Intramolecular C-H insertion reactions of (η5-Cyclopentadienyl)dicarbonyliron carbene complexes: Scope of the reactions and application to the synthesis of (±)-sterpurene and (±)-pentalenene

Article abstract of DOI:10.1021/jo001792i

(η⁵-Cyclopentadienyl)dicarbonyliron carbene complexes, [(η⁵C₅H₅) (CO)₂Fe=CHR]⁺BF₄^-, are generated as reactive intermediates from thioether derivatives, (η⁵-C₅H₅)(CO)₂FeCH(R)SPh, by S-alkylation with trimethyloxonium tetrafluoroborate and loss of thioanisole. The carbene complexes undergo intramolecular C-H insertion into appropriately situated side chains to form cyclopentane derivatives. The reaction has been developed into a general procedure employing cycloalkanones as scaffolds bearing the iron carbene moieties and the side chains at C(2) and C(3), respectively. The products of the intramolecular insertion reactions are substituted bicyclo[n.3.0]alkanones. The scope and limitations of the reaction are described. The reaction is applied to a total synthesis of sterpurene and to a formal synthesis of pentalenene. Overall, this approach to cyclopentane annulation complements the related metal-catalyzed insertion reactions of diazocarbonyl compounds, which are also believed to occur via metal carbene complexes.

Full text of DOI:10.1021/jo001792i

J . Org. Chem. 2001, 66, 3449-3458
3449
In tr a m olecu la r C-H In ser tion Rea ction s of
(η5-Cyclop en ta d ien yl)d ica r bon ylir on Ca r ben e Com p lexes: Scop e
of th e Rea ction s a n d Ap p lica tion to th e Syn th esis of
(()-Ster p u r en e a n d (()-P en ta len en e
Shingo Ishii, Shikai Zhao, Goverdhan Mehta,1 Christopher J . Knors, and Paul Helquist*
Department of Chemistry and Biochemistry, 251 Nieuwland Science Hall, University of Notre Dame,
Notre Dame, Indiana 46556
paul.helquist.1@nd.edu
Received December 26, 2000
(η5-Cyclopentadienyl)dicarbonyliron carbene complexes, [(η5-C5H5)(CO)2FedCHR]+BF4-, are gener-
ated as reactive intermediates from thioether derivatives, (η5-C5H5)(CO)2FeCH(R)SPh, by S-
alkylation with trimethyloxonium tetrafluoroborate and loss of thioanisole. The carbene complexes
undergo intramolecular C-H insertion into appropriately situated side chains to form cyclopentane
derivatives. The reaction has been developed into a general procedure employing cycloalkanones
as scaffolds bearing the iron carbene moieties and the side chains at C(2) and C(3), respectively.
The products of the intramolecular insertion reactions are substituted bicyclo[n.3.0]alkanones. The
scope and limitations of the reaction are described. The reaction is applied to a total synthesis of
sterpurene and to a formal synthesis of pentalenene. Overall, this approach to cyclopentane
annulation complements the related metal-catalyzed insertion reactions of diazocarbonyl compounds,
which are also believed to occur via metal carbene complexes.
In tr od u ction
Our work in this area had its origins in a key observa-
tion by Pettit and J olly in 1966.3 They found that when
a cyclopentadienyl(dicarbonyl)iron (or Fp) ether deriva-
tive 1 was treated with acid in the presence of cyclohex-
ene, norcarane was produced (Scheme 1). This outcome
was explained by the proposed intermediacy of the
cationic carbene complex 2 formed by protolytic loss of
methanol from the ether. Addition of the methylene
group from the carbene complex to the alkene then
accounted for cyclopropane formation. The proposed
carbene complex could not be observed directly as a result
of its high reactivity, but instead it was generated in situ
in the presence of the alkene.
Carbenes, carbenoids, and metal carbene complexes
have been heavily investigated as reactive intermedi-
ates.2 These species may be generated by numerous
methods, and once they are obtained, they are commonly
seen to undergo either addition reactions to alkenes to
give cyclopropanes or insertions into various covalent
bonds. The insertions occur either intermolecularly or
intramolecularly and are seen most frequently for C-H,
O-H, and N-H bonds. The intramolecular variants of
these insertion reactions are especially useful in synthetic
chemistry and lead to the formation of carbocyclic or
heterocyclic products. These intramolecular reactions are
usually regioselective for bonds located four atoms away
from the carbene center, and therefore these reactions
are particularly useful for the formation of five-membered
rings, although there are also many cases of other ring
sizes being produced.
Following this lead of Pettit and J olly, other investiga-
tors began detailed experimental and calculational stud-
ies of the carbene complex 2 and several derivatives.
Alternative methods were devised for the generation of
these species. Much of this work has been reviewed.4
Especially prominent are studies by Brookhart that have
led to a mechanistic understanding of the iron-promoted
cyclopropanation reaction and the development of syn-
thetically useful procedures, including asymmetric iron
reagents for enantioselective cyclopropane formation.4a,5
* Fax: (219) 631-6652.
(1) Visiting Scientist; present address: Department of Organic
Chemistry, Indian Institute of Science, Bangalore 560 012, India.
