A regiospecific synthesis of 3,3,6-trimethylindan-1-one

Article abstract of DOI:10.1081/SCC-100103256

A novel, regiospecific synthesis of 3,3,6-trimethylindan1-one (5) was achieved. The route to 5 was 6 steps and proceeded in 27% overall yield.

Full text of DOI:10.1081/SCC-100103256

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A REGIOSPECIFIC SYNTHESIS
OF 3,3,6-TRIMETHYLINDAN-1-
ONE
Paul F. Vogt a , Bruce F. Molino a & Albert J.
Robichaud b
a Department of Medicinal Chemistry , Albany
Molecular Research, Inc. , 21 Corporate Circle,
Albany, NY, 12203, U.S.A.
b The DuPont Pharmaceuticals Company ,
Chemical & Physical Sciences, Experimental
Station, Wilmington, DE, 19880, U.S.A.
Published online: 16 Aug 2006.
To cite this article: Paul F. Vogt , Bruce F. Molino & Albert J. Robichaud (2001)
A REGIOSPECIFIC SYNTHESIS OF 3,3,6-TRIMETHYLINDAN-1-ONE, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 31:5, 679-684, DOI: 10.1081/SCC-100103256
To link to this article: http://dx.doi.org/10.1081/SCC-100103256
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SYNTHETIC COMMUNICATIONS, 31(5), 679–684 (2001)
A REGIOSPECIFIC SYNTHESIS OF
3,3,6-TRIMETHYLINDAN-1-ONE
Paul F. Vogt,1, Bruce F. Molino,1 and
*
Albert J. Robichaud2
1Department of Medicinal Chemistry, Albany Molecular
Research, Inc., 21 Corporate Circle, Albany, NY 12203
2The DuPont Pharmaceuticals Company,
Chemical & Physical Sciences, Experimental Station,
Wilmington, DE 19880
ABSTRACT
A novel, regiospecific synthesis of 3,3,6-trimethylindan-
1-one (5) was achieved. The route to 5 was 6 steps and pro-
ceeded in 27% overall yield.
6-Substituted-3,3-dimethylindan-1-ones are key intermediates in the
syntheses of several biologically relevant molecules1 and in the course of a
current research project we needed to prepare multi-gram quantities of
3,3,6-trimethylindan-1-one (5). Indanone 5 is a known compound and its
synthesis from acid 4 has been reported.2 To our knowledge, however, only
one regiospecific route to acid 4, and thus to indanone 5, has appeared in
the literature prior to this discovery.3 This previous synthesis, which
began with 40-methylacetophenone, was 6 steps and produced 5 in 5–10%
overall yield.4
We envisioned that a more efficient, regiospecific route to 4, and thus to
indanone 5, could be developed. We are pleased to report that a regiospecific
* Corresponding author.
679
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

680
VOGT, MOLINO, AND ROBICHAUD
synthetic route to indanone 5 has been devised and is shown in Scheme 1.
Thus, Meldrum’s acid (1)5 was condensed with acetone to give isopropyli-
dene malonate 2 in 70% yield.6 Michael addition of the cuprate generated
from copper (I) cyanide and p-tolylmagnesium bromide, to isopropylidene
malonate 2 gave Michael adduct 3 in 66% yield.7 Michael adduct 3 was then
hydrolyzed with concentrated HCl in dioxane, followed by thermal decar-
boxylation at 200oC to provide 4 in 67% yield.8 3-Methyl-3-p-tolyl butyric
acid (4) was treated with oxalyl chloride and then cyclized to indanone 5
with aluminum chloride in one pot. The 3,3,6-trimethylindan-1-one 5 was
isolated from the crude reaction mixture in 88% yield after bulb-to-bulb
distillation.
Scheme 1.

3,3,6-TRIMETHYLINDAN-1-ONE
681
The new synthetic route presented in this report provides a means
to prepare multigram quantities of this important synthetic intermediate
regiospecifically and in higher overall yield (27%) than methods pre-
viously reported. The number of chemical steps involved in this synthetic
route is identical with previously reported syntheses.4 However, the
overall efficiency, as measured by ease of isolation and purification of
intermediates and final product is vastly improved. Also, while the final
cyclization of carboxylic acid 4 to indanone 5 is formally two distinct
chemical steps, the reactions are conducted in one pot. One final com-
ment regarding this novel route is that in principal, the regiospecific
synthesis of other 6-substituted 3,3-dimethylindan-1-ones may be possible
by introducing different para-substituted aryl grignards at the cuprate
conjugate addition step.
EXPERIMENTAL
General
Proton NMR spectra were obtained on a Bruker AC 300 spectrometer
at 300 MHz and were referenced to tetramethylsilane as an internal stan-
dard. Carbon NMR spectra were obtained on a Bruker AC 300 spectro-
meter at 75 MHz and were referenced to CDCl3. The IR spectrometer used
was a single beam Perkin-Elmer Spectrum 1000 FT-IR. All IR spectra
obtained were prepared in a pressed disc of KBr. All IR spectra obtained
were acquired with a total of 4 accumulations at a resolution of 4.00 cmÀ1
.
Melting points were obtained on a Mel-Temp II apparatus and are uncor-
rected. CI Mass spectra were obtained on a Shimadzu QP-5000 Mass
Spectrometer. FAB Mass spectra were obtained by M-Scan, Inc. of West
Chester, PA.
5-Isopropylidiene-2,2-dimethyl-(1,3)-dioxane-4,6-dione (2)
To anhydrous toluene (250ml) was added acetic acid (5.0ml,
0.09 mol), ammonium acetate (1.4 g, 0.02 mol), acetone (25 ml, 0.34 mol),
Meldrum’s acid (49.7 g, 0.34 mol) and powdered 4 A molecular sieves
(ca. 50g). After a stirring period of 6 h under nitrogen, an additional
25 ml of acetone was added. The mixture was stirred for an additional
18 h under nitrogen. The mixture was filtered to remove the molecular
sieves and the filtrate was reduced to 1/3 its original volume. The resulting
slurry was partitioned between toluene and sat. NaHCO3. The organic layer

