Oxidations of pyrrolidines and piperidines to afford CH-functionalized isopropyl-1-carboxylate congeners.

Abstract

This article describes the action of iodine(III) reagents [diacetoxyiodobenzene, PhI(OAc)₂, and iodosobenzene, (PhIO)_n] in conjunction with TMSBr which act as functional bromine equivalents in unique oxidations of saturated, carbamate protected N-heterocycles. Interestingly, during this work, treatment of the same carbamates with molecular bromine alone afforded similar products, which were sequestered by the solvent methanol.

Graphical Abstract

1. Introduction

Iminiums such as 1 (Fig. 1) are one of the most important electrophiles in synthetic organic transformations for the creation of carbon–carbon and carbon–heteroatom bonds. Covalent attachment of electron withdrawing groups at the nitrogen atom enhances its cationic character making the species a more reactive intermediate (Fig. 1) [1, 2]. Amongst these modified cations, much interest has centered around N-acyliminium ions 2 and 3, although ureas 4, N-tosyl derivatives 5, and hydrazonium ions 6 have also been studied [1]. The importance of N-acyliminium ions 2 and 3 has been demonstrated in a multitude of natural product syntheses [3–5] and exploited in secondary reactions on multi-component reaction products leading to the formation of unique small molecules [6–8].

Figure 1.

Iminium ion and its derivatives.

Typically, N-acyliminium ions or their precursors are generated in situ, being commonly prepared via direct oxidative electrochemical methods [9–12], reduction of lactams or imides through hydride addition [1, 2, 13–17], ring closure of linear amides [18–20], cuprous ion-promoted decomposition of o-diazobenzamides [21], and chemical oxidation by means of iodine(III) and TMSX (X=N₃, Cl) reagent combinations [22, 23].

Of particular interest is the use of hypervalent iodine reagents, thus named due to their ability to possess more than eight electrons in the valence shell as required by the octet rule [24]. Two oxidation states dominate the field - iodine(III) and iodine (V) [25–27]. The most widely-used iodine(V) compounds are Dess-Martin periodinane [28] and o-iodoxybenzoic acid (IBX) [29]. Conversely, iodine(III) reagents are categorized into five classes: (1) iodosylarenes (ArIO) and their acyclic derivatives (ArIX₂) (2) five-membered iodine heterocycles (benziodoxoles, and benziodazoles), (3) iodonium salts (R₂I⁺X⁻), (4) iodonium ylides (ArI=CR₂), and (5) iodonium imides (ArI=NR) [27] where each reagent has different chemical properties and synthetic applications. Iodosylarenes have broad utility as oxidizing reagents [27].

Of particular note is a series of elegant applications of the (PhIO)_n/TMSN₃ reagent combination for the β-azidonation of triisopropylsilyl (TIPS) enol ethers [22, 30–32]. Further studies demonstrated that (PhIO)_n and TMSN₃ enabled the direct α-azidonation of amides, carbamates, and ureas (Scheme 1) [33], representing the first direct chemical oxidation of N-protected pyrrolidine and piperidines to products which were readily ionized to N-acyliminium ions. Use of two different iodine(III) reagents ((PhIO)_n and IBX) revealed a slower rate of α-azidonation and lower yield of products from the piperidine series 7 (n = 2) than with the pyrrolidine 7 (n = 1) series. Optimal conversions were observed with the urea derivative (n = 1, X = NPh₂) which afforded α-azido product 8 in high yield [33].

Scheme 1.

α-Azidonation of amides, carbamates, and ureas. Reagents and conditions: (i) (PhIO)_n (2.4 eq.), TMSN₃ (4.8 eq.), CH₂Cl₂, −40 to −25 °C (n = 1 25-82% yield, n = 2 11-41 % yield) or IBX (2.4 eq.), TMSN₃ (4.8 eq.), CH₂Cl₂, reflux (n = 1, 32-64% yield; n = 2, 15-85% yield).

The downside of Magnus’ α-azidonation protocol is the instability of the putative reactive intermediate PhI(N₃)₂ which decomposes to iodobenzene and 3 moles of N₂(g) with sporadic violent explosions [23]. Interestingly, oxidative applications of Willgerodt’s reagent (PhICl₂)[23, 34] on the same starting materials were subsequently reported. Encouragingly, treatment of carbamate 9 with a modified version of Willgerodt’s reagent (dichloro(4-nitrophenyl)iodane, 10) afforded the surprising α,β,β-oxidation product 11 (R = OH) (Scheme 2). Addition of 5% MeOH to the solvent produced 11 (R = OMe) (80% yield) via ionization of 11 to the N-acyliminium ion and solvent trapping. A similar oxidation to a methoxy dichloride with tert-Butyl hypochlorite in CH₂Cl₂:MeOH has been reported in which an N-acyliminium intermediate was proposed [35].

