15-[(Z)-Phenylmethylidene]-7,14-dioxadispiro[5.1.5.2]pentadecanes: Stereoselective one-pot assembly from cyclohexanones and phenylacetylene in a KOH/DMSO suspension

Article abstract of DOI:10.1016/j.tetlet.2011.05.056

Cyclohexanones react with phenylacetylene in a KOH/DMSO suspension (80°C, 1 h) to give unexpectedly phenylmethylidene dispirocyclic ketals, 15-[(Z)-phenylmethylidene]-7,14-dioxadispiro[5.1.5.2]pentadecanes, in 16-22% yields (along with the anticipated β,γ- and α,β-ethylenic ketones).

Full text of DOI:10.1016/j.tetlet.2011.05.056

Tetrahedron Letters 52 (2011) 3772–3775
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Tetrahedron Letters
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15-[(Z)-Phenylmethylidene]-7,14-dioxadispiro[5.1.5.2]pentadecanes:
stereoselective one-pot assembly from cyclohexanones and
phenylacetylene in a KOH/DMSO suspension
Elena Yu Schmidt, Nadezhda V. Zorina, Elena V. Skitaltseva, Igor A. Ushakov, Albina I. Mikhaleva,
⇑
Boris A. Trofimov
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, 1 Favorsky Str., Irkutsk 664033, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Cyclohexanones react with phenylacetylene in a KOH/DMSO suspension (80 °C, 1 h) to give unexpectedly
phenylmethylidene dispirocyclic ketals, 15-[(Z)-phenylmethylidene]-7,14-dioxadispiro[5.1.5.2]pentade-
Received 15 February 2011
Revised 25 April 2011
Accepted 13 May 2011
Available online 19 May 2011
canes, in 16–22% yields (along with the anticipated b,
c- and
a
,b-ethylenic ketones).
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Cyclohexanones
Phenylacetylene
7,14-dioxadispiro[5.1.5.2]pentadecanes
Dispirocycles
Vinyl ketones
Super bases
The carbon–carbon bond-forming reaction using acetylenes as a
source of carbon nucleophiles is a dynamically developing method
in organic synthesis.1 Owing to the rich chemistry of acetylenes,
the resulting coupled products are often prone to further transfor-
mations to form important polycyclic structures which make them
versatile synthetic tools.1a,1e,2 Among such polycyclic ensembles,
spiroketals attract steadily growing attention as substructures of
numerous naturally occurring compounds.3 Apart from their isola-
tion from natural sources, many efforts have been undertaken to
elaborate relevant synthetic approaches, which are mostly multi-
step and laborious.3 Therefore, the molecular design of spiroketals
of controlled stereochemistry remains a standing challenge for
synthetic organic chemists.4
unsaturated substituents. As starting materials, we chose cyclo-
hexanones and phenylacetylene which were expected to produce
the corresponding tertiary acetylenic alcohols5 in situ, which pre-
sumably are capable of further spirocyclization processes with
remaining cyclohexanone molecules.
Indeed, after a series of experiments, we found that cyclohexa-
nones 1–4, when allowed to react with phenylacetylene (5) in a
KOH/DMSO suspension (ketone:phenylacetylene:KOH, molar ratio
1:1:1) at 80 °C for 1 h gave, instead of the typical tertiary acetylenic
alcohols 6, 15-[(Z)-phenylmethylidene]-7,14-dioxadispiro[5.1.5.2]
pentadecanes 7–10 in 16–22% isolated yields along with mixtures
of isomeric b,c- and a,b-ethylenic ketones 11–14 in a total yield of
26–57% (Table 1).
The synthetic potential of acetylenic compounds for the prepa-
ration of polycyclic oxygen-containing structures has been demon-
strated by one-pot syntheses of methylene-6,8-dioxabicyclo[3.2.1]
octanes2a (frontalin and brevicomin congeners) from two mole-
cules of ketones and two molecules of acetylene, and by the syn-
The structure of dispiroketals 7–10 was proved by analysis of 1H
and 13C NMR spectra (COSY, NOESY). Assignments of the 13C sig-
nals were based on 2D HSQC and HMBC spectra (Fig. 1). In the
1H NMR spectra of dispiroketals 7–10, a singlet due to the olefinic
proton
H
a
(5.01–5.13 ppm) and complex multiplets (0.87–
thesis
of
methylene-oxaazabicyclo[3.1.0]hexanes2b
from
1.83 ppm) for the CH2-protons of the cyclohexane rings were pres-
ent. The signals of the spirocyclic carbons in the 13C NMR spectra
were observed in the region 83.1–86.5 ppm (C1) and 112.8–
ketoximes, ketones and acetylene.
