A highly active catalyst for palladium-catalyzed cross-coupling reactions: Room-temperature suzuki couplings and animation of unactivated aryl chlorides [22]

Full text of DOI:10.1021/ja982250+

9722
J. Am. Chem. Soc. 1998, 120, 9722-9723
Table 1. Catalytic Aminationa of Aryl Chlorides and Bromides
A Highly Active Catalyst for Palladium-Catalyzed
Cross-Coupling Reactions: Room-Temperature
Suzuki Couplings and Amination of Unactivated Aryl
Chlorides
David W. Old, John P. Wolfe, and Stephen L. Buchwald*
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139
ReceiVed June 29, 1998
Palladium-catalyzed C-N bond-forming reactions have evolved
into a versatile and efficient synthetic transformation.1 However,
the lack of a general palladium-based catalyst for aryl chloride
substitution reactions,2,3 as well as the elevated reaction temper-
atures often required, prompted us to search for new, more active
ligands.
a Reaction conditions: 1.0 equiv of aryl halide, 1,2 equiv of amine,
1.4 equiv of NaOtBu, 0.5 mol % Pd2(dba)3, 1.5 mol % ligand (1.5
L/Pd), toluene (2 mL/mmol halide), 80 °C. Reactions were complete
in 11-27 h; reaction times have not been minimized. b Reaction run
with 0.025 mol % Pd2(dba)3. c Reaction run at 100 °C. d Reaction run
at room temperature in DME solvent. e Reaction run with 1.5 mol %
1H NMR studies in our laboratories of the amination reactions
of aryl bromides catalyzed by BINAP/Pd(OAc)2 suggested that
oxidative addition was rate limiting.4 For aryl chlorides, oxidative
addition can be anticipated to be even more sluggish. To facilitate
this slow step, we began to explore the use of electron-rich
phosphine ligands.2,3c,5a After some experimentation, we focused
our efforts on the preparation of electron-rich bidentate phos-
phines.4 We first prepared the known 2,2′-bis(dicyclohexylphos-
phino)-1,1′-binaphthyl (1)6 and found that 1/Pd(0) constituted a
reasonably effective catalyst for the coupling of pyrrolidine with
4-chlorotoluene. This important result, taken together with our
experience with bidentate monophosphines PPF-OMe and
PPFA1b prompted us to prepare aminophosphine ligand 2 (Table
1).7 In comparison to 1, use of ligand 2 is generally superior
and significantly expands the scope of palladium-catalyzed aryl
chloride transformations. Herein, we demonstrate that the
2/Pd(0) catalyst system is highly active and allows for the room-
temperature amination of aryl bromides and the first example of
a room-temperature amination of an aryl chloride. Moreover,
this system functions as the first general catalyst for room-
temperature Suzuki coupling reactions of aryl chlorides.
f
Pd2(dba)3. Reaction run with 2.5 mol % Pd2(dba)3. g Reaction run using
K3PO4, DME solvent. h Reaction run using Pd(OAc)2, K3PO4, DME
solvent. i One of the two runs only proceeded to 98% conversion.
j Reaction run with Pd(OAc)2, ligand 1, Cs2CO3 as catalyst, ligand,
and base. k Using 1 as ligand. l [ArBr] ) 1 M. m [ArBr] ) 2 M. n 1.5
equiv of benzylamine used.
To demonstrate the efficacy of the 2/Pd(0) catalyst system, we
have prepared several aniline derivatives from aryl chlorides
(Table 1, entries 1, 2, 4-6, 8, 9, 13, and 16). Secondary amines
give excellent results in the coupling procedure (Table 1, entries
1, 2, 4-6, 8, and 9), and the arylation of a primary aniline can
also be accomplished (Table 1, entry 16). Primary alkylamines
are efficient coupling partners provided the aryl chloride is
substituted at the ortho position (Table 1, entry 13), or through
the use of ligand 1 (Table 1, entries 14 and 17). Catalyst levels
as low as 0.05 mol % Pd have been achieved in the reaction of
chlorotoluene with di-n-butylamine (Table 1, entry 1).
