Ti-Catalyzed Oxidative Amination Using Anilines

Abstract

In this report, Ti-catalyzed transfer hydrogenation from anilines to alkynes is leveraged to generate nitrenes from anilines in the Ti-catalyzed [2+2+1] synthesis of N-aryl pyrroles. While there are myriad methods for accessing nitrene reactive intermediates in chemical synthesis, methods for the direct transformation of amines into nitrene equivalents are uncommon. This transfer hydrogenation-coupled [2+2+1] pyrrole synthesis is catalyzed by a recently-reported bis(phenoxide) Ti complex, (TPO)Ti(NMe₂)₂ (TPO = (3,3″-di-tert-butyl-5,5″-dimethyl-[1,1′:2′,1″-terphenyl]-2,2″-bis(olate)). Preliminary mechanistic insight indicates that a balance of the competition between alkyne insertion into titanacycle Ti-C bonds versus Ti-C aminolysis at several points along the catalytic cycle is critical for productive catalysis over unwanted side reactions such as alkyne hydroamination or alkyne cyclotrimerization.

Graphical Abstract

Introduction

The pyrrole moiety is an important synthetic target, especially as a pharmaceutical building block.¹ As such new synthesis routes are constantly being explored, and there are a wide variety of current methods for pyrrole synthesis that each has its own advantages and disadvantages. One common method is the Paal-Knorr pyrrole synthesis which involves the condensation of an amine with a diketone.^2–4 These condensation methods are attractive owing to their simplicity of execution; however, the scope is limited to accessible diketones. Recently, we have developed Ti-catalyzed [2+2+1] syntheses^5,6 in which 2 equivalents of an alkyne and 1 equivalent of a “nitrene” are coupled to form the pyrrole (Figure 1A). This catalysis is turned over via oxidation with either aryl diazenes or alkyl/aryl azides as the nitrene source. While other multicomponent Ti-catalyzed reactions have been reported en route to the synthesis of heterocycles, this reaction is somewhat unique in the context of Ti catalysis toward fine chemicals, where most processes are reductive or redox-neutral hydrofunctionalizations such as hydroamination or hydroaminoalkylation.^7,8

Figure 1:

Ti-catalyzed nitrene transfer reactions. A: [2+2+1] pyrrole synthesis using azoarene nitrene sources with alkynes. B: nitrene coupled transfer hydrogenation to form imines. C: [2+2+1] pyrrole synthesis via aniline transfer hydrogenation (this work).

Transfer hydrogenations can be catalyzed by myriad transition metals^9–11 and organocatalysts.^12–14 However, Ti-catalyzed transfer hydrogenation remains rather rare.^15–17 Previously, we reported a nitrene-coupled transfer hydrogenation reaction (Figure 1B).¹⁶ This reaction transfers an H₂ equivalent through double propargylic deprotonation of a sacrificial equivalent of 3-hexyne by strongly basic Ti-NMe₂ ligands, leading to a masked Ti^II titanacyclopentyne that can be oxidized by PhNNPh to a Ti^IV imido. In this reaction the net effect is alkyne hydroamination, or the redox-neutral addition of RNH₂ across the triple bond. In this work, we sought the reverse reaction, where an alkyne could act as a hydrogen acceptor, thus ultimately delivering an oxidized “NR” nitrene unit from a simple amine and bypassing the need for nitrene precursor synthesis. Common nitrene precursors include high energy molecules such as azides and 2H-aziridines.¹⁸ The oxidation of amines to formal nitrene precursors is typically accomplished through oxidation with high valent iodine reagents, and a transfer hydrogenation route could provide an alternative and mild strategy to access these key reactive intermediates.¹⁹ Herein, we report a new method for [2+2+1] pyrrole synthesis using amines as the nitrene source, capitalizing on a unique transfer hydrogenation mechanism to turn over the catalyst with a sacrificial equivalent of alkyne as the hydrogen acceptor (Figure 1C).

