Electronic and Steric Control - American Chemical Society

30 Electronic and Steric Control Catalytic Intramolecular Carbon-Hydrogen Insertion Reactions of Diazo Compounds

Downloaded by CORNELL UNIV on May 18, 2017 | http://pubs.acs.org Publication Date: March 1, 1992 | doi: 10.1021/ba-1992-0230.ch030

Michael P. Doyle Department of Chemistry, Trinity University, San Antonio, T X 78212

Dirhodium(II)carboxylates and carboxamides are the most effective catalysts for intramolecular carbon-hydrogen insertion reactions that result from decomposition of diazo compounds. Cyclopentanones, β -and γ-lactams, and γ-lactones are formed from diazoketones, diazoamides, and diazoesters, respectively, in moderate to high yields and, ordinarily, with a high degree of regio- and stereocontrol. Acting as metal-stabilized carbocations, the intermediate rhodium carbenes are electrophilic reagents whose reactivities and selectivities are de pendent on the electron-withdrawing capabilities of their bridging ligands. Selectivity for C-H insertion is greatly enhanced by the use of Rh (acetamide ) , and chiral dirhodium(II) carboxamide catalysts offer great potential for highly enantioselective transformations. 2

4

R.HODIUM(II) CARBOXYLATES

are now well-known catalysts for the remote functionalization of carbon-hydrogen bonds in carbenoid reactions of diazocarbonyl compounds (eq 1, Ζ = Η or C O O R ) (J, 2).

Their advantages over the more traditional copper catalysts (3) are well documented both in the yields of products obtained from intramolecular cyclization and in the selectivity that can be achieved from these reactions. 0065-2393/92/0230-0443$06.00/0 © 1992 American Chemical Society

Moser and Slocum; Homogeneous Transition Metal Catalyzed Reactions Advances in Chemistry; American Chemical Society: Washington, DC, 1992.

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Indeed, rhodium(II) compounds have become the catalysts of choice for carbenoid reactions extending from cyclopropanation (4) and insertion reactions to ylide generation-rearrangement (5-8) or dipolar addition (9-1 J). Rhodium(II) acetate, the catalyst most often employed for carbenoid reactions, is a binuclear compound with four bridging acetate ligands and D symmetry (1, R = C H ) (12-14). 3


4h

R 1 In the absence of coordinating ligands that include nitriles, alcohols, and ketones, R h ( O A c ) possesses one vacant coordination site per metal atom. When reacting as an electrophile, it undergoes addition to the diazo carbon of the reactant diazo compound (I). With diazocarbonyl compounds such as ethyl diazoacetate, this electrophilic addition takes place near -20 °C and is the rate-limiting step. Subsequent loss of dinitrogen is presumed to result in the formation of an electrophilic metal carbene that is the active intermediate in carbenoid reactions (Scheme I). 2

4

Scheme I. Although these intermediates have not been directly observed, indirect evidence from reactivity-selectivity correlations with pentacarbonyltungsten carbenes in cyclopropanation reactions suggest their formation (15, 16). With diazo compounds ranging from phenyldiazomethane and trimethylsilyldiazomethane to diazoacetates and diazoamides, reactions with Moser and Slocum; Homogeneous Transition Metal Catalyzed Reactions Advances in Chemistry; American Chemical Society: Washington, DC, 1992.

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R h ( 0 A c ) occur at room temperature. More stable diazo compounds such as diazoacetoacetates and diazoacetoacetamides require higher temperatures for efficient catalytic dinitrogen loss and carbenoid reactions. Normally reactions are performed by controlled addition of the diazo compound to the catalyst to limit the concentration of the diazo compound and minimize carbene dimer formation (17). 2

4

Carbon-Hydrogen

Insertion Reactions

Cyclopentanones. The employment of R h ( O A c ) for intramolecular carbon-hydrogen insertion reactions with diazocarbonyl compounds evolved from the prior use of copper catalysts for these transformations (3). T h e advantages of R h ( O A c ) have been clearly evident. The conversion of isopimaridiene skeleton 2 into the 16-keto steroid 3 was achieved in 60% yield with R h ( O A c ) as the catalyst (eq 2), but poor yields of 3 were obtained when C u S 0 was used (18).


