Use of a Quaternary Ammonium Salt Supported on ... - ACS Publications

Domenico Albanese, Maurizio Benaglia, Dario Landini*, Angelamaria Maia, Vittoria Lupi, and Michele Penso. Istituto CNR and Dipartimento di Chimica ...
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Ind. Eng. Chem. Res. 2002, 41, 4928-4935

Use of a Quaternary Ammonium Salt Supported on a Liposoluble Poly(ethylene glycol) Matrix for Laboratory and Industrial Synthetic Applications of Phase-Transfer Catalysis Domenico Albanese, Maurizio Benaglia, Dario Landini,* Angelamaria Maia, Vittoria Lupi, and Michele Penso Istituto CNR and Dipartimento di Chimica Organica e Industriale dell’Universita` , via Venezian 21, I-20133 Milano, Italy

A systematic study on the use of liposoluble PEG5000Bu3N+Br- (1a) as the catalyst in a series of anion-promoted reactions carried out under both liquid-liquid (LL) and solid-liquid (SL) phasetransfer catalysis (PTC) conditions is reported. A comparison of the catalytic efficiency of 1a and that of popular soluble nonsupported and/or insoluble resin-supported onium salts 1b-i is also included. Classical nucleophilic substitution reactions, i.e., Br-I exchange [reaction (1)] and SN2 displacement with a CN- ion [reaction (2)], C-, O-, and N-alkylation reactions [reactions (3)-(9)], formation and reactions of dichlorocarbenes with alkenes [reaction (10)], and sodium borohydride reductions [reaction (11)] were the standard transformations examined. The results show that 1a behaves as an efficient easily recyclable phase-transfer (PT) agent under both LLand SL-PTC conditions, with its catalytic activity being generally superior to that of insoluble resin-supported PT agents 1b,d and favorably comparable to that of popular soluble nonsupported onium salts 1c,e-i. Introduction Phase-transfer catalysis (PTC) is a very useful technique, which is widely used in industrial applications for the synthesis of pharmaceuticals, perfumes, flavorants, dyes, agricultural chemicals, monomers, and polymers and for many other applications.1 One of the most important technical problems in the industrial PTC applications using soluble phase-transfer (PT) catalysts, such as quaternary onium salts, is the need to separate the catalyst from the reaction mixture and its subsequent reuse or disposal. This problem usually increases the process costs; it may also affect the purity of the reaction products and byproduct disposal, giving rise to negative environmental impacts.1 Although, on laboratory and industrial scales, there are methods (i.e., distillation, extraction, and recently proposed nanofiltration membranes2) for the removal of the popular soluble PT catalysts, significant process simplification can, in principle, be obtained by using insoluble PT agents because of their easy separation and potential for recycle. Traditionally, insoluble polymer supported quaternary onium salts have been used as PT catalysts on a laboratory scale.1,3 However, the lack of robust physical and chemical stability, higher costs, and lower activity, owing to diffusional restrictions with respect to that of the soluble analogues, have greatly limited the industrial applications of insoluble polymer supported PT catalysts.1,3 An attractive compromise is the use of PT agents supported on a polymer matrix, which are soluble in a number of solvents, allowing for reaction catalysis under ideal homogeneous conditions. The polymer-bound catalyst is selectively insoluble, with respect to the reaction products, in other solvents, which provides for an easy * Tel: +39 0250314166. Fax: +39 0250314159. E-mail: [email protected].

separation and recycling of the immobilized catalyst by simple precipitation and filtration or centrifugation. These conditions combine the best aspects of both homogeneous and heterogeneous catalysis.4 Poly(ethylene glycol)s (PEGs) of molecular weight greater than 2000 Da are readily functionalized, inexpensive polymers that feature the above solubility properties.5 In particular, they are soluble in dimethylformamide (DMF), acetonitrile, dichloromethane, toluene, chlorobenzene, and methanol but insoluble in tertbutyl methyl ether, diisopropyl ether, diethyl ether, cold ethanol, and 2-propanol.5 In a preliminary paper, Benaglia et al.6 described the synthesis of a quaternary ammonium salt 1a (PEG5000Bu3N+Br-) on a modified monomethyl ether of PEG5000 (MeOPEG) and the use of this supported PT agent 1a for promoting some reactions under PTC conditions. Herein we report a systematic study on the use of 1a as a catalyst in a series of anion-promoted reactions carried out under both liquid-liquid (LL) and solid-liquid (SL) PTC conditions. A comparison between the catalytic efficiency of 1a and that of popular soluble nonsupported and/or insoluble resin-supported onium salts 1b-i is also included. Results and Discussion Classical nucleophilic substitution reactions {i.e., halogen exchange [reaction (1)], SN2 displacement with cyanide [reaction (2)], C-, O-, and N-alkylation reactions [reactions (3)-(9)], formation and reactions of dichlorocarbenes with alkenes [reaction (10)], and sodium borohydride reductions [reaction (11)]} were the standard transformations examined. These reactions all appear in Scheme 1. Nucleophilic Substitution Reactions. The Br-I exchange [reaction (1)] was carried out in a waterCH2Cl2 and solid salt-CH2Cl2 two-phase system, in the

10.1021/ie020188q CCC: $22.00 © 2002 American Chemical Society Published on Web 09/10/2002

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presence of catalytic amounts (0.04 mol equiv) of 1a, at 40 °C. As shown in Table 1, n-octyl bromide (2b) afforded 56% and 75% of the corresponding n-octyl iodide (2c), under LL-PTC (entry 1) and SL-PTC (entry 2) conditions, respectively, indicating that under the latter conditions the reaction rate is higher. Excellent yields (up to 97%; Table 1, entries 3 and 4) of octyl (2d) and benzyl cyanide (3d) were obtained by reacting the corresponding bromo derivatives 2b and 3b with aqueous potassium cyanide under LL-PTC conditions in the absence of organic solvent [reaction (2)]. These results show (Table 1, entries 3 and 4) that the catalytic activity of 1a is similar to that of nonimmobilized soluble onium salts7,8 and compares favorably to that of other quaternary ammonium salts anchored to insoluble polystyrene supports.3a,9 For instance, the reactions of entries 2 and 4, promoted by catalysts similar to onium salt 1a anchored on microporous polystyrene cross-linked with 2% divinylbenzene 1b, required longer reaction times (15 h)3a and/or higher temperatures (110 °C)3a,9 than those used here, for reaching comparable yields (81%9 and 85%3a). C- and O-Alkylation Reactions. The C-alkylation of phenylacetonitrile (4), chosen as a model substrate, with n-butyl bromide (5) was carried out in a dichloromethane- or acetonitrile-53% aqueous KOH twophase system in the presence of catalytic amounts (0.1-0.01 mol equiv) of 1a [reaction (3)]. Reaction (3) smoothly proceeded even at room temperature (Table 2, entries 1-5), affording the corresponding monoalkylated product, 2-phenylhexanenitrile (6), in 65-68% yields, together with minor amounts (3%) of the dialkylated derivative, 2-phenyl-2′-butylhexanenitrile (6a). Similar yields in comparable reaction times were obtained by using recycled 1a (entries 2 and 5). As expected for a PT-catalyzed process,1 reaction rates decreased upon decreasing the amount of the catalyst 1a (entries 1, 3, and 4) and increased by working at 60 °C (entry 6). The catalytic efficiency of

