Group 6 heteroatom- and non-heteroatom-stabilized carbene complexes. β,β′- and α,ββ′-Annulation reactions of cyclic enamines

Article abstract of DOI:10.1021/ja0278077

Cyclization reactions of group 6 Fischer carbene complexes with cyclopentanone and cyclohexanone enamines are described. Enamine 3a undergoes thermal β,β′-annulation with alkenylcarbene complexes 1 and 2 (THF, 60 °C), affording semibullvalenes 5. The metalate intermediates 6, resulting from β,β′-annulation of the enamines 3a and 4a, were quantitatively formed by running the reaction in hexane at room temperature. Acid-promoted demetalation of 6 afforded endo-2-bicyclo[3.2.1]octen-8-ones 7 and endo/exo-2-bicyclo[3.3.1]nonen-9-ones 8 (endo/exo = 5:1). Using (S)-methoxymethylpyrrolidinederived enamines 3b and 4b,c allowed highly enantioenriched cycloadducts endo-(+)-7 as well as endo- (-)-8 and exo-(-)-8 to be accessed. The non -heteroatom -stabilized carbene complex 10 was formed from complex 6 by Me₃SiOTf-promoted elimination of the methoxy group, characterized by ¹³C NMR, and transformed into the organic compounds 7, 7-d, and 11 as well as into bicyclo[3.2.1]octan-2,8-diones 14 and cycloheptanones 15, On the basis of this sequence, enantioenriched cycloheptanones (+)-15 were efficiently prepared in one pot from carbene complexes 2 and enamine 3b (51-55% yield, 91-96% ee). Extension of this work to simple Fischer carbene complexes 16 allowed an appropriate way to generate the nonstabilized pentacarbonyl[(phenyl(alkyl)carbene]tungsten complex 17 to be designed, for which the thermal and chemical behavior leading to compounds 18-21 is described.

Full text of DOI:10.1021/ja0278077

Published on Web 01/23/2003
Group 6 Heteroatom- and Non-Heteroatom-Stabilized Carbene
Complexes. â,â′- and r,â,â′-Annulation Reactions of Cyclic
Enamines
Jose´ Barluenga,* Alfredo Ballesteros, Ramo´n Bernardo de la Ru´a,
Javier Santamar´ıa, Eduardo Rubio, and Miguel Toma´s
Contribution from the Instituto UniVersitario de Qu´ımica Organometa´lica “Enrique Moles”,
Unidad Asociada al CSIC, UniVersidad de OViedo, Julia´n ClaVer´ıa 8, 33071-OViedo, Spain
Received July 22, 2002 ; E-mail: barluenga@sauron.quimica.uniovi.es
Abstract: Cyclization reactions of group 6 Fischer carbene complexes with cyclopentanone and cyclo-
hexanone enamines are described. Enamine 3a undergoes thermal R,â,â′-annulation with alkenylcarbene
complexes 1 and 2 (THF, 60 °C), affording semibullvalenes 5. The metalate intermediates 6, resulting
from â,â′-annulation of the enamines 3a and 4a, were quantitatively formed by running the reaction in
hexane at room temperature. Acid-promoted demetalation of 6 afforded endo-2-bicyclo[3.2.1]octen-8-ones
7 and endo/exo-2-bicyclo[3.3.1]nonen-9-ones 8 (endo/exo ) 5:1). Using (S)-methoxymethylpyrrolidine-
derived enamines 3b and 4b,c allowed highly enantioenriched cycloadducts endo-(+)-7 as well as endo-
(-)-8 and exo-(-)-8 to be accessed. The non-heteroatom-stabilized carbene complex 10 was formed from
complex 6 by Me3SiOTf-promoted elimination of the methoxy group, characterized by 13C NMR, and
transformed into the organic compounds 7, 7-d, and 11 as well as into bicyclo[3.2.1]octan-2,8-diones 14
and cycloheptanones 15. On the basis of this sequence, enantioenriched cycloheptanones (+)-15 were
efficiently prepared in one pot from carbene complexes 2 and enamine 3b (51-55% yield, 91-96% ee).
Extension of this work to simple Fischer carbene complexes 16 allowed an appropriate way to generate
the nonstabilized pentacarbonyl[(phenyl(alkyl)carbene]tungsten complex 17 to be designed, for which the
thermal and chemical behavior leading to compounds 18-21 is described.
of nitroallylic esters and enamines discovered by Seebach,3a no
highly enantioselective approaches have been reported.2f,3b
Introduction
The synthesis of polyclyclic molecules following short and
stereoselective routes constitutes one of the main challenges in
synthetic organic chemistry. In particular, much work has been
devoted to the design of efficient routes to [3.2.1] and [3.3.1]
bicyclic molecular skeletons.1 A straightforward entry into these
frameworks can be envisaged by reaction of appropriate C3-
synthons with cyclic ketones via R,R′-annulation,2 or with their
enamine derivatives via â,â′-annulation.3 For instance, a number
of two-step processes based on R-alkenylation or R-alkynylation
of cyclic ketones followed by induced ring closure have been
disclosed.2 In addition, apart from the elegant [3+3]-cyclization
Despite the fact that transition-metal complexes have played
a paramount role in the area of carbocyclization reactions,4
[3+3]-carbocyclization approaches mediated or assisted by
transition metals remain almost unexplored.5,6
On the other hand, the great potential of Fischer carbene
complexes in carbocyclization reactions has been demonstrated
in the last few years.7 In particular, alkenyl(alkoxy)carbene
complexes have become valuable C3-synthons in a number of
carbo- and heterocyclization reactions.8 For instance, we found
that tungsten alkenylcarbene complexes readily undergo [3+2]-
(4) (a) Fru¨hauf, H.-W. Chem. ReV. 1997, 97, 523. (b) Lautens, M.; Klute, W.;
Tam, W. Chem. ReV. 1996, 96, 49.
(5) For an isolated example involving Fischer alkenyl carbene complexes,
see: Barluenga, J.; Toma´s, M.; Rubio, E.; Lo´pez-Pelegr´ın, J. A.; Garc´ıa-
Granda, S.; Pe´rez-Priede, M. J. Am. Chem. Soc. 1999, 121, 3065.
(6) For a two-step [3+3]-annelation, see: Ward, D. E.; Gai, Y.; Kaller, B. F.
J. Org. Chem. 1995, 60, 7830.
(1) For reviews on bicyclo[3.2.1]- and -[3.3.1]alkanes, see, respectively: (a)
Filippini, M.-H.; Rodriguez, J. Chem. ReV. 1999, 99, 27. (b) Peters, J. A.
Synthesis 1979, 321.
(2) For selenium-induced ring closure, see: (a) Nicolaou, K. C.; Pfefferkorn,
J. A.; Cao, G.-Q.; Kim, S.; Kessabi, J. Org. Lett. 1999, 1, 807. For Hg2+
-
mediated ring closure, see: (b) Frontier, A. L.; Raghavan, S.; Danishefsky,
S. J. J. Am. Chem. Soc. 1997, 119, 6686. (c) Huang, H.; Forsyth, C. J. J.
Org. Chem. 1995, 60, 5746. For Pd(II)-mediated ring closure, see: (d)
Kende, A. S.; Roth, B.; Sanfilippo, P. J.; Blacklock, T. J. J. Am. Chem.
Soc. 1982, 104, 1784 and 5808. For free-radical ring closure, see: (e) Cole,
B. M.; Han, L.; Snider, B. B. J. Org. Chem. 1996, 61, 7832. For
enantioselective free-radical ring closure, see: (f) Garc´ıa-Ruano, J. L.;
Rumbero, A. Tetrahedron: Asymmetry 1999, 10, 4427.
(7) Recent reviews: (a) Wulff, W. D. In ComprehensiVe Organometallic
Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.;
Pergamon: New York, 1995; Vol. 12, p 469. (b) Herndon, J. W.
Tetrahedron 2000, 56, 1257. (c) Harvey, D. F.; Sigano, D. M. Chem. ReV.
1996, 96, 271. (d) Barluenga, J.; Fan˜ana´s, F. J. Tetrahedron 2000, 56, 4597.
(e) Sierra, M. A. Chem. ReV. 2000, 100, 3591. (f) de Meijere, A.; Shirmer,
H.; Duetsch, M. Angew. Chem., Int. Ed. 2000, 39, 3964.
(8) For recent work in this field, see for instance: (a) Barluenga, J.; Mart´ınez
S.; Sua´rez-Sobrino, A.-L.; Toma´s, M. J. Am. Chem. Soc. 2001, 123, 11113.
(b) Kagoshiima, H.; Okamura, T.; Akiyama, T. J. Am. Chem. Soc. 2001,
123, 7182. (c) Barluenga, J.; Alonso, J.; Rodr´ıguez, F.; Fan˜ana´s, F.-J.
