Chiral Functionalised Cyclobutylpyrrolidines and Cyclobutylamino Alcohols
33.6 (CH), 32.1 (CH3), 23.8 (CH3), 23.5 (CH2), 21.4 (CH3), 16.7 (3ϫCH3), 23.9 (CH3), 23.8 (CH2), 17.1 (CH3) ppm. HRMS (ESI-
(CH3) ppm. HRMS (ESI-TOF): calcd. for C21H33NNaO5S [M + TOF): calcd. for C19H33NNaO4 [M + Na]+ 362.2302; found
Na]+ 434.1972; found 434.1968.
362.2304.
(3S,1ЈR,3ЈR)-3-{2Ј,2Ј-Dimethyl-3Ј-(2ЈЈ-methyl[1ЈЈ,3ЈЈ]dioxolan-2ЈЈ-
yl)cyclobutyl}-N-tosylpyrrolidine (9): Triphenylphosphine (144 mg,
0.55 mmol) was added to a stirred solution of 8 (150 mg,
0.36 mmol) in anhydrous THF (12 mL) under a nitrogen atmo-
sphere. The mixture was cooled to 0 °C, and diisopropyl azodicarb-
oxylate (0.11 mL, 0.55 mmol) was added dropwise. After the ad-
dition, the ice bath was removed, and reaction was warmed to room
temperature and stirred overnight. The mixture was concentrated
and poured into cold ether to precipitate most of the triphenyl-
phosphine oxide. After filtration, the ether solution was evaporated
to dryness, and the crude product was chromatographed (CH2Cl2)
to afford 9, which was crystallised in diethyl ether/pentane (136 mg,
97% yield). White powder, m.p. 62–64 °C (diethyl ether/pentane).
(3S,1ЈR,3ЈR)-3-[2Ј,2Ј-Dimethyl-3Ј-(2ЈЈ-methyl-[1ЈЈ,3ЈЈ]-dioxolan-2ЈЈ-
yl)cyclobutyl]-N-methylpyrrolidine (13) through Boron Complex 12:
To 11[22] (240 mg, 0.9 mmol) in anhydrous THF (15 mL) at 0 °C,
1 m B2H6 in THF was added dropwise (3.6 mL, 3.6 mmol), and the
mixture was stirred for 18 h (from 0 °C to room temperature) under
a nitrogen atmosphere. MeOH was added dropwise (5 mL) until no
bubbling was observed. The intermediate boron complex 12 crys-
tallised and was characterised. White solid, m.p. 88–89 °C (CH2Cl2/
pentane). IR (ATR): ν = 2990, 2961, 2888, 2363, 2315, 1453, 1371,
˜
1247, 1226, 1180, 1165, 1078, 1035, 947, 861 cm–1 1H NMR
.
(CDCl3, 250 MHz): δ = 3.75–4.13 (complex signal,4 H, 2ϫCH2),
3.22–3.34 (complex signal, 2 H, CH2), 2.70 (s, 3 H, CH3), 2.57–
2.81 (complex signal, 2 H, CH2), 2.18–2.33 (complex signal, 2 H,
CH2), 2.10 (dd, J = 10.7 Hz, JЈ = 7.5 Hz, 1 H, CH), 1.72–1.84 (m,
1 H, CH), 1.43–1.68 (complex signal, 3 H, CH and CH2), 1.22 (s,
3 H, CH3), 1.15 (s, 3 H, CH3), 1.09 (s, 3 H, CH3) ppm. 13C NMR
(CDCl3, 90 MHz): δ = 109.7 (C), 67.7 (CH2), 65.5 (CH2), 63.7
(CH2), 63.0 (CH2), 53.2 (CH3), 49.6 (CH), 47.8 (CH), 41.2 (C),
39.1 (CH), 32.0 (CH3), 29.2 (CH2), 23.7 (CH3), 23.4 (CH2), 17.5
(CH3) ppm. C15H30NO2B (267.22): calcd. C 67.42, H 11.32, N 5.24;
found C 67.01, H 11.46, N 5.18.
