FOCUS REVIEW DOI: 10.1002/asia.201301637
Vicinal Difunctionalization of Alkenes with IodineACHTUNGRE(III) Reagents and Catalysts R. Martn Romero,[a] Thorsten H. Wçste,[a] and Kilian MuÇiz*[a, b]
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Abstract: Hypervalent iodineACHTUNGRE(III) reagents have been known for over a century, and their reaction profile is still actively investigated. Recent years have seen impressive improvements in the area of alkene difunctionalization reactions, where new methodologies have become available. Especially chiral non-racemic hypervalent iodineACHTUNGRE(III) reagents and catalysts have emerged as versatile tools for the realization of important enantioselective transformations. Keywords: alkenes · asymmetric synthesis · catalysis · hypervalent iodine · oxidation
Introduction The vicinal difunctionalization of alkenes constitutes a versatile approach to functional diversification of hydrocarbons. Its power lies in the direct introduction of two heteroatoms by formation of two new C X groups within a single transformation. Traditionally, the area has been dominated by transition metal catalysis, as exemplified by the seminal work on the Sharpless dihydroxylation and aminohydroxylation reactions.[1, 2] Recently, hypervalent iodineACHTUNGRE(III) reagents[3–5] have emerged as powerful metal-free alternatives for the creation of vicinal difunctionalization in the oxidation reaction of alkenes. In particular, the advent of chiral derivatives has provided attractive possibilities to generate vicinal difunctionalization in an enantioselective manner through a single oxidation reaction without the requirement for metal removal in the purification step. Scheme 1. Dichlorination of alkenes with PhICl2 1 as reagent.
1. General Reactivity opened by the remaining chloride resulting in selective overall trans-stereochemistry in the vicinal dichlorinated product 5. Radical pathways usually provide mixtures of stereoisomers. An alternative synchronous transfer of both chlorine atoms onto the double bond was also discussed and a potential transition state A substantiated by theoretical calculations.[9] In contrast to dichlorination reactions, the corresponding difluorination reactions are significantly more difficult to accomplish.[10] Usually, reactions of alkenes with difluoroiodineACHTUNGRE(III) reagents lead to rearrangement processes and to products that are not the vicinal but the geminal difluoride derivatives. As a noteworthy exception, Hara et al. reported that the combination of TolIF2 6 in dichloromethane with Et3N-5HF as co-solvent provided conditions that allowed for a clean difluorination of several terminal alkenes.[11] The reaction could also be conducted with the cyclohexene derivative 7 (Scheme 2, top), which gave rise to the corresponding difluoride 8 in good yield. A major importance lies in the use of Et3N-5HF as supporting agent, as related reagents fail to promote the difluorination reaction. The process is suggested to start from TolIF2 6 via an HF-assisted fluoride dissociation as in B to generate a cationic iodineACHTUNGRE(III) reagent displaying an enhanced electrophilicity, which engages in anti-selective fluoroiodination. The resulting intermediate C undergoes reductive fluorination through addition of a fluo-
1.1. Historic context The first isolated hypervalent iodineACHTUNGRE(III) reagent was dichloroiodobenzene 1, PhICl2, which was prepared by Willgerodt back in 1886.[6] This compound could already be used for alkene oxidation as demonstrated by the oxidation of a series of differently substituted alkenes that include terminal, internal, cyclic, and exocyclic double bonds.[7] Rearrangement pathways are usually excluded, thus extending the reaction scope to an effective dichlorination of terpene scaffolds as well.[8] Reaction mechanisms are depending on the actual conditions; both ionic and radical pathways have been demonstrated to be operative, resulting in different degrees of stereochemical fidelity. For the shown example of cyclohexene 2, the reaction with PhICl2 proceeds through an ionic mechanism of trans-oxidation followed by intramolecular reductive displacement of the iodineACHTUNGRE(III) from 3 (Scheme 1). The resulting chloronium intermediate 4 is [a] R. M. Romero, Dr. T. H. Wçste, Prof. Dr. K. MuÇiz Institute of Chemical Research of Catalonia (ICIQ) Av. Pasos Catalans 16, E-43007 Tarragona (Spain) Fax: (+ 34) 977-920-224 E-mail: [email protected] [b] Prof. Dr. K. MuÇiz Catalan Institution for Research and Advanced Studies (ICREA) Pg. Llus Companys 23, E-08010 Barcelona (Spain)
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1.2. Recent developments Nevado reported that the difluorination can be effectively intercepted by the addition of nitrogen nucleophiles. Oxidation of styrenes 11 with the difluoride reagent 12 in the presence of N-methyl tosylamide 13 thus furnished the corresponding aminofluorination products 14 in very good overall yields and with complete regioselectivity (Scheme 3).[14] Unfortunately, the reaction requires a six-fold excess of starting material in order to provide reasonable product formation.
R. Martn Romero was born in Mlaga, Spain in 1988. He received his Master degree under supervision of Prof. Dr. Eduardo R. Bejarano at the University of Mlaga, Spain in 2012. Currently, Martn is working as a PhD student in the group of Professor Kilian MuÇiz, funded by the Spanish Ministerio de Educacin, Cultura y Deportes. His research is focused on metal-free, hypervalent iodine catalyzed difunctionalization of alkenes.
Thorsten H. Wçste was born in 1983 in Sçgel, Germany. He received his Diploma degree under the supervision of Prof. Dr. Martin Oestreich at the Westflische Wilhelms-Universitt Mnster, Germany in 2009. During his Ph.D. in the same group he was involved in catalytic asymmetric (Mizoroki-)Heck reactions in Mnster as well as at the Technische Universitt Berlin, completing the doctorate in 2012. Currently, Thorsten is working as a postdoctoral fellow in the group of Prof. Dr. Kilian MuÇiz, funded by the Deutsche Forschungsgemeinschaft (DFG). His research is focused on metal-free, hypervalent iodine catalyzed difunctionalization of alkenes.
Scheme 2. Difluorination of alkenes with TolIF2 6 as reagent.
ride under concomitant release of TolI and fluoride to form the final difluorinated product. Still, the substrate scope excludes trisubstituted alkenes. For these compounds, ring contraction is obtained, as shown for the reaction of cyclohexene 9 to the corresponding cyclopentane derivative 10 (Scheme 2, bottom).[12] This outcome is rationalized by the assumption that the initial oxidation product suffers a rearrangement at stage D, which is initiated by the iodineACHTUNGRE(III) nucleofuge.[13] Simultaneous migration of the ring carbon located alpha to the fluorinated center under concomitant nucleophilic fluorination of the latter leads to the final product. Alternatively, this process can be described through stepwise pathways involving a cationic intermediate generated from iodine dissociation, Wagner–Meerwein-type migration, and nucleophilic fluorination of the resulting secondary exocyclic carbocation.
Kilian MuÇiz was born in 1970 in Hildesheim, Germany. He studied Chemistry at the Universities of Hannover (Germany) and Oviedo (Spain), and at the Imperial College London (UK). He received a Ph.D. from the RWTH Aachen in 1998 for work with Professor Carsten Bolm and was an AvH/JSPS-postdoctoral associate with Professor Ryoji Noyori at Nagoya University (Japan). From 2001– 2005 he was a Habilitand at Bonn University associated with Professor Karl Heinz Dçtz, before accepting a professorship at Strasbourg University. He was elected as a junior member of the Institute Universitaire de France in 2008. He moved to his present position at ICIQ in Tarragona (Spain) in 2009. Since 2010 he has also been an ICREA research professor. His research throughout the past decade has dealt with the development of new processes in the area of vicinal difunctionalization of alkenes, in particular with the oxidative diamination reaction.
Abstract in Spanish: Durante el fflltimo siglo se han estudiado en profundidad los reactivos de iodoACHTUNGRE(III) en diversas reacciones, estando vigente el inters en su reactividad. Actualmente se han producido importantes avances en el rea de las reacciones de difuncionalizacin de alquenos, convirtindose estos reactivos y catalizadores de iodoACHTUNGRE(III) en poderosas herramientas, especialmente en su versin quiral para el desarrollo de transformaciones enantioselectivas.
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Major advances in the area have recently been accomplished through reagent combinations that provide an enhanced reactivity. In particular, the notable absence of PhIACHTUNGRE(OAc)2 21 in dioxygenation reactions was attributed to the diminished electrophilicity of the central iodineACHTUNGRE(III), resulting in the absence of any reactivity in alkene oxidation reactions. Within an elegant investigation, Gade and Kang reported that the diacetoxylation reaction of alkenes with PhIACHTUNGRE(OAc)2 21 can be significantly accelerated through the presence of a strong Brønsted acid.[18] In the presence of 5 mol % triflic acid, clean diacetoxylation reactions are observed for a series of mono-, di-, and trisubstituted alkenes 22, including even a cinnamic ester, to give the corresponding vicinal diacetates 23 in good to excellent yields (Scheme 5). In a similar manner, the w-alkenyl carboxylic
Scheme 3. Intermolecular aminofluorination of styrenes.