Angew. Chem., Int. Ed. 2000, 39, 2459.
(3) (a) Seebach, D.; Missbach, M.; Calderari, G.; Eberle, M. J. Am. Chem.
Soc. 1990, 112, 7625. (b) Butkus, E.; Stoncius, A. Synlett 1999, 234. (c)
Byeon, C.-H.; Hart, D. J.; Lai, C.-S.; Unch, J. Synlett 2000, 119. (d) Buono,
F.; Tenaglia, A. J. Org. Chem. 2000, 65, 3869.
9
1834
J. AM. CHEM. SOC. 2003, 125, 1834-1842
10.1021/ja0278077 CCC: $25.00 © 2003 American Chemical Society

â,â′- and R,â,â′-Annulation of Cyclic Enamines
A R T I C L E S
Scheme 1
Figure 1.
Scheme 2
Figure 2.
cycoaddition toward enamines derived from acyclic ketones and
aldehydes to produce substituted 2-cyclopentenones and cyclo-
pentanones, respectively, in a diastereoselective and enantio-
selective way.9
Herein, we present our results on the â,â′-annulation ([3+3]-
cyclization) and R,â,â′-annulation reactions of cyclopentanone
and cyclohexanone enamines with Fischer alkenylcarbene
complexes (Figure 1).10 On the basis of such work, a prelimnary
study on the potential of non-heteroatom-stabilized alkylcarbene
complexes of type I is first reported in the second part of this
paper (Figure 1).
The present study has been undertaken using (i) pentacar-
bonyl[alkenyl(alkoxy)]carbene complexes of chromium(0) (1)
and tungsten(0) (2), (ii) cyclopentanone enamines derived from
pyrrolidine (3a) and (S)-2-methoxymethylpyrrolidine (3b), and
(iii) cyclohexanone enamines derived from pyrrolidine (4a), (S)-
2-methoxymethylpyrrolidine (4b), and (S)-2-(1-methoxymeth-
ylethyl)pyrrolidine (4c) (Figure 2).
carbene complexes. Additionally, when the chiral, nonracemic
chromium carbene complexes 1e-g, derived from (-)-menthol,
and 3a were heated in THF at 60 °C for 6 h the cycloadducts
5e-g were formed as a single diastereoisomer and isolated in
fairly good yields.
At this point we decided to run further experiments that might
shed light onto this complex process. First, we replaced the
solvent with a much less polar solvent such as hexane.
Interestingly, conducting the reaction of complexes 1a-d and
2a-d and enamine 3a in hexane at room temperature resulted
in quantitative precipitation of the metal complexes 6a-d
(Scheme 2). We observed that these metalate complexes 6 are
actually the intermediate species for the formation of semi-
bullvalenes 5 from carbene complexes 1 and 2 since 6a-c could
be smoothly transformed into 5a-c by heating in THF at 60
°C for 1.5 h. Moreover, it was important from a synthetic point
of view to find that, alternatively, compounds 6 can be
transformed very efficiently into bicyclo[3.2.1]oct-2-en-8-ones
7 by treatment with TFA/THF at 0 °C followed by warming in
the presence of water (Scheme 2). This process takes place with
high yield in most cases (60-91% overall yield from the starting
carbene complexes), the endo stereoisomer being the sole isomer
detected.
Results and Discussion
[3+3]-Cyclization of Carbene Complexes 1 and 2 and
Enamines 3 and 4. First, 1-pyrrolidinylcyclopentene 3a was
reacted with chromium or tungsten alkenylcarbene complexes
1a-c or 2a-c in THF at 60 °C for 1.5 h to furnish substituted
semibullvalenes 5a-c in nearly 90% yield after column
chromatography purification (Scheme 1).11 This one-step poly-
cyclization reaction gives ready access to the complex structure
5 and entails the formation of three carbon-carbon bonds and
five stereogenic centers with complete control of selectivity12
in a process that has no precedents in the chemistry of metal
(9) Barluenga, J.; Toma´s, M.; Ballesteros, A.; Santamar´ıa, J.; Brillet, C.; Garc´ıa-
Granda, S.; Pin˜era-Nicola´s, A.; Va´zquez, J. T. J. Am. Chem. Soc. 1999,
121, 4516.
(10) Preliminary communication: Barluenga, J.; Ballesteros, A.; Santamar´ıa,
J.; Bernardo de la Rua, R.; Rubio, E.; Toma´s, M. J. Am. Chem. Soc. 2000,
122, 12874.
(11) In general, both chromium (1) and tugnsten (2) carbene complexes have
been found to work equally well. The preparation of (+)-7, (()-8, and
enantiorenriched 8 has been undertaken using tungsten carbenes 2.
(12) The connectivity and relative stereochemistry of compounds 5 were clearly
elucidated by HMQC, HMBC, and NOESY NMR experiments.
The whole transformation can also be effected in a one-pot
fashion without isolation of the corresponding metalate complex
6. This is exemplified in Scheme 3 for the preparation of
bicyclo[3.3.1]non-2-en-9-ones 8. Thus, tungsten carbene com-
plexes 2a,b were consecutively reacted with cylohexanone
enamine 4a in THF at 0 °C, treated with TFA at the same
temperature, and allowed to reach room temperature in the
9
J. AM. CHEM. SOC. VOL. 125, NO. 7, 2003 1835

A R T I C L E S
Barluenga et al.
Scheme 3
Scheme 6
Scheme 4
Scheme 5
selectivity of the process was highly dependent on the reaction
conditions and even on the substituent R1 of the carbene
complex. Thus, the reaction of 2a (R1 ) 2-furyl) and meth-
oxymethylpyrrolidine enamine 4b (THF, -20 °C, 72 h) yielded
the cycloadduct 8a (75% yield) as a 1:2 mixture of endo/exo
isomers. Endo and exo isomers could be separated by column
chromatography, affording pure endo-(-)-8a (73% ee) and exo-
(-)-8a (98% ee). On the contrary, the corresponding endo
isomer was efficiently formed with very high face selectivity if
the reaction was run in dichloromethane as solvent and the more
sterically demanding enamine 4c was used. Thus, the reaction
between carbene complex 2a and enamine 4c (CH2Cl2, -20
°C, 72 h) afforded endo-(-)-8a in good yield and with high
selectivity (80%, endo-(-)-8a:exo-(-)-8a ) 15:1, 95% ee for
endo-(-)-8a).13 When this reaction was carried out at -50 °C,
both the endo-(-)-8a:exo-(-)-8a ratio and the ee of endo-
(-)-8a increased to >20:1 and 98%, respectively, though the
chemical yield dropped to 52%. The formation of the cycload-
duct 8b (R1 ) Ph) could be achieved with excellent stereose-
lectivity (endo-(-)-8b:exo-8b > 50:1, 94% ee) and in moderate
chemical yield (50%) by performing the reaction of carbene
2b and enamine 4c in THF (-30 °C, 7 days). All the enatiomeric
excesses for compounds 8 were determined by chiral HPLC
(Chiracel OJ).
Proposed Mechanism. We think that the formation of
semibullvalene derivatives 5 and the [3+3]-cycloadducts 7 from
carbene complexes 1 and 2 and enamines 3 can be rationalized
as depicted in Scheme 6. First, 1,4-addition of the Câ-enamine
to the electrophilic alkene carbene complex would produce the
Michael adduct II.14 The conversion of this intermediate II into
the final semibullvalene structure 5 implies simply the intra-
molecular cyclopropanation of an electron-rich carbon-carbon
double bond, specifically the CR-Câ double bond of the newly
formed enamine, by a Fischer carbene complex. In this particular
sense, the isolation of the zwitterionic species 6 does represent
an unprecedented feature for supporting the accepted polar
presence of water to furnish a ca. 5:1 mixture of endo-8 and
exo-8 cycloadducts (80-85% yield) which were separated by
routine column chromatography.
Once the diastereoselective [3+3]-cyclization leading to
racemic cycloadducts was effiently delineated, we focused on
the asymmetric synthesis of bicyclo[3.2.1]octenone and bicyclo-
[3.3.1]nonenone derivatives 7 and 8. Although the first attempts
using menthol-derived carbene complexes 1e-g and 2e-g were
unsuccessful, it was a delight to find that this goal could be
accomplished very efficiently by using chiral cyclopentanone
enamines derived from readily available (S)-2-methoxymeth-
ylpyrrolidine (Scheme 4). Thus, stirring a solution of tungsten
carbene complexes 2a-c and cyclopentanone enamine 3b (THF,
-20 °C, 6.5 h) followed by TFA quenching and warming with
water resulted in the diastereoselective formation of the enan-
tiomerically enriched endo-cycloadducts 7. Column chroma-
tography purification gave pure 7 in 85-90% yield and high
enantiomeric excess (88-93% ee) as determined by chiral
HPLC (Chiracel OB-H and OJ columns). The absolute config-
uration of 7c was determined by X-ray analysis (vide infra).
