Facile and effective synthesis of spirocycloalkanones

Article abstract of DOI:10.2174/157017811797249452

Spiroadamantane cyclopentanone and cyclohexanone have been prepared by a simple and effective method, including the synthesis of the key intermediate dinitriles and their intramolecular Thorpe-Ziegler cyclization. In this method, the key step of the dinitriles formation was accomplished by a novel base-induced allylation protocol which involved the treatment of 2-adamantanecarbonitrile precursor with lithium diisopropylamine and allylbromide. Moreover, the cyclization methodology used, allowed to obtain the respective cyanoenamine in high yields, when the respective dinitriles were treated with the previous base. Acidic hydrolysis of enamines led to the desired cycloalkanones, which constitute versatile intermediates in the synthesis of spiroadamantanamines and other bioactive molecules concerning our pharmacological studies.

Full text of DOI:10.2174/157017811797249452

Letters in Organic Chemistry, 2011, 8, 531-535
531
Facile and Effective Synthesis of Spirocycloalkanones
Grigoris Zoidis and Nicolas Kolocouris*
Faculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Athens, Panepistimioupoli-Zografou,
GR-15771 Athens, Greece
Received December 01, 2010: Revised April 01, 2011: Accepted July 07, 2011
Abstract: Spiroadamantane cyclopentanone and cyclohexanone have been prepared by a simple and effective method, in-
cluding the synthesis of the key intermediate dinitriles and their intramolecular Thorpe-Ziegler cyclization. In this method,
the key step of the dinitriles formation was accomplished by a novel base-induced allylation protocol which involved the
treatment of 2-adamantanecarbonitrile precursor with lithium diisopropylamine and allylbromide. Moreover, the cycliza-
tion methodology used, allowed to obtain the respective cyanoenamine in high yields, when the respective dinitriles were
treated with the previous base. Acidic hydrolysis of enamines led to the desired cycloalkanones, which constitute versatile
intermediates in the synthesis of spiroadamantanamines and other bioactive molecules concerning our pharmacological
studies.
Keywords: Anti-influenza A, base-induced cyclization, LDA, NMR, spiro-adamantane cyclopentanone and cyclohexanone,
spirocycloalkanones.
1
. INTRODUCTION
nitrile with a structure corresponding to the most complex
spiromotif, and then building the ketone ring. Particularly,
carbocyclic derivatives 10 and 16 appeared as useful build-
ing blocks in the preparation of our target compounds ada-
mantanospirocyclopentanamine (data shown) 19 and ada-
mantanospirocyclohexanamine 20 (data not shown), which
are endowed with promising anti-influenza A activity [8].
Spirocarbocyclic systems are of interest because they are
commonly found as subunits of many natural products such
as terpenes and terpenoids [1]. In view of the interesting
structure of the spirocyclic compounds many synthetic
methods directed to these classes of compounds have been
extensively developed [2]. In contrast to other procedures
that are described for obtaining spirocarbocyclic compounds,
there are very few general methods available for the synthe-
sis of spiroalkanones, thus are still eagerly studied [3].
Table 1. Anti-Influenza Virus A H
Activity in MDCK Cells
2 2
N (A2 Japan/305/57)
IC50 (μM)
Compounds
On the other hand, adamantane is frequently found in
biologically active compounds across a number of different
pharmacological activitives (antiviral, antibacterial, trypano-
cidal, anticancer and anti-Parkinsonic activity) [4]. The cage-
like structure of the adamantane, present in bioactive com-
pounds, improves their lipophilicity [5]. Therefore, during
last years the chemistry of adamantane has attracted consid-
erable attention [6].
NH2
1
5.0
Amantadine
H C
3
NH2
As part of our research, concerning pharmacological
studies, we were interested in preparing analogues incorpo-
rating the bulky lipophilic adamantane to the spirocarbocyc-
lic core structure. These compounds are highly functional-
ized intermediates, which are useful for further synthetic
conversions. The synthesis of spiroalkanones is well estab-
lished [7] but most of the times involved expensive starting
materials/reagents and laborious reaction sequences. Thus,
7
.1
Rimantadine
8
we synthesized the adamantane spiro cyclopentanone 10
2
1.2
and the novel adamantane spiro cyclohexanone 16, by a new
effective synthetic procedure outlined in Schemes 2 and 3.
