U. Jansen, J. Runsink, J.

Mattay 283

Notizen / Notes

from ( - )-(1R,4S)-
Diastereomeric 5,6-Dimethyl-4H-l,3-dioxin-4-ones
Menthone: Synthesis and NMR Analysis
Ursula Jansen*)')', Jan Runsink', and Jochen Mattay*

Institut fur Organische Chemie, Technische Hochschule Aachen",

Prof.-Pirlet-StraDe 1, D-5100 Aachen
Organisch-Chemisches Institut der Universitit Miinsterb,
Orlkansring 23, D-4400 Munster

Received September 14, 1990

Key Words: 4H-1,3-Dioxin-4-ones f Spirocyclic enones Menthone

The two diastereomers of spirocyclic 5,6-dimethyl-4H-1,3-di- butyl 2-methyl-3-oxobutanoate (2) with ( - )-menthone (4).
have been synthesized by acetalization of tert-
oxin-4-one (5,6) Their structures have been determined by NMR analysis.

The synthesis of enantiomerically pure compounds via chiral ace-
toacetic acid derivatives has become increasingly important in pre-
parative organic chemistry for both ground-state'.') as well as ex-
cited-state procedure^^-^). In the course of our investigations
concerning chiral olefins and dienes we synthesized the two
diastereomers of the spirocyclic acetals 5 and 6 by reaction of tert-
butyl 2-methyl-3-oxobutanoate (2) with (- Fmenthone (4) accord-
ing to a procedure which has been reported earlier by Kato" and
Demuth
The structures of 5 and 6 have been assigned by means of NMR
analysis, i.e. by comparing the data of 5 and 6 with those of 7 and
8') obtained from 'H-NMR multiplet decoupled Hetcor spectra and
I3C-NMR spectra.
First attempts to synthesize 2 from 1 according to procedures
reported by Knunyants9)(20% aq. KOH, Me2S04)or by Scolastico
et al.") (NaOEt, Me1 or NaOH, tBu4NHS04, MeI) have yielded
insufficient conversions of 1. Methylation of the enamine 3 with
dimethyl sulfate according to Mistryukov's method"' (for the syn-
thesis of the corresponding ethyl ester) has also failed in our hands,
though 3 can be synthesized from 1 and dimethylamine in 77%
yield according to Arnold's procedureI2', which has been modified
by us. The E configuration of 3 has been confirmed by NOE ex-
periments: Irradiation at 6 = 2.90 (NCHJ gives an NOE of 2.6%
at 6 = 4.50 (2-H) but no NOE is observed upon irradiation of CH3-
4. Finally, only the application of a method reported by Barrett
and Sheth"Ihas furnished 2 in high purity and in high yield.
(-)-Menthone (4) (from (-)-menthol by oxidation with chromic
acid according to Brown and GargI4), cf. experimental part)
and 2 are converted to the acetals 5 and 6 by the application of the
Kato/Demuth-procedure4~" to the synthesis of 7 and 8 from 1,
however with few modifications. The best results have been ob-
tained with equimolar mixtures of 2 and 4. An excess of 2 (up to
300 mol-%) results in a higher conversion, but, the enhanced for-
mation of sideproducts dramatically hinders the purification of 5
and 6. For more details see experimental section.
0
5 (R=CH,)
[7 (R=H)I
rkmth4)
AcZO, HZSO,

0 0
NaH, Me1
0 0
2+ -qyo 4
20 OC
*
/

DMF 4
I
1
2

I 0 The two diastereomers 5 and 6 are separated by means of HPLC.

