Synthesis and ring-opening reaction of novel 1,3-dehydroadamantanes possessing phenyl and alkoxyl substituents

Article abstract of DOI:10.1016/j.tet.2013.02.042

A series of novel 1,3-dehydroadamantanes (DHAs) possessing phenyl or alkoxyl substituents, such as 5-phenyl-1,3-dehydroadamantane, 5-butyl-7-phenyl-1,3-dehydroadamantane, 5-methoxy-1,3-dehydroadamantane, 5-butoxy-1,3-dehydroadamantane, 5-butyl-7-methoxy-1,3-dehydroadamantane, and 5-butoxy-7-butyl-1,3-dehydroadamantane were synthesized and subjected to react with acidic compounds. 1,3-Dibromoadamantanes carrying phenyl or alkoxyl substituents were converted into the corresponding DHAs via the intramolecular Wurtz-type coupling reactions with lithium metal in THF in 23-62% yields. Ring-opening reactions of DHAs readily occurred with acetic acid or methanol under acidic conditions to form various 1-acetoxyadamantanes or 1-methoxyadamantanes containing phenyl or alkoxyl groups. The resulting 1-butyl-3-methoxy-5-phenyladamantane, 1-acetoxy-3-butyl-5-phenyladamantane, 1-acetoxy-3-butyl-5-methoxyadamantane, 1-acetoxy-3-butoxy-5-butyladamantane, and 1-butoxy-3-butyl-5-methoxyadamantane possessed stereogenic center. The high reactivity of the inverted 1,3-carbon-carbon σ-bond in DHAs toward the acidic compounds indicated the high electron density, which was supported by the sp² character of cyclopropane rings in DHAs estimated by J _C-H coupling constants in the ¹³C NMR analyzes.

Full text of DOI:10.1016/j.tet.2013.02.042

Tetrahedron 69 (2013) 3238e3248
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and ring-opening reaction of novel 1,3-
dehydroadamantanes possessing phenyl and alkoxyl substituents
*
Sotaro Inomata, Yusuke Harada, Shin-ichi Matsuoka, Takashi Ishizone
Department of Organic and Polymeric Materials, Tokyo Institute of Technology, 2-12-1-S1-13 Ohokayama, Meguro-ku, Tokyo 152-8552, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel 1,3-dehydroadamantanes (DHAs) possessing phenyl or alkoxyl substituents, such as 5-
phenyl-1,3-dehydroadamantane, 5-butyl-7-phenyl-1,3-dehydroadamantane, 5-methoxy-1,3-dehydro-
adamantane, 5-butoxy-1,3-dehydroadamantane, 5-butyl-7-methoxy-1,3-dehydroadamantane, and 5-
butoxy-7-butyl-1,3-dehydroadamantane were synthesized and subjected to react with acidic com-
pounds. 1,3-Dibromoadamantanes carrying phenyl or alkoxyl substituents were converted into the corre-
sponding DHAs via the intramolecular Wurtz-type coupling reactions with lithium metal in THF in 23e62%
yields. Ring-opening reactions of DHAs readily occurred with acetic acid or methanol under acidic condi-
tions to form various 1-acetoxyadamantanes or 1-methoxyadamantanes containing phenyl or alkoxyl
groups. The resulting 1-butyl-3-methoxy-5-phenyladamantane, 1-acetoxy-3-butyl-5-phenyladamantane,
1-acetoxy-3-butyl-5-methoxyadamantane, 1-acetoxy-3-butoxy-5-butyladamantane, and 1-butoxy-3-
butyl-5-methoxyadamantane possessed stereogenic center. The high reactivity of the inverted 1,3-
Received 11 December 2012
Received in revised form 9 February 2013
Accepted 12 February 2013
Available online 19 February 2013
Keywords:
1,3-Dehydroadamantanes
5-Phenyl-1,3-dehydroadamantane
5-Methoxy-1,3-dehydroadamantane
1,3-Dibromoadamantanes
1-Acetoxyadamantanes
1-Methoxyadamantanes
Ring-opening reaction
carbonecarbon s-bond in DHAs toward the acidic compounds indicated the high electron density, which
was supported by the sp2 character of cyclopropane rings in DHAs estimated by JCeH coupling constants in
the 13C NMR analyzes.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
introduction of a bulky and rigid adamantane-1,3-diyl framework
in the main chain. These clearly indicate that 1a can be positioned
as an attractive cyclic monomer or a rigid building unit to affect the
thermal property or solubility of resulting polymers.
1,3-Dehydroadamantane (1a)1,2 is a typical highly strained
[3.3.1]propellane3,4 derivative and shows high reactivity derived
from inverted tetrahedral geometry at a bridgehead carbon similar
to other propellane derivatives,5 such as [1.1.1]-6 and [2.2.2]pro-
Although several 1,3-dehydroadamantanes (DHAs) possessing
alkyl substituents, such as 5-butyl (1b),9 5,7-dimethyl (1c),12 and
5,7-dibutyl (1d) groups10 have been synthesized from the corre-
sponding 1,3-dibromoadamantanes (3bed) (Scheme 2), the in-
troduced substituents are rather limited due to the high reactivity
of the parent DHA frameworks and the difficulty of their synthetic
pathways. 5-Bromo-1,3-dehydroadamantane (4) was produced in
situ via the debromination of 1,3,5-tribromoadamantane with n-
BuLi in Et2O in the presence of hexamethylphosphoric triamide
(HMPA), but attempts at isolation were not successful (Scheme 3).13
Pincock reported that 4 could be converted into 5-hydroxy- (5), 5-
methoxy- (13c), and 5-cyano-1,3-dehydroadamantane (6) by
treatment with hydroxide, methoxide, and cyanide, respectively.13
The resultant DHAs carrying hydroxyl and methoxyl groups, 5
and 13c, could not be isolated but easily decomposed in situ to
afford ring-opening products due to their inherent instabilities,
while a nitrile, 6, was successfully isolated and showed the usual
stability.13,14 On the other hand, alkyl-substituted DHAs, such as 1b
and 1d show the usual stability and ring-opening polymer-
izability,9,10 similar to the case of 1a. Thus, the reactivity and in-
herent stability of DHAs are largely affected by the introduced
pellanes.7 In fact, the inverted 1,3-carbonecarbon
s-bond of 1a
readily undergoes free-radical and electrophilic ring-opening re-
actions with oxygen, bromine, and sulfuric acid to form 1,3-
disubstituted adamantanes (Scheme 1).1,2,8 It is also reported that
a thermally stable insoluble polymeric product formed by heating
1a at 160 ꢀC.2 Reactions of 1a with a catalytic amount of tri-
fluoromethanesulfonic acid (TfOH) or
a,a
0-azobisisobutyronitrile
(AIBN) gave insoluble poly(1,3-adamantane)s, while no reaction of
1a occurred with nucleophilic reagents, such as n-butyllithium
(n-BuLi) or phenylmagnesium chloride.9,10 Thus, the high electron
density of 1a and the ring-opening polymerizability under cationic
and radical conditions are clearly demonstrated. More in-
terestingly, 1a readily underwent spontaneous copolymerization
with electron-deficient monomers, such as acrylonitrile or methyl
acrylate to give soluble copolymers with predominantly alternating
sequences.11 The copolymers derived from 1a showed high thermal
stability and high glass transition temperature (Tg) due to the
* Corresponding author. E-mail address: tishizon@polymer.titech.ac.jp (T. Ishizone).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.02.042

S. Inomata et al. / Tetrahedron 69 (2013) 3238e3248
3239
Scheme 1. Ring-opening reactions of 1a.
Scheme 2. Synthesis of alkyl-substituted DHAs.
Scheme 3. Synthesis and reaction of 5-bromo-1,3-dehydroadamantane (4) reported by Pincock.13
substituents and are of great interest from the viewpoints of or-
ganic chemistry and polymer chemistry.
sharp contrast to the previous literature.13 The substituent effect
observed in the 13C NMR spectra of DHAs is also discussed. The ring-
opening reactions of these DHAs with MeOH or AcOH are in-
vestigated to form the corresponding 1-methoxyadamantanes or 1-
acetoxyadamantanes. The observed reactivity should be useful to
predict the ring-opening polymerizability of these DHAs.
In order to synthesize novel DHAs, corresponding 1,3-
dibromoadamantanes are usually required as the starting mate-
rials for a lithium-mediated intramolecular Wurtz coupling reaction
to form an internal 1,3-carbonecarbon s
-bond.1,2,13,15 There are two
strong requirements in the two-stage synthetic routes of DHAs. One
is that the substituents on adamantyl skeletons should tolerate
bromination reactions, and the other is that the substituents should
be stable in the presence of excess lithium metal even after cycli-
zation. In this paper, we have developed certain synthetic pathways
for a series of novel DHAs carrying phenyl and alkoxyl substituents,
and their normal stability is demonstrated. In particular, the sta-
bility of isolated 5-methoxy-1,3-dehydroadamantane (13c) is in
2. Results and discussion
2.1. Synthesis of 1,3-dibromoadamantanes
According to the synthetic procedure reported by Eguchi,16 we
synthesized 1-phenyladamantane (8a)17 and 1-butyl-3-phenyl-
adamantane (8b) via the coupling reaction of 1-bromoadamantane

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S. Inomata et al. / Tetrahedron 69 (2013) 3238e3248
(7a) and 1-bromo-3-butyladamantane (7b) with phenylmagnesium
bromide in CH2Cl2 in 92 and 83% yields (Scheme 4). On the other
hand, 1-methoxyadamantane (9a)18 and 1-butoxyadamantane
(9c)19 were synthesized by the reactions of 7a and the sodium salt
of MeOH or 1-butanol in 89 and 85% yield, respectively (Scheme 5).
Furthermore, similar substitution reactions of 1-bromo-3-butyla-
damantane (7b) and sodium methoxide or sodium 1-butoxide
quantitatively gave the corresponding 1-adamantyl ethers, such
as 1-butyl-3-methoxyadamantane (9b, 99%) and 1-butoxy-3-
butyladamantane (9d, 95%).
Therefore, we attempted a novel bromination effective for hy-
drocarbons, including cage compounds, such as cubane and ada-
mantanes, under phase transfer reaction conditions.20,21 This reaction
proceeded in a radical mechanism, and the regioselective bromina-
tion of adamantanes carrying phenyl and alkoxyl groups was realized
to afford corresponding 1-bromoadamantanes at the bridgehead
carbon by keeping the functional groups intact.21 Interestingly, the
formation of 1,3-dibromoadamantanes was also mentioned after
a prolonged reaction in addition to 1-bromoadamantanes, although
isolation of 1,3-dibromoadamantanes was not attempted.
At first, the bromination of 8a was performed with an excess
amount of CBr4 (ca. 4 equiv) in a mixture of CH2Cl2 and aqueous
NaOH (50 wt %) in the presence of tetrabutylammonium bromide
(10 mol %) at 40 ꢀC, as shown in Scheme 8. The reaction mixture
formed a viscous brownish suspension with vigorous stirring. We
monitored the reaction by GLC measurement; 8a was very slowly
consumed and the formation of monobromide and a desired
dibromide (11a) was alternatively observed. After 26 days, the
starting material, 8a, was almost consumed, the ratio of mono-
bromide (1-bromo-3-phenyladamantane) and 11a reached 38: 62,
and the reaction was quenched.22 After removal of residual CBr4 by
sublimation from the mixture, we successfully isolated 11a in 28%
yield by the column chromatography and recrystallization. Dibro-
mination of 8b was also achieved to give 11b in 21% isolated yield
according to the similar procedure.23
Scheme 4. Synthesis of 8a and 8b.
