T-shaped molecular building blocks by combined bridgehead and bridge substitution on bicyclo[1.1.1]pentanes

Article abstract of DOI:10.1021/jo100169b

(Figure Presented) Derivatives of bicyclo[1.1.1]pentane differentially substituted in bridgehead (1,3) and bridge (2,4) positions have been synthesized. They represent a new T-shaped structural module consisting of a rigid rod with a nearly freely rotating side arm, possibly useful as a molecular building block in syntheses of more complex covalent or supramolecular scaffolds useful in bottom-up construction of molecular level devices or materials. For good chemical connectivity in the axial direction, carboxylates, ethynyls, and acetylsulfanyl groups were installed at the bridgeheads. Quinoxalines were attached in the transverse direction through a highly reactive α-diketone system located at the bridges.

Full text of DOI:10.1021/jo100169b

pubs.acs.org/joc
T-Shaped Molecular Building Blocks by Combined Bridgehead and
Bridge Substitution on Bicyclo[1.1.1]pentanes
†
Jirı Kaleta, Josef Michl, and Ctibor Mazal*
,†
ꢀ
†
ꢁꢀ ꢁ
Department of Chemistry, Faculty of Science, Masaryk University, Kotlarska 2, 611 37 Brno, Czech
Republic, ‡Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,
ꢁ
Flemingovo nam. 2, 166 10 Praha 6, Czech Republic, and Department of Chemistry and Biochemistry,
University of Colorado, Boulder, Colorado 80309-0215
mazal@chemi.muni.cz
Received February 1, 2010
Derivatives of bicyclo[1.1.1]pentane differentially substituted in bridgehead (1,3) and bridge (2,4)
positions have been synthesized. They represent a new T-shaped structural module consisting of a
rigid rod with a nearly freely rotating side arm, possibly useful as a molecular building block in
syntheses of more complex covalent or supramolecular scaffolds useful in bottom-up construction of
molecular level devices or materials. For good chemical connectivity in the axial direction,
carboxylates, ethynyls, and acetylsulfanyl groups were installed at the bridgeheads. Quinoxalines
were attached in the transverse direction through a highly reactive R-diketone system located at the
bridges.
Introduction
and we now address their use for the introduction of a T-
shaped element. This requires the preparation of derivatives
with substituents not only in the bridgehead positions 1 and
3, but also in the bridge positions 2, 4, and/or 5 of the parent
cage of 1. Some hypothetical structures that incorporate such
an element are illustrated in Chart 1.
The introduction of substituents into the bridgehead
positions of 1 is easy and was realized soon after the
discovery6 of the synthesis of tricyclo[1.1.1.01,3]pentane
(also called [1.1.1]propellane). This propellane is prone to a
facile addition across its inner bond. Such addition reactions
have afforded hundreds of 1,3-derivatives, most of which are
listed in an extensive review.5 In contrast, the installation of
additional substituents into positions other than 1 and 3
proved to be a challenging task. The most frequent retro-
synthetic pathways are depicted in Scheme 1.
While a variety of straight molecular rods are now avail-
able, both electronically fairly conducting and highly insu-
lating,1 few if any T-shaped rods with a freely rotating side
arm have been described. Yet, in many applications of the
molecular “Tinkertoy” construction set,2 such as molecular
rotors,3 freely rotatable T-shaped building blocks would be
very useful. For some time,4,5 a set of 1,3-substituted deri-
vatives of bicyclo[1.1.1]pentane (1) and [n]staffanes, electro-
nically insulating oligomeric straight-rod derivatives of 1,
has been under development as a molecular construction kit,
(1) Schwab, P. F. H.; Levin, M. D.; Michl, J. Chem. Rev. 1999, 99, 1863.
(2) Tinkertoy is a trademark of Playskool, Inc., Pawtucket, RI, and
designates a children’s toy construction set consisting of straight wooden
sticks and other simple elements insertable into spool-like connectors.
(3) Michl, J.; Sykes, E. C. H. ACS Nano 2009, 3, 1042. Kottas, G. S.;
Clarke, L. I.; Horinek, D.; Michl, J. Chem. Rev. 2005, 105, 1281.
(i) A derivatization of 1 or its suitable bridgehead deriva-
tives is very difficult due to the high strength of the bridge
(4) Kaszynski, P.; Michl, J. J. Am. Chem. Soc. 1988, 110, 5225. Kaszynski,
ꢂ
P.; Friedli, A. C.; Michl, J. J. Am. Chem. Soc. 1992, 114, 601. Mazieres, S.;
Raymond, M. K.; Raabe, G.; Prodi, A.; Michl, J. J. Am. Chem. Soc. 1997,
119, 6682–6683. Mazal, C.; Paraskos, A. J.; Michl, J. J. Org. Chem. 1998, 63,
2116. Schwab, P. F. H.; Noll, B. C.; Michl, J. J. Org. Chem. 2002, 67, 5476.
(5) Levin, M. D.; Kaszynski, P.; Michl, J. Chem. Rev. 2000, 100, 169.
(6) Wiberg, K. B.; Walker, F. H. J. Am. Chem. Soc. 1982, 104, 5239.
Semmler, K.; Szeimies, G.; Belzner, J. J. Am. Chem. Soc. 1985, 107, 6410.
2350 J. Org. Chem. 2010, 75, 2350–2356
Published on Web 03/05/2010
DOI: 10.1021/jo100169b
r
2010 American Chemical Society

Kaleta et al.
JOCArticle
CHART 1. Molecular Rotors Designed with Bridge Substi-
tuted 1
steps of our synthesis of bicyclo[1.1.1]pentane-1,2,3,4-tetra-
carboxylic acid (3) also employed this pathway.15
In the present paper we report the synthesis of differen-
tially bridgehead and bridge-substituted derivatives of 1.
