Efficient synthesis of highly functionalized indazoles and 2,3-dihydro-1,2-benzisoxazoles by reaction of stable fischer dienyl carbenes and isocyanides

Article abstract of DOI:10.1002/1521-3765(20011217)7:24<5318::AID-CHEM5318>3.0.CO;2-C

A range of stable chromium and tungsten Fischer dienyl carbenes have been prepared by [3+2] cycloaddition of alkenylethynyl carbene complexes with nitrones or diazoalkanes. Treatment of these systems with isocyanides gives entry to highly functionalized 2

Full text of DOI:10.1002/1521-3765(20011217)7:24<5318::AID-CHEM5318>3.0.CO;2-C

FULL PAPER
Efficient Synthesis of Highly Functionalized Indazoles and
2,3-Dihydro-1,2-benzisoxazoles by Reaction of Stable Fischer Dienyl
Carbenes and Isocyanides
Jose¬ Barluenga,* Fernando Aznar, and M. Angel Palomero[a]
Abstract: A range of stable chromium and tungsten Fischer dienyl carbenes have
been prepared by [3‡2] cycloaddition of alkenylethynyl carbene complexes with
nitrones or diazoalkanes. Treatment of these systems with isocyanides gives entry to
highly functionalized 2,3-dihydro-1,2-benzisoxazoles and indazoles in a completely
regioselective fashion, under mild conditions, and with high yields. This methodology
can be also applied to the preparation of analogous naphthoisoxazoles starting from
arylethynyl Fischer complexes. Reductive cleavage of the isoxazole moiety in the
prepared heterocycles also enables the efficient synthesis of highly substituted p-
aminophenols.
Keywords: benzisoxazoles
benes ¥ cycloaddition ¥ indazoles ¥
isocyanides
¥
car-
Introduction
OR
M(CO)5
OR
OR R'
N
OR
R'
R'NC
NHR'
C
N
M(CO)5
Fischer carbene complexes
M(CO)5
have been extensively used in
synthetic organic chemistry,
since they enable high-yielding
Scheme 1. Reaction of isocyanides and Fischer dienyl carbene complexes.
transformations under mild
conditions and in a regioselective fashion.[1] Alkenyl Fischer
carbenes are particularly interesting in their synthetic appli-
cations due to their tendency to undergo cyclization and co-
cyclization with unsaturated substrates. Dˆtz benzannulation
products,[2] and many other different scaffolds, arise from their
reaction with acetylenes.[3]
Isocyanides also react with carbene complexes, giving rise
to ketenimine intermediates that evolve to form various types
of organic products depending on the substitution pattern of
the starting carbenes.[4] More specifically, when an alkoxy
alkenyl complex bearing an additional double bond is used, o-
alkoxyanilines are obtained from the electrocyclic ring-
closure of the initially formed ketenimine intermediate
(Scheme 1).[5] It is noteworthy that the double bond involved
in the cyclization belongs to an aromatic ring in most cases
reported to date. This reaction has been successfully applied
to the preparation of analogues of indolocarbazole natural
products[6] and to the total synthesis of calphostins.[7]
One of the current interests of our research group focuses
on the preparation of novel Fischer dienyl carbene complexes
through cycloaddition reactions of alkynyl carbenes bearing a
vinyl substituent and suitable substrates. The reaction of
alkynyl complexes 1 with 2-amino-1,3-butadienes[8] or enol
ethers[9] gave the desired 1,3,5-metallahexatrienes 2 and 3,
respectively (Scheme 2). While the [4‡2] cycloadducts 2 were
reactive at room temperature and evolved directly to form
organic products, dienyl carbenes 3 arising from the [2‡2]
cycloaddition to enol ethers could be isolated, and further
studies of their reactivity were carried out.[10]
The next step of our study consisted of the preparation of
1,3,5-metallahexatrienes, which contain a heterocyclic five-
membered ring, by application of the well-known [3‡2]
cycloaddition of alkynyl Fischer carbenes and nitrones[11] or
diazoalkanes.[12] Both types of dipole systems underwent
cycloaddition with alkynyl carbenes 1 to afford the expected
1,3,5-metallahexatrienes. We envisaged that annulation of
these new dienyl carbenes, by reaction with isocyanides,
would provide access to highly substituted 2,3-dihydro-1,2-
benzisoxazoles or indazoles.
[a] Prof. Dr. J. Barluenga, Prof. Dr. F. Aznar, M. A. Palomero
¬
Instituto Universitario de QuÌmica Organometalica ™Enrique Moles∫
¬
Unidad Asociada al C.S.I.C., Julian ClaverÌa 8
33071 Oviedo (Spain)
Fax : (‡34)98-510-34-46
E-mail: barluenga@sauron.quimica.uniovi.es
Supporting information for this article is available on the WWW under
http://wiley-vch.de/home/chemistry/ or from the author: analytical and
spectroscopic data for all new compounds prepared.
5318
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Chem. Eur. J. 2001, 7, No. 24

5318 5324
Results and Discussion
M(CO)5
OMe
Preparation of 2,3-dihydro-1,2-benzisoxazoles 7: Treatment of
chromium or tungsten alkynyl complexes 1 with equimolar
amounts of nitrones 4 at room temperature afforded the
expected dienyl carbenes 5 in very good yields (Scheme 3,
Table 1). Cycloaddition reactions were completely chemo-
and regioselective, since only the isomer shown in Scheme 3
was obtained. This adduct results from the addition of the
oxygen atom of the nitrone to the most electrophilic b-
position of the Fischer alkynyl carbene. No products derived
from the cycloaddition to the double bond of the carbene
complex were observed. Reaction times were typically short,
both for chromium and tungsten complexes, and the starting
materials were consumed in less than half an hour in all cases.
N
N
O
R2
O
MeO
R1
M(CO)5
O
R1
THF, RT
2
M(CO)5
O
OMe
R2
R2
n
n
1
R1
3 n = 1,2
Scheme 2. Cycloaddition reactions of alkenylethynyl alkoxy Fischer com-
plexes and 2-amino-1,3-butadienes or enol ethers.
R4
R5
O
As far as we know, all the
reported approaches to these
kinds of systems are based on
the preparation of the hetero-
N
MeO
R1
M(CO)5
M(CO)5
OMe
OMe
R1
R3
R3
R6NC
R3
R4
R5
R4
R5
NHR6
R2
6
4
N
N
R2
O
O
solvent
solvent
cyclic moiety starting from
R1
preformed benzene deriva-
R2
tives,[13, 14] which imposes a lim-
1
5
7
itation when hexasubstituted
aromatic rings are required as
starting materials. However,
Scheme 3. Preparation of 1,3,5-metallahexatrienes
5 and their cyclization to afford 2,3-dihydro-1,2-
benzisoxazoles 7.
our methodology would over-
Table 1. Preparation of 1,3,5-metallahexatrienes 5.[a]
come this problem, since the aromatic ring would be
generated in the final step by means of a completely
regioselective benzannulation reaction. Therefore, the use of
three successive processes, [3‡2] cycloaddition, isonitrile-
insertion, and ring-closure, would provide a good synthetic
method for the preparation of the cited benzene fused
heterocycles.
