Effective synthetic routes to cubylcarbinol derivatives

Article abstract of DOI:10.1055/s-2002-35981

Three alternative routes for the synthesis of cubylcarbinol (1) from 4-iodocubanecarboxylic acid (5) are described.

Full text of DOI:10.1055/s-2002-35981

SHORT PAPER
2671
Effective Synthetic Routes to Cubylcarbinol Derivatives
S
ynthetic Routes
o
to Cubylcarb
n
inol
D
erivat
n
ives y Priefer, Patrick G. Farrell, David N. Harpp*
Department of Chemistry, McGill University, Montreal, Quebec, H3A 2K6, Canada
E-mail: david.harpp@mcgill.ca
Received 26 August 2002
in 84% yield (Scheme 1). However, what was initially
surprising was the one-step reduction and iodine removal
from 5 to give 1 in 91% yield using excess amounts of
LiAlH4 under reflux for an extended period of time.
Abstract: Three alternative routes for the synthesis of cubyl-
carbinol (1) from 4-iodocubanecarboxylic acid (5) are described.
Key words: cubane derivatives, 4-iodocubylcarbinol, cubylcar-
binol, iodine removal
Removal of halogens from tertiary carbons by LiAlH4 has
been reported in the past.12 Ashby has carried out consid-
erable research in this area and has shown that in some
cases the reaction occurs via a single electron transfer
(SET) mechanism13 and in reactions of trityl halides, the
trityl radical was detected using EPR spectroscopy.14 We
believe that in the conversion of 5 to 1 this is also the like-
ly mode of reaction since a SN2 mechanism is impossible
and studies of the cubyl radical are well-documented.15
Since its initial synthesis in 1964,1 cubane and cubyl com-
pounds have been shown to be far more than just simple
saturated hydrocarbons. From the potentially highly ex-
plosive (octanitrocubane)2 to a multi-substituted analog
with viral activity,3 cubane derivatives have presented fas-
cinating research challenges for decades. Monosubstitut-
ed cubane compounds have also shown some interesting
properties, e.g. cubanol has been reported to go through an
intramolecular rearrangement to open the cubane cage;4
(aminomethyl)cubane shows enzyme activity.5 The exo-
cyclic bonds of cubanes have enhanced s-character6 and
we have recently demonstrated that dicubyl disulfide pos-
sesses the shortest known quaternary C–S bond length.7
As part of our studies of convenient precursors for other
cubane chemistry,8 we needed synthetic procedures to
prepare cubylcarbinol (1) in superior yields.
Cubylcarbinol (1) has previously been prepared in three
steps from commercially available dimethyl-1,4-cubane
dicarboxylate (2).9 Partial hydrolysis of 2 yields 4-meth-
oxycarbonylcubane carboxylic acid (3) which was con-
verted to cubanecarboxylic acid (4) via a Barton
decarboxylation followed by additional hydrolysis.9a Re-
duction of 4 affords cubylcarbinol (1).9b The best litera-
ture preparation delivers 1 in 70% overall yield from 2.
Herein, we report three alternative approaches to obtain 1
in excellent overall yield (Scheme 1).
From the 4-methoxycarbonyl cubane carboxylic acid (3),
a Moriarty reaction10 followed by hydrolysis of the un-
purified intermediate yielded 4-iodocubanecarboxylic
acid (5).
Scheme 1 a) i. NaOH (1 equiv)–MeOH–THF, ii. HCl; b) i. IBDA,
I2–benzene, reflux 6 h, ii. NaOH–MeOH, iii. HCl; c) i. (COCl)2–
CH2Cl2, ii. 2-mercaptopyridine-N-oxide sodium salt hydrate, DMAP,
t-BuSH–benzene, hv, iii. NaOH/MeOH, reflux, 1 h, iv. HCl; d) i.
BuLi–THF, MeOH, –78 °C, ii. HCl; e) i. BH3 SMe2–THF, 0 °C, ii.
HCl; f) i. LiAlH4 (50 equiv), THF, reflux, 5 d, ii. HCl; g) i.
BH3 SMe2–THF, 0 °C, ii. HCl; h) i. BuLi–THF, MeOH, –78 °C, ii.
NaOMe, reflux, 1 h, iii. HCl
Three new avenues can be utilized for the synthesis of 1
from 5. The removal of iodine from 5 with BuLi, followed
by protonation with methanol delivers 4 in high yield
(88%). Reduction of 4 with borane is analogous to that re-
ported with LiAlH4,9b producing 1 in identical yield (93–
94%). Reduction of 5 with borane affords 4-(hydroxyme-
thyl)-1-iodocubane (6).11 The removal of iodine from 6
with BuLi, followed by protonation with methanol gave 1
In contrast to the trityl halides where the reaction was
completed in 5 hours with one equivalent of LiAlH4, our
system required 5 days, using 50 equivalents of LiAlH4
under reflux conditions. A possible explanation for the ex-
tended time requirement is the fact that the carboxylic
acid would first be reduced to the alkoxy anion providing
Synthesis 2002, No. 18, Print: 19 12 2002.
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© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

