Palladium/norbornene chemistry: an unexpected route to methanocarbazole derivatives via three Csp³–Csp²/Csp³–N/Csp²–N bond formations in a single synthetic sequence

Abstract

A Catellani reaction terminated by palladacycle amination leading to methanocarbazoles is reported. The outcome is the formation of three different Csp³–Csp²/Csp³–N/Csp²–N bonds through a Heck reaction/C–H activation/double amination cascade in one process.

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Selective C–C and C–N bond formation through palladium catalyzed C–H bond functionalization because of its viable and environmentally benign features is one of the most fundamental topics in modern chemistry.¹ Among the considerable efforts made, the Catellani reaction represents a promising protocol for selective multifunctionalization of aromatics through sequential aromatic ortho C–H activation/C–C bond formation followed by C–N or C–O bond construction.² This type of cascade reaction which has led to many synthetic applications is based on the cooperative action of norbornene and palladium.³ The unusual reactivity of norbornene in these reactions contributes to the construction of a palladacycle intermediate through stereoselective cis, exo insertion into the arylpalladium bond.⁴ The intermediacy of the Pd(IV) species plays a crucial role and directs the subsequent reaction steps selectively to the assembly of the product scaffold. Generally, in ortho-substituted iodoarenes regioselective Csp²–Csp² rather than Csp²–Csp³ coupling of Pd(IV) intermediates at the carbon ortho to the original C–halide bond occurs which ensures the generation of a biaryl linkage (ortho-effect).⁵ It has been also recently discovered that certain chelating groups may offset this ortho-effect and lead to a Csp²–Csp³ migratory coupling of arene and norbornene.⁶ In this context, recently Catellani and Derat developed a palladium/norbornene-catalyzed reaction of iodoarenes and ortho-bromoanilines which led to the formation of dibenzoazepine derivatives with a contrast deviation from Catellani's previous report on the formation of N-substituted carbazoles via the reaction of the same reagents having acetylated or sulfonylated amino groups (Scheme 1, path b versus path a).^6d,7 Chelation of the unprotected amino group of bromoaniline to palladium played the key role for Csp²–Csp³ bond formation followed by the subsequent cyclization to the nitrogen-containing seven-membered ring.

Scheme 1 N-heterocycles from (halo)anilines and iodoarenes.

Based on these results and in a continuation of our efforts aimed at the development of palladium-catalyzed cascade reactions, herein we report our findings on a new outcome from the palladium-catalyzed reaction of iodoarenes, anilines and either norbornene or norbornadiene (Scheme 1, path c). The presented study uncovers a different chemo- and regioselective annulation reaction to provide an interesting formation of methanocarbazole derivatives via a cascade intermolecular Heck-type reaction/intramolecular C–H activation/direct intermolecular amination. This process involves three Csp³–Csp²/Csp³–N/Csp²–N bond formations in one procedure and involves the unexpected direct amination of palladacycle which was not achieved previously. This multistep reaction proceeds in an ordered sequence and is chemo-, regio-, and stereoselective where an ortho-amination overtakes the conventional ipso-amination. The other remarkable feature of this reaction compared to commonly utilized palladium catalyzed C–H aminations,⁸ is the direct conversion of aromatic ortho C–H bond to C–N bond under atom economical, synthetically convenient and mild reaction conditions without the requisite for an external oxidant.

In a typical experiment 2-iodotoluene 1a, p-toluidine 2a and norbornene, were reacted in the presence of PdCl₂, PPh₃, Cs₂CO₃ in DME at 120 °C for 24 h. Surprisingly, 1,4-methanocarbazole 3a was obtained albeit in 22% yield (Table 1, entry 1). The reaction was optimized with respect to palladium sources and ligands where Pd(OAc)₂/PPh₃ proved to be the most effective catalytic system (entries 2–6). Employment of harder bases such as K₂CO₃, further increased the efficiency of the annulation reaction (entry 7). Next some other reaction variables including solvent and temperature were examined and the ideal results were obtained in DMF heating at 140 °C (entries 8–11). Finally, decreasing the amount of norbornene to 2 equivalents, improved the yield (entry 12). The control experiment in the absence of the catalyst resulted in the recovery of the starting materials.

