Synthesis of 2,6-dimethyltropone - A new, convenient methodology from 2,6-dimethylcyclohexanone

Article abstract of DOI:10.1055/s-2002-33709

Until now, 2,6-dialkyltropones have not been described. 2,6-Dimethyltropone (5) represents an appropriate material for synthesis of naturally occurring antiviral compounds. A new, convenient method for synthesis of 2,6-dimethyltropone (5) from 2,6-dimethy

Full text of DOI:10.1055/s-2002-33709

PAPER
1695
Synthesis of 2,6-Dimethyltropone – A New, Convenient Methodology from
2,6-Dimethylcyclohexanone
2
, 6-Dimethyltropo
m
ne
–
A Convenient
b
Methodology
r
from 2,
o
6-Dimethylc
z
yclohexanone Alm ssy,a Marek Pa ický,a Andrej Bohá ,*a Marta Sališová,a Gabriela Addová,b Myron Rosenblumc
a
Department of Organic Chemistry, Comenius University, Faculty of Natural Sciences, Mlynská dolina, 842 15 Bratislava, Slovakia
Fax +421(2)60296690; E-mail: bohac@fns.uniba.sk
b
c
Chemical Institute, Comenius University, Faculty of Natural Sciences, Mlynská dolina, 842 15 Bratislava, Slovakia
Department of Chemistry, Brandeis University, Waltham, MA 02254-9110, USA
Received 28 March 2002; revised 3 June 2002
compounds reiswigin A and B8 (Figure 1) by metal assist-
ed [3 + 2] cycloaddition reactions,9 we developed and
optimised a new, convenient method for the synthesis of
2,6-dimethyltropone (5) in overall 52% yield (Scheme 1).
Abstract: Until now, 2,6-dialkyltropones have not been described.
2,6-Dimethyltropone (5) represents an appropriate material for syn-
thesis of naturally occurring antiviral compounds. A new, conve-
nient method for synthesis of 2,6-dimethyltropone (5) from 2,6-
dimethylcyclohexanone in five optimized steps and 52% overall For starting material, the synthesis uses commercially
yield has been developed. Trimethylsilyl enol ether 1, prepared
from 2,6-dimethylcyclohexan-1-one, was treated with dichlorocar-
bene, to give 7,7-dichloro-2,6-dimethyl-1-trimethylsilyloxybicy-
available 2,6-dimethylcyclohexanone (Aldrich) – as a
mixture of syn and anti isomers (80:20, respectively).
A commercially available stereoisomer mixture of 2,6-
dimethylcyclohexan-1-one was converted to the corre-
sponding trimethylsilyl enol ether 1 in 95% yield by treat-
ment with LDA/TMSCl at low temperature (–78 °C).
Addition of dichlorocarbene, generated in situ from
CHCl3 and t-BuOK in hexane, to 1 at –30 °C gave a dia-
stereoisomeric mixture of the bicyclic adduct 2 in 98%.10
Compound 2 is sensitive to heat, and decomposes even
clo[4.1.0]heptanes (2). Acid promoted ring opening of 2 at room
temperature gave 2-chloro-3,7-dimethylcyclohept-2-ene-1-one
(3a). At higher temperatures (150–300 °C) a mixture of 3a and 2-
chloro-3,7-dimethyl-1-trimethylsilyloxycyclohepta-1,3-diene (3b)
was obtained in the ratio 2.1:1.0, respectively. Gamma bromination
of 3a by NBS/AIBN gave diastereoisomers 4a and 4b in the ratio
5:1, which were converted to 2,6-dimethyltropone (5) by Li2CO3 in
DMF at 120 °C. All new compounds were characterized by their
NMR and HRMS spectra. The relative configuration and the struc-
ture of the preferred conformer of 3a and 4a were determined by during deep freezer storage at –20 °C to give a mixture of
HMQC, COSY and NOE NMR measurements.
3a and 3b (2.1:1.0). By contrast, treatment of 2, at room
temperature, in aqueous methanol with p-toluenesulfonic
acid gave only 3a in 85% yield. The structure of 3b was
determined on the basis of its HR GC-MS spectrum and
by comparison of calculated and observed intensities of
isotopic molecular ions (from M+· + 5 to M+·) (see
Table 2).11
Key words: tropone, cycloheptanes, conjugation, ketones, ring ex-
pansion, diastereoselectivity, shielding effect in NMR
Although some 37 alkylated tropones are known, includ-
ing fourteen monoalkyltropones, fourteen dialkyl-
tropones, six trialkyltropones, two tetraalkyl and one
pentaalkyltropone,1–4 no 2,6-dialkylated tropones have
been reported. Tropones are useful synthetic intermedi-
ates for the incorporation of a seven membered ring into
polycyclic systems. They have found use in cyclisation re-
actions e.g. as dienophiles in Diels–Alder5 and other elec-
trocyclisation reactions,6 and in preparation of
heterocycles.7 As part of a program for the synthesis of
pseudoguaianolide terpenes, especially the antivairal
A plausible mechanism for the formation of 3a and 3b is
shown in Scheme 2.