We decided to investigate whether this methodology was appli-
cable for the assembly of novel dispirocyclic systems bearing
115.0 ppm (C8). NOESY correlations between H and 2-CH2 (6-
a
CH2) (Fig. 1) and the 3JH C1 ꢀ 4.2–4.5 Hz coupling values provided
a
evidence that, in all the cases, the Z-stereoisomer was formed
⇑
Corresponding author. Tel.: +7 395251 19 26; fax: +7 395241 93 46.
E-mail address: boris_trofimov@irioch.irk.ru (B.A. Trofimov).
exclusively.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.056

E. Y. Schmidt et al. / Tetrahedron Letters 52 (2011) 3772–3775
3773
Table 1
Reaction of cyclohexanones 1–4 with phenylacetylene (5) in a KOH/DMSO suspension13
R
HO
6
x
R
KOH/DMSO
80 oC, 1 h
+
R
O
5
1-4
+
ethylenic ketones 11-14
O
O
7-10
R
R
Dispiroketal, yielda (%)
Ethylenic ketones (isomer ratio),b total yield (%)
+
(11a:11b = 9:1), 57
7, 22
O
O
H
O
O
11b
12b
11a
Me
Me
Me
+
(12a:12b = 5:1), 44
O
O
8, 19
4-Me
O
O
12a
Me
Me
Me
(13a:13b:13c = 1:8:1), 34
Me
+
Me
9, 20
+
O
O
O
3-Me
13c O
O
O
O
13b
13a
Me
Me
+
+
Me
c
Me
(14a:14b:14c = 1:1:2), 26
Me10, 16
O
2-Me
O
O
Me
14a
14b
14c
a
b
c
Isolated yield after column chromatography.
Determined by 1H NMR spectroscopy.
Hexahydroazulenone was also formed in 16% yield (this result will be published elsewhere).
Thus, formation of the dispiroketals 7–10 was strictly Z-stereo-
selective: none of the corresponding E-isomers were detected in
the reaction mixture. For 4-methylcyclohexanone-derived dispi-
roketal 8, small amounts (ꢀ20%) of other diastereomers were also
observed (1H, 13C NMR). In the case of 2- and 3-methylcyclohexa-
none-derived dispiroketals 9 and 10, mixtures of regioisomers hav-
ing different mutual orientations of the methyl group were formed,
though the Z-stereoselectivity was retained for all the regioisomers
(1H, 13C NMR). Besides, these products can exist as a mixture of
diastereoisomers though it is a complex task (which is beyond
the scope of this Letter) to distinguish between the regio- and
diastereoisomers.
H
Hα
O
H
4
3
5
2
H
6
HMBC
1
15
NOESY
O
8
H
13
12
9
H
10
11
Figure 1. Characteristic NOESY and HMBC correlations of dispiroketals 7–10.

3774
E. Y. Schmidt et al. / Tetrahedron Letters 52 (2011) 3772–3775
O
R
R
-OH
-H2O
R
1-4
+
-O
A
O
1-4
R
R
H2O
-
-HO
O
O
O
-O
R
R
B
7-10
Scheme 1. A plausible mechanism for the formation of dispiroketals 7–14.
KOH/DMSO
80 oC, 1 h
+
O
O
HO
O
1
7
6
Scheme 2. Reaction of 1-(2-phenylethynyl)cyclohexanol (6) with cyclohexanone (1) in a KOH/DMSO suspension.
Further attempts to optimize the preparative features of this
phenylacetylene (5) was also detected in the reaction mixture.
Thus, another simple (even higher-yielding) route to dispiroketals
of type 7 from readily available starting materials has been
revealed.
