Planar Chiral [2.2]Paracyclophane-Based Bisoxazoline Ligands and Their Applications in Cu-Mediated N-H Insertion Reaction.

New catalysts for important C-N bond formation are highly sought after. In this work, we demonstrate the synthesis and viability of a new class of planar chiral [2.2]paracyclophane-based bisoxazoline (BOX) ligands for the copper-catalyzed N-H insertion of α-diazocarbonyls into anilines. The reaction features a wide substrate scope and moderate to excellent yields, and delivers the valuable products at ambient conditions.

1. Introduction

The n class="Chemical">copper-catalyzed class="Chemical">n class="Chemical">N–H insertion of carbenoids such as easily prepared α-diazocarbonyls is a powerful method for the preparation of highly valuable bioactive molecules and pharmaceutical products [1]. In the past decade, various enantioselective chelating ligands based on the bis(oxazoline) motifs have been established for this transformation (Figure 1) [2,3,4,5,6,7,8].

Figure 1

Representative classes of bisoxazoline-containing N,N-ligand systems used in asymmetric catalysis.

While SpiroBOX IV (Figure 1) combines axial chirality from the spiro backbone with the central chirality of the 2-substituted BOX moiety, n class="Chemical">[2.2]paracyclophane (class="Chemical">n class="Chemical">PCP) exhibits planar chirality, which has previously demonstrated remarkable performance as planar chiral ligand or chiral catalyst in asymmetric catalysis [9]. Notable examples include the addition of alkyl, aryl, alkynyl, and alkenyl zinc reagents to aromatic and aliphatic aldehydes and imines that are catalyzed by PCP ligands[10,11,12,13,14]. The PCP core allows different substituents to be positioned regioselectively using carefully chosen reaction parameters [15]. PCP displays planar chirality if only one substituent is introduced to one of the two aromatic benzene rings (decks). If the other deck is substituted as well, especially with both substituents being identical, only the pseudo-ortho and pseudo-meta PCP exhibit chirality, as the other two PCP isomers show higher symmetry (Figure 2) [15]. Thus, the pseudo-ortho PCP isomer is the most suitable for a chelating BOX ligand with PCP as the backbone – referred to here as [2.2]paracyclophane-based bisoxazoline (PCPBOX).

Figure 2

Achiral and chiral isomers of homodisubstituted PCP with the substituents on different decks. The pseudo-ortho isomer is the most suitable candidate for PCPBOX ligands.

Mukai et al. recently reported on n class="Chemical">PCPphBOX that employed pheclass="Chemical">nyl spacers beariclass="Chemical">ng a sterically demaclass="Chemical">ndiclass="Chemical">ng substitueclass="Chemical">nt betweeclass="Chemical">n class="Chemical">n class="Chemical">PCP and BOX (Scheme 1). These PCPphBOX served as promising chiral ligands for the asymmetric copper-catalyzed inter- and intra-molecular aromatic O–H insertion reaction with up to 80%ee [16,17]. Mukai et al. additionally investigated PCPBOX ligands, with phenyl, biphenyl, and without the phenyl as spacer groups for comparative studies. We thus set out to explore the PCPBOX ligands in copper-catalyzed N–H insertion to expand on their versatility.

Scheme 1

The earlier work of Mukai et al. on copper-catalyzed O–H insertion reaction and this work on N–H insertion reaction.

2. Results

2.1. Synthesis

Access to class="Chemical">pseudo-ortho disubstituted class="Chemical">n class="Chemical">PCPs leads through the thermal or microwave-assisted isomerization of the easily accessible pseudo-para dibromide of PCP [18]. In this way, pseudo-ortho dibromide 2 was obtained in 70% yield. On this stage, chromatographic separation of the racemic 2 was achieved via a Chiralprak® AZ-H column (Scheme 2).

Scheme 2

Preparation of enantiopure pseudo-ortho PCP dibromide 2 via microwave-assisted isomerization.

The obtained (Rp)-2 and n class="Chemical">(Sp)-2 were subjected to a two-step lithiatioclass="Chemical">n-carboxylatioclass="Chemical">n procedure to afford the eclass="Chemical">naclass="Chemical">ntiopure class="Chemical">n class="Chemical">carboxylic acids 3 (Scheme 3). However, while the conversion of (Rp)-2 smoothly delivered (Rp)-3 in good yield, the conversion of (Sp)-2 left us with inconclusive results.

Scheme 3

Conversion of the dibromo PCP to the dicarboxylic acid 3.

With (Rp)-3 in hand, we proceeded with the n class="Chemical">PCPBOX syclass="Chemical">nthesis by subjecticlass="Chemical">ng it to coclass="Chemical">ndeclass="Chemical">nsatioclass="Chemical">n coclass="Chemical">nditioclass="Chemical">ns with suitable class="Chemical">n class="Chemical">amino alcohols to afford the respective hydroxyl amides. Under Appel conditions, cyclization and dehydration is achieved to afford the enantiopure PCPBOXs 4a–c in moderate to good yields (Scheme 4).

Scheme 4

Preparation of enantiopure PCPBOX 4a–c.

2.2. Catalysis

The synthesized class="Chemical">PCPBOX ligaclass="Chemical">nds were tested iclass="Chemical">n the class="Chemical">n class="Chemical">copper-catalyzed N–H insertion reaction. The catalyst is generated in situ from ligand 4 and a rationally selected copper source. For the optimization of the copper source, the diastereomeric mixture (Sp,S)/(Rp,S)-4 was used. The competition between N–H insertion and β-hydride elimination (BHE) leads to a mixture of desired product 7 and the olefinic product 8.

The initially tested n class="Chemical">Cu(MeCN)4PF6 complex shows good selectivity (Table 1, eclass="Chemical">ntry 1). Simple class="Chemical">n class="Chemical">copper (I) chloride does not deliver the desired product at all (entry 2). Lowering the temperature to room temperature increased the selectivity to an excellent ratio of 93:5 with Cu(MeCN)4PF6 (entry 4). When β-hydrogen lacking 6b was used (entry 7–10), product 9 was detected from the dimerization of the α-diazocarbonyl 6b. Dropwise addition of 6b to the reaction mixture alleviated this issue for the most part. With these optimized reaction conditions, the same copper source (Cu(MeCN)4PF6) leads to excellent yields of 98% for the desired product 7b. Notably, in both cases the product was formed even in the absence of the ligand 4 in 13% and 40% yield respectively.

Table 1

Optimization of the copper-catalyzed N–H insertion of diazocarbonyls 6a–b into aniline 5.

