MSc Chemistry
Molecular Sciences
Literature Thesis
T
HE
C
ARBONYL
-O
LEFIN
M
ETATHESIS
R
EACTION
by
Mark Houtman
12262358
June 2020
12 EC
March – June 2020
Supervisor:
Second Reviewer:
Prof. Dr. Bas de Bruin
Dr. Chris Slootweg
Daily Supervisor:
Felix de Zwart MSc
Van ‘t Hoff Institute for Molecular Sciences
1
Table of Contents
Table of Contents... 1
Abstract ... 2
Introduction... 3
Photochemical and -catalyzed COM ... 6
Photochemical ... 6
Hydrazine-catalyzed COM reaction ... 8
Transition metal carbonyl-olefination and metathesis ... 10
Lewis Acid catalysts for COM reactions ... 13
Inorganic Lewis acids as COM catalysts ... 13
Organic Lewis acid catalysts in COM reactions... 16
Green Chemistry in COM ... 20
Future Prospects of COM ... 24
Modifications of TM complexes ... 24
Future prospects of LA catalysts ... 27
The scope of photo- and organo-catalyzed COM ... 27
Conclusion ... 29
2
Abstract
This thesis was about the carbonyl-olefin metathesis (COM). COM reactions are reactions that occur between a carbonyl and an olefin in a metathesis-type fashion, resulting in a new carbonyl and a new olefin. In the first part, a photochemical and a photocatalyzed method were discussed. These are the original method of COM reactions and a recently developed method that employs photoinduced hole-catalysis. Secondly, a novel hydrazine catalyzed COM was described. The hydrazine catalyzed COM reaction works on the basis of a [3+2]cycloaddition and reversion, instead of the [2+2]cycloaddition and reversion employed in the photochemical method. In the third chapter, the focus was on transition metal (TM) complexes that assist in carbonyl-olefination and subsequent olefin metathesis. TM complexes are, thus far, unable to catalyze COM reaction, however, they are able to form an olefin out of a carbonyl and perform an olefin metathesis in an uninterrupted cascade reaction. The last group to be reviewed were the Lewis acid (LA) catalyzed COM reactions. Both inorganic and organic LAs, are able to catalyze various types of COM reactions. Some provide a better scope for ring closing reactions, while other perform better in intermolecular reactions or ring opening reactions. Further, the focus was on green chemistry and a more theoretical part that focused on the future scope of the COM reaction. A possible method of a formal COM reaction via an imine-olefin metathesis reaction was discussed. It was concluded that the COM reaction is a viable method, but requires more development in order for it to become more useful in other fields of chemistry.
3
Introduction
In 1931, it was observed that propene forms ethylene and 2-butene when it is heated to 725°C, which spiked the interest of the chemical industry.1 In the years that followed, heterogeneous catalysts were employed in order to perform the propene disproportionation reaction to synthesize ethylene and 2-butene on a larger scale. In 1967, Calderon et al. proposed the name olefin metathesis and in 1974, Schrock
et al. managed to isolate the first metal-alkylidene and shortly thereafter the provided support for the
Chauvin mechanism (Scheme 1).1–4 In 1992, a ruthenium carbene metathesis catalyst was discovered by Grubbs, these catalysts became commercial around 1995.1,5
Many preparations in fields like total synthesis utilize the olefin metathesis reaction to synthesize macrocycles. Besides that, new catalysts and methods to better facilitate the reaction in a number of new circumstances and environments are still being developed.6–8 Yves Chauvin, Robert Grubbs and Richard Schrock were awarded the 2005 Nobel Prize for Chemistry the development of the olefin metathesis method in organic synthesis”.9
Scheme 1: The Chauvin mechanism for olefin metathesis.2,4,5
Alkyne-alkyne metathesis is a reaction between two alkynes. The reaction was discovered after disproportionation reaction of 2-pentyne to 2-butyne and 3-hexyne, was observed.10 The mechanism follows a similar route as the Chauvin mechanism, but with the alkynes instead of alkenes. The alkyne-alkyne metathesis reaction is being employed in total synthesis, and new developments have been reported in recent literature.11,12
4
Scheme 2: Discovery of the alkyne-alkyne metathesis and a recent example with a molybdenum catalyst.10,11
The enyne metathesis is a mix between the olefin and alkyne metathesis. An olefin will react, in presence of a catalyst, with an alkyne to form a new carbon-carbon bond and two conjugated alkenes. Reported by Katz et al. in 1985, the enyne metathesis was employed to cyclize molecules with both moieties, and the reaction remains of interest today (Scheme 3).13,14
Scheme 3: The enyne-metathesis employed by Katz et al. and the formation of cyclopentadienylbenzene derivatives via the enyne metathesis reaction with the catalyst.13,14
The carbonyl-olefin metathesis (COM) is a metathesis reaction between a carbonyl and an olefin. One of the first documented COM reactions was by Jones II et al. in 1975, where it was employed to synthesize a pheromone.15 The reaction is very similar to the other metathesis reactions. In the presence of a catalyst a carbonyl and an olefin react in a metathesis-type fashion, resulting in a new carbonyl and a new alkene (Scheme 4). The COM reaction is attractive due to the moieties involved, a metathesis
5
between a carbonyl and a substituted alkene is a useful tool. Being able to perform an intermolecular COM could be very useful in fields like total synthesis.
Scheme 4: The reaction equation for a carbonyl-olefin metathesis.
As both a carbonyl and an olefin moiety are relatively common moieties, the COM reaction can be employed in total synthesis in a similar fashion as the olefin metathesis reaction. The COM provides a large range of products and, given the right catalyst, good functional group tolerance. The reaction is becoming more of interest for various research groups, as the transformation of the moieties the reaction involves, and subsequently, produces. A number of different methods were devised, such as a photocatalyzed, hydrazine catalyzed and Lewis acid (LA) catalyzed COM reactions. The different types of COM can be classified in four categories, the photoinduced and photochemically, hydrazine catalyzed, via transition metal complexes and LA catalyzed COM reactions.16 The TM complexes are note catalysts, as they are not catalytically active and form a metal oxo compound instead of a carbonyl. However, the TM complexes provide a viable method for performing a carbonyl-olefination and subsequent olefin metathesis reaction to approximate the same result as a COM reaction.
