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Chapter 8
Carboxylic Acids and Esters
I. Introduction ......................................................................................................................158
II. Replacement of an Acyloxy Group with a Hydrogen Atom ............................................159
A. α-Acyloxy Ketones .................................................................................................159
B. Methyl Oxalyl Esters ..............................................................................................160
C. Acetates and Trifluoroacetates ...............................................................................162
D. p-Cyanobenzoates ..................................................................................................162
III. Photochemical Electron Transfer to Carboxylic Acid Esters ..........................................163
A. Acetates and Pivalates ............................................................................................163
1. Reaction Mechanism ....................................................................................163
2. Alcohol Regeneration ...................................................................................164
3. Competition from Light-Absorbing Chromophores .....................................166
B. m-(Trifluoromethyl)benzoates................................................................................167
IV. Nonphotochemical Electron Transfer to Carboxylic Acid Esters ....................................169
V. Acyloxy Group Migration................................................................................................170
A. Evolution of a Reaction Mechanism ......................................................................171
1. Possible Formation of a Cyclic Radical Intermediate ..................................171
2. A Concerted Reaction with a Cyclic Transition State ..................................172
3. Competing Concerted Reactions ..................................................................173
4. The Ion-Pair Proposal ...................................................................................174
5. Direct Observation of an Ion Pair .................................................................177
6. Probable Reaction Mechanism .....................................................................177
B. Acyloxy Group Migration in Carbohydrates .........................................................177
VI. Reactions of Carboxylic Acids ........................................................................................180
A. Electrolysis .............................................................................................................181
B. Oxidation by Hypervalent Iodine Reagents ...........................................................182
C. Decomposition of Esters of N-Hydroxypridine-2-thione .......................................184
VII. Summary ..........................................................................................................................184
VIII. References ........................................................................................................................185
I. Introduction
Carbohydrates containing typical O-acyl groups are unreactive under the reduction condi-
tions (AIBN initiation, Bu3SnH, 80-110 oC) normally used for radical reactions. This lack of
reactivity changes when O-acyl groups become part of the more complex structures found in
α-acyloxy ketones, methyl oxalyl esters, and p-cyanobenzoates. For such compounds radical
reaction with Bu3SnH under normal reaction conditions replaces the acyloxy group with a
hydrogen atom.
159 Chapter 8
There are conditions under which a less complex O-acyl group (e.g., an O-acetyl or O-ben-
zoyl group) is replaced with a hydrogen atom. One set of conditions includes raising the reaction
temperature dramatically, a change with potentially destructive consequences for the compounds
involved. A more attractive approach depends upon photochemically promoted electron transfer to
an esterified carbohydrate. Electron transfer (both photochemical and nonphotochemical) perme-
ates the radical reactions of carboxylic acid esters; that is, many of these reactions either involve
(or may involve) electron transfer.
Another way in which O-acyl groups participate in radical reactions is by group migration.
When a radical centered at C-1 in a pyranoid or furanoid ring has an O-acyl group attached to C-2,
this group will migrate to C-1 when the conditions are properly selected. Such migration provides
an effective method for producing 2-deoxy sugars.
Although esters of carboxylic acids are rich sources for substrates in radical-forming reac-
tions, the acids themselves also can produce radicals. Under the proper conditions carboxylic acids
generate carboxyl radicals, intermediates that lose carbon dioxide to form carbon-centered radi-
cals. Carboxyl radicals are generated by electrolysis of carboxylate anions and by the reaction of
carboxylic acids with hypervalent iodine compounds.
II. Replacement of an Acyloxy Group with a Hydrogen Atom
A. α-Acyloxy Ketones
α-Acyloxy ketones react with tri-n-butyltin hydride by replacing the acyloxy group with a
hydrogen atom (eq 1).1 The importance of the carbonyl group to this replacement process is
80%
( 1 ) O
O CMe2
O
O
O
CCH3
BzO
O
Me2C
O
O CMe2
O
O
O
CH3C
Me2C
O
H
Bu3SnH
C6H5CH3
110 oC
AIBN
80%
( 2 )
O
OMe
R
OCC6H5
O
O
C6H5
O
1 R =
2 R = CH(OMe)2
O
R
O
O
C6H5H
no reaction
OMe
CCH3
O
AIBN
110 oC
C6H5CH3
Bu3SnH
Carboxylic Acids and Esters 160 evident in the two reactions shown in eq 2. In the first of these a benzoate (1) containing a keto
group forms a deoxy sugar in good yield, but in the second a benzoate (2) lacking such a group is
unreactive.1 Even though reactions of α-acyloxy ketones lead to formation of deoxy sugars, the
usefulness of such reactions is limited by the relatively small number of carbohydrates that either
have the necessary substituents or easily can be converted into compounds that do.1,2
A proposed mechanism for group replacement in α-acyloxy ketones is pictured in Scheme 1.
Both addition-elimination and electron-transfer-elimination sequences are presented as possibil-
ities for acyloxy group loss. The addition-elimination possibility was proposed at the time of the
discovery of this reaction,1 but the electron-transfer option was recognized as a viable alternative
later when loss of the benzoyloxy group from α-(benzoyloxy)acetophenone was shown to involve
electron transfer from Bu3Sn· to this α-acyloxy ketone.3 There is no decisive evidence favoring
either mechanism.