The synthetic significance of these findings is also sustained by
the following facts. The dioxadispiro[5.1.5.2]pentadecane scaffold,
similar to that of the synthesized dispiroketals, is frequent in
numerous naturally occurring products possessing antibacterial,6
antiprotozoal10 and cytotoxic10b activities. Due to their fascinating
biological activities and structural features, these compounds have
ignited interest from chemical, biological and medical communi-
ties.11 Even closer in structure to dispiroketals 7–10, 14,15-diox-
reaction did not improve the yields of dispiroketals 7–10. At
60 °C (other conditions were the same as given in Table 1), the
anticipated tertiary acetylenic alcohol 6 was apparent in approxi-
mately equal ratio with dispiroketal 7 and ethylenic ketones 11
(6:7:11 = ꢀ1:1:1, GLC). At 100 °C, only mixtures of ethylenic ke-
tones 11–14 were isolated, while at higher temperature (120 °C),
resinification mainly occurred, probably due to auto-condensation
of the cyclohexanones. Against expectations, using a two-fold ex-
cess of cyclohexanone 1 (80 °C, 1 h), the yield of dispiroketal 7
dropped to 17%, the order of reactant mixing having no evident ef-
fect on the outcome. Nevertheless, despite the modest yields of
dispiroketals, their one-pot synthesis from readily available start-
ing materials under exceptionally simple conditions may have pre-
parative significance since analogous dispirocyclic ketals, even
without reactive unsaturated substituents, are usually synthesized
via multi-step laborious procedures.3,6
The ethylenic ketones 11–14 are other products of C-vinylation
of cyclohexanones. This novel C–C bond formation reaction de-
serves attention and it is now further elaborated by us (for exam-
ple, it might be expected that oxophilic Lewis acids such as
lanthanide salts will promote this reaction). Apparently, it pro-
ceeds via enolate addition (at its carbanionic site) to the acetylene
and formation of a vinyl carbanion. The first regio- and stereoselec-
tive version of this reaction was reported recently for alkylaryl ke-
tones.7 The C-vinylation of b-dicarbonyl compounds with alk-1-
enyl-lead triacetates was reported previously.8
adispiro[5.1.5.2]pentadecanes,
were
obtained
from
triethylsilyldiperoxyketals, which in the presence of SnCl4, form
peroxycarbenium ions that underwent annulation with alkenes
to form the title products10a. Dispiroketals of type 7–10 were un-
known until this work. The only congener of these dispiroketals,
octamethyl-7,14-dioxadispiro[5.1.5.2]pentadecane, was previ-
ously12 obtained upon photolysis of tetramethylcyclohexanone in
methanol.
In conclusion, the Z-stereoselective one-pot assembly of dispir-
oketals from cyclohexanones and phenylacetylene, or from 1-
phenylethynylcyclohexanols and cyclohexanones in a KOH/DMSO
suspension has been reported. Despite the modest yields of dispir-
oketals, this reaction may find applications (when optimized) as a
short-cut to valuable building blocks for drug design. An investiga-
tion of the generality and limitations of the reactions (including
extension to other cyclic ketones and acetylenes) is underway.
A plausible mechanism for the synthesis of dispiroketals 7–10
(Scheme 1) may involve, in accordance with the above expecta-
tions, the formation of deprotonated tertiary acetylenic alcohols
A, which further add to a second molecule of ketone 1–4. The anion
of the resulting hemiketal B undergoes intramolecular and stereo-
specific vinylation (complying with the trans-nucleophilic addition
rule).9
Acknowledgement
The work was carried out under financial support of the Russian
Foundation of Basic Research (Grant 11-03-00270).
To prove the key tandem sequence A?B?dispirocycle 7, acety-
lenic alcohol 6 was subjected to the reaction with cyclohexanone
(1) (KOH/DMSO, 80 °C, 1 h), and, as expected, the resulting product
turned out to be dispirocycle 7 in 37% isolated yield (Scheme 2);
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.05.056.