1a is superior to that of both soluble nonsupported onium salts, e.g., triethylbenzylammonium chloride (TEBA, 1c), (entries 1 and 3), and insoluble copoly(ester amide) 1d10 (entry 3). The O-alkylation of phenol (7) with benzyl bromide (3b) was performed in a 0.1 M aqueous NaOH- or solid NaOH-dichloromethane two-phase system at room temperature [reaction (4)]. As reported in Table 2 (entries 8 and 9), the SL-PTC system is the system of choice for carrying out reaction (3), with the yields (93%) being higher than those reported using as a PT agent both the soluble benzyltributylammonium bromide (1e; 86%)11 and insoluble supported quaternary ammonium salt 1b (72%).9 Catalyst 1a was recycled without any loss of its activity (entry 9). Its very low catalytic efficiency found under LL-PTC conditions (entry 7) can likely be due to two main factors: (i) a partial partition of 1a into the diluted aqueous phase, with a consequent reduction of the kinetic active amount of 1a into the organic phase, according to a common behavior of PT catalysts partially soluble in water;1,12 (ii) the specific hydration of phenoxide anion transferred from the aqueous into the organic phase by quaternary ammonium salt, which strongly reduces the anion reactivity.1,12,13 N-Alkylation Reactions. The catalytic activity of 1a was systematically studied in N-alkylations of a representative series of organic compounds, such as pyrrole (9), potassium phthalimide (11), trifluoro- (13) and trichloroacetamide (16), and N-[(2-nitrophenyl)sulfonyl]R-amino acid methyl esters (o-NBS-AA-OMe; 18a,b) [reactions (5)-(9)]. The N-alkylated derivatives 10, 12a,b, 15a-c, 17, and 20a,b are valuable starting materials for the synthesis of a number of important classes of organic compounds used as intermediates and/ or final products in industries such as pharmaceutical, agricultural, dyestuffs, etc.14 9 was selectively N-benzylated, affording the reaction product 10 in excellent yields (up to 98%) under both LL- and SL-PTC conditions (Table 3, entries 1 and 2) [reaction (5)]. As shown in Table 3 (entry 1), 1a was a much more efficient catalyst than soluble 1e;15 moreover, it retained its original activity after two recycles (entries 3 and 4). N-Alkylation of 11 [reaction (6)] is a very important chemical process, with the first step being of the popular Gabriel synthesis of primary amines on both laboratory and industrial scales.14b Therefore, the interest in developing advantageous protocols for carrying out this reaction is very actual. Under SL-PTC conditions in acetonitrile in the presence of catalytic amounts (0.1-0.01 mol equiv) of 1a, solid 11 easily reacted with 2b and benzyl chloride (3a) (Table 3), chosen as models of nonactivated and activated electrophiles, giving the corresponding N-octyl (12a) (entries 6-9) and N-benzyl phthalimide (12b) (entries 10-13) in very high isolated yields (up to 87 and 99%, respectively). Almost the same yields in similar reaction times were realized by using recycled 1a (entries 8 and 12). These results favorably compare with those obtained using a soluble quaternary onium salt, i.e., hexadecyltributylphosphonium bromide (1f) (entries 6 and 10), except for reactions carried out in toluene,14a where 1f was a more efficient catalyst than 1a (entry 14). Once again, the reaction times increased upon decreasing amount of the catalyst (entries 6, 7, 9-11, and 13); in the absence of the latter, the reaction did not occur at all (entry 5).

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Scheme 1

Ind. Eng. Chem. Res., Vol. 41, No. 20, 2002 4931 Scheme 1 (Continued)

Table 1. Catalytic Activity of 1a in Reaction (1) under PTC Conditionsa lit. T time yield yield b (%) entry substrate reagent conditions product (°C) (h) (%) 1 2 3 4

2b 2b 2b 3b

KIc KIc KCNe KCNe

LL-PTCd SL-PTCd LL-PTCf LL-PTCf

2c 2c 2d 3d

40 40 85 25

5 4 8 2

56 75 85 97

entry substrate product

93g 97h

a All of the reactions were carried out in a two-phase system under liquid-liquid (LL) or solid-liquid (SL) PTC conditions. The amount of catalyst 1a was 0.04 mol equiv. b GC yields, except for entry 4 (isolated yield); the remainder was starting material. c 5 mol equiv. d The organic solvent was CH Cl . e 1.7 mol equiv. 2 2 f In water without organic solvent. g 0.05 mol equiv of (nC8H17)4N+Br- (1h); toluene-H2O; 5 h, 90 °C; GC yield (ref 7). h 0.05 mol equiv of Aliquat 336 (1i); H O; 2 h, 25 °C (ref 8). 2

Table 2. Catalytic Activity of 1a in C-a and O-bAlkylation Reactions [Reactions (3) and (4)] under PTC Conditions, at 25 °C entry substrate 1 2 3 4 5 6 7 8 9

4 4 4 4 4 4 7 7 7

conditions CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH3CNh CH2Cl2-NaOHaq CH2Cl2-NaOHsolj CH2Cl2-NaOHsolj

1a lit. mol time yield yield product equiv (h) (%)c (%) 6 6 6 6 6 6 8 8 8

0.1 0.1e 0.05 0.01 0.01g 0.05 0.01 0.01 0.01e

2.5 2.5 3.5 7 7 2 22 4 4

68 67 68 69 67 71 18 93 91

Table 3. Catalytic Activity of 1a in N-Alkylation Reactions of 9a and 11b [Reactions (5) and (6)] under PTC Conditions

55d 56f

86i

a Substrate ) 0.1 mol; alkylating agent ) 0.11 mol; 53% aqueous KOH ) 48 mL; solvent ) 100 mL. b Substrate ) 0.05 mol; alkylating agent ) 0.06 mol; 0.1 mol of solid NaOH or 1 M aqueous NaOH, 100 mL; solvent ) 100 mL. c GC yields. d 0.1 mol equiv of TEBA (1c); 71% after 5 h. e Reaction carried out with catalyst 1a recycled one time. f 0.05 mol equiv of copoly(ester amide) (1d); CH2Cl2, 25 °C, 4 h (ref 10). g Reaction carried out with catalyst 1a recycled two times. h At 60 °C. i 0.01-0.1 mol equiv of n-Bu3BnN+Br- (1e), 0.3 M aqueous NaOH. j 2 mol equiv of solid NaOH.