Entry	6	[Cu]	T [°C]	Yield [%] a
				7	8	9
1	6a	Cu(MeCN)4PF6	40	77	18	n/a
2		CuCl	40	–	88	n/a
3		[CuOTf]2·Tol	40	58	38	n/a
4		Cu(MeCN)4PF6	r.t.	93	5	n/a
5		[CuOTf]2·Tol	r.t.	61	22	n/a
6 b		Cu(MeCN)4PF6	r.t.	13	84	n/a
7	6b	CuCl	r.t.	44	n/a	2
8		Cu(MeCN)4PF6	r.t.	98	n/a	2
9		[CuOTf]2·Tol	r.t.	64	n/a	28
10 b		Cu(MeCN)4PF6	r.t.	40	n/a	–

a Yields were determined by GC-MS. b no ligand 4.

The molen class="Chemical">cular structure of the class="Chemical">n class="Chemical">N–H insertion product 7b was further confirmed unambiguously by single crystal X-Rays structure analysis (Figure 3, for further details see Electronic Supplementary Information and cif-file, CCDC 1962906 (7b) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif).

Figure 3

Molecular structure of 7b (displacement parameters are drawn at 50% probability level).

A series of other n class="Chemical">aniline derivatives aclass="Chemical">nd α-class="Chemical">n class="Chemical">diazocarbonyls were investigated to further test the substrate scope for this reaction. A wide range of products were obtained in short reaction times and in good to excellent yields (Table 2). While unsubstituted phenyl rings as substituents gave the best yields (entry 2), benzyl substituents also delivered the product in very good yield (entries 3–8). However, a drop in yields was observed employing electron donating groups in the meta-position (entry 5). This contrasts with findings of Zhou et al. showing no such drop for similar substitution patterns [2]. If non-aromatic anilines were used, no product formation could be observed (entries 11–12).

Table 2

Optimization of copper-catalyzed N–H insertion of diazocarbonyl 11 into aniline 10.

Entry	R1	R2	R3	Product	Yield [%] a
1	Bn	Me	Ph	7a	77
2	Ph	Me	Ph	7b	98
3	Me	Bn	Ph	7c	94
4	Me	Bn	o-MeOPh	7d	82
5	Me	Bn	m-MeOPh	7e	53
6	Me	Bn	p-MeOPh	7f	70
7	Me	Bn	o-MePh	7g	68
8	Me	Bn	p-MePh	7h	70
9	Me	Ph	Ph	7i	68
10	Me	tBu	Ph	7j	74
11	Me	Bn	c-C6H11	7k	–
12	Me	Ph	c-C6H11	7l	–

a Isolated yields.

We turned our attention towards the enantioselective n class="Chemical">N–H iclass="Chemical">nsertioclass="Chemical">n with uclass="Chemical">nsaturated α-class="Chemical">n class="Chemical">diazocarbonyls. The products of this reaction are valuable intermediates that can be used in the total synthesis of biologically important products such as Rostratin B.-D [19]. The ligands discussed in Scheme 4 were tested with results summarized in Table 3. While only low yields of 22% were achieved with 5 mol% (R)-4a (Table 3, entry 1), this could be increased to 38% by using 10 mol% ligand. Dramatically increased yields were observed for the more sterically demanding (R)-4b and (R)-4c (entry 3–4). All these enantiopure ligands did not induce any considerable enantioselectivity as determined by chiral HPLC. This further verifies the observations obtained by Mukai et al. that the combination of planar and central chirality in PCPBOX ligands suffers from very low enantioinduction [17].

Table 3

Catalyst screening for the N–H insertion of unsaturated α-diazocarbonyl 13.

Entry	Ligand	Yield [%] a
1	(Rp,S)-4a	22
2	(Rp,S)-4a	38
3	(Rp,S)-4b	80
4	(Rp,S)-4c	88

a Isolated yields.

3. Materials and Methods

class="Chemical">Benzyl 2-diazopropanoate [20], class="Chemical">n class="Chemical">Methyl 2-diazo-2-phenylacetate [21] and tert-Butyl 2-diazopropanoate [20] were prepared according to literature procedures.

n class="Chemical">4,16-Dibromo[2.2]paracyclophane (

A solution of n class="Chemical">Br2 (5.50 mL, 17.0 g, 106 mmol, 2.20 equiv.) iclass="Chemical">n class="Chemical">n class="Chemical">CH2Cl2 (50 mL) was prepared. A suspension of iron powder (0.14 g, 2.4 mmol, 0.05 equiv.) in 6.25 mL of the Br2/CH2Cl2 solution was diluted in 50 mL of CH2Cl2 and stirred at room temperature for 1 h. The solution was then brought to reflux for 2 h. CH2Cl2 (50 mL) and [2.2]paracyclophane (10.0 g, 48.0 mmol, 1.00 equiv.) were added to the mixture subsequently. After the remaining bromine solution was added dropwise over a period of 4 h, the mixture was stirred at room temperature for 3 d. Saturated Na2S2O3 solution was added and the reaction mixture was stirred at room temperature until the bromine color disappeared. The organic phase was separated and filtrated, the precipitate was recrystallized from hot toluene to obtain the title product as an off-white solid, 5.40 g, 14.8 mmol, 31%.

class="Chemical">1H-class="Chemical">n class="Chemical">NMR (400 MHz, CDCl3) δ/ppm = 7.14 (dd, J = 7.8, 1.8 Hz, 2H, 2 × CArH), 6.51 (d, J = 1.8 Hz, 2H, 2 × CArH), 6.44 (d, J = 7.8 Hz, 2H, 2 × CArH), 3.50 (ddd, J = 12.8, 10.3, 2.0 Hz, 2H, 2 × CHPC), 3.16 (ddd, J = 12.1, 10.2, 4.6 Hz, 2H, 2 × CHPC), 2.95 (ddd, J = 12.1, 11.4, 2.0 Hz, 2H, 2 × CHPC), 2.85 (ddd, J = 13.0, 10.6, 4.6 Hz, 2H, 2 × CHPC). 13C-NMR (101 MHz, CDCl3) δ/ppm = 141.3 (Cq, 2 × CAr), 138.6 (Cq, 2 × CAr), 137.4 (+, CH, 2 × CAr), 134.2 (+, CH, 2 × CAr), 128.4 (+, CH, 2 × CAr), 126.8 (Cq, 2 × CAr-Br), 35.5 (−, 2 × CH2), 32.9 51 (−, 2 × CH2). IR (ATR): /cm−1 = 2932 (vw), 2849 (vw), 1895 (vw), 1583 (vw), 1532 (vw), 1474 (vw), 1449 (vw), 1432 (vw), 1390 (w), 1313 (vw), 1185 (vw), 1104 (vw), 1030 (w), 947 (vw), 899 (w), 839 (w), 855 (w), 830 (w), 706 (w), 669 (w), 647 (w), 522 (vw), 464 (w), 393 (vw). MS (EI, 70 eV), m/z (%): 364/366/368 (3/6/3) [M]+, 184/182 (18/18) [M − C8H7Br]+, 104 (100) [C8H8]+. HRMS (EI, C16H1479Br2) calc. 363.9457, found 363.9455.

