Dissecting the Gold(I)-Catalyzed Carboaminations of N-Allyl

Article pubs.acs.org/joc

Cite This: J. Org. Chem. 2018, 83, 898−912

Dissecting the Gold(I)-Catalyzed Carboaminations of N‑Allyl Tetrahydro-β-carbolines to Allenes Valérian Gobé,† Maxime Dousset,† Pascal Retailleau,† Vincent Gandon,†,‡ and Xavier Guinchard*,† †

Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Sud, Université Paris-Saclay, 1 av. de la Terrasse, 91198 Gif-sur-Yvette, France ‡ Institut de Chimie Moléculaire et des Matériaux d’Orsay, CNRS UMR 8182, Université Paris-Sud, Université Paris-Saclay, Bâtiment 420, 91405 Orsay cedex, France S Supporting Information *

ABSTRACT: N-Allyl tetrahydro-β-carbolines undergo gold-catalyzed cyclizations that lead to tetracyclic compounds, resulting from both ring closure and the transfer of the allylic group from the nitrogen to the carbon backbone. The final skeleton obtained depends on the nature of both the R2 group of the allene and the R3 group of the allylic residue. Mechanistic studies and DFT calculations allowed the determination of all the mechanistic pathways involved in these processes, stemming from a common intermediate that evolves differently according to the substituents nature.

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also the case in other cyclizations of this type.13c,d However, these carboaminations proceeding with an allyl migration are, to the best of our knowledge, limited to cyclizations on alkyne functions. Recently, we initiated a research program aimed at the synthesis of polycyclic indolic architectures,14 including indolo[2,3-a]quinolizidines,14a−d that are compounds present in hundreds of natural and/or bioactive compounds.15 Thus, they can be considered as privileged scaffolds for the discovery of novel bioactive compounds.16 In the course of a first approach, we reported the Pd(0)-catalyzed cyclization of N-allyltetrahydro-β-carbolines 1 bearing an allene group.14a,b In this process, the N-allyl protecting group was removed in situ and the resulting amine cyclized on the allene function, leading to a 5-membered pyrrolidine ring 2 in a good diastereoselectivity (Scheme 1, eq 3). However, when tetrahydro-β-carboline 1a (R1 = R2 = H) was reacted in the presence of a gold(I) complex, we obtained instead the tetracyclic derivative 3a (R1 = R2 = R3 = H) (Scheme 1, eq 4).14d Surprisingly, this compound resulted from an intramolecular 6-exo cyclization on the allene function, proceeding concomitantly with an allyl migration. It was found that the substitution pattern of the allene also dictates the

INTRODUCTION Gold catalysis has left infancy over the past decade and revolutionized the way of thinking retrosynthetic pathways in a number of reactions categories,1 including in an asymmetric manner.2 One of the popular reactivities is the intramolecular addition of heteroatoms to multiple bonds that leads to a number of important heterocycles.3 Most of the reported examples proceed by hydrofunctionalization4 of alkynes,5 allenes,6 or alkenes.7 On the other hand, gold complexes are also able to catalyze the addition of substituted heteroatoms to unsaturations, with a concomitant 1,3-transfer of the substitution group (Scheme 1, eq 1). Hence, alkyl,8 silyl,9 arylidene,10 propargyl,11 or allyl groups have been transferred in the course of such cyclization processes, leading to a large variety of functionalized heterocycles. In particular, cyclization of O-,12 S-,8a or N-allyl13 functions on alkynes led, not exhaustively, to pyrroles, indoles, benzopyranes, or benzofuranes. Gagosz, for instance, reported the gold-catalyzed formation of pyrroles by intramolecular 5-exo addition of an N-allylamine to an alkyne function proceeding with the migration of the allyl group (Scheme 1, eq 2).13a Very interestingly, disubstituted allyl groups (R ≠ H) were transferred with concomitant creation of a stereogenic center. This, along with other pieces of evidence, suggests an intramolecular concerted mechanism for the allyl transfer, which is © 2017 American Chemical Society

Received: November 15, 2017 Published: December 18, 2017 898

DOI: 10.1021/acs.joc.7b02900 J. Org. Chem. 2018, 83, 898−912

Article

The Journal of Organic Chemistry

Among the numerous methods available for the synthesis of enantioenriched tetrahydro-β-carbolines 1,18 we selected the chiral phosphoric acid-catalyzed Pictet−Spengler reactions19 between the corresponding protected tryptamines 6 and allenaldehydes 7.20 We targeted structural diversity on the indolic core (R1), the allyl chain (R2, R3, R4), and on the allene substitution pattern (R5). Spinol-derived chiral phosphoric acid21 8 afforded (S)-configured 1 in excellent yields and ee’s, generally higher than 93% (Table 1). Substrates 1g and 1p−r bearing an (E)-but-2-en-4-olyl chain were obtained in more modest yields due to the very low solubility of the starting tryptamine 6g under the conditions of the reaction (entries 7 and 16−18), even when the reactions were performed at higher temperature. Tetrahydro-β-carboline 1g was however obtained in 65% yield and 85% ee and could also be transformed to its silyl and acetyl analogues 1h and 1i, respectively (entries 8 and 9). Overall, this method was found to be applicable to a large variety of substrates, including all derivatives with substituted N-allyl functions (R2, R3 or R4 ≠ H), while the chiral phosphoric acid-catalyzed Pictet−Spengler reaction had previously been used with rather simple protecting groups (i.e., benzyl,19b naphthylmethyl,19c and allyl14a). Enantioenriched tetrahydro-β-carbolines 1a−f and 1h−i were then cyclized using 2 mol % of Echavarren’s catalyst 5 in toluene at 70 °C at a concentration of 0.1 M (Scheme 3). Reactions performed on the starting tetrahydro-β-carbolines 1a−d proceeded well, leading to the corresponding tetracyclic compounds 3a−d in excellent yields, showing the low influence of electron-donating or electron-withdrawing groups on the indolic core. The allyl protecting group was in all cases transferred efficiently. The cyclizing ability of substrates bearing substituted allyl groups was next investigated. The tetracyclic compound 3e was obtained in 86% yield with an efficient transfer of the methallyl group by reaction of amine 1e in the presence of catalyst 5. Compound 1f, bearing a cinnamyl group on the nitrogen, led to the branched compound 3f, resulting from the cyclization and transfer of the cinnamyl group in 48% with a good 87/13 diastereocontrol. The “branched” nature of the cinnamyl group in product 3f is highly indicative of a concerted mechanism that will be discussed later in the paper (see Scheme 11). Similarly, compounds 3h and 3i bearing protected butenolyl chains were obtained in good yields and excellent diastereoselectivities.22 The tolerance of gold complexes to oxygen, moisture, and many functional groups renders them ideal for the development of tandem catalytic processes with Brønsted acids.23 Numerous gold complexes have thence been used in addition with Brønsted acids in elegant cascade reactions developed for the synthesis of complex compounds.5c,d,24 We thus intended to establish if the sequence Pictet−Spengler/cyclization could be performed in a one-pot manner. Initial attempts combining tryptamine 6a, aldehyde 7a, diphenyl phosphate and gold(I) complex 5 resulted in a low 15% yield in product 3a, the major product being the intermediate tetrahydro-β-carboline 1a. Attempts performed in a sequential manner were much more successful. The Pictet−Spengler reaction was accordingly performed at room temperature for 24 h in the presence of the chiral catalyst 8, prior to adding the gold(I) catalyst 5. Further stirring at 70 °C for 18 h ensured full conversion of the intermediate to the cyclized product 3. Compounds 3a, 3d, and 3e were obtained according to this strategy in moderate to excellent yields (Table 2). The measurement of the ee’s of compounds 3 showed the same level of enantioselectivity than when the

Scheme 1. Known Au(I)-Catalyzed Carboheterofunctionalization of Alkynes and Our Approach on Allenes

chemoselective formation of either compounds 3 or 4. In this paper, we wish to report a full comprehensive study on these gold-catalyzed carboaminations of 1 leading to either 3, 4 and other scaffolds and on their reductions. Experimental and computational studies by DFT calculations are described, allowing the determination of the mechanism of these transformations.

