Pt(II)- or Au(III)-catalyzed [3+2] cycloaddition of metal-containing azomethine ylides: Highly efficient synthesis of the mitosene skeleton

Article abstract of DOI:10.1021/ol052610f

Only 1-3 mol % of PtCl₂ or AuBr₃ was sufficient to promote generation and [3+2] cycloaddition of transition-metal-containing azomethine ylides derived from N-(o-alkynylphenyl)imines bearing an internal alkyne moiety. A highly efficient method for the preparation of synthetically useful tricyclic indole derivatives having a substituent at the 3-position of the indole nucleus was established by this method.

Full text of DOI:10.1021/ol052610f

ORGANIC
LETTERS
2006
Vol. 8, No. 2
289-292
Pt(II)- or Au(III)-Catalyzed [3+2]
Cycloaddition of Metal-Containing
Azomethine Ylides: Highly Efficient
Synthesis of the Mitosene Skeleton
Hiroyuki Kusama, Yuichi Miyashita, 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 October 28, 2005
ABSTRACT
Only 1−3 mol % of PtCl2 or AuBr3 was sufficient to promote generation and [3+2] cycloaddition of transition-metal-containing azomethine
ylides derived from N-(o-alkynylphenyl)imines bearing an internal alkyne moiety. A highly efficient method for the preparation of synthetically
useful tricyclic indole derivatives having a substituent at the 3-position of the indole nucleus was established by this method.
In connection with our continuing research for the develop-
ment of new catalytic reactions on the basis of electrophilic
activation of alkynes by group 6 metal carbonyls,1 we
recently reported that a novel reactive species, the tungsten-
containing azomethine ylides 2 (M ) W(CO)5), could be
generated by treatment of N-(o-ethynylphenyl)imine deriva-
tives 1 (R1 ) Ph, OR; R2 ) H) with a catalytic amount of
tungsten hexacarbonyl under photoirradiation conditions.2
[3+2] Cycloaddition reactions of thus-generated ylides 2 with
electron-rich alkenes readily proceeded to give the non-
heteroatom-stabilized tungsten carbene complex intermedi-
ates 3 (M ) W(CO)5),2b which underwent facile 1,2-
hydrogen migration to afford the corresponding polycyclic
indole derivatives 4 in good yield (Scheme 1). More
interestingly, when N-(o-alkynylphenyl)imine derivatives
having an internal alkyne moiety 1 (R1 ) Ph; R2 ) alkyl,
aryl) were employed as substrate, a novel 1,2-migration2a,b,f,3
of alkyl or aryl groups was observed to give tricyclic indole
Scheme 1
(1) (a) Maeyama, K.; Iwasawa, N. J. Am. Chem. Soc. 1998, 120, 1928.
(b) Iwasawa, N.; Maeyama, K.; Kusama, H. Org. Lett. 2001, 3, 3871. (c)
Miura, T.; Iwasawa, N. J. Am. Chem. Soc. 2002, 124, 518. (d) Kusama,
H.; Yamabe, H.; Iwasawa, N. Org. Lett. 2002, 4, 2569. (e) Iwasawa, N.;
Miura, T.; Kiyota, K.; Kusama, H.; Lee, K.; Lee, P. H. Org. Lett. 2002, 4,
4463.
(2) (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. For generation
and reaction of platinum-containing carbonyl ylides, see: (f) Kusama, H.;
Funami, H.; Takaya, J.; Iwasawa, N. Org. Lett. 2004, 6, 605.
10.1021/ol052610f CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/27/2005

derivatives having a substituent at the 3-position of the indole
nucleus in good yield. Although this internal alkyne protocol
affords a highly efficient method for the preparation of
3-substituted tricyclic indole skeletons4 such as mitomycins,5,6
the efficiency of the tungsten catalyst was moderate and a
stoichiometric amount of W(CO)6 was necessary to bring
the reaction to completion. Thus, it is strongly desired to
develop highly efficient catalytic reactions employable for
the substrates containing an internal alkyne moiety. In this
paper, the excellent catalytic activity of third-row transition-
metal complexes such as Pt(II) and Au(III) for the generation
and reaction of metal-containing azomethine ylides derived
from N-(o-alkynylphenyl)imine derivatives containing an
internal alkyne moiety is described.
