Condensation reactions of guanidines with bis-electrophiles: Formation of highly nitrogenous heterocycles

Article abstract of DOI:10.1016/j.tet.2013.04.127

2-Amino-1,4-dihydropyrimidines were reacted with bis-electrophiles to produce novel fused bipyrimidine, pyrimidoaminotriazine, and pyrimidosulfonamide scaffolds. In addition, a quinazoline library was constructed using a guanidine Atwal-Biginelli reaction with 1-(quinazolin-2-yl)guanidines. The product heterocycles have novel constitutions with high nitrogen atom counts and represent valuable additions to screening libraries for the discovery of new modulators of biological targets.

Full text of DOI:10.1016/j.tet.2013.04.127

Tetrahedron xxx (2013) 1e13
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Condensation reactions of guanidines with bis-electrophiles:
formation of highly nitrogenous heterocyclesq
*
David M. Arnold, Matthew G. LaPorte, Shelby M. Anderson, Peter Wipf
University of Pittsburgh, Center for Chemical Methodologies and Library Development, Pittsburgh, PA 15260, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Amino-1,4-dihydropyrimidines were reacted with bis-electrophiles to produce novel fused bipyr-
imidine, pyrimidoaminotriazine, and pyrimidosulfonamide scaffolds. In addition, a quinazoline library
was constructed using a guanidine AtwaleBiginelli reaction with 1-(quinazolin-2-yl)guanidines. The
product heterocycles have novel constitutions with high nitrogen atom counts and represent valuable
additions to screening libraries for the discovery of new modulators of biological targets.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 3 March 2013
Received in revised form 24 April 2013
Accepted 26 April 2013
Available online xxx
Keywords:
Guanidines
Pyrimidines
Quinazolines
AtwaleBiginelli reaction
Screening library
1. Introduction
Diversity Oriented Synthesis (DOS) inspires chemists to design
or apply chemical methodologies that result in the synthesis of
structurally diverse, functionally rich and often architecturally
complex small molecule scaffolds.1,2 In many cases, new biological
targets can be explored more effectively with DOS-derived probes
and natural products than traditional aromatic ‘drug-like’ hetero-
cycles.3 Novel molecular scaffolds are therefore valuable additions
to high throughput screening libraries and improve the odds of
identifying lead compounds in drug discovery initiatives.4,5
As a continuation of our efforts in the preparation of rare het-
erocyclic scaffolds,6 we became interested in developing a conver-
gent synthetic route to 4H-pyrimido[1,2-a]pyrimidines. While
there is evidence in the literature demonstrating melanin-
concentrating hormone receptor (MCH1R) antagonistic effects,7
protein kinase inhibition,8 treatment of atherosclerosis and reste-
nosis,9 antiviral activities,10 inhibition of platelet aggregation,11 and
anti-MRSA dihydrofolate reductase activity12 of 4H-pyrimido[1,2-a]
pyrimidines 1, their synthesis and application is strikingly
rare compared to the structurally and pharmacologically
related ring-contracted imidazo[1,2-a]pyridines 2 (Fig.1). The latter
Fig. 1. The 4H-pyrimido[1,2-a]pyrimidine and imidazo[1,2-a]pyridine scaffolds 1 and
2, and selected biologically active derivatives.
heterocycle is an abundant pharmacophore in medicinal chemistry
and has been used in antiviral, antibacterial, anti-inflammatory,
analgesic, antipyretic, and anxioselective indications. Derivatives
q
Submitted in honor of Prof. Paul Wender, the recipient of the 2012 Tetrahedron
of 2 are b-amyloid formation inhibitors and constitute a novel class
Prize for Creativity in Organic Chemistry.
of orally active nonpeptide bradykinin B2 receptor antagonists.13
* Corresponding author. Tel.: þ1 412 624 8606; fax: þ1 412 624 0787; e-mail
address: pwipf@pitt.edu (P. Wipf).
Several imidazo[1,2-a]pyridines are already clinically used,
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.127
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2
D.M. Arnold et al. / Tetrahedron xxx (2013) 1e13
Table 1
including zolimidine (an anti-ulcer drug), zolpidem (a hypnotic
drug), and alpidem (a nonsedative anxiolytic). Imidazo[1,2-a]py-
rimidine moieties are also important as benzodiazepine receptor
agonists, antiviral agents, antibacterials, antifungal agents, and
calcium channel blockers.13
Using a variant of the Biginelli three-component reaction for the
preparation of cyclic guanidines,14,15 we were able to develop effi-
cient strategies for a tandem condensation with bis-electrophiles to
give bipyrimidines 3, pyrimidoaminotriazines 4, cyclic pyr-
imidosulfonamides 5, and pyrimidopyrimidines 6 (Scheme 1). In
addition, a small sub-library of quinazoline-containing heterocy-
cles 7 was assembled using AtwaleBiginelli conditions.16,17
Conversion of thioureas (8a, R¼CH3; 8b, R¼(CH2)2Ph; 8c, R¼CH(CH3)2) to thio-
imidates 9aec and 2-aminopyrimidines 10aec according to Scheme 2
Entry
8/Conditions
9/Additive/time
10/Yielda
%
1
2
3
4
5
6
7
8a/MeOTf, THF, 1.5 h
8a/MeOTf, ClCH2CH2Cl, 0.75 h
8a/MeOTf, PhCl, 3.5 h
8a/MeOTf, PhCl, 15 h
8a/(MeO)2SO2, THF, 60 h
8b/MeOTf, PhCl, 3.5 h
8c/MeOTf, PhCl, 3.5 h
9a/NH4OAc/20 h
9a/NH4OAc/15 h
9a/NH4OAc/17 h
9a/NH4Cl/21 h
9a/NH4OAc/17 h
9b/NH4OAc/17 h
9c/NH4OAc/20 h
10a/77
10a/30
10a/61
10a/51
10a/57
10b/39
10c/33
a
Isolated yield of purified product.
R
R
O
N
R
N
NH2
N
R
EtO2C
EtO2C
R1
EtO2C
R1
EtO2C
R1
N
N
NH
N
N
+
+
O
O
S
R1
N
H
NH2
N
H
N
N
N
N
R3
O
bis-electrophiles
4
5
3
or
R
R
N
Me
R
N
Me
EtO2C
R1
CO2Et
CO2Et
N
N
R1
+
+
N
NH
NH2
R1
N
H
R1
N
N
N
H
H
N
N
H
7
6
Scheme 1. Overview of heterocycles obtained by condensation of guanidines with bis-electrophiles.
New strategies for accessing structurally diverse guanidine-
based Biginelli products have previously been reported by the
Overman group.18 Specifically, triazone-protected guanidines were
found to endure the harsh acidic conditions frequently used for the
Biginelli cyclization.18 In order to access C-4 alkyl-substituted cyclic
guanidines 10, we first envisioned using thioureas 8 as starting
materials followed by an aminolysis of the corresponding methyl-
thioureas 9, in a manner similar to that reported by Kappe
(Scheme 2).19
and could safely be heated to 95e100 ꢀC under sealed tube con-
ditions (Table 1, entry 3). The aminolysis step was found to proceed
smoothly on multigram scale (2.5 g) with ammonium acetate or
ammonium chloride as additives in the presence of ammonia.
Following this one-pot reaction, the hydrochloride salts of 10aec
were prepared and subsequently used as substrates for further
cyclization reactions (vide infra).
The 4-arylated 2-aminopyrimidine 13$TFA was obtained in
a two-step sequence starting from PMBeguanidine 11 (Scheme 3).23
R
R
R
HX
S
methylation
aminolysis
NH3,
EtO2C
EtO2C
EtO2C
NH
N
N
MeX
Δ
N
H
S
N
H
N
H
NH2
8
9
10
Scheme 2. Thiourea methylation followed by aminolysis of the thioimidate provides access to 2-aminodihydropyrimidines.
2. Results and discussion
Treatment of a solution of 11 in hexafluoroisopropanol with enone
12 and sodium bicarbonate at 90 ꢀC provided the PMB-protected 13
in 42% yield. Deprotection of the PMB group was accomplished in
70% yield in TFA buffered with water, triethylsilane, and thio-
anisole.24 A three-component Biginelli reaction with guanidine
hydrochloride 14$HCl, ethyl 3-oxo-3-phenylpropanoate 15, and al-
dehydes 16 and 17 was performed to access heterocycles 18, 19, and
the hydrochloride salt 18$HCl (Scheme 4).
Thioureas 8 with R¼methyl, phenethyl, and isopropyl were
prepared through Biginelli multicomponent condensations from b-
ketoesters, aldehydes, and thiourea under standard acid-catalyzed
conditions.20 The reaction parameters for the one-pot methylation/
aminolysis were optimized on substrate 8a (R¼Me) (Table 1, entries
1e5). Initial investigations using methyl iodide resulted in deal-
kylation of the newly formed methylthiourea 9a, most likely due to
the presence of nucleophilic iodide ions in the vigorously heated
aminolysis reaction mixture.21 Accordingly, methyl triflate was
used as an alternative electrophile for the S-alkylation and proved
effective for the formation of the desired guanidine 10a in good
isolated yields. The use of dimethyl sulfate also provided 10a in 57%
yield but required prolonged reaction times (entry 5). High yields of
product 10a were achieved when THF was used as the reaction
solvent. However, the methylation step was problematic due to the
propensity of methyl triflate to polymerize THF.22 The optimal
solvent for this two-step reaction sequence was found to be chlo-
robenzene (PhCl), which was both inert to the reaction conditions
Cyclization reactions of guanidines with the bis-electrophile
1,1,3,3-tetramethoxypropane (20) were explored under micro-
wave conditions (Scheme 5 and Table 2).25,26 We found that
these reactions proceeded smoothly in 42e76% yield when the
hydrochloride salts of 10aec or 18 were combined with 20 in
a microwave vial and heated to 160 ꢀC in trifluoroethanol (21)
(entries 1e4). The use of the hydrochloride salts was essential
since the corresponding reactions with free amines did not af-
ford the cyclocondensation products. We also briefly explored
the reaction of 18 with 4-methoxybut-3-enone 26 to give 8-
methyl 4H-pyrimido[1,2-a]pyrimidine 27 in 64% yield (Table 2,
entry 5).
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D.M. Arnold et al. / Tetrahedron xxx (2013) 1e13
3
Cl
Cl
O
TFA/H2O
Et3SiH/PhSMe
CO2Et
NH
NH2
NaHCO3
PMB
TFA
N
H
50 °C
70%
(CF3)2CHOH
90 °C
EtO2C
EtO2C
N
N
Cl
PMB
N
H
N
H
42%
N
H
NH2
Scheme 3. Two-step preparation of 2-aminopyrimidine 13 from PMB-protected guanidine 11.
°
Scheme 4. Preparation of 2-aminopyrimidines from guanidine hydrochloride.
Scheme 5. Synthesis of 4H-pyrimido[1,2-a]pyrimidine-3-carboxylates.
Table 2
Additional substituents on pyrimido[1,2-a]pyrimidines could be
introduced by cyclocondensations of 18$HCl with heterocyclic
TMS-alkynones (Scheme 6).27 In the presence of sodium carbonate
and catalytic amounts of DMAP, microwave heating at 170 ꢀC for
30 min provided the 8-heteroaryl substituted pyrimidopyridines 30
and 31 in modest yields. In order to further improve the synthesis
of these interesting derivatives, we developed a one-pot Sonoga-
shira coupling/cyclocondensation approach (Scheme 7). Room
temperature conversion of acid chlorides 32e34 and trimethylsilyl
acetylene in the presence of Pd(0)-catalysts led to ynones 35e37,
which were condensed with pyrimidines 18 and 19 under micro-
wave irradiation to give pyrimidopyridines 38aed in improved
Cyclocondensation reactions of guanidines with bis-electrophiles 20 and 26 ac-
cording to Scheme 5
Entry
Reactants
Solvent/temperature/time
Product/yielda
%
1
2
3
4
5
10a$HCl and 20
10b$HCl and 20
10c$HCl and 20
18$HCl and 20
18 and 26
21/160 ꢀC/1 h
21/160 ꢀC/2 h
21/160 ꢀC/2 h
21/160 ꢀC/1.5 h
THF/150 ꢀC/0.25 h
22/76
23/71
24/71
25/42
27/64
a
Isolated yield of purified product.
Ph
Ph
O
MeOH/MeCN
EtO2C
Ph
HCl
N
EtO2C
Ph
Na2CO3, DMAP
N
N
N
X
Si
W, 170 °C
30 min
N
H
NH2
X
28; X = NH
29; X = O
30; X = NH, 25%
31; X = O, 22%
Scheme 6. Synthesis of 8-heteroaryl-4H-pyrimido[1,2-a]pyrimidine-3-carboxylates.
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4
D.M. Arnold et al. / Tetrahedron xxx (2013) 1e13
R1
R1
Ph
O
O
18 or 19, DMAP
MeOH/THF
TMS
Cl
Sonogashira
coupling
TMS
W, 170 °C
30 min
R
N
R
N
38a-d
N
32; R = H
33; R = OMe
34; R = CF3
35; R = H
36; R = OMe
37; R = CF3
R
Scheme 7. One-pot Sonogashira couplingecyclocondensation for the synthesis of 8-aryl-4H-pyrimido[1,2-a]pyrimidine-3-carboxylates.
overall yields of 28e60% (Table 3). A modest preference for NCy2Me
over Et3N in the Sonogashira coupling was noted for acid chloride
32 (entries 1, 2, 5, and 6), whereas the yield of the electron-rich acyl
chloride 33 was almost unchanged (entries 3 and 7). The efficiency
of the conversion of the electron-deficient acyl chloride 34 de-
creased in the presence of NCy2Me (entries 4 and 8). Copper- and
solvent-free reaction conditions28 also lowered yields (entries 9
and 10).
exerted between the pseudoaxial 4-aryl group and a peri-sub-
stituent at the 6-position.
