FIVE-MEMBERED RING FORMATION Membered Rings. Intramolecular S N 2 Reaction

Transcription

1 5 mbered ings FIVE-MEMBEED IG FMATI 138 C 2 C 2 PGF 2α PGE 2 irsutene Modhephane Isocumene 1. Intramolecular S 2 eactions 2. Intramolecular Aldol Condensation and Michael Addition 3. Intramolecular Wittig lefination 4. ing Expansion and Contraction eactions a. 3 5 b. 4 5 c ,3-Dipolar additions 6. azarov Cyclization 7. Arene-lefin otocyclization 8. adical Cyclizations 9. thers Synthesis 1973, 397; ACIEE 1982, 21, 480; Intramolecular S 2 eaction 5-exo-tet: favored LDA JCSCC 1973, 233 C 2 C 2 C C JACS 1974, 96, 5268

2 FIVE-MEMBEED IG FMATI C C2 2 C C 2 JACS 1979, 101, 5081 a, DMS JCSCC 1979, 817 Ts Intramolecular Aldol Condensation 5-exo-trig: favored intramolecular aldol condensation of 1,4-diketones ' ' C 3 C 3 TL 1982, 29, 2237 C 3 C 3 C 2 a, C 2 JACS 1980, 102, 4262 a JC 1983, 48, 1217 Intramolecular Michael Addition 5-exo-tet: favored rganic eactions 1995, 47, JACS 1979, 101, C

3 FIVE-MEMBEED IG FMATI 140 Intramolecular Wittig lefination Tetrahedron 1980, 36, ) () 2 P()C - 2 P() 2 2) Collins TP C 5 11 TP TP C 5 11 TP C 2 JC 1981, 46, 1954 base TP C 5 11 TP C 5 11 ing Expansion eactions - 3 5: Vinyl Cyclopropane earrangement rganic eactions 1985, 33, 247. _ S 2 TMS TMS JACS 1979, 101, : eaction of cyclobutanones with Diazomethane C 2 2 C 2 2 TL 1980, 21, 3059 C 3 C 3 C 2 2 C 3 C 3 JACS 1987,109, 4752

4 FIVE-MEMBEED IG FMATI 141 ing Contraction eactions - 6 5: Favorskii eaction rganic eactions 1960, 11, C 2 1,3-Dipolar Addition to lefins 1,3-Dipolar Cycloaddition Chemistry, vol 1 & 2 (A. Padwa ed.) (Wiley, Y 1984); ACIEE 1977, 16, 10. Chem ev. 1998, 98, 863. _ LUM 1,3-Dipole (4π) a b c 4πs 2πs Alkene (2π) M - trimethylenemethane (TMM) ACIEE 1986, 25, 1. Synlett 1992, 107. high temperature C 2, C C TMM 2 C note: TMM usually reacts poorly w/ electron defficient olefins 3 Si Ac Pd(0) _ PdLn C 2 C 3 JACS 1981, 103, Si Ac TL 1986, 27, C Pd(0), 80 C C 2 i(cd) 2, 35 C C 2 C 2 ACIEE 1985, 24, 316 TL 1983, 24, α,α'-dihaloketones FeL n Fe(C) 9 Ar Ar AC 1979, 12, 61

5 FIVE-MEMBEED IG FMATI nitrones AC 1979, 12, 396; rganic eactions, 1988, 36, itrone JACS 1964, 86, 3756, Eta 1) I 2) 2, Pd/C 2 JC 1984, 49, C S Bn - C C S Bn C 4 9 JACS 1983, 104, nitrile oxides ArC - 2 JACS 1992, 104, 4023 C 2 Et C 2 Et C 2 Et C 2 Et TP 1) TBS-, DMF, imidazole 2) nbuli, TF Bu 3 Sn (80%) Bu 2 BTf, ipr 2 Et, C 2 2, -78 C a, 2, C 2 2 TBS (88%) TP (99%) TP C 3 _ 1) PPTS, Et, 2) (C 3 ) 2 C() 2, PPTS 3) Swern (48%) 1) DP, PPTS C 2 2, 2) LA TBS (60%) TP TP Fpyridine, C 3 C, pyridine (73%) 2, aney i, 2,, B() 3 1) Swern 2) 2 Aca, (89%) TP (88%) Cassiol TL 1996, 37, 9292

6 TBS TBS FIVE-MEMBEED IG FMATI 143 TBS LA TL 1993, 34, 3017 _ 2 Arene -lefin otocyclization rganic otochemistry 1989, 10, the photochemistry of benzene is dominated by the singlet state 1 Ac Ac 2 CuLi JACS 1982, 104, 5805 JCSCC, ) FVP 2) 2, Pd/C isocume Tetrahedron 1981,37, 4445 cedrane JACS 1981, 103, 688 Ac Ac TL 1982, 23, 3983 TL 1983, 24, 5325

