Chapter 5
Acetals and Ethers
I.
II.
III.
Introduction ......................................................................................................................102
Bromination of Acetals and Ethers ..................................................................................102
Thiol-Catalyzed Reactions of Acetals: Polarity-Reversal Catalysis ................................103
A. Ring Opening of Benzylidene Acetals ...................................................................106
B. Deoxygenation of Compounds Containing O-Methoxymethyl Groups ................109
C.
Epimerization at a Ring-Carbon Atom...................................................................110
IV.
Ring Opening of Specially Designed Acetals ..................................................................114
V.
Internal Hydrogen-Atom Abstraction in Acetals and Ethers ...........................................114
A. Abstraction by Alkoxy Radicals ............................................................................114
1.
Abstraction from an Acetal ...........................................................................114
2.
Abstraction from an Ether ............................................................................116
3.
Abstraction from an α-Amino Ether .............................................................117
B. Abstraction by Carbon-Centered Radicals .............................................................118
VI.
Radical Cyclization: The Role of Ethers and Acetals ......................................................119
VII. Silyl Ether Rearrangement ...............................................................................................120
VIII. Summary ..........................................................................................................................121
IX.
References ........................................................................................................................122
I.
Introduction
Acetals are pervasive in carbohydrate chemistry. They link together saccharide units in
oligo- and polysaccharides, provide the bonding in glycosides that joins carbohydrate and aglycon
portions of a molecule, and furnish protection for hydroxyl groups during synthetic transformations. Because acetals have these vital protective and connective roles, their stability in the
presence of free radicals is critical in enabling radical reactions selectively to modify other parts of
a carbohydrate structure. Even though most acetals are stable in the presence of the carbon-centered radicals typically encountered in carbohydrate chemistry, there are reactions between heteroatom-centered radicals and acetals that are useful in carbohydrate transformation.
Ethers also serve as hydroxyl protecting groups during carbohydrate synthesis because, like
acetals, they are unreactive in the presence of most carbon-centered radicals. When reaction of an
ether or acetal does occur, it typically is hydrogen-atom abstraction from a carbon atom that has an
attached oxygen atom.
II.
Bromination of Acetals and Ethers
Free-radical bromination of acetals and ethers is discussed in Section IV of Chapter 2 (p 48).
103
Chapter 5
Scheme 1
initiation phase
(CH3)3CO OC(CH3)3
2 (CH3)3CO
(CH3)3CO
(CH3)3COH + XS
+
XSH
propagation phase
RH + XS
electroelectron philic
radical
rich
R
R'
+ XSH
nucleophilic
radical
R
electron
deficient
R
+ XSH
nucleophilic
radical
polarity matched
electron
deficient
R'
R'H + XS
polarity matched
electroelectron philic
radical
rich
= a radical derived from a carbohydrate acetal by hydrogen abstraction
R' = a radical produced from R by ring opening, -fragmentation,
or ring inversion
CH3
XSH = TDT or TBST
TDT = HSCC9H19
TBST = HSSi(OC(CH3)3)3
CH3
RS
+
R H
RS H
+ R
H = + 6 kcal/mol ( 1 )
R = (CH3)3C
96 kcal/mol
89 kcal/mol
III. Thiol-Catalyzed Reactions of Acetals: Polarity-Reversal Catalysis
Thiols act as catalysts for hydrogen-atom abstraction from acetals.1–10 The initiation phase in
these reactions generates a thiyl radical that then abstracts a hydrogen atom from the acetal in the
first propagation step (Scheme 1). This first step is reversible and a pseudo equilibrium is established that favors the reactants (RH and XS·). (The position of this equilibrium is based on the
enthalpy calculated from the bond-dissociation energies given in eq 1.11) The overall process is
driven by the second propagation step, a reaction that irreversibly converts one carbon-centered
radical (R·) into another (R’·). The final step is rapid hydrogen-atom abstraction from the thiol by
the newly formed, carbon-centered radical R’.
