Matthew D. Shair Monday, November 18, 2002 Chemistry 206 Advanced Organic Chemistry Handout 26B Synthetic Applications of -Diazocarbonyl Compounds An Evans Group Afternoon Seminar Krista B. Goodman January 15, 1999 Chem 206 Synthetic Applications of αααα -Diazocarbonyl Derivatives Krista Beaver Synthetic Applications of α -Diazocarbonyl Compounds An Evans Group Afternoon Seminar Krista Beaver January 15, 1999 Leading References: McKervey and Ye, Chem. Rev. 1994 1091 Doyle, McKervey and Ye, Modern Methods for Organic Synthesis with Diazo Compounds, Wiley, 1998 Diazocarbonyl Compounds: Structure and Nomenclature R' R O NN acid R' R O NN ? , hv or M R' R O cyclopropanation insertion rearrangementylide formation Diazocarbonyl Diazonium solvolysis rearrangement displacement Synthesis of α -Diazocarbonyl Compounds ? First synthesized by Curtius in 1883 by diazotization of α -amino acids RO H O ? Arndt-Eistert synthesis (1927) R O N 2 1. (ClCO) 2 , DMF 2. CH 2 N 2 ? Diazo Transfer R O R' RSO 2 N 3 , base R O R' N 2 ? Acyl Transfer O O N 2 N O O ROH O O N 2 R Arndt and Eistert, Ber. Dtsch. Chem. Ges. 1927 60B 1122 Pettit, JOC 1986 1282 Regitz, ACIEE 1967 733 Badet, JOC 1993 1641 For temporary activation of carbonyl compounds prior to diazo transfer, see Danheiser, JOC 1990 1960 R=Me, Ts, etc. 26B-01 11/11/01 7:59 PM Chem 206 Synthetic Applications of αααα -Diazocarbonyl Derivatives Krista Beaver R R 1 N 2 O R R 1 O XX R R 1 O HX R R 1 O HO R R R 1 O R 2 OR R R 1 O HO T s R R 1 O H O COR 2 R R 1 O HO 2 P(OR 2 ) 2 R R 1 O HS R R R 1 ORS SR R R 1 O R 2 R 3 R R 1 O HS e R R R 1 O R 2 H R R 1 O AcO SeR R R 1 O CN S S e R R R 1 OHO OH R R 1 O HN R 2 R 3 R R 1 O H SiR 3 R R 1 O HB R 2 R R 1 O HO H R R 1 O HP O ( O R ) 2 Some Reactions of α? Diazocarbonyl Compounds Adapted from McKervey, Chem. Rev. 1994 1090 Acid Catalyzed Reactions of Diazo Compounds Review: Smith, Tet. 1981 2407 H 3 C CH 3 O NN acid H 3 C CH 3 O NN Diazocarbonyl Diazonium Common acids include BF 3 ?OEt 2 , HBF 4 , TFA, etc. Mechanism of activation is unclear for both Lewis and protic acids; activation may occur by protonation on C or O Acid-Catalyzed Reactions OMe O N 2 O -25°C, 2 min (82%) O TFA Gibberrellic Acid Mander, JACS 1980 6626 Cl 3 COCO OCOCCl 3 HO O N 2 TFA, -20°C (96%) O O "Having become familiar with the peculiarities of diazoketone chemistry while preparing [other compounds] (and, I might add, inured to handling uncomfortably large quantites of diazomethane), it occurred to us that we might be able to substitute a diazo group for bromine." Lewis Mander Mander, Chem . Comm . 