Palladiunl-catalyzed C-N(sp2) bond formation: N-Arylation of aromatic and unsaturated nitrogen and the reductive elimination chemistry of palladium azolyl and methyleneamido complexes

Full text of DOI:10.1021/ja973524g

J. Am. Chem. Soc. 1998, 120, 827-828
827
Palladium-Catalyzed C-N(sp2) Bond Formation:
N-Arylation of Aromatic and Unsaturated Nitrogen
and the Reductive Elimination Chemistry of
Palladium Azolyl and Methyleneamido Complexes
Grace Mann, John F. Hartwig,* Michael S. Driver, and
Carolina Ferna´ndez-Rivas
Department of Chemistry, Yale UniVersity
P.O. Box 208107, New HaVen, Connecticut 06520-8107
Figure 1. Relative rates for C-C bond formation by reductive elimina-
tion as a function of hybridization and the unknown relationships for
C-N bond formation.
ReceiVed October 8, 1997
Palladium-catalyzed biaryl and aryl-vinyl coupling reactions
are a general and reliable synthetic tool,1 in large part because
C-C bond-forming reductive elimination that involves two
unsaturated covalent ligands is rapid.2 This type of reductive
elimination is typically faster than reductive eliminations involving
an alkyl group (Figure 1).2 Palladium-catalyzed C-N couplings
that form arylamines have recently emerged as useful methodol-
ogy3 even though the hybridization of the carbon and nitrogen
involved in the reductive elimination step of the catalysis3d-5 is
similar to that of the carbons in alkyl-aryl couplings. In contrast,
the palladium-catalyzed coupling to form the aryl-nitrogen bonds
in N-aryl azoles has not been reported, and the N-arylation of
imines has only recently been reported.6 The relationship between
reductive elimination rates for alkyl, aryl, and vinyl complexes
has been studied extensively,2 but the relationship between these
relative rates and those for reductive elimination of related amido,
azolyl, and methyleneamido complexes in Figure 1 is unknown.
We report our results on a general palladium-catalyzed arylation
of azoles and imines using DPPF-ligated palladium, along with
organometallic chemistry that answers these questions about C-N
bond-forming reductive eliminations involving unsaturated or
aromatic nitrogen.
Table 1. Palladium-Catalyzed Arylation of Azoles and
Benzophenone Imine
Palladium-catalyzed coupling reactions that form N-aryl azoles
and N-aryl imines by C-N(sp2) bond formation are summarized
in eq 1 and Table 1. N-Aryl imines are conveniently protected
(1)
arylations of azoles with only electron-poor aryl halides,10 and
copper-mediated azole arylations require high temperatures and
often toxic solvents.11 This paper includes data on imine arylation
using DPPF-ligated palladium in order to demonstrate the
differences in rates on the arylation of different types of sp2-
hybridized nitrogen using the same catalyst.
The combination of Pd(OAc)2 and DPPF catalyzed the forma-
tion of N-aryl azoles in the presence of Cs2CO3 or NaO-t-Bu with
electron-rich, electron-neutral, or electron-poor aryl halides over
the course of 12-48 h at 100-120 °C.12 Complete reaction of
electron-rich aryl halides required the higher temperatures and
longer times. This process encompassed arylations of pyrrole,
indole, and carbazole.
anilines.6 N-Aryl azoles display a variety of biological activity.7
Procedures for azole arylation are limited. Phenylation with
electrophilic aromatic main group compounds deliver only one
of several aryl groups,8,9 KF adsorbed onto alumina mediates
(1) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508-524. (b)
Stille, J. K. Pure Appl. Chem. 1985, 57, 1771-1780. (c) Miyaura, N.; Suzuki,
A. Chem. ReV. 1995, 95, 2457-2483. (d) In ComprehensiVe Organic Synthesis;
Trost, B. M., Ed.; Pergamon Press: New York, 1991; Vol. 3, pp 435-520.
(2) Collman, J. P.; Hegedus, L. S.; Norton, J. R.; Finke, R. G. In Principles
and Applications of Organotransition Metal Chemistry, 2nd ed.; University
Science Books: Mill Valley, 1987; pp 279-354.
(3) (a) For reviews, see: Hartwig, J. F. Synlett 1996, 329-340. Hartwig,
J. F. Angew. Chem., Int. Ed. Engl. In press. (b) Paul, F.; Patt, J.; Hartwig, J.
F. J. Am. Chem. Soc. 1994, 116, 5969-5970. (c) Louie, J.; Hartwig, J. F.
Tetrahedron Lett. 1995, 36, 3609. (d) Driver, M. S.; Hartwig, J. F. J. Am.
