Photoredox-catalyzed chemoselective aerobic Cα–H oxidation of propargylamines: synthesis of substituted 2-ynamide and oxazolo[2,3-a]isoquinolinone derivatives

Abstract

An efficient approach for visible-light-induced chemoselective aerobic Cα–H oxidation of propargylamines via molecular oxygen as an oxidant using rose bengal as a photoredox catalyst is reported. The photochemical protocol was employed for the direct oxygenation of Cα–H 2-propynyl-tertiary amines to 2-ynamides and further cyclization of oxazolo[2,3-a]isoquinolinone derivatives from phenylpropynyltetrahydroisoquinoline was established.

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Introduction

Ynamides are versatile intermediates in organic transformation¹ for the construction of many biologically active natural products² and heterocycles.³ In particular, natural product agonists, arteriosclerosis, [MMP]-10/-13-inhibitor and opioid receptor contains 2-ynamide motifs.^4,5 Moreover, oxazolo[2,3-a]tetrahydroisoquinolines are a unique class of heterocyclic core structures found in many isoquinoline alkaloids.⁶ They have a wide range of biological and pharmacological properties including antibacterial activity, antioxidant activity, anti-hypertensive activity and anti-mycobacterial activity.⁷ Besides, they also act as synthons for several biologically active molecules such as (−)-trolline, (+)-oleracein E, quinocarcin, and trazomine (Fig. 1).⁸

Fig. 1 Biologically active compounds containing 2-ynamides and oxazolo[2,3-a]isoquinolinone motifs.

Propargylamines are versatile building blocks for the synthesis of a wide range of nitrogen heterocyclic compounds⁹ consisting of a highly reactive amine and alkyne moiety on the backbone. In the oxidation reaction, mostly the oxidizing agent reacts with its nitrogen to give N-oxides¹⁰ and Wacker-type oxidation of acetylenes into 1,2-diketones occurs.¹¹ J. Chen et al. have investigated the oxidation of propargylamines to enaminones by the use of m-CPBA as the oxidant (Scheme 1, eqn (1)).¹² Later on, W. Ji et al. reported a visible-light-mediated oxidative formylation of N,N-di(prop-2-yn-1-yl)anilines with molecular oxygen in the absence of a photosensitizer (Scheme 1, eqn (2)).¹³ Although the Cα–H oxidation reaction of propargylamines is unknown in the literature, it's of high demand in synthetic transformations.

Scheme 1 Synthetic approach for oxidation of propargylamines.

So far, many strategies of Cα–H oxidation have been reported for the synthesis of amides directly from amines by the use of stoichiometric oxidants such as iodosobenezne, PhCO₃^tBu, ^tBuOOH, RuO₂/NaIO₄etc.¹⁴ In addition to these, many transition metal [M = Ru/Au/Cu/Fe/Mn, etc.] complexes have also been employed for the direct Cα–H oxidation.¹⁵ However, these oxidation conditions are not attractive from the economic and environmental perspectives and also limited to amides.

In recent years, visible light-mediated metal-free photoredox catalysts have been found as a powerful tool in many organic transformations,¹⁶ which offer cost-effective, mild reaction conditions and functional group tolerance and also provide an alternative to transition metal-based photocatalysts. Moreover, transition metal-free photocatalysts are capable of activating O₂ by photoinduced electron transfer (PET) processes and this activated molecular oxygen is useful for Cα–H oxidation reactions.¹⁷ Recently, S. Das and co-workers demonstrated the use of visible light-mediated metal-free photoredox catalysts for Cα–H oxidation of tertiary amines to amides using oxygen as an oxidant.¹⁸ Recently, our group reported a visible-light-driven Cu(I)-catalysed aerobic oxidative C(sp)–S coupling reaction.¹⁹ Based on all the information furnished above, we wish to report an efficient approach for visible light initiated chemoselective aerobic Cα–H oxidation of 2-propynyl-tertiaryamines in the presence of highly reactive nucleophilic amine and alkyne groups via molecular O₂ as an oxidant using rose bengal as a photoredox catalyst and further, to disclose a cyclization reaction for the synthesis of oxazolo[2,3-a]isoquinolinone derivatives.