The described procedure can be used for the synthesis of
NH2
19
complex spirocarbocyclic ketones starting from
a
unpublished results
*
Address correspondence to this author at the Faculty of Pharmacy,
NH2
Department of Pharmaceutical Chemistry, University of Athens,
Panepistimioupoli-Zografou, GR-15771, Athens, Greece; Tel: +30-210-
7
20
274809; Fax: +30-210-7274747; E-mail: zoidis@pharm.uoa.gr
1
570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers

5
32 Letters in Organic Chemistry, 2011, Vol. 8, No. 8
Zoidis and Kolocouris
2
. CHEMISTRY
the main product, probably through a mechanism that in-
volved the formation of the sulfonyl ester. The chloride 13
was finally synthesized by reaction of alcohol 12 with
The synthesis of the carbocyclic derivatives 10 and 16,
starts from nitrile 5 and proceeds smoothly in very good
overall yields. Although nitrile 5 has been synthesized by
reductive cyanation of 2-adamantanone 1 using toluenesul-
phonylmethyl isocyanide (TOSMIC) and t-BuOK [9], we
chose to prepare this important starting material through a
simple four-step procedure used for the preparation of cyclo-
hexanocarbonitrile [10], from the commercially available 2-
adamantanone, with a total yield higher than 80 % (Scheme
o
methanesulfonyl chloride and dry pyridine in DMF at 70 C
in a quantitative yield. The transformation of 2-(4-
chloropropyl)adamantane-2-carbonitrile 13 to the pure dini-
trile 14 was accomplished using KCN/18-crown-6 in reflux-
3
ing CH CN. On the other hand, we utilized the symmetric
ether 17 by reacting it with bromine, triphenylphosphine in
benzonitrile [12] to take the bromo derivative 18 in 68%
yield, which on heating for 48 h with KCN, 18-crown-6 in
acetonitrile gave dinitrile 14 in an excellent yield. The dini-
trile 14 was transformed to the cyanoenamine 15 through
Thorpe – Ziegler reaction, using LDA in THF-ether. Finally,
1
) [8]. Thus, 2-adamantanone 1 was transformed to its corre-
sponding hydrazone 2. The addition of hydrogen cyanide to
hydrazone 2 led to the cyanodiazane 3 which was dehydro-
genated to the cyanodiazene 4 using Br /NaHCO . Treatment
2 3
of compound 4 with sodium methoxide afforded the 2-
cyanoadamantane 5 [8].
2 4
acidic hydrolysis of enamine 15 with 33 % H SO yielded to
the corresponding spirocyclohexanone 16. A combination of
homonuclear (COSY and NOESY at mixing times of 1 and
3.5 s) and heteronuclear (HSQC, HMBC) 2D experiments
were used for the complete assignment of this compound.
The most important NOE correlations are depicted in Fig.
(1).
The synthesis of adamantanospirocyclopentanone is de-
picted in Scheme 2. Allylation of 2-adamantanecarbonitrile 5
and subsequent anti-Markownikoff addition of HBr to 2-(2-
propenyl)adamantane-2-carbonitrile 6 led to the 2-(3-
bromopropyl) derivative 7. The transformation of 2-(3-
bromopropyl)adamantane-2-carbonitrile 7 to the pure dini-
trile 8 was accomplished using KCN/18-crown-6 in reflux-
From these results the method presented here is found to
be quite general for the small to large-ringed ketones to give
the spiro[4 or 5.n]alkanones in good overall yields.
3
ing CH CN. The dinitrile 8 was transformed to the cyanoe-
namine 9 through Thorpe–Ziegler reaction [11], using LDA
in THF-ether. Acidic hydrolysis of enamine 9 with 33%
In this paper we have developed facile and experimen-
tally convenient protocols for the construction of spirocarbo-
cyclic compounds 10 and 16, which are obtained with low
cost and good overall yields. These ketones are key interme-
diates in the production of spirocarbocyclic aminoadaman-
tanes, which constitute an important class of pharmacologi-
cally interesting agents. Further studies focused on the
preparation of additional analogues by the functionalization
of the carbonyl group are currently in progress, and will be
reported in due course.
H
2
SO
4
led to the key spirocyclopentanone 10.
