Allenes as building blocks in heterocyclic chemistry - Springer Link

Monatsh Chem (2011) 142:681–697 DOI 10.1007/s00706-011-0505-7

REVIEW

Allenes as building blocks in heterocyclic chemistry Teresa M. V. D. Pinho e Melo

Received: 10 September 2010 / Accepted: 11 April 2011 / Published online: 10 May 2011 Ó Springer-Verlag 2011

Abstract Allenes have a unique structural feature characterized by having two cumulated double bonds. The inherent instability associated with these 1,2-dienes has been widely exploited for various synthetic purposes. Allenes have thus become important and versatile building blocks in organic chemistry. In this paper some illustrative examples of the chemistry of these building blocks in the synthesis of heterocyclic compounds are presented. Keywords Allenes Heterocyclic compounds Wittig reaction Aza-Baylis–Hillman reaction [3 ? 2] Cycloaddition

Introduction For a long time allenes were regarded as chemical curiosities because the presence of two cumulated double bonds was predicted to lead to very unstable systems [1]. Nevertheless, in 1874–1875 Van’t Hoff [2] proposed the correct structure of allenes and in 1887 Burton and von Pechmann reported the first synthesis of an allene [3]. However, only when IR and Raman spectroscopy became available as a structural assignment tool was it possible to prove the structure of allenic molecules by their characteristic allenic C–C vibration at about 1,950 cm-1 [4].

T. M. V. D. Pinho e Melo (&) Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal e-mail: [email protected]

The discovery of a significant number of natural compounds that incorporate allenic structures raised the interest in this class of molecules. Illustrative examples are the insect pheromone 1 isolated from male dried bean beetles which represents an interesting allenic target molecule for crop protection [5], the allenic alkaloids 2 and 3 isolated from the skin of the poison-dart frog [6], and panacene (4), a metabolite of the sea hare Aplysia brasiliana which acts as a fish antifeedent [7] (Fig. 1). Several of these natural products show interesting biological activities. Nowadays, an approach to ‘‘tune’’ the biological and pharmacological properties of biologically active compounds is to introduce an allenic moiety into the existing backbone of the molecule. Therefore, the development of synthetic methodologies to obtain allenes is in itself an interesting research goal. There are two interesting aspects of the reactivity of allenes which make them very versatile building blocks in organic chemistry. One is the inherent instability associated with the cumulated double bonds, which makes addition to allenes very favorable, because it involves the relief of strain. The second aspect is the possibility of exploring the selective transfer of the axial chirality of an optically active allene to central chirality as a route to chiral compounds. The chemistry of these interesting molecules has been one of our topics of research. We developed an asymmetric Wittig reaction that allows the synthesis of allenic esters with axial chirality [8]. This drove us to explore the reactivity of 2,3-butadienoates and in this paper some illustrative examples of the chemistry of these building blocks in the synthesis of heterocyclic compounds will be presented as well as some aspects of the background of the project, which included the synthesis of 2-halo-2Hazirines and 4-halo-1,3-oxazoles via a non-classical Wittig reaction.

123

682

T. M. V. D. Pinho e Melo

CO2Me

n-C8H17 •

H

•

N H

H 1

2

H

O

H H •

HO HN O 3

•

Br H

H 4

Fig. 1 Examples of natural compounds incorporating allenic structures

A non-classical Wittig reaction in the synthesis of 2-halo-2H-azirines and 4-halo-1,3-oxazoles Synthesis of tetrasubstituted alkenes via a non-classical Wittig reaction We have been interested in exploring the reactivity of phosphorus ylides, namely their use in a non-classical Wittig reaction which offers a route to tetrasubstituted alkenes. We observed that a-oxophosphorus ylides 5 react with chlorine, bromine, and electrophilic halogen-donor reagents in the presence of a range of nucleophiles to give tetrasubstituted alkenes with elimination of triphenylphosphine oxide. Several of these reactions are highly stereoselective, whereas others give both (E)- and (Z)-isomers. It was postulated that isomeric halonium ions were intermediates in the formation of the observed products. These halonium ions can interconvert via an acyclic cation 6. The opening of the two halonium ions by a nucleophile leads to the isomeric alkenes after the elimination of triphenylphosphine oxide (Scheme 1) [9].

Two selected examples in which the alkenes are obtained stereoselectively are presented in Scheme 1. Ylide 5a reacts with chlorine in the presence of potassium acetate to give, after 5 min, the diester 9 in 61% yield. Reaction of ylide 5a with hypobromous acid and acetic acid gives, after 24 h, a single crystalline product in high yield (98%). This was identified as the vinyl acetate 10 and its stereochemistry was established as (Z) by an X-ray crystal structure determination [9]. The formation of a halophosphonium salt as an intermediate is in agreement with the known halogenation of aoxophosphorus ylides, which gives the corresponding halophosphonium salt 11 (Scheme 2) [10]. On the other hand, one example is known of an intramolecular nonclassical Wittig reaction of the type described above. The reaction of a-oxophosphorus ylides bearing a terminal carboxylic acid group acting as the nucleophile with halogenating agents leads to the formation of (E)- and (Z)-halo enol lactones [11, 12]. The cyclization is also thought to proceed via a halophosphonium salt followed by loss of triphenylphosphine oxide. Scheme 2 illustrates one case in which it is possible to isolate the bromophosphonium salt 13 in the reaction of ylide 12 with bromine at 0 °C. Treatment of 13 with triethylamine gives the corresponding bromo enol lactone 14 [12]. Synthesis of 2-halo-2H-azirines from phosphorus ylides Of particular interest in this methodology for the synthesis of tetrasubstituted alkenes is the possibility of preparing haloazidoalkenes from the reaction of phosphorus ylides with N-halosuccinimide in the presence of azidotrimethylsilane because these compounds are potential precursors of 2-halo-2H-azirines. Haloazidoalkenes 15 prepared from phosphorus ylides 5 can be easily converted into the corresponding 2-halo-2H-azirines 16 [13, 14] (Scheme 3). The