Table 1 Optimization of annulation reaction of 2-iodotoluene 1a^a

Entry	Base	[Pd]	L	Solv.	T [°C]	Yield [%]
a Reaction conditions: p-toluidine 2a (0.2 mmol), 2-iodotoluene (2 equiv.), catalyst (10 mol%), ligand (22 mol%), base (2 equiv.), norbornene (3 equiv.) in a solvent (0.1 M) at 120 °C for 24 h. b Norbornene (2 equiv.).
1	Cs2CO3	PdCl2	PPh3	DME	120	22
2	Cs2CO3	Pd(OAc)2	PPh3	DME	120	30
3	Cs2CO3	Pd(dba)2	PPh3	DME	120	15
4	Cs2CO3	Pd(OAc)2	PBu3	DME	120	29
5	Cs2CO3	Pd(OAc)2	P(OEt)3	DME	120	28
6	Cs2CO3	Pd(OAc)2	P(o-Tol)3	DME	120	29
7	K2CO3	Pd(OAc)2	PPh3	DME	120	35
8	K2CO3	Pd(OAc)2	PPh3	DMF	120	47
9	K2CO3	Pd(OAc)2	PPh3	DMSO	120	33
10	K2CO3	Pd(OAc)2	PPh3	DMA	120	21
11	K2CO3	Pd(OAc)2	PPh3	DMF	140	57
12	K 2 CO 3	Pd(OAc) 2	PPh 3	DMF	140	63

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Gratifyingly, using Pd(OAc)₂ (10 mol%), PPh₃ (22 mol%), K₂CO₃ (2 equiv.), norbornene (2 equiv.) at 140 °C in DMF for 24 h led to the formation of 3a in 63% isolated yield. 1,4-Methanocarbazoles (fused indolines) are ubiquitous structural motifs in natural and synthetic compounds which exhibit various biological and pharmaceutical activities.⁹ For example, N-phenyl indoline derivatives exhibit antidepressant activities¹⁰ and hexahydrocarbazoles have a typical antipsychotic character.¹¹ Also indoline-based organic dyes have been proved to exhibit high efficiencies in dye-sensitized solar cells.¹² Accordingly, new and efficient synthetic routes to these structural motifs would find significant utility in organic synthesis.

With the optimized conditions in hand, the scope of the annulation reaction to construct various methanocarbazoles was examined. As is summarized in Table 2, a wide range of substituted iodoarenes and anilines were found to be compatible with this domino Heck reaction/double amination protocol. First the reactivity of ortho-substituted iodoarenes, 2-iodotoluene 1a and 4-iodo-m-xylene 1b with various anilines were explored where the latter behaved better resulting in the desired product 3b, in 81% yield (entry 2).

Table 2 Scope of the annulation reaction of haloarenes^a

Entry		Product	Yield [%]
a Optimized conditions. b Yields for X = Br in parentheses.
1		3a: R^2 = H, R^3 = H, R^4 = 4-Me	63
2		3b: R^2 = 7-Me, R^3 = H, R^4 = 4-NO2	81
3		3c: R^2 = H, R^3 = H, R^4 = 4-OMe	58
4		3d: R^2 = H, R^3 = 3-NO2, R^4 = H	48
5		3e: R^2 = H, R^3 = H, R^4 = H	44
6		3f: R^2 = H, R^3 = 3-NO2, R^4 = 4-F	57
7		3g: R^3 = H, R^4 = 4-NO2	73 (62)^b
8		3h: R^3 = 3-Cl, R^4 = 4-Cl	50 (37)^b
9		3i: R^3 = H, R^4 = 4-Cl	45 (36)^b
10		3j: R^3 = H, R^4 = 4-CF3	48 (35)^b
11		3k: R^3 = 4-NO2	74
12		3l: R^1 = H, R^2 = 7-Me, R^3 = 4-NO2	62
13		3m: R^1 = CF3, R^2 = H, R^3 = 4-NO2	47
14		3n: R^1 = H, R^2 = H, R^3 = 4-NO2	56 (55)^b
15		3o: R^1 = H, R^2 = H, R^3 = 2-Me	Trace

