Iron(II) triflate as a catalyst for the synthesis of indoles by intramolecular C-H amination

Article abstract of DOI:10.1021/ol2004066

A practical iron-catalyzed intramolecular C-H amination reaction and its application in the synthesis of indole derivatives are presented. As a catalyst, commercially available iron(II) triflate is used.

Full text of DOI:10.1021/ol2004066

ORGANIC
LETTERS
2011
Vol. 13, No. 8
2012–2014
Iron(II) Triflate as a Catalyst for the
Synthesis of Indoles by Intramolecular
C-H Amination
Julien Bonnamour and Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52056
Aachen, Germany
carsten.bolm@oc.rwth-aachen.de
Received February 14, 2011
ABSTRACT
A practical iron-catalyzed intramolecular C-H amination reaction and its application in the synthesis of indole derivatives are presented. As a
catalyst, commercially available iron(II) triflate is used.
Indoles are synthetically relevant compounds, and many
derivatives show important biological activities.1 Conse-
quently, synthetic approaches toward indoles have at-
tracted significant attention.2 In many cases, the well-
studied Fischer indole synthesis is the method of choice,
but often, this approach suffers from problems such as low
yield and formation of side products.3 Alternatively, in-
doles have been targeted by starting from azides, where
photo- or thermolytic conditions, like the Hemetsberger-
Knittel reaction,4 allow aminations of aromatic C-H
bonds through nitrene insertions.5 Safety concerns6 stipu-
lated the search for metal-catalyzed versions of such reac-
tions. In this context, Driver described the ring closure of
aryl azidoacrylates to give indoles and related heterocycles
using rhodium(II) perfluorobutyrate asa catalyst.7,8 Later,
it was demonstrated that aryl azides could be activated by
iron salts providing access to other heterocyclic systems.9-11
Our own interest in imination reactions under iron
catalysis12,13 led us to hypothesize that, in analogy to
Driver’s rhodium catalysis, simple iron salts could also
proveuseful fordirectindolesyntheses. Here, wereport the
results of this study and reveal that iron(II) triflate14 is a
highly suitable catalyst for such intramolecular C-H
amination reactions starting from azidoacrylates.15
(7) (a) Stokes, B. J.; Dong, H.; Leslie, B. E.; Pumphrey, A. L.; Driver,
T. G. J. Am. Chem. Soc. 2007, 129, 7500. For related work on carbazole
formations, see:(b) Stokes, B. J.; Jovanovic, B.; Dong, H.; Richert, K. J.;
Riell, R. D.; Driver, T. G. J. Org. Chem. 2009, 74, 3225. (c) Stokes, B. J.;
Richert, K. J.; Driver, T. G. J. Org. Chem. 2009, 74, 6442.
(8) For general reviews on metal nitrene formations starting from
azides, see: Katsuki, T. Chem. Lett. 2005, 34, 1304. (b) Cenini, S.; Gallo,
E.; Caselli, A.; Ragaini, F.; Fantauzzi, S.; Piangiolino, C. Coord. Chem.
Rev. 2006, 250, 1234.
(1) For biological activities of indoles, see: (a) Sundberg, R. J.
Indoles; Academic Press: London, 1996. (b) Sharma, V.; Kumar, P.; Pathak
J. Heterocycl. Chem. 2010, 47, 491.
(2) For selected reviews of indole syntheses, see: (a) Joule, J. A. In
Science of Synthesis; Thomas, E. J., Ed.; Georg Thieme Verlag: Stuttgart,
2000; Vol. 10, Chapter 10.13r. (b) Gribble, G. W. J. Chem. Soc., Perkin
Trans. 1 2000, 1045. (c) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006,
106, 2875. (d) Somei, M.; Yamada, F. Nat. Prod. Rep. 2005, 22, 73. (e)
Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9608. (f)
Cacchi, S.; Fabrizi, G.; Goggiamani, A. Org. Biomol. Chem. 2011, 9, 641.
(3) (a) For an overview, see: Hughes, D. L. Org. Prep. Proced. Int.
1993, 25, 607. (b) For a recent preparativeadvance, see: Simoneau, C. A.;
Ganem, B. Nat. Protoc. 2008, 3, 1249.
(4) (a) Hemetsberger, H.; Knittel, D. Monatsh. Chem. 1972, 103, 194.
(b) Knittel, D. Synthesis 1985, 186.
€
(5) For a review on nitrene chemistry, see: Soderberg, B. C. G. Curr.
Org. Chem. 2000, 4, 727.
(6) Wiss, J.; Fleury, C.; Onken, U. Org. Process Res. Dev. 2006, 10,
(9) (a) Shen, M.; Driver, T. G. Org. Lett. 2008, 10, 3367. (b) Stokes,
B. J.; Vogel, C. V.; Urnezis, L. K.; Pan, M.; Driver, T. G. Org. Lett. 2010,
12, 2884.
(10) For other iron-catalyzed reactions with nonaromatic azides, see:
€
(a) Bach, T.; Korber, C. Tetrahedron Lett. 1998, 39, 5015. (b) Bach, T.;
€
Korber, C. J. Org. Chem. 2000, 65, 2358. (c) Bach, T.; Schlummer, B.;
Harms, K. Chem. Commun. 2000, 287. (d) Bach, T.; Schlummer, B.;
Harms, K. Chem.;Eur. J. 2001, 7, 2581. (e) Bacci, J. P.; Greenman,
K. L.; Van Vranken, D. L. J. Org. Chem. 2003, 68, 4955. (f) Bonnamour,
J.; Bolm, C. Chem.;Eur. J. 2009, 15, 4543.
(11) 2H-Azirines were shown to undergo ring opening to give indoles
under iron catalysis. Also here, iron nitrenes have been suggested as
intermediates. Jana, S.; Clements, M. D.; Sharp, B. K; Zheng, N. Org.
Lett. 2010, 12, 3736.
349.
r
10.1021/ol2004066
Published on Web 03/11/2011
2011 American Chemical Society