Scheme 1

O R2

R1

5

PPh3 XY Y

X - OPPh3

R1

R2

Y

O X R1

X

O

R2 PPh3

R1

R1 X O

R1

- OPPh3 R2 Y PPh3

OAc

EtO2C

CO2Et 10

HOBr/HOAc - Ph3PO 98%

O

EtO

OEt O

R2 8

O Br

X

Y

6

7

123

R2 PPh3

PPh3 5a

1. Cl2/CHCl3 2. KOAc/H2O

- Ph3PO 61%

Cl

Cl

EtO2C

CO2Et 9

Allenes as building blocks

683

Scheme 2

H Ph3P=CHCOR

X2

Ph3P - C - COR X

- 70 °C

CO2Et HO2C

PPh3 O

Br2

R2

R1

PPh3 5

0 °C

O

R1(N

O

O

13

3)C

N3

C(X)R2

CO2Et

14

X

MeO2C

15

- N2

N

COPh

MeO2C

X

O

N

COPh 16

X

18a X = Br 18b X = Cl

N X R2

Ph

MeO2C

17a X = Br 17b X = Cl

Heptane, reflux 2-3 h

N

X = Cl, Br X=I

Br

NEt3

O

NCS, NBS or NIS TMSN3 DCM, rt 37-98%

R1 = R2 = CO2Et R1 = Ph; R2 = CO2Et R1 = Ph; R2 = CO2Me R1 = R2 = CO2Me R1 = CO2Me; R2 = COPh R1 = Me; R2 = CO2Me R1

CO2Et Br PPh3 Br

HO2C

12

O

11

X

Ph X

MeO2C

19a X = Br 19b X = Cl

20a X = Br 20b X = Cl

89-99% 36-85%

Scheme 3

N Ph

reaction of these ylides with N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS) is complete after 5 min. However, the reaction with N-iodosuccinimide (NIS) requires the use of excess halogenating agent and is only complete after 4.5 h. The majority of these reactions show high stereoselectivity, leading to the synthesis of alkenes as single isomers. The alkenes are converted into the corresponding 2-halo-2H-azirines upon heating in heptane for 2–3 h. 2-Chloro- and 2-bromo-2H-azirines are obtained in high yield (89–99%), whereas the yields obtained for the 2-iodo-2H-azirine derivatives range from 36 to 85%. 2-Chloro- and 2-bromo-2H-azirines with electron-withdrawing groups at C-3 decompose in the condensed phase within 2–3 days at room temperature (rt), whereas azirines with a phenyl or methyl group at C-3 showed higher stability. The 2-iodo-2H-azirines show lower stability than the corresponding chloro and bromo derivatives. The study of the reactivity and chemical behavior of these three-membered ring heterocycles has shown their usefulness as building blocks in organic synthesis [15–23]. Synthesis of 4-halo-1,3-oxazoles from phosphorus ylides In this context, we reported the thermolysis of 2-halo-2benzoyl-2H-azirines [22]. 2-Benzoyl-2-halo-2H-azirine-3-

COR 21a R = H 21b R = Ph

nonhydroxylic solvents Δ

N

O

R

Ph 22a R = H 80% 22b R = Ph 30%

Scheme 4

carboxylates 19 underwent ring expansion to give products in high yield which were identified as 4-haloisoxazoles 20. The same products were also obtained in high yield from the thermolysis of haloazidoalkenes 17 via intermediate 2-benzoyl-2-halo-2H-azirines 19. The thermolysis of 2H-azirines usually results in cleavage of the N–C2 single bond to give a transient vinylnitrene, the reverse of the cyclization of vinylnitrenes used to prepare 2H-azirines. Evidence for the existence of this intermediate comes from the thermal ring opening of 2,3-diaryl-2-cyano-2H-azirine in which the vinylnitrene was trapped with phosphanes [24]. On the other hand, it was known that heating a solution of 3-phenyl-2H-azirine2-carboxaldehyde (21a) at 200 °C leads to 3-phenylisoxazole (22a) in high yield [25]. The same isoxazole can also be obtained in 90% yield by treatment of 3-phenyl-2Hazirine-2-carboxaldehyde at 25 °C with Grubbs’ catalyst [26]. Furthermore, 2-benzoyl-3-phenyl-2H-azirine (21b) affords the corresponding isoxazole 22b upon heating in nonhydroxylic solvents (Scheme 4) [27]. These observations led us to rationalize the thermal

123

684


reaction of 2-benzoyl-2-halo-2H-azirine-3-carboxylates 19 as being the conversion into isoxazoles 20 via vinyl nitrenes 18. Matrix isolation infrared spectroscopy was used to carry out the structural and vibrational characterization of the chloro compound obtained from the thermolysis of 2H-azirine 17b [23]. This study was supported by theoretical calculations undertaken at the DFT(B3LYP)/6-311 ??G(d,p) level of theory. However, the theoretically predicted spectrum for isoxazole 20b did not match the experimental IR spectrum. Indeed, it was demonstrated that the studied compound could not be isoxazole 20b but instead the compound was the isomeric methyl 4-chloro-5-phenyl-1,3-oxazole-2-carboxylate (24). The formation of oxazole 24 from 2H-azirine 19b can be explained by considering the thermal cleavage of the C2–C3 bond to give nitrile ylide 23 followed by recyclization to give the final product. Because the oxazole is obtained in high yield (98%) we can conclude that only the reaction pathway B is observed (Scheme 5). 4-Chloro-5-phenylisoxazole-3-carboxylate 20b was also synthesized by an unambiguous route [28] and studied by matrix-isolation FTIR. It was clear from the analysis of the matrix-isolated FTIR spectra of 4-chloro-5-phenyl-1,3oxazole-2-carboxylate 24 and methyl 4-chloro-5-phenylisoxazole-3-carboxylate 20b that this technique allows one to distinguish these isomeric heterocycles easily. Therefore, it was demonstrated that methyl 2-benzoyl-2-halo2H-azirine-3-carboxylates 19 undergo thermal ring expansion to give 4-halo-5-phenyl-1,3-oxazole-2-carboxylates 24 in high yield, products which can also be obtained in high yield from haloazidoalkenes 17 (Scheme 6).

