Organic Azides
An Exploding Diversity of a Unique Class of Compounds
R N N N
R N N N
R N N N
R N N N
Changkun Li
（李长坤）
March 31st 2006
1
Dedicated to Professor Rolf Huisgen
Bräse, S. et al Angew. Chem. Int. Ed. 2005, 44, 5188 – 5240
2
1
Compounds with NN Multiple Bonds
2N
N2 X
H
N2
N
N
N N
N N
X
H
3N
Ph N
N
N
N N N
3
Organic Azides
1 Introduction
2 Synthesis of Organic Azides
3 Reactions of Organic Azides
4 Applications of Azides
5 Summary and Outlook
6 Acknowledgement
4
2
Property of Sodium Azide
5
Physicochemical Properties of Organic Azides
Ph N
N
N
1-phenyl-1H-triazirine
R N3
1
R N N N
R N N N
R N N N
1a
1b
1c
R N N N
1d
N3
O2 N
NO2
N3
N3
NO2
Kaiser, M. et al Propellants Explos. Pyrotech. 2003, 27, 7 – 11
6
3
Physicochemical Properties of Organic Azides
R N3
1
R N N N
R N N N
R N N N
1a
1b
1c
A Pseudohalide
R N N N
1d
Polarities
Boiling points
Chromatographic property
Hammett Parameters
Directing Effect
(NC + NO)/NN≥ 3
b.p. 152oC
Ν3
7
Synthesis of Organic Azides
R N N N
R N N N
R N N N
R N N N
N3
N3
N3
O
N3
8
4
Synthesis of Aryl Azides
Aryl Azides from Diazonium Compounds
Ar
ΝaΝ3
Ar-N N
N N N
N N
-N2
N N N
N N
-N2
Ar
Ar N N N
Ar
N N
-N2
N
N+
N–
-N2
Ar N
N N
N N
N N
Ar N
N N
Butler, R.N. et al J. Chem. Soc. Perkin Trans. 2, 1998, 2243 – 2247
9
Synthesis of Aryl Azides
Nucleophilic Aromatic Substitution: SNAr Reactions
Cl
N
R
NO2
N
NaN3
R
N3
NO2
N
PhMe
up to 96%
N
R
O
N
O
Wilson, W. S. et al J. Org. Chem.1990, 55, 3755 – 3761
Aryl Azides from Organometallic Reagents
I
Mes
1) nBuLi, 0oC
Mes 2) TsN3
N3
Mes
Mes
96%
Tilley, T. D. et al Organometallics 2002, 21, 5549 –5563.
10
5
Synthesis of Aryl Azides
Aryl Azides by Diazo Transfer
+
CF3SO2N3
N
aq. CuSO4, Et3N
CH2Cl2/MeOH
N
95%
N3
NH2
Tor, Y. et al Org. Lett. 2003, 5, 2571 – 2572.
Wong, C.H. et al J . Am. Chem. Soc. 2002, 124, 10773-10778-811
Synthesis of Alkenyl Azides
Hassner’s Methods
R
R
H
IN3
R
H
I
H
N3
R
H
H
-HI
R
R
N3
Hassner, A. et al J. Am. Chem. Soc. 1965, 87, 4203 –4204
Hassner, A. Acc. Chem. Res. 1971, 4, 9 – 16.
Knoevenagel Reaction of Aldehydes and Azidoacetate
OMe
CHO
N
N3CH2CO2Me
NaOMe, MeOH
OMe
CO2Me
-10oC
N
N3
o-xylene
OMe
67%
N
N
H
CO2Me
Molina, P.and Fresneda, P. M. et al J. Org. Chem. 2003, 68, 489 –499.
