Abstract
N-(2,4-Dimethoxy-1,3,5-triazinyl)amide was found to exhibit similar behavior to N-methoxy-N-methylamide (Weinreb amide) but higher reactivity for nucleophilic substitution by organometallic reagents. Triazinylamide suppresses overaddition, leading to the formation of a tertiary alcohol by the chelating ability of the triazinyl and carbonyl groups. Ureas possessing both triazinylamino and methoxy(methyl)amino groups underwent sequential nucleophilic substitution with different organometallic reagents, which furnished unsymmetrical ketones without any detectable tertiary alcohols.
Introduction
Grignard and organolithium reagents have been widely used for the synthesis of alcohols via nucleophilic addition to aldehydes or ketones. Ketones are not readily obtained when these reagents are subjected to reactions with acid derivatives such as esters and amides because ketones are more reactive than the acid derivatives, and undergo overaddition to afford tertiary alcohols. For the direct synthesis of ketones by nucleophilic substitution, electron-deficient or sterically hindered esters/amides are used as substrates.1 Nucleophilic substitution of an aromatic pyrrolyl group with organometallic reagents also yields ketones.2 Another effective approach involves stabilization of the adduct intermediate by chelation, and is a common method in modern organic syntheses, furnishing a ketone without overaddition. An amide possessing an N-methoxy-N-methylamino (MMA) group called the Weinreb amide is a representative (Figure 1, upper).3 Other chelating groups such as carbonyl,4 imino,5 and sulfonyl6 groups were found to stabilize the adduct intermediates leading to ketones; however, the amides used in most reactions are limited to cyclic amides (lactams and imides). Recently, it was demonstrated that the 1-pyrazolyl group is a good leaving group in the synthesis of ketones using Grignard reagents.7
Figure 1.
Stabilized intermediates by the chelating effect.
Although these protocols are useful, the synthesis of unsymmetrical ketones via sequential nucleophilic substitution using different organometallic reagents is still a challenge. Sarpong et al. focused on the leaving ability of the azolyl group and successfully synthesized unsymmetrical ketones using a combination of 1-pyrrolyl and MMA groups.8,9 In this reaction the substrate serves as a dicationic C1 unit to afford unsymmetrical ketones in one pot by successive nucleophilic substitution with different organometallic reagents. With regard to the successive chelation-controlled ketone synthesis, three protocols were reported. Symmetrical urea (bis-Weinreb amide) reacts with Grignard and organolithium reagents; however, in situ elimination does not proceed; thus, two-step reactions are necessary for synthesizing unsymmetrical ketones.10,11 Unsymmetrical urea (N-methoxy-N,N′,N′-trimethylurea) reacted with only organolithium reagents to afford a mixture of two amides, N,N-dimethylamide and Weinreb amide, and the former amide suffers from poor electrophilicity in the second nucleophilic substitution.11N-Methoxy-N-methyl-O-(2-pyridyl)urethane facilitates the synthesis of unsymmetrical ketones; however, selectivity is not so high because of the similar coordinating ability between Weinreb amide and the 2-pyridyl group.12 Hence, selective one-pot synthesis of unsymmetrical ketones using chelation-controlled sequential substitution has not been successfully established.
The historical background suggests that nucleophilic substitution is possible on the carbonyl group of an amide by a carbon nucleophile if a substituent with both coordinating and leaving abilities is introduced to the nitrogen atom. From this viewpoint, our attention focused on the 2,4-dimethoxy-1,3,5-triazinyl (DMT) group for two reasons: (1) the ring nitrogen of the DMT group stabilizes the adduct intermediate by forming a six-membered chelate complex to suppress overaddition and (2) the bulkiness of the triazine ring extends the bond length of the adjacent C=O bond and decreases the electron density of the carbonyl group to improve the reactivity (Figure 1, lower). Giacomelli et al. used this property to achieve the synthesis of ketones by nucleophilic substitution of O-DMT esters with Grignard/CuI reagents.13 There is limited literature on the nucleophilic substitution of N-DMT amide, where DMT-NH2 serves as a leaving group in the substitution with an aliphatic amine.14 In this study, we evaluated the reactivity of an N-DMT amide for nucleophilic substitution by organometallic reagents comparing it with N-MMA amide (Weinreb amide). Moreover, unsymmetrical ketones were synthesized by sequential nucleophilic substitution with organometallic reagents on the carbonyl moiety of 1 flanked by MMA and DMT groups.
Results and Discussion
Dual-activated urea 1 was readily prepared through a two-step reaction (Table 1). The addition of N-methoxy-N-methylamine (NMA-H) hydrochloride to isocyanate 2 in pyridine furnished the corresponding ureas 3a–l in excellent yields. The subsequent introduction of a DMT group to N-aryl ureas 3a–j was efficiently achieved upon treatment with DMT-Cl in the presence of sodium hydride (entries 1–10), although reflux conditions were necessary for electron-poor urea 3h (entry 10). In contrast, N-alkyl ureas 3k and 3l did not undergo N-modification under the same conditions. Using bulky lithium bis(trimethylsilyl)amide as a base was effective in this case to afford 1k (entry 11); however, urea 1l possessing a bulky cyclohexyl group was not obtained, even under heated conditions (entry 12).
