Synthesis of quinazolin-4(3 H)-ones via amidine N-arylation

Article abstract of DOI:10.1021/jo302515c

Pyrido[4,3-d]pyrimidin-4(3H)-one (1) was prepared by reacting 2-trifluoromethyl-4-iodo-nicotinic acid (2) with amidine 9a catalyzed by Pd ₂(dba)₃ and Xantphos, followed by cyclization effected with HBTU and subsequent demethylation u

Full text of DOI:10.1021/jo302515c

Note
pubs.acs.org/joc
Synthesis of Quinazolin-4(3H)‑ones via Amidine N‑Arylation
Bryan Li,* Lacey Samp, John Sagal, Cheryl M. Hayward, Christine Yang,† and Zhijun Zhang
Chemical R & D − Pharmaceutical Science Worldwide Research and Development, Groton Laboratories, Pfizer Inc., Groton,
Connecticut 06340, United States
S
* Supporting Information
ABSTRACT: Pyrido[4,3-d]pyrimidin-4(3H)-one (1) was pre-
pared by reacting 2-trifluoromethyl-4-iodo-nicotinic acid (2)
with amidine 9a catalyzed by Pd2(dba)3 and Xantphos, followed
by cyclization effected with HBTU and subsequent demethyla-
tion using PhBCl2. The amidine arylation method was found
applicable for the syntheses of quinazolin-4(3H)-ones. Thus,
reaction of 2-bromo or 2-iodo benzoate esters with amdidines afforded substituted quinazolin-4(3H)-ones in 44−89% yields.
uinazolin-4(3H)-ones, as an important class of hetero-
Scheme 1. Original Synthesis of 1
Q cyclic compounds, have attracted increased attention in
the pharmaceutical community for their therapeutic potential in
treating a number of diseases.1 This was evidenced by a
structure search of quinazolin-4(3H)-ones as a substructure
yielding hits of more than 300 000 compounds in SciFinder.
Among them, ∼40 000 compounds were known to be
biologically active. There are a number of synthetic methods
for the preparation of quinazolin-4(3H)-ones. The Mumm
synthesis from 2-amino benzoic acid was perhaps the first
concise approach.2,3 Other methods from precursors or
derivatives of 2-amino benzoic acids were also reported.4 In
more recent examples, organometallic catalysis was used to
facilitate the syntheses of quinazolin-4(3H)-one derivatives.5
Pyrido[4,3-d]pyrimidin-4(3H)-one, or 6-azaquinolinones,
isosteres to quinazolin-4(3H)-ones, are well-known pharmaco-
phores in drug research.6 Recently, in supporting the
development of pyrido[4,3-d]pyrimidin-4(3H)-one 1, an orally
active calcium-sensing receptor (CaR) antagonist targeted for
the treatment of osteoporosis, we were prompted to develop a
scalable synthesis of 1 to support preclinical and clinical
demands.7
attractive for scale up because (1) the oxidation step could not
be driven to completion and the use of toxic reagent DDQ and
(2) the throughput was low and the synthesis lengthy.
Additionally, there was a significant complication in handling
L-amphetamine, a controlled substance regulated by govern-
ment agencies. During chemistry development and production
activities extremely close monitoring and usage tracking were
mandated by the Environmental and Health Service of Pfizer
Inc.
We envisaged that a much shorter and convergent synthesis
of 1 was attainable if amidine arylation of 28 could be
accomplished (Scheme 2). Though N-arylations have been well
established for many compounds containing the −NH moiety
including amines, amides, oxazodiones, carbamates, ureas,
hydrazines, amidoximes, and amidine,9,10 N-arylations with N-
substituted amidines were unprecedented.
Earlier synthesis (Scheme 1) of 1 was a six-step linear
sequence from 2-trifluoromethyl-4-iodonicotinic acid (2).7
Palladium-catalyzed amination of 2, followed by deprotection
of the Boc group, gave 4-amino-2-(trifluoromethyl)nicotinic
acid 4. Amidation with L-amphetamine (5) and subsequent
condensation with O-anisaldehyde afforded 2,3-dihydropyrimi-
dinone 7. Oxidization with DDQ gave the corresponding
pyrido[4,3-d]pyrimidin-4(3H)-one 8 which, upon demethyla-
tion, afforded 1 in <10% overall yield. This route was not
Received: November 27, 2012
© XXXX American Chemical Society
A
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enabled, a multihundred gram synthesis of 1 was carried out
successfully under GMP control.
