Sequentially Pd-catalyzed processes[1 ] open the unique possibility of using an initially employed catalyst system for more than a single transformation in a one-pot fashion. Besides providing catalyst economy, the fine tuning of substrates additionally sets the stage for transition-metal-mediated syntheses of heterocyclic scaffolds, in the sense of multicomponent reactions[2 ] involving multiple catalytic steps. In recent years, we have established a sequential Pd-catalyzed process called the Masuda borylation–Suzuki coupling[3 ] for concise one-pot syntheses of unsymmetrically substituted biheteroaryl compounds (Scheme [1 ]). This sequence has been successfully applied to syntheses of natural products and biologically active compounds.[3` ]
[g ]
[h ]
,
[4 ] Particularly interesting are 7-azaindole derivatives, considered to be truncated hybrids of meridianins [2-amino-4-(indol-3-yl)pyrimidines and variolins], which have shown considerable potential as inhibitors of protein kinases.[5 ] We recently reported the application of the Masuda borylation–Suzuki coupling sequence for the synthesis of novel meriolin derivatives as potential inducers of rapid apoptosis in tumor cell lines.[3h ]
Scheme 1 One-pot Masuda borylation–Suzuki arylation synthesis of unsymmetrically biheteroaryls
On the basis of our experience in applying the Pd–Cu catalyst systems in sequentially catalyzed one-pot processes[6 ] and our general interest in transition-metal-mediated multicomponent synthesis of heterocycles,[2 ] we surmised that the Masuda–Suzuki sequence might be extended to a process involving three consecutive Pd-catalyzed steps. By employing 2,4-dichloropyrimidine as a suitable substrate for site-selective cross-coupling,[7 ] we assumed that after Masuda borylation and Suzuki arylation at the 4-position, a selective final Sonogashira alkynylation[8 ] at the 2-position might lead to novel derivatives of meriolins. We reasoned that concatenation of three catalytic processes – borylation, heteroarylation, and alkynylation – in a one-pot fashion without further Pd catalyst loading might provide a sequence that would be of practical use. Here, we report the development of a one-pot sequential Pd-catalyzed Masuda–Suzuki–Sonogashira sequence for the synthesis of meriolin derivatives, together with an experimental and computational study on the photophysical properties of selected derivatives.
Starting from the corresponding 7-azaindoles, by a one-pot two-step protocol involving iodination and tosylation, we prepared the two N -protected 3-iodo-7-azaindoles 1a and 1b in yields of 94 and 99%, respectively, as suitable substrates for our proposed sequence [for details, see the Supporting Information (SI)].[3h ] With N -tosyl-3-iodo-7-azaindole (1a ), pinacolylborane, and 2,4-dichloropyrimidine (2 ) the Masuda–Suzuki coupling of dihalide 2 to give the 2-chloropyrimidyl meriolin derivative 3a or 3b (protected or unprotected, respectively) in a selective manner was optimized by changing the base, temperature, and reaction time (Table [1 ]). Unlike our previous one-pot synthesis of apoptosis-inducing meriolins,[3h ] and due to the highly nucleophilic character of alcoholic carbonate solutions, the cosolvent for Suzuki coupling was changed to a mixture of 1,2-dimethoxyethane[9 ] and water.
Even with water as cosolvent, cesium carbonate still represented the preferred base compared with sodium carbonate (Table [1 ], entries 1 and 2). Interestingly, with a reaction time of 42 hours for the Suzuki coupling step, cleavage of the tosyl group proceeded in situ to furnish the deprotected 2-chloropyrimidyl meriolin 3b . Upon lowering the reaction temperature for the Suzuki coupling step to 80 °C, the tosyl group remained attached, permitting isolation of the N -tosylated product 3a in high yield (entries 3–6). A slight increase in the amount of pinacolylborane in the Masuda step led to an excellent yield of the N -tosyl-2-chloropyrimidyl meriolin 3a (entry 7). The selective formation of a single isomer was evident from the presence of a single set of signals in the NMR spectra, in agreement with the Pd-catalyzed 4-alkynylation of compound 2 .[10 ] Furthermore, the connectivity of the 2-chloropyrimidyl-substituted derivative 3a was unambiguously supported by 2D-ROESY-NMR spectroscopy (for details, see the SI).