Enantiopure cyclohexanone enamines 4b,c were also tested
toward tungsten complexes 2a,b (Scheme 5). We found that
these enamines are fairly less reactive than the cyclopentanone
analogues and their cycloaddition reaction to 8 required longer
reaction times. On the other hand, the endo/exo and face
(13) The replacement of enamine 4c with 4b led to poorer selectivity toward
endo-8a (endo:exo ) 5:1, 83% ee).
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â,â′- and R,â,â′-Annulation of Cyclic Enamines
A R T I C L E S
Scheme 7
pathway for the cyclopropanation reaction of electron-rich
alkenes, such as enamines, by Fischer carbene complexes (path
A).15 Moreover, the endo orientation of the M(CO)5 fragment
precludes the cyclopropanation reaction to involve the participa-
tion of a metallacyclobutane species, but rather backside attack
of the carbanion-type metal-bonded carbon to the iminium
function is thought to occur.16 Second, the formation of the
cycloadducts 7 deserves particular attention (path B). Thus, in
agreement with previous observations,17 one would suggest that
the metalate complex 6 might suffer acid-induced elimination
of methanol to form an elusive non-heteroatom-stabilized
carbene species, III, which would then undergo â-hydrogen
elimination and reductive metal elimination to yield 7 after
hydrolysis of the imonium function.
Non-Heteroatom-Stabilized Tungsten Carbene Com-
plexes. Although group 6 non-heteroatom-stabilized carbene
complexes lacking R-hydrogen atoms (such as phenyl and
diphenylcarbene derivatives) are well-known organometallic
reagents,18 the chemistry of the alkyl analogues is extremely
limited due to their high instability.19 In an elegant study,19a
Casey et al. reported some years ago that pentacarbonyl[phenyl-
(methyl)carbene]tungsten(0), which was generated from the
stabilized phenyl(methoxy)carbene complex by successive treat-
ment with MeLi and HCl, decomposed whithin 30 min at -78
°C, giving rise to a mixture of styrene and 1-methyl-1,2-
diphenylcyclopropanes. We now provide some evidence of this
type of complex and apply it to the selective ring opening of
the 8-bicyclo[3.2.1]octanone skeleton 7 to racemic and enan-
tioenriched cycloheptanones.
Scheme 8
Racemic complexes 6a,b were treated at -80 °C with
trimethylsilyl triflate in dichloromethane to generate, after 30
min, the nonstabilized carbene complexes 10a,b,20 for which
the significant carbene resonates at 369 (10a, R1 ) Ph, M )
W) and 374 (10b, R1 ) 2-furyl, M ) W) ppm in the 13C NMR
spectrum (Scheme 7). These complexes were found to be fairly
stable below -80 °C, but they quantitatively decompose above
-70 °C to the imonium salt 11, via carbon-to-metal hydrogen
shift to species IV and metal elimination. Compounds 11 were
not isolated but hydrolyzed to ketones 7.
(14) Evidence for the formation of this intermediate comes from the isolation
of the adduct 9 in the reaction of pentacarbonyl[2-methylpropenylidene-
(methoxy)]tungsten complex and enamine 3a. The initially formed carbene
complex undergoes metal elimination, affording the enol ether 9 when
subjected to SiO2 treatment.
Because of the high electron-acceptor nature of the (CO)5M
fragment,21 the CR-H deprotonation of 10 occurs readily with
different organic bases (pyridine, triethylamine, etc.) (Scheme
8). Thus, the reaction of 6 with Me3SiOTf to generate 10 as
above, followed by addition of Et3N (2 equiv, -80 °C), gave
rise to the metalate 12, which in turn underwent efficient
protonation (H2O), deuteriation (D2O), or methoxycarbonylation
(I2/MeOH)22 to afford, after imonium hydrolysis, 7, 7-d, and
13, respectively. Surprisingly, the metal carbene complex 10
does not cyclopropanate the pyrrolidine enamine 3a, but low-
temperature deprotonation (CH2Cl2, -80 °C) to the imonium
metalate complex 12 again takes place (Scheme 8).23 Moreover,
the carbene functionality of 10 could be oxidized to the
corresponding carbonyl group. This was accomplished ef-
(15) Casey, C. P.; Cesa, M. C. Organometallics 1982, 1, 87.
(16) See: Brookhart, M.; Liu, Y.; Goldman, E. W.; Timmers, D. A.; Williams,
G. D. J. Am. Chem. Soc. 1991, 113, 927. In our case, despite the fact that
the endo stereochemical orientation of the anion metal center of 6 is
exclusively observed both in the solid state and in THF-d8 solution, an
endo-exo equilibration cannot be definitively ruled out.
(17) (a) Casey, C. P.; Brunsvold, W. R. Inorg. Chem. 1977, 16, 391. (b) Rudler,
H.; Audouin, M.; Parlier, A.; Martin-Vaca, B.; Goumont, R.; Durand-
Re´ville, T.; Vaissermann, J. J. Am. Chem. Soc. 1996, 118, 12045.
(18) (a) Casey, C. P.; Burkhardt, T. J. J. Am. Chem. Soc. 1973, 95, 5833. (b)
Casey, C. P.; Polichnowski, S. M.; Shusterman, A. J.; Jones, C. R. J. Am.
Chem. Soc. 1979, 101, 7282. (c) Fischer, H.; Mauz, E.; Jaeger, M.; Fisher,
R. J. Organomet. Chem. 1992, 427, 63. (d) Fischer, H.; Hofmann, J. Chem.
Ber. 1991, 124, 981. (e) Fischer, H.; Zeuner, S.; Ackermann, K. J. Chem.
Soc., Chem. Commun. 1984, 684. (f) Pfeiffer, J.; Do¨tz, K. H. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2828. (g) Pfeiffer, J.; Nieger, M.; Do¨tz, K. H. Eur.
J. Org. Chem. 1998, 1011, 1. (h) The catalytic cyclopropanation of alkenes
via (2-furyl)carbene complexes of group 6 has been reported very recently;
see: Miki, K.; Nishino, F.; Ohe, K.; Uemura, S. J. Am. Chem. Soc. 2002,
124, 5260.
(21) For alkoxycarbene complexes, see: (a) Bernasconi, C. F.; Leyes, A. E.;
Ragains, M. L.; Shi, Y.; Wang, H.; Wulff, W. D. J. Am. Chem. Soc. 1998,
120, 8632. (b) Bernasconi, C. F.; Sun, W. J. Am. Chem. Soc. 2002, 124,
2299.
(22) For the methoxycarbonylation of tungsten(0) methoxymetalated complexes,
see: Fuchibe, K.; Iwasawa, N. Tetrahedron 2000, 56, 4907.
(23) Alkylidene complexes of tungsten(0) stabilized as pyridinium ylides are
able to cyclopropanate electron-rich alkenes. See: (a) Rudler, H.; Durand-
Re´ville, T. J. Organomet. Chem. 2001, 617-618, 571. (b) Reference 17b.
(c) Mart´ın-Vaca, B.; Durand-Re´ville, T.; Audouin, M.; Rudler, H. Synthesis
1998, 1534. (d) Mart´ın-Vaca, B.; Rudler, H. J. Chem. Soc., Perkin Trans.
1 1997, 3119.
(19) (a) Casey, C. P.; Albin, L. D.; Burkhardt, T. J. J. Am. Chem. Soc. 1977,
99, 2533. (b) For M(SnPh3)(CO)2(dCMePh)(η-C5H5), (M ) Mo, W), see:
Winter, M. J.; Woodward, S. J. Chem. Soc., Chem. Commun. 1989, 457.
(20) We found that dry acids, e.g., TFA and HBF4, are also effective for the
formation of 10.
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A R T I C L E S
Barluenga et al.
Scheme 9
ficiently by low-temperature addition of MCPBA to the complex
10, generated as above, followed by warming to room temper-
ature in the presence of 5% Na2S2O3 to furnish the diketones
14. Those compounds were not chromatographed, but we
became highly interested in the transformation of this bicyclic
framework 14 into the cycloheptane ring.24 Therefore, we
focused on the retro-Claisen-type reaction of the 1,3-diketones
14 and found that their treatment with aqueous methanoic acid
(50% v/v) at 80 °C followed by esterification with CH2N2
resulted in the formation of racemic cycloheptanones 15 in
acceptable yields (61-64% from 6) and with complete regio-
selectivity by cleavage of the C1-C8O bond.
