Dipolar Cycloadditions - The Stoltz Group

Me
SO 2
N
Ph
O
Me
SO 2 Ph
H
H
N
H
O
H
H
O
O
R
Dipolar Cycloadditions
You Love Them. You Hate Them.
You Need Them.
Mike Meyer
Stoltz Group Meeting, April 3 rd , 2006
NO 2
O
O
Et
S
O
N
O
N
Me
N
N
N
O
N
O R z
R z R N e
CO 2 Me
Me H
R e
CO 2 Me
A Guide for the Discussion of Dipolar Cycloadditions:
1. Types and Classification of 1,3 Dipoles
2. Molecular Theory Behind 1,3-Dipolar Cycloadditions
Ph
N
3. Types of Dipoles
a. Nitrones
b. Nitrile Oxides
c. Carbonyl Ylides
d. Diazoalkanes
e. Azomethine ylides
g. Miscellaneous
Good Sources:
W(CO) 5
Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765.
Gothelf,K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98, 863.
Padwa, A. Synthetic applications of 1,3-Dipolar Cycloaddition Chemistry Toward
Heterocycles and Natural Products John Wiley & Sons, 2002, p. 269-301.
O
O
N
O
Me
H
H
O
OAc
OTBS
O
O
N
O
O
CO 2 Me
H
O
O
H
N
Ph
H
O
O
N
O
R
1

Types and Classification of 1,3-Dipoles
Two Types of Dipoles:
(1) Allyl anion
Classification of the Allyl Anion Type 1,3-Dipoles
C N O
Nitrones
C O C
Carbonyl Ylide
X Y Z X Y Z
- Bent
- Y = N, O, S
C N N
Azomethine Imines
C O N
Carbonyl Imines
(2) Propargyl/allenyl anion
C N C
Azomethine Ylides
C O O
Carbonyl Oxides
X Y Z X Y Z
- Linear
- Y = Nitrogen
N N N
N N O
Azimines
Azoxy Compounds
N O N
N O O
Nitrosimines
Nitrosoxides
O N O
Nitro Compounds
O O O
Ozone
Classification of the Propargyl/Allenyl Anion Type 1,3-Dipoles
C N O
Nitrile Oxides
C N C
Nitrile Ylides
N N N
Azides
C N N
Nitrile Imines
N N C
Diazoalkanes
N N O
Nitrous Oxide
Molecular Theory Behind 1,3-Dipolar
Cycloadditions
Dipole Alkene Dipole Alkene
Dipole
Alkene
LUMO
Energy
HOMO
Type I Type II Type III
HOMO dipole —LUMO alkene
HOMO dipole —LUMO alkene
HOMO alkene —LUMO dipole
HOMO alkene —LUMO dipole
Types of
Dipoles
azomethine ylides,
azomethine imines,
nitrile ylides
nitrones,
nitrile oxides
ozone,
nitrous oxide
2

Molecular Theory Behind 1,3-Dipolar
Cycloadditions (cont'd)
What about Lewis acid activation?
Dipole
Alkene
Dipole
Alkene
Energy
Alkene-LA
Dipole-LA
LUMO
HOMO
Coordination of the LA to either the dipole or the alkene results in LUMO lowering, and a faster reaction rate.
Another Consideration: Endo vs. Exo
N O R 1
R 2 O
O
N
O
O
R 1
OR 2
N
O
O
R 1
OR 2
endo
exo
2 diastereomers (racemic)
Endo:
H
Me
O
N
R 2 O H
H
Me
R 1
O
H
Me
O
N
R 2 O H
H
Me
R 1
O
R 1
R 2 O 2 C
O
N
Me
Secondary
overlap is minimal
Exo:
H
O
R 2 O 2 C
N
Me
H
H
R 1
Me
H
O
R 2 O 2 C
N
Me
H
H
R 1
Me
R 1
R 2 O 2 C
O
N
Me
3

