Iron-catalyzed decarbonylation initiated [2 + 2 + m] annulation of benzene-linked 1,n-enynes with aliphatic aldehydes

Leiyang Lv , Xiaohui Bai , Xiaoyu Yan * and Zhiping Li *
Department of Chemistry, Renmin University of China, Beijing 100872, China. E-mail:;; Web:

Received 3rd August 2016 , Accepted 29th August 2016

First published on 30th August 2016

An iron-catalyzed decarbonylation initiated [2 + 2 + m] annulation of benzene-linked 1,n-enynes with aliphatic aldehydes has been developed. These divergent annulations allow the one-step and efficient synthesis of various fused- or spiro-polycyclic frameworks. Tertiary aldehydes undergo decarbonylation/β-C(sp3)–H cleavage to afford [2 + 2 + 2] cyclization products, whereas secondary aldehydes undergo decarbonylation/α-C(sp3)–H cleavage to generate [2 + 2 + 1] cyclization products.


Recently, transition metal catalyzed cyclization of 1,n-enynes has attracted considerable attention from organic chemists due to the fact that it allows direct, rapid and efficient access to assemble a wide range of highly functionalized polycyclic molecules.1–3,5–7 Although a little progress has been achieved in this field, the development of unique 1,n-enyne cyclization routes to construct distinctive, unconventional architectures remains a challenge. Iron catalysts are widely used in chemical syntheses and pharmaceutical industries, probably due to the extensive abundance of iron in nature, low-lost, and particular low-toxicity in living systems.4 The development of an efficient, selective and environmentally benign 1,n-enynes cyclization catalyzed by iron would be a far-reaching advance in this field.

In 2015, Tu and Li et al. realized an unprecedented iron catalyzed domino spirocyclization of benzene-linked 1,7-enynes with simple cycloalkanes by α,α-C(sp3)–H abstraction/insertion activation strategy.5 In addition, Li et al. also reported an elegant metal-free radical [2 + 2 + 1] carbocyclization of benzene-linked 1,n-enynes (n = 6,7) through dual C(sp3)–H functionalization adjacent to a heteroatom (Scheme 1, eqn (a)).6 These two alkyl radical trigged cascade spirocyclizations of 1,n-enynes are groundbreaking and pioneering and present a new synthetic method to fabricate fused [6.6.5] polycyclic architecture. Thereafter, Li et al. also realized visible light initiated or copper catalyzed annulation of 1,6-enynes with α-carbonyl alkyl bromides as the alkyl radical sources (Scheme 1b).7 Mechanistically, an intramolecular 1,5-hydride radical shift of the vinyl radical species to generate new alkyl radical intermediates was involved.8 Very recently, we reported an iron-catalyzed, radical-mediated [2 + 2 + 2] annulation of benzene linked 1,7-enynes with aromatic aldehydes (Scheme 1c).9 This aromatic aldehydic radical exhibits dual roles, which triggers and terminates the domino cyclization.

image file: c6qo00429f-s1.tif
Scheme 1 [2 + 2 + m] annulations of benzene-linked 1,n-enynes.

The ordinary secondary and tertiary alkyl radicals generated from alkyl halides are extremely challenging species due to the high steric hindrance and electron-rich nature. Moreover, the alkyl radicals are really unstable and quickly undergo isomerization, disproportionation or undesired β-hydride elimination. In our hypothesis, if decarbonylation of alkyl aldehyde can be controlled, it may be utilized as an efficient precursor of alkyl radical.10 Towards this idea, herein, we present a novel decarbonylation initiated [2 + 2 + m] annulations of benzene-linked 1,n-enynes with aliphatic aldehydes (Scheme 1d).11 Tertiary aldehydes undergo decarbonylation/β-C(sp3)–H cleavage to afford [2 + 2 + 2] cyclization products, whereas secondary aldehydes undergo decarbonylation/α-C(sp3)–H cleavage to generate [2 + 2 + 1] cyclization products.

Results and discussion

In order to optimize the reaction conditions, we commenced our studies by exploring the reactions of benzene-linked 1,7-enyne 1a with pivalaldehyde 2a (Table 1). Solvent screening showed that treatment of 1,7-enyne 1a with 2a, FeCl2 and di-tert-butyl peroxide (DTBP) in chlorobenzene led to a tricyclic product 3a in 65% yield (entries 1–4). Furthermore, catalyst screening revealed that other iron salts worked tolerably (entries 5–8), whereas other tested metal catalyst (Cu, Co, Mn, Ni and Pd) had no positive effect on the transformation (entries 9–13). Other oxidant such as tert-butyl hydroperoxide (TBHP) and tert-butyl peroxybenzoate (TBPB) reduced the efficiency of the reaction (entries 14 and 15). Notably, the reaction could also furnish product 3a in 24% yield in the absence of FeCl2 (entry 16).
Table 1 Optimization of the reaction conditionsa

