Preparation of Annulated Nitrogen ContainingHeterocycles via a One-Pot Palladium-Catalyzed

Alkylation/Direct Arylation Sequence

Christophe Blaszykowski, Evangelos Aktoudianakis, Cyril Bressy, DinoAlberico and Mark Lautens, Org. Lett. ASAP

University of Toronto

Dhanalakshmi Kasi

6 May 2006

Dhana Kasi @ Wipf Group 1 5/10/2006

Natural Products Containing Tricyclic Structure 1

Crispine A: Isolated from Carduus crispus –cyctotoxic activity

Lettowianthin: Isolated from Lettowianthus stellatus

Lammelarin D: Marine Alkaloid, potent cytotoxic.

Dhana Kasi @ Wipf Group 2 5/10/2006

Annulation of Indole via Indole Radicals: Addition ofthe 2-Indolyl Radical to Aromatic Rings

N

Br

CHO

MeCN

N

CHO

N

CHO

( )n

Bu3SnH, AIBN

( )n

( )n

+

n = 1 55% 25%

n = 2 20% 65%

n = 3 32% 37%

Fiumana, A.; Jones, K. Tet. Lett. 2000, 41, 4209-4211

Dhana Kasi @ Wipf Group 3 5/10/2006

Synthetic Applications of Aryl radical Building Blocksfor Cyclization onto Azoles

N

NMeOOC

Br

Toluene, 71%

N

NMeOOCBu3SnH, AIBN

Allin, S.M.; Bowman, W.R.; Elsegood, M.R.J.; McKee, V.; Karim, R.;Rahman, S.S. Tetrahedron 2005, 61, 2689-2696.

Dhana Kasi @ Wipf Group 4 5/10/2006

Total Synthesis of the Antitumor Active Pyrrolo[2,1-a]isoquinoline Alkaloid (±)-Crispine A

Silver(I) Promoted Oxidative Cyclization

NH

SiMe3

R

R

NR

R

AgOAc, CH2Cl2

RT, 14 h

R = H, 72 %

R = OMe, 58 %

Knolker, H.; Agarwal, S. Tet. Lett. 2005, 46, 1173-1175.

Dhana Kasi @ Wipf Group 5 5/10/2006

5,6-Dihydropyrrolo[2,1-b]isoquinolines as Scaffolds forSynthesis of Lamellarin Analogues

Intramolecular Heck Reaction

NMeOOC

Br

N COOMePd(PPh3)4, NaOAc

DMF, 125 !C, 95 %

Olsen, C.A.; Parera, N.; Albericio, F.; Alvarez, M. Tet. Lett. 2005, 46,2041-2044.

Dhana Kasi @ Wipf Group 6 5/10/2006

A Facile Route to Indolo[2,1-a]isoquinolines andDibenzopyrrocoline Alkaloids

N

OMe

OMe

IMeO

MeO

NMeO

MeO

OMe

OMe

1. K2CO3, DMF

Reflux, 1.5 d, 95 %

2. DDQ, Benzene

Reflux, 4 h, 65 %

Orito, K.; Harada, R.; Uchiito, S.; Tokuda, M. Org. Lett. 2000, 2, 1799-1801.

Dhana Kasi @ Wipf Group 7 5/10/2006

Convergent Total Synthesis of Lamellarin KIntramolecular [3+2] Cycloaddition

OMeMeO

PriO OPr

i

O

O

I

NMeO

MeO

OPri

OMeMeO

PriO OPr

i

O

O

N+MeO

MeO

PriO I

-

N

O

OPri

MeO

MeO

PriO

OPri

OMeMeO

O

+

1. DCE, 18 oC, 7 h

2. Hunig's base, 83 oC,

32 h, 81%

Banwell, M.; Flynn, B.; Hockless, D. Chem. Commun. 1997, 2259-2260.

Dhana Kasi @ Wipf Group 8 5/10/2006

Synthesis of Annulated Indoles

Bressy, C.; Alberico, D.; Lautens, M. J. Am. Chem. Soc. 2005, 127,13148-13149..

Dhana Kasi @ Wipf Group 9 5/10/2006

Synthesis of 5,6-Dihydro-pyrrolo[2,1-a]isoquinolineDerivatives

Reaction Conditions

Iodoarene: 1 equiv

Bromoalkylpyrrole: 2 equiv

Cs2CO3: 2 equiv

PdCl2: 10 mol %

Tri-2-furylphosphine: 22 mol %

Norbornene: 2 equiv

CH3CN: 0.1M

Dhana Kasi @ Wipf Group 10 5/10/2006

Synthesis of Annulated Pyrroles

Dhana Kasi @ Wipf Group 11 5/10/2006

Dhana Kasi @ Wipf Group 12 5/10/2006

Proposed Mechanism for the Synthesis of AnnulatedPyrroles

Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem.Int. Ed. Engl. 1997, 36, 119-122.Dhana Kasi @ Wipf Group 13 5/10/2006

Synthesis of Annulated Pyrazole

Dhana Kasi @ Wipf Group 14 5/10/2006

Reaction with Iodouracil

N Br+

N

NI

O

O PdCl2tri-2-furylphosphineCs2CO3, norbornene

CH3CN, 90 !C, 23h

39%

N

N

N

O

O

Dhana Kasi @ Wipf Group 15 5/10/2006

Summary

• One pot synthesis of six and seven membered annulatedpyrroles was achieved in very good yields.

• The reaction sequence involves the formation of alkyl-aryl and a heteroaryl-aryl bond in one step.

• Convenient stratergy for synthesis of otherheteroaromatics like annulated pyrazoles and uracil.

Dhana Kasi @ Wipf Group 16 5/10/2006