Starting with 2-aminopyrimidines 10aec and 18, we were
able to access two additional novel heterocyclic scaffolds, the 2-
morpholino-6H-pyrimido[1,2-a][1,3,5]triazine-7-carboxylates
40e43, and the 4-oxo-3,4,6,9-tetrahydropyrimido[2,1-c][1,2,4,6]
thiatriazine-7-carboxylate 2,2-dioxides 44 and 45 (Scheme 8).
Condensation of pyrimidines 10aec and 18 with in situ gener-
ated cyanoimine 39 furnished the pyrimidotriazines in 25e53%
yield under microwave irradiation conditions. A similar trans-
formation has been reported for the synthesis of aminotriazine-
based anti-HIV agents.29 Alternatively, treatment of 10a and 18
with chlorosulfonyl isocyanate afforded the cyclic sulfamides 44
and 45 in 15% and 40% yield, respectively. We were able to
obtain an X-ray structure of 44 that confirmed the assignment
(Fig. 3).
Heterocycles 40e43 and 44e45 are representative examples for
target scaffolds 4 and 5 shown in Scheme 1. We were also interested
in further extending our conversions of 2-aminopyrimidines and
guanidinoquinazolines to the structural variants 6 and 7, which are
only featured in very few reported examples in the literature.30,31 In
particular, we wanted to determine if aminopyrimidine 13$TFA
could be used as a substrate for a second AtwaleBiginelli conden-
sation reaction. Although prolonged reaction times were required,
we were pleased to find that the expected fused bicycle 46 was
indeed formed as a 4:1 mixture of antiesyn-isomers in 57% yield
(Scheme 9). The major anti-isomer was assigned based on literature
precedence30 as well as ab initio HF-6-311G* calculations (Fig. 4).32
The latter provided a 5.8 kcal/mol gas-phase energy difference in
favor of anti-46, suggesting that the reaction was not under com-
plete thermodynamic control. Indeed, upon heating a sample of the
product mixture for 26 h in the presence of deuterated acetic acid at
90 ꢀC in DMSO-d6, the signals characteristic for syn-46 at 7.00e6.92
and 5.35 ppm disappeared in the 1H NMR.
Table 3
Sonogashira couplingsecyclocondensations according to Scheme 7
Entry Reactants
Sonogashira coupling conditions Product/R/R1/yielda
%
1
32 and 18 Pd(PPh3)2Cl2 (2 mol %);
38a/H/H/54
CuI (4 mol %), NEt3, THF, rt
2
32 and 19 Pd(PPh3)2Cl2 (2 mol %);
38b/H/OMe/39
38c/OMe/H/32
38d/CF3/H/55
38a/H/H/60
CuI (4 mol %), NEt3, THF, rt
33 and 18 Pd(PPh3)2Cl2 (2 mol %);
CuI (4 mol %), NEt3, THF, rt
34 and 18 Pd(PPh3)2Cl2 (2 mol %);
CuI (4 mol %), NEt3, THF, rt
32 and 18 Pd(PPh3)2Cl2 (2 mol %);
CuI (4 mol %), NCy2Me, THF, rt
32 and 19 Pd(PPh3)2Cl2 (2 mol %);
CuI (4 mol %), NCy2Me, THF, rt
33 and 18 Pd(PPh3)2Cl2 (2 mol %);
CuI (4 mol %), NCy2Me, THF, rt
34 and 18 Pd(PPh3)2Cl2 (2 mol %);
CuI (4 mol %), NCy2Me, THF, rt
32 and 18 Pd(OAc)2 (1 mol %);
NCy2Me, 40 ꢀC
3
4
5
6
38b/H/OMe/51
38c/OMe/H/28
38d/CF3/H/29
38a/H/H/30
7
8
9
10
34 and 18 Pd(OAc)2 (1 mol %),
38d/CF3/H/44
NCy2Me, 40 ꢀC
a
Isolated yield of purified product.
Pyrimidopyridines 27, 30, 31, and 38aed were isolated as single
regioisomers, and their assignment was supported by an X-ray
analysis of 38d (Fig. 2). The regiochemical preference for sub-
stitution at C-8 can be explained by a destabilizing steric hindrance
In an analogous synthetic sequence, guanidinoquinazolines
47aed were converted in moderate to high yields to the amine-
linked pyrimidyl-quinazolines 49aei upon heating with 12 and
48aed in hexafluoroisopropanol (Scheme 10 and Table 4). The
cyclocondensation worked particularly well for the morpholine-
substituted enone 48d (entry 8), whereas the yield for the
dimethylamino-substituted enone 48a was consistently low (en-
tries 4 and 9). Quinazolines 47aed were prepared in a three-step
sequence from the corresponding anilines.33
3. Conclusion
Cyclocondensations of heterocyclic guanidines with bis-
electrophiles provide a rapid access to previously unexplored
or sparsely documented heterocyclic scaffolds. Specifically, we
were able to devise concise routes to new bipyrimidines,
pyrimidoaminotriazines, pyrimidosulfonamides, pyrimidopyr-
imidines, and amine-linked pyrimidoquinazolines. Several
Fig. 2. X-ray structure of 38d (CCDC 932463).
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D.M. Arnold et al. / Tetrahedron xxx (2013) 1e13
5
°
Scheme 8. Synthesis of 2-morpholino-6H-pyrimido[1,2-a][1,3,5]triazine-7-carboxylates 40e43 and 4-oxo-3,4,6,9-tetrahydropyrimido[2,1-c][1,2,4,6]thiatriazine-7-carboxylate 2,2-
dioxides 44e45.
Fig. 3. X-ray structure of 44 (CCDC 935121). Due to static disorder in the ethyl ester
group, the five ethyl hydrogen positions are uncertain and are therefore not shown.
versatile methodologies were explored in this work: (a) a one-
pot methylation/aminolysis sequence for the preparation of 2-
aminodihydropyrimidine intermediates (Scheme 2); (b) an al-
Fig. 4. HF-6-311G* structures of anti- (top) and syn- (bottom) 46.
ternative AtwaleBiginelli cyclization of
guanidine for the construction of 2-aminodihydropyrimidines
(Scheme 3); (c) one-pot tandem Sonogashira cou-
a
PMB-protected
a
4. Experimental section
plingealkynone cyclization to produce fused bipyrimidines
(Scheme 7); (d) diverse cyclocondensation strategies, including
consecutive AtwaleBiginelli reactions, to afford pyrimidopyr-
4.1. General experimental procedures
imidines,
pyrimidotriazines,
and
pyrimidothiatriazines
All moisture-sensitive reactions were performed under an at-
mosphere of dry nitrogen and all glassware was either dried in an
oven at 140 ꢀC or flame dried under high vacuum prior to use. THF
and Et2O were dried by distillation over Na/benzophenone, and
CH2Cl2 and toluene were purified using an alumina filtration system.
Reactions were monitored by either 1H NMR at 300 MHz in DMSO-
(Schemes 5, 8, and 9). Finally, quinazolineedihydropyrimidine
amines were prepared by extending AtwaleBiginelli conditions
to quinazoline guanidines (Scheme 10). We are currently ex-
ploring the activity profile of these new heterocycles in a variety
of biological screens.
°
Scheme 9. A second AtwaleBiginelli cyclocondensation reaction converts 2-aminopyrimidine 13$TFA into pyrimidopyrimidine 46.
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6
D.M. Arnold et al. / Tetrahedron xxx (2013) 1e13
°
Scheme 10. AtwaleBiginelli cyclocondensation reactions with guanidineequinazolines 47aed.
Table 4
benzyltriethylammonium chloride (0.386 g, 1.97 mmol) was heated
in a sealed tube at 75 ꢀC for 15 min. The reaction mixture turned
light yellow in color and was heated at 100e105 ꢀC for 20 h,
allowed to cool to room temperature, diluted with water (20 mL),
and stirred for 1 h. The resulting solid residue was isolated by
vacuum filtration, washed with water (70 mL), recrystallized from
boiling EtOH/H2O (3:1, 50 mL), washed with EtOH/H2O (1:1), fol-
lowed by water, and dried in vacuo to afford 8a (1.81 g, 43%) as pale
AtwaleBiginelli reactions according to Scheme 10
Entry
Reactants
Substituents R/R1/R2/R3
Product/yielda
%
1
2
3
4
5
6
7
8
9
47a and 12
47b and 12
47c and 12
47c and 48a
47b and 48b
47d and 12
47d and 48c
47d and 48d
47d and 48a
Cl/H/Cl/H
Me/H/Cl/H
F/H/Cl/H
F/H/NMe2/H
49a/56
49b/62
49c/52
49d/40
49e/67
49f/41
49g/57
49h/81
49i/45
Me/H/H/NO2
eOCH2Oe/Cl/H
eOCH2Oe/Br/H
eOCH2Oe/N((CH2CH2)2O)/H
eOCH2Oe/NMe2/H
yellow crystals: 1H NMR (300 MHz, DMSO-d6)
d 10.12 (s,1H), 9.19 (s,
1H), 4.15e4.03 (m, 3H), 2.19 (s, 3H),1.19 (t, 3H, J¼6.9 Hz),1.09 (d, 3H,
J¼6.3 Hz). The spectral data are consistent with the literature
values.20
a
Isolated yield of purified product.
d6, high resolution LC/MS (Thermo Scientific Exactive spectrome-
ter), or TLC analysis (EM Science pre-coated silica gel 60 F254 plates).
Visualization of TLCs was accomplished with a 254 nm UV light and
by staining with a p-anisaldehyde solution (2.5 mL of p-anisalde-
hyde, 2 mL of AcOH, and 3.5 mL of concd H2SO4 in 100 mL of 95%
EtOH) or a KMnO4 solution (1.5 g of KMnO4 and 1.5 g of K2CO3 in
100 mL of a 0.1% NaOH solution). Flash chromatography was per-
4.3. Ethyl 4-methyl-6-(2-phenylethyl)-2-thioxo-1,3,6-
trihydropyrimidine-5-carboxylate (8b)34
According to general procedure A, a suspension of thiourea
(1.72 g, 22.4 mmol), benzyltriethylammonium chloride (0.29 g,
1.50 mmol), hydrocinnamaldehyde (2.08 mL, 15.0 mmol), and ethyl
3-oxobutanoate (2.50 mL, 15.0 mmol) was heated at 120 ꢀC for 3 h.
The viscous orange reaction mixture was allowed to cool to room
temperature, diluted with EtOAc (150 mL), and washed with water
(3ꢁ100 mL). The organic layer was dried (Na2SO4), filtered, and
concentrated under reduced pressure. The crude light orange res-
idue was recrystallized from hexanes/EtOAc (2:1), isolated by vac-
uum filtration, washed with hexanes, and dried in vacuo to afford
8b as a pale yellow solid (2.24 g, 49%, w90% pure): 1H NMR
(300 MHz, DMSO-d6) 10.19 (s, 1H), 9.45 (s, 1H), 7.30e7.18 (m, 5H),
4.18e4.16 (m, 1H), 4.07e4.02 (m, 2H), 2.63e2.51 (m, 2H), 2.22 (s,
3H), 1.78e1.66 (m, 2H), 1.13 (t, 3H, J¼7.2 Hz). The spectral data are
consistent with the literature values.34
formed on 40e63 mm silica gel (Silicycle) or on a Teledyne ISCO
CombiFlash Rf. Melting points were determined using a Laboratory
Devices Mel-Temp II and are not corrected. Infrared spectra were
obtained on either a Nicolet Avatar 360, a Smiths Detection Identi-
fyIR FT-IR spectrometer, or Perkin Elmer ATR IR. Mass spectra were
obtained on either a Micromass Autospec double focusing in-
strument or High Res LC/MS instrument (Thermo Scientific Exactive
spectrometer). Purities were determined using an Agilent Tech-
nologies 385-ELSD. Microwave reactions were performed in a Biot-
age Initiator 2.0 Microwave reactor. 1H and 13C NMR spectra were
obtained on a Bruker Avance 300, 400, 500, or 700 MHz instrument
at room temperature unless otherwise noted. Chemical shifts (d) are
reported in parts per million (ppm) with the residual solvent peak
4.4. Ethyl 4-methyl-6-(methylethyl)-2-thioxo-1,3,6-
trihydropyrimidine-5-carboxylate (8c)20
used as an internal standard (CHCl3 d 7.26 ppm for 1H and 77.00 ppm
for 13C, DMSO
d
2.50 ppm for 1H and 40.45 ppm for 13C). 1H NMR
spectra are tabulated as follows: chemical shift, multiplicity
(s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet,
br¼broad), integration, and coupling constant(s) (J) in Hertz (Hz).
13C NMR spectra were recorded using a proton-decoupled pulse
sequence with a d1 of 5 s, and are tabulated by the chemical shifts of
the observed peaks. X-ray crystallographic data for 38d (deposition
number CCDC 932463) and 44 (CCDC 935121) were deposited with
the Cambridge Crystallographic Data Center.
