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Synlett 2009(12): 1915-1920  
DOI: 10.1055/s-0029-1217518
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Solvent-Free Synthesis of Alkylthiazolium-Based Ionic Liquids and their Use as Catalysts in the Intramolecular Stetter Reaction

Audrey Aupoix, Giang Vo-Thanh*
Laboratoire de Catalyse Moléculaire, Institut de Chimie Moléculaire et des Matériaux d’Orsay, UMR 8182, Université Paris-Sud 11, 91405 Orsay Cedex, France
Fax: +33(1)69154680; e-Mail: gvothanh@icmo.u-psud.fr;

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Publication History

Received 9 January 2009
Publication Date:
25 June 2009 (online)

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Abstract

The first synthesis of alkylthiazolium-based ionic liquids under ‘green chemistry’ conditions is described. Thiazolium salts and triethylamine have been found to catalyze efficiently the ­intramolecular Stetter reaction, giving excellent yields within very short reaction times using solvent-free microwave activation conditions.

Key words

solvent-free reaction - microwave activation - ionic liquids - thiazolium salts - Stetter reaction

Over the past decade, ionic liquids (ILs), or room temperature molten salts, have received considerable attention thanks to their ability to be used as effective reaction media for a wide range of organic reactions and other applications in chemistry. [¹] By modifying the structure of the cations or anions of ionic liquids, it has been shown that their properties can be altered in order to influence the outcomes of reactions. The details of several types of ionic liquids have been published, however, very few thiazolium salts have been described. [²] As far as we know, no synthesis of thiazolium-based ionic liquids using solvent-free microwave activation has ever been reported.

Microwave (MW) activation has emerged as a powerful technique for promoting a variety of chemical reactions and has become a useful technology in organic chemistry. [³] The combination of solvent-free conditions and MW irradiation considerably reduces reaction times, enhances conversions as well as selectivity and has environmental advantages. [4] This method has previously been successfully applied to the synthesis of several imidazolium-based ILs. [5]

In 2004, we reported the first synthesis of chiral ionic liquids possessing a chiral ephedrinium cation using solvent-free microwave irradiation conditions. [6] Recently, Cravotto et al. [7] described an effective and rapid one-pot procedure to synthesize a second-generation ionic liquid using combined microwave/ultrasound irradiation.

In view of the emerging importance of the ILs as reaction media in organic synthesis and our general interests in MW-assisted chemical processes, we report herein the first synthesis of alkylthiazolium-based ionic liquids under ‘green chemistry’ conditions. The thiazolium salts and triethylamine have subsequently been used as catalysts for the intramolecular Stetter reaction using solvent-free ­microwave activation conditions.

In our initial studies, we attempted to optimize the reaction conditions for the N-alkylation of thiazole with ­bromooctane or iodooctane. All the MW reactions were carried out in a CEM Discover monomode system with strict control of power and temperature during the reaction, in the absence of any solvent (Scheme  [¹] ). The optimum yield was obtained when performing the reaction at 150 ˚C for 1.5 hours using iodooctane as alkylating agent. Various alkyl chain lengths with iodide (as associated anion) were then tested. Generally speaking, good yields were obtained (Table  [¹] ).

Scheme 1 Solvent-free microwave-assisted N-alkylation of thia­zole

Table 1 Solvent-Free N-Alkylation of Thiazole with n-Alkyl ­Bromide or Iodides under Monomode Microwave Irradiationa
Entry R
(equiv) 		X Time (min) Temp (˚C) Conversion (%)b Isolated yield (%)
1 C8H17 (1.2) Br  90 120  76 -
2 C8H17 (1.2) I  90 120  84 -
3 C 8 H 17 (1.5) I  90 150 100 98 (88) c
4 C4H9 (1.5) I  90 150  90 90
5 C10H21 (1.5) I  90 150  98 98
6 C12H25 (1.5) I  90 150  60 59
7 C12H25 (1.5) I 120 150  75 72
a Reactions were conducted in a CEM Discover system in closed ­vessels. b Conversion estimated by ¹H NMR.
c Yield obtained under conventional heating given in brackets.

It should be noted that the synthesis of alkylthiazolium salts has been performed in the presence of organic solvents such as acetonitrile, N,N-dimethylformamide or ­acetone using classical conditions and the reactions always take a long time (around two days) to fully consume the substrate. [²] Moreover, when a thermostat-controlled oil bath (conventional heating) was used under otherwise identical reaction conditions (time, temperature, vessel, profile of rise in temperature, without solvent), a drop in yield (88%, Table  [¹] , entry 3) was observed.

