Generation and reactions of pentacyclo[4.3.0.02,4.0 3,8.05,7]non-4-ene

Article abstract of DOI:10.1021/jo0626313

(Chemical Equation Presented) The highly pyramidalized alkene, pentacyclo[4.3.0.0^2,4.0^3.8.0^5,7]non-4-ene (9), has been generated via treatment of 4,5-diiodopentacyclo[4.3.0.0 ^2.4.0^3,8.0^5,7]

Full text of DOI:10.1021/jo0626313

Generation and Reactions of Pentacyclo[4.3.0.02,4.03,8.05,7]non-4-ene
Mark A. Forman,* Caitlin Moran, Joseph P. Herres, Jason Stairs, Emily Chopko,
Anthony Pozzessere, Michael Kerrigan, Carisa Kelly, Lisa Lowchyj,
Kerry Salandria, Annemarie Gallo, and Elizabeth Loutzenhiser
Department of Chemistry, Saint Joseph’s UniVersity, 5600 City AVenue, Philadelphia, PennsylVania 19131
mforman@sju.edu
ReceiVed December 21, 2006
The highly pyramidalized alkene, pentacyclo[4.3.0.02,4.03,8.05,7]non-4-ene (9), has been generated via
treatment of 4,5-diiodopentacyclo[4.3.0.02,4.03,8.05,7]nonane (12) with n-butyllithium and tert-butyllithium.
The title alkene has also been trapped as its Diels-Alder adduct with 1,3-diphenylisobenzofuran, 2,5-
dimethylfuran, and spiro[2.4]hepta-4,6-diene. Products resulting from alkyllithium addition to the
pyramidalized double bond of 9 have been isolated and fully characterized spectroscopically. The geometry,
olefin strain energy, heat of hydrogenation, and relative HOMO/LUMO energies of 9 have been obtained
by ab initio calculations at the MP2 and B3LYP levels using the 6-31G* basis set.
Introduction
as in the syn-sesquinorbornenes 2 and related alkenes.7 Such
deviations from planarity are typically smaller, and the com-
pounds are, in many cases, stable and isolable. However,
deviations from planarity and pyramidalization can be substantial
when the carbon-carbon double bond is located at the
bridgehead positions of a polycyclic alkene. For example,
cubene (3), prepared by Eaton and Maggini in 1988, is predicted
by ab initio calculations to be the most highly pyramidalized
alkene yet known and has a fleeting existence.8 Also, in 1988,
Pyramidalized alkenes are molecules that contain carbon-
carbon double bonds in which one or both of the two sp2 carbon
atoms do not lie in the same plane as the three atoms attached
to it. Over the past 35-40 years, pyamidalized alkenes have
received significant attention both synthetically and computa-
tionally. Since Weinshenker and Greene published the synthesis
of the first substantially pyramidalized alkene 1 (Figure 1),1
numerous other pyramidalized alkenes have been prepared. In
1981, Szeimies published the first review of pyramidalized
alkenes,2 and, since that time, other reviews by Borden3 and
Keese4 have appeared. Most recently, Camps and Vazquez
published an excellent comprehensive review of the synthesis
and chemistry of pyramidalized alkenes.5 In addition to the
synthesis and chemistry summarized in the aforementioned
papers, numerous computational studies of pyramidalized alk-
enes have also been reported.6
(6) See, for example: (a) Rasul, G.; Olah, G. A.; Prakash, G. K. S. J.
Phys. Chem. A 2006, 110, 7197. (b) Williams, R. V.; Margetic, D. J. Org.
Chem. 2004, 69, 7134. (c) Margtic, D.; Williams, R. V.; Warrener, R. N.
J. Org. Chem. 2003, 68, 9186. (d) Can, H.; Zahn, D.; Balci, M.; Brickmann,
J. Eur. J. Org. Chem. 2003, 1111. (e) Vazquez, S. J. Chem. Soc., Perkin
Trans. 2002, 2, 2100. (f) Yates, B. F. J. Organomet. Chem. 2001, 635,
142. (g) Mastryukov, V. S.; Chen, K.-H.; Allinger, N. L. J. Phys. Chem. A
2001, 105, 8562. (h) Mastryukov, V. S.; Boggs, J. E. Struct. Chem. 2000,
11, 97.
(7) Borden has extensively reviewed the chemistry of the syn-sesquinor-
bornenes; see ref 3b. For selected additional examples, see: (a) Griesbeck,
A. G.; Deufel, T.; Hohlneicher, G.; Rebentisch, R.; Steinwascher, J. Eur.
J. Org. Chem. 1998, 1759. (b) Holthausen, M. C.; Koch, W. J. Phys. Chem.
1993, 97, 10021. (c) Paquette, L. A.; Shen, C. C. J. Am. Chem. Soc. 1990,
112, 1159. (d) Paquette, L. A.; Shen, C. C.; Krause, J. A. J. Am. Chem.
Soc. 1989, 111, 2351. (e) Spanget-Larsen, J.; Gleiter, R. Tetrahedron 1983,
39, 3345.
(8) (a) Lukin, K.; Eaton, P. E. J. Am. Chem. Soc. 1995, 117, 7652. (b)
Staneke, P. O.; Ingemann, S.; Eaton, P.; Nibbering, N. M. M.; Kass, S. R.
J. Am. Chem. Soc. 1994, 116, 6445. (c) Eaton, P. E.; Maggini, M. J. Am.
Chem. Soc. 1988, 110, 7230.
Deviations from planarity in pyramidalized alkenes can result
from a combination of strain and unsymmetric steric effects,
* Corresponding author. Phone: (610) 660-1781. Fax: (610) 660-1783.
(1) Weinshenker, N. M.; Greene, F. D. J. Am. Chem. Soc. 1968, 90,
506.
(2) Szeimies, G. Chimia 1981, 35, 243.
(3) (a) Borden, W. T. Synlett 1996, 711. (b) Borden, W. T. Chem. ReV.
1989, 89, 1095.
(4) Luef, W.; Keese, R. Top. Stereochem. 1991, 20, 231.
(5) Vazquez, S.; Camps, P. Tetrahedron 2005, 61, 5147.
10.1021/jo0626313 CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/15/2007
2996
J. Org. Chem. 2007, 72, 2996-3005

Pentacyclo[4.3.0.02,4.03,8.05,7]non-4-ene
FIGURE 1. Some representative pyramidalized alkenes 1-8 and pentacyclo[4.3.0.02,4.03,8.05,7]non-4-ene (9).
Borden9 and Szeimies10 independently prepared highly reactive
4(5)-homocubene (4) via alkyllithium-induced dehalogenation.
Subsequently, Szeimies provided evidence for the homocubene
derivative, 2,5-dichloropentacyclo[4.3.0.02,5.03,8.04,7]non-3-ene.11
Bishomocubene (5) has been prepared by Marchand and co-
workers, and it is also highly unstable.12 The Borden13 and
Camps and Vazquez14 groups have independently synthesized
and studied numerous members of a family of highly pyrami-
dalized alkenes containing the tricyclo[3.3.n.03,7]alk-3(7)-ene
skeleton 6. Other pyramidalized alkenes with various ring
systems, such as dodecahedrenes15 and cyclopropenes with the
bicyclo[n.1.0]-framework,16 have also appeared. Additionally,
Szeimies has thoroughly studied several different quadricy-
clenes,17 all of which contain highly pyramidalized carbon-
carbon double bonds. 1(5)-Quadricyclene (7)18 is one example
from this family of pyramidalized alkenes. Most recently,
Dolbier has reported that the double Diels-Alder reaction of
syn-4,5,13,14-bis(dehydro)octafluoroparacyclophane with an-
thracene furnishes a product 8 with the highest degree of
pyramidalization, φ ) 34.3°, as measured by X-ray crystal-
lography.19
As part of our continuing research on the synthesis and study
of strained organic molecules, we have been interested in the
synthesis of the highly pyramidalized alkene, pentacyclo-
[4.3.0.02,4.03,8.05,7]non-4-ene (9). Structurally, 9 is related to
tricyclo[3.3.n.03,7]alk-3(7)-ene 6 with n ) 1, although closer
inspection of 9 reveals the presence of cyclopropane rings and
the bicyclopropylidene ring system. In this report, we describe
the synthesis of pentacyclo[4.3.0.02,4.03,8.05,7]non-4-ene (9), its
trapping with 1,3-diphenylisobenzofuran, 2,5-dimethylfuran, and
spiro[2.4]hepta-4,6-diene, and its reactions with multiple alky-
llithiums present in the reaction mixture. We also describe
preliminary attempts to synthesize 9 via dehydrohalogenation
of 4-iodopentacyclo[4.3.0.02,4.03,8.05,7]nonane (11) and ab initio
calculations that predict the geometry, olefin strain energy, heat
of hydrogenation, and HOMO/LUMO energies of this alkene.
(9) Hrovat, D. A.; Borden, W. T. J. Am. Chem. Soc. 1988, 110, 7229.
(10) Schaefer, J.; Szeimies, G. Tetrahedron Lett. 1988, 29, 5253.
(11) Rosendorfer, K.; Jarosch, O.; Polborn, K.; Szeimies, G. Liebigs Ann.