[α]2D5 = +7 (c = 0.92, CH Cl ). IR (ATR): ν = 2953, 2877, 1344,
˜
2
2
1
1161 cm–1. H NMR (CDCl3, 250 MHz): δ = 7.73 (d, J = 8.3 Hz,
2 H, 2ϫCH), 7.35 (d, J = 8.3 Hz, 2 H, 2ϫCH), 3.78–4.05 (com-
plex signal, 4 H, 2ϫCH2), 3.18–3.39 (complex signal, 3 H, CH2
and CH2), 2.75 (dd, J = 9.7, JЈ = 7.5 Hz, 1 H, CH2), 2.47 (s, 3 H,
CH3), 2.1 (m, 2 H, 2ϫCH), 1.82 (complex signal, 2 H, CH2), 1.38–
1.51 (complex signal, 3 H, CH2 and CH2), 1.22 (s, 3 H, CH3), 1.06
(s, 3 H, CH3), 1.02 (s, 3 H, CH3) ppm. 13C NMR (CDCl3,
62.5 MHz): δ = 143.5 (CH), 133.9 (CH), 129.7 (CH), 127.4 (CH),
109.9 (C), 65.7 (CH2), 63.7 (CH2), 51.7 (CH2), 49.6 (CH2), 47.8
(CH), 45.8 (CH), 41.1 (CH2), 40.1 (CH), 31.9 (C), 30.5 (CH3), 23.7
(CH3), 23.6 (CH2), 21.5 (CH3), 17.1 (CH3) ppm. HRMS (ESI-
TOF): calcd. for C21H31NNaO4S [M + Na]+ 416.1866; found
416.1878.
Additional MeOH was added (50 mL), and the mixture was heated
to reflux for 24 h to break the N–BH3 bond formed during the
reduction of the carbonyl group. The solvents were evaporated to
dryness, and the residue was purified by flash chromatography with
silica gel (EtOAc to CH2Cl2/MeOH 9:1) to afford the pyrrolidine
13 (145 mg, 64% yield). Colourless oil. [α]2D5 = –10.9 (c = 1.4,
tert-Butyl (3S,1ЈR,3ЈR)-3-{2Ј,2Ј-Dimethyl-3Ј-(2ЈЈ-methyl-[1ЈЈ,3ЈЈ]-di-
oxolan-2ЈЈ-yl)cyclobutyl}pyrrolidine-1-carboxylate (10): To a solu-
tion of naphthalene (876 mg, 6.8 mmol) in anhydrous THF
(20 mL) was added freshly cut sodium (154 mg, 6.8 mmol), and the
resulting blue-green solution was stirred at room temperature for
2 h to give a sodium naphthalenide solution. To a solution of 9
(150 mg, 0.37 mmol) in anhydrous THF (20 mL) at –80 °C was
added sodium naphthalenide solution (1.6 mL, 0.55 mmol) under a
nitrogen atmosphere. The mixture was stirred for 1 h, more sodium
naphthalenide solution was added (1.6 mL, 0.55 mmol) at the same
temperature, and the mixture was stirred for another 1 h. A satu-
rated aqueous solution of NaHCO3 (2 mL) was added, and the
solution was warmed to room temperature and stirred for 18 h.
The mixture was filtered with the aid of CH2Cl2 (20 mL) and con-
centrated under vacuum to dryness. The crude amine was dissolved
in CH2Cl2 (15 mL) and to the resulting solution, triethylamine
(0.6 mL, 0.37 mmol), Boc2O (0.2 mL, 0.37 mmol) and DMAP
(25 mg, 0.18 mmol) were added. The mixture was stirred overnight.
