Cooperative effect in organocatalytic intramolecular hydroamination of unfunctionalized olefins

Abstract

The cooperative effect in organocatalytic hydroamination of unfunctionalized olefins was reported. In the presence of 3-hydroxy-2-naphthoic acid, N-benzyl 4-penten-1-amines and 5-hexen-1-amines produced the intramolecular cyclization products in good isolated yields.

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Nitrogen-containing heterocyclic compounds are paramount in medicinal chemistry,¹ and different methods have been developed for the preparation of nitrogen-containing heterocycles.² These methods include electrophile-induced cyclization of N-protected pent-4-en-1-amines or pent-4-en-1-imines with bromine³ or PhSeBr.⁴ The thus obtained functionalized heterocycles could be converted to 2-methylpyrrolidines upon LiAlH₄ (ref. 3) or tributylstannane⁵ reduction. Similarly, ring expansion of substituted aziridines⁶ or azetidines⁷ furnished a variety of substituted pyrrolidines and piperidines in good to excellent yields.

Among the variety of methods developed, intramolecular hydroamination of C=C double bonds should be one of the most straightforward ones for the formation of C–N bonds and N-containing heterocycles.⁸ This has been realized by using organolanthanides or other rare earth metal,⁹ group-IV metal,¹⁰ noble metal such as palladium,¹¹ platinum,¹² silver,¹³ gold,¹⁴ rhodium,¹⁵ iridium¹⁶ and ruthenium¹⁷ compounds as well as some first row transition metal compounds¹⁸ as catalysts. In addition, Brønsted acids were also used to promote the intramolecular hydroamination of several unfunctionalized olefins bearing amide functional groups. Using triflic or sulphuric acid as catalyst, intramolecular hydroamination of N-tosylamides proceeded readily, giving the corresponding N-tosyl pyrrolidines and piperidines in high yields,¹⁹ and triflic acid was effective for intermolecular hydroamination of unfunctionalized C=C bonds as well.²⁰ The rate determining step was the formation of a carbocation intermediate via proton transfer to the C=C double bond, and the hydroamination product was produced by trapping the intermediate with sulfonamide nitrogen. Based on this rationale, perfluorous sulfonic acid²¹ or heteropoly acids²² were also used to promote hydroamination of unfunctionalized olefins bearing electron deficient nitrogen atoms. In contrast, Brønsted acid-promoted electron rich nitrogen sources-involved intramolecular hydroamination of unfunctionalized olefins were rare.²³ In this communication, we wish to report the effect of cooperative catalysis on organocatalytic hydroamination of N-alkyl amino alkenes.

Benzoic acid in combination with palladium compounds has been reported to promote hydroamination of alkynes.²⁴ In our course of searching for new catalyst systems for intramolecular hydroamination of unfunctionalized olefins bearing electron-rich amino groups, we found that aromatic acids alone could also promote the hydroamination of electron-rich amine substrate N-benzyl-2,2-diphenyl-4-penten-1-amine (1a). In the presence of 20 mol% of salicylic acid, 58% of 1a was converted to hydroamination product N-benzyl 2-methyl-4,4-diphenylpyrrolidine (2a) after 24 hours (Scheme 1).

Scheme 1 Salicylic acid promoted hydroamination.

Encouraged by this result, the reaction was further studied to get detailed understanding of the reaction. Table 1 summarised the results from different solvents. These results indicated that high temperature was generally needed for an efficient hydroamination reaction, and polar solvents such as THF, DMSO or 1,4-dioxane would interact efficiently with the catalyst which would in turn affect its interaction with the substrates (entries 2, 6, and 7), and these solvents were generally unsuitable for the reaction. Xylene was found to be a suitable solvent (entry 4) for the reaction possibly due to the high boiling point of the solvent which could ensure a high temperature required for the reaction. The amount of salicylic acid also showed some impact on the reaction (entries 4, and 8–12) and 20 mol% of catalyst was enough to promote the reaction (entry 11).

