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DOI: 10.1055/s-0041-1738433
Palladium-Catalyzed C7–H (Hetero)arylation of Pyrazolo[1,5-a]pyrazines with Heteroarenes and Aryl Iodides with the Assistance of Silver Salts
L.P. and A.L. are grateful to Erasmus and Grand Est (Alsace region) for financial support during their internship stay at AstraZeneca (AZ).
Abstract
Pyrazolo[1,5-a]pyrazines coupled with heteroarenes and aryl iodides selectively at the C7 position to afford a broad library of bi(hetero)aryl structures under ligand-free palladium-catalyzed conditions. The key to the success of the reaction is the use of silver salts as the oxidant or the base, allowing the regioselective C–H bond functionalization to occur under relatively mild conditions.
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Key words
C–H bond functionalization - fused-ring systems - heteroarenes - homogeneous catalysis - synthetic methodsPyrazolo[1,5-a]pyrazines are an emerging class of 5,6-fused bicyclic heterocycles that shows huge potential in medicinal chemistry.[1] In addition, they could be employed as the direct precursor for 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazines, also important medicinal chemistry building blocks.[2] Examples of bioactive compounds bearing these two scaffolds are depicted in Figure [1], including potent tyrosine kinase 2 (TYK2) inhibitors,[1a] phosphatidylinositol 3-kinase (PI3K) inhibitors,[1b] survival motor neuron 2 (SMN2) modifiers,[1c] and ataxia telangiectasia and Rad-3 related protein (ATR) inhibitors.[2b] Synthetically, pyrazolo[1,5-a]pyrazines can be constructed from either pyrazine or pyrazole fragments using different cyclization strategies, with substituents introduced to the molecules early in the synthetic sequences.[1] [2a] [3] On the other hand, further diversification of the cores using C–H bond functionalization is still not available, even though it would be promising for the expedient exploration of the new chemical space.
The direct C–H (hetero)arylation of heteroarenes is a powerful strategy for the construction of bi(hetero)aryl motifs and has enormous applications in the synthesis of drugs, natural products, and materials.[4] Since the introduction of halides, metals (B, Sn, Si, Zn) and/or directing groups into the starting heteroarenes is avoided, the number of steps and the amount of waste in synthetic sequences are significantly reduced. Regarding the (hetero)arylating reagents, (hetero)aryl halides are the most commonly used. Under certain oxidative conditions, simple heteroarenes can be employed as (hetero)arylating reagents, leading to even more atom-economic synthetic methods.[5] The use of 5,6-fused heterocycles in this type of reactions has also been extensively reviewed and we envisioned that expanding the strategy toward the C–H (hetero)arylation of pyrazolo[1,5-a]pyrazine should be of great interest.[6]
While the direct C–H (hetero)arylation of pyrazolo[1,5-a]azines (azines = pyridines or pyrimidines) has been studied by several groups, there remained a few disadvantages such as very high temperatures, long reaction times, and unfavored solvents.[7] Furthermore, their substrate scope is relatively limited with regards to both pyrazolo[1,5-a]azines and the (hetero)arylating reagents, as only six-membered (hetero)aryl moieties were utilized. More recently, we reported the oxidative C–H/C–H cross-coupling strategy for the introduction of five-membered heteroaryls into the C7 position, thus complemented the scope of previous literature methods.[8] In addition, it is notable that our reactions occurred under significantly milder conditions, i.e. 90–110 °C, DMSO as the solvent and short reaction time (3–6 h).
Inspired by these findings, we were curious whether the mild, direct C–H bond functionalization conditions could provide a convenient and unified way to introduce both five- and six-membered (hetero)aryl substituents to the C7 position of pyrazolo[1,5-a]pyrazines, which would potentially open an unexplored chemical space. During the course of this work, a library of novel bi(hetero)aryl structures containing the pyrazolo[1,5-a]pyrazine core was successfully synthesized. Further transformations of these coupling products are also briefly discussed.
In the presence of Pd(OAc)2 as the catalyst and AgOAc as the oxidant, ethyl pyrazolo[1,5-a]pyrazine-3-carboxylate (1a) reacted with 2-methylthiophene (2a) at 90 °C overnight to afford the desired product 3aa in 71% isolated yield (Scheme [1]).
While the reaction could complete at a shorter reaction time (6 h), other modifications to the conditions, such as introducing additives or changing oxidants, were tested but none improved the result further (see Section 2 of the Supporting Information).
Encouraged by the efficiency of the oxidative C–H/C–H cross-coupling conditions, the scope of heteroarenes was examined in the reactions with 1a (Scheme [1]A). In general, thiophenes (2b–f) and benzothiophene 2g were good coupling partners, providing the desired products 3ab–ag in 47–70% yield and tolerating alcohol (3ac), ether (3ad), and amide (3ae) groups. In addition, the coupling reaction was selective at the most electron-rich site in 2f and the pyridine moiety was kept intact.
Moreover, the conditions also allowed the successful isolation and characterization of the products derived from benzofuran (3ah), thiazole (3ai), indole (3aj), and imidazo[1,2-a]pyridine (3ak), albeit in low to moderate yields. The poor isolated yield of 3ah could be explained by the low selectivity of cross-coupling (formation of 3ah) versus homocoupling (of 1a). In contrast, benzothiazole, imidazole, indazole, and oxazole, failed to provide the desired products in isolable amounts.
The scope for pyrazolo[1,5-a]pyrazines was next examined, using 2a as the coupling partner (Scheme [1]B). Different useful functional groups were tolerated at the C3 position, including amide (3ba), ketone (3ca), trifluoromethyl (3da), and bromide (3ea,fa), even though the isolated yields (45–63%) were slightly lower compared to 3aa. It is also notable that the presence of a methyl group at C6 did not hinder 1f to react with 2a, despite an obvious steric hindrance.
In the absence of C3 substituents (1g), the desired products 3ga was obtained in 47% yield, with a small amount of dithiophenylated product was observed in the crude reaction mixture (C3-thiophenylation was suspected). In addition, the conditions were found to tolerate the presence of methoxy group at the C4 position, delivering 3ha in 54% yield.
