UV Light-mediated regioselective methylsulfanyl discrimination via Pd-catalyzed cross-coupling reactions of 2,4-dimethylsulfanylpyrido[2,3-d]pyrimidines

Article abstract of DOI:10.1080/17415993.2019.1590581

An effective and novel photochemical method for the preparation of 2,4-disubstituted pyrido[2,3-d]pyrimidines is reported from 2,4-dimethylsulfanyl-pyrido[2,3-d]pyrimidines through a Liebeskind-Sroglcoupling reaction involving an original selective methyl sulfanyl discrimination using UV light as a source of energy. Our strategies involve a two-step and a one-pot approach with reaction times of 11-18 h and yields ranging between 72 and 94%. The two strategies are compared.

Full text of DOI:10.1080/17415993.2019.1590581

Journal of Sulfur Chemistry
ISSN: 1741-5993 (Print) 1741-6000 (Online) Journal homepage: https://www.tandfonline.com/loi/gsrp20
UV Light-mediated regioselective
methylsulfanyl discrimination via Pd-
catalyzed cross-coupling reactions of 2,4-
dimethylsulfanylpyrido[2,3-d]pyrimidines
Yassine Riadi
To cite this article: Yassine Riadi (2019): UV Light-mediated regioselective
methylsulfanyl discrimination via Pd-catalyzed cross-coupling reactions of 2,4-
dimethylsulfanylpyrido[2,3-d]pyrimidines, Journal of Sulfur Chemistry, DOI:
10.1080/17415993.2019.1590581
To link to this article: https://doi.org/10.1080/17415993.2019.1590581
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JOURNAL OF SULFUR CHEMISTRY
https://doi.org/10.1080/17415993.2019.1590581
UV Light-mediated regioselective methylsulfanyl
discrimination via Pd-catalyzed cross-coupling reactions of
2,4-dimethylsulfanylpyrido[2,3-d]pyrimidines
Yassine Riadi
Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University,
Al-Kharj, Saudi Arabia
ABSTRACT
ARTICLE HISTORY
Received 19 September 2018
Accepted 24 February 2019
An effective and novel photochemical method for the prepara-
tion of 2,4-disubstituted pyrido[2,3-d]pyrimidines is reported from
2,4-dimethylsulfanyl-pyrido[2,3-d]pyrimidines through aLiebeskind-
Sroglcoupling reaction involving an original selective methyl sulfanyl
discrimination using UV light as a source of energy. Our strategies
involve a two-step and a one-pot approach with reaction times of
11-18 h and yields ranging between 72 and 94%. The two strategies
are compared.
KEYWORDS
Photochemical;
pyridopyrimidines;
Liebeskind-Srogl;
regioselective;
methylsulfanyl
discrimination
1. Introduction
Palladium-catalyzed reactions including a family of cross-coupling reactions that employ
palladium complexes as catalysts [1–3], represent a powerful strategy for the synthesis
of highly substituted heterocycles. The selective activation of polyhalogenated heterocy-
cles in such reactions has been extensively investigated [4–8] and can provide a versatile
way to prepare libraries of molecules functionalized with different substituents in specific
positions of the heterocyclic scaffold.
In the search for new nitrogen-containing biocompatible heterocycles pyridopyrim-
idines appeared to be very useful candidates. Including pyridopyrimidine in more complex
CONTACT Yassine Riadi
yassinriadi@yahoo.fr
This article makes reference to supplementary material available on the publisher’s website at
https://doi.org/10.1080/17415993.2019.1590581
© 2019 Informa UK Limited, trading as Taylor & Francis Group

