Investigating direct alkynylation at the bridgehead of bicyclic cages using silver(I) acetylides

Article abstract of DOI:10.1002/ejoc.200600701

Silver(I) acetylides facilitate direct carbon-carbon bond formation at the bridgehead position of adamantane, and in some instances related systems such as carborate anions and bicyclo[2.2.2]octanes. Substrate constraints along with attempts to further un

Full text of DOI:10.1002/ejoc.200600701

FULL PAPER
DOI: 10.1002/ejoc.200600701
Investigating Direct Alkynylation at the Bridgehead of Bicyclic Cages Using
Silver(I) Acetylides
Rebecca H. Pouwer,[a] Jason B. Harper,[b] Kamesh Vyakaranam,[c] Josef Michl,[c]
Craig M. Williams,*[a] Carsten H. Jessen,[a] and Paul V. Bernhardt[a]
Keywords: Alkynylation / Silver(I) acetylides / Carbon–carbon bond formation / Bridgehead reactions / Bicyclic cages /
Adamantanes / Carborate anions
Silver(I) acetylides facilitate direct carbon–carbon bond for- attempts to further understand the underlying mechanism
mation at the bridgehead position of adamantane, and in
some instances related systems such as carborate anions and
bicyclo[2.2.2]octanes. Substrate constraints along with
are presented.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
applications, for example, addition to aldehydes,[13]
ketones,[13] acid chlorides,[12,14] pyridines[15] and nucleo-
sides.[16]
Introduction
Direct acetylenic carbon–carbon bond formation at the
bridgehead position of bicyclic cages is an area of synthetic
methodology increasingly in demand fuelled by the rapidly
growing field of nanotechnology, for example, AFM tips
(e.g. 1),[1] molecular rotors (e.g. 2),[2] nanoporous architec-
ture (e.g. 3),[3] molecular connectors (e.g. 4),[4] and poly-
meric nanomaterials[5] (Figure 1).
Not surprisingly, however, this type of direct methodol-
ogy is poorly represented[6] in the chemical literature and
even procedures which perform this task over multiple syn-
thetic steps are limited.[7] It is in this context that we initi-
ated a program aimed at addressing this deficiency in syn-
thetic methodology, results of which are disclosed herein.[8]
In the view that silver(I) salts, such as silver acetate, have
been used for converting adamantyl halides, e.g. 5, to the
corresponding acetates[9] 6, and that silver(I) acetylides of
type 7 react readily with methyl iodide to give methylated
acetylenes like 8[10] (Scheme 1), we reasoned that silver(I)
acetylides, e.g. 7, may well facilitate alkynylation at a
bridgehead position, affording products of type 9.
The reaction of silver(I) phenylacetylide (11) with 1-bro-
moadamantane (10) was investigated in the first instance.
The choice of solvent was found to be crucial as most sil-
ver(I) acetylides are notoriously insoluble in most organic
solvents and require strongly coordinating aprotic solvents,
such as, dimethyl sulfoxide (DMSO), hexamethylphos-
phoramide (HMPA) or pyridine for reaction. The use of
either DMSO or HMPA as the solvent afforded gross mix-
tures, whereas pyridine at 100 °C gave, after 24–48 h, low
yields of the desired product[17] 12 (Scheme 1). Substituting
1-bromoadamantane (10) with 1-iodoadamantane (13) in-
creased the yield to 35%, although it was obvious that
many side reactions involving pyridine were occurring.
Attempts to prevent these side reactions with related sol-
vents, such as lutidine and picoline, failed to improve the
outcome. The use of triethylamine and tetramethylethyl-
enediamine as the solvent gave no product, but N-methyl-
morpholine (NMM) increased the yield of 12 to 68%. It
should be noted that triphenylphosphane–silver(I) phenyl-
acetylide[18] gave no improvement, and copper(I) ace-
tylide[19] afforded less than 5% of the product 12. Gold(I)
phenylacetylide was also considered, however, gold sub-
strates do not have the desired stability as compared to
those of silver.[20]
Organosilver(I) compounds are generally considered un-
stable to air and water, and often decompose to the corre-
sponding organic dimer. Silver(I) acetylides, however, are
an exception to this rule,[11] and are readily synthesised as
air- and water-stable solids.[12] Surprisingly, investigations
into this class are limited only to a handful of synthetic
1-Iodoadamantane (13) was subsequently subjected to a
reaction with a range of silver(I) arylacetylides utilizing the
optimised conditions (Entries 1–9, Table 1), which afforded
the corresponding adamantylalkynes in isolated yields
ranging from 20 to 68%.
[a] School of Molecular and Microbial Sciences, University of
Queensland,
Brisbane 4072, Queensland, Australia
E-mail: c.williams3@uq.edu.au
[b] School of Chemistry, University of New South Wales,
Sydney NSW 2052, Australia
Disappointingly,
silver(I)
4-bromophenylacetylide
[c] Department of Chemistry and Biochemistry, University of
Colorado,
(Table 1, Entry 4) reacted poorly, affording less than 20%
yield. Silver(I) 3-pyridylacetylide (Table 1, Entry 8) did not
Boulder, CO 80309-0215, USA
Eur. J. Org. Chem. 2007, 241–248
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
241

C. M. Williams et al.
FULL PAPER
Figure 1. Examples of an AFM tip (1), molecular rotor (2), nanoporous architecture (3) and a molecular connector (4) containing
bridgehead acetylenic bonds.
In answer to this concern, selected silver(I) arylacetylides,
including 14, were subjected to elemental analysis and pro-
duced results within 10% of theoretical (Table 4, Exp.
Sect.). This level of accuracy allows the structure of the
derivative 14 to be depicted as shown, eliminating 16 and
17 as significant contributors to the reaction (Figure 3). IR
data obtained from previously reported silver(I) acetylides
are consistent with the literature.[19,21] Therefore, consider-
ing electrophilic arylation of adamantyl halides is well
known,[22] we are inclined to propose that in the case of 14
the electron-rich aromatic ring prefers to undergo electro-
philic aromatic substitution with 1-iodoadamantane (13),
giving 18, followed by hydrogen iodide induced dear-
gentation affording 15 (Scheme 2).
