Modular Synthesis of Dipyrroloquinolines: A Combined Synthetic and

Jan 22, 2018 - Wilhelm-Ostwald-Institute for Physical and Theoretical Chemistry, University of Leipzig, Linnéstrasse 3, D-04103 Leipzig, Germany...
0 downloads 0 Views 1MB Size
Download PDF
Article Cite This: J. Org. Chem. 2018, 83, 1737−1744

pubs.acs.org/joc

Modular Synthesis of Dipyrroloquinolines: A Combined Synthetic and Mechanistic Study Johannes Appun,† Ferdinand Stolz,‡,§ Sergej Naumov,‡ Bernd Abel,§ and Christoph Schneider*,† †

Institute of Organic Chemistry, University of Leipzig, Johannisallee 29, D-04103 Leipzig, Germany Leibniz-Institute of Surface Modification (IOM), Permoserstrasse 15, D-04318 Leipzig, Germany § Wilhelm-Ostwald-Institute for Physical and Theoretical Chemistry, University of Leipzig, Linnéstrasse 3, D-04103 Leipzig, Germany ‡

S Supporting Information *

ABSTRACT: A straightforward synthesis of [1,2-a][3′,2′c]dipyrroloquinolines has been developed generating up to eight new σ-bonds and five new stereogenic centers in a simple and modular one-pot operation. Generally good to excellent yields and moderate to good stereoselectivities in favor of the all-cis stereoisomer were observed. A detailed investigation combining synthetic studies, analytical measurements, and theoretical calculations has been conducted to elucidate the reaction mechanism using ESI- and liquid-beam IR-laser desorption mass spectrometry as well as DFT calculations. Key steps of this sequential transformation include a Lewis acid-catalyzed vinylogous Mukaiyama−Mannich reaction of bis(silyl) dienediolate 1 and a Brønsted acid-promoted Mannich−Pictet−Spengler reaction cascade reaction to complete the synthesis of the dipyrroloquinoline core of the target compounds.

■

INTRODUCTION Rapid and efficient access to complex heterocycles is one of the major challenges in the field of a diversity-oriented synthesis.1 In the pursuit of this goal, multicomponent and domino reactions serve particularly well as versatile tools to generate heterocyclic scaffolds on the basis of their flexibility, operational simplicity, and reaction efficiency.2,3 The octahydrodipyrrolo[1,2-a][3′,2′-c]quinolone motif has attracted increased attention since its identification as a core structure in the natural product incargranine B in 2013 by Lawrence et al. following a biomimetic synthesis.4 Isolation of this natural product had previously been accomplished by Zhang et al.5 Since 2013, some synthetic approaches toward this core structure have been reported. Fustero et al. developed a stereoselective synthesis based on the intramolecular hydroamination of homopropargylic amines.6 Following the same strategy, the groups of Li7 and Liu8 developed transition metal-catalyzed syntheses of dipyrroloquinolines as well as the aglycone of incargranine B in 2016. The first highly diastereoand enantioselective synthesis of the aglycone of incargranine B was established by Liu et al. by means of the formation of a chiral contact ion pair using their previously established methodology comprising the intramolecular hydroamination of homopropargylic amines.9 We recently developed a new and efficient entry point for rapid and diversity-oriented access toward complex heterocycles employing a novel bis(silyl) dienediolate 1 that could act either as a versatile 1,3-zwitterionic synthon or as a 1,2dinucleophile. As a 1,3-zwitterionic synthon, the direct and highly stereoselective access toward pyrrolobenzoxazoles10 or pyrrolobenzoxazinones and pyrroloquinazolinones11 was ac© 2018 American Chemical Society

complished through a Lewis acid-catalyzed [3 + 2] cycloannulation process. Within the manifold of its 1,2-dinucleophilic reactivity, a highly stereoselective synthesis of 2,3,5substituted tetrahydrofurans was developed through a Lewis acid-catalyzed, vinylogous aldol and Prins-type reaction.12 In addition, the conjugate addition of 1 toward α,β-unsaturated aldehydes in an organocatalytic domino-Michael−Knoevenagel process provided cyclopentenyl-α-keto esters with good yields and excellent enantioselectivity.13 Finally, a modular, flexible, and stereoselective synthesis of pyrroloquinolines 4 was accomplished through a sequential process in which three carbon−carbon bonds and one carbon−nitrogen bond as well as four stereogenic centers were formed with good stereochemical control.14 Conceptually, that process relied on a sequence of events in which a Lewis acid-catalyzed vinylogous Mukaiyama−Mannich reaction furnished silyl enol ether 3 that formally engaged a second imine in a Brønsted acid-promoted Mannich−Pictet− Spengler reaction to generate the desired pyrroloquinolines with good overall yields (Scheme 1, top). In the present study, we have now discovered that we can expand the scope of this reaction to access more complex dipyrroloquinolines 5 as well by attenuating the amount of imine employed. Specifically, we have used the cyclic imine resulting from cyclocondensation of 3 in place of a second imine equivalent as reaction partner of 3 to access dipyrroloquinolines 5 (Scheme 1, bottom). Received: September 28, 2017 Published: January 22, 2018 1737

DOI: 10.1021/acs.joc.7b02466 J. Org. Chem. 2018, 83, 1737−1744

Article

The Journal of Organic Chemistry

increased to 79% using aqueous trifluoroacetic acid for the second reaction step (entry 2). Fine tuning of the acid concentration (entry 3) and switching to aqueous HCl further improved the isolated yield of product 5a to 85% as a 60:34:6 mixture of diastereomers (entry 4). A decrease of acid equivalents deteriorated the yield (entry 5). Variation of the solvent generally led to lower overall yields and lower diastereoselectivities, making acetonitrile the solvent of choice (entries 6−11). As the diastereoselectivity was determined in the second reaction step, the reaction was performed at reduced temperature for this step. However, at the same time the isolated yields decreased, the diastereomeric ratios did not improve, and the reaction times increased sharply to 5 days at 0 °C (entry 12) and 14 days at 20 °C (entry 13). Finally, it was shown that the reaction did not proceed without Brønsted acid at room temperature, and vinylogous Mannich product 3 could be isolated instead (entry 14). Having optimal reaction conditions in hand (Table 1, entry 4), we investigated the substrate scope of this sequential onepot reaction. Different aromatic, heteroaromatic, as well as aliphatic imines were successfully employed giving rise to the corresponding dipyrroloquinolines 5 with good to excellent yields (Table 2). A broad range of imines carrying various aromatic and heteroaromatic substituents furnished the desired heterocycles with up to 96% yield and moderate diastereose-

Scheme 1. Design Plan for the Synthesis of Dipyrroloquinolines

■

RESULTS AND DISCUSSION In previous studies, we had found that the vinylogous Mukaiyama−Mannich reaction of bis(silyl) dienediolate 1 with N-aryl imines was readily catalyzed through Yb(OTf)3 (10 mol %). We employed the same reaction conditions in our model reaction of PMP-imine 2a (1.0 equiv) and bis(silyl) dienediolate 1 (1.1 equiv) in acetonitrile at rt en route to the desired dipyrroloquinolines 5 (Table 1).10,14 The second step of the sequential reaction was then initiated by the addition of the Brønsted acid (PhO)2PO2H (1.0 equiv) without further adding more imine (entry 1). Even though the reaction proceeded to full conversion within 16 h, only 22% isolated yield of a 66:34 (5a-1:5a-2) diastereomeric mixture of product 5a was obtained. To our delight, the yield could be substantially

Table 2. Substrate Scopea

Table 1. Optimization Studiesa

entry

acid

solv.

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

(PhO)2PO2H TFA (3.25 M) TFA (1.0 M) HCl (1.0 M) HCl (1.0 M)d HCl (1.0 M) HCl (1.0 M) HCl (1.0 M) HCl (1.0 M) HCl (1.0 M) HCl (1.0 M) HCl (1.0 M) HCl (1.0 M)

MeCN MeCN MeCN MeCN MeCN CH2Cl2 toluene Et2O THF DME MeOH MeCN MeCN MeCN

time 16 16 16 16 22 16 16 16 16 16 16

h h h h h h h h h h h 5d 14 d 2d

yield [%]b

drc

22 79 83 85 64 76 52 58 68 74 79 52 58 0

66:34 54:38:8 60:28:12 60:34:6 56:37:7 49:49:2 48:29:23 59:39:2 45:37:18 53:39:8 54:36:10 53:42:5 63:32:5

entry

product

R1

R2

yield [%]b

drc

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

5a 5b 5c 5d 5e 5f 5g 5h 5i 5j 5k 5l 5m 5a

4-MeC6H4 Ph 3-MeC6H4 2-MeC6H4 4-MeOC6H4 4-FC6H4 4-ClC6H4 4-NO2C6H4 2-furyl 3-thienyl n-pentyl t-butyl Ph 4-MeC6H4

MeO MeO MeO MeO MeO MeO MeO MeO MeO MeO MeO MeO Me MeO

85 79 91 96 69 98 78 82 84 90 75 85 81 94

60:34:6 49:28:23 45:15:40 50:23:27 50:28:22 43:24:33 56:19:25 51:24:25 41:41:18 39:36:25 50:46:4 7:8:85e 50:24:26 52:30:18

a Reaction conditions: imine 2 (0.3 mmol), bis(silyl)dienediolate 1 (1.1 equiv), Yb(OTf)3 (10 mol %) in 3.0 mL MeCN for 1h, then HCl (1.0 M, 1.0 equiv) for 16 h. bIsolated yield of chromatographically purified material. cThe dr was determined by 1H NMR of purified product, dr (5a-1:5a-2:other diastereomers). dReaction performed as a 3component reaction. eMajor diastereomer was 5l-3. fReaction performed on a 6.0 mmol scale.

