The Chemistry of Hypervalent Iodine
MacMillan Group Meeting
July 30, 2003
Sandra Lee
Key References:
T. Wirth, M. Ochiai, A. Varvgolis, V. V. Zhdankin, G. F. Koser, H. Tohma, Y. Kita, Topics in Current Chemistry:
Hypervalent Iodine Chemistry -/- Modern Developments in Organic Synthesis, pp. 1-248, 224. Springer-Verlag,
Berlin, 2002.
A. Varvoglis, Hypervalent Iodine in Organic Synthesis, pp. 1-223, Academic Press, London, 1997.
P. Stang, V. V. Zhdankin, Chem. Rev. 96, 1123-1178 (1996)
Background and Introduction
n Iodine is most commonly in monovalent compounds with an oxidation state of -1, however, because
it is the largest, most polarizable, and most electropositive of the group 17 elements, it also forms
stable polycoordinate, multivalent compounds.
n First polyvalent organic iodine complex, (dichloroiodo)benzene or PhICl2, was prepared was by
German chemist C. Willgerodt in 1886. Although it's oxidizing properties were known since 1893, a
renaissance in the field of polyvalent iodine has occured only in the past 20 years.
n Factors leading to resurgence of interest:
(1) Chemical properties and reactivity is similiar to the heavy metal reagents such as Hg(III),
Tl(III), Pb(IV) but without the toxicity & environmental issues.
(2) Mild reaction conditions and easy handling of hypervalent iodine compounds
(3) Commericial availaiblity of key precursors such as PhI(OAc)2.
n Topics to be covered in this talk:
Nomenclature, Structures, and Properties
Reactivity Pattern and Mechanisms of Organo-l3-Iodanes: RIL2 and R2IL
Survey of Reactive Transformations Using Hypervalent Iodine Reagents
Selected Applications in Total Synthesis
n Topics that are NOT covered in this talk: Transition Metal Mediated Reactions and Polymer
Supported Reagents
Nomenclature for Hypervalent Iodine
n The term hypervalent was established in 1969 for molecules with elements of groups 15-18 bearing
more electrons than an octet in their valence shell.
n IUPAC rules designate l as non-standard bonding; thus, H3I is l3-iodane and H5I is l5-iodane.
Most common decet structure is aryl-l3-iodane ArIL2 (L = heteroatom) and for dodecet
structure is aryl-l5-iodane ArIL4.
n Polyvalent Iodine species differ in Martin-Arduengo designation [N-X-L] where N = # of valence
electrons on central atom, X = central atom, L = # of ligands on central atom.
hypervalent
3c-4e bond
pure 5p orbital
linear L-I-L bond
Iodinanes: trivalent iodine
o
Cl
3.06 A
87.2 o
Ph
I
Ph
109 o
Ph
5sp2 hybrid
CAr-I s-bond
dCl
Ar
L
d+
L
I
92.6 o
Periodinanes: pentavalent iodine
L
dPh
L
I
L
L
2 orthogonal
3c-4e bonds
L
I
L
12-I-5
square
pyramid
anti
10-I-4
pseudotrigonal
bipyramid
bonding
10-I-3
pseudotrigonal
bipyramid
non
8-I-2
tetrahedral
n Diphenyliodonium chloride vs. Chloro(diphenyl)-l3-Iodane?
Onium salts (such as ammonium, phosphonium,oxonium, etc.) refers to a tetrahedral geometry
with an octet in the valence shell of a positively charged atom and are not hypervalent compounds.
Also, X-ray structural data of iodine(III) compounds with a coordination of 2 (as in iodonium salts)
have never been observed.
Classes of Hypervalent Iodine
n Traditional classification is based on the # of carbon ligands on central iodine.
For Iodinanes
1C-bond:
2 C-bonds:
3 C-bonds:
Iodosyl/ Iodoso compounds (RIO) and their derivatives (RIX2, where X =
non-carbon ligands and R = aryl or CF3)
Iodonium salts (R2I+X-)
(Iodanes with 3 C-I bonds are thermally unstable and not synthetically useful)
For Periodinanes
1C-bond:
Iodyl/ Iodoxy compounds (RIO2) and their derivatives (RIX4 or RIX2O)
2 C-bonds: Iodyl salts (R2IO+X-)
n Compounds with more than one formal carbon bond to iodine:
Alkenyliodonium (PhI+C=CHR X-) and Alkynyliodonium (PhI+C≡CR X-) Salts
Iodonium Ylides (PhI=CXY, where X, Y = electron acceptors)
XO
n Cyclic Iodinanes:
l3-Iodinanes: Benziodoxazoles based on o-iodosobenzoic acid.
