Traceless Solid-Phase Synthesis of Trisubstituted Quinazolines

Article abstract of DOI:10.1021/acscombsci.5b00060

(Chemical Equation Presented). A traceless polymer-supported synthesis of 4-benzoylquinazolines was developed using the following commercially available building blocks: Fmoc-α-amino acids, 2-nitrobenzensulfonyl chlorides and α-bromoacetophenones. The acy

Full text of DOI:10.1021/acscombsci.5b00060

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Article
Traceless Solid-Phase Synthesis of Trisubstituted Quinazolines
Veronika Fulopova, Lauren E. Cziesla, Megan Fleming, Yiwei Lu, Adrienne Voelker, and Viktor Krchnak
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.5b00060 • Publication Date (Web): 06 Jul 2015
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Traceless Solid-Phase Synthesis of Trisubstituted Quinazolines
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Veronika Fülöpová,a Lauren Cziesla,b Megan Fleming,b Yiwei Lu,b Adrienne Voelker,b and
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Viktor Krchňákab*
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aDepartment of Organic Chemistry, Institute of Molecular and Translational Medicine, Faculty
of Science, Palacky University, 17. listopadu 12, 771 46 Olomouc, Czech Republic
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bDepartment of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland
Science Center, Notre Dame, Indiana 46556, United States
*Corresponding author. Eꢀmail: vkrchnak@nd.edu.
TOC
Keywords: amino acids, αꢀbromoacetophenones, bromoketone, indazole oxides,
nitrobenzenesulfonyl chlorides, quinazolines, solidꢀphase synthesis, traceless synthesis
Abstract
A traceless polymerꢀsupported synthesis of 4ꢀbenzoylquinazolines was developed using the
following
commercially
available
building
blocks:
Fmocꢀα-amino
acids,
2ꢀ
nitrobenzensulfonylchlorides and αꢀbromoacetophenones. The acyclic intermediates
underwent baseꢀcatalyzed rearrangement involving CꢀC and NꢀN bond formation followed by
ring expansion and yielded resinꢀbound dihydroquinazolineꢀ2ꢀcarboxylic acids. After they
were released from the resin by treatment with trifluoroacetic acid, baseꢀmediated
decarboxylation produced the target quinazolines in moderateꢀtoꢀhigh yields and purities.
Introduction
Natural and synthetic quinazolines are a particularly important class of biologically active
nitrogenous heterocycles with known insecticidal,1 antibacterial,2 antiviral3 and anticancer4
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effects. Quinazoline derivatives are used in the agrochemical, veterinary and pharmaceutical
industries. Several commercial antitumor drugs, such as Iressa (Figure 1, structure I),
Tarceva (II) and Caprelsa (III), are potent tyrosine kinase inhibitors.5 Quinazolines
condensed with different heterocycles have been shown to act as antitumor DNA ligands that
target DNA topoisomerase.6 In this context, the development of novel synthetic routes to
access pharmacologically relevant quinazolines represents an attractive and practical task.
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Figure 1. Structures of quinazolines
Although numerous reports have described the preparation and properties of structurally
diverse quinazolines, only a few have addressed the synthesis and properties of 4ꢀketo
derivatives IV. Miyashita and coꢀworkers7 developed a method based on the reaction of 4ꢀ
chloroquinazoline with pꢀsubstituted benzaldehydes in tetrahydrofuran. The presence of a
catalytic amount of 1,3ꢀdimethylimidazolium iodide facilitated the formation of the resulting
quinazoline ketone IV. The second approach involves the introduction of aryl ketones to sp3
CꢀH groups of 4ꢀmethylquinazolines through the use of a Pd(0) catalyst with atmospheric
oxygen as the sole oxidant.8 Toh and colleagues9 reported a process involving the Cu(II)ꢀ
catalyzed preparation of the target quinazolines via intramolecular aerobic oxidation of
starting Nꢀalkynylamidines. We have recently reported a polymerꢀsupported synthesis of
quinazoline ketones from αꢀketosulfonamides via indazole oxide intermediates.10 Exposure of
αꢀketosulfonamides to 1,8ꢀdiazabicycloundecꢀ7ꢀene (DBU) led to Cꢀarylation followed by
spontaneous cyclization to the corresponding indazole oxide.11 In the present report, we
describe an efficient extension of the Cꢀarylation methodology for the traceless solidꢀphase
synthesis of derivatives of quinazoline IV with a substitution pattern not accessible by
previous syntheses. Traceless solidꢀphase synthesis is a particularly attractive methodology
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because it enables the synthesis of target compounds without any “trace” of the linker that
was used to immobilize the first building block while simultaneously taking advantage of the
very timeꢀefficient solidꢀphase synthesis method.12
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Results and Discussion
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The traceless solidꢀphase synthesis of 4ꢀbenzoylquinazolines was carried out according to
Scheme 1 using the following three commercially available building blocks: Fmocꢀprotected
α-amino acids, 2ꢀnitrobenzenesulfonyl chlorides (2ꢀNosꢀCl) and αꢀbromoacetophenones (for
the structures and numbering of the building blocks, refer to Figure 2). The first reaction step
involved the immobilization of Fmocꢀprotected αꢀamino acids on Wang resin 1 via an ester
bond. Removal of the Fmoc group provided the polymerꢀsupported amines, which underwent
sulfonylation with 2ꢀNos chlorides to yield resins 2. In the next step, the activating/protecting
2ꢀNos group allowed Fukuyama alkylation13 of the sulfonamide intermediates 2 with diversely
substituted αꢀbromoacetophenones, thereby yielding resins 3 (overall purity > 65%, as
indicated by LC traces at 205–400 nm). Alkylation of some derivatives was repeated to
achieve complete conversion (for details refer to Supporting Information).
