Palladium/Norbornene Chemistry in the Synthesis of Polycyclic Indolines with Simple Nitrogen Sources

Abstract

An efficient procedure has been developed to synthesize ­indoline derivatives through a palladium-catalyzed Heck reaction/C–H activation/dual amination cascade in one pot. This constitutes the first intermolecular catalytic approach to directly access N-alkylindolines with a broad substrate scope in the absence of any ligands. This method highlights the use of readily available amines and ureas as the required nitrogen sources in building up the indoline core.

Key words

amines - N-alkylindolines - norbornene - palladacycle - urea

The synthesis of heterocycles using various methods has been of great interest in recent decades. Indolines are one of the heterocycles that have undergone various synthetic methods in recent years.[1] The main reason for focusing on the synthesis of structures containing indoline scaffold is the unique biological and pharmacological properties of these compounds.[2] The structures with indoline skeletons are ubiquitously present in many naturally bioactive alkaloids, such as strychnine,[3] (–)-physostigmine,[4] and (+)-aspidospermidine[5] (Figure [1]). It is also a vital intermediate of the pentopril, a drug used for the treatment of hypertension (Figure [1]).[6] Recently, Du and co-workers have also isolated oleracein from the edible plant Portulaca oleracea used in Chinese traditional medicine (Figure [1]).[7] Given the importance of these structures, the synthesis of indoline derivatives has been a research topic of great interest to research chemists since the last decade.

Figure 1 Representative bioactive indolines and its derivatives

One of the most important methods for the construction of indoline scaffolds is the intramolecular Buchwald–Hartwig amination reaction of amine-tethered aryl halides (Scheme [1a]).[8] Recently, Yu et al.[9a] pioneered an alternative auxiliary directed indoline synthesis through aryl C–H activation/intramolecular amination process, which was further improved by employing various N-chelating groups and oxidizing agents such as hypervalent iodonium salts (Scheme [1b]).[9] While these methods provide an attractive entry to these ring systems, they are mostly limited to intramolecular amination reactions and rely on the use of substrates that are preinstalled with amino groups. Furthermore, Kapur et al. communicated a palladium-catalyzed intramolecular α-arylation of silyl enol ethers of β-aminoketones, which led to the formation of the 3-substituted indolines (Scheme [1c]).[10] However, the multi-step reaction and limitation of product diversity were some drawbacks of the report. Glorius et al. also developed a Rh(III)-catalyzed directed C–H activation, followed by intramolecular addition of the Csp³–Rh species to the N=N bond to afford 1-aminoindolines using Boc-protected aryldiazenes and alkenes (Scheme [1d]).[11]

Scheme 1 Transition-metal-catalyzed synthesis of indolines

In the last decade, the strategy of using norbornene for activation of C–H bonds has been used to synthesize different heterocycles. This technique benefits from the high ­reactivity of norbornene in the activation of the inactive ­ortho C–H bonds in aryl halides and palladacycle formation.

This strategy was devised by Catellani and further developed by other research groups.[12] Recently the application of palladium/norbornene (Pd/NBE) chemistry for construction of indolines via amination of aryl-norbornene-palladacycle (ANP) intermediates employing three membered strained N-containing heterocycles have become realistic (Scheme [2]). The Shi group pioneered the construction of indolines via oxidative addition of the C,C-pallada­cycle to di-tert-butyldiaziridinone (Scheme [2a]).[13]

Furthermore, Bi and Liang extended the scope of Pd/NBE chemistry employing sulfonated aziridines as electrophilic reagents for ortho-amination of iodoarenes and construction of N-tosylindolines (Scheme [2b]).[14]

Scheme 2 Pd/NBE chemistry in the synthesis of indolines

Despite the importance of these communications, the protocols showed a narrow substrate scope while the products were limited to N-tBu and N-Ts indolines, as well as cost issues linked to the use of strained three-membered N-heterocyclic rings. The last report in this context belongs to Dai and Hu who established a decarboxylative annulation of 2-haloaroyloxycarbamates with norbornene for the construction of indolines (Scheme [2c]).[15] This protocol encountered similar scope limitations on the N-substituent of indolines and required prefunctionalized starting materials. We also recently reported on a regioselective annulation reaction to provide N-arylindolines as a new outcome from the palladium-catalyzed reaction of iodoarenes, norbornene, and anilines.[16] Despite significant achievements, however, aliphatic amines remained challenging and more difficult than aromatic amines for this catalytic system. Aliphatic ureas also did not participate in this cascade. Considering the high importance of indoline scaffolds in pharmaceutics and remarkable effect of the nature of the N-substituent of N-heterocycles on their biological properties, it would be highly desirable to directly construct complicated indoline molecules from simple and readily available starting materials and more easily diversified nitrogen sources.