B. Methyl Oxalyl Esters
Methyl oxalyl esters can be prepared easily by esterification of partially protected carbo-
hydrates with methyl oxalyl chloride (Scheme 2).4 These esters react with tri-n-butyltin hydride to
replace the methyl oxalyloxy group with a hydrogen atom.4–19
Studies of noncarbohydrate esters
show that those derived from secondary and tertiary alcohols are suitable starting materials in this
Scheme 1
CCH3
H
O
OCC6H5
CCH3
O
O
OCC6H5
CCH3
O
O
OCC6H5
CCH3
OSnBu3
O
Bu3SnH
- Bu3Sn
Bu3Sn
- Bu3Sn
OCC6H5
CCH3
O
O
Bu3Sn
- Bu3Sn
CCH3
O
CCH3
O
- C6H5COSnBu3
O
- C6H5CO
O CCH3
O
H
+
electrontransfer
addition
elimination
elimination
161 Chapter 8 deoxygenation process, but esters of primary alcohols are not because they regenerate the alcohols
from which they were synthesized.20
Most of the reactions of methyl oxalyl esters of carbohydrates
are of compounds in which a tertiary hydroxyl group has been esterified. Many of these com-
pounds are nucleosides.4,7–16
One reason that most methyl oxalyl esters are formed from tertiary
alcohols is that the O-thiocarbonyl compounds commonly used for deoxygenation in the Bar-
ton-McCombie reaction (Section II in Chapter 12) sometimes have difficulty forming when an
alcohol is tertiary.6 Methyl oxalyl chloride typically esterifies tertiary alcohols without diffi-
culty.4,6–19
Another reason for selecting methyl oxalyl esters is that they are less likely to experi-
ence the thermal elimination (Chugaev reaction) that is common for tertiary O-thiocarbonyl com-
pounds. In molecules with the proper structure cyclization can precede hydrogen-atom abstract-
tion.13
A proposed mechanism for reaction of methyl oxalyl esters with tri-n-butyltin hydride is
shown in Scheme 3. According to this mechanism the tri-n-butyltin radical transfers an electron to
the π system of the ester to produce a highly stabilized radical anion (a semidione).20
(Supporting
the idea that such a transfer takes place is the observation that Bu3Sn· reacts with oxalate esters to
produce intermediates with ESR spectra characteristic of radical anions.21
) Fragmentation of such
B = N
N
OEt
O
R = CH2CH3
75%
C6H5CH3
AIBNBu3SnH
CH3OC CCl
O O
DMAPCH3CN
DMAP =
N
NMe2
OB
OHO
CH2O
Pr2Si
O
Pr2Si i
i
R
Scheme 2
25 oC
110 oC
Pr2SiiO
B
OCCOCH3O
CH2O
Pr2Si
O
i
OO
R
Pr2SiiO
B
R
O
CH2O
Pr2Si
O
i H
CH3OC-COR
O OBu3Sn
- Bu3Sn CH3O OR
O O
a semidone
R- CH3OC-CO
O O
- Bu3Sn
Bu3SnHRH
R = a carbohydrate radical
Scheme 3
Carboxylic Acids and Esters 162 a radical anion then generates a carbon-centered radical that abstracts a hydrogen atom from
Bu3SnH (Scheme 3).
There are two significant problems associated with the synthesis and reaction of methyl
oxalyl esters. One of these is the difficulty in starting-material purification that arises because
these esters hydrolyze readily, in particular, during chromatography on silica gel.4,22
A second
problem has to do with alcohol regeneration, a significant side reaction from treatment of some
methyl oxalyl esters with tri-n-butyltin hydride.5,20
C. Acetates and Trifluoroacetates
Acetylated carbohydrates do not react with tri-n-butyltin hydride under normal conditions
(80-110 oC, 2 h, AIBN initiation), but under different, more vigorous conditions (triphenylsilane,
140 oC, 12 h, two equivalents of benzoyl peroxide) these compounds produce the corresponding
deoxy sugars (eq 3).23
These more vigorous conditions cause similar reaction in O-trifluoroacetyl
substituted carbohydrates.24
The need for two equivalents of benzoyl peroxide in the reaction
shown in eq 3 indicates that a nonchain process is taking place.
D. p-Cyanobenzoates
Replacement of the benzoyl group in compound 2 with a p-cyanobenzoyl group converts an
unreactive compound (2) into a reactive one (3) (eq 4).25
One explanation for this difference in
reactivity is that because a cyano group is quite effective at stabilizing a radical anion, electron
transfer to compound 3 is taking place where analogous transfer to the unsubstituted benzoate 2
does not occur. Since radical anions can form by electron transfer from the tri-n-butyltin radical to
easily reduced organic compounds,21,26
the electron-transfer mechanism pictured in Scheme 4
O
O O
CMe2
OMe AcOCH2
(C6H5)3SiH
140 oC
12h
O
O O
CMe2
OMeCH3
71%
( 3 ) (t-BuO)2
82%
no reaction
O
OC
O
O
C6H5(MeO)2CH
R
OMe
O
O
CH(OMe)2
O
O
C6H5
OMe
2 R = H
3 R = CN
( 4 ) 110
oC
C6H5CH3
AIBNBu3SnH
163 Chapter 8 represents a possible pathway for replacement of a p-cyanobenzoyloxy group with a hydrogen
atom.