The key intermediate dinitrile 14 for the synthesis of
adamantanospirocyclohexanone 16 was prepared from dini-
trile 8, which was first converted quantitatively to cyanoester
1
1 by refluxing with a saturated ethanolic solution of gase-
ous HCl. Reduction of the latter with ꢀaꢁꢂ in di-
4
oxane/water 1/1 gave alcohol 12 in a very high yield. When
alcohol 12 reacted with thionyl chloride, instead of the re-
spective chloride 13 we isolated the symmetric ether 17 as
O
NNHCOOCH3
b
NHNHCOOCH3
N=NCOOCH3
CN
a
c
d
CN
CN
1
2
3
4
5
Scheme 1. Reagents and Conditions: (a) NH
2
NHCOOCH
3
, AcOH, MeOH, reflux, 1 h (quant.); (b) KCN, NH
4
Cl, H
2
O/MeOH, 30 °C, 24 h
(
80 %); (c) Br
2
, NaHCO
3
, CH
2
Cl
2
/H
2
O, rt (quant.); (d) MeONa/MeOH 1:1 (96 %).
CN
CH CH=CH
2
2
CH CH CH Br
CH CH CH CN
2
2
2
2
2
2
a
b
c
d
CN
CN
CN
5
6
7
8
e
CN
NH2
O
9
10
Scheme 2. Reagents and Conditions: (a) LDA, –80 °C, THF, CH
96%); (c) KCN, 18-crown-6, CH
AcOH, ethanol, reflux, 20 h (quant.).
2
=CHCH
2
Br, -65 °C, 1.5 h (88%); (b) (C
6
H
5
CO)
2
O
2
, petr. ether, HBr(g)
4
SO ,
(
3
CN, reflux, 90 h (quant.); (d) LDA, –80 °C, THF, and r.t. overnight, then water (81%); (e) 33% H
2

Facile and Effective Synthesis of Spirocycloalkanones
Letters in Organic Chemistry, 2011, Vol. 8, No. 8
533
CH CH CH COOC H
CH CH CH CH OH
2 2 2 2
CH CH CH CN
2
2
2
2
5
2
2
2
c
a
b
CN
CN
CN
11
8
12
CH CH CH CH Cl
CH CH CH CH CN
2
2
2
2
2
2
2
2
d
CN
CN
13
14
i
e
g
CH CH CH CH Br
2
2
2
2
CN
CN
NH2
18
15
h
f
CH CH CH CH OCH CH CH CH
2
2
2
2
2
2
2
2
CN
NC
17
O
1
6
Scheme 3. Reagents and Conditions: (a) Ethanol, HCl, reflux, 2 h (quant.); (b) NaBH
4
, dioxane/H
2 3 2
O 1/1, rt, 72 h, (92%); (c) CH SO Cl,
o
DMF, dry pyridine, 1h rt and then 2 h at 70 C (quant.); (d) KCN, 18-crown-6, CH
overnight, then water (21%); (f) 33% H SO , AcOH, ethanol, reflux, 27 h (63%); (g) SOCl
benzonitrile, 124 C, 4 h (68%); (i) KCN, 18-crown-6, CH CN, reflux, 48 h (quant.).
3
CN, reflux, 48 h (97%); (e) LDA, –80 °C, THF, and rt
o
2
4
2 3 2
, dry toluene, 90 C, 1.5 h (49%); (h) Ph P, Br ,
o
3
1
13
Perkin-Elmer 833 spectrometer. H and C NMR spectra
were recorded on a Bruker MSL 400 spectrometer, using
3 6
CDCl or DMSO-d as solvent and TMS as internal standard.
Carbon multiplicities were established by DEPT experi-
ments. The 2D NMR experiments (HSQC, COSY, HMBC
and NOESY) were performed for the elucidation of the
structures of the new compounds. Microanalyses were car-
ried out by the Service Central de Microanalyse (CNRS)
France, and the results obtained had a maximum deviation of
±
0.4% from the theoretical value.
3
,7
2
-Cyano-tricyclo[3.3.1.1 ]decane-2-butanoic acid Ethyl
Ester (11)
To a stirred solution of dinitrile 8 (6.00 g, 26.30 mmol) in
abs ethanol (15 mL) was added a saturated with gaseous HCl
solution of abs ethanol (75 mL) and the mixture was refluxed
for 1.5 h. Then water (1 mL) was added and the reflux went
on for 0.5 h. The excess of ethanol was evaporated and the
residue was quenched with ice-water and extracted with
Fig. (1). Graphical representation of the NOE correlations (green)
of 16 as observed experimentally in the NOESY spectrum with a
mixing time of 3.5 s.
