Intermolecular 1,5-dipolar cycloaddition reaction of tungsten-containing vinylazomethine ylides leading to seven-membered heterocycles

Article abstract of DOI:10.1021/ol0529795

Intermolecular 1,5-dipolar cycloaddition reaction of tungsten-containing vinylazomethine ylide, generated from o(alk-3-en-1-ynyl)phenylbenzaldimines and tungsten carbonyl complex, with ketene acetals proceeds efficiently to give azepino[1,2-a]indole derivatives in good yield. Formation of [5 + 2] or [3 + 2] cycloadducts can be controlled by an appropriate choice of dipolarophile.

Full text of DOI:10.1021/ol0529795

ORGANIC
LETTERS
2006
Vol. 8, No. 5
895-897
Intermolecular 1,5-Dipolar Cycloaddition
Reaction of Tungsten-Containing
Vinylazomethine Ylides Leading to
Seven-Membered Heterocycles
Hiroyuki Kusama, Yasuo Suzuki, Jun Takaya, and Nobuharu Iwasawa*
Department of Chemistry, Tokyo Institute of Technology, O-okayama, Meguro-ku,
Tokyo 152-8551, Japan
niwasawa@chem.titech.ac.jp
Received December 9, 2005
ABSTRACT
Intermolecular 1,5-dipolar cycloaddition reaction of tungsten-containing vinylazomethine ylide, generated from o-(alk-3-en-1-ynyl)phenylben-
zaldimines and tungsten carbonyl complex, with ketene acetals proceeds efficiently to give azepino[1,2-a]indole derivatives in good yield.
Formation of [5
+ 2] or [3 + 2] cycloadducts can be controlled by an appropriate choice of dipolarophile.
Nitrogen-containing seven-membered rings often constitute
the basic structure of a variety of biologically active
compounds,1 and development of useful methods for the
preparation of these molecules is highly desirable. In contrast
to the well-established 1,3-dipolar cycloaddition reaction of
azomethine ylides for the construction of nitrogen-containing
five-membered rings,2 the [5 + 2] cycloaddition reaction of
the corresponding vinylogous species, vinylazomethine
ylides, is scarcely realized3,4 because they easily undergo 1,5-
electrocyclization5 to give five-membered products or react
preferentially as a 1,3-dipole to give [3 + 2] cycloadducts
with a vinyl substituent.6 In this paper, we describe a useful
method for the preparation of various tricyclic indoles
(3) Only a few specific examples for [5 + 2] cycloaddition of 1,5-dipoles
in general have been reported; see: (a) Rothenberger, O. S.; Taylor, R. T.;
Dalrymple, D. L.; Moore, J. A. J. Org. Chem. 1972, 37, 2640. (b) Cameron,
A. F.; Freer, A. A. Acta Crystallogr. 1974, B30, 2696. (c) Saito, T.;
Nagashima, M.; Karakasa, T.; Motoki, S. J. Chem. Soc., Chem. Commun.
1992, 411. (d) Barluenga, J.; Toma´s, M.; Bieger, K.; Garc´ıa-Granda, S.;
Santiago-Garc´ıa, R. Angew. Chem., Int. Ed. Engl. 1996, 35, 896. (e)
Barluenga, J.; Toma´s, M.; Bieger, K.; Garc´ıa-Granda, S.; Santiago-Garc´ıa,
R. J. Organomet. Chem. 1997, 529, 233.
(4) (a) Wender et al. recently reported the first transition-metal-catalyzed
hetero-[5 + 2] cycloaddition; see; Wender, P. A.; Pedersen, T. M.; Scanio,
M. J. C. J. Am. Chem. Soc. 2002, 124, 15154. (b) For a pioneering work
on the metal-catalyzed [5 + 2] cycloaddition, see: Wender, P. A.; Takahashi,
H.; Witulski, B. J. Am. Chem. Soc. 1995, 117, 4720. For other examples of
metal-mediated [5 + 2] cycloaddition, see: (c) Zhang, Y.; Liebeskind, L.
S. J. Am. Chem. Soc. 2006, 128, 465. (d) Lee, S. I.; Park, S. Y.; Park, J.
H.; Jung, I. G.; Choi, S. Y.; Chung, Y. K.; Lee, B. Y. J. Org. Chem. 2006,
71, 91. (e) Wegner, H. A.; de Meijere, A.; Wender, P. A. J. Am. Chem.
