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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Am Chem Soc. Author manuscript; available in PMC 2010 June 24.
Published in final edited form as:
PMCID: PMC2724870
NIHMSID: NIHMS134067

Synthesis of a Simplified Version of Stable Bulky and Rigid Cyclic (Alkyl)(Amino)Carbenes (CAACs), and Catalytic Activity of the Ensuing Gold(I) Complex in the Three-Component Preparation of 1,2-Dihydroquinoline Derivatives

Abstract

A 95/5 mixture of cis and trans 2,4-dimethyl-3-cyclohexenecarboxaldehyde (trivertal), a common fragrance and flavor material produced in bulk quantities, serves as the precursor for the synthesis of a stable spirocyclic (alkyl)(amino)carbene, in which the 2-methyl-substituted cyclohexenyl group provides steric protection to an ensuing metal. The efficiency of this carbene as ligand for transition metal based catalysts is first illustrated by the gold(I) catalyzed hydroamination of internal alkynes with secondary dialkyl amines, a process with little precedent. The feasibility of this reaction allows for significantly enlarging the scope of the one-pot three-component synthesis of 1,2-dihydroquinoline derivatives, and related nitrogen-containing heterocycles. Indeed, two different alkynes were used, which include an internal alkyne for the first step.

Keywords: Carbenes, Gold, Hydroamination, Catalysis, Nitrogen-heterocycles

Introduction

In the last few years, spectacular results in homogeneous catalysis have been achieved using bulky phosphines1 and cyclic diaminocarbenes (NHCs)2 as strong donor ligands. Recently, we have uncovered a novel family of stable carbenes,3 the cyclic (alkyl)(amino)carbenes (CAACs) 1 (Fig. 1).4 The replacement of one of the nitrogen by a carbon center makes CAACs slightly more nucleophilic, but considerably more electrophilic than NHCs.5 Moreover, due to the presence of a quaternary carbon in a position α to the carbene center, CAACs feature steric environments that differentiate them dramatically from other ligands, including NHCs. Of particular interest, we have shown that spirocyclic CAACs 1a and 1b allow the preparation of low-coordinate metal complexes,6 hitherto not isolable with any other ligands,7 including the closely related CAAC 1c. Since low-coordinate metal complexes often play a key role in catalytic processes, it is not surprising that, with a few exceptions,8 CAACs 1a and 1b lead to the best promoters. For example, in the presence of a stoichiometric amount of KB(C6F5)4, (CAAC)AuCl complex 2a efficiently catalyzed hydroamination of alkynes and allenes with ammonia9a and basic secondary amines,9b and the formation of allenes by coupling enamines and terminal alkynes.9b, c In contrast, all attempts to isolate the corresponding (CAAC)AuCl 2c bearing the flexible CAAC 1c failed, instead the cationic di(carbene) complex 3c was obtained,10 and the latter is of course not catalytically active. The striking differences observed using CAAC 1a,b versus 1c are due to the hindrance provided by the adamantyl and menthyl substituents, which are locked in the most sterically demanding conformation with respect to the metal center. In contrast the non-substituted cyclohexyl ring of 1c can undergo a ring-flip that prevents the protection of the metal. This clearly demonstrates the importance of preventing the ring-flip and forcing the ring to be oriented such as it can protect the metal.

Figure 1
CAACs 1a–c and their precursors, and the corresponding gold complexes 2a,b and 3c.

An obvious drawback for many catalytic processes is the cost of the catalyst. Although the flexible CAAC 1c is conveniently prepared from the commercially available cyclohexane carboxaldehyde, rigid CAACs 1a and 1b have to be prepared from the more expensive 2-adamantanone and (−)-menthone, respectively, and an additional homologation step is required. Here we report the synthesis of CAAC 1d, which is build from a very cheap aldehyde. We show that in the presence of KB(C6F5)4, the corresponding gold(I) complex 2d is as efficient as the analogous complexes bearing 1a and 1b for the hydroamination1113 of internal alkynes with secondary dialkyl amines, a process which has very rare precedent.9b,14 Moreover, we demonstrate that 2d allows for the one-pot synthesis of a variety of 1,2-dihydroquinolines, a family of compounds that have been recognized as important synthetic intermediates, and which exhibit interesting biological activities and potential pharmaceutical applications.15

Results

In order to construct a readily available spiro-CAAC bearing a rigid ring oriented in the desired direction, we reasoned that the presence of a single substituent in position β of the aldehyde would be sufficient. Indeed, a reactant should attack trans to the substituent, and based on the well-known propensity of electrophiles to approach a ring from the equatorial direction, the substituent should also end up in an equatorial position. The other chair conformation would be highly adverse, and therefore the ring would be locked in the right conformation (Scheme 1). As an economically viable precursor, we chose a 95/5 mixture of cis and trans 2,4-dimethyl-3-cyclohexenecarboxaldehyde 4, also named “trivertal”, a common fragrance and flavor material produced in bulk quantities. Enamine 5 was readily prepared in 94% yield, then treated with LDA, and after addition of 3-chloro-2-methyl-1-propene, compound 6 was isolated as a single diastereomer in 90% yield. A hydroiminiumation reaction 4b using a large excess of HCl gave rise to the cyclic aldiminium salt 7 (74% yield), and subsequent deprotonation with LDA afforded the desired carbene 1d in 95% yield. Lastly, complex 2d [(1d)AuCl] was prepared in 87% yield by ligand exchange from (Me2S)AuCl. A single crystal X-ray diffraction study demonstrated that, as hypothesized, the cyclohexene ring was in the desired conformation and orientation to protect the metal center (Fig. 2).

