CC BY-ND-NC 4.0 · Synlett 2019; 30(04): 393-396
DOI: 10.1055/s-0037-1611640
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Gold-Catalyzed Cyclization/Intermolecular Methylene Transfer ­Sequence of O-Propargylic Oximes Derived from Glyoxylates

Shinya Gima
a  Department of Chemistry, Graduate School of Science, Tohoku University, 6-3 Aramaki Aza Aoba, Aoba-ku Sendai, 980-8578, Japan
,
Keigo Shiga
a  Department of Chemistry, Graduate School of Science, Tohoku University, 6-3 Aramaki Aza Aoba, Aoba-ku Sendai, 980-8578, Japan
,
a  Department of Chemistry, Graduate School of Science, Tohoku University, 6-3 Aramaki Aza Aoba, Aoba-ku Sendai, 980-8578, Japan
,
b  Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, 6-3 Aramaki Aza Aoba, Aoba-ku Sendai, 980-8578, Japan   Email: itaru-n@tohoku.ac.jp
› Author Affiliations
This work was supported by JSPS KAKENHI Grant Number JP16H00996 in Precisely Designed Catalysts with Customized Scaffolding.
Further Information

Publication History

Received: 25 September 2018

Accepted after revision: 18 November 2018

Publication Date:
06 December 2018 (eFirst)

 

Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue

Abstract

We successfully extended our gold-catalyzed skeletal rearrangement reaction of O-propargylic oximes through C=N bond cleavage to include substrates having an ester group on the oxime moiety, affording the corresponding 2-isoxazolines having an alkoxycarbonylmethylene group at the 4-position in good to high yields. Our mechanistic studies indicated that the transfer of the alkoxycarbonylmethylene group proceeded in an intermolecular manner, confirming that the reaction proceeds through cyclization followed by intermolecular transfer of the alkoxycarbonylmethylene group.


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Gold-catalyzed skeletal-rearrangement reactions are powerful methods for synthesizing highly functionalized carbo- or heterocyclic compounds from readily available starting materials in a single operation under mild conditions with high functional-group compatibility.[1] Earlier studies focused mainly on the use of 1,n-enynes[2] or propargylic esters[3] as starting materials. We recently reported that the gold-catalyzed skeletal rearrangement reactions of O-propargylic formaldoximes 1 (R3 = H) proceed through C=N bond cleavage, affording the corresponding 4-methylenated 2-isoxazolines 2 in good to excellent yields (Scheme [1]).[4]

Zoom Image
Scheme 1 Au-catalyzed skeletal rearrangement of O-propargylic oximes

Our mechanistic studies indicated that the methylene group was transferred intermolecularly. We proposed that the reaction proceeds through π-acidic Au-promoted cyclization, followed by intermolecular C–C bond formation between the iminium moiety of the cyclized vinylgold species A and the enamine form B, generated in situ by attack of a nucleophilic species (NuH), such as trace water, on another vinylgold intermediate A. This intriguing rearrangement reactions was, however, restricted to the use of substrates derived from formaldoxime (R3 = H); substrates that possessed a substituent such as an alkyl and aryl group on the oxime moiety (R3) did not undergo the transformation. This drawback is presumably because these functional groups interrupt the intermolecular C–C bond-forming process, not only by steric repulsion, but also through low electrophilicity. Accordingly, we envisioned that less-bulky and more-electron-withdrawing functional groups might be compatible as substituents on the oxime moiety, improving the synthetic utility of the present cascade reactions. Here, we report that Au-catalyzed skeletal rearrangement reactions of O-propargylic oximes derived from glyoxylates 1 (R3 = CO2R) afford the corresponding isoxazolines 2 in good to high yields (Scheme [2]).

Zoom Image
Scheme 2 Au-catalyzed cyclization/intermolecular methylene transfer sequence of O-propargylic oximes 1 derived from glyoxylates

