Synthesis of 2-oxaadamantane and 1-aryl-2-oxaadamantanes

Article abstract of DOI:10.1016/j.tetlet.2016.06.027

The direct reduction of 1-hydroxy-2-oxaadamantanes derivatives to give 2-oxaadamantanes was unsuccessful. 2-Oxaadamantanes could, however, be prepared from 1-hydroxy-2-oxaadamantes by a ring-opening reaction followed by reduction and subsequent ring-closu

Full text of DOI:10.1016/j.tetlet.2016.06.027

Tetrahedron Letters 57 (2016) 3150–3151
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Tetrahedron Letters
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Synthesis of 2-oxaadamantane and 1-aryl-2-oxaadamantanes
b
Tore Benneche a, , Marcus A. Tius
⇑
a Department of Chemistry, University of Oslo, Blindern, 0315 Oslo, Norway
b Department of Chemistry, University of Hawaii, 2545 McCarthy Mall, Honolulu, HI 96822, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The direct reduction of 1-hydroxy-2-oxaadamantanes derivatives to give 2-oxaadamantanes was unsuc-
cessful. 2-Oxaadamantanes could, however, be prepared from 1-hydroxy-2-oxaadamantes by a ring-
opening reaction followed by reduction and subsequent ring-closure.
Received 16 March 2016
Revised 13 May 2016
Accepted 6 June 2016
Available online 7 June 2016
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
2-Oxaadamantanes
Elimination
Reduction
Dehydration
Ring-opening
Ring-closing
OH
We have previously shown that cannabinoids bearing a pendant
2-oxaadamantyl group at the C3 position (Fig. 1) exhibited favor-
able affinities for both cannabinoid 1 and cannabinoid 2 receptors.1
In that paper a precursor of the 2-oxaadamantane structure was
coupled to the C3 position of the cannabinoid skeleton by a Suzuki
reaction. Another method for the synthesis of 1-arylated-2-
oxaadamantanes is direct electrophilic aromatic substitution with
1-methanesulfonate-2-oxoadamantanes catalyzed by trifluorosul-
fonic acid.2 This method has been developed for electron rich aro-
matic rings. As part of our interest in cannabinoids having an
oxaadamantane as the C3 substituent, we wanted to investigate
the possibility of making 1-aryl-2-oxaadamantanes by addition of
aryl organometallics to the known diketone 3,3 followed by reduc-
tion of the formed hydroxyoxaadamantane 2 (Scheme 1).
OH
3
O
O
Figure 1. A 2-oxaadamantyl cannabinoid.
Ar
Ar
O
Red.
ArM
O
O
O
OH
Although different organometallic compounds have been added
to diketone 3,4,5 more problematic is the reduction of hemiacetals
such as 2 to give 1. For instance 1-hydroxy-2-oxaadamantane (4)
1
2
3
Scheme 1. Retrosynthesis of 1-aryl-2-oxaadamantanes.
can be transformed into the corresponding
a-bromoether by treat-
ment with thionylbromide,6 but reduction of this
a-bromoether
with Raney-Nickel gave 2-oxaadamantane only in low yield. In line
with the retrosynthesis in Scheme 1, we wanted to study the
Compound
4 could be transformed into oxalate 5, but
attempted reduction with tributyltin hydride gave back hemiacetal
4 (Scheme 2).
possible reduction of compound
4 to 2-oxaadamantane (7).
2-Oxaadamantane has previously been synthesized in a number
Other attempts to synthesize derivatives of 4 that would be use-
ful for reduction, e.g., preparing xanthates were unsuccessful. The
problematic reduction of 4 could be ascribed to the electron-with-
drawing properties of the ring oxygen and the lack of this oxygen
to be able to stabilize an adjacent carbocation or radical. However,
of other ways.7–16
⇑
Corresponding author.
E-mail address: toreben@kjemi.uio.no (T. Benneche).
we found that compound
4
could be transformed into
http://dx.doi.org/10.1016/j.tetlet.2016.06.027
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