2
Y. RIADI
Scheme 1. General strategy.
molecules has led to a wide range of bioactive scaffolds which can be used as antimi-
crobial [9], antibacterial [10,11], antifolate [12,13], anti-inflammatory [14,15], insecticidal
[16], antiviral [17], anticancer agents [18], antihypertensive [19], antileishmanial [20], anti-
convulsants [21], diuretic and potassium-sparing activity [22,23], antituberculostatic [24],
antiaggressive [25,26], tyrosine kinase [27] and selective anti-tumoral agents [28]. This
explains the interest of chemists in developing strategies and versatile methods to obtain
and functionalize them [29].
In addition, photo-induced syntheses plays a special role in organic chemistry due to
its ecological features and simple and mild reaction conditions, and it has been used as a
source of energy for some Pd cross-coupling reaction [30,31].
Based on our previous experience with these heteroaromatic rings and photochemical
reactions [32–34] and on other reports of regio- or chemo-selective bis-arylations of related
heterocycles [35,36], we decided to develop a new methodology to access a series of iso-
meric 2,4-disubstituted pyrido[2,3-d]pyrimidines via cross-coupling reactions (Scheme 1).
In the present paper, we report a new method to access bisulfanyl derivative 3 and their
first regioselective functionalization by two different strategies using the Liebeskind-Srogl
coupling reaction [37–40].
2. Results and discussion
The synthesis of sulfanyl heterocycles has been performed by reacting 2-amino-3-pyridine
carbonitrile with carbon disulfide in DMF in the presence of KOH (Scheme 2) [41].
The alkylation of sulfanile heterocycle has been performed starting from compound 2
to obtain the di-sulfide intermediate 3 (Scheme 3) [42].
Scheme 2. Preparation of bis-thiol heterocycle 2.

JOURNAL OF SULFUR CHEMISTRY
3
Scheme 3. Preparation of bisulfide intermediate 3.
2.1. Optimization of reaction conditions
Our initial investigation was started with the reaction of compound 3 with phenyl boronic
acid under an argon atmosphere in different types of solvents.
In the absence of any light source and catalyst, the product was not obtained (Table 1,
entry 1). The reaction was then repeated in presence of Pd(PPh3)4 as catalyst and CuTC
as a cofactor in a glass tube at room temperature in the absence of any source of light, the
product also was not obtained (Table 1, entry 2) [32–34]. The reaction was repeated for a
third time using a 300 nm wavelength light source, in presence or absence of Pd(PPh3)4
and CuTC as catalyst and cofactor respectively in a glass tube at room temperature and
again the product was not obtained (Table 1, entry 3,4). Furthermore, the reaction was
repeated using a 300 nm wavelength light source at room temperature in the presence of
different catalysts and solvents. Initially, the desired product was obtained with an isolated
yield of 10% in the presence of Pd(OAc)2 as a catalyst (Table 1, entry 6). The product was
not obtained when CuMeSal was used as a cofactor (Table 1, entry 5,7). However, the use
of Pd(PPh3)4 in the presence of CuTC increases the yield to 88% (Table 1, entry 13).
Solvent screening shows that the reaction in DMF gives the best yield (88%), in com-
parison with other solvents, like DMSO, THF, MeCN, CHCl3or acetone (Table 1, entries
7-13). Optimization studies showed that light is needed for the reaction and that the yield
of the reaction is wavelength dependent (Table 1, entries 14, 15). Air significantly dimin-
ishes the yield to 20% (Table 1, entry 16) and suggests that an argon atmosphere is essential
for the success of the reaction.
2.2. Application of the methodology
Having in hand the optimal conditions, we first studied the scope of the reaction, by react-
ing compounds 3 under Liebeskind-Srogl cross-coupling reaction conditions [43]. We
were able to obtain regioselective arylation at C4. Reacting the disulfide 3 and a stoichio-
metric amount of phenylboronic acid using Pd(PPh3)4 (5 mol%) as catalyst in presence
of CuTC and DMF, we observed that the starting compound 3 was totally consumed and
only the monoarylated derivative 4ꢀ was formed in a good yield (89%) and no trace of
substituted product has been observed (Table 2, Entry 1; Column 3).1
After this result, we decided to generate the monoarylated derivatives by reaction
between compound 3 and different boronic acids. The heteroaryl (Het)Ar1 were suc-
cessfully introduced and the monoarylated derivatives were obtained after purification by