According to general procedure A, a suspension of thiourea
(2.75 g, 35.9 mmol), citric acid (2.30 g, 12.0 mmol), iso-
butyraldehyde (2.22 mL, 23.9 mmol), and ethyl 3-oxobutanoate
(4.0 mL, 23.2 mmol) was heated at 120 ꢀC for 15 h. The viscous
yellow/orange reaction mixture was allowed to cool to room tem-
perature, diluted with EtOAc (300 mL), and washed with water
(3ꢁ200 mL). The organic layer was dried (Na2SO4), filtered, and
concentrated under reduced pressure. The resulting light orange
residue was slowly triturated with EtOAc (30 mL) and hexanes
(60 mL) at room temperature. The suspension was cooled to ꢂ20 ꢀC
for 24 h and the resulting off-white precipitate was isolated by
vacuum filtration, washed with hexanes/EtOAc (3:1, 100 mL), fol-
lowed by hexanes (30 mL), and dried in vacuo to afford 8c as an off-
white solid (2.13 g, 33%, w90% pure): 1H NMR (300 MHz, DMSO-d6)
4.2. Ethyl 4,6-dimethyl-2-thioxo-1,3,6-trihydropyrimidine-5-
carboxylate (8a).20 General procedure A
A suspension of ethyl 3-oxobutanoate (2.50 mL, 19.7 mmol),
thiourea (2.20 g, 28.9 mmol), ethanal (1.10 mL, 19.7 mmol), and
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D.M. Arnold et al. / Tetrahedron xxx (2013) 1e13
7
10.09 (s, 1H), 9.23 (s, 1H), 4.15e4.02 (m, 2H), 4.00e3.97 (m, 1H),
2.23 (s, 3H), 1.71e1.65 (m, 1H), 1.20 (t, 3H, J¼7.2 Hz), 0.82 (d, 3H,
J¼6.0 Hz), 0.76 (d, 3H, J¼6.0 Hz). The spectral data are consistent
with the literature values.20
(d, 3H, J¼6.9 Hz); 13C NMR (75 MHz; DMSO-d6)
d
166.5, 161.1, 156.2,
95.7, 57.9, 54.4, 34.6, 23.5, 18.1, 15.9, 14.4; HRMS (TOF ESþ) m/z calcd
for C11H20N3O2 226.1556, found 226.1569.
4.8. Ethyl 2-imino-4,6-dimethyl-1,2,3,4-
tetrahydropyrimidine-5-carboxylate hydrochloride (10a$HCl).
General procedure C
4.5. Ethyl 2-amino-4,6-dimethyl-1,4-dihydropyrimidine-5-
carboxylate (10a). General procedure B
To a light yellow suspension of 8a (1.50 g, 7.00 mmol) in chlo-
To a suspension of 10a (0.500 g, 2.54 mmol) in MeOH (5.0 mL)
was added a solution of HCl in dioxane (1.5 mL, 3.0 mmol, 2.0 M)
dropwise at room temperature. After 10 min, the solution was clear
and the solvents were removed under reduced pressure. The
resulting oil was triturated with ether (2ꢁ10 mL), isolated by vac-
uum filtration, and dried in vacuo to afford 10a$HCl as a colorless
foam (0.54 g, 91%): IR (ATR) 3361, 3236, 3055, 2975, 2869, 1681,
robenzene (40 mL) at
0
ꢀC was added methyl tri-
fluoromethanesulfonate (0.91 mL, 7.7 mmol) in one portion. The
reaction mixture was allowed to warm to room temperature and
stirred for 3.5 h. Ammonium acetate (5.4 g, 70 mmol) was added
and ammonia gas was bubbled through the cold (0 ꢀC) reaction
mixture for 10 min. The reaction tube was sealed and heated at
95e100 ꢀC for 17 h. The reaction mixture was cooled to room
temperature, diluted with saturated Na2CO3 (250 mL) and water
(250 mL), extracted with EtOAc (3ꢁ400 mL), dried (Na2SO4), fil-
tered, and concentrated under reduced pressure. The crude residue
was recrystallized from hexanes/EtOAc (1:1, 150 mL), isolated by
vacuum filtration, washed with hexanes, and dried in vacuo to af-
ford 10a as a colorless solid (0.84 g, 61%, ELSD purity 97.3%): mp
196e198 ꢀC; IR (ATR) 3390, 3303, 3088, 2975, 1661, 1584, 1493,
1370, 1329, 1303, 1226, 1154, 1092, 1066 cmꢂ1; 1H NMR (300 MHz,
1551, 1241, 1096, 1070 cmꢂ1; 1H NMR (300 MHz, DMSO-d6)
d 10.90
(s, 1H), 9.06 (s, 1H), 7.89 (br s, 2H), 4.38e4.36 (m, 1H), 4.19e4.08 (m,
2H), 2.26 (s, 3H), 1.22 (t, 3H, J¼7.2 Hz), 1.16 (d, 3H, J¼6.3 Hz); 13C
NMR (75 MHz, DMSO-d6) d 164.9,151.8,144.1,104.5, 60.5, 45.4, 22.9,
17.9, 14.6. For additional characterization data, see 10a.
4.9. Ethyl 2-imino-6-methyl-4-(2-phenethyl)-1,2,3,4-
tetrahydropyrimidine-5-carboxylate hydrochloride (10b$HCl)
DMSO-d6)
d
6.81 (br s, 1H), 6.12 (br s, 2H), 4.18 (q, 1H, J¼6.3 Hz),
According to general procedure C,10b (0.150 g, 0.522 mmol) was
combined with a solution of HCl in ether (0.31 mL, 0.63 mmol,
2.0 M) and MeOH (1.0 mL) at room temperature to afford 10b$HCl
as a pale yellow solid (0.143 g, 85%): 1H NMR (300 MHz, DMSO-d6)
4.05e3.95 (m, 2H), 2.10 (s, 3H), 1.16 (t, 3H, J¼7.2 Hz), 0.97 (d, 3H,
J¼6.3 Hz); 13C NMR (75 MHz, DMSO-d6)
d 166.5, 160.8, 156.0, 98.6,
58.4, 45.5, 23.9, 15.0; HRMS (TOF ESþ) m/z calcd for C9H16N3O2
198.1243, found 198.1242.
d 10.59 (br s, 1H), 9.18 (br s, 1H), 7.76 (br s, 2H), 7.31e7.16 (m, 5H),
4.33e4.30 (m, 1H), 4.14e4.02 (m, 2H), 2.73e2.49 (m, 2H), 2.26 (s,
3H), 1.78e1.09 (m, 2H), 1.15 (t, 3H, J¼6.9 Hz). For additional char-
acterization data, see 10b.
4.6. Ethyl 2-amino-6-methyl-4-(2-phenethyl)-1,4-
dihydropyrimidine-5-carboxylate (10b)
According to general procedure B, a mixture of 8b (2.50 g,
8.21 mmol) and methyl trifluoromethanesulfonate (1.1 mL,
9.0 mmol) in chlorobenzene (80 mL) was treated with ammonium
acetate (6.3 g, 82 mmol) and ammonia gas to give the crude
product, which was dissolved in CH2Cl2 (20 mL) and triturated with
hexanes to yield a tan oil. This oil was isolated by decantation and
again dissolved in CH2Cl2 (20 mL), triturated with hexanes (30 mL),
and cooled to ꢂ20 ꢀC to afford 10b as a pale yellow solid (0.92 g,
39%, ELSD purity 97.3%): mp 129e134 ꢀC; IR (ATR) 3390, 3348,
2975, 1650, 1584, 1465, 1374, 1238, 1172, 1206, 1146, 1077,
4.10. Ethyl 2-imino-4-(methylethyl)-6-methyl-1,2,3,4-
tetrahydropyrimidine-5-carboxylate hydrochloride (10c$HCl)
According to general procedure C, 10c (0.150 g, 0.666 mmol) was
combined with a solution of HCl in ether (0.40 mL, 0.80 mmol,
2.0 M) in MeOH (1.5 mL) at room temperature to afford 10c$HCl as
a pale yellow solid (0.121 g, 69%): 1H NMR (300 MHz, DMSO-d6)
d
10.77 (br s, 1H), 9.14 (br s, 1H), 7.84 (br s, 2H), 4.19e4.07 (m, 3H),
2.28 (s, 3H), 1.78e1.72 (m, 1H), 1.21 (t, 3H, J¼7.2 Hz), 0.87 (d, 3H,
J¼6.9 Hz), 0.77 (d, 3H, J¼6.9 Hz). For additional characterization
data, see 10c.
1029 cmꢂ1; 1H NMR (300 MHz; DMSO-d6)
d 7.29e7.15 (m, 6H), 6.87
(br s, 2H), 4.14 (m, 1H), 3.98e3.88 (m, 2H), 2.71e2.59 (m, 1H),
2.54e2.44 (m, 1H), 2.13 (s, 3H), 1.66e1.56 (m, 2H), 1.10 (t, 3H,
4.11. 1-(4-(4-Chlorophenyl)-2-(4-methoxybenzylamino)-6-
methyl-1,4-dihydropyrimidin-5yl)butan-1-one (13). General
procedure D
J¼6.9 Hz); 13C NMR (75 MHz, DMSO-d6)
d 165.8, 158.9, 155.1, 141.7,
128.3 (2C), 128.2 (2C), 125.6, 97.8, 58.2, 48.5, 38.2, 29.7, 22.6, 14.4;
HRMS (TOF ESþ) m/z calcd for C16H22N3O2 288.1712, found
288.1720.
A microwave vial was charged with 1123 (0.63 g, 2.8 mmol) and
(CF3)2CHOH (5.0 mL). To this homogeneous solution was added
1236,37 (1.4 g, 5.5 mmol) and NaHCO3 (0.26 g, 3.0 mmol). The vial
was sealed and immersed into a pre-heated oil bath at 90 ꢀC and
heated for 16 h. The solution was allowed to cool to room tem-
perature, filtered through a small plug of Celite, and rinsed with
CH2Cl2. The filtrate was concentrated under reduced pressure and
purified by chromatography on SiO2 (ISCO-Rf, 0e10%MeOH/CH2Cl2)
to afford 13 as an orange crystalline solid (0.485 g, 42%, ELSD purity
99.7%): mp 60e64 ꢀC; IR (neat) 3311, 2929, 2830, 1661, 1574, 1512,
4.7. Ethyl 2-amino-4-(methylethyl)-6-methyl-1,4-
dihydropyrimidine-5-carboxylate (10c)
According to general procedure B, a mixture of 8c (1.80 g,
7.42 mmol) and methyl trifluoromethanesulfonate (0.96 mL,
8.2 mmol) in chlorobenzene (70 mL) was treated with ammonium
acetate (6.0 g, 78 mmol) and ammonia gas to give the crude
product, which was purified by chromatography through a plug of
SiO2 (EtOAceEtOH). The product slowly eluted with EtOH and was
recrystallized from boiling CH2Cl2/hexanes (1:1, 40 mL) to afford
10c as a white crystalline solid (0.581 g, 33%, ELSD purity 100.0%):
mp 171e173 ꢀC; IR (ATR) 3497, 3353, 2951, 2869, 1653, 1596, 1489,
1212, 1088, 818 cmꢂ1 1H NMR (300 MHz, CDCl3)
; d 7.22e7.11 (m,
6H), 6.78 (d, 2H, J¼8.4 Hz), 5.29 (s, 1H), 4.33 (d, 1H, J¼15.3 Hz), 4.25
(d, 1H, J¼15.0 Hz), 4.03 (q, 2H, J¼7.2 Hz), 3.78 (s, 3H), 2.38 (s, 3H),
1.14 (t, 3H, J¼7.2 Hz); 13C NMR (100 MHz, CDCl3)
d 166.6, 159.2,
1377, 1225, 1154, 1068, 995, 816 cmꢂ1
d6) 6.87 (br s, 1H), 6.07 (br s, 2H), 4.04e3.92 (m, 3H), 2.12 (s, 3H),
1.61e1.54 (m, 1H), 1.15 (t, 3H, J¼7.2 Hz), 0.78 (d, 3H, J¼6.9 Hz), 0.71
;
1H NMR (300 MHz, DMSO-
153.0, 143.2, 133.2 (2C), 128.9, 128.6 (2C), 128.3 (2C), 127.9 (2C),
114.2 (2C), 100.0, 59.5, 55.2, 53.7, 44.6, 22.4, 14.2; HRMS (ESIþ) m/z
calcd for C22H25O3N3Cl (MþH) 414.1579, found 414.1562.
d
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8
D.M. Arnold et al. / Tetrahedron xxx (2013) 1e13
4.12. Ethyl 2-amino-4-(4-chlorophenyl)-6-methyl-1,4-
dihydroprimidine-5-carboxylate 2,2,2-trifluoroacetate
(13$TFA)
5.23 (s,1H), 3.72 (s, 6H), 3.67 (q, 2H, J¼7.2 Hz), 0.75 (t, 3H, J¼7.2 Hz); 13
C
NMR (75 MHz, DMSO-d6) d 166.7,161.6,155.9,149.0,148.4,143.2,139.3,
128.5 (2C), 127.4, 127.3 (2C), 118.7, 112.2, 110.8, 98.0, 58.5, 56.0, 55.8,
52.9,14.2; MS (EIþ) m/z 381 (Mþ, 36), 352 (31), 308 (86), 244 (100),198
(35), 77 (56); HRMS (EIþ) m/z calcd for C21H23N3O4 381.1688, found
381.1687.
