Urea Insertion Reaction of Rhodium-Carbenoid

Abstract

We developed the first carbenoid insertion reaction into the urea C−N bond. The urea insertion reaction proceeded smoothly using Rh₂(NHPiv)₄, a rhodium catalyst previously designed by our group, to construct a diazabicyclic system. Highly functionalized bridged molecules with three adjacent stereocenters were diastereoselectively synthesized via the urea insertion reaction followed by hydride reduction or nucleophilic addition sequences in one-pot.

Activation of kinetically inert and/or thermodynamically stable chemical bonds is a powerful method for enhancing synthetic efficiency. The straightforward strategies are attracting the increasing interest of organic chemists.^1–4) Molecular transformation using highly active metal carbenoids is a classical and highly versatile strategy for direct functionalization of various chemical bonds, and could be applied to natural product syntheses.^5–11) The development of novel metal carbenoid reactions, therefore, is an attractive topic in the synthetic community.^12–16)

Ylide chemistry of metal carbenoids, which is initiated by nucleophilic attack of a certain heteroatom on the carbenoid carbon center, enables synthetically valuable transformations in addition to the usual reactivity of the metal carbenoid, such as insertion reactions into a C−H bond^17–19) and multiple bonds.²⁰⁾ Ylide intermediates and their equivalents have been utilized for heteroatom−hydrogen bond (X−H) insertions,^21–23) Stevens rearrangements,^24,25) and sigmatropic rearrangements.²⁶⁾ Metal carbenoids can also form N-ylide species with a less nucleophilic amide nitrogen,²⁷⁾ and O-ylide with an amide group contributes to cycloaddition reactions as a 1,3-dipole to construct complex molecular frameworks.^28,29)

As part of our ongoing studies, we developed amide insertion reactions of metal carbenoids that proceed via the initial formation of a rhodium-associated N-ylide intermediate with an amide nitrogen followed by N→C acyl group transfer^30–32) (Chart 1(a)). In the amide insertion reaction, the amide group is activated by ylide formation with an electron-deficient metal carbenoid and hydrogen-bond network^33,34) between the substrate and catalyst so that the C−N bond is cleaved under mild conditions,³⁰⁾ although amide linkage is inherently robust and its transformation requires harsh conditions.^35,36) As a strategy to activate the amide functionality is established, we focused on further analogous methodologic developments. Urea groups are more inert to various oxidative and reductive conditions than the corresponding amides. Indeed, to the best of our knowledge, a carbenoid insertion reaction into a urea linkage has not yet been reported.

Chart 1. Amide and Urea Insertions

In this study, we designed an intramolecular insertion reaction into cyclic urea to construct the 3,6-diazabicyclo[3.2.1]octane framework (Chart 1(b)). The bicyclic architecture containing two nitrogen atoms is found in a core structure of biologically-related compounds.³⁷⁾ The pharmaceutical activities of their derivatives, including different systems of diazabicyclic frameworks, have not been sufficiently explored.³⁸⁾ This background led us to develop the urea insertion reaction to build up bridged azacycles. Herein we report an intramolecular insertion reaction of Rh-carbenoid into a urea linkage. One-pot transformations of the resulting products are also described.

Results and Discussion

We started our research using symmetric urea derivative 1a as a model substrate to optimize the reaction conditions toward the development of the urea insertion reaction (Table 1). On the basis of our previous findings, we first examined the conditions using dioxane/dichloromethane mixed solvent and 1 mol% Rh₂(NHPiv)₄, which exhibited the best performance for the amide insertion reaction, furnishing urea insertion product 2a in 95% NMR yield (entry 1).³⁹⁾ The isolated yield of 2a decreased to 67%, however, due to its instability against silica gel and moisture. Thus, we assessed the catalyst activity by comparing the NMR yield of 2a. Widely used rhodium catalysts, such as Rh₂(OAc)₄, Rh₂(NHCOCF₃)₄, and Rh₂(esp)₂,^40,41) also afforded good results (82–91% yields, entries 2–4), but these catalysts could not improve the yield. We therefore determined that Rh₂(NHPiv)₄ was the optimal catalyst for the urea insertion reaction.⁴²⁾

Table 1. Optimization of the Reaction Conditions

Entry	Urea insertion step	Reduction step				Yield (%) [dr]
	Rh catalyst	Reducing reagent (eq)	Solvent	Temp. (°C)	Time (h)
1	Rh2(NHPiv)4	—	—	—	—	2a: 95a)
2	Rh2(OAc)4	—	—	—	—	2a: 91a)
3	Rh2(NHCOCF3)4	—	—	—	—	2a: 82a)
4	Rh2(esp)2	—	—	—	—	2a: 82a)
5	Rh2(NHPiv)4	NaBH4 (1.5)	CH3CN	−40	16	3a: 85b) [89 : 11]
6	Rh2(NHPiv)4	NaBH(OAc)3 (6)	CH3CN	0	3	3a: 71b) [60 : 40]
7	Rh2(NHPiv)4	NaBH(OAc)3 (3)	THF	−78	3	3a: 50b) [94 : 6]
8	Rh2(NHPiv)4	DIBALH (2)	THF	−78	16	3a: 22b) [93 : 7]
9	Rh2(NHPiv)4	Red-Al (3)	THF	−78	3	3a: 0%b)
10	Rh2(NHPiv)4	LiAlH(OtBu)3 (3)	THF	−78	3	3a: 96b) [>95 : 5]

a) Determined by ¹H-NMR analysis of the crude mixture. b) Isolated yield. dr=diastereomeric ratio.

