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4 [2 + 1] Cycloaddition of Alkenes with Carbenes

4 [2 + 1] Cycloaddition of Alkenes with Carbenes

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j 4 Formation of a Three Membered Ring



112



MeOOC



i



Pr

Pri

COOMe

Si

X

N2

n(H2C)



i



Pr







Si

(CH2)n

Pr X



i



76a: X = O, n = 1

b: X =CH2, n = 0



77a: X = O, n = 1 (55%)

b: X =CH2, n = 0 (68%)



Scheme 4.35



Benzophenone is a convenient triplet sensitizer for the generation of triplet carbenes,

but must be used in a large excess in order that it absorbs a large fraction of light. At any

rate, because a diazo carbonyl compounds absorb at longer wavelengths than

benzophenone, it is difficult to avoid some direct photolysis. Moreover, benzophenone

and some of its derivatives that have an n pà triplet as a lowest excited state easily

abstract hydrogen from the solvent. These shortcomings have been overcome by using

2,20 ,4,40 tetramethoxybenzophenone (TMBP), which Pastor Perez and colleagues

have shown to be an efficient triplet sensitizer for the intramolecular [2 þ 1] cyclo

addition of a diazo carbonyl compounds 78 in polar solvents such as methanol and

acetonitrile (Scheme 4.36) [57]. The same group has also recently reported studies of

the photochemistry of 78 in the presence of various hyperbranched polyether poly

mers, with benzophenone core as triplet sensitizers [58].



N2 (CH2)n

t



Bu OOC

O

78



hν, 400 > λ > 320 nm

TMBP, MeOH

n = 1 (86%)

n = 2 (71%)



t



COOBu

n(H2C)



O



79

MeO



OMe



TMBP =

MeO



O



OMe



Scheme 4.36



4.4.3

Metal-Catalyzed Cyclopropanation-Supported Photochemistry



Optically active metal complexes have been recognized as excellent catalysts for the

enantioselective cyclopropanation of carbenes with alkenes. Normally, diazo com

pounds react under metal catalysts in the dark to afford carbenoid complexes as key

intermediates. Katsuki et al. have reported the cis selective and enantioselective

cyclopropanation of styrene with a diazoacetate in the presence of optically active

(R,R) (NO ỵ )(salen)ruthenium complex 80, supported under illumination (440 nm

light or an incandescent bulb) [59]. The irradiation causes dissociation of the apical

ligand ON ỵ in 80, and thus avoids the splitting of nitrogen from the a diazoacetate.



4.4 [2 ỵ 1] Cycloaddition of Alkenes with Carbenes

hν, solvent, r.t., cat. 5 mol%

N2CHCOOBut



Ph



COOBut



Ph



Ph



cis - 81



cat.



NO N



Ru

O Cl O

Ph Ph

(aR)



COOBut



trans - 81



Yield/% cis:trans

Solvent

18

THF-styrene (10:1)

(1S,2R)

45

THF-styrene (1:1)

(1S,2R)

10

68:32

Hexane



(R)

N



+



%ee (cis)

96:4 99

93:7 97

83(1R,2S)



80

Scheme 4.37



A tetrahydrofuran (THF) styrene (10 : 1, v/v) solution of tert butyl diazoacetate in

the presence of 80 (5 mol%) under incandescent light gives the (1S,2R) cyclopropane

cis 81 in 99% ee, but the yield is only 18% (Scheme 4.37).

However, the chemical yield increases considerably as the proportion of THF is

reduced, although the stereoselectivity is slightly decreased. Interestingly, the sense

of enantioselection in the formation of cis 81 in hexane is opposite to that in THF.

Katsuki et al. applied this reaction to the intramolecular cyclopropanation, when the

irradiation of alkenyl diazoketones in the presence of 80 in THF afforded bicyclo

[3.1.0]hexan 2 ones in a highly enantioselective cyclopropanation, and in moderate

yields (Table 4.3) [60].

Table 4.3 Intramolecular cyclopropanation of alkenyl diazo ketones.