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RESULTS AND DISCUSSION We initiated our study with the establishment of catalytic systems suitable for the cyclization of N-allyl tetrahydro-β-carbolines 1 bearing either mono- or disubstituted allenes. It was found that amine 1a (R = H) reacted in toluene at 70 °C with 2 mol % of the Echavarren’s catalyst 5,17 leading to 3a in full conversion and 88% isolated yield (Scheme 2).14d The reaction of amine 1j Scheme 2. Optimized Conditions

necessitated to increase the catalytic charge to 5 mol %, the concentration to 0.2 M, and the reaction time to 16 h. Under these conditions, compound 4j, which differs from 3a by the position of the allyl group, was obtained in 82% yield (Scheme 2). These two series of compounds are sensitive to silica gel due to the presence of the enamine function using numerous eluents. However, the use of a mixture of toluene and tert-butyl methyl ether (80/20) allowed the clean isolation of compounds. 899


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The Journal of Organic Chemistry Table 1. Synthesis of Enantioenriched Tetrahydro-β-carbolines 1

entry

R1

R2

R3

R4

R5

yield (%)a

ee (%)b

1 2 3 4 5 6 7 8d 9d 10 11 12 13 14 15 16 17 18

H 5-OMe 6-OMe 5-F H H H H H H H H H H H H H H

H H H H Me H H H H H H H H H H H H H

H H H H H Ph CH2OH CH2OTBS CH2OAc H H H H Me Ph CH2OH CH2OH CH2OH

H H H H H H H H H H H H H Me H H H H

H H H H H H H H H Me iPr Ph p-ClPh Me Me Me iPr Ph

1a, 92 1b, 90 1c, 88 1d, 68 1e, 73 1f, 98 1g, 65 1h, 76 1i, 88 1j, 83 1k, 88 1l, 88 1m, 66 1n, 83 1o, 86 1p, 40 1q, 83 1r, 31

93 94 NAc 93 93 94 85 85 85 94 94 95 94 93 93 NAc NAc NAc

Isolated yields. bee’s were measured by chiral HPLC. cNA: Not applicable. These entries were performed at 70 °C using (PhO)2POOH as the catalyst. dYields reported in entries 8 and 9 refer to silylation and acetylation of tetrahydro-β-carboline 1g, respectively. a

Table 2. Tandem Sequence Combining the Pictet−Spengler Reaction and the Cyclization

Scheme 3. Scope of the Carboaminations Using Carbolines 1

entry

R1

R2

yield (%)

ee (%)

1 2 3

H 5-F H

H H Me

3a, 86 3d, 59 3e, 70

95 92 96

1n and 1o did undergo cyclizations but, unexpectedly, led to linear compounds 4n,o. In other words, the carbon pattern of the initial N-allyl group remains fully similar in the product, but connected at position 13, indicating a divergent mechanism from that of compounds 3. Likewise, cyclization of 1l or 1m (R1 = Ph and p-ClPh, respectively) showed that aryl groups were tolerated in this process (Scheme 5), however leading to inseparable mixtures of products 4l,m and pentacyclic compounds 9l,m (2/1 ratio in both cases, 80% yield of the mixture of 4m and 9m) with full conversions. Interestingly, these pentacyclic compounds were not detected in previous examples and possess a backbone in which the allyl group carbons (in blue) have been connected to both positions C-3 and C-13. This indicates that compounds 9 could result from a common intermediate that would lead to either 4 or 9 via competitive pathways depending on the nature of the R1 group on the allene.

Pictet−Spengler reaction is performed apart, which also demonstrates that the gold-catalyzed cyclization does not affect the chiral information. Tetrahydro-β-carbolines 1j−o featuring gem-disubstituted allenes were engaged into cyclization reactions under the optimized conditions (Scheme 4). Compounds 1j,k,n,o were reacted in the catalytic conditions established above, and we studied the impact of both R1 and R2 groups on the cyclization process. Overall, reaction times were longer than reactions with substrates 1a−h, and it was necessary in some cases to add another load of catalyst 5 after 24 h for the reaction to go to completion. The reaction of alkyl-substituted allenes (R1 = Me (1j), i-Pr (1k)) led to the corresponding products 4j,k in good yields. We next studied the migrating ability of prenyl and cinnamyl groups. Very interestingly, in both cases, carbolines 900


Article

The Journal of Organic Chemistry Scheme 4. 6-Exo Cyclization Reactions with Disubstituted Allenes

Figure 1. ORTEP drawing of compound 11l (thermal ellipsoids set at 50% probability).

Scheme 7. Reductions of Enamine 3a to Amine 12a and 4k to 10k

Scheme 5. Cyclization of 1l and 1m

In order to gain further insight in the cyclization using substrates with R1 = Ar and because of the difficulty to isolate and purify compounds 4 and 9 on silica gel, we intended to perform the gold-catalyzed cyclization of 1l and reduce directly the intermediate mixture 4l/9l by addition of phenylsilane in the conditions of Beller (Scheme 6).25 The whole process Scheme 6. In Situ Cyclization of 1l and Reduction to Saturated Heterocycles 10l and 11l

Figure 2. ORTEP drawing of compound 12a (thermal ellipsoids set at 50% probability).

possessing skeleton 4 are not reduced stereoselectively under these conditions (see also Scheme 6). All four diastereomers could be separated and characterized independently. Substrates 1g and 1p−r are functionalized with an (E)-but-2en-1-olyl fragment on the nitrogen. We hypothesized that the presence of the nucleophilic alcohol function may be useful to trap a potential intermediate. The gold-catalyzed cyclization of these substrates indeed furnished pentacyclic compounds 13 that differ from the previous cyclization products by the presence of an additional cycle (Scheme 8). The cyclization of 1g (R1 = H) led to compound 13g in 80% yield and in a 85/15 diastereomeric ratio. Both NMR experiments and X-ray diffraction studies (Figure 3) were decisive in the elucidation of the relative stereochemistry of the major diastereomer (the minor diastereomer of 13g is the epimer at C-13). Tetrahydroβ-carbolines 1p−r (R1 ≠ H) led to compounds 13p−r in good yields and diastereoselectivities. Interestingly, despite the disubstitution pattern of the allene that usually leads to a transfer of the allylic group at C13, the structural analysis of compounds 13p−r shows that the transfer of the (E)-but-2-en-1olyl was achieved in a branched manner to position C-3. Despite discrepancies in the relative stereochemistries at C-3 and C-4, it is important to note the close structural similarity

furnished a separable mixture of 10l and 11l in 70% yield. Compound 10l stemming from reduction of 4l was obtained as a complex mixture of diastereomers in 42% yield. Compound 11l, resulting from the reduction of enamine intermediate 9l, was obtained in 28% yield as a single diastereomer, for which the relative stereochemistry could be easily attributed by 2D NOE experiments and X-ray diffraction (Figure 1). Similar reduction using phenylsilane was performed on substrate 3a, leading to 12a in 51% yield and as a single detectable diastereomer (Scheme 7). Characterization by NMR techniques and X-ray diffraction studies showed cis relationships between H-12b, H-3, and H-4, and confirmed the chemical arrangement of the carbon backbone of compounds 3 (Figure 2). When a similar reduction was performed on substrate 4k, a mixture of four diastereoisomers of 10k (dr 22/18/18/42) was obtained in 70% yield, thereby confirming that compounds 901


Article

The Journal of Organic Chemistry Scheme 8. Synthesis of Chiral Hemiaminals 13a

Though the high level of diastereoselectivity obtained for compounds 3f−h seems to indicate an intramolecular allyl migration, a crossover experiment was performed to obtain definitive proof. To this aim, compounds 1k and 1n were submitted together to the cyclization conditions (Scheme 9), Scheme 9. Crossover Experiment Leading to 4k and 4n as Sole Products

a

The structures of the major diastereomers are shown.

leading to 4k and 4n as the sole detectable products (1H NMR and MS; see the Supporting Information), providing strong evidence for an intramolecular concerted mechanism.28 We next undertook the 1H NMR monitoring of the goldcatalyzed transformation of 1n into 4n. The reaction was performed in an NMR tube at 70 °C, and a proton spectrum was recorded every 5 min. This experiment clearly shows the formation of an intermediate (Scheme 10, t = 0 min shows the Scheme 10. 1H NMR Monitoring of Cyclization of 1n into 4n (3.7−6.4 ppm Region)