The instability of bridged bicyclic molecule 2a during column chromatography forced us to explore a sequential conversion into an isolable compound. A one-pot reduction using NaBH₄ in acetonitrile was performed as a following transformation after evaporation of the solvents used in the urea insertion reaction, diastereoselectively providing secondary alcohol 3a (89 : 11 dr, 85% yield, 2 steps, entry 5).⁴³⁾ After investigating the temperature effect and screening some reducing reagents and solvents (entries 6–10), we found that the use of LiAlH(O^tBu)₃ in tetrahydrofuran (THF) at −78°C afforded bicyclic alcohol 3a as an almost single diastereomer in 96% yield (>95 : 5 dr, entry 10).

Having identified the optimal conditions of the two-step conversion comprising the urea insertion followed by diastereoselective reduction, we next examined the scope of applicable substrates (Table 2). A substrate with quaternary carbon center adjacent to the diazocarbonyl group was usable in this protocol, affording 3b as a single diastereomer in 75% yield. Bicyclic system 3c possessing a substituent at the ortho position on arenes was also accessible from the corresponding urea derivative 1c. Substrates with an electron-donating group (1d) and an electron-withdrawing group (1e) on the benzene ring were transformed into diazabicyclic molecules 3d and 3e with excellent diastereoselectivity in 97% yield and quantitative yield, respectively. The urea having butyl substituents (1f) was also effective in this reaction.

Table 2. Substrate Scope of Urea Insertion-Hydride Reduction Sequence

a) Yield over 2 steps.

In addition, we investigated C−C bond formations instead of hydride reduction for the efficient construction of functionalized molecules in one pot (Table 3). The reaction with methyl magnesium bromide (3 eq) in THF (0.05 M) at −78°C after the urea insertion of 1a furnished 4a possessing a quaternary carbon center as a single diastereomer in 77% yield (2 steps). Vinyl magnesium bromide could be utilized to construct a new C(sp³)−C(sp²) bond, providing 4c in a stereoselective manner, although the product yield was low (>95 : 5 dr, 37% yield). Homoallylic alcohol 4d was obtained in the reaction with 1c and allyl magnesium bromide in moderate yield with excellent diastereoselectivity.

Table 3. Substrate Scope of Urea Insertion-Nucleophilic Addition Sequence

a) Yield over 2 steps.

In conclusion, we developed a urea insertion reaction of rhodium (Rh)-carbenoid followed by a hydride reduction or additional C−C bond-forming reaction sequence. Diazabicyclic frameworks with three adjacent stereocenters were diastereoselectively constructed in a tandem reaction. Further studies using metal carbenoid species are underway in our laboratory.

Experimental

General Information

NMR spectra were recorded on a JEOL ecs 400 spectrometer. Chemical shifts in CDCl₃, were reported downfield from tetramethylsilane (TMS) (=0 ppm) for ¹H-NMR. Data are reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, and br=broad), integration and coupling constants in Hz. For ¹³C-NMR, chemical shifts were reported in the scale relative to the solvent signal [CHCl₃ (77.0 ppm)] as an internal reference. Electrospray ionization (ESI)-MS were measured on JEOL AccuTOF LC-plus JMS-T100LP. IR spectra were recorded on a JASCO FT/IR 230 Fourier transform IR spectrophotometer, equipped with attenuated total reflectance (ATR) (Smiths Detection, DuraSample IR II). Melting points were measured with a SIBATA NEL-270 melting point apparatus. Analytical TLC was performed on Kieselgel 60F254, 0.25 mm thickness plates. Column chromatography was performed with silica gel 60 N (spherical, neutral 63–210 mesh). Reactions were conducted in dry solvent. Other reagents were purified by the usual methods.

Synthesis and Characterization of Diazabicyclic Compounds 3a–3f, 4a–4d

General Procedure A for the Urea Insertion-Hydride Reduction Sequence

To a stirred solution of Rh₂(NHPiv)₄ (1.2 mg, 1 mol%) in dioxane (5 mL) and CH₂Cl₂ (3 mL) was added diazocarbonyl compound 1 (0.2 mmol) in CH₂Cl₂ (2 mL) at 40°C over 1 min. After being stirred for 30 min, the reaction mixture was concentrated under reduced pressure. To a stirred solution of crude residue in THF (2 mL) was added LiAlH(O^tBu)₃ (1 M in THF) (0.6 mL) at −78°C. After being stirred for 3 h at the same temperature, the reaction was quenched with 2 M aqueous Rochelle salt solution and the mixture was extracted with AcOEt, washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (n-hexane/AcOEt, 1/4) to afford bicyclic alcohol 3.

rac-(1R,5R,8S)-3,6-Dibenzyl-8-hydroxy-3,6-diazabicyclo[3.2.1]octan-4-one (3a)