1995, 1765.
Results and Discussion
(12) Marchand, A. P.; Namboothiri, I. N. N.; Ganguly, B.; Watson, W.
H.; Bodige, S. G. Tetrahedron Lett. 1999, 40, 5105.
Synthesis of 4,5-Diiodopentacyclo[4.3.0.02,4.03,8.05,7]nonane
(12). The dehalogenation of vicinal dihalides has proven to be
a reliable method for the synthesis of a variety of strained
alkenes, including ones with pyramidalized double bonds.5
Dehalogenation is most frequently accomplished via metal-
halogen exchange with alkyllithiums, although reduction with
metals such as Zn, Mg, Na, or sodium amalgam has been utilized
successfully in several instances. Thus, we identified 4,5-
diiodopentacyclo[4.3.0.02,4.03,8.05,7]nonane (12) as a potential
precursor to 9. On the basis of previous work, we surmised
that treatment of 12 would result in iodine-lithium ex-
change followed by elimination of lithium iodide to give the
title compound 9. Alternatively, dehydrohalogenation of
(13) (a) Theophanous, F. A.; Tasiopoulos, A. J.; Nicolaides, A.; Zhou,
X.; Johnson, W. T. G.; Borden, W. T. Org. Lett. 2006, 8, 3001. (b) Smith,
J. M.; Hrovat, D. A.; Borden, W. T.; Allan, M.; Asmis, K. R.; Bulliard, C.;
Haselbach, E.; Meier, U. C. J. Am. Chem. Soc. 1993, 115, 3816. (c) Branan,
B. M.; Paquette, L. A.; Hrovat, D. A.; Borden, W. T. J. Am. Chem. Soc.
1992, 114, 774. (d) Renzoni, G. E.; Yin, T. K.; Borden, W. T. J. Am. Chem.
Soc. 1986, 108, 7121 and references cited therein and in ref 3.
(14) (a) Camps, P.; Munoz, M. R.; Vazquez, S. J. Org. Chem. 2005, 70,
1945. (b) Camps, P.; Ferna´ndez, J. A.; Font-Bardia, M.; Solans, X.; Va´zquez,
S. Tetrahedron 2005, 61, 3593. (c) Camps, P.; Ferna´ndez, J. A.; Va´zquez,
S.; Font-Bardia, M.; Solans, X. Angew. Chem., Int. Ed. 2003, 42, 4049. (d)
Camps, P.; Luque, F. J.; Orozco, M.; Pe´rez, F.; Va´zquez, S. Tetrahedron
Lett. 1996, 37, 8605. (e) Camps, P.; Font-Bardia, M.; Pe´rez, F.; Solans, X.;
Va´zquez, S. Angew. Chem., Int. Ed. Engl. 1995, 34, 912 and references
cited therein and in ref 5.
(15) See: Reinbold, J.; Sackers, E.; Osswald, T.; Weber, K.; Weiler,
A.; Voss, T.; Hunkler, D.; Worth, J.; Knothe, L.; Sommer, F.; Morgner,
N.; Von Issendorff, B.; Prinzbach, H. Chem.-Eur. J. 2002, 8, 509 and
references cited therein.
(16) See, for example: (a) Lee, G.-A.; Huang, A. N.; Chen, C.-S.; Li,
Y. C.; Jann, Y.-C. J. Org. Chem. 1997, 62, 3355. (b) Chenier, P. J.; Bauer,
M. J.; Hodge, C. L. J. Org. Chem. 1992, 57, 5959. (c) Wiberg, K. B.; Artis,
D. R.; Bonneville, G. J. Am. Chem. Soc. 1991, 113, 7969. (d) Chenier, P.
J.; Southard, D. A., Jr. J. Org. Chem. 1989, 54, 3519. (e) Wiberg, K. B.;
Bonneville, G. Tetrahedron Lett. 1982, 23, 5385. (f) Szeimies, G. In
AdVances in Strain in Organic Chemistry; Halton, B., Ed.; JAI: Greenwich,
1992; Vol. 2, p 1.
(17) (a) Szeimies, G. J. Prakt. Chem./Chem.-Ztg. 1998, 340, 11. (b)
Rosendorfer, K.; Jarosch, O.; Polborn, K.; Szeimies, G. Liebigs Ann. 1995,
1765. (c) Podlech, J.; Polborn, K.; Szeimies, G. J. Org. Chem. 1993, 58,
4113. (d) Heywang, U.; Szeimies, G. Chem. Ber. 1990, 123, 121. (e)
Harnisch, J.; Baumgaertel, O.; Szeimies, G.; Van Meerssche, M.; Germain,
G.; Declercq, J. P. J. Am. Chem. Soc. 1979, 101, 3370.
(18) Kenndoff, J.; Polborn, K.; Szeimies, G. J. Am. Chem. Soc. 1990,
112, 6117.
(19) Dolbier, W. R., Jr.; Zhai, Y.-A.; Battiste, M. A.; Abboud, K. A.;
Ghiviriga, I. J. Org. Chem. 2005, 70, 10336.
J. Org. Chem, Vol. 72, No. 8, 2007 2997

Forman et al.
Reaction of 4,5-Diiodopentacyclo[4.3.0.02,4.03,8.05,7]nonane
(12) with n-Butyllithium. With ample quantities of 12 available,
we next investigated its dehalogenation with n-butyllithium to
form 9. Initial experiments afforded 11 when the reaction of
12 with n-butyllithium was quenched at low temperature (-78
°C) prior to lithium iodide elimination (Scheme 1). Treatment
of 12 with 1.2 equiv of n-butyllithium in THF at -78 °C and
warming to 0 °C gave a mixture of products containing 22
(58.2% area ratio by GCMS), 23 (13.9%), and 26 (1%). Two
products whose molecular ions suggest structures 24 (3.5%, M•+
) 300) and 25 (11.0%, M•+ ) 174) were also detected, although
the structural assignments for these products are tentative, as
they could not be separated from one another and isolated in
pure form. As it is well known that pyramidalized alkenes react
rapidly with alkyllithiums present in the reaction mixture, we
propose the following mechanism for the formation of 22-26.
Treatment of 12 with n-butyllithium effects iodine-lithium
exchange to give 10, which loses lithium iodide to form
pyramidalized alkene 9. The highly reactive 9 then reacts with
10 to give 19, which undergoes lithium-iodine exchange with
either 12 or n-butyliodide (formed in the original iodine-lithium
exchange) to furnish 22. Alternatively, 19 may be quenched
upon workup to form 23. In addition to 10 adding across the
double bond of 9, n-butyllithium may also react with the
pyramidalized double bond of 9 giving 20, which may add to
9 to form 26 after abstraction of iodine from either 12 or
n-butyliodide. Alternatively, 20 may react with 12/n-butyliodide
to form 24 or with H+ to form 25. We also observe monoiodide
11 (8.9% area ratio by GCMS), its formation likely resulting
from reaction of 10 with H+. No cyclobutane dimers were
observed in the reaction of 12 with n-butylithium, as the highly
pyramidalized double bond of 9 reacts immediately with the
alkyllithiums present in the reaction mixture. This observation
is consistent with the reported syntheses of other highly
pyramidalized alkenes, where only alkyllithium addition prod-
ucts, and no cyclobutane dimers, were observed.25
SCHEME 1. Retrosynthetic Analysis of
Pentacyclo[4.3.0.02,4.03,8.05,7]non-4-ene (9) - Dehalogenation
of 4,5-Diiodopentacyclo[4.3.0.02,4.03,8.05,7]nonane (12) with an
Alkyllithium
4-iodopentacyclo[4.3.0.02,4.03,8.05,7]nonane (11) could give 9,
thus making 12 an attractive target.
The synthesis of diiodide 12 may be accomplished via bis-
decarboxylative iodination of the known diacid, pentacyclo-
[4.3.0.02,4.03,8.05,7]nonane-4,5-dicarboxylic acid (15).20 Diacid
15 may be conveniently prepared in only three steps from
norbornadiene and dimethylacetylene dicarboxylate, as shown
in Scheme 2. Homo Diels-Alder reaction of norbornadiene with
dimethylacetylene dicarboxylate furnished diester 13. Saponi-
fication of 13 followed by intramolecular [2+2]photocycload-
dition yielded pentacyclo[4.3.0.02,4.03,8.05,7]nonane-4,5-dicar-
boxylic acid (15).
Initially, we attempted to transform diacid 15 into diiodide
12 via bis-iododecarboxylation using the Moriarty modification21
of the Suarez method,22 iodosobenzene diacetate/I2 in standard
solvents (CCl4, CH2Cl2, benzene, cyclohexane). Indeed, Camps
and Vazquez have used this method extensively for the synthesis
of numerous vicinal diiodides, particularly those precursors
leading to pyramidalized alkenes in the tricyclo[3.3.n.03,7]alk-
3(7)-ene 6 family. However, in all of the aforementioned
solvents, yields of 12 were either very low or afforded none of
the desired vicinal diiodide product. This result is likely due to
the low solubility of diacid 15 in these solvents. The highest
yields of diiodide 12 were obtained in carbon tetrachloride (ca.
