Side-Chain Lithiation of

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Side-Chain Lithiation of $$N'$$ N ′ -(4Chlorophenethyl)- and $$N'$$ N ′ -(4Methylphenethyl)-N, N-dimethylureas: Experimental and Theoretical Approaches Mohammed B. Alshammari

Arabian Journal for Science and Engineering ISSN 2193-567X Volume 43 Number 1 Arab J Sci Eng (2018) 43:171-179 DOI 10.1007/s13369-017-2602-3

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Author's personal copy Arab J Sci Eng (2018) 43:171–179 https://doi.org/10.1007/s13369-017-2602-3

RESEARCH ARTICLE - CHEMISTRY

Side-Chain Lithiation of N  -(4-Chlorophenethyl)- and N  -(4-Methylphenethyl)-N,N-dimethylureas: Experimental and Theoretical Approaches Mohammed B. Alshammari1

Received: 11 October 2016 / Accepted: 7 May 2017 / Published online: 22 May 2017 © King Fahd University of Petroleum & Minerals 2017

Abstract α-Lithiation of N  -(4-chlorophenethyl)- and N  (4-methylphenethyl)-N ,N -dimethylureas occurs using tbutyllithium (3.3 molar equivalents) in dry tetrahydrofuran at −60 to 0 ◦ C on NH and on the CH2 next to the aryl ring. The lithium reagents generated in situ are trapped with several electrophiles (benzophenone, cyclohexanone, 2-butanone, 4anisaldehyde, and benzaldehyde) to afford the corresponding substituted ureas in 79–96% yields. The experimental results were sustained by density functional theory calculations, which show that the side chain on the CH2 adjacent to the aryl ring is the most favorable site for the α-lithiation of N  -(4-chlorophenethyl)-N ,N -dimethylurea and N  -(4methylphenethyl)-N ,N -dimethylurea. Keywords N  -(4-Chlorophenethyl)-N ,N -dimethylurea · N  -(4-Methylphenethyl)-N ,N -dimethylurea · Side-chain lithiation · Lithium reagent · Electrophile · Synthesis

1 Introduction ortho-Lithiation is a well-known [1–3] and very useful process, among other methods, to produce many substituted aromatic compounds [4–6]. The use of directing lithiation via different organic groups [7–10] plays a significant role in the production of regioselective substituted aromatic compounds [11–14]. The use of a urea moiety as a directing metalating group [15–20], in which the formed aza-substituted carbanion is a useful intermediate for the synthesis of amine

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Mohammed B. Alshammari [email protected] Chemistry Department, College of Sciences and Humanities, Prince Sattam bin Abdulaziz University, P.O. Box 83, Al-Kharij 11942, Saudi Arabia

derivatives [21–24], has been intensively studied [25–27]. 4Chlorophenylethylamine derivatives, e.g., chlorphentermine, cloforex, and etolorex, perform various biological activities and are a valuable category of chemicals in both industry and academia [28–31]. Smith’s research group found that the double lithiation of both N  -phenyl- and N  -(-4-methylphenyl)-N ,N dimethylureas occurs on NH and on one methyl of N Me2 when tert-butyllithium (t-BuLi) is used as a base at −20 to 0 ◦ C (Scheme 1) [32]. However, N  -(4-chlorophenyl)-N ,N -dimethylurea was successfully lithiated and substituted at the ortho-position using n-butyllithium (n-BuLi) at −20 to 0 ◦ C (Scheme 2) [32]. The lithiation of N  -(benzyl)-N ,N -dimethylurea using various lithium reagents under different conditions gave a mixture of ortho- and side-chain-lithiated products in low yields. However, the ortho-lithiation of N  - (4- chlorobenzyl)N ,N -dimethylurea and N  - (4- methylbenzyl)-N , N -dimethylurea was successful using excess t-BuLi at −78 ◦ C (Scheme 3). Clearly, no α-substitution products were produced under the tried conditions [24]. Smith’s research group successfully lithiated and substituted N  -phenethyl- and N  -2-(2-methylphenyl)ethyl-N , N −dimethylureas with RLi in THF at −78 or 0 ◦ C; the lithiation occurs on NH and on the side chain of the CH2 adjoining the phenyl ring (α-lithiation, Scheme 4) [25,26]. On the other hand, the lithiation of N  -2-(4-methoxyphenyl)ethyl-N ,N dimethylurea at 0 ◦ C gave a mixture of lithium reagents in which lithiation had occurred mainly on the ring as ortholithiation [33]. The lithiation site was dramatically affected by the substituents on the aromatic ring, in which side-chain lithiation was seen with the 2-Me, and ortho-lithiation was observed with the 4-OMe derivatives.

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Scheme 1 Lithiation and substitution of N  -aryl-N ,N -dimethylureas (1) [32]

Scheme 2 Lithiation and ring substitution of N  -(4-chlorophenyl)-N ,N -dimethylurea (3) [32]

Scheme 3 Lithiation and ring substitution of N  -aryl-N ,N -dimethylureas [24] 1) RLi, THF H N R

NMe2 O

7 R = H, 2-Me, 4-OMe

E

-78 or 0 °C 2) Electrophile, -78 or 0 °C

H N

R

O

3) aq NH4 Cl

H N

NMe2 or

8 R = H, 2-Me (86-98%)

R E

NMe2 O

9 R = 4-OMe (78-98%)

Scheme 4 Lithiation and substitution of N - substituted phenylethylamine derivatives (7) [25,26,33]

Here we report the side-chain lithiation of N  -(2-(4chlorophenyl)ethyl)-N ,N -dimethylurea (10) and N  -(2-(4methylphenyl)ethyl)-N ,N -dimethylurea (11) using t-BuLi at low temperature, followed by reactions with electrophiles to provide the corresponding urea derivatives in high yields. Furthermore, a DFT study at the B3LYP/6-311+G(d,p) level of theory was carried out in order to confirm the experimental results.

obtained using a Waters LCT Premier XE instrument. The Fischer Scientific silica 60A (35–70μm) used in the FT-IR spectroscopy were taken on a Jasco FT/IR-660 Plus instrument. The Fischer Scientific silica 60A (35–70μm) in column chromatography was carried out. The strength of the butyllithiums was estimated using a standard procedure [34].