Herein we report an easy and efficient preparation of highly
functionalized 2,3-dihydro-1,2-benzisoxazoles or indazoles by
reaction of isocyanides with stable 1,3,5-metallahexatrienes,
which were in turn obtained by dipolar cycloaddition of
alkenyl ethynyl Fischer carbene complexes with nitrones or
diazoalkanes. Both processes took place under mild condi-
tions, in a completely regioselective fashion, and in high
yields.
Entry
1
M
R1
R2
4
R3 R4 R5
5
Yield [%][b]
1
2
3
4
5
6
7
8
9
1a Cr
1b
1c Cr
1d Cr
(CH2)3
(CH2)3
O(CH2)3
(CH2)4
(CH2)4
Ph
4a Ph
4a Ph
4a Ph
4a Ph
4a Ph
4a Ph
H
H
H
H
H
H
H
H
H
H
tBu 5a 97
tBu 5b 98
tBu 5c 95
tBu 5d 89
tBu 5e 97
tBu 5 f 88
tBu 5g 82
tBu 5h 98
tBu 5i 81
W
1e
1 f
W
W
Me
1g Cr CH2OC(CH3)2OCH2 4a Ph
1a Cr
1c Cr
1a Cr
1a Cr
(CH2)3
O(CH2)3
(CH2)3
4b Me
4b Me
4c Ph
[c]
10
11
Bn 5j
[c]
(CH2)3
4d Me Me iPr 5k
[a] tBu ˆ tert-butyl, Bn ˆ benzyl, iPrˆ isopropyl. [b] Reaction conditions: THF,
room temperature, 0.5 h. Yields refer to isolated products after flash chroma-
tography. [c] Complex not isolated.
Results displayed in Table 1 are for reactions carried out in
tetrahydrofuran (THF), although the [3‡2] cycloadditions
proceeded with comparable yields and rates when dichloro-
methane or toluene were used as solvents. This observation, as
well as the high regioselectivity of the process, is in agreement
with the concerted mechanism proposed for the dipolar
cycloaddition of nitrones with alkynyl Fischer carbene com-
plexes.[11]
Most of the dienyl carbenes 5 were stable and could be
isolated by flash chromatography. In only one of the cases
studied, when nitrone 4c was used, did the cycloadduct 5j
decompose under the workup conditions, and, therefore, had
to be stored in solution (Table 1, entry 10).
Abstract in Spanish: Se han preparado varios ejemplos de
complejos dienil carbeno de Fischer estables, de cromo y de
¬
¬
volframio, por reaccion de cicloadicion [3‡2] entre alqueni-
letinil complejos carbeno y nitronas o diazoalcanos. El
tratamiento de estos sistemas con dos equivalentes de un
isocianuro permite obtener 2,3-dihidro-1,2-benzisoxazoles e
indazoles altamente funcionalizados de forma completamente
regioselectiva, en condiciones suaves y con altos rendimentos.
¬
La misma metodologÌa puede aplicarse a la preparacion de
naftoisoxazoles a partir de ariletinil carbenos de Fischer. La
¬
ruptura en condiciones reductoras del enlace nitrogeno-oxÌge-
no del anillo de isoxazol previamente obtenido conduce a
p-aminofenoles sustituidos con excelentes rendimientos.
2,3-Dihydro-1,2-benzisoxazoles 7 were obtained in very
good yields upon treatment of dienyl complexes 5 with two
Chem. Eur. J. 2001, 7, No. 24
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5319

J. Barluenga et al.
FULL PAPER
equivalents of tert-butyl- or benzylisocyanide (6a,b) at room
temperature (Scheme 3, Table 2). Based on reported mecha-
nistic studies,[5] the annulation process can be assumed to
occur through the insertion of one molecule of isocyanide into
nide in THF, only a 45% yield of the corresponding aniline
derivative 7i was isolated (Table 2, entry 11). On the other
hand, trimethylsilylcyanide, which is known to react through
its isomeric form with Fischer dienyl carbenes,[6] did not allow
us to efficiently prepare the desired benzisoxazole derivatives.
Although small amounts of the final product were detected in
the 1H NMR spectrum of the crude mixture, the major
product of the reaction of 5a with trimethylsilylcyanide was
the amide derived from the hydrolysis of the ketenimine
intermediate (see Experimental Section). The electrocycliza-
tion only took place to a small extent, even after heating in
THF at reflux for several days.
Since this protocol provided entry into highly substituted
2,3-dihydro-1,2-benzisoxazoles, we decided to extend this
methodology to the preparation of analogous naphthoisox-
azoles. The starting Fischer complexes 9 were prepared as
described in the literature,[11] by reaction of aryl-substituted
alkynyl carbenes 8 with nitrone 4a. Further treatment with
benzylisocyanide in THF gave rise to naphtalene derivatives
10 in moderate yields (Scheme 4). These annulation reactions
were slower than those of dienyl complexes 5 and proceeded
in lower yields. This is probably due to the higher energetic
cost required to break the aromaticity of the ring present in
the structure of 9 during the electrocyclization. It is note-
worthy that the best results were obtained when complex 9a,
bearing a non-substituted phenyl moiety, was used. The
influence of the substituents in the aromatic ring can be
explained by assuming that the electron-withdrawing group
facilitates the first step of the process, the isonitrile insertion,
but makes the intermediate more stable towards the electro-
cyclization. The opposite behavior could be proposed for a
system containing an electron-donating group. Therefore, it
seemed reasonable that the global transformation proceeded
in lower yields when substituted aromatic rings were used.