A Usefull Dipole: Nitrones (a.k.a. Azomethine
Oxides)
What is a nitrone?
N O R1 R 2
R 2
O
HN
OH
- E/Z mixtures of the nitrone can occur, resulting in mixtures
of stereoisomers
- Cyclic nitrones avoid geometrical isomers, and generally give
better selectivity
nitrone species
Examples of cyclic nitrones:
- Dipolar cycloadditions with nitrones can produce: isoxazolidines,
nucleosides, lactams, quinolizidines, indolizidines, pyrrolizidines,
peptides, amino acids (alcohols), and more
RO
N
O
OR
O
N
Bn
O
O
O
N
O
O
O O
O
N
O
O
O
O
N
Ph
OH
O
N
O
Most common reaction with nitrones:
R1
N O
R 1
R 2
R 3 R 4 R 2 N
* O
* *
R1
N O
R 3 R 4
isoxazolidine
R 2
NHR 1 OH
- 1,3-DC with nitrones can create
upto three stereogenic centers
R 2 * * * R 4
R 3
!-amino alcohols (acids)
Nitrones: In the Beginning
In the early 1970's, organic chemists began to use 1,3 DC to build complex intermediates and important building blocks in
the realm of total synthesis.
- Huisgen was the first chemist to successfully prove that 1,3 DC occur through a concerted mechanism.
Some examples involving nitrones:
Ph
Me
N
O
Me
N
O
Ph
Ph
Me N
O
H
H
Me
N
O
Ph
Bn Me
H
H
N
O
N
Ph
Me O H
H
vs.
H
Me Bn H
N
O
N
Ph
O H
Me
H
disfavored
White, J. D., et. al.; Tetrahedron, 1989, 45, 6631.
favored
PMBO
H
O
O
!
PMBO
O
O
!
O
O
H
3 simple
steps
HO
O
H O
EtO 2 C
O
N
O
N
PMBO
N
O
74% yield
N
Cordero, F.M., et. al.; Org Lett. 2000, 2, 2475.
4

Nitrones: Getting More Complicated
Thermal transannular cycloaddition:
HOHN
O
O
O
p-TsOH
MeOH, H 2 O, !
O
70% yield
O
O
N
PhMe, !
64 % yield
O
O
H
N
O
H H
1. K 2 CO 3 ,
MeOH, 88%
2. SmI 2 , rt, 64% HO
H
MeO 2 C
HO HN
H
White, J. D., et. al.; Org. Lett. 2001, 3, 413.
A three component coupling:
R 1
NHOH
R 2
R 1 = aryl, benzyl
O
R 2 = alkyl, alkenyl, aryl, heteroaryl
R 3 =alkyl, alkenyl, phenyl, heteroaryl
I
NHOH
R
O
H
H
10 mol % Yb(OTf) 3
4 Å MS
PhMe, rt, 30 min.
1. 10 mol % Yb(OTf) 3
4 Å MS, PhMe, rt, 30 min
2.
CO 2 R
CO 2 R
CO 2 R
O
N R1
CO 2 R
I
N O
R
MeO 2 C
CO 2 Me
R 1
N O R 3
R 2
RO 2 C CO 2 R
tetrahydro-1,2-oxazines
20 mol % Pd(PPh 3 ) 4
TEA, CH 3 CN, 80 °C
42-71 % yield overall
5 examples
Young, I. S.; Kerr, M. A. Org. Lett. 2003, 6, 139.
For a cat. enantiosel. 1,3-DC using a heterochiral Yb catalyst, see: Kobayashi, JACS, 1998, 120, 5840.
21 examples
66-96% yield
O
N
CO 2 Me
CO 2 Me
R
FR900482 analogs
antitumor, antibiotic
Chiral Metal Complex:
Examples of Asymmetric 1,3-Dipolar
Cycloadditions using Nitrones
M = Fe for the following table Ph
entry nitrone enal yield (%) product ee (%)
1
2
3
4
N
O
N
O
N
O
N
O
Me
Me
Me
Ph
SbF 6
H
(C 6 F 5 ) 2 P M
O
O
P(C 6 F 5 ) 2
CHO
CHO
CHO
CHO
O
92
71
75
71
H
N
H
N
H
N
H
N
M = Fe, Ru
Kündig, E. P., et. al.; J. Am. Chem. Soc. 2002, 124, 4968.
For a similar system using a Co(salen)* complex, see: Yamada, T., et. al.; Org Lett. 2002, 4, 2457.
For a similar system using a bis-TiL 2 * complex, see: Maruoka, K., et. al.; J. Am. Chem. Soc. 2005, 127, 11926.
O
O
O
O
CHO
CHO
Me
CHO
Me
Me
CHO
Me
96
>96
75
94
5