O

Ph

N A Δ

MeO2C

Cl

N

O

Ph Cl

MeO2C 20b

N

Δ - N2

COPh

MeO2C 19b

Cl

123

MeO2C

N

CO2Me

COPh

Cl N

Ph O 23

Scheme 5

Cl

17b

Cl Δ B

N3

Ph

O 24

CO2Me

X

Toluene Δ, 5h

Ph

96-97%

Toluene Δ, 7h

N O

CO2Me

95-98%

24 N MeO2C

N3

COPh X

X = Br or Cl

X

MeO2C

19

COPh 17

Scheme 6

Synthesis of chiral allenic esters via Wittig or Horner–Wadsworth–Emmons reactions Allenes can be obtained by various synthetic methods, but the use of the Wittig reaction or the Horner–Wadsworth– Emmons (HWE) reaction is of particular interest because they allow regio- and stereocontrol of the carbon–carbon double bond formation. Most of the known methods for optically active allenic compounds are based on the isomerization of propargylic derivatives bearing a stereogenic center. Little attention has been paid to the synthesis of chiral allenes through asymmetric Wittig-type reactions [29]. However, To¨mo¨sko¨zi and Bestmann have reported reactions between phosphorus ylides containing chiral alcohol units and acid chlorides in the presence of NEt3 to afford chiral allenes, although neither the absolute configurations of the products nor the levels of asymmetric induction were determined [30]. Optically active 4,4-disubstituted allenecarboxylates have been prepared by treatment of ketenes generated in situ from phenyl acetates with chiral HWE reagents (Scheme 7) [31, 32]. Enantiomeric excesses up to 84% were obtained by Fuji et al. using HWE reagents of the type shown in Scheme 7. In this study 2,6-di-tert-butyl-4methylphenyl esters (e.g., 26) were used as precursors of the ketenes. This methodology involves difficulties such as low yields in the preparation of the starting materials probably as a result of the bulkiness of the butylated hydroxytoluene group. However, a procedure for the synthesis of chiral allenecarboxylates from simpler phenyl esters has also been reported [32]. Our interest in exploring the Wittig reaction for different purposes led us to study the reactivity of phosphorus ylide 30 bearing a chiral auxiliary to promote the synthesis of allenes in a selective fashion [8] (Scheme 8). Thus, ketenes have been generated in situ from the corresponding acid chloride in the presence of triethylamine and reacted with phosphorus ylide 30 to give allenes 31 in good yields. In some cases ylides 34, the result of the acylation of 30, were also formed as minor products. Only one stereoisomer was obtained in each case and even in the Wittig reaction with ketenes having a bulky substituent such as the t-butyl group


685

Scheme 7 1) n-BuLi, ZnCl2 2) (S )-25, KHMDS

CO2

Me

H

O O P CO2Me O

26

1) LDA, ZnCl2 2) (S )-25, LDA

R1 CO2

R2

O R

Cl NEt3

O

SO2Ph

30

a R=H b R = Me c R = Et d R = i-Pr e R = t-Bu f R = Bn

H R

H O

•

O

SO2Ph

31 63-77%

O PPh3 O

R

Cl NEt3

SO2Ph O

H O SO2Ph O

33 56-86%

O O 34

H CO2Me

29 21-71% (23-89% ee)

enantioselective preparation of allenic esters via a Wittig reaction with ketenes generated in situ. The absolute configuration of the major product was assigned as (S). On the basis of the dipole–dipole interaction model developed by Aggarwal et al. to account for the selectivity of the reaction of stabilized phosphorus ylides with aldehydes [35, 36], the authors were able to explain the observed stereoselectivity. They proposed that the reaction proceeds via [2p ? 2p] cycloaddition to afford an oxaphosphetane, which is converted into the corresponding phosphine oxide and chiral allene. The ketene approaches the Re face of the ylide preferentially as a result of the steric hindrance between the substituents of the ketene and the ylide (Scheme 9).

PPh3

PPh3 O

H R

32

R

•

R1 •

28

PPh3 O

27 74% (84% ee)

25

Me

R2

CO2Me •

O SO2Ph

SO2Ph O

R

Reactivity of allenic esters

O

35

Scheme 8

the selective synthesis of the corresponding allene was observed. The stereochemical outcome of this asymmetric Wittig-type reaction can be explained by the assumption that the presence of the chiral 10-(phenylsulfonyl)isoborneol unit in the starting phosphorus ylide determines the geometry of approach of the ketene, thus allowing for asymmetric induction. The (S)-configuration was assigned to allenes 31 based on X-ray crystallographic studies. It was also established that the use of a phosphorus ylide 32 bearing a chiral auxiliary enantiomeric to the isoborneol unit of phosphorus ylide 30 allows the selective synthesis of allenes with (R)-configuration. Chiro-optical studies of the allenic esters were carried out, confirming that two sets of enantiomeric derivatives were obtained [8]. More recently, Tang et al. reported a chiral ylide-mediated synthesis of optically active allenes [33, 34]. Pseudo-C2-symmetric chiral ylides were used for the

Diastereoselective aza-Baylis–Hillman reactions: synthesis of chiral a-allenylamines and 2-azetines from allenic esters It has been demonstrated that allenes 31 and 33 are interesting building blocks for carrying out stereoselective synthetic procedures. These chiral allenoates have been used in the synthesis of chiral functionalized b-amino esters via hydride reductive amination [37, 38]. On the other hand, inverse conjugate addition of carbonucleophiles to allenic esters allows the stereoselective formation of tertiary and quaternary carbon centers [39]. Allenes 31