2 Experimental

A mixture of 2-(4-chlorophenyl)ethylamine (10.00 g, 64.25 mmol), dimethylcarbamoyl chloride (DMCC, 8.30 g, 77.10 mmol), and Et3 N (9.75 g, 96.40 mmol) in dichloromethane (DCM) (100 mL) was under reflux for 1 h. It was allowed to cool, and the precipitate was washed with H2 O (2 × 25 mL). The precipitate was crystallized from Et2 O to give pure 10 as a colorless crystalline solid, 14.26 g, 63.0 mmol, (98%); mp 139–141 ◦ C [mp 146 ◦ C [1]]. IR (FT, cm−1 ): 3377, 3028, 2978, 1651, 1519, 1465, 698.

2.1 General The melting point was measured using a Gallenkamp melting point apparatus. The 1 H (500 Mz) and 13 C NMR (125 MHz) spectra were recorded in CDCl3 using a Bruker AV500 spectrometer. The mass spectra were determined using a Waters GCT Premier spectrometer. Accurate mass data were

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2.2 Synthesis of N  -2-((4-chlorophenyl)ethyl)- N,N -dimethylurea (10)

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NMR: δ 7.20 (d, 8 Hz, 2 H, H3/H5), 7.06 (d, 8 Hz, 2 H, H2/H6), 4.30 (br., exch., 1 H, NH), 3.38 (app. q, 7 Hz, 2 H, CH2 NH), 2.79 [s, 6 H, N(CH3 )2 ], 2.72 (t, J = 7 Hz, 2 H, ArCH2 ). 13 C NMR: δ 158.2 (C=O), 138.0 (C-1), 132.1 (C4), 130.2 (C-2/C-6), 128.7 (C-3/C-5), 42.1 (CH2 NH), 36.2 [N(CH3 )2 ], 36.0 (CH2 Ar). APCI-MS (m/z, %): 229 [34, [M37 Cl + H]+ ), 227 (100, [M35 Cl + H]+ ). HRMS (APCI): m/z[M35 Cl+H]+ calcd for C11 H16 ClN2 O: 227.0951, found: 227.0949. 2.3 Lithiation of N  -2-((4-Chlorophenyl)ethyl)-N, N -dimethylurea 10: Synthesis of substituted derivatives 13-17: General procedure t-BuLi in pentane (3.50 mL, 1.9 M, 6.60 mmol) was added dropwise to a cooled and stirred solution of 10 (0.50 g, 2.2 mmol) at −60 ◦ C in dry tetrahydrofuran (THF) (20 mL) under nitrogen. The mixture was allowed to warm up from −60 to 0 ◦ C for 2 h. The electrophile (4.4 mmol) was added and stirred for 2 h at 0 ◦ C to room temperature. The mixture was quenched with sat. aq NH4 Cl (20 mL) solution and diluted with Et2 O (20 mL). It was then separated and washed with H2 O (2 × 20 mL), dried (MgSO4 ), and evaporated. The crude was purified by column chromatography (silica gel, Et2 O–hexane, 1:3) to obtain the products 16, 18-21. 2.3.1 N  -(2-(4-Chlorophenyl)-3-hydroxy-3,3diphenylpropyl)-N,N-dimethylurea (16) From benzophenone (0.80 g, 4.4 mmol): white solid in a yield of 87%, mp 164 − 165 ◦ C. IR (FT, cm−1 ): 3439, 3248, 3055, 2918, 1608, 1533, 1446, 700. 1 H NMR: δ 7.67 (d, 7 Hz, 2 H, H2/H6 of one Ph), 7.27–7.18 (m, 7 H, OH, H3/H5 of one Ph, H2/H6 of other Ph, H3/H5 of Ar), 7.09 (t, 7 Hz, 1 H, H4 of one Ph), 7.00 (d, 8 Hz, 2 H, H2/H6 of Ar), 6.93 (t, 8 Hz, 2 H, H3/H5 of other Ph), 6.82 (t, 7 Hz, 1 H, H4 of other Ph), 5.40 (br., exch., 1 H, NH), 4.09 (dd, 5, 9 Hz, 0.58 H, CH), 4.00 (dd, 9, 14 Hz, 1 H, CHa CHb ), 3.24 (m, 1 H, CHa CHb ), 2.44 [s, 6 H, N(CH3 )2 ]. 13 C NMR: δ 158.4 (C=O), 148.0 (C-1), 146.5, 138.8 (C-1 of 2 Ph), 132.1 (CCl), 131.3 (C-2/C-6), 128.0, 127.9 (C-2/C-6 of 2 Ph), 127.5 (C-3/C-5), 126.3, 125.6 (C-4 of 2 Ph), 125.55, 125.53 (C3/C-5 of 2 Ph), 78.7 (COH), 53.6 (CH), 43.1 (CH2 ), 35.9 [N(CH3 )2 ]. ES+ -MS (m/z, %): 433 ([M37 Cl + Na]+ , 38), 431 ([M35 Cl + Na]+ , 100). HRMS (ES+ ): m/z [M35 Cl]+ calcd for C24 H25 ClN2 O2 Na: 431.1502, found: 431.1511. 2.3.2 N  -(2-(4-Chlorophenyl)-2-(1-hydroxycyclohexyl) ethyl)-N,N-dimethylurea (18) From cyclohexanone (0.43 g, 4.4 mmol): white solid in a yield of 84%, mp 180–181 ◦ C. IR (FT, cm−1 ): 3311, 3267, 2924, 1616, 1548, 1450, 742. 1 H NMR: δ 7.13 (d, 8 Hz, 2 H,

