Amination: An Overview

39 Pages·2008·1.65 MB·English

Amination: An Overview
Roxanne Atienza
Long Literature Presentation
September 22, 2008
The definition of amination
- The process by which an amine group is introduced into an organic molecule
through the formation of a new C-N bond.
O
NH
R R
1 1) O KOH 1
R X R NH
2 2) H NNH 2 2
2 2
Gabriel Amine Synthesis
Gabriel, S. Ber. Dtsch. Chem. Ges. 1887, 20, 2224.
Pd0 catalyst
NaOt-Bu
X + H NR' NHR'
2
dioxane
R 100oC R
Buchwald-Hartwig Reaction
Guram, A. S.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 5969-5970.
Importance of Nitrogen
- Nitrogen is a constituent element in amino acids, proteins, and nucleic acids.
- Carbon-nitrogen bonds are found in the majority of organic molecules,
especially biologically active molecules.
- Nitrogen containing compounds are valuable and commercially important bulk
chemicals and pharmaceuticals.
- Nitrogen is involved in important biological linkers such as peptide linkers.
- The lone pair on nitrogen allows for hydrogen bonding which is key in the 3D
structures adopted by DNA and proteins.
F
F Me
NH O
2 CO H
O HN 2
N
N O
N
F N OMe
H PO H O CF
3 4 2 3
O
Januvia (Merck)
Dynemycin
inhibitor of DPP-4
promising anti-cancer drug
for treatment of type 2 diabetes
Types of Amination
- Electrophilic Amination
Combination of nucleophilic carbon and an electrophilic aminating agent
R R
1 1
+ Nuc + Z
N N
R Z R Nuc
2 2
- Reductive Amination
Conversion of a carbonyl group to an amine via an intermediate imine and its subsequent
reduction
O -H O NR1 H NHR1
R1NH + 2
2
R2 R3 R2 R3 R2 R3
- Hydroamination
Addition of an N-H bond over an alkene or alkyne
HNR NR
R 2 2 or R NR2
catalyst R Me
- Nucleophilic Amination
Introduction of an amino group via a nucleophilic aminating agent
Example: Gabriel amine synthesis
Electrophilic Amination
Combination of nucleophilic carbon and an electrophilic aminating agent
R R
1 1
N + Nuc N + Z
R Z R Nuc
2 2
- This can be accomplished through the use of various aminating agents such as:

Me O
- hydroxylamines - oxaziridines
O N NEt
H N S O 2
2
O
2 Ar
- oximes O H - azido compounds
N
R1 R2 Ar S N3
O
2
- azo compounds - nitroso compounds
CO Et O
N 2
N
N R
EtO C
2
Electrophilic Amination with hydroxylamines
- O-sulfonylhydroxylamines: synthesis of N-protected amines
O
n-BuLi
n-BuLi 71%
Me Me t-BuO N
O O H
n-BuLi
O O
t-BuO N S t-BuO N S
THF O
H O O
2 –78 oC Li 2 PhCu Ph
t-BuO N 40%
1
H
Genet, J.P.; Mallart, S.; Greck, C.; Piveteau, E. Tetrahedron Lett. 2008, 32, 2359-2362.
Asymmetric synthesis of !-amino acid derivatives
O
O O O
Ph N O 1) n-BuLi, –78 oC LiBocNOTs 1
2) CuCN, Ph Xc Ph Xc Ph Xc
–78 oC to 0 oC Li CuCN NHBoc
77%, >99% de
Zheng, N.; Armstrong III, J. D.; McWilliams, J. C.; Volante, R. P. Tetrahedron Lett. 1997, 38, 2817-2820.
Electrophilic Amination
- O-acylhydroxylamines: synthesis of secondary and tertiary amines
NH O O Ph KHD2MPFO4 N O Ph [CuORT2fZ]2n·C6H5 N R
Ph O
O O O O
O
CO Et
2
Bn Ph
N N N
80% 91% 77%
O O O
Berman, A. M.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126, 5680-5681.
- O-phosphinylhydroxylamine
NHAc
1) KOt-Bu, THF, –78 oC
OEt OEt
2) ArPO NH 2, –78 oC ~ 23 oC
2 2
O 3) Ac O, Et N O
2 3
67%
MeO
O
P
ONH
2
MeO
2
Smulik, J. A.; Vedejs, E. Org. Lett. 2003, 5, 4187-4190.
Electrophilic Amination
- O-trimethylsilylhydroxylamine
Me Si SiMe Me Si SiMe
3 3 3 3
+ R Cu(CN)Li + RCu(CN)Li + R-H
N O 2 2 N O
H Li
SiMe
3
O
Li CN Cu
SiMe
3
N SiMe
R H R N 3 R
N
Cu C Li
Casarini, A.; Dembech, P.; Lazzari, D.; Marini, E.; Reginato, G.; Ricci, A.; Seconi, G. J. Org. Chem. 1993, 58, 5620-5623.
Electrophilic Amination with oximes
General scheme
OR3 R4
N + R4M N H3O R4NH
2
R1 R2 R1 R2
(+ MOR3)
Competing side reactions
- Neber rearrangement - Beckmann rearrangement
OR3 O OR3 R1 O
R1 N R2 base R1 N R2 R1 N R2 H2O R1 R2 R1N R2 N H2O R2 NH R1
NH
H 2 R2
(+ HOR3) (+ –OR3)
Electrophilic Amination
O-tosyloximes
- tetraphenylcyclopentadienone O-tosyloxime
OSO p-Tol O O
N 2 Li N OSO2p-Tol N NH2OH NH2 N OH
Ph Ph + THF aq. pyridine +
–78 oC Ph Ph Ph Ph Ph Ph
O O
Ph Ph
Ph Ph Ph Ph 90% Ph Ph
95%
Hagopian, R. A.; Therian, M. J.; Murdoch, J. R. J. Am. Chem. Soc. 1984, 106, 5753-5754.
- bis[3,5-bis(trifluoromethyl)phenyl]ketone O-tosyloxime
OSO p-Tol
N 2 R= Ph, 96%
F C CF toluene R 1) H3O Et, 87%
3 3 + R-MgBr rt N 2) BzCl, Et3N R-NHBz t-Bu, 35%
Ar Ar Me
CF CF
3 3
98%
3
Me
Tsutsui, H.; Ichikawa, T.; Narasaka, K. Bull. Chem. Soc. Jpn. 1999, 72, 1869-1878.
Ar
OTs
N
MgCl N Ar 1) HCl aq. NHAc
Ph Me Ar Ar Ph Me 2) AcCl, Et3N Ph Me
25%, 90% ee
toluene
ca. 91% ee
–70 oC
Hoffman, R. W.; Holzer, B.; Konpff. Org. Lett. 2001, 3, 1945-1948.