The related diamination products 15 were formed as minor by-products in less than 15 % yield. Finally, various protocols have been developed for the dioxygenation of alkenes in the presence of hypervalent iodineACHTUNGRE(III) reagents using oxygen nucleophiles that may be provided by the hypervalent iodine itself.[15–17] Examples include the reagents 16–18. The corresponding reactions are again represented for cyclohexene 2 as a substrate (Scheme 4). In all three cases, the cis-configured products
Scheme 4. Dioxygenation of alkenes with reagents 16–18.
Scheme 5. Diacetoxylation of alkenes with PhIACHTUNGRE(OAc)2 21 as reagent.
19 a–c are exclusively obtained, and their formation can be rationalized from a mechanism that is initiated by dissociation of one of the oxygen groups from the iodineACHTUNGRE(III) center. The resulting enforced electrophilic character of the iodineACHTUNGRE(III) will enhance the coordination of the alkene, thus leading to the anti-addition product 20. Subsequent reductive replacement of the iodineACHTUNGRE(III) nucleofuge through a clean SN2-pathway will result in the observed syn-dioxygenated products 19 a–c. These reactions proceed well to the corresponding products 19 a–c incorporating all three oxygen groups (trifluoroacetate, perchlorate, and tosylate), which can be conveniently hydrolyzed to the free diols after the dioxygenation reaction itself.
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acid 24 undergoes clean lactonization to the deoxygenated product 25, while the corresponding phenyl-substituted alkene 26 undergoes an intermediary phenyl migration at the stage of intermediate E, resulting in the geminally dioxygenated product 27. These reactions are believed to initiate through protonmediated acetate removal from the reagent 21. The resulting cationic iodineACHTUNGRE(III) with an enhanced electrophilicity is then attacked by the alkene. A related acceleration effect had been observed by Meng and Li upon addition of a catalytic amount of borontrifluoride etherate.[19] Attempts to render the reaction catalytic in
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compatible with most functional groups. As the consequence of the involved radical mechanism for the double-bond oxidation, the diazide products 32 are obtained as diastereomeric mixtures. More defined conditions to generate the hypervalent iodineACHTUNGRE(III) compound PhI(N3)2 33 were used by Magnus and co-workers, which allowed for the diazidonation of trialkylsilyl enol ethers 34 to the diazides 35.[24] The group of Austin employed the previous method during the total synthesis of ()-dibromophakellstatin with only limited success. In this case, use of in situ formed diacetato iodate I(N3)2 provided the desired syn-diazide product 37 as the major diastereomer (41 %) from alkene 36.[25] Intramolecular amination reactions such as the transformation of 38 into 39 based on PIFA 16 (PIFA = phenyliodine bis(trifluoroacetate), Scheme 4) have been developed by Domnguez and co-workers,[26] who recently reviewed this topic (Scheme 8).[27] The general concept for this work
Scheme 6. THF synthesis through intramolecular oxygenation of an alkene.
iodine reagent have been reported with certain success;[20] however, the contribution of background reactivity to the overall product formation[21] remains to be elucidated. Finally, Fujita et al. reported intramolecular oxygenation reactions that led to cyclization of tetrahydrofurane derivatives (Scheme 6).[22] Under optimized conditions, product 30 could be obtained from the silylated alkene 29 in a chemoselective transformation using a combination of iodosobenzene 28 and borontrifluoride. Additional examples on difunctionalization include introduction of nitrogen, sulfur, and selenium groups.[8] Most of these approaches favor the in situ formation of the active hypervalent iodine reagent, mostly from the parent oxygenated compounds PhIO 28 and PhIACHTUNGRE(OAc)2 21. A good example to this end is the development of bisazidonation reactions. In 1986, Moriarty reported the diazidonation using PhIO 28 as an oxidant with NaN3 in AcOH, which allowed for facile diamination of several alkenes 31 to the diazides 32 in modest to good yields (Scheme 7).[23] Unfortunately, the overall reaction conditions were not found to be particularly
Scheme 8. Intramolecular aminooxygenation with the PIFA reagent 16.
is based on the in situ formation of I N bonds as in 40, which upon heterolysis form electrophilic nitrogen atoms as in 41 that are attacked nucleophilically by the alkene. The resulting intermediate 42 is mostly discussed to be an aziridinium, which undergoes nucleophilic opening by the trifluoroacetate from the initial PIFA oxidant 16. The final aminotrifluoroacetoxylation product 39 can be conveniently hydrolyzed to the corresponding free aminoalcohol. Alternatively, suitably placed polar groups may arrange for an intramolecular aziridinium opening. Wardrop and Bowen recently employed this strategy for the synthesis of the alka-
Scheme 7. Stoichiometric diazidonation of alkenes and enol ethers and key intermediate in the synthesis of dibromophakellstatin.
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loid swainsonine.[28a] In these cases the N-methoxy amide 43 was efficiently cyclized to the corresponding advanced intermediate 44 incorporating a carboxylate as a lactone moiety. The original Domnguez protocol allowed to cyclize 45 into intermediate 46, which could be further converted into castanospermine (Scheme 8).[28b] MuÇiz has recently reported that PhIACHTUNGRE(OAc)2 21 undergoes protonolysis events in the presence of acidic nitrogen sources such as bissulfonimides. Different reagents such as 47 and 48 were isolated and characterized. Control experiments revealed that their reactivity is optimal in the presence of additional amounts of bissulfonimide and that, under all conditions, the bisimido iodineACHTUNGRE(III) species 49 is generated in situ. The isolated reagent 49 promotes intermolecular diamination reactions of alkenes with unprecedented efficiency (Scheme 9).[29] This new approach to diamination of alkenes
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2. Enantioselective Reactions While impressive results have been accomplished so far in the field of alkene oxidation with hypervalent iodine reagents, the most important feature within their use for difunctionalization chemistry lies in the availability of developing enantioselective transformations.[5d] To this end, a series of chiral, non-racemic hypervalent iodineACHTUNGRE(III) reagents were reported over the course of recent years that suggest that hypervalent iodines can indeed serve as suitable reagents for enantioselective oxidation of alkenes. The proof of concept emerged from seminal work by Wirth and co-workers, who pioneered the application of chiral iodineACHTUNGRE(III) reagents for enantioselective oxidative 1,2difunctionalization of styrene 56 to the ditosylate 57 (Scheme 10).[32] This work led to the development of defined
Scheme 10. Pioneering enantioselective vicinal ditosylation of styrene with reagents 55.
chiral iodineACHTUNGRE(III) reagents 54 within an extensive optimization, which were subsequently converted into the more electrophilic reagents 55, which can be considered chirally modified Koser reagents. These reagents share the motif of a chiral 1-arylalkyl ether and a chelation of the ether moiety to the iodine center to provide a more rigid stereochemical environment at the iodineACHTUNGRE(III).[33] From this series of different reagents 55 that were prepared, the maximum enantiomeric excess that could be obtained amounted to 65 % ee.[34] The parent diacetate reagent also proved suitable for the transformation of 26 into 27, although the enantioselectivity remained rather low.[35] Subsequent major advances in the area benefited from the development of a new class of hypervalent iodineACHTUNGRE(III) reagents, which incorporate lactate units for chiral control (Figure 1). These reagents 58–62 were devised by Fujita et al.,[36–38] and extended to the C2-symmetric derivatives 63 and 64 reported by Ishihara and co-workers.[39] With the reagents 58–64 in hand, dioxygenation reactions were then developed further by intramolecular reaction control. Fujita employed reagents 58 and 59 for the develop-
Scheme 9. Vicinal diamination reactions of alkenes with bisimido iodoniumACHTUNGRE(III) reagent 49.
