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N-heterocyclic carbene-catalyzed reactions of C–C unsaturated bonds Xiang-Yu Chen and Song Ye*
Received 17th July 2013, Accepted 3rd October 2013 DOI: 10.1039/c3ob41469h www.rsc.org/obc
The N-heterocyclic carbene-catalyzed reactions of C–X (X = O, S, N) unsaturated bonds are well established. However, C–C unsaturated bonds are challenging substrates for NHC-catalyzed reactions. In recent years, several reports have demonstrated that NHC-catalyzed reactions of C–C unsaturated bonds are feasible, including the umpolung of Michael acceptors, the Morita–Baylis–Hillman reaction, and the annulation reactions of vinyl sulfones, nitroalkenes, allenoates and alkynes.
Introduction Carbenes are chemical species which possess a bivalent carbon atom with two non-bonding electrons. Divalent carbenes are considered to be highly reactive intermediates, and the isolation of stable carbenes has been a challenge for a long time. Bertrand and co-workers reported the synthesis of phosphinocarbene in 1988.1 Arduengo and co-workers reported the synthesis of stable imidazolium carbenes in 1991.2 Triazolium carbenes, which have showed superior activities as organocatalysts, were first introduced by Enders and co-workers in 1995.3 The earliest example of a N-heterocyclic carbene (NHC)catalyzed reaction can be traced back to 1943, when Ugai and co-workers reported the thiazolium salts-catalyzed benzoin reaction of aldehydes.4 A breakthrough was made by Breslow in 1958 when the mechanism with thiazolium carbene, generated from the thiazolium salt in the presence of a base, as the catalytically active species to generate the Breslow intermediate 2 by the addition of aldehyde 1 was first proposed for the reaction (Scheme 1).5 Since then, NHC-catalyzed reactions of aldehydes, such as the benzoin reaction6 and the Stetter reaction have been well established.7 In 2004, Rovis and co-workers reported the NHC-catalyzed conversion of α-haloaldehydes into acylating agents.8 Bode et al. and Glorius et al. independently reported NHC-catalyzed reactions of enals, involving a homoenolate generated from the addition of a carbene to the enal as the key intermediate.9 After that, NHCs were found to be efficient catalysts for various reactions involving functionalized aldehydes, such as α-haloaldehydes,10 cyclopropanecarboxaldehydes,11 epoxyaldehydes,12 bromoenals,13 ynals,14 enals15 and so on.
Beijing National Laboratory for Molecular Sciences, Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China. E-mail: [email protected]; Fax: (+86)10 6255 4449; Tel: (+86)10 6264 1156
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Scheme 1
NHC-catalyzed a1 to d1 umpolung of aldehydes.
Ye et al. and Smith et al. independently demonstrated a series of NHC-catalyzed reactions of ketenes.16 NHCs were also found to be powerful catalysts for reactions involving esters,17 acyl fluorides,18 activation of silylated nucleophiles,19 alcohols20 and amines,21 reduction of carbon dioxide,22 and other reactions.23 A number of reviews have summarized these NHCcatalyzed reactions.24 Compared to the well-established NHC-catalyzed reaction of C–X (X = O, S, N) bonds, the NHC-catalyzed reaction of C–C unsaturated bonds is far less developed. Although the addition reaction of NHC as a reagent to C–C unsaturated bonds has been developed,25 the catalytic reaction is a challenge due to the stability of the NHC-substrate adduct. However, in recent years, several reports have demonstrated that NHC-catalyzed reactions of C–C unsaturated bonds are feasible. This review will summarize the developments on this subject.
Umpolung of Michael acceptors Umpolung, which means reversing the polarity of a functional moiety, provides a new route in organic synthesis.26 Classically, NHCs have been powerful catalysts for umpolung reactions of aldehydes. In 2006, Fu and co-workers reported an unexpected NHC-catalyzed umpolung of Michael acceptors.27 While exploring the possibility of achieving a palladium-catalyzed Heck reaction with alkyl electrophiles, Fu and co-workers
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Scheme 2
Scheme 3
Organic & Biomolecular Chemistry
Scheme 4
NHC-catalyzed cross-coupling of Michael acceptors.
Scheme 5
NHC-catalyzed cross-coupling of two different Michael acceptors.