2

2

2

4

4

4

4

Similarly, only minor amounts of cyclopentanone products resulted from the CuS0 -catalyzed decomposition of l-diazo-2-octanone (4) (eq 3), where cyclohexanone formation (6) was also observed, or l-diazo-4,4-dimethyl-2pentanone (18). 4

A broad selection of a-diazo-p-ketoesters, -sulfones, and -phosphonates has been transformed in moderate to good yields to the corresponding cyclopentanone derivatives with the use of R h ( O A c ) (e.g., eqs 4-6). 2

4


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HOMOGENEOUS

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REACTIONS


Ο

11

12

Exceptional regioselectivity and diastereoselectivity were achieved (19-23). In contrast to results obtained with Rh (OAc), (eq 4), treatment of the same a-diazo^-ketoester 7 with C u S 0 produced a mixture of products with intramolecular cyclopropanation favored over carbon-hydrogen inser tion (24). 2

4

Extensive investigations of competitive intramolecular carbon-hydrogen insertion reactions (Scheme II), where the two reacting bonds are at the X.

Scheme

II.


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same formal distance from the carbenoid center, have demonstrated that reactivity decreases according to 3° C - H > 2° C - H > 1° C - H (21).


Surprisingly, in view of the electronic character of the reactant metal carbene, insertion into benzylic and allylic methylene positions was found to be disfavored relative to insertion into aliphatic methylene positions. Furthermore, in one of the most dramatic demonstrations of regiocontrol by electron-withdrawing groups, Stork and Nakatani (25) found that an ester substituent deactivated both a- and β-methylene groups toward C - H in sertion (eqs 7 and 8).

Thus, even when this intramolecular pathway is the only one possible, only carbene dimer formation is realized (25). Electronic preferences appear to control regioselectivity but, as will be seen (vide infra), conformational control of reaction selectivity provides a rational explanation for these results. Despite the apparent overwhelming preference for cyclopentanone for mation in Rh (OAc) -catalyzed C - H insertion reactions of diazo carbonyl compounds, isolated examples of preferential β- and δ - C - H insertion re actions have been reported. Whereas 17 produced both 18 and 19 in a 1.5:1.0 ratio (eq 9), only 21 was produced from the structurally similar, but more highly substituted, 20 (eq 10) (26). 2

4

Similarly, the δ-lactone 23 was the only insertion product isolated from the Rh (OAc) -catalyzed decomposition of 22 (eq 11) (26). 2

4


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TRANSITION

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REACTIONS

Rh (OAc) 83%~* 2

COOC H 2

4w

s

17

COOC,H.

(9)


COOCjH

s

18

19

Rh (OAc) ^

0

2

4

55%

OOC H 2

5

CH ι

"

3

COOC H 2

(10)

5

H c \ * ^ or only 3

21 Rh (OAc) ^ g

4

Freon 46%

22

TF

>cpo

(11)

23

These examples suggest that subtle changes in reactant structure can have an enormous influence on reaction regioselectivity and that electronic preferences alone cannot explain the selectivity for carbon-hydrogen inser tion in Rh (OAc) -eatalyzed reactions. 2

4

Lactams. Ponsford and Southgate (27) were the first to report that R h ( O A c ) was an effective catalyst for intramolecular carbon-hydrogen in2

4


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sertion reactions. Diazoacetoacetamide 24 underwent Rh (OAc) -catalyzed 2

4

decomposition at room temperature to yield β-lactam 25 in 75% yield (eq 12).


COCH 24

Ο

3

25

With C u in toluene at 90 ° C , 25 was formed in only 25% yield. Similar results were obtained with other 1,3-oxazines (28, 29) but the generality of this methodology for the synthesis of β-lactams awaited reports by Doyle and co-workers (30, 31). Treatment of a series of IV-benzyl-N-ter£-butyldiazoacetoacetamides 26 (R = C H C O ) with R h ( O A c ) (1.0 mol %) in refluxing 3

2

4

benzene resulted in the exclusive production of trans-disubstituted β-lac tams 27 in nearly quantitative yields (eq 13).