The next step in the synthesis involved anion exchange of thiazolium iodide salts 3 with an alkaline earth metal or ammonium salts of charge-delocalized soft anions (BF4 -, PF6 -, TfO- or NTf2 -). Generally, this step was carried out at reflux in a large excess of acetone as solvent for several hours or even several days. [8] Good yields were generally obtained in all cases.

As already reported by Varma et al., [³g] an anion exchange metathesis is easily performed under MW activation using a domestic oven. In this way, 1,3-dialkylimidazolium tetrafluoroborate salts were prepared in good yields after only a few minutes of reaction time. In order to simplify the overall procedure, and following our process developed for the synthesis of chiral ionic liquids derived from (-)-N-ephedrine, [6] a three-component, one-pot procedure was investigated. Thus, thiazole, iodooctane and anion exchange agent (MY) were directly submitted to MW irradiation (Scheme  [²] ). All reactions were conducted in the CEM Discover monomode system in a closed reactor under solvent-free conditions. The significant results are given in Table  [²] .

Scheme 2 One-pot synthesis of octylthiazolium-based ionic liquids

Table 2 One-Pot, Solvent-Free Microwave-Assisted Preparation of Octylthiazolium-Based Ionic Liquidsa
Entry MY Conversion (%)b Isolated yield (%)
1 NaBF4 100 93
2 KPF6 100 82
3 KOTf 100 86
4 LiNTf2 100 75c
a Reaction conditions: thiazole (1 equiv), C8H17I (1.5 equiv), MY ­
(1 equiv), 150 ˚C, 1.5 h.
b Conversion estimated by ¹H NMR.
c Two-step, one-pot sequence synthesis.

The data in Table  [²] indicate the good yields that were obtained within short reaction times. All of the thiazolium salts are viscous liquids at room temperature. It should be noted that, in the case of LiNTf2, a poor yield and, more importantly, a mixture of thiazolium salts with two associated anions (I- and NTf2 -) resulted when the reaction was performed as a three-component, one-pot procedure. In order to solve this problem, we decided to perform this reaction in a two-step but one-pot sequence reaction. The product (not isolated) resulting from the quaternisation step was directly submitted to an anion exchange step to afford 75% yield of the desired product (Table  [²] , Entry 4).

The Stetter reaction, the catalytic 1,4-addition of an activated aldehyde to an acceptor bearing an activated double bond (Scheme  [³] ), is a very simple and useful method for the synthesis of 1,4-bifunctional molecules, such as 1,4-diketones, 4-ketoesters and 4-ketonitriles, which are key intermediates in organic synthesis. [9] [¹0] The Stetter reaction is traditionally carried out in protic solvents such as alcohols or in aprotic solvents such as DMF, dioxane or aceto­nitrile, or even without solvent. Imidazolium-type ionic liquids have also been employed with success as solvents for this reaction. [¹0h] More recently, a microwave-assisted Stetter reaction has been reported which uses ionic liquids as solvents; goods yields within short reaction times were observed. [¹0k] The most widely used catalysts for the Stetter reaction are functionalized thiazolium salts 5, which are used in the presence of base, as shown in Scheme  [³] . Stetter and co-workers found that the benzyl-substituted thiazolium salt 5a gave the best results for the addition of aliphatic aldehydes, whereas the 5b and 5c were used to demonstrate the addition of aromatic aldehydes. All of these three were found to be suitable for addition with heterocyclic aldehydes. The salt 5d was used with α,β-unsaturated esters.

Scheme 3 Stetter reaction

After achieving the synthesis of different alkylthiazolium salts 4, we were interested in testing their catalytic potential for the intramolecular Stetter reaction of methyl 4-(2-formylphenoxy)but-2-enoate (6) using microwave activation (Scheme  [4] ). As reported by Yang et al., [¹0k] good yields were obtained when reactions were performed ­using microwave irradiation in imidazolium-based ionic liquids as solvents with the functionalized thiazolium salt 5c and triethylamine as catalysts. In our first experiments, the substrate 6 (Z = H), easily obtained by condensation of salicylaldehyde with methyl 4-bromocrotonate according to the reported protocol, [¹¹] was irradiated with alkyl­thiazolium 4 (R = C8H17, Y = I) in the presence of triethylamine as basic catalyst. Optimization of reaction conditions was carried out and the main results obtained are summarized in Table  [³] . Good yields were generally obtained.