The One and Only, Enantioselective
Organocatalytic 1,3-Dipolar Cycloaddition
using Nitrones
R 1
Z
N
O
R
O
20 mol% cat.
CH 3 NO 2 -H 2 O, -20 °C
3-5 d
Z
N
O
R R 1
CHO
endo
Z
N
O
R R 1
CHO
exo
Catalyst:
Ph
O
HClO 4
N
H
Me
N
Me
Me
entry Z R R 1 endo:exo yield % ee (endo)
1
2
3
Bn
Allyl
Me
Ph
Ph
Ph
Me
Me
Me
94:6
93:7
95:5
98
73
66
94
98
99
Note: The shown table is abbreviated.
4
Bn
C 6 H 4 Cl-4
Me
92:8
78
95
Overall:
15 examples
70-98% yield
90-99% ee
5
6
Bn
Bn
Cy
C 6 H 4 Cl-4
Me
H
99:1
80:20
70
80
99
91
Jen, W. S.; Weinger, J. J. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 9874.
Synthetic Applications of Nitrones Toward
Natural Product Syntheses
Gribble:
N
PhO 2 S
O
N
H
PhCH 3
!, 5 h
N
PhO 2 S
H
H
N
O
H
1. 6% Na(Hg), Na 2 HPO 4
0 °C, 40 min, 91%
2. Zn, AcOH/H 2 O, 50 °C
1.5 h, 96%
3. TFA, !, 12 h, 77%
N
H
H
H
H
N
H
(—)-hobartine
Gribble, G. W.; Barden, T. C. J. Org. Chem. 1985, 50, 5902.
Petrini (not a 1,3-DC):
MOMO
N
H
A
OMOM
30% H 2 O 2
cat. SeO 2
MOMO
N
O
OMOM
PMBMgBr
MgBr 2 (1 equiv)
CH 2 Cl 2
MOMO
N
OH
OMOM
PMB
64% yield from A
Ballini, R.; Marcantoni, E.; Petrini, M. J. Org. Chem. 1992, 57, 1316.
HO OH
1. RaNi, H 2
2. H 3 O + N
PMB
H
(—)-anisomycin
12% yield from
L-tartaric acid
6

A Guide for the Discussion of Dipolar Cycloadditions:
1. Types and Classification of 1,3 Dipoles
2. Molecular Theory Behind 1,3-Dipolar Cycloadditions
Ph
N
3. Types of Dipoles:
a. Nitrones
W(CO) 5
b. Nitrile Oxides
c. Carbonyl Ylides
d. Diazoalkanes
e. Azomethine ylides
g. Miscellaneous
O
O
O
N
O
Me
H
H OAc
O
OTBS
O
N
O
O
CO 2 Me
H
O
O
H
N
Ph
H
O
O
N
O
R
Nitrile Oxides: Powerfull Dipoles in 1,3-Dipolar
Cycloadditions
What is a nitrile oxide, and how is it made?
R
Me
Me
O
MeO
N
N
H
O
O
OMe
N
N
Bn
H
OTBDPS
N O
O
A. K., Parhi; R. W. Franck Org. Lett. 2004, 6, 3063
O-silylated hydroxamates
Tf 2 O, TEA
-40 °C to 0 °C
E. M., Carreira, et. al.; Org. Lett. 2000, 2, 539.
R
O
N
NO 2
alkyl nitro moiety
PhNCO, "Mukaiyama method"
DCC
cat. base T., Mukaiyama; T., Hoshino J. Am. Chem. Soc. 1960, 82, 5339.
M. J., Kurth, et. al.; J. Org. Chem. 2000, 65, 499.
R
nitrile oxide
A. P., Kozikowski; H., Ishida J. Am. Chem. Soc. 1980, 102, 4265.
TEA
- HCl
HO
R
N
Cl
hydroximinoyl chloride
NCS/NaOCl/Cl 2
HO
R
N
oxime
J. W., Bode; E. M. Carreira J. Am. Chem. Soc. 2001, 123, 3611.
M. J., Kurth, et. al.; Tet. Lett. 1999, 40, 3535.
7

