Synthesis of 2-Unsubstituted Pyrrolidines and Piperidines from Donor

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Synthesis of 2-Unsubstituted Pyrrolidines and Piperidines from Donor-Acceptor Cyclopropanes and Cyclobutanes: 1,3,5 Triazinanes as Surrogates for Formylimines Lennart K. B. Garve, Alexander Kreft, Peter G. Jones, and Daniel B. Werz J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01631 • Publication Date (Web): 07 Aug 2017 Downloaded from http://pubs.acs.org on August 7, 2017

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The Journal of Organic Chemistry

Synthesis of 2-Unsubstituted Pyrrolidines and Piperidines from Donor-Acceptor Cyclopropanes and Cyclobutanes: 1,3,5-Triazinanes as Surrogates for Formylimines

Lennart K. B. Garvea, Alexander Krefta, Peter G. Jonesb and Daniel B. Werza*

[a]

TU Braunschweig, Institute for Organic Chemistry, Hagenring 30, 38106 Braunschweig, Germany. [b]

TU Braunschweig, Institute for Inorganic and Analytical Chemistry, Hagenring 30, 38106 Braunschweig, Germany.

ABSTRACT: A synthetic procedure to access 2-unsubstituted pyrrolidines and piperidines is presented. In the presence of MgI2 as Lewis acid, donor-acceptor cyclopropanes or corresponding cyclobutanes were treated with 1,3,5-triazinanes, leading to the five- or six-membered ring systems under mild conditions in yields up to 93%. This protocol tolerates a great variety of functional groups and thus provides an efficient entry to this class of pyrrolidines and piperidines.

Pyrrolidines and piperidines are abundant in many natural products and pharmaceutically active compounds.1 Numerous synthetic methods have been developed to access these five- and sixmembered rings. For pyrrolidines the most prominent methods are nucleophilic substitution 1 ACS Paragon Plus Environment


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reactions and [3+2]-cycloaddition reactions.2 Using the [3+2]-approach, various retrosynthetic cuts are possible. An alkene and an azomethine ylide can be employed as starting materials to construct the five-membered ring (Scheme 1a).3 In other independent protocols Kerr, Tang and Johnson reported that donor-acceptor (D-A) cyclopropanes could be employed as three-atom components.4 In the presence of Lewis acid with a chiral ligand, an aromatic aldimine was used to insert the fourth carbon atom and the nitrogen atom. This methodology even provided access to 2,5-cis-disubstituted pyrrolidines in an asymmetric fashion (Scheme 1b). However, 2-unsubstituted pyrrolidines were not accessible by these procedures.

Scheme 1.

(a) [3+2]-Cycloaddition reaction of azomethine ylides and olefins. (b)

Formal [3+2]-cycloaddition reaction of donor-acceptor cyclopropane and aromatic aldimines.

In recent years, D-A cyclopropanes have enjoyed a renaissance as versatile building blocks in organic synthesis.5 A wide variety of different heterocyclic systems have become accessible starting from these highly strained and polarized small ring systems. The major reaction types are easily understandable when a formal 1,3-zwitterionic relationship is taken into account. [3+n]-Cycloaddition reactions lead either to five-,6 six-7 or seven-membered8 ring systems. Ring-opening reactions allow the attachment of substituents either in 1-position9 or in 1- and 3-positions10 whereas rearrangement reactions furnish five-membered rings by insertion of an acceptor moiety.11,12 2 ACS Paragon Plus Environment

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In the course of our research program aiming towards 1,3-bisfunctionalization reactions of DA cyclopropanes, we found that these strained three-membered rings undergo a formal [4+3]cycloaddition with 1,3,5-triazinanes.13 As a result 1,3-diazepanes were obtained, which were easily converted to 1,4-diamines (Scheme 2a). Our initial results had shown that the sevenmembered rings are easily formed. A more careful analysis of the side products has revealed that corresponding pyrrolidines are also formed. Therefore, we optimized the transformation again, this time aiming at pyrrolidines as major products.

Scheme 2.

(a) Synthesis of 1,3-diazepanes and 1,4-diamines using 1,3,5-triazinanes and

(b) the present work.

Furthermore, we tried to extend the method to corresponding D-A cyclobutanes, affording in a formal [4+2]-cycloaddition process the six-membered analogs, namely piperidines (Scheme 2b). In the search for an efficient and widely applicable protocol for the desired [3+2] annulation process, we focused especially on the type of Lewis acid (Table 1). Sc(OTf)3 was the Lewis

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acid of choice for the synthesis of 1,3-diazepanes. A closer look at the byproducts revealed that 6% of the pyrrolidine was also formed (Table 1, entry 1).

Table 1.

Optimization of the Reaction Conditions.

Entry

Lewis Acid

Reaction time [h] Yield 5aa [%]

Yield 3aa [%]

1a

Sc(OTf)3

14

6

88

2

Ni(ClO4)2

14

45

25

3

TiCl4

14

decomposition

4

Sn(OTf)2

14

0

0

5

Y(OTf)3

14

87

10

6

MgBr2

14

73

0

7

Mg(OTf)2

14

67

0

8

MgI2

14

92

0

9

MgI2

1.5

93

0

Reaction conditions: 1a (100 µmol), 2a (120 µmol), Lewis acid (10 mol%), CH2Cl2 (1 mL), 25 °C; yields represent isolated and purified products.

[a]

Reaction was carried out in 2 mL of

CH2Cl2.

Nickel perchlorate led to a mixture of both products in a ratio of approximately 2:1 (entry 2). The harsh Lewis acid TiCl4 led to a complete decomposition of the starting materials (entry 3), whereas Sn(OTf)2 showed no conversion of the starting materials (entry 4). 4 ACS Paragon Plus Environment

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Table 2.

Scope with Regard to the Donor-Acceptor Cyclopropane.

Reaction conditions: 1 (100 µmol), 2 (120 µmol), MgI2 (10 mol%), CH2Cl2 (1 mL), 25 °C, 1.5 h; yields represent isolated and purified products; PMP = para-methoxyphenyl

An entirely different behavior was observed with Y(OTf)3, which yielded the desired pyrrolidine in 87% yield with a product ratio of 8.7:1 (entry 5). Magnesium salts as Lewis acids yielded the five-membered ring selectively, with no trace of the 1,3-diazepane. MgBr2 and Mg(OTf)2 gave moderate yields of 73% and 67%, respectively (entry 6 and 7). The most powerful Lewis acid was MgI2, which delivered the pyrrolidine in 92% yield (entry 8). Moreover the reaction time could be decreased to 1.5 h and the product was still formed in 93% yield (entry 9). With our optimized conditions in hand, a large variety of D-A cyclopropanes were investigated (Table 2). As substituent at the nitrogen, either phenyl or the more electron-rich p-methoxyphenyl (PMP) was employed. A wide range of different donor moieties are tolerated. Methyl groups, ether, amide, halogens and even electron-withdrawing trifluoromethyl groups at the phenyl residue do not decrease the yield. 5 ACS Paragon Plus Environment


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Table 3.

Scope with Regard to the 1,3,5-Triazinane.

Reaction conditions: 1 (100 µmol), 2 (120 µmol), MgI2 (10 mol%), CH2Cl2 (1 mL), 25 °C, 1.5 h; yields represent isolated and purified products. The same holds true for the more bulky naphthyl unit, for thienyl, furyl and even vinyl. Heteroatoms as donors also yield the desired pyrrolidine. With phthalimide an excellent yield of 88% (5ma) was achieved, whereas with oxygen as donor the yield dropped to 56% (5na). Besides phenyl and PMP residues as substituents at the nitrogen, o-methoxyphenyl and p-tolyl were also investigated and produced the pyrrolidine in 83% and 78% yield, respectively (Table 3). Even para-halogen substituents of the phenyl moiety were tolerated. Moreover, the trifluoromethyl group at the meta-position of the aryl group yielded the corresponding product in 81% yield. To prove the structure of the products unambiguously, we obtained single crystals of 5eg. The X-ray crystallographic analysis14,15 confirmed the generated pyrrolidine motif (SI, Figure S60).


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In the last few years, some of the recently developed reactions have also been investigated with D-A cyclobutanes.16,17 The ring strain of these four-membered rings is only slightly less than that of the three-membered ring analogs.

Table 4.

Synthesis of Piperidines.

Reaction conditions: 6 (100 µmol), 2 (120 µmol), MgI2 (10 mol%), CH2Cl2 (1 mL), 25 °C, 3 h; yields represent isolated and purified products.

Thus, we were interested to establish whether a similar transformation would also pave the way to 2-unsubstituted piperidines. Similar conditions were applied and indeed afforded the desired 6-membered ring compounds in moderate to good yields (Table 4). Next, we explored the stereospecificity of the formal [3+2]-cycloaddition reaction with MgI2 and Y(OTf)3 as Lewis acids (Scheme 3). Interestingly, both Lewis acids accomplished the desired transformation with complete stereospecificity; however, different enantiomers were 7 ACS Paragon Plus Environment


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obtained. In the literature it is known that MgI2 reacts with net retention at the stereogenic center.18

Scheme 3. Stereospecificity Experiment.

