The role of chelating diamine ligands in the Goldberg reaction: A kinetic study on the copper-catalyzed amidation of aryl iodides

Article abstract of DOI:10.1021/ja050120c

The mechanistic details of the Cu-catalyzed amidation of aryl iodides are presented. The kinetic data suggest that the diamine ligand prevents multiple ligation of the amide. The formation of an amidocuprate species external to the catalytic cycle helped to rationalize the dependence on diamine concentration and the inverse dependence on amide concentration at low diamine concentrations. The intermediacy of a Cu(I) amidate was established through both its chemical and kinetic competency. Copyright

Full text of DOI:10.1021/ja050120c

Published on Web 02/26/2005
The Role of Chelating Diamine Ligands in the Goldberg Reaction: A Kinetic
Study on the Copper-Catalyzed Amidation of Aryl Iodides
†
‡
,†
Eric R. Strieter, Donna G. Blackmond, and Stephen L. Buchwald*
Contribution from the Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139, and the Department of Chemistry, Imperial College, London SW7 2AZ, U.K.
Received January 8, 2005; E-mail: sbuchwal@mit.edu
Copper-catalyzed C-N bond formation has long been a practical
and efficient method for the construction of aryl C-N bonds in
1
both academic and industrial settings. Recently we reported on an
2
enhanced version of the Goldberg reaction, the copper-catalyzed
amidation of aryl and heteroaryl halides, using CuI and chelating
3
1
,2-diamines in combination with K
PO
3 4
, K
2
CO
3
, or Cs
2
CO
3
. Al-
though this process displays increased activity and substrate scope
relative to its predecessors, the development of improved catalysts
hinges on our ability to understand the catalytic events. Herein we
report on a mechanistic study identifying the role of the diamine
in preventing multiple ligation of the amide4 and also demonstrate
that a copper(I) amidate can serve as a potential intermediate during
the N-arylation process.6
Figure 1. Reaction rate at 50% conversion of 1 vs [3] in the N-arylation
of 2 (0.8 M) with 1 (0.4 M) using [CuI] (0.02 M).
,5
Scheme 1. Proposed Mechanism
The reaction between 3,5-dimethyliodobenzene (1) and 2-pyr-
rolidinone (2) was selected for the kinetic studies due to its effi-
ciency (99% yield after 2 h, eq 1). The reactions were continuously
monitored in a reaction calorimeter (Omnical SuperCRC) as pre-
viously described.7 Since our initial studies focused on determining
the precise role of the diamine in this reaction, the reaction rate was
examined as a function of [3]. As shown in Figure 1, a nonlinear
relationship between [3] and the reaction rate was observed over a
,8
1
9-fold change in [3]. The observation that complete dissolution
of the copper(I) salt occurs in a mixture containing 3 and CuI in a
:1 ratio precludes an explanation for the saturation behavior based
1
6b
on a change in solubility of the active copper(I) species. A first-
order dependence on [copper]total in reactions with Cu(I):3 ratios
of both 1:2 and 1:10 also rules out catalyst decomposition.10
dependence at low [3] suggests that under these conditions the
resting state of the catalyst is the multiply amide-ligated species
C. Increasing concentrations of the diamine 3 drive the reaction
back to intermediate B in equilibrium with A. Thus, increasing
concentrations of diamine increases the reaction rate, while increas-
ing amide concentrations should suppress it. This results in the
limiting case of the rate expression of eq 2 shown in eqs 3a and
3
b. The straight-line relationship between the function rate/[ArI]
A third possibility for the saturation dependence on [3] suggests
and 1/[Amide] provided by eq 3b is borne out in Figure 2a, where
three experiments performed at different [Amide] converge into
that multiple ligation of the amide leading to an inactive copper
species may be prevented at high concentrations of 3.3
c,9
The
mechanism shown in Scheme 1 proposes that the intermediate
copper(I) amidate (B) is formed either through amide coordination
to A followed by deprotonation or through diamine association and
subsequent amide dissociation from C. Once formed, B reacts with
the aryl iodide, affording the desired N-arylated amide. The
corresponding rate expression is given by eq 2 (where quasi-
equilibria are assumed: K
1
) k
1
/k-1 and K
2
2
) k /k-2). This is
consistent with the kinetic data in Figure 1, showing saturation
kinetics in [3] with all other concentrations held constant.11
Evaluating the kinetic dependence on [Amide] provides ad-
ditional support for this model in the form of limiting cases of the
rate expression given in eq 2.12 Specifically, the first-order diamine
Figure 2. Reaction rate dependence on [amide]. (a) rate/[ArI] vs 1/[Amide]
at low [3] (10 mol % 3, 5 mol % CuI). Reaction conditions: [1] ) 0.4 M,
o
(O) [2]o ) 0.9 M, (]) [2]o ) 0.7 M, (0) [2]o ) 0.6 M. (b) rate/[Amide] vs
[ArI] at high [3] (70 mol % 3, 5 mol % CuI). Reaction conditions: (O)
†
‡
[2]o ) 0.9 M, [1]o ) 0.4 M, (]) [2]o ) 1.0 M, [1]o ) 0.6 M, (0) [2]o )
0.7, [1]o ) 0.6 M.
