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Removal of amino groups from anilines through diazonium salt-based reactions Linman He,a Guanyinsheng Qiu,b Yueqiu Gao*a and Jie Wu*b This minireview describes the applications of in situ generated diazonium salts from anilines in organic synthesis. In situ generation of diazonium salts from anilines represents an efficient and practical pathway,
Received 20th June 2014, Accepted 23rd July 2014
leading to a series of useful structures. In these transformations, the amino group of aniline formally acts
DOI: 10.1039/c4ob01286k
as a leaving group. Two distinctive kinds of mechanisms, including transition metal (especially palladium)catalyzed oxidative addition–reductive elimination and a radical process, are involved in the removal of
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amino groups from anilines, and both catalytic processes are described in this minireview.
1.
Introduction
Diazonium salt-based reactions have been employed during the course of the past century to synthesize halides, phenols, cyanides, azides, and alkenes as well as other compounds. Diazonium salts are prone to undergo a homolytic dediazoniation to provide aryl radicals. The in situ generated aryl radicals can then be trapped by other reactive species to deliver the desired products. It’s generally accepted that the availability, stability, and safety of diazonium salts are the key factors that affect the results when carrying out these transformations. Consequently, despite the achievements of diazonium salt-based chemistry to date,1,2 the multistep synthesis of diazonium salts and their hazardous profiles to some extent limit the applications of these types of reactions in organic synthesis. To improve the traditional Sandmeyer, Meerwein, and Heck–Matsuda reactions,2 the focus was shifted to avoid isolating the diazonium salts. This minireview is concerned with the recent advancement of the direct transformations of anilines, where the amino group is removed from the aniline, and thus formally acts as a leaving group (Scheme 1).
Scheme 1
Aryl amines are known to be easily accessible as well as relatively safe and highly stable, and are hence common synthons in transitional metal-catalyzed coupling reactions and nonmetal-mediated transformations.3 Usually, direct transformations of anilines involve cleavage of C–N bonds in anilines, and the amino group acts as a formal leaving group in the process. Here, diazonium salts are generated as the key intermediates via an in situ strategy without being isolated. Generally, to realize the direct transformations of anilines, some issues have to be addressed: (1) to find appropriate diazotizing reagents of anilines that provide sufficiently stable and safe diazonium salts under mild conditions; and (2) importantly, the developed aniline-diazotizing process should be suitable for the subsequent transformations. The above two issues appear to have recently been addressed by employing tBuONO (tert-butyl nitrite) and related compounds as diazotizing reagents, and the direct transformations of anilines have been successfully accomplished in the presence of metal salts and non-metal conditions. Two distinctive kinds of mechanisms, involving the use of different catalysts, are generally recognized, and their applications to removing the amino groups from anilines are reviewed here. The first pathway discussed involves transition metal (especially palladium)-catalyzed couplings, and involves the common oxidative addition and reductive elimination. The second pathway is described as a radical process, which occurs in the presence of copper salts or in the absence of metals.
Coupling reactions via C–N bond cleavage of anilines.
a
Department of Hepatology Disease, Shanghai Shuguang Hospital, Shanghai University of T.C.M., Shanghai 201203, China. E-mail: [email protected] b Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China. E-mail: [email protected]; Fax: +86 21 6564 1740; Tel: +86 21 6510 2412
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2. Transitional metal-catalyzed removal of amino groups from anilines One initially elegant example involving the palladium-catalyzed removal of an amino group from aniline 1 was developed
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Scheme 4 Palladium-catalyzed removal of amino groups from anilines with styrenes. Scheme 2 Palladium-catalyzed removal of amino groups from anilines with arylboronic acids.
in 2001 by Andrus and co-workers (Scheme 2), where arylboronic acids 2 were employed as partners of Suzuki-type reactions.4 In the transformation, in situ generated diazonium fluoroborates 4 from anilines were initially involved, and palladium–imidazolium carbene 5 was used as an efficient catalyst to form 1,1′-diphenyl 3 in moderate to good yields. The full-scope evaluation of substrates indicated that electronic and steric hindrance effects of substrates made slight impact on the outcome of reactions. For example, the arylboronic acid with o-methoxyl group 2a was compatible for the reaction, leading to compound 3a in 53% yield. According to Wang’s findings, the arylation reactions of anilines 1 with boronic acids 2 for the synthesis of biphenyl 3 went through a palladium-catalyzed oxidative addition, transmetallation and reductive elimination. As illustrated in Scheme 3, in situ diazotization of aniline provided the key intermediate 4. This intermediate was treated with Pd(0), leading to intermediate 6. Extrusion of nitrogen from intermediate 6 afforded the formation of active palladium species 7. Then transmetallation and reductive elimination were followed to afford the biaryl product 3.5 In 2002, Andrus and co-workers further expanded this strategy into the Heck–Matsuda reactions, where inactivated styrenes 9 were employed as reaction partners. The scope evaluation of substrates suggested that the electron-rich alkene 9b was unfavorable in the reaction, producing the (Z)-1,2-disubstituted alkene 10b with a 21% yield (Scheme 4).6 These two examples demonstrated that the in situ generation of diazonium salts from anilines proceeded smoothly in the presence of stoichiometric amounts of BF3·Et2O in THF and tert-butylnitrile at 0 °C.
Scheme 3 A mechanism for the palladium-catalyzed reaction of anilines with boronic acids.
