Synthesis of N-fused tricyclic indoles by a tandem [1,2] stevens-type rearrangement/1,2-alkyl migration of metal-containing ammonium ylides

Article abstract of DOI:10.1002/anie.200705517

(Chemical Equation Presented) An alkyne moiety is activated efficiently with a [W(CO)₆] or [ReBr(CO)₅] catalyst in the presence of an amine functionality in the title reaction of N-(2-alkynylphenyl)-amines. The resulting ammonium ylides undergo rearrangement to form a variety of N-fused polycyclic indole derivatives (see scheme; n = 1,2; R = alkyl, Ph).

Full text of DOI:10.1002/anie.200705517

Communications
DOI: 10.1002/anie.200705517
Heterocycle Synthesis
Synthesis of N-Fused Tricyclic Indoles by a Tandem [1,2] Stevens-Type
Rearrangement/1,2-Alkyl Migration of Metal-Containing Ammonium
Ylides**
Jun Takaya, Shuji Udagawa, Hiroyuki Kusama, and Nobuharu Iwasawa*
We reported previously that novel metal-containing carbonyl
or azomethine ylides could be generated by the nucleophilic
attack of a carbonyl oxygen atom or imino nitrogen atom onto
alkynes activated by electrophilic transition-metal complexes.
The resulting species, which behave as both ylides ([3+2]
À
cycloaddition) and carbene complexes (e.g. C H insertion,
1,2-H or 1,2-alkyl shift), can be used as intermediates for the
efficient preparation of synthetically useful, polycyclic com-
pounds.[1] To expand the concept of metal-containing ylides,
we have examined the generation and reaction of a newly
designed metal-containing ammonium ylide,[2] which would
enable concise access to a variety of polycyclic indoles with an
N-fused ring. A recent report by Zhang and co-workers on a
Scheme 1. Strategy for the generation of a metal-containing ammoni-
um ylide and its tandem [1,2] Stevens-type rearrangement/1,2-alkyl
Pt-catalyzed reaction of N-(2-alkynylphenyl)lactams[3]
migration.
prompted us to report our own approach, in which the main
difference is the use of N-(2-alkynylphenyl)amines instead of
lactams as the nucleophilic component. This transformation
requires the use of [W(CO)6] or [ReBr(CO)5] as the
alkynophilic reagent.
(Table 1, entry 1). Photoirradiation was crucial for the
efficient generation of the unsaturated tungsten species; the
reaction under thermal conditions (toluene, 808C) resulted in
lower conversion even with 300 mol% of [W(CO)6] (Table 1,
entry 2).
The underlying strategy for the catalytic process described
herein is depicted in Scheme 1: Upon the treatment of
o-alkynylphenyl pyrrolidine or piperidine derivatives 1 with
an appropriate electrophilic transition-metal complex, metal-
containing ammonium ylides A would be generated by the
nucleophilic attack of the nitrogen atom onto the electro-
philically activated alkyne moiety. Ylides A would then
undergo ring expansion through a [1,2] Stevens-type rear-
rangement[4] to give carbene complexes B, which would
undergo subsequent 1,2-alkyl migration to form N-fused
tricyclic indole derivatives 2 with regeneration of the catalyst.
After extensive screening of transition-metal catalysts and
reaction conditions with N-(2-(prop-1-ynyl)phenyl)pyrroli-
dine (1a) as the substrate, we found that the photoirradiation
of a solution of 1a and [W(CO)6] (10 mol%) in toluene in the
presence of 5-Š molecular sieves at room temperature gave
the desired tricyclic indole derivative 2a in 65% yield
Table 1: Examination of various electrophilic transition-metal complexes
as catalysts (1a: n=1,R =Me).
Entry
Catalyst (mol%)
Conditions[a]
Yield of 2a [%][b]
1
2
3
4
5
6
7
8
[W(CO)6] (10)
[W(CO)6] (300)
[ReBr(CO)5] (10)
PtCl2 (10)
[AuPPh3](SbF6) (10)
AuBr3 (10)
A
B
A
65
14
9
n.d.
n.d.
n.d.
n.d.
n.d.
A or B
A or B
B
[{IrCl(cod)}2] (5)
PtCl4 (10)
B
B or C
[a] A: 5-Š M.S., hn,toluene,room temperature,10 h; B: 5-Š M.S.,
toluene,80 8C,10 h; C: ClCH 2CH2Cl,reflux under O 2,10 h. [b] n.d. =not
detected. cod=1,5-cyclooctadiene, M.S.=molecular sieves.
