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2 Photochemical C–C Bond Formation in Solution

2 Photochemical C–C Bond Formation in Solution

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2.2 Photochemical C C Bond Formation in Solution



deserves further analysis, the generality of the reaction at this time appears to be

limited to compounds that block the more common photo Fries rearrangement by

bearing substituents in the two ortho and para positions.

2.2.2

Photoelimination of N2

2.2.2.1 Synthesis of Three-Membered Rings

One of the most synthetically useful photoelimination reactions is the photo

denitrogenation of pyrazolines for the preparation of substituted cyclopropanes.

The reaction is particularly valuable through the strategy illustrated in Scheme 2.6. It

involves the conversion of an activated olefin into the corresponding pyrazoline by a

thermal dipolar cycloaddition, followed by the photochemical elimination of N2 to

generate the three membered ring. While the regioselectivity of the cycloaddition

reaction is not relevant in the overall reaction scheme [20], a suprafacial addition

ultimately leads to the stereospecific formation of the three membered ring.

Z

+

R1



R2



Scheme 2.6



N N



Δ







Z



N



R1



Z



N

R2



R1



R2



Several interesting applications of the above reaction sequence are illustrated in

Scheme 2.7, including a general strategy for the synthesis of several naturally

occurring cyclopropyl containing amino acids in good to excellent yields [21].

Among these, compound 19 (R ¼ Cbz and Boc) was prepared in 100% yield and

photochemically transformed into compound 20 in quantitative yield. The latter

was used for the total synthesis of ( ) allo coronamic acid, ( ) allo norcoronamic

acid, ( ) (Z) 2,3 methanohomoserine, and ( ) (Z) 2,3 methanomethionine [22].

Similarly, the photochemical reaction of pyrazoline 21 led to the key cyclopropane

intermediate 22 for the synthesis of (Ỉ) carnosadine, a marine natural product

isolated from the red alga Grateloupia carnosa [21a]. Pyrazoline 23 led to the efficient

synthesis of methanoglutamic acid 25. Closely related examples include the

enantiospecific synthesis of several cyclopropyl phosphonate derivatives 26 used

in agricultural chemistry [23].

Other examples involving intermolecular dipolar cycloadditions include the total

synthesis of the cyclocolorene from precursor 28 [24], prostratin and DPP from 30

[25], and the marine diterpene halimedatrial from diazolactone 31 (Scheme 2.8) [26].

It is noteworthy that compound 28 was obtained by activating one of the a,b double

bonds of the otherwise fully conjugated tropone with an h4 iron tricarbonyl complex.

Two intramolecular versions of the dipolar cycloaddition, followed by photodeni

trogenation of the corresponding pyrazolines, are illustrated in Scheme 2.9. In the

formal synthesis of longifolene by Schultz and Pulg, the in situ generation of

diazoalkane 33 led to the formation of the tricyclic pyrazoline 34, which underwent



j31



j 2 Carbon Carbon Bond Formation by the Photoelimination of Small Molecules



32



O



O







NHR



N



N



O



O

NHR



100%



CO2Me



CO2Me



20



19



NH2



NH2



CO2Me



CO2Me



(-)-allo-norcoronamic acid



(-)-allo-coronamic acid

NH2



HS



NH2



MeS



CO2Me



CO2Me



(-)-(Z)-2,3-methanomethionine



(-)-(Z)-2,3-methanohomoserine



N

MeO2C



N



CO2Me

NHBz





toluene

78%



CO2Me

NHBz



MeO2C



21



BocN



N

N

O



O





Ph2CO

CH3CN

61%



23

N



p-X-C6H4



N



26







P(O)(OEt)2 Diastereospecific

(4 examples)



CO2H

NH2



NH

(±)-carnosadine



H

H



BocN



HCl



O

O



H



H

CO2H



HO2C



NH2



O



24



CO2R

H



O



H

N



H2N



22



O



O



11 steps



25



p-X-C6H4



P(O)(OEt)2

H



CO2R



R=



O

Ph



27



Scheme 2.7



nitrogen elimination to give the three membered ring in 35 [27]. The thermal

rearrangement of 35 to 36 had been formulated as the key component in their

strategy wherein an intramolecular 1,4 cycloaddition of a carbene intermediate to the

diene to yield the desired tricyclic structure. The tricyclic keto ester 36 had been

previously used as an intermediate in the total synthesis of longifolene. In the second

example, Ohfune et al. [28] reported the generation of diazoalkane 37 followed by an

intramolecular dipolar cycloaddition to yield azolactam 38, which gave the strained

cyclopropyl intermediate 39 upon photoinduced loss of N2. Compound 39 was

transformed in six steps into the desired mGluR2 antagonist ( þ ) LY354740.