Given the high reactivity of this catalyst, we explored the
possibility of carrying out room-temperature aminations. We
found that both aryl iodides and aryl bromides (Table 1, entries
3, 7, 10, and 15) reacted readily at room temperature when DME
was employed as the solvent. The experimentally simple
procedure did not require crown ether or other additives.1c,4
Broadly speaking, the room-temperature amination of aryl
bromides displays the same scope as the reactions of aryl chlorides
at 80 °C. Aryl bromides containing functional groups sensitive
to NaOt-Bu could be converted to the corresponding aniline
derivative by using K3PO4 as the base. In these reactions (Table
1, entries 11 and 12), heating at 80 °C was required due to the
decreased basicity and/or solubility of K3PO4.
Using 2/Pd(0), the amination of an aryl chloride (albeit an
activated one) at room temperature could also be achieved for
the first time.8 Thus, the coupling of p-chlorobenzonitrile and
morpholine was catalyzed by 2.5 mol % Pd2(dba)3, 7.5 mol % 2,
and NaOt-Bu in DME at room temperature to provide the
corresponding aniline derivative in 96% yield (Table 1, entry 9).
In light of the high reactivity of this new catalyst system in
amination reactions, we proceeded to examine its utility in several
different Pd-catalyzed C-C bond-forming reactions. Pd-catalyzed
Suzuki coupling reactions9 of aryl chlorides are usually inefficient
if the aryl halide does not contain electron-withdrawing
substituents.5a-f While nickel catalysts are more effective at
promoting Suzuki coupling reactions of unactivated aryl chlorides,
(1) (a) Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc. 1996,
118, 7215-7216. (b) Marcoux, J.-F.; Wagaw, S.; Buchwald, S. L. J. Org.
Chem. 1997, 62, 1568-1569. (c) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem.
1997, 62, 6066-6068. (d) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald,
S. L. Acc. Chem. Res., in press. (e) Driver, M. S.; Hartwig, J. F. J. Am. Chem.
Soc. 1996, 118, 7217-7218. (f) Hartwig, J. F. Synlett 1997, 329-340.
(2) Grushin, V. V.; Alper, H. Chem. ReV. 1994, 94, 1047-1062.
(3) For existing protocols for the amination of aryl chlorides, see ref 4
and: (a) Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 6054-
6058. (b) Riermeier, T. H.; Zapf, A.; Beller, M. Top. Catal. 1997, 4, 301-
309. (c) Reddy, N. P.; Tanaka, M. Tetrahedon Lett. 1997, 38, 4807-4810.
(d) Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett. 1998, 39, 617-
620. (e) Yamamoto, T.; Nishiyama, M.; Koie, Y. Tetrahedron Lett. 1998, 39,
2367-2370.
(4) Hartwig and Hamann have recently reported similar NMR experiments.
They have also shown that electron-rich bidentate bis-phosphines can be used
for the Pd-catalyzed amination of aryl chlorides and room-temperature
aminations of aryl bromides and iodides: Hamann, B. C.; Hartwig, J. F. J.
Am. Chem. Soc. 1998, 120, 7369-7370.
(5) (a) Shen, W. Tetrahedron Lett. 1997, 38, 5575-5578. (b) Beller, M.;
Fischer, H.; Herrmann, W. A.; O¨ fele, K.; Brossmer, C. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1848-1849. (c) Bumagin, N. A.; Bykov, V. V.
Tetrahedron 1997, 53, 14437-14450. (d) Mitchell, M. B.; Wallbank, P. J.
Tetrahedron Lett. 1991, 32, 2273-2276. (e) Firooznia, F.; Gude, C.; Chan,
K.; Satoh, Y. Tetrahedron Lett. 1998, 39, 3985-3988. (f) Cornils, B. Org.
Process Res. DeV. 1998, 2, 121-127. (g) Indolese, A. F. Tetrahedron Lett.
