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Synthesis 2012(4): 532-540  
DOI: 10.1055/s-0031-1289993
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Tetrasubstituted NH Pyrroles and Polysubstituted Furans via an Addition and Cyclization Strategy

Liang Li, Mi-Na Zhao, Zhi-Hui Ren, Jianli Li, Zheng-Hui Guan*
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry & Materials Science, Northwest University, Xi’an 710069, P. R. of China
e-Mail: guanzhh@nwu.edu.cn;

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Publication History

Received 5 October 2011
Publication Date:
22 December 2011 (online)

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Abstract

The FeCl3-catalyzed addition and cyclization of enamino esters with nitroolefins provides a straightforward and general method for the synthesis of tetrasubstituted NH pyrroles. This novel method tolerates a wide range of functionality, and allows for rapid elaboration of the nitroolefins into a variety of substituted pyrroles in good yields. Further, an efficient KOAc-promoted addition and cyclization protocol toward substituted furans has been described as well.

Key words

tetrasubstituted NH pyrroles - polysubstituted furans - addition - cyclization

Pyrroles have a privileged role in organic chemistry. Highly substituted pyrroles are one of the important classes of structural unit frequently found in many natural products [¹] and pharmaceuticals. [²] Furthermore, many of the substituted pyrroles have been widely used in material science [³] and supramolecular chemistry. [4] As a consequence, polysubstituted pyrroles have received considerable attention over the years and various methods for their preparation have been developed. [5]

In the past several years, transition-metal-catalyzed cyclizations [6] and multicomponent coupling reactions [7] for the preparation of substituted pyrroles have been reported. [8] Transition metals, such as palladium, [9] copper, [¹0] gold, [¹¹] silver, [¹²] and ruthenium [¹³] were shown to be active catalysts in pyrrole ring formation. However, iron-catalyzed cyclization reactions [¹4] for the construction of pyrrole rings has rarely been reported. Recently, iron salts have been extensively investigated as alternative and promising catalysts for many organic transformations due to their low price and environmentally friendly character. [¹5] In connection with our recent work on the synthesis of multisubstituted pyrroles, we wish to report herein an FeCl3-catalyzed polysubstituted NH pyrrole ring formation reaction.

Recently, we have developed an addition and cyclization reaction of enamino esters to nonhalogenated nitroolefins for the synthesis of fully substituted pyrroles. [¹6] Although this metal-free method showed good functional group tolerance, it was not suitable for the synthesis of NH pyrroles. Due to the importance of the NH pyrroles in organic chemistry, [¹7] our efforts were directed in exploring efficient methods for the synthesis of substituted NH pyrroles by using readily available enamino esters and nitroolefins as the starting materials.

The study began with the addition and cyclization reaction of enamino ester 2a with nitroolefin 1a in MeOH in the absence of catalyst. The desired NH pyrrole 3a (see Figure  [¹] for the X-ray structure) was observed in low yield (Table  [¹] , entry 1). Although glycol proved to be the most effective solvent, the NH pyrrole 3a was only obtained in moderate yield (Table  [¹] , entry 3). Thus, various potential catalysts, such as CuI, FeCl3, FeCl2, PTSA, I2, Ph3P, were screened in order to improve the efficiency of the transformation (Table  [¹] , entries 5-10). To our delight, FeCl3 was shown to be an active catalyst in the reaction, and the desired NH pyrrole 3a was obtained in 80% yield (Table  [¹] , entry 6). FeCl2 and PTSA were less effective (Table  [¹] , entries 7, 8).

Figure 1 X-ray structure of 3a

Table 1 Addition and Cyclization of Enamino Ester to Nitroolefin for Synthesis of NH Pyrrolea

Entry Catalyst Solvent Time (h) Yield (%)
 1 - MeOH  5 50
 2 - DMSO  5 n.r.b
 3 - glycol  5 63
 4 - MeCN  5 n.r.b
 5 CuI glycol 15 50c
 6 FeCl3 glycol  4 80d
 7 FeCl2 glycol  5 72e
 8 PTSA glycol  8 60f
 9 I2 glycol 15 63g
10 Ph3P glycol 15 55h
a Reaction conditions: 1a (0.5 mmol) and 2a (0.75 mmol) in solvent (3 mL) at 100 ˚C.
b n.r.: no reaction.
c CuI (10 mol%).
d FeCl3 (10 mol%).
e FeCl2 (10 mol%).
f PTSA (20 mol%).
g I2 (20 mol%).
h Ph3P (20 mol%).