Relative Reactivity of Dipolarophiles with
Nitrile Oxides
A relative reactivity guide for achiral dipolarophiles:
EWG = CO 2 Me
EWG
> EWG
X = O, Si
X
EWG > > ! Ph ! EWG
X = OR, SI, EWG, Halogen
n = 1, 2
EWG
> X > !
n Ph
EWG
8
6
2-5
1
0.4-0.7 0.01-0.30
Regioselctivity with nitrile oxides:
O N
MeO R 1 R
O N
Base
HON
MeO
R 1 R
O
R
Cl
When R 1 = H:
O
R 1 O OMe
R Yield (%) A:B
2,6-Cl 2 C 6 H 3
93
93:7
A
B
2,4,6-Me 3 C 6 H 2 99
95:5
Toward Heterocycles and Natural Products John Wiley & Sons, 2002, p. 377-
380.
CO 2 Et
C 6 H 5
COMe
Br
COPh
94
99
97
89
76
>99:1
>99:1
>99:1
95:1
>99:1
When R 1 ! H, the selectivity breaks down to give unpredictable mixtures.
A., Padwa Synthetic applications of 1,3-Dipolar Cycloaddition Chemistry
Synthetic Examples of Nitrile Oxides in 1,3-DC
reaction: In the 1980's
In the Beginning, it was Kozokowski:
(1)
AcO
NO 2
NH
PhNCO
cat. TEA
24 hrs
70-90% yield
OAc
NH
N O
AcO
O N
H
NH
Isoxazoline
HO
HN
H
H
NH
Chanoclavine I
A. P., Kozikowski; H., Ishida J. Am. Chem. Soc. 1980, 102, 4265.
(2)
THPO
NO 2
NH
PhNCO
cat. TEA
OTHP
NH
N O
THPO
O
H
N
dr = 1:1
NH
H
O
H
Me
N
Me
H
NH
(+)-paspaclavine
A. P., Kozikowski; Y. Y. Chen J. Org. Chem. 1981, 46, 5250.
8

1,3-Dipolar Cycloadditions using Nitrile
Oxides in the 1980's (cont'd)
More Kozikowski:
O
E
H
O
E = CO 2 Me
NO 2
PhNCO
cat. TEA
PhH, reflux
58% yield
O
N
O
O
E
H
N
O
H
H
O
O
E
H
L-selectride
THF, -78 °C
72% yield
H
H
N
O
O
CO 2 Me
O H
O
O
E
H
NO 2
PhNCO
cat. TEA
PhH, reflux
65% yield
O
O
E
H
H
H
H
N
O
A. P. Kozikowski, et. al.; J. Am. Chem. Soc. 1984, 106, 1845.
1,3-Dipolar Cycloadditions using Nitrile
Oxides moves into the 1990's
Curran(1987):
O 2 N
O
PhS
Me 2 OC OEt
1. p-ClC 6 H 4 NCO
TEA, 110 °C
2. mCPBA
3. NaOH, 80 °C
54% yield over
3 steps
MeO 2 C
N
H
O
H
OEt
4 steps
O
TBSO
D. P., Curran, et. al; J. Am. Chem. Soc. 1987, 109, 5280.
O
H
H
OH
OEt
O
p-phenol
O
O
H
8 steps
O
O
H
HO
OEt
Specionin
OEt
Kurth:
Ph
O
NO 2
p-Ph(NCO) 2
cat. TEA
PhH
88% yield
Ph
O
H
N
O
dr = 9:1 (syn:anti )
3 steps
Ph
O
H
N
O
Ph
O
NO 2
p-Ph(NCO) 2
cat. TEA
PhH
65% yield
H
Ph
O
O
H
N
N
O
Ph
O
M. J., Kurth, et. al; J. Org. Chem. 2000, 65, 499.
9

