Cesium Carboxylate-Promoted Iridium Catalyzed C-H Amidation/Cyclization with 2,2,2-Trichloroethoxycarbonyl Azide

Article abstract of DOI:10.1021/acs.joc.6b00818

An Ir(III)-catalyzed direct C-H amidation/cyclization of benzamides using 2,2,2-trichloroethoxycarbonyl azide (TrocN₃) as the aminocarbonyl source is reported. With the aid of cesium carboxylate, the reactions proceed efficiently and with high regioselectivity, producing various functionalized quinazoline-2,4(1H,3H)-diones, which are important building blocks and key synthetic intermediates for biologically and medicinally important compounds. During the reactions, two new C-N bonds were formed by breaking C-H and N-H bonds sequence.

Full text of DOI:10.1021/acs.joc.6b00818

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Note
Cesium Carboxylate-Promoted Iridium Catalyzed C-H
Amidation/Cyclization with 2,2,2-Trichloroethoxycarbonyl Azide
Tao Zhang, Zhen Wang, Xuejiao Hu, Meng Yu, Tianning Deng, Guigen Li, and Hongjian Lu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00818 • Publication Date (Web): 10 May 2016
Downloaded from http://pubs.acs.org on May 15, 2016
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Cesium CarboxylateꢀPromoted Iridium Catalyzed CꢀH
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Amidation/Cyclization with 2,2,2ꢀTrichloroethoxycarbonyl Azide
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Tao Zhang,† Zhen Wang,† Xuejiao Hu,† Meng Yu,† Tianning Deng,† Guigen Li‡ and
Hongjian Lu†,*
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†Institute of Chemistry and BioMedical Sciences, School of Chemistry and Chemical Engineering,
Nanjing University, Nanjing, 210093, China
‡Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas 79409ꢀ1061,
USA
ABSTRACT: An Ir(III)ꢀcatalyzed direct C−H amidation/cyclization of benzamides using
2,2,2ꢀtrichloroethoxycarbonyl azide (TrocN3) as the aminocarbonyl source is reported. With the aid of
cesium carboxylate, the reactions proceed efficiently and with high regioselectivity, producing various
functionalized quinazolineꢀ2,4(1H,3H)ꢀdiones, which are important building blocks and key synthetic
intermediates for biologically and medicinally important compounds. During the reactions, two new C−N
bonds were formed by breaking C−H and N−H bonds sequence.
Transitionꢀmetal catalyzed C−H amination allows simplification and abbreviation of synthetic procedures
and has been proved to be a powerful approach to the construction of valuable amine derivatives from
starting materials devoid of functional groups.1ꢀ2 This approach has achieved significant advances, although
most available procedures require stoichiometric quantities of external oxidants and/or bases. Recently, C−H
amination directed by functional groups using organic azides as amino sources has been less explored.3, 4 The
advantages of this approach include its dependence on easily prepared organic azides, N2 as the sole
byproduct, high tolerance of functional groups and the nonꢀoxidative reaction conditions that are used.
Various type of organic azides, such as sulfonyl,4aꢀc carbonyl,4dꢀf phosphoryl,4g, h phenyl4iꢀk and alkyl azides4lꢀn
have been utilized with an appropriate combination of chelate groups and metal catalysts. In spite of their
many benefits, these reported protocols still suffer from some substrate scope limitations and reaction
efficiency. For example, alkoxycarbonyl azides have shown low reactivity and thus been rarely used
possibly due to their electrophilicity which is weaker than that of sulfonyl or carbonyl azides,5
notwithstanding the fact that alkoxycarbonyl groups on an amino group are removable and readily
susceptible to subsequent transformations. The cascade strategy combining C−H amination has been rarely
applied,4d despite the fact that the cascade reaction has drawn much interest due to its high efficiency in
constructing multiple new bonds in a simple oneꢀpot operation.6
Quinazolineꢀ2,4(1H,3H)ꢀdione, a scaffold embedded in a variety of natural quinolone, quinazoline and
acridone alkaloids,7 contains a benzene ring and a fused pyrimidine ring with carbonyl groups at the 2 and 4
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positions, and is recognized as the benzoꢀannulated analogue of the RNA and DNA nucleotide bases uracil
and thymine. Its derivatives have drawn much attention due to their various biological activities8 and are
widely used as key structures in the production of medicinal agents.9 There are a number of synthetic
methods available for the preparation of quinazolineꢀ2,4(1H,3H)ꢀdiones,10 and oꢀaminobenzoic acid and its
analogues are commonly used starting materials (Scheme 1a). Major drawbacks in these methods include the
presence of multistep procedures, and the use of less available and expensive 1,2ꢀdifunctionalized arene
reagents. Consequently, a new facile and effective method preferably using readily available starting
materials is urgently needed. A functional group directed C−H activation would be useful because of its
inherent advantage of producing 1,2ꢀdifunctionalized arenes derived from monofunctionalized arenes. But
only one example based on metal catalytic C−H activation strategy has been reported (Path a in Scheme
1b).11 This method proceeded through a stepwise palladiumꢀcatalyzed ortho C−H carboxylation of
phenylurea followed by base promoted cyclization, and represented one of the most efficient pathways for
the synthesis of quinazolineꢀ2,4(1H,3H)ꢀdione. Here, we describe an alternative synthesis of
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quinazolineꢀ2,4(1H,3H)ꢀdiones (Path
b in Scheme 1b) from readily available benzamides with
2,2,2ꢀtrichloroethoxycarbonyl azide (TrocN3)12 as the aminocarbonyl source by
a
cesium
carboxylateꢀpromoted cascade C−H amidation/cyclization reaction.
Scheme 1. Methods for the Synthesis of Quinazolineꢀ2,4(1H, 3H)ꢀdiones
Inspired by the Irꢀcatalyzed C−H amination of arenes with organic azides developed by Chang4aꢀf, h and
others4g, and by our previous studies in C−H amination using different organic azides including TrocN3 as
amino soures,4i, l, 12, 13 we began our investigation by examining reactions of benzamides with TrocN3 (2a)
(Table 1, and Table S1 in Supporting Information [SI]). Using [IrCp*Cl2]2/AgNTf2 (4 mol %/16 mol %) to
catalyze the reaction,4f the amidated product was formed in only 29% yield (Table S1) with trace amount of
the desired cyclic product 3a even at 140 oC (Table 1, entry 1). Upon screening a variety of additives (entries
2ꢀ8), the desired product 3a was obtained efficiently when cesium carboxylate was used as the additive
(entries 7, 8). A variety of alkoxycarbonyl azides with different leaving groups (LG) were tested (entries
8ꢀ12), and TrocN3 was found to be the best choice (entry 8). Further screening indicated
[Ru(pꢀcymene)Cl2]2/AgNTf2 was not an ideal catalyst (entry 13) and no desired product was formed with
other catalysts such as [RhCp*Cl2]2/AgSbF6, Pd(OAc)2, Co(acac)2 and Ni(OTf)2 (Table S1).