is characterized by an unprecedented broad substrate scope and functional group tolerance. In total, more than sixty different diamines 51 could be generated from the corresponding alkenes 50, which comprise styrenes and other terminal alkenes and both (E)-and (Z)-configured disubstituted alkenes.[30] The reaction is understood to proceed through an initial aminoiodination to arrive at intermediate 52 followed by intramolecular nucleophilic displacement of the iodineACHTUNGRE(III) to arrive at an aziridinium 53 or an cyclic sulfamate 53’. Nucleophilic opening with a second bissulfonimide provides the vicinal diamines 51 with complete chemoselectivity.[31]
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intermediate 68. This compound collapses to 69 with an acetyl ether and the free primary alcohol, which in turn displaces the iodineACHTUNGRE(III) to furnish the final THF product 66.[37] These examples were followed up by a second report on the use of a substrate 70 with an additional chiral terpene auxiliary. While reactions with this auxiliary alone in the presence of an achiral iodineACHTUNGRE(III) promoter led to low diastereoselectivities, a double stereodifferentiation was obtained in the presence of the chiral iodine 58, thus providing the final THF product 71 in good yield and with an excellent ee value of 92 %.[38] Fujita then developed the intramolecular oxygenation reactions further by intramolecular cyclization of the 2-vinyl carboxylate derivatives 72 and 75. In the presence of 63 as the preferred iodineACHTUNGRE(III) reagent, the free carboxylic acid 72 gave a mixture of the six- and five-membered lactones 73 and 74. The desired product 73 was formed as the major product with excellent enantiomeric excess. In addition to the depicted example, the corresponding reaction leading to acetate incorporation could also be realized, leading to a 92:8 ratio with 88 % ee for the major d-lactone.[36] The reaction was then extended to the corresponding esters 75
Figure 1. Chiral non-racemic iodineACHTUNGRE(III) reagents 58–64 based on lactic esters.
ment of an enantioselective transformation of his earlier THF synthesis.[22] The reaction proceeded well for four different substrates 65, thus giving the final THF products 66 with up to 64 % ee (Scheme 11). The reaction is initiated by face selection of the alkene through the chiral iodineACHTUNGRE(III) reagent. Initial oxyiodination generates a dioxolanyl cation 67 that, in a Woodward-type reaction, adds water to arrive at
Scheme 11. Dioxygenation of alkenes using chiral iodineACHTUNGRE(III) reagents.
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Scheme 12. Dioxygenation of alkenes using chiral iodineACHTUNGRE(III) reagents.
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with a b-substituted alkene. Again, with the hypervalent reagent 63, the dioxygenation proceeded to yield single products 76 with high enantiomeric excess in the range of 90– 97 %. The overall process starts with the alkene oxidation that is based on an efficient differentiation of the prochiral face of the double bond through the chiral iodineACHTUNGRE(III) reagent. The bridged iodoniumACHTUNGRE(III) intermediate 77 undergoes regio- and stereoselective opening in the benzylic position by acetate to provide 78, from which an intramolecular nucleophilic displacement of the iodine group by the neighboring ester substituent leads to the final dioxygenated product 76. The efficiency of this dioxygenation reaction was finally demonstrated in the synthesis of the biologically active compound 80, which was isolated from Xyris pterygoblephara and could be conveniently accessed from the 2-alkenyl benzoic ester 79 in a single transformation in the presence of the chiral iodineACHTUNGRE(III) reagent ent-58.[36] The power of the present transformation was then again demonstrated within short syntheses of several polyketide metabolites.[40] For example, Fujita investigated the cyclization of the chiral homoallylic ether 81 (Scheme 13). In the
Scheme 14. Enantioselective catalytic dioxygenation of alkenes with 84.
Efforts to generate efficient enantioselective catalyses employing the chiral aryl iodides are ongoing. For example, Fujita and co-workers described catalytic conditions for the cyclization of a substrate related to 79 (Scheme 12) using mCPBA as terminal oxidant. While the catalyzed reaction exercises good stereocontrol leading to the syn-dioxygenated product with up to 96 % ee, the overall reaction yields mixtures of up to four isomers owing to a background reaction originating from oxidation with the peracid.[42] Finally, the field of intermolecular enantioselective dioxygenation of alkenes reached significant maturity with an improved protocol from Fujita on diacetoxylation. Standard chiral iodine reagents 58, 60, and 63 were again employed, which led to excellent enantioselectivity. Depending on the reaction conditions, the transformation proceeds with synselectivity in a Woodward-type mechanism. On the contrary, high anti-selectivity can be accomplished following the Prvost mechanism (Scheme 15).[43] These inductions are of high synthetic importance as they can compete with the enantiomeric excesses that are usually encountered for the asymmetric dihydroxylation (AD) of styrene in case of osmium catalysis in the AD process. Finally, Wirth extended the rearrangement reactions that were encountered in several achiral transformations to an enantioselective rearrangement of chalcones (Scheme 16).[44] In the presence of the chiral reagent 93, several activating agents were screened, resulting in the use of TMSOTf as the generally best activator. Working with a mixture of trifluoroethanol and dichloromethane, a range of chalcones 94 could be transformed into the corresponding a-arylated ketones 95, which were formed with enantiomeric excess values of up to 96 %. These examples include a broad substrate scope of arenes with different electronic substituents. The reaction can also be used for the construction of stereogenic quaternary centers. The mechanism was investigated for the selectively deuterated chalcone 96 and its transformation to 99. It is believed to include a face selection within the initial iodineACHTUNGRE(III) interaction with the double bond of
Scheme 13. Reagent control in the enantioselective intramolecular dioxygenation of alkenes.
presence of the achiral iodine reagent PhIACHTUNGRE(OAc)2 21, two diastereomers 82 and 83 are formed as equimolar mixtures, which indicates that the chiral center of the substrate does not exercise influence over the stereochemistry of the cyclization. Consequently, oxidation reactions with the chiral reagent 58 led to a reagent-controlled cyclization to generate the product 82 as a nearly pure diastereomer (98 % ee). As expected, the enantiomeric reagent ent-58 led to a similar dominance of the complementary diastereomer 83, which again is formed with 98 % ee. These results convincingly demonstrate that the dioxygenation reactions proceed under almost complete reagent control. Such transformations were recently also accomplished as catalytic versions by using 10 mol % of the corresponding chiral aryl iodide 84 in the presence of mCPBA as terminal oxidant (Scheme 14). Under such conditions, dioxygenation reactions are capable of generating a series of interesting building blocks for various syntheses of biologically interesting molecules.[40] In the cases of 87 b,c, catalyst control was operating overcoming eventual stereochemical influences through the 1,3-diol groups of the products.[41]
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the substrate. Alkoxyiodination with trifluoroethanol as nucleophile provides 97, which undergoes stereoselective migration of the aryl substituent as in 98 under concomitant formation of the acetal group with a second trifluorethanolate and release of the reduced aryl iodide. In the case of aminooxygenation reactions, no intermolecular enantioselective reactivity has so far been developed.[45] Wirth and co-workers recently reported that an intramolecular cyclization reaction of 100 could indeed proceed with suitable enantioinduction, when the chiral iodineACHTUNGRE(III) reagent 93 was pretreated with TMS triflate followed by reaction at low temperature (Scheme 17).[46, 47] The product 101
Scheme 15. IodineACHTUNGRE(III)-promoted enantioselective intermolecular bisacetoxylation of alkenes. Scheme 17. IodineACHTUNGRE(III)-promoted intramolecular enantioselective aminohydroxylation of alkenes.
could be readily converted into the corresponding (S)-2-phenylprolinol, which enlarges the family of proline derivatives. It should also be mentioned that for the case of an N-phenyl urea derivative, the authors were able to generate the corresponding cyclic urea product. This diamine derivative could be formed with 42 % ee. A related approach to aminofluorination was developed by Nevado.[14] The synthesis of the new chiral difluoroiodineACHTUNGRE(III) reagent 102 was central to this accomplishment. It was generated from the parent aryliodide by oxidation with Selectfluor in the presence of Et3N-3HF and can be considered the chiral analogue of compounds 6 and 12. This new iodineACHTUNGRE(III) reagent efficiently promotes the oxidative cyclization of alkenes 103 into the corresponding aminofluorinated products 104 (Scheme 18). The reaction proceeds with complete endo-selectivity in favor of piperidine formation. This outcome compares well with a related report by Li on the achiral cyclization using a combination of PhIACHTUNGRE(O2CtBu)2, BF3-Et2O, and pyridinium fluoride.[48] The overall reaction results in high ee values, which could be further increased upon crystallization. To rationalize the selective piperidine formation, a deuterium labeling experiment was conducted that confirmed a direct aminofluorination
Scheme 16. Enantioselective iodineACHTUNGRE(III)-mediated rearrangement of chalcones.
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Scheme 19. IodineACHTUNGRE(III)-reagents for the enantioselective diamination of alkenes.
