Palladium-Catalyzed Unimolecular Fragment Coupling of N-Allylamides Bearing a Tethered Nucleophile with the Translocation of an Amide Group

Key words

palladium catalyst - C–N bond activation - amides - isocyanates - elimination - rearrangement

Although a myriad of methods are available for constructing frameworks of a wide variety of molecules, the development of methods for modifying them lags far behind, despite the great demand for late-stage molecular transformations in organic synthesis.[1] The difficulty of editing molecular frameworks is largely attributed to the inertness of chemical bonds that constitute the frameworks, as represented by C–C bonds. However, advancements in activating strong bonds by transition metal catalysts[2] as well as the renaissance associated with photochemistry has allowed notable developments of methods for editing molecular frameworks. Methods that have been reported to date can be classified into three types: (1) insertion,[3] [4] [5] (2) deletion,[6,7] and (3) substitution[8] (Scheme [1a]). Insertion is defined as a class of reactions in which an atom or a group is inserted into the chemical bond that constitutes the framework of the substrate. Deletion is the reverse process of insertion, in which a new chemical bond is forged by the ejection of an atom or a group from the substrate with the remaining fragments being recombined. Decarbonylation[6a] and decarboxylation[6b] [c] reactions are typical examples of deletion reactions. Substitution is a type of transformation that is a combination of deletion and insertion. Namely, an atom or a group is removed from the substrate backbone and a new component is inserted into the same site. A new type of editing of molecular frameworks would be ‘cut-and-paste’ type reactions, in which a fragment of the molecular skeleton is removed and is then attached to a different site in the molecule, thus resulting in the construction of a new molecular framework. Although this mode of editing is attractive, to the best of our knowledge, it has not been reported as a single-step transformation.[9]

Scheme 1 Types of editing of molecular frameworks and migratory unimolecular fragment coupling (UFC) of amides; dcype = 1,2-bis(dicyclohexylphosphino)ethane

Scheme 2 Pd-catalyzed unimolecular fragment coupling with translocation of an amide group

Our laboratory recently reported the palladium-catalyzed unimolecular fragment coupling (UFC) of amides, in which an amide moiety is deleted from the substrate (Scheme [1b], top).[6e] In this reaction, an amide group is eliminated in the form of an isocyanate. In our preliminary study, we also found that when amide substrates bearing an unprotected alcohol group are used, the eliminated isocyanate is trapped by the alcohol moiety (Scheme [1b], bottom). The overall transformation is the catalytic translocation of an amide group, which can be viewed as a cut-and-paste type editing of a molecular framework. We report herein on a detailed investigation of this migratory UFC reaction of amides.

Scheme 3 Scope of Pd-catalyzed migratory UFC of N-allylamides. Reagents and conditions: 1 (0.10 mmol), Pd(PPh₃)₄ (0.010 mmol), dcype (0.010 mmol), toluene (1.0 mL), 100 °C, 18 h. ^a Run on a 0.050 mmol scale. ^b Run for 12 h at 140 °C. ^c Run on a 0.20 mmol scale. ^d Run on a 0.15 mmol scale. ^e Run on a 0.12 mmol scale.

In our previous investigation related to the palladium-catalyzed UFC of amides,[6e] we found that when an N-allyl­thiocarbamate bearing a primary alcohol group (e.g., 1a) is used as a substrate, the eliminated isocyanate is trapped by the hydroxy group, resulting in the formation of the carbamate product 2a in 68% yield (Scheme [2]).

On the basis of these preliminary results, we examined the UFC reactions using N-allylamides bearing various tethered nucleophiles (Scheme [3]). Regarding an allylic fragment, in addition to cinnamyl derivative 1a, non-substituted allyl (1b) and 2-methylallyl (1c) groups can also be used in the migratory UFC to form the corresponding N-allylthioesters 2b and 2c, respectively. Concerning the linker to tether a primary alcohol, a longer alkyl chain (1d) and a meta-phenylene group (1e) were also found to be acceptable, affording the translocated products 2d and 2e, respectively. We also found that this migratory UFC is not limited to C–S bond formation using N-allylthiocarbamates, but C–N bond formation using urea derivatives is also possible. For example, N-allylurea with a secondary alcohol moiety (i.e., 1f) participated in this reaction to yield carbamate 2f in 59% yield. Regarding the nature of the tethered nucleophile, not only primary alcohols, but also phenolic hydroxy (1g) and aniline (1h) groups could be used to successfully capture the eliminated isocyanate (2g: 40%; 2h: 77% yield). We also examined the effect of the nitrogen substituent that is to be eliminated. Although we routinely used p-CF₃C₆H₄ as a migrating group based on its efficient elimination behavior in our previous UFC studies, a simple phenyl group also functioned successfully, as exemplified by an efficient migratory UFC of 1h and 1i. On the other hand, the reaction did not proceed efficiently when an electron-donating methoxy group was introduced to the migrating group (i.e., 1j), as was observed in our previous UFC reaction.[6e] [10]

We next investigated whether this catalytic migratory UFC could be applied to C–C bond formation. Our previous study revealed that the use of N-allyl-β-ketoamide as a substrate allowed for the UFC of amides to form a C–C bond.[6e] Therefore, we envisioned that N-allyl-β-ketoamide with a primary alcohol moiety would also participate in this migratory UFC reaction with the formation of a C–C bond. When ketoamide 3 was reacted under the conditions used for C–C bond forming UFC reaction,[6e] the expected amide translocation product 4 was formed, along with a doubly allylated­ product 5, which was likely formed by further reaction of 4 with another π-allylpalladium species (Scheme [4]). In addition, the O-allylated product 6 was formed as a minor product, presumably because the UFC of ketoamide substrates is slower than that for thiocarbamate or urea substrates 1,[6e] thereby allowing the π-allylpalladium intermediate to react with a tethered alcohol. Compounds 4/5/6 were obtained in a combined yield of 83% and a ratio of 4.6:1:2.5.

In our previous deisocyanative UFC, the trimerization of the eliminated isocyanate to form a stable cyclic trimer (i.e., isocyanurate) serves as one of the driving forces for this reaction.[6e] In contrast, in this migratory UFC, the eliminated isocyanate is captured by a tethered nucleophile before it trimerizes. To obtain insights into the thermodynamics of these processes, the free energies of starting thiocarbamate 1a, UFC product 7, isocyanate 8, cyclic trimer 9, and migratory UFC product 2a were estimated by DFT calculations (Figure [1]). Although the UFC process of 1a to afford 7 and 8 is endothermic by 0.9 kcal/mol, the subsequent trimerization of 8 to 9 renders the overall process exothermic by 6.5 kcal/mol. The formation of 2a by the intramolecular capture of 8 provides an even greater free energy gain of 17.0 kcal/mol, thereby making the migratory UFC a highly favored pathway (ΔG = −16.1 kcal/mol).

Figure 1 Relative free energy changes in UFC and migratory UFC of 1a

In conclusion, we have reported on the palladium-catalyzed migratory UFC of N-allylamides bearing a tethered nucleo­phile, such as an alcohol. In this reaction, an amide moiety located in the middle of the molecular framework is removed and transferred to the end of the molecule. Additional developments of catalytic methods for use in this type of cut-and-paste editing of molecular frameworks is currently underway in our laboratory.

Scheme 4 Pd-catalyzed C–C bond forming migratory UFC using β-keto amides. Reagents and conditions: 3 (0.10 mmol), Pd(PPh₃)₄ (0.010 mmol), dcype (0.010 mmol), K₃PO₄ (0.10 mmol), THF (1.0 mL), 100 °C, 6 h.

