Nonpolar Solvent a Key for Highly Regioselective SNAr Reaction in

Jun 23, 2014 - Carbon−carbon and carbon−heteroatom (O, N, S) bond formation is generally achieved either by transition metal catalyzed cross coupl...
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Nonpolar Solvent a Key for Highly Regioselective SNAr Reaction in the Case of 2,4-Difluoronitrobenzene Suresh Kumar Sythana,†,‡ Surendra R. Naramreddy,† Santosh Kavitake,† Vinod Kumar CH.,*,† and Pundlik R. Bhagat*,‡ †

Pharmaceutical Development, AstraZeneca India Pvt. Ltd., Bellary Road, Bangalore, Karnataka, India-560024 Chemistry Division, School of Advanced Sciences, VIT University, Vellore, Tamilnadu, India-632014



S Supporting Information *

ABSTRACT: A practical and highly regioselective aromatic nucleophilic substitution reaction for the substrate 2,4-difluoronitrobenzene is demonstrated with various O/S/N-nucleophiles. Solvent screens substantiate the role of a nonpolar solvent in ortho-selective nucleophilic substitution through a six-membered polar transition state.

Figure 1. Ionic reaction pathway.

and so forth, along with the leaving/displacement group present at the ortho or para position. The reaction mechanism involves a nucleophile attack resulting in a resonance stabilized Meisenheimer complex which undergoes oxidative elimination of the leaving group. Our aim was to identify conditions for achieving a high regioselectivity (ortho) during the SNAr reaction of 2,4difluoronitrobenzene (1) with various nucleophiles. In this case two reactive positions (ortho/para) are available; when 1 is treated with benzyl alcohol 2 in the presence of a nonnucleophilic base, it can give a mixture of products 3a, 3b (isomer), and 3c (disubstituted) (see Scheme 1). The ratio of these products (3a−c) may vary based on several factors such as the nature of the solvent, base, temperature, or stoichiometry.



INTRODUCTION Carbon−carbon and carbon−heteroatom (O, N, S) bond formation is generally achieved either by transition metal catalyzed cross coupling reactions or aromatic nucleophilic substitution reactions (SNAr).1 Given a choice, the SNAr reaction is one of the best approaches usually utilized by the process chemist instead of transition metal mediated coupling reactions. The SNAr reactions, having substrates with electron deficient groups and two reactive sites (ortho vs para), have always posed a severe problem in achieving regioselectivity.2 Ortho:para reactivity has been studied in the literature with respect to various factors like the nature of substrates and leaving groups, solvent-polarity, nucleophiles, and so forth.3 Much research has been carried out on regioselective SNAr displacement approaches using various C/N/O/S nucleophiles with reasonable but limited success to achieve exclusive regioselectivity.4 It is particularly challenging to achieve good regioselectivity with highly reactive substrates such as 2,4difluoronitrobenzene.5 Recently, the isomer and disubstituted impurity formation challenges were successfully controlled by utilization of a flow reactor,6 albeit with the limitations such as homogeneous reaction conditions, high temperature, and so forth for utilization of the flow reactor. Herein, we have demonstrated the highly regioselective SNAr reaction (>95% ortho substitution) for the highly reactive substrate 2,4difluoronitrobenzene with different nucleophiles to form carbon−heteroatom (O, N, S) bonds using conventional chemistry.

Scheme 1. Products in SNAr reaction on 2,4difluoronitrobenzene

We investigated two obvious methods for the order of addition: Method A, where the substrate 1 is added to the nucleophile 2, wherein the starting material 1 concentration is less than nucleophile during the course of reaction, and as the reaction progresses the product formed 3a will be more available for reaction with nucleophile to give 3c. In this case controlling the formation of 3c is difficult (Scheme 2). In case



RESULTS AND DISCUSSION Although SNAr reactions can proceed through ions or radicals or a mixture of both reaction pathways,7 the majority of the SNAr reaction proceeds through the ionic pathway (Figure 1.). SNAr reactions are mainly observed in the substrates having electron deficient groups/atoms such as NO2, CN, CO, SO2R, © 2014 American Chemical Society