Scheme 18. IodineACHTUNGRE(III)-promoted intramolecular enantioselective aminofluorination of alkenes.
process, and the authors proposed a reaction that is initiated by hydrogen-bond-assisted ligand exchange at iodineACHTUNGRE(III) to form the I N intermediate 107 from 106. Such an intermediate 107 is reminiscent of the Domnguez reagent state 40 and should exercise an electrophilic character at nitrogen. Interaction with the nucleophilic alkene would provide an aziridinium intermidiate 108 that would undergo nucleophilic fluorination at the more electrophilic internal carbon atom. Synthesis of the corresponding azepane ring systems did not proceed under metal-free conditions, but could be realized in the presence of a gold catalyst. MuÇiz and co-workers investigated the use of hypervalent iodineACHTUNGRE(III) reagents 63, 110[49] , and 111[50] for an intermolecular enantioselective diamination of styrenes. Reactions with these reagents usually involve an in situ formation of the active reagent ArI[NACHTUNGRE(SO2R)2]2.[29] For a standard diamination of styrene (56), these hypervalent iodine reagents promoted the expected enantioselective diamination.[51, 52] For example, the spiro-derived reagent 110 led to 32 % ee with bistosylimide as nitrogen source,[52] while the binaphthyl derivative 111 afforded 14 % ee for the same transformation and 32 % ee for the reaction with bismesylimide.[52] Reagent 63 was identified as the most suitable iodineACHTUNGRE(III) source, leading to a product 112 with 50 % ee for bistosylimide and 66 % ee for bismesylimide (Scheme 19). The latter value could be increased to 85 % ee for a reaction at lower temperature, and the product was crystallized to enantiopurity within a single crystallization. Under the reaction conditions with 63 as chiral iodineACHTUNGRE(III) promoter, a series of styrene derivatives 113 underwent an enantioselective diamination reaction under metal-free conditions (Scheme 20).[51] A series of different substitution pat-
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Scheme 20. IodineACHTUNGRE(III)-promoted intermolecular enantioselective diamination of styrenes and enantioselective synthesis of levamisole.
terns are tolerated, and all compounds 114 could be crystallized to enantiopurity within a single crystallization step. The reaction proceeds equally efficient for internal alkenes with (E)- and (Z)-configuration, as exemplified for products 115 and 116. Their respective relative configuration is in agreement with the mechanistic discussion from Scheme 9. The synthetic importance of this first enantioselective intermolecular diamination of alkenes was further underlined by the efficient transformation of the styrene product 112 to
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the free bisammonium salt 117. After its subsequent liberation, the free enantiopure (S)-1-phenyl ethylenediamine 118 could be readily converted into the pharmaceutical levamisole within two steps. The corresponding dihalogenation reactions are far more challenging with respect to a chiral non-racemic reaction course. Lupton and co-workers investigated the possibility to provide an enantioselective dibromination of alkenes with a chiral iodine(V) promoter; however, the products were almost racemic.[10, 53] This observation underlines the importance to control the stereochemical fate of halonium intermediates in this type of reactions. An interesting alternative to the use of hypervalent iodine reactions bearing a chiral backbone for enantoselective induction was developed by Nicolaou.[54] Interest in naturally occurring vicinal dichloride units, as for example in chlorosulfolipids, led to the investigation of an enantioselective vicinal dichlorination reaction. To accomplish this aim, the addition of PhICl2 to alkenes in the presence of a catalytic amount of a Cinchona alkaloid 119 was envisioned. Under the assumption that the latter should form a chirally modified hypervalent iodine reagent, alkene oxidation should proceed enantioselectively from this reagent through an initial chloronium intermediate. Such an intermediate bears additional challenges arising from the notorious configurational instability under certain conditions. In addition, as the primary source of stereochemical induction is absent in the subsequent step of the chloronium opening, high regioselectivity is warranted for this step in order to avoid formation of a product with low enantiomeric excess. To address all these issues, the authors used cinnamic alcohols 120 as substrates, the dimeric Cinchona alkaloid derivative (DHQ)2PHAL 119 as catalyst, and the iodine reagent 4phenyl iodosobenzene dichloride 121, which was identified as the best oxidant among four candidates. The chiral pocket of (DHQ)2PHAL should pre-orientate the substrate, possibly through additional hydrogen bonding between the phthalazine spacer and the hydroxy group of the substrate. The resulting transition state 123 for alkene oxidation should provide high face selectivity in the chloronium formation. The presence of the aryl substituent provides the regioselective bias in the nucleophilic chloronium opening with the chloride nucleophile. Such a high regioselectivity preserved the initial enantioselective induction. Indeed, for cinnamic alcohol itself the reaction to the corresponding vicinal dichloride proceeds with 63 % yield and 81–85 % enantiomeric excess, and several additional dichlorination products 122 could be obtained in an enantioselective manner (Scheme 21).
Scheme 21. IodineACHTUNGRE(III)-promoted chlorination of alkenes.
enantioselective
di-
their enantioselectivity, start to compete with traditional metal-mediated reactions. The recent advent of using chiral iodineACHTUNGRE(III) reagents in catalytic amounts or the identification of suitable combinations of iodineACHTUNGRE(III) reagents and chiral ligands offers huge possibilities for the development of truly efficient methodology for enantioselective homogeneous alkene oxidation.
Acknowledgements The authors thank Fundacin ICIQ and the Spanish Ministerio de Economa y Competitividad (CTQ2011-25027) for financial support. R.M. and T.H.W. thank the Ministerio de Economa y Competitividad and the Deutsche Forschungsgemeinschaft (DFG, WO 1924/1-1) for individual fellowships.
[1] a) H. C. Kolb, M. S. VanNieuwenhze, K. B. Sharpless, Chem. Rev. 1994, 94, 2483; b) A. B. Zaitsev, H. Adolfsson, Synthesis 2006, 1725; c) C. Bolm, J. P. Hildebrand, K. MuÇiz, Catalytic Asymmetric Synthesis (Ed.: I. Ojima), Wiley-VCH, Weinheim, 2000, p. 299. [2] a) K. MuÇiz, Chem. Soc. Rev. 2004, 33, 166; b) T. J. Donohoe, C. K. A. Callens, A. Flores, A. R. Lacy, A. H. Rathi, Chem. Eur. J. 2011, 17, 58; c) K. MuÇiz, Comprehensive Chirality, Vol. 5 (Eds.: E. M. Carreira, H. Yamamoto), Elsevier, Amsterdam, 2012, pp. 183 – 197. [3] V. V. Zhdankin, Hypervalent Iodine Chemistry Preparation, Structure and Synthetic Applications of Polyvalent Iodine Compounds, Wiley, Chichester, 2013. [4] a) P. J. Stang, V. V. Zhdankin, Chem. Rev. 1996, 96, 1123; b) V. V. Zhdankin, P. J. Stang, Chem. Rev. 2002, 102, 2523; c) V. V. Zhdankin, P. J. Stang, Chem. Rev. 2008, 108, 5299. [5] Selected reviews and monographs: a) S. Sch fer, T. Wirth, Angew. Chem. Int. Ed. 2010, 49, 2786; Angew. Chem. 2010, 122, 2846; b) T. Dohi, Y. Kita, Chem. Commun. 2009, 2073; c) M. Uyanik, K. Ishihara, Chem. Commun. 2009, 2086; d) M. Ngatimin, D. W. Lupton, Aust. J. Chem. 2010, 63, 653; e) M. S. Yusubov, A. V. Maskaev, V. V. Zhdankin, Arkivoc 2011, 1, 370; f) M. A. Ciufolini, N. A. Braun, S.