Possible mechanism for a3 to d3 umpolung of Michael acceptors.
NHC-catalyzed umpolung of Michael acceptors.
found that carbon–carbon bond formation proceeded more efficiently in the presence of the NHC “ligand” and without palladium. The reaction mechanism proposed involved the addition of the NHC as a nucleophilic catalyst to the Michael acceptor 3, followed by a proton shift to form a β-anion intermediate 5 (Scheme 2). Thus the polarity of the β-carbon of the Michael acceptor was reversed from an acceptor to a donor. DFT calculations of the possible mechanisms were reported by Wang and co-workers.28 They showed that the proton transfers from 4 to 5 could easily occur due to the deoxy-Breslow intermediate 5 being thermodynamically favourable when NHC was used as the catalyst. It was found that the leaving group could be a bromide, tosylate or even a chloride. A variety of five-, six- and even fourmembered carbocycles or heterocycles 7 could be obtained in good yields (Scheme 3). In 2011, the NHC-catalyzed umpolung of Michael acceptors was expanded to the dimerization of methacrylates by
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Matsuoka and co-workers.29 Dimethyl 2,5-dimethyl-2-hexenedioates 10 was obtained by the highly selective tail-to-tail dimerization of methyl methacrylate 9 in up to 87% yield with an E/Z > 88 : 12 using the NHC precursor 8b as a catalyst (Scheme 4). Glorius and co-workers independently reported the NHCcatalyzed dimerization of Michael acceptors, and a better substrate scope was found using Glorius’ reaction conditions.30 A series of α-substituted acrylates were tolerated for the dimerization reaction. Notably, the dimerization of two different Michael acceptors was also successful in their reactions (Scheme 5).
Morita–Baylis–Hillman (MBH) reaction of cyclic enones Since Baylis and Hillman published their pioneering DABCOcatalyzed reaction of acetaldehyde with ethyl acrylate and acrylonitrile in 1972,31 the Morita–Baylis–Hillman (MBH) reaction has become one of the most useful reactions within nucleophilic catalysis. A number of tertiary amines and alkyl(aryl) phosphines were found to be active catalysts for the reaction.32,33 Instead of the nitrogen or phosphine-based nucleophilic catalysts, carbon-based nucleophilic NHCs were also demonstrated to be efficient catalysts for the intermolecular aza-MBH reaction by Ye and co-workers in 2007.34 In the presence of 10 mol% stable NHC 13a, the reaction of cyclic enones 11 with
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Scheme 6
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NHC-catalyzed reaction of cyclic enones with N-tosylarylimines.
Scheme 8
NHC-catalyzed MBH reaction of β-substituted nitroalkenes.
Reactions of vinyl sulfones Scheme 7
Chiral NHC-catalyzed MBH reaction.
a variety of N-tosylarylimines 12 proceeded smoothly to give the aza-MBH adduct 14 in good to excellent yields (Scheme 6). The enantioselective version of the NHC-catalyzed aza-MBH reaction has also been investigated by the Ye group (Scheme 7).35 Unfortunately, nearly a racemate (2% ee) of adduct 14a was obtained when 20 mol% of the chiral NHC precursor 15a, derived from L-pyroglutamic acid, was used as the precatalyst. A series of NHCs with free hydroxyl groups was designed and applied to the reaction. Interestingly, a promising 44% ee was achieved when NHC precursor 15b was employed. The possible hydrogen bonding between the hydroxyl group of the NHC catalyst and the enone 11a may play an important role in increasing the enantioselectivity. Although MBH reactions of terminal alkenes has been well developed, the corresponding MBH reactions of β-substituted alkenes remains a challenge. Namboothiri and co-workers have devoted a great effort to MBH reactions of β-substituted nitroalkenes by using stoichiometric amounts of amine or phosphine-based catalysts.36 Very recently, the catalytic MBH reaction of β-substituted nitroalkenes and azodicarboxylates was realized via NHC catalysis by Ye and co-workers (Scheme 8).37 In the presence of 5 mol% of NHC precursor 18a and 5 mol% of DMAP, the reaction of β-aryl nitroalkenes 16 and azodicarboxylate 17 proceeded smoothly to give the desired aza-MBH adduct 19 in 89–96% yields. Notably, the aliphatic nitroalkenes, which used to be unstable and difficult to react with azodicarboxylates,36b were also feasible substrates under NHC catalysis.