With the optimized conditions in hand, we have explored the substrates scope. The FeCl3-catalyzed addition and cyclization reaction of enamino ester 2a with nitroolefins 1a-j are summarized in Table  [²] . These transformations displayed high functional group tolerance. Various nitroolefins with methyl, methoxy, amino, chloro, and fluoro groups on the arene rings proceeded smoothly to give the corresponding pyrroles 3a-h in good yields (Table  [²] , entries 1-8). In general, the reaction was insensitive to the electronic effects of the aromatic substituents on the nitroolefins. A lower yield was observed for the addition and cyclization of enamino ester 2a with (Z)-2-(2-nitroprop-1-enyl)furan (1i) due to the partial decomposition of the nitroolefin 1i in the presence of the FeCl3 catalyst (Table  [²] , entry 9). Similarly, 5H-pyrrole 3j was obtained in moderate yield (Table  [²] , entry 10). In addition, the substrate derived from 3-oxo-N-phenylbutanamide underwent the desired reaction to give the corresponding product 3k in good yield (Table  [²] , entry 11). We have also extended the reaction scope to (Z)-4-aminopent-3-en-2-one. The desired pyrrole product 3l was obtained under the conditions albeit in low yields (Table  [²] , entry 12).

The plausible mechanism for the reaction is shown in Scheme  [¹] . Enamines 2 and nitroolefin 1 undergo Michael reaction to form an intermediate B. [¹4a] Then FeCl3 interacts with intermediate B to generate an electron-deficient complex C, [¹5a] [c] which undergoes intramolecular electrophilic cyclization and elimination reaction to gave the desired NH pyrrole 3. [¹4a]

Scheme 1 Proposed mechanism for the reaction

Table 2  FeCl3-Catalyzed Addition and Cyclization of Enamino Ester 2a to Nitroolefins 1 a (continued)

Entry 1
Pyrrole
 Time (h) Yield (%)
 1 1a

3a

4 80
 2 1b

3b

6 79
 3 1c

3c

6 75
 4 1d

3d

 8 74
 5 1e

3e

10 53
 6 1f

3f

10 60
 7 1g

3g

10 65
 8 1h

3h

 6 77
 9 1i

3i

 8 37
10 1j

3j

 5 42
11 1a

3k

 4 70b
12 1a

3l

 4 30c
a Reaction conditions: 1 (0.5 mmol), 2a (0.75 mmol), and FeCl3 (10 mol%) in glycol (3 mL) at 100 ˚C.
b Compound 1a (0.5 mmol), (Z)-3-amino-N-phenylbut-2-enamide (0.75 mmol), and FeCl3 (10 mol%) in glycol (3 mL) at 100 ˚C.
c Compound 1a (0.5 mmol) and (Z)-4-aminopent-3-en-2-one (0.75 mmol) in glycol-H2O (2:1, 3 mL) at 140 ˚C.

Although a number of methods have been developed for the construction of furan rings, [¹8] [¹9] a facile and general synthetic method still remains an attractive goal. Following the success of substituted pyrroles construction, our attention was turned to furan ring formation by the same strategy. Upon screening various bases, catalysts, solvents, and temperature, it was found that the combination of the nitroolefin 1a with pentane-2,4-dione (2b) or β-keto ester 2c in the presence of KOAc in MeCN at 120 ˚C gave the best result (Table  [³] ). This facile and efficient method shows a promising approach to substituted furans.

Table 3 Addition and Cyclization Reaction for the Synthesis of Substituted Furana

Entry Base Solvent Time (h) Yield (%)
 1 - glycol 7 n.r.b
 2 KOAc glycol 7 44b
 3 KOAc glycol 7 60
 4 KOAc THF 7 64
 5 KOAc DMSO 7 43
 6 KOAc H2O 7 49
 7 KOAc MeCN 6 75
 8 NaOAc MeCN 6 29
 9 K3PO4 MeCN 6 26
10 Et3N MeCN 6 46
a Reaction conditions: 1a (0.45 mmol) and 2b (0.3 mmol), base (0.6 mmol), in solvent (2 mL) at 120 ˚C.
b FeCl3 (10 mol%) was used; n.r. = no reaction.