A solution of 13 (0.420 g, 1.01 mmol) in a mixture of TFA/
Et3SiH/thioanisole/H2O (92.5:2.5:2.5:2.5, 23 mL) was stirred at
50 ꢀC for 22 h, allowed to cool to room temperature, and con-
centrated under reduced pressure. The crude orange residue was
purified by trituration with tert-butyl methyl ether, isolated by
vacuum filtration, and dried in vacuo to give trifluoroacetate salt
13$TFA (0.29 g, 70%, ELSD purity 99.9%) as a white solid: mp
207e218 ꢀC (dec); IR (neat) 3241, 3205, 3084, 2963, 2901, 1709,
4.16. Ethyl 2,4-dimethyl-4H-pyrimido[1,2-a]pyrimidine-3-
carboxylate (22). General procedure F
A suspension of 10a$HCl (0.100 g, 0.428 mmol) and 1,1,3,3-
tetramethoxypropane (20, 0.09 mL, 0.5 mmol) in trifluoroethanol
(21, 1.5 mL) was heated in a microwave reactor at 160 ꢀC for 1 h. The
resulting mixture was dissolved in EtOAc (50 mL), washed with
saturated sodium carbonate (50 mL), and extracted with EtOAc
(2ꢁ50 mL). The organic layers were combined, dried (Na2SO4),
filtered, and concentrated under reduced pressure. The resulting
red/orange oil was purified via chromatography on neutral Al2O3
(0e2% MeOH/CH2Cl2) to afford 22 as a red/orange solid (0.076 g,
76%): mp 151e152 ꢀC; IR (ATR) 3076, 2970, 1657, 1622, 1585, 1491,
1666, 1239, 1200, 1186, 1139, 1096, 848, 828, 800, 771, 726 cmꢂ1
1H NMR (300 MHz, CDCl3:MeOD, 1:1)
;
d
7.03 (d, 2H, J¼8.4 Hz), 6.94
(d, 2H, J¼8.4 Hz), 5.14 (s, 1H), 3.80 (q, 2H, J¼7.2 Hz), 2.13 (s, 3H),
0.87 (t, 3H, J¼7.2 Hz); 13C NMR (100 MHz, CDCl3:MeOD, 1:1)
d
164.0, 150.3, 143.1, 139.7, 133.7, 128.3 (2C), 127.5 (2C), 103.1, 60.1,
52.1, 16.4, 12.8; HRMS (ESIþ) m/z calcd for C14H17O2N3Cl (MþH)
294.1004, found 294.0999.
1437, 1396, 1273, 1245, 1206, 1109, 1070, 990 cmꢂ1
(300 MHz, DMSO-d6)
;
1H NMR
8.51 (dd, 1H, J¼2.4, 1.8 Hz), 8.24 (dd, 1H,
4.13. Ethyl 2-amino-4,6-diphenyl-1,4-dihydropyrimidine-5-
carboxylate (18).30 General procedure E
d
J¼2.1, 6.3 Hz), 6.70 (dd, 1H, J¼3.9, 6.3 Hz), 5.26 (q, 1H, J¼6.6 Hz),
4.18e4.03 (m, 2H), 2.25 (s, 3H), 1.23 (t, 3H, J¼7.2 Hz), 1.16 (d, 3H,
To a solution of benzaldehyde (16, 2.0 mL, 20 mmol), urea
14$HCl (3.32 g, 35.0 mmol), and NaHCO3 (6.72 g, 80.0 mmol) in
DMF (40 mL) was added ethyl 3-oxo-3-phenylpropanoate (15,
3.80 mL, 22.5 mmol) at room temperature. The reaction mixture
was heated to 70 ꢀC for 17 h, cooled to room temperature, and
slowly diluted with water (100 mL). The aqueous mixture was
stirred at room temperature for 1 h and the resulting solid was
separated by decanting and vacuum filtration. The crude product
was purified by heating in hexanes/EtOAc (1:1, 100 mL) for 30 min,
separated by vacuum filtration, and dried in vacuo to afford 18 as
J¼6.6 Hz); 13C NMR (75 MHz, DMSO-d6)
d 165.1, 163.4, 157.6, 151.5,
147.2,110.3,100.3, 59.5, 56.8, 23.4, 22.2,14.8; HRMS (ESIþ) m/z calcd
for C12H16N3O2 234.1243, found 234.1243.
4.17. Ethyl 2-methyl-4-phenethyl-4H-pyrimido[1,2-a]pyrimi-
dine-3-carboxylate (23)
According to general procedure F, a mixture of 10b$HCl (0.138 g,
0.426 mmol) and 1,1,3,3-tetramethoxypropane (20, 0.09 mL,
0.5 mmol) in trifluoroethanol (21, 2.0 mL) was heated in a micro-
wave reactor at 160 ꢀC for 2 h. The crude red/orange oil was purified
by chromatography on neutral Al2O3 (EtOAc to 5% MeOH/CH2Cl2) to
afford 23 as a yellow/brown oil (0.098 g, 71%, ELSD purity 99.5%): IR
(ATR) 2981, 2925, 1665, 1618, 1579, 1491, 1430, 1393, 1275, 1238,
a white solid (3.35 g, 52%): 1H NMR (300 MHz, DMSO-d6)
d 7.48 (s,
1H), 7.39e7.31 (m, 4H), 7.27e7.21 (m, 6H), 6.29 (s, 2H), 5.30 (s, 1H),
3.67 (q, 2H, J¼7.2 Hz), 0.73 (t, 3H, J¼7.2 Hz); MS (EIþ) m/z 321 (Mþ,
43), 292 (38), 274 (32), 248 (52), 244 (100), 104 (37), 76 (42); HRMS
(EIþ) m/z calcd for C19H19N3O4 321.1477, found 321.1476. The
spectral data are consistent with the literature values.18
1202, 1096, 1063, 774, 697 cmꢂ1 1H NMR (300 MHz, DMSO-d6)
;
d
8.52 (dd, 1H, J¼3.9, 2.1 Hz), 8.18 (dd, 1H, J¼6.6, 2.1 Hz), 7.26e7.08
4.14. Ethyl 2-imino-4,6-diphenyl-1,2,3,4-
tetrahydropyrimidine-5-carboxylate hydrochloride (18$HCl)
(m, 5H), 6.70 (dd,1H, J¼3.9, 6.3 Hz), 5.21 (t,1H, J¼5.1 Hz), 4.20e4.07
(m, 2H), 2.46e2.37 (m, 2H), 2.28 (s, 3H), 1.86e1.76 (m, 2H), 1.19 (t,
3H, J¼7.2 Hz); 13C NMR (75 MHz, DMSO-d6)
d 164.7, 162.6, 158.0,
According to general procedure C, 18 (1.28 g, 3.97 mmol) and
a solution of HCl in dioxane (1.25 mL, 5.00 mmol, 4.0 M) and
methanol (5.0 mL) afforded 18$HCl as a white crystalline solid
151.3, 147.0, 140.5, 128.4 (2C), 128.0 (2C), 125.9, 109.2, 99.0, 59.8,
59.1, 36.3, 30.3, 23.1, 14.4; HRMS (TOF ESIþ) m/z calcd for
(1.42 g, 99%): 1H NMR (300 MHz, DMSO-d6)
d 10.86 (s, 1H), 9.75 (s,
C
19H22N3O2 324.1712, found 324.1707.
1H), 8.09 (br s, 2H), 7.51e7.33 (m, 10H), 5.55 (d, 1H, J¼3.6 Hz), 3.78
(q, 2H, J¼6.9 Hz), 0.74 (t, 3H, J¼6.9 Hz); 13C NMR (75 MHz, DMSO-
4.18. Ethyl 4-isopropyl-2-methyl-4H-pyrimido[1,2-a]pyrimi-
dine-3-carboxylate (24)
d6)
d
164.6, 151.7, 144.6, 142.2, 133.7, 130.3, 129.4 (2C), 129.1 (2C),
128.8, 128.6 (2C), 127.1 (2C), 104.2, 60.4, 52.8, 13.7. For additional
characterization data, see 18.
According to general procedure F, a mixture of 10c$HCl (0.113 g,
0.432 mmol) and 1,1,3,3-tetramethoxypropane (20, 0.076 mL,
0.45 mmol) in trifluoroethanol (21, 1.5 mL) was heated in a micro-
wave reactor at 160 ꢀC for 2 h. The crude red/orange oil was purified
by chromatography on neutral Al2O3 (0e2% MeOH/CH2Cl2) to af-
ford 24 as a dark red oil (0.080 g, 71%, ELSD purity 98.4%): IR (ATR)
3064, 2964, 1670, 1620, 1579, 1491, 1432, 1378, 1294, 1234, 1204,
4.15. Ethyl 2-amino-4-(3,4-dimethoxyphenyl)-6-phenyl-1,4-
dihydropyrimidine-5-carboxylate (19)
According to general procedure E, ethyl 3-oxo-3-phenylpropanoate
(15, 3.80 mL, 22.5 mmol), 3,4-dimethoxybenzaldehyde (17, 3.32 g,
20.0 mmol), urea 14$HCl (2.31 g, 24.0 mmol), and NaHCO3 (6.33 g,
75.4 mmol) in DMF (40 mL) provided the crude product, which was
recrystallized from EtOAc/hexanes (2:1, 150 mL), isolated by vacuum
filtration, washed with hexanes (50 mL), and dried in vacuoto afford 19
as a white crystalline solid (3.11 g, 41%, ELSD purity 100.0%): mp
261e263 ꢀC (dec); IR (ATR) 3403, 3340, 2974, 1655, 1627, 1565, 1372,
1094, 1063, 999, 774 cmꢂ1 1H NMR (400 MHz, DMSO-d6)
; d 8.52
(dd, 1H, J¼4.0, 2.4 Hz), 8.21 (dd, 1H, J¼6.4, 2.0 Hz), 6.70 (dd, 1H,
J¼6.4, 4.0 Hz), 4.94 (d, 1H, J¼6.4 Hz), 4.18e4.04 (m, 2H), 2.28 (s, 3H),
1.79e1.74 (m, 1H), 1.22 (t, 3H, J¼7.2 Hz), 0.77 (d, 3H, J¼6.8 Hz), 0.63
(d, 3H, J¼6.8 Hz); 13C NMR (100 MHz, DMSO-d6)
d 165.4, 162.3,
157.6, 151.5, 147.4, 108.7, 98.3, 64.6, 59.0, 34.1, 23.1, 18.0, 17.4, 14.4;
HRMS (TOF ESIþ) m/z calcd for C14H20N3O2 262.1556, found
262.1558.
1232, 1135, 1100, 1027 cmꢂ1; 1H NMR (300 MHz, DMSO-d6)
1H), 7.25e7.21 (m, 5H), 6.98 (s, 1H), 6.93e6.86 (m, 2H), 6.28 (br s, 2H),
d 7.44 (s,
Please cite this article in press as: Arnold, D. M.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.127

D.M. Arnold et al. / Tetrahedron xxx (2013) 1e13
9
4.19. Ethyl 2,4-diphenyl-4H-pyrimido[1,2-a]pyrimidine-3-
carboxylate (25)
(0.34 mL, 8.4 mmol) and acetonitrile (2.5 mL) provided a crude
product, which was purified by chromatography on SiO2 (1:1,
EtOAc/hexanes). The resulting product was recrystallized (1:15,
EtOAc/hexanes, 16 mL), isolated by vacuum filtration, washed with
hexanes (5 mL), and dried in vacuo to afford 31 as a red/orange solid
containing w5% EtOAc (0.044 g, 22%, ELSD purity 99.1%): mp
195e196 ꢀC; IR (ATR) 3064, 2975, 1614, 1586, 1504,1474, 1446, 1430,
According to general procedure F, a solution of 18$HCl (0.100 g,
0.311 mmol) and 1,1,3,3-tetramethoxypropane (20, 0.055 mL,
0.33 mmol) in trifluoroethanol (21, 1.5 mL) was heated in a micro-
wave reactor at 150 ꢀC for 1.5 h. The crude red/orange oil was pu-
rified by chromatography on SiO2 (EtOAc) to afford 25 as a red/
orange solid containing w5e6% EtOAc (0.047 g, 42%, ELSD purity
100.0%): mp 185e186.5 ꢀC; IR (ATR) 3070, 2982, 2869, 1694, 1612,
1689, 1558, 1493, 1476, 1441, 1277, 1232, 1189, 1074 cmꢂ1; 1H NMR
1374, 1305, 1281, 1247, 1224, 1206, 1165, 1146, 1092, 761 cmꢂ1
NMR (300 MHz, DMSO-d6)
;
1H
d
8.68 (d, 1H, J¼6.6 Hz), 7.98 (s, 1H), 7.82
(d, 1H, J¼7.8 Hz), 7.71 (d, 1H, J¼8.4 Hz), 7.53e7.33 (m, 13H), 6.51 (s,
1H), 3.83 (q, 2H, J¼6.9 Hz), 0.82 (t, 3H, J¼6.9 Hz); 13C NMR
(400 MHz, DMSO-d6)
d
8.55e8.54 (m, 2H), 7.42e7.30 (m, 10H), 6.78
(125 MHz, DMSO-d6) d 165.5, 159.0, 157.6, 156.1, 151.7, 151.2, 148.3,
(dd,1H, J¼4.8. 5.6 Hz), 6.45 (s,1H), 3.80 (q, 2H, J¼7.2 Hz), 0.80 (t, 3H,
141.3, 140.3, 129.6 (2C), 129.2 (3C), 128.8, 128.4, 128.1, 127.8 (2C),
126.9 (2C), 124.6, 123.6, 113.0, 112.4, 107.2, 99.3, 63.0, 59.8, 14.0;
HRMS (TOF ESþ) m/z calcd for C30H24N3O3 474.1818, found
474.1802.
J¼7.2 Hz); 13C NMR (100 MHz, DMSO-d6)
d 165.6, 163.5, 158.5, 151.7,
147.5,141.5,141.2,129.5 (2C),129.1 (2C),128.5,127.7 (2C),126.7 (2C),
110.7, 98.7, 63.1, 59.6, 14.0; HRMS (TOF ESIþ) m/z calcd for
C
22H20N3O2 358.1556, found 358.1556.