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Vinyl sulfones are valuable reagents in organic synthesis, and can react as electrophiles in organocatalysis and organometallic reactions, and act as participants in cycloadditions.38 In 2011, an NHC-catalyzed stereoselective [3+2] cycloaddition of nitrones 20 and vinyl sulfone 21 was disclosed by Scheidt and co-workers.39 In the presence of 20 mol% of triazolium 8c and sodium tert-butoxide, the [3+2] cycloadducts 22 were obtained in good yields with high diastereoselectivities. It is interesting that the 1,1-disulfinate in the starting materials was changed to 1,2-disulfinate in the cycloadducts (Scheme 9). Azomethine imine 23 also worked well for the reaction to afford the [3+2] cycloadduct 24 in 88% yield. In addition, the NHC-catalyzed [4+2] cycloaddition reaction resulted when furan 25 was employed as the diene and vinyl sulfone 21 as the dienophile (Scheme 10). The possible mechanism for the migration of sulfinate was possibly initiated by the addition of the NHC to vinyl sulfone to generate the zwitterion 27, followed by protonation to give the intermediate 28. The β-proton in 28 was removed by the base to give the ketene aminal 29. Fragmentation of 29 by
Scheme 9
NHC-catalyzed [3+2] cyclization of vinyl sulfones with nitrones.
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Scheme 10
Scheme 11
Organic & Biomolecular Chemistry
Scheme 12
NHC-catalyzed Rauhut–Currier reactions of vinyl sulfone.
Scheme 13
NHC-catalyzed [4+2] cycloaddition of nitroalkenes with oxodienes.
Other NHC-catalyzed cycloaddition reactions of vinyl sulfones.
Possible mechanism for the migration of sulfinate.
ejection of the sulfinate moiety led to the electron-deficient alkene 30. The re-bonding of the sulfinate via a Michael addition gave the 1,2-disulfinate intermediate 31. The cyclization of trans-1,2-bis( phenylsulfonyl) with nitrones 20 afforded the final cycloadducts 22 and regenerated the NHC catalyst (Scheme 11). In 2011, Scheidt and co-workers realized the NHC-catalyzed Rauhut–Currier (RC) reaction40 of vinyl sulfone with enals (Scheme 12). In this type of reaction, the presence of 20 mol% of NHC precursor 8c and 20 mol% of sodium tert-butoxide caused the reaction of enals 32 and vinyl sulfone 21 to react well to give the RC reaction adducts 33 in good yields.41 The possible reaction mechanism involving the addition of NHC to vinyl sulfone was discussed in Scheidt’s report.
aminoalkenes and aminoacids.42 In 2013, Ye and co-workers discovered the NHC-catalyzed [4+2] annulation reaction of nitroalkenes and oxodienes (Scheme 13).43 Interestingly, the diastereoselectivity could be switched by choosing NHC catalysts with different N-substituents. In the presence of 20 mol% of NHC precursor 18b with an N-mesitylmethyl group, the 2,3trans cycloadduct 35 was isolated as the major isomer, whereas using NHC 18c with an N-3,5-di(trifluoromethyl)phenylmethyl substituent resulted in the 2,3-cis cycloadduct 36 as the major isomer. Deuteration of adduct 37, followed by elimination gives α-deuterium nitroalkenes. The addition of an NHC to the β-position of a nitroalkene can enhance the acidity of the β-proton, and thus leads to a β-deuterium nitroalkene. The deuterium experiment revealed that the reaction was possibly initiated by the addition of the NHC to the nitroalkene. 19% and 14% deuteration at the α- and β-positions of the nitroalkene 16a was observed when the compound was subjected to the NHC precursor 18b (20 mol%), 1 equivalent of base, and D2O (Scheme 14).