A range of orthoꢀ and paraꢀsubstituted benzamides were employed under the optimized conditions,
forming the corresponding quinazolinone derivatives effectively (Scheme 2). Benzamides with different
Nꢀalkyl substituents (3aꢀd), with electronꢀwithdrawing (3eꢀj) and ꢀdonating groups (3kꢀn) at the
paraꢀposition of the phenyl ring were well tolerated, the desired products being obtained in good yield. The
Table 1. Optimization of Reaction Conditionsa
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entry
1
2
cat.
additive
ꢀ
3a(%)
<5
ꢀ
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2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2a
[IrCp*Cl2]2/AgNTf2
[IrCp*Cl2]2/AgNTf2
[IrCp*Cl2]2/AgNTf2
[IrCp*Cl2]2/AgNTf2
[IrCp*Cl2]2/AgNTf2
[IrCp*Cl2]2/AgNTf2
[IrCp*Cl2]2/AgNTf2
[IrCp*Cl2]2/AgNTf2
[IrCp*Cl2]2/AgNTf2
[IrCp*Cl2]2/AgNTf2
[IrCp*Cl2]2/AgNTf2
[IrCp*Cl2]2/AgNTf2
2
Cs2CO3
AgOAc
NaOAc
K2CO3
KOtBu
CsOPiv
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
3
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<5
ꢀ
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85
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46
[Ru(pꢀcymene)Cl2]2/AgNTf2 CsOAc
a Yield was calculated based on crude 1H NMR using CH2Br2 as the standard.
Scheme 2. Scope of orthoꢀ and paraꢀsubstituted Benzamides 1a
a Isolated yield. b 1a (8.0 mmol), 2a (9.6 mmol) was used, 1.311 g of product 3a was obtained.
ortho substitution of the phenyl ring does not affect the reactivity (3oꢀp). Various functional groups, such as
ester (3e), halogens (3f, 3hꢀi, 3p), nitro (3j), methoxyl (3l) and amino (3mꢀn) groups were well tolerated,
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which is important for subsequent transformations. It could be noted that this cascade cyclization can be
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conducted on a gramꢀscale, the desired product 3a being produced facilely.
Scheme 3. Regioselectivity of C−H Amidation of metaꢀsubstituted Benzamides a
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a Isolated yield. b The ratio of the products 3/3′. c Using CsOPiv instead of CsOAc.
Various metaꢀsubstituted benzamides were employed in this reaction (Scheme 3). Metaꢀsubstitution can
affect both the steric and electron density of the reaction site, which can control the selectivity of C–H
activation.14 In this reaction, various electronꢀrich (3qꢀs) and ꢀdeficient (3tꢀw) functional groups can control
C−H amidation occurring at the less hindered position. The C−H bond at the 3ꢀposition of 2ꢀnaphthamide
could also be activated to form benzo[g]quinazolineꢀ2,4(1H,3H)ꢀdione (3x) in high yield and
regioselectivity. However, when the metaꢀposition of the benzamide was substituted with methoxyl or
bromine, a mixture of regioisomers was isolated (3y and 3y′, 3z and 3z′). This can be explained in terms of
the ortho directing effect of the strongly electronegative substituents, which was also observed in other C−H
activation reactions.4l,14 Interestingly, in addition to reactivity, the carboxylate salts can control the
regioselectivity. For example, C−H amidation took place selectively at the less hindered site when the
cesium salt with bulkier carboxylate ligand (CsOPiv) was used as the additive (3yꢀz).
In addition to the diverse array of biological activities,8 the quinazolineꢀ2,4(1H,3H)ꢀdiones (3) formed
could serve as valuable synthetic intermediates for applications in biology and medicine.9 For example, 3r is
a key intermediate in the production of FK 313279a and FK 3669b; 3w is a key intermediate in the production
of various drugs such as alfuzosin, prazosin, terazosin, doxazosin, and iodoazidoarylprazosin (IAAP).9cꢀe 3a
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can also be efficiently converted to 2,4ꢀdichloroquinazoline (8), which is the key precursor of a vaccine
adjuvant.15 Furthermore, the nonꢀoxidative reaction conditions may allow for direct use of substrates that are
bioactive relevant. For example, amidation of the estroneꢀbased substrate (4a) could provide the new
quinazolineꢀ2,4(1H,3H)ꢀdioneꢀbased estrone derivative (5a) in good yield and with good regioselectivity (Eq
1).
9
Several experiments have been performed to explore the mechanism of this reaction (Scheme 4). When
the cyclometalated Ir(III) complex (6) was used as the catalyst, the desired product (3a) was obtained in 83%
yield (Scheme 4a). This result suggests that an iridacyclic intermediate is involved in the catalytic cycle. The
electronic effect on the phenyl ring was investigated through competition experiments, and the electronꢀrich
benzamide (1l) was found to exhibit much higher reactivity (Scheme 4b). When the amount of CsOAc was
reduced and the reaction temperature was lowered, the predominant product was anthranilamide (7a), a
moiety found in many drugs and drug candidates,16 and at the same time, less than 5% of the product (3a)
was observed (Scheme 4c). Then, promoted by excess CsOAc (2.0 equiv), the amidated compound (7a)
could easily cyclize to form product 3a without side reactions. Finally, kinetic isotope effects were observed
on the basis of an intermolecular competition experiment in one vessel (PH/PD = 3.6) with no H/D
scrambling detected between substrates 1a and [D5]ꢀ1a (Scheme 4d), implying that C−H bond cleavage is
likely to be the rateꢀlimiting step.
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Scheme 4. Mechanistic Studies
In the experiments described above and previous studies, 4a, fꢀh a possible mechanistic pathway has been
proposed (Scheme 5). In this scheme, IrCp*(NTf)(OCOR) is formed by the catalytic amount of [IrCp*Cl2]2,
AgNTf2 and Cs(OCOR). This active species induces C−H bond cleavage through transition state I. In this
step, both substrate and carboxylate control the regioselectivity of the reactions when using a
metaꢀsubstituted benzamide as the substrate (Scheme 3). The cyclometalated Ir(III) complex II produced
coordinates the azide (2) to form III, which undergoes migratory insertion and release of N2 to give IV.
Protonolysis of IV regenerates the active Ir species, completing the cycle. Meanwhile, it provides the
amidation product (7) which forms the cyclic product (3) through an intramolecular substitution process with
the aid of excess cesium carboxylate.
Scheme 5. Proposed Mechanistic Pathway
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In summary, a cesium carboxylateꢀpromoted Irꢀcatalyzed C−H amidation/cyclization using TrocN3 as the
aminocarbonyl source has been achieved. Various benzamides were selectively amidated/cyclized under
nonꢀoxidative reaction conditions with excellent regioselectivity and high functionalꢀgroup tolerance. In this
reaction, two new C−N bonds are formed by breaking C−H and N−H bonds sequence. This offers a direct
and convenient route for the synthesis of functionalized quinazolineꢀ2,4(1H,3H)ꢀdiones, which are important
building blocks and key synthetic intermediates for applications in biology and medicine. The mechanistic
investigation suggests that the reactions undergo C−H activation and SN2 type intramolecular nucleophilic
substitution.