Thus, we assume that the catalyst MgI2 interacts with the D-A cyclopropanes achieving an activated and more polarized cyclopropane (Scheme 4). Then the iodide anion opens the cyclopropane in an SN2 reaction leading to (R)-9a. Enolate (R)-9a reacts with formaldimine 10a originating from the triazinane 2a. Finally, intermediate (R)-11aa cyclizes to pyrrolidine (S)-5aaˈ through an additional SN2 reaction yielding (S)-5aaˈ with net retention at the stereogenic center with respect to corresponding cyclopropane (S)-1aˈ.

Scheme 4. Mechanistic Proposal.


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In contrast to Y(OTf)3 a direct nucleophilic substitution of the nitrogen nucleophile is favored. In summary, we have developed protocols that allow the preparation of 2-unsubstituted pyrrolidines from donor-acceptor cyclopropanes and 2-unsubstituted piperidines from donoracceptor cyclobutanes. As surrogate for formylimine, 1,3,5-triazinanes were utilized. Under the influence of MgI2 as Lewis acid, decomposition of the six-membered heterocycle took place and allowed the formal [3+2]- or [4+2]-cycloaddition, respectively, in good to excellent yields.

Experimental Section General Experimental. All solvents were distilled before use unless otherwise stated. Air- and moisture-sensitive reactions were carried out in oven-dried or flame-dried glassware, septumcapped under atmospheric pressure of argon. Commercially available compounds were used without further purification unless otherwise stated. Proton (1H) and carbon (13C) NMR spectra were recorded on a 400, 500 or 600 MHz instrument using residual signals from CHCl3, δ = 7.26 ppm and δ = 77.16 ppm as internal references for 1

H and

13

C chemical shifts, respectively. Additionally, tetramethylsilane (δ = 0.0 ppm) was 9 ACS Paragon Plus Environment


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added to the NMR samples. ESI-HRMS mass spectrometry was carried out on a FTICR instrument. IR spectra were measured on an ATR spectrometer. General Procedure for the Synthesis of 2-Unsubstituted Pyrrolidines (GP 1). A flask (10 mL) containing cyclopropane (1, 100 µmol, 1.00 equiv.), triazinane (2, 120 µmol, 1.20 equiv.), and MgI2 (10 µmol, 0.10 equiv.) was evacuated and purged three times with argon. CH2Cl2 (1 mL) was added to the system, and the mixture was stirred at 25 °C for 1.5 h. The solvent was removed in vacuo, and the residue was purified by silica-gel column chromatography to give the desired compound. Dimethyl

1,5-diphenylpyrrolidine-3,3-dicarboxylate

(5aa).

Dimethyl

2-phenylcyclopropane-1,1-dicarboxylate (23.4 mg, 100 µmol, 1.00 equiv.), 1,3,5-triphenyl1,3,5-triazinane (37.8 mg, 120 µmol, 1.20 equiv.) and MgI2 (2.78 mg, 10.0 µmol, 0.10 equiv.) in CH2Cl2 (1 mL) were reacted according to GP 1. Silica gel column chromatography (n-pentane:EtOAc = 20:1) afforded the desired product 5aa (31.6 mg, 93.2 µmol, 93%) as a colorless oil. 1H-NMR (400 MHz, CDCl3): δ = 2.58 (dd, J = 13.0, 5.5 Hz, 1 H), 3.12 (dd, J = 13.0, 8.1 Hz, 1 H), 3.53 (s, 3 H), 3.77 (s, 3 H), 3.93 (d, J = 9.9 Hz, 1 H), 4.46 (d, J = 9.9 Hz, 1 H), 4.84 (dd, J = 8.0, 5.5 Hz, 1 H), 6.38 – 6.59 (m, 2 H), 6.69 (t, J = 7.3 Hz, 1 H), 7.12 – 7.17 (m, 2 H), 7.19 – 7.25 (m, 3 H), 7.26 – 7.31 (m, 2 H) ppm;

13

C-NMR (100 MHz, CDCl3):

δ = 42.8, 52.8, 53.2, 55.5, 58.4, 62.4, 113.2, 116.9, 125.8, 127.0, 128.5, 128.9, 142.5, 146.5, 170.0, 170.4 ppm. IR (ATR) v~ (cm-1): 3040, 2985, 2930, 2911, 1729, 1516, 1434, 1245, 1180; HRMS (ESI) m/z: [M + Na]+ Calcd for C20H21NO4Na 362.1363; Found 362.1364. Diethyl 1-(4-methoxyphenyl)-5-(p-tolyl)pyrrolidine-3,3-dicarboxylate (5bb). Diethyl 2-(ptolyl)cyclopropane-1,1-dicarboxylate

(27.6 mg,

100 µmol,

1.00 equiv.),

1,3,5-

tris(4-methoxyphenyl)-1,3,5-triazinane (48.6 mg, 120 µmol, 1.20 equiv.) and MgI2 (2.78 mg, 10.0 µmol, 0.10 equiv.) in CH2Cl2 (1 mL) were reacted according to GP 1. Silica gel column chromatography (n-pentane:EtOAc = 10:1) afforded the desired product 5bb (37.4 mg, 90.8 µmol, 91%) as a colorless oil. 1H-NMR (400 MHz, CDCl3): δ = 1.10 (t, J = 7.1 Hz, 3 H), 10 ACS Paragon Plus Environment

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1.24 (t, J = 7.1 Hz, 3 H), 2.30 (s, 3 H), 2.49 (dd, J = 13.0, 6.2 Hz, 1 H), 3.06 (dd, J = 13.0, 8.0 Hz, 1 H), 3.70 (s, 3 H), 3.83 (d, J = 9.7 Hz, 1 H), 3.94 – 4.15 (m, 2 H), 4.20 (qd, J = 7.1, 5.0 Hz, 2 H), 4.40 (d, J = 9.7 Hz, 1 H), 4.69 (dd, J = 7.7, 6.4 Hz, 1 H), 6.41 – 6.49 (m, 2 H), 6.70 – 6.76 (m, 2 H), 7.05 – 7.15 (m, 4 H) ppm; 13C-NMR (100 MHz, CDCl3): δ = 13.8, 14.0, 21.0, 43.1, 55.7, 56.3, 58.5, 61.7, 62.0, 62.7, 114.3, 114.5, 125.9, 129.2, 136.5, 140.0, 141.5, 151.5, 169.7, 170.3 ppm; IR (ATR) v~ (cm-1): 3045, 2982, 2936, 2907, 1730, 1511, 1465, 1240, 1181; HRMS (ESI) m/z: [M + Na]+ Calcd for C24H29NO5Na 434.1938; Found 434.1941. Diethyl 1-(4-methoxyphenyl)-5-(m-tolyl)pyrrolidine-3,3-dicarboxylate (5cb). Diethyl 2-(mtolyl)cyclopropane-1,1-dicarboxylate

(27.6 mg,

100 µmol,

1.00 equiv.),

1,3,5-

tris(4-methoxyphenyl)-1,3,5-triazinane (48.6 mg, 120 µmol, 1.20 equiv.) and MgI2 (2.78 mg, 10.0 µmol, 0.10 equiv.) in CH2Cl2 (1 mL) were reacted according to GP 1. Silica gel column chromatography (n-pentane:EtOAc = 10:1) afforded the desired product 5cb (35.1 mg, 85.4 µmol, 85%) as a colorless oil; 1H-NMR (400 MHz, CDCl3): δ = 1.10 (t, J = 7.1 Hz, 3 H), 1.24 (t, J = 7.1 Hz, 3 H), 2.30 (s, 3 H), 2.50 (dd, J = 13.0, 6.2 Hz, 1 H), 3.06 (dd, J = 13.0, 8.0 Hz, 1 H), 3.70 (s, 3 H), 3.83 (d, J = 9.8 Hz, 1 H), 3.97 – 4.11 (m, 2 H), 4.15 – 4.25 (m, 2 H), 4.41 (d, J = 9.7 Hz, 1 H), 4.67 (dd, J = 7.8, 6.3 Hz, 1 H), 6.44 – 6.50 (m, 2 H), 6.71 – 6.76 (m, 2 H), 6.97 – 7.08 (m, 3 H), 7.16 (t, J = 7.5 Hz, 1 H) ppm;

