HETEROCYCLES

Short Paper | Special issue | Vol. 86, No. 2, 2012, pp. 1583-1590
Received, 31st July, 2012, Accepted, 28th August, 2012, Published online, 6th September, 2012.
DOI: 10.3987/COM-12-S(N)105

■ PHOSPHONIUM CHLORIDE AS A NON-VOLATILE CHLORINATING REAGENT: PREPARATION AND REACTION IN NO SOLVENT OR IONIC LIQUID

Osamu Sugimoto,* Yukihiro Harada, and Ken-ichi Tanji*

Laboratory of Organic Chemistry, School of Food and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan

Abstract

Reaction of triphenylphosphine with trichloroisocyanuric acid in no solvent or an ionic liquid gave the corresponding phosphonium chloride, which can be used as a cheap and safe chlorinating reagent. Conversion of hydroxyheterocycles to chloroheterocycles, carboxylic acids to carboxylic acid chlorides, and primary amides to nitriles were accomplished by using the phosphonium chloride in excellent to good yields.

Chlorination of nitrogen-containing π-deficient heterocycles (abbreviated as heterocycles) is one of the important methods in heterocyclic chemistry because chloroheterocycles are frequently used as useful synthetic intermediates. Phosphorus oxychloride (POCl3) and phosphorus pentachloride (PCl5) are widely used for a powerful reagent for the chlorination of many hydroxyheterocycles.1-6 However, since POCl3 and PCl5 are highly reactive with water, the uses of them are troublesome at the work-up process. It was found that phosphonium chlorides prepared by reaction of triphenylphosphine (PPh3) with N-chloro compounds can be used as a chlorinating reagent.7-12 Especially, the reagent 1 which is prepared by reaction of PPh3 and trichloroisocyanuric acid (TCICA), react as a useful substitute for POCl3 or PCl5.12 This reagent 1 is usually used in an appropriate solvent, which is chosen by reactivity of the substrate. However, removal of a solvent which have high boiling point is hard at post-treatment. Since recent studies13 show that certain phosphonium salts act as ionic liquids due to their low melting points. From these points of view, development of a solvent-free preparation and reaction of 1 would be useful. In this paper, preparation and reaction of 1 in no solvent or an ionic liquid was carried out as shown in Scheme 1.

At first, preparation of 1 under solvent-free condition was examined. A mixture of TCICA and PPh3 was warmed slowly by heating bath. PPh3 melted at 100 °C, and TCICA was vigorously reacted with PPh3 at 135-140 °C to form 1. The resulting 1 at room temperature is too viscous to stir by a magnetic stirrer. However, 1 becomes less viscous enough to stir when warmed at 100 °C or above. Thus, it is expected that 1 can be used as a non-volatile and solvent-free available chlorinating reagent. As shown in Table 1, reaction of the substrate, 2(1H)-quinolinone with 1 under several conditions were carried out to optimize the condition.

The substrate was added to 1 (1 eq) and heated at 140-150 °C for 2 h to give the corresponding chlorinated product, 2-chloroquinoline in 54% yield (Entry 1). In order to clarify the stability of 1, reaction of 2(1H)-quinolinone with 1 (1 eq) which was allowed to stand at room temperature for 8 and 24 days after preparation was carried out, and 2-chloroquinoline was obtained in 50% and 42% yields, respectively (Entries 2 and 3). These results indicate that 1 is stable for at least a few days at room temperatue. Next, chlorination of 2(1H)-quinolinone with varying amounts of 1 was carried out. When excess 1 (1.5 eq and 2 eq) was used, the products were obtained in 79% and 86% yields, respectively (Entries 4 and 5). As summarized in Table 1, the phosphonium chloride 1, which is prepared from solvent-free reaction of PPh3 with TCICA, can be used as a non-volatile chlorinating reagent. It should be noted that reaction using 1 in no solvent can be manipulated at arbitrary temperature (for example, high temperature such as 140-150 °C) since 1 has extremely low vapor pressure.
Reaction of PPh3 with TCICA under solvent-free condition is a useful method to facilely generate 1. However, this method in a large scale may be troublesome since TCICA vigorously react with PPh3 at 135-140 °C. So in order to generate 1 gently and to lower the viscosity of 1, preparation and reaction of 1 in room temperature ionic liquids (RTILs) was carried out as shown in Table 2.

A mixture of PPh3 and TCICA in BMIMPF6 was stirred at several temperatures followed by reaction with 2(1H)-quinolinone at 140-150 °C for 2 h. The reaction time was reduced as the reaction temperature rose (Entries 1-4). When 2 equivalents of 1 was used, the yield of 2-chloroquinoline was improved (Entries 5-9). From the results shown in Table 1 and 2, it was found that preparation of 1 in BMIMPF6 is effective in a large reaction scale (10 mmol of 1 or above) since reaction of PPh3 with TCICA proceeds gently by using BMIMPF6.
Chlorination of hydroxyazines and hydroxydiazines using 1 in no solvent or BMIMPF6 was carried out in order to find the generality of reaction (Table 3). Azines and diazines are well known to be reactive with nucleophiles at α- or γ-position to the ring nitrogen. α-Hydroxy compound (Entries 1, 2, 7, 8, 17, and 18), γ-hydroxy compound (Entries 3-6), and dihydroxy compound (Entries 9-16) were used as substrates.