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Interestingly, Felpin and co-workers designed an unprecedented double catalytic cycle (MeSO3H and palladium) to explore the reaction of anilines 1 with α,β-unsaturated esters 11. In contrast to what was done previously, Felpin and coworkers avoided the use of stoichiometric amounts of acid as an additive, greatly improving the practicality of this transformation (Scheme 5).7 In 2011, Beller and co-workers applied the approach of in situ generation of diazonium salts from anilines 1 into Sonogashira reactions. In the transformation, anilines were used as an aryl source. As expected, various internal alkynes 19 were synthesized under standard conditions. From the scope investigation of substrates, it found that in all cases, the desired 1,2-disubstituted alkynes 19 were afforded in moderate to excellent yields. Thermally unstable phenyl propargyl ester 17b and propargyl benzoate 17c were particularly suitable under the conditions and the corresponding products 19b and 19c were formed with yields of 58% and 67%, respectively. Electronic properties of anilines 1 did not greatly affect the yields of products, as the reactions using anilines with electrondonating or electron-withdrawing groups as substrates could work well. A probe into the mechanism revealed that the in situ generation of diazonium salts 4 from anilines 1 was critical, and the result was different from that of the previous works since Beller and co-workers used HOAc as the additive in the process of in situ diazotization. Subsequent oxidative addition of diazonium salts 4 into the Pd(0) complex, deprotonation, and reductive elimination of aryl(alkenyl)palladium species 18 provided the corresponding products 19 (Scheme 6).8
Scheme 5 MeSO3H and palladium-catalyzed reaction of anilines with α,β-unsaturated esters.
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Review
summarizes radical reactions of anilines including coppermediated and metal-free Sandmeyer or Meerwein reactions.
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3.1 Copper-mediated Sandmeyer or Meerwein reactions of anilines
Scheme 6
A palladium-catalyzed reaction of anilines with alkynes.
3. Radical removal of the aniline amino group Copper-mediated Sandmeyer or Meerwein reactions are well recognized as the model of radical processes. In 1977, Doyle and co-workers studied the copper-mediated Meerwein-type reaction of anilines 1 with acrylonitrile 20, producing 2-chloro3-arylpropanenitrile 21 (Scheme 7). As presented in Scheme 7, the in situ generated diazonium salts 4 underwent a coppermediated homolytic dediazoniation, providing aryl radical 22. The subsequent radical addition into acrylonitrile 20 gave rise to a new radical 23. Nucleophilic substitution followed by oxidation of radical 23 afforded the products 21 in moderate yields. The mechanistic studies revealed that the chlorine atom was derived from a stoichiometric amount of CuCl2, and the bromine atom could be substituted into the desired products if CuBr2 was employed as the copper source.9 Recently, metal-free Sandmeyer or Meerwein reactions of anilines via radical process were reported. In these cases, a radical initiator was necessary for the formation of aryl radical 22. Metal-free reactions of anilines provided efficient alternatives to many useful building blocks. This section primarily
Scheme 7 A copper-mediated reaction of anilines with acrylonitrile via a radical process.
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Incorporation of fluoro-containing building blocks into small molecules is of high significance. Consequently, landmark progress involving copper-mediated Sandmeyer trifluoromethylation of anilines 1 was reported by Fu and co-workers, using Umemoto’s reagent as a partner with the formation of trifluorobenzene 24 with high efficiency (Scheme 8).10 From mechanistic studies, a radical process was proposed. In this process, diazotization of anilines in situ released aryl diazonium salt 4, and the reaction combining C–N bond cleavage with the formation of a C–CF3 bond delivered the products 24 with excellent functional group tolerance at low temperature. Interestingly, by altering the trifluoromethylation reagent into AgCF3, a distinctive pathway (named an oxidative addition– reductive elimination mechanism) was involved due to the strong σ-donor nature of AgCF3. The scope of substrates indicated the efficiency of silver-mediated Sandmeyer trifluoromethylation of anilines 1. From their results, it was found that counterions of diazonium salts had a significant effect on the reaction. Chloride (Cl−), bromide (Br−), and CF3CO2− were excellent candidates.11 A catalytic version of the radical reaction of anilines was reported by Felpin in 2013. As shown in Scheme 9, a room temperature copper-catalyzed radical C–H arylation of pyrroles 26 with anilines, through in situ generated diazonium salts 4, was developed under neutral conditions. Experimental and theoretical studies indicated that the CaCO3 as an additive played a crucial role.12 According to their findings, two roles for CaCO3 were proposed. Its first role was as a buffer additive, suppressing the formation of any acid-mediated azo compounds. Additionally, CaCO3 may participate in the catalytic cycle to improve the reaction efficiency. In particular, high regioselectivity was observed, leading to C2-arylated pyrroles 27. To avoid the double arylation at C2/C5 positions, an excess amount of pyrroles 26 was required. The radical C–H arylation using anilines as an aryl source could be further applied to that of benzoquinone 30, where graphite-supported copper oxide nanoparticles was used as a heterogeneous catalyst (Scheme 10). Interestingly, the reactions could occur in water. From the results, the reaction con-
Scheme 8
Sandmeyer trifluoromethylation of anilines.
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ing a key intermediate 35, which would coordinate with radial species 22 to form intermediate 36. Releasing SO3 in 36 would afford intermediate 37 followed by reductive elimination to produce the desired thioethers 34 in good yields. The substrate scope was demonstrated as well.14 In addition to the above copper-catalyzed reactions, ferrocene was also used as a catalyst in the radical reactions with anilines. Similar to the copper-catalyzed arylation mentioned above, a radical pathway in this case is possible as well. An aryl radical 22 was produced through a single-electron reduction of a diazonium intermediate with ferrocene as a catalyst. Addition of aryl radical into the unsaturated bond of vinyl ether, single-electron oxidation, and hydrolysis would then afford the desired product 39 and regenerate the ferrocene catalyst (Scheme 12).15
Scheme 9
Scheme 10 aniline.
Copper-catalyzed C–H arylation of pyrroles with anilines.
Copper-catalyzed C–H arylation of benzoquinone with
ditions were compatible with a variety of substituents including halo, carbonyl, and nitro groups etc., and the CaCO3 additive could be omitted in the process. The mechanism involving a radical process is well accepted.13 Recently, Jiang and co-workers reported an efficient and practical protocol to prepare thioethers 34 from anilines 1. As illustrated in Scheme 11, a copper-catalyzed S-transfer reaction was proposed, and a radical process is plausible. In the reactions, Na2S2O3 was treated with benzyl chloride (BnCl) produc-
Scheme 11
Copper-catalyzed S-transfer reaction of anilines.
