Synthesis of 2,7-Diazabicyclo[2.2.1]heptenes by N–O Bond Cleavage of Arylnitroso Diels–Alder 1,2-Dihydropyridine Cycloadducts

Abstract

The cleavage of the N–O bond of nitrosoarene-derived cycloadducts with 1,2-dihydropyridines gives different products depending on the protecting group of the starting dihydropyridine and reaction conditions. The use of catalytic amounts of CuCl in non-nucleophilic solvents in combination with a N-phenoxycarbonyl-protected nitrosophenyl-derived cycloadduct allowed the unprecedented formation of the 2,7-diazabicycle[2.2.1]heptene scaffold. It was also demonstrated that this novel bicyclic gem-diamine derivative is an isolable intermediate en route to pyrrole derivatives. On the other hand, the corresponding nitrosopyridine-derived cycloadduct showed to be unreactive with copper salts, but the application of different reductive conditions can deliver the corresponding bicyclic gem-diamine derivative or 3-aminotetrahydropyridine also in enantioenriched form.

Bridged diazabicycles are frequently found as structural motifs in biologically active alkaloids.[1] In particular, there are several diazabicyclic heptane derivatives [i.e., 2,5-di­azabicyclo[2.2.1]heptanes (type I) and 3,6-diazabicyclo[3.1.1]heptanes (type II)] that possess a large variety of biological activities (Figure [1]).[2] On the other hand, the preparation of the constrained 2,7-diazabicyclo[2.2.1]heptane scaffold (i.e., a bicyclic gem-diamine of type III) has not yet been described. Bicyclic gem-diamines are observed in natural products and biologically active compounds and various methods for their preparation have been reported.[3] We are aware of only one cyclization method to obtain five- and six-membered bicyclic gem-diamines involving the intermediacy of N-acyliminium ion.[4]

We recently found that the reductive cleavage of the N–O bond in nitrosobenzene-derived cycloadducts with 1,2-dihydropyridines allowed the formation of substituted pyrrole derivatives 3 (Scheme [1]).[5] This transformation occurred effectively using catalytic amounts of CuCl (20 mol%) in MeOH only when the starting 1,2-dihydropyridine 1 was protected with particular protecting groups (PG = Ac, PhCO), whereas a carbamate protecting group such as Cbz proved to give a complex mixture of products.[5] In that work, we also speculated that such a process reasonably occurred through the intermediacy of an open chain amino aldehyde A followed by intramolecular cyclization, as depicted in Scheme [1]. In fact, it is generally admitted that a cyclic hemiaminal such as 4, obtained after the cleavage of the N–O bond, exists in equilibrium with open chain species A.[6] We hypothesized that only when the protecting group of the endocyclic piperidine nitrogen was sufficiently electron-withdrawing it was possible to shift the equilibrium to open-chain species A triggering the intramolecular cyclization to provide the corresponding pyrrole derivative.

We now report decisive evidences that N-acyliminium ions and 2,7-diazabicyclic[2.2.1]heptenes are the more plausible intermediates for the preparation of pyrrole derivatives. Moreover, we report that the new constrained bicyclic diamine scaffold can be selectively obtained, also in an enantioenriched form, by a careful choice of reaction conditions and protecting groups.

At the outset of this work, control experiments showed that when isolated hemiaminal 4a, obtained by TiCl₃-mediated reduction of the corresponding phenylnitroso Diels–Alder cycloadduct,[5] was treated with catalytic amounts of CuCl in MeOH, methoxy 1,2,3,6-tetrahydropyridine 5a was isolated as a single regio- and diastereoisomer.[7] Interestingly, in this reaction condition, which does not contemplate a reductive cleavage of the N–O bond, it was still possible to obtain the corresponding pyrrole derivative 3a, albeit as a by-product (Scheme [2]). These data suggested that conjugated N-acyliminium ion 6a is a plausible key intermediate at least in the formation of methoxy tetrahydropyridine 5a. As shown before for related compounds, steric repulsion between the methoxycarbonyl methyl group at C-2 position and the acetyl group on the nitrogen disfavors conformation 6aA compared to 6aB (Scheme [2]).[8]

In accordance with previous observations obtained with imino glycals,[8b] the pseudoaxial attack of the methanol on 6aB occurs on the seemingly more hindered face, to give compound 5a with complete regio- and diastereoselectivity. However, at this point it was still possible that an open-chain mechanism via amino aldehyde present at equilibrium with hemiaminal 4a, could be the cause of the formation of the minor product (i.e., the pyrrole derivative 3a, via intermediate A, Scheme [1]).