EXPERIMENTAL SECTION
General Information. Unless otherwise mentioned, all commercial reagents and solvents were used
without further purification. Thin layer chromatography (TLC) was performed on preꢀcoated silica gel
GF254 plates. Visualization of TLC was achieved by the use of UV light (254 nm). Column chromatography
1
was performed on silica gel (300ꢀ400 mesh) using a proper eluent. H NMR was recorded on FT AM 400
(400 MHz). Chemical shifts were reported in parts per million (ppm) referenced to the appropriate solvent
peak or 0.0 ppm for tetramethylsilane or chloroformꢀd (CDCl3) at 7.26 ppm. The following abbreviations
were used to describe peak splitting patterns: br = broad, s = singlet, d = doublet, t = triplet, q = quartet, dd =
doublet of doublet, td = triplet of doublet, ddd = doublet of doublet of doublet, m = multiplet. Coupling
constants, J, were reported in hertz (Hz). The fully decoupled 13C NMR was recorded on FT AM 400 (100
MHz). Chemical shifts were reported in ppm referenced to the center of a triplet at 77.0 ppm of
chloroformꢀd. Infrared (IR) spectra were recorded neat in KBr cell. Frequencies are given in centimeter
inverse (cmꢀ1) and only selected absorbance is reported. High resolution mass spectra were obtained by using
the UHD AccurateꢀMass QꢀTOF.
General Procedure for the Preparation of Benzamides. To a solution of benzoyl chloride (5 mmol) in
o
CH2Cl2 (20 mL) were slowly added alkylamine (6 mmol) and Et3N (0.85 mL, 6 mmol) at 0 C and the
reaction mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with 1N HCl
(30 mL), extracted with CH2Cl2 for several times, and then dried over Na2SO4. The crude product was
concentrated under reduced pressure and purified by recrystallization with nꢀhexane/CH2Cl2 to give the
desired product. Physical and spectroscopic data are consistent with those reported in the literature.4l
(8R,9S,13S,14S)-N-(tert-butyl)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a
]phenanthrene-3-carboxamide (4a): TLC Rf = 0.70 (EA: PE = 1:1); yellowish solid; 1.33 g, 75% yield; mp
1
218ꢀ220 oC; [α]D25 = +113.6 (c = 1.00, CHCl3); H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 7.45 (d, J = 8.1
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Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 5.94 (s, 1H), 2.93 (dd, J = 10.8, 4.6 Hz, 2H), 2.50 (dd, J = 18.7, 8.6 Hz,
1H), 2.45ꢀ2.37 (m, 1H), 2.34ꢀ2.27 (m, 1H), 2.24ꢀ1.88 (m, 5H), 1.63ꢀ1.48 (m, 5H), 1.45 (s, 9H), 0.90 (s,
3H).13C NMR (101 MHz, CDCl3) δ 220.5, 166.8, 143.0, 136.8, 133.4, 127.6, 125.4, 123.8, 51.5, 50.5, 47.9,
44.5, 38.0, 35.8, 31.6, 29.3, 28.9, 26.3, 25.7, 21.6, 13.8; IR (neat): 2961, 2927, 2857, 1738, 1652, 1530,
1492, 1452, 1313, 1217, 1052, 757 cmꢀ1. HRMS (ESI) ([M+Na]+) Calcd. for C23H31NO2: 376.2252, found:
376.2252. The absolute configuration of compound 4a was determined from the start material
(8R,9S,13S,14S)ꢀ3ꢀhydroxyꢀ13ꢀmethylꢀ7,8,9,11,12,13,15,16ꢀoctahydroꢀ6Hꢀcyclopenta[a]phenanthrenꢀ17(14
H)ꢀone (CAS# 53ꢀ16ꢀ7 ), and The Procedure for the Preparation involved reaction of compound 4a was
found to proceed with stereo retention according to the existing reported in the literature.17
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A screwꢀcap vial equipped with a magnetic stir bar was charged with the aryl halide (1.0 mmol),
secondary amine (1.2 mmol), Pd(OAc)2 (0.01 mmol), RuPhos (0.02 mmol), and powdered NaOtBu (1.2
mmol). The vial was transferred to a preheated oil bath (120 °C). After 4 h, the reaction mixture was cooled
and dissolved in CH2Cl2/H2O mixture (1:1). The organic phase was separated, the solvent was evaporated in
vacuo, and the product (3m, 3n, 3u and 3v) was isolated by flash chromatography on a silica gel column
(CH2Cl2 or CH2Cl2/methyl tertꢀbutyl ether). Physical and spectroscopic data are consistent with those
reported in the literature.4l
General Procedure for the Preparation of Acyl Azides. To a wellꢀstirred suspension of NaN3 (1.95 g,
30 mmol) in acetone (40 mL) protected from light by aluminum foil was added acyl chloride (20 mmol) at
room temperature. The reaction was monitored by TLC. After the reaction finished, the mixture was then
poured into a flash chromatography column filled with Celite (dry) and was washed with methylene chloride
until all the product was washed out. The filtrate was collected and concentrated by rotary evaporation at
room temperature to give the product, which was further purified by flash chromatography column (silica
gel). Physical and spectroscopic data are consistent with those reported in the literature.12
1
heptyl carbonazidate (2b): TLC Rf = 0.60 (EA: PE = 1:20); colorless oil; 3.33 g, 90% yield; H NMR
(400 MHz, CDCl3) δ 4.19 (t, J = 6.7 Hz, 2H), 1.71ꢀ1.62 (m, 2H), 1.37ꢀ1.23 (m, 8H), 0.87 (t, J = 6.9 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 157.5, 68.8, 31.6, 28.8, 28.4, 25.5, 22.5, 14.0; IR (neat): 2959, 2931, 2859,
2186, 2136, 1759, 1733, 1237, 753 cmꢀ1; HRMS (DART) ([M+H]+) Calcd. for C8H15N3O2: 186.1237, found:
186.1238.
General Procedure for the IrꢀCatalyzed CꢀH Amidation/ Cyclizition. To a screw capped vial equipped
with a spinvane triangularꢀshaped Teflon stirbar were added benzamide (1, 0.2 mmol), Troc azides (2, 52.4
mg, 0.24 mmol), [IrCp*Cl2]2 (6.4 mg, 4 mol %), AgNTf2 (12.4 mg, 16 mol %), CsOAc (115.2 mg, 3 equiv.)/
CsOPiv (140.4 mg, 3 equiv.) and chlorobenzene (2 mL) under N2 conditions. The reaction mixture was
o
stirred in a preꢀheated oil bath at 140 C for 24 h. The reaction was cooled to room temperature, filtered
through a pad of celite and then washed with CH2Cl2 (10 mL x 3). The solvents were removed under reduced
pressure and the crude reaction mixture was purified by silica gel column chromatography with
nꢀHexane/EtOAc as an eluent to give the desired product.
