Download PDF
Synlett 2024; 35(03): 291-296
DOI: 10.1055/a-2131-3208
cluster
Organic Chemistry Under Visible Light: Photolytic and Photocatalytic Organic Transformations

Visible-Light-Driven Denitrogenative C–C Bond Formation and Oxidative Difunctionalization of Vinyl Azides

Santosh Sing Sardar
a   Department of Chemistry, Visva-Bharati (A Central University), Santiniketan-731235, India
,
Aramita De
a   Department of Chemistry, Visva-Bharati (A Central University), Santiniketan-731235, India
,
Satyajit Pal
a   Department of Chemistry, Visva-Bharati (A Central University), Santiniketan-731235, India
,
Subhankar Sarkar
a   Department of Chemistry, Visva-Bharati (A Central University), Santiniketan-731235, India
,
Sougata Santra 
b   Department of Organic & Biomolecular Chemistry, Chemical Engineering Institute, Ural Federal University, 19 Mira Str., Yekaterinburg, 620002, Russian Federation
,
Grigory V. Zyryanov
b   Department of Organic & Biomolecular Chemistry, Chemical Engineering Institute, Ural Federal University, 19 Mira Str., Yekaterinburg, 620002, Russian Federation
c   I. Ya. Postovskiy Institute of Organic Synthesis, Ural Division of the Russian Academy of Sciences, 22 S. Kovalevskoy Str., Yekaterinburg, 620219, Russian Federation
,
Adinath Majee∗
a   Department of Chemistry, Visva-Bharati (A Central University), Santiniketan-731235, India
› Author Affiliations

A. Majee acknowledges financial support from the Council of Scientific and Industrial Research, India (CSIR) Major Research Project (Ref. No. 02(0383)/19/EMR-II). S. Sing Sardar acknowledges CSIR for his fellowship (Award No. 09/202(0116)/2020-EMR-I). We are thankful to the Department of Science and Technology, Ministry of Science and Technology, India (DST) FIST program and the University Grants Commission (UGC) SAP program of the Department of Chemistry, Visva-Bharati.
› Further Information
 
 PDF Download Permissions and Reprints All articles of this category


Abstract

A newer synthetic protocol has been developed to synthesize α-oxyalkyl ketones from vinyl azides under transition-metal-free reaction conditions. The reaction proceeds in the presence of organic photoredox catalyst rose bengal, an oxidant tert-butyl hydroperoxide (TBHP), and ethers. A broad range of substituted vinyl azides were found to react smoothly upon visible-light irradiation, which readily furnished the related products. Several control experiments have been done to suggest a probable mechanism. The process is initiated by radical addition to vinyl azide, which triggers a cascade fragmentation mechanism driven by the loss of dinitrogen and the stabilized ether radical ultimately produces the α-oxyalkyl ketones. This method provides a simple, mild, straight forward, novel paradigm to prepare α-oxyalkyl ketones.


#

Key words

visible light - rose bengal - α-oxyalkyl ketones - oxidative difunctionalization - vinyl azides

α-Oxyalkyl ketones and cyclic ethers are important chemical raw materials because they are widely used as solvents in academic, industrial, and biological applications (Figure [1]). In recent years, the importance of α-oxyalkyl ketones has gradually increased because of their significant role as an anticancer agent, neural stem cell activator, and substrate in organic reactions as well as major reactivity towards several oxidants-based conditions.[1] [2] [3] [4] [5] [6] [7] In this regard, several researchers utilized ethers as an α-alkylating agent with various carbon nucleophiles to construct a variety of C–C bonds depending on the choice of starting materials.[8]