Table 1. Synthesis of Dual-Activated Ureas 1.
| yield (%) |
||||
|---|---|---|---|---|
| entry | R | 3 | 1 | |
| 1 | Ph | a | quant. | quant. |
| 2 | 4-MeC6H4 | b | 95 | 82 |
| 3 | 4-MeOC6H4 | c | quant. | 97 |
| 4 | 3-MeOC6H4 | d | 98 | quant. |
| 5 | 2-MeOC6H4 | e | 96 | quant. |
| 6 | 4-F3COC6H4 | f | 94 | quant. |
| 7 | 4-ClC6H4 | g | quant. | quant. |
| 8 | 4-FC6H4 | h | 92 | 98 |
| 9 | 4-F3CC6H4 | i | quant. | 84 |
| 10 | 4-O2NC6H4 | j | 92 | 89a |
| 11 | Bu | k | quant. | 32b |
| 12 | c-Hex | l | 92 | 0a,b,c |
Under reflux.
LiN (SiMe3)2 was used as the base.
1,4-Dioxane was used as the solvent.
The obtained dual-activated urea 1a was subjected to a reaction with 4-methoxyphenylmagnesium bromide at 0 °C, which resulted in the formation of N-methoxy-N-(methyl)anisamide 4(15) in high yield (Table 2, entry 1). This indicates that DMT-NPh is a good leaving group. In this reaction, the second substitution afforded a small amount of symmetrical ketone 5, but a byproduct, a tertiary alcohol, was not detected. The influence of the N-substituent on the reaction was investigated. N-Aryl ureas 1b–k (entries 2–9) exhibited similar reactivities, furnishing 4 in high yields, but the reactivity of 4-nitrophenyl derivative 1j was considerably lower (entry 10). On the other hand, N-butylurea 1k was less reactive than N-aryl ureas, furnishing only a small amount of 4 under the same conditions (entry 11). Among the ureas tested, the most readily available N-phenylurea 1a was employed as the substrate in subsequent studies.
Table 2. Substitution Reactions of Dual-Activated Ureas 1 by 4-MeOC6H4MgBr (PMPMgBr).
| urea 1 | yield (%) |
|||
|---|---|---|---|---|
| entry | R | 4 | 5 | |
| 1 | Ph | a | 82 | 17 |
| 2 | 4-MeC6H4 | b | 77 | 16 |
| 3 | 4-MeOC6H4 | c | 83 | 17 |
| 4 | 3-MeOC6H4 | d | 71 | 18 |
| 5 | 2-MeOC6H4 | e | 83 | 17 |
| 6 | 4-F3COC6H4 | f | 71 | 25 |
| 7 | 4-ClC6H4 | g | 77 | 18 |
| 8 | 4-FC6H4 | h | 75 | 19 |
| 9 | 4-F3CC6H4 | i | 71 | 13 |
| 10 | 4-O2NC6H4 | j | 44 | 3 |
| 11 | Bu | k | 20 | 4 |
To obtain insights into the different reactivities between N-aryl- and N-alkyl ureas, density functional theory (DFT) calculations for 1a and 1k were performed.16 As shown in Figure 2, the DMT ring is coplanar with the urea moiety in the case of N-butylurea 1k. In contrast, the DMT ring is not in the same plane as the carbonyl group because of steric repulsion with the phenyl group in the case of N-phenylurea 1a. This distortion suppressed the electron-donating resonance effect of the DMT-NPh group.17 The least unoccupied molecular orbital (LUMO) level of 1a was slightly lower than that of 1k. This difference was confirmed by comparing bond lengths (Table 3). The N1–C1 bond length of 1a is longer than that of 1k, which decreases the double bond property of the N1–C1 bond and increases the reactivity of the DMT-N-Ph group as a leaving group. These structural features indicate that N-aryl urea is more reactive than N-alkyl urea and that the DMT-NH group is readily substituted compared to the MMA group.
Figure 2.
Optimized structures of 1a and 1k.
Table 3. Selected Bond Angles (°) and Bond Lengths (Å) for the Calculated Structure.
| R |
R |
||||
|---|---|---|---|---|---|
| bond angle | Ph | Bu | bond length | Ph | Bu |
| C4–N1–C1–O1 | 105.2 | 122.2 | N2–C1 | 1.377 | 1.383 |
| C4–N1–C9 | 124.6 | 120.1 | C1–O1 | 1.215 | 1.220 |
| C4–N1–C1 | 116.6 | 120.0 | N1–C1 | 1.449 | 1.423 |
| C1–N1–C9 | 118.3 | 116.9 | C4–N1 | 1.375 | 1.378 |
Dual-activated urea 1a was subjected to reactions with other nucleophiles (Table 4). When urea 1a was reacted with an equimolar Grignard reagent, substitution of the DMT-NPh group predominantly proceeded to afford the Weinreb amide in 82% yield (entry 1). Using an excessive amount of the Grignard reagent was effective, increasing the yield by up to 82%, although double substitution also occurred (entry 2). When excess amounts of the nucleophile were used at room temperature, symmetrical ketone 5 was exclusively obtained without any detectable formation of a tertiary alcohol (entry 3). When the Reformatsky reagent was used instead of the Grignard reagent, no reaction was observed (entry 4). No change was observed, even when PMPMgBr was added to this reaction mixture, presumably because of the inactivation of urea by tight coordination with the zinc species. In contrast, organolithium reagents yielded symmetrical ketones 5, 9, and 11, with the recovery of urea 1a even at −78 °C; however, a tertiary alcohol was not detected (entries 5–7). Hence, the DMT group effectively chelates magnesium ions, whereas the MMA group chelates either lithium or magnesium ions.