Scheme 2. Retrosynthesis of 1 via Amidine N-Arylation
The improved route was short and convergent in synthesis
and offered much higher throughput. Furthermore, it provided
the advantage of having the key intermediate 9a that was not
considered a “controlled substance”.16 The “non-controlled”
status of the amidine 9a offered an opportunity for outsourcing
to a commercial supplier of L-amphetamine who is licensed to
handle the material,17 which relieved the burden of maintaining
a regulatory license for the handling of “controlled substances”
in an internal scale-up facility.
Because 2 is a rather electron-deficient system, it was unclear
to us whether the reaction would work similarly for other
aromatic substrates. We proceeded to explore the scope of the
reaction using commercially available starting materials. 2-
Bromo or iodo benzoate methyl esters were chosen, as we
anticipated amidine arylated intermediates would cyclize
directly to give quinazolin-4(3H)-ones under thermal con-
ditions. The results are summarized in Table 1. Using the same
Thus, amidine 9a was prepared by following the Garigipati
reaction.11 Our first attempt using CuI mediated conditions
gave the desired product 11; however, the reaction proceeds to
50% conversion at best, despite all optimization efforts with or
without ligands used in the reaction. We quickly switched over
to Pd-catalyzed methods and found the Pd2(dba)3/Xantphos
system gave complete conversion and afforded a clean reaction
profile by HPLC analysis. Furthermore, it was noted the
reaction was regiospecific at the unsubstituted nitrogen,
probably attributed to the lower steric hindrance. Encouraged
with these results, we investigated the possibility of directly
employing the phenolic amidine in the reaction and went
forward with the preparation of 9b. Unfortunately a significant
amount of O-arylation was observed under the same reaction
conditions. It was also perceived that the methyl ester of 2
could be a better starting material to further shorten the
synthesis. Unfortunately we found that the preparation of the
methyl ester only worked well when diazomethane was used.
The coupled product 11 is zwitterionic, therefore cumber-
some for its isolation. The synthesis was streamlined by directly
carrying the reaction mixture to the cyclization by employing
HBTU as the amide coupling reagent (Scheme 3). This
afforded the penultimate intermediate 8 in 70% yield overall in
two steps. The synthesis of 1 was completed with the
deprotection of the methyl ether. Use of BCl3 was complicated
with the formation of several impurities, which affected the
product quality and isolated yield.12 Other commonly used
demethylation conditions (BBr3; HBr/NaI; L-methionine/
methanesulfonic acid; TMSI; H2SO4; LiI) were also unsat-
isfactory.13 We reasoned that PhBCl2, a widely used Lewis acid
for aldol reaction, might be effective to achieve the deprotection
and mild enough to give a clean cleavage.14 Indeed, the reaction
employing PhBCl2 (1 equiv) in toluene at 70 °C (88 h) gave a
clean transformation. The reaction could be accelerated at
higher temperature (110 °C, 14 h) without compromising the
yield or quality.15 With the amidine arylation route fully
Table 1. One-Pot Synthesis of Quinazolin-4(3H)-ones
12
13
14
entry
X
R1
R2
Bn
R3
yield
product
1
2
3
4
5
6
7
8
9
Br
Br
I
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
83
44
59
63
89
72
46
65
55
14a
14b
14b
14c
14d
14e
14f
5-NO2
5-NO2
5-MeO
H
Bn
Bn
Br
Br
Br
Br
Br
Br
Ph
Ph
5-F
Ph
5-NO2
5-F
Ph
4-Cl-Ph
H
4-Cl-Ph
Ph
14g
14h
5-NO2
reaction protocol, quinazolin-4(3H)-ones were isolated in 44−
89% yields. Lower yields were observed when 12 is substituted
with a nitro group at C-5 despite its electron-withdrawing
effect.18
Again, we only observed quinazolin-4(3H)-one (14)
obtained from N-arylation at the unsubstituted nitrogen.