Scheme 1.
Aliphatic and silylated silver(I) acetylides also react with
adamantyl iodide under these conditions (Entries 1–4,
Table 2) but much higher temperatures were required and
react, most likely due to the nitrogen donor group causing the yields were found to be lower in these cases as compared
aggregation leading to oligomerisation. Silver(I) [4-(dimeth- to the arylacetylides. In the case of the silylated acetylide
ylamino)phenyl]acetylide (14) (Table 1, Entry 9) did not ef- (Entry 4, Table 2) the resulting low yield is perhaps not sur-
fect bridgehead alkynylation but instead underwent electro- prising, as silver salts are known to deprotect silylated
philic aromatic substitution (Entry 9) affording 15 as deter- acetylenes.[23] It is not clearly understood, however, why the
mined by X-ray crystallographic analysis (Figure 2).
remaining silver(I) acetylides (Entries 1–3, Table 2) react
This unexpected result raised the question as to whether poorly in comparison to the silver(I) arylacetylides. A pos-
the [4-(dimethylamino)phenyl]acetylene had actually been sible explanation could be that at these elevated tempera-
converted into the silver(I) derivative 14. Conceivably either tures the silver(I) acetylides are undergoing deargentation
a silver nitrate complex of the acetylene (e.g. 16) or silver(I) affording the starting acetylene and not a dimer (Scheme 3)
acetylide (17) (Figure 3) could have been formed instead as increased dimer formation was not observed. Evidence
which may well have facilitated the electrophilic aromatic for this unusual deargentation process was provided in the
substitution. That is, not producing a nucleophile in the reaction of silver(I) (cyclohexenyl)acetylide (19) with ada-
case of 16 or perturbing nucleophilicity in the case of 17.
mantyl iodide (Entry 3, Table 2), which in addition to the
242
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 241–248

Direct Bridgehead Alkynylation of Bicyclic Cages
FULL PAPER
Table 1. Reaction of adamantyl iodide (13) with silver(I) arylacetyl-
ides.
Scheme 2.
desired product afforded the tetrahydronaphthalene 20. The
tetrahydronaphthalene 20 is readily obtained from the
known oligomerisation of (cyclohexenyl)acetylene[24] sug-
gesting the presence of (cyclohexenyl)acetylene in our sys-
tem. This can only occur through deargentation as no cy-
clohexenyl acetylene was present in the starting silver(I) (cy-
clohexenyl)acetylide (19) (Scheme 3).
Table 2. Reaction of adamantyl iodide with silver(I) aliphatic ace-
tylides.
[a] Reaction performed at 90 °C.
[a] Reaction conducted at 150–170 °C (pressure vessel).
Figure 2. ORTEP3 drawing of compound 15 (30% probability el-
lipsoids).
Scheme 3.
Three bicyclo[2.2.2]octane iodides were treated (Entries
1–3, Table 3) with silver(I) phenylacetylide. Only in the case
of Entry 1 (Table 3) was product formation observed. This
Figure 3. Possible complexes arising from the reaction of [4-(di-
methylamino)phenyl]acetylene and silver nitrate.
Eur. J. Org. Chem. 2007, 241–248
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
243

C. M. Williams et al.
FULL PAPER
Table 3. Reaction of bicyclic cage systems with silver(I) arylacetylides.[a]
[a] Reactions performed in refluxing N-methylmorpholine. [b] Reaction conducted at 160 °C in pyridine. [c] 1-Iodo-4-methylcarbonylbicy-
clo[2.2.2]octane was synthesised according to Adcock.[32] [d] 1,4-Diiodobicyclo[2.2.2]octane was synthesised according to Kopecky.[33] [e]
Bicyclo[3.2.1]octanes used in Entries 4 and 5 were prepared using the method of Kraus.[34] [f] Carborate anions used in Entries 6–8 were
prepared according to the method of Michl.[35] [g] After the first reaction the crude material was subjected to two repeats. [h] Reaction
mixture could not be purified by HPLC. Yield is estimated using decoupled 11B NMR spectroscopy.
is consistent with the reaction proceeding through an elec- nation of HX to give the anti-Bredt system[29] (i.e. 19) which
tron-deficient intermediate; the extent of hyperconjugative could react with the silver(I) acetylide by a Michael-type
stabilisation by the substituent at the 4-position is crucial addition[30] (Scheme 5). It should be stated, however, that
and is demonstrated in Scheme 4. This shows the canonical when anti-Bredt enones are formed they usually undergo
structures which may contribute below for a carbocation dimerisation to the cyclobutane[29,31] and this was not ob-
intermediate. The same interaction can be readily envisaged served in our case. The presence of a ketone at this position
for the equivalent radical but stabilisation would be greater may limit the extent of hyperconjugative stabilisation of an
for the carbocation. Importantly, the extent of hyperconju- electron-deficient system (such as a carbocation) as demon-
gative stabilisation in these systems has been shown to in- strated by canonical forms illustrated in Scheme 6.
crease in the order CO2Me Ͻ I Ͻ CH3 Ͻ H, initially using
19F NMR chemical shifts,[25–27] though it has only been re-
cently that quantification of some of these parameters has
been proposed.[28]
Scheme 4.
Scheme 5.
Bicyclo[3.2.1] systems were also investigated (Entries 4
and 5, Table 3), however, both substrates failed to yield
In stark contrast to the bicyclo[2.2.2] and bicyclo[3.2.1]
product and no starting material could be recovered. This systems the carborate anion (1-I-CB11H12–), which, other
was somewhat unexpected as product can arise, mechan- than containing a bridgehead position, is electronically dif-
istically speaking, either from direct reaction at the bridge- ferent from adamantane,[36] was found to undergo slow but
head [carbocation, SRN1 (see below)] or through elimi- smooth reaction with silver(I) phenylacetylide. Although,
244
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 241–248

Direct Bridgehead Alkynylation of Bicyclic Cages
FULL PAPER
nucleophilic addition, the increase in the proportion of the
substitution product suggests that the initiation of the radi-
cal process may be inhibited, resulting in reaction proceed-
ing to a greater extent through the carbocationic pathway.
