Catalysts for Isocyanate Cyclotrimerization

The formation of isocyanurate via cyclotrimerization of isocyanates is widely reported to provide a variety of polyurethane materials with improved chemical and physical properties such as weatherability, mechanical properties, thermal stability and flame retardancy. The demand for development of effective and selective catalysts for cyclotrimerization of isocyanates has been increasing. This review comprehensively summarizes catalysts for the cyclotrimerization of isocyanates that have been reported in peer‐reviewed publications and provides a valuable guideline for choosing suitable catalysts to match specific requirements. The catalysts are categorized into two main classes: catalysts operating via a Lewis basic cyclotrimerization mechanism and metal‐containing catalysts. Catalyst structures, reaction conditions, reaction time, catalytic effectivity as well as types of isocyanates whose trimerization is catalyzed are described in detail. In addition, featuring the findings and viewpoints from mechanistic studies, this review aims to stimulate the design and development of new, more efficient catalysts, and to guide further study of the trimerization mechanism with different classes of catalysts.

Additionally, the catalyst choice depends not only on the yield, but also on desired material properties, which cannot be judged on published information only. Therefore, another goal of this review is to provide a large set of catalysts and knowhow of their operating principles so that they can be explored during such optimization.
We categorize catalysts for isocyanate cyclotrimerization into two main classes: catalysts operating via a Lewis basic cyclotrimerization mechanism and metal-containing catalysts. Within each class, the cyclotrimerization catalysts are further divided based on their chemical structures. The catalyst structures, reaction conditions, reaction time, catalytic effectivity as well as types of isocyanates that can be catalyzed are described in detail. Moreover, the proposed catalytic mechanisms of different types of catalysts are summarized and discussed.

Catalysts operating via Lewis basic cyclotrimerization mechanism
Catalysts that operate cyclotrimerization via a Lewis basic mechanism are generally anions, zwitterions or other functional groups with lone electron pairs ( Table 1). The catalytic mechanism of these bases has been extensively discussed in the primary literature and in textbooks: the reaction is considered to be initiated by straightforward nucleophilic addition of an anion or a lone electron pair of the catalyst to the electrophilic isocyanate carbon forming an anionic intermediate II (Scheme 1). The intermediate reacts further with a second and a third molecule of isocyanate in a stepwise manner and forms isocyanurate (V) after ring closure and elimination of the catalyst. [2,[39][40][41][42][43] In real PU systems, alcohols are present which are known to have high reactivity towards isocyanates. [2,4] The presence of adducts such as carbamates or allophanates, in combination with Lewis basic catalysts can accelerate the cyclotrimerization of isocyanates. [29] In this section, the most commonly applied carboxylate catalysts are discussed, followed Yunfei  Rint Sijbesma is a full professor in supramolecular polymer chemistry at the Eindhoven University of Technology. He received his PhD degree in 1993 with Prof. Nolte on synthetic receptor molecules. After working as a postdoctoral student with Prof. Wudl (UCSB) on C60 chemistry, he moved to Eindhoven to explore supramolecular polymers with Prof. E.W. Meijer and was appointed full professor in 2006. Over the years, Sijbesma has developed research activities in a range of topics related to dynamic polymer systems, including polymer mechanochemistry, biomimetic hydrogels, and dynamic covalent polymers. 1,3-Bis-(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene 51 Aryl, alkyl, allyl THF, bulk [72] by common tertiary amine catalysts. Finally, additional Lewis basic catalysts, carbenes with lone electron pairs as well as electron rich alkenes are discussed.

Carboxylates
Carboxylates are the most common cyclotrimerization catalysts used in industrial applications. There are quite a few literature reports of carboxylates as cyclotrimerization catalysts such as formate, acetate, 2-ethylhexanoate anions in combination with different counterions. For instance, tetramethylammonium formate (1) and 2hydroxyethyltrimethylammonium formate (2) were reported to be effective cyclotrimerization catalysts for phenyl isocyanate in acetonitrile (Table 1). [29,44] In addition, acetate is a widely reported carboxylate anions for cyclotrimerization of isocyanates. Potassium acetate is very efficient in cyclotrimerization of aromatic isocyanates. With 0.1 mol % catalyst loading and 30 mol % diethylene glycol methyl ether (DEME), cyclotrimerization of p-tolyl isocyanate reached 90 % conversion within 1.2 min at 70°C. [31] On the other hand, Nabulsi et al. reported that potassium trifluoroacetate (3) was a milder cyclotrimerization catalyst due to the lower nucleophilicity of the trifluoroacetate anion. [31] Wejchan-Judek et al. also reported that potassium acetate is an active catalyst in cyclotrimerization of isophorone diisocyanate (IPDI) and 98 % yield was obtained after reaction at 80°C for 1 h when 1 wt % of catalyst solution (15 % potassium acetate in ethyl acetate) was used. [45] Tetrabutylammonium acetate (TBAA) (4) is an efficient cyclotrimerization catalyst for aryl isocyanates and is also effective for cyclotrimerization of alkyl isocyanates. [46,47] Trimethylammonium acetate (5) is an effective cyclotrimerization catalyst for phenyl isocyanates. [29] Furthermore, several papers report that n-hydroxy-alkyl quaternary ammonium acetates (6 and 7) are cyclotrimerization catalysts with high catalytic activity which catalyze the reaction with or without the help of catalytic amounts of alcohol or urethane. [44,48,49] Based on experimental kinetic studies, Lin and Bechara proposed that ammonium salts containing a primary hydroxy group have higher catalytic activity than those with secondary hydroxy or without hydroxy groups. n-Hydroxy-alkyl quaternary ammonium salts with two hydroxy groups are more active than salts with one or three hydroxy groups. [44,48] Moreover, more nucleophilic carboxylate anions increase the catalytic effect of the n-hydroxy-alkyl quaternary ammonium carboxylates, so that the acetates have the highest catalytic activity.
Another interesting acetate catalyst in which the cation plays an important role in cyclotrimerization of isocyanates was reported by Wu et al. [50] In their work, various acid/base conjugates based on organocatalysis bases and the Brønsted acids were developed for cyclotrimerization of isocyanates. It was found that 1,5,7-triazabicyclo[4.4.0]non-5-ene-based (TBDbased) conjugates are efficient catalysts that complete the cyclotrimerization of p-tolyl isocyanate within seconds to minutes in yields that exceed 85 %. Among these catalysts, the HTBD + OAc À (8, TBD-acetic acid salt), which has the weakest conjugate acid, shows the best catalytic behavior for isocyanates (Scheme 2). With a catalyst loading as low as 0.5 mol %, it efficiently catalyzed the bulk cyclotrimerization of various aryl isocyanates in high yield (� 90 %) at room temperature under either nitrogen or air atmosphere. However, its catalytic behavior was strongly hindered by dilution with solvent and it did not effectively catalyze alkyl isocyanate trimerization, except benzyl isocyanate (81 % yield). It was suggested that due to additional hydrogen bonding between HTBD and the oxygen of isocyanate group, the oxygen atom becomes more electronegative which makes the nucleophilic attack of the acetate anion to the carbon in isocyanate group easier. After that, the anionic intermediates reacts with another two activated isocyanates in a stepwise manner and form isocyanurate after ring closure.