(2) For reviews of carbenes and carbene complexes, see: (a) Doyle,
M. P. Chem. Rev. 1986, 86, 919. (b) Maas, G. Top. Curr. Chem. 1987,
137, 75. (c) Carbene (Carbenoide). In Methoden der Organischen
Chemie (Houben-Weyl), 4th ed.; Regitz, M., Ed.; G. Thieme: Stuttgart,
1989; Vol. E19b. (d) Taber, D. F. Carbon-Carbon Bond Formation by
C-H Insertion. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pattenden, G., Vol. Ed.; Pergamon Press: Oxford,
1991; Vol. 3, pp 1045-1062. (e) Adams, J .; Spero, D. M. Tetrahedron
1991, 47, 1765-1808. (f) Padwa, A.; Krumpe, K. E. Tetrahedron 1992,
48, 5385-5453. (g) Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091-
1160. (h) Doyle, M. P. Transition Metal Carbene Complexes: Diazo-
decomposition, Ylide, and Insertion. In Comprehensive Organometallic
Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Hegedus, L.
S., Eds.; Pergamon: Oxford, 1995; Vol 12, pp 421-468. (i) Doyle, M.
P. Aldrichimica Acta 1996, 29, 3-11. (j) Doyle, M. P.; McKervey, M.
A.; Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo
Compounds: from Cyclopropanes to Ylides; Wiley: New York, 1998.
(k) Advances in Carbene Chemistry; Brinker, U., Ed.; J AI Press:
Stamford, CT, 1998; Vol. 2. (l) Sulikowski, G. A.; Cha, K. L.; Sulikowski,
M. M. Tetrahedron: Asymmetry 1998, 9, 3145-3169.
(3) (a) J olly, P. W.; Pettit, R. J . Am. Chem. Soc. 1966, 88, 5044-
5045. (b) Riley, P. E.; Capshew, C. E.; Pettit, R.; Davis, R. E. Inorg.
Chem. 1978, 17, 408-414.
(4) For reviews of the chemistry of these general types of iron
carbene complexes, see: (a) Brookhart, M.; Studabaker, W. B. Chem.
Rev. 1987, 87, 411-432. (b) Helquist, P. In Advances in Metal-Organic
Chemistry; Liebeskind, L. S., Ed.; J AI Press: London, 1991; Vol. 2, pp
143-194. (c) Fatiadi, A. J . J . Res. Natl. Inst. Stand. Technol. 1991,
96, 1-113. (d) Petz, W. Iron-Carbene Complexes; Springer-Verlag:
Berlin, 1993. (e) Guerchais, V. Bull. Soc. Chim. Fr. 1994, 131, 803-
811. (f) Ruck-Braun, K.; Mikulas, M.; Amrhein, P. Synthesis 1999,
727-744. (g) Theys, R. D.; Vargas, R. M.; Wang, Q. W.; Hossain, M.
M. Organometallics 1998, 17, 1333-1339.
(5) Brookhart, M.; Timmers, D.; Tucker, J . R.; Williams, G. D.; Husk,
G. R.; Brunner, H.; Hammer, B. J . Am. Chem. Soc. 1983, 105, 6721-
6723.
10.1021/jo001792i CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/26/2001

3450 J . Org. Chem., Vol. 66, No. 10, 2001
Ishii et al.
Sch em e 1
Among the most recent work is a method developed by
Hossain for the conversion of aldehydes into iron carbene
complexes.4g
perhydroindanone 8b was obtained as the only cycliza-
tion product (eq 4).8a
Our first contribution to this area was the development
of the sulfonium salt complex 3 as a truly practical, air-
and water-stable reagent for cyclopropanation of alkenes
(eq 1).6 Thermal dissociation of dimethyl sulfide suppos-
The formation of cyclopentane-containing products 8a
and 8b was suggestive of a carbene-like intramolecular
C-H insertion reaction. Besides the well-known tendency
of carbenes themselves to undergo this type of reaction,
previous studies had also implicated transition metal
carbene complexes in insertions.2 A few cases of these
reactions had been reported for discrete, stoichiometric-
ally generated carbene complexes,9 but more commonly,
carbene complexes are believed to be formed as interme-
diates in the well-studied metal-catalyzed insertion reac-
tions of diazo compounds.2,10 We were therefore motivated
to follow-up our preliminary observation of iron-based
insertions in more detail.8 Concurrent with our further
studies, examples of C-H and Si-H insertion reactions
of iron complexes were reported by Guerchais (eq 5)11 and
by Brookhart (eq 6),12 respectively.
edly generates the carbene complex 2. Upon development
of a streamlined one-pot procedure for its preparation,
reagent 3 became commercially available.
Over the years, we developed several extensions of this
chemistry, including an intramolecular version of the
cyclopropanation reaction (eq 2).7 Methylation of the
phenylthioalkyliron complex 4 presumably generated a
transient sulfonium salt followed by dissociation of
thioanisole and internal alkylidene delivery to the alkene.
While exploring the scope of this reaction, we investi-
gated substrate 6a (eq 3). In addition to the expected
Resu lts
Cyclic R,â-unsaturated ketones serve as scaffolds for
assembling substrates for the iron-based intramolecular
insertion reactions. The reaction sequence for preparation
(8) (a) Zhao, S.-K.; Knors, C.; Helquist, P. J . Am. Chem. Soc. 1989,
111, 8527-8528. (b) Ishii, S.; Helquist, P. Synlett. 1997, 508-510. (c)
Ishii, S.; Zhao, S.; Helquist, P. J . Am. Chem. Soc. 2000, 122, 5897-
5898.
intramolecular cyclopropanation product 7, a perhydroin-
danone 8a was also produced. On the other hand, when
the substrate 6b bearing a more hindered alkene was
employed, no cyclopropane was produced, but instead the
(9) (a) Fischer, H.; Schmid, J . J . Mol. Catal. 1988, 46, 277-285. (b)
Wang, S. L. B.; Su, J .; Wulff, W. D.; Hoogsteen, K. J . Am. Chem. Soc.
