Rearrangement Reactions Lecture Notes

O O O O NH

O SPh

See slides for key review articles The Baeyer-Villager Oxidation/Rearrangement

O O O O R O H O

Mechanism:

R1 O R O 1 RO3H O O R2 O O R R + R 2 2 R1 O O R O Criegee intermediate

Alkyl group that migrates does so with retention of configuration

More electron-rich (most substituted) alkyl group migrates in preference

For a review, see: M. Renz, B. Meunier, Eur. J. Org. Chem. 1999, 737. The Baeyer-Villager Oxidation/Rearrangement

O O O O R O H O

Mechanism:

R1 O R O 1 RO3H O O R2 O O R R + R 2 2 R1 O O R O Criegee intermediate

Alkyl group that migrates does so with retention of configuration

More electron-rich (most substituted) alkyl group migrates in preference

For a review, see: M. Renz, B. Meunier, Eur. J. Org. Chem. 1999, 737. The Baeyer-Villager Oxidation/Rearrangement

O CH3CO3H (88%) O 25 oC, 2 h O [Baeyer- O O O Villiger O oxidation]

J. Meinwald and co-workers, J. Am. Chem. Soc. 1960, 82, 5235. R. Noyori and co-workers, J. Org. Chem. 1982, 47, 902. The Baeyer-Villager Oxidation/Rearrangement

O CH3CO3H (88%) O 25 oC, 2 h O [Baeyer- O O O Villiger O oxidation]

H O H TMSOOTMS O O BF3•OEt2 H (75-80%) H [Baeyer- Villiger oxidation]

J. Meinwald and co-workers, J. Am. Chem. Soc. 1960, 82, 5235. R. Noyori and co-workers, J. Org. Chem. 1982, 47, 902. The Baeyer-Villager Oxidation/Rearrangement

O OH N N [Nitrile oxide N O 1,3-dipolar Me Me aq. NaClO, cycloaddition] CH2Cl2, 25 °C (59%) Me

OTBDPS OTBDPS OTBDPS

Zn, AcOH, (66%) 25 °C, 4 h

OTES O O OTMS Me 1. MeOH, O Me mCPBA, K CO AcOH, 25 °C Me 2 3 OH 2. TESCl; OH [Baeyer-Villiger MeO C TMSCl oxidation] 2 OTBDPS (74% overall) OTBDPS OTBDPS

T. Fukuyama and co-workers, J. Am. Chem. Soc. 1999, 121, 3791. For a review, see Classics in Total Synthesis II, Chapter 18. The Baeyer-Villager Oxidation/Rearrangement

MsCl, mCPBA LiAlH4 base (93%) (73%) (80%) [Baeyer- O OH O O Villiger O HO oxidation]

O O TFAA/ O O O H O TFA 2 2 H [Baeyer- (80%) O HO HO H Villiger H oxidation] HO O H farnesiferol C

A. P. Marchand, V. S. Kumar, H. K. Hariprakasha, J. Org. Chem. 2001, 66, 2072. F. W. Demnitz, C. Philippini, R. A. Raphael, J. Org. Chem. 1995, 60, 5114. The Baeyer-Villager Oxidation/Rearrangement

MsCl, mCPBA LiAlH4 base (93%) (73%) (80%) [Baeyer- O OH O O Villiger O HO oxidation]

O O TFAA/ O O O H O TFA 2 2 H [Baeyer- (80%) O HO HO H Villiger H oxidation] HO O H farnesiferol C

A. P. Marchand, V. S. Kumar, H. K. Hariprakasha, J. Org. Chem. 2001, 66, 2072. F. W. Demnitz, C. Philippini, R. A. Raphael, J. Org. Chem. 1995, 60, 5114. The Beckmann Rearrangement

OH OLVG N N H N H2O N O

Versatile reaction to make lactams and amides

Prepared starting from hydroxime, with many leaving groups possible

Alkyl group that migrates does so with retention of configuration, and is always anti to the oxime leaving group

E. Beckmann, Ber. Dtsch. Chem. Ges. 1886, 19, 988. The Beckmann Rearrangement

conditions OH O NH N NH O

POCl3, pyridine 98% 2%

SOCl2, pyridine 90% 10%

20% aq. H2SO4 43% 57%

HCl/Et2O 5% 95%

Need to be careful about reaction conditions not isomerizing the oxime derivative to achieve appropriate regiocontrol in the rearrangement The Beckmann Rearrangement