a

Reaction conditions: imine 2a (0.2 mmol), bis(silyl) dienediolate 1 (1.1 equiv), and Yb(OTf)3 (10 mol %) in 2.0 mL of solvent for 1 h, then Brønsted acid for 16 h. bIsolated yield of chromatographically purified material. cThe dr was determined by 1H NMR of purified product, dr (5a-1:5a-2:other diastereomers). dHCl (0.1 equiv). e Reaction temperature: 0 °C. fReaction temperature: −20 °C. 1738

DOI: 10.1021/acs.joc.7b02466 J. Org. Chem. 2018, 83, 1737−1744

Article

The Journal of Organic Chemistry lectivities in favor of the two major isomers 5-1 and 5-2, both of which could be separated by column chromatography (entries 1−10). Alkyl-substituted imines could be employed as well and delivered the target products 5k−l with good yields (entries 11 and 12). Quite interestingly, the pivalaldehyde-derived product 5l was formed with opposite diastereoselectivity, most likely on the basis of the large steric bulk of the t-Bu group. N-4-Tolyl imine 2m reacted likewise (entry 13). Occasionally, the chromatographic purification of products turned out to be difficult, and the isolated material contained minor impurities as judged by 1H NMR. The model reaction using substrate 5a was also performed on a 6.0 mmol scale giving rise to almost quantitative yield of product 5a (entry 14). The three major diastereomers were isolated in 46% (920 mg) for 5a-1, 27% (550 mg) for 5a-2, and 12% yield each (230 mg) for 5a-3, and the relative configuration could be assigned based on NOE experiments (see Supporting Information). Moreover, a three-component transformation was developed to simplify the overall operation. Mixing p-tolylaldehyde, panisidine, and nucleophile 1 (1.0 equiv each) with 10 mol % of Yb(OTf)3 in MeCN led to the formation of silyl enol ether 3a, and subsequent addition of HCl triggered the second reaction step to generate product 5a with excellent overall yield to produce a mixture of three diastereomers (Scheme 2).

Scheme 3. Mechanistic Proposal

Scheme 2. 3-Component Reaction Figure 1. Time-resolved signal intensities of different mass peaks as detected with liquid-beam IR-laser desorption mass spectrometry. The start time t = 0 is set after full conversion into silyl enol ether 3; the measurement at −15 min represents this initial solution. The symbols with error bars represent the respective time-dependent signal intensities of the most relevant mass peaks. The lines and shaded areas display the results of kinetic modeling16 with estimated uncertainties. Mass peak intensities: purple tip-down triangles: mass = 428 u, 3a; blue diamonds: mass = 356 u, 6a and 7a; yellow squares: mass = 338 u, 8a and 9a; red tip-up triangles: mass = 675 u, 5a.

After having shown its versatility, we set out to elucidate the mechanism of this new heterocycle synthesis. Silyl enol ether 3a had been identified before as intermediate in the vinylogous Mukaiyama−Mannich reaction between nucleophile 1 and imine 2a.14,15 Of central importance was now the question of which way it further reacted to dipyrroloquinolines 5. In principle, it could first undergo a normal-type Mukaiyama− Mannich reaction with an imine followed by cyclocondensation and Pictet−Spengler reaction to afford the final product. Alternatively, it could as well be first desilylated by the acid into the corresponding α-keto ester 6a. That in turn should spontaneously cyclize via hemiaminal 7a to iminium ion 8a, which should be in equilibrium with its enamine tautomer 9a. These two species could then engage in an enamine-Mannich reaction followed by a Pictet−Spengler cyclization of intermediate 10a (Scheme 3). Accordingly, we conducted liquid-beam IR-laser desorption mass spectrometry18−21 on the Brønsted acid-triggered reaction of silyl enol ether 3a as this constitutes a very sensitive tool for the online detection of reaction intermediates (Figure 1).16,17 For that purpose, the reaction mixture was transferred into the vacuum chamber as a liquid microbeam. Upon heating of the solvent with a pulsed IR laser, the analytes were desorbed into the vacuum, sampled with a skimmer, and analyzed in the mass spectrometer. Because of the desorption conditions, this technique allows for very soft desorption of molecules and ions.

For each presented measurement at different reaction times, 0.1 mL of the reaction solution was dissolved in 1.9 mL of H2O/ MeCN (1:1) and immediately analyzed. The detected timedependent signal intensities of the relevant mass peaks are presented in Figure 1. As a control measurement at t = −15 min, only silyl enol ether 3 was detected. After addition of hydrochloric acid at t = 0, which started the reaction, the measured intensity of silyl enol ether 3 fell off relatively fast whereas the respective intermediates at m/z = 356 (6a and 7a) and m/z = 338 (8a and 9a) were clearly detected. After ∼3 h, the signal intensities of these intermediates decreased, and formation of dipyrroloquinoline 5a was observed based upon the increasing signal intensity at m/z = 675. Therefore, we conclude that the mechanistic proposal depicted in Scheme 3, which involves formation of the iminium-enamine tautomeric mixture and ensuing enamine-Mannich reaction, was actually taking place as all involved species were clearly identified in the mass spectrometric measurements. To further verify details of this mechanistic proposal, we performed quantum chemical calculations for the synthesis of dipyrroloquinoline 5a (Figure 2). The calculated reaction parameters ΔH and ΔG for different reaction steps are given in Table S1. We looked at the entire reaction starting from 1739

DOI: 10.1021/acs.joc.7b02466 J. Org. Chem. 2018, 83, 1737−1744

Article

The Journal of Organic Chemistry

Figure 2. Theoretical calculations (M06-D3/LACVP**/PBF).

bis(silyl) dienediolate 1, imine 2a, and a Lewis acid (LA) for which we used ZnCl2 in place of Yb(OTf)3. Grel was calculated from the sum of Gibbs free energies of all entities. Reaction step (1) represents the exothermic (ΔH = −5.1 kcal mol−1) yet endergonic formation of a charge transfer complex 2a-LA between the imine and the LA with a partial charge shift (0.308e) of the nitrogen lone pair to the metal. Upon this electrophilic activation of the imine reaction, step (2) becomes feasible resulting in the addition of bis(silyl) dienediolate 1. Addition of one equiv of water gives rise to loss of trimethylsilanol and results in structure 3a-LA (step 3). Additional water then leads to O−Si bond scission and dissociation of a second trimethylsilanol molecule to form αketo ester-LA complex 6a-LA (step 4). This complex can undergo further transformations either through loss of LA and forming α-keto ester 6a (step 5) or through concerted H-shift from nitrogen to oxygen followed by ring-closing (step 8, formation of 7a-LA). Both 6a and 7a-LA can react to hemiaminal 7a (steps 6 and 9). By acid-catalyzed elimination of water, 7a now generates enamine 8a (step 7), whereas 7a-LA will generate iminium ion 9a(+) through loss of the ZnCl2− OH anion. In an enamine-Mannich reaction, 8a and 9a(+) react exergonically to produce intermediate 10a(+) (step 11), which finally undergoes the Pictet−Spengler cyclization to generate target dipyrroloquinoline 5a (step 12).

desorption mass spectrometry and DFT calculations. The results suggest a pathway comprising a vinylogous Mukaiyama− Mannich reaction followed by a cyclocondensation, enamineMannich reaction, and Pictet−Spengler cyclization to arrive at the target compounds. Further investigations are directed at the development of a catalytic, enantioselective process that are ongoing in our laboratories.

■

EXPERIMENTAL SECTION

General. All reactions were carried out in oven-dried glassware under an Ar atmosphere unless otherwise noted. 1H and 13C NMR spectra were recorded in CDCl3 at 26 °C. Spectra were referenced to residual chloroform (7.26 ppm; 1H; 77.16 ppm, 13C). Chemical shifts are reported in ppm; multiplicities are indicated by s (singlet), br s (broad singlet), d (doublet), t (triplet), q (quartet), p (pentet), m (multiplet), and related permutations. High-resolution mass spectra (HRMS) were recorded using an ESI-FT-ICR. Solvents were distilled from the indicated drying reagents: dichloromethane (CaH2), tetrahydrofuran (Na, benzophenone), diethyl ether (Na, benzophenone), acetonitrile (CaH2), and 1,2-dimethoxyethane (KOH). Other solvents were of technical grade and distilled from the indicated drying reagents: diethyl ether (KOH), methyl-tert-butylether (KOH), ethyl acetate (CaCl2), n-hexane (KOH), and dichloromethane (CaH2). Flash column chromatography was performed using silica gel (60 Å, 230−400 mesh size). Analytical thin-layer chromatography (TLC) was performed on precoated TLC sheets. Visualization of the spots was achieved by UV-light or with a solution of phosphomolybdic acid hydrate solution (5 g in 250 mL ethanol). Compound 1 was prepared according to a known literature procedure.10 General Procedure for the Synthesis of Dipyrroloquinoline 5. To a 10 mL round-bottom flask were successively added (E)-N-(4methoxyphenyl)-1-(p-tolyl)methanimine (68 mg, 0.30 mmol, 1.0 equiv), Yb(OTf)3 (18 mg, 0.03 mmol, 10 mol %), and acetonitrile (3.00 mL) and stirred at 20 °C. After 5 min, bis(silyl) dienediolate 1 (87 mg, 0.32 mmol, 1.1 equiv) was added dropwise, and after complete conversion (1.0 h), a 1.0 M HCl solution (300 μL, 0.30 mmol, 1.0 equiv) was added. After 16 h, 8 mL of sat. aq NaHCO3 solution and 5 mL of CH2Cl2 were added; the aq phase was extracted three times with 5 mL of CH2Cl2, and the combined organic layers were dried over Na2SO4. After filtration, the solvent was removed under reduced pressure. Flash column chromatography (hexane/

■

CONCLUSIONS In summary, we have developed a straightforward and efficient synthesis of octahydrodipyrrolo[1,2-a][3′,2′-c]quinolines generating up to eight σ-bonds and five stereogenic centers in a sequential, one-pot process from readily available starting materials. A broad range of aromatic, heteroaromatic, and aliphatic imines were tolerated in this process and formed mainly two stereoisomers selectively that were readily separable by chromatography. In addition, the reaction may be conveniently performed on a gram-scale, giving almost quantitative yield. Investigations to elucidate the reaction mechanism have been conducted using liquid-beam IR-laser 1740

