Rh(III)-Catalyzed Imidoyl C–H Carbamylation and Cyclization to Bicyclic [1,3,5]Triazinones

Abstract

A Rh(III)-catalyzed synthesis of bicyclic [1,3,5]triazinones from a diverse array of imines coupled with ethyl (pivaloyloxy)carbamate is reported. The preparation of [5,6]- and [6,6]-bicyclic heterocycles substituted with aryl, alkyl and alkoxy groups demonstrated a broad reaction scope. The efficiency of this approach was further enhanced with the development of a three-component variant featuring in situ imine formation. X-ray crystallographic characterization of a rhodacycle formed by imidoyl C-H activation provides support for the proposed mechanism.

Graphical Abstract

Fused heterocycles with ring-junction nitrogens occur in many approved drugs and clinical candidates,¹ and we have developed catalytic imidoyl C–H functionalization/annulation as a general approach for their preparation. This strategy enables the preparation of heterocycles displaying diverse functionality because the condensation of abundant aldehydes and amines provides straightforward access to an enormous number of imines that can undergo annulation with different types of coupling partners. We have previously reported the synthesis of N-fused [5,6]- and [6,6]-bicyclic heterocycles via Rh-catalyzed imidoyl C–C bond formation using alkynes, diazoesters, and sulfoxonium ylides as coupling partners (Scheme 1A).^2,3 Although less explored, we have also shown that catalytic imidoyl C–N bond formation is viable for the construction of azolo[1,3,5]triazines using dioxazolones as coupling partners (Scheme 1B).⁴

Scheme 1.

Heterocycle Synthesis via Imidoyl C–C and C–N Bond Formation

To broaden the scope of nitrogen heterocycles readily accessible via imidoyl C–H functionalization, we sought to further explore this strategy with other coupling partners. Herein, we report a rapid, new entry to fused bicyclic [1,3,5]triazinones 3⁵ using ethyl (pivaloyloxy)carbamate, 2,^6,7 as a coupling partner with imines 1 derived from diverse and commercially available aldehydes and aminopyridines or aminoimidazoles (Scheme 1C). Imine carbamylation and cyclization proceeded with a broad scope with respect to steric and electronic modification and functional group compatibility. Moreover, to further increase the efficiency of this method, a one-pot three-component protocol was developed in which imine formation occurs in situ from aldehydes 4 and amines 5. This three-component approach also expands scope to include annulations via in situ preparation and reaction of imines derived from enolizable aliphatic aldehydes. X-ray crystallographic characterization of a rhodacycle formed by imidoyl C–H activation, and demonstration of its catalytic competence, provides support for our proposed catalytic cycle.

After a thorough study of reaction parameters for the annulation of imine 1a to give 3a, we selected ethyl (pivaloyloxy)carbamate, 2, as the carbamylation reagent, the commercially available and air stable cationic catalyst [Cp*Rh(MeCN)₃][SbF₆]₂, pivalic acid (PivOH) as an additive, and 1,2-dichloroethane (DCE) as the solvent at 60 °C for 20 h (entry 1, Table 1). Other (pivaloyloxy)carbamate derivatives, ethyl N-chlorocarbamate⁸ and ethyl azidoformate⁹ were evaluated, but proved to be less effective (see Table S1 and Table S2 in the Supporting Information). The corresponding cationic Cp*Ir and Cp*Co catalysts and different Cp*Rh complexes also gave reduced yields (see Table S3). Switching to an electron deficient Rh catalyst shown to be effective for other Rh(III)-catalyzed C–H functionalization reactions,¹⁰ but gave almost no desired product (entry 2). Lowering the catalyst loading resulted in a reduced yield (entry 3) and, as expected, no desired product was observed in the absence of Rh (entry 4). When the reaction was performed with a catalytic amount of (entry 5), or without (entry 6) PivOH, only modest decreases in yield were observed. Moreover, a stoichiometric amount of other additives, such as AcOH (entry 7) or NaOAc (entry 8), instead of PivOH, were also effective. When both PivOH and NaOAc were added, a slight increase in yield was observed (entry 9). For operational simplicity, only PivOH was used as an additive when evaluating reaction scope, although for some imines, NaOAc was also found to provide a significant improvement in the reaction outcome (vide infra). Increasing the temperature lowered the yield (entry 10), presumably due to competitive decomposition of the carbamylating reagent. When dioxane was used in place of DCE only a small decrease in the yield was observed (entry 11). For protic solvents, alcohol acidity had a pronounced effect on the reaction performance. While MeOH resulted in a significantly lower yield (entry 12), only a slight decrease in yield was observed with TFE (entry 13). Additionally, either increasing or decreasing the reaction concentration had relatively little effect on the reaction outcome (entries 14 and 15).