H2NOH•HCl MsCl, Et3N MeOH, Δ CH2Cl2, O (89%) N -25 oC, 1 h OH N OMs

[Beckmann rearrangement]

Note selectivity DIBAL-H in hydroxime formation (73% over N two steps) N O H H

N. S. Mani, M. Wu, Tetrahedron: Asymmetry 2000, 11, 4687. The Beckmann Rearrangement

HO TsO O N N H H H H2NOH•HCl TsCl, Et3N MeOH, CH Cl , OTIPS Δ OTIPS 2 2 OTIPS (81%) Δ, 3 h H H H MeO OMe MeO OMe MeO OMe

[Beckmann rearrangement] (74%)

O H H Note selectivity N N in hydroxime formation N OTIPS H H MeO ibogamine OMe

J. D. White, Y. Choi, Org. Lett. 2000, 2, 2373. The Hofmann Rearrangement

Br , O H O O 2 O 2 base C or ROH H NH2 or N OR R NH2 R NHBr [Hofmann N R R R rearrange- O ment]

Mechanism:

R group that migrates does so with retention of configuration, and is always anti to the leaving group on nitrogen

A. W. Hofmann, Ber. 1881, 14, 2725; ibid. 1882, 15, 407, ibid. 1882, 15 762. The Hofmann Rearrangement

OMe PMPO OMe OMe RO PMPO PMPO Br , RO RO 2 O NaNH2, NaOMe, O O NH3 MeOH O O O [Hofmann HO HO rearrange- N O ment] C H2N O O O

(93%)

OMe OMe PMPO HO RO O R = MOM O O MeO N O NH Me (+)-cepharamine O

A. G. Schultz, A. Wang, J. Am. Chem. Soc. 1998, 120, 8259. The Curtius Rearrangement

O O P H O O PhO N O 2 PhO 3 C or ROH H N NH2 or N OR R OH (DPPA) R N3 [Curtius R R R rearrange- O ment]

Mechanism:

R group that migrates does so with retention of configuration, and is always anti to the leaving group on nitrogen

T. Curtius, Ber. 1890, 23, 3023. T. Curtius, J. Prakt. Chem. 1894, 50, 275. The Curtius Rearrangement

OMe OMe OMe TBSO OTBS O O TBSO OTBS TBSO OTBS MeO OH O O piperidine, AcOH, DPPA, Et3N, N toluene, 25 °C, 18 h toluene, N O H HO N (92%) 70 °C, 2 h O OMe O OMe

[Curtius -[N ] rearrangement] 2

OMe OMe OMe TBSO OTBS TBSO OTBS TBSO OTBS Rh[(COD)-(R,R)- + - DIPAMP] BF4 , BnOH, BnOH H H2 (3 atm) H 70 °C, 1 h BnO N BnO N (100%, 96% ee) (89%) N H C O [Asymmetric O O O OMe hydrogenation] O OMe O OMe

E. J. Corey, D. Y. Gin, R. A. Kania, J. Am. Chem. Soc. 1996, 118, 9202. The Curtius Rearrangement

O O OH C OH OBn DPPA, Et3N, N OBn HO toluene, Δ [Curtius rearrangement]

OMe OMe

(68%)

O O O O HN OH HN OBn H2, Pd/C

OMe OMe (-)-cytoxazone

M. Carda, F. Gonzalez, R. Sanchez, J. A. Marco, Tetrahedron: Asymmetry 2002, 13, 1005. The Curtius Rearrangement O MeO DPPA, Et3N, N OMe H N OMe benzene, Δ; Br N N O Br N LiOH in H2N N THF/H O BnO BnO 2 H2N Me O HO2C Me H N Me (86%) MOMO 2 MOMO HO [Curtius rearrangement] MeO MeO MeO MeO MeO MeO streptonigrone O

MeO2C N CO2Me DPPA, Et N, MeO2C N CO2Me 3 N CO2H benzene, Δ; H2N H2O/benzene H N Me O HO2C Me 2 Me Br (72%) Br HN [Curtius rearrangement] lavendamycin

D. L. Boger, K. C. Cassidy, S. Nakahara, J. Am. Chem. Soc. 1993, 115, 10733. D. L. Boger, S. R. Duff, J. S. Panek, M. Yasuda, J. Org. Chem. 1985, 50, 5789. The Curtius Rearrangement O MeO DPPA, Et3N, N OMe H N OMe benzene, Δ; Br N N O Br N LiOH in H2N N THF/H O BnO BnO 2 H2N Me O HO2C Me H N Me (86%) MOMO 2 MOMO HO [Curtius rearrangement] MeO MeO MeO MeO MeO MeO streptonigrone O

