- Email: [email protected]
UV-induced catalyst-free intramolecular formal Heck reaction
Journal of Saudi Chemical Society (2019) 23, 718–724
King Saud University
Journal of Saudi Chemical Society www.ksu.edu.sa www.sciencedirect.com
ORIGINAL ARTICLE
UV-induced catalyst-free intramolecular formal Heck reaction Wangsheng Liu a, Dongmei Ma a, Hao Guo a,c,*, Guangxin Gu b,c,* a
Department of Chemistry, Fudan University, 2005 Songhu Road, Shanghai 200438, PR China Department of Materials Science, Fudan University, 220 Handan Road, Shanghai 200433, PR China c Academy for Engineering and Technology, Fudan University, 220 Handan Road, Shanghai 200433, PR China b
Received 2 November 2018; revised 29 November 2018; accepted 12 December 2018 Available online 31 December 2018
KEYWORDS Photochemistry; Cyclization; Radical; Fluorene
Abstract A catalyst-free intramolecular formal Heck reaction has been developed, affording 9benzylidene-9H-fluorene derivatives under UV irradiation. This reaction probably proceeds via UV-induced homolytic cleavage of CAI bond, addition of the aryl radical to the alkene moiety, single electron oxidation of alkyl radical intermediate into carbocation species, and deprotonation. Ó 2018 King Saud University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction Heck reaction, which is also called Mizoroki-Heck reaction, was reported by Richard F. Heck and Tsutomu Mizoroki independently [1]. At the very beginning, the stoichiometric ArPdX complexes, which were formed from the reaction between palladium salts and aryl-metal compounds would react with olefins [2]. After few years, this reaction was done using catalytic amounts of Pd [3]. Moreover, activated CAH bond [4] and alkynes [4c,5] can also be applied on this reaction. Nowadays, Heck reaction becomes a practical synthetic protocol for the total synthesis of drugs [6], natural products [7], agrochemicals [8] and other fields [8a,9]. The Heck reaction * Corresponding authors. E-mail addresses: [email protected] (H. Guo), guangxingu@ fudan.edu.cn (G. Gu). Peer review under responsibility of King Saud University.
Production and hosting by Elsevier
results from the cleavage of CAX (X = I, Br or Cl) bond, followed by coupling with C‚C bond. Besides catalysts, photo irradiation is also a path to break CAX bonds [10]. Firstly, the substrate molecular goes into its excited state after absorbing photons. Then some bonds with lower bond energy break and take the next reaction [11]. CAX bonds, which belong to this kind of bonds, would undergo homolytic cleavage or heterolytic cleavage, forming radicals or cations under the irradiation of applied light source. Then these in situ formed radicals or cations would react with unsaturated bonds affording addition compounds or formal Heck reaction products [10f]. Early in 1986, Curran group has reported a cyclization of hex-5-ynyl iodides (Scheme 1a), where radical initiator Bu3SnH was used [12]. In the presence of Bu3SnH, homolytic cleavage of CAI bond happened, followed by 5exo cyclization and a trace amount of reduced product was formed. In 2016, our group has reported a photo chemically intramolecular haloarylation and hydroarylation of alkynes, forming a series of 9-benzylidene-9H-fluorene and 9-(halo (phenyl)methylene)-9H-fluorene derivatives (Scheme 1b) [10f]. The reaction was initiated by homolytic cleavage of CAI bonds under UV irradiation. Based on our continuous
https://doi.org/10.1016/j.jscs.2018.12.001 1319-6103 Ó 2018 King Saud University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Catalyst-free intramolecular Heck reaction
Scheme 1
Reactions initiated by the homolytic cleavage of CAX bond.
research interest in this field, we designed a photo-induced formal Heck reaction. The envisioned mechanism is shown in Scheme 2. Initially, under photo irradiation, aryl radical and iodine radical are formed by homolytic cleavage of CAI bond. Then, alkene is attacked by the aryl radical, generating 5-exo cyclization radical intermediate. After that, alkyl radical can be oxidized by iodine radical [13], forming the carbocation species which will yield the formal Heck reaction products by deprotonation. Herein, we wish to report an intramolecular formal Heck reaction of olefins under UV irradiation without any metal or organic catalyst, generating 9-benzylidene-9H-fluorene derivatives in an efficient and highly selective way. 2. Methods 2.1. General experimental methods All reactions were carried out using a Matrix-10 reactor (unless stated otherwise) as the irradiation source. Melting points were determined on a WRS-2 apparatus. IR spectra were recorded on an Avatar 360 FT-IR spectrometer. 1H (400 MHz), 13C (100 MHz) NMR spectra of samples in CDCl3 were recorded on an AVANCE III 400 spectrometer. HRMS (EI) determinations were carried out on a Water GCT CA176 spectrometer. Anhydrous THF was distilled with Na with benzophenone as an indicator. Anhydrous DCM was distilled with CaH2. 2.2. Typical procedure I for the synthesis of arene-alkenes 2.2.1. Synthesis of (Z)-2-iodo-20 -(4-methoxystyryl)-1,10 biphenyl (1a) A solution of (4-methoxybenzyl)triphenylphosphonium chloride (15.918 g, 38.0 mmol) in anhydrous THF (200 mL) was
Scheme 2
719
cooled to 78 °C under argon atmosphere. NaHMDS (2.0 M in THF, 19 mL, 38.0 mmol) was added over 30 min. The reaction mixture was stirred at 78 °C for 3 h, then a solution of 20 -iodo-2-formyl-1,10 -biphenyl (10,000 g, 32 mmol) in anhydrous THF (100 mL) was added dropwise over 1 h. The resulting solution was allowed to warm slowly to room temperature. Then the mixture was stirred for 5 h at room temperature. The resulting mixture was filtered. Then the solvent was removed and the residue was purified by flash column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 20:1) to afford 1a as a solid (28.814 g, 66%); mp 111.2–111.4 °C (petroleum ether/ethyl acetate). 1H NMR (400 MHz, CDCl3) d 7.92 (d, J = 8.0 Hz, 1H), 7.44–7.08 (m, 8H), 7.01 (t, J = 7.6 Hz, 1H), 6.73 (d, J = 8.8 Hz, 2H), 6.35 (d, J = 12.4 Hz, 1H), 6.12 (d, J = 12.4 Hz, 1H), 3.77 (s, 3H); 13C NMR (100 MHz, CDCl3) d 158.7, 146.1, 143.8, 138.9, 136.1, 130.3, 130.1, 129.94, 129.87, 129.4, 129.2, 128.7, 127.8, 127.6, 127.2, 126.9, 113.5, 99.9, 55.2; IR (neat) 1618, 1510, 1465, 1436 cm1; HRMS (EI) calcd for C21H17OI (M+) 412.0324, found 412.0326. 2.3. The following compounds were prepared according to typical procedure I 2.3.1. Synthesis of (Z)-2-iodo-20 -(4-ethoxystyryl)-1,10 -biphenyl (1b) Yield: 78%; mp 81.7–82.2 °C (petroleum ether/ethyl acetate); H NMR (400 MHz, CDCl3) d 7.93 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.36–7.14 (m, 7H), 7.07–6.96 (m, 1H), 6.72 (d, J = 8.4 Hz, 2H), 6.35 (d, J = 12.4 Hz, 1H), 6.11 (d, J = 12.4 Hz, 1H), 4.00 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 158.1, 146.1, 143.8, 138.9, 136.1, 130.2, 130.1, 130.0, 129.9, 129.2, 128.7, 127.8, 127.6, 127.0, 126.8, 114.0, 99.9, 63.3, 14.8; IR (neat) 1606, 1509, 1482, 1461, 1442, 1391 cm1; HRMS (EI) calcd for C22H19OI (M+) 426.0481, found 426.0488. 1
The envisioned mechanism for the photo-induced formal Heck reaction.