Results and Discussion

Previously, our group¹⁸ and the Hultzsch group^20,21 have explored the utility of ortho-terphenoxide complexes for hydroamination. During attempts to catalyze the hydroamination of phenylpropyne with 2,6-dimethylaniline using the ortho-bis(phenoxide) catalyst (TPO)Ti(NMe₂)₂,²² we observed the pyrrole 1-(2,6-dimethylphenyl)-2,4-dimethyl-3,5-diphenyl-1H-pyrrole (1) along with its regioisomers (37.8% combined yield, 18.9 µmol, see Figure S2 for regioisomeric ratios) as the major product of the reaction, along with a small amount of the hydroamination product N-(2,6-dimethylphenyl)-1-phenylpropan-1-imine (2) (19.8% yield, 19.8 µmol) (Figure 2). Additionally, the hydrogenated products phenylpropene (3) (1.1% yield, 1.1 µmol) and 1,3-dimethyl-2,4-diphenyl-1,3-butadiene (4) (13.3% yield, 6.7 µmol) were formed as byproducts, along with and the alkyne trimerization product (5 + regioisomer; 4.7% combined yield, 1.5 µmol, see Figure S2 for regioisomeric ratios). The net transformation of this reaction is the oxidation of aniline through transfer hydrogenation to phenylpropyne, followed by formal [2+2+1] coupling of the oxidized aniline with further equivalents of phenylpropyne to yield the pyrrole.

Figure 2:

Reaction of PhCCMe with 2,6-dimethylaniline catalyzed by (TPO)Ti(NMe₂)₂ results in oxidative amination and [2+2+1] cyclization to yield 1 through transfer hydrogenation yielding 3 and 4 as reduced byproducts. Unwanted hydroamination (2) and alkyne cyclotrimerization (5) compete with the productive reaction. Ar = 2,6-Me₂C₆H₃

Each product of this reaction can be accounted for through a proposed catalytic manifold that incorporates established, precedented mechanisms (Figure 3). The key entry point into catalysis is the imido complex (TPO)Ti(NAr) (INT1) generated initially from aminolysis of the pre-catalyst (TPO)Ti(NMe₂)₂ by 2,6-dimethylaniline. [2+2] cycloaddition to of an alkyne to INT1 can form the azatitanacyclobutene INT2.^23,24 INT2 is the first branching point of catalysis, where either (1) aminolysis of INT2 can produce the hydroamination²⁵ product 2 (in this case undesired) and regenerate INT1; or (2) insertion of an additional equivalent of phenylpropyne into INT2 can form the azatitanacyclohexadiene INT3, en route to pyrrole formation.⁵ INT3 can then undergo reductive elimination to liberate the pyrrole (1) and generate a transient Ti(II) species INT4. INT4 can be intercepted by phenylpropyne to form the titanacyclopropene INT5, which is another catalytic branching point. Aminolysis of INT5 by an equivalent of 2,6-dimethylaniline can then regenerate the imido INT1 and liberate the transfer hydrogenated Z-alkene 3, closing the catalytic cycle.^26–28 Alternatively, a second equivalent of alkyne can insert into INT5 to give titanacyclopentadiene INT6,^29,30 which can similarly undergo aminolysis by 2,6-dimethylaniline to give the transfer hydrogenated, reductively coupled diene 4 and regenerate INT1. Finally, INT6 could undergo reaction with a 3^rd equivalent of phenylpropyne en route to (undesired) alkyne cyclotrimerization,³¹ which would generate arene 5 and regenerate the Ti(II) intermediate INT4. To identify the source of H₂ in the system, a reaction with 2,6-dimethylaniline-d₂ (89% D) was carried out (Figure 4). This labelling reaction resulted in significant deuterium incorporation into 2 (>99%), 3 (68%), and 4 (76%), indicating that aniline is the primary hydrogen source for the reduction products (Figure S16). Interestingly, incomplete D incorporation was observed in 3 and 4, which may indicate that other pathways involving acid/base chemistry are also in play such as C-H activation or propargylic deprotonation, which are not uncommon with strongly basic Ti-N species.^16,32,33

Figure 3:

Proposed interconnecting pathways for transfer hydrogenation-coupled [2+2+1] pyrrole synthesis from alkynes and anilines. Parasitic hydroamination (via aminolysis) and cyclotrimerization catalytic processes are shown in teal.

Figure 4.

Isotope labeling reveals that 2,6-dimethylaniline is the source of H₂ for the hydroamination product 2 and the transfer hydrogenated products 3 and 4. Yields reported relative to 2,6-dimethylaniline-d₂.