[*] Dr. J. Takaya,S. Udagawa,Dr. H. Kusama,Prof. Dr. N. Iwasawa
Department of Chemistry
Careful analysis of the product by 2D NMR spectroscopy
confirmed the formation of a tricyclic indole system with an
N-fused six-membered ring and a methyl substituent at the
3position of the indole nucleus. This result supported the
validity of our original strategy.[5,6] Other metal catalysts, such
as PtCl2, PtCl4, [AuPPh3]SbF6, AuBr3, and [{IrCl(cod)}2], were
found to be inactive for this transformation under thermal or
photoirradiation conditions, probably as a result of deactiva-
tion of the catalyst through strong coordination of the amine
Tokyo Institute of Technology
O-okayama,Meguro-ku,Tokyo 152-8551 (Japan)
Fax: (+81)3-5734-2931
E-mail: niwasawa@chem.titech.ac.jp
[**] This research was partly supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education,Culture,Sports,Science,
and Technology of Japan.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200705517.
4906
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Table 3: Generality of the reaction (n=1).[a]
nitrogen atom to the metal center.[7] In contrast, [W(CO)6],
which has a lower affinity for harder bases, such as an amine
nitrogen atom, activates the alkyne preferentially and effec-
tively. [ReBr(CO)5] also showed some activity under photo-
irradiation conditions to give a small amount of the product
2a (Table 1, entry 3).
Entry
Substrate
Product
t [h]
Yield [%]
45
1
10
The facile introduction of substituents of various types at
the 3-position of the indole nucleus by incorporating these
substituents into the substrate at the alkyne terminus is a
valuable feature of this reaction. Tricyclic indole derivatives
functionalized with silyl or benzyl ethers were prepared
successfully in good yield (Table 2, entries 2 and 3). Further-
more, the reaction of 1e (n = 1, R = Ph), in which an aromatic
sp2-hybridized carbon atom is bonded to the alkyne terminus,
also proceeded smoothly to give the product 2e of 1,2-phenyl
migration in good yield. As the substrates can be prepared
readily by coupling reactions, and as the reaction proceeds
catalytically under mild reaction conditions, the present
protocol provides a useful method for the construction of
variously functionalized N-fused tricyclic indole skele-
tons.[8,9,10]
2
5
80[b]
3
4
5
4
4
70
68
10
52 (63[b])
Table 2: Variation of the alkyne substituent (n=1).[a]
Entry
R
Yield [%]
[a] Reaction conditions: [W(CO)6] (10 mol%),5-Š M.S.,toluene, hn,
room temperature. [b] 1 equivalent [W(CO)6].
1
2
nPr (2b)
62
74
65
65
CH2CH2OTIPS (2c)
CH2CH2OBn (2d)
Ph (2e)
3
4[b]
Table 4: Generality of the reaction (n=2).[a]
[a] Reaction conditions: [W(CO)6] (10 mol%),5-Š M.S.,toluene, hn,
room temperature,10 h. [b] 30 mol% [W(CO) 6]. Bn=benzyl; TIPS=
triisopropylsilyl.
Entry
Substrate
Product
t [h] Yield [%]
1
10
4
73
63
Table 3shows the generality of this tandem [1,2] Stevens-
type rearrangement/1,2-alkyl migration reaction of pyrroli-
dine derivatives. Other 5-membered azacycles, such as indo-
line and isoindoline derivatives, are suitable for this trans-
formation; thus, substrates 3 and 5 were converted into the
tetracyclic indole derivatives 4 and 6, respectively, in good
yield (Table 3, entries 1 and 2). The ring expansion of the
tungsten-containing ammonium ylide generated from 3
proceeded regioselectively at the sp3 carbon atom adjacent
to the N atom. The presence of an electron-donating or
electron-withdrawing group on the benzene ring did not
affect the reaction significantly (Table 3, entries 3–5).
2
3
10
74
In contrast to the reaction of pyrrolidine derivatives, the
reaction of the piperidine derivative 13 did not proceed
smoothly even with an increased loading of [W(CO)6].[11]
Reexamination of the metal catalyst revealed that
[ReBr(CO)5] was highly effective for the reaction of 13, in
remarkable contrast to that of the pyrrolidine derivative 1a,
and afforded the desired ring-expansion product 14 in good
yield (Table 4, entry 1).[12] The [ReBr(CO)5]-catalyzed reac-
tion of the silyl ether derivative 15 was also successful.
Furthermore, the Re catalyst system was effective for a
variety of 6-membered azacycles, such as the 4-phenylpiper-
idine and morpholine derivatives 17 and 19, which were
converted into the corresponding tricyclic indoles fused with a
7-membered ring in good yield (Table 4, entries 3and 4). The
4
5
10
8
75
54
[a] Reaction conditions: [ReBr(CO)5] (10 mol%),5-Š M.S.,toluene, hn,
room temperature.
high regioselectivity of the [1,2] Stevens-type rearrangement
was again observed in the reaction of the tetrahydroisoquino-
line derivative 21 (Table 4, entry 5).