Ph O R O

H

Ph P Ph

36a R = Et 36b R = t-Bu

Br

1. NaHMDS, 25 °C, THF R1 2. • O , - 78 °C R2

R1 •

RO2C

R2

37 Yield 46-80% ee 55-92%

Scheme 9

123

686


•

CO2Et

DABCO

NHTs •

Ph

NTs 38

The formation of these products can be explained as outlined in Scheme 11 [41, 42]. Nucleophilic addition of DABCO to the 2,3-allenoate produces 42, which adds to the imine to give 43. This intermediate undergoes intramolecular nucleophilic attack to give a cyclic zwitterionic intermediate 44 followed by the elimination of DABCO to afford the 2-methyleneazitidine 40. Alternatively, zwitterionic intermediate 43 can undergo proton transfer and subsequent elimination of the base to afford the a-allenylamine 41. One report on the asymmetric version of the aza-Baylis– Hillman reaction of allenes with imines is known [43]. The authors demonstrated that Boc-L-3-Pal-D-Pro-Aib-L-PheNMe2 (48) acts as a chiral catalyst in the reaction of benzyl allenoate (46) with N-benzoylimines 47 to afford a-allenylamines 49 in high yield and enantiomeric excess (ee) (Scheme 12). Studies aiming to develop asymmetric versions of the DABCO-catalyzed reaction of allenes with imines as a route to new optically active nitrogen four-membered heterocycles have also been reported [40]. The reaction of benzyl buta-2,3-dienoate (46) with a range of N-arylidenebenzenesulfonamides allowed one to confirm that the main pathway for these condensations is the formal [2 ? 2] cycloaddition leading to 2-methyleneazetidines 50 (Scheme 13). The reaction can also be carried out under microwave irradiation with a very short reaction time (100 °C, 5 min). In two cases a simultaneous formation of 2-azetine derivatives 51 was detected and these fourmembered ring heterocycles isolated. Optically active allenes 31a and 33a react with imine 52 to afford chiral 2-azetine derivatives and chiral a-allenylamines (Scheme 14). The DABCO-catalyzed reaction of allene 31a at room temperature for 1 h gave azetine 54 as the major product (45%), together with the formation of chiral a-allenylamine 53 (8%). Interestingly, by lowering the temperature to -20 °C, the chiral a-allenylamine 53 was isolated as the major product in 52% yield. The structure of this allene was determined by X-ray crystallography, allowing the assignment of the stereochemistry of the new chiral center. The reaction carried out with the

Ph

CO2Et

N Ts

Ph 39

CO2Et 41

40 r.t., 5 h MS 4A, r.t., 1 h

57% 82%

43% ---

Scheme 10

NTs

O •

OEt

CO2Et

NR3

NTs

Ph

Ph

CO2Et

NR3

NR3

42 Ph

43

NHTs NHTs

Ph

•

CO2Et

EtO2C

CO2Et

- NR3

Ph NR3

41

N NR3 Ts

45

44

- NR3

NR3 =

N N

CO2Et Ph N Ts 40

Scheme 11

and 33 also participate in diastereoselective aza-Baylis– Hillman-type reactions leading to chiral a-allenylamines and 2-azetines [40]. It is known that allenoates act as the Michael acceptor in aza-Baylis–Hillman-type reactions to give functionalized allenes, but they can also lead to 2-methyleneazetidines. The 1,4-diazabicyclo[2.2.2]octane (DABCO)-catalyzed reaction of allenoate 38 with imine 39 in the presence of molecular sieves affords the corresponding azetidine 40 as the only product, whereas in the absence of molecular sieves the azetidine 40 and a-allenylamine 41 were obtained (Scheme 10) [41, 42]. Scheme 12

O Me Me N H

N N O • 46

CO2Bn

Ph

Boc

Ar

Ar = Ph; 2-MeOC6H4; 4-BrC6H4; 4-CF3C6H4; 1-Np

123

Ph

HN

O

N 47

O

O

NH 48 (10 mol%) Toluene, 23 °C 16-24 h 45-88% 69-84% ee

O Me N Me

HN

Ph CO 2Bn

Ar •

49


687

Scheme 13

NR

• 46

Ar CO 2Bn DABCO (20 mol%) Toluene, rt 22-67% Ar

CO2Bn CH3

Ar = Ph or C6H4NO2-p 51 0-8.5%

Scheme 14

DABCO (20 mol%) Toluene

•

O O

31a

N R 50a Ar = Ph; R = SO2Ph 50b Ar = Ph; R = Ts 50c Ar = p-NO2C6H4; R = SO2Ph 50d Ar = p-MeOC6H4; R = SO2Ph 50e Ar = o,p-(NO2)2C6H3; R = SO2Ph

N PhO 2S

CO 2Bn Ar

PhO 2SHN Ph •

NSO2Ph SO 2Ph

Ph 52

CO 2R1 53

MS 4A, rt, 1 h MS 4A, - 20 °C, 24 h

O SO2Ph O

• 33a

DABCO (20 mol%) Toluene NSO2Ph Ph 52

MS 4A, rt, 1 h MS 4A, - 20 °C, 24 h

R1 =

25 [α] D

= + 33

CO 2R1

Ph N PhO2S 54

CH3

25 [α]D =

8% 52%

45% 9%

NHSO2Ph Ph

R2O2C

Ph

• R2O 2C 55

25 [α] D

+ 40

N H3C

= - 33

56

4% 46%

SO2Ph

25 [α] D

= - 40

55% 12%

R2 = SO 2Ph

enantiomeric allene 33a led to similar results. Notice that 2-azetines 54 and 56 show identical NMR spectra and values for the optical rotation with opposite sign indicating that they are enantiomers. The same can be said about the two a-allenylamines. Thus, starting from (-)-(1R)-10phenylsulfonylisobornyl buta-2,3-dienoate products with (S)-configuration are obtained, whereas the reaction with (?)-(1S)-10-phenylsulfonylisobornyl buta-2,3-dienoate leads to products with (R)-configuration. The formation of the 2-azetines can be explained as outlined in Scheme 15. Nucleophilic addition of DABCO to the 2,3-allenoate produces zwitterionic intermediates 57, which react with the imine to give 58, followed by proton transfer. Intermediate 59 undergoes a proton transfer process to afford the nitrogen anion 60. Cyclization of 60 via an intramolecular conjugate addition leads to another zwitterionic intermediate 61. Elimination of DABCO

SO2 Ph

produces the final product 62. The synthesis of these 2-azetines as single stereoisomers is explained by the selective addition of the imine to 57 leading to intermediate 58. [3 ? 2] Annulations and allenoate-Claisen rearrangement The addition of nucleophiles to electron-deficient allenes occurs at the electrophilic a,b-carbon–carbon double bond to give Michael-type adducts [44–46]. However, reactivity inversion (umpolung) can be achieved. Cristau et al. observed that in the presence of phosphines the addition takes place at the b,c-carbon–carbon double bond [47]. They found that the reaction of methyl 2,3-butadienoate (63) with triphenylphosphine followed by the addition of NaI afforded a phosphonium iodide 64, which allows the