7 Intramolecular otochemical [22] "ule of Five" FIVE-MEMBEED IG FMATI 144 JC 1975, 40, 2702 JC 1979, 44, 1380 azarov Cyclization review: Synthesis 1983, 429 rganic eaction 1994, 45, 1 - cyclization of allyl vinyl or divinyl ketones 3 P 4 /C 2 3 P 4 /C 2-1,4-hydroxy-acetylenes 2 S 4, JC 1989, 54, Silicon-Directed azarov Fe 3 Tetreahedron 1986, 42, 2821 Si 3 - Tin -directed azarov TL 1986, 27, 5947 adical Cyclization B. Giese adicals in rganic Synthesis: Formation of Carbon-Carbon Bonds (Pergamon Press; Y) 1986; Bull. Soc. Chim. Fr. 1990, 127, 675; Tetrahedron 1981, 37, 3073; Tetrahedron 1987, 43, 3541; Advances in Free adical Chemistry 1990, 1, 121. rganic eactions 1996, 48, adical Addition to multiple bonds: 1. Free radical addition is a two stage process involving an addition step followed by an atom transfer step. 2. In general, the preferred regioselectivity of the addition is in a manor to give the most stable radical (thermodynamic control)

8 FIVE-MEMBEED IG FMATI 145 Advantages of free radical reactions: 1. non-polar, little or no solvent effect 2. highly reactive- good for hindered or strained sysntems 3. insensitive to acidic protons in the substrates (i.e. hydroxyl groups do not necessarily need to be protected chanism of radical chain reactions 1. initiation 2. propagation 3. termination (bad) Formation of carbon centered radicals: tin hydride reduction of alkyl, vinyl and aryl halides, alcohol derivatives: xanthates, thionocarbonate, thiocarbonylimidazolides organosselenium & boron compounds carboxylic acid derivatives (Barton esters) reduction of organomercurials thermolysis of organolead compounds thermolysis or photolysis of azoalkanes. adical ing osure For irreversible ring closure reaction, the kinetic product will predominate. Both the 5-exo-trig and 6-endo trip are favored reactions, with the 6 exo-trig mode producing the most stable radical. owever, the 5-exo-trig is about 50 time faster k 1,5 k 1,6 kinetically favored thermodynamically favored 100 : : 0 98:2 85: : 0 3-exo-trig vs 4-endo-trig 4-exo-trig vs 5-endo-trig 5-exo-trig vs 6-endo-trig 6-exo-trig vs 7-endo-trig 7-exo-trig vs 8-endo-trig

9 and FIVE-MEMBEED IG FMATI 146 radicals open up fast and are not synthetically useful; often used as probes for radical reaction Effects of substituent on the regiochemistry of the 5-hexenyl radical cyclization 48:1 >200:1 2:3 < 1:100 Stereochemistry of 5-hexenyl radical cyclization 1-, or 3-substitued 5-hexenyl radicals give cis disubstituted cyclopentanes 2-, or 4-substituted 5-hexenyl radicals give trans disubstitued cyclopentanes 2 Bu 3 Sn 65 : 35 prefered transition state : : 17 1 Bu 3 Sn 73 : 27

10 FIVE-MEMBEED IG FMATI 147 nbusn, AIB JACS 1983, 105, 3720 C C C 2 Bu 3 Sn, AIB C 2 JACS 1990, 112, 5601 Si Bu 3 Sn Si 2 2 TP TP TP multiple cyclizations: D. Curran Advances in Free adical Chemistry 1990, 1, ) ab 4, Ce 3 2) Ac 2, Et 3 Ac 1) LDA, TF 2) TBS TBS 70 C Se, C 2 2 Se 2 2 TP CuS 2 Li TBS TP C 2 1) PPTS, Et 2) LA 3) (CF 3 S 2 ) 2 pyridine 4) Bu 4 I, I I 1) 3 Si (1.0 equiv) 2) CsF Li I Bu 3 Sn, AIB, reflux JACS 1985, 107, 1148 (±)-hirsutene C 3 Mg, CuS 2 1) I 2 2) DBU Mg CuS 2, TF 1) LA 2) C 3 S 2 3) ai 4) Li 5) Cr 3, 2 S 4, 2 C 2 1) C 3 Mg (excess) 2) 3 Si Bu 3 Sn, AIB, reflux 3 C (±)-capnellene Tetrahedron Lett. 1985, 41, 3943

11 FIVE-MEMBEED IG FMATI 148 nbusn, AIB JACS 1986, 108, 1106 C SmI 2, TF JACS 1988, 110, 5064 radical trapping Et I nbusn, AIB Et tbuc Et JACS 1986, 108, 6384 C can also be trapped with acrylate esters or acrylonitrile. Et I nbusn, AIB Et 3 Si C 5 11 Et Si 3 C ook rearrangement Et C 5 11 TMS Pd(Ac) 2, C 3 C Et 1) (S)-BIAL- 2), 2, TF C 1) Wittig 2) deprotect C 2 C 5 11 C 5 11 ()-PGF 2α Paulson-Khand eaction Tetrahedron 1985, 41, 5855; rganic eactions 1991, 40, 1. ' Co 2 (C) 6 '' '' rganometallics 1982, 1, 1560 ' ' '' Co 2 (C) 8, M JC 1992, 57, 5277

12 FIVE-MEMBEED IG FMATI 149 Et 2 C C 2 Et Cp 2 Ti 2, EtMg, C C 2 Et C 2 Et JC 1992, 57, 5803 ing-osing tathesis Tetrahedron 1998, 54, 4413, Acc. Chem. es. 1995, 25, 446. Bu 2 BTf, C 2 2, -78 C P(C 6 11 ) 3 u P(C 6 11 ) 3 C (97%) (82 %) LiB 4, TF, (78%) J. rg. Chem. 1996, 61, 4192 Diazoketones Tetrahedron 1981, 37, 2407; rganic eactions 1979, 26, BF 3 1 TL 1975, FVP of Acetylenic Ketones 1 FVP TL 1986, 27, 19