The 2-ethylhexanoate anion is another commonly used carboxylate anion in the cyclotrimerization of isocyanates. Catalysts such as potassium 2-ethylhexanoate (9), 2hydroxyethyltrimethylammonium 2-ethylhexanoate (10), and tetramethylammonium 2-ethylhexanoate (11) were reported to be effective cyclotrimerization catalysts with or without an alcohol as cocatalyst. [29,44,49,51] Some other carboxylates also show high catalytic activity in cyclotrimerization of isocyanates. Zeng et al. studied the trimerization of pentamethylene diisocyanate (PDI) using 2hydroxypropyltrimethylisooctanoate ammonium salt (12) as catalyst. [9] Using gel permeation chromatography (GPC) measurement, the composition of the oligomer mixture was determined. With optimized 0.04 wt % catalyst dosing, the resulting polymer that was obtained after reaction for 5 h at 75°C in bulk contained more trimers and pentamers without yellowing or reaching high viscosity. Based on this, the reaction time was optimized and more trimers and less higher oligomers (n � 5) were obtained after 2 h. Tetraethylammonium 2-(carbamoyl) benzoate (TEACB, 13) reported by Dekamin et. al. is an efficient catalyst as it provides additional hydrogen bonding interaction with the oxygen of isocyanate group or the negative nitrogen in the intermediates in addition to the nucleophilicity (Scheme 3). [52] Thus the anionic cyclotrimerization of various aryl isocyanates using TEACB as a catalyst was very efficient. With an optimized catalyst loading of 0.25 mol %, high yield was achieved within seconds. Moreover, tetramethylammonium benzoate (14) and tetramethylammonium phenoxyacetate (15) were also described as effective cyclotrimerization catalysts. [29] Scheme 1. Generally proposed and accepted anionic cyclotrimerization mechanism. Scheme 2. Proposed catalytic cycle for the isocyanate trimerization over HTBD + OAc À (8) catalyst. Adapted from ref. [50] Copyright (2020), with permission from Elsevier B.V.
In terms of the cyclotrimerization mechanism of the carboxylates, the cyclotrimerization still follows an anionic pathway as shown in Scheme 1, while the actual catalytic species requires further study. Hoffman's early experimental work indicated that acetate anions are converted spontaneously to acetanilide when reacting with aromatic isocyanates, which in turn act as anionic catalysts in the active cycle. [30] Based on the absence of anhydride carbonyl bands in FT-IR, Bechara et al. proposed that the catalytic active species is indeed the deprotonated carbamate-carboxylate complex formed from the reaction of the catalyst and the isocyanate. [48] Recently, Guo et al. and Siebert et al. found experimentally and computation-ally that when carboxylates are used as a catalyst, the anhydride formed from carboxylates and isocyanate decomposes at the reaction conditions (Scheme 4). [46,47] According to the density functional theory computations, the intermediate A is predicted to react intramolecularly with lower activation to form A' via acetyl migration. A strongly nucleophilic and basic deprotonated amide species A'' is formed irreversibly after elimination of a CO 2 molecule from the anhydride, which serves as the actual catalyst that catalyze the cyclotrimerization via anionic pathway.
In addition, from work by Špírková et al., there is evidence from kinetic studies that in the presence of alcohol, allophanate is first formed and then decomposes. This suggests that in isocyanate-alcohol-catalyst system, isocyanurate is formed preferably from reaction of allophanate with active isocyanate, or isocyanate-catalyst complex. [49] Moreover, according to 1 H NMR of reaction mixture of p-tolyl isocyanate and diethylene glycol methyl ether (DEME) in the presence of the catalyst potassium trifluoroacetate (3), an allophanate pathway is preferred over the generally accepted anionic pathway and isocyanurate formation is accelerated when the concentration of allophanate rises to 8 mol % of all the structures (Scheme 5). [31] During the reaction, the alcohol reacts with two isocyanates and a key intermediate allophanate is formed. The allophanate further reacts with an anionic intermediate B, followed by elimination of carbamate or alcohol and formation of structures C and D, respectively. In the final step, structure C undergo nucleophilic addition of one more isocyanate forming structure D, leading to isocyanurate formation after ring closure and elimination of catalyst.
Further, a detailed kinetic study of the cyclotrimerization in the presence of alcohol by Schwetlick et al. showed that the cyclotrimerization rate is dependent on the rate constant of Scheme 3. Proposed cyclotrimerization mechanism of isocyanates catalyzed by tetraethylammonium 2-(carbamoyl) benzoate (13). Adapted from ref. [52] Copyright (2010), with permission from Elsevier B.V. carbamate (k 1 ), allophanate (k 2 ) and isocyanurate (k 3 ) formation. [29] It was established under equimolar conditions that for the anionic catalysts, the ratio of the rate constants was k 1 < k 2 � k 3 . With greater excess of isocyanate, isocyanurate was the dominant product with carbamate and allophanate detected as intermediates. Due to their high basicity, the anionic bases actively catalyzed the reaction between alcohol and isocyanate. In agreement with Guo and Siebert's study, the formed carbamate not only reacts rapidly with isocyanate but it also deprotonates other protic groups such as urethane, allophanate, urea and biuret groups in the PU matrix, whose corresponding anions have been proposed to be active PIR catalysts. [46,47] Therefore, a mixture of catalytically active species is expected to be present during cyclotrimerization.

Brønsted basic catalysts
Another commonly used class of cyclotrimerization catalysts are tertiary amines. Because tertiary amines are Brønsted bases that are not nucleophilic enough to directly catalyze the reaction, proton donors such as alcohols, phenols or carbamates are required in the reaction. The role of tertiary amine is to deprotonate the proton donor to generate a more nucleophilic cyclotrimerization catalyst. Kogon et al. studied the cyclotrimerization of phenyl isocyanate in the presence of ethanol and found that when N-methylmorpholine (16) was used as the catalyst, triphenyl isocyanurate was obtained in 99 % yield. [15] When ethanol was replaced by ethyl carbamate, isocyanurate product was also obtained, but only dimer and allophanate were obtained in the absence of N-methylmorpholine. No isocyanurate was obtained when N-methylmorpholine was used to catalyze the cyclotrimerization of neat phenyl isocyanate. Wong et al. found that N,N',N''-pentamethyldipropylene triamine (17), N,N',N''-tris(3-dimethylaminoropyl)hexahydro-1,3,5-triazine (18), and N-(2-dimethylaminoethyl)-N-methylaminoethanol (19) catalyze not only carbamate formation but also trimer formation during the reaction between phenyl isocyanate and n-butanol. [54] Furthermore, various tertiary amines such as 1,8diazabicyclo [5.4.0]undec-7-ene (20), bis(2,6-dimethylaminomethyl)-4-methylphenol (21), 3,6-dimethyl-8-dimethylaminomethyl-3,4-dihydro-2H-1,3-benzoxazine (22) and methyl aminosulfenates (23) have been reported as cyclotrimerization catalysts. [29,55] According to kinetic study, it has been proposed that in the cyclotrimerization of isocyanates using Brønsted basic tertiary amines as catalysts, the activity of the tertiary amine catalysts increases with their basicity and decreases with steric hindrance. Compared to anionic catalysts, the catalytic activity of the amine catalysts is lower. [29] Similar to the mechanism of carboxylate catalysis in the presence of alcohol, the intermediate allophanate also plays an important role in determining the reaction rate. Moreover, it was proposed that during cyclotrimerizations with tertiary amine as catalyst, uretdione dimers are formed reversibly in the presence of alcohol or carbamate and they dissociate to isocyanates, followed by forming isocyanurate via the allophanate pathway. [15,71] On the other hand, under certain reaction condition such as high pressure, the Brønsted basic tertiary amines can catalyze the cyclotrimerization of isocyanates without the proton donors. Tertiary amines such as triethylamine (TEA, 24), N,Ndimethylethylamine (25), tributylamine (26), N-methylmorpholine (16) and N,N-dimethylaniline (27) are usually urethane catalysts and are not known to catalyze the cyclotrimerization of isocyanates. However, Taguchi et al. discovered that a high pressure of 800 MPa accelerated the cyclotrimerization of aryl and alkyl isocyanates when these tertiary amines were used as catalysts, among which TEA gave the highest conversion. [53]

Lewis basic catalysts
In addition to the specific catalytic mechanism that carboxylates and tertiary amines follow in cyclotrimerization of isocyanates, many Lewis basic catalysts have been described in literature that catalyze the reaction following the generally accepted anionic mechanism shown in Scheme 1.
