Chapter 19
Compounds With Carbon–Carbon Multiple
Bonds II: Cyclization Reactions
I. Introduction ........................................................................................................................415
II. Ease of Reaction between a Carbon-Centered Radical and a Multiple-Bond ....................415
III. Reaction Selectivity ............................................................................................................417
A. Chemoselectivity ......................................................................................................417
B. Regioselectivity ........................................................................................................418
1. Five-Membered Versus Six-Membered Ring Formation ...............................420
2. Six-Membered Versus Seven-Membered Ring Formation .............................425
3. Three- and Four-Membered Ring Formation ..................................................426
4. Seven-Membered and Larger Ring Formation ................................................427
C. Stereoselectivity ........................................................................................................428
1. Five-Membered Ring Formation.....................................................................428
2. Six-Membered Ring Formation ......................................................................435
3. Seven-Membered and Larger Ring Formation ................................................436
IV. Unsaturated Carbohydrates that Undergo Radical Cyclization ..........................................438
A. α,β-Unsatruated Carbonyl Compounds ....................................................................438
B. Silyl Ethers and Silaketals ........................................................................................440
C. Alkenyl and Alkynyl Ethers, Esters, Acetals, and Alcohols ....................................442
D. Compounds with Terminal Triple Bonds .................................................................445
E. Compounds in Which the Multiple Bond is not Electron-Deficient ........................446
V. An Organization for Carbohydrates That Undergo Radical Cyclization ...........................447
VI. Summary................................................................................... .........................................448
VII. References ..........................................................................................................................458
I. Introduction
The structural requirements for a molecule destined to undergo radical cyclization are that it
contain a substituent from which a radical (almost always a carbon-centered one) can be generated
and that it have a properly positioned multiple bond. Carbohydrates that meet these requirements
include unsaturated iodides, bromides, thionocarbonates, cyclic thionocarbonates, xanthates, and
phenyl selenides. Ring formation in the reactions of these compounds usually is regiospecific and
often highly stereoselective.
II. Ease of Reaction between a Carbon-Centered Radical and a Multiple Bond
Once structural requirements have been met, successful radical cyclization depends on re-
action rates. The basic question is “Will ring formation occur before competing reactions inter-
416 Chapter 19 vene?” The answer to this question depends upon the nature of the radical center and multiple bond
and on the separation between these two. The ability of a radical to add to a multiple bond to form
a new ring will be addressed first; then, the effect of the separation between the radical center and
the multiple bond will be considered.
O
CH2OAc
OAc
OAc
AcO Br
( 1 ) +Bu3SnH
O
CH2OAc
OAc
OAc
AcO CH2CH2CN
CH2=CHCN
V-70
Et2O25
oC
68%
V-70 = CH3OCCH2CN NCCH2COCH3
CN
CH3
CN
CH3
CH3
CH3CH3
CH3
( 2 )
AIBNO
CH2OAc
AcO Cl
OAc
HNAc
THF
O
CH2OAc
AcO CH2CH=CH2
OAc
HNAc
CH2=CHCH2SnBu3
66% (10/1)
A beginning point for discussing reactivity between a radical center and a multiple bond
during internal addition is to recall some of the findings in Chapter 18 about addition reactions that
are not internal. Such reactions take place rapidly when a radical is nucleophilic (as are most
carbon-centered radicals) and a multiple bond is electron-deficient. This description fits the reac-
tion shown in eq 1.1,2
If a multiple bond is not electron-deficient, radical addition normally is too
slow to compete with hydrogen-atom abstraction; however, minimizing or eliminating effective
hydrogen-atom donors from a reaction mixture can enable addition to occur even when the
multiple bond is not electron-deficient. An example of this type of reaction is shown in eq 2, where
Bu3SnH is not present in the reaction mixture even though Bu3Sn· is there and acts as the
chain-carrying radical.3,4
Addition of a radical to a multiple bond is potentially much faster when the reaction is
intramolecular. If a radical center and a multiple bond in a molecule are positioned so that they
frequently come within bonding distance, the rate of internal addition increases to the point that
even for a multiple bond that is not electron-deficient, cyclization competes effectively with
hydrogen-atom abstraction. In the reaction shown in eq 3, internal addition to a double bond that is
not electron-deficient takes place even in the presence of Bu3SnH.5
Compounds With Carbon–Carbon Multiple Bonds II: Cyclization Reactions 417
Bu3SnHO
O
CH2OAc
AcO
OAc I( 3 )
AIBN
C6H6
80 oC
O
O
CH2OAc
AcO
OAc
CH3
60%
III. Reaction Selectivity
Chemoselectivity, regioselectivity, and stereoselectivity are defining characteristics of radi-
cal reactions. Nowhere are they more important (particularly the latter two) than when a new ring
is being formed. Understandably then when regioselectivity and stereoselectivity were broached in
Chapters 10 and 11 of Volume I, discussion often turned to cyclization reactions. Some of the
ideas and topics from these chapters are revisited here but now with an exclusive focus on their
importance to new ring formation.
( 4 ) Bu3SnH
AIBNO
O
Si
BrCH2 OEt
CH2OR
1
R = SiMe2t-Bu
O
O
Si
OEt
CH2OR
notformed
O
O
Si
OEt
CH2OR
48%
+NaBH3CNt-BuOH
( 5 ) Bu3SnH
AIBNO
O
Si
BrCH2 OEt
CO2Et
2
O
O
Si
OEt
CH2CO2Et
not formed
O
O
Si
OEt
CO2Et
+
more electron-deficient
less electron-deficient
NaBH3CN
49%
t-BuOH
A. Chemoselectivity
Chemoselectivity enters into consideration at two places in radical cyclization reactions. The
first is during radical formation, where it determines which atom or group in a molecule will react
418 Chapter 19 to form the radical that adds to a multiple bond. Chemoselectivity next is of consequence when a
newly formed radical has the possibility of adding to more than one multiple bond. In the reaction
shown in eq 4, for example, halogen-atom abstraction from the bromide 1 produces a radical that
can add to either of two double bonds.6,7
Addition to one produces a five-membered ring while
reaction with the other forms a six-membered ring. Although these two bonds are comparable in
reactivity, the product with the five-membered ring forms more rapidly. (The reasons for usually
forming a product with a five-membered ring are discussed in the next section.) If, however, the
double bond for which reaction produces a six-membered ring, is decidedly more reactive (i.e.,
substantially more electron-deficient), as is the case in compound 2 (eq 5), the chemoselectivity of
the cyclization process changes, and only the product with the larger ring forms.6,7
O
O
OAc
CH2OAc
AcO
I Bu3Sn
Bu3SnH
Bu3Sn
Bu3SnI
O
O
OAc
CH2OAc
AcO
CH2
O
O
OAc
CH2OAc
AcO
O
O
OAc
CH2OAc
AcO
O
O
OAc
CH2OAc
AcO
CH3
88%
-
-
Scheme 1
B. Regioselectivity
Radical cyclization is nearly always a kinetically controlled process.8 Kinetic control often
leads to regiospecific formation of the less stable cyclic radical. In the reaction shown in Scheme
1,5,9
for example, even though cyclization to give a six-membered ring is possible and would
generate a more stable radical, the only reaction pathway followed leads to the smaller ring and the
less stable radical. The reaction shown in Scheme 2, where the primary radical 3 forms in pref-
erence to the tertiary radical 4, provides a particularly striking example of a kinetically controlled,
radical cyclization.10
There are cyclization reactions that take place under thermodynamic control when the proper
conditions are met. In the reaction shown in eq 6 the major product contains a six-membered ring,
Compounds With Carbon–Carbon Multiple Bonds II: Cyclization Reactions 419
Bu3Sn
NH
N
O
O
O
HOCH2 B
SeArHN
CH3
Ar = C6H5
- Bu3SnSeAr
O
HOCH2 B
HN
CH3
Bu3SnH
- Bu3Sn
O
HOCH2 B
HN
CH3
O
HOCH2 B
HNCH2
CH3
3
4
O
HOCH2 B
HNCH3
CH3
Scheme 2
73%
( 6 ) O
O
T
Si
TrO
O
O
T
Si
CH3
TrO
0.5 equiv of Bu3SnH 87% 6%
3.0 equiv of Bu3SnH 3% 75%
+
Si
O
O
C6H5Se T
TrO
Bu3SnH
T = NH
N
O
O
CH3
Tr = C(C6H5)3
when reaction is conducted in dilute Bu3SnH solution,11
but at high Bu3SnH concentration reaction
regioselectivity changes to give a product with a five-membered ring.11,12
This concentration
dependence can be explained by the more rapidly formed, but less stable, radical 5 having suf-
ficient time and energy, when the concentration of Bu3SnH is low, to be converted into the more
stable radical 6, either by a rearrangement that involves a cyclic transition state or by a fragmen-
tation-addition sequence (Scheme 3).13
At high Bu3SnH concentration hydrogen-atom abstraction
occurs before ring expansion can take place.