Chem. Soc. 1996, 118, 7217-7218. (e) Guram, A. S.; Rennels, R. A.;
Buchwald, S. L. Angew. Chem., Int. Ed. Engl. 1995, 34, 1348-1350. (f) Wolfe,
J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 7215-7216.
(g) Wolfe, J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron 1996, 52, 7525-
7546.
(7) (a) Kamat, A. G.; Gadaginamath, G. S. Ind. J. Chem. 1994, 33B, 255-
259. (b) Perregaard, J.; Arnt, J.; Bogeso, K. P.; Hyttel, J.; Sa´nchez, C. J.
Med. Chem. 1992, 35, 1092-1101. (c) Unangst, P. C.; Connor, D. T.; Stabler,
S. R.; Weikert, R. J.; Carethers, M. E.; Kennedy, J. A.; Thueson, D. O.;
Chestnut, J. C.; Adolphson, R. L.; Conroy, M. C. J. Med. Chem. 1989, 32,
683-688.
(4) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1995, 117, 4708-
4709.
(8) Lo´pez-Alvarado, P.; Avendan˜o, C.; Mene´ndez, J. C. J. Org. Chem. 1995,
60, 5678.
(5) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 8232-
8245.
(9) Barton, D. H. R.; Finet, J. P.; Khamsi, J. Tetrahedron Lett. 1986, 27,
3615-3618.
(6) Buchwald et al. reported their results on imine arylation using BINAP
during the preparation of our manuscript. Wolfe, J. P.; Åhman, J.; Sadighi, J.
P.; Singer, R. A.; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6367-6370.
(10) Smith, W. J., III; Sawyer, J. S. Tetrahedron Lett. 1996, 37, 299-302.
(11) Khan, M. A.; Polya, J. B. J. Chem. Soc. C 1970, 85-91.
S0002-7863(97)03524-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/04/1998

828 J. Am. Chem. Soc., Vol. 120, No. 4, 1998
Communications to the Editor
Scheme 1
3 reacted at 120 °C to give a mixture of phosphine-ligated Pd(0)
complexes, but N-aryl pyrrole was formed in only 11% yield.
The neutral PPh3 complex 5 also formed Pd(0) at 120 °C but
produced N-aryl azole in a modest yield of 20%. These results
contrasted the high-yielding reductive eliminations of arylamines
under mild conditions from analogous PPh3-ligated amido aryl
complexes and showed that the coupling reaction to form a C-N
bond between an aryl and a nitrogen-bound heteroaromatic ligand
is less favorable than the formation of a C-N bond between an
aryl group and an amide.5 Furthermore, C-N reductive elimina-
tion of N-aryl azoles is much less favorable than C-C reductive
elimination of biaryls.
DPPF-ligated palladium pyrrolyl aryl complexes reductively
eliminated N-aryl pyrrole in higher yields than the PPh3 analogues.
The anionic DPPF complex 4 underwent reductive elimination
in 15 h at 120 °C, but again in a modest 40% yield. However,
the neutral DPPF complex 6 underwent reductive elimination of
N-aryl pyrrole in the presence of PPh3 in 89% yield at 100 °C
over the course of 15 h. This result demonstrated that palladium
azolyl complexes with the proper ligand set do undergo C-N
bond-forming reductive elimination in high yields. Further, the
comparison in yields and rates for reaction of anionic 4 and neutral
6 showed the importance of preventing formation of anionic
pyrrolyl complexes to observe high yields in catalytic reactions.
Indeed, the reaction of 4-bromo-tert-butylbenzene with sodium
pyrrolyl catalyzed by DPPF-palladium occurred in 29% yield,
significantly lower than the reactions of aryl bromide with pyrrole
and alkoxide or carbonate base.
Methyleneamido complex 7 underwent reductive elimination
of N-aryl imine in quantitative yield in less than an hour at room
temperature. This observation confirmed our solution structural
assignment of 7 and demonstrated a large difference in reductive
elimination rates for complexes with different types of sp2-
hybridized nitrogens bound to palladium, one aromatic and one
unsaturated. The rate for reductive elimination of the N-aryl imine
is more similar to the rates of C-N bond-forming reductive
elimination of arylamines or C-C bond-forming reductive
elimination of styrenes than it is to the C-N(sp2) bond-forming
reductive elimination of N-aryl azoles.
