Synthesis of 2-Aminoquinazolinones via Carbonylative Coupling of ortho-Iodoanilines and Cyanamide

Article abstract of DOI:10.1021/acs.joc.6b00249

Herein, we describe a convenient and efficient synthesis of 2-aminoquinazolin-4(3H)-ones and N1-substituted 2-aminoquinazolin-4(1H)-ones by a domino carbonylation/cyclization process. The reaction proceeds via carbonylative coupling of readily available ortho-iodoanilines with cyanamide followed by in situ ring closure of an N-cyanobenzamide intermediate. The products were easily isolated by precipitation in moderate to excellent yields for a wide range of substrates, making this a highly attractive method for the synthesis of 2-aminoquinazolinones.

Full text of DOI:10.1021/acs.joc.6b00249

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Article
Synthesis of 2-Aminoquinazolinones via Carbonylative
Coupling of ortho-Iodoanilines and Cyanamide
Linda Åkerbladh, and Luke R. Odell
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00249 • Publication Date (Web): 11 Mar 2016
Downloaded from http://pubs.acs.org on March 16, 2016
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Synthesis of 2-Aminoquinazolinones via Carbonylative
Coupling of ortho-Iodoanilines and Cyanamide
Linda Åkerbladh, Luke R. Odell*
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Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, BMC, Uppsala
University
Box-574, SE-751 23 Uppsala, Sweden
Fax: (+46) 18 471 44 74
*Corresponding author: E-mail: luke.odell@orgfarm.uu.se
Keywords: quinazolin-4(3H)-ones, quinazolin-4(1H)-ones, N-heterocycles, palladium,
catalysis, carbonylation, molybdenum hexacarbonyl
ABSTRACT
Herein, we describe a convenient and efficient synthesis of 2-aminoquinazolin-4(3H)-ones
and N1-substituted-2-aminoquinazolin-4(1H)-ones by a domino carbonylation/cyclization
process. The reaction proceeds via carbonylative coupling of readily available ortho-
iodoanilines with cyanamide followed by in situ ring closure of an N-cyanobenzamide
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intermediate. The products were easily isolated by precipitation in moderate to excellent
yields for a wide range of substrates making this a highly attractive method for the synthesis
of 2-aminoquinazolinones.
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INTRODUCTION
The quinazolinone structure is one of the most frequently encountered heterocycles in small-
molecule drugs1 displaying a broad range of biological activities such as antimalarial,2
antitumor (thymidylate synthase inhibitors),3 protein kinase inhibition,4 anti-inflammatory,5,6
antiviral,7 antihypertensive,8 and anticonvulsant.9 Several synthetic methods are available for
the preparation of quinazolinones and 2-aminoquinazolinones10,11 including e.g. fusion of
anthranilic acid with amides,12 amidation of 2-aminobenzoic acids and its derivatives,13,14 the
reaction of resin-bound isothioureas with isatoic anhydrides,15 and acylation of ortho-
fluorobenzoic acids with substituted guanidines and subsequent ring closure.16 Furthermore,
1-aryl-2-aminoquinazolin-4-ones and 2-(arylamino)quinazolin-4-ones have been obtained
from the reaction of N-cyanoimidates and arylamines.17 However, these reactions are often
performed under harsh reaction conditions, require multistep procedures or complex
intermediates and there is still a need for new and efficient methods to prepare this important
ring system.
Pd-catalyzed carbonylation reactions such as aminocarbonylation, cross-coupling reactions
and carbonylation of alkenes are now essential tools for synthetic and medicinal chemists and
significant effort has been invested into developing safer methods for handling the toxic
carbon monoxide gas.18–20 In the last decade, several non-gaseous CO sources have been
reported for in situ and ex situ use.21 For example, formates, formamides, aldehydes and
formic acid have been reported as CO sources.20,22–24 The Pd-catalyzed decomposition of 9-
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methylfluorene-9-carbonyl chloride (COgen)25 and the liberation of CO from silacarboxylic
acids26 allow the use of substoichiometric amounts of CO as well as a possibility to label the
carbonyl carbon. Recently, the base-mediated decomposition of oxalyl chloride27,28 and
chloroform29 have been reported as efficient CO-generating strategies for carbonylation
chemistry. Finally, metal carbonyls such as Mo(CO)6 offer a convenient and easy-to-handle
solid CO suitable for in situ and ex situ gas release.30–34
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Pd-catalyzed carbonylation reactions have proved useful in the synthesis of various
heterocyclic ring systems.35 There are numerous reports where aryl halides equipped with
ortho-heteroatoms have been used in carbonylation reactions to synthesize various
heterocycles e.g. indoles,36 quinolones,37 and chromones.38 We have previously utilized this
approach to prepare 4-quinolones under mild conditions using a carbonylative Sonogashira
coupling reaction of ortho-iodoanilines followed by intramolecular cyclization.39
There are a few reports employing Pd-catalyzed carbonylative methods to prepare quinazolin-
4(3H)-ones using gaseous CO.35 The most prominent approach was developed by Larksarp
and Alper involving the cyclocarbonylation of ortho-iodoanilines with carbodiimides and
ketenimines40 to obtain 2-aminoquinazolin-4(3H)-ones and 2-alkyl-quinazolin-4(3H)-ones,
respectively (Scheme 1a). This methodology was further developed by the same group to
include carbonylation of N-(2-iodophenyl)-N’-phenyl carbodiimides41 in the presence of
secondary amines and phenols to give the corresponding 2-aminoquinazolin-4(3H)-ones and
2-phenoxyquinazolin-4(3H)-ones (Scheme 1b). Based on this work, Roberts et al. developed a
molybdenum-catalyzed cyclocarbonylation of carbodiimides using microwave irradiation
giving 2-aminoquinazolin-4(3H)-ones in moderate to good yields (Scheme 1b).42 By using
Mo(CO)6 as both catalyst and CO-source, the use of gaseous CO could be avoided. Moreover,
2-substituted-quinazolinones have been prepared by coupling ortho-iodoanilines with imidoyl
chlorides43 or by the aminocarbonylation of N-(ortho-bromophenyl)imidates with various
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amines44 (Scheme 1c). However, these methods all suffer from a number of drawbacks
including the use of high CO pressures, high reaction temperatures, complex non-
commercially available starting materials and the formation of regiosomeric mixtures.
Additionally, these methods are limited to the preparation of aminoquinazolin-4(3H)-ones and
consequently do not allow the introduction of N1-substituents. We have previously reported
the carbonylative coupling of aryl iodides with cyanamide to yield N-cyanobenzamides45 and
we reasoned that the use of readily available ortho-iodoanilines (1) would afford an ortho-
amino-N-cyanobenzamide intermediate I (Scheme 1d) which could then undergo cyclization
to give a 2-aminoquinazolin-4(3H)-one (Scheme 1d). This approach offers a number of
significant advantages including; i) the use of readily available cyanamide as the N-C-N
source, ii) increased flexibility as both unsubstituted 2-aminoquinazolin-4(3H)-ones or N1-
substituted 2-aminoquinazolin-4(1H)-ones can be accessed depending on the choice of ortho-
iodoaniline and iii) it does not require high CO pressures or the use of CO gas. Herein, we
describe the development of a facile, convenient carbonylative synthesis of 2-
aminoquinazolinones (2) from cyanamide and ortho-iodoanilines.