420 Chapter 19
Bu3SnH
5
O
SiO
SiO
Si
O
Si
Bu3SnH
6
OSi
kinetically controlledproduct
thermodynamicallycontrollled product
Scheme 3
O
Si
OSi
rearrangementpathway
elimination-additionpathway
- Bu3Sn
- Bu3Sn
high Bu3SnH
low Bu3SnH concentration
concentration
1. Five-Membered Versus Six-Membered Ring Formation
a. Five-Membered Rings
If a radical center and a multiple bond in a molecule are situated so that either a five- or
six-membered ring is possible, the smaller ring generally will form.14,15
The reason for producing
the smaller ring is that the strain engendered in reaching the transition state leading to a
six-membered ring is greater than that necessary for forming a ring with five members (Scheme
4)16–18
Both chair-like14,16
and boat-like16,19
transition-states are possible during five-mem-
bered-ring formation (Scheme 5). For the unsubstituted 5-hexenyl radical the chair-like transition
state is calculated to be lower in energy than its boat-like counterpart, but only slightly so.16
(The
“flagpole” and eclipsing interactions that contribute to making the boat conformation of cyclo-
hexane much less stable than the chair conformation are not as severe in the boat-like transition
state for radical cyclization.) Both transition states (boat-like and chair-like) leading to a
Compounds With Carbon–Carbon Multiple Bonds II: Cyclization Reactions 421
five-membered ring (Scheme 5) are calculated to be lower in energy than any transition states lead-
ing to a six-membered ring. These calculations match well the experimental observation that cycli-
zation of the 5-hexenyl radical gives a five-membered ring in a highly regioselective fashion (eq 7,
R = H).14,20
They also are consistent with the reactions shown in Schemes 1 and 2, where
five-membered rings form in preference to six-membered ones.
less strainedtransition state
more strainedtransition state
less stableradical
more stableradical
Scheme 4
R R R
+ ( 7 )
A B
A /B = 98/2 (experimental)
A /B = 91/9 (calculated)
A /B = 2/3 (experimental)
A /B = 2/2.4 (calculated)
R = H R = CH3
The greater ease of formation of five-membered rings when compared to six-membered ones
is illustrated in a quantitative fashion by the approximately fifty-fold difference in rate constants
for cyclization of the 5-hexenyl (eq 8) and 6-heptenyl (eq 9) radicals.20
A qualitative example of
this type of difference in reactivity involving a pair of carbohydrates is found in the reactions
shown in equations 10 and 11, where formation of a five-membered ring occurs in the normal
manner, but cyclization to give a six-membered ring does not take place rapidly enough to
compete with simple reduction.21
422 Chapter 19
chair-liketransition state
boat-liketransition state
Scheme 5
( 8 )
2%
15%85%
98%
k1
k2
~~k1
k2
50
+
+ ( 9 )
O
O
CH2OAc
AcO
BrCH2
O
O
CH2OAc
AcO
( 10 )
80 oC
C6H6
AIBNBu3SnH
76%
Compounds With Carbon–Carbon Multiple Bonds II: Cyclization Reactions 423
O
O
CH2OAc
AcO
BrCH2
O
O
CH2OAc
AcO
CH3
+
O
O
CH2OAc
AcO
notdetected
( 11 ) Bu3SnH
AIBN
C6H6
80 oC
b. Six-Membered Rings
Six-membered-ring formation takes place when structural features in a radical inhibit
forming a five-membered ring. Possible inhibiting factors include: a) greater ring strain at the
transition state for forming a five-membered ring as opposed to a six-membered one; b) steric
hindrance that is sufficient to make bonding difficult at the carbon atom of the multiple bond
needed to form a five-membered ring; c) structure and reactivity associated with the radical center
that favors six-membered-ring formation.22
( 12 ) O
OMe2C
CH3
O O
CMe2
7 8
O
O
Me2C
O O
CMe2
OCOC6H5
S AIBNBu3SnH
76%
cis-fusedrings
85 oC
C6H5CH3
Reactions of the phenyl thionocarbonates 7 and 9 illustrate the importance of ring strain in
determining the size of a ring being formed by radical cyclization. Compound 7 undergoes the
expected cyclization to give a product (8) with a five-membered ring (eq 12), but similar reaction
of 9 forms only a compound (10) with a six-membered ring (eq 13).22
Reaction producing the
larger ring does so because forming a five-membered ring would introduce the substantial strain at
the transition state inherent in a reaction leading to a product (11) with a pair of trans-fused,
five-membered rings.
Steric effects can have a powerful, modifying influence on the cyclization of simple organic
radicals; thus, the 5-hexenyl radical preferentially forms a five-member ring (eq 7, R = H), but the
5-methyl-5-hexenyl radical, more hindered at C-5, regioselectively generates a product with a
six-membered ring (eq 7, R = CH3).14,16
Steric effects do not exercise the control shown in eq 7 in
determining ring size in the cyclization reaction pictured in eq 12, where the C-5 substituents do
not force formation of any product with a new six-membered ring; in fact, study of 7 and similar
compounds shows that the steric effects associated with C-5 substitution are unable, by them-
selves, to promote any six-membered-ring formation.22
424 Chapter 19
( 13 )
O
OMe2C
O O
CMe2
CH39
10
O
O
Me2C
O OCMe2
OCOC6H5
S
AIBNBu3SnH
62%
O
O
Me2C
O OCMe2
C6H5CH3
85 o
C
trans-fusedrings
11
Clear examples of steric effects controlling radical cyclization in the reactions of carbohy-
drates are lacking, but the reactions shown in Scheme 6 suggest a steric component to regio-
selectivity. Formation of the spiro compound 15 takes place when R=CH3 or OBz, but when R is a
hydrogen atom, products 16 and 17 are formed (Scheme 6).23
One proposal is that larger substit-
uents favor formation of the spironucleoside 15 by sterically hindering reaction at C-2', but when
the C-2' substituent is a hydrogen atom, reaction takes place to form products 16 and 17, com-
pounds with new six-membered rings. Regioselectivity in this reaction also could be explained by
product-radical stability; that is, compound 15 forms only when the intermediate radical 12 has
stabilizing substituents at C-2'.