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δ = 13.8, 14.0, 21.5, 43.1, 55.7, 56.4, 58.6, 61.7, 62.0, 63.1, 114.3, 114.5, 123.0, 126.5, 127.7, 128.4, 138.1, 141.6, 143.1, 151.5, 169.7, 170.3 ppm; IR (ATR) v~ (cm-1): 3045, 2982, 2936, 2907, 2869, 2833, 1731, 1607, 1511, 1465, 1365, 1240, 1182; HRMS (ESI) m/z: [M + Na]+ Calcd for C24H29NO5Na 434.1938; Found 434.1939. Dimethyl 1-(4-methoxyphenyl)-5-(o-tolyl)pyrrolidine-3,3-dicarboxylate (5db). Dimethyl 2-(o-tolyl)cyclopropane-1,1-dicarboxylate

(24.8 mg,

100 µmol,

1.00 equiv.),

1,3,5-

tris(4-methoxyphenyl)-1,3,5-triazinane (48.6 mg, 120 µmol, 1.20 equiv.) and MgI2 (2.78 mg, 10.0 µmol, 0.10 equiv.) in CH2Cl2 (1 mL) were reacted according to GP 1. Silica gel column chromatography (n-pentane:EtOAc = 8:1) afforded the desired product 5db (33.7 mg, 11 ACS Paragon Plus Environment


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87.9 µmol, 88%) as a colorless oil. 1H-NMR (600 MHz, CDCl3): δ = 2.42 (s, 3 H), 2.46 (dd, J = 13.0, 5.4 Hz, 1 H), 3.13 (dd, J = 13.0, 8.4 Hz, 1 H), 3.57 (s, 3 H), 3.70 (s, 3 H), 3.77 (s, 3 H), 3.82 (d, J = 9.7 Hz, 1 H), 4.48 (d, J = 9.6 Hz, 1 H), 4.85 (dd, J = 8.4, 5.5 Hz, 1 H), 6.36 – 6.41 (m, 2 H), 6.71 – 6.75 (m, 2 H), 7.04 – 7.08 (m, 1 H), 7.11 (td, J = 7.4, 1.6 Hz, 1 H), 7.14 – 7.18 (m, 2 H) ppm; 13C-NMR (150 MHz, CDCl3): δ = 19.2, 40.8, 52.8, 53.2, 55.7, 56.0, 58.4, 60.4, 114.1, 114.6, 125.3, 126.2, 126.8, 130.6, 134.0, 140.4, 141.3, 151.6, 170.2, 170.6 ppm; IR (ATR) v~ (cm-1): 3004, 2998, 2953, 2834, 1733, 1511, 1435, 1365, 1241, 1212, 1179; HRMS (ESI) m/z: [M + Na]+ Calcd for C22H25NO5Na 406.1625; Found 406.1628. Dimethyl 5-(4-methoxyphenyl)-1-phenylpyrrolidine-3,3-dicarboxylate (5ea). Dimethyl 2-(4-methoxyphenyl)cyclopropane-1,1-dicarboxylate (26.4 mg, 100 µmol, 1.00 equiv.), 1,3,5triphenyl-1,3,5-triazinane (37.8 mg, 120 µmol, 1.20 equiv.) and MgI2 (2.78 mg, 10.0 µmol, 0.10 equiv.) in CH2Cl2 (1 mL) were reacted according to GP 1. Silica gel column chromatography (n-pentane:EtOAc = 20:1) afforded the desired product 5ea (27.3 mg, 74.0 µmol, 74%) as a colorless oil. 1H-NMR (600 MHz, CDCl3): δ = 2.54 (dd, J = 13.0, 5.5 Hz, 1 H), 3.08 (dd, J = 13.0, 8.0 Hz, 1 H), 3.56 (s, 3 H), 3.76 (s, 3 H), 3.77 (s, 3 H), 3.90 (d, J = 9.9 Hz, 1 H), 4.43 (d, J = 9.9 Hz, 1 H), 4.78 (dd, J = 7.9, 5.6 Hz, 1 H), 6.50 (d, J = 7.9 Hz, 2H), 6.68 (t, J = 7.3 Hz, 1 H), 6.77 – 6.85 (m, 2 H), 7.08 – 7.18 (m, 4 H) ppm; C-NMR (150 MHz, CDCl3): δ = 43.0, 52.8, 53.2, 55.2, 55.4, 58.3, 61.8, 113.2, 113.9, 116.9,

13

126.9, 128.9, 134.5, 146.6, 158.5, 170.1, 170.5 ppm; IR (ATR) v~ (cm-1): 3060, 3027, 2954, 2838, 1733, 1598, 1504, 1434, 1364, 1345, 1244, 1211; HRMS (ESI) m/z: [M + Na]+ Calcd for C21H23NO5Na 392.1468; Found 392.1471. Dimethyl 1-(4-methoxyphenyl)-5-(naphthalen-2-yl)pyrrolidine-3,3-dicarboxylate (5fb). Dimethyl

2-(naphthalen-2-yl)cyclopropane-1,1-dicarboxylate

(28.4 mg,

100 µmol,

1.00 equiv.), 1,3,5-tris(4-methoxyphenyl)-1,3,5-triazinane (48.6 mg, 120 µmol, 1.20 equiv.) and MgI2 (2.78 mg, 10.0 µmol, 0.10 equiv.) in CH2Cl2 (1 mL) were reacted according to GP 1. Silica gel column chromatography (n-pentane:EtOAc = 8:1) afforded the desired product 5fb 12 ACS Paragon Plus Environment

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(32.0 mg, 76.2 µmol, 76%) as a colorless oil. 1H-NMR (600 MHz, CDCl3): δ = 2.62 (dd, J = 13.1, 5.9 Hz, 1 H), 3.15 (dd, J = 13.1, 8.2 Hz, 1 H), 3.49 (s, 3 H), 3.68 (s, 3 H), 3.78 (s, 3 H), 3.89 (d, J = 9.7 Hz, 1 H), 4.51 (d, J = 9.7 Hz, 1 H), 4.88 (dd, J = 8.0, 6.0 Hz, 1 H), 6.44 – 6.58 (m, 2 H), 6.69 – 6.74 (m, 2 H), 7.37 (dd, J = 8.5, 1.8 Hz, 1 H), 7.41 – 7.48 (m, 2 H), 7.68 – 7.71 (m, 1 H), 7.73 – 7.82 (m, 3 H) ppm; 13C-NMR (150 MHz, CDCl3): δ = 42.8, 52.8, 53.2, 55.7, 56.4, 58.4, 63.3, 114.4, 114.6, 124.1, 124.7, 125.6, 126.0, 127.6, 127.8, 128.6, 132.7, 133.4, 140.5, 141.4, 151.7, 170.2, 170.6 ppm; IR (ATR) v~ (cm-1): 3333, 3089, 3050, 2984, 1733, 1666, 1516, 1467, 1313, 1237, 1207, 1187; HRMS (ESI) m/z: [M + Na]+ Calcd for C25H25NO5Na 442.1625; Found 442.1628. Diethyl 5-(4-acetamidophenyl)-1-(4-methoxyphenyl)pyrrolidine-3,3-dicarboxylate (5gb). Diethyl

2-(4-acetamidophenyl)cyclopropane-1,1-dicarboxylate

(31.9 mg,

100 µmol,

1.00 equiv.), 1,3,5-tris(4-methoxyphenyl)-1,3,5-triazinane (48.6 mg, 120 µmol, 1.20 equiv.) and MgI2 (2.78 mg, 10.0 µmol, 0.10 equiv.) in CH2Cl2 (1 mL) were reacted according to GP 1. Silica gel column chromatography (n-pentane:EtOAc = 3:1) afforded the desired product 5gb (32.4 mg, 71.2 µmol, 71%) as a colorless oil. 1H-NMR (400 MHz, CDCl3): δ = 1.11 (t, J = 7.1 Hz, 3 H), 1.23 (t, J = 7.1 Hz, 3 H), 2.13 (s, 3 H), 2.48 (dd, J = 13.1, 6.1 Hz, 1 H), 3.05 (dd, J = 13.1, 8.0 Hz, 1 H), 3.69 (s, 3 H), 3.81 (d, J = 9.8 Hz, 1 H), 3.98 – 4.11 (m, 2 H), 4.14 – 4.26 (m, 2 H), 4.39 (d, J = 9.7 Hz, 1 H), 4.63 – 4.71 (m, 1 H), 6.40 – 6.47 (m, 2 H), 6.65 – 6.78 (m, 2 H), 7.18 (d, J = 8.5 Hz, 2 H), 7.34 (s, 1 H), 7.40 (d, J = 8.5 Hz, 1 H) ppm; C-NMR (100 MHz, CDCl3): δ = 13.8, 13.9, 24.5, 42.9, 55.7, 56.3, 58.5, 61.8, 62.0, 62.6,

13

114.4, 114.5, 120.1, 126.6, 136.7, 139.0, 141.4, 151.6, 168.2, 169.8, 170.2 ppm; IR (ATR) v~ (cm-1): 3308, 3192, 3046, 2983, 1731, 1667, 1511, 1467, 1312, 1242, 1207, 1182; HRMS (ESI) m/z: [M + Na]+ Calcd for C25H30N2O6Na 477.1996; Found 477.2003. Dimethyl

1-phenyl-5-(thiophen-2-yl)pyrrolidine-3,3-dicarboxylate

(5ha).