Prepared according to the general procedure A and isolated as white powder (62 mg, 96%, 2 steps): mp 142–144°C; Rf=0.3 (AcOEt); ¹H-NMR (400 MHz, CDCl₃) δ: 2.27 (d, J=10.0 Hz, 1H), 2.47 (m, 1H), 2.92 (dd, J=11.2, 1.6 Hz, 1H), 3.24 (dd, J=10.0, 6.4 Hz, 1H), 3.48–3.52 (m, 2H), 3.60 (dd, J=11.6, 2.0 Hz, 1H), 4.02 (d, J=13.2 Hz, 1H), 4.42 (d, J=14.8 Hz, 1H), 4.55 (dd, J=5.2, 4.4 Hz, 1H), 4.87 (d, J=14.8 Hz, 1H), 7.21–7.41 (m, 10H); ¹³C-NMR (100 MHz, CDCl₃) δ: 36.9, 49.2, 50.1, 55.5, 57.0, 67.9, 70.5, 127.0, 127.4, 128.2, 128.3, 128.56, 128.58, 137.1, 138.6, 169.7; IR (ATR)γ 3338, 2916, 1628, 1494, 1452, 1359, 1249, 1180, 1133, 1071 cm⁻¹; high resolution (HR)-MS (ESI-time-of-flight (TOF)) [M+Na]⁺ Calcd for C₂₀H₂₂N₂NaO₂⁺ m/z 345.1573, Found m/z 345.1578.

rac-(1R,5R,8S)-3,6-Dibenzyl-8-hydroxy-1-methyl-3,6-diazabicyclo[3.2.1]octan-4-one (3b)

Prepared according to the general procedure A and isolated as white powder (55.9 mg, 75%, 2 steps (0.22 mmol scale)): mp 132–134°C; Rf=0.3 (n-hexane/AcOEt, 1/4); ¹H-NMR (400 MHz, CDCl₃) δ: 1.04 (s, 3H), 2.37 (d, J=10.0 Hz, 1H), 2.74 (d, J=10.8 Hz, 1H), 2.91 (dd, J=10.0, 2.0 Hz, 1H), 3.34 (dd, J=10.8, 2.0 Hz, 1H), 3.46 (d, J=13.2 Hz, 1H), 3.56 (d, J=4.8 Hz, 1H), 4.01 (d, J=13.2 Hz, 1H), 4.19 (d, J=4.8 Hz, 1H), 4.36 (d, J=14.8 Hz, 1H), 4.88 (d, J=14.8 Hz, 1H), 7.20–7.40 (m, 10H); ¹³C-NMR (100 MHz, CDCl₃) δ: 19.2, 40.9, 49.2, 55.9, 57.0, 61.9, 69.1, 74.6, 127.0, 127.4, 128.1, 128.2, 128.5, 128.6, 137.0, 138.6, 170.1; IR (ATR)γ 3348, 2907, 1633, 1495, 1453, 1360, 1256, 1206, 1129, 1092 cm⁻¹; HR-MS (ESI-TOF) [M+Na]⁺ Calcd for C₂₁H₂₄N₂NaO₂⁺ m/z 359.1730, Found m/z 359.1741.

rac-(1R,5R,8S)-8-Hydroxy-3,6-bis(2-methylbenzyl)-3,6-diazabicyclo[3.2.1]octan-4-one (3c)

Prepared according to the general procedure A and isolated as pale yellow powder (58.8 mg, 82%, 2 steps (0.21 mmol scale)): mp 38–40°C; Rf=0.4 (n-hexane/AcOEt, 1/4); ¹H-NMR (400 MHz, CDCl₃) δ: 2.32 (s, 3H), 2.36 (s, 3H), 2.37 (d, J=11.6 Hz, 1H), 2.48 (m, 1H), 2.87 (dd, J=11.6, 1.6 Hz, 1H), 3.25 (dd, J=10.0, 6.4 Hz, 1H), 3.49 (dd, J=4.0 Hz, 1H), 3.54–3.59 (m, 2H), 3.99 (d, J=13.6 Hz, 1H), 4.45 (d, J=15.2 Hz, 1H), 4.54 (dd, J=5.2, 4.8 Hz, 1H), 4.89 (d, J=15.2 Hz, 1H), 7.12–7.36 (m, 8H); ¹³C-NMR (100 MHz, CDCl₃) δ: 19.1, 19.3, 37.0, 47.0, 50.1, 55.0, 55.6, 67.9, 70.5, 125.6, 126.0, 127.0, 127.4, 128.3, 129.0, 130.1, 130.4, 134.4, 136.49, 136.51, 137.1, 170.0; IR (ATR)γ 3355, 2914, 1630, 1491, 1459, 1358, 1298, 1176, 1133, 1050 cm⁻¹; HR-MS (ESI-TOF) [M+Na]⁺ Calcd for C₂₂H₂₆N₂NaO₂⁺ m/z 373.1886, Found m/z 373.1892.

rac-(1R,5R,8S)-8-Hydroxy-3,6-bis(4-methoxybenzyl)-3,6-diazabicyclo[3.2.1]octan-4-one (3d)