Next, we aimed to develop conditions for introducing six-membered aryl substituents to the C7 position of 1a (Table [1]). Aryl iodides were chosen as the coupling partners and the optimization process was initiated by the reaction of 1a with 4-iodoanisole (4a) in the presence of AgOAc as the base (entry 1). Even though full conversion can be observed, the major product was the homodimer of 1a (judged by the observed mass but not isolated and fully characterized) while the desired cross-coupling product 5aa was formed in small amount. When Cs2CO3 was used as the base, virtually no conversion could be detected (entry 2). Gratifyingly, the use of Ag2CO3 led to full conversion of 1a and delivered the desired product 5aa in 58% yield (entry 3).
a Reaction conditions: 1a (0.2 mmol), 4a (0.4 mmol), Pd(OAc)2 (0.01 mmol), base (0.4 mmol), solvent (1 mL).
b Ratio of LCMS areas.
c Isolated yields; n.d. = not determined.
d 4-Bromoanisole instead of 4a.
e The reaction was carried out at 80 °C.
f The reaction was carried out for 6 h.
g 1.5 equiv of 4a and 1.5 equiv of Ag2CO3 were used.
h 1.2 equiv of 4a and 1.2 equiv of Ag2CO3 were used.
Next, a solvent screening was carried out (entries 4–8). While the reactions in p-xylene and 1,4-dioxane did not proceed to full conversion, it is encouraged that the formation of the homodimer of 1a was considerably suppressed (entries 4 and 5). Better conversion and cleaner reaction mixtures were obtained when either ethanol or isopropyl alcohol was used as the solvent (entries 6 and 7). tert-Butyl alcohol proved to be the best solvent as full conversion and minimalization of homocoupling was attained, with the isolated yield of 76% (entry 8). Compared to previous reports on the C–H arylation of pyrazolo[1,5-a]pyridines, the current reaction conditions were superior in terms of reaction time, temperature, and the use of sustainable solvent.[4d] The presence of the electron-withdrawing nitrogen on the pyrazine ring (N5) might attribute to the increase in reactivity.
Under identical conditions, 4-bromoanisole failed to couple with 1a, emphasizing the requirement of aryl iodide coupling partners (entry 9). Several minor modifications to the optimal conditions were also investigated (entries 10–13). While the reaction proceeded sluggishly at 80 °C (entry 10) or at a shorter reaction time (entry 11), high conversion was maintained when the amounts of 4a and Ag2CO3 were lowered to 1.5 equiv (entry 12) or even 1.2 equiv (entry 13). Nevertheless, the conditions in entry 8 were chosen to explore the substrate scope (Scheme [2]).
A variety of para-substituted phenyl iodides, bearing electron-donating (4a,b) or electron-withdrawing groups (4c–e), reacted with 1a under the optimal C–H arylation conditions and delivered the desired products 5aa–ae in moderate to good yields (Scheme [2]A). Similar reactivity was observed when meta-substituted substrates (4f,g) were used. With ortho-substituted substrates (4h), a lower yield was obtained even when a higher amount of catalyst was used. The drop in reactivity might be attributed to the inherent steric hindrance. It should also be noted that the reaction conditions tolerated a number of functional groups, including trifluoromethoxy (5ab), bromide (5ac), trifluoromethyl (5ad), ester (5ae), and chloride (5ag). In addition to substituted phenyl iodides, six-membered nitrogen-containing heteroaryl iodides (4i,j) could also be employed as the coupling partners, albeit with a lower reactivity.
In addition to 1a, the conditions were successfully applied to the C–H arylation of pyrazolo[1,5-a]pyrazines 1b,c, 1e, and 1h, to provide the desired products in moderate to good yields (Scheme [2]B). On the other hand, 1f and 1g did not react well with 4a and little or no products could be isolated. Nevertheless, it should be noted that the diversity in functional groups and substituent patterns in the starting materials were unprecedented in previous reports on the C–H arylation of pyrazolo[1,5-a]azines.
When treated with an excess amount of NaBH4 in THF/TFA (10:1 v/v), 3aa, 5aa, and 5ag smoothly underwent selective reduction of the pyrazine ring to provide the corresponding heterocycles 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazines 6a–c in excellent yields (Scheme [3]A). Thus, the combination of C–H (hetero)arylation and selective reduction led to the formal C7–H (hetero)arylation of 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazines, which is, so far, an unknown transformation.
H/D exchange control experiments were performed in order to investigate the role of silver salts in the C–H arylation reactions (Scheme [3]B). The results showed that both Cs2CO3 and Ag2CO3 could facilitate H/D exchange of 1a at the C7 position.[9] Therefore, Ag2CO3 was not crucial for cleaving the C–H bond, and the 1a-[C7]Ag complex might not be an intermediate in the catalytic cycle (although there is not enough evidence to exclude the possibility).[10] Nevertheless, the fact that Ag2CO3 was more effective than Cs2CO3 in the cross-coupling of 1a and 4a (Table [1]) suggested that the silver cation should play a special role. The silver cation might scavenge the iodide ligand from the palladium center thus (re)generating the efficient C–H bond activation catalyst, i.e. Pd(OAc)I to Pd(OAc)2, as suggested by Larrosa, Maiti, or Adimurthy.[11] Based on these pioneer reports, a plausible mechanism is depicted in Scheme [3]C.
In conclusion, two reaction conditions were established for the palladium-catalyzed C7–H (hetero)arylation of pyrazolo[1,5-a]pyrazines. In the oxidative C–H/C–H cross-coupling reactions, thiophenes appeared to be the most reactive coupling partners, while a few other heteroarenes, such as benzothiophenes, benzofurans, thiazoles, indoles, and imidazo[1,2-a]pyridine, were acceptable coupling partners. On the other hand, the cross-coupling of pyrazolo[1,5-a]pyrazines with aryl iodides utilized tert-butyl alcohol as a sustainable solvent. Pyrazolo[1,5-a]pyrazines with diverse substitution patterns could be employed in both cases, and a broad library of over 30 novel bi(hetero)aryl structures was synthesized. The cross-coupling products could be selectively reduced to the corresponding 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazines in high yields.