The nature of the radical center also can have an effect on the regioselectivity of ring for-
mation. The intermediate primary radical in the reaction shown in eq 12 forms a product with a
new, five-membered ring, but the analogous vinylic radical cyclizes to form products with new
six-membered rings (Scheme 7).22
The possibility exists that, as shown in Scheme 7, a
five-membered ring does form, but it then rearranges to a more stable six-membered-ring radical.
If such a transformation takes place, it would be reminiscent of the silyl-ether rearrangement
pictured in Scheme 3.
( 14 )
85%
Bu3SnH
Si
O
O
TrOCH2
RO
OR
SeC6H5
110 oC
C6H5CH3
AIBN
Si
O
O
TrOCH2
RO
OR
R = SiMe2t-Bu
Compounds With Carbon–Carbon Multiple Bonds II: Cyclization Reactions 425
Bu3Sn -Bu3SnBr
Scheme 6
ON
NHt-BuMe2SiO
t-BuMe2SiO R
O
O
Si
BrCH2
+
17
- Bu3Sn - Bu3SnBu3SnHBu3SnH
15
12
NSiO
R
14
OR
N
Si
OR
N
Si
NSiO
R
13
N
SiO
R
+
16
N
SiO
R
Bu3SnH
- Bu3Sn
0% R = H 32% 58%
41% R = CH3 0% 8%
75% R = OBz 0% 0%
2. Six-Membered Versus Seven-Membered Ring Formation
When constructed from carbon, nitrogen, and oxygen atoms, six-membered rings form more
rapidly than seven-membered ones, but sometimes ring formation is not fast enough to prevent
hydrogen-atom abstraction prior to cyclization. The reaction shown in eq 11 is one in which
internal radical addition to a multiple that is not electron-deficient is too slow for ring formation to
compete with simple reduction. In contrast, cyclization involving a similar double bond (i.e., one
that also is not electron-deficient) does take place in the reaction shown in eq 3 because the rate of
426 Chapter 19 competing hydrogen-atom abstraction is reduced to an insignificant level by maintaining a low
Bu3SnH concentration during the reaction.5
O
O
Me2C
O OCMe2
Bu3SnH
O OCMe2
SnBu3Bu3Sn
O OCMe2
SnBu3
O OCMe2
SnBu3
CH2
O
O
Me2C
O OCMe2
SnBu3
O
O
Me2C
O OCMe2
SnBu3
60% 4%
+
- Bu3Sn
Scheme 7
As long as the only atoms in the ring are second row elements, radical cyclization typically
produces a six-membered, rather than a seven-membered ring (eq 3). If an atom of the third-row
element silicon is present, a seven-membered ring can be produced (eq 14).24
This change in regio-
selectivity can be explained, at least in part, by longer bond lengths to silicon making approach of
the radical center to the terminal carbon atom in the double bond the lower energy pathway.25
Seven-membered ring formation depends upon the terminal carbon atom in the double bond being
unsubstituted; otherwise, steric effects raise the transition-state energy sufficiently to favor for-
mation of a six-membered ring.25
3. Three- and Four-Membered Ring Formation
Forming a three-membered ring is not a promising beginning for radical cyclization because
the strained, cyclic radical produced would open readily to its more stable, acyclic counterpart (eq
15).26
Although ring strain also hinders formation of products with four-membered rings, the lesser
Compounds With Carbon–Carbon Multiple Bonds II: Cyclization Reactions 427
magnitude of the strain increases the possibility for isolating a cyclic product;27,28
thus, the reaction
shown in Scheme 8 produces a compound with a four-membered ring.27
This reaction is kinetically
controlled; otherwise, it would lead to a less strained, five-membered ring, one that contains an
oxygen-stabilized radical.
( 15 )
O
ORO
OCMe2
O
CH2I
CO2Et
O
RO
O
CH2
CO2Et
Bu3Sn
- Bu3SnI
O
RO
O
CHCO2Et
Bu3SnH
- Bu3Sn
O
ORO
OCMe2
O
CH2CO2EtR =
O
Scheme 8
O
RO
O
CO2Et
Radical philicity, which often is a significant factor in determining regioselectivity in kine-
tically controlled reactions, rationalizes the direction of ring closure in the reaction shown in
Scheme 8. The nucleophilic, carbon-centered radical adds to the electron-deficient, β carbon atom
in the α,β-unsaturated ester portion of the molecule. Frontier-orbital interactions, also useful in
explaining kinetically controlled reactions, make the same prediction; that is, reaction should
occur at the β carbon atom in an α,β-unsaturated ester (see Section II.B.2 of Chapter 18).
4. Seven-Membered and Larger Ring Formation
Radical cyclization can be surprisingly effective in forming rings with seven,24,29,30
eight,31–37
nine,36,38–43
ten,44
or even eleven45
members. Generating these larger rings from carbohydrates
often is associated with the linking together of two monosaccharide units by a tether containing
silicon and oxygen atoms.31–36,37–42
An example of such a reaction is shown in Scheme 9, where
cyclization produces an eight-membered ring.35
Although the most common method for joining a
428 Chapter 19 radical forming group and a multiple bond is by a silicon–oxygen tether, other connecting linkages
are possible. These other tethers include phosphoramidic43
(nine-membered ring formed) and
ketal46
(nine-membered ring formed) connectors, as well as bridging units consisting of pyranoid45
(eleven-membered ring formed) and furanoid37
(eight-membered ring formed) rings.
O
BnOCH2OBn
SeC6H5BnO
O
Si
O
OSi
CH2OBn
O
O
O
Si
CH2OBn
O
O
BnOCH2OBn
BnO
OSi
O
CH2OBn
OMe
OBn
O
- Bu3SnBu3SnH
- Bu3SnSeC6H5
Bu3Sn
Scheme 9
OCH2OBn
OMeOBn
O
C. Stereoselectivity
1. Five-Membered Ring Formation
a. Chair-Like Transition States
Even though the complex substitution patterns present in many carbohydrates introduce a
variety of possibilities for steric and polar interactions, the chair-like, transition-state model
typically predicts the primary stereochemical outcome of a cyclization reaction forming a
five-membered ring (Scheme 10).14,47,48
The lowest energy transition state for such a reaction has
as many pseudoequatorial “ring substituents” as possible. An example is shown in Scheme 11,49
Compounds With Carbon–Carbon Multiple Bonds II: Cyclization Reactions 429
where if one assumes the reaction passes through a chair-like transition state that maximizes
pseudoequatorial substituents, it is possible to explain the stereochemistry in the final product.
