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Synlett 2024; 35(09): 967-972
DOI: 10.1055/a-2225-8736
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Chemical Synthesis and Catalysis in Germany

Aromatic Amine Catalysts for the O2-Mediated Cross-Dehydrogenative Phenothiazination Reaction?

Shiny Nandi
,
Alina Paffen
,
Frederic W. Patureau∗

The DFG-funded transregional collaborative research center SFB/TRR 88 ‘Cooperative effects in homo and heterometallic complexes’ (http://3MET.de) is gratefully acknowledged for financial support.
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Abstract

Metal-free aromatic amines have been utilized recently as redox-active catalysts in various oxidative coupling reactions. In this study, we investigated a series of aromatic amines and their potential redox catalytic activity, in particular compared to our previously reported amino-Te(II) catalysts. The O2-mediated cross-dehydrogenative phenothiazination of phenols was utilized as a benchmark test reaction, as well as the O2-mediated cross-dehydrogenative coupling of indoles. We thus identified a proton sponge as an effective aromatic amine redox catalyst. It was moreover found that although the proton sponge displays clear catalytic activity, it is generally less active than previously reported phenotellurazine catalysts. The insights provided by this study should guide future research efforts for the development of innovative redox-catalyzed cross-dehydrogenative coupling reactions.


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Key words

redox catalysis - proton sponge - amine catalysis - tellurium catalysis - O2 activation - cross-dehydrogenative coupling

In 2021, our group reported that phenotellurazine PTeZ1 was a competent catalyst in the O2-mediated cross-dehydrogenative phenothiazination of phenols, thus considerably expanding the scope of this oxidative click reaction concept, in particular towards phenols bearing strong electron-withdrawing substituents (Scheme [1a]).[1] The same year, Klussmann and coworkers reported an inspiring series of organic amine-catalyzed oxidative coupling reactions by using benzoyl peroxide as an oxidant (Scheme [1b]).[2] These findings taken together, as well as a recent controversy about some claimed aromatic-amine-organocatalyzed Suzuki coupling reaction, later proved to arise in fact from palladium impurities (Scheme [1c]),[3] [4] sparked our curiosity and reflection as to whether or not aromatic amines might represent worthwhile versatile redox catalysts for future research efforts.[5–16] After all, aromatic amines are quite versatile in terms of redox processes, and these redox properties can be tuned with the properly designed substitution patterns.[17–19] Moreover, the nitrogen atom can engage in intermolecular supramolecular interactions, as well as the π electrons of the arene moieties, potentially allowing for the catalytic activation of some substrates. Thus, these structures might function reasonably well as electron or electron hole catalyst reservoirs,[20] [21] [22] or simply as redox relays between substrates and terminal oxidants such as O2.[23] [24]

Zoom Image
Scheme 1 Selected key milestones that motivated this study

In this context, we wondered how essential exactly the tellurium atom is in the design of the PTeZ catalyst (Scheme [1a]),[1] which also comprises an aromatic amine functional group, and whether or not a Te-free design might also feature high redox catalytic activity. At the onset of this study, we did not know whether these investigations would lead us out of Te catalysis altogether, or in contrast, reinforce the high performance specificity of organotellurium catalysts in redox coupling reactions, in particular for the development of new cross-dehydrogenative coupling reactions.

Thus, in this study, we attempted to identify an aryl amine based, heavy-atom-free (Te-free), organo redox catalyst, for the O2-mediated cross-dehydrogenative phenothiazination of phenols. This reaction, which we originally discovered in 2015,[25] is highly specific to phenothiazines and phenols, such that it is being increasingly utilized as a benchmark oxidative coupling reaction for the development of diverse new technologies.[26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] We have likewise utilized it in order to quantify the performance of all redox catalysts investigated in the present article. The aim was to investigate how far one can go in terms of redox catalytic activity in the absence of any heavy-atom-containing additives such as tellurium.

