Ruthenium(II) porphyrin catalyzed formation of (Z)-4-alkyloxycarbonyl-methylidene-1,3-dioxolanes from γ-alkoxy-γ-diazo-β-ketoesters

Article abstract of DOI:10.1021/ol010283f

(equation presented) R¹ = aryl, allyl R²= methyl, 2,4-dimethyl-3-pentyl and (-)-menthyl Ruthenum(II) porphyrins and dirhodium(II) acetate catalyze cyclization of γ-alkoxy-α-diazo-β-ketoesters to (Z)-4-(alkyloxycarbonylmethylidene)-1,3-dioxolanes selectively (ca. 68% yield) with no formation of 3(2H)-furanones. Reacting a diazo ketoester with [Ru^II(TTP)(CO)] [H₂TTP = meso-tetrakis(p-tolyl) porphyrin] in toluene afforded a ruthenium carbenoid complex, which has been isolated and spectroscopically characterized. A mechanism involving hydrogen atom migration from the C-H bond to the ruthenium carbenoid is proposed.

Full text of DOI:10.1021/ol010283f

ORGANIC
LETTERS
2002
Vol. 4, No. 6
889-892
Ruthenium(II) Porphyrin Catalyzed
Formation of (Z)-4-Alkyloxycarbonyl-
methylidene-1,3-dioxolanes from
γ-Alkoxy-r-diazo-â-ketoesters
Shi-Long Zheng, Wing-Yiu Yu, and Chi-Ming Che*
Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of
Molecular Technology for Drug DiscoVery and Synthesis, The UniVersity of Hong
Kong, Pokfulam Road, Hong Kong
cmche@hku.hk
Received December 3, 2001
ABSTRACT
Ruthenum(II) porphyrins and dirhodium(II) acetate catalyze cyclization of γ-alkoxy-r-diazo-â-ketoesters to (Z)-4-(alkyloxycarbonylmethylidene)-
1,3-dioxolanes selectively (ca. 68% yield) with no formation of 3(2H)-furanones. Reacting a diazo ketoester with [RuII(TTP)(CO)] [H TTP )
2
meso-tetrakis(p-tolyl) porphyrin] in toluene afforded a ruthenium carbenoid complex, which has been isolated and spectroscopically characterized.
A mechanism involving hydrogen atom migration from the C−H bond to the ruthenium carbenoid is proposed.
The transition metal carbenoid mediated C-H insertion
reaction has proven to be a versatile and effective method
for organic synthesis.1 Notably “reactive rhodium carbenoid
intermediates,” derived from the reaction of dirhodium(II)
carboxylates/carboximidates with diazo compounds, have
been postulated to be active intermediates for highly stereo-
and enantioselective intra- and intermolecular C-H bond
insertions.2 However, such species are too reactive for
isolation and characterization.3 Recent studies showed that
diazo compounds4 such as diphenyldiazomethane react with
ruthenium(II) porphyrins4f to afford ruthenium carbene
complexes, some of which have been structurally charac-
terized.4c-f Of particular note is the fact that these carbenes
can catalyze styrene cyclopropanation using ethyl diazo-
acetate with high product turnovers and anti-syn diastereo-
selectivity.4f,5 Although oxo-6 and imido-ruthenium7 porphy-
rins can effect oxygen and nitrogen group insertion to
saturated C-H bonds, there are few examples of C-H bond
functionalization by ruthenium carbene complexes in the
literature.
(1) For reviews, see: (a) Taber, D. F. ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, U.K., 1991; Vol.
3, p 1045. (b) Padwa, A.; Austin, D. J. Angew. Chem., Int. Ed. Engl. 1994,
33, 1797. (c) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds; John Wiley and
Sons: New York, 1998. (d) Sulikowski, G. A.; Cha, K. L.; Sulikowski, M.
M. Tetrahedron: Asymmetry 1998, 9, 3145. (e) Pfaltz, A. ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer-Verlag: New York, 1999; Vol. 2. p 513. (f) Davies, H. M. L.;
Antoulinakis, E. G. J. Organomet. Chem. 2001, 617-618, 47.