The COM reaction is the main focus of this thesis and all four groups of catalysts will be discussed. Apart from that, the COM will be discussed from a green chemistry perspective, as green chemistry is an important concept in modern chemistry. The last part will focus on the future, what improvements to the catalysts or the reaction could improve the scope or tolerances. Perhaps new methods could be developed to improve on the current methods. The aim of this work is to give insight into the COM reaction, what methods exist and further investigation might lead to in the future.
6
Photochemical and -catalyzed COM
The first class of COM reactions are performed or catalyzed by light or a photocatalyst. The photochemical COM reaction employs light to excite the carbonyl, which results in a reaction with the alkene. The photocatalyzed COM employs a photocatalyst which is excited by a light source, then transfers a charge or radical to the alkene substrate to start the reaction.
Photochemical
First COM reaction to be employed was a photochemical method, by Jones II et al. It was devised that the reaction could be of great importance to synthesize 6-enaldehydes for better access to compounds like insect pheromones. The method is a formal COM and consists out of two steps, the first is the Paternò-Büchi reaction, which is a [2+2]cycloaddition of a carbonyl compound to an alkene to form an oxetane. The photochemical cycloaddition occurs with a disrotatory movement to form two stereochemical centers in the oxetane. The oxetane can then undergo cycloreversion by heating it, acidic conditions, or by means of a transition metal complex, to form a carbonyl and an olefin product (Scheme 4). Jones II et al. reported the cycloreversion to be stereochemically favored towards the E-alkene.15,17 Apart from this paper by Jones II et al., the focus has mainly been on the Paternò-Büchi reaction, and not the subsequent fragmentation. The division of the focus of the formal photochemical COM is likely because oxetanes are interesting group of molecules on their own.18
Scheme 5: Mechanism of the Paternò-Büchi reaction, followed by thermal [2+2]cycloreversion to perform a COM.15,18,19
Photoinduced hole-catalysis
Next the Paternò-Büchi reaction, an indirect method of photocatalytic COM reactions has been developed by Pitzer et al., the photoinduced hole-catalysis COM reaction. By employing a photocatalyst, 3,6-di-t-butyl-9,10-dimesitylacridin-10-ium tetrafluoroborate (Scheme 6), in combination with blue LEDs (λmax = 420nm) compound (1) was formed. Then TFA was added and over a 16 hour period at 60°C, which resulted in the desired product 2 (Scheme 6). This photocatalytic method allowed Pitzer et al. to synthesize multiple products with yields between 37 and 86% with E/Z ratios between 5:1 and >20:1. Through mechanistic studies an oxetane intermediate was ruled out as it should have resulted in Z-alkenes, therefore it was that the reaction proceed via an 1,3-diol intermediate.20
7
Scheme 6: Proposed mechanism by Pitzer et al. and the structure of the photocatalyst. The overall reaction consist out of two cycles, the photoactivation of the catalyst and the hole catalysis, and a dehydration reaction to form the final product.20
The Paternò-Büchi reaction coupled with the acidic cycloreversion is the earlies example of a formal COM reaction, or COM reaction in general. However, utilization of these two reactions to facilitate a COM in modern chemistry, is rarely observed. The photochemical method results in the E-alkene, which could indicate that the product isomerizes. It could also indicate that the cycloreversion occurs in two steps, allowing a rotation between the two carbon atoms, resulting in the E-alkene. The photocatalytic method employs a catalyst to perform the same reaction, but with a photoactive molecule to initiate a radical oxidation. The E-isomer is preferred, and mechanistic restrictions influence this, as an oxetane intermediate was speculated to result in the Z-isomer. Both the photochemical and the photocatalytic reaction might be valuable methods if developed further.
8
Hydrazine-catalyzed COM reaction
Besides photocatalysis, a hydrazine based organic catalyst was developed and employed by the Lambert group. A different reaction was envisioned, based on [3+2]cycloadditions and reversions, instead of [2+2]cycloadditions and reversions. The [3+2]cycloaddition and reversion were preferred, as these can be performed thermally instead of photochemically. The catalyst that was employed was an acidified 2,3-diazabicyclo[2.2.1]heptane. They were able to synthesize a broad range of products with an equally broad range of yields (Scheme 7).19,21
Scheme 7: The two reactions investigated by the Lambert group. The first reaction forms unsaturated aldehydes, and the second reaction forms 2H-chromenes.19,21
The hydrazine catalyst developed by Lambert et al. was initially reported to catalyze a COM reaction between bis(benzoxymethyl)cycloprop-2-ene with various aromatic aldehydes. The catalyst was employed in 10 mol% and the reactions were performed elevated temperatures. General yields were between 50 and 95%, with two outliers at 35% (Scheme 7). It should be noted that the ring-opening COM is likely to be driven by the opening of the cyclopropene, as cyclopropene is even more strained then a cyclopropane. The release of strain energy might thermodynamically drive the reaction.21
Besides focusing on ring-opening COM reactions, the Lambert group also performed ring-closing COM reactions with the hydrazine catalyst. The initial goal was an attempt to synthesize 2H-chromenes from allylated salicyaldehydes (Scheme 7). Different alkene substituents for the allyl-side were tested, ranging from allyl to 3,3-diphenylprop-2-en-1-yl or 2-(adamantyl-2-ylidene)eth-1-yl groups. Various solvents were also tested. The optimized reaction resulted in yields ranging from 30 to 90% with one outlier at 7%. The reaction with the 7% yield was a COM reaction with a methyl ketone, demonstrating that the reaction is favored for aldehydes. The results also included other (hetero)aromatics, with yields from 50 up to 78%. By adding different chemicals, including but not limited to pyridine, indole, benzofuran, benzothiazole, carboxylic acid, a screening was performed to determine the functional group compatibility. In almost all cases the reaction performed normal, except when an alkyl bromide or aniline was added, then the yield was significantly lower by 25% than the reactions with other additives.
In order to support the proposed mechanism, a DFT analysis was included in their results (Figure 1).21 The DFT analysis indicates an initial barrier for the transition state of the [3+2]cycloaddition (Figure 1,
TS1). Similarly, a barrier is present for the [3+2]cycloreversion transition state (Figure 1, TS2). The analysis
was perform for number of alkene substituents. The 3-ethylpent-2-en-1-yl, with pentan-3-one as ketone reaction product (yellow), does not have the lowest energy in the cycloreversion-transition state. However, complementary experimental studies resulted in the 3-ethylpent-2-en-1-yl substituent being the best performing. It was concluded that the substrates with cyclohexanone and adamantan-2-one intermediates likely suffer from a competitive intramolecular ene reaction, while the pentan-3-one does
9
not. Therefore, the pentan-3-yl was chosen to be the best leaving group for the reaction. The energies from the reactants (Figure 1, R) up to intermediate 3 (Figure 1, Int3) were only calculated for the pent-3-yl substrate.21,22 This allows for an uncertainty in the first transition state (Figure 1, TS1), where the other calculated substrates might have higher barriers than depicted in Figure 1, thereby less likely to react.
