Palladium-Catalyzed Dearomative syn-1,4-Carboamination with Grignard Reagents

Abstract

A protocol for palladium-catalyzed dearomative functionalization of simple, non-activated arenes with Grignard reagents has been established. This one-pot method features a visible-light-mediated [4+2] cycloaddition between an arene and an arenophile, and subsequent palladium-catalyzed allylic substitution of the resulting cycloadduct with Grignard reagent. A variety of arenes and Grignard reagents can participate in this process, forming carboaminated products with exclusive syn-1,4-selectivity. Moreover, the dearomatized products are amenable to further elaborations, providing functionalized alicyclic motifs and pharmacophores. For example, naphthalene was converted to sertraline, one of the most prescribed antidepressants, in only four operations. Finally, this process could also be conducted in an enantioselective fashion, as demonstrated with the desymmetrization of naphthalene.

A novel dearomative process is described using arenophile-based chemistry and Pd catalysis. A range of arenes were readily converted into the corresponding syn-1,4-carboaminated products using Grignard reagents as nucleophiles. The synthetic value of this transformation was demonstrated by several elaborations of products, including short synthesis of sertraline from naphthalene.

Graphical Abstract

Aromatic compounds are often considered as precursors for the synthesis of alicyclic hydrocarbon frameworks, exemplified by the developments of numerous versatile dearomatization processes.^[1] In addition to venerable dearomative reductions^[2] and oxidative dearomatization of phenols^[3], a wide range of dearomative transformations have been developed, enabling the construction of stereochemically complex cyclic structures that are otherwise difficult to prepare.^[4] Thus, these processes have also provided significant advantages in expediting syntheses of natural products and bioactive compounds.^[5] Nevertheless, despite these notable advancements in the field, there still remains several challenges to be addressed. For instance, the catalytic dearomatization of arenes has gained much attention in recent years,^[6] whereas the application of such transformations has largely been limited to specific classes of activated arenes such as naphthols,^[7] naphthylamines,^[8] heteroarenes,^[9] and arenes bearing benzylic heteroatoms.^[10] Dearomative conversions of simple, non-activated arenes in a catalytic manner are rare, especially the variants which concurrently introduce functionality other than hydrogen.^[11]

Recently, we have documented several dearomative functionalization methods based on in situ formation of arene–arenophile cycloadduct (I) via visible-light-mediated [4+2] cycloaddition,^[12] and subsequent elaborations (Figure 1A).^[13] Using N-methyl-1,2,4-triazoline-3,5-dione (MTAD, 1) as an arenophile, we have demonstrated transition metal-catalyzed substitutions of the resulting cycloadducts to access highly functionalized cyclohexane derivatives. Interestingly, the products obtained from Ni-^[14] and Pd-catalyzed^[15] nucleophilic substitutions exhibited complementary selectivity, providing exclusive access to anti-1,2- and syn-1,4-aminofunctionalized motifs, respectively (Figure 1A). The observed regiochemical outcomes are likely due to the difference in preferred structure of the cationic metal intermediates. Specifically, the Ni-complex forms the η⁵-cyclohexadienyl-like intermediate (II) with greater positive charge localized on the termini of the η⁵-system,^[14a] while the Pd-complex adopts the η³-allyl-like structure (III) with incoming nucleophile reacting at the remote site from the urazole.^[16] The observed stereoselectivity was in accordance with the general trends of transition metal-catalyzed allylic substitution.^[17] For example, Grignard reagents were amenable to Ni-catalyzed anti-1,2-carboamination,^[14] while Li-enolates^[15a] and amines^[15b] provided syn-1,4-aminofunctionalization under Pd-catalysis.

Figure 1.

(A) Transition metal-catalyzed arenophile-mediated dearomative aminofunctionalizations. (B) Examples of bioactive compounds with syn-1,4-carboaminated cyclohexane scaffold.