T. Benneche, M. A. Tius / Tetrahedron Letters 57 (2016) 3150–3151
3151
ClCOCO2Et
DMAP, Py
Bu3SnH, AIBN
Toluene
first preparing the mesylate of 2e followed by elimination using
silica gel in dichloromethane.5 Some 1-hydroxy-3-(3,5-dimethoxy-
phenyl)-2-oxaadamantane (2e) was also formed in the elimination
reaction. The attempted dehydration of compound 2e with concen-
trated sulfuric acid in methanol5 gave only starting material after
reflux for 3 h.
O
O
4
75 °C, 1 h
(65%)
105 °C, 1 h
OH
OCOCO2Et
4
5
Scheme 2. Attempted synthesis of 2-oxaadamantane (7) by reduction.
In summary, 2-oxaadamantane and 1-aryl-2-oxaadamantanes
could easily be made in moderate to good yields in two and three
steps from the corresponding 1-hydroxy-2-oxaadamantanes
respectively. One point that has to be addressed if this method is
to be used with more elaborate aryl metals, i.e., C3 metallated
cannabinoids, is the large excess (2–3 equiv) of the aryl metal that
has to be used in the reaction with the diketone 3 for the synthesis
of compounds 2.
I
O
O
KI, H3PO4, P2O5
NaBH4, MeOH
O
rt, 24 h
(60%)
100 °C, 2 h
(59%)
OH
4
6
7
Scheme 3. Synthesis of 2-oxaadamantane (7).
Acknowledgement
2-oxaadamantane (7) by first preparing iodo ketone 63 followed by
reduction with sodium borohydride (Scheme 3).
We thank The National Institute on Drug Abuse for generous
support of this research.
Only one diastereomer of 6 was observed. This was assigned to
be the exo isomer assuming that a concerted cleavage mechanism
operated in the formation of iodo ketone 6.9 The 13C NMR values of
compound 6 were also in very good agreement with the values
from a synthesis which assigned the exo isomer to their compound
based on comparison with estimated values for the endo isomer.3
References and notes
1. Dixon, D. D.; Sethumadhavan, D.; Benneche, T.; Banaag, A. R.; Tius, M. A.;
Thakur, G. A.; Bowman, A.; Wood, J.; Makriyannis, M. J. Med. Chem. 2010, 53,
5656–5666.
2. Pfahl, M.; Lu, X.-P.; Rideout, D.; Zhang, H. US 6 462 064 B1, 2002. CAN
137:278982.
3. Janatovic, J.; Majerski, Z. J. Org. Chem. 1980, 45, 4892–4898.
4. Stetter, H.; Gärtner, J.; Tacke, P. Chem. Ber. 1966, 99, 1435–1438.
5. Camps, P.; El Achab, R.; Font-Bardia, M.; Görbig, D.; Morral, J.; Muñoz-Torrero,
D.; Solans, X.; Simon, M. Tetrahedron 1996, 52, 5867–5880.
6. Stetter, H.; Tacke, P.; Gärtner, J. Chem. Ber. 1964, 97, 3480–3487.
7. Stetter, H.; Scwartz, E. F. Chem. Ber. 1968, 101, 2464–2467.
8. Averina, N. V.; Zefirov, N. S. Chem. Commun. 1973, 6, 197–198.
9. Cable, J.; MacLeod, J. K. Aust. J. Chem. 1973, 26, 2147–2152.
10. Subramaniam, R.; Fort, R. C., Jr. J. Org. Chem. 1984, 49, 2891–2896.
11. Suginome, H.; Yamada, S. Synthesis 1986, 741–743.
12. Krasutsky, P. A.; Kolomitsin, I. V.; Carlson, R. M.; Jones, M., Jr. Tetrahedron Lett.
1996, 37, 5673–5674.
13. Krasutsky, P. A.; Kolomitsin, I. V.; Kiprof, P.; Carlson, R. M.; Fokin, A. A. J. Org.
Chem. 2000, 65, 3926–3933.
14. Marchand, A. P.; Kumar, V. S.; Hariprakasha, H. K. J. Org. Chem. 2001, 66, 2071–
2077.
15. Alder, R. W.; Carta, F.; Reed, C. A.; Stoyanova, I.; Willis, C. L. Org. Biomol. Chem.
2010, 8, 1551–1559.
Unfortunately iodo ketone
6 reacted very slowly with
organometallic compounds. For instance it did not react with
phenylmagnesium bromide, phenylcerium chloride, n-butyl-
lithium, or 3-(methoxymethoxy)prop-1-ynyllithium at room tem-
perature in THF, but gave a low yield (20%) of 1a (Scheme 4,
