Alkyl Aluminum-Catalyzed Addition of Amines to ... - ACS Publications

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Organometallics 2009, 28, 882–887

Alkyl Aluminum-Catalyzed Addition of Amines to Carbodiimides: A Highly Efficient Route to Substituted Guanidines Wen-Xiong Zhang,*,†,‡ Dongzhen Li,† Zitao Wang,† and Zhenfeng Xi*,† Beijing National Laboratory for Molecular Sciences (BNLMS), and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking UniVersity, Beijing 100871, People’s Republic of China, and State Key Laboratory of Elemento-Organic Chemistry, Nankai UniVersity, Tianjin, 300071, People’s Republic of China ReceiVed October 28, 2008

The commercially readily available alkyl aluminums, such as AlMe3, AlEt3, and AlEt2Cl, can serve as excellent catalyst precursors for the catalytic addition of amines to carbodiimides, yielding quantitatively their corresponding trisubstituted guanidines. Aromatic C-X (X ) F, Cl, Br, and I) bonds, nitro NO2, and terminal alkyne units can survive the reaction conditions. An aluminum guanidinate species has been characterized by single-crystal X-ray structural analysis and has been confirmed to be a true catalyst species. Introduction Catalytic addition reaction of amine N-H bonds to carbodiimides (catalytic guanylation reaction of amines) is an atomeconomical and straightforward route to multisubstituted guanidines, RNdC(NR′R′′)NHR,1,2 which are an important class of N-containing compounds serving as building blocks for many biologically relevant compounds3 and also as base catalysts in synthetic organic chemistry.4 Generally, the reaction of an amine with a suitable electrophilic guanylating reagent5 or functionalization of a pre-existing guanidine core provide two typical routes for the preparation of substituted guanidines.6 Tetrabutylammonium fluoride was also reported to promote the nu* Corresponding authors. Fax: (+86)10-62759728. E-mail: wx_zhang@ pku.edu.cn; [email protected]. † Peking University. ‡ Nankai University. (1) For catalytic addition of amines to carbodiimides by M-N bond complexes, see: (a) Zhang, W.-X.; Hou, Z. Org. Biomol. Chem. 2008, 6, 1720–1730. (b) Zhang, W.-X.; Nishiura, M.; Hou, Z. Chem.-Eur. J. 2007, 13, 4037–4051. (c) Zhang, W.-X.; Nishiura, M.; Hou, Z. Synlett 2006, 1213– 1216. (d) Zhou, S.; Wang, S.; Yang, G.; Li, Q.; Zhang, L.; Yao, Z.; Zhou, Z.; Song, H.-B. Organometallics 2007, 26, 3755–3761. (e) Li, Q.; Wang, S.; Zhou, S.; Yang, G.; Zhu, X.; Liu, Y. J. Org. Chem. 2007, 72, 6763– 6767. (f) Ong, T.-G.; O’Brien, J. S.; Korobkov, I.; Richeson, D. S. Organometallics 2006, 25, 4728–4730. (g) Shen, H.; Chan, H.-S.; Xie, Z. Organometallics 2006, 25, 5515–5517. (h) Montilla, F.; del Rı´o, D.; Pastor, A.; Galindo, A. Organometallics 2006, 25, 4996–5002. (i) Du, Z.; Li, W.; Zhu, X.; Xu, F.; Shen, Q. J. Org. Chem. 2008, 73, 8966–8972. (j) Lachs, J. R.; Barrett, A. G. M.; Crimmin, M. R.; Kociok-Ko¨hn, G.; Hill, M. S.; Mahon, M. F.; Procopiou, P. A. Eur. J. Inorg. Chem. 2008, 4173–4179. (k) Crimmin, M. R.; Barrett, A. G. M.; Hill, M. S.; Hitchcock, P. B.; Procopiou, P. A. Organometallics 2008, 27, 497–499. (l) Zhang, W.-X.; Nishiura, M.; Hou, Z. Chem. Commun. 2006, 3812–3814. (m) Zhang, W.X.; Nishiura, M.; Mashiko, T.; Hou, Z. Chem.-Eur. J. 2008, 14, 2167– 2179. (2) For catalytic addition of amines to carbodiimides by MdN imido complexes, see: (a) Ong, T.-G.; Yap, G. P. A.; Richeson, D. S. J. Am. Chem. Soc. 2003, 125, 8100–8101. (b) Montilla, F.; Pastor, A.; Galindo, A. J. Organomet. Chem. 2004, 689, 993–996. (3) (a) Guanidines: Historical, Biological, Biochemical and Clinical Aspects of the Naturally Occurring Guanidino Compounds; Mori, A.; Cohen, B. D.; Lowenthal, A., Eds.; Plenum Press: New York, 1985. (b) Guanidines 2: Further Explorations of the Biological and Clinical Significance of Guanidino Compounds; Mori, A.; Cohen, B. D.; Koide, H., Eds.; Plenum Press: New York, 1987. (c) Berlinck, R. G. S.; Kossuga, M. H. Nat. Prod. Rep. 2005, 22, 516–550. (d) Berlinck, R. G. S. Nat. Prod. Rep. 2002, 19, 617–649.

cleophilic addition of some aromatic amines to carbodiimides.7 However, very few catalysts are known to promote the catalytic addition of amines to unactivated carbodiimides.1,2,8-10 The catalytic addition of primary aromatic amines to carbodiimides was reported by using titanium and vanadium imido complexes to yield the corresponding guanidines, but secondary amines could not be used in these reactions, because the catalytic process required the regeneration of a “MdN” imido moiety.2 In 2006, a half-sandwich rare earth metal alkyl complex was reported by Hou and co-workers to achieve the catalytic addition of secondary amines to carbodiimides.1a-c In this catalytic process, the nucleophilic addition of a rare earth metal-nitrogen single bond to a carbodiimide meets the requirements for a secondary amine, which is quite different from titanium and vanadium imido catalysts. Similarly, lithium silyl amido compound (Me3Si)2NLi,1f lanthanocene amido complexes,1d,e the carboranyl-alkoxy-ligated titanium amido complex,1g and heavier group 2 amides1j have been found to have high catalytic activity, presumably through the same mechanism. The search for a readily available catalyst system for efficient addition of amines to carbodiimides is therefore of obvious interest and importance. The aluminum alkyls and amides are potential bifunctional catalysts bearing a Lewis acidic Al(III) center and activated Al-C/N bonds.11,12 Although nucleophilic addition of group 13 amides to carbodiimides giving the corresponding guanidinate species is a well-established process,13,14 catalytic transformation of a group 13 guanidinate species is rare and has remained unknown until very recently.12d We report here such a catalytic transformation of an aluminum guanidinate species to prepare guanidines by alkyl aluminum catalyst precursors such as AlMe3, AlEt3, and AlEt2Cl. Aromatic carbon-halogen bonds, NO2, and terminal alkyne units survived the reaction conditions. An aluminum guanidinate species has been char(4) (a) Ishikawa, T.; Kumamoto, T. Synthesis 2006, 737–752. (b) McManus, J. C.; Genski, T.; Carey, J. S.; Taylor, R. J. K. Synlett 2003, 369–371. (c) McManus, J. C.; Carey, J. S.; Taylor, R. J. K. Synlett 2003, 365–368. (d) Ishikawa, T.; Isobe, T. Chem.-Eur. J. 2002, 8, 552–557. (e) Kovaeˇevı´, B.; Maksı´, Z. B. Org. Lett. 2001, 3, 1523–1526. (f) Costa, M.; Chiusoli, G. P.; Taffurelli, D.; Dalmonego, G. J. Chem. Soc., Perkin Trans. 1 1998, 1541–1546.

10.1021/om801035t CCC: $40.75  2009 American Chemical Society Publication on Web 01/14/2009

Efficient Route to Substituted Guanidines

Organometallics, Vol. 28, No. 3, 2009 883

acterized by X-ray single-crystal structural analysis and confirmed to be a true catalyst species.

Table 1. Catalytic Addition of an Aniline to a N,N′-Diisopropylcarbodiimidea

Results and Discussion Catalytic Addition of Primary Aromatic Amines to Carbodiimides. As a control experiment, N,N′-diisopropylcarbodiimide i PrNdCdNiPr was heated with aniline in C6D5Cl at 140 °C, but no reaction was observed in 24 h (Table 1, entry 1). In contrast, addition of a small amount (1-2 mol %) of the readily available alkyl aluminum complex AlMe3 at room temperature (5) (a) Katritzky, A. R.; Rogovoy, B. V. ArkiVoc 2005, (4), 49–87. (b) Manimala, J. C.; Anslyn, E. V. Eur. J. Org. Chem. 2002, 3909–3922. (c) Peterlin-Masˇicˇ, L.; Kikelj, D. Tetrahedron 2001, 57, 7073>7105. (d) Li, J.; Zhang, Z.; Fan, E. Tetrahedron Lett. 2004, 45, 1267–1269. (e) Convers, E.; Tye, H.; Whittaker, M. Tetrahedron Lett. 2004, 45, 3401–3404. (f) Gers, T.; Kunce, D.; Markowski, P.; Izdebski, J. Synthesis 2004, 37–42. (g) Yu, Y.; Ostresh, J. M.; Houghten, R. A. J. Org. Chem. 2002, 67, 3138–3141. (h) Wu, Y.-Q.; Hamilton, S. K.; Wilkinson, D. E.; Hamilton, G. S. J. Org. Chem. 2002, 67, 7553–7556. (i) Hopkins, T. P.; Dener, J. M.; Boldi, A. M. J. Comb. Chem. 2002, 4, 167–174. (j) Tamaki, M.; Han, G.; Hruby, V. J. J. Org. Chem. 2001, 66, 1038–1042. (k) Musiol, H.-J.; Moroder, L. Org. Lett. 2001, 3, 3859–3861. (l) Lo´pez-Cremades, P.; Molina, P.; Aller, E.; Lorenzo, A. Synlett 2000, 1411–1414. (m) Kent, D. R.; Cody, W. L.; Doherty, A. M. Tetrahedron Lett. 1996, 37, 8711–8714. (6) (a) Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 133–136. (b) Powell, D. A.; Ramsden, P. D.; Batey, R. A. J. Org. Chem. 2003, 68, 2300–2309. (c) Ghosh, A. K.; Hol, W. G. J.; Fan, E. J. Org. Chem. 2001, 66, 2161– 2164. (7) (a) Molina, P.; Aller, E.; Lorenzo, A. Synlett 2003, 714–716. (b) Molina, P.; Aller, E.; Lorenzo, A. Synthesis 1998, 283–287. (8) For examples of addition of group 3 and lanthanide amido complexes to carbodiimides, see: (a) Pi, C.; Zhang, Z.; Pang, Z.; Zhang, J.; Luo, J.; Chen, Z.; Weng, L.; Zhou, X. Organometallics 2007, 26, 1934–1946. (b) Pi, C.; Liu, R.; Zheng, P.; Chen, Z.; Zhou, X. Inorg. Chem. 2007, 46, 5252– 5259. (c) Pi, C.; Zhu, Z.; Weng, L.; Chen, Z.; Zhou, X. Chem. Commun. 2007, 2190–2192. (d) Ma, L.; Zhang, J.; Cai, R.; Chen, Z.; Zhou, X. Dalton Trans. 2007, 2718–2722. (e) Pi, C.; Zhang, Z.; Liu, R.; Weng, L.; Chen, Z.; Zhou, X. Organometallics 2006, 25, 5165–5172. (f) Ma, L.; Zhang, J.; Zhang, Z.; Cai, R.; Chen, Z.; Zhou, X. Organometallics 2006, 25, 4571– 4578. (g) Trifonov, A. A.; Lyubov, D. M.; Fukin, G. K.; Baranov, E. V.; Kurskii, Y. A. Organometallics 2006, 25, 3935–3942. (h) Ma, L.; Zhang, J.; Cai, R.; Chen, Z.; Weng, L.; Zhou, X. J. Organomet. Chem. 2005, 690, 4926–4932. (i) Zhang, J.; Zhou, X.; Cai, R.; Weng, L. Inorg. Chem. 2005, 44, 716–722. (j) Zhang, J.; Cai, R.; Weng, L.; Zhou, X. Organometallics 2004, 23, 3303–3308. (k) Luo, Y.; Yao, Y.; Shen, Q.; Yu, K.; Weng, L. Eur. J. Inorg. Chem. 2003, 318–323. (l) Zhang, J.; Cai, R.; Weng, L.; Zhou, X. Organometallics 2003, 22, 5385–5391. (m) Zhang, J.; Cai, R.; Weng, L.; Zhou, X. J. Organomet. Chem. 2003, 672, 94–99. (n) Luo, Y.; Yao, Y.; Shen, Q. Macromolecules 2002, 35, 8670–8671. (o) Zhou, Y.; Yap, G. P. A.; Richeson, D. S. Organometallics 1998, 17, 4387–4391. (9) For examples of addition of main group metal amido complexes to carbodiimides, see: (a) Otero, A.; Ferna´ndez-Baeza, J.; Antinolo, A.; Tejeda, J.; Lara-Sa´nchez, A.; Sa´nchez-Barba, L. F.; Lo´pez-Solera, I.; Rodrı´guze, A. M. Inorg. Chem. 2007, 46, 1760–1770. (b) Rowley, C. N.; DiLabio, G. A.; Barry, S. T. Inorg. Chem. 2005, 44, 1983–1991. (c) Kenney, A. P.; Yap, G. P. A.; Richeson, D. S.; Barry, S. T. Inorg. Chem. 2005, 44, 2926– 2933. (d) Giesbrecht, G. R.; Shafir, A.; Arnold, J. J. Chem. Soc., Dalton Trans. 1999, 3601–3604. (e) Coles, M. P.; Swenson, D. C.; Jordan, R. F. Organometallics 1998, 17, 4042–4048. (f) Barrett, A. G. M.; Crimmin, M. R.; Hill, M. S.; Hitchcock, P. B.; Procopiou, P. A. Dalton Trans. 2008, 4474–4481. (g) Mansfield, N. E.; Coles, M. P.; Hitchcock, P. B. Dalton Trans. 2005, 2833–2841. (10) For examples of addition of transition metal amido complexes to carbodiimides, see: (a) Shen, H.; Chan, H.-S.; Xie, Z. Organometallics 2007, 26, 2694–2704. (b) Vicente, J.; Abad, J. A.; Lo´pez-Sa´ez, M.-J.; Jones, P. G. Organometallics 2006, 25, 1851–1853. (c) Coles, M. P.; Hitchcock, P. B. Eur. J. Inorg. Chem. 2004, 2662–2672. (d) Ong, T.-G.; Yap, G. P. A.; Richeson, D. S. Chem. Commun. 2003, 2612–2613. (e) Bazinet, P.; Wood, D.; Yap, G. P. A.; Richeson, D. S. Inorg. Chem. 2003, 42, 6225–6229. (f) Duncan, A. P.; Mullins, S. M.; Arnold, J.; Bergman, R. G. Organometallics 2001, 20, 1808–1819. (g) Keaton, R. J.; Jayaratne, K. C.; Hemingsen, D. A.; Koterwas, L. A.; Sita, L. R. J. Am. Chem. Soc. 2001, 123, 6197–6198. (h) Zuckerman, R. L.; Bergman, R. G. Organometallics 2001, 20, 1792–1807. (i) Zuckerman, R. L.; Bergman, R. G. Organometallics 2000, 19, 4795– 4808. (j) Zuckerman, R. L.; Krska, S. W.; Bergman, R. G. J. Am. Chem. Soc. 2000, 122, 751–761. (k) Koterwas, L. A.; Fettinger, J. C.; Sita, L. R. Organometallics 1999, 18 (10), 4183–4190. (l) Sita, L. R.; Babcock, J. R. Organometallics 1998, 17, 5228–5230.

entry

cat. (mol %)

solvent

temp (°C)

time/h

yield (%)b

1 2 3 4 5 6 7 8 9

0 AlMe3(2) AlMe3(1) AlMe3(2) AlMe3(2) AlMe3(2) AlEt3(2) AlEt2Cl(2) AlCl3(2)

C6D6Cl C6D6 C6D6 [D8]toluene [D8]THF Et2O C6D6 C6D6 C6D6

140 rt rt rt rt rt rt rt rt

24 0.5 0.5 0.5 0.5 0.5 0.5 0.5 2

0 >99 99 >99 >99 >99 >99 >99 59

a Conditions: aniline, 0.51 mmol; N,N′-diisopropylcarbodiimide, 0.50 mmol. b Yields were determined by 1H NMR.

led to rapid addition of aniline to iPrNdCdNiPr to give the N,N′,N′′-trisubstituted guanidine 1 in high yields (Table 1, entries 2-6). The polarity of solvents did not show a significant influence on the catalytic activity in the present reaction (Table 1, entries 3-6). Other alkyl complexes such as AlEt3 and AlEt2Cl were also effective for this catalytic reaction, suggesting that the activity of the present catalyst system is not significantly affected by the initial alkyl group (Table 2, entries 7 and 8). Compared with alkyl aluminum catalyst precursors, AlCl3 showed lower catalytic activity (Table 1, entries 2-9). AlMe3 was then chosen as a catalyst for the addition reaction between various primary amines and carbodiimides having various substituents. Representative results are summarized in Table 2. In the presence of 2 mol % of AlMe3, the reaction of aniline with carbodiimides having N-aryl-N′-alkyl and N,N′dialkyl substituents was completed at room temperature to yield the corresponding substituted guanidines 1-5 quantitatively (Table 2, entries 1-5). In the case of the bulkier N,N′-di-tertbutylcarbodiimide tBuNdCdNtBu, the reaction became a little bit slower probably owing to its steric hindrance (Table 2, entry 4). A wide range of substituted anilines could be used for this reaction. The reaction was not influenced by either electron(11) (a) Saito, S. Main Group Metals in Organic Synthesis; Wiley-VCH: Weinheim, 2004; Vol. 1, pp 189-306. (b) Maruoka, K. Synthetic Utility of Bulky Aluminum Reagents as Lewis Acid Receptors. In Lewis Acid Reagents; Yamamoto, H., Ed.; Oxford University Press: Oxford, 1999; pp 5-29. (c) Negishi, E.-I.; Liu, F. Palladium-or Nickel-catalyzed Crosscoupling with Organometals Containing Zinc, Magnesium, Aluminum, and Zirconium. In Metal-catalyzed Cross-coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; pp 1-47. (12) (a) Hoerter, J. M.; Otte, K. M.; Gellman, S. H.; Cui, Q.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 647–654. (b) Hoerter, J. M.; Otte, K. M.; Gellman, S. H.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 5177–5183. (c) Dornan, P.; Rowley, C. N.; Priem, J.; Barry, S. T.; Burchell, T. J.; Woo, T. K.; Richeson, D. S. Chem. Commun. 2008, 3645–3647. Catalytic transformation of a group 13 guanidinate species was recently mentioned. See: (d) Rowley, C. N.; Ong, T.-G.; Priem, J.; Woo, T. K.; Richeson, D. S. Inorg. Chem. 2008, 47, 9660–9668. (13) For reviews of the chemistry of the guanidines and guanidinates, see: (a) Coles, M. P. Dalton Trans. 2006, 985–1001. (b) Bailey, P. J.; Pace, S. Coord. Chem. ReV. 2001, 214, 91–141. (c) Raczyn´ska, E. D.; Cyran´ski, M. K.; Gutowski, M.; Rak, J.; Gal, J.-F.; Maria, P.-C.; Darowska, M.; Duczmal, K. J. Phys. Org. Chem. 2003, 16, 91–106. (14) For examples of group 13 guanidinate complexes, see: (a) Brazeau, A. L.; DiLabio, G. A.; Kreisel, K. A.; Monillas, W.; Yap, G. P. A.; Barry, S. T. Dalton Trans. 2007, 3297–3304. (b) Rowley, C. N.; DiLabio, G. A.; Barry, S. T. Inorg. Chem. 2005, 44, 1983–1991. (c) Kenney, A. P.; Yap, G. P. A.; Richeson, D. S.; Barry, S. T. Inorg. Chem. 2005, 44, 2926–2933. (d) Aeilts, S. L.; Coles, M. P.; Swenson, D. C.; Jordan, R. F. Organometallics 1998, 17, 3265–3270. (e) Chang, C.-C.; Hsiung, C.-S.; Su, H.-L.; Srinivas, B.; Chiang, M. Y.; Lee, G.-H.; Wang, Y. Organometallics 1998, 17, 1595–1601.

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Zhang et al.

Table 2. Catalytic Addition of Various Primary Anilines to Carbodiimidesa

a

Conditions: amines, 2.02 mmol; carbodiimides, 2.00 mmol; AlMe3, 0.04 mmol; benzene, 5 mL. b Isolated yield. c Conditions: AlMe3 (5 mol %), 80 °C, 1 h. d Conditions: AlEt3 (5 mol %), 80 °C, 1 h. e THF, rt, 1 h.

withdrawing or -donating substituents or the position of the substituents at the phenyl ring (Table 2, entries 1-16). Aromatic C-F (Table 2, entry 6), C-Cl (Table 2, entry 7), C-Br (Table 2, entry 8), and C-I (Table 2, entry 9) bonds survived in the present reactions. In the case of m-aminophenylacetylene, the reaction took place selectively at the amino group, while the terminal alkyne unit remained unchanged (Table 2, entry 10), possibly because the activation energy of a proton transfer from an amine substrate to an aluminum guanidinate is lower than that of an alkyne.15g The reaction of 4-nitroaniline with i PrNdCdNiPr gave quantitatively product 15 in THF at room temperature within 1 h; on the contrary, [ethylenebis(indenyl)]lanthanide(III) amides failed to produce the corresponding guanidine product.1d

In the case of 2,6-dimethylaniline and 2,4,6-trimethylaniline, AlEt3 was less efficient and afforded only a trace amount of the corresponding guanidine products even at higher temperature (80 °C) and in the presence of higher catalyst loading (5%). The reaction of 2,6-dimethylaniline (Table 2, entry 13) and 2,4,6-trimethylaniline (Table 2, entry 14) with iPrNdCdNiPr, however, in the presence of 5 mol % of AlMe3 provided the corresponding guanidine products at 80 °C in high yields, respectively. These results are in sharp contrast with what was observed above in the reaction of aniline with carbodiimides (cf. Table 1, entries 3, and 7), showing that the effect of the alkyl group of aluminum precursors on the catalytic activity could depend on the reaction substrates. The reaction of the bulkier 2,6-diisopropylaniline with iPrNdCdNiPr in the pres-

Efficient Route to Substituted Guanidines Table 3. Catalytic Addition of Heterocyclic Primary Amines to Carbodiimidesa

a Conditions: amines, 2.02 mmol; carbodiimides, 2.00 mmol; AlMe3, 0.04 mmol; benzene, 5 mL. b Isolated yield.

Figure 1. ORTEP drawing of 5 with 30% thermal ellipsoids. Hydrogen atoms, except those on the nitrogen atoms, are omitted for clarity. Selected bond lengths [Å] and angles [deg]: N(1)-C(1) 1.353(4), N(2)-C(1) 1.382(4), N(3)-C(1) 1.301(4), N(1)-C(1)-N(2) 112.4(3), N(1)-C(1)-N(3) 120.5(3), N(2)-C(1)-N(3) 127.0(4).

ence of AlMe3 did not occur to give the corresponding guanidine even at higher temperatures (e.g., 110 °C), showing that the steric effects of substituents on phenyl rings have a great influence on the occurrence of catalytic reactions. A variety of heterocyclic primary amines such as aminosubstituted isoxazoles, pyrozoles, thiazoles, and pyridines could also be used for this reaction, as shown in Table 3. In the case of the bulkier tert-butyl-3-ethylcarbodiimide, the reaction with 5-methylisoxazol-3-amine required a higher temperature (80 °C) for completion in 1 h, probably due to steric hindrance (Table 3, entry 2). As far as amino-substituted thiazole and pyridine were concerned, the reactions with iPrNdCdNiPr became a little slower than that of amino-substituted isoxazoles and pyrozoles (Table 3, entries 1, 4, and 5). The 1H and 13C NMR spectra of the guanidine products 1, 2, 4, 6-17, and 19-21, formed by the reactions of aromatic

Organometallics, Vol. 28, No. 3, 2009 885 Scheme 1. Formation of an Aluminum Guanidinate and Its Reaction with Pyrazole 22

primary amines with the symmetric carbodiimides RNdCdNR (R ) iPr, Cy, and tBu), all showed one set of signals for the i Pr, Cy, and tBu groups, suggesting that the two iPr, Cy, and t Bu groups in each guanidine product should be in a similar environment. The 1H and 13C NMR spectra of the guanidine products 3, 5, and 18, which resulted from the reactions with the unsymmetrical carbodiimides EtNdCdNtBu and CyNd CdNPh, also suggested the presence of only one isomer in solution. The structure of 5 was confirmed by its X-ray singlecrystal structural analysis (Figure 1 and Table 2, entry 5). Mechanistic Aspects. (a) Stoichiometric Addition of Amine N-H Bonds to Carbodiimides. The 1:1:1 reaction of AlMe3, PhNH2, and iPrNdCdNiPr in C6D6 at room temperature was first carried out to give quantitatively the aluminum guanidinate complex [Me2Al{iPrNdC(NPh)(NHiPr)}]. However, in a 1:2:2 reaction of AlMe3, PhNH2, and iPrNdCdNiPr in C6D6 at room temperature, the guanidine product PhNdC(NHiPr)2 (1) was observed in addition to the aluminum guanidinate complex [Me2Al{iPrNdC(NPh)(NHiPr)}], suggesting that the protonolysis between the guanidinate unit {iPrNdC(NPh)(NHiPr)} and PhNH2 became faster than that of the second Al-Me and PhNH2 in the present conditions. An attempt to obtain suitable crystals of aluminum guanidinate [Me2Al{iPrNdC(NPh)(NHiPr)}], however, was unsuccessful owing to its good solubility in common organic solvents. Then the 1:1:1 reaction of AlMe3, aminosubstituted pyrazole 22, and iPrNdCdNiPr in C6D6 at room temperature was carried out to give the guanidinate complex 24 within 5 min at room temperature (Scheme 1). Single crystals of 24 suitable for X-ray analysis were grown in ether at room temperature overnight. This revealed that 24 adopts a monomeric structure, in which the metal center is bonded to two methyl ligands and one guanidinate unit (Figure 2). While the differing guanidine substituents result in a small degree of asymmetry, the X-ray structure clearly shows a delocalized monoanionic guanidinate with roughly symmetric Al-N bonds. At room temperature, a 1:1 mixture of 22 and 24 was observed to give slowly the corresponding guanidine compound 19 and 23(Scheme 1). However, when excess 22 and iPrNdCdNiPr (1: 1) were added to 24 in C6D6 at room temperature, catalytic formation of 19 was achieved (eq 1).

(b) Possible Mechanism. A possible catalytic cycle for the addition reaction of primary aromatic amines to carbodiimides

886 Organometallics, Vol. 28, No. 3, 2009

Figure 2. ORTEP drawing of 24 with 30% thermal ellipsoids. Hydrogen atoms, except that on the nitrogen atom N2, are omitted for clarity. Selected bond lengths (A) and angles (deg): Al(1)-N(1) 1.933(2), Al(1)-N(3) 1.950(2), Al(1)-C(1) 1.943(2), Al(1)-C(2) 1.945(3), N(1)-C(6) 1.318(3), N(2)-C(6) 1.341(3), N(3)-C(6) 1.388(3), N(1)-Al(1)-N(3) 69.22(9), N(1)-C(6)-N(3) 109.1(2), N(1)-C(6)-N(2) 127.7(3), N(2)-C(6)-N(3) 123.1(3). Scheme 2. Possible Mechanism of Catalytic Addition of Primary Aromatic Amines to Carbodiimides

is proposed in Scheme 2. The acid-base reaction between an aluminum alkyl and a primary amine N-H bond yields straightforwardly an amido species such as A. Nucleophilic addition of the amido species A to a carbodiimide would first afford the guanidinate species B, which could then quickly be rearranged to the guanidinate species C at room temperature through the intramolecular 1,3-hydrogen shift (path a).1a,b In the case of the formation of C, nucleophilic attack of the amido species A at the central carbon atom of the carbodiimide followed by 1,3-hydrogen migration from the aryl amido moiety to the more basic uncoordinated nitrogen leading to the formation of C (path b) could not be ruled out. Protonolysis of C by another molecule of primary amine would regenerate the amido A and release the guanidine D. Intramolecular 1,3-hydrogen shift in D could give the more stable, final product E. Protonolysis of B by another molecule of primary amine giving the final product E is also a possible route.13c

Conclusion Readily available alkyl aluminums such as AlMe3, AlEt3, and AlEt2Cl can serve as excellent catalyst precursors for the catalytic addition of amine N-H bonds to carbodiimides,

Zhang et al.

leading to efficient formation of a series of guanidine derivatives with a wide range of substituents on the nitrogen atoms. Functional groups such as NO2, CtCH, and aromatic C-X (X ) F, Cl, Br, I) bonds can survive the catalytic reaction conditions. The isolation and reactivity investigation of the aluminum guanidinate intermediate 24 suggest that the catalytic formation of a guanidine compound proceeds through nucleophilic addition of an aluminum amido species, formed by acid-base reaction between an Al-alkyl bond and an amine N-H bond, to a carbodiimide, followed by amine protonolysis of the resultant guanidinate species. These results have demonstrated that a guanidinate unit, though being often used as a supporting ligand for the aluminum complexes, can itself participate in a reaction in a catalytic fashion under appropriate conditions.

Experimental Section General Procedures. Unless otherwise noted, all starting materials were commercially available and were used without further purification. All reactions were carried out under a dry and oxygen-free nitrogen atmosphere by using Schlenk techniques or under a nitrogen atmosphere in a Mikrouna Super (1220/750) glovebox. The nitrogen in the glovebox was constantly circulated through a copper/molecular sieve catalyst unit. The oxygen and moisture concentrations in the glovebox atmosphere were monitored by an O2/H2O Combi-Analyzer to ensure both were always below 1 ppm. Solvents were distilled fromsodium/benzophenoneketyl,degassedbythefreeze-pump-thaw method (three times), and dried over fresh Na chips in the glovebox. [D6]Benzene, [D8]toluene, and [D8]THF (all 99+ atom % D) were obtained from Acros and were dried over fresh Na chips in the glovebox for NMR reactions. 1H and 13C NMR spectra were recorded on a JEOL-AL400 spectrometer (FT, 400 MHz for 1H; 100 MHz for 13C) or a JEOL JNM-AL300 spectrometer (FT, 300 MHz for 1H; 75 MHz for 13C) at room temperature, unless otherwise noted. Organometallic samples for NMR spectroscopic measurements were prepared in the glovebox by use of J. Young valve NMR tubes (Wilmad 528-JY). Typical Procedures for the Catalytic Reaction of Primary Aromatic Amines to Carbodiimides. (i) NMR Tube Reaction. In the glovebox, a J. Young valve NMR tube was charged with AlMe3 (10 µL, 0.01 mmol), C6D6 (0.5 mL), aniline (48 mg, 0.51 mmol), and N,N′-diisopropylcarbodiimide (63 mg, 0.50 mmol). The tube was taken outside the glovebox, and the reaction was carried out at room temperature. Formation of 1 was easily monitored by 1 H NMR spectroscopy. The reaction was quantitative and finished within 1 h. (ii) Preparative Scale Reaction. In the glovebox, a solution of aniline (188 mg, 2.02 mmol) in benzene (3 mL) was added to a solution of AlMe3 (0.04 mL, 0.04 mmol) in a Schlenk tube. N,N′Diisopropylcarbodiimide (252 mg, 2.00 mmol) was then added to the above reaction mixture. The Schlenk tube was taken outside the glovebox, and the reaction was carried out at room temperature for 1 h. After the solvent was removed under reduced pressure, the residue was extracted with ether and filtered to give a clean solution. After removing the solvent under vacuum, the residue was recrystallized in ether to provide a colorless solid, 1. 1: colorless solid, yield >99%. 1H NMR (400 MHz, C6D6): δ 0.91 (d, J ) 6.4 Hz, 12H, CH3), 3.52 (br, 2H, NH), 3.64-3.69 (m, 2H, CH), 6.90 (t, J ) 7.6 Hz, 1H, p-C6H5), 7.10 (d, J ) 7.6 Hz, 2H, o-C6H5), 7.25 (t, J ) 7.6 Hz, 2H, m-C6H5). 13C NMR (100 MHz, C6D6): δ 23.4, 43.4, 121.3, 123.7, 129.6, 149.7, 151.6.1b 3: colorless solid, yield >99%. 1H NMR (400 MHz, C6D6): δ 0.71 (t, J ) 7.2 Hz, 3H, CH2CH3), 1.29 (s, 9H, C(CH3)3), 2.70-2.73 (m, 2H, CH2CH3), 3.48 (br, 2H, NH), 6.91 (t, J ) 7.2 Hz, 1H, p-C6H5), 7.06 (d, J ) 7.2 Hz, 2H, o-C6H5), 7.23-7.26 (m, 2H,

Efficient Route to Substituted Guanidines m-C6H5). 13C NMR (100 MHz, CDCl3): δ 15.0, 29.9, 37.1, 50.7, 121.2, 123.6, 129.6, 150.0, 151.6. 4: colorless solid, yield >99%. 1H NMR (400 MHz, C6D6): δ 1.20 (s, 18H, C(CH3)3), 3.67 (br, 2H, NH), 6.92 (t, J ) 7.2 Hz, 1H, p-C6H5), 7.02 (d, J ) 7.2 Hz, 2H, o-C6H5), 7.21-7.25 (m, 2H, m-C6H5). 13C NMR (100 MHz, CDCl3): δ 30.0, 50.6, 121.4, 123.5, 129.5, 149.9, 151.5. 5: Single crystals suitable for X-ray analysis were grown in benzene at room temperature for two days; colorless crystals, yield 93%. 1H NMR (400 MHz, C6D6): δ 0.77-1.98 (m, 10H, Cy), 3.87 (br, 2H, NH and CH), 5.67 (br, 1H, NH), 6.86-7.36 (m, 10H, C6H5). 13C NMR (100 MHz, CDCl3): δ 25.2, 25.9, 33.4, 50.0, 122.7(br), 123.8, 125.0, 129.1, 129.2, 129.6, 146.8, 150.4, 151.7. 6: colorless solid, yield >99%. 1H NMR (300 MHz, C6D6): δ 0.88 (d, J ) 6.3 Hz, 12 H, CH3), 3.26-3.67 (br, 4H, 2NH and 2CH), 6.84-7.16 (br, 4H, CH). 13C NMR (75 MHz, C6D6): δ 23.2, 43.2, 116.1 (d, J ) 21.6 Hz), 124.5 (d, J ) 7.43 Hz), 147.6 (d, J ) 2.48 Hz), 150.0 (d, J ) 1.28 Hz), 160.08. 10: colorless solid, yield >99%. 1H NMR (300 MHz, C6D6): δ 0.89 (d, J ) 6.0 Hz, 12 H, CH3), 2.82 (s, 1H, CH), 3.54-3.67 (br, 4H, 2NH and 2CH), 6.99-7.17 (br, 4H, CH). 13C NMR (75 MHz, C6D6): δ 23.1, 43.2, 77.2, 84.6, 123.6, 124.6, 125.0, 127.1, 129.6, 150.1, 151.7. 12: colorless solid, yield >99%. 1H NMR (300 MHz, C6D6): δ 0.91 (d, J ) 6.3 Hz, 12 H, CH3), 1.32 (d, J ) 6.9 Hz, 6H, CH3), 3.36-3.63 (br, 5H, 2NH and 3CH), 6.94-7.33 (br, 4H, CH). 13C NMR (75 MHz, C6D6): δ 23.3, 23.4, 28.6, 43.3, 122.1, 123.0, 126.2, 126.7, 142.2, 148.5, 148.8. Isolation of the Guanidiate Complex 24. In the glovebox, a benzene solution (3 mL) of 3-methyl-1-phenyl-1H-pyrazol-5-amine (22) (173 mg, 1 mmol) was added to a benzene solution (2 mL) of AlMe3 (0.5 mL, 2 mol/L in toluene, 1 mmol) in a flask. Then N,N′diisopropylcarbodiimide (126 mg, 1 mmol) was added to the above reaction mixture. The mixture was stirred at room temperature for 5 min. After the solvent was removed under reduced pressure, the residue was extracted with ether and filtered to give a clean solution. The solution volume was reduced under vacuum to precipitate 24 as a colorless crystalline powder in 93% yield. Single crystals of 24 suitable for X-ray analysis were grown in ether at room temperature overnight. 1H NMR (400 MHz, C6D6): δ -0.54 (s, 6H, AlMe2), 0.64 (d, J ) 6.0 Hz, 6H, CH(CH3)2), 0.90 (d, J ) 6.0 Hz, 6H, CH(CH3)2), 2.27 (s, 3H, Me), 2.94-3.01 (m, 1H, CH(CH3)2), 3.49-3.58 (m, 1H, CH(CH3)2), 4.07 (d, 1H, J ) 9.6 Hz, NH), 5.62 (s, 1H, CH(pyrazolyl)), 6.96 (t, J ) 7.6 Hz, 1H, p-C6H5), 7.13-7.18 (m, 2H, m-C6H5), 7.80 (d, J ) 7.6 Hz, 2H, o-C6H5). 13C NMR (100 MHz, CDCl3): δ -9.5, 14.5, 23.0, 24.0, 44.0, 44.1, 44.9, 96.1, 124.6, 126.6, 129.1, 140.2, 145.0, 148.8, 160.8. Anal. Calcd for C19H30AlN5: C, 64.20; H, 8.51; N, 19.70. Found: C, 64.30; H, 8.76; N, 19.45.

Organometallics, Vol. 28, No. 3, 2009 887 X-ray Crystallographic Studies. Crystals for X-ray analyses of 5 and 24 were obtained as described in the preparations. The crystals were manipulated in the glovebox and were sealed in thinwalled glass capillaries. Data collections were performed at -110 °C on a Bruker CCD APEX diffractometer with a CCD area detector, using graphite-monochromated Mo KR radiation (λ ) 0.71069 Å). The determination of crystal class and unit cell parameters was carried out by the SMART program package. The raw frame data were processed using SAINT and SADABS to yield the reflection data file.16 The structures were solved by use of the SHELXTL program.17 Refinement was performed on F2 anisotropically for all the non-hydrogen atoms by the full-matrix leastsquares method. The hydrogen atoms were placed at the calculated positions and were included in the structure calculation without further refinement of the parameters. Crystal data, data collection, and processing parameters for 5 and 24 are given only in the Supporting Information. Crystallographic data (excluding structure factors) have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication nos. CCDC-706408 (5) and CCDC-706407 (24). Copies of these data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

Acknowledgment. This work was supported by the Natural Science Foundation of China (20702003, 20632010, and 20521202) and the Major State Basic Research Development Program (2006CB806105). Cheung Kong Scholars Programme, Qiu Shi Science & Technologies Foundation, BASF, Dow Corning Corporation, and Eli Lilly China are gratefully acknowledged. Supporting Information Available: Experimental details, X-ray data for 5 and 24, and scanned NMR spectra of all new products (PDF). This material is available free of charge via the Internet at http://pubs.acs.org. OM801035T (15) (a) Liu, Y.; Nishiura, M.; Wang, Y.; Hou, Z. J. Am. Chem. Soc. 2006, 128, 5592–5593. (b) Zhang, W.-X.; Nishiura, M.; Hou, Z. J. Am. Chem. Soc. 2005, 127, 16788–16789. (c) Nishiura, M.; Hou, Z. J. Mol. Catal. A 2004, 213, 101>106. (d) Nishiura, M.; Hou, Z.; Wakatsuki, Y.; Yamaki, T.; Miyamoto, T. J. Am. Chem. Soc. 2003, 125, 1184–1185. (e) Hou, Z. Bull. Chem. Soc. Jpn. 2003, 76, 2253–2266. (f) Zhang, W.-X.; Nishiura, M.; Hou, Z. Angew. Chem., Int. Ed. 2008, 47, 9700–9703. See also: (g) Rowley, C. N.; Ong, T.-G.; Priem, J.; Richeson, D. S.; Woo, T. K. Inorg. Chem. 2008, 47, 12024–12031. (16) Sheldrick, G. M. SADABS, Program for Empirical Absorption Correction of Area Detector Data; University of Go¨ttingen: Go¨ttingen, Germany, 1996. (17) Sheldrick, G. M. SHELXTL 5.10 for Windows NT, Structure Determination Software Programs; Bruker Analytical X-ray Systems, Inc.: Madison, WI, 1997.