Initially, the reaction of the (E)-oxime (E)-1a having an ethoxycarbonyl group on the oxime moiety afforded the desired product 2a in a moderate chemical yield (46%) under our previous reaction conditions by using 5 mol% of Ph3PAuNTf2 in CH2Cl2 at 30 °C (Table [1], entry 1). In contrast, the reaction of the (Z)-oxime (Z)-1a resulted in a poor chemical yield (entry 2), due to decomposition of the starting material.[5] The use of triflate, tetrafluoroborate, or perchlorate as a counteranion gave comparable result to that of the triflic imide (entries 3–5), whereas the use of hexafluoroantimonate resulted in a lower yield (entry 6). The catalytic activity depended on the electronic character of the phosphine ligand (entries 7–10), in that the use of relatively electron-deficient triarylphosphines improved the chemical yield (entries 7 and 8). In particular, the reaction using (4-F3CC6H4)3P gave 2a in a good yield (entry 8), whereas (C6F5)3P was inefficient (entry 9). The chemical yield was significantly improved by doubling the loading of the gold catalyst, to afford 2a in 81% isolated yield (entry 12).[6] The use of CH2Cl2 and MeCN was effective to afford 2a in good yields, whereas the use of MeOH resulted in formation of considerable amounts of nonmethylenated isoxazoline as a byproduct [see the Supplementary Information (SI)]. It should be noted that the Z/E stereoselectivity at the exo-olefin moiety was not significantly affected by the reaction conditions: the Z/E ratio was about 9:1 in all cases (see SI).

Table 1 Optimization of the Reaction Conditionsa

Entry

Au catalyst (mol %)

Time (h)

Yieldb (%)

1

Ph3PAuNTf2 (5)

8

46

2c

Ph3PAuNTf2 (5)

24

10

3

Ph3PAuCl (5), AgOTf (5)

24

41

4

Ph3PAuCl (5), AgBF4 (5)

8

44

5

Ph3PAuCl (5), AgClO4 (5)

8

42

6

Ph3PAuCl (5), AgSbF6 (5)

8

26

7

(4-FC6H4)3PAuNTf2 (5)

8

50

8

(4-F3CC6H4)3PAuNTf2 (5)

8

62

9

(C6F5)3PAuNTf2 (5)

8

4

10

(4-MeOC6H4)3PAuNTf2 (5)

8

28

11

Ph3PAuNTf2 (10)

2

76

12

(4-F3CC6H4)3PAuNTf2 (10)

2

(81)d

a Reaction conditions: (E)-1a (0.2 mmol), gold catalyst, CH2Cl2 (0.4 mL), 30 °C.

b Determined by 1H NMR with CH2Br2 as an internal standard.

c (Z)-1a was used instead of (E)-1a.

d Isolated yield.

Next, the scope of substrates 1 was examined (Scheme [3]). The efficiency of our reaction depended on the bulkiness of the ester group; the methyl ester 1b and the ethyl ester 1a were converted into the corresponding products 2b and 2a (see also Table [1], entry 12), respectively, in good yields, whereas the tert-butyl ester 1d required a prolonged reaction time to be fully consumed, affording the desired product 2d in low yield. It should be noted that the Z/E selectivity at the exo-olefin moiety of products 2ad was not influenced by the bulkiness of the ester group. The reaction of substrate 1e, having a dimethylcarbamoyl group instead of an ester group, gave the desired product 2e in poor yield (4%).[7] Substrate 1f, having an electron-rich 4-anisyl group at the alkyne terminus (R1) was converted into the corresponding product 2f in 63% yield, whereas the reaction of 1g having an electron-deficient 4-trifluoromethyl group resulted in a lower chemical yield (47%). In terms of alkyl substitution at R1, 1h, containing a propyl group was compatible, whereas the reaction of 1i having a bulky cyclohexyl group was sluggish.[8] An electron-deficient aryl group was tolerated at the propargylic position (R2) to furnish the corresponding isoxazoline in a good yield. Because 2k having a 4-(trifluoromethyl)phenyl group at the 5-position of the isoxazoline ring was partially isomerized to the isoxazole 3k during purification, the crude product 2k was treated with DBU in one pot to obtain 3k as a single product in good yield. In contrast, the substrate 1l, which had an electron-rich 4-anisyl group at the R2 position gave 2l in a low chemical yield of 27%. Moreover, the reaction of 1m having a less-bulky propyl group at R2 gave 2m with excellent Z-stereoselectivity. The substrate 1n, which did not possess any substituents at R2, was effectively converted into the corresponding product 2n in 83% yield.

Zoom Image
Scheme 3 Au-catalyzed reaction of 1bm. Reaction conditions: 1 (0.2 mmol), (4-F3CC6H4)3PAuNTf2 (10 mol %), CH2Cl2 (0.4 mL), 30 °C. Isolated yields of (Z)-2 are reported. The Z/E ratio was determined by 1H NMR of the crude product.a Yield determined by 1H NMR with CH2Br2 as internal standard. b 1e was used as an E/Z mixture (91:9). c The crude product 2k was treated with DBU (1 equiv) in CH2Cl2 at 30 °C for 1 h to afford the isoxazole 3k.