[2+2+2] Annulation of allenoates [4+2] Annulation of nitroalkenes with oxodienes Nitroalkenes are valuable structural motifs and have found wide application in the synthesis of biologically active compounds and complex molecules, largely because they can be further transformed into useful elaborate structures, such as
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The Lewis base-catalyzed cycloaddition of allenoates is very useful for constructing cyclic compounds.44 In 1995, Lu and co-workers pioneered the phosphine-promoted [3+2] cycloaddition of allenoates with electron-deficient olefins.45 From then on, a series of phosphine- and amine-catalyzed cycloaddition reactions of allenoates have been reported. In contrast to these well-developed reactions, the corresponding reactions catalyzed by NHCs are less well explored.
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Scheme 14
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Deuteration experiment and its rationalization.
Scheme 16
Scheme 15
Possible mechanism for NHC-catalyzed annulation of allenoates.
NHC-catalyzed [2+2+2] annulation of allenoates.
In 2011, Ye and co-workers reported an NHC-catalyzed [2+2+2] cycloaddition of allenoates with two molecules of trifluoromethylketone.46 It is very interesting that the [3+2] and [2+2] cycloadducts were afforded when phosphine and DABCO were employed, respectively, as the catalyst for the reaction (Scheme 15).47 The possible catalytic cycle of the reaction is depicted in Scheme 16. The addition of the NHC to the allenoate generates the allylic zwitterion 41, which reacts with the ketone via a γ-addition to afford adduct 42. A second molecule of the ketone reacts with the adduct 42 to give adduct 43. An intramolecular addition in 43 leads to cycloadduct 44, which fragments to furnish the final [2+2+2] product 40 and regenerate the catalyst. It is noteworthy that the [2+2] product 45 may be afforded by the cyclization of adduct 42. This reaction is found in the DABCO-catalyzed reaction47b but not in the NHC-catalyzed [2+2+2] reaction. The poorer leaving-ability of the NHC may be beneficial to the stability of adduct 42, and thus the addition to a second ketone molecule is facile.
1,3-Dipolar cycloaddition reactions of alkynes 1,3-Dipolar cycloaddition reactions of nitrile oxides with alkynes provides easy access to isoxazoles.48 In 2011, Vasam and co-workers reported an NHC-catalyzed 1,3-dipolar cycloaddition reaction of nitrile oxides and alkynes.49 A series of
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Scheme 17 NHC-catalyzed 1,3-dipolar cycloaddition of a terminal alkyne with nitrile oxides.
nitrile oxides 46 reacted well with the terminal alkyne 47 derived from isoindole under the catalytic influence of NHC 13b to give the desired isoxazoles 48 in good yields (Scheme 17). In addition, various internal alkynes 49 also worked well for the reaction to afford 3,4,5-trisubstituted isoxazoles 50 in good yields (Scheme 18). One possible mechanism for the NHC-catalyzed reaction is that it is initiated by the addition of the NHC to the alkyne. The addition of the resulting zwitterion 51 to nitrile oxides gives adducts 52. An intramolecular addition in 52 leads to
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Organic & Biomolecular Chemistry Considering the wide presence of carbon–carbon unsaturated bonds in organic compounds and the structural diversity of NHC catalysts, many more NHC-catalyzed reactions of carbon–carbon unsaturated bonds may be expected in the future. In particular, the enantioselective versions of those reactions catalyzed by chiral NHCs will be of great value and requires attention.
Acknowledgements Financial support from the National Natural Science Foundation of China (no. 21272237), the Ministry of Science and Technology of China (2011CB808600), and the Chinese Academy of Sciences is gratefully acknowledged.
Scheme 18 NHC-catalyzed 1,3-dipolar cycloaddition of internal alkynes with nitrile oxides.
Scheme 19
Possible mechanism for NHC-catalyzed cycloaddition of alkynes.
cycloadduct 53, which fragmentes to afford the final isoxazoles and regenerate the catalyst (Scheme 19).
Conclusions The NHC-catalyzed reactions of carbon–carbon unsaturated bonds have been successfully explored in recent years. NHCs have been demonstrated as effective carbon-nucleophilic catalysts compared to amines and phosphines, for the reaction of α-carbons in Michael acceptors, such as in the Morita–Baylis– Hillman reaction. The reaction of β-carbons in Michael acceptors is also successful, possible due to the stabilization of the β-carbon anion attached to the NHC motif. Furthermore, taking advantage of the reactivity of both the α- and β-carbons in Michael acceptors, the annulation reaction has also been developed.
