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Functionalized pyrroles from vinylaziridines and alkynes via rhodium-catalyzed domino ring-opening cyclization followed by CC bond migration
Tetrahedron 75 (2019) 1166e1170
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Functionalized pyrroles from vinylaziridines and alkynes via rhodiumcatalyzed domino ring-opening cyclization followed by C]C bond migration Shu-Hao Wan, Shiuh-Tzung Liu* Department of Chemistry, National Taiwan University, Taipei, 106, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 23 October 2018 Received in revised form 6 January 2019 Accepted 11 January 2019 Available online 14 January 2019
Rhodium(I)-catalyzed intermolecular cycloadditions of alkynes with vinyl aziridines bearing a conjugated carbonyl group in the olefin moiety followed by the double migration resulted in the formation of pyrrole derivatives in a one pot fashion. © 2019 Elsevier Ltd. All rights reserved.
Keywords: Cycloaddition Aziridine Pyrrole Isomerization Rhodium
1. Introduction
2. Results and discussion
Transition-metal catalysis toward the development of effective methods for carboncarbon and carbonheteroatom bond formation have been received much attention in particular for those of the synthesis of heterocycles. Quite a number of readily available compounds have been prepared in this regard. Among them, vinylsubstituted aziridines 1 are known as valuable substrates for transition-metal-catalyzed [3 þ 2], [3 þ 3], [3 þ 4] or [5 þ 2] annulation reactions with alkynes for five, six or seven membered heterocycles, respectively [1e5]. In the [3 þ 2] annulations, vinylaziridine acts as a three atom component for the five-member ring leaving the vinyl group unreacted, rendering the vinyldihydropyrrole product 2 (Scheme 1). However, this compound readily undergoes hydrolysis in the presence of a Lewis acid, giving geamino ketone 3 [3]. In fact, these two steps leading to 3 can be carried out in a one-pot fashion. In this context, not much effort has addressed about the double bond migration leading to the pyrrole 4. Here, we would like to report the preparation of vinyldihydropyrroles via the rhodium catalyzed cycloaddition and the double bond isomerization reaction leading to the corresponding pyrroles in a one-pot fashion.
The starting substrate 5 in a mixture of E/Z forms was obtained according to the reported method [1c]. Reaction of E/Z-5 with phenylacetylene in the presence of [Rh(NBD)2]BF4 in 1,2dichloroethane at ambient temperature proceeded smoothly. By
* Corresponding author. E-mail address: [email protected] (S.-T. Liu). https://doi.org/10.1016/j.tet.2019.01.022 0040-4020/© 2019 Elsevier Ltd. All rights reserved.
Scheme 1. Cycloaddition of vinyl aziridines with alkynes.
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monitoring the reaction, we found that the E-isomer was transformed into dihydropyrrole 6a within 0.5 h, but the Z-isomer remained in the solution. However, upon standing a longer time, the Z-isomer was eventually converted into 6a, indicating that the E form is more reactive than the Z isomer. Such a selectivity is similar to those reported in cycloadditions [1c,1d,6]. The trans configuration in 6a was established by 1H NMR spectroscopy. The observed J value for Ha and Hb in 6a is 15.7 Hz, which is comparable to those of the a,b-unsaturated ester in E configuration. Compound 6a was quite sensitive to water under acidic conditions, as expected, and it readily underwent ring opening reaction to yield the amino ketone 7 [3]. However, treatment of 6a with a base followed by acid workup rendered the pyrrole product 9a, indicating that the isomerization of 6a under basic condition could avoid the ring opening hydrolysis. The isomerization was studied by monitoring the reaction in CDCl3 with 1H-NMR spectroscopy. Upon addition of a base, compound 6a was converted into 8a as evidenced by the disappearance of the signal corresponding to Hg and an upfield shift of Ha to 2.7 ppm with the integration of 2H (Fig. 1a and b). The NOE experiment showed the interaction between Hε and Hb, not Ha. Thus, the stereochemistry of compound 8a is established as shown in Scheme 2 [7]. We also believed that the ester functionality in the molecule may also assist the double bond migration, presumably due to the increasing acidity of Hg [8]. Finally, the isomerization proceeded further to yield the pyrrole 9a by adjusting the medium to an acidic condition (Fig. 1c). Table 1 summarizes the study of
Fig. 1. Partial 1H NMR spectra of 6a (a), 8a (b) and 9a (c) for comparison.
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Table 1 Optimization of isomerization of 6a into 7 and 9aa.
entry
Base (amount)
t ( C)
7
9a
1 2 3 4 5 6 7 8 9 10
iPr2NH (1 eq) Pyrrolidine (1 eq) Et3N (1 eq) Pyridine (1 eq) p-DMAP (1 eq) DABCO (1 eq) DABCO (0.5 eq) DABCO (0.2 eq) DABCO (0.5 eq) None
50 50 50 50 50 50 50 50 rt rt
85% trace 11% 99% 7% trace trace 16% 57% 99%
15% 99% 89% trace 93% 99% 99% 84% 43% trace
a A sample of 6a (40 mg, 0.10 mmol) in CDCl3 (0.5 mL) was added with base. After 1 h, CF3CO2H (0.15 mmol) was added.
isomerization with various bases. Most organic bases assist this isomerization, but 1,4-diazabicyclo[2.2.2]octane (DABCO) appears to be the most efficient one. With the optimal information, a broad range of substituted phenylacetylenes were explored as substrates leading to the corresponding pyrroles in a one-pot fashion and the results are shown in Table 2. Various p-substituted phenylacetylene participated well in the reaction and furnished the corresponding pyrroles in good yields except nitro and cyano substituents. Common functional groups such as alkyl, ester, keto, ether and halogens were found compatible and the desired products were obtained in good yields. Furthermore, 2,4,6-trimethylphenylacetylene and naphthylacetylene underwent the cycloaddition followed by isomerization to give 9j (62%) and 9k (73%), respectively. Notably, 2,4,6trimethylphenylacetylene with sterically distinct substituents delivered 9j in good yield. The use of p-nitrophenylacetylene as the substrate provided a complicated mixture of products and the desired compound 6h was determined by NMR in 11% yield. However, reaction of 5 with p-cyanophenylacetylene did not give any desired product, presumably due to the coordination ability of nitrile group toward the metal center. The reactivity of diphenylacetylene appeared to be poor and the reaction only gave 9l in 19% by NMR, but acetyl phenylacetylene gave 9m in a reasonable yield. Unfortunately, alkyl substituted alkynes were not applicable to this methodology. Under the optimal conditions, reaction of 5 with 1pentyne afforded g-aminoketone 10 as the isolated product in 74% (Eqn. (1)). However, reaction of 5 with N-ethynyl-N,4dimethyl-benzenesulfonamide, a ynamide substrate, did not provide the pyrrole product under the standard conditions. In addition, a benzoyl substituted vinyl aziridine 11 underwent smoothly with phenyacetylene to yield the cycloadduct 12, and then isomerize to the pyrrole product 13 (Eqn. (2)). Notably, reaction of 1-[(4methylphenyl)sulfonyl]-2-[(1E)-2-phenylethenyl]aziridine, a substrate without an ester functionality, with phenylacetylene gave a complicated mixture of unidentified products, indicating the necessity of carbonyl functionality in aziridine components.
(1)
Scheme 2. Cycloaddition followed by isomerization to yield pyrroles.
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Table 2 Reaction of various phenylacetylene with 5 leading to pyrrolesa.
3. Summary
(2) According to the mechanism of rhodium(I)-catalyzed cycloaddition of aziridines with alkynes proposed by Zhang, reaction pathway in this work is presented in Fig. 2 [3]. Oxidative ring opening of aziridine by Rh(I) gives the p-complex I. Upon coordination of the alkyne molecule followed by the migratory insertion renders the metallocycle intermediate III, which then undergoes the reductive elimination to yield the dihydropyrrole product IV. This initial product can be either hydrolyzed to produce the gamino ketone V or isomerized under basic conditions to generate VI. Aromatization of VI provides the pyrrole product.