(A nitrone, 2-phenyl-5,5-dimethyl-1-pyrroline 1-oxide, was
also examined, but no useful information was obtained.)
The reaction was also carried out in the presence of iron(II)
bromide (SRN1 stimulant[45,47]), which decreased the
amount of coupled product and afforded 1-bromoada-
mantane (10) (ca. 35%) presumably, from reaction of bro-
mide with the adamantyl radical. Conversely, dimethoxy-
benzene (DMB) (radical sensitiser[51]) increased the amount
of the desired product 12, while the amount of the re-
duction product stayed approximately the same.
Irrespective of the relative rates of the different processes
discussed and the proportion of the substitution product 12
that arises through each of the mechanisms, both radical
and polar processes are contributing to the outcome. This
is consistent with the previous observations that there can
be a fine balance between polar and radical pathways for
bridgehead substitutions, as exemplified by the trimethyl-
stannylation of bridgehead dihalogenated polycyclic al-
kanes.[52–56]
Scheme 6.
this was not observed for the more hindered permethylated
derivative. Disilver(I) 4-phenyldiacetylide (20) also reacted
with the carborate anion but only afforded the monosubsti-
tuted product in low yield as a mixture (Entry 8, Table 3).
Considering this result was identical to that of the ada-
mantyl iodide case (Entry 7, Table 1), that is monosubstitu-
tion, we questioned the validity of our material (20) but it
was identical in all aspects to that reported.[19] This implies
a deargentation process is occurring [discussed above
(Scheme 3)] in contrast to the possibility that 21 might be
the reactant (Figure 4).
Figure 4. Bis- and mono silver(I) phenylacetylides of (4-ethyn-
ylphenyl)acetylene.
Conclusion
Initially it was considered that the addition of silver(I)
acetylides to adamantyl halides proceeded through an SRN1
mechanism [see Scheme 7 (part in black)],[37] which has
been found to operate in the substitution of bridgehead ha-
lides.[38–44]
A novel carbon–carbon bond-forming protocol is re-
ported for direct one-step alkynylation of the adamantyl
ring system, which is also applicable to certain bicyclo-
[2.2.2]octane and carborate anions. It is our hope that this
newly developed methodology will both aid those synthesis-
ing organic based nanotechnological devices, and encour-
age others to develop new procedures for this rapidly de-
veloping field.
Experimental Section
1H and 13C NMR spectra were recorded with a Bruker AV300
(300.13 MHz; 75.47 MHz), AV400 (400.13 MHz; 100.62 MHz) and
a DRX500 (500.13 MHz; 125.77 MHz) in deuteriochloroform
(CDCl3) unless otherwise stated. Coupling constants are given in
Hz and chemical shifts are expressed as δ values in ppm. 11B shifts
were referenced to BF3·Et2O [B(OMe)3 at δ = 18.1 ppm] with an
external reference contained in a capillary within the sample tube.
High- and low-resolution EI mass spectroscopic data were ob-
tained with a KRATOS MS 25 RFA. Electrospray negative and
positive ion mass spectra were measured in methanol solution using
Scheme 7.
However, in order to gain a greater appreciation of the
mechanism, the outcome of the reaction [silver(I) phenyl-
acetylide with 1-iodoadamantane (13)] was observed
(GCMS) under conditions that are known to affect radical
pathways (i.e. photostimulation,[42,43,45–47] radical traps (e.g. a Hewlett Packard 5989 API/ES/MS instrument for carborane re-
TEMPO[48]), reversible electron acceptors [e.g. p-dinitro-
lated compounds. Microanalyses were performed by the University
of Queensland Microanalytical Service. Column chromatography
was undertaken on silica gel (Flash Silica gel 230–400 mesh), with
distilled solvents. N-Methylmorpholine was distilled from calcium
hydride under argon and stored with predried sodium hydroxide
pellets. Melting points were determined with a Fischer Johns Melt-
benzene (DNB)][44,46,48]).
Both TEMPO and DNB increased the proportion of
product (and decreased the extent of formation of the re-
duction product, adamantane) indicating a radical compo-
nent to the reaction.[49] However, both these results also
ing Point apparatus and are uncorrected. Acetylenes were pur-
support the presence of a competing silver(I)-assisted
chased from the Aldrich Chem. Co. Silver(I) acetylides were stored
carbocationic mechanism [see Scheme 7 (part in grey)].[6c,50]
in the freezer in the absence of light and generally lasted for many
As TEMPO and DNB would be anticipated to have no ef-
fect on both the heterolysis of the adamantyl halide and the (250ϫ4.6 mm, 5 m) with methanol/water (containing a 1% AcOH/
months. An HPLC system employing a reverse-phase C18 column
Eur. J. Org. Chem. 2007, 241–248
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
245

C. M. Williams et al.
FULL PAPER
0.7% Et3N buffer) as the mobile phase was used for monitoring
reactions, while larger columns of the same phase were used for
semi-preparative separations.
(10). HRMS (EI): [M]+ C23H30 calcd. 306.23475, found: 306.2345.
C23H30 (306.48): calcd. C 90.13, H 9.87; found C 90.06, H 10.12.
[(4-Bromophenyl)ethynyl]adamantane: White solid, (24 mg) 20%
1
Preparation of Silver(I) Acetylides: The method of Davis[12] was
yield; m.p. 78–80 °C. H NMR: δ = 1.70 (br. t, J = 3.0 Hz, 6 H),
1.92 (m, 6 H), 1.97 (br. s, 3 H), 7.21 (d, J = 8.6 Hz, 2 H), 7.37 (d,
used (Table 4).
J = 8.6 Hz, 2 H) ppm. 13C NMR: δ = 28.0, 30.1, 36.4, 42.7, 78.4,
99.6, 121.4, 123.1, 131.3, 133.1 ppm. Near IR (neat) ν 2907, 2851,
˜
Table 4. Microanalytical results for selected silver(I) arylacetylides.
