Transketalization and regioselective aldol condensation in bicyclic ketal system

Article abstract of DOI:10.1081/SCC-100103320

A convenient one-pot transketalization reaction of bicyclic ketal compound was obtained by using NaI-AcCl in ketone, and a regioselective aldol condensation of bicyclic ketal compound was also made by using NaI-TMSCl in acetonitrile.

Full text of DOI:10.1081/SCC-100103320

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TRANSKETALIZATION AND
REGIOSELECTIVE ALDOL
CONDENSATION IN BICYCLIC
KETAL SYSTEM
Ae-Ran Kim a , In-Suk Lee a & Jong-Gab Jun b
a Department of Chemistry , Hallym University ,
Chunchon, 200-702, Korea
b Department of Chemistry , Hallym University ,
Chunchon, 200-702, Korea
Published online: 09 Nov 2006.
To cite this article: Ae-Ran Kim , In-Suk Lee & Jong-Gab Jun (2001)
TRANSKETALIZATION AND REGIOSELECTIVE ALDOL CONDENSATION IN BICYCLIC
KETAL SYSTEM, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 31:6, 853-859, DOI: 10.1081/
SCC-100103320
To link to this article: http://dx.doi.org/10.1081/SCC-100103320
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SYNTHETIC COMMUNICATIONS, 31(6), 853–859 (2001)
TRANSKETALIZATION AND
REGIOSELECTIVE ALDOL
CONDENSATION IN BICYCLIC KETAL
SYSTEM
Ae-Ran Kim, In-Suk Lee, and Jong-GabJun *
Department of Chemistry, Hallym University, Chunchon
200-702, Korea
ABSTRACT
A convenient one-pot transketalization reaction of
bicyclic ketal compound was obtained by using NaI-AcCl in
ketone, and a regioselective aldol condensation of bicyclic
ketal compound was also made by using NaI-TMSCl
in acetonitrile.
A versatile character and utility of bicyclic ketals in the 6,8-dioxabi-
cyclo[3.2.1]octane structure have been reported forming into alkenone,1
diketone,2 cyclopentanediol,3 pyridines,4,5 cyclohexenone,6 and allylic acet-
ate derivatives.7 In the continuous study of reagent/reactions that would
provide new chemistry, we found new entries into transketalization by
using NaI-AcCl-Acetone and regioselective aldol condensation by using
NaI-TMSCl-CH3CN.
The reagent system NaI-AcCl, has been used for the synthesis of ꢀ,
"-unsaturated ketone1 directly from the bicyclic ketal in ꢀ20% yield and
applied for the synthesis of the Douglas fir tussock moth pheromone.8 An
interesting result was found from the reaction study to improve the yield.
* Corresponding author.
853
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

854
KIM, LEE, AND JUN
One-pot transketalization from the bicyclic ketal 1a into 2a in 75% yield
was obtained in the reaction condition of NaI-AcCl in acetone at room
temperature for 20 h (Scheme 1). The derivatives of ketal 1b–1d also gave
the expected results even though the yield of i-Pr (1b) and phenyl (1d)
derivatives was low. 2-Butanone and cyclohexanone were used instead of
acetone to give the expected acetals 2e and 2f in 28% and 8% yield, respect-
ively. This result showed a convenient and mild transketalization reaction
by using NaI-AcCl-ketone in bicyclic ketal system.
Scheme 1.
Conjugated cyclohexenones 3 were reported as the only products in a
one-flask reaction from the ketal 1 through the aldol condensation of 1,5-
diketone 4 via the terminal enol 5 by using TMSOMs-BF3ꢁEt2O (Scheme
2).6 The formation mechanism of the diketone 4 from the ketal 1 has been
proposed, and proved by the deuterium labeled experiment in our lab.9 The
aldol condensation of the diketone 4 to give the cyclohexenone 3 was a well-
known reaction, but the regioselective aldol condensation via the internal
enol 6 to give the unconjugated cyclohexenone 7 was unusual (Scheme 3).
We found that this unusual internal enol intermediate was favored in NaI-
TMSCl reagent system.
Iodotrimethylsilane has been reported as a useful ether-cleaving
agent.10–13 An important feature of the reagent is its cleavage pattern with
dialkyl ethers, which is somewhat different from that of boron halides.
However, its hydrolytic susceptibility, sensitivity in air, and decomposition
on prolonged storage are undesirable. Due to these difficulties, in situ
generation of iodotrimethylsilane from NaI-TMSCl was developed.14,15