12
6
Synthesis of Alkenyl Azides
Via a-Oxophosphonium Ylides
X
O
R2
R1
PPh3
NBS, NCS or NIS
Me3SiN3
RT, 5min
R1
N3
O
O
R2
R1
R1
X
R1
N
X
R2
NXS
R2
R1
PPh3
O
heptane
98oC, 2-3h
37-98%
R2
PPh3
R1
O
X
Y
R2
PPh3
-OPPh3
R2
PPh3
-OPPh3
R2
PPh3
O
R1
X
R1
X
Y
R2
Y
X
Y
1
R2
R
e Melo, D. P et al Tetrahedron 2001, 57, 6203 – 6208.
13
Synthesis of Alkyl Azides
Classic Nucleophilic Substitution
OH
11
Cl2C=S, Py
DMAP(cat.)
o
CO2Et CH2Cl2, 0 C
OH
S
O
O
11
95%
CO2Et
NaN3, DMF
PPTS, 0oC
OH
87%
CO2Et
11
N3
Bittman, R. et al J. Org. Chem. 2000, 65, 7627 –7633
Ring Opening of Epoxides by Azide
O
Me3SiN3(20eq)
catalyst(0.2eq)
Et2O, 24h
N3
H
N
OH
t Bu
H
N
Cr
O Cl O
tBu
tBu
tBu
Jacobsen, E. N. et al J. Am. Chem. Soc. 1995, 117, 5897 – 5898.
14
7
Synthesis of Alkyl Azides
The Mitsunobu Reaction
Boc
NH O
OMe
Boc
PPh3, HN3
DEAD, CH2Cl2
NH O
OMe
90%
OH
Boc
H2, 10% Pd/C
EtOAc
O
OMe
99%
N3
NH
NH2
Lee, Y.S. et al Tetrahedron 2001,57, 2139 – 2145
Alkyl Azides by Diazo Transfer
H2N
Tf2O, NaN3
then CuSO4, K2CO3
CO2H
N3
CO2H
84%
Ghadiri, M. R. et al J. Am. Chem. Soc. 2003, 125, 9372 – 9376.
15
Synthesis of Alkyl Azides
Polar 1,2- and 1,4-Addition Reactions
O
Me3SiN3, HOAc
cat. NR3, CH2Cl2
O
25oC, 20h
90%
N3
Miller, S. J. et al Org. Lett. 1999, 1,1107 – 1109.
1) Ph3P
O
OMe
Br
N
Ac
OAllyl
N3
O
O
C6H6, Reflux
2) Me3SiN3, MeSO3H
M.S.(4A), CH2Cl2
OAllyl
Br
N
Ac
Kawasaki, T. et al Org. Lett. 2000, 2, 3027 – 3029.
16
8
Synthesis of Alkyl Azides
1,2-Addition to Non-Activated Double Bonds
PhI(OAc)2
(PhSe)2, NaN3
Ν3
78%
PhI(OAc)2 +
R
R
.
N3
SePh
2N3
.
+
.
PhI +
R
N3
.
R
+ PhSeSePh
+
2N3
2AcO
N3
N3
+
.
PhSe
PhSe
.
PhSeSePh
2PhSe
Tingoli, M. et al J. Org. Chem. 1991, 56, 6809 – 6813
17
Synthesis of Alkyl Azides
π-Allylpalladium Complexes
X
[Pd(dba)2], PPh3
[15]crown-5, THF
NaN3
X=OMs, OTs, OAc
81-85%
L
X
Pd
1)HS(CH2)3SH
2)(Boc)2O
N3 3) RuCl , NaIO
3
4
4) HCl
5) Dowex
42%
L
NH3
CO2
Salaön, J.et al Tetrahedron: Asymmetry 1998, 9, 1131 –1135.
C–H Activation
ΟΑc
O
IN3, MeCN
, 1h
98%
ΟΑc
O
N3
Bols, M. et al Angew.Chem. Int. Ed. 2001, 40, 623 – 625.