720
W. Liu et al.
2.3.2. Synthesis of (Z)-2-iodo-20 -(4-methylthiostyryl)-1,10 biphenyl (1c)
2.3.7. Synthesis of (E)-2-iodo-5,50 -dimethoxy-20 -(4methylstyryl)-1,10 -biphenyl (3h)
Yield: 57%; mp 71.3–71.7 °C (petroleum ether/ethyl acetate); H NMR (400 MHz, CDCl3) d 7.93 (dd, J = 8.0, 0.8 Hz, 1H), 7.39–7.26 (m, 3H), 7.25–7.14 (m, 5H), 7.10–6.98 (m, 3H), 6.35 (d, J = 12.4 Hz, 1H), 6.19 (d, J = 12.4 Hz, 1H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) d 146.0, 143.8, 138.9, 137.3, 135.8, 133.6, 130.1, 129.9, 129.8, 129.4, 129.2, 128.8, 128.6, 127.8, 127.6, 127.1, 126.0, 99.9, 15.6; IR (neat) 1595, 1493, 1461, 1434 cm1; HRMS (EI) calcd for C21H18SI (M+H+) 429.0168, found 429.0162.
Yield: 26%; mp 157.3–157.4 °C (petroleum ether/ethyl acetate); 1H NMR (400 MHz, CDCl3) d 7.80 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 6.98 (dd, J = 8.8, 2.8 Hz, 1H), 6.91 (d, J = 16.4 Hz, 1H), 6.84 (d, J = 3.2 Hz, 1H), 6.73–6.67 (m, 2H), 6.64 (d, J = 16.0 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) d 159.6, 158.4, 146.5, 144.3, 139.5, 137.0, 135.0, 129.2, 128.1, 127.6, 126.3, 126.1, 125.2, 116.0, 115.6, 114.6, 114.5, 88.5, 55.4, 21.2; IR (neat) 1602, 1592, 1563, 1514, 1463 cm1; HRMS (EI) calcd for C23H21IO2 (M+) 456.0581, found 456.0581.
1
2.3.3. Synthesis of (Z)-2-iodo-20 -(4-methylstyryl)-1,10 -biphenyl (1d) Yield: 72%; 1H NMR (400 MHz, CDCl3) d 7.93 (dd, J = 8.0, 1.2 Hz, 1H), 7.44–7.12 (m, 8H), 7.07–6.96 (m, 3H), 6.38 (d, J = 12.4 Hz, 1H), 6.17 (d, J = 12.4 Hz, 1H), 2.30 (s, 3H); 13 C NMR (100 MHz, CDCl3) d 146.1, 143.8, 138.9, 136.9, 136.0, 133.9, 130.4, 130.1, 129.9, 129.3, 128.9, 128.79, 128.75, 128.1, 127.8, 127.5, 126.9, 99.9, 21.2; IR (neat) 1510, 1461, 1441 cm1; HRMS (EI) calcd for C21H21NI (M+NH+ 4 ) 414.0713, found 414.0713. 2.3.4. Synthesis of (Z)-2-iodo-20 -styryl-1,10 -biphenyl (1e) Yield: 65%; mp 72.8–73.1 °C (petroleum ether/ethyl acetate); H NMR (400 MHz, CDCl3) d 7.93 (d, J = 8.0 Hz, 1H), 7.37–7.13 (m, 11H), 7.01 (t, J = 7.6 Hz, 1 H), 6.41 (d, J = 12.4 Hz, 1 H), 6.22 (d, J = 12.4 Hz, 1 H); 13C NMR (100 MHz, CDCl3) d 146.0, 143.9, 138.9, 136.9, 135.7, 130.5, 130.1, 129.9, 129.3, 129.0, 128.9, 128.8, 128.1, 127.9, 127.6, 127.11, 127.05, 99.9; IR (neat) 1600, 1580, 1557, 1492, 1461, 1444, 1428 cm1; HRMS (EI) calcd for C20H19NI (M +NH+ 4 ) 400.0557, found 400.0554. 1
2.3.5. Synthesis of (E)-2-iodo-5,50 -dimethoxy-20 -(4methoxystyryl)-1,10 -biphenyl (3f) Yield: 30%; mp 141.9–142.0 °C (petroleum ether/ethyl acetate); 1H NMR (400 MHz, CDCl3) d 7.80 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 6.99–6.77 (m, 5H), 6.73–6.65 (m, 2H), 6.56 (d, J = 16.0 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 6H); 13C NMR (100 MHz, CDCl3) d 159.6, 158.9, 158.3, 146.6, 144.2, 139.5, 130.7, 128.3, 127.5, 127.2, 126.0, 124.1, 116.0, 115.6, 114.60, 114.56, 114.0, 88.5, 55.4, 55.3; IR (neat) 1606, 1590, 1564, 1512, 1468, 1445 cm1; HRMS (EI) calcd for C23H21IO3 (M +) 472.0530, found 472.0529. 2.3.6. Synthesis of (E)-2-iodo-5,50 -dimethoxy-20 -(4ethoxystyryl)-1,10 -biphenyl (3g) Yield: 45%; mp 143.2–143.7 °C (petroleum ether/ethyl acetate); 1H NMR (400 MHz, CDCl3) d 7.80 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.21 (d, J = 8.4 Hz, 2H), 7.03–6.74 (m, 5H), 6.71–6.65 (m, 2H), 6.55 (d, J = 16.0 Hz, 1H), 4.00 (q, J = 6.8 Hz, 2H), 3.83 (s, 3H), 3.78 (s, 3H), 1.39 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 159.6, 158.3, 146.6, 144.2, 139.5, 130.5, 128.3, 127.5, 127.3, 126.0, 124.0, 116.0, 115.6, 114.6, 114.5, 88.5, 63.4, 55.4, 14.8; IR (neat) 1606, 1587, 1564, 1511, 1470, 1442 cm1; HRMS (EI) calcd for C24H23IO3 (M+) 486.0686, found 486.0685.
2.3.8. Synthesis of (E)-2-iodo-5,50 -dimethoxy-20 -styryl-1,10 biphenyl (3i) Yield: 38%; mp 131.1–131.3 °C (petroleum ether/ethyl acetate); 1H NMR (400 MHz, CDCl3) d 7.80 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.35–7.21 (m, 4H), 7.22–7.13 (m, 1H), 7.01–6.88 (m, 2H), 6.84 (d, J = 3.2 Hz, 1H), 6.75– 6.64 (m, 3H), 3.84 (s, 3H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3) d 159.6, 158.6, 146.4, 144.5, 139.5, 137.8, 128.5, 127.9, 127.6, 127.1, 126.3, 126.2, 126.1, 116.0, 115.6, 114.62, 114.56, 88.5, 55.4; IR (neat) 1594, 1561, 1496, 1463 cm1; HRMS (EI) calcd for C22H20IO2 (M+H+) 443.0502, found 443.0504. 2.4. Synthesis of (E)-2-iodo-20 -(4-methoxystyryl)-1,10 -biphenyl (3a) To a 250 mL three necked flask was added 20 -iodo-2-formyl1,10 -biphenyl (2.010 g, 6.5 mmol), (4-methoxybenzyl)triphenyl phosphonium (3.120 g, 8.0 mmol), LiOHH2O (411 mg, 9.8 mmol), LiCl (10.005 g, 231 mmol) and H2O (150 mL). The mixture was refluxed for 9 h. The crude product was extracted with ethyl acetate (50 mL 3). The combined organic layer was dried over MgSO4 and filtered. The solvent was removed under reduced pressure. Purification by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 40:1 to 20:1) afforded 3a as a liquid (280 mg, 10%). 1H NMR (400 MHz, CDCl3) d 7.96 (dd, J = 8.0, 0.8 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.47–7.33 (m, 2H), 7.32–7.17 (m, 4H), 7.16–6.91 (m, 3H), 6.79 (d, J = 8.8 Hz, 2H), 6.61 (d, J = 16.4 Hz, 1H), 3.75 (s, 3H); 13C NMR (100 MHz, CDCl3) d 159.2, 145.8, 143.2, 139.0, 135.5, 130.6, 130.3, 130.1, 129.2, 128.9, 128.2, 128.0, 127.8, 126.8, 124.7, 124.5, 114.0, 100.3, 55.3; IR (neat) 1609, 1508, 1450, 1439 cm1; HRMS (EI) calcd for C21H17IO (M+) 412.0319, found 412.0319. 2.5. Typical procedure II for reactions under standard condition 2.5.1. Synthesis of 9-(4-methoxybenzylidene)-9H-fluorene (2a) [10f] from 1a To a quartz reaction tube was added 1a (82 mg, 0.20 mmol) and anhydrous THF (10 mL) under argon atmosphere. The mixture was bubbling with argon for 15 min. Then the mixture was irradiated in a Matrix254-10 reactor with sixteen 254 nm lamps (10 w per lamp). The reaction was completed after 96 h as monitored by TLC (eluent: petroleum ether: ethyl acetate = 20:1). The solvent was removed and the residue was
Catalyst-free intramolecular Heck reaction
721
purified by flash chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 50:1) to afford 2a as a solid (51 mg, 89%). 1H NMR (400 MHz, CDCl3) d 7.78 (d, J = 7.2 Hz, 1H), 7.75–7.67 (m, 3H), 7.65 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.40–7.27 (m, 3H), 7.09 (t, J = 7.6 Hz, 1H), 6.99 (d, J = 8.4 Hz, 2H), 3.89 (s, 3H). 2.6. The following reactions were conducted according to typical procedure II 2.6.1. Synthesis of 9-(4-ethoxybenzylidene)-9H-fluorene (2b) from 1b Yield: 93%; mp 100.8–101.2 °C (petroleum ether/dichloromethane); 1H NMR (400 MHz, CDCl3) d 7.76 (d, J = 7.2 Hz, 1H), 7.71 (d, J = 7.6 Hz, 3H), 7.64 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.40–7.26 (m, 3H), 7.11–7.05 (m, 1H), 6.99–6.93 (m, 2H), 4.10 (q, J = 7.2 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 158.9, 141.1, 139.7, 138.9, 136.6, 135.3, 130.8, 128.9, 128.2, 127.8, 127.4, 126.9, 126.6, 124.2, 120.0, 119.7, 119.5, 114.4, 63.5, 14.8; IR (neat) 1603, 1508, 1473, 1448, 1391 cm1; HRMS (EI) calcd for C22H19O (M+H+) 299.1430, found 299.1430.
