Efficient palladium-catalyzed synthesis of substituted indoles employing a new (silanyloxyphenyl)phosphine ligand

Article abstract of DOI:10.1039/c2cc33071g

The new and easily prepared OTips-DalPhos ligand (L1) offers broad substrate scope at relatively low loadings in the palladium-catalyzed C-N cross-coupling/cyclization of o-alkynylhalo(hetero)arenes with primary amines, affording indoles and related heterocyclic derivatives in high yield.

Full text of DOI:10.1039/c2cc33071g

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Efficient palladium-catalyzed synthesis of substituted indoles employing a
new (silanyloxyphenyl)phosphine ligandw
Christopher B. Lavery,a Robert McDonaldb and Mark Stradiotto*a
Received 28th April 2012, Accepted 25th May 2012
DOI: 10.1039/c2cc33071g
The new and easily prepared OTips-DalPhos ligand (L1) offers broad
substrate scope at relatively low loadings in the palladium-catalyzed
C–N cross-coupling/cyclization of o-alkynylhalo(hetero)arenes with
primary amines, affording indoles and related heterocyclic derivatives
in high yield.
exist with regard to the demonstrated substrate scope in these4
and some closely related5 reports; neither the successful utilization
of challenging substrates such as methylamine6 nor synthons
featuring heterocycles attached to the alkynyl terminus was
documented,7 and the use of o-alkynylhalo(hetero)arene substrates
is limited to two examples from the Ackermann group,4d in
which 4-azaindoles are formed using sterically demanding
amine reaction partners.
In addition to being among the most ubiquitous heterocycles in
nature, the indole framework represents a privileged sub-structure
in the design of pharmaceutical agents, owing to the ability of such
derivatives to bind to a diversity of receptors with high affinity.1
Despite the numerous ‘‘classical’’ methods of preparing indoles,
the need for efficient synthetic protocols that enable the selective
assembly of functionalized indoles under relatively mild conditions
has inspired the examination of metal-catalyzed methodologies,
most notably those employing palladium.2 The application of
palladium catalysis has revolutionized indole synthesis, and several
novel disconnection strategies have been established, including
(but not restricted to) those starting from o-alkynylanilines or
o-haloanilines, and their derivatives.2 A complementary yet less
well-explored pathway to the indole core structure involving
palladium-catalyzed amine arylation using ortho-alkynylhaloarene
synthons (pre-formed or prepared in situ), followed by base-
mediated cyclization of the resultant 2-aminophenylacetylene,3
was pioneered by Ackermann.4 This modular C–N cross-
coupling/cyclization cascade is conceptually attractive in terms
of diversifying the indole framework, in that substituted alkynyl
moieties can be installed easily by use of Sonogashira coupling
protocols, and the substitution at nitrogen can be varied by the
choice of primary amine coupling partner. Following a brief
catalyst optimization campaign, Ackermann and co-workers4
identified Pd(OAc)2/IPrꢀHCl (5 mol% each; IPrꢀHCl = 1,3-
bis(2,6-di-isopropylphenyl)imidazolium chloride; 105–120 1C) as
being optimal when using o-alkynylhaloarenes in combination
with a range of primary amine reagents. However, some limitations
As part of our ongoing research efforts directed toward
the design and application of modular ancillary ligands for use
in metal-catalyzed transformations,8 we became interested
in utilizing such synthetically useful cascade C–N cross-
coupling/cyclization processes as a challenging testing ground
for new ligand design. In particular, we became interested
in identifying a catalyst system that could offer broad scope
in such transformations in accommodating both large and
small amine coupling partners, as well as a diversity of
o-alkynylhalo(hetero)arene substrates including those featuring
heterocyclic functionality, at relatively low catalyst loading
(o 5 mol% Pd/L). We report herein on the new and easily
prepared DalPhos8b ligand variant, OTips-DalPhos (L1),
which exhibits this desired reactivity profile.
Encouraged by the utility in palladium-catalyzed C–N and
C–C cross-coupling chemistry of our Mor-DalPhos ligand,6f,8b,9
which features an ortho-di(1-adamantyl)phosphino (P(1-Ad)2)
group appended to an N-phenylmorpholine core, we sought to
develop DalPhos variants featuring alternative heteroatom pairings,
including phosphorus and oxygen.10 In seeking modular and
expedient synthetic protocols, the silylation of phenols was
particularly attractive given the ease of Si–O bond formation,
the commercial availability of structurally diverse R3SiCl
synthons, and the well-documented chemical behaviour of
aryl silylethers. Our initial explorations have focussed on the
triisopropylsilyl derivative, owing to the anticipated stability
of the Ar-O–Si(iPr)3 motif. Treatment of ortho-bromophenol
with iPr3SiCl in the presence of imidazole afforded the known
triisopropylsilyl ether, which was converted to L1 via palladium-
catalyzed P–C bond formation employing (1-Ad)2PH in 77%
overall yield (Scheme 1w). In contrast to related dialkylarylphos-
phines featuring small ortho-alkyl ether substituents,11 only a single
rotamer of L1 is observable in solution (1H, 13C, and 31P NMR).
Presumably this rotamer corresponds to the solid state
structure (Fig. 1w), where the triisopropylsilyl moiety is distal
to the adamantyl groups.12 This orientation would appear to
a Department of Chemistry, Dalhousie University, 6274 Coburg Road,
P.O. Box 15000, Halifax, Nova Scotia, Canada B3H 4R2.
E-mail: mark.stradiotto@dal.ca; Fax: 1 902 494 1310;
Tel: 1 902 494 7190
b X-Ray Crystallography Laboratory, Department of Chemistry,
University of Alberta, Edmonton, Alberta, Canada T6G 2G2
w Electronic supplementary information (ESI) available: Experimental
details and characterization data including NMR spectra, and X-ray
data in CIF format. CCDC 871158. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c2cc33071g
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Chem. Commun., 2012, 48, 7277–7279 7277