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Scheme 1. Synthesis of Quinazolinones by Carbonylative Coupling of ortho-Iodoanilines: Previous Work and
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this Work.
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O
N
O
NH
NH2
N
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N
H
NH2
2-Aminoquinazolin-4(3H)-one
2-Aminoquinazolin-4(1H)-one
Previous work
R2
N C N
R2
O
CO
R1
carbodiimides
R1
I
R2
Y
"Pd"
N
R3
(a)
R2
N C C
NH2
N
R4
ketenimines
Y = NHR2, CH(R3)(R4)
CO, "Pd"
or
Mo(CO)6
O
N
I
R1
N
C
R1
(b)
(c)
NuH
N
N
Nu
O
N
CO, "Pd"
R3NH2
R3
R2
CO
"Pd"
I
R3
R2
N
R2
N
N
R1
R1
R1
OMe
Cl
NH2
Br
O
N
This work
NH
R1
O
NH2
I
CN
NH2CN
2a-j
N
H
R1
R1
(d)
NHR2
NHR2
ex situ CO
Mo(CO)6
O
1
I
N
R1
N
R2
2k-v
NH2
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RESULTS AND DISCUSSION
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Initially, we sought to investigate if an aminocarbonylation with cyanamide could proceed in
the presence of a potentially problematic ortho-aniline group. To test this, 2-iodoaniline (1a)
and cyanamide (3 equiv) were heated in 1,4-dioxane at 65 °C for 20 h using Pd(PPh3)4 and
triethylamine as the catalyst and base, respectively similar to the conditions reported by Mane
et al.45 To our delight, the carbonylation proceeded smoothly even with this challenging
substrate and full conversion of the starting material was observed after 20 h at 65 °C
(LCMS). Further studies revealed that the reaction produced a mixture of the fully cyclized 2-
aminoquinazolin-4(3H)-one 2a (24% isolated yield, analyzed by LCMS and NMR) and the
linear N-cyanobenzamide intermediate I (37% isolated yield, analyzed by LCMS and NMR).
This indicated the carbonylative coupling was compatible with an ortho-heteroatom on the
iodide substrate, however the subsequent ring closure required additional attention. Therefore,
the carbonylative reaction was repeated using the conditions described above and, to complete
the cyclization process, the reaction mixture in chamber 1 was transferred to a microwave vial
and heated at 140 °C for 20 min. These conditions led to full conversion of intermediate I and
2-aminoquinazolin-4(3H)-one (2a) was obtained in 70% isolated yield (Scheme 2). Notably,
2a could conveniently be isolated by precipitation in aqueous sodium bicarbonate solution
without further purification and when the experiment was repeated on a 1 mmol scale, the
isolated yield was increased to an excellent 96%.
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To investigate the generality of the reaction, a diverse set of ortho-iodoanilines was tested to
explore the scope and limitations with respect to aryl substituents (Scheme 2). Gratifyingly,
the carbonylative coupling with cyanamide followed by intramolecular cyclization proved to
be general for a wide scope of substrates with isolated yields of up to 86% (Scheme 2).
Methyl ester-substituted ortho-iodoanilines (1b and 1c) furnished the 6- and 7-substituted 2-
aminoquinazolin-4(3H)-ones (2b and 2c) in 79% and 86% isolated yield, respectively. The
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fluoro-, chloro- and bromo-substituted ortho-iodoanilines (1d-f) provided the corresponding
2-aminoquinazolin-4(3H)-ones (2d-f) in 66-76% isolated yield. As expected, the bromo
substituent in 1f was fully orthogonal to the iodide at the moderate reaction temperature and
no activation of the C-Br bond was detected (LC-MS). The introduction of strongly electron
withdrawing groups para to the aniline (e.g. 1b, 1g and 1h) reduced the rate of cyclization
due to the lower nucleophilicity of the aniline. In these reactions, the carbonylative coupling
proceeded smoothly with full conversion to the N-cyanobenzamide intermediate but the
subsequent ring closure was sluggish, and for 2b, 2g and 2h longer reaction times were
needed to drive the cyclization to completion. With the nitrile- and nitro-substituted 2-
aminoquinazolin-4(3H)-ones, this also led to competing side reactions and 2g and 2h were
isolated in reduced yields of 68% and 44% respectively. In contrast, the presence of an
electron donating methoxy group in the para position led to complete cyclization at 65 °C and
the corresponding 2-aminoquinazolin-4(3H)-one (2i) was obtained in 82% isolated yield.
However, the inductively electron donating methyl group still required additional heating and
2-iodo-4-methylaniline gave the corresponding product (2j) in 71% isolated yield.
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Scheme 2. Substrate Scope for the Synthesis of 2-Aminoquinazolin-4(3H)-ones (2a-j) from
Unsubstituted ortho-Iodoanilines (1a-j)a,b
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b
aIsolated yield. Reaction conditions: Chamber 1: a) ortho-Iodoaniline (0.5 mmol), cyanamide (3 equiv),
Pd(PPh3)4 (5 mol %), Et3N (2 equiv), 1,4-dioxane (3 mL), 65 °C, 20 h. Chamber 2: Mo(CO)6 (1 equiv), DBU (3
equiv), 1,4-dioxane (3 mL), 65 °C, 20 h. b) The reaction mixture in chamber 1 was heated under microwave
c
d
irradiation at 140 °C, 20 min. 2-Iodoaniline (1 mmol). The reaction mixture in chamber 1 was heated under
microwave irradiation at 140 °C, 40 min.
To further expand the reaction scope we sought to explore the use of N-substituted anilines as
substrates to introduce additional diversity in the N1-position of the quinazolinone ring
system. However when N-benzyl-2-iodoaninline (1k) was used as a substrate under the
standard conditions from Scheme 2, the formation of significant quantities of a side product
was noted during the carbonylation step. At first we suspected that this byproduct might be
related to elevated reaction temperatures but further analysis revealed that the formation of
byproduct was closely related to the amount of cyanamide in the reaction. Indeed, the
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byproduct had an m/z ratio that corresponded to the expected product mass plus cyanamide
(Scheme 3) and NMR spectroscopy analysis was not sufficient to fully elucidate the structure
of this product. However, we were able to crystallize the compound and obtain an X-ray
structure. The crystal structure revealed the guanidine substituted quinazolinone 3 (Figure 1)
resulting from the nucleophilic attack of the exocyclic amine group in the
aminoquinazolinone intermediate at the electrophilic center in cyanamide. This side product
was never observed for the reaction with ortho-iodoanilines 1a-j suggesting that the exocyclic
amine in N1-substituted-2-aminoquinazolinones is more nucleophilic compared to that in the
unsubstituted 2-aminoquinazolinones.
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Scheme 3. Formation of Guanidine Substituted Byproduct (3) Resulting from an Excess of
Cyanamide.
Figure 1. Structure of the byproduct (3) formed in the reaction of N-benzyl-2-iodoaniline (1k) with an excess of
cyanamide (at 50% probability level).