Table 1 Solvent effect in salicylic acid-promoted hydroamination^a

Entry	Solvent	T (°C)	Conversion^b (%)
a Reaction time: 24 hours.b Based on crude NMR analysis of the reaction mixture.c NR = no reaction.d Amount of salicylic acid: 5 mol%.e Amount of salicylic acid: 10 mol%.f Amount of salicylic acid: 15 mol%.g Amount of salicylic acid: 40 mol%.h Amount of salicylic acid: 60 mol%.
1	EDC	90	19
2	THF	70	NR^c
3	Benzene	90	Trace
4	Xylene	130	91
5	Toluene	120	58
6	DMSO	130	19
7	1,4-Dioxane	100	14
8^d	Xylene	130	26
9^e	Xylene	130	63
10^f	Xylene	130	86
11^g	Xylene	130	90
12^h	Xylene	130	91

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As a bifunctional molecule, salicylic acid could work differently to promote the reaction. While the carboxyl group would act as a Brønsted acid, the hydroxyl group could act either as a hydrogen bond donor (H atom) or as a hydrogen bond acceptor (O atom). To study the role of hydroxyl group in the reaction and to find a suitable organocatalyst for the intramolecular hydroamination of 1a, Brønsted acids with different functional groups were tested, and the results were summarised in Table 2.

Table 2 Intramolecular hydroamination of 1a with different acids^a

Entry	Catalyst	R	Yield (%)	Entry	Catalyst	Yield (%)
a Reaction conditions: solvent = xylene (reflux), reaction time = 24 hours, catalyst loading = 20 mol%.
1		o-OH	91	15		Trace
2		o-OMe	Trace	16		(R)-: 77
3		o-SH	52	17		(S)-: 85
4		o-COOH	33%	18		47
5		H	13	19		5
6		m-OH	27
7		p-OH	21
8		H	9
9		p-SO3H	9
10		NH2	No reaction
11		OH	22
12			19
13		1-OH	17
14		3-OH	99

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As indicated in Table 2, a significant cooperative effect was observed in the reaction, i. e., both the hydroxyl group and the carboxyl group were important, and they acted cooperatively to promote the intramolecular hydroamination of 1a. Carboxyl group or hydroxyl group alone was not powerful enough to promote the reaction as indicated by the results from benzoic acid (entry 5) and phenol (entry 8). Results from o-, m- and p-hydroxybenzoic acids (entries 1, 6 and 7) indicated that the distance between hydroxyl group and carboxyl group was also a very important factor governing the reaction. Further, the acidity of the Brønsted acid seemed also to be a crucial factor for the reaction, and sulfonic acids (entries 9–12) didn't show any beneficial effects on the reaction. The use of weaker Brønsted acid allows the presence of an acid base equilibrium that preserves some free acid as well as free amino group in the reaction system, and the use of a strong Brønsted acid would force the equilibrium completely towards the deprotonated species and the ammonium would not be able to undergo any hydroamination reaction. This is also the reason why previous reports mainly focused on amide substrates. Results from salicylic acid (entry 1) and o-anisic acid (entry 2) indicated that the hydroxyl group acted as a hydrogen bond donor in the reaction, and changing the hydrogen bond donor (OH in salicylic acid, entry 1) to hydrogen bond acceptor (OMe in o-anisic acid, entry 2) led to a sharp drop of the reactivity. After a thorough survey of the available acids, 3-hydroxy-2-naphthoic acid (entry 14) was found to be an ideal catalyst for intramolecular hydroamination of 1a.

Reactions of different naphthoic acid isomers (Table 2, entries 13 and 14) also showed a stereo demanding feature of the reaction. While 3-hydroxy-2-naphthoic acid (3) led to complete conversion of the substrate 1a, 1-hydroxy-2-naphthoic acid (4) gave only 17% conversion of the substrate under otherwise identical conditions. We reasoned that during the reaction, carboxyl group would act as an acid to activate the C=C double bond, and hydroxyl group will bring the amino group to the reaction centre through hydrogen bond. Due to the 1,8-repulsion of 1-hydroxy-2-naphthoic acid (4), the hydrogen bond between N-substituted amino groups and 4 may not be strong enough to initiate a reaction. In the case of compound 3, the 3-hydroxy group was open to the substrates, and the access of N-substituted amino groups was not affected (Fig. 1).