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N-heterocyclic carbene-catalyzed reactions of C–C unsaturated bonds Xiang-Yu Chen and Song Ye*
Received 17th July 2013, Accepted 3rd October 2013 DOI: 10.1039/c3ob41469h www.rsc.org/obc
The N-heterocyclic carbene-catalyzed reactions of C–X (X = O, S, N) unsaturated bonds are well established. However, C–C unsaturated bonds are challenging substrates for NHC-catalyzed reactions. In recent years, several reports have demonstrated that NHC-catalyzed reactions of C–C unsaturated bonds are feasible, including the umpolung of Michael acceptors, the Morita–Baylis–Hillman reaction, and the annulation reactions of vinyl sulfones, nitroalkenes, allenoates and alkynes.
Introduction Carbenes are chemical species which possess a bivalent carbon atom with two non-bonding electrons. Divalent carbenes are considered to be highly reactive intermediates, and the isolation of stable carbenes has been a challenge for a long time. Bertrand and co-workers reported the synthesis of phosphinocarbene in 1988.1 Arduengo and co-workers reported the synthesis of stable imidazolium carbenes in 1991.2 Triazolium carbenes, which have showed superior activities as organocatalysts, were first introduced by Enders and co-workers in 1995.3 The earliest example of a N-heterocyclic carbene (NHC)catalyzed reaction can be traced back to 1943, when Ugai and co-workers reported the thiazolium salts-catalyzed benzoin reaction of aldehydes.4 A breakthrough was made by Breslow in 1958 when the mechanism with thiazolium carbene, generated from the thiazolium salt in the presence of a base, as the catalytically active species to generate the Breslow intermediate 2 by the addition of aldehyde 1 was first proposed for the reaction (Scheme 1).5 Since then, NHC-catalyzed reactions of aldehydes, such as the benzoin reaction6 and the Stetter reaction have been well established.7 In 2004, Rovis and co-workers reported the NHC-catalyzed conversion of α-haloaldehydes into acylating agents.8 Bode et al. and Glorius et al. independently reported NHC-catalyzed reactions of enals, involving a homoenolate generated from the addition of a carbene to the enal as the key intermediate.9 After that, NHCs were found to be efficient catalysts for various reactions involving functionalized aldehydes, such as α-haloaldehydes,10 cyclopropanecarboxaldehydes,11 epoxyaldehydes,12 bromoenals,13 ynals,14 enals15 and so on.
Beijing National Laboratory for Molecular Sciences, Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China. E-mail: [email protected]; Fax: (+86)10 6255 4449; Tel: (+86)10 6264 1156
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Scheme 1
NHC-catalyzed a1 to d1 umpolung of aldehydes.
Ye et al. and Smith et al. independently demonstrated a series of NHC-catalyzed reactions of ketenes.16 NHCs were also found to be powerful catalysts for reactions involving esters,17 acyl fluorides,18 activation of silylated nucleophiles,19 alcohols20 and amines,21 reduction of carbon dioxide,22 and other reactions.23 A number of reviews have summarized these NHCcatalyzed reactions.24 Compared to the well-established NHC-catalyzed reaction of C–X (X = O, S, N) bonds, the NHC-catalyzed reaction of C–C unsaturated bonds is far less developed. Although the addition reaction of NHC as a reagent to C–C unsaturated bonds has been developed,25 the catalytic reaction is a challenge due to the stability of the NHC-substrate adduct. However, in recent years, several reports have demonstrated that NHC-catalyzed reactions of C–C unsaturated bonds are feasible. This review will summarize the developments on this subject.
Umpolung of Michael acceptors Umpolung, which means reversing the polarity of a functional moiety, provides a new route in organic synthesis.26 Classically, NHCs have been powerful catalysts for umpolung reactions of aldehydes. In 2006, Fu and co-workers reported an unexpected NHC-catalyzed umpolung of Michael acceptors.27 While exploring the possibility of achieving a palladium-catalyzed Heck reaction with alkyl electrophiles, Fu and co-workers
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Scheme 2
Scheme 3
Organic & Biomolecular Chemistry
Scheme 4
NHC-catalyzed cross-coupling of Michael acceptors.
Scheme 5
NHC-catalyzed cross-coupling of two different Michael acceptors.