10-15% based on recovered diacid 15). However, we found
these samples to be contaminated with about 10-15% of the
corresponding vicinal iodochloro derivative, this impurity
undoubtedly resulting from radical abstraction of chlorine from
the solvent. Further, we were unable to readily separate these
two vicinal dihalides using conventional methods. As an
alternative, we conducted stepwise iododecarboxylation.
Accordingly, diacid 15 was transformed into the correspond-
ing anhydride 16 via treatment with dicyclohexylcarbodiimide,
and reaction of the anhydride 16 with sodium methoxide in
methanol gave methyl hemiester 17 in good yield.23 Iodode-
carboxylation of methyl hemiester 17 using the Suarez procedure
again gave low yields, so we utilized the Barton procedure for
iodinative decarboxylation, as modified by Eaton and Tsanakt-
sidis.24 Saponification of iodoester 18 furnished the correspond-
ing iodo acid, which afforded the desired diiodide 12 after
submission to identical conditions used for the synthesis of iodo
ester 18 (Scheme 2).
The alkyllithium addition products shown in Scheme 3 all
support the formation of 9. More direct support for the formation
of alkene 9 comes from trapping experiments with dienes. Thus,
treatment of diiodide 12 with n-butyllithium in THF in the
presence of 1.2 equiv of 1,3-diphenylisobenzofuran (DPIBF)
gave crystalline Diels-Alder adduct 27 in 34% isolated yield,26
the structure of which was confirmed by single-crystal X-ray
analysis (Scheme 4). In addition to the Diels-Alder adduct 27,
we observe (5% by GCMS) monoiodide 11 in the reaction
mixture and trace amounts of alkyllithium addition products 22-
25.
Reaction of 4,5-Diiodopentacyclo[4.3.0.02,4.03,8.05,7]nonane
(12) with tert-Butyllithium. We next investigated the dehalo-
genation of 12 with tert-butyllithium (Scheme 5), as we hoped
that a switch to this alkyllithium might minimize some of the
side reactions observed with n-butyllithium. Thus, reaction of
diiodide 12 with tert-butyllithim in 20:1 heptane:ether27 fur-
nished a mixture of products 11 (24.3% by GCMS), 22 (46.2%),
(20) (a) Huebner, C. F.; Donoghue, E.; Dorfman, L.; Wenkert, E.; Streth,
W. E.; Donely, S. W. Chem. Commun. 1966, 419. (b) Prinzbach, H.;
Hunkler, D. Angew. Chem., Int. Ed. Engl. 1967, 6, 247.
(21) Moriarty, R. M.; Khosrowshahi, J. S.; Dalecki, T. M. J. Chem. Soc.,
Chem. Commun. 1987, 675.
(22) Concepcion, J. I.; Francisco, C. G.; Freire, R.; Hernandez, R.;
Salazar, J. A.; Suarez, E. J. Org. Chem. 1986, 51, 402.
(23) Arts, N. B. M.; Weenen, H.; Klunder, A. J. H.; Zwanenburg, B.
Tetrahedron 1983, 39, 2825.
(25) See, for example: (a) Camps, P.; Munoz, M. R.; Va´zquez, S.
Tetrahedron 2006, 62, 7645. (b) Camps, P.; Font-Bardia, M.; Mendez, N.;
Perez, F.; Pujol, X.; Solans, X.; Va´zquez, S.; Vilalta, M. Tetrahedron 1998,
54, 4679. (c) Branan, B. M.; Paquette, L. A.; Hrovat, D. A.; Borden, W. T.
J. Am. Chem. Soc. 1992, 114, 774 and refs 9, 10, and 14a.
(26) This yield represents the lower bound, as 27 rearranges upon
purification via flash column chromatography, even when the eluent contains
2% triethylamine to deactivate the silica gel.
(24) Tsanaktsidis, J.; Eaton, P. E. Tetrahedron Lett. 1989, 30, 6967.
2998 J. Org. Chem., Vol. 72, No. 8, 2007

Pentacyclo[4.3.0.02,4.03,8.05,7]non-4-ene
SCHEME 2. Synthesis of 4,5-Diiodopentacyclo[4.3.0.02,4.03,8.05,7]nonane (12)a
a Key: (a) dimethylacetylene dicarboxylate, MeOH, ∆, 73%; (b) KOH, MeOH, H2O then 10% HCl, 97%; (c) hν, diethylether, 25%; (d) DCC, THF; (e)
NaOMe, MeOH, 98% 2 steps; (f) (i) (COCl)2, CH2Cl2, DMF, (ii) 2-mercaptopyridine-N-oxide sodium salt, benzene, 2-iodo-1,1,1-trifluoroiodoethane, DMAP,
66%; (g) KOH, MeOH, H2O then 10% HCl, 94%; (h) (i) (COCl)2, CH2Cl2, DMF, (ii) 2-mercaptopyridine-N-oxide sodium salt, benzene, 2-iodo-1,1,1-
trifluoroiodoethane, DMAP, 53%.
SCHEME 3. Reaction of 4,5-Diiodopentacyclo[4.3.0.02,4.03,8.05,7]nonane (12) with n-Butyllithium
23 (11.7%), and 28 (6.9%). In contrast to what was observed
when dehalogenation was conducted with n-butyllithium, no
products resulting from tert-butyllithium addition to the pyra-
midalized double bond of 9 were observed. Alkyllithium
addition products 22, 23, and 28 are proposed to form in a
manner similar to that proposed in Scheme 3.
The addition of several different Diels-Alder trapping agents
to the dehalogenation reaction of 12 with tert-butyllithium led
J. Org. Chem, Vol. 72, No. 8, 2007 2999

Forman et al.
addition, the 13C NMR spectrum of 11 shows a coupling
constant 1J(13C(5)-H) ) 173.7 Hz, which corresponds to 34.8%
s-character in the C(5)-H bond.32 These values are close to,
but slightly less than, the amount of s-character present in the
C-H bonds of the aforementioned bicyclo[1.1.0]butane and
quadricyclane precursors. Nonetheless, we were interested
to see if 9 could be prepared via dehydroiodination of
4-iodopentacyclo[4.3.0.02,4.03,8.05,7]nonane (11).
SCHEME 4. Trapping of
Pentacyclo[4.3.0.02,4.03,8.05,7]non-4-ene (9) with
1,3-Diphenylisobenzofuran (DPIBF)
Monoiodide 11 was synthesized as shown in Scheme 7.
Initially, we attempted to prepare monoacid 32 by analogy to
the synthesis of diacid 15 (Scheme 3). Indeed, Prinzbach and
co-workers previously reported that the irradiation of tetracyclo-
[4.3.0.02,4.03,7]non-8-ene-8-carboxylic acid in carbon tetrachlo-
ride led to pentacyclo[4.3.0.02,4.03,8.05,7]nonane-4-carboxylic acid
(32) in 52% yield via intramolecular [2+2]photocycloaddition.
Tetracyclo[4.3.0.02,4.03,7]non-8-ene-8-carboxylic acid was, in
turn, synthesized via homo Diels-Alder reaction of 2,5-
norbornadiene with propynoic acid.20b In our hands, however,
the intramolecular photocycloaddition of tetracyclo[4.3.0.02,4.03,7]-
to the corresponding Diels-Alder adducts in moderate to low
yields. Thus, reaction of diiodide 12 with 3 equiv of tert-
butyllithium in 20:1 heptane:ether at 0 °C in the presence of
1,3-diphenylisobenzofuran, 2,5-dimethylfuran, and spiro[2.4]-
hepta-4,6-diene led to the formation of cycloadducts 27, 29,
and 30, in 45%, 22%, and 13% isolated yields, respectively
(Scheme 6). In each of these trapping reactions, small amounts
(<5% by GCMS) of 11, 22, 23, and 28 were present as side
products.
Interestingly, we were unable to effectively trap and isolate
the Diels-Alder adduct resulting from the reaction of 12 with
tert-butyllithium in the presence of 11,12-dimethylene-9,10-
dihydro-9,10-ethanoanthracene. This diene has been successfully
employed to trap other highly pyramidalized alkenes in several
cases,5 and it was reported by Eaton to be the most effective
diene for trapping cubene (when generated by treatment of the
corresponding diiodide with butyllithium).8 In the dehalogena-
tion of 12 with tert-butyllithium in the presence of 11,12-
dimethylene-9,10-dihydro-9,10-ethanoanthracene, the major prod-
ucts of this reaction are those resulting from addition of tert-
butyllithium to the diene moiety of this molecule.28 We do
observe what appears by GCMS to be the Diels-Alder adduct
of this reaction (M•+ 346); however, this adduct is formed only
in very small amounts (ca. less than 5% by GCMS) and could
not be separated from the major products in the reaction mixture.
Apparently, addition of tert-butyllithium to the 11,12-dimeth-
ylene-9,10-dihydro-9,10-ethanoanthracene trap is faster than
dehalogenation of 12 under the reaction conditions required for
generation of 9.