III. Photochemical Electron Transfer to Carboxylic Acid Esters
A. Acetates and Pivalates
Photochemical electron transfer from excited hexamethylphosphoramide (HMPA) to an
O-acyl group in a carbohydrate begins a series of events that result in replacing each O-acyl group
with a hydrogen atom. An example of a typical reaction is shown in eq 5.27
The temperature at
which this reaction can be conducted (~25 oC) is synthetically far more attractive than the 140
oC
needed for the corresponding thermal reaction of an acetylated carbohydrate (eq 3).23
Photo-
chemical electron transfer to acetates has been used for the synthesis of a number of deoxy
sugars.27–34
Esters of pivalic acid, which also can serve as substrates in this type of reaction,28,35–41
sometimes give better yields than the corresponding acetates.28,35,36
1. Reaction Mechanism
Photochemical electron transfer begins with absorption of light by HMPA to produce a
highly reactive, electronically excited molecule that ejects an electron into the solution (Scheme
5).42.43
The ejected electron is captured by the acylated carbohydrate to produce a radical anion that
cleaves to give a carboxylate anion and a carbohydrate radical (R·).43
Hydrogen-atom abstraction
by the carbohydrate radical then completes the replacement process (Scheme 5). The water present
( 5 )
OO
O
Me2C OMe
OAc
CH2OAc
h
HMPA
H2O
64%
OO
O
Me2C OMe
CH3
(Me2N)3PO (Me2N)3PO (Me2N)3PO esol*
Scheme 5
h+
R1OCR2
O
+ esol R1OCR2
O
R1 + OCR2
O
R1
hydrogen
abstraction
from HMPAR1H
R1 = carbohydrate radical R2 = CH3 or C(CH3)3
HMPA
Carboxylic Acids and Esters 164 in the reaction mixture extends the lifetime of the solvated electron and, in so doing, increases the
probability that this electron will be captured by a molecule of ester.43
(The importance of water to
the success of this process is demonstrated by the yields of the reactions shown in eq 6.44,45
)
2. Alcohol Regeneration
Ester photolysis in aqueous HMPA sometimes regenerates the alcohol from which the ester
was synthesized (eq 7).34
In some instances, alcohol formation may be due to nonphotochemical
ester hydrolysis. Nonphotochemical reaction provides a reasonable explanation for the easily
hydrolyzed, anomeric acetate shown in eq 8 undergoing only hydrolysis (no deoxygenation) when
(Me2N)3PO (Me2N)3PO (Me2N)3PO esol*
Scheme 5
h+
R1OCR2
O
+ esol R1OCR2
O
R1 + OCR2
O
R1
hydrogen
abstraction
from HMPAR1H
R1 = carbohydrate radical R2 = CH3 or C(CH3)3
AcO
Me
H
Me
H
( 6 ) h
HMPA
HMPA / H2O
solvent product yield
trace
84%
O
O
OMe2C
O
O CMe2
OCCH3
O
h
HMPAH2O
O
O
OMe2C
O
O CMe2
O
O
OMe2C
O
O CMe2
OH( 7 ) +
65% 30%
165 Chapter 8 photolyzed in aqueous HMPA.
34 Even though simple hydrolysis may be significant for some
compounds, as described below, alcohol regeneration during photolysis of other, probably most,
esters must occur in a different way.
Alcohol formation during ester photolysis cannot be explained, in general, by simple
hydrolysis because, as is shown by the reaction pictured in Scheme 6, the yield of the alcohol can
depend on the concentration of the starting ester.43
One explanation for this dependence begins
with the ester 5 capturing a solvated electron to form the radical anion 6. This radical anion then
abstracts a hydrogen atom from a second molecule of 5 to produce the anion 7, which then forms
an alkoxide ion that protonates to give the observed alcohol.43
Since, according to this explanation,
raising ester concentration should increase the rate of hydrogen-atom abstraction to give 7 but not
O
OH
O
O
O
Me2C
O
CMe2
H2OHMPA
hO
OAc
O
O
O
Me2C
O
CMe2
( 8 )
76%
Scheme 6
ROCCMe3
O
ROCCMe3
O
H
hydrogen
abstraction
from ROCCMe3 (5)
O
- Me3CCH
O
RO
ROH
R
hydrogen
abstraction
from HMPA
RHO
O
OMe2C
O
CMe2O
R =
7
ROCCMe3
O
5
esol
concentration
of 5
0.23 M
5.25 M
ROH
RH
7.8
1.2
6
hydrogenabstraction-cleavage
- Me3CCO2
pathway pathway
Carboxylic Acids and Esters 166 the rate of the competing β-cleavage that forms R·, greater ester concentration should increase the
amount of alcohol (ROH) produced at the expense of the deoxygenated product (RH).
A critical question about the mechanism for alcohol formation presented in Scheme 6 con-
cerns whether the radical anion 6 can abstract a hydrogen atom from the ester 5. The evidence
found in eq 9 supports the idea that 5 can function as a hydrogen-atom donor. Irradiation of 5 in
HMPA-d18/D2O gives a 27% yield of 8, a reduction product that contains no deuterium. Since the
only source for the second hydrogen atom at C-3 in 8 is one of the carbohydrates in the reaction
mixture and since the ester 5 is the only carbohydrate present at the beginning of the reaction,
abstraction from 5, at least in the early stages of reaction, seems unavoidable. If 5 can act as a
hydrogen-atom donor in the formation of 8, it becomes a strong candidate for the same role in the
conversion of the radical anion 6 into the alkoxide ion 7 (Scheme 6).
3. Competition from Light-Absorbing Chromophores
If an ester contains a strongly absorbing chromophore, HMPA excitation will be effectively
precluded because most of the incident light will be absorbed by the ester. Failure to excite HMPA
O
O
OMe2C
O
O CMe2
OCC(CH3)3
O
h
HMPA-d18D2O
O
O
OMe2C
O
O CMe2
D
H
O
O
OMe2C
O
O CMe2
H
H
( 9 ) +
73% 27%
5 8
OO
O
C6H5
MeO
OMePivO
O
CH2OH
PivOOMe
MeO
HO( 10 )
Piv = CC(CH3)3
O34%
h
HMPAH2O
OO
OMeO
OMePivO
CH3
CH3
( 11 )
Piv = CC(CH3)3
O
OO
OMeO
OMe
CH3
CH3
60%
h
HMPAH2O
167 Chapter 8 will forestall replacement of the acyloxy group with a hydrogen atom by preventing electron trans-
fer. The light absorbing properties of the benzoyloxy group, for example, render benzoates much
less desirable participants in these electron-transfer reactions because far less incident light
reaches the HMPA. This means that an important factor in reaction of simple acetates and pival-
ates is that these compounds contain no strongly absorbing chromophore.42
An example of an ester
that fails to undergo replacement of the acyloxy group due to the presence of a light-absorbing sub-
stituent (i.e., the 4,6-O-benzylidene group) is shown in eq 10.41
Even though the benzylidene
group is removed during photolysis, the aromatic chromophore remains in the solution and con-
tinues to absorb the incident light. Changing 4,6-O-benzylidene to 4,6-O-isopropylidene protec-
tion allows reaction to proceed in the normal fashion (eq 11).41
B. m-(Trifluoromethyl)benzoates
A m-(trifluoromethyl)benzoate will accept an electron from excited N-methylcarbazole (11)
in a reaction that leads to replacement of the acyloxy group with a hydrogen atom; for example,
hH2O
(CH3)2CHOH
N
NN
N
NH2
ORRO
ROCH2O
( 12 )
9
10
R = - CC6H4CF3(m)
O
N
NN
N
NH2
ROCH2O
C13H11N
C13H11N =
N
CH3
11
73%
( 13 )
B = HN
N
O
O
OBzOCH2 B
BzO
11
70%
N
CH3
C13H11N =
OBzOCH2
OCC6H4CF3(m)
B
BzO
O
C13H11N
(CH3)2CHOH
H2Oh
Carboxylic Acids and Esters 168 photolysis of 2',3',5'-tri-O-[m-(trifluoromethyl)benzoyl]-adenosine (9) produces the 2',3'-dide-
oxyadenosine derivative 10 (eq 12).46
(Most,46–52
but not all,48
compounds reported to undergo this
type of reaction are nucleosides.) Reactions, such as the one shown in eq 12, are regioselective
because the radical anion generated from a m-(trifluoromethyl)benzoyl group does not fragment to
give a primary radical.