image file: c6qo00429f-u1.tif

Entry Catalyst [O] Solvent 3a (%)
a Reaction conditions: 1a (0.3 mmol), 2a (1.5 mmol), catalyst (2.5 mol%), [O] (0.75 mmol), solvent (1.0 mL), 120 °C, 2 h, under N2. b Reported yields were based on 1a and determined by 1H NMR using an internal standard.
1 FeCl2 (t-BuO)2 MeCN 51
2 FeCl2 (t-BuO)2 DCE 57
3 FeCl2 (t-BuO)2 EtOAc 58
4 FeCl 2 (t-BuO) 2 PhCl 65
5 FeCl3 (t-BuO)2 PhCl 55
6 FeBr2 (t-BuO)2 PhCl 61
7 Fe(OAc)2 (t-BuO)2 PhCl 62
8 Fe(acac)2 (t-BuO)2 PhCl 51
9 CuCl2 (t-BuO)2 PhCl 50
10 CoCl2 (t-BuO)2 PhCl 39
11 MnCl2 (t-BuO)2 PhCl 42
12 NiCl2 (t-BuO)2 PhCl 30
13 PdCl2 (t-BuO)2 PhCl 32
14 FeCl2 t-BuOOH PhCl 32
15 FeCl2 PhCOOOtBu PhCl 42
16 (t-BuO)2 PhCl 24

With the optimal reaction conditions in hand, we turned our attention to investigate the scope of this decarbonylation-initiated cyclization of tertiary aldehydes 2 with 1,n-enynes 1 (Table 2). Variations on the aromatic moiety of alkynes did not reduce the efficiency of this reaction (3a–e). The aliphatic alkyne 1f was also applicable for this transformation to afford the desired 3f in 62% yield. It can be noted that 3g and 3h were generated, albeit in lower yields, when trimethylsilyl alkyne 2g and terminal alkyne 2h were applied, respectively. Moreover, N-brosyl and mesyl substituted anilines also reacted smoothly to afford the desired products 3i and 3j. It is worth noting that the fused [6.6.6] oxygen-containing skeletons 3k and tetrahydro-1H-fluorene (3l) were constructed successfully. When 1-methylcyclohexane-1-carbaldehyde 2b was applied, cyclization occurred exclusively on methylene to deliver tetracyclic hydrobenzo-phenanthridine 3m in a regiospecific manner. The structure of one major isomer was confirmed by X-ray diffraction (Fig. 1).12 In contrast, 3n and 3o were produced in comparative yields when 1-ethylcyclohexane-1-carbaldehyde 2c was investigated. These results indicated that the selectivity of C–H bond functionalization of this method most likely depends on the stability of new generated alkyl radical intermediate (see mechanism in Scheme 3).

image file: c6qo00429f-f1.tif
Fig. 1 X-ray diffraction of one major isomer of 3m.
Table 2 Reactions of 1,n-enynes with tertiary aldehydesa
a Reaction conditions:1 (0.3 mmol), 2 (1.5 mmol), FeCl2 (2.5 mol%), (t-BuO)2 (0.75 mmol), PhCl (1.0 mL), 120 °C, 2 h, under N2; reported yields were based on 1 and determined by 1H NMR using an internal standard; the isolated yields are given in parentheses.
image file: c6qo00429f-u2.tif

We next investigated the scope of the transformation using secondary aldehydes 4 under the optimized conditions (Table 3). The selective C(sp3)–H bond [2 + 2 + 1] cyclization instead of [2 + 2 + 2] cyclization exclusively took place. For example, the reaction of 1a with isobutyraldehyde 4a and 2-ethyl butyraldehyde 4b afforded products 5a and 5b in good yields. When 2-methyl butyraldehyde 4c was applied, the desired 5c could be obtained in a 70% yield with 1[thin space (1/6-em)]:[thin space (1/6-em)]1 dr ratio. Certainly, this method was appropriate for the [2 + 2 + 1] cyclization of 1,n-enynes with cyclic secondary aldehydes, and spiro products 5d–f were obtained in good yields. The carbonyl and alkene moieties on the ring were well tolerated to afford the desired 5g and 5h in good yields. In addition, a variety of 1,7-enynes could also be efficiently converted into the corresponding products (5i–n). It should be noted that the original cyclization strategy of cycloalkanes or oxa-cycloalkanes with enynes was reported by Li and Tu.5,6 However, the selectivity of these transformations depends mainly on the electronic characteristics of different C–H bonds. In our study, we employed carbonyls of aldehydes as traceless activation groups that could accomplish functionalization of a C(sp3)–H bond in a selective manner.