1D and 2D NMR spectra were recorded on Bruker 500 MHz or 600 MHz spectrometers. HRMS was recorded on Waters LCT mass spectrometer with ESI+ ionization mode. Column chromatography was performed on Biotage Selekt using Biotage Sfär HC D columns (normal phase) or Biotage Sfär C18 D columns (reversed phase). Reversed phase preparative HPLC was performed on a Gilson GX-281 chromatography system. Commercially available starting materials and catalysts were purchased and used as received. The synthesis of some starting materials is described in the Supporting Information.
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Oxidative Cross-Coupling of Pyrazolo[1,5-a]pyrazines 1 with Heteroarenes 2; General Procedure
A 20-mL screw-capped vial was charged with 1 (0.2 mmol), 2 (0.4 mmol), DMSO (1 mL), Pd(OAc)2 (4.5 mg, 0.02 mmol), and AgOAc (100 mg, 0.6 mmol). The vial was closed and stirred in a pre-heated aluminum block at 90 °C for 20 h. After cooling, the reaction mixture was diluted with EtOAc (5 mL) and filtered through a filter frit and a Whatman syringe filter (0.45 μm). Solvents were removed in vacuo and the crude material was purified by column chromatography or reversed phase preparative HPLC.
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Ethyl 7-(5-Methylthiophen-2-yl)pyrazolo[1,5-a]pyrazine-3-carboxylate (3aa)
Yellow solid; yield: 41 mg (71%).
1H NMR (500 MHz, DMSO-d 6): δ = 9.31 (s, 1 H), 8.79 (s, 1 H), 8.70 (s, 1 H), 8.18 (d, J = 3.8 Hz, 1 H), 7.04 (dt, J = 3.7, 1.1 Hz, 1 H), 4.36 (q, J = 7.1 Hz, 2 H), 2.56 (d, J = 1.0 Hz, 3 H), 1.37 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, DMSO-d 6): δ = 161.89, 145.94, 144.03, 140.42, 134.85, 130.37, 128.77, 128.39, 126.73, 126.37, 105.06, 60.43, 14.95, 14.32.
HRMS: m/z [M + H]+ calcd for C14H14N3O2S: 288.0807; found: 288.0806.
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Ethyl 7-(5-Butylthiophen-2-yl)pyrazolo[1,5-a]pyrazine-3-carboxylate (3ab)
Yellow solid; yield: 37.6 mg (57%).
1H NMR (500 MHz, DMSO-d 6): δ = 9.36 (s, 1 H), 8.85 (s, 1 H), 8.76 (s, 1 H), 8.23 (d, J = 3.8 Hz, 1 H), 7.10 (dt, J = 3.8, 0.9 Hz, 1 H), 4.39 (q, J = 7.1 Hz, 2 H), 2.92 (t, J = 7.6 Hz, 2 H), 1.69 (p, J = 7.5 Hz, 2 H), 1.39 (td, J = 7.3, 3.1 Hz, 5 H), 0.93 (t, J = 7.4 Hz, 3 H).
13C NMR (126 MHz, DMSO-d 6): δ = 161.85, 151.55, 144.03, 140.41, 134.84, 130.18, 128.77, 128.43, 126.49, 125.30, 105.01, 60.38, 33.20, 28.98, 21.63, 14.30, 13.65.
HRMS: m/z [M + H]+ calcd for C17H20N3O2S: 330.1276; found: 330.1274.
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Ethyl 7-(5-(2-Hydroxyethyl)thiophen-2-yl)pyrazolo[1,5-a]pyrazine-3-carboxylate (3ac)
Yellow solid; yield: 29.5 mg (47%).
1H NMR (500 MHz, DMSO-d 6): δ = 9.36 (s, 1 H), 8.84 (s, 1 H), 8.76 (s, 1 H), 8.22 (d, J = 3.9 Hz, 1 H), 7.12 (d, J = 3.9 Hz, 1 H), 4.91 (t, J = 5.2 Hz, 1 H), 4.38 (q, J = 7.1 Hz, 2 H), 3.70 (td, J = 6.4, 5.1 Hz, 2 H), 3.05 (t, J = 6.4 Hz, 2 H), 1.38 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, DMSO-d 6): δ = 161.86, 148.58, 144.05, 140.42, 134.86, 129.94, 128.86, 128.44, 127.03, 126.02, 105.02, 61.57, 60.39, 33.28, 14.30.
HRMS: m/z [M + H]+ calcd for C15H16N3O3S: 318.0912; found: 318.0914.
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Ethyl 7-(5-Methoxythiophen-2-yl)pyrazolo[1,5-a]pyrazine-3-carboxylate (3ad)
Orange oil; yield: 28.4 mg (47%).
1H NMR (500 MHz, DMSO-d 6): δ = 9.25 (s, 1 H), 8.77 (s, 1 H), 8.70 (s, 1 H), 8.12 (d, J = 4.3 Hz, 1 H), 6.60 (d, J = 4.4 Hz, 1 H), 4.36 (d, J = 7.1 Hz, 2 H), 3.99 (s, 3 H), 1.37 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, DMSO-d 6): δ = 171.11, 161.89, 144.00, 139.25, 134.75, 129.42, 129.08, 127.63, 114.49, 105.37, 104.77, 60.48, 60.38, 14.32.
HRMS: m/z [M + H]+ calcd for C14H14N3O3S: 304.0756; found: 304.0732.
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Ethyl 7-(5-(Dimethylcarbamoyl)thiophen-2-yl)pyrazolo[1,5-a]pyrazine-3-carboxylate (3ae)
Yellow solid; yield: 49 mg (70%).
1H NMR (600 MHz, CDCl3): δ = 9.53 (s, 1 H), 8.57 (s, 1 H), 8.56 (s, 1 H), 8.12 (d, J = 4.0 Hz, 1 H), 7.46 (d, J = 4.1 Hz, 1 H), 4.45 (q, J = 7.1 Hz, 2 H), 3.23 (s, 6 H), 1.45 (t, J = 7.1 Hz, 3 H).
13C NMR (151 MHz, CDCl3): δ = 163.73, 162.44, 144.26, 142.97, 141.73, 135.43, 132.83, 129.34, 129.15, 128.92, 128.46, 106.48, 60.87, 14.46. (CH3 peaks were hardly observed.)
HRMS: m/z [M + H]+ calcd for C16H17N4O3S: 345.1021; found: 345.1027.