A mixture of the substrate and 1, which was prepared by reaction of PPh3 with TCICA at 135-140 °C for 15 min (no solvent) or 75-80 °C for 1 h (in BMIMPF6), was heated at 140-150 °C for 2 h. All substrates reacted with 1 in no solvent or BMIMPF6 to give the corresponding chlorinated products in high to moderate yields.
Activation of carboxylic acids using 1 followed by addition of nucleophiles were carried out as shown in Scheme 2. Carboxylic acids (benzoic acid, 1-naphthoic acid, and 2-naphthoic acid) was reacted with 1 (2 eq) at 140-150 °C for 30 min to afford the corresponding carboxylic acid chlorides, which was treated with ethanol at room temperature for 1 h to give the corresponding carboxylic acid ethyl esters. Amidation of carboxylic acids were examined by a similar method. Carboxylic acid chlorides generated from carboxylic acids reacted with diethylamine at room temperature to give carboxylic acid diethylamides in excellent yields.

Dehydration of primary amides using 1 was carried out (Scheme 3). p-Methoxybenzamide as an aromatic amide and phenylacetamide as an aliphatic amide were used as substrates. Reaction of the substrates with 1 at 140-150 °C for 2 h gave the desired nitriles in excellent yields.

In conclusion, we have clarified that the phosphonium chloride 1 can be generated in no solvent or BMIMPF6 to perform as a useful substitute for conventional chlorinating reagents such as POCl3 or PCl5.

EXPERIMENTAL
All melting points were not corrected. 1H-NMR spectra were measured with Hitachi R-90H spectrometer (90 MHz) using tetramethylsilane as an internal standard.

Preparation and reaction of ((1,3,5-triazine-2,4,6-triyl)tris(oxy))tris(triphenylphosphonium) chloride (1) under solvent-free condition (General procedure): In a 50 mL of recovery flask equipped with reducing joint and balloon, a mixture of TCICA (317 mg, 1.36 mmol) and PPh3 (1050 mg, 4.00 mmol) was warmed slowly by heating bath. PPh3 melted at 100 °C, and TCICA was vigorously reacted with PPh3 at 135-140 °C followed by stirring for 5 min to give brown oil, 1. 2(1H)-Quinolinone (295 mg, 2.03 mmol) was added to 1 and heated at 140-150 °C for 2 h. White solids were sublimed to adhere to the surface of reducing joint. Et2O was added to the reaction mixture (including the sublimed solids) and basified with triethylamine. After Et2O layer was separated for 3 times, the Et2O solution was combined and concentrated followed by purification with silica gel column chromatography (eluted with hexane-EtOAc (10:1)) to give 2-chloroquinoline (287 mg, 86%).
2-Chloroquinoline: Colorless oil. 1H-NMR (CDCl3), δ: 7.38 (1H, d, J = 8.5 Hz, C3-H), 7.50-7.90 (3H, m, C5, C6, and C7-H), 8.02 (1H, d, J = 6.2 Hz, C8-H), 8.10 (1H, d, J = 8.5 Hz, C4-H).

Preparation and reaction of 1 in BMIMPF6 (General procedure): In a 50 mL of recovery flask equipped with reducing joint and balloon, a mixture of TCICA (315 mg, 1.36 mmol), PPh3 (1051 mg, 4.01 mmol), and BMIMPF6 (3 mL) was warmed at 75-80 °C until TCICA was completely consumed (for 1 h) to give BMIMPF6 solution of 1. 2(1H)-Quinolinone (290 mg, 2.00 mmol) was added to BMIMPF6 solution of 1 and heated at 140-150 °C for 2 h. White solids were sublimed to adhere to the surface of reducing joint. Et2O was added to the reaction mixture (including the sublimed solids) and basified with triethylamine. After Et2O layer was separated for 3 times, the Et2O solution was combined and concentrated followed by purification with silica gel column chromatography (eluted with hexane-EtOAc (8:1)) to give 2-chloroquinoline (275 mg, 84%).

