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A New Synthesis of Phosphorane Ylide Precursors to Vicinal Tricarbonyls from Alkyl Halides Utilizing a Novel Phenylsulfonyl Reagent
A New Synthesis of Phosphorane Ylide Precursors to Vicinal Tricarbonyls from Alkyl Halides Utilizing a Novel Phenylsulfonyl Reagent
Journal of the Korean Chemical Society. 2015. Dec, 59(6): 537-540
Copyright © 2015, Korean Chemical Society
  • Received : September 18, 2015
  • Accepted : October 02, 2015
  • Published : December 20, 2015
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Kieseung Lee

Abstract
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RESULTS AND DISCUSSION
The requisite new sulfonyl reagent 4 was successfully synthesized from phenylsulfonylacetic acid and phosphorane ylide 1 as a stable solid. 5b Owing to good solubility of 4 in THF and good handling property of NaH as the base, THF and NaH were chosen for the alkylation of 4 , and the representative results are summarized in 1 .
Deprotonation of 4 with NaH/THFaand subsequent alkylation of the resulting sulfonyl anions with alkyl halides to provide5.b
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Reaction conditions & reagents: a: 5 mL of dry THF per 0.1 mmol of 4 was used; b: NaH (1.3 eq), rt, 20 min then 0 ℃, 20 min, RCH2X (1.3 eq), 0 ℃, 1 h, then rt for designated time (h); c: Isolated yield after flash chromatography on SiO2; d: No reaction occurred; e: 87% of 4 was recovered.
Although deprotonation of 4 with NaH proceeded smoothly, alkylation of the resulting anion with benzyl chloride was found almost inactive (Entry 1). Benzyl bromide, however, furnished benzylated sulfonyl ylide 5a in 94% yield (Entry 2). This benzylated sulfonyl ylide 5a was cleanly separated by flash chromatography, and its structure was unambiguously corroborated by 1 H-NMR spectrum in which one methine proton appears at 6.63 ppm (dd, 1H, J 1 = 12.2 Hz, J 2 = 3.4 Hz) and two methylene protons of benzyl subunit appear at 3.24 (bd) and 3.03 ppm (bt), respectively. Simple alkyl halide such as octyl bromide was found almost inactive towards 4 , however, octyl iodide provided much better yield (84%) of 5b under standard conditions (Entry 3, 4). Similarly, 3- phenylpropyl iodide furnished 5c in 93% yield (Entry 5). On the other hand, alkyl bromides with an alkenyl or a heteroaryl subunit such as thiophene were smoothly coupled with 4 under standard conditions to furnish sulfonyl ylides 5d and 5e in good yields (Entry 6-7).
We next attempted desulfonylation reaction of sulfonyl ylides 5 . Among the known reductive desulfonylation reagents 7 e.g ., Al(Hg), Na(Hg), Mg/MeOH, SmI 2 , and Zn/NH 4 Cl, Na(Hg) was determined to be the best reagent and desulfonylation results are summarized in 2 .
Reductive desulfonylation of5to2'with Na(Hg)/Na2HPO4.a
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Reaction conditions & reagents: a: Na2HPO4 (4 eq), Na(Hg) (4 eq), 0 ℃, 5 h, Ar; b: (i) (3 mL of DMF + 1 mL of MeOH) per 0.1 mmol of 5a; (ii) 3 mL of MeOH per 0.1 mmol of 5b-d; (iii) (10 mL of DMF + 1 mL of MeOH) per 0.1 mmol of 5e; c: Isolated yield after flash chromatography on SiO2.
Because of the low solubility of sulfonyl ylide 5a in MeOH only, desulfonylation of 5a was carried out in a mixed solvent (DMF + MeOH) with (Na(Hg)/Na 2 HPO 4 ) at 0 ℃ for 5 h under an argon atmosphere. The desulfonylated ylide 2’a was easily separated by flash chromatography, and the structure of 2’a was clearly confirmed by 1 H-NMR spectrum which exhibited two methylene units at 2.91 ppm ( t , 2H, J = 7.8 Hz) and 3.22 ppm ( t , 2H, J = 7.8 Hz), respectively (Entry 1). However, sulfonyl ylides 5b-d were efficiently desulfonylated in MeOH only under standard conditions to afford ylides 2’b-d in 80−95% yields (Entry 2-4). Sulfonyl ylides 5e necessitated a significant amount of DMF for its dissolution, however, desulfonylation reaction was smoothly taken place to produce ylide 2e in 85% yield (Entry 5).