DOI: 10.1021/acs.joc.7b02466 J. Org. Chem. 2018, 83, 1737−1744

Article

The Journal of Organic Chemistry

1H), 4.49−4.23 (m, 2H), 4.16−4.00 (m, 2H), 3.92 (dq, J = 11.0, 7.0 Hz, 1H), 3.65 (s, 3H), 3.20 (s, 3H), 2.84 (dt′, J = 12.5, 8.0 Hz, 1H), 2.57−2.41 (m, 1H), 2.35−2.20 (m, 1H), 2.20−2.07 (m, 1H), 2.05− 1.93 (m, 1H), 1.91−1.77 (m, 1H), 1.45 (t, J = 7.0 Hz, 3H), 1.09 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.4, 174.7, 154.8, 150.1, 145.4, 144.0, 138.9, 138.7, 129.0, 128.50, 127.3, 127.0, 126.9, 126.0, 124.7, 121.5, 115.8, 115.8, 114.4, 113.9, 73.8, 72.0, 63.6, 62.6, 61.9, 61.1, 55.4, 55.0, 48.6, 36.5, 33.1, 33.0, 29.9, 14.3, 14.08; IR (cm−1, KBr) 2978, 2933, 2831, 1732, 1510; HRMS (ESI+) m/z [M + H]+ calcd for C40H43N2O6 647.3116, found 647.3111. Dipyrroloquinoline 5c. Yellow solid, 92 mg (91%, dr 45:15:40). Diastereomer 5c-1: Rf (hexane/MTBE 3:1) = 0.37; 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 8.0 Hz, 1H), 7.36−7.30 (m, 3H), 7.24− 7.17 (m, 2H), 7.08−7.01 (m, 3H), 6.70−6.59 (m, 4H), 6.55 (dd, J = 9.0, 3.0 Hz, 1H), 6.25 (d, J = 9.0 Hz, 1H), 4.70 (d, J = 10.0 Hz, 1H), 4.66 (d, J = 8.0 Hz, 1H), 4.30 (q′, J = 7.0 Hz, 2H), 4.20−4.04 (m, 2H), 3.92 (dd, J = 13.0, 6.5 Hz, 1H), 3.69 (s, 3H), 3.35 (s, 3H), 2.48−2.39 (m, 1H), 2.36 (s, 3H), 2.34 (s, 3H), 2.31−2.23 (m, 1H), 2.13 (ddd, J = 13.0, 11.5, 9.5 Hz, 1H), 2.00−1.90 (m, 2H), 1.85−1.70 (m, 1H), 1.39 (t, J = 7.0 Hz, 3H), 1.26 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.7, 173.9, 152.1, 150.7, 144.8, 144.5, 139.6, 138.3, 138.0, 137.3, 128.6, 128.5, 127.7, 127.5, 127.2, 126.8, 123.8, 123.5, 121.9, 118.3, 115.4, 114.2, 113.2, 77.2, 70.4, 68.9, 68.3, 62.2, 61.9, 55.6, 55.2, 44.2, 36.4, 36.0, 34.8, 21.8, 14.2, 14.1; IR (KBr) ṽ (cm−1) 2979, 2934, 2830, 1731, 1606, 1509; HRMS (ESI+) m/z [M + H]+ calcd for C42H47N2O6 675.3429, found 675.3426. Diastereomer 5c-2: Rf (hexane/MTBE 3:1) = 0.24; 1H NMR (400 MHz, CDCl3) δ 7.33− 7.22 (m, 5H), 7.14 (d, J = 7.5 Hz, 1H), 7.12−7.06 (m, 1H), 6.96 (d, J = 7.5 Hz, 1H), 6.77−6.66 (m, 2H), 6.60 (d, J = 9.5 Hz, 2H), 6.51 (dd, J = 9.0, 3.0 Hz, 1H), 6.26 (d, J = 9.0 Hz, 1H), 6.11 (d, J = 3.0 Hz, 1H), 4.77 (dd, J = 10.0, 3.0 Hz, 1H), 4.73−4.63 (m, 1H), 4.46−4.25 (m, 2H), 4.16−4.00 (m, 2H), 3.97−3.86 (m, 1H), 3.65 (s, 3H), 3.19 (s, 3H), 2.83 (dt, J = 12.5, 8.0 Hz, 1H), 2.54−2.43 (m, 1H), 2.42 (s, 3H), 2.29 (s, 3H), 2.19−2.11 (m, 1H), 1.98 (ddd, J = 12.5, 8.0, 1.5 Hz, 1H), 1.87−1.78 (m, 1H), 1.46 (t, J = 7.0 Hz, 3H), 1.08 (t, J = 7.0 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 175.5, 174.7, 154.9, 150.0, 145.3, 143.8, 139.0, 139.0, 138.5, 137.9, 128.8, 128.4, 128.0, 127.8, 127.7, 126.7, 124.8, 124.3, 123.0, 121.4, 115.8, 115.8, 114.3, 113.9, 77.2, 73.9, 72.1, 63.7, 62.7, 61.8, 61.1, 55.4, 55.0, 48.7, 36.6, 33.1, 33.0, 21.9, 21.6, 14.4, 14.1; IR (cm−1, KBr) 2979, 2833, 1734, 1508; HRMS (ESI+) m/ z [M + H]+ calcd for C42H47N2O6 675.3429, found 675.3426. Dipyrroloquinoline 5d. Yellow wax, 92 mg (91%, dr 50:23:27). Diastereomer 5d-1: Rf (hexane/MTBE 3:1) = 0.35; 1H NMR (400 MHz, CDCl3) δ 8.08−7.98 (m, 1H), 7.91−7.82 (m, 1H), 7.23−7.07 (m, 7H), 6.70−6.62 (m, 2H), 6.58−6.40 (m, 3H), 6.09 (d, J = 9.0 Hz, 1H), 4.87 (d, J = 9.5 Hz, 1H), 4.81 (t′, J = 8.0 Hz, 1H), 4.39−4.23 (m, 2H), 4.14 (q′, J = 7.0 Hz, 2H), 3.90 (dd, J = 13.0, 6.5 Hz, 1H), 3.68 (s, 3H), 3.34 (s, 3H), 2.59−2.49 (m, 1H), 2.41 (s, 3H), 2.35 (s, 3H), 2.32−2.24 (m, 1H), 2.15 (ddd, J = 13.0, 11.5, 9.5 Hz, 1H), 1.97 (m′, J = 1H), 1.90 (m′, 1H), 1.74−1.60 (m, 1H), 1.39 (t, J = 7.0 Hz, 3H), 1.27 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.6, 173.8, 151.9, 150.9, 141.9, 139.5, 137.2, 134.2, 133.3, 130.6, 130.5, 127.1, 126.7, 126.7, 126.6, 126.5, 122.2, 117.6, 115.2, 114.3, 114.1, 113.1, 77.2, 70.3, 68.8, 66.1, 62.3, 61.8, 58.5, 55.7, 55.2, 44.3, 36.0, 34.6, 32.2, 29.9, 19.6, 14.2, 14.0; IR (cm−1, KBr) 2977, 2954, 2831, 1731, 1499; HRMS (ESI+) m/z [M + H]+ calcd for C42H47N2O6 675.3429, found 675.3426. Diastereomer 5d-2: Rf (hexan/MTBE 3:1) = 0.28; 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.5 Hz, 1H), 7.55 (dd, J = 7.0, 2.0 Hz, 1H), 7.28−7.21 (m, 1H), 7.21−7.12 (m, 2H), 7.12−7.02 (m, 3H), 6.82−6.55 (m, 4H), 6.50 (dd, J = 9.0, 3.0 Hz, 1H), 6.10 (d, J = 3.0 Hz, 1H), 6.03 (d, J = 9.0 Hz, 1H), 4.95 (dd, J = 10.0, 3.0 Hz, 1H), 4.91 (d, J = 7.0 Hz, 1H), 4.42 (dq′, J = 11.0, 7.0 Hz, 1H), 4.32 (dq′, J = 11.0, 7.0 Hz, 1H), 4.19−4.05 (m, 2H), 3.92 (dq′, J = 11.0, 7.0 Hz, 1H), 3.65 (s, 3H), 3.19 (s, 3H), 2.90 (dt′, J = 12.5, 8.0 Hz, 1H), 2.62−2.49 (m, 1H), 2.48 (s, 3H), 2.46 (s, 3H), 2.25−2.14 (m, 1H), 2.14−2.05 (m, 1H), 2.05−1.95 (m, 1H), 1.82−1.70 (m, 1H), 1.47 (t, J = 7.0 Hz, 3H), 1.11 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.3, 174.7, 154.9, 150.0, 142.5, 141.4, 139.0, 138.9, 134.9, 134.5, 131.1, 130.3, 127.2, 126.7, 126.5, 126.4, 126.2, 124.6, 124.5, 121.3, 116.0, 115.8, 114.5, 114.0, 77.16, 73.8, 72.0, 61.8, 61.1, 59.6, 55.4, 54.9, 48.7, 34.2,

