Intramolecular [2+2+2] Cyclotrimerization of a Model Triyne to [7]Helical Indeno[2,1-c]Fluorene with Air-Stable Ni(0) and Other Precatalysts

Abstract

In this work, we demonstrated that air-stable Ni(0) complexes with phosphine ligands can effectively catalyze intramolecular cyclotrimerization of a triyne to a compound with a [7]helical indeno[2,1-c]fluorene skeleton. The obtained results are comparable to those achieved by using Rh-based catalytic systems. Screening of the reaction conditions showed that bidentate phosphine ligands with small bite angles (70–80°) gave the best results in terms of yields. The highest asymmetric induction with the investigated air-stable Ni(0) precatalyst was obtained using the PROPHOS ligand in HFIP (62% ee). Other catalytic systems, like [Rh(CH₂=CH₂)₂Cl]₂ and [CpCo(P{OEt}₃)(trans-MeO₂CHC=CHCO₂Me)], have also been investigated, showing promising results.

1. Introduction

Transition metal-catalyzed [2+2+2] cyclotrimerization reactions of alkynes are, undoubtedly, one of the most efficient pathways for building highly substituted benzene rings. Its long history started with the pioneering work of Berthelot in 1866 [1,2], who carried out the first thermal cyclotrimerization of ethyne to benzene. Another step forward was performed by Reppe and Schweckendiek [3], who described the first catalytic cyclotrimerization using Ni-complexes. Since then it has been shown that [2+2+2] cyclotrimerization can be initiated by a number of different transition metal catalysts and has become one of the standard tools in organic chemistry [4,5,6,7,8,9,10]. The main advantages of this methodology can be summarized in the following points: (i) it allows highly atom-economical formation of three new bonds in one step; (ii) it proceeds in an intermolecular, partially intramolecular, or totally intramolecular manner giving rise to products with different skeletal architecture; and (iii) a good control of the pair- and regioselectivity can be achieved depending on reaction conditions.

Over several decades, catalytic [2+2+2] cyclotrimerization processes have found a number of applications in syntheses of aromatic compounds. In this regard, cyclotrimerization has turned out to be a useful methodology for the synthesis of helicenes as demonstrated by the works of Starý et al. [11] and Tanaka et al. [12]. In a similar manner, we have recently developed a Rh-complex catalyzed intramolecular cyclotrimerization of triynes allowing the synthesis of racemic and enantioenriched helical compounds possessing the indeno[2,1-c]fluorene skeleton [13]. When 1,1'-(ethyne-1,2-diylbis(naphthalene-1,2-diyl))bis(3-(4-methoxyphenyl)prop-2-yn-1-ol) was employed as a typical substrate optimum enantioselective cyclotrimerization to [7]helical compound – 8,9-bis(4-methoxyphenyl)benzo[c]benzo[6,7]indeno[1,2-g]fluorene-7,10-dione – (90% ee, 74% yield) was achieved using the Rh(cod)₂BF₄/(S)-SEGPHOS system at 60 °C in DCE. As far as racemic cyclotrimerization is concerned, the aforementioned [7]helical compound was obtained in 86% yield using Wilkinson’s catalyst (Rh(PPh₃)₃Cl) at 180 °C under microwave irradiation [14].

Since this process turned out to be synthetically highly efficient under Rh-catalysis, our primary interest was to develop and assess the scope of the reaction with respect to air-stable Ni-based precatalysts and thus, explore possibilities of finding an alternative catalytic system for enantioselective cyclotrimerization to the Rh-catalyzed process. Our second goal was a comparison of these endeavors leading to the formation of [7]helical indeno[2,1-c]fluorene 2 with results reported for Co- or Ni-catalyzed cyclotrimerization providing tetrahydro[7]helicenes (64% for Co, 41% for Ni) [15,16] because both compounds are structurally related, have similar properties, and could be potentially used for the synthesis of other polyaromatic hydrocarbons (albeit exploration of such transformations in-solution has just started to be pursued [17,18,19,20]).