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Ethyl 7-(5-(Pyridin-3-yl)thiophen-2-yl)pyrazolo[1,5-a]pyrazine-3-carboxylate (3af)
Off-white solid; yield: 44.3 mg (63%).
1H NMR (500 MHz, DMSO-d 6): δ = 9.38 (s, 1 H), 9.02 (dd, J = 2.5, 0.9 Hz, 1 H), 8.99 (s, 1 H), 8.78 (s, 1 H), 8.57 (dd, J = 4.8, 1.5 Hz, 1 H), 8.43 (d, J = 4.1 Hz, 1 H), 8.18 (ddd, J = 8.0, 2.5, 1.6 Hz, 1 H), 7.87 (d, J = 4.1 Hz, 1 H), 7.50 (ddd, J = 8.0, 4.8, 0.9 Hz, 1 H), 4.38 (q, J = 7.1 Hz, 2 H), 1.39 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, DMSO-d 6): δ = 161.88, 149.33, 146.44, 144.69, 144.12, 141.30, 134.86, 133.11, 131.15, 129.43, 129.16, 129.14, 128.32, 125.46, 124.31, 105.43, 60.52, 14.34.
HRMS: m/z [M + H]+ calcd for C18H15N4O2S: 351.0916; found: 351.0919.
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Ethyl 7-(3-Methylbenzo[b]thiophen-2-yl)pyrazolo[1,5-a]pyrazine-3-carboxylate (3ag)
Yellow solid; yield: 32 mg (48%).
1H NMR (500 MHz, CDCl3): δ = 9.65 (s, 1 H), 8.53 (s, 1 H), 8.21 (s, 1 H), 7.79–7.95 (m, 2 H), 7.42–7.51 (m, 2 H), 4.47 (q, J = 7.1 Hz, 2 H), 2.46 (s, 3 H), 1.46 (t, J = 7.2 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 162.56, 144.78, 144.70, 140.57, 139.69, 135.77, 135.45, 133.51, 128.96, 126.14, 124.75, 124.12, 123.09, 122.57, 106.92, 60.98, 14.62, 13.85.
HRMS: m/z [M + H]+ calcd for C18H16N3O2S: 338.0963; found: 338.0980.
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Ethyl 7-(3-Methylbenzofuran-2-yl)pyrazolo[1,5-a]pyrazine-3-carboxylate (3ah)
Light yellow solid; yield: 9 mg (14%).
1H NMR (500 MHz, DMSO-d 6): δ = 9.58 (s, 1 H), 8.70 (s, 1 H), 8.51 (s, 1 H), 7.78–7.84 (m, 1 H), 7.69 (dt, J = 8.3, 0.9 Hz, 1 H), 7.48 (ddd, J = 8.4, 7.2, 1.3 Hz, 1 H), 7.39 (ddd, J = 8.0, 7.2, 1.0 Hz, 1 H), 4.40 (q, J = 7.1 Hz, 2 H), 2.39 (s, 3 H), 1.39 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, DMSO-d 6): δ = 162.22, 154.85, 145.09, 144.83, 141.08, 135.67, 133.53, 129.43, 126.91, 125.10, 123.70, 121.14, 120.13, 111.95, 106.33, 60.95, 14.76, 9.62.
HRMS: m/z [M + H]+ calcd for C18H16N3O3: 322.1191; found: 322.1179.
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Ethyl 7-(5-(2-Hydroxyethyl)-4-methylthiazol-2-yl)pyrazolo[1,5-a]pyrazine-3-carboxylate (3ai)
Yellow solid; yield: 29 mg (44%).
1H NMR (500 MHz, DMSO-d 6): δ = 9.49 (s, 1 H), 9.03 (s, 1 H), 8.82 (s, 1 H), 5.02 (s, 1 H), 4.39 (q, J = 7.1 Hz, 2 H), 3.65–3.68 (m, 2 H), 3.02 (t, J = 6.2 Hz, 2 H), 2.45 (s, 3 H), 1.38 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, DMSO-d 6): δ = 162.26, 150.46, 149.54, 144.62, 143.08, 136.28, 135.13, 129.40, 127.56, 106.27, 61.42, 61.02, 30.07, 15.36, 14.74.
HRMS: m/z [M + H]+ calcd for C15H17N4O3S: 333.1021; found: 333.1029.
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Ethyl 7-(1,2-Dimethyl-1H-indol-3-yl)pyrazolo[1,5-a]pyrazine-3-carboxylate (3aj)
Pink solid; yield: 30 mg (45%).
1H NMR (500 MHz, CDCl3): δ = 9.58 (s, 1 H), 8.49 (s, 1 H), 8.15 (s, 1 H), 7.33–7.39 (m, 2 H), 7.23–7.30 (m, 1 H), 7.13–7.16 (m, 1 H), 4.46 (q, J = 7.1 Hz, 2 H), 3.81 (s, 3 H), 2.45 (s, 3 H), 1.46 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 162.83, 144.58, 142.48, 138.33, 137.16, 136.01, 132.53, 130.90, 126.65, 122.17, 120.84, 119.38, 109.62, 106.23, 102.19, 60.78, 30.16, 14.65, 12.52.
HRMS: m/z [M + H]+ calcd for C19H19N4O2: 335.1508; found: 335.1496.
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Ethyl 7-(Imidazo[1,2-a]pyridin-3-yl)pyrazolo[1,5-a]pyrazine-3-carboxylate (3ak)
Yellow solid; yield: 21 mg (34%).
1H NMR (500 MHz, CDCl3): δ = 9.68 (s, 1 H), 8.53 (s, 1 H), 8.34 (s, 1 H), 8.17 (s, 1 H), 7.88 (dt, J = 6.9, 1.2 Hz, 1 H), 7.82 (dt, J = 9.2, 1.2 Hz, 1 H), 7.40 (ddd, J = 9.1, 6.8, 1.3 Hz, 1 H), 6.94 (td, J = 6.9, 1.2 Hz, 1 H), 4.48 (q, J = 7.1 Hz, 2 H), 1.47 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 162.45, 148.19, 144.87, 144.66, 137.61, 135.63, 132.08, 126.84, 126.42, 124.81, 118.61, 114.90, 113.30, 107.09, 61.09, 14.61.