Scheme 5. Synthesis of 9a, 9b, 9c, and 9d.
Next, we examined the bromination of adamantane derivatives
to produce 1,3-dibromoadamantanes, precursors for DHAs. How-
ever, the bromination of 8a with bromine in carbon tetrachloride
gave a para-substituted derivative, 1-(4-bromophenyl)adamantane
(10),17 in quantitative yield (Scheme 6). Mono-bromination exclu-
sively occurred on the phenyl ring in regioselective fashion prior to
bromination on the adamantane ring. In the case of 9c, 7a was
quantitatively recovered from the reaction mixture, and no 1H NMR
signal of a butoxyl group was detected in the product (Scheme 7).
Apparently, a substitution reaction of the butoxyl group on 9c with
a bromo substituent took place via the cleavage of 1-adamantyl
ether under acidic conditions.
Scheme 8. Dibromination of phenyladamantanes.
In the cases of alkoxyadamantanes, 9aed, similar radical bro-
minations were conducted in a suspension of fluorobenzene and
water at 85 ꢀC (Scheme 9). After 5e9 days, four desired new 1,3-
dibromoadamantane-carrying alkoxyl groups, 12aed, were ob-
tained in 5e24 % isolated yields. The rate of reactions using fluo-
robenzene was still slow but much faster than that using CH2Cl2. In
fact,11a and 11b were obtained in 36% and 21% isolated yield after 2
or 5 days reactions with fluorobenzene, whereas 26 and 22 days
were required to attain the same conversions using CH2Cl2.
Scheme 6. Reaction of 8a with bromine.
Scheme 9. Dibromination of alkoxyadamantanes.
Whereas the yield was rather low and a skillful technique, such
as repeating column chromatography and vacuum distillation was
often necessary for the isolation procedure, we successfully ob-
tained new 1,3-dibromo-5-phenyl- or 1,3-dibromo-5-alkoxy-
substituted adamantanes after the effective bromination pro-
cedure.22 Both the observed tolerance to functional groups and the
Scheme 7. Reaction of 9c with bromine.

S. Inomata et al. / Tetrahedron 69 (2013) 3238e3248
3241
potential of multibromination played important roles in order to
introduce two bromo substituents on the framework of phenyl-
and alkoxyl-substituted adamantanes.
at 51.0 ppm. This means that the resulting 13c certainly maintains
its DHA framework even after vacuum distillation at around 80 ꢀC,
whereas the synthetic route is different from the previous report.13
Similarly, we confirmed that the 13C NMR spectrum of butoxy-
substituted 13e showed eleven carbon signals derived from seven
signals for the DHA framework and four signals for the butoxyl side
chain. Importantly, these substantiate the fact that a series of DHAs
carrying alkoxyl groups stably exist in a C6D6 solution without
decomposition, contrary to the previous report.13
We then compared the substituent effect in the DHA framework
from the viewpoint of electronic environment, which will reflect
the reactivity of DHAs. Table 1 summarizes the selected 13C NMR
chemical shifts and JCeH coupling constants of a series of DHAs. We
first focused on the C1, C2, and C3 carbons in DHAs, which con-
stitute the highly strained cyclopropane ring. In the cases of mono-
substituted DHAs, carbon signals for C1, C2, and C3 were observed
in a highfield region compared with non-substituted 1a. In par-
ticular, those 13C NMR signals for alkoxyl-substituted DHAs (13c
and 13e) significantly shifted to the highfield region (ca. 7.0 ppm for
C1 and C3, and ca. 5.0 ppm for C2) compared with 1a. This indicates
that 5-alkoxyl substituents, such as methoxyl and butoxyl groups
certainly affect the electron density of the strained cyclopropane
2.2. Synthesis of DHAs by intramolecular lithium-mediated
coupling reactions
We then converted novel 1,3-dibromoadamantanes (11a, 11b,
and 12aed) into the corresponding DHAs (13aef) by treatment
with lithium in THF under argon at room temperature (Scheme 10),
according to our previous reports.9,10 The surface of the lithium
showed a metallic luster and the reaction mixture turned black as
the reaction proceeded. In most cases, complete consumption of
the starting 1,3-dibromoadamantanes was confirmed within 24 h
by GLC measurement, and the resulting suspensions were trans-
ferred to an all-glass apparatus with break-seals. Repeated vacuum
distillation of the mixture was performed in order to remove THF
and lithium bromide from the DHAs. 13aef were successfully ob-
tained in 23e62% yields regardless of the differences in the in-
troduced substituents.24 The resulting DHAs were diluted with
CH2Cl2 or n-heptane for a subsequent ring-opening reaction or with
C6D6 for NMR measurement. The resulting DHAs were satisfactorily
stable for at least several years without any decomposition or po-
lymerization in C6D6 in a sealed tube, while they spontaneously
reacted with oxygen to form the polymeric products containing
peroxide linkages, as previously reported for 1a.1,2 Therefore, great
care is necessary to treat DHAs under an argon atmosphere or high-
vacuum conditions to prevent contact with oxygen. It is noteworthy
that 5-methoxy-1,3-dehydroadamantane (13c) can be isolated, al-
though the cleavage of the DHA framework of 13c was suggested in
the previous report (Scheme 3).13 We thus demonstrated that the
intramolecular Wurtz-type coupling reactions of 11a, 11b, and
12aed were induced with lithium to form inverted CeC linkage in
DHAs possessing various substituents. Phenyl and alkoxyl sub-
stituents and the frameworks of DHAs were intact during the re-
action using lithium metal, similar to the alkyl-substituted
derivatives.
ring apart from the alkoxyl substituents through the
s-bond
framework without -conjugation. Similar remote electronic in-
p
teraction is observed in the unusual stabilization of the bridgehead
1-adamantyl cation by the hyperconjugation effect through the
adamantane skeleton.25 Similarly, 13C NMR chemical shifts of 5,7-
disubstituted DHAs further tended to shift to a higher field region
than the corresponding mono-substituted DHAs.
Table 1
13C NMR chemical shifts and JCeH constants of DHAs
Compound
R
R0
Position (ppm)a
JCeHb Hz
sc
%
1,3
2
5
7
1a
1b
H
H
H
H
H
37.3
36.0
35.4
30.3
30.4
34.8
34.3
28.9
29.1
49.6
48.0
47.9
44.2
44.2
46.5
46.4
42.7
42.7
54.5
64.3
67.4
91.6
91.3
63.5
66.7
91.2
90.9
54.5
53.5
53.8
52.9
52.9
63.5
63.9
63.9
64.0
156.2
155.3
155.9
160.2
160.6
155.3
155.7
155.1
154.0
31.2
31.1
31.2
32.0
32.1
31.1
31.1
31.0
30.8
C4H9
C6H5
OCH3
OC4H9
C4H9
C6H5
OCH3
OC4H9
13a
13c
13e
1d
13b
13d
13f
H
C4H9
C4H9
C4H9
C4H9
a
Measured in C6D6.
JCeH coupling constants of C2 carbon.
Estimated by ‘JCeHꢁ0.2’ according to Ref 26.
b
c
Scheme 10. Synthesis of DHAs.
We analyzed the structures of DHAs using 1H and 13C NMR
measurements in sealed tubes because of their susceptibility of
oxygen.1,2 13C NMR measurement was very effective to confirm the
structures and symmetries of the resulting DHAs. In fact, the ob-
served numbers of signals for adamantyl carbons were five (1a and
1d) and seven (1b and 13aef), reflecting their molecular symme-
tries. We focused on the structures of alkoxyl-substituted DHAs
(13c and 13e). If the DHA skeleton collapses due to the introduction
of an alkoxyl group, as shown in Scheme 3,13 a corresponding bi-
cyclic compound containing exo-methylene and vinyl ether moie-
ties would form. The resulting bicyclic compound should show ten
carbon signals because of its lower symmetry, and several carbon
signals should be observed in the olefinic region. In fact, the 13C
NMR spectrum of 13c apparently showed seven carbon signals
corresponding to the DHA skeleton and a signal assignable to CH3O
We next estimated the orbital hybridization of the distorted
cyclopropane ring in the DHA frameworks. In order to estimate the
s% value of inverted carbons (C1 and C3), the reported empirical
correlation was employed: s (%)¼JCeH (Hz)ꢁ0.2.26 This correlation
is known to be very effective to estimate the contribution of the s
character of the carbon atoms in a variety of hydrocarbon mole-
cules, including cubane27 and [1.1.1]propellane.26 The estimated s%
values were often used to predict the acidity of the CeH bonds in
those hydrocarbons. We focused on the JCeH coupling constant of
the C2 methylene group in the DHA framework, since no proton
was present on the C1 and C3 carbons. The JCeH constants and s%
values of the resulting DHAs are also summarized in Table 1. The
estimated s% values of DHAs are 30.8e32.1%, indicating their
comparable electronic environments. In fact, the cyclopropane

3242
S. Inomata et al. / Tetrahedron 69 (2013) 3238e3248
rings in the synthesized DHAs showed the similar ring-opening
reactivity to Brønsted acids as discussed below. From the view-
point of orbital hybridization, it is anticipated that cyclopropane
(32%), [1.1.1]propellane (33%),26 and DHAs (30.8e32.1%) possess
electronic environments similar to ethylene (typical sp2, s¼31%)
and their CeH bonds shown in Chart 1 might present comparable
acidity due to their sp2 characters.
phenyladamantane (14d) and 1-butoxy-3-methoxyadamantane
(14h), respectively. It is noteworthy that 1-butanol can similarly
react with 13d to yield a corresponding 1-butoxyadamantane (14i)
in the presence of MsOH. This shows the possibility of the ring-
opening reaction of DHAs with various alcohols to form a series
of 1-alkoxyadamantanes.
Next, we performed a reaction of a series of DHAs with AcOH in
n-heptane or CH2Cl2 at room temperature (Scheme 12). In each
case, the reaction rapidly proceeded, and the corresponding 1-
acetoxyadamantanes (15aeh) formed in 65e99% yields, as ex-
pected. In these reactions, 1-adamantyl cations instantaneously
form via the reaction of DHAs with AcOH, and the resulting 1-
adamantyl cations are immediately captured with AcOH to yield
1-acetoxyadamantanes (15aeh) without polymerization of DHAs.
Chart 1. JCeH constants and estimated s characters of hydrocarbons.
2.3. Ring-opening reaction of DHAs
It has been demonstrated that several DHAs exhibit high re-
activity toward various reagents, such as acids, halogens, and ox-
ygen to form corresponding ring-opening products (Scheme 1).1,2,8
We here attempt to react newly synthesized DHAs under selected
conditions to reveal their ring-opening reactivity, presumably
reflecting the ring-opening polymerizability.
We first examined the stability of 1b in MeOH. A solution of 1b
in a mixed solvent of MeOH and CH2Cl2 was stirred at room tem-
perature under argon. In fact, 1b was slowly consumed and 1-butyl-
3-methoxyadamantane (14b), an adduct of 1b and MeOH, was
newly formed in the mixture. The conversion of 1b could be
monitored by NMR and GLC measurements as 8, 48, 85, and 100%
after 10 min, 1.5 h, 6 h, and 30 h, respectively. In fact, 14b was the
only product after 30 h, indicating that the reaction of 1b with
MeOH exclusively proceeded to yield a ring-opening product even
under neutral conditions. On the other hand, all the DHAs (13aef)
rapidly reacted with MeOH to form 1-methoxyadamantanes
(14aei) in the presence of a catalytic amount of methanesulfonic
acid (MsOH) without formation of polymeric product (Scheme 11).
