MSc Chemsitry
Molecular sciences
Literature Thesis
A review of nitrene precursors and the recent progress of dioxazolones in
transition-metal catalyzed nitrene transfer reactions
by
Sem Leftin
10783520
July 2020
12 EC
November-July
Supervisor/Examiner:
Kaj van Vliet
Examiner:
Prof. dr. Bas de Bruin
2
Abstract
Amines and amine derivatives such as amides are important structural units that are often found in bioactive molecules. The amine and amide functionalities are also widely used in drug discovery and medicinal chemistry. However, the synthesis of these products is often demanding and requires multiple steps. A possible solution would be using a transition-metal catalyzed reaction. With the use of the catalyst the reaction can be performed in one step resulting in fewer byproducts being formed. The discovery of novel acyl nitrene transfer reactions have led to the improvement of transition-metal catalysts and the employment of novel precursors. The first generation of acyl nitrene transfer reactions were done using azides and iminoiodinanes. However, a newer generation of acyl nitrene transfer agents is used more frequently: the 1,4,2-dioxazol-5-ones (dioxazolones). In this review, the azides and iminoiodinanes will be compared to the dioxazolones. The comparison will allow us to determine which is the more efficient and safer precursor to use for the acyl nitrene transfer reactions. The comparison of nitrene transfer agents was done by performing a broad literature study and analyzing the results.
The iminoiodinanes outperform azides for aziridination reactions, however iminoiodinanes are far less sustainable and harder to handle. The iminoiodinanes are therefore not an optimal nitrene transfer agent. Comparing the azides to the dioxazolones the first observation is that both are green reagents only releasing N2 or CO2 when used in a reaction. Azides are less stable than dioxazolones and therefore are more susceptible to rearranging via the Curtius rearrangement. Dioxazolones have lower reaction barriers compared to azides due to stronger interaction with the metal center of the catalyst. The lower reaction barrier leads to faster reactions at lower temperatures. When comparing azides and dioxazolones using the same catalyst system the dioxazolones result in products with equal or greater yields than the azides.
Based on the comparison between azides and dioxazolones, the dioxazolones have lower reaction barriers when using an iridium catalyst. The lower reaction barriers lead to faster and more efficient amidation reaction than when acyl azides were used. Another benefit of the low reaction barriers is that the acyl nitrenes are generated at lower temperatures which reduces the problem of the Curtius rearrangement. Dioxazolones give equal or greater yields than acyl azides when used for amidation reactions using an iridium catalyst. The literature review gives a comparison between the acyl azides and dioxazolones as amidating agents. Based on the results the dioxazolones are the superior amidating agent. However, the comparison is based on a limited amount of results. The results show that dioxazolones are easier to work with and give equal or better yields than azides. Furthermore, the dioxazolones require less energy for the reaction than azides. The positive results of dioxazolones should promote further research into dioxazolones. To give a conclusive answer which amidating agent is superior more research must be done comparing dioxazolones to acyl azides.
3
Contents
Abstract ...2
The uses of nitrenes for chemistry ...5
1 Iminoiodinanes ...6
1.1 The discovery and properties of iminoiodinanes ...6
1.2 Early use of iminoiodinanes...6
1.3 Iminoiodinanes as a new aziridination reagent...6
1.4 The use of iminoiodinanes for C-H bond amination ...7
2 Azides ...9
2.1 Azide properties ...9
2.2 Main use of azides ...9
2.3 Azides being used as nitrene precursor ...9
2.3.1 Recognizing azides could form new C-N bonds ...9
2.3.2 The role of transition metals ... 10
2.3.3 The development of catalytic reactions using azides and olefins ... 10
2.3.4 Asymmetric aziridination and C-H activation using azides ... 11
2.3.5 Azides used for C-H amination ... 12
2.3.6 Examples of azides used for C-H amidation reactions ... 12
3 Dioxazolones ... 18
3.1 The development of dioxazolones and early uses ... 18
3.2 Dioxazolones used as nitrene precursor ... 19
3.2.1 Oxazolines synthesized using dioxazolones ... 19
3.2.2 Sulfimides and sulfoximines synthesized using dioxazolones ... 20
3.3 Dioxazolones used for C-H amidation ... 23
3.3.1 The use of dioxazolone as amidating agent ... 24
3.3.2 Understanding the catalytic cycle when using dioxazolones as amidating agent ... 26
3.3.3 Substrate scope of dioxazolones ... 27
4 C-H amidations using dioxazolones and rhodium catalysts ... 29
4.1 C-H amidations using a rhodium catalyst ... 29
4 4.1.2 C-H functionalizations at the C-7 position of indolic scaffolds using dioxazolones as amidating
agent ... 30
4.1.3 Amidation of unactivated C (sp3)-H bonds using dioxazolones and a rhodium catalyst ... 32
5 Using cheaper metal catalysts for the C-H amidation reactions ... 34
5.1 C-H amidation using an Ir(III) catalyst ... 35
5.1.1 Development of catalytic C-H amidation using an iridium catalyst ... 36
5.1.2 Analyzing the differences in the Ir-imido formation ... 37
5.1.3 Comparing amidating agents dioxazolone vs acyl azide ... 38
6 Using Co or Ru as catalyst instead of more expensive transition metals ... 41
6.1 The use of ruthenium for amidation reactions ... 42
6.2 The use of cobalt in amidation reactions ... 43
6.3 Comparing the catalytic activity of cobalt with iridium and rhodium ... 43
6.4 The use of a cobalt catalyst for a formal [4 + 2] cycloaddition reaction ... 44
6.5 Mechanochemical cobalt-catalyzed C-H bond reaction by ball milling ... 47
6.6 Overcoming the limitations of C-H activation due to strongly coordinating heterocycles ... 48
7 Discussion ... 51
5
The uses of nitrenes for chemistry
Nitrogen containing molecules are prevalent in a wide range of molecules such as natural products, synthetic intermediates, pharmaceutical agents and functional materials.[1] The many uses of nitrogen containing molecules have motivated synthetic chemists to develop convenient and mild amination reactions. The more conventional organic transformations mainly rely on the reactivity of functional groups. However, with the introduction of transition-metal catalysts novel methods to construct C-N bonds can be developed. Thus, offering a great opportunity to transform raw chemicals which contain little functionality into synthetically useful molecules.[2,3] The transition-metal catalyzed reaction which will be discussed in this report is the nitrene transfer reaction. Nitrene-transfer reactions can directly introduce nitrogen containing units into molecules. This method of introduction can decrease the number of steps necessary for the synthesis of molecules containing a nitrogen group. Decreasing the number of steps necessary for the synthesis of molecules leads to less resources being wasted and results in cheaper products. To perform nitrene-transfer reactions selectively the nitrenes must be generated in situ due to their high reactivity. The high reactivity of nitrenes leads to low control of selectivity. However, by using transition-metals the nitrene-transfer reaction selectivity can be controlled. Control of selectivity is achieved by generating a metal-nitrenoid as intermediate.[4] With the use of the metal-nitrenoid complexation the problem of high reactivity of the nitrene can be overcome and specific reactions can be performed. Being able to selectively perform an amidation reaction is a useful tool for synthetic chemists. The control of selectivity has prompted a lot of research into nitrene-transfer reactions. Furthermore, nitrene-transfer reactions have been investigated due to the potential of being more efficient than traditional methods. By being more efficient for the introduction of nitrogen containing groups total synthesis routes could be shortened. The most common nitrene precursors are azides and iminoiodinanes. Both azides and iminoiodinanes have their pros and cons as nitrene precursors which will be discussed in the following sections. However, since 2012 another class of molecules has seen a rise in usage as nitrene precursor being the dioxazolones. The dioxazolones are showing great potential as replacements for azides and iminoiodinanes in nitrene-transfer reactions. Transition-metal complexes are used to activate all three precursors. The use of transition-Transition-metal complexes is appealing due to their ability to tune the reactivity of the intermediates. Various ligands can be used to tune the steric and electronic properties of the transition-metal complexes.[5] In the following two sections azides and iminoiodinanes will be discussed as an introduction to nitrene precursors. Following the introduction, the dioxazolones will be discussed as nitrene precursors to eventually be able to compare all three nitrene precursors.