Massachusetts Institute of Technology.
Imperial College.
4120
9
J. AM. CHEM. SOC. 2005, 127, 4120-4121
10.1021/ja050120c CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
the same straight-line relationship with slope equal to K′. These
data confirm the inverse dependence on [Amide] at low [3]. By
contrast, under conditions of high [3], Figure 2b reveals that a
straight-line relationship is observed between the function rate/
rate-limiting step. At low concentrations of diamine, however, the
catalyst resides as a multiply ligated species, which requires the
dissociation of an amide through diamine coordination to generate
the active copper(I) amidate, an intermediate that has been
demonstrated to be both chemically and kinetically competent for
the N-arylation. These results show that both the diamine and the
amide play vital roles in the rate at which the N-arylation occurs.
[Amide] versus [ArI], suggesting the limiting form of eq 2 shown
in eq 4b. This implies that, under high [3], K [Amide] , 1 and the
1
resting state of the catalyst shifts to species A, giving first-order
kinetics in both [ArI] and [Amide] and zero-order kinetics in [3].
Acknowledgment. Support has been provided by the National
Institutes of Health (GM 58160), the American Chemical Society
rate )
(Organic Division Fellowship to E.R.S., sponsored by Albany
k K K [Cu] [ArI][Amide][Diamine]
act
2
1
2
t
Molecular Research), Merck, and Novartis. We also thank Dr. Utpal
K. Singh and Dr. Alex Shafir for insightful discussions.
Note Added after ASAP Publication: In the version published
on the Internet February 26, 2005, there were production errors in
eqs 3a, 3b, and 4a. In the final version published March 1, 2005,
and in the print version, these equations are correct.
(
2)
K [Amide] + K [Diamine] + K K [Amide][Diamine]
1
2
1 2
low [Diamine]:
k K K [Cu] [ArI][Diamine]
act
1
2
t
rate )
(3a)
Supporting Information Available: Experimental procedures,
kinetic data, and reaction rate derivation (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
[Amide]
rate
1
or
) K′‚
[Amide]
K′ ) k K [Cu] [Diamine] (3b)
act 2 t
[ArI]
References
high [Diamine]:
(
1) For reviews, see: (a) Lindley, J. Tetrahedron 1984, 40, 1433. (b) Ley, S.
V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (c) Kunz, K.;
Scholz, U.; Ganzer, D. Synlett 2003, 2428. (d) Beletskaya, I. P.;
Cheprakov, A. V. Coord. Chem. ReV. 2004, 248, 2337.
k K [Cu] [ArI][Amide]
act
1
t
rate )
≈ k K [Cu] [ArI][Amide]
act
1
t
1
+ K [Amide]
(2) (a) Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39, 1691. (b) Sugahara,
M.; Ukita, T. Chem. Pharm. Bull. 1997, 45, 719.
1
(
4a)
(3) (a) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 7727. (b) Wolter, M.; Klapars, A.; Buchwald, S. L. Org.
