Generation of cationic 2-azabutadienes from N , S -acetals and their use for the regio-and diastereoselective synthesis of 1,2,3,4-tetrahydroquinolines by intermolecular [4 π + + 2 π ] cycloadditions

Substituted 1,2,3,4-tetrahydroquinolines and related N -heterocycles are formed highly regio-and diastereoselectively with yields ranging from 57 to 100% by intermolecular polar [4 π + + 2 π ] cycloadditions of cationic 2-azabutadienes and various dienophiles. The cationic 2-azabutadienes can be generated in situ by Lewis acid mediated heterolytic cleavage of N,S - acetals. Best results have been obtained using a new mixed Lewis acid consisting of a mixture of TiCl 4 and PPh 3 .


Introduction
Tetrahydroquinolines and related ring systems have gained much attention in both natural product synthesis and medical research.Their efficient synthesis can be achieved, for example, by intermolecular cycloadditions of positively charged 2-azabutadienes 1 or neutral 2azabutadienes 4 with electron-rich alkenes 2 (Scheme 1). 1

Results and Discussion
AM1 calculations 20 indicate that cationic 2-azabutadienes such as 6 -due to their lower LUMO energies -exhibit much higher reactivity than the corresponding neutral 2-azabutadienes like 7 (Figure 1).In addition, the p-atomic orbital coefficients suggest that cationic 2-azabutadienes react much more selectively.Mechanistically, these reactions may either be seen to proceed in a concerted manner as polar [4π + + 2π] cycloadditions in terms of hetero Diels Alder reactions with inverse electron demand 2,3 (Figure 2, A) and subsequent aromatization, or as a multi-step process starting with the addition of an alkene 9 to an iminium ion 8 21 (Figure 2, B) and formation of a carbenium ion 11 as an intermediate and finally undergoing an intramolecular Friedel Crafts reaction.As far as we know the first example was reported by Swan, who reacted N,N-acetal 13 in the presence of benzoic acid with ethyl vinyl ether 14 and obtained the 4-substituted tetrahydroquinoline rac-15 (Scheme 2). 5

Scheme 2
Shono et al. demonstrated later that 2-aryl iminium ions may be generated by cleavage of N,O-acetals with Lewis acids at low temperatures.Here also, reaction with simple and electronrich olefins leads to regioselective formation of 1,2,3,4-tetrahydroquinolines.For example, The steric course of the transformation remains unknown.If formaldehyde 23 was used as the carbonyl compound the products of the double amino alkylation were isolated, whereas reaction of secondary aromatic amines such as N-methylaniline 22 with formaldehyde 23 led to tetrahydroquinolines like rac-25.

Scheme 5
Grieco and Bahsas demonstrated that cationic 2-azabutadienes like 27 could be generated in considerably milder conditions from anilinium trifluoro acetate 26 and formaldehyde 23 and then reacted with dienophiles. 14Transformation of 26 with 23 and cyclopentadiene 28 produced the diastereomeric mixture of the pentacycles rac-29 and rac-30 (Scheme 6).Here also only the double cyclization products are formed in transformations imvolving formaldehyde 23.With Grieco and Bahsas the synthesis of tetrahydroquinolines can also only be managed if they evade taking formaldehyde 23 as the aldehyde component.Following this method Mellor et al. have gained access to a large number of polycyclic systems by transforming numerous aromatic and heteroaromatic primary amines with formaldehyde and alkenes. 15They often selected amines that only allow a single cyclization.Even if few studies have so far been undertaken on the mechanism of the transformation of cationic 2-azabutadienes, the majority of findings indicates that the cyclizations proceed in a stepwise manner.Transformation of 19 and 20 producing rac-21 favors a multi-step process since it proceeds without preserving the dienophilic double bond configuration. 9In a number of cases Mellor et al. also managed to isolate follow-up products of potential intermediates which were then cyclized under reaction conditions to give the final products.15e,f From this they concluded that the reactions in these cases proceed stepwise.The present results, though, are insufficient to provide a satisfying answer to the question of which mechanism underlies these cyclizations.

Figure 3
Synthesis of N,S-acetal 35a was easily performed by reacting N-methylaniline 22 with formaldehyde 23 and thiophenol 34a in a yield of 84% (Scheme 9). 33The corresponding S-ethyl derivative 35b was produced in a similar way.Due to lower yields of 35b, most studies presented in this paper were undertaken with the S-phenyl derivative 35a.