I
O
Z
where:
Z = CO; X = H, Me, Ac, t-Bu,
SO2R, PO(OPh)2
Z = SO2; X = H
Z = CMe2 or C(CF3)2; X = H, NO2
Z = P(O)Me or P(O)OH; X = H
Z = I(OAc); X = Ac
Z = C=NH2+; X = OTs
l5-Iodinanes: Benziodoxazoles based on o-iodoxybenzoic acid. (ie. IBX and Dess-Martin
Reagent)
n m-Oxo-bridged Iodanes (PhI(X)OI(X)Ph ,where X = OTf, ClO4, BF4, PF6, SbF6)
Ph
X
I
O
Ph
I
X
Established Hypervalent Iodide Reagents
n Most Frequently Used Reagents
ICl2
IF2
di(chloroiodo)benzene
PhICl2
I(OAc)2
di(fluoroiodo)benzene
PhIF2
O
OH
iodosylbenzene*
PhI(O)
IOB
ICN, TCI America
O
I OH
O
O
O
O
NR3+
Dess-Martin Periodinane
DMP
I O
O
S
RO
CO2H O
O
O
n Newer Iodine(III) Reagents
-O OH
I O
I OH
O
AcO OAc
I OAc
2-iodoxy-benzoic acid
IBX
[(hydroxy)(tosyloxy)iodo]benzene
PhI(OH)(OTs)
HTI
Koser's Reagent
Aldrich
n IBX Related Reagents
O
[bis(trifluroacetoxy)iodo]benzene
PhI(OCOCF3)2
BTI
Aldrich, Fluka
I OH
O
I
OTs
I=O
I(OCOCF3)2
di(acetoxyiodo)benzene
PhI(OAc)2
DIB
Aldrich, Fluka,
Lancaster, Merck
O
S
I(OAc)2
I(OAc)2
N
Tf N
I(OAc)2
NHR
O
OH
OOtBu
O
t-Bu
I
O
I OH
O
R
O
O
O
O
N
R
CnF2n+1CH2
I
OTs
I
CF3
O
Physical Aspects of l3-Iodanes
n Most hypervalent iodine reagents are solid (amorphous or crystalline) and are stable to atmospheric
oxygen and moisture. Certain iodonuim salts are less stable and should be generated in situ. A mild
explosion will occur if heated in the absence of solvent for PhI(OMe)2, PhIO, PhIO2, (PhI+)2O 2BF4-,
and o-iodylbenzoic acid.
n In the solid state: Iodosylbenzene and (tosyliminoiodo)benzene are polymeric structures terminated
by water: HO(PhIO)nH. Monomeric species are generated in reactive solvents. Secondary I-O
bonds are also observed and result in macrocyclic structures.
OH
pH
o
*
O
Ph
7A
2.3 O I
2.0 o
I
4A
O
Ph
O
I
114
Ph
Ph
.3
<2
Ph
I
o
O
*
n
pH > 5.3
BF
3-
Ph
Et
2O
I
OH2
Ts
O
N
I
N
OH2
Ts
O
Ph
n In solution:
I
Ph
Ts
Ph
N
I
N
Ts
BF3
I
Ph
Ph
I
N
Ts
n
I
OEt
Diaryl-l3-iodanes
(Ar2IL, where L = BF4, Cl, Br, OAc) in polar solvents show extensive dissociation into
solvated iodonium ions (Ar2IS+ where S = H2O, MeOH, and DMSO)
Alkenyl-l3-iodanes exist in equilibrium as an iodonium ion and as a halogen-bridged dimeric and
n-C8H17
aggregate structures.
n-C8H17
I
Ph
S
+ Br
Kdissoc
n-C8H17
Kassoc
I
Ph
Br
Br
I
Br
Ph
Ph
Br
I
n-C8H17
General Reactivity of Hypervalent Iodine
n Hypervalent iodine chemistry is based on the strongly electrophilic nature of the iodine making it
suseptible to nucleophilic attack, in combination with the leaving group ability of phenyliodonio group
-IPhX (~106 times greater than triflate!!!). The favorable reduction of the hypervalent iodide to
normal valency by reductive elimination of iodobenzene is the key to its reactivity.
n Organo-l3-iodanes have reactivity based on the number of carbon and heteroatom ligands. They
generally fit in two classes:
(1) RIL2: Majority of reactions fit under this category. Performs oxidation of various functional
groups. The two heteroatoms occupying the apical sites of the pseudotrigonal
bipyramid are essential- one is used in ligand exchange and the other in reductive
elimination.
Ligand Exchange
L
Ar
L
Nu-
I
Ar
L
L-
L
I
Nu
Ar
I
L
L
Ar
L
I
Nu
Nu
12-I-4
L
L
Ar
Ar
I
I
Nu
Ar
Nu
Nu
L-
Nu
I
L
Nu
Ar
I
Nu
Nu
Reductive Elimination of the Hypernucleofuge
C
I
BF4
C
PhI
BF4
Ph
hypernucleofuge
Reductive a- and b-Elimination of RIL2 Organo-l3-Iodanes
Reductive a-Elimination: Provides a method for the generation of carbenes.
R
R
R
C
I
L
H
Ph
PhI
C
L
R
n-C8H17
D
92%D
n-C8H17
NEt3
Example:
I
Ph
n-C8H17
0 °C
D
D
89%D
BF4
Reductive b-Elimination
R
R
R
C
M
H
I
C M
PhI
(where M = C, N, O, S)
L
R
Ph
L
On carbon atoms (M=C) produces C-C multiple bonds:
O
O
SiMe3
Bu4NF
R
Ph
I
CH2Cl2, rt
N
R N3
OTf
N
N
Oxygen and nitrogen atoms (M=O and N) provides oxidation of benzylic/ allylic alcohols and amines to the
corresponding carbonyl and imine compounds. (ie. Dess-Martin l5-iodane oxidations)
H
NH
(PhIO)n
N
HO
I
Ph
OH
N
PhI
H
N
O
I
Ph
OH
NH
PhI
More Reductive Eliminations of RIL2 Organo-l3-Iodanes
Reductive Elimination with Fragmentation
OH
n-C10H21
(PhIO)n
SnBu3
BF3
CyN
C
n-C10H21
DCC
BF3-EtO2
CyN
C
NCy
CHO
PhI
Cy
N
O
Ph NCy
I
O
OCNHCy
n-C10H21
BF2
F
I
one-step synchronous fragmentation
with exclusive formation of the trans olefin
SnBu3
Ph
Reductive Elimination with Substitution: Elimination of l3-iodanes with 2 carbon ligands with attack by a
nucleophile on the carbon atom attached to the iodine(III) gives substitution products.
