Acid catalysed reaction of estrones with neopentyl glycol under forced conditions

Article abstract of DOI:10.3184/030823410X12678785299942

Upon reaction with an excess of 2,2-dimethylpropane-1,3-diol (neopentyl glycol) under acid catalysis, estrones form 17-O-[2',2'-dimethyl-2'-(5", 5"-dimethyl-1",3"-dioxanyl)ethyl] substituted estra-3,17β-diols. The reaction represents a formal reduction of a keto function under acidic conditions in the absence of a metal.

Full text of DOI:10.3184/030823410X12678785299942

158 RESEARCH PAPER
MARCH, 158–162
JOURNAL OF CHEMICAL RESEARCH 2010
Acid catalysed reaction of estrones with neopentyl glycol under
forced conditions
Cristina Oliveiraa, Goreti Ribeiro Moraisb, Masao Imaic, Eiko Inohaec, Chishou Yamamotoc,
Shuntaro Matakad and Thies Thiemannc,e*
aInstitutoTecnologico e Nuclear, Estrada Nacional 10, P-2686-953 Sacavem, Portugal
bFaculty of Pharmacy, University of Lisbon, Av. Forças Armadas, P-1649 Lisbon, Portugal
d
cInterdisciplinary Graduate School of Engineering Sciences and Institute of Materials Chemistry and Engineering Kyushu University, 6-1,
Kasuga-koh-en, Kasuga-shi 816-8580, Japan
ePresent address: Department of Chemistry, Faculty of Science, United Arab Emirates University, PO Box 17551, Al Ain, UAE
Upon reaction with an excess of 2,2-dimethylpropane-1,3-diol (neopentyl glycol) under acid catalysis, estrones form
17-O-[2’,2’-dimethyl-2’-(5’’,5’’-dimethyl-1’’,3’’-dioxanyl)ethyl] substituted estra-3,17β-diols. The reaction represents a
formal reduction of a keto function under acidic conditions in the absence of a metal.
Keywords: estrone, reductive etherification, acid catalysis
The protection of keto compounds as 1,3-dioxanes by reaction
with 1,3-diols is a commonly used method.1 Among the 1,3
diols that are used is 2,2-dimethylpropane-1,3-diol (neopentyl
glycol), and 5,5-dimethyl-1,3-dioxanes2,3 are obtained as the
protected molecules. Due to the smell of some of these com-
pounds, especially of those prepared from cyclic ketones,
the perfume industry has expressed interest in them.4,5 In the
preparation of acetals derived from steroidal ketones with neo-
pentyl glycol,6–8 the authors have often noted side products,
which were not easily separated from the desired acetals. The
following contribution details the structural identification and
the targeted synthesis of these side products.
The reaction of estrones 2 with neopentyl glycol (NPG)
in refluxing benzene with the azeotropic removal of the water
that was formed, gave the corresponding acetals 1 in good
yield within 30 min. However, when estrones 2 were heated
with an excess of neopentyl glycol in refluxing benzene or in
toluene over a prolonged period, 17-O-[2p,2p-dimethyl-2p-
(5q,5q-dimethyl-1q,3q-dioxanyl)ethyl] steroidal ethers 3 were
formed (Schemes 1 and 2).
The reaction involves a formal reduction of the C-17 keto
functionality of the steroidal ketones 2. This is of interest as
few reduction methods have been reported to date that do not
involve a metal, a metal hydride or hydrazine as reductant.9
Alcohols as reductants of ketones are known, but these mostly
involve the Meerwein–Ponndorf–Verley reduction, using alu-
minum,10–13 lithium,14,15 lanthanum16 or samarium alkoxides.16
The proposed mechanism of the current reaction is shown in
Scheme 2. The reduction of the keto function is stereospecific.