In summary, a new synthetic approach to phosphorane ylides 2’ has been developed from alkyl halides using a new sulfonyl reagent 4 as the key reagent. In view of the advantages of this new approach e.g ., easy preparation of 4 as a stable solid, mild conditions, wide scope of applicability, and good to excellent overall yields, this alkylation / desulfonylation protocol can be a method of choice for the synthesis of ylide precursors 2’ . We are currently applying this new approach to amino acid/peptide-derived halides, and the results will be reported in due course.
EXPERIMENTAL
- General
All reactions were carried out in an oven-dried glassware under Ar atmosphere. FTIR spectra were obtained on a Jasco FT-IR/410 using KBr. 1 H (400 MHz) and 13 C NMR (100 MHz) spectra were recorded on a Jeol JNM-EX400 FT NMR spectrometer using CDCl 3 as a solvent, and chemical shifts (δ) are given in ppm downfield with respect to TMS as an internal standard. Phenylsulfonylacetic acid, ( t -butoxycarbonylmethylene)-triphenylphosphorane, 1-[3-(dimethylamino)propyl]-3-ethyl-carbodiimide·HCl (EDC), 4-dimethylaminopyridine (DMAP), NaH (60% in mineral oil), alkyl bromides, and Na(Hg) (5% Na) were purchased from Aldrich Chem. Co., and used directly as received. Alkyl iodides were prepared from their corresponding bromides via Finkelstein reaction. 8 The sulfonyl ylides 5 except 5a were analyzed only by mp, IR and 1 H- & 13 C-nmr spectra, and then subjected to the desulfonylation reaction without further analysis.
t-Butyl 3-Oxo-4-(phenylsulfonyl)-2-(triphenyl5-phosphanylidene)butanoate (4) : To a stirred, precooled (0 ℃) solution of phenylsulfonylacetic acid (0.600 g, 3.0 mmol) and ( t -butoxycarbonylmethylene)triphenylphosphorane (1.139 g, 1.0 eq) in dry CH 2 Cl 2 (20 mL) were added EDC (0.575 g, 1.0 eq) and DMAP (36.7 mg, 0.1 eq), and the resulting mixture was stirred at 0 ℃ for 1 h, and then at rt for 12 h under Ar. The reaction was quenched with water (20 mL), and the organic layer was separated. The aqueous layer was extracted with CH 2 Cl 2 (10 mL × 2), and the combined organic layers were dried over MgSO 4 , filtered, and concentrated. The residue was purified by flash chromatography (SiO 2 , CH 2 Cl 2 /EtOAc = 5/1) to give 4 (1.123 g, 67%) as a white solid. mp 161−163 ℃; IR (KBr) 688, 1072, 1160, 1306, 1341, 1601, 1662, 2969, 3058 cm −1 ; 1 H NMR δ 1.02 (s, 9H), 4.95 (s, 2H), 7.22−7.78 (m, 20H); 13 C NMR δ 27.94, 63.24, 63.33, 73.21, 74.27, 79.51, 125.42, 126.35, 128.31, 128.40, 128.45, 128.59, 131.74, 131.76, 132.72, 133.17, 133.26, 140.60, 166.78, 166.90, 181.69, 181.76; Anal. calcd for C 32 H 31 O 5 PS: C, 68.80; H, 5.59. found: C, 68.65; H, 5.63.
Typical procedures for the alkylation of 4 to 5a: NaH (10.4 mg, 1.3 eq) was added to a stirred solution of 4 (111.7 mg, 0.20 mmol) in dry THF (10 mL), and the resulting slurry was stirred at rt for 40 min under Ar. To this was added benzyl bromide (30.9 mL, 1.3 eq) by syringe, and the resulting mixture was stirred at rt for 24 h under Ar. The reaction mixture was quenched with CH 2 Cl 2 (20 mL) and water (10 mL), and the organic layer was separated. The aqueous layer was extracted with CH 2 Cl 2 (10 mL × 2), and the combined organic layers were dried over MgSO 4 , filtered, and concentrated. The residue was purified by flash chromatography (SiO 2 , CH 2 Cl 2 /EtOAc = 10/1) to furnish 5a (121.3 mg, 94%) as a white solid. mp 220−222 ℃; IR (KBr) 1552, 1668 cm −1 ; 1 H NMR δ 0.96 (s, 9H), 3.03 (bt, 1H, J = 12.8 Hz), 3.24 (bd, 1H, J = 11.2 Hz), 6.63 (dd, 1H, J 1 = 12.2 Hz, J 2 = 3.4 Hz), 7.15−7.56 (m, 25H); 13 C NMR δ 27.89, 33.15, 67.82, 67.90, 75.36, 76.42, 79.28, 125.46, 126.12, 126.39, 128.12, 128.13, 128.41, 128.54, 129.52, 129.66, 131.49, 131.52, 132.78, 133.06, 133.16, 137.35, 138.27, 166.26, 166.39, 183.79, 183.84; Anal. calcd for C 39 H 37 O 5 PS: C, 72.20; H, 5.75. found: C, 71.86; H, 5.71.