Fig. 1 Low catalytic activity of 1-hydroxy-2-naphthoic acid caused by 1,8-repulsion.

After establishing a general procedure for intramolecular hydroamination of 1a, the scope of the substrates was studied. The reactions were carried out in xylene at refluxing temperature, 20 mol% of 3-hydroxy-2-naphthoic acid (3) was used as catalyst, and the results were summarised in Table 3.

Table 3 Intramolecular hydroamination of unfunctionalized olefins catalysed by 3-hydroxy-2-naphthoic acid^a

Entry	Substrate	R^1	n	R^2	Yield^b (%)
a Catalyst loading = 20 mol%.b Isolated yields.c Reaction time = 72 hours.d NR = no reaction.
1	1a	Ph	1	Bn	92
2	1b	Ph	1	4-MeBn	90
3	1c	Ph	1	4-MeOBn	83
4	1d	Ph	1	4-FBn	92
5	1e	Ph	1	4-ClBn	87
6	1f	Ph	1	4-O2NBn	58
7	1g	Ph	1	iBu	70
8	1h	Ph	1	nBu	65
9^c	1i	Ph	2	Bn	63
10^c	1j	Ph	2	4-MeBn	60
11^c	1k	Ph	2	4-MeOBn	61
12^c	1l	Ph	2	4-FBn	58
13^c	1m	Ph	2	4-ClBn	58
14	1n	Me	1	Bn	46
15^c	1o	Me	2	Bn	46
16	1p	–(CH2)5–	1	Bn	67
17	1q	Ph	1	Ts	NR^d
18	1r	H	1	nBu	NR
19	1s	H	1	Bn	NR

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As indicated in Table 3, both 2-methylpyrrolidines and 2-methylpiperdines could be prepared via intramolecular hydroamination of the open chain aminoolefins. Thorpe–Ingold effect was observed in the reaction,²⁵ and substrates without substituents on the main chain failed to react (entries 19 and 20). N-substituted 5-hexen-1-amines (entries 9–13, and entry 15) generally showed low reactivity comparing to their 4-penten-1-amine counterparts (entries 1–8), possibly due to the unfavourable entropy nature of the reaction.

On the basis of the current results, a tentative reaction mechanism was drawn in Scheme 2. At room temperature, carboxyl group and amino group would interact with each other through electrostatic interaction,¹⁹ and no reaction would occur at this stage. This also accounts for the high temperature needed for Brønsted acid-catalysed hydroamination reactions. At high temperature, interaction of free carboxyl group with C=C double bond leads to the activation of the latter, and nucleophilic attack of amino group on the activated C=C double bond produced the hydroamination product. N-tosyl amide (entry 18 of Table 3) failed to react, possibly due to the weak hydrogen bond between the catalyst hydroxyl group and the substrate amide as well as the low nucleophilicity of the nitrogen atom.

Scheme 2 A tentative mechanism of the reaction.

In summary, cooperative effect played an important role in 3-hydroxy-2-naphthoic acid-catalysed hydroamination of unfunctionalized olefins. Carboxyl group activated the C=C double bond, and hydroxyl group was responsible for bringing the amino group to the reaction centre. The current work would shed light on the design of organocatalysts for intramolecular hydroamination of unfunctionalized olefins.

Acknowledgements

We acknowledge the financial support from National Natural Science Foundation of China (NSFC 20972072, NSFC 21272121).