Herein we report an effective method for the synthesis of various polycyclic indolines via Pd/NBE chemistry employing three readily available and easily diversified building blocks including: iodoarenes, norbornene, and readily available nitrogen sources including aliphatic amines and ureas (Scheme [2d]). This protocol has the potential for construction of indoline motifs easily diversified on both arene and nitrogen sides, which has not been accomplished yet. Setting the competing ipso-amination versus ortho-amination in the presence of nucleophilic amine sources is the key step for this transformation. This reaction would offer distinct advantages over existing methods, particularly with respect to functional group compatibility on both arene and nitrogen sides, accessible and economical nitrogen sources, and excluding any requisite for phosphine-­donor ligands usually necessary in Pd-catalyzed reactions.

In a typical experiment, 2-iodotoluene (1a), propylamine (2a), and norbornene were reacted in the presence of PdCl₂, PPh₃, Cs₂CO₃ in MeCN at 110 °C for 20 hours. Under these conditions, polyclic indoline 3a was fortunately collected in 21% yield (Table [1], entry 1). The reaction was optimized with respect to Pd sources where Pd(OAc)₂ proved to be the most effective catalytic system (entries 1–3). Employing different bases, sodium bicarbonate exhibited the best performance in the annulation reaction (entries 4–7). However, conducting the reaction in the presence of a stronger base such as NaOH led to a decrease in the yield (entry 6). Gratefully, the transformation proceeded well in the absence of any added ligands rarely achieved in similar methodologies (entry 8). Therefore, the optimization of reaction was continued without using any additional ligands. Next, the effect of different solvents on this transformation was investigated (entries 8–13). Screening of the solvents showed that chlorobenzene was the best choice of solvent and gave the desired product 3a in 69% isolated yield (entry 13). Increasing the amount of norbornene to 4 equivalents did not improve the reaction yield (entry 14). Finally, reducing temperature to 90 °C led to a yield bargain (entry 15).

Table 1 Optimization of Reaction Conditions for the Annulation of 2-Iodotoluene^a

Entry	Catalyst	L	Base	Solvent	Yield (%)
1	PdCl2	PPh3	Cs2CO3	MeCN	21
2	Pd(OAc)2	PPh3	Cs2CO3	MeCN	38
3	Pd(dba)2	PPh3	Cs2CO3	MeCN	19
4	Pd(OAc)2	PPh3	K2CO3	MeCN	37
5	Pd(OAc)2	PPh3	K3PO4	MeCN	42
6	Pd(OAc)2	PPh3	NaOH	MeCN	13
7	Pd(OAc)2	PPh3	NaHCO3	MeCN	52
8	Pd(OAc)2	–	NaHCO3	MeCN	54
9	Pd(OAc)2	–	NaHCO3	toluene	28
10	Pd(OAc)2	–	NaHCO3	THF	trace
11	Pd(OAc)2	–	NaHCO3	DMF	37
12	Pd(OAc)2	–	NaHCO3	DMSO	41
13	Pd(OAc)2	–	NaHCO3	chlorobenzene	69
14b	Pd(OAc)2	–	NaHCO3	chlorobenzene	65
15c	Pd(OAc)2	–	NaHCO3	chlorobenzene	55

^a Reaction conditions: 2-iodotoluene (1a; 0.1 mmol), norbornene (2 equiv), propylamine (2a; 2 equiv), catalyst (5 mol%), ligand (10 mol%), base (2 equiv), and solvent (1 mL) at 110 °C for 20 h.

^b Norbornene: 4 equiv.

^c Reaction temperature: 90 °C.

With the optimized condition in hand, the scope of the annulation reaction to construct various polycyclic indolines was examined. As summarized in Scheme [3, a] wide range of substituted iodoarenes and amines were found to be compatible with this domino Heck reaction/double C–N bond formation.

Scheme 3 Reaction scope for construction of indolines

First the reactivity of 2-iodotoluene with various alkyl amines was examined and yields were obtained between 57–88%. Fortunately, palladium-catalyzed annulation of iodoarenes and some bulkier amines such as isopropylamine and cyclohexylamine proceeded smoothly under the optimized reaction conditions to afford the desired products 3g and 3i in 81% and 57% isolated yield, respectively. According to the biological importance of N-cyclohexylindoline derivatives, the synthesis of these compounds has received great attention.[17] Intriguingly, even iodoarene containing susceptible halo groups could be well tolerated under the reaction conditions to provide the desired product 3l in promising 89% isolated yield with preserved chloro groups. This adduct can serve as a good precursor for further functionalizations through metal-catalyzed cross-coupling reactions. In addition, the ortho-trifluoromethyl-substituted iodoarene, which due to its lower reactivity is relatively rarely used in palladium-catalyzed coupling reactions, was compatible with the current reaction conditions affording the desired polycyclic indoline 3m in 61% isolated yield. Notably, yields of 58% and 71% were still obtained for compounds 3a and 3c, respectively, when the reactions were scaled up to 4.0 mmol. Unfortunately, nitro-substituted ­iodoarene did not participate in this transformation.

Gratefully, when expanding the scope of amines to their amide derivatives 4, we found that ureas could also serve as the nitrogen sources of indolines through C–N bond cleavage.[18] Once aliphatic amines were replaced with 1,3-bis(alkyl)ureas the annulation reactions proceeded well under the same optimized reaction conditions to afford the polycyclic indolines in comparable yields (Scheme [4]).