Under the optimized conditions, the scope of the KOAc-promoted addition and cyclization reaction was investigated (Table  [4] ). This general method tolerates a wide range of functionality, and allows for rapid elaboration of the nitroolefins into a variety of substituted furans in good yields. For the electronic effects of the transformation, the electron-rich nitroolefins showed better reactivity and gave slightly higher yields than electron-deficient ones (Table  [4] , entries 3-16). Further, 4-furanyl substituted furans were achieved when 2-(2-nitroprop-1-enyl)furan (1i) was used as the substrate (Table  [4] , entries 17, 18).

Table 4 Synthesis of Polysubstituted Furans by KOAc-Promoted Addition and Cyclization Reaction of 2b,c with Nitroolefins 1 a

Entry 1
Furan 4 R² Time (h) Yield (%)
 1
 2 		1a

4a Me
4b OEt 		 5
 7 		75
74b
 3
 4 		1b

4c Me
4d OEt 		 6
 7 		75
70b
 5
 6 		1c

4e Me
4f OEt 		 6
 7 		74
70b
 7
 8 		1d

4g Me
4h OEt 		 5
 7 		75
68b
 9
10 		1e

4i Me
4j OEt 		 5
24 		58
58b
11
12 		1f

4k Me
4l OEt 		 6
 7 		67
64b
13
14 		1g

4m Me
4n OEt 		 6
 7 		60
56b
15
16 		1h

4o Me
4p OEt 		 5
 7 		66
67b
17
18 		1i

4q Me
4r OEt 		 5
11 		45
61b
a Reaction conditions: 1 (0.45 mmol), 2b (0.3 mmol), and KOAc (0.6 mmol) in MeCN (2 mL) at 120 ˚C.
b Compound 1 (0.3 mmol) and 2c (0.6 mmol).

In summary, we have developed a general protocol for FeCl3-catalyzed addition and cyclization of enamino ester and nitroolefins for the construction of tetrasubstituted NH pyrroles. This attractive addition and cyclization strategy is also suitable for substituted furans formation in the presence of KOAc. These general protocols employ readily available starting materials and tolerate a wide range of functionality. Thus, a straightforward approach to substituted NH pyrroles and furans has been developed.

Column chromatography was carried out on silica gel. ¹H NMR spectra were recorded on 400 MHz in CDCl3 and ¹³C NMR spectra were recorded on 100 MHz in CDCl3. Unless otherwise stated, all reagents and solvents were purchased from commercial suppliers and used without further purification. The nitroolefins 1 were prepared according to the literature. [²0]

Tetrasubstituted NH Pyrroles 3; General Procedure

A vial (25 mL) was charged with nitroolefin 1 (0.5 mmol), methyl (Z)-3-aminobut-2-enoate (2a; 86 mg, 0.75 mmol), and glycol (3 mL) and the mixture was stirred at 100 ˚C. After completion of the reaction (detected by TLC, eluent: hexane-EtOAc, 8:1), the reaction mixture was cooled to r.t. EtOAc (30 mL) was added to the mixture and then washed with brine (2 × 30 mL). The organic layer was concentrated in vacuo. The residue was purified by chromatography on silica gel with hexane-EtOAc-Et3N (50:5:0.1) as the eluent to afford 3 (Table  [²] ).

Methyl 2,5-Dimethyl-4-phenyl-1 H -pyrrole-3-carboxylate (3a)

Yield: 92.3 mg (80%); yellow solid; mp 165-166 ˚C.

¹H NMR (400 MHz, CDCl3): δ = 8.35 (s, 1 H), 7.34-7.30 (m, 2 H), 7.25-7.21 (m, 3 H), 3.61 (s, 3 H), 2.45 (s, 3 H), 2.06 (s, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 169.8, 139.4, 137.5, 133.6, 130.7, 129.2, 127.0, 125.7, 113.3, 53.7, 17.0, 14.5.

HRMS (ESI): m/z calcd for C14H15NO2 + Na (M + Na+): 252.0995; found: 252.0996.

Methyl 2,5-Dimethyl-4- p -tolyl-1 H -pyrrole-3-carboxylate (3b)

Yield: 96.6 mg (79%); yellow solid; mp 164-165 ˚C.

¹H NMR (400 MHz, CDCl3): δ = 8.17 (s, 1 H), 7.13 (s, 4), 3.62 (s, 3 H), 2.46 (s, 3 H), 2.34 (s, 3 H), 2.07 (s, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 166.3, 135.3, 133.9, 132.9, 130.1, 128.1, 123.5, 122.3, 110.1, 50.4, 21.2, 13.7, 11.1.

HRMS (ESI): m/z calcd for C15H17NO2 + Na (M + Na+): 266.1151; found: 266.1153.

