N. E. Stainforth et al. / Tetrahedron: Asymmetry 20 (2009) 741–743
743
as the bis(oxazolines) 10 and 11,8 pyridine-bis(oxazoline) 129 and
furan-bis(oxazoline) 13,10 failed to generate an effective catalyst
system, with only trace quantities (<5%) of the Mannich adducts
being isolated (Scheme 4).
Org. Chem. 2002, 67, 2556; (d) Trost, B. M.; Jaratjaroonphong, J.; Reutrakul, V. J.
Am. Chem. Soc. 2006, 128, 2778; Examples of direct additions employing N-
substituted nucleophiles: (e) Chowdari, N. S.; Ahmad, M.; Albertshofer, K.;
Tanaka, F.; Barbas, C. F., III Org. Lett. 2006, 8, 2839; (f) Okada, A.; Shibuguchi, T.;
Ohshima, T.; Masu, H.; Yamaguchi, K.; Shibasaki, M. Angew. Chem., Int. Ed. 2005,
44, 4564; (g) Ooi, T.; Kameda, M.; Fujii, J.-i.; Maruoka, K. Org. Lett. 2004, 6, 2397;
(h) Benardi, L.; Gothelf, A. S.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2003, 68,
2583; (i) Li, L.; Klauber, E. G.; Seidel, D. J. Am. Chem. Soc. 2008, 130, 12248.
4. (a) Willis, M. C.; Cutting, G. A.; Piccio, V. J.-D.; Durbin, M. J.; John, M. P. Angew.
Chem., Int. Ed. 2005, 44, 1543; (b) Willis, M. C.; Piccio, V. J.-D. Synlett 2002,
1625; (c) Cutting, G. A.; Stainforth, N. E.; John, M. P.; Kociok-Köhn, G.; Willis, M.
C. J. Am. Chem. Soc. 2007, 129, 10632.
Me Me
O
O
O
O
N
N
N
N
tBu
5. Willis, M. C.; Cutting, G. A.; John, M. P. Synlett 2004, 1195.
tBu
6. General procedure for the preparation of acyclic Mannich adducts (Table 1,
entry 1): 2,20-bipyridine (31 mg, 0.2 mmol, 20 mol %), activated powdered 4 Å
MS (200 mg) and magnesium perchlorate (44.5 mg, 0.2 mmol, 20 mol %) were
stirred for 30 min in THF (2.5 mL) at rt. The suspension formed was then
treated with phenyl ketone methyl carbonate (388 mg, 2.0 mmol) in THF
(2.5 mL). After 10 min benzaldehyde-derived N-tosylimine (259 mg, 1.0 mmol)
11
10
O
O
N
O
O
O
was added, followed by N-methyl morpholine (55 lL, 0.5 mmol). After 24 h the
N
N
N
N
reaction mixture was filtered through Celite, quenched with satd aq solution of
NH4Cl (10 mL) and extracted with EtOAc (2 ꢀ 30 mL). The organic layers were
washed with satd aq CuSO4 (10 mL), followed by water (30 mL) and brine
(30 mL). The organic layer was dried (MgSO4) and concentrated under reduced
pressure. The crude mixture was purified by flash chromatography (SiO2, 98:2,
DCM/EtOAc) to yield the Mannich adducts as an inseparable mixture of
13
Ph
Ph
12
Scheme 4.