Non-substituted 1a and alkyl-substituted DHAs, 1b and 1d, were
also subjected to react with MeOH under acidic conditions in order
to compare their reactivity. In these reactions, the rapid pro-
tonation of DHAs took place with the strong Brønsted acids to form
a 1-adamantyl cation and the subsequent nucleophilic attack of
MeOH provided the corresponding 1-methoxyadamantanes pos-
sessing various substituents in 75e98% yields. For example, the
acid-catalyzed reaction of 13c with MeOH gave a symmetrical 1,3-
dimethoxyadamantane (14f). On the other hand, 13a and 13e
smoothly reacted with MeOH to give asymmetrical 1-methoxy-3-
Scheme 12. Ring-opening reaction of DHAs with AcOH.
These results clearly indicate that each DHA molecule showed
high reactivity toward acids to form 1-adamantyl cations, and the
resulting 1-adamantyl cations showed high electrophilicity toward
MeOH or AcOH. In 13C NMR spectra of the ring-opening products,
14aei and 15aeh, the expected numbers of adamantyl carbons
from their molecular symmetries can be detected at the appropri-
ate chemical shifts in addition to the carbon signals of substituents.
In fact, the observed numbers of signals for adamantyl carbons are
four (14a and 15a), five (14f), seven (14bed, 14g, 14h, 15bed, and
15g), and ten (14e, 14i, 15e, 15f, and 15h). It should be emphasized
that all ten adamantyl carbons on 14e, 14i, 15e, 15f, and 15h are
nonequivalent from their pseudotetrahedral symmetries, as dis-
cussed below. Considering these examples, the reaction of DHAs
with acidic reagents is one of the powerful and practical pathways
for the preparation of functionalized adamantanes. In general, ef-
fective incorporations of acyloxyl and alkoxyl groups are attained
via the reactions of DHAs and carboxylic acids or alcohols in the
presence of acid catalysts. In other words, it is demonstrated that
DHAs are versatile starting compounds for the synthesis of multi-
substituted adamantanes.
Since an adamantane molecule has a pseudotetrahedral sym-
metry, an adamantane possessing four different substituents on the
four bridgehead tertiary carbons should have a stereogenic cen-
ter.2,28 Schreiner and his co-workers synthesized 1-bromo-3-
chloro-5-fluoroadamantane and 1-bromo-3-chloro-5-fluoro-7-
iodoadamanane via stepwise halogenations and characterized
their absolute configurations after chiral resolution.29 From the
viewpoint of the stereochemistry of adamantane, the reaction of
DHAs with acidic reagents may be very attractive, since simulta-
neous introduction of two different substituents, proton (deute-
rium) and a corresponding counter anion, is possible.30 In principle,
the ring-opening reactions of DHAs possessing two different sub-
stituents on the 5- and 7-positions with suitable acidic reagents
will afford multi-substituted adamantanes bearing a stereogenic
center. For example, 13b, 13d, and 13f afforded (R/S)-tri-
substituted-adamantanes, 15e, 15f, and 15h, after ring-opening
Scheme 11. Ring-opening reaction of DHAs with MeOH.

S. Inomata et al. / Tetrahedron 69 (2013) 3238e3248
3243
reactions with AcOH. Similarly, the acid-catalyzed ring-opening
reaction of 13b and 13f with MeOH gave (R/S)-1-butyl-3-methoxy-
5-phenyladamantane (14e) and (R/S)-1-butoxy-3-butyl-5-
4.2. Synthesis of 1-butyl-3-phenyladamantane (8b)
(Scheme 4)
methoxyadamantane (14i), respectively. As described above, the
same product, 14i, was also obtained by the reaction of 13d with 1-
butanol under acidic conditions. These successful syntheses clearly
support the effectiveness of ring-opening reactions for the prepa-
ration of chiral adamantane derivatives and the symmetry of
starting DHA molecules.
A solution of bromobenzene (29.8 g, 190 mmol) in 30 mL of Et2O
was added dropwise at 0 ꢀC to magnesium (5.55 g, 228 mmol)
activated with 1,2-dibromoethane in Et2O (30 mL) under nitrogen.
The reaction mixture was stirred at room temperature for 3 h. After
completion of the reaction, the Et2O solution of Grignard reagent
was transferred to another flask to remove the residual magnesium.
Et2O was removed in vacuo to give a solid. A solution of 7b (12.0 g,
44.2 mmol) in CH2Cl2 (40 mL) was added to the solidified Grignard
reagent diluted with CH2Cl2 (60 mL) at room temperature under
nitrogen, and then the mixture was refluxed for 2 h. After cooling,
the reaction system was carefully poured into 2 N HCl at 0 ꢀC and
the layers were separated. The aqueous layer was extracted with
hexane three times. The combined organic layer was washed with
water and dried over anhydrous MgSO4. After filtration and evap-
oration, the residue was purified by column chromatography (silica
gel, hexane) and vacuum distillation to give colorless oil of 8b
(9.80 g, 83%): bp¼113e115 ꢀC (0.12 mmHg); 1H NMR (300 MHz,
3. Conclusions
In conclusion, we have succeeded in the synthesis of a series of
novel DHAs carrying phenyl and alkoxyl substituents at the
bridgehead carbons. The synthetic key is radical bromination re-
actions of 1-phenyladamantane and 1-alkoxyadamantane de-
rivatives under phase transfer conditions with CBr4 to prepare 1,3-
dibromoadamantanes without interfering with the functional
groups. Intramolecular lithium-mediated coupling reactions of 1,3-
dibromoadamantanes yielded DHAs bearing phenyl and alkoxyl
functional groups by the construction of highly strained cyclopro-
pane rings. The substituent effect in the DHA frameworks can be
CDCl3)
d
0.86e0.91 (t, 3H, J¼5.6 Hz, C(a)H3), 1.14 (br s, 2H, C(d)H2),
1.24 (br s, 4H, C(b)H2, C(c)H2), 1.49 (s, 4H, C(8)H2, C(9)H2), 1.60 (s,
2H, C(2)H2),1.67 (s, 2H, C(6)H2), 1.84 (br s, 4H, C(4)H2, C(10)H2), 2.14
(br s, 2H, C(5)H, C(7)H), 7.14e7.18 (t, J¼7.2 Hz, 1H, C(l)H), 7.28e7.37
estimated by the chemical shifts and JCeH coupling constants in 13
C
NMR measurement. A series of novel DHAs allow ring-opening
reactions with alcohols and carboxylic acids under acidic condi-
tions to form 1-alkoxyadamantanes and 1-acyloxyadamantanes. In
fact, these ring-opening reactions of DHAs with acidic reagents are
very efficient to synthesize 1,3,5-tri-substituted adamantanes, such
as 14e, 14i, 15e, 15f, and 15h, possessing stereogenic centers. The
successful development of novel DHAs and the observed ring-
opening reactivity strongly stimulated us to investigate their ring-
opening polymerizabilities. A study on the ring-opening polymer-
ization of various DHAs carrying phenyl and alkoxyl groups is in
progress and will be reported in a forthcoming paper.
(m, 4H, C(j)H, C(k)H); 13C NMR (75 MHz, CDCl3)
d 14.4 (Ca), 23.8
(Cb), 24.9 (Cc), 29.5 (C5, C7), 33.4 (C1), 36.5 (C6), 37. 1 (C3), 41.8 (C8,
C9), 42.9 (C4, C10), 44.4 (Cd), 48.5 (C2), 125.0 (Ck), 125.7 (Cl), 128.2
(Cj), 151.2 (Ci); IR (neat) 2897, 2845, 1445, 753, 744, 695 cmꢂ1; Anal.
Calcd for C20H28 (268.44): C, 89.49; H, 10.51. Found: C, 89.13;
H, 11.03.
4.3. Reaction of 1-butoxyadamantane (9c) with bromine
(Scheme 7)
Bromine (5.0 mL, 15.5 g, 97.0 mmol) was added to the solution of
9c (500 mg, 2.40 mmol) in 10 mL of CCl4 and stirred for 12 h at room
temperature. The reaction mixture was carefully poured into
crashed ice, and excess bromine was quenched with NaHSO3 at
0 ꢀC. The aqueous layer was extracted with CHCl3 and the combined
organic layer was dried over anhydrous MgSO4. After removal of
the solvent in vacuo, 1-bromoadamantane (7a) (500 mg, 97%) not
1-bromo-3-butoxyadamantane was obtained as yellow solid: 1H
4. Experimental section
4.1. General
Commercially available AcOH, 1-butanol, bromobenzene,
fluorobenzene, tetrabutylammonium bromide (Bu4NBr), NaOH,
carbon tetrachloride (CCl4), carbon tetrabromide (CBr4), 1-
bromoadamantane, methanesulfonic acid (MsOH), bromine, lith-
ium (wire), and magnesium were used without further purification.
Methylene chloride (CH2Cl2) was distilled from CaH2 under nitro-
gen. Diethyl ether (Et2O) was dried over CaCl2, filtered off, and
stored over sodium wire. THF was refluxed over sodium wire for
3 h, distilled over LiAlH4 under nitrogen. MeOH was refluxed over
magnesium and iodine then distilled under nitrogen. 1a, 1b, 1d, 7b,
and 8a were synthesized according to our previous report.10,17 1H
NMR and 13C NMR spectra were recorded at 300 MHz and 75 MHz,
respectively, either in CDCl3 or C6D6. The chemical shifts were re-
NMR (300 MHz, CDCl3)
d
1.70 (s, 6H, C(4)H2), 2.07 (s, 3H, C(3)H),
32.6 (C3), 35.6 (C4),
2.33 (s, 6H, C(2)H2); 13C NMR (75 MHz, CDCl3)
d
49.4 (C2), 66.7 (C1). These NMR data agreed with those for a com-
mercially available 7a.
4.4. General procedure A for the synthesis of 11 (11a as an
example)
A suspension of 8a (5.63 g, 26.5 mmol), CBr4 (70.0 g, 211 mmol),
Bu4NBr (512 mg, 1.59 mmol), aqueous NaOH (50 wt%, 75 mL), and
fluorobenzene (75 mL) was stirred at 85 ꢀC. After 2 days, the re-
action mixture was cooled to room temperature and the organic
layer was decanted off. The resultant water phase (suspension) was
extracted with Et2O three times and combined organic layer was
washed with 2 N HCl and brine then dried over anhydrous MgSO4.
After removal of solvent and residual CBr4 by sublimation at 70 ꢀC
(0.10 mmHg), the residue was purified by column chromatography
(silica gel, hexane) and recrystallization from methanol to give 1,3-
dibromo-5-phenyladamantane (11a, 3.54 g, 36%) as white crystal:
ported in parts per million downfield relative to CHCl3
(d 7.26) or
C6H6 ( 77.1) or C6D6 ( C
d
7.16) for 1H NMR and CDCl3 ( 128.0) for 13
d
d
NMR as standards. IR spectra were recorded with a FT-IR in-
strument by ATR or KBr disk method. High resolution mass spectra
(HRMS) were obtained on an electrospray ionization (ESI) mass
spectrometer. The melting points of the compounds were mea-
sured by DSC under nitrogen flow.
