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
R1 RO 3H O O
O R2 O O R R2 +
R2 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
R1 RO 3H O O
O R2 O O R R2 +
R2 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

CH 3CO 3H O
(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

CH 3CO 3H O
(88%)
O
25 oC, 2 h O [Baeyer- O
O O Villiger O
oxidation]

H O H
TMSOOTMS O
O
BF 3•OEt 2
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 [Nitrile oxide
N N O
1,3-dipolar
aq. NaClO, Me cycloaddition]
Me
CH 2Cl 2, 25 °C (59%) Me

OTBDPS OTBDPS OTBDPS

Zn, AcOH,
(66%)
25 °C, 4 h

OTES O
OTMS O
1. MeOH, O mCPBA, Me
Me
K 2CO 3 AcOH, 25 °C
Me
2. TESCl; [Baeyer-Villiger OH
OH
MeO 2C TMSCl oxidation]
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 LiAlH 4 base
(93%) (73%) (80%)
[Baeyer- O OH O
O Villiger O HO
oxidation]

O
O O O
TFAA/ O
O TFA
H 2O 2
H
[Baeyer- (80%) O
HO
H Villiger HO 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 LiAlH 4 base
(93%) (73%) (80%)
[Baeyer- O OH O
O Villiger O HO
oxidation]

O
O O O
TFAA/ O
O TFA
H 2O 2
H
[Baeyer- (80%) O
HO
H Villiger HO 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 H 2O 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

POCl 3, pyridine 98% 2%

SOCl 2, pyridine 90% 10%
20% aq. H 2SO4 43% 57%
HCl/Et 2O 5% 95%

Need to be careful about reaction conditions not isomerizing the oxime

derivative to achieve appropriate regiocontrol in the rearrangement
 The Beckmann Rearrangement

H 2NOH•HCl MsCl, Et 3N
MeOH, Δ CH 2Cl 2,
O (89%) N OH -25 oC, 1 h 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
H 2NOH•HCl TsCl, Et 3N
OTIPS MeOH, Δ OTIPS CH 2Cl 2,
OTIPS
H (81%) H Δ, 3 h
MeO OMe MeO OMe H
MeO OMe

[Beckmann
rearrangement] (74%)

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

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

 The Hofmann Rearrangement

Br 2, O H 2O
O O
base C or ROH H
NH 2 or N OR
R NH 2 R NHBr [Hofmann N R R
rearrange- R
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
OMe PMPO
OMe RO
PMPO PMPO Br 2,
RO RO O
NaNH 2, NaOMe,
O NH 3 O
MeOH O
O O [Hofmann HO
HO rearrange- N
O ment] C
H 2N O
O O

(93%)

OMe OMe
PMPO
HO RO
R = MOM O
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
O PhO P N O H 2O
PhO 3 C or ROH H
N NH 2 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 DPPA, Et 3N, O
piperidine, AcOH, N
toluene, 25 °C, 18 h toluene, N
O H HO N
(92%) 70 °C, 2 h
O OMe O OMe

[Curtius -[N 2 ]
rearrangement]

OMe OMe OMe

TBSO OTBS TBSO OTBS TBSO OTBS
Rh[(COD)-(R,R)-
DIPAMP]+BF 4- , BnOH, BnOH
H H 2 (3 atm) H 70 °C, 1 h
BnO N BnO N (89%) N
(100%, 96% ee) C
H [Asymmetric O
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, Et 3N, N OBn
HO toluene, Δ
[Curtius
rearrangement]

OMe OMe

(68%)

O O
O O
HN OH HN OBn
H 2, 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, Et 3N,
N OMe H
N OMe benzene, Δ; Br N N O
Br N LiOH in H 2N N
THF/H 2O BnO
BnO H 2N Me O
HO 2C Me H 2N Me
(86%) MOMO
MOMO HO
[Curtius
rearrangement]
MeO
MeO MeO
MeO
MeO MeO
streptonigrone
O

MeO 2C N CO2Me DPPA, Et 3N, MeO 2C N CO2Me

N CO2H
benzene, Δ; H 2N
HO 2C Me H 2O/benzene H 2N Me O
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, Et 3N,
N OMe H
N OMe benzene, Δ; Br N N O
Br N LiOH in H 2N N
THF/H 2O BnO
BnO H 2N Me O
HO 2C Me H 2N Me
(86%) MOMO
MOMO HO
[Curtius
rearrangement]
MeO
MeO MeO
MeO
MeO MeO
streptonigrone
O

MeO 2C N CO2Me DPPA, Et 3N, MeO 2C N CO2Me

N CO2H
benzene, Δ; H 2N
HO 2C Me H 2O/benzene H 2N Me O
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
O N N
HN 3 -H 2O
O HN N
R R R R
R R
H 2O
-N 2

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 NaN 3, O
Bn MeSO 3H
CO2Et NH
(83%) Bn
(>95% ee)
CO2Et

MeO HO
MeO NaN 3,
H 2O,
CF 3CO 2H OMe OMe
OMe Me
Me 25 oC, 30 min, Me
NH N
65 oC, 4 h Me
O (88%)
O analog of morphine