18
9
Synthesis of Acyl Azides
R1
R1
1)SOCl2, benzene
R1
OH 2)NaN3, Et2O/H2O
O
N3
O
O
O
R2OH
O
O
OR2
N
H
, benzene
R1
N
O
C
(R3)2Cu(CN)Li2, H3O
or
R3MgX, H3O
O
R1
O
R3
N
H
O
Padwa, A. et al J. Org. Chem. 1999, 64, 3595 – 3607
O
Cl
Me
N
N
Me
Me
N
N
N
Cl
N
Cl
N
N
CH2Cl2
0-5oC
Cl
N
O
Me N
O
R
O
O
N
O
R
Cl
O
N
O
N
R
OH
O
Cl
O
NaN3
O
O
25oC
R
N3
R
Bandgar, B. P. et al Tetrahedron Lett. 2002, 43, 3413 –3414. 19
Synthesis of Acyl Azides
DPPA Activation
MeO2C
CO2Me
1) LiHMDS, tBuSCH2Cl
2) PLE, pH 7.2 buffer
PMBO
CO2Me
10% TFA
CH2Cl2
CO2Me
HN
87%
HO2C
74% yield, 91%ee
t BuS
tBuS
1)Ph2P(O)N3, Et3N
(CH2Cl)2, 100min
tBuS
O
2) PMBOH, reflux, 4h
CO2Me
N3
t BuS
72%
H2N
CO2Me
O
Kedrowski, B. L. J. Org. Chem. 2003, 68, 5403 – 5406.
Solid-phase Synthesis
O
DPPA
TEA
toluene
O
HO
O
O
O
toluene
90oC
O
N3
O
O
O
RNH2
CH2Cl2
HN
N
H
C
N
O
O
R
O
O
K2CO3
MeCN, 60oC
R
>90% yield
>70% purity
O
N
N
H
Castelhano, A. L. et al Tetrahedron Lett. 1998, 39, 7235 – 7238.
20
10
Summary : Synthesis of Organic Azides
Aryl Azides
N2
N3
O2N
Alkenyl Azides
Mes
N3
Mes
O
O
IN3
N3
N3
N
R2
1
OEt
R
PPh3
N
NBS, NCS or NIS
Me3SiN3
Alkyl Azides
O
O
PPh3, HN3
DEAD, CH2Cl2
NaN3
PhI(OAc)2
X
(PhSe)2, NaN3
Acyl Azides
Cl
N
O
R
Cl
NaN3
Cl
N
N
Me N
Cl
Ph2PON3
O
21
Organic Azides
1 Introduction
2 Synthesis of Organic Azides
3 Reactions of Organic Azides
4 Applications of Azides
5 Summary and Outlook
6 Acknowledgement
22
11
Reactions of Organic Azides
Electrophiles
Nucleophiles
Nu
E
R N3
......
R N N N
1 2 3
Nitrene Chemistry
X Y
R
Click Chemistry
Cycloaddition
23
Reactions with Electrophiles at N1
Boyer Reaction
LA
O
O
+
N3
R
N2
N
O
R
N
R
Aubé, J. et al J. Am. Chem. Soc. 1991, 113, 8965 –8966
Boyer Reaction : Asymmetric Version
N3
OH
+
O
Ph Me
Me Ph OH
BF3 .OEt2
O
Ν
N2
N
O
Aubé, J. et al J. Am. Chem. Soc. 2003, 125, 7914 –7922
24
12
Reactions with Electrophiles at N1
Boyer Reaction : Epoxides as Electrophiles
O
N3
BF3 .OEt2
CH2Cl2, 2min
N
O
94%
Murphy, J. A. et al Org. Lett. 2003, 5, 3655 – 3658
Possible Pathway
N2
N
O
N3
N
BF3 -N
2
O
BF3 .OEt2
O
BF3
N
O
BF3
N
-BF3
O
25
Reactions with Electrophiles at N1
Nitrenium Ions by Protonation of Organoazides
O
Ph
O
2HN3
H2SO4
O
NH
N
76%
O
O
HN Ph
O
Casey, M. et al ARKIVOC. 2003, 7, 310 – 327.