Et
2
O (4x80 mL). The combined extracts were washed with
O (2x50 mL), saturated solution of NaHCO (50 mL),
water again (50 mL) and dried (Na SO ). After removal of
H
2
3
EXPERIMENTAL
2
4
Materials and Instruments
the solvent, the oily residue was crystallized in the fridge to
afford pure nitrile ester 11 (7.20 g, quant.): mp 38-40 °C (n-
pentane, -20°C). IR(Nujol) v(CN) 2228 cm , v(C=O) 1733
Melting points were determined using a Büchi capillary
apparatus and are uncorrected. IR spectra were recorded on a
-
1

5
34 Letters in Organic Chemistry, 2011, Vol. 8, No. 8
Zoidis and Kolocouris
-
1
1
-1
1
cm ; ꢀ-ꢁꢂR (400 ꢂꢀz, CDCl
J=7.0 Hz, OCH CH ), 1.56-1.91 (complex m, 16H, ꢃ, ꢄ-ꢀ, 1,
, 4a, 5, 6, 7, 8, 9a, 10-H), 2.21 (br. d, 2H, 4b, 9b-H), 2.33-
3
), ꢀ (ppm) 1.25 (t, 3ꢀ,
3
jol): ꢁ(CꢀN) 2229 cm ; H-NMR (400 MHz, CDCl ) ꢀ
(ppm) 1.60-1.92 (complex m, 18H, ꢃ, ꢄ, ꢆ, 1ꢇ, 3ꢇ, 4ꢇa, 5ꢇ, 6ꢇ,
7ꢇ, 8ꢇ, 9ꢇa, 10ꢇ-H), 2.23 (br d, 2H, 4ꢇb, 9ꢇb-H), 2.39 (t, J =
6.5 Hz, 2H, ꢅ-H). C-NMR (CDCl
7.0 (2-C), 23.7 (1-C), 25.6 (3-C), 26.5 (7ꢇ-C), 27.0 (5ꢇ-C),
0.7 (4ꢇ, 9ꢇ-C), 33.3 (1ꢇ, 3ꢇ-C), 33.9 (4-C), 35.3 (8ꢇ, 10ꢇ-C),
7.8 (6ꢇ-C), 44.7 (2ꢇ-C), 119.3 (4-CN), 124.2 (2ꢇ-CN). Anal.
22 2
H N : C, 79.29; H, 9.15; N, 11.56. Found: C,
9.42; H, 9.28; N, 11.75.
2
3
3
2
1
3
13
.36 (m, 2H, ꢅ-H), 4.10 (q, 2H, J=7.0 Hz, OCH
, 100 MHz), ꢀ (ppm) 14.2 (CH ), 19.7 (ꢃ-C),
6.5 (7-C), 27.0 (5-C), 30.7 (4, 9-C), 33.2 (1, 3-C), 34.0 (ꢄ-
C), 35.3 (8, 10-C), 37.9 (6-C), 44.6 (2-C), 60.3 (CH O),
: C,
4.14; H, 9.15; N, 5.09. Found: C, 74.40; H, 9.51; N, 5.34.
2
CH
3
); C-
3
, 100 MHz), ꢆ(ppm) :
1
3
3
NMR (CDCl
3
3
2
2
Calcd for C16
7
1
7
24.2 (CN), 173.0 (C=O). Anal. Calcd for C17H25NO
2
3
,7
2-Aminospiro[cyclohex-2-ene-1,2'-tricyclo[3.3.1.13,7]decane]
2
(
-(4-Hydroxybutyl)-tricyclo[3.3.1.1 ]decane-2-carbonitrile
3
-carbonitrile (15)
12)
Sodium boronhydride (8.92 g, 236.0 mmol) was added
portionwise to a stirred solution of the nitrile-ester 11 (6.38g,
3.2 mmol) in a mixture of dioxane-water (1/1) under ice
cooling. After stirring at ambient temperature for 72 h (TLC
monitoring), the reaction mixture was hydrolyzed with a
solution of HCl 18% under ice-cooling to pH=7-8. Then wa-
ter was added and the mixture was extracted with ether. The
combined organic extracts were washed with H
mL), brine, dried (Na SO ) and evaporated to dryness under
reduced pressure. After removal of the solvent, the oily resi-
due was crystallized in the fridge to afford pure alcohol 12
4.95 g, 92%): mp 40-42 °C (petr. ether). IR(Nujol) v(OH)
3
431 cm , v(CN) 2229 cm ; ꢀ-ꢁꢂR (400 ꢂꢀz, CDCl ), ꢀ
ppm) 1.48-1.91 (complex m, 18H, ꢃ, ꢄ, ꢆ-ꢀ, 1, 3, 4a, 5, 6, 7,
, 9a, 10-H), 2.21 (br. d, 2H, 4b, 9b-H), 3.64 (m, 2H, ꢅ-H),
.67 (s, 1H, OH). Anal. Calcd for C15 23NO: C, 77.21; H,
.93; N, 6.00. Found: C, 77.49; H, 9.72; N, 5.67.