1,3-Dipolar Cycloadditions using Nitrile
Oxides in the New Millennium
Dr. Mitomycin (Fukuyama):
MeO
CO 2 Et
NOH
O
NaOCl
EtO 2 C
MeO
H
O
N
O
multiple steps
OMe
OCONH 2
OH
Me N
p-Ns
Carreira:
O
CH 2 Cl 2 , 0 °C
Me N
O
p-Ns
T., Fukuyama, et. al.; Org. Lett. 2001, 3, 2575.
Me
N O NH
FR-900482 analogue
OH
OTIPS
Me
O N
(EtO) 2 P
Me
OH
H
NOC
94% yield
O N
(EtO) 2 P
Me
O
OTIPS
(CH 2 ) 3
OH
OH
O N O
O N
NOC (EtO) 2 P
(EtO) 2 P
OH
H 79% yield
Me
Me
J. W., Bode; E. M., Carreira J. Am. Chem. Soc. 2001, 123, 3611.
OH
Me
R
O
N
Me
S
Me
O
O OH O
Epothilone A (R = H), B (R = Me)
OH
Me
A Guide for the Discussion of Dipolar Cycloadditions:
1. Types and Classification of 1,3 Dipoles
2. Molecular Theory Behind 1,3-Dipolar Cycloadditions
Ph
N
3. Types of Dipoles:
a. Nitrones
W(CO) 5
b. Nitrile Oxides
c. Carbonyl Ylides
d. Diazoalkanes
e. Azomethine ylides
g. Miscellaneous
O
O
O
N
O
Me
H
H OAc
O
OTBS
O
N
O
O
CO 2 Me
H
O
O
H
N
Ph
H
O
O
N
O
R
10

Carbonyl Ylides: How to Make the Dipole
3 types of carbonyl ylides:
(1) Unstablized ylides
(2) Stablized ylides (3) Oxidopyrylium ion
R
O
R'
O
R
O
R'
R
O
R
O
Generation of the ylides:
TMS
Ph
O
Cl
CsF
MeCN
Ph
A., Hosomi, et. al.; J. Org. Chem. 1997, 62, 8610.
N
N
O
OMe
! -N 2
CHCl 3
OMe
P. K. Sharma; J., Warkentin Tetrahedron Lett. 1995, 36, 7637.
Me
Ph
O
Ph
Me
254 nm
h"
O
Me
Ph
O
O
Ph
Me
G. W., Griffin, et. al.; Tetrahedron 1981, 37, 3345.
The most common method to generate a carbonyl ylide is from a
metallocarbenoid:
Ph
Ph
O
N 2
Rh 2 (OAc) 4
Ph
O
O
A., Padwa, et. al.; J. Am. Chem. Soc. 1990, 112, 3100.
N 2
CN
C 6 H 4 Cl
Rh 2 (OAc) 4
O
Ph
Ph
Ph H
M., Hamaguchi, et. al.; Tetrahedron Lett. 2000, 41,1457.
O
O
CN
C 6 H 4 Cl
For a plethora of examples using metallocarbenoids to generate
carbonyl ylides, see: A., Padwa Synthetic applications of 1,3-Dipolar
Cycloaddition Chemistry Toward Heterocycles and Natural Products John
Wiley & Sons, 2002, p. 269-301.
Hashimoto:
Enantioselective Catalyzed 1,3-Dipolar
Cycloaddtions using Carbonyl Ylides
entry R 1 temp (°C) yield (%) % ee
1
2
3
4
C 6 H 5
C 6 H 5
4-MeC 6 H 4
4-MeOC 6 H 4
0
-23
0
0
77
54
67
65
90
92
92
90
5
0
Note: The full table conatins 11 examples with 68-92 % ee
S.-i., Hashimoto, et. al.; J. Am. Chem. Soc. 1999, 121, 1417.
78
87
R 1
O
N 2
O
L* =
MeO 2 C
CO 2 Me
Rh 2 L 4 * (1 mol %)
CF 3 C 6 H 5 0.08 M, 5 min
i-Pr
H
O
Rh
O
O
Rh
N
O
MeO 2 C
R 1
O
CO 2 Me
O
4-ClC 6 H 4
11
Suga:
O
OMe
entry temp (°C) yield (%) endo:exo % ee
1
2
3
4
5
6
7
-10
-10
-10
-10
-25
-25
-10
96
82
53
97
84
77
84
88:12
85:15
91:9
82:18
73:27
67:37
12:88
91
82
89
93
86
83
45 (exo)
H
O
O
OMe
CHN 2
(S,S)-Pybox
M(OTf) 3
OCH 2 Ar
Rh(OAc) 2
OMe
O
O
O
endo
H., Suga, et. al; J. Am. Chem. Soc. 2002, 124, 14836.
O
O
OCH 2 Ar
OMe
O
OMe
O
O
O
exo
O
OCH 2 Ar