The aim of this review is the comparison of the three discussed nitrene precursors to determine the most efficient and versatile N-atom transfer agent. Determining the most efficient precursor is useful for the development of future synthetic routes as using a more efficient and versatile N-atom transfer agent will lead to less waste being produced and more diverse products which can be synthesized in fewer steps.
6
1
Iminoiodinanes
1.1
The discovery and properties of iminoiodinanes
Iminoiodinanes are a class of nitrene precursors. The first iminoiodinane, N-tosyliminophenyliodinane (PhI=NTs), was synthesized in 1975 by Yamada.[6] Since the discovery of iminoiodinanes by Yamada extensive research on the utility of iminoiodinanes has been done. Iminoiodinanes have been used to construct new C-N bonds. The main use of iminoiodinanes is the aziridination reaction with alkenes. Because iminoiodinanes give significantly higher yields when compared to azides in aziridination reactions, iminoiodinanes are more attractive reagents. However, there are some downsides to using iminoiodinanes which are the tedious synthesis of the compound and the low solubility in common solvents.[7] Although there are some downsides to using iminoiodinanes, the higher yields compared to azides sparked the interest of researchers. The potential of iminoiodinanes to replace azides led to extensive research on iminoiodinanes. In the following paragraphs various applications of iminoiodinanes will be discussed as nitrene source.
1.2
Early use of iminoiodinanes
The work of Yamada inspired the Breslow and Mansuy groups. The Breslow group published a paper in 1982 using an iron porphyrin catalyst and PhI=NTs for the tosylamidation of cyclohexane [8] The Mansuy group published reactions with iminoiodinanes and hexene using an iron porphyrin (Fe(TPP)(ClO4)) or a manganese porphyrin (Mn(TPP)(ClO4)) catalyst. However, during the early stage of research it was difficult to control the chemoselectivity. The poor control resulted in both the aziridination and allylic amination product being formed (fig. 1).[9] catalyst Aziridination yield% Allylic amination yield% Fe(TPP)(ClO4) 12 20 Mn(TPP)(ClO4) 2 37
Figure 1: Aziridination and allylic amination catalyzed by Iron catalyst and Manganese catalyst
1.3
Iminoiodinanes as a new aziridination reagent
A major advance for aziridination reactions was done by the work of Evans et al. in the 1990s. In 1991 they found that with the use of copper catalysts such as copper(II) acetylacetonate (Cu(acac)2) and copper(II) triflate
7 ([Cu(OTf)2]) the aziridination reaction could be performed selectively without the occurrence of the allylic amination (fig. 2a).[10] Further investigation of the copper catalyst led to another paper in 1994. In which the aziridination efficiency of an iminoiodinane was compared to an azide (fig. 2b). The iminoiodinane showed a significant better yield compared to the azide, which led to iminoiodinanes supplanting the azides for aziridination reactions. The improved efficiency for the aziridination reaction using copper inspired other researchers to investigate copper as a catalyst for aziridination. Later, various copper catalysts were reported for the aziridination reaction by the Halfen and Caulton groups.[11,12]
Figure 2: selective aziridination reaction using a copper catalyst
1.4
The use of iminoiodinanes for C-H bond amination
After the finding that iminoiodinanes have a higher yield in aziridination reactions compared to azides, researchers were inspired to further investigate iminoiodinanes for other applications. A logical next step after investigating olefins is the investigation of C(sp3)-H bonds.C-H bond activation reactions can be used for direct transformation of a C-H bond into a C-C bond making them highly attractive to use in covalent synthesis. Muller et al. reported that iminoiodinanes can be used to perform the amination of C(sp3)-H bonds.20 They reported the selective amination of cyclohexene with [N-(4-nitrobenzenesulfonyl) imino]phenyliodinane (PhI=NNs) (fig. 3). Which resulted in the allylic amide (70% yield) and the aziridination product (4% yield) using a dirhodium catalyst. The benefit of this dirhodium catalyst was that the aziridination reaction could almost completely be suppressed.
8 Inspired by the results of iminoiodinanes for C-H aminations, further investigations were done into the asymmetric aminations by iminoiodinanes. Asymmetric C-H aminations using PhI=NTs were mainly developed by the Che and Katsuki groups.[13,14] Che used a chiral ruthenium porphyrin catalyst for the asymmetric amination of various saturated C-H bonds (fig. 4)
Figure 4: asymmetric C-H amination using iminoiodinane and a ruthenium porphyrin catalyst
Based on the information presented above iminoiodinanes are valid N-atom transfer reagents. However, iminoiodinanes do have some drawbacks as nitrene precursors. Such as laborious synthesis, a short lifetime and a tendency to explode if not handled correctly. [15,16] Therefore, iminoiodinanes have not been used in large-scale synthesis. There has been research done to minimize these drawbacks of iminoiodinanes. A possible solution was proposed by Du Bois et al. in 2001. The group developed a rhodium catalyzed C-H insertion using carbamates to form oxazolidinones (fig. 5).[17]In this work they postulated that the nitrene was generated in situ based on the configuration of the final product. If cyclization occurred via a metal-nitrenoid intermediate this would lead to retention of configuration. However, if the cyclization occurred via a radical species it would likely produce a mixture of enantiomeric oxazolidinones. By analyzing the product using chiral GC and only obtaining one peak. It is most likely that the cyclization occurs via a nitrene species.
Figure 5: C-H insertion catalyzed by dirhodium complex
Although some of the drawbacks of iminoiodinanes can be circumvented by generating the compounds in situ, iminoiodinanes still are not as sustainable as azides. In the current day and age resources are becoming scarce and sustainable processes are being pursued.[18] A few of the sustainable guidelines in chemistry are less solvent, less waste and less hazardous reagents.[19] The fact that most iminoiodinanes have poor solubility and thus requiring excess amounts of solvents. Furthermore, iminoiodinanes have a tedious synthesis which results in a lot of waste and when used as reagent produce iodobenzene. The properties of iminoiodinanes when used as nitrene precursor are not in accordance with the direction of moving towards more sustainable processes. Due to
9 iminoiodinanes not being a sustainable reagent and having a lower atom economy than azides, the use of azides as nitrene precursor was investigated. Due to azides only releasing N2 when forming the nitrene intermediate, the use of azides as nitrene precursors will be discussed in the following chapter.