J = 7.6 Hz, 1H), 7.71 (d, J = 7.2 Hz, 2H), 7.67 (d, J = 7.6 Hz, 1H), 7.62 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.41–7.27 (m, 5H), 7.08 (td, J = 8.4, 0.8 Hz, 1H), 2.56 (s, 3H); 13C NMR (100 MHz, CDCl3) d 141.2, 139.5, 139.0, 138.7, 136.4, 136.2, 133.3, 129.8, 128.5, 128.1, 126.9, 126.7, 126.6, 126.0, 124.3, 120.1, 119.7, 119.5, 15.5; IR (neat) 1635, 1590, 1490, 1448, 1439 cm1; HRMS (EI) calcd for C21H17S (M+H+) 301.1045, found 301.1045. 2.6.3. Synthesis of 9-(4-methylbenzylidene)-9H-fluorene (2d) [10f] from 1d Yield: 69%; 1H NMR (400 MHz, CDCl3) d 7.78 (d, J = 7.6 Hz, 1H), 7.71 (d, J = 7.6 Hz, 2H), 7.68–7.61 (m, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.41–7.22 (m, 5H), 7.11–7.03 (m, 1H), 2.44 (s, 3H). 2.6.4. Synthesis of 9-(4-methoxybenzylidene)-9H-fluorene (2a) [10f] from 3a Yield: 87%; 1H NMR (400 MHz, CDCl3) d 7.78 (d, J = 7.2 Hz, 1H), 7.75–7.67 (m, 3H), 7.65 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.40–7.27 (m, 3H), 7.09 (t, J = 7.6 Hz, 1H), 6.99 (d, J = 8.4 Hz, 2H), 3.89 (s, 3H).
2.6.2. Synthesis of 9-(4-methylthiobenzylidene)-9H-fluorene (2c) from 1c
2.6.5. Synthesis of 3,6-dimethoxy-9-(4-methoxybenzylidene)9H-fluorene (2f) [10f] from 3f
Yield: 93%; mp 100.1–100.6 °C (petroleum ether/dichloromethane); 1H NMR (400 MHz, CDCl3) d 7.77 (d,
Yield: 83%; 1H NMR (400 MHz, CDCl3) d 7.66 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.51 (d,
Table 1
Entry
Optimization of the reaction conditions.a
Wavelength (nm)
Solvent
Time (h)
NMR Yield (%)b 1a:2a:3a
1 2 3 4 5 6 7 8 9 10
365 313 254 185 & 254 254 254 254 254 254 dark
CH3CN CH3CN CH3CN CH3CN Toluene CH3NO2 Acetone THF THF THF
24 24 24 24 24 24 24 24 96 96
75:6:17 0:52:15 0:68:16 0:66:15 0:0:57 0:26:5 22:0:74 0:65:35 0:91(89)c:0 100:0:0
a A solution of 1a (0.2 mmol) and anhydrous solvent (10 mL) in a quartz reaction tube was irradiated in a Matrix-10 reactor with sixteen lamps (10 w per lamp) at room temperature under argon atmosphere. b The yields were determined by 1H NMR (400 MHz) analysis of the crude reaction mixture with CH2Br2 (0.2 mmol) as internal standard. c Isolated yield of 2a.
722 Table 2
W. Liu et al. Scope of this reaction.a
1a
2a, 96 h, 89%
3a
2a, 96 h, 93%
1b
2b, 96 h, 93%
3f
2f, 96 h, 83%
1c
2c, 96 h, 93%
3g
2 g, 96 h, 80%
1d
2d, 168 h, 69%
3h
2 h, 96 h, traceb
1e
2e, 96 h, NR
3i
2i, 144 h, traceb
a A solution of 1 or 3 (0.2 mmol) and anhydrous THF (10 mL) was irradiated in a Matrix 254–10 reactor with sixteen 254 nm lamps (10 w per lamp) at room temperature under anargon atmosphere. Isolated yield was reported. b Some unidentified byproducts were formed.
Catalyst-free intramolecular Heck reaction
723
Scheme 3
Proposed mechanism.
J = 8.0 Hz, 2H), 7.39 (s, 1H), 7.19 (t, J = 2.8 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 6.88 (dd, J = 8.4, 2.4 Hz, 1H), 6.64 (dd, J = 8.4, 2.4 Hz, 1H), 3.92 (s, 3H), 3.883 (s, 3H), 3.876 (s, 3H). 2.6.6. Synthesis of 3,6-dimethoxy-9-(4-ethoxybenzylidene)-9Hfluorene (2g) from 3g Yield: 80%; mp 127.0–127.1 °C (petroleum ether/ethyl acetate); 1H NMR (400 MHz, CDCl3) d 7.66 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.39 (s, 1H), 7.19 (t, J = 2.4 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.88 (dd, J = 8.4, 2.0 Hz, 1H), 6.63 (dd, J = 8.4, 2.4 Hz, 1H), 4.11 (q, J = 7.2 Hz, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 1.47 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 160.1, 158.6, 142.5, 140.1, 134.5, 133.6, 130.8, 130.4, 129.3, 125.2, 123.6, 121.0, 114.3, 113.5, 112.7, 104.6, 104.3, 63.5, 55.6, 55.5, 14.9; IR (neat) 1606, 1570, 1508, 1496, 1462, 1428 cm1; HRMS (EI) calcd for C24H23O3 (M+H+) 359.1642, found 359.1640. 3. Results and discussion To optimize the reaction conditions, (Z)-2-iodo-20 -(4-methox ystyryl)-1,10 -biphenyl 1a was chosen as the model substrate. At first, the irradiation energy was optimized. As shown in Table 1, a 75% recovery yield of 1a was obtained under photo irradiation at k = 365 nm in CH3CN after 24 h (entry 1, Table 1). When 1a was irradiated at k = 313 nm, no substrate remained and the desired product 9-(4-methoxybenzylidene)9H-fluorene 2a was obtained in a 52% NMR yield. However, some isomerization product (E)-2-iodo-20 -(4-methoxystyryl)-1 ,10 -biphenyl 3a was formed (entry 2, Table 1). Higher NMR yield was gained when k = 254 nm was applied then k = 185 & 254 nm after 24 h (entries 3 and 4, Table 1). After the screening of wavelength, solvent effect was studied (entries 5–8, Table 1), among which toluene gave 3a as the solo product (entry 5, Table 1), while acetone yielded no 2a at all (entry 7, Table 1). While acetone yielded no 2a at all (entry 7, Table 1). A very low yield was observed in CH3NO2 (entry 6, Table 1). It might be due to the fact that nitromethyl radicals would be generated in the presence of iodine radicals, which might attack the substrate molecules and break the structure resulting in the low yield and recovery. Though, compared with CH3CN, a similar yield was obtained when the reaction was
done in THF, a higher yield of 3a was generated (entry 8, Table 1). Considering this cyclization is a radical path, we believed that 3a could be transferred into the desired product through a prolonged reaction time. To our delight, this hypothesis worked, a 91% NMR yield and an 89% isolated yield of 2a was obtained in THF after 96 h without the formation of side product 3a (entry 9, Table 1). Control experiment showed that the UV irradiation played an essential role in this transformation. Thus condition A (UV (k = 254 nm), THF, and rt) was applied as the standard condition for the following studies. With optimized conditions in hand, we started to examine the substrate scope. Reactants with Z-configuration were firstly studied (Table 2 left). The model substrate (1a) gave a high isolated yield. Even higher yields were obtained when ethoxy or methylthio was introduced into Ar1 (1b and 1c). Then, we tested the substrates with a weak electron-donating group. When methyl was applied, a longer reaction time was required and a moderate yield was gained (1d). Unfortunately, without any substituent in Ar1, the reaction gave no desired product under condition A (1e). Then, reactants with Econfiguration were employed to gain a better understanding of this reaction (Table 2 right). An excellent yield was gained when standard condition A was applied on (E)-2-iodo-20 -(4methoxystyryl)-1,10 -biphenyl (3a). Next, multi-substituted substrates were tested. When methoxy was applied on each aryl (3f), the desired product was obtained in a high yield. Substrate bearing ethoxy in Ar1 (3g) also gave a high yield. Although all the starting material was consumed, no desired product was observed when 3h or 3i was applied under condition A. Based on the above results and literature precedents [10,13], a plausible mechanism is shown in Scheme 3. Firstly, under UV irradiation, homolytic cleavage occurred on the C-I bond, forming an iodine radical and an aryl radical [10b,10f]. Subsequently, the aryl radical would give rise to two regiosiomeric alkyl radicals I and II through 5-exo and 6endo cyclization pathway accordingly [14]. Notably, such a radical addition step is generally reversible [15]. Thus, the unfavored intermediate II would be transferred into the favored intermediate I eventually. Then, I would be oxidized by the iodine radical via the single electron oxidation to form the carbocation species 4 [13]. Finally, deprotonation of 4 produced the final product 2.