Table 4. Synthesis of Weinreb Amides and Symmetrical Ketonesa.
| yield
of product (%) |
||||||
|---|---|---|---|---|---|---|
| entry | R-M (equiv.) | conditions | A | B | ||
| 1 | PMPMgBr (1.0) | 0 °C, 1 h | 4 | 82 | 5 | 13 |
| 2 | PMPMgBr (1.2) | 0 °C, 1 h | 4 | 82 | 5 | 17 |
| 3 | PMPMgBr (4.0) | rt, 3 h | 4 | 0 | 5 | 93 |
| 4 | PhZnBr (1.2) | 0 °C, 1 h | 6 | 0 | 7 | 0 |
| 5 | PMPLi (1.05) | –78 °C, 2 h then rt, 1 h | 4 | 2 | 5 | 30 |
| 6 | PhC≡CLi (1.1) | –78 °C, 1 h then 0 °C, 1 h | 8 | 0 | 9 | 49 |
| 7 | BuLi (1.2) | –78 °C, 10 min | 10 | 0 | 11 | 41 |
PMP: 4-MeOC6H4.
The different chelating abilities of the DMT and MMA groups prompted us to synthesize asymmetrical ketones in one pot (Table 5). First, two types of Grignard reagents were successively added to a solution of urea 1a in tetrahydrofuran (THF). In the case of aromatic Grignard reagents, sequential substitution efficiently afforded unsymmetrical benzophenone derivatives 12–15 in moderate to high yields (entries 1–4). While butylmagnesium chloride furnished ketone 16 in good yield, bulkier aliphatic Grignard reagents exhibited lower reactivity (entries 5–7). In these reactions, symmetrical ketone and Weinreb amide were only obtained as byproducts without detectable tertiary alcohol. Less reactive ethynylmagnesium bromide could not consume the intermediately formed Weinreb amide under the employed conditions (entry 8).
Table 5. Synthesis of Unsymmetrical Ketones by Sequential Substitutiona.
| product |
|||||
|---|---|---|---|---|---|
| entry | R1M (equiv.) | R2M (equiv.) | conditions | yield (%) | |
| 1 | PMPMgBr (1.2) | PhMgBr (1.4) | 0 °C then rt, 15 h | 12 | 82 |
| 2 | 3-MeOC6H4MgBr (1.2) | PhMgBr (1.4) | 0 °C then rt, 15 h | 13 | 54 |
| 3 | 2-MeOC6H4MgBr (1.2) | PhMgBr (1.4) | 0 °C then rt, 15 h | 14 | 53 |
| 4 | 4-FC6H4MgBr (1.2) | PMPMgBr (1.4) | 0 °C then rt, 15 h | 15 | 70 |
| 5 | BuMgCl (1.2)b | PMPMgBr (1.4) | –78 °C, 1 h then rt, 17 h | 16 | 68 |
| 6 | i-BuMgCl (1.2)b | PMPMgBr (1.4) | –78 °C, 1 h then rt, 17 h | 17 | 22 |
| 7 | c-HexMgCl (1.2) | PMPMgBr (1.4) | 0 °C then rt, 15 h | 18 | 30 |
| 8 | PMPMgBr (1.2) | HC≡CMgBr (1.4) | 0 °C then rt, 19 h | 19 | 34 |
| 9 | PMPMgBr (1.2) | BuLi (1.0) | –78 °C, 1 h then 0 °C, 10 min | 16 | 64 |
| 10 | PMPMgBr (1.2) | sec-BuLi (1.4) | 0 °C then rt, 19 h | 20 | 46 |
| 11 | PMPMgBr (1.2) | PyLi (1.2) | –78 °C, 1 h then rt, 20 h | 21 | 59 |
| 12 | PMPMgBr (1.2) | PhC≡CLi (1.4) | 0 °C then rt, 19 h | 22 | 58 |
| 13 | PMPMgBr (1.2) | PhDT-Li (1.3) | –78 °C, 1 h then 0 °C, 30 min | 23 | 35 |
| 14 | PMPMgBr (1.2) | BuOE-OLi (2.0) | –78 °C, 2 h | 24 | 73 |
| 15 | PMPMgBr (1.2) | (MeO)2POCH2Li (2.3) | –78 °C, 1 h then 0 °C, 1 h | 25 | 76 |
PMP: 4-MeOC6H4, Py: 2-pyridyl, PhDT: 2-phenyl-1,3-dithiane-2-yl, BuOE: 1-tert-butoxy-1-ethenyl.
