An improved synthesis of diiodonoradamantane

Article abstract of DOI:10.1016/j.tetlet.2009.08.108

Τhe synthesis of 3,7-diiodo-tricyclo[3.3.1.0^3,7]nonane, the main precursor of noradamantene, by iodination of the corresponding diol via its dimesylate affords a threefold higher yield than the direct iodination of the diol. Neither the dimesylate nor the cyclic sulfate of the diol yields noradamantene upon reduction with sodium amalgam.

Full text of DOI:10.1016/j.tetlet.2009.08.108

Tetrahedron Letters 50 (2009) 6938–6940
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Tetrahedron Letters
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An improved synthesis of diiodonoradamantane
*
Savvas Ioannou, Athanassios V. Nicolaides
Department of Chemistry, University of Cyprus, Nicosia 1678, Cyprus
a r t i c l e i n f o
a b s t r a c t
Nhe synthesis of 3,7-diiodo-tricyclo[3.3.1.03,7]nonane, the main precursor of noradamantene, by iodin-
ation of the corresponding diol via its dimesylate affords a threefold higher yield than the direct iodin-
ation of the diol. Neither the dimesylate nor the cyclic sulfate of the diol yields noradamantene upon
reduction with sodium amalgam.
Article history:
Received 23 April 2009
Revised 11 August 2009
Accepted 28 August 2009
Available online 2 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Pyramidalized alkenes1 have attracted a great deal of attention
because of their interesting properties.2,3 The homologous series of
pyramidalized alkenes 1 has been studied systematically, and the
first four members (1, n = 0–3) have been generated. Herein we de-
scribe research directed towards improving the synthesis of norad-
amantene (1, n = 1) with the aim of using this molecule as a
building block for the synthesis of other polycyclic organic
molecules.
Alkenes 1, n = 2, 3 can be easily formed at room temperature by
reduction of their corresponding dimesylates with Na/Hg.9 Dimes-
ylate 6 can be easily obtained from diol 3 following the known pro-
tocols, in almost quantitative yield.10–12 However, 6 is not reduced
by Na/Hg, neither at room temperature nor in refluxing THF. At-
tempts to form the ditosylate of diol 3 led to the quantitative for-
mation of the monotosylate, presumably due to steric hindrance.
Iodination of dimesylate 6 was attempted under a variety of
conditions (Table 2).13 No reaction was observed when ionic liq-
uids were used as solvents (Table 2, entries 1–5), even with Iꢀas
the counter ion. When methanesulfonic acid (entry 6) was used
as the solvent, only a trace of diiodide (<5%) was observed, how-
ever, some diol 3 was recovered along with starting material 6.
Concentrated phosphoric acid appears to be the best solvent
for preparing 2 from 6, in agreement with the previous reports
on the preparation of 2 from 3.4 We used commercially avail-
able 99% phosphoric acid (mp 40 °C) for this reaction. No special
precautions were taken to exclude atmospheric moisture from
the reaction mixture. The nature of the iodinating agent (Table
2, entries 7, 13, and 14) does not appear to be important since
NaI, KI, and CsI gave similar results. However, a large excess of
NaI significantly increased the yield. The optimum excess ap-
peared to be around a molar ratio of 60:1 (NaI:6) (Table 2, entry
18).
The reaction was monitored by gas chromatography. Dimesy-
late 6 was fully consumed within the first 4 h, forming diiodide 2
and a small amount of monoiodide 8.14 After an additional two
hours, only 2 was detected. Reaction times greater than one day
tended to lower the yield.
Diol 3 and dimesylate 6 react almost quantitatively (90% yield)
with concentrated sulfuric acid to give the cyclic sulfate ester 7.15
Although cyclic sulfate esters are considered quite reactive and
have found numerous synthetic applications recently, this was
not the case with 7.16 Attempts to reduce 7 to noradamantene
(1, n = 1) with Na/Hg were not successful. Also, iodination of 7
was much slower than that of 6, requiring more than four days
(CH2)n
2
3
, X=I
, X=OH
6, X=CH3SO3
8
7
1
O
O
-
HO
I
S
X
X
O
O
Noradamantene can be generated conveniently and quantita-
tively by reduction of diiodide 2.4 The only known synthetic route
to 2 is via iodination of diol 3. Diol 3 can be prepared5 from ada-
mantane in 36% overall yield (route 1),6 from adamantanone in
60% overall yield (route 2)7 or via condensation of dimethyl 1,3-
acetonedicarboxylate (4) with 1,1,3,3-tetramethoxypropane (5)8
in 50% overall yield (route 3) (Scheme 1). The third route is slightly
less efficient than the second route, but requires one less step and
simpler reactions and is the route to 3 that we have followed.