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H3/H5), 7.09 (d, 8 Hz, 2 H, H2/H6), 4.27 (br. s, exch., 1 H, NH), 3.76 (m, 1 H, CHa Hb ), 3.32 (m, 1 H, CH), 2.69 (m, 1 H, CHa Hb ), 2.59 [s, 6 H, N(CH3 )2 ], 1.93 (br. s, exch., 1 H, OH), 1.66–1.04 (m, 10 H, c-Hex). 13 C NMR: δ 158.5 (C=O), 138.9 (C-1), 132.6 (C-4), 131.1 (C-3/C-5), 128.4 (C-2/C-6), 72.9 (COH), 54.8 (CH), 41.0 (CH2 ), 36.5, 35.9 (C-3/C-5 of c-Hex), 36.0 [N(CH3 )2 ], 25.6 (C-4 of c-Hex), 21.9, 21.7 (C2/C-6 of c-Hex). EI-MS (m/z, %): 324 (3, [M35 Cl]+ ), 306 (32, [M35 Cl − H2 O]+ ). HRMS (EI): m/z [M35 Cl − H2 O]+ calcd for C17 H23 ClN2 O: 306.1501, found: 306.1499. 2.3.3 N  -(2-(4-Chlorophenyl)-3-hydroxy-3-methylpentyl)N,N-dimethylurea (19) From 2-butanone (0.32 g, 4.4 mmol): white solid in 91%, mp 128–130 ◦ C; IR (FT, cm−1 ): 3314 3265, 2970, 2935, 1612, 1541, 1456, 717 (C-Cl). 1 H NMR: δ 7.31–7.24 (m, 4 H, H2/H6 and H3/H5), 4.51, 4.36 (2 br., exch., 1 H, NH), 3.94–3.91 (m, 1 H, CHa Hb ), 3.49–3.45 (m, 1 H, CH), 2.89 (dd, 5, 9 Hz, 1 H, CHa Hb ), 2.77, 2.76 [2 s, 6 H, N(CH3 )2 ], 1.99 (br., exch., 1 H, OH), 1.58 (dd, 7, 15 Hz, 1 H, 1 H of CH2 CH3 ), 1.39 (m, 1 H, 1 H of CH2 CH3 ), 1.29, 1.05 (2 s, 3 H, CH3 C-OH), 0.98, 0.78 [2 t, 7 Hz, 3 H, CH2 CH3 ). 13 C NMR: δ 158.57, 158.53 (C=O), 139.1, 138.8 (C-1), 132.69, 132.66 (C-4), 131.1, 130.9 (C-3/C-5), 128.46, 128.44 (C2/C-6), 74.5, 74.3 (COH), 53.8, 53.7 (CH), 41.6, 41.5 (CH2 ), 36.08, 36.06 [N(CH3 )2 ], 33.8, 33.3 (CH2 CH3 ), 25.1, 24.5 (CH3 C–OH), 8.2, 8.0 (CH2 CH3 ). EI-MS (m/z, %): 280 (4, [M35 Cl − H2 O]+ ). HRMS (EI): m/z [M35 Cl − H2 O]+ calcd for C15 H21 ClN2 O: 280.1342, found: 280.1346. 2.3.4 N  -(2-(4-Chlorophenyl)-3-(4-(dimethylamino)phenyl) -3-hydroxypropyl)-N,N-dimethylurea (20) From 4-dimethylaminobenzaldehyde (0.65 g, 4.4 mmol): white solid in a yield of 92%, mp 163–165 ◦ C. IR (FT, cm−1 ): 3354, 3240), 2966, 2931, 1614, 1523, 1489, 702. 1 H NMR: δ 7.15–6.95 [m, 7 H, ArCl, H2/H6 of ArN(CH3 )2 and OH], 6.55, 6.49 [2 d, 8 Hz, 2 H, H3/H5 of ArN(CH3 )2 ], 4.77 (dd, 3, 6 Hz, 0.42 H, CHOH), 4.71 (dd, 4, 9 Hz, 0.58 H, CHOH), 4.65, 4.31 (2 t, exch., 5 Hz, 1 H, NH), 3.91 (ddd, 4, 6, 11 Hz, 0.58 H, CH), 3.63 (ddd, 6, 9, 14 Hz, 0.42 H, CH) 3.36 (dt, 5, 14 Hz, 0.58 H, CHa Hb ), 3.21 (dt, 6, 14 Hz, 0.42 H, CHa Hb ), 3.06 (quintet, 5 Hz, 1 H, CHa Hb ), 2.95 (m, 1 H, CHa Hb ), 2.83, 2.80 [2 s, 6 H, N(CH3 )2 ], 2.79, 2.71 [2 s, 6 H, N(CH3 )2 ]. 13 C NMR: δ 159.0, 158.7 (C=O), 152.8, 151.7 (C-4 of ArNMe2 ), 150.43, 150.34 (C-1), 133.5, 133.2 (C-4), 132.5, 132.2 [C-1 of ArN(CH3 )2 ], 130.4, 129.9 (C3/C-5), 128.5, 128.4 (C-2/C-6), 127.5, 127.2 [C-2/C-6 of ArN(CH3 )2 ], 112.4, 112.3 [C-3/C-5 of ArN(CH3 )2 ], 77.3, 75.1 (CHOH), 53.7, 53.2 (CH), 43.5, 43.2 (CH2 ), 40.63, 40.61 (N(CH3 )2 of ArN(CH3 )2 ], 36.27, 36.17 [ArN(CH3 )2 ]. ES+ -MS (m/z, %): 441 (33), 439 (79), 400 (39, [M37 Cl +

