Metal-free direct arylations of indoles and pyrroles with diaryliodonium salts

Article abstract of DOI:10.1021/ol200601e

Chemical equations presented. Direct arylations of indoles and pyrroles with differently substituted diaryliodonium salts were shown to efficiently proceed in the absence of metal catalysts.

Full text of DOI:10.1021/ol200601e

ORGANIC
LETTERS
2
011
Vol. 13, No. 9
358–2360
Metal-Free Direct Arylations of Indoles
and Pyrroles with Diaryliodonium Salts
2
Lutz Ackermann,* Monica Dell’Acqua, Sabine Fenner, Rub ꢀe n Vicente, and
Ren ꢀe Sandmann
Institut f u€ r Organische und Biomolekulare Chemie, Georg-August-Universit a€ t,
Tammannstrasse 2, 37077 G o€ ttingen, Germany
Lutz.Ackermann@chemie.uni-goettingen.de
Received March 7, 2011
ABSTRACT
Direct arylations of indoles and pyrroles with differently substituted diaryliodonium salts were shown to efficiently proceed in the absence of metal
catalysts.
2
Direct arylations of otherwise unreactive CÀH bonds
have emerged in recent years as attractive alternatives to
traditional cross-coupling reactions with organometallic
indole derivatives has received significant attention, be-
cause this scaffold is omnipresent in biologically active
3
compounds and natural products. Remarkable progress
in metal-catalyzed direct arylations of electron-rich
1
reagents. Particularly, the direct functionalization of
(hetero)arenes was recently accomplished through the
use of diaryliodonium salts as arylating reagents.
2
b,4
Dur-
ing studies directed toward the development of ruthenium-
(
1) Select recent reviews on metal-catalyzed CÀH bond functionali-
zations: (a) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy,
J. M.; Hartwig, J. F. Chem. Rev. 2010, 110, 890–931. (b) Willis, M. C.
Chem. Rev. 2010, 110, 725–748. (c) Ackermann, L.; Potukuchi, H. K.
Org. Biomol. Chem. 2010, 8, 4503–4513. (d) Daugulis, O. Top. Curr.
Chem. 2010, 292, 57–84. (e) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem.
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J. A. Chem. Rev. 2010, 110, 624–655. (g) Fagnou, K. Top. Curr. Chem.
5
catalyzed CÀH bond functionalizations on heteroarenes
we observed that CÀH bond arylations of indoles and
(4) Merritt, E. A.; Olofsson, B. Angew. Chem., Int. Ed. 2009, 48,
9052–9070.
2
010, 292, 35–56. (h) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-
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A.; Liu, W.; Liu, C.; Chen, M. Dalton Trans. 2010, 39, 10352–10361. (j)
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Sanford, M. S. Chem. Rev. 2010, 110, 1147–1169. (l) Dudnik, A. S.;
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Shi, B.-F.; Engle, K. M.; Maugel, N.; Yu, J.-Q. Chem. Soc. Rev. 2009, 38,
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292, 211–229. (b) Ackermann, L. Pure Appl. Chem. 2010, 82, 1403–1413.
(6) For recent progress in direct arylations under transition-metal-
free reaction conditions, see: (a) Shirakawa, E.; Itoh, K.-I.; Higashino,
T.; Hayashi, T. J. Am. Chem. Soc. 2010, 132, 15537–15539. (b) Sun, C.-
L.; Li, H.; Yu, D.-G.; Yu, M.; Zhou, X.; Lu, X.-Y.; Huang, K.; Zheng,
S.-F.; Li, B.-J.; Shi, Z.-J. Nat. Chem. 2010, 2, 1044–1049. (c) Liu, W.;
Cao, H.; Zhang, H.; Zhang, H.; Chung, K. H.; He, C.; Wang, H.;
Kwong, F. Y.; Lei, A. J. Am. Chem. Soc. 2010, 132, 16737–16740 and
references cited therein. For a pioneering example, see: (d) Yanagisawa,
S.; Ueda, K.; Taniguchi, T.; Itami, K. Org. Lett. 2008, 10, 4673–4676.
For reviews, see:(e) Yanagisawa, S.; Itami, K. ChemCatChem 2011, 3,
DOI: 10.1002/cctc.201000431. (f) Leadbeater, N. E. Nat. Chem. 2010, 2,
1007–1009.
(7) For representative recent examples of metal-free arylations with
diaryliodonium salts, see: (a) Jalalian, N.; Ishikawa, E. E.; Silva, L. F.;
Olofsson, B. Org. Lett. 2011, 13, 1552–1555. (b) Dohi, T.; Ito, M.;
Yamaoka, N.; Morimoto, K.; Fujioka, H.; Kita, Y. Angew. Chem., Int.
Ed. 2010, 49, 3334–3337. (c) Morimoto, K.; Yamaoka, N.; Ogawa, C.;
Nakae, T.; Fujioka, H.; Dohi, T.; Kita, Y. Org. Lett. 2010, 12, 3804–
3807. (d) Eastman, K.; Baran, P. S. Tetrahedron 2009, 65, 3149–3154. (e)
Kita, Y.; Morimoto, K.; Ito, M.; Ogawa, C.; Goto, A.; Dohi, T. J. Am.
Chem. Soc. 2009, 131, 1668–1669. (f) Dohi, T.; Ito, M.; Morimoto, K.;
Iwata, M.; Kita, Y. Angew. Chem., Int. Ed. 2008, 47, 1301–1304 and
references cited therein. (g) See also ref 7 in the Supporting Information.
3
(
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Ackermann, L.; Vicente, R.; Kapdi, A. Angew. Chem., Int. Ed. 2009,
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4
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(
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7
(
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1
0.1021/ol200601e r 2011 American Chemical Society
Published on Web 04/12/2011

