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Synlett 2009(2): 201-204  
DOI: 10.1055/s-0028-1087395
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

First Synthesis of Functionalized Benzonitriles by Formal [3+3] Cyclocondensations of 1,3-Bis(silyloxy)buta-1,3-dienes

Olumide Fatunsina, Mohanad Shkoora, Abdolmajid Riahia,b, Rüdiger Dedea, Helmut Reinkea, Peter Langer*a,b
a Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
b Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
Fax: +049(381)4986412; e-Mail: peter.langer@uni-rostock.de;

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Publication History

Received 22 September 2008
Publication Date:
15 January 2009 (online)

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Abstract

A variety of functionalized benzonitriles were regioselectively prepared by formal [3+3] cyclocondensation of 1,3-bis(silyloxy)buta-1,3-dienes with 3-ethoxy- and 3-silyloxy-2-cyano-2-en-1-ones.

Key Words

arenas - benzonitriles - cyclizations - regioselectivity - silyl enol ethers

Functionalized benzonitriles represent important building blocks for the synthesis of natural products, pharmaceuticals, agrochemicals, herbicides, and dyes. Their industrial scale syntheses mostly rely on the ammoxidation of toluenes. In addition, the reaction of aryl halides with copper(I) cyanide (Rosenmund-von Braun reaction) and the reaction of diazonium salts with copper(I) cyanide (Sandmeyer reaction) are frequently used. In 2003, a catalytic variant has been reported. [¹] In recent years, nickel- and palladium-catalyzed cyanations of aryl halides have been developed. [²] 5-Cyanosalicylates can be regarded as highly functionalized benzonitrile derivatives containing an additional ester and hydroxyl group. They have been prepared by classic transformation of the corresponding oximes into the nitriles, [³] by application of the Rosenmund-von Braun reaction, [4] by application of palladium(0)-catalyzed reactions using Zn(CN)2 or KCN, [5] and by Grignard reaction of 4-hydroxy-3,5-diiodobenzonitrile with carbon dioxide. [6] Despite the recent progress in this area, cyanation reactions often suffer from low catalyst productivities (compared to other palladium-catalyzed coupling reactions). In addition, reactions of ortho-substituted aryl halides are often problematic or not possible at all or require the use of toxic thallium reagents. [7] Last but not the least, the regioselective synthesis of the required starting materials, functionalized or highly substituted aryl halides or triflates, can be a difficult and tedious task.

An alternative strategy for the synthesis of functionalized benzonitriles relies on the use of appropriate cyano-substituted building blocks in cyclization reactions. For example, ethyl 4-amino-5-cyanosalicylate and related compounds have been prepared by base-mediated cyclization of ethoxymethylenemalononitrile with β-keto esters. [8] 4-Amino-5-cyano-2-hydroxyisophthalic acid diethyl ester has been synthesized by KOH-mediated cyclization of diethyl acetone-1,3-dicarboxylate with 3-oxopentanedioic acid diethyl ester. [9] 4-Amino-2-hydroxy-5-cyanoacetophenone is available by cyclization of malodinitrile with 2-acetyl-3-methoxyacrylic acid methyl ester. [¹0] Benzonitriles have been prepared also based on Diels-Alder reactions of cyano-substituted alkynes or buta-1,3-dienes. [¹¹] Recently, Pulido and Barbero have reported the synthesis of methyl 3-cyano-4-hydroxy-2-methylbenzoate by [4+2] cycloaddition of 3-cyano-2,4-bis(silyloxy)penta-1,3-diene with propynoic acid methyl ester. [¹²]

Chan and co-workers were the first to report [¹³] the synthesis of salicylates by formal [3+3] cyclizations of 1,3-bis(silyloxy)buta-1,3-dienes [¹4] with 3-silyloxy-2-en-1-ones. In recent years, this strategy has been applied to the synthesis of various functionalized arenes. [¹5] Herein, we report what are, to the best of our knowledge, the first [3+3] cyclocondensations of 1,3-bis(silyloxy)buta-1,3-dienes with cyano-substituted 3-ethoxy- and 3-silyloxy-2-en-1-ones. These reactions provide a convenient and regio­selective approach to a variety of functionalized 5-cyanosalicylates, which are not readily available by other methods.