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By decreasing the amount of cyanamide to 1.2 equiv but keeping the same reaction
temperatures as for the synthesis of 2a-j (Scheme 2) the formation of the guanidine byproduct
was able to be avoided and 2-amino-N-benzylquinazolinon-4(1H)-one (2k) was isolated in
67% yield (Scheme 4, Method A). We reasoned that additional steric hindrance from the
benzyl group might hamper the reactivity of the aryl iodide in the Pd-mediated oxidative
addition and result in a lower yield. Therefore, the reaction temperature during the
carbonylative coupling was increased to 85 °C (Scheme 4, Method B). Under these
conditions, full consumption of the N-cyanobenzamide intermediate was obtained in one step
and no further heating was required. While this made the method more convenient it did not
improve the yield and 2k was isolated in 69% yield. Still, encouraged by this development
both Method A and B were tested in the reaction with N-methyl-2-iodoaniline (1l).
Interestingly, for this substrate a slight increase in yield was observed when the higher
temperature was used in the carbonylation step (60% Method A, 66% Method B). When the
two methods were applied to N-isopropylaniline (1m) a substantially lower yield was
observed when the intermediate was cyclized at a higher temperature (44%, Method A,
microwave irradiation 140 °C) rather than during the carbonylation step (95%, Method B, 85
°C). At higher temperatures the formation of intractable solid material was observed
suggesting that the N-substituted 2-aminoquinazolin-4(1H)-one isomer may be more
susceptible to thermally induced degradation than the corresponding 2-aminoquinazolin-
4(3H)-one. With these two methods in hand, we wanted to explore the scope of N-substituted
ortho-iodoanilines (1k-v) in the synthesis of N-substituted 2-aminoquinazolin-4(1H)-ones
(2k-v, Scheme 4). Generally, the N-alkylsubstituted ortho-iodoanilines (1l-o) performed well
in the reaction using Method B returning isolated yields of 66-95%. Interestingly, compounds
with small aliphatic substituents (2l-n) were found to be unstable upon prolonged exposure to
air leading to a change in color and physical appearance. Cyclopentyl, cyclohexyl and
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cycloheptyl N-substituted ortho-iodoanilines (1p-r) gave moderate to good yields using
Method A (61-79%) and good to excellent yields using Method B (78-90%). In general, the
differences between the two methods were smaller for the cycloalkyl substituted compounds,
indicating that they may be less sensitive towards heat. Given that the aryl bromide (1f,
Scheme 2) was tolerated we wanted to investigate if N-(2-Bromobenzyl)-2-iodoaniline (1s)
could be used to synthesize 2-amino-1-(2-bromobenzyl)quinazolin-4(1H)-one (2s).
Disappointingly, 2s was isolated in only 32% yield using Method A and when the
carbonylation was carried out at 85 °C (Method B) an unidentified byproduct without the
bromine isotope pattern was formed. The reaction however performed well for other N-
benzylsubstituted-2-iodoanilines (1t-v) and N-(4-fluorobenzyl)-, N-(3-hydroxybenzyl)- and N-
(2,6-dimethoxybenzyl)-2-aminoquinazolin-4(1H)-ones (2t-v) were isolated in high yields (84-
92%).
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Scheme 4. Substrate Scope for the Synthesis of N-Substituted 2-Aminoquinazolin-4(1H)-ones
(2k-v) from N-Substituted ortho-Iodoanilines (1k-v)a,b
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NH2CN
Pd(PPh3)4, Et3N
[Mo(CO)6, DBU]
O
O
I
CN
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N
N
R1
R1
R1
H
1,4-Dioxane
NH
R2
NH
R2
N
R2
NH2
1k-v
2k-v
I
O
O
O
N
O
N
N
N
N
N
NH2
N
NH2
NH2
N
NH2
2k
2l
2m
2n
83%d
67%c, 69%d
60%c, 66%d
44%c, 95%d
O
N
O
N
O
N
O
N
N
NH2
N
NH2
N
NH2
N
NH2
2o
2p
2q
2r
73%d
79%c, 90%d
72%c, 88%d
61%c, 78%d
O
O
N
N
O
N
N
O
N
N
N
NH2
NH2
NH2
N
NH2
OMe
HO
Br
F
MeO
2s
2t
86%d
2u
2v
84%d
32%c
92%d
aIsolated yield. Reaction conditions: Chamber 1: ortho-Iodoaniline (0.5 mmol), cyanamide (1.2 equiv),
Pd(PPh3)4 (5 mol %), Et3N (2 equiv), 1,4-dioxane (3 mL). Chamber 2: Mo(CO)6 (1 equiv), DBU (3 equiv), 1,4-
dioxane (3 mL). cMethod A: a) 65 °C, 20 h. b) The reaction mixture in chamber 1 was heated under microwave
irradiation at 140 °C, 20 min. dMethod B: 85 °C, 20 h.
b
Since method B is carried out in one step and requires less cyanamide we were encouraged to
explore this method using 1a. Unfortunately, 2a was isolated in 61% as compared to 70% for
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the method used in Scheme 2. However, increasing the amount of cyanamide to 3 equiv
afforded an equivalent isolated yield of 2a (71%). The two developed methods complement
each other; where method B allows for the quinazolinones to be prepared directly in one step
and method A is better suited for substrates with potentially palladium sensitive functional
groups e.g. bromides.
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CONCLUSION
In summary, we have developed a novel synthesis of 2-aminoquinazolin-4(3H)-ones and N1-
substituted-2-aminoquinazolin-4(1H)-ones using a carbonylative coupling of ortho-
iodoanilines with cyanamide. The final products were obtained from ring closure of the N-
cyanobenzamide intermediates either by an additional heating step or directly during the
carbonylation reaction. With the developed protocol both unsubstituted and N1-substitued
quinazolinones with a free exocyclic amino group can be prepared selectively in moderate to
excellent yields. Given that cyclized products can be readily isolated by precipitation, this
strategy represents a convenient and highly attractive method for the synthesis of 2-
aminoquinazolinones.
EXPERIMENTAL SECTION
General Information. Analytical thin-layer chromatography (TLC) was performed on silica
gel 60 F-254 plates and visualized with UV light. Flash column chromatography was
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performed on silica gel 60 (40-63 µm). H and C-NMR spectra were recorded at 400 and
100 MHz, respectively. The chemical shifts for 1H NMR and 13C NMR are referenced to TMS
via residual solvent signals (1H, MeOD at 3.31 ppm, CDCl3 at 7.26 ppm and DMSO-d6 at
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2.50 ppm; 13C, MeOD at 49.0 ppm, CDCl3 at 77.0 ppm and DMSO-d6 at 39.5 ppm). The data
are reported as (s = singlet, d = doublet, t = triplet, q = quintet, sext = sextet, m = multiplet,
coupling, constant(s), integration). NMR spectra for 2a-v were recorded in DMSO-d6 at 50 °C
to avoid peak broadening resulting from tautomerism. Analytical HPLC/ESI-MS was
performed using electrospray ionization (ESI) and a C18 column (50 x 3.0 mm, 2.6 µm
particle size, 100 Å pore size) with CH3CN/H2O in 0.05% aqueous HCOOH as mobile phase
at a flow rate of 1.5 ml/min. LC purity analyses were run using a gradient of 5-100%
CH3CN/H2O in 0.05% aqueous HCOOH as mobile phase at a flow rate of 1.5 ml/min for 5
min on a C18 column unless otherwise stated. Accurate mass values were determined using a
mass spectrometer equipped with an ESI source and time-of-flight (TOF) mass analyzer.