Scheme 4 Intramolecular Stetter reaction

Table 3  Solvent-Free Microwave-Promoted Intramolecular Stetter Reactiona
Entry Solvent
(1.5 equiv)b 		Catalyst 4 (equiv) Conversion (%)c Isolated yield (%)
1 [bmim][BF4] 0.15 100 91
2 [omim][BF4] 0.15 100 96
3 [omim][PF6] 0.15 100 85
4 No solvent 0.15  89 85
5 No solvent 0.15 100d 97 (77)e
6 [bmim][BF4] 0   0 -
7 No solvent 0   0 -
8 No solvent 0.15   0f -
a Reaction conditions: 6 (1 equiv), catalyst 4 (R = C8H17, Y = I), Et3N (0.15 equiv), 30 min, 80 ˚C.
b Abbreviations used: bmim: 1-butyl-3-methylimidazolium, omim:
1-octyl-3-methylimidazolium.
c Conversion estimated by ¹H NMR.
d Temperature: 100 ˚C, time: 20 min.
e Yield obtained under conventional heating given in brackets.
f Without Et3N.

As observed by Grée [¹0h] and Yang, [¹0k] the reaction was found to perform better in imidazolium-based ionic liquids. This observation is supported and confirmed by our studies when performing the reaction under reaction conditions similar to those described by Yang, but using our simple alkylthiazolium salt 4 as catalyst. Excellent conversions and very good yields were obtained in short reaction times (Table  [³] , entries 1-3). Furthermore, in order to develop an environmentally friendly synthetic process, a solvent-free microwave activation procedure was tested. Interestingly, a comparable yield was obtained when the reaction was carried out under the same conditions without any solvent (Table  [³] , entry 4). Raising the reaction temperature from 80 to 100 ˚C, not only improved the yield of 7 (up to 97%; Table  [³] , entry 5) but, in addition, reduced the reaction time from 30 minutes to 20 minutes. It has been established by Yang’s group [¹0k] that good yields were obtained using ionic liquid as solvent under microwave irradiation. However, it must be pointed out that, in our studies, the use of solvent-free microwave activation conditions led to excellent yields in a very short reaction time. A lower yield was recorded (77%; Table  [³] , entry 5) using conventional heating under identical reaction conditions.

It was confirmed that no conversion was observed when the reaction was performed in the absence of catalyst 4 (Table  [³] , entries 6 and 7) or in the presence of catalyst but without triethylamine as basic catalyst (Table  [³] , entry 8). It is important to remember that triethylamine serves as a base to form the carbene from the thiazolium salt.

With this result in hand, we proceeded to examine the nature of the catalyst on the reaction, using no solvent, under microwave activation. To this end, a series of tests was executed using thiazolium iodide salts possessing various alkyl chain lengths as catalysts. The best yield of 96% was obtained with R = C8H17. A drop in yield was observed with R = C10H21 (Table  [4] , entries 2 and 3). The nature of the counter-ion did not affect the yield of the product. The results obtained are shown in Table  [4] .

Table 4 Solvent-Free, Microwave-Promoted Intramolecular Stetter Reactiona
Entry R Y Isolated yield (%)
1 C4H9 I 89
2 C8H17 I
BF4PF6
OTf
NTf2 		96
96
92
99
97
3 C10H21 I 75
4 C12H25 I 84
a Reaction conditions: 6 (1 equiv), catalyst 4 (0.15 equiv), base (0.15 equiv), 100 ˚C, 20 min.
Table 5 Solvent-Free, Microwave-Promoted Intramolecular Stetter Reactiona
Entry Z Isolated yield (%)
1 H 97
2 Me 93
3 MeO 90
4 Cl 90
5 Br 82
6 NO2 34b
a Reaction conditions: 6 (1 equiv), catalyst 4 (0.15 equiv), base (0.15 equiv), 100 ˚C, 20 min.
b Together with 28% yield of five-membered ring product 8.

Intramolecular Stetter reactions of substituted methyl 4-(2-formylphenoxy)but-2-enoate (6) shown in Table  [5] were accomplished with no complications, generally ­resulting in the desired product 7 in good to excellent isolated yields (82-97%, except in the case where Z = NO2) and in very short reaction times (20 min). All reactions were carried out under microwave activation, using 0.15 equivalents of thiazolium iodide 4 (R = C8H17), in the absence of any solvent. Substituents on the aromatic ring (Me, OMe, Cl and Br) have practically no effect on the yield. In the case of substrates where Z = NO2, only 34% yield of desired product was isolated. However, here we obtained another five-membered ring product 8 (28%), resulting from a retro-Michael addition as already observed by Yang and co-workers. [¹0k] The structure and the formation of 8 are represented in Scheme  [5] .

