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3 Cascade Reactions Initiated by Addition of Higher Main Group (VI)-Centered Radicals to Alkynes

3 Cascade Reactions Initiated by Addition of Higher Main Group (VI)-Centered Radicals to Alkynes

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28



INTERMOLECULAR RADICAL ADDITIONS TO ALKYNES



The facility by which CÀSn bonds can undergo homolytic fragmentation under

certain conditions has been used in a number of cyclization cascades involving

alkynes, where Sn radicals formally catalyze the rearrangement of the molecular

framework without appearing as substituents in the final product. For example,

Baldwin and Adlington have shown that in the presence of Sn radicals, 5cyclodecynone (58) undergoes rearrangement to the bicyclic a,b-unsaturated

ketone 114 (Scheme 2.22; no yield was reported).52 The vinyl radical 115 obtained

from addition of the Sn radical to the C:C triple bond undergoes 5-exo cyclization

to the carbonyl group. However, in contrast to the self-terminating cyclization

sequence shown in Scheme 2.11, where the intermediate allyloxyl radicals 62/65

undergo a 3-exo cyclization, the allyloxyl radical 116 undergoes a-cleavage to give

intermediate 117, which subsequently cyclizes in a 5-exo fashion to produce the

allylic radical 118. The cascade is terminated through b-fragmentation and

elimination of the Sn radical.

Baldwin et al.

O

Bu3SnH, AIBN

O 58



114



via:

SnBu3



SnBu3



SnBu3

5-exo



O

115



SnBu3

5-exo



O



O

116



O

118



117



− Bu3Sn



114



Bachi et al.

Bu3SnH, AIBN

N



N



O



O

CO2tBu

119



CO2t Bu

120

(19%)



via:

N

O



SnBu3



1,5-HAT



SnBu3



N



6-endo



O

CO2tBu

121



N



O

CO2tBu

122



SnBu3 − Bu3Sn

CO2tBu

123



120



SCHEME 2.22



Bachi and Bosch used Sn radicals as mediator for the cyclization of the b-lactamsubstituted alkynes 119 through a sequence consisting of radical addition and

1,5-HAT, followed by a 6-endo cyclization of the radical intermediate 122, to give

the bicyclic b-lactam 120 after b-fragmentation and release of Bu3Sn radicals

(Scheme 2.22).53 The moderately low yield of this cyclization is due to the competing

fast reduction of the vinyl radical 121 to the corresponding alkene by the tin hydride

(not shown).



29



CASCADE REACTIONS INITIATED BY ADDITION OF HIGHER MAIN GROUP



A remarkably complex cyclization/twofold ring expansion sequence that is

catalyzed by Sn radicals is shown in Scheme 2.23.54 The vinyl radical 126 formed

after radical addition to the terminal end of the alkyne bond in 124 cyclizes to the

carbonyl group in a 6-exo fashion. The resulting alkoxyl radical 127 undergoes acleavage to produce the tertiary radical 128, which is donor stabilized by the aheteroatom (it should be noted that capto-stabilizing groups in a-position lead to

significant reduction in the overall reaction rate). The first ring expansion occurs in

a 5-exo cyclization, which is followed by a 3-exo cyclization of 129, leading to the

cyclopropyloxyl radical 130. Opening of the cyclopropyl ring results in the second

ring expansion and formation of the bicyclo[6.3.0]undecane framework in 131.

The final product 125 is obtained through b-fragmentation and release of the Sn

radical.



O

O



Bu3SnH, AIBN

51%



OSiEt3

124



OSiEt3

125



O



O



O



6-exo



SnBu3



O



SnBu3

3-exo



OSiEt3

128



OSiEt3

129



SnBu3



− Bu3Sn

OSiEt3

130



O



5-exo

OSiEt3

127



OSiEt3

126

O



SnBu3



SnBu3



SnBu3



via:



125



OSiEt3

131



SCHEME 2.23



A double radical cyclization/b-fragmentation of the homolog acyclic w-yne vinyl

sulfides 132a/b that is catalyzed by Sn radicals and also involves an unusual endo

radical cyclization is shown in Scheme 2.24.55 The initially formed vinyl radicals

134a/b undergo a 5/6-exo cyclization to the C¼C double bond, which is activated by

one electron-withdrawing group (the reaction does not occur if the alkene in 132

carries two electron-withdrawing substituents). b-Fragmentation of 135a/b leads to

the thiyl radical 136a/b, which in the case of 136a cyclizes in a highly unusual 5-endo

fashion (6-endo for the larger homolog 136b) to the remaining C¼C double bond to

give allylic radical 137a/b. The reverse ring opening of the latter is prevented by a

chain terminating b-fragmentation under release of the Sn radical to give the diene

133a/b.