The first substitution was conducted at −78 °C for 1 h.
A variety of organolithium reagents were employed as second nucleophiles (entries 9–15). Alkyllithium was substituted to afford the corresponding aryl alkyl ketones in moderate yields (entries 9 and 10). This protocol facilitated the synthesis of functionalized ketones by altering the lithium reagents (Figure 3). Pyridyl ketone 21 and ynone 22 were obtained in moderate yields (entries 11 and 12, respectively). Anionic dithiane and enolate were used as nucleophiles, which are synthetic equivalents of carbonyl functions, leading to 23 and 24, respectively (entries 13 and 14). Moreover, lithiophosphonate also served as a nucleophile to afford functionalized phosphonate 25 (entry 15) in good yield.
Figure 3.
Functionalized ketones 21–25.
Conclusions
In summary, a DMT-amino group was found to activate the carbonyl group and prevent overaddition. This feature of the DMT-amino group is similar to that of the MMA group in Weinreb amides, but its reactivity is higher. Urea 1, possessing a DMT-amino and an MMA group, served as a synthetic equivalent of the dicationic carbonyl group. Indeed, urea 1 underwent sequential nucleophilic substitution with different organometallic reagents to afford unsymmetrical ketones without any detectable tertiary alcohols. This protocol is a useful tool for elaborate syntheses.
Experimental Section
General
All reagents were purchased from commercial sources and used without further purification. Dry THF was also purchased from a commercial source and used as received. Gravity column chromatography was performed using Kanto Chemical Co. spherical silica gel 60N with a particle size of 63–210 μm. 1H, 13C, and 19F NMR spectra were recorded on Bruker AVANCE III 400 spectrometer (400 MHz, 100 MHz, and 376 MHz, respectively). All chemical shifts (δ) are reported in ppm and coupling constants (J) are in Hz. The 1H and 13C NMR chemical shifts are relative to tetramethylsilane; the resonance of the residual protons of chloroform was used as an internal standard for 1H (δ 7.26 ppm) and all-d solvent peaks for 13C (δ 77.0 ppm).18 The assignments of the 13C NMR were performed by DEPT experiments. 19F NMR chemical shifts are relative to hexafluorobenzene in CDCl3 at δ = -163.0 ppm (external reference).19 High-resolution mass spectra were recorded on a JEOL JMS-700N spectrometer. Melting points were recorded on an Anatec Yanaco MP-J3 and were uncorrected. Geometrical optimization was carried out at the B3LYP/6-31g(d,p) level of theory implemented on the Gaussian 09 package.16
Preparation of Dual-Activated Urea 1
Amination of Isocyanate 2
N-Methoxy-N-methyl-N′-phenylurea (3a)
To a solution of N,O-dimethylhydroxylamine hydrochloride (0.74 g, 7.5 mmol) in pyridine (5.0 mL), phenyl isocyanate (2a, 0.54 mL, 5.0 mmol) was added dropwise at 0 °C, and the resulting mixture was warmed up to room temperature. After stirring for 1 day, the reaction was quenched with 10% aqueous NH4Cl (10 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford N-methoxy-N-methyl-N′-phenylurea (3a) (0.90 g, 5.0 mmol, quant.) as a white solid. An analytically pure sample was obtained by recrystallization from CH2Cl2/hexane (1:4). Mp 61.0–62.0 °C. 1H NMR (400 MHz, CDCl3) δ 3.18 (s, 3H), 3.75 (s, 3H), 7.06 (tt, J = 0.8, 7.6 Hz, 1H), 7.26–7.34 (m, 2H), 7.43–7.49 (m, 2H), 7.72 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 34.9 (CH3), 61.6 (CH3), 119.3 (CH), 123.4 (CH), 128.9 (CH), 137.9 (C), 157.2 (C); HRMS (EI) m/z [M+] calcd. for C9H12N2O2: 180.0899; found: 180.0895.
Other Ureas 3 Were Synthesized in the Same Way
N-Methoxy-N-methyl-N′-(4-methylphenyl)urea (3b)
White solid. Mp 95.5–96.5 °C. 1H NMR (400 MHz, CDCl3) δ 2.30 (s, 3H), 3.17 (s, 3H), 3.75 (s, 3H), 7.11 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.65 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 20.7 (CH3), 35.0 (CH3), 61.6 (CH3), 119.5 (CH), 129.4 (CH), 133.0 (C), 135.3 (C), 157.4 (C); HRMS (EI) m/z [M+] calcd. for C10H14N2O2: 194.1055; found: 194.1057.
N-Methoxy-N-methyl-N′-(4-methoxyphenyl)urea (3c)
Brown oil. 1H NMR (400 MHz, CDCl3) δ 3.17 (s, 3H), 3.75 (s, 3H), 3.78 (s, 3H), 6.85 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.61 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 35.1 (CH3), 55.4 (CH3), 61.6 (CH3), 114.1 (CH), 121.4 (CH), 130.9 (C), 156.0 (C), 157.7 (C); HRMS (EI) m/z [M+] calcd. for C10H14N2O3: 210.1004; found: 210.1003.
