Semipinacol and protoadamantane-adamantane rearrangements of 5,6-dibromoadamantan-2-one and -2-ol

Article abstract of DOI:10.1016/j.tet.2017.04.006

A number of new polybrominated adamantanes were formed by rearrangements and bromination of 2,2,6,6-tetrabromoadamantane under Friedel-Crafts conditions. Protoadamantane-4,10-dione, 10-acetoxyprotoadamantan-4-one, 1,2,6-triacetoxyadamantane and 5,6-diacetoxyadamantan-2-one were formed by successive semipinacol and protoadamantane-adamantane rearrangements of 5,6-dibromoadamantan-2-one and 5,6-dibromoadamantan-2-ol. This work may open up new pathways for the synthesis of 1,2,6-trisubstituted adamantanes.

Full text of DOI:10.1016/j.tet.2017.04.006

Tetrahedron xxx (2017) 1e5
Contents lists available at ScienceDirect
Tetrahedron
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Semipinacol and protoadamantane-adamantane rearrangements of
5,6-dibromoadamantan-2-one and -2-ol
Xiaofang Wang a, Yuxiang Dong a, Edward L. Ezell b, Jered C. Garrison a, James K. Wood c,
,
*
James P. Hagen c, Jonathan L. Vennerstrom a
a College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198, United States
b Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, NE, 68198, United States
c Department of Chemistry, University of Nebraska-Omaha, Omaha, NE, 68182, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A number of new polybrominated adamantanes were formed by rearrangements and bromination of
2,2,6,6-tetrabromoadamantane under Friedel-Crafts conditions. Protoadamantane-4,10-dione, 10-
acetoxyprotoadamantan-4-one, 1,2,6-triacetoxyadamantane and 5,6-diacetoxyadamantan-2-one were
formed by successive semipinacol and protoadamantane-adamantane rearrangements of 5,6-
dibromoadamantan-2-one and 5,6-dibromoadamantan-2-ol. This work may open up new pathways
for the synthesis of 1,2,6-trisubstituted adamantanes.
Received 18 February 2017
Received in revised form
31 March 2017
Accepted 4 April 2017
Available online xxx
© 2017 Elsevier Ltd. All rights reserved.
Keywords:
Semipinacol rearrangement
Protoadamantane-adamantane
rearrangement
Polybrominated adamantanes
1,2,6-Trisubstituted adamantanes
1. Introduction
ozonide OZ439 (3)9 (Fig. 1). However, 1,2,6-substituted ada-
mantanes are uncommon, and they are only described in theoret-
Substituted adamantanes have long been important tools in
mechanistic organic chemistry.1,2 Compounds with adamantane
substructures also play important roles in medicinal chemistry and
material science.3,4 Most mono- and disubstituted adamantane
derivatives are readily accessible, but tri- and tetrasubstituted
adamantanes are less common,5 and most of these are 1,3,5- and
1,3,5,7-bridgehead substituted adamantanes. For the synthesis of
the latter, successive bridgehead substitutions under Friedel-Crafts
conditions become more difficult due to destabilization of cationic
intermediates by electron withdrawing substituents.6 This is well
illustrated in the bromination of adamantane where, by using
increasingly more reactive Lewis acid catalysts and vigorous reac-
tion conditions, adamantane may be selectively mono-, di-, tri-, and
tetrabrominated at the bridgehead positions.7
ical studies.10,11 Our initial attempts to synthesize 1 and 2 involved
oxidation reactions of adamantane-2,6-dione (4)12 and its corre-
sponding diol esters. However, we found that 4 resisted oxidation
by chromium, oxone, periodate, and ruthenium reagents, due
presumably to bridgehead deactivation13 by the twin ketone
functional groups. This outcome parallels previous observations
that adamantanes with even one ketone functional group are
relatively resistant not only to oxidation,14,15 but also to Friedel-
Crafts bromination.16,17
2. Results and discussion
Based on aluminum halide-induced halogen migrations in 2,2-
dihaloadamantanes,18,19 and the aluminum bromide/bromine-
induced rearrangement/bromination of 2,2-dichoroadamantane
(5) to 1,3,6-tribromoadamantane (6)20 (Scheme 1), we reasoned
that a similar rearrangement of 2,2,6,6-tetrabromoadamantane (9)
under Friedel-Crafts conditions might provide an avenue to 1,2,6-
We were interested in 1,2,6-trihydroxyadamantane (1) and its
corresponding ketone, 5,6-dihydroxyadamantan-2-one (2), as
synthetic precursors to oxidative metabolites8 of the antimalarial
trisubstituted adamantanes (Scheme 2). As
a prelude, we
confirmed that exposure of 2,2-dibromoadamantane (7)21 to either
iron powder in refluxing bromine22 or aluminum bromide in
* Corresponding author.