2-Cyano-3-ethoxy-2-en-1-ones 2a-e were prepared, following a known procedure, [¹6] by reaction of ketonitriles 1a-e with ethyl orthoformiate and acetic anhydride. 1,3-Bis(silyloxy)buta-1,3-dienes 3a-l were prepared from the corresponding β-keto esters in two steps. [¹³]

The TiCl4-mediated cyclization of 2a with 3a afforded the 5-cyanosalicylate 4a (Scheme  [¹] ). The best yield was obtained when the reaction was carried out in a highly concentrated solution. [¹7] The cyclization proceeded with excellent regioselectivity. The formation of product 4a might be explained by TiCl4-mediated conjugate addition of the terminal carbon atom of 3a to 2a to give intermediate A, cyclization via the central carbon of 3a to give ­intermediate B (SN′ reaction), and subsequent aromatization.

Scheme 1 Possible mechanism of the formation of 4a

The formal [3+3] cyclization of 2-cyano-3-ethoxy-2-en-1-ones 2a-e with 1,3-bis(silyloxy)buta-1,3-dienes 3a-h afforded the 5-cyanosalicylates 4a-l in 40-61% yields (Table  [¹] ). The substituents R¹, located next to the carbonyl group of 2a-e, have no significant influence on the yields. Likewise, the substitution pattern of the diene has no significant influence on the yield.

Table 1 Synthesis of 4a-l

2 3 4 R¹ R² R³ Yield (%)a
2a 3a 4a Me H Et 33
2a 3b 4b Me Me Me 41
2a 3c 4c Me Et Et 40
2a 3d 4d Me n-Hex Me 42
2a 3e 4e Me n-Hept Me 40
2b 3b 4f Ph Me Me 43
2b 3c 4g Ph Et Et 42
2b 3f 4h Ph n-Bu Me 41
2b 3g 4i Ph n-Oct Me 40
2c 3b 4j 4-ClC6H4 Me Me 61
2d 3h 4k 4-BrC6H4 n-Non Me 57
2e 3g 4l 4-MeOC6H4 n-Oct Me 50
a Yields of isolated products.

The configuration of all products was established by spectroscopic methods (2D NMR). The structure of 4a was independently confirmed by X-ray crystal structure analysis (Figure  [¹] ). [¹8]

Figure 1 ORTEP plot of 4a (hydrogen at O3 found in the difference map and refined freely)

3-Cyano-4-(trimethylsilyloxy)pent-3-en-2-one (5) was prepared by silylation of known [¹9] 3-cyano-acetylacetone. The TiCl4-mediated [3+3] cyclocondensation of 5 with 3a,c,i-l afforded the 5-cyanosalicylates 6a-f in moderate yields (except for 6d, Table  [²] ). [²0] The best yields were again obtained when the reactions were carried out in a highly concentrated solution. The low yield of 6d can be explained by TiCl4-mediated cleavage of the tert-butyl ­ester.

Table 2 Synthesis of 6a-f: Products and Yields

3 6 R¹ R² Yield of 6 (%)a
3i 6a H Me 34
3a 6b H Et 41
3j 6c H i-Bu 40
3k 6d H t-Bu 8
3l 6e Et Me 44
3c 6f Et Et 58
a Yields of isolated products.

In conclusion, we have reported a convenient and regioselective synthesis of functionalized benzonitriles by what are, to the best of our knowledge, the first formal [3+3] cyclizations of 1,3-bis(silyloxy)buta-1,3-dienes with cyano-substituted enones. The products are not readily available by other methods. The reactions are easy to be carried out, and the starting materials are readily available. We currently study the preparative scope of the methodology and applications to the synthesis of pharmacologically active products.

Acknowledgment

Financial support by the State of Mecklenburg-Vorpommern (schol­arship for M. S.) is gratefully acknowledged.