Scheme 3. Final Synthesis of 1
B
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Scheme 4. Possible Pathways of Amidine N-Arylation of 2-Halo Benzoate Ester
(Note: Methane off gas! Exothermic. The off gas and exotherm were
controllable by the feed rate of the quench). The mixture was then
transferred to a separatory funnel. The aqueous layer was separated
and extracted with toluene (60 mL). The combined toluene phase was
treated with a conc. HCl solution (12.1 mL, 148 mmol). The mixture
was then concentrated by rotovap (60 °C, 150 mmHg) to
azeotropically remove water. After water was completely removed
(confirmed by KF test at 0.1% water), acetone (120 mL) was added,
which caused the precipitation of the product. After 2 h of stirring, the
slurry was filtered and rinsed with acetone (2 × 10 mL). The filter
cake was dried under nitrogen to give 9a (16.9 g, 55.5 mmol, 75%) as a
white solid. Mp: 162−164 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.61
(d, J = 8.78 Hz, 1 H), 9.29 (br. s., 1 H), 9.21 (s, 1 H), 7.56−7.62 (m, 1
H), 7.32−7.36 (m, 4 H), 7.25−7.29 (m, 1 H), 7.20−7.24 (m, 2 H),
7.08 (t, J = 7.53 Hz, 1 H), 4.29−4.54 (m, 1 H), 3.80 (s, 3 H), 2.90 (dd,
J = 6.90, 3.14 Hz, 2 H), 1.23 (d, J = 6.27 Hz, 3 H); 13CNMR (100
MHz, DMSO-d6) δ 160.2, 156.4, 137.7, 133.3, 129.3, 128.2, 126.5,
120.2, 119.3, 112.2, 55.9, 49.9, 40.7, 19.4. Anal. calcd for
C17H20N2O•HCl: C, 66.98; H,6.94; N, 9.19. Found: C, 66.83; H,
6.74; N, 9.09.
(R)-2-(2-Methoxyphenyl)-3-(1-phenylpropan-2-yl)-5-
(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one (8). To a
three-neck flask, equipped with a nitrogen inlet, vacuum inlet, and
reflux condenser, was charged tert-amyl alcohol (100 mL). The solvent
was sparged with dry nitrogen for 2 h. Amidine hydrochloride 9a (10.0
g, 32.8 mmol) was added, followed by cesium carbonate (36.6 g, 112
mmol), XANTPHOS (0.57 g, 0.984 mmol, 0.03 equiv), and Pd2(dba)3
(0.601 g, 0.656 mmol, 0.02 equiv). 2 (10.4 g, 32.8 mmol) was added
last, and the resulting mixture was heated to reflux (104 °C, internal
temp) under N2 and monitored by HPLC. After 10 h of heating, tert-
amyl alcohol was removed under vacuum and solvent exchanged with
toluene. The mixture was kept at the lowest stirrable volume.
Acetonitrile (150 mL) was added followed by the addition of HBTU
(14.9 g, 39.4 mmol, 1.2 equiv), and the resulting mixture was stirred
for 2 h. The reaction mixture was filtered, and the filter cake was rinsed
with EtOAc (2 × 50 mL). The filtrate and rinses were combined and
reduced to a minimum volume, EtOAc (80 mL) was added, and the
resulting solution was washed with water (80 mL), a 1 N HCl solution
(50 mL), a 10% sodium bicarbonate solution (50 mL), and a brine
solution (50 mL) successively and then concentrated (50 °C, 150
Close examination of the reaction mixture did not reveal the
presence of the other possible regioisomer (15) or its
precursors (16 and 17, Scheme 4). In view of a report10c
suggesting that transamidation occurred initially under copper-
catalyzed conditions, we carried out comparison reactions
(using substrates from entries 2 and 5, Table 1) without the
catalyst and ligand and did not observe the presence of the
amide intermediate (17). This confirmed that the amidine N-
arylation took place first followed by intramolecular trans-
amidation to form the quinazolin-4(3H)-one. NMR HMBC
studies of 14a and 14b provided further evidence of the
structural confirmation.19
We have described a concise synthesis of pyrido[4,3-d]-
pyrimidin-4(3H)-one (1) via amidine N-arylation. The
improved synthesis offered much higher throughput than the
original route. Furthermore, it provided an outsourcing
opportunity to avoid the handling of L-amphetamine, a
controlled substance, in an internal manufacturing facility. An
alternative demethylation method using dichlorophenylborane
was discovered, which allowed the isolation of high quality 1 as
the final API. The amidine N-arylation worked well with 2-
bromo or iodo benzoate methyl esters to give quinazolin-
4(3H)-ones in a one-pot synthesis.