R3
R4
R2
R1
R3
R4
R1
R2R3
R4
R1
R2
shadow chair
transition state structure
R3
R4
R1
R2
Scheme 10
OBz
CH2OR
OBz
CH2CO2Me
shadow chair
transition state structure
RO
I
OBz OBz
CH2CO2Me
OBz
CH2OR
OBz
CH2CO2Me
OBz
OBz
CH2OR
CH2CO2Me
ROCH2
MeCO2CH2
OBz
OBz
72%
Bu3SnH Bu3Sn
Bu3Sn
Bu3SnH
Scheme 11
-
-R = Si(C6H5)t-Bu
OBz
CH2OR
OBz
CH2CO2Me
=
CH2CO2Me
OBz
CH2OR
OBz
430 Chapter 19
shadow chair
Bu3Sn Bu3SnSeC6H5
OTrOB
SeC6H5
R
chair-liketransition state
boat-liketransition state
O
B
OTr
R
shadow boat
O
OTr
BR
O
R OTr
B
OBTrO
R
OBTrO
R
89% 3%
R = CO2MeNH
N
O
O
B =
Scheme 12
-
Bu3SnH, - Bu3Sn
R
O
OTr
B
b. Boat-Like Transition States
Although chair-like, transition-state structures can be used to rationalize the stereoselectivity
in most radical cyclization reactions, calculations indicate that boat-like structures should be in-
cluded as possibilities.16
In the reaction shown in Scheme 12,50
for example, the minor product can
be explained by invoking a boat-like transition state. With the structural complexity of carbo-
hydrates and the general similarity in energies between boat-like and chair-like transition states, it
is not surprising to find that the major stereoisomer in the cyclization reaction pictured in Scheme
13 appears to arise from a boat-like transition state.19,51
c. Factors Affecting Transition-State Stability
(1.) Pseudo-1,3-Diaxial Interactions
In the reaction shown in Scheme 13 it is possible to identify a psuedo-1,3-diaxial inter-
action52
in the intermediate radical 19 and the associated, chair-like transition state 21.19,51
In the
conformationally isomeric radical 18 and its associated, boat-like transition state 20 this desta-
Compounds With Carbon–Carbon Multiple Bonds II: Cyclization Reactions 431
bilizing interaction is absent. The stereochemistry of the product from ring formation indicates that
1,3-diaxial interaction is the primary factor causing reaction to occur by the pathway passing
through the boat-like transition state 20 (Scheme 13).19,51
Bu3SnH - Bu3Sn
BnO
BnO
OCImO
OC6H5
S
Bu3Sn
O
OC6H5
BnO
OBn
H
OBn
BnO
O
shadow boat
OBn
BnO
O
shadow chair
OBnO
OC6H5
BnOH
18
19
pseudo1,3-diaxialinteraction
OBnO
OC6H5
BnOH
20 21
OBnO
OC6H5
BnOH
- Bu3SnBu3SnH
OBn
O
OC6H5
BnO
CH3
H
OBn
O
OC6H5
BnOCH3
H
57% 0%
Scheme 13
- Bu3SnSC(=O)Im
pseudo1,3-diaxialinteraction
Im = N
N
432 Chapter 19
R2
H
R1 R3
R1
R2
H R3
22 23
( 16 )
R1, R2, R3 are groups sterically
larger than a hydrogen atom.
24
25allylicstrain
BnOBnO
BnO
CH2OH
5%
BnOBnO
BnO
BnOBnO
BnO CH2OH
64%
BnOBnO
BnO
I
Co(salen) complex
NaBH4, O2
Scheme 14
NaBH4, O2
BnOBnO
BnO
(2.) Allylic Strain
Another phenomenon that is credited with affecting transition-state stability is allylic strain,
which can be defined in terms of the partial structures shown in eq 16.53
Conformation 23 is
favored energetically over 22 because the destabilizing steric interaction between R1 and R3 in 22
is greater than the corresponding interaction between H and R3 in 23. Such interaction also affects
the transition-state energies for reactions from these two conformers; thus, reaction occurs pref-
erentially, sometimes exclusively, from 23. In the reaction shown in Scheme 14 allylic strain
destabilizes conformation 24, but bond rotation to give conformer 25 relieves this strain.54,55
In a
similar manner strain relief causes the reaction shown in Scheme 15 to occur primarily via a
boat-like transition state derived from 26.54,55
Compounds With Carbon–Carbon Multiple Bonds II: Cyclization Reactions 433
26
allylicstrain
BnO
BnO
CH2OH
OBn
40%
BnO
BnO CH2OH
OBn
10%
BnO
BnO
OBn
Co(salen) complex
NaBH4, O2
BnO
BnO
OBn I
BnO
BnO
OBn
Scheme 15
NaBH4, O2
O
O
CH2OBn
R2
R1
OBn
SeC6H5
Bu3SnHO
CH2OBn
R2
O
R1
Me
OBn( 17 ) +
AIBN
C6H6
80 oC
O
CH2OBn
R2
O
R1
Me
OBn
29a R1 = H, R2 = OBn
29b R1 = OBn, R2 = H
54%
86%
46%
14%
(3.) Hydrogen Bonding56,57
The energies of the transition states in the reactions shown in Scheme 16 depend upon
whether R is a hydrogen atom or a trimethylsilyl group. When the trimethylsilyl group is in place,
the chair-like transition state 28 is preferred because it places all substituents in pseudoequatorial
positions.56
If the trimethylsilyl groups are replaced by hydrogen atoms, a different, chair-like
transition state (27), one that has two pseudoaxial substituents but is stabilized by hydrogen
bonding, has lower energy. The reactions described in Scheme 16, therefore, illustrate the power
of hydrogen bonding in influencing reaction stereoselectivity.
434 Chapter 19
ORCO2Me
OR'
OR
OR'
CO2MeRO
RO
favoredwhen
R = SiMe3
favoredwhenR = H
ORCO2Me
OR'
OR
OR'
CO2MeRO
RO
2827
OR'
CO2MeRO
RO
ORCO2Me
OR'
OR
R = H
R = Me3Si
55%
9%
14%
75%
Scheme 16
R' = SiMe2t-Bu
isolated asa lactone
when R = H
Bu3SnH - Bu3SnBu3SnH - Bu3Sn
[Additional (minor) cyclic products are formed in these reactions.]
(4.) Conformation of an Existing Ring
The reactions shown in eq 17 illustrate the effect that the stereochemistry of a remote ring
substituent can have on reaction stereoselectivity.58
It is unlikely that the C-4 benzyloxy groups in
the radicals formed from the allyl ethers 29a and 29b are close enough to the radical center or the
multiple bond to influence reaction directly. A more likely possibility is that substituent stereo-
chemistry affects pyranoid-ring conformation in the intermediate radicals and that differences in
conformation (or in the mixture of accessible conformations) determine reaction stereoselectivity.
The idea that inversion of configuration at C-4 can change intermediate-radical conformation in
these reactions (eq 17) is supported by the observation that other pyranos-1-yl radicals that are
epimeric at C-4 adopt quite different radical conformations.59
Compounds With Carbon–Carbon Multiple Bonds II: Cyclization Reactions 435
Scheme 17
Bu3Sn - Bu3SnI
3031
32 33
pseudo 1,3-diaxial interaction
32/33 = 9/1
- Bu3SnBu3SnHBu3SnH - Bu3Sn
I
EtO2C
O O
O
CMe2
EtO2C
O OCO2Et
OCO2Et
CO2Et
O O
O
CMe2
O O
O
CMe2
CO2Et
EtO2C
O
2. Six-Membered Ring Formation
Chair-like transitions states also provide a basis for understanding stereoselectivity in
six-membered ring formation. In the cyclization reaction shown in Scheme 17, product formation
can be explained by assuming that two chair-like transition states (30 and 31) are accessible during
reaction.60
The difference in energy between these two depends primarily on steric interactions
involving the CH2CO2CH3 group. The transition state 31 with its pseudo-1,3-diaxial interaction
would be expected to be higher in energy than the transition state 30, which avoids such inter-
action. The highly stereoselective formation of 32 is consistent with this proposed difference in
transition-state energies (Scheme 17).
