B(C6F5)3-Catalyzed Dehydrogenation of Pyrrolidines to Form Pyrroles

Pyrroles are important N-heterocycles found in medicines and materials. The formation of pyrroles from widely accessible pyrrolidines is a potentially attractive strategy but is an underdeveloped approach due to the sensitivity of pyrroles to the oxidative conditions required to achieve such a transformation. Herein, we report a catalytic approach that employs commercially available B(C6F5)3 in an operationally simple procedure that allows pyrrolidines to serve as direct synthons for pyrroles. Mechanistic studies have revealed insights into borane-catalyzed dehydrogenative processes.

The synthesis of pyrroles typically involves ring formation or functionalization of an existing pyrrole (Scheme 1b). 11A potentially complementary approach forms pyrroles directly via the dehydrogenation of pyrrolidines.Pyrrolidines are among the most commonly encountered saturated N-heterocycles 12 and are readily accessed via well-established synthetic methods (e.g., Buchwald−Hartwig, Chan−Lam, Ullmann couplings, and annulation via bis-alkylations). 13In addition, the advantages of using pyrrolidines as synthetic equivalents to pyrroles lie in their orthogonal reactivity.While pyrroles are sensitive to acids, 14 oxidants, 15 and react with electrophiles through the carbon skeleton, 16 pyrrolidines do not.Therefore, a pyrrolidine may be more robust and able to be carried through a synthetic sequence for a pyrrole to be revealed at a later stage.While the dehydrogenation of most saturated (and partially saturated) Nheterocycles is relatively straightforward, 17 particularly those that are benzo-fused, the dehydrogenation of pyrrolidines is more challenging as pyrroles are sensitive to oxidizing conditions. 15−24 Stoichiometric reagents such as MnO 2 , 18 and DDQ 19 have been used to dehydrogenate pyrrolidines that are substituted with electronwithdrawing groups (typically carboxylic acid derivatives). 20u reported the formation of di-and tricarboxyl substituted pyrroles using Cu/TEMPO catalyst and O 2 . 21Brayton dehydrogenated unfunctionalized perhydroindoles and perhydrocarbazoles using an iridium pincer catalyst. 22Other catalytic approaches have been reported as isolated examples. 23or example, Konig discovered an iridium−nickel dual photocatalytic dehydrogenation of 1-(tert-butyl)2-methyl pyrrolidine-1,2-dicarboxylate.23a Herein, we report a catalytic approach for the direct dehydrogenation of pyrrolidines, where new classes of pyrrolidines serve as direct synthons for pyrroles for the first time (Scheme 1c).Importantly, the method does not require pyrrolidines to be substituted with electron-withdrawing groups.We employ commercially available B(C 6 F 5 ) 3 used as received from the supplier, weighed in air, and a glovebox is not required.Mechanistic investigations have revealed that the reaction proceeds via initial borane-mediated α-nitrogen hydride abstraction over a low energy barrier and that later hydride abstraction can occur at either an α-nitrogen or unusually at the γ-nitrogen positions of dihydropyrrole intermediates.The structure of key intermediates and the crucial role of the alkene-based hydrogen acceptor have also been demonstrated.