Spectroscopic
Data
of
Compounds
Obtained
in
this
Study.
3-(tert-butyl)quinazoline-2,4(1H,3H)-dione18 (3a): TLC Rf = 0.20 (EA: PE = 1:10); yellowish solid; 35.4
o
1
mg, 81% yield; mp 197ꢀ198 C; H NMR (400 MHz, CDCl3) δ 10.54 (s, 1H), 8.01 (d, J = 7.4 Hz, 1H),
7.57ꢀ7.51 (m, 1H), 7.18ꢀ7.13 (m, 1H), 7.02 (d, J = 8.0 Hz, 1H), 1.80 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
164.4, 153.5, 138.2, 134.4, 128.1, 122.8, 117.0, 114.1, 62.1, 30.0; IR (neat): 3901, 3839, 3818, 3687, 2988,
1658, 1396, 1275, 1261, 764, 750 cmꢀ1; HRMS (ESI) ([MꢀH]+) Calcd. for C12H14N2O2: 217.0977, found:
217.0976.
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3-((3s,5s,7s)-adamantan-1-yl)quinazoline-2,4(1H,3H)-dione19 (3b): TLC Rf = 0.25 (EA: PE = 1:10);
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white solid; 49.2 mg, 83% yield; mp 233ꢀ234 C; H NMR (400 MHz, CDCl3) δ 9.86 (s, 1H), 7.98 (d, J =
7.9 Hz, 1H), 7.56ꢀ7.50 (m, 1H), 7.18ꢀ7.11 (m, 1H), 6.97 (d, J = 8.0 Hz, 1H), 2.65 (d, J = 1.7 Hz, 6H), 2.19
(s, 3H), 1.82 (d, J = 11.8 Hz, 3H), 1.71 (d, J = 12.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 164.5, 153.0,
138.0, 134.2, 128.1, 122.8, 117.5, 113.8, 65.6, 40.2, 36.5, 30.7; IR (neat): 3950, 3901, 3830, 3735, 3449,
2906, 1710, 1654, 1275, 1261, 764, 751 cmꢀ1; HRMS (ESI) ([MꢀH]+) Calcd. for C18H20N2O2: 295.1447,
found: 295.1447.
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3-cyclopentylquinazoline-2,4(1H,3H)-dione20 (3c): TLC Rf = 0.40 (DCM: PE: Et2O = 10: 10: 1); white
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solid; 36.8 mg, 80% yield; mp 240ꢀ241 C; H NMR (400 MHz, Acetone) δ 10.15 (s, 1H), 8.01 (d, J = 7.9
Hz, 1H), 7.66 ꢀ7.60 (m, 1H), 7.27ꢀ7.18 (m, 2H), 5.45ꢀ5.36 (m, 1H), 2.18 (dd, J = 11.8, 7.8 Hz, 2H),
2.00ꢀ1.92 (m, 2H), 1.87ꢀ1.78 (m, 2H), 1.65ꢀ1.56 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 162.8, 152.3,
138.6, 134.8, 128.4, 123.2, 115.1, 114.7, 53.2, 28.6, 26.0; IR (neat): 3957, 3800, 3570, 3368, 2936, 1735,
1718, 1701, 1654, 1605, 1561, 1493, 1449, 1276, 1261, 763, 750 cmꢀ1; HRMS (ESI) ([MꢀH]+) Calcd. for
C13H14N2O2: 229.0977, found: 229.0977.
3-isopropylquinazoline-2,4(1H,3H)-dione18 (3d): TLC Rf = 0.38 (DCM: PE: Et2O = 10: 10: 1); white
solid; 28.2 mg, 69% yield; mp 187ꢀ188 oC; 1H NMR (400 MHz, CDCl3) δ 10.27 (s, 1H), 8.12 (d, J = 7.8 Hz,
1H), 7.60 (dd, J = 11.2, 4.2 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H), 5.29ꢀ5.40 (m, 1H),
1.58 (d, J = 6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 162.7, 152.2, 138.7, 134.8, 128.4, 123.2, 115.1,
114.6, 45.8, 19.6; IR (neat): 3509, 3359, 3067, 3005, 2971, 2936, 1712, 1655, 1624, 1493, 1445, 1410, 1387,
1276, 1264, 1070, 861, 814, 746 cmꢀ1; HRMS (ESI) ([MꢀH]+) Calcd. for C11H12N2O2: 203.0821, found:
203.0820.
methyl 3-(tert-butyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (3e): TLC Rf = 0.10 (DCM:
PE: Et2O = 10: 10: 1); white solid; 48.1 mg, 87% yield; mp 210ꢀ211 oC; 1H NMR (400 MHz, CDCl3) δ 8.90
(s, 1H), 8.10 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.67 (s, 1H), 3.99 (s, 3H), 1.81 (s, 9H); 13C NMR
(101 MHz, CDCl3) δ 165.7, 163.5, 152.0, 137.7, 135.3, 128.6, 123.3, 120.1, 115.2, 62.5, 52.7, 29.8; IR
(neat): 2954, 2925, 2854, 1721, 1668, 1605, 1520, 1436, 1398, 1366, 1294, 1233, 757 cmꢀ1; HRMS (ESI)
([MꢀH]+) Calcd. for C14H16N2O4: 275.1032, found: 275.1032.
3-(tert-butyl)-7-fluoroquinazoline-2,4(1H,3H)-dione (3f): TLC Rf = 0.25 (DCM: PE: Et2O = 10: 10: 1);
white solid; 31.2 mg, 66% yield; mp 177ꢀ178 oC; 1H NMR (400 MHz, Acetone) δ 10.02 (s, 1H), 7.96 (dd, J
= 8.7, 6.1 Hz, 1H), 6.91 (ddd, J = 19.1, 9.5, 2.3 Hz, 2H), 1.71 (s, 9H); 13C NMR (101 MHz, Acetone) δ
166.1 (d, J = 251.7 Hz, 2H), 163.1, 151.1, 140.82 (d, J = 12.9 Hz, 2H), 130.72 (d, J = 11.1 Hz, 3H), 113.56
(d, J = 2.0 Hz, 1H), 109.8 (d, J = 23.4 Hz, 1H), 100.3 (d, J = 26.5 Hz, 1H), 60.7, 29.1; 19F NMR (376 MHz,
Acetone) δ ꢀ105.9; IR (neat): 3424, 2930, 1720, 1655, 1618, 1496, 1381, 1292, 1169, 858, 766 cmꢀ1; HRMS
(ESI) ([MꢀH]+) Calcd. for C12H13FN2O2: 235.0883, found: 235.0883.
