Examination of Dianionic Diamide Ligand Structural Effects on Ti-Catalyzed Hydrohydrazination of Terminal Alkynes

Abstract

Ti-catalyzed alkyne hydrohydrazination of terminal alkynes using 1,1-disubstituted hydrazines is reported. Here, a variety of bi- or tridentate dianionic diamide or diamidoamine ligated Ti=NNPh₂ catalysts were examined, wherein fast and selective Ti=NNPh₂ catalysts have ligands with a “goldilocks” intermediate level of steric environment. Ti=NNPh₂ catalysts with ligands of high/medium steric bulk showed slower reactivity compared to the optimal catalysts. Catalysis with Ti complexes with sterically less encumbered ligands is extremely slow (requiring 5–14 days to completion). Development of a fast and selective diamidoamine catalyst with flanking N-SiMe₂Ph groups led to an expansion of the hydrazine scope and a structurally diverse set of hydrazones.

Graphical Abstract

INTRODUCTION

Hydroamination, the addition of N-H bond of an amine across the carbon-carbon multiple bonds (alkenes/ alkynes), is a particularly important strategy for C-N bond formation because it is 100% atom economic and leverages simple starting materials. Catalysts based on many metals (e.g. Ti,^1–3 Ru,⁴ Rh,^5,6 Pd,^7,6 Ln,^8,9 Au,^10,11 An,^12–14), have been reported for the hydroamination of alkenes and alkynes. Compared to hydroamination, related alkyne hydrohydrazination reactions that yield hydrazones are relatively underdeveloped (Figure 1). Hydrazones are versatile reagents in synthetic chemistry:^15–19 for example, chiral hydrazones can be used in diastereoselective C-C bond formation, and¹⁹ N-aryl hydrazones can be further functionalized to indoles in the presence of Zn salts.^20–23 After the seminal report of Ti-catalyzed alkyne hydrohydrazination by the Odom group²⁴ in 2002 with Ti amide and pyrrolide catalysts, several studies^25–36 have been conducted to expand the scope of the alkyne hydrohydrazination reaction with a variety of alkynes and several (Ph₂NNH₂, Me₂NNH₂, and PhMeNNH₂) hydrazines, and to discover new catalysts.^37,38 In most of the studies, high temperature (>60 °C) or high catalyst loading (10 mol%) are required. In that way, there is value to find other catalysts for alkyne hydrohydrazination that can operate under milder reaction conditions with a broader range of hydrazines.

Figure 1.

Overview of Ti-catalyzed alkyne hydrohydrazination, including select examples of successful catalyst classes.

In 2012, Mountford reported hydrohydrazination of a terminal arylalkyne (4-ethynyltoluene) with 1,1-diphenylhydrazine (Ph₂NNH₂) in presence of catalyst 1i (Figure 1, bottom right; R = ⁱPr), a Ti complex containing a tridentate, dianionic diamidoamine ligand with flanking ⁱPr groups.³⁹ This catalyst is particularly notable because it can catalyze arylacetylene hydrohydrazination with Ph₂NNH₂ at mild temperatures. During a prior study on Ti-catalyzed alkyne diamination with hydrazines (which shares a common [2+2] cycloadduct intermediate INT1 with alkyne hydrohydrazination), we found that a related catalyst with flanking SiMe₃ groups (R = SiMe₃, 1a), was also particularly efficient at hydrohydrazination of terminal aliphatic alkynes with 1-methyl-1-phenylhydrazine, although it catalyzed diamination with other alkynes.⁴⁰ The divergent behavior of 1a with terminal alkynes likely results from intrinsic substrate effects, where terminal alkynes generate sterically unencumbered intermediate INT1 that can (1) undergo facile intermolecular hydrazinolysis and (2) has less steric pressure for intramolecular metallacycle collapse. Based on this initial observation, we herein report a more detailed examination of diamidoamine (NNN) catalyst structural effects on terminal alkyne hydrohydrazination and provide an expanded scope of hydrazine structures capable of undergoing hydrohydrazination.

