22a (1.32 cm3, 11.393 mmol) in CH2Cl2 (1◦1 cm3) was then added
via syringe. The reaction was stirred at 0 C for 30 min and left
to stir at ambient temperature overnight. NaOH (2.0 M) was
added to increase the pH to 12. The organic layer was removed
and the aqueous phase extracted further with CH2Cl2 (4 ¥
20 cm3). The organic extracts were combined, dried (MgSO4) and
concentrated in vacuo. Purification by column chromatography
(7 : 3 CH2Cl2–hexane, Rf 0.2) yielded 23a (2.296 g, 87%) as a
crude reaction was filtered under a stream of Ar to remove the
molecular sieves. Removal of the solvent of the filtrate in vacuo
yielded a pale brown solid. Recrystallisation from cold CHCl3 and
diisopropyl ether gave 15a (0.979 g, 92%) as an off-white solid,
mp 121–123 ◦C; [a]D = -70.6 (c 1.42 in MeOH); dH (600 MHz,
20
DMSO-d6) 3.61 (1H, dd, J 15.8, 9.4), 3.73 (1H, dd, J 15.8, 8.7),
5.34 (1H, ddd, J 9.4, 8.7, 7.9), 6.13 (1H, dd, J 8.3, 7.9), 7.34 (1H,
d, J 7.2), 7.37–7.45 (3H, m), 7.49–7.51 (2H, app. t), 7.57 (1H, t, J
7.3), 7.66 (1H, t, J 7.5), 7.73–7.76 (2H, app. t), 7.92 (2H, d, J 7.5),
7.96 (2H, d, J 7.9), 9.24 (1H, d, J 8.3), 9.75 (1H, s), 11.22 (1H, s); dC
(150 MHz, DMSO-d6) 36.4, 60.1, 65.4, 120.6, 123.9, 124.7, 127.6,
127.7, 128.3, 128.6, 130.3, 130.6, 131.7, 133.5, 134.9, 137.7, 139.2,
141.4, 144.7, 167.4; nmax (neat)/cm-1 3350, 3125, 3074, 2925, 1646,
1601, 1570, 1522, 1486, 1305, 1075, 757, 687; m/z (ES) 381.1722
(M+ - ClO4. C24H21N4O requires 381.1715)
white solid, mp 170–171 ◦C; [a]D = -28.8 (c 0.94 in CHCl3);
20
dH (400 MHz, CDCl3) 2.97 (1H, dd, J 16.1, 6.5), 3.35 (1H, dd, J
16.1, 7.3), 4.22–4.27 (1H, m), 5.63 (1H, dd, J 8.0, 6.0), 6.43 (1H,
d, J 8.0), 7.28–7.36 (4H, m, (under CHCl3 resonance), 7.45–7.49
(2H, app. t), 7.54 (1H, t, J 7.4), 7.83 (2H, d J 7.4); dC (100 MHz,
CDCl3) 36.3, 60.3, 68.1 124.3, 125.1, 127.1, 127.8, 128.7, 129.0,
131.9, 133.9, 139.7, 139.8, 167.5; nmax (neat)/cm-1 3262, 3070,
2911, 2099, 1638, 1526, 1342, 743; m/z (ES) 301.1071 (M+ + Na.
C16H14N4ONa requires 301.1065.
Benzoin condensation: condition set A: K2CO3/KOH as base
(1R,2R)-trans-1-Benzoylamino-indan-2-yl-ammonium chloride
(24a). A 50 cm3 round bottomed flask equipped with a stirring
bar was charged with 23a (1.066 g, 3.832 mmol) and triphenylphos-
phine (1.005 g, 3.832 mmol), and the reaction put under an
atmosphere of Ar. THF (32 cm3) was added via syringe and the
resulting clear colourless solution was stirred at 45 ◦C for 14.5 h.
Deionised water (8.0 cm3) was added and the reaction was stirred
at 45 ◦C for an additional 24 h. Solvent was removed under reduced
pressure to give a yellow oil. This was dissolved in CH2Cl2 (40 cm3)
and HCl (3.0 M, 160 cm3) was added, forming a white solid which
dissolved slowly into the aqueous layer. The aqueous layer was
separated and washed with CH2Cl2 (4 ¥ 25 cm3). The aqueous layer
was concentrated in vacuo to give a white solid. Recrystallisation
from hot methanol gave the hydrochloride salt 24a (1.020 g, 92%)
To a 5 cm3 round-bottomed flask, equipped with a magnetic
stirring bar were added K2CO3 (99.995%, anhydrous, 8.76 mg,
0.0634 mmol) and KOH (0.79 mg, 0.0141 mmol) that had both
been finely ground using a mortar and pestle. The reaction
vessel was rigorously dried (heat) under vacuum. When cooled to
ambient temperature, the appropriate catalyst (0.088 mmol) and
(E)-stilbene (49.57 mg, 0.275 mmol) were added. The flask was
fitted with a septum seal and placed under an atmosphere of Ar.
THF (1.78 cm3) and the aldehyde (purified by a preliminary base
wash with aq. NaHCO3 followed by distillation) were then added
via syringe and the reaction was stirred at room temperature for
48 h. CH2Cl2 (3.0 cm3) and deionised H2O (3.0 cm3) were added.