Nitrenium Ions by Others
CO2Et
Tf2O, 0oC
CHCl3
EtO2C
NH2
70%
Ν3
Abramovitch, R. A. et al Tetrahedron Lett. 2003, 44, 6965 – 6967
26
13
Reactions with Electrophiles at N1
Imine Salts
Ν3
Ν3
O
Br
BrCOCOBr
N
N
N
82%
N
N
Br
N
Br
N
Br
N
PhOMe
N
N
Br
Br
Shibasaki, M. et al Angew Chem. Int. Ed. 2004, 43, 478 – 482.
HeteroCumulenes
Ν
C
N3
3
octane, 125oC
24h
93%
O
Cl
N N
N
N
O
S
O
O
S
Cl
O
3
O
G. J. Ho (Merck, USA), US Patent 13595P, 1996
27
Reactions with Electrophiles at N1
Reaction of Organoazides with Boron Compounds
B Cl +
N
HCl (excess)
N3
86%
Vaultier, M. et al Synlett , 1993, 519 – 521.
Reaction of Organoazides with Activated Alkynes
n-Bu
N
N
N
AuL
n-Bu
N
N
N
n-Bu
n-Bu
n-Bu
n-Bu
AuL
n-Bu
N
N
n-Bu
n-Bu
H
N
n-Bu
AuL
Toste, F. D. J. Am. Chem. Soc. 2005, 127, 5802-5803.
28
14
React with Nucleophiles at N3
The Staudinger Reduction
RN3 + PR'3
-N2
R N N N PR'3
H2O
R N PR'3
R NH2 + O=PR'3
Possible Mechnism
PR'3
R N N N
R N N N PR'3
R N N N PR'3
N PR'3
N N
R
N
N
PR'3
-N2
N R
R N PR'3
29
React with Nucleophiles at N3
The Staudinger Ligation
O
..
R
Ph
O
OMe
N3-R'
P
OMe
R
N2
Ph
N R'
P N R'
Ph
Ph
O
O
OMe R
P
Ph Ph
H2O
N
H
P=O
Ph
Ph
R
R'
Bertozzi, C. R. et al. Science 2000, 287, 2007 – 2010
Bertozzi, C.R. et al J. Am. Chem. Soc. 2005, 127, 2686-2695
Application in Peptides Synthesis
SH
O
1
peptide
R2P
O
PR2
SR' +
S
peptide1
peptide2
N
R2P
O
peptide2-N3
S
1
peptide
O
peptide1
O
2
N
R2P
peptide
H2O
peptide1
N
H
O
R P
peptide2 + R
HS
S
Raines, R. T. et al Org. Lett. 2000, 2, 1939 – 1941 30
15
React with Nucleophiles at N3
The Aza-Wittig Reaction
R13P N R2 +
R3
R13P O
O
+
R3
R4
R4
N R2
The Imine Synthesis
O
O
(EtO)2P
O
(EtO)2P
PR3
N3
THF
1
R
N
PR3
O
(EtO)2P
R2
THF
R2
N
1
R
Palacios, F. et al Tetrahedron 2003, 59, 2617 – 2623.
31
React with Nucleophiles at N3
The Aza-Wittig Reaction in a New Light
Ph
O
N
nBu3P, toluene
RT, 2.5h;
then , 5h
CO2Me
N3
O
N
1) KHMDS, THF
-78oC, 1h
O
2)
Cl
N3
-78oC, 30min
RT, 1h
O
N
O
N
Me
O
H
N3
O
Me
N
RT, 7h
Ph
OMe
Ph3P, toluene
RT, 12h
then , 8h
98%
N
H
Me
Ph
O
O
N
O
N
Me
Ph
N
TFA/H2O/THF
H
N
Ph
(-)-benzomalvin
Eguchi, S. et al Tetrahedron 1998, 54, 7997 – 8008.