Lett. 2001, 3, 3803. (c) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2002, 124, 7421.
rate
Amide]
or
) K′′‚[ArI] K′′ ) k K [Cu]
act 1 t
(4b)
[
(
4) For examples where increasing the [ligand] inhibits copper-promoted
reactions, see: (a) Bacon, R. G. R.; Hill, H. A. O. J. Chem. Soc. 1964,
1097. (b) Rusonik, I.; Cohen, H.; Meyerstein, D. J. Chem. Soc., Dalton
Trans. 2003, 2024. For examples of ligand-accelerated copper-catalyzed
reactions, see: (c) Goodbrand, H. B.; Hu, N. X. J. Org. Chem. 1999, 64,
670. (d) Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron Lett.
We sought to evaluate further the potential intermediacy of a
copper(I) amidate complex (B in Scheme 1) now that this species
was substantiated through kinetic analysis. To accomplish this goal,
copper(I) amidate 5 was synthesized by mixing 2 with mesityl-
copper at room temperature in toluene. As evidenced by the
1
999, 40, 2657. (e) Fagan, P. J.; Hauptman, E.; Shapiro, R.; Casalnuovo,
A. J. Am. Chem. Soc. 2000, 122, 5043.
(5) One explanation for the activity of catalysts based on 1,2-diamines is that
they increase the oxidation potential of copper(I), thus facilitating the
activation of the aryl halide; see ref 4b.
1
broadened resonances in the H NMR, 5 exists as multiple oligomers
in solution, which is consistent with the tendency of most copper-
(6) (a) Yamamoto, T.; Ehara, Y.; Kubota, M.; Yamamoto, A. Bull. Chem.
Soc. Jpn. 1980, 53, 1299. (b) Paine, A. J. J. Am. Chem. Soc. 1987, 109,
I) complexes to exist as aggregates.13 Upon addition of diamine 3
(
1
496. (c) Blue, E. D.; Davis, A.; Conner, D.; Gunnoe, T. B.; Boyle, P.
to the solution containing 5, however, a single species results as
indicated by the sharpened resonances of the copper(I) amidate
protons. Most significantly, the addition of aryl iodide 1 to this
mixture of 5 and 3 at 0 °C resulted in complete conversion of the
copper(I) amidate, affording a t1/2 of 3.1 min (eq 5).14 This
experiment establishes both the chemical and kinetic competency
of a copper(I) amidate intermediate.
D.; White, P. S. J. Am. Chem. Soc. 2003, 125, 9435.
(
7) (a) Singh, U. K.; Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J.
Am. Chem. Soc. 2002, 124, 14104. (b) Nielsen, L. P. C.; Stevenson, C.
P.; Blackmond, D. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 1360.
(
3 4
8) The use of a heterogeneous inorganic base such as K PO may limit the
reaction rate due to mass transfer effects. However, using different stirring
rates resulted in identical reaction rate profiles, thus ruling out the
possibility of a mass transfer limited process.
(
9) Bacon, R. G. R.; Karim, A. J. J. Chem. Soc., Perkin Trans. 1 1973, 272.
(
(
10) See Supporting Information.
11) Figure 1 data at constant [ArI], [Cu] , and [Amide] simplify eq 2 to the
T
form: rate ) a[3]/(1 + b[3]), where a and b are adjustable parameters.
12) Reaction rate is independent of [base] at both low and high [3]. This is
presumably due to saturation of the base in a nonpolar solvent, and thus,
the [base] is treated as a constant. See Supporting Information for more
details.
(
(13) For the synthesis of copper(I) amides, see: (a) Tsuda, T.; Watanabe, K.;
Miyata, K.; Yamamoto, H.; Saegusa, T. Inorg. Chem. 1981, 20, 2728.
(
b) Hope, H.; Power, P. P. Inorg. Chem. 1984, 23, 936. (c) Gamboratta,
S.; Bracci, M.; Floriani, C.; Chiesi-Villa, A.; Guastini, C. J. Chem. Soc.,
Dalton Trans. 1987, 1883.
In summary, the kinetic data suggest that the diamine serves to
prevent multiple ligation of the amide. Higher concentrations of
the diamine allow the activation of the aryl iodide to become the
(14) Arylation of 5 in the absence of 3 did not proceed at temperatures between
0
°C and 90 °C.
JA050120C
J. AM. CHEM. SOC.
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