Since a number of high-valent, late transition-metal
complexes were found to be efficient catalysts for electro-
philic activation of alkynes in the past decade,7 we initially
investigated the reaction of an imine derivative 1a having
an n-propyl group on the alkyne terminus with tert-butyl
vinyl ether 5 in toluene by the use of such metal complexes
instead of tungsten carbonyl, and the results are summarized
in Table 1. Interestingly, various metal complexes such as
higher catalytic activity than the tungsten carbonyl complex,
and in particular, PtCl2 and AuBr3 were found to be the best
catalysts in terms of product yield and reaction time,
respectively. The same mechanism as that for W(CO)5, as
depicted in Scheme 1, is proposed for these reactions.
Electrophilic activation of the internal alkyne moiety by these
metals induces the nucleophilic, 5-endo mode of cyclization
of the imino nitrogen onto the alkyne moiety to generate
the corresponding metal-containing azomethine ylides 2.
Successive [3+2] cycloaddition and 1,2-alkyl migration give
tricyclic indole with regeneration of the catalyst. On the
contrary, molybdenum carbonyl gave the desired product 4a
in low yield and, except for Pd(II), the reactions with some
other second-row transition-metal complexes such as RuCl3,
Ru3(CO)12/hν, and RhCl3 were rather sluggish. In addition,
catalytic activities of Pt(IV) chloride15 and Au(I)7,13,16 chloride
were lower than those of Pt(II) and Au(III), respectively.
(4) For reviews on the synthesis of indole derivatives, see: (a) Gribble,
G. W. Perkin Trans. 1 2000, 1045. (b) Cacchi, S.; Fabrizi, G. Chem. ReV.
2005, 105, 2873.
(5) (a) Galm, U.; Hager, M. H.; Van Lanen, S. G.; Ju, J.; Thorson, J. S.;
Shen, B. Chem. ReV. 2005, 105, 739. (b) Rajski, S. R.; Williams, R. M.
Chem. ReV. 1998, 98, 2723. For total synthesis of mitomycins, see: (c)
Fukuyama, T.; Yang, L. J. Am. Chem. Soc. 1987, 109, 7881. (d) Fukuyama,
T.; Yang, L. J. Am. Chem. Soc. 1989, 111, 8303. (e) Wang, Z.; Jimenez, L.
S. Tetrahedron Lett. 1996, 37, 6049 and references therein.
(6) For some recent examples of the preparation of mitosene skeletons,
see: (a) Pe´rez-Serrano, L.; Dom´ınguez, G.; Pe´rez-Castells, J. J. Org. Chem.
2004, 69, 5413. (b) Coleman, R. S.; Felpin, F.-X.; Chen, W. J. Org. Chem.
2004, 69, 7309. (c) Tsuboike, K.; Guerin, D. J.; Mennen, S. M.; Miller, S.
J. Tetrahedron 2004, 60, 7367. (d) Kim, M.; Vedejs, E. J. Org. Chem.
2004, 69, 7262 and references therein.
Table 1. Screening of Metal Complexes
(7) (a) Aubert, C.; Buisine, O.; Malacria, M. Chem. ReV. 2002, 102, 813.
(b) Lloyd-Jones, G. C. Org. Biomol. Chem. 2003, 1, 215. (c) Alonso, F.;
Beletskaya, I. P.; Yus, M. Chem. ReV. 2004, 104, 3079. (d) Echavarren, A.
M.; Nevado, C. Chem. Soc. ReV. 2004, 33, 431. (e) Beller, M.; Seayad, J.;
Tillack, A.; Jiao, H. Angew. Chem., Int. Ed. 2004, 43, 3368. (f) Bruneau,
C. Angew. Chem., Int. Ed. 2005, 44, 2328.
entry
catalyst
X/mol % time/h yield/% (cis:trans)
(8) (a) Kusama, H.; Yamabe, H.; Onizawa, Y.; Hoshino, T.; Iwasawa,
N. Angew. Chem., Int. Ed. 2005, 44, 468. (b) Ouh, L. L.; Mu¨ller, T. E.;
Yan, Y. K. J. Organomet. Chem. 2005, 690, 3774. (c) Hua, R.; Tian, X. J.
