.8, 127.4, 126.6, 116.2, 45.1, 20.6; IR

(neat): νmax = 3347, 3012, 2917, 1508, 816 cm-1; Rf 0.38 (DCM/Methanol, 9/1).

2-Amino-4-methylbenzylamine (1c):22 white solid (421 mg, 62%); 1H NMR (600 MHz,

CDCl3) δ 6.93 (d, J = 7.5 Hz, 1H), 6.52 (d, J = 7.5 Hz, 1H), 6.51 (s, 1H), 3.86 (s, 2H), 2.26 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 146.4, 139.3, 129.2, 123.6, 118.9, 116.8, 44.9, 21.3; IR

(neat): νmax = 3357, 3233, 2860, 1625, 726 cm-1; Rf 0.38 (DCM/Methanol, 9/1).

2-Amino-5-methoxylbenzylamine (1d):22 white liquid (532 mg, 70%); 1H NMR (300 MHz,

CDCl3) δ 6.69 (s, 1H), 6.68 (dd, J = 7.2, 2.4 Hz, 1H), 6.64 (dd, J = 7.2, 2.4 Hz, 1H), 3.86 (s, 2H), 3.75 (s, 3H), 2.01 (bs, 2H); IR (neat): νmax = 3352, 3225, 2832, 1504, 816 cm-1; Rf 0.30 (DCM/Methanol, 9/1). 2-Amino-4-chlorobenzylamine (1e):22 white solid (624 mg, 80%); 1H NMR (600 MHz,

CDCl3) δ 6.93 (d, J = 7.8 Hz, 1H), 6.65 - 6.62 (m, 2H), 3.85 (s, 2H), 4.69 (bs, 2H), 3.86 (s,



Page 16 of 27

2H), 1.30 (bs, 2H); 13C NMR (151 MHz, CDCl3) δ 147.7, 133.5, 130.1, 124.3, 117.5, 115.4, 44.6; IR (neat): νmax = 3354, 3220, 2866, 1494, 729 cm-1; Rf 0.50 (DCM/Methanol, 9/1).

2-Amino-5-chlorobenzylamine (1f):22 white solid (390 mg, 50%); 1H NMR (600 MHz,

CDCl3) δ 7.03 (d, J = 8.1 Hz, 1H), 7.02 (s, 1H), 6.59 (d, J = 8.1 Hz, 1H), 4.56 (bs, 2H), 3.85 (s, 1H), 1.39 (bs, 2H);

13

C NMR (151 MHz, CDCl3) δ 145.2, 129.0, 128.0, 127.8, 122.5

117.1, 45.0; IR (neat): νmax = 3354, 3222, 2860, 1490, 728 cm-1; Rf 0.50 (DCM/Methanol, 9/1).

2-Amino-3,5-dichlorobenzylamine (1g): white solid (665 mg, 70%); 1H NMR (600 MHz,

CDCl3) δ 7.18 (d, J = 1.5 Hz, 1H), 6.92 (d, J = 1.5 Hz, 1H), 5.10 (bs, 2H), 3.86 (s, 2H), 1.30 (bs, 2H); 13C NMR (151 MHz, CDCl3) δ 142.0, 128.1, 127.6, 127.5, 121.5, 120.1, 45.3; IR

(neat): νmax = 3438, 3306, 2864, 1468, 860 cm-1; HRMS m/z (EI) calc. for C7H8Cl2N2 [M+] 190.0065, found 190.0065; Rf 0.55 (DCM/Methanol, 9/1).

2-Amino-5-bromobenzylamine (1h):22 white solid (630 mg, 63%); 1H NMR (600 MHz,

CDCl3) δ 7.17 - 7.15 (m, 2H), 6.55 (d, J = 7.8 Hz, 1H), 4.58 (bs, 2H), 3.85 (s, 2H), 1.40 (bs, 2H);

13

C NMR (151 MHz, CDCl3) δ 145.7, 131.8, 131.0, 128.2, 117.5, 109.6, 45.0; IR

(neat): νmax = 3355, 3222, 2857, 1489, 815 m-1; Rf 0.50 (DCM/Methanol, 9/1).