Compounds 1j,46 1k,47 1l,48 1m,49 1s,50 2a51 and 2l52 are known and spectral data were in
agreement with the proposed structures and matched those reported in the literature.
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2-Iodo-4-methylaniline (1j). Prepared following a literature procedure53 to yield 1j as a beige
solid (759 mg, 64%).
N-Benzyl-2-iodoaniline (1k) Prepared following a literature procedure53 to yield 1k as a
colorless oil (224 mg, 67%).
2-Iodo-N-Methylaniline (1l). Prepared following a literature procedure54 to yield 1l as a
yellow oil (808 mg, 72%).
2-iodo-N-isopropylaniline (1m). Prepared following a literature procedure55 to yield 1m as a
colorless oil (867 mg, 84%).
2-Iodo-N-propylaniline (1n). Acetic acid (0.86 mL, 15 mmol) and sodium
triacetoxyborohydride (2.50 g, 11.8 mmol) were added to a solution of 2-iodoaniline (1.10 g,
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5.04 mmol) and propionaldehyde (0.43 mL, 6.0 mmol) in dry dichloromethane (70 mL) and
the reaction mixture was stirred at ambient temperature overnight. After the reaction was
deemed complete (TLC) the mixture was poured into saturated NaHCO3 (aq) (50 mL) and
then extracted into dichloromethane (2 x 50 mL). The combined organic layers were dried
over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by
silica column chromatography using pentane/ethyl acetate (100:1) to give 1n as a colorless oil
(967 mg, 74%); 1H NMR (CDCl3) δ 7.65 (dd, J = 7.8, 1.5 Hz, 1H), 7.20 (ddd, J = 8.6, 7.3, 1.5
Hz, 1H), 6.56 (dd, J = 8.2, 1.5 Hz, 1H), 6.43 (ddd, J = 7.3, 1.5 Hz, 1H), 4.15 (br s, 1H), 3.13
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(td, J = 7.0, 5.3 Hz, 2H), 1.70 (sext, J = 7.3 Hz, 2H), 1.03 (t, J = 7.4 Hz, 3H); C NMR
(CDCl3) δ 147.5, 139.1, 129.5, 118.4, 110.7, 85.5, 46.1, 22.6, 11.8; HRMS (ESI-TOF) calcd
for C9H13NI[M + H]+ 262.0093 m/z, found 262.0093; LC purity (254 nm) = >98%.
N-Hexyl-2-iodoaniline (1o). To a solution of 2-iodoaniline (1.11 g, 5.05 mmol) and hexanal
(0.74 mL, 6.02 mmol) in dry dichloromethane (70 mL) were added acetic acid (0.86 mL, 15.0
mmol) and sodium triacetoxy borohydride (2.46 g, 11.6 mmol). The reaction was stirred at
ambient temperature overnight. The reaction was poured into saturated NaHCO3 (aq) (50 mL)
and then extracted into dichloromethane (2 x 50 mL). The combined organic layers were dried
over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by
silica column chromatography using pentane/ethyl acetate (100:1) to give 1o as a colorless oil
(1.13 g, 74%); 1H NMR (CDCl3) δ 7.65 (dd, J = 7.8, 1.5 Hz, 1H), 7.20 (ddd, J = 8.1, 7.2, 1.5
Hz, 1H), 6.56 (dd, J = 8.2, 1.5 Hz, 1H), 6.42 (ddd, J = 7.8, 7.2, 1.5 Hz, 1H), 4.12 (br s, 1H),
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3.14 (td, J = 7.1, 5.2 Hz, 2H), 1.73-1.63 (m, 2H), 1.48-1.30 (m, 6H), 0.95-0.88 (m, 3H); C
NMR (CDCl3) δ 147.6, 139.1, 129.5, 118.4, 110.7, 85.5, 44.4, 31.7, 29.3, 27.0, 22.8, 14.2;
HRMS (ESI-TOF) calcd for C12H19NI [M + H]+ 304.0562 m/z, found 304.0571; LC purity
(254 nm) = >98%.
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N-Cyclopentyl-2-iodoaniline (1p). Acetic acid (0.57 mL, 10 mmol) was added to a solution of
2-iodoaniline (1.10 g, 5.03 mmol) and cyclopentanone (0.69 mL, 7.8 mmol) in dry
dichloromethane (10 mL) and the reaction mixture was stirred at ambient temperature for 2 h.
Sodium triacetoxyborohydride (1.82 g, 8.56 mmol) was added and the reaction mixture was
stirred at ambient temperature for 20 h. 1M NaOH (aq) (20 mL) was added and the organic
layer was separated. The aqueous layer was extracted with ethyl acetate (2 x 20 mL) and the
combined organic layers were washed with brine (20 mL), dried over Na2SO4 and
concentrated under reduced pressure. The residue was purified by silica column
chromatography using pentane /ethyl acetate (gradient 0-1% ethyl acetate) to give 1p as a
colorless oil (751 mg, 52%); 1H NMR (CDCl3) δ 7.66 (dd, J = 7.8, 1.5 Hz, 1H), 7.21 (ddd, J =
8.3, 7.2, 1.5 Hz, 1H), 6.62 (dd, J = 8.2, 1.5 Hz, 1H), 6.43 (ddd, J = 7.7, 7.3, 1.5 Hz, 1H), 4.17
(br s, 1H), 3.83 (h, J = 5.9 Hz, 1H), 2.11-2.01 (m, 2H), 1.85-1.51 (m, 6H); 13C NMR (CDCl3)
δ 147.1, 139.1, 129.4, 118.2, 111.4, 55.0, 33.6, 24.2; HRMS (ESI-TOF) calcd for C11H15NI
[M + H]+ 288.0249 m/z, found 288.0255; LC purity (254 nm) = 97%.
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N-Cyclohexyl-2-iodoaniline (1q). Anhydrous MgSO4 (5.82 g, 48.3 mmol) was added to a
solution of 2-iodoaniline (1.06 g, 4.85 mmol) in acetic acid (25 mL). Cyclohexanone (0.52
mL, 5.0 mmol) was added dropwise and the suspension was stirred at ambient temperature for
2.5 h. Sodium triacetoxyborohydride (2.25 g, 10.6 mmol) was added and the resulting mixture
was stirred at ambient temperature overnight. The slurry was filtered off and the filtrate was
diluted with additional ethyl acetate (50 mL) and 1 M NaOH (aq) (20 mL) was added. The
aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers
were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The
residue was purified by silica column chromatography using pentane /ethyl acetate (100:1) to
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give 1q as a colorless oil (1.10 g, 75%); H NMR (CDCl3) δ 7.64 (dd, J = 7.9, 1.5 Hz, 1H),
7.17 (ddd, J = 8.2, 7.2, 1.5 Hz, 1H), 6.58 (ddd, J = 8.2, 1.5, 0.6 Hz, 1H), 6.39 (ddd, J = 7.8,
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7.2, 1.5 Hz, 1H), 4.10 (br d, J = 7.0 Hz, 1H), 3.31 (m, 1H), 2.08-1.99 (m, 2H), 1.82-1.73 (m,
2H), 1.64 (m, 1H), 1.45-1.22 (m, 5H); 13C NMR (CDCl3) δ 146.6, 139.3, 129.5, 118.2, 111.3,
85.9, 52.0, 33.2, 26.0, 24.9; HRMS (ESI-TOF) calcd for C12H17NI [M + H]+ 302.0406 m/z,
found 302.0411; LC purity (254 nm) = >98%.