Ring opening of the dihalocyclopropanes by treatment
with Ag+ in refluxing alcohol, 12 by (EtO)2PH, by thermol-
ysis or by acidic conditions is well precedented.13
The gamma bromination of , -unsaturated ketone 3a14
was performed by treatment with NBS (1.5 mol equiv)
and AIBN (2 mol%) catalysis at 60 °C. Bromination pro-
Figure 1
Synthesis 2002, No. 12, Print: 06 09 2002.
Art Id.1437-210X,E;2002,0,12,1695,1700,ftx,en;Z05502SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1696
A. Almássy et al.
PAPER
Scheme 1
ceeded stereoselectively to give diastereoisomers 4a and trum of 3a for hydrogens HC=O–C(5) and HCl–C(6). On
4b in 95% in a ratio of 85:15, respectively. The major these grounds, the conformations of both 3a and 4a are as-
diastereoisomer 4a was obtained by crystallization of the signed the ‘boat like’ arrangements shown in Figure 2.
crude reaction mixture from hexane. Its relative configu-
Table 1 NOE NMR Results of the Major Isomer 4a
ration was established to be (4R*,7R*) by HMQC, COSY
and NOE NMR measurements (Table 1).15 The preferred
Irradiated group
H–C(4)
NOE signals
conformation of 4a shown in Figure 2 was asssigned by
consideration of the shielding effect of the C(2)=C(3)
double bond, which is located directly under HCl–C(6).
This hydrogen is significantly shifted to = 1.55, whereas
the chemical shift of the second geminal hydrogen
2
H–C(5), Me–C(3)
H–C(7)
HBr–C(5), Me–C(7)
HMe–C(3)–C(5), HH–C(7)–C(6)
HH–C(7)–C(6), H–C(7)
HCl–C(6)
Me–C(7)
HH–C(7)–C(6) is observed at
= 2.28 ( = 0.73 ).
A similar shielding effect was observed in 1H NMR spec-
Scheme 2
Synthesis 2002, No. 12, 1695–1700 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
2,6-Dimethyltropone – A Convenient Methodology from 2,6-Dimethylcyclohexanone
1697
Figure 2
tion. The obtained crude product was purified by distillation to give
1.
The crude product 4 was dehydrohalogenated and rear-
ranged to tropone 5 by treatment of Li2CO3 in DMF at
120 °C for 45 min (similar to Noyori16 and Jones17) and Yield: 10.24 g, 51.62 mmol (95%); colorless oil; bp 100 °C/31 mbar
(86–88 °C/24 mbar).18
gave 2,6-dimethyltropone (5) in 69% yield.
1H NMR (300 MHz, CDCl3): = 2.12 [ddq, 1 H, J(Me,6) = 6.8,
J(5,6) = 6.1, J(5,6) = 6.0, H–C(6)], 1.94 [m, 2 H, 2 H-C(3)], 1.77
2,6-Dimethylcyclohexanone (98% purity, mixture of syn/anti dia-
[dddd, 1 H, Jgem = 11.4, J(4,5) = 8.9, J(5,6) = 6.0, J(4,5) = 2.4, H–
stereoisomers, 80:20), trimethylsilylchloride (TMSCl) (98% puri-
C(5)], 1.62 [dddd, 1 H, Jgem = 11.7, J(4,5) = 9.2, J(3,4) = 6.2,
ty), diisopropylamine (DPA), NBS and AIBN were purchased from
J(4,5) = 2.4, H–C(4)], 1.55 [s, 3 H, Me–C(2)], 1.46 [dddd, 1 H,
Sigma-Aldrich company. Solvents were dried and purified by con-
Jgem = 11.7, J(4,5) = 8.9, J(3,4) = 6.0, J(4,5) = 2.5, H–C(4)], 1.35
ventional methods prior to use. All reactions were carried out under
[dddd, 1 H, Jgem = 11.4, J(4,5) = 9.2, J(5,6) = 6.1, J(4,5) = 2.5, H–
nitrogen or argon. TLC were carried on silica gel plates with UV or
C(5)], 1.04 [d, 3 H, J(Me,6) = 6.8, Me–C(6)], 0.17 (s, 9 H, TMSO).
I2 detection. Mps were determined on a Kofler hot stage and are un-
13C NMR (75 MHz, CDCl3): = 147.25 [s, C(1)], 112.25 [s, C(2)],
34.29, 32.49 and 31.01 [2 t, C(3), C(5) and d, C(6)], 20.70 and
19.17 [q, Me and t, C(4)], 17.05 (q, Me), 0.83 (q, 3 Me from
Me3SiO).
corrected. Distillations were made on Büchi apparatus. IR spectra:
Specord IR-80 spectrophotometer, region 400–4000 cm–1 in 0.1mm
NaCl cell in CHCl3 solution. NMR spectra were obtained with a
Varian Gemini 300 spectrometer at 299.93 MHz for protons and
75.43 MHz for carbons (solvent CDCl3, TMS as internal standard).
Listed coupling constants are in Hz. Hetcor, HMQC, COSY and
NOE techniques were used for exact assignments of the relative
configuration and prefered conformation of the products. Mass
spectra: Trace GC MS 2000 Series Thermoquest CE Instruments.