2-Amino-5-fluorobenzylamine (1i):22 white solid (329 mg, 47%); 1H NMR (600 MHz,

CDCl3) δ 6.81 - 6.77 (m, 2H), 6.59 (dd, 3J

H-F

=8.4, J= 4.8, 1H), 4.34 (bs, 2H), 3.85 (s, 2H),

1.31 (bs, 2H); 13C NMR (151 MHz, CDCl3) δ 156.1 (d, 1J C-F = 157.5 Hz), 142.3 (d, 4J C-F = 1.4 Hz), 127.8 (d, 3J

C-F

= 4.2 Hz), 116.6 (d, 3J

C-F

= 5.1 Hz), 115.6 (d, 2J

C-F

= 14.9 Hz),

114.4 (d, 2J C-F = 14.7 Hz), 49.9 (d, 4J C-F = 0.9 Hz); IR (neat): νmax = 3347, 3231, 2863, 1501, 724 m-1; Rf 0.50 (DCM/Methanol, 9/1).


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2-Amino-5-(trifluoromethoxy)benzylamine (1j): black liquid (535 mg, 52%); 1H NMR (600

MHz, CDCl3) δ 7.28 (d, J = 8.4 Hz, 1H), 7.27 (s, 1H), 6.96 (d, J = 8.4 Hz, 1H), 4.9 (bs, 2H), 4.22 (s, 1H), 1.75 (bs, 2H); 13C NMR (151 MHz, CDCl3) δ 145.5, 140.9, 126.7, 122.3, 121.3, 120.9 (q, 1J C-F = 170.9 Hz), 116.2, 45.1; IR (neat): νmax = 3349, 3235, 1504, 1154, 723 cm-1; HRMS m/z (EI) calc. for C8H9F3N2O [M+] 206.0667, found 206.0665; Rf 0.50 (DCM/Methanol, 9/1).

2-Amino-5-nitrobenzylamine (1k):22 yellow solid (484 mg, 58%); 1H NMR (600 MHz,

CDCl3) δ 8.01 (dd, J = 8.4, 2.4 Hz, 1H), 7.97 (d, J = 2.4 Hz, 1H), 6.59 (d, J = 8.4 Hz, 1H), 5.60 (bs, 2H), 3.98 (s, 1H), 1.42 (bs, 2H);

13

C NMR (151 MHz, CDCl3) δ 153.7, 125.7,

125.4, 124.3, 114.3, 45.5 (overlapped peaks present); IR (neat): νmax = 3416, 3059, 2936, 903, 724 cm-1; Rf 0.55 (DCM/Methanol, 9/1).

2-Amino-3-(aminomethyl)benzonitrile (1l): yellow liquid (485 mg, 66%); 1H NMR (600

MHz, CDCl3) δ 7.32 (dd, J = 7.8, 1.2 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 6.64 (dd, J = 7.8, 7.8 Hz, 1H), 5.63 (bs, 2H), 3.94 (s, 2H), 1.38 (bs, 2H);

13

C NMR (151 MHz, CDCl3) δ 150.6,

133.6, 131.5, 126.1, 118.2, 117.2, 96.8, 45.6; IR (neat): νmax = 3370, 3212, 2850, 2214, 1638 m-1; HRMS m/z (EI) calc. for C8H9N3 [M+] 147.0796, found 147.0795; Rf 0.63 (DCM/Methanol, 9/1).

2-Amino-3-bromo-5-nitrobenzylamine (1m): yellow solid (857 mg, 70%), m.p. 170-172 oC; 1

H NMR (600 MHz, CDCl3) δ 8.33 (d, J = 2.4 Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H), 6.26 (bs,

2H), 4.02 (s, 2H), 1.52 (bs, 2H); 13C NMR (151 MHz, CDCl3) δ 151.1, 128.2, 124.6, 124.5, 108.2, 46.1 (overlapped peaks present); IR (neat): νmax = 3430, 3180, 2850, 903, 723 m-1; HRMS m/z (EI) calc. for C7H8BrN3O2 [M+] 244.9800, found 244.9798; Rf 0.63 (DCM/Methanol, 9/1).



