Metalation vs Nucleophilic Addition in the Reactions of N

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J. Org. Chem. 1997, 62, 2080-2092

Metalation vs Nucleophilic Addition in the Reactions of N-Phenethylimides with Organolithium Reagents. Ready Access to Isoquinoline Derivatives via N-Acyliminium Ions and Parham-Type Cyclizations M. Isabel Collado, Izaskun Manteca, Nuria Sotomayor, Marı´a-Jesu´s Villa, and Esther Lete* Departamento de Quı´mica Orga´ nica, Facultad de Ciencias, Universidad del Paı´s Vasco, Apdo. 644, 48080 Bilbao, Spain Received November 18, 1996X

Sequential carbophilic addition of organolithium reagents and N-acyliminium ion cyclization of N-phenethylimides 1 affords the substituted isoquinolones 3 in high yields, with the possibility of varying the substituent at the C-1 position of the isoquinoline ring by changing the organolithium reagent. Ready access to the isoquinoline nucleus via Parham-type cyclization of imides 2 is also described. We have shown that iodinated imides 2 tolerate the metal-halogen exchange in the presence of the imide group, and the intramolecular cyclization of the so-obtained aromatic organometallic derivatives leads to the corresponding enamides 4. Both approaches have allowed the efficient preparation of various types of the isoquinoline class of alkaloids, just by changing the substitution pattern on the readily available starting imides. Thus, we have developed convenient alternative routes for the synthesis of benzo[a]quinolizidones and their 2-oxa analogs, isoindoloisoquinolones, dibenzo[a,h]quinolizidones, and thiazolo- and oxazolo[4,3-a]isoquinolones. Introduction Within the scope of the aromatic directed metalation reaction, a protocol which is enjoying increasing utility in organic synthesis, the intramolecular capture of the aryllithium intermediate by internal electrophiles (ortholithiation-cyclization strategy) has proven to be an effective method for the construction of carbocyclic and heterocyclic systems.1,2 However, certain electrophilic groups, such as ketones and imides, do not remain passive during the metalation process, and competitive nucleophilic attack by organolithium base may occur. Advantage can be taken of the very fast rate of metalhalogen exchange compared with nucleophilic addition to carbonyl groups to allow survival of acidic sites and other electrophilic groups under low-temperature RLi conditions.3 In their work on Parham-type cyclizations,3 Wolfe4 reported that the N-acyl groups of N-acyl-2bromobenzamides tolerated metal-bromine exchange when the imide nitrogen was either deprotonated by sodium hydride or carried an alkyl substituent. The resulting ortho-lithium intermediates underwent cyclization to yield 3-alkylidenephthalimidines. Narasimhan5 has described a novel synthesis of 1-arylbenzocyclobutenols and benzocyclobutenes from deoxybenzoins using a similar metal-halogen exchange strategy. Here we detail6 the utility of the reactions of Nphenethylimides with organolithium compounds for the synthesis of different isoquinoline alkaloids using two basic strategies. First, it was expected that a tandem Abstract published in Advance ACS Abstracts, March 1, 1997. (1) Snieckus, V. Chem. Rev. 1990, 90, 879. (2) Snieckus, V. Pure Appl. Chem. 1994, 66, 2155. (3) Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982, 15, 300. (4) Hendi, M. S.; Natalie, K. J.; Hendi, S. B.; Campbell, J. A.; Greenwood, T. D.; Wolfe, J. F. Tetrahedron Lett. 1989, 30, 275. (5) Aidhen, I. S.; Narasimhan, N. S. Tetrahedron Lett. 1991, 32, 2171. (6) For preliminary communications: Lete, E.; Eguiarte, A.; Sotomayor, N.; Vicente, T.; Villa, M. J. Synlett 1993, 41. Collado, M. I.; Sotomayor, N.; Villa, M. J.; Lete, E. Tetrahedron Lett. 1996, 37, 6193. Manteca, I.; Sotomayor, N.; Villa, M. J.; Lete, E. Tetrahedron Lett. 1996, 37, 7841. X

S0022-3263(96)02155-X CCC: $14.00

carbophilic addition-N-acyliminium ion cyclization sequence could be performed on N-phenethylimides 1, leading to the substituted isoquinolones 3 through a preferential attack to the imidic carbonyl group (Scheme 1). The key step involves N-acyliminium ion-mediated carbon-carbon bond-forming reactions, which have found an impressive number of synthetic applications.7 NAcyliminium ions have demonstrated significant utility as intermediates in various types of cyclization reactions using different types of π nucleophiles.8 In our strategy, the appropriate choice of the organolithium reagent at the first step would allow the introduction of functionality on the pendant side chain of 3, giving rise to useful precursors for the construction of more complex isoquinoline alkaloids, such as the Erythrina type.9 The second approach relied on assembling the isoquinoline nucleus via Parham-type cyclization of imides 2, since halogenated imides 2 could tolerate the metal-halogen exchange in the presence of the imide group, and the intramolecular cyclization of the so-obtained aromatic organometallic derivatives would lead to the corresponding enamides 4 (Scheme 1). In view of the ready availability of a wide array of substituted imides, both approaches seemed well suited to provide access to a wide variety of isoquinoline alkaloids. (7) Reviews: (a) Speckamp, W. N. Rec. Trav. Chim. Pays-Bas 1981, 100, 345. (b) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367. (c) Hiemstra, H.; Speckamp, W. N. In The Alkaloids; Academic Press: New York, 1988; Vol. 32, p 271. (d) Hiemstra, H.; Speckamp, W. N. Additions to N-Acyliminium ions. In Comprehensive Organic Chemistry; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, p 1047. (e) Maryanoff, B. E.; Rebarchak, M. C. Synthesis 1992, 1245-1248 and references therein. (8) For representative examples of π-nucleophiles, see: ref 7. For some recent examples, see: (a) Heaney, H.; Shuhaibar, K. F. Synlett 1995, 47. (b) Lee, Y. S.; Kang, D. W.; Lee, S. J.; Park, H. J. Org. Chem. 1995, 60, 7149. (c) Li, W. H.; Hanau, C. E.; Davignon, A.; Moeller, K. D. J. Org. Chem. 1995, 60, 8155. (d) Logers, M.; Overman, L. E.; Welmalker, G. S. J. Am. Chem. Soc. 1995, 117, 9139. (e) Marson, C. M.; Pink, J. H.; Smith, C. Tetrahedron Lett. 1995, 36, 8107. (f) Rigo, B.; Elghammarti, S.; Couturier, D. Tetrahedron Lett. 1996, 37, 485. (g) Yamada, H.; Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc. 1996, 118, 1054. (9) Bentley, K. W. Nat. Prod. Rep. 1994, 555.