724
W. Liu et al.
4. Conclusions In conclusion, we have developed an UV-induced catalyst-free intramolecular formal Heck reaction, forming 9-benzylidene9H-fluorene derivatives. This reaction provides a novel and practical protocol for the synthesis of substituted fluorenes. Due to the reversible of radical cyclization process, high regioselectivity is achieved. Acknowledgements We greatly acknowledge the financial support from Shanghai Science and Technology Committee (18DZ1201607) and Fundamental Research Funds for the Central Universities, Pioneering Project of Academy for Engineering and Technology, Fudan University (gyy2017-002).
[5] [6] [7]
[8]
[9]
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jscs.2018.12.001.
[10]
References [1] (a) T. Mizoroki, K. Mori, A. Ozaki, Bull. Chem. Soc. Jpn. 44 (1971) 581; (b) R.F. Heck, J.J.P. Nolley, J. Org. Chem. 37 (1972) 2320–2322. [2] (a) R.F. Heck, J. Am. Chem. Soc. 90 (1968) 5518–5526; (b) R.F. Heck, J. Am. Chem. Soc. 91 (1969) 6707–6714. [3] (a) T. Bach, S. Heuser, Chem. Eur. J. 8 (2002) 5585–5592; (b) P.-A. Enquist, P. Nilsson, P. Sjo¨berg, M. Larhed, J. Org. Chem. 71 (2006) 8779–8786; (c) H. Guthmann, M. Ko¨nemann, T. Bach, Eur. J. Org. Chem. 2007 (2007) 632–638; (d) K.M. Gligorich, M.S. Sigman, Chem. Commun. (2009) 3854–3867; (e) J. Cheng, Z. Ye, F. Chen, F. Luo, W. Wang, B. Lin, X. Jia, Synlett 2009 (2009) 2198–2200; (f) H.A. Stefani, J.M. Pena, K. Gueogjian, N. Petragnani, B.G. Vaz, M.N. Eberlin, Tetrahedron Lett. 50 (2009) 5589–5595; (g) T. Bach, S. Schweizer, Synlett 2010 (2009) 81–84; (h) S.B. Moosun, L.H. Blair, S.J. Coles, M.G. Bhowon, S. Jhaumeer-Laulloo, J. Saudi Chem. Soc. 21 (2017) 441–449. [4] (a) J. Le Bras, J. Muzart. Chem. Rev. 111 (2011) 1170–1214; (b) G.G. Pawar, G. Singh, V.K. Tiwari, M. Kapur, Adv. Syn.
[11]
[12] [13] [14] [15]
Catal. 355 (2013) 2185–2190; (c) J. Muzart, J. Le Bras, Synthesis 46 (2014) 1555–1572. Y. Yamamoto, Chem. Soc. Rev. 43 (2014) 1575–1600. A.F.P. Biajoli, C.S. Schwalm, J. Limberger, T.S. Claudino, A.L. Monteiro, J. Braz. Chem. Soc. 25 (2014) 2186–2214. (a) A.B. Dounay, L.E. Overman, Chem. Rev. 103 (2003) 2945– 2963; (b) L.F. Tietze, A. Du¨fert, Pure Appl. Chem. 82 (2010) 1375– 1392; (c) F. Klotter, A. Studer, Angew Chem. Int. Ed. 53 (2014) 2473– 2476. (a) C. Torborg, M. Beller, Adv. Synth. Catal. 351 (2009) 3027– 3043; (b) P. Devendar, R.Y. Qu, W.M. Kang, B. He, G.F. Yang, J. Agric. Food. Chem. 66 (2018) 8914–8934. (a) J.G.D. Vries, Can. J. Chem. 79 (2001) 1086–1092; (b) S. Zegar, C. Tokar, L.A. Enache, V. Rajagopol, W. Zeller, M. O’connell, J. Singh, F.W. Muellner, D.E. Zembower, Org. Process Res. Dev. 11 (2007) 747–753; (c) M. Panchal, A. Kongor, V. Mehta, M. Vora, K. Bhatt, V. Jain, J. Saudi Chem. Soc. 22 (2018) 558–568; (d) A.S. Waghmare, S.S. Pandit, J. Saudi Chem. Soc. 21 (2017) 286–290. (a) S. Protti, M. Fagnoni, A. Albini, J. Am. Chem. Soc. 128 (2006) 10670–10671; (b) M.E. Bude´n, J.F. Guastavino, R.A. Rossi, Org. Lett. 15 (2013) 1174–1177; (c) X. Zheng, L. Yang, W. Du, A. Ding, H. Guo, Chem. Asian. J. 9 (2014) 439–442; (d) L. Li, W. Liu, H. Zeng, X. Mu, G. Cosa, Z. Mi, C.J. Li, J. Am. Chem. Soc. 137 (2015) 8328–8331; (e) W. Liu, L. Li, C.J. Li, Nat. Commun. 6 (2015) 6526; (f) D. Xu, R. Rios, F. Ba, D. Ma, G. Gu, A. Ding, Y. Kuang, H. Guo, Asian J. Org. Chem. 5 (2016) 981–985; (g) A.M. Mfuh, J.D. Doyle, B. Chhetri, H.D. Arman, O.V. Larionov, J. Am. Chem. Soc. 138 (2016) 2985–2988; (h) K. Chen, S. Zhang, P. He, P. Li, Chem. Sci. 7 (2016) 3676– 3680. (a) S. Protti, M. Fagnoni, A. Albini, Angew. Chem. Int. Ed. 44 (2005) 5675–5678; (b) S. Crespi, S. Protti, M. Fagnoni, J. Org. Chem. 81 (2016) 9612–9619. D.P. Curran, M.-H. Chen, D. Kim, J. Am. Chem. Soc. 108 (1986) 2489–2490. B. Nachtsheim, P. Finkbeiner, Synthesis 45 (2013) 979–999. A. Navarro-Va´zquez, A. Garcı´ a, D. Domı´ nguez, J. Org. Chem. 67 (2002) 3213–3220. E.I. Heiba, R.M. Dessau, J. Org. Chem. 32 (1967) 3837–3840.