2.2 Photochemical C C Bond Formation in Solution



O



H



O





N

N



7 steps



28



29



H



cyclocolorenone

RO



RO N



N





H



H



H

OH



OH



O



O



OH



O



OH



OH



R: Ac = prostratin

PhCH2CO = DPP



OH



30

O



THPO



THPO

O

H



N N



OBn



31



O

O





Ph2CO

PhCH3

-70oC



H



(+)-Halimedatrial



OBn



32



Scheme 2.8



2.2.2.2 Synthesis of Cyclobutanes and Polycyclic Compounds

In a process analogous to the C C bond formation that occurs upon ring contraction

of the five membered ring pyrazolines to the three membered ring cyclopropanes,

the photoinduced denitrogenation of tetrahydropyridazines leads to the formation of

four membered rings. As illustrated in Scheme 2.10, the reaction is most useful with

bicyclic structures such as diazabicyclo[2.2.2]octane and diazabicyclo[2.2.1]heptane.

As shown in the scheme, the corresponding azo compounds are generally prepared

from a suitable diene by a Diels Alder reaction with diethyl diazene 1,2 dicarboxylate

(step i) followed by decarboxylation (step ii) and, if desired, hydrogenation of the

remaining olefin (step iii).

The subject of significant early inquiry, the denitrogenation of cyclic alzoalkanes,

has been shown to proceed in a stepwise manner through radical intermediates with

stereospecificity and chemical yields that depend on the precursor and reaction

conditions [29]. A few representative examples in Scheme 2.11 include the synthesis

of tricyclic housane 41 [30] and ladderane 43 [31] from diazenes 40 and 42,

respectively. These compounds were obtained in about 20% yield with inversion

of configuration by direct irradiation in ether at low temperature. Notably, the more

substituted and more thermally stable tricyclic diazene 44 reacted in ether at ambient

temperature to give compound 45 with retention of configuration in essentially



j33



j 2 Carbon Carbon Bond Formation by the Photoelimination of Small Molecules



34



O CO2Me



O CO2Me





O CO2Me



C6H6

N

N



N N



33



35



34

H

O



O



heat



CO2Me



CO2Me



longifolene



36

PMB



O



PMB



N



MeO2C



N



O

N



MeO2C



PMB

H



N



heat







MeO2C



O

N

H



100%



N



N

PMB = p-methoxybenzyl

37

HO2C NH2

H

6 steps



H



38



39



H

CO2H



H

(+)-LY354740

Scheme 2.9



quantitative yield (>95%) [32]. Other interesting examples include the syn spiro

cycloheptadienyl derivative 46, which was reported to give the corresponding

housane 47 in 76% yield with retention of the diazene stereochemistry upon

irradiation in acetonitrile at 78  C [33]. The last two examples illustrate the

sensitivity of the reaction to the substrate and the need to optimize reactions

conditions. While structurally analogous, the formation of quadricyclene 49 and

prismane 51 occurs very differently. While 49 is obtained in up to 90% yield upon

direct or sensitized irradiation in ether at ambient temperature [34], the best yields

of prismane 51 were obtained when irradiations were carried out in toluene at

30  C [35].



E

n +



i), ii), iii)



N

N



N







nN



E

i) Diels Alder reaction, ii) decarboxylation, iii) hydrogenation

Scheme 2.10



n



2.2 Photochemical C C Bond Formation in Solution



N





Et2O, -20oC

20%



N

40



N

N

42





COCH3

MeCN, -78oC

N

76%

N



41



46





Et2O, -20oC

18%



Ph

N



Ph



Ether, r.t.