© 1997 American Chemical Society

Reactions of N-Phenethylimides with Organolithium Reagents

J. Org. Chem., Vol. 62, No. 7, 1997 2081

Scheme 1

Scheme 3

Table 2. Products from the RLi Carbophilic Addition Step of the Sequence with 3a products Table 1. One Pot Addition-Cyclization of 1a with n-BuLi conditionsa entry n-BuLi (equiv) quenching agent yieldb (%) of product 3a 1 2 3

1.1 2.2 2.2

12 M HCl 12 M HCl TFA

26 40 92

a Reactions carried out in THF at -78 °C for 6 h. b Yields of isolated products.

entry

RLi

R

1 2 3 4 5 6 7 8

n-BuLi MeLi s-BuLi t-BuLi Me3SiCH2Li PhLi PhCtCLi CH2dCHCH2Li

a, n-Bu b, Me c, s-Bu d, t-Bu b, Me e, Ph f, PhCtC g, CH2dCHCH2

yielda (%) ratio 5/6b 61 87 52 53 60 95 61 e

4.2/1 c d d 4.8/1 1/3 d 1.9/1

a

Yields of the mixture of tautomers 5 and 6. b Determined by NMR. c Only the hydroxy lactam 5 was isolated. d Only the oxo amide 6 was isolated. e Yields could not be accurately calculated due to contamination with the stannane derivative formed in the transmetalation.

1H

Scheme 2

Results and Discussion Carbophilic Addition-N-Acyliminium Ion Cyclization. A preliminary study of the reaction conditions for the tandem one-pot addition-cyclization reaction was carried out using succinimide 1a as substrate, prepared by condensation of 3,4-dimethoxyphenethylamine with succinic anhydride. Representative results are summarized in Table 1 (Scheme 2). When 1a was treated with 1 equiv of n-BuLi at -78 °C for 6 h, quenching the reaction mixture with 12 M HCl once at room temperature, complete conversion was not accomplished, and the cyclization product 3a was isolated in low yield (26%), together with starting material (entry 1). A better yield of 3a (40%) was obtained using 2 equiv of n-BuLi under the same conditions (entry 2). However, treatment with 2 equiv of n-BuLi at -78 °C for 6 h, followed by TFA quench at room temperature, afforded 3a in high yield. As expected, conversion 1a to 3a involves the initial formation of an alkoxide derivative, via addition of the organolithium reagent to the imidic carbonyl group, followed by protonation and subsequent dehydration to produce the corresponding N-acyliminium salt. The former salt readily cyclized to the 8,9-disubstituted pyrroloisoquinolone 3a by electrophilic attack of the aromatic ring. In fact, the intermediate addition products could be isolated as tautomeric mixtures of hydroxy lactams 5 and oxo amides 6 when the reaction was quenched with water (Scheme 3). The structure of the acidic catalyst is of great influence on the outcome of the cyclization reaction, as it has been observed in other amidoalkylation reactions.7 In this case, the fact that TFA affords the pyrroloisoquinolone 3a in better yield than HCl could indicate that TFA favors the

formation of the N-acyliminium ion, which is probably the rate-determining step. In order to study the influence of steric and electronic effects in both the addition and cyclization reactions, succinimide 1a was treated with a range of organolithium reagents. Allyllithium was prepared by transmetalation of allyltriphenyltin with PhLi, according to literature procedures.10 Addition reactions were thus carried out with 2 equiv of the organolithium reagent at -78 °C over 6 h and quenched by addition of water at low temperature. After workup, equilibrium mixtures of the hydroxy lactams 5, and the corresponding tautomeric oxo amides 6 were obtained, as summarized in Table 2 (Scheme 3). The fact that no open-chain hydroxy amides resulting from RLi attack to the ketone carbonyl in 6 have been detected suggests that these oxo amides 6 are formed during aqueous workup, and not by ring opening of the intermediate lithium alkoxide. In cases a and b (R ) Bu, Me, entries 1 and 5, Table 2), the tautomers 5 and 6 could be chromatographically separated and identified by NMR, while in the other cases decomposition occurred during the purification processes. However, since the subsequent cyclization of both compounds leads to the same pyrroloisoquinolone, no previous separation is required and NMR resonances can be used in the determination of the tautomers ratio from the mixture. The most significant signals were the NH triplet for the oxo amides 6 (i.e.: 5.67 ppm for 6a) in the 1H NMR spectrum and the 13C NMR shift of the carbinolic or ketonic carbon (i.e.: 92.2 ppm for 5a and 210.1 for 6a, respectively). Both yield and product distribution are affected by the steric and electronic nature of the carbon atom directly attached to the metal in the alkyllithium used as nucleophile (Table 2). The ratio of oxo amides 6 increases (10) Seyferth, D.; Weiner, M. A. J. Org. Chem. 1961, 26, 4797.

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Collado et al.

Scheme 4

Table 3. Products from the Cyclization Step of 5 + 6 entry

substrate

conditions [time (h), T]

R

product

1 2 3 4 5 6 7

5a + 6a 5b 6c 6d 5e + 6e 6f 5g+ 6g

18, refluxa 4, rta 120, refluxb 36, refluxa 6, refluxa

n-Bu Me s-Bu t-Bu Ph PhCtC CH2dCHCH2

3a 3b 3c 3e 3f 3g

yield (%) 95 98 93 c 98 c 97d

a CH Cl was used as solvent. b CHCl was used as solvent. 2 2 3 Starting material was recovered under various reaction condid tions. Based on GC-MS analysis.

