Abstract
Described herein is a palladium(II)-catalyzed direct arylation of cyclic enaminones with arylboronic acids. The versatility of this method is that both electron-rich and electron-poor boronic acids can be coupled in high yields. A mixture of two Cu(II) additives was crucial for efficient cross-coupling. The role of each Cu(II) reagent appears to be distinct and complementary serving to assist catalyst reoxidation and transmetallation through a putative arylcopper intermediate.
Introduction
The direct conversion of C–H to C–C bonds via transition metal catalysis has streamlined the syntheses of many useful molecules.1,2 Palladium-catalysis has proven to be remarkably versatile in this respect and has added a host of valuable tools to the organic chemist's toolbox.2 In the course of our studies towards the synthesis and functionalization of the cyclic enaminones (2,3-dihydropyridin-4(1H)-ones),3,4 we discovered that these multifunctional scaffolds could serve as viable C–H donors in Pd(II)-catalyzed direct arylation3a,b and olefination3a,c reactions. Key to the success of these reactions was that the enaminone substrates were sufficiently nucleophilic to undergo electrophilic palladation. Moreover, relative to many nonaromatic enamine/enamide systems,5,6 6-membered cyclic enaminones are considerably more stable, making them ideal substrates for these reactions which require elevated temperatures and an acidic reaction medium. Furthermore, cyclic enaminones have great potential in various synthetic transformations, considering the multiple functional groups including alkene, enamine and enone that are embedded within this substrate.7 The synthetic utility of cyclic enaminones is particularly attractive when considering the ubiquity of piperidine-containing molecules. Our lab has taken interest in indolizidine and quinolizidine alkaloids,8 many of which are known to have important biological activities. In our efforts toward the synthesis of these natural products, cyclic enaminones have served as invaluable synthetic intermediates, expediting the synthesis of several members of this class including boehmeriasin A4a, ipalbidine4b and tylocrebrine.4c
To date, we have demonstrated that cyclic enaminones undergo direct arylation with aryltrifluoroborates3a and arylsilanes.3b Although these methods provide a short and convenient route to arylated enaminones, several shortcomings limit their utility and inspired us to expand the scope and efficiency of this reaction. In this regard, we have developed a new arylation protocol that accommodates boronic acids, which are more readily available than either aryltrifluoroborates or arylsilanes. Furthermore, the yield and conversion of each reaction are seemingly independent of the electronic substitutent effects on the aryl donor—a significant improvement over previous reports which exhibited a significant preference for electron-rich arenes.3a We believe that the success of this reaction can be attributed to a unique mixture of Cu(II) additives, assisting transmetallation to the palladated enaminone through an intermediate arylcopper species. Herein we report the discovery of this copper-assisted Pd(II)-catalyzed C–H arylation reaction.
Copper(I) halide additives have been shown to improve Stille9, Suzuki10 and are used in Sonogashira11 reactions. It has been postulated that Cu(I) transmetallates with organometals to generate a more reactive organocopper intermediate which assists the delivery of the aryl group to the palladium center.12 This was recently exemplified by Deng et al. showing that 2-pyridyl boronates, which are notoriously poor coupling partners, undergo high-yielding Suzuki reactions in the presence of copper but not without (Scheme 1, eq 1).12 It is also well known that arylboronic acids undergo facile transmetallation to arylcopper species in the presence of copper(II) salts (Scheme 1, eq 2).13 In our previously developed method,3a the limited scope of coupling partners implicated either the transmetallation step or the preceding hydrolysis of the trifluoroborates to their respective boronic acids as the primary cause of poor conversions.14 Thus, we hypothesized that conditions which were amenable to an in situ formation of an arylcopper species could remedy this substrate bias by increasing the efficiency of the transmetallation (Scheme 1, eq 3).
SCHEME 1.
Copper Mediated Reactions with Organoborons
Results and Discussion
We undertook an intensive screening process (Table 1) using enaminone 1 and p-methoxyphenylboronic acid (2a) as model substrates. Since the reaction conditions require an oxidant to regenerate the Pd(II) catalyst, we hypothesized that our copper source could serve a dual role as an oxidant and to assist transmetallation. As such, Pd(OAc)2 (10 mol%) and Cu(OAc)2 (2 equiv) were initially chosen based on previously optimized conditions for enaminone coupling reactions.3 Amide solvents (DMF, NMP and DMA) were superior to other solvents, however, the yields were quite low. It is worth noting that the use of a cosolvent to promote the oxidation of Pd(0)15 or increase the electrophilicity of the Pd(II) center16 did not improve yields (entries 10 and 11). We next screened various oxidants, finding no improvement in yield over Cu(OAc)2. We noted that in most reactions the majority of enaminone 1 remained unreacted and the major product was 4,4′-dimethoxy-1,1′-biphenyl, suggesting that the low yields resulted from consumption of the boronic acid and the reoxidant through a competing homodimerization pathway.
TABLE 1.