This procedure could be improved when applied to the
enantioenriched systems in the sense that the whole reaction
sequence was shortened and carried out in a one-pot fashion
from the starting carbene complexes 2 (Scheme 9). Thus,
tungsten complexes 2a-c were treated with chiral, nonracemic
(R ) CH2OMe) pyrrolidine enamine 3b in THF at -20 °C for
6 h. The resulting solution was stirred at the same temperature
with MCPBA for 5 min followed by addition of 5% Na2S2O3
and stirring at room temperature for 2 min.25 Methanoic acid
was then added and the mixture heated at 80 °C for 1 h,
extracted with Et2O, and treated with CH2N2. The reaction crude
product was purified by column chromatography to provide
substituted 4-methoxycarbonylcycloheptanones 15 in good
overall yields (51-55% yield from 2) and with very high
enantioselectivity (91-96% ee) determined by chiral HPLC
(Chiracel OB-H).26
Figure 3.
Scheme 10
Taking advantage of the methodology depicted, preliminary
studies on simple carbene complexes, for instance, pentacar-
bonyl[phenyl(methoxy)carbene]tungsten complex 16, were done
(Scheme 10). Thus, the treatment of 16 with alkyllithiums RCH2-
Li (R ) H, n-Pr) at 0 °C in THF followed by cooling to -80
°C and addition of Me3SiOTf resulted presumably in the
generation of carbene complexes 17. This species was not
characterized but was allowed (i) to reach room temperature to
furnish alkenes 18 (61-67% yield, E:Z ) 1:1), (ii) to react with
pyridine oxide at -80 °C to afford phenones 19 (40-45%
yield), (iii) to react with MeOH/Et3N/I2 at -80 °C to yield
methyl 2-phenylalkenoates 20 (70-74% yield, E:Z ) 1:5), and
(iv) to reach room temperature in the presence of aqueous 1 M
NaOH/Et4NBr to give the stable tetraethylammonium alkenyl-
metalate 21 (R ) H, 32% yield, mp 95-98 °C dec), which
was fully characterized.
Structural Characterization. The structural analysis of all
the compounds is based on spectroscopic data (1H and 13C NMR
spectra, IR spectra, and MS spectra) and elemental analyses (see
the Experimental Section). In addition, the unambiguous
characterization by X-ray analysis has been done for compounds
6c, 12b, 23, and 24 (Figure 3).
Thus, metalate complex 6c was crystallized by diffusion of
hexane into a tetrahydrofuran solution, and 12b was crystallized
in dichloromethane at - 20 °C. Compound 23 was synthesized
by thermal ring opening of 5g (H2O/MeOH (2:1), 170 °C, 2 h)
to the ketone 22 followed by derivatization with 2,4-dinitro-
phenylhydrazine to hydrazone (-)-23, which was crystallized
from methanol. To ascertain its absolute configuration, ketone
(+)-7c was reacted with (S)-(1-amino-2-methoxymethyl)-
pyrrolidine (SAMP) and the resulting hydrazone 24 crystallized
from pentane at -20 °C.
(24) The attempts were at the beginning based on the Baeyer-Villiger oxidation/
lactone hydrolysis sequence of the bicyclic ketones 7, but regioisomeric
mixtures of hydroxycycloheptenecarboxylic acids, resulting from the
insertion of oxygen into both C1-C8O and C5-C8O bonds, were
systematically obtained using various procedures and reaction conditions.
(25) It should be noted that MCPBA plays a 2-fold role: (i) acid-catalyzed
generation of the nonstabilized carbene complex and (ii) oxidation of the
carbene function as it is formed, which allows the carbene to be generated
at -20 °C.
Conclusions
Fischer alkenylcarbene complexes of chromium and tungsten
are very useful C3-synthons for the [3+3]-cycloaddition reaction
toward cyclopentanone and cyclohexanone enamines, allowing
a simple, one-step protocol for the diastereo- and enantioselec-
(26) The corresponding cyclopentanone ring, arising from cleavage of the
C1-C2O bond, was formed in negligible amounts (<5%).
9
1838 J. AM. CHEM. SOC. VOL. 125, NO. 7, 2003

â,â′- and R,â,â′-Annulation of Cyclic Enamines
A R T I C L E S
-0.184 (c 0.43, CH2Cl2). 1H NMR (CDCl3, 300 MHz): δ 0.8 (d, 3H,
J ) 7.0 Hz), 0.85 (d, 3H, J ) 7.0 Hz), 0.95 (d, 3H, J ) 6.5 Hz),
0.7-1.0 (m, 2H), 1.1 (dd, 1H, J ) 6.9, 12.1), 1.3-1.7 (m, 8H), 1.85
(m, 4H), 2.0-2.3 (m, 4H), 2.45 (dd, 1H, J ) 10.0, 12.6 Hz), 2.8 (m,
4H), 3.05 (t, 1H, J ) 7.1 Hz), 3.45 (m, 2H), 6.0 (m, 1H), 6.25 (m,
1H), 7.3 (m, 1H). 13C NMR (CDCl3, 75 MHz): δ 16.0 (CH3), 20.8
(CH3), 22.5 (CH3), 23.2 (CH2), 24.0 (2 CH2) 24.9 (CH2), 25.3 (CH),
31.4 (CH), 31.5 (CH2), 32.3 (CH2), 34.4 (CH2), 39.7 (CH), 40.6 (CH2),
42.7 (CH), 46.2 (CH), 47.2 (CH), 51.0 (2 CH2), 65.2 (C), 71.0 (C),
76.7 (CH), 105.3 (CH), 109.7 (CH), 140.8 (CH), 156.2 (C). HRMS
(m/z): calcd for C26H39NO2 397.2981, found 397.2968; Anal. Calcd
for C26H39NO2: C, 78.54; H, 9.89; N, 3.52. Found: C, 79.02; H, 9.97;
N, 3.49
Reaction of Carbene Complex 1 or 2 with Cyclopentanone
Pyrrolidine Enamine. Synthesis of Complexes 6. To a solution of
carbene complex 1a-d or 2a-d (1 mmol) in hexane (40 mL) at room
temperature was added 151 mg (1.1 mmol) of cyclopentanone pyrro-
lidine enamine in hexane (10 mL). The reaction mixture was stirred
for 2 h. Filtration of the yellow solid and washing with hexane (2 ×
15 mL) yielded complexes 6 as solids.
tive synthesis of functionalized bicyclo[3.2.1]octane and bicyclo-
[3.3.1]nonane skeletons to be designed.27 On the other hand,
the novel R,â,â′-anulation reaction of cyclopentanone enamines
and alkenylcarbene complexes described here represents the
shortest thermal access to tricyclo[3.3.0.02,8]octanes (semi-
bullvalene derivatives),28 systems known to be precursors of
molecules of interest, e.g., triquinanes.29 The isolation of key
intermediates has permitted, not only the confirmation of the
polar pathway for the cyclopropanation of enamines by Fischer
carbene complexes, but more importantly the realization that
nonstabilized alkylcarbene complexes are not elusive species,
but that they can be generated and subjected to various
transformations. Specifically, we have shown that non-heteroa-
tom-stabilized pentacarbonyl(bicyclo[3.2.1]octan-2-ylidene)-
tungsten(0) complexes 10 are readily accessible, via methoxy
desplacement from the corresponding methoxymetalate com-
plexes 6. The potential of this type of carbene makes possible
the one-pot synthesis of enantioenriched 3,4-disubstituted cy-
cloheptanones 15 from Fischer carbene complexes and cyclo-
pentanone enamines. The strategy shown here is also applicable
to simple non-heteroatom-stabilized alkylcarbene complexes, as
illustrated in the generation of 17 from 16 and its transformations
into compounds 18-21. In conclusion, we think that the results
shown here may open the door to the synthetic use of alkyl
nonstabilized group 6 carbene complexes.30
Data for Compound 6a. From 2a. Yield: 95%. Yellow solid. Mp:
1
105-110 °C dec. H NMR (THF-d8, 300 MHz): δ 1.8-1.9 (m. 1H),
2.05-2.45 (m, 7H), 2.65 (m, 1H), 2.7 (dd, 1H, J ) 4.4, 15.8 Hz), 3.25
(br d, 1H, J ) 7.0 Hz), 3.35 (s, 3H), 3.7-3.8 (m, 1H), 3.95 (dd, 1H,
J ) 1.7, 6.6 Hz), 4.05-4.25 (m, 3H), 4.35-4.45 (m, 1H), 6.3 (m, 1H),
6.45 (m, 1H), 7.5 (d, 1H, J ) 1.3 Hz). 13C NMR (THF-d8, 50 MHz):
δ 22.2 (CH2) 26.9 (2 CH2), 28.1 (CH2), 40.5 (CH2), 47.5 (CH), 50.4
(CH), 54.6 (CH3), 54.9 (CH2), 55.8 (CH2), 64.8 (CH), 108.2 (CH), 108.3
(C), 112.1 (CH), 143.5 (CH), 157.1 (C), 201.4 (C), 206.0 (CO), 206.2
(4 CO). FAB-MS (m/z): 598 (M+ + 1). Anal. Calcd for C22H23-
NO7W: C, 44.24; H, 3.88; N, 2.35. Found: C, 44.02; H, 3.61; N, 2.30.