Ph
Ph
R
I
Nu
L
Nu
O
I
L
R
Me
I
Ar
AcOH
Nu
OAc
OH
PhI(OAc)2
Example:
Ar
R
O
Ph
Ar
OAc
OAc
I
Ph
AcOH
O
AcOH
Ar
PhI
OAc
Reductive Elimination with Rearrangement: Elimination with concomitant 1,2-alkyl or aryl shift gives rearranged
products.
RCONH2
O Ph
PhI(OCOCF3)2
R
O
Ar
I
OCOCF3
RN
Ph
BF3-EtO2
MeOH
I
O
H2O
RNH2
CO2
OMe O
Ar
MeO
C
PhI
OMe O
(PhIO)n
Ph
Ph
O
I
N
H
MeO
PhI
Ph
Ar
Ph
Reductive Elimination by Ligand Coupling of RIL2 Organo-l3-Iodanes
Ligand Coupling
X
Ar1
I
Ar1 X
+
Ar2
I
Ar2 x
+
Ar1
I
D
Ar2
Br
Br
Me
Br
Me
I
minor
path
Me
Cl
Br
I
Cl
Cl
Br
Cl
+
I
d-
I
d+
Br
Cl
I
d-
d+
major
I
+
path
Cl
Me
Me
Me
Example:
R
BF4
O
O
Ph
I
+
CO2Me
t-BuOK
CO2Me
Ph
Other Mechanisms of RIL2 Organo-l3-Iodanes
Homolytic Cleavage: Photochemical decomposition of a hypervalent I-O bond generates a reactive radical.
(Diacyloxyiodo)arenes
OCOR
Ph
R
I
SO2Ph
RCO2
R
R
PhIOCOR
SO2Ph
hn, rt
SO2Ph
OCOR
SO2Ph
CO2
Alkylperoxy-l3-iodanes
O
R
O
R'
S
R
S
S
R
R'
O
O
R'
Se
R
RSR'
R'
R3P O
O
ROH, THF
R3P
RSeR
R
OR
OH
O
O
R
O
t-BuOO
I
O
t-BuOO
R
R
I
O
Ar
O
O
O
OR
O
Ar
OR
OH
R
O
Ar
NAc
R
OO-t-Bu
NAc
NAc
O
NHR
Ar
NR
OO-t-Bu
O
Other Mechanisms of RIL2 Organo-l3-Iodanes (Continued)
Single-Electron Transfer
Single-electron transfer from phenol ethers to l3-iodanes generates an arene cation radical resulting in a direct
nucleophilic substitution.
O
Me
OMe
O
OCOCF3
Ph
I
OMe
Me
O
(CF3)2CHOH
OCOCF3
O
OMe
OMe
OMe
OMe
L
Ph
Me
I
O
O
L
OMe
OMe
L = OCOCF3
The method for reactivity umpolung of diaryl-, alkenyl(aryl)-, and alkynyl(aryl)-l3-iodanes involves the generation of
organochromium(III) and nucleophilic addition to aldehydes is shown below.
Ph
H
Ph
MeO
I
Ph
BF4
Ph
CrCl2
O
Ph
DMF
75
p-MeOC6H4I
Cr(III)
I
Cr(II)
Ph
Ph
OH
OH
Cr(II)
MeO
:
PhCr(III)
75
:
25
MeO
9-I-2
p-MeOC6H4
PhI
Cr(II)
p-MeOC6H4Cr(III)
25
Reactivity of R2IL Organo-l3-Iodanes
(2) R2IL: Acts mainly to transfer a carbon ligand (R) to nucleophiles with reductive elimination of
ArI. The nature of the carbon ligands are important in determining reactivity.
Alkyl(aryl)-l3-Iodanes: Generally labile and decompose readily by heterolysis of C-I bond and reductive
elimination of ArI.
HO
(PhIO)n
Me3Si
PhH
I
Ph
BF3-Et2O
PhI
BF3-catalyzed ligand exchange of allylsilane, germane, or stannane with iodosylbenzene generates allyl-l3-iodane.
This is a highly reactive species that is equivalent to an allyl cation. Also may serve as a perfluoroalkylating agent.
Alkenyl(aryl)-l3-Iodanes
Progenitor of alkylidene carbene that are formed by base abstraction of an acidic a-hydrogen of an alkyenyl-l3-iodane.
