Palladium-catalyzed 1,2-amino carbonylation of 1,3-dienes with (N-SO₂Py)-2-iodoanilines: 2,3-dihydroquinolin-4(1H)-ones synthesis

Abstract

A palladium-catalyzed 1,2-amino carbonylation of 1,3-dienes with (N-SO₂Py)-2-iodoanilines has been developed for the construction of 2,3-dihydroquinolin-4(1H)-one scaffolds. Using benzene-1,3,5-triyl triformate (TFBen) as the CO source under the assistance of the N-SO₂Py directing group, the reaction proceeded well to afford various 2,3-dihydroquinolin-4(1H)-ones in good yields (up to 88%). The effect of the directing groups was investigated and control experiments were performed to have a better understanding of the reaction pathway.

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Introduction

1,3-Dienes represent a class of important building blocks in organic synthesis and are prevalent structural motifs in natural products.¹ Difunctionalization of 1,3-dienes provides an efficient and straightforward method to rapidly assemble complexed molecules.² Among them, pioneered by Dieck and Larock,^3,4 metal-catalyzed 1,2-carboamination of 1,3-dienes have been extensively studied for the synthesis of diverse N-containing heterocyclic compounds.^5–8 For instance, Yang and Xing developed a palladium-catalyzed intramolecular 1,2-aminoalkylation of β-ketoamide-tethered 1,3-dienes for the synthesis of pyrrolizidine derivatives.⁵ In 2016, Han's group disclosed an enantioselective annulation of 1,3-dienes by 2-iodoanilines in the presence of the palladium catalyst to give a series of chiral indolines.⁶ Very recently, Gevorgyan and co-workers realized the photoinduced palladium-catalyzed intermolecular 1,2-aminoalkylation of 1,3-dienes, furnishing a variety of allylic amines.⁷ However, to the best of our knowledge, there have been no reports on 1,2-amino carbonylation of 1,3-dienes for the expeditious construction of 2,3-dihydroquinolin-4(1H)-one scaffolds, which are frequently found in various molecules with biological activities such as anti-tumor⁹ and analgesic effects.¹⁰

Transition-metal-catalyzed carbonylative reactions have become one of the most powerful tools to access valuable carbonyl-containing compounds.¹¹ TFBen, a benign CO surrogate developed by our group, has been widely employed in carbonylative processes.¹² As a part of our continued interest in carbonylation, we now report a palladium-catalyzed carbonylation of (N-SO₂Py)-2-iodoanilines and 1,3-dienes. With the assistance of the N-SO₂Py directing group, 1,3-dienes could undergo 1,2-amino carbonylation with (N-SO₂Py)-2-iodoanilines to give various 2,3-dihydroquinolin-4(1H)-ones in good yields by using TFBen as the CO source.

Results and discussion

Initially, (N-SO₂Py)-2-iodoaniline 1a and diene 2a were treated with TFBen in the presence of Pd(OAc)₂ as the catalyst and various phosphine ligands at 110 °C for 24 h (Table 1, entries 1–5). To our delight, the reaction with DPPP gave the desired product 3aa in 39% yield (Table 1, entry 4). Then, a set of palladium catalysts was screened (Table 1, entries 6–10). It was shown that the reaction yield was significantly improved to 60% when Pd(TFA)₂ was employed (Table 1, entry 7). Furthermore, much lower yields of 3aa were obtained when other solvents such as toluene, dioxane, MeCN, and DMSO were tested (Table 1, entries 11–14). It was noted that extending the reaction time enhanced the yield to 79% (Table 1, entry 15). Finally, a few bases were investigated and the reaction with K₃PO₄ gave 84% yield of 3aa (Table 1, entry 17). Additionally, reducing the catalyst loading hampered the reaction remarkably (Table 1, entry 19). Notably, 36% yield of the target product can be obtained with a CO balloon instead of TFBen. Here, the requisite amount of TFBen is for maintaining a certain pressure of CO in the reaction tube, as carbonylation and decarbonylation are reversible. The formation of CO gas was confirmed using a CO detector.