Results
SCHEME 1. Three Main Retrosynthetic Pathways to Bridge
Substituted 1
As a good starting material for our intended syntheses the
literature14 offered the propellane 4, a precursor of the
already known 2, prepared by the general procedure of
Szeimies (Scheme 2).11
SCHEME 2. Stepwise Preparation of the [1.1.1]Propellane
Derivative 414
C-H bonds (due to their high s character) in the highly
strained cage. Only a few procedures have succeeded such as
fluorination,7 chlorination,8 and chlorocarbonylation.9 (ii)
A bridge substituted 1 also results from an insertion of
substituted carbenes into the internal bond of bicyclo-
[1.1.0]butanes.10 (iii) A third approach uses appropriate
precursors for syntheses of various substituted [1.1.1]propel-
lanes, which then afford the required derivatives of 1 by
addition across the internal bond. This last method was used
almost exclusively for carbon-based substituents. Szeimies’
group11 has prepared many such propellanes and developed
a general procedure that was used by others subsequently.
An interesting application was the preparation of C-substi-
tuted propellane homopolymers12 and copolymers.13 A simi-
lar approach has been used for the preparation of a tetra-
cyclononane derivative 2, in which an additional bridge
spans the C(2) and C(4) carbon atoms of 1.14 The initial
Some bicyclobutane derivatives such as tricyclo-
[3.1.0.02,6]hexane and tricyclo[4.1.0.02,7]heptane could be
doubly lithiated and the third cyclopropane ring then intro-
duced by reaction with chloroiodomethane, yielding the
corresponding propellanes in one step.11 Since this proce-
dure simplifies the preparation and substantially increases
the yield, we attempted to use it in our case. The intermediate
5 used in the synthesis of 4, however, could only be mono-
lithiated, and we concluded that the third cyclopropane ring
had to be constructed stepwise. We assumed that the double
lithiation would most probably work in a symmetric bicyclo-
butane derivative and therefore designed a new intermediate
6 where the both lithiated positions are equivalent. The
compound 6 is a double ketal of a known diketone 7 that
was obtained by dihydroxylation of benzvalene followed by
the Swern oxidation.16 The protection of 7 was accomplished
by a reaction with silylated ethylene glycol, catalyzed by silyl
triflate at low temperature.17 However, our attempts to
(7) Levin, M. D.; Hamrock, S. J.; Kaszynski, P.; Shtarev, A. B.; Levina,
G. A.; Noll, B. C.; Ashley, M. E.; Newmark, R.; Moore, G. G. I.; Michl, J.
J. Am. Chem. Soc. 1997, 119, 12750. Shtarev, A. B.; Pinkhassik, E.; Levin,
M. D.; Stibor, I.; Michl, J. J. Am. Chem. Soc. 2001, 123, 3484.
(8) Robinson, R. E.; Michl, J. J. Org. Chem. 1989, 54, 2051. Hamrock,
S. J.; Michl, J. J. Org. Chem. 1992, 57, 5027.
(9) Wiberg, K. B.; Williams, V. Z. J. Org. Chem. 1970, 35, 369.
(10) Potekhin, K. A.; Maleev, A. V.; Struchkov, Yu. T.; Surmina, L. S.;
Koz’min, A. S.; Zefirov, N. S. Dokl. Akad. Nauk SSSR Ser. Khim. 1988, 298,
123. Wiberg, K. B.; Dailey, W. P.; Walker, F. H.; Waddell, S. T.; Cracker,
L. S.; Newton, M. J. Am. Chem. Soc. 1985, 107, 7247. Applequist, D. E.;
Renken, T. L.; Wheeler, J. W. J. Org. Chem. 1982, 47, 4985. Applequist,
D. E.; Wheeler, J. W. Tetrahedron Lett. 1977, 3411. Hall, H. K., Jr.; Smith,
C. D.; Blanchard, E. P., Jr.; Cherkofsky, S. C.; Sieja, J. B. J. Am. Chem. Soc.
1971, 93, 121.
(11) Belzner, J.; Gareiss, B.; Polborn, K.; Schmid, W.; Semmler, K.;
Szeimies, G. Chem. Ber. 1989, 122, 1509.
(12) Freudenberger, R.; Lamer, W.; Schlueter, A. D. J. Org. Chem. 1993,
58, 6497. Opitz, K.; Schlueter, A. D. Angew. Chem., Int. Ed. 1989, 28, 456.
Angew. Chem. 1989, 101, 513.
(13) Wenzel, A.; Neubert, I.; Schlueter, A. D. Macromol. Chem. Phys.
1998, 199, 745. Freudenberger, R.; Claussen, W.; Schlueter, A. D.;
Wallmeier, H. Polymer 1994, 35, 4496. Schlueter, A. D.; Bothe, H.; Gosau,
J. M. Makromol. Chem. 1991, 192, 2497.
(14) Stulgies, B.; Pigg, D. P.; Kaszynski, P.; Kudzin, Z. H. Tetrahedron
2005, 61, 89.
ꢀ
(15) Mazal, C.; Skarka, O.; Kaleta, J.; Michl, J. Org. Lett. 2006, 8, 749.
(16) Christl, M.; Kraft, A. Angew. Chem. 1988, 100, 1427. Angew. Chem.,
Int. Ed. 1988, 27, 1369.
(17) An inspiring example was found in Rubin et al. (Rubin, Y.; Knobler,
B. C.; Diederich, F. J. Am. Chem. Soc. 1990, 112, 1607), where the method
was applied to strained cyclic ketones.
J. Org. Chem. Vol. 75, No. 7, 2010 2351

Kaleta et al.