Soc. 2005, 127, 6530. (f) Ashfeld, B. L.; Martin, S. F. Org. Lett. 2005, 7,
4535. (g) Trost, B. M.; Shen, H. C.; Horne, D. B.; Toste, F. D.; Steinmetz,
B. G.; Koradin, C. Chem.sEur. J. 2005, 11, 2577. (h) Tanino, K.; Kondo,
F.; Shimizu, T.; Miyashita, M. Org. Lett. 2002, 4, 2217. (i) Tanino, K.;
Shimizu, T.; Miyama, M.; Kuwajima, I. J. Am. Chem. Soc. 2000, 122, 6116.
(j) Malinakova, H. C.; Liebeskind, L. S. Org. Lett. 2000, 2, 3909. (k)
Malinakova, H. C.; Liebeskind, L. S. Org. Lett. 2000, 2, 4083. (l) Trost, B.
M.; Toste, F. D.; Shen, H. J. Am. Chem. Soc. 2000, 122, 2379. (m) Yueh,
T.-C.; Lush, S.-F.; Lee, G.-H.; Peng, S.-M.; Liu, R.-S. Organometallics
1996, 15, 5669.
(1) For reviews on azepine derivatives, see: (a) O’Hagan, D. Nat. Prod.
Rep. 1997, 637. (b) Evans, P. A.; Holmes, B. Tetrahedron 1991, 47, 9131.
(c) Bremner, J. B. In Progress in Heterocyclic Chemistry; Gribble, G. W.,
Joule, J. A., Eds.: Elsevier: Oxford, UK, 2003; Vol. 15, p 385. For some
natural products having an azepino[1,2-a]indole skeleton, see: (d) Angenot,
L.; Diberg, O.; Dupont, L. Tetrahedron Lett. 1975, 16, 1357. (e) Chbani,
M.; Pa¨ıs, M. J. Nat. Prod. 1993, 56, 99. (f) Massiot, G.; The´penier, P.;
Jacquier, M. J.; Delaude, C.; Le Men-Olivier, L.; Verpoorte, R. Tetrahedron
Lett. 1985, 26, 2441.
(2) For reviews on 1,3-dipolar cycloaddition of azomethine ylides, see:
(a) Padwa, A. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, U.K., 1991; vol. 4, p 1069. (b) Harwood, L.
M.; Vickers, R. J. In Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products; Padwa, A., Pearson,
W. H., Eds.; Wiley-Interscience: Hoboken, 2003; p 169. (c) Coldham, I.;
Hufton, R. Chem. ReV. 2005, 105, 2765.
10.1021/ol0529795 CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/02/2006

containing a seven-membered ring utilizing a novel [5 + 2]
cycloaddition reaction of tungsten-containing vinyl-azo-
methine ylide species.7
Scheme 2. Initial Attempt for the [5 + 2] Cycloaddition
Reaction
Our basic strategy is as follows: treatment of o-(alk-3-
en-1-ynyl)phenylbenzaldimine 1 with W(CO)5(L) gives the
tungsten-containing vinylazomethine ylide 2 through nu-
cleophilic attack of the imino nitrogen onto the W(CO)5-
activated alkyne moiety. This ylide has the ability to react
with alkenes as a 1,3-dipole or a 1,5-dipole in a [3 + 2] or
a [5 + 2] manner giving tricyclic indoles containing a
5-membered ring or a 7-membered ring, respectively (Scheme
1). Additionally, it might also give a tricyclic indole through
Scheme 1
obtained in 84% yield (Scheme 2). The product 6a was
formed by deprotonation of the R,â-unsaturated carbene
complex intermediate 3a produced by the expected [5 + 2]
cycloaddition of the tungsten-containing vinylazomethine
ylide 2a (R1 ) H) and the ketene silyl acetal 4, followed by
protonation of the generated dienyltungsten anion 5a.
Furthermore, the reaction proceeded smoothly only slightly
lowering the yield even with a catalytic amount (10 mol %)
of W(CO)6. It should be noted that, in the present reaction,
1,5-electrocyclization of the tungsten-containing vinylazo-
methine ylide intermediate 2 is inhibited probably due to its
rigid planar structure fused with the indole nucleus, in which
the two reacting sites are located far from each other.