The hydrazine catalyzed reaction has been demonstrated in just two types of reactions, a cyclopropene-ring-opening COM and a cyclisation COM. The [3+2]cycloaddition method works, but only in a small number of reactions. Further focus should be on a larger substrate scope, to broaden the scope of the reaction itself. The larger scope of the reaction also increases the usability of the reaction.
-40 -30 -20 -10 0 10 20 E (kcal /m o l)
DFT hydrazine catalyst
Figure 1: Investigation of different energies for leaving groups for mechanistic purposes, DFT by Lambert et al.
R groups: H,H = blue; Et,Et = yellow; adamantyl = grey: adamantyl; cyclohexyl = orange.
R
Int1
TS1
Int2
TS2
Int4
P
Int3
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Transition metal carbonyl-olefination and metathesis
The second group of catalysts is TM based. Unlike the photoinduced and organocatalyzed COM, the TM based method employs the aid of d-block metal complexes. The metal center coordinates to a substrate in order to stabilize it, and facilitates the reaction itself. The elegance of TM catalysis is that the ligand influences the reactivity of the metal center. If the ligand is electron donating, it promotes oxidative addition, while electron withdrawing ligands assist reductive eliminations. Besides that, ligands could also be employed to direct the stereochemistry. An example is the Noyori catalyst, where the stereochemistry of BINAP ligands dictates the stereochemistry of ketone that is hydrogenated.23
However, an important fact has been discussed in a review on COM reactions by Lambert. Namely, the TM based COM reactions are not COM reactions, as they do not form a new carbonyl, but a metal oxo compound instead. These TM catalyzed reactions have to be addressed as carbonyl-olefination reaction, followed by an olefin metathesis reaction. However, the TM complexes provide some valuable methods in achieving carbonyl olefinations, it is often included in COM reactions and referred to as such.22
Often occurring catalysts in olefin metathesis are the Grubbs, Hoveyda-Grubbs and Schrock catalysts (Figure 2).24 The Schrock complex has been employed in carbonyl olefination in stoichiometric amounts.25
Figure 2: Various TM complexes employed for the TM assisted carbonyl-olefination and olefin metathesis reaction.25–27
Besides Schrock catalysts, more often employed are the Tebbe and Petasis reagents (Figure 2), which function in a similar fashion. In 1986 and 1990, Stille and Grubbs published two papers concerning titanium metathesis-type reagents. In the 1986 paper it was demonstrated that these titanocenes, aided by 4-(N,N-dimethylamino)pyridine, could perform an olefin metathesis and open a norbornene-type molecule, via thermolysis. The resulting organotitanium (a Schrock carbene) species was being trapped by an ester nearby, and formed a cyclobutene and the corresponding titanium oxo species.26 In the second paper (1990) the same reaction was investigated, but with various 5-norbornene-endo-2,3-dicarboxylates (3 in scheme 8), do discover whether it would form the fused cyclopentane-cyclobutene product or the norbornene product. In most of the cases, nearly half was unreacted. The other half was converted to three different products, where the bulkiness of the esters determined in what yield they were obtained (Scheme 8).27
11
Scheme 8: Rearrangement experiment by Stille et al. with respective yields.27
However, in an attempt to improve on the reaction employed by Stille et al., Rainier et al. employed a combination of compounds. The goal was to synthesize Gambierol, a ladder toxin that might be related to ciguatera poisoning, which required a carbonyl-olefination reaction and olefin metathesis in order to synthesize one of the cyclohexene rings. A Takai-Utimoto reagent (lead(II) chloride, zinc and 1,1-dibromoethane) together with titanium(IV) chloride was employed to functionalize a carbonyl.28 In a follow-up paper in 2007, the reaction between the carbonyl of an ester, or amide, with an alkene was described. The reaction was performed by using the same type modified Takai-Utimoto reagent in order to synthesize dihydropyran, oxepene and oxocene moieties, with yields between 70% and 100%.29 Later Rainier et al. also published a paper on the same reaction, but for amides in order to obtain olefinic amides and lactams.30 The carbonyl olefination and metathesis with esters or amides has been employed by a few other groups besides the Rainier group, in order form cyclic products.31,32 The main advantage of the modified Takai-Utimoto reagent developed by the Rainier group, is that it is able to react with different types of carbonyls, ketones and aldehydes, sterically hindered carbonyls, but also carbonyls in esters and amides. The specific set of substrates results in a wide scope for the carbonyl-olefination and olefin metathesis reactions, and a useful tool in total synthesis.30–32
There is, however, a major downside to the reactions with TM complexes. The TM complexes have to be employed in at least a 1:1 stoichiometry with respect to the substrate.25,33,34 The ratio is required due to the titanium complex forming a titanium oxo compound during the reaction. This titanium oxo compound is unreactive, as it does not perform the metathesis reaction.
12
Since the Rainier-group first employed the modified Takai-Utimoto reagent under modified conditions in 2001, various other groups have employed the Takai-Utimoto-strategy of synthesizing (cyclic) olefinic ethers and amides (Scheme 9)).24,29–32 A Schrock metathesis reagent was occasionally employed to convert the last of the unreacted substrate to the desired olefin product.24 Although the Rainier-method of carbonyl-olefination and metathesis reaction is a viable option, the 2007 paper clearly demonstrates the downside as multiple equivalents of the metal complex were employed in order to convert one equivalent of substrate.29
Scheme 9: The reaction developed by the Rainier group and two examples of employment of the modified Takai-Utimoto reagent in total synthesis.31,32
In TM complex carbonyl-olefination and subsequent olefin metathesis reaction, the titanium complexes are still being employed as main reactant and any unreacted substrate is often converted with a Schrock metathesis reagent. Tebbe’s reagent and the Petasis reagent are substituted for the modified Takai-Utimoto reagent, developed by Rainier et al. Due to the large scope of substrates, this method is being utilized regardless of the required amounts of chemicals needed to perform reactions. Perhaps further research might improve the on the TM complexes and perhaps make the reaction catalytic.