N-Alkylated trifluoro- and trichloroacetamides 15 and 17 are versatile intermediates for organic industrial syntheses because they are easily and almost quantitatively converted into the corresponding amino derivatives, e.g., primary amines14c and R-amino acids14d,e or esters,16 depending on the alkylating agent used. As previously reported for the reactions (7a,b) catalyzed by soluble tetrabutylammonium bromide (1g)14c and benzyltriethylammonium chloride (1c),14d 1a effectively promoted the reactions (7a,b) of 13 with benzyl bromide (3b), cinnamyl bromide (14), and ethyl R-bromododecanoate (14c), under SL-PTC conditions in the presence of anhydrous potassium carbonate. As reported in Table 4 (entries 2, 4, and 8), the reaction products 15a-c were isolated as pure compounds in 61,

1 2 3 4 5 6 7 8 9 10 11 12 13 14

9 9 9 9 11 11 11 11 11 11 11 11 11 11

10 10 10 10 12a 12a 12a 12a 12a 12b 12b 12b 12b 12b

conditions CH2Cl2-NaOHaq CH2Cl2-NaOHsol CH2Cl2-NaOHsol CH2Cl2-NaOHsol CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN toluene

1a lit. mol T time yield yield equiv (°C) (h) (%) (%) 0.01 0.01 0.01 0.01 0.1 0.05 0.05 0.01 0.1 0.05 0.05 0.01 0.1

40 3 25 0.25 25 0.25 25 0.25 60 5 60 3 60 3.5 60 4 60 7 60 2 60 2.5 60 3 60 5 60 20

95 98 95d 93e

67c

86 80 82d 87 96 97 93e 99 65

86f

95g

90h

a Substrate ) 0.1 mol; alkylating agent ) 0.11 mol; 19 M aqueous NaOH ) 50 mL or solid NaOH ) 10 mol; solvent ) 120 mL. b Substrate ) 0.025 mol; alkylating agent ) 0.02 mol; solvent ) 80 mL. c 0.1 mol equiv of Et3BnN+Br- (1c), 19 M aqueous NaOH, 40 °C, 20 h. d Reaction carried out with catalyst 1a recycled one time. e Reaction carried out with catalyst 1a recycled two times. f 0.1 mol equiv of C16H33Bu3P+Br(1f), 60 °C, 8 h. g 0.1 mol equiv of C16H33Bu3P+Br- (1f), 60 °C, 2.5 h. h 0.1 mol equiv of C16H33Bu3P+Br- (1f), 60 °C, 0.33 h (ref 14b).

Table 4. Catalytic Activity of 1a in N-Alkylation Reactions of 13a and 16b [Reactions (7) and (8)] under SL-PTC Conditions

entry

substrate

product

1 2 3 4 5 6 7 8 9 10 11

13 13 13 13 13 13 13 13 13 16 16

15a 15a 15b 15b 15b 15c 15c 15c 15c 17 17

1a mol equiv 0.05 0.05 0.025 0.1 0.05 0.01 0.1 0.05

T (°C)

time (h)

yield (%)

80 80 80 80 80 80 80 80 80 25 25

6 2 6 0.75 1.5 28 2.5 2.5 7 42 60

37 61c 37 64e 51e 61 72 73 67 70 64

lit. yield (%) 71d 67f 75g 79h

a Substrate ) 0.1 mol; alkylating agent ) 0.05 mol; solid K CO 2 3 ) 0.1 mol; CH3CN ) 60 mL; 80 °C. b Substrate ) 0.04 mol; alkylating agent ) 0.01 mol; solid K2CO3 ) 0.04 mol; CH3CN ) 20 mL; 25 °C. c Together with a minor amount (16%) of N,Ndibenzyltrifluoroacetamide (15d). d 0.1 mol equiv of Bu4N+Br(1g), 2 h (ref 14c). e Together with minor amounts of N,N-di-transtrifluoroacetamide (15e). f 0.1 mol equiv of Bu4N+Br- (1g), 0.75 h (ref 14c). g 0.1 mol equiv of Et3BnN+Cl- (1c), 3.5 h (ref 14d). h 0.1 mol equiv of Et BnN+Cl- (1c), 40 h (ref 14e). 3

64, and 73% yields, respectively. The reaction rates increased by increasing the amount of the catalyst (entries 4, 5, 7, and 9); without the catalyst the reaction

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Table 5. Catalytic Activity of 1a in N-Alkylation Reactions of o-NBS-L-Val-OMea 18a and o-NBS-L-Ser-OMeb 18b [reaction (9)] under SL-PTC Conditions

entry

substrate

product

1a mol equiv

1 2 3 4 5 6

18a 18a 18a 18a 18a 18b

20a 20a 20a 20a 20a 20b

0.1 0.1d 0.1e 0.1f 0.05 0.1

T (°C)

time (h)

yield (%)

80 80 80 80 80 25

2 2 2 2 2.5 7

99 99 99 99 99 72h

lit. yield (%) 93c

94g 76i

a Substrate ) 0.01 mol; alkylating agent ) 0.0105 mol; solid K2CO3 ) 1.5 mol equiv; CH3CN ) 50 mL; 25 °C. b Substrate ) 0.01 mol; alkylating agent ) 0.0105 mol; solid K2CO3 ) 1.5 mol equiv; DMF ) 100 mL; 80 °C. c 0.1 mol equiv Et3BnN+Cl- (1c), 2 h (ref 14f). d Reaction carried out with catalyst 1a recycled one time. e Reaction carried out with catalyst 1a recycled two times. f Reaction carried out with catalyst 1a recycled three times. g 0.05 mol equiv of Et3BnN+Cl- (1c), 8 h. h Together with minor amounts (15%) of methyl 2-{N-[(o-nitrophenyl)sulfonyl]-N-allyl}amino acrylate (20d). i 0.1 mol equiv of Et3BnN+Cl- (1c), 7 h (ref 14f).