The reaction of the two equally reactive substrates 1b and 1j under the standard reaction conditions afforded equal amounts of the normal products 2b and 2j and the crossover products 2a and 2o (Scheme [4]). Neither the products nor the substrates showed crossover reactions the presence of gold catalysts (see SI), clearly indicating that transfer of the alkoxycarbonylmethylene group took place intermolecularly. In addition, the reaction of 1b or 1m in the presence of ethyl glyoxylate or 3,5-diphenylisoxazoline exclusively afforded 2b or 2m, derived from the starting material (see SI).

Zoom Image
Scheme 4 Crossover experiment

We therefore concluded that the present reaction proceeds through cyclization followed by intermolecular transfer of the alkoxycarbonylmethylene group, sequentially liberating the product 2, in the same manner of our previous reaction of O-propargylic formaldoximes.[4a] The present reaction selectively afforded the (Z)-isomer (Z)-2 (Scheme [3]). Presumably, because the exo-olefin and isoxazoline C=N bond in the (E)-isomer are not coplanar due to steric repulsion between the ester group and the substituent R1 derived from the alkyne terminus of the starting material 1, the more-stable (Z)-isomer was obtained with high stereoselectivity. It should be noted that the reactions of 1m, which has a less-bulky propyl group at the propargylic position, and of 1n, which lacks a substituent at R2, exhibited excellent stereoselectivity. These results also can be explained by relaxation of the steric repulsion between the ester group and R2 in the (Z)-isomer. The use of the gold catalyst with an electron-deficient phosphine ligand, such as (4-F3CC6H4)3P, gave a better result than that of a catalyst having an electron-rich ligand (Table [1], entry 8 versus entry 10). We assume that the cyclization process requires a higher π-acidity than that in the reaction of formaldoximes due to steric repulsion between the ester group of the (E)-oxime and the alkyne substituent R1 in the cyclization process from 1 to A (Scheme [1]).[4a] In addition, the electronic character of the gold catalyst might affect the electrophilicity of the iminium moiety of the vinylgold intermediate A (Scheme [1]) to facilitate intermolecular C–C bond formation. Further mechanistic studies are still underway in our laboratory.

In conclusion, we have successfully synthesized isoxazolines having an alkoxycarbonylmethylene group at the 4-position in an efficient manner. Because there are only a limited number of methods for synthesizing 4-alkylidene-substituted isoxazolines,[9] the present method is useful for constructing densely functionalized heterocycles.


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Supporting Information

  • References and Notes


    • For selected reviews on gold catalysis, see:
    • 1a Li Y, Li W, Zhang J. Chem. Eur. J. 2017; 23: 467
    • 1b Harris RJ, Widenhoefer RA. Chem. Soc. Rev. 2016; 45: 4533
    • 1c Yang W, Hashmi AS. K. Chem. Soc. Rev. 2014; 43: 2941
    • 1d Obradors C, Echavarren AM. Chem. Commun. 2014; 50: 16
    • 1e Hashmi AS. K. Angew. Chem. Int. Ed. 2010; 49: 5232
    • 1f Adcock HV, Davies PW. Synthesis 2012; 44: 3401
    • 1g Bhunia S, Liu R.-S. Pure Appl. Chem. 2012; 84: 1749
    • 1h Lu B.-L, Dai L, Shi M. Chem. Soc. Rev. 2012; 41: 3318
    • 1i Kirsch SF. Synthesis 2008; 3183
    • 1j Skouta R, Li C.-J. Tetrahedron 2008; 64: 4917
    • 1k Hashmi AS. K. Chem. Rev. 2007; 107: 3180

      For pioneering works, see:
    • 2a Trost BM, Tanoury GJ. J. Am. Chem. Soc. 1988; 110: 1636
    • 2b Chatani N, Morimoto T, Muto T, Murai S. J. Am. Chem. Soc. 1994; 116: 6049

    • For reviews, see:
    • 2c Wang Q, Shi M. Synlett 2017; 28: 2230
    • 2d Dorel R, Echavarren AM. J. Org. Chem. 2015; 80: 7321
    • 2e Michelet V. Top. Curr. Chem. 2015; 357: 95

      For pioneering works, see:
    • 3a Rautenstrauch V. J. Org. Chem. 1984; 49: 950
    • 3b Mainetti E, Mouriès V, Fensterbank L, Malacria M, Marco-Contelles J. Angew. Chem. Int. Ed. 2002; 41: 2132