436 Chapter 19
Si
O
O
TBSO
OTBS
TrOCH2 SeC6H5
34
Bu3Sn
Si
O
O
TBSO
OTBSTrOCH2
35
Si
O
O
TBSO
OTBS
TrOCH2
36
O
HO
TrOCH2
HO
HO
OH
85%
H2O2, KF, THF
KHCO3, MeOH
Tr = C(C6H5)3
TBS = SiMe2t-Bu
Scheme 18
Bu3SnH
- Bu3Sn
Si
O
O
- Bu3SnSeC6H5
3. Seven-Membered and Larger Ring Formation
In the reaction shown in Scheme 18 the size of the t-butyldimethylsilyl groups causes the
pyranoid ring in the phenyl selenide 34 to adopt a 1C4 conformation. If this conformation is
maintained during cyclization, as appears to be the case, radical addition to the vinyl group will
occur exclusively from the α face of the pyranoid ring in the radical 35 to give, after hydro-
gen-atom abstraction, the cyclic silyl ether 36.24,29b
When protection is provided by the less ster-
ically demanding benzyl groups, more conformational flexibility exists in the pyranoid ring (4C1
and 1C4 interconvert more easily) and radical addition occurs from either face of the ring system
(Scheme 19).24,29b
Further indications exist of the importance of radical conformation in forming rings with
seven or more members. In the reaction shown in eq 18 the rigidity of the radical derived from the
iodide 37 reduces the number of conformations possible but includes one that holds the radical
center and the double bond in close enough proximity that cyclization gives the major product; in
contrast, in the reaction shown in eq 19 the greater flexibility of the radical generated from the
iodide 38 changes the opportunity for interaction between reactive centers to the point that a
complex mixture of products is formed.61
Compounds With Carbon–Carbon Multiple Bonds II: Cyclization Reactions 437
Bu3SnH
Scheme 19
O
Si
OBnOCH2
BnO
BnO SeC6H5
Si
O
O
BnO
OBnBnOCH2 SeC6H5
Bu3Sn - Bu3SnSeC6H5
- Bu3Sn
64% 16%
OH
OBnOCH2
BnO
BnO
OH
OH
OBnOCH2
BnO
BnO
OH
KF, KHCO3, H2O2,
MeOH, THF
Si
O
O
Si
O
O
Si
O
O
Si
O
O
Si
O
O
+
KF, KHCO3, H2O2,
MeOH, THF
Bu3SnH - Bu3Sn
Bu3Sn - Bu3SnSeC6H5
( 18 )
50%
Bu3SnH
80 oC
C6H5CH3
AIBN
O O
O
O
CMe2
Me2C
OH
O O
O
O
CMe2
Me2C
OH
I
37
438 Chapter 19
( 19 ) Bu3SnH
80 oC
C6H5CH3
AIBN
O O
BnO
BzO
CMe2
OBn
I
38
complex mixtureof products
IV. Unsaturated Carbohydrates That Undergo Radical Cyclization
The unsaturated carbohydrates that undergo radical cyclization are an eclectic mixture of
compounds in which the reactive multiple bond in each typically is electron-deficient. Reduced
electron density in the multiple bond can be caused either by conjugation of this bond with a
carbonyl group or by having an electronegative substituent attached to it. Ring formation still can
occur when a double or triple bond is not electron-deficient, but as described earlier in this Chapter
(Section II), in such a situation cyclization is slower and less able to compete with other radical
reactions.
( 20 )
AIBN
C6H5CH3
110 oC
Bu3SnH
NH
NO
CH2 I
OAc
O
O
ClNH
NO
OAc
O
O
H
Cl
75%
A. α,β-Unsaturated Carbonyl Compounds
The electron-deficient double bond in an α,β-unsaturated ester is an attractive target for in-
ternal addition of a carbon-centered radical.44,60–94
The majority of reactions of this type produce
five-membered rings;62–85,93
fewer, but still a significant number, form six-membered
rings.60,81,82,86–91
Formation of smaller27
and larger27,94
rings also takes place, but such reactions are
far less common. (Examples of internal radical addition in α,β-unsaturated esters are found in the
reactions shown in Schemes 8, 16, and 17.) The radicals that participate in this type of reaction
usually are generated from halogenated carbohydrates but also can be formed from reaction of
carbohydrates containing O-thionocarbonyl,79
cyclic O-thionocarbonyl,65
O-thionocarbamoyl,72-74
phenyl seleno,50
aryl telluro,77
O-acyl-N-hydroxy-2-thiopyridonyl,88
and vinyl75,76
groups.
Other α,β-unsaturated carbonyl compounds that undergo radical cyclization include nuc-
leosides that have a carbon-centered radical in the sugar portion of the molecule. In these reactions
Compounds With Carbon–Carbon Multiple Bonds II: Cyclization Reactions 439
cyclization occurs by internal radical addition to a carbon–carbon double bond in the nitrogenous
base.95–101
Since the substrate in most of these reactions is a derivative of uridine, cyclization is, in
effect, an internal addition to an α,β-unsaturated lactam (eq 20).96
Bu3Sn
Br
N
HN
O
AcOCH2
OAc
O
Br
O
OAc
- Bu3SnBr
N
HN
O
AcOCH2
OAc
O
O
OAc
Br
H
39
N
HN
O
O
O
AcOCH2
OAc OAc
O
AcOCH2
AcO AcO
N
NH
OO
- Br
Scheme 20
40%
7%
40
NO
OAc
H Br
40
N
O
Br
AcO
H
- Br
NO
OAc
HBr
39
N
O
Br
AcO
H
440 Chapter 19
Other cyclization reactions of carbonyl compounds include internal addition to α,β-un-
saturated aldehydes,109
ketones,110,111
and lactones,112
and to lactams that are α,β- and γ,δ-unsat-
urated.102–108
Reaction of the unsaturated lactam pictured in Scheme 20 begins with halogen-atom
abstraction that is followed by 1,5-transfer of a hydrogen atom to give the interconverting radicals
39α and 39β. New rings form when these radicals react to give the cyclic, stereoisomeric radicals
40α and 40β, respectively.102
The stereoselectivity of this reaction depends upon the stereochem-
istry of the C-2' substituent and changes when the configuration at C-2' is inverted.102
O
OEt
CH2OBn
O
Me2SiCH2Br
O
O OEt
Me2Si
CH2OBn
( 21 )
AIBN
C6H6
80 oC
Bu3SnH
73%
B. Silyl Ethers and Silaketals
One method for connecting a radical forming group and a multiple bond is with a silicon–
oxygen tether. In some compounds of this type (e.g., the substrate in the reaction pictured in eq 611
)
the multiple bond is located in a substituent group,11–13,113–123
while in others23,124–133
(eq 21),124
it
is part of a ring system. As mentioned earlier in the chapter (Section III.B.4), connecting the
reacting segments of a molecule through a silicon–oxygen bond is particularly useful in producing
larger (seven-,24,29
eight-,31–36
and nine-membered38–42
) rings. An example of a reaction that forms
a larger ring is shown in Scheme 18, where an allyl group is tethered to the 2-position in the phenyl
selenide 34.24,29b
A similar tether connects the two saccharide units in the radical 41, an
intermediate destined to form an eight-membered ring that then is converted into a partially
protected C-disaccharide (Scheme 21).32
The carbon-centered radicals in these reactions usually
are generated by treating phenyl selenides with tri-n-butyltin hydride.
Having a vinyl group tethered to a radical-forming substituent through a silyl ether linkage
can provide the structure needed to form either a five-membered or a six-membered ring.11-13,113-120
It is worth recalling (Section III.B) that in compounds of this type the size of a ring formed can
depend on the concentration of the hydrogen-atom donor; thus, in the reaction shown in eq 6,
higher Bu3SnH concentration causes formation of a five-membered ring, but lower concentration
favors a six-membered one.11
Scheme 3 contains a rationalization for this concentration depend-
ence.