We have developed a synthetic method of preparation of functionalized pyrroles via rhodium-catalyzed coupling of vinylaziridines and alkynes followed by double bond migrations in onepot fashion. In this work, the double bond migration steps were investigated in detail, allowing us to understand the nature of dihydropyrroles. Current research is focused on extending the rhodium catalyzed coupling of vinylaziridines with other nucleophiles under various conditions. 4. Experimental section Manipulation was performed by using a standard Schlenk technique under dry nitrogen atmosphere. Solvents were dried using standard methods and distilled under nitrogen before use. The rhodium complex [Rh(NBD)2]BF4 [9], methyl 1-[(4methylphenyl)sulfonyl]-2-aziridinecarboxylate [10] and the ethynylarenes were prepared by following the reported method. Mass spectra were recorded with a LCQ Advantage (ESI) Mass Spectrometer. NMR spectra were determined with Bruker AvanceIII-400 or DMX-500 FT-NMR spectrometers at room temperature. 1H and
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Fig. 2. Reaction pathway for the cycloaddition and C]C bond migration.
13
C NMR spectra were obtained in CDCl3.
4.1. Preparation of ethyl 1-[(4-methylphenyl)sulfonyl]-2aziridineacrylate (5) To a solution of methyl 1-[(4-methylphenyl)sulfonyl]-2aziridinecarboxylate (2.553 g, 10.00 mmol) in CH2Cl2 (30 mL) was added diisobutylaluminum hydride (1 M, 12.0 mL, 12.0 mmol) drop-wise at 78 C under N2 atmosphere. The resulting mixture was kept at ambient temperature and stirred for 2 h. The reaction was quenched with 1N HCl (50 mL) and Et2O (3 50 mL) was added for the extraction the crude product. The organic extracts were combined, dried over anhydrous MgSO4, filtered and concentrated to give the crude aldehyde, which was used for the following step without further purification. To a suspension of NaH (60%, 600 mg, 15.0 mmol) in THF (30 mL) was added triethyl phosphonoacetate (3.0 mL, 15 mmol) drop-wise at 0 C under N2 atmosphere. The resulting mixture was stirred at ambient temperature until no H2 evolution. The freshly prepared aldehyde in THF (30 mL) was added to the above solution with stirring. The reaction was monitored by the TLC analysis to confirm the completion. The solution was washed with a saturated aqueous solution of NH4Cl (30 mL) and extracted with EtOAc (3 30 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel using EtOAc/hexane ¼ 1/4 as the eluent to give the desired vinyl aziridine 5 as colorless oil with E/ Z > 20/1. (2.245 g, 76% over 2 steps). E/Z > 20/1. E-isomer: 1H NMR (d, CDCl3): 7.82 (d, 3JHH ¼ 8.1 Hz, 2H, Ts), 7.35 (d, 3JHH ¼ 8.1 Hz, 2H, Ts), 6.55 (dd, 3JHH ¼ 15.5 Hz, 3JHH ¼ 7.4 Hz, 1H, ¼CH), 6.10 (dd, 3 JHH ¼ 15.5 Hz, 4JHH ¼ 0.7 Hz, 1H, ¼CH), 4.17 (q, 3JHH ¼ 7.1 Hz, 2H, Et), 3.37-3.32 (m, 1H, aziridine), 2.87 (d, 3JHH ¼ 7.1 Hz, 1H, aziridine), 2.45 (s, 3H, Ts), 2.27 (d, 3JHH ¼ 4.2 Hz, 1H, aziridine), 1.26 (t, 3 JHH ¼ 7.1 Hz, 3H, Et). 13C NMR (d, CDCl3): 165.64 (C]O), 145.32 (C), 141.93 (CH), 135.02 (C), 130.20 (CH), 128.27 (CH), 125.70 (CH), 61.08 (CH2), 38.92 (CH), 34.95 (CH2), 22.00 (CH3), 14.49 (CH3), which are essentially identical to the literature reported [1c]. 4.2. General procedure for preparation of pyrroles To a solution of 5 (1 equiv.) and [Rh(NBD)2]BF4 (5 mol%) in 1,2DCE (1 mL) was added the alkyne (1.5 equiv.) in 1,2-DCE (1 mL). The resulting mixture was stirred for 0.5 h. Upon the addition of 1,4-diazabicyclo[2.2.2]octane (0.5 equiv.), the mixture was heated to 50 C for 1 h. The reaction mixture was then neutralized with trifluoroacetic acid (1.5 equiv). The solvent was removed under
reduced pressure and the residue was purified by column chromatography using CH2Cl2/hexane as the eluent to give the desired pyrrole 9. 9a. Yellow oil. 51 mg, 64%. 1H NMR (d, CDCl3): 7.40-7.26 (m, 8H, Ar-H), 7.15 (d, 3JHH ¼ 8.3 Hz, 2H, Ar-H), 6.09 (d, 4JHH ¼ 1.8 Hz, 1H, pyrrole), 4.19 (q, 3JHH ¼ 7.1 Hz, 2H, Et), 2.82 (t, 3JHH ¼ 7.4 Hz, 2H, CH2), 2.62 (t, 3JHH ¼ 7.4 Hz, 2H, CH2), 2.41 (s, 3H, Ts), 1.31 (t, 3 JHH ¼ 7.1 Hz, 3H, Et). 13C NMR (d, CDCl3): 173.12 (C]O), 144.81 (C), 136.77 (C), 135.94 (C), 131.77 (C), 131.00 (CH), 129.61 (CH), 128.48 (CH), 127.63 (CH), 127.30 (CH), 126.60 (C), 121.17 (CH), 117.13 (CH), 60.75 (CH2), 34.97 (CH2), 22.44 (CH2), 21.86 (CH3), 14.53 (CH3). ESIHRMS (TOF): MHþ found 398.1459. C22H24NO4S requires 398.1426. 9b. Yellow oil. 53 mg, 65%. 1H NMR (d, CDCl3): 7.24-7.09 (m, 9H, Ar-H), 5.99 (d, 4JHH ¼ 2.1 Hz, 1H, pyrrole), 4.13 (q, 3JHH ¼ 7.3 Hz, 2H, Et), 2.74 (t, 3JHH ¼ 7.6 Hz, 2H, CH2), 2.55 (t, 3JHH ¼ 7.6 Hz, 2H, CH2), 2.39 (s, 3H, CH3), 2.35 (s, 3H, CH3), 1.24 (t, 3JHH ¼ 7.3 Hz, 3H, Et). 