2
Azides
2.1
Azide properties
Azides are a class of molecules which have properties when used as nitrene precursor that are interesting for synthetic chemists. Being the fact that azides are readily available from sodium azide. Another desirable property is that azides are an environmentally benign nitrene precursor due to only releasing N2 when a metal-nitrenoid complex is formed. By only releasing N2 azides are far more atom economical when compared to iminoiodinanes which form iodobenzene as side product. Azides are potentially explosive if not handled correctly. However, the explosive risk is manageable as azides are used in a wide range of reactions to construct new nitrogen-heteroatom bonds.[20] This class of molecules is very reactive, making it hard to control the selectivity of reactions. Although the high reactivity can be problematic, the issue can be overcome by using a transition-metal catalyst.[4] The ability to form C-N bonds and their availability have caused extensive research on azides since their discovery in 1864.[21] In the following paragraphs the development of azides as nitrene precursors will be discussed.
2.2
Main use of azides
The main use of azides has been click reactions. These reactions can increase the complexity of the synthesized molecule in one step by having the two components react in a stereoselective reaction (fig. 6).[22] The main catalyst for click reactions is a copper based catalyst.
Figure 6: General reaction scheme click reactions
2.3
Azides being used as nitrene precursor
2.3.1 Recognizing azides could form new C-N bonds
Azides were recognized early as a nitrene precursor. In 1951 the synthesis of carbazoles from o-azidobiphenyls under thermal and photochemical conditions was reported by Smith (fig. 7).[23] Using azides to form new C-N bonds sparked the interest of researchers to further investigate the use of azides as nitrene precursors. Azide reactions were implemented as steps in the total synthesis of alkaloids in the 1960s. However, the reactions had moderate yields and selectivity issues due to the high reactivity of the formed nitrene intermediate.[24]
10
2.3.2 The role of transition metals
The yields and selectivities of reactions were improved by stabilizing the nitrene intermediate with transition metals. The first reaction of azides catalyzed by a transition metal was reported by Kwart and Khan in 1967. Copper powder was used to catalyze the reaction of cyclohexene with benzenesulfonylazide (fig. 8).[25] The product distribution is consistent with a nitrene intermediate. However, a radical mechanism could also account for the observed products.[26] The findings of Kwart and Khan inspired other research groups to develop their own methods for N-atom transfer reactions. Groves et al. reported a stoichiometric N-atom transfer from a nitridomanganese porphyrin to cycloalkenes.[27]
Figure 8: First azide reaction catalyzed by a transition metal
Shortly after these reports iminoiodinanes superseded azides as nitrene precursors in transition metal catalyzed
N-atom transfer reactions to olefins. Evans et al. found that using tosyl azide (TsN3) resulted in a significantly lower yield than using N-tosyliminophenyliodinane (PhI=NTs) as nitrene precursor (fig. 9) as discussed in paragraph 1.3.[10,28] Iminoiodinanes significantly improved the yield compared to azides. However, azides have a higher atom economy and are more environmentally benign than iminoiodinanes. Due to iminoiodinanes producing a stoichiometric quantity of iodobenzene in this reaction (fig. 9). As a result of azides being the more sustainable reagent compared to iminoiodinanes further research was done on the applications of azides as nitrene precursors.
Figure 9: the reaction efficiency of iminoiodinanes versus tosyl azide using a copper catalyst
2.3.3 The development of catalytic reactions using azides and olefins
After the discovery that iminoiodinanes result in a higher yield in aziridination reaction compared to azides. The subsequent research on C-H amination was also conducted using iminoiodinanes. However, with society searching
11 for more sustainable processes. Considering the drawbacks of iminoiodinanes, a logical step would be to investigate the C-H amination capabilities of azides due to azides being a greener reagent compared to iminoiodinanes. The findings of stoichiometric N-atom transfer reactions inspired Ceneni et al. to search for catalytic reactions of aryl azides with olefins in the presence of metal porphyrins.[29] After an extensive examination of metal porphyrins, it was found that the best results were obtained with ruthenium tetraphenyl porphyrin (Ru(TPP)CO) and cobalt octaethylporphyrin.[30] Using the most active ruthenium catalyst, various olefins were used for the N-atom transfer reactions (fig. 10). Cyclohexene provided a moderate yield of 62%, however when cyclooctene was used a different product formed with a yield of only 25%. The major side products being
p-nitroaniline and the azo compound. Monosubstituted olefins were also tested. 1-hexene as substrate resulted
in the product with 29% yield, styrene had a much higher yield of 89%.
Figure 10: The N-atom transfer reactions of various olefins using a ruthenium porphyrin catalyst
2.3.4 Asymmetric aziridination and C-H activation using azides
The successful catalytic N-atom transfer reaction reported by Ceneni inspired other research groups to develop their own methods for N-atom transfer reactions. The group of Katsuki developed a method for asymmetric aziridination with a ruthenium-salen complex as the catalyst (fig. 11).[31]
12 The problem with the asymmetric aziridinations is that efficient reaction rates only occurred when p-tolylsulfonyl azide was used. Removing this group requires harsh conditions such as hydrogen bromide (HBr) and acetic acid (AcOH).[32] To circumvent this problem a more active catalyst was designed. The improved catalyst was able to perform the reaction using azides with more easily removable groups on the nitrogen such as nitrobenzenesulfonyl azide (NsN3) and 2-(trimethylsilyl)ethanesulfonyl azide (SESN3).
Using the more easily removable groups on azides higher enantioselectivities were found using the SESN3, However the p-NsN3 showed significantly higher turnover numbers. The more active catalyst was also able to perform N-atom transfer reactions on non-activated alkenes such as n-hexene.
2.3.5 Azides used for C-H amination
More recently C(sp3)-H bond amination reactions have gained a lot of attention.[33,34] Due to direct modification of the C-H bond of simple organic compounds without pre-activation enables the type of reactions to meet the intrinsic demand for environmental sustainability and atom economy.[35]
Inspired by the research done on azides and interested in C(sp3)-H bond amination reactions, the Betley group reported an iron-catalyzed amination in 2013 (fig. 12).[36] The de Bruin group studied the nitrene radical species relevant in nitrene transfer reactions using a cobalt porphyrin complex in 2015 and reported a cobalt porphyrin complex as well as various cobalt corroles which could catalyze the C-H amination reaction in 2017 (fig. 12).[37–39] The research done by Betley and de Bruin shows that with the right catalyst azides can be used for C-H activation. The direct modification of C-H bonds using azides is very useful for the synthetic chemist. Due to being able to introduce a nitrogen group into a molecule without pre-activation.
Figure 12: C-H amination catalyzed by iron complex and cobalt porphyrin complex
The reaction done by the Betley and de Bruin groups is just one of the many C-H amination reactions which uses azides as aminating agent. All the examples discussed above show the many uses of azides as nitrene precursors. Azides make a good precursor due to being readily available from sodium azide. The fact that only N2 is released when a metal nitrenoid complex is formed using an azide makes the reagent environmentally benign. Although these properties make azides an attractive nitrene precursor. Azides have some properties making them less ideal nitrene precursors, such as being potentially explosive if not handled correctly. Azides are very versatile reagents and can be used for other reactions such as amidation reactions which will be discussed in the following paragraph.