Zoom Image
Figure 1 Cyclic ether containing bioactive compounds

Recently, visible-light-mediated photoredox-catalyzed direct C–H bond functionalization has drawn significant attention from the synthetic organic chemist.[9] [10] [11] [12] [13] [14] [15] [16] Organic dyes like rose bengal (RB), eosin Y, methylene blue, etc. are considered as alternatives for transition-metal-containing photoredox catalysts due to their inexpensiveness, synthetic versatility, nontoxicity, and better environmental perspective.[17–20] Our group is actively modifying the tedious methodologies in organic synthesis. As an outcome, we have reported some important works involving biologically relevant compounds like aziridines,[21,22] azirines,[23] [24] coumarins,[25] and naphthoquinones.[26] Recently, an efficient synthesis of aza-spiro compound was reported by using photocatalysis which underwent via the intramolecular cyclization through in situ generated biradical intermediate.[27] The functionalization of vinyl azides and the development of exciting radicals with vinyl azides are still attractive. Generation of iminyl radicals using visible light would enlarge the synthetic value of N radicals. Although the traditional electrophilic addition process has been extensively accepted as the mechanism for these transformations of vinyl azides,[28] [29] [30] [31] [32] [33] [34] we could not exclude the possibility that a charge transfer[35] [36] between an electron donor and an electron acceptor took place in the reaction. Accordingly, the association of an electron-rich substrate with an electron-deficient reagent to form an aggregate was referred to as an electron donor–acceptor (EDA) complex.[37] [38] [39] [40] [41]

In 1975, Suzuki reported the reaction of vinyl azides with trialkyl boranes affording alkyl ketones.[42] This radical process proceeds via a chain mechanism involving iminyl radicals as intermediates. Other radical sources are suitable for the reaction with vinyl azides; these include trifluoromethanesulfonates,[43] [44] pyrrolidines,[45] and alkyl radicals.[46]

On the other hand, Zhang et al. reported a method for the synthesis of α-oxyalkyl ketones using a copper catalyst and tert-butyl hydroperoxide (TBHP) in the year 2009.[47] In 2012, Wang and co-workers developed a diatomite-supported manganese oxide nanoparticles catalyzed method for the synthesis of α-oxyalkyl ketones.[48] Later, a cobalt-catalyzed synthetic methodology of α-oxyalkyl ketones was developed by Li et al. in 2019.[49] In the same year, Hajra et al. developed an efficient method for synthesizing α-oxyalkyl ketones from styrene using a visible-light-promoted oxidative coupling reaction (Scheme [1a]).[50]

Zoom Image
Scheme 1 Typical strategies for the synthesis of α-oxyalkyl ketone compounds with C-centered radicals

Herein, we are pleased to report a one-pot and efficient approach for the oxidative difunctionalization of vinyl azides, which afforded the corresponding α-oxyalkyl ketone (Scheme [1b]). As shown in Scheme [1b], our designed concept envisioned that a hydrogen abstraction even might be initiated on tetrahydrofuran via synergistic interactions of visible-light stimulation, organic dye sensitization, and external oxidation, yielding a relatively long-lived α-oxy radical species.[51] Subsequent radical addition to vinyl azide would accomplish formal C–H to C–C bond conversion and furnish vinyl-functionalized tetrahydrofurans. Within this designed scenario, the choice of an external oxidant is pivotal since it could ideally function as a hydrogen acceptor and a radical precursor. Alkyl hydroperoxide substances are viable candidates for this purpose, a representative structure of TBHP. The challenge in the experimental realization of this proposal lies in identifying reaction conditions conducive to simultaneously supporting operations of all the events mentioned above.