Dimethyl

2-(thiophen-2-yl)cyclopropane-1,1-dicarboxylate (24.0 mg, 100 µmol, 1.00 equiv.), 1,3,5triphenyl-1,3,5-triazinane (37.8 mg, 120 µmol, 1.20 equiv.) and MgI2 (2.78 mg, 10.0 µmol, 13 ACS Paragon Plus Environment


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Page 14 of 28

0.10 equiv.) in CH2Cl2 (1 mL) were reacted according to GP 1. Silica gel column chromatography (n-pentane:EtOAc = 20:1) afforded the desired product 5ea (30.6 mg, 88.6 µmol, 89%) as a colorless oil. 1H-NMR (400 MHz, CDCl3): δ = 2.73 (dd, J = 13.1, 4.9 Hz, 1 H), 3.10 (dd, J = 13.1, 8.1 Hz, 1 H), 3.61 (s, 3 H), 3.76 (s, 3 H), 3.83 (d, J = 9.9 Hz, 1 H), 4.44 (d, J = 9.9 Hz, 1 H), 5.10 (dd, J = 8.0, 4.9 Hz, 1 H), 6.62 (dd, J = 8.8, 1.0 Hz, 2 H), 6.69 – 6.79 (m, 1 H), 6.86 – 6.93 (m, 2 H), 7.09 – 7.24 (m, 3 H) ppm;

13


δ = 43.0, 52.9, 53.2, 55.1, 58.5, 58.7, 113.3, 117.5, 123.9, 124.1, 126.6, 128.9, 146.5, 147.5, 169.9, 170.3 ppm; IR (ATR) v~ (cm-1): 3043, 3000, 2954, 2911, 1731, 1512, 1467, 1333, 1240, 1216, 1191. HRMS (ESI) m/z: [M + Na]+ Calcd for C18H19NO4SNa 368.0927; Found 368.0926. Dimethyl

5-(furan-2-yl)-1-(4-methoxyphenyl)pyrrolidine-3,3-dicarboxylate

(5ib).

Dimethyl 2-(furan-2-yl)cyclopropane-1,1-dicarboxylate (22.4 mg, 100 µmol, 1.00 equiv.), 1,3,5-tris(4-methoxyphenyl)-1,3,5-triazinane (48.6 mg, 120 µmol, 1.20 equiv.) and MgI2 (2.78 mg, 10.0 µmol, 0.10 equiv.) in CH2Cl2 (1 mL) were reacted according to GP 1. Silica gel column chromatography (n-pentane:EtOAc = 10:1) afforded the desired product 5ib (32.4 mg, 90.3 µmol, 90%) as a colorless oil. 1H-NMR (400 MHz, CDCl3): δ = 2.82 (dd, J = 13.1, 3.9 Hz, 1 H), 2.94 (dd, J = 13.1, 8.3 Hz, 1 H), 3.62 (s, 3 H), 3.70 (d, J = 9.5 Hz, 1 H), 3.72 (s, 3 H), 3.76 (s, 3 H), 4.31 (d, J = 9.4 Hz, 1 H), 4.82 (dd, J = 8.2, 3.9 Hz, 1 H), 6.04 (dt, J = 3.2, 0.8 Hz, 1 H), 6.23 (dd, J = 3.2, 1.8 Hz, 1 H), 6.52 – 6.58 (m, 1 H), 6.74 – 6.82 (m, 2 H), 7.32 (dd, J = 1.8, 0.9 Hz, 1 H) ppm;

13

C-NMR (100 MHz, CDCl3): δ = 38.9, 52.9, 53.2, 55.0, 55.7, 57.0, 58.6,

106.8, 110.1, 114.0, 114.6, 141.0, 141.7, 151.9, 154.8, 170.0, 170.4 ppm; IR (ATR) v~ (cm-1): 3045, 2999, 2953, 2907, 2835, 1734, 1511, 1435, 1338, 1240, 1210, 1178; HRMS (ESI) m/z: [M + Na]+ Calcd for C19H21NO6Na 382.1261; Found 382.1264. Dimethyl 5-(4-chlorophenyl)-1-(4-methoxyphenyl)pyrrolidine-3,3-dicarboxylate (5jb). Dimethyl

2-(4-chlorophenyl)cyclopropane-1,1-dicarboxylate

(26.9 mg,

100 µmol,

1.00 equiv.), 1,3,5-tris(4-methoxyphenyl)-1,3,5-triazinane (48.6 mg, 120 µmol, 1.20 equiv.) 14 ACS Paragon Plus Environment

Page 15 of 28

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and MgI2 (2.78 mg, 10.0 µmol, 0.10 equiv.) in CH2Cl2 (1 mL) were reacted according to GP 1. Silica gel column chromatography (n-pentane:EtOAc = 10:1) afforded the desired product 5jb (31.9 mg, 79.0 µmol, 79%) as a colorless oil. 1H-NMR (400 MHz, CDCl3): δ = 2.49 (dd, J = 13.1, 5.8 Hz, 1 H), 3.07 (dd, J = 13.1, 8.2 Hz, 1 H), 3.58 (s, 3 H), 3.70 (s, 3 H), 3.75 (s, 3 H), 3.81 (d, J = 9.7 Hz, 1 H), 4.42 (d, J = 9.7 Hz, 1 H), 4.68 (dd, J = 8.1, 5.8 Hz, 1 H), 6.32 – 6.50 (m, 2 H), 6.69 – 6.81 (m, 2 H), 7.10 – 7.23 (m, 2 H), 7.21 – 7.29 (m, 2 H) ppm;

13

C-

NMR (100 MHz, CDCl3): δ = 42.8, 52.9, 53.2, 55.7, 56.4, 58.3, 62.4, 114.4, 114.6, 127.4, 128.7, 132.6, 141.0, 141.5, 151.9, 170.1, 170.4 ppm; IR (ATR) v~ (cm-1): 3045, 2998, 2953, 2835, 1733, 1511, 1487, 1435, 1408, 1241, 1210, 1179; HRMS (ESI) m/z: [M + Na]+ Calcd for C21H22ClNO5Na 426.1079; Found 426.1081. Dimethyl 5-(4-bromophenyl)-1-(4-methoxyphenyl)pyrrolidine-3,3-dicarboxylate (5kb). Dimethyl

2-(4-bromophenyl)cyclopropane-1,1-dicarboxylate

(31.3 mg,

100 µmol,

1.00 equiv.), 1,3,5-tris(4-methoxyphenyl)-1,3,5-triazinane (48.6 mg, 120 µmol, 1.20 equiv.) and MgI2 (2.78 mg, 10.0 µmol, 0.10 equiv.) in CH2Cl2 (1 mL) were reacted according to GP 1. Silica gel column chromatography (n-pentane:EtOAc = 10:1) afforded the desired product 5kb (32.8 mg, 73.1 µmol, 73%) as a colorless oil. 1H-NMR (600 MHz, CDCl3): δ = 2.49 (dd, J = 13.1, 5.8 Hz, 1 H), 3.07 (dd, J = 13.1, 8.2 Hz, 1 H), 3.58 (s, 3 H), 3.70 (s, 3 H), 3.76 (s, 3 H), 3.81 (d, J = 9.7 Hz, 1 H), 4.41 (d, J = 9.7 Hz, 1 H), 4.66 (dd, J = 8.1, 5.8 Hz, 1 H), 6.39 – 6.45 (m, 2 H), 6.70 – 6.76 (m, 2 H), 7.09 – 7.13 (m, 2 H), 7.36 – 7.44 (m, 2 H) ppm; C-NMR (150 MHz, CDCl3): δ = 42.7, 52.9, 53.2, 55.7, 56.3, 58.3, 62.4, 114.4, 114.6, 120.7,

13

127.7, 131.7, 141.0, 142.0, 151.9, 170.1, 170.4 ppm; IR (ATR) v~ (cm-1): 3054, 3011, 3000, 2954, 1733, 1515, 1503, 1434, 1322, 1257; HRMS (ESI) m/z: [M + Na]+ Calcd for C21H22BrNO5Na 470.0574; Found 470.0575. Dimethyl

1-phenyl-5-(4-(trifluoromethyl)phenyl)pyrrolidine-3,3-dicarboxylate

(5la).