2.3.6 Examples of azides used for C-H amidation reactions
C-H amidation is a reaction which allows for the incorporation of an amide moiety in the target molecule. The amide functional group is relevant to biological processes and has attracted extensive research interest in areas
13 such as chemical, pharmaceutical and biological sciences.[40–42] In the following paragraphs the use of acyl azides as acyl nitrene precursors for the amidation reaction will be discussed. Acyl nitrenes are efficient because combined with the use of a well-designed catalyst the amidation reaction can be performed in one step resulting in fewer byproducts being formed. The right catalyst is important for the reaction as a well-designed catalyst will have a higher rate for the amidation reaction than for the Curtius rearrangement. The Curtius rearrangement is a reaction which transforms an acyl nitrene into an isocyanate.[43] For the synthesis of amines, carbamates and ureas the Curtius rearrangement is useful. However, for the amidation reaction the Curtius rearrangement is undesired and catalysts should be designed to favor the amidation reaction over the Curtius rearrangement. A wide range of transition metals have been investigated for C-H functionalization however, iridium has undergone significant investigation due to its high activity in the C-H bond activation.[44] The group of Chang is interested in the direct C-H functionalization and published an article on the direct installation of amines in heteroarene C-C-H bonds.[45] The positive results from the study inspired the group of Chang to investigate the Rh- and Ru- catalyzed intermolecular C-H amidation of arenes using sulfonyl, aryl or alkyl azides.[46,47] Since publishing their report several C-H amidations have been published using sulfonyl azides and a Rh or Ru catalyst system.[48] Intermolecular reactions using azides have been limited to allylic and benzylic sp3 C-H bonds.[49,50] However, to eventually compare azides to dioxazolones as amidating agents the comparison must be made using acyl azides and dioxazolones as both lead to the incorporation of an amide moiety. In the following section the direct C-H amidation reaction catalyzed by an iridium catalyst using acyl azides as amidating agent will be discussed.
Ir(III)-catalyzed C-H amidation of arenes and alkenes using acyl azides as amidating agent
The group of Chang started their investigation using a dimeric cyclopentadienyl iridium complex [Cp*Ir(III)Cl2]2, which is known to display high activity in a stoichiometric cyclometallation reaction with chelating group-containing arenes.[51,52]Different nitrogen sources were tested such as iminoiodinanes and chloramine-T which are known as facile nitrene sources, however both did not show any activity.[53] When acyl azides were tested the group was delighted to find that the C-H activation readily occurred and resulted in excellent yield (fig. 13). It should be noted that under the optimal conditions the acyl azides did not rearrange into isocyanates and when testing a Rh or Ru catalyst the yield was significantly less than when using the Ir catalyst. The Rh and Ru reactions were done at 80oC instead of at 25oC for the Ir catalyst. The reason for the lower yield of the Rh and Ru is most likely that the higher temperature led to thermal decomposition of the acyl azides (Curtius rearrangement). The activities of various catalysts prove the unique catalytic activity of the iridium catalyst system. After optimization of the reaction conditions the reaction scope was investigated.
Figure 13: optimized reaction conditions for amidation reaction using acyl azides
The scope of the reaction was determined using various benzamides in reaction with various acyl azides and resulted in structurally diverse products (fig. 14). The reaction tolerated electronic variation on the benzamides.
14 However, the yield was influenced by the electronic nature of the acyl azides. The acyl azides containing electron-withdrawing groups resulted in higher yields. Another point to mention is that substituents position did not matter for the benzamides. For the acyl azides various substituents and different types of carbonyl analogues such as cinnamoyl and aliphatic acyl azides resulted in good yields.[54]After determining the scope of the reaction the scope of chelate groups was determined. Previously reported amination reactions were often limited by the highly specific chelate groups.[55,56] However, for the amidation reaction in the study done by Chang a diverse number of chelating groups was tolerated such as acylamide, pyrrolidone, cyclic ketones and lactams.
Figure 14: the substrate scope of acyl azides and benzamides
To further improve the synthetic utility of the developed approach a series of N-acylaminobenzamides bearing peptides was synthesized. The synthesis shows that the Ir-system might have potential for peptide chemistry. Another synthetic route was investigated to determine the synthetic utility of the Ir-system and that is the direct enamide synthesis. Enamides are present in numerous natural products and drugs. Enamides also serve as synthetic intermediate in the formation of heterocycles.[57] There are quite a lot of methods to synthesize enamides, however the substrate scope and reaction conditions can still be improved in most methods.[58,59] The group of Chang was inspired to investigate the synthesis of enamides with the developed C-H amidation procedure. They were delighted to observe that the iridium catalyst system allowed a direct access to Z-enamides with excellent regio- and stereoselectivity (fig. 15).
Figure 15: scope of amidation of Z-enamides using iridium catalyst
Various acyl azides were tested in the synthesis and acyl azides containing electron withdrawing or donating groups lowered the yield slightly. However, in all cases Z-enamides were synthesized exclusively which was confirmed by 1H NMR and X-ray crystallographic analysis. The unique reactivity of the acyl azides was also specific for the iridium catalyst system as the reaction was also performed with rhodium and ruthenium catalyst systems which did not result in the direct C-H enamidation of the substrates.
To conclude, the group of Chang developed an iridium-catalyzed direct C-H amidation of arenes and alkenes using acyl azides as amidating agent. The unique activity of the iridium system was combined with the use of acyl azides
15 to enable a direct amidation reaction. The only byproduct release from the reaction is N2, making the approach environmentally benign. The iridium catalyst system has a large substrate scope and displays high functional group tolerance. Using the iridium catalyst system with acyl azides is interesting to investigate for further applications, later the use of acyl azides will be compared to dioxazolones to determine which amidating agent is more advantageous.
Orthogonal reactivity of acyl azides in C-H activation
The group of Chang published another paper in 2014 on the reactivity of acyl azides. As mentioned before acyl azides have mainly been used in organic synthesis as isocyanate precursors via the Curtius rearrangement which is most often thermally induced.[60] However, acyl azides are not optimal isocyanate precursors. Due to difficulty in controlling the dual reactivity of acyl azides which leads to a mixture of C-C and C-N bonds formed (fig. 16).
Figure 16: The dual reactivity of acyl azides forming C-C and C-N bonds depending on the catalyst used
In the previous paragraph acyl azides were used in combination with an iridium catalyst system. The results obtained inspired the group of Chang to investigate the dual reactivity of acyl azides and try to control the reactivity. In the following paragraph the method to control the reactivity of acyl azides will be discussed and mainly the C-N bond formation will be discussed.
The investigation started by determining the optimal conditions for the selective C-C amidation. As a starting point a combination of [RhCp*Cl2]2 with AgSbF6 was used as the catalyst system is widely employed in C-H functionalizations.[61,62] By adding acetonitrile (100 mol%) the highest ratio between the C-C product and C-N product was obtained. After the optimal conditions were determined the generality of the C-C amidation reaction was determined (fig. 17). The aryls reacted smoothly with various electronic substituents and the acyl azides also reacted smoothly independent of the electronic nature. Having established a selective C-C amidation procedure, the focus was put on developing a new system for selective C-N amidation.
Figure 17: scope of the C-C amidation reaction catalyzed by rhodium
The C-N amidation was unsuccessful using the rhodium catalyst, however when the catalyst was switched to a ruthenium catalyst the C-N amidation was accomplished.[63] Various additives were screened, however a Brønsted acid with high acidity was most effective for the C-N amidation reaction. After determining the optimized
16 conditions for the C-N amidation reaction, the scope was determined (fig. 18). The electronic influence of the substrates on the reaction efficiency was negligible. Substrates possessing various functional groups such as chloro, ketone, ester or aldehyde all reacted smoothly. The acyl azides containing electron donating or withdrawing groups also reacted smoothly with the substrate. More notably, the acyl azides containing ester or halide groups also amidated smoothly.