Scheme 5 Formation of compound 8

In conclusion, we have developed the first synthesis of alkylthiazolium-based ionic liquids using solvent-free synthesis or solvent-free microwave activation conditions. [¹²] We have also described an environmentally benign and highly efficient procedure for the preparation of chromanone derivatives via an intramolecular Stetter ­reaction. Thiazolium salts and triethylamine have been found to efficiently catalyze this reaction, giving excellent yields within very short reaction times, using solvent-free microwave activation conditions.

Acknowledgment

We are grateful to the Interchim Company for supporting a doctoral fellowship (A. A.), the CNRS (UMR 8182) and the Université ­Paris-Sud 11 for financial support.

12

General Procedure for the Solvent-Free N-Alkylation of Thiazole under Microwave Irradiation: A mixture of thiazole 1 (85 mg, 1 mmol) and 1-iodoalkane 2 (1.5 mmol) was irradiated (CEM Discover reactor) at 150 ˚C for the appropriate time (see Table  [¹] ). The reaction mixture was brought to room temperature and washed with Et2O (2 × 10 mL). The crude product was dried under reduced pressure to afford a yellow powder which did not need further purification.
1-Butylthiazolium Iodide M.p. 101 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 0.99 (3 H, t, J = 7.5 Hz), 1.40-1.47 (2 H, m), 2.00-2.05 (2 H, m), 4.83 (2 H, t, J = 7.5 Hz), 8.28 (1 H, d, J = 2.6 Hz), 8.34 (1 H, d, J = 3.4 Hz), 10.95 (1 H, s). ¹³C NMR (75 MHz, CDCl3): δ = 13.9, 19.8, 32.9, 56.5, 127.5, 137.0, 159.6. IR (KBr): 3434, 3020, 2945, 1989, 1829, 1637, 1543, 1434, 1256, 1144, 952, 861, 639 cm-¹. HRMS (EI): m/z [M+] calcd for C7H12NS: 142.0685; found: 142.0690.
1-Octylthiazolium Iodide M.p. 27 ˚C. ¹H NMR (300 MHz, CDCl3): δ =0.74 (3 H, t, J = 7.2 Hz), 1.21-1.26 (10 H, m), 1.91-1.96 (2 H, m), 4.73 (2 H, t, J = 7.1 Hz), 8.4 (1 H, d, J = 3.4 Hz), 8.54 (1 H, d, J = 3.8 Hz), 10.69 (1 H, s). ¹³C NMR (90 MHz, CDCl3): δ = 14.0, 22.5, 26.1, 28.8, 28.9, 30.6, 31.6, 56.3, 127.8, 136.9, 158.6. IR (NaCl): 3445, 3046, 2926, 2855, 1621, 1551, 1463, 1422, 1262, 1154, 907, 833, 749, 634 cm-¹. HRMS (EI): m/z [M+] calcd for C11H20NS: 198.1313; found: 198.1316.
1-Decylthiazolium Iodide M.p. 39 ˚C. ¹H NMR (360 MHz, CDCl3): δ = 0.79 (3 H, t, J = 6.1 Hz), 1.17-1.28 (14 H, m), 1.96-1.97 (2 H, m), 4.76 (2 H, t, J = 7.0 Hz), 8.42 (1 H, d, J = 1.8 Hz), 8.54 (1 H, d, J = 3.2 Hz), 10.72 (1 H, s). ¹³C NMR (90 MHz, CDCl3): δ = 13.7, 22.1, 25.6, 28.5, 28.7, 28.8, 28.9, 30.2, 31.3, 55.8, 127.5, 136.6, 158.2. IR (KBr): 3435, 3078, 2922, 2852, 1555, 1471, 1370, 1264, 1150, 905, 812, 630 cm-¹. HRMS (EI): m/z [M+] calcd for C13H24NS: 226.1625; found: 226.1629.
1-Dodecylthiazolium Iodide M.p. 92 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 0.86 (3 H, t, J = 7.0 Hz), 1.27-1.34 (18 H, m), 1.99-2.04 (2 H, m), 4.80 (2 H, t, J = 7.5 Hz), 8.41 (1 H, d, J = 3.4 Hz), 8.47 (1 H, d, J = 3.6 Hz), 10.79 (1 H, s). ¹³C NMR (90 MHz, CDCl3): δ = 14.0, 22.6, 26.1, 28.9, 29.2, 29.3, 29.4, 29.5, 29.6, 30.6, 31.8, 56.3, 127.6, 136.6, 159.0. IR (KBr): 3096, 3079, 2916, 2850, 1556, 1472, 1258, 1149, 908, 811 cm-¹. HRMS (EI): m/z [M+] calcd for C15H28NS: 254.1933; found: 254.1942.