As the novel [5 + 2] cycloaddition reaction of tungsten-
containing vinylazomethine ylide was found to proceed as
expected, we next examined the generality of this reaction
(Table 1). As a dipolarophile, ketene acetals also gave good
results. For example, diethyl ketene acetal or diisopropyl
ketene acetal reacted smoothly with o-(but-3-en-1-ynyl)-
phenylbenzaldimine 1a to give the same product 6a in good
yield after mild acid hydrolysis (entries 1 and 2). Further-
more, methyl- or methoxy-substituted ketene silyl acetal also
reacted smoothly under catalytic conditions to give the
corresponding substituted tricyclic indoles as a mixture of
diastereomers in good yield (entries 3 and 5). More interest-
ingly, when sterically less demanding cyclic ketene acetal 7
was employed, [3 + 2] cycloaddition followed by 1,2-vinyl
migration7a,b,g proceeded to give a dioxolane-protected
derivative of tricyclic indole 8a (R1 ) R2 ) H) containing
a five-membered ring selectively in good yield (entry 6).
Thus, [5 + 2] cycloadditions are favored over [3 + 2]
cycloadditions with bulkier dipolarophiles, probably due to
too strong steric repulsions between reacting centers in the
latter case. Concerning the generality of the imine counter-
part, the reaction of pent-3-en-1-ynyl derivative 1b (R1 )
Me) proceeded smoothly to give the desired [5 + 2]
cycloaddition product 6b (R1 ) Me, R2 ) H) in good yield
by using ketene diisopropyl acetal as dipolarophile (entries
7 and 8). Here again, use of a less bulky diethyl ketene acetal
gave the [3 + 2] cycloadduct 8b selectively in good yield
(entry 9). The terminal methyl substituent of 1b increases
the steric repulsion in the [5 + 2] cycloaddition pathway,
allowing the [3 + 2] cycloaddition reaction to proceed even
1,5-electrocyclization. We expected the mode of cyclo-
addition to be controlled by the appropriate choice of the
reactants.
After several attempts, it was found that when o-(but-3-
en-1-ynyl)phenylbenzaldimine 1a was treated with an equimo-
lar amount of W(CO)6 and 2 molar equiv of ketene isopropyl
triisopropylsilyl acetal 4 in the presence of MS4A and Et3N
under photoirradiation in toluene at ambient temperature,
followed by mild acid treatment of the crude product, the
desired azepino[1,2-a]indole derivative 6a was eventually
(5) For reviews on 1,5-electrocyclization of 1,5-dipoles, see; (a) Taylor,
E. C.; Turchi, I. J. Chem. ReV. 1979, 79, 181. (b) Huisgen, R. Angew. Chem.,
Int. Ed. Engl. 1980, 19, 947. Some recent examples for 1,5-electrocyclization
of vinylogous azomethine ylides, see: (c) Nyerges, M.; Pinte´r, AÄ .; Vira´nyi,
A.; Blasko´, G.; To´ke, L. Tetrahedron 2005, 61, 8199. (d) Voznyi, I. V.;
Novikov, M. S.; Khlebnikov, A. F. Synlett 2005, 1006. (e) Wu, P.-L.; Chung,
T.-H.; Chou, Y. J. Org. Chem. 2001, 66, 6585.
(6) (a) Epperson, M. T.; Gin, D. Y. Angew. Chem., Int. Ed. 2002, 41,
1778. (b) De Boeck, B.; Viehe, H. G. Tetrahedron 1998, 54, 513. (c)
Coldham, I.; Collis, A. J.; Mould, R. J.; Robinson, D. E. Synthesis 1995,
1147. (d) Bourhis, M.; Vercauteren, J. Tetrahedron Lett. 1994, 35, 1981.
(e) Chen, S.-F.; Ullrich, J. W.; Mariano, P. S. J. Am. Chem. Soc. 1983,
105, 6160.