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N-(2-Iodophenyl)cycloheptanamine (1r). Acetic acid (0.57 mL, 10 mmol) was added to a
solution of 2-iodoaniline (1.11 g, 5.07 mmol) and cycloheptanone (0.92 mL, 7.8 mmol) in dry
dichloromethane (10 mL) and the reaction mixture was stirred at ambient temperature for 2 h.
Sodium triacetoxyborohydride (1.82 g, 8.56 mmol) was added and the reaction mixture was
stirred at ambient temperature for 20 h. 1M NaOH (aq) (20 mL) was added and the organic
layer was separated. The aqueous layer was extracted with ethyl acetate (2 x 20 mL) and the
combined organic layers were washed with brine (20 mL), dried over Na2SO4 and
concentrated under reduced pressure. The residue was purified by silica column
chromatography using pentane /ethyl acetate (gradient 0-1% ethyl acetate) to give 1r as a
colorless oil (831 mg, 52%); 1H NMR (CDCl3) δ 7.66 (dd, J = 7.8, 1.5 Hz, 1H), 7.20 (ddd, J =
8.4, 7.2, 1.6 Hz, 1H), 6.51 (m, 1H), 6.41 (m, 1H), 4.17 (s, 1H), 3.52 (m, 1H), 2.06-1.96 (m,
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2H), 1.79-1.47 (m, 10H); C NMR (CDCl3) δ 146.4, 139.3, 129.4, 118.1, 111.3, 86.0, 54.0,
34.7, 28.4, 24.4; HRMS (ESI-TOF) calcd for C13H19NI [M + H]+ 316.0562 m/z, found
316.0576; LC purity (254 nm) = 93%.
N-(2-Bromobenzyl)-2-iodoaniline (1s). Prepared following a literature procedure50 to yield 1s
as a white solid (1.77 g, 90%).
N-(4-Fluorobenzyl)-2-iodoaniline (1t). Acetic acid (0.43 mL, 7.5 mmol) was added to a
solution of 2-iodoaniline (1.06 g, 4.86 mmol) and 4-fluorobenzaldehyde (0.80 mL, 7.5 mmol)
were dissolved in methanol (5 mL) and the reaction mixture was stirred at ambient
temperature for 30 min. The reaction mixture was cooled to 0 °C and sodium
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cyanoborohydride (549 mg, 8.74 mmol) was added. The reaction was stirred from 0 °C to
ambient temperature overnight. The reaction was quenched with saturated NaHCO3 (aq) (25
mL) and then extracted into diethyl ether (3 x 30 mL). The combined organic layers were
dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was
purified by silica column chromatography using pentane/ethyl acetate (100:1) to give 1t as a
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white solid (1.05 g, 66%); H NMR (CDCl3) δ 7.68 (dd, J = 7.8, 1.5 Hz, 1H), 7.36-7.29 (m,
2H), 7.16 (ddd, J = 8.5, 7.3, 1.5 Hz, 1H), 7.08-7.00 (m, 2H), 6.57-6.40 (m, 2H), 4.60 (br t,
1H), 4.37 (d, J = 5.4 Hz, 2H); 13C NMR (CDCl3) δ 162.2 (d, 1JCF = 245.4 Hz), 147.0 , 139.2 ,
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134.4 (d, JCF = 3.1 Hz), 129.6 , 128.9 (d, JCF = 8.1 Hz), 119.2 , 115.7 (d, JCF = 21.5 Hz),
111.1 , 85.5 , 47.8; HRMS (ESI-TOF) calcd for C13H12NFI [M + H]+ 327.9999 m/z, found
328.0004; LC purity (254 nm) = >98%.
3-(((2-Iodophenyl)amino)methyl)phenol (1u). Acetic acid (0.46 mL, 8.0 mmol) was added to
a solution of 2-iodoaniline (1.18 g, 5.41 mmol) and 3-hydroxybenzaldehyde (1.02 g, 8.34
mmol) were dissolved in methanol (5 mL) and the reaction mixture was stirred at ambient
temperature for 30 min. The reaction mixture was cooled to 0 °C and sodium
cyanoborohydride (408 mg, 6.49 mmol) was added. The reaction was stirred from 0 °C to
ambient temperature overnight. The reaction was quenched with saturated NaHCO3 (aq) (25
mL) and then extracted into diethyl ether (3 x 30 mL). The combined organic layers were
washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The
residue was purified by silica column chromatography using pentane/ethyl acetate (gradient
10-20% ethyl acetate) to give 1u as a white solid (1.50 g, 85%); 1H NMR (CDCl3) δ 7.68 (dd,
J = 7.7, 1.5 Hz, 1H), 7.22 (m, 1H), 7.15 (m, 1H), 6.93 (d, J = 7.5 Hz, 1H), 6.83 (br s, 1H),
6.74 (dd, J = 8.1, 2.6 Hz, 1H), 6.51 (dd, J = 8.1, 1.5 Hz, 1H), 6.45 (m, 1H), 4.81 (s, 1H, OH),
4.63 (br s, 1H, NH), 4.37 (d, J = 5.4 Hz, 2H); 13C NMR (CDCl3) δ 156.1, 147.1, 140.9, 139.2,
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130.2, 129.6, 119.6, 119.1, 114.4, 114.0, 111.2, 85.4, 48.2; HRMS (ESI-TOF) calcd for
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C13H13NOI[M + H]+ 326.0042 m/z, found 326.0036; LC purity (254 nm) = >98%.
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N-(2,6-Dimethoxybenzyl)-2-iodoaniline (1v). Acetic acid (0.22 mL, 3.8 mmol) was added to
a solution of 2-iodoaniline (566 mg, 2.58 mmol) and 2,6-dimethoxybenzaldehyde (536 mg,
3.23 mmol) were dissolved in methanol (5 mL) and the reaction mixture was stirred at
ambient temperature for 30 min. The reaction mixture was cooled to 0 °C and sodium
cyanoborohydride (231 mg, 3.84 mmol) was added. The reaction was stirred from 0 °C to
ambient temperature overnight. The reaction was quenched with saturated NaHCO3 (aq) (25
mL) and then extracted into diethyl ether (3 x 30 mL). The combined organic layers were
dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was
purified by silica column chromatography using pentane/ethyl acetate (gradient 1-10% ethyl
acetate) to give 1v as a white solid (806 mg, 84%); 1H NMR (CDCl3) δ 7.60 (dd, J = 7.8, 1.5
Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.17 (m, 1H), 6.91 (dd, J = 8.2, 1.5 Hz, 1H), 6.56 (d, J =
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8.4 Hz, 2H), 6.38 (m, 1H), 4.92 (br t, NH), 4.44 (d, J = 5.6 Hz, 2H), 3.88 (s, 6H); C NMR
(CDCl3) δ 158.8, 148.0, 139.0, 129.4, 128.9, 118.5, 115.0, 111.6, 104.0, 86.0, 55.9, 37.1;
HRMS (ESI-TOF) calcd for C15H17NO2I [M + H]+ 370.0304 m/z, found 370.0318; LC purity
(254 nm) = >98%.
