Reactions of Zirconocene Butadiyne or Monoyne Complexes with

Communication pubs.acs.org/Organometallics

Reactions of Zirconocene Butadiyne or Monoyne Complexes with Nitriles: Straightfoward Synthesis of Functionalized Pyrimidines Xu You, Shasha Yu, and Yuanhong Liu* State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, People’s Republic of China S Supporting Information *

ABSTRACT: Zirconium-mediated multicomponent reactions of silylbutadiynes with two molecules of aryl nitriles are described, which provide rapid access to polysubstituted pyrimidines in a regioselective manner and in one pot. Employing aliphatic nitriles results in coupling of only one nitrile, leading to the formation of enynyl ketones after hydrolysis. A zirconocene monoyne complex undergoes similar reactions with nitriles to form highly substituted pyrimidines. ive-membered group 4 metallacyclocumulenes, first reported in 1994 by Rosenthal1 et al., have attracted much attention due to their fascinating structural features and their unusual reactivities.2,3 These complexes could be synthesized by various methods, such as ligand exchange reactions of 1,3-butadiynes with the alkyne complexes Cp2M(L)(η2-Me3SiCCSiMe3) (M = Ti, L = ligandless; M = Zr, L = THF, pyridine),2a B(C6F5)3-catalyzed isomerization of bis(alkynyl)zirconocenes,3b,g reactions of diyne with dihalide metal complexes using magnesium as the reductant,2a or lightinduced rearrangement of metallocene bis-acetylides.2a However, these methods usually require expensive precursors or catalyst or are restricted to special substrates. Recently, we found a very convenient method for the monozirconation of 1,3-butadiynes with bulky silyl- or tert-butyl substituents using Negishi reagent without addition of any ligands.4 We suggested that five-membered zirconacyclocumulenes were formed in these reactions according to NMR studies of the zirconium intermediates and the single-crystal X-ray analysis of [Cp2Zr(η4-1,2,3,4-tBuC4tBu)]. These complexes show diverse and interesting reactivities toward aldehydes, carbamoyl cyanides, aroyl cyanides, and alkyl cyanoformates.4,5 We next became interested in the potential coupling reactions of zirconocene butadiyne complexes with normal nitriles. The reactivity of nitriles with group 4 metal complexes has been intensely studied over the last few decades, in which CN insertion,6 C−H activation,7 and deprotonation/proton transfer to form a zirconocene keteniminate species (when nitriles possess an acidic α-proton)8,9 have been observed. Very recently, Rosenthal et al. reported that a seven-membered zirconacyclocumulene derived from coupling of 2 equiv of 1,4-bis(trimethylsilyl)buta-1,3-diyne could react with 2 equiv of phenylacetonitrile, leading to fused azazirconacycles, in which a five-membered zirconacyclocumulene generated by elimination of one butadiyne at high temperature (100 °C) was assumed to be the reactive intermediate.10 In this communication, we report a novel multicomponent coupling reaction of a zirconocene butadiyne complex with two molecules of

F

© XXXX American Chemical Society

nitriles, which provides a straightforward route for the synthesis of pyrimidines in a regioselective manner (Scheme 1). In addition, this reaction can be extended to zirconocene monoyne complexes. To our knowledge, such a reaction mode has not been reported in zirconium chemistry. Pyrimidines exist as key structures in numerous natural products, such as vitamin B1 (thiamine), heteromine F, variolin-type alkaloids and meridianin, etc.,11 and in biologically active substances, including nimustine,12a pyrimethamine,12b phosphatidylinositol 3-kinase inhibitors,12c etc.12 Therefore, the development of an efficient synthetic route to pyrimidines is highly needed.13 It is known that nitrile couples with zirconacyclopentene, a zirconocene alkyne equivalent, to afford azazirconacyclopentadiene.6b We expected that the unique reactivity of a zirconocene butadiyne complex might lead to different reaction patterns and a new development in organic synthesis. As demonstrated in our previous study,4 reaction of the 1,3butadiyne 1 bearing bulky silyl groups with Negishi reagent resulted in the formation of zirconacyclocumulene 3 as a major product, which is possibly in equilibrium with the threemembered alkynylzirconacyclopropene 2, although the equilibrium lies predominantly on the side of 3 (see Table 1). The reaction of a zirconocene butadiyne complex derived from 1,4bis(tert-butyldimethylsilyl)buta-1,3-diyne (1a) with 3 equiv of benzonitrile in toluene was examined first. It was found that the fully substituted pyrimidine 4a was formed in 81% yield at 80 °C for 5.5 h with excellent regioselectivity. The results indicated that two molecules of nitriles incorporated into the metallacycle. To our knowledge, this type of reactivity has not been reported in group 4 metal complex mediated coupling reactions of alkynes with nitriles. We next investigated the scope of nitriles using 1a as a reaction partner in most cases. A variety of aryl nitriles could be used as effective substrates for this Received: September 3, 2013

A

dx.doi.org/10.1021/om400880r | Organometallics XXXX, XXX, XXX−XXX

Organometallics

Communication

Scheme 1

Table 2. Zirconium-Mediated Multicomponent Reactions of Monoynes with Nitriles

Table 1. Zirconium-Mediated Multicomponent Reactions of 1,3-Butadiynes with Nitrilesa

a

a

Isolated yields.