X-ray crystal structural analysis of 3e shows that ethers of
estra-3,17β-diols are formed exclusively.17 It is believed that
the key step in the mechanism is the intramolecular hydride
transfer from the terminal alcohol of the neopentyl glycol
tether to the C17 keto group. While the keto group is reduced,
the terminal alcohol function of the tether is concomitantly
oxidised. The carbaldehyde which is formed undergoes acetal-
isation immediately (Scheme 2). 1,3-Dioxane-type acetals of
aldehydes are much more stable than the corresponding spiro-
acetals of cyclic ketones. The known spiroacetals 1 of the ste-
roidal ketones are probably formed initially, even under the
more extreme reaction conditions employed here. The spiroac-
etals, however, ring open in a back reaction to hemiacetals A.
In this equilibrium of ring closure to the spiroacetal and ring
opening, some of the material then undergoes the intramolecu-
lar hydride transfer to C (Scheme 3). Indeed, during the deac-
etalisation of 1a (p-TsOH, acetone) small amounts of 3a were
observed as a side product.
Previously, a hydride transfer under acidic conditions has
been noted in the case of the reaction of tetralones with pen-
tane-2,4-diol.18 A rearrangement of m-dioxanes to β-alkoxyal-
dehydes has also been reported previously, albeit at the high
reaction temperature of 350–400 °C over a pumice catalyst19–22
or over zeolite23,24 as has the analogous rearrangement of an
m-dioxane with sulfuric acid to a 2,2-dimethyl-2-(5p,5p-
dimethyl-1p,3p-dioxanyl)ethyl alkyl ether.25
In the present case, it could not be established experiment-
ally whether the hydride transfer is the rate determining
step of the reaction. When the reaction was carried out with
deuterated neopentyl glycol (4), in order to measure a potential
isotope effect, only acetal 5 was formed (Scheme 4). This
Scheme 1 Reaction of estrones with neopentyl glycol under different conditions.
* Correspondent. E-mail: thies@uaeu.ac.ae

JOURNAL OF CHEMICAL RESEARCH 2010 159
Scheme 2 i, KOH MeI (yield 70%); ii, CH3CH=2COCl, Et3N, CH2Cl2 (80%).
17-O-[2′,2′-dimethyl-2′-(5″,5″-dimethyl-1″,3″-dioxanyl)]-3,17β-diols from estrones. nr., no reaction.
Scheme 3 Mechanism of formation of 17-O-[2′,2′-dimethyl-2′-(5″,5″-dimethyl-1″,3″-dioxanyl)ethyl]estra-3,17β-diols.

160 JOURNAL OF CHEMICAL RESEARCH 2010
Scheme 4 Acetalisation of estrone with d4-neopentylglycol under forced conditions.
suggests that an isotope effect operates, but its value could not
be ascertained. Further elevation of the temperature led to
partial decomposition of the material.
A further increase of the steric demand of the neighbouring
atoms suppresses acetal formation. Thus, spiro compound 2g
does not form the corresponding acetal with NPG under these
conditions. Also, no trace of the ether-acetal could be detected
(Table 1). 6-Ketoestrones 2c and 2d yield a separable mixtures
of 17-O-[2,2-dimethyl-2-(5p,5p-dimethyl-1p,3p-dioxanyl)ethyl-
6-ketoestra-3,17β-diols 3f/3g, 17-O-[2,2-dimethyl-2-(5p,5p-
dimethyl-1p,3p-dioxanyl)ethyl-estra-1,3,5(10),6-tetraene-3,17β-
diols 3d/3e, and estratetraen-3-ol-17-ones 2c/2d (Scheme 2).
Estratetraenes 2c, 2d, 3d, and 3e are formed by a reductive
etherification–elimination reaction of the benzylic keto func-
tion. This is a general reaction found for indanones and
tetralones reacted with NPG under forced acidic conditions
(unpublished data), similar to the reaction of tetralones with
pentane-2,4-diol.18
The ether-acetals 3 are stable under various conditions and
can be transformed further as seen in typical reactions of 3a to
3b and 3c (Scheme 2).
In conclusion, it was found that estrones are reduced to 17-
O-[2p,2p-dimethyl-2p-(5q,5q-dimethyl-1q,3q-dioxanyl)ethyl]
steroidal ethers by a prolonged reaction with neopentyl glycol
under acidic conditions. The benzylic keto function in a 6-
oxoestra-1,3,5(10)-trien-17-one is converted to a 6,7-ene.