2-Amino-N-cyanobenzamide triethylamine salt (intermediate I). To chamber 1 of an oven-
dried, bridged two-chamber system31 was added 2-iodoaniline (114 mg, 0.52 mmol),
cyanamide (71 mg, 1.7 mmol) and Pd(PPh3)4 (33 mg, 5 mol %). Mo(CO)6 (152 mg, 0.55
mmol) was added to chamber 2. The two chambers were capped with a gastight cap and the
atmosphere was exchanged for nitrogen. 1,4-Dioxane (3 mL) was added through the septa to
both chambers followed by the addition of Et3N (0.14 mL, 1.0 mmol) to chamber 1 and
finally DBU (0.23 mL, 1.5 mmol) to chamber 2. The two-chamber system was immediately
heated under vigorous stirring in a heating block at 65 °C for 20 h. The precipitate was
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filtered off and the filtrate was purified by silica column chromatography using
acetone/methanol with 2% triethylamine (gradient 1-5% methanol). Intermediate I was
obtained as a colorless oil (50 mg, 37%). 1H NMR (DMSO-d6) δ 8.94 (br s, 1H), 7.76 (ddd, J
= 7.9, 1.8, 0.5 Hz, 1H), 6.98 (m, 1H), 6.69 (br s, 2H), 6.54 (m, 1H), 6.36 (m, 1H), 3.09 (q, J =
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7.3 Hz, 6H), 1.17 (t, J = 7.3 Hz, 9H); C NMR (DMSO-d6) δ 177.1, 149.8, 130.9, 130.5,
122.2, 118.6, 115.6, 113.8, 45.8, 8.7; HRMS (ESI-TOF) calcd for C8H8N3O [M + H]+
162.0667 m/z, found 162.0667; LC purity (254 nm) = 98%.
General Procedure for the Synthesis of 2-Aminoquinazolin-4(3H)-ones (2a-j). To
chamber 1 of an oven-dried, bridged two-chamber system31 was added ortho-iodoaniline (0.5
mmol), cyanamide (63 mg, 1.5 mmol) and Pd(PPh3)4 (29 mg, 5 mol %). Mo(CO)6 (132 mg,
0.5 mmol) was added to chamber 2. The two chambers were capped with a gastight cap and
the atmosphere was exchanged for nitrogen. 1,4-Dioxane (3 mL) was added through the septa
to both chambers followed by the addition of Et3N (0.14 mL, 1.0 mmol) to chamber 1 and
finally DBU (0.23 mL, 1.5 mmol) to chamber 2. The two-chamber system was immediately
heated under vigorous stirring in a heating block at 65 °C for 20 h. After 20 h the reaction
mixture in chamber 1 was transferred to a microwave vial (Biotage 2-5 mL) and heated under
microwave irradiation at 140 °C for 20 min. The reaction mixture was poured into NaHCO3
(aq) (30 mL) and collected by filtration. The solid was washed with water (10 mL) and ethyl
acetate (10 mL) to give the pure compound.
2-Aminoquinazolin-4(3H)-one (2a).51 Prepared from 1.0 mmol 1a. Tan solid (154 mg, 96%);
1H NMR (DMSO-d6) δ 7.89 (d, J = 8.0 Hz, 1H), 7.53 (m, 1H), 7.18 (d, J = 8.3 Hz, 1H), 7.10-
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7.02 (m, 1H), 6.53 (br s, 2H); C NMR (DMSO-d6) δ 164.2, 153.5, 150.8, 133.3, 125.7,
123.0, 120.8, 117.2; LC purity (254 nm) = >98%
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Methyl 2-Amino-4-oxo-3,4-dihydroquinazoline-6-carboxylate (2b). The reaction mixture in
chamber 1 was heated under microwave irradiation at 140 °C for 40 min. Tan solid (82 mg,
79%); 1H NMR (DMSO-d6) δ 8.49 (d, J = 1.8 Hz, 1H), 8.01 (dd, J = 8.7, 2.2 Hz, 1H), 7.21 (d,
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J = 8.6 Hz, 1H), 6.84 (br s, 2H), 3.85 (s, 3H); C NMR (DMSO-d6) δ 165.6, 163.6, 155.11,
155.03, 133.2, 128.1, 123.6, 121.4, 116.6, 51.6; HRMS (ESI) calcd for C10H10N3O3 [M + H]+
220.0722 m/z, found 220.0721; LC purity (254 nm) = >98%.
Methyl 2-amino-4-oxo-3,4-dihydroquinazoline-7-carboxylate (2c). Tan solid (94 mg, 86%);
1H NMR (DMSO-d6) δ 7.99 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.56 (dd, J = 8.2,
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1.7 Hz, 1H), 6.64 (s, 2H), 3.90 (s, 3H); C NMR (DMSO-d6) δ 165.9, 164.0, 154.6, 151.2,
133.9, 126.3, 124.5, 120.3, 120.0, 52.1; HRMS (ESI-TOF) calcd for C12H13N4O3 [M +
CH3CN + H]+ 261.0988 m/z, found 261.0983; LC purity (254 nm) = >98%.
2-Amino-7-fluoroquinazolin-4(3H)-one (2d). Tan solid (64 mg, 73%); 1H NMR (DMSO-d6) δ
10.95 (br s, 1H), 7.99-7.90 (m, 1H), 6.96-6.86 (m, 2H), 6.47 (br s, 2H); 13C NMR (DMSO-d6)
δ 165.9 (d, 1JCF = 248.8 Hz), 161.5, 152.7, 128.6 (d, 3JCF = 11.5 Hz), 114.1 (d, 4JCF = 1.7 Hz),
109.5 (d, 2JCF = 23.6 Hz), 108.3 (d, 2JCF = 21.3 Hz). One carbon missing; HRMS (ESI) calcd
for C8H7N3OF [M + H]+ 180.0573 m/z, found 180.0566; LC purity (254 nm) = >98%.
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2-Amino-7-chloroquinazolin-4(3H)-one (2e). Off-white solid (70 mg, 66%); H NMR
(DMSO-d6) δ 10.99 (br s, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.21 (s, 1H), 7.10 (d, J = 8.5 Hz, 1H),
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6.49 (br s, 2H); C NMR (DMSO-d6) δ 161.6, 152.7, 138.5, 127.7, 122.6, 121.3, 115.9. One
carbon missing; HRMS (ESI) calcd for C8H7N3OCl [M + H]+ 196.0278 m/z, found 196.0272;
LC purity (254 nm) = >98%.
2-Amino-6-bromoquinazolin-4(3H)-one (2f). Tan solid (91 mg, 76%); 1H NMR (DMSO-d6) δ
11.13 (br s, 1H), 8.00-7.93 (m, 1H), 7.67 (dd, J = 8.7, 2.5 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H),
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6.46 (br s, 2H); C NMR (DMSO-d6) δ 161.6, 152.5, 149.8, 136.3, 127.7, 125.8, 118.7,
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112.7; HRMS (ESI) calcd for C8H7N3OBr [M + H]+ 239.9772 m/z, found 239.9774; LC purity
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2-Amino-4-oxo-3,4-dihydroquinazoline-6-carbonitrile (2g). The reaction mixture in chamber
1 was heated under microwave irradiation at 140 °C for 40 min. Beige solid (63 mg, 68%); 1H
NMR (DMSO-d6) δ 11.18 (br s, 1H), 8.20 (d, J = 2.1 Hz, 1H), 7.84 (dd, J = 8.6, 2.1 Hz, 1H),
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7.26 (d, J = 8.6 Hz, 1H), 6.76 (br s, 2H); C NMR (DMSO-d6) δ 160.8, 154.3 (br s due to
tautomerism), 153.7, 135.8, 131.2, 124.8, 118.7, 117.2, 102.8; HRMS (ESI) calcd for
C9H7N4O [M + H]+ 187.0620 m/z, found 187.0619; LC purity (254 nm) = >98%.
