Fe(II)-catalyzed amination of aromatic C-H bonds via ring opening of 2 H-azirines: Synthesis of 2,3-disubstituted indoles

Article abstract of DOI:10.1021/ol101130e

A general method for the synthesis of 2,3-disubstituted indoles is described. The key feature of this method is the amination of aromatic C-H bonds via FeCl₂-catalyzed ring opening of 2H-azirines. The method tolerates a variety of functional groups such as Br, F, NO₂, OMe, CF₃, OTBS, alkenes, and OPiv. The method can also be extended to synthesize azaindoles.

Full text of DOI:10.1021/ol101130e

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3736-3739
Fe(II)-Catalyzed Amination of Aromatic
C-H Bonds via Ring Opening of
2H-Azirines: Synthesis of
2,3-Disubstituted Indoles
Samaresh Jana, Mack D. Clements, Barry K. Sharp, and Nan Zheng*
Department of Chemistry and Biochemistry, UniVersity of Arkansas,
FayetteVille, Arkansas 72701
nzheng@uark.edu
Received May 17, 2010
ABSTRACT
A general method for the synthesis of 2,3-disubstituted indoles is described. The key feature of this method is the amination of aromatic C-H
bonds via FeCl2-catalyzed ring opening of 2H-azirines. The method tolerates a variety of functional groups such as Br, F, NO2, OMe, CF3,
OTBS, alkenes, and OPiv. The method can also be extended to synthesize azaindoles.
The widespread occurrence of the indole motif in bioactive
natural products and pharmaceuticals has drawn synthetic
chemists’ long-lasting interest in developing general methods
to prepare them.1a,b In fact, almost all conceivable bond
disconnections for the indole nucleus have been explored.1c,d
Yet the efficiency and the substrate scope for most of these
approaches still leave much to be desired. For example, very
few of them employ direct amination of aromatic C-H
bonds,2 which obviates the need for prefunctionalizing the
substrate. Furthermore, simultaneous introduction of sub-
stituents at C2 and C3 of the indole nucleus remains a
continual challenge for organic chemists.3 Additionally, most
of the existing methods are not particularly effective for
preparing azaindoles that are of great interest to medicinal
chemists.4
We were interested in developing a general and catalytic
method for the synthesis of 2,3-disubstituted indoles based
on the direct amination of aromatic C-H bonds. To
implement this strategy, a suitable vinyl nitrene precursor
would be needed. Vinyl azides are typically used as
precursors to generate the vinyl nitrenes.5a,b However, their
use as the vinyl nitrene precursor is often limited by their
narrow substrate scope as they are generally prepared by the
condensation of methyl azidoacetate and aromatic
(3) For some recent examples, see: (a) Shi, Z.; Zhang, C.; Li, S.; Pan,
D.; Ding, S.; Cui, Y.; Jiao, N. Angew. Chem., Int. Ed. 2009, 48, 4572–
4576. (b) Cariou, K.; Ronan, B.; Mignani, S.; Fensterbank, L.; Malacria,
M. Angew. Chem., Int. Ed. 2007, 46, 1881–1884. (c) Liu, K. G.; Robichaud,
A. J.; Lo, J. R.; Mattes, J. F.; Cai, Y. Org. Lett. 2006, 8, 5769–5771. (d)
Barluenga, J.; Jime´nez-Aquino, A.; Aznar, F.; Valde´s, C. J. Am. Chem.
Soc. 2009, 131, 4031–4041. (e) Cui, S.-L.; Wang, J.; Wang, Y.-G. J. Am.
Chem. Soc. 2008, 130, 13526–13527.
(1) For recent reviews on biological activities and synthesis of indoles,
see: (a) Kawasaki, T.; Higuchi, K. Nat. Prod. Rep. 2007, 24, 843–868. (b)
Brancale, A.; Silvestri, R. Med. Res. ReV. 2007, 27, 209–238. (c) Humphrey,
G. R.; Kuethe, J. T. Chem. ReV. 2006, 106, 2875–2911. (d) Sundberg, R. J.
Indoles; Academic Press: London, 1996.
(4) (a) Roy, P. J.; Dufresne, C.; Lachance, N.; Leclerc, J.-P.; Boisvert,
M.; Wang, Z.; Leblanc, Y. Synthesis 2005, 2751–2757. (b) Wang, T.; Yin,
Z.; Zhong, Z.; Bender, J. A.; Yang, Z.; Johnson, G.; Yang, Z.; Zadjura,
L. M.; D’Arienzo, C. J.; Parker, D. D.; Gesenberg, C.; Yamanaka, G. A.;
Gong, Y.-F.; Ho, H.-T.; Fang, H.; Zhou, N.; McAuliffe, B. V.; Eggers,
B. J.; Fan, L.; Nowicka-Sans, B.; Dicker, I. B.; Gao, Q.; Colonno, R. J.;
Lin, P.-F.; Meanwell, N. A.; Kadow, J. F. J. Med. Chem. 2009, 52, 7778–
7787.
(2) (a) Hsieh, T. H.; Dong, V. M. Tetrahedron 2009, 65, 3062–3068.
(b) Li, J.-J.; Mei, T.-S.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47, 6452–
6455. (c) Stokes, B. J.; Dong, H.; Leslie, B. E.; Pumphrey, A. L.; Driver,
T. G. J. Am. Chem. Soc. 2007, 129, 7500–7501. (d) Du, Y.; Liu, R.; Linn,
G.; Zhao, K. Org. Lett. 2006, 8, 5919–5922. (e) Carpenter, J. F. J. Org.
Chem. 1993, 58, 1607–1609. (f) Tan, Y.; Hartwig, J. F. J. Am. Chem. Soc.
2010, 132, 3676–3677.
10.1021/ol101130e  2010 American Chemical Society
Published on Web 08/03/2010

