Fluoride-promoted oxidation of Fischer alkoxy carbene complexes: Stoichiometric and catalytic conditions

Article abstract of DOI:10.1021/jo048736s

The utility of fluoride anion as promoter of the oxidation of Fischer carbene complexes is presented. Two different and complementary methods that allow the fast and convenient preparation of carbene-derived esters in good yields have been developed using

Full text of DOI:10.1021/jo048736s

cloadducts are obtained with high regioselectivity, high
diastereoselectivity, and/or increased reaction rates. For
those reasons, Fischer carbene complexes can be termed
as “superesters” or “superamides”; however, to free the
organic portion in the cycloadducts, the development of
procedures to remove the metal moiety is necessary.
In this sense, aldehydes can be obtained by reacting
FCCs with hydrobromic acid or triflic acid,6 and enoleters
can be accessed by treatment with a base (i.e., pyridine)
when the carbene complex bears acidic hydrogens in the
R-position.6b,7 Other transformations include methylena-
tion with diazomethane,6b,8 Wittig reagents,9 chlorom-
ethyllithium10 or ethylvinyl ether,11 hydrogenation lead-
ing to saturated compounds,6b,12 and reduction of amino
carbenes to amines and alkoxy carbenes to alcohols or
enol ethers by metal hydrides.13
In most cases, alkoxy FCCs are converted into their
analogous esters by treatment with oxidants such as
pyridine N-oxide (PNO),14 dimethyl sulfoxide,6b,c,15 dim-
ethyldioxyrane,16 ceric ammonium nitrate (CAN),14b,17
PhIO,14b NaOCl,18 KOCl,18 iodine,18 silica and air,19 air
alone,20 or lamp or sunlight exposition.5b However, the
strong reaction conditions sometimes required or the slow
reaction rates, resulting in long reaction times, including
weather dependence for the sunlight exposition, as well
as the unpredictable and/or low reaction yields often
caused by the formation of byproducts, encourages the
development of new methodologies for the oxidation of
F lu or id e-P r om oted Oxid a tion of F isch er
Alk oxy Ca r ben e Com p lexes:
Stoich iom etr ic a n d Ca ta lytic Con d ition s
J ose´ Barluenga,* Facundo Andina,
Manuel A. Ferna´ndez-Rodr´ıguez, Patricia Garc´ıa-Garc´ıa,
Isabel Merino, and Enrique Aguilar
Instituto Universitario de Quı´mica Organometa´lica
“Enrique Moles”, Unidad Asociada al CSIC, Universidad de
Oviedo, C/ J ulia´n Claverı´a, 8, 33006 Oviedo, Spain
barluenga@uniovi.es
Received J uly 23, 2004
Abstr a ct: The utility of fluoride anion as promoter of the
oxidation of Fischer carbene complexes is presented. Two
different and complementary methods that allow the fast
and convenient preparation of carbene-derived esters in good
yields have been developed using stoichiometric or catalytic
quantities of fluoride ion.
The utility of Fischer carbene complexes (FCCs) as
intermediates in organic synthesis has been widely
demonstrated, and it is today commonly accepted.1
Among the new chemistry originated by Fischer carbene
complexes, the Do¨tz benzannulation2 reaction appears to
be a unique tool for the construction of substituted and
functionalized phenol derivatives, while Hegedus photo-
chemical ketene generation represents also a remarkable
synthetic contribution.3 In these reactions, the carbene
carbon is incorporated as part of the skeleton of the newly
formed products and a further step to remove the metal
is not necessary. In other reactions, such as the Diels-
Alder reaction4 or 1,3-dipolar cycloadditions,5 the cy-
(6) (a) Anderson, B. A.; Wulff, W. D.; Rham, A. J . Am. Chem. Soc.
1993, 115, 4602-4611. (b) Wulff, W. D.; Yang, D. C. J . Am. Chem.
Soc. 1983, 105, 6726-6727. (c) Fischer, E. O.; Walz, S.; Kneis, G.;
Kreissl F. R. Chem. Ber. 1977, 110, 1651-1658.