13C NMR (d, CDCl3): 173.15 (C]O), 144.75 (C), 138.35 (C), 136.91 (C), 135.99 (C), 130.84 (CH), 129.59 (CH), 128.87 (C), 128.36 (CH), 127.29 (CH), 126.67 (C), 120.96 (CH), 116.95 (CH), 60.74 (CH2), 34.95 (CH2), 22.43 (CH2), 21.86 (CH3), 21.62 (CH3), 14.51 (CH3). ESI-HRMS (TOF): MHþ found 412.1599. C23H26NO4S requires 412.1583. 9c. Yellow oil. 57 mg, 67%. 1H NMR (d, CDCl3): 7.31-7.14 (m, 7H, Ar-H), 6.88 (d, 3JHH ¼ 8.5 Hz, 2H, Ar-H), 6.02 (br, 1H, pyrrole), 4.18 (q, 3 JHH ¼ 7.1 Hz, 2H, Et), 3.90 (s, 3H, OCH3), 2.80 (t, 3JHH ¼ 7.5 Hz, 2H, CH2), 2.60 (t, 3JHH ¼ 7.5 Hz, 2H, CH2), 2.40 (s, 3H, Ts), 1.30 (t, 3 JHH ¼ 7.1 Hz, 3H, Et). 13C NMR (d, CDCl3): 173.16 (C]O), 159.95 (C), 144.74 (C), 136.54 (C), 136.02 (C), 132.32 (CH), 129.61 (CH), 127.33 (CH), 126.52 (C), 124.13 (C), 120.76 (CH), 116.70 (CH), 113.08 (CH), 60.76 (CH2), 55.58 (CH3), 34.99 (CH2), 22.47 (CH2), 21.88 (CH3), 14.55 (CH3). ESI-HRMS (TOF): MHþ found 428.1548. C23H26NO5S requires 428.1532. 9d. Yellow oil. 54 mg, 63%. 1H NMR (d, CDCl3): 7.29-7.11 (m, 9H, Ar-H), 6.03 (d, 4JHH ¼ 1.9 Hz, 1H, pyrrole), 4.13 (q, 3JHH ¼ 7.1 Hz, 2H, Et), 2.75 (t, 3JHH ¼ 7.5 Hz, 2H, CH2), 2.55 (t, 3JHH ¼ 7.5 Hz, 2H, CH2), 2.36 (s, 3H, Ts), 1.24 (t, 3JHH ¼ 7.1 Hz, 3H, Et). 13C NMR (d, CDCl3): 173.05 (C]O), 145.05 (C), 135.87 (C), 135.47 (C), 134.64 (C), 132.19 (CH), 130.26 (C), 129.75 (CH), 127.93 (CH), 127.24 (CH), 126.83 (C), 121.60 (CH), 117.58 (CH), 60.80 (CH2), 34.95 (CH2), 22.40 (CH2), 21.90 (CH3), 14.55 (CH3). ESI-HRMS (TOF): MHþ found 432.1052. C22H23ClNO4S requires 432.1036. 9e. Yellow oil. 71 mg, 76%. 1H NMR (d, CDCl3): 7.56 (d, 3 JHH ¼ 8.1 Hz, 2H, Ar-H), 7.36 (d, 3JHH ¼ 8.1 Hz, 2H, Ar-H), 7.23-7.21 (m, 3H, Ar-H), 7.11 (d, 3JHH ¼ 8.1 Hz, 2H, Ar-H), 6.09 (d, 4JHH ¼ 1.8 Hz, 1H, pyrrole), 4.13 (q, 3JHH ¼ 7.0 Hz, 2H, Et), 2.76 (t, 3JHH ¼ 7.4 Hz, 2H, CH2), 2.56 (t, 3JHH ¼ 7.4 Hz, 2H, CH2), 2.36 (s, 3H, Ts), 1.25 (t, 3 JHH ¼ 7.0 Hz, 3H, Et). 13C NMR (d, CDCl3): 172.99 (C]O), 145.21 (C),
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135.68 (C), 135.41 (C), 135.23 (C), 131.06 (CH), 130.32 (q, 2 JCF ¼ 32.1 Hz, C), 129.78 (CH), 127.16 (CH), 127.09 (C), 124.62 (q, 3 JCF ¼ 3.6 Hz, CH), 124.44 (q, 1JCF ¼ 274.3 Hz, CF3), 122.19 (CH), 118.30 (CH), 60.80 (CH2), 34.88 (CH2), 22.33 (CH2), 21.86 (CH3), 14.52 (CH3). 19 F NMR (d, CDCl3): -62.56 (s, 3F, CF3). ESI-HRMS (TOF): MHþ found 466.1316. C23H23F3NO4S requires 466.1300. 9f. Yellow oil. 66 mg, 75%. 1H NMR (d, CDCl3): 7.88 (d, 3 JHH ¼ 8.4 Hz, 2H, Ar-H), 7.35 (d, 3JHH ¼ 8.4 Hz, 2H, Ar-H), 7.21-7.19 (m, 3H, Ar-H), 7.09 (d, 3JHH ¼ 8.1 Hz, 2H, Ar-H), 6.09 (d, 4JHH ¼ 1.8 Hz, 1H, pyrrole), 4.10 (q, 3JHH ¼ 7.0 Hz, 2H, Et), 2.73 (t, 3JHH ¼ 7.7 Hz, 2H, CH2), 2.61 (s, 3H, CH3), 2.53 (t, 3JHH ¼ 7.7 Hz, 2H, CH2), 2.33 (s, 3H, Ts), 1.21 (t, 3JHH ¼ 7.0 Hz, 3H, Et). 13C NMR (d, CDCl3): 197.98 (C]O), 172.89 (C]O), 145.10 (C), 136.57 (C), 136.46 (C), 135.77 (C), 135.62 (C), 130.74 (CH), 129.72 (CH), 127.66 (CH), 127.29 (C), 127.04 (CH), 122.41 (CH), 118.44 (CH), 60.70 (CH2), 34.80 (CH2), 26.90 (CH3), 22.26 (CH2), 21.80 (CH3), 14.46 (CH3). ESI-HRMS (TOF): MHþ found 440.1532. C24H26NO5S requires 440.1532. 9g. Yellow oil. 64 mg, 68%. 1H NMR (d, CDCl3): 7.98 (d, 3 JHH ¼ 8.5 Hz, 2H, Ar-H), 7.32 (d, 3JHH ¼ 8.5 Hz, 2H, Ar-H), 7.22-7.20 (m, 3H, Ar-H), 7.09 (d, 3JHH ¼ 8.5 Hz, 2H, Ar-H), 6.09 (d, 4JHH ¼ 2.1 Hz, 1H, pyrrole), 4.39 (q, 3JHH ¼ 7.1 Hz, 2H, Et), 4.12 (q, 3JHH ¼ 7.1 Hz, 2H, Et), 2.74 (t, 3JHH ¼ 7.8 Hz, 2H, CH2), 2.54 (t, 3JHH ¼ 7.8 Hz, 2H, CH2), 2.34 (s, 3H, Ts), 1.41 (t, 3JHH ¼ 7.1 Hz, 3H, Et), 1.23 (t, 3JHH ¼ 7.1 Hz, 3H, Et). 13C NMR (d, CDCl3): 172.98 (C]O), 166.68 (C]O), 145.08 (C), 136.23 (C), 135.89 (C), 135.71 (C), 130.63 (CH), 130.21 (C), 129.74 (CH), 128.89 (CH), 127.14 (CH), 122.26 (CH), 118.24 (CH), 61.35 (CH2), 60.76 (CH2), 34.89 (CH2), 22.34 (CH2), 21.86 (CH3), 14.64 (CH3), 14.52 (CH3). ESI-HRMS (TOF): MHþ found 470.1638. C25H28NO6S requires 470.1637. 9j. Yellow oil. 55 mg, 62%. 1H NMR (d, CDCl3): 7.30-7.27 (m, 3H, Ts, pyrrole), 7.14 (d, 3JHH ¼ 7.8 Hz, 2H, Ts), 6.80 (s, 2H, mesityl), 5.88 (d, 4JHH ¼ 2.1 Hz, 1H, pyrrole), 4.14 (q, 3JHH ¼ 7.1 Hz, 2H, Et), 2.81 (t, 3 JHH ¼ 7.5 Hz, 2H, CH2), 2.59 (t, 3JHH ¼ 7.5 Hz, 2H, CH2), 2.39 (s, 3H, CH3), 2.32 (s, 3H, CH3), 1.66 (s, 6H, CH3), 1.25 (t, 3JHH ¼ 7.1 Hz, 3H, Et). 13 C NMR (d, CDCl3): 173.24 (C]O), 144.90 (C), 140.06 (C), 138.76 (C), 136.00 (C), 132.80 (C), 129.67 (CH), 128.17 (CH), 127.84 (CH), 125.34 (C), 118.99 (CH), 115.72 (CH), 60.70 (CH2), 35.28 (CH2), 22.67 (CH2), 21.90 (CH3), 21.53 (CH3), 20.49 (CH3), 14.57 (CH3). ESI-HRMS (TOF): MHþ found 440.1876. C25H30NO4S requires 440.1896. 9k. Yellow oil. 65 mg, 73%. 1H NMR (d, CDCl3): 7.87-6.82 (12H, Ar-H), 6.14 (s, 1H, pyrrole), 4.16 (q, 3JHH ¼ 7.1 Hz, 2H, Et), 2.86 (t, 3 JHH ¼ 7.5 Hz, 2H, CH2), 2.64 (t, 3JHH ¼ 7.5 Hz, 2H, CH2), 2.21 (s, 3H, Ts), 1.27 (t, 3JHH ¼ 7.1 Hz, 3H, Et). 