Compound 5b : A white solid, mp 48−49 ℃; IR (KBr) 1556, 1663 cm −1 ; 1 H NMR d 0.88 (s, 3H, J = 7.0 Hz), 1.07 (s, 9H), 1.14−1.40 (m , 12H), 1.67−1.83 (m, 2H), 7.30−7.55 (m, 14H), 6.10 (dd, 1H, J 1 = 10.6 Hz, J 2 = 3.9 Hz), 7.18−7.78 (m, 25H) ); 13 C NMR δ 14.07, 22.63, 26.82, 27.53, 27.98, 29.11, 29.31, 29.45, 31.83, 67.78, 67.85, 75.30, 76.35, 79.42, 125.70, 126,63, 127.95, 128.45, 128.59, 129.53, 131.61, 131.63, 132.57, 133.13, 133.23, 138.38, 166.67, 166.79, 185.19, 185.24.
Compound 5c : A white solid, mp 167−169 ℃; IR (KBr) 1562, 1659 cm −1 ; 1 H NMR δ 1.04 (s, 9H), 1.53−1.72 (m, 2H), 1.77−1.91 (m, 2H), 2.45−2.65 (m, 2H), 6.19 (dd, 1H, J 1 = 9.4 Hz, J 2 = 5.8 Hz), 7.05−7.75 (m, 25H) ); 13 C NMR δ 27.32, 27.98, 28.92, 35.57, 67.49, 67.57, 75.34, 76.39, 79.50, 125.61, 126.55, 128.03, 128.18, 128.35, 128.49, 128.61, 129.52, 131.63, 131.66, 132.66, 133.12, 133.22, 138.32, 142.32, 166.70, 166.82, 185.01, 185.07.
Compound 5d : A white solid, mp 178−179 ℃; IR (KBr) 1552, 1660 cm −1 ; 1 H NMR δ 1.07 (s, 9H), 1.67 (d, 3H, J = 5.8 Hz), 2.37−2.58 (m, 2H), 5.33−5.58 (m, 2H), 6.18 (dd, 1H, J 1 = 11.2 Hz, J 2 = 3.4 Hz), 7.16−7.78 (m, 20H); 13 C NMR δ 12.84, 18.01, 25.38, 27.98, 30.68, 67.07, 67.15, 75.33, 76.38, 79.42, 125.71, 126.31, 126.64, 127.71, 127.98, 128.12, 128.45, 128.58, 129.41, 129.55, 131.57, 131.60, 132.65, 133.13, 133.23, 138.24, 166.68, 166.81, 184.62, 184.66.
Compound 5e : A yellow solid, mp 197−199 ℃; IR (KBr) 1667, 1555 cm −1 ; 1 H NMR δ 1.04 (s, 9H), 3.32 (d, 2H, J = 8.3 Hz), 6.58 (t, 1H, J = 8.3 Hz), 6.83 (dd, 1H, J 1 = 3.7 Hz, J 2 = 0.9 Hz), 6.92 (dd, 1H, J 1 = 5.2 Hz, J2 = 3.7 Hz), 7.15 (dd, 1H, J 1 = 5.2 Hz, J 2 = 0.9 Hz), 7.22−7.63 (m, 20H); 13 C NMR δ 14.16, 21.00, 27.56, 27.96, 60.34, 67.90, 67.98, 75.68, 79.43, 123.77, 125.46, 126.13, 126.39, 126.50, 128.17, 128.45, 128.59, 129.63, 131.52, 131.55, 132.92, 133.09, 133.19, 137.97, 139.58, 166.37, 166.50, 183.26, 183.31.