Received: April 12, 2014 Published: June 23, 2014 912

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Scheme 2. Reaction profile in Method A

Scheme 3. Reaction profile in Method B

of Method B, where base (KOtBu) is added slowly to the mixture of substrate 1 and nucleophile 2, wherein the nucleophile is generated in situ (Scheme 3). Since the concentration of the nucleophile is lower than that of 1, it can react at either the ortho or para position of substrate 1 depending on reaction conditions, leading to product 3a or 3b (isomer). In these conditions, even though the concentration of 3a will be more than 1 after certain point, the nucleophile will react with highly activated substrate 1 rather than less reactive product 3a, in turn avoiding the formation of 3c (see Scheme 3). To optimize our process, we decided to do the screening of solvent for both modes of addition using the reaction between difluoronitrobenzene 1 and benzyl alcohol 2. In Method A, the starting material 1 was slowly added to the mixture of base and nucleophile 2. As expected, the formation of 3c (disubstituted) was observed to be at a maximum (∼60%) with an increase in the polarity of the solvent. Surprisingly, in toluene, the selectivity for ortho substitution product 3a was found to be >98% with only 1.7% of 3c (disubstituted) (Table 1, Entry 1), while the isomer 3b was always less than 95% in SNAr reactions for 2,4difluoronitrobenzene was developed without utilization of flow chemistry. Clear evidence was observed for the influence of nonpolar solvent as a key for achieving high regioselectivity. Further work to explore the reactivity and selectivity using different substrates is underway.

regioselectivity in nonpolar solvent. In Method B the destruction in regioselectivity was not as high as in Method A, which is an effect of mode of addition, i.e., in situ generation of an anionic nucleophile which can either form a complex like 1a or the cation can be trapped by crown ether. Surprisingly, the results obtained with crown ether in Method A and Method B are similar to that of reactions carried out in polar solvents (see results in Table 1, entries 4−7 and Table 2, entries 5−9, respectively). This is clear evidence and support for the hypothesis that the reaction proceeds through the six-member complex 1a; formation and stability of such a complex are highly favored in nonpolar solvents which is a key to obtain regioselective ortho-substitution in 2,4-difluoronitrobenzene. The robustness of this methodology was successfully tested by carrying out reaction of 2,4-difluoronitrobenzene 1 with various alcohols primary, secondary, tertiary, aryl,and alkyl−aryl giving high regioselectivity for the entire range of alcohols. This



EXPERIMENTAL SECTION General. NMR spectra were obtained at 400 or 300 MHz. Products were analysed on HPLC coupled through an electrospray interphased to Accurate- Mass Q-TOF LC/MS. Reaction progress was monitored by a HPLC system using mobile phase A: 0.4 mM trifluoroacetic acid in water and mobile phase B: 0.4 mM trifluoroacetic acid in 3% (v/v) aqueous acetonitrile. The mobile phase was run with flow rate of 1.5 mL/min through the column Atlantis-T3 (150 × 4.6 mm

Table 4. Oxygen/sulfur/nitrogen nucelophile screening entry

Y (O/S/N)

R

method

base

temp. (°C)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

O O O O O O O O O O O O S S −NH −N− −NH −NH −N−

−CH2Ph −CH2Ph −CH3 −CH3 −C2H5 −C2H5 −CH(CH3)2 −CH(CH3)2 −C(CH3)3 −C(CH3)3 −C6H5 −C6H5 −CH2Ph −Ph −CH2Ph −[(CH2)2−O−(CH2)2)]− −nC4H9 −(CH)Ph(CH3) −[(CH2)2−N(BOC)−(CH2)2)]−

1 2 1 2 1 2 1 2 1 2 1 2 2 2 1 1 1 1 1

KOtBu KOtBu KOtBu KOtBu KOtBu KOtBu KOtBu KOtBu KOtBub KOtBub KOtBu KOtBu N(C2H5)3 N(C2H5)3 K2CO3c K2CO3c K2CO3c K2CO3c K2CO3c