6,7
pyrroles occur in the absence of transition metal catalysts,
on which we wish to report herein.
At the outset of our studies, we tested various reaction
conditionsfor the direct functionalization ofindole1awith
8
diaryliodonium salt 2a (Table 1). Interestingly, we ob-
served that direct arylations under metal-free reaction
conditions proved viable in toluene, NMP, t-AmOH, or
DMF as the solvent, the latter of which was employed for
further optimization studies.
With optimized reaction conditions in hand, we probed
the scope of metal-free direct arylations with differently
substituted indoles employing dianisyliodonium tosylate
(2b) (Scheme 1). Notably, N-alkyl indoles 1 were converted
efficiently, as were free (NH)-indoles. More hindered
2-substituted indoles 1 reacted with comparable efficacy,
thereby yielding products 3hÀ3l. Decoration on the aromatic
moiety of indoles 1was well tolerated, which among others set
the stage for the synthesis of chloro-substituted product 3o.
a
Table 1. Effect of Solvents on Direct Arylation of Indole 1a
a
Scheme 1. Scope of Metal-Free Direct Arylations of Indoles 1
entry
solvent
yield
--
1
2
3
4
5
6
7
8
9
Br
Cl
2
CHCHBr
CHCHCl
2
b
2
2
3%
1,4-dioxane
PEG-400
PhMe
11%
--
25%
b
7%
AcOH
t-AmOH
DMA
39%
b
8%
NMP
20%
38%
1
0
DMF
c
11
DMF
43%
a
Reaction conditions: 1a (0.50 mmol), 2a (0.55 mmol), solvent (2.0
b
mL), 100 °C, 22 h; isolated yields. GC-conversion with n-tridecane as
standard. 1a (1.00 mmol).
c
a
Reaction conditions: 1 (0.50 mmol), 2b (1.00 mmol), DMF (2.0 mL),
Subsequently, we probed the effect exerted by the coun-
teranions of salts 2, which showed that satisfactory results
could be obtainedwithdiaryliodonium tetrafluoroborates,
hexafluorophosphates, trifluoroacetates, or tosylates
(Table 2, entries 1À6), while the corresponding bromides
failed to deliver the desired product 3a (entry 7).
b
1
00 °C, 22 h. 2b (0.55 mmol); isolated yields.
Direct arylations of indoles 1 occurred with excellent
site-selectivities to predominantly yield the C-3 arylated
products. However, it is noteworthy that small amounts of
the C-2 functionalized indoles 3pb and 3qb were isolated
when using starting materials 1p and 1q, respectively
(Scheme 2). Here, best results were obtained with DMF
a
Table 2. Effect of the Counteranions
9
or toluene as the solvent.
The CÀH bond functionalization protocol was not
limited to the direct introduction of a 4-anisyl substitutent
but allowed for the preparation of products 3rÀ3u as well
1
0,11
(Scheme 3).
entry
X
yield
(
8) All direct arylation reactions reported herein were performed in
new glassware using new stirring bars. Representative starting materials
and 2 were analyzed by ICP-MS, which revealed only trace amounts of
transition metals (inter alia <1 ppm Pd, Rh, and Ru; <10 ppm Cu).
9) For a representative study on the effect of solvents on palladium-
1
2
3
4
5
6
7
OTf
38%
40%
58%
54%
47%
1
BF
PF
4
6
(
OTFAc
OTs
OTs
Br
catalyzed oxidative arylations of indoles with arenes, see: Potavathri, S.;
Dumas, A. S.; Dwight, T. A.; Naumiec, G. R.; Hammann, J. M.;
DeBoef, B. Tetrahedron Lett. 2008, 49, 4050–4053.
(10) Under otherwise identical reaction conditions, the addition of 2
equiv of 2,6-di-tert-butylpyridine afforded product 3s in a comparable
b
54%
---
yield of 69%.
a
Reaction conditions: 1a (0.50 mmol), 2 (0.55 mmol), DMF (2.0
(
11) Small amounts of the corresponding C-2 arylated products
2À8%) were formed during the preparation of products 3rÀ3t, as
indicated by GC/MS analysis.
b
mL), 100 °C, 22 h. 2 (1.00 mmol).
(
Org. Lett., Vol. 13, No. 9, 2011
2359