RESULTS AND DISCUSSION

Reaction Optimization.

We began our studies examining the hydrohydrazination of 1-hexyne (2a) with 1,1-MePhNNH₂ (3a) catalyzed by 1a, starting with the same reaction conditions (10 mol%, 33 °C, 0.032 M) as our previous report.⁴⁰ We chose 1-hexyne (2a) as the standard substrate because it showed preliminary reactivity in the previous report, while aryl alkynes were too reactive. These conditions led to quantitative yield of 4a after 48 h, with complete Markovnikov selectivity and only the hydrazone tautomer (4ah) observed. In our prior work, we observed that lower concentration typically led to alkyne diamination rather than hydrohydrazination. Since there is excellent selectivity for hydrohydrazination by 1a even at low concentration, we next examined reactions at higher concentration to increase the reaction rate, albeit in a nonsystematic fashion. At 1 M concentration with 5% catalyst loading at room temperature, 97% consumption of 3a in 2 h was observed, producing 93% yield of 4a, although now predominantly forming the enamine tautomer (15:85 4ah:4ae). Heating the reactions to 40 °C, or running the reaction longer, led to isomerization of the enamine to the hydrazone with reasonably high fidelity. For example, at 40 °C we observed a complete conversion of 3a with 98% combined yield with a hydrazone : enamine ratio of 72:28 after 2 h, which completely converts to hydrazone after 21.5 h. The reaction also proceeded relatively well (59% yield) with a 2.5% catalyst loading at room temperature. Interestingly, only at the 2.5% catalyst loading are both E:Z stereoisomers (4:1) of the hydrazone observed.

Catalyst Structure Effects.

Next, we examined other (NNN)Ti=NNPh₂ (1b-1j) complexes as hydrohydrazination precatalysts in the reaction of 2a with 3a under the optimal conditions derived from Table 1 in an effort to observe catalyst steric and/or electronic effects (Table 2). In order to capture differences in initial rates as well as final/total productivity, reactions were examined by ¹H NMR spectroscopy after 2 h and then followed until completion. The left-hand column of Table 2 reflects catalyst productivity after the 2 h period, while the right column provides the time at which conversion/yield/isomerization of the reaction plateaued with each catalyst. Interestingly, the hydrazone : enamine tautomeric ratios of 4a changes over time in all cases and is catalyst-dependent, implicating that the Ti catalyst is involved in the tautomerization process. The E- and Z-hydrazones are computed to be 4.3 kcal/mol and 2.6 kcal/mol more stable than the enamine tautomer respectively (see SI Page 74 and Figures S66–68), further indicating that the observed tautomeric ratio differences (and E/Z stereoisomerism differences) are a kinetic phenomenon.

Table 1.

Reaction optimization of 2a hydrohydrazination with 3a in presence of 1a.^a

1a (mol%)	Conc. (M)	T (°C)	Time (h)	Conv. (%)b	Yield (%)b	4ah:4ae
10	0.032	33	48	100	100	100:0
5	1	r.t.	2	97	93	15:85
5	1	40	2	100	98	72:28
2.5	0.78	r.t.	47	70	59	23:77

^aconditions: 0.0211 mmol (5 mol %) 1a, 0.506 mmol (1.2 equiv) alkyne, 0.422 mmol (1 equiv) hydrazine, 0.42 mL C₆D₆.

^bdetermined by ¹H NMR spectroscopy using Ph₃CH (40 mg, 0.1639 mmol) as an internal standard.

Table 2.