¹H, ¹³C, and ¹⁹F NMR spectra were recorded on a JEOL ECS-400 spectrometer in CDCl₃. The chemical shifts in the ¹H NMR spectra were recorded relative to CHCl₃ (δ = 7.26). The chemical shifts in the ¹³C NMR spectra were recorded relative to CDCl₃ (δ = 77.16). The chemical shifts in the ¹⁹F NMR spectra were recorded relative to perfluorobenzene (δ = –163.0). IR spectra were obtained using a JASCO FT/IR-4200 spectrometer. Absorption (cm^–1) is reported with the following relative intensities: s (strong), m (medium), or w (weak). HRMS was carried out using a JEOL JMS-T100LP spectrometer. Melting points were determined using a Yamato melting point apparatus. Column chromato­graphy was performed with Biotage Isolera® equipped with Biotage SNAP Ultra or SNAP Isolute NH₂ Cartridge. DFT calculations were performed with the Gaussian 09 (G09RevD.01) program. Geometry optimizations and frequency calculations for all reported structures were performed using the M06-2X density functional with the 6-31G(d,p) basis set. Compounds 1a, 1f, and 1g were prepared according to a previously reported procedure.[6e] See the Supporting Information (SI) for details.

S-[4-(2-Hydroxyethoxy)phenyl] Allyl[4-(trifluoromethyl)phenyl]carbamothioate (1b); Typical Procedure

A 100 mL two-necked flask with a magnetic stirring bar was evacuated and backfilled with nitrogen three times. After addition of triphosgene (1.4 g, 5.0 mmol) and anhydrous EtOAc (30 mL) to the flask, the mixture was cooled at 0 °C and pyridine (1.6 mL, 20 mmol) was slowly added to the flask. After the mixture had been stirred at 0 °C for 15 min, N-allyl-4-(trifluoromethyl)aniline (2.4 g, 10 mmol) was slowly added to the mixture. The mixture was warmed to rt and stirred for 6 h. The resulting mixture was carefully quenched by the addition of 1 M aq HCl (15 mL) and was extracted with EtOAc (3 × 20 mL). The organic layer was washed with H₂O and then dried over Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give the corresponding carbamoyl chloride as a dark oil. This material was used in the next step without further purification. 4-Mercapto­phenol (1.4 g, 10 mmol) and Et₃N (3.4 mL, 20 mmol) were dissolved in THF (20 mL) and the mixture was stirred at rt for 15 min. To this mixture, carbamoyl chloride and DMAP (0.20 g, 1.5 mmol) were then added and the resulting solution was stirred at rt for 12 h. The resulting mixture was quenched with H₂O (10 mL) and extracted with EtOAc­ (3 × 20 mL). The organic layer was washed with H₂O (20 mL) and dried over Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromato­graphy (silica gel, hexane/EtOAc 1:1) to afford the crude S-(4-hydroxyphenyl) allyl[4-(trifluoromethyl)phenyl]carbamothioate as a yellow solid (2.0 g, ca. 60% yield), which was used in the next step without further purification. The corresponding amide (0.36 g, 1.0 mmol) was added portionwise to a suspension of NaH (48 mg, 1.2 mmol, 60% dispersion in mineral oil) in THF (17 mL); 2-bromoethanol (0.10 mL, 1.5 mmol) was then added dropwise. The reaction mixture was stirred at rt for 12 h, and then H₂O (5.0 mL) was added. The mixture was extracted with EtOAc (3 × 10 mL), and the combined extracts were washed with brine (10 mL), dried over anhydrous Na₂SO₄, and concentrated. The resulting crude product was purified by flash chromatography­ (silica gel, hexane/EtOAc 1:1) to give 1b.

Yield: 0.21 g (53%); white solid; mp 99 °C; R_f = 0.17 (silica gel, hexane/ EtOAc 1:1).

IR (KBr): 3488 s, 1651 s, 1592 s, 1496 s, 1377 s, 1324 s, 1256 m, 1177 m, 1105 m, 1068 s, 1033 m, 937 m, 830 s, 754 m, 702 m, 683 m, 561 m cm^–1.

¹H NMR (399.78 MHz, CDCl₃): δ = 7.71 (d, J = 8.4 Hz, 2 H), 7.48 (d, J = 8.4 Hz, 2 H), 7.36 (dt, J = 9.6, 2.5 Hz, 2 H), 6.91 (dt, J = 9.5, 2.5 Hz, 2 H), 5.87 (dd, J = 16.8, 10.2 Hz, 1 H), 5.19–5.10 (m, 2 H), 4.34 (d, J = 6.4 Hz, 2 H), 4.05 (t, J = 4.6 Hz, 2 H), 3.92 (t, J = 4.4 Hz, 2 H), 2.31 (s, 1 H).

¹³C NMR (100.53 MHz, CDCl₃): δ = 167.9, 159.8, 143.6, 137.3, 132.2, 130.7 (q, J _CF = 32.6 Hz), 129.8, 126.7 (q, J _CF = 3.8 Hz), 123.8 (q, J _CF = 272.2 Hz), 119.9, 119.2, 115.3, 69.3, 61.3, 53.8.

¹⁹F NMR (376 MHz, CDCl₃): δ = –63.8.

MS: m/z (%) = 397 (34) [M⁺], 229 (14), 228 (92), 169 (11), 126 (11), 125 (89), 97 (12), 45 (25), 42 (10), 41 (100).

HRMS (DART): m/z [M + H⁺] calcd for C₁₉H₁₉NO₃F₃S: 398.1032; found: 398.1033.

S-[4-(2-Hydroxyethoxy)phenyl] (2-Methylallyl)[4-(trifluoro­methyl)phenyl]carbamothioate (1c)

Typical Procedure was followed using N-(2-methylallyl)-4-(trifluoromethyl)aniline (1.8 g, 8.2 mmol). The subsequent alkylation was run on a 3.0 mmol scale.

Yield: 0.22 g (18%); colorless oil; R_f = 0.20 (silica gel, hexane/EtOAc 1:1).

IR (KBr): 3467 s, 2946 m, 1644 s, 1592 s, 1496 s, 1376 m, 1069 m, 906 s, 858 m, 833 m, 753 s, 717 m, 620 s, 559 m cm^–1.

¹H NMR (399.78 MHz, CDCl₃): δ = 7.70 (d, J = 8.2 Hz, 2 H), 7.48 (d, J = 8.2 Hz, 2 H), 7.36 (d, J = 8.7 Hz, 2 H), 6.90 (d, J = 8.7 Hz, 2 H), 4.82 (s, 1 H), 4.77 (s, 1 H), 4.31 (s, 2 H), 4.02 (t, J = 4.6 Hz, 2 H), 3.90 (t, J = 4.4 Hz, 2 H), 2.47 (s, 1 H), 1.77 (s, 3 H).

¹³C NMR (100.53 MHz, CDCl₃): δ = 168.2, 159.8, 143.7, 139.9, 137.2, 130.5 (q, J _CF = 32.6 Hz), 129.31, 126.5 (q, J _CF = 3.8 Hz), 123.8 (q, J _CF = 272.2 Hz), 119.9, 115.3, 114.4, 69.3, 61.3, 56.9, 20.2.

¹⁹F NMR (376 MHz, CDCl₃): δ = –63.8.

MS: m/z (%) = 411 (15) [M⁺], 243 (10), 242 (73), 170 (23), 126 (15), 125 (72), 55 (100), 45 (20).

