Distinct reactivity of Pd(OTs)2: The intermolecular Pd(II)-catalyzed 1,2-carboamination of dienes

Article abstract of DOI:10.1021/ja803397y

A Pd-catalyzed intermolecular 1,2-carboamination route to indolines from N-aryl ureas and 1,3-dienes that proceeds under mild conditions in relatively nonacidic media, is presented. The in situ generation, or preformation, of a palladium tosylate emerges as a key parameter in gaining the requisite reactivity for the C-H insertion/carbopalladation/nucleophilic displacement process. Copyright

Full text of DOI:10.1021/ja803397y

Published on Web 07/10/2008
Distinct Reactivity of Pd(OTs)
2
: The Intermolecular Pd(II)-Catalyzed
1
,2-Carboamination of Dienes
†
†
‡
§
,†
Chris E. Houlden, Chris D. Bailey, J. Gair Ford, Michel R. Gagn e´ , Guy C. Lloyd-Jones,* and
,
†
Kevin I. Booker-Milburn*
School of Chemistry, Cantock’s Close, UniVersity of Bristol, Bristol, BS8 1TS, U.K., AstraZeneca PR&D, Silk Road,
Macclesfield, Cheshire, SK10 2NA, U.K., Department of Chemistry, Caudill and Kenan Laboratories, UniVersity of
North Carolina-Chapel Hill, North Carolina 27599-3290
Received May 7, 2008; E-mail: k.booker-milburn@bristol.ac.uk; guy.lloyd-jones@bristol.ac.uk
1
As a consequence of the key roles of 1,2-diamines and 1,2-
Scheme 1. Formation of 2 via o-C-H Insertion/Interrupted Heck
2
amino-alcohols as pharmacophores and as ligands for catalysis,
new routes for their synthesis are important goals. In this context,
there has been much recent activity in the area of metal-catalyzed
1,2-difunctionalization of alkenes. In particular, a number of groups
have reported synthetically useful 1,2-diamination protocols using
3
,4
a variety of diamine sources under Cu or Pd catalysis. Our prior
contribution to this area involved a Pd(II)-catalyzed 1,2-diamination
of dienes with N,N′-dialkyl ureas, using either benzoquinone (BQ)
Scheme 2. Pd(II) Carboamination of Dienes with Aryl Ureas
5
or molecular oxygen as reoxidant. Herein we report an efficient
Pd(II)-catalyzed 1,2-carboamination of dienes that proceeds under
mild conditions and facilitates the synthesis of indolines from N-aryl
6
ureas, via aryl C-H activation. We demonstrate that
(
MeCN)
ubiquitous Pd(OAc)
than a simple amide, is pivotal in attaining efficient C-H insertion.
2
Duringanongoingstudytoextendourearlierworkon(MeCN) PdCl -
2
Pd(OTs)
2
offers distinct reactivity, as compared to the
2
, and that the presence of a urea moiety, rather
2
5
catalyzed diamination we observed the low-yielding (ca. 10%)
formation of indoline 2, from R-methylstyrene and N-ethyl-N′-
7
phenyl urea (1), Scheme 1. Attempts to optimize this reaction failed
and the N,N-dimethyl-N′-phenyl urea 3a gave none of the corre-
sponding indoline whatsoever. Generation of the indoline 2 can be
envisaged to proceed via an interrupted Heck-type process that
evolves from a urea-directed ortho C-H insertion by Pd(II) (f4).
The latter step is analogous to the first part of the ortho-vinylation
of acetanilides with acrylate esters reported by de Vries and van
The reaction of the parent aryl urea 3a under conditions C was
successfully applied to a variety of electron-deficient dienes (Table
, entries 1-6). Substitution of the N-phenyl ring (entries 7-13)
proved informative. Electron donating groups in the meta and para
position of the aryl ring led to single regioisomers of the
corresponding indoline rings in moderate to excellent yields. In
1
8
Leeuwen, which requires rather acidic solvent conditions (66%
AcOH) as well as TsOH (50 mol%) as an additive.
To exploit the stability and electrophilicity of an η -allyl Pd(II)
3
intermediate (cf. 5) we switched from R-methylstyrene to the
3
contrast, CF substitution in the meta position inhibited the reaction
electron deficient diene 6a. Applying the de Vries-van Leeuwen
completely, while substitution in the para position reduced both
the rate and the yield, indicative of strong electronic deactivation
of the ortho C-H position.
Perhaps the most surprising observation, in addition to the lack
of oxidation, or double-bond migration, of 7a-n to form indoles,
was that o-methyl substitution inhibited the reaction completely
8
conditions, (A, Scheme 2) afforded indoline 7a in 37% yield from
3
a. In view of the possible sensitivity of the urea and diene to the
acidic reaction medium, we explored a variety of conditions, with
the aim of eliminating acid altogether. Significantly, in the absence
of TsOH (with or without AcOH) there was no reaction, while the
AcOH could be eliminated without any significant effect on yield
(
entry 13). It is possible that in this position the methyl substituent
(
∼35%). Eventually it became apparent that water was detrimental
prevents the urea moiety from adopting a conformation suitable
for Pd-complexation and/or ortho C-H insertion. Substitution of
the nonaryl nitrogen also proved possible (entries 14 and 15) and
in the case of N-ethyl-N′-phenyl urea 3i further in situ cyclization
of the initial indoline effected a one-pot carbodiamination sequence
to yield 7n as a single diastereoisomer (entry 15). The activating
effect of the urea moiety is highlighted by the poor yield of indoline
product 8 obtained from acetanilide (entry 16), even after prolonged
reaction times (24 h).
to the reaction and by employing molecular sieves with THF as
solvent, 7a was obtained in 80% yield after 4 h at 50 °C (B, Scheme
9
2
2). As a further refinement, use of Ac O (1 equiv) as a drying agent
consistently afforded high yields of 7a (82%, C, Scheme 2). It is
important to note that the reaction is tolerant of a range of solvents,
including anisole, DCE, 1,4-dioxane, EtOAc, PhMe, tBuOMe, and
tBuOH (78.5% average yield for 3af7a).
†
University of Bristol.
‡
The requirement for TsOH in the reaction medium suggested
the in situ formation of a reactive palladium mono- or bistosylate
AstraZeneca PR&D.
§
University of North Carolina.
1
0066 9 J. AM. CHEM. SOC. 2008, 130, 10066–10067
10.1021/ja803397y CCC: $40.75  2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Use of (MeCN)2Pd(OTs)2 as a Precatalyst
Table 1. Indoline Formation under Conditions C
carbopalladation/cyclization sequence. It enables the high-yielding
generation of functionalized indolines from readily available N-aryl
ureas, in a single operation.
A key observation is that the reaction involves in situ generation
of a reactive palladium tosylate species from the Pd(OAc)
precatalyst. These results clearly demonstrate that, in contrast to
2
1
1
previous reports, highly electrophilic Pd(II) species, capable of
aryl C-H activation, can be generated under mild reaction
conditions (relatively nonacidic media, 50 °C, 2-4 h, Scheme 3).
Acknowledgment. We thank the EPSRC (GR/R02382 and
¨
E061575) and AstraZeneca for support and Dr C. Butts for nOe
experiments.
Supporting Information Available: Full experimental details. This
material is available free of charge via the Internet at http://pubs.acs.org.
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,2-carboamination reaction, involving an ortho C-H insertion/
JA803397Y
J. AM. CHEM. SOC. 9 VOL. 130, NO. 31, 2008 10067