Reactivities of other Ti=NNPh₂ in the hydrohydrazination of 2a with 3a^a

Comparison of all catalysts at t = 2 h						Comparison of catalysts at terminal conv. (t = variable)
Entry	Precatalyst R =	t (h)	% conv.b	% yieldb	4ah:4aec	t (h)	Final % conv.b	Final % yieldb	Final 4ah:4aec	E:Zd
1	SiMe3 (1a)	2	100	98	72:28	21.5	100	98	100:0	n.d.
2	SiMe2Et (1b)	2	82	77	11:89	53.5	98	90	40:60	5.7
3	SiEt3 (1c)	2	23	18	10:90	48	95	83	39:61	9.1
4	SiMe2iPr (1d)	2	62	54	19:81	50	89.5	82	31:69	13.1
5	SiMe2tBu (1e)	2	61.5	51	11:89	51	86	77	38:62	7.4
6	SiMe2Ph (1f)	2	100	94	34:66	44	100	94	88:12	27
7	SiMePh2 (1g)	2	82	75	100:0	25	96	90	100:0	1.4
8	SiPh3 (1h)	2	62.5	59	15:85	50	73	72	65:35	1.67
9	iPr (1i)	2	6	6	30:70	125	70	65	54:46	1.94
10	Me (1j)	2	7	0	0	336	95	88	100:0	12.8
11	Cat 5e	2	35	24	29:71	67	71	58	53:47	3.3
12	Cat 5e,f	2	44	32	7:93	67	84	55	10:90	n.d.

^aConditions: 5 mol% [Ti], 1.2 eq. of alkyne, 1 eq. of hydrazine, 1 M in C₆D₆, 40 °C.

^bDetermined by ¹H NMR spectroscopy using Ph₃CH as an internal standard.

^dE:Z ratio of the final hydrazone

^eWith 5 mol% catalyst 5 instead (see Figure 2 for structure).

^fReaction with PhCCH (2b) instead of 2a.

Like 1a, the reaction with slightly more encumbered 1b (R = -SiMe₂Et) resulted in high (82%) conversion of 3a in 2 h at 40 °C to produce 4a in 77% combined yield (entry 2). Interestingly, with catalyst 1b the enamine of 4a remained the major tautomer (11:89 4ah:4ae) after 2 h. After 2 days (53.5 h), 98% of 3a is converted to yield 90% hydrazone, with a final hydrazone : enamine ratio of 40:60. Furthermore, with catalyst 1b E/Z isomerism of the hydrazone (5.7:1) was observed, which was not observed with the starting catalyst 1a. With sterically more encumbered catalyst 1c (R = -SiEt₃), the reaction is sluggish, resulting in 23% conversion (18% yield) in 2 h and a hydrazone : enamine ratio of 10:90. Catalysis continues to progress with 1c, and after 48 h, 83% yield of 4a was obtained at almost full conversion of 3a (entry 3). Similarly, reactions catalyzed by 1d (R = SiMe₂ⁱPr) and 1e (R = SiMe₂^tBu) were slower than catalysis by 1a, producing only approx. 50% yield after 2 h before reaching final yields of approx. 80% after 50 h (entry 4, 5). Although 1d and 1e have a larger substituent (ⁱPr, ^tBu) relative to 1c (Et), their effective % buried volumes are likely lower because the large groups can rotate away from the Ti center and instead have rate profiles similar to 1b.

Importantly, adding phenyl groups on the ligand backbone of the Ti catalysts (1f, 1g; R = -SiMe₂Ph or -SiMePh₂ respectively) showed comparable reactivities to 1a or 1b (entry 6, 7). For example, with 1f complete conversion of 3a occurs in 2 h with 94% combined yield and a 34:66 ratio of hydrazone to enamine, which after 44 h converts fully to hydrazone. Interestingly, only the hydrazone tautomer was observed in catalysis with 1g, even after just 2 h. Catalysis with 1h (entry 8) with even more sterically demanding -SiPh₃ substituent also proceeds well, albeit at a slightly decreased rate (72% yield after 50 h) similar to other medium-bulky catalysts 1d or 1e.