Table 2. Preparation of 2,3-dihydro-1,2-benzisoxazoles 7.[a]
Entry
5
6
R6
7
Yield [%][b]
Stepwise One-pot
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5 f
5g
5h
5i
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6b
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
Bn
7a
7a
7b
7c
7c
7d
7e
7 f
7g
7h
7i
89
90
78
91
87
72
82
88
94
77
72
61
79
10
11
12
5j
5k
5a
83
45
75
7j
92
[a] tBu ˆ tert-butyl, Bn ˆ benzyl. [b] Yields refer to reactions carried out in
THF.
the metal carbon bond of the starting carbene to afford a
pentacarbonylmetal-complexed dienyl ketenimine intermedi-
ate, followed by a six-electron electrocyclic ring-closure and
tautomerism of the resulting imine, to produce the final
aniline derivative.[15] The second equivalent of isocyanide is
required to demetalate the intermediate formed during the
metathesis process. The ketenimine complex has not been
detected since the electrocyclization is very fast at room
temperature, but its existence is supported by the previous
characterization of an analogous species.[16]
Reactions were monitored by TLC analyses, and total
consumption of the starting carbenes 5 was observed in less
than three hours in all the cases. The benzannulation process
was neither metal nor solvent dependent, and similar yields
and reaction times were observed with both chromium and
tungsten starting complexes (Table 2, entries 1, 2, 4, and 5),
and when THF, diethyl ether, dichloromethane, or toluene
were used. Yields shown in Table 2 refer to the reactions
carried out in THF. 2,3-Dihydro-1,2-benzisoxazoles 7 can also
be obtained in a one-pot process from alkynyl carbenes 1:
once the [3‡2] cycloadduct was formed, isocyanide was added
to the crude reaction mixture to afford compounds 7 without
noticeable loss in the yields (Table 2, entries 1, 2, 6, 7, and 12).
This fact enabled us to directly
Preparation of indazoles 13: Trimethylsilyl diazomethane was
chosen as the most suitable dipole for the preparation of 1,3,5-
metallahexatrienes from complexes 1, since it is known that
[3‡2] cycloadditions of this system with alkynyl Fischer
carbenes are more chemoselective for the carbon carbon
triple bond than those of diazomethane.[12] According to
literature procedures, a 2m solution of trimethylsilyl diazo-
methane in hexanes was slowly added to chromium or
tungsten alkynyl complexes 1 in THF at 08C. The reaction
mixture immediately changed from red to dark orange, and
tBu
synthesize product 7h, for
N
O
MeO
Cr(CO)5
Cr(CO)5
OMe
OMe
which metallahexatriene pre-
cursor 5j could not be isolated
(Table 2, entry 10).
Ph
tBu N
Ph
tBu N
Ph
NHBn
R
BnNC
THF
4a
O
O
THF
The benzannulation process,
however, appeared to be sensi-
tive to the substrate. Thus,
when the dienyl carbene arising
from the reaction of 1a with the
sterically hindered nitrone, N-
(1-methylethylidene)-1-methyl-
ethylamine-N-oxide (4d) was
treated with tert-butylisocya-
R
R
8a R = H
9a 95%
9b 83%
9c 84%
10a 82 %
10b 68 %
10c 63 %
8b R = OMe
8c R = Cl
Scheme 4. Preparation of 1,3,5-metallahexatrienes 9 and their cyclization to afford naphthoisoxazole derivatives
10.
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Chem. Eur. J. 2001, 7, No. 24

Synthesis of Indazoles and Isoxazoles
5318 5324
acetic acid and palladium-cata-
lyzed hydrogenation, did not
give satisfactory results. The
former conditions led to com-
plex mixtures of products, and
catalytic hydrogenation with
10% Pd/C under 20 bars of
hydrogen pressure only result-
ed in a small conversion of the
starting material. The reductive
MeO
R1
M(CO)5
M(CO)5
OMe
OMe
R1
H
NHtBu
N
N
TMSCH2N2
THF/hexane
tBuNC
N
N
R2
R2
R1
TMS
R2
1
12
13
Scheme 5. Preparation of indazoles 13.
TLC analysis revealed the formation of a new material,
presumably metallahexatriene 12 (Scheme 5). These dienyl
carbenes decomposed very rapidly when solvents were
removed, which prevented their isolation and characteriza-
tion, but were stable enough to be handled in solution. This
behavior is similar to that of metallahexatriene 5j (Scheme 3,
Table 2) and this encouraged us to attempt the tandem
isocyanide insertion electrocyclization. Addition of two
equivalents of tert-butylisocyanide to the reaction mixture at
08C indeed gave indazole derivatives 13, isolated as single
regioisomers, in good yields (Scheme 5, Table 3), and no
cleavage was finally accomplished by reaction of 7 with Raney
nickel in methanol, under a hydrogen atmosphere, to give
aminoalcohols 14 in almost quantitative yields (Scheme 6,
Table 4). When dihydrobenzisoxazole 7j, arising from meta-
thesis with benzyl isocyanide, was used, not only was the ring
cleaved, but the N-benzyl group was also removed to directly
afford aniline derivative 14h. The lower yield observed in this
case may be due to the instability of the unprotected aniline
towards oxidation (Table 4, entry 8).
OMe
R3 OMe
R3
tBu N
NHR6
R2
NHR6
R2
Raney-Ni
tBuHN
HO
Table 3. Preparation of indazoles 13.
MeOH, H2
O
Entry
1
M
R1
R2
13
Yield [%]
R1
R1
1
2
3
4
5
1a
1b
1c
1d
1h
Cr
W
Cr
Cr
Cr
(CH2)3
(CH2)3
O(CH2)3
(CH2)4
13a
13a
13b
13c
13d
73
76
78
79
81
6 = tBu
6 = Bn
R6 = tBu
14a-e
7a-e
7j
R
R
R6 = H
14f
Me
Ph
Scheme 6. Reductive cleavage of the isoxazole moiety of 7 to afford p-
aminophenols 14.
products derived from the decomposition of either the
starting complex 1, or the precursor dienyl carbene 12, were
detected. Thus, we can deduce that the dipolar cycloaddition
of the alkynyl complex 1 and trimethylsilyl diazomethane
proceeded regioselectively to afford the intermediate com-
plexes 12, which underwent benzannulation, again in a
regioselective manner. The trimethylsilyl group was probably
removed during the workup, upon exposure to air and
sunlight, to cleave the pentacarbonylmetal isocyanide com-
plex formed in the metathesis process.
À
Table 4. Reduction of isoxazole N O bond to prepare 14.
Entry
7
t [h]
14
Yield [%]
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7 f
7g
7e
7j
12
24
12
12
24
24
48
48
14a
14b
14c
14d
14e
14 f
97
98
95
89
98
94
97
58
14g
14h[a]
[a] Benzyl moiety was cleaved in the reduction process.