4.23. 1-Phenyl-3-(trimethylsilyl)prop-2-yn-1-one (35)27,35
4.20. Ethyl 8-methyl-2,4-diphenyl-4H-pyrimido[1,2-a]pyrimi-
dine-3-carboxylate (27)
To a suspension of bis(triphenylphosphine)palladium(II) chlo-
ride (0.035 g, 0.050 mmol) and copper iodide (0.019 g, 0.10 mmol)
in freshly distilled THF (10 mL) were added sequentially Et3N
(0.35 mL, 2.5 mmol), benzoyl chloride (0.29 mL, 2.5 mmol), and
TMS-acetylene (0.35 mL, 2.5 mmol). The reaction mixture turned
from dark orange to pale yellow forming the Et3N$HCl precipitate
over a 1 h period. TLC analysis (10:1, hexanes/EtOAc, product
Rf¼0.59) showed full conversion after 1 h. The Et3N$HCl salt was
filtered off and the filtrate was concentrated under reduced pres-
sure. The crude product was purified by chromatography on SiO2
(10:1:0.1, hexanes/EtOAc/Et3N) to afford 35 as a pale orange oil
(0.48 g, 95%): Rf 0.59 (10:1, hexanes/EtOAc); 1H NMR (300 MHz,
A suspension of 18 (0.161 g, 0.500 mmol) and 26 (0.051 mL,
0.500 mmol) in distilled THF (1.0 mL) was heated in a microwave
reactor for 15 min at 150 ꢀC. The crude reaction mixture was
recrystallized from hexanes/EtOAc (4:1, 20 mL), isolated by vacuum
filtration, washed with hexanes, and dried in vacuo to afford 27 as
a yellowꢀ-orange solid (0.12 g, 64%, ELSD purity 99.5%): mp
185e187 C; IR (ATR) 3068, 2969, 1705, 1625, 1511, 1448, 1241, 1196,
1085 cmꢂ1; 1H NMR (300 MHz, DMSO-d6)
d
8.38 (d, 1H, J¼6.9 Hz),
7.42e7.32 (m, 10H), 6.72 (d, 1H, J¼6.6 Hz), 6.38 (s, 1H), 3.79 (q, 2H,
J¼7.2 Hz), 2.32 (s, 3H), 0.79 (t, 3H, J¼7.2 Hz); 13C NMR (75 MHz,
DMSO-d6)
d 173.3, 165.7, 159.1, 151.4, 146.2, 141.8, 141.4, 129.4 (2C),
CDCl3)
d 8.18e8.14 (m, 2H), 7.63e7.60 (m, 1H), 7.53e7.48 (m, 2H),
129.1, 129.0 (2C), 128.5, 127.6 (2C), 126.7 (2C), 111.2, 98.1, 62.8, 59.5,
25.1, 14.0; MS (EIþ) m/z 371 (Mþ, 43), 342 (51), 298 (100), 278 (63),
93 (69), 66 (52); HRMS (EIþ) m/z calcd for C23H21N3O2 371.1634,
found 371.1618.
0.33 (s, 9H); MS (EIþ) m/z 202 (Mþ, 43),187 (100),159 (38),105 (24),
76 (31); HRMS (EI) m/z calcd for C12H14OSi 202.0814, found
202.0814. The spectral data are consistent with the literature
values.27,35
4.21. Ethyl 8-(1H-indol-2-yl)-2,4-diphenyl-4H-pyrimido[1,2-
a]pyrimidine-3-carboxylate (30). General procedure G
4.24. Ethyl 2,4,8-triphenyl-4H-pyrimido[1,2-a]pyrimidine-3-
carboxylate (38a). General procedure H
A suspension of 18$HCl (0.150 g, 0.419 mmol), 28 (0.111 g,
0.461 mmol), sodium carbonate (0.067 g, 0.63 mmol), and DMAP
(0.013 g, 0.10 mmol) in MeOH (0.34 mL, 8.4 mmol) and acetonitrile
(2.5 mL) was heated in a microwave reactor at 170 ꢀC for 30 min.
The dark red/orange reaction mixture was concentrated under re-
duced pressure and purified by chromatography on SiO2 (1:1,
EtOAc/hexanes). The resulting product was recrystallized from
boiling hexanes/EtOAc (6:1), isolated by vacuum filtration, washed
with hexanes, and dried under high vacuum to afford 30 as a red
solid (0.050 g, 25%, ELSD purity 99.6%): mp 170e172 ꢀC; IR (ATR)
3202, 3057, 2975, 1666, 1610, 1472, 1435, 1277, 1251, 1221, 1195,
To a suspension of bis(triphenylphosphine)palladium(II) chlo-
ride (0.007 g, 0.01 mmol) and copper iodide (0.004 g, 0.02 mmol) in
freshly distilled THF (0.75 mL) was added sequentially N,N-dicy-
clohexylmethylamine (0.11 mL, 0.50 mmol), benzoyl chloride
(0.058 mL, 0.50 mmol), and TMS-acetylene (0.071 mL, 0.50 mmol).
The reaction mixture turned from dark orange to pale yellow
forming the Cy2MeN$HCl precipitate over a 1.5 h period. TLC
analysis (10:1 hexanes/EtOAc; Rf¼0.62) showed a quantitative for-
mation of 35 after 1.5 h. The mixture was diluted to 0.15 M with THF
(2.3 mL), and 18 (0.13 g, 0.40 mmol), DMAP (0.012 g, 0.10 mmol),
and MeOH (0.40 mL) were added. The solution was heated in
a microwave reactor at 170 ꢀC for 30 min. The dark red-black re-
action mixture was diluted with CH2Cl2 (30 mL) and washed with
saturated NaHCO3 (1ꢁ30 mL). The organic layer was dried (Na2SO4)
and concentrated under reduced pressure. The resulting dark red
oil was purified by chromatography on SiO2 (1:1, hexanes/EtOAc) to
afford 38a as a red solid (0.11 g, 60%, ELSD purity 100%): mp
210e211 ꢀC; IR (ATR) 3068, 2995, 1705, 1616, 1502, 1446, 1210,
1092, 753 cmꢂ1; 1H NMR (400 MHz, DMSO-d6)
d 12.01 (s, 1H), 8.49
(d, 1H, J¼6.8 Hz), 7.63 (d, 1H, J¼8.0 Hz), 7.50e7.32 (m, 13H), 7.22 (t,
1H, J¼7.2 Hz), 7.05 (t, 1H, J¼7.2 Hz), 6.42 (s, 1H), 3.83 (q, 2H,
J¼7.2 Hz), 0.83 (t, 3H, J¼7.2 Hz); 13C NMR (100 MHz, DMSO-d6)
d
165.3, 160.2, 158.7, 151.3, 146.2, 141.5, 140.8, 138.6, 133.7, 129.0
(2C), 128.8 (2C), 128.5, 128.1, 127.7, 127.1 (2C), 126.2 (2C), 124.9,
121.7, 120.2, 112.7, 108.1, 106.6, 97.8, 62.2, 59.0, 13.6; HRMS (TOF
ESþ) m/z calcd for C30H25N4O2 473.1978, found 473.1993.
1075 cmꢂ1; 1H NMR (300 MHz, DMSO-d6)
d
8.63 (d, 1H, J¼6.9 Hz),
4.22. Ethyl 8-(benzofuran-2-yl)-2,4-diphenyl-4H-pyrimido
[1,2-a]pyrimidine-3-carboxylate (31)
8.16 (d, 2H, J¼6.9 Hz), 7.60e7.32 (m, 14H), 6.49 (s, 1H), 3.81 (q, 2H,
J¼6.9 Hz), 0.80 (t, 3H, J¼6.9 Hz); 13C NMR (100 MHz, DMSO-d6)
d
166.9,165.2,158.5,151.1,147.4,141.3,140.9,134.9,132.4,129.0 (4C),
According to general procedure G, a suspension of 18$HCl
(0.150 g, 0.419 mmol), 29 (0.112 g, 0.461 mmol), sodium carbonate
(0.067 g, 0.63 mmol), and DMAP (0.013 g, 0.10 mmol) in MeOH
128.6 (3C), 128.0, 127.8 (2C), 127.2 (2C), 126.3 (2C), 106.7, 98.2, 62.3,
59.1, 13.6; HRMS (TOF MS ES) m/z calcd for C28H24N3O2 (MþH)
434.1869, found 434.1882.
Please cite this article in press as: Arnold, D. M.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.127

10
D.M. Arnold et al. / Tetrahedron xxx (2013) 1e13
4.25. Synthesis of 38a under copper- and solvent-free
conditions
and cooling to ꢂ20 ꢀC. The crystalline solid was isolated by vacuum
filtration, washed with hexanes, and dried in vacuo to afford 38c as
a red/orange solid (0.060 g, 28%, ELSD purity 99.8%): Rf 0.31 (1:1,
hexanes/EtOAc); mp 210e212 ꢀC; IR (ATR) 2969, 1700, 1594, 1493,
A mixture of palladium(II) acetate (0.001 g, 0.005 mmol), ben-
zoyl chloride (0.058 mL, 0.50 mmol), TMS-acetylene (0.078 mL,
0.55 mmol), and N,N-dicyclohexylmethylamine (0.11 mL,
0.50 mmol) was heated in a sealed tube at 40 ꢀC for 2 h. The re-
action mixture turned heterogeneous and dark brown. After 2 h,
TLC analysis (10:1, hexanes/EtOAc; Rf¼0.63) showed a nearly
quantitative formation of 35. The reaction mixture was diluted to
a concentration of 0.15 M with THF (3.0 mL) and 18 (0.129 g,
0.400 mmol), DMAP (0.012 g, 0.10 mmol), and MeOH (0.40 mL)
were added. The solution was heated in a microwave reactor at
170 ꢀC for 30 min. The resulting dark red reaction mixture was
diluted with CH2Cl2 (30 mL) and washed with saturated NaHCO3
solution (1ꢁ30 mL). The organic layer was dried (Na2SO4), con-
centrated under reduced pressure, and the crude residue was pu-
rified by chromatography on SiO2 (2:1 to 1:1, hexanes/EtOAc). The
resulting red solid was dissolved in EtOAc (1.0 mL) and crystallized
by slowly adding hexanes (20 mL) at 0 ꢀC. The solid was isolated by
vacuum filtration, washed with hexanes, and dried in vacuo to af-
ford 38a (0.053 g, 30%). The spectral data are consistent with the
values obtained in Section 4.24.
1439, 1297, 1241, 1212, 1169, 1075, 1023, 697 cmꢂ1 1H NMR
;
(300 MHz, DMSO-d6)
d
8.54 (d, 1H, J¼6.9 Hz), 8.15 (d, 2H, J¼9.0 Hz),
7.48e7.29 (m, 11H), 7.08 (d, 2H, J¼8.7 Hz), 6.44 (s, 1H), 3.84 (s, 3H),
3.77 (q, 2H, J¼7.2 Hz), 0.80 (t, 3H, J¼7.2 Hz); 13C NMR (125 MHz,
DMSO-d6) d 166.2, 165.2, 162.8, 158.8, 151.2, 146.8, 141.4, 141.0, 129.8
(2C), 129.0 (2C), 128.6 (3C), 127.9, 127.1 (3C), 126.3 (2C), 114.4 (2C),
106.2, 97.9, 62.2, 59.0, 55.5, 13.5; HRMS (TOF ESþ) m/z calcd for
C29H26N3O3 464.1974, found 464.1975.
4.28. Ethyl 2,4-diphenyl-8-(4-(trifluoromethyl)phenyl)-4H-
pyrimido[1,2-a]pyrimidine-3-carboxylate (38d)
According to general procedure H,
a solution of bis(-
triphenylphosphine)palladium(II) chloride (0.007 g, 0.01 mmol),
copper iodide (0.004 g, 0.02 mmol), 4-(trifluoromethyl)benzoyl
chloride (0.074 mL, 0.50 mmol), TMS-acetylene (0.071 mL,
0.50 mmol), and Et3N (0.071 mL, 0.50 mmol) in freshly distilled THF
(3.0 mL) led to 37 (Rf¼0.64; 10:1, hexanes/EtOAc), which was
treated with 18 (0.129 g, 0.400 mmol), DMAP (0.012 g, 0.10 mmol),
and MeOH (0.40 mL) to give a crude product, which was purified by
chromatography on SiO2 (2:1 to 1:1, EtOAc/hexanes) to afford 38d
as a red crystalline solid (0.11 g, 55%, ELSD purity 100.0%): Rf 0.31
(1:1, EtOAc/hexanes); mp 206e208 ꢀC; IR (ATR) 3068, 2974, 1705,
1618, 1506, 1456, 1323, 1114, 1066 cmꢂ1; 1H NMR (300 MHz, DMSO-
4.26. Ethyl 4-(3,4-dimethoxyphenyl)-2,8-diphenyl-4H-pyr-
imido[1,2-a]pyrimidine-3-carboxylate (38b)
According to general procedure H,
a solution of bis(-
triphenylphosphine)palladium(II) chloride (0.007 g, 0.01 mmol),
copper iodide (0.004 g, 0.02 mmol), benzoyl chloride (0.058 mL,
0.50 mmol), TMS-acetylene (0.071 mL, 0.50 mmol), and N,N-dicy-
clohexylmethylamine (0.11 mL, 0.50 mmol) in freshly distilled THF
(0.75 mL) provided 35. After addition of THF (2.3 mL), treatment
with 19 (0.15 g, 0.40 mmol), DMAP (0.012 g, 0.10 mmol), and MeOH
(0.40 mL) provided the crude product, which was purified by
chromatography on SiO2 (1:1 to 2:1, EtOAc/hexanes). The resulting
solid was dissolved in EtOAc (1.0 mL) and crystallized by slowly
adding hexanes (20 mL) at 0 ꢀC. The precipitated solid was isolated
by vacuum filtration, washed with hexanes, and dried in vacuo to
afford 38b as an orange solid (0.10 g, 51%, ELSD purity 99.9%): Rf
0.21 (2:1, EtOAc/hexanes); mp 95e96 ꢀC; IR (ATR) 3086, 2987, 2932,
d6)
d
8.70 (d, 1H, J¼6.9 Hz), 8.35 (d, 2H, J¼8.1 Hz), 7.91 (d, 2H,
J¼8.4 Hz), 7.54e7.30 (m, 11H), 6.52 (s, 1H), 3.81 (q, 2H, J¼6.9 Hz),
0.80 (t, 3H, J¼7.2 Hz); 13C NMR (150 MHz, DMSO-d6)
d 165.6, 165.2,
158.2, 150.9, 148.0, 141.1, 140.7, 138.7, 131.7 (q, JCF¼33.0 Hz), 129.1
(2C), 128.7, 128.6 (4C), 128.1, 127.2 (2C), 126.4 (2C), 125.8 (q, 2C,
JCF¼4.5 Hz), 123.9 (q, JCF¼271.5 Hz), 107.0, 98.5, 62.3, 59.1, 13.5; MS
(EI) m/z 501 (Mþ, 11), 428 (100), 278 (14), 223 (17); HRMS (EI) m/z
calcd for C29H22N3O2F3 501.1664, found 501.1658. X-ray crystallo-
graphic data for 38d were deposited with the Cambridge Crystal-
lographic Data Center (deposition number CCDC 932463).
