Radical reaction is a powerful tool in synthetic chemistry, and has been widely used in the total synthesis of natural products . However, most free radical reactions are uncontrollable and poorly enantioselective, owing to their sprightly reactivity. To overcome these drawbacks, a new approach toward radical reactions of this nature is urgently required. Starting from development of new initiators for radicals, our efforts are divided into two parts, namely, non-metal-mediated radical reactions and metal-mediated radical reactions respectively. Traditional non-metal initiators are explosive and hazardous diazo or peroxide derivatives, which deter synthetic usage on a large scale. Abundant oxygen is a safe and green reagent, which can perform as an ideal radical initiator (Fig. 1a). Recently, we reported an aerobic oxidative cleavage of the carbon-carbon bond in α-hydroxy ketones via a disuperoxide radical intermediate in the presence of O2, halide and base (Scheme 1) . Typical metal-mediated radical reactions most commonly feature tin hydrides, which have been extensively investigated in the past . However, the high toxicity of n-Bu3SnH is an environmental hazard, which restricts its application in industry. On the basis of our investigations, the ability of palladium to initiate radical has received our attention, and has inspired us to seek ways to replace tin derivatives with palladium catalysts as radical initiators (Fig. 1b).
Transition-metal-catalyzed cross coupling reactions have been developed into an indispensable tool for modern organic synthesis . Among the transition metals, palladium has caught particular attention, due to superior functional group tolerance and the ability to catalyze a variety of reactions . It is well known that Pd(0) undergoes oxidative addition with organic halides, especially Csp2−X bonds, as a first step in the Heck reaction, Suzuki coupling, Stille coupling and Sonogashira coupling, etc. However, palladium-catalyzed couplings of unactivated Csp3−X bonds bearing β-hydrogen have always been a challenge to chemists, owing to competition from facile β-H elimination. In the past decade, Fu has done pioneering work on cross couplings involving the Csp3−X bond . Hu’s group reported a series of nickel and copper-catalyzed cross coupling reactions of non-activated alkyl halides . Cook et al. described a palladium-catalyzed alkyne insertion/Suzuki reaction with unactivated alkyl iodides without exotic ligands . Alexanian et al. demonstrated two interesting Heck-type cyclizations of unactivated alkyl halides . An unexpected C−H activation/C−C cross-coupling reaction between pyridine N-oxides and general unactivated secondary and tertiary alkyl bromides was described by Fu and Liu et al. . The intermediacy of Pd(IV) species generated from Pd(II) and alkyl halides has been demonstrated by Lautens  and Chen . In Tong’s research on the construction of Csp3−I via Pd(II) intermediate, they found that 1,1′-bis(diphenylphosphino)ferrocene (dppf) could partially inhibit the β-hydrogen elimination . In connection with our objectives in transition-metal-catalyzed transformations of Csp3−X bonds, we briefly summarize herein our results in the areas of Pd-catalyzed intramolecular atom transfer cyclization of unactivated alkyl iodide (Scheme 2a) , Pd-catalyzed double C−S bond formation coupling reaction by using Na2S2O3 as sulfurating reagent (Scheme 2b) , and Pd-catalyzed intramolecular reductive cross coupling of Csp2−Csp3 bond formation (Scheme 2c).
Palladium-catalyzed intramolecular atom transfer cyclization of unactivated alkyl iodide
In the beginning, substrate 1i was designed to examine the radical cyclization. In the presence of AIBN and n-Bu3SnH, product 2′ was obtained in 48% yield, which indicated the radical cyclization could proceed smoothly affording reductive cyclization product (Scheme 3a). Then the palladium-mediated radical cyclization was investigated (Scheme 3b).