Regioselective preparation of highly substituted p-amino-
phenols 14 by reductive cleavage of 2,3-dihydro-1,2-benzisox-
azoles 7: The synthetic utility of the reaction sequence that
leads to 2,3-dihydro-1,2-benzisoxazoles 7 could be enhanced
by subsequent transformations which gave entry to new
organic structures. It is well known that isoxazole rings are
reductively cleaved to give 1,3-enaminoketones, and that their
dihydro, tetrahydro, and benzo derivatives also undergo ring-
opening to furnish different types of compounds depending
on the reduction conditions and the substitution pattern of the
starting heterocycles.[17] We decided to take advantage of this
behavior to prepare benzene derivatives with three or four
electron-donating groups, which appeared to be very inter-
esting compounds, from the 2,3-dihydro-1,2-benzisoxazoles
we had just obtained.
Conclusion
In summary, we have developed an efficient method for the
synthesis of highly substituted 2,3-dihydro-1,2-benzisoxazoles
7 or indazoles 13. [3‡2] Cycloaddition of alkynyl Fischer
carbene complexes 1, bearing an alkenyl substituent, with
nitrones or trimethylsilyl diazomethane gave rise to novel
1,3,5-metallahexatrienes, which were stable and sometimes
isolable compounds. It was also possible to carry out their
benzannulation reaction with isocyanides. Both processes
proceeded under mild conditions, in a completely regioselec-
tive fashion, and with high yields. The final benzene-fused
heterocycles could be obtained by two successive reactions or,
more conveniently, by a one-pot process starting from alkynyl
complexes 1.
Our first attempts to reduce the nitrogen oxygen bond of
compounds 7, which included treatment with zinc in refluxing
Chem. Eur. J. 2001, 7, No. 24
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J. Barluenga et al.
FULL PAPER
{[2-tert-Butyl-5-(1-cyclopentenyl)-2,3-dihydro-3-phenylisoxazol-4-yl]meth-
oxymethylene}pentacarbonylchromium(0) (5a): Prepared from 1a and 4a
according to the general procedure described above to afford, after flash
chromatography (hexane/dichloromethane 5:1), 5a in 97% yield as a dark
orange solid. Rf ˆ 0.17; 1H NMR (300 MHz, CDCl3): d ˆ 1.28 (s, 9H), 2.01
(dt, 3J(H,H) ˆ 7.8, 7.0 Hz, 2H), 2.53 (dd, 3J(H,H) ˆ 7.8, 7.0 Hz, 4H), 4.09 (s,
3H), 6.09 (s, 1H), 6.24 6.25 (m, 1H), 7.26 7.42 (m, 5H); 13C NMR
(75 MHz, CDCl3): d ˆ 23.3 (CH2), 24.9 (3CH3), 32.7 (CH2), 33.2 (CH2), 61.1
(C), 65.1 (CH3), 71.2 (CH), 127.5 (2CH), 127.7 (CH), 128.5 (2CH), 130.8
(C), 138.4 (CH), 143.0 (C), 143.1 (C), 146.5 (C), 216.6 (4C), 223.2 (C), 337.9
(C); IR (CH2Cl2): nÄ ˆ 2064, 1939 cmÀ1; elemental analysis calcd (%) for
C25H25CrNO7: C 59.64, H 5.01, N 2.78; found: C 59.41, H 4.87, N 2.90.
Our protocol provides a good alternative to the reported
methods for the synthesis of compounds 7 and 13, since it does
not require highly substituted aromatic rings as starting
materials. Instead, the benzene moiety is prepared in the last
step by means of a regioselective annulation reaction.
Further transformation of 2,3-dihydro-1,2-benzisoxazoles 7
was carried out to give hexasubstituted aromatic rings 14,
which have at least three electron-donating groups.
{[2-tert-Butyl-5-(1-cyclopentenyl)-2,3-dihydro-3-phenylisoxazol-4-yl]meth-
oxymethylene}pentacarbonyltungsten(0) (5b): Prepared from 1b and 4a
according to the general procedure described above to afford, after flash
chromatography (hexane: dichloromethane 1:1), 5b in 98% yield as a dark
orange solid. Rf ˆ 0.57; 1H NMR (300 MHz, CDCl3): d ˆ 1.25 (s, 9H), 2.07
(quint, 3J(H,H) ˆ 7.6 Hz, 2H), 2.55 2.64 (m, 2H), 2.67 (t, 3J(H,H) ˆ 7.6 Hz,
2H), 4.34 (s, 3H), 5.89 (s, 1H), 6.46 6.49 (m, 1H), 7.34 7.36 (m, 5H);
13C NMR (75 MHz, CDCl3): d ˆ 23.3 (CH2), 25.1 (3CH3), 33.5 (CH2), 33.6
(CH2), 61.5 (C), 67.5 (CH3), 71.0 (CH), 127.5 (2CH), 127.6 (CH), 128.5
(2CH), 131.9 (C), 132.9 (C), 142.2 (CH), 143.0 (C), 157.8 (C), 197.6 (4C),
202.1 (C), 300.6 (C); IR (CH2Cl2): nÄ ˆ 2058, 1942 cmÀ1; elemental analysis
calcd (%) for C25H25NO7W: C 47.26, H 3.97, N 2.20; found: C 47.08, H 4.12,
N 2.51.
Experimental Section
General methods: All reactions were performed under N2 atmosphere.
Tetrahydrofuran (THF), diethyl ether, dichloromethane, and toluene were
dried and distilled by standard procedures before use. Column chromatog-
raphy eluents were distilled prior to use. All other reagents used in the
reactions were of the best commercial grade available. Column chroma-
tography was carried out on silica gel 60 (230 400 mesh). Rf data refer to
the solvent system in which column chromatography was performed. All
melting points are uncorrected. NMR spectra were recorded at 300 or
200 MHz for 1H, and 75 or 50.3 MHz for 13C, with tetramethylsilane as
internal standard for 1H and the residual solvent signals as standard for 13C.
Chemical shifts are given in ppm. Mass spectra were obtained by EI (70 eV)
or MALDI-tof. IR spectra are given in cmÀ1. General procedures for the
preparation and characterization of new compounds are given here with
selected specific examples. Analytical and spectroscopic data for all new
compounds prepared are available as Supporting Information.
General procedure for the preparation of 2,3-dihydro-1,2-benzisoxazoles 7
(procedure A): A solution of complex 5 (0.5 mmol) and isocyanide 6
(1 mmol) in dry THF (10 mL) was stirred under nitrogen atmosphere until
TLC analysis revealed the complete consumption of the starting material
and the formation of a new compound. For reactions arising from
chromium complexes, removal of THF under vacuum, addition of hexane
(50 mL), and exposure to sunlight and air for 12 h, followed by flash
chromatography afforded the title compounds. For tungsten complexes, the
residue was loaded directly onto a silica gel column without previous
exposure to light and air.