(7) Fischer, E. O.; Plabst, D. Chem. Ber. 1974, 107, 3326-3331.
(8) Casey, C. P.; Betz, S. H.; Burkhardt, T. J . Tetrahedron Lett.
1973, 14, 1421-1424.
(9) Casey, C. P.; Burkhardt, T. J . J . Am. Chem. Soc. 1972, 94, 6543-
6544.
(1) Selected reviews regarding synthetic applications of Fischer
carbene complexes in the last 5 years: (a) Barluenga, J .; Santamar´ıa,
J .; Toma´s, M. Chem. Rev. 2004, 104, 2259-2284. (b) Barluenga, J .;
Flo´rez, J .; Fan˜ana´s, F. J . J . Organomet. Chem. 2001, 624, 5-17. (c)
Do¨tz, K. H.; J akel, C.; Haase, W. C. J . Organomet. Chem. 2001, 617-
618, 119-132. (d) de Meijere, A.; Schirmer, H.; Duestsch, M. Angew.
Chem., Int. Ed. 2000, 39, 3964-4002. (e) Barluenga, J .; Fan˜ana´s, F.
J . Tetrahedron 2000, 56, 4597-4628. (f) Herndon, J . W. Tetrahedron
2000, 56, 1257-1280. (g) Sierra, M. A. Chem. Rev. 2000, 100, 3591-
3638. (h) Zaragoza Do¨rwald, F. In Metal Carbenes in Organic Synthesis;
Wiley-VCH: New York, 1999.
(10) Barluenga, J .; Bernard, P. L., J r.; Concello´n, J . M. Tetrahedron
Lett. 1994, 35, 9471-9472.
(11) Fischer, E. O.; Do¨tz, K. H. Chem. Ber. 1972, 105, 3966-3973.
(12) Casey, C. P.; Neumann, M. J . Am. Chem. Soc. 1977, 99, 1651-
1652.
(13) (a) Ram´ırez-Lo´pez, P.; Go´mez-Gallego, M.; Manchen˜o, M. J .;
Sierra, M. A.; Bilurbina, M.; Ricart, S. J . Org. Chem. 2003, 68, 3538-
3545 and references cited therein. (b) Barluenga, J .; Granados, A.;
Rodr´ıguez, F.; Vadecard, J .; Fan˜ana´s, F. J . Tetrahedron Lett. 1997,
38, 6465-6466. (c) Baldoli, C.; del Buttero, P.; Licandro, E.; Maiorana,
S.; Papagni, A.; Zanotti-Gerosa, A. Synlett 1994, 677-678. (d) Connor,
J . A.; Fischer, E. O. J . Chem. Soc., Chem. Commun. 1967, 1024.
(14) (a) Erker, G.; Sosna, F. Organometallics 1990, 9, 1949-1953.
(b) Lukehart, C. M.; Zeile, J . V. J . Organomet. Chem. 1975, 97, 421-
428.
(15) Casey, C. P.; Burkhardt, T. J .; Bunnell, C. A.; Calabrese, J . C.
J . Am. Chem. Soc. 1977, 99, 2127-2134.
(16) Lluch, A. M.; J ordi, L.; Sa´nchez-Baeza, F.; Ricart, S.; Camps,
F.; Messeguer, A.; Moreto´, J . M. Tetrahedron Lett. 1992, 33, 3021-
3022 and references therein.
(17) (a) Quayle, P.; Rahman, S.; Ward, E.; Lucy, M.; Herbert, J .
Tetrahedron Lett. 1994, 35, 3801-3804. (b) Do¨tz, K. H.; Fu¨gen-Ko¨ster,
B.; Neugebauer, D. J . Organomet. Chem. 1979, 182, 489-498. (c)
Casey, C. P.; Boggs, R. A.; Anderson, R. L. J . Am. Chem. Soc. 1972,
94, 8947-8949.