Photochemical electron transfer involving m-(trifluoromethyl)benzoates and N-methylcar-
bazole (11) has several advantages over electron transfer between HMPA and acetates or pival-
ates. One of these is that N-methylcarbazole has greater molar absorptivity than HMPA, a fact that
renders the carbohydrate reactant less likely to stop the reaction by absorbing the incident light.52
( 14 )
O
OMe
OBz
O
O
C6H5OAc
hMg(ClO4)2
0 oC
84%
O
OMeO
O
C6H5OAc
C16H17N
N
CH2CH3
CH3 CH3
C16H17N =
12
(CH3)2CHOH
R = carbohydrate moiety
N
CH3
N
CH2CH3
CH3 CH3
11 12
carbazole + ArCOR
O
backelectrontransfer
hcarbazole ArCOR
O
13
-fragmentation
ArCO
O
+Rabstraction
RHhydrogen
Ar = C6H5, C6H4CF3(m)
11 or 12
Scheme 7
169 Chapter 8 From a safety point of view, eliminating HMPA from the reaction mixture avoids handling a
highly toxic, cancer-suspect agent. Because the m-(trifluoromethyl)benzoyl group is an effective
electron acceptor (better than an acetyl or pivaloyl group) few substituents in the carbohydrate will
compete with this group for an electron donated by excited N-methylcarbazole (11); consequently,
reactions of m-(trifluoromethyl)benzoates usually are highly chemoselective. An example of this
selectivity is shown in eq 13, where the benzoyl group remains bonded to C-3' while the m-(tri-
fluoromethyl)benzoyl group at C-2' is replaced by a hydrogen atom.49
When reaction is conducted in the presence of Mg(ClO4)2, it is possible to replace even an
unsubstituted benzoyloxy group with a hydrogen atom (eq 1450
).50–52
Magnesium perchlorate
affects this reaction by hindering back electron transfer, a process that competes with the fragmen-
tation of the radical anion 13 (Scheme 7). Another factor that affects the reaction of a benzoyloxy
group is the choice of the electron donor; thus, replacing N-methylcarbazole (11) with 3,6-di-
methyl-9-ethylcarbazole (12) causes deoxygenation to take place more rapidly.50
Compound 12 is
superior to 11 because it forms a more stable radical cation upon electron transfer.50,53,54
IV. Nonphotochemcal Electron Transfer to Carboxylic Acid Esters
Electron transfer to carboxylic acid esters also can occur via nonphotochemical reaction.
Transfer of an electron from SmI2 to a carbohydrate p-methylbenzoate produces a radical anion
that fragments to give a carbon-centered, carbohydrate radical and a p-methylbenzoate anion
(Scheme 8).54.55
The carbohydrate radical abstracts a hydrogen atom from a donor present in the
solution to form a deoxy sugar. An example of such a reaction is shown in eq 15.
ROCAr
Ohydrogen
abstraction
SmI2 - ArCO2R
Scheme 8
Ar = C6H4CH3 (p)
ROCAr
O
RH
R = a carbohydrate radical
- SmI2
60%
( 15 ) O
O CMe2
O
O
O
OCC6H4CH3(p)
H
Me2C
O
O
O CMe2
O
O
O
H
Me2C
H
SmI2HMPA
THF
Carboxylic Acids and Esters 170
V. Acyloxy Group Migration
Group migration in radical reactions follows one of two basic pathways. For aldehydo,
cyano, and aryl groups, migration takes place by a sequence of elementary reactions consisting of
cyclization and β-fragmentation steps. (An example of this type of reaction is shown in Scheme 8
of Chapter 10). Group migration in esters is governed by a different mechanism, one that has been
the subject of considerable investigation. To follow the progress in understanding this reaction, it
is useful to view the advances in mechanistic discovery in a chronological order.
