New Developments inNew Developments inPd(II)Pd(II)--Catalysed CyclisationsCatalysed Cyclisations

of Aminoalkenitolsof Aminoalkenitols

Dr. Peter SzolcsányiDepartment of Organic ChemistrySlovak University of Technology

Bratislava, Slovak Republic

Pd(II)-Catalysed chlorocyclisation and N,O-bicyclisation

of polyhydroxylated aminoalkenitols

Synthetic versatility of chloromethyl piperidines

Where did the idea come from ?

P. Szolcsányi et al.: Tetrahedron: Asymmetry 2000, 11, 2579-2597.

Known precedents of Pd(II)/CuCl2-catalysedchloroaminocyclisation

M. Wada, H. Aiura, K. Akiba: Heterocycles 1987, 26, 929-934.

A. Lei, X. Lu, G. Liu: Tetrahedron Lett. 2004, 45, 1785-1788.

Preparation of substrates - D-gluco compound

Preparation of substrates - D-galacto compound

Pd(II)/CuCl2-catalysed chlorocyclisation-D-gluco serie

Entry Solvent Time & TemperatureIsolated yield

(after FLC)HPLC ratio of

L-ido / D-gluco (d.e.)

1 AcOH 48 hrs, 23oC 70% 19 / 1 (90%)

2 DMF 24 hrs, 30oC 21% 8 / 1 (82%)

3 CH2Cl2 24 hrs, 30oC 65% 6 / 1 (71%)

4 THF 24 hrs, 30oC 60% 6 / 1 (71%)

5 MeOH 24 hrs, 23°C 59% 5 / 1 (67%)

6 Toluene 48 hrs, 30oC 56% 3 / 1 (33%)

Pd(II)/CuCl2-catalysed chlorocyclisation-D-galacto serie

Entry Solvent Catalyst & Additive(s)Time &

TemperatureChlorides/bicycle (yield after FLC)

HPLC ratio ofL-altro/D-gala

(d.e.)

1 AcOH 0.1 eq. PdCl2, 3 eq. CuCl2, 3 eq. AcONa 24 hrs, 25oC 28% / 49% 19 / 1 (90%)

2 DMF - detto - 19 hrs, 25oC 53% / 11% 15 / 1 (88%)

3 CH2Cl2 - detto - 24 hrs, 29oC 36% / 8% 5 / 1 (67%)

4 THF - detto - 24 hrs, 25oC 54% / 10% 2 / 1 (33%)

5 Toluene - detto - 24 hrs, 29oC 43% / 9% 1 / 2 (33%)

6 MeOH - detto - 24 hrs, 25oC 32% / 7% 1 / 3 (50%)

7 AcOH 0.1 eq. PdCl2, 2 eq. CuCl2, 2 eq. AcONa 48 hrs, 30oC 35% / 52% 19 / 1 (90%)

8 AcOH 0.1 eq. PdCl2, 1 eq. CuCl2, 1 eq. AcONa 48 hrs, 28oC 25% / 48% 19 / 1 (90%)

9 AcOH 0.1 eq. PdCl2, 3 eq. CuCl2 24 hrs, 30oC 27% / 50% 19 / 1 (90%)

10 AcOH 1 eq. PdCl2, 3 eq. AcONa 96 hrs, 28oC 0% / 0% -

11 AcOH 0.1 eq. Pd(OAc)2, 2 eq. BQ, 3 eq. AcONa 24 hrs, 30oC - / 0% -

Mechanistic proposal of the Pd(II)/CuCl2-catalysedchloroaminocyclisation and bicyclisation

Synthesis of new analogues of iminoalditols

H. Takahata, Y. Banba, H. Ouchi, H. Nemoto: Org. Lett. 2003, 5, 2527-2529.

New type of the Pd(II)/CuCl2-catalysed bicyclisation ???

Analogous to: T. M. Cokley et al.: Tetrahedron Lett. 1996, 37, 1905-1908.

Preparation of model substrate for the bicyclisation

OH

NHR

NR

Ocat. Pd(II)-saltn eq.CuCl2

n eq. AcONasolvent(s)

Model screening of Pd(II)/CuCl2-catalysed bicyclisation

Entry Solvent Catalyst & Additive(s) Time & Temperature Yield after FLC

1 AcOH 0.1 eq. PdCl2, 3 eq. CuCl2, 3 eq. AcONa 20°C, 24 hrs 45%

2 AcOH 0.2 eq. Pd(OAc)2, 3 eq. Cu(OAc)2 30°C, 48 hrs Complex mixture

3 THF 0.2 eq. PdCl2, 1.1 eq. BQ, 2 eq. LiCl 45°C, 48 hrs Complex mixture

4 AcOH 0.1 eq. PdCl2, 3 eq. CuCl2 35°C, 24 hrs 71%

5 AcOH 0.1 eq. PdCl2, 2 eq. CuCl2 40°C, 48 hrs 65%

6 AcOH 0.1 eq. PdCl2, 1 eq. CuCl2 40°C, 48 hrs 74%

7 CH2Cl2 0.1 eq. PdCl2, 2 eq. CuCl2 35°C, 22 hrs 71%

8 THF 0.1 eq. PdCl2, 2 eq. CuCl2 35°C, 22 hrs 47%

9 AcOH 0.1 eq. Pd(OAc)2, 2 eq. CuCl2 40°C, 12 hrs 64%

10 AcOH 0.1 eq. PdCl2(MeCN)2, 2 eq. CuCl2 40°C, 12 hrs 69%

11 AcOH 1 eq. PdCl2 40°C, 26 hrs 0%

Mechanistic proposal of Pd(II)/CuCl2-catalysed bicyclisation

P. Szolcsányi, T. Gracza: Chem. Commun. 2005, 3948-3950.

Acknowledgments

Generous support Prof. Dr. Tibor Gracza

HPLC Dr. Katarína Hroboňová

NMR Dr. Naďa Prónayová

IR Ms. Silvia Markusová

MALDI Dr. Ivan Špánik

Grant APVT-20-000904