3-(tert-butyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (3g): TLC Rf = 0.25 (EA: PE = 1: 10);
white solid; 46.9 mg, 82% yield; mp 197ꢀ198 oC; 1H NMR (400 MHz, Acetone) δ 10.13 (s, 1H), 8.10 (d, J =
8.2 Hz, 1H), 7.49 (s, 1H), 7.45 (d, J = 8.3 Hz, 1H), 1.73 (s, 9H); 13C NMR (101 MHz, Acetone) δ 163.1,
150.8, 139.2, 134.7 (q, J = 32.6 Hz), 129.0, 123.6 (q, J = 273.2 Hz), 119.6, 118.1 (q, J = 3.6 Hz), 111.3 (q, J
= 4.2 Hz), 61.0, 28.9; 19F NMR (376 MHz, Acetone) δ ꢀ63.9; IR (neat): 3954, 3773, 3454, 3004, 1716, 1655,
1610, 1493, 1420, 1322, 1262, 1169, 1138, 882, 765, 750 cmꢀ1; HRMS (ESI) ([MꢀH]+) Calcd. for
C13H13F3N2O2: 285.0851, found: 285.0855.
3-(tert-butyl)-7-chloroquinazoline-2,4(1H,3H)-dione (3h): TLC Rf = 0.35 (EA: PE = 1: 10); white solid;
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33.9 mg, 67% yield; mp 189ꢀ190 oC; H NMR (400 MHz, CDCl3) δ 9.80 (s, 1H), 7.94 (d, J = 8.5 Hz, 1H),
7.12 (dd, J = 8.5, 1.7 Hz, 1H), 6.98 (d, J = 1.8 Hz, 1H), 1.78 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 163.4,
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152.8, 140.5, 138.8, 129.7, 123.5, 115.4, 113.8, 62.5, 29.9; IR (neat): 3005, 2990, 2303, 1654, 1467, 1275,
1261, 750 cmꢀ1; HRMS (ESI) ([MꢀH]+) Calcd. for C12H13ClN2O2: 251.0588, found: 251.0588.
7-bromo-3-(tert-butyl)quinazoline-2,4(1H,3H)-dione (3i): TLC Rf = 0.20 (DCM: PE: Et2O = 10: 10: 1);
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white solid; 35.1 mg, 59% yield; mp 199ꢀ200 C; 1H NMR (400 MHz, CDCl3) δ 10.14 (s, 1H), 7.86 (d, J =
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8.5 Hz, 1H), 7.29ꢀ7.26 (m, 1H), 7.17 (d, J = 1.6 Hz, 1H), 1.79 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 163.,
153.0, 138.9, 129.7, 128.9, 126.3, 116.9, 115.8, 62.5, 29.9; IR (neat): 2923, 1709, 1654, 1601, 1412, 1367,
1276, 1261, 1140, 858, 805, 750 cmꢀ1; HRMS (ESI) ([MꢀH]+) Calcd. for C12H13BrN2O2: 295.0082, found:
295.0083.
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3-(tert-butyl)-7-nitroquinazoline-2,4(1H,3H)-dione (3j): TLC Rf = 0.35 (DCM: PE: Et2O = 10: 10: 1);
yellowish solid; 45.3 mg, 86% yield; mp 348ꢀ349 oC; 1H NMR (400 MHz, CDCl3) δ 10.19 (s, 1H), 8.20 (d,
J = 8.6 Hz, 1H), 7.97 (dd, J = 8.6, 2.0 Hz, 1H), 7.86 (d, J = 2.0 Hz, 1H), 1.81 (s, 9H); 13C NMR (101 MHz,
CDCl3) δ 162.6, 152.6, 151.4, 138.4, 130.2, 121.1, 117.1, 109.5, 63.2, 29.8; IR (neat): 3901, 3688, 2931,
1720, 1667, 1537, 1421, 750 cmꢀ1; HRMS (ESI) ([MꢀH]+) Calcd. for C12H13N3O4: 262.0828, found:
262.0828.
3-(tert-butyl)-7-methylquinazoline-2,4(1H,3H)-dione (3k): TLC Rf = 0.25 (EA: PE = 1: 10); yellowish
solid; 33.0 mg, 71% yield; mp 173ꢀ174 oC; 1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H), 7.88 (d, J = 8.1 Hz,
1H), 6.96 (d, J = 8.1 Hz, 1H), 6.78 (s, 1H), 2.40 (s, 3H), 1.80 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 164.4,
153.5, 145.5, 138.2, 128.0, 124.2, 114.6, 114.0, 61.9, 30.0, 21.9; IR (neat): 3974, 3848, 3800, 3726, 3705,
3635, 2977, 1708, 1654, 1605, 1483, 1412, 1366, 1288, 1177, 1139, 1021, 867, 773 cmꢀ1; HRMS (ESI)
([MꢀH]+) Calcd. for C13H16N2O2: 231.1134, found: 231.1135.
3-(tert-butyl)-7-methoxyquinazoline-2,4(1H,3H)-dione (3l): TLC Rf = 0.20 (EA: PE = 1: 3); white solid;
43.2 mg, 87% yield; mp 159ꢀ160 oC; 1H NMR (400 MHz, CDCl3) δ 10.35 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H),
6.70 (dd, J = 8.8, 2.3 Hz, 1H), 6.43 (d, J = 2.3 Hz, 1H), 3.85 (s, 3H), 1.79 (s, 9H); 13C NMR (101 MHz,
CDCl3) δ 164.6, 164.0, 153.7, 134.0, 130.0, 111.0, 110.3, 97.1, 61.9, 55.6, 30.1; IR (neat): 3950, 3688, 3026,
2973, 2939, 1707, 1652, 1608, 1517, 1423, 1364, 1216, 1177, 1129, 1021, 832, 773, 708 cmꢀ1; HRMS (ESI)
([MꢀH]+) Calcd. for C13H16N2O3: 247.1083, found: 247.1087.
3-(tert-butyl)-7-(methyl(phenyl)amino)quinazoline-2,4(1H,3H)-dione (3m): TLC Rf = 0.45 (EA: PE = 1:
5); white solid; 50.4 mg, 78% yield; mp 193ꢀ194 oC; 1H NMR (400 MHz, CDCl3) δ 9.69 (s, 1H), 7.76 (d, J =
8.9 Hz, 1H), 7.42 (t, J = 7.8 Hz, 2H), 7.28ꢀ7.19 (m, 3H), 6.51 (dd, J = 8.9, 2.1 Hz, 1H), 6.13 (d, J = 2.1 Hz,
1H), 3.35 (s, 3H), 1.71 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 164.2, 153.8, 153.6, 146.9, 139.7, 123.0,
129.2, 126.6, 126.2, 110.1, 107.2, 96.2, 61.5, 40.3, 30.2; IR (neat): 3506, 3454, 3259, 2922, 1701, 1654,
1625, 1590, 1561, 1493, 1420, 1389, 1276, 1261, 765, 750 cmꢀ1; HRMS (ESI) ([MꢀH]+) Calcd. for
C19H21N3O2: 322.1556, found: 322.1556.
