Page 179 - Academic Press Encyclopedia of Physical Science and Technology 3rd Organic Chemistry
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              Heterocyclic Chemistry                                                                      335

                Several of the early chemotherapeutic agents used in a  Fully unsaturated five-membered heterocyclic rings are
              wide variety of cancer treatments depend upon an three-  often synthesized by the ring closure of 1,4-dicarbonyl
              membered ring undergoing nucleophilic attack by an oxy-  compounds to give, with ammonia or primary amines,
              gen or nitrogen atom in DNA of the cancer cells. Examples  pyrroles (Paal–Knorr synthesis); with dehydrating agents,
              include cyclophosphamide (which can eject chloride with  furan; and with phosphorus pentasulfide, thiophenes.
              the formation of an aziridinium ring, a powerful elec-
              trophile) and mitomycin. In contrast, epoxides derived by  R 1  R 2  +  R NH 2  ∆  R 1  R 2
                                                                                    3
              metabolism of many polybenzenoid hydrocarbons are          O  O                     N
                                                                                                  R 3
              highly toxic because the epoxides form covalent linkages
                                                                             Paal-Knorr synthesis of pyrroles
              with normal cell DNA.
                                                                  Another important synthesis of pyrroles is the Knorr
                                   O
                                                                pyrrole synthesis, in which alpha-aminoketones or their
                                    H   H
                        HO        HN     S                      equivalent are condensed with carbonyl compounds con-
                                                                taining active alphamethylene groups.
                                       N       OAc
                        O  H  NH 2  O
                                                                                                   COOEt
                                         COOH
                             cephalosporin C                            O        COOEt
                                                                                       KOH
                                                                            +
                                                                         +                       N   COOH
                                                                       _  NH 3  O  COOMe         H
              B. Five-Membered Heterocycles                           Cl
                                                                                Knorr pyrrole synthesis
                 with One Heteroatom
                                                                  Indoles (benzo[b]pyrroles) are frequently prepared by
                1. Synthesis                                    the Fischer indole synthesis, in which aryl hydrazones
              Pyrrole, furan, and thiophene are the most important par-  undergo rearrangement on heating, usually in the presence
              ent heterocycles of this class, and their annelated deriva-  of acid. The important drug indomethacin, used to combat
              tives constitute a vast array of both naturally occurring and  rheumatoid arthritis, has been synthesized by this method.
              synthetic compounds.                                                                     COOH
                The ring closure of a four-carbon chain with the incor-             COOH
              poration of one heteroatom is very easy.             MeO                      MeO
                                                                                +
                                  sulfide                                     NH 2  O                  N
                                                                            N                        N
                       Br       Br                                          H                        H
                                          S
                                     tetrahydrothiophene
                                                                                COOH                COOH
                                                                    MeO                 MeO
                                     heat
                               COOH
                        H 2 N                  O
                                           N                                  N                   N
                                           H                                  H
                                         pyrrolidone                                            O
                                                                            synthesis of indomethacin
                A special case of this is the Hofmann–Loeffler–Freytag                                     Cl
              reaction, in which pyrrolidines (or piperidines) are formed
              by the decomposition of protonated N-haloamines.    2. Naturally Occurring Five-Membered
                                                                    Heterocycles
                            H +
                        H          H                O           Pyrrole (Gk·pyr = fire) was first isolated from bone py-
                      N  Cl      + N            N
                                                                rolyzate; it imparts a bright red color to pinewood moist-
                      R           R             R
                                                                ened with concentrated hydrochloric acid.
                       conversion of N-chloramines into pyrrolidines
                                                                  Condensation of suitable pyrroles in the presence of
                This particular free-radical mechanism confers high se-  acid leads to dipyrromethene cations, which are precursors
              lectivity in the formation of products owing to a preferred  to porphyrins, a group of compounds found in all living
              six-membered transition state. Another common route to  matter and forming the basis of respiratory pigments.
              five-membered heterocycles is via 1,3-dipolar cycload-
                                                                         H
              dition.
                                                                           O
                                            MeOOC                          +         HBr          +
                             MeOOC     AgNO 3 , Et 3 N                 NH   HN               NH  HN
               Ph  N  COOMe +
                                        MeCN                                                      _
                                              Ph  N   COOMe                                      Br
                                                  H
                    formation of pyrrolidines via cycloaddition                          a dipyrromethene cation
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