Conclusions The recent focus on the application of hypervalent iodineACHTUNGRE(III) reagents has greatly improved the synthetic arsenal for oxidative difunctionalization of alkenes. A number of important transformations are now available that, with respect to
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[6]
[7]
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[11] [12] [13] [14] [15]
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[26] A. Correa, I. Tellitu, E. Domnguez, R. SanMartin, J. Org. Chem. 2006, 71, 8316. [27] I. Tellitu, E. Domnguez, Trends Heterocycl. Chem. 2011, 15, 23. [28] a) D. J. Wardrop, E. G. Bowen, Org. Lett. 2011, 13, 2376; b) E. G. Bowen, D. J. Wardrop, Org. Lett. 2010, 12, 5330. [29] J. A. Souto, C. Martnez, I. Velilla, K. MuÇiz, Angew. Chem. Int. Ed. 2013, 52, 1324; Angew. Chem. 2013, 125, 1363. [30] J. A. Souto, Y. Gonzlez, A. Iglesias, D. Zian, A. Lishchynskyi, K. MuÇiz, Chem. Asian J. 2012, 7, 1103. [31] For a related process in an intra-/intermolecular diamination reaction: A. Kong, S. B. Blakey, Synthesis 2012, 44, 1190. [32] U. H. Hirt, B. Spingler, T. Wirth, J. Org. Chem. 1998, 63, 7674. [33] T. Wirth, U. H. Hirt, Tetrahedron: Asymmetry 1997, 8, 23. [34] U. H. Hirt, M. F. H. Schuster, A. N. French, O. G. Wiest, T. Wirth, Eur. J. Org. Chem. 2001, 1569. [35] A. C. Boye, D. Meyer, C. K. Ingison, A. N. French, T. Wirth, Org. Lett. 2003, 5, 2157. [36] M. Fujita, Y. Yoshida, K. Miyata, A. Wakisaka, T. Sugimura, Angew. Chem. Int. Ed. 2010, 49, 7068; Angew. Chem. 2010, 122, 7222. [37] M. Fujita, S. Okuno, H. J. Lee, T. Sugimura, T. Okuyama, Tetrahedron Lett. 2007, 48, 8691. [38] M. Fujita, Y. Ookubo, T. Sugimura, Tetrahedron Lett. 2009, 50, 1298. [39] a) M. Uyanik, T. Yasui, K. Ishihara, Angew. Chem. Int. Ed. 2010, 49, 2175; Angew. Chem. 2010, 122, 2221; b) M. Uyanik, T. Yasui, K. Ishihara, Tetrahedron 2010, 66, 5841. [40] M. Fujita, K. Mori, M. Shimogaki, T. Sugimura, Org. Lett. 2012, 14, 1294. [41] M. Fujita, K. Mori, M. Shimogaki, T. Sugimura, RSC Adv. 2013, 3, 17717. [42] M. Shimogaki, M. Fujita, T. Sugimura, Eur. J. Org. Chem. 2013, 7128. [43] M. Fujita, M. Wakita, T. Sugimura, Chem. Commun. 2011, 47, 3983. [44] U. Farid, F. Malmedy, R. Claveau, L. Albers, T. Wirth, Angew. Chem. Int. Ed. 2013, 52, 7018; Angew. Chem. 2013, 125, 7156. [45] For an example of intramolecular aziridination followed by acidmediated ring opening with methanol or aniline to provide vicinal aminoethers or diamines, see: Q.-H. Deng, J.-C. Wang, Z.-J. Xu, C.Y. Zhou, C.-M. Che, Synthesis 2011, 2959. [46] U. Farid, T. Wirth, Angew. Chem. Int. Ed. 2012, 51, 3462; Angew. Chem. 2012, 124, 3518. [47] U. Farid, PhD Thesis, University of Cardiff, 2013. [48] Q. Wang, W. Zhong, X. Wei, M. Ning, X. Meng, Z. Li, Org. Biomol. Chem. 2012, 10, 8566. [49] T. Dohi, A. Maruyama, N. Takenaga, K. Senami, Y. Minamitsuji, H. Fujioka, S. B. Caemmerer, Y. Kita, Angew. Chem. Int. Ed. 2008, 47, 3787; Angew. Chem. 2008, 120, 3847. [50] M. Ochiai, Y. Takaoka, Y. Masaka, Y. Nagao, M. Shiro, J. Am. Chem. Soc. 1990, 112, 5677. [51] C. Rçben, J. A. Souto, Y. Gonzlez, A. Lishchynskyi, K. MuÇiz, Angew. Chem. Int. Ed. 2011, 50, 9478; Angew. Chem. 2011, 123, 9650. [52] C. Rçben, J. A. Souto, E. C. Escudero-Adn, K. MuÇiz, Org. Lett. 2013, 15, 1008. [53] M. Ngatimin, C. J. Gartshore, J. P. Kindler, S. Naidu, D. W. Lupton, Tetrahedron Lett. 2009, 50, 6008. [54] K. C. Nicolaou, N. L. Simmons, Y. Ying, P. M. Heretsch, J. S. Chen, J. Am. Chem. Soc. 2011, 133, 8134. Received: December 10, 2013 Published online: March 3, 2014
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Vicinal Difunctionalization of Alkenes with IodineACHTUNGRE(III) Reagents and Catalysts R. Martn Romero,[a] Thorsten H. Wçste,[a] and Kilian MuÇiz*[a, b]
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Abstract: Hypervalent iodineACHTUNGRE(III) reagents have been known for over a century, and their reaction profile is still actively investigated. Recent years have seen impressive improvements in the area of alkene difunctionalization reactions, where new methodologies have become available. Especially chiral non-racemic hypervalent iodineACHTUNGRE(III) reagents and catalysts have emerged as versatile tools for the realization of important enantioselective transformations. Keywords: alkenes · asymmetric synthesis · catalysis · hypervalent iodine · oxidation
Introduction The vicinal difunctionalization of alkenes constitutes a versatile approach to functional diversification of hydrocarbons. Its power lies in the direct introduction of two heteroatoms by formation of two new C X groups within a single transformation. Traditionally, the area has been dominated by transition metal catalysis, as exemplified by the seminal work on the Sharpless dihydroxylation and aminohydroxylation reactions.[1, 2] Recently, hypervalent iodineACHTUNGRE(III) reagents[3–5] have emerged as powerful metal-free alternatives for the creation of vicinal difunctionalization in the oxidation reaction of alkenes. In particular, the advent of chiral derivatives has provided attractive possibilities to generate vicinal difunctionalization in an enantioselective manner through a single oxidation reaction without the requirement for metal removal in the purification step. Scheme 1. Dichlorination of alkenes with PhICl2 1 as reagent.
1. General Reactivity opened by the remaining chloride resulting in selective overall trans-stereochemistry in the vicinal dichlorinated product 5. Radical pathways usually provide mixtures of stereoisomers. An alternative synchronous transfer of both chlorine atoms onto the double bond was also discussed and a potential transition state A substantiated by theoretical calculations.[9] In contrast to dichlorination reactions, the corresponding difluorination reactions are significantly more difficult to accomplish.[10] Usually, reactions of alkenes with difluoroiodineACHTUNGRE(III) reagents lead to rearrangement processes and to products that are not the vicinal but the geminal difluoride derivatives. As a noteworthy exception, Hara et al. reported that the combination of TolIF2 6 in dichloromethane with Et3N-5HF as co-solvent provided conditions that allowed for a clean difluorination of several terminal alkenes.[11] The reaction could also be conducted with the cyclohexene derivative 7 (Scheme 2, top), which gave rise to the corresponding difluoride 8 in good yield. A major importance lies in the use of Et3N-5HF as supporting agent, as related reagents fail to promote the difluorination reaction. The process is suggested to start from TolIF2 6 via an HF-assisted fluoride dissociation as in B to generate a cationic iodineACHTUNGRE(III) reagent displaying an enhanced electrophilicity, which engages in anti-selective fluoroiodination. The resulting intermediate C undergoes reductive fluorination through addition of a fluo-
1.1. Historic context The first isolated hypervalent iodineACHTUNGRE(III) reagent was dichloroiodobenzene 1, PhICl2, which was prepared by Willgerodt back in 1886.[6] This compound could already be used for alkene oxidation as demonstrated by the oxidation of a series of differently substituted alkenes that include terminal, internal, cyclic, and exocyclic double bonds.[7] Rearrangement pathways are usually excluded, thus extending the reaction scope to an effective dichlorination of terpene scaffolds as well.[8] Reaction mechanisms are depending on the actual conditions; both ionic and radical pathways have been demonstrated to be operative, resulting in different degrees of stereochemical fidelity. For the shown example of cyclohexene 2, the reaction with PhICl2 proceeds through an ionic mechanism of trans-oxidation followed by intramolecular reductive displacement of the iodineACHTUNGRE(III) from 3 (Scheme 1). The resulting chloronium intermediate 4 is [a] R. M. Romero, Dr. T. H. Wçste, Prof. Dr. K. MuÇiz Institute of Chemical Research of Catalonia (ICIQ) Av. Pasos Catalans 16, E-43007 Tarragona (Spain) Fax: (+ 34) 977-920-224 E-mail: [email protected] [b] Prof. Dr. K. MuÇiz Catalan Institution for Research and Advanced Studies (ICREA) Pg. Llus Companys 23, E-08010 Barcelona (Spain)
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1.2. Recent developments Nevado reported that the difluorination can be effectively intercepted by the addition of nitrogen nucleophiles. Oxidation of styrenes 11 with the difluoride reagent 12 in the presence of N-methyl tosylamide 13 thus furnished the corresponding aminofluorination products 14 in very good overall yields and with complete regioselectivity (Scheme 3).[14] Unfortunately, the reaction requires a six-fold excess of starting material in order to provide reasonable product formation.
R. Martn Romero was born in Mlaga, Spain in 1988. He received his Master degree under supervision of Prof. Dr. Eduardo R. Bejarano at the University of Mlaga, Spain in 2012. Currently, Martn is working as a PhD student in the group of Professor Kilian MuÇiz, funded by the Spanish Ministerio de Educacin, Cultura y Deportes. His research is focused on metal-free, hypervalent iodine catalyzed difunctionalization of alkenes.