123

688


Scheme 15

NSO2Ph

O •

OR*

CO2R*

NR3

NSO2Ph Ph

Ph

CO 2R*

NR3

NR3

57 Ph

NHSO2Ph

PhO2SN

Ph

CO2R*

CO2R*

NR3

NR3

CO2R*

Ph

N Ph O2S

Ph

NR3

Scheme 16

N 62

CO2Me 63

nucleophilic attack at the c-carbon leading to the synthesis of 4-substituted-but-2-enoate 65 (Scheme 16). Lu et al. explored the reactivity of the intermediates generated from butadienoates and phosphines as the threecarbon synthon in [3 ? 2] annulation reactions. They reported that the reaction with electron-deficient alkenes [48] and N-tosylimines [49, 50] leads to the formation of five-membered formal [3 ? 2] cycloadducts. In the presence of a catalytic amount of phosphine ethyl butadienoate (38) reacts with electron-deficient alkenes to afford a regioisomeric mixture of cyclopentenes [48]. Thus, the 1,3-dipole 69 generated from the allenic ester and phosphine reacts with the alkene to form a cyclic intermediate 70, which is in equilibrium with 71 via hydrogen shift. Elimination of phosphine affords the corresponding cycloadduct (Scheme 17). The reaction of diethyl fumarate and diethyl maleate with ethyl butadienoate led to trans-74 and cis-74 as single products (Scheme 18). On the other hand, Lu et al. reported that 3-pyrrolines are obtained regioselectively and in high yield from the reaction of methyl butadienoate with aromatic N-tosylimines in the presence of triphenylphosphine [49, 50]. The reaction is also triggered by the triphenylphosphine attack to the b-carbon of the allene to give dipolar intermediate 77, which reacts with the imine to form an open-chain intermediate 78.

NR3

59

Ph O2S

1. PPh3, H2SO4 2. NaI, H2O

•

CO2R*

CO2R*

- NR3

61

123

NHSO2Ph

Ph

60

58

PPh3 I

MeOH CO2Me NaOMe

74% 64

MeO CO2Me 65

Intramolecular nucleophilic addition gives 79 followed by hydrogen shift to generate 80. Elimination of triphenylphosphine releases the cycloadduct (Scheme 19). The reaction of N-tosylimines with ethyl 2,3-butadienoate and ethyl penta-2,3-dienoate has been systematically studied in the presence of various nitrogen and phosphine Lewis base promoters [51, 52]. More nucleophilic phosphines, such as tributylphosphine, instead of triphenylphosphine are required to carry out the reaction of N-sulfonylimines with sterically demanding c-substituted allenoates [53]. In the case of ethyl c-(t-butyl)-allenoate (81) attempts to promote the annulation reaction with triphenylphosphine did not lead to any product. However, quantitative yields of the 2,5-disubstituted-3-pyrroline-3-carboxylates (e.g., 82) and high diastereoselectivity was obtained using tributylphosphine as catalyst (Scheme 20). Solid-phase synthesis of 3-pyrrolines using resin-bounded allenoates has been reported [54]. The allenoic acids 83 were coupled to the benzyl alcohol unit of the SynPhase-PS lanterns grafted with Wang resin. The allenoates 84 were treated with N-tosyltolualdimine and 50 mol% triphenylphosphine (for 84a) or tributylphosphine (for 84b) to afford the polymer-bond 3-pyrrolines 85. These heterocycles were cleaved from the resin using 2.5% trifluoroacetic acid (TFA) in dichloromethane (DCM) to


689

Scheme 17

CO2Et

CO2Et

E

Ph3P (10 mol%) Benzene, rt, 5 h 55-81% 67:68 (63:37 - 83:17)

• 38

66

CO2Et

E E 68

67

E = CO2Et, CO2Me, COMe CN

CO2Et CO2Et • Major product

E

Ph3P

CO2Et

CO2Et

Ph3P

PPh3

71

E

CO2Et

69

E

Ph3P

70 EtO2C CO2Et 72

CO2Et

CO2Et

Ph3P (10 mol%) Benzene, rt, 5 h

CO2Et

CO2Et CO2Et

38 73

CO2Et

Ph3P (10 mol%) Benzene, rt, 5 h

Synthesis of functionalized N-vinyl nitrogen-containing heterocycles

CO2Et

trans-74 67%

•

E

CO2Et CO2Et cis-74 46%

Scheme 18

give the corresponding acids 86 in 91–93% yield with high diastereoselectivity (dr = 99:1 for 86b) (Scheme 21). The use of chiral phosphines as catalysts for the formal enantioselective [3 ? 2] cycloaddition of electron-deficient allenes with electron-deficient alkenes and imines has also been reported [54–64]. The formal [3 ? 2] cycloaddition reactions of butadienoates with N-benzylidenebenzenesulfonamide and electron-deficient alkenes can be carried out under microwave irradiation (MW) [65]. The methodology was shown to be efficient for the one-step synthesis of 3-pyrrolines and cyclopentenes in a regio- and diastereoselective manner (e.g., 88 and 89). This formal [3 ? 2] cycloaddition is complete within 5 min (Scheme 22).

The majority of biologically relevant molecules, namely drugs and natural products, contain nitrogen, thus justifying the continuous efforts by the scientific community to develop synthetic strategies for structures incorporating this heteroatom. Enamines are particularly interesting building blocks for introducing nitrogen-containing moieties in a synthetic sequence [66–69], and aziridines [70, 71] are valuable strained small heterocycles of interest in preparative organic synthesis. In this context, the synthesis of N-vinyl nitrogen-containing heterocyclic compounds via microwave-assisted 1,3-dipolar cycloaddition of the azomethine ylide generated by ring opening of a N-vinylaziridine has been reported [72]. Michael addition of an aziridine derivative to benzyl 2,3-butadienoate afforded the corresponding N-vinyl aziridine 91. Under microwave irradiation at 150 °C for 10 min the reaction of N-vinylaziridine 91 with dimethyl acetylenedicarboxylate (DMAD) led to 3-pyrroline 93 in 75% yield and in a selective way. The microwave methodology for the conrotatory ring opening of aziridine 91 leading to 1,3-dipole 92 and the subsequent cycloaddition proved to be more efficient than the conventional reaction conditions. When the reaction was carried out in refluxing toluene for 6 h, 3-pyrroline 93 was obtained in 40% yield. The microwave-assisted 1,3-dipolar cycloaddition of the in situ generated azomethine ylide 92 in the presence of methyl vinyl ketone (MVK) led to the regio- and