One category of these Lewis basic catalysts is formed by salts that consist of catalytically active anions and counterions that modulate their catalytic properties. Cyclotrimerization catalysts with anionic nitrogen atoms have been reported by several research groups. Shi et al. found that amide anions such as lithium, sodium, or potassium dibenzylamide (28), lithium diethylamide, and lithium diisopropylamide (29) catalyze cyclotrimerization of phenyl isocyanate and some other aryl isocyanates efficiently with 0.1 mol % catalyst loading at room temperature. [56] In the cyclotrimerization of phenyl isocyanate with lithium diethylamide as the catalyst, reducing the catalyst loading to 0.01 mol % hardly influenced the yield. However, lithium diethylamide could not effectively catalyze the cyclotrimerization of alkyl isocyanate, while 0.1 mol % sodium dibenzylamide catalyzed the cyclotrimerization of cyclohexyl isocyanate in 99 % yield in 30 min, due to its stronger Lewis Scheme 5. Proposed cyclotrimerization mechanism in presence of alcohol when potassium acetate or potassium trifluoroacetate (3) is used as the catalyst. Adapted from ref. [31] Copyright (2018), with permission from the Royal Society of Chemistry. basicity. A similar high activity in the cyclotrimerization of different aryl isocyanates was found for sodium saccharin (a sulfonamide, 30) as a catalyst with the help of tetrabutylammonium iodide (TBAI) as a phase transfer catalyst (PTC). More than 80 % yield was obtained at 110°C in bulk. [57] Functional groups that contain negatively charged oxygen such as nitrate, sulfinate, sulfite or sulfate have also been reported as cyclotrimerization catalysts. Khajavi et. al. found that sodium nitrite and potassium nitrite (31) are heterogeneous cyclotrimerization catalysts which catalyzed cyclotrimerization of aryl or alkyl isocyanates in bulk, giving moderate yields under strict, moisture-free reaction conditions, a high (10 mol %) catalyst loading, and temperatures as high as 140°C. [58] Moghaddam et al. reported several sulfur-based catalysts such as sulfinate, sulfate and sulfite. Sodium p-toluenesulfinate (32) was reported to catalyze cyclotrimerization of various aryl isocyanates efficiently and selectively at 140°C in bulk with an optimal catalyst loading of 1.25 mol % (Scheme 6). [39] They proposed that the heterogeneous catalyst forms a colloidal suspension with isocyanates at 140°C and that the reaction follows an anionic pathway afterwards. With the help of 0.1 mol % TBAI, 0.2 mol % sodium p-toluenesulfinate catalyzed the cyclotrimerization at a lower temperature of 70°C and a higher yield was achieved within a shorter reaction time. This combination of catalyst and PTC was also able to cyclotrimerize alkyl isocyanates such as ethyl and butyl isocyanates, although long reaction times were required. Some inorganic sulfur containing salts are also catalytically active. With 0.33 mol % of potassium sulfate (K 2 SO 4 , 33) as a catalyst, 95 % conversion was achieved within 1 h in the cyclotrimerization of phenyl isocyanate in bulk at 70°C. [42] The yield was a little bit higher for the cyclotrimerization of isocyanates with electron-withdrawing groups (> 94 %) than the ones with electron-donating groups (> 84 %). With the help of a PTC (ammonium salts that contained anions such as bromide, iodide, tetrafluoroborate or perchlorate), the reaction time was shortened from 1 h to less than 15 min while the final conversion is independent of the presence of a PTC. The co-catalytic effect of PTCs was studied further. It was found that potassium sulfite (K 2 SO 3 , 34) shows catalytic activity only in the presence of a PTC, which improves the solubility and nucleophilicity of K 2 SO 3 in the organic phase. [59] With an optimal catalyst loading of 0.33 mol % K 2 SO 3 and 0.33 mol % tetrabutylammonium bromide, the cyclotrimerization of various aryl isocyanates was carried out at 70°C in bulk and yields of 80-90 % were obtained. Using K 2 SO 3 as a catalyst, the catalytic activity was optimized by selection of ammonium salts of Br À , I À , BF 4 À , or ClO 4 À as PTC. The highest yield was obtained with cetyltrimethylammonium bromide (92 %).
In Section 2.2, we discussed that the deprotonated alcohols, phenols and carbamates by Brønsted bases can be cyclotrimerization catalysts. On the other hand, many catalysts containing deprotonated hydroxy groups themselves, such as anionic alcoholates and phenolates, have widely been reported as anionic cyclotrimerization catalysts without the extra addition of proton donors. Dekamin et. al. reported that tetrabutylammonium phthalimide-N-oxyl (TBAPINO, 35) efficiently catalyzed the bulk cyclotrimerization of aryl isocyanates at room temperature or 50°C with a minimum catalyst loading of 0.025 mol %. [52] High yields, albeit at longer reaction times, were also obtained with some alkyl or allyl isocyanates. 2,4,6tris(dimethylaminomethyl)phenol (21) is reported to catalyze the cyclotrimerization without addition of proton donors while high catalyst dosing (5 %) and high temperature (80°C) were required. [45] Certain acyl aminimides with hydroxyl groups (36) are active cyclotrimerization catalysts; primary hydroxy groups are more active than secondary hydroxy groups. [60] Potassium polyoxyethylene glycolates (PEGÀ K, 37) catalyzed linear polymerization of phenyl isocyanate via an anionic pathway at 30°C in carbon tetrachloride while formation of isocyanurate from back-biting of isocyanate polymer was only observed with a very low rate constant. [61] Alkali metal cyanates (MOCN, M=Li, Na, K, 38) reacted with organic isocyanates and provided the metal isocyanuric acid salts in dipolar aprotic solvents, during which the isocyanurate was formed as a side product. [62] Alkyl isocyanates formed more isocyanurate (> 50 %) than aryl isocyanates (< 50 %), and the formation of isocyanurate increased with higher isocyanate concentration as well as addition of electrolyte.
Some other anions are also effective anionic cyclotrimerization catalysts. For instance, fluoride anion catalyzes the cyclotrimerization with specific counterions and the cyclotrimerization follows anionic pathway. Nambu el. al found that cesium fluoride (CsF, 43) catalyzes the cyclotrimerization of phenyl isocyanate giving 80 % yield at room temperature while 91 % yield was obtained at 130°C. [40] Fluoride was also efficient and selective in cyclotrimerization of some other aryl isocyanates. In Scheme 6. Proposed cyclotrimerization mechanism of isocyanates catalyzed by sodium p-toluenesulfinate in presence of TBAI (32). Adapted with from ref. [39] Copyright (2002), with permission from The Chemical Society of Japan. comparison, tetrabutylammonium fluoride (TBAF, 44) was a more efficient cyclotrimerization catalyst with better catalytic activity due to its larger counterion. When phenyl isocyanate was cyclotrimerized with TBAF as a catalyst at room temperature, higher conversion (99 %) was achieved within 5 min without formation of dimers, though it was more difficult to remove TBAF from the product due to its high solubility.
Khajavi et al. found that with an optimized catalyst loading of 0.5 mol % and at optimal reaction temperature of 110°C, sodium piperidinedithiocarbamate and potassium piperidinedithiocarbamate (45) catalyze bulk cyclotrimerization of aryl and alkyl isocyanates, giving yields higher than 70 %, especially higher than 91 % for phenyl isocyanate. [58] The yield was mainly dependent on the substituents of the isocyanate.
In addition to forming Lewis basic salts, phosphines are strong nucleophiles that generate zwitterionic species after reacting with an isocyanate, followed by catalyzing the cyclotrimerization via an anionic pathway.