SCHEME 4. Syntheses Starting from Enolate of 2
JOCArticle
SCHEME 3. Attempted Direct Preparation of a [1.1.1]Propel-
lane Derivative from 7
lithiate 6 with an excess of n-butyllithium did not show any
evidence of the expected double lithiation, and the sub-
sequent reaction with chloroiodomethane failed. When
quenched with deuterium oxide, the reaction mixture gave
only the singly deuterated product 8 (Scheme 3).
The failure of the alternative approach along with the poor
yield of 6 prompted us to return to the original procedure for
the preparation of 4 and then also 2. Both compounds offer a
good option to install functionalities to the bridgeheads, and
to introduce a transverse functionality after removing the
acetonide protection. (i) Carboxylate, (ii) ethynyl, and (iii)
acetylsulfanyl were chosen as bridgehead substituents of
interest.
SCHEME 5. Construction of a Laterally Substituted Molecular
Rod by Sonogashira Cross-Coupling of the Diyne 12
(i) The bridgehead acetyl groups of the diketone 2 were
oxidized indirectly by ozonation of the corresponding vinyl
silyl ether 9. It can be easily prepared in excellent yield by
deprotonation of 2 with LDA and silylation of the resulting
dilithium dienolate with chlorotrimethylsilane. Ozonation
of 9 followed by diazomethane esterification afforded the
dimethyl diester 10 in a reasonable yield (Scheme 4).
(ii) As for the bridgehead ethynyls, we again took advan-
tage of the easy formation of the enolate and treated it with
diethyl chlorophosphate obtaining the diethyl phosphate 11.
Its elimination reaction with LDA in THF yielded the diyne
12 in 64%, which means acceptable 28% overall yield from
the diketone 2 (Scheme 4). The enolate of 2 was also reacted
with perfluorobutanesulfonyl fluoride (NfF). A nonaflate
13, obtained in the low yield reaction, eliminated ana-
logously as 11 and afforded a comparable yield of the diyne
12. The reactivity of the diyne 12 in the Sonogashira cross-
coupling reaction was tested with methyl 4-bromobenzoate
under standard conditions. The unoptimized isolated yield
of the coupling product 14, 58%, was very encouraging
(Scheme 5).
(iii) Acetylsulfanyl groups can be introduced by an addi-
tion of diacetyl disulfide to the propellane 4. The reaction
gave a complex mixture of products where no starting 4 was
detected. The only products containing the original unrear-
ranged ring system, as proved by 1H NMR, were the
bisacetylsulfanyl derivative 15 and a small amount of the
monoacetylsulfanyl derivative 16 (Scheme 6), which were
successfully isolated by repeated column chromatography.
No oligomers resulted in the reaction. The structure of 16
was assigned by means of NOESY NMR when positive NOE
was found between signals of the methyl protons of the
acetysulfanyl group and the protons in positions 1 and 7 of
the 8,10-dioxatetracyclo[5.3.0.02,5.03,6]decane skeleton of 16.
SCHEME 6. Addition of Diacetyl Disulfide to Propellane 4
To introduce a transverse fuctionality to the previously
prepared derivatives with different bridgehead substitu-
ents, their acetonide protection had to be removed and
the resulting vicinal cis-diols transformed further. The
acetonide protected compounds 10, 14, 15, and 16 were
deprotected by treatment with HCl in the mixture of THF
and methanol yielding the corresponding diols 17-20,
respectively, in good yields (Scheme 7). Only in the case of
14 did chloroform have to be added to the reaction mix-
ture to accommodate a limited solubility of the starting
material.
The deprotection was followed by Swern oxidation of the
diols using the same protocol, which has been successfully
used in the case of 7.16 Good yields of R-diketones 21-24
were obtained also this time. The reaction of the very
unstable diketones 21 and 22 with 1,2-benzendiamine gave
the more stable quinoxalines 25 and 26, respectively, in
moderate yield (Scheme 7).
2352 J. Org. Chem. Vol. 75, No. 7, 2010

Kaleta et al.
SCHEME 7. Removal of Acetonide Protection, Oxidation of the Corresponding Diols to R-Diketones, and Syntheses of Quinoxalines
JOCArticle
aChloroform had to be used in the case of 14 due to limited solubility. bYield of the crude product. cFor two last steps.
Discussion
liquid ammonia.23 This method failed in our case since the
hydrogen chloride generated in the first step is incompatible
with the acetonide protection and with the presence of the
strained cage. Inspired by the easy enolization and formation
of the vinyl ether 9, we decided to use Negishi’s24 elimination
of vinyl phosphates, which was successful in the case of the
adamantane bridgehead.25 In our case, a satisfactory yield
was obtained only when the original one-pot process was
carried out stepwise. Our attempts to substitute the very
toxic diethyl chlorophosphate with a less dangerous per-
fluorobutanesulfonyl fluoride, which was recently used in
similar elimination reactions including that at the adaman-
tane bridgehead,26 produced poor results mainly due to a
very low yield of the nonaflate 13. The yield of the elimina-
tion step was slightly inferior, too.
(iii) Acetylsulfanyl groups were deemed useful for attach-
ment to metal surfaces. They were introduced by photoaddi-
tion of diacetyl disulfide across the propellane 4. In contrast
to a similar reaction of [1.1.1]propellane, where reasonable
yields of the first five oligomers ([n]staffanes with n=1-5)
were formed,27 no oligomers resulted in the reaction with 4.
This process thus resembles the photoreaction of 4 with
biacetyl,14 where no oligomerization was observed, either.
The presence of the singly substituted adduct 16 complicated
the separation of products. An attempt to promote the
oligomerization by decreasing the amount of diacetyl disul-
fide used in the reaction merely led to an increase in the
amount of 16 formed. Not surprisingly, the structure of 16
implies that the acetylsulfanyl radical attacks the propellane
from the more accessible side. An intermediate bridgehead
radical is then sterically hindered and fails to react with
another molecule of propellane to yield a dimer or higher
oligomers. It prefers to react with another molecule of
diacetyl disulfide or to abstract a hydrogen atom from the
solvent or one of the other compounds present.