Assignments for substituents
mp¼87e89 ꢀC. 1H NMR (300 MHz, CDCl3)
d 1.91 (s, 2H, C(6)H2),
2.32 (s, 4H, C(8)H2, C(10)H2), 2.41 (br s, 1H, C(7)H), 2.48 (s, 4H, C(4)
H2, C(9)H2), 2.90 (s, 2H, C(2)H2),7.26e7.37 (m, 5H, C(j)H, C(k)H, C(l)
H); 13C NMR (75 MHz, CDCl3):
d
34.8 (C7), 39.5 (C6), 44.5 (C5), 46.3
(C8, C10), 52.5 (C4, C9), 58.3 (C2), 61.7 (C1, C3),124.7 (Ck),126.8 (Cl),

3244
S. Inomata et al. / Tetrahedron 69 (2013) 3238e3248
128.7 (Cj), 146.5 (Ci); IR (KBr) 3055, 2919, 2851, 1319, 696 cmꢂ1
;
2H, C(h)H2); 13C NMR (75 MHz, CDCl3)
d 14.1 (Ce),19.6 (Cf), 30.7 (C3),
HRMS (ESI-TOF) m/z Calcd for C16H18Br2Na [MþNa]þ 390.9667,
found 390.9678; Anal. Calcd for C16H18Br2 (370.12): C, 51.92; H,
4.90. Found: C, 51.82; H, 4.68.
33.0 (Cg), 36.7 (C4), 41.8 (C2), 59.6 (Ch), 71.8 (C1); IR (neat) 2904,
2851, 1454, 1354, 1306, 1116, 1091, 1046 cmꢂ1; HRMS (ESI-TOF) m/z
calcd for C14H24NaO [MþNa]þ 231.1719, found 231.1723.
4.4.1. 1,3-Dibromo-5-butyl-7-phenyladamantane (11b). The re-
action was performed following general procedure A, starting from
8b (24.6 g, 91.6 mmol) for 5 days. After similar extraction pro-
cedure, column chromatography (silica gel, hexane) afforded 11b
(8.14 g, 21%) as pale yellow oil. 1H NMR (300 MHz, CDCl3)
4.6.1. 1-Butoxy-3-butyladamantane (9d). The reaction was per-
formed following general procedure C, starting from 7b (30.9 g,
114 mmol) to yield 9d (28.5 g, 95%) as colorless oil: 1H NMR
(300 MHz, CDCl3) d 0.86e0.93 (m, 6H, C(a)H3, C(e)H3), 1.13e1.50 (m,
10H, C(b)H2, C(c)H2, C(d)H2, C(f)H2, C(g)H2), 1.36 (s, 4H, C(4)H2,
C(10)H2), 1.44 (s, 4H, C(8)H2, C(9)H2), 1.52 (s, 2H, C(2)H2), 1.65e1.67
(m, 2H, C(6)H2), 2.15e2.16 (m, 2H, C(5)H, C(7)H), 3.36e3.41 (t,
d
0.88e0.97 (m, 3H, C(a)H3), 1.19 (br s, 6H, C(b)H2, C(c)H2, C(d)H2),
1.66 (s, 2H, C(6)H2), 2.09 (s,4H, C(4)H2, C(19)H2), 2.41 (s, 4H, C(8)H2,
C(9)H2), 2.83 (s, 2H, C(2)H2), 7.21e7.37 (m, 5H, C(j)H, C(k)H, C(l)H);
J¼6.6 Hz, 2H, C(h)H2); 13C NMR (75 MHz, CDCl3)
d 14.1 (Ce), 14.3
13C NMR (75 MHz, CDCl3)
d
14.2 (Ca), 23.4 (Cb), 25.0 (Cc), 41.4 (C5),
(Ca), 19.6 (Cf), 23.8 (Cb), 25.1 (Cc), 30.7 (C5, C7), 33.0 (Cg), 35.8 (C3),
36.3 (C6), 41.3 (C4, C10), 41.7 (C8, C9), 43.8 (C2), 46.6 (Cd), 59.7 (Ch),
72.7 (C1); IR (neat) 2922, 2901, 2853, 1453, 1146, 1112, 1081,
1047 cmꢂ1; HRMS (ESI-TOF) m/z calcd for C18H32NaO [MþNa]þ
287.2345, found 287.2353.
42.4 (Cd), 44.5 (C7), 45.0 (C6), 51.3 (C4, C10), 52.1 (C8, C9), 57.8 (C2),
62.0 (C1, C3), 124.7 (Ck), 126.8 (Cl), 128.7 (Cj), 146.4 (Ci); IR (neat)
2928, 2857, 1445, 1315, 847, 714, 696 cmꢂ1; HRMS (ESI-TOF) m/z
Calcd for C20H26Br2Cl [MþCl]ꢂ 459.0095, found 459.0088.
4.5. General procedure B for the synthesis of 1-
methoxyadamantanes (9a as an example) (Scheme 5)
4.7. General procedure D for the synthesis of 12 (12a as an
example) (Scheme 9)
1-Bromoadamantane (7a, 43.0 g, 200 mmol) was added to
a MeOH solution of sodium methoxide prepared by reaction of
sodium (8.30 g, 361 mmol) in dry MeOH (400 mL) and refluxed at
80 ꢀC under nitrogen. After 10 days, the reaction mixture was
cooled to room temperature and quenched with 2 N HCl. The
aqueous layer was extracted with Et2O three times. The combined
organic layer was dried over anhydrous MgSO4. After removal of
solvent, the residue was purified by column chromatography (silica
gel, hexane/Et2O 10:0e9:1) to afford 1-methoxyadamantane18 (9a,
29.5 g, 89%) as colorless oil: bp¼37e39 ꢀC (4.0 mmHg); 1H NMR
A suspension of 9a (17.4 g, 105 mmol), CBr4 (200 g, 603 mmol),
Bu4NBr (4.86 g, 15.1 mmol), aqueous NaOH (50wt%, 250 mL), and
fluorobenzene (350 mL) was stirred at 85 ꢀC. After 5 days, the re-
action mixture was cooled to room temperature, the resultant
suspension was extracted with Et2O three times. The combined
organic layer was washed with 2 N HCl and dried over anhydrous
MgSO4. After filtration and removal of solvent in vacuo, the residual
CBr4 was removed by column chromatography (silica gel, hexane/
Et2O¼100/0e90/10), and the resulting crude product was purified
by second column chromatography (silica gel, hexane/Et2O¼96/4)
followed by recrystallization from methanol to give 1,3-dibromo-5-
methoxyadamantane (12a, 10.3 g, 30%) as white crystal:
bp¼89e91 ꢀC (0.15 mmHg), mp¼41e43 ꢀC; 1H NMR (300 MHz,
(300 MHz, CDCl3)
2.13 (s, 3H, C(3)H), 3.21 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3)
30.6 (C3), 36.6 (C4), 41.1 (C2), 47.9 (OCH3), 72.0 (C1); IR (neat):
2903, 2850, 1451, 1354, 1177, 1115, 1089, 1051, 893 cmꢂ1
d 1.53e1.66 (m, 6H, C(4)H2), 1.71 (s, 6H, C(2)H2),
d
.
CDCl3)
2.26e2.28 (m, 4H, C(8)H2, C(10)H2), 2.35e2.37 (m, 1H, C(7)H), 2.73
(s, 2H, C(2)H2), 3.23 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3)
33.8
d 1.70e1.71 (2s, 2H, C(6)H2), 2.19e2.22 (2s, C(4)H2, C(9)H2),
4.5.1. 1-Butyl-3-methoxyadamantane (9b). The reaction was per-
formed following general procedure B, starting from 7b (26.7 g,
98.4 mmol) to yield 9b (21.6 g, 99%) as colorless oil: 1H NMR
d
(C7), 37.9 (C6), 46.0 (C4, C9), 49.1 (OCH3), 50.7 (C8, C10), 57.9 (C2),
59.5 (C1, C3), 75.2 (C5); IR (neat) 2912, 2859, 2829, 1451, 1352, 1193,
(300 MHz, CDCl3)
d
0.88e0.92 (t, J¼6.9 Hz, 3H, C(a)H3), 1.12e1.26
1138, 1106, 894, 566 cmꢂ1
; HRMS (ESI-TOF) m/z calcd for
(m, 6H, C(b)H2, C(c)H2, C(d)H2), 1.36 (br s, 4H, C(8)H2, C(9)H2), 1.42
(br s, 2H, C(6)H2), 1.52 (br s, 2H, C(2)H2), 1.64e1.66 (m, 4H, C(4)H2,
C(10)H2), 2.16e2.18 (m, 2H, C(5)H, C(7)H), 3.22 (s, 3H, OCH3); 13C
C11H16Br2NaO [MþNa]þ 344.9460, found 344.9464.
4.7.1. 1,3-Dibromo-5-butyl-7-methoxyadamantane (12b). The re-
action was performed following general procedure D, starting from
9b (27.0 g, 121 mmol) for 6 days. After similar extraction procedure,
the residual CBr4 was removed by column chromatography (silica
gel, hexane/Et2O¼100/0e90/10), and the resulting crude product
was purified by vacuum distillation followed by column chroma-
tography (silica gel, hexane/Et2O¼95/5) to give 12b (11.3 g, 24%) as
yellow oil: bp¼99e101 ꢀC (0.15 mmHg); 1H NMR (300 MHz, CDCl3)
NMR (75 MHz, CDCl3) d 14.3 (Ca), 23.7 (Cb), 25.0 (Cc), 30.7 (C5, C7),
35.8 (C1), 36.2 (C6), 40.7 (C8, C9), 41.6 (C4, C10), 43.7 (C2), 45.9 (Cd),
48.0 (OCH3), 73.0 (C3); IR (neat) 2901, 2851, 1465, 1452, 1354, 1112,
1080, 879, 629 cmꢂ1; HRMS (ESI-TOF) m/z calcd for C15H26NaO
[MþNa]þ 245.1876, found 245.1869.
4.6. General procedure C for the synthesis of 1-
butoxyadamantanes (9c as an example) (Scheme 5)
d
0.87e0.91 (t, J¼7.0 Hz, 3H, C(a)H3), 1.23e1.28 (m, 6H, C(b)H2, C(c)
H2, C(d)H2), 1.48 (s, 2H, C(6)H2), 1.95 (s, 4H, C(8)H2, C(10)H2),
1-Bromoadamantane (7a, 43.0 g, 200 mmol) was added to a so-
lution of sodium 1-butoxide prepared by reaction of sodium (9.20 g,
400 mmol) in 1-butanol (500 mL) and refluxed at 140 ꢀC under ni-
trogen. After 10 days, the reaction mixture was cooled to room
temperature and quenched with 2 N HCl. The aqueous layer was
extracted with Et2O three times. The combined organic layer was
washed with water and dried over anhydrous MgSO4. After filtration
and removal of solvent in vacuo, the residue was purified by column
chromatography (silica gel, hexane/Et2O 90:10) to afford 1-
butoxyadamantane19 (9c, 35.4 g, 85%) as colorless oil: 1H NMR
2.16e2.28 (2d, 4H, C(4)H2, C(9)H2), 2.62e2.72 (m, 2H, C(2)H2), 3.24
(s, 3H, OCH3); 13C NMR (75 MHz, CDCl3)
d 14.2 (Ca), 23.4 (Cb), 25.1
(Cc), 41.1 (C6), 41.8 (Cd), 43.1 (C5), 49.2 (OCH3), 50.3 (C8, C10), 51.2
(C4, C9), 57.6 (C2), 59.5 (C1, C3), 75.5 (C7); IR (neat): 2929, 2858,
1327, 1314, 1089, 880, 847, 714, 629 cmꢂ1. HRMS (ESI-TOF) m/z calcd
for C15H24Br2NaO [MþNa]þ 401.0086, found 401.0098.