Thorsten H. Wçste was born in 1983 in Sçgel, Germany. He received his Diploma degree under the supervision of Prof. Dr. Martin Oestreich at the Westflische Wilhelms-Universitt Mnster, Germany in 2009. During his Ph.D. in the same group he was involved in catalytic asymmetric (Mizoroki-)Heck reactions in Mnster as well as at the Technische Universitt Berlin, completing the doctorate in 2012. Currently, Thorsten is working as a postdoctoral fellow in the group of Prof. Dr. Kilian MuÇiz, funded by the Deutsche Forschungsgemeinschaft (DFG). His research is focused on metal-free, hypervalent iodine catalyzed difunctionalization of alkenes.
Scheme 2. Difluorination of alkenes with TolIF2 6 as reagent.
ride under concomitant release of TolI and fluoride to form the final difluorinated product. Still, the substrate scope excludes trisubstituted alkenes. For these compounds, ring contraction is obtained, as shown for the reaction of cyclohexene 9 to the corresponding cyclopentane derivative 10 (Scheme 2, bottom).[12] This outcome is rationalized by the assumption that the initial oxidation product suffers a rearrangement at stage D, which is initiated by the iodineACHTUNGRE(III) nucleofuge.[13] Simultaneous migration of the ring carbon located alpha to the fluorinated center under concomitant nucleophilic fluorination of the latter leads to the final product. Alternatively, this process can be described through stepwise pathways involving a cationic intermediate generated from iodine dissociation, Wagner–Meerwein-type migration, and nucleophilic fluorination of the resulting secondary exocyclic carbocation.
Kilian MuÇiz was born in 1970 in Hildesheim, Germany. He studied Chemistry at the Universities of Hannover (Germany) and Oviedo (Spain), and at the Imperial College London (UK). He received a Ph.D. from the RWTH Aachen in 1998 for work with Professor Carsten Bolm and was an AvH/JSPS-postdoctoral associate with Professor Ryoji Noyori at Nagoya University (Japan). From 2001– 2005 he was a Habilitand at Bonn University associated with Professor Karl Heinz Dçtz, before accepting a professorship at Strasbourg University. He was elected as a junior member of the Institute Universitaire de France in 2008. He moved to his present position at ICIQ in Tarragona (Spain) in 2009. Since 2010 he has also been an ICREA research professor. His research throughout the past decade has dealt with the development of new processes in the area of vicinal difunctionalization of alkenes, in particular with the oxidative diamination reaction.
Abstract in Spanish: Durante el fflltimo siglo se han estudiado en profundidad los reactivos de iodoACHTUNGRE(III) en diversas reacciones, estando vigente el inters en su reactividad. Actualmente se han producido importantes avances en el rea de las reacciones de difuncionalizacin de alquenos, convirtindose estos reactivos y catalizadores de iodoACHTUNGRE(III) en poderosas herramientas, especialmente en su versin quiral para el desarrollo de transformaciones enantioselectivas.
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Major advances in the area have recently been accomplished through reagent combinations that provide an enhanced reactivity. In particular, the notable absence of PhIACHTUNGRE(OAc)2 21 in dioxygenation reactions was attributed to the diminished electrophilicity of the central iodineACHTUNGRE(III), resulting in the absence of any reactivity in alkene oxidation reactions. Within an elegant investigation, Gade and Kang reported that the diacetoxylation reaction of alkenes with PhIACHTUNGRE(OAc)2 21 can be significantly accelerated through the presence of a strong Brønsted acid.[18] In the presence of 5 mol % triflic acid, clean diacetoxylation reactions are observed for a series of mono-, di-, and trisubstituted alkenes 22, including even a cinnamic ester, to give the corresponding vicinal diacetates 23 in good to excellent yields (Scheme 5). In a similar manner, the w-alkenyl carboxylic
Scheme 3. Intermolecular aminofluorination of styrenes.
The related diamination products 15 were formed as minor by-products in less than 15 % yield. Finally, various protocols have been developed for the dioxygenation of alkenes in the presence of hypervalent iodineACHTUNGRE(III) reagents using oxygen nucleophiles that may be provided by the hypervalent iodine itself.[15–17] Examples include the reagents 16–18. The corresponding reactions are again represented for cyclohexene 2 as a substrate (Scheme 4). In all three cases, the cis-configured products
Scheme 4. Dioxygenation of alkenes with reagents 16–18.
Scheme 5. Diacetoxylation of alkenes with PhIACHTUNGRE(OAc)2 21 as reagent.
19 a–c are exclusively obtained, and their formation can be rationalized from a mechanism that is initiated by dissociation of one of the oxygen groups from the iodineACHTUNGRE(III) center. The resulting enforced electrophilic character of the iodineACHTUNGRE(III) will enhance the coordination of the alkene, thus leading to the anti-addition product 20. Subsequent reductive replacement of the iodineACHTUNGRE(III) nucleofuge through a clean SN2-pathway will result in the observed syn-dioxygenated products 19 a–c. These reactions proceed well to the corresponding products 19 a–c incorporating all three oxygen groups (trifluoroacetate, perchlorate, and tosylate), which can be conveniently hydrolyzed to the free diols after the dioxygenation reaction itself.
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acid 24 undergoes clean lactonization to the deoxygenated product 25, while the corresponding phenyl-substituted alkene 26 undergoes an intermediary phenyl migration at the stage of intermediate E, resulting in the geminally dioxygenated product 27. These reactions are believed to initiate through protonmediated acetate removal from the reagent 21. The resulting cationic iodineACHTUNGRE(III) with an enhanced electrophilicity is then attacked by the alkene. A related acceleration effect had been observed by Meng and Li upon addition of a catalytic amount of borontrifluoride etherate.[19] Attempts to render the reaction catalytic in
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compatible with most functional groups. As the consequence of the involved radical mechanism for the double-bond oxidation, the diazide products 32 are obtained as diastereomeric mixtures. More defined conditions to generate the hypervalent iodineACHTUNGRE(III) compound PhI(N3)2 33 were used by Magnus and co-workers, which allowed for the diazidonation of trialkylsilyl enol ethers 34 to the diazides 35.[24] The group of Austin employed the previous method during the total synthesis of ()-dibromophakellstatin with only limited success. In this case, use of in situ formed diacetato iodate I(N3)2 provided the desired syn-diazide product 37 as the major diastereomer (41 %) from alkene 36.[25] Intramolecular amination reactions such as the transformation of 38 into 39 based on PIFA 16 (PIFA = phenyliodine bis(trifluoroacetate), Scheme 4) have been developed by Domnguez and co-workers,[26] who recently reviewed this topic (Scheme 8).[27] The general concept for this work
Scheme 6. THF synthesis through intramolecular oxygenation of an alkene.
iodine reagent have been reported with certain success;[20] however, the contribution of background reactivity to the overall product formation[21] remains to be elucidated. Finally, Fujita et al. reported intramolecular oxygenation reactions that led to cyclization of tetrahydrofurane derivatives (Scheme 6).[22] Under optimized conditions, product 30 could be obtained from the silylated alkene 29 in a chemoselective transformation using a combination of iodosobenzene 28 and borontrifluoride. Additional examples on difunctionalization include introduction of nitrogen, sulfur, and selenium groups.[8] Most of these approaches favor the in situ formation of the active hypervalent iodine reagent, mostly from the parent oxygenated compounds PhIO 28 and PhIACHTUNGRE(OAc)2 21. A good example to this end is the development of bisazidonation reactions. In 1986, Moriarty reported the diazidonation using PhIO 28 as an oxidant with NaN3 in AcOH, which allowed for facile diamination of several alkenes 31 to the diazides 32 in modest to good yields (Scheme 7).[23] Unfortunately, the overall reaction conditions were not found to be particularly
Scheme 8. Intramolecular aminooxygenation with the PIFA reagent 16.
is based on the in situ formation of I N bonds as in 40, which upon heterolysis form electrophilic nitrogen atoms as in 41 that are attacked nucleophilically by the alkene. The resulting intermediate 42 is mostly discussed to be an aziridinium, which undergoes nucleophilic opening by the trifluoroacetate from the initial PIFA oxidant 16. The final aminotrifluoroacetoxylation product 39 can be conveniently hydrolyzed to the corresponding free aminoalcohol. Alternatively, suitably placed polar groups may arrange for an intramolecular aziridinium opening. Wardrop and Bowen recently employed this strategy for the synthesis of the alka-
Scheme 7. Stoichiometric diazidonation of alkenes and enol ethers and key intermediate in the synthesis of dibromophakellstatin.