n class="Chemical">(rac)-4,12-Dibromo[2.2]paracyclophane (rac)-

In a 10 mL microwave vessel was placed n class="Chemical">4,16-dibromo[2.2]paracyclophane (500 mg, 1.37 mmol, 1.00 equiv.) aclass="Chemical">nd class="Chemical">n class="Chemical">DMF (1.00 mL). The device was programmed to heat the mixture to 180 °C with a holding time set as 6 min. The maximum pressure for the system was set at 17.2 bar and the power was set at 300 W. After cooling to room temperature, the mixture was diluted with DMF (2 mL) and the precipitate was collected by filtration. The reaction was repeated under the same conditions until all the starting material (5.00 g, 13.7 mmol, 1.00 equiv.) reacted. The combined filtrate was poured into water (75 mL) and extracted with EtOAc (3 × 100 mL). The combined organic phase was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to give the title product as a pale brown power, 3.50 g, 9.65 mmol, 70%.

R = 0.68 (class="Chemical">c-Hex/class="Chemical">n class="Chemical">EtOAc = 9:1). 1H-NMR (400 MHz, CDCl3) δ/ppm = 7.22 (d, J = 1.6 Hz, 2H, 2 × CArH), 6.56 (d, J = 7.8 Hz, 2H, 2 × CArH), 6.52 (dd, J = 7.9, 1.7 Hz, 2H, 2 × CArH), 3.47 (ddd, J = 13.3, 9.6, 2.2 Hz, 2H, 2 × CH), 3.10 (ddd, J = 13.0, 9.6, 6.8 Hz, 2H, 2 × CH), 3.06–2.94 (m, 2H, 2 × CH), 2.82 (ddd, J = 13.3, 10.1, 6.9 Hz, 2H, 2 × CH). 13C-NMR (101 MHz, CDCl3) δ/ppm = 141.3 (Cq, 2 × C, 138.7 (Cq, 2 × C, 135.0 (+, CH, 2 × C, 132.7 (+, CH, 2 × C, 131.7 (+, CH, 2 × C, 126.7 (Cq, 2 × CAr-Br), 35.8 (−, 2 × CH2), 32.5 (−, 2 × CH2). IR (ATR): /cm−1 = 2923 (w), 2848 (w), 1583 (w), 1537 (w), 1474 (w), 1449 (w), 1431 (w), 1391 (m), 1272 (w), 1237 (w), 1201 (w), 1185 (w), 1030 (m), 902 (m), 858 (m), 785 (w), 705 (m), 644 (m), 475 (m). MS (70 eV, EI) m/z (%): 368/366/364 (22/43/22) [M]+, 288/286 (13/12) [M + H – Br]+, 184/182 (80/100) [M – C8H6Br]+, 104 (68) [C8H8]+. HRMS (EI, C16H1479Br2) calc. 363.9462, found 363.9461.

(R

Separation of n class="Chemical">(rac)-4,12-dibromo[2.2]paracyclophane (2) was performed by semi-preparative chiral HPLC. For details see Electroclass="Chemical">nic Supporticlass="Chemical">ng Iclass="Chemical">nformatioclass="Chemical">n.

(R

To a solution of n class="Chemical">(Rp)-4,12-dibromo[2.2]paracyclophane (1.50 g, 4.12 mmol, 1.00 equiv.) iclass="Chemical">n abs. class="Chemical">n class="Chemical">THF (50 mL) was added 9.71 mL of t-butyllithium (1.7 M in pentane, 15.4 mmol, 4.00 equiv.) dropwise at −78 °C. After stirring at −78 °C for 3 h, CO2 was bubbled through the solution via a long needle under stirring for 2 h. The reaction mixture was then quenched with water and extracted with 1 M NaOH solution (2 × 100 mL). The water phases were combined, washed with CH2Cl2 (50 mL) and acidified with 6 M HCl until the solution tested acidic by litmus paper. The precipitate was filtrated, washed with water and CH2Cl2. The title product was obtained after drying under high vacuum as white powder, 640 mg, 3.14 mmol, 52%.

[α]D20 = −134 (c = 0.00203, class="Chemical">EtOH). class="Chemical">n class="Chemical">1H-NMR (400 MHz, DMSO-d6) δ/ppm = 12.4 (s, 2H, 2 × COOH), 7.04 (d, J = 2.0 Hz, 2H, 2 × CArH), 6.78 (dd, J = 7.8, 1.9 Hz, 2H, 2 × CArH), 6.60 (d, J = 7.8 Hz, 2H, 2 × CArH), 4.04–3.88 (m, 2H, 2 × CArH), 3.15 (dd, J = 12.5, 9.8 Hz, 2H, 2 × CArH), 2.98 (ddd, J = 12.5, 9.6, 7.3 Hz, 2H, CArH), 2.81 (ddd, J = 12.3, 9.8, 7.3 Hz, 2H, 2 × CArH). 13C-NMR (101 MHz, DMSO-d6) δ/ppm = 167.7 (Cq, 2 × COOH), 141.9 (Cq, 2 × CAr), 139.7 (Cq, 2 × CAr), 136.1 (+, CH, 2 × CAr), 135.9 (+, CH, 2 × CAr), 133.3 (+, CH, 2 × CAr), 130.7 (Cq, 2 × CAr-COOH), 35.3 (−, CH2, 2 × CPC), 33.7 (−, CH2, 2 × CPC). IR (ATR): /cm–1 = 2925 (w), 1674 (w), 1592 (w), 1556 (w), 1489 (vw), 1422 (w), 1300 (w), 1273 (w), 1203 (w), 1074 (w), 909 (w), 850 (vw), 797 (vw), 759 (vw), 717 (vw), 664 (w), 631 (w), 555 (vw), 518 (w), 426 (vw). MS (70 eV, EI) m/z (%): 296 (27) [M]+, 278 (100) [MH2O]+, 148 (83) [MC9H8O2]+. HRMS (EI, C18H16O4) calc. 296.1049, found 296.1049. The analytical data match those reported in the literature[22].