>95%



N



Ph



N



N

50



49







N



Ph

45



44





pentane

up to 90%



48







COCH3

47



N



43



j35



toluene

8%



51



Scheme 2.11



An application of the N2 photoelimination reaction was recently reported in the

total synthesis of (Ỉ) pentacycloanemmoxic acid (Scheme 2.12) [36]. It is interesting

that all four membered rings in the ladderane structure were obtained by photo

chemical reactions. The key diazene intermediate 52 was prepared with a protocol

analogous to that illustrated in Scheme 2.10, and led to the formation of 53 upon

irradiation in acetic acid and water. It is worth mentioning that rings 3 and 4 were

obtained by a 2p ỵ 2p cycloaddition involving cyclopentenone, while rings 1 and 2

were formed by the elimination of N2 from the diazabicyclo[2.2.2]octane 52, and

cyclobutane ring 5 was formed by a photoinduced Wolff rearrangement of a

diazoketone. As the reaction of 52 proceeded in a very low yield (6%), a subsequent

enantioselective synthesis was based on a more efficient strategy based on iterative

2p ỵ 2p cycloadditions and Wolf rearrangements [37].

N

N



1

O

O

52



2

3



h



O



O

AcOH/H2O

6%



O



4

5



7

53



OH



pentacycloanammoxic acid



Scheme 2.12



2.2.3

Photoelimination of CO from Ketones in Solution



The two steps involved in the photoinduced decarbonylation of ketones in solution

are among the most studied elementary processes in excited state and

radical chemistry. and many reviews have dealt with various aspects of the



j 2 Carbon Carbon Bond Formation by the Photoelimination of Small Molecules



36



O

R1

R2



R3



R3







R1

R2



-CO



R1

R2

R3



R1

R2

R3



+



+

R1



Diethyl ketone

Diisopropy ketone



2%

51%



Ditertbutyl ketone



>99%



R2



R1



R2

R3



Scheme 2.13



reaction [38, 39]. It is well known that the a cleavage step, or Norrish type I reaction,

takes places from both singlet and triplet n,pà excited states to give an alkyl acyl

radical pair of the corresponding multiplicity. As aliphatic ketones have a relatively

slow rate of intersystem crossing from the singlet excited state to the triplet state, a

cleavage often occurs from both singlet and triplet manifolds. As expected for

dissociative processes, the rate and efficiency of the excited state reaction and the

rate of decarbonylation from the acyl radical depend on the bond dissociation energy

of a bonds. This is nicely illustrated by examples in Scheme 2.13 [40]. An increase in

the chemical yield of photodecarbonylation products occurs with the number of a

methyl substituents as the reaction proceeds through primary (diethyl ketone),

secondary (isopropyl ketone), and tertiary (tert butyl ketone) radicals. It is interesting

to point out that the reaction of tert butyl ketone occurs with similar efficiency from

the singlet (43%) and triplet states (57%).

Synthetic applications of the reaction are somewhat limited as the highly reactive

biradicals and radical pairs tend to undergo reactions that compete with C C bond

formation. As in previous cases, the reaction may have synthetic value for the

synthesis of strained structures involving small rings. For example, the preparation of

the simplest [2] ladderane 55 by photodecarbonylation of bicyclo[3.2.0]heptan 3

one 54 gave the bicyclic structure in 5% yield with a ring opened 1,5 heptadiene

being the dominant product (Scheme 2.14) [41].

O

54





55



Scheme 2.14



Studies by Lee Ruff and coworkers indicate that the photodecarbonylation of

substituted cyclobutanones in solution has some synthetic potential in the prepa

ration of three membered rings. As indicated in the box of Scheme 2.15, the reaction

starts by formation of a 1,4 acyl alkyl biradical, which may undergo: (i) the desired

decarbonylation to give the 1,3 dialkyl analogue; (ii) a cycloelimination reaction to

give the corresponding alkene and ketene components; or (iii) form a ring expanded

oxacarbene intermediate (the latter is typically observed in polar protic media) [42].