Recent Examples of Carbonyl Ylides used in
Natural Product Syntheses
Boger:
O
O
O
N
Me
N
[4 + 2]
N
O
N
R Z R E
CO 2 Me
N
Me
N
N
R Z
N O R E
CO 2 Me
1. - N 2
2. [3 + 2]
60-88% yield
11 examples
Me
N
N
O R Z
R E
H
CO 2 Me
Padwa:
O
H
Me
O
H
H
O
74 % yield
dr = 4:1 (exo)
A
D. L., Boger; et. al.; J. Am. Chem. Soc. 2002, 124, 11292.
O O
Rh II Rh
H
II
O
Cl CN
N 2
illudin core and ptaquilosin core
Me
Cl
O
O
CN
68 % yield
dr = 3:1
A., Padwa, et. al.; J. Am. Chem. Soc. 1994, 116, 2667.
B
H
Core of vinoline
HO
Me
Me
O
OH
Me
Illudin M (R = H)
Illudin S (R = OH)
CH 2 R
Synthetic Examples of 1,3-Dipolar
Cycloadditions Using Oxidopyrylium Ylide
Wender:
TBSO
AcO
O
H
H
O
O
H OAc
OAc DBU Me
CH 2 Cl 2 , rt
O
Me
OTBS
AcO
Me
H
O
O
OTBS
K. C., Nicolaou; S. A., Snyder Classics in Total Synthesis II Wiley-VCH, 2003, Ch. 6.
HO OH
Me
H
H H
OH
OH
OH
O
phorbol
Magnus:
Me
HO
O
Me
O
TFA, CH 2 Cl 2 , rt
82% yield
Me
O
Me
O
Me
Me
O
O
cyathin core
P., Magnus; L., Shen Tetrahedron, 1999, 55, 3553.
12

A Guide for the Discussion of Dipolar Cycloadditions:
1. Types and Classification of 1,3 Dipoles
2. Molecular Theory Behind 1,3-Dipolar Cycloadditions
Ph
N
3. Types of Dipoles:
a. Nitrones
W(CO) 5
b. Nitrile Oxides
c. Carbonyl Ylides
d. Diazoalkanes
e. Azomethine ylides
g. Miscellaneous
O
O
O
N
O
Me
H
H OAc
O
OTBS
O
N
O
O
CO 2 Me
H
O
O
H
N
Ph
H
O
O
N
O
R
Using TMSCHN 2 in 1,3-Dipolar Cycloadditions
Carreira:
(1) Methodology
O
TMSCHN 2
R 1 N
n-Hex:PhMe (1:1)
O 2 S
R 2 Carreira, E. M., et. al.; J. Am. Chem. Soc. 1997, 119, 8379.
TMS
R 1 O
R 2
N N
X c
TFA
CH 2 Cl 2
R 1 O
R 2
X c
N NH
65-78% yield
1. NaCNBH 3
MeCN
2. Mg(OMe) 2
MeOH
R 1 O
R 2
HN NH
OMe
dr = 9-9.5:1
pyrazolidines
(2) Total Synthesis
Me
O
N
O 2 S
TMSCHN 2
then acid workup
65% yield
dr = 94:6
N
O
Me
NH
N
O 2 S
5 M NaOH
150 °C, 5h
68% yield
O
HO
OH
O Me NH 2
C ! -methyl aspartic acid
H., Sasaki; E. M., Carreira Synthesis 2000, 1, 135.
H
N
Me
H
N
O
Me
Me
ent-stellettamide A
Me
Me
R
O
OH
H
N
NH 2
X c
HN
O
N
OBn
13