Figure 2
Molecular structure of one enantiomer of 2d (50% thermal ellipsoids are shown). Hydrogen atoms have been omitted for clarity.
Scheme 1
Synthesis of carbene 1d and gold chloride complex 2da (2d has been redrawn)

We first tested the catalytic activity of 2d, in the presence of one equivalent KB(C6F5)4, for the addition of diethylamine to three representative internal alkynes. These reactions were chosen because, although numerous catalytic systems promote the hydroamination of alkynes,1113 so far, only complex 2a9a–b has been reported to catalyze the intermolecular addition of dialkylamines to internal alkynes. We were pleased to find that 2d was as efficient as 2a (Table 1).

Table 1
Compared efficiency of Gold(I) complexes 2, bearing CAAC ligand 1a and 1d for the hydroamination of internal alkynes with Et2NHa

Having in hand a readily available precatalyst, we wanted to take advantage of its unusual ability to promote hydroamination of internal alkynes with secondary amines. Inspired by the recent works of Yi et al.,16 and Che et al.,17,18 we chose to study the one-pot three-component synthesis of 1,2-dihydroquinoline derivatives. Yi and co-workers reported a ruthenium based catalytic system leading to quinoline derivatives from an aryl amine and excess terminal alkyne, via hydroamination and C-H bond activation reactions. For the hydroamination step, only terminal alkynes can be used, since a ruthenium acetylide complex is involved, and therefore the C2 substituent can only be a methyl group; moreover the second molecule of alkyne reacts quickly, and therefore the C2 and C4 substituents are the same (Scheme 2, Eq. 1). The same limitations apply for the reaction developed by Che et al., also a tandem hydroamination-hydroarylation protocol, but microwave assisted, and using a gold(I) catalyst of type (NHC)AuCl/AgSbF6.

Scheme 2
Scope of previously reported catalytic systems (Eq.1),16,17 compared to the one described here (Eq. 2)

Since the gold(I) catalytic system19 based on 1d allows for the hydroamination of internal alkynes, even with strongly basic amines, it became clear that the only serious limitation, for the three component cyclization, would be the use of a terminal alkyne for the second step. Consequently the dihydroquinoline skeleton could be readily decorated with three different R1, R2 and R3 substituents (Scheme 2, Eq. 2). The process was initially tested with N-methylaniline (9a), 3-hexyne (8b), and phenyl acetylene (10a) (Table 2). Using 5 mol% of complex 2d and one equivalent of KB(C6F5)4 in C6D6, the hydroamination of the internal alkyne 8b was monitored by NMR spectroscopy. After complete conversion of the reactants, the terminal alkyne 10a was added. As shown in Table 2, the 2-ethyl-2-propyl-4-phenyl trisubstituted derivative 11a was obtained in 70% yield, and its structure was unambiguously confirmed by single crystal X-ray analysis. Note, that despite the formation of two regioisomers in the hydroamination of 8b, only one dihydroquinoline is formed, as expected based on previous studies.16,17

Table 2
Gold(I)-catalyzed three-component coupling reactions of arylamines, internal alkynes, and terminal alkynesa

The scope of the reaction was surveyed using different arylamines (9a–e), and internal (8b,c) and terminal alkynes (10a,b). Aryl amines featuring p-Cl (9b) and p-OMe (9c) substituents are well tolerated. Benzocyclic amines 9d,e can also be used, giving rise to tricyclic quinoline derivatives, which are important synthetic intermediates and common substructures found in a variety of complex natural products.20 Both aryl- (10a) and alkyl-substituted terminal acetylenes (10b) are suitable for the reaction. Lastly, it is interesting to note that the hydroamination of the unsymmetrical internal alkyne 8c leads to only one cyclization product (11c,d,f,h,k,l), although the hydroamination step gives rise to the Markovnikov and anti-Markovnikov regioisomers in 85/15 to 60/40 ratios, depending on the amine. Examination of the crude reaction mixture reveals that, probably because of steric hindrance, only one enamine regioisomer undergoes the cyclization, the other remaining unchanged.

Summary

This study shows that a stable CAAC, which provides steric protection to an ensuing metal, is readily available, from a cheap aldehyde precursor. Its efficiency as a ligand for transition metal based catalysts is illustrated. The corresponding gold(I) complex allows the addition of secondary dialkyl amines to internal alkynes, a process that has little precedent. The feasibility of this reaction allows for significantly enlarging the scope of the one-pot three-component synthesis of 1,2-dihydroquinoline derivatives, and related nitrogen-containing heterocycles. Indeed, two different alkynes can be used, which includes an internal alkyne for the first step.

Experimental Section

General Considerations

All reactions were performed under an atmosphere of argon by using standard Schlenk or dry box techniques. Solvents were dried over Na metal or CaH2. Reagents were of analytical grade, obtained from commercial suppliers and used without further purification. 1H NMR, and 13C NMR spectra were obtained with a Bruker Advance 300 spectrometer at 298 K. 1H and 13C chemical shifts (δ) are reported in parts per million (ppm) referenced to TMS, and were measured relative to the residual solvent peak. NMR multiplicities are abbreviated as follows: s = singlet, d = doublet, t = triplet, sept. = septet, m = multiplet, br = broad signal. Coupling constants J are given in Hz. Electrospray ionization (ESI) mass spectra were obtained at the UC Riverside Mass Spectrometry Laboratory. Melting points were measured with a Büchi melting point apparatus system. The Bruker X8-APEX (Sxvii) X-ray diffraction instrument with Mo-radiation was used for data collection.

