Ritter Reaction

Lisa Marie Ambrosini

Synthesis Literacy Meeting
August 8, 2008
Seminal Papers

1948: Ritter, NYU
1) H2SO4
R' AcOH O R' R'
+ R CN R'' NaOH R''
R'' 2) H2O R N Me H2O HN Me
H

1) H2SO4
R' R''' O R' R'
AcOH NaOH R''
OH + R CN R''
R'' 2) H2O R N R''' H2O HN R'''
H

Yields: 12-90 %

Mechanism

R' R''' O R' O

R' R' R''' OH R''
H H
R''' N CR N C R N C R R''' N R
R'' R'' R'' H

Limitations:
-Only works for species that can form a stable carbocation
- Very harsh acidic conditions

Ritter, J. J., Minieri, P.P., J. Am. Chem. Soc., 1948, 70, 4045.
Ritter, J. J., Kalish, J., J. Am. Chem. Soc., 1948, 70, 4048.
Activation of Primary and Secondary Alcohols

Activation by Chlorodiphenylmethylium Hexachloroantimonate

1) Ph2CClSbCl6
H
R' OH
RCN N R
R'
2) H2O
O

- 12 examples with ranging from 50-86 %

Mechanism
R'' Ph R'' Ph R'
Cl -HCl RCN
R' O Ph R' O Ph R'' N CR
H

Barton, D. H. R., et. al, JCS Perkin Trans. 1, 1974, 2101.

Activation by Triflic Anhydride

R' R''' 1) Tf2O, RCN O R'

R''
OH
CH2Cl2
R N R'''
R'' 2) NaHCO3 H

Yield
Primary 75-90 %
Secondary 68-75 %
Tertiary 50 %

Martinez, A. G., et. al, Tet. Lett., 1989, 30, 581.

Modification for Synthesis of N-Primary-alkyl Amides

Methyl and primary alkyl donors

1) alkyl donor O
R CN acid
R'
2) H2O R N
H

R' = Me, Et
acid = H2SO4, PPA, TfOH, ClSO3H

O O O
alkyl donors: R'OH P B(OR)3 O
Me OR' R'O OR' R' SO2Me
OR' R'O OR'

- yields range from 48-95 %

- temp: 100-140 °C

Reactive species
MeOH + H2SO4 MeHSO4

O H
O
+ H2SO4
Me OMe Me OMe

- Offer equivalents of electrophilic methyl

Lebedev, M. Y., et. al, Tet. Lett., 2002, 43, 1397.

Other Alkyl Donors

tert-Butyl Amides from tert-Butyl Acetate

O Me
CN Me
O Me H2SO4 (cat)
+ Me N Me
42 °C H
Me O Me
X
X

X: H, Me, OH, MeO, CF3, CF3O, F, Br, SMe

Ar: phenyl, naphtyl, pyridyl, thiophenyl

- yields 88-95 %
- only requires catalytic acid
- 2-6 hr

Reddy, K. L., Tet. Lett., 2003, 44, 1453.

HCN Equivalent for Synthesis of Formamides

Intermediate in synthesis of a series of tachykinin NK3 antagonist analogues
H O
Ph OH 1) NaCN Ph Ph N
H2SO4
AcOH +
N
2) H2O N
N
Bn Bn Bn
80 % 17 %

H O
Ph OH 1) Me3SiCN Ph N
H2SO4
AcOH - 14 examples range in yields from 14-95 %
for tertiary and secondary alcohols
N
2) H2O N
Bn Bn
70 %

Mechanism
H H
R' R' R''' O
H H R' R''' O
R''' N CSiMe3 N C SiMe3 N C SiMe3
R'' R'' R''
O
H H

-HOSiMe3, -H+

R' O R' R''' OH

R''
N C H
R''' N H R''
H

Chen, H. G., et. al, Tet. Lett., 1996, 37, 8129.

Transition Metal Activation

Chromium Tricarbonyl Complexes of Benzyl Alcohol Derivatives

R' R'
R R''CN R O
Cr OH H2SO4 Cr HN
OC CO OC CO R''
CO CO

R: Me, OMe, H
R': H, Me, Ph yields: 82-99 %
R'': Me, Ph

Complex provides stereochemical control

O
OH NH
Me
MeCN
Cr
H2SO4
Cr
OC CO OC CO
CO CO

racemic mixture 89 % yield

optically pure

- asymmetric induction
- complete inversion of configuration

Jaouen, G., et. al, J. Org. Chem., 1981, 46, 78.

Electrophilic Activation

Electrophilic activation of Ritter Reaction
O
E
H
E MeCN HN Me N Me
R + E + R
R H2O E
R O

- Heteroatoms shown to mediate reaction: F, Br, I, N, Se, S

Warren, S., et. al, Synthesis., 2002, 17, 2124

Selenium-Mediated Reaction and references therein.

PhSeCl SePh
TfOH H2O2/H2O
O O
MeCN/H2O THF
NH NH
Me Me

-14 examples range in yields from 36-98 %

Sulfur-Mediated Reaction O
OH
TfOH Ph HN Me
SPh H
S
C5F5 MeCN/H2O SPh
R C5F5
95 % yield
97 % ee
- 8 examples range in yields 68-96 % and ee's of 86-100 %

Toshimitsu, A., et. al, J. Org. Chem., 1981, 46, 4727.