Table 1 Screening of the reaction conditions^a

Entry	[Pd]	Ligand	Base	Solvent	Yield (%)
a Reaction conditions: 1a (0.5 mmol, 1.0 equiv.), 2a (1.5 mmol, 3.0 equiv.), Pd catalyst (20 mol%), ligand (20 mol%), TFBen (2.0 mmol, 4.0 equiv.), base (1.0 mmol, 2.0 equiv.), solvent (3.0 mL), 110 °C, 24 h, isolated yield. b 30 h. c Pd catalyst (10 mol%).
1	Pd(OAc)2	PPh3	Et3N	THF	n.r.
2	Pd(OAc)2	PCy3	Et3N	THF	n.r.
3	Pd(OAc)2	Xphos	Et3N	THF	n.r.
4	Pd(OAc)2	DPPP	Et3N	THF	39
5	Pd(OAc)2	DPPB	Et3N	THF	Trace
6	Pd(acac)2	DPPP	Et3N	THF	10
7	Pd(TFA)2	DPPP	Et3N	THF	60
8	Pd(PPh3)4	DPPP	Et3N	THF	31
9	Pd2(dba)3	DPPP	Et3N	THF	23
10	PdCl2	DPPP	Et3N	THF	20
11	Pd(TFA)2	DPPP	Et3N	Toluene	Trace
12	Pd(TFA)2	DPPP	Et3N	Dioxane	Trace
13	Pd(TFA)2	DPPP	Et3N	MeCN	40
14	Pd(TFA)2	DPPP	Et3N	DMSO	n.r.
15^b	Pd(TFA)2	DPPP	Et3N	THF	79
16^b	Pd(TFA)2	DPPP	DBU	THF	n.r.
17	Pd(TFA) 2	DPPP	K 3 PO 4	THF	84
18^b	Pd(TFA)2	DPPP	Cs2CO3	THF	n.r.
19^b^,^c	Pd(TFA)2	DPPP	K3PO4	THF	18

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With the optimal reaction conditions in hand (Table 1, entry 17), the scope of (N-SO₂Py)-2-iodoanilines 1 was examined (Scheme 1). For compounds bearing electron-donating or withdrawing substituents, the reaction gave the corresponding products 3ba–ia in good yields (75–86%). It was found that the reaction of the substrate with a phenyl unit gave product 3ja in 77% yield. Moreover, 86% yield of product 3ka was achieved when 4,5-dimethyl-(N-SO₂Py)-2-iodoaniline 1k was subjected to the reaction system.

Scheme 1 Scope of (N-SO₂Py)-2-iodoanilines. Reaction condition: 1a (0.5 mmol, 1.0 equiv.), 2 (1.5 mmol, 3.0 equiv.), Pd(TFA)₂ (20 mol%), DPPP (20 mol%), TFBen (2.0 mmol, 4.0 equiv.), K₃PO₄ (1.0 mmol, 2.0 equiv.), THF (3.0 mL), 110 °C, 30 h, isolated yield.

Subsequently, the scope of 1,3-dienes 2 was investigated as shown in Scheme 2. The reaction of the phenyl-substituted 1,3-dienes having para-electron-donating or withdrawing groups proceeded well to give the expected products 3ab–ai in high yields (70–86%). For the meta-substituted compounds 2j–l, the reaction led to the desired products 3aj–al in 70–84% yields. In addition, it was shown that ortho-substituted 1,3-dienes can also be successfully converted to product 3am and 3an in high yields. In addition, 88% yield of product 3ap was obtained in the reaction of the naphthyl-substituted 1,3-diene 2p. Notably, compound 2q containing a thiophene ring was smoothly transformed into the target product 3aq in 80% yield. Unfortunately, 1,1-disubsituted, 1,2-disubsituted, and alkyl-substituted 1,3-dienes 2r–t failed to undergo the designed reactions.

Scheme 2 Scope of 1,3-dienes. Reaction condition: 1a (0.5 mmol, 1.0 equiv.), 2 (1.5 mmol, 3.0 equiv.), Pd(TFA)₂ (20 mol%), DPPP (20 mol%), TFBen (2.0 mmol, 4.0 equiv.), K₃PO₄ (1.0 mmol, 2.0 equiv.), THF (3.0 mL), 110 °C, 30 h, isolated yield.

Gratifyingly, treatment of product 3aa with excess zinc powder in a mixed solvent (THF/NH₄Cl(_aq) = 1 : 1) at 60 °C for 12 h could smoothly remove the N-SO₂Py directing group to give the corresponding free amino compound 4 in 88% yield. Therefore, further derivatizations on the N-position of 2,3-dihydroquinolin-4(1H)-one skeletons could be realized easily (Scheme 3, eqn (1)). In order to demonstrate the utility of this protocol, a few transformations of product 3aa were completed as well. When 3aa was reacted with hydroxylamine hydrochloride in the presence of pyridine at 80 °C for 10 h, 87% yield of the oxime 5 was obtained (Scheme 3, eqn (2)).¹⁴ Reduction of 3aa with NaBH₄ afforded the alcohol 6 in 90% yield with 2.5 : 1 diastereoselectivity (Scheme 3, eqn (3)).¹⁵

Scheme 3 Removal of the N-SO₂Py directing group and transformations of product 3aa.