Attempted Dehydrohalogenation of 4-Iodopentacyclo-
[4.3.0.02,4.03,8.05,7]nonane (11). Whereas the dehalogenation of
vicinal dihalides has proven to be a useful procedure for the
formation of highly pyramidalized alkenes, the elimination of
hydrogen halide from appropriately substituted precursors has
been much less successful. There are exceptions, however, but
most of these involve the treatment of bridgehead-halogen-
substituted bicyclo[1.1.0]butanes or quadricyclanes with a strong
base,29 and pyramidalized alkenes synthesized by this method
thus have substantial s-character in the C-H bond of the
precursors. The percent s-character in the carbon-4 (or carbon-
5) C-H bond of pentacyclo[4.3.0.02,4.03,8.05,7]nonane (33) has
been experimentally estimated to be 34.2%30 and has been
calculated to be 30.1% at the HF/6-31G* level of theory.31 In
non-8-ene-8-carboxylic
acid
leading
to
penta-
cyclo[4.3.0.02,4.03,8.05,7]nonane-4-carboxylic acid (32) was prob-
lematic, as product mixtures were often intractable and little, if
any, 32 could be isolated. Given that we had already prepared
iodo ester 18 in conjunction with the synthesis of diiodide 12,
we elected to synthesize monoacid 32 by reduction of 18 with
tri-n-butylstannane33 followed by saponification. Barton iodode-
carboxylation then furnished 4-iodopentacyclo[4.3.0.02,4.03,8.05,7]-
nonane (11).
Reaction of 11 with tert-butyllithium followed by quenching
with methanol gave pentacyclo[4.3.0.02,4.03,8.05,7]nonane (33)
as the only reaction product. Evidently, the kinetic acidity of
the C-5 hydrogen in 11 is not high enough to compete with
iodine-lithium exchange under these conditions. This is similar
to what was observed by Eaton and Maggini in their attempted
synthesis of cubene (3) via treatment of iodocubane with tert-
butyllithium. Alternatively, reaction of 11 with a variety of
strong bases such as LDA and potassium tert-butoxide gave
only unreacted starting material 11 even after prolonged reaction
time. There is no evidence to invoke the formation of 9 under
these conditions.
It may be possible that the corresponding chloro deriv-
ative,
4-chloropentacyclo[4.3.0.02,4.03,8.05,7]nonane,
will
give 9 upon treatment with tert-butyllithium. The chlorine atom
of 4-chloropentacyclo[4.3.0.02,4.03,8.05,7]nonane should enhance
the acidity of the hydrogen on adjacent C-5. Moreover,
chlorine-lithium exchange is much slower than iodine-lithium
exchange, possibly giving dehydrohalogenation a chance to
compete with the exchange reaction. We are currently investi-
gating this possibility.
Calculations. To calculate the geometric parameters of the
title alkene 9 as well as predict the olefin strain energy, heat of
hydrogenation, and relative HOMO/LUMO energies, we carried
out ab initio calculations on this molecule. Recent studies have
shown that density functional theory (DFT) can be used to
reliably model highly pyramidalized alkenes and gives results
similar to those obtained using more costly correlated (MP2)
methods.34 In this study, we have used both the B3LYP/6-31G*
(27) We are grateful to Professor William Bailey (University of Con-
necticut) for calling our attention to the importance of this solvent for
effecting lithium-iodine exchange with tert-butyllithium. See: J. Org.
Chem. 1990, 55, 5404.
(28) (a) Herres, J. P.; Forman, M. A.; Wheeler, K. A. Acta Crystallogr.,
Sect. E 2005, E61, o3961. (b) Herres, J. P.; Forman, M. A.; Wheeler, K.
A.; Yap, G. P. A. Acta Crystallogr., Sect. E 2005, E61, o1223. We also
observe this same reaction with n-butyllithium.
1
13
(32) We used the relationship between J C-H and the % s character in
the carbon hybrid orbital, as proposed by Muller and Pritchard. (a) Muller,
N.; Pritchard, D. E. J. Chem. Phys. 1959, 31, 1471. (b) Muller, N.; Pritchard,
D. E. J. Chem. Phys. 1959, 31, 768.
(33) Leibner, J. E.; Jacobus, J. J. Org. Chem. 1979, 44, 449.
(34) See, for example, refs 6f and 14a-c.
(29) See, for example, refs 16 and 17.
(30) Hamlin, J. E.; Toyne, K. J. J. Chem. Soc., Perkin Trans. 1981, 1,
2731.
(31) Craciun, L.; Jackson, J. E. J. Phys. Chem. A 1998, 102, 3738.
3000 J. Org. Chem., Vol. 72, No. 8, 2007

Pentacyclo[4.3.0.02,4.03,8.05,7]non-4-ene
SCHEME 5. Reaction of 4,5-Diiodopentacyclo[4.3.0.02,4.03,8.05,7]nonane (12) with tert-Butyllithium
and the MP2/6-31G* methods, as implemented in Gaussian 03,35
to calculate the structures and energies of 9.
SCHEME 6. Trapping of
Pentacyclo[4.3.0.02,4.03,8.05,7]non-4-ene (9) with
1,3-Diphenylisobenzofuran (DPIBF), 2,5-Dimethylfuran, and
Spiro[2.4]hepta-4,6-diene To Furnish 27, 29, and 30,
Respectively
Figure 2 shows the carbon-carbon bond lengths for the ring
bonds of 9 and the pyramidalization angle, φ, calculated at both
the B3LYP/6-31G* and the MP2/6-31G* levels of theory. Not
surprisingly, the optimized geometries for 9 using the two
methods give similar bond lengths (maximum difference of
0.023 Å) and pyramidalization angles. It is known that the MP2
method generally overestimates carbon-carbon double bond
lengths, and this lengthening was observed in the calculated
geometry for 9 (1.354 Å for B3LYP/6-31G* and 1.377 Å for
MP2/6-31G*). Additionally, we observe the expected lengthen-
ing of the carbon-carbon double bond of 9 as compared to the
unbridged alkene, bicyclo[3.3.0]oct-1(5)-ene (1.337 Å for
bicyclo[3.3.0]oct-1(5)-ene25b vs 1.354 Å for 9 using B3LYP/
6-31G*). Moreover, the carbon-carbon double bond lengths
calculated for 9 are similar to those previously calculated for
other highly pyramidalized alkenes. The pyramidalization angle
calculated for 9 (64.2° using B3LYP/6-31G* and 65.1° using
MP2/6-31G*) is among the highest for a molecule where
evidence for its formation exists.
The olefin strain energy (OSE)36 provides a measure of the
extra strain introduced into a system upon introduction of a
(35) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A.
D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A.
G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham,
M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian
03, revision C.02; Gaussian, Inc.: Wallingford, CT, 2004.
double bond. As first pointed out by Hrovat and Borden,9 the
OSE of pyramidalized alkenes (the olefin pyramidalization
energy) may be calculated by taking the difference between the
hydrogenation energy of the alkene and that of a bicyclic
reference compound. For the tricyclo[3.3.n.03,7]alk-3(7)-enes 6,
the unbridged alkene bicyclo[3.3.0]oct-1(5)-ene has been used
as the reference compound, and we have used this alkene as
the reference compound in the current study. The OSE for 9
was calculated to be 75.8 and 73.4 kcal/mol at the B3LYP/6-
31G* and MP2/6-31G* levels of theory, respectively. These
values are very close to those calculated for the tricyclo-
[3.3.n.03,7]alk-3(7)-enes 6. Nonetheless, these calculated values
(36) Schleyer, P. v. R.; Maier, W. F. J. Am. Chem. Soc. 1981, 103, 1891.
J. Org. Chem, Vol. 72, No. 8, 2007 3001

Forman et al.
SCHEME 7. Synthesis of
products such as 33. However, we have not observed 33 in any
of the reactions of 12 with tert-butyllithium leading to 9.
Finally, as first noted by Borden, highly pyramidalized
alkenes such as 9 can be expected to have some diradical
character, and thus at least a two-configuration wave function
should be used. A coupled cluster ((CCSDCT)/6-31G*) single
point energy was computed at the B3LYP/6-31G* optimized
geometry to gauge the degree of multireference character in 9.
The configuration with the largest amplitude corresponds to the
promotion of both electrons from the HOMO to the LUMO.
The magnitude of this amplitude is significant (0.16) and
indicates a notable degree of multireference character. We are
currently investigating the thermodynamic properties of 9 and
related alkenes comparing CCSD(T) and (2/2)CASPT2 methods
and will report these results in due course.
4-Iodopentacyclo[4.3.0.02,4.03,8.05,7]nonane (11) and
Pentacyclo[4.3.0.02,4.03,8.05,7]nonane (33)a
Conclusions
a (a) Bu3SnH, benzene, ∆, 93%; (b) KOH, MeOH, H2O then 10% HCl,
96%; (c) (i) (COCl)2, CH2Cl2, (ii) 2-mercaptopyridine-N-oxide sodium salt,
benzene, 2-iodo-1,1,1-trifluoroiodoethane, DMAP, 65%; (d) tert-butyl-
lithium, 20:1 heptane:diethylether, 0 °C.