King Saud University
Journal of Saudi Chemical Society www.ksu.edu.sa www.sciencedirect.com
ORIGINAL ARTICLE
UV-induced catalyst-free intramolecular formal Heck reaction Wangsheng Liu a, Dongmei Ma a, Hao Guo a,c,*, Guangxin Gu b,c,* a
Department of Chemistry, Fudan University, 2005 Songhu Road, Shanghai 200438, PR China Department of Materials Science, Fudan University, 220 Handan Road, Shanghai 200433, PR China c Academy for Engineering and Technology, Fudan University, 220 Handan Road, Shanghai 200433, PR China b
Received 2 November 2018; revised 29 November 2018; accepted 12 December 2018 Available online 31 December 2018
KEYWORDS Photochemistry; Cyclization; Radical; Fluorene
Abstract A catalyst-free intramolecular formal Heck reaction has been developed, affording 9benzylidene-9H-fluorene derivatives under UV irradiation. This reaction probably proceeds via UV-induced homolytic cleavage of CAI bond, addition of the aryl radical to the alkene moiety, single electron oxidation of alkyl radical intermediate into carbocation species, and deprotonation. Ó 2018 King Saud University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction Heck reaction, which is also called Mizoroki-Heck reaction, was reported by Richard F. Heck and Tsutomu Mizoroki independently [1]. At the very beginning, the stoichiometric ArPdX complexes, which were formed from the reaction between palladium salts and aryl-metal compounds would react with olefins [2]. After few years, this reaction was done using catalytic amounts of Pd [3]. Moreover, activated CAH bond [4] and alkynes [4c,5] can also be applied on this reaction. Nowadays, Heck reaction becomes a practical synthetic protocol for the total synthesis of drugs [6], natural products [7], agrochemicals [8] and other fields [8a,9]. The Heck reaction * Corresponding authors. E-mail addresses: [email protected] (H. Guo), guangxingu@ fudan.edu.cn (G. Gu). Peer review under responsibility of King Saud University.
Production and hosting by Elsevier
results from the cleavage of CAX (X = I, Br or Cl) bond, followed by coupling with C‚C bond. Besides catalysts, photo irradiation is also a path to break CAX bonds [10]. Firstly, the substrate molecular goes into its excited state after absorbing photons. Then some bonds with lower bond energy break and take the next reaction [11]. CAX bonds, which belong to this kind of bonds, would undergo homolytic cleavage or heterolytic cleavage, forming radicals or cations under the irradiation of applied light source. Then these in situ formed radicals or cations would react with unsaturated bonds affording addition compounds or formal Heck reaction products [10f]. Early in 1986, Curran group has reported a cyclization of hex-5-ynyl iodides (Scheme 1a), where radical initiator Bu3SnH was used [12]. In the presence of Bu3SnH, homolytic cleavage of CAI bond happened, followed by 5exo cyclization and a trace amount of reduced product was formed. In 2016, our group has reported a photo chemically intramolecular haloarylation and hydroarylation of alkynes, forming a series of 9-benzylidene-9H-fluorene and 9-(halo (phenyl)methylene)-9H-fluorene derivatives (Scheme 1b) [10f]. The reaction was initiated by homolytic cleavage of CAI bonds under UV irradiation. Based on our continuous
https://doi.org/10.1016/j.jscs.2018.12.001 1319-6103 Ó 2018 King Saud University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Catalyst-free intramolecular Heck reaction
Scheme 1
Reactions initiated by the homolytic cleavage of CAX bond.
research interest in this field, we designed a photo-induced formal Heck reaction. The envisioned mechanism is shown in Scheme 2. Initially, under photo irradiation, aryl radical and iodine radical are formed by homolytic cleavage of CAI bond. Then, alkene is attacked by the aryl radical, generating 5-exo cyclization radical intermediate. After that, alkyl radical can be oxidized by iodine radical [13], forming the carbocation species which will yield the formal Heck reaction products by deprotonation. Herein, we wish to report an intramolecular formal Heck reaction of olefins under UV irradiation without any metal or organic catalyst, generating 9-benzylidene-9H-fluorene derivatives in an efficient and highly selective way. 2. Methods 2.1. General experimental methods All reactions were carried out using a Matrix-10 reactor (unless stated otherwise) as the irradiation source. Melting points were determined on a WRS-2 apparatus. IR spectra were recorded on an Avatar 360 FT-IR spectrometer. 1H (400 MHz), 13C (100 MHz) NMR spectra of samples in CDCl3 were recorded on an AVANCE III 400 spectrometer. HRMS (EI) determinations were carried out on a Water GCT CA176 spectrometer. Anhydrous THF was distilled with Na with benzophenone as an indicator. Anhydrous DCM was distilled with CaH2. 2.2. Typical procedure I for the synthesis of arene-alkenes 2.2.1. Synthesis of (Z)-2-iodo-20 -(4-methoxystyryl)-1,10 biphenyl (1a) A solution of (4-methoxybenzyl)triphenylphosphonium chloride (15.918 g, 38.0 mmol) in anhydrous THF (200 mL) was
Scheme 2
719
cooled to 78 °C under argon atmosphere. NaHMDS (2.0 M in THF, 19 mL, 38.0 mmol) was added over 30 min. The reaction mixture was stirred at 78 °C for 3 h, then a solution of 20 -iodo-2-formyl-1,10 -biphenyl (10,000 g, 32 mmol) in anhydrous THF (100 mL) was added dropwise over 1 h. The resulting solution was allowed to warm slowly to room temperature. Then the mixture was stirred for 5 h at room temperature. The resulting mixture was filtered. Then the solvent was removed and the residue was purified by flash column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 20:1) to afford 1a as a solid (28.814 g, 66%); mp 111.2–111.4 °C (petroleum ether/ethyl acetate). 1H NMR (400 MHz, CDCl3) d 7.92 (d, J = 8.0 Hz, 1H), 7.44–7.08 (m, 8H), 7.01 (t, J = 7.6 Hz, 1H), 6.73 (d, J = 8.8 Hz, 2H), 6.35 (d, J = 12.4 Hz, 1H), 6.12 (d, J = 12.4 Hz, 1H), 3.77 (s, 3H); 13C NMR (100 MHz, CDCl3) d 158.7, 146.1, 143.8, 138.9, 136.1, 130.3, 130.1, 129.94, 129.87, 129.4, 129.2, 128.7, 127.8, 127.6, 127.2, 126.9, 113.5, 99.9, 55.2; IR (neat) 1618, 1510, 1465, 1436 cm1; HRMS (EI) calcd for C21H17OI (M+) 412.0324, found 412.0326. 2.3. The following compounds were prepared according to typical procedure I 2.3.1. Synthesis of (Z)-2-iodo-20 -(4-ethoxystyryl)-1,10 -biphenyl (1b) Yield: 78%; mp 81.7–82.2 °C (petroleum ether/ethyl acetate); H NMR (400 MHz, CDCl3) d 7.93 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.36–7.14 (m, 7H), 7.07–6.96 (m, 1H), 6.72 (d, J = 8.4 Hz, 2H), 6.35 (d, J = 12.4 Hz, 1H), 6.11 (d, J = 12.4 Hz, 1H), 4.00 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 158.1, 146.1, 143.8, 138.9, 136.1, 130.2, 130.1, 130.0, 129.9, 129.2, 128.7, 127.8, 127.6, 127.0, 126.8, 114.0, 99.9, 63.3, 14.8; IR (neat) 1606, 1509, 1482, 1461, 1442, 1391 cm1; HRMS (EI) calcd for C22H19OI (M+) 426.0481, found 426.0488. 1
The envisioned mechanism for the photo-induced formal Heck reaction.
