A synthetic method for palladium-catalyzed stannylation at the 5- and 6-benzo positions of indoles

Article abstract of DOI:10.1021/ol302076d

The stannylation of indole derivatives proceeds in good yields under palladium catalysis (5 mol %) without protection of the indolic nitrogen. The general utility of both PdCl₂(PhCN)₂/PCy₃ and Pd₂dba₃/PCy₃ as catalytic systems for the stannylation of three indole derivatives, with varying degrees of electron density, is presented.

Full text of DOI:10.1021/ol302076d

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4630–4633
A Synthetic Method for
Palladium-Catalyzed Stannylation at the
5- and 6‑Benzo Positions of Indoles
Emily B. Corcoran, Anna B. Williams, and Robert N. Hanson*
Department of Chemistry and Chemical Biology, Northeastern University, Boston,
Massachusetts 02115, United States
r.hanson@neu.edu
Received July 26, 2012
ABSTRACT
The stannylation of indole derivatives proceeds in good yields under palladium catalysis (5 mol %) without protection of the indolic nitrogen. The
general utility of both PdCl2(PhCN)2/PCy3 and Pd2dba3/PCy3 as catalytic systems for the stannylation of three indole derivatives, with varying
degrees of electron density, is presented.
The indole scaffold is ubiquitous in nature and performs
diverse biological roles, such as signal transduction, plant
hormones, and amino acids, as well as being present in
many natural products of pharmacological interest. In our
ongoing program to design and prepare PET and SPECT
radiotracers as probes of biological systems, we undertook
the preparation and evaluation of radiohalogenated indole
derivatives featuring an iodine-123 or fluorine-18 radio-
nuclide at the benzo positions of the indole ring system. We
focused on the radiohalogenation of benzo positions, partic-
ularly C5 and C6, of the indole scaffold as modification of the
C2 or C3 substituents may jeopardize biological activity.
The benzo positions, unlike the C2 and C3 positions, are
not preferred positions for electrophilic substitution. Non-
radioactive halogens can be introduced into these benzo
positions through use of either haloaniline or halophenyl-
hydrazine precursors (via palladium-catalyzed cyclization
or Fischer indole synthesis) or alternatively diazonium
salts. These strategies, however, are incompatible with
radiohalogens which possess short half-lives and for which
high specific activity is necessary. The criteria associated
with synthesis of radiotracers for SPECT and PET focused
our efforts on thedevelopment ofnew methods forlabeling
this important class of compounds.
The radiohalogenation of indoles at the benzo positions
is typically achieved by the following methods: (1) acid-
or copper-catalyzed halogenÀradiohalogen exchange,1À3
(2) decomposition of diazonium fluoroborates,4 or (3)
halodemetalation reactions in which electrophilic halogen
displaces an alkylmetal moiety.5À8 Of these methods, the
indirect halogenÀradiohalogen exchange via halodestan-
nylation is preferable as its mild reaction conditions pro-
vide radiohalogenated products that are readily sepa-
rable from their metalated precursors in high specific
activity (Scheme 1). Although these reactions proceed
(1) Chezal, J.-M.; Papon, J.; Labarre, P.; Lartigue, C.; Galmier,
M.-J.; Decombat, C.; Chavignon, O.; Maublant, J.; Teulade, J.-C.;
Madelmont, J.-C.; Moins, N. J. Med. Chem. 2008, 51, 3133.
(2) Chirakal, R.; Sayer, B. G.; Firnau, G.; Garnett, E. S. J. Labelled
Compd. Radiopharm. 1988, 25, 63.
(3) Kinter, C. M.; Lever, J. R. Nucl. Med. Biol. 1995, 22, 599.
(4) Atkins, H. L.; Christman, D. R.; Fowler, J. S.; Hauser, W.; Hoyte,
R. M.; Klopper, J. F.; Lin, S. S.; Wolf, A. P. J. Nucl. Med. 1972, 13, 713.
(5) Wheeler, W. J.; Swanson, S. P.; Varie, D. L.; O’Bannon, D. D.
J. Labelled Compd. Rad. 2005, 48, 139.
(6) Yang, Y.; Duan, X.-H.; Deng, J.-Y.; Jin, B.; Jia, H.-M.; Liu, B.-L.
Bioorg. Med. Chem. Lett. 2011, 21, 5594.
(7) Watanabe, H.; Ono, M.; Haratake, M.; Kobashi, N.; Saji, H.;
Nakayama, M. Bioorg. Med. Chem. 2010, 18, 4740.
(8) Van, D. M. E.; Lee, K. C.; Hamilton, C. A.; Rehemtulla, A.; Ross,
B. D. Mol. Imaging 2008, 7, 187.
r
10.1021/ol302076d
Published on Web 08/28/2012
2012 American Chemical Society