Dimethyl 2-(4-(trifluoromethyl)phenyl)cyclopropane-1,1-dicarboxylate (30.2 mg, 100 µmol, 1.00 equiv.), 1,3,5-triphenyl-1,3,5-triazinane (37.8 mg, 120 µmol, 1.20 equiv.) and MgI2 15 ACS Paragon Plus Environment


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Page 16 of 28

(2.78 mg, 10.0 µmol, 0.10 equiv.) in CH2Cl2 (1 mL) were reacted according to GP 1. Silica gel column chromatography (n-pentane:EtOAc = 20:1) afforded the desired product 5la (31.7 mg, 77.7 µmol, 78%) as a colorless oil. 1H-NMR (400 MHz, CDCl3): δ = 2.56 (dd, J = 13.1, 5.4 Hz, 1 H), 3.15 (dd, J = 13.1, 8.3 Hz, 1 H), 3.53 (s, 3 H), 3.77 (s, 3 H), 3.93 (d, J = 9.9 Hz, 1 H), 4.48 (d, J = 9.9 Hz, 1 H), 4.89 (dd, J = 8.2, 5.4 Hz, 1 H), 6.48 (dd, J = 8.7, 0.9 Hz, 2 H), 6.68 – 6.77 (m, 1 H), 7.07 – 7.23 (m, 2 H), 7.35 (d, J = 8.6 Hz, 2 H), 7.55 (d, J = 8.1 Hz, 2 H) ppm; C-NMR (100 MHz, CDCl3): δ = 42.5, 52.8, 53.3, 55.6, 58.3, 62.1, 110.9, 113.3, 115.1, 117.5,

13

118.5, 124.1 (q, 1J = 272.0 Hz), 125.6 (q, 3J = 3.8 Hz), 126.3, 128.1, 129.0, 129.4 (q, 2J = 32.3 Hz), 146.2, 146.8, 169.8, 170.2 ppm; 19F-NMR (400 MHz, CDCl3): δ = - 62.8 ppm; IR (ATR) v~ (cm-1): 3063, 3031, 3009, 2955, 1735, 1599, 1503, 1435, 1323, 1254, 1212; HRMS (ESI)

m/z: [M + Na]+ Calcd for C21H20F3NO4Na 430.1237; Found 430.1239. Dimethyl

5-(1,3-dioxoisoindolin-2-yl)-1-phenylpyrrolidine-3,3-dicarboxylate

(5ma).

Dimethyl 2-(1,3-dioxoisoindolin-2-yl)cyclopropane-1,1-dicarboxylate (30.3 mg, 100 µmol, 1.00 equiv.), 1,3,5-triphenyl-1,3,5-triazinane (37.8 mg, 120 µmol, 1.20 equiv.) and MgI2 (2.78 mg, 10.0 µmol, 0.10 equiv.) in CH2Cl2 (1 mL) were reacted according to GP 1. Silica gel column chromatography (n-pentane:EtOAc = 4:1) afforded the desired product 5ma (35.9 mg, 88.4 µmol, 88%) as a colorless oil. 1H-NMR (600 MHz, CDCl3): δ = 2.97 (dd, J = 14.0, 4.9 Hz, 1 H), 3.23 (dd, J = 13.9, 8.3 Hz, 1 H), 3.77 (s, 3 H), 3.84 (s, 3 H), 4.16 (d, J = 9.5 Hz, 1 H), 4.40 (d, J = 9.5 Hz, 1 H), 6.33 (dd, J = 8.2, 4.9 Hz, 1 H), 6.65 (d, J = 7.9 Hz, 2 H), 6.71 (t, J = 7.3 Hz, 1 H), 7.16 (td, J = 7.4, 1.9 Hz, 2 H), 7.66 (dd, J = 5.5, 3.0 Hz, 2 H), 7.76 (dd, J = 5.5, 3.0 Hz, 2 H) ppm; 13C-NMR (150 MHz, CDCl3): δ = 37.5, 53.2, 53.5, 54.2, 58.8, 63.8, 113.3, 118.2, 123.4, 129.3, 131.6, 134.1, 143.4, 167.9, 169.5, 170.9 ppm; IR (ATR) v~ (cm-1): 3030, 2954, 2887, 1735, 1708, 1599, 1504, 1354, 1307, 1258, 1203, 1124; HRMS (ESI) m/z: [M + Na]+ Calcd for C22H20N2O6Na 431.1214; Found 431.1216. Dimethyl

5-phenoxy-1-phenylpyrrolidine-3,3-dicarboxylate

(5na).

Dimethyl

2-phenoxycyclopropane-1,1-dicarboxylate (25.0 mg, 100 µmol, 1.00 equiv.), 1,3,5-triphenyl16 ACS Paragon Plus Environment

Page 17 of 28

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1,3,5-triazinane (37.8 mg, 120 µmol, 1.20 equiv.) and MgI2 (2.78 mg, 10.0 µmol, 0.10 equiv.) in CH2Cl2 (1 mL) were reacted according to GP 1. Silica gel column chromatography (n-pentane:EtOAc = 10:1) afforded the desired product 5na (20.0 mg, 56.4 µmol, 56%) as a colorless oil. 1H-NMR (600 MHz, CDCl3): δ = 3.32 (dd, J = 11.9, 4.4 Hz, 1 H), 3.42 (dd, J = 11.9, 7.9 Hz, 1 H), 3.43 (s, 3 H), 3.65 (d, J = 10.6 Hz, 1 H), 3.74 (s, 3 H), 4.21 (d, J = 10.6 Hz, 1 H), 5.10 (d, J = 8.3 Hz, 1 H), 6.62 (t, J = 7.6 Hz, 1 H), 6.74 – 6.81 (m, 2 H), 6.89 (ddt, J = 8.3, 5.7, 1.0 Hz, 1 H), 7.02 (dd, J = 8.7, 1.0 Hz, 1 H), 7.08 (d, J = 7.6 Hz, 1 H), 7.23 – 7.32 (m, 4 H) ppm;

C-NMR (150 MHz, CDCl3): δ = 45.9, 50.5, 52.6, 53.1, 54.4, 56.7,

13

60.7112.9, 116.5, 118.4, 120.1, 120.1, 124.2, 126.3, 129.2, 129.3, 141.4, 147.9, 148.7, 169.6, 170.9 ppm; IR (ATR) v~ (cm-1): 3063, 3025, 2959, 2987, 2856, 1733, 1519, 1249, 1233, 1177; HRMS (ESI) m/z: [M + Na]+ Calcd for C20H21NO5Na 378.1312; Found 378.1315. Dimethyl 1-(4-methoxyphenyl)-5-vinylpyrrolidine-3,3-dicarboxylate (5ob). Dimethyl 2-vinylcyclopropane-1,1-dicarboxylate

(18.4 mg,

100 µmol,

1.00 equiv.),

1,3,5-

tris(4-methoxyphenyl)-1,3,5-triazinane (48.6 mg, 120 µmol, 1.20 equiv.) and MgI2 (2.78 mg, 10.0 µmol, 0.10 equiv.) in CH2Cl2 (1 mL) were reacted according to GP 1. Silica gel column chromatography (n-pentane:EtOAc = 10:1) afforded the desired product 5ob (29.1 mg, 91.1 µmol, 91%) as a colorless oil. 1H-NMR (600 MHz, CDCl3): δ = 2.45 (dd, J = 13.1, 5.1 Hz, 1 H), 2.82 (dd, J = 13.1, 8.3 Hz, 1 H), 3.68 (d, J = 9.7 Hz, 1 H), 3.74 (s, 6 H), 3.75 (s, 3 H), 4.15 – 4.21 (m, 2 H), 5.11 (dt, J = 10.2, 1.3 Hz, 1 H), 5.19 (dt, J = 17.2, 1.4 Hz, 1 H), 5.72 (ddd, J = 17.1, 10.2, 6.2 Hz, 1 H), 6.54 – 6.64 (m, 2 H), 6.79 – 6.83 (m, 2 H) ppm; C-NMR (150 MHz, CDCl3): δ = 39.6, 52.9, 53.1, 55.6, 55.8, 58.3, 61.4, 114.3, 114.6, 115.8,

13

139.3, 141.5, 151.7, 170.4, 170.6 ppm; IR (ATR) v~ (cm-1): 3043, 2999, 2954, 2909, 2836, 1734, 1511, 1435, 1241, 1213, 1180; HRMS (ESI) m/z: [M + Na]+ Calcd for C17H21NO5Na 342.1312; Found 342.1314. Dimethyl 1-(4-methoxyphenyl)-5-phenylpyrrolidine-3,3-dicarboxylate (5ab). Dimethyl 2-phenylcyclopropane-1,1-dicarboxylate (23.4 mg, 100 µmol, 1.00 equiv.), 1,3,5-tris(417 ACS Paragon Plus Environment