(7) For generation and reaction of tungsten-containing azomethine ylides,
see: (a) Kusama, H.; Takaya, J.; Iwasawa, N. J. Am. Chem. Soc. 2002,
124, 11592. (b) Takaya, J.; Kusama, H.; Iwasawa, N. Chem. Lett. 2004,
33, 16. For generation and reaction of tungsten-containing carbonyl ylides,
see: (c) Kusama, H.; Funami, H.; Shido, M.; Hara, Y.; Takaya, J.; Iwasawa,
N. J. Am. Chem. Soc. 2005, 127, 2709. (d) Iwasawa, N.; Shido, M.; Kusama,
H. J. Am. Chem. Soc. 2001, 123, 5814. See also: (e) Shin, S.; Gupta, A.
K.; Rhim, C. Y.; Oh, C. H. Chem. Commun. 2005, 4429. (f) Kim, N.; Kim,
Y.; Park, W.; Sung, D.; Gupta, A. K.; Oh, C. H. Org. Lett. 2005, 7, 5289.
For generation of platinum-containing carbonyl ylides, see: (g) Kusama,
H.; Funami, H.; Takaya, J.; Iwasawa, N. Org. Lett. 2004, 6, 605.
896
Org. Lett., Vol. 8, No. 5, 2006

Finally, the reaction of cinnamaldimine derivative 11 was
examined. In this case, another interesting 7-membered ring
formation was found to proceed smoothly.
Table 1. Generality of Intermolecular [5 + 2] Cycloaddition
Treatment of imine 11 with a stoichiometric amount of
W(CO)6 under photoirradiation gave another azepino[1,2-
a]indole derivative 13 in 84% yield. The reaction could
proceed even with a catalytic amount of W(CO)6, although
the yield was lowered to 50%. This product was produced
by 1,7-electrocyclization8 of the tungsten-containing 1,5-
dipole 12, followed by Et3N-induced deprotonation-proto-
nation of the carbene complex intermediate.
yield (%)
W(CO)6
entry
R1
R2
R3
i-Pr
Et
TIPS
TIPS
R4
(mol %)
6
8
1
2
H
H
H
H
H
H
Me
OMe
i-Pr
Et
Et
10
100
10
100
10
62
79
72
71
61
<15
3a
4a
5a
6
7
8c
9
Et
In conclusion, we have developed a novel method for the
construction of tricyclic indoles containing a seven-mem-
bered ring utilizing [5 + 2] cycloaddition reaction of
tungsten-containing vinylazomethine ylides. This reaction is
a very rare example of 1,5-dipolar cycloaddition and affords
a useful method for the preparation of various synthetically
valuable compounds.
H
Me
H
H
-CH2CH2- 7
100
100
20
76b
28
24
76
i-Pr
i-Pr
64
60
6
Me
H
Et
Et
100
a To neat Et3N and dipolarophile was slowly added an imine solution
for 6-7.5 h. The product was obtained as a mixture of diastereomers (ca.
1:1). b The product was isolated as a ketal without acidic workup. c The
reaction was performed at 10 °C.
Acknowledgment. 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.
with diethyl ketene acetal. Thus, either [5 + 2] or [3 + 2]
cycloadduct could be obtained selectively by appropriate
choice of the dipolarophile.
Furthermore, imines were found to be good dipolarophiles
in this reaction. For example, reaction of 1a with imine 9
gave the diazepine derivative 10 as a mixture of diastereo-
mers in good yield. This reaction proceeded even with a
catalytic amount of W(CO)6.
Supporting Information Available: Preparative methods
and spectral and analytical data of compounds 1, 6, 8, 10,
11, and 13. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0529795
(8) For reviews on 1,7-electrocyclization, see: (a) Zecchi, G. Synthesis
1991, 181. (b) Groundwater, P. W.; Nyerges, M. In AdVances in Heterocyclic
Chemistry; Katritzky, A. R., Ed.; Academic Press: New York, 1999; Vol.
73, p 97. For some recent examples for 1,7-electrocyclization, see: (c)
Knobloch, K.; Koch, J.; Keller, M.; Eberbach, W. Eur. J. Org. Chem. 2005,
2715. (d) Nyerges, M.; Pinte´r, AÄ .; Vira´nyi, A.; Bitter, I.; To´ke, L.
Tetrahedron Lett. 2005, 46, 377. (e) Reisser, M.; Maas, G. J. Org. Chem.
2004, 69, 4913 and references therein.
Org. Lett., Vol. 8, No. 5, 2006
897