4
Y. RIADI
Table 1. Optimizing conditions of reaction.a
Entry
Catalyst
Cofactor
Hv
Solvent
Yields (%) (Time)
1
2
3
4
5
6
7
8
–
–
CuTC
–
–
–
DMF
DMF
DMF
DMF
DMF
0 (24 h)
0 (24 h)
0 (24 h)
0 (24 h)
0 (9 h)
Pd(PPh3)4
Pd(PPh3)4
–
300 nm
300 nm
300 nm
300 nm
300 nm
300 nm
300 nm
300 nm
300 nm
300 nm
300 nm
> 280 nm
Visible light
300 nm
CuTC
CuMeSal
CuTC
CuMeSal
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
DMF
10 (9 h)
0 (9 h)
MeCN
MeCN
THF
DMSO
acetone
CHCl3
DMF
DMF
DMF
DMF
60 (9 h)
41(9 h)
18 (9 h)
26 (9 h)
34 (9 h)
89 (8 h)
41 (8 h)
58 (8 h)
20 (8 h)
9
10
11
12
13
14
15
16c
aYield of pure isolated product. Reaction conditions: C6H5B(OH)2, Pd(PPh3)4 (5 mol %), DMF (5 mL), CuTC, hv, under argon
atmosphere.
bIsolated yields.
cReaction run in air.
chromatography on silica gel. The yields of isolated products ranged between 76 and 89%
for a reaction time of 8–9 h (Table 2).
Then, the monoarylated products were engaged in a second Liebeskind-Srogl coupling
reaction to afford to the diarylated derivatives 4.2 The second heteroaryl groups, (Het)Ar2,
were successfully introduced and the expected products were obtained after purification
by chromatography on silica gel. Yields of isolated products oscillated between 72 and 90%
in a total reaction time of 16–18 h (Table 2; Columns 4, 5, and 6).
We then envisioned a one-pot arylation at the C2 and C4 position. The ethanol was used
as co-solvent to get the best yield (Table 3).3
The two heteroaryl (Het) Ar1 and (Het) Ar2 were successfully introduced and the
expected heterocycles were obtained after purification by chromatography on silica gel.
The yields of isolated products ranged between 77 and 94% for a reaction time of 11–13 h
(Table 3). This one-pot method, compared to the two-step strategy, produced the products
in approximately the same yields but in less time. This result proves the importance of the
one-pot strategy.
Structure of final product 4a was determined by X-ray analysis (Figure 1).
Based on the studies by Handy and co-authors, we can justify the order and site
1
of the coupling using the H NMR chemical shift values of the parent non-sulfited
heteroaromatics. Indeed, we found that palladium cross-coupling reactions were carried

JOURNAL OF SULFUR CHEMISTRY
5
Table 2. Reactivity of compounds 3 with different boronic acids.
Entry
1
(het)Ar1
Yields of monoarylatedb (%) (Time (h))
89 (8 h)
(het)Ar2
Products
Yieldsb (%) (Time)
90 (8 h)
4a
2
3
86 (8 h)
76 (8 h)
4b
4c
84 (8 h)
76 (8 h)
O
O
4
5
88 (9 h)
88 (9 h)
4d
4e
74 (8 h)
85 (9 h)
O
O
O
6
7
88 (9 h)
76 (8 h)
4f
78 (10 h)
72 (10 h)
O
O
4g
S
O
8
9
88 (9 h)
88 (9 h)
4h
4i
84 (10 h)
78 (9 h)
S
O
aYields are given for isolated products.

6
Y. RIADI
Table 3. Reactivity of di-sulfide compound 3 with different boronic acids.
Entry
1
(het)Ar1
(het)Ar2
Products
Yieldsb (%) (Time)
94 (11 h)
4a
2
3
4
5
4b
4c
4d
4e
87 (11 h)
79 (11 h)
77 (11 h)
89 (13 h)
6
7
4f
82 (13 h)
78 (13 h)
4g
8
9
4h
4i
90 (13 h)
86 (13 h)
aYields are given for isolated products.