Typical procedures for the reductive desulfonylation of 5a to 2’a: To a stirred, precooled (0 ℃) solution of 5a (129.7 mg, 0.20 mmol) in a mixed solvent (8 mL, DMF/MeOH = 3/1) were added Na 2 HPO 4 (113.6 mg, 4.0 eq) and Na(Hg) (367.8 mg, 5%, 4.0 eq), and the reaction mixture was stirred at 0 ℃ for 5 h under Ar. EtOAc (20 mL) was added to the reaction mixture with vigorous stirring followed by H 2 O (20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (10 mL × 3). The combined organic layers were dried over MgSO 4 , filtered, and concentrated. Residual DMF was removed under high vacuum to afford a solid residue, which was purified by flash chromatography (SiO 2 , Hex/EtOAc = 2/1) to give 2’a (72.6 mg, 71%) as a white solid. mp 156−158 ℃ (lit 5a 160−162 ℃); IR (KBr) 1552, 1663 cm −1 ; 1 H NMR δ 1.03 (s, 9H), 2.91 (t, 2H, J = 7.8 Hz), 3.22 (t, 2H, J = 7.8 Hz), 7.10 −7.74 (m, 20H).
Compound 2’b : A colorless liquid 5a ; IR (KBr) 1551, 1664 cm −1 ; 1 H NMR δ 0.87 (t, 3H, J = 7.1 Hz), 1.06 (s, 9H), 1.17−1.36 (m, 12H), 1.50−1.64 (m, 2H), 2.84 (t, 2H, J = 7.6 Hz), 7.37−7.77 (m, 15H).
Compound 2’c : A white solid, mp 133−134 ℃; IR (KBr) 1551, 1663 cm −1 ; 1 H NMR δ 1.06 (s, 9H), 1.56−1.74 (m, 4H), 2.59 (t, 2H, J = 7.6 Hz), 2.90 (t, 2H, J = 7.1 Hz), 5.36−5.53 (m, 2H), 7.09−7.78 (m, 20H); 13 C NMR δ 25.59, 28.08, 31.41, 35.92, 39.57, 39.63, 70.68, 71.76, 78.33, 125.28, 126.83, 127.76, 128.01, 128.28, 128.37, 128.40, 131.24, 131.26, 131.88, 131.98, 132.08, 132.84, 132.93, 143.06, 167.15, 167.29, 197.39, 197.43; Anal. calcd for C 35 H 37 O 3 P: C, 78.33; H, 6.95. found: C, 78.50; H, 7.66.
Compound 2’d : A white solid; mp 153−154 ℃; IR (KBr) 1549, 1654 cm −1 ; 1 H NMR δ 1.06 (s, 9H), 1.61 (d, 3H, J = 4.9 Hz), 2.23−2.37 (m, 2H), 2.92 (t, 2H, J = 7.6 Hz), 5.36−5.53 (m, 2H), 7.37−7.79 (m, 15H); 13 C NMR δ 12.74, 17.92, 23.34, 28.11, 28.80, 39.69, 39.76, 70.55, 71.63, 78.33, 123.45, 124.25, 126.89, 127.81, 128.30, 128.42, 128.65, 131.24, 131.28, 131.51, 132.90, 132.99, 167.15, 167.28, 196.95, 196.98; Anal. calcd for C 30 H 33 O 3 P: C, 76.25; H, 7.04. found: C, 76.49; H, 7.19.
Compound 2’e : A white solid, mp 171−172 ℃; IR (KBr) 1548, 1655 cm −1 ; 1 H NMR δ 1.06 (s, 9H), 3.11 (t, 2H, J = 7.4 Hz), 3.28 (t, 2H, J = 7.4 Hz), 6.77 (dd, 1H, J 1 = 3.4 Hz, J 2 = 1.1 Hz), 6.87 (dd, 1H, J 1 = 5.1 Hz, J 2 = 3.4 Hz), 7.05 (dd, 1H, J 1 = 5.1 Hz, J 2 = 1.1 Hz), 7.36−7.75 (m, 15H); 13 C NMR δ 25.58, 28.13, 41.32, 41.39, 70.78, 71.86, 78.48, 122.48, 124.11, 126.41, 126.67, 127.60, 128.35, 128.48, 131.32, 131.34, 132.92, 133.02, 145.73, 167.15, 167.29, 195.38, 195.42; Anal. calcd for C 31 H 31 O 3 PS: C, 72.35; H, 6.07. found: C, 71.88; H, 5.90.
Acknowledgements
This work was financially supported by the Woosuk University Research Fund in 2015. The author deeply appreciates the support and the encouragement of M.-Y. Kim throughout this project.
References
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