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3.2
Metal-free Sandmeyer or Meerwein reactions of anilines
One of the key challenges in the direct Sandmeyer-type functionalization of anilines is the achievement of metal-free transformations. Wang and co-workers realized the direct Sandmeyer-type borylation of anilines in the absence of metals (Scheme 13). In the reactions, diboron pinacol (B2pin2) 42 was used as a borylating reagent. Notably, benzoyl peroxide (BPO) as a radical initiator guaranteed this metal-free borylation of anilines at room temperature. Control experiments revealed that the borylation became sluggish when the radical scavenger 2,2,6,6-tetramethyl-1-piperidin-1-oxyl (TEMPO) was added. The direct borylation of a wide range of aniline substrates proceeded smoothly, and functional groups were compatible under the conditions. For example, reaction of 4-nitroaniline worked well, leading to the boronate 43a with a 91% yield.
Scheme 12
Ferrocene-catalyzed reaction of anilines with vinyl ether.
Scheme 13 pinacol.
Direct metal-free borylation of anilines with diboron
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Reaction of 4-carbonyl-substituted aniline afforded the corresponding product 43b with a 67% yield. However, sterically hindered substrates were unfavorable for the transformation. For instance, the borylation of 2-cyanoaniline under standard conditions produced the boronate 43c with only a 22% yield.16 To effect the direct metal-free Sandmeyer borylation of anilines with potentially sterically hindering groups, Wang and co-workers further explored the transformation by elevating the reaction temperature to 80 °C without any additive. The desired process worked very well with excellent function tolerance. It is noteworthy that high reactivities of electrondeficient heterocyclic amines were displayed. In contrast, the electron-rich heterocyclic amines were prone to being oxidized, resulting in low yields. Interestingly, the direct borylation of para-substituted anilines worked better than that of ortho-, meta-substituted, and multi-substituted arylamines (Scheme 14).17 The power of this metal-free direct borylation of anilines was elegantly illustrated by gram-scale production. Studies of the mechanism revealed that the reactions proceeded through a free-radical process (Scheme 15). Subsequently, a Sandmeyer-type stannylation of anilines under mild conditions was disclosed by Wang, leading to aryl trimethylstannanes 45 in moderate to good yields in most
Scheme 14 Direct metal-free Sandmeyer borylation of anilines at relatively high temperatures.
Scheme 15 of anilines.
Review
cases. The results revealed that the presence of TsOH as an additive was crucial to provide more stable diazonium salt intermediates. A study of the mechanism indicated that a radical process could account for this Sandmeyer-type stannylation of anilines (Scheme 16). The substrate generality of this direct stannylation of anilines was explored. It was found that the reaction proceeded smoothly with a broad scope of substrates. Different functional groups including cyano, nitro, alkynyl, halo, amino, carbonyl, and amidyl groups attached at para-, meta-, and ortho-positions of anilines were compatible during the stannylation process. Additionally, the direct stannylation of heterocyclic arylamines proceeded smoothly as well with the formation of heterocyclic aryl stannanes. For example, when 5-methoxypyridin-3-amine was employed as the substrate, the pyridine stannane 45c was afforded with a 50% yield.18 Recently, Zhu and co-workers developed a one-pot protocol to construct arylphenanthridines 47, using anilines 1 and 2-isocyanobiphenyl 46 as the starting materials (Scheme 17). In the reaction, an aryl source was derived from anilines. BPO was described as a radical initiator, and both DMEDA and NaOAc were used as bases. Mechanistic studies suggested that the radical 48 was the key intermediate. Two competitive pathways including electrophilic aromatic substitution (SEAr) and homolytic aromatic substitution (HAS) of 48 are plausible.19 Wu and co-workers applied the strategy of in situ generation of diazonium fluoroborate 4 from anilines into sulfur dioxide insertion reactions, yielding aryl N-aminosulfonamides 51 in moderate to excellent yields with good function tolerance.20
Scheme 16
Metal-free Sandmeyer-type stannylation of anilines.
Scheme 17
Arylative cyclization of isocyanobiphenyl and anilines.
The mechanism of direct metal-free Sandmeyer borylation
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Scheme 18 Synthesis of aryl N-aminosulfonamides from anilines via the in situ generation of diazonium salts.
2 According to their findings, the process was believed to undergo a radical pathway, and the combination of DABSO 49 and hydrazines 50 made the formation of aryl radical possible.21 Heterocyclic amines were suitable substrates as well in the transformations (Scheme 18).
4.
Conclusions
Thriving chemistry involving the in situ generation of diazonium salts from anilines described in this minireview represents an inexpensive, environmentally clean, and safe alternative for the formation of carbon–carbon bonds and carbon–heteroatom bonds. Considerable progress has recently been achieved in this field. Moreover, two types of reactions are revealed, and which one is used depends upon the catalyst. The first is the palladium-catalyzed arylative reaction, where anilines are used as the aryl source. The second involving the in situ generation of diazonium salts from anilines is a radical reaction. In general, copper-mediated Sandmeyer or Meerwein radical reactions and metal-free radical reactions have both been developed. A series of useful chemical structures are synthesized through the in situ generation of diazonium salts. There is in our opinion a broad field to be explored for other types of reactions involving the removal of amino groups from anilines, and we expect continued progress to be reported in the near future.