A further and decisive mechanistic insight was obtained using phenoxycarbonyl-protected cycloadduct 2b (Scheme [3]). The precursor, unsubstituted 1,2-dihydropyridine 1b, is stable and easily available in multigram amounts by the application of a Fowler-type procedure.[9]

When compound 2b was treated with a catalytic amount of CuCl a complex mixture of products was obtained. As judged by ¹H NMR analysis, this mixture consisted of mainly regioisomeric methoxy tetrahydropyridines, which resulted as unseparable after chromatographic purification, without trace of the corresponding expected pyrrole derivative. It was curious that the novel bicyclic gem-N,N-acetal 7b was isolated in 15% yield from this crude mixture as a stable solid (Scheme [3]). The structure of 7b structure was determined by NMR experiments (2D COSY, DEPT, HMQC) (for details, see the Supporting Information).

In order to maximize the formation of compound 7b without having collateral reactions, a screening of reaction conditions was undertaken. We found that the use of catalytic­ amounts of several copper(I) salts (CuBr, CuCl, CuBr·SMe₂) in a non-nucleophilic solvent (THF, MeCN, DMF, toluene, CH₂Cl₂) afforded the desired bicyclic compound 7b as the main product with the best results obtained using 20 mol% of CuCl in anhydrous CH₂Cl₂ in the presence of 3 equivalents of isopropyl alcohol. In this reaction conditions, it was possible to obtain compound 7b with 65% isolated yield after a simple chromatographic purification on silica gel (Scheme [4]). At this point, we were curious to test the stability of this unusual strained gem-diamine derivative (for details, see the Supporting Information). Interestingly, the treatment of a solution of compound 7b in dichloroethane (DCE) at 75 °C in the presence of 0.2 equivalent of CuCl afforded pyrrole 3b as the main product (Scheme [4]). When the reaction was carried out in the same reaction conditions without the presence of CuCl, only decomposition products were obtained indicating the fundamental role exerted by copper(I) in this rearrangement.

Therefore, the data obtained in this work support the notion that the preparation of pyrrole derivatives from phenylnitroso cycloadduct can occur by the intermediacy of 2,7-diazabicycloheptenes of type 7. Thus, it is plausible that the initial copper-catalyzed cleavage of the N–O bond is followed by the putative formation of a conjugated N-acyliminium ion 6 that undergoes intramolecular amination to deliver the isolable 2,7-diazabicycloheptene 7 (Scheme [5]).[10] A subsequent [3.3] hetero-Cope rearrangement could give a 4,4a,5,7a-tetrahydropyrrole[2,3-e]-1,3-oxazine derivative B that after electronic reorganization and aromatization can afford the pyrrole derivative 3.[11] Probably, in the cases where the 1,2-dihydropyridine is protected with more electron-withdrawing groups, such as amide derivatives (R = Me, Ph),[5] the corresponding 2,7-di­azabicycle heptene of type 7 can not be observed due to a plausible faster intramolecular amination-rearrangement process under copper-catalyzed conditions occurring also at room temperature. On the other hand, when using a protecting group possessing a lower electron-withdrawing ability (such as, R = OCH₂Ph) only a complex mixture of regioisomeric methoxy tetrahydropyridines using MeOH as the reaction solvent can be obtained.[5] The phenoxycarbonyl protection (R = OPh) seems to have the right balance of electron-withdrawing ability to allow the isolation of the corresponding strained bicyclic gem-diamine 7b even in MeOH.