13C NMR (d, CDCl3): 173.18 (C]O), 144.63 (C), 135.46 (C), 133.93 (C), 133.22 (C), 132.60 (C), 130.63 (CH), 129.43 (CH), 129.35 (CH), 128.97 (C), 128.01 (CH), 127.49 (CH), 126.09 (CH), 125.64 (CH), 125.55 (C), 125.48 (CH), 124.69 (CH), 119.96 (CH), 117.73 (CH), 60.74 (CH2), 35.14 (CH2), 22.56 (CH2), 21.67 (CH3), 14.55 (CH3). ESI-HRMS (TOF): MHþ found 448.1610. C26H26NO4S requires 448.1583. 9m. Yellow oil. 50 mg, 57%. 1H NMR (d, CDCl3): 7.44 (t, 3 JHH ¼ 7.7 Hz, 1H, Ar-H), 7.32-7.28 (m, 3H, Ar-H), 7.16 (d, 3 JHH ¼ 8.6 Hz, 2H, Ar-H), 7.11 (d, 3JHH ¼ 8.6 Hz, 2H, Ar-H), 7.05 (d, 3 JHH ¼ 7.1 Hz, 2H, Ar-H), 4.15 (q, 3JHH ¼ 7.1 Hz, 2H, Et), 3.00 (t, 3 JHH ¼ 7.4 Hz, 2H, CH2), 2.62 (t, 3JHH ¼ 7.4 Hz, 2H, CH2), 2.38 (s, 3H, Ts), 1.65 (s, 3H, CH3), 1.27 (t, 3JHH ¼ 7.1 Hz, 3H, Et). 13C NMR (d, CDCl3): 197.06 (C]O), 173.43 (C]O), 145.64 (C), 138.16 (C), 135.52 (C), 132.22 (CH), 130.46 (C), 129.93 (CH), 129.89 (CH), 128.06 (CH), 127.86 (CH), 125.76 (C), 120.53 (CH), 60.67 (CH2), 34.68 (CH2), 30.78 (CH3), 22.32 (CH2), 21.97 (CH3), 14.62 (CH3). ESI-HRMS (TOF): MHþ found 440.1544. C24H26NO5S requires 440.1532. 12. Colorless oil. 47 mg, 55%. 1H NMR (d, CDCl3): 7.85 (d, 3 JHH ¼ 7.8 Hz, 2H, Ar-H), 7.60-7.39 (m, 10H, Ar-H), 7.21 (d,
3
JHH ¼ 7.8 Hz, 2H, Ar-H), 6.58 (d, 3JHH ¼ 15.2 Hz, 1H, ¼CH), 6.34 (dd, JHH ¼ 15.2 Hz, 3JHH ¼ 7.1 Hz, 1H, ¼CH), 5.36 (d, 3JHH ¼ 2.8 Hz, 1H, ¼CH), 4.31 (dd, 2JHH ¼ 13.1 Hz, 3JHH ¼ 9.5 Hz, 1H, CHH), 3.87 (dd, 2 JHH ¼ 13.1 Hz, 3JHH ¼ 6.7 Hz, 1H, CHH), 3.40-3.34 (m, 1H, CH), 2.27 (s, 3H, Ts). 13C NMR (d, CDCl3): 189.79 (C]O), 147.32 (CH), 147.05 (C), 144.75 (C), 137.59 (C), 133.31 (CH), 132.67 (C), 129.93 (CH), 129.51 (CH), 128.91 (CH), 128.77 (CH), 128.35 (CH), 128.30 (CH), 128.21 (CH), 125.88 (CH), 117.42 (CH), 56.52 (CH2), 43.69 (CH), 21.73 (CH3). ESI-HRMS (TOF): MHþ found 430.1474. C26H24NO3S requires 430.1477. 13. Yellow oil. 1H NMR (d, CDCl3): 7.97 (d, 3JHH ¼ 7.8 Hz, 2H, ArH), 7.57 (t, 3JHH ¼ 7.4 Hz, 1H, Ar-H), 7.47 (t, 3JHH ¼ 7.8 Hz, 2H, Ar-H), 7.35-7.20 (m, 8H, Ar-H), 7.07 (d, 3JHH ¼ 8.1 Hz, 2H, Ar-H), 6.08 (d, 4 JHH ¼ 1.8 Hz, 1H, pyrrole), 3.24 (t, 3JHH ¼ 7.4 Hz, 2H, CH2), 2.88 (t, 3 JHH ¼ 7.4 Hz, 2H, CH2), 2.34 (s, 3H, Ts). 13C NMR (d, CDCl3): 199.01 (C]O), 144.39 (C), 136.77 (C), 136.41 (C), 135.51 (C), 133.03 (CH), 131.40 (C), 130.60 (CH), 129.22 (CH), 128.55 (CH), 128.08 (CH), 127.94 (CH), 127.25 (CH), 126.93 (CH), 126.80 (C), 120.85 (CH), 117.03 (CH), 38.80 (CH2), 21.48 (CH3), 21.08 (CH2). ESI-HRMS (TOF): MHþ found 430.1470. C26H24NO3S requires 430.1477. 3
Acknowledgments We thank the Ministry of Science and Technology, Taiwan (Grant No. MOST106-2113-M-002-018) for the financial support. We also thank “National Taiwan University Mass Spectrometry-based Proteomics Core Facility” for the measurement of ESI mass data. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.tet.2019.01.022. References [1] (a) J.-J. Feng, J. Zhang, ACS Catal. 6 (2016) 6651e6661; (b) C.-Z. Zhu, J.-J. Feng, J. Zhang, Angew. Chem. Int. Ed. 56 (2017) 1351e1355; (c) J.-J. Feng, T.-Y. Lin, H.-H. Wu, J. Zhang, J. Am. Chem. Soc. 137 (2015) 3787e3790; (d) J.-J. Feng, T.-Y. Lin, H.-H. Wu, J. Zhang, Angew. Chem. Int. Ed. 54 (2015) 15854e18558. [2] (a) T. Li, G. Zhang, J. Guo, S. Wang, X. Leng, Y. Chen, Organometallics 35 (2016) 1565e1572; (b) T. Kaicharla, A. Jacob, R.G. Gonnade, A.T. Biju, Chem. Commun. 53 (2017) 8219e8222; (c) A.L. Cardoso, T.M.V.D. Pinho e Melo, Eur. J. Org. Chem. (2012) 6479e6501; (d) B. Wang, M. Liang, J. Tang, Y. Deng, J. Zhao, H. Sun, C.-H. Tung, J. Jia, Z. Xu, Org. Lett. 18 (2016) 4614e4617; (e) T.-Y. Lin, H.-H. Wu, J.-J. Feng, J. Zhang, Org. Lett. 19 (2017) 6526e6529; (f) M. Sengoden, A. Bhowmick, T. Punniyamurthy, Org. Lett. 19 (2017) 158e161; (g) K. Spielmann, E. Tosi, A. Lebrun, G. Niel, A. van der Lee, R.M. de Figueiredo, J.-M. Campagne, Tetrahedron 74 (2018) 6497e6511; (h) C.-Z. Zhu, J.-J. Feng, J. Zhang, Chem. Commun. 54 (2018) 2401e2404; (i) T.-Y. Lin, C.-Z. Zhu, P. Zhang, Y. Wang, H.-H. Wu, J.-J. Feng, J. Zhang, Angew. Chem. Int. Ed. 55 (2016) 10844e10848. [3] J.-J. Feng, T.-Y. Lin, C.-Z. Zhu, H. Wang, H.-H. Wu, J. Zhang, J. Am. Chem. Soc. 138 (2016) 2178e2181. [4] C.-Z. Zhu, J.-J. Feng, J. Zhang, Chem. Commun. 53 (2017) 4688e4691. [5] F. Jiang, F.-R. Yuan, L.-W. Jin, G.-J. Mei, F. Shi, ACS Catal. 8 (2018) 10234e10240. [6] L. Zhu, X. Qi, Y. Lan, Organometallics 35 (2016) 771e777. [7] R.A. Doohan, J.J. Hannan, N.W.A. Geraghty, Org. Biomol. Chem. 4 (2006) 942e952. [8] F. Antras, S. Laurent, M. Ahmar, H. Chermette, B. Cazes, Eur. J. Org. Chem. (2010) 3312e3336. , Y. Díaz, M.I. Matheu, S. Castillo n, Org. Lett. 10 (2008) 4735e4738. [9] P. Marce [10] Z. Na, S. Pan, M. Uttamchandani, S.Q. Yao, Angew. Chem. Int. Ed. 53 (2014) 8421e8426.
