Ru-Catalyzed Decarbonylative Arylation of sp3 C Centers
A R T I C L E S
Scheme 1. Decarbonylative Arylation Proceeds in Preference to the C-H Arylation
Figure 1. Proposed mechanistic rationale for the new decarbonylative arylation at sp3 carbon centers and its relationship to the sp3 C-H arylation. Both
transformations access a similar metal alkoxide intermediate (e.g., 5a/5b), which undergoes transmetallation and C-C bond formation to afford the product
(e.g., 6).
Also, palladium-catalyzed couplings of activated carboxylate
esters with arylboronate esters, to produce aryl ketones,7,8 and
with alkenes, to afford the Heck coupling products, were
reported.9 Moreover, carboxylic anhydrides as activated sub-
strates were reported to undergo decarbonylative arylation with
arene boronates and other arene donors.10
The catalytic decarboxylative transformation of allyl- and
benzyl-esters belongs to a mechanistically distinct class of
reactions, initiated by the cleavage of the C-O bond linking
the allyl group and acyloxy moiety, leading to a loss of CO2
and formation of new C-C bonds.11 Catalytic cross-couplings
of free arene carboxylic acids with haloarenes and alkenes have
recently been reported; these reactions also proceed via a
decarboxylative mechanism.12
To the best of our knowledge, the decarbonylative arylation
disclosed here represents a new catalytic transformation, achiev-
ing a direct substitution of an unactivated ester with an aryl
ring at the sp3 carbon center. From a synthetic perspective, this
reaction enables regioselective preparation of mono-arylated
nitrogen heterocycles starting from readily available cyclic
R-amino esters (e.g., proline, hydroxyproline, pipecolinic acid
esters) and, thus, complements the C-H arylation method which
provides a mixture of mono- and bis-arylated products (Figure
2). The “overfunctionalization” of substrates containing two
C-H bonds of similar reactivities is a common problem of many
catalytic directed C-H functionalization processes, developed
for both aromatic and saturated substrates.13 The significant
difference in rates between the decarbonylative arylation and
the C-H arylation allows for selective synthesis of mono-
arylated amines and thus represents a promising alternative for
the preparation of these compounds under neutral catalytic
conditions. In the following pages, we describe the development
and the scope of this transformation.
Results
Optimization of Reaction Conditions and Arene Donor
Substrate Scope. Guided by the mechanistic rationale provided
above, the reaction conditions were optimized. With regard to
the catalyst, only low-valent ruthenium complexes afford the
desired product. Ru3(CO)12 is the best catalyst; RuH2(CO)-
(PPh3)3 is less effective, showing lower reaction rates as well
as side product formation. In accord with the mechanistic
proposal, the ketone reagent (required for the C-H arylation
process, Figure 1) is not needed. Both arylboronic acids and
esters can be used as coupling partners. The best results for
arylation with arylboronate esters are achieved in m-xylene at
130 °C employing 1 equiv of ester; under these conditions, the
reaction is completed within several hours. Arylation with
arylboronic acids gave the best results when performed in DMF
employing a slight excess of acid (1.1 equiv). However, there
was no clear trend in yields when using arylboronic acids. For
example, phenyl-, 4-fluorophenyl-, and 4-(dimethylamino)-
phenylboronic acids gave yields superior to those obtained with
corresponding neo-pentanediol derived esters (Table 1, forma-
tion of 3a, 3b, 3f), whereas 4-(trifluoromethyl)phenyl- and
indole-5-boronic acids (Table 1, formation of 3d, 3k) gave
inferior amounts of arylation products. These results can be
attributed to differences in stability between free boronic acids
and esters under the reaction conditions. Importantly, since CO
is released as a byproduct, the reaction shows lower efficiency
when conducted in lower boiling solvents, such as dioxane or
(7) (a) Kakino, R.; Shimizu, I.; Yamamoto, A. Bull. Chem. Soc. Jpn. 2001,
74, 371-376. (b) Tatamidani, H.; Kakiuchi, F.; Chatani, N. Org. Lett. 2004,
6, 3597-3599.
(8) For synthesis of ketones via palladium-catalyzed coupling of thioesters and
boronic acids, see: Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000,
122, 11260-11261.
(9) Gooâen, L. J.; Paetzold, J. Angew. Chem., Int. Ed. 2002, 41, 1237-1241.
(10) (a) Gooâen, L. J.; Paetzold, J. AdV. Synth. Catal. 2004, 346, 1665-1668.
(b) O’Brien, E. M.; Bercot, E. A.; Rovis, T. J. Am. Chem. Soc. 2003, 125,
10498-10499.
(11) (a) Burger, E. C.; Tunge, J. A. J. Am. Chem. Soc. 2006, 128, 10002-
10003. (b) Rayabarapu, D. K.; Tunge, J. A. J. Am. Chem. Soc. 2005, 127,
13510-13511 and references therein. (c) Mohr, J. T.; Nishimata, T.;
Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11348-11349.
(d) Kuwano, R.; Yokogi, M. Chem. Commun. 2005, 5899-5901.
(12) (a) Catalytic decarboxylative arylation of free carboxylic acids with
haloarenes has recently been reported: Forgione, P.; Brochu, M.-C.; St-
Onge, M.; Thesen, K. H.; Bailey, M. D.; Bilodeau, F. J. Am. Chem. Soc.
2006, 128, 11350-11351. (b) Gooâen, L. J.; Deng, G.; Levy, L. M. Science
2006, 133, 662-664. Catalytic cross-coupling of free arene carboxylic acids
with alkenes (decarboxylative olefination): (c) Myers, A. G.; Tanaka, D.;
Mannion, M. R. J. Am. Chem. Soc. 2002, 124, 11250-11251. (d) Tanaka,
D.; Romeril, S. P.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 10323-
10333.
(13) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal. 2003, 345, 1077-1101.
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