Methyl 2,5-Dimethyl-4- m -tolyl-1 H -pyrrole-3-carboxylate (3c)

Yield: 92.2 mg (75%); yellow solid; mp 118-120 ˚C.

¹H NMR (400 MHz, CDCl3): δ = 8.30 (s, 1 H), 7.24-7.19 (t, J = 8.0 Hz, 1 H), 7.05-7.03 (m, 3 H), 3.62 (s, 3 H), 2.45 (s, 3 H), 2.34 (s, 3 H), 2.06 (s, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 166.7, 137.0, 136.2, 134.4, 131.2, 127.7, 127.5, 126.9, 123.9, 122.6, 110.3, 50.7, 21.8, 13.9, 11.5.

HRMS (ESI): m/z calcd for C15H17NO2 + Na (M + Na+): 266.1151; found: 266.1154.

Methyl 4-(4-Methoxyphenyl)-2,5-dimethyl-1 H -pyrrole-3-carboxylate (3d)

Yield: 96.4 mg (74%); yellow solid; mp 143-145 ˚C.

¹H NMR (400 MHz, CDCl3): δ = 8.34 (s, 1 H), 7.17-7.14 (d, J = 8.4 Hz, 2 H), 6.88-6.86 (d, J = 8.8 Hz, 2 H), 3.79 (s, 3 H), 3.62 (s, 3 H), 2.44 (s, 3 H), 2.04 (s, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 169.7, 161.0, 137.3, 134.6, 131.7, 126.9, 125.2, 116.2, 113.3, 58.5, 53.7, 17.1, 14.4.

HRMS (ESI): m/z calcd for C15H17NO3 + Na (M + Na+): 282.1101; found: 282.1099.

Methyl 4-[4-(Dimethylamino)phenyl]-2,5-dimethyl-1 H -pyrrole-3-carboxylate (3e)

Yield: 71.5 mg (53%); brown solid; mp 175-176 ˚C.

¹H NMR (400 MHz, CDCl3): δ = 8.30 (s, 1 H), 7.14-7.12 (d, J = 7.6 Hz, 2 H), 6.75-6.73 (d, J = 8.4 Hz, 2 H), 3.63 (s, 3 H), 2.94 (s, 6 H), 2.44 (s, 3 H), 2.06 (s, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 166.8, 149.1, 134.1, 131.2, 124.6, 123.6, 122.5, 112.3, 110.3, 50.7, 41.0, 14.1, 11.5.

HRMS (ESI): m/z calcd for C16H20N2O2 + Na (M + Na+): 295.1417; found: 295.1415.

Methyl 4-(2-Chlorophenyl)-2,5-dimethyl-1 H -pyrrole-3-carboxylate (3f)

Yield: 78.9 mg (60%); yellow solid; mp 155-156 ˚C.

¹H NMR (400 MHz, CDCl3): δ = 8.27 (s, 1 H), 7.39-7.37 (m, 1 H), 7.24-7.17 (m, 3 H), 3.56 (s, 3 H), 2.48 (s, 3 H), 1.98 (s, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 166.3, 135.7, 135.0, 134.2, 132.5, 129.1, 128.0, 126.2, 124.4, 119.8, 111.0, 50.8, 13.9, 11.4.

HRMS (ESI): m/z calcd for C14H14ClNO2 + Na (M + Na+): 286.0605; found: 286.0602.

Methyl 4-(2,4-Dichlorophenyl)-2,5-dimethyl-1 H -pyrrole-3-carboxylate (3g)

Yield: 96 mg (65%); yellow solid; mp 185-186 ˚C.

¹H NMR (400 MHz, DMSO-d 6): δ = 11.24 (s, 1 H), 7.54 (s, 1 H), 7.34-7.32 (m, 2 H), 7.19-7.18 (m, 2 H), 3.43 (s, 3 H), 2.38 (s, 3 H), 1.90 (s, 3 H).

¹³C NMR (100 MHz, DMSO-d 6): δ = 164.9, 134.9, 134.8, 133.7, 131.4, 128.1, 126.4, 124.3, 117.2, 109.6, 50.1, 13.1, 10.8.

HRMS (ESI): m/z calcd for C14H13Cl2NO2 + Na (M + Na+): 320.0216; found: 320.0207.

Methyl 4-(4-Fluorophenyl)-2,5-dimethyl-1 H -pyrrole-3-carboxylate (3h)

Yield: 94.5 mg (77%); white solid; mp 187-189 ˚C.