Scheme 3

Isolated yields. bContaining a small amount of impurity.

Scheme 2

reaction. It was found that the aromatic rings of nitriles bearing an electron-donating or an electron-withdrawing group were all compatible under the reaction conditions. For example, p-Cl-, p-Br-, and p-CF3-substituted aryl nitriles afforded 4b,c,g in 83− 88% yields. The use of p-CH3-, p-tBu-, and p-MeO-substituted aryl nitriles afforded 4h−j in similar yields of 83−87%. The results indicated that the electronic nature of the aryl substituents on nitriles had little influence on the product yields. However, when 2-fluorobenzonitrile was employed, only 38% of 4e was obtained, possibly due to steric interactions. Heteroaryl-substituted nitriles such as 2-thiophenecarbonitrile

or 1-methyl-1H-indole-3-carbonitrile were also suitable for this reaction, furnishing the corresponding 4k,l in 76% and 79% yields, respectively. When TBS on the diyne terminus was replaced by the more bulky Si(iPr)3 (TIPS) group, a lower yield B

dx.doi.org/10.1021/om400880r | Organometallics XXXX, XXX, XXX−XXX

Organometallics

Communication

Scheme 4

insertion reactions.18 Alternatively, 11 undergoes [4 + 2] cycloaddition with nitrile followed by elimination of low-valent zirconium species to afford 4 (path b).19 The released “Cp2ZrII” might be trapped by excess nitrile. According to the above reaction mechanism, it is possible to couple one butadiyne with two different nitriles. Interestingly, when 2a was treated with 1 equiv of p-MeOC6H4CN and stirred at 50 °C for 1 h, a large amount of red solid precipitated. The insolubility of this solid species in the usual solvents precluded their characterization by NMR. To the thus formed reaction mixture was added p-BrC6H4CN and the mixture was stirred at 80 °C for 3 h; pyrimidine 4n with two different aryl groups was formed in 32% yield, together with 4c in 45% yield (Scheme 4). The structure of pyrimidine 4n was also confirmed by X-ray crystallographic analyses.14 During this period, the amount of the solid component gradually decreased. The results indicated that an intermediate such as azazirconacyclopentadiene might undergo a β,β′-C−C bond cleavage reaction in the presence of a second nitrile to form a new azazirconacycle, while the first nitrile was released. Although zirconacycles such as zirconacyclopentenes and zirconacyclopentadienes are known to undergo a β,β′-C−C bond cleavage reaction under the appropriate conditions,6b,8,20 there has been no report for such fragmentation reactions of azazirconacycles.21 In summary, we have developed a new cycloaddition reaction of zirconocene butadiyne complexes with aryl nitriles, which provided an efficient route to polysubstituted pyrimidines in a regioselective manner. Employing aliphatic nitriles resulted in a coupling of only one nitrile, leading to the formation of enynyl ketones after hydrolysis. The reaction has been extended to zirconocene monoyne complexes. Clarification of the reaction mechanism and further application of this chemistry are in progress.