Acetals and Ethers
104
Scheme 2
initiation phase
(CH3)3CO
OC(CH3)3
(CH3)3CO
+
2 (CH3)3CO
(CH3)3COH + R
RH
propagation phase
R
R'
+ RH
R'
nucleophilic electron
radical
rich
R
R'H + R
polarity mismatched
nucleoelectron philic
rich radical
= a radical derived from a carbohydrate acetal by hydrogen abstraction
R' = a radical produced from R by ring opening, -fragmentation,
or ring inversion
R
H R'
1
R H R'
2
R
H R'
3
R H
R'
4
Figure 1. Valence-bond structures describing the
transition-state for hydrogen abstraction
Hydrogen-atom abstraction from a molecule of substrate should have a lower transition-state
energy when the abstracting radical is sulfur-centered (Scheme 1) rather than carbon-centered
(Scheme 2). In reactions of this type the transition state can be described as a hybrid of valence-bond structures 1-4 (Figure 1).10 If the abstracting radical is carbon-centered, structures 1
and 2 are the major contributors to the hybrid; the charge-separated structures 3 and 4 are of little
consequence. If, however, abstraction is done by a thiyl radical, not only are structures 1 and 2
important, but contribution from the charge-separated structure 3 also is significant.10 (In the case
where a thiyl radical abstracts a hydrogen atom from an acetal, the valence-bond structures 1-4 can
be represented in the more descriptive manner shown in Figure 2.) Significant contribution from 3
means that the energy required to reach the transition state for abstraction of a hydrogen atom is
less than that needed when a carbon-centered radical abstracts the same hydrogen atom. Faster
hydrogen-atom abstraction in propagation step 1 (Scheme 1) means that as R· is converted into R’·
in step 2, the R· needed to continue the propagation sequence will be replenished more rapidly.
105
Chapter 5
ROC
ROC H
H SR
SR
2
1

ROC
ROC
H
H
ROC
SR
4
H

SR
SR
3
Figure 2. Representations for the transition state in hydrogenatom transfer between carbon and sulfur atoms
A structure such as 3 is a transition-state-stabilizing contributor in any hydrogen-atom
abstraction reaction where a change in radical philicity takes place. Such a change occurs in
propagation steps 1 and 3 in the thiol-catalyzed mechanism pictured in Scheme 1, but it does not
take place at all in the uncatalyzed mechanism shown in Scheme 2. When a change in radical
philicity occurs during a reaction, either due to abstraction of an electron-rich hydrogen atom by an
electrophilic radical or abstraction of an electron-deficient hydrogen atom by a nucleophilic
radical (propagation steps 1 and 3, respectively, in Scheme 1), the reaction is described as polarity-matched.4,10 If one radical must be converted into another by hydrogen-atom abstraction
without benefit from a change in radical philicity (step 2 in Scheme 2), the reaction is described as
being polarity-mismatched. The transition state for a polarity-matched reaction will be stabilized
by contribution from the charge-separated, valence-bond structure 3 (Figures 1 and 2), but a polarity-mismatched reaction will not experience similar, transition-state stabilization. A polarity-matched reaction, therefore, will have transition-state stabilization that is denied to a polarity-mismatched reaction.
CH3
O
O
C 6H 5
OAc
catalyst
(CH 3) 3 COOC(CH 3 ) 3
5
CH3
TDT = HSCC9H19
CH3
TBST = HSSi(OC(CH3)3)3
(2)
OMe
OAc
BzO
OMe
OAc
O
O
OAc
6
conditions
catalyst
% yield
heat
none
41%
octane, collidine,
C6 H5 Cl, 140 oC
TDT
85%
octane, collidine,
C6 H5 Cl, 140 oC
TBST
98%
Acetals and Ethers
106
Although the combination of steps 1 and 3 in Scheme 1 achieves the same result as step 2 in
Scheme 2 (see Figure 3), the polarity-matched steps in Scheme 1 can be fast enough that in combination they are more rapid, sometimes much more rapid, than the single, polarity-mismatched
step in Scheme 2. When this occurs, the added thiol is said to catalyze the entire reaction by
polarity-reversal catalysis.10 The next three sections describe reactions that either are made possible by or have improved yields due to polarity-reversal catalysis.
R
R'
+ RH
step 1
R'
R'H + R
RH + XS
R'
R
+ XSH
R
step 2
The uncatalyzed reaction
shown in Scheme 2
When these steps replace step 2
in the uncatalyzed reaction
(Scheme 2), they convert it into
a catalyzed reaction (Scheme 1).