EXPERIMENTAL SECTION
■
(R)-2-Methoxy-N′-(1-phenylpropan-2-yl)benzimidamide hy-
drochloride salt) (9a). 2-Methoxybenzonitrile (11.8 g, 88.8 mmol)
was charged to a 500 mL three-neck flask under nitrogen, equipped
with a reflux condenser and a thermocouple. To the reaction was
added L-amphetamine (10.0 g, 74.0 mmol, 1.0 equiv) and toluene (100
mL). A 2.0 M solution of AlMe3 in toluene (55.5 mL, 111.0 mmol)
was added via a drop funnel while keeping the reaction in an ice bath
(Note: Highly exothermic addition! The exotherm is dose-controlled
however). The ice bath was removed after the addition was complete.
The mixture was heated at reflux (115 °C) for 14 h and then cooled to
rt. The reaction was quenched by slowly pouring the mixture into a
beaker containing 2 N NaOH (80 mL) stirring at 0 °C in an ice bath
C
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mmHg) to a low stirrable volume (∼20 mL EtOAc remained). The
resulting mixture was stirred at RT overnight to give a thick slurry. The
product was collected by filtration, and the filter was rinsed with cold
EtOAc (10 mL). This gave the coupled product 8 (15.1 g, 23.0 mmol,
70%) as a white solid after drying under nitrogen. Mp: 145−147 °C.
1H NMR (400 MHz, CDCl3) δ 8.87−8.80 (m, 1 H), 7.81−7.64 (m, 1
H), 7.61−7.43 (m, 1 H), 7.36−7.31 (m, 1 H), 7.27−7.09 (m, 4 H),
7.03−6.91 (m, 2 H), 6.83−6.77 (m, 2 H), 6.38 (dd, J = 1.5, 7.5 Hz, 1
H), 4.23 (ddd, J = 5.5, 6.7, 9.7 Hz, 1 H), 3.86−3.81 (m, 4 H), 3.65
(dd, J = 9.8, 13.6 Hz, 1 H), 3.37−3.28 (m, 1 H), 2.92 (dd, J = 5.5, 13.6
Hz, 1 H), 1.77 (d, J = 6.8 Hz, 3 H), 1.42 (d, J = 6.8 Hz, 1 H); 13C
NMR (100 MHz, CDCl3) δ 160.7, 158.7, 154.8, 150.2, 138.1, 131.7,
129.6, 129.1, 129.0, 128.6, 128.6, 128.3, 126.7, 126.5, 124.5, 123.9,
121.4, 121.0, 116.3, 111.2, 110.4, 77.4, 77.0, 76.7, 61.3, 55.3, 38.6, 18.2,
16.2. Anal. calcd for C24H20F3N3O2•0.3C4H8O2: C, 64.97; H, 4.85; N,
9.02. Found: C, 64.80; H, 4.85; N, 9.04.
4−14 h depending on the substrate. Upon completion, the reaction
mixture was passed through a 2″ pad of silica gel with 10−100% ethyl
acetate/heptanes. The purest fractions were combined, concentrated,
and then recrystallized with dichloromethane/heptanes. Melting
points, characterization data, and elemental analyses were obtained
on the isolated compounds.
3-Benzyl-2-phenylquinazolin-4(3H)-one (14a). 125 mg, 83%;
mp 140−142 °C; 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 7.78 Hz,
1 H), 7.76−7.86 (m, 2 H), 7.53−7.59 (m, 1 H), 7.47−7.52 (m, 1 H),
7.43 (t, J = 7.53 Hz, 2 H), 7.34−7.39 (m, 2 H), 7.20−7.25 (m, 3 H),
6.92−6.99 (m, 2 H), 5.30 (s, 2 H); 13C NMR (100 MHz, CDCl3): δ
162.5, 156.4, 147.3, 136.6, 135.3, 134.6, 129.9, 128.6, 128.5, 128.0,
127.6, 127.5, 127.2, 127.1, 127.0, 120.9, 48.8. Anal. calcd for
C21H16N2O•0.56 CH2Cl2: C, 71.95; H, 4.79; N, 7.78. Found: C,
72.17; H, 4.47; N, 8.03.
