Synthesis of (E)-3-styryl-2,5-dihydro-1H-pyrrole derivatives via Pd-catalyzed addition of indoles to hydroxy 1,6-enynes

Abstract

A mild Pd-catalyzed addition of indoles to hydroxy 1,6-enynes has been developed. In this reaction, hydroxy 1,6-enynes were selectively transformed into (E)-3-styryl-2,5-dihydro-1H-pyrrole derivatives.

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Pd-catalyzed cycloisomerization of 1,6-enynes has emerged as a powerful method for the construction of five- and six- membered heterocycles and carboncycles in recent years.¹ These compounds are important intermediates for the synthesis of pharmaceutically and biologically active molecules, such as (−)-domoic acid,^2a isodomoic acid H,^2b kainic acid,^2c conessine^2d,e and (+)-intricarene.^2f–h Lately, attack of a nucleophile toward 1,6-enynes has expanded the diversity of these products. However, most of the Pd-catalyzed reactions were restricted to water,^3a halogen^3b–e and OAc^3f–j as nucleophiles. Several years ago, Echavarren group reported gold(I)-catalyzed addition reactions of electron-rich arenes and indoles to the 1,6-enynes.^4a,b Veronique Michelet also developed asymmetric gold-catalyzed hydroarylation/cyclization reactions.^4c To our knowledge, Pd-catalyzed intermolecular reaction of 1,6-enynes and indoles has not yet been reported. In the context of our ongoing efforts on Pd-catalyzed cyclization of enynols to construct hetero- and carbo-cyclic structures,^1i,5a,b we wish to report the Pd-catalyzed addition of indoles to the hydroxyl 1,6-enynes.

Our initial investigations were focused on 1,6-enynol 1a due to its stability and reactivity. After some optimization, we were pleased to find that treatment of 1a with 3 equiv. of N-methyl indole, 1 equiv. of TBHP, 10 mol% of Pd(acac)₂ in AcOH at 70 °C gave the product 3aa (E)-1-methyl-3-(phenyl(4-styryl-1-tosyl-2,5-dihydro-1H-pyrrol-3-yl)methyl)-1H-indole in 47% yield after 1.5 h (Table 1, entry 1). The structure of 3aa was unambiguously confirmed by X-ray crystallographic analysis (see ESI†). A screen of various phosphine ligands revealed that electron-withdrawing groups on the ligand were beneficial for this reaction, (C₆F₅)₃P improved the yield to 59% (entries 2–5). Although other Pd catalysts were also tested, no better result was obtained (entries 6–8). To our surprise, solvent investigations revealed that AcOH was essential for this reaction and no reaction occurred in other solvents (entries 9–11). With this result in mind, we tested cosolvents. Using MeNO₂ as a cosolvent with AcOH improved the yield of 3aa. After certain optimization of the MeNO₂/AcOH, the yield improved to 66% under MeNO₂–AcOH (1 : 1) (entries 12–14). When the temperature reduced to 60 °C, we could get a higher yield to 71%, lower temperature gave a negative result (entries 14–16). Other cosolvents showed to be less effective (entries 17–18). As expected, no reaction occurred in the absence of Pd catalyst (entry 19).

Table 1 Pd-catalyzed reactions of 1a with indole under various conditions^a

Entry	Catalyst	Ligand	Solvent	T/°C	t/h	Yield^b/%
a Unless otherwise noted, all of the reaction were carried out using 0.1 mmol of 1a, 3 equiv. of 2a, 10 mol% catalyst, 20 mol% ligand and 1 equiv. of TBHP (t-butyl hydroperoxide) under Ar in 1 mL solvent.b Isolated yields.c No reaction.
1	Pd(acac)2	—	AcOH	70	1.5	47
2	Pd(acac)2	P(2-furyl)3	AcOH	70	1	47
3	Pd(acac)2	X-Phos	AcOH	70	2	54
4	Pd(acac)2	P[O(o-tol)]3	AcOH	70	2.5	52
5	Pd(acac)2	(C6F5)3P	AcOH	50	5	59
6	Pd(OAc)2	(C6F5)3P	AcOH	70	3.5	44
7	Pd(CF3CO2)2	(C6F5)3P	AcOH	70	3.5	51
8	PdCl2	(C6F5)3P	AcOH	70	1	—^c
9	Pd(acac)2	(C6F5)3P	MeCN	70	1	—
10	Pd(acac)2	(C6F5)3P	DCE	70	1	—
11	Pd(acac)2	(C6F5)3P	THF	70	1	—
12	Pd(acac)2	(C6F5)3P	MeNO2–AcOH (10 : 1)	70	2	63
13	Pd(acac)2	(C6F5)3P	MeNO2–AcOH (1 : 10)	70	1.5	64
14	Pd(acac)2	(C6F5)3P	MeNO2–AcOH (1 : 1)	70	1.5	66
15	Pd(acac)2	(C6F5)3P	MeNO2–AcOH (1 : 1)	60	1.5	71
16	Pd(acac)2	(C6F5)3P	MeNO2–AcOH (1 : 1)	50	5	30
17	Pd(acac)2	(C6F5)3P	DCE–AcOH (1 : 1)	70	2.5	56
18	Pd(acac)2	(C6F5)3P	DCM–AcOH (1 : 1)	60	1	59
19	—	(C6F5)3P	MeNO2–AcOH (1 : 1)	60	1	—

