Modular Synthesis of Dipyrroloquinolines â A Combined Synthetic and

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Modular Synthesis of Dipyrroloquinolines – A Combined Synthetic and Mechanistic Study Johannes Appun, Ferdinand Stolz, Sergej Naumov, Bernd Abel, and Christoph Schneider J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02466 • Publication Date (Web): 22 Jan 2018 Downloaded from http://pubs.acs.org on January 22, 2018

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The Journal of Organic Chemistry

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 *Email: [email protected]

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 stereoselectivity 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 ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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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 The 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 multi-component- 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 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 diastereo- and 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 the rapid and diversity-oriented access toward complex heterocycles employing a novel bis(silyl) dienediolate 1 which could act either as a versatile 1,3-zwitterionic synthon or as a 1,2-dinucleophile. As a 1,3zwitterionic

synthon,

pyrrolobenzoxazoles10

the or

direct

and

highly

pyrrolobenzoxazinones

stereoselective and

access

toward

pyrroloquinazolinones11

was

accomplished through a Lewis acid-catalyzed [3+2]-cycloannulation process. Within the ACS Paragon Plus Environment

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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 which 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 and 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). SCHEME 1. Design Plan for the Synthesis of Dipyrroloquinolines

RESULTS AND DISCUSSION

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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 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 went up sharply to 5 days at 0 °C (entry 12) and 14 days at 20 °C (entry 13). Finally, it was shown that the reaction does not proceed without Brønsted acid at room temperature and the vinylogous Mannich product 3 could be isolated instead (entry 14). Table 1. Optimization Studiesa


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entry acid

solv.

time yield [%]b drc

1

(PhO)2PO2H

MeCN

16 h 22

66:34

2

TFA (3.25 M) MeCN

16 h 79

54:38:8

3

TFA (1.0 M)

MeCN

16 h 83

60:28:12

4

HCl (1.0 M)

MeCN

16 h 85

60:34:6

5

HCl (1.0 M)d

MeCN

22 h 64

56:37:7

6

HCl (1.0 M)

CH2Cl2 16 h 76

49:49:2

7

HCl (1.0 M)

toluene 16 h 52

48:29:23

8

HCl (1.0 M)

Et2O

16 h 58

59:39:2

9

HCl (1.0 M)

THF

16 h 68

45:37:18

10

HCl (1.0 M)

DME

16 h 74

53:39:8

11

HCl (1.0 M)

MeOH

16 h 79

54:36:10

12e

HCl (1.0 M)

MeCN

5d

52

53:42:5

13f

HCl (1.0 M)

MeCN

14 d 58

63:32:5

14

-

MeCN

2d

-

a

0

Reaction conditions: imine 2a (0.2 mmol), bis(silyl) dienediolate 1 (1.1 equiv.), Yb(OTf)3

(10 mol %) in 2.0 mL solvent, 1 h, then Brønsted acid, 16 h.

b

Isolated yield of

chromatographically purified material. cdr determined by 1H NMR of purified product, dr (5a1:5a-2:other diastereomers).

d

HCl (0.1 equiv.). eReaction temperature: 0 °C. fReaction

temperature: –20 °C.

Having optimal reaction conditions in hand (Table 1, entry 4), we investigated the substrate scope of this sequential, one-pot 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 ACS Paragon Plus Environment


with up to 96% yield and moderate diastereoselectivities in favor of the two major isomers 51 and 5-2 both of which could be separated by column chromatography (entries 1–10). Alkylsubstituted imines could be employed as well and delivered the target products 5k-l with good yields (entries 11-12). 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-Bugroup. 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. Table 2. Substrate Scopea

entry product

R1

R2

yield [%]b

drc

1

5a

4-MeC6H4

MeO

85

60:34:6

2

5b

Ph

MeO

79

49:28:23

3

5c

3-MeC6H4

MeO

91

45:15:40

4

5d

2-MeC6H4

MeO

96

50:23:27

5

5e

4-MeOC6H4 MeO

69

50:28:22

6

5f

4-FC6H4

MeO

98

43:24:33

7

5g

4-ClC6H4

MeO

78

56:19:25

8

5h

4-NO2C6H4

MeO

82

51:24:25


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9

5i

2-furyl

MeO

84

41:41:18

10

5j

3-thienyl

MeO

90

39:36:25

11d

5k

n-pentyl

MeO

75

50:46:4

12d

5l

t-butyl

MeO

85

7:8:85e

13

5m

Ph

Me

81

50:24:26

14f

5a

4-MeC6H4

MeO

94

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, 1h, then HCl (1.0 M; 1.0 equiv.), 16 h. bIsolated yield of chromatographically purified material. cdr determined by 1H-NMR of purified product, dr (5a-1:5a-2:other diastereomers). dReaction performed as a 3-component reaction. eMajor diastereomer was 5l-3. fReaction performed on a 6.0 mmol scale.

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 SI). Moreover, a three-component transformation was developed to simplify the overall operation. Mixing p-tolylaldehyde, p-anisidine 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 2. 3-Component Reaction



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 by 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). SCHEME 3. Mechanistic Proposal PMP NH

SiMe3 CO2Et O

PMP H

R

+

– SiMe3+

3 m/z[M+H]+ 428

O NH

CO2Et +

~H

R

R 6 m/z[M+H]+ 356

PMP OH N CO2Et

7 m/z[M+H]+ 356 – H2O

5 m/z[M+H]+ 675

– H+

R

PMP N Z

R PMP

Z

N R

10

+ H+ – H2O

PMP N CO2Et 8 m/z[M+H]+ 338

EtO2C

PMP N R

– H+ 9


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FIGURE 1. Time-resolved MS Measurements

Figure1: 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 minutes 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 & 7a; yellow squares: mass = 338 u, 8a & 9a; red tip-up triangles: mass = 675 u, 5a.