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loid swainsonine.[28a] In these cases the N-methoxy amide 43 was efficiently cyclized to the corresponding advanced intermediate 44 incorporating a carboxylate as a lactone moiety. The original Domnguez protocol allowed to cyclize 45 into intermediate 46, which could be further converted into castanospermine (Scheme 8).[28b] MuÇiz has recently reported that PhIACHTUNGRE(OAc)2 21 undergoes protonolysis events in the presence of acidic nitrogen sources such as bissulfonimides. Different reagents such as 47 and 48 were isolated and characterized. Control experiments revealed that their reactivity is optimal in the presence of additional amounts of bissulfonimide and that, under all conditions, the bisimido iodineACHTUNGRE(III) species 49 is generated in situ. The isolated reagent 49 promotes intermolecular diamination reactions of alkenes with unprecedented efficiency (Scheme 9).[29] This new approach to diamination of alkenes
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2. Enantioselective Reactions While impressive results have been accomplished so far in the field of alkene oxidation with hypervalent iodine reagents, the most important feature within their use for difunctionalization chemistry lies in the availability of developing enantioselective transformations.[5d] To this end, a series of chiral, non-racemic hypervalent iodineACHTUNGRE(III) reagents were reported over the course of recent years that suggest that hypervalent iodines can indeed serve as suitable reagents for enantioselective oxidation of alkenes. The proof of concept emerged from seminal work by Wirth and co-workers, who pioneered the application of chiral iodineACHTUNGRE(III) reagents for enantioselective oxidative 1,2difunctionalization of styrene 56 to the ditosylate 57 (Scheme 10).[32] This work led to the development of defined
Scheme 10. Pioneering enantioselective vicinal ditosylation of styrene with reagents 55.
chiral iodineACHTUNGRE(III) reagents 54 within an extensive optimization, which were subsequently converted into the more electrophilic reagents 55, which can be considered chirally modified Koser reagents. These reagents share the motif of a chiral 1-arylalkyl ether and a chelation of the ether moiety to the iodine center to provide a more rigid stereochemical environment at the iodineACHTUNGRE(III).[33] From this series of different reagents 55 that were prepared, the maximum enantiomeric excess that could be obtained amounted to 65 % ee.[34] The parent diacetate reagent also proved suitable for the transformation of 26 into 27, although the enantioselectivity remained rather low.[35] Subsequent major advances in the area benefited from the development of a new class of hypervalent iodineACHTUNGRE(III) reagents, which incorporate lactate units for chiral control (Figure 1). These reagents 58–62 were devised by Fujita et al.,[36–38] and extended to the C2-symmetric derivatives 63 and 64 reported by Ishihara and co-workers.[39] With the reagents 58–64 in hand, dioxygenation reactions were then developed further by intramolecular reaction control. Fujita employed reagents 58 and 59 for the develop-
Scheme 9. Vicinal diamination reactions of alkenes with bisimido iodoniumACHTUNGRE(III) reagent 49.
is characterized by an unprecedented broad substrate scope and functional group tolerance. In total, more than sixty different diamines 51 could be generated from the corresponding alkenes 50, which comprise styrenes and other terminal alkenes and both (E)-and (Z)-configured disubstituted alkenes.[30] The reaction is understood to proceed through an initial aminoiodination to arrive at intermediate 52 followed by intramolecular nucleophilic displacement of the iodineACHTUNGRE(III) to arrive at an aziridinium 53 or an cyclic sulfamate 53’. Nucleophilic opening with a second bissulfonimide provides the vicinal diamines 51 with complete chemoselectivity.[31]
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intermediate 68. This compound collapses to 69 with an acetyl ether and the free primary alcohol, which in turn displaces the iodineACHTUNGRE(III) to furnish the final THF product 66.[37] These examples were followed up by a second report on the use of a substrate 70 with an additional chiral terpene auxiliary. While reactions with this auxiliary alone in the presence of an achiral iodineACHTUNGRE(III) promoter led to low diastereoselectivities, a double stereodifferentiation was obtained in the presence of the chiral iodine 58, thus providing the final THF product 71 in good yield and with an excellent ee value of 92 %.[38] Fujita then developed the intramolecular oxygenation reactions further by intramolecular cyclization of the 2-vinyl carboxylate derivatives 72 and 75. In the presence of 63 as the preferred iodineACHTUNGRE(III) reagent, the free carboxylic acid 72 gave a mixture of the six- and five-membered lactones 73 and 74. The desired product 73 was formed as the major product with excellent enantiomeric excess. In addition to the depicted example, the corresponding reaction leading to acetate incorporation could also be realized, leading to a 92:8 ratio with 88 % ee for the major d-lactone.[36] The reaction was then extended to the corresponding esters 75
Figure 1. Chiral non-racemic iodineACHTUNGRE(III) reagents 58–64 based on lactic esters.
ment of an enantioselective transformation of his earlier THF synthesis.[22] The reaction proceeded well for four different substrates 65, thus giving the final THF products 66 with up to 64 % ee (Scheme 11). The reaction is initiated by face selection of the alkene through the chiral iodineACHTUNGRE(III) reagent. Initial oxyiodination generates a dioxolanyl cation 67 that, in a Woodward-type reaction, adds water to arrive at
Scheme 11. Dioxygenation of alkenes using chiral iodineACHTUNGRE(III) reagents.
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Scheme 12. Dioxygenation of alkenes using chiral iodineACHTUNGRE(III) reagents.
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with a b-substituted alkene. Again, with the hypervalent reagent 63, the dioxygenation proceeded to yield single products 76 with high enantiomeric excess in the range of 90– 97 %. The overall process starts with the alkene oxidation that is based on an efficient differentiation of the prochiral face of the double bond through the chiral iodineACHTUNGRE(III) reagent. The bridged iodoniumACHTUNGRE(III) intermediate 77 undergoes regio- and stereoselective opening in the benzylic position by acetate to provide 78, from which an intramolecular nucleophilic displacement of the iodine group by the neighboring ester substituent leads to the final dioxygenated product 76. The efficiency of this dioxygenation reaction was finally demonstrated in the synthesis of the biologically active compound 80, which was isolated from Xyris pterygoblephara and could be conveniently accessed from the 2-alkenyl benzoic ester 79 in a single transformation in the presence of the chiral iodineACHTUNGRE(III) reagent ent-58.[36] The power of the present transformation was then again demonstrated within short syntheses of several polyketide metabolites.[40] For example, Fujita investigated the cyclization of the chiral homoallylic ether 81 (Scheme 13). In the
Scheme 14. Enantioselective catalytic dioxygenation of alkenes with 84.
Efforts to generate efficient enantioselective catalyses employing the chiral aryl iodides are ongoing. For example, Fujita and co-workers described catalytic conditions for the cyclization of a substrate related to 79 (Scheme 12) using mCPBA as terminal oxidant. While the catalyzed reaction exercises good stereocontrol leading to the syn-dioxygenated product with up to 96 % ee, the overall reaction yields mixtures of up to four isomers owing to a background reaction originating from oxidation with the peracid.[42] Finally, the field of intermolecular enantioselective dioxygenation of alkenes reached significant maturity with an improved protocol from Fujita on diacetoxylation. Standard chiral iodine reagents 58, 60, and 63 were again employed, which led to excellent enantioselectivity. Depending on the reaction conditions, the transformation proceeds with synselectivity in a Woodward-type mechanism. On the contrary, high anti-selectivity can be accomplished following the Prvost mechanism (Scheme 15).[43] These inductions are of high synthetic importance as they can compete with the enantiomeric excesses that are usually encountered for the asymmetric dihydroxylation (AD) of styrene in case of osmium catalysis in the AD process. Finally, Wirth extended the rearrangement reactions that were encountered in several achiral transformations to an enantioselective rearrangement of chalcones (Scheme 16).[44] In the presence of the chiral reagent 93, several activating agents were screened, resulting in the use of TMSOTf as the generally best activator. Working with a mixture of trifluoroethanol and dichloromethane, a range of chalcones 94 could be transformed into the corresponding a-arylated ketones 95, which were formed with enantiomeric excess values of up to 96 %. These examples include a broad substrate scope of arenes with different electronic substituents. The reaction can also be used for the construction of stereogenic quaternary centers. The mechanism was investigated for the selectively deuterated chalcone 96 and its transformation to 99. It is believed to include a face selection within the initial iodineACHTUNGRE(III) interaction with the double bond of
Scheme 13. Reagent control in the enantioselective intramolecular dioxygenation of alkenes.