R2



hν, cat. 5 mol%,

r.t., 16 h, THF



R1

N2HC



2



R



R1



O



H



O



H



Entry



R1



R2



Yield (%)



ee (%)



1

2

3

4

5



Ph

i Pentyl

CH3

PhCC

H



H

CH3

CH3

H

Ph



78

72

65

82

62



94

93

87

84

79



4.4.4

Novel Precursors of Carbenes



The influence of substituents on the electronic structure and stability of carbenes has

been investigated, and many stable carbenes have been prepared. Bertrand et al.



j113



j 4 Formation of a Three Membered Ring



114



Ph

Ph



But

N

P

N

But



TMS



Ph







N2



Ph



But

N

P

N

But



COOMe



TMS



Ph



(S,S)-83



(S,S)-82



Ph

S8

Ph



Ph



But

N S

P

N

But



But

N

P

N

But



TMS

COOMe



(S,S,R,R)-84



TMS

COOMe



(S,S,R,R)-85

85%, de>98%

Scheme 4.38



reported the synthesis of stable, optically pure phosphino(silyl)carbenes, and

subsequently a highly diastereoselective cyclopropanation [61]. The photolysis of

enantiomerically pure phosphino(silyl)diazo compound (S,S) 82 in toluene gives

(S,S) 83. The addition of two equivalents of methyl acrylate to the toluene solution

yielded (S,S,R,R) 84, which was then converted into the thioxo compound (S,S,R,R)

85 (85% yield, >98% de) by the addition of elemental sulfur (Scheme 4.38). The

enantiomer (R,R,S,S) 85 could be readily obtained from the reaction of (R,R) 82.

Recently, new photochemical carbene precursors which differed from diazo com

pounds and diazirines have been reported [62, 63]. Platz et al. synthesized a photo

sensitive precursor 86 to phenylsulfanylcarbene 87 (Scheme 4.39) [62]. The photolysis

of 86 in the presence of 2,3 dimethyl 2 butene yielded the [2 þ 1] cycloadduct 88 in

80% yield. In contrast, Jenks et al. reported that S,C ylides of malonates were

photochemical precursors of carbene 90 [63]. Thus, the S,C ylide 89 was irradiated

at 254 nm in acetonitrile with 10% cyclohexene to give 91 in 44% yield (Scheme 4.40).

PhS



H

hν, 300 nm



PhS

H



86



87



PhS

80%



H

88



Scheme 4.39



4.5

Formation of a Cyclopropane via Intramolecular Hydrogen Abstraction



In photochemistry, intermolecular and intramolecular hydrogen abstractions by

excited carbonyl oxygen are often encountered [64]. If an intramolecular b hydrogen



4.5 Formation of a Cyclopropane via Intramolecular Hydrogen Abstraction



COOMe

COOMe -



+

S



COOMe



COOMe





S



44%



COOMe



89



j115



COOMe



91



90



Scheme 4.40



abstraction takes place, then cyclopropanols will be obtained. Although reports of the

formation of cyclopropanols by intramolecular b hydrogen abstraction are fewer in

number than those involving g or d hydrogen abstraction, the synthesis of cyclo

propanes via a photochemical intramolecular hydrogen abstraction has the potential

to become an extremely useful synthetic tool for molecular design and retrosynthesis.

4.5.1

Formation of Cyclopropanol via Intramolecular b-Hydrogen Abstraction



In 1970, the first example of the formation of cyclopropanols by b hydrogen

abstraction was reported by Roth [65]. In addition, b morphorinopropiophenones

92 were irradiated to give cyclopropanols 93 stereoselectively in good yields

(Scheme 4.41). The initial step was a PET from the b amino group to the excited

triplet carbonyl in b morpholinopropiophenones, rather than from a straightfor

ward b hydrogen abstraction. Likewise, b aminopropiophenones 94 and 98 and b

(p amino or methoxy)phenylpropiophenones 93 were shown to undergo an intra

molecular PET to give the cyclopropanols 95, 97, and 99 (Schemes 4.42 to 4.44)

[66 68]. The efficient formation of cyclopropanols should be considered when

planning the molecular structure for substituents at the a and b positions in b

aminoketones.

Nonetheless, there are some examples of cyclopropanol formation by straightfor

ward b hydrogen abstraction. The Diels Alder adduct 100 prepared from o quino

R2



O



HO R2





N

1



R



R1 = CH3, R2 = H (80%)

R1 = Ph, R2 = H (95%)



N



O



R1



92



O



1



2



R = H, R = Ph (85%)



93



Scheme 4.41



O



hν, 366 nm, PhH



Ph



NMe2

R

94



Scheme 4.42



HO NMe2

Ph

R

95



H

H



R = H (95%)

R = Ph (73%)

R = Bn (24%) (68% in MeOH)



j 4 Formation of a Three Membered Ring



116



R2

R1 = H, R2 = NMe2 (50%)



O

hν, 366 nm, PhH



R1 = Ph, R2 = NMe2 (88%)



HO



Ph

R1



R2



H

H



Ph

R1



96



R1 = Bn, R2 = NMe2 (65%)

1



2



R = Ph, R = OMe (49%)



97



Scheme 4.43



O



HO

NMe2



hν, MeCN



NMe2

H



70%

99



98

Scheme 4.44



dimethane and 2,3 dimethyl 1,4 naphthoquinone was irradiated in acetonitrile to

give a cyclopropanol 101 in 35% yield (see Scheme 4.45) [69]. Also, b hydroxy or

b alkohoxypropiophenones 102 were shown to give cyclopropanes 103 via a straight

forward b hydrogen abstraction by excited carbonyl oxygen (Scheme 4.46) [70].