2. Results and Discussion

First, our attention turned to a simple catalytic system based on a combination of NiCl₂(PPh₃)₂ + Zn powder in MeCN (25 °C, 4 days), which was previously successfully applied to the cyclotrimerization of diynes with alkynes [21]. Disappointingly, the intramolecular reaction of compound 1 did not proceed and the starting material remained intact. In the next step, to avoid the use of Ni(COD)₂-based systems, air-stable Ni precatalysts, Ni(COD)(DQ) ((1,5-cyclooctadiene)(duroquinone)nickel(0)) [22] and Ni(⁴-tBustb)₃ (tris((E)-1,2-bis(4-(tert-butyl)phenyl)ethene)nickel(0)) [23], were used in combination with various phosphines. It should be emphasized that the content of the respective reaction mixtures was first subjected to oxidation with PCC, yielding diketone 2, thus avoiding analyses of mixtures of diastereoisomeric diols and then checked by ¹H NMR analysis.

Initially, cyclotrimerization of triyne 1 was carried out in a combination of Ni(COD)(DQ) (10 mol%) with monodentate ligands such as PPh₃ and PCy₃ (20 mol%) on 0.1 mmol scale at 100 °C in toluene (Table 1, Entries 1 and 2). However, in the former case, desired compound 2 was formed in only 33% yield (¹H NMR) along with unidentified side products. In the latter case, compound 2 was formed in traces (~10%) and isolated as an inseparable mixture with side products. The presence of diketone 4, dialdehyde 3, and perhaps aldehyde 5 was noticed in the crude reaction mixture after the final workup. Then, screening of the course of the reaction using catalytic systems with bidentate ligands such as dppm, dppe, dppBz, dppp, dppb, dppf, BINAP, DPEPhos, and xantphos, was conducted (Entries 3–11). The best results in terms of product yield and selectivity were obtained for the combination of Ni(COD)(DQ)/dppm and dppBz, ligands with small bite angles, where compound 2 was obtained in 70 and 77% yield (¹H NMR), and in 65 and 55% isolated yields (Entries 3 and 5). The use of dppe, dppp, dppb, BINAP, DPEPhos, and xantphos ligands with medium bite angles, provided compound 2 in the range of 32–56% yield (¹H NMR) (Entries 4, 6, 7, 9–11). The use of dppf failed to produce any products. When the reactions were carried out at lower temperatures in the range of 40–80 °C, cyclotrimerization gave either low yields of compound 2, the reaction did not proceed, or the formation of side product 3 was observed. Apparently, these temperatures were not high enough to promote sufficient displacement of DQ and cod by phosphine ligands and form catalytically active species. Changing the solvent to THF had a detrimental effect on the course of the reactions, where it did not proceed. It should also be noted that a combination of Ni(COD)(DQ) with bipy provided compound 2 in 33% yield (¹H NMR) (Entry 12), while with phenanthroline only traces of compound 2 were detected.

The formation of side products deserves closer discussion. The formation of diketone 4 is not surprising, as it arises from the oxidation of the unreacted triyne 1 in the reaction mixture. On the other hand, the formation of dialdehyde 3 is unexpected and might be the result of Ni-induced retro-alkynylation of 1. The structure of 3 was confirmed by comparison of the recorded NMR values with known data [14]. Although Rh-complex catalyzed retro-alkynylation is a known process [24], such a reaction has not been reported for Ni-catalyzed processes so far, to the best of our knowledge. The presence of other aldehydic signals could be assigned to mono retro-alkynylated product 5, which should be an intermediate in the formation of 3, but it is fair to admit that it has not been isolated.

Table 1. Intramolecular cyclotrimerization of triyne 1 with Ni(COD)(DQ) in the presence of various mono- and bidentate phosphines ¹.

Entry	Ligand (20 mol%)	Bite Angle (°) 2	2 (%) 3
1	PPh3	-	33 (19) 4,5
2	PCy3	-	~10 (n.i.) 5
3	dppm	71	70 (65)
4	dppe	83	40 (23) 4,5
5	dppBz	82	77 (55)
6	dppp	91	50 (47)
7	dppb	97	56 (44)
8	dppf	99	n.i.
9	BINAP	93	32 (18) 4,5
10	DPEPhos	101	43 (39)
11	Xantphos	105	42 (37)
12	Bipy	-	33 (26) 4,5

¹ Ni(COD)(DQ) (10 mol%), ligand (20 mol%), 1 (0.1 mmol), toluene, 100 °C, 16 h. Oxidation with PCC (3 equiv.), Celite^®® (same mass as PCC) in CH₂Cl₂ at 25 °C for 3 h. ² Average values from X-ray structures [25]. ^{3 1}H NMR yields with durene as an internal standard. In parentheses are isolated yields with analytical purity ≥98%. n.i. = not isolated. ⁴ Contains small amounts of unknown impurities. ⁵ Dialdehyde 3 and diketone 4 were detected in the final reaction mixture.