To a solution of LDA in dry ether (15 mL) - prepared by
the addition of an ethereal solution of freshly distilled diiso-
propylamine (3.48 g, 34.6 mmol) to a solution of n-BuLi
2
(
12.1 mL, 2.5 M or 30.2 mmol) in hexanes and stirring the
resulting solution for 30 min at –80 °C under argon atmos-
phere - was added dropwise a solution of dinitrile 14 (5.24 g,
2
1.6 mmol) in dry THF (30 mL) and the mixture was left
overnight to slowly reach room temperature. The mixture
was treated with an ice-water mixture, extracted with ether
and the organic phase was washed with water, HCl 5 %, wa-
2
O (1x50
2
4
ter, dried (Na
rial obtained was chromatographed on a silica gel column
Et O/Petr. ether 4:1) to afford 1.06 g of enamine 15: yield
1%; mp 175-177 °C (dec.) (ether-n-pentane); IR (Nujol)
2 4
SO ) and evaporated in vacuo. The solid mate-
(
3
(
8
3
9
(
2
-
1
-1 1
2
-1 1
ꢁ
(ꢁꢀ
ꢆ(ppm) : 1.46-2.10 (complex m, 18H, 5, 6, 1ꢇ, 3ꢇ, 4ꢇ, 5ꢇ, 6ꢇ,
ꢇ, 8ꢇ, 9ꢇ, 10ꢇ-H), 2.26-2.29 (t, 2H, 4-H), 4.76 (br. s, 2H,
NH ).
2 3
) 3368, (CꢀN) 2174 cm ; H-NMR (400MHz, CDCl ),
H
7
2
3
,7
3
,7
2
-(4-Chlorobutyl)-tricyclo[3.3.1.1 ]decane-2-carbonitrile
Spiro[cyclohexane-1,2'-tricyclo[3.3.1.1 ]decan]-2-one (16)
(
13)
A vigorously stirring mixture of enamine nitrile 15 (0.87
To a stirred solution of alcohol 12 (1.58 g, 6.8 mmol) and
g, 3.59 mmol) and conc. H SO (6 mL) was gently refluxed.
2
4
dry pyridine (0.58 g, 7.3 mmol) in DMF (3mL), methanosul-
fonyl chloride (0.83 g, 7.2 mmol) was added dropwise. After
stirring at room temperature for 1 h and 2 h at 70 °C (TLC
monitoring) the mixture was poured into water and extracted
with ether. The combined organic extracts were washed with
After 10 min refluxing, glacial acetic acid (7.5 mL) was
added; the mixture was refluxed for an additional 24 h period
and cooled at room temperature. Water was added, the mix-
ture was extracted with ether and the organic phase was
washed with water, aqueous ꢁaOH, water, and dried
H
2
O (1x50 mL), aq. HCl 5%, brine, dried (Na
2
SO
4
) and
(Na SO ). After solvent evaporation, the viscous oily mate-
2 4
-2
evaporated to dryness under reduced pressure. After removal
of the solvent, the oily residue was crystallized in the fridge
to afford pure chloride 13 (1.70 g, quant): mp 40-42 °C (petr.