E-mail address: jvenners@unmc.edu (J.L. Vennerstrom).
http://dx.doi.org/10.1016/j.tet.2017.04.006
0040-4020/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Wang X, et al., Semipinacol and protoadamantane-adamantane rearrangements of 5,6-dibromoadamantan-2-
one and -2-ol, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.04.006

2
X. Wang et al. / Tetrahedron xxx (2017) 1e5
Fig. 1. Structures of 1e4.
Scheme 1. Model rearrangement/bromination reactions of adamantane geminal
dihalides 5 and 7.
bromine at rt readily formed the desired 6 in 70% yield after a single
crystallization from EtOH (Scheme 1). 1,3,6-Tribromoadamantane
(6) was then hydrolyzed to 1,3,6-trihydroxyadamantane (8) with
Ag2SO4 in concentrated H2SO4 in 69% yield according to a modi-
fied23 procedure of Song and le Noble.17 We thus had confidence to
move forward with a parallel reaction sequence for 9 (Scheme 2).
Fig. 2. Thermal ellipsoid plot of 1,2,5,6-tetrabromoadamantane (12).
Exposure of
4 to hot thionyl bromide afforded 2,2,6,6-
tetrabromoadamantane (9) in 72% yield. Subjecting the latter to
various Friedel-Crafts reaction conditions led to the formation of
various proportions of 2,2,5,6-tetrabromoadamantane (10),
also gave complex mixtures which we attribute in part to dispro-
portionation reactions of the geminal dibromide substructure in
the acidic media. However, we found that treatment of 10 with
Ag2O in AcOH at 120 ꢀC afforded 13 in 56% yield (Scheme 3); un-
expectedly, the bridgehead bromine atom was completely stable
under these more weakly acidic conditions.28 As these reactions
reveal, with the strongly deactivating ketone functional group,
bromine atoms become more difficult to remove just as they were
more difficult to introduce with a carbonyl group in the substrate.
Since we had previously succeeded in converting 6 to 8 with
Ag2SO4 in concentrated H2SO4 at 80 ꢀC (Scheme 1), we used these
same conditions in an attempt to hydrolyze 13 to 2. However, this
reaction led to skeletal rearrangement to produce proto-
adamantane-4,10-dione (14)29 instead of the desired product
(Scheme 3). One plausible mechanism to account for the formation
of 14 is by a semipinacol-type rearrangement30 of an intermediate
6-adamantyl carbocation. The structure of diketone 14 was strongly
suggested by ten signals in the 13C{1H } NMR spectrum including
two downfield signals at 212.1 and 212.8 ppm and a molecular
formula of C10H12O2 determined by HRMS. This structural assign-
ment was confirmed by key COSY correlations between the 3-H
methine hydrogen and its vicinal hydrogen partners on C-2 and
C-8 and HMBC correlations between 3-H and C-4, 1-H and C-3, H-6
and C-4, and one of the C-5 methylene hydrogens and C-10.