In summary, we have provided strong evidence for the
generation of the highly pyramidalized alkene, pentacyclo-
[4.3.0.02,4.03,8.05,7]non-4-ene (9). Although 9 is highly reactive
and undergoes rapid reaction with alkyllithiums present in the
reaction mixture, we were able to trap this alkene as its Diels-
Alder adduct with 1,3-diphenylisobenzofuran, 2,5-dimethylfuran,
and spiro[2.4]hepta-4,6-diene. Even in the cases where 9 was
trapped as its Diels-Alder adduct, alkyllithium addition products
were present in the product mixture as side products. Thus, we
are currently investigating the synthesis of precursors to 9 that
do not utilize alkyllithiums for its generation. Attempted
dehydrohalogenation of 4-iodopentacyclo[4.3.0.02,4.03,8.05,7]-
nonane (11) to form 9 was unsuccessful.
Ab initio calculations on 9 predict pyramidalization angles
(φ) of 64.2° and 65.1° at the B3LYP/6-31G* and MP2/6-31G*
levels of theory, respectively. Thus, 9 is predicted to be one of
the most highly pyramidalized alkenes for which there are
experimental results to support its existence.
FIGURE 2. B3LYP/6-31G* and MP2/6-31G* (in italics) optimized
geometries with carbon-carbon bond lengths (Å) and pyramidalization
angles, φ, for pentacyclo[4.3.0.02,4.03,8.05,7]non-4-ene (9).
Experimental Section
Dimethyl Tetracyclo[4.3.0.02,4.03,7]non-8-ene-8,9-dicarboxylate
(13). A solution of 2,5-norbornadiene (129.5 mL, 117.3 g, 1.27
mol), dimethylacetylene dicarboxylate (48.3 mL, 56.0 g, 0.394 mol),
and hydroquinone (0.631 g, 5.73 mmol) in 4 mL of methanol was
heated under mild reflux for 14 h. The solvent and excess 2,5-
norbornadiene were removed in vacuo, and the orange oil was
recrystallized from absolute ethanol to yield diester 13 (67.4 g,
are only as good as the suitability of bicyclo[3.3.0]oct-1(5)-
ene as the reference compound.
The heat of hydrogenation for 9 was calculated as the
difference between the heat of formation of it and the corre-
sponding alkane, pentacyclo[4.3.0.02,4.03,8.05,7]nonane (33). The
calculated heats of hydrogenation, -101.0 kcal/mol (B3LYP/
6-31G*) and -99.9 kcal/mol (MP2/6-31G*), have been cor-
rected for the difference in zero-point energies of reactants and
products and for the changes in heats of formation on going
from 0 to 298 K. These values are similar to, although slightly
more exothermic than, those computed for the tricyclo[3.3.n.03,7]-
alk-3(7)-enes 6.
73.0%). mp 64-66 °C (lit.20 66 °C). IR (KBr): 1731, 1640 cm-1
.
1H NMR (400 MHz, CDCl3) δ: 3.77 (s, 6H), 3.01 (t, J ) 1.1 Hz,
2H), 2.24 (brs, 1H), 1.86 (m, 1H), 1.60 (m, 4H). 13C NMR (100.5
MHz, CDCl3) δ: 165.7 (CdO), 144.7 (Cd), 57.0 (CH), 52.0 (CH),
51.6 (CH3), 32.6 (CH2), 27.2 (CH), 23.7 (CH). MS (EI) m/z (%):
234 (M•+, 2), 203 [(M - MeO)+, 14], 187 (31), 174 [(M -
HCOOMe), 46], 143 (22), 129 (18), 115 [(M- (COOMe-
COOMe), 100). Anal. Calcd for C13H14O4: C, 66.65; H, 6.02.
Found: C, 66.64; H, 6.05.
Tetracyclo[4.3.0.02,4.03,7]non-8-ene-8,9-dicarboxylic Acid (14).
To a solution of diester 13 (21.0 g, 89.7 mmol) in methanol (435
mL) was added a solution of KOH (52.3 g, 0.934 mol) in 171 mL
of water. The yellow solution was stirred overnight at room
temperature under nitrogen. The methanol was removed in vacuo,
and the remaining solution was acidified to pH 2 with ca. 76.2 mL
of 12 N HCl, diluted with 209 mL of water, extracted with ethyl
acetate (3 × 100 mL), dried (anhydrous Na2SO4), and concentrated
in vacuo to give 14 as an off-white solid (17.8 g, 96.3%). This
solid was used without further purification in the following
photochemical step. An analytical sample was obtained by recrys-
As pointed out by Hrovat and Borden, the HOMO/LUMO
gap in pyramidalized alkenes is much lower than that in normal
alkenes. The observed bathochromic shifts in these compounds
reflect a small decrease in the HOMO energy coupled with a
much larger decrease in the LUMO energy. In the case of 9,
the calculated HOMO/LUMO energy gap is smaller (3.71 eV
using B3LYP/6-31G*) than the related alkene 6 with n ) 1
(4.79 eV using B3LYP/6-31G*). As noted by Borden,13c tert-
butyllithium may transfer one electron into the very low-lying
LUMO of pyramidalized alkenes such as 9 giving reduction
3002 J. Org. Chem., Vol. 72, No. 8, 2007

Pentacyclo[4.3.0.02,4.03,8.05,7]non-4-ene
tallization from acetone. mp 228-230 °C (lit.20 230 °C; 228-230
°C). IR (KBr): 1704, 1620, 1571 cm-1. 1H NMR (400 MHz, CD3-
OD) δ: 3.30 (m, 2H), 2.21 (br d, 1H), 1.92 (m, J ) 1.5 Hz, 1H),
1.67 (t, J ) 1.5 Hz, 2H), 1.61 (dd, 2H). 13C NMR (100.5 MHz,
CD3OD) δ: 167.3 (CdO), 148.3 (Cd), 55.8 (CH), 52.1 (CH), 47.0
(CH2), 27.3 (CH), 23.5 (CH). Anal. Calcd for C11H10O4: C, 64.07;
H, 4.89. Found: C, 64.11; H, 5.00.
MHz, CDCl3) δ: 168.3 (CdO), 59.6 (CH2), 53.8 (C), 51.8 (CH3),
51.0 (CH), 49.5 (CH), 42.9 (CH), 7.4 (C-I). HRMS calcd for
C11H11IO2 (M•+) 301.9804, found 301.9814. Anal. Calcd for C11H11-
IO2: C, 43.73; H, 3.67. Found: C, 43.80; H, 3.71.
5-Iodopentacyclo[4.3.0.02,4.03,8.05,7]nonane-4-carboxylic Acid.
To a solution of iodoester 18 (420 mg, 1.39 mmol) in methanol
(3.4 mL) was added a solution of sodium hydroxide (390 mg, 9.75
mmol) in 1.3 mL of water. The reaction mixture was stirred under
nitrogen at room temperature for 12 h. At this time, the methanol
was removed in vacuo, and the remaining solution was acidified
to pH 2 with 12 N HCl (ca. 1.2 mL). The mixture was then extracted
with ethyl acetate (4 × 10 mL), dried (anhydrous Na2SO4), and
concentrated in vacuo to give the iodoacid as a white crystalline
solid (374 mg, 93.5%). This solid was used without further
purification in the synthesis of diiodide 12.
Pentacyclo[4.3.0.02,4.03,8.05,7]nonane-4,5-dicarboxylic Acid (15).
A vigorously stirred solution/suspension of 14 (7.50 g, 36.4 mmol)
in anhydrous ether (1000 mL) was irradiated in a Rayonet
photochemical reactor under nitrogen for 14 h. Most of the solvent
was removed in vacuo (leaving ca. 100 mL of ether), and the
suspended product was cooled in an ice bath and filtered under
vacuum to furnish 15. Yields were variable and ranged from 10%
to 30% with typical yields around 20-25%. Diacid 15 was used
in the following step without further purification. An analytical
sample was obtained by recrystallization from acetone. mp 228-
230 °C (lit.20 228-229 °C). IR (KBr): 3436, 1686, 1611, 1469,
4,5-Diiodopentacyclo[4.3.0.02,4.03,8.05,7]nonane (12). A mixture
of the crude iodoacid (1.17 g, 4.16 mmol) from the previous step,
oxalyl chloride (5.1 mL, 2.0 M in CH2Cl2, 2.5 equiv), and N,N-
dimethylformamide (cat.) in dry CH2Cl2 (3.1 mL) was stirred at
room temperature under argon for 1 h. The resulting mixture was
concentrated in vacuo, and the residue was redissolved in dry
thiophene-free benzene (6.0 mL). In a separate flask, a stirred
suspension of N-hydroxypyridine-2-thione sodium salt (670 mg,
4.49 mmol), 2,2,2-trifluoroiodoethane (2.0 mL, 4.26 g, 20.3 mmol,
5 equiv), and DMAP (cat.) in dry thiophene-free benzene (15 mL)
was brought to reflux and irradiated with a 300 W tungsten lamp
under argon. The benzene solution of the acid chloride was added
dropwise via cannula over 10-15 min, and the reaction was
refluxed for an additional 1 h. After the reaction mixture was cooled,
the solution was washed with water (1 × 15 mL), 12 N HCl (1 ×
15 mL), water (1 × 15 mL), dried (50:50 anhydrous MgSO4:K2-
CO3), and concentrated in vacuo to give 12 as a light brown oil.