The free alkylidene carbene can form solvent-alkylidene carbene complexes (ie. in ethereal solvents an oxonium ylide is
observed)
Me
Me
Me
Me
Me
Me
Me
Ph
Me
I
NEt3
BF4
Me
Me
Me
PhI
Et3N+ HBF4-
Me
Performs nucleophilic vinylic substiutions by SN2 reaction with inversion of configuration. Nucleophiles that undergo vinylic
SN2 reactions are sulfides, selenides, carboxylic acids, amides, thioamides, and phosphoroselenoates.
n-C8H17
reductive
Ph
H
n-C8H17
syn b-elimination
I
Cl
n-C8H17
H
Cl
n-C8H17
Bu4NCl
Ph
n-C8H17
Cl
H
I
H
I
Cl
Ph
Cl
Reactivity of RIL2 Organo-l3-Iodanes (Continued)
Alkynyl(aryl)-l3-Iodanes
The highly electron-deficient nature of the b-acetylenic carbon atom make these reagents good Michael acceptors towards
soft nucleophiles (O, N, and S) and undergo tandem Michael-carbene insertion (MCI) to give cyclopentene annulation
products. (ie. substituted furans)
R
I
BF4
R
Nu
Nu
Ph
R
I+Ph
Nu
R1
[5+0] MCI Reaction
1
R
R=
R1
H
H
[2+3] MCI Reaction
Nu
Nu
R
R
Nu =
R1
H
H
R1
Because the electron-deficient nature of the carbenic center of the alkylidene carbene, nucleophiles with high tendency
to migrate undergo Michael-carbene rearrangements (MCR). When the migratory apptitude of a nucleophile is poor, the
MCI pathway competes with the MCR reaction
R
I
BF4
R
Nu
R
Nu
Ph
Nu
Nu = NSC, TsS, (RO)2P(S)S, ArS, RSO3, RCO2, (RO)2P(O)O, Ph2N, Br, I
Example:
PhSO2Na
n-C8H17
I
Ph
BF4
n-C5H11
+
H2O
PhSO2
74
:
n-C8H17
SO2Ph
26
Other useful reactions include Diels-Alder reactoins, 1,3-dipolar cycloadditions, and reactions with transition metal
complexes.
Transformations Enacted by Hypervalent Iodide Reagents
n C-C Bond Bond Forming Reactions
Radical Decarboxylation of Organic Substrates
Spirolactonization of para- and ortho-Substituted Phenols
Intramolecular Oxidative Coupling of Phenol Ethers
Reactions of Iodonium Salts and Ylides
n C-Heteroatom Bond Forming Reactions (N, O, P, S, Se, Te, X)
Reactions of Aryl-l3-Iodanes
Arylations and Alkenylations of Nucleophiles
Reactions of Alkynyl(aryl)iodonium Salt
Cyanation with Cyanobenziodoxoles
Aziridations and Amidations by Sulfonyliminoiodane
Reactions of Iodonium Enolates
n Heteroatom-Heteroatom Bond Forming Reactions
Reactions of Aryl-l3-Iodanes
Reactions of Sulfonylimino(aryl)iodanes
n Oxidations and Rearrangements
Sulfoxides from Sulfides
Oxdations of Alcohols, Phenols, Heteroaromatic Compounds
Functionalization of Carbonyl Compounds
Functionalization in the a-position
Forming a,b-Unsaturation
Oxidation of C-H Bonds
Rearrangements
C-C Bond Forming Rxns: Radical Decarboxylative Alkylation of [Bis(acyloxy)iodo]arenes
OCOR
Ph
Hg - hn or D
I
R
-PhI, -CO2
OCOR
n Alkylation of Nitrogen Heterocycles
O
+
N
R
PhI(CO2CF3)
OH
R
hn or heat
N
where R = 1-adamantyl, cyclohexyl, 2-PhCH2, PhOCH2, PhC(O), etc. and
Me
CN
Br
=
,
N
N
N
,
N
N
, etc.
,
S
N
n Radical Alkylation of Electron-Deficient Alkenes
Yield of products depends on the stability and nucleophilicity of the alkyl radicals (tertiary > secondary > primary).
R1
R1
Z
+
PhI(O2CR)2
hn, 1,4-cyclohexadiene
44-99%
where Z = SO2Ph, SOPh, CO2Me, P(O)(OEt)2; R1 = H, Me
R = 1-adamantyl, cyclohexyl, 2-PhCH2CH2, etc.
R
Z
C-C Bond Forming Rxns: Oxidative Cyclization of Phenols and Phenol Ethers
X
O
I
Ph
OH
PhIX2
R1
-HX
1
O
-PhI
-XNu
O
O
Nu
R1
Nu
R
-PhI
-X-
R1
Nu
R1
Nu
X = OAc or OCOCF3
Imporant in constructing of various polycyclic systems from p- or o-substituted phenols with an external or internal nucleophile
like alcohols, fluoride ions, amides, allylsilanes, and electron-rich aromatic rings.
O
O
HO
X
PhI(COCF3)2
Example:
N
H
O
where R = H, TMS, TBDM; X = C or N
CF3CH2OH
rt, 20 min
30-76%
X
O
X
N
H
X
O
Oxidation of phenol ether in the presence of an external or internal nucleophileaffords products of nucleophilic substitution
via formation of a cation radical intermediate.
Ph
OMe
PhI(COCF3)2
I
H
OCOCF3
OMe
OCOCF3
MeO
OMe
R
R
Nu
SET
-PhI
CF3CHOH
or CF3CH2OH
charge-transfer
complex
R
R
R = alkyl, alkoxy, halogen, etc.