4.7.2. 1,3-Dibromo-5-butoxyadamantane (12c). The reaction was
performed following general procedure D, starting from 9c (25.0 g,
120 mmol) for 5 days. After similar extraction procedure, the re-
sidual CBr4 was removed by column chromatography (silica gel,
hexane/Et2O¼100/0e90/10). The resulting crude product was pu-
rified by vacuum distillation followed by column chromatography
(300 MHz, CDCl3)
d
0.88e0.92 (t, J¼7.4 Hz, 3H, C(e)H3),1.31e1.41 (m,
2H, C(f)H2), 1.45e1.54 (m, 2H, C(g)H2), 1.60 (br s, 6H, C(4)H2),
1.73e1.74 (2s, 6H, C(2)H2), 2.34 (s, 3H, C(3)H), 3.36e3.41 (t, J¼6.6 Hz,

S. Inomata et al. / Tetrahedron 69 (2013) 3238e3248
3245
(silica gel, hexane/Et2O¼99/1) to give 12c (7.21 g, 16%) as pale
yellow oil: bp¼140e142 ꢀC (0.15 mmHg); 1H NMR (300 MHz,
13.5 mmol) to yield 13c (1.28 g, 58%) as colorless oil: 1H NMR
(300 MHz, C6D6)
d
0.90e0.94 (d, J¼11 Hz, 2H, one of C(8)H2, one of
CDCl3)
d
0.88e0.93 (t, J¼7.3 Hz, 3H, C(e)H3), 1.25e1.36 (m, 2H, C(f)
C(10)H2), 1.39e1.42 (d, J¼10 Hz, 2H, one of C(4)H2, one of C(9)H2),
1.62e1.67 (m, 3H, one of C(2)H2, one of C(8)H2, one of C(10)H2),
1.76e1.78 (m, 1H, one of C(2)H2), 1.83e1.88 (m, 4H, C(6)H2, one of
H2), 1.47e1.51 (m, 2H, C(g)H2), 1.72 (s, 2H, C(6)H2), 2.15 (s, 4H, C(4)
H2, C(9)H2), 2.25e2.33 (m, 4H, C(8)H2, C(10)H2), 2.34e2.35 (m, 1H,
C(7)H), 2.74 (s, 2H, C(2)H2), 3.37e3.42 (t, J¼6.4 Hz, 2H, C(h)H2); 13
C
C(4)H2, one of C(9)H2), 2.69 (br s, 1H, C(7)H), 3.09 (s, 3H, OCH3); 13
C
NMR (75 MHz, CDCl3):
d
14.0 (Ce),19.5 (Cf), 32.5 (Cg), 33.9 (C7), 38.5
NMR (75 MHz, C6D6)
d 30.3 (C1, C3), 41.7 (C6), 44.2 (C2), 44.3 (C8,
(C6), 46.1 (C4, C9), 51.3 (C8, C10), 58.0 (C2), 59.7 (C1, C3), 60.9 (Ch),
75.1 (C5); IR (neat) 2935, 2862, 1453, 1315, 1284, 1111, 920, 832,
706 cmꢂ1; HRMS (ESI-TOF) m/z calcd for C14H22Br2NaO [MþNa]þ
386.9930, found 386.9941.
C10), 46.0 (C4, C9), 51.0 (OCH3), 52.9 (C7), 91.6 (C5).
4.8.3. 5-Butyl-7-methoxy-1,3-dehydroadamantane (13d). The re-
action was performed following general procedure E, starting from
12b (6.51 g, 17.1 mmol) to yield 13d (2.26 g, 60%) as colorless oil: 1H
4.7.3. 1,3-Dibromo-5-butoxy-7-butyladamantane (12d). The re-
action was performed following general procedure D, starting from
9d (28.5 g, 108 mmol) for 9 days. After similar extraction procedure,
the residual CBr4 was removed by column chromatography (silica
gel, hexane/Et2O¼100/0e90/10). The resulting crude product was
purified by column chromatography (silica gel, hexane/Et2O¼95/5)
followed by vacuum distillation twice to give 12d (2.20 g, 5%) as
yellow oil: bp¼122e124 ꢀC (0.15 mmHg); 1H NMR (300 MHz, CDCl3)
NMR (300 MHz, C6D6) d 0.85e0.94 (m, 5H, C(a)H3, one of C(8)H2,
one of C(10)H2), 1.12e1.24 (m, 6H, C(b)H2, C(c)H2, C(d)H2),
1.36e1.39 (d, J¼10 Hz, one of C(4)H2, one of C(9)H2), 1.51e1.57(m,
3H, one of C(2)H2, one of C(8)H2, one of C(10)H2) 1.73e1.86 (m, 5H,
one of C(2)H2, C(6)H2, one of C(4)H2, one of C(9)H2), 3.14 (s, 3H,
OCH3); 13C NMR (75 MHz, C6D6)
d 14.4 (Ca), 24.1 (Cb), 27.9 (Cc), 28.9
(C1, C3), 36.6 (Cd), 42.7 (C2), 45.3 (C8, C10), 46.7 (C6), 48.3 (C4, C9),
51.2 (OCH3), 63.9 (C5), 91.2 (C7).
d
0.87e0.93 (m, 6H, C(a)H3, C(e)H3), 1.23e1.46 (m, 8H, C(b)H2, C(c)
H2, C(d)H2, C(f)H2), 1.49 (s, 2H, C(6)H2), 1.51e1.72 (m, 2H, C(g)H2),
1.95 (s, 4H, C(4)H2, C(9)H2), 2.00e2.31 (m, 4H, C(8)H2, C(10)H2),
4.8.4. 5-Butoxy-1,3-dehydroadamantane (13e). The reaction was
performed following general procedure E, starting from 12c (7.21 g,
19.7 mmol) to yield 13e (2.31 g, 57%) as colorless oil: 1H NMR
2.62e2.72 (m, 2H, C(2)H2), 3.37e3.41 (t, J¼6.4 Hz, 2H, C(h)H2); 13
C
NMR (75 MHz, CDCl3)
d
14.1 (Ce), 14.2 (Ca), 19.5 (Cf), 23.4 (Cb), 25.1
(300 MHz, C6D6) d 0.85e0.96 (m, 5H, C(e)H3, one of C(8)H2, one of
(Cc), 32.5 (Cg), 41.1 (C6), 41.9 (Cd), 43.7 (C7), 50.8 (C4, C9), 51.3 (C8,
C10), 57.6 (C2), 59.7 (C1, C3), 60.9 (Ch), 75.3 (C7); IR (neat) 2954,
2926, 2859, 1456, 1236, 1088, 848, 629 cmꢂ1; HRMS (ESI-TOF) m/z
calcd for C18H30Br2NaO [MþNa]þ 443.0556, found 443.0543.
C(10)H2), 1.36e1.58 (m, 6H, C(f)H2, C(g)H2, one of C(4)H2, one of
C(9)H2), 1.66e1.69 (m, 3H, one of C(2)H2, one of C(8)H2, one of C(10)
H2), 1.78e1.80 (m, 1H, one of C(2)H2), 1.90e1.93 (C(6)H2, one of C(4)
H2, one of C(9)H2), 2.72 (br s, 1H, C(7)H), 3.28e3.32 (t, J¼6.3 Hz, 2H,
C(h)H2); 13C NMR (75 MHz, C6D6)
d 14.2 (Ce), 19.8 (Cf), 30.4 (C1, C3),
4.8. General procedure E for the synthesis of DHAs (13) (13a as
an example) (Scheme 10)
33.1 (Cg), 42.1 (C6), 44.2 (C2), 44.3 (C8, C10), 46.8 (C4, C9), 52.9 (C7),
63.0 (Ch), 91.3 (C5).
A mixture of 11a (7.90 g, 21.3 mmol) and lithium (1.50 g,
216 mmol) in dry THF (35 mL) was reacted at room temperature for
24 h under argon. The resulting suspension was transferred into
a round bottom flask equipped with a break-seal, and THF was
thoroughly removed from the suspension on the vacuum line. The
residue was sealed off under high-vacuum conditions. Repeating
vacuum distillations in the all-glass apparatus gave a white solid of
5-phenyl-1,3-dehydroadamantane (13a, 2.10 g, 47%). For the NMR
measurement, the sample was diluted with C6D6. For ring-opening
reactions, the sample was diluted with CH2Cl2 or n-heptane: 1H
4.8.5. 5-Butoxy-7-butyl-1,3-dehydroadamantane (13f). The reaction
was performed following general procedure E, starting from 12d
(2.33 g, 5.52 mmol) to yield 13f (904 mg, 62%) as colorless oil: 1H
NMR (300 MHz, C6D6)
d 0.87e0.95 (m, 8H, C(a)H3, C(e)H3, one of
C(8)H2, one of C(10)H2), 1.16e1.22 (m, 6H, C(b)H2, C(c)H2, C(d)H2),
1.36e1.59 (m, 9H, one of C(2)H2, one of C(4)H2, one of C(8)H2, one of
C(9)H2, one of C(10)H2, C(f)H2, C(g)H2),1.74e1.77 (m,1H, one of C(2)
H2), 1.83e1.86 (m, 4H, C(6)H2, one of C(4)H2, one of C(9)H2),
3.31e3.35 (t, J¼6.3 Hz, 2H, C(h)H2); 13C NMR (75 MHz, C6D6)
d 14.3
(Ce), 14.4 (Ca), 19.9 (Cf), 24.1 (Cb), 28.0 (Cc), 29.1 (C1, C3), 33.2 (Cg),
36.7 (Cd), 42.7 (C2), 46.0 (C4, C9), 47.1 (C6), 48.4 (C8, C10), 63.1 (Ch),
64.0 (C5), 90.9 (C7).
NMR (300 MHz, C6D6)
d
1.10e1.14 (d, J¼11 Hz, 2H, one of C(8)H2,
one of C(10)H2),1.43e1.47 (d, J¼11 Hz, 2H, one of C(4)H2, one of C(9)
H2), 1.87e2.03 (m, 6H, C(2)H2, C(6)H2, one of C(8)H2, one of C(10)
H2), 2.18e2.23 (m, 2H, one of C(4)H2, one of C(9)H), 2.79 (s, 1H, C(7)
H), 7.05e7.20 (m, 5H, C(j)H, C(k)H, C(l)H); 13C NMR (75 MHz, C6D6)
4.9. General procedure F for the synthesis of 14: reaction of
DHAs with MeOH (14a as an example) (Scheme 11)
d
35.4 (C1, C3), 44.9 (C8, C10), 45.1 (C6), 47.9 (C2), 50.1 (C4, C9), 53.8
(C7), 67.4 (C5), 126.1 (Ck), 126.5 (Cl), 128.4 (Cj), 146.7 (Ci).
A MeOH solution of MsOH (0.145 M, 0.145 mmol, 1 mL) was
added to a solution of 1a (372 mg, 2.77 mmol) in CH2Cl2 (4.5 mL)
and then the mixture was stirred at room temperature under ni-
trogen atmosphere for 3.5 h. After removal of solvent in vacuo, 1-
methoxyadamantane (14a, 383 mg, 83%) was obtained as color-
less oil. The NMR data agreed with those for 9a synthesized sepa-
rately by following general procedure B.