Notes and references

1. (a) B. Alcaide, P. Almendros and C. Aragoncillo, Curr. Opin. Drug Discovery Dev., 2010, 13, 685–697; (b) K. Salat, A. Moniczewski and T. Librowski, Mini-Rev. Med. Chem., 2013, 13, 335–352; (c) A. Verma, M. R. Yadav, R. Giridhar, N. Prajapati, A. C. Tripathi and S. K. Saraf, Comb. Chem. High Throughput Screening, 2013, 16, 345–393.
2. (a) H. Kiyota, in Bioactive Heterocycles I, ed. S. Eguchi, 2006, pp. 181–214; (b) K. C. Majumdar, S. Muhuri, R. U. Islam and B. Chattopadhyay, Heterocycles, 2009, 78, 1109–1169; (c) R. Ferraccioli, Synthesis-Stuttgart, 2013, 45, 581–591.
3. N. de Kimpe, M. Boelens, J. Piqueur and J. Baele, Tetrahedron Lett., 1994, 35, 1925–1928.
4. N. De Kimpe and M. Boelens, J. Chem. Soc., Chem. Commun., 1993, 916–918.
5. D. De Smaele and N. De Kimpe, J. Chem. Soc., Chem. Commun., 1995, 2029–2030.
6. M. D'Hooghe, W. Aelterman and N. De Kimpe, Org. Biomol. Chem., 2009, 7, 135–141.
7. W. Van Brabandt, R. Van Landeghem and N. De Kimpe, Org. Lett., 2006, 8, 1105–1108.
8. (a) M. Nobis and B. Driessen-Holscher, Angew. Chem., Int. Ed., 2001, 40, 3983–3985; (b) J. F. Hartwig, Pure Appl. Chem., 2004, 76, 507–516; (c) T. E. Muller, K. C. Hultzsch, M. Yus, F. Foubelo and M. Tada, Chem. Rev., 2008, 108, 3795–3892; (d) J. Hannedouche and E. Schulz, Chem. – Eur. J., 2013, 19, 4972–4985.
9. (a) S. Hong and T. J. Marks, Acc. Chem. Res., 2004, 37, 673–686; (b) K. C. Hultzsch, D. V. Gribkov and F. Hampel, J. Organomet. Chem., 2005, 690, 4441–4452.
10. (a) I. Bytschkov and S. Doye, Eur. J. Org. Chem., 2003, 935–946; (b) A. V. Lee and L. L. Schafer, Eur. J. Inorg. Chem., 2007, 2243–2255; (c) G. F. Zi, J. Organomet. Chem., 2011, 696, 68–75.
11. (a) M. Meguro and Y. Yamamoto, Tetrahedron Lett., 1998, 39, 5421–5424; (b) M. Kawatsura and J. F. Hartwig, J. Am. Chem. Soc., 2000, 122, 9546–9547; (c) U. Nettekoven and J. F. Hartwig, J. Am. Chem. Soc., 2002, 124, 1166–1167; (d) A. M. Johns, M. Utsunomiya, C. D. Incarvito and J. F. Hartwig, J. Am. Chem. Soc., 2006, 128, 1828–1839; (e) F. E. Michael and B. M. Cochran, J. Am. Chem. Soc., 2006, 128, 4246–4247.
12. (a) J. J. Brunet, M. Cadena, N. C. Chu, O. Diallo, K. Jacob and E. Mothes, Organometallics, 2004, 23, 1264–1268; (b) C. F. Bender and R. A. Widenhoefer, J. Am. Chem. Soc., 2005, 127, 1070–1071; (c) D. Karshtedt, A. T. Bell and T. D. Tilley, J. Am. Chem. Soc., 2005, 127, 12640–12646.
13. X. Giner and C. Najera, Synlett, 2009, 3211–3213.
14. (a) C. F. Bender and R. A. Widenhoefer, Chem. Commun., 2006, 4143–4144; (b) C. Brouwer and C. He, Angew. Chem., Int. Ed., 2006, 45, 1744–1747; (c) X. Q. Han and R. A. Widenhoefer, Angew. Chem., Int. Ed., 2006, 45, 1747–1749.
15. (a) M. Beller, H. Trauthwein, M. Eichberger, C. Breindl, J. Herwig, T. E. Muller and O. R. Thiel, Chem. – Eur. J., 1999, 5, 1306–1319; (b) M. Utsunomiya, R. Kuwano, M. Kawatsura and J. F. Hartwig, J. Am. Chem. Soc., 2003, 125, 5608–5609; (c) X. Q. Shen and S. L. Buchwald, Angew. Chem., Int. Ed., 2010, 49, 564–567.