3
4 5 6 7
8
Notes and references 1 For recent selected examples, see (a) F. Mo, G. Dong, Y. Zhang and J. Wang, Org. Biomol. Chem., 2013, 11, 1582 and references therein; (b) U. M. V. Basavanag, A. D. Santos, L. E. Kaim, R. Gámez-Montaño and L. Grimaud, Angew. Chem., Int. Ed., 2013, 52, 7194; (c) G. Danoun, B. Bayarmagnai, M. F. Grünberg and L. Gooβen, Angew. Chem., Int. Ed., 2013, 52, 7172; (d) D. P. Hari and B. König, Angew. Chem., Int. Ed., 2013, 52, 4734 and references therein; (e) Z. Xia and Q. Zhu, Org. Lett., 2013, 15, 4110; (f ) Q. Huang, P. Richardson, N. Sach, J. Zhu, K. Liu and G. Smith, Org. Process Res. Dev., 2011, 15, 556; (g) L. Malet-Sanz, J. Madrzak, S. Ley and I. Baxendale,
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9 10 11
12 13 14 15
Org. Biomol. Chem., 2010, 8, 5324; (h) K. Menzel, F. Machrouhi, M. Bodenstein, A. Alorati, C. Cowden, A. Gibson, B. Bishop, N. Ikemoto, T. Nelson, M. Kress and D. Frantz, Org. Process Res. Dev., 2009, 13, 519; (i) C. Molinaro, J. Mowat, F. Gosselin, P. O’Shea, J.-F. Marcoux, R. Angelaud and L. Davies, J. Org. Chem., 2007, 72, 1856; ( j) A. Roglans, A. Pla-Quintana and M. Moreno-Maňas, Chem. Rev., 2006, 106, 4622; (k) M. A. Nielsen, M. K. Nielsen and T. Pittelkow, Org. Process Res. Dev., 2004, 8, 1059; (l) R. Fortt, R. Wootton and A. De Mello, Org. Process Res. Dev., 2003, 7, 762. For selected reviews of Sandmeyer reactions: (a) D. L. Browne, Angew. Chem., Int. Ed., 2014, 53, 1482; (b) D. K. Kölmel, N. Jung and S. Bräse, Aust. J. Chem., 2014, 67, 328; (c) J. M. Richter, Name reactions for homologations: Sandmeyer Reactions, John Wiley & Sons, Inc., 2009; (d) I. S. Young, Name reactions in heterocyclic chemistry II: Sandmeyer isatin synthesis, John Wiley & Sons, Inc., 2011. For selected reviews of Meerwein reactions: (e) D. P. Hari and B. König, Angew. Chem., Int. Ed., 2013, 52, 4734; (f ) M. R. Heinrich, Chem. – Eur. J., 2009, 15, 820; (g) C. Rondestvedt, Org. React., 1976, 24, 225. For selected reviews of Heck–Matsuda reactions: (h) J. G. Taylor, A. V. Moro and C. R. Correia, Eur. J. Org. Chem., 2011, 1403; (i) F.-X. Felpin, L. Nassar-Hardy, F. L. Callonnec and E. Fouguet, Tetrahedron, 2011, 67, 2815. For recent selected examples, see: (a) D. Surry and S. Buchwald, Angew. Chem., Int. Ed., 2008, 47, 6338; (b) J. F. Hartwig, Acc. Chem. Res., 2008, 41, 1534; (c) D. Ma and Q. Cai, Acc. Chem. Res., 2008, 41, 1450. M. B. Andrus and C. Song, Org. Lett., 2001, 3, 3761. F. Mo, D. Qiu, Y. Jiang and J. Wang, Tetrahedron Lett., 2011, 52, 518. B. Andrus, C. Song and J. Zhang, Org. Lett., 2002, 4, 2079. (a) F. L. Callonec, E. Fouquet and F.-X. Felpin, Org. Lett., 2011, 13, 2646; (b) N. Susperregui, K. Miqueu, J.-M. Sotiropoulos, F. L. Callonnec, E. Fouqet and F.-X. Felpin, Chem. – Eur. J., 2012, 18, 7210. X.-F. Wu, H. Neumann and M. Beller, Chem. Commun., 2011, 47, 7959. M. P. Doyle, B. Siegfried, R. C. Elliott and J. F. Dellaria, J. Org. Chem., 1977, 42, 2431. J.-J. Dai, C. Fang, B. Xiao, J. Yi, J. Xu, Z.-J. Liu, L. Liu and Y. Fu, J. Am. Chem. Soc., 2013, 135, 843. X. Wang, Y. Xu, F. Mo, G. Ji, D. Qiu, J. Feng, Y. Ye, S. Zhang, Y. Zhang and J. Wang, J. Am. Chem. Soc., 2013, 135, 10330. A. Honraedt, M.-A. Raux, E. L. Grognec, D. Jacquemin and F.-X. Felpin, Chem. Commun., 2014, 50, 5236. A. Honraedt, F. L. Callonnec, E. L. Grongnec, V. Fernandez and F.-X. Felpin, J. Org. Chem., 2013, 78, 4604. Y. Li, J. Pu and X. Jiang, Org. Lett., 2014, 16, 2692. N. Chernyak and S. Buchwald, J. Am. Chem. Soc., 2012, 134, 12466.
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19 Z. Xia, J. Huang, Y. He, J. Zhao, J. Lei and Q. Zhu, Org. Lett., 2014, 16, 2546. 20 D. Zheng, Y. Li, Y. An and J. Wu, Chem. Commun., 2014, 50, 8886. 21 D. Zheng, Y. An, Z. Li and J. Wu, Angew. Chem., Int. Ed., 2014, 53, 2451.
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16 F. Mo, Y. Jiang, D. Qiu, Y. Zhang and J. Wang, Angew. Chem., Int. Ed., 2010, 49, 1846. 17 D. Qiu, L. Jin, Z. Zheng, H. Meng, F. Mo, X. Wang, Y. Zhang and J. Wang, J. Org. Chem., 2013, 78, 1923. 18 D. Qiu, H. Meng, L. Jin, S. Wang, S. Tang, X. Wang, F. Mo, Y. Zhang and J. Wang, Angew. Chem., Int. Ed., 2013, 52, 11581.