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Functionalized pyrroles from vinylaziridines and alkynes via rhodiumcatalyzed domino ring-opening cyclization followed by C]C bond migration Shu-Hao Wan, Shiuh-Tzung Liu* Department of Chemistry, National Taiwan University, Taipei, 106, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 23 October 2018 Received in revised form 6 January 2019 Accepted 11 January 2019 Available online 14 January 2019
Rhodium(I)-catalyzed intermolecular cycloadditions of alkynes with vinyl aziridines bearing a conjugated carbonyl group in the olefin moiety followed by the double migration resulted in the formation of pyrrole derivatives in a one pot fashion. © 2019 Elsevier Ltd. All rights reserved.
Keywords: Cycloaddition Aziridine Pyrrole Isomerization Rhodium
1. Introduction
2. Results and discussion
Transition-metal catalysis toward the development of effective methods for carboncarbon and carbonheteroatom bond formation have been received much attention in particular for those of the synthesis of heterocycles. Quite a number of readily available compounds have been prepared in this regard. Among them, vinylsubstituted aziridines 1 are known as valuable substrates for transition-metal-catalyzed [3 þ 2], [3 þ 3], [3 þ 4] or [5 þ 2] annulation reactions with alkynes for five, six or seven membered heterocycles, respectively [1e5]. In the [3 þ 2] annulations, vinylaziridine acts as a three atom component for the five-member ring leaving the vinyl group unreacted, rendering the vinyldihydropyrrole product 2 (Scheme 1). However, this compound readily undergoes hydrolysis in the presence of a Lewis acid, giving geamino ketone 3 [3]. In fact, these two steps leading to 3 can be carried out in a one-pot fashion. In this context, not much effort has addressed about the double bond migration leading to the pyrrole 4. Here, we would like to report the preparation of vinyldihydropyrroles via the rhodium catalyzed cycloaddition and the double bond isomerization reaction leading to the corresponding pyrroles in a one-pot fashion.
The starting substrate 5 in a mixture of E/Z forms was obtained according to the reported method [1c]. Reaction of E/Z-5 with phenylacetylene in the presence of [Rh(NBD)2]BF4 in 1,2dichloroethane at ambient temperature proceeded smoothly. By
* Corresponding author. E-mail address: [email protected] (S.-T. Liu). https://doi.org/10.1016/j.tet.2019.01.022 0040-4020/© 2019 Elsevier Ltd. All rights reserved.
Scheme 1. Cycloaddition of vinyl aziridines with alkynes.
S.-H. Wan, S.-T. Liu / Tetrahedron 75 (2019) 1166e1170
monitoring the reaction, we found that the E-isomer was transformed into dihydropyrrole 6a within 0.5 h, but the Z-isomer remained in the solution. However, upon standing a longer time, the Z-isomer was eventually converted into 6a, indicating that the E form is more reactive than the Z isomer. Such a selectivity is similar to those reported in cycloadditions [1c,1d,6]. The trans configuration in 6a was established by 1H NMR spectroscopy. The observed J value for Ha and Hb in 6a is 15.7 Hz, which is comparable to those of the a,b-unsaturated ester in E configuration. Compound 6a was quite sensitive to water under acidic conditions, as expected, and it readily underwent ring opening reaction to yield the amino ketone 7 [3]. However, treatment of 6a with a base followed by acid workup rendered the pyrrole product 9a, indicating that the isomerization of 6a under basic condition could avoid the ring opening hydrolysis. The isomerization was studied by monitoring the reaction in CDCl3 with 1H-NMR spectroscopy. Upon addition of a base, compound 6a was converted into 8a as evidenced by the disappearance of the signal corresponding to Hg and an upfield shift of Ha to 2.7 ppm with the integration of 2H (Fig. 1a and b). The NOE experiment showed the interaction between Hε and Hb, not Ha. Thus, the stereochemistry of compound 8a is established as shown in Scheme 2 [7]. We also believed that the ester functionality in the molecule may also assist the double bond migration, presumably due to the increasing acidity of Hg [8]. Finally, the isomerization proceeded further to yield the pyrrole 9a by adjusting the medium to an acidic condition (Fig. 1c). Table 1 summarizes the study of
Fig. 1. Partial 1H NMR spectra of 6a (a), 8a (b) and 9a (c) for comparison.
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Table 1 Optimization of isomerization of 6a into 7 and 9aa.
entry
Base (amount)
t ( C)
7
9a
1 2 3 4 5 6 7 8 9 10
iPr2NH (1 eq) Pyrrolidine (1 eq) Et3N (1 eq) Pyridine (1 eq) p-DMAP (1 eq) DABCO (1 eq) DABCO (0.5 eq) DABCO (0.2 eq) DABCO (0.5 eq) None
50 50 50 50 50 50 50 50 rt rt
85% trace 11% 99% 7% trace trace 16% 57% 99%
15% 99% 89% trace 93% 99% 99% 84% 43% trace
a A sample of 6a (40 mg, 0.10 mmol) in CDCl3 (0.5 mL) was added with base. After 1 h, CF3CO2H (0.15 mmol) was added.
isomerization with various bases. Most organic bases assist this isomerization, but 1,4-diazabicyclo[2.2.2]octane (DABCO) appears to be the most efficient one. With the optimal information, a broad range of substituted phenylacetylenes were explored as substrates leading to the corresponding pyrroles in a one-pot fashion and the results are shown in Table 2. Various p-substituted phenylacetylene participated well in the reaction and furnished the corresponding pyrroles in good yields except nitro and cyano substituents. Common functional groups such as alkyl, ester, keto, ether and halogens were found compatible and the desired products were obtained in good yields. Furthermore, 2,4,6-trimethylphenylacetylene and naphthylacetylene underwent the cycloaddition followed by isomerization to give 9j (62%) and 9k (73%), respectively. Notably, 2,4,6trimethylphenylacetylene with sterically distinct substituents delivered 9j in good yield. The use of p-nitrophenylacetylene as the substrate provided a complicated mixture of products and the desired compound 6h was determined by NMR in 11% yield. However, reaction of 5 with p-cyanophenylacetylene did not give any desired product, presumably due to the coordination ability of nitrile group toward the metal center. The reactivity of diphenylacetylene appeared to be poor and the reaction only gave 9l in 19% by NMR, but acetyl phenylacetylene gave 9m in a reasonable yield. Unfortunately, alkyl substituted alkynes were not applicable to this methodology. Under the optimal conditions, reaction of 5 with 1pentyne afforded g-aminoketone 10 as the isolated product in 74% (Eqn. (1)). However, reaction of 5 with N-ethynyl-N,4dimethyl-benzenesulfonamide, a ynamide substrate, did not provide the pyrrole product under the standard conditions. In addition, a benzoyl substituted vinyl aziridine 11 underwent smoothly with phenyacetylene to yield the cycloadduct 12, and then isomerize to the pyrrole product 13 (Eqn. (2)). Notably, reaction of 1-[(4methylphenyl)sulfonyl]-2-[(1E)-2-phenylethenyl]aziridine, a substrate without an ester functionality, with phenylacetylene gave a complicated mixture of unidentified products, indicating the necessity of carbonyl functionality in aziridine components.
(1)
Scheme 2. Cycloaddition followed by isomerization to yield pyrroles.
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Table 2 Reaction of various phenylacetylene with 5 leading to pyrrolesa.
3. Summary
(2) According to the mechanism of rhodium(I)-catalyzed cycloaddition of aziridines with alkynes proposed by Zhang, reaction pathway in this work is presented in Fig. 2 [3]. Oxidative ring opening of aziridine by Rh(I) gives the p-complex I. Upon coordination of the alkyne molecule followed by the migratory insertion renders the metallocycle intermediate III, which then undergoes the reductive elimination to yield the dihydropyrrole product IV. This initial product can be either hydrolyzed to produce the gamino ketone V or isomerized under basic conditions to generate VI. Aromatization of VI provides the pyrrole product.