Arylamines and alkynes are commercially available from Sigma-Aldrich and Acros Organics. Gold complex 2a and KB(C6F5)4 were prepared according to the literature.9c The spectroscopic data observed for the products of hydroamination of internal alkynes with Et2NH (Table 1) are identical to those reported in the literature. 9b

Synthesis of compound 5

2,6-Diisopropylaniline (10.00 mL, 9.40 g, 53.0 mmol) was added at room temperature to a reaction flask containing molecular sieves (15 g) and a toluene solution (25 mL) of trivertal 4 (8.05 mL, 7.54 g, 54.6 mmol). The reaction mixture was stirred for 16 h at 100 °C. Molecular sieves were removed by filtration, and toluene was removed under vacuum. Excess of trivertal 4 was removed by a short path distillation at 60 °C under high vacuum to afford 14.57 g of imine 5 as a yellow oil (94% yield). 1H NMR (300 MHz, CDCl3): δ = 7.83 (d, 3J = 5.6 Hz, 1H, NCHtrans), 7.73 (d, 3J = 5.4 Hz, 1H, NCHcis), 7.29-7.18 (m, 3H, CH), 5.52 (s, 1H, CHtrans), 5.46 (s, 1H, CHcis), 3.13 (sept, 3J = 6.8 Hz, 2H, CH(CH3)2), 2.63-2.55 (m, 1H, CH), 2.46-2.41 (m, 1H, CH), 2.21-2.14 (m, 4H, CH2), 1.87 (s, 3H, CH3cis), 1.83 (s, 3H, CH3trans), 1.44 (d, 3J = 6.7 Hz, 3H, CH3trans), 1.33 (d, 3J = 6.8 Hz, 12H, CH3cis); 13C NMR (75 MHz, CDCl3): δ = 170.9 (NCHcis), 170.2 (NCHtrans), 149.1 (Cq), 137.7 (Cq), 133.3 (Cq), 127.0 (CHtrans), 126.5 (CHcis), 124.0 (CHcis), 123.7 (CHtrans), 122.9 (CH), 48.0 (CHcis), 44.6 (CHtrans), 32.8 (CHcis), 32.2 (CHtrans), 29.1 (CH2cis), 28.4 (CH2trans), 28.0 (CHtrans), 27.7 (CHcis), 25.8 (CH2), 23.6 (CH3cis), 22.6 (CH3trans), 20.8 (CH3cis), 18.1 (CH3trans); HRMS (ESI): m/z calcd for C21H32N: 298.2535 [(M+H)]+; found: 298.2537.

Synthesis of compound 6

A solution of 5 (7.07 g, 23.8 mmol) in Et2O (15 mL) was added slowly to a solution of lithium diisopropylamine (LDA) (2.62 g, 24.5 mmol) in Et2O (30 mL) at −78 °C. The mixture was stirred and allowed to warm-up to room temperature, then stirred for an additional 3 h. All volatiles were removed under vacuum, and Et2O (30 mL) was added. After the solution was cooled to −78 °C, 3-chloro-2-methyl-1-propene (2.22 g, 2.40 mL, 24.5 mmol) was slowly added under stirring. After stirring for 2 h, all volatiles were removed under vacuum. Hexanes (20 mL) was added and the suspension was filtered via a filter-cannula. The solvent was evaporated to give 7.52 g of compound 6 as a pale yellow oil (90% yield). 1H NMR (300 MHz, C6D6): δ = 7.70 (s, 1H, NCH), 7.19-7.09 (m, 3H, CH), 5.22 (s, 1H, CH), 4.99 (s, 1H, CH2), 4.84 (s, 1H, CH2), 3.15 (sept, 3J = 6.8 Hz, 2H, CH(CH3)2), 2.61 (s, 2H, CH2), 2.50-2.48 (m, 1H, CH), 1.94-1.84 (m, 4H, CH2), 1.77 (s, 3H, CH3), 1.62 (s, 3H, CH3), 1.23 (d, 3J = 6.8 Hz, 12H, CH3), 1.04 (d, 3J = 7.0 Hz, 3H, CH3); 13C NMR (75 MHz, C6D6): δ = 171.0 (NCH), 150.1 (Cq), 142.9 (Cq), 137.9 (Cq), 133.7 (Cq), 127.2 (CH), 124.6 (CH), 123.6 (CH), 116.2 (CH2), 45.9 (Cq), 43.8 (CH2), 35.8 (CH), 31.3 (CH2), 28.8 (CH2), 28.1 (CH), 24.2 (CH3), 23.6 (CH3), 21.3 (CH3), 17.2 (CH3); HRMS (ESI): m/z calcd for C25H38N: 352.3004 [(M+H)]+; found: 352.2996.