The iodination of 3 to 2 requires harsh conditions [48 h at
110 °C in 95% phosphoric acid and an excess (six times the required
stoichiometric amount) of NaI] with a reported yield of 40%.4 Our
efforts to produce 2 from 3 under similar conditions resulted in
yields of 20% at best (Table 1).
* Corresponding author. Tel.: +357 2289 2784.
E-mail address: athan@ucy.ac.cy (A.V. Nicolaides).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.108

S. Ioannou, A. V. Nicolaides / Tetrahedron Letters 50 (2009) 6938–6940
6939
Route 3
O
Route 2
Route 1
O
O
2
MeO
OMe
4
+
MeO
OMe
O
OMe OMe
Br2
61%
BBr3 / AlBr3
5
m-CPBA
98%
70%
pH=7.5, r.t.
Br
85%
Br
O
O
MeOOC
MeOOC
NaOH
COOMe
COOMe
LiAlH4
96%
OH
OH
OH
75%
O
CH2
HCl, AcOH
reflux
OH
O3
85%
PDC
82%
O
O
Zn/Hg,
HCl, MeOH
reflux
85%
HO
OH
3
Scheme 1. Synthetic routes to diol 3.
and resulting in a yield of less than 15%. We attribute this relative
lack of reactivity to the structure of 7, which unlike other known
cyclic sulfates, is formally derived from a bis-tertiary vicinal diol.
In addition, the tricyclic cage is such that neither rear attack nor
the facile formation of a (pyramidal) tertiary carbocation is
possible.
In conclusion, the best precursor for the generation of norada-
mantene under ambient conditions remains diiodide 2 which is
Table 1
Synthesis of diiodide 2 from diol 3
Entry
Diol 3 (mmol)
Solvent (%)
NaI:3a
Tb (°C)
t (d)
% Yield of 2c
1
2
3
4
5
6
1.9
1.3
0.4
0.6
6.5
0.6
H3PO4 (85)
H3PO4 (85)
H3PO4 (85)
H3PO4 (99)
H3PO4 (99)
H3PO4 (99)
15
15
15
15
15
50
120
120
140
150
150
130
7
2
3
2
4
1
10
13
8
15
20
18
a
b
c
Molar ratio of NaI to 3.
External bath temperature.
Yield of crude product.

6940
S. Ioannou, A. V. Nicolaides / Tetrahedron Letters 50 (2009) 6938–6940
6. (a) Baughman, G. L. J. Org. Chem. 1964, 29, 238; (b) Gagneux, A. R.; Meier, R.
Table 2
Synthesis13 of diiodide 2 from dimesylate 6
Tetrahedron Lett. 1969, 17, 1365; (c) Stetter, H.; Tacke, P. Chem. Ber. 1963, 25,
694.
7. Zalikowski, J. A.; Gilbert, K. E.; Borden, W. T. J. Org. Chem. 1980, 45, 346.
8. Bertz, S. H. J. Org. Chem. 1985, 50, 35.
a
Entry Solvent
NaI:6
Tb
t (d) % Yield of 2c
(°C)
9. Nicolaides, A.; Smith, J. M.; Kumar, A.; Barnhart, D. M.; Borden, W. T.
Organometallics 1995, 14, 3475.
10. (a) Cabri, W.; Roletto, J.; Olmo, S.; Fonte, P.; Ghetti, P.; Songia, S.; Mapelli, E.;
Alpegiani, M.; Paissoni, P. Org. Process Res. Dev. 2006, 10, 198; (b) Kshirsagar, T.
A.; Hurley, L. H. J. Org. Chem. 1998, 63, 5722.