0−5 0−5 0−5 0−5 0−5 0−5 0−5 0−5 0−5 0−5 0−5 0−5 0−5 0−5 45−50 45−50 45−50 45−50 45−50

product-aa (%) 98.2 99.4 83.2 94.9 98.4 97.7 97.1 94.3 97.6 82.3 98.5 98.3 98.7 97.7 99.2 99.0 99.8 99.5 99.0

(3a) (3a) (4a), 15.2 (7a) (4a) (5a) (5a) (6a) (6a) (7a) (7a) (8a) (8a) (9a) (10a) (11a) (12a) (13a) (14a) (15a)

a

Isolated yields are quantitative with the respective reaction conversion. bBase potassium tert-butoxide utilized as a nucleophile. cThe reaction rate is fast at 45−50 °C. 914

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× 3.5 um); the column oven was maintained 40 °C. A reaction sample (5 μL) was injected, and the progress of reaction was monitored at 220 nm. The gradient program used was as follows: 40% B at 0.0 min, 95% B at 8.0 min, 95% B up to 12.0 min, 40% B at 12.1 min. The post-run column equilibrium time was 3 min. Reaction sample preparation for HPLC analysis proceeded as follows: ∼0.1 mL of reaction sample was diluted to 10 mL with 10% aqueous methanol, and the sample was analysed. Spectroscopic data and HPLC chromatograms are given in the Supporting Information. Experimental Procedure (Method A) for 3a−10a. The alcohol or thiol (6.29 mmol) was dissolved in toluene (10 mL) and the contents cooled to 0−5 °C. To this reaction mixture the base was slowly added (6.60 mmol) at 0−5 °C, and the reaction mixture was stirred for 15 min. The 2,4-difluoro-1nitrobenzene (6.29 mmol) was slowly added to the above mixture at 0−5 °C. The reaction progress was monitored by HPLC. After completion of reaction, the reaction mass was quenched with water (10 mL), the organic layer separated, and sample concentrated to get the desired product. General Experimental Procedure (Method B) for 3a− 10a. To the solution of 2,4-difluoro-1-nitrobenzene (6.29 mmol) in toluene (10 mL), alcohol or thiol (6.29 mmol) was added at 0−5 °C. The base (6.60 mmol) was slowly added to the above reaction contents at 0−5 °C. The reaction progress was monitored by HPLC. After completion of the reaction, the reaction mass was quenched with water (10 mL), the organic layer separated, and sample concentrated to get the desired product. 2,4-Difluoro-1-nitrobenzene 1 (DFN Benzene). 1H NMR (400 MHz, CDCl3): δ 8.07−8.13 (m, 1H), 6.94−7.00 (m, 2H); 13C NMR (100 MHz, CDCl3): δ = 164.7 (dd, J = 255 Hz, 11 Hz, C4 carbon coupled with F and C2−F), 155.9 (dd, J = 266 Hz, 13 Hz, C2 carbon coupled with F and C4−F), 133.1 (C1 carbon), 127.2 (dd, J = 11, 2 Hz, CH, C6 carbon coupled with C2−F and C4−F), 111.2 (dd J = 23 Hz, 4 Hz, CH, C5 carbon coupled with C4−F and C2−F), 105.8 (dd, J = 26 Hz, 24 Hz CH, C3 carbon coupled with C2−F and C4−F).

Product 3b [(4-Benzyloxy-2-fluoro-1-nitrobenzene) (O-Bn FNB Isomer)]. 1H NMR (400 MHz, CDCl3): δ = 7.99−8.03 (m, 1H), 7.28−7.37 (m, 5H), 6.71−6.77 (m, 2H), 5.07 (s, 2H); 13C NMR (100 MHz, CDCl3): δ = 164.3 (d, J = 11 Hz, C4, C4 carbon coupled with C2−F), 157.5 (d, J = 264 Hz, C2, C2 carbon coupled with F), 134.9 (C), 130.9 (d, J = 6 Hz, C1, C1 carbon coupled with C2−F), 128.9 (2CH), 128.7 (CH), 127.9 (CH, C5, no coupling due to long space i.e. para f luoro), 127.5 (2CH), 111.1 (d, J = 3 Hz, CH, C6 carbon coupled with C2−F), 104.1 (d, J = 24 Hz, CH, C3 carbon coupled with C2−F), 71.1 (CH2-O-Ph). HRMS calcd for [C13H10FNO3·NH4]+: 265.0988, found 265.0980.