Synthesis of iminium salt 7

To a solution of 6 (7.52 g, 23.8 mmol) in hexanes (10 mL) was added a solution of HCl in Et2O (2M, 25.0 mL, 50.0 mmol) at −78 °C. Precipitation of a white powder was immediately observed. The mixture was warmed to room temperature and stirred for 30 min. Filtration of the precipitate, washing with hexanes (20 mL), and drying under vacuum afforded a white powder. Toluene (25 mL) was added and the reaction mixture heated for 16 h at 110 °C. Volatiles were removed under vacuum to afford 7 as a white powder (7.45 g, 74%). Mp: 218 °C; 1H NMR (300 MHz, CDCl3): δ = 10.67 (br, HCl2), 10.07 (s, 1H, NCH), 7.40 (t, 3J = 7.7 Hz, 1H, CH), 7.21 (d, 3J = 7.7 Hz, 2H, CH), 5.25 (s, 1H, CH), 2.53 (sept, 3J = 6.6 Hz, 2H, CH(CH3)2), 2.49-2.46 (m, 1H), 2.36 (s, 2H), 2.01 (t, 3J = 6.2 Hz, 2H, CH2), 1.89-1.80 (m, 2H), 1.62 (s, 3H, CH3), 1.48 (s, 3H, CH3), 1.46 (s, 3H, CH3), 1.24 (d, 3J = 6.6 Hz, 6H, CH3), 1.18-1.13 (m, 6H, CH3), 1.09 (d, 3J = 6.6 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3): δ = 193.3 (NCH), 144.6 (Cq), 144.0 (Cq), 134.0 (Cq), 131.9 (CH), 129.1 (Cq), 125.4 (CH), 125.3 (CH), 123.9 (CH), 83.0 (Cq), 55.1 (Cq), 46.1 (CH2), 39.7 (CH), 30.4 (CH2), 30.0 (CH3), 29.9 (CH3), 29.2 (CH), 28.3, 26.8 (CH3), 26.7 (CH3), 26.3 (CH2), 23.4 (CH3), 22.2 (CH3), 18.8 (CH3); HRMS (ESI): m/z calcd for C25H38N: 352.3004 [M]+; found: 352.3000.

Synthesis of CAAC 1d

To an Et2O solution (10 mL) of iminium salt 7 (1.00 g, 2.36 mmol) was added at −78 °C a solution of LDA (0.51 g, 4.72 mmol) in Et2O (10 mL). The mixture was warmed to room temperature and stirred for 2 h. The solvent was removed in vacuo, and the residue was extracted twice with hexane (10 mL). Removal of the solvent under vacuum afforded 0.79 g of carbene 1d as a white solid (95% yield). 1H NMR (300 MHz, C6D6): δ = 7.27-7.12 (m, 3H), 5.61 (m, 1H, CH), 3.17 (sept, 3J = 6.8 Hz, 2H, CH(CH3)2), 3.16 (sept, 3J = 6.7 Hz, 1H, CH(CH3)2), 2.45-2.37 (m, 1H), 2.32-2.24 (m, 2H), 2.08-1.92 (m, 2H), 1.79 (s, 2H), 1.62 (m, 3H), 1.38 (d, 3J = 7.2 Hz, 3H, CH3), 1.26 (d, 3J = 6.9 Hz, 6H, CH3), 1.20 (d, 3J = 6.7 Hz, 3H, CH3), 1.16-1.14 (m, 9H, CH3); 13C NMR (75 MHz, C6D6): δ = 320.3 (NCC), 146.4 (Cq), 146.3 (Cq), 138.8 (Cq), 133.1 (Cq), 128.4 (CH), 128.1 (CH), 124.1 (CH), 81.0 (Cq), 65.2 (Cq), 48.7 (CH2), 41.1, 33.7 (CH2), 30.0, 29.8, 29.7, 29.4 (CH2), 26.7, 26.6, 24.4, 22.3, 19.3.

Synthesis of complex 2d

A THF solution (5 mL) of the free carbene 1d (390 mg, 1.11 mmol) was added to a THF solution (5 mL) of AuCl(SMe2) (324 mg, 1.10 mmol). The reaction mixture was stirred at room temperature in darkness for 12 h. The solvent was removed under vacuum, and the residue was washed twice with hexane (5 mL). The residue was extracted twice with methylene chloride (10 mL), and the solvent was removed under vacuum, affording complex 2d as a white solid (564 mg, 87% yield). Mp: 240 °C; 1H NMR (300 MHz, C6D6): δ = 7.11 (m, 1H), 7.01 (m, 2H), 5.37 (s, 1H, CH), 2.68 (sept, 3J = 6.6 Hz, 2H, CH(CH3)2), 2.49 (m, 1H, CH(CH3)2), 2.11 (s, 1H), 2.09 (m, 2H), 1.83 (s, 3H, CH3), 1.77-1.61 (m, 2H), 1.53 (d, 3J = 6.5 Hz, 3H, CH3), 1.47 (d, 3J = 6.6 Hz, 3H, CH3), 1.43-1.38 (m, 1H), 1.23 (d, 3J = 7.0 Hz, 3H, CH3), 1.12 (d, 3J = 6.4 Hz, 3H, CH3), 1.10 (d, 3J = 6.5 Hz, 3H, CH3), 0.91 (s, 3H, CH3), 0.88 (s, 3H, CH3); 13C NMR (75 MHz, C6D6): δ = 240.1 (NCC), 145.5 (Cq), 145.4 (Cq), 135.8 (Cq), 134.1 (Cq), 130.4 (CH), 127.0 (CH), 125.5 (CH), 125.3 (CH), 78.1 (Cq), 60.3 (Cq), 48.1 (CH2), 40.0 (CH), 35.2 (CH2), 29.8 (CH), 29.7 (CH2), 29.6 (CH3), 29.5 (CH), 29.3 (CH3), 27.4 (CH3), 27.3 (CH3), 23.7 (CH3), 23.4 (CH3), 23.0 (CH3), 19.1 (CH3); HRMS (ESI; CH3CN): m/z calcd for C27H40AuN2: 589.2857 [MCl+CH3CN]+; found: 589.2865.