HRMS (DART): m/z [M + H⁺] calcd for C₂₀H₂₁NO₃F₃S: 412.1189; found: 412.1193.

S-[4-(4-Hydroxybutoxy)phenyl] Cinnamyl[4-(trifluoromethyl)phenyl]carbamothioate (1d)

Typical Procedure was followed using 4-bromobutan-1-ol (0.16 g, 1.05 mmol). The subsequent alkylation was run on a 0.70 mmol scale.

Yield: 30 mg (10%); white solid; mp 124 °C; R_f = 0.40 (silica gel, hexane/EtOAc 1:1).

IR (KBr): 3535 m, 1648 s, 1609 s, 1593 s, 1570 m, 1495 s, 1367 m, 1323 s, 1242 s, 1193 m, 1170 s, 1121 s, 1105 m, 1066 m, 1018 m, 967 m, 831 s, 751 m, 619 m cm^–1.

¹H NMR (399.78 MHz, CDCl₃,): δ = 7.71 (d, J = 8.2 Hz, 2 H), 7.51 (d, J = 8.2 Hz, 2 H), 7.38–7.25 (m, 7 H), 6.92–6.89 (m, 2 H), 6.42 (d, J = 15.6 Hz, 1 H), 6.31–6.25 (m, 1 H), 4.49 (d, J = 6.9 Hz, 2 H), 4.01 (t, J = 6.2 Hz, 2 H), 3.71 (t, J = 6.4 Hz, 2 H), 1.90–1.85 (m, 2 H), 1.78–1.70 (m, 3 H).

¹³C NMR (100.53 MHz, CDCl₃): δ = 168.1, 160.1, 143.7, 137.2, 136.3, 134.4, 130.8 (q, J _CF = 30.7 Hz), 130.0, 128.7, 128.1, 126.8 (q, J _CF = 3.8 Hz), 126.6, 123.8 (q, J _CF = 272.2 Hz), 123.4, 119.4, 115.3, 67.9, 62.6, 53.5, 29.5, 25.8.

¹⁹F NMR (376 MHz, CDCl₃): δ = –63.8.

MS: m/z (%) = 501 (1) [M⁺], 118 (10), 117 (100), 115 (14).

HRMS (DART): m/z [M + H⁺] calcd for C₂₇H₂₇NO₃F₃S: 502.1658; found: 502.1656.

(3-(2-Hydroxyethoxy)phenyl) Cinnamyl[4-(trifluoromethyl)phenyl]­carbamothioate (1e)

Typical Procedure was followed using 3-mercaptophenol (1.1 mL, 11 mmol). The subsequent alkylation was run on a 1.3 mmol scale.

Yield: 0.14 g (22%); colorless oil; R_f = 0.20 (silica gel, hexane/EtOAc 1:1).

IR (KBr): 3419 w, 1806 m, 1775 m, 1669 m, 1612 m, 1589 m, 1477 w, 1371 w, 1324 s, 1246 m, 1167 m, 1127 m, 1068 m, 968 w, 774 m, 691 w, 620 w cm^–1.

¹H NMR (399.78 MHz, CDCl₃): δ = 7.72 (d, J = 8.4 Hz, 2 H), 7.51 (d, J = 8.4 Hz, 2 H), 7.35–7.27 (m, 6 H), 7.10–7.04 (m, 2 H), 6.98–6.94 (m, 1 H), 6.42 (d, J = 15.6 Hz, 1 H), 6.30–6.25 (m, 1 H), 4.49 (d, J = 6.9 Hz, 2 H), 4.08 (t, J = 4.6 Hz, 2 H), 3.94 (q, J = 4.3 Hz, 2 H), 2.05 (t, J = 6.0 Hz, 1 H).

¹³C NMR (100.53 MHz, CDCl₃): δ = 167.1, 158.8, 143.5, 136.3, 134.5, 131.0 (q, J _CF = 32.6 Hz), 130.1, 130.0, 129.9, 128.8, 128.3, 128.2, 126.8 (q, J _CF = 2.9 Hz), 126.7, 123.8 (q, J _CF = 272.2 Hz), 123.2, 121.4, 116.2, 69.4, 61.5, 53.6.

¹⁹F NMR (376 MHz, CDCl₃): δ = –63.9.

MS: m/z (%) = 473 (2) [M⁺], 118 (11), 117 (100), 115 (17).

HRMS (DART): m/z [M + H⁺] calcd for C₂₅H₂₃NO₃F₃S: 474.1345; found: 474.1338.

S-[4-(2-Hydroxyethoxy)phenyl] Cinnamyl(phenyl)carbamothioate (1i)

Typical Procedure was followed using N-cinnamylaniline (2.1 g, 10 mmol). The subsequent alkylation was run on a 1.0 mmol scale.

Yield: 61 mg (15%); white solid; mp 127 °C; R_f = 0.20 (silica gel, hexane­/EtOAc 1:1).

IR (KBr): 3489 s, 1657 s, 1639 s, 1591 s, 1572 m, 1494 s, 1483 m, 1374 s, 1301 m, 1288 s, 1273 s, 1253 s, 1219 m, 1175 m, 1068 m, 1036 m, 963 m, 834 s, 727 s, 695 m cm^–1.

¹H NMR (399.78 MHz, CDCl₃): δ = 7.48–7.24 (m, 12 H), 6.92 (d, J = 8.7 Hz, 2 H), 6.44–6.27 (m, 2 H), 4.48 (d, J = 6.4 Hz, 2 H), 4.07 (t, J = 4.6 Hz, 2 H), 3.94 (t, J = 4.6 Hz, 2 H), 2.23 (s, 1 H).

¹³C NMR (100.53 MHz, CDCl₃): δ = 168.2, 159.6, 140.2, 137.2, 136.6, 134.0, 129.8, 129.6, 129.0, 128.6, 127.9, 126.6, 123.8, 120.7, 115.2, 69.3, 61.3, 53.5.

MS: m/z (%) = 405 (1) [M⁺], 118 (10), 117 (100), 115 (17).

HRMS (DART): m/z [M + H⁺] calcd for C₂₄H₂₄NO₃S: 406.1471; found: 406.1472.

S-[4-(2-Hydroxyethoxy)phenyl] Cinnamyl(4-methoxyphenyl)carbamothioate (1j)

Typical Procedure was followed using N-cinnamyl-4-(methoxy)aniline (2.4 g, 10 mmol). The subsequent alkylation was run on a 1.0 mmol scale.

Yield: 0.11g (25%); white solid; mp 96 °C; R_f = 0.20 (silica gel, hexane/EtOAc 1:1).

IR (KBr): 3421 m, 1672 s, 1646 s, 1593 m, 1509 s, 1493 s, 1455 m, 1375 m, 1297 w, 1242 s, 1174 m, 1093 w, 916 m, 834 s, 733 m, 629 w, 465 w, 444 m, 433 m, 420 m, 410 m cm^–1.

¹H NMR (399.78 MHz, CDCl₃): δ = 7.40–7.24 (m, 9 H), 6.96–6.91 (m, 4 H), 6.40 (d, J = 16.0 Hz, 1 H), 6.27 (d, J = 15.6 Hz, 1 H), 4.43 (d, J = 6.4 Hz, 2 H), 4.07 (t, J = 4.6 Hz, 2 H), 3.94 (t, J = 4.4 Hz, 2 H), 3.84 (s, 3 H), 2.15 (s, 1 H).