3-Benzyl-6-nitro-2-phenylquinazolin-4(3H)-one (14b). 87 mg,
1
(R)-2-(2-Hydroxyphenyl)-3-(1-phenylpropan-2-yl)-5-
(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one (1). Method
A. The coupled product 8 (15.1g, 23.0 mmol) was combined with
toluene (30 mL). The resulting solution was concentrated and then
cooled. Dichloromethane (290 mL) was added, and the resulting
solution was cooled to 0 °C. A boron trichloride solution in
dichloromethane (5.4 g, 45 mmol) was added to the reaction mixture
while keeping the reaction cold. The resulting mixture was stirred until
the reaction was deemed complete by HPLC and inversely quenched
into a stirred mixture of diethanolamine (15.7g, 149.5 mmol) and
water (350 mL). The layers were separated, and the aqueous layer was
extracted with dichloromethane. The combined dichloromethane
phase was washed with aqueous hydrochloric acid and a brine solution
successively. The organic phase is stirred with silica gel supported thiol
(Ultra pure Silicycle Thiol) and anhydrous magnesium sulfate. The
mixture was stirred and filtered. The filtrate was concentrated. The
resulting crude product was chromatographed on silica gel eluting with
a mixture of ethyl acetate and heptanes. The product-rich fractions
were combined and filtered to render the solution free of particulates.
The filtrate was then concentrated and cooled to induce crystallization.
The resulting slurry was stirred at room temperature overnight. The
solids were collected by filtration, washed with heptanes, and dried to
provide 1 (5.64 g, 38.9%) as a white solid: Mp 198 °C; 1HNMR (400
MHz, CDCl3) δ 8.76 (d, J = 5.52 Hz, 1 H), 8.32 (br. s., 1 H), 7.50 (d, J
= 5.27 Hz, 1 H), 7.40 (t, J = 7.91 Hz, 1 H), 7.01−7.12 (m, 4 H), 6.95−
7.01 (m, 2 H), 6.79 (d, J = 7.03 Hz, 2 H), 4.68 (dt, J = 9.60, 6.62 Hz, 1
H), 3.55 (dd, J = 13.80, 9.79 Hz, 1 H), 3.04 (dd, J = 13.80, 6.02 Hz, 1
H), 1.90 (d, J = 6.78 Hz, 3 H), 1.70 (br. s, 1 H); 13CNMR (100 MHz,
CDCl3) δ 181.6, 161.5, 159.1, 156.1, 155.7, 153.3, 150.5, 137.5, 132.9,
128.6, 128.6, 126.8, 123.4, 122.5, 120.1, 119.2, 118.1, 115.7, 62.4, 38.9,
19.0 ppm. HRMS (ESI, ion trap) m/z calcd for C23H19F3N3O2
426.14239, found 426.14228.
Method B. The coupled product 8 (4.98 g, 11.33 mmol) was
combined in toluene (100 mL). The flask was purged with nitrogen.
Dichlorophenylborane (3 mL, 22.89 mmol) was then added, and the
resulting reaction was heated at 70 °C under nitrogen for 88 h. Upon
completion, the reaction was reversely quenched into a stirred mixture
of diethanolamine (10 mL, 103.86 mmol) and water (125 mL) at
room temperature. The layers were separated, and the aqueous layer
was extracted with toluene (40 mL). The combined organic layers
were washed with saturated sodium bicarbonate (150 mL). The
organic layer was washed with 1 N HCl (150 mL) and then dried over
magnesium sulfate, filtered, and concentrated to dryness. The residue
was dissolved in isopropyl alcohol and recrystallized with water. The
mixture was stirred for 1 h, filtered, and dried overnight in a vacuum
oven to give 1 (4.48 g, 92.9%) as an off-white solid. Spectroscopic data
were identical to those of the product obtained from the BCl3 method.
General Procedure for Synthesis of Quinazolin-4(3H)-ones.