Page 18 of 27

Analytic Data of α,α,α-Tribromotoluenes (2a-2c, 2e, 2f)

(Tribromomethyl)benzene (2a):23 white solid (3120 mg, 96%); 1H NMR (600 MHz, CDCl3) δ 8.01 (d, J = 7.2, 2H), 7.40 (dd, J = 7.2, 7.2 Hz, 2H), 7.34 (t, J = 7.2, 1H); 13C NMR (151

MHz, CDCl3) δ 147.2, 130.3, 128.3, 126.7, 36.5; IR (neat): νmax = 3061, 1489, 1443, 722, 652 cm-1; Rf 0.49 (hexane).

1-Methyl-4-(tribromomethyl)benzene (2b):23 white solid (1223 mg, 36%); 1H NMR (600

MHz, CDCl3) δ 7.89 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 2.41 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 144.7, 140.7, 128.8, 126.6, 36.3, 21.2; IR (neat): νmax = 3029, 2920, 1607, 717, 649 cm-1; Rf 0.47 (hexane).

1-Bromo-4-(tribromomethyl)benzene (2c):23 white solid (3256 mg, 80%); 1H NMR (600

MHz, CDCl3) δ 7.88 (d, J = 9 Hz, 2H), 7.53 (d, J = 9 Hz, 2H); 13C NMR (151 MHz, CDCl3) δ 146.3, 131.3, 128.4, 124.8, 34.5; IR (neat): νmax = 3086, 1581, 903, 728, 649 cm-1; Rf 0.53 (hexane).

1-Chloro-2-(tribromomethyl)benzene (2e):23 white liquid (2952 mg, 82%); 1H NMR (600

MHz, CDCl3) δ 8.27 - 8.24 (m, 1H), 7.51 - 7.48 (m, 1H), 7.33 - 7.30 (m, 2H);

13

C NMR

(151 MHz, CDCl3) δ 140.4, 133.7, 133.2, 131.7, 129.6, 126.6, 30.8; IR (neat): νmax = 3053, 1687, 1592, 744, 647 cm-1; Rf 0.45 (hexane).

1-Fluoro-4-(tribromomethyl)benzene (2f):23 pale yellow liquid (2470 mg, 72%); 1H NMR

(600 MHz, CDCl3) δ 8.02 (dd, J = 9.0, 4J H-F = 4.8 Hz, 2H), 7.07 (dd, J = 9.0, 3J H-F = 8.7 Hz, 2H); 13C NMR (151 MHz, CDCl3) δ 163.3 (d, 1J C-F = 169.0 Hz), 143.4 (d, 4J C-F = 2.2 Hz),


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129.0 (d, 3J

C-F

= 5.9 Hz), 115.0 (d, 2J

C-F

= 14.8 Hz), 34.4; IR (neat): νmax = 3076, 1602,

1503, 725, 526 cm-1; Rf 0.48 (hexane).

Analytic Data of 2-Arylquinazolines (3aa – 3af)

2-Phenylquinazoline (3aa):6c white solid (46 mg, 75%, condition A); 1H NMR (600 MHz,

CDCl3) δ 9.45 (s, 1H), 8.63 (d, J = 7.0 Hz, 2H), 8.09 (d, J = 8.4 Hz, 1H), 7.93 – 7.87 (m, 2H), 7.59 (dd, J = 7.8, 6.6 Hz, 1H), 7.56 – 7.50 (m, 3H);

13

C NMR (151 MHz, CDCl3) δ

161.3, 160.7, 151.0, 138.3, 134.3, 130.8, 128.84, 128.82, 128.78, 127.4, 127.3, 123.8; IR

(neat): νmax = 3062, 2924, 1617, 1585, 1550, 1485, 1402, 704 cm-1; Rf 0.35 (hexane/EtOAc, 9/1).

6-Methyl-2-phenylquinazoline (3ba):6c off-white solid (42 mg, 64%, condition A); 1H NMR

(600 MHz, CDCl3) δ 9.35 (s, 1H), 8.60 (d, J = 6.9 Hz, 2H), 7.97 (d, J = 8.6 Hz, 1H), 7.70 (dd, J = 8.6, 1.9 Hz, 1H), 7.63 (s, 1H), 7.56 – 7.48 (m, 3H), 2.53 (s, 3H);

13

C NMR (151

MHz, CDCl3) δ 160.6, 159.9, 149.5, 138.6, 137.6, 136.5, 130.5, 128.8, 128.6, 128.4, 125.9, 123.8, 21.8; IR (neat): νmax = 3056, 2919, 1588, 1556, 1425, 1371, 707 cm-1; Rf 0.35 (hexane/EtOAc, 9/1).