2221, 1743, 1485, 1451, 1066, 1008, 819 cm–1. MS (EI): m/z
=(GCMS) 317 (24) [M+·], 316 (87), 315 (23), 314 (100), 259 (29),
257 (31), 222 (12), 220 (14), 193 (15), 192 (15), 191 (11), 180 (10),
179 (29), 178 (69), 167 (11), 165 (24), 152 (23), 141 (12), 139 (10),
126 (12), 115 (14), 96 (11), 94 (22), 93 (14), 91 (15), 89 (21), 82
(11), 79 (31), 79 (31), 77 (16), 44 (27), 41 (25), 39 (33). HRMS (EI):
[M]+ C18H19Br calcd. 314.0670; found: 314.0681.
Silver(I) arylacetylide
Found (%)
Calculated (%)
C
H
N
C
H
N
[4-(Dimethylamino)phenyl]acetylide 44.07 3.81 6.07 47.65 4.00 5.56
Phenylacetylide
45.67 2.34
34.61 1.50 1.56 33.34 1.19
55.97 5.52
39.22 1.61
44.84 2.92
0
45.98 2.41
–
–
–
–
–
(1,4-Diethynylphenyl)acetylide
(4-Pentylphenyl)acetylide
(2-Chlorophenyl)acetylide
(4-Methoxyphenyl)acetylide
0
0
0
55.94 5.42
39.47 1.66
45.22 2.95
[(2-Chlorophenyl)ethynyl]adamantane: Colourless crystals, (64 mg)
62% yield; m.p. 63–64 °C. 1H NMR: δ = 1.71 (br. s, 6 H), 1.98 (br.
s, 9 H), 7.13–7.16 (m, 2 H) 7.33–7.35 (m, 1 H), 7.39–7.40 (m, 1 H)
ppm. 13C NMR: δ = 28.0, 30.4, 36.4, 42.7, 76.3, 104.0, 123.9, 126.2,
Representative Procedure: For Tables 1, 2, and 3: All subsequent
reactions involving 1-iodoadamantane were performed on
0.38 mmol (100 mg) scale. Silver(I) phenylacetylide (159 mg,
0.76 mmol) was added to a solution of 1-iodoadamantane (100 mg,
0.38 mmol) in anhydrous N-methylmorpholine (3 mL) and the sus-
pension heated at reflux under argon in the dark. After 16–24 h
the solvent was removed under high vacuum; the residue diluted
with dichloromethane (ca. 3 mL) and passed through celite. The
filtrate was then washed with a solution (0.1 ) of sodium azide
(20 mL), dried (Na2SO4) and the solvents evaporated. Column
chromatography [petroleum spirit (40–60 °C)] of the crude on silica
gel gave 1-(phenylethynyl)adamantane as a white solid (60 mg,
67%), which was recrystallised from petroleum spirit (colourless
128.3, 129.0, 133.1, 135.8 ppm. Near IR (neat): ν = 2903, 2850,
˜
2226, 1509, 1452, 751 cm–1. MS (EI): m/z = 272 (39), 271 (23), 270
(100) [M+·], 227 (13), 215 (13), 213 (38), 179 (12), 178 (26), 165
(17), 115 (11), 94 (14), 93 (16), 91 (23), 86 (27), 84 (29), 80 (20), 79
(24), 77 (20), 55 (16), 51 (21), 49 (58), 44 (11), 41 (27), 40 (16), 39
(14). HRMS (EI): [M]+ C18H19Cl calcd. 270.1175, found: 270.1180.
C18H19Cl (270.80): calcd. C 79.84, H 7.07; found C 79.82, H 7.12.
[(4-Methoxyphenyl)ethynyl]adamantane: Reaction performed at
90 °C. Colourless crystals (52 mg), 51% yield; m.p. 112–114 °C. 1H
NMR: δ = 1.68–1.70 (m, 6 H), 1.92–1.93 (m, 6 H), 1.95–1.97 (m,
3 H), 3.77 (s, 3 H), 6.77 (d, J = 6.8 Hz, 2 H), 7.27 (d, J = 6.8 Hz,
2 H) ppm. 13C NMR: δ = 28.0, 30.0, 36.4, 43.0, 55.2, 79.0, 96.8,
1
needles), m.p. 82–84 °C. H NMR: δ = 1.70–1.74 (m, 6 H), 1.93–
113.7, 116.2, 132.9, 158.9 ppm. Near IR (neat): ν 2906, 2849, 2139,
˜
1604, 1508, 1452, 1244, 1087, 1026, 927, 824, 809 cm–1. MS (EI):
m/z = 267 (42), 266 (100) [M+·], 223 (8), 210 (14), 209 (61), 194 (7),
172 (10), 165 (9), 145 (6), 133 (6), 121 (7), 115 (6), 91 (9), 79 (6),
77 (6), 41 (8), 39 (5). HRMS (EI): [M]+ C19H22O calcd. 266.1671;
found: 266.1673. C19H22O (266.38): calcd. C 85.67, H 8.32; found
C 85.74, H 8.53.
1.96 (m, 6 H), 1.96–2.03 (m, 3 H), 7.22–7.29 (m, 3 H), 7.36–7.40
(m, 2 H) ppm. 13C NMR: δ = 28.0, 30.0, 36.4, 42.9, 79.3, 98.4,
124.1, 127.3, 128.1, 131.6 ppm. Near IR (neat) ν 2900, 2219, 1597,
˜
1493, 1451, 753, 695 cm–1. MS (EI): m/z = 236 (100) [M+·], 193
(10), 179 (60), 167 (7), 165 (11), 149 (9), 143 (8), 141 (7), 131 (8),
119 (5), 97 (7). HRMS (EI): [M]+ C18H20 calcd. 236.1565, found:
236.1563. C18H20 (236.35): calcd. C 91.47, H 8.53; found: C 91.41,
H 8.61.
[(4-Ethynylphenyl)ethynyl]adamantane: Pale yellow oil, (20 mg,
1
yield based on 2 equiv. 1-iodoadamantane) 40% yield. H NMR:
Warning: Silver azide is potentially explosive, although, no in-
stances occurred in our laboratories.