The selective Masuda–Suzuki formation of the 2-chloropyrimidyl-substituted derivative 3a set the stage for concatenation of a concluding alkynylation. In a consecutive one-pot fashion, starting from N -tosyl 3-iodo-7-azaindoles 1 , pinacolylborane, and 2,4-dichloropyrimidine (2 ), and upon addition of an alkyne 4 and a catalytic amount of copper iodide, the corresponding 2-alkynyl-4-(7-azaindol-3-yl)pyrimidines 5 were isolated after single flash chromatography in moderate to good yields (Scheme [2 ]).Whereas copper iodide and the appropriate alkyne were added at this stage, no additional triethylamine or palladium catalyst needed to be added to the reaction mixture. Interestingly, a loading of 3.0 mol% of tetrakis(triphenylphosphine)palladium(0) proved to be sufficient to catalyze all three reaction steps in this novel Masuda–Suzuki–Sonogashira sequence. The structures of the products 5 were unambiguously supported by NMR spectroscopy, mass spectrometry, and the elemental composition as determined by combustion analysis.
Table 1 Optimization of the Masuda–Suzuki Synthesis of 2-Chloropyrimidyl Meriolin Derivatives 3
Entry
Base (equiv)
Temp (°C)
Time (h)
Product
Yield (%)
1
Na2 CO3 (2.5)
100
42
3b
30
2
Cs2 CO3 (2.5)
100
42
3b
65
3
Cs2 CO3 (2.5)
80
42
3a
82
4
Cs2 CO3 (2.5)
80
16
3a
70
5
Cs2 CO3 (2.5)
60
20
3a
70
6
Cs2 CO3 (2.5)
80
20
3a
86
7a
Cs2 CO3 (2.5)
80
18
3a
94
a HBpin (1.7 equiv) was used in the Masuda borylation step.
Scheme 2 Consecutive three-component Masuda borylation–Suzuki arylation–Sonogashira alkynylation synthesis of 2-alkynyl-4-(7-azaindol-3-yl)pyrimidines 5
The isolated yields of the title compounds 5 ranged from 24 to 83%, which equates to an average yield per bond-forming step in this consecutive three-component process of 62–94%. A variety of alkynes 4 , ranging from electron-deficient to electron-rich aromatic or aliphatic alkynes, as well as alkynes containing unprotected alcohol (5h ) or TIPS groups (5l and 5n ), were well tolerated, highlighting the breadth of diversity of potential reactants. With 3-iodo-4-methoxy-7-azaindole (1b ) as a substrate, targets substituted in the azaindole moiety were synthesized uneventfully (e.g., 5n ).
All the 2-alkynyl-4-(7-azaindol-3-yl) pyrimidines 5 produced intense blue-to-green emissions on excitation with UV light (λexc = 365 nm). We therefore recorded the absorption and emission spectra of 12 compounds (Table [2 ]). Almost all compounds 5 displayed similar absorption behaviors with intense maxima between 293 and 296 nm; the molar decadic absorption coefficients ε were in the range 23100–43900 L mol–1 cm–1 for aliphatic substituents and 48000–77000 L mol–1 cm–1 for aromatic substituents. Notably, the two strong donor-substituted derivatives 5e and 5g possessed red-shifted absorption maxima at 306 and 366 nm, respectively. Interestingly, the emission maxima were almost identical irrespective of the nature of the substituent R2 , with exception of p -(dimethylamino)phenyl- (5g ), cyclohexyl- (5i ), and propyl-substituted derivatives (5j ). All other compounds fluoresced with emission maxima at about 447 nm. The Stokes shifts were remarkably high and amounted to 10300 to 11900 cm–1 , with exception of compound 5g (8300 cm–1 ).
Table 2 Summary of the UV/Vis-Absorption- and Emission-Specific Properties of the Alkyne-Substituted Meriolin Derivatives 6 in Dichloromethane at 293 K
Compound
R2
Absorption λmax,abs. (nm) (ε) (L·mol–1 ·cm–1 )a
Emission λmax,em (nm)b
Stokes shift Δν̃ (cm–1 )c
5a
Ph
295 (48900)
447
11600
5b
indol-1-ylmethyl
293 (27800)
447
11800
5c
cyclopropyl
293 (23100)
447
11700
5d
4-Tol
295 (48400)
447
11600
5e
4-MeOC6 H4
306 (49900)
447
10300
5f
2,4-Me2 C6 H3
294 (63200)
447
11600
5g
4-Me2 NC6 H4
366 (61700)
525
8300
5h
4-HO(CH2 )4
296 (26000)
448
11500
5i
Cy
296 (32800)
430
10600
5j
Pr
296 (24800)
429
10500
5l
TIPS
298 (43900)
447
11200
5m
4-FC6 H4
293 (76700)
447
11900
a [5 ] = 10–5 m .
b [5 ] = 10–7 m , λexc = λmax,abs .
c Δν̃ = 1/λmax,abs – 1/λmax,em (cm–1 ).