with ease, challenges in the preparation of the stannylated
intermediates often preclude the use of this technology
with unactivated, electron-rich substrates. The most com-
mon method for preparation of benzo-stannylated indoles
entails a preliminary hydrogen or halogenÀlithium ex-
change and subsequent transmetalation with trialkylstan-
nyl chloride.5,9 While effective for simple indoles, these
reactions have very limited functional group tolerance and
more complex derivatives require milder conditions, such as
those associated with palladium catalysis. Palladium-catalyzed
stannylation of the indolic benzo positions, unless the sub-
strate is otherwise activated,10 has posed a difficult synthetic
challenge with most reactions suffering from low yields (less
than 50%) and high catalyst loading (10 mol %).11
Table 1. Selected Optimization Reactions toward the Synthesis
of the 5-/6-Tributylstannyl-1H-indol-3-carbaldehydesa
entry ArX
catalyst
ligand
none
solvent
yieldb (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
2
2
2
2
Pd(PPh3)4
PdCl2dppf
PdCl2dppf
toluene
toluene
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
0
0
none
none
24
82
79
22
0
PdCl2(PhCN)2 PCy3
PdCl2(PhCN)2 dppe
PdCl2(PhCN)2 PCy3
PdCl2(PhCN)2 P(tBu)3
PdCl2(PhCN)2 dppe
Scheme 1. Indirect HalogenÀRadiohalogen Exchange at the
Benzo Positions of Indole Derivatives
60
79
PdCl2(PhCN)2 PCy2bph dioxane
a Unless otherwise noted, reactions were carried out using 1 or 2
(1 equiv), [Pd] (0.05 equiv), ligand (0.1 equiv), and hexa-n-butylditin
(3 equiv) at 110À120 °C under an atmosphere of argon for 12À24 h.
b Isolated yields reported as an average of two runs.
yields of 82% and 79%, respectively. Unlike 1, compound
2 failed to react favorably with the PdCl2(PhCN)2/PCy3
catalytic system, giving 4 in only 22% yield (Table 1,
entry 6). Increasing the basicity of the ligand by use of
P(tBu)3 (Table 1, entry 7) did not promote any formation
of 4, while the use of less basic ligands dppe and PCy2bph
(Table 1, entries 8 and 9) gave 4 in moderate to good yields
(60% and 79%, respectively).
Herein we describe a general method for efficient
palladium-catalyzed C5-/C6-stannylation of indole deri-
vatives which features lower palladium loadings (5 mol %)
and obviates protection of the indolic nitrogen. Our
investigation focused on the preparation of the 5- and
6-tributylstannyl derivatives of three indole scaffolds
featuring electronically diverse C3 substituents: 1H-indole,
indole-3-carbaldehyde, and gramine. The initial steps of
this project pertained to the stannylation of the 5-/6-
bromo-1H-indole-3-carbaldehyde derivatives 1 and 2.
Common transmetalation conditions (Table 1, entry 1),
in which 1 was refluxed in toluene with hexabutylditin in
the presence of tetrakis(triphenylphosphine), showed no
evidence of any reaction progress over a period of 24 h.
Similar results were obtained with PdCl2dppf in toluene;
however, the same conditions in dioxane gave the desired
product 3 in a 24% isolated yield (Table 1, entry 3). Use of
more basic ligands, PCy3 and dppe, with PdCl2(PhCN)2 as
the precatalyst (Table 1, entries 4 and 5) gave 3 in increased
We were pleased to discover that PCy3, in conjunction
with either PdCl2(PhCN)2 or Pd2dba3, was capable of
promoting the stannylation of the unsubstituted indoles
5 and 6 to form 7 and 8 in good yields, ranging from
90 to 97%, after only 3 h (Table 2, entries 1, 4, 5, and 8).
Less basic ligands, such as PCy2bph and dppe, gave
only moderate yields after 12 h for both 7 and 8, ranging
from 29 to 58% (Table 2, entries 2, 3, 6, and 7). Unlike the
3-carbaldehyde derivatives, the C3 unsubstituted indole
derivatives demonstrated no appreciable differences be-
tween the C5 and C6 positions with regard to optimal
reaction conditions. Although the preparation of 7 and 8
was accomplished easily under these conditions, the isola-
tion of these compounds posed a challenge because of the
extremely acid-sensitive nature of these compounds. Use
of silica chromatography, despite pretreatment with 5%
triethylamine in hexanes, resulted in substantial hydrodes-
tannylation of 7 and 8 to form unsubstituted 1H-indole.
Similar results were observed using basic alumina chro-
matography. Minimal loss of product during isolation
was achieved by reversed-phase chromatography using
an isocratic acetonitrile mobile phase; use of water during
the reversed-phase purification process also led to signifi-
cant formation of the destannylated byproduct.
(9) Cherry, K.; Lebegue, N.; Leclerc, V.; Carato, P.; Yous, S.;
Berthelot, P. Tetrahedron Lett. 2007, 48, 5751.
(10) Sheppard, G. S.; Davidsen, S. K.; Carrera, G. M., Jr.; Pireh, D.;
Holms, J. H.; Heyman, H. R.; Steinman, D. H.; Curtin, M. L.; Conway,
R. G.; Rhein, D. A.; Albert, D. H.; Tapang, P.; Magoc, T. J.; Summers,
J. B. Bioorg. Med. Chem. Lett. 1995, 5, 2913.
(11) Yamada, Y.; Akiba, A.; Arima, S.; Okada, C.; Yoshida, K.;
Itou, F.; Kai, T.; Satou, T.; Takeda, K.; Harigaya, Y. Chem. Pharm.
Bull. 2005, 53, 1277.
Lastly, we undertook the stannylation of the electron-
rich gramine derivatives 9 and 10. To the best of our
Org. Lett., Vol. 14, No. 17, 2012
4631