Note that steric characteristics of the atoms neighbouring to
the carbonyl function play a role not only in the stability of the
acetals and but also influence the kinetics of the ring closure–
ring opening equilibrium. While it is known, that spiroacetals
of five-membered cycloalkanones possess a different stability
in comparison to the six-membered cycloalkanones, this fact
seems not to be the overriding factor for the course of the reac-
tion discussed here, i.e. acetal formation versus hydride migra-
tion. Thus, reaction of cyclohexanone and of cyclopentanone
under the normal reaction conditions used (NPG, p-TsOH,
benzene, reflux 36h; then acetone, p-TsOH, RT, 12h) furnishes
only the corresponding acetals. It is interesting that acid-
catalysed reaction of the spiroacetal of cyclopentanone 8 with
cyclohexanone (6) leads to a much smaller amount of trans
acetalisation, than that of steroidal 17,17-spiroacetals 1 with
cyclohexanone (6), where the reaction leads to a complete
conversion to the ketosteroids 2 within short reaction times
(Scheme 5). Again this reveals that the different stability of the
spiroacetals is due to different steric requisites of the starting
materials.
Scheme 5 Transacetalisation of cyclopentanone spriroacetals with cyclohexanone (6).

JOURNAL OF CHEMICAL RESEARCH 2010 161
(C=O), 1493, 1460, 1111; δ (400 MHz) 0.71 (3H, s, CH3), 0.77 (3H,
s, CH3), 0.94 (3H, s, CH3), 0H.95 (3H, s, CH3), 1.13–1.69 (8H, m), 1.18
(3H, s, CH3), 1.24 (3H, t, 3J = 7.5 Hz, CH3), 1.84–1.88 (2H, m), 1.95–
2.04 (2H, m), 2.17–2.29 (2H, m), 2.57 (2H, q, 3J = 7.5 Hz), 2.83–2.87
(2H, m), 3.21 (1H, d, J = 8.4 Hz), 3.27 (1H, d, J = 8.4 Hz), 3.33 (2H,
d, 2J = 10.6 Hz), 3.60 (2H, d, 2J = 10.6 Hz), 4.29 (1H, s), 6.78 (1H, d,
Experimental
Melting points were measured on a Yanaco microscopic Hotstage and
are uncorrected. IR spectra were measured with JASCO IR-700 and
Nippon Denshi JIR-AQ2OM instruments. H and 13C NMR spectra
1
were recorded with a JEOL EX-270 spectrometer (1H at 270 MHz, 13
C
at 67.8 MHz) and a JEOL Lambda 400 FT-NMR spectrometer (1H at
395.7 MHz, 13C at 99.45 MHz). The assignments of the carbon signals
were aided by DEPT 90 and DEPT 135 experiments (DEPT = Distor-
tionless Enhancement by Polarisation Transfer). The chemical shifts
are relative to TMS (solvent CDCl3, unless otherwise noted). Mass
spectra were measured with a JMS-01-SG-2 spectrometer. Column
chromatography was carried out on Wakogel 300.
3
4
4J = 2.2 Hz), 6.83 (1H, dd, J = 8.5 Hz, J = 2.2 Hz), 7.27 (1H, d,
3J = 8.5 Hz); δC (99.45 MHz) 9.2, 11.6, 19.5, 19.8, 21.7, 22.9, 23.2,
26.3, 27.1, 27.8, 27.9, 29.6, 30.3, 31.6, 37.9, 38.3, 39.3, 43.4, 44.2,
50.3, 75.7, 89.1, 104.9, 118.5, 121.4, 126.3, 138.1, 148.4, 173.3; MS
(EI, 70 eV) m/z (%) = 498 (2.3) [M+], 115 (100).