1992, 114, 10665-10666. (c) Aumann, R.; La¨ge, M.; Krebs, B. Chem.
Ber. 1994, 127, 731-738. (d) Barluenga, J .; Rodr´ıguez, F.; Vadecard,
J .; Bendix, M.; Fan˜ana´s, F. J .; Lo´pez-Ortiz, F. J . Am. Chem. Soc. 1996,
118, 6090-6091. (e) Barluenga, J .; Aznar, F.; Fernandez, M. Chem.
Eur. J . 1997, 3, 1629-1637. (f) Takeda, K.; Okamoto, Y.; Nakajima,
A.; Yoshii, E.; Koizumi, T. Synlett 1997 1181. (g) Barluenga, J .;
Rodr´ıguez, F.; Vadecard, J .; Bendix, M.; Fan˜ana´s, F. J .; Lo´pez-Ortiz,
F.; Rodr´ıguez, M. A. J . Am. Chem. Soc. 1999, 121, 8776-8782.
(6) (a) Brandt, S.; Helquist, P. J . Am. Chem. Soc. 1979, 101, 6473-
6475. (b) O’Connor, E. J .; Brandt, S.; Helquist, P. J . Am. Chem. Soc.
1987, 109, 3739-3747. (c) Mattson, M. N.; O’Connor, E. J .; Helquist,
P. Org. Synth. 1991, 70, 177-194.
(7) Iyer, R. S.; Kuo, G.-H.; Helquist, P. J . Org. Chem. 1985, 50,
5898-5900.

Intramolecular C-H Insertion Reactions
J . Org. Chem., Vol. 66, No. 10, 2001 3451
Sch em e 2
Sch em e 3
of the iron carbene precursors and their cyclization is
shown in Scheme 2 (Cp ) cyclopentadienyl).
salts. Spontaneous loss of thioanisole generates carbene
complexes 11 which undergo C-H insertion to give the
fused cyclopentanes 8.
Silyl enol ethers 9 are prepared by copper-promoted
conjugate addition of Grignard reagents to cycloalkenones
in the presence of trimethylsilyl chloride.13 The silyl
derivatives react with methyllithium to regenerate eno-
lates. Addition to the thiocarbene complex Cp(CO)2-
The results of several cyclizations are summarized in
Table 1. A general observation is that C-H insertion
occurs regioselectively at a carbon atom located four
positions away from the carbene center, thus resulting
in cyclopentane formation. Furthermore, the insertions
occur with higher yields at positions bearing substituents
that are regarded as being good cation stabilizing groups.
Examples include insertions into benzylic (entries c-f,
l, and o) and tertiary alkyl positions (entries j, k, and
m). Secondary positions are not as effective (entries g, i,
and n), although the â-effect of a silyl group17 appears to
provide a favorable influence at a secondary carbon (entry
h). Allylic positions face the complication of competing
cyclopropanation (entry a) and possibly allylic strain
effects (entry b). Cyclohexanones, cycloheptanones, and
cyclooctanones all function as good scaffolds for permit-
ting appropriate proximity of the reactive carbene and
C-H insertion sites.
Fe+)CHSPh PF6 (10)14 produces the substrates 6 as
-
mixtures of diastereomers with respect to the iron-
bearing carbon atom. For characterization purposes,
these complexes may be purified by column chromatog-
raphy under a nitrogen atmosphere15 to give yellow-
brown oils or solids. Separate diastereomers are not
required for the following cyclization step, and the
complexes may be used in crude form. Treatment with
trimethyloxonium tetrafluoroborate16 forms sulfonium
(10) (a) Taber, D. F.; Ruckle, R. E., J r. J . Am. Chem. Soc. 1986, 108,
7686-7693. (b) Demonceau, A.; Noels, A. F.; Costa, J .-L.; Hubert, A.
J . J . Mol. Catal. 1990, 58, 21-26. (c) Spero, D. M.; Adams, J .
Tetrahedron Lett. 1992, 33, 1143-1146. (d) Doyle, M. P.; Westrum, L.
J .; Wolthuis, W. N. E.; See, M. M.; Boone, W. P.; Bagheri, V.; Pearson,
M. M. J . Am. Chem. Soc. 1993, 115, 958-964. (e) Wang, P.; Adams, J .
J . Am. Chem. Soc. 1994, 116, 3296-3305. (f) Pirrung, M. C.; Morehead,
A. T., J r. J . Am. Chem. Soc. 1994, 116, 8991-9000. (g) Doyle, M. P.;
Dyatkin, A. B.; Autry, C. I. J . Chem. Soc., Perkin Trans. 1 1995, 619-
621. (h) Taber, D. F.; You, K. K.; Rheingold, A. L. J . Am. Chem. Soc.