¹³C NMR (100.53 MHz, CDCl₃): δ = 168.6, 159.9, 159.6, 137.2, 136.6, 134.0, 132.7, 131.1, 128.6, 127.9, 126.6, 123.9, 121.1, 115.2, 114.7, 69.3, 61.4, 55.6, 53.6.

MS: m/z (%) = 435 (1) [M⁺], 118 (10), 117 (100), 115 (15).

HRMS (DART): m/z [M + H⁺] calcd for C₂₅H₂₆NO₄S: 436.1571; found: 436.1579.

S-(4-Aminophenyl) Allyl(phenyl)carbamothioate (1h)

N-Benzylidene-protected 1h was prepared using (E)-4-(benzylideneamino)benzenethiol[11] according to the typical procedure on a 10 mmol scale. A white solid (3.7 g, ca. 98%) was obtained, and this material was used in the next step without further purification. Thus obtained protected 1h (3.7 g, ca. 10 mmol) was dissolved in 1.0 M aq HCl (80 mL), and the solution was stirred at rt for 1 h. The mixture was then quenched with 2.0 M aq NaOH (100 mL), and the resulting mixture was extracted with EtOAc (3 × 30 mL). The combined extracts were washed with brine (50 mL), dried over anhydrous Na₂SO₄, and concentrated. The resulting crude product was purified by flash chromatography­ (hexane/EtOAc 1:1) to give 1h.

Yield: 1.53 g (54%); white solid; mp 96 °C; R_f = 0.32 (silica gel, hexane/EtOAc 1:1).

IR (KBr): 3651 m, 3373 s, 1655 m, 1652 w, 1618 w, 1592 w, 1514 s, 1452 w, 1435 m, 1363 s, 1335 w, 1295 s, 1250 s, 1217 s, 1176 s, 1170 s, 1128 w, 1073 m, 1018 w, 1003 w cm^–1.

¹H NMR (399.78 MHz, CDCl₃): δ = 7.46–7.42 (m, 3 H), 7.35 (d, J = 8.0 Hz, 2 H), 7.21 (d, J = 8.0 Hz, 2 H), 6.62 (d, J = 8.0 Hz, 2 H), 5.95–5.85 (m, 1 H), 5.16–5.10 (m, 2 H), 4.33 (d, J = 6.4 Hz, 2 H), 3.76 (s, 2 H).

¹³C NMR (100.53 MHz, CDCl₃): δ = 168.7, 147.8, 140.4, 137.0, 132.8, 129.6, 129.4, 128.7, 118.5, 116.6, 115.4, 53.8.

MS: m/z (%) = 284 (33) [M⁺], 160 (64), 132 (27), 125 (10), 123 (72), 80 (26), 41 (100).

HRMS (DART): m/z [M + H⁺] calcd for C₁₆H₁₇N₂OS: 285.1056; found: 285.1056.

N-Allyl-2-[4-(hydroxymethyl)benzyl]-1-oxo-N-phenyl-2,3-di­hydro-1H-indene-2-carboxamide (3)

N-Allyl-2-{4-[(tert-butyldimethylsiloxy)methyl]benzyl}-1-oxo-N-phenyl-2,3-dihydro-1H-indene-2-carboxamide (TBS-protected 3)

A 100 mL two-necked flask with a magnetic stirring bar was evacuated and backfilled with nitrogen three times. Methyl 1-oxo-2,3-di­hydro-1H-indene-2-carboxylate (2.2 g, 12 mmol) and N-allylaniline (5.0 mL, 24 mmol) were added to the flask. The mixture was stirred at 70 °C for 48 h, and then cooled to rt. The residue was concentrated and purified by column chromatography (silica gel, hexane/EtOAc 9:1) to afford crude N-allyl-1-oxo-N-phenyl-2,3-dihydro-1H-indene-2-carboxamide as a yellow solid (0.92 g, ca. 28% yield), which was used in the next step without further purification. This amide (0.60 g, 2.0 mmol) was added to a suspension of NaH (0.16 g, 4 mmol, 60% dispersion in mineral oil) in THF, and [4-(bromomethyl)benzyl](tert-butyl)dimethylsilane (10 mmol, 0.61 mL) was then added dropwise. The reaction mixture was stirred at rt for 12 h, and then H₂O (15 mL) was added. The residue was extracted with EtOAc (3 × 15 mL), and the combined organic extracts were washed with brine, dried over anhydrous Na₂SO₄, and concentrated. The resulting crude product was purified by flash chromatography (silica gel, hexane/EtOAc 8:2) to give TBS-protected 3.

Yield: 0.42 g (81%); white solid; mp 108 °C; R_f = 0.54 (silica gel, hexane/EtOAc 1:1).

IR (KBr): 1703 s, 1652 m, 1641 s, 1494 w, 1381 w, 1272 w, 1258 w, 1092 w, 1079 m, 835 m, 784 w, 703 m cm^–1.

¹H NMR (399.78 MHz, CDCl₃): δ = 7.12–7.08 (m, 2 H), 6.89 (q, J = 8.1 Hz, 9 H), 6.82 (d, J = 7.8 Hz, 1 H), 6.75 (t, J = 6.9 Hz, 1 H), 5.91–5.84 (m, 1 H), 5.09–4.99 (m, 2 H), 4.46 (s, 2 H), 4.22 (dd, J = 7.8, 6.4 Hz, 2 H), 3.47–3.34 (m, 3 H), 3.16 (d, J = 17.9 Hz, 1 H), 0.80 (t, J = 2.7 Hz, 9 H), –0.12 (q, J = 2.7 Hz, 6 H).

¹³C NMR (100.53 MHz, CDCl₃): δ = 205.5, 171.1, 151.3, 139.4, 139.0, 137.1, 134.2, 134.0, 132.7, 130.4, 128.3, 126.6, 125.4, 125.2, 123.4, 118.1, 64.6, 60.4, 55.1, 42.0, 37.0, 25.9, 18.3, –5.3.

MS: m/z (%) = 525 (2) [M⁺], 393 (28), 349 (29), 348 (100), 233 (26), 133 (15), 132 (35), 104 (36), 91 (13), 75 (16), 73 (62), 41 (29).

HRMS (DART): m/z [M + H⁺] calcd for C₃₃H₄₀NO₃Si: 526.2772; found: 526.2768.

Carboxamide 3 by Deprotection of TBS-protected 3

TBS-protected 3 (0.42 g, 0.80 mmol) was dissolved in THF (15 mL), and 1.0 M TBAF in THF (1.4 mL, 14 mmol) was added to it. The mixture was stirred at rt overnight. The mixture was then quenched with sat. aq NH₄Cl (5.0 mL), and the resulting mixture was extracted with EtOAc (3 × 6.0 mL). The combined extracts were washed with brine (6.0 mL), dried over anhydrous Na₂SO₄, and concentrated. The resulting crude product was purified by flash chromatography (hexane/ EtOAc 1:9) to give 3.

Yield: 0.29 g (88%); white solid; mp 88 °C; R_f = 0.49 (silica gel, EtOAc).

IR (KBr): 3470 m, 1713 s, 1635 s, 1608 m, 1594 m, 1495 m, 1436 m, 1387 s, 1258 s, 1015 m, 983 m, 922 m, 745 m, 702 s cm^–1.

¹H NMR (399.78 MHz, CDCl₃): δ = 7.15 (q, J = 6.6 Hz, 2 H), 6.97–6.85 (m, 10 H), 6.79 (s, 2 H), 5.94–5.84 (m, 1 H), 5.12–5.02 (m, 2 H), 4.44 (s, 2 H), 4.24 (m, 2 H), 3.47–3.37 (m, 3 H), 3.16 (d, J = 18.3 Hz, 1 H).