Data for Compound 6c. From pentacarbonyl[(E)-2-(4-methoxy-
phenyl)ethenyl(methoxy)carbene]tungsten (2c). Yield: 97%. Yellow
Experimental Section31
Reaction of Carbene Complex 1 or 2 with Cyclopentanone
Pyrrolidine Enamine 3a. Synthesis of Semibullvalenes 5. To a
solution of carbene complex 1 or 2 (1 mmol) in THF (50 mL) was
added at room temperature 178 mg (1.3 mmol) of cyclopentanone
pyrrolidine enamine 3a. The reaction mixture was heated at 60 °C for
1.5 h (5a-c) or 6 h (5e-g). Removal of solvent at reduced pressure
and column chromatography (hexanes-ethyl acetate-triethylamine,
20:1:1) afforded the semibullvalenes 5 as pale yellow oils.
1
solid. Mp: 89-91 °C dec. H NMR (THF-d8, 300 MHz): δ 1.7 (m.
1H), 2.0-2.45 (m, 7H), 2.5 (br s, 1H), 2.6 (dd, 1H, J ) 4.3, 15.6 Hz),
3.05 (br d, 1H, J ) 6.8 Hz), 3.3 (s, 3H), 3.6-3.7 (m, 1H), 3.8 (s, 3H),
3.9 (d, 1H, J ) 6.9 Hz), 4.0-4.2 (m, 3H), 4.3-4.5 (m, 1H), 6.9 (d,
2H, J ) 8.7 Hz), 7.25 (d, 2H, J ) 8.7 Hz). 13C NMR (THF-d8, 75
MHz): δ 21.6 (CH2) 26.9 (2 CH2), 28.3 (CH2), 41.6 (CH2), 50.4 (CH),
54.5 (CH3), 54.6 (CH2) 55.1 (CH), 55.8 (CH2) 56.5 (CH3), 64.8 (CH),
108.3 (C), 115.7 (2 CH), 130.4 (2 CH), 135.6 (C), 160.9 (C), 201.5
(C), 206.0 (CO), 206.2 (4 CO); FAB-MS (m/z): 638 (M+ + 1). Anal.
Calcd for C25H27NO7W: C, 47.11; H, 4.27; N, 2.20. Found: C, 47.41;
H, 4.51; N, 2.11.
Synthesis of Bicyclo[3.2.1]oct-2-en-8-ones 7. Method A: Hydroly-
sis of Complexes 6. To a solution of complex 6 (1 mmol) in THF (40
mL) at 0 °C was added 1 mL of trifluoroacetic acid in THF (10 mL).
The reaction mixture was stirred for 10 min, 10 mL of H2O was added,
and the solution was allowed to reach room temperature and stirred
for an additional 2 h. The mixture was extracted with methylene
dichloride (3 × 30 mL) and the organic layer washed with 20 mL of
a saturated solution of sodium hydrogen carbonate and 20 mL of water.
The resulting solution was dried over Na2SO4. After removal of the
solvents, chromatographic purification of the residue on silica gel (5%
ethyl acetate in hexane) gave the pure bicyclic ketones 7.
Method B. To 50 mL of a 0.02 M THF solution of the alkenyl
Fischer carbene complex 1 or 2 at 0 °C was added 180 mg (1.3 mmol)
of the enamine 3a. The mixture was stirred at 0 °C for 6 h. Then, 1
mL of trifluoroacetic acid and 10 mL of water were subsequently added.
The solution was allowed to reach room temperature and stirred for an
additional 2 h. The mixture was extracted with methylene dichloride
(3 × 30 mL) and the organic layer washed with 20 mL of a saturated
solution of sodium hydrogen carbonate and 20 mL of water. The
resulting solution was dried over Na2SO4. After removal of the solvents,
chromatographic purification of the residue on silica gel (5% ethyl
acetate in hexane) gave the pure bicyclic ketones 7.
Data for Compound 5a. From pentacarbonyl[(E)-2-(2-furyl)ethenyl-
1
(methoxy)carbene]tungsten (2a). Yield: 85%. H NMR (CDCl3, 400
MHz): δ 1.1 (dd, 1H, J ) 7.1, 12.5 Hz), 1.4 (m, 1H), 1.55 (m, 1H),
1.7 (d, 1H, J ) 6.5 Hz), 1.8 (m, 4H), 2.05 (m, 1H), 2.1 (dd, 1H, J )
10.8, 13.0 Hz), 2.4 (dd, 1H, J ) 10.3, 13.0 Hz), 2.8 (m, 4H), 3.0 (t,
1H, J ) 7.1 Hz), 3.35 (s, 3H), 3.4 (m, 1H), 6.0 (m, 1H), 6.25 (m, 1H),
7.3 (m, 1H). 13C NMR (CDCl3, 100 MHz): δ 23.9 (2 CH2), 25.0 (CH2),
30.7 (CH2), 32.8 (CH2), 36.8 (CH), 42.4 (CH), 45.2 (CH), 51.2 (2 CH2),
56.4 (CH3), 68.1 (C), 75.6 (C), 105.3 (CH), 109.6 (CH), 140.9 (CH),
156.0 (C). HRMS (m/z): calcd for C17H23NO2 273.1729, found
273.1718. Anal. Calcd for C17H23NO2: C, 74.69; H, 8.48; N, 5.12.
Found: C, 74.77; H, 8.58; N, 5.09.
Data for Compound 5e. From pentacarbonyl[(E)-2-(2-furyl)ethenyl-
[(1R,2S,5R)-menthyloxy]carbene]tungsten (2e). Yield: 70%. [R]20
)
D
(27) The bicyclo[3.3.1]nonan-2-one skeleton is the central part of a number of
terpenes. For instance, see refs 2a-d.
(28) (a) For the arene-alkene photocyclization, see: Wender, P. A.; Siggel,
L.; Nuss, J. M. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: New York, 1991; Vol. 5, pp 645-673. (b) For the
oxadi-π-methane rearrangement of bicyclo[2.2.2]octenones to semi-
bullvalenes, see: Lee, T.-H.; Rao, P. D.; Liao, C.-C. Chem. Commun. 1999,
801.
(29) Singh, V. Acc. Chem. Res. 1999, 32, 324.
(30) Rudler et al. have reported that the reduction of alkoxycarbene complexes
with dihydropyridine generates a different type of nonstabilized group 6
carbene complexes, which are stabilized and characterized as pyridinium
ylides. See refs 23a-d. Specific nonstabilized carbene complexes of
tungsten(0) have been reported to be formed via nucleophilic endo-attack
of the carbonyl oxygen/imine nitrogen of the o-alkynylphenyl ketone/N-
(o-alkynylphenyl)imine derivatives; see, respectively: (a) Iwasawa, N.;
Shido, M.; Kusama, H. J. Am. Chem. Soc. 2001, 123, 5814. (b) Kusama,
H.; Takaya, J.; Iwasawa, N. J. Am. Chem. Soc. 2002, 124, 11592.
(31) General information, experimental procedures, and spectral data for
compounds not described here are provided in the Supporting Information.
9
J. AM. CHEM. SOC. VOL. 125, NO. 7, 2003 1839

A R T I C L E S
Barluenga et al.
1
Data for Compound (()-7a. Yield: 87%. Colorless oil. H NMR
(CDCl3, 300 MHz): δ 1.7-1.9 (m, 2H), 1.9-2.0 (m, 2H), 2.55 (m,
1H), 2.65 (m, 1H), 4.4 (m, 1H), 5.7 (ddd, 1H, J ) 1.2, 2.3, 9.3 Hz),
6.05 (ddd, 1H, J ) 2.7, 7.0, 9.4 Hz), 6.15 (m, 1H), 6.35 (m, 1H), 7.4
(m, 1H). 13C NMR (CDCl3, 75 MHz): δ 19.8 (CH2), 28.6 (CH2), 44.6
(CH), 46.9 (CH), 49.5 (CH), 107.0 (CH), 110.0 (CH), 125.1 (CH),
133.7 (CH), 141.8 (CH), 153.8 (C), 215.1 (C). HRMS (m/z): calcd for
C12H12O2 188.0837, found 188.0827. Anal. Calcd for C12H12O2: C,
76.57; H, 6.42. Found: C, 76.45; H, 6.33.
ratio was determined by HPLC (Chiracel OB-H column, 250 × 4.6
mm; 0.8 mL/min; hexane/2-propanol, 50:1): retention times 13.6 (6%)
and 14.9 (94%) min.