Review
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REVIEW
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Removal of amino groups from anilines through diazonium salt-based reactions Linman He,a Guanyinsheng Qiu,b Yueqiu Gao*a and Jie Wu*b This minireview describes the applications of in situ generated diazonium salts from anilines in organic synthesis. In situ generation of diazonium salts from anilines represents an efficient and practical pathway,
Received 20th June 2014, Accepted 23rd July 2014
leading to a series of useful structures. In these transformations, the amino group of aniline formally acts
DOI: 10.1039/c4ob01286k
as a leaving group. Two distinctive kinds of mechanisms, including transition metal (especially palladium)catalyzed oxidative addition–reductive elimination and a radical process, are involved in the removal of
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amino groups from anilines, and both catalytic processes are described in this minireview.
1.
Introduction
Diazonium salt-based reactions have been employed during the course of the past century to synthesize halides, phenols, cyanides, azides, and alkenes as well as other compounds. Diazonium salts are prone to undergo a homolytic dediazoniation to provide aryl radicals. The in situ generated aryl radicals can then be trapped by other reactive species to deliver the desired products. It’s generally accepted that the availability, stability, and safety of diazonium salts are the key factors that affect the results when carrying out these transformations. Consequently, despite the achievements of diazonium salt-based chemistry to date,1,2 the multistep synthesis of diazonium salts and their hazardous profiles to some extent limit the applications of these types of reactions in organic synthesis. To improve the traditional Sandmeyer, Meerwein, and Heck–Matsuda reactions,2 the focus was shifted to avoid isolating the diazonium salts. This minireview is concerned with the recent advancement of the direct transformations of anilines, where the amino group is removed from the aniline, and thus formally acts as a leaving group (Scheme 1).
Scheme 1
Aryl amines are known to be easily accessible as well as relatively safe and highly stable, and are hence common synthons in transitional metal-catalyzed coupling reactions and nonmetal-mediated transformations.3 Usually, direct transformations of anilines involve cleavage of C–N bonds in anilines, and the amino group acts as a formal leaving group in the process. Here, diazonium salts are generated as the key intermediates via an in situ strategy without being isolated. Generally, to realize the direct transformations of anilines, some issues have to be addressed: (1) to find appropriate diazotizing reagents of anilines that provide sufficiently stable and safe diazonium salts under mild conditions; and (2) importantly, the developed aniline-diazotizing process should be suitable for the subsequent transformations. The above two issues appear to have recently been addressed by employing tBuONO (tert-butyl nitrite) and related compounds as diazotizing reagents, and the direct transformations of anilines have been successfully accomplished in the presence of metal salts and non-metal conditions. Two distinctive kinds of mechanisms, involving the use of different catalysts, are generally recognized, and their applications to removing the amino groups from anilines are reviewed here. The first pathway discussed involves transition metal (especially palladium)-catalyzed couplings, and involves the common oxidative addition and reductive elimination. The second pathway is described as a radical process, which occurs in the presence of copper salts or in the absence of metals.
Coupling reactions via C–N bond cleavage of anilines.
a
Department of Hepatology Disease, Shanghai Shuguang Hospital, Shanghai University of T.C.M., Shanghai 201203, China. E-mail: [email protected] b Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China. E-mail: [email protected]; Fax: +86 21 6564 1740; Tel: +86 21 6510 2412
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2. Transitional metal-catalyzed removal of amino groups from anilines One initially elegant example involving the palladium-catalyzed removal of an amino group from aniline 1 was developed
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Scheme 4 Palladium-catalyzed removal of amino groups from anilines with styrenes. Scheme 2 Palladium-catalyzed removal of amino groups from anilines with arylboronic acids.
in 2001 by Andrus and co-workers (Scheme 2), where arylboronic acids 2 were employed as partners of Suzuki-type reactions.4 In the transformation, in situ generated diazonium fluoroborates 4 from anilines were initially involved, and palladium–imidazolium carbene 5 was used as an efficient catalyst to form 1,1′-diphenyl 3 in moderate to good yields. The full-scope evaluation of substrates indicated that electronic and steric hindrance effects of substrates made slight impact on the outcome of reactions. For example, the arylboronic acid with o-methoxyl group 2a was compatible for the reaction, leading to compound 3a in 53% yield. According to Wang’s findings, the arylation reactions of anilines 1 with boronic acids 2 for the synthesis of biphenyl 3 went through a palladium-catalyzed oxidative addition, transmetallation and reductive elimination. As illustrated in Scheme 3, in situ diazotization of aniline provided the key intermediate 4. This intermediate was treated with Pd(0), leading to intermediate 6. Extrusion of nitrogen from intermediate 6 afforded the formation of active palladium species 7. Then transmetallation and reductive elimination were followed to afford the biaryl product 3.5 In 2002, Andrus and co-workers further expanded this strategy into the Heck–Matsuda reactions, where inactivated styrenes 9 were employed as reaction partners. The scope evaluation of substrates suggested that the electron-rich alkene 9b was unfavorable in the reaction, producing the (Z)-1,2-disubstituted alkene 10b with a 21% yield (Scheme 4).6 These two examples demonstrated that the in situ generation of diazonium salts from anilines proceeded smoothly in the presence of stoichiometric amounts of BF3·Et2O in THF and tert-butylnitrile at 0 °C.
Scheme 3 A mechanism for the palladium-catalyzed reaction of anilines with boronic acids.
