Investigation of a Domino Heck Reaction for the Rapid Synthesis of Bicyclic Natural Products

Abstract

Dedicated to Professor JosØ Barluenga on the occasion of his 70th birthdayThe Heck reaction has proven to be an exceptionally useful tool for the construction of carbon-carbon bonds. The traditional Heck reaction consists of oxidative addition by palladium(0) to a carbon-halogen bond, followed by migratory insertion into a carbon-carbon p-system and finally b-hydrogen elimination. A number of clever domino reactions [1] have been implemented using either sequential Heck reactions [2] or an initial Heck reaction in tandem with another palladium catalyzed process. [3] During efforts toward the synthesis of FR900482, [4] we intended to utilize an 8-exo-trig Heck reaction to forge the benzazacine core of the molecule (Scheme 1). Instead when 3 was exposed to Heck reaction conditions [5] a remarkable result was obtained. Rather than the expected exocyclic olefin 2, bicycle 6 was formed in remarkable yield with no trace of the expected Heck product [Eq. (1)]. This result represented an unprecedented domino Heck/alkylation, even in the presence of geometrically accessible b-hydrogen atoms. We were intrigued by this demonstration that b-hydrogen elimination may not always be kinetically preferred over alternative terminating steps. This possibility would open many alternative synthetic disconnections if it could be employed in a predictable manner.Several mechanistic scenarios could account for this remarkable transformation (Scheme 2). We believe the most likely mechanism for the observed product is oxidative addition of Pd 0 to the carbon-iodine bond of 3 yielding 3 a, followed by migratory insertion through an 8-exo-trig pathway to afford intermediate 3 d. Rather than the expected b-hydrogen elimination, which is not geometrically inaccessible, a transannular alkylation reaction ensued. This most likely occurs by nucleophilic displacement of palladium by nitrogen, which regenerated the Pd 0 catalyst and yielded tetracycle 6. A reductive elimination pathway to form the C À N bond is also conceivable, however, the lack of reported C À N reductive elimination with this catalyst system causes us to favor an alkylation pathway. The surprising reluctance of 3 d[a] Prof.

Determination of the Metastable Zone Width by a Simple Optical Probe

“…It is worth noting that many interesting and important reactions have been reported utilizing the benzylation of imines,11 hydroamination of alkynes/reduction,12 and reductive amination of ketones13 for formation of N ‐(1,2‐diphenylethyl)anilines, which are structural constituents of pharmacologically interesting compounds (Scheme ) 14. However, oxidants are required for preparation of aldehydes from alcohols, and stoichiometric zinc reagents are chemically unstable.…”

Palladium-Catalyzed Benzylation of Unprotected Anthranilic Acids with Benzyl Alcohols in Water

“…To our surprise, dibenzylated product 3a was obtained in good yield despite the possibility of forming the mono- N -benzylated product 4a (Table , entry 1). In general, benzylation of imines, hydroamination of alkynes/reduction, and reductive amination of ketones are used for formation of N -(1,2-diphenylethyl)amines, which are structural constituents of pharmacologically interesting compounds . After 1 h, the reaction afforded 3a in 64% yield along with 4a in 24% yield (entry 2).…”

Preparation of Amino-Substituted Indenes and 1,4-Dihydronaphthalenes Using a One-Pot Multireaction Approach: Total Synthesis of Oxybenzo[c]phenanthridine Alkaloids

“…4,5-Methylenedioxy-2-vinylbenzaldehyde (6c). 32 The reaction was carried out according to the previously described procedure for 2-vinylbenzaldehyde (6a) using 2-bromo-4,5-methylenedioxybenzaldehyde (5c) (0.400 g, 1.75 mmol). This gave 4,5-methylenedioxy-2vinylbenzaldehyde (6c) (0.296 g, 96%) as a yellow solid.…”

“…Mp 50−53 °C (lit. 32 52−54 °C); 1 H NMR (500 MHz, CDCl 3 ) δ 5.48 (dd, J 10.9, 0.8 Hz, 1H), 5.62 (dd, J 17.3, 0.8 Hz, 1H), 6.05 (s, 2H), 6.98 (s,1H),7.31 (s,1H),7.41 (dd,J 17.3,10.9 Hz,1H) 5-Fluoro-2-vinylbenzaldehyde (6d). 31 The reaction was carried out according to the previously described procedure for 2-vinylbenzaldehyde (6a) using 2-bromo-5-fluorobenzaldehyde (5d) (0.500 g, 2.46 mmol) and potassium vinyltrifluoroborate (0.396 g, 2.96 mmol).…”

“…31 1 H NMR (400 MHz, CDCl 3 ) δ 5.50 (d,J 11.0 Hz,1H), 5.62 (d,J 17.4 Hz,1H),1H),7.38 (dd,J 17.4,11.0 Hz,1H),2H), 10.24 (s, 1H); 13 C NMR (101 MHz, CDCl 3 ) δ 116.1 (CH, d, 2 J CF 22.1 Hz), 119.9 (CH 2 ), 121.1 (CH, d, 2 J CF 21.9 Hz), 129.7 (CH, d, 3 J CF 7. 3 Hz), 132.0 (CH), 134.4 (C, d, 3 J CF 5.9 Hz), 137.0 (C, d, 4 J CF 3.4 Hz), 162.3 (C, d, 1 J CF 249.5 Hz), 190.6 (CH); MS (EI) m/z 150 (M + , 79), 122 (100), 121 (63), 101 (61), 96 (52), 75 (32).…”