Data for Compound (+)-7c. Yield: 90%. [R]20 ) +81 (c 0.1,
D
CH2Cl2). For spectroscopic data, see those for (()-7c. The enantiomeric
ratio was determined by HPLC (Chiracel OJ column, 250 × 4.6 mm;
0.8 mL/min; hexane/2-propanol, 50:1): retention times 39.8 (3.5%)
and 44.7 (96.5%) min.
Synthesis of Optically Active Ketones 8. To 50 mL of a 0.02 M
solution (in the appropriate solvent) of the alkenyl Fischer carbene
complex 2 was added 1.3 mmol of the enamine 4b,c. After the mixture
was stirred at low temperature, 390 µL (5 mmol) of trifluoroacetic acid
and 10 mL of water were subsequently added. The solution was allowed
to reach room temperature and stirred for an additional 2 h. The mixture
was extracted with methylene dichloride (3 × 30 mL) and the organic
layer washed with 20 mL of a saturated solution of sodium bicarbonate
and 20 mL of water. The resulting solution was dried over Na2SO4,
and the solvents were removed. Purification of the residue by
chromatography on silica gel (5% ethyl acetate in hexane) gave the
optically active bicyclic ketones 8.
Data for Compound (-)-endo-8a. Solvent: CH2Cl2. Temperature:
-50 °C. Reaction time: 7 days. Yield: 52%. [R]20D ) -17.6 (c 0.23,
CH2Cl2). For spectroscopic data, see the those for (()-endo-8a. The
enantiomeric ratio was determined by HPLC (Chiracel OJ column, 250
× 4.6 mm; 0.8 mL/min; hexane/2-propanol, 200:1): retention times
15.8 (1%) and 18.2 (99%) min.
Data for Compound (-)-exo-8a. Solvent: THF. Temperature: -20
°C. Reaction time: 72 h. endo:exo ratio 1:2. For spectroscopic data,
see those of (()-exo-8a. The enantiomeric ratio was determined by
HPLC (Chiracel OJ column, 250 × 4.6 mm; 0.8 mL/min; hexane/2-
propanol, 200:1): retention times 20.2 (99%) and 22.3 (1%) min.
Reaction of Pentacarbonyl[1-pentenyl(methoxy)carbene]tungsten
(2d) with Cyclopentanone Pyrrolidine Enamine 3a. Synthesis of
Enol Ether 9. To a solution of carbene complex (1 mmol) in THF (50
mL) was added at 0 °C 178 mg (1.3 mmol) of cyclopentanone
pyrrolidine enamine 3a. The reaction was stirred at 25 °C for 2 h. Then,
1 mL of trifluoroacetic acid and 10 mL of water were added. The
mixture was extracted with methylene dichloride (3 × 30 mL) and the
organic layer washed with water (2 × 20 mL). The resulting solution
was dried over Na2SO4. After removal of the solvents, chromatographic
purification of the residue on silica gel (5% ethyl acetate in hexane)
gave the pure enol ether 9.
1H NMR (CDCl3, 300 MHz): δ 1.5 (d, 3H, J ) 1.32 Hz), 1.5-1.9
(m, 2H), 1.9-2.4 (m, 7H), 3.5 (s, 3H), 5.85 (m, 1H). 13C NMR (CDCl3,
75 MHz): δ 17.1 (CH3), 20.5 (CH2), 28.9 (CH2), 29.0 (CH2), 38.1
(CH2), 47.2 (CH), 59.1 (CH3), 111.6 (C), 143.0 (CH), 219.5 (C). HRMS
(m/z): calcd for C10H16O2 168.1150, found 168.1154. Anal. Calcd for
C10H16O2: C, 71.39; H, 9.59. Found: C, 71.57; H, 9.64.
Reaction of Nonstabilized Carbene Complex 10 with Bases.
Synthesis of Complexes 12. A 1 mmol sample of racemic complex 6
was cooled to -80 °C and then suspended in CH2Cl2 (25 mL), and
290 µL (1.6 mmol) of trimethylsilyl triflate was added at this
temperature. After 30 min the reaction mixture became a dark red
solution. A 291 µL (2 mmol) sample of enamine 3a was added to form
a deep yellow solution which was allowed to reach room temperature.
The solvents were evaporated, and the yellow solid crude product was
dissolved in the minimum of methylene dichloride (1.5 mL). Cooling
the solution at -20 °C for 14 h afforded yellow crystals, which were
filtered and washed with cold CH2Cl2. Other common bases such as
triethylamine, pyridine, etc. are suitable, but they do not allow isolation
of the metalate. In turn, they are the used to the in situ reaction better
than enamine.
Data for Compound (()-7c. Yield: 91%. White solid. Mp: 110-
111 °C. H NMR (CDCl3, 300 MHz): δ 1.6-1.9 (m, 2H), 1.9-2.1
1
(m, 2H), 2.45 (m, 1H), 2.55 (m, 1H), 3.8 (s, 3H), 4.4 (m, 1H), 5.7 (br
d, 1H, J ) 9.9 Hz), 6.1 (ddd, 1H, J ) 2.5, 7.2, 9.5 Hz), 6.9 (d, 2H, J
) 8.6 Hz), 7.1 (d, 2H, J ) 8.6 Hz). 13C NMR (CDCl3, 75 MHz): δ
18.9 (CH2), 28.6 (CH2), 44.4 (CH), 50.1 (CH), 54.3 (CH3), 55.0 (CH),
113.8 (2 CH), 128.1 (CH), 129.0 (2 CH), 132.6 (C), 133.5 (CH), 158.4
(C), 215.9 (C); HRMS (m/z): calcd for C15H16O2 228.1150, found
228.1144. Anal. Calcd for C15H16O2: C, 78.92; H, 7.06. Found: C,
78.56; H, 7.14.
Synthesis of Bicyclo[3.3.1]non-2-en-9-ones 8. A 200 mg (1.3 mmol)
sample of the cyclohexanone pyrrolidine enamine 4a was added to a
solution of 1 mmol of the alkenyl Fischer carbene complex 1 or 2 in
50 mL of THF at 0 °C. The mixture was stirred at 0 °C for 12 h. Then,
390 µL (5 mmol) of trifluoroacetic acid and 10 mL of water were
subsequently added and, the solution was allowed to reach room
temperature and stirred for an additional 2 h. The resulting mixture
was extracted with methylene dichloride (3 × 30 mL) and the organic
layer washed with 20 mL of a saturated solution of sodium hydrogen
carbonate and 20 mL of water and finally dried over Na2SO4. The
solvents were removed, and subsequent chromatographic purification
of the residue on silica gel (5% ethyl acetate in hexane) yielded the
pure bicyclic ketones 8.
Data for Compound (()-endo-8a. Yield: 67%. White solid. Mp:
49-50 °C. 1H NMR (CDCl3, 300 MHz): δ 1.3 (m, 1H), 1.4-1.65 (m,
2H), 1.8-2.0 (m, 3H), 2.8 (m, 1H), 2.95 (m, 1H), 4.15 (m, 1H), 5.8
(ddd, 1H, J ) 2.9, 5.9, 9.9), 6.05 (dd, 1H, J ) 2.3, 9.9 Hz), 6.2(m
1H), 6.35 (m, 1H), 7.35 (m, 1H). 13C NMR (CDCl3, 75 MHz): δ 16.9
(CH2), 31.4 (CH2), 32.5 (CH2), 44.2 (CH), 47.4 (CH), 49.6 (CH), 106.8
(CH), 110.0 (CH), 128.5 (CH), 129.4 (CH), 141.7 (CH), 154.0 (C),
214.7 (C); HRMS (m/z): calcd for C13H14O2 202.0994, found 202.0992.
Anal. Calcd for C13H14O2: C, 77.20; H, 6.98. Found: C, 77.42; H,
6.80.
1
Data for Compound (()-exo-8a. Yield: 13%. Colorless oil. H
NMR (CDCl3, 200 MHz): δ 1.5-1.7 (m, 2H), 1.8-2.2 (m, 4H), 2.7
(m, 1H), 2.9 (m, 1H), 3.95 (m, 1H), 5.75 (m, 1H), 5.95 (m, 1H), 6.05
(m, 1H), 6.25 (m, 1H), 7.3 (m, 1H). 13C NMR (CDCl3, 75 MHz): δ
17.0 (CH2), 32.6 (CH2), 36.0 (CH2), 47.3 (CH), 47.4 (CH), 41.0 (CH),
105.2 (CH), 110.2 (CH), 128.5 (CH), 129.8 (CH), 141.7 (CH), 155.3
(C), 214.8 (C). HRMS (m/z): calcd for C13H14O2 202.0994, found
202.1002. Anal. Calcd for C13H14O2: C, 77.20; H, 6.98. Found: C,
77.45; H, 7.09.