Scheme 9
When N,S-acetal 35a was reacted with styrene 36 and TiCl 4 as a Lewis acid the single cycloadduct produced was the tetrahydroquinoline rac-37 in 61% yield (Scheme 10) (Table 1, Entry 1), which indicates that in 35a the only cleavage taking place is in the C-S bond resulting in the formation of the iminium salt 38; obviously, cleavage of the C-N bond to give 39 does not occur (Scheme 11).

Scheme 11
If TiCl 4 was replaced by SnCl 4 , tetrahydroquinoline rac-37 was isolated after 1 h at -78 °C, also in 61% yield (Table 1, Entry 2).Performing the reaction with 1.0 equivalents of SnCl 4 at higher temperatures (Table 1, Entry 3) raises the yield to 81%.A further increase may be achieved -even though more modestly -by employing 2.0 equivalents of SnCl 4 (Table 1, Entry 4).Since both TiCl 4 and SnCl 4 led to partial decomposition of the N,S-acetal weaker Lewis acids were also included in this study.Mixtures of TiCl 4 and triphenylphosphine turned out to be particularly promising.In a 1 : 1 ratio they have already been successfully applied as a Lewis acid in a number of cases. 34f 35a was reacted with styrene (36) and a 1 : 1 mixture of TiCl4 and triphenylphosphine no formation of rac-37 could be observed (Table 1, Entry 8).On the other hand, rac-37 was isolated in quantitative yield if the reaction was performed with a 2 : 1 mixture of TiCl 4 and triphenylphosphine (Table 1, Entry 9).Since the corresponding transformation with S-ethyl derivative 35b produced tetrahydroquinoline in a yield of no more than 80% (Table 1, Entry 10), S-phenyl-derivative 35a was employed for all transformations with other dienophiles.
Here we found that N,S-acetal 35a may be reacted with a number of dienophiles to give the corresponding tetrahydroquinolines (Table 2).In addition to styrene (36), 35a was also reacted with singly and triply substituted acyclic alkenes 40 and 42, with the allyl ether 44 and the allylsilane 46 (Table 2, Entries 1-5).Furthermore, the cyclic alkenes cyclopentene (48) and cyclopentadiene (28) could be converted into the products 49 and 50 as expected (Table 2, Entries 6, 7).The cycloadducts were obtained in yields ranging from 57 to 100%.
A total surprise, though, was encountered with the products isolated from the reactions of N,S-acetals with enol ethers and silyl enol ethers.While no reaction could be observed between 35a and dihydropyran 51, the transformation with ethyl vinyl ether 14 gave thioether rac-52 as the sole cycloadduct (Scheme 12).The same product was formed by reaction with n-butyl vinyl ether 53.
Faced with these results we assumed that the transformation of the vinyl ethers 56 into the corresponding vinyl sulfides 57 proceed in situ under the influence of Lewis acids in a manner illustrated in Figure 4, which then react with 2-azabutadiene.
In accordance with these findings we expected the formation of the ethyl thio ether 58 when the S-ethyl derivative 35b was reacted with enol ethers such as 53; this assumption turned out to be correct (Scheme 14).

Scheme 14
According to FMO theory the regioselective formation of the cycloadducts can be interpreted as a result of the most favourable (strong/strong and weak/weak) frontier orbital interactions  It has already been mentioned that the reactions discussed here can either proceed in a concerted manner as an intermolecular polar [4π + + 2π] cycloaddition or in a cationic multi-step process.