Org. Chem. 2004, 69, 5782. (d) Kuninobu, Y.; Kawata, A.; Takai, K. Org.
Lett. 2005, 7, 4823.
(9) (a) Chatani, N.; Inoue, H.; Morimoto, T.; Muto, T.; Murai, S. J. Org.
Chem. 2001, 66, 4433. (b) Genin, E.; Antoniotti, S.; Michelet, V.; Geneˆt,
J.-P. Angew. Chem., Int. Ed. 2005, 44, 4949. (c) Shibata, T.; Kobayashi,
Y.; Maekawa, S.; Toshida, N.; Takagi, K. Tetrahedron 2005, 61, 9018.
(10) (a) Zeni, G.; Larock, R. C. Chem. ReV. 2004, 104, 2285. (b) Muzart,
J. Tetrahedron 2005, 61, 5955.
1
2
3
4
5a
6
7
8
9
10a
11a
Mo(CO)6/hν
Re(CO)5Cl/hν
[IrCl(cod)]2
PdCl2(CH3CN)2
PtCl2
PtCl4
AuCl
AuCl3
AuBr3
100
10
5
16
5.5
26
2
9.5
25
29
1.2
0.5
13
22
15
70
73
71
90
57
49
82
70
76
33
(21:79)
(64:36)
(19:81)
(54:46)
(58:42)
(49:51)
(55:45)
(57:43)
(53:47)
(22:78)
(17:83)
11
10
10
10
10
10
100
10
(11) Pioneering studies on PtCl2-catalyzed cycloisomerization of
enynes: (a) Chatani, N.; Morimoto, T.; Muto, T.; Murai, S. J. Am. Chem.
Soc. 1994, 116, 6049. (b) Chatani, N.; Furukawa, N.; Sakurai, H.; Murai,
S. Organometallics 1996, 15, 901.
W(CO)6/hν
a 10 equiv of vinyl ether was used.
(12) For recent examples of electrophilic alkyne activation by a Pt(II)
complex, see: (a) Mainetti, E.; Mourie`s, V.; Fensterbank, L.; Malacria,
M.; Marco-Contelles, J. Angew. Chem., Int. Ed. 2002, 41, 2132. (b) Shimada,
T.; Nakamura, I.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 10546. (c)
Bajracharya, G. B.; Nakamura, I.; Yamamoto, Y. J. Org. Chem. 2005, 70,
892. (d) Nevado, C.; Echavarren, A. M. Chem.-Eur. J. 2005, 11, 3155.
(e) Fu¨rstner, A.; Davies, P. W.; Gress, T. J. Am. Chem. Soc. 2005, 127,
8244. (f) Bhanu Prasad, B. A.; Yoshimoto, F. K.; Sarpong, R. J. Am. Chem.
Soc. 2005, 127, 12468. (g) Nakamura, I.; Mizushima, Y.; Yamamoto, Y. J.
Am. Chem. Soc. 2005, 127, 15022. (h) Fu¨rstner, A.; Davies, P. W. J. Am.
Chem. Soc. 2005, 127, 15024.
Re(I),8 Ir(I),9 Pd(II),10 Pt(II),7,11,12 and Au(III)13,14 are found
to catalyze this reaction efficiently, giving the same product
4a as that obtained by the tungsten-promoted reaction2a in
good to excellent yield. These metal complexes exhibit much
(3) For other examples of the 1,2-alkyl migration of transition-metal
carbene intermediates, see: (a) Do¨rwald, F. Z. Metal Carbenes in Organic
Synthesis; Wiley-VCH: Weinheim, Germany, 1999; p 193. (b) Zora, M.;
Herndon, J. W.; Li, Y.; Rossi, J. Tetrahedron 2001, 57, 5097 and references
therein. (c) Nagao, K.; Chiba, M.; Kim, S.-W. Synthesis 1983, 197. (d)
Bly, R. S.; Bly, R. K.; Hossain, M. M.; Lebioda, L.; Raja, M. J. Am. Chem.
Soc. 1988, 110, 7723. (e) Jiang, N.; Ma, Z.; Qu, Z.; Xing, X.; Xie, L.;
Wang, J. J. Org. Chem. 2003, 68, 893. (f) Zhang, L.; Kozmin, S. A. J. Am.
