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

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

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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



32



INTERMOLECULAR RADICAL ADDITIONS TO ALKYNES

H



PhSSPh, hν



via:



149a



SPh



H



+



72%



52



PhS



SPh



+



150



149b

SPh



SPh

52 + PhS



Z-151



E-151

SPh

Z-151



SPh



Z-152



PhS



150



153b



E-152

PhS + PhSSPh



[H]



6-exo



1,6-HAT



149a/b



153a



SPh

E-151



[H]



6-exo



1,6-HAT



SPh

H



SSPh



154



PhS

H



SSPh



155



SCHEME 2.27



S-centered radicals were also explored in self-terminating radical cyclizations

(Scheme 2.27).60 Using the 10-membered cyclic alkyne 52 as a model system, reaction

with PhS radicals, which were photogenerated from diphenyl disulfide, leads to the

cis- and trans-fused bicyclic thioethers 149a/b and 150 possessing a decalin framework, which were identified through a combination of independent synthesis, X-ray

analysis and computational studies. Formation of the cis-configured diastereomeric

thioethers 149a/b should proceed through the usual pathway involving an initially

formed Z-configured vinyl radical Z-151, followed by 1,6-HAT and 6-exo cyclization

to give the a-thio radical 153a, which undergoes subsequent reduction from both faces

of the planar radical center. The trans-configured product 150 results from a similar

radical addition / translocation cascade involving the isomeric vinyl radical E-151.

Computational studies revealed that E-151 is not formed through E/Z isomerization of

the vinyl radical Z-151, which requires a surprisingly high activation energy due to ring

strain in the ten-membered ring, but through reversible addition of PhSl to the alkyne

C:C bond in 52. According to GC/MS studies, the hydrogen donor in this system is

believed to be the radical adduct 154, which results from addition of PhS to

diphenyl disulfide. Homolytic b-fragmentation of the SÀC bond in 153a/b to yield

thioketones, in accordance with the general mechanism of self-terminating radical

cyclizations, is not possible in this case because highly unstable phenyl radicals

would be released.

Keck and Wagner used a diastereoselective thiyl radical addition/cyclization

sequence to generate the key compound 157 for a total synthesis of ent-lycoricine

158 (Scheme 2.28).61 In this sequence, photogenerated PhS undergo exclusive

addition at the b-site of the C:C triple bond in the starting alkyne 156 to

produce the resonance-stabilized vinyl radical 159 (interestingly, with Bu3Sn ,

.



.



.



.



33



CASCADE REACTIONS INITIATED BY ADDITION OF HIGHER MAIN GROUP



only addition at the a-carbon was found, which may be a result of the sterical

hindrance imposed by the substituents at tin). The subsequent 6-exo radical

cyclization of 159 proceeds, due to the presence of the cis fused dioxolane ring,

in a highly diastereoselective fashion through a boat-like transition state, in which

the imine C¼N double bond and the hydroxy substituent both assume a pseudoequatorial position. This leads to a cis arrangement of the hydroxy and amino

substituents in the cyclized intermediate 160, which is subsequently reduced to 157

in a radical chain process.



OH

β



α



O

R



N



91%



OBn



O



O



O



HN

OBn

R

157

(R = CO2Me)



156

(R = CO2Me)

via:

N



O

HO



OH

PhS



O



N



OBn

Ar



O PhS



O

Ar



OH



O



PhSH, hν



O

O



OH



OH

PhS



O



6-exo

Ar =



OBn



159



O



O



OH

NH



O

O

158



OH

PhS



O



Ar



O

N



PhSH

− PhS



157



OBn



160

MeO2C



O



SCHEME 2.28



A diastereoselective formal addition of a trans-2-(phenylthio)vinyl moiety to

a-hydroxyhydrazones through a radical pathway is shown in Scheme 2.29.62 To

overcome the lack of a viable intermolecular vinyl radical addition to C¼N double

bonds, not to mention a reaction proceeding with stereocontrol, this procedure

employs a temporary silicon tether, which is used to hold the alkyne unit in place

so that the vinyl radical addition could proceed intramolecularly. Thus, intermolecular

addition of PhS to the alkyne moiety in the chiral alkyne 161 leads to vinyl radical 163,

which cyclizes in a 5-exo fashion, according to the Beckwith–Houk predictions, to

give aminyl radical 164 with an anti-arrangement between the ether and the amino

group. Radical reduction and removal of the silicon tether without prior isolation of the

end product of the radical cyclization cascade, 165, yields the a-amino alcohol 162.