Table 1.

Reaction Parameters for Annulation to 3a^a

entry	variation	yield %b
1	none	76 (76)c
2	[CpERhCl2]2 (5 mol %) + AgSbF6 (20 mol %)	2
3	5 mol% of Rh	21
4	no Rh	0
5	PivOH (0.1 equiv)	72
6	no PivOH	68
7	AcOH instead of PivOH	70
8	NaOAc instead of PivOH	77
9	PivOH + NaOAc	80
10	80 °C	47
11	dioxane as solvent	70
12	MeOH as solvent	23
13	TFE as solvent	74
14	0.4 M	59
15	0.1 M	67

^aConditions: 1a (0.10 mmol), 2 (0.15 mmol).

^bYields determined by ¹H integration relative to trimethyl(phenyl)silane as external standard.

^cIsolated yield at 0.2 mmol scale of limiting reagent 1a.

Having established the optimal reaction conditions, we set out to explore the scope and generality of this transformation. We began by investigating imines 1 prepared from diverse aldehydes (Scheme 2). In addition to the benzaldehyde-derived imine 1a, the reaction proceeded efficiently with substrates that were either electron-rich (3b) or electron-deficient (3c-3d). Imines derived from aromatic aldehydes substituted with halogens at either the meta (3e) or ortho positions (3f and 3g) successfully underwent carbamylation despite the potential for steric hindrance. With 2,6-dichloro substitution (3h), incomplete cyclization was observed after carbamylation, and a higher reaction temperature was necessary to drive cyclization to completion. An 80 °C reaction temperature was also necessary to obtain high yields for imines featuring 5- and 6-membered basic nitrogen heterocycles, including pyridyl (3i), chloropyridyl (3j), and pyrazyl (3k) functionalities. Imines derived from furan (3l) and thiophene (3m) carboxaldehydes also coupled efficiently. Broad functional group compatibility was observed with high yields obtained for bromo and chloro substituents (3e-3h and 3j) amenable to further elaboration, as well as electro-philic ester (3n), acidic phenol (3o) and secondary anilide (3p) functionalities. With minor modifications to the reaction conditions, cyclopropyl (3q) and alkoxy (3r) groups could also be incorporated directly onto the triazinone core.

Scheme 2. Scope of the R Substituent in Imine 1^a.

^aStandard Conditions: 1 (0.20 mmol), 2 (0.30 mmol). ^bReaction performed at 80 °C. ^cNaOAc (1 equiv) was used. ^dReaction performed with TFE as solvent. Isolated yields are reported.

We next examined imines derived from diverse heteroaromatic amine functionalities (Scheme 3). Methyl groups were used to evaluate substitution at each position on the pyridine ring. For methyl substituents at the 3-, 4- and 5-positions, the products 3s-3u were obtained in good yields. Even for the sterically congested 6-methyl-derivative, the methylated product 3v could be obtained in a moderate yield by performing the reaction at 80 °C with NaOAc as an additive. A chloro substituent (3w), useful for diversification, and an electron-withdrawing trifluoromethyl group (3x) were compatible with the transformation. Additionally, imines formed from other amino-substituted heterocycles provided different [6,6]- and [5,6]-N-heterocyclic motifs as demonstrated for those derived from 6-methylpyridazin-3-amine (3y), 1-methyl-imidazol-2-amine (3z), and 2-amino-1-methylbenzimidazole (3aa).

Scheme 3. Scope of Heteroaromatic Framework in Imine 1^a.

^aStandard Conditions: 1 (0.20 mmol), 2 (0.30 mmol). ^bReaction performed at 80 °C. ^cNaOAc (1 equiv) was used. Isolated yields are reported.