General procedure for the preparation of alkynyl carbene complexes 1:
Fischer carbene complexes 1 were prepared by standard methodology from
the corresponding acetylenes. 1-Ethynylcyclopentene and 1-ethynylcyclo-
hexene were prepared by dehydratation of 1-ethynylcyclopentanol and of
1-ethynylcyclohexanol, respectively, with POCl3 and pyridine.[18] 6-Ethynyl-
3,4-dihydro-2H-pyrane was synthesized from 3-bromo-2-ethynyltetrahy-
dropyran, which was in turn obtained by successive treatment of 3,4-
dihydro-2H-pyran with bromine and ethynylmagnesium bromide.[19]
3-Methyl-4-phenylbut-2-en-1-yne, 4-methoxyphenylethyne, and 4-chloro-
phenylethyne were prepared by the Corey Fuchs method starting from
the corresponding aldehydes.[20] 5-Ethynyl-4,7-dihydro-2,2-dimethyl-1,3-
dioxepine was prepared in our research group by a three-step reaction
General procedure for the preparation of 2,3-dihydro-1,2-benzisoxazoles 7
by a one-pot process from carbene complexes 1 (Procedure B): A solution
of complex 1 (1 mmol) and nitrone 4a or 4b (1 mmol) in dry THF (10 mL)
was stirred at RT, under nitrogen atmosphere, until TLC analysis revealed
the formation of the corresponding cycloadduct. At that point, isocyanide 6
(2 equiv) was added and the mixture was stirred until the dienyl complex
was totally consumed. The same reaction workup described above (sun-
light- and air-induced decomplexation, and flash chromatography in the
case of chromium complexes, and flash chromatography only for tungsten
complexes) led to compounds 7.
sequence.[21] Complexes 1a
f have already been synthesized in our
research group,[8, 9] and 1g was obtained by the same experimental
procedure: butyllithium (1.6m in hexanes, 11 mmol) was added dropwise
to a solution of chromium or tungsten hexacarbonyl (10 mmol) and the
acetylene (11 mmol) in THF (20 mL) at À808C. The mixture was allowed
to reach RTovernight and then treated with methyl triflate (20 mmol) at
À208C. Hydrolysis with a saturated solution of Na2CO3 and extractive
workup, followed by flash chromatography afforded Fischer carbenes 1.
When the complexes were solids they were further purified by recrystal-
lization in hexanes at À208C.
2-tert-Butyl-5-tert-butylamino-3,6,7,8-tetrahydro-4-methoxy-3-phenyl-2H-
indeno[5,4:d]isoxazole (7a): Prepared according to general procedures A
and B described above, both from chromium and tungsten complexes, to
afford, after flash chromatography (hexane/ethyl acetate 5:1), 7a as a light
yellow solid. Rf ˆ 0.33; m.p. 134 1368C; 1H NMR (300 MHz, CDCl3): d ˆ
1.16 (s, 9H), 1.21 (s, 9H), 2.08 (tt, 3J(H,H) ˆ 7.4, 7.0 Hz, 2H), 2.68 (brs, 1H),
2.87 (t, 3J(H,H) ˆ 7.4 Hz, 2H), 2.87 (t, 3J(H,H) ˆ 7.0 Hz, 2H), 3.40 (s, 3H),
5.68 (s, 1H), 7.22 7.37 (m, 5H); 13C NMR (75 MHz, CDCl3): d ˆ 25.4
(3CH3), 25.8 (CH2), 29.1 (CH2), 30.3 (3CH3), 32.5 (CH2), 54.7 (C), 58.3
(CH3), 60.9 (C), 65.6 (CH), 116.4 (C), 118.9 (C), 127.0 (CH), 127.5 (2CH),
128.2 (2CH), 143.5 (C), 143.6 (C), 149.3 (C), 149.3 (C), 150.2 (C); HRMS:
m/z calcd for C25H34N2O2: 394.2620; found: 394.2615; MS (70 eV): m/z (%):
394 (27), 338 (40), 281 (100), 266 (50), 105 (25), 83 (54); elemental analysis
calcd (%) for C25H34N2O2: C 76.10, H 8.69, N 7.10; found: C 75.91, H 8.35, N
6.89.
{Pentacarbonyl[(4,7-dihydro-2,2-dimethyl-1,3-dioxepin-5-yl)ethynyl]meth-
oxymethylene}chromium(0) (1g): Prepared from 5-ethynyl-4,7-dihydro-
2,2-dimethyl-1,3-dioxepine according to the general procedure described
above to afford, after flash chromatography (hexane/dichloromethane 1:1),
1g in 52% yield as a red solid. Rf ˆ 0.36; 1H NMR (300 MHz, CDCl3): d ˆ
1.44 (s, 6H), 4.28 (s, 3H), 4.40 (s, 4H), 6.39 (brs, 1H); 13C NMR (75 MHz,
CDCl3): d ˆ 23.5 (2CH3), 61.4 (CH2), 62.9 (CH2), 65.6 (CH3), 92.2 (C), 102.5
(C), 123.8 (C), 133.8 (C), 144.4 (CH), 216.0 (C), 225.4 (C), 314.5 (C); IR
(CH2Cl2): nÄ ˆ 2059, 1942 cmÀ1
; elemental analysis calcd (%) for
C16H14CrO8: C 49.75, H 3.65; found: C 49.99, H 3.57.
2-tert-Butyl-5-tert-butylamino-3,6,7,8-tetrahydro-4-methoxy-3-methyl-2H-
indeno[5,4:d]isoxazole (7 f): Prepared according to general procedure A to
afford, after flash chromatography (hexane/ethyl acetate 5:1), 7 f as a light
yellow solid. Rf ˆ 0.28; m.p. 93 958C (decomp); 1H NMR (300 MHz,
CDCl3): d ˆ 1.12 (s, 9H), 1.14 (s, 9H), 1.42 (d, 3J(H,H) ˆ 6.1 Hz, 3H), 2.01
(quint, 3J(H,H) ˆ 7.0 Hz, 2H), 2.73 (t, 3J(H,H) ˆ 7.0 Hz, 2H), 2.80 (t,
3J(H,H) ˆ 7.0 Hz, 2H), 3.82 (s, 3H), 4.69 (q, 3J(H,H) ˆ 6.1 Hz, 1H);
13C NMR (75 MHz, CDCl3): d ˆ 23.3 (CH3), 25.1 (3CH3), 25.9 (CH2),
29.0 (CH2), 30.3 (3CH3), 32.6 (CH2), 54.8 (C), 57.5 (CH3), 58.8 (CH), 60.3
(C), 116.5 (C), 119.5 (C), 127.8 (C), 143.1 (C), 149.1 (C), 149.9 (C); HRMS:
General procedure for the reaction of nitrones 4a or 4b with alkynyl
carbene complexes 1: Dienyl carbene complexes 5a i were prepared by
reaction of the corresponding complex 1 (1 mmol) and nitrone 4a or 4b
(1 mmol) in dry THF (10 mL) at RT, under nitrogen atmosphere. The
progress of the reaction was monitored by TLC. When the starting complex
was consumed (typically after less than half an hour), solvents were
removed under vacuum (0.1 mmHg), and the crude reaction mixture was
directly purified by chromatography to afford the title compounds.