17

Typical Experimental Procedure for the Synthesis of 4a-l To a stirred solution of CH2Cl2 (3 mL per 1.0 mmol of 2a-e) of 2a-e was added 3a-h (1.1 mmol) and, subsequently, TiCl4 (1.1 mmol) at -78 ˚C under argon atmosphere. The temperature of the reaction mixture was allowed to rise to 20 ˚C over 14 h with stirring. To the solution was added HCl (10%, 20 mL) and the organic and the aqueous layer were separated. The latter was extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were dried (Na2SO4), filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2, heptanes-EtOAc) to give 4a-l. Starting with 2a (0.209 g, 1.5 mmol) and 3a (0.446 g, 1.65 mmol), 4a was isolated as a colorless solid (101 mg, 33%), mp 86-87 ˚C. ¹H NMR (250 MHz, CDCl3): δ = 1.39 (t, ³ J = 7.1 Hz, 3 H, OCH2CH 3), 2.72 (s, 3 H, CH3), 4.42 (q, ³ J = 7.1 Hz, 2 H, OCH 2CH3), 6.84 (d, ³ J = 8.8 Hz, 1 H, Ar), 7.53 (d, ³ J = 8.8 Hz, 1 H, Ar), 11.78 (s, 1 H, OH). ¹³C NMR (75 MHz, CDCl3): δ = 13.1 (CH3), 20.8 (OCH2 CH3), 61.7 (OCH2), 104.8 (CCN), 112.6 (CCO2Et), 116.0 (CH), 117.4 (CN), 136.7 (CH), 145.5 (CCH3), 164.8 (COH), 169.6 (C=O). IR (neat): ν = 3072 (w), 2991 (w), 2923 (w), 2851 (w), 2777 (w), 2692 (w), 2589 (w), 2224 (w), 1660 (s), 1588 (m), 1570 (w), 1476 (m), 1450 (w), 1398 (m), 1375 (s), 1348 (m), 1318 (m), 1302 (m), 1231 (s), 1182 (w), 1146 (m), 1108 (w), 1057 (w), 1021 (m), 996 (w), 909 (w), 856 (m), 831 (m), 723 (w), 632 (w), 609 (w), 558 (w) cm-¹. MS (GC-MS, 70 eV): m/z (%) = 205 (26) [M+], 159 (100), 130 (22), 103 (8), 77 (12), 51 (6). HRMS (EI): m/z calcd for C11H11NO3: 205.07334; found: 205.073572.

18

CCDC-703181 contains all crystallographic details of this publication and is available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or can be ordered from the following address: Cambridge Crystallo-graphic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK; fax: +44 (1223)336033; or deposit@ccdc.cam.ac.uk.

20

Typical Experimental Procedure for the Synthesis of 6a-f To a CH2Cl2 solution of 5 was added TiCl4 at -78 ˚C in the presence of MS (4 Å). The appropriate bis(silyl enol ether) 3 was subsequently added. The reaction mixture was allowed to warm to 20 ˚C during 20 h and was stirred for further 4 h. To the solution was added CH2Cl2, the MS were removed, and a sat. aq soln of NaHCO3 was added. The organic layer was separated, and the aqueous layer was repeatedly extracted with CH2Cl2. All organic extracts were combined, dried (Na2SO4), and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2) to give salicylates 6. Starting with 5 (188 mg, 0.95 mmol), CH2Cl2 (3.0 mL), MS (4 Å, 0.4 g), TiCl4 (0.11 mL, 1.0 mmol), and 3i (356 mg, 1.4 mmol), compound 6a was isolated by column chromatography (SiO2; n-heptane-EtOAc, 10:1) as a colorless solid (67 mg, 34%), mp 109-110 ˚C; R f  = 0.21 (n-heptane-EtOAc, 10:1); reaction time 21 h. ¹H NMR (250 MHz, CDCl3): δ = 2.48 (d, 4 J = 0.9 Hz, 3 H, ArCH3), 2.75 (s, 3 H, ArCH3), 3.98 (s, 3 H, OCH3), 6.76 (s, 1 H, CHAr), 11.72 (s, 1 H, OH). ¹³C NMR (75 MHz, CDCl3): δ = 21.4, 21.8 (ArCH3), 52.7 (OCH3), 107.0, 111.0, 117.3 (2 × CAr, CN), 117.4 (CHAr), 146.6, 148.4 (CAr), 165.1, 171.0 (CArOH, CO). IR (KBr): ν = 3431 (br, m), 2957 (m), 2217 (s), 1668 (s), 1601 (s), 1581 (s), 1442 (s), 1368 (s), 1358 (s), 1319 (s), 1241 (s), 810 (s) cm-¹. MS (EI, 70 eV): m/z (%) = 205 (83) [M+], 174 (76), 173 (100), 145 (66), 144 (37), 116 (20), 91 (14). Anal. Calcd for C11H11NO3 (205.21): C, 64.38; H, 5.40; N, 6.83. Found: C, 64.64; H, 5.52; N, 6.65.