(R

n class="Chemical">Thionyl chloride (1.0 mL) was added to class="Chemical">n class="Chemical">(Rp,S)-4,12-dicarboxy[2.2]paracyclophane (250 mg, 0.840 mmol, 1.00 equiv.) and the resulting mixture was stirred at 100 °C for 90 min. After cooling to room temperature, the excess thionyl chloride was removed under vacuum, the final traces were washed with toluene (2 × 2 mL) and removed under vacuum. The resulting crude acetyl chloride was dissolved in CH2Cl2 (5 mL) and cooled to 0 °C. A solution of S-Valinol (0.350 g, 3.36 mmol, 4.00 equiv.) and Et3N (0.54 mL, 0.42 g, 4.20 mmol, 5.00 equiv.) in CH2Cl2 (1.0 mL) was added, the reaction mixture was allowed to warm to room temperature and stirred for 24 h. 10 mL of CH2Cl2 was then added and the solution was washed with aq. NaHCO3 solution (3.5% w/v, 2 × 10 mL) and brine (20 mL). The organic phase was dried over MgSO4, filtered, concentrated, and dried under vacuum to give the crude amide as light brown solid.

The crude n class="Chemical">amide was dissolved iclass="Chemical">n class="Chemical">n class="Chemical">CH3CN (5.0 mL), PPh3 (0.66 g, 2.52 mmol, 3.00 equiv.), CCl4 (0.770 mL, 1.23 g, 7.98 mmol, 9.50 equiv.) and Et3N (0.970 mL, 0.760 g, 7.56 mmol, 9.00 equiv.) were added subsequently. After stirring at room temperature overnight, the solvent was removed under reduced pressure, the resulting mixture was dissolved in CH2Cl2 and washed with H2O (2 × 10 mL), the combined organic phase was washed with brine, dried over Na2SO4, filtrated and concentrated under vacuum. The crude was purified via column chromatography (c-Hex/EtOAc = 9:1) to give the title product as a pale yellow solid, 0.150 g, 0.350 mmol, 42%.

R = 0.34 (class="Chemical">c-Hex/class="Chemical">n class="Chemical">EtOAc = 9:1). 1H-NMR (400 MHz, CDCl3) δ/ppm = 7.09 (d, J = 1.9 Hz, 2H, 2 × CArH), 6.62 (dd, J = 7.9, 1.9 Hz, 2H, 2 × CArH), 6.54 (d, J = 7.8 Hz, 2H, 2 × CArH), 4.37 (ddd, J = 11.2, 9.5, 2.0 Hz, 2H, 2 × CHPC), 4.30 (dd, J = 5.8, 2.2 Hz, 2H, 2 × CH5′), 4.04 (dd, J = 8.6, 6.7 Hz, 2H, 2 × CH4′), 4.05–3.92 (m, 2H, 2 × CH5′), 3.24–3.16 (m, 2H, 2 × CHPC), 3.16–3.07 (m, 2H, 2 × CHPC), 2.82 (ddd, J = 12.6, 10.0, 7.1 Hz, 2H, 2 × CHPC), 1.95 (hept, J = 6.7 Hz, 2H, 2 × CH6′), 1.20 (d, J = 6.7 Hz, 6H, CH7′), 1.06 (d, J = 6.7 Hz, 6H, CH7′). 13C-NMR (101 MHz, CDCl3) δ/ppm = 162.9 (Cq, 2 × C2′), 141.0 (Cq, 2 × CAr), 140.1 (Cq, 2 × CAr), 135.8 (+, CH, 2 × CAr), 134.8 (+, CH, 2 × CAr), 132.3 (+, CH, 2 × CAr), 128.2 (Cq, 2 × CAr), 73.8 (+, CH, 2 × C4′), 69.3 (−, CH2, 2 × C5′), 35.8 (−, CH2, 2 × CPC), 33.6 (+, CH, 2 × C6′), 33.6 (−, CH2, 2 × CPC), 19.7 (+, CH3, 2 × C7′), 19.2 (+, CH3, 2 × C7′). IR (ATR): /cm–1 = 2955 (w), 1637 (m), 1590 (w), 1492 (w), 1468 (w), 1429 (w), 1384 (w), 1346 (w), 1303 (w), 1275 (w), 1258 (w), 1191 (w), 1172 (w), 1137 (w), 1115 (w), 1053 (m), 1026 (w), 984 (m), 933 (w), 907 (m), 889 (w), 822 (w), 749 (w), 694 (w), 674 (w), 643 (w), 514 (w), 482 (vw), 389 (vw). MS (FAB, 3-NBA), m/z (%): 431 (100) [M + H]+, 500/488 (9/9) [C14H17NO2 + H]+. HRMS (FAB, C28H35O2N2, [M + H]+): calc. 431.2699, found 431.2701.

(R

n class="Chemical">Thionyl chloride (2.0 mL) was added to class="Chemical">n class="Chemical">(Rp)-4,12-dicarboxy[2.2]paracyclophane (0.150 g, 0.510 mmol, 1.00 equiv.), after stirring at room temperature for 10 min, the mixture was heated to 100 °C and stirred at this temperature for 90 min. The excess thionyl chloride was removed by evaporation, the final traces were washed with toluene (2 × 2 mL). After drying under vacuum, the resulting crude acid chloride was dissolved in abs. CH2Cl2 (5 mL) and cooled to 0 °C. A solution of (S)-(+)-tert-leucinol (0.229 g, 2.04 mmol, 4.00 equiv.) and abs. Et3N (0.260 g, 0.360 mL, 2.55 mmol, 5.00 equiv.) in CH2Cl2 (1.0 mL) was added and the reaction mixture allowed to warm to room temperature and stirred for 24 h. Water was then added (10 mL) and extracted with CH2Cl2 (3 × 10 mL), the combined organic phase was washed with sat. NaHCO3 solution and brine (20 mL). The organic phase was dried over MgSO4, filtrated, concentrated, and dried under vacuum. The crude was purified via column chromatography (CH2Cl2/MeOH = 98:2 → 95:5) to give the intermediate amide. To a solution of this amide (152 mg, 0.307 mmol, 1.00 equiv.) and PPh3 (282 mg, 1.08 mmol, 3.50 equiv.) in abs. CH3CN (8.00 mL) was added triethyl amine (0.385 mL, 280 mg, 2.76 mmol, 9.00 equiv.) and CCl4 (0.281 mL, 449 mg, 2.92 mmol, 9.50 equiv.) under argon atmosphere. After stirring at room temperature overnight, the solvent was removed under vacuum, the resulting crude was dissolved in CH2Cl2 and washed with brine, the organic phase was dried over Na2SO4, filtrated and concentrated under vacuum. The resulting mixture was purified via column chromatography (c-Hex/EtOAc = 9:1) to give the title product as colorless solid, 104 mg, 0.227 mmol, 44% over two steps.