¹³C NMR (100.53 MHz, CDCl₃): δ = 205.4, 171.2, 151.4, 139.1, 139.0, 137.1, 135.3, 134.2, 132.8, 131.0, 128.4, 128.3, 126.8, 126.4, 125.4, 123.7, 118.3, 65.1, 60.6, 55.3, 42.2, 37.2.

MS: m/z (%) = 411 (7) [M⁺], 393 (11), 290 (19), 262 (12), 261 (20), 251 (10), 233 (26), 157 (20), 133 (30), 132 (100), 131 (11), 121 (67), 115 (24), 106 (13), 105 (21), 104 (23), 93 (34), 91 (77), 77 (50), 41 (29).

HRMS (DART): m/z [M + H⁺] calcd for C₂₇H₂₆NO₃: 412.1907; found: 412.1913.

2-[4-(Allylthio)phenoxy]ethyl [4-(Trifluoromethyl)phenyl]carbamate (2b); Typical Procedure

In a glovebox filled with nitrogen, Pd(PPh₃)₄ (11.6 mg, 0.010 mmol), dcype (4.7 mg, 0.010 mmol), and toluene (1.0 mL) were added to a 10 mL vial with a Teflon-sealed screwcap, and the mixture was stirred at rt for 5 min. Amide 1b (39.7 mg, 0.10 mmol) was then added, and the vial was sealed with the cap. The vessel was heated at 100 °C for 18 h, after which it was cooled to rt and the crude mixture was filtered through a pad of Celite. The crude product was purified by flash column chromatography (silica gel) to give 2b.

Yield: 36.5 mg (92%); white solid; mp 103 °C; R_f = 0.68 (silica gel, hexane/EtOAc 1:1).

IR (KBr): 3322 s, 1702 s, 1597 s, 1540 s, 1495 s, 1455 m, 1413 m, 1329 s, 1281 m, 1232 m, 1118 m, 1091 m, 1069 m, 1016 m, 931 m, 831 m, 648 m, 515 m cm^–1.

¹H NMR (399.78 MHz, CDCl₃): δ = 7.57 (d, J = 8.7 Hz, 2 H), 7.50 (d, J = 8.7 Hz, 2 H), 7.34 (td, J = 6.0, 3.5 Hz, 2 H), 6.91 (s, 1 H), 6.85 (dt, J = 9.5, 2.6 Hz, 2 H), 5.87–5.79 (m, 1 H), 5.03–4.97 (m, 2 H), 4.54 (dd, J = 5.3, 3.9 Hz, 2 H), 4.20 (t, J = 4.6 Hz, 2 H), 3.44 (dt, J = 7.0, 1.1 Hz, 2 H).

¹³C NMR (100.53 MHz, CDCl₃): δ = 157.8, 152.9, 140.8, 134.0, 133.8, 126.8, 126.5 (q, J _CF = 3.8 Hz), 125.5 (q, J _CF = 32.6 Hz), 124.2 (q, J _CF = 271.2 Hz), 118.2, 117.5, 115.1, 66.2, 63.9, 39.2.

¹⁹F NMR (376 MHz, CDCl₃): δ = –63.3.

MS: m/z (%) = 397 (7) [M⁺], 233 (11), 232 (100), 188 (13), 166 (36), 160 (10), 145 (11), 125 (31), 45 (49), 41 (21).

HRMS (DART): m/z [M + H⁺] calcd for C₁₉H₁₉NO₃F₃S: 398.1032; found: 398.1031.

CCDC 2220352 (2b) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.

2-{4-[(2-Methylallyl)thio]phenoxy}ethyl [4-(Trifluoromethyl)phenyl]carbamate (2c)

Yield: 27.2 mg (65%); white solid; mp 101 °C; R_f = 0.72 (silica gel, hexane/EtOAc 1:1).

IR (KBr): 3269 s, 1693 s, 1597 m, 1545 m, 1495 s, 1455 m, 1408 m, 1339 s, 1282 m, 1236 m, 1164 s, 1114 m, 1082 m, 1070 m, 904 s, 832 s, 784 m, 767 m, 672 m, 530 m, 508 m cm^–1.

¹H NMR (399.78 MHz, CDCl₃): δ = 7.56 (d, J = 8.4 Hz, 2 H), 7.49 (d, J = 8.4 Hz, 2 H), 7.33 (td, J = 4.6, 2.4 Hz, 2 H), 6.90 (s, 1 H), 6.86–6.83 (m, 2 H), 4.74 (q, J = 1.5 Hz, 1 H), 4.65 (d, J = 0.9 Hz, 1 H), 4.54 (t, J = 4.6 Hz, 2 H), 4.20 (dd, J = 5.3, 3.9 Hz, 2 H), 3.41 (d, J = 0.9 Hz, 2 H), 1.84 (s, 3 H).

¹³C NMR (100.53 MHz, CDCl₃): δ = 157.8, 152.9, 141.2, 140.9, 133.9, 127.4, 126.5 (q, J _CF = 3.1 Hz), 125.6 (q, J _CF = 32.3 Hz), 124.2 (q, J _CF = 272.2 Hz), 118.2, 115.1, 114.0, 66.2, 64.0, 44.0, 21.1.

¹⁹F NMR (376 MHz, CDCl₃,): δ = –63.3.

MS: m/z (%) = 411 (9) [M⁺], 233 (11), 232 (100), 207 (19), 188 (13), 180 (40), 160 (10), 147 (17), 125 (24), 55 (32), 45 (46).

HRMS (DART): m/z [M + H⁺] calcd for C₂₀H₂₁NO₃F₃S: 412.1189; found: 412.1191.

4-[4-(Cinnamylthio)phenoxy]butyl [4-(Trifluoromethyl)phenyl]carbamate (2d)

Run on a 0.050 mmol scale.

Yield: 14.2 mg (56%); white solid; mp 138 °C; R_f = 0.68 (silica gel, hexane/EtOAc 1:1).

IR (KBr): 3355 w, 1710 s, 1619 w, 1598 w, 1539 m, 1517 m, 1493 m, 1473 w, 1413 w, 1336 s, 1269 w, 1233 s, 1182 w, 1164 w, 1114 m, 1072 m, 819 w, 505 w, 433 w, 422 w cm^–1.

¹H NMR (399.78 MHz, CDCl₃): δ = 7.56 (d, J = 8.7 Hz, 2 H), 7.48 (d, J = 8.7 Hz, 2 H), 7.38–7.28 (m, 6 H), 7.22 (dt, J = 6.1, 2.5 Hz, 1 H), 6.81 (dt, J = 9.5, 2.6 Hz, 2 H), 6.73 (s, 1 H), 6.30–6.20 (m, 2 H), 4.26 (t, J = 6.0 Hz, 2 H), 3.98 (t, J = 5.7 Hz, 2 H), 3.58 (q, J = 3.1 Hz, 2 H), 1.90–1.87 (m, 4 H).

¹³C NMR (100.53 MHz, CDCl₃): δ = 158.6, 153.3, 141.1, 137.0, 134.5, 132.6, 128.6, 127.6, 126.5 (q, J _CF = 3.8 Hz), 126.4, 125.9, 125.7, 125.3 (q, J _CF = 32.6 Hz), 124.3 (q, J _CF = 272.2 Hz), 118.1, 115.1, 67.4, 65.4, 39.3, 25.9, 25.8.