Prior to use, nitrogen was bubbled through the tert-amyl alcohol at
room temperature for 1 h. To a 20 dram vial were added amidine (1−
2 mmol), cesium carbonate (2 equiv), Pd2(dba)3 (0.02 equiv),
Xantphos (0.03 equiv), and tert-amyl alcohol (10 mL/g). The mixture
was then flushed with nitrogen. The substituted 2-halo benzoate (1
equiv) was added, and the resulting mixture was heated to 100 °C for
59%; mp 177−179 °C; H NMR (400 MHz, CDCl3) δ 9.26 (d, J =
2.51 Hz, 1 H), 8.59 (dd, J = 2.64, 8.91 Hz, 1 H), 7.89 (d, J = 9.03 Hz, 1
H), 7.53−7.59 (m, 1 H), 7.48 (t, J = 7.65 Hz, 2 H), 7.38−7.43 (m, 2
H), 7.23−7.28 (m, 3 H), 6.92−6.98 (m, 2 H), 5.34 (s, 2 H); 13C NMR
(100 MHz, CDCl3) δ 161.5, 159.7, 151.2, 145.9, 135.8, 134.6, 130.6,
129.2, 128.8, 128.7, 128.6, 127.9, 127.9, 127.1, 123.9, 121.0, 49.3. Anal.
calcd for C21H15N3O3•0.19 CH2Cl2: C, 68.14; H, 4.15; N, 11.25.
Found: C, 67.96; H, 4.04; N, 11.32
6-Methoxy-2,3-diphenylquinazolin-4(3H)-one (14c). 104 mg,
1
63%; mp 202−204 °C; H NMR (400 MHz, CDCl3): δ 7.79 (d, J =
8.8 Hz, 1 H), 7.75 (d, J = 3.0 Hz, 1 H), 7.44 (dd, J = 8.9, 2.9 Hz, 1 H),
7.34 (q, J = 6.6 Hz, 5 H), 7.27−7.30 (m, 1 H), 7.21−7.27 (m, 3 H),
7.18 (d, J = 7.5 Hz, 2 H), 3.97 ppm (s, 3 H); 13C NMR (101 MHz,
CDCl3): δ 162.2, 158.8, 153.0, 142.2, 137.9, 135.5, 129.4, 129.1, 129.1,
129.0, 129.0, 128.4, 128.0, 124.9, 121.8, 106.6, 55.9. Anal. calcd for
C21H16N2O2•0.05 CH2Cl2: C, 76.01; H, 4.88; N, 8.42. Found:
C,76.35; H, 4.44; N, 8.51.
2,3-Diphenylquinazolin-4(3H)-one (14d). 134 mg, 89%; mp
1
157−159 °C; H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 8.0 Hz, 1
H), 7.88−7.81 (m, 2 H), 7.60−7.52 (m, 1 H), 7.39−7.34 (m, 3 H),
7.34−7.31 (m, 1 H), 7.31−7.27 (m, 1 H), 7.27−7.25 (m, 1 H), 7.25−
7.20 (m, 1 H), 7.18 (d, J = 7.8 Hz, 2 H); 13C NMR (100 MHz,
CDCl3) δ 162.3, 155.2, 147.5, 137.7, 135.5, 134.8, 129.3, 129.1,
129.0(2C), 128.4, 128.0, 127.8, 127.3, 127.2, 121.0. Anal. calcd for
C20H14N2O•0.03 CH2Cl2: C, 79.96; H, 4.71; N, 9.31. Found: C,
79.97; H, 4.57; N, 9.24.
6-Fluoro-2,3-diphenylquinazolin-4(3H)-one (14e). 115 mg,
1
72%; mp 153−155 °C; H NMR (400 MHz, CDCl3) δ 8.01 (dd, J
= 2.6, 8.4 Hz, 1 H), 7.86 (dd, J = 4.9, 8.9 Hz, 1 H), 7.56 (dt, J = 2.5,
8.4 Hz, 1 H), 7.39−7.21 (m, 9 H), 7.17 (d, J = 7.3 Hz, 2 H); 13C NMR
(100 MHz, CDCl3) δ 162.5, 161.6 (d, J = 3.7 Hz), 160.0, 154.6 (d, J =
2.2 Hz), 144.2 (d, J = 2.2 Hz), 137.5, 135.2, 130.2 (d, J = 8.8 Hz),
129.4, 129.1 (J = 2.2 Hz), 129.0, 128.6, 128.0, 123.3 (d, J = 24.2 Hz),
122.3 (d, J = 8.8 Hz), 112.1 (d, J = 23.5 Hz). Anal. calcd for
C20H13FN2O•0.04 CH2Cl2: C, 75.28; H, 4.12; N, 8.76. Found: C,
74.94; H, 3.99; N, 8.60.