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Na]+ ), 398 (100, [M35 Cl + Na]+ ), 358 (63), 270 (52), 258 (65), 243 (40). HRMS (ES+ ): m/z [M35 Cl + Na]+ calcd for C20 H26 N3 ClO2 Na: 398.1611, found: 398.1607. 2.3.5 N  -(2-(4-Chlorophenyl)-3-hydroxy-3-phenylpropyl)N,N-dimethylurea (21) From benzaldehyde (0.46 g, 4.4 mmol): yellow oil in a yield of 96%. IR (FT, cm−1 ): 3365, 3267, 3033, 2928, 1643, 1537, 1455, 700. 1 H NMR: δ 7.13–6.90 (m, 10 H, Ar and Ph and OH), 4.91 (d, 4 Hz, 0.33 H, CHOH), 4.76 (d, 8 Hz, 0.66 H, CHOH), 4.83, 4,23 (2 br., exch., 1 H, NH), 3.90 (ddd, 4, 7, 11 Hz, 0.66 H, CH), 3.85 (ddd, 7, 10, 14 Hz, 0.33 H, CH), 3.36, 3.18 (2 dt, 5, 11 Hz, 1 H, CHa Hb ), 3.04, 2.90 (2 q, 4, 10 Hz, 1 H, CHa Hb ), 2.79, 2.77 [2 s, 6 H, N(CH3 )2 ]. 13 C NMR: δ 159.2, 159.0 (C=O), 142.6, 142.1 (C-1 of Ar), 139.5, 137.4 (C-1 of Ph), 132.5, 132.4 (C-4 of Ar), 130.6, 129.8 (C-3/C-5 of Ph), 128.5, 128.1 (C-3/C-5 of Ar), 128.0, 127.9 (C-2/C-6 of Ph), 127.2, 126.5 (C-2/C-6 of Ar), 126.9, 126.1 (C-4 of Ph), 75.0, 73.2 (COH), 54.0, 53.7 (CH), 43.1, 43.0 (CH2 ), 36.29, 36.27 [N(CH3 )2 ]. ES− -MS (m/z, %): 333 (20, [M37 Cl−H]+ ), 331 (100, [M35 Cl−H]+ ). HRMS (ES− ): m/z [M35 Cl−H]+ calcd for C19 H20 ClN2 O2 : 331.1213, found: 331.1226. 2.4 Synthesis of N  -2-((4-methylphenyl)ethyl) -N, N-dimethylurea (11) 2- p-Tolylethanamine (10 g, 74.01 mmol), dimethylcarbamoyl chloride (DMCC, 9.50 g, 88.82 mmol), and Et3 N (11.22 g, 111.01 mmol) in DCM (100 mL) were under reflux for 1 h. They were allowed to cool, and the precipitate was washed with H2 O (2 × 25 mL). The crude product was crystallized using Et2 O, and gave 11 as colorless crystals, 13.88 g, 67.34 mmol, (91%), mp 127–129 ◦ C [mp 138 ◦ C [1]]. IR (FT, cm−1 ): 3331, 2935, 1627, 1537, 1454. 1 H NMR: δ 7.20 (dd, 8.1, 13.8 Hz, 4 H, Ar), 4.47 (br., exch., 1 H, NH), 3.46 (dd, 6.8, 12.6 Hz, 2 H, CH2 NH), 2.87 [s, 6 H, N(CH3 )2 ], 2.79 (t, 7 Hz, 2 H, CH2 Ar), 2.33 (s, 3 H, ArCH3 ). 13 C NMR: δ 158.4 (s, C=O), 136.4 (s, C-1), 135.8 (s, C-4), 129.2 (d, C-3/C-5), 128.7 (d, C-2/C-6), 42.3 (t, CH2 NH), 36.1 [q, N(CH3 )2 ], 36.0 (t, CH2 C6 H5 ), 21.1 (q, ArCH3 ). APCI-MS (m/z, %): 208 (20, [M + 2H]), 207 (100, [M + H]+ ). HRMS (APCI): m/z [M+H]+ calcd for C12 H18 N2 O: 207.1497, found: 207.1489. 2.5 Lithiation of N  -2-((4-methylphenyl)ethyl)-N, N -dimethylurea 11: synthesis of substituted derivatives 17, 22-24, general procedure t-BuLi in pentane (3.50 mL, 1.9 M, 6.60 mmol) was added dropwise to a cooled solution of 11 (0.50 g, 2.42 mmol) at −78 ◦ C in dry THF (20 mL) under a N2 atmosphere.