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

Page 18 of 28

methoxyphenyl)-1,3,5-triazinane (48.6 mg, 120 µmol, 1.20 equiv.) and MgI2 (2.78 mg, 10.0 µmol, 0.10 equiv.) in CH2Cl2 (1 mL) were reacted according to GP 1. Silica gel column chromatography (n-pentane:EtOAc = 10:1) afforded the desired product 5ab (33.8 mg, 91.6 µmol, 92%) as a colorless oil. 1H-NMR (600 MHz, CDCl3): δ = 2.54 (dd, J = 13.1, 5.9 Hz, 1 H), 3.08 (dd, J = 13.0, 8.1 Hz, 1 H), 3.56 (s, 3 H), 3.70 (s, 3 H), 3.76 (s, 3 H), 3.84 (d, J = 9.7 Hz, 1 H), 4.42 (d, J = 9.7 Hz, 1 H), 4.72 (dd, J = 7.9, 6.0 Hz, 1 H), 6.35 – 6.50 (m, 2 H), 6.66 – 6.78 (m, 2 H), 7.18 – 7.24 (m, 3 H), 7.26 – 7.30 (m, 2 H) ppm;

13

C-NMR (150 MHz,

CDCl3): δ = 43.0, 52.8, 53.2, 55.7, 56.3, 58.4, 62.9, 114.3, 114.6, 125.9, 127.0, 128.6, 141.3, 142.9, 151.6, 170.2, 170.6 ppm; IR (ATR) v~ (cm-1): 3059, 3030, 2954, 2826, 1731, 1594, 1516, 1452, 1425, 1187; HRMS (ESI) m/z: [2M + Na]+ Calcd for C42H46N2O10Na 761.2693; Found 761.2694. Dimethyl 1-(2-methoxyphenyl)-5-phenylpyrrolidine-3,3-dicarboxylate (5ac). Dimethyl 2-phenylcyclopropane-1,1-dicarboxylate (23.4 mg, 100 µmol, 1.00 equiv.), 1,3,5-tris(2methoxyphenyl)-1,3,5-triazinane (48.6 mg, 120 µmol, 1.20 equiv.) and MgI2 (2.78 mg, 10.0 µmol, 0.10 equiv.) in CH2Cl2 (1 mL) were reacted according to GP 1. Silica gel column chromatography (n-pentane:EtOAc = 5:1) afforded the desired product 5ac (30.7 mg, 83.0 µmol, 83%) as a colorless oil; 1H-NMR (600 MHz, CDCl3): δ = 2.36 (dd, J = 13.0, 9.9 Hz, 1 H), 2.99 (dd, J = 13.0, 6.5 Hz, 1 H), 3.66 (d, J = 10.7 Hz, 1 H), 3.76 (s, 3 H), 3.76 (s, 3 H), 3.82 (s, 3 H), 4.69 (d, J = 10.8 Hz, 1 H), 4.83 (dd, J = 9.9, 6.5 Hz, 1 H), 6.57 – 6.61 (m, 1 H), 6.68 (ddd, J = 8.0, 6.5, 2.3 Hz, 1 H), 6.74 – 6.82 (m, 2 H), 7.11 – 7.17 (m, 1 H), 7.19 – 7.24 (m, 2 H), 7.28 (dd, J = 8.1, 1.1 Hz, 2 H) ppm; 13C-NMR (150 MHz, CDCl3): δ = 43.1, 52.9, 53.0, 55.6, 58.3, 58.6, 62.9, 112.0, 117.7, 120.8, 120.8, 126.4, 127.0, 128.4, 137.4, 142.1, 151.2, 170.7, 171.4 ppm; IR (ATR) v~ (cm-1): 3062, 3029, 2953, 2836, 1732, 1595, 1501, 1453, 1435, 1250; HRMS (ESI) m/z: [M + Na]+ Calcd for C21H23NO5Na 392.1468; Found 392.1472. Dimethyl

5-phenyl-1-(p-tolyl)pyrrolidine-3,3-dicarboxylate

(5ad).

Dimethyl

2-phenylcyclopropane-1,1-dicarboxylate (23.4 mg, 100 µmol, 1.00 equiv.), 1,3,5-tri-p-tolyl18 ACS Paragon Plus Environment

Page 19 of 28

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1,3,5-triazinane (42.8 mg, 120 µmol, 1.20 equiv.) and MgI2 (2.78 mg, 10.0 µmol, 0.10 equiv.) in CH2Cl2 (1 mL) were reacted according to GP 1. Silica gel column chromatography (n-pentane:EtOAc = 15:1) afforded the desired product 5ad (27.5 mg, 77.9 µmol, 78%) as a colorless oil. 1H-NMR (500 MHz, CDCl3): δ = 2.19 (s, 3 H), 2.54 (dd, J = 13.0, 5.7 Hz, 1 H), 3.09 (dd, J = 13.0, 8.1 Hz, 1 H), 3.52 (s, 3 H), 3.74 (s, 3 H), 3.88 (d, J = 9.8 Hz, 1 H), 4.43 (d, J = 9.8 Hz, 1 H), 4.77 (dd, J = 8.0, 5.8 Hz, 1 H), 6.35 – 6.48 (m, 2 H), 6.87 – 6.99 (m, 2 H), 7.12 – 7.32 (m, 5 H) ppm; 13C-NMR (125 MHz, CDCl3): δ = 20.2, 42.9, 52.7, 53.1, 55.8, 58.3, 62.5, 113.2, 125.8, 126.0, 126.9, 128.5, 129.4, 142.8, 144.4, 170.0, 170.5 ppm; IR (ATR) v~ (cm-1):3062, 3028, 3009, 2861, 1733, 1618, 1518, 1450, 1343, 1249; HRMS (ESI) m/z: [M + Na]+ Calcd for C21H23NO4Na 376.1519; Found 376.1522. Dimethyl

1-(4-fluorophenyl)-5-phenylpyrrolidine-3,3-dicarboxylate

(5ae).

Dimethyl

2-phenylcyclopropane-1,1-dicarboxylate (23.4 mg, 100 µmol, 1.00 equiv.), 1,3,5-tris(4fluorophenyl)-1,3,5-triazinane (44.3 mg, 120 µmol, 1.20 equiv.) and MgI2 (2.78 mg, 10.0 µmol, 0.10 equiv.) in CH2Cl2 (1 mL) were reacted according to GP 1. Silica gel column chromatography (n-pentane:EtOAc = 12:1) afforded the desired product 5ae (24.0 mg, 67.1 µmol, 67%) as a colorless oil. 1H-NMR (500 MHz, CDCl3): δ = 2.56 (dd, J = 13.1, 5.9 Hz, 1 H), 3.10 (dd, J = 13.1, 8.1 Hz, 1 H), 3.55 (s, 3 H), 3.77 (s, 3 H), 3.88 (d, J = 9.7 Hz, 1 H), 4.41 (d, J = 9.7 Hz, 1 H), 4.75 (dd, J = 7.9, 6.0 Hz, 1 H), 6.28 – 6.49 (m, 2 H), 6.73 – 6.90 (m, 2 H), 7.19 – 7.23 (m, 3 H), 7.27 – 7.31 (m, 2 H) ppm; 13C-NMR (125 MHz, CDCl3): δ = 43.0, 52.8, 53.2, 56.1, 58.4, 62.8, 113.9 (d, 3J = 7.3 Hz), 115.3 (d, 2J = 22.2 Hz), 125.8, 127.1, 128.6, 142.4, 143.1, 155.5 (d, 1J = 235.4 Hz), 170.0, 170.5 ppm;

19

F-NMR (283 MHz, CDCl3):

δ = -133.0 ppm; IR (ATR) v~ (cm-1): 3056, 3028, 2954, 2848, 1734, 1506, 1451, 1365, 1254, 1210; HRMS (ESI) m/z: [M + Na]+ Calcd for C20H20FNO4Na 380.1269; Found 380.1271. Dimethyl

1-(4-chlorophenyl)-5-phenylpyrrolidine-3,3-dicarboxylate

(5af).

Dimethyl

2-phenylcyclopropane-1,1-dicarboxylate (23.4 mg, 100 µmol, 1.00 equiv.), 1,3,5-tris(4chlorophenyl)-1,3,5-triazinane (50.2 mg, 120 µmol, 1.20 equiv.) and MgI2 (2.78 mg, 19 ACS Paragon Plus Environment


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Page 20 of 28

10.0 µmol, 0.10 equiv.) in CH2Cl2 (1 mL) were reacted according to GP 1. Silica gel column chromatography (n-pentane:EtOAc = 15:1) afforded the desired product 5af (29.6 mg, 79.2 µmol, 79%) as a colorless oil. 1H-NMR (400 MHz, CDCl3): δ = 2.44 – 2.69 (m, 1 H), 3.11 (dd, J = 13.1, 8.0 Hz, 1 H), 3.54 (s, 3 H), 3.76 (s, 3 H), 3.91 (d, J = 9.9 Hz, 1 H), 4.38 (d, J = 9.9 Hz, 1 H), 4.78 (dd, J = 7.8, 6.0 Hz, 1 H), 6.29 – 6.50 (m, 2 H), 7.00 – 7.12 (m, 2 H), 7.15 – 7.23 (m, 3 H), 7.24 – 7.34 (m, 2 H) ppm; 13C-NMR (100 MHz, CDCl3): δ = 42.9, 52.9, 53.3, 55.7, 58.4, 62.5, 114.3, 122.0, 125.8, 127.2, 128.7, 128.7, 142.0, 145.0, 169.8, 170.4 ppm; IR (ATR) v~ (cm-1):3028, 3004, 2953, 2848, 1733, 1599, 1496, 1450, 1434, 1364, 1251, 1211; HRMS

