Intramolecular addition of stabilized enolates to (η6-arene)ruthenium complexes: Synthesis of Ru-coordinated azaspirocycles

Article abstract of DOI:10.1021/ol991123v

(formula presented) Stabilized enolates attached to cationic (arene)Ru^IICp complexes via an amide linkage were found to participate in nucleophilic aromatic addition reactions resulting in the formation of novel cyclohexadienyl-Ru azaspirocycles. Enolate addition to the activated arene ring was found to proceed with complete stereoselectivity.

Full text of DOI:10.1021/ol991123v

ORGANIC
LETTERS
1999
Vol. 1, No. 11
1851-1854
Intramolecular Addition of Stabilized
Enolates to (η6-Arene)ruthenium
Complexes: Synthesis of
Ru-Coordinated Azaspirocycles
F. Christopher Pigge,* Shiyue Fang, and Nigam P. Rath
Department of Chemistry, UniVersity of MissourisSt. Louis,
St. Louis, Missouri 63121-4499
piggec@jinx.umsl.edu
Received October 5, 1999
ABSTRACT
Stabilized enolates attached to cationic (arene)RuIICp complexes via an amide linkage were found to participate in nucleophilic aromatic
addition reactions resulting in the formation of novel cyclohexadienyl−Ru azaspirocycles. Enolate addition to the activated arene ring was
found to proceed with complete stereoselectivity.
Arene-metal complexes are well-recognized as versatile
intermediates in organic synthesis. The reactivity of an arene
ring is dramatically altered upon coordination to a transition
metal fragment and normally unfavorable processes, such
as nucleophilic aromatic substitution and benzylic deproto-
nation, are greatly facilitated.1 Moreover, the metal center
is oftentimes capable of acting as a stereocontrol element
during synthetic manipulations. Of the (η6-arene)metal
complexes that have been characterized, those involving
coordination of a tricarbonylchromium fragment are the most
thoroughly investigated and numerous synthetic applications
have been reported.2 Arene complexes incorporating cyclo-
pentadienyl (Cp) iron3 and tricarbonylmanganese4 fragments
also have received considerable attention. In contrast, (η6-
arene)RuIICp cations have been scarcely utilized in organic
synthesis although these complexes are easily prepared and
exhibit excellent air and moisture stability.5 Furthermore,
methods are available to recover the CpRuII moiety in a
reusable form upon removal of the arene ligand.5a To date,
however, the most significant synthetic applications of
(arene)RuCp complexes have been for the preparation of the
biaryl ether functionality found in the vancomycin class of
antibiotics.6
In connection with ongoing efforts aimed at expanding
the utility of arene-Ru(II) complexes in synthesis,7
a
(1) (a) Semmelhack, M. F. In ComprehensiVe Organometallic Chemistry
II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Elsevier Science,
Ltd.: Oxford, 1995; Vol. 12, pp 979-1015. (b) Davies, S. G.; McCarthy,
T. D. In ComprehensiVe Organometallic Chemistry II; Abel, E. W., Stone,
F. G. A., Wilkinson, G., Eds.; Elsevier Science Ltd.: Oxford, 1995; Vol.
12, pp 1039-1070. (c) Pike, R. D.; Sweigart, D. A. Coord. Chem. ReV.
1999, 187, 183.
(2) (a) Semmelhack, M. F. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4, pp 517-549.
(b) Uemura, M. In AdVances in Metal-Organic Chemistry; Liebeskind, L.
S., Ed.; Jai Press Ltd.: Greenwich, CT, 1991; Vol. 2, pp 195-245.
(3) Pearson, A. J. Iron Compounds in Organic Synthesis; Academic
Press: New York, 1994; Chapter 6.
potentially versatile means of preparing tetrahydroisoquino-
(4) Sun, S.; Dullaghan, C. A.; Sweigart, D. A. J. Chem. Soc., Dalton
Trans. 1996, 4493.
(5) (a) Gill, T. P.; Mann, K. R. Organometallics 1982, 1, 485. (b)
Moriarty, R. M.; Gill, U. S.; Ku, Y. Y. J. Organomet. Chem. 1988, 350,
157.
(6) (a) Pearson, A. J.; Chelliah, M. V. J. Org. Chem. 1998, 63, 3087.
(b) Janetka, J. W.; Rich, D. H. J. Am. Chem. Soc. 1997, 119, 6488.
(7) Pigge, F. C.; Fang, S.; Rath, N. P. Tetrahedron Lett. 1999, 40, 2251.
(8) Ru¨ba, E.; Simanko, W.; Mauthner, K.; Soldouzi, K. M.; Slugovc,
C.; Mereiter, K.; Schmid, R.; Kirchner, K. Organometallics 1999, 18, 3843.
10.1021/ol991123v CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/04/1999