5322
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0947-6539/01/0724-5322 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 24

Synthesis of Indazoles and Isoxazoles
5318 5324
m/z calcd for C20H32N2O2: 332.2464; found: 332.2464; MS (70 eV): m/z (%):
332 (35), 276 (46), 261 (37), 219 (100), 205 (60), 193 (18); elemental analysis
calcd (%) for C20H32N2O2: C 72.25, H 9.70, N 8.43; found C 72.08, H 9.99, N
8.05.
(C), 151.2 (C); HRMS: m/z calcd for C29H30N2O2: 438.2307; found:
438.2296; MS (70 eV): m/z (%): 438 (7), 361 (46), 305 (100), 291 (22), 105
(92), 77 (30); elemental analysis calcd (%) for C29H30N2O2: C 79.42, H 6.89,
N 6.39; found: C 79.09, H 7.02, N 6.53.
4-(Aminocarbonylmethoxymethyl)-2-tert-butyl-5-cyclopent-1-enyl-3-phe-
nyl-2,3-dihydroisoxazole (15): This compound was obtained from the
reaction 5a and trimethylsilyl cyanide (Scheme 7). The protocol was
analogous to procedure A, but in this case, the reacting mixture was heated
at reflux in THF for 48 h. Flash chromatography (hexane/ethyl acetate 5:1)
gave 15 in 43% yield as a light yellow solid. Rf ˆ 0.30; m.p. 102 1048C;
1H NMR (200 MHz, CDCl3): d ˆ 1.17 (s, 9H), 1.98 2.02 (m, 2H), 2.48
2.67 (m, 4H), 3.42 (s, 3H), 4.90 (s, 1H), 5.26 (s, 1H), 6.21 6.22 (m, 1H),
7.34 7.44 (m, 5H); 13C NMR (50.3 MHz, CDCl3): d ˆ 23.1 (CH2), 24.8
(3CH3), 32.8 (CH2), 33.0 (CH2), 57.3 (CH), 61.0 (C), 64.5 (CH3), 68.1 (CH3),
103.8 (C), 115.2 (C), 127.9 (2CH), 127.9 (CH), 128.4 (2CH), 129.9 (C), 136.4
(CH), 141.8 (C), 150.6 (C); elemental analysis calcd (%) for C21H28N2O3: C
72.46, H 9.35, N 8.19; found: C 72.79, H 9.12, N 8.28.
General procedure for the preparation of indazoles 13: Trimethylsilyldi-
azomethane (1.1 mmol, 2.0m in hexanes) was added dropwise over 10 min
to a solution of complex 1 (1 mmol) in dry THF (10 mL) under a nitrogen
atmosphere at 08C. The resulting mixture was stirred at the same
temperature until TLC analysis revealed the formation of the correspond-
ing cycloadduct. At that point, isocyanide 6a (2 equiv) was added by
syringe and stirring was continued, at RT, until the dienyl complex was
totally consumed. For reactions arising from chromium complexes, removal
of THF under vacuum, addition of hexane (50 mL) and exposure to
sunlight and air for 12 h, followed by flash chromatography, afforded
compounds 13. For tungsten complexes, the residue was loaded directly
onto a silica gel column without exposure to light and air.
5-tert-Butylamino-3,6,7,8-tetrahydro-4-methoxycyclopenta[e]indazole
(13a): Prepared from 1a or 1b according to the general procedure
described above to afford, after flash chromatography (hexane/ethyl
acetate 1:1), 13a in 73% yield as a light yellow solid. Rf ˆ 0.40; m.p.
132 1348C; 1H NMR (200 MHz, CDCl3): d ˆ 1.30 (s, 9H), 2.00 (quint,
3J(H,H) ˆ 7.4 Hz, 2H), 2.95 (t, 3J(H,H) ˆ 7.4 Hz, 2H), 3.12 (t, 3J(H,H) ˆ
7.4 Hz, 2H), 3.94 (s, 3H), 7.96 (brs, 1H); 13C NMR (50.3 MHz, CDCl3): d ˆ
25.3 (CH2), 30.6 (3CH3), 31.9 (CH2), 32.2 (CH2), 55.1 (C), 59.1 (CH3), 118.1
(C), 130.2 (C), 133.3 (CH), 133.8 (C), 134.2 (C), 135.2 (C), 135.9 (C);
HRMS: m/z calcd for C15H21N3O: 259.1685; found 259.1683; MS (70 eV):
m/z (%): 171 (100), 158 (38), 149 (36), 143 (65), 131 (40), 116 (62);
elemental analysis calcd (%) for C15H21N3O: C 69.47, H 8.16, N 16.20;
found: C 69.20, H 8.26, N 16.35.
H2N
O
Cr(CO)5
OMe
Ph
Ph
TMSCN
OMe
tBu N
tBu N
O
O
THF, reflux
5a
15
Scheme 7. Preparation of amide 15 by reaction of metallahexatriene 5a
and trimethylsilylcyanide.
5-tert-Butylamino-3,6,7,8-tetrahydro-4-methoxypyran[2,3:e]indazole
(13b): Prepared from 1c according to the general procedure described
above to afford, after flash chromatography (hexane: ethyl acetate 1:1),
13b in 78% yield as a light yellow solid. Rf ˆ 0.28; m.p. 144 1458C;
1H NMR (300 MHz, CDCl3): d ˆ 1.27 (s, 9H), 2.05 (tt, 3J(H,H) ˆ 6.3,
5.1 Hz, 2H), 2.95 (t, 3J(H,H) ˆ 6.3 Hz, 2H), 3.85 (s, 3H), 3.12 (t, 3J(H,H) ˆ
5.1 Hz, 2H), 8.04 (s, 1H); 13C NMR (75 MHz, CDCl3): d ˆ 22.5 (CH2), 22.5
(CH2), 30.7 (3CH3), 55.0 (C), 59.1 (CH3), 65.8 (CH2), 109.2 (C), 112.9 (C),
131.6 (C), 132.4 (CH), 134.9 (C), 136.4 (C), 143.7 (C); LRMS (MALDI-tof):
m/z calcd for C15H21N3O2: 275; found: 275; elemental analysis calcd (%) for
C15H21N3O2: C 65.43, H 7.69, N 15.26; found: C 65.19, H 7.84, N 14.99.