(ESI) m/z: [M + Na]+ Calcd for C20H20ClNO4Na 396.0973; Found 396.0976. Dimethyl 1-(4-bromophenyl)-5-(4-methoxyphenyl)pyrrolidine-3,3-dicarboxylate (5eg). Dimethyl

2-(4-methoxyphenyl)cyclopropane-1,1-dicarboxylate

(26.4 mg,

100 µmol,

1.00 equiv.), 1,3,5-tris(4-bromophenyl)-1,3,5-triazinane (66.2 mg, 120 µmol, 1.20 equiv.) and MgI2 (2.78 mg, 10.0 µmol, 0.10 equiv.) in CH2Cl2 (1 mL) were reacted according to GP 1. Silica gel column chromatography (n-pentane:EtOAc = 10:1) afforded the desired product 5eg (35.9 mg, 80.0 µmol, 80%) as a colorless solid. m.p. = 80-83 °C; 1H-NMR (600 MHz, CDCl3): δ = 2.52 (dd, J = 13.1, 6.0 Hz, 1 H), 3.07 (dd, J = 13.1, 7.9 Hz, 1 H), 3.57 (s, 3 H), 3.76 (s, 3 H), 3.77 (s, 3 H), 3.88 (d, J = 9.9 Hz, 1 H), 4.36 (d, J = 9.9 Hz, 1 H), 4.72 (dd, J = 7.6, 6.2 Hz, 1 H), 6.32 – 6.38 (m, 2 H), 6.78 – 6.84 (m, 2 H), 7.07 – 7.11 (m, 2 H), 7.17 – 7.23 (m, 2 H) ppm; C-NMR (150 MHz, CDCl3): δ = 43.1, 52.9, 53.3, 55.2, 55.5, 58.3, 61.9, 109.1, 114.0, 114.8,

13

126.9, 131.6, 133.8, 145.5, 158.7, 169.9, 170.4 ppm; IR (ATR) v~ (cm-1): 3001, 2954, 2838, 1733, 1591, 1509, 1494, 1434, 1366, 1245, 1211, 1170; HRMS (ESI) m/z: [M + Na]+ Calcd for C21H22BrNO5Na 470.0574; Found 470.0572. Dimethyl

5-phenyl-1-(3-(trifluoromethyl)phenyl)pyrrolidine-3,3-dicarboxylate

(5ah).

Dimethyl 2-phenylcyclopropane-1,1-dicarboxylate (23.4 mg, 100 µmol, 1.00 equiv.), 1,3,5tris(3-(trifluoromethyl)phenyl)-1,3,5-triazinane (62.8 mg, 120 µmol, 1.20 equiv.) and MgI2 (2.78 mg, 10.0 µmol, 0.10 equiv.) in CH2Cl2 (1 mL) were reacted according to GP 1. Silica gel 20 ACS Paragon Plus Environment

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column chromatography (n-pentane:EtOAc = 15:1) afforded the desired product 5ah (33.2 mg, 81.4 µmol, 81%) as a colorless oil. 1H-NMR (500 MHz, CD3CN): δ = 2.51 (dd, J = 13.2, 6.5 Hz, 1 H), 3.10 (ddd, J = 13.2, 7.8, 0.6 Hz, 1 H), 3.56 (s, 3 H), 3.72 (s, 3 H), 4.01 (d, J = 10.2 Hz, 1 H), 4.34 (d, J = 10.2 Hz, 1 H), 4.85 – 4.92 (m, 1 H), 6.67 – 6.76 (m, 2 H), 6.87 – 6.92 (m, 1 H), 7.20 – 7.27 (m, 4 H), 7.28 – 7.34 (m, 2 H) ppm; 13C-NMR (125 MHz, CD3CN): δ = 43.5, 53.6, 53.9, 56.2, 59.4, 62.9, 110.1 (q, 3J = 4.1 Hz), 113.8 (q, 3J = 3.9 Hz), 117.6, 125.6 (d, 1J = 271.6 Hz) 127.0, 128.3, 129.7, 130.5, 131.4 (q, 2J = 31.3 Hz), 143.3, 147.8, 170.6, 171.2 ppm; 19

F-NMR (283 MHz, CD3CN): δ = -62.3 ppm; IR (ATR) v~ (cm-1): 3062, 3031, 3006, 2956,

1735, 1611, 1586, 1498, 1456, 1371, 1254; HRMS (ESI) m/z: [M + Na]+ Calcd for C21H20F3NO4Na 430.1237; Found 430.1241. General Procedure 2 for the Synthesis of 2-Unsubstituted Piperidines. A flask (10 mL) containing cyclobutane (6; 100 µmol, 1.00 equiv.), triazinane (2, 120 µmol, 1.20 equiv.) and MgI2 (0.10 µmol, 0.10 equiv.) was evacuated and purged three times with argon. CH2Cl2 (1 mL) was added to the system, and the mixture was stirred at 25 °C for 3 h. The solvent was removed in vacuo, and the residue was purified by silica-gel column chromatography to give the desired compound. Dimethyl 1,6-diphenylpiperidine-3,3-dicarboxylate (7aa). Dimethyl 2-phenylcyclobutane1,1-dicarboxylate (24.8 mg, 100 µmol, 1.00 equiv.), 1,3,5-triphenyl-1,3,5-triazinane (37.8 mg, 120 µmol, 1.20 equiv.) and MgI2 (2.78 mg, 10.0 µmol, 0.10 equiv.) in CH2Cl2 (1 mL) were reacted according to GP 2. Silica gel column chromatography (n-pentane:EtOAc = 20:1) afforded the desired product 7aa (19.9 mg, 56.3 µmol, 56%) as a colorless oil. 1HNMR (400 MHz, CDCl3): δ = 2.03 – 2.16 (m, 3 H), 2.21 – 2.36 (m, 1 H), 3.72 (s, 3 H), 3.75 (d, J = 13.1 Hz, 1 H), 3.84 (s, 3 H), 3.92 (dd, J = 13.1, 1.1 Hz, 1 H), 4.40 (t, J = 5.9 Hz, 1 H), 6.80 (tt, J = 7.5, 1.1 Hz, 1 H), 6.90 – 6.96 (m, 2 H), 7.09 – 7.17 (m, 3 H), 7.17 – 7.25 (m, 4 H) ppm; C-NMR (100 MHz, CDCl3): δ = 28.4, 30.7, 52.6, 52.7, 54.8, 55.5, 60.3, 120.0, 120.8, 126.6,

13

127.1, 128.3, 128.7, 141.9, 150.8, 170.6, 170.7 ppm; IR (ATR) v~ (cm-1): 3084, 3060, 3027, 21 ACS Paragon Plus Environment