HRMS: m/z [M + H]+ calcd for C16H14N5O2: 308.1147; found: 308.1154.
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N,N-Dimethyl-7-(5-methylthiophen-2-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide (3ba)
Yellow solid; yield: 32 mg (56%).
1H NMR (500 MHz, DMSO-d 6): δ = 9.25 (s, 1 H), 8.69 (s, 1 H), 8.62 (s, 1 H), 8.14–8.19 (m, 1 H), 7.04 (dq, J = 3.8, 1.0 Hz, 1 H), 3.16 (br, 6 H), 2.56 (d, J = 1.0 Hz, 3 H).
13C NMR (126 MHz, DMSO-d 6): δ = 162.81, 145.31, 141.60, 141.53, 135.54, 129.92, 128.19, 127.50, 127.10, 126.31, 108.68, 14.99. (CH3 peaks were hardly observed.)
HRMS: m/z [M + H]+ calcd for C14H15N4OS: 287.0966; found: 287.0960.
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1-(7-(5-Methylthiophen-2-yl)pyrazolo[1,5-a]pyrazin-3-yl)ethan-1-one (3ca)
Yellow solid; yield: 24.1 mg (47%).
1H NMR (500 MHz, DMSO-d 6): δ = 9.44 (s, 1 H), 8.96 (s, 1 H), 8.87 (s, 1 H), 8.23 (d, J = 3.8 Hz, 1 H), 7.07 (dq, J = 3.9, 1.2 Hz, 1 H), 2.62 (s, 3 H), 2.58 (d, J = 1.0 Hz, 3 H).
13C NMR (126 MHz, DMSO-d 6): δ = 191.98, 146.03, 144.91, 140.78, 134.09, 130.43, 129.09, 128.70, 126.79, 126.40, 113.95, 28.25, 14.96.
HRMS: m/z [M + H]+ calcd for C13H12N3OS: 258.0701; found: 258.0695.
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7-(5-Methylthiophen-2-yl)-3-(trifluoromethyl)pyrazolo[1,5-a]pyrazine (3da)
Yellow solid; yield: 30.7 mg (54%).
1H NMR (500 MHz, DMSO-d 6): δ = 9.21 (s, 1 H), 8.85 (s, 1 H), 8.84 (s, 1 H), 8.22 (d, J = 3.8 Hz, 1 H), 7.07 (dq, J = 3.7, 1.0 Hz, 1 H), 2.58 (d, J = 1.0 Hz, 3 H).
13C NMR (126 MHz, DMSO-d 6): δ = 145.93, 140.36 (q, J = 3.1 Hz), 138.83, 132.86 (d, J = 2.8 Hz), 130.44, 128.60, 128.11, 126.62, 126.40, 122.94 (q, J = 266.1 Hz), 102.32 (q, J = 38.9 Hz), 14.94.
19F NMR (470 MHz, DMSO-d 6): δ = –53.58.
HRMS: m/z [M + H]+ calcd for C12H9F3N3S: 284.0469; found: 284.0443.
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3-Bromo-7-(5-methylthiophen-2-yl)-2-(trifluoromethyl)pyrazolo[1,5-a]pyrazine (3ea)
Yellow solid; yield: 32.8 mg (45%).
1H NMR (500 MHz, DMSO-d 6): δ = 9.17 (s, 1 H), 8.84 (s, 1 H), 8.18 (d, J = 3.8 Hz, 1 H), 7.07–7.08 (m, 1 H), 2.59 (d, J = 1.1 Hz, 3 H).
13C NMR (126 MHz, DMSO-d 6): δ = 145.83, 140.68, 139.70 (q, J = 36.7 Hz), 135.17, 130.45, 129.09, 128.23, 126.48, 126.03, 120.78 (q, J = 270.4 Hz), 84.63, 14.97.
19F NMR (470 MHz, DMSO-d 6): δ = –60.19.
HRMS: m/z [M + H]+ calcd for C12H8BrF3N3S: 361.9574; found: 361.9561.
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Ethyl 3-Bromo-6-methyl-7-(5-methylthiophen-2-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate (3fa)
Orange solid; yield: 48.2 mg (63%).
1H NMR (500 MHz, DMSO-d 6): δ = 9.12 (s, 1 H), 7.39 (d, J = 3.5 Hz, 1 H), 7.02 (dt, J = 3.6, 1.1 Hz, 1 H), 4.38 (q, J = 7.1 Hz, 2 H), 2.58 (d, J = 1.1 Hz, 3 H), 2.55 (s, 3 H), 1.33 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, DMSO-d 6): δ = 160.46, 143.99, 142.26, 140.44, 140.21, 133.98, 132.35, 125.81, 125.64, 124.97, 88.90, 61.33, 21.71, 14.96, 14.10.
HRMS: m/z [M + H]+ calcd for C15H15BrN3O2S: 380.0068; found: 380.0078.
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Ethyl 7-(5-Methylthiophen-2-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate (3ga)
Orange solid; yield: 27 mg (47%).
1H NMR (500 MHz, DMSO-d 6): δ = 9.19 (s, 1 H), 8.64 (s, 1 H), 8.18 (d, J = 3.8 Hz, 1 H), 7.55 (s, 1 H), 7.05 (dq, J = 3.8, 1.1 Hz, 1 H), 4.42 (q, J = 7.1 Hz, 2 H), 2.58 (d, J = 1.1 Hz, 3 H), 1.37 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, DMSO-d 6): δ = 161.83, 145.35, 144.58, 143.25, 136.89, 130.35, 128.48, 128.38, 127.54, 126.80, 102.93, 61.63, 15.45, 14.66.
HRMS: m/z [M + H]+ calcd for C14H14N3O2S: 288.0807; found: 288.0801.
#
Methyl 4-Methoxy-7-(5-methylthiophen-2-yl)pyrazolo[1,5-a]pyrazine-3-carboxylate (3ha)
Yellow solid; yield: 32 mg (54%).
1H NMR (500 MHz, DMSO-d 6): δ = 8.59 (s, 1 H), 8.16 (s, 1 H), 7.85 (d, J = 3.7 Hz, 1 H), 6.93–6.96 (m, 1 H), 4.06 (s, 3 H), 3.83 (s, 3 H), 2.52 (d, J = 1.1 Hz, 3 H).