4.8.1. 5-Butyl-7-phenyl-1,3-dehydroadamantane (13b). The re-
action was performed following general procedure E, starting from
11b (6.44 g, 15.1 mmol) to yield 13b (830 mg, 23%) as colorless oil:
1H NMR (300 MHz, C6D6)
d
0.87e0.91 (t, J¼6.7 Hz, 3H, C(a)H3),
1.06e1.10 (d, J¼10 Hz, 2H, one of C(4)H2, one of C(9)H2), 1.18e1.24
(m, 6H C(b)H2, C(c)H2, C(d)H2), 1.40e1.44 (d, J¼10 Hz, 2H, one of
C(8)H2, one of C(10)H2), 1.71 (m, 2H, one of C(4)H2, one of C(9)H2),
1.86 (s, 2H, C(6)H2), 1.94 (s, 2H, C(2)H2), 2.16 (m, 2H, one of C(8)H2,
one of C(10)H2), 7.10e7.20 (m, 5H, C(j)H, C(k)H, C(l)H); 13C NMR
4.9.1. 1-Butyl-3-methoxyadamantane (14b). The reaction was per-
formed following general procedure F, starting from 1b (670 mg,
3.52 mmol) to yield 14b (590 mg, 75%) as colorless oil. The NMR
data agreed with those for 9b synthesized separately by following
general procedure B.
(75 MHz, C6D6)
d 14.4 (Ca), 24.1 (Cb), 27.8 (Cc), 34.3 (C1, C3), 37.4
(Cd), 46.4 (C2), 48.8 (C4, C9), 49.3 (C8, C10), 50.4 (C6), 63.9 (C5),
66.7 (C7), 126.2 (Ck), 126.7 (Cl) 128.4 (Cj) 146.8 (Ci).
4.9.2. 1,3-Dibutyl-5-methoxyadamantane (14c). The reaction was
performed following general procedure F, starting from 1d
(293 mg, 1.19 mmol) to yield 14c (276 mg, 83%) as colorless oil: 1H
4.8.2. 5-Methoxy-1,3-dehydroadamantane (13c). The reaction was
performed following general procedure E, starting from 12a (4.37 g,

3246
S. Inomata et al. / Tetrahedron 69 (2013) 3238e3248
NMR (300 MHz, CDCl3)
(m, 22H, C(b)H2, C(c)H2, C(d)H2, C(4)H2, C(6)H2, C(8)H2, C(9)H2,
d
0.86 (t, J¼6.5 Hz, 6H, C(a)H3), 1.04e1.40
(br s, 2H, C(5)H, C(7)H), 3.20 (s, 3H, OCH3), 3.36 (t, J¼6.6 Hz, 2H, C(h)
H2); 13C NMR (75 MHz, CDCl3)
14.0 (Ce), 19.5 (Cf), 30.7 (C5, C7),
d
C(10)H2), 1.57e1.58 (2s, 2H, C(2)H2), 2.17e2.21 (br s, 1H, C(7)H),
32.7 (Cg), 35.5 (C6), 40.1 (C4, C10), 40.6 (C8, C9), 44.9 (C2), 48.3
(OCH3), 60.0 (Ch), 74.0, 74.3 (C1, C3); IR (neat) 2928, 2909, 2856,
1455, 1350, 1121, 1080 cmꢂ1; HRMS (ESI-TOF) m/z calcd for
C15H26NaO2 [MþNa]þ 261.1825, found 261.1832.
3.20 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3)
d 14.1 (Ca), 23.7 (Cb),
25.1 (Cc), 30.9 (C7), 36.2 (C1, C3), 40.3 (C6), 41.4 (C8, C10), 43.5 (C4,
C9), 45.6 (Cd), 47.0 (C2), 47.9 (OCH3), 74.3 (C5); IR (neat) 2954, 2925,
2854, 1455, 1335, 1193, 1052, 867, 728, 560 cmꢂ1; HRMS (ESI-TOF)
m/z calcd for C19H34NaO [MþNa]þ 301.2502, found 301.2508.
4.9.8. (R/S)-1-Butoxy-3-butyl-5-methoxyadamantane (14i). The re-
action was performed following general procedure F, starting from
13f (134 mg, 0.511 mmol) to yield 14i (140 mg, 93%) as colorless oil:
4.9.3. 1-Methoxy-3-phenyladamantane (14d). The reaction was
performed following general procedure F, starting from 13a
(521 mg, 2.48 mmol) to afford 14d (518 mg, 86%) as colorless oil: 1H
NMR (300 MHz, CDCl3) d 1.61 (s, 2H, C(6)H2), 1.76e1.80 (m, 8H, C(4)
H2, C(8)H2, C(9)H2, C(10)H2), 1.87 (s, 2H, C(2)H2), 2.31 (br s, 2H, C(5)
1H NMR (300 MHz, CDCl3)
d 0.84e0.91 (m, 6H, C(a)H3, C(e)H3),
1.19e1.68 (m, 20H, C(b)H2, C(c)H2, C(d)H2, C(f)H2, C(g)H2, C(2)H2,
C(4)H2, C(6)H2, C(8)H2, C(10)H2), 2.29e2.31 (m, 1H, C(7)H), 3.22 (s,
3H, OCH3), 3.37 (t, J¼6.6 Hz, 2H, C(h)H2); 13C NMR (75 MHz, CDCl3)
H, C(7)H), 3.24 (s, 3H, OCH3), 7.14e7.21 (m, 1H, C(l)H), 7.26e7.34 (m,
d 14.0 (Ce), 14.2 (Ca), 19.5 (Cf), 23.6 (Cb), 25.2 (Cc), 30.5 (C7), 32.8
4H, C(j)H, C(k)H); 13C NMR (75 MHz, CDCl3)
d
30.6 (C5, C7), 35.5
(Cg), 37.1 (C3), 39.8, 40.2, 40.7, 43.0, 44.5, 45.2 (C2, C4, C6, C8, C9,
C10), 45.8 (Cd), 48.4 (OCH3), 60.2 (Ch), 74.7, 75.0 (C1, C5); IR (neat)
2927, 2857, 1457, 1334, 1160, 1083, 930 cmꢂ1; HRMS (ESI-TOF) m/z
calcd for C19H34NaO2 [MþNa]þ 317.2451, found 317.2447.
(C6), 39.5 (C3), 40.1 (C4, C10), 41.8 (C8, C9), 46.3 (C2), 47.9 (OCH3),
72.9 (C1), 124.8 (Ck), 125.8 (Cl), 128.2 (Cj), 149.5 (Ci); IR (neat) 2903,
2852, 1496, 1445, 1337, 1112, 1089, 754, 696 cmꢂ1; HRMS (ESI-TOF)
m/z calcd for C17H22NaO [MþNa]þ 265.1563, found 265.1558.
4.10. Reaction of 13d with 1-butanol in the presence of MsOH
4.9.4. (R/S)-1-Butyl-3-methoxy-5-phenyladamantane (14e). The re-
action was performed following general procedure F, starting from
13b (70.8 mg, 0.266 mmol) to afford 14e (78.0 mg, 98%) as pale
To a solution of 13d (604 mg, 2.74 mmol) in CH2Cl2 (3.7 mL),
MsOH (12.1 mg, 0.126 mmol) in 1-butanol (5.0 mL) was added at
room temperature under nitrogen. After 17 h, the solvent was
evaporated, and the residue was diluted with Et2O. The Et2O solu-
tion was washed with water three times and dried over anhydrous
MgSO4. After removal of solvent in vacuo, (R/S)-1-butoxy-3-butyl-
5-methoxyadamantane (14i) (527 mg, 1.79 mmol, 65%) was ob-
yellow oil: 1H NMR (300 MHz, CDCl3)
d
0.92e0.96 (t, J¼6.4 Hz, 3H,
C(a)H3), 1.29 (br s, 6H, C(b)H2, C(c)H2, C(d)H2), 1.46 (s, 2H, C(9)H2),
1.55 (s, 2H, C(6)H2), 1.60 (s, 2H, C(8)H2), 1.76 (s, 2H, C(10)H2), 1.81 (s,
2H, C(2)H2), 1.89 (s, 2H, C(4)H2), 2.40e2.44 (m, 1H, C(7)H), 3.32 (s,
3H, OCH3), 7.23e7.28 (m, 1H, C(l)H), 7.34e7.42 (m, 4H, C(j)H, C(k)
H); 13C NMR (75 MHz, CDCl3)
d
14.3 (Ca), 23.7 (Cb), 25.1 (Cc), 30.9
tained as colorless oil: 1H NMR (300 MHz, CDCl3)
d 0.86e0.93 (m,
(C7), 36.3 (C1), 39.8, 40.0, 40.8, 41.9, 43.5, 45.1, 46.0, 47.8 (Cd, C2, C4,
C5, C6, C8, C9, C10), 48.2 (OCH3), 73.9 (C3), 125.0 (Ck), 126.0 (Cl),
128.3 (Cj), 149.7 (Ci); IR (neat) 2925, 2852, 1445, 1338, 1083, 904,
752 cmꢂ1; HRMS (ESI-TOF) m/z calcd for C21H30NaO [MþNa]þ
321.2189, found 321.2190.
6H, C(a)H3, C(e)H3), 1.21e1.71 (m, 20H, C(b)H2, C(c)H2, C(d)H2, C(f)
H2, C(g)H2, C(2)H2, C(4)H2, C(6)H2, C(8)H2, C(10)H2), 2.30e2.33 (m,
1H, C(7)H), 3.23 (s, 3H, OCH3), 3.39 (t, J¼6.7 Hz, 2H, C(h)H2); 13C
NMR (75 MHz, CDCl3) d 14.1 (Ce), 14.3 (Ca), 19.6 (Cf), 23.6 (Cb), 25.3
(Cc), 30.6 (C7), 32.9 (Cg), 37.1 (C3), 40.1, 40.5, 41.0, 43.3, 44.8, 45.5
(C2, C4, C6, C8, C9, C10), 46.1 (Cd), 48.8 (OCH3), 60.5 (Ch), 74.7, 74.9
(C1, C5); HRMS (ESI-TOF) m/z calcd for C19H34NaO2 [MþNa]þ
317.2451, found 317.2445. These data agreed with those for 14i
synthesized separately by following general procedure F using 13f
as shown above.
4.9.5. 1,3-Dimethoxyadamantane (14f). The reaction was per-
formed following general procedure F, starting from 13c (332 mg,
2.02 mmol) to afford 14f (309 mg, 78%) as colorless oil: 1H NMR
(300 MHz, CDCl3)
C(8)H2C(9)H2, C(10)H2), 1.71 (s, 2H, C(2)H2), 2.30 (br s, 2H, C(5)H,
C(7)H), 3.22 (s, 6H, OCH3); 13C NMR (75 MHz, CDCl3)
30.8 (C5, C7),
d 1.47 (br s, 2H, C(6)H2), 1.64e1.65 (2s, 8H, C(4)H2,
d
4.11. Reaction of 1b with MeOH in the absence of acids
35.4 (C6), 40.1 (C4, C8, C9, C10), 44.4 (C2), 48.4 (OCH3), 74.4 (C1, C3);
IR (neat) 2930, 2908, 2855, 1452, 1351, 1308, 1120, 1079, 1054, 984,
918, 874 cmꢂ1; HRMS (ESI-TOF) m/z calcd for C12H20NaO2 [MþNa]þ
219.1356, found 219.1358.