The use of phenoxycarbonyl protected pyridine-nitroso cycloadduct 2c revealed to be particularly interesting (Scheme [6]). First of all, this compound was obtained in enantioenriched form (85:15 er) by the application of the asymmetric NDA reaction between 2-nitrosopyridine and 1,2-dihydropyridine 1b catalyzed by 10 mol% of [CuPF₆(MeCN)₄]/Walphos-CF₃.[12] Another advantage of the use of pyridine nitroso derivatives resides in the possibility of deprotection to the free amine, thus circumventing the problems usually connected with the metabolism of aniline-derived compounds.[13] Compound 2c showed to be unreactive with copper salts in solvents such as CH₂Cl₂ or MeOH due to a plausible chelation of the metal with the pyridine nitrogen and the oxygen of the bicycle (Scheme [6, a]). On the other hand, the use of stoichiometric amounts of Cp₂Ti(III)Cl at low temperatures,[5] [14] readily afforded (30 min at –30 °C) 1,2,3,6-tetrahydropyridine 8c resulting from the cleavage of the N–O bond followed by deoxygenation of the expected amino alcohol (Scheme [6, b]). Considering the importance of 3-aminopiperidine in medicinal chemistry,[15] [16] our approach allows the preparation of this class of compounds in enantioenriched form in a very simple manner.[17] Moreover, the presence of an adjacent double bond gives the possibility for further transformations of this drug-like scaffold. After screening of other reductive reaction conditions by not contemplating the use of copper(I) salts, we found that the use of a stoichiometric amount of Mo(CO)₆ in a MeCN–H₂O mixture at 65 °C for few hours afforded the corresponding bicyclic gem-diamine 7c (Scheme [6, c]).

In summary, we have established a simple and rapid access to novel 2,7-diazabicyclo[2.2.1]heptene derivatives of type 7 and 3-amino-1,2,3,6-tetrahydropyridine 8c. These scaffolds can also be obtained in enantioenriched form and could be of interest in a diversity-oriented search for new bioactive compounds. We have also reported new experimental evidences on the mechanism of the manifold reactivity of nitroso Diels–Alder cycloadducts with 1,2-dihydropyridines by the use of transition metals.

All reagents were purchased from commercially available sources. The Zn dust was activated by washing it in a separatory funnel with 10% aq HCl, followed by H₂O, EtOH, Et₂O, and by drying overnight at 100 °C. Anhydrous CH₂Cl₂ (dried on molecular sieves) and MeOH (HPLC grade) were used as the reaction solvents without any further purification. THF was distilled on Na/benzophenone ketyl. Solvents for extraction and chromatography were distilled before use. TLC analyses were performed on silica gel sheets with detection by exposure to ultraviolet light (254 nm) and/or by immersion in an acidic staining solution of p-anisaldehyde in EtOH. Silica gel 60 was used for flash chromatography. Automated column chromatography was performed using prepacked silica gel cartridges on a Biotage Isolera 1.5.2 (27–53 μm). ¹H NMR spectra were recorded at 250 MHz. Chemical shifts are reported in ppm downfield from TMS with the solvent resonance as the internal standard (CDCl₃: δ = 7.26, CD₃CN: δ = 1.94). Standard signal patterns are used to indicate multiplicities. Coupling constants (J) are given in hertz (Hz). ¹³C NMR spectra were recorded at 62.5 MHz, with complete proton decoupling. Chemical shifts are reported in ppm downfield from TMS with the solvent resonance as the internal standard (CDCl₃: δ = 77.16; CD₃CN: δ = 1.32). Melting points were determined on a Kofler apparatus and are uncorrected. HRMS-ESI were acquired in positive ion mode on a Q-TOF premier spectrometer equipped with a nanoelectrospray ion source.

CuCl-Catalyzed Methanolysis of Hemiaminal 4a

To a solution of 4a (46 mg, 0.15 mmol) in MeOH (1.15 mL) was added anhydrous CuCl (3.0 mg, 0.03 mmol) and the mixture was allowed to react for 16 h at r.t. Removal of solvent in vacuum gave a residue, which was rinsed with CH₂Cl₂ and diluted with H₂O (1.0 mL). The aqueous layer was extracted with CH₂Cl₂ (3 × 4 mL) and the combined organic fractions were dried (MgSO₄), filtered, and concentrated. Subsequent flash chromatography (hexanes–EtOAc, 7:3) afforded the known compounds 5a [5] (21 mg, 44%; R_f = 0.41), and 3a [5] (2.6 mg, 6%; R_f  = 0.22).