+ XSH
R'H + XS
= a radical derived from a carbohydrate acetal by hydrogen abstraction
R' = a radical produced from R by ring opening, -fragmentation,
or ring inversion
CH3
XSH = TDT or TBST
TDT = HSCC9H19
TBST = HSSi(OC(CH3)3)3
CH3
Figure 3. Catalyzed and uncatalyzed hydrogen-atom transfer
A. Ring Opening of Benzylidene Acetals
Heating the benzylidene acetal 5 with di-t-butyl peroxide as the solvent affords a 41% yield
of the ring-open benzoate 6 (eq 2).12 This yield improves considerably when reaction includes
either of the catalysts t-dodecanethiol (TDT) or tri-t-butoxysilanethiol (TBST) (eq 2).1 Proposed
mechanisms for the uncatalyzed and catalyzed reactions are given in Schemes 3 and 4, respectively. The first propagation step in each mechanism is a polarity-matched reaction. The second
step in each is a ring-opening, in fact, the same ring-opening. The final step in each reaction is the
distinguishing one. In the uncatalyzed reaction this step requires the nucleophilic radical 8 to
abstract a hydrogen atom from the benzylidene acetal 5 to generate the nucleophilic radical 7 and
the benzoate 6. This reaction is hindered by a polarity mismatch, a condition that contributes to a
low product yield (eq 2). The final step in the catalyzed reaction has the nucleophilic radical 8
abstracting an electron-deficient hydrogen atom from the thiol RSH in a polarity-matched reaction. Thiols are effective hydrogen-atom donors even without polarity matching, but the transition-state stabilization that accompanies polarity-matched, hydrogen-atom abstraction assists in
making this reaction faster, fast enough that other reactions of the radical 8 do not compete
effectively.
107
Chapter 5
Scheme 3
O
O
Ar
O
H
Ar
OAc
(CH3)3CO
+
OMe
OAc
O
5
OAc
electrophilic
radical
O
7
polarity-matched reaction
nucleophilic
radical
CH2
O
Ar = C6H5
+ (CH3)3COH
Ar
OAc
O
O
OAc
ArCO
7
CH2
Ar
8
CH3
O
O
Ar
O
OAc
+
H
OAc
O
ArCO
8
nucleophilic
radical
O
OAc
ArCO
5
+
OAc
O
6
polarity-mismatched reaction
7
nucleophilic
radical
An initially surprising aspect of ring opening of the radical 7 is that it produces the primary
radical 8, rather the secondary radical 9 (Scheme 5). This direction in ring opening is attributed to
greater angle strain in the transition-state structure leading to the secondary radical.2,3 Calculation
of the transition-state energies for formation of the radicals 8 and 9 supports this view.2,3 Although
ring opening to give a primary radical rather than a secondary one is unusual, it is not unprecedented.13
Investigation of additional benzylidene acetals helps in understanding the direction of their
ring opening. When epimeric acetals 10 and 11 are compared, they exhibit a regioselectivity in
ring opening that depends upon their C-4 configurations.2,3 Reaction of 10, a substrate with
trans-fused, six-membered rings, gives primarily the ring-open product 12, a compound derived
from formation of a primary radical (eq 3); in contrast, the epimer 11 with cis-fused, six-membered
rings, regioselectively produces the ring-open product 13, a compound arising from formation of
an intermediate secondary radical (eq 4). This difference in reactivity is associated with angle
strain at the transition state during ring opening. The more flexible cis-fused ring system does not
experience sufficient angle strain to prevent it from opening to form a secondary radical, but the
less flexible, trans-fused ring system experiences enough angle strain when opening to form a
secondary radical that formation of a primary radical has a lower energy transition state.
Acetals and Ethers
108
Scheme 4
initiation phase
(CH3)3CO OC(CH3)3
2 (CH3)3CO
(CH3)3CO
(CH3)3COH + XS
XSH
+
propagation phase
O
Ar
O
O
H
Ar
OAc
electrophilic
radical
OMe
OAc
O
OAc
RS
+
O
7
5
nucleophilic
radical
polarity-matched reaction
CH2
O
Ar = C6H5
Ar
OAc
OAc
O
O
ArCO
8
7
CH3
CH2
O
OAc
+ RSH
+
O
RSH
OAc
+
RS
ArCO
ArCO
6
8
electrophilic
radical
nucleophilic
radical
polarity-matched reaction
RSH = TDT or TBST (see eq 2 for structures)
Scheme 5
O
ArCOCH2
CH2
O
O
Ar
OAc
OAc
OMe
OAc
O
9
Ar = C6H5
O
7
OAc
ArCO
8
109
Chapter 5
C 6H 5
BzOCH2
CH3
O
H
O
OMe
O
peroxide
((CH 3 ) 3CO) 3SiSH
CH 3(CH2 ) 6CH 3
OMe
collidine
125 oC
OMe
H
H
OMe
BzO
(3)
OMe
+
H
12
13
10
12/13 = 93/7
BzOCH2
CH3
O
O
C 6H 5
O
OMe
H
peroxide
((CH3 ) 3CO) 3SiSH
CH3(CH2 ) 6CH3
OMe
collidine
125 oC
OMe
BzO
H
OMe
H
(4)
OMe
+
H
14
13
11
14/13 = 38/62
B.