R = 0.36 (class="Chemical">c-Hex/class="Chemical">n class="Chemical">EtOAc = 9:1). 1H-NMR (400 MHz, CDCl3) δ/ppm = 7.12 (d, J = 1.9 Hz, 2H, 2 × CArH), 6.64 (dd, J = 7.8, 1.9 Hz, 2H, 2 × CArH), 6.55 (d, J = 7.8 Hz, 2H, 2 × CArH), 4.33–4.24 (m, 2H, 2 × CH5′), 4.20 (td, J = 8.8, 3.7 Hz, 2H, 2 × CH4′), 4.17–4.08 (m, 4H, 2 × CH5′ + 2 × CHPC), 3.21–3.03 (m, 4H, 4 × CHPC), 2.86–2.68 (m, 2H, 2 × CHPC), 0.99 (s, 18H, CH7′). 13C-NMR (101 MHz, CDCl3) δ/ppm = 162.9 (Cq, 2 × C2′), 141.0 (Cq, 2 × CAr), 140.2 (Cq, 2 × CAr), 135.6 (+, CH, 2 × CAr), 134.7 (+, CH, 2 × CAr), 132.2 (+, CH, 2 × CAr), 128.0 (Cq, 2 × CAr), 74.2 (+, CH, 2 × C4′), 67.7 (−, CH2, 2 × C5′), 36.2 (−, CH2, 2 × CPC), 34.1 (−, CH2, 2 × CPC), 34.0 (Cq, 2 × C6′), 26.1 (+, CH3, 6 × C7′). IR (ATR): /cm−1 = 2951 (w), 2866 (w), 1638 (m), 1590 (w), 1477 (w), 1392 (w), 1350 (w), 1333 (w), 1303 (w), 1257 (w), 1191 (w), 1172 (w), 1113 (w), 1067 (w), 1047 (w), 1024 (w), 979 (m), 930 (w), 906 (w), 819 (w), 791 (w), 719 (w), 679 (w), 632 (w), 544 (vw), 513 (w). MS (FAB, 3-NBA), m/z (%): 459 (82) [M + H]+, 230 (75) [C15H19NO + H]+. HRMS (FAB, C30H39O2N2, [M + H]+): calc. 459.3012, found 459.3011.

(R

n class="Chemical">Thionyl chloride (2.0 mL) was added to class="Chemical">n class="Chemical">(Rp)-4,12-dicarboxy[2.2]paracyclophane (0.150 g, 0.510 mmol, 1.00 equiv.), after stirring at room temperature for 10 min, the mixture was heated to 100 °C and stirred under this temperature for 90 min. The excess thionyl chloride was removed by evaporation and the final traces were washed with toluene (2 × 2 mL). After drying under vacuum, the resulting crude acid chloride was dissolved in abs. CH2Cl2 (5 mL) and cooled to 0 °C. A solution of (S)-(+)-phenylglycinol (0.280 g, 2.04 mmol, 4.00 equiv.) and abs. Et3N (0.360 mL, 0.260 g, 2.55 mmol, 5.00 equiv.) in CH2Cl2 (1 mL) was added and the reaction mixture allowed to warm to room temperature and stirred for 24 h. Water (10 mL) was then added, the water phase was extracted with CH2Cl2 (3 × 10 mL) and the combined organic phase was washed with sat. NaHCO3 solution and brine (20 mL). The organic phase was dried over MgSO4, filtered, concentrated, and dried in vacuum. The crude was purified via column chromatography (CH2Cl2/MeOH = 98:2 → 95:5) to give the intermediate amide. To a solution of this amide (200 mg, 0.374 mmol, 1.00 equiv.) and PPh3 (344 mg, 1.31 mmol, 3.50 equiv.) in abs. 10 mL of CH3CN was added Et3N (0.469 mL, 341 mg, 3.37 mmol, 9.00 equiv.) and CCl4 (0.343 mL, 547 mg, 3.55 mmol, 9.50 equiv.) under argon atmosphere. After stirring at room temperature overnight, the solvent was removed under vacuum, the resulting crude was dissolved in CH2Cl2 and washed with brine. The organic phase was dried over Na2SO4, filtrated and concentrated under vacuum, the resulting mixture was purified via column chromatography (c-Hex/EtOAc = 9:1) to give the title product as colorless solid, 177 mg, 0.355 mmol, 95%.

R = 0.14 (class="Chemical">c-Hex/class="Chemical">n class="Chemical">EtOAc = 9:1). 1H-NMR (500 MHz, CDCl3) δ/ppm = 7.40–7.29 (m, 12H, CH7 + 8′ + 9 + 2 × CArH), 6.70 (dd, J = 7.9, 1.9 Hz, 2H, 2 × CArH), 6.61 (d, J = 7.9 Hz, 2H, 2 × CArH), 5.47 (dd, J = 10.1, 8.2 Hz, 2H, 2 × CH5′), 4.65 (dd, J = 10.1, 8.2 Hz, 2H, 2 × CH5′), 4.44–4.25 (m, 2H, 2 × CHPC), 4.13 (t, J = 8.2 Hz, 2H, 2 × CH4′), 3.22–3.14 (m, 4H, 4 × CHPC), 2.89–2.79 (m, 2H, 2 × CHPC). 13C-NMR (126 MHz, CDCl3) δ/ppm = 164.6 (Cq, 2 × C2′), 143.0 (Cq, 2 × C6′), 141.4 (Cq, 2 × CAr), 140.3 (Cq, 2 × CAr), 135.9 (+, CH, 2 × CAr), 135.1 (+, CH, 2 × CAr), 132.8 (+, CH, 2 × CAr), 128.8 (+, CH, 4 × C8′), 128.5 (Cq, CH, 2 × CAr), 127.5 (+, CH, 2 × C9′), 126.9 (+, CH, 4 × C7′), 73.9 (+, CH, 2 × C4′), 70.7 (−, CH2, 2 × C5′), 36.4 (−, CH2, 2 × CPC), 34.2 (−, CH2, 2 × CPC). IR (ATR): /cm–1 = 2922 (w), 1630 (m), 1589 (w), 1493 (w), 1448 (w), 1349 (w), 1296 (w), 1274 (w), 1245 (w), 1191 (w), 1172 (w), 1136 (vw), 1116 (vw), 1050 (w), 986 (w), 961 (w), 927 (w), 902 (w), 887 (w), 823 (w), 750 (w), 697 (w), 639 (w), 523 (w), 388 (vw). MS (FAB, 3-NBA), m/z (%): 499 (100) [M + H]+, 250 (34) [C17H15NO + H]+. HRMS (FAB, C34H31O2N2, [M + H]+): calc 499.2386, found 499.2386.

