Diphosphine-Catalyzed Mixed Double-Michael Reaction: A Unified Synthesis of Indolines, Dihydropyrrolopyridines, Benzimidazolines, Tetrahydroquinolines, Tetrahydroisoquinolines, Dihydrobenzo-1,4-oxazines, and Dihydrobenzo-3,1-oxazines

Abstract

Seven different types of benzannulated N-heterocycles—indolines, dihydropyrrolopyridines, benzimidazolines, dihydrobenzo-3,1-oxazines, benzomorpholines, tetrahydroquinolines, and tetrahydroisoquinolines—can be obtained from simple dinucleophiles and electron-deficient acetylenes in one synthetic step. This powerful methodology was made possible through the use of diphenylphosphinopropane (DPPP) as the catalyst, with acetic acid and sodium acetate used as additives in some cases. The benzannulated N-heterocycles were isolated in excellent yields under mild metal-free conditions; they were purified without the need for aqueous work-ups.

Functionalized saturated benzannulated N-heterocycles (e.g., indoline, dihydropyrrolopyridine, benzimidazoline, tetrahydroquinoline, tetrahydroisoquinoline, dihydrobenzo-1,4-oxazine, dihydrobenzo-3,1-oxazine) have been of interest to chemists for over a century because of their seemingly ubiquitous presence in natural products¹ and pharmaceutical drugs.² Not surprisingly, several useful strategies are available for the synthesis of these heterocycles, with the majority of them typically generating one or two of the compounds mentioned above.³ Based on our recent finding of a diphosphine-catalyzed mixed double-Michael reaction that proceeds through a [4 + 1] annulation, in this paper we report a unified protocol for the synthesis of the title heterocycles under robust metal-free reaction conditions (Scheme 1).⁴ Our approach is highly modular and particularly well suited for the preparation of substituted saturated benzannulated N-heterocycles. The requisite dinucleophiles are readily assembled from commercially available starting materials.⁵ Given the common occurrence of the title heterocycles in a large number of bioactive molecules, this methodology should provide new avenues toward the preparation of compounds relevant to the development of human medicines.

Scheme 1.

Formation of Benzannulated Heterocycles

As a test case for the construction of aniline-containing benzannulated heterocycles, we subjected the nucleophile 1a and acetylacetylene (2a) to our previously reported mixed double-Michael reaction conditions: i.e., 20 mol % diphenylphosphinopropane (DPPP) in CH₃CN (Table 1, entry 1). The desired indoline 3a was obtained in 79% yield.⁶ Although this yield is acceptable synthetically, the reaction efficiency was markedly poorer than that for pyrrolidine formation from a corresponding aliphatic amine-derived nucleophile (91% vs. 79%). To improve the reaction efficiency, we tested Brønsted acid additives that are known to be compatible with nucleophilic phosphine catalysis.⁷ To our delight, addition of 50 mol % AcOH provided a reaction efficiency comparable with that of aliphatic amine-derived nucleophiles (entry 5; 92% yield).⁸ The combination of a Brønsted acid and its conjugate base performed even better; we obtained indoline 3a in 99% yield in the presence of AcOH and NaOAc (50 mol % each).⁹ Indeed, for several common Brønsted acid additives, pairs of acids and bases, rather than the acids or bases alone, consistently provided higher product yields (entries 5–11).¹⁰ Although there was no clear correlation between the pK_a of the Brønsted acid and the reaction efficiency, additives of low pK_a completely shut down the reaction, presumably through quenching of the reactive zwitterionic intermediates (entries 2–4).¹¹ Notably, one inorganic acid/base pair (NaHCO₃/CO₃²⁻) improved the reaction yield by 8%, whereas another (H₂O/NaOH) did not (entries 8 and 11).¹² The added acid/base pair presumably facilitated the proton transfer steps involved in the double-Michael process.

Table 1.

Evaluation of Conditions for the Formation of Indoline 3a^a

				yield (%)c
entry	acid	pKab	conjugate base	with acid	with acid/base
1	none		none	79	N/D
2	CF3CO2H	−0.25d	CF3CO2Na	0	0
3	H3PO4	2.1d	N/A	0	N/D
4	2,4-dinitrophenol	5.1	N/A	0	N/D
5	CH3CO2H	12.6	CH3CO2Na	92	99
6	bi(2-naphthol)	16.2	+n-BuLi	81	94
7	thiourea	21.0	+n-BuLi	57	68
8	NaHCO3	10.2d	Na2CO3	80	87
9	CF3CH2OH	23.5	CF3CH2ONa	91	93
10	urea	26.9	+n-BuLi	82	85
11	H2O	31.4	NaOH	67	75

^aAll reactions were performed using 1.0 mmol of 1a, 1.1 mmol of acetylacetylene (2a), 20 mol % of DPPP, and 0.50 mmol of the additive(s).