rial was filtered through silica gel and sublimed (10 mmHg,
heated over a Bunsen burner flame) to yield 0.50 g of ketone
16 (63%); mp 72 °C (petr. ether cooled at –20°C); IR (Nujol)
-
1
1
-1
1
ether). IR(Nujol) v(CN) 2225 cm ; ꢀ-ꢁꢂR (400 ꢂꢀz,
CDCl ), ꢀ (ppm) 1.58-1.93 (complex m, 18H, 1, 2, 3, 1ꢇ, 3ꢇ,
ꢇa, 5ꢇ, 6ꢇ, 7ꢇ, 8ꢇ, 9ꢇa, 10ꢇ-H), 2.25 (br. d, 2H, 4ꢇb, 9ꢇb-H),
ꢁ(C=ꢈ) 1707 cm ; H-NMR (400 MHz, CDCl
3
) ꢀ (ppm)
1
4
1
3
.53-1.57 (br. d, 2H, 4ꢇa, 9ꢇa-H), 1.60-1.66 (complex m, 8H,
3
, 5, 6ꢇ, 8ꢇ-H), 1.80-1.89 (complex m, 6H, 6, 5ꢇ, 7ꢇ, 10ꢇ-H),
.98 (br. d, 2H, J=2.38 Hz, 4ꢇb, 9ꢇb-H), 2.13 (br. s, 2H, 1ꢇ,
4
3
1
3
3
.56 (t, 2H, 4-H). C NMR (100 MHz, CDCl ): ꢀ= 21.7 (2-
1
3
3
ꢇ-H), 2.39 (t, 2H, 3-H).; C-NMR (CDCl , 100 MHz) ꢀ
C), 26.5 (7ꢇ-C), 27.0 (5ꢇ-C), 30.7 (4ꢇ, 9ꢇ-C), 32.6 (1-C), 33.3
1ꢇ, 3ꢇ-C), 35.3 (8ꢇ, 10ꢇ-C), 37.9 (6ꢇ-C), 44.5 (4-C), 44.8 (2ꢇ-
C), 124.4 (CN). Anal. Calcd for C15 22ClN: C, 71.55; H,
.81; N, 5.56. Found: C, 71.17; H, 8.52; N, 5.90.
(
(
(
ppm) 19.9 (5-C), 27.4 (7ꢇ-C), 28.1 (5ꢇ-C), 30.3 (6-C), 31.9
4ꢇ, 9’-C), 32.3 (1ꢇ, 3ꢇ-C), 34.3 (8ꢇ, 10ꢇ-C), 37.7 (6ꢇ-C), 38.3
4-C), 38.6 (3-C), 55.2 (1, 2ꢇ-C), 203.5 (2-C). Anal. Calcd.
(
H
8
for C15
H
22O: C, 82.52; H, 10.16; N, 7.33. Found: C, 82.80;
3
,7
2
-Cyano-tricyclo[3.3.1.1 ]decane-2-pentanenitrile (14)
H, 10.32; N, 7.18.
3
,7
A mixture of chloronitrile 13 (6.00 g, 23.8 mmol), anhy-
2
,2'-[Oxybis(4,1-butanediyl)]bis-tricyclo[3.3.1.1 ]decane-
drous KCN (5.35 g, 82.2 mmol) and 18-6 crown ether (0.70
g, 2.6 mmol) in dry acetonitrile (30 mL) was refluxed for 12
h (TLC monitoring using ether/n-hexane 2:1). The mixture
was cooled at room temperature, water was added and the
precipitate formed was filtered off, washed with water and
dried. The solid residue was recrystallized (EtOH-water) and
2
-carbonitrile (17)
To a stirring solution of alcohol 12 (4.91 g, 21.0 mmol)
in dry toluene (20 mL) was added in one portion freshly dis-
tilled thionylchloride (14.16 g, 147.0 mmol). The mixture
was heated at 90-100 °C for 1,5 h. The solvent was then
evaporated under reduced pressure, and the residue was ex-
filtered on a silica gel column (Et
2
O) to afford pure dinitrile
O-petr. ether); IR (Nu-
3
tracted with ether, washed with water, NaHCO 10%, brine
1
4 (5.60 g, 97%); mp 63-65 °C (Et
2

Facile and Effective Synthesis of Spirocycloalkanones
Letters in Organic Chemistry, 2011, Vol. 8, No. 8
535
pounds via Cycloaddition Routes. Synthesis, 1978, 77-126; c) San-
nigrahi, M. Stereocontrolled synthesis of spirocyclics. Tetrahedron,
and dried (ꢀꢁ
der reduced pressure affording a viscous oil, which was puri-
fied by column chromatography on silica gel, using Et O-n-
hexane 6:1 to give back 2.32 g of the starting material and
.55 g of ether 17, which was triturated with cold ether.
2 4
SO ). The ethereal phase was evaporated un-
1
999, 55, 9007-9071.