N-Methoxy-N-methyl-N′-(3-methoxyphenyl)urea (3d)
Pale yellow solid. Mp 88.5–90.0 °C. 1H NMR (400 MHz, CDCl3) δ 3.18 (s, 3H), 3.76 (s, 3H), 3.80 (s, 3H), 6.60–6.65 (m, 1H), 6.90–6.95 (m, 1H), 7.16–7.22 (m, 1H), 7.23–7.25 (m, 1H), 7.71 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 34.9 (CH3), 55.2 (CH3), 61.6 (CH3), 104.8 (CH), 109.5 (CH), 111.5 (CH), 129.6 (CH), 139.2 (C), 157.1 (C), 160.2 (C); HRMS (EI) m/z [M+] calcd. for C10H14N2O3: 210.1004; found: 210.1004.
N-Methoxy-N-methyl-N′-(2-methoxyphenyl)urea (3e)
Colorless oil. 1H NMR (400 MHz, CDCl3) δ 3.18 (s, 3H), 3.77 (s, 3H), 3.87 (s, 3H), 6.86 (dd, J = 2.0, 7.6 Hz, 1H), 6.92–7.02 (m, 2H), 8.21 (dd, J = 2.0, 7.6 Hz, 1H), 8.32 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 34.9 (CH3), 55.7 (CH3), 61.5 (CH3), 109.8 (CH), 118.6 (CH), 121.0 (CH), 122.6 (CH), 127.7 (C), 147.9 (C), 157.1 (C); HRMS (EI) m/z [M+] calcd. for C10H14N2O3: 210.1004; found: 210.1001.
N-Methoxy-N-methyl-N′-[4-(trifluoromethoxy)phenyl]urea (3f)
White solid. Mp 73.5–74.5 °C. 1H NMR (400 MHz, CDCl3) δ 3.19 (s, 3H), 3.77 (s, 3H), 7.16 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H), 7.75 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 34.8 (CH3), 61.7 (CH3), 120.4 (CH), 120.5 (q, J = 255.1 Hz, CF3), 121.7 (CH), 136.7 (C), 144.8 (d, J = 1.6 Hz, C), 157.1 (C); 19F NMR (376 MHz, CDCl3) δ −59.4; HRMS (EI) m/z [M+] calcd. for C10H11F3N2O3: 264.0722; found: 264.0724.
N-Methoxy-N-methyl-N′-(4-chlorophenyl)urea (3g)
White solid. Mp 77.0–77.5 °C. 1H NMR (400 MHz, CDCl3) δ 3.18 (s, 3H), 3.76 (s, 3H), 7.26 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H), 7.71 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 34.8 (CH3), 61.7 (CH3), 120.6 (CH), 128.4 (C), 128.9 (CH), 136.6 (C), 157.0 (C); HRMS (EI) m/z [M+] calcd. for C9H11ClN2O2: 214.0509; found: 214.0509.
N-Methoxy-N-methyl-N′-(4-fluorophenyl)urea (3h)
White solid. Mp 71.5–72.5 °C. 1H NMR (400 MHz, CDCl3) δ 3.18 (s, 3H), 3.76 (s, 3H), 7.00 (dd, J = 8.8, 8.8 Hz, 2H), 7.41 (dd, J = 4.8, 8.8 Hz, 2H), 7.69 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 34.9 (CH3), 61.6 (CH3), 115.5 (d, J = 22.2 Hz, CH), 121.2 (d, J = 7.9 Hz, CH), 133.9 (d, J = 2.6 Hz, C), 157.3 (C), 159.0 (d, J = 240.8 Hz, C); 19F NMR (376 MHz, CDCl3) δ −120.82 to −120.73; HRMS (EI) m/z [M+] calcd. for C9H11FN2O2: 198.0805; found: 198.0802.
N-Methoxy-N-methyl-N′-[4-(trifluoromethyl)phenyl]urea (3i)
White solid. Mp 91.0–92.0 °C. 1H NMR (400 MHz, CDCl3) δ 3.21 (s, 3H), 3.78 (s, 3H), 7.56 (d, J = 9.2 Hz, 2H), 7.59 (d, J = 9.2 Hz, 2H), 7.86 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 34.6 (CH3), 61.7 (CH3), 118.7 (CH), 124.2 (q, J = 269.7 Hz, CF3), 125.1 (q, J = 32.6 Hz, C), 126.2 (q, J = 3.7 Hz, CH), 141.2 (C), 156.6 (C); 19F NMR (376 MHz, CDCl3) δ −63.3; HRMS (EI) m/z [M+] calcd. for C10H11F3N2O2: 248.0773; found: 248.0773.