3-O-Methyl-17-O-[2p,2p-dimethyl-2p-(5q,5q-dimethyl-1q,3q-dioxanyl)
ethyl]-estra-1,3,5(10),6-tetraen-3,17-diol (3d): 2c was reacted accord-
ing to General procedure A, and 3d was obtained as a slowly crystal-
lising, low melting, colourless solid. (Found: M+, 454.3090. C29H42O4
requires M+, 454.3083). νmax (neat/cm−1) 3018, 2924, 1603, 1570,
1476, 1258, 1214, 1113, 1043, 757; δ 0.69 (3H, s, CH ), 0.78 (3H, s,
CH3), 0.95 (3H, s, CH3), 0.96 (3H, s,HCH3), 1.17 (3H, 3s, CH3), 1.28–
Estrone (WAKO) was acquired commercially. 3-O-Methylestrone
(2b)26 and 2g27 were synthesised according to literature procedures.
Estra-1,3,5(10),6-tetraen-3-ol-17-ones 2c and 2d were prepared via
the corresponding 6-ketoestra-1,3,5(10)-trien-17-one 17,17-acetals 2e
and 2f.6
17-O-[2p,2p-Dimethyl-2p-(5q,5q-dimethyl-1q,3q-dioxanyl)ethyl]-estra-
1,3,5(10)-trien-3,17-diol (3a); general procedure A: A solution of
estrone (2a, 1.0 g, 3.7 mmol), neopentylglycol (462 mg, 4.4 mmol)
and p-TsOH monohydrate (100 mg, 0.53 mmol) in benzene (30 mL)
was refluxed for 36h with the azeotropic removal of water. Then,
the solution was concentrated in vacuo and acetone (20 mL) was
added to the residue. The resulting solution was stirred for 14h at RT.
The solution was concentrated in vacuo and the residue was separated
by column chromatography on silica gel (ether/hexane/CHCl3 1:1:1)
to yield 3a (654 mg, 40%) as a slowly crystallising, low melting solid.
(Found: M+, 442.3085. C28H42O4 requires M+, 442.3083). νmax (KBr/
cm−1) 3324 (OH), 2938, 2854, 1611, 1587, 1504, 1475, 1212, 1138,
1103, 1033, 1020, 1006, 989, 927; δH 0.70 (3H, s, CH3), 0.76 (3H,
s, CH3), 0.94 (3H, s, CH3), 0.95 (3H, s, CH3), 1.16 (3H, s, CH3), 1.29–
2.20 (13H, m), 2.78–2.82 (2H, m), 3.19–3.31 (3H, m), 3.38 (2H, d, 2J
= 11.1 Hz), 3.60 (2H, d, 2J = 11.1 Hz), 4.29 (1H, s), 4.58 (1H, s), 6.55
(1H, 4J = 2.7 Hz), 6.62 (1H, dd, 3J = 8.4 Hz, 4J = 2.7 Hz), 7.15 (1H, d,
3J = 8.4 Hz); δC (99.45 MHz) 11.6, 19.5, 19.8, 21.7, 22.9, 23.2, 26.5,
27.2, 27.9, 29.7, 30.3, 37.9, 38.6, 39.3, 43.4, 44.0, 75.6, 89.2, 104.9,
112.6, 115.2, 126.5, 132.9, 138.3, 153.2; MS (EI, 70 eV) m/z (%)
= 442 (6) [M+], 115 (100).