Deoxygenation of Compounds Containing O-Methoxymethyl Groups
The deoxygenation reaction shown in eq 5 begins with abstraction of a hydrogen atom by a
thiyl radical from the O-methoxymethyl group of the acetal 15.4,5 Since hydrogen-atom transfer in
each direction in the first propagation step in this reaction involves a change in radical philicity, the
forward and reverse reactions both are polarity-matched (Scheme 6). Even though the first step in
this reaction is reversible, the β-fragmentation that takes place in the second step is not; hence, the
second step drives the reaction toward product formation. The final propagation step is another
polarity-matched, hydrogen-atom abstraction.
Me2C
O
Me2C
O
peroxide
((CH3 ) 3CO) 3SiSH
O
CH3
O
CH3OCH2O
O
CH3(CH2 ) 6CH3
collidine
CMe2
125 oC
O
O
O
O
+ HCOMe ( 5 )
R1
O
R2
O
CMe2
15
R1 = CH3, R2 = H
8%
R1 = H, R2 = CH3
82%
Polarity matching can assist with abstraction of certain hydrogen atoms in a molecule, but it
does not insure success of an overall reaction because sometimes this success depends on a propagation step that is not polarity driven. This situation is illustrated by comparing the reactions of
the acetals 15 (eq 5) and 16 (eq 6). For 15 the irreversible conversion of one radical into another in
Acetals and Ethers
110
the second propagation step (Scheme 6) is driven by factors such as the stabilization derived from
formation of both a tertiary radical and a carbon–oxygen double bond and stabilization gained
from elimination of dipole-dipole interaction between the C–O bonds at C-2 and C-3. Reaction of
the acetal 16 has a pair of polarity-matched propagation steps analogous to those for the acetal 15,
but 16 fails to produce a significant, deoxy sugar yield (eq 6).5 The probable reason for this failure
is that the second propagation step in reaction of 16 is more difficult than the comparable step for
15 because reaction of 16 is forced to produce a secondary radical and does not benefit from
elimination of the dipole-dipole interaction arising from the C–O bonds at C-2 and C-3.
Scheme 6
XS
XSH + ROCHOMe
+ ROCH2OMe
electrophilic
radical
nucleophilic
radical
15 or 16
polarity-matched reaction
O
ROCHOMe
R
+ XSH
R
+
RH
HCOMe
+ XS
nucleophilic
radical
electrophilic
radical
polarity-matched reaction
Me2C
O
Me2C
O
O
CH3
15 R =
XSH = ((CH3 )3CO)3SiSH
O
O
O
O
Me2C
O
16 R =
CMe2
O
O
O
O
peroxide
((CH3 ) 3CO) 3SiSH
O
O
CMe2
Me2C
O
O
O
CH3(CH2 ) 6CH3
O
collidine
125 oC
O CMe2
CH3OCH2
16
(6)
O
O
CMe2
17
15%
C.
Epimerization at a Ring-Carbon Atom
When the acetal 17 is heated under the conditions shown in eq 7, equilibrium is established
between 17 and its C-5 epimer 18. The ratio of 17 to 18 is 68/32; this ratio is reached by heating
either epimer. No equilibration takes place in the absence of the catalyst (Me3CO)3SiSH.7,8 The
111
Chapter 5
epimer ratio at equilibrium shows that 17 is more stable than 18, an observation that is in agreement with the results from molecular-mechanics calculations.