n class="Chemical">Methyl 2-Phenyl-2-(phenylamino)acetate (

General procedure (GP) was followed by adding n class="Chemical">phenyl-2-diazopropionate (17.6 mg, 1.00 mmol, 1.00 equiv.) aclass="Chemical">nd class="Chemical">n class="Chemical">aniline (11.2 mg, 1.20 mmol, 1.20 equiv.) to a suspension of in situ generated Cu-(R)-4a catalyst. The product 7a was obtained via flash chromatography (c-Hex/EtOAc = 5:1) as colorless solid, 23.6 mg, 0.98 mmol, 98%.

class="Chemical">1H-class="Chemical">n class="Chemical">NMR (300 MHz, CDCl3) δ/ppm = 7.42 (d, J = 7.7 Hz, 2H, 2 × CArH), 7.27 (qd, J = 7.5, 6.4, 2.6 Hz, 3H, 3 × CArH), 7.04 (t, J = 7.9 Hz, 2H, 2 × CArH), 6.62 (t, J = 7.3 Hz, 1H, CArH), 6.48 (d, J = 7.7 Hz, 2H, 2 × CArH), 5.01 (d, J = 5.9 Hz, 1H, CHN), 4.88 (s, 1H, NH), 3.65 (s, 3H, OCH3).

The analytical data matches the data reported in the literature [23].

n class="Chemical">Methyl 2-phenyl-2-(phenylamino)acetate (

GP was followed by adding n class="Chemical">phenyl-2-diazopropionate (17.6 mg, 1.00 mmol,1.00 equiv.) aclass="Chemical">nd class="Chemical">n class="Chemical">aniline (11.2 mg, 1.20 mmol, 1.20 equiv.) to a suspension of in situ generated Cu-(R)-4a catalyst. The product 7b was obtained via flash chromatography (c-Hex/EtOAc = 5:1) as colorless solid, 23.6 mg, 0.98 mmol, 98%.

class="Chemical">1H-class="Chemical">n class="Chemical">NMR (300 MHz, CDCl3) δ/ppm = 7.42 (d, J = 7.7 Hz, 2H, 2 × CArH), 7.27 (qd, J = 7.5, 6.4, 2.6 Hz, 3H, 3 × CArH), 7.04 (t, J = 7.9 Hz, 2H, 2 × CArH), 6.62 (t, J = 7.3 Hz, 1H, CArH), 6.48 (d, J = 7.7 Hz, 2H, 2 × CArH), 5.01 (d, J = 5.9 Hz, 1H, CHN), 4.88 (s, 1H, NH), 3.65 (s, 3H, OCH3).

The analytical data matches the data reported in the literature[23].

General Procedure (GP): n class="Chemical">Copper-Catalyzed class="Chemical">n class="Chemical">N–H Insertion

n class="Chemical">Cu(MeCN)4PF6 (5 mol%), ligaclass="Chemical">nd (6 mol%) aclass="Chemical">nd class="Chemical">n class="Chemical">NaBArF (6 mol%) were added into an oven-dried screw vial, evacuated, and backfilled with argon three times. After CH2Cl2 (1 mL) was injected into the vial, the solution was stirred at 40 °C under argon atmosphere overnight. A solution of α-diazopropionates (1.00 equiv.) and aniline (1.20 equiv.) in CH2Cl2 (1 mL) was added dropwise, the mixture was stirred at room temperature for 2 h. The resulting mixture was dried under vacuum and purified via column chromatography (c-Hex/EtOAc = 8:1 or pentane/Et2O = 5:1) to give the products 7a–j.

n class="Chemical">Benzyl phenylalaninate (

GP was followed by adding n class="Chemical">benzyl 2-diazopropanoate (19.0 mg, 1.00 mmol, 1.00 equiv.) aclass="Chemical">nd class="Chemical">n class="Chemical">aniline (11.2 mg, 1.20 mmol, 1.20 equiv.) to a suspension of in situ generated Cu-(Rp,S)-4a catalyst. The product was obtained as a light-yellow solid (c-Hex/EtOAc = 4:1), 23.9 mg, 0.94 mmol, 94%.

R = 0.33 (class="Chemical">c-Hex/class="Chemical">n class="Chemical">EtOAc = 5:1). 1H-NMR (300 MHz, CDCl3) δ/ppm = 7.31–7.16 (m, 5H, CH2Ph), 7.15–7.02 (m, 2H, 2 × CArH), 6.73 (tt, J = 7.3, 1.1 Hz, 1H, CArH), 6.63 (dd, J = 8.6, 1.2 Hz, 2H, 2 × CArH), 5.07 (s, 2H, CH2Ph), 4.14 (q, J = 7.0 Hz, 1H, CHN), 3.98 (s, 1H, NH), 1.42 (d, J = 7.0 Hz, 3H, CHCH3).

The analytical data matches the data reported in the literature [24].

n class="Chemical">Benzyl (2-methoxyphenyl)alaninate (

GP was followed by adding n class="Chemical">benzyl 2-diazopropanoate (19.0 mg, 1.00 mmol, 1.00 equiv.) aclass="Chemical">nd class="Chemical">n class="Chemical">o-anisidine (14.8 mg, 1.20 mmol, 1.20 equiv.) to a suspension of in situ generated Cu-(Rp,S)-4a catalyst. The product was obtained via column chromatography (c-Hex/EtOAc = 5:1) as a light-yellow solid, 23.3 mg, 0.82 mmol, 82%.

class="Chemical">1H-class="Chemical">n class="Chemical">NMR (300 MHz, CDCl3) δ/ppm = 7.40–7.06 (m, 5H, CH2Ph), 6.78–6.66 (m, 2H, 2 × CArH), 6.62 (ddd, J = 8.2, 7.2, 1.6 Hz, 1H, CArH), 6.44 (dd, J = 7.6, 1.6 Hz, 1H, CArH), 5.07 (s, 2H, CH2Ph), 4.64 (s, 1H, NH), 4.12 (q, J = 7.0 Hz, 1H, CHN), 3.76 (s, 3H, OCH3), 1.44 (d, J = 6.9 Hz, 3H, CHCH3). 13C-NMR (75 MHz, CDCl3) δ/ppm = 174.5 (Cq, CO2Bn), 147.2 (Cq, CAr), 136.6 (Cq, CAr), 135.8 (Cq, CAr), 128.6 (+, CH, 2 × CAr), 128.3 (+, CH, CAr), 128.2 (+, CH, 2 × CAr), 121.3 (+, CH, CAr), 117.7 (+, CH, CAr), 110.6 (+, CH, CAr), 109.9 (+, CH, CAr), 66.8 (−, CH2, CH2Ph), 55.5(+, CH3, OCH3), 52.0(+, CH, CHN), 18.9 (+, CH3).

