Y. Takemoto et al.
9.5 mg) in toluene (0.4 mL) was stirred at room temperature for 24 h.
Without any other manipulation, the reaction mixture was purified by
silica gel column chromatography with hexane/EtOAc (95:5!9:1!4:1)
to afford desired product 9 (59.2 mg, 83%). 1H NMR (CDCl3, 400 MHz)
d=7.34–7.23 (m, 5H), 4.95–4.83 (m, 2H), 4.27–4.18 (m, 3H), 4.01 (q, J=
7.08 Hz), 3.82 (d, J=9.28 Hz), 1.26 (t, J=7.08 Hz), 1.05 ppm (t, J=
7.08 Hz); HPLC: Chiralcel AD-H, hexane/EtOH 9:1, 1 mLminꢀ1
254 nm, retention times: 11.7 min (major), 15.5 min (minor).
,
Typical procedure for enantioselective amination reaction: Compound
11a (46.7 mg, 1.1 equiv) and quinazoline-4-one catalyst 2b (6.2 mg, 10
mol%) were added to a stirred solution of di-tert-butylazodicarboxylate
(47.8 mg, 0.21 mmol) in toluene (2.0 mL) at room temperature. After 5 h,
the reaction mixture was purified by silica gel column chromatography
with hexane/EtOAc (9:1!1:1) to afford desired 11a (83.5 mg, 97%) as a
Scheme 7. Tandem isomerization: [3+2] cycloaddition.
the synthesis of more advanced compounds. Mechanistic
studies regarding these novel catalysts are currently under-
way.
1
white solid. H NMR (CDCl3, 500 MHz) d=7.89–7.70 (br, 1H), 7.49–7.29
(br, 1H), 7.25–7.01 (br, 2H), 6.31 (brs, 1H), 3.72 (s, 3H), 3.50–3.08 (br,
1H), 3.08–2.75 (br, 1H), 2.74–2.43 (br, 1H), 1.38–0.79 ppm (m, 18H);
HPLC: Chiralcel OD-H, hexane/isopropanol=95:5, 0.5 mLminꢀ1
,
254 nm, retention times: 15.5 min (major), 18.2 min (minor).
Experimental Section
Typical procedures for preparation of alkynyl esters: tert-Butyl diazoace-
tate (855 mg, 6.01 mmol) was added slowly to a mixture of phenylacety-
lene (614 mg, 6.01 mmol), MeCN (5.0 mL), and CuI (619 mg, 3.25 mmol)
at room temperature and stirred at the same temperature for 13 h under
an argon atmosphere. The reaction mixture was concentrated in vacuo
and purified by silica gel column chromatography with hexane/chloro-
form=7:3 to afford desired product as yellow oil (910 mg, 70% with cor-
responding allenoate 13a as inseparable minor product (5%)). The alle-
noate 13a could be removed by a known procedure.[19] tert-Butyl-4-phe-
nylbut-3-ynoate (12a): yellow oil; 1H NMR (CDCl3, 400 MHz) d=7.47–
7.40 (m, 2H), 7.32–7.21 (m, 3H), 3.41 (s, 2H), 1.49 ppm (s, 9H);
13C NMR (CDCl3, 100 MHz) d=167.4, 131.7, 128.2, 128.1, 123.2, 83.3,
81.9, 81.8, 27.9, 27.8 ppm; HPLC: Chiralpak IC, hexane/isopropanol 98:2,
0.5 mLminꢀ1, 254 nm, retention time: 12.6 min.
Typical procedure for the synthesis of the quinazoline catalyst: Com-
pound 5a (393 mg, 2.18 mmol) was added to a mixture of N1,N1-dime-
thylcyclohexanediamine (282 mg, 1.98 mmol) and triethylamine (0.3 mL,
2.14 mmol) in isoamylalcohol (4.0 mL) and stirred at 1308C for 13 h.
Then, the reaction mixture was extracted with CHCl3 three times. The
extract was dried over K2CO3 and purified by silica gel column chroma-
tography (EtOAc/MeOH/triethylamine 97:0:3 to 80:15:5) to afford qui-
nazoline 2a (yellow amorphous, 537 mg, 88%). [a]2D5 =ꢀ30 (c=0.93 in
1
CHCl3); H NMR (CDCl3, 400 MHz) d=8.10 (dd, J1 =7.9 Hz, J2 =1.4 Hz,
1H), 7.52 (ddd, J1 =J2 =7.9 Hz, J3 =1.4 Hz, 1H), 7.22 (d, J=7.9 Hz, 1H),
7.12 (dd, J1 =J2 =7.9 Hz, 1H), 3.69–3.57 (m, 1H), 2.52 (ddd, J1 =J2 =
10.3 Hz, J3 =2.9 Hz, 1H), 2.45–2.32 (m, 1H), 2.36 (s, 6H), 1.96–1.87 (m,
1H), 1.87–1.69 (m, 2H), 1.52–1.16 ppm (m, 4H); 13C NMR ((CD3)2CO
,
Typical procedure for enantioselective isomerization of alkynyl esters or
126 MHz) d=165.5, 153.3, 150.7, 134.6, 127.1, 124.1, 122.5, 118.7, 67.5,
amides to allenes:
A solution of tert-butylalkynoate (12a; 67.0 mg,
53.0, 40.4, 33.7, 25.8, 25.4, 22.7 ppm; IR (KBr) n˜ =3254, 1679, 1606 cmꢀ1
;
0.32 mmol) and benzothiadiazine catalyst 3a (2.1 mg, 0.0065 mmol) in
THF (3.0 mL) was stirred at 258C for 24 h. The resulting mixture was di-
rectly purified by silica gel column chromatography to afford a mixture
of corresponding allenoate 13a and alkynoate 12a (69.2 mg, 98%, 13a/
12a 64:36). The ratio of allenoate/alkynoate was determined by the inte-
LRMS (FAB+): m/z: 287 [M+H+] (100); HRMS (FAB+): m/z: calcd for
[C16H23N4O]+: 287.1872; found: 287.1881.