This strategy, which could also be applied to the diastereoselective synthesis of

polyhydroxylated amines (not shown), can be considered as synthetic equivalent of an

acetaldehyde Mannich reaction with acyclic stereocontrol.

Renaud and coworkers applied a radical addition/translocation/cyclization cascade

as a key step in the diastereoselective synthesis of the spirocyclic compound (À)erythrodiene 168 (Scheme 2.30).63 Addition of photogenerated PhS to the terminal

.



.



34



INTERMOLECULAR RADICAL ADDITIONS TO ALKYNES

NNPh2



R



H

O



NHNPh2



1) PhSH, AIBN

2) TBAF



R

OH



R = H, Me, iBu, iPr, Ph



161



O R



via:

NNPh2

R

Si



162



NPh2

N



Si



N NPh2



HN NPh2



R



H

O



SPh



51–70%



Si



SPh

5-exo



SPh



PhSH

O Si



163



SPh



R



TBAF

O Si



− PhS



164



162



SPh



165



SCHEME 2.29



alkyne in 166 gives vinyl radicals 169, which undergo a regioselective 1,5-HAT,

followed by 5-exo cyclization of the intermediate tertiary radical 170 and subsequent

reduction of 171 to yield 167 as a mixture of four diastereomers. The high trans

selectivity of this cyclization can be explained by a transition state where a new axial

CÀC bond is formed, but it should be noted, however, that the stereochemical outcome

was found to be very sensitive to reaction temperature and solvent polarity. A very

similar thiophenol-mediated radical cyclization cascade has also been applied to the

synthesis of various 1-azabicyclic alkanes from N-homopropargylic amines (not

shown).64



O



O



1) mCPBA (96%)

2) DMSO, NaHCO3

(microwave heating, 70%)

3) Ph3P+MeBr−, BuLi (70%)



O



PhSH, AIBN





+



65%



SPh



166

(cis/trans 8:1)



SPh



167

4 diastereomers

(d.r. 67:31:1:1, trans/cis 98:2)



168

(96% ee)

O



via:

O



O



O

SPh 1,5-HAT



SPh



SPh



PhSH



5-exo



169



167



SPh − PhS

171



170



SCHEME 2.30



An interesting four-component radical cascade that leads to formation of b-arylthiosubstituted acrylamides 172 and involves thiyl radicals, aromatic acetylenes, and



35



CASCADE REACTIONS INITIATED BY ADDITION OF HIGHER MAIN GROUP



isonitriles, as well as an oxidant, has been reported by Nanni and coworkers

(Scheme 2.31).65 The sequence is initiated by chemoselective addition of photogenerated PhS to the C:C triple bond in phenylacetylene (which is more electron rich

than the isonitrile p system), leading to the vinyl radical 173, which is subsequently

trapped by intermolecular addition to the isonitrile N:C triple bond. The resulting

imidoyl radical 174 is captured by m-dinitrobenzene, which acts as an oxidant to

produce the amidyl radical 176 via the intermediate 175. Subsequent hydrogen transfer,

presumably through an intermediate of type 154 (see Scheme 2.27), terminates the

cascade.

.