MTBE 10:1 to 3:1) afforded the corresponding product 5a (86 mg, 85%, dr 60:34:6) as a yellow wax. Diastereomer 5a-1: Rf (hexan/ MTBE 3:1) = 0.32; 1H NMR (300 MHz, CDCl3) δ 7.45 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.17−7.13 (m, 2H), 7.13−7.08 (m, 2H), 7.03 (d, J = 3.0 Hz, 1H), 6.66 (d, J = 9.5 Hz, 2H), 6.62 (d, J = 9.5 Hz, 2H), 6.54 (dd, J = 9.0, 3.0 Hz, 1H), 6.24 (d, J = 9.0 Hz, 1H), 4.71 (d, J = 8.5 Hz, 1H), 4.66 (d, J = 7.5 Hz, 1H), 4.35−4.21 (m, 2H), 4.19−4.01 (m, 2H), 3.89 (dd, J = 13.0, 6.5 Hz, 1H), 3.68 (s, 3H), 3.34 (s, 3H), 2.48−2.36 (m, 1H), 2.34 (s, 3H), 2.32 (s, 3H), 2.25 (ddd, J = 12.0, 6.5, 3.0 Hz, 1H), 2.12 (ddd′, J = 13.0, 11.5, 9.5 Hz, 1H), 1.99− 1.87 (m, 2H), 1.83−1.68 (m, 1H), 1.37 (t, J = 7.0 Hz, 3H), 1.25 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.6, 173.8, 152.2, 150.7, 141.7, 141.5, 139.6, 137.2, 136.4, 136.2, 129.4, 129.2, 126.6, 126.2, 121.8, 118.4, 115.3, 114.2, 114.0, 113.3, 70.4, 68.9, 67.9, 62.2, 61.6, 61.4, 55.6, 55.2, 44.2, 36.4, 35.9, 34.8, 21.2, 21.2, 14.2, 13.98; IR (cm−1, KBr) 2979, 2930, 2833, 1732, 1509; HRMS (ESI+) m/z [M + H]+ calcd for C42H47N2O6 675.3429, found 675.3426. Diastereomer 5a-2: Rf (hexan/MTBE 3:1) = 0.26; 1H NMR (300 MHz, CDCl3) δ 7.38 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 6.76−6.62 (m, 2H), 6.61 (d, J = 9.0 Hz, 2H), 6.51 (dd, J = 9.0, 3.0 Hz, 1H), 6.27 (d, J = 9.0 Hz, 1H), 6.15 (d, J = 3.0 Hz, 1H), 4.80 (dd, J = 10.0, 3.0 Hz, 1H), 4.70 (dd, J = 8.5, 6.0 Hz, 1H), 4.47−4.24 (m, 2H), 4.18−4.11 (m, 1H), 4.10−4.01 (m, 1H), 3.92 (dq, J = 11.0, 7.0 Hz, 1H), 3.65 (s, 3H), 3.20 (s, 3H), 2.82 (dt′, J = 12., 8.0 Hz, 1H), 2.57−2.40 (m, 1H), 2.38 (s, 3H), 2.28 (s, 3H), 2.29−2.18 (m, 1H), 2.19−2.09 (m, 1H), 1.98 (dd, J = 13.0, 8.0 Hz, 1H), 1.83 (ddd′, J = 12.0, 8.0, 2.5 Hz, 1H), 1.46 (t, J = 7.0 Hz, 3H), 1.09 (t, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 175.5, 174.7, 154.7, 150.0, 142.5, 140.9, 139.0, 138.8, 136.5, 136.3, 129.6, 129.2, 127.2, 126.0, 124.6, 121.5, 115.8, 115.8, 114.3, 113.9, 77.2, 73.8, 72.0, 63.3, 62.3, 61.8, 61.1, 55.4, 55.0, 48.6, 36.5, 33.2, 33.0, 21.2, 14.3, 14.1; IR (cm−1, KBr) 2979, 2952, 2831, 1732, 1509; HRMS (ESI+) m/z [M + H]+ calcd for C42H47N2O6 [M + H]+ 675.3429, found 675.3426. Diastereomer 5a-3: Rf (hexan/MTBE 3:1) = 0.40; 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 3.0 Hz, 1H), 6.64 (d, J = 9.0 Hz, 2H), 6.50 (dd, J = 9.0, 3.0 Hz, 1H), 6.46 (d, J = 9.0 Hz, 1H), 6.43 (d, J = 9.0 Hz, 2H), 4.76 (d, J = 8.5 Hz, 1H), 4.55 (dd, J = 10.0, 6.5 Hz, 1H), 4.35 (q′, J = 7.0 Hz, 2H), 4.22−4.04 (m, 2H), 3.68 (s, 3H), 3.62 (dd, J = 13.0, 5.5 Hz, 1H), 3.41 (s, 3H), 2.62 (dd, J = 12.5, 6.0 Hz, 1H), 2.38 (s, 3H), 2.35 (s, 3H), 2.34−2.27 (m, 1H), 2.23 (dt, J = 13.0, 6.5 Hz, 1H), 1.87 (td, J = 12.5, 6.5 Hz, 1H), 1.68 (dd, J = 11.5, 5.5 Hz, 1H), 1.61 (ddd, J = 13.0, 6.5, 3.5 Hz, 1H), 1.36 (t, J = 7.0 Hz, 3H), 1.20 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 174.9, 174.8, 153.2, 151.4, 144.1, 140.9, 139.6, 138.9, 136.5, 136.3, 129.3, 129.3, 128.4, 127.2, 126.5, 122.6, 115.8, 114.4, 114.3, 112.5, 77.2, 70.9, 69.9, 69.1, 62.5, 62.4, 61.1, 55.3, 55.2, 52.9, 38.2, 37.5, 35.5, 21.3, 21.2, 14.4, 14.2; IR (KBr) ṽ (cm−1) 2981, 2832, 1731, 1614, 1512; HRMS (ESI+) calcd for C42H47N2O6 [M + H]+ 675.3429, found 675.3426. Dipyrroloquinoline 5b. Yellow wax, 77 mg (79%, dr 49:28:23). Diastereomer 5b-1: Rf (hexane/MTBE 2:1) = 0.50; 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 7.5 Hz, 2H), 7.52 (d, J = 7.5 Hz, 2H), 7.36−7.28 (m, 4H), 7.25−7.19 (m, 2H), 7.04 (d, J = 3.0 Hz, 1H), 6.67 (d, J = 9.5 Hz, 2H), 6.63 (d, J = 9.5 Hz, 2H), 6.55 (dd, J = 9.0, 3.0 Hz, 1H), 6.23 (d, J = 9.0 Hz, 1H), 4.75 (d, J = 9.0 Hz), 4.71 (d, J = 8.0 Hz, 1H), 4.37−4.22 (m, 2H), 4.19−4.04 (m, 2H), 3.92 (dd, J = 13.0, 6.5 Hz, 1H), 3.68 (s, 3H), 3.35 (s, 3H), 2.51−2.40 (m, 1H), 2.34−2.24 (m, 1H), 2.22−2.09 (m, 1H), 2.05−1.89 (m, 2H), 1.86−1.73 (m, 1H), 1.38 (t, J = 7.0 Hz, 3H), 1.25 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.6, 173.7, 152.3, 150.8, 144.7, 144.4, 139.5, 137.1, 128.7, 128.5, 126.9, 126.7, 126.7, 126.3, 121.8, 118.6, 115.6, 114.2, 114.1, 113.4, 70.5, 69.0, 68.1, 62.3, 61.7, 61.7, 55.6, 55.2, 44.2, 36.3, 36.0, 34.8, 14.2, 14.0; IR (cm−1, KBr) 2978, 2933, 2831, 1732, 1510; HRMS (ESI+) m/z [M + H]+ calcd for C40H43N2O6 647.3116, found 647.3111. Diastereomer 5b-2: Rf (hexane/MTBE 2:1) = 0.39; 1H NMR (300 MHz, CDCl3) δ 7.53−7.35 (m, 6H), 7.31−7.19 (m, 3H), 7.19−7.09 (m, 1H), 6.72 (d, J = 9.5 Hz, 2H), 6.60 (d, J = 9.5 Hz, 2H), 6.50 (dd, J = 9.0, 3.0 Hz, 1H), 6.25 (d, J = 9.0 Hz, 1H), 6.15 (d, J = 3.0 Hz, 1H), 4.82 (dd, J = 10.0, 3.0 Hz, 1H), 4.74 (dd, J = 8.5, 6.0 Hz, 1741