Screening of Solvents and Oxidantsa
| |||
|---|---|---|---|
| entry | solvent | reoxidant | 3a (%) |
| 1 | t-BuOH | Cu(OAc)2 | 6 |
| 2 | t-AmOH | Cu(OAc)2 | < 3 |
| 3 | toluene | Cu(OAc)2 | < 3 |
| 4 | DMSO | Cu(OAc)2 | 11 |
| 5 | AcOH | Cu(OAc)2 | 4 |
| 6 | DMF | Cu(OAc)2 | 18 |
| 7 | DMA | Cu(OAc)2 | 18 |
| 8 | NMP | Cu(OAc)2 | 14 |
| 9 | dioxane | Cu(OAc)2 | < 3 |
| 10 | DMF/DMSO = 20/1 | Cu(OAc)2 | 9 |
| 11 | DMF/AcOH = 4/1 | Cu(OAc)2 | < 3 |
| 12 | DMF/AcOH/DMSO = 20/5/1 | Cu(OAc)2 | 15 |
| 13 | DMF/H2O = 9/1 | Cu(OAc)2 | 15 |
| 14 | MeCN | Cu(OAc)2 | 9 |
| 15 | DMF | Cu(OTf)2 | 11 |
| 16 | DMF | duroquinone | < 3 |
| 17 | DMF | PhCO3t-Bub | < 3 |
| 18 | DMF | Ag2O | < 3 |
| 19 | DMF | AgOAc | 15 |
| 20 | DMF | O2c | 0 |
| 21 | DMSO | O2c | 0 |
| 22 | DMF | Cu(OAc)2b + Ag2Ob | 16 |
| 23 | DMF | Cu(OAc)2b + air | 8 |
| 24 | DMF | Cu(OAc)2b + O2c | 8 |
| 25 | DMF | CuCl2 | 18 |
| 26 | DMF | CuCl2b + O2c | 15 |
Reaction conditions unless otherwise specified: 1 (0.2 M), 2a (2 equiv), Pd(OAc)2 (10 mol%), reoxidant (2 equiv) under N2 at 60 °C for 20 h, the yield was determined by 1H NMR analysis of the crude product using Ph3SiMe (1 equiv) as the internal standard. (PMP = p-methoxyphenyl)
1 equiv.
ballon pressure.
Next we turned to screening various additives to improve our low reaction yields (Table 2). We were pleased to find that many organic and inorganic additives improved yields. Most notably, the addition of potassium salts (entries 3 and 9), acetate salts (entries 8–10) or chloride salts (entries 16–24) seemed to have beneficial effects. The advantageous effects of CuCl2 (entry 24) led us to examine alternative sources of copper and optimal quantities of these additives (entries 24–29). As seen in entries 26 and 27, the highest yields (81%) were obtained when using at least two equivalents of CuCl2. Interestingly, CuCl only moderately improved yields and CuI completely suppressed product formation. We also investigated the time that it takes to complete the reaction (see SI and Table 3) and found that reaction for 1 h at 60 °C provided the same yield of 3a (81%) as obtained from a 20 h reaction time (Table 2).
TABLE 2.
Screening of Additivesa
| |||||
|---|---|---|---|---|---|
| entry | additive (equiv) | 3a (%) | entry | additive (equiv) | 3a (%) |
| 1 | none | 18 | 16 | HClc (1) | 22 |
| 2 | NaF (2) | 16 | 17 | LiCl (1) | 55 |
| 3 | KF (2) | 41 | 18 | NaCl (1) | 18 |
| 4 | CsF (2) | 28 | 19 | KCl (1) | 16 |
| 5 | TBAFb (2) | 11 | 20 | CsCl (1) | 34 |
| 6 | KTFA (1) | 33 | 21 | MgCl2 (1) | 51 |
| 7 | LiBF4 (1) | 17 | 22 | CaCl2 (1) | 25 |
| 8 | NaOAc (1) | 29 | 23 | BiCl3 (1) | 61 |
| 9 | KOAc (1) | 47 | 24 | CuCl2 (0.5) | 60 |
| 10 | CsOAc (1) | 28 | 25 | CuCl2 (1) | 73 |
| 11 | K2CO3 (1) | 34 | 26 | CuCl2 (2) | 81 |
| 12 | Cs2CO3 (1) | 17 | 27 | CuCl2 (3) | 81 |
| 13 | K3PO4 (1) | 31 | 28 | CuCl (2) | 31 |
| 14 | Me3CCO2H (1) | 16 | 29 | CuI (2) | 0 |
| 15 | TFA (0.1) | 31 | |||
Reaction conditions: 1 (1 equiv), 2a (2 equiv), Pd(OAc)2 (10 mol%), Cu(OAc)2 (2 equiv), DMF (0.2 M) under N2 for 20 h at 60 °C, the yield was determined by 1H NMR analysis of the crude product using Ph3,SiMe (1 equiv) as the internal standard.
1.0 M in THF.
12.1 M.
TABLE 3.
Scope of Arylboronic Acids
|
Having established a high-yielding protocol for cross-coupling, we applied our optimized conditions to a collection of electronically diverse arylboronic acids (Table 3). In contrast to our previously reported method using trifluoroborates,3a both electron-rich and electron-poor arylboronic acids coupled smoothly and in high yields. As exemplified by the lower yields of o-methoxy substituted arenes (Table 3, 3c) compared with those of p- and m-methoxy substituted arenes (Table 3, 3a and 3b), steric factors clearly reduced cross-coupling efficiency, albeit to a lesser extent than we had previously noted in reactions with trifluoroborates.3a
In general, this method was found to have excellent functional group compatibility. A phenol (Table 3, 3f), an aryl bromide (Table 3, 3i), a 1° amide (Table 3, 3k), a ketone (Table 3, 3l) and an aldehyde (Table 3, 3o) were all well tolerated. However, thienylboronic acid coupled in low yield (Table 3, 3q) and furanylboronic acid did not afford any product (Table 3, 3r).
Next we varied the enaminone component 4, and used p-methoxyphenylboronic acid (2a) as a model boronic acid (Table 4). As we observed previously,3a mono- and bicyclic enaminones with N-alkyl substituents were all suitable substrates in this transformation (Table 4, 5a–5e). Notably, N-phenyl enaminone 5b was also formed in comparable yields to N-benzyl (Table 4, 5a) or N-methyl (Table 4, 5c) analogs despite its tempered nucleophilicity. In contrast, the arylation of N-carbamylated enaminone 5h was not observed. A methyl group in the C6 position was surprisingly well-tolerated, furnishing tetrasubstituted olefinic compound 5j. However, substrates with more sterically demanding groups at C6, such as tert-butyl or phenyl, did not react.
TABLE 4.