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895; for the synthesis of oxacycles, see: e) H. Kusama, H.
Funami, M. Shido, Y. Hara, J. Takaya, N. Iwasawa, J. Am. Chem.
Soc. 2005, 127, 2709; f) N. Iwasawa, M. Shido, H. Kusama, J. Am.
Chem. Soc. 2001, 123, 5814; g) H. Kusama, H. Funami, N.
Iwasawa, Synthesis 2007, 2014; h) H. Kusama, H. Funami, J.
Takaya, N. Iwasawa, Org. Lett. 2004, 6, 605; see also: i) H.
Kusama, N. Iwasawa, Chem. Lett. 2006, 35, 1082.
Finally, the intermediacy of carbene complex B was
confirmed by the following trapping experiment: The treat-
ment of 1c with a stoichiometric amount of [W(CO)6] in the
presence of triethylsilane (10 equiv) under photoirradiation
gave the Et3Si-substituted tricyclic indoline derivative 24 in
7% yield along with the usual tricyclic indole product in 71%
yield (Scheme 2). The formation of 24 indicates unambigu-
ously the existence of the carbene complex 23 as an
intermediate. Such species are the key intermediates of the
[1,2] Stevens-type rearrangement of metal-containing ammo-
nium ylides, and the intermediacy of 23 strongly supports the
proposed mechanism of this reaction.[13,14]
[2] a) F. G. West, J. S. Clark in Nitrogen, Oxygen and Sulfur Ylide
Chemistry (Ed.: J. S. Clark), Oxford University Press, Oxford,
2002, p. 115; b) Y. Sato in Nitrogen, Oxygen and Sulfur Ylide
Chemistry (Ed.: J. S. Clark), Oxford University Press, Oxford,
2002, p. 134; c) M. P. Doyle, D. C. Forbes in Nitrogen, Oxygen
and Sulfur Ylide Chemistry (Ed.: J. S. Clark), Oxford University
Press, Oxford, 2002, p. 141; d) A. Padwa, S. F. Hornbuckle,
Chem. Rev. 1991, 91, 263; e) E. Vedejs, F. G. West, Chem. Rev.
1986, 86, 941; f) S. H. Pine, Org. React. 1970, 18, 403.
[3] G. Li, X. Huang, L. Zhang, Angew. Chem. 2008, 120, 352; Angew.
Chem. Int. Ed. 2008, 47, 346.
[4] a) T. S. Stevens, E. M. Creighton, A. B. Gordon, M. MacNicol, J.
Chem. Soc. 1928, 3193; b) J. A. Vanecko, H. Wan, F. G. West,
Tetrahedron 2006, 62, 1043, and references therein.
[5] This type of [1,2] Stevens-type rearrangement of ylide species A
is unprecedented, except for the recent example reported by
Zhang and co-workers of a 1,2-migration reaction of lactam
derivatives. In the latter reaction, an acylium intermediate
generated from the alkenyl metal intermediate is proposed as a
key intermediate; see Ref. [3]
Scheme 2. Trapping of the intermediate carbene complex.
[6] For 1,3-migration reactions of allyl, methoxymethyl, acyl, and
sulfonyl groups from alkenyl palladium or gold zwitterionic
intermediates related to A, see: a) I. Nakamura, Y. Mizushima,
U. Yamagishi, Y. Yamamoto, Tetrahedron 2007, 63, 8670; b) I.
Nakamura, U. Yamagishi, D. Song, S. Konta, Y. Yamamoto,
Angew. Chem. 2007, 119, 23 3 4A; ngew. Chem. Int. Ed. 2007, 46,
2284; c) A. Fꢀrstner, P. W. Davies, J. Am. Chem. Soc. 2005, 127,
15024; d) T. Shimada, I. Nakamura, Y. Yamamoto, J. Am. Chem.
Soc. 2004, 126, 10546; see also: e) F. M. Istrate, F. Gagosz, Org.
Lett. 2007, 9, 3181; f) K. Cariou, B. Ronan, S. Mignani, L.
Fensterbank, M. Malacria, Angew. Chem. 2007, 119, 1913;
Angew. Chem. Int. Ed. 2007, 46, 1881; g) S. Cacchi, G. Fabrizi, P.
Pace, J. Org. Chem. 1998, 63, 1001; for the synthesis of 3-
substituted benzofurans and benzothiophenes via related inter-
mediates, see: h) I. Nakamura, T. Sato, M. Terada, Y. Yamamoto,
Org. Lett. 2007, 9, 4081; i) A. Fꢀrstner, E. K. Heilmann, P. W.
Davies, Angew. Chem. 2007, 119, 4844; Angew. Chem. Int. Ed.
2007, 46, 4760; j) I. Nakamura, T. Sato, Y. Yamamoto, Angew.