Figure 3. ORTEP structures for hemiaminals 13g, 13q, and 13r (thermal elipsoids set at 50% probability).

between compounds 13g and 13p−r. For these compounds, the use of substrates with R1 = H or R1 ≠ H consequently did not induce structural changes in the observed product. The mechanism of these cyclizations was next investigated. In related migrations of allyl groups from heteroatoms to alkyne functions catalyzed by gold12a,b,13a−c or platinum26 complexes, two distinct mechanisms have been reported. A dissociative mechanism is involved in most cases of allyl transfer from an oxygen atom,12a,b but it is usually proven that N-allyl functions migrate via a concerted aza-Cope rearrangement.13,27 We hypothesized that a similar process is involved in our cyclizations.

spectrum of starting 1n, t = 5 h shows the spectrum of 4n) that increases over time and decreases for the benefit of product 4n. This intermediate clearly presents a vinyl group (signals at 6.4 and 5.3 ppm), two singlets in the vinyl region (δ = 4.77 and 4.35 ppm), 902


Article

The Journal of Organic Chemistry and a CH very close to H-12b of 1n (δ = 3.95 ppm). With these elements, we hypothesized that intermediate 14n is the actual product of the gold-catalyzed cyclization. This transient intermediate is next converted under the conditions of the reaction to 4n. All of these experiments and observations led us to propose the following catalytic cycle (Scheme 11). After complexation

Scheme 12. Further Evolution of 14-[Au]

Scheme 11. Postulated Catalytic Cycle

Scheme 13 shows the steps studied for the monosubstituted allene complex AH (R = H) and the disubstituted allene AMe (R = Me). Four modes of cyclization were envisaged: (i) 5-exotrig; (ii) 7-endo-trig; (iii) 6-endo-dig; (iv) 6-exo-dig. Only pathways iii and iv would account for the experimentally observed [5,6,6] tricyclic core. The Gibbs free energy profiles computed for the transformations depicted in Scheme 13 are shown in Scheme 14. In the case of R = H, the cyclization barriers corresponding to pathways i−iv to BH−EH clearly favor the 5-exo mode (1.6 kcal/mol) < 6-endo (3.8 kcal/mol) < 6-exo (7.3 kcal/mol) < 7-endo (12.7 kcal/mol). The cyclizations are all exergonic, the 5-exo and 6-exo modes releasing the greatest free energy (22.2 and 19.4 kcal/mol, respectively). However, under the experimental conditions used, the unproductive 5-exo cyclization should remain reversible. Thus, the 6-endo pathway iii is also likely since its barrier remains low. This cyclization mode, which releases 11.8 kcal/mol of free energy, leads to the η1-allylgold complex D, which is a regioisomer of E. These two regioisomers can interconvert through a transition state lying 6.3 kcal/mol above AH. The direct transformation of AH into EH is also possible, but the transition state lies 7.3 kcal/mol above AH. The asynchronous allyl shift converting EH into GH requires 25.2 kcal/mol (3.0 kcal/mol above AH (see Figure 4 for the geometries). This step releases 31.4 kcal/mol of free energy. Complex GH appears as a resonance hybrid between a σ-alkyliminium complex and a π-enamine derivative.33 Indeed, a great level of delocalization of the enamine moiety is revealed by the C−N and C−C bond lengths (1.34 and 1.43 Å, respectively). Product 3a would be obtained from complex GH after decoordination of the metal34 and double bond migration. The direct conversion of EH to FH implies reaching a transition state lying 39.5 kcal/mol above EH (17.3 kcal/mol above AH),35 and would finally afford GH-iso. In addition to being highly demanding in energy, this transformation would lead to the wrong carbon distribution in the allyl fragment compared to the experimental results obtained in the substituted allyl series, such as compounds 3f−h. What is expected is that the red carbon of AH in Scheme 13 becomes sp3 hybridized in the final product, which is not the case in GH-iso.

of the gold-catalyst to the allene, 6-exo-dig addition of the amine of 1-[Au] on the activated allene function would lead to the intermediate 15-[Au]. The aza-Cope rearrangement27 would then deliver 14-[Au]. At this stage, the allyl moiety has been transferred at position C-3 in a branched manner. Depending on the nature of R1, 14-[Au] will evolve differently to release products 3, 4, or 9. The fate of compounds 14-[Au] would actually depend on the nature of the R1 group: compounds with R1 = H would undergo an isomerization to the more stable internal olefin prior to protodeauration, releasing 3. Substrates with R1 ≠ H would undergo, after deauration, either an additional [3,3] Cope rearrangement to afford compounds 4 when R1 = Alk or Ar, or an additional gold-catalyzed reaction to afford compounds 9 when R1 = Ar (Scheme 12, eq 1). Compounds possessing an R2 = CH2OH group would react in a competing manner by trapping the iminium of 14-[Au], leading to 13-[Au] converted into 13 upon protodeauration (Scheme 12, eq 2). To get further insights and verify the viability of these hypotheses, we performed calculations on the postulated intermediates. All structures were optimized using the Gaussian 09 software package29 at the B3LYP30 level of density functional theory (DFT). The effective-core potential of Hay and Wadt with a double-ξ valence basis set (LANL2DZ) was used to describe Au.31 The other atoms were described by the 6-31G(d,p) basis set. Thermal corrections to the Gibbs free energy were obtained at the same level of theory. Single-point energy calculations were carried out at the M0632 level with the quadruple-ζ valence def2-QZVP basis set for Au and the 6-311+G(2d,p) basis set for the other elements. This level was also chosen to obtain the solvation energy in toluene using the CPCM model. The values presented herein are Gibbs free energies (kcal/mol) obtained from the M06/def2-QZVP(Au)6-311+G(2d,p)//B3LYP/LANL2DZ(Au)-6-31G(d,p) calculations in toluene (ΔG298, kcal/mol). 903


Article

The Journal of Organic Chemistry Scheme 13. Reactions of A Studied by Means of DFT Computations (L = (2-Biphenyl)di-tert-butylphosphine)a

a

To save space, the Ph ring of the indole moiety has been replaced by a dashed line.

Scheme 14. Free Energy Profile (ΔG298, kcal/mol) Relative to Complex AHa

a

Free energies of the transition states are in italics.

for the EMe → FMe transition state. Besides, the carbon distribution of FMe does not fit with the experimental pattern obtained in compounds 4. As noted before in the R = H series, the EMe → GMe step is greatly exergonic (ΔG298 −26.7 kcal/mol). Again, GMe can be considered as a resonance hybrid between a σ- and a π-complex (Figure 4). Its conversion to FMe-iso, for which the carbon distribution corresponds to the experimental products 4, requires a high free energy of activation of 36.1 kcal/mol. Moreover, FMe-iso is less stable than GMe by 3.4 kcal/mol. From these calculations, it appears that GMe is the actual product obtained in the gold-catalyzed step and that the experimental isolation of compounds 4 results from another reaction pathway.36 The above computations rationalize well the synthetic pathways involved in the formation of the intermediates G that are the actual products resulting from the gold-catalyzed reaction. However, it is clear from the experimental results that G evolves in the reaction according to further pathways that depend strongly on the nature of the substituent on the allene, leading

The case of the disubstituted allene complex AMe was next considered in order to explain the formation of products 4 (Scheme 15). This time, the 5-exo-dig cyclization transition state leading to BMe could not be computed. Our trials actually strongly suggest that this step is close to being barrierless, so the starting complex readily collapses to the cyclized product BMe. The AMe → BMe transformation is exergonic by only 10.6 kcal/mol; thus, the cyclization should be reversible under the experimental conditions. The other three cyclization modes appear in the following order of free energy of activation: 6-exo (0.3 kcal/mol) < 6-endo (10.6 kcal/mol) < 7-endo (12.8 kcal/mol). Again, they are all exergonic, but the exergonicity associated with the 6-exo cyclization to give EMe is the greatest (−23.0 kcal/mol vs −13.1 and −3.0 kcal/mol for CMe and DMe, respectively). The cyclization barrier to EMe is so low that the concerted process is now more favorable than the two-step A-D-E sequence. The formation of GMe from EMe was again found much more favorable than that of FMe since the EMe → GMe transition state lies 3.3 kcal/mol above AMe, vs 19.7 kcal/mol 904