A Pd(0)-catalyzed iodide atom transfer radical cyclization of alkyl iodide was developed under the optimized conditions: Pd(OAc)2 (10 mol%) and dppf (30 mol%) in toluene at 130oC for 24 h. As far as we know, this is the first example related to Pd(0)-catalyzed atom transfer radical cyclization of unactivated alkyl iodide. The reaction scope was examined and the results were summarized in Table 1. Various 5-hexenyl iodides could be converted to the alkyl iodide derivatives 2 in moderate to high yields under the optimized conditions. A wide tolerance of substitutions on C5-position was demonstrated; even the bulky isobutyl group is compatible (Table 1, entry 3). An oxygen-functionalized tether could also be introduced into C5-position, which could provide good results (Table 2, entries 5 and 6). However, when the C5-position was substituted by benzyl, the yield was decreased to 35% isolated yield (Table 1, entry 4). The transformation is also tolerant with 2-substituted substrates 1g and 1h, delivering the corresponding atom transfer radical cyclization products 2g and 2h in the yields of 81% (d.r.= 4:1) and 76% (d.r.= 10:1), respectively (Table 1, entries 7 and 8). It is worth noting that substrate 1i without substituent at C5-position affords not only desired product 2i in 68% yield, but also Heck-type byproduct 3 in 8% yield (Scheme 4).
To investigate the mechanism of the Pd(0)-catalyzed atom transfer radical cyclization, TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl) was combined with optimized conditions to probe the potential carbon-centered radical intermediates. To our delight, the reaction of substrate 1a with 2 equivalents of TEMPO yielded adducts 4a and 5a in the yields of 8% and 3%, respectively (Scheme 5). While substrate 1i was tested under the same conditions, only 5i was isolated in the yield of 5%, without the detection of 4i, implying that the corresponding 5-exo radical addition might be a faster step due to less steric hindrance (Scheme 5).
Based on these observations, three pathways were discussed in Scheme 6. In the presence of Pd(0) catalyst, LnPdI species and a carbon-centered free radical 6 was generated. Then a second carbon-centered free radical 7 was produced via intramolecular radical addition. According to the related research results on metal-catalyzed atom transfer radical cyclization , intermediate 7 is believed to abstract iodide atom from LnPdI species to deliver the desired product 2i with concomitant regeneration of the Pd(0) catalyst (Scheme 6, path a). Alternatively, intermediate 7 could also abstract iodide atom from substrate 1i, resulting in the product 2i and intermediate 6, during which Pd(0) catalyst just serves as a radical initiator (Scheme 6, path b) .Besides these two possible reaction pathways, a hybrid organometallic-radical mechanism was taken into consideration (Scheme 6, path c) . Alkylpalladium intermediate 8 could be formed by interception of intermediate 7 by the LnPdI species. Because alkylpalladium complex 8 could rapidly undergo β-H elimination, the reductive elimination of intermediate 8 sounds like difficult, indicating that the hybrid organometallic-radical mechanism path c is impossible. On the other hand, intermediate 8 could be generated via oxidative addition of 2i to Pd(0) species, which undergoes β-H elimination to yield the Heck-type byproduct 3 and IPdH species. In the absence of base, IPdH species could not regenerate Pd(0) catalyst, rendering compound 3i being isolated only in 8% yield.
Palladium-catalyzed double C-S bond formation using Na2S2O3 as sulfurating reagent
A novel one-pot palladium-catalyzed double C−S bond formation reaction using Na2S2O3 as the sulfurating reagent was developed. The construction of C−S bond has been less studied due to deactivation of the metal catalysts by the strong coordinating properties of sulfur compounds . The reaction was carried out under the conditions of PdCl2(dppf) (10 mol%), dppf (5 mol%), Cs2CO3 (3.0 equiv.), Na2S2O3. 5H2O (5.0 equiv.) and TBAB (30 mol%) in MeCN:H2O (20:1) at 150oC.