The diiodide was purified via column chromatography (silica gel).
Elution with petroleum ether gave pure 12 (0.800 g, 53.1%) as a
colorless oil. Crystallization from pentane at -30 °C yielded
colorless crystals. mp 47-48 °C. Rf 0.5 (petroleum ether). IR, no
1
1320, 1245 cm-1. H NMR (400 MHz, CD3OD) δ: 2.88 (t, J )
2.6 Hz, 4H), 2.80 (brm, 2H), 1.98 (brs, 2H). 13C NMR (100.5 MHz,
CD3OD) δ: 173.7 (CdO), 60.5 (CH2), 52.0 (CH), 49.6 (C), 41.0
(CH). Anal. Calcd for C11H10O4: C, 64.07; H, 4.89. Found: C,
64.13; H, 5.01.
5-(Methoxycarbonyl)pentacyclo[4.3.0.02,4.03,8.05,7]nonane-4-
carboxylic Acid (17). The synthesis of 17 was accomplished using
the method of Zwanenburg et al.,23 with modifications. To a solution
of diacid 15 (2.0 g, 9.7 mmol) in dry THF (50 mL) was added
DCC (2.0 g, 9.7 mmol) all at once. The bright yellow suspension
was stirred for 2 h, and the precipitated dicyclohexylurea (DCU)
was filtered under vacuum. The filtrate was diluted with water (30
mL), extracted with CH2Cl2 (1 × 60 mL), dried (anhydrous Na2-
SO4), and concentrated in vacuo to give the anhydride 16 as an
off-white solid. Yields for this reaction were often above 100%
(105-110%), as not all of the precipitated DCU was removed via
this procedure. Nonetheless, 16 was used without any further
treatment or purification in the synthesis of the hemi ester 17.
To a stirred solution of the anhydride 16 from the previous step
in methanol (60 mL) was added a catalytic amount of sodium
methoxide. After the mixture was stirred for 7.5 h, water (25 mL)
was added and the mixture was extracted with CH2Cl2 (5 × 20
mL). The organic layer was dried (anhydrous Na2SO4) and
concentrated in vacuo to yield an off-white crystalline solid (2.1 g,
98% two-step crude yield). The spectroscopic properties of 17
obtained by this procedure were identical to those previously
reported.23 This solid was used without further purification in the
synthesis of 18.
1
significant bands. H NMR (400 MHz, CDCl3) δ: 2.75 (s, 2H),
2.39 (t, 4H, J ) 2.6 Hz), 1.97 (s, 2H). 13C NMR (100.5 MHz,
CDCl3) δ: 58.2 (CH2), 49.9 (CH), 43.8 (CH), 22.9 (C-I). HRMS
calcd for C9H8I2 (M•+) 369.8715, found 369.8721.
Reaction of 4,5-Diiodopentacyclo[4.3.0.02,4.03,8.05,7]nonane (12)
with n-Butyllithium To Form Bi(5-iodopentacyclo[4.3.0.02,4.03,8.05,7]-
non-4-yl) (22), 4-Iodo-5-{pentacyclo[4.3.0.02,4.03,8.05,7]non-4-yl}-
pentacyclo[4.3.0.02,4.03,8.05,7]nonane (23), 4-Butyl-5-iodopentacyclo-
[4.3.0.02,4.03,8.05,7]nonane (24), 4-Butylpentacyclo[4.3.0.02,4.03,8.05,7]-
nonane (25), and 4-n-Butyl-5-{5-iodopentacyclo[4.3.0.02,4.03,8.05,7]-
non-4-yl}pentacyclo[4.3.0.02,4.03,8.05,7]nonane (26). To a solution
of diiodide 12 (320 mg, 0.865 mmol) in dry THF (9.4 mL) at -78
°C was added dropwise a solution of n-butyllithium in hexanes
(850 µL, 1.20 equiv, 1.04 mmol, 1.22 M) under argon. The mixture
was allowed to warm to 0 °C, stirred at this temperature for 2 h,
and quenched with methanol (5 mL). Water (15 mL) was added,
and the mixture was extracted with CH2Cl2 (2 × 25 mL), dried
(Na2SO4), and concentrated in vacuo. GCMS of the crude reaction
mixture showed the following product mixture: 22 (58.2% area
Methyl 5-Iodopentacyclo[4.3.0.02,4.03,8.05,7]nonane-4-carboxy-
late (18). A mixture of hemi ester 17 (2.02 g, 9.17 mmol), oxalyl
chloride (11.5 mL, 23.0 mmol, 2.0 M in CH2Cl2, 2.5 equiv), and
N,N-dimethylformamide (cat.) in dry CH2Cl2 (2.7 mL) was stirred
at room temperature under argon for 1 h. The resulting mixture
was concentrated in vacuo, and the residue was redissolved in dry
thiophene-free benzene (16.2 mL). In a separate flask, a stirred
suspension of N-hydroxypyridine-2-thione sodium salt (1.51 g,
10.12 mmol), 2,2,2-trifluoroiodoethane (4.5 mL, 9.59 g, 45.7 mmol),
and DMAP (cat.) in dry thiophene-free benzene (33.1 mL) was
brought to reflux and irradiated with a 300 W tungsten lamp under
argon. The benzene solution of the acid chloride was added
dropwise via cannula over 10-15 min, and the reaction was
refluxed for an additional 1 h. After the reaction mixture was cooled,
the solution was washed with water (1 × 15 mL), 12 N HCl (1 ×
15 mL), water (1 × 15 mL), dried (50:50 anhydrous MgSO4:K2-
CO3), and concentrated in vacuo to give 18 as a light brown oil.
The iodoester was purified via column chromatography (silica gel).
Elution with 95:5 petroleum ether/diethyl ether gave pure 18 (1.82
g, 65.6%). mp 47-48 °C. Rf 0.25 (95:5 pet ether/ether). IR: 2949,
1734, 1435, 1347, 1293, 1087 cm-1. 1H NMR (400 MHz, CDCl3)
δ: 3.63 (s, 3H), 2.72-2.75 (m, 4H), 2.39 (q, 2H), 2.07 (d, 1H, J
) 8.8 Hz), 1.77 (d of t, 1H, J ) 8.8 Hz, 1.46 Hz). 13C NMR (100.5
ratio), 23 (13.9%), 24 (3.5%, M•+ ) 300), 25 (11.0% , M•+
)
174), 26 (1%). The entire mixture was subjected to silica gel
chromatography using petroleum ether as the eluent. Additional
product 22 (white crystalline solid) was obtained pure from this
first column. To obtain pure samples of 23 and 26, a second silica
gel column was performed.
1
22: mp 103-104 °C. IR, no significant bands. H NMR (600
MHz, CDCl3) δ: 2.84-2.85 (m, 2H), 2.59-2.60 (m, 2H), 2.38-
2.39 (m, 2H), 2.33-2.34 (m, 2H), 2.28-2.29 (m, 2H), 1.95-1.97
(d of m, 2H), 1.71-1.72 (d of m, 2H), 1.66 (m, 2H). 13C NMR
(150.9 MHz, CDCl3) δ: 58.8 (CH2), 55.1 (C), 50.6 (CH), 49.4 (CH),
46.2 (CH), 46.1 (CH), 43.5 (CH), 43.1 (CH), 19.0 (C-I). HRMS
calcd for C18H16I2 (M•+) 485.9342, found 485.9332. Anal. Calcd
for C18H16I2: C, 44.47; H, 3.32. Found: C, 44.15; H, 3.37.
J. Org. Chem, Vol. 72, No. 8, 2007 3003

Forman et al.
23: IR, no significant bands. 1H NMR (600 MHz, C6D6) δ: 2.64
(m, 2H), 2.36 (m, 1H), 2.35 (m, 2H), 2.20-2.21 (q, 2H, J ) 4
Hz), 2.02 (m, 2H), 1.90 (br d, 2H), 1.85 (m, 2H), 1.77 (m, 2H),
1.75 (d of t, 1H), 1.49 (d of t, 1H, J ) 1.5 Hz). 13C NMR (150.9
MHz, C6D6) δ: 60.3 (CH2), 59.4 (CH2), 55.5 (C) 53.7 (C), 50.4
(CH), 46.6 (CH), 45.4 (CH), 43.9 (CH), 43.3 (CH), 42.5 (CH),
40.9 (CH), 18.1 (C-I). HRMS calcd for C18H17I [(M + H)+]
361.0453, found 361.0527.
pure samples of 11, 23, and 28, a second silica gel column was
performed. Dimer 28 was obtained as a colorless oil.
28: IR, no significant bands. H NMR (400 MHz, CDCl3) δ:
2.54-2.55 (br m, 4H), 2.03-2.06 (t of d, 2H, J ) 1.8 Hz, J ) 6.5
Hz), 1.90-1.95 (m, 4H), 1.73-1.83 (m, 8H). 13C NMR (100.5
MHz, CDCl3) δ: 59.7 (CH2), 51.8 (C), 44.8 (CH), 42.8 (CH), 40.6
(CH), 39.3 (CH). HRMS calcd for C18H18 (M•+) 234.1409, found
234.1408.