Synthesis of Optically Active Ketones 7. To a solution of 1 mmol
of the alkenyl Fischer carbene complex 2 in 50 mL of THF at -20 °C
was added 180 mg (1.3 mmol) of cyclopentanone methoxymethyl-
pyrrolidine enamine 3b. After 6.5 h of stirring at -20 °C, 390 µL (5
mmol) of trifluoroacetic acid was added, the resulting mixture was
stirred for 0.5 h, 10 mL of water was added, and the mixture was
allowed to react for an additional 2 h at room temperature. Then the
mixture was extracted with methylene dichloride (3 × 30 mL) and the
organic layer washed with 20 mL of a saturated solution of sodium
hydrogen carbonate and 20 mL of water and dried over Na2SO4. After
removal of the solvents, chromatographic purification of the residue
on silica gel (5% ethyl acetate in hexane) gave the optically active
ketones 7.
Data for Compound 12a. Yield: 65%. Yellow solid. Mp: 160-
1
162 °C dec. H NMR (CD2Cl2, 300 MHz): δ 1.6-1.8 (m, 2H), 1.8-
Data for Compound (+)-7a. Yield: 85%. [R]20 ) +2.8 (c 0.8,
CH2Cl2). For spectroscopic data, see those for (()-7a. The enantiomeric
2.0 (m, 1H), 2.0-2.2 (m, 1H), 2.2-2.5 (m, 4H), 3.1 (br s, 1H), 3.8 (br
s, 1H), 3.9-4.2 (m, 4H), 4.8 (m, 1H), 5.3 (m, 1H), 7.2-7.5 (m, 5H).
D
9
1840 J. AM. CHEM. SOC. VOL. 125, NO. 7, 2003

â,â′- and R,â,â′-Annulation of Cyclic Enamines
A R T I C L E S
13C NMR (CD2Cl2, 75 MHz): δ 22.1 (CH2), 25.0 (CH2), 25.1 (CH2),
30.0 (CH2), 48.5 (CH), 52.4 (CH2), 53.9 (CH2), 62.1 (CH), 66.9 (CH),
127.4 (CH), 128.7 (2 CH), 128.8 (2 CH), 134.2 (CH), 141.1 (C), 169.7
(C), 199.5 (C), 203.3 (4 C), 206.9 (C). FAB-HRMS (m/z): calcd for
C23H22NO5184W 576.1007, found 576.1003. Anal. Calcd for C23H21-
NO5W: C, 48.02; H, 3.68; N, 2.43. Found: C, 47.96; H, 3.59; N, 2.35.
Synthesis of Deuterated Derivatives Bicyclo[3.2.1]oc-2-en-8-ones
7-d. To a solution of complex 12 (1 mmol) in THF (10 mL) at room
temperature were subsequently added 1 mL of deuterated water and
0.15 mL (2 mmol) of deuterated trifluoroacetic acid. After 15 min the
mixture was extracted with methylene dichloride (3 × 10 mL), and
the combined organic layers were washed with 20 mL of a 5% solution
of sodium hydrogen carbonate and 20 mL of water. The resulting
solution was dried over sodium sulfate and filtered. After removal of
the solvents, chromatographic purification of the residue on silica gel
(5% ethyl acetate in hexane) gave the pure bicyclic ketones 7-d.
organic layers were washed with water. Filtration and solvent removal
afford the crude reaction product, which contains diketone 14 and
3-chlorobenzoic acid. Basic extraction or chromatographic purification
affords mixtures of retro-Claisen-type products from diketone 14, and
then nonanalytically pure samples were obtained. The signals belong
to 14b in the NMR reaction crude product analysis.
1
Data for Compound 14b. H NMR (CDCl3, 300 MHz): δ 2.0-
2.1 (m, 3H), 2.2 (m, 1H), 2.7 (m, 1H), 2.9-3.0 (m, 2H), 3.2-3.4 (m,
2H), 6.1 (m, 1H), 6.3 (m, 1H), 7.4 (m, 1H). 13C NMR (CDCl3, 75
MHz): δ 18.1 (CH2), 23.2 (CH2), 34.6 (CH), 37.6 (CH2), 48.3 (CH),
63.6 (CH), 106.6 (CH), 110.2 (CH), 142.5 (CH), 152.7 (C), 203.9 (C),
207.5 (C).
Synthesis of Methoxycarbonylcycloheptanones 15. The crude
product of 1 mmol formation of 14 is placed into a flask and dissolved
in 10 mL of methanoic acid (50% v/v). The mixture was stirred and
heated at 80 °C for 1 h. After the mixture was cooled at room
temperature, the methanoic acid was evaporated and the crude product
diluted with water and extracted with diethyl ether (4 × 40 mL). The
combined organic layers were washed with water and filtered. To the
filtrate was added 10 mL of a 0.3 M solution of diazomethane in ether.
(The diazomethane excess was destroyed with 0.3 mL of acetic acid.)
Removal of solvents at reduced pressure and column chromatography
(20% ethyl acetate in hexane) afforded the cycloheptanones 15.
Data for Compound (()-15a. Yield: 64%. White solid. Mp: 96-
1
Data for Compound 7a-d. Yield: 91%. Colorless oil. H NMR
(CDCl3, 300 MHz): δ 1.6-18 (m, 2H), 1.9-2.1 (m, 2H), 2.5 (m, 1H),
2.6 (m, 1H), 4.4 (s, 1H), 5.7 (s, 1H), 7.1-7.5 (m, 5H). 13C NMR
(CDCl3, 75 MHz): δ 19.0 (CH2), 28.6 (CH2), 44.5 (CH), 49.8 (CH),
55.0 (CH), 126.8 (CH), 127.7 (CH), 128.1 (2 CH), 128.4 (2 CH), 133.6
(CD, t, J ) 28.1 Hz), 140.5 (C), 215.9 (C). HRMS (m/z): calcd for
C14H13DO 199.1107, found 199.1100. Anal. Calcd for C14H13DO: C,
84.38; H, 7.59. Found: C, 84.28; H, 7.68.
1
98 °C. H NMR (CDCl3, 300 MHz): δ 1.7 (m, 1H), 1.9 (m, 1H), 2.1
Methoxycarbonylation of Complexes 12. Synthesis of Ketones
13. Method A. To a solution of complex 12 (1 mmol) in THF (40
mL) at -80 °C were subsequently added 1 mL of methanol, 1.5 mL
of triethylamine, and 1 g of iodine in THF (4 mL). After 15 min at
this temperature the reaction was quenched with 50 mL of 5% Na2S2O3
solution. The solution was allowed to reach room temperature and
extracted with methylene dichloride (3 × 30 mL). The combined
organic layers were washed with water and dried over sodium sulfate.
After removal of the solvents, chromatographic purification on silica
gel (5% ethyl acetate in hexane) gave the pure bicyclic ketones 13.
Method B. To 50 mL of a 0.02 M THF solution of the alkenyl
Fischer carbene complex 1 or 2 at 0 °C was added 180 mg (1.3 mmol)
of the enamine 3a. The mixture was stirred at 0 °C for 6 h. Then, 361
µL (2 mmol) of trimethylsilyl triflate was added at -80 °C. After 30
min at this temperature, 418 µL (3 mmol) of triethylamine was added.
The dark red solution became yellow, and 1 mL of methanol, 1.5 mL
of triethylamine, and 1 g of iodine in THF (4 mL) were subsequently
added. After 15 min at this temperature the reaction was quenched with
50 mL of 5% Na2S2O3 solution. The solution was allowed to reach
room temperature and extracted with methylene dichloride (3 × 40
mL). The combined organic layers were washed with water and dried
over sodium sulfate. After removal of the solvents, chromatographic
purification on silica gel (5% ethyl acetate in hexane) gave the pure
bicyclic ketones 13.
(m, 1H), 2.2 (m, 1H),2.6 (m, 3H), 2.9 (dt, 1H, J ) 2.80, 10.85 Hz),
3.1 (m, 2H), 3.4 (s, 3H), 7.1-7.4 (m, 5H). 13C NMR (CDCl3, 75
MHz): δ 22.0 (CH2), 31.9 (CH2), 43.2 (CH2), 44.4 (CH), 49.5 (CH2),
51.4 (CH3), 54.8 (CH), 126.9 (3 CH), 128.5 (2 CH), 143.4 (C), 174.5
(C), 211.9 (C). FAB-HRMS (M + 1) (m/z): calcd for C15H19O3
247.1334, found 247.1325. Anal. Calcd for C15H18O3: C, 73.15; H,
7.37. Found: C, 73.19; H, 7.32.
Synthesis of Optically Active Cycloheptanones 15. To 50 mL of
a 0.02 M THF solution of the alkenyl Fischer carbene complex 2a-c
at -20 °C was added 0.235 mg (1.3 mmol) of the enamine 3b. The
mixture was stirred at this temperature for 6 h. Then, 0.448 g (2 mmol)
of 3-chloroperbenzoic acid was added. After 5 min, 40 mL of a 5%
Na2S2O3 solution and 10 mL of methanoic acid were subsequently
added. The reaction was stirred at 80 °C for 1 h. Volatiles was removed,
and the mixture was extracted with diethyl ether (4 × 40 mL). The
combined organic layers were washed with water and filtered. To the
filtrate was added 20 mL of a 0.3 M solution of diazomethane in ether.