We then postulated that reducing the ketone functional group of
13 to an alcohol (15) (or alcohol derivative) could improve the
2,2,5,6,6-pentabromoadamantane
(11),
and
1,2,5,6-
tetrabromoadamantane (12) (Scheme 2). For example, treatment
of 9 with aluminum bromide (3.6 mol equiv) in bromine24 at
40e50 ꢀC for 48 h gave a mixture of 10 (31%) and 11 (25%), isolated
by chromatography and crystallization, respectively. We were
pleased to discover that using less aluminum bromide (1.8 mol
equiv) and a slightly higher temperature (50e60 ꢀC) for 24 h led to
the formation of a 79:17 ratio (GC-MS data) of 10:12 as the major
products. From the crude reaction product, 10 was isolated in 54%
yield after a single crystallization from ethanol and 12 was isolated
in 10% yield after chromatographic purification. Unlike the racemic
pair 10, we anticipated that 12 would be a pair of diastereomers, but
the NMR data for 12 indicated that it was a single diastereomer. X-
ray crystallographic data25 for 12 revealed that the pairs of bromine
atoms on C-1 and C-6 and on C-2 and C-5 were in a cis configura-
tion (Fig. 2). As was the case for the parallel rearrangement of 7 to 6,
we surmise that the reaction sequence to form 10, 11, and 12 from 9
proceeded by disproportionation-comproportionation pathways
involving intermolecular hydride shifts.7,18,26,27 For both reactions,
we also observed small quantities of unidentified isomeric tetra-
bromo and pentabromoadamantanes (GC-MS data).
All attempts to directly convert 10 to 5,6-dihydroxyadamantan-
2-one (2) using Ag2SO4 in concentrated H2SO4 failed. Further at-
tempts to hydrolyze 10 or 11 with 1 M HCl in THF/EtOH at 50e60 ꢀC
Scheme 2. Rearrangement/bromination of 9 to form 10e12.
Please cite this article in press as: Wang X, et al., Semipinacol and protoadamantane-adamantane rearrangements of 5,6-dibromoadamantan-2-
one and -2-ol, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.04.006

X. Wang et al. / Tetrahedron xxx (2017) 1e5
3
Scheme 3. Selective solvolysis of 10 to 13 and semipinacol rearrangement of 13 to 14.
Scheme 4. Reduction of 13 to 15, semipinacol rearrangement of 15 to 16, and protoadamantane-adamantane rearrangement of 16 to 17.
reactivity of the C-6 C-Br bond for substitution reactions. When 15
(mixture of diasteromers) was treated with Ag2O in AcOH at
110e120 ꢀC (conditions under which 13 was stable), the semi-
pinacol rearrangement product 10-acetoxyprotoadamantan-4-one
(16) was formed (Scheme 4). Although this was not the desired
1,2,6-triacetoxyadamantane (17), the formation of 16 implied that
the proposed strategy was working e that is, the C-Br bonds of 15
were sufficiently reactive for substitution reactions using Ag2O in
AcOH. Since protoadamantan-4-one rearranges to 1,2-
diacetoxyadamantane with BF3 Et2O in acetic anhydride at rt,31
we were pleased that exposure of 16 to these same conditions
afforded 17 (mixture of diastereomers) as the only product in 71%
yield.
Heartened by the successful conversion of 16 to 17, we revisited
our earlier but unsuccessful attempts to coax dione 14 to undergo a
parallel protoadamantane-adamantane rearrangement. The key
was to lower the reaction temperature; exposure of 14 to BF3 Et2O
in acetic anhydride at 0 ꢀC for 5 h with quenching at 0 ꢀC formed the
desired rearrangement product 18 in 55% yield (Scheme 5). The
structure of the racemic 5,6-diacetoxyadamantan-2-one 18 was
suggested by fourteen signals in the 13C{1H } NMR including three
downfield signals at 170.13, 170.15, and 214.1 ppm and a molecular
formula of C14H18O5 determined by HRMS. This structural assign-
ment was consistent with COSY correlations between 1-H and and
its vicinal hydrogen partners on C-8 and C-9, and between 3-H and
its vicinal hydrogen partners on C-4 and C-10. HMBC correlations
between 6-H and C-13, and between methylene carbon C-4, C-8, C-
9, and C-10 hydrogen atoms and C-6 added further evidence for the
structural assignment of 18.32
adamantanes by rearrangements/bromination of 2,2,6,6-
tetrabromoadamantane (9) under Friedel-Crafts conditions. We
also isolated protoadamantane-4,10-dione (14), 10-
acetoxyprotoadamantan-4-one (16), 1,2,6-triacetoxyadamantane
(17) and 5,6-diacetoxyadamantan-2-one (18) by semipinacol and
protoadamantane-adamantane rearrangements. This work may
open up new pathways for the synthesis of 1,2,6-trisubstituted
adamantanes.