c

with the substitution (entries 1-4). Thus, only the cyclic tautomer was isolated when the reaction was carried out with MeLi (entry 2), and it is the major tautomer in the reaction with n-BuLi. Just in one experiment, formation of the 4-oxopentanamide 6b (R ) CH3) could be detected by 1H NMR of the crude reaction mixture, in a 4.8/1 ratio favoring the hydroxy lactam 5b. The ratio is inverted in the case of s-BuLi and t-BuLi (entries 3 and 4), where oxo amides 6c and 6d were the only products isolated. However, in the case of R ) s-Bu, the presence of a minor amount of hydroxy lactam could be detected by 1H NMR of the crude reaction mixture, whose ratio could not be determined due to overlapping of representative signals, and could not be isolated. A GC-MS analysis showed the presence of a peak of mass 303 (M+ - 18) that could correspond to hydroxy lactam 5c in a 19/1 6c/5c ratio. The use of Me3SiCH2Li (entry 5) afforded a mixture of 5b and 6b (R ) Me) in a 4.8/1 ratio favoring the hydroxy lactam. This result can be rationalized assuming that a carbon to oxygen migration of the trimethylsilyl group11-13 had occurred, followed by hydrolysis of the O-Si bond during workup. Both tautomers could be separated by column chromatography and identified. As one can see from Table 2, hybridization change on the nucleophilic carbon atom of the organolithium reagent also exerts a strong effect, inverting the 5/6 ratio. In fact, the hydroxy lactams 5e and 5f (entries 6 and 7) are more unstable due to inductive effects on C-4, which favor the equilibrium toward the open chain isomer 6.14 Yield of the tautomeric mixture of 5/6g could not be accurately calculated due to contamination with the stannane derivative formed in the transmetalation, even after chromatography, but conversion was complete and NMR spectra of the crude reaction mixtures only showed signals due to both tautomers and the organotin compound. However, hydroxy lactam 5g decomposed during chromatography, and only the corresponding oxo amide 6g could be isolated and identified. Cyclization of the tautomeric mixture of 5 and 6 was accomplished with TFA in CH2Cl2 or CHCl3 to afford the desired 10b-substituted tetrahydropyrroloisoquinolones 3 (Scheme 4). As shown on Table 3, high cyclization yields were generally obtained, though the rate was strongly influenced by the nature of the R group at C-10b. Higher temperatures and longer reaction times are required as the steric bulk increases (entry 2 vs 1 and 3) or as the R group diminishes the electrophility of the intermediate N-acyliminium ion by resonance effect (11) Brook, A. G. Acc. Chem. Res. 1974, 7, 77. (12) Hudrlick, P. F.; Peterson, D.; Rona, R. J. J. Org. Chem. 1975, 40, 2263. (13) Tietze, L. F.; Geisler, H.; Gewert, J. A.; Jacobi, U. Synlett 1994, 511. (14) Maryanoff, D. F.; McComsey, D. F.; Dhul-Emswiler, B. A. J. Org. Chem. 1983, 48, 5062.

(entry 5). The fact that no cyclization products were observed in the case of 6d (R ) t-Bu, entry 4) and in 6f (R ) PhCtC, entry 6) could be explained by the above mentioned steric and electronic effects, respectively. In the other cases, yields were quantitative, and pure products were obtained from the crude reaction mixtures (GC analysis). A rational extension of this methodology into other synthetically useful fields consists in the variation of the imide skeleton, thus providing a rapid, mild, and regiospecific entry to several heterocyclic systems, such as benzo[a]quinolizidones and their 2-oxa analogs, isoindoloisoquinolones, dibenzo[a,h]quinolizidones, and thiazoloand oxazolo[4,3-a]isoquinolones. Thus, a series of imides 1i-p were prepared as depicted in Scheme 5. Condensation of 3,4-dimethoxyphenethylamine 7 with cyclic anhydrides 8 under classical conditions afforded imides 1il, while imides 1n and 1p were prepared by Mitsunobu reaction of 3,4-dimethoxyphenethyl alcohol 9 and imides 10. Reaction of imides 1l and 1n with LDA/MeI yielded the corresponding dimethylated derivatives 1m and 1o (Scheme 5). The sequence of carbophilic addition-N-acyliminium ion cyclization was applied on these substrates under the usual conditions affording the heterocyclic systems in high overall yields. As in the previous cases described, when imides 1i-k were subjected to reaction with n-BuLi (2 equiv), a smooth nucleophilic addition of the organolithium reagent was observed. A simple aqueous workup yielded the oxo amides 6i-j or the cyclic tautomer, hydroxy lactam 5k, in excellent yields. Subsequent treatment of these addition products with TFA in dichloromethane at room temperature resulted in the quantitative formation of the corresponding isoquinoline derivatives: benzo[a]quinolizidone 3i, its 2-oxa analogue 3j, and nuevamine-type isoindoloisoquinolone 3k (Scheme 6). Comparable yields of isoquinoline derivatives 3i-k were obtained by quenching the n-BuLi addition reactions with TFA, though in some cases, conversions were lower. NMR data, including 1H-1H homodecoupling and DEPT experiments, proved to be useful for structure determinations here. In the case of benzo[a]quinolizidone 3i, owing to the complex NMR spectra, 1H and 13C resonances were assigned by analysis of 2D 1H-1H COSY and HMQC spectra. The latter spectrum was particularly helpful to distinguish between vicinal and geminal proton signals in the CH2CH2 and CH2CH2CH2 parts of quinolizidone ring. The homophthalimide 1l underwent rapid deprotonation at the benzylic position using the n-BuLi addition conditions (D2O quench). Therefore, 1l was converted in its silyl enol derivative by deprotonation with n-BuLi (1.1 equiv) in THF at -78 °C, followed by addition of TMSCl, and then treated with n-BuLi in one pot. By this