(The diazomethane excess was destroyed with 0.3 mL of acetic acid.)
Removal of solvents at reduced pressure and column chromatography
on silica gel (20% ethyl acetate in hexane) afforded the optically active
cycloheptanones 15.
Data for Compound (+)-15a. Yield: 51%. [R]20D ) +61.0 (c 0.92,
CH2Cl2). For spectroscopic data, see those of (()-15a. The enantiomeric
ratio was determined by HPLC (chiracel OB-H column, 250 × 4.6
mm; 0.8 mL/min; hexane/ethanol, 99:1): retention times 24.9 (3.5%)
and 30.7 (96.5%) min.
Data for Compound 13a. Yield: 61% (method A, from complex
12b), 55% (method B, from alkenyl Fischer carbene complex 1b or
1
2b). Colorless oil. H NMR (CDCl3, 300 MHz): δ 1.6-1.8 (m, 2H),
Formation of Simple Nonstabilized Carbene Complexes 17. To
a solution of carbene complex 16 (1 mmol) in THF (25 mL) was added
1.6 mmol of the appropriate alkyllitium (methyllithium as a complex
with lithium bromide, 1.5 M in ether, or butyllithium, 1.6 M solution
in hexanes). The bright yellow mixture was cooled to -80 °C, and
then 361 µL (2 mmol) of freshly distilled trimethylsilyl triflate was
added. The color change to dark brown was due to the new carbene
formed “in situ”.
Synthesis of Alkenes 18. The THF solution of carbene 17 formed
as above was allowed to reach room temperature. Solvent removal and
chromatographic purification on silica gel (5% ethyl acetate in hexane)
afforded the well-known styrene (18a) (67% yield) and 1-phenyl-1-
pentene (18b) (61% yield).
2.0-2.2 (m, 2H), 2.5 (m, 1H), 3.2 (m, 1H), 3.7 (s, 3H), 4.5 (m, 1H),
7.0 (m, 1H), 7.1-7.5 (m, 5H). 13C NMR (CDCl3, 75 MHz): δ 19.2
(CH2), 28.7 (CH2), 43.6 (CH), 49.0 (CH), 52.2 (CH3), 53.0 (CH), 127.3
(CH), 128.2 (2 CH), 128.7 (2 CH), 137.2 (C), 138.2 (CH), 139.1 (C),
165.0 (C), 214.3 (C). HRMS (m/z): calcd for C16H16O3 256.1099, found
256.1100. Anal. Calcd. for C16H16O3: C, 74.98; H, 6.29. Found: C,
74.89; H, 6.36.
Nonstabilized Carbene Complex 10 Oxidation. Formation of
Diketones 14. A 1 mmol sample of racemic complex 6 was cooled to
-80 °C and then suspended in CH2Cl2 (25 mL), and 290 µL (1.6 mmol)
of trimethylsilyl triflate was added at this temperature. After 30 min at
-80 °C, 0.448 g (2 mmol) of 3-chloroperbenzoic acid (77%) was added.
After 5 min the reaction was quenched with 50 mL of 5% Na2S2O3
solution. The reaction was allowed to reach room temperature. The
mixture was extracted with diethyl ether (3 × 40 mL), and the combined
Synthesis of Ketones 19. To the THF solution of 17 at -80 °C
was added 0.285 g (3 mmol) of pyridine N-oxide. After 30 min the
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J. AM. CHEM. SOC. VOL. 125, NO. 7, 2003 1841

A R T I C L E S
Barluenga et al.
reaction was quenched with 50 mL of a 5% solution of Na2S2O3. After
being warmed to room temperature, the mixture was extracted with
methylene chloride (3 × 30 mL), and the combined organic layers were
washed with water. Filtration and chromatographic purification (5%
ethyl acetate in hexane) afforded the pure ketones acetophenone (19a)
and valerophenone (19b) in 45% and 40% yields, respectively.
Synthesis of Methyl 2-Phenylalk-2-enoates 20. To the THF solution
of carbene 17 at -80 °C was added 418 µL (3 mmol) of triethylamine.
Then, 1 mL of methanol, 1.5 mL of triethylamine, and 1 g of iodine in
THF (4 mL) were subsequently added. After 15 min at this temperature
the reaction was quenched with 50 mL of 5% Na2S2O3 solution. The
solution was allowed to reach room temperature and extracted with
methylene dichloride (3 × 40 mL). The combined organic layers were
washed with water and dried over sodium sulfate. After removal of
the solvents, chromatographic purification on silica gel (5% ethyl acetate
in hexane) gave the pure alkenoates 20.
for C13H16O2 204.1150, found 204.1142. Anal. Calcd for C13H16O2:
C, 76.44; H, 7.90. Found: C, 76.50; H, 7.83.
Synthesis of Alkenylmetalates 21. To the THF solution of carbene
17 was added 10 mL of a deoxygenated 1 M NaOH solution which
contains 0.5 g of tetraethylammonium bromide. When the mixture
reached room temperature, THF was removed at reduced pressure until
an orange solid was formed. The water was decanted and the solid
washed with degassed water (2 × 10 mL) and diethyl ether (2 × 10
mL).
Yield: 32%. Yellow solid. Mp: 95-98 °C dec. 1H NMR (CD2Cl2,
300 MHz): 1.2-1.4 (m, 12H), 2.9-3.1 (c, 8H, J ) 7.4 Hz), 5.5 (d,
1H, J ) 5.8 Hz), 5.9 (d, 1H, J ) 5.8 Hz), 6.9-7.2 (m, 5H). 13C NMR
(CD2Cl2, 75 MHz): δ 7.7 (4 CH3), 52.9 (4 CH2), 122.4 (CH), 125.1
(CH2), 125.3 (2 CH), 127.0 (2 CH), 163.9 (C), 174.2 (C), 204.6 (4 C),
209.0 (C). Anal. Calcd for C17H27NO5W: C, 40.10; H, 5.34; N, 2.75.
Found: C, 39.95; H, 5.26, N 2.65.
1
Yield: 74%. Colorless oil. H NMR (CDCl3, 300 MHz): 3.8 (s,
Acknowledgment. This research was supported by DGI
(Grant BQU-2001-3853) and FYCYT (Grant PR-01-GE-09).
A predoctoral fellowship (FYCYT) to R.B.R. is gratefully
acknowledged.
3H), 5.9 (s, 1H), 6.4 (s, 1H), 7.3-7.5 (m, 5H). 13C NMR (CDCl3, 75
MHz): δ 52.1 (CH3), 126.8 (CH2), 128.0 (2 CH), 128.1 (CH), 128.2
(2 CH), 136.6 (C), 141.1 (C), 167.1 (C). HRMS (m/z): calcd for
C10H10O2 162.0681, found 162.0685. Anal. Calcd for C10H10O2: C,
74.06; H, 6.21. Found: C, 74.11; H, 6.12.
Supporting Information Available: Characterization data for
5b,f, 6b,d, 7b,d, 8b, 12b,c, 7b-d, 13b, 15b,c, (+)-22, (-)-23,
and (+)-24 and HPLC data for racemic 7 and 8 and enantioen-
riched 7 and 8 (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
Data for Compound (Z)-20b (Major). Yield: 70%. Colorless oil.
1H NMR (CDCl3, 300 MHz): 1.0 (t, 3H, J ) 7.4 Hz), 1.5-1.6 (m,
2H), 2.4 (c, 2H, J ) 7.5 Hz), 3.8 (s, 3H), 6.2 (t, 1H, J ) 7.5 Hz),
7.3-7.5 (m, 5H). 13C NMR (CDCl3, 75 MHz): δ 13.7 (CH3), 22.5
(CH2), 32.0 (CH2), 51.6 (CH3), 127.2 (2 CH), 127.4 (CH), 128.2 (2
CH), 134.4 (C), 138.0 (C), 140.6 (CH), 168.6 (C). HRMS (m/z): calcd
JA0278077
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1842 J. AM. CHEM. SOC. VOL. 125, NO. 7, 2003