123

690


Scheme 19

CO2Me

CO2Me

N

•

R 63

75

Ts

R

Ph3P (10 mol%) Benzene, rt 88-98%

N

Ts 76 R = Ph, o-MeOC6H4, p-MeOC6H4, p-MeC6H4 p-ClC6H4, p-NO2C6H4, 1-Naphthyl

CO2Me

R

CO2Me

N

•

Ts

76

Ph3P

CO2Me

Ph3P

R

CO2Me

N

PPh3

77

Ts

80

PPh3

CO2Me

Ph3P

N

CO2Me

R

R

N

N Ts

Ts 79

R

78

Scheme 20

t-Bu

Ph

•

N

PBu3 (20 mol%) Benzene, rt, 8 h

Ts

CO2Et

Ts N

t -Bu

Ph

CO2Et 82 99%

39

81

Ts

Scheme 21 Cl

R

HO2C

I

O

•

OH

Tol

N

CO2H DIPEA or NEt3, CH2Cl2 - 78 °C to rt, 4-12 h 83a R = H 83b R = Et PPh3 or PBu3 (50 mol%) Benzene, 60 °C, 1-5 d Ts

N R

Tol

2.5% TFA CH2Cl2, rt, 12 h

Ts N

O

R O

86a R = H 91% overall yield 86b R = Et 92% overall yield

123

85

•

O 84

Tol

N

Ts

R


691

Scheme 22

R •

NSO2Ph

PR3 (20 mol%) Toluene

Ph

MW, 100 °C, 5 min

CO2Bn

SO2Ph N Ph

R

CO2Bn 46 R = H 87a R = t-Bu 87b R = Me

52

88a R = H 88b R = t-Bu 88c R = Me

CO2Et • CO2Bn EtO2C 46

64% 50% 43%

CO2Et

PBu3 (10 mol%) Toluene MW, 50 °C, 5 min

CO2Et CO2Bn

72

89 75% Scheme 23 Toluene, reflux, 6 h 40% MW, 150 °C, 10 min 75%

DMAD

CO2Bn

Ph

CO2Et

MeO2C

93 R N

CO2Bn

MeOH rt, 48 h

H N

R N

Ph

Δ

N

• CO2Bn

Ph

CO2Et

91 78%

90

CO2Bn

MVK Ph

N

H

MW, 150 ° C 10 min

CO2Et

92

Ph

CO2Me

O

EtO2C N N CO2Et

CO2Et

Me

MW, 150 °C, 10 min

R=

CO2Et

94 70% R N

Ph

CO2Et

N N EtO 2C

CO2Et 95 75%

Scheme 24

CO2Bn

CO2Bn

CO2Bn MW, 150 °C, 10 min

N Ph

N-phenylmaleimide

CO2Et

91

Ph

N

H O

CO2Et H

N Ph

O

96 59%

diastereoselective synthesis of pyrrolidine 94 in 70% yield. Dipole 92 can also be trapped by 1,3-dipolar cycloaddition with diethyl diazene-1,2-dicarboxylate to afford pentasubstituted-1,2,4-triazolidine 95 in 75% yield (Scheme 23). Microwave irradiation of a solution of aziridine 91 and N-phenylmaleimide led to the synthesis of two octahydropyrrolo[3,4-c]pyrrole derivatives 96 (59%) and 97 (29%) resulting from the exo and endo approach of the dipole and dipolarophile (Scheme 24). Reactivity of allenoates toward aziridines: synthesis of functionalized methylenepyrrolidines and pyrroles Allenes can participate in cycloadditions as dipolarophiles with a variety of 1,3-dipoles namely nitrile oxides,

Ph

N

H O

CO2Et H

N Ph

O

97 29%

nitrones, carbonyl ylides, nitrile imines, azides, and diazomethanes, but their 1,3-dipolar cycloaddition with azomethine ylides is an almost unexplored research topic [3, 73–76]. Nevertheless, the enantioselective synthesis of methylenepyrrolidines via bisphosphoric acid catalyzed 1,3-dipolar cycloaddition of allenoates and azomethine ylides generated in situ from aldehydes and amino esters has been reported [77] (Scheme 25). The cycloaddition of azomethine ylides generated from aziridines via conrotatory electrocyclic ring opening with buta-2,3-dienoates is known [78, 79] (Scheme 26). The microwave-assisted 1,3-dipolar cycloaddition of azomethine ylide 101 generated in situ from cis-1-benzyl-2benzoyl-3-phenylaziridine (100) with benzyl buta-2,3-dienoates 46, 87, and 102 carried out at 150 °C for 15 min

123

692


Scheme 25 O O O P O OH

CO2Et

R2CHO

•

H2N

CO2R1

O O HO P O

H N

R2

98 (10 mol %)

CO2Et

Toluene, rt

CO2Et

CO2Et

R1O2C 99 up to 96% ee

Scheme 26 Bn N Ph

Δ

Ph

COPh 101

100 Toluene MW, 150 °C 15 min

Ph

Bn N

• 104

COPh

•

COPh

CO2Bn 46 87b 87a 102

R=H R = Me R = t-Bu R = Ph

BnO2C R 103a 103b 103c 103d

R=H R = Me R = t-Bu R = Ph

73% 59% 46% 43%

Bn N

BnO2C

Ph

106 23%

105 30%

R

Cy N

Toluene COPh

107

Cy N

•

BnO 2C

CO2Bn R = H, Me, Ph, Bn

Ph

Cy N

COPh

BnO 2C R

108b 108c 108d 108e

R=H R = Me R = Ph R = Bn

Reflux, 1.5 h Reflux, 1.5 h MW, 150 °C, 15 min Reflux, 1.5 h MW, 150 °C, 15 min

afforded the corresponding 4-methylenepyrrolidine 103 in a site-, regio-, and stereoselective fashion. A different outcome was observed from the reaction of aziridine 100 with benzyl 5-phenylpenta-2,3-dienoate (104). The expected 4-methylenepyrrolidine 105 was obtained in 30% yield together with the formation of pyrrole 106 in 23% yield resulting from a formal [3 ? 2] cycloaddition. trans-2-Benzoyl-1-cyclohexyl-3-phenylaziridine 107 also reacts with benzyl buta-2,3-dienoates to give the corresponding pyrroles 108 exclusively or as the major product together with the formation of 4-methylenepyrrolidine