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It was allowed to warm up from −40 to −20 ◦ C for 2 h, and an electrophile solution (3.5 mmol) was added. After 2 h at 0 ◦ C to room temperature, sat. aq NH4 Cl (20 mL) was added and the mixture was diluted with Et2 O (20 mL). It was separated and washed with H2 O (2 × 20 mL), dried (MgSO4 ), and evaporated. The crude was purified by column chromatography (silica gel; Et2 O–hexane, 1:3) to get 17, 22– 24. 2.5.1 N  -(3-Hydroxy-3,3-diphenyl-2-p-tolylpropyl)-N,Ndimethylurea (17) From benzophenone (0.64 g, 3.5 mmol): white solid in a yield of 91%, mp 206–208 ◦ C. IR (FT, cm−1 ): 3384, 3216, 2920, 1613, 1540, 1382. 1 H NMR: δ 7.68 (d, 7.3 Hz, 2 H, H2/H6 of one Ph), 7.27 (d, 7.3 Hz, 2 H, H2/H6 of other Ph), 7.23 (t, 8.1 Hz, 2 H, H3/H5 of one Ph), 7.14 (d, 8.0 Hz, 2 H, H2/H6 of Ar), 7.08 (t, 7.3 Hz, 1 H, H4 of one Ph), 6.95 (t, 8.1 Hz, 2 H, H3/H5 of other Ph), 6.85 (d, 7.9 Hz, 2 H, H3/H5 of Ar), 6.83 (t, 7.3 Hz, 1 H, H4 of other Ph), 5.07 (br., exch., 1 H, NH), 4.08 (dd, 5.9, 8.4 Hz, 1 H, CH), 3.97 (ddd, 8.5, 17.0, 22.7 Hz, 1 H, CHa CHb ), 3.27 (dq, 4.2, 10.1 Hz, 1 H, CHa CHb ), 2.44 [s, 6 H, N(CH3 )2 ], 2.13 (s, 3 H, ArCH3 ). 13 C NMR: δ 158.5 (s, C=O), 148.0, 146.9 (2 s, C-1 of 2 Ph), 136.8 (s, C-1 of Ar), 135.8 (s, C-4 of Ar), 129.9, 128.7 (2 d, C-3/C-5 of 2 Ph), 127.9, 127.5 (2 d, C2/C-6 of 2 Ph), 126.2 (d, C-4 of one Ph), 125.7 (d, C-3/C-5 of Ar), 125.6 (2 d, C-2/C-6 of Ar), 125.5 (d, C-4 of other Ph), 78.9 (d, COH), 53.6 (d, CH), 43.0 (t, CH2 ), 35.8 [q, N(CH3 )2 ], 21.0 (q, ArCH3 ). ES+ -MS (m/z,%): 411(100, [M + 23Na]+ ), 412 (25, [M + H + 23Na]+ ). HRMS (ES+ ): m/z [M+23Na]+ calcd for C25 H28 N2 O2 23Na: 411.2048, found: 411.2049. 2.5.2 N  -(2-(1-Hydroxycyclohexyl)-2-p-tolylethyl)-N,Ndimethylurea (22) From cyclohexanone (0.34 g, 3.5 mmol): white solid in a yield of 93%, mp 160–163 ◦ C. IR (FT, cm−1 ): 3316, 3273, 2938, 1619, 1555, 1380. 1 H NMR: δ 7.18 (d, 8 Hz, 2 H, H3/H5), 7.13 (d, 8 Hz, 2 H, H2/H6), 4.43 (br. s, exch., 1 H, NH), 3.96 (dd, 5.0, 13.5 Hz, 1 H 1 H, CHa Hb ), 3.48 (app. q, 9.1, 13.4 Hz, 1 H, CH), 2.82 (app. q, 5.1, 9.1 Hz, 1 H, CHa Hb ), 2.74 [s, 6 H, N(CH3 )2 ], 2.35 (s, 3 H, ArCH3 ), 1.86 (br. s, exch., 1 H, OH), 1.62-1.16 (m, 10 H, c-Hex). 13 C NMR: 158.6 (s, C=O), 136.8 (s, C-1), 136.4 (s, C-4), δ 129.6 (d, C-3/C-5), 129.0 (d, C-2/C-6), 72.9 (s, COH), 55.1 (d, CH), 40.9 (t, CH2 ), 36.1 35.9 (2 t, C-3/C-5 of c-Hex), 36.0 [q, N(CH3 )2 ], 25.6 (t, C-4 of c-Hex), 21.9, 21.7 (2 t, C-2/C-6 of c-Hex), 21.0 (q, ArCH3 ). EI-MS (m/z, %): 304 (3, [M]+ ), 286 (17, [M − H2 O]+ ). HRMS (EI): m/z [M − H2 O]+ calcd for C18 H26 N2 O: 286.2045, found: 286.2047.

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2.5.3 N  -(3-Hydroxy-3-methyl-2-p-tolylpentyl)-N,Ndimethylurea (23) From 2-butanone (0.25 g, 3.5 mmol): yellow oil in a yield of 79%. IR (FT, cm−1 ): 3334, 3273, 2981, 1616, 1547, 1385. 1 H NMR: 7.10–7.02 (m, 5 H, Ar and OH), 4.41, 4.25 (2 δ br., exch., 1 H, NH), 3.85 (dd, 5.3, 13.4 Hz, 0.68 H, CHa Hb ), 3.83 (dd, 4.9, 11.7 Hz, 0.32 H, CHa Hb ), 3.36 (m, 1 H, 2 CH), 2.76 (m, 1 H, 2 CHa Hb ), 2.66, 2.63 [2 s, 6 H, N(CH3 )2 ], 2.24, 2.20 (s, 3 H, ArCH3 ), 1.44 (q, 7.4 Hz, 1.36 H, CH2 CH3 ), 1.37-1.28 (m, 0.64 H, CH2 CH3 ), 1.15, 0.98 (2 s, 3 H, CH3 COH), 0.86, 0.79 (2 t, 7.5 Hz, 3 H, CH2 CH3 ). 13 C NMR: δ 158.66, 158.60 (2 s, C=O), 137.1, 136.6 (2 s, C-1), 136.49, 136.47 (2 s, C-4), 129.6, 129.4 (2 d, C–3/C-5), 129.14, 129.10 (2 d, C-2/C-6), 74.6, 74.2 (2 s, COH), 54.19, 54.10 (2 d, CH), 41.47, 41.40 (2 t, CH2 ), 36.05, 36.02 [2 q, N(CH3 )2 ], 33.4, 33.1 (2 t, CH2 CH3 ), 25.8, 24.2 (2 q, CH3 C–OH), 21.07, 21.09 (2 s, ArCH3 ), 8.09, 8.00 (2 q, CH2 CH3 ). EIMS (m/z, %): 278 (4, [M]+ ), 260 (39, [M–H2 O]+ ). HRMS (EI): m/z [M]+ calcd for C16 H26 N2 O2 : 278.1987, found: 278.1994. 2.5.4