Product 3c [(2,4-Dibenzyloxy-1-nitrobenzene) (O-Bn Disubstituted)]. 1H NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 9.2 Hz, 1H), 7.24−7.40 (m, 10H), 6.58 (d, J = 2 Hz, 1H), 6.51 (dd, J = 9.2 Hz, 2 Hz, 1H), 5.11 (s, 2H), 5.02 (s, 2H); 13C NMR (100 MHz, CDCl3): δ = 163.6 (C4), 154.5 (C2), 135.5 (C, 2C), 135.4 (C1), 128.8 (2CH), 128.7 (2CH), 128.5 (CH), 128.4 (CH), 128.2 (CH, C6), 127.5 (2CH), 126.9 (2CH), 106.1 (CH, C5), 102.0 (CH, C3), 71.5 (CH2-O-Ph), 70.7 (CH2O-Ph). HRMS calcd for [C20H17NO4·H]+: 336.1230, found 336.1233.

Product 4a [(4-Fluoro-2-methoxy-1-nitrobenzene) (OMe FNB)]. 1H NMR (400 MHz, CDCl3): δ = 7.87−7.91 (m, 1H), 6.71−6.74 (m, 1H), 6.64−6.68 (m, 1H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 165.8 (d, J = 255 Hz, C4, C4 carbon coupled with F), 155.3 (d, J = 11 Hz, C2, C2 carbon coupled with C4−F), 135.9 (C1 carbon), 128.2 (d, J = 11 Hz, CH, C6 carbon coupled with C4−F), 107.3 (d, J = 23 Hz, CH, C5 carbon coupled with C4−F), 101.4 (d, J = 27 Hz, CH, C3 carbon coupled with C4−F), 56.8 (CH3-O). HRMS calcd for [C7H6FNO3·H]+: 172.0404, found 172.0368.

Product 3a [(2-Benzyloxy-4-fluoro-1-nitrobenzene) (O-Bn FNB)]. 1H NMR (400 MHz, CDCl3): δ = 7.86−7.88 (m, 1H), 7.25−7.39 (m, 5H), 6.73−6.76 (m, 1H), 6.62−6.67 (m, 1H), 5.13 (s, 2H); 13C NMR (100 MHz, CDCl3): δ = 165.6 (d, J = 255 Hz, C4 carbon coupled with F), 154.2 (d, J = 11 Hz, C, C2 carbon coupled C4−F), 136.4 (C1 carbon), 134.8 (C), 128.8 (2CH), 128.5 (CH), 128.1 (d, J = 11 Hz, C6 carbon coupled with C4−F), 126.9 (2CH), 107.7 (d, J = 23 Hz, CH, C5 carbon coupled C4−F), 102.9 (d, J = 26 Hz, CH, C3 coupled with C4−F), 71.5 (CH2-O-Ph); HRMS calcd for [C13H10FNO3·Na]+: 270.0537, found 270.0537.

Product 5a [(2-Ethoxy-4-fluoro-1-nitrobenzene) (O-Et FNB)]. 1H NMR (400 MHz, CDCl3): δ = 7.83−7.87 (m, 1H), 6.67−6.70 (m, 1H), 6.61−6.65 (m, 1H), 4.09 (q, J = 6.8, 2H), 1.41 (t, J = 6.8, 3H); 13C NMR (100 MHz, CDCl3): δ = 165.7 (d, J = 254 Hz, C4, C4 carbon coupled with F), 154.6 (d, J = 11 Hz, C2, C2 carbon coupled with C4−F), 136.2 (C1 carbon), 127.9 (d, J = 12 Hz, CH, C6 carbon coupled with C4−F), 107.1 (d, J = 24 Hz, CH, C5 carbon coupled with C4−F), 102.1 (d, J = 26 Hz, CH, C3 carbon coupled with C4−F), 65.8 (CH2-O), 14.3 (CH3). HRMS calcd for [C8H8FNO3·Na]+: 208.0380, found 208.0380. 915