13C NMR (126 MHz, DMSO-d 6): δ = 161.54, 154.52, 144.02, 143.03, 128.20, 127.57, 126.18, 125.87, 125.30, 124.34, 106.80, 54.43, 51.93, 14.95.
HRMS: m/z [M + H]+ calcd for C14H14N3O3S: 304.0756; found: 304.0750.
#
C–H Arylation of Pyrazolo[1,5-a]pyrazines 1 with Aryl Iodides 4; General Procedure
A 20-mL Biotage microwave tube was charged with 1 (0.2 mmol), 4 (0.4 mmol), t-BuOH (1 mL), Pd(OAc)2 (2.2 mg, 0.01 mmol), and Ag2CO3 (110 mg, 0.4 mmol). The vial was sealed and stirred in a pre-heated aluminum block at 100 °C for 24 h. After cooling, the reaction mixture was diluted with EtOAc (5 mL) and filtered through a filter frit and a Whatman syringe filter (0.45 μm). Solvents were removed in vacuo and the crude material was purified by column chromatography.
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Ethyl 7-(4-Methoxyphenyl)pyrazolo[1,5-a]pyrazine-3-carboxylate (5aa)
Off-white solid; yield: 45 mg (76%).
1H NMR (500 MHz, DMSO-d 6): δ = 9.44 (s, 1 H), 8.64 (s, 1 H), 8.33 (s, 1 H), 7.97–8.04 (m, 2 H), 7.12–7.19 (m, 2 H), 4.38 (q, J = 7.1 Hz, 2 H), 3.86 (s, 3 H), 1.38 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, DMSO-d 6): δ = 161.90, 160.89, 144.15, 142.18, 135.24, 133.75, 131.18, 130.54, 121.31, 114.04, 105.06, 60.35, 55.45, 14.32.
HRMS: m/z [M + H]+ calcd for C16H16N3O3: 298.1191; found: 298.1186.
#
Ethyl 7-(4-(Trifluoromethoxy)phenyl)pyrazolo[1,5-a]pyrazine-3-carboxylate (5ab)
Off-white solid; yield: 54.7 mg (78%).
1H NMR (500 MHz, DMSO-d 6): δ = 9.51 (s, 1 H), 8.65 (s, 1 H), 8.40 (s, 1 H), 8.14 (m, 2 H), 7.61 (dq, J = 7.9, 1.0 Hz, 2 H), 4.39 (q, J = 7.1 Hz, 2 H), 1.38 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, DMSO-d 6): δ = 161.83, 149.53, 144.18, 143.49, 135.14, 132.58, 131.92, 131.27, 128.52, 121.06, 120.05 (q, J = 257.1 Hz), 105.46, 60.43, 14.30.
19F NMR (471 MHz, DMSO-d 6): δ = –56.67.
HRMS: m/z [M + H]+ calcd for C16H13F3N3O3: 352.0909; found: 352.0891.
#
Ethyl 7-(4-Bromophenyl)pyrazolo[1,5-a]pyrazine-3-carboxylate (5ac)
White solid; yield: 33 mg (48%).
1H NMR (500 MHz, DMSO-d 6): δ = 9.51 (s, 1 H), 8.66 (s, 1 H), 8.39 (s, 1 H), 7.95–8.02 (m, 2 H), 7.79–7.85 (m, 2 H), 4.39 (q, J = 7.1 Hz, 2 H), 1.38 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, DMSO-d 6): δ = 161.84, 144.20, 143.38, 135.18, 132.86, 131.64, 131.60, 131.12, 128.50, 124.02, 105.43, 60.42, 14.31.
HRMS: m/z [M + H]+ calcd for C15H13BrN3O2: 346.0191; found: 346.0170.
#
Ethyl 7-(4-(Trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrazine-3-carboxylate (5ad)
White solid; yield: 45 mg (67%).
1H NMR (500 MHz, DMSO-d 6): δ = 9.53 (s, 1 H), 8.66 (s, 1 H), 8.44 (s, 1 H), 8.23 (m, 2 H), 7.98 (d, J = 8.3 Hz, 2 H), 4.39 (q, J = 7.1 Hz, 2 H), 1.38 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, DMSO-d 6): δ = 161.80, 144.21, 143.96, 135.13, 133.38, 132.47, 131.56, 130.57, 130.38 (q, J = 32 Hz), 125.43 (q, J = 3.8 Hz), 123.98 (q, J = 272 Hz), 105.60, 60.46, 14.30.
19F NMR (471 MHz, DMSO-d 6): δ = –56.67.
HRMS: m/z [M + H]+ calcd for C16H13F3N3O2: 336.0960; found: 336.0954.
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Ethyl 7-(4-(tert-Butoxycarbonyl)phenyl)pyrazolo[1,5-a]pyrazine-3-carboxylate (5ae)
Yellow gum; yield: 49 mg (67%).
1H NMR (500 MHz, CDCl3): δ = 9.62 (s, 1 H), 8.49 (s, 1 H), 8.15–8.21 (m, 3 H), 7.99 (d, J = 8.5 Hz, 2 H), 4.45 (t, J = 7.1 Hz, 2 H), 1.62 (s, 9 H), 1.46 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 165.03, 162.58, 144.66, 135.80, 133.96, 133.85, 133.38, 131.28, 129.91, 129.40, 106.68, 81.77, 60.95, 28.33, 14.60.
HRMS: m/z [M + H]+ calcd for C20H22N3O4: 368.1610; found: 368.1617.
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Ethyl 7-(3-Methoxyphenyl)pyrazolo[1,5-a]pyrazine-3-carboxylate (5af)
White solid; yield: 45.7 mg (77%).
1H NMR (500 MHz, DMSO-d 6): δ = 9.48 (s, 1 H), 8.64 (s, 1 H), 8.37 (s, 1 H), 7.56 (m, 2 H), 7.51 (t, J = 7.9 Hz, 1 H), 7.17 (m, 1 H), 4.38 (m, 2 H), 3.84 (s, 3 H), 1.38 (td, J = 7.1, 0.8 Hz, 3 H).
13C NMR (126 MHz, DMSO-d 6): δ = 161.86, 159.13, 144.18, 143.09, 135.19, 133.67, 131.14, 130.47, 129.71, 121.83, 115.97, 115.22, 105.27, 60.38, 55.37, 14.31.
