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Tetrahedron Tetrahedron: Sciencedirect Sciencedirect
Tetrahedron Tetrahedron: Sciencedirect Sciencedirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
a r t i c l e i n f o a b s t r a c t
Article history: Iron(III) chloride was discovered highly effective as catalyst in the Friedel–Crafts reactions of electron-
Received 5 December 2007 rich arenes with imines or aziridines. It was found that reactions of imines were highly substrate-
Received in revised form 21 March 2008 dependent, which generated mono- or double-addition products, while arenes reacted with aziridines
Accepted 25 March 2008
regioselectively leading to the formation of desired ring-opening products in 2 min with moderate to
Available online 28 March 2008
good yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Iron(III) chloride
Friedel–Crafts reaction
Arene
Imine
Aziridine
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.081
5014 Z. Wang et al. / Tetrahedron 64 (2008) 5013–5018
OMe
MeO OMe
+ R3 NTs FeCl3 (5 mol%)
CH3NO2, r.t.
MeO OMe (1)
OMe 12 h NHTs
2a: R3 = H R1
1a
2b: R3 = 4-F
3a: R3 = H, 72% yield;
3b: R3 = 4-F, 52% yield.
OMe
OMe
OMe
NTs FeCl3 (5 mol%)
+ R3 (2)
OMe CH3NO2, r.t. OMe
12 h R1
1b 2a: R3 = H
2b: R3 = 4-F OMe
4a: R3 = H, 20% yield;
4b: R3 = 4-F, 21% yield.
Scheme 1.
Aziridine is a versatile building block for the synthesis of many 1,2-dimethoxybenzene 1b (1.1 equiv) in CH3NO2 at room temper-
nitrogen-containing biologically active molecules.11 Among the ature (Table 1, entry 1). This reaction was found highly efficient,
procedures of ring opening of aziridines, a nucleophilic ring- which was finished in 2 min, and the desired product 6b was
opening reaction is one of the major routes to highly functionalized afforded in 90% yield. Furthermore, under this catalytic condition,
compounds.11 Although ring-opening reactions of aziridines with regiospecificity was observed and the only isomer, which was from
various nucleophiles (such as thiols, amines, alcohols, and silylated attack on the benzylic position of N-tosyl-2-phenylaziridine 5a was
nucleophiles) have been developed, there are only few examples of obtained. Even in the analysis of 1H NMR spectra of crude mixture,
utilizing arenes as substrates, which employed Lewis acids [AlCl3,12 we still could not find the peak of isomer. It may be due to electron
BF3$OEt2,13 In(OTf)3,14 AuCl3,15 and AgPF616] as the promoter or effect since the benzylic position of N-tosyl-2-arylaziridine is highly
catalyst. For example, stoichiometric amount of AlCl3 or BF3$OEt2 positive. When CH3NO2 was replaced by other solvents, lower
had to be utilized as a promoter for reactions of aziridines with yields were observed. For instance, 27% yield or 25% of product 6b
arenes.12,13 Indium triflate was also employed for the reaction of was obtained, respectively, when the reaction was performed in
aziridines with arenes.14 The reaction was usually completed in CH2Cl2 or ClCH2CH2Cl (Table 1, entries 2 and 3). Only trace amount
several hours in the presence of catalytic amount of In(OTf)3 (5– of product was detected when THF was employed as the solvent
10 mol %) and afforded the product as mixture of regioisomers in (Table 1, entry 4). The reaction was retarded when 1 mol % of FeCl3
most cases. Prompted by these results and our efforts for aziridine was utilized in the reaction (12 h, 48% yield, Table 1, entry 5). It is
transformation,15 we envisaged that aziridine might also be presumably due to the fact that the resulting amine product might
employed as substrate in the iron(III)-catalyzed reaction of arenes, act as a Lewis base to deactivate or inhibit the iron(III) catalyst.