1971 773 Tet ., 1991 134 26B-02 12/20/99 4:05 PM Chem 206 Synthetic Applications of αααα -Diazocarbonyl Derivatives Krista Beaver Smith, TL 1975 4225 Me Me O N 2 BF 3 ?OEt 2 O Me Me (40 - 65%) O Me Me Lindlar's cat. (100%) Smith's cyclopentenone annulation: More Acid Catalysis Olefins as nucleophiles: Me O N 2 Me O Me Me Cl HCl (100%) Mander J asmone O R N 2 O R O OBF 3 N 2 O O R BF 3 ?OEt 2 Mander, Aust. J. Chem. 1979 1975 N 2 O Rearrangement:Polyene cyclizations: O MeMe O MeMe 46% 12% + Smith, JACS 1981 2009 BF 3 ?OEt 2 EtO H O N 2 SnCl 2 EtO O R' O O Me Me Me O O Me Me Me O CO 2 Et RH O BF 3 ?OEt 2 Roskamp, JOC 1989 3258 Ghosh, Chem. Comm. 1988 1421 + EtO 2 CCH N 2 (81%) O Me Me Me Me Br Aplysin (50 - 90%) ββββ -Ketoester synthesis: Ring expansion: Yields are good when R is aliphatic; moderate when aromatic TESO O R H BF 3 ?OEt 2 BnO 2 CCH N 2 (53 - 87%) O RO H CO 2 Et Angle, TL 1998 3119 N S N 2 O O O Me Me CO 2 CH 2 CCl 3 H N S O O O Me Me CO 2 CH 2 CCl 3 H John and Thomas TL 1978 995 ROH, BF 3 ?OEt 2 RO ">60%" Thiols also work well TL 1998 8195 Diastereoselectivity increases with size of R; independent of Lewis acid or protecting group diastereoselection 3:1 - 20:1 Substitution: Tetrahydrofuran Synthesis: 26B-03 12/20/99 4:14 PM Chem 206 Synthetic Applications of αααα -Diazocarbonyl Derivatives Krista Beaver Substitution Reactions N S H 2 NO O O Me Me COOH H NaNO 2 , Br 2 N S O O O Me Me COOH H Br Br Kapur and Fasel, TL 1985 3875 Synthesis of αααα -substituted chiral acids: Me COOH H 2 NH Me N 2 H O OH O Me H O Nu - Me COOH Nu H Ingold, Nature 1950 179 (90%) Nu = Br, Cl, F Displacement occurs with retention of stereochemistry For other examples, see McKervey, Chem. Rev. 1994 1091 Deamination: N S O O O Me Me COOH H Mg Reaction with Boranes BH 3 B 3 EtO 2 CCHN 2 , then D 2 O CO 2 Et DH (97%, 100% d 1 ) O N 2 Bu 3 B OBBu 2 Bu n -BuLi, t hen MeI O BuMe Hooz, JACS 1969 6195 Wojtkowski, JOC 1971 1790 (61%) Base-Induced Reactions R Li O N 2 R O N 2 R 2 OH R 1 R 1 R 2 O Pellicciari, JCS Perkins I 1985 493 Rapoport, JOC 1985 5223 N 2 Li CO 2 Et CO 2 Et N 2 O + O O CO 2 Et O O Rh 2 (OAc) 4 100% + Aldol-type reactions:Ester alkylation:Gilbert-Seyferth Reagent: N 2 H (MeO) 2 OP R 1 R 2 O KO t- Bu R 1 R 2 + Seyferth, JOC 1971 1379 Gilbert, JOC 1982 1837 LDA is the optimal base for lithiation HO N 2 O O MeO O CF 3 COOH Mechanism? 