Figure 18: scope of the C-N amidation reaction using ruthenium catalyst
To shed light on the orthogonal reactivity of the acyl azides depending on the catalyst system used further investigations were done. The rhodacycle containing an acetonitrile ligand reacted with the isocyanate to form the C-C amidated product, but no reaction occurred with the acyl azide to form the C-N amidated product. However, a rhodacycle containing a 2-phenylpyridine ligand formed both the C-C and C-N amidated product. The difference in reactivity between the rhodacycles clearly indicates the importance of the acetonitrile ligand for the selectivity of the process. When examining the ruthenacycle an interesting dual activity was found for both the C-C and C-C-N amidations under identical conditions. The ruthenacycle was further investigated and it was postulated that the high selectivity of the ruthenacycle depends on the relative conditions of acyl azides and isocyanates present in the reaction mixture. To verify the hypothesis a series of experiments were done. When equimolar amounts of acyl azide and isocyanate could react with 2-phenylpyridine under the Ru-catalyzed conditions, the isocyanate showed higher reactivity than the acyl azide. Additionally, when the reaction with both reactants was performed at 70 oC the product was a mixture of both products, however when the reaction was performed at 50oC the product was exclusively the C-N amidated product. The higher selectivity at lower temperature is most likely due to the slower decomposition of the azide at a lower temperature. Based on the findings above the high chemoselectivity for the C-N amidation using a ruthenium catalyst is due to the fast amidation while the Curtius rearrangement remains slow.
In summary, the dual reactivity of acyl azides for C-H amidation can be controlled by varying the catalyst used. By using a rhodium catalyst, the amidation reaction will lead to C-C bond formation due to generating isocyanates from the acyl azides. However, when a ruthenium catalyst is employed the amidation reaction will lead to C-N bond formation. By further studying the rhodium and ruthenium catalysts more insight can be gained into the dual reactivity of azides as nitrogen or carbon donor. Better control of the reactivity of acyl azides could open more possibilities for C-H amidation reactions.
Ir(III)-catalyzed direct C-7 amidation of indolines using azides
7-substituted indolines are important molecules due to their presence in numerous biologically active compounds.[64] Therefore, a simple method of preparation would be convenient. There are some methods which can selectively amidate the C-7 position of indolines. However, most of these approaches have some constraints such as limited substrate scope and harsh reaction conditions.[65] Therefore, a simple and efficient method for the
17 amidation of C-7 indolines is highly desirable. Based on the problems with the existing methods, the group of Li came up with a general approach for the amidation of the C-H bond at the C-7 position of indolines. The developed method relies on an iridium catalyst, which will be discussed in the following paragraphs.
The investigation started by optimizing the reaction conditions for the amidation reaction. The optimization was done with N-acetylindoline and tosyl azide. Various catalysts were tested such as rhodium and ruthenium systems however, the iridium catalyst resulted in the highest yield when dichloroethane (DCE) was used as solvent (fig. 19).
Figure 19: optimized reaction conditions for direct C-H amidation
With the optimized conditions in hand the scope of the sulfonyl azides was examined. The scope of sulfonyl azides was large and indifferent to the electronic nature of the substituents of the sulfonyl azides. Based on the positive results obtained by using sulfonyl azides the investigation was shifted to acyl azides as amidating agent. The group of Li was delighted that in contrast to previous results the acyl azides amidated the substrates smoothly (fig. 20).[65] Acyl azides containing electron withdrawing, electron donating groups were tolerated and resulted in products with good yields.
Figure 20: products of amidation reaction using indolines and acyl azides
In summary, the group of Li developed a general method for the C-7 selective amidation of indolines using an iridium catalyst and using sulfonyl and acyl azides as amidating agents. In paragraph 4.1.2, the C-7 amidation done by the group of Li will be compared to the C-7 amidation reaction of indolines with dioxazolones as amidating agent to compare which amidating agent is more efficient.
18
3
Dioxazolones
In the previous chapters azides and iminoiodinanes have been discussed as nitrene precursors. Iminoiodinanes outperform azides in aziridination reactions however, azides are a more sustainable reagent than iminoiodinanes. Based on the unsustainable properties of iminoiodinanes, it is unlikely that iminoiodinanes will be common for applications in the future. Both azides and iminoiodinanes have their own drawbacks. The drawbacks led research to focus on developing new reagents that have better properties than both azides and iminoiodinanes. In the following chapter a class of nitrene precursors which have only been used as acyl nitrene precursors since 2012 will be discussed; the 1,4,2-dioxazol-5-ones (dioxazolones). A brief history of these compounds will be given. The current applications of the dioxazolones will be given to eventually be able to compare azides to dioxazolones. This comparison of application and properties of azides and dioxazolones will provide a handle to determine which acyl nitrene precursor is most suitable for which kind of reaction and which one is more sustainable.
3.1
The development of dioxazolones and early uses
The dioxazolones are a class of acyl nitrene precursors which have been used for this purpose since 2012. Dioxazolones are stable up to 100oC, which makes them more stable than similar acyl azides.[66] Dioxazolones form the reactive nitrene species by releasing CO2 (fig. 21).[66] Dioxazolones were first synthesized in 1951 by Beck, however not much research was done into the application of dioxazolones.[67] However, in 1968 Mayer and Sauer reported the decarboxylative thermolysis and photolysis of dioxazolones.[66] The thermolysis of dioxazolones gave acyl nitrenes which subsequently transformed into isocyanates via the Curtius rearrangement (fig. 21). The Curtius rearrangement is not a desired reaction when trying to apply dioxazolones as acyl nitrene precursors. Due to the rearrangement the carbon atom becomes more electrophilic than the nitrogen atom. The increase in electrophilicity of the carbon atom leads to isocyanates forming new bonds from the carbon atom in a reaction, in contrast to nitrenes forming new bonds from the nitrogen atom. That is why the Curtius rearrangement is undesired when working with acyl nitrene precursors.
Figure 21: thermolysis of dioxazolones generating the nitrene and subsequent Curtius rearrangement into an isocyanate
Dioxazolones were initially used as isocyanate precursors. After the Curtius rearrangement the isocyanates can react with alcohols or amines and give carbamates or ureas. The use of dioxazolones as isocyanate precursors was reported by Dube.[68]The group of Dube reported the synthesis of various carbamates and ureas using various dioxazolones as precursors (fig. 22).
19
3.2
Dioxazolones used as nitrene precursor
3.2.1 Oxazolines synthesized using dioxazolones
To be able to use dioxazolones as nitrene precursors, the Curtius rearrangement must be avoided. The first use of dioxazolones as nitrene precursors was reported by He et al.[69] Dioxazolones were synthesized by treating the carboxylic acid with hydroxylamine hydrochloride (NH2OH∙HCl) and subsequently with carbonyldiimidazole (CDI) (fig. 23).
Figure 23: the synthesis of dioxazolone precursors
The synthesized dioxazolones reacted with styrene derivatives which contained various R-groups to form oxazolines (fig. 24). The group of He experimented with various catalysts such as ZnCl2, Hg(OAc)2, Rh2(OAc)4, or RhCl3. However, the only catalyst combination which produced oxazolines was the ruthenium-porphyrin/copper chloride catalyst combination (Ru(TTP)CO)/CuCl2. The conditions for the formation of oxazolines were further investigated and optimized. Various oxidants were tested such as manganese dioxide (MnO2), iodine (I2) and oxygen (O2). MnO2 decreased the reaction yield. However, O2 increased the reaction speed but did not increase the yield. I2 increased the yield of the reaction. The reaction temperature was optimized at 50°C. Higher temperatures did not improve the yield.