N-Methoxy-N-methyl-N′-(4-nitrophenyl)urea (3j)
Yellow solid. Mp 147.0–148.5 °C. 1H NMR (400 MHz, CDCl3) δ 3.25 (s, 3H), 3.83 (s, 3H), 7.67 (d, J = 9.2 Hz, 2H), 8.05 (br s, 1H), 8.22 (d, J = 9.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 34.4 (CH3), 61.8 (CH3), 118.3 (CH), 125.1 (CH), 142.9 (C), 144.1 (C), 156.0 (C); HRMS (EI) m/z [M+] calcd. for C9H11N3O4: 225.0750; found: 225.0749.
N-Methoxy-N-methyl-N′-butylurea (3k)
Colorless oil. 1H NMR (400 MHz, CDCl3) δ 0.93 (t, J = 7.2 Hz, 3H), 1.29–1.42 (m, 2H), 1.46–1.56 (m, 2H), 3.08 (s, 3H), 3.19–3.27 (m, 2H), 3.66 (s, 3H), 5.83 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 13.7 (CH3), 19.9 (CH2), 32.1 (CH2), 35.5 (CH3), 39.6 (CH2), 61.2 (CH3), 160.4 (C); HRMS (EI) m/z [M+] calcd. for C7H16N2O2: 160.1212; found: 160.1212.
N-Methoxy-N-methyl-N′-cyclohexylurea (3l)
White solid. Mp 89.5–90.5 °C. 1H NMR (400 MHz, CDCl3) δ 1.10–1.23 (m, 3H), 1.30–1.44 (m, 2H), 1.57–1.66 (m, 1H), 1.66–1.76 (m, 2H), 1.89–1.98 (m, 2H), 3.08 (s, 3H), 3.55–3.67 (m, 1H), 3.65 (s, 3H), 5.66 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 24.9 (CH2), 25.5 (CH2), 33.6 (CH2), 35.6 (CH3), 48.6 (CH), 61.2 (CH3), 159.6 (C); HRMS (EI) m/z [M+] calcd. for C9H18N2O2: 186.1368; found: 186.1368.
N-Triazinylation of 3
N-Methoxy-N-methyl-N′-(4,6-dimethoxyl-1,3,5-triazin-2-yl)-N′-phenylurea (3a)
To a solution of urea 3a (0.18 g, 1.0 mmol) in THF (4.0 mL) was added portionwise NaH (60% dispersion in mineral oil, 0.16 g, 4.0 mmol) at 0 °C, and the resulting mixture was allowed to warm up to room temperature. After stirring for 30 min, 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.25 g, 1.4 mmol) was added, and the mixture was stirred at room temperature for another 1 day. The reaction was quenched with 10% aqueous NH4Cl and extracted with ethyl acetate (20 mL × 2). The combined organic layer was washed with brine (20 mL × 1), dried over Na2SO4, and concentrated under reduced pressure to give a white solid as a residue. Further purification was performed by column chromatography on silica gel to afford N-methoxy-N′-(4,6-dimethoxy-1,3,5-triazin-2-yl)-N-methyl-N′-phenylurea (1a) (eluted with hexane/ethyl acetate = 2/1, 0.32 g, 1.0 mmol, quant.) as a white solid. Mp 63.5–64.5 °C. 1H NMR (400 MHz, CDCl3) δ 3.32 (s, 3H), 3.65 (s, 3H), 3.93 (s, 6H), 7.26–7.33 (m, 1H), 7.37–7.44 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 35.1 (CH3), 54.9 (CH3), 61.3 (CH3), 126.1 (CH), 127.1 (CH), 129.1 (CH), 137.7 (C), 154.8 (C), 167.3 (C), 172.5 (C); HRMS (EI) m/z [M+] calcd. for C14H17N5O4: 319.1281; found: 319.1280.
N-Methoxy-N-methyl-N′-(4,6-dimethoxyl-1,3,5-triazin-2-yl)-N′-(4-methylphenyl)urea (1b)
White solid. Mp 95.0–96.5 °C. 1H NMR (400 MHz, CDCl3) δ 2.36 (s, 3H), 3.32 (s, 3H), 3.66 (s, 3H), 3.92 (s, 6H), 7.15 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 21.0 (CH3), 35.1 (CH3), 54.9 (CH3), 61.3 (CH3), 126.0 (CH), 129.7 (CH), 135.0 (C), 137.1 (C), 154.9 (C), 167.3 (C), 172.4 (C); HRMS (EI) m/z [M+] calcd. for C15H19N5O4: 333.1437; found: 333.1437.
N-methoxy-N-methyl-N′-(4,6-dimethoxyl-1,3,5-triazin-2-yl)-N′-(4-methoxyphenyl)urea (1c)
White solid. Mp 92.5–93.5 °C. 1H NMR (400 MHz, CDCl3) δ 3.32 (s, 3H), 3.67 (s, 3H), 3.82 (s, 3H), 3.92 (s, 6H), 6.92 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 35.1 (CH3), 54.9 (CH3), 55.4 (CH3), 61.3 (CH3), 114.3 (CH), 127.9 (CH), 130.4 (C), 154.9 (C), 158.6 (C), 167.5 (C), 172.4 (C); HRMS (EI) m/z [M+] calcd. for C15H19N5O5: 349.1386; found: 349.1385.
