C O M M U N I C A T I O N S
Table 1. Cross-Coupling Reactions of Electron-Deficient Anilines
with ArCl Using a Weak Basea
Figure 4. 31P{1H} NMR spectra of (a) 7 in toluene/PhCl at -40 °C and
(b) 7 in toluene/PhCl w/LHMDS (1 equiv) after 110 min at -40 °C.
The ability to generate L1Pd(0) complexes in the absence of
competing ligands is also very useful for mechanistic investigations.
Precatalyst 9 was employed at room temperature to conduct a direct
Hammett study of the oxidative addition of aryl chlorides to the
XPhosPd(0) complex (see Supporting Information). The slope of
F ) +2.3 for Hammett’s correlation is consistent with results
previously obtained from (PPh3)2Pd(0) with aryl iodides, suggesting
a concerted three-centered transition state for oxidative addition.11
This is the first information of this type available for the reaction
of aryl chlorides with monodentate ligands.12
a ArCl (1 mmol), amine (1.2 mmol), K2CO3 (1.4 mmol); average
isolated yields of two runs. b Reaction time ) 2 h. c Using precatalyst 6.
Table 2. Rapid C-N Bond-Forming Reactions with 0.1% Catalysta
In summary, we have developed a new class of Pd precatalysts
bearing biarylphosphine ligands that are particularly useful in cases
where a highly active Pd complex is required to promote a difficult
cross-coupling reaction or where functional group instability
requires the use of low temperatures. We have additionally
demonstrated that an unactivated aryl chloride can undergo oxidative
addition to SPhosPd(0) at temperatures as low as -40 °C. The use
of these precatalysts should greatly expand the general scope of
Pd-catalyzed cross-coupling reactions.
a ArCl (1 mmol), amine (1.2 mmol), base (1.2 mmol); average
isolated yields of two runs.
Table 3. C-N Bond-Forming Reactions Using ArCl at or below
Room Temperaturea
Acknowledgment. We thank the National Institutes of Health
(NIH) for support (GM-058160). M.R.B. thanks the NIH for a
postdoctoral fellowship (GM-F32-75685). We also thank Amgen,
Merck, and Boehringer Ingelheim for unrestricted funds, and Dr.
Timothy E. Barder for solving the X-ray structure of 5.
Supporting Information Available: Procedural, spectral, and
crystallographic data. This material is available free of charge via the
a ArCl (1 mmol), amine (1.2 mmol), base (1.2 mmol); average yield
of two runs. b LHMDS (2.4 mmol). c NaOt-Am (1.02 mmol). d In DME.
References
To show the ease with which 4-6 can be activated, we performed
numerous C-N cross-coupling reactions at or below room tem-
perature (Table 3). These precatalysts are particularly useful for
substrate combinations that are incompatible with elevated reaction
temperatures. Previously, 4 days were required to achieve a 61%
yield in the formation of the coupling product of dibutylamine and
3-chlorophenethyl alcohol.7 Using 4, we can now obtain an isolated
yield of 94% in only 4 h. Similarly, the less reactive 4-chlorophen-
ethyl alcohol can now be successfully employed as an analogous
reaction. In addition, we have successfully demonstrated the
compatibility of esters of secondary alcohols in room temperature
cross-coupling reactions using an alkoxide base. Our ability to
perform amination reactions of an aryl chloride at -10 °C further
illustrates the ease with which these precatalysts undergo activation.
To demonstrate the reactivity of a L1Pd(0) complex in the
absence of competitive coordinating ligands, we prepared the N-Me
derivatives of precatalysts 5 and 4 (7 and 9, respectively).8 As
shown in Figure 4, chlorobenzene undergoes facile oxidative
addition to SPhosPd(0) generated by deprotonation of 7 at -40
°C.9 This suggests that aryl chlorides should be usable in low-
temperature C-C cross-coupling reactions using precatalysts 4-6.
Previously, only aryl iodides have been employed in cross-coupling
reactions conducted at such low temperatures.10
(1) (a) Jiang, L.; Buchwald, S. L. In Metal-Catalyzed Cross-Coupling Reactions,
2nd ed. de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim,
Germany, 2004. (b) Hartwig, J. F Synlett 2006, 1283.
(2) With NHC ligands: Marion, N.; Navarro, O.; Mei, J.; Stevens, E. D.; Scott,
N. M.; Nolan, S. P. J. Am. Chem. Soc. 2006, 128, 4101.
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(4) Pd precatalysts: (a) Zim, D.; Buchwald, S. L. Org. Lett. 2003, 5, 2413. (b)
See ref 2. (c) Stambuli, J. P.; Kuwano, R.; Hartwig, J. F. Angew. Chem.,
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(5) Biscoe, M. R.; Barder, T. E.; Buchwald, S. L. Angew. Chem., Int. Ed. 2007,
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(6) (a) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald,
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(7) Harris, M. C.; Huang, X.; Buchwald, S. L. Org. Lett. 2002, 4, 2885.
(8) 7 generates N-Me indoline as a byproduct, which will not undergo ensuing
C-N bond formation. Thus, formation of 8 can be monitored.
(9) Complex 8 has been previously isolated by our group. See: Barder, T. E.;
Biscoe, M. R.; Buchwald, S. L. Organometallics 2007, 26, 2183.
(10) Martin, R.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3844.
(11) (a) Amatore, C.; Pfluger, F. Organometallics 1990, 9, 2276. (b) Jutand,
A.; Mosleh, A. Organometallics 1995, 14, 1810.
(12) The use of a bidentate ligand gave the higher correlation value of F )
+5.2. See: Portnoy, M.; Milstein, D. Organometallics 1993, 12, 1665.
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