1997, 38, 3513-3516. (h) Saito, S.; Oh-tani, S.; Miyaura, N. J. Org. Chem.
1997, 62, 8024-8030.
(6) Zhang, X.; Mashima, K.; Koyano, K.; Sayo, N.; Kumobayashi, H.;
Akutagawa, S.; Takaya, H. J. Chem. Soc., Perkin Trans. 1 1994, 2309-2322.
(7) (a) Ligand 2 was prepared in three steps from N,N-dimethyl-2-
bromoaniline. It is obtained as a crystalline solid and is stored and handled in
the air without any special precautions. (b) See Supporting Information for
complete experimental details.
(8) Control experiments conducted in the absence of palladium afforded
no coupled products after 24 h at room temperature.
(9) Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions; Diederich,
F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998; Chapter 2.
S0002-7863(98)02250-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/09/1998

Communications to the Editor
J. Am. Chem. Soc., Vol. 120, No. 37, 1998 9723
Table 2. Suzuki Couplinga and Ketone Arylation
Figure 1.
While the precise mechanistic details of the reactions promoted
by the 2/Pd(0) catalyst system remain unknown, we believe that
the overall catalytic cycle for the amination reaction is similar to
that postulated for the BINAP/Pd-catalyzed amination of aryl
bromides.1a However, in reactions catalyzed by 2/Pd, there may
be different pathways available for the amine coordination/
deprotonation step. Our current view of the course of the reaction
involves binding of the amine to four-coordinate complex I,
followed by deprotonation of the resulting five-coordinate com-
plex II to give III (Figure 1, path A). Alternatively, coordination
of the amine substrate may occur after initial dissociation of the
dimethylamino moiety of the ligand, followed by nucleophilic
attack of the amine substrate on three-coordinate16b complex IV
to give V. Deprotonation of V is followed by rapid recomplex-
ation of the ligand amine group to give III (Figure 1, path B).16
If path B is operative, the recomplexation of the amine is
presumably fast relative to â-hydride elimination since little or
no reduced side product is observed. This notion is supported
by the fact that Cy2PPh was not an effective ligand for any of
these Pd-catalyzed processes;7b,12 amination reactions conducted
with electron-rich monodentate phosphines as ligands such as
Cy3P or Cy2PPh demonstrated that reduction via â-hydride
elimination can be a significant problem without a chelating group
on the ligand. The relatively small size of the amine group in 2
allows for the efficient coupling of both cyclic and acyclic
secondary amines.1b That 2/Pd(0) can be employed in an
amination procedure at the 0.05 mol % level (Table 1, entry 1)
suggests that the dimethylamino group also contributes to the
stability of the catalyst.
a Reaction conditions: 1.0 equiv of aryl halide, 1.5 equiv of boron
reagent, 3.0 equiv of CsF, 0.5-2.0 mol % Pd(OAc)2, 0.75-3.0 mol %
2 (1.5 L/Pd), dioxane (3 mL/mmol halide). Reactions were complete
in 19-30 h; reaction times have not been minimized. b 2.0 equiv of
K3PO4 used in place of CsF. c One of two runs only proceeded to 98%
conversion. d Pd2(dba)3, NaOtBu used as catalyst, base. e Pd2(dba)3,
NaHMDS used as catalyst, base.
sterically hindered substrates are often problematic.5g,h Further-
more, examples of Suzuki coupling reactions that proceed at room
temperature are rare10 and often require stoichiometric amounts
of highly toxic thallium hydroxide.10b,c To the best of our
knowledge, no examples of room-temperature Suzuki couplings
of an aryl chloride have been reported.
Suzuki coupling reactions of both aryl bromides and aryl
chlorides proceed in high yield at room temperature using the
2/Pd(0) catalyst system and CsF11 in dioxane solvent (Table 2,
entries 2, 5, and 7-10).7b,12 These conditions allow for the
coupling of both electron-rich and electron-deficient aryl chlorides
and tolerate the presence of base-sensitive functional groups. An
aryl-alkyl coupling reaction of an aryl chloride using an
alkylboron reagent generated in situ from 1-hexene and 9-BBN13
was achieved at 50 °C. Suzuki coupling reactions of electron-
rich aryl chlorides could also be carried out using inexpensive
K3PO4 with only 0.5 mol % palladium catalyst, although
temperatures of 100 °C were required.