Having established a rough reactivity landscape for transfer hydrogenation-coupled [2+2+1] pyrrole formation, we next sought to optimize the reaction and favor formation of 1 over the unwanted hydroamination (2) and cyclotrimerization (5) byproducts (Table 1). From a perspective of atom-economy, an ideal phenylpropyne : 2,6-dimethylaniline ratio would be 3 : 1 based on the reaction stoichiometry (2 alkynes needed for the pyrrole 1, and 1 alkyne serving as the hydrogen acceptor forming 3). However, conducting the reaction at the 3 : 1 ratio (Table 1, entry D) results in significant competition from the unwanted hydroamination reaction, yielding only a 2.2 : 1 ratio of 1 to 2. Formation of the hydroaminated 2 occurs because of the competition between aminolysis (forming 2) and 2nd alkyne insertion (forming INT3, en route to 1) from INT2 (c.f. Figure 3). Increasing the concentration of alkyne relative to aniline (Table 1, entries A-C) thus favors productive formation of 1 over 2, resulting in good yields and high selectivity for 1, with a maximum yield of 80% (based on the limiting reagent, 2,6-dimethylaniline) and a 6.8 : 1 selectivity at 5.2 equivalents of phenylpropyne (Table 1, entry B). Conversely, at lower concentrations of alkyne (Table 1, entries D-F), hydroamination competition is significant, resulting in lower (56%) yields of 1 and selectivities as low as 1.1 : 1 (Table 1, entry F). The competition between aminolysis and alkyne insertion in this multicatalytic cycle can also be observed when comparing the reactions with isotopically-labeled 2,6-dimethylaniline (Figure 4 vs. Table 1, Entry C). Here, aminolysis with 2,6-dimethylaniline-d₂ should be globally slower than with aminolysis with 2,6-dimethylaniline-H₂. As a result, the reactions with 2,6-dimethylaniline-d₂ have a higher percentage of all products that result from more productive alkyne vs amine competition: a higher ratio of 1 : 2 (owing to competition at INT2); a higher ratio of 4 : 3 (owing to competition at INT5); and significantly more cyclotrimerization to 5 (owing to competition at INT6). Unfortunately, these competition reactions complicate further optimization of the reaction’s atom economy: the excess alkyne conditions necessary to favor 1 over 2 negatively impacts the selectivity of aminolysis from INT5 to produce 3 (the most atom economical transfer hydrogenation), instead favoring alkyne coupling to INT6 prior to aminolysis to 4. Thus, under optimized conditions, the overall reaction stoichiometry is closer to requiring two sacrificial alkynes (making 4) for the transfer hydrogenation.

Table 1:

Optimization of alkyne : aniline ratio in transfer hydrogenation-coupled [2+2+1] pyrrole formation.^a

Entry	A	B	C	D	E	F
X : Y Ratio	6	5.2	4.4	3	2.4	1.8
% Conversion PhCCMe	81	79	87	98	99	98
% Conversion ArNH2	98	98	98	85	81	71
% Yield 1 (µmol)	79 (40)	75 (37)	80 (40)	63 (31)	50 (25)	56 (28)
% Yield 2 (µmol)	18 (9)	12 (6)	11 (7)	28 (14)	32 (16)	57 (28)
1 : 2 Selectivity	4.4 : 1	6.8 : 1	6.3 : 1	2.2 : 1	1.6 : 1	1.1 : 1
Yield 3 (µmol)	8	5	6	14	13	18
Yield 4 (µmol)	23	13	13	14	9	10
Yield 5 (µmol)	15	7	6	7	5	4

^aConditions: Phenylpropyne (170–280 µmol), 2,6 dimethylaniline (50–200 µmol), 10 µmol (TPO)Ti(NMe₂)₂, in 0.55 mL tol-d₈ with dodecane standard (20 µmol), 130 °C, 20 h, sealed in J-Young NMR tube. % yields of 1 and 2 are relative to limiting reagent aniline (entries A-C) or alkyne (entries D-F); yields of 3, 4, and 5 are provided in absolute molar quantities to simplify comparison.

Next, a small scope of alkynes and anilines were examined by reacting 0.250 mmol (4.5 equiv) alkyne with 0.056 mmol aniline (1 equiv) with catalyst (TPO)Ti(NMe₂)₂ in toluene-d₈ (Table 2). First, a suite of alkynes was reacted with 2,6-dimethylaniline (Table 2, entries A-D, Table S1, entries M-R). Under these conditions, phenylpropyne reacts effectively with 2,6-dimethylaniline (Table 2, entry A), resulting in a 80% yield of 1A. The electron rich phenylpropyne derivative, (p-OMePh)CCMe (Table 2, entry B), underwent pyrrole formation with 2,6-dimethylaniline with a somewhat lower yield of 1B (43%) to unsubstituted phenylpropyne, despite similar amounts of alkene and diene formed. In contrast, electron deficient (p-CF₃Ph)CCMe showed very low conversion with 2,6-dimethylaniline, and the major product of the reaction was the dienamine that results from protonation of INT3 (See Figure S25). The p-CF₃ functional group remains a problematic group for reactions catalyzed by Ti-imidos, and often leads to decomposition.²² 3-hexyne (Table 2, entry D) performs well in the reaction, leading to a 67% yield of the pyrrole 1D along with less alkyne trimerization byproduct than the reactions with phenylpropyne derivatives. The success of 3-hexyne is particularly important, as it demonstrates that the transfer-hydrogenation coupled [2+2+1] pyrrole synthesis is not limited to electronically-activated alkynes. Additional internal (TMSCCMe, ⁱPrCCMe) and terminal (PhCCH, ⁿBuCCH, ^tBuCCH) were also examined (Table S1). Unfortunately, the internal alkynes failed to undergo the reaction (which is consistent with their poor reactivity toward Ti=NR [2+2] cycloaddition), while alkyne trimerization outcompeted productive pyrrole formation for the terminal alkynes.