Prepared according to the general procedure A and isolated as pale yellow powder (74.4 mg, 97%, 2 steps): mp 121–123°C; Rf=0.2 (AcOEt); ¹H-NMR (400 MHz, CDCl₃) δ: 2.20 (d, J=10.0 Hz, 1H), 2.43 (m, 1H), 2.88 (dd, J=10.8, 0.4 Hz, 1H), 3.18 (dd, J=10.0, 6.4 Hz, 1H), 3.40 (d, J=13.2 Hz, 1H), 3.46 (d, J=4.8 Hz, 1H), 3.57 (dd, J=12.0, 2.4 Hz, 1H), 3.77 (s, 3H), 3.78 (s, 3H), 3.92 (d, J=13.2 Hz, 1H), 4.28 (d, J=14.0 Hz, 1H), 4.49 (dd, J=4.8, 4.8 Hz, 1H), 4.83 (d, J=14.0 Hz, 1H), 6.83 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 7.21 (d, J=8.8 Hz, 2H), 7.28 (d, J=8.8 Hz, 2H); ¹³C-NMR (100 MHz, CDCl₃) δ: 36.8, 48.5, 49.9, 55.18, 55.19, 55.3, 56.3, 67.8, 70.2, 113.5, 113.9, 129.1, 129.5, 129.7, 130.6, 158.5, 158.9, 169.9; IR (ATR)γ 3340, 2909, 1628, 1510, 1441, 1358, 1301, 1242, 1174, 1132 cm⁻¹; HR-MS (ESI-TOF) [M+Na]⁺ Calcd for C₂₂H₂₆N₂NaO₆⁺ m/z 405.1785, Found m/z 405.1789.

rac-(1R,5R,8S)-3,6-Bis(4-chlorobenzyl)-8-hydroxy-3,6-diazabicyclo[3.2.1]octan-4-one (3e)

Prepared according to the general procedure A and isolated as white powder (78.2 mg, quant., 2 steps): mp 128–130°C; Rf=0.4 (AcOEt); ¹H-NMR (400 MHz, CDCl₃) δ: 2.25 (d, J=10.0 Hz, 1H), 2.47 (m, 1H), 2.90 (dd, J=11.2, 2.0 Hz, 1H), 3.25 (dd, J=10.0, 6.0 Hz, 1H), 3.38 (d, J=4.0 Hz, 1H), 3.43 (d, J=13.6 Hz, 1H), 3.61 (dd, J=11.2, 1.6 Hz, 1H), 3.89 (d, J=13.6 Hz, 1H), 4.45–4.50 (m, 2H), 4.64 (d, J=15.2 Hz, 1H), 7.19–7.30 (m, 8H); ¹³C-NMR (100 MHz, CDCl₃) δ: 36.9, 48.8, 50.4, 55.6, 56.4, 67.5, 70.2, 128.4, 128.7, 129.4, 129.8, 132.7, 133.2, 135.4, 136.9, 170.0; IR (ATR)γ 3319, 2918, 1629, 1408, 1356, 1181, 1089, 1014, 907, 797 cm⁻¹; HR-MS (ESI-TOF) [M+Na]⁺ Calcd for C₂₀H₂₀Cl₂N₂NaO₂⁺ m/z 413.0794, Found m/z 413.0798.

rac-(1R,5R,8S)-3,6-Dibutyl-8-hydroxy-3,6-diazabicyclo[3.2.1]octan-4-one (3f)

Prepared according to the general procedure A and isolated as yellow oil (39.4 mg, 77%, 2 steps): Rf=0.5 (AcOEt/MeOH, 10/1); ¹H-NMR (400 MHz, CDCl₃) δ: 0.88 (t, J=6.8 Hz, 3H), 0.93 (t, J=6.8 Hz, 3H), 1.22-1.59 (m, 8H), 2.28–2.36 (m, 2H), 2.50 (m, 1H), 2.61 (dd, J=11.6, 9.6 Hz, 1H), 2.96 (dd, J=10.8, 2.0 Hz, 1H), 3.18–3.27 (m, 1H), 3.30 (d, J=8.4 Hz, 1H), 3.38–3.48 (m, 2H), 3.67 (dd, J=10.8, 2.0 Hz, 1H), 4.45 (dd, J=5.2, 4.4 Hz, 1H); ¹³C-NMR (100 MHz, CDCl₃) δ13.8, 13.9, 20.0, 20.3, 29.1, 30.3, 36.7, 45.6, 50.7, 52.8, 56.0, 67.3, 70.0, 169.5; IR (ATR)γ 3348, 2929, 1628, 1493, 1458, 1355, 1304, 1244, 1188, 1137 cm⁻¹; HR-MS (ESI-TOF) [M+H]⁺ Calcd for C₁₄H₂₇N₂O₂⁺ m/z 255.2067, Found m/z 255.2073.

General Procedure B for Urea Insertion-Nucleophilic Addition Sequence

To a stirred solution of Rh₂(NHPiv)₄ (1.2 mg, 1 mol%) in dioxane (5 mL) and CH₂Cl₂ (3 mL) was added diazocarbonyl compound 1 (0.2 mmol) in CH₂Cl₂ (2 mL) at 40°C over 1 min. After being stirred for 30 min, the reaction mixture was concentrated under reduced pressure. To a stirred solution of crude residue in THF (4 mL) was added RMgBr (3 M in Et₂O, R=Me, 0.2 mL), (1 M in THF, R=Vinyl, 0.6 mL), (1 M in Et₂O, R=Allyl, 0.6 mL) at −78°C. After being stirred for 3 h at the same temperature, the reaction was quenched with saturated aqueous solution of NaHCO₃ and the mixture was extracted with AcOEt, washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (n-hexane/AcOEt, 1/1) to afford 4.

rac-(1R,5R,8S)-3,6-Dibenzyl-8-hydroxy-8-methyl-3,6-diazabicyclo[3.2.1]octan-4-one (4a)