¹⁹F NMR (376 MHz, CDCl₃): δ = –63.3.

MS: m/z (%) = 501 (0) [M⁺], 314 (6) [M⁺ – isocyanate], 126 (42), 118 (12), 117 (100), 115 (26), 91 (11).

HRMS (DART): m/z [M + H⁺] calcd for C₂₇H₂₇NO₃F₃S: 502.1658; found: 502.1652.

2-[3-(Cinnamylthio)phenoxy]ethyl [4-(Trifluoromethyl)phenyl]carbamate (2e)

Yield: 25.7 mg (54%); white solid; mp 98 °C; R_f = 0.57 (silica gel, hexane/EtOAc 1:1).

IR (KBr): 3330 m, 2361 s, 2340 m, 1704 s, 1592 m, 1567 m, 1540 s, 1475 m, 1457 m, 1416 m, 1336 s, 1283 m, 1232 m, 1161 m, 1113 m, 1088 m, 971 m, 945 m, 836 m, 757 m, 505 m, 473 m, 422 m, 412 m cm^–1.

¹H NMR (399.78 MHz, CDCl₃,): δ = 7.57 (d, J = 8.7 Hz, 2 H), 7.49 (d, J = 8.7 Hz, 2 H), 7.33–7.27 (m, 4 H), 7.23–7.19 (m, 2 H), 6.99 (d, J = 7.8 Hz, 1 H), 6.94 (t, J = 1.8 Hz, 1 H), 6.87 (s, 1 H), 6.75 (dd, J = 8.2, 2.3 Hz, 1 H), 6.46 (d, J = 15.6 Hz, 1 H), 6.29–6.22 (m, 1 H), 4.50 (t, J = 4.6 Hz, 2 H), 4.16 (t, J = 4.4 Hz, 2 H), 3.73–3.71 (m, 2 H).

¹³C NMR (100.53 MHz, CDCl₃,): δ = 158.6, 152.9, 140.9, 137.6, 136.8, 133.1, 129.9, 128.7, 127.8, 126.53 (q, J _CF = 3.8 Hz), 126.46, 125.5 (q, J _CF = 32.6 Hz), 125.0, 124.2 (q, J _CF = 271.3 Hz), 122.7, 118.2, 116.0, 112.8, 66.2, 63.9, 36.9.

¹⁹F NMR (376 MHz, CDCl₃,): δ = –63.3.

MS: m/z (%) = 473 (0) [[M⁺], 286 (4) [M⁺ – isocyanate], 118 (10), 117 8100), 115 (28), 91 (11).

HRMS (DART): m/z [M + H⁺] calcd for C₂₅H₂₃NO₃F₃S: 474.1345; found: 474.1347.

1-Cinnamylpiperidin-4-yl [4-(Trifluoromethyl)phenyl]carbamate (2f)

Yield: 24 mg (59%); white solid; mp 128 °C; R_f = 0.16 (silica gel, EtOAc).

In addition to 2f, an UFC product (isocyanate is not trapped by the OH group) was obtained (4.1 mg, 19% isolated yield). Note that 2f decomposed to form the UFC product when NH silica was used for its isolation.

IR (KBr): 3342 m, 1700 s, 1617 m, 1536 m, 1511 m, 1410 m, 1331 s, 1238 m, 1162 m, 1121 s, 1072 s, 833 m, 691 m cm^–1.

¹H NMR (399.78 MHz, CDCl₃): δ = 7.53 (dd, J = 19.5, 8.9 Hz, 4 H), 7.39–7.37 (m, 2 H), 7.31 (t, J = 7.6 Hz, 2 H), 7.26–7.22 (m, 1 H), 7.04 (s, 1 H), 6.52 (d, J = 15.6 Hz, 1 H), 6.27 (dt, J = 15.6, 6.9 Hz, 1 H), 4.85–4.81 (m, 1 H), 3.19–3.17 (m, 2 H), 2.82 (br, 2 H), 2.32 (br, 2 H), 2.04–2.00 (m, 2 H), 1.83–1.74 (m, 2 H).

¹³C NMR (100.53 MHz, CDCl₃): δ = 152.8, 141.3, 136.9, 133.3, 128.7, 127.7, 126.5 (q, J _CF = 4.8 Hz), 126.4, 125.2 (q, J _CF = 32.6 Hz), 122.1, 121.6 (q, J _CF = 271.3 Hz), 118.1, 71.7, 61.1, 51.0, 31.2.

¹⁹F NMR (376 MHz, CDCl₃): δ = –63.2.

MS: m/z (%) = 404 (31) [M⁺], 281 (16), 207 (33), 118 (100), 73 (11).

HRMS (DART): m/z [M + H⁺] calcd for C₂₂H₂₄N₂O₂F₃: 405.1784; found: 405.1782.

4-(Cinnamylthio)phenyl [4-(Trifluoromethyl)phenyl]carbamate (2g)

Yield: 17.1 mg (40%); white solid; mp 179 °C; R_f = 0.43 (silica gel, hexane/EtOAc 2:1).

IR (KBr): 2931 m, 2853 w, 1748 m, 1615 m, 1540 m, 1478 m, 1411 w, 1324 s, 1198 s, 1184 s, 1163 m, 1115 m, 1067 s, 1004 w, 842 m, 753 w, 433 m, 422 m, 411 w cm^–1.

¹H NMR (399.78 MHz, CDCl₃): δ = 7.58 (q, J = 9.2 Hz, 4 H), 7.42 (d, J = 8.7 Hz, 2 H), 7.34–7.23 (m, 5 H), 7.12 (d, J = 8.7 Hz, 2 H), 7.08 (s, 1 H), 6.43 (d, J = 15.6 Hz, 1 H), 6.29–6.21 (m, 1 H), 3.70 (d, J = 6.9 Hz, 2 H).

¹³C NMR (100.53 MHz, CDCl₃): δ = 151.2, 149.2, 140.5, 136.8, 133.4, 133.1, 132.0, 128.7, 127.8, 126.6 (q, J _CF = 2.9 Hz), 126.5, 125.7 (q, J _CF = 33.6 Hz), 125.0, 124.2 (q, J _CF = 271.3 Hz), 122.1, 118.4, 37.9.

¹⁹F NMR (376 MHz, CDCl₃): δ = –63.4.

MS: m/z (%) = 429 (1) [M⁺], 118 (10), 117 (100), 115 (19).

HRMS (DART): m/z [M + H⁺] calcd for C₂₃H₁₉NO₂F₃S: 430.1083; found: 430.1089.

1-[4-(Allylthio)phenyl]-3-phenylurea (2h)

Run on a 0.20 mmol scale.

Yield: 43.6 mg (77%); white solid; mp 126 °C; R_f = 0.80 (silica gel, EtOAc).

IR (KBr): 3306 m, 1639 s, 1594 s, 1585 m, 1562 m, 1557 s, 1552 s, 1538 w, 1532 w, 1519 w, 1496 m, 1443 m, 1439 m, 1395 w, 1313 w, 1294 w, 1288 w, 1261 w, 1234 m, 924 w cm^–1.

¹H NMR (399.78 MHz, CDCl₃): δ = 7.25–7.20 (m, 5 H), 7.14 (dd, J = 11.4, 8.7 Hz, 3 H), 7.09–7.04 (m, 1 H), 5.87–5.77 (m, 1 H), 5.07–5.01 (m, 2 H), 3.44 (d, J = 6.9 Hz, 2 H).