N  -(3-(4-(Dimethylamino)phenyl)-3-hydroxy-2-ptolylpropyl)-N,N-dimethylurea (24)

From 4-dimethylaminobenzaldehyde (0.52 g, 3.5 mmol): white solid in a yield of 88%, mp 178–180 ◦ C. IR (FT, cm−1 ): 3312, 3152, 2920, 1619, 1542, 1360. 1 H NMR: δ 7.18–7.03 [m, 7 H, Ar and H2/H6 of ArN(CH3 )2 and OH], 6.69, 6.59 [2 d, 8.6 Hz, 2 H, H3/H5 of ArN(CH3 )2 ], 4.84 [d, 8.6 Hz, 0.64 H, CH OH), 4.80 (d, 7.1 Hz, 0.36 H, CH OH), 4.70, 4.22 (2 t, exch., 5.1 Hz, 1 H, NH), 4.01 (ddd, 4.6, 6.9, 11.6 Hz, 0.64 H, CH), 3.57 (quintet, 6.7 Hz, 0.36 H, CH), 3.45 (dt, 5.1, 14.1 Hz 0.64 H, CHa Hb ), 3.30 (dt, 5.1, 7.2, 12.5 Hz 0.36 H, CHa Hb ), 3.14 (quintet, 4.4 Hz, 0.64 H, CHa Hb ), 3.05 (m, 0.35 H, CHa Hb ), 2.93, 2.88 [2 s, 6 H, ArN(CH3 )2 ], 2.87, 2.72 [2 s, 6 H, N(CH3 )2 ], 2.34, 2.28 (2 s, 3 H, ArCH3 ). 13 C NMR: δ 159.03, 159.00 (2 s, C=O), 149.75, 149.71 [2 s, C-4 of ArN(CH3 )2 ], 138.1, 136.5 (2 s, C-1), 135.9, 135.3 (2 s, C-4), 130.9, 130.8 [2 s, C-1 of ArN(CH3 )2 ], 129.3, 129.1 (2 d, C-3/C-5), 128.7, 128.4 [2 d, C-2/C-6 of ArN(CH3 )2 ], 127.5, 127.2 (2 d, C-2/C-6), 112.5, 112.3 [2 d, C-3/C-5 of ArN(CH3 )2 ], 75.9, 74.8 (2 d, CHOH), 53.7, 53.3 (2 d, CH), 43.5, 43.2 (2 t, CH2 ), 40.73, 40.70 [2 q, ArN(CH3 )2 ], 36.2, 36.0 [2 q, N(CH3 )2 ], 21.1, 21.0 (2 q, ArCH3 ). ES+ MS (m/z,%): 337 (55, [M − H2 O]+ ). HRMS (ES+ ): m/z [M-H2 O]+ calcd for C21 H27 N3 O: 337.2154, found: 337.2160. 2.6 DFT calculations The DFT method was applied to investigate the formation of the final products from the starting materials, compounds

175

10 and 11. The geometrical optimization of stable conformations of neutral, cationic, and anionic forms of 10 and 11 was obtained at the B3LYP/6-311+G(d,p) level of theory. The minima of the optimized structures were confirmed by the absence of imaginary frequencies. To rationalize the synthesis of the final products from 10 and 11, electrophilic Fukui indices were calculated using the Mulliken population analysis method [35] and natural population analysis approaches using the following formula: Fk+ = qk (N + 1) − qk (N )

(1)

where N and N + 1 are the total number of electrons in the neutral compound and its corresponding anionic form after the addition of one electron. Furthermore, the most favorable site substitutions were affirmed by predicting the acidity of X–H (X=C, N) of starting materials 10 and 11 by calculating the bond dissociation enthalpies (BDE) of X–H (X=C, N) using the following formula: BDE (X − H) = H (Anionic form) − H (neutral form) (2) where H (neutral form) and H (Anionic form) are the enthalpies of the neutral starting materials (10 and 11) and their anionic forms corresponding to the heterolytic dissociation of the X–H (X=C, N) bonds. The solvent effects (tetrahydrofuran, ε = 7.4257) were taken into account implicitly by using the polarizable continuum model formalism PCM [36]. The proton and carbon chemical shifts related to the C7-H group in 10, 11 and the final products were predicted according to the GIAO approach at the same level of theory, i.e., PCM (chloroform, ε = 4.7113)//B3LYP/6-311+G(d,p) [36,37]. Theoretical calculations were done as implemented in the Gaussian09 package [38,39].