General Procedure for Solvent-Free ‘One-Pot’ Preparation of Alkylthiazolium 4 from 1 under Microwave Irradiation: A mixture of thiazole 1 (85 mg, 1 mmol), 1-iodooctane (360 mg, 1.5 mmol) and alkaline salt MY (1.5 mmol), was irradiated (CEM Discover reactor) at 150 ˚C for 1.3 h (see Table  [²] ). The reaction mixture was brought to room temperature and CH2Cl2 (10 mL) were added. After filtration, the solvent was evaporated. The crude product was washed with Et2O (2 × 10 mL) and dried under reduced pressure to afford a yellow viscous oil which did not need further purification.
1-Octylthiazolium Trifluoromethanesulfonate ¹H NMR (250 MHz, CDCl3): δ = 0.84 (3 H, t, J = 4.8 Hz), 1.23-1.32 (10 H, m), 1.96-2.02 (2 H, m), 4.68 (2 H, t, J = 7.3 Hz), 8.29 (1 H, d, J = 3.8 Hz), 8.38 (1 H, d, J = 3.8 Hz), 10.42 (1 H, s). ¹³C NMR (90 MHz, CDCl3): δ = 14.0, 22.5, 26.1, 28.8, 28.9, 30.5, 31.6, 56.1, 127.1, 137.0, 158.2. IR (NaCl): 3500, 3084, 2928, 2858, 1633, 1553, 1468, 1258, 1225, 1162, 1030, 914, 836, 757, 639 cm-¹. HRMS (EI): m/z [M+] calcd for C11H20NS: 198.1308; found: 198.1316.
1-Octylthiazolium Hexafluorophosphate
M.p. 27 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 0.83 (3 H, t, J = 6.0 Hz), 1.22-1.31 (10 H, m), 1.98-2.02 (2 H, m), 4.73 (2 H, t, J = 7.5 Hz), 8.36 (1 H, d, J = 2.6 Hz), 8.44 (1 H, d, J = 3.8 Hz), 10.54 (1 H, s). ¹³C NMR (90 MHz, CDCl3): δ = 13.9, 22.3, 25.8, 28.7, 28.8, 30.5, 31.4, 56.0, 127.6, 136.7, 158.3. IR (NaCl): 3440, 3084, 2929, 2856, 1602, 1553, 1469, 1174, 1012, 905, 750 cm-¹. HRMS (EI): m/z [M+] calcd for C11H20NS: 198.1309; found: 198.1316. 1-Octylthiazolium Tetrafluoroborate ¹H NMR (300 MHz, CDCl3): δ = 0.83 (3 H, t, J = 7.1 Hz), 1.28-1.32 (10 H, m), 1.99-2.03 (2 H, m), 4.79 (2 H, t, J = 7.5 Hz), 8.42 (1 H, d, J = 3.4 Hz), 8.52 (1 H, d, J = 3.4 Hz), 10.57 (1 H, s). ¹³C NMR (90 MHz, CDCl3): δ = 14.3, 22.8, 26.4, 29.1, 29.2, 30.8, 31.9, 56.6, 127.2, 137.2, 158.6. IR (NaCl): 3445, 3094, 2929, 2858, 1607, 1553, 1469, 1352, 1194, 1058, 915, 740 cm-¹. HRMS (EI): m/z [M+] calcd for C11H20NS: 198.1308; found: 198.1309.
Solvent-Free Microwave-Promoted ‘Two-Step, One-Pot Sequence’ Preparation of Octylthiazolium Bis(trifluoromethanesulfonyl)imide: A mixture of thiazole 1 (85 mg, 1 mmol) and 1-bromooctane (360 mg, 1.5 mmol) was irradiated (CEM Discover reactor) at 150 ˚C for 1.3 h. Lithium bis(tstrifluoromethanesulfonyl)imide (373 mg, 1.5 mmol) was added and the resulting mixture was then placed under MW irradiation for an additional period of 30 min at 100 ˚C. The reaction mixture was brought to room temperature and CH2Cl2 (10 mL) was added. After filtration, the solvent was evaporated. The crude product was washed with Et2O (2 × 10 mL) and dried under reduced pressure to afford a yellow viscous oil (356 mg, 75%) which did not need further purification.
1-Octylthiazolium Bis(trifluoromethanesulfonyl)imide M.p. 30 ˚C. ¹H NMR (360 MHz, CDCl3): δ = 0.84 (3 H, t, J = 6.6 Hz), 1.25-1.35 (10 H, m), 1.97-2.05 (2 H, m), 4.73 (2 H, t, J = 7.5 Hz), 8.35 (1 H, d, J = 3.6 Hz), 8.42 (1 H, d, J = 3.6 Hz), 10.52 (1 H, s). ¹³C NMR (90 MHz, CDCl3): δ = 13.4, 21.9, 25.5, 28.2, 28.3, 30.1, 31.0, 55.7, 127.2, 136.4, 158.1. IR (NaCl): 3436, 3064, 2926, 2855, 1622, 1553, 1463, 1267, 1154, 906, 834 cm-¹. HRMS (EI): m/z [M+] calcd for C11H20NS: 198.1314; found: 198.1316.