Toshimitsu, A., et. al, Tet. Lett., 1991, 32, 4317.
Mercury Activation

Mercury-Mediated Reaction
Me
O
1) Hg(NO3)2 N ONO2
R MeCN/H2O HN Me
2) NaBH4 R
R Me
NaOH HgNO3

- 6 examples ranging in yields of 50-95 %

Brown, H. C., et. al, J. Am. Chem. Soc., 1969, 5647.

Heathcock's Total Synthesis of Aristotelone

CN Me Me
1) Hg(NO3)2 Me O
HN
CH2Cl2 H N
+ H Me
2) NaBH4 N
N Me
H MeOH N
H Me
(+)-Aristotelone
39 % over 2 steps
(+)-Makomakine

Heathcock, C. H., Stoermer, D.l J. Org. Chem., 1993, 58, 564.

Lewis Acid Catalyzed Reactions

Metal Triflate Catalysis

Me Me O
1) Bi(OTf)3 (20 mol %) Me
RCN +Me OH
Me
2) H2O Me N R
H
R = alkyl, aryl
- 19 examples ranging in yields from 50-95 %
- only tertiary alcohols

Callens, E., et. al, Tet. Lett., 2006, 8699.

Synthesis of Ureas, Acylureas, and Sulfonylureas

Me O Me
R Me
BF3•Et2O
N C N + Me OH R
N N Me
Ar Me H
Ar
R = aryl, acyl, sulfonyl
- 18 examples ranging in yields of 37-84 %

Anatol, J., et. al, Synthesis, 1975, 111.

Intramolecular Ritter Reactions

Diastereoselective Synthesis of NK1-antagonists

- potential dopamine receptor ligand O
O OMe
O
RMgBr OMe TfOH
OMe
CN PhCl
CN R HN
R OH
O O
R = Me, Ph, thienyl yields: 67-92 %
e.e. : 50 - 98 %

Compernolle, F., et. al, Org. Lett., 2000, 2, 3083.

Unexpected Dimerization
O O
Me O
Me Me Me Me
H2SO4 HN
+ N NH
Me CN NH
Me Me Me
Me N
O Me Me

4 % yield 27 % yield not observed

Duckner, J.W., et. al, Aust. J. Chem., 1968, 21, 2809.

 Diastereoselective Ritter Reactions

Diastereoselective synthesis of acylaminopyrrolidines
OBn O iPr OH
iPrCN 6M HCl
N
O OH O NHCOiPr
N BF3•Et2O N MeOH O N
Bn Bn
Bn
70 % yield
95 % e.e.

Mechanism
OBn

OBn OBn iPrCN

O N N CiPr
BF3•Et2O Bn
O N OH O N
Bn Bn iPrCN
OBn

O N N CiPr
Bn

Bn
O O iPr
O Me iPr iPrCN
Me H2O C N Bn +
N N
NHBn O O N
Me N
Me Bn Bn

Morgan, I. R., et. al, J. Org. Chem., 2008, 73, 2943.

Tandem Reactions

Tandem Prins-Ritter
O
NH
Me
O
CeCl3•H2O
H + AcCl
OH O
MeCN
RT
88 % yield
- primary and secondary homoallylic alcohols
- aromatic aldehydes, aliphatic ketones
- yields range from 80-94 %
- complete cis selectivity

Mechanism
CR''
R' N
O CeCl3
R'
O R R'
R H HO O R
O CeCl3
H
AcO-

O R''

HN N OAc
R' R''
O R R'
O R

Yadav, J. S., et. al, Tet. Lett., 2007, 48, 4903.

Tandem Reactions

Phosphomolybdic Acid Catalysis O
NH
Me
O

H
PMA (20 mol %)
+ OH O
MeCN
RT
90 % yield

- essentially same substrate scope, but protic acid instead

Yadav, J. S., et. al, Tetrahedron, 2008, 64, 3025.

O

Sakurai-Prins-Ritter NH
O Me
+ TMS Bi(OTf)3 (10 mol %)
R H MeCN R O R
2 eq. RT
R = aryl, alkyl
- 11 examples with yields ranging 60-98 %
-high diasteroselectivity
-also show other aromatic and aliphatic nitriles

Yadav, J. S., et. al, Tet. Lett. accepted manuscript.

Examples from Total Synthesis

Ho's Total Synthesis of Isocyanoallopupukeanane

H O
Me N
Me 1) NaCN Me Me H
AcOH/H2SO4
2) H2O
Me Me
Me 70 % Me

OTs
N
NC
Me Me H
TsCl Me Me
pyridine
90 % Me
Me
Me
Me

(±)-isocyanoallopupukeanane

Ho, T. -L., et. al, J. Org. Chem., 2000, 65, 5774.

Modified Ritter for Synthesis

Janin's Synthesis of a library of analogues of PK11195

- series of eletron-rich carboxylisoquinolines

O Me
CN
N
O
+ HBF4
MeO OMe O Et2O
OMe O 17 % MeO OMe
OMe

- standard Ritter conditions led to extensive decomposition

Janin, Y. L., et. al, Tetrahedron, 2004, 60, 5481.

 Ritter Reaction in Pharmaceutical Synthesis

Indinavir (Crixivan)
N OH OH
H
N N
-HIV protease inhibitor N Me
-introduced by Merck in 1996 Me
O
Me N O
H

N Me NH2
Jacobsen O
epoxidation oleum 1) H2O
O OH
MeCN 2) L-tartaric acid
base
> 99% e.e.
78 % yield 50 % yield

Mechanism H
N Me

O
N CMe fast
O
H+ MeCN
OH OH

slow H Me
N

Reider, P. J., et. al, Tet. Lett., 1995, 36, 3993.