Reactions of N-Phenethylimides with Organolithium Reagents

J. Org. Chem., Vol. 62, No. 7, 1997 2083

Scheme 5a

Scheme 6a

procedure, both the benzylic position and the adjacent carbonyl group were protected against deprotonation and addition, respectively, and hydroxy lactam 5l and oxo amide 6l were obtained with complete regioselectivity in a 1/1.5 ratio and were chromatographically separated. However, when these n-BuLi addition products were submitted to cyclization with TFA, separately or directly from the crude reaction mixture, the 1-n-butyl-N-(3,4dimethoxyphenethyl)-3-hydroxy isoquinolinium salt 11 was obtained as the major product (Scheme 7). In this case, the facile aromatization of the initially formed N-acyliminium salt prevented the cyclization. This problem could be circumvented using the dimethylated homophthalimide 1m. Two potential reaction pathways are possible. Addition to the carbonyl group in conjugation with the aromatic ring would result in the formation of a dibenzo[a,h]quinolizidinone, while attack to the carbonyl group at C-3 would lead to protoberberine system. Thus, when homophthalimide 1m was subjected to the RLi addition-cyclization conditions, treatment with n-BuLi and TFA in the one-pot sequence afforded quantitatively a 1:1.7 mixture of the corresponding protoberberinone 3m and dibenzo[a,h]quinolizidinone 3m′. In a separate experiment, hydroxy lactams 5m and 5m′ were chromatographically separated, identified, and cyclized to the protoberberinone 3m

Scheme 7a

Scheme 8a

(75% yield) and dibenzo[a,h]quinolizidinone 3m′ (95% yield), respectively (Scheme 8). The organolithium addition to this unsymmetrical imide was attended with modest regioselectivity, with preferential addition to the less hindered carbonyl group. The relative regiochemistry of the products was determined by a combination of NOE measurements and

2084 J. Org. Chem., Vol. 62, No. 7, 1997

Collado et al.

Scheme 9a

Figure 1.

comparison of trends in the NMR data. When one examines 1H NMR resonances, a downfield shift of one aromatic proton for protoberberine 3m can be observed, relative to the other regioisomer (δ 8.14 for 3m vs δ 7.64 for 3m′). These values are consistent with the proposed structure, and the downfield shift observed may be attributed to the anisotropy of the carbonyl group. Besides, the conjugation of one of the carbonyl groups with the aromatic ring is also reflected in the difference of chemical shifts of the two carbonyl carbons in their 13C NMR spectra (δ 163.6 for 3m vs δ 175.7 for 3m′). Although these data are in accordance with those reported for similar systems,15 one should ideally have both isomers in order to compare values for unambiguous use of these spectroscopic data as diagnosis. Nevertheless, nuclear Overhauser effect difference spectroscopy can be used to confirm the regiochemistry and solve the problem. Thus, protoberberinone 3m demonstrated an enhancement of the signal of the methyl protons at C-13 upon irradiation of the methylene protons of the n-butyl group (those directly bonded to the heterocyclic ring), and vice versa. On the other hand, dibenzoquinolizidinone 3m′ showed no NOE between the above-mentioned methyl and methylene protons. Similar criteria were used to distinguish the hydroxy lactams 5m and 5m′ and to assign the structure of their analogue 5l. The extension of this methodology to other heteroatominserted imide derivatives was anticipated. It should be noted that heterocycle-fused isoquinolines, such as thiazolo- and oxazolo[4,3-a]isoquinolines, would be attractive for their potentially biological activities.16 Addition of n-BuLi to heteroatom-inserted imides 1o and 1p occurred with high regioselectivity at the more electrophilic amide carbonyl group (Scheme 9), affording the hydroxy lactams 5o and 5p as the major products (75% and 58%, respectively). Addition to the carbamate or thiocarbamate carbonyl groups also occurred, and the oxo amides 6o and 6p could be isolated in minor amounts (8% and 16%, respectively). In this case, the open chain oxo amide is favored versus the cyclic hydroxy lactam, due to the inductive effect of the oxygen or sulfur atom, as previously discussed. In fact, cyclization attempts of oxo amides 6o and 6p failed, due to the lower reactivity of (15) Vicente, T.; Martı´nez de Marigorta, E.; Domı´nguez, E.; Carrillo, L.; Badı´a, M. D. Heterocycles 1993, 36, 2067. (16) Kano, S.; Yuasa, Y.; Shibuya, S. Synth. Commun. 1985, 15, 883.

the ester or thio ester carbonyl groups toward nucleophilic attack of the amide nitrogen. On the contrary, treatment of the hydroxy lactams 5o and 5p with TFA provided in high yields the corresponding heterocyclefused isoquinolines 3o and 3p, respectively. In addition to high field 1H and 13C NMR spectra, COSY, NOESY, and HMQC spectra were necessary to confirm the regiochemistry, due to the complexity of the spectra. These 2D NMR techniques have also allowed us to unequivocally assign the chemical shifts of all protons and carbons. The diagnostic carbonyl carbon and n-Bu-C-N quaternary carbon resonances, together with the presence or absence of NOE among the methyl protons at C-13 and the methylene protons of the n-butyl group (those directly bonded to the heterocyclic ring), are the most significant facts. Besides, the NOE observed between the methyl group at C-13 and the aromatic H-10 proton in the isoquinoline derivatives also supported the assignments. Parham Cyclizations. Our next concern was the synthesis of isoquinolones 4 by Parham cyclization of the halogenated imides 2. A preliminary study of the reaction conditions for the Parham cyclization reaction was carried out using brominated succinimide 2a (Scheme 1, X ) Br) as substrate, prepared by treatment of 1a with bromine in acetic acid.17 Although a variety of experimental conditions were tested, the desired pyrroloisoquinolines 4 could not be detected in the crude product mixture from 2a. When 2a was treated with n-BuLi (1 equiv) at -78 °C for 2.5 h and the reaction quenched by the addition of HCl, 3a was isolated as the major product (34%). Metalation of 2a took place partially because debromination was observed, but lithium-bromine exchange is not fast enough to compete effectively with n-BuLi addition to the imide carbonyl group. In fact, when 2a was treated under the same conditions previously used for 1a, the 10b-substituted pyrroloisoquinolone 3a was isolated in a similar yield (52%). When the reaction was quenched by the addition of water it afforded the hydroxy lactam 5a (45%), while using more diluted acid (6 M HCl) enamide 12 was obtained as the major product (26%) (Figure 1). This compound also cyclized to 3a when stronger acidic medium (TFA or 12 M HCl) and/or prolonged stirring times were used. The use of t-BuLi gave also addition to the carbonyl group, together with bromine-lithium exchange. Thus, when 2a was treated with t-BuLi (2.1 equiv) at -78 °C, only the oxo amide 6d was isolated (40%). In addition, when a larger excess of t-BuLi (4 equiv) was used and the reaction mixture stirred for 4 h at -78 °C before quenching, a dimeric byproduct (mass spectroscopy, elemental analysis) was also isolated (15-18%) (Figure (17) Domı´nguez, E.; Lete, E.; Iriondo, C.; Villa, M. J. Bull. Soc. Chim. Belg. 1984, 93, 1099.