A mixture of 1b (190 mg, 1.0 mmol), CH2Cl2 (1.6 mL), and MeOH
(1.0 mL) was stirred at room temperature under argon. 1b was
slowly consumed, and 14b was newly formed in the mixture. The
conversion of 1b was monitored by NMR and GLC measurements as
8, 48, 85, and, 100% after 10 min, 1.5 h, 6 h, and 30 h, respectively.
Finally, 14b was recovered as an only product after 30 h: 1H NMR
4.9.6. 1-Butyl-3,5-dimethoxyadamantane (14g). The reaction was
performed following general procedure F, starting from 13d
(392 mg, 1.78 mmol) to yield of 14g (439 mg, 98%) as colorless oil;
(300 MHz, CDCl3)
s, 4H), 1.43 (s, 2H), 1.53 (br s, 2H), 1.64e1.68 (m, 4H), 2.18 (br s, 2H),
3.22 (s, 3H); 13C NMR (75 MHz, CDCl3)
14.3, 23.7, 25.1, 30.7, 35.8,
d
0.88 (t, J¼6.9 Hz, 3H), 1.13e1.25 (m, 6H), 1.37 (br
1H NMR (300 MHz, CDCl3)
d
0.79e0.86 (t, J¼6.8 Hz, 3H, C(a)H3),
1.20e1.27 (m, 8H, C(8)H2, C(b)H2, C(c)H2, C(d)H2), 1.39 (s, 4H, C(2)
H2, C(9)H2), 1.53e1.71 (m, C(4)H2, C(6)H2, C(10)H2), 2.31 (br s, 1H,
d
36.3, 40.7, 41.6, 43.8, 45.9, 48.0, 73.0. These data agreed with those
for 9b synthesized separately by following general procedure B.
C(7)H), 3.22 (s, 6H, OCH3); 13C NMR (75 MHz, CDCl3)
d
14.2 (Ca),
23.6 (Cb), 25.2 (Cc), 30.4 (C7), 37.1 (C1), 39.6 (C6, C10), 40.5 (C8),
42.9 (C4), 43.9 (Cd), 45.0 (C2, C9), 48.5 (OCH3), 75.0 (C3, C5); IR
(neat) 2927, 2856, 1457, 1334, 1193, 1157, 1081, 922 cmꢂ1; HRMS
(ESI-TOF) m/z calcd for C16H28NaO2 [MþNa]þ 275.1982, found
275.1988.
4.12. General procedure G for the synthesis of 15: reaction of
DHAs with AcOH (15b as an example) (Scheme 12)
AcOH (1 mL, 17.5 mmol) was added to a solution of 1b (698 mg,
3.67 mmol) in CH2Cl2 (7.7 mL) and stirred for 5 min under nitrogen
atmosphere. After removal of solvent in vacuo, 1-acetoxy-3-
butyladamantane (15b, 910 mg, 99%) was obtained as colorless
4.9.7. 1-Butoxy-3-methoxyadamantane (14h). The reaction was
performed following general procedure F, starting from 13e
(72.8 mg, 0.353 mmol) to yield 14h (82.4 mg, 98%) as colorless oil:
oil: 1H NMR (300 MHz, CDCl3)
1.12e1.54 (m, 12H, C(b)H2, C(c)H2, C(d)H2, C(4)H2, C(6)H2, C(10)H2),
1.81 (s, 2H, C(2)H2), 1.96 (s, 3H, COCH3), 2.01e2.09 (m, 4H, C(8)H2,
C(9)H2), 2.18e2.19 (br s, 2H, C(5)H, C(7)H); 13C NMR (75 MHz,
d
0.86e0.90 (t, J¼6.6 Hz, 3H, C(a)H3),
1H NMR (300 MHz, CDCl3)
1.25e1.35 (m, 2H, C(f)H2),1.38e1.51 (m, 4H, C(g)H2, C(6)H2),1.63 (br
d
0.85e0.89 (t, J¼7.3 Hz, 3H, C(e)H3),
s, 8H, C(4)H2, C(8)H2, C(9)H2, C(10)H2), 1.71 (s, 2H, C(2)H2), 2.28

S. Inomata et al. / Tetrahedron 69 (2013) 3238e3248
3247
CDCl3):
d
14.2 (Ca), 22.8 (COCH3), 23.6 (Cb), 24.9 (Cc), 30.9 (C5, C7),
2927, 1732, 1236, 1087, 1034, 888 cmꢂ1; HRMS (ESI-TOF) m/z calcd
for C17H28NaO3 [MþNa]þ 303.1931, found 303.1934.
35.9 (C6), 36.2 (C3), 40.9 (C8, C9), 41.2 (C4, C10), 43.4 (Cd), 45.9 (C2),
81.3 (C1), 170.4 (C]O); IR (NaCl) 2960, 2855, 1731, 1455, 1365, 1238,
1139, 1024, 864, 606 cmꢂ1
;
HRMS (ESI-TOF) m/z calcd for
4.12.6. 1-Acetoxy-3-butoxyadamantane (15g). The reaction was
performed following general procedure G in CH2Cl2, starting from
13e (91.0 mg, 0.441 mmol) to yield 15g (76.2 mg, 65%) as colorless
C16H26NaO2 [MþNa]þ 273.1825, found 273.1820.
4.12.1. 1-Acetoxyadamantane (15a). The reaction was performed
following general procedure G in n-heptane, starting from 1a
(913 mg, 6.80 mmol) to yield 15a (860 mg, 65%) as colorless oil: 1H
NMR (300 MHz, CDCl3)
2.05 (s, 6H, C(2)H2), 2.11 (br s, 3H, C(3)H); 13C NMR (75 MHz,
CDCl3) 22.8 (COCH3), 30.8 (C3), 36.2 (C4), 41.3 (C2), 80.3 (C1),
oil: 1H NMR (300 MHz, CDCl3)
d
0.83e0.88 (t, J¼7.2 Hz, 3H, C(e)H3),
1.26e1.34 (m, 2H, C(f)H2), 1.42e1.47 (m, 4H, C(g)H2, C(6)H2),
1.58e1.73 (m, 4H, C(4)H2, C(10)H2), 1.92 (s, 3H, COCH3), 1.93e2.06
(m, 6H, C(2)H2, C(8)H2, C(9)H2), 2.18 (br s, 2H, C(5)H, C(7)H),
d 1.66 (s, 6H, C(4)H2), 1.96 (s, 3H, COCH3),
3.33e3.37 (t, J¼6.6 Hz, 2H, C(h)H2); 13C NMR (75 MHz, CDCl3)
d 14.0
d
(Ce), 19.4 (Cf), 22.6 (COCH3), 31.0 (C5, C7), 32.7 (Cg), 35.2 (C6), 40.3
(C4, C10), 40.6 (C8, C9), 45.1 (C2), 60.0 (Ch), 73.8 (C3), 81.4 (C1),
170.2 (C]O); IR (neat) 2913, 2863, 1733, 1456, 1365, 1352, 1234,
170.3 (C]O).
4.12.2. 1-Acetoxy-3,5-dibutyladamantane (15c). The reaction was
performed following general procedure G, starting from 1d
(293 mg, 1.19 mmol) to yield 15c (353 mg, 97%) as colorless oil: 1H
1117, 1034, 987, 868 cmꢂ1
; HRMS (ESI-TOF) m/z calcd for
C16H26NaO3 [MþNa]þ 289.1774, found 289.1767.
NMR (300 MHz, CDCl3)
d
0.84e0.88 (t, J¼6.8 Hz, 6H, C(a)H3),
4.12.7. (R/S)-1-Acetoxy-3-butoxy-5-butyladamantane (15h). The re-
action was performed following general procedure G in CH2Cl2,
starting from 13f (396 mg, 1.51 mmol) to yield of 15h (438 mg, 90%)
1.01e1.40 (m, 18H, C(b)H2, C(c)H2, C(d)H2, C(6)H2, C(8)H2, C(10)H2),
1.68e1.80 (m, 4H, C(2)H2, C(9)H2), 1.93 (s, 3H, COCH3), 1.95e1.96
(2s, 2H, C(4)H2), 2.18 (br s, 1H, C(7)H); 13C NMR (75 MHz, CDCl3)
as colorless oil: 1H NMR (300 MHz, C6D6):
d 0.85e0.93 (m, 6H, C(a)
d
14.3 (Ca), 22.8 (COCH3), 23.7 (Cb), 25.1 (Cc), 30.9 (C7), 36.4 (C3,
H3, C(e)H3), 1.07e1.18 (m, 6H, C(b)H2, C(c)H2, C(d)H2), 1.34e1.35 (m,
2H, C(6)H2), 1.36e1.54 (m, 6H, C(10)H2, C(f)H2, C(g)H2), 1.62e1.63
(m, 2H, C(4)H2), 1.74 (s, 3H, COCH3), 1.84e1.90 (m, 2H, C(8)H2), 2.04
(s, 3H, C(7)H, C(9)H2), 2.20e2.30 (m, 2H, C(2)H2), 3.28e3.32 (t,
C5), 40.5 (C8), 41.0 (C6, C10), 43.3 (C2, C9), 44.4 (Cd), 46.6 (C4), 82.2
(C1), 170.5 (C]O); IR (neat) 2924, 2858, 1733, 1456, 1363, 1240,
1168, 1023 cmꢂ1; HRMS (ESI-TOF) m/z calcd for C20H34NaO2
[MþNa]þ 329.2451, found 329.2444.
J¼6.3 Hz, 2H, C(h)H2); 13C NMR (75 MHz, C6D6):
d 14.3 (Ce), 14.5
(Ca), 20.0 (Cf), 22.4 (COCH3), 24.0 (Cb), 25.5 (Cc), 31.1 (C7), 33.2 (Cg),
37.4 (C5), 40.4 (C6), 40.6 (C10), 40.7 (C8), 43.2 (Cd), 45.5 (C4), 45.7
(C9), 46.1 (C2), 60.2 (Ch), 74.3 (C3), 81.8 (C1), 169.6 (C]O); IR (neat)
4.12.3. 1-Acetoxy-3-phenyladamantane (15d). The reaction was
performed following general procedure G, starting from 13a
(488 mg, 2.32 mmol) to yield 15d (572 mg, 91%) as colorless oil: 1H
2926, 2860, 1734, 1456, 1364, 1335, 1236, 1156, 1088, 1021 cmꢂ1
;
NMR (300 MHz, CDCl3)
d
1.63e1.77 (m, 4H, C(4)H2, C(10)H2), 1.87
HRMS (ESI-TOF) m/z calcd for C20H34NaO3 [MþNa]þ 345.2400,
(br s, 2H, C(6)H2), 1.99 (s, 3H, COCH3), 2.07e2.23 (m, 4H, C(8)H2,
C(9)H2), 2.26 (br s, 2H, C(2)H2), 2.35 (br s, 2H, C(5)H, C(7)H)
7.15e7.40 (m. 5H, C(j)H, C(k)H, C(l)H); 13C NMR (75 MHz, CDCl3)
found 345.2409.