Possible mechanism for a3 to d3 umpolung of Michael acceptors.
NHC-catalyzed umpolung of Michael acceptors.
found that carbon–carbon bond formation proceeded more efficiently in the presence of the NHC “ligand” and without palladium. The reaction mechanism proposed involved the addition of the NHC as a nucleophilic catalyst to the Michael acceptor 3, followed by a proton shift to form a β-anion intermediate 5 (Scheme 2). Thus the polarity of the β-carbon of the Michael acceptor was reversed from an acceptor to a donor. DFT calculations of the possible mechanisms were reported by Wang and co-workers.28 They showed that the proton transfers from 4 to 5 could easily occur due to the deoxy-Breslow intermediate 5 being thermodynamically favourable when NHC was used as the catalyst. It was found that the leaving group could be a bromide, tosylate or even a chloride. A variety of five-, six- and even fourmembered carbocycles or heterocycles 7 could be obtained in good yields (Scheme 3). In 2011, the NHC-catalyzed umpolung of Michael acceptors was expanded to the dimerization of methacrylates by
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Matsuoka and co-workers.29 Dimethyl 2,5-dimethyl-2-hexenedioates 10 was obtained by the highly selective tail-to-tail dimerization of methyl methacrylate 9 in up to 87% yield with an E/Z > 88 : 12 using the NHC precursor 8b as a catalyst (Scheme 4). Glorius and co-workers independently reported the NHCcatalyzed dimerization of Michael acceptors, and a better substrate scope was found using Glorius’ reaction conditions.30 A series of α-substituted acrylates were tolerated for the dimerization reaction. Notably, the dimerization of two different Michael acceptors was also successful in their reactions (Scheme 5).
Morita–Baylis–Hillman (MBH) reaction of cyclic enones Since Baylis and Hillman published their pioneering DABCOcatalyzed reaction of acetaldehyde with ethyl acrylate and acrylonitrile in 1972,31 the Morita–Baylis–Hillman (MBH) reaction has become one of the most useful reactions within nucleophilic catalysis. A number of tertiary amines and alkyl(aryl) phosphines were found to be active catalysts for the reaction.32,33 Instead of the nitrogen or phosphine-based nucleophilic catalysts, carbon-based nucleophilic NHCs were also demonstrated to be efficient catalysts for the intermolecular aza-MBH reaction by Ye and co-workers in 2007.34 In the presence of 10 mol% stable NHC 13a, the reaction of cyclic enones 11 with
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Scheme 6
Emerging Area
NHC-catalyzed reaction of cyclic enones with N-tosylarylimines.
Scheme 8
NHC-catalyzed MBH reaction of β-substituted nitroalkenes.
Reactions of vinyl sulfones Scheme 7
Chiral NHC-catalyzed MBH reaction.
a variety of N-tosylarylimines 12 proceeded smoothly to give the aza-MBH adduct 14 in good to excellent yields (Scheme 6). The enantioselective version of the NHC-catalyzed aza-MBH reaction has also been investigated by the Ye group (Scheme 7).35 Unfortunately, nearly a racemate (2% ee) of adduct 14a was obtained when 20 mol% of the chiral NHC precursor 15a, derived from L-pyroglutamic acid, was used as the precatalyst. A series of NHCs with free hydroxyl groups was designed and applied to the reaction. Interestingly, a promising 44% ee was achieved when NHC precursor 15b was employed. The possible hydrogen bonding between the hydroxyl group of the NHC catalyst and the enone 11a may play an important role in increasing the enantioselectivity. Although MBH reactions of terminal alkenes has been well developed, the corresponding MBH reactions of β-substituted alkenes remains a challenge. Namboothiri and co-workers have devoted a great effort to MBH reactions of β-substituted nitroalkenes by using stoichiometric amounts of amine or phosphine-based catalysts.36 Very recently, the catalytic MBH reaction of β-substituted nitroalkenes and azodicarboxylates was realized via NHC catalysis by Ye and co-workers (Scheme 8).37 In the presence of 5 mol% of NHC precursor 18a and 5 mol% of DMAP, the reaction of β-aryl nitroalkenes 16 and azodicarboxylate 17 proceeded smoothly to give the desired aza-MBH adduct 19 in 89–96% yields. Notably, the aliphatic nitroalkenes, which used to be unstable and difficult to react with azodicarboxylates,36b were also feasible substrates under NHC catalysis.