MeO2C N CO2Me DPPA, Et N, MeO2C N CO2Me 3 N CO2H benzene, Δ; H2N H2O/benzene H N Me O HO2C Me 2 Me Br (72%) Br HN [Curtius rearrangement] lavendamycin

D. L. Boger, K. C. Cassidy, S. Nakahara, J. Am. Chem. Soc. 1993, 115, 10733. D. L. Boger, S. R. Duff, J. S. Panek, M. Yasuda, J. Org. Chem. 1985, 50, 5789. The Schmidt Reaction

General name for three individual reactions

1) Conversion of ketones into amides

N N N N O HN -H O 3 O HN 2 N R R R R R R

H2O

-N2

O R R HN N R R N H R O OH2

Most studied; similar to Beckmann rearrangement with similar migratory aptitude in the vast majority of cases

K. F. Schmidt, Angew. Chem. 1923, 36, 511. The Schmidt Reaction

O NaN3, O Bn MeSO3H CO Et NH 2 (83%) Bn (>95% ee) CO2Et

HO MeO MeO NaN3, H2O, OMe CF3CO2H OMe OMe Me Me o Me 25 C, 30 min, N 65 oC, 4 h NH Me O (88%) O analog of morphine

O O O TiCl 4; N H O N 3 2 H H N N O (62%) O O (+)-sparteine

G. Georg and co-workers, Bioorg. Med. Chem. Lett. 1991, 1, 125 A. G. Schultz and co-workers, J. Med. Chem. 1996, 39, 1956. B. T. Smith, J. A. Wendt, J. Aube, Org Lett. 2002, 4, 2577. The Schmidt Reaction

O NaN3, O Bn MeSO3H CO Et NH 2 (83%) Bn (>95% ee) CO2Et

HO MeO MeO NaN3, H2O, OMe CF3CO2H OMe OMe Me Me o Me 25 C, 30 min, N 65 oC, 4 h NH Me O (88%) O analog of morphine

O O O TiCl 4; N H O N 3 2 H H N N O (62%) O O (+)-sparteine

O NaN3, O Bn MeSO3H CO Et NH 2 (83%) Bn (>95% ee) CO2Et

HO MeO MeO NaN3, H2O, OMe CF3CO2H OMe OMe Me Me o Me 25 C, 30 min, N 65 oC, 4 h NH Me O (88%) O analog of morphine

O O O TiCl 4; N H O N 3 2 H H N N O (62%) O O (+)-sparteine

G. Georg and co-workers, Bioorg. Med. Chem. Lett. 1991, 1, 125 A. G. Schultz and co-workers, J. Med. Chem. 1996, 39, 1956. B. T. Smith, J. A. Wendt, J. Aube, Org Lett. 2002, 4, 2577. Hoffmann-LaRoche Total Syntheses of Quinine (1970s)

O O O NH NH NaN3, PPA, 120 °C, 30 min H2, Rh/Al2O3 H

H (63%) H (98%) H (5:1 mixture N N N Bz of regioisomers) Bz Bz [Schmidt rearrangement] N O (100%) PPA = polyphosphoric acid 2 4 O O N N H

H N Bz

M.R. Uskokovic and co-workers, J. Am. Chem. Soc. 1978, 100, 581 and 589 and references cited therein Hoffmann-LaRoche Total Syntheses of Quinine (1970s)

O O O NH NH NaN3, PPA, 120 °C, 30 min H2, Rh/Al2O3 H

H (63%) H (98%) H (5:1 mixture N N N Bz of regioisomers) Bz Bz [Schmidt rearrangement] N O (100%) PPA = polyphosphoric acid 2 4 O O N ". . . after ca. 10 seconds, a N neat, relatively violent reaction H occurred which was accompanied 125 °C, 1 h by a dense cloud of white smoke H and change in color from the N characteristic yellow-green of the Bz starting material to a dark brown."