Table 3. Iron-Catalyzed Synthesis of Indole Derivativesa
Table 1. Iron-Catalyzed C-H Amination of Azide 1a: Influence
of the Solvent
entry
solvent
DMF
yield of 2a (%)a
1
--
2
acetonitrile
EtOH
--
3
--
4
water
--
5
hexane
toluene
xylene
58
46
38
46
16
28
63
41
26
78 (75)b
6
7
8
chloroform
diethyl ether
MTBE
9
10
11
12
13
14
DME
anisole
dioxane
THF
a After chromatography. b In parentheses, the result from an experi-
ment performed with 10 mol % of iron triflate.
Table 2. Metal-Catalyzed Conversion Synthesis of Indole 2a
entry
catalyst
temp (°C)
t (h)
yield (%)a
1
2
Fe(OTf)2
---
80
80
60
r.t.
80
80
80
80
80
80
24
24
24
24
5
75 (40)b
--
3
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
TfOH
24
0
4
5
44
13
--
6
1
7
24
24
24
24
a Azidoacrylate 1 (1 equiv), Fe(OTf)2 (0.10 equiv), THF (3 mL/mmol
of 1), 80 °C, 24 h. b After chromatography.
8
TfONa
CuOTf
Cu(OTf)2
--
9
--
10
--
1a that we expected to be converted into 2-carboxy-sub-
stituted indole 2a.
a After chromatography. b In parentheses, the result from an experi-
ment performed with 1 mol % of iron triflate.
Asinotheriron catalyses, the solvent playeda majorrole
in this reaction. Various solvents were screened, and the
results are summarized in Table 1. Reactions performed
(with 30 mol % of iron triflate at 80 °C) in DMF,
acetonitrile, or protic polar solvents such as water and
ethanol gave no product (entries 1-4). In hexane, toluene,
and xylene (entries 5-7) as well as other solvents of low
polarity, the yields were moderate to good (up to 58% for
hexane). Ethers such as MTBE, DME, and others (entries
9-14) proved suitable too, and finally, THF was found to
Recently, much work has been devoted to iron
catalysis,16 and commonly the applied iron salts are con-
sidered as inexpensive, nontoxic, and environmentally
friendly. In sulfoxide iminations we had identified iron(II)
triflate as a highly efficient and robust catalyst being
superior to many other iron salts.13e,f Consequently, we
started our current investigation using this particular iron
salt as a catalyst. The test substrate was phenyl azidoacrylate
Org. Lett., Vol. 13, No. 8, 2011
2013