due to the unique activity of iron catalyst for functionalization of Moreover, it is noteworthy that the product, which could be easily
arenes.8 generated from attacking of aziridine 5a by chloride, was not ob-
Initial studies were performed by using FeCl3 (5 mol %) as served during the reaction process. Other iron salts with different
catalyst in the reaction of N-tosyl-2-phenylaziridine 5a with forms were also screened in the reaction of aziridine 5a with arene
Table 1
Reaction of aziridine 5a and arene 1b catalyzed by iron salt at room temperaturea
OMe
OMe
Ts OMe
OMe N OMe
[Fe] NHTs
+ +
NHTs
OMe
1b 5a 6b 6b'
Table 2 OMe
Reaction of aziridine 5 and arene 1 catalyzed by FeCl3 (5 mol %) in CH3NO2 at room 16 5c 6p 50
temperaturea MeO 1e
MeO OMe O
NTs
19 5d 6s 71
1 6a 61 O 1d
5a OMe 1a a
Reaction conditions: aziridine 1 (0.5 mmol), arene 2 (0.6 mmol, 1.2 equiv), FeCl3
(5 mol %), CH3NO2 (2.0 mL), rt, <2 min.
OMe b
Isolated yield based on aziridine 1.
2 5a 6b 90
OMe 1b
electron-rich arenes, which afforded the expected product in
3 5a 6c 82
moderate to good yields (Table 2, entries 11–19).
1c Moreover, we tested other aziridines under the conditions
shown in Table 2. For instance, aziridine 5e reacted with 1,2-
O
4 5a 6d 77
dimethoxybenzene 1b leading to the formation of regioisomers 6t
O 1d and 6t0 in 70% yield (Scheme 2, Eq. 1). When N-tosyl group was
replaced by N-nosyl group, the reaction also proceeded smoothly to
OMe afford the desired product in good yield (Scheme 2, Eq. 2). However,
5 5a 6e 60
no product was detected when aziridine 7a or 7b was utilized as
MeO 1e substrate in the reaction of 1,2-dimethoxybenzene 1b, and only
(continued) starting material was recovered after 12 h at room temperature
5016 Z. Wang et al. / Tetrahedron 64 (2008) 5013–5018
(s, 2H), 7.13–7.25 (m, 7H), 7.64 (d, J¼8.2 Hz, 2H). 13C NMR (100 MHz, 21.5, 45.2, 46.6, 107.0, 110.2, 127.1, 127.5, 127.9, 128.9, 129.7, 136.9,
CDCl3) 21.4, 39.6, 45.2, 55.2, 55.4, 91.0, 108.8, 125.9, 127.0, 127.6, 138.7, 142.0, 143.5, 154.0. IR (KBr): 3298, 2919, 1597, 1321, 1155,
127.9, 129.4, 137.0, 141.8, 142.8, 159.2, 160.3. IR (KBr): 3288, 2939, 1086, 816 cm1. MS (ESI): m/z 342.0 (Mþþ1).
2837, 1609, 1325, 1152, 809 cm1. MS (ESI): m/z 442.0 (Mþþ1). Anal.