7-Methyl-2-phenylquinazoline (3ca):12b off-white solid (40 mg, 60%, condition B); 1H NMR

(600 MHz, CDCl3) δ 9.37 (s, 1H), 8.61 (d, J = 8.3 Hz, 2H), 7.86 (s, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.57 – 7.47 (m, 3H), 7.41 (d, J = 8.3 Hz, 1H), 2.59 (s, 3H);

13

C NMR (151 MHz,

CDCl3) δ 161.3, 160.0, 151.2, 145.3, 138.4, 130.7, 129.7, 128.8, 128.7, 127.8, 126.9, 122.1, 22.5; IR (neat): νmax = 3058, 2922, 1622, 1589, 1548, 1401, 705 cm-1; Rf 0.32 (hexane/EtOAc, 9/1).



6-Methoxy-2-phenylquinazoline (3da):6c yellow solid (46 mg, 65%, condition B); 1H NMR

(600 MHz, CDCl3) δ 9.32 (s, 1H), 8.58 (d, J = 7.5 Hz, 2H), 7.97 (d, J = 9.2 Hz, 1H), 7.54 – 7.50 (m, 3H), 7.48 (dd, J = 7.5, 6.9 Hz, 1H), 7.09 (d, J = 2.8 Hz, 1H), 3.91 (s, 3H); 13C NMR

(151 MHz, CDCl3) δ 159.5, 158.9, 158.4, 147.1, 138.4, 130.3, 130.3, 128.7, 128.4, 127.3, 124.6, 104.0, 55.8; IR (neat): νmax = 3061, 2999, 1620, 1572, 1489, 1164, 1026, 762, 707 cm1

; Rf 0.34 (hexane/EtOAc, 4/1).

6-Bromo-2-phenylquinazoline (3ea):6c white solid (52 mg, 61%, condition B); 1H NMR (600

MHz, CDCl3) δ 9.39 (s, 1H), 8.60 (dd, J = 6.7, 1.5 Hz, 2H), 8.09 (d, J = 1.5 Hz, 1H), 7.96 (d, J = 1.4 Hz, 2H), 7.56 – 7.50 (m, 3H); 13C NMR (151 MHz, CDCl3) δ 161.6, 159.6, 149.7, 137.8, 131.1, 130.7, 129.5, 128.9, 128.8, 128.8, 124.7, 120.9; IR (neat): νmax = 2923, 1572, 1543, 1476, 1276, 837, 704 cm-1; Rf 0.51 (hexane/EtOAc, 9/1).

6-Chloro-2-phenylquinazoline (3fa):6c white solid (48 mg, 67%, condition A); 1H NMR (600

MHz, CDCl3) δ 9.36 (s, 1H), 8.59 (dd, J = 7.9, 1.9 Hz, 2H), 8.01 (d, J = 9.0 Hz, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.80 (dd, J = 9.0, 2.4 Hz, 1H), 7.57 – 7.50 (m, 3H).; 13C NMR (151 MHz, CDCl3) δ 161.5, 159.7, 149.4, 137.8, 135.2, 133.0, 131.0, 130.6, 128.9, 128.8, 126.0, 124.2; IR (neat): νmax = 3057, 2923, 2853, 1573, 1547, 1478, 1430, 1277, 833, 703 cm-1; Rf 0.46 (hexane/EtOAc, 9/1).

7-Chloro-2-phenylquinazoline (3ga):12a white solid (50 mg, 70%, condition A); 1H NMR

(600 MHz, CDCl3) δ 9.43 (s, 1H), 8.61 (dd, J = 7.3, 1.9 Hz, 2H), 8.09 (d, J = 1.3 Hz, 1H), 7.86 (d, J = 8.6 Hz, 1H), 7.61 – 7.47 (m, 4H); 13C NMR (151 MHz, CDCl3) δ 162.1, 160.4, 151.6, 140.6, 137.8, 131.2, 128.9, 128.9, 128.7, 128.6, 128.0, 122.2; IR (neat): νmax = 2970, 1613, 1543, 1452, 1377, 873, 701 cm-1; Rf 0.40 (hexane/EtOAc, 9/1).