Scheme 4 Scope of ureas as efficient nitrogen sources in the construction of indolines

Remarkably, when an asymmetric N-alkyl,N-arylurea was picked as a coupling partner in this transformation, a high regioselectivity was observed in the conversion. It is interesting to note that in this catalytic system, selectivity favored N-alkylation versus N-arylation of C–H bonds for construction of N-alkylindoline 3a in 59% yield and phenyl isocyanate was removed from the reaction pot as the by-product (Scheme [5]).

Scheme 5 Regioselectivity of the reaction with unsymmetrical ureas

A mechanistic rationale is summarized in Scheme [6]. In the catalytic cycle, when amine is used as the coupling partner, the oxidative addition of aryl halide to Pd(0), followed by a carbopalladation reaction with NBE and subsequent intramolecular C–H activation, results in the C,C-palladacycle intermediate 5. Next a transmetalation between two Pd(II) centers, palladacycle 5 and Pd(II) coordinated to nitrogen, put forward by Cardenas and Echavarren[19] and developed by Derat and Catellani,[20] generates a binuclear Pd(II) intermediate 6.

Scheme 6 Mechanistic rationale

After reductive elimination, Pd(0) is released and the first C–N bond is forged (intermediate 7). Next the intramolecular coordination of nitrogen to the remaining Pd(II) center forms intermediate 8, which on the second reductive elimination releases the next Pd(0) and installs nitrogen on two Csp³ and Csp² bonds to give rise to polycyclic indoline 3.

In summary, we have developed an efficient method for construction of polycyclic indolines via amination of aryl-norbornene-palladacycle as the key intermediate in Pd/NBE chemistry, employing readily available nitrogen sources such as aliphatic amines and ureas and building three Csp³–Csp²/Csp³–N/Csp²–N bonds in a single synthetic process. This approach provides a general platform to introduce various N-alkyl groups to the arene ortho-position and to provide various N-alkyl-substituted indolines. The reaction features broad substrate scope and proceeds smoothly without any added phosphine-donor ligands usually as a prerequisite in palladium-catalyzed reactions. Employing unsymmetrical N-alkyl,N-arylurea, a high regioselectivity via ortho N-alkylation versus N-arylation of iodoarene was perceived.

All reagents were commercially available and used as received. Column chromatography was carried out on silica gel (230–400 mesh). ¹H NMR spectra were recorded at r.t. on a Bruker 500 MHz spectrometer using DMSO-d ₆ and CDCl₃ as solvent. Chemical shifts are reported in ppm with TMS as an internal standard. ¹³C NMR spectra are referenced from the solvent central peak. Chemical shifts are given in ppm. Elemental analyses (CHN) were recorded on a Thermo Finnigan Flash EA 1112 elemental analyzer.

5-Methyl-9-propyl-2,3,4,4a,9,9a-hexahydro-1H-1,4-methanocarbazole (3a); Typical Procedure

A vial equipped with a stir bar was charged with 2-iodotoluene (1a; 21.8 mg, 0.10 mmol), propylamine (2a; 11.8 mg, 0.2 mmol, 2 equiv), Pd(OAc)₂ (1.1 mg, 5 mol%), norbornene (18.8 mg, 0.2 mmol, 2 equiv), NaHCO₃ (16.8 mg, 0.2 mmol, 2 equiv), and chlorobenzene (1 mL) was added, and the vial was capped. The resulting mixture was heated in a sand bath at 110 °C for 20 h, cooled, then filtered through a short plug of silica gel. Removal of the solvent gave a crude mixture, which was purified by column chromatography (hexane/EtOAc gradient) to give indoline 3a; yield: 17 mg (69%); yellow oil.

¹H NMR (500 MHz, CDCl₃): δ = 0.96 (t, J = 7.4 Hz, 3 H), 1.14–1.23 (m, 2 H), 1.33–1.39 (m, 1 H), 1.53–1.67 (m, 5 H), 2.24 (s, 3 H), 2.37 (s, 1 H), 2.41 (s, 1 H), 3.03–3.15 (m, 2 H), 3.21 (d, J = 8.3 Hz, 1 H), 3.63 (d, J = 8.3 Hz, 1 H), 6.12 (d, J = 7.1 Hz, 1 H), 6.35 (d, J = 7.5 Hz, 1 H), 6.94 (t, J = 7.65 Hz, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 11.7, 18.4, 21.0, 25.0, 29.0, 32.7, 41.0, 41.4, 49.4, 50.3, 71.9, 102.1, 117.3, 127.7, 129.6, 133.9, 153.6.

EI-MS: m/z (%) = 241 (M^•+, 100), 173 (49), 198 (27).

Anal. Calcd for C₁₇H₂₃N: C, 84.59; H, 9.60; N, 5.80. Found: C, 84.93; H, 9.74; N, 6.09.