Calcd for C24H27NO5S: C, 65.28; H, 6.16; N, 3.17. Found: C, 65.40; H, 4.1.2.9. N-(2-(4-Chlorophenyl)-2-(3,4-dimethoxyphenyl)ethyl)-4-meth-
6.05; N, 3.01. ylbenzenesulfonamide (6k).14 1H NMR (400 MHz, CDCl3) 2.42 (s,
3H), 3.42–3.49 (m, 2H), 3.74 (s, 3H), 3.79 (s, 3H), 4.00 (t, J¼7.8 Hz,
4.1.2.2. N-(2-(3,4-Dimethoxyphenyl)-2-phenylethyl)-4-methylbenz- 1H), 4.96 (t, J¼6.4 Hz, 1H), 6.55 (d, J¼2.0 Hz, 1H), 6.62 (d, J¼
enesulfonamide (6b).14 1H NMR (400 MHz, CDCl3) 2.41 (s, 3H), 8.3 Hz, 1H), 6.74 (d, J¼8.3 Hz, 1H), 7.03 (d, J¼8.8 Hz, 2H), 7.17 (d,
3.45–3.53 (m, 2H), 3.74 (s, 3H), 3.81 (s, 3H), 4.02 (t, J¼7.8 Hz, 1H), J¼8.3 Hz, 2H), 7.23 (d, J¼8.3 Hz, 2H), 7.62 (d, J¼8.3 Hz, 2H). 13C NMR
4.65 (t, J¼5.9 Hz, 1H), 6.58 (s, 1H), 6.65 (d, J¼8.3 Hz, 1H), 6.74 (d, (100 MHz, CDCl3) 21.4, 47.1, 49.4, 55.6, 55.7, 111.1, 111.2, 119.6, 126.8,
J¼8.3 Hz, 1H), 7.09 (d, J¼7.3 Hz, 2H), 7.18–7.27 (m, 5H), 7.65 (d, 128.6, 129.0, 129.6, 132.5, 132.7, 136.5, 139.7, 143.4, 147.9, 149.0. IR
J¼8.3 Hz, 2H). 13C NMR (100 MHz, CDCl3) 21.3, 47.3, 50.0, 55.7, 55.8, (KBr): 3291, 2932, 1516, 1318, 1151, 1090, 817 cm1. MS (ESI): m/z
111.2, 111.3, 119.7, 126.9, 127.0, 127.7, 128.7, 129.6, 133.0, 136.7, 141.0, 446.0 (Mþþ1).
143.4, 148.0, 149.1. IR (KBr): 3265, 2935, 1593, 1324, 1152, 804 cm1.
MS (ESI): m/z 412.0 (Mþþ1). 4.1.2.10. N-(2-(Benzo[d][1,3]dioxol-5-yl)-2-(4-chlorophenyl)ethyl)-
4-methylbenzenesulfonamide (6l).14 1H NMR (400 MHz, CDCl3) 2.42
4.1.2.3. N-(2-(3,4-Dimethoxyphenyl)-1-phenylethyl)-4-methylbenz- (s, 3H), 3.38–3.48 (m, 2H), 3.96 (t, J¼7.8 Hz, 1H), 4.82 (t, J¼6.4 Hz,
enesulfonamide (6b0 ).14 1H NMR (400 MHz, CDCl3) 2.40 (s, 3H), 1H), 5.87 (s, 2H), 6.48 (d, J¼1.5 Hz, 1H), 6.54 (d, J¼8.3 Hz, 1H), 6.66
2.93–3.28 (m, 2H), 3.87 (s, 3H), 3.90 (s, 3H), 4.72 (m, 1H), 4.96 (m, (d, J¼7.8 Hz, 1H), 7.0 (d, J¼8.3 Hz, 2H), 7.17 (d, J¼8.3 Hz, 2H), 7.25 (d,
1H), 6.84 (s, 1H), 6.95–7.03 (m, 2H), 7.19–7.34 (m, 5H), 7.60–7.63 (m, J¼7.8 Hz, 2H), 7.63 (d, J¼8.3 Hz, 2H). 13C NMR (100 MHz, CDCl3)
2H), 7.72 (d, J¼8.2 Hz, 2H). IR (KBr): 3265, 2935, 1593, 1324, 1152, 21.5, 47.1, 49.6, 101.0, 108.1, 108.4, 120.9, 127.0, 128.8, 129.1, 129.7,
804 cm1. MS (ESI): m/z 412.0 (Mþþ1). 132.7, 134.1, 136.5, 139.5, 143.5, 146.6, 148.0. IR (KBr): 3279, 2878,
1593, 1489, 1320, 1153, 1096, 817 cm1. MS (ESI): m/z 430.0 (Mþþ1).