Page 20 of 27

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6,8-Dichloro-2-phenylquinazoline (3ha): pale yellow solid (65 mg, 79%, condition B), m.p. 132-134 oC; 1H NMR (600 MHz, CDCl3) δ 9.39 (s, 1H), 8.68 (dd, J = 8.6, 1.2 Hz, 2H), 7.96 (d, J = 2.2 Hz, 1H), 7.83 (d, J = 2.2 Hz, 1H), 7.57 – 7.52 (m, 3H);

13

C NMR (151 MHz,

CDCl3) δ 161.9, 160.1, 146.3, 137.4, 134.8, 134.7, 132.4, 131.5, 129.1, 129.0, 125.0, 124.8; IR (neat): νmax = 3067, 1573, 1540, 1461, 1436, 1329, 769, 707 cm-1; HRMS m/z (EI) calc. for C14H8Cl2N2 [M+] 274.0065, found 274.0067; Rf 0.53 (hexane/EtOAc, 9/1).

6-Fluoro-2-phenylquinazoline (3ia):10c white solid (50 mg, 75%, condition B); 1H NMR (600

MHz, CDCl3) δ 9.42 (s, 1H), 8.60 (dd, J = 8.1, 1.6 Hz, 2H), 8.09 (dd, J = 9.2, 5.0 Hz, 1H), 7.67 (ddd, J = 9.2, 8.4, 2.8 Hz, 1H), 7.56 – 7.50 (m, 4H);

13


160.6 (d, 1JC-F = 251.3 Hz), 160.9, 160.6 (d, 4JC-F = 5.4 Hz), 148.1, 137.9, 131.6 (d, 3JC-F = 8.6 Hz), 130.9, 128.9, 128.7, 124.7 (d, 2JC-F = 25.8 Hz), 124.1 (d, 3JC-F = 9.4 Hz), 110.3 (d, 2

JC-F = 21.9 Hz); IR (neat): νmax = 3065, 1630, 1590, 1552, 1493, 1353, 1212, 837, 701 cm-1 ;

Rf 0.30 (hexane/EtOAc, 9/1).

2-Phenyl-6-(trifluoromethoxy)quinazoline (3ja):6c off-white solid (70 mg, 81%, condition B); 1

H NMR (600 MHz, CDCl3) δ 9.45 (s, 1H), 8.61 (dd, J = 7.8, 1.9 Hz, 2H), 8.12 (dd, J = 7.8,

1.9 Hz, 1H), 7.78 – 7.69 (m, 2H), 7.59 – 7.49 (m, 3H);

13


161.8, 160.4, 149.3, 147.3 (q, 3JC-F = 2.0 Hz), 137.7, 131.4, 131.1, 128.9, 128.8, 128.4, 123.7, 120.7 (q, 1JC-F = 259.0 Hz), 117.1; IR (neat): νmax = 3070, 2914, 1590, 1557, 1487, 1351, 1256, 904, 725 cm-1; Rf 0.60 (hexane/EtOAc, 9/1).

2-Phenylquinazoline-8-carbonitrile (3ka): pale yellow solid (38 mg, 55%, condition B), m.p. 155-157 oC; 1H NMR (600 MHz, CDCl3) δ 9.54 (s, 1H), 8.78 – 8.71 (m, 2H), 8.28 (dd, J = 7.2, 1.4 Hz, 1H), 8.16 (dd, J = 8.2, 1.4 Hz, 1H), 7.67 (dd, J = 8.2, 7.2 Hz, 1H), 7.56 -7.54 (m, 3H); 13C NMR (151 MHz, CDCl3) δ 162.9, 161.1, 150.7, 139.9, 136.9, 132.1, 131.9, 129.4,



129.0, 126.6, 123.5, 116.2, 112.9; IR (neat): νmax = 3065, 1607, 1583, 1569, 1470, 1401, 1320, 768, 713 cm-1; HRMS m/z (EI) calc. for C15H9N3 [M+] 231.0796, found 231.0797; Rf 0.34 (hexane/EtOAc, 2/1).