682
VOGT, MOLINO, AND ROBICHAUD
was washed with NaHCO3 (2Â), brine (1Â), dried over MgSO4, filtered and
concentrated to yield a yellow solid. This solid was triturated with hexanes,
filtered, and dried to yield a white solid (44.6 g, 70%): mp 68–71oC (lit.6a mp
1
73–78.5oC); IR 1751, 1719, 1286 cmÀ1; H NMR (CDCl3) ꢀ 1.73 (s, 6H),
2.52 (s, 6H); 13C NMR (CDCl3) 26.4, 26.8, 103.1, 116.4, 160.8, 176.9 ppm;
FAB MS m/z [M þ H]þ ¼ 185.
5-(2-p-Tolylpropane)-(2,2)-dimethyl-(1,3)-dioxane-4,6-dione (3)
Copper (I) cyanide (60.8 g, 0.68 mol) was suspended in anhydrous
THF and cooled in an ice/water bath with vigorous stirring. To the cold
suspension was added dropwise, p-tolylmagnesium bromide (1.4 l of a 1.0M
etheral solution, 1.4 mol) over 1 h. The ice bath was removed and the reac-
tion stirred at room temperature for 1 h. The mixture was cooled again in an
ice/water bath and charged with a solution of 2 (59.6 g, 0.32 mol) in THF
(250ml) portionwise over 15 min. The ice bath was removed and the reac-
tion mixture was stirred at room temperature for 16 h. The mixture was then
quenched by addition of saturated aqueous NH4Cl. The organic layer was
separated and the aqueous layer was extracted with ether (3Â). The com-
bined ether layers were washed with brine, dried over Na2SO4, filtered, and
concentrated to give a yellow solid. This yellow solid was triturated with
hexanes, filtered, and dried to give an off-white solid (59.1 g, 66%): mp
98–101ꢀC; IR 1791, 1749, 1316 cmÀ1; H NMR (CDCl3) ꢀ 1.27 (s, 3H),
1
1.62 (s, 3H), 1.65 (s, 3H), 2.31 (s, 3H), 3.57 (s, 1H), 7.13 (d, J ¼ 6.0Hz,
2H), 7.23 (d, J ¼ 9.0Hz, 2H); 13C NMR (CDCl3) 20.8, 27.3, 27.8, 29.2,
42.3, 57.6, 105.0, 126.0, 128.9, 136.5, 141.6, 164.2 ppm; FAB MS m/z
[C10H13] ¼ 133.
3-Methyl-3-p-tolyl-butyric acid (4)
Michael adduct 3 (21.9 g, 0.08 mol) was dissolved in dioxane (125 ml)
and concentrated HCl (50ml) and was refluxed for 18 h. The reaction mix-
ture was cooled to room temperature and concentrated. The resulting
slurry was partitioned between water and methylene chloride. The organic
layer was washed with water, dried over Na2SO4, filtered, and concentrated.
The resulting brown solid was heated to 200oC in an oil bath for 1 h.
The mixture was cooled to room temperature and the resulting solids
were recrystallized from petroleum ether to yield a light brown solid
(10.2 g, 67%): mp 76–78ꢀC (lit.2c mp 77ꢀC); IR 2978, 1698, 1315 cmÀ1
1H NMR (CDCl3) ꢀ 1.44 (s, 6H), 2.32 (s, 3H), 2.63 (s, 2H), 7.12
;

3,3,6-TRIMETHYLINDAN-1-ONE
683
(d, J ¼ 9.0Hz, 2H), 7.25 (d, J ¼ 6.0Hz, 2H); 13C NMR (CDCl3) 20.8, 28.8,
37.1, 48.0, 67.0, 125.3, 128.9, 136.2, 145.9, 177.8 ppm; FAB MS m/z
[C10H13] ¼ 133.
3,3,6-Trimethylindan-1-one (5)
Acid 4 (29.8 g, 0.16 mol) was dissolved in 2,2-dichloroethane (250 ml)
and DMF (0.5 ml). The reaction mixture was cooled in an ice/water bath
and charged with oxalyl chloride (19.0ml, 0.22 mol). The reaction mixture
stirred at room temperature, under N2, for 24 h. The reaction mixture was
concentrated and the resulting brown oil was dissolved in 2,2-dichloro-
ethane (250ml) and cooled in an ice/water bath. To the cooled solution
was added aluminum chloride (26 g, 0.20 mol) and the reaction mixture
stirred for 14 h at room temperature. The reaction mixture was poured
into ice water and stirred for 2 h. The layers were separated and the aqueous
layer was extracted with CH2Cl2 (3Â). The combined organic layers were
washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered, and
concentrated. The resulting brown oil was purified by bulb-to-bulb distilla-
tion (100–110oC, 0.1 mm Hg) to give a white solid (22.9 g, 88%): mp 35ꢀC
(lit.2a mp 42–43ꢀC); IR 2953, 1699, 1283 cmÀ1; 1H NMR (CDCl3) ꢀ 1.40(s,
6H), 2.39 (s, 3H), 2.58 (s, 2H), 7.49–7.37 (m, 2H), 7.51 (s, 1H); 13C NMR
(CDCl3) 20.8, 29.8, 37.9, 53.1, 123.0, 135.2, 135.9, 137.1, 161.1, 205.5 ppm;
CIMS m/z [MþH]þ ¼ 175.
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Received in the U.S.A. June 10, 2000