Table 1. Intramolecular cyclotrimerization of triyne 1 with Ni(COD)(DQ) in the presence of various mono- and bidentate phosphines ¹.

Entry	Ligand (20 mol%)	Bite Angle (°) 2	2 (%) 3
1	PPh3	-	33 (19) 4,5
2	PCy3	-	~10 (n.i.) 5
3	dppm	71	70 (65)
4	dppe	83	40 (23) 4,5
5	dppBz	82	77 (55)
6	dppp	91	50 (47)
7	dppb	97	56 (44)
8	dppf	99	n.i.
9	BINAP	93	32 (18) 4,5
10	DPEPhos	101	43 (39)
11	Xantphos	105	42 (37)
12	Bipy	-	33 (26) 4,5

¹ Ni(COD)(DQ) (10 mol%), ligand (20 mol%), 1 (0.1 mmol), toluene, 100 °C, 16 h. Oxidation with PCC (3 equiv.), Celite^®® (same mass as PCC) in CH₂Cl₂ at 25 °C for 3 h. ² Average values from X-ray structures [25]. ^{3 1}H NMR yields with durene as an internal standard. In parentheses are isolated yields with analytical purity ≥98%. n.i. = not isolated. ⁴ Contains small amounts of unknown impurities. ⁵ Dialdehyde 3 and diketone 4 were detected in the final reaction mixture.

In the next step, we aimed to explore the scope of enantioselective Ni-catalyzed cyclotrimerization (Table 2). Given the aforementioned results, all the reactions were carried out at 100 °C. Initially, bidentate phosphines with axial chirality were tested (Entries 1–8). Disappointingly, asymmetric induction was rather marginal, if any (0–12% ee). Interestingly, the use of PROPHOS (Entry 9), a phosphine with central chirality, resulted in the quantitative formation of compound 2, albeit with a marginal asymmetric induction of ~4% ee. Once again, the formation of diketone 4 and dialdehyde 3 was noted in many cases.

The use of Ni(⁴-tBustb)₃ as the 2nd generation of air-stable precatalysts seemed to be a better option with respect to ligand displacement. The reactions conducted at 100 °C gave essentially similar results to those obtained with Ni(COD)(DQ). Attempts to perform the reactions at 80 °C were met with mixed results. Although the cyclotrimerization in the presence of PROPHOS did not proceed in toluene (Entry 10), it yielded compound 2 in 27% (¹H NMR) and 10% ee in THF (Entry 11). Interestingly, performing the cyclotrimerization in HFIP (hexafluoroisopropanol) had a beneficial effect on asymmetric induction, which reached 62% ee (Entry 12), albeit in a low yield of 12% (¹H NMR). Although the yield of compound 2 was rather low, the obtained asymmetric induction was the highest in comparison to Ni-catalyzed processes forming enantioenriched tetrahydro[7]helicenes. The previously reported results demonstrated that asymmetric induction did not exceed 54% ee using Ni(cod)₂ (20 mol%) and a chiral phosphine (40 mol%) in THF at 20 °C [15,16] or 20% ee using a chiral Cp cobalt complex at (10 mol%) in THF at 20 °C [26]. Data for enantioenriched tetrahydro[6]helicenes can be found elsewhere [16,26,27,28]. Regarding the effect of HFIP on asymmetric induction, its origin is mechanistically not clear. On the other hand, its positive effect on transition metal-catalyzed asymmetric reactions [29] including enantioselective cyclotrimerization [30] has been reported. However, no mechanistic rationale for the effect has been offered. The use of bidentate chiral phosphines, e.g., SEGPHOS, etc., did not have any beneficial effect on asymmetric induction.