26B-04 12/20/99 4:24 PM Chem 206 Synthetic Applications of αααα -Diazocarbonyl Derivatives Krista Beaver O O Carbenoid Reactions: The Catalysts Rh Rh O O O O O O Me Me Me Me L L Rhodium Acetate Decomposition can be catalyzed by: Heat or light Transition metals, including Cu II , Rh II , Mn II , Fe II , Co II , Ni 0 , Ni II , Zn II , Mo II , Ru II , Ru III , Pd III Most common catalysts: Copper (I):Rhodium (II): Rhodium Carboxylates: Rhodium Carboxamidates: CuOTf, Cu(OTf) 2 , CuSO 4 , CuX, Cu(acac) 2 Much milder catalyst than Cu (introduced in 1973 by Tessié) Structures generally contain bridging ligands and contain a Rh-Rh single bond Rh 2 (OAc) 4 , Rh 2 (tfa) 4 , Rh 2 (oct) 4 , Rh 2 (tpa) 4 , Rh 2 (pfb) 4 Rh 2 (acm) 4 , Rh 2 (cap) 4 , Rh 2 (CF 3 CF 2 CF 2 CONH) 4 Reaction pathways are highly sensitive to steric and electronic effects Review: Padwa, ACIEE 1994 1797 L n MC R 2 N 2 L n MC R 2 B ML n B S: N 2 N 2 R 2 C Transition M etal Catalyzed Diazo Decomposition L n M SCR 2 Doyle, Chem . Rev . 1986 919 Ligand Effects: Selectivity O N 2 O O O O O Rh 2 (OAc) 4 90:10 Rh 2 (pfb) 4 38:61 Rh 2 (acam) 4 100:0 H 3 C N 2 CH 3 O CH 3 H 3 C O H 3 CC H 3 O Rh 2 (OAc) 4 44:56 Rh 2 (pfb) 4 0:100 Rh 2 (cap) 4 100:0 + + Rh(II ) Rh(II ) Doyle, JACS 1993 958 Padwa and Doyle, JACS 1993 8669 Methine versus methyl: Cyclopropanation versus C-H Insertion: H 3 C O H 3 COC H 3 COC Dipolar Cycloaddition versus C-H insertion: HC H 3 N 2 O O Rh(II ) EE O O Ar CH 3 EE O O CH 3 + Rh 2 (OAc) 4 75:25 Rh 2 (pfb) 4 0:100 Rh 2 (cap) 4 100:0 Padwa and Moody, Tet . 1993 5109 More Competition Experiments These results imply that the metal is involved in the transition state Reaction pathways can be controlled by tuning the ligands on the metal Conclusions: 26B-05 12/20/99 4:33 PM Chem 206 Synthetic Applications of αααα -Diazocarbonyl Derivatives Krista Beaver Generalizations: Sigma Bond InsertionOnly intramolecular processes are generally useful ? When X is a heteroatom, insertion is facile Order of selectivity: methine > methylene > methyl 5 - membered ring formation is favored in general ? When X is carbon: R N 2 OEt O X-H catalyst R OEt O XH Reviews O-H Insertion: Moody Tet. 1995 10811 C-H Insertion: Sulikowski Tet. Asymm. 1998 3145 O-H Insertion Reactions CO 2 Me OH OMEM MeO 2 CC O 2 Me N 2 Rh 2 (OAc) 4 CO 2 Me O OMEM CO 2 Me CO 2 Me COOH O OH COOH Chorismic Acid Ganem, JACS 1982 6787 O AcO Me H O H TMSO H H O Me O AcO Me H TMSO H H O Me EtO 2 C P O(OEt) 2 N 2 Rh 2 (OAc) 4 , then NaH (75%, 2 steps) Fuchs, TL 1994 7163 (75%) CO 2 Et "the most complex alkoxyphosphonate yet described" Tandem O-H Insertion/Claisen Rearrangement Me OMe O N 2 O Me OH + Me OCH 3 HO O O Me Wood, JACS 1997 9641 98% ee 95% ee Rh 2 (OAc) 4 O O H Me CO 2 Me Me [3,3] O O H Me CO 2 Me Me slow fast (66%) Wood, JACS 1999 , in press Me OCH 3 HO O O Me Me OMe O O O Me PhH, ? , 