Many proazaphosphatranes with various substituents have been reported as efficient cyclotrimerization catalysts for isocyanates with almost no side reactions. Additionally, they have a high solubility in various organic solvents and allow mild reaction conditions. Tang et al. found that when cyclotrimeriza-tion was carried out with or without solvent at room temperature with only 0.33 mol % proazaphosphatrane ([P-(MeNCH 2 CH 2 ) 3 N], 47), a high conversion (94-99 %) was achieved regardless of the electronic nature of substituents on aryl isocyanates or alkyl isocyanates. [64,65] With this catalyst, a yield as high as 95 % of aryl isocyanurate could still be obtained in dilute solution. The proazaphosphatrane catalyst also catalyzed cyclotrimerization of allyl isocyanates. Raders et al. studied proazaphosphatranes containing various substituents in the cyclotrimerization of isocyanates. [66] Although all studied proazaphosphatranes provided more than 91 % conversion in cyclotrimerization of a variety of aryl isocyanates at room temperature with only 0.1 mol % catalyst loading, the reaction time varied due to different basicity of the catalysts. Both Tang and Raders proposed that during the cyclotrimerization, 'superbase' proazaphosphatrane serves as a deprotonation agent. The basicity of proazaphosphatrane increases with increasing electron donating effect of alkyl substituents on the nitrogen atoms that are adjacent to the phosphorus while it decreases with increasing size of the alkyl substituents. Although the electron withdrawing nature of the phenyl substituents reduces the basicity of proazaphosphatrane, the presence of electron donating groups on the phenyl ring increases its pKa. After trimerization of the isocyanates following an anionic pathway, the increasing electron density on the PÀ C carbon weakens the transannular bond, leading to ring closure of the isocyanurate and regeneration of the catalyst.
The excellent cyclotrimerization performance of proazaphosphatrane was further studied computationally by Gibb et al. based on density functional theory. [67] Reaction barriers of uncatalyzed cyclo-oligomerization of methyl and phenyl isocyanate in toluene and gas phase were first calculated and showed that the isocyanurate trimer preferentially forms via uretdione regardless of the solvent effect. However, when proazaphosphatrane is present, the reaction profile indicates that the isocyanurate trimer is directly formed via linear proazaphosphatrane-activated isocyanate oligomers instead of uretdione (Scheme 8). After the addition of isocyanate on phosphorus atom in proazaphosphatrane, a zwitterion is generated. The five-membered atrane ring formed from N ax À P transannulation is crucial to provide high basicity and catalytic performance of the proazaphosphatranes.
In addition to proazaphosphatrane, trialkylphosphine was also reported as a cyclotrimerization catalyst for isocyanates, although its catalytic effectivity is not as high as proazaphosphatrane. Pusztai et al. studied the cyclotrimerization mechanism of alkyl isocyanates using tri-n-butylphosphine (48) as cyclotrimerization catalyst and n-butyl and n-hexyl isocyanates as model compounds (Scheme 9). [68] With the help of 1 H, 13 C, and 31 P NMR and FT-IR, it was established that the phosphine nucleophile first attacks the carbonyl group, forming a zwitterion H, followed by cyclotrimerization with a zwitterionic pathway. During the cyclotrimerization, uretdiones and iminooxadiazinediones side products were formed together with isocyanurate, of which only the formation of uretdiones was a reversible process. In a related study, Helberg et al. studied the cyclotrimerization mechanism of aliphatic isocyanates using trialkylphosphine as catalysts. [69] According to low temperature 31 P and 15 N NMR spectroscopy and in line with computational results, formation of a cyclic pentacoordinate phosphine structure I instead of linear intermediate H was proposed.
Juenge et al. also used triethylphosphine as catalyst to study cyclotrimerization of vinyl isocyanate and co-cyclotrimerization of vinyl isocyanate with other isocyanates. [70] When 8 mol % of triethylphosphine was used, only 55 % yield of isocyanurate was obtained in the cyclotrimerization of vinyl isocyanate at room temperature for 2 h. Under the same reaction conditions, vinyl isocyanate co-cyclotrimerized with various alkyl isocyanates, providing co-trimers in more than 62 % yield.

Carbenes and alkenes
Catalysts with lone electron pair such as carbenes are good nucleophiles. They effectively catalyze cyclotrimerization of isocyanates via an anionic pathway.
Duong et al. studied a variety of N-heterocyclic carbenes and discovered that the saturated carbene, 1,3-bis-(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene (SIPr, 51) displayed high catalytic activity for both aryl and alkyl isocyanates with or without solvent. [72] High yields of isocyanurate (> 97 %) were obtained with only 0.1 mol % catalyst loading at room temperature, but only 85 % yield was obtained in the cyclotrimerization of 4-methoxybenzyl isocyanate due to its electron-donating para substituent. More than 95 % conversion was still reached even with catalyst loading as low as 0.001 mol % with phenyl isocyanate or 1 mol % with cyclohexyl isocyanate as a substrate.
A polymer supported, CO 2 -protected N-heterocyclic carbene (52) was synthesized by Pawar et al. [73] With 1.2 mol % catalyst loading, the bulk cyclotrimerization of aryl isocyanates at 65°C led to 75-92 % conversion within 60-90 min. In addition, based on experimental and computational study on thermodynamics, Norris et al. developed N-heterocyclic carbene-isothiocyanate adducts (53) as a latent catalyst for the cyclotrimerization of phenyl isocyanate based on thermal reversibility of the reaction between NHCs (1,3-dimesitylimidazolylidene, J) and isothiocyanate (Scheme 10). [74] Once the adduct was activated at high temperature, the separated catalytically active NHCs started the cyclotrimerization of phenyl isocyanate following a mechanism similar to anionic cyclotrimerization pathway. With 20 mol % of adduct, 82 % of conversion was obtained after 24 h reaction in toluene at 120°C. Although this catalyst loading is impractically high, it was interesting to observe that variation of structure and electronic properties of the isothiocyanate in the adduct modulate the catalytic performance and the activation temperature.
In addition to carbenes, electron rich alkenes have been reported as cyclotrimerization catalysts. It was proposed that the alkenes form a zwitterion after the reaction of alkene and an isocyanate, followed by cyclotrimerization of isocyanates via an anionic pathway.
Li et al. found that 1,3-dimethyl-4,5-diphenyl-2-(propan-2ylidene)-2,3-dihydro-1H-imidazole (NHO, 54), an N-heterocyclic olefin, is a very efficient cyclotrimerization catalyst. [41] When bulk cyclotrimerization was carried out with 1 mol % catalyst loading at room temperature, more than 95 % conversion was achieved in a few minutes with various aryl isocyanates regardless of the electronic properties of their substituents. The catalyst was also effective in cyclotrimerization of alkyl isocyanates, giving yields higher than 90 %. Furthermore, with the help of a catalytic amount of toluene, NHO was capable of catalyzing the reaction with a catalyst loading as low as 0.1 mol % at room temperature, giving yields higher than 95 % for aryl isocyanates in a few minutes and higher than 88 % for aliphatic isocyanates, although longer reaction times were needed with these substrates. Based on a detailed NMR study, it was proposed that the NHO catalyze the cyclotrimerization of isocyanates via zwitterionic pathway as shown in Scheme 11. After linear addition of three isocyanates on the double bond of NHO, a ring closure takes place and an isocyanurate is formed.