General catalytic procedure for the hydroamination of internal alkynes with Et2NH

In a dried J-Young-Tube, CAAC(AuCl) complex 2a or 2d (0.025 mmol) and KB(C6F5)4 (0.025 mmol) were loaded under an argon atmosphere. C6D6 (0.4 mL) and the internal standard, benzyl methyl ether, were added and after shaking the tube, the internal alkyne 8 (0.5 mmol) and Et2NH (0.5 mmol) were loaded. The tube was sealed, placed in an oil bath behind a blast shield, and heated at the specified temperature (Table 1). The reaction was monitored by NMR spectroscopy. The products were purified by removal of the solvent and extraction with n-hexane.

General catalytic procedure for the three-component coupling reaction of arylamines 9, internal alkynes 8, and terminal alkynes 10

In a dried J-Young-Tube, complex 2d (0.025 mmol) and KB(C6F5)4 (0.025 mmol) were loaded under an argon atmosphere. C6D6 (0.4 mL) and the internal standard benzyl methyl ether were added and after shaking the tube, internal alkyne 8 (0.55 mmol) and arylamine 9 (0.5 mmol) were loaded. The tube was sealed, placed in an oil bath behind a blast shield, heated at the corresponding temperature, and the reaction was monitored by NMR spectroscopy. After complete conversion of the reactants, a terminal alkyne 10 (0.5 mmol) was added, and the reaction mixture heated at 100 °C for 24 h. The products were purified by column chromatography.

Characterization of heterocycles 11 resulting from the three-component coupling reactions

11a

1H NMR (300 MHz, CDCl3): δ = 7.42-7.36 (m, 5H, CH), 7.09 (td, 3J = 6.8 Hz, 4J = 1.5 Hz, 1H, CH), 6.80 (d, 3J = 7.4 Hz, 1H, CH), 6.49 (t, 3J = 7.0 Hz, 2H, CH), 5.08 (s, 1H, CH), 2.80 (s, 3H, CH3), 1.36-1.27 (m, 6H, CH2), 1.00 (t, 3J = 7.4 Hz, 3H, CH3), 0.94 (t, 3J = 7.2 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3): δ = 146.8 (Cq), 140.3 (Cq), 138.5 (Cq), 129.3 (CH), 129.2 (CH), 128.3 (CH), 128.1 (CH), 127.3 (CH), 125.8 (CH), 121.0 (Cq), 114.9 (CH), 108.8 (CH), 64.1 (Cq), 44.2 (CH2), 34.3 (CH2), 30.2 (CH3), 18.2 (CH2), 14.7 (CH3), 9.1 (CH3); HRMS (ESI): m/z calcd for C21H26N: 292.2065 [M+H]+; found: 292.2064. Mp: 93–94 °C; Crystals suitable for X-ray diffraction study were obtained by slow evaporation of a hexane solution.

11b

1H NMR (300 MHz, C6D6): δ = 7.14 (t, J = 1.7 Hz, 1H, CH), 7.12 (t, J = 1.5 Hz, 1H, CH), 6.68 (dd, 3J = 7.5 Hz, J = 0.8 Hz, 1H, CH), 6.39 (d, 3J = 7.1 Hz, 1H, CH), 4.78 (s, 1H, CH), 2.38 (s, 3H, CH3), 2.34 (t, 3J = 7.7 Hz, 2H, CH2), 1.62-1.48 (m, 6H, CH2), 1.39-1.22 (m, 4H, CH2), 1.03-0.81 (m, 9H, CH3); 13C NMR (75 MHz, CDCl3): δ = 147.6 (Cq), 135.8 (Cq), 129.6 (CH), 125.5 (CH), 123.8 (CH), 121.3 (Cq), 115.9 (CH), 109.4 (CH), 63.9 (Cq), 44.7 (CH2), 34.8 (CH2), 32.7 (CH2), 31.6 (CH2), 30.2 (CH3), 23.4 (CH2), 18.6 (CH2), 15.1 (CH3), 14.5 (CH3), 9.4 (CH3); HRMS (ESI): m/z calcd for C19H30N: 272.2378 [M+H]+; found: 272.2381.

11c

1H NMR (300 MHz, C6D6): δ = 7.37 (dd, 3J = 7.9 Hz, J = 1.6 Hz, 4H, CH), 7.19-7.03 (m, 7H, CH), 6.60 (t, 3J = 7.5 Hz, 2H, CH), 6.52 (d, 3J = 8.2 Hz, 1H, CH), 5.18 (s, 1H, CH), 2.89 (d, 2J = 12.9 Hz, 1H, CH2), 2.54 (s, 3H, CH3), 2.49 (d, 2J = 12.9 Hz, 1H, CH2), 1.26 (s, 3H, CH3); 13C NMR (75 MHz, C6D6): δ = 146.5 (Cq), 140.8 (Cq), 138.2 (Cq), 137.5 (Cq), 131.4 (CH), 129.8 (CH), 129.7 (CH), 129.7 (CH), 128.8 (CH), 128.6 (CH), 128.2 (CH), 127.8 (CH), 126.7 (CH), 120.7 (Cq), 117.1 (CH), 112.0 (CH), 59.9 (Cq), 44.3 (CH2), 31.4 (CH3), 27.5 (CH3); HRMS (ESI): m/z calcd for C24H24N: 326.1909 [M+H]+; found: 326.1913.