Moving to less sterically encumbered N-substituents, catalyst 1i (R = -iPr) showed limited reactivity with 2a, leading to 6% conversion/yield after 2 h and only reaching good (70%) conversion and yield (65%) after 5 days (entry 9). Similarly, 1j (R = -Me) was even slower, reaching full conversion (95%) and yield (88%) after 2 weeks (entry 10), and producing predominantly the hydrazone tautomer of 4a. Previously, we demonstrated that smaller NNN ligands like those in 1j can lead to bridging hydrazide dimers,⁴⁰ which likely impedes productive catalysis through off-cycle dimerization.⁴¹

Finally, we next examined whether a tridenate diamide ligand was necessary for productive hydrohydrazination and synthesized 5 as a test case (Figure 2). Reaction of py₃TiCl₂=NNPh₂ and the dilithium salt 5-Li₂ in cold, dry toluene produced (NN)Ti=NNPh₂(py) (5) in 70% yield. With this ligand framework, it appears important to have the steric protection of -Dipp group on the NN ligand: similar attempted reactions with -Mes, -Xylyl groups in place of -Dipp instead yielded intractable mixtures.

Figure 2.

Synthesis of diamide precatalyst 5.

Reaction of 2a and 3a catalyzed by 5 resulted in 35% conversion and 24% yield of 4a (29:71 ratio of h:e) after 2 h, and a 71% conversion and 58% yield of 4a (53:47 ratio of h:e) after 67 h (entry 11). Thus, while hydrohydrazination catalysis is successful with the bidentate NN ligand, its rates are more comparable to the slower (too bulky, or not bulky enough) tridentate NNN ligands—indicating that either the sterics of the -Dipp groups inhibits catalysis or more facile dimerization occurs because of additional open coordination sites on 5.

Interestingly, 5 is also a somewhat active hydrohydrazination catalyst for phenylacetylene (2b) (entry 12), forming 32% yield of hydrazone (mixture of both regioisomers) on 44% conversion of 3a after 2 h, or 55% yield (both regioisomers) at 87% conversion after 67 h. Previously, we reported that 1a or 1f only produced intractable mixtures with terminal aryl alkynes such as 2b because they were too reactive.⁴⁰ In this regard, catalysis with 5 and arylacetylenes occurs in a manner more similar to the less-reactive 1i precatalyst initially reported by Mountford.

In summary, it can be said that Ti complexes with silyl substituted NNN ligands are better hydrohydrazination catalysts compared to the Ti complexes with alkyl substituted NNN ligands. While all of these catalysts likely proceed through the same mechanism with rate-determining hydrazinolysis,³⁸ the less sterically-encumbered alkyl substituted 1i and 1j suffer from off-cycle dimerization that reduces reactivity.^{40–41,42,43} Out of the all the silyl-substituted diamide ligands, the optimum level sterics is required for efficient catalysis lies around the -SiMe₃ and SiMe₂Ph size, where additional sterics likely slows down intermolecular steps such as cycloaddition or hydrazinolysis.

Hydrazine Substrate Scope.

Having established that precatalyst 1f is particularly effective at hydrohydrazination of 2a, we next explored hydrohydrazination with various differently substituted hydrazine derivatives (3b-3f), which all underwent successful hydrohydrazination within ~ 6 h with 1f (Table 3). In all cases, both tautomers were observed in crude reaction mixtures, but isolated products showed only hydrazone isomers in various E/Z ratios. Electron-rich 1-methyl-1-(4-methylphenyl)hydrazine (3b) and 1-methyl-1-(4- methoxyphenyl)hydrazine (3c) produced the desired hydrazone 4b and 4c in excellent yield (78–85%). Electronically neutral 1-methyl-1-(4-fluorophenyl)hydrazine (3d) generated 83% hydrazone 4d. Electron-deficient derivatives such as 1-methyl-1-(4-chlorophenyl)hydrazine (3e), 1-methyl-1-(4-bromophenyl)hydrazine (3f) underwent successful hydrohydrazination with 1f to produce 4e-4f in excellent yields (77–80%). We also tried two other 1-alkyl-1-phenylhydrazines (3g, 3h), which also worked well under the mentioned reaction conditions. 1-Ethyl-1-phenylhydrazine (3g) resulted in 74% hydrazone 4g in 2.5:1 E/Z ratio after 6 h. Similarly, 1-isopropyl-1-phenylhydrazine (3h) produced 65% hydrazone 4h in 1.9:1 E/Z ratio, although the reaction took longer time (~ 30 h) to finish.