We initially started the screening of the Te-free organocatalysts using the same conditions previously reported by us for the Te-catalyzed phenothiazination of phenol using O2 as an oxidant.[1] 4-Phenylphenol (2a ) and phenothiazine (1a) were chosen as the model substrates. We then evaluated a number of commercially available amines as prospective catalysts, in the absence of tellurium. We found that aryl amines are more effective catalysts compared to alkyl amines (cat1 to cat16, Table [1]). For example, N,N-dimethylaniline (cat2) and p-OMe-N,N-dimethylaniline (cat4) provided 33% and 50% yields of the coupled product, respectively (Table [1], entries 2, 4), whereas N,N,N-triethylamine (cat3) and TMEDA (cat6) provided only 22% and 11% yields of isolated products respectively (Table [1], entries 3, 6), which are in fact inferior to the noncatalyzed controls (22% in ODCB, see reference 1, 33% in p-xylene, see Table [1], entry 24).[1] Inspired by the organocatalyst design of Klussmann,[2] we also investigated p-iodo-N,N-dimethylaniline (cat1), however, leading to a disappointing outcome (Table [1], entry 1). Simple iodobenzene proved likewise to be an ineffective catalyst. From this, it can be concluded that the iodide functional group does not display catalytic enhancement under these reaction conditions, in spite of its known redox versatility,[51] [52] as well as its proximity to tellurium in the periodic table.

Encouraged by the performance of cat4, we continued to explore the catalytic behavior of more electron-rich amines. Under the same reaction conditions, tris(4-methylphenyl)amine (cat9) and 1,4-bis(dimethylamino)benzene (cat7) provided 41% and 58% of the product (entries 9 and 7). Utilizing cat7 afforded no better results after attempting lower catalyst loading, higher reaction temperature, and higher stoichiometry of phenol substrate. The catalytic efficiency of cat7 indicated that aryl diamines might perform better as organocatalysts for this particular reaction. Employing a variety of amines (cat10, cat11, cat12, and cat13) as catalysts (entries 10–13) led to the desired product formation in low to moderate yields. We were; however; delighted to find that commercially available proton sponge[53] [54] [55] (cat14, Table [1], entry 14) showed one of the best efficiencies as Te-free catalyst, in contrast to ditolylamine (cat15), or phenoselenazine (cat16, respectively, entries 15 and 16). Interestingly, cat14 was already previously utilized as a catalyst, however, not so far in the context of a cross-dehydrogenative coupling reaction, to the best of our knowledge. This result prompted us to perform a few key optimization verifications with cat14 (entries 17–23), in search of an improved yield. When 1 mL of p-xylene was utilized (entry 23) instead of 1.5 mL of ortho-dichlorobenzene (ODCB) we observed an improved product formation which is comparable to the strategy using the original PTeZ1 catalyst (Scheme [2]).[1] It has to be noted at this point that the reaction in p-xylene gives slightly superior results than in ODCB also for uncatalyzed reactions. Moreover, interestingly, the two closest catalyst contenders, cat4 and cat7, were found inferior under the new reaction conditions in p-xylene (entry 25 and 26), with 37% (average of two experiments) and 64% product yield (average of three experiments, with some unidentified side products noted), respectively. This solvent-dependent inferiority suggests an important catalyst/solvent relationship with respect to catalyst stability. Catalyst cat14 was therefore elected for the subsequent investigations.

Table 1 Optimization of the Reaction Conditionsa

Entry

Catalyst

Solvent

Salt/base

Yield of 3aa (%)