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The amounts of the additive and N-methyl indole were also important, 3 equiv. of N-methyl indole and 1 equiv. of TBHP was optimum (Table 2, entries 4–9). It is worth mentioning that the reaction could proceed in the absence of oxidant (entry 4). The result indicates that TBHP only plays a supporting role in the reaction. Thus, the optimized reaction conditions were affirmed as follows: 3 equiv. of indole as nucleophile, 10 mol% Pd(acac)₂ as catalyst, 20 mol% (C₆F₅)₃P as ligand and 1 equiv. of TBHP as the additive under Ar in MeNO₂/AcOH (1 : 1) at 60 °C for 1.5 h.

Table 2 Optimization studies for the amounts of reagents^a

Entry	Oxidant (equiv.)	Pd(acac)2 (mol%)	(C6F5)3P (mol%)	Equiv. of 2a	t/h	Yield^b/%
a Unless otherwise noted, all of the reaction were carried out using 0.1 mmol of 1, N-methyl indole, Pd(acac)2, (C6F5)3P and TBHP under Ar in 1 mL MeNO2–AcOH (1 : 1) at 60 °C.b Isolated yields.c No reaction.
1	K2S2O8 (1)	10	20	3	4.5	65
2	O2 (1 atm)	10	20	3	4.5	66
3	BQ (1)	10	20	3	1	—^c
4	—	10	20	3	4	64
5	TBHP (0.2)	10	20	3	3	68
6	TBHP (2)	10	20	3	5	55
7	TBHP (1)	10	20	1.1	3	64
8	TBHP (1)	10	20	2	3	69
9	TBHP (1)	10	20	5	3	70
10	TBHP (1)	5	10	3	6	63
11	TBHP (1)	10	10	3	2	65
12	TBHP (1)	10	30	3	2	57

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Having identified the optimal conditions, we next examined the scope and limitations of the Pd-catalyzed cyclization reaction. As can be seen in Table 3, the reaction tolerated both electron-withdrawing and -donating groups on the aromatic R², the corresponding products 3ba–3ea were obtained in moderate yields (Table 3, entries 2–5). Compound 1e, containing a naphthalene moiety, was a good substrate for this reaction, and 3ea was obtained in 74% yield (entry 5). The substrates with an aliphatic or a heterocyclic R² group can also smoothly converted into the corresponding products in moderate yields (entries 6–7). Substrate 1 h, with aliphatic R¹ and R² groups, affords the desired product in 50% yield (entry 8). The reaction efficiency was somewhat affected by the substituents on the C–C double bond. Terminal olefin 1i only provides 3ia in 27% yield (entry 9). Notably, carbon-tethered 1,6-enynol were also applicable to this reaction, giving 3ja in 63% yield (entry 10).