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(C1 carbon), 133.1 (C), 128.1 (2CH), 128.0 (2CH), 127.9 (d J = 8 Hz, C6, C6 coupled with C4−F), 127.0 (CH), 112.3 (d, J = 27 Hz, CH, C5 carbon coupled with C4−F), 110.9 (d, J = 24 Hz, CH, C3 carbon coupled with C4−F), 36.7 (CH2−S). HRMS calcd for [C13H10FNO2S. Na]+: 286.0314, found 286.0309.

Product 6a [(4-Fluoro-2-isopropoxy-1-nitrobenzene) (O-iPr FNB)]. 1H NMR (400 MHz, CDCl3): δ = 7.76−7.80 (m, 1H), 6.65−6.69 (m, 1H), 6.56−6.61 (m, 1H), 4.54 (p, J = 6 Hz, 1H), 1.27 (d, J = 6, 6H); 13C NMR (100 MHz, CDCl3): δ = 165.5 (d, J = 254 Hz, C4, C4 carbon coupled with F), 153.6 (d, J = 11 Hz, C2, C2 carbon coupled with C4−F), 137.2 (C1 carbon), 127.8 (d, J = 11 Hz, CH, C6, coupled with C4−F), 107.1 (d, J = 23 Hz, CH, C5 coupled with C4−F), 103.3 (d, J = 26 Hz, CH, C3 coupled with C4−F), 73.2 (O-CH(CH3)2), 21.7 ((CH3)2). HRMS calcd for [C9H10FNO3·Na]+: 222.0537, found 222.0540.

Product 10a [(4-Fluoro-1-nitro-2-phenylsulfanylbenzene) (S-Ph FNB)]. 1H NMR (400 MHz, CDCl3): δ = 8.21− 8.25 (m, 1H), 7.42−7.53 (m, 5H), 6.78−6.83 (m, 1H), 6.38− 6.41 (m, 1H); 13C NMR (100 MHz, CDCl3): δ = 165.2 (d, J = 257 Hz, C4, C4 coupling with F), 143.9 (d, J = 9 Hz, C2, C2 carbon coupled with C4−F), 140.9 (C1 carbon), 136.1 (2CH), 130.6 (CH), 130.4 (2CH), 130.1 (C), 128.6 (d, J = 11 Hz, CH, C6 coupled with C4−F), 114.5 (d, J = 27 Hz, CH, C5 coupled with C4−F), 112.4 (d, J = 23 Hz, CH, C3 coupled with C4−F). HRMS calcd for [C12H8FNO2S·Na]+: 272.0157, found 272.0151.

Product 7a [(2-tert-Butoxy-4-fluoro-1-nitrobenzene) (O-tert-Bu FNB)]. 1H NMR (400 MHz, CDCl3): δ = 7.71− 7.74 (m, 1H), 6.83−6.86 (m, 1H), 6.72−6.77 (m, 1H), 1.38 (s, 9H); 13C NMR (100 MHz, CDCl3): δ = 164.3 (d, J = 254 Hz, C4, C4 coupled with F), 151.6 (d, J = 11 Hz, C2, C2 coupled with C4−F), 141.5 (C1 carbon), 126.8 (d, J = 11 Hz, CH, C6 coupled with C4−F), 111.0 (d, J = 24 Hz, CH, C5 coupled with C4−F), 109.6 (d, J = 24 Hz, CH, C3 coupled with C4−F), 83.7 (C−O(CH3)3), 28.7 (CH3)3); HRMS calcd for [C10H12FNO3· Na]+: 236.0693, found 236.0701.