of 70% was observed for 4m in comparison with 4a using benzonitrile as a coupling partner. The structure of pyrimidine 4 was unambiguously confirmed by an X-ray crystallographic analysis of 4c.14 The reactions of 1a with aliphatic nitriles such as acetonitrile and 2-(2-bromophenyl)acetonitrile were also examined. However, only enynyl ketones 6a,b resulting from the insertion of one CN bond into the zirconocene butadiyne complex were obtained in 64% and 32% yields, respectively, after quenching the reaction mixture with 3 N HCl (Scheme 2). The desired pyrimidines were not observed. This might be due to the lower reactivity of alkyl nitriles or the presence of acidic α-proton in arylacetonitriles, leading to undesired reactions such as deprotonation.8,10 The above reactions could be extended to monoynes. For example, reactions of the phosphine-stabilized zirconocene alkyne complex 715 with aryl nitriles at 80 °C in toluene generated aryl-substituted pyrimidines 814 in moderate yields (Table 2). These results make this chemistry very useful due to the extended substrate scope. Recently, a NbCl5-mediated cycloaddition of monoynes and nitriles has been reported; however, the use of a diarylacetylene such as diphenylacetylene could not produce the desired pyrimidine in their system.16 The reaction is also quite different with that of titaniummediated coupling of alkynes with nitriles (restricted to αmethoxyacetonitrile), in which double addition of the nitrile to the titanium alkyne complex occurs to form diimines after hydrolysis. The dimines could be transformed into pyrroles upon acidic workup.17 We tentatively propose the following reaction mechanism for this novel transformation using butadiyne as substrates (Scheme 3): first of all, an equilibrium between zirconacyclopentatriene 3 and zirconacyclopropene 2 exists in the reaction mixture, in which 3 is likely to be the dominant species, whereas 2 is more reactive.3l,4 An SE2′-type addition of a nitrile CN bond to the less hindered propargyl zirconium moiety in complex 2 takes place to deliver the azazirconacyclocumulene 10, which might isomerize to azazirconacyclopentadiene 11. Zirconacycle 11 might also be formed by direct insertion of a CN bond into the Zr−C(sp2) bond close to the TBS group of 2. However, attack of the nitrile from this side may encounter large steric hindrance. Next, insertion of the CN bond of the second nitrile into the Zr−N bond of zirconacycle 11 via attack of the imine nitrogen atom at nitrile followed by reductive elimination furnishes the pyrimidine product 4 (path a). It should be noted that, despite the large number of zirconacycles containing Zr−N bonds, only a few known complexes such as the (η2-1,2-diphenylhydrazido)zirconocene complex Cp2Zr(N2Ph2) and an azaoxazirconacycle underwent Zr−N bond

■

ASSOCIATED CONTENT

* Supporting Information S

Text, figures, tables, and CIF files giving general experimental methods, synthesis and characterization of 4a−m, 6a,b, 8a−e, and 4n, X-ray crystal structures of 4c,n and 8a, and NMR spectra of all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

■

AUTHOR INFORMATION

Corresponding Author

*Y.L.: fax, (+86) 021-64166128; e-mail, [email protected]. Notes

The authors declare no competing financial interest. C

dx.doi.org/10.1021/om400880r | Organometallics XXXX, XXX, XXX−XXX

Organometallics

■

Communication

(c) Walker, S. R.; Carter, E. J.; Huff, B. C.; Morris, J. C. Chem. Rev. 2009, 109, 3080. (12) (a) Nagourney, R. A.; Fox, P.; Schein, P. S. Cancer Res. 1978, 38, 65. (b) Russell, P. B.; Hitchings, G. H. J. Am. Chem. Soc. 1951, 73, 3763. (c) Large, J. M.; Torr, J. E.; Raynaud, F. I.; Clarke, P. A.; Clarke, A.; Hayes, A.; de Stefano, F.; Urban, F.; Shuttleworth, S. J.; Saghir, N.; Sheldrake, P.; Workman, P.; McDonald, E. Bioorg. Med. Chem. 2011, 19, 836. (13) For recent reviews on the synthesis of pyrimidines, see: (a) Radi, M.; Schenone, S.; Botta, M. Org. Biomol. Chem. 2009, 7, 2841. (b) Hill, M. D.; Movassaghi, M. Chem. Eur. J. 2008, 14, 6836. (c) For recent reports on the formation of pyrimidines, see: Lin, M.; Chen, Q.-Z.; Zhu, Y.; Chen, X.-L.; Cai, J.-J.; Pan, Y.-M.; Zhan, Z.-P. Synlett 2011, 1179. (d) Sasada, T.; Aoki, Y.; Ikeda, R.; Sakai, N.; Konakahara, T. Chem. Eur. J. 2011, 17, 9385. (e) Sasada, T.; Kobayashi, F.; Sakai, N.; Konakahara, T. Org. Lett. 2009, 11, 2161. (f) Alacid, E.; Nájera, C. Org, Lett. 2008, 10, 5011. (g) Muller, T. J. J.; Braun, R.; Ansorge, M. Org. Lett. 2000, 2, 1967. (14) X-ray crystal structures of compounds 4c,n and 8a are given in the Supporting Information. (15) Negishi, E.; Holmes, S. J.; Tour, J. M.; Miller, J. A.; Cederbaum, F. E.; Swanson, D. R.; Takahashi, T. J. Am. Chem. Soc. 1989, 111, 3336. (16) Satoh, Y.; Yasuda, K.; Obora, Y. Organometallics 2012, 31, 5235. (17) Suzuki, D.; Nobe, Y.; Watai, Y.; Tanaka, R.; Takayama, Y.; Sato, F.; Urabe, H. J. Am. Chem. Soc. 2005, 127, 7474. (18) (a) Walsh, P. J.; Hollander, F. J.; Bergman, R. G. J. Am. Chem. Soc. 1990, 112, 894. (b) Carney, M. J.; Walsh, P. J.; Hollander, F. J.; Bergman, R. G. J. Am. Chem. Soc. 1989, 111, 8751. (19) For related cycloadditions of azatitanacyclopentadienes with alkynes, see: (a) Reference 17. For cycloaddition of titanacyclopentadienes with nitriles, see: (b) Suzuki, D.; Tanaka, R.; Urabe, H.; Sato, F. J. Am. Chem. Soc. 2002, 124, 3518. For cycloadditions of titanacyclopentadienes with alkynes, see: (c) Suzuki, D.; Urabe, H.; Sato, F. J. Am. Chem. Soc. 2001, 123, 7925. (20) (a) Buchwald, S. L.; Nielsen, R. B. J. Am. Chem. Soc. 1989, 111, 2870. (c) Suzuki, N.; Kondakov, D. Y.; Kageyama, M.; Kotora, M.; Hara, R.; Takahashi, T. Tetrahedron 1995, 51, 4519. (b) Hara, R.; Xi, Z.; Kotora, M.; Kotora, M.; Xi, C.; Takahashi, T. Chem. Lett. 1996, 1003. (c) Liu, J.; Zhang, W.-X.; Guo, X.; Hou, Z.; Xi, Z. Organometallics 2007, 26, 6812. (d) Miller, A. D.; McBee, J. L.; Tilley, T. D. J. Am. Chem. Soc. 2008, 130, 4992. (21) During the submission process, Rosenthal et al. reported that a nitrile exchange reaction could occur through the reaction of diazametallacyclopentadienes (M = Ti, Zr) with CH3CN; see: Becker, L.; Arndt, P.; Jiao, H.; Spannenberg, A.; Rosenthal, U. Angew. Chem., Int. Ed. 2013, DOI: 10.1002/anie.201303748.