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Figure 4. Geometries of selected computed species shown in Schemes 14 and 15 (distances in Å).

but significantly lower than in the gold complex series. Moreover, this rearrangement is now exergonic, leading to KMe (compound 4j). Interestingly, the [3,3] allyl shift from JH (compound 14a), that would cost 30.4 kcal/mol, does not take place. However, if the formation of the products 4 accounts for the intermediates G, the experimental results obtained with an aromatic substituent leading to compounds 9 (and their reduced counterparts 11; see Schemes 5 and 6) suggest that another synthetic pathway may also arise from intermediates G. We hypothesized that a ligand exchange from enamines G to olefin complexes L may occur and computed the intramolecular gold-catalyzed additions of enamines LMe and LPh to the

either to 3 (R = H), 4 (R = Alk), or 9 (R = Ar). Scheme 16 summarizes our hypotheses on the fate of intermediates G. Intermediate GH is formed in the R = H series. We think that, in this series, the elimination to complex HH is fast and leads, after protodeauration, to the final product IH, which is actually compound 3a. In the R = Me series, because the formation and the disappearance of an intermediate corresponding to the organic backbone of G can be monitored by NMR (compound 14c; see Scheme 10), we envisaged that a second [3,3]-shift takes place directly on the free enamine JMe arising from the decomplexation of LAu+ from GMe. The barrier corresponding to this sigmatropic shift remains high (ΔG⧧298 31.2 kcal/mol), 905


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The Journal of Organic Chemistry Scheme 15. Free Energy Profiles (ΔG298, kcal/mol) Relative to Complex AMea

a

Free energies of the transition states are in italics.

Scheme 16. Final Transformation of Complexes G to the Final Products 3, 4, and 9 with the Computed Free Energies of the Allyl Shift and the Additional Cyclization Step (kcal/mol)

activated olefins, in order to explain why GMe leads selectively to compounds 4j while GPh gives a mixture of 4l and 9l. We found that the LMe → MMe transition state lies at 32.0 kcal/mol, the transformation being endergonic by 3.8 kcal/mol. On the contrary, the similar transformation involving phenyl-substituted LPh is by far more favorable with an energy barrier of 14.3 kcal/mol and releasing 12.8 kcal/mol (Scheme 16). An elimination and a protodeauration would then deliver skeletons 9. The conducted computations on all series corroborate the experimental results. One of the more relevant information is that the 5-exo-trig addition A → B is the more favorable addition among the four possibilities, because of their low energy barriers and high exergonicities. This mode of cyclization is, however, not productive because the 5-exo intermediates B are dead-ends. Under the experimental conditions, it is likely that the reaction is reversible and then evolves via the 6-exo or endo modes that are interconverting and can go further through the aza-Cope rearrangement. These modes of cyclizations are however intriguing since the addition of a heteroatom to a 1,5-heteroallene results in most cases to a 5-exo-trig addition both with silver37 and gold3e complexes, with some rare exceptions.38 Indeed, we also verified this experimentally by cyclizing the nonprotected compound 15

with 5 mol % of catalyst 5 and obtained the tetracyclic compound 2a in 68% yield as a 29/71 diastereomeric ratio (syn-2a/anti-2a), resulting exclusively from the 5-exo-trig hydroamination (Scheme 17). Scheme 17. Gold-Catalyzed Cyclization of Secondary Amine 15

Computations performed on the four possible modes of addition from complex ANH showed that the 5-exo-trig addition to BNH is the more favorable pathway, with a low 6.2 kcal/mol energy of activation (Scheme 18). The product 2a, resulting from the complex BNH, is consequently the kinetic product of the reaction. In addition to providing a three-carbon synthon transfer over the course of the cyclization, the presence of an allyl group (and substituted allyls) in the starting material forces the reaction to proceed with a different regioselectivity than with unprotected 906


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The Journal of Organic Chemistry Scheme 18. Free Energy Profiles (ΔG298, kcal/mol) Relative to Complex ANHa

a

Free energies of the transition states are in italics. Infrared spectra (IR) were recorded on a PerkinElmer FT-IR system using diamond window Dura SamplIR II, and the data are reported in reciprocal centimeters (cm−1). Optical rotations were measured on a Anton Paar MCP 300 polarimeter at 589 nm. [α]D is expressed in deg·cm3·g−1·dm−1, and c is expressed in g/100 cm3. Melting points were recorded in open capillary tubes on a Büchi B-540 apparatus and are uncorrected. High resolution mass spectra (HRMS) were recorded using a Micromass LCT Premier XE instrument (Waters) and were determined by electrospray ionization (ESI) with a TOF analyzer. Synthesis of N-(2-(1H-Indol-3-yl)ethyl)-3-methylbut-2-en-1amine (6h). A mixture of N-(2-(1H-indol-3-yl)ethyl)-4-nitrobenzenesulfonamide (1.25 g, 3.62 mmol), 3,3-dimethylallyl bromide (0.54 g, 3.62 mmol), and K2CO3 (2.50 g, 18.0 mmol) in anhydrous DMSO (10 mL) was stirred at room temperature for 2 h. Thiophenol (1.10 mL, 10.8 mmol) was added and stirring was continued overnight. The reaction was quenched with water, and NH4Cl solution, and the aqueous phase was extracted twice by EtOAc. Combined organic layers were dried with MgSO4, filtered, and concentrated under vacuum. The crude was purified by flash chromatography on silica (eluent: DCM/MeOH, 9/1 to 85/15) to give an oil. The oil was washed with NaOH 2 M, then extracted twice by DCM to give 6h as a solid (630 mg, 2.75 mmol, 76%). IR (neat) νmax 3401, 32341634, 1618 cm−1. 1H NMR (500 MHz, CDCl3) 7.95 (s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1Hr), 7.24 (t, J = 7.5 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 7.03 (s, 1H), 5.22 (t, J = 5.8 Hz, 1H), 3.22 (d, J = 7.5 Hz, 2H), 2.98 (m, 4H), 1.67 (s, 3H), 1.59 (s, 3H). 13C NMR (75 MHz, CDCl3) 136.6 (Cq), 134.3 (Cq), 127.6 (Cq), 123.2 (CH), 122.2 (CH), 122.1 (CH), 119.3 (CH), 119.1 (CH), 114.1 (Cq), 111.3 (CH), 49.7 (CH2), 47.4 (CH2), 26.0 (CH2), 25.9 (CH3), 18.1 (CH3). HRMS (ESI) calc for C15H21N2 [M + H]+ 229.1705, found 229.1707. Synthesis of Tetrahydro-β-carbolines 1. A mixture of Nβ-allyl tryptamine 6 (1 equiv), catalyst 8 (0.02 equiv), and 4 Å molecular sieves (0.23 g for 0.35 mmol of 6, powdered) in toluene (1.5 mL for 0.1 mmol of 6) was stirred for 5 min at room temperature under an argon atmosphere. Subsequently, aldehyde 7 (3 equiv) was added, and the mixture was stirred at rt for 16 h. The reaction mixture was filtered over silica pad. The filtrate was concentrated under vacuum and purified by flash chromatography to give the desired product 1. 2-Allyl-1-(3-phenylpenta-3,4-dien-1-yl)-2,3,4,9-tetrahydro-1Hpyrido[3,4-b]indole 1l. 1l was prepared according to the general procedure from Nβ-allyl tryptamine 6a (80 mg, 0.4 mmol), aldehyde 7d (134 mg, 0.8 mmol), catalyst 8 (5.9 mg, 0.008 mmol), and 4 Å molecular sieves (160 mg) in PhMe (6 mL). 1l was obtained after column chromatography on silica gel (eluent: EtOAc/Petroleum ether, 5/95) as a yellow oil (90 mg, 0.35 mmol, 88%). Rf = 0.33 (EtOAc/ Petroleum ether, 10/90). [α]26D = +22.7 (c 1.00, CHCl3). ee = 95%, determined on a Chiralpak AD-H column [Heptane 0.1% Et3N: IPA 0.1% Et3N, 97:3, 1 mL/min, λ = 277 nm, retention times: 5.25 min (minor)

secondary amines and paves the way to other uncommon series of compounds.

