Exploiting the chemistry of strained rings: Synthesis of indoles via domino reaction of aryl iodides with 2 H-azirines

Article abstract of DOI:10.1021/ol100975b

(Equation Presented). The highly strained 2H-azirine ring system has been the source of considerable theoretical and synthetic work. The reaction of these strained heterocycles with transition metals has been documented to give rise to ring opening and subsequent formation of varied heterocycles. An interesting domino reaction is described wherein the strained bicyclic alkene, norbornene, mediates the reaction of 2H-azirines with aryl iodides under palladium catalysis to provide indole or polycyclic dihydroimidazole heterocycles.

Full text of DOI:10.1021/ol100975b

ORGANIC
LETTERS
2010
Vol. 12, No. 15
3312-3315
Exploiting the Chemistry of Strained
Rings: Synthesis of Indoles via Domino
Reaction of Aryl Iodides with
2H-Azirines
David A. Candito and Mark Lautens*
Department of Chemistry, UniVersity of Toronto, 80 St. George Street, Toronto,
Ontario M5S 3H6, Canada
mlautens@chem.utoronto.ca
Received May 14, 2010
ABSTRACT
The highly strained 2H-azirine ring system has been the source of considerable theoretical and synthetic work. The reaction of these strained
heterocycles with transition metals has been documented to give rise to ring opening and subsequent formation of varied heterocycles. An
interesting domino reaction is described wherein the strained bicyclic alkene, norbornene, mediates the reaction of 2H-azirines with aryl
iodides under palladium catalysis to provide indole or polycyclic dihydroimidazole heterocycles.
There is often spectacular and unexpected reactivity that
results from the drive to alleviate strain in an organic
molecule. A major area of focus in our group has been the
investigation of a palladium-catalyzed domino reaction of
aryl electrophiles in which the strained bicyclic alkene,
norbornene (∼20 kcal/mol),1a mediates a C-H activation
event (Catellani reaction).2 The correct sequence of events
is of central importance in this domino reaction, and it is
the fast and reversible carbopalladation of norbornene that
allows for timely bond formation. Recently we disclosed a
very efficient process for the formation of the phenanthridine
nucleus via a sequence of direct arylation followed by
N-arylation.3 We envisioned that the same strategy could
be applied to the synthesis of indoles by alteration of the
imine coupling partner.
Initial studies focused on the reaction of aryl iodides and
R-haloimines. It was hypothesized that C-alkylation would
occur followed by N-arylation and subsequent tautomeriza-
tion to give the indole. To evaluate this hypothesis, io-
(1) (a) Khoury, P. R.; Goddard, J. D.; Tam, W. Tetrahedron 2004, 60,
8103. (b) Calvo-Losada, S.; Quirante, J. J.; Sua´rez, D.; Sordo, T. L.
J. Comput. Chem. 1998, 19, 912.
(2) Reviews: (a) Chiusoli, G. P.; Catellani, M.; Costa, M.; Motti, E.;
Della Ca’, N.; Maestri, G. Coord. Chem. ReV. 2010, 254, 456. (b) Lautens,
M.; Alberico, D.; Bressy, C.; Fang, Y.-Q.; Mariampillai, B.; Wilhelm, T.
Pure Appl. Chem. 2006, 78, 351.
(3) Candito, D. A.; Lautens, M. Angew. Chem., Int. Ed. 2009, 48, 6713.
10.1021/ol100975b  2010 American Chemical Society
Published on Web 07/02/2010