line derivatives that would exploit both the activating and
stereodirecting effects of a CpRuII fragment was devised.
The approach (Scheme 1) was envisioned to proceed via
tion reactions with (haloarene) transition metal complexes;10
consequently, the intramolecular substitution of the chlorine
atom in 6 was not anticipated to be a difficult transformation.
Unfortunately, all attempts to convert 6 to 7 (eq 1) resulted
Scheme 1
in either formation of intractable mixtures or recovery of
unreacted starting material. This reaction was attempted
under both basic (K2CO3/DMSO; NaH/THF; NaH/DMF;
Ag2CO3/THF; KOtBu/tBuOH; KOH/H2O/DMSO) and acidic
(TFA/THF) conditions at various temperatures, all to no
avail.
Unwilling to accept that the activated arene present in 6
was unreactive, an effort was made to trap any intermediate
species formed by initial nucleophilic addition to the aromatic
nucleus. Thus, a THF suspension of 6 was treated with
KOtBu and 18-crown-6 (18-C-6) and heated to reflux
(Scheme 3). After several hours, methyl tosylate (MeOTs)
intramolecular nucleophilic aromatic substitution between a
stabilized enolate and a haloarene functional group present
in complex 1 to provide complex 2. Stereoselective alkylation
at the benzylic position7 and functional group manipulation
(including decomplexation) would ultimately yield 3.
To determine the feasibility of this approach, a CpRuII
complex of the type 1 was required. A suitable arene ligand
(5) was prepared in high yield via routine functional group
manipulation starting from 2-chlorobenzylamine (Scheme 2).
Scheme 2
Scheme 3
Successful η6-coordination of 5 to a CpRuII moiety using
Mann’s procedure5a was not, however, a forgone conclusion
given the presence of a potentially competitive â-dicarbonyl
ligand.8 Gratifyingly, treatment of 5 with (CH3CN)3RuCp‚
PF6 in warm 1,2-dichloroethane resulted in smooth com-
plexation of the aromatic ring and 6 was isolated as a
crystalline solid in excellent (94%) yield.9 Stabilized enolates
generated from â-dicarbonyl compounds are known to
participate in intermolecular nucleophilic aromatic substitu-
was added, and the reaction was maintained at reflux several
additional hours. Analysis of the reaction mixture by thin-
layer chromatography revealed the presence of a new UV-
active compound. Isolation and purification of this material
using flash column chromatography (SiO2) afforded a
colorless crystalline solid assigned the novel structure 8 on
the basis of extensive 1D and 2D-NMR spectroscopic
(11) All crystallographic data will be deposited in the Cambridge
Structural Database.
(12) (a) Robertson, D. R.; Stephenson, T. A. J. Organomet. Chem. 1977,
142, C31. (b) Robertson, I. W.; Stephenson, T. A.; Tocher, D. A. J.
Organomet. Chem. 1982, 228, 171. (c) Vol’kenau, N. A.; Bolesova, I. N.;
Shul’pina, L. S.; Kitaigorodskii, A. N. J. Organomet. Chem. 1984, 267,
313.
(13) Semmelhack, M. F.; Yamashita, A. J. Am. Chem. Soc. 1980, 102,
5924. See also: Chamberlin, S.; Wulff, W. D. J. Am. Chem. Soc. 1992,
114, 10667.
(9) All new compounds exhibited spectral (1H-NMR, 13C-NMR, and IR)
and analytical (combustion analysis) data consistent with the assigned
structures.
(10) (a) Semmelhack, M. F.; Hall, H. T. J. Am. Chem. Soc. 1974, 96,
7091. (b) Moriarty, R. M.; Ku, Y. Y.; Gill, U. S. Organometallics 1988, 7,
660. (c) Moriarty, R. M.; Gill, U. S. Organometallics 1986, 5, 253. (d)
Abd-El-Aziz, A. S.; Lee, C. C.; Pio´rko, A.; Sutherland, R. G. J. Organomet.
Chem. 1988, 348, 95. (e) Pio´rko, A.; Abd-El-Aziz, A. S.; Lee, C. C.;
Sutherland, R. G. J. Chem. Soc., Perkin Trans. 1 1989, 469.
(14) Complexes 9 and 10 were prepared from the corresponding
benzylamines using a route analogous to that shown in Scheme 2.
1852
Org. Lett., Vol. 1, No. 11, 1999