5-Methyl-9-propyl-2,3,4,4a,9,9a-hexahydro-1H-1,4-methano­carbazole (3b)

Yield: 18 mg (78%); yellow oil.

¹H NMR (500 MHz, CDCl₃): δ = 0.89–0.92 (m, 1 H), 1.14 (t, J = 6.9 Hz, 3 H), 1.28 (s, 3 H), 1.52–1.59 (m, 2 H), 2.23 (s, 3 H), 2.34 (s, 1 H), 2.40 (s, 1 H), 3.17–3.23 (m, 3 H), 3.62 (d, J = 10.0 Hz, 1 H), 6.12 (d, J = 7.8 Hz, 1 H), 6.34 (d, J = 7.5 Hz, 1 H), 6.93 (t, J = 7.65 Hz, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 12.4, 18.3, 24.9, 29.0, 29.7, 32.6, 41.1, 41.5, 50.2, 70.8, 102.3, 117.4, 127.7, 129.8, 133.9, 152.9.

EI-MS: m/z (%) = 227 (M^•+, 100), 159 (45), 198 (24).

Anal. Calcd for C₁₆H₂₁N: C, 84.53; H, 9.31; N, 6.16. Found: C, 84.20; H, 9.19; N, 5.93.

9-Benzyl-5-methyl-2,3,4,4a,9,9a-hexahydro-1H-1,4-methano­carbazole (3c)

Yield: 22 mg (76%); pale oil.

¹H NMR (500 MHz, CDCl₃): δ = 1.15–1.20 (m, 1 H), 1.29–1.37 (m, 2 H), 1.49–1.60 (m, 3 H), 2.27 (s, 4 H), 2.46 (s, 1 H), 3.26 (d, J = 8.3 Hz, 1 H), 3.7 (d, J = 8.4 Hz, 1 H), 4.34–4.42 (m, 2 H), 6.08 (d, J = 7.7 Hz, 1 H), 6.4 (d, J = 7.5 Hz, 1 H), 6.90 (t, J = 7.7 Hz, 1 H), 7.30–7.35 (m, 5 H).

¹³C NMR (125 MHz, CDCl₃): δ = 18.4, 24.8, 29.0, 32.8, 41.0, 41.1, 50.3, 51.4, 72.2, 102.3, 117.9, 126.7, 127.0, 127.8, 128.4, 129.4, 134.0, 139.6, 153.5.

EI-MS: m/z (%) = 289 (M^•+, 100), 221 (51), 198 (30).

Anal. Calcd for C₂₁H₂₃N: C, 87.15; H, 8.01; N, 4.84. Found: C, 87.04; H, 7.89; N, 4.51.

9-Butyl-5-methyl-2,3,4,4a,9,9a-hexahydro-1H-1,4-methanocarbazole (3d)

Yield: 18 mg (72%); yellow oil.

¹H NMR (500 MHz, CDCl₃): δ = 0.96 (t, J = 7.3 Hz, 3 H), 1.11–1.16 (m, 2 H), 1.33–1.38 (m, 3 H), 1.50–1.59 (m, 5 H), 2.23 (s, 3 H), 2.35 (s, 1 H), 2.40 (s, 1 H), 3.12 (d, J = 7.6 Hz, 2 H), 3.18 (d, J = 8.4 Hz, 1 H), 3.61 (d, J = 8.4 Hz, 1 H), 6.11 (d, J = 7.8 Hz, 1 H), 6.34 (d, J = 7.5 Hz, 1 H), 6.92 (t, J = 7.6 Hz, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 14.0, 18.3, 20.4, 24.9, 29.0, 29.9, 32.6, 41.0, 41.4, 47.1, 50.2, 71.6, 102.1, 117.3, 127.7, 129.5, 133.8, 153.4.

EI-MS: m/z (%) = 255 (M^•+, 100), 187 (54), 198 (29).

Anal. Calcd for C₁₈H₂₅N: C, 84.65; H, 9.87; N, 5.48. Found: C, 85.02; H, 10.00; N, 5.71.

5-Methyl-9-phenethyl-2,3,4,4a,9,9a-hexahydro-1H-1,4-methanocarbazole (3e)

Yield: 21 mg (68%); brown oil.

¹H NMR (500 MHz, CDCl₃): δ = 1.15–1.24 (m, 2 H), 1.36–1.40 (m, 1 H), 1.56–1.61 (m, 3 H), 2.27 (s, 3 H), 2.31 (s, 1 H), 2.44 (s, 1 H), 2.83–2.96 (m, 2 H), 3.23 (d, J = 8.3 Hz, 1 H), 3.41 (t, J = 7.8 Hz, 2 H), 3.65 (d, J = 8.2 Hz, 1 H), 6.18 (d, J = 7.8 Hz, 1 H), 6.41 (d, J = 7.5 Hz, 1 H), 6.98 (t, J = 7.6 Hz, 1 H), 7.25–7.29 (m, 3 H), 7.35 (t, J = 7.3 Hz, 2 H).