4. Experimental
4.1. General experimental details
Melting points are uncorrected.1D 1H and 13C NMR spectra were
recorded on a 500 MHz spectrometer using CDCl3 (6, 7, 9e18) D2O
(8), or DMSO-d6 (8) as solvents. 2D NMR spectra for 14 and 18 were
obtained on a 400 MHz spectrometer using CDCl3 as solvent. All
chemical shifts are reported in parts per million (ppm) and are
relative to internal (CH3)4Si (0 ppm) for 1H and CDCl3 (77.0 ppm) or
DMSO-d6 (39.7 ppm) for 13C NMR. Peak multiplicites are indicated
by the following abbreviations: s (singlet), d (doublet), t (triplet), q
(quartet), and m (multiplet). EI GC-MS data were obtained using a
quadrapole mass spectrometer with 30 m DB-5 type columns and a
He flow rate of 1 mL/min. Silica gel (sg) particle size 40e63 mm was
used for all flash column chromatography. Reported reaction tem-
peratures are those of the oil bath.
4.2. 1,3,6-Tribromoadamantane (6)
Iron powder (5.0 g, 89.3 mmol) was added at 0 ꢀC to bromine
(25 mL, 78.0 g, 490 mmol) and the resulting mixture was stirred for
30 min at 0 ꢀC. Then 7 (8.0 g, 27.2 mmol) was added in portions and
the reaction mixture was refluxed overnight before pouring on a
mixture of 1 M HCl and ice. The resulting suspension was treated
with Na2SO3 and filtered to give the crude product as a yellow solid.
Purification by crystallization from EtOH afforded 6 (7.1 g, 70%) as a
colorless solid. mp 169e170 ꢀC, lit.1 mp 169e170 ꢀC; 1H NMR
3. Conclusion
In summary, we synthesized a number of new polybrominated
(CDCl3)
d
2.16 (d, J ¼ 12.5 Hz, 2H), 2.34e2.48 (m, 6H), 2.88 (s, 2H),
2.92 (d, J ¼ 13.0 Hz, 2H), 4.47 (s, 1H); 13C NMR (CDCl3)
d 41.0, 42.2,
47.3, 55.1, 58.2, 59.0, 59.4.
4.3. 2,2-Dibromoadamantane (7)
Scheme 5. Protoadamantane-adamantane rearrangement of 14 to 18.
A mixture of 2-adamantanone (5.0 g, 30 mmol) and thionyl
Please cite this article in press as: Wang X, et al., Semipinacol and protoadamantane-adamantane rearrangements of 5,6-dibromoadamantan-2-
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4
X. Wang et al. / Tetrahedron xxx (2017) 1e5
bromide (10 mL, 26.8 g, 129 mmol) was stirred at rt for 12 h. The
excess thionyl bromide was removed in vacuo and the residue
was diluted with ice water. The solid was collected by filtration
to afford 7 as pale yellow solid (9.7 g, 99%). mp 163e164 ꢀC, lit.2
then cooled to rt. At this time, GC-MS data indicated a 79:17:4 ratio
of 10:12:unidentified tetrabromoadamantane isomers. The reac-
tion mixture was quenched with ice water, treated with saturated
aq. Na2SO3, and filtered to give 1.5 g of a crude product. Crystalli-
zation of the latter from EtOH afforded 10 (1.08 g, 54%). The residue
from the mother liquor was purified by sg chromatography (EtOAc-
hexanes) to afford 12 (0.20 g, 10%) as a pale yellow solid. mp
mp 164e165 ꢀC; 1H NMR (CDCl3)
d 1.74e1.84 (m, 6H), 1.87e1.95
(m, 2H), 2.50e2.63 (m, 6H); 13C NMR (CDCl3)
d 26.5, 35.4, 38.9,
46.8, 85.9.
184e185 ꢀC. 1H NMR (CDCl3)
2.56 (d, J ¼ 2.5 Hz, 2H), 3.11 (s, 2H), 3.26 (d, J ¼ 13.5 Hz, 2H), 4.58 (s,
2H); 13C NMR (CDCl3)
36.6, 41.3, 42.1, 46.6, 61.5, 63.8. HRMS (ESI-
TOF) m/z: [M]þ Calcd for C10
d
2.07 (s, 2H), 2.29 (d, J ¼ 14.0 Hz, 2H),
4.4. 1,3,6-Trihydroxyadamantane (8).1
d
79
To a mixture of 6 (5.0 g, 13.4 mmol) and silver sulfate (5.0 g,
16.0 mmol) at rt was added concentrated sulfuric acid (10 mL). The
reaction mixture was heated at 80 ꢀC for 3 h, cooled to rt, filtered
and the solid was washed with water. The filtrate was neutralized
with solid KOH and filtered, and the solid was washed with EtOH.