δ = 1.69–1.70 (m, 6 H), 1.92–1.94 (m, 6 H), 1.96–1.98 (m, 3 H),
3.10 (s, 1 H), 7.31 (d, J = 8.5 Hz, 2 H), 7.36 (d, J = 8.5 Hz, 2 H)
ppm. 13C NMR: δ = 27.9, 30.1, 36.3, 42.7, 78.3, 79.0, 83.5, 100.6,
[(4-Methylphenyl)ethynyl]adamantane: Colourless crystals, (42 mg)
44% yield; m.p. 88–89 °C. 1H NMR: δ = 1.68–1.70 (m, 6 H), 1.93–
1.94 (m, 6 H), 1.95–1.98 (m, 3 H), 2.30 (s, 3 H), 7.05 (d, J = 8.0 Hz,
2 H), 7.25 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR: δ = 21.4, 28.1,
30.0, 36.4, 42.9, 79.3, 97.6, 121.0, 128.8, 131.5, 137.2 ppm. Near
120.8, 124.7, 131.5, 131.8 ppm. Near IR (neat): ν 3206, 2907, 2853,
˜
2361, 2221, 774 cm–1. MS (EI): m/z = 261 (22), 260 (100) [M +
100], 204 (16), 203 (47), 202 (48), 189 (14), 166 (16), 165 (13), 151
(10), 139 (15), 115 (13), 91 (15). HRMS (EI): [M]+ C20H20 calcd.
260.1565; found: 260.1564.
IR (neat): ν = 2908, 2852, 2135, 1503, 1451, 805 cm–1. MS (EI):
˜
m/z = 251 (12), 250 (55) [M+·], 194 (5), 193 (22), 178 (6), 156 (6),
115 (5), 91 (6). HRMS (EI): [M]+ C19H22 calcd. M+ 250.17215,
found: 250.1718. C19H22 (250.38): calcd. C 91.14, H, 8.86; found C
91.38, H 9.11.
1-Adamantyl-2-dimethylamino-5-ethynylbenzene (15): Pale yellow
crystals, (21 mg) 20% yield; m.p. 70–71 °C. 1H NMR: δ = 1.73–
1.74 (m, 6 H), 2.03–2.05 (m, 3 H), 2.12–2.14 (m, 6 H) 2.56 (s, 6 H),
2.99 (s, 1 H), 7.26 (d, J = 8.1 Hz, 1 H), 7.31 (dd, J = 8.1, 2.0 Hz,
1 H), 7.42 (d, J = 2.0 Hz, 1 H) ppm. 13C NMR: δ = 29.2, 37.0,
37.5, 41.3, 47.2, 76.0, 84.3, 119.1, 125.4, 130.4, 131.2, 147.6, 156.5.
MS (EI): m/z = 249 (7), 240 (6), 169 (8), 168 (40), 158 (7), 156 (6),
155 (7), 144 (7), 135 (5), 115 (6), 91 (6), 79 (6), 77 (6), 41 (9) ppm.
HRMS (EI): [M]+ C20H25N calcd. 279.1987; found: 279.1989.
C20H25N (279.42): calcd. C 85.97, H 9.02, N 5.01; found: C 85.96,
H 9.14, N 4.80.
[(4-Pentylphenyl)ethynyl]adamantane: Colourless crystals, (66 mg)
1
57% yield; m.p. 71–76 °C. H NMR: δ =0.86 (t, J = 7.2 Hz, 3 H),
1.24–1.38 (m, 4 H), 1.52–1.60 (m, 2 H), 1.69–1.70 (m, 6 H), 1.93–
1.94 (m, 6 H) 1.96–1.97 (m, 3 H), 2.55 (t, J = 7.6 Hz, 2 H), 7.05
(d, J = 8.4 Hz, 2 H), 7.27 (d, J = 8.3 Hz, 2 H) ppm. 13C NMR: δ
= 14.0, 22.5, 28.0, 30.0, 31.0, 31.4, 35.7, 36.4, 42.9, 79.3, 97.6,
121.2, 128.2, 131.5, 142.3 ppm. Near IR (neat): ν = 2901, 2850,
˜
2220, 1509, 1451, 811 cm–1. MS (EI): m/z = 308 (5), 301 (39), 306
1-Adamantyl-1-hexyne: Colourless oil, (24 mg) 29% yield. 1H
(100) [M+·], 250 (19), 249 (74), 193 (6), 179 (8), 178 (7), 165 (6), NMR: δ = 0.88 (t, J = 7.2 Hz, 3 H), 1.34–1.45 (m, 4 H), 1.64–1.65
155 (7), 153 (6), 141 (5), 128 (5), 115 (7), 91 (9), 79 (9), 43 (17), 41 (m, 6 H), 1.80–1.81 (m, 6 H), 1.91 (m, 3 H), 2.14 (t, J = 7.1 Hz, 2
246
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 241–248

Direct Bridgehead Alkynylation of Bicyclic Cages
FULL PAPER
H) ppm. 13C NMR: δ = 13.6, 18.4, 21.8, 28.1, 29.4, 31.4, 36.4, 43.4,
78.8, 89.0 ppm. MS (EI): m/z = 217 (8), 216 (49) [M+·], 201 (38),
188 (6), 176 (6), 175 (26), 174 (10), 161 (5), 160 (26), 149 (6), 145
(10), 136 (10), 135 (100), 133 (7), 132 (5), 131 (15), 129 (5), 121
Water (15 mL) was added to the combined ether layers and the
diethyl ether was evaporated. The aqueous solution was filtered
and treated with excess tetraphenylphosphonium chloride (ca.
1 equiv.) to yield a white solid precipitate affording tetraphen-
(10), 119 (10), 118 (7), 117 (25), 115 (8), 107 (7), 106 (7), 105 (13), ylphosphonium 1-phenylethynylcarba-closo-dodecaborate as an
95 (8), 94 (10), 93 (18), 92 (9), 91 (35), 85 (5), 81 (17), 80 (13), 79 off-white solid (18 mg, 41%).
(27), 77 (14), 69 (6), 67 (11), 65 (6), 57 (10), 55 (14), 53 (7), 43 (9),
Note: This product was then converted into the cesium salt by ion
exchange to avoid aromatic signal overlap in the NMR spectra.