BICYCLIC KETAL COMPOUND
855
Interestingly, unconjugated cyclohexenone 7a was produced directly
from the bicyclic ketal 1a in 80% yield by using NaI-TMSCl in acetonitrile
at reflux for 20 h. But the ketal derivatives 1b (R¼i-Pr), 1c (R¼t-Bu), and 1d
(R¼phenyl) yielded only the 1,5-diketones, 4b (68%), 4c (67%), and 4d
(40%), respectively instead of the expected unconjugated cyclohexenones,
7b–d. No further reaction resulted after 48 h reflux in this reagent system,
but the conjugated cyclohexenones, 3b (83%), 3c (88%), and 3d (72%) were
easily obtained within 15 h reflux by using TMSOMs-BF3ꢁEt2O. This result
indicates that the internal enols 6b–d were favored in NaI-TMSCl reagent
system, even though the steric congestion of the internal enols did not allow
the aldol condensation that would give the unconjugated cyclohexenones. In
conclusion, the different behavior of NaI-TMSCl reagent from that of
boron halides shows not only in ether cleavage reaction, but also in the
formation of enolate.
Yield (%)
Entry
R
3
4
a
bi-Pr
Me
83
80
0
0
c
d
t-Bu
Ph
88
72
0
0
Scheme 2.
EXPERIMENTAL
The NMR spectra were recorded on a Varian Gemini-200 MHz
FT-NMR, with the chemical shifts (ꢀ) reported in parts per million (ppm)
relative to TMS and the coupling constants (J) quoted in Hz. CDCl3 was
used as a solvent and an internal standard. Infrared spectra were recorded
on a Shimadzu IR-435 spectrometer. GLC analyses were performed using
a Shimadzu GC-7A equipped with a 11-ftÂ1/4-inch, 10% OV-17 column.
Most of the chemicals were purchased from Aldrich and were used without
further purification unless noted otherwise. Flash chromatography was

856
KIM, LEE, AND JUN
Yield (%)
Entry
R
7
4
0
a
bi-Pr
c
Me
0
t-Bu
Ph
80
68
0
67
40
d
0
Scheme 3.
carried out using silica gel Merck 60 (230–400 mesh). Thin-layer chromato-
graphy (TLC) was performed on DC-Plastikfolien 60, F254 (Merck, layer
thickness 0.2 mm) plastic-backed silica gel plates with visualization by UV
light (254 nm) or by treatment with p-anisaldehyde.
Typical Procedure for the Preparation of Dioxolane 2 from Bicyclic
Ketal 1
To a solution of dry sodium iodide (0.10 g, 0.67 mmol) in acetone
(15 mL) under nitrogen atmosphere at 0ꢂC was added slowly acetyl chloride
(0.02 mL, 0.29 mmol) and stirred for 10 m. Bicyclic ketal 1a (0.03 g,
0.19 mmol) was added to the solution and stirred for 20 h at room tempera-
ture. The reaction was quenched by the addition of 10% aqueous sodium
bisulfite solution (10 mL). The organic product was extracted with ethyl
acetate (3 Â mL) and washed with saturated sodium bicarbonate (30 mL)
and saturated brine (30 mL). The solvent was dried over magnesium sulfate
and removed via
a
rotary evaporator. Flash chromatography
(ether:hexane¼1:1) yielded the dioxolane 2a (0.03 g, 75% yield).
2,2,4,4-Tetramethyl-5-(4-petanoyl)-1,3-dioxolane (2a)
1H NMR (CDCl3) ꢀ 3.66 (1H, dd, J¼9 and 4 Hz, C5-H), 2.50 (2H, m,
C30-H), 2.15 (3H, s, C50-H), l.90–l.40 (4H, m, C10 and C20-H), 1.44 (3H, s,