Table 1. Optimizationa
entry
2 (equiv)
L
norbornene (equiv)
concn (M)b
yield (%)c
ratio 3a:4ac
1
2
3
4
5
6
7
2
1
1
2
2
2
2
2
1
1
1
1
1
2
4
4
4
P(C6H5)3
P(C6H5)3
P(C6H5)3
P(o-Me-C6H4)3
P(p-F-C6H4)3
P(C6F5)3
P(o-CF3-C6H4)3
P(m-Cl-C6H4)3
P(m-Cl-C6H4)3
P(m-Cl-C6H4)3
P(m-Cl-C6H4)3
P(m-Cl-C6H4)3
P(m-Cl-C6H4)3
P(m-Cl-C6H4)3
P(m-Cl-C6H4)3
P(m-Cl-C6H4)3
P(m-Cl-C6H4)3
8
8
8
8
8
8
8
8
8
4
2
1
2
8
8
8
8
0.05
0.025
0.0125
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.10
0.20
66d
36
18
e
62
e
0.7:1
0.7:1
3.4:1
0.7:1
e
8
71
74
83
95d
84
90
95
99
84i
0.7:1
>20:1
>20:1
>20:1
>20:1
10:1
1:2.5
1:5
<1:5
9f
10f
11f
12f
13g
14h
15h
16h
17h
86d i
<1:5
,
a Reaction conditions: reactions run in sealed tube on 0.2 mmol scale with respect to iodonaphthalene, unless otherwise noted. b Final total concentration
based on iodonaphthalene. c Determined by HPLC. d Isolated yield. e Aryl iodide recovered. f Slow addition of solution of 2a in MeCN (rate ) 0.26 mL/h,
0.1 M in azirine) to refluxing reaction mixture. g Slow addition of solution of 2a in MeCN (rate ) 1.4 mL/h, 0.1 M in azirine) to refluxing reaction mixture.
h 45 mol % of ligand used. i Yield of 4a.
donaphthalene was reacted with a haloimine under previously
developed conditions.3 The desired product was obtained in
57% yield (eq 1). As the investigation progressed it became
evident that the synthesis of the requisite R-haloimines was
low-yielding and often accompanied by decomposition of
the imine, limiting this approach.
go on to furnish the desired indole.5 To evaluate this
hypothesis, iodonaphthalene was reacted with azirine 2a
(Table 1, entry 1). The desired indole 3a was observed in
31% yield along with 35% of the unusual tetracyclic
dihydroimidazole 4a. The remainder of the mass balance was
undefined byproducts and dimerized azirine.
Although the transition-metal-catalyzed intramolecular
reaction of 2H-azirines to form indoles has been known for
many years, the involvement of 2H-azirines in domino
processes and their reactions with aryl palladium intermedi-
ates are, to our knowledge, unprecedented.5
An optimization of the reaction conditions was undertaken
using 2a and iodonaphthalene as a model system (Table 1).
Attempts to reduce the amount of product 4a by decreasing
the total concentration of the reaction mixture were ineffec-
tive and led to a decrease in overall yield and only a modest
shift in the product ratio (entries 1-3). Starting material was
recovered when electron-deficient phosphines or phosphines
Conceptually, a 1,3-dipole is required to carry out the
intended transformation. The ring cleavage reactions of
highly strained 2H-azirines (44-48 kcal/mol of strain for
the parent azirine)1b under thermal, photochemical, and
transition metal catalysis has been well documented, and
varied heterocyclic structures are the outcome of such
reactions.4 Pioneering work carried out by the groups of
Hassner, Padwa, Alper, and others on the photochemical and
transition-metal-catalyzed reactions of azirines suggested that
cleavage of the azirine ring system under our reaction
conditions would generate a 1,3-dipole equivalent that could
(5) (a) Padwa, A.; Stengel, T. Tetrahedron Lett. 2004, 45, 5991. (b)
Alper, H.; Mahatantila, C. P. Heterocycles 1983, 20, 2025. (c) Izumi, T.;
Alper, H. Organometallics 1982, 1, 322. (d) Alper, H.; Perera, C. P.
Organometallics 1982, 1, 70. (e) Alper, H.; Perera, C. P.; Ahmed, F. R.
J. Am. Chem. Soc. 1981, 103, 1289. (f) Sakakibara, T.; Alper, T. J. Chem.
Soc., Chem. Commun. 1979, 458. (g) Hassner, A.; Fowler, F. W. J. Am.
Chem. Soc. 1968, 90, 2869. (h) Alper, H.; Wollowitz, S. J. Am. Chem.
Soc. 1975, 97, 3541. (i) Isomura, K.; Uto, K.; Taniguchi, H. J. Chem. Soc.,
Chem. Commun. 1977, 664. (j) Hassner, A.; Bunnell, C. A.; Haltiwanger,
K. J. J. Org. Chem. 1978, 43, 57. (k) dos Santos Filho, P. F.; Schuchardt,
U. J. Organomet. Chem. 1984, 263, 385. (l) Inada, A.; Heimgartner, H.
HelV. Chim. Acta 1982, 65, 1489. (m) Leonard, N. J.; Zwanenburg, B. J. Am.
Chem. Soc. 1967, 89, 4456.
(4) Reviews: (a) Palacios, F.; de Retana, A. M. O.; de Marigorta, E. M.;
de los Santos, J. M. Org. Prep. Proced. Int. 2002, 34, 219. (b) Palacios, F.;
de Retana, A. M. O.; de Marigorta, E. M.; de los Santos, J. M. Eur. J. Org.
Chem. 2001, 2401.
Org. Lett., Vol. 12, No. 15, 2010
3313