Reactions of N-Phenethylimides with Organolithium Reagents Scheme 10a

1). The 1H and 13C NMR indicated the presence of four methoxyl groups, six aromatic protons, and seven methylene groups. Further spectroscopic analysis, which included 1H-1H decoupling experiments and 2D C-H correlation, led us to propose the structure of N-(3,4dimethoxyphenethyl)-5-[N-(3,4-dimethoxyphenethyl)succinimid-3-ylidene]-2-pyrrolidinone (13) for this dimeric product. Its formation could be explained by aldol-type condensation of the succinimide. Analogous succinimide enolate formation have been reported.18 In view of these results the iodinated succinimide 2b, prepared by treatment of 1a with ICl, was tested as a substrate for the Parham cyclization. As expected, iodine-lithium exchange was faster than addition to the carbonyl group of the imide, and the initially formed anion was trapped intramolecularly by the imide carbonyl to afford an intermediate 10b-hydroxypyrroloisoquinolone, that dehydrated during workup to afford 4a (75%) (Scheme 10). These conditions were applied to the synthesis of more complex isoquinoline alkaloids. Thus, the iodinated imides 2c and 2d were prepared by treatment of 1i and 1j with ICl in glacial acetic acid. When 2c and 2d were treated under the previously tested conditions, the 11bhydroxylated benzo[a]quinolizidone 14b and its 2-oxa analogue 14c were obtained in high yields. These products spontaneously dehydrated to the corresponding 1,11b-didehydrobenzo[a]quinolizidones 4b and 4c in chloroform solution (Scheme 11). Similarly, the hydroxysubstituted isoindoloisoquinolone 14d and dibenzo[a,h]quinolizidone 14e were obtained from the iodinated imides 2e and 2f (Scheme 12). In the latter case, cyclization took place regioselectively at the less hindered carbonyl group. The structures were also established by NMR analysis through the observation of coupling constants, anisotropic shielding, C-H correlations, and NOEs, following the criteria previously explained (vide supra). Conclusions In summary, the application of the carbophilic addition-N-acyliminium ion cyclization sequence on imides 1a, i-p constitutes an effective route to several types of isoquinoline alkaloids, with the ability to introduce a variety of substituents R at the C-1 position of the isoquinoline unit by changing the organolithium reagent (18) Speckamp, W. N. Heterocycles 1984, 21, 211.

J. Org. Chem., Vol. 62, No. 7, 1997 2085 Scheme 11a

Scheme 12a

used in the first step. It has also been shown that the tautomeric oxo amide-hydroxy lactam equilibrium and the N-acyliminium ion cyclization are strongly influenced by the stereoelectronic effects of the substituent R. Alternatively, bromine-lithium exchange in 2a is not fast enough to compete effectively with organolithium addition to the imide carbonyl group. However, iodinated imides 2b-f tolerate fast iodine-lithium exchange, giving rise to the isoquinoline nucleus via a Parham-type cyclization. Thus, convenient alternative routes for the synthesis of benzo[a]quinolizidones and their 2-oxa analogs, isoindoloisoquinolones, dibenzo[a,h]quinolizidones, and thiazolo- and oxazolo [4,3-a]isoquinolones19 have been developed.

Experimental Section General. Melting points were determined in unsealed capillary tubes and are uncorrected. IR spectra were obtained on KBr pellets (solids) or CHCl3 solution (oils). NMR spectra (19) For a few representative examples, see: (a) Benzo[a]quinolizidines: ref 14; Orito, L.; Matsuzaki, T.; Suginome, H. Heterocycles 1988, 27, 2403. (b) Isoindoloisoquinolines: Alonso, R.; Castedo, L.; Domı´nguez, D. Tetrahedron Lett. 1985, 26, 2925. Heaney, H.; Shuhaibar, K. F. Tetrahedron Lett. 1994, 35, 2751; ref 8a. (c) Dibenzo[a,h]quinolizidines: Kametani, T.; Fukumoto, K. In Heterocyclic Compounds. Isoquinolines. Part 1; Grethe, G., Ed.; John Wiley & Sons: New York, 1981; vol. 38, p 183. (d) Heterocycle-fused isoquinolines: Hamersma, J. A. M.; Speckamp, W. N. Tetrahedron 1982, 38, 3255. Kohn, H.; Liao, Z.-K. J. Org. Chem. 1982, 47, 2787. Kano, S.; Yuasa, Y.; Yokomatsu, T.; Shibuya, S. J. Org. Chem. 1983, 48, 38353837. Kano, S., Yuasa, Y.; Shibuya, S. Heterocycles 1985, 23, 395.