30



INTERMOLECULAR RADICAL ADDITIONS TO ALKYNES

nBu



CO2Et

CO2Et



Bu3SnH, AIBN

S ()

n



S

( )n

132a: n = 1

132b: n = 2

E:Z = 45:55

via:



nBu



Bu3Sn



CO2Et

5-exo (134a) Bu3Sn

6-exo (134b)



nBu

CO2Et

S



S

( )n

134a: n = 1

134b: n = 2

5-endo (136a)

6-endo (136b)



nBu



133a: n = 1, 62%

133b: n = 2, 78%



( )n

135a: n = 1

135b: n = 2



CO2Et

SnBu3

S

( )n

nBu

136a: n = 1

136b: n = 2



SnBu3

CO2Et

S ()

n



nBu



− Bu3Sn



133a/b



137a: n = 1

137b: n = 2



SCHEME 2.24



2.4 CASCADE REACTIONS INITIATED BY ADDITION OF HIGHER

MAIN GROUP (VI)-CENTERED RADICALS TO ALKYNES

The vast majority of radical cascades initiated by addition of higher main group (VI)centered radicals to alkynes focus predominantly on S-centered radicals, mainly thiyl

radicals, whereas considerably fewer intermolecular addition reactions involving

radicals with the unpaired electron located on selenium or even tellurium are known.

2.4.1 Cascade Reactions Initiated by Addition of S-Centered

Radicals to Alkynes

One of the earliest radical cyclization cascades initiated by addition of S-centered

radicals to alkynes was reported in 1987 by Broka and Reichert (Scheme 2.25).56

Thiophenyl radicals, PhS , which were generated under radical chain conditions,

undergo addition to the terminal end of the C:C triple bond in enyne 138.

The resulting vinyl radical 141 can undergo cyclization in both 6-endo (preferred)

and 5-exo fashion, and reduction of the radical intermediates 142 and 143 leads to the

final observed products 139 and 140, respectively.

The apparent chemoselectivity for the addition of the electrophilic S-centered

radicals to the less electron-rich alkyne moiety in enyne 138 can be rationalized by

the fact that addition of S radicals to both alkenes and alkynes proceeds smoothly (the

rate constants for addition of S radicals to alkenes are about three orders of magnitude

larger than those for the addition to alkynes),57 but is also reversible. However, the

reversibility is less pronounced for the radical addition to alkynes, due to the high

reactivity of the vinyl radicals formed (compared to alkyl radicals), which undergo

subsequent reactions at faster rates than undergoing fragmentation back to the S

.



31



CASCADE REACTIONS INITIATED BY ADDITION OF HIGHER MAIN GROUP



PhSH, AIBN



PhS



+ PhS



138



139

52%



140

8%



6-endo PhS



PhSH



via:

142



PhS



PhSH



5-exo



141



139



− PhS



PhS



− PhS



140



143



SCHEME 2.25



radical and alkyne. Therefore, S radicals ultimately can promote cyclization of enynes

through a mechanism consisting of radical addition to the C:C triple bond, followed

by cyclization to the alkene moiety.58 A similar behavior is also observed in the

reactions of other electrophilic heteroatom-centered radicals with enynes (see below).

A highly complex radical addition/cyclization/rearrangement reaction is shown

in Scheme 2.26.59 Addition of thiyl radicals derived from 144, under radical

chain conditions, to the alkynyl azide 145 leads to vinyl radical 147, which cyclizes

in a 5-exo fashion to the aromatic ring to give the spiro radical intermediate 148. The

presence of the para cyano group is crucial, as it leads to a significant radical

stabilization—indeed, the 5-exo cyclization does not occur in systems lacking a

radical stabilizing substituent at the aromatic ring; in these cases, the vinyl radical is

directly reduced to the corresponding S-substituted alkene (not shown). Reduction of

the aryl radical 148, followed by opening of the S-heterocyclic ring and rearomatization, yields the final product 146 in 65% overall yield.



CN



NC



N3



+



AIBN

65%



SH

144



MeS

N3



145



146



via:

CN

S



5-exo



S



CN



N3

147



N3

148



SCHEME 2.26



144

146



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