Table 2:

Examination of aniline and alkyne scope in transfer hydrogenation-coupled [2+2+1] pyrrole synthesis.^a

Entry	R1	R2	R3	% Conversion (aniline)	% Yield 1 (µmol)	% Yield 2 (µmol)	Yield 3 (µmol)	Yield 4 (µmol)	Yield 5 (µmol)
A	2,6-Me2C6H3	Ph	Me	98	80 (40)	11 (7)	6	13	7
B	2,6-Me2C6H3	p-(OMe)C6H4	Me	93	43 (24)	12 (6)	7	12	6
C	2,6-Me2C6H3	p-(CF3)C6H4	Me	38	13.4* (16)	5 (3)	0	0	0
D	2,6-Me2C6H3	Et	Et	88	67 (38)	0 (0)	0	13	4
E	2,6-iPr2C6H3	Ph	Me	45	30 (17)	0	5	10	6
F	2,6-iPr2C6H3	Et	Et	32	24 (14)	0	<1	5	17
G	Ph	Ph	Me	>99	2 (1)	77 (43)	0	0	0
H	Ph	Et	Et	>99	4 (2)	53 (30)	0	2	5
I	p-(OMe)C6H4	Ph	Me	46	0 (0)	75 (42)	<1	3	3
J	p-(OMe)C6H4	Et	Et	>99	2 (1)	52 (30)	<1	1	7
K	p-(OCF3)C6H4	Ph	Me	>99	3 (2)	57 (32)	0	<1	<1
L	p-(OCF3)C6H4	Et	Et	>99	6 (3)	56 (31)	3	<1	2

^aConditions: 4.5 equiv. alkyne (250 µmol), 1 equiv. aniline (56 µmol), 17% catalyst loading (10 µmol), in 0.55 mL tol-d₈ with dodecane standard (68 µmol). 130 °C, 20 h, sealed in J-Young tube. % yields of 1 and 2 are relative to aniline (limiting reagent); yields of 3, 4, and 5 are provided in absolute molar quantities to simplify comparison.

^*identified as dienamine rather than pyrrole; see Figure S25.

Next, the scope of anilines was examined with both phenylpropyne and 3-hexyne, revealing a quite narrow steric window for the transfer hydrogenation-coupled [2+2+1] reaction. Reactions with more sterically encumbered 2,6-diisopropylaniline (Table 2, entries E and F) still yielded productive catalysis to form pyrroles 1E and 1F, albeit with lower yields (24–30%) than reactions 2,6-dimethylaniline (67–71%). Interestingly, these reactions showed no formation of the hydroamination products 2E or 2F, which is likely because all aminolysis pathways with the sterically encumbered anilines are comparatively slower. In fact, this aminolysis relative rate suppression can also be seen in the greater propensity for the formation of the cyclotrimerization products 5E and 5F in the reactions with 2,6-diisopropylaniline. Reactions of phenylpropyne and 3-hexyne with aniline (Table 2, entries G and H) result primarily in alkyne hydroamination. Aniline has frequently been used in both phenylpropyne and 3-hexyne hydroamination reactions.^34–36 Similar results are seen with electronically-modified p-substituted anilines (Table 2, entries I-L) regardless of the N-H pKa.³⁷ Taken together, these results indicate that with sterically unencumbered anilines the rates of aminolysis of INT2 effectively outcompete alkyne insertion, and that further catalyst modification is needed to promote the transfer hydrogenation-coupled [2+2+1] reaction.