Ph

R

Reaction Conditions

123

Ph

Bn N

R

CO2Bn

Bn

COPh

Bn

Ph

H

Toluene MW, 150 °C 15 min

Bn

BnO2C

Scheme 27

Bn N

109f R = Me 109g R = Ph 109h R = Bn Product (Yield %) 108b (55.5%) 108c (62%) 108d (64%) 108e (26%) 108e (65%)

--109f (19%) 109g (10%) 109h (23%) ---

derivatives 109 (Scheme 27). The reaction of allenoates with cis-2-benzoyl-1-cyclohexyl-3-phenylaziridine was characterized by the same reactivity pattern shown by trans2-benzoyl-1-cyclohexyl-3-phenylaziridine 107, indicating that the outcome of the reaction is not determined by the stereochemistry of the starting aziridine. cis-2-Benzoyl-3-phenylaziridine 110 bearing a bulky Nt-butyl substituent leads to the formation of pyrroles upon reaction with allenes 46 and 87b (Scheme 28). No reaction was observed between allene 102 and cis-2-benzoyl-1-tbutyl 3-phenylaziridine (110).


Toluene 80 °C, 4 h

N Ph

COPh 110

693 Bn N

R N Ph

R • CO2Bn 46 R = H 87b R = Me

Toluene

BnO2C

CO2Et

Ph

118

111a R = H 65% 111b R = Me 38%

Scheme 28 Cy N

Ph MW, 150 °C, 15 min R BnO2C • CO2Bn 119a R = H, Me, t-Bu, Ph, Bn 119b 119c 119d 119e Toluene

Ph

Bn N

CO2Et

R R = H 73% R = Me 50% R = t-Bu 71% R = Ph 48% R = Bn 56% Cy N CO Et

These results indicate that the nature of the N-substituent of the 2-benzoyl-3-phenylaziridines determines the chemical behavior of these three-membered heterocycles in the presence of allenoates. The bulkier cyclohexyl or t-butyl N-substituent seems to hinder the 1,3-dipolar cycloaddition in favor of the formal [3 ? 2] cycloaddition. However, this reaction pathway becomes less favorable with allenoates with a bulkier C-4 substituent. The formation of the pyrrole derivatives can be explained as outlined in Scheme 29. Nucleophilic addition of the aziridine to the activated allene double bond gives intermediate 112 followed by the intramolecular attack of the carbanion center on the aziridine ring to afford the fivemembered heterocycles 113 via C–N bond cleavage. Tautomerizations and the subsequent aromatization lead to pyrrole 114 bearing a hydroxybenzyl side chain, which is converted into the final product and benzaldehyde via retro-aldol type fragmentation. N-Benzyl- and N-cyclohexyl-cis-3-phenylaziridine-2carboxylates react with allenoates to give the corresponding 1,3-cycloadducts (Scheme 30). The microwaveinduced conrotatory electrocyclic ring opening of aziridine 118 is followed by 1,3-dipolar cycloaddition of the in situ

Allenes have been used to generate cyclic and acyclic nitrones through the reaction with hydroxylamines [3]. On the other hand, the main strategy to obtain 4-isoxazolines (2,3-dihydroisoxazoles) has been the 1,3-dipolar cycloaddition between nitrones and alkynes or allenes [3, 80, 81]. These heterocycles are also particularly interesting synthons for cyclic and acyclic compounds owing to their readiness to undergo rearrangement reactions, the driving force being the relatively low thermochemical stability of the N–O bond [81, 82].

Scheme 29

R1

Ph

CO2Et

BnO2C

• CO2Bn

46

120

121 62%

Scheme 30

generated azomethine ylide with allenoates to afford methylenepyrrolidines 119 in good yields. A similar chemical behavior was observed between ethyl N-cyclohexylcis-3-phenylaziridine-2-carboxylate (120) and benzyl buta2,3-dienoate (46). 4-Isoxazolines and pyrroles from allenoates

R1

R2 N

•

Ph

BnO2C

COPh

R2

R1

2

MW, 150 °C, 15 min

N

Ph

BnO2C R2

R1

OH

112

R2

R1

OH

N

N

COPh

COPh

R2 N

Ph

Ph BnO2C

Ph

BnO2C

113

R1

Ph 114

R2

O H

N Ph BnO2C

Ph

116

BnO2C

Ph

115 R1

- PhCHO retro-aldol type fragmentation

R2 N

BnO2C

Ph

117

123

694


• CO2Bn

The synthesis of 4-isoxazolines via 1,3-dipolar cycloaddition of nitrones generated from allenoates and the subsequent thermal rearrangement to pyrrole derivatives was further explored [83]. Buta-2,3-dienoates are efficiently converted into the corresponding nitrones 122 upon reaction with N-methylhydroxylamine at room temperature in the presence of triethylamine or sodium hydrogencarbonate (Scheme 31). Nitrone 122a reacts with DMAD at room temperature for 15 min to give the corresponding 1,3-dipolar cycloadduct 123 in 66% overall yield. Interestingly, at 120 °C 3-hydroxy-2,3-dihydro-1H-pyrrole 124 is obtained as the only product. Under microwave irradiation and with the selection of appropriated temperature and reaction time the cycloaddition of nitrone 122a and DMAD affords 4-isoxazoline 123 or pyrrole 125 selectively [83] (Scheme 32). Reaction conditions can also be selected for the synthesis of 4-isoxazolines 126 or pyrroles 127 from the cycloaddition of nitrones 122b and 122c with DMAD. On the other hand, nitrones 122 react with ethyl phenylpropiolate under mild reaction conditions to afford 4-isoxazolines 128 in a regioselective fashion, whereas under forcing reaction conditions the corresponding pyrroles 129 were isolated as single products. The synthetic methodology was successful using either conventional reaction conditions or under microwave irradiation [83] (Scheme 33). The formation of 4-isoxazolines and pyrroles from allenoates can be explained as outlined in Scheme 34. The initial 1,3-dipolar cycloaddition of the nitrones generated from allenoates affords the target 4-isoxazolines. These heterocycles undergo thermal rearrangement to 2-acylaziridines via N–O bond cleavage. The corresponding azomethine ylides generated via conrotatory aziridine ring opening undergo a proton shift followed by 5-exo-trig

R

MeNHOH.HCl NEt3 or NaHCO3 DCM, rt, 1.5 h

R

O

R = H, Me, Ph

CO2Bn

N Me

122a R = H 86% 122b R = Me 88% 122c R = Ph 89%

Scheme 31

BnO2C • 46

Me N 1. MeNHOH.HCl / Base BnO2C O DCM, rt, 1.5 h Me 2. DMAD, Toluene MeO2C CO2Me 123

Me BnO2C

Entry

Me N

Me

CO2Me

OH CO2Me 124

Reaction conditions

BnO2C

Me N

CO2Me CO2Me

125

Products (overall yield %)

(Second step) 1

rt, 15 min

123 (66%)

2

120 °C, 3 h

124 (45%)

3

MW, 50 °C, 1 min

123 (60%)

4

MW, 200 °C, 15 mina 125 (46%)

5

MW, 250 °C, 5 mina a

125 (43%)

Carried out in trichlorobenzene.