Ο

27 28 ( %)

27 (%)

26

99

S = 3,4-di-OCH m-OCHi H

89

m-Br

92

P-NO2

92

94 93

—

3

95 90 98

N O T E : — means this experiment was not performed.


450

HOMOGENEOUS

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In contrast, the N-benzyl-N-ferr-butyldiazoacetamides 26 (R = H) underwent exclusive carbene addition to the aromatic ring (28) when treated with a catalytic amount of R h ( O A c ) in dichloromethane at room temper ature (32). The acetyl group of the diazo carbon obviously inhibits carbenoid addition to the electron-rich aromatic ring, even when substituted with two methoxy groups to enhance its nucleophilic reactivity. 2

4

The influence of the iV-tert-butyl group is seen from results obtained with diazoacetoacetamides having smaller N-alkyl substituents. When the fert-butyl group of 26 (R = C H C O ) is replaced by isopropyl, only 60% of the reaction products result from insertion into the benzylic position. The remaining 40% arise from insertion into the methine hydrogen of the iso propyl substituent. With ethyl as the N-alkyl substituent, only 17% of the reaction products result from insertion into the benzylic position. The re mainder are due to insertion into the ethyl group: 60% into the primary methyl group to form the corresponding y-lactam and 23% into the secondary methylene group.


3

The selectivity observed in these reactions does not appear to be a function of electronic influences by substituents on the reacting C - H bond, as was reported by Taber and Ruckle (21) for cyclopentanone formation by carbon-hydrogen insertion. Rather, these results can be explained by in sertion into a C - H bond that is held in close proximity to the carbenoid center (29).

29 Overlap of the nitrogen nonbonded electrons with the carbonyl π-system fixes the amide conformation so that the larger nitrogen substituent is ori ented toward the carbonyl group. Steric effects by the carbenoid substituents on benzylic substituents force the aryl group away from the acetyl group and coordinated metal and place the benzylic hydrogens within the reactive environment of the carbenoid center. Consistent with this interpretation, decomposition of 30 in refluxing benzene, catalyzed by R h ( O A c ) , forms βlactam 31, solely as the trans isomer, in 96% isolated yield (eq 14) (31). 2

4

Ο

30

31


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In addition, in the most convincing demonstration of conformational preferences in carbenoid insertion reactions, diazoacetoacetamide 32 under goes high-yield conversion (89%) to the cis-disubstituted β-laetam 33 in rhodium(II)-perfluorobutyrate-catalyzed

reactions

performed in refluxing

dichloromethane (eq 15) (31). If electronic factors controlled carbenoid C - H insertion reactions, these results would not have been anticipated on the basis of conclusions drawn from eqs 7 and 8.

Ο ,C(CH ) Downloaded by CORNELL UNIV on May 18, 2017 | http://pubs.acs.org Publication Date: March 1, 1992 | doi: 10.1021/ba-1992-0230.ch030

3 3

N,

k

4T

Rh (pfb) 2

4

CH CI 2

(15) 2

COOEt

EtOOC'

\

C

(

CH )3 3

33

32

What, then, is the cause of the apparent difference between the regiocontrol observed for β-lactam formation and that for cyclopentanone formation? We believe that the metal carbenes derived from reactions of rhodium(II)

carboxylates

and diazo compounds

should be viewed as

metal-stabilized carbocations (34a), with their inherent stability arising from electron donation through the dirhodium framework (34b).

R

R

R 34a

R 34b

Carbon-hydrogen insertion occurs by interaction of the p-orbital on the carbenic carbon with the σ - C - H bond. It results in bond formation between the carbene carbon and both carbon and hydrogen of the reacting car bon-hydrogen bond (Scheme III). As this bond formation progresses,

the metal bound to the carbene

carbon dissociates and product formation is realized. T h e mechanistic de piction in Scheme III also accounts for the diastereoselectivity that is ob served in these reactions. Steric interactions between R and C O O R ' desta bilize the conformation in which the R group is in the axial position. T h e exception appears to be the formation of the cis-disubstituted β-lactam in eq 15. However, in this case the C - H insertion that would have resulted


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HOMOGENEOUS

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R'OOC

O;