2
2
2.41 (11H, m), 3.23 (1H, d, J = 8.5 Hz), 3.29 (1H, d, J = 8.5 Hz),
3.33 (1H, m), 3.41 (2H, d, 2J = 10.8 Hz), 3.61 (2H, 2J = 10.8 Hz), 3.80
(3H, s, OCH3), 4.29 (1H, s), 5.98 (1H, dd, J = 9.3 Hz, J = 1.7 Hz),
3
3
4
6.44 (1H, dd, J = 9.3 Hz, J = 2.7 Hz), 6.64 (1H, J = 2.7 Hz), 6.74
(1H, dd, 3J = 8.7 Hz, 4J = 2.7 Hz), 7.17 (1H, d, 3J = 8.7 Hz); δ (67.8
MHz, CDCl3, DEPT 90, DEPT 135) 11.4 (+, CH3), 19.5 (+, CH3C), 19.8
(+, CH3), 21.7 (+, CH3), 22.9 (+, CH3), 23.1 (–), 24.3 (–), 27.8 (–),
30.3 (Cquat), 37.4 (–), 38.6 (+, CH), 39.3 (Cquat), 42.1 (+, CH), 44.0
(Cquat), 48.5 (+, CH), 55.3 (+, OCH3), 75.7 (–), 77.3 (–), 77.4 (–), 88.9
(+, CH), 104.9 (+, CH), 111.7 (+, CH), 111.8 (+, CH), 124.3 (+, CH),
127.7 (+, CH), 131.6 (Cquat), 133.2 (+, CH), 135.4 (Cquat), 158.0 (Cquat);
MS (FAB, 3-nitrobenzyl alcohol) m/z (%) = 454 (25) [M+].
Reaction of 2f with NPG under forced conditions: A solution of 2f
(386 mg, 1.0 mmol), p-TsOH (104 mg, 0.54 mmol) and NPG (574
mg, 5.5 mmol) in toluene (25 mL) was stirred under reflux for 12 h.
The solvent was then evaporated, and acetone (50 mL) was added.
The reaction mixture was stirred at RT. After 4 h, the solvent was
evaporated and a 10% aq. NaHCO3 solution (50 mL) was added, and
the mixture was extracted with CHCl3 (2 x 50 mL). The organic phase
was washed with water (50 mL), dried over anhydrous MgSO ,
filtered and concentrated. The crude product was chromatographe4d
on silica gel (hexane/ether/CHCl3 1:1:1) to afford 3e (73 mg, 14%),
3g (90 mg, 16%) and 2d (125 mg, 34 %). 3-O-benzoyl-17-O-[2p,2p-
dimethyl-2p-(5q,5q-dimethyl-1q,3q-dioxanyl)ethyl]-estra-1,3,5(10),
6-tetraene-3,17β-diol (3e): Colourless solid, m.p. 153–157 °C.
(Found: M+, 544.3188. C35H44O5 requires M+, 544.3189). νmax (KBr/
cm−1) 2938, 2848, 1738, 1477, 1450, 1260, 1235, 1145, 1116, 1080,
1063, 1027, 703; δH (270 MHz, CDCl3) 0.70 (3H, s, CH3), 0.78 (3H,
s, CH ), 0.95 (6H, s, 2 CH ), 1.16 (3H, s, CH3), 1.25–2.49 (10H, m),
3-O-Methyl-17-O-[2p,2p-dimethyl-2p-(5q,5q-dimethyl-1q,3q-dioxanyl)
ethyl]-estra-1,3,5(10)-trien-3,17-diol (3b) A: 2b was reacted accord-
ing General procedure A and 3b obtained as a slowly crystallising,
low melting, colourless solid; (Found: M+, 456.3246. C29H44O4
requires M+, 456.3240). ν (KBr/cm−1) 2950, 2846, 1612, 1501,
1468, 1392, 1256, 1237, 11m4a0x, 1112, 1042; δ 0.70 (3H, s, CH3), 0.77
(3H, s, CH3), 0.95 (3H, s, CH3), 0.96 (3H, s, HCH3), 1.17 (3H, s, CH3),
1.31–2.20 (13H, m), 2.85 (2H, m), 3.23 (1H, d, 2J = 8.5 Hz), 3.29 (1H,
3
3
3
3.20–3.62 (7H, m),44.28 (1H, s), 6.01 (1H, dd, 3J = 1.7 Hz, J =49.5 Hz,
2
2
d, J = 8.5 Hz), 3.33 (1H, m), 3.41 (2H, d, J = 10.8 Hz), 3.61 (2H,
2J = 10.8 Hz), 3.77 (3H, s, OCH3), 4.28 (1H, s), 6.62 (1H, d, 4J = 2.7
Hz), 6.72 (1H, dd, 3J = 7.6 Hz, 4J = 2.7 Hz), 7.21 (1H, d, 3J = 7.6 Hz);
δ (99.45 MHz, CDCl3) 11.6, 19.5, 19.8, 21.7, 22.9, 23.2, 26.5, 27.3,
2C7.9, 29.9, 30.2, 37.9, 38.7, 39.3, 43.4, 44.0, 50.2, 55.2, 75.6, 77.3,
89.2, 104.9, 111.4, 113.7, 126.3, 132.8, 138.0; MS (EI, 70 eV) m/z
(%) = 456 (6) [M+], 269 (10), 173 (31), 147 (20), 115 (69), 85 (33),
69 (100).