DOI: 10.1021/acs.joc.7b02466 J. Org. Chem. 2018, 83, 1737−1744

Article

The Journal of Organic Chemistry 32.9, 31.2, 19.7, 19.6, 14.3, 14.1; IR (cm−1, KBr) 2979, 2831, 1734, 1508; HRMS (ESI+) m/z [M + H]+ calcd for C42H47N2O6 675.3429, found 675.3426. Dipyrroloquinoline 5e. Yellow wax, 73 mg (69%, dr 50:28:22). Diastereomer 5e-1: Rf (hexane/MTBE 2:1) = 0.32. Note: NMR data of 5e-1 was obtained from a dr 2:1 mixture; 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 8.5 Hz, 2H), 7.01 (d, J = 3.0 Hz, 1H), 6.87 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 6.66 (d, J = 9.5 Hz, 2H), 6.62 (d, J = 9.5 Hz, 2H), 6.54 (dd, J = 9.0, 3.0 Hz, 1H), 6.25 (d, J = 9.0 Hz, 1H), 4.69 (d, J = 9.5 Hz, 1H), 4.65 (d, J = 7.5 Hz, 1H), 4.34−4.20 (m, 2H), 4.18−4.01 (m, 2H), 3.95−3.85 (m, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 3.68 (s, 3H), 3.34 (s, 3H), 2.50−2.37 (m, 1H), 2.32−2.22 (m, 1H), 2.17−2.04 (m, 1H), 2.03−1.88 (m, 2H), 1.84−1.65 (m, 1H), 1.36 (t, J = 7.0, 3H), 1.25 (d, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 175.6, 173.8, 158.6, 158.5, 152.2, 150.7, 139.5, 137.2, 136.7, 136.5, 127.7, 127.4, 124.8, 121.8, 118.6, 115.3, 114.2, 114.1, 114.0, 113.4, 70.5, 68.9, 67.5, 62.2, 61.7, 61.1, 55.6, 55.4, 55.4, 55.2, 44.2, 36.4, 35.9, 34.9, 14.2, 14.0; IR (cm−1, film) 2954, 2923, 2834, 1731, 1611; HRMS (ESI+) m/z [M + H]+ calcd for C42H47N2O8 707.3327, found 707.3322. Diastereomer 5e-2: Rf (hexane/MTBE 2:1) = 0.30; 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 8.5 Hz, 2H), 6.78 (d, J = 8.5 Hz, 2H), 6.73−6.67 (m, 2H), 6.60 (d, J = 9.0 Hz, 2H), 6.50 (dd, J = 9.0, 3.0 Hz, 1H), 6.26 (d, J = 9.0 Hz, 1H), 6.12 (d, J = 3.0 Hz, 1H), 4.76 (dd, J = 10.0, 3.0 Hz, 1H), 4.66 (dd, J = 8.5, 6.5 Hz, 1H), 4.40 (dq, J = 11.0, 7.0 Hz, 1H), 4.28 (dq, J = 11.0, 7.0 Hz, 1H), 4.15−4.01 (m, 2H), 3.90 (dq, J = 11.0, 7.0 Hz, 1H), 3.83 (s, 3H), 3.74 (s, 3H), 3.65 (s, 3H), 3.19 (s, 3H), 2.78 (dt′, J = 12.0, 8.0 Hz, 1H), 2.55−2.36 (m, 1H), 2.24 (ddd, J = 12.5, 10.0, 6.0 Hz, 1H), 2.18−2.08 (m, 1H), 2.02−1.93 (m, 1H), 1.85−1.75 (m, 1H), 1.44 (t, J = 7.0 Hz, 3H), 1.07 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.5, 174.7, 158.6, 158.5, 154.8, 150.0, 138.9, 138.8, 137.5, 135.9, 128.3, 127.0, 124.8, 121.5, 115.8, 115.8, 114.3, 114.3, 113.9, 113.9, 73.7, 72.0, 63.0, 62.1, 61.8, 61.1, 55.6, 55.5, 55.3, 55.0, 48.6, 36.5, 33.2, 33.0, 14.3, 14.0; IR (cm−1, film) 2979, 2834, 1732, 1611, 1510; HRMS (ESI+) m/ z [M + H]+ calcd for C42H47N2O8 707.3327, found 707.3322. Dipyrroloquinoline 5f. Yellow wax, 100 mg (98%, dr 43:24:33). Diastereomer 5f-1: Rf (hexane/MTBE 3:1) = 0.28; 1H NMR (300 MHz, CDCl3) δ 7.60−7.43 (m, 4H), 7.16−6.84 (m, 5H), 6.71−6.49 (m, 5H), 6.18 (d, J = 9.0 Hz, 1H), 4.72 (d, J = 9.0 Hz, 1H), 4.68 (d, J = 8.0 Hz, 1H), 4.44−4.17 (m, 2H), 4.17−4.01 (m, 2H), 3.87 (dd, J = 13.0, 6.5 Hz, 1H), 3.69 (s, 3H), 3.35 (s, 3H), 2.51−2.38 (m, 1H), 2.37−2.22 (m, 1H), 2.20−2.04 (m, 1H), 2.04−1.85 (m, 2H), 1.86− 1.66 (m, 1H), 1.36 (t, J = 7.0 Hz, 3H), 1.24 (t, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 175.46, 173.6, 161.9 (d, J = 244.5 Hz), 161.8 (d, J = 244.5 Hz), 152.5, 150.8, 140.2 (d, J = 3.0 Hz), 139.9 (d, J = 3.0 Hz), 139.2, 136.8, 128.2 (d, J = 8.0 Hz), 127.9 (d, J = 8.0 Hz), 121.7, 118.8, 115.6 (d, J = 21.5 Hz), 115.3 (d, J = 21.5 Hz), 115.3, 114.3, 113.9, 113.5, 70.5, 68.9, 67.3, 62.3, 61.8, 61.0, 55.6, 55.2, 44.1, 36.3, 35.9, 34.8, 14.2, 14.0; IR (cm−1, KBr) 2979, 2918, 2849, 1731, 1604; HRMS (ESI+) m/z [M + H]+ calcd for C40H41F2N2O6 683.2927, found 683.2927. Diastereomer 5f-2: Rf (hexane/MTBE 3:1) = 0.17; 1H NMR (400 MHz, CDCl3) δ 7.45−7.35 (m, 4H), 7.05 (t, J = 8.5 Hz, 2H), 6.90 (t, J = 8.5 Hz, 2H), 6.75−6.62 (m, 2H), 6.61− 6.56 (m, 2H), 6.48 (dd, J = 9.0, 3.0 Hz, 1H), 6.18 (d, J = 9.0 Hz, 1H), 6.07 (d, J = 3.0 Hz, 1H), 4.77 (dd, J = 10.0, 3.0 Hz, 1H), 4.66 (dd, J = 8.5, 6.0 Hz, 1H), 4.37 (dq, J = 10.5, 7.0 Hz, 1H), 4.26 (dq, J = 10.5, 7.0 Hz, 1H), 4.12−3.99 (m, 2H), 3.88 (dq, J = 10.5, 7.0 Hz, 1H), 3.63 (s, 3H), 3.17 (s, 3H), 2.74 (dt′, J = 12.5, 8.0 Hz, 1H), 2.52−2.39 (m, 1H), 2.20 (ddd, J = 12.5, 10.0, 6.0 Hz, 1H), 2.11 (td′, J = 12.0, 8.5 Hz, 1H), 1.97 (ddd, J = 12.5, 8.0, 1.5 Hz, 1H), 1.83−1.73 (m, 1H), 1.41 (t, J = 7.0 Hz, 3H), 1.05 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.2, 174.5, 161.9 (d, J = 245.0 Hz), 161.8 (d, J = 244.5 Hz), 155.1, 150.2, 141.0 (d, J = 3.0 Hz), 139.5 (d, J = 3.0 Hz), 138.5, 138.5, 128.7 (d, J = 8.0 Hz), 127.4 (d, J = 8.0 Hz), 125.0, 121.4, 116.0, 115.8 (d, J = 21.5 Hz), 115.8, 115.3 (d, J = 21.5 Hz), 114.3, 114.0, 73.8, 72.0, 63.0, 62.0, 61.9, 61.2, 55.5, 55.0, 48.5, 36.4, 33.1, 32.9, 14.3, 14.1; IR (cm−1, KBr) 2981, 2834, 1735, 1604; HRMS (ESI+) m/z [M + H]+ calcd for C40H41F2N2O6 683.2927, found 683.2927.