Reaction of 4,5-Diiodopentacyclo[4.3.0.02,4.03,8.05,7]nonane (12)
with tert-Butyllithium in the Presence of DPIBF To Form 1,-
11-Diphenyl-18-oxa-octacyclo[9.6.1.02,4.02,10.03,7.05,9.08,10.012,17]-
octadeca-12,14,16-triene (27). To a solution of diiodide 12 (304
mg, 0.822 mmol) and 1,3-diphenylisobenzofuran (267 mg, 0.986
mmol, 1.2 equiv) in dry heptane (10.3 mL) and dry ether (731 µL)
at -78 °C was added dropwise a solution of tert-butyllithium in
heptane (1.2 mL, 1.40 mmol, 1.53 M) under argon. The mixture
was allowed to warm to 0 °C, stirred at this temperature for 2 h,
and quenched with methanol (6 mL). Water (20 mL) was added,
and the mixture was extracted with CH2Cl2 (3 × 20 mL), dried
(Na2SO4), and concentrated in vacuo to yield crude 27 (418 mg).
The Diels-Alder adduct is moderately unstable to silica gel
chromatography, and it was purified as described previously to
furnish 143 mg (45%) of pure, crystalline 27.
1
26: IR, no significant bands. 1H NMR (600 MHz, CDCl3, -55
°C) δ: 2.68 (br s, 1H), 2.57 (br s, 1H), 2.46 (br s, 1H), 2.34 (br s
, 1H), 2.28 (m, 1H), 2.22 (m, 1H), 2.08 (m, 2H), 1.84-1.96 (m,
3H), 1.75 (s, 1H), 1.62-1.69 (m, 3H), 1.52-1.53 (m, 1H), 1.48-
1.51 (m, 1H), 1.18-1.28 (m, 2H), 0.88-0.96 (m, 1H), 0.83-0.88
(m, 1H), 0.81 (t, 3H, J ) 7.2 Hz). 13C NMR (150.9 MHz, CDCl3)
δ: 59.6 (CH2), 58.8 (CH2), 53.2 (C), 53.2 (C), 51.1 (C), 50.3 (CH),
48.5 (CH), 46.6 (CH), 45.5 (CH), 44.4 (CH), 44.2 (CH), 43.6 (CH),
42.9 (CH), 42.2 (CH), 42.1 (CH), 42.1 (CH), 41.9 (CH), 29.5 (CH2),
28.9 (CH2), 23.4 (CH2), 19.8 (C-I), 14.3 (CH3). HRMS calcd for
C22H25I [(M + H)+] 417.1079, found 417.1245.
24: MS (EI), m/z % 300 (M•+, 14), 257 [(M - Pr)+, 11], 131
(55), 117 (100), 91 (43).
25: MS (EI), m/z % 174 (M•+, 7), 131 [(M - Pr)+, 56], 117
(100), 91 (43).
Reaction of 4,5-Diiodopentacyclo[4.3.0.02,4.03,8.05,7]nonane (12)
with n-Butyllithium in the Presence of DPIBF To Form 1,11-
Diphenyl-18-oxa-octacyclo[9.6.1.02,4.02,10.03,7.05,9.08,10.012,17]octadeca-
12,14,16-triene (27). To a solution of diiodide 12 (275 mg, 0.744
mmol) and 1,3-diphenylisobenzofuran (241 mg, 0.893 mmol, 1.2
equiv) in dry THF (8.0 mL) at -78 °C was added dropwise a
solution of n-butyllithium in hexanes (732 µL, 0.893 mmol, 1.2
equiv, 1.22 M in hexanes) under argon. The mixture was allowed
to warm to 0 °C, stirred at this temperature for 2 h, and quenched
with methanol (5 mL). Water (30 mL) was added, and the mixture
was extracted with CH2Cl2 (3 × 30 mL), dried (Na2SO4), and
concentrated in vacuo. The Diels-Alder adduct is moderately
unstable to silica gel chromatography, and thus isolation and
purification was carried out in one of two ways. (1) The crude
product was dissolved in CH2Cl2 and maleic anhydride was added,
and the mixture was allowed to stand at room temperature for 1 h.
Pentane (5 mL) was added to precipitate out the maleic anhydride-
DPIBF adduct and excess maleic anhydride. This mixture was
filtered, and the filtrate was concentrated in vacuo. The resultant
off-white solid was recrystallized by slow evaporation from benzene
to yield pure product. (2) The crude product was subjected to silica
gel chromatography using gradient elution of 100% petroleum ether
to 80:20 petroleum ether:diethyl ether. mp 243-244 °C. IR: 3043,
2973, 1602, 1499, 1448, 964, 742, 697 cm-1. 1H NMR (400 MHz,
CDCl3) δ: 7.3-7.5 (m, 10H), 6.94-7.16 (m, 4H), 2.79-2.88 (brs,
2H), 2.07-2.3 (m, 4H), 1.65-1.74 (brs, 2H). 13C NMR (100.5
MHz, CDCl3) δ: 149.0 (C), 136.6 (C), 128.3 (CH), 127.5 (CH),
126.3 (CH), 125.2 (CH), 118.9 (CH), 87.7 (C), 69.6 (C), 58.3 (CH2),
50.7 (CH), 48.7 (CH), 41.6 (CH), 37.6 (CH). Anal. Calcd for
C29H22O: C, 90.12; H, 5.74. Found: C, 90.03; H, 5.84.
Reaction of 4,5-Diiodopentacyclo[4.3.0.02,4.03,8.05,7]nonane (12)
with tert-Butyllithium in the Presence of 2,5-Dimethylfuran To
Form 1,11-Dimethyl-14-oxa-heptacyclo[9.2.1.02,4.02,10.03,7.05,9.08,10]-
tetradec-12-ene (29). To a solution of 2,5-dimethylfuran (2.2 mL,
20.8 mmol, 20 equiv) in dry pentane (250 µL) and dry ether (209
µL) at -78 °C was added dropwise a solution of tert-butyllithium
in pentane (1.8 mL, 3.12 mmol, 1.70 M, 3 equiv) under argon. To
this solution was added a solution of diiodide 12 (385 mg, 1.04
mmol) in dry pentane (3.0 mL). The mixture was stirred at -78
°C for 30 min, then allowed to warm to 0 °C, stirred at this
temperature for 2 h, and quenched with methanol (6.6 mL). Water
(20 mL) was added, and the mixture was extracted with CH2Cl2 (3
× 30 mL), dried (Na2SO4), and concentrated in vacuo to yield crude
29 (128 mg). The Diels-Alder adduct is unstable to silica gel
chromatography, and thus isolation and purification was carried
out by chromatography using a C-18 stationary phase. Elution with
75:25 methanol:water gave pure 29 (47.5 mg, 22.0%) as a semi-
volatile liquid (care must be taken not to subject 29 to high vacuum).
IR (gas phase): 3038, 2981, 2953, 2867, 1445, 1384, 1312, 1253,
1
1144, 859 cm-1. H NMR (400 MHz, CDCl3) δ: 6.39 (s, 2H),
2.99-3.01 (m, 1H), 2.86-2.87 (m, 1H), 2.10-2.12 (m, 2H), 1.79-
1.81 (m, 2H), 1.73 (s, 2H), 1.33 (s, 6H). 13C NMR (100.5 MHz,
CDCl3) δ: 140.8 (CH), 85.3 (C), 70.3 (C), 58.5 (CH2), 50.8 (CH),
50.8 (CH), 38.3 (CH), 36.1 (CH), 15.8 (CH3). HRMS calcd for
C15H16O (M•+) 212.1201, found 212.1200.