3 Results and discussion 3.1 Lithiation of N  -(2-(4-Chlorophenyl)ethyl)-N, Ndimethylurea (10) The initial study was performed by examining the lithiation of 10 by n−BuLi (2.5 equivalents) in dry THF under a nitrogen atmosphere at −78 ◦ C for 2 h. A solution of benzophenone (1.5 equivalents) in dry THF was added to the reaction mixture. In the follow-up work, the TLC showed the presence of a new product along with the unreacted 10. The crude mixture was purified by column chromatography (silica gel, hexane-Et2 O 1:1 by volume). The new product was isolated and identified as N  -(2-(4-chlorophenyl)-3-hydroxy3,3-diphenylpropyl)-N , N -dimethylurea (16). Clearly, the

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H N

Scheme 5 Lithiation of 10 and 11 with t-BuLi, and substitution with benzophenone

10 (X = Cl) 11 (X = Me)

Ph

X

T (◦ C)

16(X = Cl) 17 (X = Me)

Yield (%) of 16a

17a

1

n-BuLi (2.5)

−78

12

18

2

n-BuLi (3.3)

−30 to −20

20

49

3

n-BuLi (3.3)

−60 to 0b

28

71

4

t-BuLi (2.5)

−78

65

35

5

t-BuLi (3.3)

−30 to −20

66

70

6

t-BuLi (3.3)

−60 to 0b

87

91

a

Isolated yield after purification by column chromatography. Starting materials 10 and 11 were also recovered (10–86%) b Initial addition of BuLi was at −60 ◦ C

lithiation of 10 generated monolithium reagent 12 due to lithiation on NH, when one mole equivalent of n-BuLi was added, followed by lithiation on the methylene group next to the aryl ring to give the dilithium reagent 14 (Scheme 5) when the second mole equivalent of n-BuLi was added. The reaction of 14 with benzophenone gave 16 (Scheme 5) in a 12% yield. The reaction was repeated with n-BuLi (3.3 equivalents) at a higher temperature of −30 to −20 ◦ C for 2 h, and −60 to 0 ◦ C for 3 h. Following the purification, product 16 was isolated in 20 and 28%, and with 78 and 60% of the starting material 10, respectively (Table 1, Entries 2 and 3). The use of t-BuLi (2.5 equivalents) at −78 ◦ C improved the yield H N X

10 (X = Cl) 11 (X = Me)

NMe2 O

N

1) Ph2 CO 2) aq. NH4 Cl

NMe2 OLi

X

14(X = Cl) 15 (X = Me)

of 16–65% (Table 1, Entry 4). A higher yield of 16 (66% at −30 to −20 ◦ C) was obtained when 3.3 equivalents of t−BuLi were used (Table 1, Entry 5). The yield of 16 was at its maximum (87%) when t-BuLi (3.3 equivalents) was used at −60 to 0 ◦ C (Table 1, Entry 6). To explore the scope of the reaction, various electrophiles were used to test the generality of the reaction. Consequently, reactions of 10 under the conditions shown in Table 1 (Entry 6) with several other electrophiles (cyclohexanone, 2-butanone, 4-dimethylaminobenzaldehyde, and benzaldehyde) were carried out to afford the corresponding substituted ureas 16, 18–21 (Scheme 6). The yields are shown in Table 2. The 13 C NMR spectra of compounds 16 and 18 confirmed that the carbons of the two phenyl groups and the two sides of the cyclohexane ring, respectively, appeared as separate signals, thus indicating they are diastereotopic. Similarly, the CH2 protons in compounds 16 and 18 are also diastereotopic.

3.2 Lithiation of N  -(2-(4-Methylphenyl)ethyl)-N, N -dimethylurea (11) Similarly, the lithiation of N  -(2-(4-methylphenyl)ethyl)N , N -dimethylurea (11) was investigated using different lithium reagents and reaction conditions with benzophenone used as an electrophile. The obtained yields of N  -(3hydroxy-3,3-diphenyl-2- p-tolylpropyl)-N , N -dimethylurea (17) were within the 18–91% range, depending on the numbers of moles of alkyl lithium (n-BiLi and t-BuLi) and/or the

2) Electrophile, 0 °C to r.t., 2 h 3) aq. NH4 Cl

Scheme 6 Lithiation and substitution of 10 and 11 under optimized conditions

123

12(X = Cl) 13 (X = Me)

Li

E

NMe2 1) t-BuLi (3.3eq) , THF, -60 to 0 °C O

OLi

X

OH Ph

Table 1 Lithiation and substitution of 10 and 11 under various reaction conditions RLi

NMe2

RLi, THF Low Temp. H N

Entry

RLi, THF Low Temp.

O

X

N

NMe2

X

H N

NMe2 O

16, 18-21 (84-96%) 17, 22-24 (79-93%)

Author's personal copy Arab J Sci Eng (2018) 43:171–179 Table 2 Synthesis of substituted derivatives 16, 18–21 from the lithiation and substitution of 10

177

Product

Electrophile

E

Yield (%)a

16

Ph2 CO

Ph2 C(OH)

87

18

(CH2 )5 CO

(CH2 )5 C(OH)

84

19

EtCOMe

EtC(OH)Me

91b,c

20

4-Me2 NC6 H4 CHO

4-Me2 NC6 H4 CH(OH)

92b

21

PhCOH

PhC(OH)H

96b

a b c

Table 3 Synthesis of substituted derivatives 17, 22–24 from the lithiation and substitution of 11

Isolated yield after purification by flash column chromatography The NMR spectra showed two diastereoisomers in approximately equal proportions The NMR spectra showed that the CH2 protons of the ethyl group are diastereotopic