BICYCLIC KETAL COMPOUND
857
C2-methyl), 1.33 (3H, s, C2-methyl), 1.24 (3H, s, C4-methyl), 1.08 (3H, s,
C4-methyl); 13C NMR (CDCl3) ꢀ 209.9 (C¼O), 106.9 (C2), 83.6 (C5), 80.5
(C4), 43.8 (C30), 30.3 (C50), 29.1 (C10), 28.9 (C2-methyl), 27.2 (C2-methyl),
26.3(C4-methyl), 23.2 (C4-methyl), 21.7 (C20); IR(neat): 2942, 1714 (C¼O),
1371, 1235, 1201, 1115, 1007, 912, 733 cmꢃ1
.
4-Isopropyl-2,2,4-trimethyl-5-(4-pentanoyl)-1,3-dioxolane (2b)
1H NMR (CDCl3) ꢀ 3.79 (1H, dd, J¼8 and 4 Hz, C5-H), 2.50 (2H, br t,
J¼7 Hz, C30-H), 2.15 (3H, s, C50-H), 1.90–1.40 (5H, m, C10, C20 and
C4-isopropyl H), 1.41 (3H, s, C2-methyl), 1.30 (3H, s, C2-methyl), 1.00
(3H, s, C4-methyl), 0.94 (3H, d, J¼14 Hz, C4-isopropyl-methyl), 0.91 (3H,
d, J¼14 Hz, C4-isopropyl-methyl); 13C NMR (CDCl3) ꢀ 208.9 (C¼O), 106.4
(C2), 84.7 (C5), 81.2 (C4), 43.4 (C30), 36.4 (isopropyl C), 30.2 (C50), 29.9
(C10), 28.9 (C2-methyl), 26.9 (C2-methyl), 21.8 (C20), 18.0 (C4-methyl), 17.8
(isopropyl-methyl), 17.5 (isopropyl-methyl); IR(neat): 2981, 1716 (C¼O),
1373, 1273, 1215, 1093, 920, 912, 732 cmꢃ1
.
4-t-Butyl-2,2,4-trimethyl-5-(4-pentanoyl)-1,3-dioxolane (2c)
1H NMR (CDCl3) ꢀ 3.94 (1H, m, C5-H), 2.52 (2H, m, C30-H), 2.16
(3H, s, C50-H), 1.90–1.40 (4H, m, C10 and C20-H), 1.47 (3H, s, C2-methyl),
1.37 (3H, s, C2-methyl), 1.27 (3H, s, C4-methyl), 0.98 (9H, s, t-butyl);
13C NMR (CDCl3) ꢀ 207.4 (C¼O), 104.5, (C2), 84.7 (C5), 76.9 (C4), 41.8
(C30), 34.1 (t-butyl-C), 29.1 (C50), 28.2 (C10), 27.4 (C2-methyl), 25.1
(C2-methyl), 24.5 (3ÂC, t-butyl), 20.4 (C4-methyl), 15.7 (C20); IR(neat):
2980, 1719 (C¼O), 1371, 1257, 1218, 1091, 1012 cmꢃ1
.
4-Phenyl-2,2,4-trimethyl-5-(4-pentanoyl)-1,3-dioxolane (2d)
1H NMR (CDCl3) ꢀ 7.50–7.25 (5H, m, phenyl), 3.81 (1H, t, J¼6 Hz,
C5-H), 2.46 (2H, br t, J¼6 Hz, C30-H), 2.11 (3H, s, C50-H), 1.90–1.40 (4H,
m, C10 and C20-H), 1.54 (3H, s, C4-methyl), 1.45 (3H, s, C2-methyl), 1.43
(3H, s, C2-methyl); 13C NMR (CDCl3) ꢀ 207.1 (C¼O), 142.7 (C10-phenyl),
126.7 (2ÂC30-phenyl), 125.5 (C40-phenyl), 123.3 (2ÂC20-phenyl), 105.8 (C2),
82.4 (C5), 82.1 (C4), 41.6 (C30), 28.2 (C50), 27.0 (C2-methyl), 26.6
(C2-methyl), 24.7 (C10), 20.6 (C4-methyl), 19.8 (C20); IR(neat): 3061,
2938, 1718 (C¼O), 1622, 1495, 1447, 1372, 1241, 1218, 1108, 1116, 1067,
1004, 762, 700 cmꢃ1
.