■

CONCLUSION We consequently have reported the intramolecular gold-catalyzed ring closure of N-allyltryptamines on allenes via carboamination reactions. The substitution pattern of the allene function resulted in the obtaining of different series of compounds. In all cases, the reaction was initiated by a carboamination that delivers a compound in which the allyl moiety has migrated from the nitrogen to the carbon backbone. This unprecedented reactivity was studied through experimental, mechanistic, and theoretical studies. Interestingly, the obtained scaffolds result from 1,6-cyclizations, which diverge from the product obtained from free deprotected amines. The allyl group that could initially be seen as a protecting group necessary to achieve the Pictet−Spengler reaction is transferred through the cyclizing process in a valuable three-carbon synthon that may be useful for subsequent transformations.

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EXPERIMENTAL SECTION

General Information. Reactions were performed using oven-dried glassware under an atmosphere of argon. All separations were carried out under flash-chromatographic conditions on silica gel (Redi Sep prepacked column, 230−400 mesh) at medium pressure (20 psi) with the use of a CombiFlash Companion. Reactions were monitored by thin-layer chromatography on Merck silica gel plates (60 F254 aluminum sheets) which were rendered visible by ultraviolet and spraying with vanillin (15%) + sulfuric acid (2.5%) in EtOH, followed by heating. THF, CH2Cl2, DMF, MeOH, and MTBE (i.e., methyl tertbutyl ether) were purchased at the highest commercial quality and used without further purification. Reagent-grade chemicals were obtained from diverse commercial suppliers and used as received. 1 H NMR (500 or 300 MHz) and 13C NMR (125 or 75 MHz) spectra were recorded on Brüker Avance spectrometers at 298 K unless otherwise stated. Chemical shifts are given in ppm (δ) and are referenced to the internal solvent signal or to TMS used as an internal standard. Multiplicities are declared as follows: s (singlet), brs (broad singlet), d (doublet), t (triplet), q (quadruplet), dd (doublet of doublet), ddd (doublet of doublet of doublet), dt (doublet of triplet), m (multiplet), AB = AB quartet, ABX = ABX system. Coupling constants J are given in Hz. Carbon multiplicities were determined by DEPT135 experiment. Diagnostic correlations were obtained by two-dimensional COSY, HSQC, and NOESY experiments. Attributions are reported for compounds for which NOESY experiments are given in the SI. 907


Article

The Journal of Organic Chemistry and 8.4 min (major)]. IR (neat) νmax 3412, 3056, 2935, 2843, 1939, 1451 cm−1. 1H NMR (300 MHz, CDCl3) δ 7.62 (s, 1H), 7.49 (d, J = 7.3 Hz), 7.42 (d, J = 7.5 Hz, 2H), 7.34−7.18 (m, 5H), 7.15−7.04 (m, 2H), 5.97−5.84 (m, 1H), 5.20−5.08 (m, 4H), 3.83 (t, J = 6.4 Hz, 1H), 3.28−3.22 (m, 2H), 3.28−3.22 (m, 1H), 3.00−2.93 (m, 1H), 2.88−2.78 (m, 1H), 2.65−2.52 (m, 1H), 2.65−2.52 (m, 2H), 2.01 (q, J = 7.3 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 208.8 (Cq), 136.9 (CH), 136.3 (Cq), 135.9 (2Cq), 135.1, 128.6 (2CH), 127.4 (Cq), 127.0 (CH), 126.3 (2CH), 121.5 (CH), 119.5 (CH), 118.2 (CH), 117.4 (CH2), 110.8 (CH), 108.3 (Cq), 105.2 (Cq), 78.8 (CH2), 56.6 (CH2), 55.5 (CH), 45.1 (CH2), 32.4 (CH2), 25.9 (CH2), 18.0 (CH2). HRMS (ESI) calc for C25H27N2 [M + H]+ 355.2174, found 355.2170. 2-Allyl-1-(3-(4-chlorophenyl)penta-3,4-dien-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 1m. 1m was prepared according to the general procedure from Nβ-allyl tryptamine 6a (40 mg, 0.2 mmol), aldehyde 7e (84 mg, 0.4 mmol), catalyst 8 (6.3 mg, 0.004 mmol), and 4 Å molecular sieves (130 mg) in PhMe (3 mL). 1m was obtained after column chromatography on silica gel (eluent: EtOAc/Petroleum ether, 5/95 to 10/90) as a colorless oil (51 mg, 0.13 mmol, 66%). Rf = 0.20 (EtOAc/Petroleum ether, 10/90). [α]26D = +14.9 (c 1.00, CHCl3). ee = 94%, determined on a Chiralpak AD-H column [Heptane 0.1% Et3N: IPA 0.1% Et3N, 98:2, 1 mL/min, λ = 277 nm, retention times: 12.74 min (minor) and 20.10 min (major)]. IR (neat) νmax 3408, 3055, 2935, 2843, 1939, 1490, 1011, 736 cm−1. 1H NMR (300 MHz, CDCl3) δ 7.65 (s, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.34−7.26 (m, 5H), 7.17−7.06 (m, 2H), 5.91 (dtt, J = 17.1, 10.1, and 6.4 Hz, 1H), 5.17−5.09 (m, 4H), 3.79 (t, J = 6.2 Hz, 1H), 3.28−3.19 (m, 3H), 3.00−2.93 (m, 1H), 2.89−2.79 (m, 1H), 2.62−2.54 (m, 3H), 2.01−1.93 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 208.7 (Cq), 136.0 (Cq), 135.0 (Cq), 132.6 (Cq), 136.9 (CH), 128.7 (2CH), 127.5 (2CH), 121.7 (CH), 119.6 (CH), 118.3 (CH), 117.4 (CH2), 110.9 (CH), 108.5 (Cq), 104.5 (Cq), 79.3 (CH2), 56.6 (CH2), 55.5 (CH), 45.3 (CH2), 32.3 (CH2), 25.7 (CH2), 18.1 (CH2). HRMS (ESI) calc for C25H26ClN2 [M + H]+ 389.1785, found 389.1803. Gold-Catalyzed Carboaminations. General Procedure 1. Tetrahydro-β-carboline 1 (1 equiv) and Echavarren’s catalyst 5 (2 mol %) were introduced in a Schlenck under an argon atmosphere. Toluene (1.0 mL for 0.1 mmol of 1) was then added. The resulting mixture was stirred at 70 °C for 4−6 h. The reaction mixture was then filtered over a silica pad, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography on silica gel to afford the desired product 3. General Procedure 2. Tetrahydro-β-carboline 1 (1 equiv) and Echavarren’s catalyst 5 (5 mol %) were introduced in a Schlenck tube under an argon atmosphere. Toluene (0.5 mL for 0.1 mmol of 1) was then added. The resulting mixture was stirred at 70 °C for 16 h. The reaction mixture was then filtered over a silica pad, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography on silica gel to afford the desired product 4. Chiral Phosphoric Acid-Catalyzed Pictet−Spengler/Au(I)Catalyzed Cyclization Sequence. Asymmetric one-pot synthesis of 3a was performed using a one-pot procedure. Nβ-allyl tryptamine 6a (40 mg, 0.20 mmol), aldehyde 7a (39 mg, 0.40 mmol), catalyst 8 (3.0 mg, 0.004 mmol), and 4 Å molecular sieves (130 mg) in PhMe (3 mL) were introduced in a reaction flask that was purged with argon. After 16 h at 70 °C, catalyst 5 (7.7 mg, 0.01 mmol) was introduced. The resulting mixture was stirred at 70 °C for 18 h. The reaction mixture was then filtered over a silica pad, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (eluent: Toluene/MTBE, 60/40 to 20/80) on silica gel to afford 3a (48 mg, 0.017 mmol, 86%). ee = 95%. Chiralpak AD-H column Heptane 0.1% Et3N: IPA 0.1% Et3N, 80:20, 1 mL/min, λ = 277 nm, retention times: 3.09 min (minor) and 4.24 min (major). Asymmetric one-pot synthesis of 3d was performed using a one-pot procedure. Nβ-allyl tryptamine 6d (44 mg, 0.20 mmol), aldehyde 7a (39 mg, 0.40 mmol), catalyst 8 (3.0 mg, 0.004 mmol), and 4 Å molecular sieves (130 mg) in PhMe (3 mL) were introduced in a reaction flask that was purged with argon. After 16 h at 70 °C, catalyst 5 (7.7 mg, 0.01 mmol) was introduced. The resulting mixture was stirred at 70 °C for 18 h. The reaction mixture was then filtered over a