Scheme 1. Synthetic route for the preparation of the target 4ꢀbenzoylquinazolinesa
aReagents: (i) Wang resin, Fmocꢀprotected αꢀamino acid, DMAP, DIC, dichloromethane
(DCM)/DMF (1:1), rt, overnight; (ii) 50% piperidine in DMF, rt, 15 min; (iii) 2ꢀNosꢀCl, 2,6ꢀ
lutidine, DCM, rt, overnight; (iv) αꢀbromoacetophenone, DIEA, DMF, rt, overnight; (v) DBU,
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DMF, rt, 30 min to overnight (see Supporting Information); (vi) 50% TFA in DCM, rt, 1 h; (vii)
neutralization with ammonium acetate, C18 cartridge, see Table 1 for decarboxylation time.
Figure 2. Fmocꢀprotected αꢀamino acids, 2ꢀNosꢀCl and αꢀbromoacetophenones used for the
synthesis
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Polymerꢀsupported acyclic alkylated sulfonamides 3 were treated with DBU to trigger baseꢀ
catalyzed tandem CꢀC bond formation followed by cyclization to indazole oxides via NꢀN
bond formation11 and conversion of the indazole oxides to quinazolines 4.10 Resinꢀbound
quinazolines were cleaved from the polymer support by a cleavage cocktail of 50% TFA in
DCM, yielding carboxylates 5 with acceptable purities (51 – 70%) for a 6ꢀstep synthesis
(Table 1). LC/MS analysis of crude preparations did not reveal any presence of the
decarboxylated compounds 6. Only a trace amount of decarboxylated product 6 was
detected by LC/MS analysis after HPLC purification in acetonitrile/aqueous 0.1% TFA and
freeze drying overnight.
To determine the decarboxylation reaction conditions, cleaved crude samples were purified
by reversedꢀphase HPLC in an aqueous ammonium acetate buffer/acetonitrile. Compounds
5 spontaneously decarboxylated in aqueous ammonium acetate/acetonitrile solution at
ambient temperature. The rate of decarboxylation, which was monitored by LC/MS, was
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dependent on the character of the substituents on the aromatic rings; it was typically done
after overnight exposure, it slowed, as expected, in the case of electronꢀwithdrawing
substituents (Table 1).
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Because the decarboxylation occurred under mild conditions (ambient temperature,
ammonium acetate buffer that can be removed by freeze drying) we did not search for
alternative reaction conditions and used the following protocol for the synthesis on
preparative scale (typically 250 mg of resin). Solution of crude sample was neutralized with
ammonium acetate, adsorbed onto octadecylꢀfunctionalized silica gel, eluted with 80%
acetonitrile in aqueous ammonium acetate buffer and left at ambient temperature to
decarboxylate (Table 1). The final products 6 were purified by semiꢀpreparative HPLC in
aqueous ammonium acetate/acetonitrile and isolated after freeze drying.
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To address the scope and limitations of this route for quinazolines, we prepared resinꢀbound
intermediates 3 using a set of αꢀamino acids, 2ꢀNos chlorides and αꢀbromoacetophenones
containing electronꢀwithdrawing and electronꢀdonating groups (Figure 2). The synthesis was
fully compatible with all of the tested building blocks, with the exception of 4ꢀmethoxyꢀ2ꢀ
nitrobenzenesulfonyl chloride, which contained the electronꢀdonating OCH3 group. The
purities of the final crude compounds ranged from 52% to 70%, and the total yields were
respectable given the 7ꢀstep synthesis (Table 1).
Table 1. Synthesized derivatives of quinazolines 6
Yieldc
[%]
Puritya
[%]
Decarb.