Upon direct photolysis, the a (1 hydroxyalkyl) substituted a,b unsaturated

ketones 104 gave 1,4 diketones 106 in moderate yields (Scheme 4.47) [71], with the

reaction involving an intermolecular b hydrogen abstraction. The resultant vinyli

denecyclopropanols 105 underwent a formal double tautomerization to afford 106.



O



H3C



O



H3C



OH



hν, MeCN



+



35%

H3C



O



H3C



O



100



O



101



Scheme 4.45



O



OR1

R2



Ph



102



Scheme 4.46



hν, MeOH



HO OR1

R2



Ph



103



R1

H

Me

Me

Me

Et

Et



R2

Ph

Me

Ph

OMe

Me

Ph



Yield / %

95

82

92

88

82

92



cis:trans

89:6

6:4

9:1

5:2

6:1



4.5 Formation of a Cyclopropane via Intramolecular Hydrogen Abstraction



OH OH



OH



O







R2



R1



R1



R2



R1



j117



HO



104



R2

HO

105



O

R2



1



41-66%



R



O



R1 = Me or Ph,

R2 = Me, Et, Ph, p -MeOC6H4, or p-ClC6H4



106

Scheme 4.47



4.5.2

Formation of Cyclopropane Ring via Intramolecular g-Hydrogen Abstraction



The intramolecular g hydrogen abstraction by the excited carbonyl oxygen of ketones

is a favorable pathway, and the resultant 1,4 biradical subsequently cyclizes to

cyclobutanol [64]. This reaction, which is referred to as the “Yang reaction,” will

be described in detail in Chapters 5 and 6. Wessig and colleagues have shown

that ketones with a variety of leaving groups, such as OMs (OSO2CH3),

OTs (OSO2C6H4CH3 p), OPO(OEt)2, or ONO2, at the a position lead to cyclo

propyl ketones via intramolecular g hydrogen abstraction upon direct irradiation

(Scheme 4.48) [72]. These result from acid elimination from the 1,4 biradical

intermediates, and for a successful reaction N methylimidazole as an acid scavenger

must be added to the solution [72]. Wessig et al. applied this reaction to the syntheses

of bicyclo[n.1.0]alkyl (n ¼ 4, 3, or 2) (Scheme 4.49) and heterobicyclo[4.1.0]alkyl

ketones [72a]. In addition, the photochemistry of enantiomer rich samples of

the ketones 107 showed a 1,2 chirality transfer (Scheme 4.50) [73]. Although the

ketones 107 give the cyclopropyl ketones 108 at room temperature in 28 52% ee

yields, the rise in temperature enhances the stereoselectivity. This behavior has been

explained by the compensation of entropic and enthalpic influences.

Furthermore, Wessig and M€

uhling were successful in synthesizing highly strained

spiro[2.2]pentanes in 1,1,2 trichloro 1,2,2 trifluoroethane (R113) (Scheme 4.51) [74].



hν, > 300 nm, CH2Cl2,

2 eq. N-methylimidazole



O



Ph



Ph



O



OH

-MsOH



Ph



OMs



OMs



63%



O

Ph



90%

hν, > 300 nm, CH2Cl2,

2 eq. N-methylimidazole



O



Ph



Ph

OMs



Scheme 4.48



O



OH

-MsOH

OMs



Ph



j 4 Formation of a Three Membered Ring



118



COPh



O



(CH2)n



hν, > 300 nm, CH2Cl2,

2 eq. N-methylimidazole



Ph



H



n = 1 (61%)

n = 2 (80%)

n = 3 (86%)



H

(CH2)n



OTs

Scheme 4.49



O



COPh



hν, > 300 nm, CH2Cl2, 25 oC,



X



2 eq. N-methylimidazole



H



Ph

OTs



H

X

108



107

X = O (74%, 28%ee)

X = NTs (78%, 38%ee)

X = NBOC (69%, 23%ee)

t



X = CHBu (79%, 52%ee)

Scheme 4.50



O



hν, > 300 nm, R113,

2 eq. N-methylimidazole



O

Ph



Ph



29%

OMs



Scheme 4.51



The direct irradiation of 4 propanoyl 6 methylpyrimidine 109 in tert butyl alcohol

containing 5% benzene (>340 nm) leads to cyclopropanol 110 in 98% yield

(Scheme 4.52) [75]. This reaction proceeds through g hydrogen abstraction by N

(3), but not by N(1) or by O.