2-Chloro-4-methylquinoline: Slight yellow solids. Mp 52.5 °C (lit.,14 55-57 °C). 1H-NMR (CDCl3), δ: 7.24 (1H, s, C3-H), 7.43-7.83 (2H, m, C6 and C7-H), 7.83-8.11 (2H, m, C5 and C8-H).
4-Chloroquinoline: Colorless oil. 1H-NMR (CDCl3), δ: 7.49 (1H, d, J = 4.8 Hz, C3-H), 7.59-7.95 (2H, m, C6 and C7-H), 7.95-8.42 (2H, m, C5 and C8-H), 8.78 (1H, d, J = 4.8 Hz, C2-H).
4,7-Dichloroquinoline: White solids. Mp 86.9 °C (lit.,15 86.4-87.4 °C). 1H-NMR (CDCl3), δ: 7.48 (1H, d, J = 4.7 Hz, C3-H), 7.50-7.71 (1H, m, C6-H), 7.99-8.31 (1H, m, C5-H), 8.12 (1H, s, C8-H), 8.77 (1H, d, J = 4.7 Hz, C2-H).
1-Chloroisoquinoline: Slight yellow solids. Mp 30.1 °C (lit.,16 35-37 °C). 1H-NMR (CDCl3), δ: 7.42-7.98 (4H, m, C4, C5, C6, and C7-H), 8.13-8.47 (2H, m, C3 and C8-H).
2,4-Dichloroquinoline: Pale yellow solids. Mp 62.3 °C (lit.,17 66-67 °C). 1H-NMR (CDCl3), δ: 7.51 (1H, s, C3-H), 7.59-7.91 (2H, m, C6 and C7-H), 7.91-8.30 (2H, m, C5 and C8-H).
2,4-Dichloropyrimidine: White solids. Mp 58-59 °C (lit.,18 60-61 °C). 1H-NMR (CDCl3), δ: 7.33 (1H, d, J = 5.3 Hz, C5-H), 8.52 (1H, d, J = 5.3 Hz, C6 -H).
2,4-Dichloroquinazoline: White solids. Mp 120 °C (lit.,19 120-121 °C). 1H-NMR (CDCl3), δ: 7.51 (1H, s, C3-H), 7.59-7.91 (2H, m, C6 and C7-H), 7.91-8.30 (2H, m, C5 and C8-H).
2,3-Dichloroquinoxaline: White solids. Mp 157.2 °C (lit.,20 152-153 °C). 1H-NMR (CDCl3), δ: 7.60-7.90 (2H, m, C6 and C7-H), 7.90-8.17 (2H, m, C5 and C8-H).
2-Chloroquinoxaline: White solids. Mp 47.1 °C (lit.,21 47-47.5 °C). 1H-NMR (CDCl3), δ: 7.60-7.90 (2H, m, C6 and C7-H), 7.90-8.30 (2H, m, C5 and C8-H), 8.78 (1H, s, C3-H).
Ethyl benzoate: Colorless liquids. 1H-NMR (CDCl3), δ: 1.40 (3H, t, J = 7.1 Hz, CH3), 4.38 (2H, q, J=7.1 Hz, CH2), 7.28-7.71 (3H, m, phenyl-H), 7.92-8.19 (2H, m, phenyl-H).
Ethyl 1-naphthoate: Colorless liquids. 1H-NMR (CDCl3), δ: 1.45 (3H, t, J = 7.1 Hz, CH3), 4.47 (2H, q, J = 7.1 Hz, CH2), 7.31-7.73 (3H, m, aromatic-H), 7.73-8.27 (3H, m, aromatic-H), 8.90 (1H, d, J = 8.2 Hz, aromatic-H).
Ethyl 2-naphthoate: Colorless liquids. 1H-NMR (CDCl3), δ: 1.44 (3H, t, J = 7.1 Hz, CH3), 4.44 (2H, q, J = 7.1 Hz, CH2), 7.38-7.70 (2H, m, aromatic-H), 7.70-8.20 (4H, m, aromatic-H), 8.60 (1H, s, aromatic-H).
N,N-Diethylbenzamide: Slight yellow liquids. 1H-NMR (CDCl3), δ: 1.17 (6H, t, J = 6.8 Hz, CH3 × 2), 3.40 (4H, brs, CH2 × 2), 7.37 (5H, s, phenyl-H).
N,N-Diethyl-1-naphthamide: Slight yellow oil. 1H-NMR (CDCl3), δ: 0.99 (3H, t, J = 7.1 Hz, CH3), 1.37 (3H, t, J = 7.1 Hz, CH3), 3.10 (2H, q, J = 7.1 Hz, CH2), 3.69 (2H, brs, CH2), 7.28-7.64 (4H, m, aromatic-H), 7.64-8.00 (3H, m, aromatic-H).
N,N-Diethyl-2-naphthamide: Slight yellow oil. 1H-NMR (CDCl3), δ: 1.20 (6H, t, J = 6.9 Hz, CH3 × 2), 3.43 (4H, brs, CH2 × 2), 7.30-7.66 (3H, m, aromatic-H), 7.66-8.01 (4H, m, aromatic-H).
4-Methoxybenzonitrile: White solids. Mp 56.1 °C (lit.,22 55-57 °C). 1H-NMR (CDCl3), δ: 3.86 (3H, s, CH3), 6.94 (2H, d, J = 8.8 Hz, aromatic-H), 7.58 (2H, d, J = 8.8 Hz, aromatic-H).
Phenylacetonitrile: Slight yellow liquids. 1H-NMR (CDCl3), δ: 3.74 (2H, s, CH2), 7.34 (5H, s, phenyl-H).

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