13
Lewis Acid catalysts for COM reactions
The final group of catalysts to be discussed are the Lewis acids (LA). These catalysts have been of major interest in the past two decades. An LA has an empty orbital that is capable of accepting an electron pair from a Lewis base. A Lewis base is a molecule where a non-bonded electron pair is present, like a carbonyl. The interaction between the LA and the Lewis base results in an increase of the electropositivity of the carbon atom in the carbonyl. This electropositivity facilitates the subsequent nucleophilic attack by the alkene. The LAs can be both inorganic and organic.
Inorganic Lewis acids as COM catalysts
The LA catalysis of COM reactions started in 2006, by Khripach et al. While attempting to synthesize a steroid, an unusual product had formed. The substrate for the reaction contained an (E)-cyclodec-5-en-1-one ring (4 in scheme 10) and it was attempted to form two fused cyclohexane rings (5), to form the steroid backbone. Boron trifluoride was used as the catalyst and it catalyzed a ring contracting COM reaction, forming a cyclopentene (6).35
Scheme 10: Serendipitous discovery of a LA catalyzed COM by Khripach et al. The target molecule was steroid 5, via an intramolecular cyclisation. However, product 6 was formed instead.35
The main advantage of LA catalyzed COM reactions over the carbonyl-olefination and metathesis reaction with TM complexes, is that catalytic amounts of LA are required to perform the reaction. The Schindler group has published various papers on this type of COM, generally with iron(III) chloride as LA catalyst. In the paper published in 2017, a screening of various LAs was performed for their catalytic activities in COM reactions, including iron(III) chloride, gallium(III) chloride, scandium(III) triflate and boron trifluoride. Besides that, two Brønsted acids, p-toluenesulfonic acid and hydrochloric acid, were also examined. The p-toluenesulfonic acid to rule out Brønsted acid catalysis The hydrochloric acid was also employed to rule it out as the active catalyst, as iron(III) chloride can form hydrochloric acid in the presence of water. The four other iron salts (hexahydrate, iron(II) chloride, iron(III) triflate and iron(III) bromide) were also employed for the COM, to test if those compounds catalyzed the COM as well. All LAs tested proved to be capable of catalyzing the COM, except iron(II) chloride and zinc(II) bromide. Both triflate salts had low
14
yields and al iron(III) chloride catalysts yielded 96% or more product. The FeCl3-catalyzed COM proved best and was examined further by testing various purities. Both attempts to the Brønsted acid-catalyzed COMs proved unsuccessful, even when equimolar anhydrous hydrochloric acid in dichloroethane (DCE). The reported iron(III) chloride catalyzed ring-closing COMs proved successful as every reaction had a minimum of 96% yield (Scheme 11). Anhydrous iron(III) chloride (99.9% purity) was compared to the hexahydrate (99% purity). Both these reactions resulted in 96% yield, indicating that the water present in the hydrate does not interfere with the reaction.36
Scheme 11: LA catalyzed intramolecular COM developed by Schindler et al.37
Further investigation showed that lower loadings of 5 mol% FeCl3 resulted in similar yields, between 55 and 99% and one outlier at 12%. Initially the starting material was β-ketoester 7, but it was shown that sulfonates, amides (Scheme 12) and a select group of alkyl sidechains also led to product (22 substrates between 55 and 99%, two below 50%). Two possible mechanisms were proposed, a concerted mechanism and a stepwise mechanism and were subsequently investigated.16,38
Scheme 12: Further investivation into the FeCl3 catalyzed intramolecular COM, by the Schindler group, focussing on the
formation of N-heterocycles.16,38
The second paper published in 2017 by the Schindler group, focused on the mechanistic investigations of the FeCl3-catalyzed COM reaction. A set of experiments were performed in order to clarify on the mechanism. A compound similar to compound 7 was employed to clarify on the mechanism. A pendant alcohol in the compound would trap any benzylic carbocations. The isoprenyl-derived alcohols resulted in the COM products. The styrene-derived substituents, however, resulted in a significantly lower yield, but no trapped intermediates were isolated. DFT calculations were made and both pathways were supported by the results of the analysis. Whenever an isoprenyl-derived substrate was employed the reaction followed a concerted mechanism. The reaction followed a stepwise mechanism when a styreneyl-derived substrate was chosen (Scheme 13).36 The different mechanism could be due to the stabilizing nature of the phenyl-moiety directly next to the carbocation (8 in Scheme 13).