Me2C
O
O
O
peroxide Me2C
((CH3 ) 3CO) 3SiSH
O
O
O
CMe2
O
17
O
CH3(CH2 ) 6CH3
collidine
125 oC
(7)
O
O
CMe2
18
17/18 = 68/32
Scheme 7
Me2C
O
O
Me2C
H
O
+
O
O
+
XS
XSH
electrophilic
radical
CMe2
O
O
nucleophilic
radical
17
19
Me2C
O
Me2C H
O
O
+
XSH
O
O
+
O
O
nucleophilic
radical
XS
electrophilic
radical
CMe2
18
19
XSH = ((CH3 )3CO)3SiSH
A mechanism for the equilibration shown in eq 7 is proposed in Scheme 7. Catalysis of this
reaction by the thiol (Me3CO)3SiSH depends on the ability of the corresponding thiyl radical to
abstract H-5 from both 17 and 18 and upon the ability of the thiol to transfer a hydrogen atom to
C-5 of the intermediate radical 19. Hydrogen-atom transfer from a thiol to a carbon-centered
radical (step 2, Scheme 7) is a fast reaction, fast enough (k1 x 107 M-1s-1 at 50 oC, see Table 4 in
Chapter 8) to occur before reactions that typically might compete with it. Hydrogen-atom
abstraction by a thiyl radical from a carbon-hydrogen bond (step 1, Scheme 7) is a much slower
process, one that requires considerably higher temperatures (125 oC or greater) for reaction to
occur.8 Thus, although all the hydrogen-atom abstraction reactions shown in Scheme 7 are
polarity-matched, abstraction from an S–H bond by a carbon-centered radical is far more rapid
than abstraction from a C–H bond by a thiyl radical.
Acetals and Ethers
112
O
O OMe
H
H
O
peroxide
((CH3 ) 3CO) 3SiSH
R
CH3(CH 2 ) 6CH3
collidine
125 oC
H
O OMe
H
O
O
(8)
R
CMe2
CMe2
20 R = H
93% (21)
22 R = OCH3
0%
Scheme 8
O OMe
strained ring
OH
formation
OH
more
electron-rich,
less shielded
hydrogen atom
less
electron-rich,
more shielded
hydrogen atom
O OMe
H
O
RS
H
O
Me2C
- RSH
O OMe
H
20
RSH
- RS
O OMe
acetal
hydrolysis
O
CMe2
O OMe
H
H
RSH = ((CH3) 3CO)3SiSH
O
OH OH
O
O
CMe2
21
O
peroxide
O OMe ((CH ) CO) SiSH
3 3
3
H
H
O
H
MeO
CMe2
22
CH3(CH2 ) 6CH3
collidine
151 oC
H
CMe2
O OMe
O O
(9)
MeO
H
H
30%
(unreacted 22 remained
after normal reaction time)
In the reaction described in eq 7 the epimeric acetals 17 and 18 are similar enough in energy
that their equilibration produces a mixture containing substantial amounts of each stereoisomer. If
in a pair of equilibrating acetals one is substantially more stable than the other, the less stable
compound will be converted essentially completely into the more stable one. This type of conversion takes place in the reaction shown in eq 8 where 20 isomerizes into 21. Reaction of 20 can
113
Chapter 5
be incorporated into a sequence (Scheme 8) that has been described as “contra-thermodynamic
radical-chain epimerization”.6,8 The basic idea behind this process is to create a strained ring system and then relieve the strain by epimerization. In the example shown in Scheme 8 the O-isopropylidene derivative 21 is calculated to be 18.9 kJ/mol more stable than its C-3 epimer 20.8 This
difference in energy provides a driving force for reaction, and the thiol catalyst lowers the transition-state energy for hydrogen-atom abstraction sufficiently for reaction to occur.
The information in equations 8 and 9 shows that being able to abstract a particular hydrogen
atom in a molecule can depend on the substituents at nearby carbon atoms.6,8 For compound 22 (eq
8) the methoxy group at C-4 shields H-3 from abstraction and makes it slightly less electron-rich.
Both changes reduce the ability of the thiyl radical to catalyze epimerization at C-3 because they
make H-3 less easily abstracted by an electrophilic thiyl radical. Because in compounds 20 and 22
the potentially reactive atom H-2 is shielded by the methoxy group bonded to C-1 and also made
less electron rich by the oxygen atoms attached to C-1, epimerization at C-2 does not occur at all in
20 and only takes place in 22 if forcing conditions are used (eq 9).8
Scheme 9
I CN
CN
Bu3Sn
- Bu3SnI
OBn
O
O
O
BnO
OR
24
23
CN
N
OBn
O
O
O
BnO
OR
OBn
O
O
O
ArCH2CO
BnO
Bu3SnH
OR
- Bu3Sn
ArCH2CO
BnO
CH3 OBn
O
OR
25
76%
OCH3
R=
CN
CH3
O
O
O
CMe2
Ar =
Acetals and Ethers
114
IV. Ring Opening of Specially Designed Acetals
Search for compounds with more versatile reactivity than that provided by a 4,6-O-benzylidene group has stimulated development of some specially designed structures.14–18 The acetal 23,
which fits into this “specially designed” category, reacts with Bu3Sn· to form the aryl radical 24.