Ar = C6H5) after heating at reflux for 2 h with excess phenyllithium.
1-Aryl-2-oxaadamantanes 1, on the other hand, could be readily
synthesized from hemiacetals 217 by dehydration to unsaturated
ketones 8 followed by reduction and cyclization18 (Scheme 4,
Table 1).
When the Ar substituent in 2 was 3,5-dimethoxyphenyl the cor-
responding unsaturated ketone 8e could not be formed using
sodium iodide/trimethylsilyl chloride due to concomitant cleavage
of the methoxy groups. However, compound 8e could be made by
16. Mikhailov, B. M.; Shchegoleva, T. A.; Shashkova, E. M.; Kiselev, V. G. J.
Organomet. Chem. 1983, 250, 23–31.
Ar
OH
O
17. Typical procedure for the synthesis of 1-hydroxy-1-aryl-2-oxaadamantanes: 1-
Hydroxy-3-(3-chlorophenyl)-2-oxaadamantane 2b. 3-Chlorophenylmagnesium
bromide (7.0 mL, 0.5 M in THF, 3.5 mmol) was added to a solution of (1S,5S)-
bicyclo[3.3.1]nonane-3,7-dione (3) (215 mg, 1.4 mmol) at 0 °C. The mixture
was stirred at rt for 30 min, then heated at 70 °C for 6 h before it was cooled to
rt and acidified using HCl (1 M). The product was extracted with DCM
(3 Â 10 mL) and purified by flash chromatography (SiO2, hexanes/EtOAc 4:1).
Yield: 191 mg (52%); dH (400 MHz, CDCl3) 1.75–2.00 (m, 10H), 2.49 (s, 2H),
7.21–7.38 (m, 3H), 7.51 (s, 1H); dC (101 MHz, CDCl3) 29.8, 33.8, 40.4, 41.2, 95.1,
122.3, 124.7, 126.9, 129.4, 134.2, 148.9; MS (ESI+): 287 (M+Na+, 100%). HRMS
calcd for C15H17ClNaO2O 287.0810 found 287.0809.
ArM, THF
Ref. 1
O
O
0-70 °C,
6-12 h
OH
OH
3
2
Ar
Ar
i. NaBH4, MeOH,
0 °C, 30 min
NaI, TMSCl,
MeCN
O
O
rt, 2-3 h
ii. TsOH, DCM
rt, 24-36 h
18. Typical procedure for the synthesis of 1-aryl-2-oxaadamantanes: ( )-7-
Phenylbicyclo[3.3.1]non-6-en-3-one 8a.5 TMSCl (0.5 mL, 5.4 mmol) was added
dropwise at 0 °C to a solution of NaI (135 mg, 0.9 mmol) and 1-hydroxy-3-
phenyl-2-oxaadamantane (2a)4 (41 mg, 0.18 mmol) in MeCN (3 mL). The
reaction mixture was stirred for 2.5 h at rt before it was poured into H2O
(10 mL) and extracted with Et2O (3 Â 10 mL). The Et2O phase was washed with
aq NaHCO3 (15 mL), aq NaS2O3 (15 mL) and dried (MgSO4). The crude product
was purified by flash chromatography (hexane/EtOAc 5:1). Yield: 30 mg (85%);
dH (300 MHz, CDCl3) 2.00–2.97 (m, 10H), 6.10 (d, 1H, J = 6.4), 7.18–7.38 (Ar,
5H). 1-Phenyl-2-oxaadamantane 1a. NaBH4 (19 mg, 0.50 mmol) was added to a
8
1
Scheme 4. Synthesis of 1-aryl-2-oxaadamantanes from 1,3-adamantanediol.
Table 1
Preparation of compounds 2, 8, and 1
ArM
Yield 2 (%)
Yield 8 (%)
Yield 1 (%)
solution
of
( )-7-phenylbicyclo[3.3.1]non-6-en-3-one
(8a)5
(33 mg,
0.16 mmol) in MeOH (2 mL) at 0 °C. The reaction mixture was stirred for
20 min before aq NaHCO3 (10 mL) was added and extracted with Et2O
(3 Â 7 mL). The crude product was dissolved in DCM (3 mL) and catalytic p-
toluenesulfonic acid monohydrate (ca 2 mg) was added. The mixture was
stirred for 24 h, evaporated, and purified by flash chromatography (hexane/
EtOAc 19:1). Yield: 26 mg (76%); dH (300 MHz, CDCl3) 1.64–2.31 (m, 12H), 4.27
(s, 1H), 7.18–7.50 (Ar, 5H); dC (75 MHz, CDCl3) 27.6, 35.1, 35.5, 69.1, 72.4,
124.1, 126.5, 128.1, 148.0; MS (EI+) 214 (M+, 69), 171 (7) 158 (14) 157 (100),
121 (23) 105 (26), 94 (37). HRMS calcd for C15H18O 214.1357 found 214.1359.
a
b
c
C6H5Li
78
52
36
—
36
52
—
85
59
57
—
65
48a
—
76
62
73
38a
55
40
3-ClC6H4MgBr
4-ClC6H4MgBr
4-ClC6H4MgBr
4-MeC6H4MgBr
3,5-(MeO)2C6H3MgBr
3,5-(MeO)2C6H3MgBr
c
d
e
e
30a
a
Yield from 2 using: (i) MsCl, DMAP, py; (ii) SiO2, DCM.5