Carbon-nitrogen bond formation involving well-defined aryl-copper(III) complexes

Article abstract of DOI:10.1021/ja802123p

Carbon-heteroatom bond formation from copper(III) is commonly invoked as a key step in catalytic reactions, including the century-old Ullmann reactions. Well-defined examples of such reactions have never been observed. Here, we demonstrate that a well-defined Cu(III)-aryl species reacts with a variety nitrogen nucleophiles to undergo facile carbon-nitrogen bond formation. Copyright

Full text of DOI:10.1021/ja802123p

Published on Web 06/27/2008
Carbon-Nitrogen Bond Formation Involving Well-Defined Aryl-Copper(III)
Complexes
Lauren M. Huffman and Shannon S. Stahl*
Department of Chemistry, UniVersity of Wisconsin-Madison, 1101 UniVersity AVenue, Madison, Wisconsin 53706
Received March 21, 2008; E-mail: stahl@chem.wisc.edu
Copper-mediated carbon-carbon and carbon-heteroatom coupling
reactions have been known for more than 100 years;1,2 however, these
reactions have been overshadowed by the scope and versatility of
analogous Pd-catalyzed coupling methods. The dramatic success of Pd
catalysis can be attributed, in part, to the availability of sophisticated insights
into the fundamental organometallic chemistry of palladium, including
knowledge of the reactivity of organopalladium complexes in oxidation
states ranging from Pd0 to PdIV. Fundamental studies of organocopper
chemistry could play a similar role in Cu catalysis, yet the organometallic
chemistry of copper in oxidation states higher than +1 is almost completely
unexplored.3 Only a small number of structurally characterized organo-
copper(III) complexes are known (Chart 1),4 and no studies of their
Figure 1. 1H NMR spectra of the CuIII-aryl complex 1 (bottom), pyridone
reactivity toward C-C or C-X bond formation have been reported. Here,
we present the first reactions of this type and provide preliminary
mechanistic insights into C-N bond-forming reactions that arise from
(middle), and the crude product mixture obtained upon mixing 1 and
pyridone in a 1:1 ratio (top).
the reaction of arylcopper(III) complexes with neutral carboxamides and
The rate exhibited a first-order dependence on both [1] and [phthalimide]
related nucleophiles. These observations complement recent in situ
(Figure 2). No evidence was obtained for kinetic saturation in [phthalimide]
spectroscopic studies that provide evidence for alkylcopper(III) intermedi-
up to 50 equiv of the nucleophile, and no intermediate was detected in
ates in reactions of organocuprates,5 and they provide an important starting
the reaction. Activation parameters for the reaction were obtained by
point for characterization of the fundamental organometallic chemistry of
monitoring the rate at different temperatures (20-60 °C): ∆Hq ) 13.3 (
copper(III).
0.3 kcal ·mol-1 and ∆Sq ) -17 ( 2 cal ·mol-1 ·K-1
.
Chart 1. Examples of Well-Defined Organometallic CuIII Complexes
Aryl amination reactions are among the most widely used Cu-
catalyzed coupling reactions,2,6,7 and arylcopper(III) species are
commonly speculated as intermediates in these reactions.2 CuIII-aryl
complex 1, originally reported by Llobet, Stack, and co-workers,4d
drew our attention because it features a Cu-Caryl bond within a square-
planar CuIII coordination environment that resembles the proposed
intermediates in C-N coupling reactions.2c This recognition prompted
us to investigate whether 1 could react with nitrogen nucleophiles
commonly employed in copper-catalyzed aryl-amination reactions.
Reactions between 1 and amide-type nitrogen nucleophiles proved to
be very facile. Addition of pyridone (2a) to a solution of 1 in acetonitrile
resulted in a color change of the solution from orange to colorless within
minutes at ambient temperature. Conversion of 1 to a single ligand-derived
product was evident from the 1H NMR spectrum of the crude reaction
mixture (Figure 1), and full characterization of the product by NMR
spectroscopy (1H, 13C, 2D NOESY), mass spectrometry (ESI-MS), and
X-ray crystallography established the product as the N-aryl pyridone
C-N coupling product 3a. The CuI byproduct, [Cu(NCMe)4]ClO4,
was also isolated from the reaction mixture.