times were much longer (up to 11 times) and the yields lower (entries 1, 3, and 6). Similar results (Table 4, entries 10 and 11) were obtained when 16 reacted with ethyl R-bromopropanoate (14d) under SL-PTC conditions at room temperature [reaction (8)]. As previously found,14e attempts to reduce reaction times by working at higher temperature failed, owing to the side decomposition of 16. N-Alkylated N-[(nitrophenyl)sulfonyl]-R-amino acid methyl esters 18 were recently introduced as key starting materials for the synthesis of optically pure N-alkyl-R-amino acids and esters, in turn very important intermediates in the preparation of a number of biologically active compounds.14f As shown in Table 5 (entry 1), 1a was a very efficient PT agent for promoting the N-alkylation of optically pure N-[(o-nitrophenyl)sulfonyl]-L-valine methyl ester (o-NBS-L-Val-OMe; 18a), chosen as a sterically hindered model substrate, with allyl bromide (19), in the solid potassium carbonate-acetonitrile two-phase system at 80 °C [reaction (9)]. Under these conditions the corresponding o-NBS-N-allyl-L-Val-OMe (20a) was isolated, as an enantiopure compound, in almost quantitative yield in very short reaction times (2-2.5 h). The catalytic activity of 1a did not change after at least three recycles (entries 2-4) and was higher than that of 1c (entries 1 and 5).14f As previously found in the case of reaction (9) promoted by 1c,14f by working at room temperature in DMF instead of acetonitrile under SL-PTC conditions, N-[(onitrophenyl)sulfonyl]-L-serine methyl ester (o-NBS-LSer-OMe; 18b) was N-allylated, affording the o-NBSN-allyl-L-Ser-OMe (20b) with high selectivity (72%), together with minor amounts (15%) of methyl 2-{N-[(onitrophenyl)sulfonyl]-N-allyl}amino acrylate (20d; Table 5, entry 6). The ester 20d likely derives from the intermediate of o-NBS-N,O-diallyl-L-Ser-OMe (20c), via a base-promoted β-elimination of a molecule of allyl alcohol.14f These results indicate that, also in the reaction catalyzed by PEG5000Bu3N+Br- (1a), both temperature and solvent are crucial factors for the outcome of the N-monoalkylation. On the reasonable assumption that a common mechanism is at work in the alkylation catalyzed by 1c and 1a, the rationale for this behavior should be the same, already discussed in the former case.14f

Generation and Reaction of Dihalocarbene with Alkenes. Generation and reaction of dihalocarbenes with alkenes have received great attention in PTC applications because of the ease and advantages of generating these kinds of carbenes under LL-PTC conditions.1 Indeed, this process simply involves mixing of a haloform, such as chloroform, a PT catalyst, and the appropriate alkene in the presence of a concentrated aqueous alkaline solution, e.g., 50% aqueous NaOH.1 We found that, in the chloroform/dichloromethane50% aqueous NaOH two-phase system, dichlorocyclopropanation of styrene (21), chosen as a model reaction, smoothly occurred in 2.5 h at 40-60 °C in the presence of catalytic amounts (0.04 mol equiv) of PT agent 1a, affording the corresponding 1,1-dichloro-2-phenylcyclopropane (22) in 95% yields [reaction (10)]. These yields were higher than those (88%) reported in the literature for the reaction (10) catalyzed by popular TEBA under the same conditions17 and remained almost unaltered (93%) by using recycled 1a. Sodium Borohydride Reduction. The reduction of 2-octanone (23) to 2-octanol (24) by sodium borohydride in the presence of catalytic amounts (0.01 mol equiv) of 1a under SL-PTC conditions was the last reaction examined [reaction (11)]. In line with previous reports,1b,c under the above conditions ketone 23 was practically inert, but it was reduced in 18 h at room temperature, giving 24 in 82% yield by adding catalytic amounts (0.1 mol equiv) of Ti(OPri)4, which activated the carbonyl group.10 These results compare favorably to those obtained using copoly(ester amide) 1d10 as the PT agent (84% of 24 was obtained in 6 h in the presence of 0.1 mol equiv of 1d). Conclusions The results as a whole show that 1a behaves as an efficient and easily recyclable PT agent under both LLand SL-PTC conditions. Its catalytic activity is generally superior to that of insoluble resin-supported PT agents 1b,d and compares favorably to that of popular soluble nonsupported onium salts 1c,e-i. Indeed, 1a smoothly promoted anion PTC reactions, such as nucleophilic substitutions [reactions (1) and (2)], C-, O-, and N-alkylations [reactions (3)-(9)], generation and reactions of dihalocarbenes with alkenes [reaction (10)], and ketone reductions with sodium borohydride [reaction (11)], to afford the reaction products in good to excellent yields. In all cases examined, 1a was recovered (up to five times6) in almost quantitative yields and reused without any appreciable loss of its catalytic activity. This demonstrates a high chemical stability under the reaction conditions used. Finally, as previously reported,6 the ammonium moiety was found to be essential in realizing the catalytic efficiency of 1a. Indeed, in test runs the precursor alcohol 1j, used as a PT agent, showed a very limited catalytic activity in comparison to that of 1a.6 Following suggestions of one of the reviewers, we compared the catalytic activity of 1a to that of PEG2000 dimethyl ether 1k. As expected,6 also 1k showed a restricted catalytic activity in comparison with 1a: e.g., the benzylation of 9, catalyzed by 1k under the same conditions as those reported in Table 3 (entries 1 and 2), after the same reaction times afforded 1-benzylpyrrole 10 in 10 and 32% yields, respectively. All of these features indicate that 1a is a PT agent of choice for promoting anion reactions on both laboratory and industrial scales, combining the best performances