32
16
React with Nucleophiles at N3
The Aza-Wittig Reaction in a New Light
O
O
N3
1) LDA (2eq)
THF, -78oC
2) PBu3, THF
24h, 45oC
O
+
OEt
OH O
H
N
64%
Ph3
O PO
O
O
O
OEt
NH
OEt
N PPh
3
OEt
O
Langer, P. et al Chem. Commun. 2003, 3044 –3045.
Reaction of Iminophosphoranes with other Electrophiles
TBDPSO
O
HO
N3 O
O
PPh3
o-xylene,
TBDPSO
99%
O
NH O
O
Imanishi, T.et al Tetrahedron Lett. 2003, 44, 5267 – 5270;
33
Nitrene Chemistry
Intermolecular Cycloadditions of Nitrenes
Hirsch, A. et al J. Am. Chem. Soc. 2003, 125, 8566 – 8580.
34
17
Nitrene Chemistry
Nitrenes to C=X Double Bonds
N3
..
Y
X
N
Y
X
hν,
R
N Y
X
R
N O
N O
R
R2
N N
N O
R
R2
R1
R1
N N
N
R1
N
N
R1
N
Application in Indole Syntheis
N3
H
H
N
hν or
hν or
H
N3
35
Nitrene Chemistry
Nitrenes to C=X Double Bonds
Ο
O
Ο
109oC
N3
TBDPSO
87%
O
O
N
TBDPSO
RLi
O
NH
R
TBDPSO
Bergmeier, S. C. et al J. Org. Chem. 1999, 64, 2852 –2859
CO2Et
H
H
86%
N3
HO2C
hν, toluene
CO2Me
EtO2C
N
CO2Me
Cl
N
H
OMe
Shirahama, H. et al Tetrahedron 1996, 52, 10609 – 10630
36
18
Nitrene Chemistry
Insertion into C-H Bonds
sp 3 C-H Bonds
CO2Me
CO2Me
DMF,
N3
N
NH
N
60%
OMe
OMe
Moody, C.J. et al J. Chem. Soc. Perkin Trans. 1, 1984, 2895 – 2901
Addition of Nitrenes to Heteroatoms
1
R S
R
2
Boc
BocN3
FeCl2, DMF
R1
R2
R2
N
S
Boc
N
SR1
Bach, T. et al J. Org. Chem. 2000, 65, 2358 – 2367.
37
Nitrene Chemistry
Rearrangement of Nitrenes
N3
1
N
N
N
hν
H
N
NuH
Nu
ISC
3
N
N
N
Warmuth, R.et al J. Am. Chem. Soc. 2005, 127, 1084 – 1085
Bally,T. and Albini, A. et al J. Am. Chem. Soc. 2005, 127, 5552 – 5562
Application of Rearrangement
N3
Hex
hν, λ > 345nm
O
H
N
Hex
H2O, MeCN, 25oC, 3h
65%
Bräse, S. et al unpublished results.
38
19
Nitrene Chemistry
Fragmentation of azides
O
O
t-Bu
t-Bu
N3
N3
t-Bu
C
O
N
-N2
O
t-Bu
N
N
N
CN
+
N
N
t-Bu
C
N
N
N
O
t-Bu
O
O
t-Bu
t-Bu
C
NC
C
O
-N2
N
PhH
C6H11 N
, 84%
C6H11 N C N C6H11
CN
N C6H11
t-Bu O
Moore, H.W. et al J. Am. Chem. Soc. 1970, 92, 4132 –4133
39
Cycloadditions
Cycloaddition with Olefines
Ν3
OMe
NO2
N
N
N
CDCl3
NO2
MeO
+
OMe
N
NO2
6
1
:
Bräse, S. et al Chem. Commun. 2002, 1296 – 1297
L-proline, NsN3, Ethanol
RT, 1 day
O
Me
∗
38%
89% ee
Ph
Ns
NH
O
Ph
Me
H2O
N
CO2H
Me
Ph
NsN3
Ns
CO2H N N
∗ N
N
Ph Me
Ns
CO2H N
N
∗
Ph
N
Me
N
CO2H
N
Ns
N
∗
Ph Me
Bräse, S. et al unpublished results.