Table 2. Intramolecular cyclotrimerization of triyne 1 with Ni(COD)(DQ) and Ni(⁴-tBustb)₃ in the presence of various mono- and bidentate phosphines ¹.

Entry	Precatalyst	Ligand 2	Solvent	T (°)	2 (%) 3	e.r.
1	Ni(COD)(DQ)	(S)-DIFLUORPHOS	toluene	100	46 (19) 4	56:44
2		(S)-SEGPHOS	toluene	100	40 (26) 4	50:50
3		(S)-BINAP	toluene	100	30 (19) 4,5	52:48
4		(R)-SEGPHOS	toluene	100	46 (20)	52:48
5		(R)-Xyl-Garphos	toluene	100	23 (18) 4,5	54:46
6		(R)-DMM-Garphos	toluene	100	38 (17) 4,5	52:48
7		Me-MeoBiphep	toluene	100	n.i 5
8		t-Bu-MeoBiphep	toluene	100	n.i 5
9		(R)-PROPHOS	toluene	100	100 (60)	52:48
10	Ni(4-tBustb)3	(R)-PROPHOS	toluene	80	n.i. 5
11		(R)-PROPHOS	THF	80	27 (13) 5	55:45
12		(R)-PROPHOS	HFIP	80	13 (12) 4,5	19:81

¹ Ni(COD)(DQ) or Ni(⁴-tBustb)₃ (10 mol%), ligand (20 mol%), 1 (0.1 mmol), toluene, 16 h. Oxidation with PCC (3 equiv.), Celite^®® (same mass as PCC) in CH₂Cl₂ at 25 °C for 3 h. ² Bite angles for (S)-DIFLUORPHOS, (S)-SEGPHOS, (S)-BINAP are 73°, 73°, and 79°, respectively [31]. Regarding bite angle values for Xyl-Garphos, DMM-Garphos, Me-MeoBiphep, and t-Bu-MeoBiphep, they are considered to be close to that of MeoBiphep (~76°). ^{3 1}H NMR yields with durene as an internal standard. In parentheses are isolated yields with analytical purity ≥98%. n.i. = not isolated. ⁴ Contains small amounts of unknown impurities. ⁵ Dialdehyde 3 and diketone 4 were detected in the final reaction mixture.

Table 2. Intramolecular cyclotrimerization of triyne 1 with Ni(COD)(DQ) and Ni(⁴-tBustb)₃ in the presence of various mono- and bidentate phosphines ¹.

Entry	Precatalyst	Ligand 2	Solvent	T (°)	2 (%) 3	e.r.
1	Ni(COD)(DQ)	(S)-DIFLUORPHOS	toluene	100	46 (19) 4	56:44
2		(S)-SEGPHOS	toluene	100	40 (26) 4	50:50
3		(S)-BINAP	toluene	100	30 (19) 4,5	52:48
4		(R)-SEGPHOS	toluene	100	46 (20)	52:48
5		(R)-Xyl-Garphos	toluene	100	23 (18) 4,5	54:46
6		(R)-DMM-Garphos	toluene	100	38 (17) 4,5	52:48
7		Me-MeoBiphep	toluene	100	n.i 5
8		t-Bu-MeoBiphep	toluene	100	n.i 5
9		(R)-PROPHOS	toluene	100	100 (60)	52:48
10	Ni(4-tBustb)3	(R)-PROPHOS	toluene	80	n.i. 5
11		(R)-PROPHOS	THF	80	27 (13) 5	55:45
12		(R)-PROPHOS	HFIP	80	13 (12) 4,5	19:81

¹ Ni(COD)(DQ) or Ni(⁴-tBustb)₃ (10 mol%), ligand (20 mol%), 1 (0.1 mmol), toluene, 16 h. Oxidation with PCC (3 equiv.), Celite^®® (same mass as PCC) in CH₂Cl₂ at 25 °C for 3 h. ² Bite angles for (S)-DIFLUORPHOS, (S)-SEGPHOS, (S)-BINAP are 73°, 73°, and 79°, respectively [31]. Regarding bite angle values for Xyl-Garphos, DMM-Garphos, Me-MeoBiphep, and t-Bu-MeoBiphep, they are considered to be close to that of MeoBiphep (~76°). ^{3 1}H NMR yields with durene as an internal standard. In parentheses are isolated yields with analytical purity ≥98%. n.i. = not isolated. ⁴ Contains small amounts of unknown impurities. ⁵ Dialdehyde 3 and diketone 4 were detected in the final reaction mixture.