6

1N



5



O



hν, >340 nm,

5%PhH/t-BuOH

98%



4



N

3

2

109



O

N



HO



OH

N



N



NH



98%



N



N

110



Scheme 4.52



4.6 [3 ỵ 2] Cycloaddition of Arenes with Alkenes



j119



4.6

[3 ỵ 2] Cycloaddition of Arenes with Alkenes



The rst photochemical [3 ỵ 2] cycloadditions of arenes with alkenes were reported

by two groups in 1966 [76, 77]. This is one of three types of cycloaddition reaction

(ortho, meta, and para) of arenes with alkenes, and is referred to as the meta

cycloaddition reaction. There are many combinations of arenes and alkenes and,

indeed, a large number of reports and reviews have been made on the regiochemistry

and stereochemistry [78]. Because this reaction can be used easily to construct a

tricyclo[3.3.0.02,8]oct 3 ene framework, the organic syntheses of many natural com

pounds using this method have been attempted [79], in which the photochemical

[3 ỵ 2] cycloaddition plays a key role.

4.6.1

Intermolecular [3 ỵ 2] Cycloaddition



The b silyl effect has been found to be operative in excited states, where this group

exerts a remarkable effect on the yield and selectivity of intermolecular [3 þ 2]

cycloaddition (Scheme 4.53) [80]. Although cyclohexene and cis cyclooctene each

produce poor yields and poor selectivities with substrates such as toluene and anisole,

this reaction is capable of producing intermolecular [3 þ 2] cycloadducts with a few

cycloalkenes.

The reaction of methyl 1,3 dihydroisoindole 2 carboxylate 111 with cyclopentene

affords two endo products 112 and 113 in 90% yield (Scheme 4.54) [81].

4.6.2

Intramolecular [3 ỵ 2] Cycloaddition



The photochemical intramolecular [3 ỵ 2] cycloaddition of arenes with a tethered

alkene leads to polycyclic compounds. This reaction is better suited to the synthesis of

natural products than to intermolecular [3 ỵ 2] cycloaddition. A carbonyl group in the

tether fails to produce any good results, because this chromophore can quench the

TMS

hν,



(CH2)n



TMS

(CH2)n



n = 1 (80%, endo : exo = >10 :1)

n = 2 (78%, endo : exo = >10 :1)

n = 3 (81%, endo : exo = >10 :1)

n = 4 (93%, endo : exo = 4 :1)



TMS

hν, n(H2C)



(CH2)n

(CH2)n n = 1 (65%, endo : exo = >10 :1)

n = 2 (89%, endo : exo = >10 :1)

n(H2C)



Scheme 4.53



j 4 Formation of a Three Membered Ring



120



N COOMe



COOMe



hν, MeCN



+



MeOOC

N



N



+



112:113 =

8:5 (90%)



113



112



111

Scheme 4.54



R



R

N



X



N



X







R = Me, X = COOMe (80%)

R = OMe, X = COOMe (80%)

R = Me, X = COCF3 (38%)

Scheme 4.55



exciplex between an arene and an alkene [82]. The length of tether length should be

( C )3 or 4 due to the formation of a favorable intramolecular charge transfer (CT)

complex between an arene and an alkene. When a heteroatom such as N [83, 84],

O [85], or Si [86] is incorporated in the place of a carbon atom in the tether, the [3 þ 2]

cycloadducts are formed in good yields with high regioselectivity (Schemes 4.55

to 4.57). When the b cyclodextrin complex of 5 (3 butenyloxy) 1,2,3,4 tetrahydro

naphthalene was irradiated in the solid phase, an effect of the cyclodextrin (CD)

hosting on the regioselectivity and enantioselectivity was found (Scheme 4.57) [87].

R



MeO



Si



R = OMe



Si





R=H



85%



Si

60%



Scheme 4.56



O



13%ee



hν, β-CD

R -R = -(CH2)4-



R

R



O





R=H



O



51%



Scheme 4.57



Jenkins et al. have reported on diastereocontrol in the intramolecular [3 ỵ 2]

cycloaddition. Here, (3R,5S)/(3S,5R) 5 phenyl 1 hepten 3 ol 114 was irradiated to

give a diastereopure [3 ỵ 2] cycloadduct 115 (Scheme 4.58) [88]. The other diaste

reomer (3S,5S)/(3R,5R) 114 gave an unresolved mixture.



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