+I New address: Institut fur Anorganische Chemie, Technische
Hochschule Aachen, Prof.-Pirlet-StraBe 1, D-5100 Aachen.
Since none of them are crystalline we have performed the structural
assignment on the basis of NMR spectral data. Accurate 'H-NMR
chemical shifts for the acetals 5, 6 and 7,8 were determined from
'H-NMR multiplet decoupled Hetcor spectra. In addition the I3C-
NMR chemical shifts have been measured. T h e complete data are
summarized in the experimental part. Here we only focus on the

Liebigs Ann. Chem. 1991, 283-285 OVCH Verlagsgesellschaft mbH, D-6940 Weinheim, 1991 0170-2041/91/0303-0283 $ 3.50+.25/0
284 U. Jansen, J. Runsink, J. Mattay

chemical shifts which are typical for the main products 5 and 7 as ous solution of sodium sulfite (loo/,) and water. After drying with
well as the minor products 6 and 8 (see Tables 1 and 2). magnesium sulfate and removal of the solvent the remaining oil is
fractionated in a spinning band column (reflux ratio 120:5) to give
Table 1. Significant NMR data of 5 and 6"' 2 with 98% purity. Yield 24.1 g (70%), b.p. 106-108"C/48-51
Torr (ref.'31b.p. 66-67"C/6 Torr). - 'H NMR (CDCI,): 6 = 1.28
Nucleus 5 6 AS (d, J = 7.05 Hz, 3H, CHCH,), 1.47 (s, 9H, tBu), 2.23 (s, 3H,
-~ - CH,CO), 3.42 (q, J = 7.05 Hz, 1 H, CHCH,). - l3CNMR (CDC13):
5-H 1.74 1.56 -0.18 6 = 12.6 (CHCH,), 21.8 (CH,CO), 27.9 [C(CH,),], 54.7 (CHCH3),
8-H 2.24 2.35 +0.11 81.6 [C(CH,)J, 169.7 (COO), 203.8 (CO).
c-5 28.48 29.73 + 1.25 tert-Butyl (E)-3-(Dimethylamino)-2-butenoate (3): Gaseous di-
c-8 25.32 25.00 -0.32 methylamine is passed through 50 g (0.31 mol) of neat 1 at 40°C
within 5 h. After 12 h unreacted amine is evaporated under reduced
'H and I3C NMR. Varian VXR 300 (300 MHz/75 MHz), TMS pressure, and the residue is crystallized from pentane at - 20 "C to
as internal standard, in CDCI?, 6.
yield 45.1 g (77%) of 3, m.p. 43 - 45 "C (ref. ") 43 "C). - IR (CDC13):
P = 3007 cm-' (=CH), 1683 (C=O), 1583 (C=C). - 'H NMR
Table 2. Significant NMR data of 7 and Sahsc) (CDCI,): 6 = 1.46 [s, 9H, C(CH,),], 2.41 (s, 3H, =CCH3) 2.90 [s,
6H, N(CH&], 4.50 (s, lH, =CH). - I3C NMR (CDCI,): 6 = 15.2
Nucleus 7 8 AS (=CCH3), 28.7 [C(CH,),], 39.6 [N(CH,)J, 77.3 [C(CH,),], 86.4
(=CH), 160.8 (=C-N), 169.0 (CO). -MS (70 eV): m/z (YO)= 185
5-H 1.78 1.57 -0.21 (22) [M'], 129 (36), 112 (65), 84 (loo), 44 (34), 42 (24).
8-H 2.21 2.34 +0.13
29.77 +1.12 (-)-(fR,IS)-Menthone (4): A solution of 10 g (0.04 ml) of so-
c-5 28.65
c-8 25.68 25.14 -0.54 dium dichromate in 7.5 ml of sulfuric acid (96%) and 42.5 ml of
water is added to 15.6 g (0.01 mol) of (-)-menthol in 40 ml of
See footnote a) of Table 1. - cf. ref.4aJ.- For complete data diethyl ether within 30 min. The temperature is kept below 25°C.
see also ref. '1. After stirring for 3.5 h again one tenth of the above mentioned
chromic acid solution is added. This is repeated twice. According
to GC analysis the reaction mixture now contains less than 1YOof
Both sets of diastereomers 5/7 and 6/8 do correspond to each the starting material. After extraction with diethyl ether (3 x
other indicating the same basic structure. Since the structure of 8 20 ml), drying with magnesium sulfate, and evaporation of the sol-
has been confirmed by X-ray analysis4a1we now can assign the vent at 10 Torr the remaining oil is fractionated through a 20-cm
(2S,2'S,5R) configuration to 5 and the (2S,2'R,5R) configuration Vigreux column. Yield of 4 14.2 g (%!YO), b.p. 88-93"C/14 Torr
to 6. (ref. 14), 84%, b.p. 66 - 67 "C/4 Torr).