16. (a) R. Dorta, P. Egli, F. Zurcher and A. Togni, J. Am. Chem. Soc., 1997, 119, 10857–10858; (b) J. R. Zhou and J. F. Hartwig, J. Am. Chem. Soc., 2008, 130, 12220–12221; (c) K. D. Hesp, S. Tobisch and M. Stradiotto, J. Am. Chem. Soc., 2010, 132, 413–426.
17. (a) H. Schaffrath and W. Keim, J. Mol. Catal. A: Chem., 2001, 168, 9–14; (b) M. Utsunomiya and J. F. Hartwig, J. Am. Chem. Soc., 2004, 126, 2702–2703; (c) C. S. Yi and S. Y. Yun, Org. Lett., 2005, 7, 2181–2183.
18. (a) A. Zulys, M. Dochnahl, D. Hollmann, K. Lohnwitz, J. S. Herrmann, P. W. Roesky and S. Blechert, Angew. Chem., Int. Ed., 2005, 44, 7794–7798; (b) M. Dochnahl, J. W. Pissarek, S. Blechert, K. Lohnwitz and P. W. Roesky, Chem. Commun., 2006, 3405–3407; (c) J. G. Taylor, N. Whittall and K. K. Hii, Org. Lett., 2006, 8, 3561–3564; (d) H. Ohmiya, T. Moriya and M. Sawamura, Org. Lett., 2009, 11, 2145–2147; (e) L. Zhou, D. S. Bohle, H. F. Jiang and C. J. Li, Synlett, 2009, 937–940; (f) M. Dochnahl, K. Lohnwitz, A. Luhl, J. W. Pissarek, M. Biyikal, P. W. Roesky and S. Blechert, Organometallics, 2010, 29, 2637–2645; (g) W. D. Rao, P. Kothandaraman, C. B. Koh and P. W. H. Chan, Adv. Synth. Catal., 2010, 352, 2521–2530; (h) A. Luhl, H. P. Nayek, S. Blechert and P. W. Roesky, Chem. Commun., 2011, 47, 8280–8282; (i) G. Q. Liu and Y. M. Li, Tetrahedron Lett., 2011, 52, 7168–7170; (j) J. Jenter, A. Luhl, P. W. Roesky and S. Blechert, J. Organomet. Chem., 2011, 696, 406–418; (k) A. Mukherjee, T. K. Sen, P. K. Ghorai, P. P. Samuel, C. Schulzke and S. K. Mandal, Chem. – Eur. J., 2012, 18, 10530–10545; (l) B. W. Turnpenny, K. L. Hyman and S. R. Chemler, Organometallics, 2012, 31, 7819–7822.
19. B. Schlummer and J. F. Hartwig, Org. Lett., 2002, 4, 1471–1474.
20. D. C. Rosenfeld, S. Shekhar, A. Takemiya, M. Utsunomiya and J. F. Hartwig, Org. Lett., 2006, 8, 4179–4182.
21. (a) Y. Yin and G. Zhao, Chimica Oggi/Chemistry Today, 2007, 25, 42–45; (b) Y. Yin and G. Zhao, J. Fluorine Chem., 2007, 128, 40–45.
22. (a) L. Yang, L. W. Xu and C. G. Xia, Tetrahedron Lett., 2008, 49, 2882–2885; (b) N. Lingaiah, N. S. Babu, K. M. Reddy, P. S. S. Prasad and I. Suryanarayana, Chem. Commun., 2007, 278–279.
23. (a) L. Ackermann and A. Althammer, Synlett, 2008, 995–998; (b) J. G. Taylor, L. A. Adrio and K. K. Hii, Dalton Trans., 2010, 39, 1171–1175.
24. (a) I. Kadota, A. Shibuya, L. M. Lutete and Y. Yamamoto, J. Org. Chem., 1999, 64, 4570–4571; (b) L. M. Lutete, I. Kadota, A. Shibuya and Y. Yamamoto, Heterocycles, 2002, 58, 347–357.
25. (a) R. M. Beesley, C. K. Ingold and J. F. Thorpe, J. Chem. Soc., Trans., 1915, 107, 1080–1106; (b) J. Kaneti, A. J. Kirby, A. H. Koedjikov and I. G. Pojarlieff, Org. Biomol. Chem., 2004, 2, 1098–1103; (c) M. R. Crimmin, M. Arrowsmith, A. G. M. Barrett, I. J. Casely, M. S. Hill and P. A. Procopiou, J. Am. Chem. Soc., 2009, 131, 9670–9685.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3ra47060a

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