O O
O TiCl 4;
N3 H 2O H N H N
(62%) N
O 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 NaN 3, O
Bn MeSO 3H
CO2Et NH
(83%) Bn
(>95% ee)
CO2Et

MeO HO
MeO NaN 3,
H 2O,
CF 3CO 2H OMe OMe
OMe Me
Me 25 oC, 30 min, Me
NH N
65 oC, 4 h Me
O (88%)
O analog of morphine

O O
O TiCl 4;
N3 H 2O H N H N
(62%) N
O 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 NaN 3, O
Bn MeSO 3H
CO2Et NH
(83%) Bn
(>95% ee)
CO2Et

MeO HO
MeO NaN 3,
H 2O,
CF 3CO 2H OMe OMe
OMe Me
Me 25 oC, 30 min, Me
NH N
65 oC, 4 h Me
O (88%)
O analog of morphine

O O
O TiCl 4;
N3 H 2O H N H N
(62%) N
O 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 of regioisomers) N N
Bz Bz Bz
[Schmidt
rearrangement]
N2O4 (100%)
PPA = polyphosphoric acid
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 of regioisomers) N N
Bz Bz Bz
[Schmidt
rearrangement]
N2O4 (100%)
PPA = polyphosphoric acid
O
O N
". . . after ca. 10 seconds, a N
relatively violent reaction neat,
125 °C, 1 h H
occurred which was accompanied
by a dense cloud of white smoke H
and change in color from the
characteristic yellow-green of the N
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 of regioisomers) N N
Bz Bz Bz
[Schmidt
rearrangement]
N2O4 (100%)
PPA = polyphosphoric acid
O
O O N
CO2R N
O N N
H neat,
-[N2] H 125 °C, 1 h H
H
H H
N
Bz N N
Bz Bz
R=H CH2N2
R = Me

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 2O
O HN 3 H
C or ROH NH 2 + N OR
R OH N R R
HA cat. R
[Schmidt O
reaction]

Acid catalyst usually is H 2SO4, 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 2O
O HN 3 H
C or ROH NH 2 + N OR
R OH N R R
HA cat. R
[Schmidt O
reaction]
-H 2O
Mechanism for process
is not fully elucidated/agreed
O O
upon by the community
R N3
R

Acid catalyst usually is H 2SO4, 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 HN 3 N
R H HA cat. R
[Schmidt
reaction]
mechanism?

O
CN
HN 3
Elmorsy and co-workers,
SiCl4 Tetrahedron Lett, 1995, 36, 2639.
N Br 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 HN 3 N
R H HA cat. R
[Schmidt
reaction]
mechanism?

O
CN
HN 3
Elmorsy and co-workers,
SiCl4 Tetrahedron Lett, 1995, 36, 2639.
N Br 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 S CO2H SH CO2H
S CO2H Ph Ph +
Ph H 2O
OH O

Pummerer Rearrangement (Modern version)

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

Activating agents: HCl, H 2SO4, Ac2O, TFAA, TMSX, PCl 3, 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 S CO2H SH CO2H
S CO2H Ph Ph +
Ph H 2O
OH O

Pummerer Rearrangement (Modern version)

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

Activating agents: HCl, H 2SO4, Ac2O, TFAA, TMSX, PCl 3, 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, CH 2Cl 2; Me
Me CH 2N 2, Et 2O O
O O O SEt
O O SEt 2. PhCO 2Ag,
C5H 9 O
C5H 9 O t-BuOH, 50 °C O
O [Arndt-Eistert CO2Me
CO2Me homologation] C8H15
C8H15
CO2H t-BuO2C
1. mCPBA [Pummerer
2. TFAA, i-Pr 2NEt, rearrangement]
toluene, 0 °C
O Me
H Me
C5H 9 O O O O
O O OO O
O C5H 9 O
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

O Ph Ph
S Ac2O, S
OTBS HO NaOAc; OTBS AcO
then H 2O OH

[Pummerer
rearrangement]

TBDPSO TBDPSO

(37%)

OTBS OTBS AcO 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
CO2Me CO2Me ment] CO2Me

(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 H H OTMS (69% H H
[Pummerer
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
rearrange-
ment]

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

Δ O PR 3 OH
S
[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
rearrange-
ment]

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

Δ O PR 3 OH
S
[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

[2,3- O
R base R R
rearrange-
ment]

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

[2,3- O
R base R R
rearrange-
ment]

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)

NaNH 2,
NH 3 N
N [2,3-
I rearrange-
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

N CO2Me
N CO2Me N Me N CO2Me
N N
NC Me
NC Me t-BuOK NC Me
BnO
BnO [2,3- BnO
rearrange-
MeO ment]
MeO MeO
MeO
MeO MeO
O
oxalic acid,
MeO H 2O
N CO2Me Me N CO2Me Me N CO2Me
H 2N N
HO
O O
H 2N Me Me Me
NC
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
Me 2N
base [2,3-
rearrange-
ment] 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.