Cesium 1-Phenylethynylcarba-closo-dodecaborate: 1H NMR [Varian
41 (24), 39 (11). HRMS (EI): [M]+ C16H24 calcd. 216.1878; found:
216.1875.
1-Adamantyl-3,3-dimethyl-1-butyne: Colourless oil, (35 mg) 42%
Inova-500, (CD3)2CO]: δ = 7.24 (m, 3 H), 7.42 (m, 2 H) ppm. 11B
yield. 1H NMR: δ = 1.15 (s, 9 H), 1.63–1.65 (m, 6 H), 1.77–1.79
NMR [Varian VXR-300, (CD3)2CO]: δ = –6.8 (s, 1 B), –13.21 (s, 5
(m, 6 H), 1.88–1.90 (m, 3 H) ppm. 13C NMR: δ = 27.1, 28.2, 29.2,
B), –16.24 (s, 5 B) ppm. 13C NMR [Varian Inova-400, (CD3)2CO]:
31.6, 36.5, 43.5, 87.2, 87.5 ppm. MS (EI): m/z = 217 (6), 216 (28)
δ = 68.2, 78.6, 83.6, 122.6, 128.8, 129.1, 132.1 ppm. Near IR (KBr
[M+·], 202 (17), 201 (100), 173 (7), 160 (5), 159 (22), 145 (24), 143
pellet): ν 3010, 2945, 2890, 2850, 2250, 1410, 1375, 1292, 908 cm–1.
˜
(74), 121 (19), 119 (18), 117 (23), 115 (16), 109 (7), 108 (8), 107
(23), 106 (7), 105 (33), 103 (7), 95 (15), 94 (10), 93 (35), 92 (11), 91
(66), 81 (20), 80 (10), 79 (57), 63 (6), 57 (14), 55 (25), 53 (23),
52 (5), 51 (12). HRMS (EI): [M]+ C16H24 calcd. 216.1878; found:
216.1878.
HRMS (ESI) [M–] calcd. 245.2275, found 245.2289.
Cesium [(4-Ethynylphenyl)ethynyl]carba-closo-dodecaborate: This
product could not be purified from the starting material (1-I-
CB11H11– Cs+) and the yield is estimated at Ͻ10%. Reported spec-
troscopic data have had starting material resonances removed. 11B
NMR [Bruker AV400, (CD3)2CO]: δ = –6.7 (s, 1 B), –13.2 (s, 5
B), –16.3 (s, 5 B) ppm. HRMS (ESI) [M–] calcd. 269.2276; found:
269.2255.
1-Adamantyl-2-(cyclohex-1-enyl)ethyne: Pale yellow oil, (23 mg)
1
25% yield. H NMR: δ = 1.50–1.62 (m, 4 H), 1.65–1.67 (m, 6 H),
1.83–1.85 (m, 6 H), 1.91–1.93 (m, 3 H), 2.02–2.08 (m, 4 H), 5.97–
5.99 (m, 1 H) ppm. 13C NMR: δ = 21.6, 22.4, 25.6, 28.1, 29.8, 29.8,
X-ray Crystallography: Crystallographic data were collected with
an Enraf–Nonius CAD4 diffractometer with graphite-monochro-
matized Mo-Kα radiation, λ = 0.71073 Å operating in the ω-2θ scan
mode. Data reduction and corrections for decay and absorption
were performed with the WINGX package.[58] Structures were
solved by direct methods with SHELXS and refined by full-matrix
refinement on F2 with SHELXL.[59] The molecular structure dia-
gram was produced with the program ORTEP3.[60]
36.4, 43.1, 80.9, 95.7, 120.9, 133.2 ppm. Near IR (neat) ν 2908,
˜
2852, 2206, 1450, 773 cm–1. MS (EI): m/z = 241 (8), 240 (38) [M+·],
212 (8), 183 (7), 141 (5), 135 (24), 129 (7), 128 (5), 115 (6), 105 (7),
93 (6), 91 (12), 79 (10), 77 (8), 67 (5), 55(6), 41 (10), 38 (7), 36 (24).
HRMS (EI): [M]+ C18H24 calcd. 240.1878; found: 240.1879.
1-Adamantyl-2-(triisopropylsilyl)ethyne: Opaque oil, (30 mg) 25%
yield. 1H NMR: δ = 0.96–1.04 (m, 3 H), 1.02 (d, J = 7.0 Hz, 18
H), 1.65–1.66 (m, 6 H), 1.85–1.86 (m, 6 H), 1.89–1.93 (m, 3 H)
ppm. 13C NMR (C6D6): δ = 11.7, 19.1, 28.4, 30.8, 36.7, 43.5, 78.0,
118.8 ppm. MS (EI): m/z = 316 (1) [M+·], 274 (9), 273 (38), 203
(11), 74 (23). HRMS (EI): [M]+ C21H36Si calcd. 316.2586; found:
316.2583.
CCDC-615077 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
1-Adamantyl-2-dimethylamino-5-ethynylbenzene (15): C20H25N, M
= 279.41, triclinic, space group P1, a = 10.413(4), b = 11.300(2), c
4-Methyl-1-(2-phenylethynyl)bicyclo[2.2.2]octane: 1-Iodo-4-methyl-
bicyclo[2.2.2]octane[57] (100 mg, 0.4 mmol) and silver(I) phenylace-
tylide (250 mg, 1.2 mmol) were dissolved in anhydrous pyridine
(4 mL) under argon. The mixture was heated at 150 °C in the dark
for 24 h in a pressure vessel. On cooling the solvent was removed
in vacuo, the residue dissolved in dichloromethane, and filtered
through a pad of celite. The solvent was removed and the residue
purified by silica gel column chromatography (petroleum spirits)
affording the title compound as a white solid, (28 mg) 31% yield.