Another electron-rich alkene, tetrakis(dimethylamino)ethylene (TDAE, 55), was reported by Giuglio-Tonolo et al. as an efficient and selective cyclotrimerization catalyst for aryl isocyanates. [75] After optimization of reaction conditions using phenyl isocyanate as the model compound, 2 mol % of TDAE gave 81 % yield of triphenyl isocyanurate at room temperature within 10 s in bulk under air. High conversion (> 91 %) was also achieved in the bulk cyclotrimerization of other liquid aryl isocyanates, regardless of the electronic properties of substituents on the aromatic ring. A solvent such as ethyl acetate was required to dissolve solid aryl isocyanates, which reduced the conversion to around 76-90 % due to the dilution.
Fukuda et al. found that ketene cyclic N,O-acetal, 2isopropylidene-3-methyl-1,3-oxazolizine (NO, 56), is an effective trimerization catalyst for phenyl isocyanates. [76] When a reaction was carried out in acetonitrile at À 30°C, a high yield of isocyanurate was obtained within 1 h without the formation of side products K (Scheme 12). With a 10 mol % catalyst loading, 92 % conversion was reached and with 1 mol % catalyst loading, conversion was 88 %. Same result was obtained when the reaction was carried out in DMF at À 55°C using 1 mol % catalyst. However, when the polar solvent DMAc was used or when the reaction was carried out at a lower temperature, polymerization instead of cyclotrimerization took place, forming nylon-1 structure L (Scheme 12). In addition, 1,2-dimethylimidazole (57) has been used as catalyst for cyclotrimerization of benzyl isocyanate as well as substituted benzyl isocyanates but low yields were obtained. [77] Mizuya et al. discovered that alkoxyallenes (58) catalyzed the cyclotrimerization of electrophilic isocyanates such as phenyl isocyanate, p-tolyl isocyanate and 4-chlorophenyl isocyanate in DMF at room temperature. [78] A reaction with 5 mol % catalyst loading gave a yield of 70-80 % (Scheme 13).

Other catalysts
Besides the typical catalysts listed in the previous sections, some Lewis basic catalysts catalyze cyclotrimerization of isocyanates under special reaction conditions or have unique catalytic pathway. A secondary amine, hexamethyldisilazane (HMDS, 59), is reported to be a cyclotrimerization catalyst with a unique catalytic pathway (Scheme 14). [79] During cyclotrimerization of octyl isocyanate, it was found that HMDS first reacts with isocyanate to form a urea, followed by intramolecular migration of a trimethylsilyl group. In the next step, a less sterically hindered urea, N,N'-bis(trimethylsilyl)octylurea is formed. This urea reversibly decomposes to a TMS-isocyanate and a TMS-octyl amine (M), the latter being the actual cyclotrimerization catalyst. The removal of TMS-isocyanate shifts the equilibrium to the formation of TMS-octyl amine and consequently increases the formation rate of isocyanurate. It was proposed that the catalytic activity of the catalyst is not only caused by its nucleophilicity, but also by the active migration of the TMS group during the catalytic process.
Catalysts that operate via a Lewis basic cyclotrimerization mechanism are generally environmentally friendly as they are heavy-metal-free. It should be highlighted that some of these catalysts are able to catalyze cyclotrimerization in bulk and most of them are well-soluble in isocyanate monomers except for some of the heterogeneous catalysts mentioned previously such as sodium nitrite, potassium nitrite and sodium ptoluenesulfinate. [39,58] Solvent-free reactions are advantageous for industrial large-scale production and for compliance with stricter regulations, although a (preferably non-toxic) solvent is still necessary for cyclotrimerization of solid isocyanates.

Metal-containing catalysts
Metal-containing catalysts such as organotin compounds are commonly applied in the synthesis of urethanes from isocyanates due to their high reactivity and selectivity. [2,4] However, many papers also report the potential use of metal-containing catalysts in cyclotrimerization of isocyanates. Most of these cyclotrimerization catalysts are coordination complexes, while some of them are heavy metal salts with an organic counterion. In this section, catalysts are categorized by metal ( Table 2). The cyclotrimerization mechanism of metal-containing catalysts varies. Some of the catalysts promote cyclotrimerization following an anionic catalytic pathway (Scheme 1), while other catalysts operate via a Lewis acid pathway (Scheme 15). In the latter mechanism, unlike in the anionic pathway, the catalyst first coordinates to an isocyanate and generates a partially positive charge on the isocyanate carbon atom (II'), which increases its electrophilicity towards other isocyanates. The positively charged carbon atom then attacks the nitrogen of other isocyanates in a stepwise manner to form isocyanurate. [80][81][82][83] Some special metal-containing species catalyze cyclotrimerization of isocyanates via repeated insertion of isocyanates in the metal coordination bond, followed by elimination of isocyanurate and regeneration of catalyst. [84][85][86][87][88] The coordination-insertion cyclotrimerization mechanism, as well as some other specific metal-catalyzed mechanisms such as intramolecular rearrangement are described below for selected catalysts.

Main-group metals
Organotin catalysts are common urethane catalysts. Tin is also developed as a cyclotrimerization catalyst for isocyanates. Foley et al. synthesized cyclic tin tetrasulfido complexes with methyl or tert-butyl substituents (60) which have high catalytic activity in the cyclotrimerization of aryl isocyanates without forming side products. [89] When 2 mol % methyl substituted tin catalyst was used, a yield as high as 95 % yield was achieved within 12 min in the cyclotrimerization of phenyl isocyanate or pmethoxybenzyl isocyanate. However, the cyclotrimerization catalyzed by the tert-butyl substituted tin complex gave a lower yield and required a longer reaction time. More recently, tin or germanium amidinato amido complexes (61) have been ex-      (63) slowly catalyze cyclotrimerization of isocyanates by insertion of isocyanate in a tin-carbon bond. [90,91] Similarly, Dabi et al. reported cyclotrimerization of phenyl isocyanate with the help of 20 vol % DMSO at room temperature using tributyltin oxide as a catalyst. A quantitative yield was achieved within 10 min. [92,93] The reaction time decreased when more DMSO was present, and increased when a reaction solvent with lower dielectric constant was used. However, cyclotrimerization of alkyl isocyanates was slow even in highly polar solvents or when strong nucleophiles were used. [94] Wakeshima et al. were the first to find that when tin(II) bis(acetylacetonate) (Sn(acac) 2 , 64) reacts with excess phenyl isocyanate at room temperature in hexane, triphenyl isocyanurate is obtained, although in a low yield (33 %). [95] Based on this observation, several organotin(II) compounds containing SnÀ OÀ C bonds were developed as improved catalysts. [96] Tin(II) bis(2-dimethylaminoethanolate) (65) and tin(II) bis(2-methoxyethanolate) (66) had high catalytic activity for the cyclotrimerization of phenyl isocyanate and quantitative conversion was achieved at 80°C for 3 h in benzene with 2 mol % catalyst loading. Tin(II) ethoxide (67) showed better catalytic performance on alkyl isocyanates where almost full conversion was achieved within 2 h from the cyclotrimerization of triethyl isocyanurate at 80°C. It was proposed that the nucleophilicity of the oxygen atom of Sn(II)-OR bonds affected the catalytic activity of Sn(II) compounds and that the reaction follows a four-centered intermolecular coordination mechanism (Scheme 16).