JOURNAL OF SULFUR CHEMISTRY
7
Figure 1. Ortep of compound 4a.
Figure 2. Cross-coupling order based upon the 1H NMR chemical shift values.
out successively in the sequence C4 first and C2 second (Figure 2) [44], which means that
the carbon with the most deshielded proton is the most reactive carbon.
The current research describes the first photochemical access to 2,4-disubstituted
pyrido[2,3-d]pyrimidine and its first use to build substituted pyrido[2,3-d]pyrimidines
using a novel and highly effective strategy. An efficient and simple strategy was adopted
to prepare highly substituted pyrido[2,3-d]pyrimidines which facilitate the orchestration
of selective palladium-catalyzed cross-coupling reactions for the preparation of focused
libraries of biologically active compounds. The one-pot and step-by-step processes were
synthetically compared. The great value of the one-pot methodology is a result of good
yields and fast turnover.
Notes
1. General procedure for the synthesis of 4: A solution containing 2,4-dimethylsulfanylpyrido[2,3-
d]pyrimidine 3 (0.35 mmol), the (het)aryl boronic acid (1.1 equiv), CuTC (2.2 equiv) and
Pd(PPh3)4 (0.05 equiv) in dry DMF (5 mL) was flushed with argon for 15 min. The brown
suspension was irradiated under argon for 8 h. After complete disappearance of starting mate-
rial 3, a saturated aqueous solution of NaHCO3 was added, and the mixture was extracted
with dichloromethane (3 × 15 mL). The combined organic layers were washed with saturated
NaHCO3 (2 × 10 mL). The solvent were evaporated under reduced pressure the residue was
next purified by flash chromatography to give the attempted monoarylated products. General
procedure for the synthesis of 4ꢀ via Liebeskind-Srogl cross-coupling reaction:
2. A solution containing 4-heteroaryl-2-methylsulfanylpyrido[2,3-d]pyrimidine 4ꢀ (0.35 mmol),
the (het)aryl boronic acid (2.2 equiv), CuTC (2.2 equiv) and Pd(PPh3)4 (0.05 equiv) in dry