6-Nitro-2-phenylquinazoline (3la):8b white solid (46 mg, 61%, condition B); 1H NMR (600

MHz, CDCl3) δ 9.61 (s, 1H), 8.85 (s, 1H), 8.70 – 8.61 (m, 3H), 8.19 (dd, J = 9.4, 2.3 Hz, 1H), 7.56-7.55 (m, 3H); 13C NMR (151 MHz, CDCl3) δ 164.2, 162.4, 153.3, 146.0, 137.2, 132.1, 130.9, 129.5, 129.0, 127.6, 124.1, 122.5; IR (neat): νmax = 2922, 2851, 1624, 1555, 1525,1436, 1345, 853, 701 cm-1; Rf 0.54 (hexane/EtOAc, 4/1).

8-Bromo-6-nitro-2-phenylquinazoline (3ma): off-white solid (63 mg, 64%, condition B), m.p. 255-257 oC; 1H NMR (600 MHz, DMSO-D6) δ 9.95 (s, 1H), 9.17 (d, J = 2.4 Hz, 1H), 8.93 (d, J = 2.4 Hz, 1H), 8.65 (dd, J = 7.8, 1.9 Hz, 2H), 7.64 – 7.60 (m, 3H); 13C NMR (151

MHz, DMSO-D6) δ 164.6, 163.8, 150.3, 145.7, 136.9, 132.5, 130.9, 129.4, 129.4, 124.9, 124.7, 123.4; IR (neat): νmax = 2922, 2851, 1660, 1530, 1432, 1349, 821, 702 cm-1; HRMS m/z (EI) calc. for C14H8BrN3O2 [M+] 328.9800, found 328.9798; Rf 0.54 (hexane/EtOAc, 4/1).

2-(p-Tolyl)quinazoline (3ab):6c off-white solid (50 mg, 76%, condition A); 1H NMR (600

MHz, CDCl3) δ 9.44 (s, 1H), 8.52 (d, J = 8.2 Hz, 2H), 8.07 (d, J = 8.5 Hz, 1H), 7.92 – 7.86 (m, 2H), 7.58 (dd, J = 8.0, 6.9 Hz, 1H), 7.35 (d, J = 8.2 Hz, 2H), 2.45 (s, 3H); 13C NMR (151

MHz, CDCl3) δ 161.4, 160.6, 151.0, 141.1, 135.6, 134.2, 129.6, 128.8, 128.7, 127.3, 127.2, 123.7, 21.7; IR (neat): νmax = 3016, 2919, 1611, 1586, 1550, 1486, 1399, 1377, 1174, 1056, 796, 726 cm-1; Rf 0.43 (hexane/EtOAc, 9/1).

2-(4-Bromophenyl)quinazoline (3ac):6c white solid (56 mg, 66%, condition B); 1H NMR

(600 MHz, CDCl3) δ 9.43 (s, 1H), 8.49 (d, J = 8.6 Hz, 2H), 8.06 (dd, J = 7.8, 1.1 Hz, 1H),


Page 22 of 27

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7.90 (dd, J = 7.8, 7.2 Hz, 2H), 7.65 (d, J = 8.6 Hz, 2H), 7.61 (td, J = 7.2, 1.1 Hz, 1H);

13

C

NMR (151 MHz, CDCl3) δ 160.7, 160.3, 150.9, 137.2, 134.5, 132.0, 130.4, 128.8, 127.7, 127.3, 125.6, 123.8; IR (neat): νmax = 3056, 1618, 1581, 1546, 1487, 1404, 906, 725 cm-1; Rf 0.43 (hexane/EtOAc, 9/1).

2-(4-Chlorophenyl)quinazoline (3ad):6c white solid (49 mg, 68%, condition B); 1H NMR

(600 MHz, CDCl3) δ 9.44 (s, 1H), 8.57 (d, J = 8.6 Hz, 2H), 8.06 (d, J = 8.3 Hz, 1H), 7.927.89 (m, 2H), 7.62 (dd, J = 8.2, 7.0 Hz, 1H), 7.49 (d, J = 8.6 Hz, 2H); 13C NMR (151 MHz,

CDCl3) δ 160.7, 160.3, 150.9, 137.0, 136.7, 134.4, 130.1, 129.0, 128.8, 127.7, 127.4, 123.8; IR (neat): νmax = 3056, 1620, 1585, 1550, 1490, 1408, 1291, 1085, 846, 796, 726 cm-1; Rf 0.43 (hexane/EtOAc, 9/1).