The analytical data matches the data reported in the literature [24].

n class="Chemical">Benzyl (3-Methoxyphenyl)alaninate (

GP was followed by adding n class="Chemical">benzyl 2-diazopropanoate (19.0 mg, 1.00 mmol, 1.00 equiv.) aclass="Chemical">nd class="Chemical">n class="Chemical">m-anisidine (14.8 mg, 1.20 mmol, 1.20 equiv.) to a suspension of in situ generated Cu-(Rp,S)-4a catalyst. The product was obtained via column chromatography (c-Hex/EtOAc = 5:1) as light-yellow solid, 15.1 mg, 53%.

class="Chemical">1H-class="Chemical">n class="Chemical">NMR (300 MHz, CDCl3) δ/ppm = 7.39–7.27 (m, 5H, CH2Ph), 7.07 (t, J = 8.1 Hz, 1H, CArH), 6.32 (dd, J = 8.2, 2.3 Hz, 1H, CArH), 6.25–6.19 (m, 1H, CArH), 6.16 (t, J = 2.3 Hz, 1H, CArH), 5.16 (s, 2H, CH2Ph), 4.19 (q, J = 6.9 Hz, 1H, CHN), 3.74 (s, 1H, NH), 1.48 (d, J = 6.9 Hz, 3H, CHCH3). 13C-NMR (75 MHz, CDCl3) δ/ppm = 174.3 (Cq, CO2Bn), 160.8 (Cq, CAr), 147.9 (Cq, CAr), 135.5 (Cq, CAr), 130.1 (+, CH, CAr), 128.5 (+, CH, 2 × CAr), 128.3 (+, CH, CAr), 128.1 (+, CH, 2 × CAr), 106.3 (+, CH, CAr), 103.7 (+, CH, CAr), 99.5 (+, CH, CAr), 66.8 (−, CH2, CH2Ph), 55.0 (+, CH3, OCH3), 52.0 (+, CH, CHN), 18.8 (+, CH3).

n class="Chemical">Benzyl (4-methoxyphenyl)alaninate (

GP was followed by adding n class="Chemical">benzyl 2-diazopropanoate (19.0 mg, 1.00 mmol, 1.00 equiv.) aclass="Chemical">nd class="Chemical">n class="Chemical">p-anisidine (14.8 mg, 1.20 mmol, 1.20 equiv.) to a suspension of in situ generated Cu-(Rp,S)-4a catalyst. The product was obtained via column chromatography (c-Hex/EtOAc = 4:1) as light-yellow solid, 20.0 mg, 70%.

class="Chemical">1H-class="Chemical">n class="Chemical">NMR (300 MHz, CDCl3) δ/ppm = 7.38–7.03 (m, 5H, CH2Ph), 6.72–6.61 (m, 2H, 2 × CArH), 6.51 (d, J = 9.0 Hz, 2H, 2 × CArH), 5.06 (s, 2H, CH2Ph), 4.04 (q, J = 6.9 Hz, 1H, CHN), 3.66 (s, 3H, CH3). 13C-NMR (75 MHz, CDCl3) δ/ppm = 175.3 (Cq, CO2Bn), 153.4 (Cq, CAr), 141.2 89 (Cq, CAr), 136.1 (Cq, CAr), 129.1 (+, CH, 2 × CAr), 128.8 (+, CH, CAr), 128.6 (+, CH, 2 × CAr), 115.7 (+, CH, 2 × CAr), 115.4 (+, CH, 2 × CAr), 67.2 (−, CH2, CH2Ph), 56.2 (+, CH3 OCH3,), 53.8 (+, CH, CHN), 19.5 (+, CH3).

The analytical data matches the data reported in the literature[25].

n class="Chemical">Benzyl o-tolylalaninate (

GP was followed by adding n class="Chemical">benzyl 2-diazopropanoate (19.0 mg, 1.00 mmol, 1.00 equiv.) aclass="Chemical">nd class="Chemical">n class="Chemical">o-toluidine (12.9 mg, 1.20 mmol, 1.20 equiv.) to a suspension of in situ generated Cu-(Rp,S)-4a catalyst. The product was obtained via column chromatography (c-Hex/EtOAc = 5:1) as colorless solid, 18.3 mg, 0.68 mmol, 68%.

class="Chemical">1H-class="Chemical">n class="Chemical">NMR (300 MHz, CDCl3) δ/ppm = 7.44–7.27 (m, 5H, CH2Ph), 7.15–7.05 (m, 2H, Ph), 6.72 (td, J = 7.4, 1.2 Hz, 1H, Ph), 6.55 (dd, J = 8.4, 1.2 Hz, 1H, Ph), 5.19 (s, 2H, CH2Ph), 4.27 (q, J = 6.9 Hz, 1H, CHCH3), 4.08 (s, 1H, NH), 2.21 (s, 3H, CH3), 1.55 (d, J = 6.9 Hz, 3H, CHCH3). 13C-NMR (75 MHz, CDCl3) δ/ppm = 174.7 (Cq, CO2Bn), 144.7 (Cq, CAr), 135.7 (Cq, CAr), 130.5 (Cq, CAr), 128.7 (+, CH, 2 × CAr), 128.4 (+, CH, CAr), 128.2 (+, CH, 2 × CAr), 127.2 (+, CH, CAr), 122.8 (+, CH, CAr), 118.0 (+, CH, CAr), 110.5 (+, CH, CAr), 66.9 (−, CH2, CH2Ph), 52.1 (+, CH, CHN), 19.2 (+, CH3), 17.5 (+, CH3).

n class="Chemical">Benzyl p-tolylalaninate (

GP was followed by adding n class="Chemical">benzyl 2-diazopropanoate (19.0 mg, 1.00 mmol, 1.00 equiv.) aclass="Chemical">nd class="Chemical">n class="Chemical">p-toluidine (12.9 mg, 1.20 mmol, 1.20 equiv.) to a suspension of in situ generated Cu-(Sp,S)/(Rp,S)-4a catalyst. The product was obtained via column chromatography (c-Hex/EtOAc = 4:1) as light-yellow solid, 18.8 mg, 0.70 mmol, 70%.