aldehydes.5c Thermal rearrangement of 2-aryl-2H-azirines
via vinyl nitrene intermediates6a provides an efficient route
to indoles, although it remains in scattered use in indole
syntheses (Scheme 1).6 This rearrangement could be cata-
general method for the synthesis of 2,3-disubstituted indoles
and azaindole via ring opening of 2H-azirines catalyzed by
inexpensive FeCl2, offering a solution to the unmet needs in
indole synthesis mentioned above and probes toward the
mechanism.
2H-Azirines can be readily prepared from ketones using
modified Neber rearrangement processes via hydrazones in three
steps developed by Padwa7b,10 or oximes in two steps
developed by Taber6b (Scheme 2). Azirine 1a6b,7 was chosen
Scheme 1. Rearrangement of 2H-Azirines to Indoles
Scheme 2.
Synthesis of 2H-Azirinesa
a Y ) CH: (a) NH2NMe2, NaOAc, AcOH; (b) MeI; (c) NaH. Y ) N:
(a) NH2OH·HCl, NaOAc; (b) MsCl, Et3N; (c) DBU (one pot).
as the model substrate to study the rearrangement of 2-aryl-
2H-azirines to indoles. Among the catalysts screened, FeCl2
was found to be particularly effective to catalyze the
rearrangement (Table 1). With 5 mol % FeCl2 in THF at rt,
lyzed by Pd(PhCN)2Cl27a or Rh2[OC(O)CF3]4.7b The catalytic
variant of the rearrangement has also received little attention
from the chemistry community and only two reports have
been published to date.7 Although a vinyl nitrene metal
complex was speculated to be involved in one of the
catalyzed rearrangements, no mechanistic studies were
performed.7b Only one example of azaindoles prepared by
the thermal rearrangement has been reported,4a while the
catalyzed process has not been applied to azaindole synthesis.
Since a wide variety of 2H-azirines have been reported in
the literature,8 they could be potentially a much better vinyl
nitrene precursor than the vinyl azides. We also sought
alternative catalysts that could intercept the vinyl nitrene
intermediates. Iron stands out among commonly used metals
because it is far cheaper than Pd or Rh, abundant, and
generally nontoxic. FeCl2 has been reported to catalyze
cleavage of azirines to form N-N bonds9a,b or open azirine
rings as a stoichiometric one-electron donor.9c To the best
of our knowledge, the rearrangement of azirines to indoles
is not known to be catalyzed by FeCl2. Herein we report a
Table 1. Optimization of Catalytic Conditions
entry
catalyst (mol %)
temp (°C), time
2a, yield (%)
1
2
3
4
5
6
7
8
FeCl2 (5)
FeCl2 (5)
none
FeBr2 (5)
FeI2 (5)
Fe(OAc)2 (5)
FeCl3 (5)
CuCl (5)
CuCl2 (5)
AlCl3 (100)
BF3·Et2O (100)
HCl/Et2O (100)
rt, 12 h
70, 24 h
70, 24 h
rt, 12 h
rt, 12 h
rt, 12 h
rt, 12 h
rt, 12 h
rt, 12 h
70, 24 h
70, 24 h
70, 24 h
75a
77a
0
69a
60a
0
0
27b c
,
traceb d
,
9
10
11
12
0d
0d
0d
a Yield after chromatography. b NMR yield using hexamethyl benzene
as an internal standard. c 1a (40%) was recovered. d None of 1a was
recovered.
(5) (a) So¨derberg, B. C. G. Curr. Org. Chem. 2004, 6, 743–746. (b)
L’abbe´, G. Angew. Chem., Int. Ed. 1975, 14, 775–782. (c) Henn, L.; Hickey,
D. M. B.; Moody, C. J.; Rees, C. W. J. Chem. Soc., Perkin Trans. 1 1984,
2189–2196.
(6) (a) Isomura, K.; Ayabe, G.-I.; Hatano, S.; Taniguchi, H. J. Chem.
Soc., Chem. Commun. 1980, 1252–1253. (b) Taber, D. F.; Tian, W. J. Am.
Chem. Soc. 2006, 128, 1058–1059. (c) Isomura, K.; Kobayashi, S.;
Taniguchi, H. Tetrahedron Lett. 1968, 9, 3499–3502. (d) Padwa, A.; Carlsen,
P. H. J. J. Org. Chem. 1978, 43, 2029–2037. (e) Li, X.; Du, Y.; Liang, Z.;
Li, X.; Pan, Y.; Zhao, K. Org. Lett. 2009, 11, 2643–2646.
(7) (a) Isomura, K.; Uto, K.; Taniguchi, H. J. Chem. Soc., Chem.
Commun. 1977, 664–665. (b) Chiba, S.; Hattoti, G.; Narasaka, K. Chem.
Lett. 2007, 36, 52–53.
the rearrangement was complete after 12 h to provide indole
2a in 75% yield (entry 1). The rearrangement was cleaner at
(9) (a) Stevens, K. L.; Jung, D. K.; Alberti, M. J.; Badiang, J. G.;
Peckham, G. E.; Veal, J. M.; Cheung, M.; Harris, P. A.; Chamberlain, S. D.;
Peel, M. R. Org. Lett. 2005, 7, 4753–4756. (b) Fitzgerald, R. N.; Jung,
D. K.; Eaddy, J. F. PCT Int. Appl. WO0183479A2, 2001. (c) Auricchio, S.;
Grassi, S.; Malpezzi, L.; Sartori, A. S.; Truscello, A. M. Eur. J. Org Chem.
(8) (a) Palac`ıos, F.; de Retana, A. M. O.; de Marigorta, E. M.; de los
Santos, J. M. Org. Prep. Proced. Int. 2002, 34, 219–269. (b) Palac`ıos, F.;
de Retana, A. M. O.; de Marigorta, E. M.; de los Santos, J. M. Eur. J. Org.
Chem. 2001, 2001, 2401–2414.
2001, 2001, 1183–1187
(10) Padwa, A.; Rosenthal, R. J.; Dent, W.; Filho, P.; Turro, N. J.;
Hrovat, D. A.; Gould, I. R. J. Org. Chem. 1984, 49, 3174–3180
.
.
Org. Lett., Vol. 12, No. 17, 2010
3737