At the outset of this study, it was unclear whether the reductive
eliminations of N-aryl azoles and imines would be rapid in
analogy to biaryl and styrene formation, or whether these reactions
would be slow because arylamine reductive elimination rates
decrease with decreasing amide group nucleophilicity.3d,5 Our
data show that reductive eliminations that form N-aryl azoles
require higher temperatures than do reductive eliminations that
form the C-C bonds in biaryls or the C-N bond in anilines,
while elimination of N-aryl imines occurs at rates comparable to
those of C-C reductive elimination. These data raise the
possibility that the nucleophilicity of the nitrogen electron pair
is an important factor in dictating reaction rates15 because the
nitrogen electron pair in azoles is involved in the heterocyclic
aromatic system. Detailed kinetic studies that probe the mech-
anism and electronics of the different reductive elimination
reactions and synthetic applications of these new C-N coupling
processes will be the subject of future studies.
The palladium-catalyzed arylations of imines with DPPF-ligated
palladium were markedly faster than the azole arylations. The
combination of Pd(OAc)2 and DPPF catalyzed the arylation of
benzophenone imine, which contains an sp2-hybridized nitrogen
with a more basic electron pair, at 65-95 °C over the course of
several hours. The imine arylation with DPPF-ligated palladium
is general for electron-poor, electron-rich, and sterically hindered
aryl halides. For reactions of aryl halides with electron-donating
substituents, NaO-t-Bu was a superior base to Cs2CO3. Reactions
of these substrates with Cs2CO3 as base produced substantial
amounts of products resulting from exchange of the aryl halide
with the phosphine aryl groups, and they were not pursued in
detail.
The important fundamental question raised by this catalytic
chemistry concerns the rates for reductive elimination of potential
azolyl and methyleneamido intermediates, since the rates of the
catalytic reaction may or may not reflect the rates for the actual
C-N bond-forming step. Thus, we prepared palladium azolyl
and methyleneamido aryl complexes with both DPPF and PPh3
ligands, as shown in Scheme 1. Reaction of DPPF- or PPh3-
ligated aryl halide complexes 1 or 2 with excess potassium or
sodium pyrrolyl formed anionic complexes 3 and 4 by displace-
ment of one of the palladium-phosphine linkages. Neutral bis-
phosphine complexes 5 and 6 were prepared by addition of 1.05
equiv of potassium pyrrolyl. Palladium aryl methyleneamido
complexes could not be isolated because they were more reactive
toward reductive elimination, but they were generated in high
1
yield and characterized in solution by H and 31P NMR spec-
trometry, as well as by IR spectroscopy. Reaction of KNdCPh2
with (DPPF)Pd(C6H4-t-Bu)(Br) formed (DPPF)Pd(C6H4-t-Bu)-
(NdCPh2) (7) after minutes at room temperature. Alternatively,
this complex was generated at -10 °C by reaction of HNdCPh2
with (DPPF)Pd(C6H4-t-Bu)(O-t-Bu).13,14
The importance of using a chelating phosphine and a base that
generates only small amounts of pyrrolyl anion was shown by
the reaction chemistry in Scheme 1. The anionic PPh3 complex
Acknowledgment. This work was supported by the NIH and the
DOE. We thank Johnson-Matthey Alpha/Aesar for a loan of palladium
chloride. C.F.-R. thanks the Ministerio de Educatcio´n y Ciencia for a
fellowship through Universidad Auto´noma de Madrid.
Supporting Information Available: General procedures, 1H,13C
NMR and mass spectra of all products in Table 1, literature references
to previously reported products, and experimental procedures and spectral
data for new compounds (55 pages). See any current masthead page for
ordering and Internet access instructions.
(12) Pd(dba)2 (dba ) bis(dibenzylidene)acetone) was an equally effective
catalyst precursor in these reactions, but it was difficult to purify the reaction
products from the dba that remained in the final reaction solution. Pd(dba)2
was synthesized according to: Takahashi, Y.; Ito, Ts.; Sakai, S.; Ishii, Y. J.
Chem. Soc., Chem. Commun. 1970, 1065-6.
(13) Mann, G.; Hartwig, J. J. Am. Chem. Soc. 1996, 118, 13109-13110.
(14) Characteristic spectroscopic features of 7 included two new doublet
resonances in the 31P NMR spectrum, four new cyclopentadienyl resonances
(δ 3.82, 3.93, 4.28, 4.44) and one tert-butyl resonance (δ 1.12 ppm) in the 1H
NMR spectrum, and a νCdN band at 1604 cm-1 in the IR spectrum.
JA973524G
(15) Knight, D. A.; Dewey, M. A.; Stark, G. A.; Bennett, B. K.; Arif, A.
M.; Gladysz, J. A. Organometallics 1993, 12, 4523-4534.