Of special importance is that the results presented herein
indicate that the reactions of aryl chlorides in Pd-catalyzed
processes need not be limited by the rate of the oxidative addition
step.2 Efforts to design catalysts that maintain this high activity
for oxidative addition, but in which the rates of other processes
(e.g., transmetalation, reductive elimination, migratory insertion)
are enhanced, are currently underway in our laboratories.
Acknowledgment. We thank Amgen, the National Science Founda-
tion, and the National Cancer Institute (Training Grant NCI CI
T32CA09112) for financial support. Additional unrestricted support from
Pfizer, Merck, and Novartis and fellowships from the Division of Organic
Chemistry of the ACS sponsored by Schering-Plough and from Boeh-
ringer-Ingelheim are gratefully acknowledged. We also thank Dr. Michael
Palucki for his contribution which ultimately led to the preparation of
ligand 2. We also thank Professors John F. Hartwig and Greg Fu for
sharing related results on aromatic amination and Suzuki coupling
processes, respectively, prior to publication.
The 2/Pd(0) catalyst system was also effective for the Pd-
catalyzed R-arylation of ketones14 at room temperature using
NaHMDS as base (Table 2, entry 12). Interestingly, while the
BINAP catalyst system was selective at promoting the mono-
arylation of methyl ketones, 2/Pd was selective for the diarylation
of methyl ketones (Table 2, entry 11). This may be due to the
decreased steric bulk of 2 relative to BINAP.15
(10) (a) Campi, E. M.; Jackson, W. R.; Marcuccio, S. M.; Naeslund, C. G.
M. J. Chem. Soc., Chem. Commun. 1994, 2395. (b) Anderson, J. C.; Namli,
H.; Roberts, C. A. Tetrahedron 1997, 53, 15123-15134. (c) Uenishi, J.-i.;
Beau, J.-M.; Armstrong, R. W.; Kishi, Y. J. Am. Chem. Soc. 1987, 109, 4756-
4758.
Supporting Information Available: Complete experimental proce-
dures and characterization data for all new compounds (13 pages, print/
PDF). See any current masthead page for ordering and Internet access
instructions. See any current masthead page for ordering information
and Web access instructions.
(11) Wright, S. W.; Hageman, D. L.; McClure, L. D. J. Org. Chem. 1994,
59, 6095-6097.
(12) Control experiments conducted using dicyclohexylphenylphos-
phine in place of 2 gave low conversions and low yields of products.7b
(13) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.; Suzuki,
A. J. Am. Chem. Soc. 1989, 111, 314-321.
JA982250+
(16) (a) It is also possible that reductive elimination occurs from a three-
coordinate intermediate1f formed by deprotonation of V. (b) There is precedent
for the dissociation of one phosphine of a chelating bis-phosphine.1f (c) In
reactions that employ NaOt-Bu as base, it is possible that complexes shown
in Figure 1 may contain X ) OtBu: Mann, G.; Hartwig, J. F. J. Am. Chem.
Soc. 1996, 118, 13109-13110. In reactions that employ Cs2CO3 or K3PO4 as
base, it is unlikely that carbonate or phosphate complexes form due to the
low solubility and low nucleophilicity of Cs2CO3 and K3PO4 relative to NaOt-
Bu.
(14) (a) Palucki, M.; Buchwald. S. L. J. Am. Chem. Soc. 1997, 119, 11108-
11109. (b) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 12382-
12383.
(15) Other Pd-catalyzed cross couplings of aryl chlorides were surveyed
using this catalyst. Stille couplings, Sonogashira couplings, and cross-couplings
of aryl halides with organozinc reagents gave no detectable products. The
Heck arylation of styrene gave some conversion to product at 110 °C.