858
KIM, LEE, AND JUN
2-Ethyl-2,4,4-trimethyl-5-(4-pentanoyl)-1,3-dioxolane (2e)
1H NMR (CDCl3) ꢀ 3.67 (1H, m, C5-H), 2.51 (2H, t, J¼8 Hz, C30-H),
2.16 (3H, s, C50-H), 2.00–1.40 (6H, m, C10, C20-H and C2-ethyl), 1.35 (3H, s,
C2-methyl), 1.26 (3H, s, C4-methyl), 1.10 (3H, s, C4-methyl), 0.91 (3H, t,
J¼8 Hz, C2-ethyl-methyl); 13C NMR (CDCl3) ꢀ 209.0 (C¼O), 108.8 (C2),
83.6 (C5), 80.1 (C4), 43.5, 34.1, 32.9, 28.9, 26.7, 26.0, 25.6, 24.2, 21.5;
IR(neat): 2975, 1713 (C¼O), 1372, 1245, 1189, 1113, 1045, 1006, 914,
730 cmꢃ1
.
4,4-Dimethyl-2,2-pentamethylene-5-(4-pentanoyl)-1,3-dioxolane (2f )
1H NMR (CDCl3) ꢀ 3.65 (1H, m, C5-H), 2.53 (2H, t, J¼8 Hz, C30-H),
2.16 (3H, s, C50-H), l.90–1.40 (14H), 1.24 (3H, s, C4-methyl), 1.06 (3H, s,
C4-methyl); 13C NMR (CDCl3) ꢀ 209.5 (C¼O), 109.2 (C2), 83.2 (C5), 81.1
(C4), 43.7, 34.6, 33.9, 31.5, 29.2, 28.2, 27.9, 26.2, 24.3, 23.5, 21.3; IR(neat):
2969, 1715 (C¼O), 1376, 1235, 1209, 1091, 920 cmꢃ1
.
The typical procedure for the preparation of cyclohexenone 3 from
bicyclic ketal 1 was reported.6
Typical Procedure for the Preparation of Cyclohexenone 7 from
Bicyclic Ketal 1
To a solution of dry sodium iodide (1.92 g, 12.80 mmol) in acetonitrile
(25 mL) under nitrogen atmosphere at ꢃ20ꢂC was added slowly trimethyl-
silyl chloride (0.81 mL, 6.40 mmol) and stirred until the color change to
yellow. Bicyclic ketal 1a (0.50 g, 3.20 mmol) was added to the solution and
refluxed for 20 h. After being cooled to room temperature, saturated sodium
bicarbonate (30 mL) was added. The organic product was extracted with
diethyl ether (3 Â 30 mL). The ether layer was washed with saturated brine
(30 mL), dried over magnesium sulfate, and the solvent was removed via a
rotary evaporator. Flash chromatography (ether:hexane ¼ 1:1) gave the
unsaturated cyclohexenone 7a (0.35 g, 80% yield).
2,2,3-Trimethyl-3-cyclohexen-1-one (7a)
1H NMR (CDCl3) ꢀ 5.53 (1H, brs, C4-H), 2.56 (2H, t, J¼7 Hz, C6-H),
2.36 (2H, m, C5-H), 1.72 (3H, br s, C3-methyl), 1.19 (6H, s, C2-dimethyl);
13C NMR (CDCl3) ꢀ 215.4 (C¼O), 140.5 (C3), 121.0 (C4), 47.7 (C2), 35.7

BICYCLIC KETAL COMPOUND
859
(C6), 25.0 (C5), 23.9 (2ÂC2-methyl), 18.3 (C3-methyl); IR(neat): 2971, 1714
(C¼O), 1463, 1379, 1237, 1190 cmꢃ1
.
ACKNOWLEDGMENT
This work was supported by the Hallym Academy of Sciences, Hallym
University, Korea.
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Received in Japan April 6, 2000