Figure 24: the synthesis of oxazoles from dioxazolones and styrene derivatives
The role of I2 was determined to gain a better understanding of reaction process. In the presence of I2 the dioxazolones had disappeared from the reaction mixture within an hour. However, without I2 the disappearance of the dioxazolones took up to 4 hours. Based on the observations it can be concluded that I2 aids with the decomposition of the dioxazolones. The role of CuCl2 was investigated by synthesizing the aziridine (A) using a method from literature.[70] The synthesized aziridine (A) could be converted into the oxazoline (E) using CuCl2 in the presence of I2.
Based on all the above experimental findings a catalytic cycle was proposed (fig. 25). The dioxazolone decomposes and releases CO2 and forms a nitrenoid complex with ruthenium. This nitrenoid complex can then react with styrene present in the reaction mixture forming intermediate A. Intermediate A then coordinates to copper and forms B. Complex B is unstable and thus follows a rearrangement forming the carbonium ion C. Intermediate C undergoes cyclization via the oxygen atom and forms D. Complex D then allows for the regeneration of CuCl2 and gives the oxazoline E.
20 Figure 25: Catalytic cycle to form oxazolines
3.2.2 Sulfimides and sulfoximines synthesized using dioxazolones
The report by He et al. inspired others to research the application of dioxazolones as nitrene precursors. The following report of dioxazolones used as nitrene precursors was done by Bolm et al. in 2014.[71] Bolm reported the synthesis of sulfimides and sulfoximines. The most common approaches to produce sulfimides and sulfoximines are done using sulfur imidations of sulfides and sulfoxides respectively. However, there are only a few synthetic methods that give direct access to N-acylated sulfimides and sulfoximines.[72–75] One of the methods uses nitridomanganese(V) complexes with trifluoroacetic anhydride.[76] All methods seem to involve the formation of metal nitrenoid complexes. However, the previous methods all used harsh reagents. The group of Bolm was inspired by the Mayer and Sauer paper on dioxazolones in which they found that dioxazolones can decarboxylate thermally or photochemically to form a nitrene species.[66] In the paper of Mayer and Sauer the formed nitrenes would then rearrange into isocyanates. The group of Bolm came up with an alternative approach. The alternative approach was based on the observed formation of N-acyl sulfoximines when the decarboxylation of dioxazolones was performed in DMSO at 150oC in the Mayer and Sauer paper (fig. 26).
21 Although the yields of the reaction in DMSO were moderate, the interest of the group of Bolm was sparked. To improve the yield of the reaction the use of transition metals as catalyst was investigated. Inspired by the He et al. paper discussed above, the group of Bolm came up with a reaction to synthesize sulfoximines (Fig. 27).
Figure 27: the optimized reaction of dioxazolone with sulfoxide to produce sulfoximine
Initially the reaction formed a mixture of F and G. The formation of G is undesired and led Bolm to further optimize the reaction conditions to only form F. It was found that water played an important role in the formation of G and thus the reaction was performed under inert conditions. Using the optimized conditions led to the formation of F in 99% yield. The group then tested the importance of light and the catalyst. The yield of F was significantly lower when only light or the catalyst was used in the reaction. Indicating that both light and the ruthenium catalyst are necessary for the formation of A at room temperature. The yield of F at thermal conditions was 42%, which is significantly lower than when using light activation. It is assumed that the light activation provides the energy to form the metal nitrenoid species, without reaching higher energy levels necessary for the Curtius rearrangement.[77,78]
Motivated by the positive results of the performed reactions a one-pot synthesis of N-protected sulfoximines was performed (fig. 28). The group of Bolm hypothesized that this one-pot reaction could work due to the ruthenium catalyst which is used. It is known that [Ru(TPP)CO] can react with an oxidant to form [Ru(TPP)O2], which is able to oxidize sulfides.[79,80]First the optimized conditions to produce sulfoximines were used, however the yield of the reaction was fairly low. The disappointing yield led to further optimization of the conditions and it was found that using CH2Cl2/H2O (2:1) was optimal. The biphasic system allowed better solubility of the oxidant resulting in a yield of 99%.
Figure 28: one-pot imidation/oxidation reaction
To gain a better understanding of the reaction a mechanistic study was performed. By mixing various aminating agents it was shown that the dioxazolone was responsible for the formed product H (fig. 29). A subsequent experiment showed that the sulfide and benzamide did not react. Based on the experiments it was proven that using the dioxazolone was crucial in forming the sulfimide.
22 Figure 29: importance of aminating agent to form sulfimide
The structure of the catalyst was investigated by changing the substituted groups. It was found that with tolyl groups the reaction proceeded smoothly, but with mesityl or pentafluorphenyl groups the reaction showed low catalytic activity. The catalytic activities of the complexes were interpreted as a basis for the importance of the metal center having reasonable electron density. To prove the electron transfer events, play a significant role in the imidation reactions. An electron acceptor (p-nitrobenzene) was added to a reaction mixture of dioxazolone and sulfide. The yield of the reaction when an electron acceptor was present dropped significantly from 99% to 23%. When the ruthenium complex was replaced for other photosensitizers no reaction occurred, which strengthened the hypothesis that a N-bound nitrene/ruthenium species was crucial for the imidation process. The
N-bound nitrene/ruthenium species was found by analyzing the reaction mixtures using mass spectrometry (MS).
With the detection of the nitrene/ruthenium species the following catalytic cycle for the imidation process was proposed (fig. 30).
23 It starts by exciting the [Ru(TPP)CO] complex (l) using light which allows the carbon monoxide (CO) which is bound to dissociate. The dissociation of CO allows for the binding of the dioxazolones leading to complex ll. Loss of carbon dioxide (CO2) gives the N-acyl-nitrene complex lll. The sulfide interacts with complex lll resulting in complex lV. The acyl-nitrene transfer reaction is completed when the imidated product J is released from complex lV and this completes the imidation cycle. Ruthenium complex l can then enter a second catalytic cycle which performs the oxidation of compound J. Complex l is oxidized using sodium periodate (NaIO4) and this creates the oxo-ruthenium species V. Complex V upon interaction with compound J forms complex Vl. The catalytic cycle is completed when sulfoximine K is released and the ruthenium complex is regenerated.
3.3
Dioxazolones used for C-H amidation
The groundwork done by He and Bolm using dioxazolones as acyl nitrene precursors inspired other groups to investigate the potential of dioxazolones. In 2015 Chang reported the C-H amination using a rhodium catalyst and dioxazolone as amidating agent.[81] Up until then the interaction between the metal and dioxazolones had not been studied in detail. However, Chang et al. performed an in-depth mechanistic study on the rhodium dioxazolone system. The findings of their research will be discussed in the following paragraph.
Previously the group op Chang reported the rhodium catalyzed direct amidation of arene, alkene and alkane C-H bonds using organic azides as nitrogen source.[82] However, there was one interesting observation about the system. The rhodium system would be able to perform the individual reactions such as C-N bond formation (fig. 31) with a rhodacycle and protodemetalation of the formed amido rhodium complex (fig. 32). The problem with the rhodium system occurred when all components were mixed and the catalytic conversion using this system would not occur (fig. 33). The unexpected result of no reaction occurring when all components were mixed. Led to an in-depth investigation on this system to find out why the system did not react under catalytic conditions.