Table 2. Scope of Indole Formationa
aryl iodide
R3
azirine
R
entry
1
R2
R4
2
R1
3
yield (%)b
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1c
1d
1f
1g
1h
1a
1a
1a
1a
1a
2a
2b
2c
2d
2e
2f
2a
2a
2a
2a
2a
2a
2g
2h
2i
Ph
4-F-C6H4
4-Cl-C6H4
4-MeO-C6H4
2-MeO-C6H4
2,5-Me2-C6H3
H
H
H
H
H
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
95
95
86
86
67
60
54
55
64
64
55
68
c
MeO
Me
Cl
Me
Me
Me
H
H
H
CF3
F
H
H
H
H
H
9
10
11
12
13
14
15
16
17
3j
3k
3l
H
NHAc
Ph
Ph
Bn
CO2Bn
CONMe2
Me
CO2Me
H
H
H
c
c
c
c
2j
2k
a Reaction conditions: aryl iodide (0.2 mmol, 1.0 equiv), Pd(OAc)2 (10 mol %), P(m-Cl-C6H4)3 (25 mol %), Cs2CO3 (3 equiv), and norbornene (2 equiv)
were heated to reflux (oil bath temperature ) 110 °C) in MeCN (2 mL). The azirine (1.0 equiv, 0.1 M in MeCN) was added slowly via syringe pump (rate
) 0.26 mL/h). b Isolated yields. c Aryl iodide recovered and azirine was consumed.
with ortho substituents were employed (entries 4-7). It was
found that P(m-Cl-C6H4)3 possessed the best combination
of steric and electronic properties, and the optimization was
continued using this ligand (entry 8). Slow addition of 2a
over 8 h effectively eliminated the formation of 4a (entry
9). The crude reaction mixture revealed that byproducts
resulting from the incorporation of norbornene accompanied
3a, and reduction in the amount of norbornene led to a
decrease in their formation and a corresponding increase in
the yield of 3a (entries 9-12). Ultimately, 3a could be
obtained in 95% isolated yield without the formation of 4a.
With conditions in hand to obtain the indole product in
good yield and selectivity, an investigation into the scope
was undertaken (Table 2). Various 2H-azirines could be
prepared in a straightforward manner via thermolysis of the
corresponding vinyl azides or oxidation of the corresponding
aziridine.6 Alkyl- and aryl-substituted azirines can be isolated
and stored; however, 3-carbonyl-substituted azirines are
unstable and in these cases the vinyl azides were pyrolyzed
and the crude azirines (g95% by NMR) were utilized
immediately.6 Substitution of the aryl ring of the azirine
proved to be tolerated, as electron-donating and -withdrawing
groups appeared to have little impact on the yields (entries
1-4). Furthermore, azirines with groups at the ortho position
of the aryl ring were tolerated, although a decrease in yield
was observed (entries 5 and 6). Variation of the aryl iodide
was also possible; however, the yields were reduced when
compared with the model system (entries 7-12). The yields
reported were not optimized on a case by case basis, and
despite this the developed reaction conditions were able to
provide synthetically useful yields of the indoles. This
method is suited to the rapid synthesis of a library of
compounds where the aryl iodide can be readily varied. There
are a number of cases in which the azirines failed to provide
the desired indole products under the reaction conditions
(entries 13-17). When a substituent is placed on the
2-position or when an alkyl or carbonyl group is placed at
the 3-position of the azirine ring system, the starting azirine
was completely consumed while the aryl iodide could be
recovered (entries 13-17). Further, studies are required to
determine the reason why these azirines did not undergo the
desired reaction.
We have also identified conditions for the selective
formation of 4a (the structure of 4a was confirmed by X-ray
crystallography, see Supporting Information). As anticipated,
the yield of 4a increased with increasing the amount of 2a
present in the reaction mixture and by increasing the total
concentration (Table 1, entries 14-17). It was also found
(6) (a) Gentilucci, L.; Grijzen, Y.; Thijs, L.; Zwanenburg, B. Tetrahedron
Lett. 1995, 36, 4665. (b) Padwa, A.; Carlsen, P. H. J. J. Am. Chem. Soc.
1977, 99, 1514. (c) Gilchrist, T. L.; Mendonc¸a, R. ARKIVOC 2000, 1, 769.
(d) Time´n, Å. S.; Risberg, E.; Somfai, P. Tetrahedron Lett. 2003, 44, 5339.
(e) Fowler, F. W.; Hassner, A.; Levy, L. A. J. Am. Chem. Soc. 1967, 89,
2077. (f) Hortmann, A. G.; Robertson, D. A.; Gillard, B. K. J. Org. Chem.
1972, 37, 322.
3314
Org. Lett., Vol. 12, No. 15, 2010