Chem. Soc. 2004, 126, 11806. (g) Lian, J.-J.; Odedra, A.; Wu, C.-J.; Liu,
R.-S. J. Am. Chem. Soc. 2005, 127, 4186.
(13) For reviews on gold-catalyzed reactions, see: (a) Hashmi, A. S. K.
Gold Bull. 2003, 36, 3. (b) Hashmi, A. S. K. Gold Bull. 2004, 37, 51.
(14) For recent examples of electrophilic alkyne activation by a Au(III)
complex, see: (a) Alfonsi, M.; Arcadi, A.; Aschi, M.; Bianchi, G.; Marinelli,
F. J. Org. Chem. 2005, 70, 2265. (b) Hashmi, A. S. K.; Rudolph, M.;
Weyrauch, J. P.; Wo¨lfle, M.; Frey, W.; Bats, J. W. Angew. Chem., Int. Ed.
2005, 44, 2798. (c) Hashmi, A. S. K.; Grundl, L. Tetrahedron 2005, 61,
6231. (d) Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc. 2005, 127, 6962.
(e) Antoniotti, S.; Genin, E.; Michelet, V.; Gene´t, J.-P. J. Am. Chem. Soc.
2005, 127, 9976.
290
Org. Lett., Vol. 8, No. 2, 2006

These results indicate that soft-metal complexes, such as
third-row transition-metal complexes, with moderate Lewis
acidity are the catalysts of choice for the present reaction.
Further optimization of the reaction conditions for the
Pt(II)- and Au(III)-catalyzed reactions revealed that both
catalysts have equally excellent catalytic activity. For
example, the reaction of 1a with tert-butyl vinyl ether was
completed within 2.5 h at room temperature by using only
3 mol % of AuBr3, giving the desired product 4a in 80%
yield (Table 2, entry 1). Even when the amount of the catalyst
mol % of PtCl2, and the corresponding product 4a was
obtained in 89 or 74% yield, respectively (entries 8 and 9).
Both Au(III) and Pt(II) catalysts showed a wide generality
of substrates, as summarized in Table 2. The reactions of
methyl-substituted derivative 1b (entries 3 and 10) and bulky
cyclohexyl derivative 1c (entries 4 and 11) proceeded
smoothly with either catalyst to give the desired tricyclic
indoles possessing the corresponding alkyl group at the
3-position of the indole nucleus in high yield. The phenyl
substituent was also employable as a migrating group (entries
5 and 12). Furthermore, not only aldimine derivatives but
also an imidate 1e could be a precursor of the metal-
containing azomethine ylide (entries 6 and 13). In this case,
the Pt(II)-catalyzed reaction (3 mol %) gave a much superior
result (95% yield) as compared with the Au(III)-catalyzed
one (10 mol % of AuBr3, 60% yield). The obtained indole
4e has a synthetically useful N,O-acetal moiety, and further
functionalization of the product would be possible.
Table 2. Generality of the [3+2] Cycloaddition Reaction
Catalyzed by PtCl2 or AuBr3
The reaction of 1e with para-methoxybenzyl vinyl ether
6 also proceeded without any problems by the catalytic use
of PtCl2 to give the desired tricyclic indole 4f, having a
benzyloxy group on the pyrrolidine ring, in high yield.
entry
R1
Ph
R2
catalyst X/mol % time/h
yield/%a
1
2b
3
4
5
n-Pr 1a AuBr3
n-Pr 1a
Me
c-Hex 1c
Ph 1d
3
1
2.5 4a
42
80
81
81
89
62
60
81
89
74
88
84
84
95
4a
4b
4c
1b
3
3
22
2
3
0.5 4d
6b,c O-i-Pr n-Pr 1e
7
8d
9d,e
10d
10
3
3
1
72
6
4e
4a
4a
Ph
n-Pr 1a PtCl2
n-Pr 1a
n-Pr 1a
Me
c-Hex 1c
Ph 1d
1
3
16.5 4a
3.5 4b
As already mentioned, the present results strongly sug-
gested that platinum(II) and gold(III) carbene complexes,
plausible reaction intermediates, readily underwent 1,2-
migration of an adjacent substituent to the carbene carbon,
giving the corresponding tricyclic indoles. Because primary
and secondary alkyl groups as well as the phenyl group
appeared to be applicable as a migrating group, we further
investigated the 1,2-migration of a functionalized substituent
to expand the scope of this reaction, and a siloxymethyl group
was chosen considering the application to the synthesis of
the mitosene family.5,6 Gratifyingly, the desired [3+2]
cycloaddition of platinum-containing azomethine ylide 7 and
the 1,2-migration of the siloxymethyl group occurred smoothly
to give the corresponding tricyclic indole 4g in good yield.