The iodine-atom abstraction that generates 24 is the first step in a sequence of radical reactions that
culminates in producing the protected glycoside 25 (Scheme 9).14–16 An example of the synthetic
usefulness of this reaction is found in the conversion of a tetrasaccharide containing four such
protecting groups into one in which each group is transformed into an O-benzoyl group.15 The
glycoside 26 is another cyclic benzylidene acetal with an aromatic iodo substituent that undergoes
a sequential radical reaction that leads to the corresponding deoxy benzoate 27 (eq 10).17 The reactions pictured in Scheme 9 and eq 10 are two more examples (in addition to those shown in equations 2 and 3) where trans-fused rings open to produce primary rather than a secondary radicals.
Ring opening of the 4,6-O-benzylidene acetal 28 to give a secondary radical (eq 11) further
supports the proposal made for the acetal 11 (eq 4) that for a more flexible, cis-fused ring system
the direction of ring opening is controlled by radical stability rather than ring strain at the transition
state.
O C SCH2CH2C6H4I(o)
C6H5
AIBN
Bu3SnH
C6 H5 CH3
110 oC
O
O
O
AcO
OMe
OAc
CH3
O
BzO
AcO
( 10 )
OMe
OAc
27
82%
26
V. Internal Hydrogen-Atom Abstraction in Acetals and Ethers
A. Abstraction by Alkoxy Radicals
Hydrogen-atom abstraction by alkoxy radicals from acetals and ethers is described in the
next several sections. More information about the formation and reactions of alkoxy radicals is
found in Chapter 6.
1.
Abstraction from an Acetal
Intramolecular hydrogen-atom abstraction by an oxygen-centered radical from the central
carbon atom in an acetal linkage is the “key” step in the orthoester formation pictured in Scheme
10.19 The radical phase of this reaction begins with photochemically initiated fragmentation of the
hypoiodite 29. Internal hydrogen-atom abstraction followed by carbon–iodine bond formation
completes the radical phase of the reaction. Formation of the orthoester 31 from the iodide 30 then
occurs by an ionic process.
115
Chapter 5
CH2OBz
O
O C SCH2CH2C6H4I(o)
C 6H 5
AcO
OMe
OAc
AIBN
Bu3SnH
O
89%
C 6 H 5 CH3
110 oC
O
+
O
BzO
AcO
( 11 )
CH3
OMe
O
OAc
AcO
28
OMe
OAc
9%
Scheme 10
CH2OAc
O
O
h
OAc
-I
IO
AcO
OAc
O
O
O
H O
OAc
O
HO
OAc
29
I
or I2, - I
or ROI, - RO
CH2OAc
O
O
-H
OAc
O
O
HO
O
AcO
-I
OAc
O
O
I HO
OAc
OAc
31
30
Scheme 11
O
OH
AcOI
- AcOH
OCH 2C 6H 5
O
C 6H 5
O
- HI
I
O
I
h
OCH 2C 6H5
OCH2C6H5
OH
I
OH
OCHC 6H 5
OCHC 6H 5
I
32
Acetals and Ethers
2.
116
Abstraction from an Ether
Internal hydrogen-atom abstraction from a benzyloxy group produces a highly stabilized
radical (32) that can be an intermediate in the formation of a benzylidene acetal (Scheme 11). This
type of reaction takes place in good yield when the substrate contains adjacent O-benzyl and
hydroxyl groups (Scheme 11).20 The reaction in Scheme 12 illustrates the type of transformation
possible. In this reaction the hypoiodite 33 is not just assumed to exist but is actually observed by
13
C NMR spectroscopy. Such direct observation of a hypoiodite is rare.
Scheme 12
CH2OI
CH2OH
O
BnO
BnO
I2
BnO
BnO
O
BnO
C6 H 5 I(OAc)2
BnO
OMe
OMe
33
h
H
C 6H 5
or 
O
O
O
BnO
BnO
OMe
84%
Scheme 13
IOCH2
OCH2
O OMe
MeO
HOCH2
CH3O
CH2O
h
OMe
OMe
35
34
O
H 2C
ROI (34)
- RO (35)
CH2
O OMe
O
OMe
OMe
HOCH2
-H
CH2=O
HOCH2
-I
ICH2O
117
Chapter 5
It is not essential to have aromatic stabilization in the developing radical for internal hydrogen-atom abstraction to take place.21–23 In the alkoxy radical 35 abstraction from a nearby methoxy
group begins a process that ultimately unites the interacting groups as an acetal (Scheme 13).21
This reaction constitutes a regioselective transformation of a methoxy group that is in close proximity to an oxygen-centered radical.