Prepared according to the general procedure B and isolated as white powder (52.0 mg, 77%, 2 steps): mp 135−136°C; Rf=0.4 (n-hexane/AcOEt, 1/4); ¹H-NMR (400 MHz, CDCl₃) δ: 1.49 (s, 3H), 2.08–2.16 (m, 2H), 2.89 (d, J=10.0 Hz, 1H), 3.16 (dd, J=10.0, 6.4 Hz, 1H), 3.19 (s, 1H), 3.48 (d, J=13.6 Hz, 1H), 3.66 (d, J=10.0 Hz, 1H), 4.07 (d, J=13.6 Hz, 1H), 4.50 (d, J=15.2 Hz, 1H), 4.79 (d, J=15.2 Hz, 1H), 4.81 (s, 1H), 7.20–7.44 (m, 10H); ¹³C-NMR (100 MHz, CDCl₃) δ: 24.9, 41.8, 49.2, 52.0, 55.3, 56.5, 72.4, 74.8, 126.8, 127.2, 127.9, 128.1, 128.2, 128,5, 137.1, 139.0, 171.8; IR (ATR)γ 3312, 2931, 1631, 1494, 1452, 1371, 1266, 1216, 1028, 943 cm⁻¹; HR-MS (ESI-TOF) [M+Na]⁺ Calcd for C₂₁H₂₄N₂NaO₂⁺ m/z 359.1730, Found m/z 359.1721.

rac-(1R,5R,8S)-8-Hydroxy-8-methyl-3,6-bis(2-methylbenzyl)-3,6-diazabicyclo[3.2.1]octan-4-one (4b)

Prepared according to the general procedure B and isolated as white powder (51.5 mg, 71%, 2 steps): mp 152–153°C; Rf=0.4 (n-hexane/AcOEt, 1/2); ¹H-NMR (400 MHz, CDCl₃) δ: 1.47 (s, 3H), 2.11 (m, 1H), 2.25 (d, J=10.0 Hz, 1H), 2.32 (s, 3H), 2.34 (s, 3H), 2.84 (d, J=10.8 Hz, 1H), 3.14 (dd, J=10.0, 6.0 Hz, 1H), 3.18 (s, 1H), 3.54 (d, J=14.0 Hz, 1H), 3.59 (d, J=10.8 Hz, 1H), 3.99 (d, J=14.0 Hz, 1H), 4.56 (d, J=15.2 Hz, 1H), 4.68 (s, 1H), 4.77 (d, J=15.2 Hz, 1H), 7.08–7.40 (m, 8H); ¹³C-NMR (100 MHz, CDCl₃) δ: 19.0, 19.3, 25.0, 41.9, 47.1, 52.0, 54.6, 55.3, 72.3, 74.9, 125.5, 126.0, 126.9, 127.2, 128.1, 128.9, 130.1, 130.3, 134.5, 136.3, 136.8, 137.1, 171.9; IR (ATR)γ 3334, 2930, 1629, 1491, 1459, 1370, 1283, 1215, 1185, 1132 cm⁻¹; HR-MS (ESI-TOF) [M+Na]⁺ Calcd for C₂₃H₂₈N₂NaO₂⁺ m/z 387.2043, Found m/z 387.2038.

rac-(1R,5R,8S)-8-Hydroxy-3,6-bis(2-methylbenzyl)-8-vinyl-3,6-diazabicyclo[3.2.1]octan-4-one (4c)

Prepared according to the general procedure B and isolated as white powder (27.7 mg, 37%, 2 steps): mp 148–150°C; Rf=0.3 (n-hexane/AcOEt, 1/1); ¹H-NMR (400 MHz, CDCl₃) δ: 2.28 (m, 1H), 2.31 (s, 3H), 2.32 (d, J=10.0 Hz, 1H), 2.37 (s, 3H), 2.91 (d, J=11.2 Hz, 1H), 3.14 (dd, J=10.0, 6.4 Hz, 1H), 3.32–3.37 (m, 2H), 3.54–3.59 (m, 2H), 4.01 (d, J=13.6 Hz, 1H), 4.48 (d, J=15.2 Hz, 1H), 4.86 (d, J=15.2 Hz, 1H), 5.23 (d, J=10.8 Hz, 1H), 5.51 (d, J=17.2 Hz, 1H), 6.32 (dd, J=17.2, 10.8 Hz, 1H), 7.11–7.40 (m, 8H); ¹³C-NMR (100 MHz, CDCl₃) δ: 19.1, 19.4, 41.3, 46.9, 51.5, 54.5, 55.1, 71.5, 76.9, 114.4, 125.5, 126.0, 127.0, 127.4, 128.5, 129.1, 130.1, 130.4, 134.5, 136.5, 136.6, 137.2, 140.6, 170.1; IR (ATR)γ 3330, 2918, 1633, 1491, 1453, 1360, 1282, 1220, 1049, 987 cm⁻¹; HR-MS (ESI-TOF) [M+Na]⁺ Calcd for C₂₄H₂₈N₂NaO₂⁺ m/z 399.2043, Found m/z 399.2025.

rac-(1R,5R,8S)-8-Allyl-8-hydroxy-3,6-bis(2-methylbenzyl)-3,6-diazabicyclo[3.2.1]octan-4-one (4d)