Then, we examined the effect of the directing group on 2-iodoanilines and performed some control experiments as well to gain more insights into the reaction mechanism (Scheme 4). The reaction with the unprotected 2-iodoaniline 7 led to complicated mixtures with no observation of the expected product (Scheme 4, eqn (1)). It was shown that the reaction did not occur when N-Me-2-iodoaniline 8 or N-Boc-2-iodoaniline 9 was subjected to the standard conditions, respectively (Scheme 4, eqn (2) and (3)). Interestingly, N-picolinyl-2-iodoaniline 10 was converted to the corresponding Heck coupling product 11 in 47% yield and the target product 12 was not obtained (Scheme 4, eqn (4)). It suggested that the sulfuryl unit on the directing group was crucial in promoting the carbonylation. Notably, when the N-benzenesulfonyl-2-iodoaniline 13 was tested, complicated mixtures were obtained, which indicated that the N atom on N-SO₂Py of 2-iodoanilines played an important role in this reaction (Scheme 4, eqn (5)). Furthermore, when 1a was treated with Pd(TFA)₂ (1.0 equiv.) and PPh₃ (2.0 equiv.) under the standard conditions, the acylpalladium intermediate 14 was obtained in 98% yield, whose structure was unambiguously confirmed by X-ray crystallography (CCDC 2058728, see the ESI†) (Scheme 4, eqn (6)).¹³ An attempt to obtain a similar complex with DPPP failed, perhaps due to its high reactivity. Finally, the reaction of 14 with the diene 2a in the presence of DPPP (1.0 equiv.) furnished the desired product 3aa in 27% yield with 56% of 14 recovered (Scheme 4, eqn (7)). These results revealed that a similar intermediate like 14 could be formed in this reaction through the coordination of the palladium catalyst with the N atom on N-SO₂Py of 2-iodoanilines.

Scheme 4 Effect of directing groups and control experiments.

On the basis of the previous reports^3–5,8 and our experimental results, a plausible mechanism for this palladium-catalyzed 1,2-amino carbonylation of 1,3-dienes with (N-SO₂Py)-2-iodoanilines is proposed (Scheme 5). Initially, the active Pd(0) species, generated from Pd(TFA)₂ and DPPP, undergoes oxidative addition with (N-SO₂Py)-2-iodoaniline 1a to afford Pd(II) complex A. Then, the insertion of CO which was released from TFBen to A with the aid of a base gives the acyl Pd(II) intermediate B. Subsequently, the π-allyl Pd(II) intermediate C is formed via the insertion of diene 2a to B and which is further converted into Pd(II) complex D. Finally, reductive elimination of D leads to the desired product 3aa and regenerates the active Pd(0) species for the next catalytic cycle.

Scheme 5 Plausible mechanism.

Conclusions

In conclusion, we have developed a facile and straightforward method to synthesize important 2,3-dihydroquinolin-4(1H)-one scaffolds via a palladium-catalyzed 1,2-amino carbonylation of 1,3-dienes with (N-SO₂Py)-2-iodoanilines. This protocol can be realized to give various 2,3-dihydroquinolin-4(1H)-ones by utilizing TFBen as the CO source and N-SO₂Py as the directing group.

Experimental

The (N-SO₂Py)-2-iodoanilines 1 (0.5 mmol, 1.0 equiv.), Pd(TFA)₂ (33.2 mg, 0.1 mmol, 20 mol%), dppp (41.2 mg, 0.1 mmol, 20 mol%), K₃PO₄ (212.3 mg, 1.0 mmol, 2.0 equiv.) and a 2.5 mL vial containing TFBen (420.3 mg, 2.0 mmol, 4.0 equiv.) were added to an oven-dried tube (15.0 mL) which was then placed under vacuum and refilled with nitrogen three times.¹⁶ The 1,3-dienes 2 (1.5 mmol, 3.0 equiv.) and THF (3.0 mL) were added into the tube via a syringe. The tube was sealed and stirred at 110 °C for 30 h. When the reaction was completed, the resulting mixture was concentrated under vacuum and purified by silica gel column using chromatography (petroleum ether/dichloromethane = 2 : 1) to obtain the products 3.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We acknowledge the financial support from the Joint Funds of Zhejiang Natural Science Foundation and Taizhou (LTY21B020001).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: General comments, general procedure, analytic data, and NMR spectra. CCDC 2058728. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d1qo00290b

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