Nu = N3, OAc, SAr, SCN, etc.
or internal nucleophilic group
R
Examples in Total Synthesis: Epoxysorbicillinol and Bisorbicillinol
n Hypervalent Iodide(III) Induced Oxidative Dearomatization
F3COCO
O
Ph
I
O
O
O
HO
O
Me
O
O
N
HO
Me
OH
Me
Me
Me
Me
2.2 equiv BIT
O
DEAD, PPh3
CH2Cl2
O
OH
OH
O
O
N
Me
N
O
Me
O
O
O
O
O
Me
O
O
O
CH2Cl2/ MeNO2
(spiroannulation/
epoxidation) 40%
N
Me
O
Me
O
HO
Me
or
Epoxysorbicillinol
OH
O
Me
O
HO
O
Me
HO
O
Me
Me
Bisorbicillinol
(Pettus:Org. Lett. 2001,3, 905)
Examples in Total Synthesis: Quinone-Imine Formation in Dynemicin A
n Danishefsky's Approach (J. Am. Chem Soc. 1996,118, 9509)
MOMO
O
1)
Me
Me
TEOC
DIB
CO2MOM
N
O
MOMO
CO2MOM
N
O
THF, 0°C
49%
OMe
O
Me
O
LHMDS
2) BTI, THF, 0C
OMe
CO2MOM
O
OMe
MOMO
O
OH
N
MOMO
OH
1) air, daylight
THF
high conc.
2) MgBr2
OH
TEOC: trimethylsilylethoxycarbonyl
Me
OH
O
HN
CO2MOM
O
OMe
n Myers' Approach (J. Am. Chem Soc. 1997,119, 6072)
OH
Alloc
N
MeO
Me
Alloc
N
CO2TIPS
O
OMe
N
Bu3SnH
Pd(II)
IOB
MeOH
89%
CH2Cl-H2O
78%
OH
OH
OH
Alloc: allyloxycarbonyl
C-C Bond Forming Rxns: Reactions of Iodonium Salts
n Stabilized Alkyliodonium Salts
RCnF2n+1
(60-80%)
PhC CCnF2n+1
(100%)
PhC CH
CH3OH
F2n+1Cn
RMgCl
CnF2n+1
pyridine
(46%)
I
OTf H2C CH2
Ph
n = 2-8
CnF2n+1CH2CH2OCH3
CH3OH
(50%)
OSiMe3
Me
O
C
CH2
CnF2n+1
pyridine
C
Me
CH2CnF2n+1
(88%)
(97%)
O
O
Ph
Ph
(63%)
SiMe3
(90%)
Ph
C
O
CH2IPh
BF4
OSiMe3
Ar
C
CH2
OSiMe3
O
Ph
O
O
(50%)
Ph
Ar
Ar = Ph, 4-MeC6H4, 4-NO2C6H4, 4-MeOC6H4
O
(30-60%)
O
OH
Dynemicin A
C-C Bond Forming Rxns: Reactions of Iodonium Salts (Continued)
n Stabilized Alkenyliodonium Salts
O
t-BuOK
Me
Generation of Akylidienecarbenes
O
H
O
Me
Me
THF, -78 C
BF4
Ph
H
IPh
(61%)
I BF4
O
O
R
+
Alkenylation of C-Nucleophiles
R
THF, rt, 1-4 hr
K
R = Ph, Me
(86%)
O
t-Bu
O
t-Bu
Transition Metal Mediated Cross-Coupling with Cu, Zn, Sn, Pd
n Stabilized Aryliodonium Salts
EtO2C
Arylation of C-Nucleophiles
1. NaH, DMF
CO2Et
EtO2C
+ -
2. Ar2I X , rt to 70C, 2-4 hr
R
CO2Et
R
Ar
R = H, CH3,, CH2CH=CH2
Ar = Ph, 4-MeC6H4
X = BF4, OTf
(27-95%)
Generation of Benzynes
S
Ar
Ar
S C
H
(44-45%)
SiMe3
Ar
Bu4NF
R
-CO
O
Ph
Ph
Ph
Ph
(86%)
O
O
Me
O
Ph
Ph
Ph
CH2Cl2
0 to rt
IPh
OTf
(100%)
O
(100%)
Ph
Ph
Ph
Ph
(100%)
Me
Ph
C-C Bond Forming Rxns: Reactions of Iodonium Salts (Continued)
n Alkynyliodonium Salts
product of acetylenic
nucleophilic substitution
R
C
C
Nu
carbene
rearrangement
Nu
Nu
R
C
C
b
a
IPh
C
R
C
H
-PhI
IPh
Nu
C
C
R
C-H carbene insertion
(R or N must be >C3 chain)
R
five-membered
carbocycle or heterocycle Nu
R
or
Nu
R
MeC
Example of Indole Synthesis:
R
Li
N
C-I(Ph)OTf
Me
46-66%
R
Ts
Example of [4+2] Cycloaddition:
I(Ph)OTf
R
I(Ph)OTf
RC
C-l(Ph)OTf
MeCN, 20 C
Me
Me
R
I(Ph)OTf
Me
Me
R
Me
+
N
N
Ts
Ts
R = H, Me,
OMe,
COMe,
CO2-t-Bu
C-C Bond Forming Rxns: Reactions with Iodonium Ylides and Cyanation
n Reactions with Iodonium Ylides
CF3SO2
PhICH2(SO2CF3)2
(40%)
CH2Cl2, hn
Cycloaddition product
CF3SO2
(61-72%)
(CF3SO2)2HC
C-H insertion product
R
R
where R = H or Me
R2
2
R
n
Intramolecular Cycloaddition Example:
CuCl
O
1
R
n
CH2Cl2, -45°C
PhI
R
1
O
CO2Me
CO2Me
(65-90%)
n Cyanation with Cyanobenziodoxoles
NC
I
O
R
Prepared in one step by cyanomethylsilane and hydroxybenziodoxoles and a stable radical precursor
for an otherwise unstable I-CN bond. Efficient cyanating agents towards N,N-dialkylarylamines.