2672
R. Priefer et al.
SHORT PAPER
tion of BuLi in hexanes (0.80 mL, 2.1 mmol). Cold MeOH (5 mL)
was added after 5 min, and the solution was slowly allowed to reach
r.t. Hexanes (25 mL) were added and the solution was extracted
with H2O (3 50 mL). The aqueous layer was acidified to pH <1
with concd HCl, and extracted with CHCl3 (3 50 mL). The com-
bined organic layers were dried (MgSO4), filtered, and evaporated
to dryness, affording pure cubanecarboxylic acid (4); yield: 0.05 g
(88%); mp 124–125 °C (Lit.1,9a mp 124–125 °C).
a charged species that would not be very soluble in THF.
This is supported by the fact that after 24 hours, the start-
ing acid 5 was converted to a mixture of alcohols 6 and 1.
We thus have a simple procedure to convert 4-iodocuban-
ecarboxylic acid (5) into cubylcarbinol (1) in excellent
yield. From 2, we can obtain 1 in an overall yield of 77%.
These routes provide a less expensive synthesis of 1 in ad-
dition to the fact that, depending upon the reducing agent
employed, two different cubylcarbinols 1 and 6 can be ob-
tained through the single precursor, 5. In addition, 5 is a
versatile intermediate, where it is possible to manipulate
either the acid group3,8,9b,11,16 and/or the iodo functional-
ity.7,11,17
4-(Hydroxymethyl)-1-iodocubane (6)
BH3 SMe2 complex (2.0 mL, 21 mmol) was added to a solution of
4-iodocubanecarboxylic acid (5; 3.62 g, 13.2 mmol) dissolved in
anhyd THF (125 mL) under N2 and cooled to 0 °C. The mixture was
stirred at 0 °C for 20 min, then at r.t. for 4 h. The solution was
quenched with H2O (20 mL) and stirred overnight. EtOAc (75 mL)
was added and the organic layer was washed with H2O (2 50mL)
and brine (50 mL), dried (MgSO4), filtered, and evaporated to dry-
ness. Column chromatography (CHCl3–EtOAc, 1:1) afforded 4-
(hydroxymethyl)-1-iodocubane (6) as a white solid (3.25 g, 95%);
mp 109–111 °C (Lit.11 mp 108–110 °C).
1H NMR (400 MHz, CDCl3): = 1.39 (t, 1 H, OH), 3.78 (d, 2 H,
CH2), 4.05 (m, 3 H, H-3,5,7), 4.21 (m, 3 H, H-2,6,8).
13C NMR (100.6 MHz, CDCl3): = 38.9 (C-1), 47.9 (C-2,6,8), 54.7
(C-3,5,7), 59.0 (C-4), 63.2 (CH2).
4-Methoxycarbonylcubane Carboxylic Acid (3)
This compound was prepared according to the literature procedure
of Eaton.9a
Dimethyl 1,4-cubanedicarboxylate (2; 5.06 g, 23.0 mmol) yielded
4.33 g (92%) of 4-methoxycarbonylcubane carboxylic acid (3); mp
182–183 °C (Lit.4,9a,18 mp 182–183 °C, 176–179 °C19).
1H NMR (400 MHz, MeOD): = 3.69 (s, 3 H, CH3), 4.19 (s, 6 H,
cubyl H).
Cubylcarbinol (1) from 5
LiAlH4 (16.62 g, 438 mmol) was added to a solution of 4-iodocu-
banecarboxylic acid (5; 2.59 g, 9.46 mol) in anhyd THF (200 mL)
under N2 and refluxed for 5 d. The solution was cooled to 0 °C, and
the mixture was very, very slowly quenched with cold MeOH. Once
all the excess LiAH4 was destroyed, the solution was acidified to pH
<1 with concd HCl. Hexanes (200 mL) were added, and the organic
layer was washed with H2O (3 200mL) and brine (150 mL), dried
(MgSO4), filtered, and evaporated to dryness. Column chromatog-
raphy (hexanes–EtOAc, 3:1) afforded 1.16 g (91%) of cubyl-
carbinol (1); mp 62–63 °C (Lit.9b mp 62–62.5 °C).
1H NMR (300 MHz, CDCl3): = 1.32 (t, 1 H, OH), 3.72 (d, 2 H,
CH2), 3.89 (m, 6 H, H-2,3,5,6,7,8), 4.21 (m, 1 H, H-4).
13C NMR (75.5 MHz, CDCl3): = 44.6, 47.9 (cubyl CH), 48.9 (C-
4), 58.6 (C-1), 64.1 (CH2).
13C NMR (100.6 MHz, MeOD): = 48.1, 48.2 (cubyl CH), 52.1
(CH3), 57.4, 57.6 (cubyl C), 173.4 (C=O), 175.0 (C=O).
4-Iodocubanecarboxylic Acid (5)