CO2
N
∗
Ns
NH
Ph Me
40
20
Cycloadditions
Cycloaddition with Olefines
R1
R2
N3
+
2
R1 R
N
N
N
Me3SiOTf
CH2Cl2, 0oC to RT
O
a
O
R1
R1
2
R1 R
N
-N2
bN N
O
-N2
a
N R2
O
N
b
R
68%
HN R2
H
N 2
R
O
R2
1
R1
O
O
Aubé, J. et al Org. Lett. 2003, 5, 3899 – 3902
Cycloaddition with Alkynes (Huisgen Reaction)
R
O
MeO-PEG
RCH2N3, PhMe
110oC, 12h
O
O
73-86%
O
N N
N +
O
MeO-PEG
O
O
O
1
:
N N
N
R
2
Norris, P. et al Tetrahedron Lett 1998, 39, 7027-7030
41
Cycloadditions
Cycloaddition with Alkynes
A Breakthrough
O
O
FGFG
R-N3, CuI, DIPEA
0.1M NaOH(aq)
74-95%
R N
N N
FGFG OH
Meldal, M. et al J. Org. Chem. 2002, 67, 3057 – 3064
O
+
N3
CuSO4 . 5H2O, 1mol%
Sodium Ascorbate, 5mol%
H2O/tBuOH, 2:1,RT, 8h
91%
N
N
N
O
Sharpless, K.B. et al Angew. Chem. Int. Ed. 2002, 41, 2596 – 2599
42
21
A Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed
Regioselective Ligation Azides and Terminal Alkynes
Proposed catalytic cycle for the CuI-catalyzed ligation.
Sharpless, K.B et al Angew. Chem. Int. Ed. 2002, 41, 2596 -2599
Fokin,V.V. and Finn, M. G. et al Angew. Chem. Int. Ed. 2005, 44, 2210-2215
Noodleman, L.Sharpless, K.B. and Fokin, V.V.et alJ. Am. Chem.Soc. 2005, 127, 15998-15999 43
“Click Chemistry”
Following natures lead, we endeavor to generate substances by
joining small units together with heteroatom links(C-X-C). The
goal is to develop an expanding set of powerful, selective, and
modular “blocks” that work reliably in both small- and large-scale
applications. We have termed the foundation of this approach “click
chemistry”.
———— K. B. Sharpless
Sharpless, K. B. et al Angew.Chem. Int. Ed. 2001, 40, 2004-2021
44
22
“Click Chemistry”
Stringent criteria that a process must meet to be useful
1) Modular, wide in scope, give very high yields, generate only inoffensive
byproducts that can be removed by non-chromatographic methods, and be
stereospecific. Product must be stable under physiological conditions.
2) Simple reaction conditions (ideally, the process should be insensitive to
oxygen and water), readily available starting materials and reagents, the
use of no solvent or a solvent that is benign (such as water) or easily
removed, and simple product isolation.
3) Having a high thermodynamic driving force, usually greater than 20 kcal/ mol.