The filtrate was concentrated in vacuo and then purified by silica
gel chromatography with an EtOAc eluant to provide the 8 as a
H Br4 447.7672; Found 447.7687.
12
4.8. 5,6-Dibromo-2-adamantanone (13)
A mixture of 10 (2.63 g, 2.21 mmol), silver oxide (2.20 g,
9.50 mmol) and acetic acid (30 mL) was heated at 120 ꢀC for 12 h.
The reaction mixture was cooled to rt, filtered and the resulting
solid was washed with CH2Cl2 (20 mL). The filtrate was concen-
trated in vacuo to afford 13 as white solid (1.01 g, 56%). mp
white solid (1.7 g, 69%). mp 272e273 ꢀC dec.; 1H NMR (D2O)
d 1.40
(d, J ¼ 12.5 Hz, 2H), 1.56e1.70 (m, 4H), 1.66 (s, 2H), 1.88 (d,
J ¼ 12.0 Hz, 2H), 2.13 (s, 2H), 3.73 (s, 1H); 1H NMR (DMSO-d6)
d
1.15
183e184 ꢀC. 1H NMR (CDCl3)
d
1.93 (d, J ¼ 12.5 Hz, 1H), 2.16e2.28
(d, J ¼ 11.0 Hz, 2H), 1.36e1.52 (m, 4H), 1.48 (s, 2H), 1.86 (d,
(m, 2H), 2.41 (d, J ¼ 13.0 Hz, 1H), 2.54e2.72 (m, 4H), 2.78 (dd,
J ¼ 13.5, 3.0 Hz, 1H), 2.94 (d, J ¼ 11.0 Hz, 1H), 3.05 (dt, J ¼ 13.5,
J ¼ 11.0 Hz, 2H),1.90 (s, 2H), 3.46 (s, 1H); 13C NMR (DMSO-d6)
d 36.9,
38.2, 42.6, 53.8, 68.3, 68.4, 70.5.
3.0 Hz, 1H), 4.85 (s, 1H); 13C NMR (CDCl3)
d 31.7, 38.5, 38.6, 42.8,
47.9, 48.1, 49.5, 61.1, 65.2, 212.8. HRMS (ESI-TOF) m/z: [M]þ Calcd for
79
4.5. 2,2,6,6-Tetrabromoadamantane (9)
C H Br2O 305.9255; Found 305.9265.
10 12
A mixture of adamantane-2,6-dione (4) (1.0 g, 6.10 mmol) and
thionyl bromide (2 mL, 1.12 g, 54 mmol) was refluxed at 80 ꢀC for
12 h. The excess thionyl bromide was removed in vacuo and the
residue was diluted with ice water and then filtered to afford 9 as
pale yellow solid (1.98 g, 72%). mp 134e135 ꢀC. 1H NMR (CDCl3)
4.9. Protoadamantane-4,10-dione (14)
A mixture of 13 (1.00 g, 3.25 mmol), silver sulfate (2.20 g,
7.06 mmol) and concentrated sulfuric acid (6 mL) was heated at
0 ꢀC for 3 h and then cooled to rt. The reaction mixture was diluted
with THF (30 mL) and neutralized with solid potassium carbonate.
The solid was removed by filtration and rinsed with THF. The
filtrate was then concentrated in vacuo. Purification of the residue
by sg chromatography (EtOAc) afforded 14 (0.22 g, 42%) as a white
d
2.49 (s, 4H), 2.59 (s, 8H); 13C NMR (CDCl3)
d 32.5, 44.7, 82.6. HRMS
79
(ESI-TOF) m/z: [M]þ Calcd for C10
H Br4 447.7672; Found 447.7678.