Guanidinate stabilized germanium(II) and tin(II) amide complexes (68 and 69) were synthesized by Barman et al. as efficient catalysts for cyclotrimerization of aryl isocyanates. [97] With 2 mol % catalyst loading, the bulk cyclotrimerization was carried out at room temperature for 1 h and around 93-96 %  (74). [99] With 1 mol % of 73, the cyclotrimerization of phenyl isocyanate was carried out in bulk or in solution at room temperature. In each case, more than 98 % conversion was achieved after 30 min. In addition, when THF was used as the solvent, the catalyst loading could be reduced to 0.05 mol % and 98 % yield was achieved within 3 h. With the same catalyst loading, more than 90 % conversion was always achieved regardless of the electronic nature (electron-donating or electron-withdrawing) of the substituents. Meanwhile, 74 also had good catalytic performance -92 % yield of triphenyl isocyanurate -with only 0.05 mol % catalyst loading. It was proposed that with these basic bidentate pyrrole ligands (70)(71)(72)(73)(74), the cyclotrimerization with either lithium or potassium complex as catalyst follows an anionic pathway, similar to Lewis base catalysts.  (77). [100] It was found that the magnesium and zinc complexes gave moderate to good yield during the cyclotrimerization of phenyl isocyanate, while the lithium complex was a highly effective cyclotrimerization catalyst. With catalyst loading as low as 0.1 mol % of lithium complex 75, the cyclotrimerization of phenyl isocyanate at room temperature in diethyl ether gave more than 99 % yield within 12 h. More than 95 % conversion was also achieved in bulk or in various solvents. Under the same reaction conditions, the lithium complex catalyzed cyclotrimerization of various aryl isocyanates giving yields higher than 97 %, whereas only moderate yields were obtained with alkyl isocyanates. It was proposed that the cyclotrimerization of isocyanates by these catalysts is also similar to the reactions catalyzed by Lewis bases.
Another lithium complex (78) synthesized by Guo's group, stabilized by 2-amino-functionalized benzoylpyrrole, was also an efficient and selective cyclotrimerization catalyst for aryl isocyanates. [101] When the cyclotrimerization of different aryl isocyanates was carried out in diethyl ether at room temperature, more than 95 % conversion was achieved within 0.5-3 h with only 0.05-1 mol % catalyst loading. The solvent plays an important role in the catalytic performance of this catalyst with which a higher yield was achieved in diethyl ether than in other solvents such as toluene, THF, hexane or in bulk.
Orzechowski et al. synthesized a monomeric calcium carbene complex with chelating iminophosphorane substituents (79). [102] This complex catalyzed the cyclotrimerization of phenyl isocyanate at room temperature with 1 mol % catalyst loading and 90 % yield was achieved within 3 h. However, the catalyst had very low catalytic activity with alkyl isocyanates such as cyclohexyl isocyanate as a substrate. It was proposed that the cyclotrimerization using calcium carbene complex as catalyst follows an anionic trimerization pathway based on the capture of a complex formed from double insertion of isocyanates to the catalyst (Figure 2).
Bahili et al. synthesized a hemi-labile aluminium pyridylbis(iminophenolate) complex (80) and found that it was highly effective in the cyclotrimerization of alkyl, allyl and aryl  isocyanates under mild conditions. [85] Cyclotrimerization of different aryl and alkyl isocyanates was carried out at room temperature or 50°C with 0.2 mol % catalyst loading and higher than 95 % yield was achieved, while for allyl isocyanate, the yield was 59 %. Based on density functional theory computations, Bahili proposed that the catalytic mechanism follows a coordination-insertion process and that the presence of a hemilabile pyridyl donor plays an important role in the high activity of the aluminum alkoxide complex during cyclotrimerization of isocyanates.
Herbstman reported that tri-n-butylantimony and triisobutylarsenic oxides (81 and 82) effectively catalyze cyclotrimerization of phenyl and m-chloro phenyl isocyanate at room temperature in bulk with 2 mol % catalyst loading; higher than 94 % conversion was achieved in 15 min to 1 h. [103] In heptane or DMSO solution, tri-n-butylantimony oxide also catalyzed the conversion of aryl isocyanates at room temperature, giving yields higher than 95 %, except when the aryl ring carried electron-donating substituents. Moderate yields were achieved in the cyclotrimerization of alkyl isocyanates, e. g., ethyl isocyanate, giving triethyl isocyanurate in 77 % yield.

Transition metals
The coordination chemistry of transition metals has been studied in more detail than main-group metal complexes. Palladium is one of the transition metals that has been used for cyclotrimerization of isocyanates. Paul et al. synthesized a Pd(0)diimine complex (86) and found that the catalytic performance of the complex was strongly influenced by solvent polarity and reaction temperature (Scheme 17). [105] With 0.3 mol % catalyst dosing, cyclotrimerization of phenyl isocyanate in nitrobenzene at room temperature gave 99 % yield within 14 h. Electronwithdrawing substituents on the aromatic ring increased the reactivity and shortened the reaction time, whereas steric crowding in the isocyanate prevented cyclotrimerization. In a combined experimental and computational study, it was found that the mechanism of the first steps in catalytic cyclotrimerization of Pd(0)-diimine complex is similar to that of anionic trimerization. The Pd(0) center initiates zwitterion-like intermediates N or N' after a nucleophilic attack with isocyanate via coordination through C=N bond of C=O bond respectively. The intermediates react with two isocyanates in a stepwise manner, leading to a seven-membered metallacycle O which cyclizes at the metal center and forms isocyanurate. During the chaingrowth process, the intermediates also tend to cyclize at the metal center, leading to several side products such as uretdione and structure P.
Organozinc compounds have also been developed as a cyclotrimerization catalysts. Guo et al. studied tridentate pyrrolylzinc compounds as well as the reaction products of these compounds with tert-butylphenol (92)(93)(94)(95). [108] When cyclotrimerization of phenyl isocyanate was carried out at room temperature in diethyl ether with 5 mol % catalyst loading, all catalysts showed quite good catalytic performance giving yields from 71 % to 92 % after 12 h, among which the catalyst [C 4 H 2 N(2,5-CH 2 N(CH 2 ) 5 ) 2 ]ZnC 2 H 5 (93 with piperidinyl) showed the best catalytic activity. This catalyst was also active in the trimerization of other aryl isocyanates such as 4-chloro, 4-methyl and 4methoxy phenyl isocyanate, giving yields higher than 88 %.
Noltes et al. found that organozinc amine EtZnNPh 2 (96) effectively catalyzes the cyclotrimerization of alkyl isocyanates such as methyl, ethyl and hexyl isocyanate in benzene; near quantitative yields were obtained with a trace amount of urea as side product (Scheme 18). [109] EtZnNPh 2 first reacts with an alkyl isocyanate to form the urea structure EtZnNR·CO·NPh 2 (R = alkyl), which is the actual catalytic species in the reaction. It was proposed that EtZnNR · CO · NPh 2 forms a complex with oxygens of three isocyanate molecules (R 1 ) coordinated to zinc and there is strong interaction between the electrophilic carbon and the nucleophilic nitrogen of the neighbor isocyanates. With insertion of excess isocyanate (R 2 ) and hydrolysis of the isocyanate-catalyst adduct, bond rearrangement occurs and isocyanurate is generated.
In addition, Sharpe et al. reported that two-coordinated and three-coordinated m-terphenyl complexes (97 and 98) containing manganese or iron, catalyzed the cyclotrimerization of alkyl isocyanates via a Lewis acid pathway (Scheme 19). [81] During the study of cyclotrimerization of alkyl isocyanates such as ethyl isocyanate, propyl isocyanate, hexyl isocyanate and benzyl isocyanate, only (2,6-Tmp 2 C 6 H 3 ) 2 Fe(THF) showed low catalytic activity. On the other hand, (2,6-Tmp 2 C 6 H 3 ) 2 Mn(THF) and (2,6-Mes 2 C 6 H 3 ) 2 M (M = Mn, Fe) showed high efficiency at room temperature with 5 mol % catalyst loading and higher than 97 % yield of isocyanurate. It was also found that the catalysts (98) were effective for primary aliphatic isocyanates but, due to the steric hindrance, have much lower efficiency for cyclotrimerization of secondary and tertiary aliphatic isocyanates, while they almost show no catalytic effect on aromatic isocyanates.