optimized condition (5 mol % of FeCl2, 70 °C, 24 h in THF).
As shown in Scheme 3, functional groups are generally well
tolerated, as a variety of groups such as amides, aryl,
cyclopropyl, CF3, halides, OTBS, and OPiv can be incor-
porated into the indoles. Particularly, the method tolerates
substitution on the aromatic ring undergoing functionalization
and substituents with a wide range of electronic properties
from electron-donating (OMe) to electron-withdrawing groups
(NO2) can be accommodated. The rearrangement is also quite
tolerant of the C2 and C3 substituents of 2H-azirine 1 as
aryl and alkyl groups with various steric sizes are generally
compatible. In the cases where two regioisomeric products
could be obtained, cyclization onto more electron-rich
aromatic rings is generally favored. Modest to excellent
regioselectivities were observed depending on the substituent.
It is worth noting that thermal rearrangement of 1h provided
indole 2h with modest selectivity (3.4:1),6b whereas this
method provided 2h as the only product. The method also
proves particularly effective for preparing electron-rich
indoles. The low yields of 2g and 2j were due to their
isolation, since they were notoriously prone to air oxidation.
The method can be also extended to synthesize 6-azaindoles,
but a higher catalyst loading (50 mol %) was required to
obtain an acceptable yield of 2n.11 The method has one
limitation about its substrate scope: the C2 carbon of 1a-n
needs to be disubstituted (R′ * H), and R′ can be alkyl,
cyclopropyl, aryl, or amide groups.
Scheme 3. Substrate Scopea b
,
Scheme 4 shows our proposed catalytic cycle: initial
coordination of Fe(II) to the imine nitrogen atom of 2H-
azirine 1 would form iron azirine complex 6; subsequent
Scheme 4. Proposed Catalytic Cycle
a Isolated yield. b Yields in parentheses refer to overall yields from the
corresponding ketones. The synthesis of 2H-azirines was not optimized.
c Two steps (a 2:1 mixture of two isomers). Indole 2g was reduced to 2g′
by NaBH3(CN). d 2i:2i′ ) 1:1.8. e Two steps. Indole 2j was oxidized to 2j′
by O2. f 50 mol % FeCl2. g NaHMDS then ClCO2Et.
70 °C (entry 2). In the absence of FeCl2, no indole (2a) was
formed, and azirine 1a was completely recovered (entry 3).
Other Fe(II) halide salts such as Br and I also catalyzed the
reaction, although they were not as effective as FeCl2 (Entries
4 and 5). Fe(OAc)2 and FeCl3 show no catalytic activity (entries
6 and 7). CuCl was only moderately effective for catalyzing
the rearrangement, and CuCl2 led to a mixture of unidentified
products with a trace amount of indole 2a (entries 8 and 9).
Treatment of 1a with common Lewis acids (AlCl3 and
BF3·Et2O) or Brønsted acids (HCl) led to complete conversion
to unidentified products (entries 10-12). The rearrangement
was very sensitive to the solvent used. Among the solvents
screened at rt (THF, DME, CH2Cl2, 1,2-dichloroethane, and
toluene), the rearrangement occurred in only THF. At 70 °C,
in addition to THF, 1,2-dichloroethane was also suitable yet
less effective (see Supporting Information).
cleavage of the C-N bond would provide iron vinyl nitrene
complex 7; and finally, indole 2 could be formed by a five-
centered 6-π electrocyclization12 of 7 via intermediate 8.
We think that the rearrangement likely involves an iron
nitrene complex such as 7. This hypothesis was consistent with
(11) Compound 2n was converted to 2n′ because we were unable to
purify 2n to the degree required for publication.
(12) Davies, I. W.; Guner, V. A.; Houk, K. N. Org. Lett. 2004, 6, 743–
746.
With these screening results in hand, we sought to examine
the scope and the generality of the method under the
3738
Org. Lett., Vol. 12, No. 17, 2010