Scheme 15 Scheme 16
AM1 and PM3 calculations 20 predict that -independent of the equatorial or axial position of the methyl group at C-3 and the pseudoequatorial and pseudoaxial position of the phenyl group at C-4, respectively -the trans product 60 (Table 3, Entries 1,2) is more stable than the cis product 61 (Table 3, Entries 3,4).In case of a thermodynamically controlled reaction we would expect -regardless of the configuration of the dienophile employed -the products to be formed in proportion to their stabilities and thus the preferred formation of the more stable trans product 60.Isomerization experiments with rac-60 and rac-61 showed that their relative configuration does not alter under reaction conditions, meaning that isomerization does not take place (Table 4).Exclusive formation of the less stable cis product rac-61 from 35a and (Z)-methylstyrene (Z)-( 59) is suggestive of a concerted process of the polar [4π + + 2π] cycloaddition with cationic 2-azabutadienes.This assumption is also supported by the absence of follow-up products of the potential intermediates of an alternative cationic multi-step process.This finding is all the more remarkable as the studies so far published indicate that reactions of this type follow a multi-step cationic mechanism.
It should be noted, though, that exclusive formation of the less stable cis product rac-61 from 35a and (Z)-methylstyrene (Z)-( 59) does not offer unambiguous proof of a concerted reaction mechanism.This result could also very well be attributed to the fact that the cyclization of the benzyl cation rac-62 into rac-61 proceeds much quicker than the conversion into the more stable benzyl cation rac-63 by rotation around the C,C single bond (Figure 6).But regardless of the reaction mechanism the method presented here guarantees the regio-and diastereoselective construction of 1,2,3,4-tetrahydroquinolines and related systems.

Figure 6
Assignment of the relative configuration of rac-60 and rac-61 was undertaken by 1 H NMR spectroscopy and comparison of the two spectra.The trans arrangement of the protons attached to C-3 and C-4 in rac-60 follows from the signal for 4-H resonating at δ = 3.64 ppm as a doublet with a vicinal coupling constant of 3 J 3H,4H = 8.5 Hz (Figure 7).The value of the coupling constant of J = 8.5 Hz for the vicinal coupling between 2-H ax and 3-H indicates that 3-H is In the 1 H NMR spectrum of rac-61 the signal for 4-H at δ = 3.98 ppm appears as a doublet with a vicinal coupling constant of 3 J 3H,4H = 5.0 Hz (Figure 8).Comparison to the 8.0 Hz coupling constant for the corresponding coupling in rac-60 provides sound evidence for the cis arrangement of the protons at C-3 and C-4.The equatorial position of 3-H can be derived from the values of the coupling constants of the vicinal couplings between 3-H and the protons at C-2. Accordingly, in rac-61 an axial arrangement is inferred for the methyl group at C-3 and a pseudoequatorial arrangement of the phenyl group at C-4.

Conclusions
Substituted 1,2,3,4-tetrahydroquinolines can be synthesized by polar [4π + + 2π] cycloadditions of cationic 2-azabutadienes with alkenes.We found that cationic 2-azabutadienes can be generated in situ by Lewis acid mediated heterolytic cleavage of N,S-acetals.Their actions with different dienophiles have been studied and found to yield the corresponding cycloadducts as single products with yields ranging from 57 to 100%.Best results have been obtained using a new mixed Lewis acid consisting of a mixture of TiCl 4 and PPh 3 .Surprisingly little is known about the stereochemistry and mechanism of these [4π + + 2π] cycloadditions.Here we present stereochemical evidence to support a concerted mechanism.We have shown that the reactions of an N,S-acetal with either (E)-or (Z)-methylstyrene proceed with complete preservation of the stereochemistry of the dienophiles to yield the corresponding diastereomerically pure trans-and cis-cycloadducts, respectively.These results strongly point to a concerted mechanism being operative in the reactions studied.

Experimental Section
General Procedures.All moisture-sensitive reactions were performed in dried flasks (140 °C, 2 h) under argon using syringe techniques.Solvents were dried and purified by conventional methods prior to use.Dichloromethane was freshly destilled from P Methoxymethyl-methyl-phenyl-amine (16).24.0 ml (0.30 mol) of 37 % aqueous formaldehyde solution 23 were added to a solution of 21.8 g (0.20 mol) N-methylaniline 22 in 9.50 g (0.30 mol) methanol at room temp.with stirring.The mixture was heated under reflux until Nmethylaniline 22 had reacted completely (TLC monitoring, diethyl ether/petroleum ether 1:6).After cooling the reaction mixture was saturated with K 2 CO 3 and stirred for 30 min at room temp.The layers were separated and the aqueous layer was extracted with diethyl ether (2 × 25 ml).The combined organic extracts were dried (K 2 CO 3 ).The solvent was removed under reduced pressure and the crude product purified by fractional destillation to yield 16 (10.75