2086 J. Org. Chem., Vol. 62, No. 7, 1997 were recorded at 20-25 °C, running at 250 MHz for 1H and 62.8 MHz for 13C in CDCl3 solutions, unless otherwise stated. Assignment of individual 13C resonances are supported by DEPT experiments. 1H-{1H} NOE experiments were carried out in the difference mode by irradiation of all the lines of a multiplet.20 1H-{1H} COSY, NOESY, and HMQC spectra were recorded at 300 MHz for 1H and 75.5 MHz for 13C in CDCl3 solutions. Mass spectra were recorded under electron impact at 70 eV. GC-MS analyses were performed using a HP-5 column (5% phenyl methyl polysiloxane, 30 m × 0.25 mm × 0.25 µm). TLC was carried out with 0.2 mm thick silica gel plates (Merck Kiesegel GF254). Visualization was accomplished by UV light or by spraying with Dragendorff’s reagent.21 Flash column chromatography22 on silica gel was performed with Merck Kiesegel 60 (230-400 mesh). HPLC was performed using a LiChrosorb Si60 (7 µm) column with a refraction index detector. All solvents used in reactions were anhydrous and purified according to standard procedures.23 Organolithium reagents were titrated with diphenylacetic acid periodically prior to use. All air- or moisture-sensitive reactions were performed under argon; the glassware was dried (130 °C) and purged with argon. N-[2-(3,4-Dimethoxyphenyl)ethyl]succinimide (1a). A solution of homoveratrylamine 7 (3 g, 16.5 mmol) and succinic anhydride (2.97 g, 29.7 mmol) in glacial acetic acid (35 mL) was heated at reflux overnight. The mixture was cooled, and the acetic acid was evaporated under reduced pressure. Pure imide 1a was obtained by recrystallization from MeOH (3.46 g, 79%): mp 124-125 °C; IR (KBr) 1700, 1770 cm-1; 1H NMR (CDCl3) 2.5 (s, 4H), 2.68 (t, J ) 7.7 Hz, 2H), 3.57 (t, J ) 7.7 Hz, 2H), 3.71 (s, 3H), 3.73 (s, 3H), 6.58-6.67 (m, 3H); 13C NMR (CDCl3) 27.5, 32.5, 39.3, 55.3, 110.7, 110.8, 120.3, 129.7, 147.4, 148.3, 176.5; MS (EI) m/z (rel intensity) 263 (M+, 23), 164 (100), 151 (52), 107 (9), 91 (8), 77 (9), 65 (6), 55 (13). Anal. Calcd for C14H17NO4: C, 63.87, H, 6.51, N, 5.32. Found: C, 63.96, H, 6.47, N, 5.37. 10b-Butyl-8,9-dimethoxy-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one (3a). One-Pot Procedure. To a solution of the succinimide 1a (263 mg, 1 mmol) in dry THF (20 mL), was added n-BuLi (1.45 mL of a 1.5 M solution in hexane, 2.2 mmol) at -78 °C. The resulting mixture was stirred at this temperature for 6 h, allowed to warm to 20 °C, and then quenched by addition of TFA (0.5 mL). Et2O (5 mL) and H2O (10 mL) were added, the organic layer was separated, and the aqueous phase was extracted with CH2Cl2 (3 × 10 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. Flash column chromatography (silica gel, 20% CH2Cl2/AcOEt) afforded the pyrroloisoquinolone 3a (288 mg, 92%): IR (CHCl3) 1680, 1515 cm-1; 1H NMR (CDCl3) 0.89 (t, J ) 7.0 Hz, 3H), 1.26-1.35 (m, 4H), 1.88 (t, J ) 7.8 Hz, 2H), 2.35-2.45 (m, 1H), 2.61-2.70 (m, 1H), 2.76-3.04 (m, 4H), 3.34 (ddd, J ) 13.2, 10.2, 5.5 Hz, 1H), 3.87 (s, 3H), 3.89 (s, 3H), 4.27 (ddd, J ) 13.2, 6.2, 2.3 Hz, 1H), 6.57 (s, 1H), 6.65 (s, 1H); 13C NMR (CDCl3) 13.5, 22.6, 26.0, 27.2, 30.6, 31.6, 36.6, 41.4, 56.0, 56.2, 68.0, 108.3, 112.0, 124.5, 133.5, 147.6, 147.6, 173.1; MS (EI) m/z (rel intensity) 303 (M+, 1), 246 (100), 230 (2), 202 (8), 185 (4), 123 (8), 109 (4), 87 (3), 77 (4). Addition of RLi to Succinimide 1a. Preparation of Hydroxy Lactams 5 and Oxo Amides 6. General Procedure. To a solution of the succinimide 1a (263 mg, 1 mmol) in dry THF (20 mL) was added RLi (2.2 mmol) at -78 °C. The resulting mixture was stirred at this temperature for 6 h, quenched by the addition of H2O (5 mL), and allowed to warm to 20 °C. Et2O (5 mL) was added, the organic layer was separated, and the aqueous phase was extracted with CH2Cl2 (3 × 10 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to afford mixtures of hydroxy lactams 5 and oxo amides 6. Addition of n-BuLi. 4-Butyl-N-[2-(3,4-dimethoxyphenyl)ethyl]-4-hydroxy-γ-lactam (5a) and N-[2-(3,4-Dimeth(20) Kinss, M.; Sanders, J. K. M. J. Magn. Reson. 1984, 56, 518. (21) Stahl, E. Thin-Layer Chromatography; 2nd ed.; Springer Verlag: Berlin, 1969. (22) Still, W. C.; Kann, H.; Mitra, A. J. Org. Chem. 1978, 43, 2923. (23) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals, 3rd ed.; Pergamon Press: Berlin, 1988.