Dipyrroloquinoline 5g. Yellow oil, 84 mg (78%, dr 56:19:25). Diastereomer 5g-1: Rf (hexane/MTBE 3:1) = 0.27; 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H), 7.33−7.25 (m, 4H), 7.00 (d, J = 3.0 Hz, 1H), 6.71−6.64 (m, 2H), 6.59 (d, J = 9.0 Hz, 2H), 6.55 (dd, J = 9.0, 3.0 Hz, 1H), 6.15 (d, J = 9.0 Hz, 1H), 4.71 (d, J = 10.0 Hz, 1H), 4.66 (d, J = 8.0 Hz, 1H), 4.37−4.19 (m, 2H), 4.16−4.05 (m, 2H), 3.85 (dd, J = 13.0, 6.5 Hz, 1H), 3.69 (s, 3H), 3.35 (s, 3H), 2.45 (dtd′, J = 12.5, 7.0, 3.0 Hz, 1H), 2.27 (ddd, J = 12.5, 6.5, 3.0 Hz, 1H), 2.17−2.05 (m, 1H), 1.99−1.86 (m, 2H), 1.81− 1.66 (m, 1H), 1.35 (t, J = 7.0 Hz, 3H), 1.24 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.4, 173.5, 152.6, 150.9, 143.1, 142.8, 139.1, 136.7, 132.6, 132.4, 128.9, 128.7, 128.1, 127.8, 121.7, 118.7, 115.3, 114.3, 113.9, 113.6, 70.5, 68.9, 67.3, 62.4, 61.9, 61.1, 55.6, 55.2, 44.1, 36.2, 35.9, 34.6, 14.2, 14.0; IR (cm−1, KBr) 2979, 2928, 2853, 1732; HRMS (ESI+) m/z [M + H]+ calcd for C40H41Cl2N2O6 715.2336, found 715.2335. Diastereomer 5g-2: Rf (hexane/MTBE 3:1) = 0.19; 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.5 Hz, 2H), 7.37 (s, 4H), 7.21 (d, J = 8.5 Hz, 2H), 6.74−6.66 (m, 2H), 6.61 (d, J = 9.5 Hz, 2H), 6.51 (dd, J = 9.0, 3.0 Hz, 1H), 6.19 (d, J = 9.0 Hz, 1H), 6.10 (d, J = 3.0 Hz, 1H), 4.78 (dd, J = 10.0, 3.0 Hz, 1H), 4.68 (dd, J = 8.5, 6.5 Hz, 1H), 4.40 (dq, J = 11.0, 7.0 Hz, 1H), 4.28 (dq, J = 11.0, 7.0 Hz, 1H), 4.14−4.01 (m, 2H), 3.99−3.84 (m, 1H), 3.66 (s, 3H), 3.20 (s, 3H), 2.76 (dt′, J = 12.5, 8.5 Hz, 1H), 2.58−2.41 (m, 1H), 2.22 (ddd, J = 12.5, 10.0, 6.0 Hz, 1H), 2.12 (td′, J = 12.5, 12.0, 9.0 Hz, 1H), 2.00 (ddd, J = 13.0, 8.0, 1.5 Hz, 1H), 1.85−1.75 (m, 1H), 1.44 (t, J = 7.0 Hz, 3H), 1.08 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.1, 174.5, 155.2, 150.3, 143.9, 142.5, 138.4, 138.4, 132.7, 132.5, 129.1, 128.7, 128.6, 127.4, 125.0, 121.5, 116.1, 115.9, 114.3, 114.0, 73.8, 72.0, 63.2, 62.1, 62.0, 61.3, 55.5, 55.0, 48.5, 36.3, 33.0, 32.9, 14.3, 14.1; IR (cm−1, KBr) 2979, 2931, 2833, 1733, 1509; HRMS (ESI+) m/z [M + H]+ calcd for C40H41Cl2N2O6 715.2336, found 715.2335. Dipyrroloquinoline 5h. Yellow oil, 91 mg (82%, dr 51:24:25). Diastereomer 5h-1: Rf (hexane/MTBE 1/1): 0.13; 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 9.0 Hz, 2H), 8.17 (d, J = 9.0 Hz, 2H), 7.75 (d, J = 9.0 Hz, 2H), 7.69 (d, J = 9.0 Hz, 2H), 6.98 (d, J = 3.0 Hz, 1H), 6.69 (d, J = 9.0 Hz, 2H), 6.60 (d, J = 9.0 Hz, 2H), 6.55 (dd, J = 9.0, 3.0 Hz, 1H), 6.03 (d, J = 9.0 Hz, 1H), 4.84 (d, J = 9.0 Hz, 1H), 4.80 (d, J = 8.0 Hz, 1H), 4.36−4.24 (m, 2H), 4.13 (dq, J = 7.0, 1.5 Hz, 2H), 3.88 (dd, J = 13.0, 6.5 Hz, 1H), 3.69 (s, 3H), 3.36 (s, 3H), 2.59− 2.49 (m, 1H), 2.38−2.28 (m, 1H), 2.26−2.16 (m, 1H), 2.03−1.90 (m, 2H), 1.76 (m′, 1H), 1.38 (t, J = 7.0 Hz, 3H), 1.25 (t, J = 7.0 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 175.0, 173.2, 153.1, 152.2, 151.8, 151.2, 147.3, 147.2, 138.5, 136.0, 127.6, 127.3, 124.2, 124.1, 121.6, 119.1, 115.4, 114.5, 113.9, 113.6, 76.8, 70.6, 68.9, 67.1, 62.6, 62.1, 61.3, 55.6, 55.3, 44.2, 35.8, 35.8, 34.2, 29.9, 14.2, 14.0; IR (cm−1, KBr) = 2981, 2935, 2833, 1733, 1516; HRMS (ESI+) m/z [M + Na]+ calcd for C40H41N4O10Na 759.2637, found 759.2632. Dipyrroloquinoline 5i. Yellow oil, 79 mg (84%, dr 41:41:18). Diastereomer 5i-1: Rf (hexane/MTBE 2:1) = 0.39; 1H NMR (300 MHz, CDCl3) δ 7.37−7.34 (m, 1H), 7.32 (dd, J = 2.0, 1.0 Hz, 1H), 6.87 (d, J = 3.0 Hz, 1H), 6.73−6.67 (m, 4H), 6.66 (d, J = 3.0 Hz, 1H), 6.53 (d, J = 9.0 Hz, 1H), 6.46 (dt′, J = 3.0, 1.0 Hz, 1H), 6.36 (dd, J = 9.0, 3.0 Hz, 1H), 6.31 (dd, J = 3.5, 2.0 Hz, 1H), 6.26 (dd, J = 3.5, 2.0 Hz, 1H), 4.91−4.78 (m, 2H), 4.31−4.15 (m, 2H), 4.13−3.94 (m, 2H), 3.81 (dd, J = 12.5, 6.5 Hz, 1H), 3.71 (s, 3H), 3.35 (s, 3H), 2.44−2.26 (m, 2H), 2.20−1.96 (m, 4H), 1.32 (t, J = 7.0 Hz, 3H), 1.17 (t, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 175.5, 173.9, 156.5, 156.5, 153.0, 151.0, 141.3, 141.3, 139.2, 136.6, 121.7, 119.6, 115.8, 114.3, 114.2, 113.7, 110.6, 110.4, 107.1, 107.0, 70.1, 68.0, 62.2, 62.0, 61.5, 56.7, 55.6, 55.2, 45.9, 35.7, 32.6, 31.0, 14.1, 14.0; IR (cm−1, KBr) 2979, 2929, 2834, 2341, 1729; HRMS (ESI+) m/z [M + H]+ calcd for C36H39N2O8 627.2701, found 627.2703. Diastereomer 5i-2: Rf (hexane/MTBE 2:1) = 0.31; 1H NMR (400 MHz, CDCl3) δ 7.36 (dd, J = 2.0, 1.0 Hz, 1H), 7.29 (dd, J = 2.0, 1.0 Hz, 1H), 6.80−6.72 (m, 2H), 6.72−6.65 (m, 2H), 6.61 (dd, J = 9.0, 3.0 Hz, 1H), 6.47 (d, J = 9.0 Hz, 1H), 6.33−6.30 (m, 1H), 6.30−6.28 (m, 2H), 6.25−6.20 (m, 2H), 4.91 (d, J = 9.5 z, 1H), 4.82 (dd, J = 8.5, 4.0 Hz, 1H), 4.41−4.17 (m, 2H), 4.09−3.94 (m, 2H), 3.96−3.88 (m, 1H), 3.70 (s, 3H), 3.24 (s, 3H), 2.60 (ddd, J = 12.0, 10.0, 8.5 Hz, 1H), 2.37 (ddd, J = 12.0, 8.5, 4.0 Hz, 1H), 2.33−2.20 (m, 2H), 2.09−1.96 (m, 2H), 1.39 (t, J = 7.0 1742

DOI: 10.1021/acs.joc.7b02466 J. Org. Chem. 2018, 83, 1737−1744

Article

The Journal of Organic Chemistry Hz, 3H), 1.09 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.2, 174.7, 156.8, 156.7, 154.7, 150.2, 141.7, 141.2, 138.9, 137.0, 123.9, 121.4, 115.9, 115.4, 114.0, 113.1, 110.4, 110.3, 106.9, 105.9, 77.2, 72.4, 70.7, 62.0, 61.2, 57.6, 55.9, 55.5, 55.1, 47.8, 33.7, 32.3, 29.7, 14.3, 14.1; IR (KBr) ṽ (cm−1) 2882, 2918, 2849, 1731, 1507; HRMS (ESI+) m/z [M + H]+ calcd for C36H39N2O8 627.2701, found 627.2703. Dipyrroloquinoline 5j. Yellow oil, 89 mg (90%, dr 39:36:25). Diastereomer 5j-1: Rf (hexane/MTBE 2:1) = 0.51; 1H NMR (400 MHz, CDCl3) δ 7.43 (dt, J = 3.0, 1.0 Hz, 1H), 7.32 (dt, J = 3.0, 1.0 Hz, 1H), 7.29−7.26 (m, 1H), 7.15 (dd, J = 5.0, 1.5 Hz, 1H), 7.11 (dd, J = 5.0, 1.5 Hz, 1H), 7.02−6.98 (m, 2H), 6.69 (d, J = 9.5 Hz, 2H), 6.63 (d, J = 9.5 Hz, 2H), 6.61−6.58 (m, 1H), 6.36 (d, J = 9.0 Hz, 1H), 4.91− 4.86 (m, 1H), 4.80 (t, J = 7.5 Hz, 1H), 4.34−4.18 (m, 2H), 4.17−4.05 (m, 2H), 3.86 (dd, J = 12.5, 6.5 Hz, 1H), 3.70 (s, 3H), 3.36 (s, 3H), 2.42 (dtd, J = 12.5, 7.5, 5.0 Hz, 1H), 2.32−2.23 (m, 1H), 2.17−1.93 (m, 3H), 1.89−1.79 (m, 1H), 1.34 (t, J = 7.0 Hz, 3H), 1.23 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.6, 173.9, 150.8, 145.8, 145.8, 139.4, 129.5, 126.5, 126.5, 126.0, 121.8, 121.6, 121.2, 118.4, 115.4, 114.2, 113.9, 113.9, 113.8, 113.5, 70.3, 68.5, 64.5, 62.3, 61.7, 58.1, 55.6, 55.3, 44.8, 35.9, 35.3, 33.7, 14.2, 14.0; IR (cm−1, KBr) 2978, 2934, 2831, 1730, 1509; HRMS (ESI+) m/z [M + H]+ calcd for C36H39N2O6S2 659.2244, found 659.2249. Diastereomer 5j-2: Rf (hexane/MTBE 2:1) = 0.37; 1H NMR (400 MHz, CDCl3) δ 7.33 (dd, J = 5.0, 3.0 Hz, 1H), 7.24−7.18 (m, 1H), 7.21−7.15 (m, 2H), 7.14 (dd, J = 5.0, 1.5 Hz, 1H), 7.09 (dd, J = 5.0, 1.5 Hz, 1H), 6.79− 6.69 (m, 2H), 6.68−6.60 (m, 2H), 6.56 (dd, J = 9.0, 3.0 Hz, 1H), 6.35 (d, J = 9.0 Hz, 1H), 6.21 (d, J = 3.0 Hz, 1H), 4.93 (dd, J = 10.0, 2.5 Hz, 1H), 4.84 (dd, J = 8.5, 5.0 Hz, 1H), 4.37 (dq, J = 11.0, 7.0 Hz, 1H), 4.27 (dq, J = 11.0, 7.0 Hz, 1H), 4.12−3.98 (m, 2H), 3.91 (dq, J = 10.5, 7.0 Hz, 1H), 3.68 (s, 3H), 3.22 (s, 3H), 2.67 (dt′, J = 12.0, 8.5 Hz, 1H), 2.50−2.35 (m, 1H), 2.27 (ddd, J = 12.0, 9.0, 5.0 Hz, 1H), 2.14 (td′, J = 12.0, 8.0 Hz, 1H), 2.07−1.97 (m, 1H), 1.93−1.84 (m, 1H), 1.42 (t, J = 7.0 Hz, 3H), 1.08 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.3, 174.7, 154.7, 150.1, 146.6, 145.5, 139.0, 138.2, 126.8, 126.5, 126.0, 125.9, 124.2, 121.6, 121.4, 120.1, 115.9, 115.7, 114.0, 113.9, 73.3, 71.6, 61.9, 61.2, 59.5, 58.6, 55.5, 55.0, 48.2, 35.2, 33.2, 32.0, 14.3, 14.1; IR (cm−1, KBr) 2979, 2904, 2833, 1731, 1508; HRMS (ESI+) m/z [M + H]+ calcd for C36H39N2O6S2 659.2244, found 659.2249. Dipyrroloquinoline 5k. Yellow oil, 43 mg (45%, dr 50:46:4). Diastereomer 5k-1: Rf (hexane/MTBE 3:1) = 0.39; 1H NMR (300 MHz, CDCl3) δ 6.77 (s, 4H), 6.69 (dd, J = 9.0, 3.0 Hz, 1H), 6.42 (d, J = 9.0 Hz, 1H), 6.39 (d, J = 3.0 Hz, 1H), 4.23 (dq, J = 11.0, 7.0 Hz, 1H), 4.16−4.04 (m, 1H), 4.04−3.89 (m, 2H), 3.87−3.77 (m, 1H), 3.76 (s, 3H), 3.74−3.64 (m, 1H), 3.53−3.41 (m, 1H), 3.29 (s, 3H), 2.39−2.21 (m, 1H), 2.19−2.04 (m, 2H), 2.04−1.92 (m, 1H), 1.90− 1.74 (m, 2H), 1.72−1.53 (m, 2H), 1.47−1.06 (m, 20H), 0.99−0.75 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 176.4, 174.1, 154.3, 149.2, 139.7, 136.9, 123.6, 119.8, 115.7, 115.0, 114.2, 111.7, 71.7, 67.6, 61.7, 61.7, 61.1, 57.9, 55.7, 55.2, 47.0, 34.9, 33.7, 33.5, 32.1, 32.0, 30.5, 29.8, 27.0, 26.1, 22.9, 22.8, 14.2, 14.1, 14.0; IR (cm−1, film) 2955, 2930, 2856, 1732, 1506; HRMS (ESI+) m/z [M + H]+ calcd for C38H55N2O6 635.4054, found 635.4050. Diastereomer 5k-2: Rf (hexane/MTBE 3:1) = 0.29; 1H NMR (400 MHz, CDCl3) δ 6.74 (s, 4H), 6.66 (dd, J = 9.0, 3.0 Hz, 1H), 6.44 (d, J = 9.0 Hz, 1H), 5.89 (d, J = 3.0 Hz, 1H), 4.35−4.06 (m, 3H), 3.99−3.77 (m, 3H), 3.74 (s, 3H), 3.46−3.35 (m, 1H), 3.22 (s, 3H), 2.96−2.79 (m, 1H), 2.69−2.51 (m, 1H), 2.17−1.81 (m, 3H), 1.76−1.50 (m, 2H), 1.48−1.06 (m, 15H), 1.00 (t, J = 7.0 Hz, 3H), 0.96−0.76 (m, 9H); 13C NMR (100 MHz, CDCl3) δ 175.8, 175.0, 155.5, 149.1, 139.3, 138.6, 126.3, 120.8, 116.4, 115.8, 114.0, 112.0, 74.0, 71.5, 61.5, 60.9, 59.3, 58.0, 55.6, 55.1, 48.6, 34.2, 33.9, 33.3, 32.1, 32.1, 31.4, 27.6, 26.4, 26.0, 22.9, 22.8, 14.3, 14.2, 14.2, 14.0; IR (cm−1, film) 2956, 2929, 2856, 1732, 1507; HRMS (ESI+) m/z [M + H]+ calcd for C38H55N2O6 635.4054, found 635.4050. Dipyrroloquinoline 5l. Yellow wax, 77 mg (85%, dr 7:8:85). Diastereomer 5l-3: Rf (hexane/MTBE 3:1) = 0.38; 1H NMR (400 MHz, CDCl3) δ 6.88 (dd, J = 8.5, 2.5 Hz, 1H), 6.82 (dd, J = 8.5, 2.5 Hz, 1H), 6.77 (dd, J = 8.5, 3.0 Hz, 1H), 6.73 (dd, J = 9.0, 3.0 Hz, 1H),