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Various electron-rich and -deficient anilines with methoxy, nitro and fluoro substituents were also tolerated under the optimized reaction conditions, affording the annulated products in moderate to good yields (entries 3–6). It is noteworthy that methanocarbazole derivatives of 4-nitroanilines may have potential applications in construction of pigments and synthetic organic dyes containing a new type of indoline structure.¹³

Intriguingly, even iodoarenes lacking ortho-substituents reacted well with anilines under the optimized reaction conditions to give the same annulated products. 4-Methoxy-substituted iodoarenes reacted successfully with anilines to afford the related methanocarbazoles in moderate to good yields (entries 7–10). Notably, bromoarenes were also tolerated under the reaction conditions where comparable yields of 3g–3j were attained employing 1-bromo-4-methoxybenzene. Furthermore, chlorinated anilines also survived the reaction conditions and afforded 3h and 3i in moderate yields (entries 8 and 9). Albeit in moderate yields, this is a synthetically interesting result as such substituents are versatile handles for further functionalization and facilitating the practical synthesis of highly functionalized molecules. Notably, the more sterically encumbered 2-iodonaphthalene was also successfully converted to the corresponding methanocarbazole 3k in 74% yield (entry 11). Even the ortho-trifluoromethyl substituted iodoarene, which, due to its inferior reactivity, is rarely used as a coupling partner in direct arylation reactions, was compatible with the reaction conditions (entry 13). Besides substituted haloarenes, iodo- and bromobenzene were also found to be amenable to the sequential Heck/amination reaction (entry 14). Unfortunately, more electron deficient haloarenes bearing nitro groups were not tolerated under the reaction conditions, affording only the N-arylated products. A competing reaction was also observed using 4-nitroaniline. An amino palladation of norbornene was followed by a sequential Heck reaction/cyclization to furnish dimethanocarbazole 4 (Scheme 2).¹⁴ Other anilines gave no or negligible amounts of such byproducts.

Scheme 2 Amino-palladation/Heck reaction/cyclization reaction leading to the side product dimethanocarbazole.

It is significant that 1,3-bis(4-nitrophenyl)urea also survived the reaction conditions where annulation and deprotection of anilines proceeded smoothly leading to the desired indolines in moderate to good yields (Scheme 3).

Scheme 3 Urea coupling partner in the annulation reaction.

Lastly, the reaction of iodoarene 1b and norbornadiene with a higher reactivity compared to norbornene was explored. Pleasingly, the norbornadiene adduct 5 was constructed in a satisfactory yield (Scheme 4).

Scheme 4 Norbornadiene in the annulation reaction.

Our plausible mechanistic hypothesis shown in Scheme 5, seems to involve an interconversion between Pd⁰ and Pd^II species. The first step involves oxidative addition of aryl halide to Pd(0) followed by stereoselective insertion of norbornene into the arylpalladium bond, leading to the formation of the cis, exo-arylnorbornylpalladium species which readily undergoes cyclization via C–H bond activation to the five membered palladacycle 6. The activation of the unsaturated carbon–hydrogen bond of arene can be induced by its coordination to the metal, which makes the bond susceptible to the amination reaction. Next, association of the aniline to the palladium species¹⁵ (instead of oxidative addition of haloarene to form the Pd(IV) species) and subsequent reductive elimination, converts intermediate 7 to product 3 and Pd(0). Likely, nitrogen chelation to the palladium plays the key role for the selective addition of aniline to the palladacycle and formation of the indolines instead of unsymmetrical biaryls. Two alternative routes to the desired methanocarbazoles were also considered which were discarded according to experimental evidence (see the ESI† for details).

Scheme 5 Plausible reaction mechanism.