In the radical reactions of the unsaturated silyl ethers pictured in Schemes 18, 19, and 21 and
eq 21, the final step is hydrogen-atom abstraction from Bu3SnH. When the substrate is an unsat-
urated iodide and no Bu3SnH is present in the reaction mixture, the cyclic product is a silyl ether
that contains an iodine atom (Scheme 22).119b
Reaction of this product with fluoride ion eliminates
Compounds With Carbon–Carbon Multiple Bonds II: Cyclization Reactions 441
both the silicon-containing group and an iodide ion and introduces additional unsaturation into the
final product.
Bu3SnSeAr
OCH3
OO
CMe2
SeAr
O
Si
OO
O
O
OMe
C6H5
Scheme 21
Bu3Sn
OO
OC6H5
O
OMeSi
O
CH3
O
OMe2C
O
41
Bu3SnH - Bu3Sn
OO
OC6H5
O
OMeSi
O
O
OMe2C
OCH3
OO
OC6H5
HO
OMe
OCH3
OO
CMe2
OH
Bu4NF
H2O
THF
I
O
O
O
O
OMe
Me2Si H
Ar
42 43
O
O
OMe
Me2Si H
O
O
OMe
Me2Si
H
- I
O
O
HO
O
OMe
Ar
H
O
O
OMe
Me2Si
H
I
Ar = C6H5
F
- Me2SiF2
- I
Scheme 22
42 - 43
442 Chapter 19
A process similar to that shown in Scheme 22 takes place in the reaction pictured in Scheme
23, where homolytic cleavage of the C–Se bond is followed by ring formation to generate the
cyclic radical 44. If diphenyl diselenide (C6H5SeSeC6H5) is added to the reaction mixture, the
yield of the unsaturated nucleoside 45 increases from 47% to 77%. Diphenyl diselenide reduces
competing radical reactions (e.g., hydrogen-atom abstraction) by rapidly reacting with 44 to form
an intermediate selenide from which the product 45 is produced by an elimination reaction.115b
i-Pr2Si
O
O
O
O
i-Pr2Si
SeC6H5
B
OMe2Si
Scheme 23
OB
O
Me2Si
h
- C6H5Se
OB
O SiMe2
44
- C6H5Se(C6H5Se)2
OB
O SiMe2
SeC6H5
O
HO
HO B
OH
Bu4NF
THF
45
C. Alkenyl and Alkynyl Ethers, Esters, Acetals, and Alcohols
A molecule with an O-allyl5,9,45,58,134–146
or an O-propargyl21,147–157
group and a properly
positioned, radical-forming substituent will react to form a new ring system. Equations 22136
and
23152
describe reactions of compounds of this type. These reactions take place even though ring
formation produces highly reactive radicals, a primary radical from an allyl ether (eq 24) and a
vinylic one from a propargyl ether (eq 25). Not surprisingly, ring formation takes place readily in
compounds where cyclization does not need to produce such reactive radicals; in fact; as long as
reactive centers can come within bonding distance, radical cyclization occurs in a wide variety of
unsaturated radicals.158–186
Some specific examples are shown in equations 26 and 27, where ring
formation takes place in molecules in which the multiple bond is located in an existing ring system
(eq 26)159
or is part of an acyclic structure (eq 27).185
( 22 ) AIBN
C6H6
80 oC
Bu3SnHO
BnO
BnOCH2
BnO
BnO
O
I O
BnO
BnOCH2
BnO
BnO
O
CH3
H
Compounds With Carbon–Carbon Multiple Bonds II: Cyclization Reactions 443
( 23 )
AIBN
C6H6
80 oC
Bu3SnHOAcOCH2
AcO
AcO
O
I
OAcOCH2
AcO
AcO
O64%
( 24 )
O O
CH2
( 25 )
O O
O
OEt
CH2OTr
O
EtOCHCH2I
O
O OEt
CH2OTr
EtO
( 26 )
AIBN
C6H6
80 o
C
Bu3SnH
85%
Cyclization takes a different course in its final stage when a radical is formed by electron
transfer from samarium(II) iodide.187
In such a reaction the cyclic radical reacts with additional
SmI2 to form an organosamarium intermediate that undergoes elimination to produce a carbon–
carbon double bond (Scheme 24).164
In the reaction shown in Scheme 24 an O-acetyl group is
eliminated, but even a hydroxyl group (presumably complexed with SmI2) can depart in forming
the double bond (eq 28).164
( 27 )
AIBN
C6H6
80 oC
(C6H5)3SnH
70%
OMe
MeO
HO
I
OMe
OMeHO
444 Chapter 19
Scheme 24
I
AcO
O O
CMe2
OAc
AcO
O O
CMe2
OAc
AcO
O O
CMe2
OAc
AcO
O O
CMe2
SmI2
OAc
AcO
O O
CMe2
AcO
O O
CMe2
6%76%
+
SmI2
- SmI3
SmI2
- AcOSmI2
( 28 )
51%
HMPA
SmI2
THFMeOH
HO
O O
CMe2
I
HO
O O
CMe2
OH
The course of radical cyclization in allyl ethers and related compounds sometimes is altered
by internal hydrogen-atom abstraction.58,88,134,138,171,172,185
Hydrogen-atom abstraction by a
carbon-centered radical from a C–H bond does not take place readily. The best possibility for this
type of reaction occurs when a radical is particularly reactive [e.g., the primary radical produced
from an allyl ether (eq 24) or the vinylic radical from a propargyl ether (eq 25)] and the abstraction
is internal. Such reaction happens following cyclization of the pyranos-1-yl radical 46 (Scheme
25).58,134,138
Although the radicals 47 and 48, produced in this reaction, are both primary, only 48
has the proper stereochemistry for internal hydrogen-atom abstraction. In a similar reaction the
vinylic radical 49, produced during ring formation, abstracts a hydrogen atom from the
Compounds With Carbon–Carbon Multiple Bonds II: Cyclization Reactions 445
neighboring O-benzyl group in route to formation of a mixture of cyclic compounds (Scheme
26).172
- Bu3Sn
OBnOCH2
BnO
BnOO
Scheme 25
O
BnOCH2
OH
CH2
46
47 48
H
O
BnOCH2
OCH2
H
O
BnOCH2
OCH3
H
O
BnOCH2
BnO
BnOO
HCH2D
55% 10% 35%
O
BnOCH2
BnO
BnOO
CH2DH
D
O
BnOCH2
BnO
BnOO
CH3
H
Bu3SnD - Bu3Sn- Bu3Sn
Bu3SnDBu3SnD
internalhydrogen
abstraction
+
D. Compounds with Terminal Triple Bonds
A triple bond in a molecule can have more than one role in a radical cyclization reaction. In
addition to being the multiple bond that combines with a radical centered on a carbon atom else-
where in the molecule, as occurs in the reaction shown in eq 27, a triple bond also can be the source
for a carbon-centered radical that adds to another multiple bond.188
When a radical (usually the
tri-n-butyltin radical) reacts with the triple bond in a compound such as the propargyl ether 50 to
form a vinylic radical, rapid internal reaction of this radical takes place if there is a second multiple
bond within bonding distance (Scheme 27190
).189–200
Although the tri-n-butyltin radical also can add to a double bond,75
triple bond addition is a
far more likely beginning step in a cyclization reaction.193,201
The difference in reactivity between
a double and a triple bond is apparent in the reaction shown in eq 29,193
where a triple bond reacts
in preference to a similarly positioned double bond. These differences in reactivity between double
and triple bonds are determined by the rate of radical cyclization rather than stannyl radical addi-
tion. The stannyl radical actually adds more rapidly to a double bond than to triple bond, but the
446 Chapter 19 adduct radical from addition to a double bond reverts more rapidly and cyclizes more slowly than
that from addition to a triple bond.201
OBn
BnO
HO
OCH2C6H5
OBnHO
H
OBn
BnO
HO
I
- Bu3SnI
Bu3Sn
49
- C6H5CHO
OBnHO
HH
Bu3SnH
- Bu3Sn
OBnHO
HHCH3
OBnHO
62% 18%
+
Scheme 26
OCHC6H5
OBnHO
H H
- Bu3Sn
O
CH3
O OR
SnBu3
Scheme 27
O
CH3
O OR
O
CH3
O OR
SnBu3
- AcOSnBu3
HOAcO
CH3
O OR
SnBu3
O
CH3
O OR
93%
50
SnBu3
Bu3SnH
E. Compounds in Which the Multiple Bond is not Electron-Deficient
If a carbon-centered radical and a multiple bond are in separate molecules, radical addition
only competes effectively with other radical reactions (e.g., hydrogen-atom abstraction) when the
Compounds With Carbon–Carbon Multiple Bonds II: Cyclization Reactions 447
multiple bond is electron-deficient. If this bond is not electron-deficient, successful addition is rare
and requires conditions that minimize competing reactions. When the two reactive centers are in
the same molecule and can come into close proximity, cyclization can be competitive when the
multiple bond is not electron-deficient (eq 35).