The organic layer was removed and the aqueous layer was washed
with CH2Cl2 (4 ¥ 3.0 cm3). The organic layers were combined, dried
(MgSO4), filtered and the solvent removed under reduced pressure.
The product was purified using column chromatography. For full
characterisation and CSP-HPLC conditions please see the ESI.†
as a white solid, mp 285–287 ◦C; [a]D = -19.8 (c 0.88 in MeOH);
20
dH (400 MHz, DMSO-d6) 3.00 (1H, dd, J 15.6, 9.0), 3.34–3.40
(1H, m (under H2O resonance)), 3.96–4.02 (1H, app. q), 5.70–5.74
(1H, app. t), 7.18 (1H, d, J 7.0), 7.20–7.33 (3H, m), 7.50 (2H, app.
t), 7.56 (1H, t, J 7.0), 7.97 (2H, d, J 7.8), 8.63, (3H, s (broad)), 9.04
(1H, d, J 8.5); dC (100 MHz, DMSO-d6) 34.6, 56.4, 57.6, 123.7,
124.8, 127.4, 127.6, 128.2, 128.3, 131.5, 134.0, 138.4, 141.0, 166.9;
Notes and references
max (neat)/cm-1 3323, 2860, 2768, 1636, 1526, 1492, 748, 731, 694;
1 F. Wo¨hler and J. Liebig, Ann. Pharm., 1832, 3, 249.
2 (a) N. Zinin, Ann. Pharm., 1839, 31, 329; (b) N. Zinin, Ann. Pharm.,
1840, 34, 329.
n
m/z (ES) 253.1345 (M+ - Cl. C16H17N2O requires 253.1341).
3 (a) Recent reviews: D. Enders, O. Niemeier and A. Henseler, Chem.
Rev., 2007, 107, 5506; (b) N. Marion, S. Diez-Gonzalez and S. P. Nolan,
Angew. Chem., Int. Ed., 2007, 46, 2988; (c) K. Zeitler, Angew. Chem.,
Int. Ed., 2005, 44, 7506; (d) M. Christmann, Angew. Chem., Int. Ed.,
2005, 44, 2632; (e) D. Enders and T. Balensiefer, Acc. Chem. Res., 2004,
37, 534; (f) J. S. Johnson, Angew. Chem., Int. Ed., 2004, 43, 1326.
4 T. Ukai, R. Tanaka and T. Dokawa, J. Pharm. Soc. Jpn., 1943, 63, 269.
5 S. Mizuhara and P. Handler, J. Am. Chem. Soc., 1954, 76, 571.
6 (a) R. Breslow, J. Am. Chem. Soc., 1958, 80, 3719; (b) For a more recent
kinetic study see: M. J. White and F. J. Leeper, J. Org. Chem., 2001, 66,
5124.
7 J. Sheehan and D. H. Hunnemann, J. Am. Chem. Soc., 1966, 88, 3666.
8 J. Sheehan and T. Hara, J. Org. Chem., 1974, 39, 1196.
9 Rawal later improved the yield of this process substantially to 48%:
C. A. Dvorak and V. H. Rawal, Tetrahedron Lett., 1998, 39, 2925.
10 W. Takagi, Y. Tamura and Y. Yano, Bull. Chem. Soc. Jpn., 1980, 53,
478.
(1R,2R)-trans-4-(1-Benzoylamino-indan-2-yl)-1-phenyl-4H-
[1,2,4]triazol-1-ium perchlorate (15a). To an oven-dried 25 cm3
round bottomed flask equipped with a magnetic stirring bar and
˚
oven-dried molecular sieves (4 A, 2.26 g) was charged 25 (0.571 g,
2.316 mmol) and the reaction quickly put under an atmosphere of
Ar. Hydrochloride salt 24a (0.701 g, 2.427 mmol) was converted
to the corresponding free base by dissolving the salt in NaOH
(2.0 M, 5 cm3) and washing with CH2Cl2 (4 ¥ 10 cm3). The organic
extracts were combined, dried (MgSO4) and solvent removed in
vacuo to give the free-based amine of 24a as a translucent solid. A
solution of the amine (0.556 g, 2.206 mmol) in CH3CN (10.3 cm3)
was added via syringe. The resulting pale orange solution was
stirred overnight at ambient temperature. Removal of the solvent
left a pale brown solid, crude intermediate, which was not isolated
11 J. Marti, J. Castells and F. Lopez-Calahora, Tetrahedron Lett., 1993,
34, 521.
as per the procedure for synthesis of 28. Oven-dried molecular
12 Y. Tachibana, N. Kihara and T. Takata, J. Am. Chem. Soc., 2004, 126,
3438.
3
˚
sieves (4A, 2.40 g) and CH3CN (9 cm ) were added to the crude
reaction. The flask was fitted with a reflux condenser and heated
13 (a) R. L. Knight and F. J. Leeper, Tetrahedron Lett., 1997, 38, 3611;
under reflux at 90 ◦C for 5 d under an atmosphere of Ar. The
(b) A. U. Gerhard and F. J. Leeper, Tetrahedron Lett., 1997, 38, 3615.
3592 | Org. Biomol. Chem., 2009, 7, 3584–3593
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