(2) Selected examples: (a) Demonceau, A.; Noels, A. F.; Hubert, A. J.;
Teyssie´, P. J. Chem. Soc., Chem. Commun. 1981, 688. (b) Callot, H. J.;
Metz, F. Tetrahedron Lett. 1982, 23, 4321. (c) Davies, H. M. L.; Hansen,
T. J. Am. Chem. Soc. 1997, 119, 9075. (d) Davies, H. M. L.; Hansen, T.;
Churchill, M. R. J. Am. Chem. Soc. 2000, 122, 3063.
(3) For isolation of a stable dirhodium tetracarboxylate carbenoid:
Snyder, J. P.; Padwa, A.; Stengel, T.; Arduengo III, A. J.; Jockisch, A.;
Kim, H.-J. J. Am. Chem. Soc. 2001, 123, 11318.
(4) (a) Collman, J. P.; Brothers, P. J.; McElwee-White, L.; Rose, E.;
Wright, L. J. J. Am. Chem. Soc. 1985, 107, 4570. (b) Collman, J. P.; Rose,
E.; Venburg, G. D. J. Chem. Soc., Chem. Commun. 1993, 934. (c) Park,
S.-B.; Sakata, N.; Nishiyama, H. Chem. Eur. J. 1996, 2, 303. (d) Galardon,
E.; Le Maux, P.; Toupet, L.; Simonneaux, G. Organometallics 1998, 17,
565. (e) Klose, A.; Solari, E.; Floriani, C.; Geremia, S.; Randaccio, L.
Angew. Chem., Int. Ed. 1998, 37, 148. (f) Che, C.-M.; Huang, J.-S.; Lee,
F.-W.; Li, Y.; Lai, T.-S.; Kwong, H.-L.; Teng, P.-F.; Lee, W.-S.; Lo, W.-
C.; Peng, S.-M.; Zhou, Z.-Y. J. Am. Chem. Soc. 2001, 123, 4119.
10.1021/ol010283f CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/21/2002

Recently, we prepared a bis(diphenylcarbene)osmium
porphyrin complex, [OsII(TPFPP)(CO)] [H2TPFPP ) meso-
tetrakis(pentafluorophenyl)porphyrin], which can undergo
allylic C-H insertion reactions with cycloalkenes.8 This has
prompted us to investigate the reactivity of ruthenium carbene
complexes toward C-H insertion. We were attracted to the
finding by Adams and co-workers that dirhodium(II) acetate
mediated stereoselective cyclization of γ-alkoxy-R-diazo
ketones to 3(2H)-furanones via carbenoid insertion into the
C-H bond adjacent to an ether oxygen.9,10 Here we report
that ruthenium porphyrins (Figure 1) and dirhodium acetate
Scheme 1. Synthetic Route for γ-Alkoxy-R-diazo-â-ketoesters
mesyl azide furnished the γ-alkoxy-R-diazo-â-ketoesters 1
in overall yields of about 40%.13
When diazo ketoester 1a (0.5 mmol) was treated with a
catalytic quantity of [RuII(TTP)(CO)] [H2TTP ) meso-
tetrakis(p-tolyl)porphyrin; 3 mol %] in refluxing dry toluene
under an inert atmosphere, the dioxolane product 2a was
produced in 68% isolated yield (Table 1, entry 1). Diazo
esters 1b-e bearing bulky ester groups such as 2,4-dimethyl-
3-pentyl and (-)-menthyl groups also underwent facile
conversion to their corresponding dioxolanes 2b-e in 55-
67% yields (entries 2-6). When the diastereoselectivity of
cyclization of 1c to dioxolane 2c was analyzed by chiral
HPLC (chiral OJ column; 1% propan-2-ol, 99% hexane),
less than 7% de was observed. However, after recrystalli-
zation of 2c by diffusing hexane into the dichloromethane
solution, we obtained a diastereomerically pure (>99% de)
crystalline solid according to chiral HPLC analysis. The
molecular structure of 2c was confirmed by X-ray crystal-
lography (see Supporting Information).