( 16 )
O R
OO R
O
O
CH2OAc
Br
OCCH3
OAc
AcO
O
O
CH2OAc
OCCH3
OAc
AcO
O
O
CH2OAc
OAc
AcO OCCH3
O
O
CH2OAc
OAc
AcO OCCH3
O
Bu3Sn
Bu3SnBr
Bu3SnH
Bu3Sn-
-
Scheme 9
OO
CH3
CH3
CH3
14 1516
OO
CH3
CH3
CH3
O O
CH3
CH3
CH3
Scheme 10
171 Chapter 8
A. Evolution of a Reaction Mechanism
In the late 1960’s reports first appeared of a reaction in which an acyloxy group migrated to a
radical center located on a neighboring carbon atom (eq 16).56,57
Curiosity about this process grad-
ually increased as its complexity began to unfold. Interest intensified as the synthetic potential of
this reaction began to be recognized. An early indication of the synthetic possibilities came from
the study of carbohydrates, where acyloxy group migration provided the basis for a new synthesis
of 2-deoxy sugars (Scheme 9).58–62
1. Possible Formation of a Cyclic Radical Intermediate
The first proposed mechanism for acyloxy group migration involved the intermediate forma-
tion of a 1,3-dioxolan-2-yl radical.57
Although formation of this cyclic intermediate represented a
reasonable possibility, subsequent studies showed that such a radical could not be involved in this
reaction.63–66
The line of investigation that first pointed to this conclusion was based on the finding
that the radical 14 was converted to 15 under conditions where the proposed, intermediate 1,3-di-
oxolan-2-yl radical 16 did not undergo ring opening fast enough to account for group migration
(Scheme 10).63–65
The evidence that a cyclic intermediate was not involved in acyloxy group migration was
reinforced by the reactions shown in Schemes 11 and 12.65
In the first of these reactions the radical
18 was converted into a new radical (19) by group migration (Scheme 11). The question at this
point concerned whether the cyclic radical 20 was involved in the process. The answer came in the
second reaction where 20 was generated independently under conditions that would allow acyloxy
group migration, but opening of the cyclopropane ring took place rather than dioxolane ring
opening (Scheme 12). These results eliminated 20 as a possible intermediate in the migration reac-
18
20
19
OO
CH3
CH3
O O
CH3
CH3
OO
CH3
CH3
Scheme 11
17
OO
CH3
CH3 Br
h
- Br
possibleintermediate
Carboxylic Acids and Esters 172 tion and supported the idea that 1,3-dioxolan-2-yl radicals are not involved in acyloxy group
migration.
2. A Concerted Reaction with a Cyclic Transition State
Eliminating the 1,3-dioxolan-2-yl radical as a potential reaction intermediate left a mechan-
istic void that was filled by the proposal of a concerted process in which the transition state had the
structure 21 (Scheme 13).63
Consistent with this proposal was the finding that migration of acyloxy
groups containing 18
O-labeled carbonyl oxygen atoms yielded products with carbonyl and ether
oxygen atoms transposed.63
Kinetic studies supported the mechanism shown in Scheme 13.63,65,67
The findings from one
of these investigations indicated the existence of a transition state in which C–O bond breaking
was virtually complete before the beginning of new bonding between the carbonyl oxygen atom
and the radical center. Acceleration of the migration process by an electron-withdrawing R group
was consistent with the charge-separated transition state 22 proposed for the reaction shown in
Scheme 14.67
Also supporting charge separation in the transition state was the observation that the
OO
CH3
CH3
Scheme 12
OO
CH3
CH3
20
OO
CH3
CH3
H
O O
CH3
CH3
19
RO
- ROH
Scheme 13
= oxygen label
OC
R
O
R = an aryl or alkyl group
21
OCR
O
R
OC
O
173 Chapter 8 rate of acetoxy group migration was faster in a more polar solvent (water) than in a less polar one
(t-butylbenzene).67
3. Competing, Concerted Reactions
At this point the mechanism shown in Scheme 13 (with the added charge separation shown in
Scheme 14) explained the existing information. Subsequent discovery of migration reactions in
which transposition of ether and carbonyl oxygen atoms was incomplete forced a reevaluation of
this position.68,69
To be acceptable, any new mechanistic proposal also needed to account for par-
tial oxygen-atom transposition in some reactions and for the fact that migration with complete
transposition (eq 17) takes place more slowly than reaction in which transposition is incomplete
(eq 18).69
One solution to this problem was to add a second, concerted mechanism (Scheme 15) and
propose that the two reactions shown in Schemes 13 and 15 were competing.70–74
A basic differ-
OO
R
CH3
CH3
22
OO
R
CH3
CH3
O O
R
CH3
CH3
Scheme 14
R = CH3 k = 4.5 x 102 s-1 at 75 oC
R = CF3 k = 7.0 x 104 s-1 at 75 oC
CH3
O CH3
O
CH3
( 17 )
CH3
O
O CH3
CH3
krel = 1 (100% oxygen transposition)
1818
OCC3H7O
O
( 18 )
22 (33% oxygen transposition) ~_krel
18
OCC3H7O
O
18+
24 25
24/25 = 2/1
18
23
O C3H7
OO
Carboxylic Acids and Esters 174 ence between these two was that in one (Scheme 15) the same oxygen atom was bonded to the
carbon-atom framework both before and after migration, but in the other (Scheme 13) the
framework had a different oxygen atom attached after migration. Proposing migration via a
combination of these two reactions made it possible to explain experiments with oxygen-labeled
substrates in which only a portion of the labeled oxygen was attached to the carbon-atom
framework after migration. The findings at first favored this two-reaction explanation,70–74
but
results from later investigations required a new proposal because these later studies indicated that
ionic intermediates were likely to be involved in the migration process.
4. The Ion-Pair Proposal
Formation of a contact ion pair (CIP) consisting of a carboxylate anion and a radical cation
(27) was the defining step in the next mechanistic proposal for acyloxy group migration (Scheme
16).68,69,75
This proposal extended the idea of a charge-separated transition state to formation of an
intermediate (27) in which there was complete ionization. If the anion and radical cation in 27 were
held together sufficiently strongly (i.e., a very “tight” ion pair), no reorientation of the atoms
should occur, and recombination should produce a product radical (28) in which there was com-
plete transposition of the carbonyl and ether oxygen atoms (Scheme 16).