4.29. Ethyl 4-amino-6,8-dimethyl-2-morpholino-6H-pyr-
imido[1,2-a][1,3,5]triazine-7-carboxylate (40). General pro-
cedure I
1662, 1618, 1517, 1435, 1215, 1075, 1027 cmꢂ1
DMSO-d6)
;
1H NMR (300 MHz,
d
8.66 (d, 1H, J¼6.9 Hz), 8.14 (d, 2H, J¼7.2 Hz), 7.60e7.51
(m, 3H), 7.46e7.36 (m, 6H), 7.14 (s, 1H), 7.00e6.94 (m, 2H), 6.39 (s,
1H), 3.79 (q, 2H, J¼7.2 Hz), 3.73 (s, 3H), 3.71 (s, 3H), 0.81 (t, 3H,
To a solution of 3,3-diphenoxy-2-azaprop-2-enenitrile (0.133 g,
0.558 mmol) in THF (1.0 mL) was added morpholine (0.049 mL,
0.56 mmol) in one portion at room temperature. The homogeneous
colorless reaction mixture was stirred at room temperature for 2 h
to form 39 (Rf¼0.33; 1:1, hexanes/EtOAc). To the reaction mixture
was added 10a (0.100 g, 0.507 mmol) and the resulting suspension
was heated in a microwave reactor at 110 ꢀC for 45 min. The mix-
ture was purified by chromatography on SiO2 (EtOH) to afford 40 as
a white foam (0.090 g, 53%, ELSD purity 99.8%): Rf 0.17 (EtOH); IR
(ATR) 3327, 2969, 2906, 2855, 1651, 1584, 1551, 1482, 1420, 1264,
1232, 1107, 1059, 1023, 885, 775 cmꢂ1; 1H NMR (300 MHz, DMSO-
J¼7.2 Hz); 13C NMR (75 MHz, DMSO-d6)
d 166.8, 165.2, 158.3, 150.9,
149.0, 148.8, 147.3, 141.1, 134.9, 133.7, 132.3, 129.0 (2C), 128.5 (2C),
127.9, 127.8 (2C), 127.2 (2C), 118.9, 112.0, 110.2, 106.6, 98.3, 62.3,
59.0, 55.5 (2C), 13.6; MS (EIþ) m/z 493 (Mþ, 29), 420 (100), 338 (34),
155 (21); HRMS (EIþ) m/z calcd for C30H27N3O4 493.2001, found
493.1977.
4.27. Ethyl 8-(4-methoxyphenyl)-2,4-diphenyl-4H-pyrimido
[1,2-a]pyrimidine-3-carboxylate (38c)
d6)
d
7.89 (br s, 2H), 5.15 (q, 1H, J¼6.0 Hz), 4.14e4.01 (m, 2H),
According to general procedure H,
a
solution of bis(-
3.65e3.58 (m, 8H), 2.16 (s, 3H), 1.22 (t, 3H, J¼7.2 Hz), 1.08 (d, 3H,
triphenylphosphine)palladium(II) chloride (0.007 g, 0.009 mmol),
copper iodide (0.004 g, 0.02 mmol), p-anisoyl chloride (0.099 g,
0.58 mmol), TMS-acetylene (0.083 mL, 0.58 mmol), and N,N-dicy-
clohexylmethylamine (0.12 mL, 0.58 mmol) in freshly distilled THF
(0.75 mL) led to 36 (Rf¼0.17; 20:1, hexanes/EtOAc), which was
dissolved in THF (2.3 mL) and treated with 18 (0.150 g, 0.467 mmol),
DMAP (0.012 g, 0.093 mmol), and MeOH (0.4 mL) to provide a crude
product, which was purified by chromatography on SiO2 (1:1,
hexanes/EtOAc). The resulting red/orange solid was dissolved in
CH2Cl2 (1.0 mL) and crystallized by slowly adding hexanes (5.0 mL)
J¼6.0 Hz); 13C NMR (75 MHz, DMSO-d6)
d 165.2, 160.8, 158.4, 156.2,
152.1, 100.3, 65.9 (2C), 58.8, 47.7, 43.5 (2C), 23.2, 19.4, 14.4; HRMS
(TOF ESIþ) m/z calcd for C15H23N6O3 335.1832, found 335.1825.
4.30. Ethyl 4-amino-8-methyl-2-morpholino-6-phenethyl-
6H-pyrimido[1,2-a][1,3,5]triazine-7-carboxylate (41)
According to general procedure I, a solution of 3,3-diphenoxy-2-
azaprop-2-enenitrile (0.091 g, 0.38 mmol) and morpholine
(0.034 mL, 0.38 mmol) in THF (1.0 mL) led to 39, which was treated
Please cite this article in press as: Arnold, D. M.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.127

D.M. Arnold et al. / Tetrahedron xxx (2013) 1e13
11
with 10b (0.100 g, 0.348 mmol). The reaction mixture was purified
by chromatography on SiO2 (EtOH) to afford 41 as a pale yellow
foam (0.037 g, 25%): Rf 0.82 (EtOH); IR (ATR) 3308, 2913, 2850,1638,
and stirred for an additional 4 h. The resulting clear pale yellow
solution was diluted with EtOAc (30 mL) and concentrated under
reduced pressure after addition of SiO2 (1.0 g). The resulting mix-
ture was added directly to the top of a pre-flushed column and
purified by chromatography on SiO2 (1:1, hexanes/EtOAc to EtOAc).
The resulting product was recrystallized from boiling CH2Cl2/hex-
anes (1:1.5, 2.5 mL), isolated by vacuum filtration, washed with
hexanes, and dried in vacuo to afford 44 as a white solid (0.024 g,
15%): mp 219e220 ꢀC; IR (ATR) 3308, 3239, 3184, 2988, 1707, 1609,
1471, 1329,1294, 1253, 1189, 1161, 1083, 902, 753, 738, 662 cmꢂ1; 1H
1581, 1551, 1482, 1424, 1266, 1232, 1096, 1059, 1023, 889, 781 cmꢂ1
;
1H NMR (300 MHz, DMSO-d6)
d 7.90 (br s, 2H), 7.25e7.06 (m, 5H),
5.31 (t, 1H, J¼5.4 Hz), 4.17e4.02 (m, 2H), 3.65e3.59 (m, 8H),
2.58e2.40 (m, 2H), 2.20 (s, 3H), 1.86e1.73 (m, 2H), 1.23 (t, 3H,
J¼7.2 Hz); 13C NMR (125 MHz, DMSO-d6)
d 165.4,160.6,159.4,156.3,
152.6, 141.3, 128.3 (2C), 127.9 (2C), 125.7, 98.6, 65.9 (2C), 58.8, 51.3,
43.6 (2C), 35.6, 29.6, 23.1, 14.4; HRMS (TOF ESIþ) m/z calcd for
C
22H29N6O3 425.2301, found 425.2301.
NMR (300 MHz, DMSO-d6)
d
10.89 (s, 1H), 5.45 (q, 1H, J¼6.3 Hz),
4.25e4.08 (m, 2H), 2.27 (s, 3H), 1.24 (t, 3H, J¼6.9 Hz), 1.17 (d, 3H,
4.31. Ethyl 4-amino-6-isopropyl-8-methyl-2-morpholino-6H-
pyrimido[1,2-a][1,3,5]triazine-7-carboxylate (42)
J¼6.3 Hz); 13C NMR (75 MHz, DMSO-d6)
d 168.0, 151.9, 151.1, 149.2,
108.5, 64.1, 49.9, 23.8, 21.0, 18.1; HRMS (TOF ESIþ) m/z calcd for
C10H15N4O5S 303.0763, found 303.0755. X-ray crystallographic data
According to general procedure I, a solution of 3,3-diphenoxy-2-
azaprop-2-enenitrile (0.116 g, 0.488 mmol) and morpholine
(0.043 mL, 0.49 mmol) in THF (1.0 mL) led to 39, which was treated
with 10c (0.100 g, 0.444 mmol). The reaction mixture was purified
by chromatography on SiO2 (EtOH) to afford 42 as a pale yellow
foam (0.070 g, 43%, ELSD purity 99.7%): Rf 0.80 (EtOH); IR (ATR)
3341, 3152, 2964,1655,1577,1547,1480,1424,1275,1227,1111,1079,
for 44 were deposited with the Cambridge Crystallographic Data
Center (deposition number CCDC 935121).
4.34. Ethyl 4-oxo-6,8-diphenyl-3,4,6,9-tetrahydropyrimido
[2,1-c][1,2,4,6]thiatriazine-7-carboxylate 2,2-dioxide (45)
According to general procedure J, a solution of 18 (0.250 g,
0.778 mmol), DIPEA (0.19 mL, 1.2 mmol), and chlorosulfonyl iso-
cyanate (0.10 mL, 1.2 mmol) in THF (2.5 mL) led to crude product,
which was diluted with EtOAc (30 mL), concentrated under re-
duced pressure with SiO2 (1.0 g), and purified by chromatography
on SiO2 (1:1, hexanes/EtOAc to EtOAc) to afford 45 as a white foam
(0.132 g, 40%, ELSD purity 99.7%): IR (ATR) 3202, 3057, 2982, 1700,
1022, 893, 787 cmꢂ1; 1H NMR (300 MHz, DMSO-d6)
d 7.86 (br s, 2H),
5.09 (d, 1H, J¼5.4 Hz), 4.16e4.00 (m, 2H), 3.65e3.50 (m, 8H), 2.19 (s,
3H), 1.86e1.77 (m, 1H), 1.23 (t, 3H, J¼6.9 Hz), 0.75 (d, 3H, J¼6.9 Hz),
0.72 (d, 3H, J¼6.9 Hz); 13C NMR (75 MHz, DMSO-d6)
d 166.0, 160.5,
158.6, 156.7, 152.7, 98.0, 65.9 (2C), 58.7, 55.4, 43.6 (2C), 34.1, 23.0,
17.8, 17.6, 14.4; HRMS (TOF ESIþ) m/z calcd for C17H27N6O3 363.2145,
found 363.2136.
1594, 1444, 1331, 1249, 1163, 1100, 979, 749, 693 cmꢂ1 1H NMR
;
(300 MHz, DMSO-d6) d 11.18 (s, 1H), 7.47e7.37 (m, 11H), 6.66 (s, 1H),
4.32. Ethyl 4-amino-2-morpholino-6,8-diphenyl-6H-pyr-
imido[1,2-a][1,3,5]triazine-7-carboxylate (43)
3.84 (q, 2H, J¼6.9 Hz), 0.78 (t, 3H, J¼6.9 Hz); 13C NMR (75 MHz,
DMSO-d6)
d 164.1, 148.5, 147.5, 146.4, 139.1, 132.9, 129.8, 129.1 (2C),
129.0 (2C), 128.7,128.0 (2C),126.2 (2C), 104.5, 60.2, 51.8, 13.4; HRMS
According to general procedure I, a solution of 3,3-diphenoxy-2-
azaprop-2-enenitrile (0.163 g, 0.685 mmol) and morpholine
(0.060 mL, 0.68 mmol) in THF (1.0 mL) led to 39, which was treated
with 18 (0.200 g, 0.622 mmol). The reaction mixture was cooled to
room temperature, diluted with ether (1.5 mL), and cooled to
ꢂ20 ꢀC for 1 h. The resulting precipitate was isolated by vacuum
filtration and washed with ether (15 mL). The crude precipitate was
recrystallized from boiling hexanes/EtOAc (4:1, 35 mL), isolated by
vacuum filtration, washed with hexanes, and dried in vacuo to af-
ford 43 as a yellow/green foam (0.130 g, 46%, ELSD purity 99.9%): IR
(ATR) 3334, 3165, 2975, 2855, 1646, 1549, 1476, 1418, 1271, 1230,
1105, 1087, 1021, 995, 764, 695 cmꢂ1; 1H NMR (300 MHz, DMSO-d6)
(TOF ESIþ) m/z calcd for C20H19N4O5S 427.1076, found 427.1077.