4.1.2.4. N-(2-(3,4-Dimethylphenyl)-2-phenylethyl)-4-methylbenz-
enesulfonamide (6c).14 1H NMR (400 MHz, CDCl3) 2.16 (s, 3H), 2.18 4.1.2.11. N-(2-(4-Chlorophenyl)-2-(2,5-dimethoxyphenyl)ethyl)-4-
(s, 3H), 2.41 (s, 3H), 3.45–3.54 (m, 2H), 3.98 (t, J¼7.8 Hz, 1H), 4.52 (t, methylbenzenesulfonamide (6m).14 1H NMR (400 MHz, CDCl3) 2.43
J¼5.8 Hz, 1H), 6.78–6.84 (m, 2H), 6.98–7.27 (m, 8H), 7.65 (d, (s, 3H), 3.44–3.52 (m, 2H), 3.67 (s, 3H), 3.68 (s, 3H), 4.42 (t, J¼7.8 Hz,
J¼8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3) 19.4, 19.9, 21.7, 47.4, 50.2, 1H), 4.50 (t, J¼5.9 Hz, 1H), 6.48 (d, J¼2.9 Hz, 1H), 6.69–6.76 (m, 2H),
125.3, 127.1, 127.3, 127.9, 128.9, 129.4, 129.8, 130.2, 135.6, 136.9, 7.04 (d, J¼8.3 Hz, 2H), 7.18 (d, J¼8.3 Hz, 2H), 7.25 (d, J¼8.3 Hz, 2H),
137.2, 138.1, 141.2, 143.6. IR (KBr): 3277, 2919, 1598, 1328, 1159, 1091, 7.63 (d, J¼8.3 Hz, 2H). 13C NMR (100 MHz, CDCl3) 21.4, 43.2, 46.1,
817 cm1. MS (ESI): m/z 380.0 (Mþþ1). 55.6, 55.9, 111.7, 111.8, 114.8, 127.1, 128.6, 129.4, 129.6, 129.8, 132.6,
136.7, 139.1, 143.4, 151.2, 153.6. IR (KBr): 3255, 2943, 1589, 1497,
4.1.2.5. N-(2-(Benzo[d][1,3]dioxol-5-yl)-2-phenylethyl)-4-methylbenz- 1329, 1162, 1092, 817 cm1. MS (ESI): m/z 446.0 (Mþþ1).
enesulfonamide (6d).14 1H NMR (400 MHz, CDCl3) 2.41 (s, 3H),
3.41–3.51 (m, 2H), 3.97 (t, J¼7.8 Hz, 1H), 4.70 (br, 1H), 5.84 (s, 4.1.2.12. N-(2-(3,4-Dimethoxyphenyl)-2-p-tolylethyl)-4-methylbenz-
2H), 6.51–6.57 (m, 2H), 6.65 (d, J¼7.8 Hz, 1H), 7.06 (d, J¼7.3 Hz, 2H), enesulfonamide (6n).14 1H NMR (400 MHz, CDCl3) 2.27 (s, 3H), 2.40
7.15–7.26 (m, 5H), 7.65 (d, J¼8.3 Hz, 2H). 13C NMR (100 MHz, CDCl3) (s, 3H), 3.43–3.49 (m, 2H), 3.74 (s, 3H), 3.79 (s, 3H), 3.98 (t, J¼7.8 Hz,
21.5, 47.2, 50.1, 100.9, 108.2, 108.3, 120.9, 126.9, 127.0, 127.6, 128.7, 1H), 4.68 (t, J¼5.8 Hz, 1H), 6.59 (s, 1H), 6.64 (d, J¼7.8 Hz, 1H), 6.73 (d,
129.6, 134.5, 136.6, 140.8, 143.4, 146.4, 147.9. IR (KBr): 3277, 2914, J¼8.3 Hz, 1H), 6.97 (d, J¼7.8 Hz, 2H), 7.04 (d, J¼7.8 Hz, 2H), 7.25 (d,
1599, 1325, 1147, 1091, 819 cm1. MS (ESI): m/z 396.0 (Mþþ1). J¼8.3 Hz, 2H), 7.64 (d, J¼8.3 Hz, 2H). 13C NMR (100 MHz, CDCl3) 20.9,
21.4, 47.3, 49.6, 55.6, 55.7, 111.1, 111.2, 119.6, 127.0, 127.5, 129.3, 129.6,
4.1.2.6. N-(2-(2,4-Dimethoxyphenyl)-2-phenylethyl)-4-methylbenz- 133.3, 136.5, 136.6, 137.9, 143.3, 147.8, 149.0. IR (KBr): 3294, 2929,
enesulfonamide (6e).14 1H NMR (400 MHz, CDCl3) 2.41 (s, 3H), 3.44– 1593, 1514, 1331, 1155, 1086, 810 cm1. MS (ESI): m/z 426.0 (Mþþ1).