(18) Perdicchia, D.; Licandro, E.; Maiorana, S.; Vandoni, B.; Baldoli,
C. Org. Lett. 2002, 4, 827-830.
(19) (a) Neidlein, R.; Gurtler, S. Synthesis 1995, 325-329. (b)
Aumann, R.; Schroeder, J .; Heinen, H. Chem. Ber. 1990, 123, 1369-
1374.
(2) (a) Barluenga, J .; Aznar, F.; Gutie´rrez, I.; Mart´ın, A.; Garc´ıa-
Granda, S.; Llorca-Baragan˜o, M. A. J . Am. Chem. Soc. 2000, 122,
1314-1324. (b) Do¨tz, K. H. Angew. Chem., Int. Ed. Engl. 1975, 14,
644-645.
(3) Representative references: (a) Hegedus, L. S. Tetrahedron 1997,
53, 4105-4128. (b) Hegedus, L. S. Transition Metal Carbene Com-
plexes: Photochemical Reactions of Carbene Complexes. In Compre-
hensive Organometallic Chemistry II; Abel, E. W., Stone, F. G. A.,
Wilkinson, G., Eds.; Pergamon: Oxford, 1995; Vol. 12, pp 549-576.
(4) Selected references: (a) Barluenga, J .; Aznar, F.; Barluenga,
S.; Ferna´ndez, M.; Mart´ın, A.; Garc´ıa-Granda, S.; Pin˜era-Nicola´s, A.
Chem. Eur. J . 1998, 4, 2280-2298. (b) Barluenga, J .; Canteli, R. M.;
Flo´rez, J .; Garc´ıa-Granda, S.; Gutie´rrez-Rodr´ıguez, A. J . Am. Chem.
Soc. 1994, 116, 6949-6950. (c) Merlic, C. A.; Xu, D. J . Am. Chem. Soc.
1991, 113, 7418-7420. (d) Do¨tz, K. H.; Kuhn, W.; Mu¨ller, G.; Huber,
B.; Alt, H. G. Angew. Chem., Int. Ed. Engl. 1986, 25, 812-817. (e)
Wulff, W. D.; Yang, D. C. J . Am. Chem. Soc. 1984, 106, 7565-7567.
(5) (a) For an excellent review, see: Alcaide, B.; Casarrubias, L.;
Dom´ınguez, G.; Sierra, M. A. Curr. Org. Chem. 1998, 2, 551-574. See
also: (b) Barluenga, J .; Ferna´ndez-Rodr´ıguez, M. A.; Aguilar, E.;
Ferna´ndez-Mar´ı, F.; Olano, B.; Salinas, A. Chem. Eur. J . 2001, 7,
3533-3544; Chem. Eur. J . 2001, 7, 4323 (corrigendum) and references
therein.
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1968, 1313.
10.1021/jo048736s CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/11/2004
7352
J . Org. Chem. 2004, 69, 7352-7354

TABLE 1. F lu or id e-P r om oted Oxid a tion of Ca r ben e
Com p lex 1a
We tried to extend the methodology to other alkoxy
FCCs, using KF or Bu4NF as fluoride sources.21 Thus,
entrya
FS
solvent
reaction time
yieldb (%)
1
2e
3
NBu4F
NBu4F
NBu4F
NBu4F
NBu4F
CsF
CsF
KF
KF
KF
KF
KF
KF
KF
THF
THF
17 min
5 min
12 min
35 min
2 h
22 h
48 h
36 h
40 h
nr
43c,d
27
CH2Cl2
DME
DME
THF
DME
THF
CH3CN
CH2Cl2
CH3OH
DME
DME
DME
61c
68
4
5f
6
79
86c,d
80
7
8
9
10
11
12
13h
14i
78c,d
68
2 h
24 h
24 h
33g
76
77
j
a
All reactions were carried out at room temperature unless
b
otherwise stated. Yield of isolated product after flash chroma-
tography unless otherwise stated. c The reaction product was not
completely purified after flash chromatography; this number
represents the combined yield of the isolated mixture (assuming
d
that all the products have the same molecular weight). Products
resulting from THF ring opening and/or polymerization were also
detected. e Reaction performed with solid NBu4F at
a 5-fold
g
concentration. f Reaction carried out at 0 °C. A 16% yield of
methyl 3-phenylpropanoate 5d (resulting from double-bond reduc-
h
i
tion) was also isolated. Reaction carried out at 40 °C. Reaction
j
carried out at reflux. DME polymerization products were ob-
served; no carbene-derived products were identified.