4.35. Diethyl 4,6-bis(4-chlorophenyl)-2,8-dimethyl-4,6-
dihydro-1H-pyrimido[1,2-a]pyrimidine-3,7-dicarboxylate (46)
According to general procedure D, a solution of 13$TFA (0.030 g,
0.074 mmol), 12 (0.074 g, 0.29 mmol), and NaHCO3 (0.014 g,
0.016 mmol) in (CF3)2CHOH (0.25 mL) was heated for 24 h. LC/MS
analysis demonstrated an approximately 50% conversion of 13, and
two more equivalents of 12 (0.037 g, 0.15 mmol) were added. The
reaction mixture was stirred at 90 ꢀC for an additional 18 h after
which complete consumption of the starting material was observed
via LC/MS. Product 46 (0.022 g, 57%) was obtained as a yellow
crystalline 4:1 mixture of antiesyn-isomers that could not be fur-
ther separated: Rf 0.42 (MeOH/CH2Cl2, 0.2:10); mp 70e75 ꢀC; IR
(CH2Cl2) 2979, 2922, 1677, 1622, 1544, 1490, 1446, 1369, 1274, 1228,
d
8.04 (s, 2H), 7.47e7.44 (m, 2H), 7.37e7.27 (m, 8H), 6.30 (s, 1H),
3.79e3.69 (m, 4H), 3.58 (s, 6H), 0.77 (t, 3H, J¼7.2 Hz); 13C NMR
(75 MHz, DMSO-d6)
d 165.5, 160.6, 159.0, 156.3, 152.5, 141.7, 141.5,
128.6 (2C), 128.2 (2C), 128.1, 127.5, 127.0 (2C), 126.5 (2C), 100.4, 65.9
(2C), 58.7, 54.6, 43.6, 43.4, 13.5; HRMS (TOF ESIþ) m/z calcd for
1199, 1088, 1014, 830, 736 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d 12.05
C
25H27N6O3 459.2145, found 459.2135.
(s, 1H), 11.95 (s, 0.2H), 7.43e7.41 (d, 2H, J¼8.4 Hz), 7.31e7.29 (d, 2ꢁ
2H, J¼8.4 Hz), 6.97e6.94 (d, 2ꢁ 0.5H, J¼8.8 Hz), 5.38 (s, 2ꢁ 0.25H),
5.18 (s, 2ꢁ 1H), 4.10e4.01 (m, 2ꢁ 4H), 2.49 (s, 2ꢁ 3H), 1.17e1.13 (t,
4.33. Ethyl 6,8-dimethyl-4-oxo-3,4,6,9-tetrahydropyrimido
[2,1-c][1,2,4,6]thiatriazine-7-carboxylate 2,2-dioxide (44).
General procedure J
2ꢁ 3H, J¼7.2 Hz); 13C NMR (100 MHz, CDCl3)
d 164.3, 164.0 (2C),
148.2, 145.6, 144.7, 138.6, 137.7, 135.3, 134.4, 129.5 (2C), 129.1, 128.9
(2C), 128.3, 105.1, 103.4, 64.8, 62.3, 60.8, 56.6, 19.3, 14.0; HRMS
(ESIþ) m/z calcd for C27H28O4N3Cl2 (MþH) 528.1451, found
528.1441.
To a suspension of 10a (0.100 g, 0.507 mmol) and DIPEA
(0.13 mL, 0.76 mmol) in THF (2.5 mL) at 0 ꢀC was added chlor-
osulfonyl isocyanate (0.068 mL, 0.76 mmol) in one portion. The
reaction mixture became homogeneous within 5 min after the
addition of the isocyanate. The solution was stirred for 3 h at 0 ꢀC
and warmed to room temperature for 14 h. 1H NMR analysis in-
dicated a 47% conversion, and therefore the mixture was treated at
4.36. Ethyl 2-(4-morpholinobenzylidene)-3-oxobutanoate
(48d)36
A solution of L-proline (1.21 g, 10.5 mmol) in DMSO (10 mL) was
0
ꢀC with additional DIPEA (0.084 mL, 0.51 mmol) and chlor-
treated with 4-morpholinebenzaldehyde (1.12 g, 5.86 mmol) at
room temperature. After 10 min, ethyl acetoacetate (0.80 mL,
6.3 mmol) was added and the mixture was stirred for 17 h. The
osulfonyl isocyanate (0.045 mL, 0.51 mmol). The reaction mixture
was stirred at 0 ꢀC for 2 h, allowed to warm to room temperature,
Please cite this article in press as: Arnold, D. M.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.127

12
D.M. Arnold et al. / Tetrahedron xxx (2013) 1e13
yellow solution was treated with EtOAc, followed by water, and the
organic layer was washed with brine, dried (Na2SO4), filtered, and
concentrated. The resulting oil was purified by chromatography on
SiO2 (ISCO-Rf, 20e100% EtOAc/hexanes, 15 min gradient) to give
48d as a sticky yellow 4.4:1 mixture of inseparable Z/E isomers
(0.713 g, 40%): mp 94e96 ꢀC; IR (neat) 2974, 1713, 1588, 1514, 1260,
(d, JCF¼22.1 Hz), 99.5, 58.7, 51.9, 20.9, 18.1, 13.5; HRMS (ESIþ) m/z
calcd for C23H22N5O2ClF (MþH) 454.1441, found 454.1435.
4.40. Ethyl 4-(4-dimethylaminophenyl)-2-(6-fluoro-4-
methylquinazolin-2-ylamino)-6-methyl-1,4-
dihydropyrimidine-5-carboxylate (49d)
1163, 982 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d 7.53 (s, 0.2 H), 7.43 (s,
1H), 7.35 (d, 2H, J¼7.8 Hz), 7.28 (d, 0.4H, J¼8.8 Hz), 6.82e6.78
(overlap d, 2.4H), 4.33 (q, 2H, J¼7.2 Hz), 4.23 (q, 0.4H, J¼7.2 Hz),
3.80e3.78 (m, 5H), 3.24e3.21 (m, 5H), 2.37 (s, 0.6H), 2.34 (s, 3H),
1.31e1.28 (2 overlapping t, 3.7H); 13C NMR (100 MHz, CDCl3)
According to general procedure D, a solution of 47c (0.032 g,
0.15 mmol), 48a36,37 (0.15 g, 0.59 mmol), and NaHCO3 (0.027 g,
0.32 mmol) in (CF3)2CHOH (0.60 mL) gave 49d as an orange solid
(0.027 g, 40%, ELSD purity 99.4%): mp >220 ꢀC; IR (neat) 3059,
d
204.0, 194.5, 168.4, 164.6, 152.4, 152.1, 141.1, 140.3, 131.5, 131.4,
2974, 1655, 1543, 1420, 1307, 1215, 1077, 838 cmꢂ1
;
1H NMR
130.6,129.7,122.9,122.6,114.0,113.9, 66.2, 61.2, 60.9, 47.3, 47.2, 31.0,
26.0, 14.0, 13.8; HRMS (ESIþ) m/z calcd for C17H22NO4 (MþH)
304.1543, found 304.1535.
(400 MHz, DMSO-d6) d 10.57 (br s, 2H), 7.84e7.81 (m, 2H), 7.71e7.67
(m, 1H), 7.15 (d, 2H, J¼8.4 Hz), 6.63 (d, 2H, J¼8.4 Hz), 5.57 (s, 1H),
4.06 (q, 2H, J¼6.8 Hz), 2.82 (s, 6H), 2.74 (s, 3H), 2.38 (s, 3H); 1.19 (t,
3H, J¼6.8 Hz); 13C NMR (100 MHz, DMSO-d6)
168.9 (d, JCF¼4.0 Hz),
d
165.3, 161.3, 157.8 (d, JCF¼242.5 Hz), 151.6, 149.7, 147.4, 146.5, 132.2,
128.6 (d, JCF¼8.1 Hz), 126.7, 123.1 (d, JCF¼25.2 Hz), 119.5 (d,
JCF¼9.1 Hz), 112.3, 109.3 (d, JCF¼22.1 Hz), 100.2, 59.2, 51.8, 40.1, 21.8,
18.2,14.2; HRMS (ESIþ) m/z calcd for C25H28N6O2F (MþH) 463.2252,
found 463.2248.
4.37. Ethyl 2-(6-chloro-4-methylquinazolin-2-ylamino)-4-(4-
chlorophenyl)-6-methyl-1,4-dihydropyrimidine-5-
carboxylate (49a)
According to general procedure D, a solution of 47a (0.029 g,
0.12 mmol), 1236,37 (0.23 g, 0.90 mmol), and NaHCO3 (0.026 g,
0.31 mmol) in (CF3)2CHOH (0.40 mL) afforded 49a as a light yellow
solid (0.053 g, 56%, ELSD purity 95.4%): mp >200 ꢀC; IR (neat) 3059,
4.41. Ethyl 2-(4.6-dimethylquinazolin-2-ylamino)-6-methyl-
4-(3-nitrophenyl)-1,4-dihydropyrimidine-5-carboxylate (49e)
2975, 1650, 1575, 1461, 1420, 1305, 1215, 1094, 838 cmꢂ1
;
1H NMR
According to general procedure D, a solution of 47b (0.043 g,
0.20 mmol), 48b36,38 (0.16 g, 0.60 mmol), and NaHCO3 (0.057 g,
0.68 mmol) in (CF3)2CHOH (0.60 mL) gave 49e as a light yellow
solid (0.062 g, 67%, ELSD purity 90.4%): mp >200 ꢀC; IR (neat) 3059,
(400 MHz, DMSO-d6)
d 10.87 (br s, 1H), 10.43 (br s, 1H), 8.11 (d, 1H,
J¼1.6 Hz), 7.85e7.79 (m, 2H), 7.39 (d, 2H, J¼8.8 Hz), 7.36 (d, 2H,
J¼8.8 Hz), 5.70 (s, 1H), 4.07 (q, 2H, J¼7.2 Hz), 2.77 (s, 3H), 2.39 (s,
3H), 1.17 (t, 3H, J¼7.2 Hz); 13C NMR (100 MHz, DMSO-d6)
d 169.3,
2974, 1668, 1525, 1450, 1420, 1340, 1215, 1077, 734, 692 cmꢂ1
;
1H
165.6, 161.8, 151.8, 149.0, 148.8, 144.0, 134.3, 132.5, 128.9, 128.7,
128.5, 124.9, 120.8, 100.4, 59.8, 52.7, 21.9, 18.9, 14.6; HRMS (ESIþ) m/
z calcd for C23H22N5O2Cl2 (MþH) 470.1145, found 470.1146.
NMR (400 MHz, DMSO-d6)
d 10.94 (br s, 1H), 10.53 (br s, 1H), 8.23
(app t, 1H, J¼1.6 Hz), 8.12e8.09 (m, 1H), 7.85 (s, 1H), 7.80 (d, 1H,
J¼7.6 Hz), 7.73 (d,1H, J¼8.4 Hz), 7.67e7.63 (m, 2H), 5.85 (s, 1H), 4.08
(q, 2H, J¼7.2 Hz), 2.77 (s, 3H), 2.47 (s, 3H), 2.40 (s, 3H), 1.17 (t, 3H,
J¼7.2 Hz); 13C NMR (75 MHz, DMSO-d6)
d 169.0, 165.1, 159.8, 151.1,
4.38. Ethyl 4-(4-chlorophenyl)-2-(4,6-dimethylquinazolin-2-
ylamino)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
(49b)
147.8, 147.5, 147.0, 135.6, 133.8, 132.8, 130.3, 126.0, 124.3, 122.3,
121.0, 119.6, 98.7, 59.4, 51.9, 21.6, 21.0, 19.0, 14.1; HRMS (ESIþ) m/z
calcd for C24H25N6O4 (MþH) 461.1932, found 461.1913.
According to general procedure D, a solution of 47b (0.055 g,
0.26 mmol), 1236,37 (0.28 g, 1.09 mmol), and NaHCO3 (0.049 g,
0.58 mmol) in (CF3)2CHOH (0.40 mL) afforded 49b as a light yellow
solid (0.073 g, 62%, ELSD purity 98.4%): mp >200 ꢀC; IR (neat) 3058,
4.42. Ethyl 4-(4-chlorophenyl)-6-methyl-2-(8-methyl-[1,3]di-
oxolo[4,5-g]quinazolin-6-ylamino)-1,4-dihydropyrimidine-5-
carboxylate (49f)
2975, 1655, 1535, 1450, 1420, 1316, 1215, 1077, 839 cmꢂ1
;
1H NMR
(400 MHz, DMSO-d6)
d 10.72 (br s, 2H), 7.83 (s, 1H), 7.70 (d, 1H,
According to general procedure D, a solution of 47d (0.029 g,
0.12 mmol), 1236,37 (0.035 g, 0.14 mmol), and NaHCO3 (0.026 g,
0.31 mmol) in (CF3)2CHOH (0.40 mL) afforded 49f as a light yellow
solid (0.024 g, 41%, ELSD purity 98.2%): mp >200 ꢀC; IR (neat) 3059,
J¼8.4 Hz), 7.63 (d, 1H, J¼8.4 Hz), 7.38 (app s, 4H), 5.71 (s, 1H), 4.06
(q, 2H, J¼6.4 Hz), 2.75 (s, 3H), 2.45 (s, 3H), 2.39 (s, 3H), 1.16 (t, 3H,
J¼6.8 Hz); 13C NMR (100 MHz, DMSO-d6, 100 ꢀC)
d 168.1, 164.8,
2974, 1649, 1450, 1420, 1215, 1094, 1077, 768 cmꢂ1
;
1H NMR
159.3,150.4,149.1,147.4,143.3,135.0,133.2,131.4,127.8,127.5,125.4,
123.6, 119.3, 99.3, 58.6, 51.9, 20.7, 20.3, 18.4, 13.5; HRMS (ESIþ) m/z
calcd for C24H25N5O2Cl (MþH) 450.1691, found 450.1680.