3.55 (m, 2H), 3.65 (s, 3H), 3.67 (s, 3H), 4.46 (t, J¼7.8 Hz, 1H), 4.56 (t,
J¼5.9 Hz, 1H), 6.51 (d, J¼3.0 Hz, 1H), 6.66–6.75 (m, 2H), 7.09 (d, 4.1.2.13. N-(2-(Benzo[d][1,3]dioxol-5-yl)-2-p-tolylethyl)-4-methyl-
J¼6.9 Hz, 2H), 7.15–7.27 (m, 5H), 7.64 (d, J¼7.8 Hz, 2H). 13C NMR benzenesulfonamide (6o). 1H NMR (400 MHz, CDCl3) 2.29 (s, 3H),
(100 MHz, CDCl3) 21.5, 43.5, 46.2, 55.4, 55.9, 111.5, 111.7, 114.9, 126.8, 2.44 (s, 3H), 3.45–3.47 (m, 2H), 3.92 (t, J¼7.8 Hz, 1H), 4.28 (t,
127.0, 128.0, 128.5, 129.5, 130.3, 136.7, 140.3, 143.2, 151.2, 153.5. IR J¼5.8 Hz, 1H), 5.90 (s, 2H), 6.51–6.53 (m, 2H), 6.69 (d, J¼7.8 Hz, 1H),
(KBr): 3293, 2934, 1597, 1495, 1328, 1159, 1052, 813 cm1. MS (ESI): 6.95 (d, J¼8.2 Hz, 2H), 7.04 (d, J¼8.2 Hz, 2H), 7.30 (d, J¼8.2 Hz, 2H),
m/z 412.0 (Mþþ1). 7.68 (d, J¼8.2 Hz, 2H). 13C NMR (100 MHz, CDCl3) 20.9, 21.5, 47.2,
49.7, 101.0, 108.1, 108.3, 120.8, 127.0, 127.5, 129.4. 129.6, 134.7, 136.6,
4.1.2.7. N-(2-(4-Methoxyphenyl)-2-phenylethyl)-4-methylbenzene- 136.7, 137.7, 143.4, 146.4, 147.9. IR (KBr): 3288, 2914, 1588, 1490,
sulfonamide (6f).14 1H NMR (400 MHz, CDCl3) 2.43 (s, 3H), 3.46– 1321, 1147, 1086, 815 cm1. MS (ESI): m/z 410.0 (Mþþ1). Anal. Calcd
3.52 (m, 2H), 3.75 (s, 3H), 4.0 (t, J¼7.8 Hz, 1H), 4.43 (t, J¼5.8 Hz, 1H), for C23H23NO4S: C, 67.46; H, 5.66; N, 3.42. Found: C, 67.35; H, 5.81;
6.78 (d, J¼8.3 Hz, 2H), 7.0 (d, J¼8.8 Hz, 2H), 7.07 (d, J¼6.8 Hz, 2H), N, 3.53.