In conclusion, we have uncovered a simple route to construct three Csp³–Csp²/Csp³–N/Csp²–N bonds in a single synthetic process based on the ordered sequences of Heck reaction/C–H activation/amination cascade which leads to the formation of interesting methanocarbazole derivatives, using readily accessible starting materials. Consecutive construction of double C–N bonds which is not often feasible in the absence of oxidants and complicated ligands is readily achieved using this course and may be applicable in construction of interesting fused heterocycles. Furthermore, a deviation from the conventional palladium/norbornene catalyzed reactions is launched.

Notes and references

1. For selected reviews on metal-catalyzed C–H bond functionalizations see: (a) J. Wencel-Delord, T. Droge, F. Liu and F. Glorius, Chem. Soc. Rev., 2011, 40, 4740; (b) C. S. Yeung and M. V. Dong, Chem. Rev., 2011, 111, 1215; (c) J. F. Hartwig, Chem. Soc. Rev., 2011, 40, 1992; (d) L. McMurray, F. OHara and M. Gaunt, Chem. Soc. Rev., 2011, 40, 1885; (e) T. W. Lyons and M. Sanford, Chem. Rev., 2010, 110, 1147; (f) D. A. Colby, R. G. Bergman and J. A. Ellman, Chem. Rev., 2010, 110, 624; (g) L.-M. Xu, B.-J. Li, Z. Yang and Z.-J. Shi, Chem. Soc. Rev., 2010, 39, 712; (h) L. Ackermann, R. Vicente and A. R. Kapdi, Angew. Chem., Int. Ed., 2009, 48, 9792; (i) C.-J. Li, Acc. Chem. Res., 2009, 42, 335; (j) X. Chen, K. M. Engle, D.-H. Wang and J.-Q. Yu, Angew. Chem., Int. Ed., 2009, 48, 5094; (k) R. Giri, B.-F. Shi, K. M. Engle, N. Maugel and J.-Q. Yu, Chem. Soc. Rev., 2009, 38, 3242; (l) I. V. Seregin and V. Gevorgyan, Chem. Soc. Rev., 2007, 36, 1173; (m) L.-C. Campeau and K. Fagnou, Chem. Soc. Rev., 2007, 36, 1058; (n) L.-C. Campeau and K. Fagnou, Chem. Commun., 2006, 1253; (o) O. Daugulis, V. G. Zaitzev, D. Shabashov, Q.-N. Pham and A. Lazareva, Synlett, 2006, 3382.
2. (a) M. Catellani, F. Frignani and A. Rangoni, Angew. Chem., Int. Ed., 1997, 36, 119; (b) M. Catellani and M. C. Fagnola, Angew. Chem., Int. Ed., 1994, 33, 2421 ; for selected reviews, see: ; (c) P. Sehnal, R. J. K. Taylor and I. J. S. Fairlamb, Chem. Rev., 2010, 110, 824; (d) G. P. Chiusoli, M. Catellani, M. Costa, E. Motti, N. Della Ca' and G. Maestri, Coord. Chem. Rev., 2010, 254, 456; (e) A. Martins, B. Mariampillai and M. Lautens, Top. Curr. Chem., 2010, 292, 1; (f) K. Muniz, Angew. Chem., Int. Ed., 2009, 48, 9412; (g) M. Catellani, E. Motti and N. Della Ca, Acc. Chem. Res., 2008, 41, 1512; (h) D. Alberico, M. E. Scott and M. Lautens, Chem. Rev., 2007, 107, 174; (i) M. Lautens, D. Alberico, C. Bressy, Y.-Q. Fang, B. Mariampillai and T. Wilhelm, Pure Appl. Chem., 2006, 78, 351; (j) M. Catellani, E. Motti, F. Faccini and R. Ferraccioli, Pure Appl. Chem., 2005, 77, 1243; (k) M. Catellani, Top. Organomet. Chem., 2005, 14, 21.
