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SYNTHESIS OF COMPOUNDS CONTAINING

RINGSCHAPTER 6

Singlet carbenes are formed by treatment of CHCl3 with t-BuOK (results in loss of HCl

to give :CCl2), by loss of N2 from diazo compounds, such as diazomethane (CH2N2), or

by reaction of CH2I2 with zinc-copper amalgam (cyclopropanation with the resulting :CH2 synthetic equivalent, called a carbenoid, is the Simmons–Smith reaction)

RETROSYNTHESIS OF CYCLOPROPANE TMS

B SYNTHESIS OF CYCLOBUTANES

Cyclobutane rings are also strained structures that are nearly impossible to form by ring-closing reactions The most common method for constructing a four-membered ring is using a [2 + 2] cycloaddition reaction that involves the interaction of a two-electron π system with another two-electron π system (hence the “2 + 2” description)

RETROSYNTHESIS OF CYCLOBUTANE TMS

C SYNTHESIS OF FIVE-MEMBERED RINGS (RADICAL CYCLIZATION REACTIONS)

Treatment of an alkenyl halide with a tributyltin radical (Bu3Sn , generated by the ⋅reaction of Bu3SnH with the radical initiator AIBN) causes the abstraction of the halide atom An alkenyl phenyl selenide can also serve as a precursor to a radical intermediate The resulting radical can add intramolecularly to an appropriately placed alkene, forming a ring and creating a new radical Depending on the reaction conditions, this radical can abstract either a hydrogen or a halogen to give a cyclic alkane or alkyl halide product, respectively

Baldwin’s rules: The addition of the radical shown above to the trigonal-planar, sp2 alkene to form a fivemembered cyclic intermediate with the radical located outside of

the ring (called a “5-exo-trig” addition) is the favored mechanism Less favorable is the

formation of a 6-membered ring that has the radical on one of the carbons within the

ring, called a “6-endo-trig” addition

RETROSYNTHESIS OF METHYLCYCLOPENTANE TMS

EXAMPLE: METHYLCYCLOPENTANE TM

D SYNTHESIS OF SIX-MEMBERED RINGS (DIELS–ALDER REACTION)

THE DIENOPHILE (E+)

The dienophile behaves as the electrophilic species, so the reaction is facilitated by the presence of one or more electronwithdrawing groups (EWG), such as a carbonyl (e.g., an ester –CO2R), a nitro (–NO2), or a cyano (–C≡N) group Such groups make the alkene more electronpoor, and, therefore, a better electrophile

Stereochemistry of Dienophile Is Retained

THE DIENE (NU:)

The Diels–Alder reaction requires the diene to have an s-cis conformation, to allow the ends of the diene and dienophile to overlap in a concerted manner

Stereochemistry of Bicyclic Diels–Alder Products

REGIOCHEMISTRY OF THE DIELS–ALDER

RETROSYNTHESIS OF CYCLOHEXENES (DIELS–ALDER)

RETROSYNTHESIS OF 1,4-CYCLOHEXADIENES

1,4-Cyclohexadiene derivatives can be prepared either by a Diels–Alder reaction with an alkyne, or by a Birch reduction of a benzene derivative

1 Propose a possible disconnection/retrosynthesis for each of the following cyclic target molecules Include a ring in your disconnection and consider the pattern of functional groups when determining the best bond(s) to break.

2 Provide a synthesis for each of the following target molecules Each synthesis must form at least one new carbon–carbon bond It may help to first do a retrosynthesis of the TM.