M.R. Uskokovic and co-workers, J. Am. Chem. Soc. 1978, 100, 581 and 589 and references cited therein Hoffmann-LaRoche Total Syntheses of Quinine (1970s)

O O O NH NH NaN3, PPA, 120 °C, 30 min H2, Rh/Al2O3 H

H (63%) H (98%) H (5:1 mixture N N N Bz of regioisomers) Bz Bz [Schmidt rearrangement] N O (100%) PPA = polyphosphoric acid 2 4 O O O N CO2R N O N N H neat, H H -[N2] 125 °C, 1 h H H H N Bz N N Bz Bz R = H CH N R = Me 2 2

M.R. Uskokovic and co-workers, J. Am. Chem. Soc. 1978, 100, 581 and 589 and references cited therein The Schmidt Reaction

General name for three individual reactions

2) Conversion of carboxylic acids into amines

O H O O 2 H HN3 C or ROH NH2 + N OR R OH N R R HA cat. R [Schmidt O reaction]

Acid catalyst usually is H2SO4, PPA, TFA/TFAA, or a Lewis acid Especially good for cases where R is hindered Harsher conditions than Curtius/Hofmann rearrangements, but done in fewer steps

K. F. Schmidt, Angew. Chem. 1923, 36, 511. The Schmidt Reaction

General name for three individual reactions

2) Conversion of carboxylic acids into amines

O H O O 2 H HN3 C or ROH NH2 + N OR R OH N R R HA cat. R [Schmidt O reaction] -H2O Mechanism for process is not fully elucidated/agreed O O upon by the community R N R 3

Acid catalyst usually is H2SO4, PPA, TFA/TFAA, or a Lewis acid Especially good for cases where R is hindered Harsher conditions than Curtius/Hofmann rearrangements, but done in fewer steps

K. F. Schmidt, Angew. Chem. 1923, 36, 511. The Schmidt Reaction

General name for three individual reactions

3) Conversion of aldehydes into nitriles

O HN3 N R H HA cat. R [Schmidt reaction] mechanism?

O CN HN 3 Elmorsy and co-workers, SiCl Tetrahedron Lett, 1995, 36, 2639. N Br 4 N Br H (50%) H

Particularly effective for aromatic aldehydes Schmidt rearrangement is the usual by-product What would be a more common, two step way to do the same thing?

K. F. Schmidt, Angew. Chem. 1923, 36, 511. The Schmidt Reaction

General name for three individual reactions

3) Conversion of aldehydes into nitriles

O HN3 N R H HA cat. R [Schmidt reaction] mechanism?

O CN HN 3 Elmorsy and co-workers, SiCl Tetrahedron Lett, 1995, 36, 2639. N Br 4 N Br H (50%) H

Particularly effective for aromatic aldehydes Schmidt rearrangement is the usual by-product What would be a more common, two step way to do the same thing?

K. F. Schmidt, Angew. Chem. 1923, 36, 511. The Pummerer Rearrangement

Original discovery (1909)

O HA SH CO2H S CO H S CO2H Ph + Ph 2 Ph H2O OH O

Pummerer Rearrangement (Modern version)

O activating S R H O agent S R3 Nu 3 3 SH O R3 S R3 R R1 + R1 1 Nu R1 R R2 R R2 2 2

Activating agents: HCl, H2SO4, Ac2O, TFAA, TMSX, PCl3, Sn(OTf)2 Nucleophile: OH, OR, OAr, acids, halogens, thiols, amines

R. Pummerer, Ber. 1909, 42, 2282. For a review, see: A. Padwa, D. E. Gunn, M. H. Osterhout, Synthesis 1997, 1353. The Pummerer Rearrangement

Original discovery (1909)

O HA SH CO2H S CO H S CO2H Ph + Ph 2 Ph H2O OH O

Pummerer Rearrangement (Modern version)

O activating S R H O agent S R3 Nu 3 3 SH O R3 S R3 R R1 + R1 1 Nu R1 R R2 R R2 2 2

Activating agents: HCl, H2SO4, Ac2O, TFAA, TMSX, PCl3, Sn(OTf)2 Nucleophile: OH, OR, OAr, acids, halogens, thiols, amines

R. Pummerer, Ber. 1909, 42, 2282. For a review, see: A. Padwa, D. E. Gunn, M. H. Osterhout, Synthesis 1997, 1353. The Pummerer Rearrangement

Mechanism: The Pummerer Rearrangement

Me Me 1. (COCl)2, CH2Cl2; Me Me CH N , Et O O O 2 2 2 2. PhCO Ag, O SEt O SEt 2 O O O O t-BuOH, 50 °C C5H9 C5H9 O O [Arndt-Eistert CO2Me CO2Me homologation] C8H15 C8H15 t-BuO2C CO2H 1. mCPBA [Pummerer 2. TFAA, i-Pr2NEt, rearrangement] toluene, 0 °C O Me H Me O O C5H9 O O O O O O O O O C5H9 O C8H15 CO2Me HOOC C8H15