3. For selected examples of Catellani reaction see: (a) P.-X. Zhou, L. Zheng, J.-W. Ma, Y.-Y. Ye, X.-Y. Liu, P.-F. Xu and Y.-M. Liang, Chem. – Eur. J., 2014, 20, 6745; (b) Z.-Y. Chen, C.-Q. Ye, H. Zhu, X.-P. Zeng and J.-J. Yuan, Chem. – Eur. J., 2014, 20, 4237; (c) H. Weinstabl, M. Suhartono, Z. Qureshi and M. Lautens, Angew. Chem., Int. Ed., 2013, 52, 5305; (d) L. Jiao and T. Bach, Angew. Chem., Int. Ed., 2013, 52, 6080; (e) Z. Dong and G. Dong, J. Am. Chem. Soc., 2013, 135, 18350; (f) H. Liu, M. El-Salfiti and M. Lautens, Angew. Chem., Int. Ed., 2012, 51, 9846; (g) F. Jafarpour and N. Jalalimanesh, Tetrahedron, 2012, 68, 10286; (h) D. I. Chai, P. Thansandote and M. Lautens, Chem. – Eur. J., 2011, 17, 8175; (i) L. Jiao and T. Bach, J. Am. Chem. Soc., 2011, 133, 12990; (j) M. Blanchot, D. A. Candito, F. Larnaud and M. Lautens, Org. Lett., 2011, 13, 1486; (k) D. A. Candito and M. Lautens, Org. Lett., 2010, 12, 3312; (l) G. Maestri, M.-H. Larraufie, E. Derat, C. Ollivier, L. Fensterbank, E. Lacote and M. Malacria, Org. Lett., 2010, 12, 5692; (m) E. Motti, N. Della Ca, S. Deledda, E. Fava, F. Panciroli and M. Catellani, Chem. Commun., 2010, 46, 4291; (n) P. Thansandote, E. Chong, K.-O. Feldmann and M. Lautens, J. Org. Chem., 2010, 75, 3495; (o) F. Jafarpour and H. Hazrati, Adv. Synth. Catal., 2010, 352, 363; (p) N. Della Ca, E. Motti, A. Mega and M. Catellani, Adv. Synth. Catal., 2010, 352, 1451; (q) D. A. Candito and M. Lautens, Angew. Chem., Int. Ed., 2009, 48, 6713; (r) A. Rudolph and M. Lautens, Angew. Chem., Int. Ed., 2009, 48, 2656; (s) F. Jafarpour and P. T. Ashtiani, J. Org. Chem., 2009, 74, 1364; (t) Y. B. Zhao, B. Mariampillai, D. A. Candito, B. Laleu, M. Z. Li and M. Lautens, Angew. Chem., Int. Ed., 2009, 48, 1849; (u) K. M. Gericke, D. I. Chai, N. Bieler and M. Lautens, Angew. Chem., Int. Ed., 2009, 48, 1447; (v) N. Della Ca, G. Maestri and M. Catellani, Chem. – Eur. J., 2009, 15, 7850; (w) G. Maestri, N. Della Ca and M. Catellani, Chem. Commun., 2009, 4892; (x) N. Della Ca', E. Motti and M. Catellani, Adv. Synth. Catal., 2008, 350, 2513; (y) D. G. Hulcoop and M. Lautens, Org. Lett., 2007, 9, 1761; (z) F. Jafarpour and M. Lautens, Org. Lett., 2006, 8, 3601.
4. (a) M. Catellani, C. Mealli, E. Motti, P. Paoli, E. Perez-Carreno and P. S. Pregosin, J. Am. Chem. Soc., 2002, 124, 4336; (b) C.-S. Li, C.-H. Cheng, F.-L. Liao and S.-L. Wang, Chem. Commun., 1991, 710.
5. G. Maestri, E. Motti, N. Della Ca, M. Malacria, E. Derat and M. Ctellani, J. Am. Chem. Soc., 2011, 133, 8574.