(300 MHz, DMSO-d6)
d 10.76 (br s, 2H), 7.43 (s, 1H), 7.38 (d, 2H,
J¼8.8 Hz), 7.34 (d, 2H, J¼8.7 Hz), 7.26 (s, 1H), 6.19 (br s, 2H), 5.65 (s,
1H), 4.06 (q, 2H, J¼7.2 Hz), 2.65 (s, 3H), 2.37 (s, 3H), 1.16 (t, 3H,
4.39. Ethyl 4-(4-chlorophenyl)-2-(6-fluoro-4-
methylquinazolin-2-ylamino)-6-methyl-1,4-
dihydropyrimidine-5-carboxylate (49c)
J¼7.2 Hz); 13C NMR (125 MHz, DMSO-d6)
d 166.7, 165.2, 159.6, 153.3,
150.9,148.5, 145.8, 143.7, 131.8, 128.5,127.9, 115.6,102.9,102.1, 101.0,
99.0, 59.2, 51.6, 21.8, 18.9, 14.2; HRMS (ESIþ) m/z calcd for
C24H23N5O4Cl (MþH) 480.1433, found 480.1431.
According to general procedure D, a solution of 47c (0.048 g,
0.22 mmol), 12 (0.22 g, 0.86 mmol), and NaHCO3 (0.043 g,
0.51 mmol) in (CF3)2CHOH (0.40 mL) afforded 49c as a yellow solid
(0.051 g, 52%, ELSD purity 90%): mp >200 ꢀC; IR (neat) 3059, 2975,
4.43. Ethyl 4-(4-bromophenyl)-6-methyl-2-(8-methyl-[1,3]di-
oxolo[4,5-g]quinazolin-6-ylamino)-1,4-dihydropyrimidine-5-
carboxylate (49g)
1663, 1536, 1450, 1420, 1310, 1215, 1077, 826 cmꢂ1
;
1H NMR
(400 MHz, DMSO-d6)
d
10.71 (br s, 2H), 7.93e7.83 (m, 2H), 7.72
According to general procedure D, a solution of 47d (0.041 g,
0.17 mmol), 48c,36,37 and NaHCO3 (0.031 g, 0.37 mmol) in
(CF3)2CHOH (0.40 mL) afforded 49g as a yellow solid (0.039 g, 57%,
ELSD purity 98.2%): mp >200 ꢀC; IR (neat) 3059, 2974, 1700, 1629,
1536, 1420, 1192, 1077, 1028, 839 cmꢂ1; 1H NMR (400 MHz, DMSO-
(ddd, 1H, J¼2.4, 8.8, 8.8 Hz), 7.39e7.35 (m, 4H), 5.70 (s, 1H), 4.07 (q,
2H, J¼7.2 Hz), 2.75 (s, 3H), 2.39 (s, 3H), 1.16 (t, 3H, J¼7.2 Hz); 13C
NMR (100 MHz, DMSO-d6, 100 ꢀC)
d 168.5, 164.7, 159.9, 157.6 (d,
JCF¼243.5 Hz), 150.5, 148.2, 146.3, 143.0, 131.5, 128.2 (d, JCF¼8.1 Hz),
127.9, 127.7, 127.5, 122.7 (d, JCF¼25.2 Hz), 119.3 (d, JCF¼8.1 Hz), 108.6
d6)
d
10.61 (br s, 2H), 7.51 (d, 2H, J¼8.4 Hz), 7.41 (s, 1H), 7.29 (d, 2H,
Please cite this article in press as: Arnold, D. M.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.127

D.M. Arnold et al. / Tetrahedron xxx (2013) 1e13
13
Manteau, B.; Nghiem, P.; Quade, B.; Seguin, S. P.; Wipf, P. Proc. Natl. Acad. Sci. U.S.
A. 2011, 108, 6757e6762; (c) Zaware, N.; LaPorte, M. G.; Farid, R.; Liu, L.; Wipf, P.;
Floreancig, P. E. Molecules 2011, 16, 3648e3662; (d) Hammill, J. T.; Contreras-
Garcia, J.; Virshup, A. M.; Beratan, D. N.; Yang, W.; Wipf, P. Tetrahedron 2010, 66,
5852e5862; (e) Wipf, P.; Stephenson, C. R. J.; Walczak, M. A. A. Org. Lett. 2004,
6, 3009e3012.
J¼8.4 Hz), 7.25 (s, 1H), 6.20 (br s, 2H), 5.66 (s, 1H), 4.06 (q, 2H,
J¼7.2 Hz), 2.66 (s, 3H), 2.38 (s, 3H), 1.16 (t, 3H, J¼7.2 Hz); 13C NMR
(100 MHz, DMSO-d6) d 166.6, 165.2, 159.7, 153.2, 151.0, 148.5, 145.8,
144.1, 131.4, 128.3, 120.3, 115.5, 102.9, 102.1, 101.0, 98.9, 59.2, 51.7,
21.8, 19.0, 14.2; HRMS (ESIþ) m/z calcd for C24H23N5O4Br (MþH)
524.0928, found 524.0915.
3. Kim, Y.-K.; Arai, M. A.; Arai, T.; Lamenzo, J. O.; Dean, E. F.; Patterson, N.;
Clemons, P. A.; Schreiber, S. L. J. Am. Chem. Soc. 2004, 126, 14740e14745.
ꢀ
4. Wipf, P.; Fang, Z.; Ferrie, L.; Ueda, M.; Walczak, M. A. A.; Yan, Y.; Yang, M. Pure
4.44. Ethyl 6-methyl-2-(8-methyl-[1,3]dioxolo[4,5-g]quinazo-
lin-6-ylamino)-4-(4-morpholinophenyl)-1,4-
dihydropyrimidine-5-carboxylate (49h)
Appl. Chem. 2013, 85 in press.
5. (a) Macarron, R.; Banks, M. N.; Bojanic, D.; Burns, D. J.; Cirovic, D. A.; Garyantes,
T.; Green, D. V. S.; Hertzberg, R. P.; Janzen, W. P.; Paslay, J. W.; Schopfer, U.;
Sittampalam, G. S. Nat. Rev. Drug Discovery 2011, 10, 188e195; (b) Haggarty, S. J.
Curr. Opin. Chem. Biol. 2005, 9, 296e303.
6. (a) Walczak, M. A. A.; Wipf, P. J. Am. Chem. Soc. 2008, 130, 6924e6925; (b) Wipf,
P.; Walczak, M. A. A. Angew. Chem., Int. Ed. 2006, 45, 4172e4175.
7. Guo, T.; Hunter, R. C.; Zhang, R.; Greenlee, W. J. Tetrahedron Lett. 2007, 48,
613e615.
8. Jimenez, J. -M.; Patel, S.; Kay, D.; Knegtel, R.; Philps, O. U.S. Patent 7,855,214 B2,
2010.
According to general procedure D, a solution of 47d (0.046 g,
0.17 mmol), 48d (0.21 g, 0.70 mmol), and NaHCO3 (0.032 g,
0.38 mmol) in CF3CHOH (0.40 mL) gave 49h as a yellow solid
(0.073 g, 81%, ELSD purity 99.7%): mp >220 ꢀC; IR (neat) 3058,
2816, 1655, 1543, 1450, 1420, 1316, 1215, 1077, 1028, 956 cmꢂ1
;
1H
9. Wathen, M. W.; Wathen, L. K. WO 019940 A1, 2004.
NMR (400 MHz, DMSO-d6)
d 10.56 (br s, 2H), 7.41 (s, 1H), 7.24 (s,
10. Bundy, G. L.; Ciske, F. L.; Genin, M. J.; Heasley, S. E.; Larsen, S. D.; Lee, B. H.; May,
P. D.; Palmer, J. R.; Schnute, M. E.; Vaillancourt, V. A.; Thorarensen, A.; Wolf, A.
J.; Wicnienski, N. A.; Wilhite, D. WO 04444 A2, 2002.
11. Hellberg, M.; Stubbins, J. F.; Glennon, R. A. Bioorg. Med. Chem. 2000, 8,
1917e1923.
12. (a) Wyatt, E. E.; Fergus, S.; Galloway, W. R. J. D.; Bender, A.; Fox, D. J.; Plowright,
A. T.; Jessiman, A. S.; Welch, M.; Spring, D. R. Chem. Commun. 2006, 3296e3298;
(b) Wyatt, E. E.; Galloway, W. R. J. D.; Thomas, G. L.; Welch, M.; Loiseleur, O.;
Plowright, A. T.; Spring, D. R. Chem. Commun. 2008, 4962e4964.
13. See: Katritzky, A. R.; Xu, Y.-J.; Tu, H. J. Org. Chem 2003, 68, 4935e4937 and
references cited therein.
1H), 7.19 (d, 2H, J¼8.0 Hz), 6.86 (d, 2H, J¼8.0 Hz), 6.19 (br s, 2H), 5.58
(s, 1H), 4.06 (app t, 2H, J¼6.0 Hz), 3.68 (br s, 4H), 3.03 (br s, 4H), 2.65
(s, 3H), 2.37 (s, 3H), 1.17 (t, 3H, J¼6.8 Hz); 13C NMR (100 MHz,
DMSO-d6) d 166.5,165.4,160.1,153.2,151.2,150.2,148.6,145.7,135.4,
126.7, 115.4, 115.0, 102.9, 102.1, 101.0, 99.8, 66.0, 59.1, 51.6, 48.3, 21.9,
18.7, 14.2; HRMS (ESIþ) m/z calcd for C28H31N6O2 (MþH) 531.2350,
found 531.2338.
14. (a) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360e416; (b) Kappe, C. O.; Stadler, A.
Org. React. 2004, 63, 1e116.
4.45. Ethyl 4-(4-(dimethylamino)phenyl)-6-methyl-2-(8-
methyl-[1,3]dioxolo[4,5-g]quinazolin-6-ylamino)-1,4-
dihydropyrimidine-5-carboxylate (49i)
15. (a) Mishra, J. K.; Wipf, P.; Sinha, S. C. J. Comb. Chem. 2010, 12, 609e612; (b)
Werner, S.; Turner, D. M.; Lyon, M. A.; Huryn, D. M.; Wipf, P. Synlett 2006,
2334e2338; (c) Studer, A.; Jeger, P.; Wipf, P.; Curran, D. P. J. Org. Chem. 1997, 62,
2917e2924; (d) Wipf, P.; Cunningham, A. Tetrahedron Lett. 1995, 36,
7819e7822.
According to general procedure D, a solution of 47d (0.043 g,
0.17 mmol), 48a36,37 (0.18 g, 0.69 mmol), and NaHCO3 (0.031 g,
0.37 mmol) in (CF3)2CHOH (0.60 mL) gave 49i as an off-white solid
(0.038 g, 45%, ELSD purity 100%): mp >220 ꢀC; IR (neat) 3059, 2934,
16. Atwal, K. S.; Rovnyak, G. C.; O’Reilly, B. C.; Schwartz, J. J. Org. Chem. 1989, 54,
5898e5907.
17. Tabouazat, M.; El Louzi, A.; Ahmar, M.; Cazes, B. Synlett 2008, 2495e2499.
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19. Kappe, C. O. Bioorg. Med. Chem. Lett. 2000, 10, 49e52.
20. (a) Mobinikhaledi, A.; Forughifar, N.; Safari, J. A.; Amini, E. J. Heterocycl. Chem.
2007, 44, 697e699; (b) Ramu, E.; Kotra, V.; Bansal, N.; Varala, R.; Adapa, S. R.
Rasayan J. Chem. 2008, 1, 188e194.
21. (a) Elliott, M. C.; Long, M. S. Org. Biomol. Chem. 2004, 2, 2003e2011; (b) Butters,
M.; Davies, C. D.; Elliott, M. C.; Cousins, J. H.; Kariuki, B. M.; Ooi, L.-L.; Wood, J. L.;
Wordingham, S. V. Org. Biomol. Chem. 2009, 7, 5001e5009.
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J. Macromol. Rapid Commun. 2000, 21, 1185e1190; (b) Hoogenboom, R.; Andres,
P. R.; Kickelbick, G.; Schubert, U. S. Synlett 2004, 1779e1783.
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Chem. 2012, 77, 417e423.
1663, 1549, 1450, 1420, 1215, 1077, 1029, 839 cmꢂ1
;
1H NMR
(400 MHz, DMSO-d6)
d 10.61 (br s, 2H), 7.42 (s, 1H), 7.24 (s, 1H), 7.14
(d, 2H, J¼8.4 Hz), 6.64 (d, 2H, J¼8.8 Hz), 6.19 (br s, 2H), 5.54 (s, 1H),
4.06 (q, 2H, J¼6.8 Hz), 2.82 (s, 6H), 2.66 (s, 3H), 2.37 (s, 3H), 1.18 (t,
3H, J¼6.8 Hz); 13C NMR (100 MHz, DMSO-d6)
d 166.4, 165.4, 160.1,
153.1, 151.1, 149.7, 148.6, 145.6, 132.4, 126.7, 115.4, 112.3, 102.9, 102.1,
101.0, 100.0, 59.1, 51.6, 40.1, 21.8, 18.7, 14.2; HRMS (ESIþ) m/z calcd
for C26H29N6O4 (MþH) 489.2245, found 489.2237.
Acknowledgements
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€
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We thank Dr. Steven Geib for X-ray analyses, Dr. Dimas J. da Paz
Lima for the preparation of intermediates 47aed, Dr. Ki Bum Hong
for the preparation of ynones 28 and 29, and the National Institutes
of Health (GM067082; P50 Centers for Chemical Methodologies
and Library Development, as well as P41GM081275) for financial
support.
€
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Supplementary data
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5032e5035.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.04.127.
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Please cite this article in press as: Arnold, D. M.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.127