In summary, 2 and 3 alkyl substituted cyclobutanones provide cyclopropanes in low

to moderate yields, with diastereoselectivities that are probably determined by



2.2 Photochemical C C Bond Formation in Solution



-CO

O



O





C O



+



elimination



O

oxacarbene



BzO



O



BzO





Acetone



BzO



57

(20% yield, 9% ee)



56

Me



+ 4.9% cleavage

BzO



O



Me



Bz



+

e



58

Me



Bz



one

cet



O



Bz



Bz

60 (27%)



61 (41%)



+ 4% cleavage



A



59

Me



Me



Me Me



O





+ trace of cleavage



Acetone

Bz



Me



Ac hν

eto

n



62



Bz



63 (72%)



Scheme 2.15



substituents in the configurationally uncompromised 3 position. Among several

examples studied by Lee Ruff and coworkers, it was shown that the optically pure

chiral trans 2,3 disubstituted cyclobutanone 56 reacts under triplet sensitized

irradiation in acetone to yield cyclopropane 57 in a significantly diastereospecific

manner, with a 79% enantiomeric excess (ee), but in a relative low yield (20%) [42].

While the authors preferred a mechanism that compromises the configuration of C2

at the stage of the acyl alkyl biradical, it is also possible that the observed enantios

electivity is the result of an equilibrium to give the more stable trans product

determined by the substituent at C3. The latter suggestion is supported by results

with epimeric cyclobutanones 58 and 59, which give an identical product mixture of

cyclopropanes 60 and 61 [43]. The best results in these studies were obtained with the

optically pure a,a dimethyl cyclobutanone 62, which gave exclusively cyclopropane

63 in 72% yield. It is worth noting that direct irradiation in these examples was

reported to yield primarily the cycloelimination products, which suggested that the



j37



j 2 Carbon Carbon Bond Formation by the Photoelimination of Small Molecules



38



O

O

O

(-)-64a



O

O







O



O



H+



-CO



O



O



O

O



O



65



66

O



O

O



O



CHO



O







H+



O



O -CO



CHO

OH

OH

OH

OH

D-ribose



O



O



OH

OH

D-lyxose



68



67



HO

HO



O



O

TBSO O

(+)-64b



O



O



TBSO



O

O







O

O

O



CHO

OH

OH

OH



H+



-CO



O



TBSO



HO



O



69



OH

L-talose



70



CHO

O

TBSO



O



O

O

O

O



71





-CO



O

TBSO



H+



HO

HO



O O



OH

HO



72



OH

L-gulose



Scheme 2.16



longer lived triplet acyl alkyl biradical provides an opportunity for decarbonylation to

take place. The authors also showed the a,a dichlorocyclobutanones to yield exclu

sively the elimination products [43].

An interesting set of examples illustrating the use of the reaction with substrates

possessing limited options to compromise the configuration of the ketone a centers

involves the photochemistry of ketones 65 71 (Scheme 2.16) [44]. Compounds 65



2.2 Photochemical C C Bond Formation in Solution



and 67 were prepared from the optically active a,b unsaturated ( ) 64a and com

pounds 69 and 71 from analogue ( ỵ ) 64b. All four ketones were shown to photo

decarbonylate to give their corresponding products by enantiospecific radical radical

combination reactions in reasonable to low (41% to 11%) chemical yields. The utility

of this reaction for a novel strategy for carbohydrate synthesis was nicely demon

strated with reactions leading to the synthesis of D ribose and D lyxose, as well as

L talose and L gulose.

2.2.4

Photoelimination of CO2 from Lactones



The photodecarboxylation of lactones has not been as widely used as the photo

decarbonylation of ketones [45]. In an interesting application to the synthesis of

epimaalienone 76 [46], Green et al. took advantage of an observation regarding the

direct photodecarboxylation of dihydro santonin (Scheme 2.17, 73 R ¼ H) to the

cyclopropane derivative 75 in good yield by exposure to sunlight after about 10

days [47, 48]. Epimaalienone was later used for the synthesis of a cyperone and

b cyperone, which differ only by the position of the B ring double bond. In a

subsequent example by Murai et al., epimaalienone 76 was used for the synthesis

of Aubergenone, a stress metabolite found in diseased eggplants [48].

While the reaction of 73 is stereoselective, it has been shown that the photo

decarboxylation of simple g butyrolactones gives product selectivities that depend on

the nature of the substrate. From the phenyl substituted lactones 77 80, only 79 gives

rise to phenyl cyclopropane in low yields (Scheme 2.18) [49]. Diphenyl substituted

lactones cis 80 and trans 80 give identical mixtures of cis and trans 1,2 diphenylcy

clopropane in 50 60% yield. Cyano lactone 81 was the most efficient of the set, giving

cis and trans 1 cyano 2 phenylcyclopropanes in 44% and 48% yields. The simple

trend that surfaces from this small number of examples (i.e., 73 and 77 81) is that

radical stabilizing substituents alpha to the lactone carbonyl may be important for the

reaction to take place.