15
Scheme 13: Left the stepwise catalytic cyle if the substrate is styrenyl-substituted, right the concerted catalytic cycle if the substrate is isoprenyl-derived.36
In 2018, Schindler et al. employed the same method was applied to synthesize 3-aryl-2,5-dihydropyrroles. Tosylated N-isoprenyl-2-aminoacetophenones were employed as substrates and 50 mol% of FeCl3 were added as catalyst (Scheme 14). The yields obtained were between 50 and 99% and one at 32%. The synthesis of 5-phenyl-1,2,3,6-tetrahydropyridine was also reported.38 Secondly, it was investigated if GaCl3 could function in a similar fashion as FeCl3. By reacting an aromatic aldehyde and a cyclopentene, with the employment of GaCl3 in a 10 mol% ratio, Schindler et al. obtained various products (Scheme 14). There was one major downside to the GaCl3 catalyzed COM reactions, all were below 50% yield. It was stated that a carbonyl-ene reaction is competing with the COM reaction attempted.39
Scheme 14: Both published by Schindler et al., a closing COM catalysed by iron(III) chloride and an intermolecular ring-opening COM catalyzed by gallium(III) chloride.38,39
Being inspired by the recent developments by the Lambert and Schindler groups, Wang et al. envisioned a powerful LA catalyst, similar to iron(III) chloride. Initially 21 different LAs were tested under the same conditions: β-ketoester 7 with an intramolecular alkene (same as Schinder et al., Scheme 11) and 5 mol% of LA, in DCE.16 Out of all the 21 LAs employed in the experiments, only gold(III) chloride, bismuth(III) chloride and resulted in product, 99%, 80% and 55% yield respectively. After further examination a similar
16
range of products was obtained as the Schindler group, and more (Scheme 15). Besides ring-closing and ring-opening COMs and synthesizing 3-aryl-2,5-dihydropyrroles, 6,7-dihydro-5H-benzo[7]annulenes were also synthesized with good yields (72-99%).40
Scheme 15: Gold(III) chloride catalyzed ring-closing COM reaction to form 6,7-dihydro-5H-benzo[7]annulenes.40
A more mild COM reaction was attempted by Tran et al. The idea of a neat reaction, with the employment of molecular iodine (I2) as catalyst, was described (Scheme 17). Various reaction additives, forms of I2 and conditions were examined. The neat I2-catalyzed COM worked both with normal air and nitrogen, in light or darkness in the forms of N-iodosuccinimide (over 72 hours) and iodine chloride (over 72 hours). Occasionally, a minor secondary product was found, due to the isomerization of the alkene in the final product was observed, as proton-shifts occurred to form a more stable alkene. Only experiments that would form a cyclopentene would react, while others either did not react at all or formed 2,3-dihydro-2H-pyran rings. Yields obtained for an intramolecular COM were generally between 50-96% with a few below 40%, down to 27% as absolute minimum. Intermolecular and ring-opening COM reactions were also performed with limited success, as the reported yields never exceed 50%.41
Scheme 16: The proposed mechanism of the I2 catalyzed COM reaction, researched by Tran et al.41
Organic Lewis acid catalysts in COM reactions
Naidu et al. sought to employ the tritylium ion as catalyst, in the form of tritylium tetrafluoroborate, to perform intermolecular COM reactions. As the tritylium ion is an organic LA, the idea was that it would function in a similar fashion as the inorganic LAs and therefore should be able to catalyze COM reactions (Scheme 16). First, it was compared to various LAs in a reaction with benzaldehyde and 2-methyl-2-butene with a 20 mol% catalyst. According to their results, it provided higher yields than boron trifluoride. Furthermore, the scope was investigated by reacting various substituted benzaldehydes with alkene
17
derivatives. The results were mixed, as some performed better at -78°C, some at -20°C and others at room temperature. Reaction times also varied between 30 and 135 hours. Overall the yields were between 40 and 85%, two (4-methoxybenzaldehyde; one at rt one at -78°C) below 20% and one (4-nitrobenzaldehyde) with no yield. More interesting, the attempt to react benzaldehyde with 2,3-dimethylbut-2-ene did not work, the reaction was tested over a period of 7 hours at room temperature, which is significantly shorter reaction time than any of the other reactions attempted. As a second test, an aliphatic aldehyde was attempted to react with 2-methylbut-2-ene, but no reaction occurred and the aldehyde decomposed over a period of 88 hours.42 It could be that the aromatic aldehyde is of importance, as π-π interaction between the benzaldehyde and the tritylium carbocation could be key for successful catalysis.
Scheme 17: The tritylium carbocation catalyzed intermolecular COM reaction by Naidu et al. and three different tropylium catalyzed COM reactions by Tran et al.42,43
Following the work of Naidu, Tran et al. employed the tropylium carbocation. Whereas all previous LA catalysts are capable of catalyzing one specific type of com, the ring-closing, ring-opening or , the tropylium ion was used to attempt to do three different COM reactions: ring-closing, intermolecular and ring-opening COM (Scheme 16). In the experiment to react various cyclic alkenes with benzaldehyde, only the 1-methylcyclobut-1-ene and 1-methylcyclopent-1-ene had reacted.43
Various types of LA COM catalysts have been shown, or are being, developed. Each catalyst has demonstrated to work for at least one type of COM, be it intramolecular, ring-opening or intermolecular (Table 1). Clearly, not every LA is able to be employed as catalyst, at least, under the currently investigated conditions (Scheme 18). The iron, gallium and gold LAs have proven to be useful to form cyclic alkenes, including heterocyclic alkenes, with a large diversity in possible products. However, the organic LA catalyst developed by Tran et al., has more diversity than the other LAs, as it is able to catalyze all three different COM reactions. The tropylium LA is capable of catalyzing all three different COM reactions. Oppositely, the tritylium ion by Naidu et al. employed, is less versatile. Thus far, it has only been demonstrated to work on aromatic aldehydes and isoprenyl derived alkenes.
18
The neat iodine catalyzed COM has first been reported in 2019. This reaction has demonstrated to be effective and clean, as it is simple and does not require any solvents or heating like the other LA catalyzed reactions. The tropylium carbocation catalyzed reaction was also compared by Tran et al., to the iron(III) chloride developed by the Schindler group, tritylium carbocation by Naidu et al. and tetrafluoroboric acid in two reactions: an intramolecular ring-closing COM and an intermolecular COM reaction. The ring-closing COM had similar yields as the iron(III) chloride, and intermolecular COM resulted in similar yields as the tritylium carboncation (Scheme 18).43
Table 1: Six LA catalysts discussed and what reactions they can catalyse.