6.64 (d, J = 2.5 Hz, 2H), 5.99 (d, J = 2.5 Hz, 1H), 4.28−4.10 (m, 2H), 4.05 (dq, J = 10.5, 7.0 Hz, 1H), 3.93−3.79 (m, 2H), 3.76 (s, 3H), 3.66 (dd, J = 13.0, 7.0 Hz, 1H), 3.51 (d, J = 9.5 Hz, 1H), 3.25 (s, 3H), 2.47 (dt′, J = 14.0, 11.0 Hz, 1H), 2.27 (ddd, J = 14.0, 7.0, 4.5 Hz, 1H), 1.97 (ddd, J = 12.5, 7.0, 1.5 Hz, 1H), 1.92−1.85 (m, 2H), 1.84−1.76 (m, 1H), 1.31 (t, J = 7.0 Hz, 3H), 1.12 (t, J = 7.0 Hz, 3H), 0.95 (s, 9H), 0.76 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 176.2, 173.7, 156.1, 148.1, 142.8, 138.4, 129.7, 128.7, 118.7, 116.3, 115.0, 114.2, 113.5, 71.6, 71.2, 68.1, 67.4, 61.4, 60.9, 55.5, 54.9, 48.6, 37.8, 37.6, 36.0, 28.9, 27.8, 27.8, 26.9, 14.1, 14.0; IR (cm−1, KBr) 2979, 2953, 2872, 1735, 1508; HRMS (ESI+) m/z [M + H]+ calcd for C36H51N2O6 607.3742, found 607.3742. Dipyrroloquinoline 5m. Yellow wax, 75 mg (81%, dr 50:24:26). Diastereomer 5m-1: Rf (hexane/MTBE 3:1) = 0.48; 1H NMR (300 MHz, CDCl3) δ 7.62−7.51 (m, 4H), 7.39−7.29 (m, 5H), 7.30−7.18 (m, 2H), 6.87 (d, J = 8.0 Hz, 2H), 6.76 (dd, J = 8.5, 1.5 Hz, 1H), 6.52 (d, J = 8.0 Hz, 2H), 6.22 (d, J = 8.5 Hz, 1H), 4.81 (d, J = 9.0 Hz, 1H), 4.72 (t′, J = 8.0 Hz, 1H), 4.38−4.21 (m, 2H), 4.20−4.02 (m, 2H), 3.89 (dd, J = 13.5, 6.0 Hz, 1H), 2.54−2.40 (m, 1H), 2.31−2.20 (m, 1H), 2.20 (s, 3H), 2.18−2.08 (m, 1H), 1.99 (s, 3H), 1.97−1.85 (m, 2H), 1.85−1.71 (m, 1H), 1.38 (t, J = 7.0 Hz, 3H), 1.23 (t, J = 7.0 Hz, 3H); 13 C NMR (75 MHz, CDCl3) δ 175.5, 173.9, 144.6, 144.0, 143.1, 140.5, 129.3, 129.0, 128.7, 128.6, 128.4, 126.8, 126.7, 126.6, 126.4, 126.2, 125.6, 121.5, 116.0, 113.2, 69.9, 68.8, 67.7, 62.3, 61.8, 61.6, 43.5, 36.4, 36.3, 34.4, 20.8, 20.4, 14.1, 14.0; IR (cm−1, KBr) 2979, 2859, 1731, 1618, 1519; HRMS (ESI+) m/z [M + H]+ calcd for C40H43N2O4 615.3217, found 615.3219. Diastereomer 5m-2: Rf (hexane/MTBE 3:1) = 0.41; 1H NMR (400 MHz, CDCl3) δ 7.58−7.47 (m, 2H), 7.44−7.32 (m, 4H), 7.31−7.22 (m, 3H), 7.20−7.11 (m, 1H), 6.83 (d, J = 8.0 Hz, 2H), 6.72−6.66 (m, 2H), 6.62 (d, J = 8.0 Hz, 2H), 6.19 (d, J = 9.0 Hz, 1H), 4.91−4.79 (m, 2H), 4.44−4.26 (m, 2H), 4.14−3.91 (m, 3H), 2.84 (dt′, J = 12.0, 9.0 Hz, 1H), 2.46 (tdd′, J = 12.5, 10.0, 7.5 Hz, 1H), 2.26 (ddd, J = 11.5, 8.5, 4.5 Hz, 1H), 2.17 (s, 3H), 2.16−2.06 (m, 1H), 2.02−1.93 (m, 1H), 1.86 (s, 3H), 1.84−1.76 (m, 1H), 1.45 (t, J = 7.0 Hz, 3H), 1.13 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.2, 175.0, 145.4, 144.4, 142.9, 140.9, 131.5, 129.5, 128.9, 128.9, 128.5, 127.1, 1267.0, 126.8, 126.0, 125.3, 121.5, 121.0, 113.5, 77.2, 72.6, 71.3, 62.7, 62.3, 62.0, 61.3, 47.3, 46.0, 36.2, 33.2, 32.9, 20.7, 20.6, 14.2, 14.09; IR (cm−1, KBr) 2979, 2857, 1732, 1617, 1504; HRMS (ESI+) m/z [M + H]+ calcd for C40H43N2O4 615.3217, found 615.3219. General Procedure for the 3-Component Synthesis of Dipyrroloquinoline 5a. To a 10 mL round-bottom flask were successively added p-anisidine (37 mg, 0.30 mmol, 1.0 equiv), ptolylaldehyde (45 mg, 0.38 mmol, 1.3 equiv), Yb(OTf)3 (18 mg, 0.03 mmol, 10 mol %), and acetonitrile (3.00 mL) and stirred at 20 °C. After 5 min, bis(silyl)dienediolate 1 (87 mg, 0.32 mmol, 1.1 equiv) was added dropwise, and after complete conversion (1.0 h), a 1.0 M HCl solution (300 μL, 0.30 mmol, 1.0 equiv) was added. After 16 h, 8 mL of sat. aq NaHCO3 solution and 5 mL of CH2Cl2 were added; the aq phase was extracted three times with 5 mL of CH2Cl2, and the combined organic layers were dried over Na2SO4. After filtration, the solvent was removed under reduced pressure. Flash column chromatography (hexane/MTBE 10:1 to 3:1) afforded the corresponding product 5a (87 mg, 86%, dr 52:30:18) as a yellow wax. Liquid Beam IR-Laser Desorption Mass Spectrometry. A liquid beam is injected into high vacuum through a quartz nozzle (diameter = 20 μm). A stable flow speed of 0.4 mL/min (corresponding to a beam speed of 20 m/s) is achieved by using a HPLC-pump (Techlab GmbH, ECONOMY 2/ED). A high-pressure valve (Rheodyne) was used to inject the analyte solution into the liquid beamline. The IR laser (Photonics Industries, dp20-OPO) was operated at a wavelength of 2900 nm and a frequency of 1 kHz. This wavelength is chosen specifically to excite the OH-stretch vibration of the solvent. By absorbing the laser energy, the liquid beam is rapidly heated up and disperses into (charged) droplets. Protonated or deprotonated molecular species emerging form these droplets are then detectable via mass spectrometry (Kaesdorf, reflection-type time-offlight mass spectrometer). Because the single photon energy is below any ionization level, the laser absorption is specifically selective to the 1743