Azomethine Ylides: How they are generated
R 1 CHO
aldehydes
RNHCH 2 R 2
R
R
R
N
R 1 N R 2
R 1 N R 2
R 1 R 2
aziridines
azomethine ylide
imines
R
N
R 1
O
R 3 R 2 COR 3
For a general review of azomethine ylides, see: I., Coldham; R., Hufton Chem. Rev. 2005, 105, 2765.
Azomethine Ylides: A quick look at FMO
+3
LUMO
+1.4
0
+1
+2
Z = electron deficient
HOMO
H
N
-6.9
-8
-9 -9
-10.9
Z C R X
C = conjugated
R = alkyl
X = electron rich
Dipole
Dipolarophiles
Intramolecular Tethers:
R
N
Type I
R
N
R
N
Type II
N
N
N
I., Coldham; R., Hufton Chem. Rev. 2005, 105, 2765.
14

Azomethine Ylides Generated From Aldehydes
Kanemasa:
O
CHO
Ph
MeHN
CO 2 Me
PhMe, !, 10 h
O
Ph
N CO 2 Me
Me
O
H
H
Ph
N
Me
CO 2 Me
95% yield
single diastereomer
S., Kanemasa; K., Doi; E., Wada Bull. Chem. Soc. Jpn. 1990, 63, 2866.
Harwood:
Ph
H
N
O
O
CHO
PhH, !
O
O
H
N
Ph
H
Ph
H
N
O
H
O
61% yield
single diastereomer
L. M., Harwood; L. C., Kitchen Tetrahedron Lett. 1993, 34, 6603.
Azomethine Ylides Generated From Imines
Parsons:
TIPSO
9
O
CO 2 Et
TEA, MeCN
N Ph
36% yield
single diastereomer
TIPSO
9
H
O
CO 2 Et
Ph
NH
H
H 3 CO
Cl
O
NH
N
roseophilin
P. J., Parsons, et. al.; Synlett. 2003, 1856.
Livinghouse:
MeO
MeO
— OTf
MeO
MeO
O
N
TfO
TMS
MeO
O
N
TMS
CsF
DME, 65 °C
70% yield
MeO
O
N
H
single diastereomer
erythrinane skeleton
T., Livinghouse, et. al.; J. Org. Chem. 1996, 51, 1159.
15

Azomethine Ylides Generated From Aziridines
Ar
Ar
Huisgen:
N
N
EtO 2 C
110 °C
Conrotatory
CO 2 Et
EtO 2 C
1
h!
2
Disrotatory
CO 2 Et
110 °C
Conrotatory
Ar
N
CO 2 Et
EtO 2 C
Ar
N
Ar
N
EtO 2 C
Ar
N
CO 2 Et
EtO 2 C
S
trans-1
S
CO 2 Et
EtO 2 C
CO 2 Et
U
cis-2
W
EtO 2 C
CO 2 Et
Ar = p-MeOC 6 H 4
EtO 2 C
CO 2 Et
EtO 2 C
CO 2 Et
EtO 2 C
N
Ar
CO 2 Et
EtO 2 C
R., Huisgen, et. al.; J. Am. Chem. Soc. 1967, 89, 1753.
R., Huisgen, et. al.; Tetrahedron Lett. 1966, 397.
N
Ar
CO 2 Et
A Guide for the Discussion of Dipolar Cycloadditions:
1. Types and Classification of 1,3 Dipoles
2. Molecular Theory Behind 1,3-Dipolar Cycloadditions
Ph
N
3. Types of Dipoles:
a. Nitrones
W(CO) 5
b. Nitrile Oxides
c. Carbonyl Ylides
d. Diazoalkanes
e. Azomethine ylides
g. Miscellaneous
O
O
O
N
O
Me
H
H OAc
O
OTBS
O
N
O
O
CO 2 Me
H
O
O
H
N
Ph
H
O
O
N
O
R
16