11d

1H NMR (300 MHz, C6D6): δ = 7.28 (dd, 3J = 7.9 Hz, 4J = 1.9 Hz, 2H, CH), 7.14-7.06 (m, 4H, CH), 6.73 (td, 3J = 7.4 Hz, 4J = 1.8 Hz, 2H, CH), 6.48 (d, J = 8.3 Hz, 1H, CH), 5.04 (s, 1H, CH), 2.90 (d, 2J = 12.8 Hz, 1H, CH2), 2.51 (s, 3H, CH3), 2.45 (d, 2J = 12.3 Hz, 1H, CH2), 2.28 (t, 3J = 7.8 Hz, 2H, CH2), 1.49-1.43 (m, 4H, CH2), 1.24 (s, 3H, CH3), 0.84 (t, 3J = 7.2 Hz, 3H, CH3); 13C NMR (75 MHz, C6D6): δ = 146.4 (Cq), 138.5 (Cq), 134.0 (Cq), 131.3 (CH), 129.3 (CH), 128.2 (CH), 127.7 (CH), 126.6 (CH), 123.8 (CH), 121.9 (Cq), 116.9 (CH), 111.7 (CH), 59.9 (Cq), 45.1 (CH2), 32.4 (CH2), 31.4 (CH3), 31.3 (CH2), 27.5 (CH3), 23.4 (CH2), 14.5 (CH3); HRMS (ESI): m/z calcd for C22H28N: 306.2222 [M+H]+; found: 306.2217.

11e

1H NMR (300 MHz, C6D6): δ = 7.19 (d, J = 1.7 Hz, 1H, CH), 7.07 (dd, J = 8.4 Hz, J = 1.6 Hz, 1H, CH), 6.07 (d, J = 8.6 Hz, 1H, CH), 4.72 (s, 1H, CH), 2.23 (s, 3H, CH3), 2.14 (t, 3J = 7.5 Hz, 2H, CH2), 1.49-1.35 (m, 6H, CH2), 1.28-1.16 (m, 4H, CH2), 0.96-0.82 (m, 9H, CH3); 13C NMR (75 MHz, CDCl3): δ = 146.0 (Cq), 134.9 (Cq), 129.7 (Cq), 128.7 (CH), 126.8 (CH), 123.7 (CH), 123.0 (Cq), 110.3 (CH), 64.1 (Cq), 44.6 (CH2), 34.7 (CH2), 32.2 (CH2), 31.1 (CH2), 30.2 (CH3), 23.2 (CH2), 18.5 (CH2), 15.0 (CH3), 14.4 (CH3), 9.3 (CH3); HRMS (ESI): m/z calcd for C19H29NCl: 306.1989 [M+H]+; found: 306.1987.

11f

1H NMR (300 MHz, C6D6): δ = 7.19 (t, J = 2.4 Hz, 2H, CH), 7.13-7.12 (m, 4H, CH), 6.97 (d, 3J = 7.8 Hz, 2H, CH), 4.98 (s, 1H, CH), 2.76 (d, 2J = 13.1 Hz, 1H, CH2), 2.41 (d, 2J = 13.1 Hz, 1H, CH2), 2.37 (s, 3H, CH3), 2.09 (t, 3J = 6.7 Hz, 2H, CH2), 1.39-1.30 (m, 4H, CH2), 1.17 (s, 3H, CH3), 0.79 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (75 MHz, C6D6): δ = 144.9 (Cq), 138.1 (Cq), 133.4 (Cq), 131.2 (CH), 128.8 (CH), 128.6 (CH), 128.3 (CH), 127.6 (Cq), 126.8 (CH), 123.6 (CH), 124.6 (Cq), 112.5 (CH), 60.1 (Cq), 45.3 (CH2), 31.9 (CH2), 31.4 (CH3), 30.8 (CH2), 27.5 (CH3), 23.2 (CH2), 14.4 (CH3); HRMS (ESI): m/z calcd for C22H27NCl: 340.1832 [M+H]+; found: 340.1836.

11g

1H NMR (300 MHz, C6D6): δ = 6.97 (d, J = 2.9 Hz, 1H, CH), 6.72 (dd, J = 8.7 Hz, J = 2.9 Hz, 1H, CH), 6.31 (d, J = 8.7 Hz, 1H, CH), 4.86 (s, 1H, CH), 3.48 (s, 3H, CH3), 2.42 (s, 3H, CH3), 2.31 (t, 3J = 7.5 Hz, 2H, CH2), 1.66-1.56 (m, 2H, CH2), 1.54-1.46 (m, 4H, CH2), 1.35-1.26 (m, 4H, CH2), 0.91 (t, 3J = 7.2 Hz, 3H, CH3), 0.84 (t, 3J = 7.3 Hz, 6H, CH3); 13C NMR (75 MHz, CDCl3): δ = 151.7 (Cq), 142.3 (Cq), 135.5 (Cq), 127.2 (CH), 122.8 (Cq), 113.6 (CH), 111.7 (CH), 109.6 (CH), 63.5 (Cq), 55.8 (CH3), 44.3 (CH2), 34.4 (CH2), 32.7 (CH2), 31.5 (CH2), 30.4 (CH3), 23.3 (CH2), 18.6 (CH2), 15.1 (CH3), 14.5 (CH3), 9.5 (CH3); HRMS (ESI): m/z calcd for C20H32NO: 302.2484 [M+H]+; found: 302.2479.