R
CH3
Ar
N
R = Me, CF3, O
1. ClCH2CH2Cl, reflux, 1 hr
2. KOH, H2O
CH3
Ar
(80-96%)
CH3
where Ar = Ph, 4-BrC6H4, 4-MeC6H4, 1-naphthyl, etc.
N
CH2CN
C-Heteroatom Bond Forming Rxns: Aryl-l3-Iodanes
L
Ar
L
+
I
Nu
Ar
I
L
+
L
Nu
n Azidonation
Applications have been on TIPS enol ethers, glycals, dihydropyrans, aryl N,N-dialkylamines, cyclic amides, and cyclic sulfides.
OTIPS
OTIPS
TIPSO
PhIO/ TMSN3
"PhI(N3)2"
N3
N3
+
CH2Cl2
N3
A
-78 C
-45 C
-20 C
(A : B)
(9:1)
(1:1)
(1:20)
B
n Oxidative Addition of C,C-Multiple Bonds
C,C-Double Bonds: DIB with appropriate reagents results in co-introduction of equivalent/ non-equivalent heteroatom groups.
Dithiocyanation: TMSNCS
Phenylselenyl-thiocyanation: TMSNCS and (PhSe)2
Phenylselenyl-acetoxylation: (PhSe)2
Azido-phenylselenation: NaN3 and (PhSe)2
Haloacetoxylation: Ph4P+IO
Haloazidonation: Et4N+X- and TMSN3
C,C-Triple Bonds
R1
R2
+
I2, rt
O
I
R
R
+
Ph
R
R2
I
O
OH
2
1
ClCH2CH2Cl
OTs
1
TsO
I2, rt
I
O
R
P
O
R
ClCH2CH2Cl
R2PO
R1
R2
I
R = OPh, Ph
R1, R2 = Ph, Ph
Ph, H
Ph, Me
n-Pr,n-Pr
n-Bu, H
C-Heteroatom Bond Forming Rxns: Aryl-l3-Iodanes (Continued)
n Functionalization of Aromatic Compounds
OMe
OMe
OMe
OCOCF3
+
Ph
(CF3)CH2OH
I
Nu
TMS-Nu
OCOCF3
R
R
R
Nu = N3, OAc, -SCN, SPh (from PhSH)
OH
O
BTI or DIB
MeOH
R'n
R
R'n
R
R = alkyl, alkoxy
OMe
n a-Functionalization of Carbonyl Compounds
L1
O
R'
R
+ Ph
I
O
Koser's Salt
R'
R
L2
+
L1H
+ PhI
L2
L2 = OH, OR, OCOR, OSO2R, OPO(OR)2
n C-Fluorine Bond Formations
p-(Difluoroiodo)toluene (DFIT) with appropriate reagents results in C-fluorine bond formation.
vicinal-difluorination of terminal alkynes: Et3N 5HF
trans-iodofluorination of terminal alkynes: Et3N 5HF then CuI/ KI
monofluorination of b-dicarbonyl: (DFIT generated in situ)
difluorination of dithioketals of benzophenone (to diarylfluoromethanes): (in situ generated p-(difluoroiodo)anisole)
fluorination of a-phenylsulfanyl esters and lactones: (DFIT-induced fluoro-Pummerer rxn)
alcohols to 1°- and 2 °-alkyl fluorides: converion to xanthate esters followed by DFIT
C-Heteroatom Bond Forming Rxns: Diaryliodonium and Alkenyl(aryl)iodonium Salts
n Diaryliodonium Salts
Ar2I+X- + M+Nu-
solvent
Ar
Nu +
ArI +
MX
D
O
Nu (solvent) = (RO)2P=O (DMF), R
O
O
S (DMF), Ar S S (MeCN)
O
(RO)2P-S (cyclohexane), ArSe- (DMF), ArTe- (DMF)
Arylations of weak organic nucleophiles are best with iodonium salts with nucleofugic anions and in some cases can be
faciliated with transistion metal catalysts (Cu, Pd)
n Alkenyl(aryl)iodonium Salts
Alkenylations of heteroatom nucleophiles occur by a variety of mechanisms; SN1, SN2, alkylidene carbene, and additionelimination pathways.