Scheme 32

Scheme 33

BnO2C

R 1. MeNHOH.HCl Base DCM, rt, 1.5 h 2. DMAD, Toluene

• BnO2C 87b R = Me 107 R = Ph

R

Me N O

MeO2C

BnO2C • BnO2C R = H, Me, Ph

123

CO2Me

126a R = Me 126b R = Ph

R R 1. MeNHOH.HCl Base DCM, rt, 1.5 h 2. Toluene EtO2C Ph

EtO2C

Me N

R

Me N O Ph

128a R = H 128b R = Me 128c R = Ph

BnO2C

CO2Me CO2Me

127a R = Me 127b R = Ph

R

BnO2C

Me N

CO2Et Ph

129a R = H 129b R = Me 129c R = Ph


695

Scheme 34

R R •

MeNHOH CO2Bn

O

Me N

R ring contraction

CO2Bn

N Me

R COR2 R1

BnO2C

H-shift

BnO2C

N H

Pathway A

H N O

130

O

N H

130

131 Pathway B

H N

H N

O

R2

5-exo-trig cyclization

R

Me N

Me N

R1

O

R2

Me N

R R1 OH R2

BnO2C

R N Me O

R2

- H2O

R1 R2

BnO2C

TS (130-131) 152.8

O

132

H N O

133

R1

O

132

Scheme 35

cyclization leading to 2,3-dihydro-1H-pyrroles, which are converted into 1H-pyrroles via dehydration. This is the most general reactivity pattern of 4-isoxazolines bearing a methyl or methylene group at C-3. However, thermally induced conversion of 4-isoxazolines into azomethine ylides via an alternative mechanism has been proposed. The formation of stable azomethine ylides from isoxazolo[3,2-a]isoquinolines has been rationalized by considering a mechanism involving consecutive C3–C4 bond heterolysis and 1,3-sigmatropic shift rather than the accepted mechanism pathway involving acylaziridines as intermediates [84]. Therefore, quantum chemical calculations have been carried out to study the isomerization of the parent system 130 (Scheme 35). However, transition states could only be found for the pathway involving the generation of 2-acylaziridine 131 (Pathway A). The potential energy profile for thermal isomerization of 4-isoxazoline (130) to azomethine ylide 132 is shown in Fig. 2. As can be seen, the ring contraction of 4-isoxazoline to 2-acylaziridine is a very favorable process. On the other hand, the aziridine and the 1,3-dipole resulting from the aziridine ring opening have similar potential energy. The generation of the azomethine ylide is always followed by a stabilizing process, either a ring closure to an oxazoline or a proton shift followed by cyclization leading to pyrroles

Relative energy / kJ mol-1

O

Me N

CO2Bn

R1

R2

R1

CO2Bn

R

1,3-dipolar cycloaddition

TS (131-132) 43.5

0.00

O

N H

147.4

130

-103.4

-103.8

H N

H N

O

O 131

132

Reaction coordinate

Fig. 2 Potential energy profile for thermal isomerization of 4-isoxazoline 130 to azomethine ylide 131 calculated at B3LYP/6-31G* level of theory

(for derivatives having a methyl or methylene group at C-4). Thus, the quantum chemical calculations corroborate the favorability of the 4-isoxazoline rearrangement to fivemembered heterocyles via 2-acylaziridine intermediates.

Conclusion This review deals with the chemistry of allenes as building blocks in heterocyclic chemistry (Scheme 36). Allenoates

123

696


Scheme 36

CO2Et

CO2Bn

CO2Et N

Ph

R

CO2Et

X X R1

CO2Bn

R=H

CO2Bn

R CO2Bn

N R

BnO2C

R3

R

R3

R N R1 O

R

R1

SO2Ph R=H

Ph

CO2R*

PhO2SHN

N

R1 N

N

PhO2S

can be used as dipolarophiles or dipole precursors for the construction of cyclic compounds. Allenoates react with aziridines as 2p components to afford 4-methylenepyrrolidines or pyrroles via [3 ? 2] or formal [3 ? 2] cycloadditions. Dipolar species obtained from the reaction of allenes with phosphines participate in microwaveinduced [3 ? 2] annulations with N-benzylidenebenzenesulfonamide and electron-deficient alkenes to afford 3-pyrrolines and cyclopentenes. Conrotatory ring opening of N-vinyl aziridines resulting from the Michael addition of allenoates to aziridines in the presence of dipolarophiles allow the synthesis of five-membered heterocycles. Allenoates have also been used in the synthesis of functionalized N-vinyl nitrogen-containing heterocycles. On the other hand, formal [2 ? 2] cycloaddition of buta-2,3-dienoates with N-arylidenebenzenesulfonamides in the presence of DABCO yields mainly 2-methyleneazetidines, whereas the DABCO-catalyzed reaction of 2,3-allenoates bearing a chiral auxiliary in the ester moiety with N-arylidenebenzenesulfonamides allows the synthesis of optically active a-allenylamines and 2-azetines. Acknowledgments Thanks are due to FCT (Project PTDC/QUI/ 64470/2006) COMPETE, QREN, and FEDER for financial support.

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CH3

CO2R*

R2

R BnO2C

123

O O

Ph

R2 N

H •

CO2Bn

R2

•

Ar

R1

H R

CO2Bn R=H

R2

X = C or N

SO2Ph N Ph

R3

Stereoselective Synthesis α−Allenylamines and 2-Azetines

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