11h

1H NMR (300 MHz, C6D6): δ = 7.32 (d, 3J = 7.0 Hz, 1H, CH), 7.12-7.05 (m, 5H, CH), 7.01 (d, J = 2.8 Hz, 1H, CH), 6.84 (d, J = 8.7 Hz, 1H, CH), 5.11 (s, 1H, CH), 3.48 (s, 3H, CH3), 2.91 (d, 2J = 13.2 Hz, 1H, CH2), 2.54 (s, 3H, CH3), 2.48 (d, 2J = 13.2 Hz, 1H, CH2), 2.30 (t, 3J = 7.1 Hz, 2H, CH2), 1.53-1.41 (m, 4H, CH2), 1.26 (s, 3H, CH3), 0.78 (t, 3J = 7.2 Hz, 3H, CH3); 13C NMR (75 MHz, C6D6): δ = 152.4 (Cq), 145.5 (Cq), 138.7 (Cq), 133.9 (Cq), 131.3 (CH), 129.0 (CH), 128.2 (CH), 127.4 (Cq), 126.9 (CH), 121.0 (CH), 115.5 (CH), 114.1 (CH), 59.5 (Cq), 55.6 (CH3), 44.0 (CH2), 32.4 (CH2), 31.6 (CH3), 31.2 (CH2), 26.8 (CH3), 23.3 (CH2), 14.5 (CH3); HRMS (ESI): m/z calcd for C23H30NO: 336.2327 [M+H]+; found: 336.2324.

11i

1H NMR (300 MHz, C6D6): δ = 7.37 (d, J = 1.8 Hz, 1H, CH), 7.35 (d, J = 1.4 Hz, 1H, CH), 7.20-7.17 (m, 3H, CH), 6.90 (d, 3J = 7.5 Hz, 1H, CH), 6.81 (dd, 3J = 7.3 Hz, 4J = 0.7 Hz, 1H, CH), 6.44 (t, 3J = 7.4 Hz, 1H, CH), 4.88 (s, 1H, CH), 2.84 (t, J = 5.4 Hz, 2H, CH2), 2.56 (t, J = 5.3 Hz, 2H, CH2), 1.71-1.60 (m, 6H, CH2), 1.49-1.42 (m, 2H, CH2), 1.04-0.98 (m, 3H, CH3), 0.88 (t, 3J = 7.1 Hz, 3H, CH3); 13C NMR (75 MHz, C6D6): δ = 143.7 (Cq), 141.4 (Cq), 139.7 (Cq), 130.3 (CH), 129.8 (CH), 128.8 (CH), 127.7 (CH), 127.5 (CH), 125.4 (CH), 121.1 (Cq), 120.3 (Cq), 115.5 (CH), 63.7 (Cq), 43.7 (CH2), 41.8 (CH2), 33.7 (CH2), 29.1 (CH2), 22.4 (CH2), 18.8 (CH2), 15.2 (CH3), 9.6 (CH3); HRMS (ESI): m/z calcd for C23H28N: 318.2222 [M+H]+; found: 318.2215.

11j

1H NMR (300 MHz, C6D6): δ = 6.98 (d, 3J = 7.5 Hz, 1H, CH), 6.81 (d, 3J = 7.2 Hz, 1H, CH), 6.56 (t, 3J = 7.4 Hz, 1H, CH), 4.74 (s, 1H, CH), 2.83 (t, J = 5.4 Hz, 2H, CH2), 2.55 (t, J = 6.2 Hz, 2H, CH2), 2.33 (t, 3J = 7.4 Hz, 2H, CH2), 1.69-1.49 (m, 8H, CH2), 1.41-1.27 (m, 4H, CH2), 1.02-0.94 (m, 6H, CH3), 0.87 (t, 3J = 7.2 Hz, 3H, CH3); 13C NMR (75 MHz, C6D6): δ = 143.8 (Cq), 135.9 (Cq), 130.0 (CH), 125.0 (CH), 122.5 (CH), 120.6 (Cq), 119.9 (Cq), 115.4 (CH), 63.5 (Cq), 44.1 (CH2), 41.8 (CH2), 34.0 (CH2), 33.1 (CH2), 31.7 (CH2), 29.3 (CH2), 23.5 (CH2), 22.4 (CH2), 18.6 (CH2), 15.2 (CH3), 14.5 (CH3), 9.6 (CH3); HRMS (ESI): m/z calcd for C21H32N: 298.2535 [M+H]+; found: 298.2527.

11k

1H NMR (300 MHz, C6D6): δ = 7.41 (d, 3J = 6.9 Hz, 2H, CH), 7.19-7.14 (m, 5H, CH), 7.08-7.03 (m, 4H, CH), 6.87 (d, 3J = 7.3 Hz, 1H, CH), 6.56 (t, 3J = 7.4 Hz, 1H, CH), 5.16 (s, 1H, CH), 2.99 (d, 2J = 12.7 Hz, 1H, CH2), 2.91-2.86 (m, 2H, CH2), 2.61 (d, 2J = 12.7 Hz, 1H, CH2), 2.53 (t, 3J = 7.0 Hz, 2H, CH2), 1.66 (t, 3J = 7.8 Hz, 2H, CH2), 1.27 (s, 3H, CH3); 13C NMR (75 MHz, C6D6): δ = 142.5 (Cq), 141.2 (Cq), 138.4 (Cq), 137.6 (Cq), 131.5 (CH), 129.7 (CH), 129.6 (CH), 129.2 (CH), 128.8 (CH), 128.3 (CH), 127.8 (CH), 127.5 (Cq), 126.7 (CH), 125.5 (CH), 123.2 (Cq), 116.6 (CH), 59.2 (Cq), 43.1 (2CH2), 28.9 (CH2), 26.6 (CH3), 22.8 (CH2); HRMS (ESI): m/z calcd for C26H26N: 352.2065 [M+H]+; found: 352.2060.