Table 3. Scope of Dihydroimidazole Formationa
Scheme 1. Proposed Mechanism of Indole Formation
2
4
yield (%)b
1
2
3
2a
2b
2d
4a
4b
4c
86
63
41
a Reaction conditions: aryl iodide (0.2 mmol, 1.0 equiv), azirine (4
equiv), Pd(OAc)2 (10 mol %), P(m-Cl-C6H4)3 (45 mol %), Cs2CO3 (3.0
equiv), and norbornene (8 equiv) in MeCN (0.2 M) were heated in a sealed
tube at 90 °C for 16-24 h. b Yield of isolated products
that increasing the amount of ligand present in the reaction
mixture favored the formation of 4a.
A few interesting polycyclic dihydroimidazoles could be
formed selectively and efficiently (Table 3). It appears that
the efficiency of the reaction to form products of type 4 is
more sensistive to the electronic nature of the aryl susbtituent
on the 2H-azirine than observed for the formation of indoles
3. In these cases it is difficult to completely preclude the
formation of the indole product under the reaction conditions,
and the crude reaction mixtures contain small amounts of
the indole (∼10% by NMR); however, careful chromatog-
raphy is capable of removing the indole product.
The transformation requires that norbornene be present in
the reaction mixture as in its absence the starting aryl iodide
is recovered and the azirine is consumed, forming dimeric
products. It is anticipated that this process follows a similar
catalytic cycle to that of other norbornene mediated C-H
functionalizations (Scheme 1).7 Oxidative addition of the aryl
iodide, carbopalladation of norbornene, and electrophilic
metalation followed by deprotonation can yield palladacyclic
intermediate I. Complexes of azirines and palladium(II) are
well-known and have been demonstrated to coordinate to
the metal center through the nitrogen lone pair.5j,k Binding
of the 2H-azirine is expected to yield complex II (L is taken
to be any suitable ligand in the reaction mixture), and in
doing so the bonds of the ligand are weakened, ultimately
leading to fission of the N-C single bond via oxidative
addition. The fission of the N-C single bond is commonly
observed in the reactions of azirines with transition
metals.5c,e,h-l The complex resulting from metal-mediated
ring opening of the azirine ligand can be formulated as
complex III (other conformations of these representations
cannot be excluded, and the ones depicted may not be the
lowest in energy).5e,h,k Chemoselective C-C bond formation
is expected to yield IV initially, which can subsequently
decarbopalladate to give intermediate V. Reductive elimina-
tion from V can provide VI, which tautomerizes to give the
indole product (tautomerization of intermediates at an earlier
stage of the catalytic cycle is also possible). The dihydroimi-
dazoles 4 can be derived from a palladium(0)-catalyzed
formal [3 + 2] reaction of an azirine with the C-N double
bond of intermediate VI. Efforts toward mechanistic inves-
tigations are currently in progress.
In conclusion, we have described the first intermolecular
reaction of aryl palladium intermediates with 2H-azirines to
furnish indoles and polycyclic dihydroimidazoles. It is
interesting to note that in this reaction the strain energy in
two small molecules is exploited to bring about a complex
transformation. Further work in this area will focus on
gaining insight into the mechanism and other synthetic
applications of azirines when under the influence of transition
metal catalysis.
Acknowledgment. We thank NSERC (Canada), Merck-
Frosst (IRC), and the University of Toronto for support of
these studies.
Supporting Information Available: Experimental pro-
cedures and full characterization for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(7) (a) Catellani, M.; Fagnola, M. C. Angew. Chem., Int. Ed. 1994, 33,
2421. (b) Catellani, M. Synlett 2003, 298. (c) Motti, E.; Ippomei, G.;
Deledda, S.; Catellani, M. Synthesis 2003, 2671. (d) Faccini, F.; Motti, E.;
Catellani, M. J. Am. Chem. Soc. 2004, 126, 78.
OL100975B
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3315