As for other catalytic systems, the use of [Rh(CH₂=CH₂)₂Cl]₂ precatalyst under the reported reaction conditions (DCE, 60 °C, 16 h) and with the same ligand, (S)-SEGPHOS, gave compound 2 in 42% yield and ~5% ee (Table S1, Entry 1), which is different in comparison with the Rh(cod)₂BF₄ (74%, 90% ee) based system [13]. Apparently, the cationic Rh-complex with a non-coordinating anion is a more efficient precatalyst. A higher efficacy of Rh-cationic complexes in terms of yields and asymmetric induction has been previously reported in [2+2+2]cycloaddition [32] and [2+2+1]cycloaddition [33]. The better performance can be attributed to the fact that a cationic rhodium(I) catalyst has an additional coordination site on the rhodium for interaction with a substrate than neutral ones.

The use of other solvents such as TBAc (t-butyl acetate), as an alternative to chlorinated solvents [34], did not furnish desired diketone 2. Interestingly, the use of HFIP as a solvent or in combination with DCE (Table S1, Entries 3–6) had a visible effect on the course of the reaction in terms of asymmetric induction and yield. It did affect the yield, increasing it from ~40% to >95% (¹H NMR) and it also gave compound 2 in the range of 76–91% ee, which is typical for the original cationic Rh-complex-based system [13]. For details, see Table S1.

It is worth noting that the use of [CpCo(P{OEt}₃)(trans-MeO₂CHC=CHCO₂Me)] precatalyst [35,36] was successful (Scheme 1). The initial attempt to catalyze cyclotrimerization at room temperature under blue LED irradiation failed to produce any product. However, carrying out the reaction at 140 °C under microwave irradiation for 2 h furnished compound 2 in 98% yield (¹H NMR). The formation of small amounts of unknown side products was observed (~2%). Lowering the reaction temperature (120 °C) and decreasing the reaction time to 30 min provided only traces of compound 2.

3. Materials and Methods

Experimental procedures are described in the Supplementary Materials Section. Figure S1: HPLC analysis: 19:81 e.r. (column Chiralpak IB (Heptane/i-PrOH = 90/10, flow rate 1 mL/min, temperature 25° C, UV 400 nm, t_major = 27.2 min; t_min = 18.9 min); Table S1: Cyclotrimerization of triyne 1 with [Rh(CH₂=CH₂)₂Cl]₂ precatalyst.

4. Conclusions

The above-mentioned results can be summarized in the following terms. Regarding the Ni-based air-stable precatalysts: (a) cyclotrimerization is feasible and efficient as the previously reported Rh-catalyzed methodology in terms of the conversion of 1 to the product; (b) the best results in terms of yields can be achieved when bidentate ligands with small bite angles such as dppm and dppBz were used; (c) interestingly, the highest efficacy regarding the yield of compound 2 (quantitative yield) was achieved in the presence of the PROPHOS ligand. As for asymmetric induction, it was low in most cases, which might be caused by a rather high reaction temperature. Interestingly, running the reactions in the presence of both bidentate as well as monodentate ligands provided similar asymmetric induction. However, the result of cyclotrimerization carried out in HFIP indicates that the proper choice of solvent might result in enhanced enantioselectivity (62% ee) which is much higher than those obtained with Ni(cod)₂/chiral ligand systems. As for Rh precatalysts, a comparison of results obtained with [Rh(CH₂=CH₂)₂Cl]₂ with those of Rh(cod)₂BF₄ precatalyst shows the same effectiveness. Finally, the [CpCo(P{OEt}₃)(trans-MeO₂CHC=CHCO₂Me)] precatalyst turned out to be highly efficient under microwave irradiation.

In conclusion, Ni and Co precatalysts are as efficient for cyclotrimerization as the previously developed Rh-catalytic system. Regarding asymmetric induction, further fine tuning of the reaction condition is needed, and the currently used Rh(I)/SEGPHOS system is still the most efficient one, albeit the results obtained with the Ni(0)/PROPHOS system in HFIP opens further possibilities for future endeavors.