Timeb
Entry
R1
R2
H
H
H
H
H
R3
6{1,1,1}
6{1,1,2}
6{1,1,3}
6{1,1,5}
6{1,1,6}
CH3
CH3
CH3
CH3
CH3
Ph
52
53
70
66
61
1 d
2 d
1 d
1 d
1 d
12
56
16
47
39
4ꢀCH3ꢀC6H4
4ꢀCH3OꢀC6H4
4ꢀClꢀC6H4
4ꢀCNꢀC6H4
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6{1,3,1}
6{1,4,1}
6{2,1,1}
6{3,1,2}
6{4,1,1}
6{4,1,4}
6{5,1,1}
6{6,1,1}
CH3
CH3
CF3
NO2
H
Ph
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69
64
52
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63
51
59
4 d
5 d
1 d
1 d
1 d
5 d
1 d
1 d
41
8
Ph
CH2OH
Ph
4ꢀCH3ꢀC6H4
Ph
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35
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28
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38
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(CH2)4NH2
CH(CH3)2
CH(CH3)2
CH2Ph
H
H
H
4ꢀCF3ꢀC6H4
Ph
H
(CH2)2CO2H
H
Ph
aPurity of the crude product 5 after a 6ꢀstep synthesis. Decarboxylation time at ambient
b
temperature. cYield of HPLCꢀpurified compound 6 after a 7ꢀstep synthesis.
The LC/MS analysis of crude decarboxylated products revealed one common sideꢀproduct,
quinazoline 1ꢀoxide, typically present in a relatively small amount (below 10%). To confirm
the structure of the Nꢀoxide, we isolated and characterized the Nꢀoxides 7{1,1,1} and 7{1,4,1}
(Figure 3). In those two cases the yields of compounds 6{1,1,1} and 6{1,4,1} were
substantially lower compared to those of the other compounds and the Nꢀoxides were major
components of the crude preparation.
Figure 3. Formation of the Nꢀoxide sideꢀproducts 7
Conclusion
Traceless solidꢀphase synthesis of quinazolines using commercially available or easily
accessible building blocks, including Fmocꢀαꢀamino acids, 2ꢀnitrobenzenesulfonyl chlorides
and αꢀbromoacetophenones, represents a convenient route to an important class of
pharmacologically relevant nitrogenous heterocycles. The synthesis was compatible with a
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range of substituents on all of the building blocks, proceeded under mild reaction conditions,
included three positions of diversity and provided the target compounds in good overall yields
and crude purities.
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Experimental Section
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General: The solidꢀphase syntheses were performed in plastic reaction vessels (syringes,
each equipped with a porous disc) using a manually operated synthesizer.14 Commercially
available Wang resin (100ꢀ200 mesh, 1.0 mmol/g) was used. The volume of wash solvent
was 10 mL per 1 g of resin. For washing, the resin slurry was shaken with fresh solvent for at
least 1 min before the solvent was changed. The yields of the crude products were
calculated with respect to the loading of the first building block. Individual reaction steps for
the syntheses of resins 4 are described elsewhere.10
Cleavage, decarboxylation and isolation of quinazolines 6
Resin 4 (typically 100ꢀ250 mg) was treated with 50% TFA in DCM (1ꢀ3 mL) at rt for 90 min.
The TFA solution was collected, the resin was washed 3× with 50% TFA in DCM (3 mL), and
the combined extracts were evaporated by a stream of nitrogen. The oily residue 5 was
dissolved in 2 mL of MeCN and diluted with 18 mL of 10 mM aqueous ammonium acetate.
Depending on the type of compound, a solution or opalescent solution, occasionally with
precipitation, was formed. The pH of the solution was adjusted to approximately 8 using solid
ammonium acetate. A 10 mL SPE column was charged with 2 g of octadecylꢀfunctionalized
silica gel, and the plug was covered with a porous disc. The sorbent was wetted with 5 mL of
MeCN and washed with 5 mL of 10 mM aqueous ammonium acetate. The solution of the
target compound was passed through the column and washed with 5 mL of 10 mM aqueous
ammonium acetate. The target compound was eluted with 10 mL of 80% MeCN in aqueous
ammonium acetate. The solution was analyzed by LC/MS to determine the decarboxylation
progress. After decarboxylation was complete, typically overnight, the target compound was
purified by semiꢀpreparative reversedꢀphase HPLC. All products 6 were isolated as
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amorphous solids by freeze drying and were subsequently characterized by LC/MS, HRMS
and 1H and 13C NMR.
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Acknowledgement
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This research was supported by the Department of Chemistry and Biochemistry University of
Notre Dame, by the projects CZ.1.07/2.4.00/17.0015 from the European Social Fund .We
gratefully appreciate the use of the NMR facility at the University of Notre Dame.
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Supporting Information Available:
Details of experimental procedures, spectroscopic data for synthesized compounds, and
copies of NMR spectra. This material is available free of charge via the Internet at
http://pubs.acs.org.
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