Methyl-phenyl-phenylsulfanylmethyl-amine (35a
).An emulsion of N-methylaniline 22 (32.2 g, 0.30 mol) and water (66 ml) was prepared and paraformaldehyde 23 (9.00 g, 0.30 mol) was added with stirring.Then a solution of thiophenol 34a (32.4 g, 0.30 mol) in diethyl ether (75 ml) and K 2 CO 3 (41.5 g, 0.30 mol) were added, whereby the mixture warmed.After cooling the reaction mixture was stirred for 48 h at room temp.and monitored by TLC (diethyl ether/petroleum ether, 1:6).The layers were separated and the aqueous layer was extracted with diethyl ether (2 × 75 ml).The combined organic extracts were washed with saturated Na 2 CO 3 (2 × 100 ml) and NaCl (1 × 100 ml) solutions and dried (Na 2 SO 4 ).The solvent was evaporated and the crude product destilled to yield 35a (57.89 g, 84%) as a colorless oil, b.p. 120 °C/0.001mbar.To obtain an analytically pure product, 35a was purified by column chromatography (diethyl ether/petroleum ether, 1:15).In addition to 35a, 5% of the minor product diphenyldisulfide Ethylsulfanylmethyl-methyl-phenyl-amine (35b).Paraformaldehyde 23 (9.00 g, 0.30 mol) was added to a mixture of N-methylaniline 22 (32.2 g, 0.30 mol) and water (66 ml) under stirring.The reaction mixture was saturated with K 2 CO 3 and warmed.A solution of ethyl mercaptan 34b (18.6 g, 0.30 mol) in diethyl ether (75 ml) was dropped slowly into the warmed mixture and stirred for 12 h at room temp.Monitoring was performed by TLC (diethyl ether/petroleum ether, 1:6).The reaction mixture was extracted with diethyl ether (2 × 75 ml).The combined organic extracts were washed with saturated Na 2 CO 3 (2 × 100 ml) and NaCl (1 × 100 ml) solutions and dried (K 2 CO 3 ).The solvent was removed under reduced pressure and the crude product purified by fractional destillation to yield 35b (28.1.14 g (5.00 mmol) of 35a were dissolved in 5 ml dry dichloromethane, treated with the equiv.Lewis acid provided in Table 1 at the given temperature and stirred for 5 min at the reaction temp.Then 1.3 -3.0 equiv.styrene 36 was added.The mixture was stirred at the temperature and for the time given in Table 1.For work-up the reaction mixture was treated with 5 ml sat.sodium hydrogen carbonate solution: The layers were separated and the aqueous layer extracted with dichloromethane (2 x 10 ml ).The combined organic layers were dried (Na 2 SO 4 ) and the solvent removed in vacuo.The crude product was purified by column chromatography on 100 g silica gel (diethyl ether / petroleum ether, 1 : 15) (Table 1, No. 1 -9).

General procedure for the synthesis of tetrahydroquinolines
Triphenylphosphine (1.0 equiv.) in dichloromethane (1 M) was added to a stirred solution of TiCl 4 (2.0 equiv.) in dichloromethane (1 ml/1 mmol TiCl 4 ) at 0°C.The solution which turned deep red, was stirred for another 15 min at 0 °C and added dropwise to a solution of methylphenyl-phenylsulfanylmethylamine 35a (1.0 equiv) in dichloromethane (5 ml dichloromethane/1 mmol 35a) at 0°C.After 10 min at 0 °C the appropriate dienophile (1.5 equiv.) was added dropwise, the resulting solution was warmed up to room temp.and stirred until completion (TLC).The reaction was quenched by addition of saturated Na 2 CO 3 solution (10 ml/2 mmol TiCl 4 ) and stirred for 20 min.After extraction with dichloromethane (3 × 15 ml/1 mmol 35a) the combined organic layers were dried (Na 2 SO 4 ), the solvent was removed in vacuo and the residue was purified by column chromatography on silica gel.

Figure 2 .
Figure 2. Alternative mechanism for the formation of tetrahydroquinolines 12 from the reaction of cationic 2-azabutadienes 8 with alkenes 9.

Figure 4 .
Scheme 12 between the LUMO of the diene 6 and the HOMO of the corresponding dienophile (see for example Figure5).35

Scheme 10 Table 1 .
Reactions of the N,S-acetals 35a,b with styrene 36 using different Lewis acids