11l

1H NMR (300 MHz, C6D6): δ = 7.15-7.05 (m, 6H, CH), 6.87 (d, 3J = 6.8 Hz, 1H, CH), 6.68 (t, 3J = 7.5 Hz, 1H, CH), 5.03 (s, 1H, CH), 3.00–2.89 (m, 3H, CH2), 2.62-2.51 (m, 3H, CH2), 2.32 (t, J = 8.0 Hz, 2H, CH2), 1.63-1.57 (m, 4H, CH2), 1.51-1.44 (m, 2H, CH2), 1.26 (s, 3H, CH3), 0.84 (t, 3J = 7.3 Hz, 3H, CH3); 13C NMR (75 MHz, C6D6): δ = 142.4 (Cq), 138.7 (Cq), 134.2 (Cq), 131.4 (CH), 128.6 (CH), 128.2 (CH), 127.6 (Cq), 127.3 (Cq), 127.1 (CH), 126.5 (CH), 122.6 (CH), 116.5 (CH), 59.2 (Cq), 44.0 (CH2), 42.9 (CH2), 32.7 (CH2), 31.3 (CH2), 29.0 (CH2), 26.6 (CH3), 23.4 (CH2), 22.6 (CH2), 14.5 (CH3); HRMS (ESI): m/z calcd for C24H30N: 332.2378 [M+H]+; found: 332.2373.

11m

1H NMR (300 MHz, C6D6): δ = 7.41 (d, 3J = 7.8 Hz, 2H, CH), 7.21-7.17 (m, 3H, CH), 6.92 (d, 3J = 7.6 Hz, 1H, CH), 6.85 (d, 3J = 7.2 Hz, 1H, CH), 6.46 (t, 3J = 7.1 Hz, 1H, CH), 4.89 (s, 1H, CH), 3.12 (t, 3J = 7.1 Hz, 2H, CH2), 2.73 (t, 3J = 6.9 Hz, 2H, CH2), 1.63-1.49 (m, 4H, CH2), 1.10-1.05 (m, 2H, CH2), 1.01 (t, 3J = 6.9 Hz, 3H, CH3), 0.87 (t, 3J = 6.9 Hz, 3H, CH3); 13C NMR (75 MHz, C6D6): δ = 150.9 (Cq), 140.1 (Cq), 139.2 (Cq), 129.3 (CH), 128.9 (CH), 127.9 (CH), 127.3 (Cq), 127.0 (CH), 125.3 (Cq), 124.9 (CH), 123.3 (CH), 116.3 (CH), 62.7 (Cq), 45.3 (CH2), 43.3 (CH2), 33.4 (CH2), 28.6 (CH2), 18.8 (CH2), 15.2 (CH3), 9.7 (CH3); HRMS (ESI): m/z calcd for C22H26N: 304.2065 [M+H]+; found: 304.2062.

11n

1H NMR (300 MHz, C6D6): δ = 6.92 (d, 3J = 7.6 Hz, 1H, CH), 6.86 (dd, 3J = 7.3 Hz, 4J = 1.0 Hz, 1H, CH), 6.57 (t, 3J = 7.4 Hz, 1H, CH), 4.70 (s, 1H, CH), 3.10 (t, J = 8.7 Hz, 2H, CH2), 2.71 (t, J = 8.5 Hz, 2H, CH2), 2.34 (t, 3J = 7.1 Hz, 2H, CH2), 1.61-1.50 (m, 6H, CH2), 1.38-1.30 (m, 4H, CH2), 0.99 (t, 3J = 7.1 Hz, 3H, CH3), 0.88 (t, 3J = 7.3 Hz, 3H, CH3), 0.86 (t, 3J = 7.2 Hz, 3H, CH3); 13C NMR (75 MHz, C6D6): δ = 151.0 (Cq), 136.3 (Cq), 127.2 (Cq), 125.0 (Cq), 124.5 (CH), 124.1 (CH), 121.3 (CH), 116.1 (CH), 62.3 (Cq), 45.2 (CH2), 43.5 (CH2), 33.5 (CH2), 31.9 (CH2), 31.7 (CH2), 28.6 (CH2), 23.3 (CH2), 18.7 (CH2), 15.2 (CH3), 14.5 (CH3), 9.7 (CH3); HRMS (ESI): m/z calcd for C20H30N: 284.2378 [M+H]+; found: 284.2371.

Supplementary Material

1_si_001

2_si_002

Acknowledgment

We are grateful to the NIH (R01 GM 68825) for financial support of this work, the China Scholarship Council (X.Z.), the Alexander von Humboldt Foundation (G.D.F.), and the Japanese Society for Promotion of Science (R.K.) for Fellowships.

Footnotes

BRIEFS. A gold(I) complex, bearing a stable spirocyclic (alkyl)(amino)carbene, built from a very cheap aldehyde precursor, allows for the one-pot three-component synthesis of 1,2-dihydroquinoline derivatives from secondary (aryl(alkyl) amines, internal and terminal alkynes.

Supporting Information Available. Crystallographic data for 2d (CCDC number: 723865) and 11a (CCDC number: 723864), and 1H and 13C NMR spectra for compounds 1d, 2d, 5, 7, and 11a,b,e,i,j. This material is available free of charge via the internet at http://pubs.acs.org.

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