The reaction was quenched with a saturated aqueous solution of
NaHCO3 (10 mL) and extracted with CH2Cl2 (3ϫ 15 mL). The
combined organic extracts were dried with MgSO4, and the sol-
vents were evaporated to dryness. The crude residue was purified
by column chromatography (EtOAc/hexane 3:1) to afford 10
(90 mg, 72% yield, two steps). Colourless oil. [α]2D5 = +8 (c = 1.1,
CH Cl ). IR (ATR): ν = 2949, 2873, 2767, 1449, 1367, 1250,
˜
2
2
1153 cm–1. H NMR (CDCl3, 360 MHz): δ = 3.79–4.01 (complex
signal, 4 H, 2ϫCH2), 2.44–2.66 (complex signal, 3 H, CH2 and
CH2), 2.35 (s, 3 H, CH3), 2.08–2.26 (complex signal, 2 H, CH and
CH2), 2.07 (dd, J = 11.2 Hz, JЈ = 7.6 Hz, 1 H, CH), 1.85 (dt, J =
9.7, JЈ = 7.6 Hz, 1 H, CH2), 1.82 (m, 1 H, CH), 1.71 (dt, J =
10.4 Hz, JЈ = 7.6 Hz, 1 H, CH2), 1.48 (m, 1 H, CH2), 1.36–1.45
(m, 1 H, CH2), 1.23 (s, 3 H, CH3), 1.14 (s, 3 H, CH3), 1.05 (s, 3 H,
CH3) ppm. 13C NMR (CDCl3, 90 MHz): δ = 110.4 (C), 65.9 (CH2),
64.1 (CH2), 61.2 (CH2), 56.9 (CH2), 49.7 (CH), 48.5 (CH), 42.8
(CH3), 40.2 (C), 39.7 (CH), 32.5 (CH3), 30.6 (CH2), 24.5 (CH2),
24.2 (CH3), 17.9 (CH3) ppm. HRMS (ESI-TOF): calcd. for
C15H28NO2 [M + H]+ 254.2115; found 254.2112.
1
(1ЈR,3ЈR,3ЈЈS)-3Ј-[2Ј,2Ј-Dimethyl-3Ј-(1ЈЈ-isopropylpyrrolidin-3ЈЈ-yl)-
cyclobutyl]methanol (15): A 1 m solution of LiBEt3H in THF
(10.5 mL, 10.5 mmol) was added to a solution of ester 14[8]
(380 mg, 1.42 mmol) in anhydrous THF (50 mL). The mixture was
heated to reflux under a nitrogen atmosphere for 18 h. The excess
hydride was eliminated by the slow addition of methanol (5 mL),
and then water (30 mL) was added. The resultant solution was ex-
tracted with dichloromethane (3ϫ 30 mL), and the combined ex-
tracts were dried with MgSO4. The solvents were removed under
CH Cl ). IR (ATR): ν = 2954, 2973, 1693, 1402, 1167 cm–1. 1H reduced pressure, and the residue was chromatographed (CH2Cl2/
˜
2
2
NMR (CDCl3, 250 MHz): δ = 3.86–4.16 (complex signal, 4 H,
MeOH, 20:1) to provide alcohol 15 as a colourless oil (250 mg,
2ϫCH2), 3.34 (m, 2 H, CH2), 3.26 (m, 1 H, CH2), 2.83 (m, 1 H, 78% yield). [α]D = –9 (c = 3, CH Cl ). IR (ATR): ν = 3377, 2968,
˜
2
2
CH), 2.11 (m, 2 H, CH and CH2), 1.93 (s, 3 H, CH3), 1.87 (m, 2 1461, 1366, 1011 cm–1. 1H NMR (360 MHz, CDCl3, 25 °C): δ =
H, 2ϫCH2), 1.62 (m, 2 H, CH and CH2), 1.47 (s, 10 H, CH2 and 0.95 (s, 3 H, CH3), 1.06 (d, J = 4 Hz, 3 H, CH3), 1.06 (d, 3J =
3ϫCH3), 1.24 (s, 3 H, CH3), 1.14 (s, 3 H, CH3), 1.10 (s, 3 H, CH3) 4 Hz, 3 H, CH3), 1.11 (s, 3 H, CH3), 1.27 (complex signal, 2 H,
ppm. 13C NMR (CDCl3, 62.5 MHz): δ = 154.8 (C), 109.8 (C), 78.9
CH2 and CH),1.71 (m, 1 H, CH2), 1.94 (complex signal, 3 H, CH2
(C), 65.7 (CH2), 63.7 (CH2), 51.0 (CH), 49.6 (CH2), 45.8 (CH2), and CH), 2.07 (m, 1 H, CH), 2.26 (m, 1 H, CH2), 2.42 (complex
41.2 (CH2), 41.0 (CH), 31.8 (CH3), 31.2 (C), 30.1 (CH2), 28.6 signal, 2 H, CH2 and CH), 2.79 (complex signal, 3 H, CH2 and
Eur. J. Org. Chem. 2015, 810–819
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
817