General procedure for the reaction of nitrone 4a with alkynyl carbene
complexes 8: Dienyl carbene complexes 9a c were prepared by reaction
of the corresponding complex 8 (1 mmol) with nitrone 4a (1 mmol) in dry
THF (10 mL), at RT, under nitrogen atmosphere. The progress of the
reaction was monitored by TLC. When the starting complex was consumed,
solvents were removed under vacuum (0.1 mmHg), and the crude reaction
mixture was purified by chromatography to afford the title compounds.
{[2-tert-Butyl-2,3-dihydro-3,5-diphenylisoxazol-4-yl]methoxymethylene}-
pentacarbonylchromium(0) (9a): Prepared from 8a and 4a according to
the general procedure described above. This carbene complex has already
been reported in the literature.[11]
À
General procedure for the reductive N O bond cleavage of benzisoxazoles
7: An excess of Raney nickel (ca. 1 g of 50% slurry in water) was dried
under vacuum (0.1 mmHg) and suspended in dry methanol (20 mL), under
1 atmosphere of hydrogen. Compound 7 (0.5 mmol) dissolved in methanol
(5 mL) was added by syringe and the mixture was stirred at RT. The
reactions were monitored by 1H NMR analysis every 12 h, and stopped
when all the starting material had been transformed into the product 14.
{[2-tert-Butyl-2,3-dihydro-5-(4-methoxyphenyl)-3-phenylisoxazol-4-yl]-
methoxymethylene}pentacarbonylchromium(0) (9b): Prepared from 8b
and 4a according to the general procedure described above to afford, after
flash chromatography (hexane/dichloromethane 5:1), 9b in 83% yield, as a
dark orange oil. Rf ˆ 0.34; 1H NMR (200 MHz, CDCl3): d ˆ 1.34 (s, 9H),
3.88 (s, 3H), 4.08 (s, 3H), 6.19 (s, 1H), 7.00 (d, 3J(H,H) ˆ 8.7 Hz, 2H), 7.30
7.51 (m, 7H); 13C NMR (50.3 MHz, CDCl3): d ˆ 25.1 (3CH3), 55.2 (CH3),
61.3 (C), 65.2 (CH), 71.7 (CH3), 114.0 (2CH), 120.4 (C), 127.2 (2CH), 127.2
(C), 127.6 (CH), 128.6 (2CH), 129.8 (2CH), 143.1 (C), 151.0 (C), 161.4 (C),
Filtration of the Raney nickel through
a pad of Celite and flash
chromatography afforded the corresponding amino alcohols.
5-tert-Butylamino-7-(tert-butylaminophenylmethyl)-6-methoxychroman-
8-ol (14b): Prepared from 7b according to the general procedure described
above to afford, after flash chromatography (hexane/ethyl acetate 1:1), 14b
in 98% yield as a white solid. Rf ˆ 0.27; m.p. 161 1638C; 1H NMR
(200 MHz, CDCl3): d ˆ 1.12 (s, 9H), 1.21 (s, 9H), 1.96 2.02 (m, 2H), 2.67
(t, 3J(H,H) ˆ 6.4 Hz, 2H), 3.30 (s, 3H), 4.20 4.28 (m, 2H), 5.56 (s, 1H),
7.22 7.42 (m, 5H); 13C NMR (75 MHz, CDCl3): d ˆ 22.3 (CH2), 22.7 (CH2),
28.5 (3CH3), 30.5 (3CH3), 52.6 (C), 54.6 (C), 56.5 (CH3), 59.1 (CH), 65.9
(CH2), 117.8 (C), 118.8 (C), 127.4 (CH), 127.8 (2CH), 128.2 (C), 128.9
(2CH), 139.9 (C), 143.8 (C), 143.9 (C), 145.6 (C); HRMS: m/z calcd for
C25H36N2O3: 412.2726; found: 412.2720; MS (70 eV): m/z (%): 412 (5), 339
(27), 324 (20), 268 (100), 58 (30); elemental analysis calcd (%) for
C25H36N2O3: C 72.78, H 8.80, N 6.79; found: C 72.94, H 8.45, N 6.92.
216.5 (4C), 223.0 (C), 335.3(C); IR (CH2Cl2): nÄ ˆ 2058, 1943 cmÀ1
;
elemental analysis calcd (%) for C27H25CrNO8: C 59.67, H 4.64, N 2.58;
found: C 59.47, H 4.86, N 2.91.
General procedure for the preparation of naphthoisoxazoles 10: A solution
of complex 9 (0.5 mmol) and benzylisocyanide 6b (1 mmol) in dry THF
(10 mL) was stirred under nitrogen atmosphere, until TLC analysis
revealed the consumption of the starting material and the formation of a
new compound. Removal of THF under vacuum, addition of hexane
(50 mL) and exposure to sunlight and air for 12 h, followed by flash
chromatography, afforded compounds 10.
2-tert-Butyl-5-tert-butylamino-2,3-dihydro-4-methoxy-3-phenylnaphtho-
[2,1:d]isoxazole (10a): Prepared from 9a and 4b according to the general
procedure described above to afford, after flash chromatography (hexane:
ethyl acetate 5:1), 10a in 82% yield as a light yellow oil. Rf ˆ 0.32; 1H NMR
4-tert-Butylamino-2-(tert-butylaminophenylmethyl)-3-methoxy-5,6,7,8-tet-
rahydronaphtho-1-ol (14c): Prepared from 7c according to the general
procedure described above to afford, after flash chromatography (hexane/
ethyl acetate 5:1), 14c in 95% yield as a white solid. RK ˆ 0.45; m.p. 159
1618C; 1H NMR (300 MHz, CDCl3): d ˆ 1.13 (s, 9H), 1.20 (s, 9H), 1.76
1.78 (m, 4H), 2.60 2.61 (m, 2H), 2.71 2.73 (m, 2H), 3.35 (s, 3H), 5.59 (s,
1H), 7.19 7.32 (m, 3H), 7.38 7.41 (m, 2H); 13C NMR (75 MHz, CDCl3):
d ˆ 22.5 (CH2), 23.1 (CH2), 23.1 (CH2), 26.4 (CH2), 28.6 (3CH3), 30.6
2
(200 MHz, CDCl3): d ˆ 1.38 (s, 9H), 2.51 (d, J(H,H) ˆ 14.2 Hz, 1H), 3.09
2
(s, 3H), 3.11 (d, J(H,H) ˆ 14.2 Hz, 1H), 5.54 (s, 1H), 7.10 7.15 (m, 2H),
7.31 7.58 (m, 12H); 13C NMR (75 MHz, CDCl3): d ˆ 24.8 (3CH3), 46.8
(CH2), 53.4 (CH), 60.9 (C), 71.8 (CH3), 78.2 (C), 104.8 (C), 116.3 (C), 126.2
(CH), 127.2 (CH), 127.8 (2CH), 127.8 (2CH), 127.9 (2CH), 128.0 (C), 128.5
(CH), 128.7 (2CH), 128.9 (2CH), 129.0 (CH), 129.0 (C), 134.0 (C), 143.1
Chem. Eur. J. 2001, 7, No. 24
¹ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0724-5323 $ 17.50+.50/0
5323