¹³C NMR (100.53 MHz, CDCl₃): δ = 154.7, 137.8, 136.8, 133.6, 131.6, 130.1, 129.1, 124.0, 121.2, 120.7, 117.7, 38.2.

MS: m/z (%) = 284 (0) [M⁺], 165 (22) [M⁺ – isocyanate], 124 (100), 80 (26).

HRMS (DART): m/z [M + H⁺] calcd for C₁₆H₁₇N₂OS: 285.1056; found: 285.1058.

2-[4-(Cinnamylthio)phenoxy]ethyl Phenylcarbamate (2i)

Run on a 0.15 mmol scale.

Yield: 47.7 mg (78%); white solid; mp 106 °C; R_f = 0.73 (silica gel, hexane/EtOAc 1:1).

IR (KBr): 3293 m, 1698 s, 1597 m, 1537 m, 1492 m, 1442 m, 1312 w, 1243 m, 1224 m, 1176 w, 1064 m, 1025 w, 928 w, 834 m, 420 w cm^–1.

¹H NMR (399.78 MHz, CDCl₃): δ = 7.38–7.26 (m, 10 H), 7.23–7.20 (m, 1 H), 7.10–7.05 (m, 1 H), 6.85 (dt, J = 9.5, 2.5 Hz, 2 H), 6.71 (s, 1 H), 6.31–6.18 (m, 2 H), 4.52–4.50 (m, 2 H), 4.18 (t, J = 4.8 Hz, 2 H), 3.59 (d, J = 6.4 Hz, 2 H).

¹³C NMR (100.53 MH, CDCl₃): δ = 158.2, 153.3, 137.7, 137.0, 134.4, 132.6, 129.3, 128.7, 127.6, 126.6, 126.4, 125.6, 123.8, 118.9, 115.2, 66.5, 63.6, 39.2.

MS: m/z (%) = 405 (0) [M⁺], 286 (8) [M⁺ – isocyanate], 118 (10), 117 (100), 115 (26).

HRMS (DART): m/z [M + H⁺] calcd for C₂₄H₂₄NO₃S: 406.1471; found: 406.1464.

2-[4-(Cinnamylthio)phenoxy]ethyl (4-Methoxyphenyl)carbamate (2j)

Run on a 0.12 mmol scale.

Yield: 8.0 mg (15%); white solid; mp 139 °C; R_f = 0.62 (silica gel, hexane/EtOAc 1:1).

IR (KBr): 3344 m, 1698 s, 1535 m, 1491 m, 1451 w, 1415 w, 1240 s, 1222 s, 1185 w, 1088 m, 1066 m, 1024 m, 970 w, 816 m, 758 m cm^–1.

¹H NMR (399.78 MHz, CDCl₃): δ = 7.38–7.33 (m, 2 H), 7.31–7.28 (m, 7 H), 7.22 (td, J = 4.2, 2.1 Hz, 1 H), 6.86–6.84 (m, 4 H), 6.30–6.19 (m, 2 H), 4.49 (t, J = 4.6 Hz, 2 H), 4.18 (t, J = 4.6 Hz, 2 H), 3.78 (s, 3 H), 3.59 (d, J = 6.4 Hz, 2 H).

¹³C NMR (100.53 MHz, CDCl₃): δ = 158.2, 156.3, 137.0, 134.4, 134.3, 132.6, 130.7, 128.7, 127.6, 126.5, 126.4, 125.6, 120.9, 115.2, 114.4, 66.5, 63.5, 55.6, 39.2.

MS: m/z (%) = 435 (0) [M⁺], 286 (8) [M⁺ – isocyanate], 118 (10), 117 (100), 115 (26), 91 (10).

HRMS (DART): m/z [M + H⁺] calcd for C₂₅H₂₆NO₄S: 436.1577; found: 436.1574.

Products 4, 5, and 6 by Palladium-Catalyzed Elimination of Isocyanate from Carboxamide 3

In a glovebox filled with nitrogen, Pd(PPh₃)₄ (11.6 mg, 0.010 mmol), dcype (4.7 mg, 0.010 mmol), and THF (1.0 mL) were added to a 10 mL vial with a Teflon-sealed screwcap, and the mixture was stirred at rt for 5 min. Amide 3 (41.1 mg, 0.10 mmol) and K₃PO₄ (13.8 mg, 0.10 mmol) were then added, and the cap was applied to seal the vial. The vessel was heated at 100 °C for 6 h, then cooled to rt; the crude mixture was filtered through a pad of Celite. The crude product was purified by flash column chromatography (silica gel) to give a mixture of 4, 5, and 6.

Yield: 35 mg (83%); 4/5/6 = 4.2:1:2.5 (ratio by ¹H NMR analysis); colorless oil; R_f = 0.70 (silica gel, hexane/EtOAc 1:1).

A part of each product was obtained in pure form through purification by GPC.

4-[(2-Allyl-1-oxo-2,3-dihydro-1H-inden-2-yl)methyl]benzyl Phenylcarbamate (4)

IR (KBr): 1717 w, 1704 m, 1700 m, 1696 m, 1558 w, 1539 m, 786 s, 757 s, 418 m cm^–1.

¹H NMR (399.78 MHz, CDCl₃): δ = 7.70 (d, J = 7.8 Hz, 1 H), 7.51–7.47 (m, 1 H), 7.36 (d, J = 7.8 Hz, 2 H), 7.31–7.26 (m, 4 H), 7.20 (d, J = 7.8 Hz, 2 H), 7.11 (d, J = 7.8 Hz, 2 H), 7.08–7.04 (m, 1 H), 6.67 (s, 1 H), 5.63–5.53 (m, 1 H), 5.08–5.04 (m, 3 H), 4.99–4.96 (m, 1 H), 3.13–3.07 (m, 2 H), 2.95 (d, J = 17.4 Hz, 1 H), 2.82 (d, J = 13.5 Hz, 1 H), 2.53 (q, J = 6.7 Hz, 1 H), 2.30 (dd, J = 13.5, 8.0 Hz, 1 H).

¹³C NMR (100.53 MHz CDCl₃): δ = 210.2, 153.1, 137.9, 137.8, 136.8, 135.0, 134.2, 133.4, 130.6, 129.2, 128.3, 127.4, 126.5, 124.0, 123.6, 118.9, 118.7, 66.8, 53.9, 42.6, 42.4, 35.5.

MS: m/z (%) = 411 (0) [M⁺], 292 (3) [M⁺ – isocyanate], 236 (29), 235 (32), 234 (43), 132 (22), 131 (44), 120 (15), 119 (21), 117 (11), 115 (18), 105 (24), 104 (100), 103 (22), 91 (82), 90 (12), 89 (10), 77 (15), 41 (22).

HRMS (DART): m/z [M + H⁺] calcd for C₂₇H₂₆NO₃: 412.1907; found: 412.1909.

4-[(2-Allyl-1-oxo-2,3-dihydro-1H-inden-2-yl)methyl]benzyl Allyl(phenyl)carbamate (5)

IR (KBr): 1706 s, 1607 w, 1598 w, 1496 m, 1464 w, 1443 w, 1436 w, 1396 m, 1360 w, 1295 m, 1275 m, 1253 m, 1229 m, 1147 m, 1018 w, 993 w, 921 w, 700 m cm^–1.