Product 8a [(4-Fluoro-1-nitro-2-phenoxybenzene) (OPh FNB)]. 1H NMR (400 MHz, CDCl3): δ = 7.93−7.97 (m, 1H), 7.32−7.36 (m, 2H), 7.18 (s, 1H), 7.0 (d, J = 8 Hz, 2H), 6.74−6.79 (m, 1H), 6.52−6.55 (m, 1H); 13C NMR (100 MHz, CDCl3): δ = 165.4 (d, J = 255 Hz, C4, C4 coupled with F), 154.6 (C), 153.5 (d, J = 11 Hz, C2, C2 coupled with C4−F), 137.1 (C1 carbon), 130.4 (2CH), 128.1 (d, J = 11 Hz, CH, C6, C6 coupled with C4−F), 125.6 (CH), 119.9 (2CH), 109.9 (d, J = 24 Hz, CH, C5 coupled with C4−F), 106.3 (d, J = 26 Hz, CH, C3 coupled with C4−F); HRMS calcd for [C12H8FNO3· Na]+: 256.0380, found 256.0381.

General Experimental Procedure (Method A) for 11− 15a. To a suspension of potassium carbonate (3.30 mmol) in toluene (10 mL) specified amine (6.29 mmol) was charged and the reaction mass temperature raised to 45−50 °C and maintained for 15 min. The 2,4-difluoro-1-nitrobenzene (6.29 mmol) was slowly added to the above reaction mixture at 45− 50 °C. The reaction progress was monitored by HPLC. After completion of reaction, the reaction mass was quenched with water (10 mL), the organic layer separated, and the sample concentrated to get the desired product. Product 11a [(N-Benzyl-5-fluoro-2-nitroaniline) (N-Bn FNB)]. 1H NMR (400 MHz, CDCl3): δ = 8.55 (s, br, NH), 8.22−8.26 (m, 1H), 7.31−7.40 (m, 5H), 6.36−6.48 (m, 2H),4.51 (d, J = 5.2, 2H); 13C NMR (100 MHz, CDCl3): δ = 167.5 (d, J = 255 Hz, C4, C4 coupled with F), 147.3 (d, J = 13 Hz, C2, C2 carbon coupled with C4−F), 136.6 (C1 carbon), 130.0 (d J = 12 Hz, CH, C6 coupled with C4−F), 129.2 (C), 129.1 (2CH), 127.9 (CH), 127.1 (2CH), 104.4 (d, J = 25 Hz, CH, C5 coupled with C4−F), 99.9 (d, J = 27 Hz, CH, C3 coupled with C4−F), 47.3 (CH2−N). HRMS calcd for [C13H11FN2O2·H]+: 247.0877, found 247.0880.

Product 9a [(2-Benzylsulfanyl-4-fluoro-1-nitrobenzene) (S-Bn FNB)]. 1H NMR (400 MHz, CDCl3): δ = 8.21−8.25 (m, 1H), 7.22−7.36 (m, 5H), 7.05−7.08 (m, 1H), 6.83−6.88 (m, 1H), 4.09 (s, 2H); 13C NMR (100 MHz, CDCl3): δ = 164.2 (d, J = 257 Hz, C4, C4 carbon coupled with F), 141.1 (d, J = 9 Hz, C2, C2 carbon coupled with C4−F), 140.6

Product 12a [(4-(5-Fluoro-2-nitrophenyl)morpholine) (N-Morph FNB)]. 1H NMR (400 MHz, CDCl3): δ = 7.81− 7.85 (m, 1H), 6.63−6.72 (m, 2H), 3.77−3.39 (m, 4H), 2.98− 3.00 (m, 4H); 13C NMR (100 MHz, CDCl3): δ = 165.5 (d, J = 254 Hz, C4, C4 coupled with F), 148.5 (d, J = 10 Hz, C2, C2 916

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coupled with C4−F), 138.6 (C1 carbon), 129.0 (d J = 11 Hz, CH, C6 carbon coupled with C4−F), 108.6 (d, J = 23 Hz, CH, C5 coupled with C4−F), 107.2 (d, J = 25 Hz, CH, C3 carbon coupled with C4−F), 66.6 (2CH2−O), 51.7 (2CH2−N). HRMS calcd for [C 10 H 11 FN 2 O 3 ·H] +: 227.0832, found 227.0825.