Scheme 2.

α,β,β-Oxidations of carbamates. Reagents and conditions: (i) 10 (4-5 eq.), MeCN, 45 °C (85% yield) (1 h) or MW 150 °C (5 min) (71% yield).

As such, this clearly suggested that the study of alternate (PhIO)_n/TMSX combinations was warranted, in particular the reactivity of the short-lived species PhIBr₂ 14 [36] (Scheme 3). Especially when photochemical oxidations to ethoxy dibromo species have been demonstrated with pyrrolidine-2-ones [37].

Scheme 3.

In situ generation of PhIBr₂.

2. Results and Discussion

Pilot studies utilized the acid-stable carbamate 15 to avoid deprotection by HBr, a side product of the expected reaction. Thus, exposure of 15 to Ph(IO)_n 12 (2 eq.) and TMSBr (4 eq.) afforded the α,β,β-oxidized product 16 albeit in low yield (Table 1, entry 1) (0 °C to rt, o/n). Nonetheless, unequivocal structural confirmation of 16 was provided by X-ray crystallography (Fig. 2) [38]. The yield was not improved upon changing the solvent to MeCN (Table 1, entry 2), lowering the temperature to –60 °C (Table 1, entry 3), or using an excess of reagents (Table 1, entry 4). However, improvement was observed after microwave irradiation at 80 °C for 5 min (Table 1, entry 5), (22% yield, 22% recovered starting material). The use of phenyliodine(III) diacetate (PIDA) 17 with TMSBr [39] afforded a significant improvement in the yield of 16 to 40% (5 d, rt) (Table 1, entry 6). Subsequent yields after microwave irradiation continued to improve with prolonged reaction time from 5 to 20 min at 80 °C, ranging from 48 to 69% (Table 1, entry 8-10) with dichloromethane superior to acetonitrile (Table 1, entry 11). Stoichiometry studies at elevated temperature (Table 1, entries 12-15) demonstrated linear yield improvements. The scope of the reaction was also demonstrated by the use of different substrates (Table 2), proving compatible with 6-, 7- and 8-membered rings.

Table 1.

Reaction optimization using (PhIO)_n and PIDA hypervalent iodine reagents.

Entry	Solvent	T	t	Ph(IO)n (eq.)	PhI(OAc)2 (eq.)	TMSBr (eq.)	Yield 16 (%)
1	CH2Cl2	0 °C to r.t.	19.5 h	2	-	4	9%
2	MeCN	0 °C to r.t.	17.5 h	2	-	4	3%
3	CH2Cl2	−60 °C	3 h	2	-	4	5%
4a	CH2Cl2	0 °C to r.t.	20 h	10	-	20	6%
5b	CH2Cl2	80 °C	5 min	2	-	4	22%
6	CH2Cl2	0 °C to r.t.	5 d	-	4	8	40%
7	CH2Cl2	60 °C	20 min	-	4	8	48%
8	CH2Cl2	80 °C	5 min	-	4	8	48%
9	CH2Cl2	80 °C	10 min	-	4	8	62%
10	CH2Cl2	80 °C	20 min	-	4	8	69%
11	MeCN	80 °C	20 min	-	4	8	39%
12	CH2Cl2	120 °C	20 min	-	1	2	14%
13	CH2Cl2	120 °C	20 min	-	2	4	35%
14	CH2Cl2	120 °C	20 min	-	3	6	56%
15	CH2Cl2	120 °C	20 min	-	4	8	65%

^a56% starting material was recovered

^b22% starting material was recovered.

Figure 2.

X-ray crystal structure of 16.

Table 2.

Scope of substrates.

Substrate	n	Product	Yield (%)
18	2	21	76
19	3	22	62
20	4	23	56

During the reactions, we observed the rapid formation of a dark orange color which was repeated upon mixing (PhIO)_n or PIDA with TMSBr in CH₂Cl₂ and deemed indicative of the generation of molecular bromine. Indeed, prior reports describe the intermediate derived from the PIDA/TMSBr reagent combination decomposing to iodobenzene and bromine after only 5 minutes (Scheme 4) [40]. This clearly suggested that study of molecular bromine as a potential oxidant was warranted, assuming that (PhIO)_n/TMSBr was a functional equivalent. Indeed, when 15 was treated with bromine in CH₂Cl₂ and irradiated at 80 °C for 1 h, product 16 was isolated (43% yield) (Table 3, entry 1) suggesting the occurrence of photo-bromination [41] in conjunction with or, more likely, in place of the assumed action of PhIBr₂ 14. At an elevated temperature or when excess bromine was employed (Table 3, entry 2 and 3), comparable yields of 16 were attained. However, when the reaction was conducted in a nucleophilic solvent (MeOH), a new α,β-oxidized product 24 was isolated (39% yield) (Table 3, entry 4). It is important to note that when an amide was used as the starting material (N-benzoyl-piperidine), no conversion was observed (Table 4, entry 1). Similarly, no product was furnished when employing Boc-protection (Table 4, entry 2), presumably due to the production of HBr (Scheme 5) with subsequent starting material and/or product decomposition. Cbz-protection proved amenable to α,β-oxidation albeit in low yield (Table 4, entry 3 and 4). This was also not surprising as N-Cbz deprotection is known to occur with HBr in glacial acetic acid [42, 43].