20 min O Me HO CO 2 Me Me PhH, ? , 18 hrs Z-Enol Transition State E-Enol Transition State 47% ee (75%) The opposite enantiomer is observed! Merck Thienamycin Process NH H Me OH H N 2 O O ON O 2 O Rh 2 (oct) 4 N H Me OH H O OH CO 2 p -NB PhH, 80 °C 100% N H OH H O S CO 2 NH 3 Salzmann, JACS 1980 6161 Thienamycin 26B-06 12/20/99 4:39 PM Chem 206 Synthetic Applications of αααα -Diazocarbonyl Derivatives Krista Beaver C-H Insertion: Reactions Ph N N 2 O S CO 2 Me Me Me N S Ph H H O CO 2 Me MeMe hv Me AcO Me H H N 2 O OAc Me Me Me H H AcO Me OAc O Rh 2 (OAc) 4 Corey, JACS 1965 2518 Wenkert, JOC 1982 3243 (59%) Rh 2 (OAc) 4 AcO H 3 CO O N 2 AcO H 3 CO AcO H 3 CO O O + (65%) Diastereoselection > 99:1 Adams, JACS 1994 3296 BnO O N 2 O BnO Rh 2 ( 5R -MEPY) 4 O O BnOH 2 C OBn 97% ee O O BnOH 2 C OBn 50% ee Diastereoselection 93:7 Doyle, JACS 1994 4507 + For a review of catalytic enantioselective carbene reactions, see: Doyle, Chem . Rev . 1998 911 Generalizations: Cyclopropanation R N 2 OEt O catalyst R OEt O R 2 R 1 R 1 R 2 + Electron rich olefins work bestBoth concerted asynchronous and stepwise mechanisms have been proposedCyclopropanes can participate in tandem reactions Reviews: Davies, Ald . Acta . 1997 107 Davies, Tet . 1993 5203 For subsequent reactions: Calter, Evening Seminar 1992 Cyclopropanation Followed by Rearrangement Rh 2 (oct) 4 MeO 2 C N 2 OEt H CO 2 Me OEt EtO CO 2 Me Davies, JOC 1992 4309; TL 1992 453 TBSO Me O O TBSO O Me O H TBSO O Me O H Et 2 AlCl (80%) TBSO O Me O O O OH Me HO CO 2 Me H Antheridic Acid Corey, JACS 1985 5574 Cu(TBS) 2 (84%) (87%) Et 2 AlCl (88%) N 2 26B-07 12/20/99 4:46 PM Chem 206 Synthetic Applications of αααα -Diazocarbonyl Derivatives Krista Beaver H Davies, TL 1994 8939 More Cyclopropanation NH NH N O O DMB N 2 Rh 2 (OAc) 4 pinacolone 120°C NH NH N O O DMB NH NH N O DMB Wood, JACS 1997 9461 Rh 2 (TBSP) 4 Ph CO 2 Me N 2 Me Ph CO 2 Me 90% ee Staurosporine (62%) + Me CO 2 Me Ph Me (79%) Corey, TL 1994 5373 Ph OMe N 2 O Rh 2 ( S -TBSP) 4 94% ee 1. KMnO 4 , NaIO 4 2. Me 2 SO 4 , K 2 CO 3 , acetone Li 2 CuCnAr 2 CO 2 Me CO 2 Me Cl Cl 1. 6N HCl, ? 2. ClSO 3 H Cl Cl O + Davies, TL 1993 7243 (79%) (97%, two steps) (82%) (84%) H CO 2 Me Ph Ph H CO 2 Me CO 2 Me Ph Reaction with Aromatic Rings ? Discovered by Büchner (1893) N 2 OEt O E E Büchner, Liebigs Ann. Chem. 1893 214 Doering, JACS 1956 5448 ? Initial experiments gave poor selectivity, but transition metals help... OCH 3 N 2 OEt O ? E H 3 CO + 6 other products N 2 OEt O E H 3 CO Rh (II) + E OCH 3 + Tessié, Chem. Comm. 1980 765 (35%) (73%) JOC 1981 873 hv Büchner Reaction: Confertin