1

cat1

ODCB

K2HPO4

10

2

cat2

ODCB

K2HPO4

33

3

cat3

ODCB

K2HPO4

22

4

cat4

ODCB

K2HPO4

50

 5

cat5

ODCB

K2HPO4

34

 6

cat6

ODCB

K2HPO4

11

 7

cat7

ODCB

K2HPO4

58

 8

cat8

ODCB

K2HPO4

35

 9

cat9

ODCB

K2HPO4

41

10

cat10

ODCB

K2HPO4

40

11

cat11

ODCB

K2HPO4

38

12

cat12

ODCB

K2HPO4

34

13

cat13

ODCB

K2HPO4

45

14

cat14

ODCB

K2HPO4

55

15

cat15

ODCB

K2HPO4

29

16

cat16

ODCB

K2HPO4

34

17

cat14

p-xylene

K2HPO4

60

18

cat14

PhCF3

K2HPO4

47

19

cat14

ODCB

KF

36

20

cat14

ODCB

NaHCO3

55

21

cat14

ODCB

K2CO3

19

22

cat14

cumeneb

K2HPO4

60

23

cat14

p-xyleneb

K2HPO4

70c

24

–

p-xyleneb

K2HPO4

33c

25

cat4

p-xyleneb

K2HPO4

37

26

cat7

p-xyleneb

K2HPO4

64

a Reaction conditions: 1 (0.5 mmol, 1.0 equiv.), 2 (1.5 mmol, 3.0 equiv.), K2HPO4 /KF/NaHCO3/K2CO3 (1 equiv.), and amine catalyst (10 mol%) were dissolved in an above-stated solvent (1.5 mL) under oxygen atmosphere (1 atm) and were stirred at 500 rpm at 130 °C for 3 h reaction time. Yields of isolated products are given; ODCB: ortho-dichlorobenzene.

b 1 mL solvent was used.

c For 2 mmol scale catalyzed yield of 3aa was 56% and uncatalyzed yield was 32%.

Zoom Image
Scheme 2 Yield comparison between PTeZ1-catalyzed and amine-catalyzed (cat14) CDC reaction

After having the optimized conditions in hand, the catalytic activity of cat14 was evaluated over a selected range of substrates. Electron-donating and electron-withdrawing substituents were well tolerated under cat14-catalyzed conditions compared to catalyst-free conditions (18 examples in total, Scheme [3]). Moreover, in all cases, the product yield is typically between two and nine times higher under cat14 catalysis than under catalyst-free conditions at 3 h reaction time. This suggests considerably accelerated initial reactions rates. In order to confirm the absence of possible catalytically active impurities in the cat14 commercial batch, we re-examined its catalytic efficiency after recrystallization. Importantly, the yields obtained after recrystallizing the catalyst were comparable or slightly higher. Particular attention was also paid to clean glassware and stirring bars, such that active metal contamination can be reasonably neglected. Moreover, we verified that when cat14 was purchased from different commercial source, similar catalytic activity is observed. These precautions and verifications give overall confidence that cat14 is probably responsible for the observed catalytic activity. It should be noted, however, that these results are in general slightly inferior to those previously obtained with the PTeZ1 catalyst, in comparable reaction conditions and time.[1] This is particularly the case for phenols bearing electron-withdrawing substituents, such as in product 3ab.[1]

Zoom Image
Scheme 3 O2-mediated cat14-catalyzed cross-dehydrogenative coupling between phenothiazines and phenols. Reagents and conditions: phenothiazine (0.5 mmol, 1.0 equiv.), phenol (1.5 mmol, 3.0 equiv.), K2HPO4 (1 equiv.), and proton sponge (10 mol%) were dissolved in p-xylene (1 mL) under oxygen atmosphere (1 atm) and were stirred at 500 rpm at 130 °C for 3 h reaction time. Yields of isolated products are given.

Mechanistically, we assume that cat14 might function in a similar redox-catalytic relay fashion compared to PTeZ1.[1] Thus, the terminal oxidant O2 would first generate the radical cation of cat14 by one-electron oxidation (species I, Scheme [4]). The plausibility and relevance of this process was further confirmed when we measured the oxidation potential of the main components of the reaction by CV measurements. Indeed, we found that the oxidation potential of cat14 is significantly lower than that of either substrate (Figure [1]). The electron hole would then propagate, leading to the known intermediates of the reaction: the persistent phenothiazine-based N-centered neutral radical species II, as well as phenoxy radical III. The coupling product is then achieved by radical recombination of persistent species II with less persistent radical species III, a mechanism that has been well investigated over the years by us and others.[27] [28] It should be noted at this point that cat14 may also catalyze the oxidation of the phenol coupling partner by proton-sponge effect through ammonium intermediate IV. This pathway would maintain a phenolate reservoir that would undergo faster one-electron oxidation. 1H NMR experiments combining cat14 with phenol 2a on the one hand, and with phenothiazine 1a on the other, were inconclusive as to whether acid/base relationships are significant in these processes.