To further extend the utility of these arenophile-mediated catalytic dearomative processes, we decided to test Grignard reagents in combination with Pd catalysis. Gratifyingly, preliminary experiments revealed complementary selectivity compared to Ni-catalysis, as Pd-derived carboaminated products were formed with the exclusive syn-1,4-selectivity. Importantly, this type of cyclohexane derivatives with syn-1,4-carboaminated pattern are commonly found in natural products and bioactive compounds, exemplified by the antidepressant sertraline (2),^[18] antitumor splicing inhibitor sudemycin K (3),^[19] and lipase inhibitor tetrahydropyrimidinedione 4 (Figure 1B).^[20] Therefore, considering the general need to access these important structural motifs, we disclose herein the use of Grignard reagents in Pd-catalyzed dearomative carboaminations with simple arenes, which delivered products with syn-1,4-selectivity. A wide variety of commercially available and simple arenes, as well as Grignard reagents were amenable to this process. Moreover, the synthetic utility of the method was demonstrated by several elaborations of the resulting unsaturated products, as well as the concise synthesis of sertraline from naphthalene. Finally, the proof-of-concept was established for enantioselective desymmetrization using naphthalene or its MTAD cycloadduct.

Our investigation began by employing benzene (5), MTAD (1), and phenylmagnesium bromide with different palladium complexes as catalysts (Table 1). Accordingly, when the cycloaddition was conducted in dichloromethane at cryogenic temperature (–78 ºC), followed by the addition of PhMgBr and Pd(PPh₃)₄ as the catalyst, and slow warming of the resulting mixture from to 0 ºC over 5 h, we observed formation of the syn-1,4-carboaminated product 6a in 35% yield (entry 1, see Table 2 for the X-ray of this compound). Importantly, other constitutional- and diastereoisomers were not observed by ¹H NMR analysis of the crude mixture. This net-retentive stereochemical outcome was unexpected, considering that double inversion is generally observed in transition metal-catalyzed allylic substitutions with non-stabilized (hard) nucleophiles through transmetalation and subsequent inner-sphere reductive elimination.^[17] Although, there are a few reports of net-retentive Pd-catalyzed allylic substitution with relatively hard nucleophiles,^[21] to the best of our knowledge, there are no examples using Grignard reagents.^[22]

Table 1.

Optimization of reaction conditions.^[a]

entry	x (eq.)	[Pd]	ligand	yield (%)[b]
1	2.5	Pd(PPh3)4	–	35
2	2.5	Pd(dba)2	dppf	<5
3	2.5	Pd(dba)2	P(p-FC6H4)3	34
4	2.5	Pd(dba)2	P(p-MeC6H4)3	<5
5	2.5	Pd(dba)2	P(o-MeC6H4)3	63
6	1.5	Pd(dba)2	P(o-MeC6H4)3	63
7[c]	1.5	Pd(dba)2	P(o-MeC6H4)3	61
8[c,d]	1.5	Pd(dba)2	P(o-MeC6H4)3	78 (75)

^[a]Reaction conditions: benzene (5, 5.0 mmol, 10 eq.), MTAD (1, 0.5 mmol, 1.0 eq.), CH₂Cl₂ (0.1 M), visible light, –78 ºC; then addition of PhMgBr (3.0 M in Et₂O), [Pd] catalyst in THF.

^[b]Determined by ¹H NMR analysis relative to the internal standard. Isolated yield shown in parentheses.

^[c]CH₂Cl₂ (0.2 M).

^[d]Substitution step was conducted from –50 to 15 ºC over 10 h.

Table 2.

Grignard reagent scope for Pd-catalyzed dearomative syn-1,4-carboamination.^[a]

^[a]Reaction conditions: benzene (5, 5.0 mmol, 10 eq.), MTAD (1, 0.5 mmol, 1.0 eq.), CH₂Cl₂ (0.2 M), visible light, –78 ºC; then addition of Grignard reagents (1.5 eq. in Et₂O or THF), Pd(dba)₂/P(o-MeC₆H₄)₃ (5.0 mol%/12 mol%) in THF, –50 to 15 ºC, 10 h. Yields of isolated product after column chromatography.