Reaction of of 4,5-Diiodopentacyclo[4.3.0.02,4.03,8.05,7]nonane
(12) with tert-Butyllithium in the Presence of Spiro[2.4]hepta-
4,6-diene
To
Form
Spiro[cyclopropane-1,14′-hepta-
cyclo[9.2.1.02,4.02,10.03,7.05,9.08,10]tetradecane]-12′-ene (30). To a
solution of spiro[2.4]hepta-4,6-diene (0.810 µL, 8.10 mmol, 7.5
equiv) in dry pentane (250 µL) and dry ether (216 µL) at -78 °C
was added dropwise a solution of tert-butyllithium in pentane (1.9
mL, 3.25 mmol, 1.7 M, 3 equiv) under argon. To this solution was
added a solution of diiodide 12 (401 mg, 1.08 mmol) in dry pentane
(3.2 mL). The mixture was stirred at -78 °C for 10 min, then
allowed to warm to 0 °C, stirred at this temperature for 2 h, and
quenched with methanol (6.9 mL). Water (20 mL) was added, and
the mixture was extracted with CH2Cl2 (3 × 30 mL), dried (Na2-
SO4), and concentrated in vacuo to yield crude 30 (470 mg). The
Diels-Alder adduct is unstable to silica gel chromatography, and
thus isolation and purification was carried out by chromatography
using a C-18 stationary phase. Gradient elution with methanol:water
from 88:12 to 100% methanol) gave semi-pure 30 (44.2 mg, 20%)
as a semi-volatile liquid (care must be taken not to subject 30 to
high vacuum). A second column was run to obtain an analytical
sample of pure 30 (28.1 mg, 13%). IR (gas phase): 3070, 3040,
Reaction of 4,5-Diiodopentacyclo[4.3.0.02,4.03,8.05,7]nonane (12)
with tert-Butyllithium To Form 11, 22, 23, and Bi(pentacyclo-
[4.3.0.02,4.03,8.05,7]non-4-yl) (28). To a solution of diiodide 12 (609
mg, 1.65 mmol) in dry heptane (20.6 mL) and dry ether (1.5 mL)
at -78 °C was added dropwise a solution of tert-butyllithium in
heptane (2.40 mL, 3.61 mmol, 1.53 M) under argon. The mixture
was allowed to warm to 0 °C, stirred at this temperature for 2 h,
and quenched with methanol (10 mL). Water (40 mL) was added,
and the mixture was extracted with CH2Cl2 (3 × 60 mL), dried
(Na2SO4), and concentrated in vacuo to yield a crude mixture of
11, 22, 23, and 28 (332 mg total) as a light brown oil. GCMS of
the crude reaction mixture showed the following products: 11
(24.3% by GCMS), 22 (46.2%), 23 (11.7%), and 28 (6.9%). The
entire mixture was subjected to silica gel chromatography using
petroleum ether as the eluent. Additional product 22 (white
crystalline solid) was obtained pure from this first column. To obtain
3004 J. Org. Chem., Vol. 72, No. 8, 2007

Pentacyclo[4.3.0.02,4.03,8.05,7]non-4-ene
2977, 2948, 2864, 1286, 1007, 920, 815, 753, 689 cm-1. 1H NMR
(400 MHz, CDCl3) δ: 6.40 (t, 2H, J ) 1.8 Hz), 2.86-2.89 (m,
1H), 2.71-2.74 (m, 1H), 1.89-1.93 (m, 2H, J ) 4.0 Hz, 3.7 Hz),
1.88 (t, 2H, J ) 1.8 Hz), 1.73-1.77 (m, 2H, J ) 4.0 Hz, 3.7 Hz),
1.72 (t, 2H, J ) 1.5 Hz), 0.62-0.68 (m, 2H), 0.47-0.52 (m, 2H).
13C NMR (100.5 MHz, CDCl3) δ: 137.3 (CH), 66.0 (C), 58.4
(CH2), 50.4 (C), 49.8 (CH), 49.3 (CH), 48.7 (CH), 39.7 (CH), 36.6
(CH), 8.3 (CH2), 5.9 (CH2). HRMS calcd for C16H16 (M•+)
208.1252, found 208.1236.
droxypyridine-2-thione sodium salt (381.6 mg, 2.56 mmol) in dry
thiophene-free benzene (8.4 mL) containing 2,2,2-trifluoroiodoet-
hane (1.1 mL, 11.6 mmol) and a catalytic amount of 4-N,N-
dimethylaminopyridine was brought to reflux and irradiated with
a 300 W tungsten lamp. The benzene solution of acid chloride was
added dropwise over 10-15 min via cannula. After a further 1 h
at reflux, the solution was cooled, washed successively with portions
of water (1 × 15 mL), conc. HCl (1 × 15 mL), and water (1 × 15
mL), dried (50:50 anhydrous MgSO4:K2CO3), and concentrated in
vacuo. The light brown oil was purified by column chromatography
with petroleum ether to furnish monoiodide 11 (371 mg, 65%) as
a colorless oil. Rf 0.5 (petroleum ether). IR, no significant bands.
1H NMR (400 MHz, CDCl3) δ: 2.71 (m, 2H), 2.41 (t of d, 1H, J
) 6.2 Hz, J ) 2.2 Hz), 2.26 (d, 2H, J ) 1.8 Hz), 2.05 (m, 2H),
2.02 (d, 1H, J ) 8.8 Hz), 1.70 (dm, 1H, J ) 8.8 Hz, 2.2 Hz, 1.5
Hz). 13C NMR (100.5 MHz, CDCl3) δ: 58.5 (CH2), 50.0 (CH),
47.8 (CH), 43.5 (CH), 40.8 (CH), 11.4 (C-I). HRMS calcd for
C9H9I (M•+) 243.9749, found 243.9778.
Reaction of 4-Iodopentacyclo[4.3.0.02,4.03,8.05,7]nonane (11)
with tert-Butyllithium To Form Pentacyclo[4.3.0.02,4.03,8.05,7]-
nonane (33). To a solution of monoiodide 11 (180 mg, 0.737 mmol)
in dry heptane (7.0 mL) and dry ether (423 µL) at -78 °C was
added dropwise a solution of tert-butyllithium in heptane (1.45 mL,
2.21 mmol, 1.53 M) under argon. The mixture was allowed to warm
to 0 °C, stirred at this temperature for 30 min, and quenched with
methanol (3 mL). Water (20 mL) was added, and the mixture was
extracted with CH2Cl2 (3 × 20 mL), dried (Na2SO4), and carefully
concentrated in vacuo to yield 33, whose spectral properties were
identical to those previously reported.30
Methyl Pentacyclo[4.3.0.02,4.03,8.05,7]nonane-4-carboxylate (31).
A solution of iodoester 18 (651 mg, 2.15 mmol), tri-n-butyltin
hydride (0.95 mL), and dry benzene (9.2 mL) was heated at reflux
under nitrogen for 27 h. After the mixture was cooled to room
temperature, the benzene was removed in vacuo and the residue
was dissolved in diethyl ether (9.4 mL). The ethereal solution was
then treated with excess 10% KF in water (10 mL). After the
mixture was stirred for several hours, the precipitated tri-n-butyltin
fluoride was filtered under vacuum, and the filtrate was dried (Na2-
SO4). The ether was removed in vacuo to yield an off-white solid.
The ester 31 was purified via column chromatography (silica gel).
Elution with 95:5 petroleum ether/diethyl ether gave pure 31 (0.352
g, 92.7%). mp 48-50 °C (lit.23 48-49 °C) °C. Rf 0.30 (97.5:2.5
pet ether/ether). IR: 2951, 1711, 1437, 1373, 1299, 1203, 1092,
1
1061 cm-1. H NMR (400 MHz, CDCl3) δ: 3.66 (s, 3H), 2.69
(brs, 4H), 2.51-2.52 (t of d, 1H), 2.08-2.09 (m, 2H), 1.89-1.91
(d of m, 1H), 1.82-1.84 (d of m, 1H). 13C NMR (100.5 MHz,
CDCl3) δ: 171.5 (CdO), 60.3 (CH2), 52.8 (C), 51.7 (CH3), 51.2
(CH), 43.0 (CH), 39.5 (CH), 37.0 (CH). MS (EI), m/z % 176 (M•+,
3), 161 [(M - Me)+, 4], 145 [(M - OMe), 13], 133 (4), 117 (100),
91 (23).
Pentacyclo[4.3.0.02,4.03,8.05,7]nonane-4-carboxylic Acid (32). To
a solution of ester 31 (429 mg, 2.44 mmol) in methanol (6.0 mL)
was added a solution of sodium hydroxide (1 g, 25 mmol) in 2.5
mL of water. The reaction mixture was stirred under nitrogen at
room temperature overnight. At this time, the methanol was
removed in vacuo and the remaining organic washed with ether (2
× 5 mL). The aqueous layer was then acidified to pH 2 with 12 N
HCl. The mixture was then extracted CH2Cl2 (3 × 10 mL), dried
(anhydrous Na2SO4), and concentrated in vacuo to give 32 as a
white crystalline solid (378 mg, 96%). This solid was used without
further purification in the synthesis of monoiodide 11.
Acknowledgment. We acknowledge the Donors of the
American Chemical Society Petroleum Research Fund Type B.
M.A.F. also thanks Dr. Santiago Vazquez for help using the
POLCYC program to name several of the compounds described
herein. A.G., J.P.H., M.K., and L.L. gratefully acknowledge
Pfizer, Inc., for Summer Undergraduate Research Fellowships.
We also thank Dr. Patrick J. Carroll of the University of
Pennsylvania for the X-ray structure determination of 27.
Supporting Information Available: Copies of NMR spectra,
including 2-D NMR spectra for all compounds. X-ray crystal-
lographic data (ORTEP drawing and experimental) for compound
27. Cartesian coordinates and total energy for compound 9 [B3LYP/
6-31G(d) and MP2/6-31g(d)]. This material is available free of
charge via the Internet at http://pubs.acs.org.
4-Iodopentacyclo[4.3.0.02,4.03,8.05,7]nonane (11). A mixture of
monoacid 32 (378 mg, 2.33 mmol), oxalyl chloride (2.9 mL, 2 M
in CH2Cl2, 5.84 mmol), N,N-dimethylformamide (1 drop), and dry
dichloromethane (1.7 mL) was stirred at room temperature until
homogeneous (1 h), then concentrated in vacuo and released to
nitrogen. The residue was then taken up in dry thiophene-free
benzene (4.1 mL). Separately, a well-stirred suspension of N-hy-
JO0626313
J. Org. Chem, Vol. 72, No. 8, 2007 3005