Scope of Cyclic Enaminonesa
|
The expanded substrate scope and lack of dependency on the electronic nature of boronic acids led us to speculate that this reaction was proceeding through a mechanism which was distinct from our previously reported method using trifluoroborates.3a To shed light on the mechanism and respective roles of each reagent, we investigated the optimized reaction conditions in further detail (Tables 5 and 6). We first noted that subjecting boronic acid 2a to the cross-coupling conditions in the absence of an enaminone coupling partner resulted in high yields of the homocoupled by-product (Table 5 entry 1).17 Similar results were obtained in the absence of CuCl2 (entry 2), but yields were considerably lower in the absence of Cu(OAc)2 or Pd(OAc)2 (entries 3–6). Notably, under palladium-free condition (entry 4), we observed rapid and near complete (> 95%) consumption of the boronic acid in under 15 min.18 In the presence of the enaminone coupling partner, cross-coupling was only observed in the presence of palladium (Table 6). Thus, in contrast to boronic acid homocoupling, cyclic enaminone cross-coupling is an exclusively Pd-mediated process. Indeed, the reaction proceeds, albeit in modest yield, in the absence of any copper source when using 100 mol% of Pd(OAc)2 (entry 9). Nevertheless, under these stoichiometric conditions, which presumably minimizes the necessity of a reoxidant, product formation was improved upon the addition of Cu(OAc)2, CuCl2 or both (entries 10–12). Interestingly, the beneficial effects of the mixed Cu(OAc)2/CuCl2 system was enhanced when Pd(OAc)2 was employed catalytically (entry 5). Neither Cu(OAc)2 or CuCl2 alone provided high yields of arylated enaminone 3a. Additionally, doubling the quantity of Cu(OAc)2 (entry 8) did not significantly improve the coupling reaction, thereby indicating that the effects of the Cu(OAc)2 and CuCl2 system are cooperative and not merely additive.
TABLE 5.
Homocoupling of Arylboronic Acidsa
| ||||
|---|---|---|---|---|
| entry | Pd(OAc)2 | Cu(OAc)2 | CuCl2 | 6 (%) |
| 1 | 10 mol% | 2 equiv | 2 equiv | 70 |
| 2 | 10 mol% | 2 equiv | none | 82 |
| 3 | 10 mol% | none | 2 equiv | 9 |
| 4 | none | 2 equiv | 2 equiv | 14 |
| 5 | none | 2 equiv | none | 25 |
| 6 | none | none | 2 equiv | 6 |
Reaction conditions: 2a (0.4 M) in DMF under N2 at 60 °C for 1 h.
TABLE 6.
Cross Coupling of Cyclic Enaminone and Arylboronic Acida
| ||||
|---|---|---|---|---|
| entry | Pd(OAc)2 | Cu(OAc)2 | CuCl2 | 3a (%) |
| 1 | none | 2 equiv | 2 equiv | 0 |
| 2 | none | 2 equiv | none | 0 |
| 3 | none | none | 2 equiv | 0 |
| 4 | 10 mol% | none | none | < 5 |
| 5 | 10 mol% | 2 equiv | 2 equiv | 81 |
| 6 | 10 mol% | 2 equiv | none | 18 |
| 7 | 10 mol% | none | 2 equiv | 18 |
| 8 | 10 mol% | 4 equiv | none | 25 |
| 9 | 100 mol% | none | none | 30 |
| 10 | 100 mol% | 2 equiv | 2 equiv | 66 |
| 11 | 100 mol% | 2 equiv | none | 49 |
| 12 | 100 mol% | none | 2 equiv | 60 |
Reaction conditions: 1 (1 equiv), 2a (2 equiv), DMF (0.2 M) under N2 at 60 °C for 1 h, the yield was determined by 1H NMR analysis of the crude product using Ph3SiMe (1 equiv) as the internal standard.
We propose a mechanism that could explain these observations. We envision that electrophilic palladation initially furnishes an enaminone-palladium complex, which has previously been shown to occur within minutes at room temperature.3c Once this palladium-enaminone complex has formed, the aryl group is delivered to the palladium center via transmetallation, which could transpire directly from the boronic acid or from a putative arylcopper intermediate. Although the former cannot be completely ruled out, we believe that the latter mechanism is plausible considering: (1) boronic acids are known to readily transmetallate with Cu(OAc)2 to form organocopper species;13 (2) the arylboronic acid is rapidly consumed upon exposure to the Cu(OAc)2/CuCl2 mixture in the absence of palladium; (3) in contrast to our previously developed trifluoroborate cross-coupling method,3a the rate of reaction is extremely fast;19 and (4) the reaction efficiency is seemingly independent of the electronic nature of the boronic acid. Collectively, these data suggest that Cu(OAc)2 and CuCl2 have mutual roles on improving the efficiency of cross-coupling, presumably through facilitating the delivery of the aryl moiety to the Pd-center via an aryl-copper intermediate. However, the precise roles of each reagent in this process remain elusive.
Conclusion
In summary, we have developed a new method for the C–H arylation of cyclic enaminones using boronic acids as aryl donors. In large part, the success of this reaction is due to a mixture of Cu(OAc)2 and CuCl2 that appear to be cooperative and allows for efficient cross-coupling with a diverse set of arylboronic acids without the previously observed preference for electron-rich coupling partners.3a Although the exact role of each copper additive is not clear, we believe that these reagents not only serve as Pd-reoxidants, but also assist aryl delivery to the palladated enaminone through a putative arylcopper intermediate. As such, this reaction represents a significant advancement over previously developed methods for enaminone arylation and leads us to speculate that this copper additive mixture could be of more general utility in boronic acid cross-coupling reactions where transmetallation is disfavored.