2-(2-Chlorophenyl)quinazoline (3ae):6c pale yellow liquid (42 mg, 58%, condition B); 1H

NMR (300 MHz, CDCl3) δ 9.53 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.98 (dd, J = 7.8, 6.3 Hz, 1H), 7.96 (dd, J = 8.4, 7.8 Hz, 1H), 7.83 (dd, J = 6.6, 6.0 Hz, 1H), 7.70 (dd, J = 8.1, 7.2 Hz, 1H), 7.54 (dd, J = 7.2, 6.3 Hz, 1H), 7.42 - 7.39 (m, 2H);

13


162.2, 160.4, 150.5, 138.5, 134.6, 133.1, 132.0, 130.7, 130.5, 128.8, 128.2, 127.3, 127.1, 123.5; IR (neat): νmax = 3059, 2924, 1619, 1553, 1486, 1399, 1033, 765, 731 cm-1; Rf 0.31 (hexane/EtOAc, 4/1).

2-(4-Fluorophenyl)quinazoline (3af):12b white solid (48 mg, 71%, condition A); 1H NMR

(600 MHz, CDCl3) δ 9.41 (s, 1H), 8.63 - 8.60 (m, 2H), 8.05 (d, J = 8.2 Hz, 1H), 7.88 (dd, J = 8.4, 7.2 Hz, 2H), 7.58 (dd, J = 8.4, 7.2 Hz, 1H), 7.20 (dd, J = 8.4, 7.2 Hz, 2H);

13

C NMR

(151 MHz, CDCl3) δ 164.9 (d, 1JC-F = 250.7 Hz), 160.7, 160.3, 150.9, 134.40 (d, 4JC-F = 3.0 Hz), 134.35, 130.85 (d, 3JC-F = 8.6 Hz), 128.7, 127.43, 127.30, 123.7, 115.71 (d, 2JC-F = 21.7



Hz); IR (neat): νmax = 3059, 2924, 1600, 1582, 1508, 1402, 1221, 1147, 800, 731 cm-1; Rf 0.40 (hexane/EtOAc, 9/1).

Analytic Data of 2-phenyl-3,4-dihydroquinazoline (3aa′)

2-Phenyl-3,4-dihydroquinazoline (3aa′):24 off-white solid (125 mg, 60%, 1 mmol scale); 1H

NMR (600 MHz, CDCl3) δ 7.75 (d, J = 7.2 Hz, 2H), 7.43 (dd, J = 8.3, 6.8 Hz, 1H), 7.38 (dd, J = 8.3, 7.2 Hz, 2H), 7.18 (dd, J = 7.9, 6.8 Hz, 1H), 7.06 (d, J = 7.9 Hz, 1H), 7.02 (d, J = 7.4 Hz, 1H), 6.92 (d, J = 7.4 Hz, 1H), 5.83 (s, 1H), 4.71 (s, 2H); 13C NMR (151 MHz, CDCl3) δ 155.1, 141.7, 135.7, 130.6 128.7, 128.2, 126.6, 125.6, 124.5, 121.8, 120.4, 44.9.

ASSOCIATED CONTENT

Supporting Information

The Supporting Information is available free of charge on the ACS Publications website at DOI: Additional experimental results (unsuccessful reactions and radical quenching experiments) and copies of NMR spectra (1H NMR spectrum of KIE experiment, 1H and 13C NMR spectra for all synthesized compounds).

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]

Notes


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The authors declare no competing financial interest.

ACKNOWLEDGEMENTS

This research was supported by the Chung-Ang University Graduate Research Scholarship in 2017 for Dong In Kim. We gratefully acknowledge the National Research Foundation of Korea [NRF-2012M3A7B4049657, NRF-2014-011165, NRF-2016K1A3A1A19945930, and NRF-2017R1A2B2004082].

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Base-Promoted Synthesis of 2-Aryl Quinazolines from 2

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