■ RESULTS AND DISCUSSION
Optimization.We began by considering if the ability of B(C 6 F 5 ) 3 to oxidize amines via α-nitrogen hydride abstraction 25 could be used for the catalytic dehydrogenation of pyrrolidines.Recently, Grimme and Paradies, 26 Kanai, 27 and Ogoshi and Hoshimoto 28 reported the B(C 6 F 5 ) 3 -catalyzed dehydrogenation of various benzo-fused N-heterocycles, such as indolines 29 and 1,2,3,4-tetrahydroquinolines, but pyrrolidines were absent from the scope in all cases.B(C 6 F 5 ) 3 also catalyzes the dehydrogenative β-functionalization of amines. 30otably, Yang and Ma reported a B(C 6 F 5 ) 3 -catalyzed βfunctionalization of pyrrolidines with isatins and subsequent dehydrogenation of the intermediate exocyclic alkenyl products (tautomeric equivalents to a dihydropyrrole).30a However, the B(C 6 F 5 ) 3 -catalyzed direct dehydrogenation of pyrrolidines has not been reported.Furthermore, the challenges of forming pyrroles from pyrrolidines in a B(C 6 F 5 ) 3 -catalyzed process is highlighted by Resconi and coworkers where pyrroles are reported to react directly with B(C 6 F 5 ) 3 in an S E Ar manner to form boronate products, providing a potential route to catalyst poisoning. 31espite this unfavorable precedence, we started with the dehydrogenation of N-mesityl pyrrolidine (1a) in an acceptorless approach (Scheme 2).We were pleased to obtain an initial hit with the formation of pyrrole 3a in 34% yield using B(C 6 F 5 ) 3 (20 mol %) and 1,2-dichlorobenzene (ODCB) as the solvent.Despite extensive optimization, 32 including varying solvents and catalytic additives, we were unable to improve the yield.
It should be noted that B(C 6 F 5 ) 3 is often supplied as H 2 O• B(C 6 F 5 ) 3 requiring purification before use and is normally handled in its water-free form inside an inert atmosphere glovebox.With a view to operational simplicity and accessibility, our procedure uses commercially available B(C 6 F 5 ) 3 as supplied, which is weighed in air on the open bench.We use commercially available Et 3 SiH [2 equiv, relative to B(C 6 F 5 ) 3 ] to free B(C 6 F 5 ) 3 from its water adduct in situ, 33,34 and therefore standard glassware and syringe septa techniques can be used.
Pyrrole 3a was also prepared on a 3 mmol scale and isolated in 67% yield.In addition, we applied the methodology to the dehydrogenation of anesthetic rolicyclidine to form tetradehydro-rolicyclidine 3af (58%) and the formation of estrone derivative 3ag (71%) and 3ah (70%), a derivative of the antiseptic chloroxylenol (Scheme 3).
There are several methods for the conversion of indolines to indoles, 37 but elevated temperatures are typically required.For example, Grimme and Paradies reported the B(C 6 F 5 ) 3 (5 mol %)-catalyzed acceptorless dehydrogenation of a variety of indolines in high yield at 120 °C. 26Using our acceptor-based approach, we have developed a complementary method and found that indoles 5 were efficiently formed under mild conditions (40 °C) using 5 mol % of B(C 6 F 5 ) 3 without the need for a glovebox (Scheme 4).