8
Y. RIADI
DMF (5 mL) was flushed with argon for 15 min. The brown suspension was irradiated under
argon for 8 h. After complete disappearance of starting material 4ꢀ, a saturated aqueous solu-
tion of NaHCO3 was added, and the mixture was extracted with dichloromethane (3 × 15 mL).
The combined organic layers were washed with saturated NaHCO3 (2 × 10 mL). The solvent
were evaporated under reduced pressure the residue was next purified by flash chromatography
to give the attempted biarylated products types 4. 4-Phenyl-2-(4-methoxyphenyl)pyrido[2,3-
d]pyrimidine 4a: was isolated after flash chromatography (DCM) as a white solid. Mp 128-
130°C; IR (ATR-Ge, cm−1) ν 1592, 1456, 1314, 1262, 1078, 914, 856, 789; 1H RMN (250 MHz,
CDCl3) δ 3.92 (s, 3H, OCH3), 7.12 (d, J = 7.5 Hz, 2H, HAr), 7.50 (m, 4H, J = 2.5, 7.5 Hz, HAr,
H6), 7.86 (dd, 2H, J = 2.5, 7.5 Hz, HAr), 8.51 (d, 1H, J = 7.5 Hz, H5), 8.80 (dd, 2H, J = 2.5,
7.5 Hz, HAr), 9.21 (d, 1H, J = 2.5 Hz, H7); 13C RMN (62.5 MHz, CDCl3) δ 55.66 (CH3),
114.33 (2 × CH), 116.32 (Cq), 122.25 (CH), 128.55 (2 × CH), 129.20 (Cq), 129.28 (2 × CH),
131.28 (CH), 132.03 (2 × CH), 136.52 (CH), 137.48 (Cq), 157.44 (CH), 160.08 (Cq), 161.78
(Cq), 163.49 (Cq), 169.46 (Cq); HRMS (EIMS): m/z calcd for C20H15N3O: 314.1287, found:
314.1289.
3. General procedure for the one-pot synthesis of 3 via Liebeskind-Srogl cross-coupling reac-
tion: A solution containing 2,4-bimethylsulfanylpyrido[2,3-d]pyrimidine 3 (0.35 mmol), the
(het)aryl boronic acid (1.1 equiv), CuTC (2.2 equiv) and Pd(PPh3)4 (0.05 equiv) in dry DMF
(5 mL) was flushed with argon for 15 min. The brown suspension was irradiated under argon.
After complete disappearance of starting material 3, the second (het)aryl boronic acid (1.5
equiv) dissolved in ethanol and added to the reaction. After complete of reaction, a saturated
aqueous solution of NaHCO3 was added, and the mixture was extracted with dichloromethane
(3 × 15 mL). The combined organic layers were washed with saturated NaHCO3 (2 × 10 mL).
The solvent were evaporated under reduced pressure the residue was next purified by flash
chromatography to give the attempted biarylated products types 4. 2-(4-Methoxyphenyl)-4-
(3-thienyl)pyrido[2,3-d]pyrimidine 4c: was isolated after flash chromatography (DCM) as a
white solid. Mp 182–184°C; IR (ATR-Ge, cm−1) ν 1616, 1522, 1436, 1382, 1334, 1204, 944, 747
; 1H RMN (250 MHz, CDCl3) δ 3.89 (s, 3H, OCH3), 7.08 (d, 2H, J = 8.0 Hz, HAr), 7.37 (d, 1H,
J = 8.0 Hz, HHet), 7.42 (dd, 1H, J = 4.0, 8.0 Hz, H6), 7.80 (d, 2H, J = 8.0 Hz, HAr), 8.16 (d, 1H,
J = 4.0 Hz, HHet), 8.44 (d, 1H, J = 8.0 Hz, H5), 8.58 (dd, 1H, J = 4.0, 8.0 Hz, HHet), 9.15 (d, 1H,
J = 4.0 Hz, H7); 13C RMN (62.5 MHz, CDCl3) δ 55.50 (CH3), 114.25 (2 × CH), 116.06 (Cq),
121.96 (CH), 125.90 (CH), 128.19 (CH), 128.96 (Cq), 129.94 (CH), 131.90 (2 × CH), 136.50
(CH), 141.81 (Cq), 157.30 (CH), 159.97 (Cq), 160.46 (Cq), 161.71 (Cq), 169.51 (Cq); HRMS
(EIMS): m/z calcd for C18H13N3OS: 320.0858, found: 320.0854.
Acknowledgment
The authors would like to thank the College of Pharmacy at Prince Sattam Bin Abdulaziz University
for providing the necessary facilities to carry out this research work.
Disclosure statement
No potential conflict of interest was reported by the author.
References
[1] Peng Z, Hu G, Qiao H, et al. Palladium-catalyzed Suzuki cross-coupling of arylhydrazines via
C–N bond cleavage. J Org Chem. 2014;79:2733–2738.
[2] Duda ML, Michael FE. Palladium-catalyzed cross-coupling of N-Sulfonylaziridines with
boronic acids. J Am Chem Soc. 2013;135:18347–18349.
[3] Kalinin VN. Carbon-carbon bond formation in heterocycles using Ni- and Pd-catalyzed
reactions. Synthesis (Mass). 1992: 413–432.
[4] Schröter S, Stock C, Bach T. Regioselective cross-coupling reactions of multiple halogenated
nitrogen-, oxygen-, and sulfur-containing heterocycles. Tetrahedron. 2005;61:2245–2267.