presence of the achiral iodine reagent PhIACHTUNGRE(OAc)2 21, two diastereomers 82 and 83 are formed as equimolar mixtures, which indicates that the chiral center of the substrate does not exercise influence over the stereochemistry of the cyclization. Consequently, oxidation reactions with the chiral reagent 58 led to a reagent-controlled cyclization to generate the product 82 as a nearly pure diastereomer (98 % ee). As expected, the enantiomeric reagent ent-58 led to a similar dominance of the complementary diastereomer 83, which again is formed with 98 % ee. These results convincingly demonstrate that the dioxygenation reactions proceed under almost complete reagent control. Such transformations were recently also accomplished as catalytic versions by using 10 mol % of the corresponding chiral aryl iodide 84 in the presence of mCPBA as terminal oxidant (Scheme 14). Under such conditions, dioxygenation reactions are capable of generating a series of interesting building blocks for various syntheses of biologically interesting molecules.[40] In the cases of 87 b,c, catalyst control was operating overcoming eventual stereochemical influences through the 1,3-diol groups of the products.[41]
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the substrate. Alkoxyiodination with trifluoroethanol as nucleophile provides 97, which undergoes stereoselective migration of the aryl substituent as in 98 under concomitant formation of the acetal group with a second trifluorethanolate and release of the reduced aryl iodide. In the case of aminooxygenation reactions, no intermolecular enantioselective reactivity has so far been developed.[45] Wirth and co-workers recently reported that an intramolecular cyclization reaction of 100 could indeed proceed with suitable enantioinduction, when the chiral iodineACHTUNGRE(III) reagent 93 was pretreated with TMS triflate followed by reaction at low temperature (Scheme 17).[46, 47] The product 101
Scheme 15. IodineACHTUNGRE(III)-promoted enantioselective intermolecular bisacetoxylation of alkenes. Scheme 17. IodineACHTUNGRE(III)-promoted intramolecular enantioselective aminohydroxylation of alkenes.
could be readily converted into the corresponding (S)-2-phenylprolinol, which enlarges the family of proline derivatives. It should also be mentioned that for the case of an N-phenyl urea derivative, the authors were able to generate the corresponding cyclic urea product. This diamine derivative could be formed with 42 % ee. A related approach to aminofluorination was developed by Nevado.[14] The synthesis of the new chiral difluoroiodineACHTUNGRE(III) reagent 102 was central to this accomplishment. It was generated from the parent aryliodide by oxidation with Selectfluor in the presence of Et3N-3HF and can be considered the chiral analogue of compounds 6 and 12. This new iodineACHTUNGRE(III) reagent efficiently promotes the oxidative cyclization of alkenes 103 into the corresponding aminofluorinated products 104 (Scheme 18). The reaction proceeds with complete endo-selectivity in favor of piperidine formation. This outcome compares well with a related report by Li on the achiral cyclization using a combination of PhIACHTUNGRE(O2CtBu)2, BF3-Et2O, and pyridinium fluoride.[48] The overall reaction results in high ee values, which could be further increased upon crystallization. To rationalize the selective piperidine formation, a deuterium labeling experiment was conducted that confirmed a direct aminofluorination
Scheme 16. Enantioselective iodineACHTUNGRE(III)-mediated rearrangement of chalcones.
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Scheme 19. IodineACHTUNGRE(III)-reagents for the enantioselective diamination of alkenes.
Scheme 18. IodineACHTUNGRE(III)-promoted intramolecular enantioselective aminofluorination of alkenes.
process, and the authors proposed a reaction that is initiated by hydrogen-bond-assisted ligand exchange at iodineACHTUNGRE(III) to form the I N intermediate 107 from 106. Such an intermediate 107 is reminiscent of the Domnguez reagent state 40 and should exercise an electrophilic character at nitrogen. Interaction with the nucleophilic alkene would provide an aziridinium intermidiate 108 that would undergo nucleophilic fluorination at the more electrophilic internal carbon atom. Synthesis of the corresponding azepane ring systems did not proceed under metal-free conditions, but could be realized in the presence of a gold catalyst. MuÇiz and co-workers investigated the use of hypervalent iodineACHTUNGRE(III) reagents 63, 110[49] , and 111[50] for an intermolecular enantioselective diamination of styrenes. Reactions with these reagents usually involve an in situ formation of the active reagent ArI[NACHTUNGRE(SO2R)2]2.[29] For a standard diamination of styrene (56), these hypervalent iodine reagents promoted the expected enantioselective diamination.[51, 52] For example, the spiro-derived reagent 110 led to 32 % ee with bistosylimide as nitrogen source,[52] while the binaphthyl derivative 111 afforded 14 % ee for the same transformation and 32 % ee for the reaction with bismesylimide.[52] Reagent 63 was identified as the most suitable iodineACHTUNGRE(III) source, leading to a product 112 with 50 % ee for bistosylimide and 66 % ee for bismesylimide (Scheme 19). The latter value could be increased to 85 % ee for a reaction at lower temperature, and the product was crystallized to enantiopurity within a single crystallization. Under the reaction conditions with 63 as chiral iodineACHTUNGRE(III) promoter, a series of styrene derivatives 113 underwent an enantioselective diamination reaction under metal-free conditions (Scheme 20).[51] A series of different substitution pat-
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Scheme 20. IodineACHTUNGRE(III)-promoted intermolecular enantioselective diamination of styrenes and enantioselective synthesis of levamisole.
terns are tolerated, and all compounds 114 could be crystallized to enantiopurity within a single crystallization step. The reaction proceeds equally efficient for internal alkenes with (E)- and (Z)-configuration, as exemplified for products 115 and 116. Their respective relative configuration is in agreement with the mechanistic discussion from Scheme 9. The synthetic importance of this first enantioselective intermolecular diamination of alkenes was further underlined by the efficient transformation of the styrene product 112 to
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the free bisammonium salt 117. After its subsequent liberation, the free enantiopure (S)-1-phenyl ethylenediamine 118 could be readily converted into the pharmaceutical levamisole within two steps. The corresponding dihalogenation reactions are far more challenging with respect to a chiral non-racemic reaction course. Lupton and co-workers investigated the possibility to provide an enantioselective dibromination of alkenes with a chiral iodine(V) promoter; however, the products were almost racemic.[10, 53] This observation underlines the importance to control the stereochemical fate of halonium intermediates in this type of reactions. An interesting alternative to the use of hypervalent iodine reactions bearing a chiral backbone for enantoselective induction was developed by Nicolaou.[54] Interest in naturally occurring vicinal dichloride units, as for example in chlorosulfolipids, led to the investigation of an enantioselective vicinal dichlorination reaction. To accomplish this aim, the addition of PhICl2 to alkenes in the presence of a catalytic amount of a Cinchona alkaloid 119 was envisioned. Under the assumption that the latter should form a chirally modified hypervalent iodine reagent, alkene oxidation should proceed enantioselectively from this reagent through an initial chloronium intermediate. Such an intermediate bears additional challenges arising from the notorious configurational instability under certain conditions. In addition, as the primary source of stereochemical induction is absent in the subsequent step of the chloronium opening, high regioselectivity is warranted for this step in order to avoid formation of a product with low enantiomeric excess. To address all these issues, the authors used cinnamic alcohols 120 as substrates, the dimeric Cinchona alkaloid derivative (DHQ)2PHAL 119 as catalyst, and the iodine reagent 4phenyl iodosobenzene dichloride 121, which was identified as the best oxidant among four candidates. The chiral pocket of (DHQ)2PHAL should pre-orientate the substrate, possibly through additional hydrogen bonding between the phthalazine spacer and the hydroxy group of the substrate. The resulting transition state 123 for alkene oxidation should provide high face selectivity in the chloronium formation. The presence of the aryl substituent provides the regioselective bias in the nucleophilic chloronium opening with the chloride nucleophile. Such a high regioselectivity preserved the initial enantioselective induction. Indeed, for cinnamic alcohol itself the reaction to the corresponding vicinal dichloride proceeds with 63 % yield and 81–85 % enantiomeric excess, and several additional dichlorination products 122 could be obtained in an enantioselective manner (Scheme 21).
Scheme 21. IodineACHTUNGRE(III)-promoted chlorination of alkenes.
enantioselective
di-
their enantioselectivity, start to compete with traditional metal-mediated reactions. The recent advent of using chiral iodineACHTUNGRE(III) reagents in catalytic amounts or the identification of suitable combinations of iodineACHTUNGRE(III) reagents and chiral ligands offers huge possibilities for the development of truly efficient methodology for enantioselective homogeneous alkene oxidation.
Acknowledgements The authors thank Fundacin ICIQ and the Spanish Ministerio de Economa y Competitividad (CTQ2011-25027) for financial support. R.M. and T.H.W. thank the Ministerio de Economa y Competitividad and the Deutsche Forschungsgemeinschaft (DFG, WO 1924/1-1) for individual fellowships.
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