5,183,202–210 In fact, even if this bond is electron-rich,
ring formation can take place (eq 30211
).211–221
( 29 )
54%
O
O
CH2OR
O
(C6H5)3SnH
Et3B-O2
C6H5CH3
R = Si(C6H5)2t-Bu
O
O
CH2OR
OH
(C6H5)3Sn
+two minorproducts
( 30 )
AIBN
C6H6
80 oC
Bu3SnH
80%
BrO
O
O
O
C6H5
OEt
O
O
O
O
C6H5
OEt
CH2
Figure 1. Possible carbohydrate frameworks
pyranoid ring furanoid ring open-chain structure
C3 C2
C1
OC5
C4
C6
The framework in a typical sugar has one of the three structural typesshown above. (A hexose is used as an example.) A framework radicalis one centered on a numbered carbon atom, and a framework multiplebond is one involving at least one of these atoms.
C3 C2
C1
C5
C4
C6
C5
C6
C4
C3 C2
C1
O
V. An Organization for Carbohydrates That Undergo Radical Cyclization
It is useful in organizing radical cyclization reactions to divide them into groups that have
common features. One method for doing this places radicals of similar structure together. Where
carbohydrates are concerned, such a plan can be based on the location of the radical center and the
multiple bond. A radical center can exist on an atom that is part of the molecular framework
448 Chapter 19 (Figure 1) or part of a substituent group. The same possibilities exist for the multiple bond. Cyc-
lization reactions of carbohydrates then naturally divide into the four basic types shown in Figure
2. (A short-hand terminology describing these four types has been proposed45
and is included in
Figure 2.) This division provides the basis for constructing Tables 1-4. In addition to these four
tables, two smaller ones are included in recognition of the importance of radical cyclization reac-
tions in the synthesis of nucleosides (Table 5) and carbon-linked disaccharides (Table 6.)
Figure 2. Possible types of cyclization reaction for carbohydrate derivatives
O
O
O
O
O
O
Si
CH2
O
Si
O
a framework radical adding to a framework multiple bind
O
OO
O
O O
a framework radical adding to a substituent multiple bond
a substituent radical adding toa framework multiple bond
a substituent radical adding toa substituent multiple bond
S CC=C
C SC=C
C CC=C
S SC=C
VI. Summary
Forming a new ring by internal addition of a carbon-centered radical to a multiple bond is a
powerful tool in carbohydrate synthesis. Regioselectivity and stereoselectivity are vital aspects of
Compounds With Carbon–Carbon Multiple Bonds II: Cyclization Reactions 449
this type of reaction. Being able to predict regioselectivity is critical because a cyclization reaction
potentially can form rings of two sizes. Since the newly formed ring nearly always has an addi-
tional chiral center (sometimes two), understanding stereoselectivity is essential in predicting
stereochemistry in the cyclic product.
Compounds with five-membered rings are the ones most often produced by radical cycli-
zation. Reactions that form five-membered rings are capable of generating six-membered rings
also, but rarely do so because the transition state leading to the larger ring has greater ring strain.
Compounds with six-membered rings are the major products when cyclization is capable of
forming either six- or seven-membered rings consisting only of second row elements. Larger rings
(seven or more members) are created when a radical center and a distant multiple bond are linked
by a tether, usually one containing a silicon–oxygen bond.
The stereoselectivity of reactions that produce five- and six-membered rings usually can be
rationalized by assuming that the reaction passes through a chair-like transition state. The lowest
energy transition state for such a reaction has as many substituents as possible in pseudoequatorial
positions. A variety of factors (pseudo-1,3-diaxial interaction, allylic strain, hydrogen bonding,
conformation of an existing ring) affect transition-state energy and can, on occasion, cause a
boat-like transition state to be more stable than a chair-like one.
Various types of unsaturated carbohydrates, often α,β-unsaturated esters, undergo radical
cyclization. Also prominent among reactive compounds are those in which the radical-forming
part of the molecule and the portion containing the multiple bond are connected by a silicon–
oxygen tether. A third group of compounds that cyclize readily includes allyl and propargyl ethers
and related compounds.
450 Chapter 19
radical formingsubstituent
type ofmultiple bond
number of atomsin the new ring
references
Table 1. Framework Radical Reacting With a Framework Multiple Bond
CH CHCH2O
CH2 CHCH O
CH2 CHCH O
CH2 CHCH O
CH CHCH O
HC CCH O
CH CHCO2R
CH CHCO2Et
CH CHCO2Me
HC CCH O
HC CCH O
C6H5C CCH O
C6H5C CCH O
Me2SiC CC O
C CCO2Me
C CHCO2R
CH CHCO2Me
Br
Br
I
I
CH CH CO
N
Br
I
I
I
I
I
I
I
I
I
I
I
I
I
5
5
6
7
5
5
6
7
5
6
7
6
7
5
5
5
5
5
164, 182
54, 55
168
166
61, 168
49
87, 89
91, 92
172
172
61
61
171, 172, 185
186
61
171, 174
60, 64, 68, 69,85, 92, 164
62, 66, 67, 69,70, 84, 91, 93
210
207
22
208, 210
5
5
6
5
MeSC(=S)O
MeSC(=S)O
MeSC(=S)O
CH CH O
CH2 CHCH CH
CH2 CCH O
CH2 CHCH2MeSC(=S)O
Compounds With Carbon–Carbon Multiple Bonds II: Cyclization Reactions 451
radical formingsubstituent
type ofmultiple bond