^bpK_a in DMSO.

^cIsolated yield.

^dpK_a in H₂O.

The combination of DPPP catalyst and AcOH/NaOAc additives provided a variety of aniline-containing heterocycles efficiently (Table 2).¹³ With the phenylmalonate nucleophile 1a, both benzoylacetylene and methyl propiolate were suitable Michael acceptors (entries 1 and 2). A variety of substituents on the benzene ring (cf. entries 6 and 12) as well as heteroaromatic rings were compatible with the reaction. For instance, the pyridylmalonate 1d provided the dihydropyrrolopyridines 3d and 3e in excellent yields at elevated temperature (entries 3 and 4). The 1,2-benzenediamine-derived nucleophile 1f also underwent the double-Michael reaction to provide the benzimidazoline 3f (entry 5). This result is in stark contrast with Lu’s report of the tandem umpolung addition/Michael reactions of 1,2-di(p-toluenesulfonamido) ethane onto acetylenes.¹⁴ Benzimidazolines are not only important biologically—they are used as sources of organic hydrides and hydrogen storage materials.¹⁵

Table 2.

Syntheses of Benzannulated N-Heterocycles^a

entry	nucleophile	product	yield (%)b
1	1a	3b	92
2	1a	3c	87
3c	1d	3d	94
4c	1d	3e	96
5c	1f	3f	81
6c	1g	3g	88
7d	1h	3h	81
8d	1h	3i	80
9d	1j	3j	91
10d	1j	3k	92
11e	1l	3l	83
12e	1m	3m	82

^aPerformed using 1.0 mmol of the nucleophile, 1.1 mmol of the acetylene, 20 mol % of DPPP, and 0.50 mmol of AcOH and NaOAc in CH₃CN at rt, unless otherwise noted.

^bIsolated yields after chromatographic purification.

^cReactions were performed under reflux.

^dReactions were run in the absence of AcOH/NaOAc in CH₃CN under reflux.

^eIn the absence of AcOH/NaOAc in CH₃CN at rt.

Next, we extended this chemistry to 1,5- dinucleophiles for the synthesis of six-membered ring-fused benzannulated heterocycles via [5 + 1] annulation. The benzyl alcohol 1g reacted well under the optimized reaction conditions, providing the dihydrobenzo-3,1-oxazine 3g in 88% isolated yield (entry 6). A notable extension of this methodology is represented by the annulations of the related nitrogen–carbon dinucleophile 1h to give the benzomorpholines 3h and 3i (entries 7 and 8), which slowly decomposed in the presence of AcOH and NaOAc in refluxing CH₃CN; we found, however, that catalytic DPPP alone provided slightly better product yields.¹⁶ Dihydrobenzo-1,4- and -3,1-oxazines have long been recognized for their wide range of medicinal activities (e.g., antibacterial, neuroprotectant, cardiovascular, antitumor).¹⁷

We further extended this [5 + 1] annulation to the synthesis of tetrahydroquinolines and tetrahydroisoquinolines (Table 2, entries 9–12). The benzylmalonate 1j, when mixed with electron-deficient acetylenes and catalytic DPPP, generated the tetrahydroquinolines 3j and 3k in excellent yields (entries 9 and 10). The tetrahydroisoquinolines 3l and 3m were formed from the corresponding benzylamine-derived pronucleophiles 1l and 1m (entries 11 and 12). Tetrahydroquinolines and -isoquinolines are present in many natural products and exhibit a wide range of pharmacological activities.¹⁸

To summarize, seven different types of bicyclic heterocycles—indoline, dihydropyrrolopyridine, benzimidazoline, dihydrobenzo-3,1-oxazine, dihydrobenzo-1,4-oxazine, tetrahydroquinoline, and tetrahydroisoquinoline—can be synthesized in one step, in excellent yields, from simple dinucleophiles and electron-deficient acetylenes. The Michael reaction is one of the most important fundamental organic reactions; our study highlights the power of the Michael reaction when applied to the right combination of starting materials under suitable reaction conditions. This versatile catalysis was mediated by DPPP with, in some cases, AcOH/NaOAc additives. This DPPP-catalyzed mixed double-Michael reaction should be further expandable to the assembly of other heterocycles—one goal for our future endeavors.