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have proven useful in the synthesis and functionalization of
indoles (L214 and L34). Among the ligands surveyed, only L1
afforded each of the four target indoles (1–4) in high yield
under the test conditions employed. The use of MeNH2 served
to differentiate L1 from each of L10, L2 and L3 (in addition to
the poor performance of L2 with 1-AdNH2). In contrast, while
L4 performed reasonably well in combination with MeNH2
(76%), the yields obtained with the other substrates (18–63%)
were markedly inferior to those obtained using L1.
Scheme 1 Synthesis of OTips-DalPhos (L1).
Having established L1 as an effective ligand for the desired
C–N cross-coupling/cyclization processes, the scope in the amine
and o-alkynylhalo(hetero)arene reaction partners was explored
further (Fig. 3). In building upon the results featured in Fig. 2,
1-bromo-2-(phenylethynyl)benzene, as well as the chloro derivative,
Fig. 1 ORTEP diagram for L1 shown with 50% ellipsoids and with
hydrogen atoms omitted for clarity. Selected interatomic distances (A):
P-Caryl, 1.8460(13); O-Caryl, 1.3726(16); Si–O, 1.6716(10).
enable the binding of both phosphorus and oxygen to palladium
as needed during catalysis.
In a preliminary effort to assess the ability of Pd/L1 (2.5 mol%
each) catalyst mixtures to furnish indoles via C–N cross-coupling/
cyclization processes, the reaction of 1-bromo-2-(phenylethynyl)-
benzene with structurally diverse primary amines was surveyed
(Fig. 2).13 Our choice of palladium precursor was based on the
success of the [Pd(cinnamyl)Cl]2/Mor-DalPhos catalyst system,9
and for comparison parallel reactions were conducted with the
para-isomer of OTips-DalPhos (L10), as well as DavePhos (L2),
IPr (L3) and Mor-DalPhos (L4). These comparator ligands were
selected in order to explore both the influence of the ligand
connectivity (L1 vs. L10) and choice of ortho-heteroatomic
fragment (L1 vs. L49), as well as to benchmark the observed
catalytic performance of L1 against prominent ligands that
Fig. 2 Ligand screen for the Pd-catalyzed synthesis of 2-phenylindoles
from 1-bromo-2-(phenylethynyl)benzene. Isolated yield for L1, otherwise
yields are given on the basis of calibrated GC data (see ESIw).
Fig. 3 Scope of the [Pd(cinnamyl)Cl]2/L1 catalyzed cross-coupling of
primary amines with 2-alkynylhaloarenes. Isolated yields for X = Br; for
X = Cl, yield determined on the basis of calibrated GC data (see ESIw).
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proved to be suitable substrates in combination with a range of
amine coupling partners, providing the target indoles derived
from tBuNH2 (5), various hindered and unhindered aryl
amines including those featuring electron-donating and
electron-withdrawing substituents (6–10), and for the first time,
N-methylpiperazine (11) in 61–96% yield. The use of a methylated
variant of 1-bromo-2-(phenylethynyl)benzene was also tolerated,
affording the corresponding indoles derived from MeNH2
(88%, 12), 1-AdNH2 (91%, 13), and (2,6-Me2C6H3)NH2
(89%, 14) in high isolated yield. A fluorine-containing
o-alkynylbromoarene substrate also worked well with the
[Pd(cinnamyl)Cl]2/L1 catalyst system, enabling the isolation
of indoles derived from MeNH2 (83%, 15), 1-AdNH2 (90%, 16),
and DippNH2 (Dipp = (2,6-iPr2)C6H3; 93%, 17) in excellent yield.
The use of o-alkynylbromoarene substrates featuring substitu-
tion on the alkynyl terminus other than phenyl was also successful.
In the case of the reaction of 1-bromo-2-(trimethylsilylethynyl)-
benzene with 1-AdNH2, concurrent desilylation was observed,
thereby providing access to the corresponding parent indole