We initiated our reaction by taking α-phenyl vinyl azide (1a, 0.5 mmol) as the model substrate in 2 mL of tetrahydrofuran (THF) solvent at room temperature in the presence of blue LED as a visible-light source, rose bengal (RB, 2 mol%) as organic dye and TBHP (3.00 equiv., 5–6 M in decane) as oxidant. And we have observed the formation of the desired product 1-phenyl-2-(tetrahydrofuran-2-yl)ethan-1-one (3a) in 35% yield after 24 h (entry 1, Table [1]). Here THF acted as both solvent and reactant. Here it is worth mentioning that we have selected these parameters based on the literature survey where the authors used these types of reagent combinations (THF, TBHP, RB etc.).[47] [48] [49] [50] After this result, different types of solvent were used with THF in this reaction in a 1:1 ratio, such as CH2Cl2, toluene, CH3CN, DMSO, 1,2-DCE, and MeOH (entries 2–7, Table [1]). We got the maximum yield (85%) using the 1:1 mixture of THF and 1,2-DCE (entry 6, Table [1]). Later, different types of oxidants like PIDA, K2S2O8, and H2O2 (entries 8–10) were introduced in this reaction to improve the yield, and maximum yield has been isolated in the presence of TBHP. Other different types of dye and metal photocatalysts were used for suitable photocatalyst (entry 11–13, Table [1]). However, RB gave the maximum amount of the desired product under these conditions. The product yield decreased with decreasing the loading of RB (entry 14, Table [1]). However, no significant improvement in the reaction yield was found with increasing the amount of the catalyst (entry 15, Table [1]). No further increment of yield was observed with an increment of TBHP (4.00 equiv., entry 16, Table [1]). When we performed this reaction under white LED instead of blue LED, we got 60% yield (entry 17, Table [1]). Furthermore, the yield of the desired product decreased under dark conditions (entry 18, Table [1]) and as well as in the absence of PC (entry 19, Table [1]). Finally, we carried out this reaction for different reaction times for getting optimized conditions (entries 20 and 21, Table [1]), but a maximum amount of yield was observed in 24 h. Thus, the optimized yield (85%) was achieved using 2 mol% RB in 1,2-DCE and THF solvent (1:1, 2 mL) under irradiation with a 34 W blue LED for 24 h at room temperature under aerobic conditions (entry 6, Table [1]).

Table 1 Identification of the Optimal Reaction Conditionsa

Entry

PC (2 mol%)

Oxidant

Solvents (2 mL)

Yield (%)b

 1

RB

TBHP (3 equiv.)

THF

35

 2

RB

TBHP (3 equiv.)

CH2Cl2/THF (1:1)

50

 3

RB

TBHP (3 equiv.)

toluene/THF (1:1)

75

 4

RB

TBHP (3 equiv.)

CH3CN/THF (1:1)

70

 5

RB

TBHP (3 equiv.)

DMSO/THF (1:1)

25

 6

RB

TBHP (3 equiv.)

1,2-DCE/THF (1:1)

85

 7

RB

TBHP (3 equiv.)

MeOH/THF (1:1)

10

 8

RB

PIDA (3 equiv.)

1,2-DCE/THF (1:1)

80

 9

RB

K2S2O8 (3 equiv.)

1,2-DCE/THF (1:1)

trace

10

RB

H2O2 (3 equiv.)

1,2-DCE/THF (1:1)

14

11

eosin Y

TBHP (3 equiv.)

1,2-DCE/THF (1:1)

80

12

Ru(bpy)3Cl2

TBHP (3 equiv.)

1,2-DCE/THF (1:1)

trace

13

Ir(ppy)3

TBHP (3 equiv.)

1,2-DCE/THF (1:1)

10

14

RB

TBHP (3 equiv.)

1,2-DCE/THF (1:1)

54c

15

RB

TBHP (3 equiv.)

1,2-DCE/THF (1:1)

86d

16

RB

TBHP (4 equiv.)

1,2-DCE/THF (1:1)

85

17

RB

TBHP (3 equiv.)

1,2-DCE/THF (1:1)

60e

18

RB

TBHP (3 equiv.)

1,2-DCE/THF (1:1)

10f

19

–

TBHP (3 equiv.)

1,2-DCE/THF (1:1)

20g

20

RB

TBHP (3 equiv.)

1,2-DCE/THF (1:1)

42h

21

RB

TBHP (3 equiv.)

1,2-DCE/THF (1:1)

76i

a Reaction conditions: reactions were carried out at room temperature for 24 h taking 1a (0.5 mmol) in solvent (2 mL), in the presence of oxidant, photocatalyst (PC, 2 mol%) and blue LED.

b Isolated yield.

c 1 mol% RB was used.

d 3 mol% RB were used.

e Using white LED.

f The reaction was carried out under dark conditions.

g Absence of photocatalyst.

h Reaction time 12 h.

i Reaction time 36 h.