Montilla et al. studied the catalytic behavior of CpCo(CO) 2 (99), CpCoPPh 3 Me 2 (100) and Ni(cod) 2 (101) in the cyclotrimerization of phenyl isocyanate in bulk at room temperature. [110] Full conversion was achieved within 12 h when Ni(cod) 2 /PPh 3 (2 mol %) or CpCoPPh 3 Me 2 (1.5 mol %) was used as catalyst, while for other isocyanates, low conversion was achieved with any of the three catalysts even at high temperature.
Dabi et al. found that with the help of DMSO or some other aprotic solvents, Zr(OBu) 4 and Ti(OBu) 4 (102) were efficient cyclotrimerization catalysts for phenyl isocyanate but inefficient for alkyl isocyanates. [92,94] Similar to tributyltin oxide (63), these catalysts were proposed to catalyze the cyclotrimerization by first reacting with an isocyanate to form an active catalytic species. Furthermore, naphthenates of Pb, Zr and Co (103 and 104), in the presence of DMSO, also showed high catalytic effect on both phenyl isocyanate and some alkyl isocyanates. However, the induction time and reaction time for cyclotrimerization at room temperature were longer for alkyl isocyanates than for aryl isocyanates, and were strongly dependent on the concentration of polar solvent. It was proposed that the naphthenates catalyzed the cyclotrimerization in a Lewis acid pathway. In addition, Dabi discovered that the combinations of organometallic catalysts discussed above had strong synergistic catalytic effects in the cyclotrimerization of aryl, alkyl or strongly hindered isocyanates, with the help of strongly dipolar aprotic solvents such as DMF and DMSO at relatively low temperature (20-50°C). [93] When a combination of oxides and naphthenates was used as catalyst for cyclotrimerization of phenyl isocyanate in DMSO/toluene mixed solvent, the reaction time was shortened compared to these catalysts separately. For instance, with 0.1 mol % Pb-naphthenate-Zr-(OBu) 4 , the reaction time was 2 min; with 0.75 mol % Pbnaphthenate-tributyltin oxide, the reaction time was 4 min and with 0.1 mol % Co-naphthenate-tributyltin oxide, the reaction time was 5.6 min.
Some other transition-metal catalysts based on iron, manganese, niobocene as well as zirconocene are also good cyclotrimerization catalysts. Yilmaz et al. found that Pruitt-Baggett adduct (PBA, 105), formed from the reaction between propylene oxide and FeCl 3 , catalyzed polymerization and cyclotrimerization of isocyanates. [111] PBA catalyzed the polymerization of n-butyl isocyanate at low temperatures (À 23 to 25°C) in bulk while the extent of polymerization decreased with higher temperature and trimers were selectively obtained when the reaction was carried out above 40°C. Aromatic and ether solvents such as benzene, toluene and diethyl ether also helped to selectively form trimers during the reaction. The polymerization and cyclotrimerization of isocyanates by PBA was proposed to follow a cationic coordination mechanism. [112] First, a coordination complex is formed from the reaction of PBA and a n-butyl isocyanate. After intramolecular rearrangement, a carbamate was obtained (Scheme 20). The polymer chain starts to propagate by addition of isocyanates to the carbamate. During the process, trimers are formed from backbiting of the polymer chain or direct cyclization of the linear trimer.
Another manganese complex [(η 5 -C 5 H 4 Me)Mn(CO) 2 (THF)] (106) was synthesized by Martelli et al., which catalyzes cyclotrimerization of aryl isocyanates at room temperature giving 80 % yield. [113] It was proposed that a mono-adduct is first formed between the isocyanate and the catalyst, followed by addition of two isocyanates and the isocyanurate ring is built up on the metal center.
Blacque et al. discovered that oxo niobocene complexes [Cp* 2 Nb(O)R] (R=H, OMe) (107) catalyze the cyclotrimerization of phenyl isocyanate, although limited selectivity of the catalysts led to the formation of dimers as side product. [114] In comparison, Ozaki et al. developed a more active low-valent alkoxyniobium species, Nb(OEt) 5 , in combination with Grignard reagent ethylmagnesium chloride (EtMgCl) (108), for cyclotrimerization of isocyanates. [115] The catalytic performance of Nb(OEt) 5 /EtMgCl is independent of solvent effect but dependent on reaction temperature and catalyst loading. Under optimized conditions (10 mol % Nb(OEt) 5 and 10 mol % EtMgCl), cyclotrimerization of hexyl isocyanate at 60°C in THF gave 83 % yield. This reagent system is able to catalyze cyclotrimerization of various aryl isocyanates and moderate amounts of isocyanurate are formed (> 50 %). In addition, some other reducing agents such as i-PrMgCl, n-BuLi and LiAlH 4 in combination with Nb(OEt) 5 also provide good yields, though not as high as EtMgCl.
Li et al. developed several zirconocene compounds as cyclotrimerization catalysts. [116] With 10 mol % of the zirconium 1-butene complex stabilized by trimethyl phosphine (109), 71 % yield was obtained after cyclotrimerization of phenyl isocyanate in THF at room temperature for 6 h. Using dibutyl zirconocene and dibutyl hafnocene (110), 82 % yield was achieved and 79 % yield was achieved using zirconocene t-butylcyclopentadienyl complex (111), under smoother reaction condition. For different aryl isocyanates, more than 60 % isocyanurate was obtained with 10 mol % dibutyl zirconocene, whereas a stoichiometric amount of catalyst was required to catalyze cyclotrimerization of alkyl isocyanates. Some other transition metal containing catalysts, however, are not very active or form side products during isocyanurate formation. For example, titanium bipyridyl complex (112) reacts with phenyl isocyanate at room temperature in bulk giving 65 % yield of isocyanurate. [117] Chromium(salphen) complex (113) catalyzes the reaction of epoxide and halogen contained isocyanates at 80°C in toluene, forming small amount of isocyanurate and oxazolidinone. [82] Diethyldipyridylnickel (114) both trimerizes (56 % yield) and polymerizes (34 % yield) phenyl isocyanate at room temperature in toluene with around 4 wt % of catalyst loading, while it selectively trimerizes ethyl isocyanate and n-butyl isocyanate with 81 % and 67 % yield respectively. [118] On the contrary, bis(dipyridyl)nickel (115) and tetrakis(triphenylphosphine)nickel (116) selectively trimerize phenyl isocyanate giving 85 % and 45 % yield respectively, but both initiate polymerization of ethyl and n-butyl isocyanates. Copper (II) bromide (117) catalyzes cyclotrimerization of methyl and ethyl isocyanate very slowly at room temperature but faster at around 130°C in bulk. [83] Nickel (II) chloride (118) also catalyzes cyclotrimerization of methyl isocyanate at higher temperature than 110°C. Both of these two inorganic metal catalysts were claimed to follow a Lewis acid pathway, but no conversion was mentioned. A tungsten-vanadium complex (119) was found to be a moderately active cyclotrimerization catalyst giving a modest yield (49 %) of triphenyl isocyanurate with a lot of side products such as urea when 7 mol % catalyst was used. [119]

Rare-earth metals
Rare-earth metals include the lanthanide elements as well as the chemically similar elements scandium and yttrium. Zhu  (6), Sm (7)) (120) and [C 6 H 5 N-(Me 2 Si)N(C 6 H 5 )(Me 2 SiO)LnN(SiMe 3 ) 2 ] 2 (Ln = Yb) (121), which showed quite high catalytic activity and selectivity in the cyclotrimerization of isocyanates (Scheme 21). [86] Using 0.25 mol % of catalysts 120(1-5) or 121, the cyclotrimerization was carried out at 40°C in THF and 92-98 % conversion was reached. However, more catalyst was needed for 120(6-7) (1 mol %) and higher than 95 % conversion was achieved after 1 day reaction at 60°C. It was found that the catalysts 120(1,2) and 120(4) exhibit high catalytic activity for various aryl isocyanates -higher than 93 % conversion was achieved except with 4-nitrophenyl isocyanate as substrate. However, catalytic activity of 120(1,2) and 120(4) was lower for alky isocyanates and many side products were formed. Wu [120] When the yttrium complex was used as the catalyst, 99 % yield of trimer was achieved in solvents such as toluene, THF or CH 2 Cl 2 with 1-3 mol % catalyst dosing at relatively low temperature (room temperature to 80°C). The catalytic activity of the catalyst in THF was higher than that in toluene or CH 2 Cl 2 . With 1 mol % catalyst loading, all five rare earth metal amides showed excellent catalytic activity in cyclotrimerization of phenyl isocyanate in THF at room temperature or toluene at 80°C with nearly quantitative yields. Moreover, the Yb and Y complexes gave quantitative yields of various aryl isocyanates (except 4nitrophenyl isocyanate) after 12 h reaction at room temperature in THF. Low yields were obtained for alkyl isocyanates at 50°C and no cyclotrimerization of allyl isocyanates was achieved.