Results and discussion

To start with, investigation of the Cα–H amine oxidation of 4-(3-phenylprop-2-yn-1-yl)morpholine 1aa (0.5 mmol) was done in the presence of rose bengal (RB) (2 mol%) and DBU (0.5 mmol) with an O₂ atmosphere in ACN under blue LED irradiation to afford the ynamide 2aa in 94% isolated yield. Inspired by the result, three other photosensitizers such as 9-mesityl-10-methylacridinium tetrafluoroborate (Acr⁺-Mes), methylene blue, and rhodamine B were examined. However, they led to lower yields of 71%, 35%, and 15%, respectively (Table 1, entries 2–4). Other bases, such as K₂CO₃, Et₃N, and 2,6-lutidine were found to be inferior to DBU (Table 1, entries 5–7). Screening solvents such as DCE, acetone, MeOH, and ACN : H₂O provided only a moderate yield of 2aa (Table 1, entries 8–11). Control experiments (Table 1, entries 12–15) revealed that rose bengal, DBU, visible light and O₂ are essential for the current Cα–H amine oxidation reaction.

Table 1 Optimization table for the synthesis of ynamides 2aa from 4-(3-phenylprop-2-yn-1-yl)morpholine 1aa ^a

Entry	Variation from the standard conditions	Yield^b (%)
a Reaction conditions: 0.5 mmol (1aa) and 2 mol% of catalyst and 0.5 mmol DBU in 4 mL of solvent were irradiated with blue light in the presence of an O2 atmosphere. b Yields were determined after purification of the compound. n.r. = no reaction.
1	None	94
2	Acr^+-Mes instead of RB	71
3	Methylene blue instead of RB	35
4	Rhodamine B instead of RB	15
5	K2CO3 instead of DBU	Trace
6	Et3N instead of DBU	35
7	2,6-Lutidine instead of DBU	25
8	DCE instead of ACN	60
9	Acetone instead of ACN	75
10	MeOH instead of ACN	24
11	ACN : H2O (1 : 1) instead of ACN	10
12	Under air	84
13	Absence of DBU	n.r.
14	Absence of rose bengal	n.r.
15	Absence of light	n.r.

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Encouraged by the optimization results for the Cα–H oxidation reaction, the substrate scopes of the different substituted aryl groups were investigated and the results are shown in Table 2. A propargylamine bearing electron-donating substituents (4-Me, 4-^tBu, 4-OMe and 3-NH₂,) on aromatic rings underwent the Cα–H oxidation with molecular oxygen, affording the corresponding ynamides 2ba–2ea in 75–91% yields. Furthermore, a propargylamine containing an electron-withdrawing group, including 2-Cl, 4-Cl, 4-Br, 4-NO₂, 2-CN, 4-CN, 4-COOMe, and 4-COPh, at the aromatic rings had a smooth reaction with molecular oxygen to furnish the corresponding ynamides 2fa–2ma in 85–90% yields. Overall, para-substituted substrates delivered higher yields than ortho and meta-substituted substrates. Moreover, the oxidation reaction of biphenyl, naphthalene and pyrene at the terminal position of the triple bonds (1oa–1qa) also furnished the corresponding ynamides (2oa–2qa) in 71–90% yields. Besides, the heteroaryl 1na and aliphatic alkyne substituted 1ra and 1sa were examined to react with molecular oxygen, providing the ynamide products 2na, 2ra and 2sa in 70%, 76% and 75% yields, respectively. Next, the 1,4- and 1,3-bis propargylamines 1ta, 1ua and 1va also effectively underwent oxidation to provide bis-ynamides (2ta–2va) in good yields.

Table 2 Scope of various alkynes for the synthesis of ynamides^a

a Standard conditions. Yields were determined after purification of the compound.

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To expand the substrate scope, a variety of amines were examined as substrates for the photosensitized reaction with oxygen, and the results are shown in Table 3. To our delight, a series of alicyclic (1ab, 1bb, 1fb and 1gb) and acyclic (1cb–1eb) amines smoothly underwent the Cα–H oxidation reaction to furnish the corresponding ynamides (2ab–2hb) in 60–93% yields. In contrast, propargylamine 1ib gave a trace amount of ynamides 2ib. Next, 1,4-bis-propargylamines 1jb and 1kb were examined for the oxidation reaction affording the mono oxidative ynamides 2jb and 2kb in 71% and 75% yields, respectively.