spring-loaded nature
Provide a foundation for the rapid assembly of new and pure molecular entities
45
“Click Chemistry”
Click Chemistry in Water
1) Greater free energies in water
2) Hydrogen-bonding situations arise
3) Reaction of two solutes is usually
faster than side-reaction with water
4)Heat capacity , boiling temperature
5)Hard & soft differentiating leverage
6) Protecting groups is avoided
46
23
Cycloadditions
Controllable Selectivity
Ν3
N
[Ru]
+
N
N
N
N
N
+
Ru(OAc)2(PPh3)2
100%
CpRuCl(PPh3)2
85%
Cp*RuCl(PPh3)2
100%
Cp*RuCl(NBO)
100%
15%
Fokin, V. V. and Jia, G. et al J. Am. Chem.Soc. 2005, 127, 15998-15999
Possible Mechanism
47
Cycloadditions
Combination with Pd Chemistry
R
R
H +
OCO2Me + TMSN3
cat Pd(0), cat Cu(I)
N
N
N
Yamamoto, Y et al J. Am. Chem. Soc. 2003, 125, 7786 – 7787
R
Possible Mechanism
H
N
N
N
OCO2Me + TMSN3
LnCu
R
Pd(0)
HX
CuXLn
H
CO2 + TMSOMe
R
R
N
CuLn
N
N Pd
Pd N3
48
24
Cycloadditions
Cycloaddition with Allene
N N N
CH3
.
.
N N
N
toluene
100oC
N
-N2
N
.
.
.
CH3
N
CH3
H
CH3
CH3
N
N
CH3
CH3
not observed
Feldman, K. S. et al J. Am. Chem.Soc. 2005, 127, 4590-4591
Sulfonyl Azides and Copper(I) Acetylides Cycloaddition
Cu
.
R1
1
R
2
Cu, Base
3 4
+ R SO2N3 + HNR R / H2O
1
R
HNR3R4
NSO2R2
Cu
H2O
N
NSO2R2
R1
N
N SO R2
2
NR3R4
O
R1
N
H
SO2R2
Chang, S. et al J. Am. Chem.Soc. 2005, 127, 2038-2039
J. Am. Chem.Soc. 2005, 127, 16046-16047 49
Cycloadditions
Sulfonyl Azides and Copper(I) Acetylides Cycloaddition
R1
H
2
R
+
N
CuI, 2mol%
TBTA, 2mol%
Na ascorbate, 4mol%
R2
R1
NaHCO3, 1 equiv
tBuOH/H2O, 2:1
RT, 2-8h
27-83%
N N S
O2
H
N
O
S
O2
Fokin, V.V. et al Angew. Chem. Int. Ed. 2006, 45, asap, DOI: 10.1002/anie.200503805
R
1
2
+ R SO2N3 +
Ph
R1
Ν
Cu
Cu, Base
Ph
N
N
N SO R2
2
Cu
R1
.
R1
NSO2R2
Ph
NSO2R2
N
Ph
Fokin, V.V. et al Angew. Chem. Int. Ed. 2006, 45, asap, DOI: 10.1002/anie.200503936
50
25
Cycloadditions
Tetrazoles
N
N3
S
DMF
110-130oC
N N
N
S
N
>90%
n
n
N
N3
O
O
n
DMF
110oC
O
>90%
O
N N
N
N
n
Sharpless, K. B. et al Org. Lett. 2001, 3, 4091 – 4094.
Cycloaddition with Other Dipolarophiles
MeO
BF3.OEt2
CH2Cl2
-78oC-RT
OTES
Ν3
R
R
O
O
N
R
O
OBF3
N
N
N
N
+
NH
N
R
0-4%
38-54%
Rh2(OAc)4, 77%-quant.
Aubé, J. et al Org. Lett. 2000, 2, 1657 – 1659.
51
Other Reactions
The Curtius Rearrangement and Related Reactions
CON3 CON3
CON3
1) 37% HCl, THF, reflux
NCO NCO
2)Dowex 550 A, OH , CH3OH
NCO
Dioxane,
quant.
NH2 NH2
NH2
52%
Menger, F.M. et al Angew. Chem. Int. Ed. 2002, 41, 2581 – 2584.
The Schmidt Rearrangement
OH
HN3 / H2SO4
CH2Cl2, 0oC
N
65%
NaBH3CN
MeOH
68%
N methylation
H
N
Me
-H
+H
N3
NH
N
N
Plat, M. M. et al Tetrahedron Lett. 1983, 24, 1937 – 1940.