JOURNAL OF SULFUR CHEMISTRY
9
[5] Theeramunkong S, Caldarelli A, Massarotti A, et al. Regioselective Suzuki coupling of dihalo-
heteroaromatic compounds as a rapid strategy to synthesize potent rigid combretastatin
analogues. J Med Chem. 2011;54:4977–4986.
[6] Parks EL, Sandford G, Christopher JA, et al. Perhalogenated pyrimidine scaffolds. Reactions of
5-chloro- 2,4,6-trifluoropyrimidine with nitrogen centred nucleophiles. Beilstein J. Org. Chem.
2008;4:22–28.
[7] Tumkevicius S, Dodonova J. Functionalization of pyrrolo[2,3-d]pyrimidine by palladium-
catalyzed cross-coupling reactions (review). Chem Heterocycl Comp. 2012;48:258–279.
[8] Skardziute L, Dodonova J, Voitechovicius A, et al. Synthesis and optical properties of the iso-
meric pyrimidine and carbazole derivatives: effects of polar substituents and linking topology.
Dyes Pigm. 2015;118:118–128.
[9] Reck F, Alm R, Brassil P, et al. Novel N-linked aminopiperidine inhibitors of bacterial topoiso-
merase type II: broad-spectrum antibacterial agents with reduced hERG activity. J Med Chem.
2011;54:7834–7847.
[10] Rajesh SM, Kumar RS, Libertsen LA, et al. A green expedient synthesis of pyridopyrimidine-2-
thiones and their antitubercular activity. Bioorg Med Chem Lett. 2011;21:3012–
3016.
[11] Ribble W, Hill WE, Ochsner UA, et al. Mechanisms of action: physiological effects discovery
and analysis of 4H-pyridopyrimidines, a class of selective bacterial protein synthesis inhibitors.
Antimicrob Agents Chemother. 2010;54:4648–4657.
[12] Rosowsky A, Mota CE, Queener SF. Synthesis and antifolate activity of 2,4-diamino-5,6,7,8-
tetrahydropyrido[4,3-d]pyrimidine analogues of trimetrexate and piritrexim. J Heterocyclic
Chem. 1995;32:335–340.
[13] Grivsky EM, Lee S, Sigel CW, et al. Synthesis and antitumor activity of 2,4-diamino-6-(2,5-
dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine. J Med Chem. 1980;23:327–329.
[14] Nofal ZM, Fahmy HH, Zarea ES, et al. Synthesis of new pyrimidine derivatives with evaluation
of their anti-inflammatory and analgesis activities. Acta Pol Pharm. 2011;68:507–517.
[15] Ghilsoo N, Cheol MY, Euikyung K, et al. Syntheses and evaluation of pyrido[2,3-d]pyrimidine-
2,4-diones as PDE 4 inhibitors. Bioorg Med Chem Lett. 2001;11:611–614.
[16] Singh G, Singh G, Yadav AK, et al. Synthesis and antimicrobial evaluation of some new
pyrido[2,3-d]pyrimidines and their ribofuranosides. Indian J Chem Sect B: Org Chem Incl
Med Chem. 2002;41:430–432.
[17] Liu KK, Huang X, Bagrodia S, et al. Quinazolines with intra-molecular hydrogen bond-
ing scaffold (iMHBS) as PI3 K/mTOR dual inhibitors. Bioorg Med Chem Lett. 2011;21:
1270–1274.
[18] El-Subbagh HI, Abu-Zaid SM, Mahran MA, et al. Synthesis and biological evaluation of certain
α,β-unsaturated ketones and their corresponding fused pyridines as antiviral and cytotoxic
agents. J Med Chem. 2000;43:2915–2921.
[19] Bennett LR, Blankley CJ, Fleming RW, et al. Antihypertensive activity of 6-arylpyrido[2,3-
d]pyrimidin-7-amine derivatives. J Med Chem. 1981;24:382–389.
[20] Agarwal A, Ramesh R, Ashutosh A, et al. Dihydropyrido[2,3-d]pyrimidines as a new class of
antileishmanial agents. Bioorg Med Chem. 2005;13:6678–6684.
[21] Mahmoud MR, El-Bordany EAA, Hassan NF, et al. Utility of nitriles in synthe-
sis of pyrido[2,3-d]pyrimidines, thiazolo[3,2-a]pyridines, pyrano[2,3-b]benzopyrrole, and
pyrido[2,3-d]benzopyrroles. Phosphorus Sulfur Silicon Relat. Elem. 2007;182:2507–2521.
[22] Bulicz J, Daniela CG, Bertarelli DCG, et al. Synthesis and pharmacology of pyrido[2,3-
d]pyrimidinediones bearing polar substituents as adenosine receptor antagonists. Bioorg. Med.
Chem. 2006;14:2837–2849.
[23] Monge A, Martinez-Merino V, Sanmartin C, et al. 2-Arylamino-4-oxo-3,4-dihydropyrido[2,3-
d]pyrimidines: synthesis and diuretic activity. Eur J Med Chem. 1989;24:209–216.
[24] El-Gazzar ABA, Gaffar AM, Youssef MM, et al. Synthesis and anti-oxidant activity of novel
pyrimido[4,5-b]quinolin-4-one derivatives with a new ring system. Phosphorus Sulfur Silicon
Relat Elem. 2007;182:2009–2037.