2
[
3]
Some selected recent papers for the synthesis of spirocycles: a)
Clive, D. L. J.; Huang, X. Stereocontrolled formation of spiro
enones by radical cyclization of bromo acetals. Tetrahedron, 2001,
57, 3845-3857; b) Oesterreich, K.; Klein, I.; Spitzner, D. ‘One-pot’
Reactions: Total Synthesis of the Spirocyclic Marine Sesquiter-
pene, (+)-Axenol. Synlett, 2002, 1712-1715; c) Du, Y.; Lu, X.; Yu,
Y. Highly Regioselective Construction of Spirocycles via
Phosphine-Catalyzed [3 + 2]-Cycloaddition. J. Org. Chem. 2002,
2
o
Yield 49 %; mp 100-102 C (Et
2
O); IR (Nujol) ꢀ (CꢀN) 2228
cm ; H NMR (400 MHz, CDCl ) ꢁ (ppm) 1.55-1.91 (com-
plex m, 36H, ꢂ, ꢃ, ꢄ-ꢅ, 1ꢆ, 3ꢆ, 4ꢆa, 5ꢆ, 6ꢆ, 7ꢆ, 8ꢆ, 9ꢆa, 10ꢆ-H),
-
1 1
3
1
3
2
.23 (br. d, 4H, 4ꢆb, 9ꢆb-H), 3.80-4.13 (m, 4H, ꢁ-H); C-
NMR (CDCl , 100 MHz), ꢄ(ppm) 20.8 (2xꢃ-C), 26.5 (2x7ꢆ-
C), 27.0 (2x5ꢆ-C), 29.6 (2xꢄ-C), 30.8 (2x4ꢆ-C, 2x9ꢆ-C), 33.2
2x1ꢆ-C), 33.3 (2x3ꢆ-C), 34.3 (2xꢂ-C), 35.2 (2x8ꢆ-C, 2x10’-
C), 33.8 (2x6ꢆ-C), 47.8 (2x2ꢆ-C), 61.8 (2xꢁ-C), 124.3
6
7, 8901-8905.
3
[
4]
a) De Clercq, E. Antiviral agents active against Influenza A vi-
ruses. Nat. Rev.Drug Discov. 2006, 5, 1015-1025; b) Zoidis, G.;
Kolocouris, N.; Naesens, L.; De Clercq, E. Design and synthesis of
1,2-annulated adamantane piperidines with anti-influenza virus ac-
tivity. ꢂioorg. Med. Chem., 2009, 17, 1534-1541; c) Zoidis, G.;
Benaki, D.; Myrianthopoulos, V.; Naesens, L.; De Clercq, E.;
Mikros, E.; Kolocouris, N. Synthesis of 1,2-annulated adamantane
heterocycles: structural determination studies of a bioactive cyclic
sulfite. Tetrahedron Letters, 2009, 50, 2671-2675; d) Zoidis, G.;
Kolocouris, N.; Kelly, J. M.; Prathalingam, R. S.; Naesens, L.; De
Clercq, E. Design and synthesis of bioactive adamantanaminoalco-
hols and adamantanamines. Eur. J. Med. Chem., 2010, 45, 5022-
(
(
2xCN). Anal. Calcd. for C30
H
44
N
2
O: C, 80.30; H, 9.88.
Found: C, 80.21; H, 9.77.
3
,7
2
-(4-Bromobutyl)-tricyclo[3.3.1.1 ]decane-2-carbonitrile
(
18)
A solution of triphenyldibromophosphorane was pre-
pared by the dropwise addition of Br (0.55 g, 3.5 mmol) in
benzonitrile (2.5 mL) to a solution of triphenylphosphine
0.91 g, 3.5 mmol) in benzonitrile (15 mL) and the resulting
2
5
030; e) Fytas, C.; Kolocouris, A.; Fytas, G.; Zoidis, G.; Valmas,
C.; Basler, C.F. Influence of an additional amino group on the po-
tency of aminoadamantanes against influenza virus A. II - Synthe-
sis of spiropiperazines and in vitro activity against influenza A
H3N2 virus. Bioorganic Chemistry, 2010, 38, 247-251.
Gish, D. T.; Kelly, R. C.; Camiener, G. W.; Wechter, W. J. Nucleic
acids. 11. Synthesis of 5ꢇ-esters of 1-ꢂ-D-arabinofuranosylcytosine
possessing antileukemic and immunosuppressive activity.
J.Med.Chem. 1971, 14, 1159-1162.