(1S*,4R*)-2-Phenyl-3-oxa-2,5-diazabicyclo[2.2.2]oct-7-ene-5-carboxylic Acid Phenyl Ester (2b)

A solution of 1,2-dihydropyridine 1b (202 mg, 1.0 mmol) was dissolved in CH₂Cl₂ (2.0 mL) to give a yellowish solution. The subsequent addition of nitrosobenzene (215 mg, 2.0 mmol) turned the solution to dark green, and after 1 h of vigorous stirring, the removal of the solvent gave a crude solid, which was triturated with EtOAc to afford a white solid; yield: 256 mg (83%); mp 120–121 °C.

¹H NMR (250 MHz, CDCl₃): δ = 7.47–6.99 (m, 11 H), 6.86–6.74 (m, 1 H), 6.40–6.23 (m, 2 H), 4.72–4.61 (m, 1 H), 4.27 (dd, J = 10.7, 2.7 Hz, 1 H, major rotamer), 4.11 (dd, J = 11.0, 2.7 Hz, 1 H, minor rotamer), 3.52 (dd, J = 10.7, 2.1 Hz, 1 H, major rotamer), 3.40 (dd, J = 11.0, 2.1 Hz, 1 H, minor rotamer).

¹³C NMR (63 MHz, CDCl₃): δ = 153.1, 152.3, 150.9, 150.4, 130.6, 130.1, 129.5, 129.5, 128.8, 127.6, 127.3, 125.7, 123.3, 121.7, 117.7, 117.6, 75.9, 75.1, 56.9, 56.9, 45.4, 45.2.

HRMS (ESI): m/z [M + Na⁺] calcd for C₁₈H₁₆N₂O₃ + Na: 331.1053; found: 331.1050.

(1S,4R)-2-Pyridin-2-yl-3-oxa-2,5-diazabicyclo[2.2.2]oct-7-ene-5-carboxylic Acid Phenyl Ester (2c)

Following a modification of the previously described method,[12] a flame-dried 50 mL Schlenk tube was charged with (R,Rp)-Walphos-CF₃ ligand (78.7 mg, 0.082 mmol) and [Cu(MeCN)₄]PF₆ (31 mg, 0.082 mg) followed by CH₂Cl₂ (11.7 mL). The resulting yellow solution was stirred for 1 h and cooled to –78 °C and treated with 2-nitrosopyridine (86 mg, 0.82 mmol). Subsequently, a solution of 1b (202 mg, 1 mmol) in CH₂Cl₂ (5.6 mL) was added dropwise over 1 h. A color change to dark brown was observed. The reaction mixture was allowed to stir for 90 min at –78 °C. The solvent was evaporated to give a solid crude, which was subjected to flash chromatography (hexanes–EtOAc, 6:4; R_f = 0.25) to give the title compound as a yellow solid; yield: 182 mg (71%); mp 116–117 °C; [α]_D ²⁰ –2.3 (c = 0.27, CHCl₃).

Enantiomeric ratio (85:15) was determined by HPLC on a Daicel Chiralcel OD-H column (hexane–i-PrOH, 90:10); flow rate: 0.5 mL/min; t _R (minor) = 33.3 min, t _R (major) = 51.9 min.

¹H NMR (250 MHz, CDCl₃): δ = 8.24 (d, J = 4.6 Hz, 1 H), 7.64–7.52 (m, 1 H), 7.44–7.29 (m, 2 H), 7.29–7.07 (m, 3 H), 6.97 (dd, J = 8.3, 2.5 Hz, 1 H), 6.87 (dd, J = 6.9, 5.2 Hz, 1 H), 6.71–6.59 (m, 1 H), 6.49–6.38 (m, 1 H), 6.36–6.25 (m, 1 H), 5.63–5.51 (m, 1 H), 4.19 (dd, J = 10.8, 2.8 Hz, 1 H, major rotamer), 3.55 (dd, J = 10.8, 2.1 Hz, 1 H, major rotamer).