featuring a hydrogen at the C2 position (18, 82%). Alternatively,
the use of 1-bromo-2-(propylethynyl)benzene afforded cleanly
the corresponding indoles derived from MeNH2 (67%, 19),
1-AdNH2 (86%, 20), and (2,6-Me2C6H3)NH2 (89%, 21).
Having succeeded in applying the [Pd(cinnamyl)Cl]2/L1
catalyst system to the synthesis of indoles featuring primarily
hydrocarbon substituents, we turned our attention to sub-
strates featuring heterocyclic moieties. Despite the relevance of
hetero-functionalized indoles in medicinal chemistry, scant
attention has been paid thus far to the synthesis of such species
via palladium-catalyzed C–N cross-coupling/cyclization protocols.
Gratifyingly, the incorporation of a thiophen-3-yl fragment onto
the alkynyl terminus was well tolerated, affording N-substituted
indoles featuring a C2-thiophen-3-yl substituent (84–92%, 22–24).
Furthermore, the synthesis of thienopyrroles and 7-azaindoles was
achieved for the first time by use of palladium-catalyzed C–N
cross-coupling/cyclization methods, thereby enabling the isolation
of these ring-fused polyheterocyclic compounds in high yield
(76–91%, 25–28).
our knowledge, this represents the most extensive and varied
substrate scope to be demonstrated thus far in the literature for this
class of transformations (11 amines, 8 o-alkynylhalo(hetero)arenes,
28 examples in total). Encouraged by the desirable performance of
L1 in this catalytic application, we are currently probing the
applicability of L1 and related ligands more broadly in addressing
challenges in metal-catalyzed chemical synthesis. We will report on
the results of these studies in due course.
Acknowledgment is made to the NSERC of Canada, and
Dalhousie University for their support of this work.
Notes and references
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6 For examples of Buchwald–Hartwig amination chemistry employing
methylamine, see: (a) J. J. Li, Z. Wang and L. H. Mitchell, J. Org.
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7 The use of methylamine as a synthon in cascade C–N cross-
coupling/cyclization processes has recently been disclosed.6e
8 (a) M. Stradiotto, K. D. Hesp and R. J. Lundgren, Angew. Chem.,
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11 M. Bornand, S. Torker and P. Chen, Organometallics, 2007,
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In summary, the catalytic utility of the new and easily prepared
DalPhos ligand variant, OTips-DalPhos (L1) was established
through an investigation of the palladium-catalyzed cascade
C–N cross-coupling/cyclization of o-alkynylhalo(hetero)arene
substrates with primary amines. At relatively low loadings, the
[Pd(cinnamyl)Cl]2/L1 catalyst system offers remarkably broad
scope in the amine reaction partner, enabling the use of small
(e.g. MeNH2) and large (e.g. 1-AdNH2) alkylamines, various
hindered and unhindered aryl amines including those featuring
electron-donating and electron-withdrawing substituents, as
well as N-methylpiperazine. Significant structural variation
within the o-alkynylhalo(hetero)arene substrates was also
well-tolerated, leading to indoles featuring alkyl, aryl, and
heteroaryl substitution at the C2 position, as well as to
substituted thienopyrroles and 7-azaindoles. To the best of
.
12 See the ESIw for complete crystallographic data collection, solution
and refinement details, including tabulated data (Table S1).
13 Control experiments confirmed the stability of L1 under the
catalytic conditions employed; see the ESIw.
14 D. W. Old, M. C. Harris and S. L. Buchwald, Org. Lett., 2000, 2, 1403.
c
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Chem. Commun., 2012, 48, 7277–7279 7279