Scheme 14
O
O
HN
O
HN
CH3
H
N
R1OCH2
O
O
R1OCH2
I
O
h
CH3
H
N
O
I
O
H
R 2O
R 2O
36
1,5-translocation
O
O
HN
O
HN
CH3
H
N
R1OCH2
HO
O
I
or
I2, - I
O
CH3
H
N
R1OCH2
HO
O
I
I
R 2O
R 2O
37
- HI
i-Pr2Si
R1, R2 =
O
i-Pr2Si
H
N
O
R1OCH2
O
O
N
O
R 2O
CH3
H
38
3.
Abstraction from an α-Aminoether
Internal hydrogen-atom abstraction by an alkoxy radical from an α-aminoether linkage can
lead to the same type of ring formation observed in reactions of acetals and other ethers. For
example, 1,5-hydrogen-atom abstraction converts the alkoxy radical 36 into the α-amino radical
37. Combination of 37 with an iodine atom or reaction of 37 with I2 then produces a reactive iodide
that cyclizes to give the spiro nucleoside 38 (Scheme 14).24,25
Acetals and Ethers
118
Scheme 15
H
I
CHAr
O
O
Ar3Sn
OBn
OCH2Ar
Ar3SnH
- Ar3Sn
- Ar3SnI
HO
H
H
H
H
CH2Ar
OBn
HO
OBn
HO
40
39
Ar = C6H5
8%
Ar3SnH
- Ar3Sn
H
H
H
- ArCHO
HO
OBn
H
OCHAr
HO
OBn
Ar3SnH - Ar3Sn
H
H
OBn
HO
41
B.
CH3
OBn
HO
80%
42
Abstraction by Carbon-Centered Radicals
Although internal hydrogen-atom abstraction usually involves an alkoxy radical, some carbon-centered radicals are capable of such reaction. One element associated with successful hydrogen-atom abstraction is that ring strain in the transition state be minimal. (Ring strain usually is
minimized when hydrogen-atom abstraction involves a six-membered-ring transition state.26 Such
a reaction can be described as a 1,5-hydrogen-atom transfer or 1,5-HAT.) A second characteristic
of successful abstraction is that stabilization of the developing radical contribute to lowering the
transition-state barrier.26 The need for radical stabilization means that primary27 and vinylic28,29
radicals are prime candidates for hydrogen-atom abstraction because their reactions typically lead
to much more stable radicals; however, even a secondary radical will abstract a hydrogen atom
internally if the developing radical is sufficiently stabilized.30 In the reaction shown in Scheme 15,
the vinylic radical 39 abstracts a hydrogen atom from the adjacent O-benzyl group in route to the
119
Chapter 5
major products 41 and 42 (80% combined yield). The product 40, formed when 39 abstracts a
hydrogen atom from (C6H5)3SnH, is produced in only 8% yield, demonstrating that intermolecular
reaction from this tin hydride has difficulty competing with internal hydrogen-atom abstraction.29
It is often difficult to predict the extent of internal hydrogen-atom abstraction when a reactive,
carbon-centered radical is formed in the presence of an effective hydrogen-atom donor. For
example, generating the radical 39 with (C6H5)3SnH present in solution still results primarily in
internal reaction (Scheme 15);29 in contrast, in the reaction shown in eq 12 deuterium incorporation demonstrates that even though a primary radical is formed, abstraction from Bu3SnH is more
rapid than internal 1,4- or 1,5-HAT.31
CH2OAc
O OCH2CH2D
CH2OAc
O OCH2CH2Br
OAc H
AcO
H
OAc
AIBN
Bu3SnD
C6 H6
80 oC
OAc H
AcO
( 12 )
H
OAc
Scheme 16
TrOCH2
O
SeC6H5
Cl
O SeC6H5
CH2=CHCH2SiMe2
OR
RO
OH
AIBN
Bu3SnH
O
C6 H5 CH3
110 oC
DMAP, Et3N
C6 H5 CH3
O
O
Si
44
Si
43
aq. H2 O2
KF, KHCO3
MeOH, THF
R = SiMe2t-Bu
DMAP = Me2N
N
TrOCH2
O
OH
HO
OH
OH
VI. Radical Cyclization: The Role of Ethers and Acetals
Radical cyclization depends upon having a radical center and multiple bond held in close
enough proximity for internal addition to take place. In carbohydrates an ether linkage often is the
means for connecting these two reactive centers. In the reaction shown in Scheme 16, for example,
a carbohydrate (43) with a radical precursor at C-1 is connected by a silyl ether linkage at C-2 to a
substituent containing a double bond.32 Radical cyclization to give the silyl ether 44 creates a new
carbon–carbon bond. Nonradical ring opening of 44 produces a silicon-free carbohydrate with an
extended, carbon-atom chain.