HRMS: m/z [M + H]+ calcd for C16H16N3O3: 298.1191; found: 298.1197.
#
Ethyl 7-(3-Chlorophenyl)pyrazolo[1,5-a]pyrazine-3-carboxylate (5ag)
White solid; yield: 43.4 mg (72%).
1H NMR (500 MHz, DMSO-d 6): δ = 9.51 (s, 1 H), 8.67 (s, 1 H), 8.41 (s, 1 H), 8.12 (t, J = 1.9 Hz, 1 H), 7.96 (dt, J = 7.5, 1.4 Hz, 1 H), 7.68 (ddd, J = 8.1, 2.2, 1.3 Hz, 1 H), 7.64 (t, J = 7.8 Hz, 1 H), 4.39 (q, J = 7.1 Hz, 2 H), 1.38 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, DMSO-d 6): δ = 161.83, 144.22, 143.62, 135.14, 133.14, 132.41, 131.37, 131.28, 130.50, 130.32, 129.32, 128.33, 105.47, 60.43, 14.31.
HRMS: m/z [M + H]+ calcd for C15H13ClN3O2: 302.0696; found: 302.0716.
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Ethyl 7-(2-Methoxyphenyl)pyrazolo[1,5-a]pyrazine-3-carboxylate (5ah)
Colorless oil; yield: 22.7 mg (38%).
1H NMR (500 MHz, DMSO-d 6): δ = 9.51 (s, 1 H), 8.56 (s, 1 H), 8.19 (s, 1 H), 7.59 (ddd, J = 8.4, 7.5, 1.7 Hz, 1 H), 7.52 (dd, J = 7.5, 1.7 Hz, 1 H), 7.24 (dd, J = 8.5, 1.0 Hz, 1 H), 7.14 (td, J = 7.5, 1.0 Hz, 1 H), 4.38 (q, J = 7.1 Hz, 2 H), 3.70 (s, 3 H), 1.38 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, DMSO-d 6): δ = 161.88, 157.64, 143.98, 143.25, 134.69, 132.27, 132.09, 131.85, 131.28, 120.46, 118.53, 111.74, 105.09, 60.33, 55.67, 14.33.
HRMS: m/z [M + H]+ calcd for C16H16N3O3: 298.1191; found: 298.1176.
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Ethyl 7-(Pyrimidin-5-yl)pyrazolo[1,5-a]pyrazine-3-carboxylate (5ai)
Light yellow solid; yield: 14.5 mg (27%).
1H NMR (500 MHz, DMSO-d 6): δ = 9.55 (s, 1 H), 9.44 (s, 2 H), 9.38 (s, 1 H), 8.69 (s, 1 H), 8.57 (s, 1 H), 4.39 (q, J = 7.1 Hz, 2 H), 1.39 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, DMSO-d 6): δ = 161.69, 159.18, 157.19, 144.43, 144.22, 134.93, 131.54, 128.73, 124.25, 105.81, 60.47, 14.26.
HRMS: m/z [M + H]+ calcd for C13H12N5O2: 270.0991; found: 270.0963.
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Ethyl 7-(6-Methylpyridin-3-yl)pyrazolo[1,5-a]pyrazine-3-carboxylate (5aj)
Off-white solid; yield: 17.5 mg (31%).
1H NMR (500 MHz, DMSO-d 6): δ = 9.51 (s, 1 H), 9.02 (m, 1 H), 8.66 (s, 1 H), 8.43 (s, 1 H), 8.34 (dd, J = 8.1, 2.4 Hz, 1 H), 7.50 (d, J = 8.2 Hz, 1 H), 4.39 (q, J = 7.1 Hz, 2 H), 2.59 (s, 3 H), 1.38 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, DMSO-d 6): δ = 161.80, 160.03, 149.03, 144.18, 143.43, 137.37, 135.11, 131.53, 131.00, 122.77, 122.69, 105.46, 60.40, 24.12, 14.29.
HRMS: m/z [M + H]+ calcd for C15H15N4O2: 283.1195; found: 283.1172.
#
7-(4-Methoxyphenyl)-N,N-dimethylpyrazolo[1,5-a]pyrazine-3-carboxamide (5ba)
White solid; yield: 31.0 mg (52%).
1H NMR (500 MHz, DMSO-d 6): δ = 9.33 (s, 1 H), 8.52 (s, 1 H), 8.20 (s, 1 H), 7.99–8.02 (m, 2 H), 7.13–7.16 (m, 2 H), 3.86 (s, 3 H), 3.16 (br, 6 H).
13C NMR (126 MHz, DMSO-d 6): δ = 162.85, 160.74, 143.11, 141.64, 135.82, 133.13, 131.02, 129.55, 121.67, 114.02, 108.65, 55.44. (CH3 peaks were hardly observed.)
HRMS: m/z [M + H]+ calcd for C16H17N4O2: 297.1351; found: 297.1354.
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1-(7-(4-Methoxyphenyl)pyrazolo[1,5-a]pyrazin-3-yl)ethan-1-one (5ca)
Pale yellow solid; yield: 18.7 mg (35%).
1H NMR (500 MHz, DMSO-d 6): δ = 9.54 (s, 1 H), 8.86 (s, 1 H), 8.36 (s, 1 H), 8.01 (m, 2 H), 7.16 (m, 2 H), 3.87 (s, 3 H), 2.61 (s, 3 H).
13C NMR (126 MHz, DMSO-d 6): δ = 191.95, 160.90, 145.01, 142.54, 134.46, 133.68, 131.25, 131.21, 121.36, 114.07, 114.00, 55.45, 28.25.
HRMS: m/z [M + H]+ calcd for C15H14N3O2: 268.1086; found: 268.1073.
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3-Bromo-7-(4-methoxyphenyl)-2-(trifluoromethyl)pyrazolo[1,5-a]pyrazine (5ea)
White solid; yield: 22 mg (29%).
1H NMR (500 MHz, DMSO-d 6): δ = 9.24 (d, J = 0.8 Hz, 1 H), 8.34 (d, J = 0.8 Hz, 1 H), 7.95 (m, 2 H), 7.18 (m, 2 H), 3.86 (d, J = 0.6 Hz, 3 H).