The syntheses described in the Results section demon-
strate that the propellane 4 is a good starting material for
structures that could serve as T-shaped molecular building
blocks combining an essentially free rotation around an axis
with a possibility to install an additional transverse functiona-
lity. Three groups that provide good connectivity in the
axial direction were used: (i) carboxylate, (ii) ethynyl, and
(iii) acetylsulfanyl.
(i) Carboxylates are useful in the construction of various
metal-organic frameworks18 and are readily transformed
into many other functional groups. Because of the lability of
the diketone 2 obtained by a known procedure from 4, we
were unable to use the haloform oxidation of bridgehead
acetyls,19 the most widely used procedure for installing
carboxyls at the bridgeheads of 1. This reaction was not fully
compatible with the acetonide protection in 2, and yielded a
deprotected diacid in less than 5% yield. Fortunately the
diketone 2 enolized easily and yielded the corresponding silyl
enol ether 9, permitting the use of a modified ozonation
procedure successful in some other cases of sensitive
compounds.20
(ii) Ethynyl substituents were chosen for the bridgeheads
in order to permit the Sonogashira coupling reaction to be
used for incorporation of the T-shaped building block. This
coupling is a very popular method for construction of giant
molecules such as aryleneethynylenes,21 has a wide scope,
and tolerates a wide choice of functional groups.22 Since
bridgehead halides on 1 do not undergo an oxidative addi-
tion of metal catalysts, the acetylene units need to be carried
by the bridgeheads. The usual procedure for transforming a
bridgehead acetyl on 1 into ethynyl is fusion with triphenyl-
phosphine and hexachloroethane, which produces chlorovi-
nyl derivatives, followed by treatment with sodium amide in
The compatibility of the bridgehead acetylsulfanyl groups
with the deprotection and Swern oxidation in the conversion
of 15 and 16 to the R-diketones 23 and 24 is important if such
(18) Perry, J. J., IV.; Perman, J. A.; Zaworotko, M. J. Chem. Soc. Rev.
2009, 38, 1400.
(19) Levin, M. D.; Kaszynski, P.; Michl, J. Organic Syntheses; Wiley:
New York, 2004; Collect. Vol. X, p 86. Levin, M. D.; Kaszynski, P.; Michl, J.
Org. Synth. 2000, 77, 249.
(20) Cesati, R. R.; Armas, J. de; Hoveyda, A. H. J. Am. Chem. Soc. 2004,
126, 96. Makaev, F. Z.; Galin, F. Z.; Tolstikov, G. A. Izv. Akad. Nauk, Ser.
Khim. 1995, 314. Kasatkin, A. N.; Romanova, T. Yu.; Podlipchuk, I. P.;
Tolstikov, G. A. Khim. Prir. Soedin. 1993, 3, 459.
(23) Schwab, P. F. H.; Noll, B. C.; Michl, J. J. Org. Chem. 2002, 67, 5476.
Gleiter, R.; Pfeifer, K.-H.; Szeimies, G.; Bunz, U. Angew. Chem. 1990, 102,
418. Angew. Chem., Int. Ed. 1990, 29, 413. Bunz, U.; Szeimies, G. Tetra-
hedron Lett. 1990, 31, 651.
(21) For some recent examples see: Blaszczyk, A.; Fischer, M.; von
Haenisch, C.; Mayor, M. Eur. J. Org. Chem. 2007, 16, 2630. Wang, C.;
Batsanov, A. S.; Bryce, M. R.; Sage, I. Org. Lett. 2004, 6, 2181. Kang, Y.;
Wang, S. Tetrahedron Lett. 2002, 43, 3711. Wang, C.; Batsanov, A. S.; Bryce,
M. R. J. Org. Chem. 2006, 71, 108.
(24) Negishi, E.; King, A. O.; Klima, W. L. J. Org. Chem. 1980, 45, 2526.
€
(25) Stulgies, B.; Prinz, P.; Magull, J.; Rauch, K.; Meindl, K.; Ruhl, S.;
de Meijere, A. Chem.;Eur. J. 2005, 11, 308.
(26) Lyapkalo, I. M.; Vogel, M. A. K.; Boltukhina, E. V.; Vavrık, J.
Synlett 2009, 558.
ꢀ
(22) For the scope of the coupling reaction see: Sonogashira, K. In Metal-
catalyzed Cross-coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-
VCH: Weinheim, Germany, 1998; pp 203-229.
(27) Friedli, A. C.; Kaszynski, P.; Michl, J. Tetrahedron Lett. 1989, 30,
455. Kaszynski, P.; Michl, J. J. Am. Chem. Soc. 1988, 110, 5225. Kaszynski,
P.; Friedli, A. C.; Michl, J. J. Am. Chem. Soc. 1992, 114, 601.
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Kaleta et al.
JOCArticle
derivatives are needed for metal surface applications. The R-
diketone moiety can be used for construction of additional
functionalities in a direction perpendicular to the axis of the
expected rotation of the T-shaped building block. R-Dike-
tones are rather unstable in general, particularly when
strained, as is the case here. However, they can be easily
transformed into various heterocycles. The quinoxalines 25
and 26 yielded the first examples of T-shaped molecular
building blocks with a heterocyclic unit in the bridge plane of
1. The rod-like 26 represents a good example of a molecular
rod with an essentially freely rotatable transverse rigid arm
attached alongside a rod. It promises to be useful for the
construction of more complex covalent scaffolds.
The limited stability of the strained R-diketone is respon-
sible for the difficulties encountered in the attempts to
protect the intermediate 7 on the alternative pathway to
the propellane analogous to 4. The intermediate 7 was very
sensitive to acidic conditions generally needed to protect a
carbonyl group,28 and a very mild procedure had to be used.