6-Nitro-2,3-diphenylquinazolin-4(3H)-one (14f). 78 mg, 46%;
mp 218−220 °C; 1H NMR (400 MHz, CDCl3): δ 9.22 (d, J = 2.5 Hz,
1 H), 8.62 (dd, J = 8.8, 2.5 Hz, 1 H), 7.96 (d, J = 9.0 Hz, 1 H), 7.36−
7.42 (m, 5 H), 7.30−7.36 (m, 2 H), 7.24−7.30 (m, 3 H), 7.19 ppm (d,
J = 6.8 Hz, 2 H); 13C NMR (100 MHz, CDCl3): δ 161.2, 158.4, 151.5,
146.0, 137.0, 134.7, 130.1, 129.4, 129.3, 129.0, 129.0, 128.9 128.8,
128.2, 123.9, 121.2. Anal. calcd for C20H13N3O3•0.05 CH2Cl2: C,
69.28; H, 3.80; N, 12.09. Found: C, 69.22; H, 3.44; N, 11.97.
2,3-Bis(4-chlorophenyl)-6-fluoroquinazolin-4(3H)-one (14g).
98 mg, 65%; mp 238−240 °C; 1H NMR (400 MHz, CDCl3) δ 7.04−
7.11 (m, 2 H), 7.20−7.29 (m, 5 H), 7.30−7.37 (m, 2 H), 7.53 (td, J =
8.49, 2.93 Hz, 1 H), 7.80 (dd, J = 8.98, 4.68 Hz, 1 H), 7.95 (dd, J =
8.20, 3.12 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 172.2, 162.6,
161.4, 161.3, 160.1, 153.0, 153.0, 144.0, 143.9, 136.0, 135.8, 134.9,
133.4, 130.4, 130.4, 130.3, 130.3, 129.6, 128.6, 123.7, 123.5, 122.1,
122.1, 112.3, 112.1. Anal. calcd for C20H11Cl2FN2O•0.1 CH2Cl2: C,
61.32; H, 2.87; N, 7.12. Found: C, 61.02; H, 2.49; N, 6.88.
D
dx.doi.org/10.1021/jo302515c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
6-Nitro-2-phenylquinazolin-4(3H)-one (14h). 373 mg, 55% mp
316−318 °C; H NMR (400 MHz, DMSO-d6) δ 13.01 (br. s., 1 H),
Bridges, A. J.; Cody, D. R.; Zhou, H.; Fry, D. W.; McMichael, A.;
Denny, W. A. J. Med. Chem. 1996, 39, 1823.
1
8.85 (d, J = 2.51 Hz, 1 H), 8.57 (dd, J = 9.16, 2.64 Hz, 1 H), 8.24 (d, J
= 7.78 Hz, 2 H), 7.93 (d, J = 9.03 Hz, 1 H), 7.66 (d, J = 6.78 Hz, 1 H),
7.56−7.63 (m, 2 H); 13C NMR (100 MHz, DMSO-d6) δ 155.7, 144.7,
132.3, 132.0, 128.7, 128.5, 128.2, 122.0, 121.0. Anal. calcd for
C14H9N3O3•0.05 CH2Cl2: C, 62.16; H, 3.38; N, 15.48. Found: C,
62.11; H, 3.38; N, 15.50.
(7) (a) Didiuk, M. T.; Griffith, D. A.; Benbow, J. W.; Liu, K. C.;
Walker, P.; Bi, C.; Morris, J.; Guzman-Perez, A.; Gao, H.; Bechle, B.