Further optimization of the reaction conditions revealed that monodentate phosphines in combination with Pd(dba)₂ performed better that bidentate, with P(o-MeC₆H₄)₃ being identified as an optimal ligand (entries 2–5, see Supporting Information for full details). With this result in hand, the reaction parameters were examined next. Accordingly, decreasing the amount of PhMgBr, or increasing the solvent concentration to 0.2 M had minimal effect on the reaction outcome (entries 6–7). On the other hand, increasing the reaction temperature during the substitution step from –50 to 15 ºC over 10 h, rather than up to 0 ºC over 5 h, had significant impact in improving the overall yield, as 75% isolated yield of the desired syn-1,4-carboaminated product 6a was obtained (entry 8). Importantly, ¹H-NMR analysis of the crude reaction mixture did not reveal any detectable side-products.

With optimized conditions in hand, the scope of the Grignard reagent was evaluated with benzene as an archetypical nonactivated aromatic substrate (Table 2). Accordingly, a variety of mononuclear arylmagnesium bromides bearing both electron-rich and deficient functional groups, as well as sterically encumbering o-substituents were well tolerated (6a–6f). Also, other aryl Grignard reagents, such as 3,4-methylenedioxyphenyl- and 1-naphthylmagnesium bromide proved to be viable substrates (6g, 6h). In addition to arenes, vinyl groups with different degrees of substitution (6i, 6j), allyl- (6k), and alkyl motifs (6l–6n) could also be installed with this dearomative carboamination. Finally, in all cases, the products were obtained as a single constitutional- and diastereoisomer with exclusive syn-1,4-selectivity.

Next, we turned our attention towards the evaluation of the scope of the arenes (Table 3). In contrast to the optimized conditions for benzene, bis[(2-diphenylphosphino)phenyl] ether (DPEphos) turned out to be the most effective ligand for substituted arenes. Monosubstituted arenes bearing alkyl-, alkylhalide, or silyl substituents were well tolerated in this process, providing products as single constitutional isomers (8a–8e). Additionally, carboamination of naphthalene proceeded smoothly to form product 8f, of which the relative stereochemistry was unambiguously determined by an X-ray analysis. Several other polynuclear arenes such as mono- and disubstituted naphthalenes (8g–8i), as well bromoquinoline (8k), delivered desired products with high selectivities of constitutional isomers, albeit with diminished yields.^[23] On the other hand, described carboamination of phenanthrene gave a mixture of two constitutional isomers (8j and 8j’).

Table 3.

Arene scope of Pd-catalyzed dearomative syn-1,4-carboamination.^[a]

^[a]Reaction conditions for mononuclear arene: arene 7 (5.0 mmol, 10 eq.), MTAD (1, 0.5 mmol, 1.0 eq.), CH₂Cl₂ (0.2 M), visible light, –78 ºC; then addition of PhMgBr (1.5 eq., 3.0 M in Et₂O), Pd(dba)₂/DPEphos (5.0 mol%/10 mol%) in THF, –50 to 15 ºC, 10 h. Reaction conditions for polynuclear arene: arene 7 (1.0 mmol, 2.0 eq.), MTAD (1, 0.5 mmol, 1.0 eq.), CH₂Cl₂ (0.1 M), visible light, –50 ºC; then addition of PhMgBr (1.5 eq., 3.0 M in Et₂O), Pd(dba)₂/DPEphos (10 mol%/20 mol%) in THF, –50 to 15 ºC, 10 h. Yields of isolated product after column chromatography. Ratio of the constitutional isomers are determined by ¹H NMR analysis of the crude reaction mixture (shown in parenthesis).