Experimental Section
General Procedure for Enaminone Arylation
The cyclic enaminone (0.20 mmol), Pd(OAc)2 (4.5 mg, 0.02 mmol), Cu(OAc)2 (73 mg, 0.40 mmol) and CuCl2 (54 mg, 0.40 mmol,) were combined in DMF (1.0 mL) under N2 and stirred for 5 min (Note: Solvents were used without purification or degassing). The resulting solution was heated to 60 °C and the arylboronic acid (0.40 mmol) was added in one portion. After stirring for 1 h the reaction mixture was cooled to room temperature and diluted with EtOAc (5 mL). The precipitate was filtered through Celite using EtOAc as the eluent. The filtrate was concentrated and purified by flash column chromatography on silica gel using hexanes and an increasing proportion of EtOAc as eluent.
1-Benzyl-2,5-bis(4-methoxyphenyl)-2,3-dihydropyridin-4(1H)-one (3a)
Compound 3a was prepared by the general procedure described above and 65 mg (81%) was isolated as light yellow oil. Rf 0.48 (hexanes/EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.39–7.31 (m, 5H), 7.22–7.14 (m, 4H), 6.92–6.85 (m, 4H), 4.51 (dd, J = 8.6, 6.8 Hz, 1H), 4.38 (d, J = 15.1 Hz, 1H), 4.18 (d, J = 15.1 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 2.92 (dd, J = 16.2, 6.7 Hz, 1H), 2.82 (dd, J = 16.2, 8.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 188.2, 159.6, 157.9, 152.7, 136.1, 130.6, 129.0, 128.9, 128.6, 128.4, 128.2, 127.7, 114.3, 113.7, 111.1, 60.4, 57.2, 55.3, 44.5; FTIR (KBr, cm-1) 3030, 2932, 2835, 1634, 1594, 1440, 1357, 1302, 1246, 1177, 1124, 1033, 837, 735, 699; HRMS (ESI, TOF) m/e calculated for [M+H]+ C26H26NO3: 400.1913, found 400.1902.
1-Benzyl-5-(3-methoxyphenyl)-2-(4-methoxyphenyl)-2,3-dihydropyridin-4(1H)-one (3b)
Compound 3b was prepared by the general procedure described above and 64 mg (81%) was isolated as light yellow oil. Rf 0.50 (hexanes/EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 7.55 (s, 1H), 7.40–7.30 (m, 3H), 7.26–7.13 (m, 5H), 7.09–7.06 (m, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.90–6.83 (m, 2H), 6.78–6.71 (m, 1H), 4.51 (dd, J = 7.9, 7.1 Hz, 1H), 4.40 (d, J = 15.1 Hz, 1H), 4.20 (d, J = 15.1 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 2.94 (dd, J = 16.2, 6.8 Hz, 1H), 2.81 (dd, J = 16.2, 8.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 187.7, 159.6, 159.4, 153.2, 137.5, 135.8, 130.3, 129.0, 128.9, 128.3, 128.2, 127.7, 119.8, 114.4, 113.3, 111.3, 110.8, 60.2, 57.4, 55.3, 55.2, 44.5; FTIR (KBr, cm-1) 3030, 2957, 2835, 1635, 1594, 1511, 1453, 1357, 1253, 1178, 1121, 1036, 833, 734, 699; HRMS (ESI, TOF) m/e calculated for [M+H]+ C26H26NO3: 400.1913, found 400.1901.
1-Benzyl-5-(2-methoxyphenyl)-2-(4-methoxyphenyl)-2,3-dihydropyridin-4(1H)-one (3c)
Compound 3c was prepared by the general procedure described above and 41 mg (51%) was isolated as a light yellow solid (mp 102–105 °C). Rf 0.31 (hexanes/EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 7.52 (s, 1H), 7.38–7.30 (m, 4H), 7.26–7.17 (m, 5H), 6.99–6.85 (m, 4H), 4.53 (dd, J = 9.0, 6.8 Hz, 1H), 4.34 (d, J = 15.1 Hz, 1H), 4.14 (d, J = 15.1 Hz, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 2.91 (dd, J = 16.2, 6.8 Hz, 1H), 2.84 (dd, J = 16.1, 9.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 187.8, 159.6, 157.1, 155.2, 136.1, 132.0, 130.8, 128.8, 128.6, 128.1, 127.8, 127.6, 124.9, 120.6, 114.3, 111.4, 107.4, 60.6, 57.2, 55.7, 55.3, 44.5; FTIR (KBr, cm-1) 3030, 2932, 2835, 1634, 1593, 1512, 1455, 1376, 1306, 1250, 1178, 1129, 1029, 836, 753, 699; HRMS (ESI, TOF) m/e calculated for [M+H]+ C26H26NO3: 400.1913, found 400.1898.
1-Benzyl-2-(4-methoxyphenyl)-5-phenyl-2,3-dihydropyridin-4(1H)-one (3d)
Compound 3d was prepared by the general procedure described above and 59 mg (80%) was isolated as light yellow oil. Rf 0.60 (hexanes/EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.46–7.42 (m, 2H), 7.39–7.29 (m, 5H), 7.23–7.14 (m, 5H), 6.90–6.85 (m, 2H), 4.52 (dd, J = 8.2, 6.9 Hz, 1H), 4.40 (d, J = 15.1 Hz, 1H), 4.20 (d, J = 15.1 Hz, 1H), 3.81 (s, 3H), 2.95 (dd, J = 16.2, 6.8 Hz, 1H), 2.82 (dd, J = 16.2, 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 187.9, 159.6, 153.1, 136.1, 135.9, 130.5, 129.0, 128.4, 128.3, 128.2, 127.7, 127.7, 125.8, 114.4, 111.3, 60.4, 57.4, 55.3, 44.5; FTIR (KBr, cm-1) 3030, 2918, 2836, 1635, 1595, 1512, 1452, 1375, 1358, 1304, 1251, 1178, 1124, 1030, 699; HRMS (ESI, TOF) m/e calculated for [M+H]+ C25H24NO2: 370.1807, found 370.1810.