J. Barluenga et al.
FULL PAPER
(3CH3), 52.4 (C), 54.3 (C), 56.3 (CH3), 58.6 (CH), 116.3 (C), 120.6 (C), 127.2
(CH), 127.7 (2CH), 128.5 (C), 128.8 (2CH), 133.4 (C), 144.3 (C), 150.4 (C),
152.8 (C); HRMS: m/z calcd for C26H38N2O2: 410.2933; found: 410.2947;
MS (70 eV): m/z (%): 410 (15), 337 (58), 281 (32), 266 (100), 238 (20), 83
(45); elemental analysis calcd (%) for C26H38N2O2: C 70.06, H 9.33, N 6.82;
found: C 70.27, H 9.01, N 6.98.
[7] a) C. A. Merlic, C. C. Aldrich, J. Albaneze-Walker, A. Saghatelian, J.
Am. Chem. Soc. 2000, 122, 3224; b) C. A. Merlic, C. C. Aldrich, J.
Albaneze-Walker, A. Saghatelian, J. Mammen, J. Org. Chem. 2001, 66,
1297.
¬
[8] J. Barluenga, F. Aznar, S. Barluenga, M. Fernandez, A. MartÌn, S.
ƒ
¬
GarcÌa-Granda, A. Pinera-Nicolas, Chem. Eur. J. 1998, 4, 2280.
[9] J. Barluenga, F. Aznar, M. A. Palomero, S. Barluenga, Organic Lett.
1999, 1, 541.
[10] J. Barluenga, F. Aznar, M. A. Palomero, Angew. Chem. 2000, 112,
4514; Angew. Chem. Int. Ed. 2000, 39, 4346.
Acknowledgements
[11] K. S. Chan, M. L. Yeung, W. Chan, R. Wang, T. C. W. Mak, J. Org.
Chem. 1995, 60, 1741.
This research was supported by the DGICYT (Grant PB97 1271). M.A.P.
gratefully acknowledges M.E.C. for a predoctoral fellowship.
[12] K. S. Chan, W. D. Wulff, J. Am. Chem. Soc. 1986, 108, 5229.
[13] For the preparation of 2,3-dihydro-1,2-benzisoxazoles see: a) P. D.
Lokhande, B. J. Ghiya, J. Indian Chem. Soc. 1991, 68, 412; b) T.
Matsumoto, T. Sohma, S. Hatazaki, K. Suzaki, Synlett 1993, 843.
[14] For a revision in the preparation of indazoles see: L. C. Behr in
Pyrazolines, Pyrazolidines, Indazoles and Condensed Rings (Ed.:
R. H. Wiley), Wiley, New York, 1967, p. 289.
[15] A referee has pointed out that in this transformation isocyanides can
be viewed as 1,1-dipole equivalents, a strategy that has some literature
precedent: a) D. P. Curran, H. Liu, J. Am. Chem. Soc. 1991, 113, 2127;
b) J. H. Rigby, M. Qabar, J. Am. Chem. Soc. 1991, 113, 8975.
[16] a) R. Aumann, E. O. Fischer, Chem. Ber. 1968, 101, 954; b) C. G.
Kreiter, R. Aumann, Chem. Ber. 1978, 111, 1223; c) R. Aumann, H.
Heinen, C. Kr¸ger, Y. H. Tsay, Chem. Ber. 1986, 119, 3141.
[17] M. Sainsbury, in Comprehensive Organic Synthesis, Vol. 8 (Eds.: B. M.
Trost, I. Fleming), Pergamon, Oxford, 1991, p. 635.
[1] For reviews on the synthetic applications of Fischer carbene com-
plexes see: a) K. H. Dˆtz, Angew. Chem. 1984, 96, 573; Angew. Chem.
Int. Ed. Engl. 1984, 23, 587; b) W. D. Wulff in Comprehensive
Organometallic Chemistry II, Vol. 12 (Eds.: E. W. Abel, F. G. A.
Stone, G. Wilkinson), Pergamon, New York, 1995, p. 469; c) L. S.
Hegedus in Comprehensive Organometallic Chemistry II, Vol. 12
(Eds.: E. W. Abel, F. G. A. Stone, G. Wilkinson), Pergamon, New
York, 1995, p. 549; d) M. Doyle in Comprehensive Organometallic
Chemistry II, Vol. 12 (Eds.: E. W. Abel, F. G. A. Stone, G. Wilkinson),
Pergamon, New York, 1995, p. 387; e) D. F. Harvey, D. M. Sigano,
Chem. Rev. 1996, 96, 271; f) F. Z. Dˆrwald, Metal Carbenes in Organic
Synthesis, Wiley-VCH, 1999.
[2] a) K. H. Dˆtz, Angew. Chem. 1975, 87, 674; Angew. Chem. Int. Ed.
Engl. 1975, 14, 644; b) K. H. Dˆtz, P. Tomuschat, Chem. Soc. Rev.
1999, 28, 187.
[3] A. De Meijere, H. Schirmer, M. Duetsch, Angew. Chem. 2000, 112,
4124; Angew. Chem. Int. Ed. 2000, 39, 3964.
[18] L. Bradsma in Preparative Acetylenic Chemistry, Elsevier, Amsterdam
1988, p. 203.
[19] L. Bradsma in Preparative Acetylenic Chemistry, Elsevier, Amsterdam
1988, p. 207.
[20] E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 3769.
[21] J. Barluenga, F. Aznar, H. Valle, C. P. Cabal, unpublished results.
[4] R. Aumann, Angew. Chem. 1988, 100, 1512; Angew. Chem. Int. Ed.
Engl. 1988, 27, 1456.
[5] a) C. A. Merlic, E. E. Burns, D. Xu, S. Y. Chen, J. Am. Chem. Soc.
1992, 114, 8722; b) C. A. Merlic, E. E. Burns, Tetrahedron Lett. 1993,
34, 5401.
[6] C. A. Merlic, D. McInnes, Y. You, Tetrahedron Lett. 1997, 39, 6787.
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