720
W. Liu et al.
2.3.2. Synthesis of (Z)-2-iodo-20 -(4-methylthiostyryl)-1,10 biphenyl (1c)
2.3.7. Synthesis of (E)-2-iodo-5,50 -dimethoxy-20 -(4methylstyryl)-1,10 -biphenyl (3h)
Yield: 57%; mp 71.3–71.7 °C (petroleum ether/ethyl acetate); H NMR (400 MHz, CDCl3) d 7.93 (dd, J = 8.0, 0.8 Hz, 1H), 7.39–7.26 (m, 3H), 7.25–7.14 (m, 5H), 7.10–6.98 (m, 3H), 6.35 (d, J = 12.4 Hz, 1H), 6.19 (d, J = 12.4 Hz, 1H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) d 146.0, 143.8, 138.9, 137.3, 135.8, 133.6, 130.1, 129.9, 129.8, 129.4, 129.2, 128.8, 128.6, 127.8, 127.6, 127.1, 126.0, 99.9, 15.6; IR (neat) 1595, 1493, 1461, 1434 cm1; HRMS (EI) calcd for C21H18SI (M+H+) 429.0168, found 429.0162.
Yield: 26%; mp 157.3–157.4 °C (petroleum ether/ethyl acetate); 1H NMR (400 MHz, CDCl3) d 7.80 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 6.98 (dd, J = 8.8, 2.8 Hz, 1H), 6.91 (d, J = 16.4 Hz, 1H), 6.84 (d, J = 3.2 Hz, 1H), 6.73–6.67 (m, 2H), 6.64 (d, J = 16.0 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) d 159.6, 158.4, 146.5, 144.3, 139.5, 137.0, 135.0, 129.2, 128.1, 127.6, 126.3, 126.1, 125.2, 116.0, 115.6, 114.6, 114.5, 88.5, 55.4, 21.2; IR (neat) 1602, 1592, 1563, 1514, 1463 cm1; HRMS (EI) calcd for C23H21IO2 (M+) 456.0581, found 456.0581.
1
2.3.3. Synthesis of (Z)-2-iodo-20 -(4-methylstyryl)-1,10 -biphenyl (1d) Yield: 72%; 1H NMR (400 MHz, CDCl3) d 7.93 (dd, J = 8.0, 1.2 Hz, 1H), 7.44–7.12 (m, 8H), 7.07–6.96 (m, 3H), 6.38 (d, J = 12.4 Hz, 1H), 6.17 (d, J = 12.4 Hz, 1H), 2.30 (s, 3H); 13 C NMR (100 MHz, CDCl3) d 146.1, 143.8, 138.9, 136.9, 136.0, 133.9, 130.4, 130.1, 129.9, 129.3, 128.9, 128.79, 128.75, 128.1, 127.8, 127.5, 126.9, 99.9, 21.2; IR (neat) 1510, 1461, 1441 cm1; HRMS (EI) calcd for C21H21NI (M+NH+ 4 ) 414.0713, found 414.0713. 2.3.4. Synthesis of (Z)-2-iodo-20 -styryl-1,10 -biphenyl (1e) Yield: 65%; mp 72.8–73.1 °C (petroleum ether/ethyl acetate); H NMR (400 MHz, CDCl3) d 7.93 (d, J = 8.0 Hz, 1H), 7.37–7.13 (m, 11H), 7.01 (t, J = 7.6 Hz, 1 H), 6.41 (d, J = 12.4 Hz, 1 H), 6.22 (d, J = 12.4 Hz, 1 H); 13C NMR (100 MHz, CDCl3) d 146.0, 143.9, 138.9, 136.9, 135.7, 130.5, 130.1, 129.9, 129.3, 129.0, 128.9, 128.8, 128.1, 127.9, 127.6, 127.11, 127.05, 99.9; IR (neat) 1600, 1580, 1557, 1492, 1461, 1444, 1428 cm1; HRMS (EI) calcd for C20H19NI (M +NH+ 4 ) 400.0557, found 400.0554. 1
2.3.5. Synthesis of (E)-2-iodo-5,50 -dimethoxy-20 -(4methoxystyryl)-1,10 -biphenyl (3f) Yield: 30%; mp 141.9–142.0 °C (petroleum ether/ethyl acetate); 1H NMR (400 MHz, CDCl3) d 7.80 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 6.99–6.77 (m, 5H), 6.73–6.65 (m, 2H), 6.56 (d, J = 16.0 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 6H); 13C NMR (100 MHz, CDCl3) d 159.6, 158.9, 158.3, 146.6, 144.2, 139.5, 130.7, 128.3, 127.5, 127.2, 126.0, 124.1, 116.0, 115.6, 114.60, 114.56, 114.0, 88.5, 55.4, 55.3; IR (neat) 1606, 1590, 1564, 1512, 1468, 1445 cm1; HRMS (EI) calcd for C23H21IO3 (M +) 472.0530, found 472.0529. 2.3.6. Synthesis of (E)-2-iodo-5,50 -dimethoxy-20 -(4ethoxystyryl)-1,10 -biphenyl (3g) Yield: 45%; mp 143.2–143.7 °C (petroleum ether/ethyl acetate); 1H NMR (400 MHz, CDCl3) d 7.80 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.21 (d, J = 8.4 Hz, 2H), 7.03–6.74 (m, 5H), 6.71–6.65 (m, 2H), 6.55 (d, J = 16.0 Hz, 1H), 4.00 (q, J = 6.8 Hz, 2H), 3.83 (s, 3H), 3.78 (s, 3H), 1.39 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 159.6, 158.3, 146.6, 144.2, 139.5, 130.5, 128.3, 127.5, 127.3, 126.0, 124.0, 116.0, 115.6, 114.6, 114.5, 88.5, 63.4, 55.4, 14.8; IR (neat) 1606, 1587, 1564, 1511, 1470, 1442 cm1; HRMS (EI) calcd for C24H23IO3 (M+) 486.0686, found 486.0685.
2.3.8. Synthesis of (E)-2-iodo-5,50 -dimethoxy-20 -styryl-1,10 biphenyl (3i) Yield: 38%; mp 131.1–131.3 °C (petroleum ether/ethyl acetate); 1H NMR (400 MHz, CDCl3) d 7.80 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.35–7.21 (m, 4H), 7.22–7.13 (m, 1H), 7.01–6.88 (m, 2H), 6.84 (d, J = 3.2 Hz, 1H), 6.75– 6.64 (m, 3H), 3.84 (s, 3H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3) d 159.6, 158.6, 146.4, 144.5, 139.5, 137.8, 128.5, 127.9, 127.6, 127.1, 126.3, 126.2, 126.1, 116.0, 115.6, 114.62, 114.56, 88.5, 55.4; IR (neat) 1594, 1561, 1496, 1463 cm1; HRMS (EI) calcd for C22H20IO2 (M+H+) 443.0502, found 443.0504. 2.4. Synthesis of (E)-2-iodo-20 -(4-methoxystyryl)-1,10 -biphenyl (3a) To a 250 mL three necked flask was added 20 -iodo-2-formyl1,10 -biphenyl (2.010 g, 6.5 mmol), (4-methoxybenzyl)triphenyl phosphonium (3.120 g, 8.0 mmol), LiOHH2O (411 mg, 9.8 mmol), LiCl (10.005 g, 231 mmol) and H2O (150 mL). The mixture was refluxed for 9 h. The crude product was extracted with ethyl acetate (50 mL 3). The combined organic layer was dried over MgSO4 and filtered. The solvent was removed under reduced pressure. Purification by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 40:1 to 20:1) afforded 3a as a liquid (280 mg, 10%). 1H NMR (400 MHz, CDCl3) d 7.96 (dd, J = 8.0, 0.8 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.47–7.33 (m, 2H), 7.32–7.17 (m, 4H), 7.16–6.91 (m, 3H), 6.79 (d, J = 8.8 Hz, 2H), 6.61 (d, J = 16.4 Hz, 1H), 3.75 (s, 3H); 13C NMR (100 MHz, CDCl3) d 159.2, 145.8, 143.2, 139.0, 135.5, 130.6, 130.3, 130.1, 129.2, 128.9, 128.2, 128.0, 127.8, 126.8, 124.7, 124.5, 114.0, 100.3, 55.3; IR (neat) 1609, 1508, 1450, 1439 cm1; HRMS (EI) calcd for C21H17IO (M+) 412.0319, found 412.0319. 2.5. Typical procedure II for reactions under standard condition 2.5.1. Synthesis of 9-(4-methoxybenzylidene)-9H-fluorene (2a) [10f] from 1a To a quartz reaction tube was added 1a (82 mg, 0.20 mmol) and anhydrous THF (10 mL) under argon atmosphere. The mixture was bubbling with argon for 15 min. Then the mixture was irradiated in a Matrix254-10 reactor with sixteen 254 nm lamps (10 w per lamp). The reaction was completed after 96 h as monitored by TLC (eluent: petroleum ether: ethyl acetate = 20:1). The solvent was removed and the residue was
Catalyst-free intramolecular Heck reaction
721
purified by flash chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 50:1) to afford 2a as a solid (51 mg, 89%). 1H NMR (400 MHz, CDCl3) d 7.78 (d, J = 7.2 Hz, 1H), 7.75–7.67 (m, 3H), 7.65 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.40–7.27 (m, 3H), 7.09 (t, J = 7.6 Hz, 1H), 6.99 (d, J = 8.4 Hz, 2H), 3.89 (s, 3H). 2.6. The following reactions were conducted according to typical procedure II 2.6.1. Synthesis of 9-(4-ethoxybenzylidene)-9H-fluorene (2b) from 1b Yield: 93%; mp 100.8–101.2 °C (petroleum ether/dichloromethane); 1H NMR (400 MHz, CDCl3) d 7.76 (d, J = 7.2 Hz, 1H), 7.71 (d, J = 7.6 Hz, 3H), 7.64 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.40–7.26 (m, 3H), 7.11–7.05 (m, 1H), 6.99–6.93 (m, 2H), 4.10 (q, J = 7.2 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 158.9, 141.1, 139.7, 138.9, 136.6, 135.3, 130.8, 128.9, 128.2, 127.8, 127.4, 126.9, 126.6, 124.2, 120.0, 119.7, 119.5, 114.4, 63.5, 14.8; IR (neat) 1603, 1508, 1473, 1448, 1391 cm1; HRMS (EI) calcd for C22H19O (M+H+) 299.1430, found 299.1430.