12
4.6. 1,2,6,6-Tetrabromoadamantane (10) and 1,2,2,6,6-
pentabromoadamantane (11)
solid. mp 222e223 ꢀC. 1H NMR (CDCl3)
d 1.75e1.83 (m, 1H),
1.88e2.25 (m, 5H), 2.38e2.48 (m, 1H), 2.58e2.66 (m, 1H), 2.80 (s,
Tetrabromoadamantane 9 (2.0 g, 2.12 mmol) was added to a
mixture of AlBr3 (2.0 g, 7.5 mmol) and bromine (10 mL, 31.2 g,
195 mmol) at 0 ꢀC. The resulting reaction mixture was heated at
40e50 ꢀC for 48 h (monitored by GC-MS until starting material
disappeared) and then cooled to rt. The reaction mixture was
quenched with ice water, treated with saturated aq. Na2SO3, and
then filtered to give a mixture of 10 and 11. Crystallization of the
crude product from EtOH afforded pure 11 (0.60 g, 26%). mp
1H), 2.89 (s, 1H), 3.00 (s, 1H), 3.06 (t, J ¼ 9.0 Hz, 1H); 13C NMR
(CDCl3)
d 34.1, 35.2, 35.9, 40.9, 41.1, 45.1, 49.6, 52.4, 212.0, 212.7.
HRMS (ESI-TOF) m/z: [M]þ Calcd for C10H12O2 164.0837; Found
164.0840.
4.10. 2-Hydroxy-5,6-dibromoadamane (15)
NaBH4 (0.20 g, 5.26 mmol) was added slowly to a solution of 13
(0.8 g, 2.60 mmol) in EtOH (20 mL) at 0 ꢀC. The resulting mixture
was stirred at rt for 24 h and then quenched with water (10 mL) and
1 M aq. NaOH (5 mL). The mixture was concentrated under reduced
pressure to about 15 mL and then filtered to afford 15 (mixture of
diastereomers) as a white solid (0.60 g, 74%). mp 147e149 ꢀC. 1H
139e140 ꢀC. 1H NMR (CDCl3)
d
2.55 (s, 2H), 2.61 (d, J ¼ 14.5 Hz, 2H),
2.67 (d, J ¼ 14.5 Hz, 2H), 2.85 (s,1H), 2.96 (d, J ¼ 13.5 Hz, 2H), 3.19 (d,
J ¼ 13.5 Hz, 2H); 13C NMR (CDCl3)
d 31.48, 42.3, 47.01, 48.7, 66.9,
79
78.7, 84.7. HRMS (ESI-TOF) m/z: [M]þ Calcd for C10
H
Br481Br
11
527.6757; Found 527.6756. The residue from the mother liquor was
purified by sg chromatography (EtOAc-hexanes) to afford 10 as
NMR (CDCl3)
d
1.55e2.55 (m, 10H), 2.59 (d, J ¼ 13.0 Hz, 0.3H), 2.69
white solid (0.63 g, 31.5%). mp 137e138 ꢀC. 1H NMR (CDCl3)
d
1.93
(d, J ¼ 13.5 Hz, 0.7H), 2.86 (dt, J ¼ 13.5, 3.5 Hz, 0.7H), 3.05 (dt,
J ¼ 13.0, 3.5 Hz, 0.3H), 3.87 (s, 0.3H), 3.97 (s, 0.7H), 4.65 (s, 0.3H),
(dd, J ¼ 14.0, 2.5 Hz,1H), 2.34e2.53 (m, 4H), 2.55 (s,1H), 2.63 (s,1H),
2.70e2.82 (m, 2H), 2.97 (dd, J ¼ 13.0, 1.5 Hz, 1H), 3.47 (dt, J ¼ 13.5,
4.68 (s, 0.7H); 13C NMR (CDCl3)
d 23.6, 28.8, 31.1, 35.7, 36.5, 37.2,
3.0 Hz, 1H), 4.64 (s, 1H); 13C NMR (CDCl3)
d
27.9, 35.0, 37.3, 39.8,
37.6, 37.8, 38.1, 38.3, 39.1, 41.6, 43.4, 48.1, 64.0, 65.0, 67.6, 67.7, 71.7,
46.3, 48.9, 49.2, 61.0, 67.1, 78.5. HRMS (ESI-TOF) m/z: [M]þ Calcd for
72.3. HRMS (ESI-TOF) m/z: [M]þ Calcd for C10
H
Br2O 307.9411;
79
14
79
C
H
Br4 447.7672; Found 447.7684.