If the ions in 27 are sufficiently stable to be held loosely enough for their relative motion to
allow the ion pairs 29, 30, and then 31 to form, combination of the ions in 31 will produce a pro-
= oxygen label
OC
O
R
OC
O
R
R = an aryl or alkyl group
OC
O
R
Scheme 15
OO
R
X
OO
R
X
O O
R
X
Scheme 16
X
OO
R
2627
28
= oxygen label X = a substituent group
175 Chapter 8 duct radical (32) with no oxygen-atom transposition (i.e., the oxygen label in still in the carbonyl
group), but combination of the ions in 27 will give a product radical (28) in which the label no
longer is with the carbonyl group (Scheme 17).75
Factors that stabilize either component of the ion
pair should increase the probability of partial oxygen-atom transposition by reducing the
“tightness” of the ion pair. These same factors also should increase the rate of acyloxy group
migration by stabilizing the charge-separated transition state leading to the contact ion pair 27;
thus, the ion-pair proposal explains the correlation between oxygen-atom transposition and
reaction rate (equations 17 and 18).75
If 27, 29, 30, and 31 (Scheme 17) are all contact ion pairs, the radical cation member of each
pair should not react with added nucleophiles during the migration process. Testing for this type of
reaction by addition of benzoate or azide ions or methanol to the reaction mixture during rear-
rangement did not generate any products from capture of a radical cation by a nucleophile.76
Even
radicals containing a nucleophile that could react internally with a radical cation did not form any
products from such internal trapping during group migration.77
OO
R
X
O O
R
X
OO
R
27
transition state
31
OO
R
X
O O
R
X
X
Scheme 17
= oxygen label
X = a substituent group
32
OO
R
X
OR
O
X
29
RO
O
X
30
26
28
Carboxylic Acids and Esters 176
In addition to undergoing reaction with partial oxygen-atom transposition (eq 18) the radical
23 also gives a small amount of oxygen-atom mixing in recovered starting material (Scheme 18).69
The ion-pair mechanism explains this oxygen-atom transposition in the starting material as
O C3H7
OO
23
O C3H7
OO
33
hydrogen abstraction
O C3H7
OO
O C3H7
OO
34/35 = 16
hydrogenabstraction
34 35
Scheme 18
18
18
18
18
(initially formed radical)
a contact ion-pair permittingoxygen-labelinterchange
24 + 25
CIP SSIP
Scheme 19
Ar
OP
ORRO
O
Ar
OOP
ORRO
Ar
OOP
ORRO
36
37 39
O
Ar
38
OP
ORRO
Ar
OOP
ORRO
40
free ionsmigrationproduct
Ar = C6H5
177 Chapter 8 resulting from conversion of 23 into a contact ion pair that usually reacts further to give the
group-migrated radicals 24 and 25 but sometimes collapses to the oxygen-atom transposed radical
33. Formation of a small amount of 33 accounts for the distribution of the oxygen-atom label in the
products 34 and 35 formed by reduction (without migration) of radicals 23 and 33, respectively
(Scheme 18).
5. Direct Observation of an Ion Pair
Phosphatoxy groups undergo migration that is similar to that of acyloxy groups.70,78,79
The
rate constants for phosphatoxy group migration usually are greater by at least two orders of magni-
tude than those for acyloxy groups,80,81
but basic mechanistic findings support the idea that these
two group migration reactions are similar. This similarity takes on added significance in light of
the results from flash-photolysis experiments.
Critical support for the ion-pair mechanism for phosphatoxy group migration comes from
laser-flash-photolysis (LFP) experiments.79,82
Both the solvent-separated ion pair (SSIP) 39 and
the diffusively free radical cation 40 can be detected in studies where LFP generates the radical 36
(Scheme 19).79
Evidence for the contact ion pair (CIP) 37 in this reaction is indirect because its
lifetime, presumably, is too short to permit direct detection. Study of reaction rates in solvents of
different polarity supports the idea that the radical 36 is passing through a common intermediate in
forming either the rearranged radical 38 or the SSIP 39. A reasonable conclusion is that the
common intermediate is the CIP 37 (Scheme 19).79
Entropies of activation, which are the same for
ion-pair formation in high polarity solvents and group migration in solvents of low polarity, also
favor a common intermediate for which 37 is the prime candidate.79,83
Generalizing these results
leads to the reaction mechanism shown in Scheme 20. (Reactions of radicals containing phospha-
toxy groups are described in Chapter 9).
6. Probable Reaction Mechanism
Other studies also show similarities between acyloxy and phosphatoxy group migration.83,84
Since the ion-pair mechanism (Scheme 20) is firmly in place for phosphatoxy group migration,
such similarities reinforce the idea that migration of an acyloxy group also involves formation of a
contact ion pair. Where acyloxy group migration is concerned, however, the failure actually to
observe any type of ion pair makes this mechanistic pathway less certain. Not being able to detect
ions in these reactions easily could be due to very rapid, ion-pair collapse to the product radical.
Without such detection or a similarly definitive observation, however, the possibility remains that
acyloxy group migration, at least in some cases, may be a concerted process.
B. Acyloxy Group Migration in Carbohydrates
Because 2-deoxy sugars can be difficult to synthesize, acyloxy group migration represents an
attractive route to this important class of compounds (Scheme 9). For group migration to be
Carboxylic Acids and Esters 178 effective, it must take place before the initially formed radical reacts with a hydrogen-atom donor.
To allow sufficient time for group migration, the concentration of a reactive hydrogen-atom donor,
such as tri-n-butyltin hydride, needs to be maintained at a low level by adding it slowly to the
reaction mixture. Under these conditions the yields of 2-deoxy sugars are good.58–60
An alternative
to this slow addition is to use a less reactive hydrogen-atom donor; thus, when tris(trimethyl-
silyl)silane fills this role, slow addition is not necessary in order to observe the migration shown in
Scheme 9.61
As might be expected, the very effective hydrogen-atom donors thiophenol85
and
benzeneselenol86
dramatically inhibit the migration process by rapidly donating a hydrogen atom
to the initially formed carbohydrate radical.
Starting sugars for acyloxy group migration usually are pyranosyl or furanosyl bro-
mides.58-62,85,87
Glycosyl selenides59,88
also are acceptable substrates and, in fact, are better for
reaction of furanosyl compounds (eq 19)59
because the corresponding bromides are quite thermo-
labile.