Representative Procedure for Microwave-Assisted Intramolecular Stetter Reaction: A mixture of methyl 4-(2-formylphenoxy)but-2-enoate 6 (Z = H; 0.11 g, 0.5 mmol), Et3N (51 mg, 0.5 mmol) and octylthiazolium iodide (25 mg, 15% mol) was irradiated at 100 ˚C for 20 minutes. The reaction was quenched with 0.1 N HCl and extracted with CH2Cl2. The organic phase was washed with H2O, dried over MgSO4, filtered and concentrated in vacuum to afford a pale-orange oil 7 (107 mg, 97% yield).


Methyl 2-(3,4-Dihydro-4-oxo-2 H -chromen-3-yl)acetate ¹H NMR (250 MHz, CDCl3): δ = 2.42 (1 H, dd, J = 8.2, 16.8 Hz), 2.92 (1 H, dd, J = 5.1, 17.1 Hz), 3.28-3.36 (1 H, m), 3.71 (3 H, s), 4. 28 (1 H, t, J = 11.7 Hz), 4.58 (1 H, dd, J = 5.4, 11.1 Hz), 6.99 (1 H, dd, J = 8.8, 15.5 Hz), 7.46 (1 H, t, J = 8.2 Hz), 7.86 (1 H, d, J = 7.9 Hz). ¹³C NMR (90 MHz, CDCl3): δ = 29.9, 42.4, 51.9, 70.1, 117.7, 121.4, 135.9, 161.4, 171.7, 192.4. IR (NaCl): 3583, 2953, 1738, 1694, 1606, 1580, 1480, 1324, 1301, 1215, 1014, 870, 760 cm-¹. HRMS (EI): m/z [M + Na+] calcd for C12H12O4Na: 243.0627; found: 243.0633.