Collado et al. oxyphenyl)ethyl]-4-oxooctanamide (6a). According to General Procedure, imide 1a (526 mg, 2 mmol) was treated with n-BuLi (4.90 mL of a 0.9 M solution in hexanes, 4.4 mmol) to afford hydroxy lactam 5a and oxo amide 6a (370 mg, 61% overall) in a 5a/6a 4.2/1 ratio. Both tautomers were separated by column chromatography (silica gel, 5% CH2Cl2/MeOH). Hydroxy lactam 5a: IR (CHCl3) 3380, 1740, 1520 cm-1; 1H NMR (CDCl3) 0.86 (t, J ) 7.8 Hz, 3H), 1.15-1.33 (m, 4H), 1.52 (t, J ) 7.3 Hz, 2H), 1.68-1.93 (m, 2H), 2.10-2.95 (m, 4H), 3.10-3.35 (m, 3H), 3.78 (s, 3H), 3.80 (s, 3H), 6.60-6.80 (m, 3H); 13C NMR (CDCl3) 13.6, 22.6, 25.4, 29.1, 34.5, 37.4, 40.6, 41.0, 55.7, 92.2, 114.1, 114.6, 120.7, 137.0, 147.4, 148.7, 171.9; MS (EI) m/z (rel intensity) 303 (M+ - 18, 2), 274 (1), 164 (100), 151 (9), 124 (3), 105 (2), 91 (3), 77(3). Anal. Calcd for C18H27NO4: C, 67.26, H, 8.47, N, 4.36. Found: C, 67.20, H, 9.17, N, 4.22. Oxo amide 6a: IR (CHCl3) 3380, 1720, 1660, 1520, 1265 cm-1; 1H NMR (CDCl3) 0.89 (t, J ) 7.3 Hz, 3H), 1.31-1.49 (m, 2H), 1.52-1.60 (m, 2H), 2.38 (t, J ) 6.7 Hz, 2H), 2.41 (t, J ) 7.3 Hz, 2H), 2.72 (t, J ) 6.7 Hz, 2H), 2.75 (t, J ) 7.0 Hz, 2H), 3.46 (dt, J ) 7.0, 6.2 Hz, 2H), 3.86 (s, 3H), 3.88 (s, 3H), 5.67 (broad s, 1H), 6.60-6.80 (m, 3H); 13C NMR (CDCl3) 13.8, 22.3, 25.9, 29.9, 32.2, 35.2, 37.6, 42.5, 55.8, 111.3, 111.9, 120.6, 131.4, 147.6, 149.0, 171.9, 210.1; MS (EI) m/z (rel intensity) 321 (M+, 2), 264 (1), 164 (100), 151 (13), 121 (3), 107 (4), 85 (6), 77(4), 57 (10). Addition of MeLi. N-[2-(3,4-dimethoxyphenyl)ethyl]4-hydroxy-4-methyl-γ-lactam (5b). According to General Procedure, imide 1a (526 mg, 2 mmol) was treated with MeLi (2.75 mL of a 1.6 M solution in Et2O, 4.4 mmol) to afford hydroxy lactam 5b (460 mg, 87%) that was purified by column chromatography (silica gel, 5% CH2Cl2/MeOH): mp (CH2Cl2/ MeOH) 81-83 °C; IR (CHCl3) 3360, 1740, 1520; 1H NMR (CDCl3) 1.39 (s, 3H), 1.95-2.13 (m, 2H), 2.38-2.2 (m, 1H), 2.56-2.40 (m, 1H), 2.95-2.67 (m, 3H), 3.50-3.29 (m, 2H), 3.81 (s, 3H), 3.83 (s, 3H), 6.68-6.80 (m, 3H); 13C NMR (CDCl3) 26.1, 29.1, 34.5, 34.7, 40.7, 55.5, 89.7, 111.1, 111.9, 120.5, 131.6, 147.2, 148.6, 174.5; MS (EI) m/z (rel intensity) 261 (M+ - 18, 8), 164 (100), 151 (30), 110 (10), 91 (11), 82 (29). Anal. Calcd for C15H21NO4: C, 64.50, H, 7.58, N, 5.01. Found: C, 64.23, H, 7.71, N, 4.96. Addition of s-BuLi. N-[2-(3,4-Dimethoxyphenyl)ethyl]5-methyl-4-oxoheptanamide (6c). According to General Procedure, imide 1a (526 mg, 2 mmol) was treated with s-BuLi (5.50 mL of a 0.8 M solution in pentane, 4.4 mmol) to afford oxo amide 6c that was purified by column chromatography (silica gel, 60% hexane/AcOEt) (315 mg, 52% overall): IR (CHCl3) 1715, 1660 cm-1; 1H NMR (CDCl3) 0.84 (t, J ) 7.5 Hz, 3H), 1.04 (d, J ) 6.9 Hz, 3H), 1.31-1.42 (m, 1H), 1.601.68 (m, 1H), 2.35 (t, J ) 6.5 Hz, 2H), 2.45 (q, J ) 6.9 Hz, 1H), 2.68-2.78 (m, 4H), 3.43 (m, 2H), 3.82 (s, 3H), 3.84 (s, 3H), 5.70 (broad s, 1H), 6.68-6.79 (m, 3H); 13C NMR (CDCl3) 11.5, 15.7, 25.8, 29.8, 35.2, 36.1, 40.7, 47.6, 55.7, 111.2, 111.8, 120.5, 131.4, 147.5, 148.9, 171.8, 213.7; MS (EI) m/z (rel intensity) 321 (M+, 2), 264 (2), 165 (16), 164 (100), 151 (11), 149 (9), 141 (3), 121 (2), 85 (5), 57 (8). Addition of t-BuLi. N-[2-(3,4-Dimethoxyphenyl)ethyl]5,5-dimethyl-4-oxohexanamide (6d). According to General Procedure, imide 1a (526 mg, 2 mmol) was treated with t-BuLi (3.85 mL of a 1.3 M solution in pentane, 4.4 mmol). After workup, the residue was purified by flash column chromatography (silica gel, 20% CH2Cl2/AcOEt) to afford oxo amide 6d (340 mg, 53%): mp (Et2O) 134-136 °C, IR (CHCl3) 1710, 1660 cm-1; 1H NMR (CDCl3) 1.07 (s, 9H), 2.29 (t, J ) 6.5 Hz, 2H), 2.66 (t, J ) 6.5 Hz, 2H), 2.77 (t, J ) 6.7 Hz, 2H), 3.38 (q, J ) 6.7 Hz, 2H), 3.78 (s, 3H), 3.80 (s, 3H), 5.78 (broad s, 1H), 6.636.74 (m, 3H); 13C NMR (CDCl3) 26.3, 30.0, 32.0, 35.1, 40.7, 43.8, 55.7, 55.8, 111.2, 111.8, 120.5, 131.3, 147.4, 148.8, 172.0, 215.0; MS (EI) m/z (rel intensity) 321 (M+, 2), 264 (4), 165 (21), 164 (100), 151 (11), 149 (10), 113 (7), 77 (3), 57 (8). Addition of TMS-CH2Li. N-[2-(3,4-Dimethoxyphenyl)ethyl]-4-hydroxy-4-methyl-γ-lactam (5b) and N-[2-(3,4Dimethoxyphenyl)ethyl]-4-oxopentanamide (6b). According to General Procedure, imide 1a (526 mg, 2 mmol) was treated with TMS-CH2Li (5.5 mL of a 0.8 M solution in pentane, 4.4 mmol) to afford hydroxy lactam 5b and oxo amide 6b (335 mg, 60% overall) in a 5b/6b 4.8/1 ratio, that were