Typical procedure for the synthesis of the benzothiadiazine catalyst:
ClSO2NCO (1.17 mL, 13.4 mmol) was added to a solution of 6a (1.04 g,
11.2 mmol) was added at ꢀ408C and stirred at room temperature. After
30 min, AlCl3 (2.00 g, 15.0 mmol) was added and stirred at 1108C for
30 min. Then the reaction mixture was poured into ice water, and the re-
sulting brown precipitate was washed with water. This crude product was
used without further purification. 2,6-Lutidine (0.507 mL, 4.35 mmol) was
added to a mixture of the crude solids and POCl3 (5.10 mL, 54.4 mmol)
at room temperature and stirred at 1108C for 12 h. Then the reaction
mixture was cooled to 08C, quenched with water, and the resulting
brown precipitate was washed with water. This crude product was used
without further purification. N1,N1-dimethylcyclohexanediamine (498 mg,
3.50 mmol) and triethylamine (0.488 mL, 3.50 mmol) were added to a so-
lution of the crude solids in isoamylalcohol (15 mL) and stirred at 1308C
for 24 h. Then the reaction mixture was evaporated in vacuo, extracted
with CHCl3 three times, dried over Na2SO4, and evaporated in vacuo.
The resulting residue was purified by silica gel column chromatography
(CHCl3/MeOH/30% NH3 (aq)=85:15:1) to afford benzothiadiazine 3a
(white solid, 866 mg, 24% from 6a). M.p. 222–2238C (hexane/ethyl ace-
tate); [a]2D5 = +32.6 (c=0.97, CHCl3). 1H NMR (CDCl3, 400 MHz) d=
7.88 (d, J=7.80 Hz, 1H), 7.42 (dd, J1 =J2 =7.80 Hz, 1H), 7.22 (dd, J1 =
J2 =7.80 Hz, 1H), 6.91 (d, J=7.80 Hz, 1H), 6.19–4.96 (br, 1H), 3.60–3.40
(m, 1H), 2.48–2.19 (m, 1H), 2.34 (s, 6H), 1.96–1.85 (m, 1H), 1.85–1.77
(m, 1H), 1.77–1.64 (m, 1H), 1.33–1.06 ppm (m, 4H); 13C NMR (CDCl3,
126 MHz) d=151.8, 136.1, 132.5, 124.0, 123.6, 122.1, 116.7, 67.0, 52.5,
40.2, 32.9, 24.6, 24.4, 22.1 ppm; IR (ATR) n˜ =3292, 1626, 1583, 1500,
1
gration values of H NMR spectroscopy. The absolute configuration of al-
lenes were determined by the Lowe–Brewster rule.[20] (S)-tert-Butyl-4-
phenylbuta-2,3-dienoate (13a): Yellow oil; 1H NMR (CDCl3, 400 MHz)
d=7.37–7.19 (m, 5H), 6.54 (d, J=6.4 Hz, 1H), 5.92 (d, J=6.4 Hz, 1H),
1.48 ppm (s, 9H); HPLC: Chiralpak IC, hexane/isopropanol=98:2,
0.5 mLminꢀ1
(minor), 98% ee.
, 254 nm, retention times: 10.8 min (major), 13.6 min
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Research (B)
(Y.T.), a Grant-in-Aid for Young Scientists (start-up) (21890112) (T.I.),
and the “Targeted Proteins Research Program” from the Ministry of
Education, Culture, Sports, Science and Technology. We thank Prof.
Takasu for determining the X-ray crystal structure of 3c.
sel, H. Grçger, Asymmetric Organocatalysis: From Biomimetic Con-
cepts to Applications in Asymmetric Synthesis, Wiley-VCH, Wein-
1257, 1153 cmꢀ1 LRMS (FAB+): m/z: 323 [M+H+] (100); HRMS
;
(FAB+): m/z: calcd for [C15H23N4O2S]+: 323.1536; found: 323.1544.
Typical procedure for enantioselective Michael addition of malonate to
nitroolefin: A mixture of trans-b-nitrostylene 8 (34.3 mg, 0.23 mmol), di-
ethyl malonate (2.0 equiv, 0.065 mL), and thiourea catalyst 1a (10 mol%,
10476
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 10470 – 10477