Scheme 4.

Decomposition of PIDA/TMSBr to PhI and Br₂.

Table 3.

Bromination of carbamate 15.

Entry	Solvent	T	t	Br2 (eq.)	Product	Yield (%)
1	CH2Cl2	80 °C	1 h	3	16	43
2	CH2Cl2	120 °C	20 min	3	16	41
3	CH2Cl2	80 °C	20 min	5	16	46
4	MeOH	80 °C	1 h	6	24	39

Table 4.

Scope of the bromination.

Entry	Substrate	n	R	Br2 (eq.)	Product	Yield (%)
1	25	2	Ph	6	28	NR
2	26	1	O-tBu	3	29	0 a
3	27	1	O-Bn	3	30	11b
4	27	1	O-Bn	6	30	15c

NR = no reaction.

^aNo recovered product or starting material.

^b52% recovered starting material.

^c5% recovered starting material.

Scheme 5.

Proposed radical mechanism for the α,β- and α,β,β-carbamate oxidations.

With this data in-hand, it seemed likely the transformation would also occur upon exposure to N-bromosuccinimide (NBS) and the radical initiator azoisiisobutyronitrile (AIBN) (Table 5). As such, Boc-protected pyrrolidines afforded no discernible products (Table 5, entry 1). Conversely, N-Cbz-pyrrolidines furnished the α,β-product 30 in 30% yield (Table 5, entry 2), higher than the corresponding yield with methanolic bromine (Table 4, entry 3 and 4). Finally, the reaction of N-isopropyloxy-pyrrolidine 15 with NBS/AIBN, produced 24, isolated in comparable yield (41%) to treatment with Br₂ in MeOH (Table 5, entry 3).

Table 5.

Radical bromination.

Entry	Starting material	R	T	t	NBS (eq.)	AIBN (eq.)	Product	Yield (%)
1	26	O-tBu	65 °C	reflux, 4 h	1.05	0.05	29	0a
2	27	O-Bn	80 °C	MW, 1 h	10	0.5	30	30b
3	15	O-iPr	80 °C	MW, 1 h	10	0.5	24	41

^aNo recovered starting material or desired product.

^b32% recovered starting material.

A mechanism was proposed to explain formation of the observed products (Scheme 5). Exposure of carbamate 15 to either (i) NBS and AIBN (ii) molecular bromine or (iii) in situ generated bromine from Ph(IO)_n and TMSBr, furnishes 31 [10, 21]. Subsequent formation of α-bromo-carbamate 32 follows which is readily ionized to 33. β-proton removal furnishes enamide 34 and evolution of hydrobromic acid. Enamide reaction with bromine readily affords the β-Br N-acyliminium ion 35. The latter is trapped by methanol to give the α,β-product 24. Conversely, in a non-nucleophilic aprotic solvent (CH₂Cl₂), the reaction proceeds through bromo-enamide 36 to the β,β-dibromo-N-acyliminium ion 37, which upon basic work-up furnishes the final α,β,β-product 16. Intrigued by the N-acyl–α-hydroxy-β,β-dibromo-functionality, sub-structure searching on Scifinder revealed no precedents, although Reaxys revealed apparent reports by Leuchs 100 years ago detailing the action of molecular bromine on a strychnine analog [44]. In this case, an acyl-pyrrolidine ring is formed upon rearrangement of a strychnine derivative, to afford two open α– and β-methylene carbon atoms primed for further reaction with molecular bromine to afford the α-hydroxy-β,β-dibromo- congener. Irrespective of this report, we feel that publication of this non-electrochemical transformation on simple ‘deconstructed’ saturated nitrogen heterocycles warrants reporting.

3. Conclusion

Herein, we report new oxidation chemistry mediated by hypervalent iodine(III) reagents in conjunction with TMSBr to furnish α-hydroxy-β,β-dibromine functionalized N-isopropyloxy protected pyrrolidines and piperidines. Moreover, additional studies demonstrate that molecular bromine promotes these transformations, with yields improved through use of NBS and the radical initiator AIBN. In addition, the α-methoxy-β-bromine derivative of N-isopropyloxy-pyrrolidine was produced when utilizing a methanolic bromine solution.