¹³C NMR (62.5 MHz, CDCl₃): δ = 162.6, 153.2, 150.9, 147.5, 147.4, 138.0, 138.0, 130.1, 129.9, 129.6, 129.5, 129.48, 125.8, 121.8, 117.9, 111.8, 111.7, 76.3, 75.6, 52.4, 52.3, 45.1, 44.9.

HRMS (ESI): m/z [M + Na⁺] calcd for C₁₇H₁₅N₃O₃ + Na: 332.1006; found: 332.1003.

(1-Phenyl-1H-pyrrol-2-ylmethyl)carbamic Acid Phenyl Ester (3b)

A pyrex vial was charged with 7b (59 mg, 0.20 mmol), CuCl (4.0 mg, 0.04 mmol), and 1,2-dichloroethane (1.55 mL), and placed in a preheated oil bath at 75 °C. The reaction mixture was allowed to stir for 18 h, filtered through a short pad of Celite, and washed several times with CH₂Cl₂. Removal of the solvent gave a semi-solid, which was subjected to flash chromatography (hexanes–EtOAc, 7:3) to give 3b as an amorphous solid; yield: 44 mg (70%).

¹H NMR (250 MHz, CDCl₃): δ = 7.53–7.15 (m, 8 H), 7.03 (d, J = 7.5 Hz, 2 H), 6.84 (dd, J = 2.6, 1.8 Hz, 1 H), 6.33 (s, 1 H), 6.26 (t, J = 3.1 Hz, 1 H), 5.00 (br s, 1 H), 4.42 (d, J = 5.3 Hz, 2 H).

¹³C NMR (62.5 MHz, CDCl₃): δ = 154.0, 151.1, 139.7, 129.6, 129.4, 129.3, 127.9, 126.1, 125.4, 123.5, 121.7, 109.9, 108.6, 37.7.

HRMS (ESI): m/z [M + Na⁺] calcd for C₁₈H₁₆N₂O₂ + Na: 315.1104; found: 315.1101.

(1S*,4S*)-7-Phenyl-2,7-diazabicyclo[2.2.1]hept-5-ene-2-carboxylic Acid Phenyl Ester (7b)

A solution of cycloadduct 2b (93 mg, 0.30 mmol) in CH₂Cl₂ (2.3 mL) was added with i-PrOH (69 μL, 0.90 mmol) and CuCl (5.9 mg, 0.06 mmol), and allowed to stir for 18 h at r.t. The reaction mixture was quenched with sat. aq NH₄Cl (3.0 mL) and the aqueous phase was extracted with CH₂Cl₂ (3 × 5.0 mL). The combined organic layers were dried (MgSO₄), and concentrated under vacuum. Flash chromatography (hexanes–EtOAc, 1:1; R_f = 0.16) afforded pure compound 7b as a yellowish solid; yield: 62 mg (65%); mp 133–135 °C.

¹H NMR (250 MHz, CDCl₃): δ = 7.47–7.06 (m, 10 H), 6.77 (t, J = 7.3 Hz, 1 H), 6.69 (d, J = 7.8 Hz, 2 H), 6.09 (d, J = 10.1 Hz, 1 H), 6.02–5.79 (m, 2 H), 4.52 (dd, J = 12.4, 5.5 Hz, 1 H), 4.22 (br s, 1 H), 3.17–2.84 (m, 1 H).

¹³C NMR (62.5 MHz, CDCl₃): δ = 150.9, 146.2, 133.3, 129.7, 129.6, 127.1, 126.0, 121.8, 118.6, 113.6, 73.2, 47.9, 42.7.

HRMS (ESI): m/z [M + Na⁺] calcd for C₁₈H₁₆N₂O₂ + Na: 315.1104; found: 315.1108.