Figure 31: C-N bond formation using rhodium system and azide
Figure 32: protodemetalation of amido rhodium species using 2-phenylpyridine
24 It was hypothesized that the cycle could be divided into 4 steps. Step 1: generation of a cationic rhodacycle from the resting state. Step 2: coordination of the azide to the metal to form an intermediate. Step 3: insertion of an imido moiety into the Rh-C bond to form the C-N bond. Step 4: protodemetalation which gives rise to the product and subsequent C-H activation of another substrate to regain the active species. As seen from fig. 31,32 steps 2-4 occurred without a problem at room temperature. Thus, further investigation was mainly focused on the generation of a cationic rhodacycle from the resting state. Previous studies performed by Chang et al. showed that a substrate will occupy a vacant site of a cationic rhodacycle and generate a resting species (fig. 34).[82]
Figure 34: formation of resting species from a rhodium cationic complex
Consistent with the hypothesis of a resting species being formed. The reaction between the resting species and an azide was performed resulting in a negligible amount of the amidation product being formed (fig. 35). The poor reactivity of the resting species implies that the azide species cannot effectively bind to a rhodium center in the presence of 2-phenylpyridine. Based on the low reactivity of the resting species, the C-N bond formation and protodemetalation occurring at room temperature. The limiting factor for reactivity of the complex is the competition in binding to the metal complex between the substrate and azide. The generation of an active species becomes crucial for an efficient C-H amidation reaction. Due to azides not being able to displace 2-phenylpyridine in the resting state (fig. 35), alternative amidating agents were investigated.
Figure 35: acylamido inserting into resting species by displacing 2-phenylpyridine
3.3.1 The use of dioxazolone as amidating agent
The class of molecules which caught the interest of Chang et al. were the dioxazolones. The fact that N-acyl nitrenes can be generated from dioxazolones and similar to azides the dioxazolones can undergo thermal or photochemical decomposition to form the N-acyl nitrenes.[66] The group of Chang was also inspired by previous work done by Bolm et al. which was discussed above. Bolm used the generation of N-acyl nitrenes from dioxazolones to form sulfimides.[71] Based on the similarities between azides and dioxazolones and the fact that dioxazolones have been used as nitrene precursor in previous reactions. The group of Chang envisioned that dioxazolones could be an efficient nitrene source.
25 Based on observations by Ellman and Shi that imines showed similar binding ability to 2-phenylpyridine.[83,84] It was hypothesized that dioxazolones would have a higher binding affinity than acyl azides. Thus, leading to a higher efficiency for the amidation reaction. To validate the hypothesis a catalytic system was designed using a cationic rhodium cycle generated from [Cp*RhCl2]2 and AgNTf2. Various dioxazolones were tested, however the highest activity was obtained using dioxazol-5-one, which was active at room temperature. 3-pheny-1,4,2-dioxazol-5-one, was used for further optimization of the catalytic system. To determine the origin of the high reactivity of 3-pheny-1,4,2-dioxazol-5-one, with the catalytic system further experiments were performed. The first experiment was the reaction of 3-pheny-1,4,2-dioxazol-5-one, with the cationic rhodium species (fig. 36). Both the cationic rhodium species and the resting species were immediately converted into the amido product. This was measured using time resolved IR. The displacement of 2-phenylpyridine from the resting species by 3-pheny-1,4,2-dioxazol-5-one, is much faster than the displacement from the azide previously mentioned (fig. 35).
Figure 36: Stoichiometric reactions of dioxazolones with cationic rhodium complex
It can be concluded that 3-pheny-1,4,2-dioxazol-5-one, readily displaces 2-phenylpyridine from the cationic rhodium species. The displacement ability of dioxazolones is far higher than that of an acyl azide. To determine the difference in reactivity between benzoyl azide and 3-pheny-1,4,2-dioxazol-5-one, with the cationic rhodium complex. A competition experiment was performed. The cationic rhodium species could react with an equal mixture of 3-pheny-1,4,2-dioxazol-5-one, and deuterium labelled benzoyl azide. NMR analysis of the formed product showed no deuterium incorporation. The results suggest that the reactivity of 3-pheny-1,4,2-dioxazol-5-one, is far higher than benzoyl azide under these conditions. For an even better understanding of the differences in reactivity a DFT study was performed on the amino sources. The difference in coordination equilibrium between acyl azide and 3-pheny-1,4,2-dioxazol-5-one, was calculated and the following results were obtained (fig. 37).
26 These results confirm the higher activity of the dioxazolones compared to the azides due to having a lower ∆G for the displacement of 2-phenylpyridine. Further calculations were done on the subsequent rhodium nitrenoid species. It was found that the reaction of 3-pheny-1,4,2-dioxazol-5-one, (CO2 release) with the rhodium complex was lower by 12.7 kcal/mol than with the acyl azide (N2 release): 20.3 versus 33.0 kcal/mol (fig. 38)
Figure 38: potential energy surfaces for the formation of rhodium-nitrenoid species with azide or dioxazolone[81]
The energy difference may be the reason for the difference in reaction efficiency between the amino sources. Based on the findings from the DFT study the reactivity of 3-pheny-1,4,2-dioxazol-5-one can be attributed to two complementary effects. The first one being facilitation of the nitrenoid formation. The second being a more favorable replacement of a substrate in the resting species.
3.3.2 Understanding the catalytic cycle when using dioxazolones as amidating agent
The next step in the investigation for Chang et al. was to characterize the intermediates in the amido transfer process. While several catalytic systems have been developed for C-H aminations. Only a few examples report the isolation of nitrogen-containing intermediates in the amido transfer process.[85,86] The group of Chang isolated an intermediate which was the product of a rhodacycle and 3-phenyl-5,5-dimethyl-1,4,2-dioxazole. X-ray analysis confirmed the coordination of the N-atom to the rhodium center. The isolated intermediate was able to undergo an imido insertion at 100 oC to form an amido rhodacycle (fig. 39).
Figure 39: stepwise C-N bond formation with isolation of the intermediate product.
Based on the obtained mechanistic results Chang et al. came up with the following catalytic cycle (fig. 40). The rhodium dimer is broken due to addition of a silver salt and then 2-phenylpyridine binds to rhodium leaving a
27 vacant site (a). The cationic rhodium complex is present in a resting state (b) in which two molecules of 2-phenylpyridine are bound. The added dioxazolone can displace one of the 2-2-phenylpyridine molecules and form a rhodacycle intermediate (c). Then CO2 is released and the rhodium nitrenoid species is formed (d). Subsequently C-H amidation occurs forming the C-N bond and generating the rhodium amido complex (e). Finally, protodemetalation and C-H activation of a second substrate occur, thus releasing the product (f) and regenerating the active species (a) in the catalytic cycle.
Figure 40: catalytic cycle of the C-H amination procedure described by Chang
3.3.3 Substrate scope of dioxazolones
With all the gained knowledge about the reaction mechanism of the C-H amidation using dioxazolones the next step was to determine the substrate scope. This was done at 40oC and all reactions were completed within 12h. The catalyst which was used was a dimeric rhodium catalyst (1 mol %) with AgNTf2 (4 mol %) (fig. 41).