1996, 118, 547-556. (i) Taber, D. F.; Song, Y. J . Org. Chem. 1996, 61,
6706-6712. (j) Clark, J . S.; Dossetter, A. G.; Russell, C. A.; Whitting-
ham, W. G. J . Org. Chem. 1997, 62, 4910-4911. (k) Wang, J .; Chen,
B.; Bao, J . J . Org. Chem. 1998, 63, 1853-1862. (l) Wang, J .; Liang, F.;
Chen, B. J . Org. Chem. 1998, 63, 8589-8594. (m) White, J . D.; Hrnciar,
P. J . Org. Chem. 1999, 64, 7271-7273. (n) Sulikowski, G. A.; Lee, S.
Tetrahedron Lett. 1999, 40, 8035-8038.
High diastereoselectivity is seen in most cases whereby
one major isomer is usually detected with respect to the
substituent on the cyclopentane ring. Retention of con-
figuration is observed when the site of C-H insertion is
of defined configuration (entries e and f).8c Simple
secondary cases show poor stereoselectivity (entries g and
n). Insertion into a secondary position of a cyclohexyl ring
presents special difficulties (entry i). A major product is
obtained in a modest yield of 52% along with two minor
components in 6% yield each. Although good character-
ization of them has not been possible, they appear to be
isomers of the major product on the basis of their mass
(11) Guerchais, V.; Sinbandhit, S. J . Chem. Soc., Chem. Commun.
1990, 1550-1552.
(12) Scharrer, E.; Brookhart, M. J . Organomet. Chem. 1995, 497,
61-71.
1
(13) (a) Corey, E. J .; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6019-
6022. (b) Alexakis, A.; Berlan, J .; Besace, Y. Tetrahedron Lett. 1986,
27, 1047-1050. (c) Horiguchi, Y.; Matsuzawa, S.; Nakamura, E.;
Kuwajima, I. Tetrahedron Lett. 1986, 27, 4025-4028. (d) Horiguchi,
Y.; Nakamura, E.; Kuwajima, I. J . Org. Chem. 1986, 51, 4323-4325.
(e) J ohnson, C. R.; Marren, T. J . Tetrahedron Lett. 1987, 28, 27-30.
(f) Zhao, S.; Helquist, P. Tetrahedron Lett. 1991, 32, 447-448. (g)
Nakamura, E.; Yamanaka, M.; Mori, S. J . Am. Chem. Soc. 2000, 122,
1826-1827.
spectra. Because of poor H NMR chemical shift disper-
sion even at high field strengths, measurement of cou-
pling constants of the ring fusion protons has not been
possible. The structure of the major product is postulated
as being 8i, on the basis of the favorable chair-chair-chair
conformation depicted for transition state 12i (Scheme
3; see also Discussion).
Stereochemical assignments for the cyclization prod-
ucts were generally made through use of 1H NMR
NOESY spectra. To corroborate these assignments, one
(14) (a) Knors, C.; Kuo, G.-H.; Lauher, J . W.; Eigenbrot, C.; Helquist,
P. Organometallics 1987, 6, 988-995. (b) Knors, C.; Helquist, P.
Organomet. Synth. 1988, 4, 205-209.
(15) Kremer, K. A. M.; Helquist, P. Organometallics 1984, 3, 1743-
1745.
(16) Trimethyloxonium tetrafluoroborate is commercially available
(Aldrich), but we normally prepare it according to the procedure
described in: Meerwein, H Organic Syntheses; Wiley: New York, 1973;
Collect. Vol. V, pp 1096-1098.
(17) Wierschke, S. G.; Chandrasekher, J .; J orgensen, W. L. J . Am.
Chem. Soc. 1985, 107, 1496-1500. (b) Lambert, J . B.; Wang, G.; Finzel,
R. B.; Teramura, D. H. J . Am. Chem. Soc. 1987, 109, 7838-7845.

3452 J . Org. Chem., Vol. 66, No. 10, 2001
Ta ble 1. Su bstr a tes a n d Resu lts of Ir on Ca r ben e Cycliza tion Rea ction s
Ishii et al.

Intramolecular C-H Insertion Reactions
J . Org. Chem., Vol. 66, No. 10, 2001 3453
Ta ble 1 (Con tin u ed )
a
b
Yield from enone precursor (see Scheme 2). Yields obtained from 9; reported as mixtures of diastereomers. Fp ) cyclopentadienyl-
(dicarbonyl)iron. c Yield of pure, isolated product from iron complex 6 unless otherwise indicated. Overall yield from enol ether precursor
d
9. The yield from the iron complex 6b is 63%. e 3:1 mixture of cis- and trans-isobutyl isomers obtained from addition to the enone; pure
cis-isomer isolated and used in subsequent step. f Diastereomer ratio not determined; crude mixture used directly in the cyclization reaction.
of the products, 8d , was studied by single-crystal X-ray
diffraction. The resulting structure (see Supporting In-
formation) is in full agreement with the spectroscopic
assignment.
To test the conclusion that benzylic positions are more
favorable sites of insertion than simple 2° positions,
substrate 13 was prepared. Under the usual cyclization
conditions, a mixture of cyclopentane derivatives 14 and
15 is obtained in a ratio of 10:1, respectively (eq 7); each
mers. The regioselectivity seen in this case therefore
serves to confirm the earlier inference concerning pre-
ferred sites of insertion.
Some important limitations have been observed for
these insertion reactions. Attempts to extend them to the
use of a cyclopentanone scaffold were unsuccessful. Iron
complex 6q gives a complex mixture of products from
which only the methylene ketone 16q resulting from
â-hydride elimination is isolated in very low yield (eq 8).