Acknowledgements
d
22.9 (COCH3), 31.1 (C5, C7), 35.5 (C6), 40.0 (C3), 40.6, 42.2 (C4, C8,
C9, C10), 46.6 (C2), 81.1 (C1), 125.0, 126.0, 128.4 (Cj, Ck, Cl), 149.0
This work was partly supported by Grant-in Aid (No. 14550833
and 18550105) from the Ministry of Education, Science, Sports, and
Culture, Japan. T.I. appreciates the financial support from the Yazaki
foundation.
(Ci), 170.5 (C]O); IR (neat) 2909, 2852, 1729, 1248, 1235, 697 cmꢂ1
;
HRMS (ESI-TOF) m/z calcd for C18H22NaO2 [MþNa]þ 293.1512,
found 293.1516.
4.12.4. (R/S)-1-Acetoxy-3-butyl-5-phenyladamantane (15e). The re-
action was performed following general procedure G in CH2Cl2,
starting from 13b (90.0 mg, 0.338 mmol) to yield (108 mg, 98%) 15e
Supplementary data
Syntheses of 9c, isolation of 1,3,5-tribromoadamantanes, copies
of 1H and 13C NMR spectra for all new compounds, and Figs. S1eS3.
Supplementary data related to this article can be found at Sup-
plementary data can be found at http://dx.doi.org/10.1016/
j.tet.2013.02.042.
as colorless oil; 1H NMR (300 MHz, CDCl3)
d 0.94e0.96 (br s, 3H,
C(a)H3), 1.29 (br s, 6H, C(b)H2, C(c)H2, C(d)H2), 1.48e1.65 (m, 4H,
C(6)H2, C(10)H2), 1.83e2.96 (m, 4H, C(4)H2, C(8)H2), 2.03 (s, 3H,
COCH3), 2.13 (br s, 2H, C(2)H2), 2.26 (br s, 2H, C(9)H2), 2.41e2.42 (br
s, 1H, C(7)H), 7.21e7.28 (m, 1H, C(l)H), 7.33e7.41 (m, 4H, C(j)H, C(k)
H); 13C NMR (75 MHz, CDCl3)
d 14.2 (Ca), 22.8 (COCH3), 23.6 (Cb),
References and notes
25.0 (Cc), 31.1 (C7), 36.7 (C3), 40.1, 40.2, 40.5, 41.7, 43.3, 45.2, 46.1,
47.5 (Cd, C2, C4, C5, C6, C8, C9, C10), 82.0 (C1), 125.0, 126.0 (Cj, Ck),
128.3 (Cl), 149.1 (Ci), 170.6 (C]O); IR (neat) 2925, 2858, 1712, 1446,
1. Pincock, R. E.; Torupka, E. J. J. Am. Chem. Soc. 1969, 91, 4593.
2. Pincock, R. E.; Scott, W. B.; Torupka, E. J. Can. J. Chem. 1972, 50, 3958e3964.
3. Warner, P.; LaRose, R.; Schleis, T. Tetrahedron Lett. 1974, 15, 1409e1412.
4. Fokin, A. A.; Schreiner, P. R.; Schleyer, P.; von, R.; Gunchenko, P. A. J. Org. Chem.
1998, 63, 6494e6502 The strain energies of 1a and [3.3.1]propellane were
estimated to be 55.5 and 36.1 kcal molꢂ1, which were much higher than those
of cyclopropane (27.2 kcal molꢂ1) and cyclobutane (26.4 kcal molꢂ1).
5. (a) Gassman, P. G.; Steppel, R. N.; Armour, E. A. Tetrahedron Lett. 1973, 14,
3287e3290; (b) Wiberg, K. B.; Bailey, W. F.; Jason, M. E. J. Org. Chem. 1976, 41,
2711e2714; (c) Wiberg, K. B. Acc. Chem. Res. 1984, 17, 379e386; (d) Wiberg, K. B.
Chem. Rev. 1989, 89, 975e983.
6. Wiberg, K. B.; Walker, F. H. J. Am. Chem. Soc. 1982, 104, 5239e5240.
7. Eaton, P. E.; Temme, G. H., III. J. Am. Chem. Soc. 1973, 95, 7508e7510.
8. Wiberg, K. B.; Connon, H. A.; Pratt, W. E. J. Am. Chem. Soc. 1979, 101, 6970e6972.
9. (a) Ishizone, T.; Matsuoka, S.; Sakai, S.; Harada, W.; Tajima, H. Macromolecules
2004, 37, 7069e7071; (b) Matsuoka, S.; Ogiwara, N.; Uehara, Y.; Ishizone, T.
Macromol. Symp. 2006, 240, 206e212.
1246, 1026, 753, 697 cmꢂ1
; HRMS (ESI-TOF) m/z calcd for
C22H30NaO2 [MþNa]þ 349.2138, found 349.2130.
4.12.5. (R/S)-1-Acetoxy-3-butyl-5-methoxyadamantane (15f). The
reaction was performed following general procedure G in CH2Cl2,
starting from 13d (366 mg, 1.66 mmol) to yield 15f (394 mg, 85%) as
colorless oil: 1H NMR (300 MHz, CDCl3)
d
0.84e0.88 (t, J¼6.2 Hz, 3H,
C(a)H3), 1.19e1.38 (m, 10H, C(b)H2, C(c)H2, C(d)H2, C(6)H2, C(10)H2),
1.46e1.55 (m, 2H, C(2)H2), 1.67e1.83 (m, 3H, C(4)H2, one of C(8)H2),
1.95 (br s, 4H, COCH3, one of C(8)H2), 2.01e2.08 (m, 2H, C(9)H2),
2.29e2.32 (br s, 1H, C(7)H), 3.22 (s, 3H, OCH3); 13C NMR (75 MHz,
10. Inomata, S.; Matsuoka, S.; Sakai, S.; Tajima, H.; Ishizone, T. Macromolecules
CDCl3) d 14.2 (Ca), 22.7 (COCH3), 23.5 (Cb), 25.1 (Cc), 30.6 (C7), 37.4
(C3), 39.6, 39.8, 40.3 (C6, C8, C10), 42.7 (Cd), 44.2 (C9), 45.0, 45.1
(C2, C4), 48.5 (OCH3), 74.7 (C5), 82.0 (C1), 170.4 (C]O); IR (neat)
2012, 45, 4184e4195.
11. Matsuoka, S.; Ogiwara, N.; Ishizone, T. J. Am. Chem. Soc. 2006, 128, 8708e8709.
12. Pincock, R. E.; Fung, F.-N. Tetrahedron Lett. 1980, 21, 19e22.

3248
S. Inomata et al. / Tetrahedron 69 (2013) 3238e3248
13. Scott, W. B.; Pincock, R. E. J. Am. Chem. Soc. 1973, 95, 2040e2041.
14. Gibbons, C. S.; Trotter, J. Can. J. Chem. 1973, 51, 87e91.
for 22 days was necessary to achieve the same conversion in CH2Cl2. After
workup, 11b could be isolated in 21% yield.
15. Adcock, W.; Clark, C. I. J. Org. Chem. 1993, 58, 7341e7349.
16. Ohno, M.; Shimizu, K.; Ishizaki, K.; Sasaki, T.; Eguchi, S. J. Org. Chem. 1988, 53,
729e733.
24. In several cases, trace amounts of corresponding adamantanes were obtained
along with the desired DHAs probably due to the reduction of 1,3-
dibromoadamantanes with lithium metal.
17. (a) Kobayashi, S.; Matsuzawa, T.; Matsuoka, S.; Tajima, H.; Ishizone, T. Macro-
molecules 2006, 39, 5979e5986; (b) Kobayashi, S.; Kataoka, H.; Ishizone, T.;
Kato, T.; Ono, T.; Kobukata, S.; Ogi, H. Macromolecules 2008, 41, 5502e5508.
18. (a) Kevill, D. N.; Kolwyck, K. C.; Weitl, F. L. J. Am. Chem. Soc. 1970, 92,
7300e7306; (b) Poindexter, G. S.; Kropp, P. J. J. Org. Chem. 1976, 41, 1215e1218;
(c) Davidson, R. I.; Kropp, P. I. J. Org. Chem. 1982, 47, 1904e1909; (d) Moss, R. A.;
Tian, J.; Sauers, R. R. Org. Lett. 2004, 6, 4293e4296.
19. Ledneczki, I.; Molnar A. Synth. Commun. 2004, 34, 3683e3690.
20. (a) Schreiner, P. R.; Lauenstein, O.; Kolomitsyn, I. V.; Nadi, S.; Fokin, A. A. Angew.
Chem., Int. Ed. 1998, 37, 1895e1897; (b) Fokin, A. A.; Schreiner, P. R. Adv. Synth.
Catal. 2003, 345, 1035e1052.
25. (a) Schleyer, P.; von, R.; Fort, R. C., Jr.; Watts, W. E.; Comisarow, M. B.; Olah, G. A.
J. Am. Chem. Soc. 1964, 86, 4195e4197; (b) Olah, G. A.; Prakash, G. K. S.; Shin, J.
G.; Krishnamurthy, V. V.; Mateescu, G. D.; Liang, G.; Sipos, G.; Buss, V.; Gund, T.
M.; Schleyer, P.; von, R. J. Am. Chem. Soc. 1985, 107, 2764e2772; (c) Takeuchi, K.;
Okazaki, T.; Kitagawa, T.; Ushino, T.; Ueda, K.; Endo, T. J. Org. Chem. 2001, 66,
2034e2043.
26. (a) Jarret, R. M.; Cusumano, L. Tetrahedron Lett. 1990, 31, 171e174; (b) Frei, K.;
Bernstein, H. J. J. Chem. Phys. 1963, 38, 1216e1227.
27. Eaton, P. E. Angew. Chem., Int. Ed. Engl. 1992, 31, 1421e1436.
28. Jasys, V. J.; Lombardo, F.; Appleton, T. A.; Bordner, J.; Ziliox, M.; Volkmann, R. A.
J. Am. Chem. Soc. 2000, 122, 466e473.
ꢀ
ꢀ
21. Schreiner, P. R.; Lauenstein, O.; Butova, E. D.; Gunchenko, P. A.; Kolomitsin, I. V.;
Wittkopp, A.; Feder, G.; Fokin, A. A. Chem.dEur. J. 2001, 7, 4996e5003.
22. It should be noted that considerable amounts (w15%) of tribromides of 1-phenyl-
and 1-alkoxyadamantanes, such as 1,3,5-tribromo-7-phenyladamantane, 1,3,5-
tribromo-7-methoxyadamantane, and 1,3,5-tribromo-7-butoxyadamantane
certainly formed in the reaction mixtures using mono-substituted ada-
mantanes, such as 8a, 9a, and 9c after the prolonged reaction (See Supplementary
data).
29. Schreiner, P. R.; Fokin, A. A.; Lauenstein;Okamoto, Y.;Wakita, T.;Rinderspacher, C.;
Robinson, G. H.; Vohs, J. K.; Campana, C. F. J. Am. Chem. Soc. 2002, 124,
13348e13349.
30. Ref. 2. The simultaneous introduction of two different substituents on ada-
mantyl framework was also attained to form 1-bromo-3-ethoxyadamantane by
the reaction of 1a in the presence of bromine in diethyl ether. The reaction of
1a with bromine gave a 3-bromo-1-adamantyl cation, and the cation reacted
with nucleophilic diethyl ether to provide an oxonium salt. The following
elimination of oxonium salt afforded 1-bromo-3-ethoxyadamantane as a major
product from 1a.
23. Similar radical bromination of 8b proceeded by using fluorobenzene as organic
phase and the conversion of 8b reached 96% after 5 days, while longer reaction