Wang et al. developed a praseodymium benzenethiolate complex (123) as cyclotrimerization catalyst (Scheme 23). The catalytic performance of the catalyst was strongly dependent on solvent (higher yield in THF), temperature (higher yield at high temperature) and catalyst loading. [87] This catalyst showed high catalytic activity and selectivity in case of aryl isocyanates giving yields higher than 91 %, while no cyclotrimerization was observed for alkyl isocyanates.
Zhu, [86] Wu [120] and Wang [87] all proposed that the cyclotrimerization followed the coordination-insertion pathway depicted in Schemes 21-23. For example, with the praseodymium complex (123) (Scheme 23), isocyanate is first coordinated to the central metal atom by replacing a coordinated THF molecule and the migration insertion of the isocyanate forms an intermediate Q with a four-membered ring. After that, intermediate Q reacts with two more isocyanates in a stepwise manner through an insertion reaction and generates isocyanurate with release of the catalyst.
In addition, Liu et al. synthesized a yttrium dialkyl complex containing sterically demanding silaamidine ligand (124) that effectively catalyzed cyclotrimerization of 3-methylphenyl isocyanate in THF. [121] When the reaction was carried out at room temperature with 0.25 mol % catalyst loading, 98 % yield was obtained within 12 h, while the catalytic activity decreased a lot by changing solvent from THF to less polar solvents such as diethyl ether or toluene. Under the same condition, the yttrium complex catalyzed cyclotrimerization of various aryl isocyanates giving yields higher than 88 %, except 2-nitrophenyl isocyanate, which gave a yield of 64 %. However, the Yttrium complex did not catalyze cyclotrimerization of alkyl isocyanates except benzyl isocyanate (56 %). The authors proposed that the mechanism follows a coordination-insertion pathway (Scheme 24). After a migratory insertion reaction of an isocyanate with the catalyst, intermediate R is formed. It was proposed that the isocyanates grow linearly on the complex R instead of forming a ring as in Schemes 21-23. After insertion of three more isocyanates, isocyanurate is eliminated after ring closure with the release of intermediate R.
Yi et al. synthesized an organoyttrium phosphide (Tp Me2 )CpYPPh 2 (THF) (125) which catalyzes the cyclotrimerization of phenyl isocyanate in THF at room temperature with 10 mol % catalyst loading, and 83 % yield was obtained. [88] The cyclotrimerization mechanism was proposed to follow a stepwise insertion of isocyanates into the YÀ P or N bond (Scheme 25).
A polynuclear yttrium trifluoroethoxide (126) was synthesized by Peng et al. that catalyzes the cyclotrimerization of phenyl isocyanate giving 74-85 % yield with 0.33 mol % or 0.1 mol % catalyst. The catalytic activity was independent of reaction temperature, but there were some side products such as dimer or other oligomers formed during cyclotrimerization. [122] In addition, new Yttrium complexes incorporating amidinate ligands (127) were found to catalyze the cyclotrimerization of phenyl isocyanate with 77 % conversion at room temperature in THF with 7 mol % catalyst loading. [123] (Diisopropylamido)bis (methylcyclopentadienyl) lanthanides (128) catalyzed the cyclotrimerization of phenyl isocyanate at 30°C with 0.33 mol % catalyst loading in 39 % yield. [124] A bimetallic neodymium-crown ether complex (129) was reported to be a cyclotrimerization catalyst where the nucleophilic oxygen atoms of two isocyanate groups were proposed to be strongly coordinated with two electrophilic neodymium metals (Scheme 26). [125] Afterwards, additional isocyanate react with the intermediate complex, leading to formation of isocyanurate.

Other catalysts
Along with more common cyclotrimerization catalysts, a few catalysts outside the categories listed above have been reported to show activity in cyclotrimerization of isocyanates (Table 3).
Corriu et al. investigated the activity of pentacoordinated hydrosilane (130) as trimerization catalyst. [126] With 3 mol % catalyst loading, cyclotrimerization of phenyl isocyanate was carried out at room temperature in CCl 4 and 85 % conversion was achieved within 5 h. The N-silylformamide that was obtained from the reaction of pentacoordinated hydrosilane and one phenyl isocyanate was also found to exhibit catalytic activity in the cyclotrimerization.
Servos et al. reported that when phenyl isocyanate was reduced by potassium metal (131) in solvent such as THF where Scheme 24. Proposed mechanism of cyclotrimerization using yttrium alkyl complex (124) as catalyst. Adapted from ref. [121] Copyright (2019), with permission from the Royal Society of Chemistry.

Summary and outlook
Selective catalysis of isocyanate cyclotrimerization is considered as one of the most important methods for efficient production of isocyanurates. This overview of catalysts aims to provide a guideline for the choice of suitable catalysts to match a range of requirements. Heavy metal-free, solvent-free catalysts are more favorable in industrial applications due to the concerns on environmental impact and cost saving. Efficient catalysts lead to high conversion as well as fewer side products within a short reaction time, while fast reaction rate minimizes operation time. It is also necessary to consider the reaction temperature of the catalysts. Catalysts that operate at low temperature are obviously preferable over ones that require high temperature. While aryl isocyanates have higher reactivity than alkyl or allyl isocyanates, it is easier for catalysts to catalyze the cyclotrimerization of aryl isocyanates than alkyl or allyl isocyanates. [2] However, some metal-containing catalysts show catalytic activity specifically in alkyl isocyanate cyclotrimerization, which is useful in applications that require selective cyclotrimerization. As a general reminder, model isocyanates such as phenyl, tolyl, hexyl isocyanates were used in the majority of the cyclotrimerization catalyst studies from literature. In industrial PU synthesis, the presence of polyols and water, the bulk condition, the compatibility of catalysts, and the large-scale reaction can all influence the efficiency of the cyclotrimerization catalysts. Therefore, various factors should be considered when comparing these catalysts with benchmark catalysts such as potassium acetate. In addition, as many cyclotrimerization reactions reported in the papers are not optimized (e. g. catalysts amount, reaction temperature), and some references only focus on studying the underlying cyclotrimerization mechanisms, we cannot give a general advice for the efficiency of the catalysts only based on the literature.
We expect that the overview of the catalysts will facilitate the development of new and better cyclotrimerization catalysts. The catalytic activity and selectivity of the catalysts can be improved by changing their chemical structures such as the counterions of the Lewis basic salts, the coordinated ligands on the metal, the basicity of the catalysts, etc. In addition to proposing a catalytic mechanism based on experimental observations, advanced computational studies have recently been used to clarify catalytic pathways by simulations and calculations. [43,67,69,85,105,129] Using this powerful tool, mechanistic investigations can be performed faster and intermediates that are not easily identified experimentally can be identified. We also foresee that the use of computational studies will become an important trend in the discovery of new catalysts for isocyanate cyclotrimerization. [46,47,130]