¹H NMR (399.78 MHz, CDCl₃): δ = 7.69 (d, J = 7.3 Hz, 1 H), 7.48 (td, J = 7.4, 1.1 Hz, 1 H), 7.33–7.27 (m, 4 H), 7.23–7.18 (m, 3 H), 7.06 (s, 4 H), 5.92–5.82 (m, 1 H), 5.61–5.53 (m, 1 H), 5.12–4.96 (m, 6 H), 4.24 (dt, J = 6.0, 1.4 Hz, 2 H), 3.10–3.05 (m, 2 H), 2.94 (d, J = 17.4 Hz, 1 H), 2.79 (d, J = 13.3 Hz, 1 H), 2.53 (q, J = 6.6 Hz, 1 H), 2.30 (dd, J = 13.7, 8.2 Hz, 1 H).

¹³C NMR (100.53 MHz, CDCl₃): δ = 210.3, 155.3, 153.1, 137.1, 136.8, 135.0, 134.8, 133.8, 133.4, 130.4, 129.0, 127.5, 127.4, 126.8, 126.6, 126.5, 123.9, 118.9, 117.4, 117.2, 67.1, 53.9, 53.4, 42.6, 42.4, 35.5

MS: m/z (%) = 451 (1) [M⁺], 407 (13), 281 (19), 276 (11), 275 (42), 236 (12), 235 (71), 234 (100), 233 (11), 208 (12), 207 (59), 132 (14), 131 (12), 128 (10), 117 (12), 115 (12), 105 (13), 104 (39), 103 (14), 91 (28), 77 (14), 73 (17), 41 (16).

HRMS (DART): m/z [M + H⁺] calcd for C₃₀H₃₀NO₃: 452.2220; found: 452.2219.

2-{4-[(Allyloxy)methyl]benzyl}-1-oxo-N-phenyl-2,3-dihydro-1H-indene-2-carboxamide (6)

IR (KBr): 3328 w, 2854 w, 1699 s, 1598 s, 1539 s, 1498 w, 1466 w, 1442 w, 1311 m, 1299 w, 1080 w, 935 w, 913 w, 755 m, 692 m, 505 w cm^–1.

¹H NMR (399.78 MHz, CDCl₃): δ = 9.20 (s, 1 H), 7.75 (d, J = 7.8 Hz, 1 H), 7.60–7.54 (m, 3 H), 7.36 (td, J = 15.5, 7.8 Hz, 4 H), 7.17–7.07 (m, 5 H), 5.96–5.86 (m, 1 H), 5.29–5.17 (m, 2 H), 4.43 (s, 2 H), 3.97–3.92 (m, 3 H), 3.35 (d, J = 13.7 Hz, 1 H), 3.26 (d, J = 3.7 Hz, 1 H), 3.22 (d, J = 8.2 Hz, 1 H).

¹³C NMR (100.53 MHz, CDCl₃): δ = 207.2, 167.6, 153.5, 137.8, 137.5, 136.3, 135.1, 134.8, 134.6, 130.1, 129.1, 127.8, 127.7, 126.7, 124.6, 124.5, 120.1, 117.3, 71.8, 71.1, 62.2, 45.3, 34.9.

MS: m/z (%) = 411 (0) [M⁺], 292 (41) [M⁺ – isocyanate], 234 (22), 233 (479, 171 812), 161 (18), 131 (13), 129 (10), 128 (20), 119 (52), 117 (11), 115 (19), 105 (20), 104 (27), 91 (100), 90 (11), 55 (10), 41 (37).

HRMS (DART): m/z [M + H⁺] calcd for C₂₇H₂₆NO₃: 412.1907; found: 412.1908.

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• 3a Xue Y, Dong G. Acc. Chem. Res. 2022; 55: 2341
• 3b Murakami M, Ishida N. Chem. Rev. 2021; 121: 264

For selected recent work involving insertion of more than one atom into C–C bonds, see:
• 4a Denton EH, Lee YH, Roediger S, Boehm P, Fellert M, Morandi B. Angew. Chem. Int. Ed. 2021; 60: 23435
• 4b Liao L.-L, Cao G.-M, Jiang Y.-X, Jin X.-H, Hu X.-L, Chruma JJ, Sun G.-Q, Gui Y.-Y, Yu D.-G. J. Am. Chem. Soc. 2021; 143: 2812
• 4c Ito Y, Nakatani S, Shiraki R, Kodama T, Tobisu M. J. Am. Chem. Soc. 2022; 144: 662

For selected recent work involving single atom insertion, see:
• 5a Hyland EE, Kelly PQ, McKillop AM, Dherange BD, Levin MD. J. Am. Chem. Soc. 2022; 144: 19258
• 5b Liu S, Cheng X. Nat. Commun. 2022; 13: 425
• 5c Reisenbauer JC, Green O, Franchino A, Finkelstein P, Morandi B. Science 2022; 377: 1104
• 5d Kelly PQ, Filatov AS, Levin MD. Angew. Chem. Int. Ed. 2022; 61: e202213041
• 5e Saito H, Yorimitsu H. Chem. Lett. 2019; 48: 1019 ; see also ref. 1d

For decarbonylation, see:
• 6a Lu H, Yu T.-Y, Xu P.-F, Wei H. Chem. Rev. 2021; 121: 365

For decarboxylation, see:
• 6b Weaver JD, Recio A, Grenning AJ, Tunge JA. Chem. Rev. 2011; 111: 1846
• 6c Tunge JA. Isr. J. Chem. 2020; 60: 351

For desulfonylation, see:
• 6d Nambo M, Maekawa Y, Crudden CM. ACS Catal. 2022; 12: 3013

For deisocyanation, see:
• 6e Shimazumi R, Tanimoto R, Kodama T, Tobisu M. J. Am. Chem. Soc. 2022; 144: 11033

For selected recent work on single-atom deletion, see:
• 7a Woo J, Christian AH, Burgess SA, Jiang Y, Mansoor UF, Levin MD. Science 2022; 376: 527
• 7b Cao Z.-C, Shi Z.-J. J. Am. Chem. Soc. 2017; 139: 6546
• 7c Nwachukwu CI, McFadden TP, Roberts AG. J. Org. Chem. 2020; 85: 9979 ; see also ref. 1d

For reviews on substitution-type editing of molecular frameworks, see:
• 8a Kurahashi T, Matsubara S. Acc. Chem. Res. 2015; 48: 170
• 8b Vasu D, Yorimitsu H, Osuka A. Angew. Chem. Int. Ed. 2015; 54: 7162

For selected recent work, see:
• 8c Luu QH, Li J. Chem. Sci. 2022; 13: 1095
• 8d Patel SC, Burns NZ. J. Am. Chem. Soc. 2022; 144: 17797
• 8e Gary S, Bloom S. ACS Cent. Sci. 2022; 8: 1537
• 8f Bartholomew GL, Carpaneto F, Sarpong R. J. Am. Chem. Soc. 2022; 144: 22309 ; see also refs. 4a–c for substitution via decarbonylation and decarboxylation. Other related examples can also be found in ref. 1d
• 9 The allylic substitution of allyl carbamates bearing a tethered nucleophile was reported to give products with CO₂ incorporation. However, such reactions are not classified as cut-and-paste type editing, because part of the group in the substrate (i.e., a MeO group) is eliminated as a result of the transformation. See: Feng H. Chem. Heterocycl. Compd. (Engl. Transl.) 2020; 56: 506
• 10 The low reactivity of electron-rich isocyanates against nucleophiles is another potential reason. See: Rawling T, McDonagh AM, Tattam B, Murray M. Tetrahedron 2012; 68: 6065
• 11 Sangeeth CS. S, Demissie AT, Yuan L, Wang T, Frisbie CD, Nijhuis CA. J. Am. Chem. Soc. 2016; 138: 7305