J = 7.6 Hz, 1H), 7.71 (d, J = 7.2 Hz, 2H), 7.67 (d, J = 7.6 Hz, 1H), 7.62 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.41–7.27 (m, 5H), 7.08 (td, J = 8.4, 0.8 Hz, 1H), 2.56 (s, 3H); 13C NMR (100 MHz, CDCl3) d 141.2, 139.5, 139.0, 138.7, 136.4, 136.2, 133.3, 129.8, 128.5, 128.1, 126.9, 126.7, 126.6, 126.0, 124.3, 120.1, 119.7, 119.5, 15.5; IR (neat) 1635, 1590, 1490, 1448, 1439 cm1; HRMS (EI) calcd for C21H17S (M+H+) 301.1045, found 301.1045. 2.6.3. Synthesis of 9-(4-methylbenzylidene)-9H-fluorene (2d) [10f] from 1d Yield: 69%; 1H NMR (400 MHz, CDCl3) d 7.78 (d, J = 7.6 Hz, 1H), 7.71 (d, J = 7.6 Hz, 2H), 7.68–7.61 (m, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.41–7.22 (m, 5H), 7.11–7.03 (m, 1H), 2.44 (s, 3H). 2.6.4. Synthesis of 9-(4-methoxybenzylidene)-9H-fluorene (2a) [10f] from 3a Yield: 87%; 1H NMR (400 MHz, CDCl3) d 7.78 (d, J = 7.2 Hz, 1H), 7.75–7.67 (m, 3H), 7.65 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.40–7.27 (m, 3H), 7.09 (t, J = 7.6 Hz, 1H), 6.99 (d, J = 8.4 Hz, 2H), 3.89 (s, 3H).
2.6.2. Synthesis of 9-(4-methylthiobenzylidene)-9H-fluorene (2c) from 1c
2.6.5. Synthesis of 3,6-dimethoxy-9-(4-methoxybenzylidene)9H-fluorene (2f) [10f] from 3f
Yield: 93%; mp 100.1–100.6 °C (petroleum ether/dichloromethane); 1H NMR (400 MHz, CDCl3) d 7.77 (d,
Yield: 83%; 1H NMR (400 MHz, CDCl3) d 7.66 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.51 (d,
Table 1
Entry
Optimization of the reaction conditions.a
Wavelength (nm)
Solvent
Time (h)
NMR Yield (%)b 1a:2a:3a
1 2 3 4 5 6 7 8 9 10
365 313 254 185 & 254 254 254 254 254 254 dark
CH3CN CH3CN CH3CN CH3CN Toluene CH3NO2 Acetone THF THF THF
24 24 24 24 24 24 24 24 96 96
75:6:17 0:52:15 0:68:16 0:66:15 0:0:57 0:26:5 22:0:74 0:65:35 0:91(89)c:0 100:0:0
a A solution of 1a (0.2 mmol) and anhydrous solvent (10 mL) in a quartz reaction tube was irradiated in a Matrix-10 reactor with sixteen lamps (10 w per lamp) at room temperature under argon atmosphere. b The yields were determined by 1H NMR (400 MHz) analysis of the crude reaction mixture with CH2Br2 (0.2 mmol) as internal standard. c Isolated yield of 2a.
722 Table 2
W. Liu et al. Scope of this reaction.a
1a
2a, 96 h, 89%
3a
2a, 96 h, 93%
1b
2b, 96 h, 93%
3f
2f, 96 h, 83%
1c
2c, 96 h, 93%
3g
2 g, 96 h, 80%
1d
2d, 168 h, 69%
3h
2 h, 96 h, traceb
1e
2e, 96 h, NR
3i
2i, 144 h, traceb
a A solution of 1 or 3 (0.2 mmol) and anhydrous THF (10 mL) was irradiated in a Matrix 254–10 reactor with sixteen 254 nm lamps (10 w per lamp) at room temperature under anargon atmosphere. Isolated yield was reported. b Some unidentified byproducts were formed.
Catalyst-free intramolecular Heck reaction
723
Scheme 3
Proposed mechanism.
J = 8.0 Hz, 2H), 7.39 (s, 1H), 7.19 (t, J = 2.8 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 6.88 (dd, J = 8.4, 2.4 Hz, 1H), 6.64 (dd, J = 8.4, 2.4 Hz, 1H), 3.92 (s, 3H), 3.883 (s, 3H), 3.876 (s, 3H). 2.6.6. Synthesis of 3,6-dimethoxy-9-(4-ethoxybenzylidene)-9Hfluorene (2g) from 3g Yield: 80%; mp 127.0–127.1 °C (petroleum ether/ethyl acetate); 1H NMR (400 MHz, CDCl3) d 7.66 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.39 (s, 1H), 7.19 (t, J = 2.4 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.88 (dd, J = 8.4, 2.0 Hz, 1H), 6.63 (dd, J = 8.4, 2.4 Hz, 1H), 4.11 (q, J = 7.2 Hz, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 1.47 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 160.1, 158.6, 142.5, 140.1, 134.5, 133.6, 130.8, 130.4, 129.3, 125.2, 123.6, 121.0, 114.3, 113.5, 112.7, 104.6, 104.3, 63.5, 55.6, 55.5, 14.9; IR (neat) 1606, 1570, 1508, 1496, 1462, 1428 cm1; HRMS (EI) calcd for C24H23O3 (M+H+) 359.1642, found 359.1640. 3. Results and discussion To optimize the reaction conditions, (Z)-2-iodo-20 -(4-methox ystyryl)-1,10 -biphenyl 1a was chosen as the model substrate. At first, the irradiation energy was optimized. As shown in Table 1, a 75% recovery yield of 1a was obtained under photo irradiation at k = 365 nm in CH3CN after 24 h (entry 1, Table 1). When 1a was irradiated at k = 313 nm, no substrate remained and the desired product 9-(4-methoxybenzylidene)9H-fluorene 2a was obtained in a 52% NMR yield. However, some isomerization product (E)-2-iodo-20 -(4-methoxystyryl)-1 ,10 -biphenyl 3a was formed (entry 2, Table 1). Higher NMR yield was gained when k = 254 nm was applied then k = 185 & 254 nm after 24 h (entries 3 and 4, Table 1). After the screening of wavelength, solvent effect was studied (entries 5–8, Table 1), among which toluene gave 3a as the solo product (entry 5, Table 1), while acetone yielded no 2a at all (entry 7, Table 1). While acetone yielded no 2a at all (entry 7, Table 1). A very low yield was observed in CH3NO2 (entry 6, Table 1). It might be due to the fact that nitromethyl radicals would be generated in the presence of iodine radicals, which might attack the substrate molecules and break the structure resulting in the low yield and recovery. Though, compared with CH3CN, a similar yield was obtained when the reaction was
done in THF, a higher yield of 3a was generated (entry 8, Table 1). Considering this cyclization is a radical path, we believed that 3a could be transferred into the desired product through a prolonged reaction time. To our delight, this hypothesis worked, a 91% NMR yield and an 89% isolated yield of 2a was obtained in THF after 96 h without the formation of side product 3a (entry 9, Table 1). Control experiment showed that the UV irradiation played an essential role in this transformation. Thus condition A (UV (k = 254 nm), THF, and rt) was applied as the standard condition for the following studies. With optimized conditions in hand, we started to examine the substrate scope. Reactants with Z-configuration were firstly studied (Table 2 left). The model substrate (1a) gave a high isolated yield. Even higher yields were obtained when ethoxy or methylthio was introduced into Ar1 (1b and 1c). Then, we tested the substrates with a weak electron-donating group. When methyl was applied, a longer reaction time was required and a moderate yield was gained (1d). Unfortunately, without any substituent in Ar1, the reaction gave no desired product under condition A (1e). Then, reactants with Econfiguration were employed to gain a better understanding of this reaction (Table 2 right). An excellent yield was gained when standard condition A was applied on (E)-2-iodo-20 -(4methoxystyryl)-1,10 -biphenyl (3a). Next, multi-substituted substrates were tested. When methoxy was applied on each aryl (3f), the desired product was obtained in a high yield. Substrate bearing ethoxy in Ar1 (3g) also gave a high yield. Although all the starting material was consumed, no desired product was observed when 3h or 3i was applied under condition A. Based on the above results and literature precedents [10,13], a plausible mechanism is shown in Scheme 3. Firstly, under UV irradiation, homolytic cleavage occurred on the C-I bond, forming an iodine radical and an aryl radical [10b,10f]. Subsequently, the aryl radical would give rise to two regiosiomeric alkyl radicals I and II through 5-exo and 6endo cyclization pathway accordingly [14]. Notably, such a radical addition step is generally reversible [15]. Thus, the unfavored intermediate II would be transferred into the favored intermediate I eventually. Then, I would be oxidized by the iodine radical via the single electron oxidation to form the carbocation species 4 [13]. Finally, deprotonation of 4 produced the final product 2.