3-(tert-butyl)-7-(pyrrolidin-1-yl)quinazoline-2,4(1H,3H)-dione (3n): TLC Rf = 0.30 (EA: PE = 1: 5);
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white solid; 47.7 mg, 83% yield; mp 360ꢀ361 oC; H NMR (400 MHz, DMSO) δ 10.59 (s, 1H), 7.58 (d, J =
8.8 Hz, 1H), 6.36 (dd, J = 8.9, 2.1 Hz, 1H), 5.99 (d, J = 2.0 Hz, 1H), 3.26 (t, J = 6.5 Hz, 4H), 1.96 (t, J = 6.5
Hz, 4H), 1.64 (s, 9H); 13C NMR (101 MHz, DMSO) δ 164.1, 152.2, 151.8, 140.8, 129.1, 108.2, 104.8, 93.8,
60.0, 47.8, 30.3, 25.4; IR (neat): 3415, 3334, 2956, 1735, 1701, 1618, 1483, 1414 cmꢀ1; HRMS (ESI)
([MꢀH]+) Calcd. for C16H21N3O2: 286.1556, found: 286.1558.
3-(tert-butyl)-5-methylquinazoline-2,4(1H,3H)-dione (3o): TLC Rf = 0.30 (EA: PE = 1: 10); yellowish
solid; 35.3 mg, 76% yield; mp 212ꢀ213 oC; 1H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 7.36 (t, J = 7.8 Hz,
1H), 6.93 (d, J = 7.5 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 2.67 (s, 3H), 1.77 (s, 9H); 13C NMR (101 MHz,
CDCl3) δ 165.3, 153.0, 141.1, 139.0, 133.0, 125.8, 115.9, 112.2, 61.1, 29.7, 22.0; IR (neat): 2923, 1710,
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1654, 1617, 1561, 1438, 1396, 1275, 1261, 764, 750 cmꢀ1; HRMS (ESI) ([MꢀH]+) Calcd. for C13H16N2O2:
231.1134, found: 231.1139.
3-(tert-butyl)-5-iodoquinazoline-2,4(1H,3H)-dione (3p): TLC Rf = 0.40 (EA: PE = 1: 5); yellowish solid;
58.5 mg, 85% yield; mp 219ꢀ220 oC; 1H NMR (400 MHz, CDCl3) δ 10.65 (s, 1H), 7.78 (d, J = 7.6 Hz, 1H),
7.13 (t, J = 7.9 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 1.76 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 162.9, 152.5,
139.4, 136.7, 134.1, 117.5, 114.8, 93.5, 61.9, 29.6; IR (neat): 3187, 3119, 2977, 2924, 1715, 1665, 1600,
1583, 1430, 1363, 1276, 1224, 1128, 790 cmꢀ1; HRMS (ESI) ([MꢀH]+) Calcd. for C12H13IN2O2: 342.9944,
found: 342.9944.
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3-(tert-butyl)-6-fluoroquinazoline-2,4(1H,3H)-dione (3q): TLC Rf = 0.35 (EA: PE = 1: 10); white solid;
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34.5 mg, 73% yield; mp 213ꢀ214 oC; H NMR (400 MHz, CDCl3) δ 9.01 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H),
7.33ꢀ7.27 (m, 1H), 7.08 (td, J = 8.1, 4.8 Hz, 1H), 1.77 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 163.3, 151.5,
148.6 (d, J = 247.7 Hz), 127.2 (d, J = 14.1 Hz), 123.4 (d, J = 3.8 Hz), 122.3 (d, J = 6.4 Hz), 119.3 (d, J =
16.6 Hz), 118.9 (d, J = 1.7 Hz), 62.4, 29.8; 19F NMR (376 MHz, CDCl3) δ ꢀ135.3; IR (neat): 2923, 1715,
1660, 1458, 1387, 1275, 1261, 764, 750 cmꢀ1; HRMS (ESI) ([MꢀH]+) Calcd. for C12H13FN2O2: 235.0883,
found: 235.0885.
3-(tert-butyl)-6-chloroquinazoline-2,4(1H,3H)-dione (3r): TLC Rf = 0.40 (EA: PE = 1: 10); yellowish
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solid; 30.8 mg, 61% yield; mp 171ꢀ172 oC; H NMR (400 MHz, CDCl3) δ 9.25 (s, 1H), 7.99 (d, J = 2.3 Hz,
1H), 7.48 (dd, J = 8.5, 2.3 Hz, 1H), 6.91 (d, J = 8.6 Hz, 1H), 1.77 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
163.1, 152.2, 136.3, 134.5, 128.4, 127.8, 118.1, 115.3, 62.5, 29.8; IR (neat): 3747, 3006, 1275, 1261, 764,
750 cmꢀ1; HRMS (ESI) ([MꢀH]+) Calcd. for C12H13ClN2O2: 251.0588, found: 251.0587.
3-(tert-butyl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (3s): TLC Rf = 0.20 (EA: PE = 1: 10);
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yellowish solid; 48.7 mg, 85% yield; mp 172ꢀ173 C; H NMR (400 MHz, CDCl3) δ 10.24 (s, 1H), 8.32 (s,
1H), 7.77 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 1.80 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 163.1,
152.8, 140.3, 131.0 (q, J = 3.5 Hz), 126.2 (q, J = 4.1 Hz), 125.4 (q, J = 34.1 Hz), 122.3, 116.8, 114.6, 62.8,
29.8; 19F NMR (376 MHz, CDCl3) δ ꢀ62.2; IR (neat): 3954, 3800, 3602, 3418, 2926, 1734, 1671, 1618,
1367, 1320, 1299, 1256, 1129, 1067, 841, 786 cmꢀ1; HRMS (ESI) ([MꢀH]+) Calcd. for C13H13F3N2O2:
285.0851, found: 285.0859.
3-(tert-butyl)-6-methylquinazoline-2,4(1H,3H)-dione (3t): TLC Rf = 0.20 (EA: PE = 1: 10); yellowish
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solid; 38.6 mg, 83% yield; mp 189ꢀ190 C; H NMR (400 MHz, CDCl3) δ 10.36 (s, 1H), 7.80 (s, 1H), 7.35
(dd, J = 8.2, 1.2 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 2.36 (s, 3H), 1.79 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
164.5, 153.4, 136.0, 135.4, 132.5, 127.6, 116.8, 114.0, 61.9, 30.0, 20.8; IR (neat): 3935, 3357, 2974, 1719,
1655, 1519, 1427, 1365, 1275, 1261, 822, 764, 750 cmꢀ1; HRMS (ESI) ([MꢀH]+) Calcd. for C13H16N2O2:
231.1134, found: 231.1137.