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Vinyl sulfones are valuable reagents in organic synthesis, and can react as electrophiles in organocatalysis and organometallic reactions, and act as participants in cycloadditions.38 In 2011, an NHC-catalyzed stereoselective [3+2] cycloaddition of nitrones 20 and vinyl sulfone 21 was disclosed by Scheidt and co-workers.39 In the presence of 20 mol% of triazolium 8c and sodium tert-butoxide, the [3+2] cycloadducts 22 were obtained in good yields with high diastereoselectivities. It is interesting that the 1,1-disulfinate in the starting materials was changed to 1,2-disulfinate in the cycloadducts (Scheme 9). Azomethine imine 23 also worked well for the reaction to afford the [3+2] cycloadduct 24 in 88% yield. In addition, the NHC-catalyzed [4+2] cycloaddition reaction resulted when furan 25 was employed as the diene and vinyl sulfone 21 as the dienophile (Scheme 10). The possible mechanism for the migration of sulfinate was possibly initiated by the addition of the NHC to vinyl sulfone to generate the zwitterion 27, followed by protonation to give the intermediate 28. The β-proton in 28 was removed by the base to give the ketene aminal 29. Fragmentation of 29 by
Scheme 9
NHC-catalyzed [3+2] cyclization of vinyl sulfones with nitrones.
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Scheme 10
Scheme 11
Organic & Biomolecular Chemistry
Scheme 12
NHC-catalyzed Rauhut–Currier reactions of vinyl sulfone.
Scheme 13
NHC-catalyzed [4+2] cycloaddition of nitroalkenes with oxodienes.
Other NHC-catalyzed cycloaddition reactions of vinyl sulfones.
Possible mechanism for the migration of sulfinate.
ejection of the sulfinate moiety led to the electron-deficient alkene 30. The re-bonding of the sulfinate via a Michael addition gave the 1,2-disulfinate intermediate 31. The cyclization of trans-1,2-bis( phenylsulfonyl) with nitrones 20 afforded the final cycloadducts 22 and regenerated the NHC catalyst (Scheme 11). In 2011, Scheidt and co-workers realized the NHC-catalyzed Rauhut–Currier (RC) reaction40 of vinyl sulfone with enals (Scheme 12). In this type of reaction, the presence of 20 mol% of NHC precursor 8c and 20 mol% of sodium tert-butoxide caused the reaction of enals 32 and vinyl sulfone 21 to react well to give the RC reaction adducts 33 in good yields.41 The possible reaction mechanism involving the addition of NHC to vinyl sulfone was discussed in Scheidt’s report.
aminoalkenes and aminoacids.42 In 2013, Ye and co-workers discovered the NHC-catalyzed [4+2] annulation reaction of nitroalkenes and oxodienes (Scheme 13).43 Interestingly, the diastereoselectivity could be switched by choosing NHC catalysts with different N-substituents. In the presence of 20 mol% of NHC precursor 18b with an N-mesitylmethyl group, the 2,3trans cycloadduct 35 was isolated as the major isomer, whereas using NHC 18c with an N-3,5-di(trifluoromethyl)phenylmethyl substituent resulted in the 2,3-cis cycloadduct 36 as the major isomer. Deuteration of adduct 37, followed by elimination gives α-deuterium nitroalkenes. The addition of an NHC to the β-position of a nitroalkene can enhance the acidity of the β-proton, and thus leads to a β-deuterium nitroalkene. The deuterium experiment revealed that the reaction was possibly initiated by the addition of the NHC to the nitroalkene. 19% and 14% deuteration at the α- and β-positions of the nitroalkene 16a was observed when the compound was subjected to the NHC precursor 18b (20 mol%), 1 equivalent of base, and D2O (Scheme 14).