1-Benzyl-2-(4-methoxyphenyl)-5-(p-tolyl)-2,3-dihydropyridin-4(1H)-one (3e)
Compound 3e was prepared by the general procedure described above and 58 mg (75%) was isolated as a light yellow solid (mp 88–90 °C). Rf 0.45 (hexanes/EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 7.49 (s, 1H), 7.38–7.29 (m, 5H), 7.22–7.12 (m, 6H), 6.90–6.84 (m, 2H), 4.51 (dd, J = 8.5, 6.8 Hz, 1H), 4.39 (d, J = 15.1 Hz, 1H), 4.18 (d, J = 15.1 Hz, 1H), 3.81 (s, 3H), 2.93 (dd, J = 16.2, 6.7 Hz, 1H), 2.82 (dd, J = 16.2, 8.6 Hz, 1H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 188.0, 159.6, 152.9, 136.0, 135.4, 133.1, 130.6, 129.0, 128.9, 128.4, 128.2, 127.7, 127.6, 114.4, 111.4, 60.5, 57.3, 55.3, 44.6, 21.1; FTIR (KBr, cm-1) 3028, 2919, 1637, 1595, 1512, 1440, 1357, 1303, 1252, 1178, 1122, 1032, 836, 810, 699; HRMS (ESI, TOF) m/e calculated for [M+H]+ C26H26NO2: 384.1964, found 384.1964.
1-Benzyl-5-(4-hydroxyphenyl)-2-(4-methoxyphenyl)-2,3-dihydropyridin-4(1H)-one (3f)
Compound 3f was prepared by the general procedure described above and 48 mg (62%) was isolated as colorless oil. Rf 0.21 (hexanes/EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.39–7.29 (m, 3H), 7.28–7.26 (m, 1H), 7.25 (d, J = 2.9 Hz, 1H), 7.22–7.13 (m, 4H), 6.93– 6.85 (m, 2H), 6.80–6.74 (m, 2H), 5.39 (s, 1H), 4.51 (dd, J = 8.6, 6.8 Hz, 1H), 4.38 (d, J = 15.1 Hz, 1H), 4.18 (d, J = 15.1 Hz, 1H), 3.81 (s, 3H), 2.93 (dd, J = 16.3, 6.8 Hz, 1H), 2.82 (dd, J = 16.3, 8.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 188.4, 159.6, 154.2, 153.1, 136.0, 130.4, 129.2, 129.0, 128.4, 128.3, 128.2, 127.7, 115.3, 114.4, 111.3, 60.4, 57.3, 55.4, 44.4; FTIR (KBr, cm-1) 3326, 1606, 1566, 1511, 1370, 1294, 1248, 1129, 1031, 957, 823, 731, 695, 612, 585; HRMS (ESI, TOF) m/e calculated for [M+H]+ C26H24NO3: 398.1756, found 398.1747.
1-Benzyl-5-(4-fluorophenyl)-2-(4-methoxyphenyl)-2,3-dihydropyridin-4(1H)-one (3g)
Compound 3g was prepared by the general procedure described above and 66 mg (85%) was isolated as a yellow solid (mp 131–134 °C). Rf 0.45 (hexanes/EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.43–7.30 (m, 5H), 7.22–7.13 (m, 4H), 7.06–6.97 (m, 2H), 6.91–6.85 (m, 2H), 4.52 (dd, J = 8.2, 6.9 Hz, 1H), 4.40 (d, J = 15.1 Hz, 1H), 4.20 (d, J = 15.1 Hz, 1H), 3.81 (s, 3H), 2.94 (dd, J = 16.3, 6.8 Hz, 1H), 2.81 (dd, J = 16.3, 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 187.9, 161.2 (d, J = 244.3 Hz), 159.7, 152.9, 135.9, 132.0 (d, J = 3.2 Hz), 130.3, 129.2 (d, J = 7.7 Hz), 128.7 (d, J = 63.5 Hz), 128.4, 127.7, 115.1, 114.9, 114.4, 110.4, 60.4, 57.4, 55.3, 44.4; 19F NMR (376 MHz, CDCl3) δ –117.3; FTIR (KBr, cm-1) 3031, 2931, 2837, 1634, 1595, 1509, 1441, 1357, 1295, 1252, 1178, 1123, 1032, 840, 735, 699; HRMS (ESI, TOF) m/e calculated for [M+H]+ C25H23FNO2: 388.1713, found 388.1704.
1-Benzyl-5-(4-chlorophenyl)-2-(4-methoxyphenyl)-2,3-dihydropyridin-4(1H)-one (3h)
Compound 3h was prepared by the general procedure described above and 63 mg (78%) was isolated as a yellow solid (mp 129–132 °C). Rf 0.55 (hexanes/EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.41–7.33 (m, 5H), 7.31–7.24 (m, 2H), 7.21–7.13 (m, 4H), 6.93–6.82 (m, 2H), 4.52 (t, J = 7.4 Hz 1H), 4.41 (d, J = 15.1 Hz, 1H), 4.21 (d, J = 15.1 Hz, 1H), 3.81 (s, 3H), 2.94 (dd, J = 16.3, 6.8 Hz, 1H), 2.81 (dd, J = 16.3, 8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 187.7, 159.7, 152.9, 135.8, 134.6, 131.3, 130.2, 129.0, 128.8, 128.4, 128.3, 127.7, 114.5, 110.0, 60.3, 57.5, 55.3, 44.3; FTIR (KBr, cm-1) 3030, 2928, 2836, 1634, 1598, 1511, 1440, 1372, 1294, 1251, 1178, 1124, 1032, 837, 735, 698; HRMS (ESI, TOF) m/e calculated for [M+H]+ C25H23ClNO2: 404.1417, found 404.1411.