11. Storck, P.; Aubertin, A. M.; Grierson, D. S. Tetrahedron Lett. 2005, 46, 2919.
12. Synthesis of tricyclo[3.3.1.03,7]nonane-3,7-diyl dimesylate (6). To a solution of diol
3 (1.00 g, 6.49 mmol) in pyridine (10 mL), mesyl chloride (CH3SO2Cl) (5.02 mL,
65 mmol) was added slowly with stirring at ambient temperature. The mixture
was then heated at 120 °C for 5 h. After cooling, crushed ice (100 g) was added
and the mixture was extracted with CH2Cl2 (5 Â 20 mL). The combined organic
phase was washed with 2 M HCl (2 Â 40 mL), H2O (2 Â 20 mL), saturated
aqueous NaHCO3 (2 Â 20 mL), and dried (Na2SO4). After filtration and removal
of the solvent under reduced pressure, a brown solid (1.92 g, 96%) was isolated.
Recrystallization from THF/hexane afforded pure 6 (1.71 g, 85%) as colorless
1d,e
2d,e
3d,e
4f
[bmim][BF4]/CH3CN
10 (KI)
10 (KI)
20 (KI)
—
100
150
150
130
160
1
1
1
1
1
—
—
—
—
—
[bmim][BF4]
[bmim][BF4]/ H3PO4 99%
PMIMI
Tetrabutylammonium
iodide
CH3SO3H (70%)
H3PO4 (99%)
H3PO4 (99%)
H3PO4 (99%)
H3PO4 (99%)
H3PO4 (99%)
H3PO4 (99%)
H3PO4 (99%)
H3PO4 (99%)
5
—
6
7
8
9
10
40
40
60
100
200
16
40 (KI)
40
(CsI)
60
60
120
170
150
150
150
150
150
170
170
1
1
3
1
1
1
2
1
1
<5
46
52
72
73
75
54
44
40
10
11
12
13
14
crystals, mp 127–128 °C; mmax(KBr) 3449, 2943, 1464, 1414, 1341, 1190, 1169,
1101, 1018, 976, 955, 856, 824, 802, 760, 669, 615, 565, 515, 474 cmÀ1; dH
(300 MHz, CDCl3) 3.10 (6H, –CH3, s), 2.50 (6H(4eq+2CH), d, J 6.9 Hz), 2.26 (4Hax, d,
J 9.0 Hz), 1.51 (2Hbridge, s); dC (75.5 MHz, CDCl3) 91.30 (–CO), 47.42 (–CH2),
40.60 (–CH3), 34.98 (–CH), 32.28 (–CH2 bridge). Anal. Calcd for C11H18O6S2: C,
42.6; H, 5.8; S, 20.7. Found: C, 42.3; H, 5.7; S, 20.3. HRMS (TOF MS ES+) calcd for
C11H1906S2 311.0623 found: 311.0629.
15g
16g
17h
18g
H3PO4 (99%)
H3PO4 (99%)
H3PO4 (99%)
H3PO4 (99%)
100
170
150
150
1
1
6 h
6 h
35
45
77
75
200
60
13. Synthesis of 3,7-diiodo-tricyclo[3.3.1.03,7]nonane 2.5 In a round-bottomed flask
equipped with a reflux condenser, H3PO4 (99%, 15 g), dimesylate 3 (80 mg,
0.26 mmol), and NaI (7.74 g, 52 mmol) were added. The mixture was stirred at
150 °C for 6 h. After cooling, H2O (100 mL) was added slowly to the mixture.
The resulting purple solution was extracted with CH2Cl2 (4 Â 50 mL) and the
combined organic phase was washed with aqueous sodium thiosulfate
(1 Â 50 mL), dried (Na2SO4) and the solvent was removed under vacuum to
give 2 (74 mg, 77%). Purification by dry flash chromatography (100% hexane)
a
b
c
Molar ratio of NaI to 6. On a scale of 0.16 mmol of 6 unless otherwise specified.
External bath temperature.
Yield of crude product.
bmim = 1-n-butyl-3-methylimidazolium.
On a scale of 0.5 mmol of 6.
PMIMI = 1-methyl-3-propylimidazolium iodide.