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3003, 2953, 1730, 1597, 1493, 1434, 1391, 1374, 1234; HRMS (ESI) m/z: [M + Na]+ Calcd for C21H23NO4Na 376.1519; Found 376.1521. Dimethyl 6-(3,4-dimethoxyphenyl)-1-phenylpiperidine-3,3-dicarboxylate (7ba). Dimethyl 2-(3,4-dimethoxyphenyl)cyclobutane-1,1-dicarboxylate (30.8 mg, 100 µmol, 1.00 equiv.), 1,3,5-triphenyl-1,3,5-triazinane (37.8 mg, 120 µmol, 1.20 equiv.) and MgI2 (2.78 mg, 10.0 µmol, 0.10 equiv.) in CH2Cl2 (1 mL) were reacted according to GP 2. Silica gel column chromatography (n-pentane:EtOAc = 4:1) afforded the desired product 7ba (27.8 mg, 67.2 µmol, 67%) as a colorless oil. 1H-NMR (400 MHz, CDCl3): δ = 2.07 (tq, J = 8.4, 3.7 Hz, 3 H), 2.23 – 2.36 (m, 1 H), 3.71 (s, 3 H), 3.73 (s, 3 H), 3.77 (d, J = 6.2 Hz, 1 H), 3.80 (s, 3 H), 3.83 (s, 3 H), 3.86 (d, J = 6.2 Hz, 1 H), 4.33 (t, J = 5.9 Hz, 1 H), 6.67 – 6.73 (m, 3 H), 6.77 – 6.83 (m, 1 H), 6.89 – 6.97 (m, 2 H), 7.12 (tt, J = 7.4, 2.1 Hz, 2 H) ppm; 13C-NMR (100 MHz, CDCl3): δ = 28.4, 30.6, 52.6, 54.8, 55.6, 55.7, 55.7, 60.0, 110.4, 110.8, 119.3, 120.2, 120.9, 128.7, 134.5, 147.5, 148.8, 151.0, 170.6, 170.7 ppm; IR (ATR) v~ (cm-1): 3058, 3000, 2953, 2836, 1731, 1593, 1513, 1436, 1255, 1231, 1136; HRMS (ESI) m/z: [M + Na]+ Calcd for C23H27NO6Na 436.1731; Found 436.1731. Dimethyl 6-(4-methoxyphenyl)-1-phenylpiperidine-3,3-dicarboxylate (7ca). Dimethyl 2-(4-methoxyphenyl)cyclobutane-1,1-dicarboxylate (27.8 mg, 100 µmol, 1.00 equiv.), 1,3,5triphenyl-1,3,5-triazinane (37.8 mg, 120 µmol, 1.20 equiv.) and MgI2 (2.78 mg, 10.0 µmol, 0.10 equiv.) in CH2Cl2 (1 mL) were reacted according to GP 2. Silica gel column chromatography (n-pentane:EtOAc = 8:1) afforded the desired product 7ca (28.6 mg, 74.7 µmol, 75%) as a colorless oil. 1H-NMR (400 MHz, CDCl3): δ = 2.02 – 2.13 (m, 3 H), 2.21 – 2.32 (m, 1 H), 3.72 (s, 3 H), 3.73 (s, 3 H), 3.75 (d, J = 12.9 Hz, 1 H), 3.83 (s, 3 H), 3.88 (dd, J = 13.1, 1.0 Hz, 1 H), 4.36 (t, J = 5.8 Hz, 1 H), 6.72 – 6.77 (m, 2 H), 6.80 (tt, J = 7.6, 1.1 Hz, 1 H), 6.89 – 6.95 (m, 2 H), 7.06 – 7.19 (m, 4 H) ppm; 13C-NMR (100 MHz, CDCl3): δ = 28.4, 30.6, 52.6, 52.7, 54.8, 55.1, 55.4, 59.6, 113.7, 120.0, 120.7, 128.2, 128.7, , 133.8, 150.9, 158.1,


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170.6, 170.7 ppm; IR (ATR) v~ (cm-1): 3011, 3001, 2955, 2865, 1728, 1592, 1502, 1497, 1265, 1223; HRMS (ESI) m/z: [M + Na]+ Calcd for C22H25NO5Na 406.1625; Found 406.1629. Dimethyl Dimethyl

1-(4-chlorophenyl)-6-(4-methoxyphenyl)piperidine-3,3-dicarboxylate 2-(4-methoxyphenyl)cyclobutane-1,1-dicarboxylate

(27.8 mg,

(7cb).

100 µmol,

1.00 equiv.), 1,3,5-tris(4-chlorophenyl)-1,3,5-triazinane (50.2 mg, 120 µmol, 1.20 equiv.) and MgI2 (2.78 mg, 10.0 µmol, 0.10 equiv.) in CH2Cl2 (1 mL) were reacted according to GP 2. Silica gel column chromatography (n-pentane:EtOAc = 8:1) afforded the desired product 7cb (28.8 mg, 68.9 µmol, 69%) as a colorless oil. 1H-NMR (400 MHz, CDCl3): δ = 1.98 – 2.11 (m, 3 H), 2.28 (td, J = 10.8, 6.6 Hz, 1 H), 3.65 (d, J = 13.0 Hz, 1 H), 3.72 (s, 3 H), 3.73 (s, 3 H), 3.83 (s, 3 H), 3.88 (d, J = 13.1 Hz, 1 H), 4.27 (t, J = 4.8 Hz, 1 H), 6.71 – 6.78 (m, 2 H), 6.81 – 6.86 (m, 2 H), 7.03 – 7.09 (m, 4 H) ppm; 13C-NMR (100 MHz, CDCl3): δ = 28.4, 30.8, 52.7, 54.8, 55.1, 55.6, 60.0, 68.7, 113.8, 119.0, 121.5, 125.8, 128.1, 128.6, 129.0, 129.2, 133.5, 149.5, 158.2, 170.4, 170.6 ppm; IR (ATR) v~ (cm-1): 3033, 2999, 2953, 2837, 1731, 1594, 1510, 1492, 1278, 1234; HRMS (ESI) m/z: [M + Na]+ Calcd for C22H24ClNO5Na 440.1235; Found 440.1237. Dimethyl 1,6-bis(4-methoxyphenyl)piperidine-3,3-dicarboxylate (7cc). Dimethyl 2-(4methoxyphenyl)cyclobutane-1,1-dicarboxylate (27.8 mg, 100 µmol, 1.00 equiv.), 1,3,5-tris(4methoxyphenyl)-1,3,5-triazinane (48.6 mg, 120 µmol, 1.20 equiv.) and MgI2 (2.78 mg, 10.0 µmol, 0.10 equiv.) in CH2Cl2 (1 mL) were reacted according to GP 2. Silica gel column chromatography (n-pentane:EtOAc = 5:1) afforded the desired product 7cc (29.2 mg, 70.6 µmol, 71%) as a colorless oil. 1H-NMR (500 MHz, CD3CN): δ = 1.84 (ddd, J = 7.8, 4.6, 2.7 Hz, 3 H), 2.38 – 2.44 (m, 1 H), 3.12 (d, J = 12.2 Hz, 1 H), 3.64 (s, 3 H), 3.65 (s, 3 H), 3.66 (s, 3 H), 3.75 (dd, J = 12.2, 2.2 Hz, 1 H), 3.85 (s, 3 H), 3.98 – 4.02 (m, 1 H), 6.63 – 6.72 (m, 4 H), 6.88 – 6.93 (m, 2 H), 7.06 – 7.12 (m, 2 H) ppm; 13C-NMR (125 MHz, CD3CN): δ = 30.7, 34.1, 53.2, 53.3, 55.7, 55.8, 56.1, 61.6, 63.6, 114.3, 114.7, 126.3, 129.5, 137.1, 146.3, 156.7,



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159.2, 171.3, 171.8 ppm; IR (ATR) v~ (cm-1): 3034, 2997, 2952, 2835, 1730, 1611, 1507, 1437, 1278, 1233; HRMS (ESI) m/z: [M + Na]+ Calcd for C23H27NO6Na 436.1731; Found 436.1733. Dimethyl 6-(4-methoxyphenyl)-1-(p-tolyl)piperidine-3,3-dicarboxylate (7cd). Dimethyl 2-(4-methoxyphenyl)cyclobutane-1,1-dicarboxylate (27.8 mg, 100 µmol, 1.00 equiv.), 1,3,5tri-p-tolyl-1,3,5-triazinane (42.8 mg, 120 µmol, 1.20 equiv.) and MgI2 (2.78 mg, 10.0 µmol, 0.10 equiv.) in CH2Cl2 (1 mL) were reacted according to GP 2. Silica gel column chromatography (n-pentane:EtOAc = 5:1) afforded the desired product 7cd (29.0 mg, 72.9 µmol, 73%) as a colorless oil. 1H-NMR (500 MHz, CD3CN): δ = 1.85 – 1.91 (m, 3 H), 2.15 (s, 3 H), 2.34 (ddt, J = 8.5, 3.9, 2.3 Hz, 1 H), 3.27 (d, J = 12.4 Hz, 1 H), 3.65 (s, 3 H), 3.67 (s, 3 H), 3.79 (dd, J = 12.4, 1.9 Hz, 1 H), 3.83 (s, 3 H), 4.14 (dd, J = 8.4, 4.6 Hz, 1 H), 6.66 – 6.73 (m, 2 H), 6.82 – 6.88 (m, 2 H), 6.92 (ddt, J = 9.0, 2.5, 1.3 Hz, 2 H), 7.07 – 7.12 (m, 2 H) ppm;

13

C-NMR (125 MHz, CD3CN): δ = 20.6, 30.2, 33.4, 53.3, 53.3, 55.7, 55.9, 59.9, 62.2,

114.4, 123.7, 129.4, 130.2, 132.7, 136.7, 150.4, 159.2, 171.3, 171.7 ppm; IR (ATR) v~ (cm-1): 2999, 2952, 2857, 2836, 1731, 1612, 1510, 1435, 1237; HRMS (ESI) m/z: [M + Na]+ Calcd for C23H27NO5Na 420.1781; Found 420.1784.

ASSOCIATED CONTENT Supporting Information Copies of 1H and

13

C NMR spectra of all new compounds. X-ray crystallographic data of

compound 5eg. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] Notes 24 ACS Paragon Plus Environment

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The authors declare no competing financial interest. ORCID Daniel B. Werz: 0000-0002-3973-2212 Acknowledgments. This work was supported by the Studienstiftung des deutschen Volkes (Ph.D. fellowship to L.K.B.G.) and CaSuS program (Catalysis for Sustainable Synthesis) of the State of Lower Saxony (Lichtenberg fellowship to A.K.).

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