(
o
solution was stirred at 124 C under argon atmosphere. To
this solution was added in one portion the ether 17 (1.38 g,
[
5]
6]
o
3
.0 mmol) and the mixture was heated at 124 C for 4 h. The
mixture was cooled to room temperature, n-pentane was
added and the precipitate formed was removed by filtration
and washed with n-pentane. The washings were combined
and the upper layer was removed and evaporated under vac-
uum to give a viscous oil. The product was purified by frac-
[
a) Kolocouris, N.; Zoidis G. and Fytas, C. Facile synthetic routes to
2
-oxo-1-adamantanalkanoic acids. Synlett, 2007, 7, 1063-1066; b)
Fytas, C.; Zoidis, G.; Fytas, G. A facile and effective synthesis of
lipophilic 2,6-diketopiperazine analogues. Tetrahedron, 2008, 64,
o
6
749-6754.
tional distillation in vacuo to give 18 (Eb0.01mmHg 160 C),
[7]
Satoh, T.; Kawashima, T.; Takahashi, S.; Sakai, K. A new synthe-
sis, including asymmetric synthesis, of spiro[4.n]alkenones from
three components: cyclic ketones, chloromethyl p-tolyl sulfoxide,
and acetonitrile; and a formal total synthesis of racemic acorone.
Tetrahedron, 2003, 59, 9599-9607.
Zoidis, G.; Kolocouris, N.; Foscolos, G. B.; Kolocouris, A.; Fytas,
G.; Karayannis, P.; Padalko, E.; Neyts, J.; De Clercq, E. Are the 2-
isomers of the drug rimantadine active anti-influenza A agents? An-
tiviral Chem. Chemother., 2003, 14, 153-164.
which was further purified by flash column chromatography
by using a mixture of Et
2
O/AcOEt 2/1 as eluents. Yield 1.25
o
g, 68%; mp 60-62 C (petr. ether); IR (Nujol) ꢀ (CꢀN) 2231
-
1 1
cm ; H NMR (400 MHz, CDCl
plex m, 18H, 1, 2, 3, 1ꢆ, 3ꢆ, 4ꢆa, 5ꢆ, 6ꢆ, 7ꢆ, 8ꢆ, 9ꢆa, 10ꢆ-H),
.25 (br. d, 2H, 4ꢆb, 9ꢆb-H), 3.42 (t, J = 7.2 Hz, 2H, 4-H);
Anal. Calcd. for C15 22BrN: C, 60.81; H, 7.49; N, 4.73.
3
) ꢁ (ppm) 1.56-1.91 (com-
[
[
[
8]
2
H
9]
Oldenziel, O. H.; van Leusen, D.; van Leusen, A. M. A general
one-step synthesis of nitriles from ketones using tosylmethyl iso-
cyanide. Introduction of a one-carbon unit. J. Org. Chem., 1977,
Found: C, 61.11; H, 7.82; N, 5.01.
4
2, 3114-3118.
ACKNOWLEDGEMENTS
10]
Ziegler, F. E.; Wender, P. A. Methyldialkylcyanodiazenecarboxy-
lates as intermediates for transforming aliphatic ketones into ni-
triles. J. Org. Chem., 1977, 42, 2001-2003.
Schaefer, J. P. ; Bloomfield, J. J. Thorpe-Ziegler reaction. Org.
React., 1967, 15, 1-203.
a)Anderson, A.; Freenor, F. Ether cleavage by triphenyldibromo-
phosphorane. J. Org. Chem., 1972, 37, 626-630; b) Zoidis, G.;
Tsotinis, A.; Kolocouris, N.; Kelly, J. M.; Prathalingham, R. S.;
Naesens, L.; De Clercq, E. Design and synthesis of bioactive 1,2-
annulated adamantane derivatives. Org. Biomol. Chem., 2008, 6,
Dr. Zoidis would like to thank the State Scholarship
Foundation of Greece and the University of Athens (ELKE
Account) for the financial support.
[
11]
12]
[
REFERENCES AND NOTES
[1]
Ho, T.-L. Carbocyclic Construction in Terpene Synthesis; VCH:
Weinheim, 1988.
[2]
For reviews, see: a) Krapcho, A. P. Synthesis of Carbocyclic Spiro
Compounds via Intramolecular Alkylation Routes Synthesis, 1974,
3
177-3185.
3
83-419; b) Krapcho, A. P. Synthesis of Carbocyclic Spiro Com-