We have developed a synthetic method of preparation of functionalized pyrroles via rhodium-catalyzed coupling of vinylaziridines and alkynes followed by double bond migrations in onepot fashion. In this work, the double bond migration steps were investigated in detail, allowing us to understand the nature of dihydropyrroles. Current research is focused on extending the rhodium catalyzed coupling of vinylaziridines with other nucleophiles under various conditions. 4. Experimental section Manipulation was performed by using a standard Schlenk technique under dry nitrogen atmosphere. Solvents were dried using standard methods and distilled under nitrogen before use. The rhodium complex [Rh(NBD)2]BF4 [9], methyl 1-[(4methylphenyl)sulfonyl]-2-aziridinecarboxylate [10] and the ethynylarenes were prepared by following the reported method. Mass spectra were recorded with a LCQ Advantage (ESI) Mass Spectrometer. NMR spectra were determined with Bruker AvanceIII-400 or DMX-500 FT-NMR spectrometers at room temperature. 1H and
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Fig. 2. Reaction pathway for the cycloaddition and C]C bond migration.
13
C NMR spectra were obtained in CDCl3.
4.1. Preparation of ethyl 1-[(4-methylphenyl)sulfonyl]-2aziridineacrylate (5) To a solution of methyl 1-[(4-methylphenyl)sulfonyl]-2aziridinecarboxylate (2.553 g, 10.00 mmol) in CH2Cl2 (30 mL) was added diisobutylaluminum hydride (1 M, 12.0 mL, 12.0 mmol) drop-wise at 78 C under N2 atmosphere. The resulting mixture was kept at ambient temperature and stirred for 2 h. The reaction was quenched with 1N HCl (50 mL) and Et2O (3 50 mL) was added for the extraction the crude product. The organic extracts were combined, dried over anhydrous MgSO4, filtered and concentrated to give the crude aldehyde, which was used for the following step without further purification. To a suspension of NaH (60%, 600 mg, 15.0 mmol) in THF (30 mL) was added triethyl phosphonoacetate (3.0 mL, 15 mmol) drop-wise at 0 C under N2 atmosphere. The resulting mixture was stirred at ambient temperature until no H2 evolution. The freshly prepared aldehyde in THF (30 mL) was added to the above solution with stirring. The reaction was monitored by the TLC analysis to confirm the completion. The solution was washed with a saturated aqueous solution of NH4Cl (30 mL) and extracted with EtOAc (3 30 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel using EtOAc/hexane ¼ 1/4 as the eluent to give the desired vinyl aziridine 5 as colorless oil with E/ Z > 20/1. (2.245 g, 76% over 2 steps). E/Z > 20/1. E-isomer: 1H NMR (d, CDCl3): 7.82 (d, 3JHH ¼ 8.1 Hz, 2H, Ts), 7.35 (d, 3JHH ¼ 8.1 Hz, 2H, Ts), 6.55 (dd, 3JHH ¼ 15.5 Hz, 3JHH ¼ 7.4 Hz, 1H, ¼CH), 6.10 (dd, 3 JHH ¼ 15.5 Hz, 4JHH ¼ 0.7 Hz, 1H, ¼CH), 4.17 (q, 3JHH ¼ 7.1 Hz, 2H, Et), 3.37-3.32 (m, 1H, aziridine), 2.87 (d, 3JHH ¼ 7.1 Hz, 1H, aziridine), 2.45 (s, 3H, Ts), 2.27 (d, 3JHH ¼ 4.2 Hz, 1H, aziridine), 1.26 (t, 3 JHH ¼ 7.1 Hz, 3H, Et). 13C NMR (d, CDCl3): 165.64 (C]O), 145.32 (C), 141.93 (CH), 135.02 (C), 130.20 (CH), 128.27 (CH), 125.70 (CH), 61.08 (CH2), 38.92 (CH), 34.95 (CH2), 22.00 (CH3), 14.49 (CH3), which are essentially identical to the literature reported [1c]. 4.2. General procedure for preparation of pyrroles To a solution of 5 (1 equiv.) and [Rh(NBD)2]BF4 (5 mol%) in 1,2DCE (1 mL) was added the alkyne (1.5 equiv.) in 1,2-DCE (1 mL). The resulting mixture was stirred for 0.5 h. Upon the addition of 1,4-diazabicyclo[2.2.2]octane (0.5 equiv.), the mixture was heated to 50 C for 1 h. The reaction mixture was then neutralized with trifluoroacetic acid (1.5 equiv). The solvent was removed under
reduced pressure and the residue was purified by column chromatography using CH2Cl2/hexane as the eluent to give the desired pyrrole 9. 9a. Yellow oil. 51 mg, 64%. 1H NMR (d, CDCl3): 7.40-7.26 (m, 8H, Ar-H), 7.15 (d, 3JHH ¼ 8.3 Hz, 2H, Ar-H), 6.09 (d, 4JHH ¼ 1.8 Hz, 1H, pyrrole), 4.19 (q, 3JHH ¼ 7.1 Hz, 2H, Et), 2.82 (t, 3JHH ¼ 7.4 Hz, 2H, CH2), 2.62 (t, 3JHH ¼ 7.4 Hz, 2H, CH2), 2.41 (s, 3H, Ts), 1.31 (t, 3 JHH ¼ 7.1 Hz, 3H, Et). 13C NMR (d, CDCl3): 173.12 (C]O), 144.81 (C), 136.77 (C), 135.94 (C), 131.77 (C), 131.00 (CH), 129.61 (CH), 128.48 (CH), 127.63 (CH), 127.30 (CH), 126.60 (C), 121.17 (CH), 117.13 (CH), 60.75 (CH2), 34.97 (CH2), 22.44 (CH2), 21.86 (CH3), 14.53 (CH3). ESIHRMS (TOF): MHþ found 398.1459. C22H24NO4S requires 398.1426. 9b. Yellow oil. 53 mg, 65%. 1H NMR (d, CDCl3): 7.24-7.09 (m, 9H, Ar-H), 5.99 (d, 4JHH ¼ 2.1 Hz, 1H, pyrrole), 4.13 (q, 3JHH ¼ 7.3 Hz, 2H, Et), 2.74 (t, 3JHH ¼ 7.6 Hz, 2H, CH2), 2.55 (t, 3JHH ¼ 7.6 Hz, 2H, CH2), 2.39 (s, 3H, CH3), 2.35 (s, 3H, CH3), 1.24 (t, 3JHH ¼ 7.3 Hz, 3H, Et). 