Reactions of N-Phenethylimides with Organolithium Reagents separated by flash column chromatography (silica gel, 5% CH2Cl2/MeOH). Data for 5b were identical to those previously reported (vide supra). Data for 6b: IR (CHCl3) 3370, 1725, 1660, 1530 cm-1; 1H NMR (CDCl3) 2.18 (s, 3H), 2.35 (t, J ) 6.4 Hz, 2H), 2.72 (t, J ) 7.0 Hz, 2H), 2.75 (t, J ) 6.4 Hz, 2H), 3.40 (dt, J ) 7.0, 5.8 Hz, 2H), 3.85 (s, 3H), 3.87 (s, 3H), 5.7 (broad s, 1H), 6.69-6.78 (m, 3H); 13C NMR (CDCl3) 29.6, 35.0, 38.3, 40.6, 55.6, 111.1, 111.8, 120.4, 131.3, 147.4, 148.7, 171.6, 209.8. Addition of PhLi. N-[2-(3,4-Dimethoxyphenyl)ethyl]4-phenyl-4-hydroxy-γ-lactam (5e) and 3-Benzoyl-N-[2(3,4-dimethoxyphenyl)ethyl]propionamide (6e). According to General Procedure, imide 1a (526 mg, 2 mmol) was treated with PhLi (2.2 mL of a 2 M solution in benzene/Et2O, 4.4 mmol) to afford hydroxy lactam 5e and oxo amide 6e in a 5e/6e 1/3 ratio (650 mg, 95% overall). Tautomers could not be separated due to decomposition on elution through silica gel: IR (CHCl3) 3350, 3340, 1700, 1690, 1620, 1520 cm-1; 1H NMR (CDCl3) 2.35-2.45 (m, 2H, 5e), 2.56 (t, J ) 6.5 Hz, 2H, 6e) 2.48-2.95 (m, 4H, 5e), 3.00-3.18 (m, 2H, 5e), 3.27 (t, J ) 6.5 Hz, 2H, 6e), 3.44 (dt, J ) 7.1, 6.2 Hz, 2H, 6e), 3.70 (s, 3H, 5e), 3.74 (s, 3H, 5e), 3.78 (s, 3H, 6e), 3.82 (s, 3H, 6e), 5.08 (s, 1H, 5e), 6.29 (distorted t, 1H, 6e), 6.53-6.72 (m, 3H, both tautomers), 7.24-7.57 (m, 3H, both tautomers), 7.92 (dd, J ) 7.7, 1.4 Hz, 2H, both tautomers); 13C NMR (CDCl3) 29.6 (5e), 30.1 (6e), 34.0 (6e), 34.4 (5e), 35.2 (5e), 37.7 (6e), 40.9 (5e), 42.0 (6e), 55.7 (both tautomers), 55.8 (both tautomers), 93.0 (5e), 111.2 (5e), 111.4 (5e), 112.0 (6e), 112.1 (6e), 120.7 (both tautomers), 127.1 (6e), 127.3, 128.0, 128.4, 128.6, 128.8 (both tautomers), 131.5 (both tautomers), 136.5 (6e), 141.12 (5e), 147.6 (6e), 148.9 (6e), 172.2 (6e), 175.4 (5e), 199.0 (6e); MS (EI) m/z (rel intensity) 341 (M+, 2), 164 (100), 133 (5), 105 (17), 91 (5), 77 (19). Addition of PhCtCLi. N-[2-(3,4-Dimethoxyphenyl)ethyl]-6-phenyl-4-oxohex-5-ynamide (6f). According to General Procedure, imide 1a (526 mg, 2 mmol) was treated with PhCtCLi (4.4 mL of a 1.0 M solution in THF, 4.4 mmol). After workup, the residue was purified by flash column chromatography (silica gel, 5% CH2Cl2/MeOH) to afford oxo amide 6f (445 mg, 61%): IR (CHCl3) 3340, 2200, 1700, 1670, 1520 cm-1; 1H NMR (CDCl3) 2.49 (t, J ) 6.4 Hz, 2H), 2.76 (t, J ) 6.9 Hz, 2H), 3.07 (t, J ) 6.4 Hz, 2H), 3.49 (dt, J ) 6.9, 5.8 Hz, 2H), 3.85 (s, 3H), 3.88 (s, 3H), 5.67 (broad s, 1H), 6.696.83 (m, 3H), 7.33-7.61 (m, 5H); 13C NMR (CDCl3) 29.9, 35.2, 40.7, 40.8, 55.9, 87.5, 91.4, 111.4, 111.9, 119.7, 120.6, 128.6, 130.8, 131.3, 133.0, 147.7, 149.0, 171.1, 186.2; MS (EI) m/z (rel intensity) 365 (M+, 6), 207 (2), 165 (13), 164 (100), 151 (24), 149 (15), 129 (8), 107 (6), 91 (10), 77 (10). Addition of Allyllithium. N-[2-(3,4-Dimethoxyphenyl)ethyl]-4-oxohept-6-enamide (6g). PhLi (15 mL of a 1.2 M solution in benzene/ether, 18 mmol) was added over a suspension of allyltriphenyltin (6.39 g, 16 mmol) in Et2O (32 mL), under argon, and the reaction mixture was stirred for 30 min. The so obtained yellow allyllithium solution was titrated with diphenylacetic acid, resulting in a 0.1 M solution. Allyllithium (22 mL, 2.2 mmol of the freshly prepared 0.1 M solution) was then added over a solution of imide 1a (263 mg, 1 mmol) at -78 °C, according to General Procedure. After workup, 1H NMR of the crude reaction mixture showed the quantitative formation of hydroxy lactam 5g and oxo amide 6g in a 1.9/1 ratio. Purification by column chromatography (silica gel, 5% CH2Cl2/MeOH) gave only oxo amide 6g, though contaminated with Ph4Sn: IR (CHCl3) 3350, 1660, 1640, 1515 cm-1; 1H NMR (CDCl3) 1.87-2.05 (m, 2H) 2.12-2.22 (m, 2H), 2.49-2.68 (m, 2H), 2.7 (t, J ) 6.9 Hz, 2H), 3.41 (dt, J ) 6.9, 5.1 Hz, 2H), 3.84 (s, 3H), 3.85 (s, 3H), 4.95-5.10 (m, 2H), 5.45 (broad s, 1H), 5.63 (ddt, J ) 11.0, 7.3, 5.3 Hz, 1H), 6.69-6.78 (m, 3H); 13C NMR (CDCl ) 31.1, 35.0, 37.0, 40.7, 48.4, 55.8, 55.9, 111.3, 3 111.8, 119.0, 120.6, 131.2, 133.6, 145.5, 147.7, 173.8, 209.7; MS (EI) m/z (rel intensity) 305 (M+,