17

Typical Experimental Procedure for the Synthesis of 4a-l To a stirred solution of CH2Cl2 (3 mL per 1.0 mmol of 2a-e) of 2a-e was added 3a-h (1.1 mmol) and, subsequently, TiCl4 (1.1 mmol) at -78 ˚C under argon atmosphere. The temperature of the reaction mixture was allowed to rise to 20 ˚C over 14 h with stirring. To the solution was added HCl (10%, 20 mL) and the organic and the aqueous layer were separated. The latter was extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were dried (Na2SO4), filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2, heptanes-EtOAc) to give 4a-l. Starting with 2a (0.209 g, 1.5 mmol) and 3a (0.446 g, 1.65 mmol), 4a was isolated as a colorless solid (101 mg, 33%), mp 86-87 ˚C. ¹H NMR (250 MHz, CDCl3): δ = 1.39 (t, ³ J = 7.1 Hz, 3 H, OCH2CH 3), 2.72 (s, 3 H, CH3), 4.42 (q, ³ J = 7.1 Hz, 2 H, OCH 2CH3), 6.84 (d, ³ J = 8.8 Hz, 1 H, Ar), 7.53 (d, ³ J = 8.8 Hz, 1 H, Ar), 11.78 (s, 1 H, OH). ¹³C NMR (75 MHz, CDCl3): δ = 13.1 (CH3), 20.8 (OCH2 CH3), 61.7 (OCH2), 104.8 (CCN), 112.6 (CCO2Et), 116.0 (CH), 117.4 (CN), 136.7 (CH), 145.5 (CCH3), 164.8 (COH), 169.6 (C=O). IR (neat): ν = 3072 (w), 2991 (w), 2923 (w), 2851 (w), 2777 (w), 2692 (w), 2589 (w), 2224 (w), 1660 (s), 1588 (m), 1570 (w), 1476 (m), 1450 (w), 1398 (m), 1375 (s), 1348 (m), 1318 (m), 1302 (m), 1231 (s), 1182 (w), 1146 (m), 1108 (w), 1057 (w), 1021 (m), 996 (w), 909 (w), 856 (m), 831 (m), 723 (w), 632 (w), 609 (w), 558 (w) cm-¹. MS (GC-MS, 70 eV): m/z (%) = 205 (26) [M+], 159 (100), 130 (22), 103 (8), 77 (12), 51 (6). HRMS (EI): m/z calcd for C11H11NO3: 205.07334; found: 205.073572.

18

CCDC-703181 contains all crystallographic details of this publication and is available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or can be ordered from the following address: Cambridge Crystallo-graphic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK; fax: +44 (1223)336033; or deposit@ccdc.cam.ac.uk.

20

Typical Experimental Procedure for the Synthesis of 6a-f To a CH2Cl2 solution of 5 was added TiCl4 at -78 ˚C in the presence of MS (4 Å). The appropriate bis(silyl enol ether) 3 was subsequently added. The reaction mixture was allowed to warm to 20 ˚C during 20 h and was stirred for further 4 h. To the solution was added CH2Cl2, the MS were removed, and a sat. aq soln of NaHCO3 was added. The organic layer was separated, and the aqueous layer was repeatedly extracted with CH2Cl2. All organic extracts were combined, dried (Na2SO4), and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2) to give salicylates 6. Starting with 5 (188 mg, 0.95 mmol), CH2Cl2 (3.0 mL), MS (4 Å, 0.4 g), TiCl4 (0.11 mL, 1.0 mmol), and 3i (356 mg, 1.4 mmol), compound 6a was isolated by column chromatography (SiO2; n-heptane-EtOAc, 10:1) as a colorless solid (67 mg, 34%), mp 109-110 ˚C; R f  = 0.21 (n-heptane-EtOAc, 10:1); reaction time 21 h. ¹H NMR (250 MHz, CDCl3): δ = 2.48 (d, 4 J = 0.9 Hz, 3 H, ArCH3), 2.75 (s, 3 H, ArCH3), 3.98 (s, 3 H, OCH3), 6.76 (s, 1 H, CHAr), 11.72 (s, 1 H, OH). ¹³C NMR (75 MHz, CDCl3): δ = 21.4, 21.8 (ArCH3), 52.7 (OCH3), 107.0, 111.0, 117.3 (2 × CAr, CN), 117.4 (CHAr), 146.6, 148.4 (CAr), 165.1, 171.0 (CArOH, CO). IR (KBr): ν = 3431 (br, m), 2957 (m), 2217 (s), 1668 (s), 1601 (s), 1581 (s), 1442 (s), 1368 (s), 1358 (s), 1319 (s), 1241 (s), 810 (s) cm-¹. MS (EI, 70 eV): m/z (%) = 205 (83) [M+], 174 (76), 173 (100), 145 (66), 144 (37), 116 (20), 91 (14). Anal. Calcd for C11H11NO3 (205.21): C, 64.38; H, 5.40; N, 6.83. Found: C, 64.64; H, 5.52; N, 6.65.

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Scheme 1 Possible mechanism of the formation of 4a

Figure 1 ORTEP plot of 4a (hydrogen at O3 found in the difference map and refined freely)