2-Amino-6-nitroquinazolin-4(3H)-one (2h). The reaction mixture in chamber 1 was heated
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under microwave irradiation at 140 °C for 40 min. Yellow solid (47 mg, 44%); H NMR
(DMSO-d6) δ 8.62 (d, J = 2.8 Hz, 1H), 8.29 (dd, J = 9.1, 2.8 Hz, 1H), 7.27 (d, J = 9.1 Hz,
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1H); C NMR (DMSO-d6) δ 162.0, 156.7 (br s due to tautomerism), 154.8, 140.5, 128.3,
124.9, 122.7, 116.3; HRMS (ESI) calcd for C10H10N5O3 [M +CH3CN + H]+ 248.0784 m/z,
found 248.0791; LC purity (254 nm) = >98%.
2-Amino-6-methoxyquinazolin-4(3H)-one (2i). Tan solid (95 mg, 82%); 1H NMR (DMSO-d6)
δ 7.31 (s, 1H), 7.34-7.09 (m, 2H), 6.48 (br s, 2H, NH2), 3.77 (s, 3H); 13C NMR (DMSO-d6) δ
164.2, 153.9, 152.5, 145.5 (br s due to tautomerism), 124.9, 123.4, 117.4, 106.1, 55.3; HRMS
(ESI) calcd for C9H10N3O2 [M + H]+ 192.0773 m/z, found 192.0781; LC purity (254 nm) =
98%.
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2-Amino-6-methylquinazolin-4(3H)-one (2j). Off-white solid (66 mg, 71%); H NMR
(DMSO-d6) δ 10.78 (br s, 1H), 7.70 (s, 1H), 7.39 (dd, J = 8.4, 2.2 Hz, 1H), 7.16-7.06 (m, 1H),
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6.18 (br s, 2H), 2.35 (s, 3H); C NMR (CDCl3/MeOD + 1 drop conc. HCl) δ 159.2, 150.9,
137.4, 136.2, 135.6, 127.2, 117.0, 115.2, 20.5; HRMS (ESI) calcd for C9H10N3O [M + H]+
176.0824 m/z, found 176.0830; LC purity (254 nm) = >98%.
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General Procedure for the Synthesis of 2-Aminoquinazolin-4(1H)-ones (2k-v). To
chamber 1 of an oven-dried, bridged two-chamber system31 was added ortho-iodoaniline (0.5
mmol), cyanamide (25 mg, 0.6 mmol) and Pd(PPh3)4 (29 mg, 5 mol %). Mo(CO)6 (132 mg,
0.5 mmol) was added to chamber 2. The two chambers were capped with a gastight cap and
the atmosphere was exchanged for nitrogen. 1,4-Dioxane (3 mL) was added through the septa
to both chambers followed by the addition of Et3N (0.14 mL, 1.0 mmol) to chamber 1 and
finally DBU (0.23 mL, 1.5 mmol) to chamber 2. The two-chamber system was immediately
heated under vigorous stirring in a heating block at either (Method A): 65 °C for 20 h. After
20 h the reaction mixture in chamber 1 was transferred to a microwave vial (Biotage 2-5 mL)
and heated under microwave irradiation at 140 °C for 20 min or (Method B): 85 °C for 20 h.
The reaction mixture was poured into iso-hexane (30 mL) and collected by filtration. The
solid was washed with water (10 mL) and ethyl acetate (10 mL) to give the pure compound.
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2-Amino-1-benzylquinazolin-4(1H)-one (2k). Method A: Tan solid (81 mg, 67%); Method B:
Tan solid (82 mg, 69%); 1H NMR (DMSO-d6) δ 7.99 (dd, J = 7.7, 1.7 Hz, 1H), 7.51 (ddd, J =
8.8, 7.1, 1.8 Hz, 1H), 7.39-7.32 (m, 2H), 7.31-7.16 (m, 7H), 5.37 (s, 2H); 13C NMR (DMSO-
d6) δ 167.2, 156.3, 140.7, 135.5, 132.4, 128.5, 127.1, 126.9, 125.9, 122.7, 119.0, 114.5, 47.1;
HRMS (ESI-TOF) calcd for C15H14N3O [M + H]+ 252.1137 m/z, found 252.1138; LC purity
(254 nm) = >98%.
2-Amino-1-methylquinazolin-4(1H)-one (2l).52 Method A: Beige solid (51 mg, 60%); Method
B: White solid (56 mg, 66%); 1H NMR (DMSO-d6) δ 8.04 (dd, J = 7.8, 1.7 Hz, 1H), 7.79 (m,
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1H), 7.61 (d, J = 8.5 Hz, 1H), 7.40 (m, 1H), 3.57 (s, 3H); C NMR (DMSO-d6) δ 163.2,
153.9, 140.7, 134.2, 126.9, 123.9, 117.7, 115.1, 32.7; HRMS (ESI-TOF) calcd for C9H10N3O
[M + H]+ 176.0824 m/z, found 176.0817; LC purity (254 nm) = >98%.
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2-Amino-1-isopropylquinazolin-4(1H)-one (2m). Method A: Tan solid (46 mg, 44%); Method
B: Tan solid (96 mg, 95%); 1H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 7.8 Hz, 1H), 7.80-
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7.70 (m, 2H), 7.39 (m, 1H), 4.89 (m, 1H), 1.61 (d, J = 7.0 Hz, 6H); C NMR (DMSO-d6) δ
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163.6, 153.6, 139.4, 134.0, 127.4, 124.2, 118.8, 117.3, 50.4, 19.4; HRMS (ESI-TOF) calcd for
C11H14N3O [M + H]+ 204.1137 m/z, found 204.1127; LC purity (254 nm) = >98%.
2-Amino-1-propylquinazolin-4(1H)-one (2n). Method B: White solid (89 mg, 83%); 1H NMR
(DMSO-d6) δ 8.04 (m, 1H), 7.75 (m, 1H), 7.60 (m, 1H), 7.36 (m, 1H), 4.06-3.96 (m, 2H),
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1.74-1.60 (m, 2H), 1.07-0.93 (m, 3H); C NMR (DMSO-d6) δ 165.0, 154.2, 140.1, 134.2,
127.3, 123.8, 118.1, 115.1, 45.5, 19.9, 10.4; HRMS (ESI-TOF) calcd for C11H14N3O [M + H]+
204.1137 m/z, found 204.1131; LC purity (254 nm) = 98%.