M.p. 56–57 °C 1H NMR (300 MHz, CDCl3): δ = 0.77 (s, 3 H),
1.36–1.41 (m, 6 H), 1.78–1.83 (m, 6 H), 7.21–7.25 (m, 3 H), 7.33–
7.36 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 27.0, 27.3,
28.2, 32.7, 32.9, 80.3, 97.5, 124.1, 127.3, 128.1, 131.6 ppm. Near
¯
= 22.497(5) Å, α = 78.81(2), β = 79.50(3), γ = 74.69(2)°, V =
2481(1) Å3, Z = 6, Dcalcd. = 1.122 gcm–3, T = 293 K, µ =
0.064 mm–1,
F(000)
=
912,
colourless
prism
(0.60ϫ0.40ϫ0.33 mm); total reflections 9133, unique reflections
8618 (Rint = 0.0266). Final refinement: data/restraints/parameters
8618/0/568, goodness-of-fit on F2 = 1.01, R1 = 0.0516 [for 3989
obs. reflns IϾ2σ(I)], wR2 = 0.1667 (all data).
Acknowledgments
The authors thank The University of Queensland and the US
National Science Foundation (CHE-0446688) for financial sup-
port, A/Prof. W. Adcock for 1-iodo-4-methylbicyclo[2.2.2]octane,
Prof. D. StC. Black for a sample of 5,5-dimethyl-2-phenyl-1-pyrro-
line 1-oxide, and Brett Schwartz, Heiko Schill and Achim Porzelle
for cover picture preparation assistance.
IR (neat) ν 2941, 2901, 2856, 2228, 1596, 1454, 754, 692 cm–1. MS
˜
(EI): m/z = 224 (56) [M+], 196 (10), 195 (55), 167 (11), 165 (13),
155 (19), 154 (100), 153 (41), 152 (12), 126 (10), 115 (21), 77 (11).
HRMS (EI): [M]+ C17H20 calcd. 224.1565; found: 224.1571.
Representative Procedure for Carborate Anions: Silver(I) phenylace-
–
tylide (32 mg, 0.15 mmol) was added to a solution of 1-I-CB11H11
Cs+ (30 mg, 0.075 mmol) in anhydrous N-methylmorpholine
(1.5 mL) and the suspension was heated at reflux under argon in
the dark. After 16 h the solvent was removed under high vacuum,
the residue diluted with dichloromethane (ca. 3 mL) and passed
through celite. The solvent was removed under high vacuum and
the above procedure was repeated twice. The crude solid was puri-
fied by reverse phase HPLC. The white residue was then dissolved
in 4  HCl (25 mL) and extracted with diethyl ether (3ϫ15 mL).
[1] A. V. Rukavishnikov, A. Phadke, M. D. Lee, D. H. LaMunyon,
P. A. Petukhov, J. F. W. Keana, Tetrahedron Lett. 1999, 40,
6353.
[2] T. R. Kelly, Acc. Chem. Res. 2001, 34, 514.
[3] T. Müller, J. Hulliger, W. Seichter, E. Weber, T. Weber, M.
Wübbenhorst, Chem. Eur. J. 2000, 6, 54.
[4] P. F. H. Schwab, B. C. Noll, J. Michl, J. Org. Chem. 2002, 67,
5476.
Eur. J. Org. Chem. 2007, 241–248
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
247

C. M. Williams et al.
P. M. Warner, Chem. Rev. 1989, 89, 1067.
Silver(I) acetylides are known to undergo 1,4-conjugate ad-
dition, see T. Kauffmann, A. Hülsdünker, D. Menges, H. Nien-
aber, S. Robbe, D. Scherler, J. Schrickel, D. Wingbermühle, Tet-
rahedron Lett. 1990, 31, 1553.
FULL PAPER
[5] T. G. Archibald, A. A. Malik, K. Baum, M. R. Unroe, Macro-
molecules 1991, 24, 5261–5265.
[6] a) G. Capozzi, R. Ottaná, G. Romeo, F. Marcuzzi, Gazz. Chim.
Ital. 1985, 115, 311–314 and references cited therein; b) J. Xi-
ang, P. L. Fuchs, Tetrahedron Lett. 1998, 39, 8597–8600 and
references cited therein; c) E.-i. Negishi, S. Baba, J. Am. Chem.
Soc. 1975, 97, 7385–7387.
[29]
[30]
[31]
H. O. House, R. J. Outcalt, M. D. Cliffton, J. Org. Chem. 1982,
47, 2413–2419.
[7] See, for example,Q. B. Broxterman, H. Hogeveen, R. F.
Kingma, Tetrahedron Lett. 1986, 27, 1055; M. A. Fox, T. E.
Baines, D. Albesa-Jové, J. A. K. Howard, P. J. Low, J. Or-
ganomet. Chem. 2006, 691, 3889–3894.
[8] Part of this work has already appeared in communication form,
see R. H. Pouwer, C. M. Williams, A. L. Raine, J. B. Harper,
Org. Lett. 2005, 7, 1323–1325.
[32]
[33]
[34]
[35]
W. Adcock, G. B. Kok, J. Org. Chem. 1985, 50, 1079–1087.
J. Kopecky, J. Smejkal, Tetrahedron Lett. 1967, 40, 3889–3891.
G. A. Kraus, Q. Su, Synlett 1994, 237.
K. Vyakaranam, Z. Janousek, L. Eriksson, J. Michl, Heteroat.
Chem. 2006, 17, 217–223.
B. T. King, I. Zharov, J. Michl, Chem. Innov. 2001, 31, 23.
R. A. Rossi, A. B. Pierini, A. B. Peñéñory, Chem. Rev. 2003,
103, 71–167.
M. Ohno, K. Shimizu, K. Ishizaki, T. Sasaki, S. Eguchi, J. Org.
Chem. 1988, 53, 729–733.
[36]
[37]
[9] H. Duddeck, M. Spitzer, G. Bolte, Liebigs Ann. Chem. 1985,
545–554.
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[10] M. E. Isabelle, L. C. Leitch, Can. J. Chem. 1958, 36, 440–448.
[11] a) G. Bähr, P. Burba,, in Houben-Weyl Methoden der Organis-
che Chemie, (Ed.: E. Müller), Georg Thieme Verlag, Stuttgart,
1970, vol. 13/1, p. 774; b) G. Van Koten, J. G. Noltes, in Com-
prehensive Organometallic Chemistry, (Eds.: G. Wilkinson,
R. G. A. Stone, E. W. Abel), 1982, vol. 2, p. 709; c) Comprehen-
sive Organometallic Chemistry II, 1982–1994, vol 3, p. 71; d)
Gmelin Handbuch, der Anorganischen Chemie, 8. Ed, part B5.