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of both soluble nonsupported and insoluble resin-supported onium salts. Acknowledgment This work was supported by MURST (Progetto Nazionale Stereoselezione in Sintesi Organica, Metodologie e Applicazioni) and CNR. Appendix: Experimental Section General Remarks. Melting points were determined on a Bu¨chi 535 apparatus. [R]D’s were measured at 589 nm on a Perkin-Elmer 241 polarimeter using a 10 cm × 5 mL cell, and c is in g/100 mL. 1H NMR spectra were recorded on a Bruker AC 300 spectrometer operating at 300.133 MHz; tetramethylsilane was used as the external reference; δ are in ppm, and J are in Hz. 19F NMR spectra were performed at 282 MHz, and chemical shifts are reported upfield from CFCl3 as the external standard. Petroleum ether (PE) having a boiling point range of 40-60 °C and silica gel of 240-400 mesh were used in the chromatographic purifications. Gas-liquid chromatographic (GLC) analyses were obtained with a HP-5 capillary column (cross-linked 5% PH ME Siloxane 30 m × 0.32 mm × 0.2 µm) or an OV 101-5% WAW 100/120 mesh column (51 cm × 1.6 mm). Experimental Apparatus. The apparatus was a 100-250 mL, three-neck, jacketed flask fitted with a flat-bladed stirring paddle, reflux condenser, and sampling port. The stirring speed (800 rpm) was determined using a strobe light, and the temperature was controlled by a thermostated bath. Materials. KI, KCN, KOH, NaOH, and NaBH4 were Analar-grade commercially available materials, used as purchased. NaOH, used in the SL-PTC reactions, was ground with a mortar in a drybox. K2CO3 was carefully dried by heating at 140 °C under vacuum (0.05 mm) for 6 h. Analar-grade CH3CN and DMF were dried over 0.3 nm molecular sieves and used as such. Quaternary onium salts (1c,e-i), octyl bromide (2b), butyl bromide (5), benzyl chloride and bromide (3a,b), allyl bromide (19), cinnamyl bromide (14), phenol (7), phenylacetonitrile (4), pyrrole (9), styrene (21), 2-ottanone (23), potassium phthalimide (11), and ethyl 2-bromopropanoate (14d) and -dodecanoate (14c) were Analargrade commercially available compounds, used without further purification. Commercial trifluoro- and trichloroacetamide (13 and 16) were recrystallized from chloroform before use; mp 71-72 and 143 °C, respectively. N-[(o-Nitrophenyl)sulfonyl]-L-valine methyl ester (oNBS-L-Val-OMe; 18a) and N-[(o-nitrophenyl)sulfonyl]L-serine methyl ester (o-NBS-L-Ser-OMe; 18b) were prepared according to a previously reported procedure.14f The catalyst 1a was prepared as already described.6 To avoid moisture in the final product, all synthetic steps were carried out under a nitrogen atmosphere. PEG2000 dimethyl ether 1k was a commecially available compound, used as purchased. Recovery of Catalyst 1a from the Reaction Mixture. The catalyst 1a recovery from the reaction mixture involved evaporation of the reaction solvent in a vacuum and addition of the residue dissolved in CH2Cl2 (2 mL/g of 1a) to a stirred solution of diisopropyl ether (25 mL/g of 1a) cooled at 0 °C in order to cause precipitation of 1a. After 20-30 min of stirring at 0 °C, the obtained suspension was filtered through a sintered glass filter and the solid was repeatedly washed on the

filter with diisopropyl ether (up to 80 mL of ether/g of polymer, overall). When CH2Cl2 was used as the solvent, the reaction mixture was concentrated in order to reach a 2 mL/g of 1a ratio. The purity of the 1a recovered was determined by 300 MHz 1H NMR analysis in CDCl3 with a presaturation of the methylene signals of the polymer at 3.63 ppm. In recording the NMR spectra, a relaxation delay of 6 s and an acquisition time of 4 s were used to ensure complete relaxation and accuracy of integration. The relaxation delay was selected after T1 measurements.6 Halogen-Halogen Exchange. A round-bottomed flask was charged with 2b (1.93 g, 0.01 mol), KI (8.3 g, 0.05 mol), catalyst 1a (2.2 g, 0.0004 mol), and CH2Cl2 (60 mL). The reaction was stirred at room temperature for 4 h. After concentration and catalyst 1a recovery, the solvent evaporation under vacuum afforded 1-octyl iodide (2c; 75%), identified by comparison with an authentic sample18 (GLC analysis). When this reaction was carried out under liquid-liquid conditions, a 5:1 CH2Cl2-H2O mixture was used as the solvent. SN2 Reaction with Potassium Cyanide. A roundbottomed flask was charged with 5 (1.93 g, 0.01 mol) or 3b (1.71 g, 0.01 mol), KCN (1.32 g, 0.02 mol), catalyst 1a (2.2 g, 0.0004 mol), and H2O (10 mL). The reaction mixture was stirred at room temperature for the time indicated in Table 1, and then CH2Cl2 (5 mL) was added. After catalyst 1a recovery, solvent evaporation under vacuum afforded 2d (87%) or 3d (97%), both identified by comparison with an authentic sample18 (GLC analysis). Alkylation of 4 with 1-Bromobutane. A mixture of 4 (11.72 g, 0.1 mol), 2b (15.07 g, 0.11 mol), catalyst 1a (27.5 g, 0.005 mol), CH2Cl2 (100 mL), and 53% aqueous KOH (48 mL) was stirred at room temperature until no starting nitrile 4 was detectable (TLC analysis or GLC analysis; 3.5 h). The reaction mixture was diluted with water (50 mL). The organic layer was separated, washed with 10% aqueous HCl and water, and dried with Na2SO4. After concentration, the catalyst 1a was recovered and the residue was subjected to flash chromatography (1:1 AcOEt-PE), affording 6: oil (11.8 g, 68%); n23D ) 1.5015 (lit.10 n23D ) 1.5015); 1H NMR (CDCl3) δ 7.30-7.35 (m, 5H), 3.75 (dd, 1H), 1.86 (m, 2H), 1.34-1.47 (m, 4H), 0.89 (t, 3H). 2-Butyl-2-phenylhexanenitrile (6a): oil (0.69 g, 3%); n21D ) 1.4956 (lit.19 n21D ) 1.4954); 1H NMR (CDCl3) δ 7.30-7.35 (m, 5H), 1.761.91, (m, 4H), 1.00-1.47 (m, 8H), 0.77 (t, 6H). Benzylation of 7. A round-bottomed flask was charged with solid ground NaOH (4 g, 0.1 mol), 7 (4.71 g, 0.05 mol), catalyst 1a (27.5 g, 0.005 mol), 3b (10.26 g, 0.06 mol), and CH2Cl2 (100 mL). The reaction mixture was stirred at room temperature and for the time indicated in Table 2. Solid inorganic material was separated by filtration. After concentration, catalyst precipitation, and solvent evaporation, the crude product was purified by flash chromatography (5:95 AcOEtPE), affording benzyl phenyl ether (8; 8.56 g, 93%): mp 39-40 °C (lit.20 mp 40 °C); 1H NMR (CDCl3) δ 7.057.45 (m, 10H), 5.10 (s, 2H). When this reaction was carried out under liquid-liquid conditions, a 1:1 CH2Cl2-1 M aqueous NaOH mixture was used as the solvent (100 mL). N-Alkylation of 9. A round-bottomed flask was charged with solid ground NaOH (40 g, 1 mol), 9 (6.71 g, 0.1 mol), catalyst 1a (5.5 g, 0.001 mol), 3b (18.81 g, 0.11 mol), and CH2Cl2 (120 mL), added in this order.