Reaction in which a carbon-centered radical stabilized by an attached oxygen atom translo-
cates during acyloxy group migration to become an unstabilized radical (Scheme 9) seems like an
O
OP
O
RO OR
R = an aryl or alkyl group
OP(OR)2
O
O
CIP
O
O
P(OR)2O
SSIP
O
O
P(OR)2O
free ions
O
Scheme 20
low polaritysolvent
high polaritysolvent
OP(OR)2
O
O
SeC6H5
OBzBzO
BzOCH2
O
OBz
BzO
BzOCH2AIBNBu3SnH
C6H5CH3
110 oC
75%
( 19 )
179 Chapter 8 unpromising basis for group migration. The reason this reaction takes place is that migration also
creates an acetal linkage involving C-1.59,62
Calculations on model systems suggest that forming a
second C–O bond at an oxygen-substituted carbon atom stabilizes the system by about 15
kcal/mol,89
enough of this stabilization apparently exists at the transition state to allow the reaction
shown in Scheme 9 to take place.59,62
The calculated stabilization is less that 5 kcal/mol if one of
the oxygen atoms in the model system is replaced by a sulfur atom.89
This reduced stabilization
accounts for the failure of the substrate 41 to undergo group migration (eq 20).62
An acyloxy group at C-1' in a nucleoside can undergo migration from C-1' to C-2' (eq
2190,91
).90–94
This type of reaction sometimes is referred to as a “reverse 1,2-shift” because the
acyloxy group moves in the opposite direction from that observed in reaction of pyranos-1-yl and
furanos-1-yl radicals. The transition state in the reaction shown in eq 21 is believed to be a polar
one92
and may lead to a contact ion pair (Scheme 21).93
Stabilization of the rearranged radical 42
by a uracil (or adenine) moiety is sufficient to allow the rearranged radical to form.91
The stereo-
chemistry at C-1' is determined by approach of the hydrogen-atom donor to the less hindered face
of the five-membered ring.91
The reaction shown in eq 21 further illustrates the advantage of the
S
CH2OAc
Br
OCCH3
OAc
AcO
O41
80 oC
C6H6
Bu3SnHAIBN S
CH2OAc
OCCH3
OAc
AcO
O
( 20 )
O
OPiv
RO
ROCH2 B
Br
AIBN
C6H6
80 oC
( 21 ) O
RO
ROCH2
OPiv
B
+O
RO
ROCH2
OPiv
B
NH
N
O
O
B = R = SiMe2 t-Bu
hydrogenO
OPiv
RO
ROCH2 B
+
hydrogen donor
(Me3Si)3SiH (4 eq) 84%
16%
-
2%
3%
-
donor
7%
Bu3SnH (5 eq)
80%Bu3SnH (2 eq)
95%
CC(CH3)3
O
Piv =
Carboxylic Acids and Esters 180 less reactive hydrogen-atom donor (Me3Si)3SiH in allowing sufficient opportunity for migration to
take place.
VI. Reactions of Carboxylic Acids
Carboxylic acids cannot be converted directly into carboxyl radicals, but they can form these
radicals indirectly. One method for indirect formation calls for converting the acid into its anion,
which then is subjected to electrolysis (Scheme 22).95
Other indirect methods require formation of
Scheme 21
42
B
OC
R
O
B
R = C(CH3)3
OC
O
B
RCIP
OC
O
B
R
H
(Me3Si)3SiHB =
NH
N
O
O
- (Me3Si)3Si
OCR
O
RCO2HHO
- H2ORCO2 RCO2
- e
Scheme 22
- CO2R
hRCON
S
O
+RCO2H HON
S
C6H5N=C=NC6H5
- C6H5NHCNHC6H5
O
- C5H4NS RCO2
Scheme 23
+RCO2 R CO2 ( 22 )
181 Chapter 8 carboxylic acid derivatives, such as esters of N-hydroxypyridine-2-thione, compounds that pro-
duce carboxyl radicals by photochemically initiated reaction (Scheme 23).96
Carboxyl radicals
expel carbon dioxide to produce carbon-centered radicals (eq 22).
A. Electrolysis
The carbon-centered radicals resulting from electrolysis of carboxylate anions (Scheme 22)
either undergo radical reactions (usually radical combination), or they are further oxidized to car-
bocations. Whether or not oxidation to give a cation takes place depends on the reaction conditions
and on the structure of the carbon-centered radical produced. If this radical is capable of forming a
stabilized carbocation, it will be further oxidized; for example, in the reaction shown in Scheme 24
oxidation of the radical 44 to the oxygen-stabilized cation 45 is the major, if no exclusive, reaction
pathway.97
O
CO2H
O
OO
CMe2
O
Me2C 44
CH3O
- CH3OH
O
CO2
OO
CMe2- CO2
- e
OO
OCMe2
43 - e
45
OO
OCMe2
O
OCH3
O
OO
CMe2
O
Me2C 46
CH3OH
- H
85%
Scheme 24
31%
( 23 )
MeOH
Pt
10 eq
electrolysisO
CO2H
O
OO
CMe2
O
Me2C
CH3(CH2)6CO2H+
1 eq
43
O
(CH2)6CH3
O
OO
CMe2
O
Me2C 47
O
OMe
O
OO
CMe2
O
Me2C 46
+
Carboxylic Acids and Esters 182
A modest yield of the unsymmetrical radical coupling product 47 forms during electrolysis
of the carboxylic acid 43 in the presence of a ten-fold excess of octanoic acid (eq 23).97
Isolation of
orthoester 46 from this reaction indicates that the cation 45 (Scheme 24) still is produced under
these new conditions. Formation of the radical coupling product 47 under conditions where the
carbocation 45 also is formed, has led to the proposal that simultaneous decarboxylation of coacids
may account for radical coupling occurring before further oxidation to 45 can take place.97
Oxidation of a radical to a carbocation does not happen if the potential cation is an unsta-
bilized one (e.g., a primary cation with no stabilizing groups attached); thus, in the reaction shown
in eq 24, radical oxidation to a primary cation does not take place. The only carbohydrate products
isolated in this reaction arise either from unsymmetrical radical coupling (48) or disproportion-
ation (49 and 50).98
Although the carbon-centered radicals produced by electrolysis and loss of
carbon dioxide are considered to be “free”, their locally high concentration at the electrode where
they are formed would promote radical coupling even if simultaneous decarboxylation of coacids
does not occur.99
B. Oxidation by Hypervalent Iodine Reagents
Decarboxylation of carboxylic acids by their reaction with hypervalent iodine reagents
{(diacetoxyiodo)benzene,100
[bis(trifluoroacetoxy)iodo]benzene,101,102
[bis(trifluoroacetoxy)io-
do]pentafluorobenzene,101,102
and (diacetoxyiodo)benzene–I2.103
} is another process that generates
carbon-centered, carbohydrate radicals (Scheme 25).100–103
When reaction is conducted in the
CO2H
CH2
AcO
OAc
OAc
CH2OAc
+ CH3(CH2)4CO2Helectrolysis
10 eq
Pt
MeOH
(CH2)4CH3
CH2
AcO
OAc
OAc
CH2OAc
+
( 24 )
48
69%
+
49
5%
50
5%
CH3
AcO
OAc
OAc
CH2OAc
CH2
AcO
OAc
OAc
CH2OAc
183 Chapter 8 presence of a heteroaromatic base, the carbohydrate radical adds to the base (eq 25
102).