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Interestingly, Felpin and co-workers designed an unprecedented double catalytic cycle (MeSO3H and palladium) to explore the reaction of anilines 1 with α,β-unsaturated esters 11. In contrast to what was done previously, Felpin and coworkers avoided the use of stoichiometric amounts of acid as an additive, greatly improving the practicality of this transformation (Scheme 5).7 In 2011, Beller and co-workers applied the approach of in situ generation of diazonium salts from anilines 1 into Sonogashira reactions. In the transformation, anilines were used as an aryl source. As expected, various internal alkynes 19 were synthesized under standard conditions. From the scope investigation of substrates, it found that in all cases, the desired 1,2-disubstituted alkynes 19 were afforded in moderate to excellent yields. Thermally unstable phenyl propargyl ester 17b and propargyl benzoate 17c were particularly suitable under the conditions and the corresponding products 19b and 19c were formed with yields of 58% and 67%, respectively. Electronic properties of anilines 1 did not greatly affect the yields of products, as the reactions using anilines with electrondonating or electron-withdrawing groups as substrates could work well. A probe into the mechanism revealed that the in situ generation of diazonium salts 4 from anilines 1 was critical, and the result was different from that of the previous works since Beller and co-workers used HOAc as the additive in the process of in situ diazotization. Subsequent oxidative addition of diazonium salts 4 into the Pd(0) complex, deprotonation, and reductive elimination of aryl(alkenyl)palladium species 18 provided the corresponding products 19 (Scheme 6).8
Scheme 5 MeSO3H and palladium-catalyzed reaction of anilines with α,β-unsaturated esters.
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Review
summarizes radical reactions of anilines including coppermediated and metal-free Sandmeyer or Meerwein reactions.
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3.1 Copper-mediated Sandmeyer or Meerwein reactions of anilines
Scheme 6
A palladium-catalyzed reaction of anilines with alkynes.
3. Radical removal of the aniline amino group Copper-mediated Sandmeyer or Meerwein reactions are well recognized as the model of radical processes. In 1977, Doyle and co-workers studied the copper-mediated Meerwein-type reaction of anilines 1 with acrylonitrile 20, producing 2-chloro3-arylpropanenitrile 21 (Scheme 7). As presented in Scheme 7, the in situ generated diazonium salts 4 underwent a coppermediated homolytic dediazoniation, providing aryl radical 22. The subsequent radical addition into acrylonitrile 20 gave rise to a new radical 23. Nucleophilic substitution followed by oxidation of radical 23 afforded the products 21 in moderate yields. The mechanistic studies revealed that the chlorine atom was derived from a stoichiometric amount of CuCl2, and the bromine atom could be substituted into the desired products if CuBr2 was employed as the copper source.9 Recently, metal-free Sandmeyer or Meerwein reactions of anilines via radical process were reported. In these cases, a radical initiator was necessary for the formation of aryl radical 22. Metal-free reactions of anilines provided efficient alternatives to many useful building blocks. This section primarily
Scheme 7 A copper-mediated reaction of anilines with acrylonitrile via a radical process.
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Incorporation of fluoro-containing building blocks into small molecules is of high significance. Consequently, landmark progress involving copper-mediated Sandmeyer trifluoromethylation of anilines 1 was reported by Fu and co-workers, using Umemoto’s reagent as a partner with the formation of trifluorobenzene 24 with high efficiency (Scheme 8).10 From mechanistic studies, a radical process was proposed. In this process, diazotization of anilines in situ released aryl diazonium salt 4, and the reaction combining C–N bond cleavage with the formation of a C–CF3 bond delivered the products 24 with excellent functional group tolerance at low temperature. Interestingly, by altering the trifluoromethylation reagent into AgCF3, a distinctive pathway (named an oxidative addition– reductive elimination mechanism) was involved due to the strong σ-donor nature of AgCF3. The scope of substrates indicated the efficiency of silver-mediated Sandmeyer trifluoromethylation of anilines 1. From their results, it was found that counterions of diazonium salts had a significant effect on the reaction. Chloride (Cl−), bromide (Br−), and CF3CO2− were excellent candidates.11 A catalytic version of the radical reaction of anilines was reported by Felpin in 2013. As shown in Scheme 9, a room temperature copper-catalyzed radical C–H arylation of pyrroles 26 with anilines, through in situ generated diazonium salts 4, was developed under neutral conditions. Experimental and theoretical studies indicated that the CaCO3 as an additive played a crucial role.12 According to their findings, two roles for CaCO3 were proposed. Its first role was as a buffer additive, suppressing the formation of any acid-mediated azo compounds. Additionally, CaCO3 may participate in the catalytic cycle to improve the reaction efficiency. In particular, high regioselectivity was observed, leading to C2-arylated pyrroles 27. To avoid the double arylation at C2/C5 positions, an excess amount of pyrroles 26 was required. The radical C–H arylation using anilines as an aryl source could be further applied to that of benzoquinone 30, where graphite-supported copper oxide nanoparticles was used as a heterogeneous catalyst (Scheme 10). Interestingly, the reactions could occur in water. From the results, the reaction con-
Scheme 8
Sandmeyer trifluoromethylation of anilines.
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ing a key intermediate 35, which would coordinate with radial species 22 to form intermediate 36. Releasing SO3 in 36 would afford intermediate 37 followed by reductive elimination to produce the desired thioethers 34 in good yields. The substrate scope was demonstrated as well.14 In addition to the above copper-catalyzed reactions, ferrocene was also used as a catalyst in the radical reactions with anilines. Similar to the copper-catalyzed arylation mentioned above, a radical pathway in this case is possible as well. An aryl radical 22 was produced through a single-electron reduction of a diazonium intermediate with ferrocene as a catalyst. Addition of aryl radical into the unsaturated bond of vinyl ether, single-electron oxidation, and hydrolysis would then afford the desired product 39 and regenerate the ferrocene catalyst (Scheme 12).15
Scheme 9
Scheme 10 aniline.
Copper-catalyzed C–H arylation of pyrroles with anilines.
Copper-catalyzed C–H arylation of benzoquinone with
ditions were compatible with a variety of substituents including halo, carbonyl, and nitro groups etc., and the CaCO3 additive could be omitted in the process. The mechanism involving a radical process is well accepted.13 Recently, Jiang and co-workers reported an efficient and practical protocol to prepare thioethers 34 from anilines 1. As illustrated in Scheme 11, a copper-catalyzed S-transfer reaction was proposed, and a radical process is plausible. In the reactions, Na2S2O3 was treated with benzyl chloride (BnCl) produc-
Scheme 11
Copper-catalyzed S-transfer reaction of anilines.