(−)-CP-263,114 t-BuO2C

N. Waizumi, T. Itoh, T. Fukuyama, J. Am. Chem. Soc. 2000, 122, 7825. The Pummerer Rearrangement

Ph O Ph S S Ac2O, OTBS NaOAc; OTBSAcO HO OH then H2O [Pummerer rearrangement]

TBDPSO TBDPSO

(37%)

OTBS OTBSAcO O O OMOM

TBDPSO TBDPSO

W. R. Roush, C. Limberakis, R. K. Kunz, D. A. Barda, Org. Lett. 2002, 4, 1543. The Pummerer Rearrangement

O S S S Ph N Ph N Ph N H TFAA, TFA, H H 80 oC, 2 h H H H [Pummerer N N rearrange- N ment] CO Me CO2Me CO2Me 2

(63%)

N N S N H H Ph H hν Raney Ni H H H N (64% over N N H two steps) CO2Me CO2Me CO2Me deethylibophyllidine

J. Bonjoch, J. Catena, N. Valls, J. Org. Chem. 1996, 61, 7106. The Pummerer Rearrangement

O O O O O S Ph TMSOTf, O S Ph O O TMSNEt 2 TBAF H H OTMS H H [Pummerer (69% H H OMe rearrange- OMe overall) OMe ment] solanopyrone D

H. Hagiwara and co-workers, J. Org. Chem. 2002, 67, 5969. [2,3]-Sigmatropic Rearrangements

M. Julia, Tetrahedron Lett. 1974, 2077.

Base - CN CN CN CN O O [2,3- O O rearrangement]

D. A. Evans, Acc. Chem. Res. 1974, 7, 147.

Δ O PR OH S 3 [2,3- S S rearrange- O O ment] [2,3]-Sigmatropic Rearrangements

M. Julia, Tetrahedron Lett. 1974, 2077.

Base - CN CN CN CN O O [2,3- O O rearrangement]

D. A. Evans, Acc. Chem. Res. 1974, 7, 147.

Δ O PR OH S 3 [2,3- S S rearrange- O O ment] [2,3]-Sigmatropic Rearrangements

W. C. Still, J. Am. Chem. Soc. 1978, 100, 1927.

OH I SnBu3 O SnBu3 n-BuLi O R O R base R R [2,3- rearrangement]

E. Vedejs, J. Am. Chem. Soc. 1975, 97, 6878.

Br base (65%) S S S [2,3- rearrange- S ment] [2,3]-Sigmatropic Rearrangements

W. C. Still, J. Am. Chem. Soc. 1978, 100, 1927.

OH I SnBu3 O SnBu3 n-BuLi O R O R base R R [2,3- rearrangement]

E. Vedejs, J. Am. Chem. Soc. 1975, 97, 6878.

Br base (65%) S S S [2,3- rearrange- S ment] The Sommelet-Hauser Rearrangement

Sommelet (1937)

H heat N N N (145 oC) N [2,3- [rearoma- rearrange- tization] ment]

M. Sommelet, Compt. Rend. 1937, 205, 56. S. W. Kantor, C. R. Hauser, J. Am. Chem. Soc. 1951, 73, 4122. The Sommelet-Hauser Rearrangement

Sommelet (1937)

H heat N N N (145 oC) N [2,3- [rearoma- rearrange- tization] ment]

Hauser (1951)

NaNH2, NH3 N N [2,3- I rearrangement]

M. Sommelet, Compt. Rend. 1937, 205, 56. S. W. Kantor, C. R. Hauser, J. Am. Chem. Soc. 1951, 73, 4122. The Sommelet-Hauser Rearrangement

N CO2Me N CO2Me N Me N CO2Me N N NC Me NC Me t-BuOK Me BnO NC BnO [2,3- BnO rearrange- MeO ment] MeO MeO MeO MeO MeO O oxalic acid, MeO H2O

N CO2Me Me N CO Me Me N CO Me H2N N 2 2 HO O O H2N Me Me NC Me HO BnO BnO (35% overall) MeO MeO MeO MeO MeO MeO streptonigrin S. M. Weinreb and co-workers, J. Am. Chem. Soc. 1982, 104, 536. The Sommelet-Hauser Rearrangement

Me Me Me Me PhS N PhS N SPh Me OMe OMe OMe Me2N base [2,3- rearrangement] MeO MeO MeO Me Me Me

aqueous acid (27% overall)

Me Me OH OMe O

MeO MeO Me Me juncusol

D. L. Boger, M. D. Mullican, J. Org. Chem. 1984, 49, 4045.