¹H NMR (400 MHz, DMSO-d 6): δ = 11.16 (s, 1 H), 7.15 (s, 2 H), 7.09-7.08 (m, 2 H), 3.47 (s, 3 H), 2.38 (s, 3 H), 1.99 (s, 3 H).

¹³C NMR (100 MHz, DMSO-d 6): δ = 165.2, 161.7 (d, J C,F  = 240.9 Hz), 133.8, 132.5, 131.9 (d, J C,F  = 7.8 Hz), 123.7, 120.2, 114.0 (d, J C,F  = 20.5 Hz), 108.9, 49.9, 13.3, 10.9.

HRMS (ESI): m/z calcd for C14H14FNO2 + Na (M + Na+): 270.0901; found: 270.0905.

Methyl 4-(Furan-2-yl)-2,5-dimethyl-1 H -pyrrole-3-carboxylate (3i)

Yield: 41.1 mg (37%); white solid; mp 125-127 ˚C.

¹H NMR (400 MHz, CDCl3): δ = 8.37 (s, 1 H), 7.39 (s, 1 H), 6.39 (s, 1 H), 6.31 (s, 1 H), 3.69 (s, 3 H), 2.41 (s, 3 H), 2.17 (s, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 165.9, 149.3, 140.9, 134.3, 126.2, 111.8, 110.4, 110.1, 107.8, 50.7, 13.5, 11.7.

HRMS (ESI): m/z calcd for C12H13NO3 + Na (M + Na+): 242.0788; found: 242.0793.

Methyl 2-Methyl-4-phenyl-1 H -pyrrole-3-carboxylate (3j)

Yield: 45.2 mg (42%); brown solid; mp 126-128 ˚C.

¹H NMR (400 MHz, CDCl3): δ = 8.52 (s, 1 H), 7.39-7.22 (m, 5 H), 6.50 (s, 1 H), 3.68 (s, 3 H), 2.49 (s, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 166.3, 136.3, 135.7, 129.1, 127.6, 127.0, 126.2, 115.6, 109.4, 50.5, 13.9.

HRMS (ESI): m/z calcd for C13H13NO2 + Na (M + Na+): 238.0838; found: 238.0838.

2,5-Dimethyl- N ,4-diphenyl-1 H -pyrrole-3-carboxamide (3k)

Yield: 100.1 mg (70%); yellow solid; mp 178-180 ˚C.

¹H NMR (400 MHz, CDCl3): δ = 8.94 (s, 1 H), 7.46-7.43 (m, 2 H), 7.39-7.34 (m, 3 H), 7.18-7.14 (m, 2 H), 7.08-7.07 (m, 3 H), 6.97-6.93 (m, 1 H), 2.54 (s, 3 H), 2.05 (s, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 164.4, 138.3, 135.3, 133.5, 130.9, 128.8, 128.7, 127.3, 123.6, 123.2, 119.2, 119.1, 113.2, 13.3, 10.9.

1-(2,5-Dimethyl-4-phenyl-1 H -pyrrol-3-yl)ethanone (3l)

Yield: 32.2 mg (30%); brown solid; mp 118-120 ˚C.

¹H NMR (400 MHz, CDCl3): δ = 8.70 (s, 1 H), 7.39-7.36 (m, 2 H), 7.32-7.24 (m, 3 H), 2.51 (s, 3 H), 2.08 (s, 3 H), 1.92 (s, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 197.1, 136.7, 133.6, 130.4, 128.1, 126.5, 123.5, 122.1, 121.2, 30.6, 14.1, 10.9.

Substituted Furans 4; General Procedure

A 25 mL round-bottomed flask was charged with nitroolefin 1 (0.45 mmol; 0.3 mmol for 2c), KOAc (59 mg, 0.6 mmol), pentane-2,4-dione (2b; 30 mg, 0.3 mmol) or ethyl acetoacetate (2c; 78 mg, 0.6 mmol), and MeCN (2 mL), and the reaction mixture was stirred at 120 ˚C. After completion of the reaction (detected by TLC, eluent: hexane-EtOAc, 20:1), the mixture was cooled to r.t. The reaction mixture was diluted with EtOAc (15 mL) and then washed with H2O (2 × 10 mL). The organic layer was concentrated in vacuo and the residue was purified by chromatography on silica gel with hexane-EtOAc (60:1) as the eluent to afford 4 (Table  [4] ).