(1S,4R)-7-Pyridin-2-yl-2,7-diazabicyclo[2.2.1]hept-5-ene-2-carboxylic Acid Phenyl Ester (7c)

A 10 mL pyrex vial was charged with a solution of racemic 2c (62 mg, 0.20 mmol) in MeCN (1 mL). H₂O (60 μL, 3.33 mmol) and Mo(CO)₆ (65 mg, 0.24 mmol) were added to give a heterogeneous yellow solution. The reaction mixture was placed in a preheated oil bath at 65 °C and stirred for 2.5 h. Upon heating, a color change to dark green was observed. The mixture was filtered through a short pad of Celite and washed several times with CH₂Cl₂. The filtrate was concentrated and the residue was purified by flash chromatography (hexanes–EtOAc, 3:7; R_f = 0.26) to give compound 7c as a white solid; yield: 33 mg (56%); mp 112–114 °C.

¹H NMR (250 MHz, CD₃CN): δ = 8.10–7.99 (m, 1 H), 7.50–7.13 (m, 5 H), 6.64–6.48 (m, 2 H), 6.08–5.94 (m, 1 H), 5.94–5.75 (m, 2 H), 5.12 (s, 1 H), 4.76–4.61 (m, 1 H), 4.44 (dd, J = 12.4, 5.4 Hz, 1 H), 4.08 (s, 1 H), 2.99 (t, J = 11.4 Hz, 1 H).

¹³C NMR (62.5 MHz, CDCl₃): δ (major rotamer) = 157.4, 151.0, 148.3, 137.8 133.2, 129.5, 129.4, 127.2, 125.9, 121.9, 113.9, 108.6, 73.1, 46.2, 42.5.

HRMS (ESI): m/z [M + Na⁺] calcd for C₁₇H₁₅N₃O₂ + Na: 316.1056; found: 316.1052.

(3R)-3-(Pyridin-2-ylamino)-3,6-dihydro-2H-pyridine-1-carboxylic Acid Phenyl Ester (8c)

In a 10 mL flame-dried Schlenk tube, Cp₂TiCl₂ (127 mg, 0.496 mmol) was diluted, under argon protection, with of freshly distilled THF (2.5 mL). After the addition of activated Zn dust (66 mg, 0.99 mmol), the reaction mixture was stirred at r.t. for 50 min and then cooled to –30 °C. A solution of 2c (61 mg, 0.2 mmol) in MeOH (2.0 mL) was added over 5 min and the resulting solution was allowed to stir for 30 min at –30 °C. The reaction was quenched with H₂O (6.5 mL), followed by sat. aq NaHCO₃ (2.0 mL), and allowed to reach r.t. The aqueous phase was extracted with EtOAc (3 × 8 mL) and the combined organic layers were dried (MgSO₄), filtered, and concentrated. Subsequent flash chromatography (hexane–EtOAc, 1:1; R_f = 0.22) afforded the title compound as a white amorphous semi-solid; yield: 27 mg (45%); [α]_D ²⁰ +6.3 (c = 0.24, CHCl₃).

Enantiomeric ratio (>90:<10, not complete baseline separation) was determined by HPLC on a Daicel Chiralpak AD-H column (hexane–i-PrOH, 90:10); flow rate 1.0 mL/min; t _R (minor) = 17.7 min, t _R (major) = 16.9 min.

¹H NMR (250 MHz, CDCl₃): δ = 8.09 (s, 1 H), 7.50–6.86 (m, 3 H), 6.60 (dd, J = 12.3, 6.8 Hz, 1 H), 6.44 (d, J = 8.3 Hz, 1 H), 5.99 (d, J = 13.0 Hz, 1 H), 4.58 (s, 1 H), 4.37–3.40 (m, 2 H).

¹³C NMR (62.5 MHz, CDCl₃): δ = 157.5, 154.3, 151.4, 148.3, 148.2, 137.8, 137.6, 129.5, 129.3, 127.8, 126.8, 126.4, 125.8, 125.3, 121.7, 113.9, 113.6, 108.3, 108.0, 46.1, 45.6, 43.8.

HRMS (ESI): m/z [M + Na⁺] Calcd for C₁₇H₁₇N₃O₂ + Na: 318.1213; found: 318.1217.

Acknowledgment

This work was supported by the University of Pisa.

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