Table 3.

Hydrazine substrate scope for the hydrohydrazination of 2a catalyzed by 1f^a.

^aConditions: 5 mol% 1f, 1.2 eq. of alkyne, 1 eq. of hydrazine, 1 M in C₆D₆, 40 °C.

^b0.66 M in C₆D₆.

^c0.57 M in C₆D₆.

^dDetermined by ¹H NMR spectroscopy using Ph₃CH as an internal standard.

^e0.198 M in C₆D₆.

^f0.96 M in C₆D₆.

1,1-Diarylhydrazine derivatives (3i−3k) are also good substrates for hydrohydrazination, yielding high-yield reactions with catalyst 1f. However, compared to N-alkyl-N-aryl hydrazines (3b-3f), they react more slowly (70 – 120 h) with 2a. For example, reaction of 1,1-diphenylhydrazine (3i) takes > 3 days for full conversion to produce 76% of 4i. Electron-rich (3j) and electron-poor (3k) 1,1-diarylhydrazine derivatives produced the desired products (4j-4k) in good to moderate yields (82–57%) after 70 – 120 h, respectively. Due to the poor solubility of 3l in benzene, the yield of 4l is compromised.

The reaction of 1-aminopiperidine (3m) with 2a produced 37% of 4m after 2 days. Unfortunately, the reaction of 1,1-dimethylhydrazine (3n) with 2a only produced trace amount of hydrazone, probably due to the instability of (NNN)Ti=NNMe₂ intermediate, which quickly dimerizes or decomposes in the reaction mixture.^23,42,43 Similarly, the reaction with mono-substituted hydrazine such as 3o also didn’t result in successful hydrohydrazination, probably due to rapid decomposition of 1f in presence of hydrazine.⁴⁰

CONCLUSION

The catalytic alkyne hydrohydrazination reactivity of 10 different diamido-ligated Ti=NNPh₂ complexes (1a-j) with varying sterics and electronics was examined to understand the effects on reaction rate and overall catalytic productivity. In all cases, alkyne hydrohydrazination reactivity prevailed over the related diamination reaction, indicating the strong preference for terminal alkyne substrates to undergo hydrohydrazination. Overall, it can be concluded that Ti precatalysts with N-SiR₃ substituents (1a-h) are better (faster) for hydrohydrazination compared to N-R substituted catalysts (1i-j, 5). Ti complexes with intermediate ligand sterics (1a, 1b, 1f-g) perform the best compared to others with too much (1c-e, 1h) or too little sterics (1i-j). Interestingly, although there is a narrow steric window for rapid catalysis, a much wider range of complexes ultimately lead to productive, medium-to-high yielding catalysis, albeit over much longer timeframes. In situ analysis of the catalytic reactions reveals that enamine tautomers appear to be formed first, which undergo catalyst-dependent tautomerization to the thermodynamically favored hydrazone over time. In addition to catalyst structure exploration, we took the opportunity to carry out a small hydrazine scope study with precatalyst 1f, revealing a broad tolerance of 1-alkyl-1-aryl hydrazines (3a-h), while diaryl hydrazines (3i-l) react more slowly. Some dialkyl hydrazines are tolerated but are generally less effective substrates.

Supplementary Material

The Supporting Information is available free of charge on the ACS Publications website.

NMR spectra for new compounds and reactions, and computational methods (.pdf)

Coordinates for all computed structures (.xyz)