Cooperation of the Neutral and the Cationic Leaving Group Pathways

Jul 13, 2018 - The reaction profile of acid-catalyzed O-benzylation with 2,4,6-tris(benzyloxy)-1,3,5-triazine (TriBOT) was analyzed to study the react...
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Cooperation of the Neutral and the Cationic Leaving Group Pathways in Acid-Catalyzed O‑Benzylation of TriBOT Hikaru Fujita, Naoko Hayakawa, and Munetaka Kunishima* Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan

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S Supporting Information *

ABSTRACT: The reaction profile of acid-catalyzed O-benzylation with 2,4,6-tris(benzyloxy)-1,3,5-triazine (TriBOT) was analyzed to study the reaction kinetics. The first-order kinetic constant for the formation of benzyl cation species from N-protonated TriBOT (neutral leaving group pathway) was estimated and compared with that of the model compound for TriBOT. Since rapid consumption of TriBOT in the late stage could not be explained solely by this pathway, cooperation of another reaction mechanism, the cationic leaving group pathway, was proposed to rationalize the rate acceleration.

I

where resulting coproducts like DiBOT and 2 have no charge.11 Herein we analyze the reaction profile of TriBOT (80 mM) with TfOH (40 mM), at 25 °C, to study the kinetics of TriBOT, which is still not clearly understood (Scheme 2). The

n 2012, we developed 2,4,6-tris(benzyloxy)-1,3,5-triazine (TriBOT, Scheme 1) as an acid-catalyzed benzylating

Scheme 1. Neutral LG Pathway of Triazine-Based Benzylating Reagents

Scheme 2. Acid-Catalyzed O-Benzylation with TriBOT in the Presence of TfOH (40 mM, 50 mol %)

reagent, which was designed to be the formal trimer of the smallest unit of alkyl imidate.1,2 This versatile concept has been applied to the introduction of p-methoxybenzyl,3 fluorous benzyl,4 tert-butyl,5 allyl, and substituted allyl groups.6 After we reported TriBOT, it was utilized for the synthesis of sugar derivatives,7a−c natural products,8a,b and other compounds.9a−c The standard reaction conditions of TriBOT employ trifluoromethanesulfonic acid (TfOH) as a catalyst (40 mM, 50 mol % based on 80 mM TriBOT) in 1,4-dioxane at room temperature in the presence of a nucleophile (200 mM) such as an alcohol. Powdered molecular sieves (5 Å) are added as a dehydrating agent to remove residual moisture. The protonated TriBOT (TriBOT-H+) formed in situ generates benzyl cation species, most likely benzyl trifluoromethanesulfonate, and DiBOT as a leaving group (LG). The nucleophile is benzylated by the benzyl cation species and regenerates the acid catalyst. We previously carried out a kinetic study for the model compound of TriBOT, 2-benzyloxy-4,6-dimethoxy1,3,5-triazine (1, Scheme 1), whose protonated form (1-H+) gave the benzyl cation species and LG 2 following first-order kinetics.10 We refer to this kind of reaction mechanism for triazine-based alkylating reagents as a neutral LG pathway, © XXXX American Chemical Society

final product from TriBOT is isocyanuric acid, formed due to the intermediates, DiBOT and MonoBOT (Scheme 2), also generating the benzyl cation species in the presence of TfOH. In this study, a nucleophile (3-phenylpropanol, 3) was used in excess (1200 mM) to suppress the known side reaction, which affords N-benzylisocyanuric acid ( TriBOT ≈ MonoBOT > isocyanuric acid, an alcohol, and 1,4-dioxane. TriBOT and DiBOT will behave as dominant bases because the concentration of MonoBOT was too low to detect during the reaction. Therefore, [TriBOT-H+] was estimated to be [H+]total − [DiBOT]obs in the region of [TriBOT]obs > [TriBOT-H+], where [H+]total represents the sum of acidic protons in the reaction mixture. Since the reaction between the benzyl cation species and 3 produces H+ rapidly, [H+]total will be constant and equal to the amount of TfOH (40 mM) used during the reaction. As a result, [TriBOT-H+] was almost constant during 30−120 min (purple dashed line, 31.4 ± 1.0 mM). Consequently, the decrease in [TriBOT]obs in this region, virtually followed pseudozero-order kinetics if TriBOT was consumed via the neutral LG pathway. The kinetic constant kn was estimated to be 10.3 × 10−3 min−1 (25 °C), from the calculation using [TriBOT-H+] = 31.4 mM and the slope of [TriBOT]obs in Figure 1. It is worth comparing kn with the corresponding kinetic constant of 1 under the analogous conditions since 1 was prepared as a model of TriBOT. As expected, first-order kinetics were observed in the reaction of 1 (42.4 mM) with TfOH (40 mM, 95 mol % based on 1) in the presence of excess 3 (1200 mM) at 25 °C (Scheme 3). The rate constant for the neutral LG pathway of 1 was obtained as k′n = 1.88 × 10−3 min−1, which was 5.5 times smaller than kn.12 A plausible factor for this difference is the number of benzyl groups in the molecules. The reaction of TriBOT is expected to be Scheme 3. Acid-Catalyzed O-Benzylation with 1 in the Presence of TfOH (40 mM, 95 mol %)