3
H7), 6.46 (1H, dd,4 J = 2.6 Hz,3 J = 9.5 Hz, H6), 6.91 (1H, d, J = 2.1
Hz), 7.01 (dd, 1H, J = 2.1 Hz, J = 8.1 Hz), 7.27–1.30 (2H, m), 7.50–
6.63 (3H, m), 8.18–8.21 (2H, m); δ (67.8 MHz, CDCl3) 11.4, 19.5,
19.8, 21.7, 22.9, 23.1, 24.2, 27.8, 3C0.3, 37.3, 38.2, 39.3, 42.3, 24.0,
48.6, 75.7, 88.9, 104.9, 118.8, 119.5, 124.4, 127.3, 128.5 (2C), 129.7,
130.2 (2C), 133.5, 133.6, 135.8, 136.9, 149.4, 165.3; MS (FAB,
3-nitrobenzyl alcohol) m/z (%) = 544 (7.3) [M+], 105 (100); 3-O-
benzoyl-17-O-[2p,2p-dimethyl-2p-(5q,5q-dimethyl-1q,3q-dioxanyl)ethyl]-
6-oxo-estra-1,3,5(10)-triene-3,17β-diol (3g): Colourless solid, mp.
120–124 °C. (Found: MH+, 561.3217. C35H45O6 requires MH+,
561.3216). ν (KBr/cm−1) 2950, 2846, 1739, 1682, 1603, 1483,
1253, 1193, 1m1a1x2, 1080, 704; δH (270 MHz, CDCl3) 0.71 (3H, s, CH3),
0.79 (3H, s, CH ), 0.953(6H, s, 2 CH ), 1.16 (3H, s, CH ), 1.25–2.65
B. Finely ground KOH (51 mg, 0.91 mmol) was added to DMSO
(1 mL) and the resulting mixture was stirred for 25 min at RT. Then,
3a (100 mg, 0.23 mmol) was added and the mixture was stirred for
a further 20 min at RT. Then the methyl iodide (28 μL, 64 mg,
0.45 mmol) was added. The mixture was stirred for 10 min at RT.
Then, it was poured into water (10 mL) and extracted with chloroform
(3 × 10 mL). The organic phase was dried over anhydrous MgSO4
and concentrated in vacuo. The residue was subjected to column
chromatography on silica gel (hexane/ether/CHCl3 4:1:1) to give 3b
(73 mg, 70%).
3-O-Propanoyl-17-O-[2p,2p-dimethyl-2p-(5q,5q-dimethyl-1q,3q-dioxanyl)
ethyl]-estra-1,3,5(10)-trien-3,17-diol (3c): To a solution of 3a
(100 mg, 0.23 mmol) in dry CH2Cl2 (5 mL) was added dry triethyl-
amine (114 mg, 157 μL) and then propionyl chloride (104 mg, 97 μL).
The reaction mixture was stirred at RT for 20 min. It was poured into
cold water (15 mL) and extracted immediately with chloroform (3 ×
15 mL). The organic phase was washed with a 2N aq. Na2CO3 solu-
tion, dried over anhydrous MgSO4 and concentrated in vacuo to give
3c (92 mg, 80%) as a slowly solidifying oil. (Found: M+, 498.3347.