number of atomsin the new ring
references
Table 1. Framework Radical Reacting With a Framework Multiple Bond (Continued)
C6H5OC(=S)O
C6H5OC(=S)O
C6H5OC(=S)O
C6H5OC(=S)O
C6H5OC(=S)O
CH2 CCH O
CH2 CCH O
HC CCH O
HC CCH O
C6H5C CCH
ImC(=S)O
ImC(=S)O
ImC(=S)O CH2 CHCH O
OCH CH
HC CCH O
O
O
S CH CHCO2Me
S
C
S
NOC
O
S
NOC
O
S
CH CHCO2R
HC CCH2
CH CHCO2Me
O
C CH CCO2t-Bu
CH
O
CH CHCH CH2
5
6
5
6
6
5
5
5
5
5
6
5
6
5
22, 201
22, 201
178, 181
179, 180, 219
175, 176
51, 160, 213
51, 160, 213
181
57, 63, 65, 83
70, 89
88
202
86
207
158
158
6
5
C6H5S
C6H5S
CH2 CHCH2
CH2 CHCH O
CH CHCO2MeMeSC(=S)O 5 210
452 Chapter 19
C CCH O
CH CHCO2Et
CH CHCO2R
CH CHCH O
CH2 CHCO
CH2 CHCH O
CH CHCO2Me
C6H5S
MeOC6H4Te
H2C C
HC C
HC C
HC C
HC C
5
5
5
6
6
6
7
158
77
75, 76
166
22
196, 201
61
Table 1. Framework Radical Reacting With a Framework Multiple Bond (Continued)
references number of atomsin the new ring
type ofmultiple bond
radical formingsubstituent
Compounds With Carbon–Carbon Multiple Bonds II: Cyclization Reactions 453
CH2 CHCH O
CH2 CHCH2O
CH2 CHCH2
Me3SiCH CHCH O
(CH3)3CCH CHCH2O
CH CHCO2Et
HC CCH2O
Me3SiC CCH O
C CCH2O
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
5
6
6
6
5
5
5
5
4
5
6
5 + 6
6
5
5
6
5, 136, 144, 189
206
5, 152
204
189
152
9
107
96, 97, 99, 100
9, 144, 169, 170
112
27
91
60, 91
114
5, 152
CH2 CHCH O
CH2 CHSiO
C6H5CH CHCH2O
CH CHCO2Et
CH CHCO2Et
CH CHCO2Et
CH CHCO2
82
5
CH CHC(=O)NH
CH CHC CHC(=O)NH
I
I
I
C6H5C CCH2
5 177, 189
I 1525
Table 2. Framework Radical Reacting With a Substituent Multiple Bond
referencesnumber of atomsin the new ring
type ofmultiple bond
radical formingsubstituent
Br
Br
Br
Br CH2 CHCH2O
123
148
203, 206, 209
143, 144, 145, 149
5 + 6
5
6
5
CH2 CHSiO
CH2 CHC(Me)2O
CH2 CHCH2
454 Chapter 19
CH CHCO2
C CHCO2Me
5
5
6
7
5
5
6
5
6
143
27, 203
99
27
102-106, 108
84
143, 148, 151
143, 151
27CH CHCO2Et
CH CHCO2Et
HC CCH2
C CCHO 109
5
CH CC(=O)NH
Br
Br
Br
CH CHCO2R
Br
Br
Br
Br
Br
Br
Br
HC CCH2O
CH CHC CHC(=O)NH
Br 1435C CCH2O
radical formingsubstituent
type ofmultiple bond
number of atomsin the new ring
references
Table 2. Framework Radical Reacting With a Substituent Multiple Bond (Continued)
CH2 CHCH2O
CH2 CHCH2O 6
CH2 CHCH O
CH2 CHSiO
CH2 CHSiO
CH2 CHSiO
9
7
8
6
5
C6H5Se
C6H5Se
C6H5Se
C6H5Se
C6H5Se
C6H5Se
C6H5Se
C6H5Se
C6H5Se
C6H5Se CH2 CHSiO
36
58, 134, 135,138, 139, 146, 157
139, 140
140, 157
161
24, 28, 29
36
13, 28, 118
115, 116, 119
11, 12, 113-116
5
5
5
5 + 6
C CHCH2O
CH2 CHCH2SiO
CH2 CHCH2SiO
C CHCH2NH 5C6H5Se 10
Compounds With Carbon–Carbon Multiple Bonds II: Cyclization Reactions 455
5
6 95
140
10, 167C6H5Se
C6H5Se
C6H5Se
C6H5Se
C6H5Se
C6H5Se
C6H5Se
5
5
5
7
6
CH2 CHCH2NH
CH CHCO2
CH CHC(=O)N
121
134
58, 134, 135,138, 139, 146, 157
HC CCH2O
Me3SiC CCH2O
Me3SiC CSi
RC CCH2O 173
Table 2. Framework Radical Reacting With a Substituent Multiple Bond (Continued)
references number of atomsin the new ring
type ofmultiple bond
radical formingsubstituent
8OCH CHCO2Et
7OCH CHCO2Et
6OCH CHCO2Et
RC CSiOArSO2
5
CH2 CHSiO
5CH CHCO2
6
5
5
CH2 CHC N
CH2 CHCH2O
HC CCH2O
CH2 CHCH O
CH2 CHCH2O
C(=O)H
NO2
C CH
C CH
C CH
C CH
C6H5SO2
ArSO2
ImC(=S)O
C6H5OC(=S)O
C6H5OC(=S)O
CH3SC(=O)O
CH3SC(=O)O
CH3SC(=O)O
HC CCH2O
101CH CC(=O)NH
OCH CHCO2Et
CH2 CHCH2O
5
5
199
72, 73, 74
199
199
117
199
137
153
117
220
157
149, 150, 154, 155
165
141, 142
6
5
5
5
5
456 Chapter 19
CH2 CCO2Me
CH2 CHCH O
CH CHCH O
CH CCH O
C C O
CH C O
N
Br
I
I
I
5
5
6
6 + 7
6
5
5
5
21, 6, 7,109, 159
6, 7
185
21, 81, 109,124-127,129,132, 159, 163
184
152, 162
130
94
94
124, 133, 183, 211,212, 214, 218
7
23, 216
71
37
109
CH CHCO2Et
HC CCH O
5Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
8CH2 CHCH O
5
23
23, 215, 217
6
5
5 + 6C C O
N
C C O
N
CH CCO2Me
6
9
9
CH CHCO2Et
CH2 CCN
CH CCHO
O
CH CHCH O
CH CHCH O
radical formingsubstituent
type ofmultiple bond
number of atomsin the new ring
references
Table 3. Substituent Radical Reacting With a Framework Multiple Bond
C C O
CH CHCH O
C6H5C(=S)O
CH2C CH
C CH
C CH
5
5
5
CH CHCO
CH CHCH O
5 21, 190-193, 195
192, 214
195
221
Compounds With Carbon–Carbon Multiple Bonds II: Cyclization Reactions 457
CH2 CHCH2O
CH CHCO2
HC CCH2O
I
I
I
5
5
11
110, 111
111
98
44
45
156
200
197
197, 198
194
111, 205
CH2 CH
10
Br
Br
Br
6CH2 CHC
5 + 6
CH2 CHCH
CH CC O
5
I
CH CC(=O)NH
HC C
5
CH2 CHCH2O
HC C CH CHC 5
HC C
5 + 6
HC C
(CH3)2C CHCH2O
CH CHC(=O)N 6
6 147HC O
HC C 194
5CH CHC
Table 4. Substituent Radical Reacting With a Substituent Multiple Bond
referencesnumber of atomsin the new ring
type ofmultiple bond
radical formingsubstituent
radical formingsubstituent
type ofmultiple bond
number of atomsin the new ring
references
Table 5. Nucleoside Synthesis
Br 5
5
80
50
79
CH CHCO2Et
5C6H5Se
C6H5OC(=S)O
CH CHCO2Me
CH CHCO2Et
458 Chapter 19
radical formingsubstituent
type ofmultiple bond
number of atomsin the new ring
references
Table 6. Carbon-Linked Saccharides
I
I
I
5 9
33
31
31, 32, 35, 38, 43
38-41, 43, 46
33, 34
117
42
38
5SiC CCH O
C6H5Se
C6H5Se
C6H5Se
C6H5Se
C6H5Se
C6H5SO2
C6H4NSO2
8
8
7
8
9
11
8
9
30
CH CHCH O
CH2 CO
CF2 CO
CH2 CCH O
CH2 CCH O
CH2 CCH O
CH2 CCH O
CH2 CO
CH2 CCH O
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