7.18–7.29 (m, 5H), 7.66 (d, J¼7.8 Hz, 2H). 13C NMR (100 MHz, CDCl3)
21.5, 47.3, 49.7, 55.2, 114.2, 126.9, 127.1, 127.8, 128.8, 128.9, 129.7, 4.1.2.14. N-(2-(2,5-Dimethoxyphenyl)-2-p-tolylethyl)-4-methylbenz-
132.6, 136.7, 141.1, 143.5, 158.5. IR (KBr): 3277, 2926, 1610, 1512, enesulfonamide (6p).14 1H NMR (400 MHz, CDCl3) 2.28 (s, 3H), 2.43
1326, 1156, 818 cm1. MS (ESI): m/z 382.0 (Mþþ1). (s, 3H), 3.43–3.53 (m, 2H), 3.66 (s, 3H), 3.68 (s, 3H), 4.12 (t, J¼7.8 Hz,
1H), 4.48 (s, 1H), 6.49 (d, J¼2.9 Hz, 1H), 6.66–6.74 (m, 2H), 6.98 (d,
4.1.2.8. N-(2-(Furan-2-yl)-2-phenylethyl)-4-methylbenzenesulfona- J¼8.3 Hz, 2H), 7.04 (d, J¼7.8 Hz, 2H), 7.25 (d, J¼7.8 Hz, 2H), 7.64 (d,
mide (6h).18 1H NMR (400 MHz, CDCl3) 2.43 (s, 3H), 3.37–3.43 (m, J¼7.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) 20.9, 21.5, 43.1, 46.3, 55.5,
1H), 3.54–3.61 (m, 1H), 4.09 (t, J¼7.6 Hz, 1H), 4.51 (t, J¼6.4 Hz, 1H), 55.9, 111.4, 111.7, 114.9, 127.1, 128.0, 129.3, 129.6, 130.5, 136.5, 136.8,
6.00 (d, J¼2.8 Hz, 1H), 6.27 (d, J¼3.2 Hz, 1H), 7.11 (d, J¼6.4 Hz, 2H), 137.2, 143.2, 151.3, 153.6. IR (KBr): 3288, 2929, 1593, 1495, 1321,
7.24–7.31 (m, 6H), 7.68 (d, J¼8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) 1158, 1086, 819 cm1. MS (ESI): m/z 426.0 (Mþþ1).
5018 Z. Wang et al. / Tetrahedron 64 (2008) 5013–5018
4.1.2.15. N-(2-(4-Fluorophenyl)-2-(2,4,6-trimethoxyphenyl)ethyl)- 443.0 (Mþþ1). Anal. Calcd for C22H22N2O6S: C, 59.72; H, 5.01; N,
4-methylbenzenesulfonamide (6q). 1H NMR (400 MHz, CDCl3) 2.42 6.33. Found: C, 60.07; H, 5.05; N, 6.41.
(s, 3H), 3.61 (s, 6H), 3.65–3.71 (m, 2H), 3.78 (s, 3H), 4.39–4.41 (m,
1H), 4.62 (d, J¼8.3 Hz, 1H), 6.04 (s, 2H), 6.85 (d, J¼8.7 Hz, 2H), 7.08– Acknowledgements
7.11 (m, 2H), 7.25 (d, J¼7.8 Hz, 2H), 7.64 (d, J¼7.8 Hz, 2H). 13C NMR
(100 MHz, CDCl3) 21.4, 38.9, 45.2, 55.2, 55.4, 90.9, 108.6, 114.5, 114.7, We thank Dr. Renhua Fan for his invaluable advice during the
127.0, 129.1, 129.2, 129.4, 136.9, 137.4, 142.9, 159.0, 160.3. IR (KBr): course of this research. Financial support from National Natural
3334, 2939, 2841, 1604, 1329, 1157, 815 cm1. MS (ESI): m/z 460.0 Science Foundation of China (20772018), Shanghai Pujiang Pro-
(Mþþ1). Anal. Calcd for C24H26FNO5S: C, 62.73; H, 5.70; N, 3.05. gram, and Program for New Century Excellent Talents in University
Found: C, 62.90; H, 5.96; N, 3.01. (NCET-07-0208) is gratefully acknowledged.