1-(2,5-Dimethyl-4-phenylfuran-3-yl)ethanone (4a)

Yield: 48.4 mg (75%); orange oil.

¹H NMR (400 MHz, CDCl3): δ = 7.43-7.34 (m, 3 H), 7.26-7.24 (d, J = 6.0 Hz, 2 H), 2.54 (s, 3 H), 2.17 (s, 3 H), 1.94 (s, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 196.1, 156.1, 146.9, 133.7, 129.8, 128.4, 127.3, 122.9, 120.8, 30.7, 14.2, 11.6.

Ethyl 2,5-Dimethyl-4-phenylfuran-3-carboxylate (4b)

Yield: 54.5 mg (74%); yellow oil.

¹H NMR (400 MHz, CDCl3): δ = 7.39-7.26 (m, 5 H), 4.16-4.10 (m, 2 H), 2.59 (s, 3 H), 2.21 (s, 3 H), 1.13-1.09 (t, J = 7.6 Hz, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 164.3, 157.4, 147.1, 133.2, 129.9, 127.6, 126.7, 121.3, 113.4, 59.7, 14.0, 13.9, 11.7.

1-(2,5-Dimethyl-4- p -tolylfuran-3-yl)ethanone (4c)

Yield: 51.5 mg (75%); yellow solid; mp 54-56 ˚C.

¹H NMR (400 MHz, CDCl3): δ = 7.22-7.20 (m, 2 H), 7.14-7.12 (m, 2 H), 2.53 (s, 3 H), 2.39 (s, 3 H), 2.16 (s, 3 H), 1.94 (s, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 196.3, 156.0, 146.8, 136.9, 130.6, 129.7, 129.1, 122.9, 120.6, 30.7, 21.2, 14.2, 11.6.

Ethyl 2,5-Dimethyl-4- p -tolylfuran-3-carboxylate (4d)

Yield: 54.2 mg (70%); yellow oil.

¹H NMR (400 MHz, CDCl3): δ = 7.19-7.14 (m, 4 H), 4.17-4.12 (m, 2 H), 2.57 (s, 3 H), 2.38 (s, 3 H), 2.20 (s, 3 H) 1.17-1.12 (m, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 164.3, 157.2, 146.9, 136.3, 130.1, 129.8, 128.3, 121.2, 113.4, 59.7, 21.2, 14.1, 13.9, 11.7.

1-(2,5-Dimethyl-4- m -tolylfuran-3-yl)ethanone (4e)

Yield: 50.3 mg (74%); yellow oil.

¹H NMR (400 MHz, CDCl3): δ = 7.31-7.27 (t, J = 7.6 Hz, 1 H), 7.16-7.15 (d, J = 7.2 Hz, 1 H), 7.05-7.03 (m, 2 H), 2.53 (s, 3 H), 2.38 (s, 3 H), 2.17 (s, 3 H), 1.93 (s, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 196.3, 156.0, 146.8, 137.9, 133.6, 130.5, 128.3, 128.0, 126.9, 122.9, 120.8, 30.7, 21.4, 14.2, 11.6.

HRMS (ESI): m/z calcd for C15H16O2 + Na (M + Na+): 251.1043; found: 251.1049.

Ethyl 2,5-Dimethyl-4- m -tolylfuran-3-carboxylate (4f)

Yield: 53.9 mg (70%); yellow oil.

¹H NMR (400 MHz, CDCl3): δ = 7.28-7.24 (m, 1 H), 7.13-7.06 (m, 3 H), 4.17-4.11 (m, 2 H), 2.59 (s, 3 H), 2.38 (s, 3 H), 2.21 (s, 3 H), 1.14-1.10 (m, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 164.3, 157.3, 146.9, 136.9, 133.1, 130.7, 127.5, 127.0, 121.3, 113.5, 59.6, 21.4, 14.0, 13.9, 11.7.

HRMS (ESI): m/z calcd for C16H18O3 + Na (M + Na+): 281.1148; found: 281.1151.

1-[4-(4-Methoxyphenyl)-2,5-dimethylfuran-3-yl]ethanone (4g)

Yield: 55.1 mg (75%); yellow oil.

¹H NMR (400 MHz, CDCl3): δ = 7.17-7.15 (d, J = 9.2 Hz, 2 H), 6.96-6.93 (d, J = 8.8 Hz, 2 H), 3.85 (s, 3 H), 2.53 (s, 3 H), 2.15 (s, 3 H), 1.95 (s, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 196.2, 158.8, 156.0, 146.8, 130.9, 125.7, 122.9, 120.2, 113.8, 55.1, 30.7, 14.2, 11.5.