Figure 41: general reaction scheme of C-H amination performed by Chang
A large scope of substrates was tested (fig. 42). First the substituents on 2-phenylpyridine were investigated (3a-g). It was found that the reaction proceeded smoothly regardless of electronic or steric variations. However, a
28 substrate bearing an ortho-ester substituent was ineffective under the standard reaction conditions (3d). A wide range of functional groups which are potentially chelating such as ester, ketone and aldehyde did not affect the reaction. Next substituent effects on the dioxazolones were investigated. Substituents on the phenyl moiety did not affect the efficiency (3ia-3ic). However, the reaction with a dioxazolones containing a methoxy group at the 4 position (3id) only proceeded with a moderate yield (49%).
Being able to introduce N-acyl amide groups (3j-k) is of special interest. Considering the fact that Chang developed a procedure using alkyl acyl azides as amidating agents previously (discussed in paragraph 1.3.6).[54] Which gave rise to the same products, however the azides were less convenient to work with due to being prone to rearrange into isocyanates.[87] Additionally alkyl acyl azides of low molecular weight often require special handling due to safety issues.[88] With the problems of azides in mind, dioxazolones can be seen as safer and more convenient alternative to acyl azides. Finally, various modified directing groups were investigated such as amide (3l-m), ketoxime (3n) and N-oxide (3o). All these directing groups reacted smoothly; however slightly higher temperatures were needed. The only directing group which did not react was the ketone (3p). In conclusion the group of Chang developed an efficient C-H amidation using dioxazolones. The dioxazolones showed higher reaction efficiency compared to acyl azides. Additionally, dioxazolones are more convenient to prepare, store and use when compared to acyl azides.
29
4
C-H amidations using dioxazolones and rhodium catalysts
Since the publishing of the research done by Che, Bolm and Chang. Many other research groups have published analogous C-H amidation reactions.[89–93] The main differences were the directing groups used in the reactions. Another factor which was different in the reactions was the metal used. There are several reports of amidation reaction being performed with rhodium, iridium, cobalt and ruthenium. In the following chapters several examples will be given of the reactions performed using different metal catalysts.
4.1
C-H amidations using a rhodium catalyst
4.1.1 C-H amidation by ball milling
The first example which will be discussed is the use of a rhodium catalyst for C-H amidation which was done by the group of Bolm. The group was inspired by the reports of Chang which were previously discussed in the paragraphs above. The report of Chang showed that a [Cp*Rh(III)] catalyst was highly efficient.[81] Although the rhodium catalyst used by Chang was highly efficient, Bolm identified certain problems which limited the sustainability of the process. The problems are that in the C-H amidations previously discussed significant amounts of solvents are used and often harsh conditions are required. To deal with the sustainability problems Bolm came up with a creative solution using ball milling. In the past decades ball milling has been established as a useful tool for organic transformations by using mechanochemical activation.[94] The group of Bolm has previously reported on the use of ball milling for catalytic mechanochemical C-H bond functionalization.[95,96] The use of mechanochemical activation often provides advantages compared to traditional solvent based methods. The advantages include higher yields, shorter reaction times, lower catalyst loadings, and most important performing the reaction without solvent and elevated reaction temperatures.[97,98]
To investigate if the high performing rhodium catalyst could be used, the group of Bolm used conditions which were like the conditions reported by Chang.[81]To the satisfaction of Bolm the product was obtained in 76% yield after only 99 minutes of ball milling. After the initial screening the reaction was further optimized and the product was obtained in 97% yield.[99]
Figure 43: optimized reaction conditions for the mechanochemical C-H amidation reaction using a rhodium catalyst and the products of the reactions
30 Once the optimal conditions were achieved the substituents were varied on the benzamide, on the benzamide nitrogen and on the amidating agent. The benzamide derivatives resulted in products with good to moderate yield (fig. 43). The scope of the reaction was investigated even further by using various directing groups. Analogous to the results of Chang discussed above the reaction also proceeded smoothly with various directing groups.[81] To gain a better understanding of the reaction cycle a rhodacycle was synthesized and added to a mixture of phenylpyridine and the dioxazolone, resulting in the amidated product (fig. 44). Although altered reactivity profiles can occur when ball milling.[100] The results of using the rhodacycle as catalyst indicate that the rhodacycle is a likely intermediate in the catalytic cycle. However, further research needs to be done to confirm the catalytic cycle.
Figure 44: determining the reaction mechanism by testing the catalytic ability of the rhodacycle
There are three takeaways from these results which are notable. First by using mechanochemical activation no solvent was needed to perform the reaction. The ortho amidated benzamides were obtained in high yields by using similar catalyst loading to the reactions performed in solvent.[81] Second, the time to complete a reaction was significantly shorter (99 min) than when the reaction was performed using a solvent (12 h). Finally, no additional heating was required. The results show that dioxazolones can be used to perform amidation reactions by ball milling. The advantages of ball milling make the amidating reactions more sustainable when compared to the traditional method of performing the reaction in a solvent.
4.1.2 C-H functionalizations at the C-7 position of indolic scaffolds using dioxazolones as amidating
agent
Another interesting application of dioxazolones was the work of Kim et al.[101] In the research the C-H functionalization of indolic scaffolds was explored. Indolic scaffolds are found in many natural products and pharmaceuticals.[102] Specifically C7-amidated indolines have attracted considerable attention due to the discovery of interesting biological properties.[103,104] Indolines have shown diverse properties such as tubulin polymerization inhibition, inhibition for hypocholesterolemic action and antiproliferative activity.[105,106] Due to the various properties indolic scaffolds can have, a great deal of effort has been devoted to the C-H functionalization of the indolic scaffolds with coupling partners. Especially the directing group-assisted C-7 functionalization of indolines have been intensively researched due to the prevalence in many pharmaceutical agents.[64,107] Previously the C7-amidations of indolines with organic azides were reported by the groups of Zhu and Chang using various transition metal catalysts.[65,108] Inspired by the reports of dioxazolones as new amidating agents.[82] The group of Kim decided to investigate the C7-amidation of indolic scaffolds using dioxazolones. Kim used a rhodium(III) catalyst for the direct C-H amidation of indolines with dioxazolone as the amidating agent. The synthesized products were also tested for biological activity, which will be discussed in the following paragraph. The reaction conditions for the amidation of indolines was optimized by reacting pyrimidin-2-yl indoline and 3-phenyl-1,4,2-dioxazol-5-one using a rhodium catalyst. The optimal conditions were a rhodium catalyst (2.5 mol%) and AgNTf2 (10 mol%) (fig. 45).
31 Figure 45: Optimized conditions for the amidation of indolines using a rhodium catalyst
With the optimized conditions determined, various substituted indolines were screened (fig. 46). The C2, C3 and C5 substituted indolines were obtained in good yield. The C4 substituted indolines resulted in a moderate yield when the reaction was performed at room temperature. However, the products of the reaction were obtained in high yield when the reaction was performed at 80oC. The C6 substituted indoline was found to be less reactive even when the reaction was carried out at 80oC.
Figure 46: substrate scope tested in the indoline amidation reaction
After having screened the substituted indolines, the substrate scope of dioxazolones was investigated. The dioxazolones were found in good to excellent yields when they contained either electrondonating or -withdrawing groups at the para and meta positions of the aromatic ring. Another important point to mention is that nitro or chloro groups were tolerated and could act as a handle for further modifications.
An interesting thing to note is that the dioxazolones containing the p-chloro substituted aromatic ring gave a higher yield than when the azide containing the chloro group was used (fig. 47).[109] Although the comparison isn’t conclusive due to different reaction times being used with both procedures. The difference in yield does indicate that dioxazolones might be a superior amidating agent when compared to azides for specific applications. However, to determine which amidating is superior more research needs to be done.