Increased ring strain in the transition state for formation
of a trans-bicyclo[3.3.0]octanone derivative apparently
prevents the intramolecular C-H reaction from occur-
ring. Substrate 6r was prepared to provide an alternative
benzylic site for prospective C-H insertion leading to a
of these products is produced as a mixture of diastereo-

3454 J . Org. Chem., Vol. 66, No. 10, 2001
Ishii et al.
less strained, fused six-membered ring of a bicyclo[4.3.0]-
nonanone system. However, an elimination product 16r
is again obtained in very low yield as the only character-
ized product (eq 9). This latter result may be regarded
as yet another indication of the strong propensity of metal
carbenes to undergo C-H insertions leading to five-
membered rings, even when otherwise satisfactory sites
for reaction are available for formation of other ring sizes.
This point is reinforced by the reaction of iron complex
6s, which again presents a benzylic site for six-membered
ring formation. Instead, a five-membered ring product
8c is formed in low yield as a mixture of diastereomers
by insertion at a nonbenzylic 2° site together with a low
yield of the elimination product 16s (eq 10). Similar
lecular alkene addition of the cationic intermediate 11u
to give carbocation 19 (eq 13). Subsequent 1,2-hydride
shifts followed by 1,2-acyl migration and iron elimination
would account for the observed products. This behavior
is consistent with other cationic cyclizations of iron
carbene complexes that we have observed previously for
alkene-containing substrates.18 The higher degree of
alkene substitution in substrate 6t probably hinders an
analogous cyclization from occurring in that case (see eq
11 above).
Another important limitation of these insertion reac-
tions is that they appear to require a fairly rigid scaffold
as exemplified by the several cycloalkanone substrates
in Table 1. Less conformationally constrained substrates
either give much lower yields of insertion products, or
the insertion reactions fail entirely. For example, the
substrate 13, which was designed to probe regioselectivity
issues (see eq 7 above), gives low yields of the cyclization
products 14 and 15. The closely related substrate 20
affords very low yields (<25%) of the desired cyclization
product 21 and the competing elimination product 22 (eq
14). The even more conformationally mobile substrate 23
results are obtained with the 4-methoxyphenyl analogue
of 6s having presumably an even better benzylic activat-
ing group. For all practical purposes, substrate 6s (and
its methoxyphenyl analogue) behaves much like the
3-butylcyclohexanone derivative 6g, which also provides
a simple 2° site for insertion (Table 1, entry g).
In yet another attempt to promote six-membered ring
formation, the isobutenylcyclohexanone derivative 6t was
prepared. However, the usual cyclization conditions lead
to formation of the elimination product 16t instead of a
fused cyclohexene which would have resulted from allylic
C-H insertion (eq 11).
produces the elimination product 24 in very low yield as
part of a complex mixture (eq 15); a cyclopentane product
is not detected.
In a related system directed at the usual five-
membered ring formation, isopropenylcyclohexanone de-
rivative 6u was employed. Under the standard conditions
for iron carbene generation, none of the expected meth-
ylenecyclopentane annulation product is detected. In-
stead, very low yields of the methylcyclopentene products
17 and 18 are obtained (eq 12). This result can be
explained on the basis of a difficult 5-endo-trig intramo-
(18) (a) Seutet, P.; Helquist, P. Tetrahedron Lett. 1988, 29, 4921-
4922. (b) Baker, C. T.; Mattson, M. N.; Helquist, P. Tetrahedron Lett.
1995, 36, 7015-7018.

Intramolecular C-H Insertion Reactions
J . Org. Chem., Vol. 66, No. 10, 2001 3455
Likewise, the ester substrate 25 undergoes elimination
to give a complex mixture containing a small amount of
benzyl acrylate as the only identifiable product with no
evidence of intramolecular insertion adjacent to the ester
oxygen tether (eq 16).
enolate to thiocarbene complex 10. The synthesis is
completed as in Little’s route20b by addition of methyl-
lithium to tricyclic ketone 28 and dehydration of the
resulting alcohol. The (()-sterpurene thus obtained is
identical to previously obtained material by direct com-
1
parison of H and 13C NMR spectra.19,20d
Pentalenene (34), an angular triquinane, is the parent
hydrocarbon of the pentalenolactone family of antibiotic
metabolites. It was first synthesized by Ohfune, Shira-
hama, and Matsumoto in 1976 as part of a study of
biosynthetic cyclizations,22 but it was not actually re-
ported as a naturally occurring compound until 1980
when it was isolated from Streptomyces griseochromo-
genes.23 Numerous syntheses of pentalenene have sub-
sequently been published.24 As another application of our
insertion reaction, we have accomplished a formal syn-
thesis of (()-pentalenene that merges with a late inter-
mediate in Pattenden’s earlier synthesis.24f
The basic strategy (Scheme 6) follows from a biomi-
metic, acid-catalyzed, transannular cyclization of fused
1,5-cyclooctadiene 35. This intermediate, which was
employed by Pattenden,24f is available from unsaturated
ketone 36. This ketone is the focus of our formal
synthesis, featuring the formation of bicyclic ketone 37
from complex 38. This carbene precursor is, in turn,
prepared by the usual sequence from enone 39.
The synthesis commences with commercially available
1,5-cyclooctanediol (40, Scheme 7), which is oxidized with
J ones reagent to give 5-hydroxycyclooctanone in the form
of bicyclic hemiketal 41.25 Protection with tert-butyldi-
methylsilyl chloride26 gives monocyclic siloxy ketone 42.