Figure 2. Kinetic study of the reaction of CuIII-aryl complex 1 with
phthalimide. Reaction conditions: [1] ) 0.8 mM, [nucleophile] ) 8.0-40
mM, CH3CN, 30 °C.
CuIII-aryl derivatives 1X (X ) CH3, H, NO2; Chart 2A),8 were
used to evaluate electronic effects on the relative rates of the net C-N
bond-forming reaction. All three analogues reacted cleanly with
phthalimide to yield the C-N coupling product, and the reaction of
the electron-deficient derivative 1NO2 proceeded significantly more
rapidly than the reactions of 1H and 1CH3: t1/2 ) 5 min (1NO2) versus
82 and 115 min (1H and 1CH3, respectively).9 Although the precise
mechanism of the C-N bond-forming step is not yet known, these
results are consistent with the expectation that more-electrophilic CuIII-
aryl species should react more rapidly with nitrogen nucleophiles.
Electronic effects associated with the nitrogen nucleophile were
examined by monitoring the reaction of 1 with nucleophiles that vary
The reaction of phthalimide (2b) with 1 (eq 1) proceeded at a rate
somewhat slower than that with pyridone, enabling the reaction kinetics
to be monitored conveniently by 1H NMR and UV-visible spectroscopy.
9
9196 J. AM. CHEM. SOC. 2008, 130, 9196–9197
10.1021/ja802123p CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Chart 2. Substrates Used to Probe Electronic Effects
(1) a three-centered C-N reductive elimination from an (unobserved)
CuIII(aryl)(amidate) intermediate or (2) bimolecular nucleophilic attack
of an amidate on the ipso carbon of the aryl ligand.12 Further studies will
be necessary to distinguish between these possibilities and to address other
open mechanistic questions, including the identity of the base that
participates in amide deprotonation and the origin of deviations from
linearity in the Brønsted plot (Figure 3).13
The results of this study reveal the extraordinary reactivity of the
CuIII-aryl fragment: C-N bond formation is facile despite stabilization
of the Cu-aryl ligand within a macrocyclic chelate and the use of
neutral amide-type substrates that are only weakly nucleophilic. That
reactions of this type have not been described previously, despite the
century-long history of Cu-mediated coupling reactions, highlights the
dearth of fundamental insights into the organometallic chemistry of
copper. Further characterization of the reactivity of high-valent
organocopper species should play an important role in the ongoing
discovery and development of copper-catalyzed reactions.
Acknowledgment. We are grateful to the DOE (DE-FG02-
05ER15690) and Bristol-Myers Squibb for financial support of this
work, and we thank Ilia A. Guzei for X-ray crystallographic analysis
of 3a·(TsOH)3.
with respect to the acidity of the N-H bond, pKa(DMSO) ) 13.4-23.3
(Chart 2B). Reactions with each of the substrates 2a-h exhibited
pseudo-first-order kinetic behavior over >4 half-lives in the presence
of excess nucleophile (g10 equiv). Nucleophiles 2a-e produced the
corresponding C-N coupling products 3a-e in quantitative yield. The
remaining nucleophiles 2f-h, which have less-acidic N-H bonds,
reacted more slowly, and yielded two different products: the intermo-
lecular C-N coupling products 3f-h together with an intramolecular
C-N coupling product 4, arising from an unusual trans C-N reductive
elimination reaction (eq 2). The latter product formed quantitatively
upon heating a solution of the arylcopper(III) complex 1 in the absence
of added nucleophile.10
Supporting Information Available: Experimental procedures and
kinetic and compound characterization data. This material is available free
of charge via the Internet at http://pubs.acs.org.
References
(1) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382–2384.
(2) Cu-mediated coupling reactions continue to be the focus of extensive
interest. For reviews, see: (a) Beletskaya, I. P.; Cheprakov, A. V. Coord.
Chem. ReV. 2004, 248, 2337–2364. (b) Hassan, J.; Sévignon, M.; Gozzi,
C.; Schulz, E.; Lemaire, M. Chem. ReV. 2002, 102, 1359–1469. (c) Ley,
S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400–5449.
(3) Krause, N. Modern Organocopper Chemistry; Wiley-VCH: Weinheim,
Germany, 2002.