Financial support by the Deutsche Forschungsgemeinschaft, the Preparation of the Spiro Compounds 5 and 6: 15.4 g (0.10 mol) of
Minister ,fur Wissenschaft und Forschung des Landes Nordrhein- (-)-methone (4), 17.2 g (0.10 mol) of 2, and 100 ml (1 mol) of an-
Westfalen, and the Fonds der Chenzischen Industrie is gratefully ac- hydrous acetic acid are filled into a 250-ml three-necked flask
knowledged. We also thank the Bayer AG for generous gifts of equipped with gas-inlet tube, thermometer, and dropping funnel.
chemicals. The structural assignment of 5 and 6 on the basis of The mixture is cooled with stirring to - 15"C. Then 7.5 ml of conc.
NMR spectral data was only possible by M. Demuth's help, who sulfuric acid is added dropwise over 2-2.5 h such that the tem-
provided us with two samples of 7 and 8. perature of the mixture does not exceed -1O'C. After the addition
has been terminated the temp. of the mixture is allowed to rise to
room temperature. The end of the reaction is determined by GC:
Experimental analysis. Then 1.4 1 of an aqueous solution of sodium hydrogen-
All reactions were carried out under nitrogen, and the solvents carbonate (10%) is added by cooling with ice (pH 7.0-7.5). The
were dried before use. Commercially available tert-butyl 3-oxobu- aqueous solution is extracted three times with 400 ml of diethyl
tanoate (1) was purified by distillation in a spinning band column ether, and the combined organic layers are washed first with 200 ml
(Normag). (-)-Menthol (99%) and iodomethane (990/,) were used of saturated Na2C03solution and then with 200 ml of water. After
without further purfication. - Liquid chromatography: Silica gel drying with magnesium sulfate and evaporating the remaining oil
60 (0.063 -0.200 pm) from Woelm and Celite 545 from Bayer (for (40 g) is worked up as follows:
filtration). - HPLC: Kontron 420 chromatograph and chromo- (i) (R)-3-Menthenyl acetate (fully characterized by NMR and m. p.
sorb Si 60 columns (250 x 20 mm). - GC: Siemens Sichromat 3 155- 156°C) is removed at 0.001 Torr at room temp. to yield 14.3 g
or Sichromat 1-4, 25 m H P Ultra 2. - IR: Perkin Elmer 1700. - of a viscous oil.
'H and '3C NMR: Varian VXR 300 (300 MHz/75 MHz), TMS as (ii) In order to separate the oil from polymeric material it is
internal standard, Hetcor, multiplet decoupled, 'H resolution 4 filtered over a 40-cm column containing silica gel with cyclohexane]
Hz. - MS: Varian MAT 212, 70 eV. - Microanalyses: Mikroan- ethyl acetate (90: 10) as eluent to give 12.4 g (49%) of a yellow oil.
alytisches Laboratorium der Technischen Hochschule Aachen. which only contains the two compounds 5 and 6 according to NMR
analysis (56 = 4.2: 1).
tert-Butyl 2-Methyl-3-oxobutanoate (2): 31.6 g (0.20 mol) of tert-
(iii) Separation of the two diastereomers is performed by HPLC
butyl 3-oxobutanoate (1) is added dropwise to a mixture of 5.0 g
with cyclohexane/ethyl acetate (90: 10) as eluent.
(0.2 mol) of NaH (97% in white oil) in 150 ml of THF at 0°C. Then
28.4 g (0.20 mol) of iodomethane is slowly added, and the mixture (2S,2'S,SR) -2-Isopropyl-S,5',6'-trirnethylspiro(cyclohexane-I,.?.
is stirred for 12 h. After evaporation of the solvent the residue is [4H/(1,3]dioxin]-4'-one (5): IR (CDCI,): P = 1725 cm-' (C =O),
dissolved in some water and the solution extracted with three por- 1651 (C=C). - 'H NMR (CDCI,): 6 = 0.85 (7-H), 0.88 (10-H),0.89
tions of ether. The combined ether layers are washed with an aque- (4-H, ax), 0.93 (9-H), 0.95 (6-H, ax), 1.45 (2-H), 1.56 (3-H, ax), 1.65