Various Dipoles and Dipolarophiles in Dipolar
Cycloadditions
Finney:
OAc
AcO
O
OAc
RN 3 , CH(OEt) 3
reflux, 24-36 h
AcO
OAc
O
OAc
R
N
N
N
h!, (CH 3 ) 2 CO
10-12 h
AcO
OAc
O
OAc
NR
NaH, Nu-H
cat. Sc(OTf) 3
THF, 3-4 h
AcO
OAc
O
OAc
Nu
NHR
R. S., Dahl; N. S., Finney J. Am. Chem. Soc. 2003, 126, 8356.
Nair (1,4-Dipolar Cycloaddition):
N
CO 2 Me
CO 2 Me
R
NTs
DME, rt, 3 h
7 examples, 43-92% yields
5-10:1 dr
NTs
H
Ts
N
N
R
CO 2 Me
CO 2 Me
N
CO 2 Me
CO 2 Me
Ar
1,4-Dipolar Cycloaddition
V., Nair, et. al.; Org. Lett. 2002, 4, 3575.
Various Dipoles Used to Access
Complex Alkaloid Core Structures
N
N
O
isoschizizygane core
Padwa:
S
H 5 C 2
o-NO 2 C 6 H 4
NH
O C C C O
C 2 H 5
o-NO 2 C 6 H 4
O
S
N
O
!
C 2 H 5
o-NO 2 C 6 H 4
S
O
N O
C 2 H 5
o-NO 2 C 6 H 4
N
O
66% yield
single diastereomer
o-NH 2 C 6 H 4
1. H 2 , (Pd/C)
2. LAH
H + HOAc
N
N
C
N O
N
2 H 5 N
H
H
C 2 H 5
C 2 H 5
1 : 6
A., Padwa, et. al.; Org. Lett. 2005, 7, 2925.
17

Dipoles Generated by Catalytic Methods Using
Various Metals
Iwasawa:
Ph
Ph
OTIPS
Ph
OTIPS
N
10 mol % W(CO) 6
Et 3 N, MS4Å, h!
PhMe, rt
N
O-i-Pr
N
O-i-Pr
H
Et 3 N
W(CO) 5
W(CO) 5
Ph
N
OTIPS
O-i-Pr
Et 3 N-H
H 3 O
Ph
N
O
100 mol % = 84%
10 mol % = 71%
W(CO) 5
W(CO) 5
N., Iwasawa, et. al.; Org. Lett. 2006, 8, 895.
Oh:
O
Me
EtO 2 C
3 mol % AuBr 3
1,2-DCE, rt, 8 h
CO 2 Et
Me
O
AuBr 3
CO 2 Et
CO 2 Et
O
Me
80% yield
CO 2 Et
CO 2 Et
C. H., Oh, et. al.; Org. Lett. 2005, 7, 5289.
One Old Friend, and One Friendly Molecule
Maruoka, Taichi Kano:
CHO
N
N
O
OEt
Ti(OiPr) 4
10 mol % BINOL
CH 2 Cl 2 , -40 °C
N NH
Me
EtO 2 C
CHO
42% yield, 88% ee
4 steps
HO 2 C
N
NH
O
N
H
Br
Manzacidin A
T., Kano, T., Hashimoto, K., Maruoka J. Am. Chem. Soc. 2006, 128, 2174.
Pandey:
O
O
O
H
OH
N
AgF
TMS
R
CH 3 CN
TMS
N
R
O
O
56% yield
N
R
H
O
O
N
Pancracine
H
OH
R = CH 2 CH 2 OBz
"Overman Talk"
G., Pandey, et. al; Org. Lett. 2005, 3713.
18

Some Conclusions
- 1,3 DC are extremely powerful reactions that can generate multiple chiral centers, various heterocyclic or carbocyclic
ring sizes, as well as a wide array of final products.
- There are many different dipoles, and there are various ways to make the more popular dipoles.
- Asymmetric 1,3 DC have good ee's, however lack a wide substrate scope for specific dipoles. This area is still
underexplored and will continue to draw interest.
THE END
19