silica pad, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (eluent: Toluene/MTBE, 60/40 to 20/80) on silica gel to afford 3d (35 mg, 0.118 mmol, 59%). ee = 92%. Chiralpak AD-H column Heptane 0.1% Et3N: IPA 0.1% Et3N, 80:20, 1 mL/min, λ = 277 nm, retention times: 2.90 min (minor) and 4.43 min (major). Asymmetric one-pot synthesis of 3e was performed using a one-pot procedure. Nβ-allyl tryptamine 6e (43 mg, 0.20 mmol), aldehyde 7a (39 mg, 0.40 mmol), catalyst 8 (3.0 mg, 0.004 mmol), and 4 Å molecular sieves (130 mg) in PhMe (3 mL) were introduced in a reaction flask that was purged with argon. After 16 h at 70 °C, catalyst 5 (7.7 mg, 0.01 mmol) was introduced. The resulting mixture was stirred at 70 °C for 18 h. The reaction mixture was then filtered over a silica pad, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (eluent: Toluene/MTBE, 60/40 to 20/80) on silica gel to afford 3e (41 mg, 0.14 mmol, 70%). ee = 96%. Chiralpak AD-H column Heptane 0.1% Et3N: IPA 0.1% Et3N, 80:20, 1 mL/min, λ = 277 nm, retention times: 2.98 min (minor) and 4.07 min (major). Gold-Catalyzed Carboamination to Hemiaminal 13g.

5a-Methyl-3-vinyl-1,2,2a,3,4,5a,7,8,13,13b-decahydrofuro[2,3-f ]indolo[2,3-a]quinolizine 13g was prepared according to the general procedure 1 from 1g (31 mg, 0.10 mmol), catalyst 5 (1.6 mg, 0.002 mmol) in PhMe (1.5 mL). Column chromatography on silica gel (eluent: Heptane/EtOAc, 90/10 to 10/90) yielded a mixture of diastereomers of 13g (dr 85/15, 25 mg, 0.08 mmol, 80%) as an oil. Mp 148−150 °C. IR (neat) vmax 3415, 2974, 2916, 1454, 1385, 1301, 1229, 1145, 1124, 1071, 1032 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.69 (s, 1H, H13), 7.49 (d, J = 7.6 Hz, 1H, Har), 7.29 (d, J = 7.6 Hz, 1H, Har), 7.15−7.06 (m, 2H, Har), 5.98 (td, J = 9. 8, 17.1 Hz, 1H, H14), 4.94 (dd, J = 2.1, 17.0 Hz, 1H, H15), 4.84 (dd, J = 2.1, 9.9 Hz, 1H, H15), 4.07 (t, J = 8.4 Hz, 1H, H4a), 3.79 (dd, J = 6.7, 8.5 Hz, 1H, H4b), 3.74 (d, J = 11.2 Hz, 1H, H13b), 3.58−3.52 (m, 1H, H7a), 3.00−2.90 (m, 1H, H3), 2.79−2.66 (m, 2H, H8), 2.37 (dt, J = 3.9, 11.2 Hz, 1H, H7b), 2.14 (ddd, J = 2.4, 5.4, 11.0 Hz, 1H, H2a), 1.92−1.77 (m, 3H, H2 and H1a), 1.62 (dq, J = 6.5, 12.2 Hz, 1H, H1b), 1.34 (s, 3H, H16). 13 C NMR (125 MHz, CDCl3) δ 141.7 (CH, C14), 136.5 (Cq), 136.3 (Cq), 127.5 (Cq), 121.5 (CH), 119.6 (CH), 118.3 (CH), 115.6 (CH2, C15), 110.8 (CH), 109.6 (Cq), 94.2 (Cq, C5a), 70.7 (CH2, C4), 53.6 (CH, C13b), 48.1 (CH, C2a), 47.7 (CH, C3), 41.7 (CH2, C7), 29.2 (CH2, C1), 22.5 (CH, C8), 21.4 (CH2, C2), 15.0 (CH3, C16). HRMS (ESI) calc for C20H25N2O [M + H]+ 309.1967, found 309.1957. Gold-Catalyzed Cyclization of 1m: (S)-4-(But-3-en-1-yl)-3phenyl-1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine 4m and (2aS,4S,13bS)-2a-(4-Chlorophenyl)-4-methyl2,2a,3,4,7,8,13,13b-octahydro-1H-cyclopenta[f]indolo[2,3-a]quinolizine 9m. 4m and 9m were prepared according to the general procedure 2 from 1m (50 mg, 0.129 mmol), catalyst 5 (5.0 mg, 0.0065 mmol) in PhMe (0.75 mL). After stirring for 18 h at 70 °C, an additional portion of 5 (2 mg, 2.6 μmol) was added, and the resulting mixture was further stirred for 5 h. Column chromatography on silica gel (eluent: Toluene/MTBE, 80/30 to 20/80) yielded a mixture of 4m and 9m (ratio 4m:9m 2/1, 40 mg, 0.103 mmol, 80%) as a yellow oil. This mixture could not be further correctly separated. Fractions enriched in 4m and 9m could be obtained, allowing the determination of most significant signals, given below. The 13C NMR spectra of both products could be attributed with HMQC experiment. Data for 4m. 1H NMR (500 MHz, CDCl3) δ 7.76 (s, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.17−7.05 (m, 5H), 4.92 (d, J = 17.4 Hz, 1H), 4.88 (d, J = 10.1 Hz, 1H), 4.25 (d, J = 9.2 Hz, 1H), 3.40−3.33 (m, 1H), 3.21−3.12 (m, 1H), 2.84−2.75 (m, 2H), 2.39−1.94 (m, 8H). 13C NMR (125 MHz, CDCl3) δ 138.4 (CH), 114.7 (CH2), 56.3 (CH), 43.9 (CH2), 33.0 (CH2), 30.3 (CH2), 29.2 (CH2), 26.4 (CH2), 22.4 (CH2). 908


Article

The Journal of Organic Chemistry Data for 9m. 1H NMR (500 MHz, CDCl3) δ 7.61 (s, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.5 Hz, 2H), 7.12−7.05 (m, 2H), 4.92 (d, J = 2.7 Hz, 1H), 3.85−3.73 (m, 3H), 3.05−2.91 (m, 2H), 2.85−2.79 (m, 1H), 2.70−2.61 (m, 1H), 2.44 (td, J = 3.1, 12.8 Hz), 2.31−2.25 (m, 1H), 1.92 (d, J = 12.5 Hz), 1.90−1.84 (m, 1H), 1.79 (dt, J = 3.2, 13.2 Hz), 0.68 (d, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, CDCl3): 108.4 (CH), 57.9 (CH), 49.6 (CH2), 47.0 (CH2), 40.1 (CH2), 36.2 (CH), 26.9 (CH2), 21.9 (CH3), 21.8 (CH2). 13C NMR peaks for CH and Cq carbons of 4m and 9m: δ 110.9 (CH), 111.0 (CH), 118.3 (CH), 118.3 (CH), 119.7 (CH), 119.8 (CH), 121.8 (CH), 127.9 (CH), 127.3 (Cq), 127.4 (Cq), 127.9 (Cq), 128.4 (CH), 129.5 (CH), 130.8 (CH), 131.19 (Cq), 131.89 (Cq), 134.79 (Cq), 135.39 (Cq), 136.19 (Cq), 136.39 (Cq), 142.19 (Cq), 143.09 (Cq), 148.79 (Cq), 151.19 (Cq). Gold-Catalyzed Cyclization of 1l and Concomitant Reduction of 4l: (2aS,4S,5aS,13bS)-4-Methyl-2a-phenyl2,2a,3,4,5,5a,7,8,13,13b-decahydro-1H-cyclopenta[f ]indolo[2,3-a]quinolizine (11l).