The described dearomative syn-1,4-carboamination provides novel access to a diverse array of functionalized alicyclic structures from simple arenes (Figure 2). For example, naphthalene-derived product 8f was successfully converted to the corresponding amine 9,^[24] dihydronaphthalenes 10 and 11, or to ketone 12, and α–chloroketone 13 using standard chemistry. Moreover, this method also enabled facile preparation of compounds of medicinal significance. Specifically, we showcase the utility of this Grignard-mediated syn-1,4-carboamination by preparing the antidepressant agent sertraline (2) from naphthalene (Figure 3).^[25] Thus, a dearomative carboamination with naphthalene and 3,4-dichlorophenylmagnesium bromide, followed by a chemoselective reduction of the alkene, provided sertraline precursor 15. At this stage, the urazole was fragmented into urea 16 by N-alkylation with α–bromoacetophenone and subsequent basic cleavage.^[24] Finally, the reduction of the urea moiety with LiAl(OMe)₃H^[25b] provided the requisite amine functionality to complete the synthesis of sertraline (2). Importantly, by using this fragmentation/reduction maneuver, the arenophile moiety served as a masked equivalent of methylamine.

Figure 2.

Diversification of product 8f. Reagents and conditions [1] (i) Rh/Al₂O₃ (cat.), H₂, 96%; (ii) α–bromoacetophenone, K₂CO₃, 56%; (iii) KOH, 95%; [2] Li, NH₃, 83%; [3] (i) Rh/Al₂O₃ (cat.), H₂, 96%; (ii) HCl, 59%; [4] (i) Rh/Al₂O₃ (cat.), H₂, 96%; (ii) tBuOCl, AcOH, 73%; [5] (i) Rh/Al₂O₃ (cat.), H₂, 96%; (ii) tBuOCl, 68%.

Figure 3.

Synthesis of sertraline (2) from naphthalene (7f) and establishment of enantioselectivity of dearomative syn-1,4-carboamination.^[a] Reagents and conditions: [1] naphthalene (7f, 1.0 mmol, 2.0 eq.), MTAD (1, 0.5 mmol, 1.0 eq.), CH₂Cl₂ (0.1 M), visible light, –50 ºC; then addition of PhMgBr (2.0 eq., 2.0 M in THF), Pd₂(dba)₃·CHCl₃/DPEphos (10 mol%/20 mol%) in THF, –50 to 15 ºC, 10 h, 58%. [2] Rh/Al₂O₃ (cat.), H₂, 98%. [3] α-bromoacetophenone, NaOEt, EtOH, then KOH, 51%. [4] LiAl(OMe)₃H, 65%.

We have also examined if this dearomative carboamination process could be conducted in an enantioselective fashion (Figure 3, inset). Considering that the MTAD-naphthalene cycloadduct could undergo desymmetrization, a range of chiral ligands were evaluated under our standard conditions using 3,4-dichlorophenylmagnesium bromide as a nucleophile (see Supporting information for full details). The highest levels of enantioinduction were obtained with (S)-DIFLUORPHOS, delivering product 14 with 85:15 er, albeit with the modest yield. Though extensive optimization did not provide any further improvements, we did observe higher yield and selectivity when we carried out the carboamination as a two-step protocol. Accordingly, when the isolated naphthalene-derived cycloadduct 17 was employed directly, improvements in both the product yield and the enantiopurity were achieved (45% yield, 92:8 er).

In conclusion, we have developed a Pd-catalyzed dearomative syn-1,4-carboamination of simple arenes with Grignard reagents. Not only was the scope of Grignard nucleophiles broad, but a wide variety of mononuclear- and polynuclear arenes were also amenable to this process. The synthetic utility of the syn-1,4-carboaminated products was demonstrated through a series of product diversifications, showcasing how arenophile motif (urazole) could be converted into an amine, a ketone, or be reduced or eliminated. Importantly, the synthetic value of the reported method was highlighted by a concise synthesis of sertraline starting from the simple hydrocarbon naphthalene. Finally, also an asymmetric variant of this dearomatization strategy was established. Further mechanistic studies and applications of this transformation are ongoing and will be reported in due course.