diastereomers (3:1, anti:syn) as a white foam (305 mg, 67%); m
max(KBr)/cmꢁ1
3231, 2954–2854, 1761, 1702, 1427, 1186; anti-Diastereomer dH (300 MHz;
CDCl3) 7.76–7.69 (2H, m), 7.62–7.52 (3H, m), 7.47–7.36 (2H, m), 7.18–7.03 (5H,
m), 6.98–6.89 (2H, m), 6.11 (1H, d, J 3.8), 5.76 (1H, d, J 8.3), 5.01 (1H, dd, J 8.3,
3.8), 3.75 (3H, s), 2.34 (3H, s, Me); syn-Diastereomer dH (300 MHz; CDCl3) 7.76–
7.69 (2H, m), 7.62–7.52 (3H, m), 7.47–7.36 (2H, m), 7.18–7.03 (5H, m), 6.98–
6.89 (2H, m) 5.83 (1H, d, J 3.0), 5.55 (1H, d, J 8.1), 4.98 (1H, dd, J 8.1, 3.0), 3.65
(3H, s), 2.23 (3H, s); dC (75 MHz; CDCl3) 192.1, 191.8, 153.6, 153.5, 142.4, 142.1,
136.05, 136.03, 135.9, 133.7, 133.4, 133.0, 132.9, 132.8, 128.5, 128.2, 127.9,
127.8, 127.7, 127.4, 127.3, 127.2, 126.4, 126.0, 125.96, 125.89, 78.8, 78.3, 56.9,
56.7, 54.5, 54.4, 20.4, 20.0 (2 ꢀ Ar signals not observed); m/z LRMS (EI+) 471.2
([M+NH4]+, 100%), 397.2 ([M+NH4, –CO2Me, –Me]+, 40%); HRMS (ESI+):
C24H27O6N2S, [M+NH4]+ requires 471.1590. Found 471.1582.
3. Conclusion
In conclusion, we have demonstrated that
tionalized ketones undergo direct addition to aryl N-Ts imines un-
der the action of a Mg(ClO4)2/bipy/NMM catalyst system, to deliver
a
-carbonate-func-
a-hydroxy-b-aminoketone products. The use of methyl carbonate-
substituted nucleophiles delivers acyclic adducts with moderate to
good anti-selectivity. In contrast, the use of isopropenyl-substi-
tuted nucleophiles provides cyclic carbamate products, with gen-
erally good anti-Mannich diastereoselectivity. Good variation of
the imine component was shown to be possible, however, attempts
to develop an enantioselective variant of the process have so far
been unsuccessful.
7. General procedure for the preparation of cyclic Mannich adducts (Table 2, entry
1): 2,20-bipyridine (21 mg, 0.14 mmol, 20 mol %), activated powdered 4 Å MS
(200 mg) and magnesium perchlorate (30 mg, 0.14 mmol, 20 mol %) were
stirred for 30 min in THF at rt. The suspension formed was then treated with
the phenyl ketone isopropenyl carbonate (330 mg, 1.36 mmol, 2 equiv) in THF
(2.5 mL). After 10 min benzaldehyde-derived N-tosylimine (194 mg,
0.68 mmol, 1 equiv) was added followed by N-methyl morpholine (37 lL,
Acknowledgements
0.34 mmol, 50 mol %). After 48 h the reaction mixture was filtered through
Celite and quenched with a satd aq solution of NH4Cl (10 mL) and extracted
with EtOAc (2 ꢀ 30 mL). The organic layers were washed with satd aq CuSO4
(10 mL), water (30 mL) and brine (30 mL). The organic layer was dried (MgSO4)
and concentrated under reduced pressure. The crude mixture was purified by
flash chromatography (SiO2, 98:2, DCM/EtOAc) to yield the cyclic Mannich
This work was supported by the EPSRC and GlaxoSmithKline.
References
adducts (203 mg, 71%) as a 20:1 ratio of diastereomers (cis:trans); mmax(KBr)/
cmꢁ1 2961, 1783, 1702, 1375, 1169; dH (400 MHz; CDCl3) 7.56–7.47 (3H, m),
7.39–7.29 (4H, m), 7.14 (1H, t, J 7.3), 7.06 (2H, d, J 8.3), 6.97 (2H, t, J 7.7), 6.78
(2H, d, J 7.3), 6.15 (1H, d, J 8.4), 5.82 (1H, d, J 8.4), 2.35 (3H, s); dC (100 MHz;
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[M+Na]+ requires 444.0882. Found 444.0886.
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