Willgerodt‐Kindler
Reac1on


Yong
Guan
Jan.
30,
2009


Introduc5on


•  The
Willgerodt
rearrangement
or
Willgerodt
reac5on
is
an
organic
reac5on
conver5ng
an
aryl
alky
ketone
to
the
corresponding
amide
by
reac5on
with
ammonium
polysulfide,
named
aEer
Conrad
Willgerodt.


•  The
related
Willgerodt‐Kindler
reac5on
takes
place
with
elemental
sulfur
and
an
amine
like
morpholine.
The
reac5on
is
named
aEer
Karl
Kindler.


Ar

O

n

HNR2, S8Ar NR2

Shydrolysis

heat n Ar OH

O

n

+ H2S + HNR2

(a) Willgerodt, C. Ber. Dtsch. Chem. Ges. 1888, 21, 534–536. (b) Kindler, K. Liebigs Ann. Chem 1923, 431, 187–207.

Mechanism


Ar

O OHN

Ar

O N

O

H

protontransfer

Ar

HO N

O

H

- H2O NAr

HH

OS8

NAr

SH

O

H

protontransfer NAr

SH

O

H

keto-enoltautomerism NAr

SH

O

N O

Ar

HS

Ar

NSH

O

keto-enoltautomerism

ArN

S

O

ArOH

O

H2O

hydrolysis

Name Reactions and Reagents in Organic Synthesis, 2nd ed; Bradford P. Mundy, Michael G. Ellerd, Frank G., Jr. Favaloro; Wiley-Interscience, pp 690.

Alipha5c
Substrates


Cavalieri, L; Pattison, D. B.; Carmack, M. J. Am. Chem. Soc., 1945, 67,1783.

O

OO O

NH2(NH4)2Sx

20-50%

O

Aroma5c
Substrates


Darabi, H., et al. Tetrahedron Lett., 1999, 40, 7549.

OS8, morpholine

microwave S

NO

81%

OS8, morpholine

microwave S

NO

55-74%

G G

G=Cl, Me, NH2, OMe

Darabi, H., et al. Tetrahedron Lett., 1999, 40, 7549.

Prepara5on
of
Amides
and
Acids


DeTar, D. F.; Carmack, M. J. Am. Chem. Soc. 1946, 68, 2025. Davies, I. W., et al. J. Org. Chem., 2000, 65, 8415.

MeO2S

O1) S8, morpholine

2) NaOH MeO2S

COOH

57%

Three
Components
Reac5ons


Kanbara, T., et al. Synlett, 2007, 17, 2687.

Kanbara, T., et al. Synlett, 2007, 17, 2687.

Three
Components
Reac5ons


Kanbara, T., et al. Synlett, 2007, 17, 2687.

Three
Components
Reac5ons


Kanbara, T., et al. Synlett, 2007, 17, 2687.

The addition of a small amount of Na2S·9H2O into the reaction mixture of sulfur with aniline caused a color change of the reaction system, from pale yellow to deep blue

Protected
Carbonyl
Compounds


Darabi, H., et al. Tetrahedron Lett., 2004, 45, 4167.

Darabi, H., et al. Tetrahedron Lett., 2004, 45, 4167.

Darabi, H., et al. Tetrahedron Lett., 2004, 45, 4167.

Domino
Reac5ons


Neckers, D. C., et al. J. Org. Chem., 2007, 72, 3122.

2-aminobenzo[b]thiophenes

Neckers, D. C., et al. J. Org. Chem., 2007, 72, 3122.