The corresponding enone 39 is obtained by reaction of
the ketone with benzeneselenenyl chloride followed by
oxidative elimination of the selenide with hydrogen
peroxide27 or alternatively by conversion of the ketone
to the silyl enol ether and use of the Saegusa procedure
Ap p lica tion s
Sterpurene (27) was reported by Ayer as a metabolite
of Stereum purpureum, a fungus that is responsible for
silver leaf disease of a variety of trees and scrubs.19
Syntheses of racemic and nonracemic sterpurene have
been reported by several investigators.20 We recognized
this compound as a possible synthetic target for the
application of our insertion reaction.
A necessary focus of any total synthesis of sterpurene
is the construction of the 4/6/5 tricyclic carbon skeleton
(Scheme 4). We anticipated that the tricyclic ketone 28
could be obtained by an insertion reaction employing
complex 29. In turn, our usual route to cyclization
precursors would utilize bicyclic enone 30, itself available
by photochemical cycloaddition of ethylene and a cyclo-
hexenone followed by reintroduction of unsaturation.21
This strategy was implemented successfully (Scheme
5). Commercially available 3-methyl-2-cyclohexenone
undergoes photochemical cycloaddition of ethylene, and
R-bromination of the resulting bicyclic ketone 31 followed
by dehydrobromination generates enone 30.21 Copper(I)-
catalyzed conjugate addition13 of isobutylmagnesium
bromide provides ketone 32 as a 3:1 to 4:1 mixture of â
and R isomers favoring the former. After chromatographic
separation, the â isomer is converted to enol silyl ether
33. Enolate regeneration and trapping with thiocarbene
complex 10 affords iron complex 29. Treatment with
trimethyloxonium tetrafluoroborate leads to the desired
tricyclic ketone 28 as an inconsequential mixture of trans-
and cis-fused isomers. This key step occurs in yields
ranging from 80% to 90% from precursor 29. However,
the overall cyclopentane annulation is operationally
simpler when iron complex 29 is not isolated or purified,
in which case the overall yield of tricyclic ketone 28 is
48% from silyl enol ether 33. The main limitation on the
overall yield for this ring construction appears to be
incomplete reaction of the enolate derived from 33 in that
20-30% of ketone 32 is recovered after exposure of the
(22) (a) Ohfune, Y.; Shirahama, H.; Matsumoto, T. Tetrahedron Lett.
1976, 17, 2869-2872. For more recent biosynthetic studies, see: (b)
Cane, D. E.; Oliver. J . S.; Harrison, P. H. M.; Abell, C.; Hubbard, B.
R.; Kane, C. T.; Lattman, R. J . Am. Chem. Soc. 1990, 112, 4513-4524.
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Papadopolous, P. Tetrahedron 1987, 43, 5685-5721. (h) Piers, E.;
Karunaratne, V. Can. J . Chem. 1989, 67, 160-164. (i) Imanishi, T.;
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Bull. 1990, 38, 1124-1128. (j) Shizuri, Y.; Maki, S.; Ohkubo, M.;
Yamamura, S. Tetrahedron Lett. 1990, 31, 7167-7168. (k) Wu, Y. J .;
Burnell, D. J . J . Chem. Soc., Chem. Commun. 1991, 764-765. (l) Zhao,
S.; Mehta, G.; Helquist, P. Tetrahedron Lett. 1991, 32, 5753-5756.
(m) Rowley, E. G.; Schore, N. E. J . Org. Chem. 1992, 57, 6853-6861.
(n) Ihara, M. J . Pharm. Soc. J pn. 1992, 112, 516-533. (o) Patel, H.
A.; Stothers, J . B.; Thomas, S. E. Can. J . Chem. 1994, 72, 56-68. (p)
Wu, Y.-J .; Zhu, Y.-Y.; Burnell, D. J . J . Org. Chem. 1994, 59, 104-110.
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Zhu, Y.-Y.; Burnell, D. J . Tetrahedron: Asymmetry 1996, 7, 3295-
3304. (s) Hatanaka, M.; Ueno, F.; Ueda, I. Tetrahedron Lett. 1996, 37,
89-90. (t) Tormo, J .; Moyano, A.; Pericas, M. A.; Riera, A. J . Org.
Chem. 1997, 62, 2, 4851-4856. (u) Miesch, M.; Gross-Miesch, L.;
Franck-Neumann, M., Tetrahedron 1997, 53, 2111-2118. (v) Kim, S.;
Cheong, J . H.; Yoo, J . Synlett 1998, 981-982. (w) Seo, J .; Fain, H.;
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Harrington-Frost, N. M.; Pattenden G. Tetrahedron Lett. 2000, 41,
403-405.
(19) Ayer, W. A.; Saeedi-Ghomi, M. H. Can. J . Chem. 1981, 59,
2536-2538.
(20) (a) Murata, Y.; Ohtsuta, T.; Shirahama, H.; Matsumoto, T.