Figure 2. Late-stage kinetics of TriBOT in O-benzylation of 3 (1200 mM) with TriBOT (80 mM) and TfOH (40 mM). B

DOI: 10.1021/acs.joc.8b01505 J. Org. Chem. XXXX, XXX, XXX−XXX

Note

The Journal of Organic Chemistry

ability for “spontaneous in situ rate acceleration” as observed for TriBOT. This property is unique and advantageous over most organic reactions, which require extended reaction times due to the slowdown of the reaction in the late stage.

mechanism of triazine-based alkylating reagents, a cationic LG pathway (Scheme 4) where the carbocation species were Scheme 4. Cationic LG Pathway of Triazine-Based Benzylating Reagents

EXPERIMENTAL SECTION



ASSOCIATED CONTENT

General Information. Reagents were commercial grade and were used without any purification. Known compounds (TriBOT,1 DiBOT,10 MonoBOT,10 and 110) were prepared as described in the literature. HPLC analysis was carried out using Mightysil RP-18Gp Aqua at a flow rate of 1.0 mL/min with UV detection at 254 nm. Concentrations of compounds were determined using calibration curves generated with p-nitrotoluene as an internal standard and with samples of known concentrations. The calibration curves for HPLC analysis were previously reported.10 General Procedure for HPLC Monitoring of Acid-Catalyzed O-Benzylation. TfOH (40−80 mM) was added to a solution of 3 (40−1200 mM), a triazine-based benzylating reagent [TriBOT (67− 80 mM) or 1 (42.4 mM)], p-nitrotoluene (15−30 mM), and powdered MS5A (5.0 mg/mL) in 1,4-dioxane at 25 ± 0.5 °C or at room temperature. Aliquots were withdrawn from the reaction mixture at recorded intervals, diluted 50 times with a pyridine solution (2.0 mM) in H2O/MeCN (1:1), and filtered. HPLC analysis was performed using p-nitrotoluene as an internal standard. HPLC conditions of the reaction with TriBOT: gradient of 0.1% TFA in H2O (solvent A) and 0.1% TFA in MeCN (solvent B), 80% A + 20% B to 65% A + 35% B (0−10 min), 65% A + 35% B (10−20 min), 65% A + 35% B to 40% A + 60% B (20−25 min), 40% A + 60% B (25−40 min), 40% A + 60% B to 20% A + 80% B (40−45 min). HPLC conditions of the reaction with 1: gradient of 80% H2O + 20% MeCN to 65% H2O + 35% MeCN (0−10 min), 65% H2O + 35% MeCN to 30% H2O + 70% MeCN (10−25 min), 30% H2O + 70% MeCN to 10% H2O + 90% MeCN (25−26 min).

generated rapidly from N,N′-diprotonated triazines formed in the presence of excess H + with a small equilibrium concentration.11 We also provided the rate law for this pathway in the O-benzylation reaction on the basis of kinetic studies using a model compound. Using the rate law, the decrease in [TriBOT]obs ([TriBOT-H+]) after 137.9 min can be given by eq 1 if both the neutral and the cationic LG pathways were operative. −



d[TriBOT]obs = (k n + kc[excess H+]2 )[TriBOT]obs dt (1)

Here, kc is the observed first-order kinetic constant for the cationic LG pathways of TriBOT, while [excess H+] after 137.9 min is described to be 40 − ([TriBOT]obs + [DiBOT]obs) (black dashed line, Figure 2). Curve fitting using the resulting equation for [TriBOT]obs obtained curve B (red curve, r2 = 0.999) with kc = 7.71 × 10−5 min−1 mM−2 at 25 °C. (The details can be found in the Supporting Information.) To demonstrate the cationic LG pathways of TriBOT under typical conditions, we carried out acid-catalyzed O-benzylation reactions for 3 (200 mM) using TriBOT (67 mM) and TfOH (Table 1). When 40 mM of TfOH (60 mol % based on

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01505. Kinetic study of O-benzylation with 1 and curve fitting for the late-stage kinetics of TriBOT (PDF)

Table 1. Effect of the TfOH Concentration on the Reaction Rate of TriBOT



AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. entry

TfOH (mol % based on TriBOT)

time of TriBOT disappearance (min)a

1 2

60 120

60−65