Regioselective Alkylation of an Oxonaphthalene-Annelated Pyrrol System

Abstract

The regioselective alkylation of an oxonaphthalene-annelated pyrrole system is reported. The regioselectivity of alkylation can be controlled by the selection of the solvent.

Introduction

Nitrogen mustards were the first clinically effective cancer therapeutic agents. Chlorambucil is one of numerous aromatic derivatives of compounds with a nitrogen mustard moiety that have been synthesized. It has been a clinical agent for many years and remains in common use at the present time. The cytotoxic effects are based on the highly active aziridinium cation intermediates arising from the bis(2-chloroethyl)amine moiety [1]. In continuation of our department’s previous studies in the field of antitumor agents [2,3,4,5,6,7], the pyrrole derivative 1 [8] was chosen as an educt for the synthesis of new chlorambucil analogs. Here, we wish to describe the synthesis of the two key intermediates 2a and 2b from 1 by regioselective alkylation with the BOC-protected 4-aminobenzyl bromide building block 1a.

Results and Discussion

Starting from pyrrole 1, the alkylation procedure with 1a, using NaH as a base in DMF solution afforded only the expected N-alkylated product 2a. On the other hand, use of THF as solvent was found to give selectively access to the C-1 alkylated product 2b. Based on comparison with previously reported ¹H- and ¹³C-NMR data of 1 [8,9], it was possible to assign to the latter compound (2b) the structure of a C-1 alkylated product and to exclude a C-3 alkylated isomer. Thus, a regioselective approach to either 2a or 2b, respectively, is possible simply by selection of the appropriate solvent. Since the pyrrole derivative 1 is in conjugation with a strongly electron-withdrawing carbonyl group, previously published studies (see below) on C- vs. N-alkylation of pyrrole are not fully comparable and thus cannot give a clear explanation of these results: K. Sukata had described increasing C-alkylation vs. N-alkylation of pyrrole in protic solvents such as PEG or water, in aprotic solvents such as PEG-ethers N-alkylation was preferred [10]; D. Y. Chi had developed an ionic liquid methodology for pyrrole to achieve regioselective N- and C-alkylation, respectively [11,12].

After cleavage of the N-BOC protecting group, both compounds will now serve as starting materials for the syntheses of new anticancer drugs with a nitrogen mustard moiety, the results will be reported elsewhere.

Experimental

General procedure for the preparation of 2a or 2b

A solution of 1 (1.17 g, 5.54 mmol) in 10 mL of dry DMF (for 2a) or 10 mL of dry THF (for 2b) was added dropwise under argon to a suspension of NaH (0.20 g of a 60% dispersion in mineral oil; washed with hexane; 8.31 mmol) in 12.5 mL of dry DMF or THF, respectively (see above). After stirring for 0.5 h at 0 °C, a solution of tert-butyl[4-(bromomethyl)phenyl]carbamate (1a) (2.50 g, 8.31 mmol) in dry DMF or THF, respectively (see above), was added. The reaction mixture was heated for 3 h (50 °C for DMF or 66 °C for THF). The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were dried (Na₂SO₄), filtered, and concentrated. The resulting crude product was purified by column chromatography (silica gel, ethyl acetate/light petroleum, 70/30 + 1% triethylamine) to afford 1.31 g (57%) of 2a or 0.80 g (35%) of 2b, respectively.

tert-Butyl[4-[(5,5-dimethyl-4-oxo-4,5-dihydro-2H-benzo[e]isoindol-2-yl)methyl]phenyl]carbamte (2a): M.p. 74-76 °C (light petroleum/ethyl acetate). IR (KBr): 3312, 1724, 1650, 1526, 1240, 1155 cm^-1. MS (EI, 70 eV) m/z: 416 (M⁺, 3%), 106 (11), 57 (43), 45 (14) 44 (15), 43 (100), 42 (18), 41 (40). ¹H NMR (CDCl₃, 200 MHz) δ = 9.38 (s_br, 1H, NH), 7.60 (d, J = 1.5 Hz, 1H, 3-H), 7.64-7.42 (m, 5H, 1-H, 6-H, 9-H, 2’-H, 6’-H), 7.27 (d, J = 8.5 Hz, 2H, 3’-H, 5’-H), 7.18 (m, 2H, 7-H, 8-H), 5.12 (s, 2H, CH₂), 1.44 (s, 9H, (CH₃)₃), 1.35 (s, 6H, (CH₃)₂). ¹³C NMR (CDCl₃, 50 MHz) δ = 196.5 (C-4), 152.7 (COO), 143.4 (C-5a), 139.3 (C-1’), 130.8 (C-4’), 128.5 (C-3’, C-5’), 127.1 (C-6), 126.8 (C-9a), 126.4 (C-7), 126.3 (C-8), 124.2 (C-9b), 123.7 (C-3), 122.7 (C-9), 118.2 (C-2’, C-6’), 117.3 (C-3a), 116.3 (C-1), 79.1 (C(CH₃)₃), 52.7 (CH₂N), 46.8 (C-5), 28.1 ((CH₃)₃), 27.97 ((CH₃)₂). HRMS calcd. for C₂₆H₂₈N₂O₂: 416.2099. Found: 416.2103.

tert-Butyl[4-[(5,5-dimethyl-4-oxo-4,5-dihydro-2H-benzo[e]isoindol-1-yl)methyl]phenyl]carbamte (2b): M.p. 135-137 °C (light petroleum/ethyl acetate). IR (KBr): 3345, 3249, 1697, 1644, 1527, 1238, 1156 cm⁻¹. MS (EI, 70 eV) m/z: 416 (M⁺, 6%), 360 (13), 106 (12), 71 (7), 59 (11), 57 (100), 56 (27), 55 (19). ¹H NMR (CDCl₃, 200 MHz) δ = 11.88 (s_br, 1H, NH), 9.24 (s, 1H, NH), 7.53-7.44 (m, 3H, 3-H, 6-H, 9-H), 7.36 (d, J = 8.5 Hz, 2H, 2’-H, 6’-H), 7.14-7.04 (m, 4H, 7-H, 8-H, 3’-H, 5’-H), 4.24 (s, 2H, CH₂), 1.43 (s, 9H, (CH₃)₃), 1.37 (s, 6H, (CH₃)₂) . ¹³C NMR (CDCl₃, 200 MHz) δ = 197.1 (C-4), 152.8 (COO), 143.6 (C-5a), 137.7 (C-1’), 132.2 (C-4’), 128.0 (C-3’, C-5’), 128.2/126.6 (C-9a/C-9b), 127.1 (C-6), 126.2 (C-7), 125.6 (C-8), 123.0 (C-9), 119.4 (C-3), 118.4 (C-2’, C-6’), 118.4/117.9 (C-1/C-3a), 78.9 (C(CH₃)₃), 46.9 (C-5), 32.1 (CH₂), 28.1 ((CH₃)₃), 28.0 ((CH₃)₂). HRMS calcd. for C₂₆H₂₈N₂O₂: 416.2099. Found: 416.210.