C31H46O5 requires M+, 498.3345). νmax (neat/cm−1) 2950, 2866, 1762
2
3
3
3
(12H, m), 2.75 (1H, dd, J = 34.2 Hz, J = 136.8 Hz, H7), 3.23–3.62 (7H,
m), 4.28 (1H, s),47.4 (1H, dd, J = 2.4 Hz, J = 8.1 Hz), 7.48–7.70 (5H,
3
m), 7.87 (1H, d, J = 2.4 Hz), 8.19 (1H, d, J = 8.1 Hz); δC (67.8 MHz,
CDCl3) 11.4, 19.6, 19.7, 21.7, 22.9, 25.6, 27.7, 30.2, 37.4, 39.3, 39.7,
43.2, 43.3, 44.0, 50.2, 70.1, 75.7, 88.7, 104.9, 120.0, 126.8, 127.0,
128.6 (2C), 129.3, 130.2 (2C), 133.7, 133.8, 144.7, 149.6, 165.3,
197.2; MS (FAB, 3-nitrobenzyl alcohol) m/z (%) = 561 (16) (MH+),
105 (100); 3-O-benzoyl-estra-1,3,5(10),6-tetraen-3-ol-17-one (2d):
Colourless solid; mp. 188–191 °C. (Found: MH+, 373.1803. C25H25O3
requires MH+, 373.1804). νmax (KBr/cm−1) 2920, 2856, 1736, 1648,
1603, 1451, 1267, 1236, 1063; δ (270 MHz, CDCl ) 0.93 (3H, s,
3
3
CH ), 1.43–2.62 (113H, m), 6.11H(1H, d, J = 9.6 Hz, H7), 6.54
4
4
3
(1H, dd, 4J = 2.7 Hz,3 J = 9.6 Hz, H6), 6.95 (1H, d, J = 2.4 Hz), 7.05
3
(1H, dd, J = 2.4 Hz, J = 8.1 Hz), 7.30 (1H, d, J = 8.1 Hz), 7.48–7.54

162 JOURNAL OF CHEMICAL RESEARCH 2010
(2H, m), 7.61–7.64 (1H, m), 8.18–8.22 (2H, m); δC (67.8 MHz, CDCl3)
13.6, 21.6, 23.6, 31.0, 35.7, 37.8, 42.3, 48.5, 48.8, 119.1, 119.9, 124.5,
128.6 (2C), 130.2, 133.6, 128.1, 131.5, 135.6, 136.2, 149.5, 220.2;
MS (FAB, 3-nitrobenzyl alcohol) m/z (%) = 373 (MH+) (36), 105
(100).
G. R. Morais thanks Fundacao para a Ciencia e Tecnologia for
grant BD/6673/2001. Ms Y. Tanaka is thanked for MS and
HRMS measurements of the compounds.
Received 17 January 2010; accepted 25 February 2010
Paper 100975 doi: 10.3184/030823410X12678785299942
Published online: 23 March 2010
3-O-Methyl-17-O-[2p,2p-dimethyl-2p-(5q,5q-dimethyl-1q,3q-dioxanyl)
ethyl]-6-ketoestra-1,3,5(10)-trien-3,17β-diol (3f): This was obtained
from 2e using a method analogous to the reaction of 2f (see above)
as a colourless solid, m.p. 136 °C. (Found: MH+, 471.3113. C29H43O5
requires MH+, 471.3110 [FAB]). νmax (KBr/cm−1) 2954, 2870, 1675,
1608, 1495, 1473, 1335, 1321, 1288, 1254, 1110, 1034; δ 0.71 (3H,
s, CH3), 0.78 (3H, s, CH3), 0.94 (3H, s, CH3), 0.95 (3H, s,HCH3), 1.16
(3H, s, CH3), 1.20–2.53 (11H, m), 2.21 (1H, dd, 2J = 16.3 Hz, 3J = 13.2
Hz), 2.74 (1H, dd, 2J = 16.3 Hz, 3J = 3.6 Hz), 3.23 (1H, d, 2J = 8.7 Hz),
3.28 (1H, d, 2J = 8.7 Hz), 3.31 (1H, dd, 3J = 8.2 Hz, 3J = 8.2 Hz), 3.39
(2H, d, 2J = 11.3 Hz), 3.60 (2H, d, 2J = 11.3 Hz), 3.84 (3H, s, OCH3),
References
1
2
3
4
5
T.W. Greene and P.G.M. Wuts, Protective groups in organic synthesis, 2nd