52
26
Other Reactions
Radical Additions to Organoazides
Bu3SnH
AIBN,
N N+ N–
R
R
H
N
SnBu3
R'OH
R'
O
Bu3Sn
N
N
.N
R
SnBu3
NH2
SnBu3 + R
PhSiH3
Bu3SnH
-N2
R
N
SnBu3
R'
O
SiH2Ph
Application of Radical Addition
Bu3SnH(cat.)
PhSiH3
nPrOH, AIBN, 80oC
OEt
N3
75%
Ph
OEt
NH
H
Ph
Bu3Sn , -N2
OEt
OEt
N
N
SnBu3
Ph
SnBu3
Ph
Fu, G. C. et al J. Org. Chem. 1998, 63, 2796 – 2797
53
Other Reactions
[3,3] Sigmatropic Rearrangements
N
N N N
N
N
R
R
N3
N3
O
[CuI]
MCPBA
N3
Ph
N
H
N
N
Ph
Sharpless, K. B. and Fokin, V.V. et al J. Am. Chem. Soc. 2005, 127, 13444 – 13445
NHFmoc
N3
OH
.
R
HN3
PPh3
DEAD
.
O3
R
HO2C
R
NBoc
RCM
R
Spino, C. et al Org. Lett. 2005, 7, 4769-4771.
54
27
Other Reactions
Azide Ions as Leaving Groups
Ph
SiMe2Ph
CO2Et
1) LDA, -78oC
2) TrisylN3, 2h
anti/syn >98:2
Ph
SiMe2Ph
TBAF, THF, 2h
CO2Et
86%
CO2Et
Ph
N3
Landais,Y. et al Tetrahedron Lett. 2003, 44, 6995 – 6998.
Azides to Nitriles
RCH2 N N N
BrF3
RCH2 N N N
F
RCH2 N N N
-[BrF]
-N2
F Br F
F Br F
F
RCH2 N
F -2HF
F
RCN
Rozen, S. et al Org. Lett. 2003, 7, 2177-2179.
55
Summary : Reactions of Organic Azides
Electrophiles
Nucleophiles
Nu
E
R N3
R N N N
1 2 3
......
Nitrene Chemistry
X Y
R
others
Cycloaddition
Click Chemistry
56
28
Applications of Azides
For Industry Uses
Azides as Explosives and Propellants
Herbicides and Pesticides
Polymerization Initiators
Blowing Agent and Gas Generators
Photoresists and Printing Plates
Rubber Vulcanization
Cross-linking of other Polymers
Adhesives
Dyes
Photoaffinity Labeling
.
.
..
..
57
Applications of Azides
For Academic Research
Azides
Heterocyclic Compounds
Biologically Active Compounds Synthesis
In Natural Products Synthesis
Goal of “Click Chemistry”
Cross-linking Agents
Material Science
58
29
Applications of Azides
Combination of "Click Chemistry" and Living Radical Polymerization
Haddleton, M. et al J. Am. Chem. Soc. 2006, 128, asap , ja058364k
Macrocyclic Polymers via "Click" Cyclization
Grayson S.M et al J. Am. Chem. Soc. 2006, 128, asap , ja0585836
59
Applications of Azides
Bis(imino)pyridine Iron Imides
Chirik, P. J. et al J. Am. Chem. Soc. 2006, 128, asap , ja057165y
60
30
Summary and Outlook
R N3
R N N N
R N N N
R N N N
1a
1b
1c
1
R N N N
R N N N
R N N N
1d
R N N N
R N N N
Nu
E
R N3
R N N N
1 2 3
X Y
R
......
61
Outlook
M
RN3
N3
R N N N
.
.
..
..
62
31
Acknowledgement
Professor Wang
Professors in Organic Institute
All labmates
63
32
33
34