Only a low yield of 6 resulted in the reaction of 7 with
silylated ethylene glycol under silyl triflate catalysis, which is
mild enough and runs fast enough even at low temperature,
and this route had to be abandoned.
spectra were recorded for neat samples on NaCl plates. GC-MS
spectra were measured on an instrument with a fused silica
capillary column (cross-linked 5% phenyl methyl silicone).
Dispiro[(1,3-dioxolane)-2,30-tricyclo[3.1.0.02,6]hexane-40,200-
(1,3-dioxolane)] (6). A flame-dried Schlenk flask was charged
with diketone 7 (287 mg, 2.652 mmol) in dry dichloromethane
(60 mL) and with 1,2-bis[(trimethylsilyl)oxy]ethane (3.00 mL,
12.237 mmol). The solution was cooled to -50 °C and tri-
methylsilyl trifluoromethanesulfonate (235 μL, 1.300 mmol)
was added. The cooling was interrupted and the reaction
mixture was slowly heated to -30 °C in 30 min and then stirred
at that temperature for 30 min. Subsequently, dry triethylamine
(350 μL) was added, which turned the color of the reaction
mixture yellow immediately. The mixture was heated to room
temperature. Then, volatiles were evaporated under reduced
pressure. Column chromatography (alumina, CH2Cl2/hexanes
1:2, then CH2Cl2/hexanes 1:1) yielded 6 as a colorless oil (97 mg,
0.494 mmol, 19%). 1H NMR (500 MHz, CDCl3): δ 2.20 (t, J=
1.93 Hz, 2H), 2.46 (t, J=1.93 Hz, 2H), 3.82-3.91 (m, 8H). 13
C
NMR (125 MHz, CDCl3): δ 2.8, 39.7, 60.2, 98.4. MS (ESIþ,
CH3CN), m/z: 197.1 ([M þ H]þ), 203.1 ([M þ Li]þ), 219.1 ([M þ
Na]þ).
9,9-Dimethyl-3,5-bis(1-(trimethylsilyloxy)vinyl)-8,10-dioxa-
tetracyclo[5.3.0.02,5.03,6]decane (9). A solution of diketone 2
(533 mg, 2.130 mmol) in THF (10 mL) was slowly added to a
stirred solution of LDA at -78 °C, freshly prepared from
diisopropylamine (848 μL, 6.0 mmol) in THF (20 mL) and n-
butyllithium in hexane (2.5 M, 2.04 mL, 5.1 mmol). After 2 h of
stirring at this temperature, the reaction mixture was slowly
heated to room temperature and stirred for an additional 15
min. Then it was cooled back to -78 °C and trimethylsilyl
chloride (1.39 mL, 11.0 mmol) was added. The reaction mixture
was stirred for an additional 1 h, then slowly warmed to room
temperature and stirred for 1.5 h. Volatiles were removed under
reduced pressure and the crude product 9 was extracted with
pentane (3 ꢀ 20 mL) as a colorless oil (781 mg, 93%). 1H NMR
(300 MHz, CDCl3): δ 0.21 (s, 18H), 1.31 (s, 3H), 1.44 (s, 3H),
2.01 (s, 2H), 2.89 (s, 2H), 3.99 (d, J=1.37 Hz, 1H), 4.05 (d, J=
1.37 Hz, 1H), 4.17 (d, J=0.77 Hz, 1H), 4.37 (d, J=0.77 Hz, 1H),
4.87 (br s, 2H). 13C NMR (75 MHz, CDCl3): δ -0.04, 0.3, 23.9,
24.0, 42.7, 45.6, 52.9, 63.4, 82.2, 90.0, 92.2, 113.9, 154.8, 155.6.
IR (neat): 2966, 2902, 1630, 1535, 1456, 1373, 1309, 1255, 1223,
1198, 1053, 1016, 847, 752 cm-1. GC-MS, m/z (%): 394 (M, 1),
379 (M - CH3, 1), 336 (8), 308 (7), 293 (11), 279 (7), 246 (8), 217
(9), 203 (7), 180 (5), 156 (7), 147 (9), 117 (5), 73 (100), 43 (4).
9,9-Dimethyl-8,10-dioxatetracyclo[5.3.0.02,5.03,6]decane-3,5-
dicarboxylic Acid Dimethyl Ester (10). Ozone was introduced
into a solution of silyl enol ether 9 (781 mg, 1.98 mmol) in
dichloromethane (50 mL) at -78 °C until a slightly blue color of
the solution indicated the end of the reaction (∼40 min). An
excess of ozone was purged off with a stream of argon at -78 °C.
Methanol (1.20 mL) and then an excess of an ethereal
diazomethane solution was added (until the reaction mixture
turned yellow). The solution was stirred for 12 h at room
temperature. Column chromatography on silica gel (ethyl ace-
tate/hexane 1:1) yielded diester 10 as a white crystalline solid
(173 mg, 31%). Mp 95.4-96.2 °C. 1H NMR (300 MHz, CDCl3):
δ 1.34 (s, 6H), 2.43 (s, 2H), 3.35 (s, 2H), 3.68 (s, 3H), 3.71 (s, 3H),
4.92 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 24.0, 24.5, 42.30,
42.34, 49.4, 51.6, 51.8, 65.9, 81.1, 114.6, 168.1, 168.5. IR (KBr):
3442, 2985, 2948, 2902, 1730, 1630, 1435, 1377, 1313, 1288, 1269,
1198, 1153, 1101, 1051, 980, 858 cm-1. GC-MS, m/z (%): 283 (M
þ H, <1), 267 (M - CH3, 100), 251 (M - OCH3, 5), 207 (6), 193
(51), 165 (62), 133 (19), 105 (15), 91 (10), 77 (12), 59 (14), 43 (34).