R
IPh BF4
M+Nusolvent
R
Nu
R = Ph or n-C4H9
MNu (solvent) = R1R2NCS2Na (THF), ROCS2K (THF), RSCS2K (THF),
(RO)2P(O)SK (THF, CuI), (RO)SP(O)SeK (THF),
(RO)sPS2K (THF, CuI), ArSeNa (EtOH), ArTeNa (EtOH)
C-Heteroatom Bond Forming Rxns: Alkynyl(aryl)iodonium Salts
n Alkynylation
R
solvent
M+Nu-
+
IPh OTs
R
Nu
+
PhI
MNu = (RO)2PONa (DMF, EtOH), ArSeNa (DMF), ArTeNa (DMF)
N
NK
, (THF, t-BuOH, CH2Cl2)
N
1) n-BuLi, PhMe
2) TMS
I Ph OTs
H
Ts
N
H
TMS
R
N
(28-89%)
R
R = n-Bu, PhCH2, CH2=CH(CH2)2, CH2=CHCH(Ph)CH2,CH2=CHCH2CH(Ph),
CH2=CHCH2CH(CH2)3CH3, (CH2=CHCH2)2CH
n C-H Bond Insertions
R1
R1
R2
H
1) n-BuLi
2) Me
I Ph OTs
R2
H N H
Ts
Ts
H
H
TsN
N
Me
Me
R1
R2
R1, R2 = Ph, Me; H, Ph; H, Me; TBSMS, (CH2)4
Intramolecular C-H bond insertions result in bicyclizations
R1
H
R1
O
R2
2
n
N
R
O
Ts
R
O
R
N
R3
OBn
C-Heteroatom Bond Forming Rxns: Alkynyl(aryl)iodonium Salts and Enolates
n C-Heteroatom Bond Insertions
n Cyclocondensations
R
O
p-tolSO2-Na+
O
IPh
OTs
R
O
THF, 65°C
R2
Ts
OR
(0-27%)
R
O
Ts
R1
I Ph A
Ar
R = TBDMS,
,
O
R
,
Me
IPh X
LiOEt, THF
H
,
O
IPh
R
H
O
O
Example:
n-C8H17
IPh Br
H
+
R2
Se
R1
N
HS
S
R1 = aryl, alkyl, CH2OR; A- = MsO- or TsO-
O
X = Br, BF4; R = Me, n-C8H17, t-Bu
AcO
R1
O
n Iodonium Enolates
AcO
S
N
H2NCS2NH4
DMF, H2O
O
R2
NH2
MeOH, Et3N
Ts
O
N
NH2
solvent, base
Se
Ts
(35-68%)
R1
S
H
+
R
H
LiOEt, THF
H
-30 °C
R
O
n-C8H17
H
E/Z = 85:15 to 96:4
(57-91%)
R = R'C6H4 (R' = H, 2-Me, 4-Me, 4-F, 4-Cl, 4-Br, 4-NO2), Et, n-C9H19, i-Pr, iBu, (E)-MeCH=CH
C-Heteroatom Bond Forming Rxns: Sulfonylimino(aryl)iodanes
n Aziridation
PhI=NTs as a nitrene transfer agents has been demonstrated with Mn(III)- and Fe(III) porphyrins and more generally with Cu(I)/
Cu(II) salts (Evan's aziridation reaction) on cyclic/ acylic alkenes, arylalkenes, and a,b-unsaturated esters.
Ts
R1
+
R2
PhI
Cu(I) or Cu(II)
(5-10 mol%)
R1
MeCN, 25°C
R2
NTs
R3
(5 equiv)
N
R3
(1 equiv)
R1, R2, R3 = H, alkyl, aryl, CO2Me
Product yields increase with substition on the arenesulfonyl moiety (p-OMe > p-Me > p-NO2).
Chiral ligands (bis(oxazolines) and bis(benzylidene)diaminocyclohexanes give asymmetric tosylaziridations (e.e. = 66%-94%)
More reactive are [nosylimino)iodo]benzene (PhI=NNs) and [(2-trimethylsilylethanesulfonylimino)iodo]benzene (PhI=NSes).
n Amidations
PhI NTs
CuCl4
TMSO
R1
O
R
MeCN
-20 - 0 °C
(53-75%)
R2
R1
R2
1
R2
TMS
NTs
R1
PhI NTs
Cu(OTf)2
R2
NHTs
MeCN or PhH
(37-78%)
R1, R2 = Ph, H; Ph, Me; n-Butyl, H; (CH2)4;
R1, R2 = H, H; CH2Cl, H; CH2OAc, H; H, Ph
CH2CH2
Chiral allylic and benzylictosylamidations are performed with salen-Mn(III) complexes, Ru(II) and Mn(III)-porphyrins, and
Ru(II)- and Ru(III)-amine complexes as catalysts. (e.e. = 41-67% for cyclic compounds and 12-53% for acyclic
compounds)
Heteroatom-Heteroatom Bond Forming Rxns
n Aryl-l3-Iodanes: Oxidation of S, P, Se, Te, Sn, & Bi
Diaryldisulfide Oxidation
Sulfide Oxidation
1
R
S
R
R1
or IOB, p-TsOH (10 mol%)
S
O
BTI, CH2Cl2
O
PhICl2 or DIB or BTI
2
R2
Ar
S
S
(80-100%)
Ar
BTI, ROH
R1
R1, R2 = alkyl or aryl
S
S
Ar (51-83%)
O
O
Ar
S
OH (51-90%)
Ar = alkyl; R = Me, Et, i-Pr, t-Bu
n Sulfonylimino(aryl)iodanes: Constructing P-N, S-N, Se-N, As-N Bonds
Phosphorous and Arsenic Ylide Formation
R3P
NSO2C6H4R
PPh3
O
(56-78%)
N
R1
S
R2
R1, R2 = Me, Me;
Ph, Ph; Me,p-tolyl
R2
(82-90%)
C6H4R
(65-85%)
t-Bu
S
O
I
AsPh3
NSO2C6H4R
NTs
R = Me, H, 4-Cl, 3-NO2
I
O
R1 S
PhI=NTs Reaction Products
Ph3As
S
Ph
NTs
O
Ar
O
NTs
PR3
(83-88%)
R3P
NTs
R = Ph, n-Bu
Se
Me
Ar
NTs
N
Me
Me Me
S
R
O
S
Me
O
TsN
Bn
Me
Me
S
N
O
N
Me
O
N
Summary of Oxidations with Hypervalent Iodine Compounds
n Chalcogen Oxidation
n Oxidations of Phenols
Sulfides to sulfoxides with IOB and BTI.