LA catalyst Intramolecular Intermolecular Ring-opening
Boron trifluoride
(Khripach et al.)35 Yes No Yes
Iron(III) chloride
(Schindler group)16 Yes No No
Gallium(III) chloride
(Schindler group)39 No No Yes
Gold(III) choride
(Wang et al.)40 Yes No No
Tritylium tetrafluoroborate
(Naidu et al.)42 No Yes Yes
Tropylium tetrafluoroborate
19
Scheme 18: Comparissons of two COM reaction performed by Tran et al. into the various LAs, and one Bronsted acid, regarding the the possible applications.43
20
Green Chemistry in COM
Green chemistry is an important concept in modern chemistry. Reactions often require hazardous chemicals or produces hazardous waste, reaction conditions could be harsh or starting materials or reactant preparations could be energy intensive. Various groups are focusing on the concept of green chemistry, in order to improve on reactions. Green chemical reactions often employ simple catalysts, naturally occurring substrates and have little to no dangerous waste products. If they have waste or byproducts, these are often cleaned up or used in other reactions.44
Photocatalyzed
In light of the above principles, the COM reported by Jones II et al. in 1975 could be considered a somewhat green reaction. They performed the Paternò-Büchi reaction with cyclohexadiene and propanal in acetonitrile. The reaction employed a 450W light source for the reaction, which is a substantial amount of required power. Besides that, the final product was a pheromone, which occurs in nature in low concentrations.15
Employing LEDs for the photoinduced hole-catalysis COM is beneficial for the greenness of a reaction, as LEDs require little power to provide light. The catalyst is not commercially available, but can be synthesized in only two steps with around 50% total yield. Unfortunately, no quantum yield is given for this photocatalytic reaction Besides that, the reactions is performed in a mixture of dichloroethane, water and formic acid with a 5:1:1 ratio. Dichloroethane is not considered a green solvent due to the toxicity, and should be substituted if possible.45,46
Hydrazine-catalyzed
The hydrazine-based catalyst developed by the Lambert group could initially be viewed as “green”. However, when looking deeper in the synthesis of the catalyst, it becomes evident that the synthesis of the hydrazine catalyst is not that green. The synthesis already starts with derivatization by reacting di-tert-butyl dicarbonate with hydrazine, as hydrazine is a gas. The tert-di-tert-butylcarbonates were removed later on in the synthesis. Apart from that, the synthesis contains a step that requires bromine, and various reactions are performed in dichloromethane.21,22
TM complex assisted carbonyl-olefination and olefin metathesis
When observing the TM complexes in carbonyl-olefin and subsequent metathesis reaction, the major focus of research has been made clear. Stoichiometric amount of TM complexes are required to perform these two reactions (table 2).29 To clarify the stoichiometry problem further, the environmental-factor (E-factor) is calculated for a reaction with the modified Takai-Utimoto reagent. The E-factor gives insight in the greenness of a chemical reaction, based on the added chemicals and solvents. Industrial chemistry has a very low E-factor, as minimal waste is produced. The pharmaceutical industry has a much higher E-factor, as the products are much more complex than bulk chemistry. The E-factor is defined as the amount of waste, divided by the amount of product, in kilograms. The factor itself resembles the amount of waste produced, whenever one kilogram of product is synthesized.47
When the E-factor is calculated for the carbonyl-olefination and metathesis reaction developed by the Rainier group (Scheme 19), and the two employments in total synthesis in Scheme 9 (table 1), the downside of the reaction becomes visible. The three E-factors are calculated with the chemicals employed for the reaction only, the workup has not been taken in account. To gain a better perspective over these
21
numbers, the pharmaceutical industry generally has an E-factor between 50 and 100. The reactions have high amounts of waste per kilogram product.29,47
Scheme 19: General procedure by Rainier et al.29
Table 2: The E-factor calculated for three applied carbonyl-olefination and metathesis reactions.
The utilized metals contribute to the greenness of a reaction to. In order to obtain the complexes, the metals have to be extracted from the Earth and purified before they can be employed in chemistry. In green chemistry, the focus is also on these extraction an purification processes. Titanium is an abundant metal on Earth. Besides that, it is viewed as an environmentally friendly and non-toxic metal.48,49 The same is considered for aluminium.50 The reactions, however, require stoichiometric amounts of TM complex to work due to the formation of the inactive titanium oxo species. The Schrock metathesis complexes mentioned were molybdenum and tungsten based. Bystrzanowska et al. ranked 18 metals on toxicity, endangered elements and life cycles assessment (Figure 3). The weighted results for molybdenum was in each class the second best. Also, molybdenum is a relatively abundant metal and has a good lifecycle.51 Tungsten however is a lot less green. It is rare in nature and the production of tungsten is low. Tungsten is produced at around 81 thousand metric tons in the year 2013. Compared to molybdenum, which is produced at around 260 thousand metric tons the same year, China only produces 101 thousand metric tons a year. Comparing these numbers to aluminium, which is produced at around 48 million metric tons in 2013, demonstrates difference in both usage and greenness of the metals.51–53
Reference E-factor
Rainier (Scheme 19)29 734
Keck et al. - Total Synthesis of Bryostatin 131 272 Nocket et al. - Total Synthesis of Myrioneurinol32 132
22
Figure 3: The ranking of TMs by their toxicity. The chart was made via toxicity data. Besides that, the hazard and precaution statements have been taken into act, as well as boiling point, carcinogenicity rating from the International Agency for Research
on Cancer and how endangerd the metals are. Image by Bystrzanowska et al.51
The method described by Rainier employs titanium, zinc and lead complexes. The zinc and lead complexes are in lower equivalents relative to titanium, as titanium is the active Schrock-type complex. The titanium complex is the only oxidized species and the reaction could, theoretically, kept running by adding more substrate and titanium. The molybdenum complex was only used afterwards, to convert any unreacted material and because of this, the reaction is greener than employing the Schrock metathesis complex for the full carbonyl-olefination reaction and olefin metathesis reaction.24,28,29
23
Figure 4: The relative natural abundance of elements by atoms per 106 atoms of silicon.53
LA-catalyzed
The LA catalysts discussed are, unlike the TM complexes, employed in catalytic amounts. The catalysts employed often have small chemical building blocks, as in most cases the metal cation is surrounded by chloride anions. Attempts have been made to make synthetic routes more green by, among other things, applying an iron LA as a catalyst for various reactions.54–58 Gallium(III) chloride has also been employed as green catalyst in various reactions.50,59,60 Some research has been done in produce and byproduct interference of COM reactions with iron(III) chloride and gallium(III) chloride. Hanson et al. loaded the reaction with additional carbonyl compounds that would not react. The unreacted carbonyl compounds would form complexes with the catalyst. The reaction still proceeded, although slower, indicating that the substrate can exchange with carbonyls that complexate to the catalyst. If too much byproduct-carbonyl compounds would be present, the inhabitance could become significant, which could be solved by adding more catalyst.61
Both the TrBF4 and C7H7BF4 are relatively safe, however, both these chemicals should be treated with care.62,63 Therefore, they could be considered as relatively green, depending on the other conditions of the reaction.
The iodine catalyzed COM reaction has only three or four chemicals involved, namely the substrate (or substrates in a few cases), the product and molecular iodine. No solvents are required, as it is a neat reaction. Besides that, no heating is involved as the reaction proceeds at room temperature. Iodine is considered a green compound, so the greenness of the COM is dependent on how green the substrates and products are.41,64,65
So, overall the COM is not by definition a green reaction. The TM complexes employed form inactive metal oxo species and can therefore only be employed in stoichiometric amounts, which is, compare to LA catalysts, not green. Attempts have been made by using organic catalysts, like the hydrazine and the photocatalytic methods. LAs have also been utilized and methods have been developed to support catalytic COM reactions. Thereby increasing the greenness of the reaction.