ASSOCIATED CONTENT

S Supporting Information *

Spectroscopic data (1H NMR, 13C NMR, DEPT, and HRMS) for 1, 3a, 3b, 3c, and 4a−15a, HPLC chromatograms for the reaction monitoring in Method A and Method B, and HPLC chromatograms of reaction profiles for 3a−15a. This material is available free of charge via the Internet at http://pubs.acs.org.

Product 13a [(N-Butyl-5-fluoro-2-nitroaniline) (N-Bu FNB)]. 1H NMR (400 MHz, CDCl3): δ = 8.09−8.16 (m, 1H), 6.39−6.42 (m, 1H), 6.25−6.30 (m, 1H), 3.16−3.20 (m, 2H), 1.61−1.69 (m, 2H), 1.36−1.46 (m, 2H), 0.92 (t, J = 7.2, 3H); 13 C NMR (100 MHz, CDCl3): δ = 167.6 (d, J = 255 Hz, C4, C4 carbon coupled with F), 147.6 (d, J = 13 Hz, C2, C2 carbon coupled with C4−F), 130.0 (d J = 12 Hz, CH, C6 carbon coupled with C4−F), 128.7 (C1 carbon), 103.8 (d, J = 25 Hz, CH, C5 carbon coupled with C4−F), 99.2 (d, J = 27 Hz, CH, C3 carbon coupled with C4−F), 42.9 (CH2−N), 30.7 (CH2), 20.2 (CH2), 13.7 (CH3). HRMS calcd for [C10H13FN2O2·H]+: 213.1039, found 213.1037.



AUTHOR INFORMATION

Corresponding Authors

*Telephone: +91 9047289073. E-mail: drprbhagat111@gmail. com. *Telephone: +91 9945699029. E-mail: vinod.kumar@ astrazeneca.com. Notes

The authors declare no competing financial interest.



ACKNOWLEDGMENTS We thank Dr. Sudhir Nambiar (AstraZeneca India Pvt. Ltd.) for mentoring, Arun Bharadwaj (AstraZeneca India Pvt. Ltd.) for analytical support, M. Papu (AstraZeneca India Pvt. Ltd.) for his assistance, and the management of AstraZeneca India Pvt. Ltd. for providing laboratory facilities and chemicals for this research work and also SIF, Chemistry Division, VIT University, Vellore.

Product 14a [(5-Fluoro-2-nitro-N-(1-phenylethyl)amine) (N-PEA FNB)]. 1H NMR (400 MHz, CDCl3): δ = 8.47 (s, br, NH), 8.12−8.16 (m, 1H), 7.21−7.29 (m, 5H), 6.19−6.27 (m, 2H), 4.49−4.56 (m, 1H), 1.57 (d, J = 6.8, 3H); 13 C NMR (100 MHz, CDCl3): δ = 165.7 (d, J = 254 Hz, C4, C4 carbon coupled with F), 145.0 (d, J = 13 Hz, C2, C2 coupled with C4−F), 141.3 (C), 128.3 (d J = 12 Hz, CH, C6 carbon coupled with C4−F), 127.6 (2CH), 127.5 (C1 carbon), 126.1 (CH), 124.0 (2CH), 102.7 (d, J = 24 Hz, CH, C5 coupled with C4−F), 99.2 (d, J = 27 Hz, CH, C3 coupled with C4−F), 51.9 (CH-N), 23.2 (CH3). HRMS calcd for [C14H13FN2O2· H]+: 261.1039, found 261.1031.