Previously, McKervey and co-workers10a described that
[Rh2(CH3CO2)4] and derivatives catalyzed cyclization of
γ-alkoxy-R-diazo-â-ketoesters via C-H insertion to form
3(2H)-furanones selectively. Recently Clark and co-workers10e,f
reported a similar Rh-catalyzed reaction of R-diazo ketones
in which 3(2H)-furanones were formed as major product; a
minor formation of dioxolanes (ca. 10-40% yield) was also
observed. In this work, we found that [Rh2(CH3CO2)4] (3
mol %) also catalyzed cyclization of the diazo ketoester 1a
in dichloromethane at room temperature to afford dioxolane
2a selectively (Table 1, entry 1); no C-H insertion product
[i.e., 3(2H)-furanone] was detected. Likewise, other sterically
encumbered diazo ketoesters 1b-e were found to give the
corresponding dioxolanes in 51-67% yields.
Figure 1. Ruthenium(II) porphyrins.
can catalyze intramolecular cyclization of γ-alkoxy-R-diazo-
â-ketoesters to afford (Z)-4-(alkyloxycarbonylmethylidene)-
1,3-dioxolanes exclusively and that the formation of C-H
insertion products [i.e., 3(2H)-furanones] was not detected.
Our preliminary results suggest that the reactions proceed
by H-atom migration to ruthenium carbene complexes.
γ-Alkoxy-R-diazo-â-ketoesters 1 were prepared according
to Scheme 1. Methyl γ-bromoacetoacetate was converted to
its γ-alkoxy derivatives by reaction with appropriate alco-
hols;11 subsequent transesterification with other alcohol
derivatives gave γ-alkoxy-â-ketoesters.12 Diazo transfer with
(5) For chiral ruthenium porphyrin-catalyzed asymmetric alkene cyclo-
propanations: (a) Lo, W.-C.; Che, C.-M.; Cheng, K.-F.; Mak, T. C.-W. J.
Chem. Soc., Chem. Commun. 1997, 1205. (b) Galardon, E.; Le Maux, P.;
Simonneaux, G. J. Chem. Soc., Chem. Commun. 1997, 927. (c) Frauenkron,
M.; Berkessel, A. Tetrahedron Lett. 1997, 38, 7175. (d) Gross, Z.; Galili,
N.; Simkhovich, L. Tetrahedron Lett. 1999, 40, 1571. (e) Galardon, E.; Le
Maux, P.; Simonneaux, G. Tetrahedron 2000, 56, 615. (f) See ref 4f.
(6) (a) Groves, J. T.; Quinn, R. J. Am. Chem. Soc. 1985, 107, 5790. (b)
Leung, W.-H.; Che, C.-M. J. Am. Chem. Soc. 1989, 111, 8812. (c) Ho, C.;
Leung, W.-H.; Che, C.-M. J. Chem. Soc., Dalton Trans. 1991, 2933. (d)
Zhang, R.; Yu, W.-Y.; Lai, T.-S.; Che, C.-M. Chem. Commun. 1999, 1791.
(e) Che, C.-M.; Yu, W.-Y. Pure Appl. Chem. 1999, 71, 281.
(7) (a) Au, S.-M.; Fung, W.-H.; Cheng, M.-C.; Che, C.-M.; Peng, S.-M.
Chem. Commun. 1997, 1655. (b) Au, S.-M.; Huang, J.-S.; Yu, W.-Y.; Fung,
W.-H.; Che, C.-M. J. Am. Chem. Soc. 1999, 121, 9120.
(8) Li, Y.; Huang, J.-S.; Zhou, Z.-Y.; Che, C.-M. J. Am. Chem. Soc.
2001, 123, 4843.
(9) (a) Adams, J.; Poupart, M. A.; Grenier, L.; Schaller, C.; Quimet, N.;
Frenette, R. Tetrahedron Lett. 1989, 30, 1749. (b) Adams, J.; Poupart, M.
A.; Grenier, L. Tetrahedron Lett. 1989, 30, 1753.
(10) See also: (a) Ye, T.; McKervey, M. A.; Brandes, B. D.; Doyle, M.