Mechanistic Investigations.
The mechanism that underpins the B(C 6 F 5 ) 3 -catalyzed dehydrogenation of pyrrolidines was probed experimentally and via DFT calculations.The reaction of one equivalent of pyrrolidine 1a and one equivalent of B(C 6 F 5 ) 3 at ambient temperature formed quantitatively a 1:1 mixture of ammonium borohydride 6a and zwitterion 7a (Scheme 5a).Ammonium borohydride 6a was independently synthesized (via the corresponding ammonium chloride, H 2 O• B(C 6 F 5 ) 3 and triethylsilane) 38 and characterized by NMR spectroscopy and X-ray crystallography.The borohydride counterion is readily identified in the 11 B NMR spectrum as a doublet at −25.1 ppm (J HB = 88.0Hz). 39The structural parameters of 6a are unremarkable, except for the observed NH---HB distance of 2.21(3) Å, potentially indicating a weak dihydrogen bond in the solid state. 40witterion 7a was characterized in situ via 1 H, 11 B, 13 C, and 19 F NMR, and the data was consistent with similar zwitterions derived from B(C 6 F 5 ) 3 and an enamine. 41We were unable to isolate 7a from the reaction or independently synthesize it for further structural characterization.
We also performed a 1:1 reaction between B(C 6 F 5 ) 3 and 2methyl pyrrolidine 1e in the presence of alkene 2a and observed the precipitation of zwitterion 8e.Zwitterion 8e was characterized via X-ray crystallography and in situ NMR spectroscopy (Scheme 5b).Presumably, 8e is formed via the addition of an isomeric enamine to B(C 6 F 5 ) 3 (cf.enamine/ dihydropyrrole 10 and discussion below).In CDCl 3 , 8e slowly equilibrated to a 1:1 mixture with a compound assigned as zwitterion 7e (an analogous structure to 7a), which was characterized in situ via NMR spectroscopy.To note, the hydrogenation product of alkene 2a (isobutyltrimethylsilane, H 2 •2a) was observed in all acceptor-based reactions (see SI). 42 It is also worth noting that while pyrroles are reported to react directly with B(C 6 F 5 ) 3 in a S E Ar manner to form boronate products, 31 we did not observe any S E Ar products that would have otherwise removed B(C 6 F 5 ) 3 from the catalytic cycle.
We investigated the catalytic competency of the potential intermediates ammonium borohydride 6a and zwitterion 8e in the dehydrogenation of 1a under the optimized conditions.We found that in both cases, pyrrole 3a was formed in similar quantities to when B(C 6 F 5 ) 3 [prepared in situ from H 2 O• B(C 6 F 5 ) 3 /Et 3 SiH or pure B(C 6 F 5 ) 3 ] was used (Scheme 5c).
DFT calculations at the B3LYP-D3/6-311G(d,p)//(SMD)-M06−2x/6-311G(d,p) level of theory provided detailed mechanistic insight into the catalytic dehydrogenation of pyrrolidine 1a leading to the formation of pyrrole 3a (Figure 1).B(C 6 F 5 ) 3 abstracts hydride from the α-nitrogen position of 1a, resulting in the formation of the iminium ion pair 9.The formation of 9 occurs through a low barrier transition state TS1 with a free energy barrier of 4.0 kcal/mol.Deprotonation of 9 by allyl silane 2a via transition state TS3 is computed to have a free energy barrier of 28.3 kcal/mol.In contrast, the deprotonation of 9 by pyrrolidine 1a, resulting in the formation of ammonium borohydride 6a and dihydropyrrole 10, was observed to be more favorable kinetically, with a lower energy barrier of 11.5 kcal/mol at transition state TS2.Subsequently, two potential competing pathways leading to the formation of pyrroles 3a and ammonium borohydride 6a have been calculated.In pathway 1 (orange, 10a-TS5-11-TS7), abstraction of hydride at C5 of dihydropyrrole 10a (αnitrogen) precedes deprotonation at C4.Alternatively, in pathway 2 (blue, 10a-TS4-12-TS8), hydride abstraction at C4 (γ-nitrogen) takes place before deprotonation at C5.The calculated results reveal that the free energy barriers of transition states TS4 and TS5 (1.4 vs 1.3 kcal/mol), as well as TS7 and TS8 (−2.1 vs −1.9 kcal/mol), are similar, signifying that both pathways are viable options.Of note, boranemediated γ-nitrogen hydride abstraction has only been previously observed with Hantzsch esters 43 and 2-alkylideneimidazolines. 44he formation of out-of-cycle zwitterion 7a from 10a and B(C 6 F 5 ) 3 was also calculated and exhibited a lower energy barrier via TS6 of 9.1 kcal/mol compared to the barriers observed in either pathway 1 or 2. Upon analysis of the free energy curves thermodynamically, it becomes apparent that the decrease in free energy of 11.7 kcal/mol observed for 7a is outweighed by the significantly more exothermic formation of pyrrole 3a, as indicated by a substantial decrease in free energy of 28.7 kcal/mol.
To evaluate the regeneration of the B(C 6 F 5 ) 3 catalyst, the free energy curves in Figure 2 were utilized.The acceptorless reaction involving the direct H 2 formation from 6a proceeded via TS10.The acceptor-based process proceeds via the twostep hydrogenation of alkene 2a by ammonium borohydride 6a, where carbocation 13 is formed via transition state TS9, and subsequent hydride transfer forms B(C 6 F 5 ) 3 and alkane H 2 •2a.The free energy of TS10 (32.1 kcal/mol) was significantly higher than that of TS9 (20.2 kcal/mol), indicating the hydrogenation of alkene 2a by ammonium borohydride 6a is more favorable and is consistent with the experimental observations.This result highlights the critical importance of the alkene acceptor.
Based on the experimental and computational evidence, we propose the following mechanism (Scheme 6).Active B(C 6 F 5 ) 3 is formed in situ from H 2 O•B(C 6 F 5 ) 3 and Et 3 SiH.B(C 6 F 5 ) 3 mediated α-nitrogen hydride abstraction in pyrrolidine 1 forms iminium borohydride 9.The iminium portion of 9 is deprotonated by starting pyrrolidine 1 to form ammonium borohydride 6 and dihydropyrrole 10, thus removing the first equivalent of H 2 from the amine.The B(C 6 F 5 ) 3 catalyst is regenerated during the irreversible hydrogenation of alkene 2a by ammonium borohydride 6 to form alkane H 2 •2a, 42 completing Cycle 1. Dihydropyrrole 10 (an enamine) is reversibly trapped with B(C 6 F 5 ) 3 to form the zwitterion 7, and it is the likely resting state of the catalyst.Zwitterions 7 may serve as a reservoir for otherwise highly reactive dihydropyrroles 10.Dihydropyrrole 10 can then undergo B(C 6 F 5 ) 3 mediated hydride abstraction at either C5 (α-nitrogen) or C4 (γ-nitrogen) to form iminium borohydrides 11 or 12, respectively.Deprotonation of 11 or 12 yields pyrrole 3 and ammonium borohydride 6, which in turn hydrogenates alkene 2a, closing Cycle 2.