Iodobenzene diacetate (IBDA, 18.32 g, 56.9 mmol) and I2 (14.45 g,
56.9 mmol) were added to a suspension of 4-methoxycarbonylcu-
bane carboxylic acid (3; 3.91 g, 19.0 mmol) in anhyd benzene (300
mL) under N2. After refluxing for 7 h, the mixture was cooled to r.t.,
whereupon pentane (150 mL) was added. The solution was washed
with sat. aq Na2SO3 (2 50 mL), H2O (50 mL) and brine (50 mL),
dried (MgSO4), filtered, and evaporated to near dryness. The red-
brown liquid that remained was dissolved in THF (100 mL), and to
it, NaOH (7.67 g, 19.2 mmol) dissolved in MeOH (75mL) and H2O
(25 mL) was added and stirred overnight at r.t. The solution was
evaporated to near dryness, dissolved in H2O (50 mL) and acidified
with concd HCl (pH <1). The white precipitate was collected, and
kept under vacuum to constant weight affording 4-iodocubanecar-
boxylic acid (5); yield: 4.76 g (92%); mp 215 °C (dec.) (Lit.20 mp
174–178 °C).
Cubylcarbinol (1) from 4
To a solution of cubanecarboxylic acid (4; 0.48 g, 3.2 mmol) dis-
solved in anhyd THF (50 mL) under N2 at 0 °C was added
BH3 SMe2 (0.50 mL, 5.3 mmol). After 20 min at 0 °C, the solution
was warmed and stirred for an addition 2 h at r.t. The solution was
quenched with H2O (10 mL) and stirred overnight. EtOAc (25 mL)
was added, the organic layer was washed with H2O (2 20mL) and
brine (20mL), dried (MgSO4), filtered, and evaporated to dryness.
Column chromatography (hexanes–EtOAc, 3:1) afforded 0.41 g
(94%) of cubylcarbinol (1); mp 61–62 °C (Lit.9b mp 62–62.5 °C).
1H NMR (400 MHz, MeOD): = 4.23 (m, 3 H, H-2,6,8), 4.35 (m,
3 H, H-3,5,7).
13C NMR (100.6 MHz, MeOD): = 37.0 (C-4), 51.2, 56.0 (cubyl
CH), 57.9 (C-1), 174.8 (C=O).
Cubanecarboxylic Acid (4) from 3
This compound was prepared according to the literature procedure
of Eaton.9a
Cubylcarbinol (1) from 6
4-(Hydroxymethyl)-1-iodocubane (6; 0.32 g, 1.2 mmol) was dis-
solved in anhyd THF (50 mL) under N2 and cooled to –78 °C,
whereupon a 1.6 M solution of BuLi in hexanes (5.0 mL, 8.0 mmol)
was added. After 25 min at –78 °C, cold MeOH (6 mL) was added
and the solution was allowed to warm to r.t. and stirred for 1 h;
25wt% NaOMe in MeOH (5.6 mL) was added and the mixture was
refluxed for 1 h. The solution was cooled, and hexanes (25 mL)
were added. The organic layer was washed with H2O (2 25mL)
and brine (25 mL), dried (MgSO4), filtered, and evaporated. Col-
umn chromatography (hexanes–EtOAc, 3:1) afforded 0.13 g (84%)
of cubylcarbinol (1); mp 59–61 °C (Lit.9b mp 62–62.5 °C).
4-Methoxycarbonylcubane carboxylic acid (3; 0.50 g, 2.4 mmol)
yielded 0.27 g (76%) of cubanecarboxylic acid (4);21 mp 124–
125 °C (Lit.1,9a mp 124–125 °C).
1H NMR (400 MHz, CDCl3): = 4.01 (m, 4 H, H-3,4,5,7), 4.28 (m,
3 H, H-2,6,8), 11.12 (s, 1 H, CO2H).
13C NMR (75.5 MHz, CDCl3): = 45.2 (C-3,5,7), 47.9 (C-4), 49.5
(C-2,6,8), 55.3 (C-1), 117.8 (C=O).
Cubanecarboxylic Acid (4) from 5
To 4-iodocubanecarboxylic acid (5; 0.10 g, 0.37 mmol) dissolved in
anhyd THF (50 mL) under N2 at –78 °C, was added a 2.63 M solu-
Synthesis 2002, No. 18, 2671–2673 ISSN 0039-7881 © Thieme Stuttgart · New York

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Synthetic Routes to Cubylcarbinol Derivatives
2673
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Acknowledgement
We thank the NSERC (Canada) for financial support of this work.
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Synthesis 2002, No. 18, 2671–2673 ISSN 0039-7881 © Thieme Stuttgart · New York