¹³C NMR (125 MHz, CDCl₃): δ = 18.4, 24.9, 29.0, 32.7, 34.0, 41.1, 41.4, 49.5, 50.3, 71.8, 102.2, 117.8, 126.1, 127.8, 128.4, 128.8, 129.7, 134.0, 140.0, 152.9.

EI-MS: m/z (%) = 303 (M^•+, 100), 235 (57), 198 (41).

Anal. Calcd for C₂₂H₂₅N: C, 87.08; H, 8.30; N, 4.62. Found: C, 86.76; H, 8.16; N, 4.43.

9-Hexyl-5-methyl-2,3,4,4a,9,9a-hexahydro-1H-1,4-methanocarbazole (3f)

Yield: 25 mg (88%); yellow oil.

¹H NMR (500 MHz, CDCl₃): δ = 0.92–0.96 (m, 4 H), 1.33–1.38 (m, 8 H), 1.54–1.63 (m, 5 H), 2.24 (s, 3 H), 2.37 (s, 1 H), 2.42 (s, 1 H), 3.12 (t, J = 7.8 Hz, 2 H), 3.20 (d, J = 8.3 Hz, 1 H), 3.62 (d, J = 8.3 Hz, 1 H), 6.12 (d, J = 7.8 Hz, 1 H), 6.35 (d, J = 6.5 Hz, 1 H), 6.93 (t, J = 7.6 Hz, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 14.0, 18.3, 22.7, 25.0, 27.0, 27.7, 29.0, 31.7, 32.6, 41.1, 41.4, 47.5, 50.2, 71.7, 102.1, 117.3, 127.7, 129.5, 133.8, 153.5.

EI-MS: m/z (%) = 283 (M^•+, 100), 215 (44), 198 (37).

Anal. Calcd for C₂₀H₂₉N: C, 84.75; H, 10.31; N, 4.94. Found: C, 85.06; H, 10.43; N, 5.17.

9-Isopropyl-5-methyl-2,3,4,4a,9,9a-hexahydro-1H-1,4-methanocarbazole (3g)

Yield: 20 mg (81%); pale oil.

¹H NMR (500 MHz, CDCl₃): δ = 1.13 (d, J = 6.5 Hz, 3 H), 1.22–1.25 (m, 1 H), 1.29 (d, J = 6.65 Hz, 4 H), 1.32–1.36 (m, 1 H), 1.51–1.58 (m, 3 H), 2.24 (s, 3 H), 2.29 (s, 1 H), 2.41 (s, 1 H), 3.20 (d, J = 8.5 Hz, 1 H), 3.67 (d, J = 8.5 Hz, 1 H), 3.71–3.79 (m, 1 H), 6.20 (d, J = 7.8 Hz, 1 H), 6.38 (d, J = 7.5 Hz, 1 H), 6.94 (t, J = 7.7 Hz, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 17.6, 18.4, 21.7, 25.2, 29.0, 32.5, 41.0, 43.8, 47.4, 50.5, 66.8, 104.0, 117.8, 127.6, 130.4, 133.8, 152.9.

EI-MS: m/z (%) = 241 (M^•+, 100), 173 (38), 198 (17).

Anal. Calcd for C₁₇H₂₃N: C, 84.59; H, 9.60; N, 5.80. Found: C, 84.22; H, 9.47; N, 5.52.

9-Isobutyl-5-methyl-2,3,4,4a,9,9a-hexahydro-1H-1,4-methanocarbazole (3h)

Yield: 17 mg (66%); yellow oil.

¹H NMR (500 MHz, CDCl₃): δ = 0.92 (d, J = 6.7 Hz, 3 H), 0.96 (d, J = 6.7 Hz, 3 H), 1.09–1.16 (m, 2 H), 1.51–1.59 (m, 4 H), 1.94–2.05 (m, 1 H), 2.23 (s, 3 H), 2.36–2.41 (m, 2 H), 2.83–2.96 (m, 2 H), 3.21 (d, J = 8.3 Hz, 1 H), 3.58 (d, J = 8.3 Hz, 1 H), 6.11 (d, J = 7.8 Hz, 1 H), 6.33 (d, J = 7.5 Hz, 1 H), 6.91 (t, J = 7.7 Hz, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 18.3, 20.5, 20.6, 25.0, 27.9, 28.9, 32.6, 41.0, 41.2, 50.3, 56.5, 72.9, 102.2, 117.3, 117.3, 127.6, 129.3, 133.8.

EI-MS: m/z (%) = 255 (M^•+, 100), 187 (54), 198 (51).

Anal. Calcd for C₁₈H₂₅N: C, 84.65; H, 9.87; N, 5.48; Found: C, 84.98; H, 9.99; N, 5.70.

9-Cyclohexyl-5-methyl-2,3,4,4a,9,9a-hexahydro-1H-1,4-methanocarbazole (3i)

Yield: 16 mg (57%); yellow oil.