σ

H

Rh 36

35


Scheme HI. in the fnws-disubstituted β-lactam would have had to occur from a confor mation in which the carboxylate group was juxtaposed against the catalyst face. Steric and stereoelectronic factors disfavor this conformation. The cause of the apparent electronic destabilization by ester functional groups on β - C - H insertion that was reported by Stork and Nakatani (25) is probably due to repulsion of the carboxylate by the bridging ligands of the dirhodium catalyst (35). A similar explanation can be made for the apparent lower reactivity of benzylic methylene C - H bonds described by Taber and Ruckle (21). The influence of catalyst structure on selectivity is minimized too often in mechanistic considerations of catalytic reactions. However, in sertion into a C - H bond α to a carboxylate group is certainly subject to electronic destabilization of the transition state leading to products. Simi larly, insertion into a C - H bond α to nitrogen is subject to electronic sta bilization of this state. Application of this methodology to other aliphatic systems in which both β- and y - C - H insertion are possible demonstrates its broad applicability for the construction of β-lactams. Rhodium(II)-acetate-catalyzed decomposition of the diazoacetoacetamides derived from diisopropylamine, dicyclohexylamine, and irano-2,6-dimethylpiperidine in benzene formed the corresponding β-lactam products 37-39 exclusively and in high yield: 37 (89%), 38 (100%), and 39 (90%, isomer ratio = 1.4) (30).

The corresponding diazoacetamides also formed β-lactam products but, in these systems, competition between β - C - H and y - C - H insertion occurred to a limited extent (30). Moser and Slocum; Homogeneous Transition Metal Catalyzed Reactions Advances in Chemistry; American Chemical Society: Washington, DC, 1992.

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As is implied from consideration of the metal-stabilized carbocation (34) hypothesis for carbene reactivity, significant manipulation of product dis tributions in catalytic transformations of diazoamides could be achieved by changing the catalyst from the indiscriminate Rh (pfb) (33, 34) through R h ( O A c ) to the electronically selective Rh (acam) (pfb is perfluorobutyrate, and acam is acetamide) (4, 34). 2


2

4

2

4

4

For example, decomposition of iV-tert-butyl-N-(2-phenylethyl)diazoacetoacetamide (40, R = C O C H ) yields both β-lactam and y-lactam products (Scheme IV). 3

Each product is formed exclusively as the trans diastereoisomer, and they are formed in approximately equal amounts, with R h ( O A c ) as the catalyst. However, use of Rh (pfb) favors the β-lactam product, and Rh (acam) favors formation of y-lactam. The corresponding diazoacetamide (40, R = H) produces products from both y - C - H insertion (43) and aromatic addition (44) upon catalytic decomposition. Effective control of product se lectivity is achieved with the use of Rh (pfb) and Rh (acam) . In all cases product yields are greater than 90%. Similarly, decomposition of N-n-butylN-terf-butyldiazoaeetoacetamide (45, R = C O C H ) with these catalysts ex hibits a significant catalyst-ligand-dependent variation in the relative yields for formation of β-lactam and y-lactam products (Scheme V). 2

2

2

4

4

4

2

4

2

4

3

However, the corresponding diazoacetamide (45, R = H) formed the y-lactam 48 with only minor amounts (2-7%) of β-lactam product, using the same set of rhodium(II) catalysts. Relative to R h ( O A c ) , the metal carbene derived from Rh (acam) is projected to be more stable and, consequently, more susceptible to product development control in intramolecular reactions. In contrast, the metal car bene derived from Rh (pfb) is less stable and more electrophilic. Therefore, it is more reactive toward electron-rich substituents, as in the formation of 44, and less discriminate. The conditions that favor y-lactam formation—use of diazoace tam ides rather than diazoacetoacetamides, the absence of an electron-withdrawing group at the site of insertion, and use of the less electrophilic Rh (acam) — signify the importance of stereoelectronic considerations in predicting the outcome of these C - H insertion reactions. β - L a c t a m formation is not the preferred pathway for the catalytic decomposition of diazoamides. When there is a competitive choice between β-lactam and y-lactam production, as with 45, the y-lactam predominates. The reason that Rh (pfb) enhances β2

4

2

2

4

4

2

2

4


4

HOMOGENEOUS

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Electronic and Steric Control - American Chemical Society

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