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The reaction mixture was stirred at room temperature and for the time indicated in Table 3. Solid inorganic material was separated by filtration. After organic layer concentration, catalyst recovery, and solvent evaporation, the crude product was purified by distillation, giving 1-benzylpyrrole (10): oil (15.4 g, 98%), bp 8991 °C (0.9 mm) [lit.15 88-90 °C (0.8-0.9 mm)]; 1H NMR (CDCl3) δ 7.15-7.45 (m, 10H), 6.15-6.70 (m, 4H), 5.035.30 (m, 2H). When this reaction was carried out under liquid-liquid conditions, a 1:1 CH2Cl2-19 M aqueous NaOH mixture was used as the solvent (50 mL). Alkylation of 11. An acetonitrile solution (80 mL) of 2b (3.86 g, 0.02 mol) and catalyst 1a (11 g, 0.002 mol) and solid 11 (4.63 g, 0.025 mol) were placed in a flask, equipped with a reflux condenser, and heated at 60 °C under stirring. The extent of the reaction was monitored by following the disappearence of 2b (GLC analysis, using decane as the internal standard). At the end of the reaction (3 h), the cooled reaction mixture was filtered, and the inorganic precipitate was washed with acetonitrile. The organic solvent was then recovered by evaporation under pressure, the residue was dissolved in CH2Cl2 (25 mL), and the catalyst 1a was recovered. The solvent was evaporated, and the crude product was purified by flash chromatography (1:20 AcOEt-PE), affording N-octylphthalimide (12a; 4.45 g, 86%): mp 48 °C (lit.14b mp 47-49 °C); 1H NMR (CDCl3) δ 7.67-7.83 (m, 4H), 3.65 (t, 2H), 1.64 (m, 2H), 1.26 (m 10H), 0.84 (t, 3H). Under the same conditions, 11 (4.63 g, 0.025 mol) reacted with 3a (2.53 g, 0.02 mol), affording N-benzylphthalimide (12b; 4.56 g, 96%): mp 115 °C (lit.14b mp 110-112 °C); 1H NMR (CDCl3) δ 7.70-7.84 (m, 4H), 7.20-7.45 (m, 5H), 4.84 (s, 2H). General Method for the N-Alkylation of CF3CONH2 (13) with Alkyl Bromides 3b and 14. An acetonitrile (60 mL) solution of CF3CONH2 (13; 11.3 g, 0.1 mol), alkylating agent 3b or 14 (0.05 mol), and catalyst 1a (13.75 g, 0.0025 mol) and solid anhydrous potassium carbonate (13.8 g, 0.1 mol) were placed in a flask equipped with a reflux condenser and a mechanical stirrer, protected from moisture, and heated at 80 °C with stirring. The mixture was stirred until no starting alkyl halide was detectable (TLC analysis). Then the cooled reaction mixture was filtered, and the inorganic precipitate was washed with acetonitrile. The organic solvent was recovered by evaporation under pressure, the residue was dissolved in CH2Cl2 (28 mL), and the catalyst 1a was recovered. The solvent was evaporated, and the crude product was flash chromatographed (1:4 AcOEt-PE) to give N-alkyltrifluoroacetamides 15a,c together minor amounts of N,N-dialkyl derivatives 15d,e. The starting alkyl halide, reaction time, yield, and physical and analytical data of 15a,c are as follows. N-Benzyltrifluoroacetamide (15a): benzyl bromide (3b), 2 h, 6.2 g (61%), mp 70-71 °C (lit.14c mp 7071 °C); 1H NMR (CDCl3) δ 7.28-7.41 (m, 5H), 6.51 (s, 1H), 4.54 (d, 2H); 19F NMR (CDCl3) δ -76.21 (s, CF3). N,N-Dibenzyltrifluoroacetamide (15d): oil, 1.11 g (15%), bp 140-143 °C (0.4 mm) [lit.14c bp 140-142 °C (0.4 mm)]. 1H NMR (CDCl3) δ 7.15-7.41 (m, 10H), 4.52 (s, 4H); 19F NMR (CDCl3) δ -68.2 (s, CF3). N-trans-Cinnamyltrifluoroacetamide (15b): cinnamyl bromide (14), 0.45 h, 7.3 g (64%), mp 100-102 °C (lit.14c mp 100-102 °C); 1H NMR (CDCl3) δ 7.277.38 (m, 5H), 6.60 (d, 1H), 6.43 (s, 1H), (6.18, d, 1H), 4.15 (t, 2H); 19F NMR (CDCl3) δ -76.25 (s, CF3).