1-Benzyl-5-(4-bromophenyl)-2-(4-methoxyphenyl)-2,3-dihydropyridin-4(1H)-one (3i)
Compound 3i was prepared by the general procedure described above and 77 mg (86%) was isolated as yellow oil. Rf 0.60 (hexanes/EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 7.56–7.47 (m, 1H), 7.45–7.38 (m, 2H), 7.37–7.29 (m, 5H), 7.20–7.11 (m, 4H), 6.89–6.82 (m, 2H), 4.50 (t, J = 7.5 Hz, 1H), 4.40 (d, J = 15.1 Hz, 1H), 4.20 (d, J = 15.1 Hz, 1H), 3.79 (s, 3H), 2.92 (dd, J = 16.3, 6.9 Hz, 1H), 2.78 (dd, J = 16.3, 8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 187.6, 159.7, 152.9, 135.7, 135.0, 131.2, 130.2, 129.1, 129.0, 128.3, 127.7, 119.3, 114.5, 110.0, 60.3, 57.5, 55.3, 44.3; FTIR (KBr, cm-1) 3030, 2932, 2835, 1634, 1596, 1511, 1440, 1356, 1294, 1252, 1178, 1123, 1032, 836, 811, 735, 698; HRMS (ESI, TOF) m/e calculated for [M+H]+ C25H23BrNO2: 448.0912, found 448.0898.
1-Benzyl-2-(4-methoxyphenyl)-5-(4-(trifluoromethyl)phenyl)-2,3-dihydropyridin-4(1H)-one (3j)
Compound 3j was prepared by the general procedure described above and 70 mg (80%) was isolated as yellow oil. Rf 0.55 (hexanes/EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 7.59–7.53 (m, 4H), 7.43–7.30 (m, 3H), 7.21–7.14 (m, 4H), 6.92–6.85 (m, 2H), 4.55 (t, J = 7.4 Hz, 1H), 4.45 (d, J = 15.1 Hz, 1H), 4.25 (d, J = 15.1 Hz, 1H), 3.81 (s, 3H), 2.97 (dd, J = 16.3, 6.9 Hz, 1H), 2.82 (dd, J = 16.3, 7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 187.5, 159.8, 153.3, 139.8, 135.6, 130.1, 129.1, 128.5, 128.3, 127.7, 127.4 (q, J = 32.2 Hz), 127.3, 125.1 (q, J = 3.8 Hz), 124.5 (q, J = 272 Hz), 114.5, 109.6, 60.2, 57.7, 55.3, 44.3; 19F NMR (376 MHz, CDCl3) δ 62.8; FTIR (KBr, cm-1) 3032, 2934, 2838, 1639, 1596, 1512, 1443, 1374, 1325, 1253, 1161, 1112, 1067, 847, 736, 699; HRMS (ESI, TOF) m/e calculated for [M+H]+ C26H23F3NO2: 438.1681, found 438.1692
4-(1-Benzyl-6-(4-methoxyphenyl)-4-oxo-1,4,5,6-tetrahydropyridin-3-yl)benzamide (3k)
Compound 3k was prepared by the general procedure described above and 61 mg (74%) was isolated as a light yellow solid (mp 194–197 °C). Rf 0.47 (EtOAc). 1H NMR (400 MHz, DMSO) δ 8.24 (s, 1H), 7.85 (s, 1H), 7.78 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H), 7.42–7.35 (m, 2H), 7.35–7.29 (m, 3H), 7.24 (d, J = 8.7 Hz, 2H), 7.21 (s, 1H), 6.92 (d, J = 8.7 Hz, 2H), 4.86 (d, J = 15.2 Hz, 1H), 4.64 (dd, J = 7.0, 4.9 Hz, 1H), 4.23 (d, J = 15.2 Hz, 1H), 3.73 (s, 3H), 2.96 (dd, J = 16.0, 7.3 Hz, 1H), 2.54 (dd, J = 16.0, 4.8 Hz, 1H); 13C NMR (100 MHz, DMSO) δ 186.1, 167.8, 158.8, 154.3, 139.7, 136.9, 130.0, 129.9, 128.7, 127.8, 127.8, 127.6, 127.1, 125.7, 114.2, 107.3, 58.4, 56.8, 55.1, 43.9; FTIR (KBr, cm-1) 3346, 3194, 2925, 1669, 1594, 1511, 1378, 1250, 1027, 820, 774, 734, 699; HRMS (ESI, TOF) m/e calculated for [M+H]+ C26H25N2O3: 413.1865, found 413.1860.
4-(1-Benzyl-6-(4-methoxyphenyl)-4-oxo-1,4,5,6-tetrahydropyridin-3-yl)benzamide (3l)
Compound 3l was prepared by the general procedure described above and 67 mg (82%) was isolated as yellow oil. Rf 0.41 (hexanes/EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 7.95–7.87 (m, 2H), 7.68 (s, 1H), 7.61–7.56 (m, 2H), 7.41–7.32 (m, 3H), 7.22–7.12 (m, 4H), 6.91–6.84 (m, 2H), 4.55 (t, J = 7.3 Hz, 1H), 4.48 (d, J = 15.1 Hz, 1H), 4.26 (d, J = 15.1 Hz, 1H), 3.81 (s, 3H), 2.98 (dd, J = 16.2, 7.0 Hz, 1H), 2.81 (dd, J = 16.2, 7.6 Hz, 1H), 2.57 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.7, 187.5, 159.7, 153.5, 141.3, 135.5, 134.1, 130.0, 129.1, 128.5, 128.4, 128.3, 127.7, 126.8, 114.5, 109.6, 60.1, 57.8, 55.3, 44.3, 26.5; FTIR (KBr, cm-1) 3032, 3003, 2961, 2837, 1673, 1634, 1591, 1512, 1442, 1358, 1269, 1180, 1124, 1032, 957, 844, 734, 700; HRMS (ESI, TOF) m/e calculated for [M+H]+ C27H26NO3: 412.1913, found 412.1913.