Ethyl 4-(4-Methoxyphenyl)-2,5-dimethylfuran-3-carboxylate (4h)

Yield: 56.3 mg (68%); yellow oil.

¹H NMR (400 MHz, CDCl3): δ = 7.20-7.18 (d, J = 8.8 Hz, 2 H), 6.93-6.90 (d, J = 8.8 Hz, 2 H), 4.16-4.14 (m, 2 H), 3.84 (s, 3 H), 2.58 (s, 3 H), 2.19 (s, 3 H), 1.17-1.13 (m, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 164.4, 158.4, 157.3, 146.9, 131.1, 125.4, 120.9, 113.5, 113.0, 59.7, 55.2, 14.1, 11.7.

1-{4-[4-(Dimethylamino)phenyl]-2,5-dimethylfuran-3-yl}ethanone (4i)

Yield: 45 mg (58%); yellow solid; mp 85-87 ˚C.

¹H NMR (400 MHz, CDCl3): δ = 7.10-7.08 (d, J = 8.8 Hz, 2 H), 6.76-6.74 (d, J = 8.8 Hz, 2 H), 2.98 (s, 6 H), 2.52 (s, 3 H), 2.16 (s, 3 H), 1.96 (s, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 196.8, 155.8, 149.6, 146.6, 130.5, 123.1, 121.0, 120.7, 112.2, 40.4, 30.7, 14.2, 11.6.

HRMS (ESI): m/z calcd for C16H19NO2 + Na (M + Na+): 280.1308; found: 280.1307.

Ethyl 4-[4-(Dimethylamino)phenyl]-2,5-dimethylfuran-3-carboxylate (4j)

Yield: 49.9 mg (58%); yellow solid; mp 47-48 ˚C.

¹H NMR (400 MHz, CDCl3): δ = 7.17-7.15 (d, J = 8.8 Hz, 2 H), 6.78-6.75 (d, J = 9.2 Hz, 2 H), 4.19-4.16 (m, 2 H), 2.98 (s, 6 H), 2.58 (s, 3 H), 2.23 (s, 3 H), 1.21-1.17 (m, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 164.5, 157.0, 149.4, 146.7, 130.7, 121.2, 120.9, 113.5, 111.8, 59.7, 40.6, 14.2, 11.8.

HRMS (ESI): m/z calcd for C17H22NO3 (M + H+): 288.1594; found (M + H+): 288.1593.

1-[4-(2-Chlorophenyl)-2,5-dimethylfuran-3-yl]ethanone (4k)

Yield: 49.5 mg (67%); yellow oil.

¹H NMR (400 MHz, CDCl3): δ = 7.47-7.45 (m, 1 H), 7.32-7.25 (m, 3 H), 2.56 (s, 3 H), 2.08 (s, 3 H), 1.91 (s, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 195.1, 156.6, 147.5, 134.7, 132.8, 131.9, 129.6, 129.2, 126.8, 122.6, 117.9, 29.8, 14.5, 11.6.

HRMS (ESI): m/z calcd for C14H13ClO2 + Na (M + Na+): 271.0496; found: 271.0500.

Ethyl 4-(2-Chlorophenyl)-2,5-dimethylfuran-3-carboxylate (4l)

Yield: 53.5 mg (64%); yellow oil.

¹H NMR (400 MHz, CDCl3): δ = 7.42-7.40 (m, 1 H), 7.27-7.21 (m, 3 H), 4.12-3.99 (m, 2 H), 2.59 (s, 3 H), 2.12 (s, 3 H), 1.02-0.98 (m, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 164.0, 157.4, 147.4, 134.7, 132.7, 131.7, 128.9, 128.5, 126.1, 118.6, 113.9, 59.6, 13.9, 13.6, 11.7.

HRMS (ESI): m/z calcd for C15H15ClO3 + Na (M + Na+): 301.0602; found: 301.0597.

1-[4-(2,4-Dichlorophenyl)-2,5-dimethylfuran-3-yl]ethanone (4m)

Yield: 51.1 mg (60%); yellow oil.

¹H NMR (400 MHz, CDCl3): δ = 7.48 (s, 1 H), 7.31-7.28 (m, 1 H), 7.19-7.18 (m, 1 H), 2.56 (s, 3 H), 2.08 (s, 3 H), 1.97 (s, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 194.6, 156.8, 147.7, 135.4, 134.3, 132.6, 131.4, 129.5, 127.2, 122.5, 117.0, 29.9, 14.5, 11.6.