Table 3 Reactions of 1,n-enynes with secondary aldehydesa
a Reaction conditions: 1 (0.3 mmol), 4 (1.5 mmol), FeCl2 (2.5 mol%), (t-BuO)2 (0.75 mmol), PhCl (1.0 mL), 120 °C, 2 h, under N2; reported yields were based on 1 and determined by 1H NMR using an internal standard; the isolated yields are given in parentheses.
image file: c6qo00429f-u3.tif

Furthermore, the reaction of 1a with aldehyde 6, a metabolite of cholesterol, was investigated under the standard reaction conditions (Scheme 2). The expected spiro product 7 was obtained in 48% yield. This result indicated that the method could be a potential synthetic tool for the late-stage modification of complex molecules.

image file: c6qo00429f-s2.tif
Scheme 2 Late stage modification of cholesterol metabolite.

When a primary aldehyde, such as propionaldehyde 8, was applied, the product 10 was obtained in 33% yield, accompanied by similar amount of cyclopentenone 11 (Scheme 3a). Considering the low decarbonylative constant of primary aldehydes,13 we rationalized that the ethyl radical, which was generated by the dealkylation of intermediate 9, reacted with 1a to afford 10.14 In order to gain further insight into the selectivity of H-abstraction, iso-valeraldehyde 12 was submitted to react with 1a (Scheme 3b). The generation of 13 significantly exceeded than that of 14, supporting that (1) intramolecular 1,5-H transfer is much faster than 1,6-H transfer;8,15 (2) the reactivity of C(sp3)–H bonds is related to the stability of the carbon radical generated by H-abstraction of 15.

image file: c6qo00429f-s3.tif
Scheme 3 Reactions of 1a with primary aldehydes.

The reaction of 1a with 4a was completely suppressed when radical inhibitors, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) or butylated hydroxytoluene (BHT), was added under the standard reaction conditions (Scheme 4). The TEMPO-isopropyl adduct 16 was detected by GC-MS, which suggested that a radical pathway might be involved in this process.

image file: c6qo00429f-s4.tif
Scheme 4 Radical trapping experiments.

On the basis of the abovementioned results and previous reports,5–10 a possible mechanism for this decarbonylation-initiated selective C(sp3)–H cyclization is depicted in Scheme 5. Initially, the aldehyde 2 or 4 undergoes oxidative decarbonylation to produce alkyl radical A. Then, radical tandem annulation of A with enyne 1 leads to the key vinyl radical intermediate B, an H-acceptor. In the case of tertiary aldehydes 2, 1,6-H abstraction takes place to afford intermediate C. The subsequent intramolecular radical cyclization and irreversible oxidation give a stable benzyl cation E. We hypothesized that an iron catalyst greatly promotes this oxidation step. Finally, deprotonation of E delivers the six-membered product 3. In contrast, when secondary aldehydes are applied, 1,5-H abstraction occurs exclusively and produces the five-membered product 5 followed by the same process.

image file: c6qo00429f-s5.tif
Scheme 5 Proposed mechanism.


In summary, we demonstrated a new iron-catalyzed decarbonylation initiated [2 + 2 + m] annulation of benzene-linked 1,n-enynes with aliphatic aldehydes. Tertiary aldehydes undergo decarbonylation/β-C(sp3)–H cleavage to afford [2 + 2 + 2] cyclization products, whereas secondary aldehydes undergo decarbonylation/α-C(sp3)–H cleavage to generate [2 + 2 + 1] cyclization products. The late stage functionalization of cholesterol metabolite was also reported. By the feasibilities of decarbonylation of aliphatic aldehydes and radical-initiated cyclization of enynes, the application of this protocol for inert alkyl C(sp3)–H bond functionalization is envisioned. Further studies on the scope and applications of this strategy are in progress.

Experimental procedure

To a mixture of aliphatic aldehyde 2 or 4 (1.5 mmol), enyne 1 (0.3 mmol) and FeCl2 (1.0 mg, 2.5 mol%), chlorobenzene (1.0 mL) was added under a nitrogen atmosphere at room temperature. Then, pure di-tert-butyl peroxide (137 μL, 0.75 mmol) was dropped into the mixture. The resulting mixture was stirred at 120 °C for 2 hours. After the mixture was cooled to room temperature, the resulting solution was directly filtered through a pad of silica by EtOAc. The solvent was evaporated in vacuo to afford the crude products. NMR yields were determined by 1H NMR using dibromomethane as an internal standard. The residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether) to afford the pure product 3 or 5.


Financial support from the National Science Foundation of China (21272267 and 21672259) and the Fundamental Research Funds for the Central Universities, the Research Funds of Renmin University of China (10XNL017) is greatly acknowledged.

Notes and references

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Electronic supplementary information (ESI) available: Copies of 1H NMR and 13C NMR Spectra for new compounds. CCDC 1494076. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6qo00429f

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