24
Future Prospects of COM
Future developments are the most interesting part regarding chemical reactions, as it often paves the road towards new reactions, substrates and possible applications. The same is true for COM reactions, as there are a lot things to be optimized for all types of COM reactions and catalysts, such as the stoichiometry of the complexes required, or widening of the substrate scope. The COM reaction can become a very important and useful reaction within chemistry, but more research is needed to improve the COM even further.
Modifications of TM complexes
The modified Takai-Utimoto reagent has been discussed extensively and it can be expected that it will make more appearances in future chemistry because of the tolerances towards functional groups. Numerous times before it has been mentioned that the carbonyl-olefination and olefin metathesis reaction requires high equivalents of titanium tetrachloride because of the formation of the inactive titanium-oxo species. As titanium is an early TM and many early TMs are oxophilic, including titanium. Opposite of that, mid and late TMs have a lower oxophilicity. If these TMs were adapted to function in the same fashion as titanium tetrachloride, could open up possibilities to perform the COM catalytically.66–68 This “double modified” Takai-Utimoto reagent could be envisioned to work in one of two ways. First, the reaction can proceed and form a metal-oxo species which is also active instead of deactivated. The second option is to have a separate reaction to reactivate the complex. To reactivate the complex in situ, requires alteration of the reaction conditions, and could be achieved by means of a biphasic liquid-liquid system. Or perhaps even a liquid-solid system, where the solid phase could be a heterogeneous catalyst that reduces the metal oxo back to the active complex.
Application of olefin-imine metathesis
Another type of route towards a COM reaction is theoretically feasible, due to the possibility of converting a carbonyl to an imine. This allows for reactions with imines, like the imine metathesis reaction. This reaction is catalyzed by a zirconium catalyst (similar to the Petasis reagent) and interchanges two imine moieties, it has been researched in 1994 (Scheme 20).69,70 As modification on the imine metathesis, the option of an imine metathesis reaction is also being researched. Like COM reactions, the olefin-imine metathesis is a reaction between an alkene and an olefin-imine, facilitated by a TM catalyst.
Scheme 20: imine-metathesis with a bis-cyclopentadienyl-zirconium catalyst.69
In 2019, Bousquet et al. demonstrated a cross-metathesis between an alkene and a diazene, with employment of a ruthenium metathesis catalyst. The intent was to pursue the possibility of an alkene-diazene cross metathesis. The experiments resulted in synthesizing small quantities of the imine product, but also deactivation of the ruthenium complex occurred and an unidentified phosphorus compound was formed. The DFT calculations indicated that the energy barrier of the transition state, from 9 to form the imine product and new carbene, was too high (48 kcal/mol) in order to successfully sustain a catalytic cycle
25
(Scheme 21). It was concluded that a phosphite ligands could lower the this energy barrier and have a better result in a catalytic alkene-diazene metathesis.71
Scheme 21: Devised catalytic cycle by Bousquet et al. for an alkene-diazene metathesis. Two cycles, one base on the nitrene and the other on the carbene, both resulting from the dissociation step of the opposite cycle.71
The imine metathesis and the alkene-diazene metathesis could be invaluable for developing a formal COM reaction. The nitrogen of the imine poses a different reactivity. In the original Petasis, Tebbe’s or modified Takai-Utimoto reagents, titanium is the metal which performs the carbonyl-olefination and metathesis reaction. The major downside, the formation of the titanium-oxo species, could be avoided due to the presence of an imine instead of carbonyl. Therefore, the reacting carbonyl will not react with the catalyst, disabling the reaction from forming a metal-oxo byproduct. A method via the imine analog might provide a good foundation for a formal COM reaction with catalytic amounts of a TM catalyst.
This formal COM reaction can be envisioned as an amine and carbonyl that form an imine, either in a separate reaction or in situ (Scheme 22). The catalytic cycle begins with the reaction of the imine (9) with a metal carbene (10), forming a nitrogen-containing metallacycle (11). The nitrogen-containing metallacycle then eliminates the new imine (12) and reforms a carbene (13). The imine can be hydrolyzed to form the new carbonyl, while carbene 13 would react with an alkene (14) to form a second metallacycle (15). The cycle will proceed like an olefin metathesis by eliminating a new alkene (16). Herein, the starting carbene 10 is reformed and the catalytic cycle is concluded. The TM catalyst could possibly be zirconium- or ruthenium-based (or both, in a cooperative fashion), as these metals are employed in other, similar, reactions.69–71 However, as a formal TM catalyzed COM has not been demonstrated, the catalyst is not confined to be zirconium or ruthenium and other metals might prove better.
26
Scheme 22: Possible catalytic cycle of a formal COM via an imine. Right, the imine is formed or removed. For convenience it is described as an in situ process, whilst it is also possible to perform this reaction separately.
There are, however, a couple of problems to be solved. First, if a reaction like Scheme 21 is performed with a ruthenium catalyst, there is a competitive reaction involved. Namely, the reaction between the ruthenium carbene and the imine, as described by Ranocchiari et al., to form an aziridine.72,73 The side-reaction would hinder the side-reaction, as the catalyst would not react further.
The secondly, a ruthenium metallacycle like complex 10 has not been reported in literature. A metallacycle with an amine coordinated to the metal has been reported. In the case of an imine metathesis, the formed metallacycle has two nitrogen atoms coordinated to the metal center (17, Figure 4).69,70 In the mechanism proposed by Bousquet et al., there are two metallacycles, both with a nitrogen coordinated to the metal (9 and 18, Scheme 21 and Figure 4).71 In other studies, similar metallacycles, with coordinated nitrogen atoms, were identified (19, Figure 4).74 However, instead of a ruthenium metallacycle, a platinum metallacycle has been reported. This platinum metallacycle was reported by McCrindle et al. published a paper in 1990. A reaction between chloromethylplatinum(II) phosphine complexes with 1,1,-dimethoxy-N,N-dimethylmethanamine was described. The result was a 3-platina-azetidinium moiety (20, Figure 4), which is a similar complex as metallacycle 11.75 It is clear that the desired metallacycle for the formal COM reaction is unfavored, however, not impossible. It could be that the energy required is too high, or electronically unfavoured, these could be solved by employment of the correct electron donating or withdrawing ligands. Besides that, it is likely that the metallacycle will follow a similar mechanism as the Chauvin mechanism, resulting in each step being reversible. If the dissociation energy barrier of the new imine is too high, the metallacycle might revert back to the carbene and imine. Gathering up all the evidence, it is likely that the proposed metallacycle, with a carbon atom coordinated to the metal, instead of a nitrogen atom, is unable to form. However, there is no conclusive evidence that the proposed metallacycle cannot be formed at all.