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2-Amino-1-hexylquinazolin-4(1H)-one (2o). Method B: White solid (87 mg, 73%); H NMR
(DMSO-d6) δ 8.02 (dd, J = 7.8, 1.7 Hz, 1H), 7.71 (ddd, J = 8.7, 7.2, 1.8 Hz, 1H), 7.50 (d, J =
8.5 Hz, 1H), 7.31 (m, 1H), 4.16-3.96 (m, 2H), 1.69-1.58 (m, 2H), 1.47-1.37 (m, 2H), 1.36-
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1.25 (m, 4H), 0.92-0.83 (m, 3H); C NMR (DMSO-d6) δ 165.3, 154.6, 140.1, 133.3, 127.1,
123.1, 118.4, 114.4, 44.0, 30.8, 26.5, 25.1, 21.8, 13.6; HRMS (ESI-TOF) calcd for C14H20N3O
[M + H]+ 246.1606 m/z, found 246.1603; LC purity (254 nm) = >98%.
2-Amino-1-cyclopentylquinazolin-4(1H)-one (2p). Method A: Gray solid (92 mg, 79%).
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Method B: Tan solid (106 mg, 90%); H NMR (DMSO-d6) δ 8.07 (dd, J = 7.7, 1.7 Hz, 1H),
7.75 (m, 1H), 7.48 (d, J = 8.6 Hz, 1H), 7.39 (m, 1H), 4.93 (q, J = 9.2 Hz, 1H), 2.23-1.97 (m,
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6H), 1.79-1.66 (m, 2H); C NMR (DMSO-d6) δ 163.1, 154.3, 138.5, 133.3, 127.4, 123.9,
119.0, 116.8, 58.3, 26.9, 24.1; HRMS (ESI-TOF) calcd for C13H16N3O [M + H]+ 230.1293
m/z, found 230.1285; LC purity (254 nm) = >98%.
2-Amino-1-cyclohexylquinazolin-4(1H)-one (2q). Method A: Gray solid (88 mg, 72%).
Method B: White solid (108 mg, 88%); 1H NMR (DMSO-d6) δ 8.03 (dd, J = 7.7, 1.7 Hz, 1H),
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7.87 (d, J = 8.6 Hz, 1H), 7.73 (ddd, J = 8.8, 7.1, 1.8 Hz, 1H), 7.38 (m, 1H), 4.51-4.16 (m, 1H),
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2.43-2.29 (m, 2H), 1.90-1.77 (m, 4H), 1.69-1.12 (m, 4H); C NMR (DMSO-d6) δ 163.6,
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calcd for C14H18N3O [M + H]+ 244.1450 m/z, found 244.1440; LC purity (254 nm) = >98%.
2-Amino-1-cycloheptylquinazolin-4(1H)-one (2r). Method A: Tan solid (77 mg, 61%).
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Method B: Tan solid (97 mg, 78%); H NMR (DMSO-d6) δ 8.02 (dd, J = 7.9, 1.7 Hz, 1H),
7.70 (m, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.33 (m, 1H), 4.55 (m, 1H), 2.44-2.29 (m, 2H), 2.01-
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1.88 (m, 2H), 1.88-1.76 (m, 2H), 1.77-1.53 (m, 6H); C NMR (DMSO-d6) δ 164.4, 153.9,
139.3, 133.1, 127.2, 123.5, 119.1, 116.8, 59.9, 30.6, 27.1, 26.0; HRMS (ESI-TOF) calcd for
C15H20N3O [M + H]+ 258.1606 m/z, found 258.1614; LC purity (254 nm) = 96%.
2-Amino-1-(2-bromobenzyl)quinazolin-4(1H)-one (2s). Method A: Off-white solid (53 mg,
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32%); H NMR (DMSO-d6) δ 8.02 (dd, J = 7.8, 1.7 Hz, 1H), 7.74 (dd, J = 7.7, 1.5 Hz, 1H),
7.53 (ddd, J = 8.7, 7.2, 1.7 Hz, 1H), 7.34-7.22 (m, 3H), 6.91 (d, J = 8.5 Hz, 1H), 6.82 (dd, J =
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7.6, 1.9 Hz, 1H), 5.27 (s, 2H); C NMR (DMSO-d6) δ 167.5, 156.5, 140.5, 134.0, 133.1,
133.0, 129.4, 128.3, 127.2, 126.4, 123.2, 122.1, 119.1, 114.2, 48.7; HRMS (ESI-TOF) calcd
for C15H13N3OBr [M + H]+ 330.0242 m/z, found 330.0246; LC purity (254 nm) = 95%.
2-Amino-1-(4-fluorobenzyl)quinazolin-4(1H)-one (2t). Method B: White solid (120 mg,
86%); 1H NMR (DMSO-d6) δ 7.99 (dd, J = 7.7, 1.7 Hz, 1H), 7.53 (m, 1H), 7.31-7.12 (m, 8H),
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5.35 (s, 2H); C NMR (DMSO-d6) δ 167.8, 161.8 (d, JCF = 243.1 Hz), 156.8, 141.1, 133.2,
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132.2 (d, JCF = 2.9 Hz), 128.6 (d, JCF = 8.2 Hz), 127.5, 123.5, 119.5, 116.0 (d, JCF = 21.5
Hz), 115.1, 47.0; HRMS (ESI-TOF) calcd for C15H13N3OF [M + H]+ 270.1043 m/z, found
270.1048; LC purity (254 nm) = >98%.
2-Amino-1-(3-hydroxybenzyl)quinazolin-4(1H)-one (2u). Method B: Pale yellow solid (127
mg, 92%); 1H NMR (DMSO-d6) δ 9.32 (br s, 1H, OH), 7.99 (m, 1H), 7.52 (m, 1H), 7.30-7.19
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(m, 2H), 7.14 (m, 1H), 6.69-6.62 (m, 2H), 6.56 (m, 1H), 5.28 (s, 2H); 13C NMR (DMSO-d6) δ
167.5, 157.7, 156.5, 140.8, 137.1, 132.7, 129.8, 127.0, 123.0, 119.0, 116.7, 114.8, 114.2,
112.6, 47.1; HRMS (ESI-TOF) calcd for C15H14N3O2 [M + H]+ 268.1086 m/z, found
268.1092; LC purity (254 nm) = 98%.
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2-Amino-1-(2,6-dimethoxybenzyl)quinazolin-4(1H)-one (2v). Method B: Off-white solid
(137 mg, 84%); 1H NMR (DMSO-d6) δ 7.91 (m, 1H), 7.48 (m, 1H), 7.41 (m, 1H), 7.25 (t, J =
8.3 Hz, 1H), 7.16 (m, 1H), 7.07 (br s, NH2), 6.67 (d, J = 8.3 Hz, 2H), 5.23 (s, 2H), 3.74 (s,
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6H); C NMR (DMSO-d6) δ 167.2, 158.0, 156.8, 140.8, 131.8, 129.6, 126.6, 122.3, 119.1,
114.6, 110.8, 104.4, 55.8, 39.0 (overlaps with residual solvent signal); HRMS (ESI-TOF)
calcd for C17H18N3O3 [M + H]+ 312.1348 m/z, found 312.1352; LC purity (254 nm) = >98%.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge at http://pubs.acs.org.
Copies of 1H and 13C NMR spectra and chromatograms for all compounds obtained and X-ray
crystallographic data (PDF)
X-ray crystallographic data for 3 (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: luke.odell@orgfarm.uu.se
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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We thank Alfred Svan (Uppsala University) and Dr Lisa D. Haigh (Imperial College London,
U.K.) for assistance with accurate mass determination. The research was supported by
Uppsala University.
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