Chem. 2006, 118, 4585; Angew. Chem. Int. Ed. 2006, 45, 4473;
k) I. Nakamura, Y. Mizushima, Y. Yamamoto, J. Am. Chem. Soc.
2005, 127, 15022; l) A. Fꢀrstner, F. Stelzer, H. Szillat, J. Am.
Chem. Soc. 2001, 123, 11863; m) A. Fꢀrstner, H. Szillat, F.
Stelzer, J. Am. Chem. Soc. 2000, 122, 6785.
In conclusion, we have developed an efficient method for
the preparation of N-fused tricyclic indole derivatives through
a tandem [1,2] Stevens-type rearrangement/1,2-alkyl migra-
tion reaction of newly designed metal-containing ammonium
ylides. By using [W(CO)6] or [ReBr(CO)5] as the catalyst, the
alkyne moiety was activated efficiently even in the presence
of the amine functionality.
Experimental Section
General procedure: An N-(o-alkynylphenyl)amine (0.150 mmol) was
added as a solution in toluene (1.0 mL) to a suspension of tungsten
hexacarbonyl or bromopentacarbonylrhenium (0.015 mmol) and 5-Š
molecular sieves in toluene (1.0 mL) at room temperature. The
resulting mixture was irradiated with a high-pressure Hg lamp at
room temperature until the complete disappearance of the starting
material was confirmed by TLC. The mixture was then filtered
through a short pad of celite, and the filtrate was concentrated under
reduced pressure. The residue was purified by preparative TLC to
afford the corresponding polycyclic indole derivative.
[7] In entries 5 and 7 of Table 1, N-(4-X-butyl)-2-methylindole (X =
Br or Cl), which probably resulted from a ring-opening reaction
of the ylide A upon attack by a halide anion, was obtained in low
yield (< 20%) along with recovered starting material.
[8] Avast number of alkaloids have polycyclic indole skeletons; see:
a) W. Gul, M. T. Hamann, Life Sci. 2005, 78, 442; b) G. A.
Cordell, The Alkaloids: Chemistry and Biology, Vol. 60, Elsevier
Science, San Diego, 2003.
Received: December 3, 2007
Revised: February 19, 2008
Published online: May 26, 2008
Keywords: ammonium ylides · carbene ligands · rhenium ·
.
Stevens rearrangement · tungsten
[9] These substrates can be prepared readily through a Pd-catalyzed
amination and Sonogashira coupling reaction of 1-bromo-2-
iodobenzene.
[10] Classical methods for the generation of ammonium ylides
require the use of a strong base or a fluoride source to form
the anion; see Ref. [2e,f].
[11] With 1 equivalent of [W(CO)6], the product 14 was obtained in
only 16% yield, and 51% of the starting material was recovered.
[1] For the synthesis of azacycles, see: a) H. Kusama, J. Takaya, N.
Iwasawa, J. Am. Chem. Soc. 2002, 124, 11592; b) J. Takaya, H.
Kusama, N. Iwasawa, Chem. Lett. 2004, 33, 16; c) H. Kusama, Y.
Miyashita, J. Takaya, N. Iwasawa, Org. Lett. 2006, 8, 289; d) H.
Kusama, Y. Suzuki, J. Takaya, N. Iwasawa, Org. Lett. 2006, 8,
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[12] For examples of [ReX(CO)5]-catalyzed reactions (X = Cl, Br)
through the electrophilic activation of alkynes, see: a) H.
Kusama, H. Yamabe, Y. Onizawa, T. Hoshino, N. Iwasawa,
Angew. Chem. 2005, 117, 472; Angew. Chem. Int. Ed. 2005, 44,
468; b) L. L. Ouh, T. E. Mꢀller, Y. K. Yan, J. Organomet. Chem.
2005, 690, 3774; c) R. Hua, X. Tian, J. Org. Chem. 2004, 69, 5782;
see also: d) Y. Kuninobu, A. Kawata, K. Takai, Org. Lett. 2005, 7,
4823and Ref. [1c].
Connor, J. P. Day, R. M. Turner, J. Chem. Soc. Dalton Trans.
1976, 108; see also Ref. [1e].
[14] Although the exact mechanism of the present [1,2] Stevens-type
rearrangement is not yet clear, the ring expansion with cationic
intermediates proposed by Zhang and co-workers[3] seems less
likely in our case, as primary alkyl cations, which are not usually
generated in a nonpolar solvent, such as toluene, must be
involved. Furthermore, the formation of Friedel–Crafts-type
products, which are side products in the reaction described by
Zhang and co-workers, was not observed in our reaction.
À
[13] Metal carbenoids are well known to insert readily into the Si H
bond of silanes, even intermolecularly; see: a) J. A. Connor, P. D.
Rose, R. M. Turner, J. Organomet. Chem. 1973, 55, 111; b) J. A.
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