Scheme 2. Direct Arylations of 2,3-Unsubstituted Indoles 1p
and 1q
Scheme 5. Intramolecular Competition Experiment with Salt 2c
a strong correlation with Mayr’s nucleophilicity parameter
1
2
N
(Scheme 6).
Scheme 6. Intermolecular Competition Experiment
Scheme 3. Scope of Direct Arylations with [Ar I][OTs] 2
2
On the basis of these experiments, we finally probed
pyrrole 4 as a substrate (1,2,5-trimethylpyrrole: N =
1
.69), which delivered the desired product 5 (Scheme 7).
3
8
Scheme 7. Direct Arylation of Pyrrole 4
Likewise, unsymmetrically substituted diaryliodonium
salts 2 were found to be suitable arylating reagents, which
resulted in the preferential transfer of the less sterically
hindered aromatic moiety (Scheme 4).
In summary, we have reported on efficient direct aryla-
tions of indoles with diaryliodonium salts in the absence of
metal catalysts. Importantly, the protocol proved broadly
applicable, thereby enabling CÀH bond functionalizations
of free (NH)- as well as N-substituted indoles and pyrroles.
Scheme 4. Direct Arylations with Unsymmetrically Substituted
Salts 2
Acknowledgment. We thank Dr. Klaus Simon and
Prof. Dr. Gerhard W o€ rner (Geowissenschaftliches Zen-
trum G o€ ttingen) for ICP-MS analyses. Support by the
DFG and the Alexander-von-Humboldt Foundation
(fellowship to R.V.) is gratefully acknowledged.
Supporting Information Available. Experimental pro-
1
13
cedures, characterization data, and H and C NMR
spectra for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
An additional intramolecular competition experi-
ment with iodonium salt 2c bearing two different aryl
substituents with comparable steric demand high-
lighted that the less electron-rich group is introduced
predominantly (Scheme 5).
(
12) (a) Lakhdar, S.; Westermaier, M.; Terrier, F.; Goumont, R.;
Boubaker, T.; Ofial, A. R.; Mayr, H. J. Org. Chem. 2006, 71, 9088–9095.
b) A review: Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003,
6, 66–77.
13) Nigst, T. A.; Westermaier, M.; Ofial, A. R.; Mayr, H. Eur. J.
Org. Chem. 2008, 2369–2374.
(
3
Moreover, intermolecularcompetition experiments with
an excess of differently substituted indoles clearly revealed
(
2
360
Org. Lett., Vol. 13, No. 9, 2011