Table 3 Pd-catalyzed reactions of hydroxy 1,6-enynes with nucleophiles^a

Entry	Enyne	X	R^1	R^2	R^3	Indole	R^4	R^5	Product	t/h	Yield^b/%
a Unless otherwise noted, all of the reaction were carried out using 0.1 mmol of 1, 3 equiv. of 2, 10 mol% Pd(acac)2, 20 mol% (C6F5)3P and 1 equiv. of TBHP under Ar in 1 mL MeNO2–AcOH (1 : 1) at 60 °C.b Isolated yields.
1	1a	NTs	Ph	Ph	H	2a	H	Me	3aa	1.5	71
2	1b	NTs	Ph	4-Me Ph	H	2a	H	Me	3ba	3	65
3	1c	NTs	Ph	4-Br Ph	H	2a	H	Me	3ca	3	64
4	1d	NTs	Ph	4-OMe Ph	H	2a	H	Me	3da	3	60
5	1e	NTs	Ph	1-Naphthyl	H	2a	H	Me	3ea	3	74
6	1f	NTs	Ph	1-Furyl	H	2a	H	Me	3fa	1.5	64
7	1g	NTs	Ph	n-C6H13	H	2a	H	Me	3ga	5	62
8	1h	NTs	Ph	Me	Me	2a	H	Me	3ha	12	50
9	1i	NTs	H	Ph	H	2a	H	Me	3ia	2	27
10	1j	C(CO2Me)2	Ph	Ph	H	2a	H	Me	3ja	4	63
11	1a	NTs	Ph	Ph	H	2b	H	H	3ab	2.5	66
12	1a	NTs	Ph	Ph	H	2c	5-OMe	Me	3ac	4	50
13	1a	NTs	Ph	Ph	H	2d	5-CN	Me	3ad	12	44
14	1a	NTs	Ph	Ph	H	2e	7-Me	Me	3ae	2.5	63
15	1a	NTs	Ph	Ph	H	2f	4-OMe	H	3af	4	53
16	1a	NTs	Ph	Ph	H	2g	6-Cl	H	3ag	4	63
17	1a	NTs	Ph	Ph	H	2h	7-Me	H	3ah	4	70
18	1a	NTs	Ph	Ph	H	2i	H	Bn	3ai	2	70

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To further expand the scope of this reaction, unprotected indole was tested. To our delight, the reaction proceeds smoothly under the standard condition (entry 11). Therefore, we investigated a range of indoles and N-methyl indoles. A weak electron-donating or electron-withdrawing group is most favorable for this reaction (entries 14, 16 and 17), but a strong electron-donating or electron-withdrawing group is less effective (entries 12, 13 and 15). N-benzyl-substituted indole lead to a good result in 70% yield (entry 18). We also attempted other nucleophiles, such as furan and 2,6-dimethylphenol. To our disappointment, no desired product was observed.

To gain more insight into the mechanism of the present reaction, we applied the optimal condition on 1a without nucleophiles, AcOH react with the 1,6 enyne 1a and gave the product 4a (Scheme 1, eqn (1)). Meanwhile, we investigated the origin of the proton incorporated into the cyclic product by using deuterium labeled AcOH. Deuterium labeled product 4a-d₄ was obtained when AcOH-d₄ was used in the absence of nucleophiles (Scheme 1, eqn (2)). However, when treating 1a and indole 2g with AcOH-d₄, a 60 : 40 mixture of 3ag-d₄ and 3ag was obtained in 50% yield (Scheme 1, eqn (3)). The low deuterium incorporation observed in the reaction with indole and AcOH-d₄ could be due to H/D exchange between the acidic proton of the acid and the proton in C-3 of the indole. So protonolysis of a C–Pd bond was involved in the mechanism.

Scheme 1 Mechanism investigation.

Based on the above observations together with previous literature reports,⁶ a plausible mechanism for this reaction is proposed (Scheme 2). Coordination of catalyst with ligand affords active PdL₂X₂ species. The PdL₂X₂ would coordinate to the enyne to form complex 5. Cyclization of 5 would give cyclopropylpalladium carbene complex 6. The attack of indole at the cyclopropyl carbon give the intermediate 7 and a proton is released at the same time. 8 would formed from the protonolysis of 7, which undergoes 1,4-elimination to give the final product 3aa.⁷ It is worth to notice that H/D exchange between the acidic proton of the acid and the proton in C-3 of the indole leads to the low deuterium incorporation observed in the reaction with indole and AcOH-d₄. However, when the reaction carried out in the absence of indole, AcOH attack the intermediate 6 to form 9, which undergoes 1,4-elimination to give 10. In this case, AcOH is the sole origin of proton and deuterium labeled product would obtained in the solvent AcOH-d₄.

Scheme 2 Reaction mechanism of Pd(acac)₂-catalyzed reaction of 1,6-enyne with N-methyl indole.

Conclusions

In summary, we have developed a mild Pd-catalyzed addition of indoles to hydroxyl 1,6-enynes. In this reaction, 1,6-enynes were selectively transformed into (E)-3-styryl-2,5-dihydro-1H-pyrrole derivatives. A variety of substituted enynes and indoles can proceed this reaction in moderate yields. We are currently investigating Pd-catalyzed addition of other nucleophiles to 1,6-enynes.

Acknowledgements

The authors gratefully acknowledge National Basic Research Program of China (973 program) and “111” program of MOE. We thank the NSF (NSF-21072080, NSF-20732002) for financial support. We also thank Project and Program for Changjiang Scholars and innovative Research Team in University (IRT1138).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and analysis data for new compounds. CCDC 969442–969443. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ra47647b

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