Disulfides to sulfinic esters or thiosulfonic S-esters.
Diselenides to seleosulfonates.
Ditellurides to mixed arenetellurinic anhydrides.
H
N
Iodine (V) Reagents
IBX:
Phenol to ortho -quinone only
DMP + water: Anilides to o -imidoquinones and
p -anilines to para -quinones
DMP, H2O
n Alcohols to Carbonyls
Iodine (III) Reagents
Iodine (V) Reagents
O
BIT or DIB:
DMP or IBX:
alcohol to aldehydes & ketones
IBX + Wittig Ylides: benzylic, allylic, propargylic
O
OH
alcohol to a,b-unsaturated ester
I
: (water soluable reagent) benzylic,
O
allylic, propargylic alc. oxidation
O
R'
R
Phenols to quinones by oxidations at
o - or p -position.
DIB + water: Phenols or anilines to p -quinones
N
O
R'
R
n Oxidations of Heteroaromatic Compounds
Aromatization of 5 and 6 membered rings using BIT or DIB
CO2H O
R
Iodine (III) Reagents
R
N N
DIB + TEMPO: selective 1° alcohol to aldehyde
IOB + cat. KBr: 1° alcohol to RCO2H,
2 ° alcohol to ketone
DIB + TMSN3: desilation and oxidation of glycals
R''
R'
MeO2C
O K
(PhO)n
Ar
HO
N
H
R
MeO2C
CO2Me
CO2Me
BTI
Me
I
R''
(52-70%)
R'
Ph
N N
DIB
R'
Ar
CO2Me
Me
N
(25%)
Br
O K
KBr
Ph
I
O
R'
O
H
R'
R
O
IOB
R
O
DIB
R
R
PhI, H2O, O
O
O
O
R
Oxidations & Rearrangements Using Hypervalent Iodine Compounds
n a-Functionalization of Carbonyl Cmpds
n Rearrangements
(Nucleophilic attack on phenyliodinated intermediate)
Hofmann-type Rearrangements
IBX/ BID/ IOB + base: Yields a-hydroxylated acetals
HTI: a-tosylation of ketone (silyl enol ethers)
TsO
OH
I
4
R
BID: Cyclizations of aromatic amides with a nucleophile in the
ortho -position.
OR1:
O
a-tosylation wtih about 40% e.e.
2
R3
R
Y
n Introduction of a,b-Unsaturation
N+
O
HO O
O N+
O
: Dehydrogenation of enone via in situ
formation of silyl enol ether
H
N
DIB
NH2
R
O
R
X
Y
(52-84%)
X
Y = CH, N; X = O, NR'
Rearrangement of Amidines
BID: Forms urea derivatives via carbodiimide intermediate.
O
IBX: Dehydrogenation by single electron transfer process
OH
NR'
R
O
NR'
DIB
NHR'
AcOH
NH2
O
NR
R = aliphatic or aromatic
NHR
(28-83%)
Cyclization of Unsaturated Carboxylic Acids
O
O
AcO
DIB
R
CO2H
I
O
Ph
O
R
n Oxidation of C-H Bonds
t -BuOO
I
O
O
: Oxidation of benzyl, allyl, or propargyl
ethers to esters by a radical process.
: Removal of benzyl ether protecting grps
R=H
AcO
O
R
O
O
R = Ph
Ph
R
O
O
O
Rearrangements Using Hypervalent Iodine Compounds
n Rearrangements (Continued)
Rearrangement of Chalcones
BTI: 1,2-phenyl migration and formation of b-acetal
O
O
OMe
BTI
Ar
Ar' MeOH
D
Ar
OMe
Ar'
up to 56%
Iodonio-Claisen Rearrangement
Alkenyl(phenyl)iodine(III) compounds or
DIB derivatives + propargyl silanes: Access to propynyl cmpds.
I(OAc)2
+
R
SiMe3
R'
R
AcO
R
R
AcO
I
I
R
[3,3]
NuH
Nu
R'
(49-91%)
R'
(41-96%)
Alkynyl(phenyl)iodine(III) coupounds:
Thioamides yield thiazoles
Furan derivative ring enlargements to yield pyrones
Conclusions and Future Direction of the Hypervalent Iodine Chemistry
n Future Goals
Searching for newer reagents that will lead to new reaction transformations.
Recycleable polymer supported reagents
Broadening the scope of reactivity by studying transistion metal-mediated reactions
n Conclusions
The chemistry of hypervalent iodine reagents is cool because:
(1) Fundamental reactions with versatility have been developed
(2) Mild reactivity with good yields
(3) Readily available reagents that easy to work with
(4) Non-toxic, enviromentally-friendly reagents