Prepared according to the general procedure B and isolated as white powder (46.2 mg, 59%, 2 steps): mp 125–127°C; Rf=0.4 (n-hexane/AcOEt, 1/1); ¹H-NMR (400 MHz, CDCl₃) δ: 2.20 (m, 1H), 2.28 (d, J=10.0 Hz, 1H), 2.33 (s, 3H), 2.36 (s, 3H), 2.45 (dd, J=14.0, 8.0 Hz, 1H), 2.63 (dd, J=14.0, 7.2 Hz, 1H), 2.86 (dd, J=11.2, 2.0 Hz, 1H), 3.12 (dd, J=10.0, 7.6 Hz, 1H), 3.26 (s, 1H), 3.51–3.56 (m, 2H), 3.60 (s, 1H), 4.02 (d, J=13.6 Hz, 1H), 4.54 (d, J=14.8 Hz, 1H), 4.80 (d, J=14.8 Hz, 1H), 5.13–5.21 (m, 2H), 5.93 (m, 1H), 7.11–7.40 (m, 8H); ¹³C-NMR (100 MHz, CDCl₃) δ: 19.0, 19.4, 39.8, 41.2, 47.0, 51.7, 54.4, 54.9, 70.6, 76.5, 120.0, 125.5, 126.0, 127.0, 127.3, 128.3, 129.1, 130.1, 130.3, 132.8, 134.5, 136.4, 136.6, 137.2, 170.1; IR (ATR)γ 3360, 2907, 1630, 1491, 1459, 1358, 1332, 1246, 1193, 1169 cm⁻¹; HR-MS (ESI-TOF) [M+Na]⁺ Calcd for C₂₅H₃₀N₂NaO₂⁺ m/z 413.2199, Found m/z 413.2179.

Synthesis and Characterization of Substrates

General Procedure C for the Synthesis of Cyclic Urea Compounds

To a stirred solution of ethyl 2-(bromomethyl)acrylate in CH₃CN (0.2 M) was added ArCH₂NH₂ (3 eq) at room temperature (r.t.). After being stirred for 12 h, the reaction was quenched with saturated aqueous solution of NaHCO₃ and the mixture was extracted with AcOEt, washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. To a stirred solution of crude residue in THF (0.5 M) was added CDI (0.5 eq) at r.t. After being stirred for 12 h, the reaction was concentrated under reduced pressure. Aqueous solution of HCl (1 N) was added and the mixture was extracted with AcOEt, washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (n-hexane/AcOEt, 1/1) to afford the corresponding cyclic urea compound.

Ethyl 1,3-Dibenzyl-2-oxohexahydropyrimidine-5-carboxylate (s1a)

Prepared according to the general procedure C and isolated as a yellow oil (37%, 2 steps): Rf=0.4 (n-hexane/AcOEt, 1/1); ¹H-NMR (400 MHz, CDCl₃) δ: 1.15 (t, J=6.8 Hz, 3H), 2.92 (dddd, J=8.4, 8.4, 4.8, 4.8 Hz, 1H), 3.37 (dd, J=12.0, 4.8 Hz, 2H), 3.44 (dd, J=12.0, 8.4 Hz, 2H), 4.05 (q, J=6.8 Hz, 2H), 4.57 (d, J=14.8 Hz, 2H), 4.68 (d, J=14.8 Hz, 2H), 7.24–7.37 (m, 10H); ¹³C-NMR (100 MHz, CDCl₃) δ: 13.8, 37.9, 46.3, 51.5, 61.1, 127.1, 127.8, 128.4, 137.9, 155.6, 170.3; IR (ATR)γ 2905, 1731, 1632, 1498, 1446, 1357, 1254, 1200, 1133, 1077 cm⁻¹; HR-MS (ESI-TOF) [M+Na]⁺ Calcd for C₂₁H₂₄N₂NaO₃⁺ m/z 375.1679, Found m/z 375.1668.

Ethyl 1,3-Bis(2-methylbenzyl)-2-oxohexahydropyrimidine-5-carboxylate (s1c)

Prepared according to the general procedure C and isolated as white powder (19%, 2 steps): mp 88–90°C; Rf=0.5 (n-hexane/AcOEt, 1/1); ¹H-NMR (400 MHz, CDCl₃) δ: 1.14 (t, J=6.8 Hz, 3H), 2.33 (s, 6H), 2.91 (dddd, J=7.6, 7.6, 4.4, 4.4 Hz, 1H), 3.34 (dd, J=12.0, 4.4 Hz, 2H), 3.41 (dd, J=12.0, 7.6 Hz, 2H), 4.02 (q, J=6.8 Hz, 2H), 4.61 (d, J=15.2 Hz, 2H), 4.72 (d, J=15.2 Hz, 2H), 7.12–7.23 (m, 8H); ¹³C-NMR (100 MHz, CDCl₃) δ: 13.9, 19.0, 38.0, 46.1, 49.4, 61.1, 125.8, 127.2, 128.1, 130.4, 135.4, 136.6, 155.3, 170.5; IR (ATR)γ 2867, 1732, 1633, 1500, 1441, 1354, 1253, 1197, 1073, 1051 cm⁻¹; HR-MS (ESI-TOF) [M+Na]⁺ Calcd for C₂₃H₂₈N₂NaO₃⁺ m/z 403.1992, Found m/z 403.1991.