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3
4
4.28 (1H, s), 7.10 (1H, dd, J = 8.6 Hz, J = 2.7 Hz), 7.34 (1H, d,
3J = 8.6 Hz), 7.56 (1H, d, 4J = 2.7 Hz); δ (67.8 MHz, DEPT 90, DEPT
135) 11.5 (+, CH3), 19.6 (+, CH3), 19.7C(+, CH3), 21.7 (+, CH3), 22.9
(–), 25.7 (–), 27.7 (–), 30.3, 37.4, 39.3, 40.0, 43.0, 43.2, 44.1 (–),
50.1 (+, OCH3), 55.5 (Cquat), 75.7 (–), 77.3 (–), 88.8 (+, CH), 104.9 (+,
CH), 109.5 (+, CH), 121.5 (+, CH), 126.6 (+, CH), 133.4 (Cquat), 140.0
(Cquat), 158.2 (Cquat), 198.1 (Cquat); MS (FAB, 3-nitrobenzyl alcohol)
m/z (%) = 471 (81) [MH+]. 3d and 2c are also produced in the
reaction.
6
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d4-Neopentylglycol (4). To a suspension of LiAlD4 (1.0 g, 25 mmol)
in dry ether (100 mL) was added dimethyl malonate (1.0 g,
6.25 mmol) within 10 min at 0 °C. The reaction mixture was heated
under reflux for 1h. Ethanol (10 mL) was then added, and the mixture
was stirred at RT for 30 min. The solvents were removed in vacuo, and
the residue was extracted with ether (3 × 50 mL). The combined
organic phase was dried over anhydrous MgSO4. Concentration of the
organic layer led to crystallisation of d4- neopentyl glycol (4, 332 g,
49.5%), colourless solid; m.p. 115 °C; νmax (KBr/cm−1) 3308, 2958,
2866, 2210, 2092, 1469, 1376, 1115, 1101, 974, 716; δH 0.89 (6H, s,
2 CH3), 3.02–3.29 (2H, bs, 2 OH); δC (67.8 MHz) 21.2, 36.1, 70.8
(quint, 2JC-D = 20.7 Hz); MS (EI, 70 eV) m/z (%) = 108 (M+) (11).
3-O-Methylestra-1,3,5(10)-trien-3-ol-17-one17,17-O,O-[2p-(4p,4p,6p,6p-
tetradeuterio-5q,5q-dimethyl-1q,3q-dioxane)] (5): 3-Methoxyestrone
(2b, 175 mg, 0.61 mmol), d4-neopentylglycol (4, 150 mg, 2.5 mmol)
and p-toluenesulfonic acid monohydrate (30 mg) in benzene (20 mL)
were heated under reflux for 15 hours with the continuous azeotropic
removal of water (Dean–Stark condenser). The reaction was cooled to
room temperature, poured into a saturated aqueous Na2CO3 solution
and the organic layer was separated. The organic layer was washed
with brine, and dried over anhydrous MgSO4. Concentration of
the solution in vacuo and column chromatography (ether hexane/1:1)
to give 5 (95 mg, 41%); δH 0.72 (3H, s, CH3), 0.83 (3H, s, CH3),
1.16 (3H, s, CH3), 1.25–1.76 (10H, m), 1.85–1.96 (1H, m), 2.22–2.27
(2H, m), 2.81–2.87 (2H, m), 3.77 (3H, m), 6.62 (1H, d, 4J = 3.0 Hz),
6.70 (1H, dd, 3J = 8.6 Hz, 4J = 3.0 Hz), 7.21 (1H, d, 3J = 8.6 Hz); MS
(70 eV) m/z (%) = 374 (35) [M+], 312 (23), 266 (88), 145 (100).
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