3-(tert-butyl)-6-morpholinoquinazoline-2,4(1H,3H)-dione (3u): TLC Rf = 0.50 (EA: PE = 1: 1); yellowish
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solid; 52.8 mg, 87% yield; mp 189ꢀ190 oC; H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 7.47 (d, J = 2.6 Hz,
1H), 7.21 (dd, J = 8.8, 2.7 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 3.90ꢀ3.83 (m, 4H), 3.18ꢀ3.10 (m, 4H), 1.78 (s,
9H); 13C NMR (101 MHz, CDCl3) δ 164.5, 152.8, 147.4, 131.8, 124.3, 117.5, 115.0, 113.2, 66.8, 62.0, 50.0,
30.0; IR (neat): 3207, 2962, 2924, 2854, 1710, 1660, 1622, 1516, 1431, 1368, 1264, 1121, 892, 813 cmꢀ1;
HRMS (ESI) ([MꢀH]+) Calcd. for C16H21N3O3: 302.1505, found: 302.1488.
3-(tert-butyl)-6-(methyl(phenyl)amino)quinazoline-2,4(1H,3H)-dione (3v): TLC Rf = 0.45 (EA: PE = 1:
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5); yellowish solid; 52.4 mg, 81% yield; mp 185ꢀ186 C; H NMR (400 MHz, CDCl3) δ 9.81 (s, 1H), 7.64
(d, J = 2.5 Hz, 1H), 7.27 (dt, J = 8.1, 6.5 Hz, 3H), 6.97 (t, J = 6.9 Hz, 3H), 6.89 (d, J = 8.7 Hz, 1H), 3.32 (s,
3H), 1.79 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 164.3, 152.9, 148.9, 144.8, 132.7, 129.4, 128.5, 121.6,
120.3, 118.1, 117.8, 114.9, 62.1, 40.6, 30.0; IR (neat): 3201, 3065, 3030, 2955, 2925, 1712, 1662, 1625,
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1515, 1496, 1433, 1367, 1284, 1188, 1111, 695 cmꢀ1; HRMS (ESI) ([MꢀH]+) Calcd. for C19H21N3O2:
322.1556, found: 322.1552.
3-(tert-butyl)-6,7-dimethoxyquinazoline-2,4(1H,3H)-dione (3w): TLC Rf = 0.10 (EA: PE = 1: 3);
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yellowish solid; 37.3 mg, 67% yield; mp 180ꢀ181 C; H NMR (400 MHz, CDCl3) δ 10.30 (s, 1H), 7.40 (s,
1H), 6.45 (s, 1H), 3.93 (s, 3H), 3.91 (s, 3H), 1.80 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 164.1, 155.0,
153.6, 145.7, 133.8, 109.0, 108.2, 96.3, 62.1, 56.3, 56.2, 30.2; IR (neat): 3345, 3145, 2938, 1704, 1650,
1510, 1423, 1275, 1260, 764, 750 cmꢀ1; HRMS (ESI) ([MꢀH]+) Calcd. for C14H18N2O4: 277.1189, found:
277.1197.
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3-(tert-butyl)benzo[g]quinazoline-2,4(1H,3H)-dione (3x): TLC Rf = 0.10 (EA: PE = 1: 10); yellowish
solid; 40.2 mg, 75% yield; mp 223ꢀ224 oC; 1H NMR (400 MHz, Acetone) δ 9.96 (s, 1H), 8.57 (s, 1H), 8.04
(d, J = 8.3 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.60ꢀ7.55 (m, 1H), 7.52 (s, 1H), 7.47ꢀ7.41 (m, 1H), 1.75 (s,
9H); 13C NMR (101 MHz, Acetone) δ 164.0, 151.1, 136.6, 134.9, 129.4, 129.2, 129.0, 128.8, 126.7, 124.7,
118.0, 109.1, 60.4, 29.1; IR (neat): 3953, 3601, 3508, 3369, 1703, 1660, 1417, 1396, 1188, 873, 779, 761,
737 cmꢀ1; HRMS (ESI) ([MꢀH]+) Calcd. for C16H16N2O2: 267.1134, found: 267.1134.
3-(tert-butyl)-6-methoxyquinazoline-2,4(1H,3H)-dione (3y): TLC Rf = 0.30 (EA: PE = 1: 5); yellowish
solid; 40.7 mg, 82% yield; mp 186ꢀ187 oC; 1H NMR (400 MHz, CDCl3) δ 10.01 (s, 1H), 7.46 (d, J = 2.8 Hz,
1H), 7.15 (dd, J = 8.8, 2.9 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 3.84 (s, 3H), 1.80 (s, 9H); 13C NMR (101 MHz,
CDCl3) δ 164.3, 155.5, 153.0, 132.3, 123.9, 117.5, 115.5, 108.9, 62.1, 55.8, 30.0; IR (neat): 2958, 2925,
1713, 1659, 1515, 1368, 1265, 1189, 1109, 1034, 822, 754, 680 cmꢀ1; HRMS (ESI) ([MꢀH]+) Calcd. for
C13H16N2O3: 247.1083, found: 247.1089.
3-(tert-butyl)-8-methoxyquinazoline-2,4(1H,3H)-dione (3y'): TLC Rf = 0.30 (EA: PE = 1: 5); yellowish
1
solid; 21.4 mg, 43% yield; mp 180ꢀ181 oC; H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 7.57 (d, J = 7.9 Hz,
1H), 7.07 (t, J = 7.9 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 3.93 (s, 3H), 1.76 (s, 9H); 13C NMR (101 MHz,
CDCl3) δ 164.3, 151.6, 145.1, 128.5, 122.3, 119.1, 117.4, 113.7, 61.9, 56.1, 29.9; IR (neat): 2945, 2925,
1716, 1656, 1520, 1270, 1109, 1035, 820, 754 cmꢀ1; HRMS (ESI) ([MꢀH]+) Calcd. for C13H16N2O3:
247.1083, found: 247.1089.
6-bromo-3-(tert-butyl)quinazoline-2,4(1H,3H)-dione (3z): TLC Rf = 0.30 (EA: PE = 1: 10); yellowish
1
solid; 33.9 mg, 57% yield; mp 143ꢀ144 oC; H NMR (400 MHz, CDCl3) δ 9.49 (s, 1H), 8.14 (d, J = 1.8 Hz,
1H), 7.62 (dd, J = 8.5, 2.1 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 1.77 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
163.0, 152.5, 137.2, 136.8, 130.8, 118.5, 115.7, 115.4, 62.5, 29.8; IR (neat): 3402, 2932, 1735, 1719, 1701,
1685, 1654, 1617, 1561, 1512, 1500, 1483, 1421, 1366, 1276, 750 cmꢀ1; HRMS (ESI) ([MꢀH]+) Calcd. for
C12H13BrN2O2: 295.0082, found: 295.0082.