After demonstrating reaction scope for imidoyl carbamylation and cyclization, we decided to pursue a three-component approach with in situ imine formation. This approach would enhance step-economy and potentially broaden scope by circumventing the need for isolation of potentially unstable imines, such as those derived from enolizable alkyl aldehydes. A variety of reaction parameters were evaluated to optimize the yield in the three-component coupling reaction (see Table S4). The most significant modifications were the addition of 3Å molecular sieves and a switch to HFIP from DCE. The use of 2 equiv of the aldehyde was also found to be beneficial. With these modified conditions, the three-component method afforded 3a (Scheme 4) in a comparable yield to that previously observed using imine 1a (see Scheme 1).

Scheme 4. Three-Component Coupling Scope^a.

^aStandard conditions: 4 (0.4 mmol), 5 (0.2 mmol), 2 (0.3 mmol).

^b1.0 mmol scale using 5 mol % of catalyst. Isolated yields are reported.

Three-component coupling was effective with both electron-rich (3b) and electron-deficient (3d) aldehydes, and the basic N-methyl-1H-pyrazole carboxaldehyde also coupled efficiently to provide 3k (Scheme 4). Five- and six-membered heterocyclic amines also provided compounds 3y and 3aa in useful but lower yields than when two-component annulation of the corresponding imines were carried out (see Scheme 3).

Most importantly, the three-component approach proved to be applicable to a range of aliphatic aldehyde inputs. Using cyclopropanecarboxaldehyde, 3q was obtained in a comparably high yield relative to the two-component reaction (See Scheme 2). Moreover, propionaldehyde, which is much more susceptible to tautomerization and resultant side reactions, provided product 3ab in a synthetically useful yield. Cyclic α-branched aldehydes featuring ether and Boc-protected amine functionalities were highly effective, producing 3ac and 3ad, respectively, in excellent yields. To demonstrate the scalability of this three-component procedure, a 1.0 mmol scale reaction was performed with a reduced catalyst loading of 5 mol % to give 3ac in 90% yield.

To gain insight into the reaction mechanism, we isolated and characterized rhodacycle 6 by X-ray crystallography (Scheme 5A).¹¹ We then tested this rhodacycle under our two-component reaction conditions to assess its viability as a C–H activation intermediate. Imine 1a was coupled with 2 in the presence of rhodacycle 6 (10 mol %) and AgSbF₆ (10 mol %), producing product 3a in 68% yield (Scheme 5B). This result is consistent with a cationic Rh(III) rhodacycle formed via imidoyl C–H activation as a plausible intermediate along the catalytic pathway.

Scheme 5. Isolation and Reaction of Rhodacycle 6.

^aYield determined by ¹H integration relative to trimethyl(phenyl)silane as external standard.

A possible catalytic cycle for the two-component coupling of model substrate 1a is presented in Scheme 6. Based on the results shown in Scheme 5, we propose that imine 1a undergoes a concerted metalation-deprotonation to generate rhodacycle A.^2a Both the starting imine 1a and heterocyclic product 3a contain basic nitrogen sites that could serve as the base for this and other steps.¹² Next, coordination of the carbamylating reagent 2 to the Rh(III) center followed by insertion and loss of PivOH leads to the formation of intermediate C.^6,13 Proto-demetalation releases the Rh(III) catalyst and carbamate D, which can then cyclize to form product 3a. The cyclization of carbamate D was shown to occur with equal efficiency in the presence and absence of the Rh(III) catalyst, indicating that this catalyst does not participate in this step (see Table S5).

Scheme 6.

Proposed Reaction Mechanism

In conclusion, we have developed a Rh(III)-catalyzed synthesis of [5,6]- and [6,6]-bicyclic [1,3,5]triazinones via coupling of imines with ethyl (pivaloyloxy)carbamate and subsequent cyclization. Imines derived from aldehydes of varying electronic profiles reacted efficiently, and a diverse set of functionalities was compatible with the reaction conditions. A range of different N-heterocycles were successfully incorporated into the bicyclic framework, and aromatic, aliphatic and alkoxy groups were all effectively introduced on the triazinone ring. This method was further developed in a one-pot three-component procedure. By forming imines in situ, practicality was enhanced, and the scope was extended to include enolizable aliphatic aldehydes. X-ray crystallographic characterization of a rhodacyle corresponding to a likely catalytic intermediate was also obtained, and a plausible mechanistic pathway is proposed.