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 micro-beam. 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. Due to 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 were dissolved in 1.9 mL 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 the silyl enol ether 3 fell off relatively fast, while the respective intermediates at m/z = 356 (6a & 7a) and m/z = 338 (8a & 9a) were clearly detected. After ca. 3 h the signal intensities of these intermediates decreased and formation of the 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 quantum chemical calculations were performed for the synthesis of dipyrroloquinoline 5a (Figure 2). The calculated reaction parameters ∆H and ∆G for different reaction steps are given in Table 1 in the Supporting Information. We looked at the entire reaction starting from 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 (∆H= -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 equivalent 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 α-keto ester-LAcomplex 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 the target dipyrroloquinoline 5a (step 12 ). Figure 2. Theoretical Calculations (M06-D3/LACVP**/PBF)


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Page 12 of 29

CONCLUSION In summary,

we have

developed a straightforward and efficient synthesis of

octahydrodipyrrolo[1,2-a][3’,2’-c]quinolines generating up to 8 σ-bonds and 5 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 which 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 desorption mass spectrometry and DFT-calculations. The results suggest a pathway comprising a vinylogous Mukaiyama-Mannich reaction followed by a cyclocondensation, enamine-Mannich reaction and Pictet-Spengler cyclization to arrive at the target compounds. Further investigations are directed at the development of a catalytic, enantioselective process which 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

13

C-NMR spectra were recorded in CDCl3 at 26°C. Spectra

were referenced to residual chloroform (7.26 ppm, 1H; 77.16 ppm,

13

C). 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 a ESI-FT-ICR. Solvents were distilled from the indicated drying reagents: dichloromethane (CaH2), tetrahydrofuran (Na, benzophenone), diethyl ether (Na, benzophenone), acetonitrile (CaH2), 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, ACS Paragon Plus Environment

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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-(4-methoxyphenyl)-1-(p-tolyl)methanimine (68 mg, 0.30 mmol, 1.0 equiv.), Yb(OTf)3 (18 mg, 0.03 mmol, 10 mol%), acetonitrile (3.00 mL) and stirred at 20 °C. After 5 minutes, 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 sat. aq. NaHCO3-solution and 5 mL CH2Cl2 were added, the aq. phase was extracted three times with 5 mL 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 (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);

13

C 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 ACS Paragon Plus Environment


(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);

13

C-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):ߥ෤ (cm-1) 2981, 2832, 1731, 1614, 1512; HRMS (ESI+) Calc 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, ACS Paragon Plus Environment

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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);

13

C 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, 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);

13

C 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 0.37 (hexane/MTBE 3/1); 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 ACS Paragon Plus Environment


Page 16 of 29

(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);

13

C 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):ߥ෤ (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 ACS Paragon Plus Environment

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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);

13

C 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, 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; remark: NMR-Data of 5e-1 was obtained from a dr 2:1 mixture; 1

H 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);

13

C NMR (75 MHz, CDCl3) δ 175.6, 173.8, 158.6, 158.5, 152.2, ACS Paragon Plus Environment


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. ACS Paragon Plus Environment

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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; 1

H 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);

13

C 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 = 7.0Hz, 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 ACS Paragon Plus Environment


C40H41Cl2N2O6 715.2336; Found: 715.2335. Diastereomer 5g-2: Rf (hexane/MTBE 3/1): 0.19; 1

H 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); 13C 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.


Page 20 of 29

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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);

13

C 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 Hz, 3H), 1.09 (t, J = 7.0 Hz, 3H);

13

C 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):ߥ෤ (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), ACS Paragon Plus Environment


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);

13

C 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 – ACS Paragon Plus Environment

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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).

13

C 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);

13

C 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. ACS Paragon Plus Environment


Page 24 of 29

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);

13

C 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.), p-tolylaldehyde (45 mg, 0.38 mmol, 1.3 equiv.), Yb(OTf)3 (18 mg, 0.03 mmol, 10 mol%), acetonitrile (3.00 mL) and stirred at 20 °C. After 5 minutes, bis (silyl) dienediolate 1 (87 mg, ACS Paragon Plus Environment

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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 sat. aq. NaHCO3solution and 5 mL CH2Cl2 were added, the aq. phase was extracted three times with 5 mL 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 beam line. 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, reflectron-type time-of-flight mass spectrometer). Since the single photon energy is below any ionization level the laser absorption is specifically selective to the 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. Therefor for all measurement discussed here 0.1 mL of the reaction solution were diluted in 1.9 mL of a mixture of water (Millipore, Direct-Q3) 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 parameterized for organometallic and noncovalent interactions.23 It includes physically and chemically important London dispersion ACS Paragon Plus Environment


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 631G(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 ∆H and Gibbs free energies of reaction ∆G were calculated as a difference of H and G between the reactants and products, respectively. To take solvent effects (acetonitrile in our case) on the structure and reaction parameters of studied molecules into account the calculations were done 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 the 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, to simplify the optimization of possible structures formed during reaction pathways, ZnCl2 was used for further calculations.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. 1H and 13C NMR spectral data for all new compounds and DFT-details (PDF).

AUTHOR INFORMATION ACS Paragon Plus Environment

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Corresponding Author Email: [email protected]

Notes The authors declare no competing financial interests.

ACKNOWLEDGEMENTS 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.

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