Synthesis AcO Me O N 2Me Me AcO Me O Rh 2 (mandalate) 4 Me O Me OTBS H Me Me O H O HH Me Confertin McKervey, Chem. Comm. 1988 1028 JCS Perkins I 1991 2565 26B-08 12/20/99 4:59 PM Chem 206 Synthetic Applications of αααα -Diazocarbonyl Derivatives Krista Beaver Ylide Formation R N 2 OEt O R 2 X catalyst R X OEt O RR X is generally S, O or N and can be sp 2 or sp 3 hybridized Ylides often undergo sigmatropic rearrangements or cycloadditions Reviews: Barnes, Evening Seminar, March 16, 1993 Padwa, Chem. Rev. 1991 263 Padwa, Chem. Rev . 1996 223 [2,3]-Sigmatropic rearrangement:Stevens Rearrangement ([1,2] alkyl shift): R 2 N N 2 R 1 O Rh 2 (OAc) 4 N O R 1 R 2 N O R 2 R 1 West, JACS 1993 1177 OMe SPh O N 2 O S Ph O E SPh E O Rh 2 (OAc) 4 Acorenone B Kido and Kato, JCS Perkins 1 1992 229 H H Dipolar Cycloadditions: Carbonyl Ylides O CO 2 Et N 2 O H HH OAc Me Me HH O O CO 2 Et H AcO Me Me HH O CO 2 Et O Me Me AcO H Dauben, JOC 1993 7635 O R O MeO 2 C N 2 TMSO Rh 2 (OAc) 4 O R O MeO 2 C TMSO O R O MeO 2 C Merck, TL 1994 9185 TMSO (66%) Tigilane Skeleton Zaragozic Acid Skeleton Rh 2 (OAc) 4 (86%) N N OMe O Me O N 2 O Bz N Bz O N MeO 2 C O Me N Bz N O MeO 2 C O Me H H Rh 2 (pfb) 4 N N O Et Me CO 2 Me O N N O Et Me CO 2 Me O O N OO CO 2 Me N 2 Et N Me Rh 2 (OAc) 4 (95%) Padwa, JOC 1995 6258 Padwa, JOC 1995 2704 Lysergic Acid Skeleton Vindoline Skeleton (93%) 26B-09 12/20/99 5:14 PM Chem 206 Synthetic Applications of αααα -Diazocarbonyl Derivatives Krista Beaver Wolff Rearrangement H N 2 R 1 O H R 1 O R 1 O H N 2 OMe Me O OMe OMe O 2 N Ag + , H 2 O COOH OMe Me OMe OMe O 2 N Arndt-Eistert Homologation: Evans, JOC 1993 471 Wolff Rearrangement - [2+2] Cycloaddition O H O O Me TMS N 2 H Me O TMS O O [2+2] Me TMS O Me OE SiO 2 Aphidicolin O O MeH O Ireland, JACS 1981 2446; JOC 1984 1001 (60%) R R Catalyst Glossary Rh 2 (pfb) 4 Rh 2 (OAc) 4 Rh 2 (cap) 4 Rh 2 (MEPY) 4 Rh 2 (MEOX) 4 Rh 2 (MPPIM) 4 Rh 2 (MACIM) 4 Rh 2 ( S -TBSP) 4 Rh 2 ( S -DOSP) 4 Rh 2 (oct) 4 Rh 2 (tfa) 4 Rh 2 (tpa) 4 Rh 2 (acam) 4 or Rh 2 (acm) 4 Rhodium Perfluorobutyrate CF 3 CF 2 CF 2 CO 2 Rhodium Acetate CH 3 CO 2 Rhodium Trifluoroacetate CF 3 CO 2 Rhodium Triphenylacetate Ph 3 CC O 2 Rhodium Octanoate CH 3 (CH 2 ) 6 CO 2 Rhodium Acetamidate CH 3 CONH Rhodium Caprolactamate N M O M Rh 2 (tfm) 4 NH O CO 2 Me N NH O CO 2 Me N NH O CO 2 Me O NH O CO 2 Me O Ph Rhodium Trifluoroacetamidate Copper t -Butylsalicylaldimine N t -Bu OH CF 3 CONH Cu(TBS) 2 Ac N CO 2 TsN CO 2 (CH 2 ) 11 CH 3 O O Rh Rh O O O O O O R R R R All ligands on Rhodium are bridging through the carboxylate or the amide 26B-10 12/20/99 5:22 PM