Ethyl 1,3-Bis(4-methoxybenzyl)-2-oxohexahydropyrimidine-5-carboxylate (s1d)

Prepared according to the general procedure C and isolated as a yellow oil (20%, 2 steps): Rf=0.3 (n-hexane/AcOEt, 1/1); ¹H-NMR (400 MHz, CDCl₃) δ: 1.15 (t, J=7.2 Hz, 3H), 2.88 (dddd, J=7.6, 7.6, 4.8, 4.8 Hz, 1H), 3.33 (dd, J=12.0, 4.8 Hz, 2H), 3.39 (dd, J=11.6, 7.6 Hz, 2H), 3.79 (s, 6H), 4.04 (q, J=6.8 Hz, 2H), 4.49 (d, J=15.2 Hz, 2H), 4.59 (d, J=15.2 Hz, 2H), 6.86 (d, J=8.4 Hz, 4H), 7.24 (d, J=8.4 Hz, 4H); ¹³C-NMR (100 MHz, CDCl₃) δ: 13.9, 38.0, 46.2, 50.9, 55.1, 61.1, 113.8, 129.2, 130.1, 155.6, 158.7, 170.5; IR (ATR)γ 2905, 1731, 1632, 1611, 1507, 1444, 1355, 1240, 1172, 1133 cm⁻¹; HR-MS (ESI-TOF) [M+Na]⁺ Calcd for C₂₃H₂₈N₂NaO₅⁺ m/z 435.1890, Found m/z 435.1891.

Ethyl 1,3-Bis(4-chlorobenzyl)-2-oxohexahydropyrimidine-5-carboxylate (s1e)

Prepared according to the general procedure C (the second step was carried out at 100°C) and isolated as white powder (14%, 2 steps): mp 97–99°C; Rf=0.4 (n-hexane/AcOEt, 1/1); ¹H-NMR (400 MHz, CDCl₃) δ: 1.16 (t, J=6.8 Hz, 3H), 2.91 (dddd, J=8.0, 8.0, 4.8, 4.8 Hz, 1H), 3.36 (dd, J=12.0, 4.8 Hz, 2H), 3.44 (dd, J=12.0, 8.0 Hz, 2H), 4.05 (q, J=6.8 Hz, 2H), 4.54 (d, J=14.8 Hz, 2H), 4.59 (d, J=14.8 Hz, 2H), 7.24 (d, J=8.0 Hz, 4H), 7.31 (d, J=8.4 Hz, 4H); ¹³C-NMR (100 MHz, CDCl₃) δ: 14.0, 38.0, 46.5, 51.1, 61.4, 128.7, 129.4, 133.1, 136.4, 155.6, 170.3; IR (ATR)γ 2906, 1732, 1632, 1500, 1445, 1407, 1371, 1352, 1254, 1200 cm⁻¹; HR-MS (ESI-TOF) [M+Na]⁺ Calcd for C₂₁H₂₂Cl₂N₂NaO₃⁺ m/z 443.0900, Found m/z 443.0889.

General Procedure D for the Synthesis of Diazocarbonyl Compounds

To a stirred solution of cyclic urea compound in MeOH (0.4 M) was added 1 N aqueous solution of LiOH (0.4 M) at r.t. After being stirred for 1 h, the reaction mixture was concentrated under reduced pressure and saturated aqueous solution of NaHCO₃ was added. The mixture was washed with Et₂O, and the water layer was acidified with 1 N aqueous solution of HCl to pH=1, extracted with AcOEt, washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. To a stirred solution of crude residue in CH₂Cl₂ (1 M) was added (COCl)₂ (1.3 eq) at r.t. After being stirred for 10 min, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in CH₃CN (0.2 M) and TMSCHN₂ solution (2.0 M solution in Et₂O) (3 eq) was added at 0°C. After being stirred for 1 h, the reaction mixture was quenched with saturated aqueous solution of NaHCO₃, extracted with AcOEt, washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (n-hexane/AcOEt, 1/1) to afford the corresponding diazocarbonyl compound.

1,3-Dibenzyl-5-(2-diazoacetyl)tetrahydropyrimidin-2(1H)-one (1a)

Prepared according to the general procedure D and isolated as yellow solid (66%, 3 steps): mp 130–131°C; Rf=0.4 (n-hexane/AcOEt, 1/4); ¹H-NMR (400 MHz, CDCl₃) δ: 2.77 (m, 1H), 3.26 (dd, J=12.0, 4.8 Hz, 2H), 3.39 (dd, J=12.0, 8.8 Hz, 2H), 4.56 (d, J=14.8 Hz, 2H), 4.65 (d, J=14.8 Hz, 2H), 5.11 (s, 1H), 7.16–7.37 (m, 10H); ¹³C-NMR (100 MHz, CDCl₃) δ: 42.8, 46.6, 51.6, 55.0, 127.3, 128.0, 128.5, 137.8, 155.6, 191.3; IR (ATR)γ 2910, 2102, 1621, 1503, 1448, 1376, 1255, 1147, 1078, 1029 cm⁻¹; HR-MS (ESI-TOF) [M+Na]⁺ Calcd for C₂₀H₂₀Cl₂N₄NaO₂⁺ m/z 371.1478, Found m/z 371.1492.