Table 2. Optimization of the Stannylation of C3-Unsubstituted
Indolesa
Table 3. Optimization of the Stannylation of Gramine Derivativesa
entry
ArX
catalyst
ligand
yieldb (%)
entry
Ar-X
catalyst
ligand
PCy3
yieldb (%)
1c
2
5
5
5
5
6
6
6
6
PdCl2(PhCN)2
PdCl2(PhCN)2
Pd2dba3
PCy3
dppe
dppe
PCy3
PCy3
dppe
dppe
PCy3
92
57
29
90
90
58
43
97
1
2
3
4
5
6
7
8
9
9
PdCl2(PhCN)2
Pd2dba3
82
28
11
5
PCy3
3
9
PdCl2(PhCN)2
Pd2dba3
dppe
4c
5c
6
Pd2dba3
9
PCy2bph
PCy3
PdCl2(PhCN)2
PdCl2(PhCN)2
Pd2dba3
10
10
10
10
PdCl2(PhCN)2
Pd2dba3
70
15
33
13
PCy3
7
8c
PdCl2(PhCN)2
Pd2dba3
dppe
Pd2dba3
PCy2bph
a Unless otherwise noted, reactions were carried out using 5 or 6
(1 equiv), [Pd] (0.05 equiv), ligand (0.1 equiv), and hexa-n-butylditin
(3 equiv) at 110À120 °C under an atmosphere of argon for 12 h.
b Isolated yields reported as an average of two runs. c Reaction heated
at 110 °C for 3 h.
a Unless otherwise noted, reactions were carried out using 9 or 10
(1 equiv), [Pd] (0.05 equiv), ligand (0.1 equiv), and hexa-n-butylditin
(3 equiv) at 110À120 °C under an atmosphere of argon for 12 h.
b Isolated yields reported as an average of two runs.
Throughout our investigations, the PdCl2(PhCN)2/
PCy3 catalytic system demonstrated a general utility in
promoting the stannylation of the C5 and C6 positions of
each indole derivative, with the only exception of 2, for
which less basic ligands were significantly more effective.
For the carbaldehyde and unsubstituted indoles, Pd2dba3
and PdCl2(PhCN)2 performed comparably well, but iso-
lation of product was accomplished more easily from
reaction mixtures containing PdCl2(PhCN)2 as Pd2dba3
often coeluted with the product during chromatography.
Inconclusion, wehave reported a general methodfor the
efficient preparation of C5- and C6-stannylated indole
derivatives. In contrast to previous methods, this method
eliminates the need for high catalyst loadings and pro-
tection of the indolic nitrogen. Additionally, it tolerates
diverse functional groups unlike the common lithium-
mediated procedures for the preparation of electron-rich
stannanes. This synthetic methodology provides access to
a variety of previously inaccessible stannylated indole
derivatives, the preparation of which has been a bottleneck
in the production of biologically relevant radiohaloge-
nated indole derivatives for use in medical imaging as well
as other applications. This work is also applicable to the
preparation of electron-rich stannanes for use in Stille
cross-coupling reactions. To date, access to diverse stan-
nylated indole derivatives has been extremely challenging,
thus limiting the role of indoles to that of the aryl halide
rather than the metalated species, in Stille reactions.14 The
focus of further work will be the extension of this metho-
dology toward the preparation of C4- and C7-stannylated
indole derivatives as well as the stannylation of indole
derivatives featuring more complex substitution patterns.