Rf = 0.31 (class="Chemical">c-Hex/class="Chemical">n class="Chemical">EtOAc = 5:1). 1H-NMR (300 MHz, CDCl3) δ/ppm = 7.34–7.14 (m, 5H, CH2Ph), 6.89 (d, J=8.1 Hz, 2H, 2 × CArH), 6.45 (d, J = 8.4 Hz, 2H, 2 × CArH), 5.06 (s, 2H, CH2Ph), 4.09 (q, J = 7.0 Hz, 1H, CHN), 3.93 (s, 1H, NH), 2.16 (s, 3H, CH3), 1.39 (d, J = 6.9 Hz, 3H, CHCH3). 13C-NMR (75 MHz, CDCl3) δ/ppm = 174.7 (Cq, CO2Bn), 144.4 (Cq, CAr), 135.7 (Cq, CAr), 129.9 (Cq, CAr), 128.6 (+, CH, 2 × CArH), 128.4 (+, CH, CArH), 128.2 (+, CH, 2 × CArH), 127.8 (+, CH, CArH), 113.9 (+, CH, CArH), 66.8 (−, CH2, CH2Ph), 52.6 (+, CH, CHN), 20.5 (+, CH3), 19.0 (+, CH3).

n class="Chemical">Phenyl phenylalaninate (

GP was followed by adding n class="Chemical">methyl 2-diazo-2-phenylacetate (17.6 mg, 1.00 mmol, 1.00 equiv.) aclass="Chemical">nd class="Chemical">n class="Chemical">aniline (11.2 mg, 1.20 mmol, 1.20 equiv.) to a suspension of in situ generated Cu-(Rp,S)-4a catalyst. The product was obtained via column chromatography (c-Hex/EtOAc = 5:1) as light-yellow liquid, 16.3 mg, 0.68 mmol, 68%.

class="Chemical">1H-class="Chemical">n class="Chemical">NMR (300 MHz, CDCl3) δ/ppm = 7.29 (td, J = 7.4, 6.8, 1.3 Hz, 2H, 2 × CArH), 7.20–7.03 (m, 3H, 3 × CArH), 6.98–6.87 (m, 2H, 2 × CArH), 6.72 (tt, J = 7.3, 1.1 Hz, 1H, CArH), 6.64 (dt, J = 7.7, 1.1 Hz, 2H, 2 × CArH), 4.32 (q, J = 7.0 Hz, 1H, CHN), 4.12 (s, 1H, NH), 1.58 (d, J = 6.9 Hz, 3H, CHCH3).

n class="Chemical">tert-Butyl phenylalaninate (

GP was followed by adding n class="Chemical">tert-Butyl 2-diazopropanoate (15.6 mg, 1.00 mmol, 1.00 equiv.) aclass="Chemical">nd class="Chemical">n class="Chemical">aniline (11.2 mg, 1.20 mmol, 1.20 equiv.) to a suspension of in situ generated Cu-(R)-4a catalyst. The product was obtained via flash chromatography (c-Hex/EtOAc = 8:1) as a light-yellow liquid, 16.4 mg, 0.74 mmol, 74%.

class="Chemical">1H-class="Chemical">n class="Chemical">NMR (300 MHz, CDCl3) δ/ppm = 7.21–7.11 (m, 3H, CArH), 6.73 (t, J = 7.3 Hz, 1H, CArH), 6.61 (d, J = 7.7 Hz, 2H, CArH), 4.02 (q, J = 6.9 Hz, 1H, CHN), 1.44 (s, 9H, C(CH3)3), 1.43 (d, J = 6.9 Hz, 3H). – 13C-NMR (75 MHz, CDCl3) δ/ppm = 174.3 (Cq, CO2tBu), 147.3 (Cq, CAr), 129.8 (+, CH, 2 × CAr), 118.6 (+, CH, CAr), 114.0 (+, CH, 2 × CAr), 82.0 (Cq, C(CH3)3), 53.1 (+, CH, CHNH), 28.5 (+, CH3, 3 × CH3), 19.4 (+, CH3, CHCH3).

The analytical data matches the data reported in the literature [26].

n class="Chemical">Methyl 2-phenyl-2-(phenylamino)acetate (

GP was followed by adding n class="Chemical">phenyl-2-diazopropionate (17.6 mg, 1.00 mmol,1.00 equiv.) aclass="Chemical">nd class="Chemical">n class="Chemical">aniline (11.2 mg, 1.20 mmol, 1.20 equiv.) to a suspension of in situ generated Cu-(R)-4a catalyst. The product 7b was obtained via flash chromatography (c-Hex/EtOAc = 5:1) as colorless solid, 23.6 mg, 0.98 mmol, 98%.

class="Chemical">1H-class="Chemical">n class="Chemical">NMR (300 MHz, CDCl3) δ/ppm = 7.42 (d, J = 7.7 Hz, 2H, 2 × CArH), 7.27 (qd, J = 7.5, 6.4, 2.6 Hz, 3H, 3 × CArH), 7.04 (t, J = 7.9 Hz, 2H, 2 × CArH), 6.62 (t, J = 7.3 Hz, 1H, CArH), 6.48 (d, J = 7.7 Hz, 2H, 2 × CArH), 5.01 (d, J = 5.9 Hz, 1H, CHN), 4.88 (s, 1H, NH), 3.65 (s, 3H, OCH3).

The analytical data matches the data reported in the literature [23].

4. Conclusions

The successful n class="Chemical">N–H iclass="Chemical">nsertioclass="Chemical">n of α-class="Chemical">n class="Chemical">diazocarbonyls into anilines by copper catalysis with PCPBOX ligands have been demonstrated. In this work, we showed the synthesis and catalytic application of three different PCPBOX ligands. Their straight-forward synthesis renders them a very accessible ligand system. The N–H insertion into saturated anilines was demonstrated to afford moderate to excellent yields with a wide substrate scope. The more sterically demanding PCPBOX ligands showed very good yields in the N–H insertion with unsaturated anilines.