O2N



NO2



MeO



O



hν,

+ MeO



PhSSPh + Ph



NC



N

H



40%



SPh

Ph

172



via:

PhS



O2N



MeO

MeO

Ph



Ph

173



NO2



NC

N



SPh



SPh

Ph

174



3-NO2-Ph

N

O

O



MeO



N

Ph



MeO

SPh ON





NO2



O



[H]



N



SPh



172



Ph

176



175



SCHEME 2.31



In the case of S radicals, where sulfur is in a higher oxidation state, sulfonyl radicals

(RSO2 ) have gained considerable synthetic value, since their addition to p systems,

usually C¼C double bonds, provides a facile method to introduce the sulfonyl moiety

into a molecule. Although in sulfonyl radicals the spin density is delocalized over

sulfur and both oxygen atoms, they react with p systems exclusively to form CÀS

bonds.57 Simpkins and coworkers used a tandem sequence triggered by the addition of

sulfonyl radicals to alkynes of type 177 for the synthesis of N-containing heterocycles

178 (Scheme 2.32).66 The initially formed vinyl radical 179 undergoes a 5-exo

cyclization to the remaining C¼C double bond, leading to the bicyclic radical

intermediate 180, which is transformed into the final product through homolytic

substitution in a chain propagating step. The stereochemistry of the latter step can be

understood on the basis that the substitution takes place from the less hindered site of

the molecule.

A related radical addition/5-exo cyclization cascade involving addition of sulfonyl

radicals to alkynes has been used for the diastereoselective synthesis of bicyclic

b-lactams 182 from the b-lactamic enyne precursor 181 (Scheme 2.33).67 In this

radical chain sequence, where tosyl bromide is used as source of sulfonyl radicals, the

final product is a mixture of epimers (90 : 10) at the newly formed exocyclic chiral

center.

.



36



INTERMOLECULAR RADICAL ADDITIONS TO ALKYNES



MeO2C



MeO2C

N



H



N



SO2Tol



TolSO2SePh, AIBN



H



78%

177



SePh



178

SO2Ph



via:



MeO2C

177



MeO2C



N



N



H



5-exo



TolSO2



SO2Tol



TolSO2SePh



H

TolSO2



180



179



178



SCHEME 2.32

O



O



O

Ph



N

Ph



TolSO2Br, AIBN



Ph



Ph



80%, d.r. 90:10



N



O Br

H

N

N



O



O

181



SO2Tol



182



via:

O



O



O

Ph



N



5-exo



Ph

N

O



O

N



H



TolSO2Br



Ph

N



SO2Ph



Ph



O

184



183



SO2Tol



182



TolSO2



SCHEME 2.33



2.4.2 Cascade Reactions Initiated by Addition of Se-Centered

Radicals to Alkynes

In contrast to the large amount of S radical-mediated cascade reactions, only a few

examples for radical cascades that are triggered by intermolecular Se radical addition

to an alkyne are reported in the literature. Ogawa and coworkers described a highly

selective four-component radical coupling reaction of unsaturated compounds that is

mediated by phenylselenyl radicals, PhSe (Scheme 2.34).68 The reaction of diphenyl

diselenide with ethyl propiolate and a large excess of alkenes with an electronwithdrawing group (EWG; e.g., acrylates) and with an electron-donating substituent

(e.g., 2-methoxypropene) leads to formation of the highly substituted cyclopentane

systems 185a–c in good to excellent yields. This reaction proceeds through a

sequential addition of PhSe to the alkyne, of the resulting highly electrophilic vinyl

radical 186 to the electron-rich olefin, followed by addition of the nucleophilic radical

.



.



37



CASCADE REACTIONS INITIATED BY ADDITION OF HIGHER MAIN GROUP

EWG



PhSeSePh + EtO2C

MeO

+

+ EWG



SePh



EWG



SePh

CO2Et





41–76%



MeO



185a



+



SePh

SePh

CO2Et



MeO



185b



185c



(major)



via:

PhSe



EWG



SePh

CO2Et



+



MeO

EWG = CO2tBu, CO2Me, CN, Ac



SePh



MeO

EtO2C



EtO2C



SePh

OMe CO2Et



SePh



186

MeO

EWG



SePh

CO2Et



MeO



188



EWG



187

SePh

EtO2C

EWG



EWG



SePh

CO2Et



5-exo



PhSeSePh

− PhSe



185a



MeO



189



SCHEME 2.34



adduct 187 to the electron-poor olefin. The subsequent 5-exo cyclization of 188

proceeds with high preference through a chair-like transition state, according to the

Beckwith–Houk predictions, with the electron-withdrawing substituent at the radical

center assuming an axial position (to minimize sterical interaction with the C¼C

double bond in the late transition state, as a result of the radical stabilizing effect of the

EWG group). Trapping of the cyclized intermediate 189 by phenyl selenide gives

185a. The minor diastereomers 185b and 185c result from 5-exo cyclizations with an

axial methoxy group and/or a pseudo-equatorial EWG substituent in the respective

transition states (not shown).



2.5 CASCADE REACTIONS INITIATED BY ADDITION OF HIGHER

MAIN GROUP (V)-CENTERED RADICALS TO ALKYNES

Of the higher main group (V) elements, only P-centered radicals have been used in

intermolecular radical additions to alkynes, whereas radical reactions with the

unpaired electron located at the higher metallic elements arsenic, antimony, and

bismuth have not been reported.

2.5.1 Cascade Reactions Initiated by Addition of P-Centered

Radicals to Alkynes

Phosphorous hydrides, such as phosphites, (RO)2P(O)H, thiophosphites, (RO)2P(S)H,

and phosphinates, R(RO)P(O)H, have received considerable attention in the recent

years as nontoxic alternative to tin hydrides commonly used in radical chain reactions.



38



INTERMOLECULAR RADICAL ADDITIONS TO ALKYNES



However, their intermolecular addition reactions with alkynes are mostly aimed at

synthesizing substituted alkenes,69,70 and only very few cascade reactions that are

initiated by P radical addition to C:C triple bonds have been reported. Renaud and

coworkers developed a simple one-pot procedure for the cyclization of terminal

alkynes mediated by dialkyl phosphites (Scheme 2.35).71 In this radical chain

procedure, dialkyl phosphite radicals, (RO)2P ¼O, undergo addition to the C:C

triple bond in 190, which triggers a radical translocation (1,5-HAT)/5-exo cyclization

cascade. The sequence is terminated by hydrogen transfer from dialkyl phosphite to

the intermediate 194 and regeneration of P-centered radicals.

.



O



RO



( )n



P



O



H



RO

(RO2)P(O)H, DLP



MeO2C CO2Me



( )n

H

CO2Me



MeO2C



190

(n = 1, 2)



191

n = 1, R = Me: 71%, d.r. 85:15

n = 2, R = Et: 84%, d.r. 61:39



DLP = dilauryl peroxide

via:



P(O)(RO)2 O

O



O



190



( )n



(RO)2P



P(O)(RO)2 O

1,5-HAT



( )n



MeO2C CO2Me



MeO2C CO2Me



192



193



(RO)2(O)P



H



5-exo



O

( )n



MeO2C



H

CO2Me



(RO2)P(O)H

O



191



(RO)2P



194



SCHEME 2.35



.



Diphenylphosphanyl radicals, Ph2P , generated from diphenylphosphane in the

presence of a radical initiator were used to cyclize the alkynyl-substituted carbohydrate derivative 195 in a radical addition/5-exo cyclization sequence to give the

bicyclic deoxysugar derivative 196 (Scheme 2.36).66 Ph2P have also been used as

promoters for the cyclization of alkynyl b-lactam 181 for a highly efficient, diastereoselective synthesis of bicyclic b-lactams (see Scheme 2.33).67

.



AcO



O



O



37%



AcO



O



Ph2PH, AIBN AcO



O



AcO

196

Z/E = 6:1



195



PPh2



via:

AcO



O



O



5-exo AcO

PPh2



AcO



O



O



Ph2PH



AcO



197



198



SCHEME 2.36



PPh2



Ph2P



196



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