3 A CCELERATED Z INCATIONS FOR AN E FFICIENT AND M ILD

F

A

H

3.1

INTRODUCTION

As already mentioned, the directed ortho-metalation of aromatic and heterocyclic compounds is an efficient method for the functionalization of these scaffolds.89 _{Besides conventional lithium bases a}

range of new bimetallic ate-bases have been introduced by Kondo, Mulvey, Mongin and Uchiyama.91

These bases allow a smooth metalation of a number of unsaturated systems due to synergetic effects between the two metals. Alternatively, Schwesinger’s P4 tBu-base128 or Hagadorn’s TMP2Zn129 can be

used for the generation of carbanions. However, these ate bases and the phosphazene lack atom- economy, whereas TMP2Zn is only sufficient for the metalation of highly activated substrates. Thus, it

allows for the generation of Zn-enolates and the metalation of very electron-poor substrates, such as pyridine N-oxides or DMSO. Recently, Knochel and coworkers have reported highly soluble metal amides complexed by LiCl such as TMPMgCl·LiCl (3), (TMP = 2,2,6,6-tetramethylpiperidyl), TMP2Mg·2LiCl (4), TMPZnCl·LiCl (5), TMP2Zn·2MgCl2·2LiCl (6) and [(tBuCH(iPr))(tBu)N]3Al·3LiCl (7)

which allowed a chemo- and regioselective metalation of a broad range of functionalized aromatics and heteroaromatics. An additional procedure involving a complexation of some organic substrates with ZnCl2 prior to the addition of TMP2Mg·2LiCl (4), which led to improved metalation yields has also

been reported.130 _{However, this last method had several drawbacks: (i) the stability of TMP}

2Mg·2LiCl

(4) is limited due to its high kinetic basicity;131 (ii) the tolerance of functional groups and sensitive heterocycles is also moderate. In contrast, the zinc amides 5 and 6 tolerate a wide range of functional groups in the organic substrate. Nevertheless, either highly activated arenes or heteroaromatics are needed, otherwise only a sluggish metalation occurs. Since especially functionalized heterocycles are of interest for pharmaceutical industry (Figure 5), an improved zincation protocol would be desirable.

Figure 5: Heterocyclic pharmaceuticals.

128

a) R. Schwesinger, H. Schlemper, Angew. Chem. 1987, 99, 1212; Angew. Chem. Int. Ed. Engl.1987, 26, 1167; b) R. Schwesinger, H. Schlemper, C. Hasenfratz, J. Willaredt, T. Dambacher, T. Breuer, C. Ottaway, M. Fletschinger, J. Boele, H. Fritz, D. Putzas, H. W. Rotter, F. G. Bordwell, A. V. Satish, G.-Z. Ji, E.-M. Peters, K. Peters, H. G. von Schnering, L. Walz,

Liebigs Ann.1996, 1055; c) T. Imahori, Y. Kondo, J. Am. Chem. Soc.2003, 125, 8082.

129

a) M. L. Hlavinka, J. R. Hagadorn, Organometallics2007, 26, 4105; b) M. L. Hlavinka, J. F. Greco J. R. Hagadorn, Chem. Comm. 2005, 5304; c) M. L. Hlavinka and J. R. Hagadorn, Tetrahedron Lett.2006, 47, 5049; d) W. Rees, O. Just. H. Schumann, R. Weimann, Polyhedron1998, 17, 1001.

130

Z. Dong, G. Clososki, S. Wunderlich, A. Unsinn, J. Li, P. Knochel, Chem. Eur. J. 2009, 15, 457.

131

ESULTS AND ISCUSSION

3.2

ACCELERATED ZINCATIONS

Since zincations may be performed at elevated temperatures,132 the use of the transmetalation energy to perform fast and efficient zincations at moderately elevated temperatures (reaction temperature up to 40 °C) has been envisoined. Remarkably, we wish to report that this moderate increase of temperature leads to a dramatic decrease in the reaction time. Remarkably, this small temperature increase (10-15 °C) is sufficient to provide a rate acceleration of up to 50 times.

Thus, whereas the zincation of coumarin (26) with TMP2Zn·2MgCl2·2LiCl (6) requires 4 h at 25 °C to

reach >95% conversion, the sequential treatment of 26 with ZnCl2 (0.5 equiv) followed by the

addition of TMPMgCl·LiCl (3; 1.1 equiv) leads to the zincated species 27 within 2 h. If ZnCl2·LiCl133

(0.5 equiv) is used followed by the addition of TMPMgCl·LiCl (3; 1.1 equiv) 27 is obtained in 5 min (Figure 6, Scheme 29).