27
Figure 5: Metallacycles proposed by various research groups. The general metallacycle structure present is where the nitrogen is bonded to the metal center, while the opposite is required for the proposed mechanism. 69,71,74,75
Future prospects of LA catalysts
The LA catalyzed COM reactions have proven to be effective in a large variety of scenarios. The Schindler group has already demonstrated that hydrated FeCl3 is also capable of catalyzing COM reactions. Besides that, the ability to facilitate the same reaction to form N-heterocycles enlarges the scope of the FeCl3 catalyzed COM.36,38 The organic LAs described by Naidu et al. and Tran et al. also are capable of ring-opening and intermolecular metathesis reactions, apart from the ring-closing COM also described by the Schindler group. The diversity in applicable situations widens the of substrate scope and thereby the employment of this reaction in other fields of chemistry. Total synthesis could benefit from LA catalyzed COM reactions, as it allows for easier access to more complex molecules. Further research in LA catalyzed COM reactions might prove beneficial to the variation of LAs to be employed.
Six LA catalysts for COM reaction have been described, each with benefits and limitations. Most of the LAs investigated are able to catalyze the intramolecular and ring-opening COM reactions, while only the two organic LAs are capable of intermolecular COM reactions. It is likely that other LAs could provide access to more versatile reactions for different purposes and could result in better functional group tolerance, or improved reaction times. Perhaps further research provides even more possible LA catalysts and possibly a basis for LA catalyzed COM in greener solvents than dichloroethane.16
The scope of photo- and organo-catalyzed COM
The Patèrno-Büchi reaction has been employed in order to oxetanes and developments are mainly focused on understanding the stereochemistry of the reaction. However, the follow up reaction, the thermal or acidic cycloreversion, has been researched a lot less in the past years. The Patèrno-Büchi reaction-cycloreversion combination to perform COM reactions is rarely employed, likely due the method developed by the Rainier group, which took preference in papers.31,32 Functional group tolerance of the modified Takai-Utimoto reagent, especially against esters and amides, is likely the cause of this preference.30
28
Hydrazine
The hydrazine-based COM, developed by the Lambert group has proven to be a viable option. However, there are two drawbacks. The first being that the catalyst is not readily available and has to be prepared in a five-step synthesis, with about 45% total yield. The second is that, thus far, it has only been proven to work for two reactions. One being the ring-opening COM of cyclopropenes, likely driven by ring strain in the cyclopropene.19 The other being the ring-closing COM to synthesize 2H-chromenes. However, the best leaving group for the hydrazine-catalyzed ring-closing COM has been identified to be pent-3-yl. If the leaving group is only favored in the case of the 2H-chromene synthesis, has yet to be researched. All factors considered, it is very likely that more research will be done into viable substrates, and possibly leaving groups, to increase the scope of the hydrazine catalyzed COM reaction further. Making the substrate scope larger, increases the attractiveness to employ the hydrazine-catalyzed COM in other applications. 21
In order to make a hydrazine-catalyzed COM more accessible, the attention should also be on the catalyst itself. A more easily accessible catalyst can assist in making the hydrazine catalyzed COM usable in other fields of chemistry. And thirdly, different hydrazine catalysts could be capable of catalyzing other types of COM reaction, the intermolecular and the ring-opening COM.
Photoinduced hole-catalysis
The reaction developed by Pitzer et al. employs a 9,10-dimesityl-acridinium type catalyst for a novel type of COM. The initial studies by Pitzer et al. show that the photocatalyst works for intermolecular COM reactions between benzaldehyde-type and β,β-dimethylstyrene-type substrates. A single example of a ring-closing COM has been given and no ring-opening experiments were performed.20 It is expected the photoinduced hole-catalysis method will be investigated further. Improvements could be done by having a different photocatalyst, and more focus on the substrate scope could increase the usefulness of the method. The photoinduced hole-catalysis method might become a viable option to perform COM reactions.
Iodine
Even more recent than the photoinduced hole-catalysis COM, it has been demonstrated that molecular iodine can be employed as catalyst for COM reactions. It is especially useful in catalyzing a neat ring-closing COM for a range of substrates in order to synthesize substituted cyclopentenes, phenanthrenes, indenes and N-tosyl-2,5-dihydro-1H-pyrroles. However, it has proven to be less successful for intermolecular and ring-opening COM reactions. No general reaction solvents were used for the experiments, perhaps organic solvents are able to stabilize the intermediates or transition states of the intermolecular and ring-opening reactions. The stabilization of the intermediates or transition states could lead to successfully forming product for these two types of reactions. Further research into the stabilization might lead to an even more effective method, but for now it is a viable option to perform ring-closing metathesis, even on gram-scale reactions.
29
Conclusion
The COM reaction has been discussed, mainly focusing on the catalysts required for the reaction. Even though various groups have put effort in developing the reaction and the catalysts, actual applications in other fields of chemistry are rare. The rarity in using the COM reaction is somewhat unexpected, as COM reactions can be useful for a wide variety of situations. Two different substrates with each a required moiety, or both a carbonyl group and alkene in the same molecule, results in giving the COM a large range of substrates. The ability to either fuse these functional groups together to form a new alkene, or to break the alkene in a ring-opening, can be viewed as a valuable addition to the chemists toolbox. COM reactions can be employed for both blunt reactions, to mend two molecules together. Opposite of that, it can be used for carefully designed ring-closing metathesis reactions in total synthesis, with retention of stereochemical centers.
The large variety of catalysts available might be overwhelming, but each type of COM has advantages and disadvantages. Some are more green, like molecular iodine, or FeCl3, but have a smaller range of substrates. Others, like the modified Takai-Utimoto reagent, have the ability to react carbonyls from esters and amide with carbonyls, but require multiple equivalents of catalyst over the substrate to function properly.
Besides discussing various catalysts for the COM reaction, the green aspects have also been discussed. As the methods are still being developed, the focus is more on what is possible, instead of what is green. Nevertheless, some groups have developed methods that conform to the 12 green chemistry concept principles.
In time, the COM reaction will be utilized more often in fields like total synthesis, possibly also industrial processes or perhaps when medical applications are considered. The COM reaction may prove to become a versatile reaction variety of applications.
30
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