724
W. Liu et al.
4. Conclusions In conclusion, we have developed an UV-induced catalyst-free intramolecular formal Heck reaction, forming 9-benzylidene9H-fluorene derivatives. This reaction provides a novel and practical protocol for the synthesis of substituted fluorenes. Due to the reversible of radical cyclization process, high regioselectivity is achieved. Acknowledgements We greatly acknowledge the financial support from Shanghai Science and Technology Committee (18DZ1201607) and Fundamental Research Funds for the Central Universities, Pioneering Project of Academy for Engineering and Technology, Fudan University (gyy2017-002).
[5] [6] [7]
[8]
[9]
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jscs.2018.12.001.
[10]
References [1] (a) T. Mizoroki, K. Mori, A. Ozaki, Bull. Chem. Soc. Jpn. 44 (1971) 581; (b) R.F. Heck, J.J.P. Nolley, J. Org. Chem. 37 (1972) 2320–2322. [2] (a) R.F. Heck, J. Am. Chem. Soc. 90 (1968) 5518–5526; (b) R.F. Heck, J. Am. Chem. Soc. 91 (1969) 6707–6714. [3] (a) T. Bach, S. Heuser, Chem. Eur. J. 8 (2002) 5585–5592; (b) P.-A. Enquist, P. Nilsson, P. Sjo¨berg, M. Larhed, J. Org. Chem. 71 (2006) 8779–8786; (c) H. Guthmann, M. Ko¨nemann, T. Bach, Eur. J. Org. Chem. 2007 (2007) 632–638; (d) K.M. Gligorich, M.S. Sigman, Chem. Commun. (2009) 3854–3867; (e) J. Cheng, Z. Ye, F. Chen, F. Luo, W. Wang, B. Lin, X. Jia, Synlett 2009 (2009) 2198–2200; (f) H.A. Stefani, J.M. Pena, K. Gueogjian, N. Petragnani, B.G. Vaz, M.N. Eberlin, Tetrahedron Lett. 50 (2009) 5589–5595; (g) T. Bach, S. Schweizer, Synlett 2010 (2009) 81–84; (h) S.B. Moosun, L.H. Blair, S.J. Coles, M.G. Bhowon, S. Jhaumeer-Laulloo, J. Saudi Chem. Soc. 21 (2017) 441–449. [4] (a) J. Le Bras, J. Muzart. Chem. Rev. 111 (2011) 1170–1214; (b) G.G. Pawar, G. Singh, V.K. Tiwari, M. Kapur, Adv. Syn.
[11]
[12] [13] [14] [15]
Catal. 355 (2013) 2185–2190; (c) J. Muzart, J. Le Bras, Synthesis 46 (2014) 1555–1572. Y. Yamamoto, Chem. Soc. Rev. 43 (2014) 1575–1600. A.F.P. Biajoli, C.S. Schwalm, J. Limberger, T.S. Claudino, A.L. Monteiro, J. Braz. Chem. Soc. 25 (2014) 2186–2214. (a) A.B. Dounay, L.E. Overman, Chem. Rev. 103 (2003) 2945– 2963; (b) L.F. Tietze, A. Du¨fert, Pure Appl. Chem. 82 (2010) 1375– 1392; (c) F. Klotter, A. Studer, Angew Chem. Int. Ed. 53 (2014) 2473– 2476. (a) C. Torborg, M. Beller, Adv. Synth. Catal. 351 (2009) 3027– 3043; (b) P. Devendar, R.Y. Qu, W.M. Kang, B. He, G.F. Yang, J. Agric. Food. Chem. 66 (2018) 8914–8934. (a) J.G.D. Vries, Can. J. Chem. 79 (2001) 1086–1092; (b) S. Zegar, C. Tokar, L.A. Enache, V. Rajagopol, W. Zeller, M. O’connell, J. Singh, F.W. Muellner, D.E. Zembower, Org. Process Res. Dev. 11 (2007) 747–753; (c) M. Panchal, A. Kongor, V. Mehta, M. Vora, K. Bhatt, V. Jain, J. Saudi Chem. Soc. 22 (2018) 558–568; (d) A.S. Waghmare, S.S. Pandit, J. Saudi Chem. Soc. 21 (2017) 286–290. (a) S. Protti, M. Fagnoni, A. Albini, J. Am. Chem. Soc. 128 (2006) 10670–10671; (b) M.E. Bude´n, J.F. Guastavino, R.A. Rossi, Org. Lett. 15 (2013) 1174–1177; (c) X. Zheng, L. Yang, W. Du, A. Ding, H. Guo, Chem. Asian. J. 9 (2014) 439–442; (d) L. Li, W. Liu, H. Zeng, X. Mu, G. Cosa, Z. Mi, C.J. Li, J. Am. Chem. Soc. 137 (2015) 8328–8331; (e) W. Liu, L. Li, C.J. Li, Nat. Commun. 6 (2015) 6526; (f) D. Xu, R. Rios, F. Ba, D. Ma, G. Gu, A. Ding, Y. Kuang, H. Guo, Asian J. Org. Chem. 5 (2016) 981–985; (g) A.M. Mfuh, J.D. Doyle, B. Chhetri, H.D. Arman, O.V. Larionov, J. Am. Chem. Soc. 138 (2016) 2985–2988; (h) K. Chen, S. Zhang, P. He, P. Li, Chem. Sci. 7 (2016) 3676– 3680. (a) S. Protti, M. Fagnoni, A. Albini, Angew. Chem. Int. Ed. 44 (2005) 5675–5678; (b) S. Crespi, S. Protti, M. Fagnoni, J. Org. Chem. 81 (2016) 9612–9619. D.P. Curran, M.-H. Chen, D. Kim, J. Am. Chem. Soc. 108 (1986) 2489–2490. B. Nachtsheim, P. Finkbeiner, Synthesis 45 (2013) 979–999. A. Navarro-Va´zquez, A. Garcı´ a, D. Domı´ nguez, J. Org. Chem. 67 (2002) 3213–3220. E.I. Heiba, R.M. Dessau, J. Org. Chem. 32 (1967) 3837–3840.