Zoom Image
Scheme 4 Proposed mechanism

At this point, we were quite curious in moving forward in the frontal comparison of the catalytic activities of cat14 and PTeZ1 and its derivatives. However, cat14 was found completely inactive in another benchmark cross-dehydrogenative coupling reaction recently reported by us to operate under PTeZ1 or PTeZ2 catalysis, which involves indole substrates (Scheme [5]).[56] In that previous study, control experiments were also conducted in order to rule out catalytically active impurities. Therefore, while cat14 yielded interesting catalytic properties in the present study, it seems that the phenotellurazine scaffold features a broader scope in the herein investigated oxidative coupling reactions.

Zoom Image
Figure 1 CV plots of the main component of the redox coupling reaction. CV plots (rt) were measured in 0.1 (M) of n-Bu4NPF6 in DCM, using platinum wire as working electrode, platinum wire as counterelectrode and Ag/AgCl. Values are reported versus Ag/Ag+, Eo 1/2 = 0.30, 0.23, 0.42 for 2a, cat14, 1a, respectively.
Zoom Image
Scheme 5 The O2-mediated Te(II) redox catalysis for the cross-dehydrogenative coupling of indoles[56]

In conclusion, phenotellurazines PTeZ1 and PTeZ2 outperform the herein optimized best Te-free organocatalyst cat14 in both considered benchmark cross-dehydrogenative coupling reactions.[57] Thus, the catalytic role of tellurium cannot be satisfyingly mimicked by any light-atom organic structure in our hands. Interestingly though, several aromatic-amine-based candidates seem to display some measurable catalytic activity in the herein considered redox processes, even after repurification in order to suppress potential catalytically active impurities (cat14). However, these catalytic effects remain relatively modest. Overall, this study therefore reinforces the contours of the concept of phenotellurazine redox catalysis, in particular in the context of cross-dehydrogenative couplings. Research efforts are currently ongoing in our laboratory in order to further improve the phenotellurazine scaffold and other metal containing redox catalysts.


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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-2225-8736.
  • Supporting Information

Corresponding Author

Frederic W. Patureau
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen
Germany   

Publication History

Received: 04 September 2023

Accepted after revision: 11 December 2023

Accepted Manuscript online:
11 December 2023

Article published online:
09 February 2024

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   Permissions and Reprints All articles of this category
Zoom Image
Scheme 1 Selected key milestones that motivated this study
Zoom Image
Scheme 2 Yield comparison between PTeZ1-catalyzed and amine-catalyzed (cat14) CDC reaction
Zoom Image
Scheme 3 O2-mediated cat14-catalyzed cross-dehydrogenative coupling between phenothiazines and phenols. Reagents and conditions: phenothiazine (0.5 mmol, 1.0 equiv.), phenol (1.5 mmol, 3.0 equiv.), K2HPO4 (1 equiv.), and proton sponge (10 mol%) were dissolved in p-xylene (1 mL) under oxygen atmosphere (1 atm) and were stirred at 500 rpm at 130 °C for 3 h reaction time. Yields of isolated products are given.
Zoom Image
Scheme 4 Proposed mechanism
Zoom Image
Figure 1 CV plots of the main component of the redox coupling reaction. CV plots (rt) were measured in 0.1 (M) of n-Bu4NPF6 in DCM, using platinum wire as working electrode, platinum wire as counterelectrode and Ag/AgCl. Values are reported versus Ag/Ag+, Eo 1/2 = 0.30, 0.23, 0.42 for 2a, cat14, 1a, respectively.
Zoom Image
Scheme 5 The O2-mediated Te(II) redox catalysis for the cross-dehydrogenative coupling of indoles[56]