E. Y. Schmidt et al. / Tetrahedron Letters 52 (2011) 3772–3775
3775
12. Nemeroff, N.; Joullie, M. M.; Preti, G. J. Org. Chem. 1978, 43, 331–334.
13. Typical procedure for the synthesis of dispiroketals 7–10. mixture of
References and notes
A
cyclohexanone (1) (2.00 g, 20.4 mmol), phenylacetylene (5) (2.08 g,
20.4 mmol) and KOHÁ0.5H2O (1.33 g, 20.4 mmol) in DMSO (20 mL) was
heated (80 °C) and stirred for 1 h. The reaction mixture, after cooling (20–
22 °C), was diluted with H2O (50 mL), neutralized with NH4Cl and extracted
with Et2O (10 mL Â 4). The organic extract was washed with H2O (10 mL Â 3)
and dried (K2CO3) overnight. After removal of the solvent, a crude residue
(3.79 g) was obtained. Column chromatography (SiO2, benzene) gave the pure
dispiroketal 7 (0.67 g, 22%) and a mixture of vinyl ketones 11a,b (2.32 g, 57%).
15-[(Z)-Phenylmethylidene]-7,14-dioxadispiro[5.1.5.2]pentadecane (7). Yellow
oil. Anal. Calcd for C20H26O2 (298.42): C, 80.50; H, 8.78. Found: C, 80.68; H,
1. (a) Trofimov, B. A. Curr. Org. Chem. 2002, 6, 1121–1162; (b) Knöpfel, T. F.;
Boyall, D.; Carreira, E. M. Org. Lett. 2004, 6, 2281–2283; (c) Knöpfel, T. F.;
Carreira, E. M. J. Am. Chem. Soc. 2003, 125, 6054–6055; (d) Trost, B. M.; Weiss, A.
H. Adv. Synth. Catal. 2009, 351, 963–983; (e) Li, C.-J. Acc. Chem. Res. 2010, 43,
581–590.
2. (a) Trofimov, B. A.; Schmidt, E. Y.; Ushakov, I. A.; Mikhaleva, A. I.; Zorina, N. V.;
Protsuk, N. I.; Senotrusova, E. Y.; Skital’tseva, E. V.; Kazheva, O. N.; Alexandrov,
G. G.; Dyachenko, O. A. Eur. J. Org. Chem. 2009, 5142–5145; (b) Trofimov, B. A.;
Schmidt, E. Y.; Mikhaleva, A. I.; Ushakov, I. A.; Protsuk, N. I.; Senotrusova, E. Y.;
Kazheva, O. N.; Aleksandrov, G. G.; Dyachenko, O. A. Tetrahedron Lett. 2009, 50,
3314–3317.
8.79. IR (film) mmax: 3086, 3058, 2934, 2860, 1679, 1601, 1497, 1448, 1396,
1332, 1271, 1258, 1224, 1191, 1159, 1143, 1117, 1090, 1064, 1030, 992, 961,
953, 908, 808, 748, 694, 503. 1H NMR (400.13 MHz, CDCl3) d: 7.62–7.60 (m, 2H;
Ho), 7.34 (m, 2H; Hm), 7.12 (m, 1H; Hp), 5.13 (s, 1H; @CH), 1.80–1.59 (m,
20Hcyclohexane). 13C NMR (101.61 MHz, CDCl3) d: 159.3 (C15), 136.7 (Ci), 128.4
(Cm) 127.4 (Co), 125.0 (Cp), 112.8 (C8), 95.0 (@CH), 83.5 (C1), 39.0, 38.1 (C2, C6,
C9, C13), 25.3, 25.0 (C4, C11), 24.1, 22.6 (C3, C5, C10, C12).
3. Raju, B. R.; Saikia, A. K. Molecules 2008, 13, 1942–2038.
4. Paley, R. S.; Laupheimer, M. C.; Erskine, N. A. K.; Rablen, P. R.; Pike, R. D.; Jones,
J. S. Org. Lett. 2011, 13, 58–61.
5. (a) Favorsky, A. E. Zh. Ross. Khim. Obshch. 1906, 37, 643; (b) Smith, M.; March, J.
March’s Advanced Organic Chemistry, sixth ed.; Wiley: New York, 2007. p. 1360.
6. Yadav, J. S.; Rao, K. V. R.; Ravindar, K.; Reddy, B. V. S. Synlett 2010, 51–54.
7. Trofimov, B. A.; Schmidt, E. Y.; Ushakov, I. A.; Zorina, N. V.; Skital’tseva, E. V.;
Protsuk, N. I.; Mikhaleva, A. I. Chem. Eur. J. 2010, 16, 8516–8521.