the following observations. FeCl2 was unique and effective for
the rearrangement, whereas other salts such as FeCl3 and
common Lewis and Brønsted acids were completely ineffective.
Pyridines that are generally inert in electrophilic substitution
reactions participated in the rearrangement. Other potential
pathways such as opening of the azirine ring via a radical
pathway9c were ruled out on the basis of the formation of indole
2g with the cyclopropyl group intact. Submission of penta-
deuterated substrate 1o to the optimized condition revealed a
kinetic isotope effect of 1.3 (eq 1). The magnitude of the kinetic
isotope effect is more consistent with the 6-π electrocyclization
where the C-H bond breaking event is not the rate-determining
step.2c,6b
In conclusion, we have developed a catalytic and general
method for the synthesis of 2,3-disubstituted indoles whose
syntheses still lack a general solution. The method employing
inexpensive and nontoxic FeCl2 has a broader substrate scope
than the similar processes catalyzed by Pd(PhCN)2Cl2 or
Rh2[OC(O)CF3]4.
Acknowledgment. We thank the University of Arkansas,
the Arkansas Bioscience Institute, and the NIH NCRR
COBRE grant (P20 RR15569) for generous support of this
research. Core facilities were funded by the NIH NCRR
COBRE grant (P20 RR15569) and the Arkansas Bioscience
Institute.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL101130E
Org. Lett., Vol. 12, No. 17, 2010
3739