R

O

O

O

73 (R=H)

74 (R=Me)



Me



O



Me

Me



75 R=H

76 R=Me, Epimaalienone



OH



76



Aubergenone

Scheme 2.17



O



γ



δ



ε

ζ



α-Cyperone (ε,ζ-ene)

β-Cyperone (γ,δ-ene)



j39



j 2 Carbon Carbon Bond Formation by the Photoelimination of Small Molecules



40



O



O

Ph



O

O



O



O

O



Ph

77



Ph



79



NC



O



Ph

78



O

O



Ph

80

(cis and trans)



Ph

81



Scheme 2.18



2.2.5

Photoelimination of Sulfur from Sulfides, Sulfoxides, and Sulfones



The formation of C C bonds by the photochemical extrusion of sulfur from cyclic

and bridged disulfides was originally suggested by Corey and Block [50]. As

illustrated in Scheme 2.19 with 1,5 cyclooctadiene 82, the formation of bridged

disulfides includes the reaction of sulfur dichloride with a nonconjugated diene to

form the bridged dihalosulfide 83, followed by reductive elimination of the halogen

substituents to form the bridged sulfide 84 [51]. The reaction is thought to proceed by

homolysis of an a bond in 84, followed by removal of the intermediate sulfur radical

by a trivalent phosphorous species such as trialkylphosphites, which are used as

solvents, with the reaction culminating with the radical radical C C bond formation

to yield 85. While yields in the original study were relatively low, they correlated with

the relative stability of the intermediate biradical or radical pair. It is, therefore, not

surprising that the reaction has been most successfully used for the synthesis of

several cyclophanes where the intermediate biradicals are benzylic. As illustrated in

Scheme 2.20, the photoelimination of S to form cylcophanes has been remarkably

robust over a wide range of structural variations.

The photochemical elimination of SO from sulfoxides was recently reviewed and

analyzed by Jenks et al. [52]. In general, the photoelimination of SO is rare, perhaps

associated to the fact that SO, like O2, has a ground state triplet. A few known

examples involving formal chelotropic reactions resulted in the formation of

conjugated systems rather than C C bond formation. While a cleavage is a relatively

.

common reaction, the cleavage of sulfinyl radicals RSO to form SO is highly

endothermic [53]. The most common process after a cleavage is bond formation

at the oxygen atom to form the corresponding sulfenates, RS OR0 . In contrast to

sulfoxides, there are several examples of photochemical SO2 elimination from

sulfones, suggesting that further analysis may be warranted. The chemical efficiency

of the photochemical reaction varies from excellent to low. As illustrated in



SCl2



S



Cl



H-



S



R3 P



Cl

82

Scheme 2.19







83



84



85

(ca. 20%)



2.3 Reactions in the Solid State



j41



S

Ar





(EtO)3P



Ar



Ar



Ar +Et3P=S



S

OMe

N



OMe



MeO



MeO



CO2Me



Br



CO2Me



OMe



MeO



MeO2C



CO2Me



Br



CO2Me



CO2Me



CO2Me



CO2Me



MeO2C



OMe



MeO



MeO



CO2Me



OMe



F



F



F



F F



F



F



F



F



F F



F



Scheme 2.20



Scheme 2.21, simple cyclic sulfones such as 86 [54] and 88 [55] give the photo

elimination and C C bond formation products 87 and 89, respectively, in yields that

vary from 88% to 95%. In contrast, when the sulfone moiety is part of a lactam (90),

the formation of b lactam 91 occurs in only 10% yield.

Another interesting example of sulfone photochemistry pertains to diyne 92,

which was investigated as an early approach for the synthesis of the highly unstable

nine membered ene diyne ring of neocarzinostatin Chrom A:1 by Wender et al. [56].

The benzophenone sensitized desulfonation of 92 resulted in the formation of the

desired, but highly unstable, compound 93 in 9 15% yield (Scheme 2.22).

2.3

Reactions in the Solid State



Many of the above described examples highlight the limitations of radical reactions in

solution. However, the potential of a highly exothermic and diffusion controlled C C



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