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3.2
Metal-free Sandmeyer or Meerwein reactions of anilines
One of the key challenges in the direct Sandmeyer-type functionalization of anilines is the achievement of metal-free transformations. Wang and co-workers realized the direct Sandmeyer-type borylation of anilines in the absence of metals (Scheme 13). In the reactions, diboron pinacol (B2pin2) 42 was used as a borylating reagent. Notably, benzoyl peroxide (BPO) as a radical initiator guaranteed this metal-free borylation of anilines at room temperature. Control experiments revealed that the borylation became sluggish when the radical scavenger 2,2,6,6-tetramethyl-1-piperidin-1-oxyl (TEMPO) was added. The direct borylation of a wide range of aniline substrates proceeded smoothly, and functional groups were compatible under the conditions. For example, reaction of 4-nitroaniline worked well, leading to the boronate 43a with a 91% yield.
Scheme 12
Ferrocene-catalyzed reaction of anilines with vinyl ether.
Scheme 13 pinacol.
Direct metal-free borylation of anilines with diboron
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Reaction of 4-carbonyl-substituted aniline afforded the corresponding product 43b with a 67% yield. However, sterically hindered substrates were unfavorable for the transformation. For instance, the borylation of 2-cyanoaniline under standard conditions produced the boronate 43c with only a 22% yield.16 To effect the direct metal-free Sandmeyer borylation of anilines with potentially sterically hindering groups, Wang and co-workers further explored the transformation by elevating the reaction temperature to 80 °C without any additive. The desired process worked very well with excellent function tolerance. It is noteworthy that high reactivities of electrondeficient heterocyclic amines were displayed. In contrast, the electron-rich heterocyclic amines were prone to being oxidized, resulting in low yields. Interestingly, the direct borylation of para-substituted anilines worked better than that of ortho-, meta-substituted, and multi-substituted arylamines (Scheme 14).17 The power of this metal-free direct borylation of anilines was elegantly illustrated by gram-scale production. Studies of the mechanism revealed that the reactions proceeded through a free-radical process (Scheme 15). Subsequently, a Sandmeyer-type stannylation of anilines under mild conditions was disclosed by Wang, leading to aryl trimethylstannanes 45 in moderate to good yields in most
Scheme 14 Direct metal-free Sandmeyer borylation of anilines at relatively high temperatures.
Scheme 15 of anilines.
Review
cases. The results revealed that the presence of TsOH as an additive was crucial to provide more stable diazonium salt intermediates. A study of the mechanism indicated that a radical process could account for this Sandmeyer-type stannylation of anilines (Scheme 16). The substrate generality of this direct stannylation of anilines was explored. It was found that the reaction proceeded smoothly with a broad scope of substrates. Different functional groups including cyano, nitro, alkynyl, halo, amino, carbonyl, and amidyl groups attached at para-, meta-, and ortho-positions of anilines were compatible during the stannylation process. Additionally, the direct stannylation of heterocyclic arylamines proceeded smoothly as well with the formation of heterocyclic aryl stannanes. For example, when 5-methoxypyridin-3-amine was employed as the substrate, the pyridine stannane 45c was afforded with a 50% yield.18 Recently, Zhu and co-workers developed a one-pot protocol to construct arylphenanthridines 47, using anilines 1 and 2-isocyanobiphenyl 46 as the starting materials (Scheme 17). In the reaction, an aryl source was derived from anilines. BPO was described as a radical initiator, and both DMEDA and NaOAc were used as bases. Mechanistic studies suggested that the radical 48 was the key intermediate. Two competitive pathways including electrophilic aromatic substitution (SEAr) and homolytic aromatic substitution (HAS) of 48 are plausible.19 Wu and co-workers applied the strategy of in situ generation of diazonium fluoroborate 4 from anilines into sulfur dioxide insertion reactions, yielding aryl N-aminosulfonamides 51 in moderate to excellent yields with good function tolerance.20
Scheme 16
Metal-free Sandmeyer-type stannylation of anilines.
Scheme 17
Arylative cyclization of isocyanobiphenyl and anilines.
The mechanism of direct metal-free Sandmeyer borylation
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Scheme 18 Synthesis of aryl N-aminosulfonamides from anilines via the in situ generation of diazonium salts.
2 According to their findings, the process was believed to undergo a radical pathway, and the combination of DABSO 49 and hydrazines 50 made the formation of aryl radical possible.21 Heterocyclic amines were suitable substrates as well in the transformations (Scheme 18).
4.
Conclusions
Thriving chemistry involving the in situ generation of diazonium salts from anilines described in this minireview represents an inexpensive, environmentally clean, and safe alternative for the formation of carbon–carbon bonds and carbon–heteroatom bonds. Considerable progress has recently been achieved in this field. Moreover, two types of reactions are revealed, and which one is used depends upon the catalyst. The first is the palladium-catalyzed arylative reaction, where anilines are used as the aryl source. The second involving the in situ generation of diazonium salts from anilines is a radical reaction. In general, copper-mediated Sandmeyer or Meerwein radical reactions and metal-free radical reactions have both been developed. A series of useful chemical structures are synthesized through the in situ generation of diazonium salts. There is in our opinion a broad field to be explored for other types of reactions involving the removal of amino groups from anilines, and we expect continued progress to be reported in the near future.