[2+2+2] Annulation of allenoates [4+2] Annulation of nitroalkenes with oxodienes Nitroalkenes are valuable structural motifs and have found wide application in the synthesis of biologically active compounds and complex molecules, largely because they can be further transformed into useful elaborate structures, such as
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The Lewis base-catalyzed cycloaddition of allenoates is very useful for constructing cyclic compounds.44 In 1995, Lu and co-workers pioneered the phosphine-promoted [3+2] cycloaddition of allenoates with electron-deficient olefins.45 From then on, a series of phosphine- and amine-catalyzed cycloaddition reactions of allenoates have been reported. In contrast to these well-developed reactions, the corresponding reactions catalyzed by NHCs are less well explored.
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Scheme 14
Emerging Area
Deuteration experiment and its rationalization.
Scheme 16
Scheme 15
Possible mechanism for NHC-catalyzed annulation of allenoates.
NHC-catalyzed [2+2+2] annulation of allenoates.
In 2011, Ye and co-workers reported an NHC-catalyzed [2+2+2] cycloaddition of allenoates with two molecules of trifluoromethylketone.46 It is very interesting that the [3+2] and [2+2] cycloadducts were afforded when phosphine and DABCO were employed, respectively, as the catalyst for the reaction (Scheme 15).47 The possible catalytic cycle of the reaction is depicted in Scheme 16. The addition of the NHC to the allenoate generates the allylic zwitterion 41, which reacts with the ketone via a γ-addition to afford adduct 42. A second molecule of the ketone reacts with the adduct 42 to give adduct 43. An intramolecular addition in 43 leads to cycloadduct 44, which fragments to furnish the final [2+2+2] product 40 and regenerate the catalyst. It is noteworthy that the [2+2] product 45 may be afforded by the cyclization of adduct 42. This reaction is found in the DABCO-catalyzed reaction47b but not in the NHC-catalyzed [2+2+2] reaction. The poorer leaving-ability of the NHC may be beneficial to the stability of adduct 42, and thus the addition to a second ketone molecule is facile.
1,3-Dipolar cycloaddition reactions of alkynes 1,3-Dipolar cycloaddition reactions of nitrile oxides with alkynes provides easy access to isoxazoles.48 In 2011, Vasam and co-workers reported an NHC-catalyzed 1,3-dipolar cycloaddition reaction of nitrile oxides and alkynes.49 A series of
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Scheme 17 NHC-catalyzed 1,3-dipolar cycloaddition of a terminal alkyne with nitrile oxides.
nitrile oxides 46 reacted well with the terminal alkyne 47 derived from isoindole under the catalytic influence of NHC 13b to give the desired isoxazoles 48 in good yields (Scheme 17). In addition, various internal alkynes 49 also worked well for the reaction to afford 3,4,5-trisubstituted isoxazoles 50 in good yields (Scheme 18). One possible mechanism for the NHC-catalyzed reaction is that it is initiated by the addition of the NHC to the alkyne. The addition of the resulting zwitterion 51 to nitrile oxides gives adducts 52. An intramolecular addition in 52 leads to
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Organic & Biomolecular Chemistry Considering the wide presence of carbon–carbon unsaturated bonds in organic compounds and the structural diversity of NHC catalysts, many more NHC-catalyzed reactions of carbon–carbon unsaturated bonds may be expected in the future. In particular, the enantioselective versions of those reactions catalyzed by chiral NHCs will be of great value and requires attention.
Acknowledgements Financial support from the National Natural Science Foundation of China (no. 21272237), the Ministry of Science and Technology of China (2011CB808600), and the Chinese Academy of Sciences is gratefully acknowledged.
Scheme 18 NHC-catalyzed 1,3-dipolar cycloaddition of internal alkynes with nitrile oxides.
Scheme 19
Possible mechanism for NHC-catalyzed cycloaddition of alkynes.
cycloadduct 53, which fragmentes to afford the final isoxazoles and regenerate the catalyst (Scheme 19).
Conclusions The NHC-catalyzed reactions of carbon–carbon unsaturated bonds have been successfully explored in recent years. NHCs have been demonstrated as effective carbon-nucleophilic catalysts compared to amines and phosphines, for the reaction of α-carbons in Michael acceptors, such as in the Morita–Baylis– Hillman reaction. The reaction of β-carbons in Michael acceptors is also successful, possible due to the stabilization of the β-carbon anion attached to the NHC motif. Furthermore, taking advantage of the reactivity of both the α- and β-carbons in Michael acceptors, the annulation reaction has also been developed.
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