Under the optimized reaction conditions, the substrates scope was examined and the results were shown in Table 2. Substrates bearing Csp3−I, Br, Cl, OMs and OTs on the Csp3 could produce 10a in good to excellent yields (Table 2, entry 1). Chloro and fluoro atoms are well-tolerated resulting in 90–94% yields respectively (Table 2, 10b and 10c). But a bromo substitution at C4 is more sensitive to give product 10d in 46% yield (Table 2, 10d). Both electron-withdrawing and electron-donating substitutions on the aromatic ring gave the corresponding products in good yields (Table 2, 10e–10l). It is worth mentioning that substrate 9j with free alcohol proceeds smoothly to give 42% yield. The coupling reaction was not affected by sulfur atom including of the substrate 9k (Table 2, 10k). Multi-substituted iodobenzene could also afford the desired product in good yield (Table 2, 10m). Substrate with Ns (4-Nitrobenzenesulfonyl) on nitrogen did not change the reactivity (Table 2, 10n). Five, six- and seven-membered ring 10p, 10q and 10o could be obtained in moderate yields. Carbon tethered substrates could also afford the corresponding products in good yield (Table 2, 10p and 10q).
Control experiments were tentatively examined to investigate how the sulfur was introduced to this system from Na2S2O3. We proposed straightforward alkylated thiolsulfate intermediate 11via SN2 replacement (Table 3, eq. 1) . However, when compound 12 was subjected to the standard conditions, no reaction was detected and starting metarial was almost fully recovered (Table 3, entry 1). Without PdCl2(dppf) (Table 3, entry 2) or Cs2CO3 (Table 3, entry 3), no intermediate 11 was formed. Another possible transformation was that the intermediate 11 might be hydrolyzed to thiol 13 which could be converted to 10avia Pd-catalyzed ullmann coupling. However, when compound 13 was tested, no product 10a was detected but the C−N bond cleavage product 14 was isolated in 34% yield (Table 3, entry 4). These evidences indicated that Na2S2O3 might not react with Csp3−I in the first step. However, the exact reaction pathway was unclear. Trials to elucidate the reaction pathway are ongoing in our group.
Palladium-catalyzed intramolecular reductive cross coupling of CSP2 −CSP3 bond formation
The research on the formation of Csp2−Csp3 bond via reductive cross coupling reaction is relatively rare due to the facile β-hydrogen elimination in palladium chemistry. In connection with our goal in the transition-metal-catalyzed transformations of Csp3−X, we planned to investigate the palladium-catalyzed intramolecular reductive cross coupling of Csp2−I and Csp3−X bonds through double oxidative addition and reductive elimination via a Pd(IV) intermediate (Scheme 7).
The Ullmann reaction, initially reported in 1901 , is one of the most efficient reductive cross-coupling in constructing C−C bonds between two aryl halides using stoichiometric copper. Ni(0)-catalyzed reductive cross-coupling to form Csp2−Csp3 bond have been investigated by Weix , Gong , and Peng groups . However, there are no reports on palladium-catalyzed reductive cross-coupling to construct Csp2−Csp3 bond. On the basis of our previous work, we have made an effort on this project and some promising results have been obtained. The detail work will be published in due course.
From the results of palladium-catalyzed Csp3−I mentioned above, it shows that the unactivated Csp3−I bond could be successfully applied in the palladium-catalyzed transformations without β-H elimination. Palladium possesses abilities of initiating radicals, which exhibits potential possibility of replacing Tin as radical initiator. This might provide a new opportunity to the total synthesis of natural products and drugs. More novel methodologies focusing on Csp3−I bond and synthetic applications are ongoing in our laboratory.
Financial support was provided by NSFC (21272075, 21302057), NCET (120178), DFMEC (20130076110023), “Shanghai Pujiang Program” (12PJ1402500), CPSF (2012M520858), program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning and program for Changjiang Scholar and Innovative Research Team in University.
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A collection of invited papers based on presentations at the 17th International IUPAC Conference on Organometallic Chemistry Directed Towards Organic Synthesis (OMCOS-17), Fort Collins, Colorado, USA, 28 July–1 August 2013.