To a solution of tetracyclic compound 3a (40 mg, 0.14 mmol) in DCM (4 mL) was added PhSiH3 (60 mg, 0.56 mmol), and the resulting mixture was stirred at rt for 16 h. It was then concentrated under vacuum and purified on silica gel (eluent: Heptane/EtOAc, 90/10 to 10/90), providing pure 12a (20 mg, 0.07 mmol, 51%). [α]25D = −40.0 (c 0.33, CHCl3). Mp 144 °C. IR (neat) vmax 3284, 2944, 2788, 1448, 1302 cm−1. 1H NMR (300 MHz, CDCl3) δ 7.70 (s, 1H, H12), 7.45 (dd, J = 1.6, 7.3 Hz, 1H, Har), 7.11 (dt, J = 1.5, 7.2 Hz, 1H, Har), 7.06 (dt, J = 1.3, 7.2 Hz, 1H, Har), 5.73 (dddd, J = 7.1, 7.3, 10.2, 16.9 Hz, 1H, H14), 5.03−4.92 (m, 2H, H15), 3.38 (ddd, J = 2.0, 5.8, 11.6 Hz, 1H, H6a), 3.31 (d, J = 10.5 Hz, 1H, H12b), 2.95−2.79 (m, 1H, H7), 2.74−2.64 (m, 1H, H7), 2.65−2.56 (m, 1H, H4), 2.32−2.24 (m, 2H, H13), 2.21 (dt, J = 4.3, 11.3 Hz, 1H, H6b), 1.96−1.87 (m, 1H, H2a), 1.87−1.79 (m, 1H, H1b), 1.79−1.70 (m, 1H, H1a), 1.71−1.62 (m, 1H, H3), 1.96−1.87 (m, 1H, H2a), 1.66−1.57 (m, 1H, H2b), 1.20 (d, J = 6.6 Hz, 3H, H16). 13C NMR (75 MHz, CDCl3) δ 138.8 (C14), 136.2 (Cq), 136.0 (Cq), 127.6 (Cq), 121.4 (CH), 119.5 (CH), 118.3 (CH), 115.6 (CH2, C15), 110.9 (CH), 108.5 (Cq), 61.3 (CH, C12b), 60.6 (CH, C4), 47.6 (CH2, C6), 40.2 (CH2, C3), 30.2 (CH2, C13), 27.4 (CH2, C2), 22.3 (CH2, C7), 19.7 (CH3, C16). HRMS (ESI) calc for C19H25N2 [M + H]+ 281.2018, found 281.2005. Reduction of 4k to 10k: (12bS)-3-Isopropyl-4-methyl1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine 10k. To a solution of tetracyclic compound 4k (40 mg, 0.125 mmol) in DCM (1 mL) was added PhSiH3 (41 mg, 0.375 mmol), and the resulting mixture was stirred at rt for 18 h. It was then concentrated under vacuum and purified on silica gel (eluent: Heptane/EtOAc, 90/10 to 10/90), providing pure 10k (28.5 mg, 0.089 mmol, 71%). Four diastereomers could further be separated by preparative HPLC and characterized. 10ka.

Tetrahydro-β-carboline 1l (88 mg, 0.24 mmol) and Echavarren’s catalyst 5 (13 mg, 0.017 mmol) were introduced in a Schlenck tube under an argon atmosphere. Toluene (2 mL) was then added, and the resulting mixture was stirred at 80 °C for 48 h. The reaction mixture was cooled to troom temperature, and PhSiH3 (43 mg, 0.4 mmol) and (p-NO2PhO)2POOH (6 mg, 0.017 mmol) were added. The resulting mixture was further stirred at rt for 24 h. It was then directly purified on silica gel (eluent: Heptane/EtOAc, 90/10 to 10/90). The pure compound 11l was obtained (24 mg, 0.067 mmol, 28%), along with mixtures of diastereomers of 10l (36 mg, 0.10 mmol, 42%) that could not be further separated. Data for 11l: IR (neat) vmax 2961, 2928, 1451, 1075, 1048 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.97 (d, J = 7.6 Hz, 2H), 7.63 (s, 1H, H12), 7.51−7.45 (m, 1H, Har), 7.28−7.22 (m, 1H, Har), 7.18−7.12 (m, 2H, Har), 7.12−7.05 (m, 2H, Har), 7.03 (t, J = 7.6 Hz, 1H, Har), 3.44 (dd, J = 11.3 and 5.8 Hz, 1H, H7b), 3.27 (d, J = 11.6 Hz, 1H, H13b), 3.08 (dddd, J = 2., 6.1, 11.6, and 15.2 Hz, 1H, H8b), 2.81−2.74 (m, 1H, H8a), 2.57 (dd, J = 6. Seven and 13.1 Hz, 1H, H5a), 2.4 (dt, J = 4.16 and 11.44 Hz, 1H, H7a, 2.25 (ddd, J = 6.7, 8.6, and 11.3 Hz, 1H, H5a), 2.21−2.12 (m, 2H, H2b and H4), 2.03 (dd, J = 2.1 and 12.7 Hz, 1H, H3b), 1.93 (dd, J = 10.1 and 12.7 Hz, 1H, H3a), 1.77 (dd, J = 3.5 and 13.1 Hz, 1H, H1a), 1.71−1.61 (m, 2H, H5b and H2a), 1.42 (ddt, J = 3.5, 12.0, 12.7 Hz, 1H, H1b), 0.55 (d, J = 7.1 Hz, 3H, H14). 13C NMR (125 MHz, CDCl3) δ 147.2 (Cq), 136.0 (Cq), 135.7 (Cq), 130.6 (CH), 127.7 (CH), 127.3 (CH), 125.0 (CH), 121.4 (CH), 119.6 (CH), 118.2 (CH), 111.0 (CH), 108.4 (Cq), 73.7 (CH, C5), 62.2 (CH, C13b), 49.9 (CH2, C7), 48.2 (CH2, C3), 41.3 (CH2, C2), 35.8 (CH2, C5), 29.2 (CH, C4), 26.8 (CH2, C1), 23.1 (CH3, C14), 22.5 (CH2, C8). HRMS (ESI) calc for C25H29N2 [M + H]+ 357.2331, found 357.2327. One diastereoisomer of 10l could be isolated as a relatively pure compound: 1H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 7.3 Hz, 2H), 7.68 (s, 1H, H12), 7.51 (d, J = 7.3 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.22−7.17 (m, 2H, Har), 7.16−7.06 (m, 3H, Har), 5.76−5.64 (m, 1H), 4.98−4.86 (m, 2H), 3.59 (dd, J = 11.0 and 5.2 Hz, 1H), 3.44 (d, J = 10.7 Hz, 1H), 3.06−2.93 (m, 2H), 2.80−2.72 (m, 1H), 2.67 (quint., J = 4.0 Hz, 1H), 2.23 (dt, J = 11.3 and 3.7 Hz, 1H), 2.08−1.95 (m, 4H), 1.95−1.79 (m, 3H), 1.44−1.32 (m, 1H). HRMS (ESI) calc for C25H29N2 [M + H]+ 357.2331, found 357.2325. Reduction of 3a to 12a: (3R,4S,12bS)-3-Allyl-4-methyl1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine 12a.