P. Tetrahedron Lett. 1994, 35, 7269. (b) Taber, D. F.; Song, Y. J. Org.
Chem. 1996, 61, 6706. (c) Lee, E.; Choi, I.; Song, S. Y. J. Chem. Soc.,
Chem. Commun. 1995, 321. (d) Mander, L. N.; Owen, D. J. Tetrahedron
Lett. 1996, 37, 723. (e) Clark, J. S.; Dossetter, A. G. J. Org. Chem. 1997,
62, 4910. (f) Clark, J. S.; Wong, Y.-S.; Townsend, R. J. Tetrahedron Lett.
2001, 42, 6187.
Using benzyl R,R-d2-alcohol (98% D) as starting material,
we prepared a deuterium-labeled diazo ketoester 1c′. Under
the reaction conditions denoted in Table 1, both [RuII(TTP)-
(CO)] and [Rh2(CH3CO2)4] were found to effect cyclization
of 1c′ to dioxolane 2c′ (ca. 68% yield) (Table 1, entry 4).
1
On the basis of H NMR and mass spectroscopic analyses,
the deuterium content was conserved upon cyclization to
dioxolane. The NMR spectrum of 2c′ unequivocally reveals
that the deuterium atom at the exocyclic CdC bond
(11) Seebach, D.; Eberle, M. Synthesis 1986, 37.
(12) Taber, D. F.; Amedio, J. C.; Patel, Y. K. J. Org. Chem. 1985, 50,
3618.
(13) Taber, D. F.; Ruckle, R. E., Jr.; Hennessy, M. J. J. Org. Chem.
1986, 51, 4077.
890
Org. Lett., Vol. 4, No. 6, 2002

Table 1. Metal-Catalyzed Cyclization of γ-Alkoxy-R-diazo-â-ketoesters to Dioxolanesd
a Isolated yield. b Yield determined by 1H NMR analysis of the crude reaction mixture. c No formation of dioxolanes was detected by 1H NMR. d Reaction
conditions: A mixture of diazo ketoesters 1 (0.5 mmol) and metal catalyst (3 mol %) was stirred in refluxing toluene (25 mL) (for Ru) or dichloromethane
at room temperature (for Rh). The reaction was monitored by TLC for complete disappearance of starting materials. The solvent was then removed by
vacuum evaporation and, the residue was purified by flash chromatography.
originates from the benzylic C-D bond. This result suggests
that the Ru-/Rh-catalyzed intramolecular cyclization reaction
involves cleavage of the benzylic C-H bond as the principal
step.
to be the solvent of choice for the ruthenium-catalyzed
reactions; other solvents such as benzene and acetonitrile
gave considerably lower product yields of 45 and 26%,
respectively. When the ruthenium-catalyzed reaction was
performed in chloroform, tetrahydrofuran and dichloro-
methane, no dioxolane formation was observed and the
starting material was recovered (ca. 85%).
Employing 1c as the substrate, we have examined the
effect of different ruthenium catalysts on the cyclization of
γ-alkoxy-R-diazo-â-diketoesters (Table 2). Other ruthenium-
Apart from activation of benzylic C-H bonds, both
[RuII(TTP)(CO)] and [Rh2(CH3CO2)4] can catalyze cycliza-
tion of diazo esters such as 1f and 1g containing allylic C-H
bonds to produce dioxolanes in ca. 55% yields (entries 7
and 8). In all cases, the diazo esters were completely con-
1
sumed after the reactions. H NMR analysis of the crude
reaction mixtures revealed the dioxolane compounds as the
only identifiable products; no cyclopropanation products were
found.