carbene complexes. During the course of our research in
1,3-dipolar cycloadditions of Fischer carbene complexes
with azomethine ylides,5b we found that, under certain
conditions, high yields of carbene oxidation products were
obtained instead of the desired cycloadducts. A close
examination led us to conclude that the oxidation was
being promoted by the fluoride anion used to in situ
generate the 1,3-dipole, and we then decided to optimize
the conditions in order to develope a new and mild
carbene oxidation methodology. The following alkoxy
FCCs 1-3 have been oxidized in this work.
R,â-Unsaturated FCC 1a was used as the model sys-
tem; several conditions were evaluated, and some of them
are listed in Table 1. In all cases, 1.5 equiv of a fluoride
source were employed, and 1,2-dimethoxyethane (DME)
proved to be by far the optimum solvent among all the
solvents examined (entries 1, 3, 4, and 8-12). KF, CsF,
and Bu4NF were tested as fluoride sources, and the oxi-
dation with all of them led to similar yields; however, in
terms of kinetics, the reactions proceeded faster with KF
than with CsF (entry 7 vs 12), with Bu4NF as the fluoride
source that allowed the best results (entry 4) when 1,2-
DME was used as solvent. The use of a higher concentra-
tion caused a faster although low-yielding oxidation. The
reaction worked well at room temperature, and the em-
ployment of higher temperatures did not result in ap-
preciable increases of the reaction rate, producing similar
or even lower yields (entries 12-14). Decreasing the
reaction temperature was appropriate for carbene com-
plex 1a (entry 5 vs 4), but the reaction rate was almost
4-fold diminished, which resulted inconvenient for the
oxidation of other carbene complexes (vide infra).
when menthol-derived carbene 1b was employed, the rate
differences in using KF or Bu4NF as fluoride source in-
creased (Table 2, entry 1 vs 2); the increment is spectac-
ular for the more stable tungsten carbene complex 1e
(entry 6 vs 7), which is also oxidized under those condi-
tions.
As expected, the steric hindrance surrounding the
carbene carbon played a decisive role in the reaction rate.
In this sense, 8-phenylmenthol-derived alkenyl carbenes
were oxidized much more slowly than menthol-derived
alkenyl carbenes when using KF as fluoride source
(21) CsF was discarded as it was more expensive and led to the
slowest reaction rates.
J . Org. Chem, Vol. 69, No. 21, 2004 7353

TABLE 2. F lu or id e-P r om oted Oxid a tion of Alk oxy
F CCs 1-3
TABLE 3. Ca ta lytic F lu or id e-P r om oted Oxid a tion of
Alk oxy F CCs 1-3
entry
1-3
cat. (%)
reaction time (h)
4-6
yielda (%)
entry
1-3
FS
KF
Bu4NF
KF
Bu4NF
KF
KF
Bu4NF
Bu4NF
Bu4NF
Bu4NF
KF
Bu4NF
KF
reaction time
4-6
yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1a
1a
1a
1a
1b
2a
2b
2c
3a
3a
3b
3c
3d
10
5
2
1.5
6
8
36
36
36
12
5
12
8
24
24
14
14
4a
4a
4a
4a
4a
4b
5a
5b
5c
6a
6a
6b
6c
6d
84
88
89
80
83
86
86
85
88
61
63
33b
87
91
1
2
3
4
5
6
7
8
9
10
11
12
13
1b
1b
1c
1c
1d
1e
1e
2a
2b
2c
3a
3a
3b
100 h
45 min
7 d
18 min
13 d
4b
4b
4c
4c
4d
4b
4b
5a
5b
5c
6a
6a
6b
67
65
61
65
62
44
63
69
76
55
84
15c
41
1
0.5
10
10
5
10
5
2
2
5
5
15 d
15 min
b
10 min
10 min
27 h
5 min
84 h
a
a
Yield of isolated product after flash chromatography unless
Yield of isolated product after flash chromatography unless
otherwise stated. The reaction is instantaneous. c A 15% yield
b
b
otherwise stated. For this substrate, higher fluoride loading (5%)
of partially reduced product 4a was also isolated.
resulted in an even lower yield.