M.; Kelley, R. M.; Yang, X.; Dirico, K.; Ahmed, S.; Hungerford, W.;
DiBrinno, J.; Zawistoski, M. P.; Bagley, S. W.; Li, J.; Zeng, Y.; Santucci,
S.; Oliver, R.; Corbett, M.; Olson, T.; Chen, C.; Li, M.; Paralkar, V.
M.; Riccardi, K. A.; Healy, D. R.; Kalgutkar, A. S.; Maurer, T. S.;
Nguyen, H. T.; Frederick, K. S. Bioorg. Med. Chem. Lett. 2009, 19,
4555. (b) Kalgutkar, A. S.; Griffith, D. A.; Ryder, T.; Sun, H.; Miao, Z.;
Bauman, J. N.; Didiuk, M. T.; Frederick, K. S.; Zhao, S. X.; Prakash, C.;
Soglia, J. R.; Bagley, S. W.; Bechle, B. M.; Kelley, R. M.; Dirico, K.;
Zawistoski, M.; Li, J.; Oliver, R.; Guzman-Perez, A.; Liu, K. K. C.;
Walker, D. P.; Benbow, J. W.; Morris, J. Chem. Res. Toxicol. 2010, 23,
1115.
ASSOCIATED CONTENT
■
S
* Supporting Information
Full compound characterization data as well as copies of 1H and
13C NMR spectra are given. This material is available free of
charge via the Internet at http://pubs.acs.org.
(8) Li, B.; Bi, F. C.; Buzon, R. A.; Kang, M.; Oliver, R. M.; Sagal, J. S.;
Samp, L.; Walker, D. P.; Zhang, Z. Synlett 2010, 14, 2133.
(9) For recent reviews: see: (a) Surry, D. S.; Buchwald, S. L. Chem.
Sci. 2011, 2, 27. (b) Surry, D. S.; Buchwald, S. L. Angew. Chem. 2008,
47, 6338. (c) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534.
(d) Anbazhagan, M.; Stephens, C. E.; Boykin, D. W. Tetrahedron Lett.
2002, 43, 4221.
(10) After completion of this work in 2007, copper-catalyzed
arylation of amidines (N, N′-unsubstituted) was reported: (a) Cortes-
Salva, M.; Garvin, C.; Antilla, J. J. Org. Chem. 2010, 76, 1456.
(b) Zhou, J.; Fu, L.; Lv, M.; Liu, J.; Pei, D.; Ding, K. Synthesis 2008, 24,
3974. (c) Huang, C.; Fu, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Chem. Commun.
2008, 6333. (d) Liu, X.; Fu, H.; Jiang, Y.; Zhao, Y. Angew. Chem., Int.
Ed. 2009, 48, 348.
AUTHOR INFORMATION
Corresponding Author
*E-mail: bryan.li@pfizer.com.
Present Address
■
†Summer intern in Chemical R & D, Worldwide Research and
Development, Pfizer Groton Laboratories from June to August,
2008. Current Address: School of Medicine, University of
Connecticut, Farmington, CT 06030
Notes
The authors declare no competing financial interest.
(11) Garigipati, R. S. Tetrahedron Lett. 1990, 31, 1969.
(12) The BCl3 method gave 74% yield at best and the isolated
product was still contaminated with a single impurity at 0.4% level. To
achieve active pharmaceutical ingredient (API), two crystallizations
were needed, which further lowered the yield.
(13) Greene, T. W.; Wuts, P. G. M. In Protective Groups in Organic
Synthesis, 4th ed.; Wiley: New York, 2007, pp372−382.
(14) Hamana, H.; Sasakura, K.; Sugasawa, T. Chem. Lett. 1984, 10,
1729.
(15) Product isolated was of superior purity to that from BCl3
method (Achiral HPLC purity: 99.6%; Chiral HPLC purity: 100%).
(16) Opined by the Drug Enforcement Agency (DEA), U.S.
Department of Justice in a letter to Pfizer EHS in 2006.
(17) In the original synthesis, such outsourcing opportunity did not
exist because both 6 and 7 were deemed derivatives of a “controlled
substance” that could be used to generate L-amphetamine.
(18) Similar findings were documented in the literature with nitro
substitutions, see: Ferreira, I. C. F. R.; Queiroz, M-J R. P.; Kirsch, G.
Tetrahedron 2003, 59, 975.
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