Figure 6: Progress of the metalation of coumarin (26) using different metalation procedures.

After a Pd-catalyzed Negishi cross-coupling106 with 4-iodoanisole, the expected coumarin derivative 28 is obtained in 82% yield (Scheme 29). A similar behavior is found for quinoxaline (29). The addition of TMP2Zn·2MgCl2·2LiCl (6, 0.55 equiv) provides the diheteroaryl zinc reagent 30 after 5 h at 25 °C.

Whereas the sequential treatment of the substrate with ZnCl2 (0.5 equiv) followed by the addition of

TMPMgCl·LiCl (3; 1.1 equiv) leads to the zincated species 30 in >95% within 2 h. In this case also the

132

S. H. Wunderlich, P. Knochel, Org. Lett.2008, 10, 4705.

133

for the effects of LiCl see: E. Hevia, R. E. Mulvey Angew. Chem.2011, 123, 6576; Angew. Chem. Int. Ed.2011, 50, 6448.

0 10 20 30 40 50 60 70 80 90 100 0 0,5 1 1,5 2 2,5 3 3,5 4 4,5 t [h] 0.55 equiv TMP2Zn·2MgCl2·2LiCl (6) 1) 0.5 equiv ZnCl2 2) 1.1 equiv TMPMgCl·LiCl (3) 1) 0.5 equiv ZnCl2·LiCl 2) 1.1 equiv TMPMgCl·LiCl (3) co n ve rs io n [ % ]

usage of ZnCl2·LiCl (0.5 equiv) followed by TMPMgCl·LiCl (3; 1.1 equiv) accelerates the metalation and

leads to complete conversion within 1 h. The reaction can be further accelerated by addition of one extra equivalent of LiCl. Thus, if the monomeric complex ZnCl2·2LiCl134 (0.5 equiv) is used instead,

followed by the addition of TMPMgCl·LiCl (3; 1.1 equiv), 30 is obtained within 15 min (Figure 7).

Figure 7: Progress of the metalation of quinoxaline (29) using different metalation procedures.

Careful monitoring of the reaction temperature (20 mmol scale experiments) indicates that the temperature increases moderately to reach 34 °C when the addition of TMPMgCl·LiCl (3) to the substrate/ZnCl2 solution is complete. Whereas the temperature rises to 38 °C in the case of

substrate/ZnCl2·2LiCl solution. This high rate increase in the metalation for a comparatively small

temperature increase may be rationalized by an alternative reaction pathway, where the organic substrate is activated by forming a Lewis acid adduct with ZnCl2·2LiCl and then reacts with kinetically

enhanced TMPMgCl·LiCl (3), to generate in situ an organomagnesium intermediate, which can then easily transmetalate with carbophilic ZnCl2 already present in the solution. On the other hand, these

results may be an indication for a species different from TMP2Zn·2MgCl2·2LiCl (6) being present in the

metalation. The alternative species TMP3Zn has been proven to be unstable.135

134

a) B. Brehler, H. Jacobi, Naturwissenschaften1964, 51, 11; b) I. Solinas, H. D. Lutz, J. of Solid State Chem.1995, 117, 34.

135

a) J-M. L’Helgoual’ch, A. Seggio, F. Chevallier, M. Yonehara, E. Jeanneau, M. Uchiyama, F. Mongin, J. Org. Chem.2008,

73, 177; b) R. E. Mulvey, Chem. Comm.2001, 1049; c) P. García-Álvarez, R. E. Mulvey, J. A. Parkinson, Angew. Chem.

2011, 123, 9842; Angew. Chem. Int. Ed.2011, 50, 9668.

0 10 20 30 40 50 60 70 80 90 100 0 1 2 3 4 5 6 t [h] co n ve rs io n [ % ] 0.55 equiv TMP2Zn·2MgCl2·2LiCl (6) 1) 0.5 equiv ZnCl2 2) 1.1 equiv TMPMgCl·LiCl (3) 1) 0.5 equiv ZnCl2·LiCl 2) 1.1 equiv TMPMgCl·LiCl (3) 1) 0.5 equiv ZnCl2·2LiCl 2) 1.1 equiv TMPMgCl·LiCl (3)

ESULTS AND ISCUSSION

Pd-catalyzed cross-coupling of 30 with ethyl 4-iodobenzoate (25 °C, 3 h) furnishes the expected product 31 in 79% yield (Scheme 29).