This product contains a hydroxymethyl equivalent, a com-
monly observed functionality in mitosenes, at the desired
position of the indole nucleus and would be a highly useful
synthetic precursor for mitomycins and their analogues.5,6
1b
11c,d
12d
3
3
35
7
4c
4d
4e
13c,f O-i-Pr n-Pr 1e
3
2
a The diastereomer ratio of the product 4 is described in the Supporting
Information. b Concentration of 1 was 0.03 M. c 10 equiv of vinyl ether
was used. d The reactions were carried out at 50 °C. e Concentration of 1
was 0.3 M. f The reaction was carried out at 50 °C in the presence of MS5A.
was further reduced to 1 mol %, the reaction still proceeded
at room temperature without decreasing the yield of 4a,
although much more time (42 h) was required to complete
the reaction (entry 2). In the case of PtCl2 (3 mol %), the
reaction proceeded very slowly at room temperature and a
small amount of the starting material 1a was recovered even
after 72 h (entry 7). However, the starting material was
consumed by carrying out the reaction at 50 °C with 3 or 1
(15) For recent examples of electrophilic alkyne activation by a Pt(IV)
complex, see: (a) Oh, C. H.; Bang, S. Y.; Rhim, C. Y. Bull. Korean Chem.
Soc. 2003, 24, 887. (b) Pastine, S. J.; Youn, S. W.; Sames, D. Tetrahedron
2003, 59, 8859.
(16) For recent examples of electrophilic alkyne activation by a Au(I)
complex, see: (a) Shi, X.; Gorin, D. J.; Toste, F. D. J. Am. Chem. Soc.
2005, 127, 5802. (b) Nieto-Oberhuber, C.; Lo´pez, S.; Echavarren, A. M. J.
Am. Chem. Soc. 2005, 127, 6178. (c) Markham, J. P.; Staben, S. T.; Toste,
F. D. J. Am. Chem. Soc. 2005, 127, 9708. (d) Gorin, D. J.; Davis, N. R.;
Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260. (e) Nieto-Oberhuber, C.;
Lo´pez, S.; Mun˜oz, M. P.; Ca´rdenas, D. J.; Bun˜uel, E.; Nevado, C.;
Echavarren, A. M. Angew. Chem., Int. Ed. 2005, 44, 6146. (f) Suhre, M.
H.; Reif, M.; Kirsch, S. F. Org. Lett. 2005, 7, 3925. (g) Gagosz, F. Org.
Lett. 2005, 7, 4129. (h) Me´zailles, N.; Ricard, L.; Gagosz, F. Org. Lett.
2005, 7, 4133. See also ref 14e.
Org. Lett., Vol. 8, No. 2, 2006
291

In conclusion, we have successfully established the
generality and efficiency of the reaction of transition-metal-
containing azomethine ylides. Third-row transition-metal
complexes, especially PtCl2 and AuBr3, turned out to be
highly efficient catalysts for the reaction of internal alkyne
substrates.17 The present results demonstrate novel aspects
of transition-metal-containing dipoles and their high utility
as a synthetic method for the construction of various
synthetically valuable indole derivatives.
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. We thank Ms. Sachiyo Kubo for performing X-ray
analyses.
Supporting Information Available: Preparative methods
and spectral and analytical data of compounds 1 and 4 and
X-ray data for trans-4c (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
(17) The reactions of a terminal alkyne substrate with a catalytic amount
of PtCl2 or AuBr3 were rather sluggish, and the corresponding tungsten-
catalyzed reaction gave the desired tricyclic indole in high yield as previously
reported.2a
OL052610F
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Org. Lett., Vol. 8, No. 2, 2006