13C NMR (126 MHz, DMSO-d 6): δ = 161.06, 142.40, 139.81 (q, J = 36.6 Hz), 135.40, 133.21, 131.15, 131.01, 120.83 (q, J = 270.5 Hz), 120.47, 114.19, 84.42, 55.45.
19F NMR (471 MHz, DMSO-d 6): δ = –60.13.
HRMS: m/z [M + H]+ calcd for C14H10BrF3N3O: 371.9959; found: 371.9951.
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Methyl 4-Methoxy-7-(4-methoxyphenyl)pyrazolo[1,5-a]pyrazine-3-carboxylate (5ha)
Light yellow solid; yield: 41 mg (66%).
1H NMR (500 MHz, CDCl3): δ = 8.39 (s, 1 H), 7.72 (d, J = 8.8 Hz, 2 H), 7.55 (s, 1 H), 7.06 (d, J = 8.8 Hz, 2 H), 4.19 (s, 3 H), 3.93 (s, 3 H), 3.88 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 162.44, 160.78, 155.86, 144.61, 130.91, 129.81, 127.43, 126.99, 122.54, 114.29, 107.29, 55.57, 54.61, 51.99.
HRMS: m/z [M + H]+ calcd for C16H16N3O4: 314.1141; found: 314.1145.
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Selective Reduction of Coupling Products for the Synthesis of 4,5,6,7-Tetrahydropyrazolo[1,5-a]pyrazines 6; General Procedure
A 20-mL screw-capped vial was charged with 3 or 5 (0.15–0.17 mmol) and a mixture of THF (2 mL) and TFA (0.2 mL). The resulting solution was treated with NaBH4 (5 equiv) and stirred at r.t. for 4 h. The reaction was diluted with DCM (5 mL) and washed with sat. NaHCO3 solution (2 mL) then brine (2 mL). The organic phase was evaporated to provide a crude product which was further purified on a SCX-2 column to afford the pure amines.
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Ethyl 7-(5-Methylthiophen-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (6a)
Colorless oil; yield: 41.8 mg (96%).
1H NMR (500 MHz, CDCl3): δ = 7.91 (s, 1 H), 6.70 (m, 1 H), 6.62 (dt, J = 3.5, 1.1 Hz, 1 H), 5.52 (t, J = 4.3 Hz, 1 H), 4.47 (d, J = 17.9 Hz, 1 H), 4.33 (d, J = 18.0 Hz, 1 H), 4.28 (q, J = 7.2 Hz, 2 H), 3.54 (dd, J = 13.6, 4.3 Hz, 1 H), 3.41 (ddd, J = 13.7, 4.3, 0.7 Hz, 1 H), 2.43 (d, J = 1.1 Hz, 3 H), 2.01 (br. s, 1 H), 1.34 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 163.48, 141.74, 141.28, 140.71, 138.76, 126.23, 125.09, 109.91, 60.20, 57.17, 50.47, 43.38, 15.47, 14.57.
HRMS: m/z [M + H]+ calcd for C14H18N3O2S: 292.1120; found: 292.1128.
#
Ethyl 7-(4-Methoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (6b)
White solid; yield: 44 mg (83%).
1H NMR (500 MHz, CDCl3): δ = 7.91 (s, 1 H), 6.84–6.93 (m, 4 H), 5.32 (t, J = 4.6 Hz, 1 H), 4.46 (d, J = 18.0 Hz, 1 H), 4.36 (d, J = 18.1 Hz, 1 H), 4.30 (q, J = 7.1 Hz, 2 H), 3.78 (s, 3 H), 3.52 (dd, J = 13.7, 4.5 Hz, 1 H), 3.25 (dd, J = 13.6, 4.8 Hz, 1 H), 1.73 (br. s, 1 H), 1.36 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 163.63, 159.57, 142.98, 141.27, 131.19, 127.71, 114.45, 109.60, 60.74, 60.17, 55.48, 51.20, 43.63, 14.60.
HRMS: m/z [M + H]+ calcd for C16H20N3O3: 302.1505; found: 302.1480.
#
Ethyl 7-(3-Chlorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate (6c)
Colorless oil; yield: 39.5 mg (87%).
1H NMR (500 MHz, CDCl3): δ = 7.93 (s, 1 H), 7.27–7.31 (m, 2 H), 6.94 (dt, J = 1.7, 1.1 Hz, 1 H), 6.81–6.89 (m, 1 H), 5.34 (t, J = 4.4 Hz, 1 H), 4.48 (d, J = 18.0 Hz, 1 H), 4.34 (d, J = 18.3 Hz, 1 H), 4.28–4.34 (m, 2 H), 3.56 (dd, J = 13.7, 4.6 Hz, 1 H), 3.24–3.31 (m, 1 H), 1.58 (br. s, 1 H), 1.37 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 163.51, 143.09, 141.51, 141.38, 135.06, 130.30, 128.53, 126.76, 124.77, 109.82, 60.64, 60.26, 50.93, 43.59, 14.59.
HRMS: m/z [M + H]+ calcd for C15H17ClN3O2: 306.1009; found: 306.1005.
#
#
Conflict of Interest
The authors declare no conflict of interest.
Acknowledgment
The authors thank Dr. Richard Lewis (AZ) for 2D NMR discussion and Dr. Cristina Gardelli (AZ) for her support.
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0041-1738433.
- Supporting Information
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Several reviews on C–H arylation, see:
Formation of (hetero)arene-Ag complex was generally proposed when silver salt was indispensable for C–H bond cleavage (experimentally confirmed when Ag salt was crucial for H/D exchange), for example, see:
Silver cation could act as iodide scavenger to remove iodide from palladium, see:
Corresponding Authors
Publication History
Received: 13 December 2022
Accepted after revision: 30 January 2023
Article published online:
06 March 2023
© 2023. Thieme. All rights reserved
Georg Thieme Verlag KG
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Several reviews on C–H arylation, see:
Formation of (hetero)arene-Ag complex was generally proposed when silver salt was indispensable for C–H bond cleavage (experimentally confirmed when Ag salt was crucial for H/D exchange), for example, see:
Silver cation could act as iodide scavenger to remove iodide from palladium, see:
