Gilman-Type versus Lipshutz-Type Reagents: Competition in

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Gilman-Type versus Lipshutz-Type Reagents: Competition in Lithiocuprate Chemistry Joanna Haywood, James V. Morey, and Andrew E. H. Wheatley* Department of Chemistry, UniVersity of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.

Ching-Yuan Liu AdVanced Elements Chemistry Laboratory, The Institute of Physical and Chemical Research, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan, and Organization for Frontier Research in Pharmaceutical Sciences, Hokuriku UniVersity, Kanagawa-machi, Kanazawa 920-1181, Japan

Shuji Yasuike and Jyoji Kurita Faculty of Pharmaceutical Sciences, Hokuriku UniVersity, Kanagawa-machi, Kanazawa 920-1181, Japan

Masanobu Uchiyama* AdVanced Elements Chemistry Laboratory, The Institute of Physical and Chemical Research, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan

Paul R. Raithby Department of Chemistry, UniVersity of Bath, ClaVerton Down, Bath BA2 7AY, U.K. ReceiVed NoVember 19, 2008 Summary: CuCN reacts with RLi and TMPLi (TMP ) 2,2,6,6tetramethylpiperidide)togiVeGilman-typecupratesR(TMP)CuLi·nL (R ) Ph, n ) 3, L ) THF 2; R ) Me, n ) 1, L ) TMEDA 3). 3 and 3·LiCN haVe been tested in directed ortho cupration with data suggesting enhanced efficiency for Lipshutz-type 3·LiCN; competition between Lipshutz- and Gilman-type formulations is rationalized by DFT methods. It has recently been established that amido ligand components of homoleptic cuprates can act as bases in the directed ortho cupration (DoC) of functionalized arenes.1 The nontransferable and potentially chiral nature of amido ligands in heteroleptic cuprates is already theoretically established,2 and it is this which has formed the basis of their deployment in synthetic chemistry.3 Whereas homoleptic bis(alkyl)cuprates have been the focus of both synthetic applications and structural investigations,4 structure studies on heteroleptic organo(amido)cuprates are harder to come by.5 It is only lately that Davies et al. reported the first isolation and solid-state characterization of an organo(amido)cuprate,6 the head-to-tail dimeric structure of MesCu(NBn2)Li * To whom correspondence should be addressed. Fax: Int +44-1223336362 (A.E.H.W.); Int +81-48-467-2879 (M.U.). E-mail: [email protected] (A.E.H.W.); [email protected]. (1) Usui, S.; Hashimoto, Y.; Morey, J. V.; Wheatley, A. E. H.; Uchiyama, M. J. Am. Chem. Soc. 2007, 129, 15102. (2) Yamanaka, M.; Nakamura, E. J. Am. Chem. Soc. 2005, 127, 4697. (3) (a) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135. (b) Modern Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim, Germany, 2002. (c) Compounds of Groups 12 and 11 (Zn, Cd, Hg, Cu, Ag, Au); O’Neil, I., Ed.; Georg Thieme: Stuttgart, Germany, 2004; Science of Synthesis, Vol. 3. (4) E.g.: (a) Bertz, S. H.; Chopra, A.; Eriksson, M.; Ogle, C. A.; Seagle, P. Chem. Eur. J. 1999, 5, 2680. (b) Henze, W.; Vyater, A.; Krause, N.; Gschwind, R. M. J. Am. Chem. Soc. 2005, 127, 17335. (5) Gschwind, R. M. Chem. ReV. 2008, 108, 3029. (6) Davies, R. P.; Hornauer, S.; Hitchcock, P. B. Angew. Chem., Int. Ed. 2007, 46, 5191.

(Bn ) benzyl) confirming theoretical expectations.7 In spite of the observation of a complex Schlenk equilibrium, the dimeric MesCu(NBn2)Li system showed negligible signs of deaggregation in solution. While a deaggregated organo(amido)cuprate has been established in solutionsa monomeric π-complex between n-butyl{(R)-N-methyl-1-phenyl-2-(1-pyrrolidinyl)ethanamido}cuprate and cyclohexanone being invoked in the Cumediated 1,4-alkylation of R,β-unsaturated ketones8ssuch a species has not hitherto been isolated. In seeking to extend the field of directed aromatic deprotonation using heterobimetallic reagents,9 we have probed the utility of both Gilman- and Lipshutz-type10 organo(amido)cuprates in DoC reactions and found that the latter type represent substantially more effective substrates.1 During the course of this work, we established that the treatment of CuCN with 2 equiv of TMPLi afforded the isolable Lipshutz-type complex (TMP)2Cu(CN)Li2 · THF (1), which revealed a dimeric formulation in the solid state, fundamental to the integrity of which was (i) the ability of [TMP]- to act as an intermetal bridge between Cu and Li and (ii) the retention of [CN]- in the dimer core (Scheme 1). We next sought to investigate whether the retention of cyanide (Lipshutz characteristics) occurred in heteroleptic organo(amido)cuprates since metallo intermediates, (7) (a) Dieter, R. K.; Tokles, M. J. Am. Chem. Soc. 1987, 109, 2040. (b) Dieter, R. K.; Hanks, T. W. Organometallics 1992, 11, 3549. (c) Rossiter, B. E.; Eguchi, M.; Miao, G.; Swingle, N. M.; Hernandez, A. E.; Vickers, D.; Fluckiger, E.; Patterson, R. G.; Reddy, K. V. Tetrahedron 1993, 49, 965. (8) Eriksson, J.; Davidsson, O. Organometallics 2001, 20, 4763. (9) Mulvey, R. E.; Mongin, F.; Uchiyama, M.; Kondo, Y. Angew. Chem., Int. Ed. 2007, 46, 3802, and references cited therein. (10) (a) Lipshutz, B. H.; Wilhelm, R. S.; Floyd, D. M. J. Am. Chem. Soc. 1981, 103, 7672. (b) Lipshutz, B. H.; Wilhelm, R. S.; Kozlowski, J. A. Tetrahedron 1984, 40, 5005. (c) Lipshutz, B. H.; Kozlowski, J. A.; Wilhelm, R. S. J. Org. Chem. 1984, 49, 3943. (d) Lipshutz, B. H. Synthesis 1987, 325. (e) Lipshutz, B. H.; Sharma, S.; Ellsworth, E. L. J. Am. Chem. Soc. 1990, 112, 4032.

10.1021/om801101u CCC: $40.75  2009 American Chemical Society Publication on Web 12/11/2008

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Organometallics, Vol. 28, No. 1, 2009 39 Scheme 1

putatively of the type R(TMP)Cu(CN)Li2, have recently been shown to be proficient DoC reagents.1 Notably, recent theoretical work has suggested the importance of the seven-membered X2Cu(CN)Li2 metallacycle in the chemistry of cyanide-containing higher order cuprates.11 Interestingly, however, whereas several reports of cyanide-containing lower order cuprates exist,12 the only fully characterized higher order cuprates to incorporate cyanide are homoleptic. Whereas metallacycle formation was noted in 1,1 the poor bridging ability of tBu groups combined with the presence of strong Lewis base incurs ion separation in [(tBu)2Cu]-[(CN){Li( · THF) · PMDETA}2]+,13 while in (2-Me2NCH2C6H4)2Cu(CN){Li( · 2THF)}2 the bridging ligands favor polymerization instead.14 Herein we present the preliminary structural results obtained when organo(cyano)cuprates are treated with a lithium amide. Data suggest that, in contrast to the 2:1 reaction of lithium amide with CuCN, the 1:1 reaction of RCu(CN)Li (R ) alkyl, aryl) with a lithium amide results in the expulsion of LiCN, that Gilman-type products compete with the corresponding Lipshutz-type species, and that solvent interactions prevent aggregation. The recently reported synthesis and isolation of 1 resulted from the treatment of CuCN with excess TMPLi, after which the solvent was removed and replaced by toluene for recrystallization.1 The homoleptic product was shown to effect DoC of the representative substrate N,N-diisopropylbenzamide with the TMP ligand acting as a base, enabling homocoupling to give a 2,2-biaryl through oxidation by PhNO2. Conversely, the synthesis of heterocoupled 2-RC6H4C(O)NiPr2 (R ) Me, Ph) was enabled by the use of the corresponding putative heteroleptic cuprates R(TMP)Cu(CN)Li2. In seeking to probe the identity of the aryl cuprate (R ) Ph), we sequentially treated a slurry of CuCN in THF with THF stock solutions of PhLi and TMPLi (1 equiv each). The resulting solution was concentrated prior to storage at -30 °C, after which colorless plates of 2 were obtained (Scheme 2). However, importantly, whereas the spectroscopic analysis of bulk 1 supplied evidence for the inclusion of cyanide (clearly seen at δ 167.1 by 13C NMR spectroscopy and 2104.1 cm-1 by IR spectroscopysreplaced by a strong signal at 2129.2 cm-1 upon hydrolysis),15 comparable analysis of bulk 2 demonstrated the complete absence of both the 13C NMR resonance and the infrared stretching modes attributable to cyanide. Instead, 1H NMR spectroscopy yielded signals suggesting the presence of phenyl, TMP, and THF in a (11) (a) Nakamura, E.; Mori, S. Angew. Chem., Int. Ed. 2000, 39, 3750. (b) Mori, S.; Nakamura, E.; Morokuma, K. J. Am. Chem. Soc. 2000, 122, 7294. (12) (a) Hwang, C.-S.; Power, P. P. J. Am. Chem. Soc. 1998, 120, 6409. (b) Hwang, C.-S.; Power, P. P. J. Am. Chem. Soc. 1999, 18, 697. (c) Eaborn, C.; Hill, M. S.; Hitchcock, P. B.; Smith, J. D. Organometallics 2000, 19, 5780. (d) Bosold, F.; Marsch, M.; Harms, K.; Boche, G. Z. Kristallogr. New Cryst. Struct. 2001, 216, 143. (e) Eaborn, C.; El-Hamruni, S. M.; Hill, M. S.; Hitchcock, P. B. Dalton Trans. 2002, n/a, 3975. (f) Davies, R. P.; Hornauer, S. Eur. J. Inorg. Chem. 2005, 51. (13) Boche, G.; Bosold, F.; Marsch, M.; Harms, K. Angew. Chem., Int. Ed. 1998, 37, 1684. (14) Kronenburg, C. M. P.; Jastrzebski, J. T. B. H.; Spek, A. L.; van Koten, G. J. Am. Chem. Soc. 1998, 120, 9688. (15) See the Supporting Information.

Figure 1. Structure of 2 at the 40% probability level with H atoms and disorder omitted. Selected bond lengths (Å): C10-Cu1 ) 1.903(2), N1-Cu1 ) 1.9116(18), N1-Li1 ) 2.188(4). Scheme 2

1:1:3 ratio and therefore pointing to a Gilman-type formulation. This was confirmed crystallographically, with 2 depositing in the triclinic crystal system P1j, and the crystal structure (Figure 1) revealing the monomeric complex PhCu(µ-TMP)Li · 3THF in which the copper center adopts a near-linear geometry (N1-Cu1-C10 ) 176.36(8)°) and the amide acts as an intermetal bridge (Cu1-N1-Li1 ) 87.04(12)°). While such behavior has been seen in the metallacyclic M(µ-R)(µ-N)Li cores of related aluminates16 and zincates,9,17 and equivocally in manganates,18 the motif seen here, in which essentially linear geometry at Cu19 prevents the formation of a four-membered metallacycle, bears close comparison to homoleptic 1 (Cu-N-Li ) 91.12(13), 94.92(14)°)1 and (Ph2N)2Cu(Ph2N)Li2 · 2OEt2 (Cu-N-Li ) 88.3(2)° in a six-membered ring),20 heteroleptic MesNHCu(PhNH)Li · DME (Cu-N-Li ) 105.9(4), 107.2(5)° in an eight-membered ring),20 and the aryl(amido)cuprate MesCu(NBn2)Li (Cu-N-Li ) 89.96°).6 The observation of a terminal Cu-Ph interaction (1.903(2) Å) is highly unusual. While this interaction is known from other fields of organocopper chemistry,21 the only precedents in lithiocuprate chem(16) (a) Naka, H.; Uchiyama, M.; Matsumoto, Y.; Wheatley, A. E. H.; McPartlin, M.; Morey, J. V.; Kondo, Y. J. Am. Chem. Soc. 2007, 129, 1921. ´ lvarez, J.; Hevia, E.; Kennedy, A. R.; Klett, J.; Mulvey, R. E. (b) Garcı´a-A Chem. Commun. 2007, 2402. (17) (a) Clegg, W.; Dale, S. H.; Hevia, E.; Honeyman, G. W.; Mulvey, R. E. Angew. Chem., Int. Ed. 2006, 45, 2370. (b) Uchiyama, M.; Matsumoto, Y.; Nobuto, D.; Furuyama, T.; Yamaguchi, K.; Morokuma, K. J. Am. Chem. Soc. 2006, 128, 8748. (c) Kondo, Y.; Morey, J. V.; Morgan, J. M.; Raithby, P. R.; Nobuto, D.; Uchiyama, M.; Wheatley, A. E. H. J. Am. Chem. Soc. ´ lvarez, J.; Garcia-A ´ lvarez, P.; 2007, 129, 12734. (d) Clegg, W.; Garcia-A Graham, D. V.; Harrington, R. W.; Hevia, E.; Kennedy, A. R.; Mulvey, R. E.; Russo, L. Organometallics 2008, 27, 2654. ´ lvarez, J.; Kennedy, A. R.; Klett, J.; Mulvey, R. E. Angew. (18) Garcia-A Chem., Int. Ed. 2007, 46, 1105. (19) Power, P. P.; Ruhlandt-Senge, K.; Shoner, S. C. Inorg. Chem. 1991, 30, 5013. (20) Reiss, P.; Fenske, D. Z. Anorg. Allg. Chem. 2000, 626, 1317. (21) (a) Gambarotta, S.; Strologo, S.; Floriani, C; Chiesi-Villa, A. Organometallics 1984, 3, 1444. (b) Dattelbaum, A. M.; Martin, J. D. Polyhedron 2006, 25, 349. (c) Fischer, R.; Gorls, H.; Westerhausen, M. Organometallics 2007, 26, 3269. (22) (a) Hope, H.; Olmstead, M. M.; Power, P. P.; Sandell, J.; Xu, X. J. Am. Chem. Soc. 1985, 107, 4337. (b) Davies, R. P.; Hornauer, S. Eur. J. Inorg. Chem. 2005, 51.

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Scheme 3

istry are the longer 1.925(10) and 1.916 Å (mean) bonds noted in the ion separates [Ph2Cu]-[Li · 2(12-crown-4)]+ and {[Ph2Cu]-}2[(Cu( · 2PPh3){(CN)Li}2 · 5THF)2]2+,22 while the remaining reported terminal Cu-Ar bonds in this area feature kinetically protective Mes,23 C6H3-2,6-Mes2,24 or C6H3-2,6-Trip2 (Trip ) C6H2-2,4,6-iPr3).12a,b Consistent with the high level of external solvation of the alkali metal (O-Li1 range 2.041(4)2.067(4) Å), N1-Li1 is, at 2.188(4) Å, relatively long (viz. 1.982(5)and1.995(4)Åin1and1.969(10)ÅinMesCu(NBn2)Li).1,6 The ability of the putative cuprate Me(TMP)Cu(CN)Li2 to achieve the heterocoupled product 2-MeC6H4C(O)NiPr2 led us to probe the identity of the heterometallic species isolable from a MeLi/CuCN/TMPLi mixture. Accordingly, a slurry of CuCN in THF was sequentially treated with etherate solutions of MeLi and TMPLi (1 equiv each). Concentration of the resulting solution gave an oil, the storage of which at -30 °C failed to yield any isolable material. However, a surprising modification of the protocol led to greater success. Thus, a stock solution of TMPLi (1 equiv) in dry toluene was added to a slurry containing equimolar MeLi and CuCN in dry TMEDA at -78 °C. The resulting cream-colored slurry changed color from medium yellow to pale yellow and was left to reach 0 °C, whereupon the introduction of THF gave a solution. The storage of this mixture at -30 °C for 24 h produced colorless needles (Scheme 3). As for 2, 13C NMR and infrared spectroscopy again clearly showed the complete absence of cyanide. 1H NMR spectroscopy in C6D6 showed signals attributable to only Me, TMP, and TMEDA, with the respective integrations (1:1:1) suggesting a Gilman-type cuprate akin to 2, namely MeCu(µ-TMP)Li · TMEDA (3). The most notable spectroscopic feature of this formulation is the cuprated methyl group, and this was plainly observable by both 1H and 13C NMR methods at δ -0.07 and -11.0, respectively. X-ray crystallography confirmed the proposed formulation of 3, with the crystals depositing in the orthorhombic system Pmcn. For each molecule of MeCu(µ-TMP)Li · TMEDA there resides one unit of lattice THF, though analysis suggests that this is largely removed in vacuo during isolation.15 The structure demonstrates a monomer in spite of a reduction in the coordination state of the alkali metal from distorted tetrahedral in 2 to essentially trigonal planar in 3 (sum of angles at Li1 359.9°; Figure 2). The TMEDA-Li interactions are 2.120(11) and 2.081(9) Å. However, in response to the decreased group 1 metal coordination state, the lithium-amide distance is, at 1.992(9) Å, rather short for a N-Li bond25 and significantly less than the analogous interaction in 2. The angles at both the intermetal amide bridge (Cu1-N1-Li1 ) 92.1(3)°) and the copper atom (178.2(2)°) are comparable to those in 2. However, both bonds to copper are extended in 3 relative to those in 2 (N1-Cu1 ) 1.942(4) Å and C1-Cu1 ) 1.927(5) Å). As with that of the Cu-Ph bond in 2, the characterization of a Cu-Me interaction in the solid state is, in itself, unusual. Homoleptic (23) Davies, R. P.; Hornauer, S. Chem. Commun. 2007, 304. (24) (a) Niemeyer, M. Organometallics 1998, 17, 4649. (b) Hwang, C.S.; Power, P. P. Bull. Korean Chem. Soc. 2003, 24, 605. (25) Gregory, K.; Schleyer, P. v. R.; Snaith, R. AdV. Inorg. Chem. 1991, 37, 47.

Figure 2. Structure of 3 at the 40% probability level with TMEDA disorder and lattice THF and H atoms omitted. Selected bond lengths (Å) and angles (deg): C1-Cu1 ) 1.927(5), N1-Cu1 ) 1.942(4), N1-Li1 ) 1.992(9); Cu1-N1-Li1 ) 92.1(3), N1-Li1-N2 ) 139.2(5), N1-Li1-N3 ) 133.6(5).

dimethylcuprate ions have been noted in [Me2Cu]-[Li · nL]+ (n ) 2, L ) 12-crown-4, C-Cu ) 1.935(8) Å; n ) 3, L ) DME, mean C-Cu ) 1.933 Å)22,26 and, of the alkyl(phosphido)cuprates RCu{µ-P(tBu)2}Li · 3THF (R ) Me, nBu, sBu, tBu), the methyl homologue has been fully characterized (C-Cu ) 1.940(4) Å).27 We have previously shown that Gilman-type cuprates represent inferior DoC substrates when they are compared to their Lipshutz-type analogues.1 Accordingly, we conducted experiments that proved the importance of LiCN inclusion in amidocuprate chemistry by revealing the ortho iodination of benzonitrile in 74% yield employing (TMP)2CuLi · LiCN but complete failure of the reaction if (TMP)2CuLi · LiI is used instead. To further test this idea, here we have treated N,Ndiisopropylbenzamide both with preisolated 3 and solutions containing 3 and LiCN and, thereafter, with I2.15 Data reveal that iodination proceeds in both cases but affords only 37% 2-iodo-N,N-diisopropylbenzamide when employing preisolated 3. This improved to 89% using a solution from which 3 had deposited at -30 °C (and which logically therefore contained LiCN) prior to its redissolution at ambient temperature. Having noted this discrepancy, we sought to probe the nature of the relationship between Lipshutz- and Gilman-type species theoretically (B3LYP method, SVP basis set for Cu and 6-31+G* basis set for other atoms).15 The calculation of a negative ∆E value of -3.5 kcal/mol suggests that in the presence of an excess of etherate solvent (Me2O) the modeled heteroleptic (methyl/ dimethylamido) Lipshutz-type cuprate Me(Me2N)Cu(CN)Li2 · 2OMe2 (viz. 1) exists in facile equilibrium with its Gilmantype analogue MeCu(NMe2)Li · 3OMe2 (viz. the tris(THF) solvate 2, Scheme 4a). Of particular interest is the theoretical observation that the corresponding homoleptic bis(amido)cuprate (Me2N)2Cu(CN)Li2 · 2OMe2 dominates the modeled equilibrium between itself and the Gilman-type species Me2NCu(NMe2)Li · 3OMe2 (∆E ) +9.1 kcal/mol, Scheme 4b). Not only are these data consistent with our previous isolation and characterization of 1,1 but the computed ability of Me(Me2N)Cu(CN)Li2 · 2OMe2 to dissociate accounts for the tandem observations that a solution containing 3 and LiCN gives a high synthetic yield of 2-iodo-N,N-diisopropylbenzamide yet deposits Gilman-type 3. (26) John, M.; Auel, C.; Behrens, C.; Marsch, M.; Harms, K.; Bosold, F.; Gschwind, R. M.; Rajamohanan, P. R.; Boche, G. Chem. Eur. J. 2000, 6, 3060. (27) Martin, S. F.; Fishpaugh, J. R.; Power, J. M.; Giolando, D. M.; Jones, R. A.; Nunn, C. M.; Cowley, A. H. J. Am. Chem. Soc. 1988, 110, 7226.

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Organometallics, Vol. 28, No. 1, 2009 41 Scheme 4

In summary, the isolation of 2 and 3 allows the first direct observation of organo(amido)cuprate monomers. In line with previous work on organo(amido)cuprates,6 the structures suggest a predilection for crystallization of the Gilman-type species RCu(amido)Li with the concomitant exclusion of LiCN. These data are in contrast with the recent isolation and characterization of a homoleptic Lipshutz-type bis(amido)cuprate and offer an explanation for cyanide retention therein and the previous observation of a seven-membered N2Cu(CN)Li2 metallacycle. Hence, the crystal structures of 2 and 3 suggest that the ability of a cuprate structure to exhibit Li(µ-CN)Li bonding must be combined with a high affinity for intermetal bridging in both of the Cu-bonded ligands in order to achieve the theoretically expected X2Cu(CN)Li2 Lipshutz-type metallacycle.11a DFT studies rationalize these data and, moreover, suggest the facile interconversion of Lipshutz- and Gilman-type structures in etherate solvent of heteroleptic alkyl(amido)cuprates. This behavior explains the crystallographic observation of 2 and 3. Moreover, calculations point to the contrasting tendency for homoleptic bis(amido)cuprates to favor LiCN inclusion, as

observed previously by ourselves.1 Finally, conscious that Gilman-type complexes are inefficient DoC substrates but that the putative cuprate Me(TMP)Cu(CN)Li2 is an effective DoC reagent,1 we have tested both preisolated 3 and solutions containing 3 and LiCN and have noted the enhanced reactivity of the Lipshutz-type species in the DoC of a representative benzamide.

Acknowledgment. This work was supported by the U.K. EPSRC (J.V.M., J.H.) and Hoansha and KAKENHI (Young Scientist (A), Houga, and Priority Area No. 452 and 459) (M.U.). The calculations were performed on the RIKEN Super Combined Cluster (RSCC). Supporting Information Available: Text, figures, and tables giving synthetic and spectroscopic data and crystallographic data for 1, 2, and 3 and a CIF file giving crystal data for 3. This material is available free of charge via the Internet at http://pubs.acs.org. OM801101U