Table 2. Effect of Ruthenium Porphyrin Catalysts on
Cyclization of (-)-Menthyl-γ-benzyloxy-R-diazo-â-ketoesterd
Cyclization of the diazo ketoesters containing aliphatic
alkoxy substituents (Table 1, entries 9-11) was also at-
tempted. Subjecting these diazo esters to the ruthenium-
catalyzed conditions (i.e. substrate ) 0.5 mmol, Ru ) 3 mol
% in refluxing toluene) afforded no detectable dioxolanes,
and complete substrate decomposition was observed accord-
ing to NMR analysis. In contrast, [Rh2(CH3CO2)4] was found
to be an effective catalyst for the cyclization of 1h-j under
ambient conditions, and 2h-j were isolated in 73-76%
yields (Table 1 entries 9-11). The molecular structure of 2i
has been determined by X-ray crystal analysis (see Support-
ing Information). Analogous to 2c, while low diastereo-
selectivity (<5% de) was obtained for the intramolecular
cyclization, analysis of the recrystallized sample of 2i by
chiral HPLC registered a diastereomeric purity of >99% de.
In the absence of the ruthenium or rhodium catalyst,
heating 1a in refluxing toluene resulted in complete substrate
a See text for notations. b Isolated yield. c Based on 1H NMR analysis
of crude reaction mixture. d Reaction conditions: A mixture of 1c (0.5
mmol) and Ru catalyst (3 mol %) was heated in refluxing toluene under an
inert atmosphere for 2 h.
1
decomposition, and no dioxolane 2a was detected by H
NMR analysis of the reaction mixture. Toluene was found
Org. Lett., Vol. 4, No. 6, 2002
891

(II) porphyrin complexes [RuII(Por)(CO)] (H2Por: H2OEP
) octaethylporphyrin; H2-p-F-TPP ) meso-tetrakis(p-fluoro-
phenyl)porphyrin; H2-3,4,5-MeO-TPP ) meso-tetrakis(3,4,5-
trimethoxyphenyl)porphyrin) were found to exhibit compa-
rable catalytic activities to [RuII(TTP)(CO)], and similar
yields (ca. 60%) of dioxolane 2c were obtained (Table 2,
entries 1-3). However, when [RuII(TDCPP)(CO)] [H2-
TDCPP ) meso-tetrakis(2,6-dichlorophenyl)porphyrin] or
[RuII(TMP)(CO)] [H2TMP ) meso-tetramesitylporphyrin]
was employed as catalyst, 2c was formed in <5% yield
(entries 4 and 5). It should be noted that the reaction of 1c
with [RuII(TDCPP)(CO)] or [RuII(TMP)(CO)] in toluene did
not give any ruthenium carbene complexes (see later sec-
tions). It is likely that steric hindrance of the bulky ortho-
substituents at the porphyrin ligand would disfavor the
carbene formation.
Some non-porphyrin-type ruthenium catalysts such as
[(Me3tacn)RuIII(CF3CO2)3 ‚H2O] (Me3tacn ) 1,4,7-trimethyl-
1,4,7-triazacyclononane)14 and [RuII(6,6′-Cl2-bpy)2(H2O)2](CF3-
SO3)2 (6,6′-Cl2-bpy ) 6,6′-dichloro-2,2′-bipyridine)15 were
found to exhibit negligible catalytic activity under the
standard experimental conditions [i.e., 1c (0.5 mmol) and
Ru catalysts (3%mol) in refluxing toluene]. No dioxolane
product 2c was obtained, and the diazo substrate was
completely decomposed. When RuII(PPh3)3Cl2 was used as
catalyst,16 heating diazo compound 1c in refluxing toluene
gave 2c in 18% yield. Yet when the same reaction was
carried out at room temperature, no dioxolane was produced
and the substrate was completely recovered.
Scheme 2. Proposed Mechanism
spectrum showed a downfield absorption at δC 287.5 ppm,
which is characteristic of a RudC moiety.4 FAB-MS analysis
of the sample showed a molecular ion peak [M+ + 1] at m/z
) 1011; this is consistent with the [(TTP)RudCR1R2] [R1
) C(O)C4H9; R2 ) C(O)OC7H13] formulation based on the
excellent agreement between the experimental and calculated
isotopic distributions.
To account for the dioxolane formation in the ruthenium
catalyzed cyclization of diazo esters, we propose that H-atom
migration to the electrophilic carbenoid carbon atom would
afford a reactive oxonium ion intermediate; intramolecular
attack by the carbonyl oxygen would furnish the dioxolane
compound. A similar mechanism was proposed by Clark and
co-workers to explain the minor formation of dioxolanes in
the rhodium-catalyzed intramolecular C-H insertion reac-
tions.