13C NMR (d, CDCl3): 173.15 (C]O), 144.75 (C), 138.35 (C), 136.91 (C), 135.99 (C), 130.84 (CH), 129.59 (CH), 128.87 (C), 128.36 (CH), 127.29 (CH), 126.67 (C), 120.96 (CH), 116.95 (CH), 60.74 (CH2), 34.95 (CH2), 22.43 (CH2), 21.86 (CH3), 21.62 (CH3), 14.51 (CH3). ESI-HRMS (TOF): MHþ found 412.1599. C23H26NO4S requires 412.1583. 9c. Yellow oil. 57 mg, 67%. 1H NMR (d, CDCl3): 7.31-7.14 (m, 7H, Ar-H), 6.88 (d, 3JHH ¼ 8.5 Hz, 2H, Ar-H), 6.02 (br, 1H, pyrrole), 4.18 (q, 3 JHH ¼ 7.1 Hz, 2H, Et), 3.90 (s, 3H, OCH3), 2.80 (t, 3JHH ¼ 7.5 Hz, 2H, CH2), 2.60 (t, 3JHH ¼ 7.5 Hz, 2H, CH2), 2.40 (s, 3H, Ts), 1.30 (t, 3 JHH ¼ 7.1 Hz, 3H, Et). 13C NMR (d, CDCl3): 173.16 (C]O), 159.95 (C), 144.74 (C), 136.54 (C), 136.02 (C), 132.32 (CH), 129.61 (CH), 127.33 (CH), 126.52 (C), 124.13 (C), 120.76 (CH), 116.70 (CH), 113.08 (CH), 60.76 (CH2), 55.58 (CH3), 34.99 (CH2), 22.47 (CH2), 21.88 (CH3), 14.55 (CH3). ESI-HRMS (TOF): MHþ found 428.1548. C23H26NO5S requires 428.1532. 9d. Yellow oil. 54 mg, 63%. 1H NMR (d, CDCl3): 7.29-7.11 (m, 9H, Ar-H), 6.03 (d, 4JHH ¼ 1.9 Hz, 1H, pyrrole), 4.13 (q, 3JHH ¼ 7.1 Hz, 2H, Et), 2.75 (t, 3JHH ¼ 7.5 Hz, 2H, CH2), 2.55 (t, 3JHH ¼ 7.5 Hz, 2H, CH2), 2.36 (s, 3H, Ts), 1.24 (t, 3JHH ¼ 7.1 Hz, 3H, Et). 13C NMR (d, CDCl3): 173.05 (C]O), 145.05 (C), 135.87 (C), 135.47 (C), 134.64 (C), 132.19 (CH), 130.26 (C), 129.75 (CH), 127.93 (CH), 127.24 (CH), 126.83 (C), 121.60 (CH), 117.58 (CH), 60.80 (CH2), 34.95 (CH2), 22.40 (CH2), 21.90 (CH3), 14.55 (CH3). ESI-HRMS (TOF): MHþ found 432.1052. C22H23ClNO4S requires 432.1036. 9e. Yellow oil. 71 mg, 76%. 1H NMR (d, CDCl3): 7.56 (d, 3 JHH ¼ 8.1 Hz, 2H, Ar-H), 7.36 (d, 3JHH ¼ 8.1 Hz, 2H, Ar-H), 7.23-7.21 (m, 3H, Ar-H), 7.11 (d, 3JHH ¼ 8.1 Hz, 2H, Ar-H), 6.09 (d, 4JHH ¼ 1.8 Hz, 1H, pyrrole), 4.13 (q, 3JHH ¼ 7.0 Hz, 2H, Et), 2.76 (t, 3JHH ¼ 7.4 Hz, 2H, CH2), 2.56 (t, 3JHH ¼ 7.4 Hz, 2H, CH2), 2.36 (s, 3H, Ts), 1.25 (t, 3 JHH ¼ 7.0 Hz, 3H, Et). 13C NMR (d, CDCl3): 172.99 (C]O), 145.21 (C),
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135.68 (C), 135.41 (C), 135.23 (C), 131.06 (CH), 130.32 (q, 2 JCF ¼ 32.1 Hz, C), 129.78 (CH), 127.16 (CH), 127.09 (C), 124.62 (q, 3 JCF ¼ 3.6 Hz, CH), 124.44 (q, 1JCF ¼ 274.3 Hz, CF3), 122.19 (CH), 118.30 (CH), 60.80 (CH2), 34.88 (CH2), 22.33 (CH2), 21.86 (CH3), 14.52 (CH3). 19 F NMR (d, CDCl3): -62.56 (s, 3F, CF3). ESI-HRMS (TOF): MHþ found 466.1316. C23H23F3NO4S requires 466.1300. 9f. Yellow oil. 66 mg, 75%. 1H NMR (d, CDCl3): 7.88 (d, 3 JHH ¼ 8.4 Hz, 2H, Ar-H), 7.35 (d, 3JHH ¼ 8.4 Hz, 2H, Ar-H), 7.21-7.19 (m, 3H, Ar-H), 7.09 (d, 3JHH ¼ 8.1 Hz, 2H, Ar-H), 6.09 (d, 4JHH ¼ 1.8 Hz, 1H, pyrrole), 4.10 (q, 3JHH ¼ 7.0 Hz, 2H, Et), 2.73 (t, 3JHH ¼ 7.7 Hz, 2H, CH2), 2.61 (s, 3H, CH3), 2.53 (t, 3JHH ¼ 7.7 Hz, 2H, CH2), 2.33 (s, 3H, Ts), 1.21 (t, 3JHH ¼ 7.0 Hz, 3H, Et). 13C NMR (d, CDCl3): 197.98 (C]O), 172.89 (C]O), 145.10 (C), 136.57 (C), 136.46 (C), 135.77 (C), 135.62 (C), 130.74 (CH), 129.72 (CH), 127.66 (CH), 127.29 (C), 127.04 (CH), 122.41 (CH), 118.44 (CH), 60.70 (CH2), 34.80 (CH2), 26.90 (CH3), 22.26 (CH2), 21.80 (CH3), 14.46 (CH3). ESI-HRMS (TOF): MHþ found 440.1532. C24H26NO5S requires 440.1532. 9g. Yellow oil. 64 mg, 68%. 1H NMR (d, CDCl3): 7.98 (d, 3 JHH ¼ 8.5 Hz, 2H, Ar-H), 7.32 (d, 3JHH ¼ 8.5 Hz, 2H, Ar-H), 7.22-7.20 (m, 3H, Ar-H), 7.09 (d, 3JHH ¼ 8.5 Hz, 2H, Ar-H), 6.09 (d, 4JHH ¼ 2.1 Hz, 1H, pyrrole), 4.39 (q, 3JHH ¼ 7.1 Hz, 2H, Et), 4.12 (q, 3JHH ¼ 7.1 Hz, 2H, Et), 2.74 (t, 3JHH ¼ 7.8 Hz, 2H, CH2), 2.54 (t, 3JHH ¼ 7.8 Hz, 2H, CH2), 2.34 (s, 3H, Ts), 1.41 (t, 3JHH ¼ 7.1 Hz, 3H, Et), 1.23 (t, 3JHH ¼ 7.1 Hz, 3H, Et). 13C NMR (d, CDCl3): 172.98 (C]O), 166.68 (C]O), 145.08 (C), 136.23 (C), 135.89 (C), 135.71 (C), 130.63 (CH), 130.21 (C), 129.74 (CH), 128.89 (CH), 127.14 (CH), 122.26 (CH), 118.24 (CH), 61.35 (CH2), 60.76 (CH2), 34.89 (CH2), 22.34 (CH2), 21.86 (CH3), 14.64 (CH3), 14.52 (CH3). ESI-HRMS (TOF): MHþ found 470.1638. C25H28NO6S requires 470.1637. 9j. Yellow oil. 55 mg, 62%. 1H NMR (d, CDCl3): 7.30-7.27 (m, 3H, Ts, pyrrole), 7.14 (d, 3JHH ¼ 7.8 Hz, 2H, Ts), 6.80 (s, 2H, mesityl), 5.88 (d, 4JHH ¼ 2.1 Hz, 1H, pyrrole), 4.14 (q, 3JHH ¼ 7.1 Hz, 2H, Et), 2.81 (t, 3 JHH ¼ 7.5 Hz, 2H, CH2), 2.59 (t, 3JHH ¼ 7.5 Hz, 2H, CH2), 2.39 (s, 3H, CH3), 2.32 (s, 3H, CH3), 1.66 (s, 6H, CH3), 1.25 (t, 3JHH ¼ 7.1 Hz, 3H, Et). 13 C NMR (d, CDCl3): 173.24 (C]O), 144.90 (C), 140.06 (C), 138.76 (C), 136.00 (C), 132.80 (C), 129.67 (CH), 128.17 (CH), 127.84 (CH), 125.34 (C), 118.99 (CH), 115.72 (CH), 60.70 (CH2), 35.28 (CH2), 22.67 (CH2), 21.90 (CH3), 21.53 (CH3), 20.49 (CH3), 14.57 (CH3). ESI-HRMS (TOF): MHþ found 440.1876. C25H30NO4S requires 440.1896. 9k. Yellow oil. 65 mg, 73%. 1H NMR (d, CDCl3): 7.87-6.82 (12H, Ar-H), 6.14 (s, 1H, pyrrole), 4.16 (q, 3JHH ¼ 7.1 Hz, 2H, Et), 2.86 (t, 3 JHH ¼ 7.5 Hz, 2H, CH2), 2.64 (t, 3JHH ¼ 7.5 Hz, 2H, CH2), 2.21 (s, 3H, Ts), 1.27 (t, 3JHH ¼ 7.1 Hz, 3H, Et). 