DOI: 10.1021/acs.joc.7b02466 J. Org. Chem. 2018, 83, 1737−1744

Article

The Journal of Organic Chemistry

W. R. J. D.; Isidro-Llobet, A.; Spring, D. R. Nat. Commun. 2010, 1, 1− 13. (c) Burke, M. D.; Schreiber, S. L. Angew. Chem. 2004, 116, 48−60 and refs cited therein. (2) Representative reviews: (a) Marson, C. M. Chem. Soc. Rev. 2012, 41, 7712−7722. (b) de Graaff, C.; Ruijter, E.; Orru, R. V. A. Chem. Soc. Rev. 2012, 41, 3969−4009. (c) Ganem, B. Acc. Chem. Res. 2009, 42, 463−472 and refs cited therein. (3) Representative reviews: (a) Tietze, L. F. Domino reactions: Concepts for efficient organic synthesis; Wiley-VCH: Weinheim, Germany, 2014. (b) Tietze, L. F. Chem. Rev. 1996, 96, 115−136 and refs cited therein. (4) Brown, P. D.; Willis, A. C.; Sherburn, M. S.; Lawrence, A. L. Angew. Chem., Int. Ed. 2013, 52, 13273−13275. (5) Shen, Y.-H.; Su, Y.-Q.; Tian, J.-M.; Lin, S.; Li, H.-L.; Tang, J.; Zhang, W.-D. Helv. Chim. Acta 2010, 93, 2393−2396. (6) Fustero, S.; Bello, P.; Miro, J.; Sanchez-Rosello, M.; Maestro, M. A.; Gonzalez, J.; del Pozo, C. Chem. Commun. 2013, 49, 1336−1338. (7) Liu, L.; Wang, C.; Liu, Q.; Kong, Y.; Chang, W.; Li, J. Eur. J. Org. Chem. 2016, 2016, 3684−3690. (8) Ma, C.-L.; Li, X.-H.; Yu, X.-L.; Zhu, X.-L.; Hu, Y.-Z.; Dong, X.W.; Tan, B.; Liu, X.-Y. Org. Chem. Front. 2016, 3, 324−329. (9) Yu, X.-L.; Kuang, L.; Chen, S.; Zhu, X.-L.; Li, Z.-L.; Tan, B.; Liu, X.-Y. ACS Catal. 2016, 6, 6182−6190. (10) Boomhoff, M.; Schneider, C. Chem. - Eur. J. 2012, 18, 4185− 4189. (11) Boomhoff, M.; Ukis, R.; Schneider, C. J. Org. Chem. 2015, 80, 8236−8244. (12) Appun, J.; Boomhoff, M.; Hoffmeyer, P.; Kallweit, I.; Pahl, M.; Belder, D.; Schneider, C. Angew. Chem., Int. Ed. 2017, 56, 6758−6761. (13) Nareddy, P. R.; Schneider, C. Chem. Commun. 2015, 51, 14797−14800. (14) Boomhoff, M.; Yadav, A. K.; Appun, J.; Schneider, C. Org. Lett. 2014, 16, 6236−6239. (15) For characterization of compound 3a, see ref 14. (16) Stolz, F.; Appun, J.; Naumov, S.; Schneider, C.; Abel, B. ChemPlusChem 2017, 82, 233−240. (17) Schulze, S.; Pahl, M.; Stolz, F.; Appun, J.; Abel, B.; Schneider, C.; Belder, D. Anal. Chem. 2017, 89, 6175−6181. (18) Charvat, A.; Lugovoj, E.; Faubel, M.; Abel, B. Rev. Sci. Instrum. 2004, 75, 1209−1218. (19) Charvat, A.; Bogehold, A.; Abel, B. Aust. J. Chem. 2006, 59, 81− 103. (20) Kleinekofort, W.; Avdiev, J.; Brutschy, B. Int. J. Mass Spectrom. Ion Processes 1996, 152, 135−142. (21) Wattenberg, A.; Sobott, F.; Barth, H.-D.; Brutschy, B. Int. J. Mass Spectrom. 2000, 203, 49−57. (22) Wiederschein, F.; Vöhringer-Martinez, E.; Beinsen, A.; Postberg, F.; Schmidt, J.; Srama, R.; Stolz, F.; Grubmüller, H.; Abel, B. Phys. Chem. Chem. Phys. 2015, 17, 6858−6864. (23) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215−241. (24) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. J. Chem. Phys. 2010, 132, 1−20. (25) Elsner, C.; Prager, A.; Decker, U.; Naumov, S.; Abel, B. Am. J. Nano Res. Appl. 2014, 2, 1−8. (26) Kahnt, A.; Peuntinger, K.; Dammann, C.; Drewello, T.; Hermann, R.; Naumov, S.; Abel, B.; Guldi, D. M. J. Phys. Chem. A 2014, 118, 4382−4391. (27) Beyer, N.; Steinfeld, G.; Lozan, V.; Naumov, S.; Flyunt, R.; Abel, B.; Kersting, B. Chem. - Eur. J. 2017, 23, 2303−2314. (28) Jaguar, version 9.3; Schrodinger, Inc.: New York, NY, 2016. (29) Wadt, W. R.; Hay, P. J. J. Chem. Phys. 1985, 82, 284−298. (30) Tannor, D. J.; Marten, B.; Murphy, R.; Friesner, R. A.; Sitkoff, D.; Nicholls, A.; Ringnalda, M.; Goddard, W. A., III; Honig, B. J. Am. Chem. Soc. 1994, 116, 11875−11882.

solvent, and the desorption process can be regarded as very soft, no real ionization occurs.22 The technique requires at least 15% of the solvent to be absorbent at the laser wavelength. Here, this translates to at least 15% of an OH group-containing solvent, e.g., water or alcohols. Therefore, for all measurements discussed here, 0.1 mL of the reaction solution was diluted in 1.9 mL of a mixture of water (Millipore, DirectQ3) and acetonitrile (VWR Chemicals, HPLC-Super Gradient) with a volume fraction of 50% each. Theory. Density functional theory (DFT) calculations were carried out using the M06-D3 density functional. The MO6-D3 functional is parametrized for organometallic and noncovalent interactions.23 It includes physically and chemically important London dispersion interactions.24 This computational model was already successfully used for calculations of metal−organic complexes in our previous studies.16,25−27 The molecular geometries and energies of all calculated molecules were calculated at the M06-D3/LACVP** level of theory as implemented in the program Jaguar 9.3.28 The LACVP** basis set uses the standard 6-31G(d,p) basis set for light elements and the LAC pseudopotential29 for heavier elements, such as Zn in this case. Frequency calculations were done at the same level of theory to characterize the stationary points on the potential surface and to obtain total enthalpy (H) and Gibbs free energy (G) at a standard temperature of 298.15 K using unscaled vibrations. The reaction enthalpies ΔH and Gibbs free energies of reaction ΔG were calculated as a difference of H and G between the reactants and products, respectively. For the solvent effects (acetonitrile in our case) on the structure and reaction parameters of studied molecules to be taken into account, the calculations were performed using Jaguar dielectric continuum Poisson−Boltzmann solver (PBF),30 which fits the field produced by the solvent dielectric continuum to another set of point charges. ZnCl2 was used as Lewis acid (LA) in these study because it was shown that the charge transfer complex formation between ZnCl2 as LA and reactants shows similar stability, corresponding charge shift in complex, and the effect of the Lewis acid on the HOMO and LUMO energy levels of the Lewis acid-coordinated complex as in the case of Zn(OTf)2 and Yb(OTf)3 used as Lewis acid.16 Therefore, for simplifying the optimization of possible structures formed during reaction pathways, ZnCl2 was used for further calculations.

■

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02466. 1 H and 13C NMR spectral data for all new compounds and DFT details (PDF)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Christoph Schneider: 0000-0001-7392-9556 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This work was generously supported by the Deutsche Forschungsgemeinschaft within the research unit FOR 2177 “Integrated Chemical Microlaboratories” and through generous gifts of chemicals from BASF and Evonik. We thank Dr. Lothar Hennig (University of Leipzig) for helpful discussions concerning the NMR data.

■

REFERENCES

(1) Representative reviews: (a) O’ Connor, C. J.; Beckmann, H. S. G.; Spring, D. R. Chem. Soc. Rev. 2012, 41, 4444−4456. (b) Galloway, 1744

DOI: 10.1021/acs.joc.7b02466 J. Org. Chem. 2018, 83, 1737−1744