6. For exceptions to ortho-effect see: (a) M. Cheng, J. Yan, F. Hu, H. Chen and Y. Hu, Chem. Sci., 2013, 4, 526; (b) S. A. Lopez and K. N. Houk, J. Org. Chem., 2013, 78, 1778; (c) M. H. Larraufie, G. Maestri, A. Beaume, E. Derat, C. Ollivier, L. Fensterbank, C. Courillon, E. Lacote, M. Catellani and M. Malacria, Angew. Chem., Int. Ed., 2011, 50, 12253; (d) N. Della Ca, G. Maestri, M. Malacria, E. Derat and M. Catellani, Angew. Chem., Int. Ed., 2011, 50, 12257.
7. N. Della Ca', G. Sassi and M. Catellani, Adv. Synth. Catal., 2008, 350, 2179.
8. For reviews of C–H amination, see: (a) S. H. Cho, J. Y. Kim, J. Kwak and S. Chang, Chem. Soc. Rev., 2011, 40, 5068; (b) H. M. L. Davies and J. R. Manning, Nature, 2008, 451, 417; (c) A. R. Dick and M. S. Sanford, Tetrahedron, 2006, 62, 2439; (d) H. M. L. Davies and M. S. Long, Angew. Chem., Int. Ed., 2005, 44, 3518; (e) P. Mueller and C. Fruit, Chem. Rev., 2003, 103, 2905.
9. (a) E. Fattorusso and O. Taglialatela-Scafati, Modern Alkaloids: Structure, Isolation, Synthesis and Biology, Wiley-VCH, Weinheim, 2008; (b) H. Kazuhiro and T. Kawassaki, Nat. Prod. Rep., 2007, 24, 843; (c) P. M. Dewick, Medicinal Natural Products: A Biosynthetic Approach, John Wiley & Sons, New York, 2nd edn, 2002.
10. (a) S. Archer, D. W. Wylie, L. S. Harris, T. R. Lewis, J. W. Schulenberg, M. R. Bell, R. K. Kullnig and A. Arnold, J. Am. Chem. Soc., 1962, 84, 1306; (b) D. W. Wylie and S. Archer, J. Med. Pharm. Chem., 1962, 5, 932.
11. (a) J. M. Walker, W. D. Bowen, F. O. Walker, R. R. Matsumoto, B. de Costa and K. C. Rice, Pharmacol. Rev., 1990, 42, 355; (b) M. R. Munetz, S. C. Schulz, M. Bellin and I. Harty, Drug Dev. Res., 1989, 16, 79; (c) W. M. Welch, C. A. Herbert, A. Weissman and B. K. Koe, J. Med. Chem., 1986, 29, 2093; (d) J. Lehmann, F. Knoch and N. Jiang, Arch. Pharm., 1993, 326, 947.
12. (a) H.-M. Cheng and W.-F. Hsieh, Energy Environ. Sci., 2010, 3, 442; (b) D. Kuang, S. Uchida, R. Humphry-Baker, S. M. Zakeeruddin and M. Grätzel, Angew. Chem., Int. Ed., 2008, 47, 1923; (c) T. Horiuchi, H. Miura, K. Sumioka and S. Uchida, J. Am. Chem. Soc., 2004, 126, 12218.
13. (a) W. Li, B. Liu, Y. Wu, S. Zhu, Q. Zhang and W. Zhu, Dyes Pigm., 2013, 99, 176; (b) M. Ashraf, A. Teshome, A. J. Kay, G. J. Gainsford, M. D. H. Bhuiyan, I. Asselberghs and K. Clays, Dyes Pigm., 2012, 95, 455; (c) Q. Li, L. Lu, C. Zhong, J. Shi, Q. Huang, X. Jin, T. Peng, J. Qin and Z. Li, J. Phys. Chem. B, 2009, 113, 14588.
14. J. L. Brice, J. E. Harang, V. I. Timokhin, N. R. Anastasi and S. S. Stahl, J. Am. Chem. Soc., 2005, 127, 2868.
15. (a) H. Zheng, Y. Zhu and Y. Shi, Angew. Chem., Int. Ed., 2014, 53, 11280 and references cited therein; (b) T. A. Ramirez, Q. Wang, Y. Zhu, H. Zheng, X. Peng, R. G. Cornwall and Y. Shi, Org. Lett., 2013, 15, 4210.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and characterization data. See DOI: 10.1039/c4cc06789d

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