It has been reported that diazo compounds react with
[RuII(Por)(CO)] (H2Por ) tetraphenylporphyrin,4c 5,10,15,
20-tetrakis{(1S,4R,5R,8S)-1,2,3,4,5,6,7,8-octahydro-1,4:5,8-
dimethanoanthracene-9-yl}porphyrin)4f to give ruthenium
carbene complexes. In this work, when [RuII(TTP)(CO)]
reacted with 2,4-dimethyl-3-pentyl 2-diazo-3-oxo-heptanoate
(2 equiv) in refluxing toluene for 3 h under an argon
atmosphere, a color change from red to dark brown was
observed. After purification with flash chromatography
[hexane/ethyl acetate ) 95:5 (v/v)], a dark red solid was
isolated. The UV-visible spectrum of the ruthenium product
in CHCl3 shows an intense Soret band and a Q-band at λmax
) 407 and 534 nm, respectively. The 1H NMR spectrum is
characterized by two upfield doublet signals at δH 0.01 and
-0.23 ppm that could be assigned to the methyl protons of
the 2,4-dimethyl-3-pentyl moiety. The R-methylene protons
were also found to exhibit significant upfield shifts relative
to that in the unbound diazo ketoester. The 13C NMR
In conclusion, we have discovered that ruthenium por-
phyrins catalyze effective cyclization of γ-alkoxy-R-diazo-
â-ketoesters to form dioxolanes exclusively. With the
isolation of ruthenium carbene intermediates, the parallel
reactivity pattern for the reactions catalyzed by ruthenium-
(II) porphyrins and dirhodium(II) acetate supports postulation
of reactive rhodium carbenoid species for the latter reactions.3
Acknowledgment. This work was supported by the Areas
of Excellence Scheme established under the University
Grants Committee of the Hong Kong Special Administrative
Region, China (Project AoE/P-10/01), The University of
Hong Kong (Generic Drugs Research Program) and the Hong
Kong Research Grants Council (HKU7077/01P). Sincere
thanks are given to Dr. Tao Ye for many helpful discussions
and Dr. Nian-Yong Zhu for solving the crystal structures of
the dioxolanes.
Supporting Information Available: Experimental details
and characterization data for the products and crystal-
lographic data for dioxolanes 2c and 2i. This material is
available free of charge via the Internet at http://pubs.acs.org.
(14) (a) Cheng, W.-C.; Fung, W.-H.; Che, C.-M. J. Mol. Catal. A: Chem.
1996, 113, 311. (b) Fung, W.-H.; Yu, W.-Y.; Che, C.-M. J. Org. Chem.
1998, 68, 2873. (c) Che, C.-M.; Yu, W.-Y.; Chan, P.-M.; Cheng, W.-C.;
Peng, S.-M.; Lau, K.-C.; Li, W.-K. J. Am. Chem. Soc. 2000, 122, 11380.
(15) (a) Che, C.-M.; Leung, W.-H. J. Chem. Soc., Chem. Commun. 1987,
1376. (b) Lau, T.-C.; Che, C.-M.; Lee, W.-O.; Poon, C.-K. J. Chem. Soc.,
Chem. Commun. 1988, 1406. (c) Che, C.-M.; Ho, C.; Lau, T.-C. J. Chem.
Soc., Dalton Trans. 1991, 1901. (d) Che, C.-M.; Cheng, K.-W.; Chan, M.
C.-W.; Lau, T.-C.; Mak, C.-K. J. Org. Chem. 2000, 65, 7996.
(16) Schwab, P. Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100.
OL010283F
(17) A related hydride transfer mechanism has been proposed by Doyle
and White; see: (a) Doyle, M. P.; Dyatkin, A. B.; Autry, C. L. J. Chem.
Soc., Perkin Trans. 1 1995, 619. (b) White, J. D.; Hrnciar, P. J. Org. Chem.
1999, 64, 7271.
892
Org. Lett., Vol. 4, No. 6, 2002