N,N-Di-trans-Cinnamyltrifluoroacetamide (15e): oil, 1.4 g (16%); 1H NMR (CDCl3) δ 7.26-7.41 (m, 10H), 6.53-6.60 (d, J ) 15, 2H), 6.05-6.20 (dxt, J ) 15 and 5.5, 2H), 4.21 (t, J ) 6.0, 4H), identical with that reported for the authentic compound (15e).21 N-Alkylation of Trihaloacetamides 13 and 16 with 2-Bromocarboxylic Esters 14c,d. An acetonitrile (40 mL) solution of CF3CONH2 (13; 4.52 g, 0.04 mol), 2-bromo ester 14c (6.14 g, 0.02 mol), and catalyst 1a (11 g, 0.002 mol) and solid anhydrous potassium carbonate (5.52 g, 0.04 mol) were placed in a flask equipped with a reflux condenser and a mechanical stirrer, protected from moisture, and heated at 80 °C under stirring until complete disappearance of ester 14c (2.5 h; TLC analysis). The cooled reaction mixture was then filtered on Celite, the inorganic precipitate was washed with acetonitrile, and the solvent was recovered by evaporation. The residue was dissolved in CH2Cl2 (22 mL) and the catalyst 1a recovered. The solvent was evaporated, and the crude product was flash chromatographed (1:14 AcOEt-PE) to give ethyl N-(trifluoroacetyl)-2-aminododecanoate (15c; 4.95 g, 73%): mp 54-55 °C (lit.14d mp 54-55 °C); 1H NMR (CDCl3) δ 6.83 (br s, 1H), 4.55 (m, 1H), 4.18 (q, 1H, J ) 7), 1.60-1.85 (m, 2H), 1.18-1.25 (m, 19H), 0.80 (t, 3H). Similarly, trichloroacetamide (16; 6.49 g, 0.04 mol) reacted at 25 °C with ethyl 2-bromopropanoate (14d; 1.81 g, 0.01 mol) in the presence of catalyst 1a (5.5 g, 0.001 mol) and solid anhydrous potassium carbonate (5.52 g, 0.04 mol) to afford after 40 h ethyl N-(trichloroacetyl)-2-aminopropanoate (17): solid (1.84 g, 70%); mp 40-41 °C (lit.14e mp 41 °C); 1H NMR (CDCl3) δ 7.33 (br s, 1H), 4.52 (m, 1H), 4.25 (q, J ) 7, 1H), 1.51 (d, 3H), 1.31 (t, 3H). General Method for the Alkylation of Sulfonamides 18a,b. In a dried flask connected to a CaCl2 tube, anhydrous potassium carbonate (2.07 g, 0.015 mol) was added to an acetonitrile solution (50 mL) of o-NBS-LVal-OMe (18a; 3.16 g, 0.01 mol), 19b (1.27 g, 0.0105 mol), and catalyst 1a (2.75 g, 0.0005 mmol). The heterogeneous mixture was stirred at 80 °C until no starting material 18a was detected (TLC analysis; 1:1 AcOEt-PE; 2.5 h). Then the cooled reaction mixture was filtered, and the inorganic precipitate was washed with acetonitrile. The filtrate was evaporated under reduced pressure, the residue was dissolved in CH2Cl2 (10 mL), and the catalyst 1a was recovered. Evaporation of the solvent under vacuum afforded pure o-NBS-Nallyl-L-Val-OMe (20a): oil (3.53 g, 99%); [R]20D ) -61.9 (c ) 3.5 in CHCl3) {lit.22 [R]20D ) -62.4 (c ) 3.6 in CHCl3)}. The alkylation of o-NBS-L-Ser-OMe (18b; 3.04 g, 0.01 mol), carried out at 25 °C for 7 h using anhydrous DMF (50 mL) instead of acetonitrile, afforded after purification by flash chromatography (1:2 AcOEt-PE) o-NBSN-allyl-Ser-OMe (20b) {oil (2.48 g, 72%); [R]23D ) -11.5 (c ) 3.5 in CHCl3) (lit.21 [R]23D ) -12.2) (c ) 2.4 in CHCl3)} and methyl 2-[N-[(o-nitrophenyl)sulfonyl]-Nallyl]amino acrylate (20d) [oil14f (0.49 g, 15%)]. Dichlorocyclopropanation of 21. A round-bottomed flask was charged with 21 (10.41 g, 0.1 mol), CHCl3 (10 mL), catalyst 1a (22 g, 0.004 mol), a 19 M aqueous solution of NaOH (20 mL), and CH2Cl2 (5 mL). The reaction was stirred at 40-60 °C for 2.5 h. After dilution with water, the organic layer was separated, washed with water, and dried over magnesium sulfate, and the catalyst was recovered. Evaporation of the solvent and purification by fractional distillation af-

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forded 1,1-dichloro-2-phenylcyclopropane (22; 18.7 g, 95%): bp 118-120 °C (16 mm) [lit.17 bp 118-120 °C (16 mm)]. Reduction of 2-Octanone (23). 23 (12.8 g, 0.1 mol), CH2Cl2 (150 mL), sodium borohydride (3.78 g, 0.1 mol), Ti(OPri)4 (2.84 g, 0.001 mol), and catalyst 1a (5.5 g, 0.001mol) were mixed in a flask and vigorously stirred at room temperature for 18 h under a nitrogen atmosphere. After the addition of water, the organic layer was separated and washed first with hydrochloric acid and then with water. The organic layer was dried with sodium sulfate and concentrated under reduced pressure. After catalyst recovery and solvent evaporation, the crude product was purified by distillation to afford 2-octanol (24): oil (10.7 g, 82%), bp 178-180 °C (760 mm), n20D ) 1.4201 (lit.22 bp 180 °C, n20D ) 1.4203), 1H NMR (CDCl3) δ 3.72-3.83 (m, 1H), 1.17-1.45 (m, 13H), 0.88 (t, 3H). Literature Cited (1) See inter alia: (a) Montanari, F.; Landini, D.; Rolla, F. Phase Transfer Catalyzed Reactions. Top. Curr. Chem. 1982, 101, 145. (b) Dehmlow, V. V.; Dehmlow, S. S. Phase Transfer Catalysis; Verlag Chemie: Weinheim, Germany, 1993. (c) Starks, C. M.; Liotta, C. L.; Halpern, M. Phase-Transfer Catalysis, Fundamentals, Applications, and Industrial Perspectives; Chapman & Hall: New York, 1994. (d) Makosza, M.; Fedorynski, M. Advances in Catalysis; Academic Press Inc.: New York, 1988; Vol. 35. (e) Handbook of Phase Tansfer Catalysis; Sasson, Y., Neumann, R., Eds.; Blackie Academic & Professional: London, 1997. (f) Naik, S. D.; Doraiswamy, L. K. Phase Transfer Catalysis: Chemistry and Engineering. AIChE J. 1998, 44, 612. (2) Luthra, S. S.; Yang, X.; Freitas dos Santos, L. M.; White, L. S.; Livingston, A. G. Phase-Transfer Catalyst Separation and Reuse by Solvent Resistant Nanofiltration Membranes. J. Chem. Soc., Chem. Commun. 2001, 1468. (3) See inter alia: (a) Regen, S. L. Triphase Catalysis. Applications to Organic Synthesis. J. Org. Chem. 1977, 42, 875. (b) Regen, S. L. Triphase Catalysis. Angew. Chem., Int. Ed. Engl. 1979, 18, 421. (c) Molinari, H.; Montanari, F.; Quici, S.; Tundo, P. PolymerSupported Phase-Transfer Catalysis. High catalytic Activity of Ammonium and Phosphonium Salts Bonded to a Polystyrene Matrix. J. Am. Chem. Soc. 1979, 101, 3920. (d) Ford, W. T.; Tomoi, M. Polymer-Supported Phase Transfer Catalysis: Reaction Mechanisms. Adv. Polym. Sci. 1984, 55, 49. (e) Desikan, S.; Doraiswamy, L. K. The Diffusion-Reaction Problem in Triphase Catalysis. Ind. Eng. Chem. Res. 1995, 34, 3524. (4) (a) Bergbreiter, D. E.; Zhang, L.; Mariagnanam, V. M. Smart Ligands that Regulate Homogeneously Catalyzed Reactions. J. Am. Chem. Soc. 1993, 115, 9295. (b) Neumann, R.; Cohen, M. Solvent-Anchored Supported Liquid-Phase Catalysis: Polyoxometallate-Catalyzed Oxidations. Angew. Chem., Int. Ed. 1997, 36, 1738-1740. (c) Bergbreiter, D. E. Alternative Polymer Supports for Organic Chemistry. Med. Res. Rev. 1999, 19, 439. (5) (a) Gravert, D. J.; Janda, K. D. Organic Synthesis on Soluble Polymer Supports: Liquid-Phase Methodologies. Chem. Rev. 1997, 97, 489. (b) Wentworth, P., Jr.; Janda, K. D. Liquid-Phase Chemistry: Recent Advances in Soluble Polymer-Supported Catalysts, Reagents and Synthesis. J. Chem. Soc., Chem. Commun. 1999, 1917. (c) Toy, P. H.; Janda, K. D. Soluble Polymer-Supported Organic Synthesis. Acc. Chem. Res. 2000, 33, 546 and references therein. (6) (a) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Tocco, G. A Poly(ethylene glycol)-Supported Quaternary Ammonium Salt: an Efficient, Recoverable, and Recyclable PhaseTransfer Catalyst. Org. Lett. 2000, 2, 1737. (b) Benaglia, M.; Cinquini, M.; Cozzi, F.; Tocco, G. Synthesis of a Poly(ethylene glycol)-supported Tetrakis Ammonium Salt: a Recyclable PhaseTransfer Catalyst of Improved Catalytic Efficiency. Tetrahedron Lett. 2002, 43, 3391.

