LETTER
Macrocycles: Construction, Chemistry and Nanotechnology
Macrocyclic Cyclophane Derivatives
2187
1 H), 4.12 (q, J = 7.1 Hz, 4 H), 4.88–4.97 (m, 2 H), 5.66–
5.70 (m, 1 H). 13C NMR (100 MHz, CDCl3): δ = 13.90,
26.38, 28.02, 33.14, 51.69, 61.05, 114.83, 137.77, 169.23.
IR (neat): 2929, 2859, 1741, 1640, 1464, 1368, 1183 cm–1.
HRMS (Q-Tof): m/z [M + Na] calcd for C12H20O4Na:
251.1259; found: 251.1265.
Applications; John Wiley and Sons Ltd: Chichester, 2011.
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Alkylation of Ethyl Acetoacetate; General Procedure: In
a 100 mL round-bottomed flask equipped with a nitrogen gas
inlet, ethyl acetoacetate 4 (1 equiv) was added dropwise at
r.t. to K2CO3 (4 equiv) in acetonitrile and the mixture was
stirred for 1 h. Bromide 5c (1.1 equiv) was added and the
reaction mixture was stirred at r.t. for 12 h under a nitrogen
atmosphere. At the conclusion of the reaction (TLC
monitoring), the crude mixture was filtered through a Celite
pad and extracted with diethyl ether. The organic layer was
washed with brine and dried with Na2SO4 and concentrated
under reduced pressure. The crude product was purified by
column chromatography (silica gel; EtOAc–petroleum
ether, 4%) to afford alkylated ethyl acetoacetate derivative
8c (68%) as a liquid. 1H NMR (400 MHz, CDCl3): δ = 1.28
(t, J = 7.2 Hz, 3 H), 1.32–1.44 (m, 2 H), 1.80–1.92 (m, 2 H),
2.00–2.10 (m, 2 H), 2.22 (s, 3 H), 3.41 (t, J = 7.4 Hz, 1 H),
4.19 (q, J = 7.2 Hz, 2 H), 4.94–5.04 (m, 2 H), 5.72–5.82 (m,
1 H). 13C NMR (100 MHz, CDCl3): δ = 14.16, 26.64, 27.62,
28.82, 33.41, 59.77, 61.37, 115.13, 137.96, 169.88, 203.24.
IR (neat): 2991, 2934, 1742, 1716, 1641, 1448, 1360,
1216 cm–1. HRMS (Q-Tof): m/z [M + H] calcd for C11H19O3:
199.1334; found: 199.1334.
General Procedure for 10c: To a suspension of NaH
(3 equiv) in THF was added alkylated malonate ester 6c
(1 equiv) dropwise at 0 °C. The reaction mixture was
warmed to r.t. and stirred for 1 h. Dibromide 1 (0.5 equiv)
was added and the reaction mixture was stirred at r.t. for 12
h under nitrogen. The organic layer was washed with brine,
dried with Na2SO4, and concentrated under reduced
pressure. The crude product was purified by column
chromatography (silica gel; EtOAc–petroleum ether, 8%) to
afford bis-alkene malonate derivative 10c (65%) as a white
solid material. Mp 60–65 °C. 1H NMR (400 MHz, CDCl3):
δ = 1.22 (t, J = 7.1 Hz, 12 H), 1.34–1.41 (m, 4 H), 1.70–1.74
(m, 4 H), 1.99 (q, J = 7.1 Hz, 4 H), 3.24 (s, 4 H), 3.64 (s,
6 H), 4.08–4.23 (m, 8 H), 4.89–5.00 (m, 4 H), 5.70–5.81 (m,
2 H), 6.52 (s, 2 H). 13C NMR (100 MHz, CDCl3): δ = 14.21,
23.87, 31.73, 31.97, 34.18, 55.68, 58.72, 61.13, 114.04,
114.76, 124.20, 138.52, 151.87, 171.76. IR (neat): 3054,
2989, 1729, 1641, 1422, 1266 cm–1. HRMS (Q-Tof): m/z [M
+ H] calcd for C34H51O10: 619.3482; found: 619.3499.
General Procedure for 11c: To a suspension of NaH
(3 equiv) in THF was added alkylated malonate ester 6c
(1 equiv) dropwise at 0 °C. The reaction mixture was
warmed to r.t. and stirred for 1 h. p-Xylylene dibromide 2
(0.5 equiv) was added and the reaction mixture was stirred at
r.t. for 12 h under nitrogen. At the conclusion of the reaction
(TLC monitoring), the reaction was quenched with H2O and
extracted with diethyl ether. The organic layer was washed
with brine, dried with Na2SO4, and concentrated under
reduced pressure. The crude product was purified by column
chromatography (silica gel; EtOAc–petroleum ether, 8%) to
afford bis-alkene malonate ester derivative 11c (62%) as a
white solid material. Mp 60–65 °C. 1H NMR (400 MHz,
CDCl3): δ = 1.23 (t, J = 7.2 Hz, 12 H), 1.34–1.40 (m, 4 H),
1.73–1.77 (m, 4 H), 2.04 (q, J = 7.2 Hz, 4 H), 3.19 (s, 4 H),
4.10–4.22 (m, 8 H), 4.97–5.03 (m, 4 H), 5.78–5.80 (m, 2 H),
6.95 (s, 4 H). 13C NMR (100 MHz, CDCl3): δ = 14.22, 23.72,
31.54, 33.90, 37.87, 58.90, 61.33, 115.16, 129.92, 134.97,
138.21, 171.45. IR (neat): 3054, 2989, 1729, 1641, 1422,
1266 cm–1. HRMS (Q-Tof): m/z [M + H] calcd for C32H47O8:
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(17) We have determined the E/Z ratio of RCM products 16–19
(Figure 2), based on 1H NMR spectral data. In most of the
cases, we observed E-configured compounds as the major
product; this assumption was based on our earlier experience
on cyclophane derivatives. See reference 11i.
(18) Alkene Derivatives of Malonate Ester; General
Procedure: To a suspension of NaH (3 equiv) in THF was
added 3 (1 equiv) dropwise at 0 °C. The reaction mixture
was warmed to r.t. and stirred for 1 h. Bromide 5c (1.1 equiv)
was added and the reaction mixture was stirred at r.t. for
12 h under nitrogen. At the conclusion of the reaction (TLC
monitoring), the reaction mixture was quenched with H2O
and extracted with diethyl ether. The organic layer was
washed with brine, dried with Na2SO4, and concentrated
under reduced pressure. The crude product was purified by
column chromatography (silica gel; EtOAc–petroleum
ether, 4%) to afford 6c (67%) as a liquid. 1H NMR (400
MHz, CDCl3): δ = 1.18–1.22 (m, 6 H), 1.35–1.40 (m, 2 H),
1.81–1.90 (m, 2 H), 2.01–2.05 (m, 2 H), 3.26 (t, J = 7.2 Hz,
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2183–2188