REFERENCES

(1) Rosenthal, U.; Ohff, A.; Baumann, W.; Kempe, R.; Tillack, A.; Burlakov, V. V. Angew. Chem., Int. Ed. 1994, 33, 1605. (2) For reviews, see: (a) Rosenthal, U.; Burlakov, V. V.; Arndt, P.; Baumann, W.; Spannenberg, A. Organometallics 2005, 24, 456. (b) Rosenthal, U.; Burlakov, V. V.; Arndt, P.; Baumann, W.; Spannenberg, A. Organometallics 2003, 22, 884. (c) Rosenthal, U.; Pellny, P. -M.; Kirchbauer, F. G.; Burlakov, V. V. Acc. Chem. Res. 2000, 33, 119. (3) For selected papers on the reactions of 1,3-butadiynes with group 4 metal complexes, see: (a) Hsu, D. P.; Davis, W. M.; Buchwald, S. L. J. Am. Chem. Soc. 1993, 115, 10394. (b) Temme, B.; Erker, G.; Fröhlich, R.; Grehl, M. Angew. Chem., Int. Ed. 1994, 33, 1480. (c) Takahashi, T.; Xi, Z.; Nishihara, Y.; Huo, S.; Kasai, K.; Aoyagi, K.; Denisov, V.; Negishi, E. Tetrahedron 1997, 53, 9123. (d) Liu, Y.; Sun, W.; Nakajima, K.; Takahashi, T. Chem. Commun. 1998, 1133. (e) Bredeau, S.; Delmas, G.; Pirio, N.; Richard, P.; Donnadieu, B.; Meunier, P. Organometallics 2000, 19, 4463. (f) Delas, C.; Urabe, H.; Sato, F. Chem. Commun. 2002, 272. (g) Erker, G.; Venne-Dunker, S.; Kehr, G.; Kleigrewe, N.; Fröhlich, R.; Mück-Lichtenfeld, C.; Grimme, S. Organometallics 2004, 23, 4391. (h) Liu, Y.; Gao, H.; Zhou, S. Angew. Chem., Int. Ed. 2006, 45, 4163. (i) Chen, J.; Liu, Y. Tetrahedron Lett. 2008, 49, 6655. (j) Fu, X.; Chen, J.; Li, G.; Liu, Y. Angew. Chem., Int. Ed. 2009, 48, 5500. (k) Bredeau, S.; Ortega, E.; Delmas, G.; Richard, P.; Fröhlich, R.; Donnadieu, B.; Kehr, G.; Pirio, N.; Erker, G.; Meunier, P. Organometallics 2009, 28, 181. (l) Fu, X.; Liu, Y.; Li, Y. Organometallics 2010, 29, 3012. (m) Chen, J.; Liu, Y. Organometallics 2010, 29, 505. (n) Burlakov, V. V.; Bogdanov, V. S.; Lyssenko, K. A.; Strunkina, L. I.; Minacheva, M. Kh.; Strunin, B. N.; Rosenthal, U.; Shur, V. B. Russ. Chem. Bull. Int. Ed. 2010, 59, 668. (o) Burlakov, V. V.; Kaleta, K.; Beweries, T.; Arndt, P.; Baumann, W.; Spannenberg, A.; Shur, V. B.; Rosenthal, U. Organometallics 2011, 30, 1157. (p) Roy, S.; Jemmis, E. D.; Ruhmann, M.; Schulz, A.; Kaleta, K.; Beweries, T.; Rosenthal, U. Organometallics 2011, 30, 2670. (q) Burlakov, V. V.; Bogdanov, V. S.; Lyssenko, K. A.; Spannenberg, A.; Baumann, W.; Arndt, P.; Minacheva, M. Kh.; Strunkina, L. I.; Rosenthal, U.; Shur, V. B. Izv. Akad. Nauk, Ser. Chim. 2012, 163. (4) Fu, X.; Yu, S.; Fan, G.; Liu, Y.; Li, Y. Organometallics 2012, 31, 531. (5) Yu, S.; You, X.; Liu, Y. Chem. Eur. J. 2012, 18, 13936. (6) For insertions of CN triple bonds of nitriles into Zr−C bonds, see: (a) Buchwald, S. L.; Watson, B. T.; Lum, R. T.; Nugent, W. A. J. Am. Chem. Soc. 1987, 109, 7137. (b) Takahashi, T.; Xi, C.; Xi, Z.; Kageyma, M.; Fischer, R.; Nakajima, K.; Negishi, E. J. Org. Chem. 1998, 63, 6802. (c) Zhou, S.; Liu, D.; Liu, Y. Organometallics 2004, 23, 5900. (d) Sun, X.; Wang, C.; Li, Z.; Zhang, S.; Xi, Z. J. Am. Chem. Soc. 2004, 126, 7172. (e) Zhang, W.; Zhang, S.; Sun, X.; Nishiura, M.; Hou, Z.; Xi, Z. Angew. Chem., Int. Ed. 2009, 48, 7227. (f) Zhang, S.; Zhang, W.; Xi, Z. Chem. Eur. J. 2010, 16, 8419. (g) Zhang, S.; Zhang, W.; Zhao, J.; Xi, Z. J. Am. Chem. Soc. 2010, 132, 14042. (h) Zhang, S.; Zhang, W.; Zhao, J.; Xi, Z. Chem. Eur. J. 2011, 17, 2442. (7) Fulton, J. R.; Hanna, T. A.; Bergman, R. G. Organometallics 2000, 19, 602. (8) Zhao, J.; Zhang, S.; Zhang, W.; Xi, Z. Organometallics 2011, 30, 3464. (9) For examples of the deprotonation process by other metals, see: (a) Tellers, D. M.; Ritter, J. C. M.; Bergman, R. G. Inorg. Chem. 1999, 38, 4810. (b) Iravani, E.; Neumüller, B. Organometallics 2003, 22, 4129. (c) Fedushkin, I. L.; Morozov, A. G.; Rassadin, O. V.; Fukin, G. K. Chem. Eur. J. 2005, 11, 5749. (d) Zarges, W.; Marsch, M.; Harms, K.; Boche, G. Angew. Chem. 1989, 101, 1424; Angew. Chem., Int. Ed. 1989, 28, 1392. (e) Fedushkin, I. L.; Morozov, A. G.; Chudakova, V. A.; Fukin, G. K.; Cherkasov, V. K. Eur. J. Inorg. Chem. 2009, 4995. (10) Becker, L.; Burlakov, V. V.; Arndt, P.; Spannenberg, A.; Baumann, W.; Jiao, H.; Rosenthal, U. Chem. Eur. J. 2013, 19, 4230. (11) For reviews, see: (a) Lagoja, I. M. Chem. Biodiversity 2005, 2, 1. (b) Undheim, K.; Benneche, T. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Ress, C. W., Scriven, E. F. V., Mckillop, A., Eds.; Pergamon: Oxford, U.K., 1996; Vol. 6, p 93. D

dx.doi.org/10.1021/om400880r | Organometallics XXXX, XXX, XXX−XXX