Acetals and Ethers
120
Acetals and nonsilyl ethers also act as tethers that connect reactive centers during radical
cyclization. In the reaction shown in Scheme 17, for example, the acetal linkage holds the double
bond and the radical center in 45 close enough for ring formation to occur.33 In a similar manner an
ether linkage connects the reactive centers during the cyclization reaction shown in eq 13.34 Unlike
silyl ethers, the rings formed when acetals and nonsilyl ethers act as tethers usually are not
destined for immediate ring opening. (Section IV.C of Chapter 19 contains additional examples of
ethers and acetals serving as tethers in radical cyclization reactions.)
Scheme 17
CH2OAc
CH2OAc
O
- Bu3Sn
- Bu3SnBr
AcO
O
Bu3SnH
Bu3Sn
O
O
O
BrCH2
AcO
O
CH2
45
CH2OBn
R1
O SeC6H5
OBn
R2
AIBN
Bu3SnH
C6 H6
80 oC
O
CH2OBn
R1
O
OBn
R2
O
+
CH3
CH2OBn
R1
O
OBn
R2
( 13 )
CH3
O
R1 = H, R2 = OBn
54%
46%
R1 = OBn, R2 = H
86%
14%
VII. Silyl Ether Rearrangement
Rearrangement takes place during radical cyclization involving some silyl ethers. The primary evidence for this rearrangement is the dependence of product ring size on the concentration
of Bu3SnH, the hydrogen-atom donor in these reactions. When the reaction shown in eq 14 is
conducted in dilute Bu3SnH solution, the major product contains a six-membered ring,35 but at
high Bu3SnH concentration reaction regioselectivity changes to give a product with a five-membered ring.36,37 This concentration dependence can be explained by the more rapidly formed, but
less stable, radical 46 having sufficient time and energy, when the concentration of Bu3SnH is low,
to be converted into the more stable radical 47, either by a rearrangement that involves a cyclic
transition state or by a fragmentation-addition sequence (Scheme 18).37 At high Bu3SnH concentration hydrogen-atom abstraction occurs before ring expansion can take place.
121
Chapter 5
Scheme 18
Bu3SnH
O
O
Si
Si
O
- Bu3Sn
Si
high Bu3SnH
concentration
46
O
Si
O
Si
O
Si
47
migration
pathway
- Bu3Sn
Bu3SnH
low Bu3SnH concentration
O
Si
C6H5Se
TrO
T
O
fragmentationaddition
pathway
TrO
T
Bu3SnH
O
T
O
+
( 14 )
CH3
TrO
O
Si
Si
O
Si
O
0.5 equiv of Bu3SnH
87%
6%
3.0 equiv of Bu3SnH
3%
75%
VIII. Summary
The free-radical bromination of a benzylidene acetal is a standard procedure in carbohydrate
chemistry for ring opening that results in the formation of bromodeoxy sugars. Ring opening in the
absence of bromine occurs when 4,6-O-benzylidene acetals react with peroxides in the presence of
a thiol catalyst. Hydrogen-atom abstraction by an electrophilic, thiyl radical is the first step in this
Acetals and Ethers
122
reaction. This is also the first step in reactions of other acetals leading to epimerization and deoxygenation.
Ethers, like acetals, serve as protecting groups during carbohydrate synthesis, but this protection is not total because both ethers and acetals undergo hydrogen-atom abstraction in the
presence of reactive, electrophilic radicals. These reactive radicals can be sulfur-, oxygen-, or
bromine-centered. When hydrogen-atom abstraction by an alkoxy radical is intramolecular, it
typically is highly regioselective and can lead to formation of a new ring system.
Acetals and ethers, including silyl ethers, have a connective role in radical cyclization
reactions. The radical center and the multiple bond involved in a cyclization reaction are often
joined together by an acetal or ether linkage.
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3.
4.
5.
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