N-Methoxy-N-methyl-N′-(4,6-dimethoxyl-1,3,5-triazin-2-yl)-N′-(3-methoxyphenyl)urea (1d)
Light brown solid. Mp 68.0–69.5 °C. 1H NMR (400 MHz, CDCl3) δ 3.32 (s, 3H), 3.67 (s, 3H), 3.80 (s, 3H), 3.93 (s, 6H), 6.82–6.86 (m, 1H), 6.97–7.02 (m, 2H), 7.27–7.33 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 35.2 (CH3), 54.9 (CH3), 55.3 (CH3), 61.3 (CH3), 111.9 (CH), 112.8 (CH), 118.4 (CH), 129.6 (CH), 138.7 (C), 154.7 (C), 160.0 (C), 167.2 (C), 172.5 (C); HRMS (EI) m/z [M+] calcd. for C15H19N5O5: 349.1386; found: 349.1386.
N-Methoxy-N-methyl-N′-(4,6-dimethoxyl-1,3,5-triazin-2-yl)-N′-(2-methoxyphenyl)urea (1e)
Light brown solid. Mp 103.0–104.0 °C. 1H NMR (400 MHz, CDCl3) δ 3.33 (s, 3H), 3.68 (s, 3H), 3.79 (s, 3H), 3.90 (s, 6H), 6.94–7.01 (m, 2H), 7.27–7.33 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 35.2 (CH3), 54.8 (CH3), 55.6 (CH3), 60.9 (CH3), 112.0 (CH), 120.9 (CH), 127.3 (C), 128.5 (CH), 129.1 (CH), 154.8 (C), 155.0 (C), 168.0 (C), 172.5 (C); HRMS (EI) m/z [M+] calcd. for C15H19N5O5: 349.1386; found: 349.1385.
N-Methoxy-N-methyl-N′-(4,6-dimethoxyl-1,3,5-triazin-2-yl)-N′-[4-(trifluoromethoxy)phenyl]urea (1f)
White solid. Mp 105.0–106.0 °C. 1H NMR (400 MHz, CDCl3) δ 3.34 (s, 3H), 3.67 (s, 3H), 3.94 (s, 6H), 7.22–7.28 (m, 2H), 7.46 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 35.1 (CH3), 55.0 (CH3), 61.5 (CH3), 120.4 (q, J = 256.3 Hz, CF3), 121.5 (CH), 127.7 (CH), 136.2 (C), 147.7 (C), 154.6 (C), 167.2 (C), 172.5 (C); 19F NMR (376 MHz, CDCl3) δ −59.1; HRMS (EI) m/z [M+] calcd. for C15H16 F3N5O5: 403.1104; found: 403.1103.
N-Methoxy-N-methyl-N′-(4,6-dimethoxyl-1,3,5-triazin-2-yl)-N′-(4-chlorophenyl)urea (1g)
White solid. Mp 108.5–109.5 °C. 1H NMR (400 MHz, CDCl3) δ 3.32 (s, 3H), 3.66 (s, 3H), 3.94 (s, 6H), 7.33–7.40 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 35.1 (CH3), 55.0 (CH3), 61.4 (CH3), 127.5 (CH), 129.2 (CH), 132.8 (C), 136.3 (C), 154.5 (C), 167.2 (C), 172.5 (C); HRMS (EI) m/z [M+] calcd. for C14H16ClN5O4: 353.0891; found: 353.0890.
N-Methoxy-N-methyl-N′-(4,6-dimethoxyl-1,3,5-triazin-2-yl)-N′-(4-fluorophenyl)urea (1h)
Pale yellow solid. Mp 71.5–72.5 °C. 1H NMR (400 MHz, CDCl3) δ 3.33 (s, 3H), 3.67 (s, 3H), 3.93 (s, 6H), 7.06–7.13 (m, 2H), 7.35–7.42 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 35.0 (CH3), 54.9 (CH3), 61.4 (CH3), 116.0 (d, J = 22.6 Hz, CH), 128.4 (d, J = 8.4 Hz, CH), 133.7 (d, J = 3.1 Hz, C), 154.7 (C), 161.5 (d, J = 246.0 Hz, C), 167.4 (C), 172.4 (C); 19F NMR (376 MHz, CDCl3) δ −115.47 to −115.36; HRMS (EI) m/z [M+] calcd. for C14H16FN5O4: 337.1186; found: 337.1186.
N-Methoxy-N-methyl-N′-(4,6-dimethoxyl-1,3,5-triazin-2-yl)-N′-[4-(trifluoromethyl)phenyl]urea (1i)
White solid. Mp 102.5–103.5 °C. 1H NMR (400 MHz, CDCl3) δ 3.34 (s, 3H), 3.66 (s, 3H), 3.96 (s, 6H), 7.54 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 35.1 (CH3), 55.1 (CH3), 61.5 (CH3), 123.8 (q, J = 270.3 Hz, CF3), 125.7 (CH), 126.2 (q, J = 3.6 Hz, CH), 128.7 (q, J = 32.6 Hz, C), 141.0 (C), 154.4 (C), 167.0 (C), 172.5 (C); 19F NMR (376 MHz, CDCl3) δ −63.8; HRMS (EI) m/z [M+] calcd. for C15H16F3N5O4: 387.1154; found: 387.1153.