12

General Procedure for the Solvent-Free N-Alkylation of Thiazole under Microwave Irradiation: A mixture of thiazole 1 (85 mg, 1 mmol) and 1-iodoalkane 2 (1.5 mmol) was irradiated (CEM Discover reactor) at 150 ˚C for the appropriate time (see Table  [¹] ). The reaction mixture was brought to room temperature and washed with Et2O (2 × 10 mL). The crude product was dried under reduced pressure to afford a yellow powder which did not need further purification.
1-Butylthiazolium Iodide M.p. 101 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 0.99 (3 H, t, J = 7.5 Hz), 1.40-1.47 (2 H, m), 2.00-2.05 (2 H, m), 4.83 (2 H, t, J = 7.5 Hz), 8.28 (1 H, d, J = 2.6 Hz), 8.34 (1 H, d, J = 3.4 Hz), 10.95 (1 H, s). ¹³C NMR (75 MHz, CDCl3): δ = 13.9, 19.8, 32.9, 56.5, 127.5, 137.0, 159.6. IR (KBr): 3434, 3020, 2945, 1989, 1829, 1637, 1543, 1434, 1256, 1144, 952, 861, 639 cm-¹. HRMS (EI): m/z [M+] calcd for C7H12NS: 142.0685; found: 142.0690.
1-Octylthiazolium Iodide M.p. 27 ˚C. ¹H NMR (300 MHz, CDCl3): δ =0.74 (3 H, t, J = 7.2 Hz), 1.21-1.26 (10 H, m), 1.91-1.96 (2 H, m), 4.73 (2 H, t, J = 7.1 Hz), 8.4 (1 H, d, J = 3.4 Hz), 8.54 (1 H, d, J = 3.8 Hz), 10.69 (1 H, s). ¹³C NMR (90 MHz, CDCl3): δ = 14.0, 22.5, 26.1, 28.8, 28.9, 30.6, 31.6, 56.3, 127.8, 136.9, 158.6. IR (NaCl): 3445, 3046, 2926, 2855, 1621, 1551, 1463, 1422, 1262, 1154, 907, 833, 749, 634 cm-¹. HRMS (EI): m/z [M+] calcd for C11H20NS: 198.1313; found: 198.1316.
1-Decylthiazolium Iodide M.p. 39 ˚C. ¹H NMR (360 MHz, CDCl3): δ = 0.79 (3 H, t, J = 6.1 Hz), 1.17-1.28 (14 H, m), 1.96-1.97 (2 H, m), 4.76 (2 H, t, J = 7.0 Hz), 8.42 (1 H, d, J = 1.8 Hz), 8.54 (1 H, d, J = 3.2 Hz), 10.72 (1 H, s). ¹³C NMR (90 MHz, CDCl3): δ = 13.7, 22.1, 25.6, 28.5, 28.7, 28.8, 28.9, 30.2, 31.3, 55.8, 127.5, 136.6, 158.2. IR (KBr): 3435, 3078, 2922, 2852, 1555, 1471, 1370, 1264, 1150, 905, 812, 630 cm-¹. HRMS (EI): m/z [M+] calcd for C13H24NS: 226.1625; found: 226.1629.
1-Dodecylthiazolium Iodide M.p. 92 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 0.86 (3 H, t, J = 7.0 Hz), 1.27-1.34 (18 H, m), 1.99-2.04 (2 H, m), 4.80 (2 H, t, J = 7.5 Hz), 8.41 (1 H, d, J = 3.4 Hz), 8.47 (1 H, d, J = 3.6 Hz), 10.79 (1 H, s). ¹³C NMR (90 MHz, CDCl3): δ = 14.0, 22.6, 26.1, 28.9, 29.2, 29.3, 29.4, 29.5, 29.6, 30.6, 31.8, 56.3, 127.6, 136.6, 159.0. IR (KBr): 3096, 3079, 2916, 2850, 1556, 1472, 1258, 1149, 908, 811 cm-¹. HRMS (EI): m/z [M+] calcd for C15H28NS: 254.1933; found: 254.1942.
General Procedure for Solvent-Free ‘One-Pot’ Preparation of Alkylthiazolium 4 from 1 under Microwave Irradiation: A mixture of thiazole 1 (85 mg, 1 mmol), 1-iodooctane (360 mg, 1.5 mmol) and alkaline salt MY (1.5 mmol), was irradiated (CEM Discover reactor) at 150 ˚C for 1.3 h (see Table  [²] ). The reaction mixture was brought to room temperature and CH2Cl2 (10 mL) were added. After filtration, the solvent was evaporated. The crude product was washed with Et2O (2 × 10 mL) and dried under reduced pressure to afford a yellow viscous oil which did not need further purification.
1-Octylthiazolium Trifluoromethanesulfonate ¹H NMR (250 MHz, CDCl3): δ = 0.84 (3 H, t, J = 4.8 Hz), 1.23-1.32 (10 H, m), 1.96-2.02 (2 H, m), 4.68 (2 H, t, J = 7.3 Hz), 8.29 (1 H, d, J = 3.8 Hz), 8.38 (1 H, d, J = 3.8 Hz), 10.42 (1 H, s). ¹³C NMR (90 MHz, CDCl3): δ = 14.0, 22.5, 26.1, 28.8, 28.9, 30.5, 31.6, 56.1, 127.1, 137.0, 158.2. IR (NaCl): 3500, 3084, 2928, 2858, 1633, 1553, 1468, 1258, 1225, 1162, 1030, 914, 836, 757, 639 cm-¹. HRMS (EI): m/z [M+] calcd for C11H20NS: 198.1308; found: 198.1316.
1-Octylthiazolium Hexafluorophosphate
M.p. 27 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 0.83 (3 H, t, J = 6.0 Hz), 1.22-1.31 (10 H, m), 1.98-2.02 (2 H, m), 4.73 (2 H, t, J = 7.5 Hz), 8.36 (1 H, d, J = 2.6 Hz), 8.44 (1 H, d, J = 3.8 Hz), 10.54 (1 H, s). ¹³C NMR (90 MHz, CDCl3): δ = 13.9, 22.3, 25.8, 28.7, 28.8, 30.5, 31.4, 56.0, 127.6, 136.7, 158.3. IR (NaCl): 3440, 3084, 2929, 2856, 1602, 1553, 1469, 1174, 1012, 905, 750 cm-¹. HRMS (EI): m/z [M+] calcd for C11H20NS: 198.1309; found: 198.1316. 1-Octylthiazolium Tetrafluoroborate ¹H NMR (300 MHz, CDCl3): δ = 0.83 (3 H, t, J = 7.1 Hz), 1.28-1.32 (10 H, m), 1.99-2.03 (2 H, m), 4.79 (2 H, t, J = 7.5 Hz), 8.42 (1 H, d, J = 3.4 Hz), 8.52 (1 H, d, J = 3.4 Hz), 10.57 (1 H, s). ¹³C NMR (90 MHz, CDCl3): δ = 14.3, 22.8, 26.4, 29.1, 29.2, 30.8, 31.9, 56.6, 127.2, 137.2, 158.6. IR (NaCl): 3445, 3094, 2929, 2858, 1607, 1553, 1469, 1352, 1194, 1058, 915, 740 cm-¹. HRMS (EI): m/z [M+] calcd for C11H20NS: 198.1308; found: 198.1309.
Solvent-Free Microwave-Promoted ‘Two-Step, One-Pot Sequence’ Preparation of Octylthiazolium Bis(trifluoromethanesulfonyl)imide: A mixture of thiazole 1 (85 mg, 1 mmol) and 1-bromooctane (360 mg, 1.5 mmol) was irradiated (CEM Discover reactor) at 150 ˚C for 1.3 h. Lithium bis(tstrifluoromethanesulfonyl)imide (373 mg, 1.5 mmol) was added and the resulting mixture was then placed under MW irradiation for an additional period of 30 min at 100 ˚C. The reaction mixture was brought to room temperature and CH2Cl2 (10 mL) was added. After filtration, the solvent was evaporated. The crude product was washed with Et2O (2 × 10 mL) and dried under reduced pressure to afford a yellow viscous oil (356 mg, 75%) which did not need further purification.
1-Octylthiazolium Bis(trifluoromethanesulfonyl)imide M.p. 30 ˚C. ¹H NMR (360 MHz, CDCl3): δ = 0.84 (3 H, t, J = 6.6 Hz), 1.25-1.35 (10 H, m), 1.97-2.05 (2 H, m), 4.73 (2 H, t, J = 7.5 Hz), 8.35 (1 H, d, J = 3.6 Hz), 8.42 (1 H, d, J = 3.6 Hz), 10.52 (1 H, s). ¹³C NMR (90 MHz, CDCl3): δ = 13.4, 21.9, 25.5, 28.2, 28.3, 30.1, 31.0, 55.7, 127.2, 136.4, 158.1. IR (NaCl): 3436, 3064, 2926, 2855, 1622, 1553, 1463, 1267, 1154, 906, 834 cm-¹. HRMS (EI): m/z [M+] calcd for C11H20NS: 198.1314; found: 198.1316.