On a scale of 0.32 mmol of 6.
d
e
f
g
h
afforded 2 (69 mg, 72%) as colorless crystals, mp 130–131 °C;
1450, 1433, 1333, 1290, 1229, 1151, 1103, 1024, 970, 930, 903, 862, 849, 793,
770, 500 (C-I) cmÀ1; dH (300 MHz, CDCl3) 2.76 (4Heq, d, J = 12.0 Hz), 2.45 (4Hax
mmax(KBr) 2926,
On a scale of 0.26 mmol of 6.
,
d, J = 10.8 Hz), 1.91 (2H, s, –CH), 1.63 (2H, s, –CH2 bridge); dC (75.5 MHz, CDCl3)
57.69 (–CH2), 53.34 (–CI), 39.38 (–CH), 30.60 (–CH2 bridge).
accessible from diol 3. Indirect iodination of 3 via dimesylate 6, can
be achieved within six hours in 60% overall yield. This indirect
iodination method may be useful for other tertiary alcohols that
do not form stable carbocations.
14. In partially completed iodination reactions small amounts of 3-iodo-7-
hydroxy-tricyclo[3.3.1.03,7]nonane (8) were present. Compound
8
was
light-yellow
max(KBr) 3228 (O–H), 2930, 1722, 1454,
1398, 1344, 1331, 1300, 1244, 1215, 1184, 1136, 1109, 1063, 1007, 962, 937,
907, 870, 816, 718, 631, 520, 459, 422, 411; dH (300 MHz, CDCl3) 2.68 (2Heq-I
isolated by chromatography (20% hexane/CH2Cl2) as
crystalline solid: mp 52–54 °C;
a
m
Acknowledgements
,
dd, J >2, 12.9 Hz), 2.40 (2Hax-I, dd, J = 2.1, 11.1 Hz), 2.31 (2H, s, –CH), 2.10 (1H, s,
–OH), 1.98 (2Heq-OH, dd, J >2, 12.3 Hz), 1.88 (2Hax-OH, dd, J >2, 10.8 Hz), 1.55
(2H, s, CH2 bridge); dC (75.5 MHz, CDCl3) 82.46 (–CO), 57.33 (–CH2), 54.62 (–CI),
48.59 (–CH2), 37.92 (–CH), 31.69 (–CH2 bridge).
Financial support from the Research Promotion Foundation of
Cyprus (TNNFN0308/01) and the University of Cyprus (SRP) is
gratefully acknowledged. The A.G. Leventis Foundation is gratefully
acknowledged for a generous donation which enabled the pur-
chase of the NMR spectrometer at the University of Cyprus.
15. Synthesis of tricyclo[3.3.1.03,7]nonane-3,7-diol cyclic sulfate 7. Diol 3 (500 mg,
3.25 mmol) was added to concd H2SO4 (95–97%, 5 mL) and the resulting
mixture was stirred at 130 °C for 1 h. After cooling, H2O (100 mL) was added
very slowly. The solution was extracted with CH2Cl2 (4 Â 20 mL), and the
combined organic phase was dried (Na2SO4) and the solvent was removed
under vacuum to give crude 7 (629 mg, 90%). Mp 117–118 °C; mmax(KBr) 2955,
References and notes
2922, 2853, 1460, 1382, 1337, 1306, 1242, 1202, 1090, 960, 837, 812, 777; dH
(300 MHz, CDCl3) 2.65 (2H, s, –CH), 2.32 (4Heq, d, J = 11.1 Hz), 2.19 (4Hax, d,
J = 10.8 Hz), 1.55 (2H, s, –CH2 bridge); dC (75.5 MHz, CDCl3) 94.47 (C–O), 46.44
(CH2), 37.04 (CH), 33.00 (CH2 bridge). Fnal. Calcd for C9H12O4S: C, 50.0; H, 5.6;
S, 14.8. Found: C, 50.4; H, 5.6; S, 14.4.
1. (a) Borden, W. T. Chem. Rev. 1989, 89, 1095; (b) Borden, W. T. Synlett 1996, 711.
2. Vazquez, S.; Camps, P. Tetrahedron 2005, 61, 5147.
3. Nicolaides, A. In Strained Hydrocarbons. Beyond the van’t Hoff and Lebel
Hypothesis; Dodziuk, H., Ed.; Wiley-VCH, 2009; pp 112–122.
4. Renzoni, G. E.; Yin, T.; Borden, W. T. J. Am. Chem. Soc. 1986, 108, 7121.
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