¹H NMR (500 MHz, CDCl₃): δ = 1.07–1.13 (m, 1 H), 1.25–1.29 (m, 3 H), 1.29–1.36 (m, 3 H), 1.49–1.58 (m, 4 H), 1.64–1.76 (m, 2 H), 1.78–1.88 (m, 2 H), 1.94–2.02 (m, 1 H), 2.21 (s, 3 H), 2.26 (s, 1 H), 2.39 (s, 1 H), 3.17 (d, J = 8.4 Hz, 1 H), 3.21–3.31 (m, 1 H), 3.68 (d, J = 8.4 Hz, 1 H), 6.16 (d, J = 7.7 Hz, 1 H), 6.33 (d, J = 7.3 Hz, 1 H), 6.90 (t, J = 7.6 Hz, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 18.4, 25.1, 26.0, 26.3, 28.0, 29.0, 29.6, 32.4, 32.5, 41.0, 43.9, 50.5, 56.1, 67.4, 103.6, 117.6, 127.5, 130.2, 133.8, 152.8.

EI-MS: m/z (%) = 281 (M^•+, 100), 213 (37), 198 (21).

Anal. Calcd for C₂₀H₂₇N: C, 85.35; H, 9.67; N, 4.98. Found: C, 85.11; H, 9.53; N, 4.84.

9-(2-Methoxyethyl)-5-methyl-2,3,4,4a,9,9a-hexahydro-1H-1,4-methanocarbazole (3j)

Yield: 19 mg (74%); yellow oil.

¹H NMR (500 MHz, CDCl₃): δ = 1.10–1.15 (m, 1 H), 1.27 (s, 1 H), 1.47–1.52 (m, 1 H), 1.53–1.58 (m, 2 H), 2.22 (s, 3 H), 2.35–2.41 (m, 2 H), 3.19 (d, J = 8.4 Hz, 1 H), 3.25–3.32 (m, 1 H), 3.34–3.40 (m, 4 H), 3.47–3.58 (m, 2 H), 3.66 (d, J = 8.3 Hz, 1 H), 6.13 (d, J = 7.8 Hz, 1 H), 6.35 (d, J = 7.5 Hz), 6.91 (t, J = 7.6 Hz, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 18.3, 24.9, 28.9, 32.5, 41.0, 41.5, 47.1, 50.3, 58.9, 70.7, 72.3, 102.0, 117.7, 127.7, 129.5, 133.9, 153.1.

EI-MS: m/z (%) = 257 (M^•+, 100), 189 (44), 198 (31).

Anal. Calcd for C₁₇H₂₃NO: C, 79.33; H, 9.01; N, 5.44. Found: C, 79.65; H, 9.17; N, 5.68.

9-Butyl-5-ethyl-2,3,4,4a,9,9a-hexahydro-1H-1,4-methanocarbazole (3k)

Yield: 15 mg (54%); pale oil.

¹H NMR (500 MHz, CDCl₃): δ = 0.99 (t, J = 7.3 Hz, 3 H), 1.13–1.20 (m, 2 H), 1.27 (t, J = 7.7 Hz, 3 H), 1.36–1.40 (m, 2 H), 1.53–1.65 (m, 6 H), 2.36–2.42 (m, 2 H), 2.55–2.65 (m, 2 H), 3.11–3.18 (m, 2 H), 3.24 (d, J = 8.3 Hz, 1 H), 3.63 (d, J = 8.4 Hz, 1 H), 6.13 (d, J = 7.7 Hz, 1 H), 6.42 (d, J = 7.5 Hz, 1 H), 7.00 (t, J = 7.7 Hz, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 14.1, 14.7, 20.5, 24.9, 25.1, 29.1, 30.0, 32.6, 41.4, 41.9, 47.2, 49.9, 71.8, 102.0, 115.2, 127.9, 128.9, 140.0, 153.5.

EI-MS: m/z (%) = 269 (M^•+, 100), 201 (55), 212 (34).

Anal. Calcd for C₁₉H₂₇N: C, 84.70; H, 10.10; N, 5.20. Found: C, 84.38; H, 9.96; N, 4.93.

9-Benzyl-6,8-dichloro-2,3,4,4a,9,9a-hexahydro-1H-1,4-methanocarbazole (3l)

Yield: 30 mg (89%); orange oil.

¹H NMR (500 MHz, CDCl₃): δ = 1.04–1.08 (m, 1 H), 1.14–1.17 (m, 1 H), 1.28–1.32 (m, 3 H), 2.20 (d, J = 4.9 Hz, 1 H), 2.25–2.28 (m, 1 H), 3.26–3.29 (m, 1 H), 3.56–3.62 (m, 2 H), 4.71 (d, J = 16.2 Hz, 1 H), 4.88 (d, J = 16.2 Hz, 1 H), 6.84–6.90 (m, 1 H), 6.95–7.0 (m, 1 H), 7.29–7.36 (m, 5 H).

¹³C NMR (125 MHz, CDCl₃): δ = 25.1, 28.5, 32.6, 41.8, 43.4, 50.8, 52.6, 73.1, 113.2, 121.9, 123.3, 126.9, 127.4, 128.4, 128.9, 137.1, 139.6, 147.5.