13C NMR (d, CDCl3): 173.18 (C]O), 144.63 (C), 135.46 (C), 133.93 (C), 133.22 (C), 132.60 (C), 130.63 (CH), 129.43 (CH), 129.35 (CH), 128.97 (C), 128.01 (CH), 127.49 (CH), 126.09 (CH), 125.64 (CH), 125.55 (C), 125.48 (CH), 124.69 (CH), 119.96 (CH), 117.73 (CH), 60.74 (CH2), 35.14 (CH2), 22.56 (CH2), 21.67 (CH3), 14.55 (CH3). ESI-HRMS (TOF): MHþ found 448.1610. C26H26NO4S requires 448.1583. 9m. Yellow oil. 50 mg, 57%. 1H NMR (d, CDCl3): 7.44 (t, 3 JHH ¼ 7.7 Hz, 1H, Ar-H), 7.32-7.28 (m, 3H, Ar-H), 7.16 (d, 3 JHH ¼ 8.6 Hz, 2H, Ar-H), 7.11 (d, 3JHH ¼ 8.6 Hz, 2H, Ar-H), 7.05 (d, 3 JHH ¼ 7.1 Hz, 2H, Ar-H), 4.15 (q, 3JHH ¼ 7.1 Hz, 2H, Et), 3.00 (t, 3 JHH ¼ 7.4 Hz, 2H, CH2), 2.62 (t, 3JHH ¼ 7.4 Hz, 2H, CH2), 2.38 (s, 3H, Ts), 1.65 (s, 3H, CH3), 1.27 (t, 3JHH ¼ 7.1 Hz, 3H, Et). 13C NMR (d, CDCl3): 197.06 (C]O), 173.43 (C]O), 145.64 (C), 138.16 (C), 135.52 (C), 132.22 (CH), 130.46 (C), 129.93 (CH), 129.89 (CH), 128.06 (CH), 127.86 (CH), 125.76 (C), 120.53 (CH), 60.67 (CH2), 34.68 (CH2), 30.78 (CH3), 22.32 (CH2), 21.97 (CH3), 14.62 (CH3). ESI-HRMS (TOF): MHþ found 440.1544. C24H26NO5S requires 440.1532. 12. Colorless oil. 47 mg, 55%. 1H NMR (d, CDCl3): 7.85 (d, 3 JHH ¼ 7.8 Hz, 2H, Ar-H), 7.60-7.39 (m, 10H, Ar-H), 7.21 (d,
3
JHH ¼ 7.8 Hz, 2H, Ar-H), 6.58 (d, 3JHH ¼ 15.2 Hz, 1H, ¼CH), 6.34 (dd, JHH ¼ 15.2 Hz, 3JHH ¼ 7.1 Hz, 1H, ¼CH), 5.36 (d, 3JHH ¼ 2.8 Hz, 1H, ¼CH), 4.31 (dd, 2JHH ¼ 13.1 Hz, 3JHH ¼ 9.5 Hz, 1H, CHH), 3.87 (dd, 2 JHH ¼ 13.1 Hz, 3JHH ¼ 6.7 Hz, 1H, CHH), 3.40-3.34 (m, 1H, CH), 2.27 (s, 3H, Ts). 13C NMR (d, CDCl3): 189.79 (C]O), 147.32 (CH), 147.05 (C), 144.75 (C), 137.59 (C), 133.31 (CH), 132.67 (C), 129.93 (CH), 129.51 (CH), 128.91 (CH), 128.77 (CH), 128.35 (CH), 128.30 (CH), 128.21 (CH), 125.88 (CH), 117.42 (CH), 56.52 (CH2), 43.69 (CH), 21.73 (CH3). ESI-HRMS (TOF): MHþ found 430.1474. C26H24NO3S requires 430.1477. 13. Yellow oil. 1H NMR (d, CDCl3): 7.97 (d, 3JHH ¼ 7.8 Hz, 2H, ArH), 7.57 (t, 3JHH ¼ 7.4 Hz, 1H, Ar-H), 7.47 (t, 3JHH ¼ 7.8 Hz, 2H, Ar-H), 7.35-7.20 (m, 8H, Ar-H), 7.07 (d, 3JHH ¼ 8.1 Hz, 2H, Ar-H), 6.08 (d, 4 JHH ¼ 1.8 Hz, 1H, pyrrole), 3.24 (t, 3JHH ¼ 7.4 Hz, 2H, CH2), 2.88 (t, 3 JHH ¼ 7.4 Hz, 2H, CH2), 2.34 (s, 3H, Ts). 13C NMR (d, CDCl3): 199.01 (C]O), 144.39 (C), 136.77 (C), 136.41 (C), 135.51 (C), 133.03 (CH), 131.40 (C), 130.60 (CH), 129.22 (CH), 128.55 (CH), 128.08 (CH), 127.94 (CH), 127.25 (CH), 126.93 (CH), 126.80 (C), 120.85 (CH), 117.03 (CH), 38.80 (CH2), 21.48 (CH3), 21.08 (CH2). ESI-HRMS (TOF): MHþ found 430.1470. C26H24NO3S requires 430.1477. 3
Acknowledgments We thank the Ministry of Science and Technology, Taiwan (Grant No. MOST106-2113-M-002-018) for the financial support. We also thank “National Taiwan University Mass Spectrometry-based Proteomics Core Facility” for the measurement of ESI mass data. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.tet.2019.01.022. References [1] (a) J.-J. Feng, J. Zhang, ACS Catal. 6 (2016) 6651e6661; (b) C.-Z. Zhu, J.-J. Feng, J. Zhang, Angew. Chem. Int. Ed. 56 (2017) 1351e1355; (c) J.-J. Feng, T.-Y. Lin, H.-H. Wu, J. Zhang, J. Am. Chem. Soc. 137 (2015) 3787e3790; (d) J.-J. Feng, T.-Y. Lin, H.-H. Wu, J. Zhang, Angew. Chem. Int. Ed. 54 (2015) 15854e18558. [2] (a) T. Li, G. Zhang, J. Guo, S. Wang, X. Leng, Y. Chen, Organometallics 35 (2016) 1565e1572; (b) T. Kaicharla, A. Jacob, R.G. Gonnade, A.T. Biju, Chem. Commun. 53 (2017) 8219e8222; (c) A.L. Cardoso, T.M.V.D. Pinho e Melo, Eur. J. Org. Chem. (2012) 6479e6501; (d) B. Wang, M. Liang, J. Tang, Y. Deng, J. Zhao, H. Sun, C.-H. Tung, J. Jia, Z. Xu, Org. Lett. 18 (2016) 4614e4617; (e) T.-Y. Lin, H.-H. Wu, J.-J. Feng, J. Zhang, Org. Lett. 19 (2017) 6526e6529; (f) M. Sengoden, A. Bhowmick, T. Punniyamurthy, Org. Lett. 19 (2017) 158e161; (g) K. Spielmann, E. Tosi, A. Lebrun, G. Niel, A. van der Lee, R.M. de Figueiredo, J.-M. Campagne, Tetrahedron 74 (2018) 6497e6511; (h) C.-Z. Zhu, J.-J. Feng, J. Zhang, Chem. Commun. 54 (2018) 2401e2404; (i) T.-Y. Lin, C.-Z. Zhu, P. Zhang, Y. Wang, H.-H. Wu, J.-J. Feng, J. Zhang, Angew. Chem. Int. Ed. 55 (2016) 10844e10848. [3] J.-J. Feng, T.-Y. Lin, C.-Z. Zhu, H. Wang, H.-H. Wu, J. Zhang, J. Am. Chem. Soc. 138 (2016) 2178e2181. [4] C.-Z. Zhu, J.-J. Feng, J. Zhang, Chem. Commun. 53 (2017) 4688e4691. [5] F. Jiang, F.-R. Yuan, L.-W. Jin, G.-J. Mei, F. Shi, ACS Catal. 8 (2018) 10234e10240. [6] L. Zhu, X. Qi, Y. Lan, Organometallics 35 (2016) 771e777. [7] R.A. Doohan, J.J. Hannan, N.W.A. Geraghty, Org. Biomol. Chem. 4 (2006) 942e952. [8] F. Antras, S. Laurent, M. Ahmar, H. Chermette, B. Cazes, Eur. J. Org. Chem. (2010) 3312e3336. , Y. Díaz, M.I. Matheu, S. Castillo n, Org. Lett. 10 (2008) 4735e4738. [9] P. Marce [10] Z. Na, S. Pan, M. Uttamchandani, S.Q. Yao, Angew. Chem. Int. Ed. 53 (2014) 8421e8426.