■ CONCLUSIONS
In conclusion, we have reported the direct borane-catalyzed dehydrogenation of pyrrolidines to form pyrroles.The relative stability of pyrrolidines means that they can be carried through a synthetic sequence, and the pyrrole can be unmasked at a later stage.While pyrroles are sensitive to oxidative conditions and, therefore, previous methods typically required the presence of electron-withdrawing groups, the method presented here does not have these constraints, and new classes of pyrrolidines can serve as direct synthons for pyrroles for the first time.The borane catalyst is commercially available, and the method is operationally simple where standard glassware and techniques are used.These factors, and the wide and easy accessibility of pyrrolidines, render the boranecatalyzed approach presented here as a valuable strategy for the synthesis of pyrroles.In addition, we report a mild method for the dehydrogenation of indolines to form indoles.The  mechanism has been studied and is proposed to operate via facile B(C 6 F 5 ) 3 -mediated α-nitrogen hydride abstraction in pyrrolidines, followed by deprotonation of the generated iminium salt to form a dihydropyrrole and an ammonium borohydride.The dihydropyrrole is reversibly trapped by B(C 6 F 5 ) 3 to form adducts that may serve as reservoirs for the reactive dihydropyrrole.A second hydride abstraction event occurs either at the αor unusually at the γ-nitrogen positions.Observation of this unusual regioselectivity may lead to new catalytic processes for the remote functionalization of amines.Regeneration of B(C 6 F 5 ) 3 via direct hydrogen evolution from ammonium borohydride was found to be extremely high in energy, but this challenge was solved by the addition of a crucial alkene hydrogen acceptor.
CCDC reference numbers for X-ray crystallography data: 2305442 (6a); X-ray crystal structure of 6a (CIF) CCDC reference numbers for X-ray crystallography data: 2296869 (8e); X-ray crystal structure of 8e (CIF) Calculated coordinates (XYZ) Experimental procedures, computational details, and characterization data including NMR spectra and X-ray data (PDF) ■ AUTHOR INFORMATION

Figure 1 .
Figure 1.Gibbs free energy profiles (in kcal/mol) for the catalytic dehydrogenation of pyrrolidines.

Figure 2 .
Figure 2. Gibbs free energy profiles (in kcal/mol) for the acceptor versus acceptorless catalytic dehydrogenation of pyrrolidines.