EI-MS: m/z (%) = 343 (M^•+, 100), 275 (52), 252 (19).

Anal. Calcd for C₂₀H₁₉Cl₂N: C, 69.77; H, 5.56; N, 4.07. Found: C, 70.11; H, 5.67; N, 4.29.

9-Isobutyl-5-(trifluoromethyl)-2,3,4,4a,9,9a-hexahydro-1H-1,4-methanocarbazole (3m)

Yield: 19 mg (61%); pale oil.

¹H NMR (500 MHz, CDCl₃): δ = 0.93 (d, J = 6.6 Hz, 3 H), 0.97 (d, J = 6.6 Hz, 3 H), 1.28 (s, 3 H), 1.55–1.60 (m, 2 H), 1.97–2.0 (m, 1 H), 2.39–2.44 (m, 1 H), 2.51 (s, 1 H), 2.89–2.99 (m, 3 H), 3.44 (d, J = 8.8 Hz, 1 H), 3.69 (d, J = 8.3 Hz, 1 H), 6.34 (d, J = 8 Hz, 1 H), 6.69 (d, J = 7.8 Hz, 1 H), 7.05 (t, J = 7.9 Hz, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 20.4, 20.5, 24.8, 27.6, 29.0, 32.3, 41.0, 42.9, 50.0, 55.5, 72.8, 107.0, 112.29 (q, J = 5Hz), 126.0, 126.7 (q, J = 12.5 Hz), 127.5, 128.1, 155.0.

EI-MS: m/z (%) = 309 (M^•+, 100), 241 (59), 252 (33), 240 (14).

Anal. Calcd for C₁₈H₂₂F₃N: C, 69.88; H, 7.17; N, 4.53. Found: C, 70.21; H, 7.28; N, 4.69.

Acknowledgment

We gratefully acknowledge financial support from the University of Tehran and Kharazmi University.

• References


For reviews, see:
• 1a Liu D, Zhao G, Xiang L. Eur. J. Org. Chem. 2010; 3975
• 1b Silva TS, Rodrigues MT. Jr, Santos H, Zeoly LA, Almeida WP, Barcelos RC, Gomes RC, Fernandes FS, Coelho F. Tetrahedron 2019; 75: 2063
• 2a Rosato RR, Stephen EL, Pannier WL. Toxicol. Appl. Pharmacol. 1976; 35: 107
• 2b Bermudez J, Dabbs S, Joiner KA, King FD. J. Med. Chem. 1990; 33: 1929
• 2c Holsy PB, Anthoni U, Christophersen C, Nielsen PH. J. Nat. Prod. 1994; 57: 997
• 2d Triggle DJ, Mitchell JM, Filler R. CNS Drug Rev. 1998; 4: 87
• 2e Austin JF, Kim S.-G, Sinz CJ, Xiao W.-J, Macmillan DW. C. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 5482
• 2f Gul W, Hamann MT. Life Sci. 2005; 78: 442
• 2g Rode MA, Rindhe SS, Karale B. J. Sreb. Chem. Soc. 2009; 74: 1377
• 2h Ruiz-Sanchis P, Savina SA, Albericio F, Álvarez M. Chem. Eur. J. 2011; 17: 1388
• 2i Annedi SC, Ramnauth J, Maddaford SP, Renton P, Rakhit S, Mladenova G, Dove P, Silverman S, Andrews JS, Felice MD, Porreca F. J. Med. Chem. 2012; 55: 943
• 3 Zhang H, Boonsombat J, Padwa A. Org. Lett. 2007; 9: 279
• 4 Bui T, Syed S, Barbas CF. III. J. Am. Chem. Soc. 2009; 131: 8758
• 5 Iyengar R, Schildknegt K, Morton M, Aube J. J. Org. Chem. 2005; 70: 10645
• 6 Rakhit A, Hurley ME, Tipnis V, Coleman J, Rommel A, Brunner HR. J. Clin. Pharmacol. 1986; 26: 156
• 7 Xiang L, Xing D, Wang W, Wang R, Ding Y, Du L. Phytochemistry 2005; 66: 2595

For Buchwald–Hartwig amination, see:
• 8a Guram AS, Rennels RA, Buchwald SL. Angew. Chem. Int. Ed. 1995; 34: 1348
• 8b Peat AJ, Buchwald SL. J. Am. Chem. Soc. 1996; 118: 1028