HRMS, (ESIþ) for (C14H18O6 þ Hþ): calcd 283.1173, found
283.1176.
Conclusions
We have prepared an electronically insulating T-shaped
molecular connector with a nearly freely rotating side arm,
based on a bridge-substituted bicyclo[1.1.1]pentane cage. We
have provided an illustration of the ways in which this unit
can be extended, through carboxylate, thiol, or acetylene
chemistry at the bridgehead position, and through a highly
reactive R-diketone moiety in the transverse direction, as
demonstrated with quinoxaline.
Experimental Section
All reactions were carried out under argon atmosphere
with dry solvents, freshly distilled under anhydrous conditions,
unless otherwise noted. Standard Schlenk and vacuum line
techniques were employed for all manipulations of air or
moisture sensitive compounds. Yields refer to isolated, chroma-
tographically and spectroscopically homogeneous materials,
unless otherwise stated. 3,5-Diacetyl-9,9-dimethyl-8,10-dioxa-
tetracyclo[5.3.0.02,5.03,6]decane (2),14 tricyclo[3.1.0.02,6]hexane-
3,4-dione (7),16 diacetyl disulfide,29 and an ethereal solution of
diazomethane30 were prepared according to previously pub-
lished procedures.
1,2-Benzenediamine was purchased and sublimed prior to
use. Trimethylsilyl chloride, perfluorobutanesulfonyl fluoride,
diethyl chlorophosphate, oxalyl chloride, dimethyl sulfoxide,
diisopropylamine, Pd(PPh3)4, and methyl 4-bromobenzoate
were purchased and used without further purification. Triethy-
lamine and dichloromethane were distilled from CaH2 under
argon immediately prior to use.
Melting points were determined with a standard apparatus
and are uncorrected. 1H, 13C, 19F, and 31P spectra were acquired
at 25 °C with 300 and 500 MHz (1H frequencies) spectrometers.
1H and 13C spectra were referenced to residual solvent peaks. IR
(28) Green, T. W.; Wuts, P. G. M. In Protective Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999.
(29) Kaszynski, P.; Friedli, C. A.; Michl, J. J. Am. Chem. Soc. 1992, 114,
601.
ꢀ
(30) Cerny, J. V.; Cerny, M.; Palecek, M.; Prochazka, M. In Organicka
ꢀ
Enol Phosphate 11. A solution of diketone 2 (1.150 g, 4.59
mmol) in THF (15 mL) was slowly added to the cold (-78 °C)
ꢁ
ꢁ
ꢀ
synthesa; Academia: Prague, Czech Republic, 1971.
ꢁ
ꢁ
2354 J. Org. Chem. Vol. 75, No. 7, 2010

Kaleta et al.
JOCArticle
solution of LDA freshly prepared from diisopropylamine (1.623
mL, 11.49 mmol) in THF (30 mL) and n-butyllithium in hexane
(2.5 M, 4.227 mL, 10.57 mmol). The mixture was stirred at this
temperature for 2 h, slowly warmed to -30 °C, and cooled again
to -78 °C. A yellowish solid precipitated. Subsequently, diethyl
chlorophosphate (1.660 mL, 11.49 mmol) was added and the
mixture was stirred for 2 h at -78 °C, and then slowly warmed to
room temperature. The yellowish precipitate disappeared leav-
ing a brown-orange solution. Volatiles were removed under
reduced pressure yielding brown oil that was dissolved in ether
(140 mL) and washed with water (2 ꢀ 30 mL). Combined water
layers were extracted with ether (2 ꢀ 20 mL) and the organic
extract was dried over Na2SO4. Evaporation of solvents fol-
lowed by the column chromatography on silica gel with ethyl
acetate yielded enol phosphate 11 as a colorless oil (1.032 g,
43%). 1H NMR (300 MHz, CDCl3): δ 1.26 (s, 3H), 1.28-1.34
(m, 12 H), 1.37 (s, 3H), 2.18 (s, 2H), 3.06 (s, 2H), 4.07-4.17 (m,
8H), 4.43-4.44 (m, 1H), 4.76-4.78 (m, 1H), 4.83 (s, 2H),
4.88-4.90 (m, 1H), 4.95-4.96 (m, 1H). 13C NMR (75 MHz,
CDCl3): δ 15.9 (d, J=2.93 Hz), 16.0 (d, J=2.89 Hz), 23.9, 43.8,
44.6 (d, J=7.62 Hz), 51.7 (d, J=7.49 Hz), 64.0, 64.1 (d, J=6.13
Hz), 64.4 (d, J=6.11 Hz), 81.6, 98.1 (d, J=3.23 Hz), 98.9 (d, J=
CDCl3): δ 1.37 (s, 3H), 1.55 (s, 3H), 2.58 (s, 2H), 3.34 (s, 2H),
3.86 (s, 3H), 3.88 (s, 3H), 4.97 (s, 2H), 7.41-7.46 (m, 4H),
7.91-7.95 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 24.3, 24.6,
35.2, 42.3, 47.7, 52.0, 52.1, 70.8, 80.8, 81.8, 82.8, 87.2, 90.6,
114.9, 126.9, 127.8, 129.29, 129.34, 129.7, 131.5, 131.6, 166.2,
166.3. IR (KBr): 3440, 2983, 2933, 2893, 2222, 1722, 1603, 1437,
1377, 1281, 1200, 1111, 1074, 968, 854, 766 cm-1. MS, m/z (%):
482 (M, 2), 467 (M - CH3, 9), 451 (M - OCH3, 18), 424 (43), 407
(12), 395 (100), 382 (19), 365 (51), 337 (58), 307 (37), 289 (33), 276
(56), 239 (19), 223 (22), 202 (20), 163 (25), 59 (58), 43 (39).
HRMS (APCI) for (C30H26O6 þ Hþ): calcd 483.1802, found
483.1797.