    • For reviews, see:
    • 3c Boyle JW, Zhao Y, Chan PW. H. Synthesis 2018; 50: 1402
    • 3d Fensterbank L, Malacria M. Acc. Chem. Res. 2014; 47: 953
    • 3e Mauleon P, Toste FD. In Modern Gold Catalyzed Synthesis . Chap. 4, Hashmi SK, Toste FD. Wiley-VCH; Weinheim: 2012: 75
    • 4a Nakamura I, Gima S, Kudo Y, Terada M. Angew. Chem. Int. Ed. 2015; 54: 7154
    • 4b Gima S, Nakamura I, Terada M. Eur. J. Org. Chem. 2017; 4375
  • 5 Identifiable byproducts were not obtained from the reaction of (Z)-1a. It is therefore unclear at the present stage why the reaction of (Z)-1a resulted in a low chemical yield.
  • 6 Ethyl (2Z)-(3,5-Diphenylisoxazol-4(5H)-ylidene)acetate [(Z)-2a]; Typical ProcedureOxime (E)-1a (61.5 mg, 0.2 mmol) in CH2Cl2 (0.4 mL) was added to (4-F3CC6H4)3PAuNTf2 (18.9 mg, 0.02 mmol) in a V-vial under argon, and the mixture was stirred at 30 °C for 2 h. The mixture was then passed through a short pad of silica gel, eluting with CH2Cl2 (50 mL). The solvents were evaporated in vacuo, and the crude product was purified by flash column chromatography [silica gel, hexane–EtOAc (8:1)] to give a colorless liquid; yield: 50 mg (81%, Z/E = 90:10). IR (neat): 3063, 3033, 2981, 2939, 2903, 1709, 1641, 1494, 1455, 1444, 1367, 1331, 1310, 1299, 1269, 1199, 1130, 1096, 1077, 1035, 1007, 912, 899, 873 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.67–7.62 (m, 2 H), 7.55–7.50 (m, 3 H), 7.39–7.31 (m, 5 H), 6.76 (d, J = 3.2 Hz, 1 H), 6.32 (d, J = 3.2 Hz, 1 H), 4.06 (q, J = 7.3 Hz, 2 H), 1.14 (t, J = 7.3 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 165.22, 157.47, 155.10, 137.69, 130.36, 129.07, 128.70, 128.63, 128.33, 127.58, 127.39, 115.57, 88.03, 60.83, 14.01. HRMS (ESI): m/z [M + Na]+ calcd for C19H17NNaO3: 330.1101; found: 330.1100.
  • 7 A substrate having a trichloromethyl group was not converted into the desired product under the optimal reaction conditions; 60% of the starting material was recovered. Preparations from substrates having a cyano or keto group instead of an ester group failed.
  • 8 The reaction of 1i at 50 °C afforded the desired product 2i in 12% yield.
    • 9a Dunn PJ, Graham AB, Grigg R, Higginson P, Sridharan V, Thornton-Pett M. Chem. Commun. 2001; 1968
    • 9b Broggini G, Bruché L, Zecchi G, Pilati T. J. Chem. Soc., Perkin Trans. 1 1990; 533

  • References and Notes


    • For selected reviews on gold catalysis, see:
    • 1a Li Y, Li W, Zhang J. Chem. Eur. J. 2017; 23: 467
    • 1b Harris RJ, Widenhoefer RA. Chem. Soc. Rev. 2016; 45: 4533
    • 1c Yang W, Hashmi AS. K. Chem. Soc. Rev. 2014; 43: 2941
    • 1d Obradors C, Echavarren AM. Chem. Commun. 2014; 50: 16
    • 1e Hashmi AS. K. Angew. Chem. Int. Ed. 2010; 49: 5232
    • 1f Adcock HV, Davies PW. Synthesis 2012; 44: 3401
    • 1g Bhunia S, Liu R.-S. Pure Appl. Chem. 2012; 84: 1749
    • 1h Lu B.-L, Dai L, Shi M. Chem. Soc. Rev. 2012; 41: 3318
    • 1i Kirsch SF. Synthesis 2008; 3183
    • 1j Skouta R, Li C.-J. Tetrahedron 2008; 64: 4917
    • 1k Hashmi AS. K. Chem. Rev. 2007; 107: 3180

      For pioneering works, see:
    • 2a Trost BM, Tanoury GJ. J. Am. Chem. Soc. 1988; 110: 1636
    • 2b Chatani N, Morimoto T, Muto T, Murai S. J. Am. Chem. Soc. 1994; 116: 6049