8. (a) Moloney, M. G.; Pinhey, J. T. J. Chem. Soc., Chem. Commun. 1984, 965–966;
(b) Moloney, M. G.; Pinhey, J. T. J. Chem. Soc., Perkin Trans. 1 1988, 2847–2854.
9. Dickstein, J. I.; Miller, S. I. In The Chemistry of the Carbon-Carbon Triple Bond Part
2; Patai, S., Ed.; Wiley: New York, 1978.
10. (a) Chin, Y.-W.; Salim, A. A.; Su, B.-N.; Mi, Q.; Chai, H.-B.; Riswan, S.; Kardono, L.
B. S.; Ruskandi, A.; Farnsworth, N. R.; Swanson, S. M.; Kinghorn, A. D. J. Nat.
Prod. 2008, 71, 390–395; (b) Heilmann, J.; Mayr, S.; Brun, R.; Rali, T.; Sticher, O.
Helv. Chim. Acta 2000, 83, 2939–2945.
11. (a) Wang, X.; Dong, Y.; Wittlin, S.; Creek, D.; Chollet, J.; Charman, S. A.; Tomas, J.
S.; Scheurer, C.; Snyder, C.; Vennerstrom, J. L. J. Med. Chem. 2007, 50, 5840–
5847; (b) Salim, A. A.; Su, B.-N.; Chai, H.-B.; Riswan, S.; Kardono, L. B. S.;
Ruskandi, A.; Farnsworth, N. R.; Swanson, S. M.; Kinghorn, A. D. Tetrahedron
Lett. 2007, 48, 1849–1853; (c) Zhen, Z. B.; Gao, J.; Wu, Y. J. Org. Chem. 2008, 73,
7310–7316.
Vinyl ketones 11a,b as a mixture. Yellow oil. Anal. Calcd for C14H16O (200.28): C,
83.96; H, 8.05. Found: C, 84.10; H, 8.09. IR (film) mmax: 3027, 2937, 2863, 1951,
1709, 1613, 1495, 1450, 1249, 1143, 1127, 1071, 966, 748, 696, 495. 1H NMR
(400.13 MHz, CDCl3) for 11a d: 7.40 (m, 2H; Ho), 7.31 (m, 2H; Hm), 7.23 (m, 1H;
Hp), 6.46 (dd, J = 16.1 Hz, 3J = 6.4 Hz, 1H; H ), 6.39 (d, J = 16.1 Hz, 1H; Hb),
a
3.21–-3.15 (m, 1H; H2), 2.45–2.34 (m, 2H; 6-CH2), 2.16–1.72 (m, 2H; 3-CH2),
2.01–1.72 (m, 2H; 4-CH2), 1.91–1.73 (m, 2H; 5-CH2). 13C NMR (101.61 MHz,
CDCl3) for 11a d: 211.2 (C@O), 131.5 (C ), 137.3 (Ci), 128.6 (Cm), 127.6 (Cb),
a
127.4 (Cp), 126.4 (Co), 54.1 (C2), 41.8 (C6), 34.5 (C3), 27.7 (C4), 24.5 (C5). 1H
NMR (400.13 MHz, CDCl3) for 11b d: 7.25 (m, 2H; Hm), 7.20 (m, 1H; Hp), 7.16
(m, 2H; Ho), 6.75 (tt, 3J = 7.8 Hz, 4J = 2.2 Hz, 1H; H ), 3.42 (d, 3J = 7.8 Hz, 2H;
a
CH2-Ph), 2.59, 2.20 (m, 2H; 3-CH2), 2.40, 2.29 (m, 2H; 6-CH2), 1.90, 1.70 (m, 2H;
5-CH2), 1.75, 1.65 (m, 2H; 4-CH2).13C NMR (101.61 MHz, CDCl3) for 11b d:
201.1 (C@O), 138.9 (Ci), 137.2 (C ), 135.8 (C2), 128.7 (Co), 127.4 (Cp), 126.4
a
(Cm), 40.3 (C6), 34.0 (CH2-Ph), 26.9 (C3), 23.7 (C5), 23.4 (C4).