Tetrahedron Lett. 1981, 22, 4313-4314. (b) Moe¨ns, L.; Baizer, M. M.;
Little, R. D. J . Org. Chem. 1986, 51, 4497-4498. (c) Gibbs, R. A.;
Okamura, W. H. J . Am. Chem. Soc. 1988, 110, 4062-4063. (d) Gibbs,
R. A.; Bartels, K.; Lee, R. W. K.; Okamura, W. H. J . Am. Chem. Soc.
1989, 111, 3717-3725. (e) Zhao, S.-K.; Helquist, P. J . Org. Chem. 1990,
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(25) Meier, H.; Petersen, H. Synthesis 1978, 596-598. This com-
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6190-6191.
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Am. Chem. Soc. 1970, 92, 425-427. (b) Cargill, R. L.; Dalton, J . R.;
Morton, G. H.; Caldwell, W. E. Org. Synth. 1984, 62, 118-124. (c)
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Wiley: New York, 1988; Collect. Vol. VI, pp 175-178.

3456 J . Org. Chem., Vol. 66, No. 10, 2001
Ishii et al.
Sch em e 4
Sch em e 5
Sch em e 6
and boron trifluoride promoted transannular cyclization.
1
We have not repeated this reaction sequence, but the H
and 13C NMR spectra of our synthetic 36 match the
corresponding data kindly provided by Professor Pat-
tenden.29
Discu ssion
We have developed a general procedure for cyclopen-
tane annulation based upon intramolecular C-H inser-
tion of cationic iron carbene complexes as reactive
intermediates. The substrates are prepared from R,â-
unsaturated ketones by copper-catalyzed conjugate ad-
dition of a side chain that provides a site for C-H
insertion and enolate alkylation with a thiocarbene
complex that provides the reactive center for the cycliza-
tion reaction. The key ring-forming step occurs in modest
to high yields and with high diastereoselectivity for a
wide range of substrates. The most effective sites of
insertion are tertiary alkyl and benzylic C-H bonds.
Depending upon the degree of substitution, an alkene
side chain can serve as the site of either carbene addition
to give fused cyclopropanes or of allylic C-H insertion
to give fused alkenylcyclopentanes.
The stereoselectivity seen in these reactions can be
accommodated by assuming a favorable chairlike con-
formation for the C-H insertion transition state 12c as
depicted for entry c from Table 1 as a representative case
(Scheme 8). This pathway is supported by a separate
study of several deuterium-labeled substrates.8c
There are some important limitations on the scope of
this reaction. Most importantly, the carbene center and
the side chain site of C-H insertion must be somewhat
constrained to conformations that favor approach of the
respective centers for bond formation. This need is met
for palladium-promoted oxidative elimination28 (95%
yield). Conjugate addition of isobutylmagnesium bromide
to the enone provides silyl enol ether 43 as a 57:43
mixture of two diastereomers. Regeneration of the eno-
late with methyllithium and alkylation with thiocarbene
complex 10 gives iron complex 38, which is immediately
treated with trimethyloxonium tetrafluoroborate to afford
fused ketone 37. Addition of methyllithium and dehydra-
tion of tertiary alcohol 44 with thionyl chloride and
pyridine produces alkene 45. Treatment with J ones
reagent results in hydrolysis of the silyl enol ether and
oxidation of the intermediate alcohol to give the desired
unsaturated ketone 36. Alternatively, the silyl ether
group in 45 can be cleaved with tetra-n-butylammonium
fluoride followed by J ones oxidation, but the overall yield
for the two steps is somewhat lower (35% vs 44%). At
this point, a formal synthesis of pentalenene is achieved
in that 36 has been converted into pentalenene by
Pattenden24f and others22,24 through use, for example, of
a Wittig reaction, RhCl3-catalyzed alkene isomerization,
(28) Ito, Y.; Hirao, T.; Saegusa, T. J . Org. Chem. 1978, 43, 1011-
1013.
(29) Pattenden, G., personal correspondence.

Intramolecular C-H Insertion Reactions
J . Org. Chem., Vol. 66, No. 10, 2001 3457
Sch em e 7
Sch em e 8
by using at least somewhat rigid cyclic compounds as
scaffolds, which in turn result in the formation of fused
ring systems. When attempts are made to employ more
conformationally mobile, open-chain substrates, compet-
ing elimination reactions of the intermediate carbene
complexes predominate over the ring-forming, intramo-
lecular insertion reactions. Another limitation is that
simple secondary alkyl C-H bonds are much less effec-
tive sites of insertion compared to tertiary alkyl and
benzylic positions. Simple primary alkyl sites do not
appear to participate to any significant extent in these
reactions.
Con clu sion s
Iron carbene complexes have previously been found to
be useful intermediates in a number of reactions. Prior
work had placed emphasis on the role of these intermedi-
ates in cyclopropanation reactions. Now they can also be
recognized for their utility in intramolecular C-H inser-
tion reactions to afford cyclopentane derivatives. These
reactions add noteworthy flexibility to the choices that
are available for synthetic applications requiring cyclo-
pentane formation.
Substantial further work is required to develop these
reactions to satisfy additional needs. Although iron is the
least expensive of all metals and certainly more readily
available than metals such as rhodium, the presently
reported reactions would be even more attractive if they
were to employ iron in a catalytic rather than stoichio-
metric fashion. Also, the use of chiral forms of the iron
moiety may be attractive in permitting enantioselective
C-H insertion reactions.