3
4 5 6 7
8
Notes and references 1 For recent selected examples, see (a) F. Mo, G. Dong, Y. Zhang and J. Wang, Org. Biomol. Chem., 2013, 11, 1582 and references therein; (b) U. M. V. Basavanag, A. D. Santos, L. E. Kaim, R. Gámez-Montaño and L. Grimaud, Angew. Chem., Int. Ed., 2013, 52, 7194; (c) G. Danoun, B. Bayarmagnai, M. F. Grünberg and L. Gooβen, Angew. Chem., Int. Ed., 2013, 52, 7172; (d) D. P. Hari and B. König, Angew. Chem., Int. Ed., 2013, 52, 4734 and references therein; (e) Z. Xia and Q. Zhu, Org. Lett., 2013, 15, 4110; (f ) Q. Huang, P. Richardson, N. Sach, J. Zhu, K. Liu and G. Smith, Org. Process Res. Dev., 2011, 15, 556; (g) L. Malet-Sanz, J. Madrzak, S. Ley and I. Baxendale,
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9 10 11
12 13 14 15
Org. Biomol. Chem., 2010, 8, 5324; (h) K. Menzel, F. Machrouhi, M. Bodenstein, A. Alorati, C. Cowden, A. Gibson, B. Bishop, N. Ikemoto, T. Nelson, M. Kress and D. Frantz, Org. Process Res. Dev., 2009, 13, 519; (i) C. Molinaro, J. Mowat, F. Gosselin, P. O’Shea, J.-F. Marcoux, R. Angelaud and L. Davies, J. Org. Chem., 2007, 72, 1856; ( j) A. Roglans, A. Pla-Quintana and M. Moreno-Maňas, Chem. Rev., 2006, 106, 4622; (k) M. A. Nielsen, M. K. Nielsen and T. Pittelkow, Org. Process Res. Dev., 2004, 8, 1059; (l) R. Fortt, R. Wootton and A. De Mello, Org. Process Res. Dev., 2003, 7, 762. For selected reviews of Sandmeyer reactions: (a) D. L. Browne, Angew. Chem., Int. Ed., 2014, 53, 1482; (b) D. K. Kölmel, N. Jung and S. Bräse, Aust. J. Chem., 2014, 67, 328; (c) J. M. Richter, Name reactions for homologations: Sandmeyer Reactions, John Wiley & Sons, Inc., 2009; (d) I. S. Young, Name reactions in heterocyclic chemistry II: Sandmeyer isatin synthesis, John Wiley & Sons, Inc., 2011. For selected reviews of Meerwein reactions: (e) D. P. Hari and B. König, Angew. Chem., Int. Ed., 2013, 52, 4734; (f ) M. R. Heinrich, Chem. – Eur. J., 2009, 15, 820; (g) C. Rondestvedt, Org. React., 1976, 24, 225. For selected reviews of Heck–Matsuda reactions: (h) J. G. Taylor, A. V. Moro and C. R. Correia, Eur. J. Org. Chem., 2011, 1403; (i) F.-X. Felpin, L. Nassar-Hardy, F. L. Callonnec and E. Fouguet, Tetrahedron, 2011, 67, 2815. For recent selected examples, see: (a) D. Surry and S. Buchwald, Angew. Chem., Int. Ed., 2008, 47, 6338; (b) J. F. Hartwig, Acc. Chem. Res., 2008, 41, 1534; (c) D. Ma and Q. Cai, Acc. Chem. Res., 2008, 41, 1450. M. B. Andrus and C. Song, Org. Lett., 2001, 3, 3761. F. Mo, D. Qiu, Y. Jiang and J. Wang, Tetrahedron Lett., 2011, 52, 518. B. Andrus, C. Song and J. Zhang, Org. Lett., 2002, 4, 2079. (a) F. L. Callonec, E. Fouquet and F.-X. Felpin, Org. Lett., 2011, 13, 2646; (b) N. Susperregui, K. Miqueu, J.-M. Sotiropoulos, F. L. Callonnec, E. Fouqet and F.-X. Felpin, Chem. – Eur. J., 2012, 18, 7210. X.-F. Wu, H. Neumann and M. Beller, Chem. Commun., 2011, 47, 7959. M. P. Doyle, B. Siegfried, R. C. Elliott and J. F. Dellaria, J. Org. Chem., 1977, 42, 2431. J.-J. Dai, C. Fang, B. Xiao, J. Yi, J. Xu, Z.-J. Liu, L. Liu and Y. Fu, J. Am. Chem. Soc., 2013, 135, 843. X. Wang, Y. Xu, F. Mo, G. Ji, D. Qiu, J. Feng, Y. Ye, S. Zhang, Y. Zhang and J. Wang, J. Am. Chem. Soc., 2013, 135, 10330. A. Honraedt, M.-A. Raux, E. L. Grognec, D. Jacquemin and F.-X. Felpin, Chem. Commun., 2014, 50, 5236. A. Honraedt, F. L. Callonnec, E. L. Grongnec, V. Fernandez and F.-X. Felpin, J. Org. Chem., 2013, 78, 4604. Y. Li, J. Pu and X. Jiang, Org. Lett., 2014, 16, 2692. N. Chernyak and S. Buchwald, J. Am. Chem. Soc., 2012, 134, 12466.
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19 Z. Xia, J. Huang, Y. He, J. Zhao, J. Lei and Q. Zhu, Org. Lett., 2014, 16, 2546. 20 D. Zheng, Y. Li, Y. An and J. Wu, Chem. Commun., 2014, 50, 8886. 21 D. Zheng, Y. An, Z. Li and J. Wu, Angew. Chem., Int. Ed., 2014, 53, 2451.
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16 F. Mo, Y. Jiang, D. Qiu, Y. Zhang and J. Wang, Angew. Chem., Int. Ed., 2010, 49, 1846. 17 D. Qiu, L. Jin, Z. Zheng, H. Meng, F. Mo, X. Wang, Y. Zhang and J. Wang, J. Org. Chem., 2013, 78, 1923. 18 D. Qiu, H. Meng, L. Jin, S. Wang, S. Tang, X. Wang, F. Mo, Y. Zhang and J. Wang, Angew. Chem., Int. Ed., 2013, 52, 11581.
Review
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