analysis.9 Confirmation of this structural assignment was
secured through single-crystal X-ray diffraction and the
molecular structure of 8 is shown in Figure 1.11 Evidently,
spirocycles via nucleophilic addition to certain arene-
chromium complexes as first reported by Semmelhack nearly
20 years ago.13 Thus, efforts were directed toward optimizing
conditions leading to spirocyclic products and toward obtain-
ing an initial indication of the generality of the reaction. A
number of reaction conditions were screened in the course
of this study, and the best isolated yield of 8 (83%) was
obtained using the protocol illustrated in Scheme 3 (lower
arrow). Dimethyl sulfoxide proved to be a superior solvent
as compared to THF, DMF, and CH3CN. The use of KOtBu
as well as K2CO3 and the addition of 18-C-6 also were
important for obtaining high yields of 8. Finally, dimethyl
sulfate (Me2SO4) proved to be a more effective electrophile
than methyl tosylate.
With the identification of an acceptable set of reaction
conditions, the influence of substituents on the arene nucleus
was next examined. As shown in Scheme 4, neither the
Scheme 4
Figure 1. X-ray structure of cyclohexadienyl Ru complex 8.
under these reaction conditions the stabilized enolate gener-
ated by deprotonation of 6 adds regio- and stereoselectively
to the ipso carbon from the face opposite the Ru center to
form the observed neutral spirocyclic cyclohexadienyl-
cyclopentadienyl-Ru(II) complex. Further deprotonation of
the initially formed spirocycle results in production of a
second stabilized enolate that is then trapped via O-alkylation
to afford the E-enol ether exclusively. Currently, it is not
known whether the spirocyclic ring system represents the
thermodynamically favored arene addition product or whether
subtle conformational effects operative in the benzylamide
substituent are responsible for the observed regioselectivity.
Whatever the underlying reason for the formation of 8, this
organometallic complex possesses an intriguing structure that
merits further discussion. First, 8 exhibits remarkable stability
as a solid and in solution. Crystals of 8 can be stored at
room temperature open to the air for extended periods of
time with no evidence of decomposition. The complex also
is amenable to purification by flash column chromatography.
Finally, while simple cyclohexadienyl cyclopentadienyl
complexes of Ru(II) have been prepared and spectroscopi-
cally characterized by addition of nucleophiles (hydride, RLi)
to arene complexes,5b,12 8 appears to be the first such complex
structurally characterized via X-ray crystallography.
presence of a strong electron-donating substituent in the ortho
position (9, X ) OMe) nor the absence of a substituent (10,
X ) H) had a profound effect on the efficiency of spirocycle
formation.14 In each case the spirocyclic products (11 and
12) were isolated as single stereoisomers, the structures being
assigned on the basis of extensive NMR spectroscopic
measurements and by analogy to 8.9 The modest decrease
in isolated yield observed in the preparation of 11 and 12
relative to 8 may be indicative of a small electronic
substituent effect and experiments are underway to determine
if this is the case.15 Complex 10 was chosen to assay the
suitability of alternative electrophiles in the reaction. Sub-
stituting Ac2O for Me2SO4 in Scheme 4 resulted in stereo-
selective formation of enol acetate 13 in 64% yield, whereas
use of allyl tosylate led to isolation of allyl vinyl ether 14 in
somewhat more modest (27%) yield, again as a single
stereoisomer.9 Allyl bromide was found to be an ineffective
reaction partner.
While the formation of 8 was unexpected, the transforma-
tion depicted in Scheme 3 may represent a potentially general
route to important azaspirocyclic ring systems. Moreover,
the formation of spirocycles via intramolecular nucleophilic
addition to arene-metal complexes is a rarely observed
reaction manifold. In fact, it appears the only other notable
examples of such a process involve formation of carbocyclic
In conclusion, a novel, stereoselective, and potentially
general route for the preparation of stable azaspirocyclic
Org. Lett., Vol. 1, No. 11, 1999
1853