1-Benzyl-2-(4-methoxyphenyl)-5-(4-nitrophenyl)-2,3-dihydropyridin-4(1H)-one (3m)
Compound 3m was prepared by the general procedure described above and 75 mg (90%) was isolated as a brown solid (mp 98–101 °C). Rf 0.45 (hexanes/EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 8.15–8.11 (m, 2H), 7.75 (s, 1H), 7.67–7.63 (m, 2H), 7.42–7.34 (m, 3H), 7.21–7.15 (m, 4H), 6.90–6.86 (m, 2H), 4.58 (t, J = 7.1 Hz, 1H), 4.52 (d, J = 15.1 Hz, 1H), 4.30 (d, J = 15.1 Hz, 1H), 3.81 (s, 3H), 3.00 (dd, J = 16.3, 7.1 Hz, 1H), 2.81 (dd, J = 16.3, 7.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 187.3, 159.8, 153.8, 144.9, 143.4, 135.2, 129.7, 129.2, 128.6, 128.2, 127.7, 126.8, 123.6, 114.6, 108.4, 60.0, 58.0, 55.3, 44.1; FTIR (KBr, cm-1) 3031, 2914, 2837, 1638, 1578, 1510, 1443, 1329, 1251, 1179, 1107, 1031, 854, 735, 698; HRMS (ESI, TOF) m/e calculated for [M+H]+ C25H23N2O4: 415.1658, found 415.1651.
1-Benzyl-2-(4-methoxyphenyl)-5-(4-nitrophenyl)-2,3-dihydropyridin-4(1H)-one (3n)
Compound 3n was prepared by the general procedure described above and 62 mg (78%) was isolated as yellow oil. Rf 0.43 (hexanes/EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.62–7.54 (m, 4H), 7.42–7.32 (m, 3H), 7.19–7.15 (m, 4H), 6.92–6.85 (m, 2H), 4.56 (t, J = 7.2 Hz, 1H), 4.48 (d, J = 15.1 Hz, 1H), 4.28 (d, J = 15.1 Hz, 1H), 3.81 (s, 3H), 2.98 (dd, J = 16.3, 7.0 Hz, 1H), 2.81 (dd, J = 16.3, 7.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 187.3, 159.8, 153.4, 141.1, 135.3, 132.0, 129.8, 129.2, 128.6, 128.2, 127.7, 127.2, 119.6, 114.6, 108.9, 108.3, 60.1, 57.9, 55.4, 44.2; FTIR (KBr, cm-1) 3032, 2932, 2837, 2221, 1634, 1575, 1512, 1443, 1353, 1253, 1179, 1123, 1032, 962, 844, 735, 700; HRMS (ESI, TOF) m/e calculated for [M+H]+ C26H23N2O2: 395.1760, found 395.1751.
4-(1-Benzyl-6-(4-methoxyphenyl)-4-oxo-1,4,5,6-tetrahydropyridin-3-yl)benzaldehyde (3o)
Compound 3o was prepared by the general procedure described above and 66 mg (83%) was isolated as yellow oil. Rf 0.36 (hexanes/EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 7.85–7.76 (m, 2H), 7.71 (s, 1H), 7.68–7.65 (m, 2H), 7.42–7.32 (m, 3H), 7.22–7.13 (m, 4H), 6.92– 6.85 (m, 2H), 4.56 (t, J = 7.2 Hz, 1H), 4.49 (d, J = 15.1 Hz, 1H), 4.28 (d, J = 15.1 Hz, 1H), 3.81 (s, 3H), 2.99 (dd, J = 16.2, 7.0 Hz, 1H), 2.82 (dd, J = 16.2, 7.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 191.9, 187.4, 159.8, 153.6, 142.9, 135.4, 133.5, 129.9, 129.1, 128.5, 128.3, 127.7, 127.1, 114.5, 109.4, 60.1, 57.9, 55.3, 44.3; FTIR (KBr, cm-1) 3031, 2933, 2837, 1693, 1590, 1512, 1443, 1353, 1305, 1251, 1176, 1123, 1031, 833, 735, 700; HRMS (ESI, TOF) m/e calculated for [M+H]+ C26H24NO3: 398.1756, found 398.1747.
1-Benzyl-2-(4-methoxyphenyl)-5-(naphthalen-2-yl)-2,3-dihydropyridin-4(1H)-one (3p)
Compound 3p was prepared by the general procedure described above and 70 mg (83%) was isolated as brown oil. Rf 0.43 (hexanes/EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.79 (dd, J = 8.3, 5.8 Hz, 3H), 7.68–7.59 (m, 2H), 7.46–7.29 (m, 5H), 7.26–7.13 (m, 4H), 6.93–6.85 (m, 2H), 4.53 (t, J = 7.5 Hz, 1H), 4.43 (d, J = 15.2 Hz, 1H), 4.21 (d, J = 15.1 Hz, 1H), 3.80 (s, 3H), 2.98 (dd, J = 16.2, 6.8 Hz, 1H), 2.84 (dd, J = 16.2, 8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 188.0, 159.6, 153.4, 135.9, 133.8, 133.7, 131.9, 130.4, 129.0, 128.4, 128.3, 127.7, 127.7, 127.5, 127.5, 126.7, 125.7, 125.3, 125.0, 114.4, 111.0, 60.3, 57.5, 55.3, 44.5; FTIR (KBr, cm-1) 3054, 2960, 2836, 1635, 1592, 1511, 1441, 1360, 1303, 1251, 1178, 1107, 1032, 818, 734, 699; HRMS (ESI, TOF) m/e calculated for [M+H]+ C29H26NO2: 420.1964, found 420.1953.