1,3-Dibenzyl-5-(2-diazoacetyl)-5-methyltetrahydropyrimidin-2(1H)-one (1b)

To a stirred solution of cyclic urea compound in THF (0.1 M) was added LHMDS (1.6 M solution in THF) (1.3 eq) at −78°C. After being stirred for 1 h, methyl iodide (MeI) (1.3 eq) was added and the reaction mixture was warmed slowly from −78°C to r.t. over 4 h. The reaction mixture was quenched with saturated aqueous solution of NH₄Cl and the mixture was extracted with Et₂O, washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure to give crude ester. The crude ester was converted to diazocarbonyl compound according to the general procedure D and isolated as a yellow oil (58%, 4 steps): Rf=0.5 (n-hexane/AcOEt, 1/4); ¹H-NMR (400 MHz, CDCl₃) δ: 1.02 (s, 3H), 3.02 (d, J=12.0 Hz, 2H), 3.37 (d, J=12.0 Hz, 2H), 4.52 (d, J=14.4 Hz, 2H), 4.65 (d, J=14.4 Hz, 2H), 4.89 (s, 1H), 7.23–7.37 (m, 10H); ¹³C-NMR (100 MHz, CDCl₃) δ: 20.8, 43.7, 51.6, 52.3, 53.2, 127.3, 128.3, 128.4, 137.7, 155.3, 195.0; IR (ATR)γ 2911, 2100, 1620, 1503, 1453, 1358, 1312, 1253, 1215, 1173 cm⁻¹; HR-MS (ESI-TOF) [M+Na]⁺ Calcd for C₂₁H₂₂N₄NaO₂⁺ m/z 385.1635, Found m/z 385.1630.

5-(2-Diazoacetyl)-1,3-bis(2-methylbenzyl)tetrahydropyrimidin-2(1H)-one (1c)

Prepared according to the general procedure D and isolated as a yellow oil (92%, 3 steps): Rf=0.5 (n-hexane/AcOEt, 1/4); ¹H-NMR (400 MHz, CDCl₃) δ: 2.33 (s, 6H), 2.79 (m, 1H), 3.22 (dd, J=12.0, 4.8 Hz, 2H), 3.37 (dd, J=12.0, 8.0 Hz, 2H), 4.62 (d, J=15.2 Hz, 2H), 4.71 (d, J=15.2 Hz, 2H), 5.05 (s, 1H), 7.15–7.20 (m, 8H); ¹³C-NMR (100 MHz, CDCl₃) δ: 19.1, 42.7, 46.2, 49.3, 54.8, 125.9, 127.4, 128.4, 130.5, 135.3, 136.8, 155.3, 191.3; IR (ATR)γ 2920, 2102, 1623, 1504, 1445, 1375, 1255, 1148, 1050, 972 cm⁻¹; HR-MS (ESI-TOF) [M+Na]⁺ Calcd for C₂₂H₂₄N₄NaO₂⁺ m/z 399.1791, Found m/z 399.1792.

5-(2-Diazoacetyl)-1,3-bis(4-methoxybenzyl)tetrahydropyrimidin-2(1H)-one (1d)

Prepared according to the general procedure D and isolated as yellow powder (83%, 3 steps): mp 100–101°C; Rf=0.4 (n-hexane/AcOEt, 1/4); ¹H-NMR (400 MHz, CDCl₃) δ: 2.74 (m, 1H), 3.24 (dd, J=12.0, 4.8 Hz, 2H), 3.36 (dd, J=12.0, 8.4 Hz, 2H), 3.80 (s, 6H), 4.49 (d, J=14.8 Hz, 2H), 4.58 (d, J=14.8 Hz, 2H), 5.11 (s, 1H), 6.84–6.89 (m, 4H), 7.21–7.27 (m, 4H); ¹³C-NMR (100 MHz, CDCl₃) δ: 42.8, 46.4, 50.9, 55.0, 55.2, 113.9, 129.5, 130.0, 155.5, 158.9, 191.6; IR (ATR)γ 2907, 2105, 1626, 1509, 1447, 1377, 1244, 1174, 1033, 818 cm⁻¹; HR-MS (ESI-TOF) [M+Na]⁺ Calcd for C₂₂H₂₄N₄NaO₄⁺ m/z 431.1690, Found m/z 431.1692.

1,3-Bis(4-chlorobenzyl)-5-(2-diazoacetyl)tetrahydropyrimidin-2(1H)-one (1e)

Prepared according to the general procedure D and isolated as yellow powder (84%, 3 steps): mp 131–133°C; Rf=0.3 (n-hexane/AcOEt, 1/4); ¹H-NMR (400 MHz, CDCl₃) δ: 2.79 (m, 1H), 3.25 (dd, J=12.0, 4.4 Hz, 2H), 3.39 (dd, J=11.6, 9.2 Hz, 2H), 4.52 (d, J=15.2 Hz, 2H), 4.59 (d, J=15.2 Hz, 2H), 5.17 (s, 1H), 7.16–7.37 (m, 8H); ¹³C-NMR (100 MHz, CDCl₃) δ: 42.7, 46.7, 51.0, 55.1, 128.7, 129.4, 133.2, 136.3, 155.4, 190.9; IR (ATR)γ 2908, 2105, 1623, 1503, 1490, 1448, 1407, 1376, 1256, 1146 cm⁻¹; HR-MS (ESI-TOF) [M+Na]⁺ Calcd for C₂₀H₁₈Cl₂N₄NaO₂⁺ m/z 439.0699, Found m/z 439.0708.

Acknowledgments

This work was supported by the Nagai Memorial Research Scholarship from the Pharmaceutical Society of Japan, by Futaba Electronics Memorial Foundation, JSPS KAKENHI Grant Numbers JP18K05098 and 18H02550.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

The online version of this article contains supplementary materials.

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