8-bromo-3-(tert-butyl)quinazoline-2,4(1H,3H)-dione (3z'): TLC Rf = 0.50 (EA: PE = 1: 10); yellowish
1
solid; 18.4 mg, 31% yield; mp 169ꢀ170 oC; H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 7.8 Hz, 1H), 7.83 (s,
1H), 7.72 (dd, J = 7.9, 1.1 Hz, 1H), 7.05 (t, J = 7.9 Hz, 1H), 1.75 (s, 9H). 13C NMR (101 MHz, CDCl3) δ
163.3, 150.5, 137.0, 135.9, 127.8, 123.5, 118.2, 107.4, 62.3, 29.7；IR (neat): 3392, 2930, 1726, 1716, 1680,
1620, 1555, 1512, 1500, 1480, 1370, 1266, 755 cmꢀ1; HRMS (ESI) ([MꢀH]+) Calcd. for C12H13BrN2O2:
295.0082, found: 295.0080.
(3aS,3bR,11bS,13aS)-8-(tert-butyl)-13a-methyl-3,3a,4,5,8,10,11b,12,13,13a-decahydro-1H-cyclopenta[5,
6]naphtho[2,1-g]quinazoline-1,7,9(2H,3bH)-trione (5a): TLC Rf = 0.55 (EA: PE = 1: 1); yellowish solid;
o
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57.6 mg, 73% yield; mp 233ꢀ234 C; [α]D = +91.2 (c = 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ 9.73
(s, 1H), 7.71 (s, 1H), 6.90 (s, 1H), 2.99ꢀ2.87 (m, 2H), 2.52 (dd, J = 18.7, 8.6 Hz, 1H), 2.36ꢀ2.28 (m, 2H),
2.20ꢀ1.95 (m, 5H), 1.78 (s, 9H), 1.60ꢀ1.47 (m, 5H), 0.91 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 220.4,
164.4, 153.2, 147.5, 136.0, 131.7, 127.7, 114.9, 110.5, 61.9, 50.6, 47.8, 44.6, 37.6, 35.8, 31.5, 30.0, 28.5,
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26.3, 25.5, 21.6, 13.8; IR (neat): 3196, 3111, 3061, 3028, 2251, 1740, 1712, 1659, 1629, 1421, 1366, 1187,
913, 732 cmꢀ1; HRMS (ESI) ([MꢀH]+) Calcd. for C24H30N2O3: 393.2178, found: 393.2162. The absolute
configuration
of
compound
5a
was
determined
from
the
start
material
(8R,9S,13S,14S)ꢀ3ꢀhydroxyꢀ13ꢀmethylꢀ7,8,9,11,12,13,15,16ꢀoctahydroꢀ6Hꢀcyclopenta[a]phenanthrenꢀ17(14
H)ꢀone (CAS# 53ꢀ16ꢀ7 ) and compound 4a. The Procedure for the Preparation involved reaction of
compound 5a was found to proceed with stereo retention according to the existing reported in the literature.17
2,2,2-trichloroethyl (2-(tert-butylcarbamoyl)phenyl)carbamate (7a): TLC Rf = 0.50 (EA: PE = 1: 10);
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white solid, 57.4 mg, 78% yield; mp 137ꢀ138 oC; H NMR (400 MHz, CDCl3) δ 10.68 (s, 1H), 8.28 (d, J =
8.4 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.06 (s, 1H), 4.82 (s,
2H), 1.47 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 168.4, 152.0, 138.8, 132.2, 126.6, 122.5,121.9, 120.3,
95.4, 74.3, 52.2, 28.8. IR (neat): 3351, 2968, 2927, 1751, 1648, 1590, 1522, 1448, 1208, 1114, 756 cmꢀ1;
HRMS (ESI) ([M+Na]+) Calcd. for C14H17Cl3N2O3: 389.0202, found: 389.0192.4f
Preparation of Cyclometallated Complex and Catalytic Reaction. Complex 6 was prepared according
to literature report.21 To a screw capped vial equipped with a spinvane triangularꢀshaped Teflon stirbar were
added benzamide (1a, 35.4 mg, 0.2 mmol), Troc azides (2a, 52.4 mg, 0.24 mmol), Complex 6 (5.2 mg, 4
mol %), AgNTf2 (12.4 mg, 16 mol %), CsOAc (115.2 mg, 3 equiv.) and chlorobenzene (2 mL) under N2
o
conditions. The reaction mixture was stirred in a preꢀheated oil bath at 140 C for 24 h. The reaction was
cooled to room temperature, filtered through a pad of celite and then washed with CH2Cl2 (10 mL x 3). The
solvents were removed under reduced pressure, and the crude yield was measured by 1H NMR spectroscopy
using CH2Br2 as an internal standard.
Intermolecular Competition Experiments. To a screw capped vial equipped with a spinvane
triangularꢀshaped Teflon stirbar were added Nꢀtertbutylꢀ4ꢀ(trifluoromethyl)benzamide (1g, 49.0 mg, 0.2
mmol), Nꢀtertbutylꢀ4ꢀ(methoxyphenyl)benzamide (1l, 41.5 mg, 0.2 mmol), Troc azides (2a, 52.4 mg, 0.24
mmol), [IrCp*Cl2]2 (6.4 mg, 4 mol %), AgNTf2 (12.4 mg, 16 mol %), CsOAc (115.2 mg, 3 equiv.) and
chlorobenzene (2 mL) under N2 conditions. The reaction mixture was stirred in an oil bath at 140 oC for 12 h
with vigorous stirring. The reaction mixture was cooled to room temperature, filtered through a pad of celite
and then washed with CH2Cl2 (10 mL x 3). The solvents were removed under reduced pressure and 1H NMR
yield of the desired product was determined by integration using CH2Br2 as an internal standard.
Synthetic transformations of compound 3a. In a screw capped vial equipped with a spinvane
triangularꢀshaped Teflon stirbar was placed compound 3a (43.7 mg, 0.2 mmol) in Phosphoryl trichloride (2
mL), and then the solution were slowly added DIPEA (33.1 ꢁL, 0.2 mmol) under air conditions. The reaction
mixture was stirred at 100 oC for 4 h, then allow to cool to room temperature, and poured on ice. The water
layer was extracted with EtOAc (10 mL x 3). The organic layer was dried on MgSO4, and the solvent was
evaporated. Purification by flash column chromatography with DCM as the eluent provided the compound 8
as a white solid in 93% yield (37.0 mg).2,4-dichloroquinazoline (8): TLC Rf = 0.50 (DCM: PE = 2: 1);
o
1
white solid, 37.0 mg, 93% yield; mp 119ꢀ120 C; H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 8.4 Hz, 1H),
8.05ꢀ7.95 (m, 2H), 7.75 (ddd, J = 8.2, 5.3, 2.8 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 164.0, 155.2, 152.4,
136.1, 129.2, 128.0, 126.1, 122.4; IR (neat): 2925, 1611, 1544, 1480, 1446, 1371, 1340, 1267, 1185, 766,
cmꢀ1.22
ASSOCIATED CONTENT
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Experimental details, characterization data for the products, and NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
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Corresponding Author
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* Email: hongjianlu@nju.edu.cn.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We are grateful for financial support by National Natural Science Foundation of China (21332005, 21472085) and
Qing Lan Project.
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