With this optimized reaction conditions, we became interested in exploring the substrate scope of this oxidative difunctionalization reaction of various substituted α-phenyl vinyl azides 1 with THF (2) that is described in Scheme [2]. We observed that simple α-phenyl vinyl azide (1a) produced the desired product 1-phenyl-2-(tetrahydrofuran-2-yl)ethan-1-one (3a) in 85% yield. α-Phenyl vinyl azide bearing electron-donating substituent (such as methyl) at para and meta positions of the phenyl ring efficiently reacted with THF to provide good yields (3b, 81%; 3c, 84%). Similarly, α-phenyl vinyl azide with halogen groups (fluoro, chloro, and bromo) in different positions of the phenyl ring underwent smooth reaction and afforded the corresponding products in satisfactory yields (3d, 80%; 3e, 82%; 3f, 77%; 3g, 72%). We further found that strong electron-withdrawing substituent (such as CF3) underwent smooth reaction under optimal reaction conditions (3h, 70%). α-Phenyl vinyl azide substituted with 4-phenyl and 2-naphthyl moieties produced the corresponding products smoothly (3i, 76% and 3j, 80%).

Zoom Image
Scheme 2 Reactivity screenings on THF. Reagents and conditions: 1a (0.5 mmol), solvent (2/1,2-DCE, 1:1, 2 mL), TBHP (3.00 equiv., 5–6 M in decane), RB (2 mol%), blue LED, rt, 24 h.
Zoom Image
Scheme 3 Reactivity screenings on other ethers. Reagents and conditions: 1a (0.5 mmol), solvent (2/1,2-DCE, 1:1, 2 mL), TBHP (3.00 equiv., 5–6 M in decane), RB (2 mol%), blue LED, rt, 24 h.

The protocol was further extended to other cyclic and chain ethers 4. The results are summarized in Scheme [3]. A wide range of substrates was readily implementable, and the observed reactivities are virtually irrespective of ether substitutions, as their corresponding products 5 were consistently furnished in 62–82% isolated yields. Different types of cyclic as well as acyclic ethers, such as 1,4-dioxane (4a–c), 1,3-dioxolane (4d–g), 2-methyltetrahydrofuran (4h–k), and diethyl ether (4l–n) performed accordingly to give moderate to good yields under standard conditions (5a–n). In addition, tetrahydropyran (THP) also reacted smoothly under the optimal reaction conditions affording 60% yield (5o). None of these reactions is sensitive to air and moisture. It is worth mentioning that an inert atmosphere was not necessary, and the reaction was carried out under an open reaction tube. No decomposition of the product, polymerization, or byproducts has been observed during the reaction, proving the mild reaction conditions. Comparison of spectral data revealed the structural conformation of the known compounds. Both spectral and analytical data were used to characterize the new compounds.

According to our laboratory setup, the scale-up experimental investigation evaluates the synthetic value of the present protocol. We observed 497 mg of 3a in 65% yield, which shows a demanding application of our methodology in the large-scale synthesis of the compound 1-phenyl-2-(tetrahydrofuran-2-yl)ethan-1-one (Scheme [4]).

Zoom Image
Scheme 4 Gram-scale synthesis

Various experiments were conducted for the mechanistic investigation to predict the probable reaction pathway for this reaction (Scheme [5]). The reaction yields dropped significantly in the presence of radical scavengers such as 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and 2,6-di-tert-butyl-4-methyl phenol (BHT, Scheme [5a]). Moreover, a trace amount of product was produced under dark conditions, and when the reaction was carried out at room temperature to 80 °C, 50% product was obtained (Scheme [5b]). Thus, the reaction involved a radical pathway that required light irradiation. Another additional control experiment was run by using 1,4-diazabicyclo[2.2.2]octane (DABCO) to accomplish the involvement of singlet oxygen (1O2) in the reaction pathway (Scheme [5c]). From the result, it is clear that we can exclude the triplet oxygen (3O2) to singlet oxygen (1O2) route in the mechanistic pathway of the reaction.