Although Ti-catalyzed alkyne hydroamination has been known for decades, (TPO)Ti(NMe₂)₂ is the first catalyst that instead performs transfer hydrogenation-coupled [2+2+1] pyrrole synthesis under conditions that would normally lead to alkyne hydroamination. To explore the specific role of the catalyst structure further, a suite of structurally related Ti complexes was investigated as potential catalysts for the transfer hydrogenation-coupled reaction with phenylpropyne and 2,6-dimethylaniline (Table 3). First, the simple imido precatalyst [py₂TiCl₂NPh]₂ (Table 3, catalyst B) which is capable of alkyne hydroamination and is perhaps the most robust precatalyst for [2+2+1] pyrrole synthesis using nitrenes,^5,6 was examined. Under optimized reaction conditions, catalyst B was an ineffective catalyst for our reaction of interest. Next, Ti(NMe₂)₄ (Table 3, catalyst C), which is a simple and active alkyne hydroamination precatalyst, was investigated, which led to a 41% yield of the hydroamination product 2 under the optimized conditions, along with no detectable pyrrole, alkyne reduction, or alkyne trimerization. The negative catalytic results with B and C demonstrate that the transfer hydrogenation-coupled [2+2+1] reaction is not simply a function of reaction conditions/stoichiometry, but instead a function of catalyst effects. This observation next led to the examination of structurally similar bis(phenoxide)Ti complexes (Table 3, catalysts D and E) to understand the ligand structure requirements better. First, an in situ formed “(Ar’O)₂Ti(NMe₂)₂” catalyst, containing the same 2-tBu-4-Me substitution pattern as TPO, was examined (Table 3, catalyst D), which also resulted in very low yields of only alkyne hydroamination. (ONO)TiBn₂ (Table 3, catalyst E) had previously been shown to substoichiometrically produce pyrroles during 2-butyne hydroamination,³⁸ but under optimized conditions here led only to the formation of a gel-like material with 91% conversion of alkyne, which we presume is the polymerization product of phenylpropyne.^39,40 Taken together, this examination of potential precatalysts reveals the necessity of both the bis aryloxide and the ortho substitution on the TPO framework for productive catalysis. Overall, only sterically bulky amines in combination with the sterically encumbered (TPO)Ti catalyst show catalytic transformation into pyrrole. The combination of bulk of the catalyst and the substrates work together to decrease the rate of protonolysis toward imine formation, presumably by increasing the association energy of the aniline to the metal center as compared to the association energy of alkyne, allowing for alkyne insertion. According to DFT calculations (See SI page S102 for computational details), the bulky ligand apparently disfavors aniline coordination at the [2+2] cycloadduct stage, as the ΔG for binding aniline to the metallacycle for the TPO ligand is 6.25 kcal/mol compared to 2.7 kcal/mol for catalyst B, where hydroamination outcompetes the second alkyne insertion.

Table 3.

Examination of alternative precatalysts for the transfer hydrogenation-coupled [2+2+1] pyrrole synthesis.

Catalyst	A	B	C	Da	E b
Aniline conv. (%)	98	36	100	74	88
% Yield 1	71	-	-	-	-
% Yield 2	11	-	41	29	12
Yield 3 (µmol)	6	-	-	-	-
Yield 4 (µmol)	13	-	-	-	<1
Yield 5 (µmol)	6	-	-	-	2

Conditions: 4.4 equiv. phenylpropyne (0.250 mmol), 1 equiv. aniline (0.057 mmol), 10% catalyst loading (0.010 mmol), in 0.55 mL tol-d₈ with dodecane standard (0.020 mmol). 130 °C, 20 h, sealed in J-Young tube. Yields are relative to alkyne.

^aCatalyst synthesized in situ through addition of 2 equiv. of 2-(tert-butyl)-4-methylphenol to Ti(NMe₂)₄

^bSolid formed in NMR tube, presumably polymerized phenylpropyne.

Conclusion

In conclusion, we have reported a new strategy for accessing formal nitrene units through a transfer hydrogenation from anilines to alkynes. This strategy allows for the use of anilines as starting materials in Ti-catalyzed oxidative amination reactions, subverting the need for oxidized sources of nitrogen such as azides or diazoarenes. Preliminary mechanistic analysis indicates that the transfer hydrogenation-coupled [2+2+1] reaction necessarily competes with alkyne hydroamination and alkyne cyclotrimerization, in which the competition is a function of the sterics and electronics of both alkyne and aniline. A small screen of catalysts reveals that the (TPO)Ti catalyst framework is currently uniquely capable of carrying out this transformation; however, the sensitivity to the substrate structure indicates that a wider sweep of structure-activity relationships may reveal this as a more general reaction, ultimately unlocking chemoselective transfer hydrogenation coupled reactions or regioselective pyrrole syntheses.⁴¹ Moving forward, we are exploring other hydrogen acceptors in an effort to broaden the utility of this reaction.