Table 3 Scope of various amines for the synthesis of ynamides^a

a Standard conditions. Yields were determined after purification of the compound.

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On further utilization of this protocol, we demonstrated the photocatalytic cyclization reaction for the novel synthesis of (Z)-2-benzylidene-5,6-dihydro-2H-oxazolo[2,3-a]isoquinolin-3(10bH)-one 2ac from phenylpropynyl-tetrahydroisoquinoline 1ac shown in Table 4. Initially, the oxidative cyclization reaction of 1ac was investigated in the presence of rose bengal (2 mol%) and DBU (0.3 mmol) under an O₂ atmosphere in ACN under blue LED irradiation to afford the oxazolo[2,3-a]isoquinolinone 2ac and 3,4-dihydroisoquinolinone 2ad in 45% and 25% yields, respectively. Among the screened solvents (Table 4, entries 1–4), ACN was found to be the best one. A slight enhancement of the yield of 2ac was observed by the addition of CuCl (5 mol%). However, after the addition of different amounts of AgOTf (Table 4, entries 6 and 7), 10 mol% was proved to improve the yield of 2ac maximum up to 61%. Moreover, addition of AgOAc and AgBr provided a lower yield of 2ac (Table 4, entries 8 and 9). When the reaction was performed without blue LED irradiation, no reaction was observed.

Table 4 Optimization table for synthesis of oxazolo[2,3-a]isoquinolinones 2ac from propargylamines 1ac ^a

Entry	Variation from the standard conditions	2ac (%)	2ad (%)
a Reaction conditions: 0.3 mmol (1ac) and 2 mol% of catalyst, AgOTf 10 mol% and 0.3 mmol DBU in 4 mL of solvent were irradiated with blue light in the presence of an O2 atmosphere. b Yields were determined after the purification of the compound. n.r. = no reaction.
1	None	45	25
2	EtOH instead of ACN	35	15
3	DCE instead of ACN	38	17
4	DMF instead of ACN	41	25
5	Addition of CuCl (5 mol%)	47	23
6	Addition of AgOTf (5 mol%)	56	15
7	Addition of AgOTf (10 mol%)	61	Trace
8	Addition of AgOAc (10 mol%)	54	18
9	Addition of AgBr (10 mol%)	51	20
10	Without blue LED	n.r	n.r.

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After optimizing reaction conditions, we next focused our attention on exploring the scope of the photocatalytic cyclization reaction with various alkyne substituted tetrahydroisoquinolines. As shown in Table 5, a wide range of alkynes with different substituents (R = 2-Cl, 3-Cl, 4-Cl, 3-Br, 4-Br, 4-Ph, 2-CN, 4-CN, 3-NO₂, 4-NO₂, 4-COPh & 4-COOMe) were subjected to the photocatalytic cyclization reaction, furnishing the corresponding oxazolo[2,3-a]isoquinolinones 2ac–2lc and 2oc in 45–71% yields. However, alkynes (R = Me and OMe) also underwent a cyclization reaction, generating a complex mixture of products 2mc and 2nc (inseparable), respectively.²⁰ Napthalene, anthracene, pyrene and meta-terphenyl substituted alkynes were also tolerated in the cyclization reaction, affording 2pc–2sc in 45–52% yields. Nitro bearing tetrahydroisoquinoline 1tc also smoothly underwent the photocatalystic cyclization affording the product 2tc in 59% yield. In contrast, under the optimized conditions, 3-aminophenylacetylene and n-alkyl substituted alkynes 1uc, 1vc and 1wc failed to produce the corresponding oxazolo[2,3-a]isoquinolinones 2uc, 2vc and 2wc.

Table 5 Scope of the various terminal alkynes 1ac–wc for the synthesis of oxazolo[2,3-a]isoquinolinones^a,a,c

a Standard conditions. b Yields were determined after purification of the compound. c Trace amounts of 3,4-dihydroisoquinolinone derivatives were obtained in all the cases.

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To gain mechanistic insights, a number of control experiments were carried out (Scheme 2). First, ynamide 2aa was tested for further Cα–H oxidation, and no reaction was observed. To understand the possible formation of the reaction intermediate, 2ad was tested for further Cα–H oxidation with and without blue LED light; however, the corresponding cyclized product 2ac was not observed.