N-Methoxy-N-methyl-N′-(4,6-dimethoxyl-1,3,5-triazin-2-yl)-N′-(4-nitrophenyl)urea (1j)
Pale yellow solid. Mp 120.0–120.5 °C. 1H NMR (400 MHz, CDCl3) δ 3.36 (s, 3H), 3.66 (s, 3H), 3.98 (s, 6H), 7.61 (d, J = 9.2 Hz, 2H), 8.27 (d, J = 9.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 35.1 (CH3), 55.2 (CH3), 61.7 (CH3), 124.6 (CH), 125.1 (CH), 143.7 (C), 145.4 (C), 154.1 (C), 166.8 (C), 172.5 (C); HRMS (EI) m/z [M+] calcd. for C14H16N6O6: 364.1131; found: 364.1131.
N-Methoxy-N-methyl-N′-(4,6-dimethoxyl-1,3,5-triazin-2-yl)-N′-butylurea (1k)
Colorless oil. 1H NMR (400 MHz, CDCl3) δ 0.95 (t, J = 7.2 Hz, 3H), 1.31–1.43 (m, 2H), 1.62–1.72 (m, 2H), 3.28 (s, 3H), 3.67 (s, 3H), 3.78–3.84 (m, 2H), 3.96 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 13.7 (CH3), 20.1 (CH2), 30.6 (CH2), 35.2 (CH3), 46.4 (CH2), 54.8 (CH3), 61.2 (CH3), 156.1 (C), 167.3 (C), 172.3 (C); HRMS (EI) m/z [M+] calcd. for C12H21N5O4: 299.1594; found: 299.1592.
Reaction of Urea 1 with Organometallic Reagent
To a solution of 1a (R = Ph, 96 mg, 0.30 mmol) in dry THF (1.5 mL), 4-methoxyphenylmagnesium bromide (0.5 M in THF, 0.72 mL, 0.36 mmol) was added dropwise at 0 °C under an argon atmosphere, and the resulting mixture was stirred at the same temperature for 1 h. After quenching the reaction with 10% aqueous NH4Cl, the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic layer was washed with brine (20 mL × 1), dried over Na2SO4, and concentrated under reduced pressure to afford a white solid as a residue. Yields of Weinreb amide 4a and symmetrical ketone 5a were determined by a comparison of integral values with those of 1,1,2,2-tetrachloroethane as an internal standard in the 1H NMR of the crude mixture.15
When other ureas, organometallic reagents, and other reaction conditions were used, experiments were conducted in the same way. Each product could be isolated by column chromatography on silica gel using hexane/ethyl acetate (3/1 to 2/1) as an eluent. All of the products are known compounds and their structures were confirmed by the comparison of the 1H NMR spectrum with that of authentic samples.20
Sequential Substitution of Urea 1 with Organometallic Reagents
To a solution of 1a (54.6 mg, 0.171 mmol) in dry THF (2.0 mL), 4-methoxyphenylmagnesium bromide (0.5 M in THF, 0.42 mL, 0.210 mmol) was added dropwise under an argon atmosphere at 0 °C, and the resulting mixture was stirred at the same temperature for another 1 h. Then, phenylmagnesium bromide (1.0 M in THF, 0.24 mL, 0.240 mmol) was added dropwise at 0 °C. After gradually warming up to room temperature, the mixture was stirred for 15 h. The reaction was quenched with 10% aqueous NH4Cl and extracted with ethyl acetate (20 mL × 2). The combined organic layer was washed with brine (20 mL × 1), dried over Na2SO4, and concentrated under reduced pressure to afford a white solid as a residue. Each product could be isolated by column chromatography on silica gel using hexane/ethyl acetate (3/1 to 2/1) as an eluent. Structures of the products, Weinreb amide and ketone, were confirmed by a comparison of the 1H NMR spectrum with that of authentic samples.5 Yields of Weinreb amide 4a and symmetrical ketone 5a were determined by a comparison of integral values with those of 1,1,2,2-tetrachloroethane as an internal standard in the 1H NMR using CDCl3 as a solvent.
When other ureas, organometallic reagents, and other reaction conditions were used, experiments were conducted in the same way. Each product could be isolated by column chromatography on silica gel using hexane/ethyl acetate (3/1 to 2/1) as an eluent. All of the products are known compounds and the structures were confirmed by a comparison of the 1H NMR spectrum with that of authentic samples.20
Acknowledgments
The authors thank the Office for Research Initiative and Development of Nagasaki University for analysis support.
Supporting Information Available
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.2c06756.
Experimental procedures, characterization of compounds, and NMR spectral data of urea 1 and 3 (PDF)
The authors declare no competing financial interest.
Supplementary Material
References
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