(4) For representative examples, see: (a) Willert-Porada, M. A.; Burton, D. J.;
Baenziger, N. C. J. Chem. Soc., Chem. Commun. 1989, 1633–1634. (b)
Naumann, D.; Roy, T.; Tebbe, K.-F.; Crump, W. Angew. Chem., Int. Ed.
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B.; Mahía, J.; Parella, T.; Xifra, R.; Hedman, B.; Hodgson, K. O.; Llobet,
A.; Stack, T. D. P. Angew. Chem., Int. Ed. 2002, 41, 2991–2994. (e) Santo,
R.; Miyamoto, R.; Tanaka, R.; Nishioka, T.; Sato, K.; Toyota, K.; Obata,
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Ed. 2006, 45, 7611–7614.
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Chem. Soc. 2007, 129, 7208–7209. (b) Hu, H.; Snyder, J. P. J. Am. Chem.
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T.; Henze, W.; Gschwind, R. M. J. Am. Chem. Soc. 2007, 129, 11362–
11363.
(6) For recent development of efficient Cu-catalyzed C-N coupling reactions,
see the following leading references: (a) Klapars, A.; Antilla, J. C.; Huang,
X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727–7729. (b) Shafir,
A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742–8743.
(7) In addition to aryl-halide cross-coupling reactions (ref 6), Cu-catalyzed
oxidative C-N coupling reactions aryl boronic acids have been reported: (a)
Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron
Lett. 1998, 39, 2933–2936. (b) Lam, P. Y. S.; Clark, C. G.; Saubern, S.;
Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett.
1998, 39, 2941–2944.
A rough correlation is evident between the logarithm of the pseudo-
first-order rate constant for intermolecular C-N coupling and the pKa
of the nitrogen nucleophile (not including pyridone; Figure 3). The
negative slope evident in this plot indicates that more-acidic substrates
(those with lower pKa values) react more rapidly. This correlation is
opposite to that expected if the bimolecular rate law (see above) arises
from a reaction of the neutral amide with the CuIII-aryl species.
Substrates with lower pKa values should be less coordinating and/or
nucleophilic and, therefore, react more slowly. Instead, the trend
suggests that the nitrogen nucleophile undergoes deprotonation before
(or in) the rate-limiting step of the reaction. The anomalously rapid
rate observed with pyridone may reflect the fact that pyridone has a
readily accessible tautomer, 2-hydroxypyridine (eq 3),11 which may
be capable of reacting without prior substrate deprotonation.
(8) Xifra, R.; Ribas, X.; Llobet, A.; Poater, A.; Duran, M.; Solà, M.; Stack,
T. D. P.; Benet-Buchholz, J.; Donnadieu, B.; Mahía, J.; Parella, T.
Chem.sEur. J. 2005, 11, 5146–5156.
(9) Reaction conditions: [1x] ) 9 mM, [phthalimide] ) 50 mM, CD3CN, 24 °C.
(10) See section 1 of the Supporting Information for further details.
(11) In acetonitrile at 25 °C, the pyridone tautomer is more stable than
2-hydroxypyridine by approx 3 kcal/mol: Frank, J.; Katritzky, A. R.
J. Chem. Soc., Perkin Trans. 2 1976, 1428–1431.
(12) Mechanistic evidence suggests the nitrogen nucleophile coordinates to the
Cu center before C-N bond formation in Cu-catalyzed cross-coupling
reactions. See, for example: Strieter, E. R.; Blackmond, D. G.; Buchwald,
S. L. J. Am. Chem. Soc. 2005, 127, 4120–4121.
Figure 3. Correlation between the rate of intermolecular C-N bond
formation and the acidity of the nitrogen nucleophile. Reaction conditions:
[1] ) 0.8 mM, [nucleophile] ) 8.0 mM, CH3CN, 50 °C.
(13) The deviations do not appear to reflect a major change in the reaction
mechanism. The reaction of benzamide, a slow nucleophile, exhibits
bimolecular reaction kinetics and a negative ∆Sq (-9.4 ( 2.5 eu), similar
to that observed with phthalimide, and more-acidic benzamide derivatives
(i.e., 4-Br and 4-NO2) react more rapidly than benzamide (see section 2 of
the Supporting Information for details).
The kinetic data and electronic effects obtained for these reactions are
consistent with at least two different mechanisms for C-N bond formation:
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