10
Y. RIADI
[25] Taylor EC, Palmer DC, George TJ, et al. Synthesis and biological activity of L-5-deazafolic
acid and L-deazaaminopterin: synthetic strategies to 5-deazapteridines. J Org Chem.
1983;48:4852–4860.
[26] Degraw JI, Christie PH, Colwell WT, et al. Synthesis and antifolate properties of 5,10-ethano-
5,10-dideazaaminopterin. J Med Chem. 1992;35:320–324.
[27] Saurat T, Buron F, Rodrigues N, et al. Design, synthesis, and biological activity of pyridopyrim-
idine scaffolds as novel PI3 K/mTOR dual inhibitors. J Med Chem. 2014;57:613–631.
[28] Font M, González Á, Palop JA, et al. New insights into the structural requirements for pro-
apoptotic agents based on 2,4-diaminoquinazoline, 2,4-diaminopyrido[2,3-d]pyrimidine and
2,4-diaminopyrimidine derivatives. Eur J Med Chem. 2011;46:3887–3899.
[29] Sako M. In Science of Synthesis. Vol. 16. Yamamoto Y, editor. Thieme: Stuttgart; 2004. p. 1155.
[30] Mitchell LJ, Lewis W, Moody CJ. Solar photochemistry: optimisation of the photo Friedel-
Crafts acylation of naphthoquinones. Green Chem. 2013:15:2830.
[31] Ravelli D, Fagnoni M, Albini A. Photoorganocatalysis what for? Chem Soc Rev. 2013;42:
97–113.
[32] Riadi Y, Massip S, Leger JM, et al. Convenient synthesis of 2,4-disubstituted pyrido[2,3-
d]pyrimidines via regioselective palladium-catalyzed reactions. Tetrahedron. 2012;68:
5018–5024.
[33] Riadi Y, Geesi M, Dehbi O, et al. Novel animal-bone-meal-supported palladium as a green and
efficient catalyst for Suzuki coupling reaction in water, under sunlight. Green Chem Lett Rev.
2017;10:101–106.
[34] Riadi Y, Geesi M. Photochemical route for the synthesis of novel 2-monosubstituted
pyrido[2,3-d]pyrimidines by palladium-catalyzed cross-coupling reactions. Chem Pap.
2018;72:697–701.
[35] Krömer M, Klečka M, Slavětínská L, et al. Chemoselective synthesis of 4,5-diarylpyrrolo[2,3-
d]pyrimidines (6,7-diaryl-7-deazapurines) by consecutive Suzuki and Liebeskind-Srogl cross-
couplings. Eur J Org Chem. 2014;32:7203–7210.
[36] Čerňová M, Pohl R, Klepetářová B, et al. A general regioselective synthesis of 2,4-
diarylpyrimidines from 2-Thiouracil through two orthogonal cross-coupling reactions. Syn-
lett. 2012;23:1305–1308.
[37] Liebeskind LS, Srogl J. Thiol ester−boronic acid coupling. A Mechanistically unprecedented
and general ketone synthesis. J. Am. Chem. Soc. 2000;122:11260–11261.
[38] Liebeskind LS, Srogl J. Heteroaromatic thioether−boronic acid cross-coupling under neutral
reaction conditions. Org. Lett. 2002;4:979–981.
[39] Egi M, Liebeskind LS. Heteroaromatic thioether−organostannane cross-coupling. Org. Lett.
2003;5:801–802.
[40] Maingot L, Dehbi O, Buron F, et al. Regioselective syntheses of 2,7-(Het)arylpyrido[2,3-
d]pyrimidines by an orthogonal cross-coupling. Strategy. 2012;23:2449–2452.
[41] El-Remaily MAA, El Hady OM, Abo Zaid HS, et al. Synthesis and in vitro antibacterial activity
of some novel fused pyridopyrimidine derivatives. J Heterocyclic Chem. 2016;53:1304–1309.
[42] Abdel-Mohsen SA, Geies AA. Synthesis of pyrido[2ꢀ,3ꢀ:4,5]thieno[2,3-d ]pyrimidines through
Friedländer reactions. J Chem Res. 2007;12:689–692.
[43] Yu Y, Liebeskind LS. Copper-mediated, palladium-catalyzed coupling of thiol esters with
aliphatic organoboron reagents. J Org Chem. 2004;69:3554–3557.
[44] Handy ST, Zhang Y. A simple guide for predicting regioselectivity in the coupling of polyhalo-
heteroaromatics. Chem Commun. 2006;299–301.