Additional studies into the use of the reported stannylated
knowledge, this constitutes the first application of palla-
dium catalysis toward the metalation of the benzo posi-
tions of the gramine scaffold. The only reported stannyla-
tion of gramine was accomplished at the C4 position
through lithiumÀhydrogen exchange and subsequent re-
action with Sn(nBu)3Cl.12 The stannylation of these sub-
strates proved more challenging than the other indole
derivatives. Although the PdCl2(PhCN)2/PCy3 catalytic
system (Table 3, entries 1 and 5) was effective at promoting
the stannylation of the gramine derivatives in moderately
good yields (70À82%), other catalytic systems which were
effective for other substrates gave only minimal product
formation. Mostnotably,Pd2dba3, in combination with the
PCy3 ligand, failed to catalyze the stannylation of gramines
in decent yields. Indeed, all other ligands screened resulted
in minimal product formation (Table 3, entries 2À4 and
6À8). We are uncertain as to the source of this discrepancy
between the unsubstituted indoles and the gramines, as
reported NMR chemical shifts for these compounds de-
monstrate that these two classes of substrates are electro-
nically equivalent at the C5 and C6 positions.13 One
possible explanation is that the presence of the tertiary
amine is poisoning the catalyst, leaving a large portion of
the bromogramine starting material unconsumed. As our
goal of using low (5 mol %) catalyst loading to effect these
stannylations was met using PdCl2(PhCN)2 with PCy3,
further optimization using other catalytic systems at higher
loadings was not pursued. Similar to 7 and 8, compounds
11 and 12 were successfully isolated in good yields solely
with reversed-phase chromatography using an isocratic
acetonitrile mobile phase. Contact with acid, even one as
weak as water, led to significant destannylation.
(12) Iwao, M. Heterocycles 1993, 36, 29.
(13) Burton, G.; Ghini, A. A.; Gros, E. G. Magn. Reson. Chem. 1986,
24, 829–831.
(14) Mentzel, U. V.; Tanner, D.; Tønder, J. E. J. Org. Chem. 2006, 71,
5807–5810.
4632
Org. Lett., Vol. 14, No. 17, 2012

indole intermediates for the development of radiotracers
are underway.
spectrometer (CHE 0443618) used for this work. We also
thank Rein Kirss of Northeastern University for insightful
discussions and kind donation of phosphine ligands.
Acknowledgment. We thank the U.S. Department of
Energy’s Office of Biological and Environmental Research
(DE-SC0001781) for support of this research. We are
grateful to Norman Lee and the Chemical Interpretation
Center at Boston University for their assistance with high-
resolution mass spectra and to the National Science Foun-
dation for the purchase of the high-resolution Waters mass
Supporting Information Available. Experimental pro-
cedures and spectral data for unknown compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
4633