Product

Electrophile

E

Yield (%)a

17

Ph2 CO

Ph2 C(OH)

91

22

(CH2 )5 CO

(CH2 )5 C(OH)

93

23

EtCOMe

EtC(OH)Me

79b,c

24

4-Me2 NC6 H4 CHO

4-Me2 NC6 H4 CH(OH)

88b

a b c

Isolated yield after purification by flash column chromatography The NMR spectra showed two diastereoisomers in approximately equal proportions The NMR spectra showed that the CH2 protons of the ethyl group are diastereotopic

Fig. 1 Optimized structures of compounds 10 (left) and 11 (right)

temperature (−78 to 0 ◦ C) (Table 1). The best yield was 91% when t-BuLi (3.3 equivalents) was used at −60 to 0 ◦ C. In general, the reactions of 11 when t-BuLi (3.3 equivalents) was used at −60 to 0 ◦ C, with different electrophiles (cyclohexanone, 2-butanone, and 4-dimethylaminobenzaldehyde) were carried out (Scheme 6) to afford 17, 22–24 in high yields (Table 3). The 13 C NMR spectra of compounds 17 and 22 indicated that the carbons of the two phenyl groups and the two sides of the cyclohexane ring, respectively, appeared as separate signals, thus confirming they are diastereotopic. For compounds 23 and 24, two diastereoisomers were formed in approximately equal proportions. The CH2 protons in the ethyl group of both diastereoisomers of compound 23 and the CH2 protons next to the NH group in all of the compounds 17, 22–24 are also diastereotopic. 3.3 Density functional theory (DFT) investigation The experimental results showed that the reaction of 10 and 11 (Scheme 5) gave the corresponding dianions 14 and 15

(Scheme 5). On the one hand, the calculation of the electrophilicity of the atomic sites in 10 and 11 (Fig. 1) revealed that the α-carbon atom (C7 in the numbering scheme used for the calculations) has the highest positive electrophilic index, and as a result it is the most favorable site for deprotonation, with F+ k = 0.121, 0.211, respectively (Table 4). On the other hand, the calculation of the electrophilicity of atomic sites in 7 (Scheme 4, Fig. 1) revealed that the carbon atom in meta position with respect to OMe group in benzene ring in 7 (C2 in the numbering scheme used for the calculations) has the highest positive electrophilic index of 1.15 (Table 4). Therefore, C2 is considered to be the most favorable site for the deprotonation. The above result is also supported by the lowest bond dissociation enthalpies for the hydrogen atoms of the C7 CH2 groups in 10 and 11, with bond dissociation enthalpies of 325 and 329.6 kcal/mol, respectively (Table 5). For compound 7, the lowest dissociation energy was obtained for the C1–H bond with an energy of 327 Kcal/mol indicating that electrophilic substitution reaction is favorable at C1 as a nucleophilic site (meta position of OMe group on the

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Table 4 Fukui indices of the active atoms in compounds 10, 11 and 7 calculated at the B3LYP/6-311+G(d,p) level of theory

Start materials

C1

C2

C3

C4

C5

C6

C7

C8

C9

0.03

10

0.101

0.012

−0.357

−0.023

−0.405

0.121

−0.024

−0.015

11

0.017

0.160

0.108

0.005

0.182

0.093

0.211

0.092

−0.409

−0.982

1.150

−0.181

0.282

0.908

0.393

0.146

0.355

0.010

7

Table 5 Bond dissociation enthalpies of the C–H bonds of compounds 10, 11 and 7 calculated at the B3LYP/6-311+G(d,p) level of theory Start materials

C2–H

C3–H

C7–H

C8–H

C10–H

C11–H

10

334

332

325

346

345

337

11

339.7

343.5

329.6

347.1

345.4

337.5

7

327

338

331

347

334

337

benzene ring) which is in good agreement with observed results. The proton and carbon NMR predictions using the DFT method showed that the substitution of the side-chain CH2 of 10 and 11 induces an upfield shift for both proton and carbon chemical shifts at C7. On the one hand, with 10 as the starting material,  δ variations of 1.3 and 18 ppm were found for proton and carbon, respectively. On the other hand, with 11 as the starting material,  δ variations of 1.5 and 16.3 ppm were found for proton and carbon, respectively. These results are similar to those observed (e.g., for 10  δ they are 1.31 and 17.6 ppm for 1 H-NMR and 13 C-NMR, respectively).

4 Conclusion In conclusion, both N  -2-((4-methylphenyl)ethyl)-N , N -dimethylurea and N  -2-((4-chlorophenyl)ethyl)-N , N -dimethylurea were lithiated using t-BuLi at −60 to 0 ◦ C, on the NH and on the CH2 on the side chain next to the aryl ring. The dilithium reagents obtained when treated with electrophiles afforded high yields of substituted ureas. The DFT calculations suggest that lithiation on the CH2 on the sidechain (α-lithiation) is the most favorable course of action. Clearly, the substituent in the ring causes the lithiation site to be in the side chain for 10 (Cl) and 11 (Me); this is different from 7 (OMe), which is ortho-lithiation, and which could increase the electron density at position 4 of the ring, thus leading to a reduction in the acidity of the proton at the α-position. Acknowledgements This project was supported by the Deanship of Scientific Research at Prince Sattam bin Abdulaziz University under the research project 2015/01/5162. The author would like to thank Dr. El Hassane Anouar (Chemistry Department, College of Sciences and Humanities, Prince Sattam bin Abdulaziz) for his help in the DFT study. He would also like to thank Professors Gamal El-Hiti and Keith Smith for their useful discussions.

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