The normalized absorption and emission spectra of the conjugated p -phenyl-substituted derivatives 5a , 5d , 5e , and 5e are almost superimposable (for details, see Figure S1, SI ), indicating they have quite similar electronic structures. However, for the p -(dimethylamino)phenyl-substituted derivative 5g in particular, in comparison to the phenyl- (5a ), cyclohexyl- (5i ), and propyl-substituted (5j ) derivatives, the significant redshifts in the absorption (366 nm) and emission (525 nm) maximum can be ascribed to a change in the dominant underlying chromophore (Figure [1 ]). Compound 5g consists of a strongly polarizable donor–acceptor chromophore with the p -(dimethylamino)phenyl moiety as an electron donor and the pyrimidyl unit as an acceptor. This chromophore axis is significantly different from the transition dipole orientation of the other derivatives, which are presumably oriented along the 7-azaindole–pyrimidine axis.
Figure 1 Normalized absorption (solid lines; [5 ] = 10–5 m ) and emission (dashed lines; [5 ] = 10–7 m ) spectra of selected derivatives 5 in dichloromethane at 293 K (λexc = λmax,abs )
To achieve a qualitative understanding of the electronic structure of the absorption spectrum of compounds 5 , time-dependent density-functional theory (TDDFT) calculations for compounds 5a (R2 = Ph) and 5g (R2 = p -Me2 NC6 H4 ) were performed with the PBE functional and the 6-31G** basis set as implemented in Gaussian 09 .[11 ] The calculated longest wavelength absorption bands are best represented by vertical Franck–Condon transitions, as represented by the Kohn–Sham frontier molecular orbitals (FMOs) HOMO and LUMO (Figure [2 ]), and these are in reasonably good agreement with the experimentally determined absorption bands (5a : calcd 287 nm; experimental 295 nm; 5g : calcd 365 nm; experimental 366 nm).
Figure 2 TDDFT-computed Kohn–Sham FMOs of dyes 5a and 5g , representing contributions of the TDDFT-computed longest wavelength Franck–Condon absorption band [PBEh1PBE/6-31G(d,p), PCM CH2 Cl2 , isosurface value at 0.04 a.u.]
However, the character of these transitions is substantially different. Whereas for compound 5a (R2 = Ph), coefficient densities of both the HOMO and LUMO are mainly localized on the 2-(phenylethynyl)pyrimidin-4-yl part, the strong donor part of compound 5g (R2 = p -Me2 NC6 H4 ) creates a dominant push–pull chromophore in which the HOMO and LUMO coefficient densities are spatially separated from each other and overlap only on the central pyrimidyl core. Whereas the HOMO coefficient density is mostly localized on the [p -(dimethylamino)phenyl]ethynyl part, the LUMO coefficient density is localized in the 3-pyrimid-4-yl-7-azaindole moiety. This spatial separation accounts for a significant charge-transfer character of the longest wavelength absorption band of structure 5g . In the experimental spectrum, the strong bathochromic shift is accompanied by a strong absorption coefficient ε (62000 L mol–1 cm–1 ).
In conclusion, a novel sequentially Pd-catalyzed Masuda–Suzuki–Sonogashira synthesis of 2-alkynyl-4-(7-azaindol-3-yl)pyrimidines (i.e., alkynyl meriolin derivatives) was developed in the form of a consecutive three-component reaction.[12 ] This novel process not only concatenates three catalytic reactions – borylation, arylation, and alkynylation – efficiently and efficaciously in a single vessel without further addition of the initial palladium catalyst source, but also provides easy access to interesting novel fluorophores. The broad variety of the alkynes used underlines the fact that variable functionalities can be introduced. Whereas strong donor substituents furnish significantly red-shifted fluorophores with excitations near the visible region, silyl alkynyl moieties permit tagging for further functionalization. The combination of the 7-azaindole substructure with functional alkynyl sidechains with substantial fluorescence suggests that this concise synthetic concept might be useful for protein-target-fishing strategies and for confocal microscopy in biophysical analytics. Expansion of the methodological scope of this novel one-pot process and its application to the development of new functional materials and probes is currently underway.