    • For reviews, see:
    • 2c Wang Q, Shi M. Synlett 2017; 28: 2230
    • 2d Dorel R, Echavarren AM. J. Org. Chem. 2015; 80: 7321
    • 2e Michelet V. Top. Curr. Chem. 2015; 357: 95

      For pioneering works, see:
    • 3a Rautenstrauch V. J. Org. Chem. 1984; 49: 950
    • 3b Mainetti E, Mouriès V, Fensterbank L, Malacria M, Marco-Contelles J. Angew. Chem. Int. Ed. 2002; 41: 2132

    • For reviews, see:
    • 3c Boyle JW, Zhao Y, Chan PW. H. Synthesis 2018; 50: 1402
    • 3d Fensterbank L, Malacria M. Acc. Chem. Res. 2014; 47: 953
    • 3e Mauleon P, Toste FD. In Modern Gold Catalyzed Synthesis . Chap. 4, Hashmi SK, Toste FD. Wiley-VCH; Weinheim: 2012: 75
    • 4a Nakamura I, Gima S, Kudo Y, Terada M. Angew. Chem. Int. Ed. 2015; 54: 7154
    • 4b Gima S, Nakamura I, Terada M. Eur. J. Org. Chem. 2017; 4375
  • 5 Identifiable byproducts were not obtained from the reaction of (Z)-1a. It is therefore unclear at the present stage why the reaction of (Z)-1a resulted in a low chemical yield.
  • 6 Ethyl (2Z)-(3,5-Diphenylisoxazol-4(5H)-ylidene)acetate [(Z)-2a]; Typical ProcedureOxime (E)-1a (61.5 mg, 0.2 mmol) in CH2Cl2 (0.4 mL) was added to (4-F3CC6H4)3PAuNTf2 (18.9 mg, 0.02 mmol) in a V-vial under argon, and the mixture was stirred at 30 °C for 2 h. The mixture was then passed through a short pad of silica gel, eluting with CH2Cl2 (50 mL). The solvents were evaporated in vacuo, and the crude product was purified by flash column chromatography [silica gel, hexane–EtOAc (8:1)] to give a colorless liquid; yield: 50 mg (81%, Z/E = 90:10). IR (neat): 3063, 3033, 2981, 2939, 2903, 1709, 1641, 1494, 1455, 1444, 1367, 1331, 1310, 1299, 1269, 1199, 1130, 1096, 1077, 1035, 1007, 912, 899, 873 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.67–7.62 (m, 2 H), 7.55–7.50 (m, 3 H), 7.39–7.31 (m, 5 H), 6.76 (d, J = 3.2 Hz, 1 H), 6.32 (d, J = 3.2 Hz, 1 H), 4.06 (q, J = 7.3 Hz, 2 H), 1.14 (t, J = 7.3 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 165.22, 157.47, 155.10, 137.69, 130.36, 129.07, 128.70, 128.63, 128.33, 127.58, 127.39, 115.57, 88.03, 60.83, 14.01. HRMS (ESI): m/z [M + Na]+ calcd for C19H17NNaO3: 330.1101; found: 330.1100.
  • 7 A substrate having a trichloromethyl group was not converted into the desired product under the optimal reaction conditions; 60% of the starting material was recovered. Preparations from substrates having a cyano or keto group instead of an ester group failed.
  • 8 The reaction of 1i at 50 °C afforded the desired product 2i in 12% yield.
    • 9a Dunn PJ, Graham AB, Grigg R, Higginson P, Sridharan V, Thornton-Pett M. Chem. Commun. 2001; 1968
    • 9b Broggini G, Bruché L, Zecchi G, Pilati T. J. Chem. Soc., Perkin Trans. 1 1990; 533

  
Zoom Image
Scheme 1 Au-catalyzed skeletal rearrangement of O-propargylic oximes
Zoom Image
Scheme 2 Au-catalyzed cyclization/intermolecular methylene transfer sequence of O-propargylic oximes 1 derived from glyoxylates
Zoom Image
Scheme 3 Au-catalyzed reaction of 1bm. Reaction conditions: 1 (0.2 mmol), (4-F3CC6H4)3PAuNTf2 (10 mol %), CH2Cl2 (0.4 mL), 30 °C. Isolated yields of (Z)-2 are reported. The Z/E ratio was determined by 1H NMR of the crude product.a Yield determined by 1H NMR with CH2Br2 as internal standard. b 1e was used as an E/Z mixture (91:9). c The crude product 2k was treated with DBU (1 equiv) in CH2Cl2 at 30 °C for 1 h to afford the isoxazole 3k.
Zoom Image
Scheme 4 Crossover experiment