Representative Procedure for Microwave-Assisted Intramolecular Stetter Reaction: A mixture of methyl 4-(2-formylphenoxy)but-2-enoate 6 (Z = H; 0.11 g, 0.5 mmol), Et3N (51 mg, 0.5 mmol) and octylthiazolium iodide (25 mg, 15% mol) was irradiated at 100 ˚C for 20 minutes. The reaction was quenched with 0.1 N HCl and extracted with CH2Cl2. The organic phase was washed with H2O, dried over MgSO4, filtered and concentrated in vacuum to afford a pale-orange oil 7 (107 mg, 97% yield).


Methyl 2-(3,4-Dihydro-4-oxo-2 H -chromen-3-yl)acetate ¹H NMR (250 MHz, CDCl3): δ = 2.42 (1 H, dd, J = 8.2, 16.8 Hz), 2.92 (1 H, dd, J = 5.1, 17.1 Hz), 3.28-3.36 (1 H, m), 3.71 (3 H, s), 4. 28 (1 H, t, J = 11.7 Hz), 4.58 (1 H, dd, J = 5.4, 11.1 Hz), 6.99 (1 H, dd, J = 8.8, 15.5 Hz), 7.46 (1 H, t, J = 8.2 Hz), 7.86 (1 H, d, J = 7.9 Hz). ¹³C NMR (90 MHz, CDCl3): δ = 29.9, 42.4, 51.9, 70.1, 117.7, 121.4, 135.9, 161.4, 171.7, 192.4. IR (NaCl): 3583, 2953, 1738, 1694, 1606, 1580, 1480, 1324, 1301, 1215, 1014, 870, 760 cm-¹. HRMS (EI): m/z [M + Na+] calcd for C12H12O4Na: 243.0627; found: 243.0633.

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Scheme 1 Solvent-free microwave-assisted N-alkylation of thia­zole

Scheme 2 One-pot synthesis of octylthiazolium-based ionic liquids

Scheme 3 Stetter reaction

Scheme 4 Intramolecular Stetter reaction

Scheme 5 Formation of compound 8