REFERENCES

(1) (a) Terrier, F. Modern Nucleophilic Aromatic Substitution; WileyVCH Verlag GmbH and Co., KGaA: Weinheim, Germany, 2013; pp 1−472. (b) Buncel, E.; Dust, J. M.; Terrier, F. Chem. Rev. 1995, 95, 2261−2280. (c) Bunnett, J. F.; Zahler, R. E. Chem. Rev. 1951, 49, 273−412. (2) (a) Liljenberg, M.; Brinck, T.; Herschend, B.; Rein, T.; Tomasi, S.; Svensson, M. J. Org. Chem. 2012, 77, 3262−3269. (b) Scales, S.; Johnson, S.; Hu, Q.; Do, Q. Q.; Richardson, P.; Wang, F.; Braganza, J.; Ren, S.; Wan, Y.; Zheng, B.; Faizi, D.; McAlpine, I. Org. Lett. 2013, 15, 2156−2159. (c) Furet, P.; Kallen, J.; Lorber, J.; Masuya, K. 3Imidazolylindoles as MDM2 and MDM4 inhibitors and their preparation. World Patent WO 2012176123 A1, 2012. (d) Atherton, P. J. H.; Page, M. I. J. Org. Chem. 2011, 76, 3286−3295. (E) Nguyen, T. B.; Ermolenko, L.; Al-Mourabit, A. Org. Lett. 2013, 15 (16), 4218− 4221. (3) (a) Bamkole, T. O.; Hirst, J.; Udoessien, E. I. J. Chem. Soc., Perkin Trans. 2 1973, 110−114. (b) Bamkole, T. O.; Hirst, J.; Udoessien, E. I. J. Chem. Soc., Perkin Trans. 2 1973, 2114−2119. (c) Bunnett, J. F.; Morath, R. J. J. Am. Chem. Soc. 1955, 5051−5055. (4) (a) Politanskaya, L.; Malykhin, E.; Shteingarts, V. Eur. J. Org. Chem. 2001, 405−411. (b) Wu, L.; Gang, L. Chin. J. Chem. 2011, 29, 983−990. (c) Akkirala, V. N. Catal. Lett. 2008, 121, 81−84. (d) Bella, M.; Kobbelgaard, S.; Jorgensen, K. A. J. Am. Chem. Soc. 2005, 127, 3670−3671. (e) Narsaiah, A. V.; Nagaiah, K. Indian J. Chem., Sect. B 2004, 43B, 2478−2481. (f) Raeppel, S.; Raeppel, F.; Suffert, J. Synlett. 1998, 794−796. (5) (a) Gerhard, K.; Jean-Francois, B. Tetrasubstituted benzenes for treatment of early onset Alzheimer’s disease. World Patent WO2013106328 A1, 2013. (b) Leleti, M. R.; Li, Y.; Mali, V. R.; Powers, J.; Yang, J. Preparation of benzimidazole derivatives for use as CCR4 antagonists. World Patent WO2013082429 A1, 2013.

Product 15a [(tert-Butyl-4-(5-fluoro-2-nitrophenyl)piperazine-1-carboxylate) (N-Boc Piperazine FNB)]. 1H NMR (400 MHz, CDCl3): δ = 7.83−7.86 (m, 1H), 6.64−6.71 (m, 2H), 3.53 (t, J = 4.8 Hz, 4H), 2.96 (t, J = 4.8 Hz, 4H), 1.4 (s, 9H); 13C NMR (100 MHz, CDCl3): δ = 165.4 (d, J = 255 Hz, C4, C4 carbon coupled with F), 154.6 (CO), 148.6 (d, J = 10 Hz, C2, C2 carbon coupled with C4−F), 138.7 (C1 carbon), 129.0 (d J = 11 Hz, CH, C6 carbon coupled C4−F), 108.8 (d, J = 24 Hz, CH, C5 carbon coupled with C4−F), 107.6 (d, J = 25 Hz, CH, C3 carbon coupled with C4−F), 80.2 (C), 51.4 (2CH2−N), 43.4 (2CH2-N), 28.4 ((CH3)3). HRMS calcd for [C15H20FN3O4·H]+: 326.1516, found 326.1516. 917

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Organic Process Research & Development

Communication

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