Scheme 2 Control experiments for oxidation of propargylamines.

To recognize the reactive oxygen species and the mechanism of the Cα–H oxidation reaction, several quenching experiments were carried out, as shown in Table 6. First, subjecting radical scavengers, namely 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO) or tert-butyl hydroperoxide (TBHP) under the optimized conditions afforded a trace yield of 2aa, implying that the reaction proceeds via a radical pathway. Next, the singlet oxygen quencher 1,4-diazabicyclo[2.2.2]octane and the superoxide radical anion quencher benzoquinone failed to produce the 2-ynamide 2aa, due to the presence of both singlet oxygen and superoxide radical anions. Moreover, addition of CuCl₂ dramatically suppressed the yield, thereby revealing that the single electron process is also involved. Hence the quenching reactions indicate the involvement of both singlet oxygen (¹O₂) and superoxide radical anions (O₂⁻˙) in the photocatalytic Cα–H oxidation.

Table 6 Quenching experiments for oxidation of 4-(3-phenylprop-2-yn-1-yl)morpholine

S. no.	Quencher	Equiv.	Yield (%)	Conclusion
1	TEMPO	0.5	35	Radical
2	TEMPO	1	Trace	Radical
3	TBHP	1	Trace	Radical
4	DABCO	1	0	Singlet oxygen
5	Benzoquinone	1	0	Superoxide radical
6	CuCl2	1	Trace	Single electron

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Based on the above and quenching experiment results and literature reports,²¹ a plausible mechanism is proposed in Scheme 3. Initially, Rose Bengal (RB) was excited upon irradiation of visible light to form [RB]*. The [RB]* underwent reductive quenching with A to generate a nitrogen radical cation B and [RB]⁻˙. In parallel, [RB]* reacts with O₂ to form singlet oxygen (¹O₂) by photoinduced energy transfer (PET) and it regenerates [RB]. Subsequently, [RB]⁻˙ reduces O₂ to form a superoxide radical anion (O₂⁻˙) by single electron transfer (SET) and recycles the photoredox [RB].²¹ The resulting radical cation B loses a proton in the presence of a base to give the aminomethyl radical C. The in situ generated ¹O₂ and O₂⁻˙ reacted with intermediate C to generate hydroperoxy intermediate D. Finally, intermediate D was converted to the observed ynamide E. Similarly, [RB]* underwent reductive quenching with propargylamine 1ac to generate a nitrogen radical cation F. The formed F loses H_a in the presence of DBU followed by a reaction with ¹O₂ and O₂⁻˙ to give a minor product 2ad. In another way, the AgOTf coordinated electron-deficient triple bond of the radical cation loses H_b in the presence of DBU followed by a reaction with ¹O₂ and O₂⁻˙ to produce product I. The intermediate I underwent further oxidation reaction under the same protocol to produce imides J. The imides J then underwent nucleophilic attack with activated carbonyl oxygen, affording cyclized iminium K. Finally, the RB cycle induces a single electron transfer (SET) process,²² which donates an electron to the iminium L to afford the desired major product 2ac.

Scheme 3 Plausible mechanism for the Cα–H oxidation of 2-propynyl-tertiaryamine.

Conclusions

In conclusion, we have developed a new protocol for visible light-mediated chemoselective Cα–H oxidation of propargylamines in the presence of highly reactive amine and alkyne groups under molecular oxygen and rose bengal as a photoredox catalyst. This photochemical protocol was employed for the synthesis of 2-ynamides from propargylamines and further cyclization for the synthesis of oxazolo[2,3-a]isoquinolinone analogs from phenylpropynyltetrahydroisoquinoline was achieved. The quenching, control experiment and mechanistic studies indicated the involvement of singlet oxygen and superoxide radical anions via photoinduced energy transfer (PET)/single electron transfer (SET) between the photoredox catalyst and oxygen.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The authors thank DST-SERB for a research grant (vide Grant No: EEQ/2018/001129) and DST-FIST for providing NMR and HRMS facilities to the Department of Organic Chemistry. The authors also thank the Department of Chemistry, IIT Madras for X-ray crystallographic analysis. MBR and NN acknowledge DST-SERB, New Delhi, for a fellowship.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, spectral data for all new compounds, and the crystal data of compound 2oc. CCDC 1988860. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d0qo01220c

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