[α]25D = −33.5 (c 0.2, CHCl3). IR (neat) vmax 2952, 2921, 1454, 1387, 1302, 1169 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.62 (s, 1H, H12), 7.44 (d, J = 7.3 Hz, 1H, Har), 7.27 (d, J = 7.3 Hz, 1H, Har), 7.12−7.02 (m, 2H, Har), 5.85 (dddd, J = 6.4, 7.0, 10.2, 17.1 Hz, 1H, H15), 5.04 (d, J = 17.3 Hz, 1H, H16), 4.96 (d, J = 9.9 Hz, 1H, H16), 3.71−3.59 (m, 1H, H12b), 3.22 (dd, J = 5.25, 10.8 Hz, 1H, H6), 2.94−2.84 (m, 1H, H6), 2.72−2.53 (m, 3H, H4+H6+H7), 2.28−2.05 (m, 2H), 2.00−1.88 (m, 1H), 1.85−1.47 (m, 7H), 0.97 (d, J = 6.6 Hz, 3H, H18), 0.94 (d, J = 6.6 Hz, 3H, H18). 13C NMR (125 MHz, CDCl3) δ 139.4 (CH, C15), 136.9 (Cq), 136.2 (Cq), 127.6 (Cq), 121.3 (CH), 119.5 (CH), 118.2 (CH), 114.6 (CH2, C16), 110.9 (CH), 108.7 (Cq), 64.3 (CH, C4), 57.3 (CH, C12b), 49.9 (CH2, C6), 41.2 (CH, C3), 31.7 (CH2), 31.6 (CH2), 28.2 (CH, C17), 27.4 (CH2), 24.2 (CH2), 22.9 (CH2), 22.0 (CH3, C18). HRMS (ESI) calc for C22H31N2 [M + H]+ 323.2487, found 323.2476. 10kb.

[α]25D = −30.3 (c 0.34, CHCl3). IR (neat) vmax 2959, 2931, 1639, 1465, 1453, 1324, 1305, 1165 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.66 (s, 1H, H12), 7.44 (d, J = 7.3 Hz, 1H, Har), 7.27 (d, J = 7.3 Hz, 1H, Har), 7.14−7.01 (m, 2H, Har), 5.88 (m, 1H, H15), 5.04 (d, J = 17.3 Hz, 1H, H16), 4.95 (d, J = 10.0 Hz, 1H, H16), 3.48 (d, J = 11.3 Hz, 1H, H12b), 3.35−3.25 (m, 1H, H6), 2.90−2.69 (m, 2H, H7), 2.50−2.35 (m, 2H, H4+H6), 2.22−2.08 (m, 2H), 2.06−1.91 (m, 2H), 1.90−1.77 (m, 2H), 1.75−1.55 (m, 4H), 1.54−1.44 (m, 1H, H3), 1.35−1.23 (m, 1H), 0.93 (d, J = 6.9 Hz, 3H, H18), 0.80 (d, J = 6.9 Hz, 909


Article

The Journal of Organic Chemistry 3H, H18). 13C NMR (125 MHz, CDCl3) δ 139.4 (CH, C15), 136.5 (Cq), 136.2 (Cq), 127.6 (Cq), 121.4 (CH), 119.5 (CH), 118.3 (CH), 114.3 (CH2, C16), 110.8 (CH), 108.6 (Cq), 64.0 (CH, C4), 59.9 (CH, C12b), 44.8 (CH2, C6), 42.6 (CH, C3), 29.4 (CH2), 29.0 (CH2), 28.9 (CH2), 27.4 (CH, C17), 23.1 (CH2), 22.4 (CH2), 21.9 (CH3, C18), 22.0 (CH3, C18). HRMS (ESI) calc for C22H31N2 [M + H]+ 323.2487, found 323.2510. 10kc.

X-ray crystallographic data for compounds 11l, 12a, 13g; H NMR and 13C NMR for all new compounds and compounds reported by new routes; computational data for all computed intermediates and their connecting transition states (PDF) X-ray crystallographic data for compounds 11l, 12a, 13g (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID [α]25D = +12.8 (c 0.25, CHCl3). IR (neat) vmax 2928, 2866, 1468, 1454, 1385, 1366, 1325, 1162 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.62 (s, 1H, H12), 7.44 (d, J = 7.6 Hz, 1H, Har), 7.27 (d, J = 7.6 Hz, 1H, Har), 7.13−7.01 (m, 2H, Har), 5.89−5.75 (m, 1H, H15), 5.01 (d, J = 17.0 Hz, 1H, H16), 4.94 (d, J = 9.8 Hz, 1H, H16), 3.87 (d, J = 11.3 Hz, 1H, H12b), 3.28−3.11 (m, 1H, H6a), 3.09−2.99 (m, 1H, H4), 2.90−2.71 (m, 3H, H6b+H7), 2.30−2.08 (m, 2H), 1.92−1.71 (m, 3H), 1.67−1.24 (m, 7H), 0.94−0.88 (m; 6H, H18). 13C NMR (150 MHz, CDCl3) δ 139.3 (CH, C15), 136.9 (Cq), 136.2 (Cq), 127.5 (Cq), 121.3 (CH), 119.4 (CH), 118.2 (CH), 114.6 (CH2, C16), 110.9 (CH), 62.5 (CH, C4), 50.1 (CH2, C6), 49.5 (CH, C12b), 45.2 (CH, C3), 33.5 (CH2), 30.1 (CH2), 29.2 (CH, C17), 23.8 (CH2), 22.9 (CH2), 22.6 (CH2), 21.3 (CH3, C18), 21.2 (CH3, C18). HRMS (ESI) calc for C22H31N2 [M + H]+ 323.2487, found 323.2503. 10kd.

Vincent Gandon: 0000-0003-1108-9410 Xavier Guinchard: 0000-0003-2353-8236 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Vincent Servajean (ICSN) is thanked for technical assistance. V. Gobé thanks the ICSN for financial support. M. Dousset thanks the CHARMMMAT Laboratory of Excellence for financial support. X. Guinchard warmly thanks Dr. Angela Marinetti (ICSN) for her support. V. Gandon thanks the IUF. We used the computing facility of the CRIANN, Centre Régional d’Informatique et d’Applications Numériques de Normandie (project 2006-013).

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[α]25D = +73.4 (c 0.7, CHCl3). IR (neat) vmax 2938, 2870, 1451, 1366, 1320, 1164 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.63 (s, 1H, H12), 7.44 (d, J = 7.3 Hz, 1H, Har), 7.27 (d, J = 7.3 Hz, 1H, Har), 7.12−7.02 (m, 2H, Har), 5.83 (tdd, J = 6.7, 10.2, 17.1 Hz, 1H, H15), 5.04 (d, J = 17.1 Hz, 1H, H16), 4.97 (d, J = 10.1 Hz, 1H, H16), 3.85 (d, J = 9.5 Hz, 1H, H12b), 2.98−2.80 (m, 4H, H6+H4+H1), 2.67−2.59 (m, 1H, H1), 2.19−2.04 (m, 2H, H13a+H17), 1.96 (sext, J = 7.9 Hz, 1H, H13b), 1.84−1.55 (m, 6H), 1.18−1.10 (m, 1H, H3), 0.91 (d, J = 6.6 Hz, 3H, H18), 0.83 (d, J = 6.6 Hz, 3H, H18). 13C NMR (150 MHz, CDCl3) δ 139.0 (CH, C15), 136.4 (Cq), 136.2 (Cq), 127.6 (Cq), 121.2 (CH), 119.4 (CH), 118.2 (CH), 114.8 (CH2, C16), 110.9 (CH), 108.4 (Cq), 60.9 (CH, C4), 52.3 (CH, C12b), 50.4 (CH2, C6), 42.7 (CH, C3), 31.7 (CH2), 29.9 (CH2), 27.2 (CH, C17), 26.4 (CH2), 23.7 (CH2), 22.2 (CH3, C18) 21.9 (CH2, C7), 21.0 (CH2), 20.6 (CH3, C18). HRMS (ESI) calc for C22H31N2 [M + H]+ 323.2487, found 323.2489. Gold-Catalyzed Hydroamination of 15: (11bS,3R)-3-Vinyl2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole (syn-2a) and (11bS,3S)-3-Vinyl-2,3,5,6,11,11b-hexahydro-1Hindolizino[8,7-b]indole (anti-2a). To a solution of 15 (25 mg, 0.105 mmol) in DCM (1 mL) was added catalyst 5 (4.0 mg, 0.005 mmol, 5 mol %), and the resulting mixture was stirred at 50 °C for 24 h. It was then concentrated under vacuum and purified by column chromatography on silica gel (eluent: MTBE/Petroleum ether, 1/1 then EtOAc), yielding syn-2a (5 mg mg, 0.0.02 mmol, 20%) and anti-2a (12 mg, 0.05 mmol, 48%). These molecules were already described by us in the course of a palladium-catalyzed cyclization.14a,b

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02900. 910


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Dissecting the Gold(I)-Catalyzed Carboaminations of N-Allyl

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