1-Benzyl-2-(4-methoxyphenyl)-5-(thiophen-3-yl)-2,3-dihydropyridin-4(1H)-one (3q)
Compound 3q was prepared by the general procedure described above and 18 mg (24%) was isolated as yellow oil. Rf 0.50 (hexanes/EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.60 (dd, J = 3.0, 1.1 Hz, 1H), 7.39–7.31 (m, 3H), 7.27 (dd, J = 5.0, 3.0 Hz, 1H), 7.22 (dd, J = 5.0, 1.1 Hz, 1H), 7.20–7.14 (m, 4H), 6.90–6.84 (m, 2H), 4.50 (t, J = 7.5 Hz, 1H), 4.42 (d, J = 15.1 Hz, 1H), 4.21 (d, J = 15.1 Hz, 1H), 3.81 (s, 3H), 2.94 (dd, J = 16.3, 6.9 Hz, 1H), 2.80 (dd, J = 16.3, 8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 187.8, 159.6, 152.3, 135.9, 130.3, 129.0, 128.4, 128.3, 127.7, 125.6, 124.5, 118.9, 114.4, 106.9, 60.2, 57.5, 55.3, 44.3; FTIR (KBr, cm-1) 3030, 2925, 2853, 1598, 1511, 1440, 1296, 1252, 1178, 1112, 1031, 838, 783, 734, 699; HRMS (ESI, TOF) m/e calculated for [M+H]+ C23H22NO2S: 376.1371, found 376.1370.
1-Benzyl-5-(4-methoxyphenyl)-2,3-dihydropyridin-4(1H)-one (5a)
Compound 5a was prepared by the general procedure described above and 41 mg (70%) was isolated as yellow oil. Spectral data of the title compound was identical to that in our previous report.3a
5-(4-Methoxyphenyl)-1-phenyl-2,3-dihydropyridin-4(1H)-one (5b)
Compound 5b was prepared by the general procedure described above and 34 mg (60%) was isolated as a brown solid (mp 129–132 °C). Rf 0.26 (hexanes/EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.42–7.31 (m, 4H), 7.18–7.10 (m, 3H), 6.91–6.85 (m, 2H), 4.06 (t, J = 7.6 Hz, 2H), 3.79 (s, 3H), 2.79 (t, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 189.7, 158.3, 147.7, 145.2, 129.7, 129.3, 128.2, 124.2, 118.0, 114.4, 113.7, 55.3, 47.6, 36.6; FTIR (KBr, cm-1) 3052, 2952, 2835, 1645, 1583, 1510, 1386, 1302, 1243, 1178, 1130, 1029, 831, 760, 698; HRMS (ESI, TOF) m/e calculated for [M+H]+ C18H18NO2: 280.1338, found 280.1339.
5-(4-Methoxyphenyl)-1-methyl-2,3-dihydropyridin-4(1H)-one (5c)
Compound 5c was prepared by the general procedure described above and 28 mg (65%) was isolated as yellow oil. Spectral data of the title compound was identical to that in our previous report.3
3-(4-Methoxyphenyl)-7,8,9,9a-tetrahydro-1H-quinolizin-2(6H)-one (5d)
Compound 5d was prepared by the general procedure described above and 42 mg (82%) was isolated as a pale yellow solid. Spectral data of the title compound was identical to that in our previous report.3a
6-(4-Methoxyphenyl)-2,3,8,8a-tetrahydroindolizin-7(1H)-one (5e)
Compound 5e was prepared by the general procedure described above and 27 mg (56%) was isolated as a pale yellow solid. Spectral data of the title compound was identical to that in our previous report.3a
(cis)-3-(4-Methoxyphenyl)-1-methyl-4a,5,6,7,8,8a-hexahydroquinolin-4(1H)-one (5f)
Compound 5f was prepared by the general procedure described above and 41 mg (76%) was isolated as colorless oil. Spectral data of the title compound was identical to that in our previous report.3a
(trans)-3-(4-Methoxyphenyl)-1-methyl-4a,5,6,7,8,8a-hexahydroquinolin-4(1H)-one (5g)
Compound 5g was prepared by the general procedure described above and 45 mg (83%) was isolated as a pale yellow solid. Spectral data of the title compound was identical to that in our previous report.3a
1-Benzyl-5-(4-methoxyphenyl)-6-methyl-2,3-dihydropyridin-4(1H)-one (5j)
Compound 5j was prepared by the general procedure described above and 38 mg (61%) was isolated as a yellow solid (mp 92–95 °C). Rf 0.32 (hexanes/acetone, 1:1). 1H NMR (400 MHz, CDCl3) δ 7.43–7.36 (m, 2H), δ 7.34–7.30 (m, 1H), 7.27–7.22 (m, 2H), 7.09–7.04 (m, 2H), 6.90–6.85 (m, 2H), 4.58 (s, 2H), 3.79 (s, 3H), 3.56 (t, J = 7.6 Hz, 2H), 2.57 (t, J = 7.6 Hz, 2H), 1.96 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 189.2, 159.9, 158.0, 137.0, 132.7, 129.8, 129.0, 127.8, 126.4, 113.6, 113.4, 55.3, 55.2, 48.8, 36.1, 18.6; FTIR (KBr, cm-1) 3030, 2959, 2834, 1621, 1538, 1469, 1297, 1240, 1160, 1098, 1028, 835, 732, 698; HRMS (ESI, TOF) m/e calculated for [M+H]+ C20H22NO2: 308.1610, found 308.1630.
Supplementary Material
Acknowledgment
This work was supported by the NIH (GM081267) and the University of Minnesota through the Vince and McKnight Endowed Chairs (to G.I.G) and an ACS Division of Medicinal Chemistry Predoctoral Fellowship (to M. J. N).
Footnotes
Supporting information
Optimization studies of reaction temperature and time, and copies of 1H/13C NMR spectra of all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
References
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- 19.See Supporting Information
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