(7) Hodge, P.; Khosdel, E.; Waterhouse, J. Preparation of Some Polymer-Supported Crown Ethers and Their Use as PhaseTransfer Catalysts. J. Chem. Soc., Perkin Trans. 1 1984, 2451. (8) Bram, G.; Loupy, A.; Pedoussant, M. Ame´liorations et Semplifications de la Synthe´se de Nitriles par Alkylation de l’Anion Cyanure: Catalyse par Tranfer de Phase Solide-Liquide sans Solvant. Bull. Soc. Chim. Fr. 1986, 124. (9) Chiles, M. S.; Jackson, D. D.; Reeves, P. C. Preparation and Synthetic Utility of Phase-Transfer Catalysts Anchored to Polystyrene. J. Org. Chem. 1980, 45, 2915. (10) Montanari, F.; Penso, M. Copolyesteramides Containing Poly(ethylene oxide) Soft Segments as New and Efficient PhaseTransfer Catalysts. Gazz. Chim. Ital. 1985, 115, 427. (11) McKillop, A.; Fiaud, J. C.; Hug, R. P. The Use of PhaseTransfer Catalysis for the Synthesis of Phenol Ethers. Tetrahedron 1974, 30, 1379. (12) Albanese, D.; Landini, D.; Maia, A.; Penso, M. Key Role of Water for Nucleophilic Substitutions in Phase-Transfer-Catalyzed Processes: A Mini-Review. Ind. Eng. Chem. Res. 2001, 40, 2396. (13) Landini, D.; Maia, A.; Rampoldi, A. Specific Hydration and Nucleophilic Reactivity of Organic Anions under Phase-Transfer Catalysis and Homogeneous Conditions. Gazz. Chim. Ital. 1989, 119, 513. (14) See inter alia: (a) Cuadro, A. M.; Matia, M. P.; Garsia, J. L.; Vaquero, J. J.; Alvarez-Builla, J. Synthesis of N-(Aminoethyl) Azoles under Phase Transfer Catalysis. Synth. Commun. 1991, 21, 535 and references therein. (b) Landini, D.; Rolla, F. A Convenient Synthesis of N-Phthalimides in Solid-Liquid TwoPhase System in the Presence of Phase-Transfer Catalysts. Synthesis 1976, 389 and references therein. (c) Landini, D.; Penso, M. A Convenient Synthesis of N-Alkyl and N,N-Dialkyltrifluoroacetamides in a Solid-Liquid Two-Phase System in the Presence of Phase-Tansfer Catalysts. Synth. Commun. 1988, 18, 791 and references therein. (d) Landini, D.; Penso, M. N-Alkylation of Trifluoroacetamide with 2-Bromo Carboxylic Esters under PTC Conditions: A New Procedure for the Synthesis of R-Amino Acids. J. Org. Chem. 1991, 56, 420. (e) Albanese, D.; Landini, D.; Penso, M. Synthesis of 2-Amino Acids via Selective Mono-N-Alkylation of Trichloroacetamides by 2-Bromo Carboxylic Esters under SolidLiquid-Phase Transfer Catalysis Conditions. J. Org. Chem. 1992, 57, 1603. (f) Albanese, D.; Landini, D.; Lupi, V.; Penso, M. N-Monoalkylation of R-Amino Acid Esters under Solid-Liquid PTC Conditions. Eur. J. Org. Chem. 2000, 1443 and references therein. (15) Wang, N. C.; Teo, K. E.; Anderson, H. J. Pyrrole Chemistry. XVII. Alkylation of Pyrrolyl Ambident Anion. Can. J. Chem. 1977, 55, 4112. (16) Albanese, D.; Corcella, F.; Landini, D.; Maia, A.; Penso, M. Chemoselective N-Deprotection of tert-Butyl 2-(Trifluoroacetylamino) Esters under PTC Conditions: Synthesis of tert-Butyl 2-Aminocarboxylates. J. Chem. Soc., Perkin Trans. 1 1997, 247. (17) Crossland, I. Atropaldehyde. Org. Synth. 1981, 60, 6. (18) Weast, R. C. Handbook of Chemistry and Physics, 55th ed.; CRC Press: Boca Raton, FL, 1976-1977. (19) Normant, H.; Cuvigny, T. Formation des Anions en Milieu Hexametapol. IV. Carbanions De´rive´s de Compose´s Divers a Carbon Active´. Bull. Soc. Chim. Fr. 1965, 1881. (20) Normant, H.; Cuvigny, T. Formation et Reaction de Carbanions en Milieu Hexametapol. II. Anions aux he´te´ratomes (O, S, N). Bull. Soc. Chim. Fr. 1965, 1881. (21) Oppolzer, W.; Achini, R.; Pfenninger, E.; Weber, H. P. Stereoselective Synthesis of Benzo[f]isoindoline-Derivative by Intramolecular Cycloaddition of Styrene to Olefins. Helv. Chim. Acta 1976, 59, 1186. (22) Bowman, W. R.; Coghlan, D. A Facile Method for the N-Alkylation of R-Amino Esters. Tetrahedron 1997, 53, 15787.

Received for review March 11, 2002 Revised manuscript received May 11, 2002 Accepted July 28, 2002 IE020188Q