100–102 Base
protonation greatly increases its reactivity with carbohydrate radicals (most of which are nucleo-
philic); thus, product yields are reported to be best when the reaction mixture is decidedly
acidic.100
Oxidative decarboxylation also takes place when a carboxylic acid reacts with (diacetoxy-
iodo)benzene in the presence of molecular iodine (eq 26).103
(No reaction takes place in the
absence of iodine.103
) One explanation for the role of iodine is that it is necessary for formation of
an acyl hypoiodite, an intermediate that then decomposes to give a carboxyl radical and an iodine
atom (Scheme 26).104
A proposed mechanism for reaction of the carboxyl radical 51 is given in
Scheme 27. According to this mechanism 51 expels carbon dioxide to give the carbon-centered
radical 52. Iodine capture then produces the iodide 54, which ionizes to give the carbocation 53.
RCO2H
RCO2
Scheme 25
+ B RCO2 + BH
(CF3CO2)2IC6F5 + 2 RCO2 (RCO2)2IC6F5 + 2 CF3CO2
(RCO2)2IC6F5- RCO2IC6F5
h - CO2R
B = a heteroaromatic base R = a carbohydrate moiety
RCO2HCH2Cl2
( 25 )
N
CO2Me
O
BzO
BzO
+(CF3CO2)2IC6F5
h
N
CO2Me
R
R =
42%
= 5/1
+ h
CH3CN
25 oC
O
OO
CMe2
OBnCO2H
O
OO
CMe2
OBnAcO
O
OO
CMe2
OBnAcNH
(AcO)2IC6H5 + I2 + ( 26 )
1eq 3 eq 1.2 eq 53% 36%
1eq 3 eq 0 eq 0% 0%
Carboxylic Acids and Esters 184 Supporting this pathway is the observation that in compounds where ionization cannot produce a
stabilized carbocation, iodides are isolated.104
Formation of the iodide 54 would be expected to
occur rapidly because the carbon-centered radical 52 should react with the I2 present in the reaction
mixture at or near the rate of diffusion.105,106
(The rate constant for iodine-atom abstraction from I2
by the cyclohexyl radical is 1.2 x 1010
M-1
s-1
.105
)
C. Decomposition of Esters of N-Hydroxypyridine-2-thione
Photochemically initiated reactions of carboxylic acid esters of N-hydroxypryidine-2-thione
represent another route to carboxyl radicals. These reactions are discussed in Chapter 12.
VII. Summary
Carbohydrates with simple acyloxy groups are unreactive under conditions normally used in
reduction reactions. Reduction does occur, however, if the reaction temperature is raised to 140 oC
and the reaction time is greatly extended. Esters with special structural features undergo reduction
RCO2H
Scheme 26
+
+
(AcO)2IC6H5
+ 2 RCO2I
(RCO2) 2IC6H5 + 2 AcOH
(RCO2)2IC6H5 I2 IC6H5
RCO2I RCO2 + I
O
OO
CMe2
OBnCO2
O
OO
CMe2
OBnI
Scheme 27
O
OO
CMe2
OBn
- CO2
- I
I2
51 52
O
OO
CMe2
OBn
53
- I
O
OO
CMe2
OBnOCH3
- HCH3OH
54
185 Chapter 8 at lower temperatures; thus, both α-acyloxy ketones and methyl oxalyl esters react with tri-n-butyl-
tin hydride at or below 110 oC.
Photochemical electron transfer provides a way for acyloxy groups to be replaced by hy-
drogen atoms under mild reaction conditions (at room temperature in neutral solution). Electron
transfer occurs when either excited HMPA or N-methylcarbazole donates an electron to an ester to
form a radical anion. Fragmentation of the radical anion generates a carbon-centered radical that
then abstracts a hydrogen atom to produce a deoxygenated compound. Regeneration of the par-
tially protected carbohydrate from which the ester was synthesized sometimes competes with
deoxygenation.
Acyloxy group migration to a radical center on an adjacent carbon atom is a reaction that is
useful in the synthesis of 2-deoxy sugars. Early proposals for the mechanism of this reaction
turned out not to be correct. The considerable investigation that has taken place since then has
shown that this reaction is likely to involve the formation of an intimate ion pair consisting of a
carboxylate anion and a radical cation. Recombination of this pair produces a new radical, one that
has undergone group migration.
Carboxylic acids produce carboxyl radicals by reaction with hypervalent iodine reagents or
electrolysis of carboxylate anions. These radicals expel carbon dioxide to form carbon-centered
radicals. Electrochemical reaction results in radical coupling, or if the radical is further oxidized,
carbocation formation. Reaction of carboxylic acids with hypervalent iodine reagents often is
conducted in the presence of heteroaromatic compounds, where radical addition to the aromatic
ring takes place.
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