Liebigs Ann. Chem. 1991, 283-285

 from (-)-(I R,4S)-Menthone
Diastereomeric 5,6-Dimethyl-4H-1,3-dioxin-4-ones
(3-H, eq), 1.74 (5-H, ax), 1.75 (4-H, eq), 1.78 (5’-CH3),1.95 (6’-CH3),
2.24 (8-H), 2.58 (6-H, eq). - I3C NMR (CDCI,): 6 = 10.37 (5’-
CH,), 17.58 (6’-CH3), 18.43 (C-lo), 21.50 (C-7),22.17 (C-3), 23.22 (C-
9), 25.32 (C-8),28.48 (C-5), 34.20 (C-4), 41.10 (C-6),49.51 (C-2),99.55
(C-53, 107.93 (C-I), 162.40 (C-6’), 162.68 (C-4). - MS (70 eV):
m/z (%) = 252 (17) [M’], 210 (13), 55 (59), 154 (86), 139 (52), 136
(36), 112 (IOO), 111 (15), 99 (25), 98 (12), 70 (16), 69 (19), 55 (26), 43
(31), 41 (42). - [ c L ] ~ = f8.6 (C = 1.019, CH2C1,).
C1SH2403 (252.4) Calcd. C 71.39 H 9.59
Found C 71.22 H 9.38
(2S,2’R,5R)-2-Isopropyl-5,5’,6-trimethylspiro[cyclohexane-1,2’-
[4H](1,3]dioxin]-4’-one (6): IR (CDC13):F = 1710 cm-’ (C=O),
1652 (C=C). - ‘H NMR (CDCI3): 6 = 0.88 (9-H), 0.89 (7-H), 0.95
(10-H), 0.97 (4-H, ax), 1.06 (6-H, ax), 1.51 (2-H), 1.53 (3-H, ax), 1.56
(5-H, ax), 1.70 (3-H, eq). 1.78 (4-H, eq), 1.82 (5’-CH3),2.00 (6’-CH3),
2.35 (8-H), 2.60 (6-H, eq). -I3C NMR (CDCI3):6 = 10.36 (5’-CH3),
17.54 (6’-CH3), 18.15 (C-9), 21.66 (C-7), 21.77 (C-3), 23.16 (C-lo),
25.00 (C-8), 29.73 (C-5), 34.02 (C-4), 40.54 (C-6), 49.33 (C-2), 100.15
(C-5’), 107.82 (C-l), 162.11 (C-4’), 162.93 (C-6’).
CAS Registry Numbers
1: 1694-31-1 1 2 : 39149-65-0 / 3 : 131635-40-0 / 4: 14073-97-3 ,I5: 13) A. G. M. Barrett, H. G . Sheth, J. Org. Chem. 48 (1983) 5017.
131682-97-8 / 6: 131722-65-1
Liebigs Ann. Chem. 1991, 283-285
285
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Aachen, 1989.
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Engl. 25 (1986) 1117. - 4h) M. Demuth, G. Mikhail, Synthesis
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M. Sato, K. Sekiguchi, H. Ogasawara, C. Kaneko, Synthesis
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*) We are indebted to M . Demuth for providing us with samples
of the acetals 7 and 8.
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