be the best solvent for this iron catalysis providing 2a in
78% yield (entry 14).
affording the corresponding indoles 2 in yields up to
80% (Table 3, entries 2-8). An ortho methoxy substituent
had no significant impact, and product 2i was obtained in
70% yield. Substrates with meta and para disubstituted
aryl groups afforded only single isomers (entries 10-13
and 15), and in all cases the yields were exceptionally high
(88-99%). In order to ensure that other esters could be
converted, the syntheses of isopropyl and menthyl esters2n
and 2o, respectively, were studied. To our delight, those
products also could be obtained in moderate to very high
yields (35 and 93%, entries 14 and 16).
In summary, we have demonstrated that a variety of
indoles can be obtained from the corresponding aryl
azidoacrylate commercially available iron(II) triflate cat-
alyst. Further studies are directed toward an expansion of
the substrate scope with a particular focus on the prepara-
tion of other heterocycles.
Next, other reaction parameters were evaluated. The
catalyst loading could be reduced from 30 to 10 mol %
without significantly affecting the yield of 2a (Table 2,
entry 1). With 1 mol % for iron triflate, however, a sharp
drop in yield was observed (Table 2, entry 1). As expected,
no product was formed in the absence of the catalyst
(Table 2, entry 2).
Both lowering the temperature (from 80 °C to ambient
temperature) and shortening the reaction time decreased
the yield (Table 2, entries 3-6). In order to ensure that iron
was essential for the conversion of 1a, sodium triflate and
triflic acid were tested, but both proved inactive (entries 7
and 8). Based on previous observations17 we felt obliged to
test if copper showed catalytic activity. Neither copper(I)
triflate nor copper(II) triflate was able to catalyze the
formation of indole 2a from azidoacrylate 1a (Table 2,
entries 9 and 10).
Acknowledgment. We are grateful to the Fonds der
Chemischen Industrie for financial support.
Finally, the reaction scope was investigated. The cata-
lysis proceeded well with substrates having various sub-
stituents irrespective of the position at the aryl ring. Thus,
azidoacrylates with methoxy, alkyl, trifluoromethyl, halo,
and phenyl groups in the para position reacted well
Supporting Information Available. Experimental pro-
cedures, full characterization of new products, and copies
of NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
(12) For a theoretical investigation, see: Moreau, Y.; Chen, H.;
Derat, E.; Hirao, H.; Bolm, C.; Shaik, S. J. Phys. Chem. B 2007, 111,
10288.
~
´
(13) (a) Garcıa Mancheno, O.; Bolm, C. Org. Lett. 2006, 8, 2349. (b)
~
Garcıa Mancheno, O.; Bolm, C. Chem.;Eur. J. 2007, 13, 6674. (c)
´
(16) Reviews: (a) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem.
€
Rev. 2004, 104, 6217. (b) Furstner, A.; Martin, R. Chem. Lett. 2005, 34,
~
624. (c) Correa, A.; Garcıa Mancheno, O.; Bolm, C. Chem. Soc. Rev.
´
Mayer, A. C.; Salit, A.-F.; Bolm, C. Chem. Commun. 2008, 5975. (d)
Nakanishi, M.; Salit, A.-F.; Bolm, C. Adv. Synth. Catal. 2008, 350, 1835.
(e) Garcı
€
2008, 37, 1108. (d) Sherry, B. D.; Furstner, A. Acc. Chem. Res. 2008, 41,
1500. (e) Enthaler, S.; Junge, K.; Beller, M. Angew. Chem., Int. Ed. 2008,
47, 3317. (f) Bauer, E. B. Curr. Org. Chem. 2008, 12, 1341. (g) Gaillard,
~
´
a Mancheno, O.; Dallimore, J.; Plant, A.; Bolm, C. Org. Lett.
~
a Mancheno, O.; Dallimore, J.; Plant, A.; Bolm,
2009, 11, 2429. (f) Garcı
´
€
S.; Renaud, J.-L. ChemSusChem 2008, 1, 505. (h) Furstner, A. Angew.
Chem., Int. Ed. 2009, 48, 1364. (i) Czaplik, W. M.; Mayer, M.; Cvengros,
C. Adv. Synth. Catal. 2010, 352, 309.
(14) In this study, commercially available iron(II) triflate (98% from
abcr) was used.
(15) While this work was in progress, Che and co-workers described a
very related iron-catalyzed amination of a C-H bond using aryl azides
as a nitrogen source. There, however, a rather expensive iron porphyrin
[Fe(F20TPP)Cl where H2F20TPP stands for meso-tetrakis-
(pentafluorophenyl)porphyrin] in toxic 1,2-dichloroethan was used as
a catalyst. See: Liu, Y.; Wei, J.; Che, C.-M. Chem. Commun. 2010, 46,
6926.
ꢀ
J.; Jacobi von Wangelin, A. ChemSusChem 2009, 2, 396. (j) Bolm, C.
Nat. Chem. 2009, 1, 420. (k) Sarhan, A. A. O.; Bolm, C. Chem. Soc. Rev.
2009, 38, 2730.
(17) (a) Buchwald, S. L.; Bolm, C. Angew. Chem., Int. Ed. 2009, 48,
5586. (b) Larsson, P.-F.; Correa, A.; Carril, M.; Norrby, P.-O.; Bolm, C.
Angew. Chem., Int. Ed. 2009, 48, 5691. (c) Bonnamour, J.; Piedrafita, M.;
Bolm, C. Adv. Synth. Catal. 2010, 352, 1577. (d) Zuidema, E.; Bolm, C.
Chem.;Eur. J. 2010, 16, 4181. (e) Larsson, P.-F.; Norrby, P.-O.; Bolm,
C. Chem.;Eur. J. 2010, 16, 13613.
2014
Org. Lett., Vol. 13, No. 8, 2011