For representative indoline synthesis using Buchwald–Hartwig amination reactions, see:
• 8c Yang BH, Buchwald SL. Org. Lett. 1999; 1: 35
• 8d Yamada K, Kubo T, Tokuyama H, Fukuyama T. Synlett 2002; 231
• 8e Omar-Amrani R, Thomas A, Brenner E, Schneider R, Fort Y. Org. Lett. 2003; 5: 2311
• 8f Omar-Amrani R, Schneider R, Fort Y. Synthesis 2004; 2527
• 8g Anderson JC, Noble A, Tocher DA. J. Org. Chem. 2012; 77: 6703
• 8h Harada R, Nishida N, Uchiito S, Onozaki Y, Kurono N, Senboku H, Masao T, Ohkuma T, Orito K. Eur. J. Org. Chem. 2012; 366
• 8i Ghorai MK, Nanaji Y. J. Org. Chem. 2013; 78: 3867
• 8j Sirvent JA, Foubelo F, Yus M. J. Org. Chem. 2014; 79: 1356
• 8k Sayyad M, Nanaji Y, Ghorai M. J. Org. Chem. 2015; 80: 12659
• 8l Presset M, Pignon A, Paul J, Le Gall E, Leonel E, Martens T. J. Org. Chem. 2017; 82: 3302
• 8m De Souza Fernandes F, Cormanich RA, Zeoly LA, Formiga AL. B, Coelho F. Eur. J. Org. Chem. 2018; 3211
• 9a Li J.-J, Mei T.-S, Yu J.-Q. Angew. Chem. Int. Ed. 2008; 47: 6452
• 9b He G, Zhao Y, Zhang S, Lu C, Chen G. J. Am. Chem. Soc. 2012; 134: 3
• 9c Nadres ET, Daugulis O. J. Am. Chem. Soc. 2012; 134: 7
• 9d He G, Lu C, Zhao Y, Nack WA, Chen G. Org. Lett. 2012; 14: 2944
• 9e Mei T.-S, Leow D, Xiao H, Laforteza BN, Yu J.-Q. Org. Lett. 2013; 15: 3058
• 9f Ye X, He Z, Ahmed T, Weise K, Akhmedov NG, Petersen JL, Shi X. Chem. Sci. 2013; 4: 3712
• 9g Wang C, Chen C, Zhang J, Han J, Wang Q, Guo K, Liu P, Guan M, Yao Y, Zhao Y. Angew. Chem. Int. Ed. 2014; 53: 9884
• 9h He Y.-P, Zhang C, Fan M, Wu Z, Ma D. Org. Lett. 2015; 17: 496
• 9i Takamatsu K, Hirano K, Satoh T, Miura M. J. Org. Chem. 2015; 80: 3242
• 9j Zheng Y, Song W, Zhu Y, Wei B, Xuan L. Org. Biomol. Chem. 2018; 16: 2402
• 9k Henry MC, Senn HM, Sutherland A. J. Org. Chem. 2019; 84: 346
• 10 Kumar GS, Singh D, Kumar M, Kapur M. J. Org. Chem. 2018; 83: 3941
• 11 Zhao D, Vásquez-Céspedes S, Glorius F. Angew. Chem. Int. Ed. 2015; 54: 1657

For reviews, see:
• 12a Catellani M. Synlett 2003; 298
• 12b Catellani M. Top. Organomet. Chem. 2005; 14: 21
• 12c Catellani M, Motti E, Della Ca’ N. Acc. Chem. Res. 2008; 41: 1512
• 12d Martins A, Mariampillai B, Lautens M. Top. Curr. Chem. 2009; 292: 1
• 12e Ye J, Lautens M. Nat. Chem. 2015; 7: 863
• 12f Della Ca’ N, Fontana M, Motti E, Catellani M. Acc. Chem. Res. 2016; 49: 1389
• 12g Liu Z.-S, Gao Q, Cheng H.-G, Zhou Q. Chem. Eur. J. 2018; 24: 15461
• 12h Zhao K, Ding L, Gu Z. Synlett 2019; 30: 129
• 12i Wang J, Dong G. Chem. Rev. 2019; 119: 7478
• 13 Zheng H, Zhu Y, Shi Y. Angew. Chem. Int. Ed. 2014; 53: 11280
• 14 Liu C, Liang Y, Zheng N, Zhang B.-S, Feng Y, Bi S, Liang Y.-M. Chem. Commun. 2018; 54: 3407
• 15 Wang Z, Li P, Fu H, Dai Q, Hu C. Adv. Synth. Catal. 2019; 361: 192
• 16 Jafarpour F, Jalalimanesh N, Teimouri M, Shamsianpour M. Chem. Commun. 2015; 51: 225
• 17 Annedi SC, Ramnauth J, Maddaford SP, Renton P, Rakhit S, Mladenova G, Dove P, Silverman S, Andrews JS, Felice MD, Porreca F. J. Med. Chem. 2012; 55: 943

For related reviews on C–N single bond cleavage reactions, see:
• 18a Ouyang K, Hao W, Zhang W.-X, Xi Z. Chem. Rev. 2015; 115: 12045
• 18b Desnoyer AN, Love JA. Chem. Soc. Rev. 2017; 46: 197
• 19 Cardenas DJ, Martin-Matute B, Echavarren AM. J. Am. Chem. Soc. 2006; 128: 5033
• 20 Maestri G, Motti E, Della Ca’ N, Malacria M, Derat E, Catellani M. J. Am. Chem. Soc. 2011; 133: 8574