Zoom Image
Scheme 5 Control experiments
Zoom Image
Scheme 6 Proposed reaction mechanism

The mechanism of the formation of α-oxyalkyl ketone derivatives has been explained based on the control experiments and literature survey.[52] [53] [54] [55] So, the observed reactivity and the above investigations collectively point to a plausible mechanistic pathway shown in Scheme [6]. At first, in the presence of blue LED irradiation, RB is excited from the ground state to the excited state RB*. Then, the excited rose bengal (RB*) transfers its energy to t-BuOOH (TBHP) and returns to its ground state. Due to the effect of energy transfer, homolytic bond cleavage of the weak O–O bond of TBHP takes place. As a result of homolysis, two radical species are formed simultaneously: hydroxyl radical (HO•) and tert-butoxy radical (t-BuO•).[52] [53] There might be another possible pathway of energy transfer of RB* to the ground-state triplet oxygen (3O2) and convert it into the singlet oxygen (1O2). This possible pathway might be excluded based on the result of the control experiment (Scheme [5c]), where DABCO is known as a singlet oxygen (1O2) quencher.[54] Then, tert-butoxyradical (t-BuO•) abstracts hydrogen from THF (2) to generate an α-oxy radical intermediate I. Hydroxyl radical (HO•) might react with α-oxy radicals I, leading to the formation of the byproduct tetrahydrofuran-2-ol (II). Subsequently, α-oxy radical I reacts with the vinyl azide 1 to form the iminyl radicals intermediate IV.[55] After that, intermediate VI was formed via two possible pathways: one is the H abstraction (a) of iminyl radical, another undergoes the SET (b), then H+ abstraction of intermediate V. Finally, the radical intermediate VI undergoes hydrolysis to convert the intermediate into the final product α-oxyalkylketones (products 3 and 5).[56] [57] [58] [59]

In summary, we are motivated by an initial design concept of exploring the direct synthesis of α-oxyalkyl ketone from vinyl azides by combining the power of C–H functionalization and visible-light photocatalysis.[60] We have established a straightforward, versatile protocol and operated under mild reaction conditions. The strategic point of this protocol is likely to identify mutual and synergistic parameters that allow reliable generation of tetrahydrofuran α-oxy radical intermediates. With this robust reactive species, many further synthetic utilities could be conceived in a broader platform of visible-light photocatalysis. New developments will thus be continuously pursued and reported in due course.


#

Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2131-3208.
  • Supporting Information

Corresponding Author

Adinath Majee
Department of Chemistry, Visva-Bharati (A Central University)
Santiniketan-731235
India   

Publication History

Received: 23 May 2023

Accepted after revision: 17 July 2023

Accepted Manuscript online:
17 July 2023

Article published online:
12 September 2023

© 2023. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany


   Permissions and Reprints All articles of this category
Zoom Image
Figure 1 Cyclic ether containing bioactive compounds
Zoom Image
Scheme 1 Typical strategies for the synthesis of α-oxyalkyl ketone compounds with C-centered radicals
Zoom Image
Scheme 2 Reactivity screenings on THF. Reagents and conditions: 1a (0.5 mmol), solvent (2/1,2-DCE, 1:1, 2 mL), TBHP (3.00 equiv., 5–6 M in decane), RB (2 mol%), blue LED, rt, 24 h.
Zoom Image
Scheme 3 Reactivity screenings on other ethers. Reagents and conditions: 1a (0.5 mmol), solvent (2/1,2-DCE, 1:1, 2 mL), TBHP (3.00 equiv., 5–6 M in decane), RB (2 mol%), blue LED, rt, 24 h.
Zoom Image
Scheme 4 Gram-scale synthesis
Zoom Image
Scheme 5 Control experiments
Zoom Image
Scheme 6 Proposed reaction mechanism