Addition of Diacetyl Disulfide to Propellane 4. Freshly distilled
(AcS)2 (2.000 g, 13.314 mmol) was added to a solution of pro-
pellane 4 in ether/hexanes (30 mL, 1:2) prepared from 3-bromo-
4-chloromethyl-8,8-dimethyl-7,9-dioxatetracyclo[4.3.0.02,4.03,5]-
nonane (Scheme 2) (554 mg, 1.982 mmol). The solution was
stirred in a quartz reactor in an ice-water bath and irradiated by
450 W medium-pressure mercury lamp for 4.5 h under argon.
Solvents were distilled under reduced pressure and the excess of
(AcS)2 was removed from the remaining reddish oil by distilla-
tion in a Kugelrohr apparatus (60 °C, 0.5 Torr). Separation
of the distillation residue by column chromatography on silica
gel (CH2Cl2, then ethyl acetate/hexane 1:4) provided two non-
rearranged products, the bis- and monoacetylsulfanyl deriva-
tives 15 (198 mg, 32%) and 16 (41 mg, 9%), respectively, as white
solids.
3.24 Hz), 114.4, 150.5 (d, J=2.82 Hz), 150.6 (d, J=2.80 Hz). 31
P
NMR (300 MHz, CDCl3): δ -5.34, -5.52. IR (neat): 2983,
2937, 2912, 1651, 1479, 1444, 1371, 1271, 1225, 1192, 1163, 1032,
995, 949, 858 cm-1. MS, m/z (%): 523 (M þ H, 19), 507 (M -
CH3, 8), 447 (11), 310 (17), 291 (20), 263 (58), 235 (34), 207 (28),
179 (33), 161 (53), 155 (69), 127 (51), 99 (92), 81 (35), 45 (28).
HRMS, (ESIþ) for (C22H36O10P2 þ Naþ): calcd 545.1676,
found 545.1674.
S-(5-Acetylsulfanyl-9,9-dimethyl-8,10-dioxatetracyclo[5.3.0.
2,5.03,6]decane-3-yl) thioacetate (15): Mp 72.3-73.9 °C. 1H
0
NMR (500 MHz, CDCl3): δ 1.30 (s, 3H), 1.56 (s, 3H), 2.25 (s,
3,5-Diethynyl-9,9-dimethyl-8,10-dioxatetracyclo[5.3.0.02,5.03,6]-
decane (12). The enol phosphate 11 (427 mg, 0.817 mmol) in
THF (5 mL) was slowly added to the stirred solution of LDA,
prepared from diisopropylamine (1.39 mL, 9.804 mmol) in THF
(15 mL) and n-butyllithium (2.5 M, 3.59 mL, 8.987 mmol) in
hexane at -78 °C. The reaction mixture turned red immediately.
The dark red solution was stirred at that temperature for 1 h,
then slowly warmed to room temperature and stirred for 3 h.
Then it was poured into pentane (120 mL) and washed with
water (3 ꢀ 20 mL). The combined water layers were extracted
with pentane (2 ꢀ 20 mL) and the organic extract was dried over
Na2SO4. Volatiles were removed under reduced pressure and the
resulting yellowish solid was purified by the column chroma-
tography on silica gel (diethyl ether/pentane 2:1) providing
diacetylene 12 as white needles (112 mg, 64%). Mp
3H), 2.26 (s, 3H), 2.82 (s, 2H), 3.58 (br s, 2H), 4.73 (m, 2H). 13
C
NMR (125 MHz, CDCl3): δ 23.9, 24.9, 31.0, 31.1, 44.7, 48.8,
51.3, 68.3, 81.2, 114.7, 194.3, 195.4. MS (ESIþ, CHCl3), m/z:
315.1 ([M þ H]þ), 321.1 ([M þ Li]þ), 337.1 ([M þ Na]þ).
S-(1RS,2SR,6RS,7SR)-(9,9-Dimethyl-8,10-dioxatetracyclo-
[5.3.0.02,5.03,6]decane-3-yl) thioacetate (16): Mp 59.5-60.8 °C.
1H NMR (500 MHz, CDCl3): δ 1.32 (s, 3H), 1.43 (s, 3H), 2.25 (s,
3H), 2.35 (s, 2H), 3.01 (s, 1H), 3.22 (br s, 2H), 4.72 (br s, 2H). 13
C
NMR (125 MHz, CDCl3): δ 24.4, 26.0, 31.3, 34.5, 43.4, 52.6,
66.1, 81.6, 113.9, 195.3. MS (ESIþ, CHCl3), m/z: 241.1 ([M þ
H]þ), 247.1 ([M þ Li]þ), 263.1 ([M þ Na]þ).
Liberation of Diol 18 from Acetonide 14. The acetonide 14 (115
mg, 0.238 mmol) was dissolved in a mixture of chloroform
(5 mL), methanol (6 mL), and concentrated hydrochloric acid
(1.3 mL). The yellowish reaction mixture was stirred at room
temperature for 22 h. Then the solution was diluted with ether
(75 mL) and washed with 10% NaHCO3 (3 ꢀ 15 mL). Water
layers were extracted with ether (3 ꢀ 15 mL) and the combined
organic layers were dried over Na2SO4. Evaporation of solvents
followed by column chromatography on silica gel (chloroform/
ethyl acetate 4:3) provided a white solid that was dissolved in
chloroform and precipitated with pentane yielding an analyti-
cally pure sample of diol 18 in the form of long white needles (91
mg, 87%). Mp 235.5-237.3 °C. 1H NMR (300 MHz, CDCl3): δ
2.58 (s, 2H), 2.66-2.68 (m, 2H), 3.36 (s, 2H), 3.90 (s, 3H), 3.91 (s,
3H), 4.52 (d, J=4.25 Hz, 2H), 7.41-7.46 (m, 4H), 7.92-7.97 (m,
4H). 13C NMR (75 MHz, CDCl3): δ 33.4, 35.7, 48.2, 52.19,
52.22, 72.7, 73.5, 81.3, 81.9, 87.4, 89.8, 127.0, 127.3, 129.37,
129.43, 129.6, 129.8, 131.7, 166.4, 166.5. IR (KBr): 3533, 3423,
3321, 2978, 2949, 2891, 2222, 1714, 1603, 1404, 1284, 1178, 1105,
1014, 858, 769 cm-1. MS, m/z (%): 442 (M, <1), 424 (4), 411 (M
- OCH3, 4), 395 (16), 382 (5), 365 (8), 337 (11), 323 (5), 277 (15),
265 (14), 252 (9), 240 (9), 237 (9), 203 (15), 187 (9), 163 (100), 149
(19), 135 (11), 115 (11), 64 (15), 59 (36). HRMS (ESIþ) for
(C27H22O6 þ Naþ): calcd 465.1309, found 465.1307.