cyclohexadienyl-cyclopentadienyl-Ru(II) complexes has
been uncovered. Significantly, removal of the azaspiro[4,5]-
decane ligand from the metal center would provide access
to highly functionalized compounds structurally related to
several classes of biologically active natural products, such
as the triticones,16 spirostaphylotrichins,17 histrionicotoxins,18
and certain Nitraria alkaloids.19 Studies aimed at achieving
this goal are underway. Additionally, the scope and limita-
tions of this methodology, particularly as a means of
accessing alternative spirocyclic ring systems, is also being
examined. Finally, it is noteworthy that ortho-disubstituted
arene-Ru complexes (e.g., 6 and 9) potentially are available
as optically pure planar-chiral materials which would allow
for the construction of azaspirocyclic ring systems with
control of absolute stereochemistry.
Acknowledgment. Financial support for this work was
provided by the donors of the Petroleum Research Fund,
administered by the American Chemical Society (ACS-PRF
32756-G1), the UM-St. Louis Graduate School (S.F., summer
research fellowship, 1999), and Mallinckrodt, Inc. (S.F.).
Support for departmental instrumentation facilities (NMR and
X-ray) was provided by grants from the NSF (CHE-9318696
and CHE-9309690) and the U.S. Department of Energy (DE-
FG02-92-CH10499).
(15) For a discussion of regioselectivity in nucleophilic additions to
substituted (arene)metal complexes, see: Sutherland, R. G.; Zhang, C.;
Pio´rko, A. J. Organomet. Chem. 1991, 419, 357 and references therein.
(16) Hallock, Y. F.; Lu, H. S. M.; Clardy, J.; Strobel, G. A.; Sugawara,
F.; Samsoedin, R.; Yoshida, S. J. Nat. Prod. 1993, 56, 747.
(17) Walser-Volken, P.; Tamm, Ch. In Progress in the Chemistry of
Organic Natural Products; Herz, W., Kirby, G. W., Moore, R. E., Steglich,
W., Tamm, Ch., Eds.; Springer: New York, 1996; Vol. 67, pp 125-165.
(18) Daly, J. W.; Garraffo, H. M.; Spande, T. F. In The Alkaloids; Cordell,
G. A., Ed.; Academic Press: New York, 1993; Vol. 43, pp 186-288.
(19) Franc¸ois, D.; Lallemand, M.-C.; Selkti, M.; Tomas, A.; Kunesch,
N.; Husson, H.-P. Angew. Chem., Int. Ed. Engl. 1998, 37, 104 and references
therein.
Supporting Information Available: Complete crystal-
lographic details for 8. This material is available free of
charge via the Internet at http://pubs.acs.org.
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