(entries 3, 5 vs 1), and the latter were oxidized more
slowly than the less hindered methanol-derived alkenyl
carbenes either using KF or Bu4NF as fluoride sources
(see Table 2, entries 1, 2 vs Table 1, entries 11, 3). In
these slow transformations there is a background oxida-
tion by air to some extent, but there is indeed a fluoride
effect that accelerates the reaction; for example, the
oxidation of carbene complex 1b was incomplete in DME
after 120 h in the absence of any fluoride source (compare
to Table 2, entry 1).
In general, when 1.5 equiv of Bu4NF is used, the
oxidation is complete within minutes. The methodology
allowed also the oxidation of alkyl (Table 2, entry 8), aryl
(entries 9, 10), and alkynyl (entries 11-13) carbene
complexes.
We have performed other experiments to determine the
stability of FCCs in the absence of air but in the presence
of stoichiometric amounts of fluoride anion. We can
conclude that FCCs can tolerate fluoride in the absence
of air at low temperature. In fact, they are fairly stable
at temperatures below -10 °C, while they decompose at
low but noticeable rates at 0 °C and the decomposition
becomes faster above that temperature.
We have also explored the possibility of an alternative
catalytic fluoride-promoted (Bu4NF) oxidation of Fischer
alkoxy carbene complexes, and the results are summar-
ized in Table 3. The oxidation, under catalytic conditions,
usually led to higher yields of isolated products. The cata-
lyst loading, for carbene complex 1a , could be reduced to
0.5% (entry 5), although the reaction time increased con-
siderably as the amount of catalyst was reduced (entries
1-5). Most of the oxidations were fast enough with 2-5%
of catalyst loading, but menthol-derived carbenes re-
quired a 10% of catalyst to be oxidized in useful times
(entries 6, 7, and 9), probably for steric reasons. Conse-
quently, 8-phenylmentol-derived carbene complexes were
not tested under these conditions. This procedure allowed
also the oxidation of alkyl, aryl and alkynyl carbene
complexes (entries 6-14), even when the latter bear
bulky triple bond substituents (entries 13, 14).22 Catalytic
fluoride-promoted oxidation of tungsten carbene complex
1e was very slow; most of the starting material remained
unreacted after 72 h for a 10% of catalyst loading.
In summary, we have developed two easy-to-work,
convenient, low-cost, and complementary procedures to
remove the metal moiety of Fischer alkoxy carbene
complexes by fluoride-promoted (KF or Bu4NF) oxidation
to the analogous esters. When 1.5 equiv of Bu4NF in 1,2-
DME was used, moderate to good yields of the oxidized
products were obtained in a few minutes. Depending on
both the steric demand of the carbene carbon and the
nature of the metal, catalytic amounts of fluoride may
be employed, which usually produces higher yields.
Research to uncover the mechanistic insights of this
transformation is currently underway, and it will be
reported in due course.
Ack n ow led gm en t. This research was supported by
MCYT (BQU2001-3858) and Consejer´ıa de Educacio´n
y Cultura del Principado de Asturias (PR-01-GE-9). F.A.
thanks the Universidad de Oviedo and CSIC for under-
graduate fellowships. P.G.-G. thanks the Ministerio de
Educacio´n y Cultura (Spain) for a FPU-graduate fel-
lowship.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O048736S
(22) Alkoxy alkynyl carbene complexes 3c,d had been oxidized with
PNO in 67-68% yield: Barluenga, J .; Ferna´ndez-Rodr´ıguez, M. A.;
Aguilar, E. Org. Lett. 2002, 4, 3659-3662.
7354 J . Org. Chem., Vol. 69, No. 21, 2004