Found 307.9423.
10 12
4.7. 1,2,6,6-Tetrabromoadamantane (10) and 1,2,5,6-
tetrabromoadamantane (12)
4.11. 10-Acetoxyprotoadamantan-4-one (16)
A mixture of 15 (0.50 g, 1.61 mmol), silver oxide (1.00 g,
4.32 mmol) and AcOH (10 mL) was heated at 120 ꢀC for 36 h, cooled
to rt, filtered and the resulting solid was washed with CH2Cl2. The
filtrate was then concentrated in vacuo to afford a residue that was
purified by sg chromatography (EtOAc-hexanes) to afford 16
Tetrabromoadamantane 9 (2.0 g, 2.12 mmol) was added to a
mixture of AlBr3 (1.0 g, 3.75 mmol) and bromine (10 mL, 31.2 g,
195 mmol) at 0 ꢀC. The reaction mixture was heated at 50e60 ꢀC for
24 h (monitored by GC-MS until starting material disappeared) and
Please cite this article in press as: Wang X, et al., Semipinacol and protoadamantane-adamantane rearrangements of 5,6-dibromoadamantan-2-
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X. Wang et al. / Tetrahedron xxx (2017) 1e5
5
(mixture of diastereomers) as a white solid (0.21 g, 62%). mp
85e87 ꢀC.1H NMR (CDCl3)
1.42e1.49 (m, 0.4H),1.56e1.66 (m,1H),
generous support of this research. We acknowledge the NIH
(P30CA036727) and the Nebraska Research Initiative for their
support of the Eppley Structural Biology NMR Facility.
d
1.68e1.74 (m, 1.2H), 1.76e2.12 (m, 4H), 2.10 (s, 3H), 1.15e2.21 (m,
0.4H), 2.26e2.34 (m, 0.4H), 2.44e2.52 (m,1H), 2.53e2.58 (m, 0.4H),
2.60e2.68 (m, 1.6H), 2.71e2.80 (m, 1H), 2.86e2.94 (m, 0.6H), 4.91
Appendix A. Supplementary data
(s, 0.4H), 5.09 (t, J ¼ 2.5 Hz, 0.6H); 13C NMR (CDCl3)
d 21.26, 21.34,
31.1, 32.4, 32.9, 33.0, 33.5, 34.2, 35.97, 36.02, 36.4, 37.7, 39.5, 40.6,
41.4, 41.6, 49.6, 50.2, 74.6, 170.1, 170.2, 214.5, 215.0. HRMS (ESI-TOF)
m/z: [M]þ Calcd for C12H16O3 208.1099; Found 208.1105.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2017.04.006.
References
4.12. 1,2,6-Triacetoxyadamantane (17)
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0 ꢀC for 5 h and then quenched with ice water (5 mL). The mixture
was extracted with EtOAc (3 ꢁ 10 mL) and the combined extracts
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the data can be obtained, free of charge, on application to CCDC, 12 Union
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one (13).
a colorless oil (0.16 g, 55%). 1H NMR (CDCl3)
d 1.73e1.80 (m,1H),1.97
(s, 3H), 1.99e2.06 (m, 1H), 2.08e2.20 (m, 1H), 2.15 (s, 3H),
2.26e2.33 (m, 1H), 2.34e2.48 (m, 3H), 2.50e2.57 (m, 1H),
2.57e2.70 (m, 3H), 5.70 (s, 1H); 13C NMR (CDCl3)
d
21.05, 22.07,
32.40, 33.50, 36.45, 36.65, 38.91, 45.81, 45.96, 74.01, 77.52, 169.79,
169.81, 214.14. HRMS (ESI-TOF) m/z: [M
Na]þ Calcd for
14H18O5Na 289.1052; Found 289.1052.
þ
29. We were unable to form crystals of 14 or a derivative of 14 suitable for X-ray
crystallography.
C
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tween the 6-H and 7-H methine hydrogen atoms and their vicinal hydrogen
partners (see supplementary data).
Acknowledgment
We thank the Medicines for Malaria Venture (MMV) for
Please cite this article in press as: Wang X, et al., Semipinacol and protoadamantane-adamantane rearrangements of 5,6-dibromoadamantan-2-
one and -2-ol, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.04.006