HRMS (ESI): m/z calcd for C14H12Cl2O2 + Na (M + Na+): 305.0107; found: 305.0108.

Ethyl 4-(2,4-Dichlorophenyl)-2,5-dimethylfuran-3-carboxylate (4n)

Yield: 52.5 mg (56%); yellow oil.

¹H NMR (400 MHz, CDCl3): δ = 7.46-7.45 (s, 1 H), 7.27-7.25 (m, 1 H), 7.17-7.15 (m, 1 H) 4.12-4.06 (m, 2 H), 2.59 (s, 3 H), 2.12 (s, 3 H), 1.09-1.05 (m, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 163.8, 157.6, 147.7, 135.5, 133.6, 132.5, 131.4, 128.9, 126.5, 117.7, 113.8, 59.8, 13.9, 13.8, 11.7.

HRMS (ESI): m/z calcd for C15H14Cl2O3 +Na (M + Na+): 335.0212; found: 335.0214.

1-[4-(4-Fluorophenyl)-2,5-dimethylfuran-3-yl]ethanone (4o)

Yield: 46.2 mg (66%); yellow oil.

¹H NMR (400 MHz, CDCl3): δ = 7.23-7.20 (m, 2 H), 7.12-7.08 (m, 2 H), 2.54 (s, 3 H), 2.15 (s, 3 H), 1.96 (s, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 195.6, 163.3 (d, J C,F  = 245.4 Hz), 156.3, 147.1, 131.5 (d, J C,F = 8.2 Hz), 129.6, 122.8, 119.7, 115.5 (d, J C,F  = 21.4 Hz), 30.7, 14.3, 11.5.

HRMS (ESI): m/z calcd for C14H13FO2 + Na (M + Na+): 225.0792; found: 225.0791.

Ethyl 4-(4-Fluorophenyl)-2,5-dimethylfuran-3-carboxylate (4p)

Yield: 52.4 mg (67%); yellow oil.

¹H NMR (400 MHz, CDCl3): δ = 7.23-7.19 (m, 2 H), 7.07-7.03 (m, 2 H), 4.14-4.10 (m, 2 H), 2.57 (s, 3 H), 2.18 (s, 3 H), 1.14-1.10 (m, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 164.2, 163.1 (d, J C,F  = 244.1 Hz), 157.5, 147.1, 131.6 (d, J C,F  = 8.2 Hz), 129.1, 120.3, 114.6 (d, J C,F  = 21.4 Hz), 113.3, 59.7, 14.1, 13.9, 11.6.

HRMS (ESI): m/z calcd for C15H15FO3 + Na (M + Na+): 285.0897; found: 285.0902.

1-[4-(Furan-2-yl)-2,5-dimethylfuran-3-yl]ethanone (4q)

Yield: 27.4 mg (45%); yellow oil.

¹H NMR (400 MHz, CDCl3): δ = 7.50 (s, 1 H), 6.48 (s, 1 H), 6.35 (s, 1 H), 2.52 (s, 3 H), 2.26 (s, 3 H), 2.07 (s, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 195.6, 156.5, 149.4, 146.1, 142.3, 121.9, 111.2, 111.0, 109.6, 29.6, 14.2, 11.9.

HRMS (ESI): m/z calcd for C12H12O3 + Na (M + Na+): 227.0679; found: 227.0687.

Ethyl 4-(Furan-2-yl)-2,5-dimethylfuran-3-carboxylate (4r)

Yield: 42.9 mg (61%); yellow oil.

¹H NMR (400 MHz, CDCl3): δ = 7.47-7.46 (s, 1 H), 6.49-6.45 (m, 2 H), 4.25-4.23 (m, 2 H), 2.54 (s, 3 H), 2.35 (s, 3 H), 1.27-1.24 (m, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 163.9, 157.5, 149.1, 146.6, 141.5, 112.9, 111.8, 110.6, 108.9, 59.9, 14.1, 13.9, 12.5.

HRMS (ESI): m/z calcd for C13H14O4 + Na (M + Na+): 257.0784; found: 257.0795.

Acknowledgment

This research was supported by National Natural Science Foun­dation of China (NSFC-21002077), Education Department of Shaanxi Provincial Government (2010JK869), and Northwest University (PR09037).

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Figure 1 X-ray structure of 3a

Scheme 1 Proposed mechanism for the reaction