The most heavily developed of the synthetically useful
methods for intramolecular carbene insertion reactions
are the metal-catalyzed reactions of R-diazocarbonyl
compounds. Rhodium catalysts are especially effective in
these reactions.1,10 To a certain extent, these diazocar-
bonyl reactions and the present iron carbene insertions
complement each other with respect to synthetic applica-
tions and strategies. Whereas the rhodium-catalyzed
reactions generally show a preference for C-H insertion
in the relative order of 3° > 2° > 1°, allylic, benzylic
sites,10 the order of preference for the iron carbene
insertions falls in the order of 3°, benzylic, allylic > 2° >
1°. Also, whereas the use of diazocarbonyl compounds
provides products having carbonyl groups R to the site
of ring formation, the cycloalkanone scaffolds that we
have employed for the iron-based reactions generate
products having carbonyl groups â to the site of ring
closure. These differences in the two approaches allow
for flexibility in the choice of methods to meet the needs
of desired synthetic applications.
Exp er im en ta l Section
Gen er a l P r oced u r e for th e P r ep a r a tion of Silyl En ol
Eth er s (9) via Con ju ga te Ad d ition to En on es. Copper(I)
bromide-dimethyl sulfide complex30 (0.063 g, 0.3 mmol) was
placed under nitrogen in a 100-mL round-bottom flask fitted
with a septum. A Grignard reagent (9.0 mmol) in THF (15 mL)
was added, and the suspension immediately turned blue.
HMPA (2.6 mL, 15 mmol) was then added, and the suspension
was cooled to -78 °C with stirring. Into the flask was added
(30) House, H. O.; Chu, C.-Y.; Wilkins, J . M.; Umen, M. J . J . Org.
Chem. 1975, 40, 1460-1469.

3458 J . Org. Chem., Vol. 66, No. 10, 2001
Ishii et al.
a solution of 2-cycloalkenone (7.5 mmol) and (CH3)3SiCl (1.9
mL, 15 mmol) in THF (5.0 mL) over a 5-min period. After the
mixture was stirred for 3 h at -78 °C, triethylamine (2.0 mL)
was added followed by hexanes (40 mL). The mixture was
transferred to a separatory funnel, and the organic layer was
washed with H2O (3 × 20 mL) and saturated aqueous NH4Cl
(30 mL), dried (MgSO4), and concentrated by rotary evapora-
tion. The product was partially purified by Kugelrohr distil-
lation or medium-pressure liquid chromatography and was
used shortly thereafter in the next step.
Gen er a l P r oced u r e for P r ep a r a tion of Th ioa lk ylir on
Com p lexes (6) by Rea ction of En ola tes w ith (η5-Cyclo-
pentadienyl)dicarbonyl[(phenylthio)carbenium]iron Hexa-
flu or op h osp h a te (10). A silyl enol ether 9 (1 mmol) in THF
(5 mL) was placed in a 10-mL pear-shaped flask and cooled to
0 °C under nitrogen. Methyllithium (0.72 mL, 1 mmol, 1.4 M
solution in diethyl ether) was added dropwise with stirring
over a 2-min period. After 0.5 h, the ice bath was removed,
and the solution was allowed to warm to 25 °C and stirred for
0.5 h. This enolate solution was cooled to -78 °C. Iron carbene
complex 10 (0.444 g, 1.0 mmol) was placed in a Schlenk
apparatus, consisting of two reaction vessels connected to each
other by a filter tube and connected to a nitrogen manifold,
and cooled to -78 °C prior to the addition of precooled THF (4
mL, -78 °C). Into the brown suspension was cannulated the
freshly prepared enolate all at once. After the addition was
complete, the mixture was stirred until all of the solid carbene
complex was consumed (ca. 5-10 min). The mixture was
stirred an additional 1 h and slowly warmed to ca. -30 °C.
Precooled hexanes (20 mL, -78 °C) were cannulated by
vacuum into the dark brown, homogeneous mixture. After 5
min, stirring was stopped, and the mixture was filtered by
inverting the apparatus, thus removing the insoluble salts.
Removal of the solvent from the filtrate under oil pump
vacuum left an orange or red oil that was purified by column
chromatography under a nitrogen atmosphere.15
Gen er a l P r oced u r e for Gen er a tion of Ir on Alk ylid en e
Com p lexes (11) a n d Th eir Cycliza tion Rea ction s to
P r od u ce Cyclop en ta n es (8). Into the reaction vessel con-
taining the thioalkyliron complex 6 (0.5 mmol) was added
methylene chloride (20 mL), and the solution was cannulated
into a flask containing trimethyloxonium tetrafluoroborate (1.5
mmol) at 0 °C under nitrogen. The mixture was warmed to 25
°C over a 1-h period and was stirred for 2 h. The dark red
solution was diluted with hexanes (25 mL) and stirred for 5
min to precipitate metal-containing material. The mixture was
filtered through a pad of Celite, and the pad was washed with
hexanes (30 mL). The solvent was removed by rotary evapora-
tion, and the residue was purified by flash or medium-pressure
liquid chromatography.
Ack n ow led gm en t. We thank Donald Schifferl and
Dr. J aroslav Zajicek for NMR assistance, Dr. Bruce
Plashko, Mr. David Griffith, and Dr. William Bogess for
mass spectrometry assistance, and Dr. Kenneth J .
Haller for X-ray crystallography assistance. We are
grateful for financial support from the National Science
Foundation (USA) and the University of Notre Dame.
S.I. and C.J .K. are grateful for Reilly Fellowships.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and characterization data are provided for the compounds
reported in this paper. Details are also provided for the single-
crystal X-ray structure determination of compound 8d . This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O001792I