[12] R. B. Davis, D. H. Scheiber, J. Am. Chem. Soc. 1956, 78, 1675–
1678.
G. Molle, J. E. Dubois, P. Bauer, Can. J. Chem. 1987, 65, 2428–
2433.
E. Osawa, Z. Majerski, P. v. R. Schleyer, J. Org. Chem. 1971,
36, 205–207.
J. E. Baldwin, R. M. Adlington, D. J. Birch, J. A. Crawford,
J. B. Sweeney, J. Chem. Soc., Chem. Commun. 1986, 1339–1340.
S. M. Palacios, A. N. Santiago, R. A. Rossi, J. Org. Chem.
1984, 49, 4609–4613.
G. L. Borosky, A. B. Pierini, R. A. Rossi, J. Org. Chem. 1990,
55, 3705–3707.
P. Camps, A. E. Lukach, R. A. Rossi, J. Org. Chem. 2001, 66,
5366–5373.
[13] S. P. Shahi, K. Koide, Angew. Chem. Int. Ed. 2004, 43, 2525–
2527.
[14] a) J. Inanaga, T. Katsuki, S. Takimoto, S. Ouchida, K. Inoue,
A. Nakano, N. Okukado, M. Yamaguchi, Chem. Lett. 1979,
1021–1024; b) L. V. Yerino, M. E. Osborn, P. S. Mariano, Tet-
rahedron 1982, 38, 1579–1591.
[45] M. A. Nazareno, R. A. Rossi, J. Org. Chem. 1996, 61, 1645–
1649.
[15] a) N. Nishiwaki, S. Minakata, M. Komatsu, Y. Ohshiro, Chem.
Lett. 1989, 773–776; b) T. Agawa, S. I. Miller, J. Am. Chem.
Soc. 1961, 83, 449–453.
[16] a) F. G. De Las Heras, S. Y.-K. Tam, R. S. Klein, J. J. Fox, J.
Org. Chem. 1976, 41, 84–90; b) H. P. Albrecht, D. B. Repke,
J. G. Moffatt, J. Org. Chem. 1974, 39, 2176–2182.
[17] A. L. Raine, C. M. Williams, P. V. Bernhardt, Acta Crystallogr.
Sect. E 2002, 58, o1439–o1440.
[46] M. B. Maquieira, A. B. Peñéñory, R. A. Rossi, J. Org. Chem.
2002, 67, 1012–1015.
[47] M. C. Murguia, R. A. Rossi, Tetrahedron Lett. 1997, 38, 1355–
1358.
[48] A. B. Peñéñory, R. A. Rossi, Gazz. Chim. Ital. 1995, 125, 605–
609.
[49] Mechanistic studies were evaluated using GC/MS on the reac-
tion of silver(I) phenylacetylide (50 mg, 2 equiv.) and 1-iodoad-
amantane (30 mg, 1 equiv.) in N-methylmorpholine (1.0 mL) at
116 °C under argon for 16 h.
[18] M. I. Bruce, M. G. Humphrey, J. G. Matisons, S. K. Roy, A. G.
Swincer, Aust. J. Chem. 1984, 37, 1955–1961.
[19] a) E. C. Royer, M. C. Barral, V. Moreno, A. Santos, J. Inorg.
Nucl. Chem. 1981, 43, 705–709; b) V. T. Aleksanyan, I. A. Gar-
buzova, I. R. Gol’ding, A. M. Sladkov, Spectrochim. Acta 1975,
31A, 517–524.
[20] M. I. Bruce, E. Horn, J. G. Matisons, M. R. Snow, Aust. J.
Chem. 1984, 37, 1163–1170.
[21] O. M. Salah, M. I. Bruce, Aust. J. Chem. 1977, 30, 2639–2646.
[22] S. Bräse, B. Waegell, A. de Meijere, Synthesis 1998, 148–152,
and references cited therein.
[50] Y. Kitano, K. Chiba, M. Tada, Synthesis 2001, 437.
[51] T. Mori, M. Takamoto, T. Wada, Y. Inoue, Helv. Chim. Acta
2001, 84, 2693.
[52] W. Adcock, H. Gangodawila, J. Org. Chem. 1989, 54, 6040–
6047.
[53] W. Adcock, C. I. Clark, J. Org. Chem. 1993, 58, 7341–7349.
[54] W. Adcock, C. I. Clark, J. Org. Chem. 1995, 60, 723–724.
[55] A. N. Santiago, C. A. Toledo, R. A. Rossi, J. Org. Chem. 2002,
67, 2494–2500.
[23] A. Carpita, L. Mannocci, R. Rossi, Eur. J. Org. Chem. 2005,
[56] W. Adcock, C. I. Clark, N. A. Trout, J. Org. Chem. 2001, 66,
1859–1864.
3362–3371.
[24] J. Yang, J. G. Verkada, Organometallics 2000, 19, 893–900.
[25] W. Adcock, V. S. Iyar, J. Org. Chem. 1988, 53, 5259–5266.
[26] W. Adcock, A. N. Abeywickrema, J. Org. Chem. 1982, 47,
2957.
[57] J. Kepecky, J. Smejkal, Collect. Czech. Chem. Commun. 1980,
45, 2965–2970.
[58] L. J. Farrugia, J. Appl. Crystallogr. 1999, 32, 837.
[59] G. M. Sheldrick, SHELX97, Programs for Crystal Structure
Analysis, University of Göttingen, Germany, 1997.
[60] L. J. Farrugia, J. Appl. Crystallogr. 1997, 30, 565.
Received: August 11, 2006
[27] W. Adcock, A. N. Abeywickrema, J. Org. Chem. 1984, 49,
1387.
[28] D. J. Lawes, R. Darwish, T. Clark, J. B. Harper, G. E. Ball, An-
gew. Chem. Int. Ed. 2006, 45, 4486–4490.
Published Online: October 23, 2006
248
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 241–248