1
111.2-113.1 °C. H NMR (300 MHz, CDCl3): δ 1.37 (s, 3H),
1.59 (s, 3H), 2.17 (s, 1H), 2.18 (s, 1H), 2.43 (s, 2H), 3.18 (s, 2H),
4.90 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 24.2, 24.3, 34.2,
41.3, 47.3, 70.0, 70.1, 71.6, 78.7, 81.5, 81.8, 115.0. IR (KBr):
3251, 2985, 2935, 2897, 1379, 1342, 1265, 1219, 1201, 1157, 1068,
1047, 972, 850 cm-1. GC-MS, m/z (%): 215 (M þ H, 2), 199 (M
- CH3, 79), 155 (11), 139 (54), 127 (97), 105 (49), 77 (28), 43
(100). HRMS, (EI) for (C14H13O2þ): calcd 213.0916, found
213.0918.
Sonogashira Cross-Coupling Reaction of Diyne 12 with Methyl
4-Bromobenzoate. A flame-dried Schlenk flask was charged with
diyne 12 (112 mg, 0.523 mmol), methyl 4-bromobenzoate (337
mg, 1.569 mmol), Pd(PPh3)4 (49 mg, 0.042 mmol, 8 mol %), and
CuI (6 mg, 0.031 mmol, 6 mol %). After three successive
vacuum/argon cycles, dry and degassed THF (7 mL) and
triethylamine (6 mL) were added via syringe. The yellow reac-
tion mixture was stirred for 16 h at 55 °C. A white solid
precipitated. The solution was cooled to room temperature,
diluted with ether (75 mL), and washed with water (3 ꢀ 15 mL).
The yellow organic phase was dried over Na2SO4. After eva-
poration of volatiles, the pure product 14 was isolated as a white
solid (146 mg, 58%) by chromatography on silica gel (CHCl3/
Swern Oxidation of the Diol 18 and the Reaction of Resulting
Diketone 22 with 1,2-Benzenediamine to Quinoxaline 26. To a
solution of DMSO (51 μL, 0.724 mmol) in dichloromethane
1
ethyl acetate 35:1). Mp 227.6-229.1 °C. H NMR (300 MHz,
J. Org. Chem. Vol. 75, No. 7, 2010 2355

Kaleta et al.
JOCArticle
(2 mL) was added oxalyl chloride (48 μL, 0.543 mmol) at -78 °C.
After 5 min, the diol 18 (80 mg, 0.181 mmol) in dichloromethane
(18 mL) was slowly introduced, and the resulting milky solution
was stirred for 1 h at -78 °C. Then triethylamine (151 μL, 1.086
mmol) was added. The mixture was stirred for 10 min and then
warmed to room temperature. The solution became yellow.
Volatiles were removed under reduced pressure and the resulting
yellowish solid was dissolved in a mixture of chloroform and
ethyl acetate (2:1) and filtered through a short silica gel column.
A careful evaporation of solvents yielded the crude diketone 22
(58 mg) as an unstable yellowish solid, which was immediately
dissolved in THF (6 mL). Freshly sublimed 1,2-benzenediamine
(20 mg, 0.185 mmol) was added, and the brownish reaction
mixture was stirred at room temperature for 2 h. Volatiles were
removed under reduced pressure and the resulting brown solid
was chromatographed on silica gel (chloroform/ethyl acetate
1:1) yielding the quinoxaline 26 as a yellowish solid (19 mg,
20%). Mp 243 °C dec. 1H NMR (300 MHz, CDCl3): δ 3.05 (s,
2H), 3.84 (s, 6H), 4.24 (s, 2H), 7.32-7.34 (m, 4H), 7.62-7.65 (m,
2H), 7.86-7.88(m, 4H), 7.99-8.02 (m, 4H). 13C NMR (75 MHz,
CDCl3): δ 29.6, 49.2, 52.1, 73.7, 85.5, 85.9, 126.2, 128.8, 129.0,
129.2, 129.9, 131.7, 140.5, 163.0, 166.1. IR (KBr): 2981, 2949,
2896, 2214, 1724, 1602, 1436, 1371, 1291, 1193, 1103, 1056, 851,
763. HRMS (ESIþ) for (C33H22N2O4 þ Hþ): calcd 511.1658,
found 511.1652.
Acknowledgment. This work was supported by the U.S.
National Science Foundation (CHE 0848477, OISE-
0532040) and Ministry of Education, Youth and Sports of
the Czech Republic (joint grant in aid KONTAKT ME
09114 and grant MSM0021622410). J.K. greatly acknowl-
edges financial support from Synthon s.r.o., CZ.
Supporting Information Available: Experimental proce-
dures for compounds 13, 17, 19-21, and 23-25 and NMR
spectra of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
2356 J. Org. Chem. Vol. 75, No. 7, 2010