Quadrupole conditions: electron energy 70 eV, emission current
150 A and ion source temperature 150 °C. Supelco OV-1, 10 m
length, 0.32 mm ID, 0.2 m film thickness, carrier gas helium, inlet
pressure 40 kPa, injector temperature 250 °C (or 150 °C). Temper-
ature program was adjusted from 40 °C to 300 °C, 15 °C/min. Ele-
Anal. Calcd for C11H22OSi: C, 66.60; H, 11.18. Found: C, 66.52; H,
11.07.
7,7-Dichloro-2,6-dimethyl-1-trimethylsilyloxybicyclo [4.1.0]
heptane (2)
To a cooled, stirred suspension of t-BuOK (40.59 g, 361.7 mmol,
10.0 mol equiv) in anhyd hexane (50 mL) under nitrogen, a solution
of 1 (7.14 g, 36.0 mmol, 1.0 mol equiv) in dry hexane (7 mL) was
added at –30 °C within 10 min. At the same temperature anhyd
CHCl3 (59 mL, 87.23 g, 730.7 mmol, 20.3 mol equiv) in anhyd
hexane (50 mL) was added over 4.5 h. After addition the mixture
was stirred another 3 h and the temperature raised spontaneously to
r.t. The precipitate was filtered off by suction. The filtration cake
was washed with hexane (4 50 mL) and solvent was removed in
vacuo to yield crude 2 as a yellow oil as a mixture of two diastere-
oisomers in the ratio 1.1:1.0 (determined by 1H NMR TMSO sin-
mental analyses (C,H) were obtained with
Strumentazione Model 1106 elemental analyzer.
a Carlo Erba
2,6-Dimethyl-1-trimethylsilyloxycyclohex-1-ene (1)
To a cooled, stirred solution of BuLi (1.6 M; 42 mL, 67.20 mmol,
1.24 mol equiv) in hexanes under a nitrogen atmosphere, a solution
of anhyd DPA (9.8 mL, 7.08 g, 69.92 mmol, 1.29 mol equiv) in an-
hyd THF (14 mL) was added over 10 min at –30 °C. The mixture
was stirred 2.5 h at –30 to –20 °C. The reaction mixture was then
cooled to –78 °C, and a solution of 2,6-dimethylcyclohexa-none
(7.6 mL, 7.00 g, 54.36 mmol, 1.00 mol equiv) (98% purity) in dry
THF (11 mL) was added within 30 min. After 1 h at –78 °C the 2,6-
dimethylcyclohexanonelithium enolate was quenched by TMSCl
(14.0 mL, 11.98 g, 108.06 mmol, 1.99 mol equiv) (98% purity). The
mixture was stirred overnight under nitrogen and the temperature
was allowed to rise from –78 °C to r.t. The volatile parts of the mix-
ture were removed by rotory vacuum evaporator (RVE) evapora-
glets at
= 0.25 for the major and at 0.21 for the minor
diastereoisomer). The obtained compound is thermolabile and sen-
sitive to acid conditions. It decomposed thermally to give mainly 3.
The crude product was used without further purification for the next
step.
Yield: 9.88 g, 35.1 mmol (98%).
HR GC-MS (EI, 70eV): m/z (%) Calcd for C12H22Cl2OSi
(280.08): 247 (M+· + 2 – Cl, 25), 246 (M+· + 1 – Cl, 23), 245 (M+· –
Cl, 43), 137 (C9H13O+, 19), 119 (C9H11+, 17), 109 (C8H13+, 14), 95
(C7H11+, 19), 93 (32), 75 (C2H5OSi+, 15), 73 (Me3Si+, 100), 67
+
(C5H7 , 22).
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A. Almássy et al.
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2-Chloro-3,7-dimethylcyclohept-2-ene-1-one (3a)
crude product was a mixture of two diastereoisomers (85:15 as de-
termined by 1H NMR). The major isomer was isolated by fractional
crystallization of the crude mixture from hexane. Its structure was
determined by NOE NMR experiments.
A solution of crude 2 (10.12 g, ca 36.0 mmol, ca 1.00 mol equiv),
H2O (2.0 mL, 2.00 g, 110 mmol, 3.05 mol equiv) and p-TsOH H2O
(1.00 g, 5.26 mmol, 15 mol%) in MeOH (100 mL) was allowed to
stand for 20 h at r.t. The conversion of 2 to 3a and 3b was monitored
by TLC. The reaction mixture was then diluted with H2O (20 mL).
Sat. aq Na2CO3 was added to adjust the pH to 7. MeOH was evap-
orated on RVE and the mixture was extracted with Et2O (4 100
mL). The resulting organic solution was dried (Na2SO4), the drying
agent was filtered off, and the volatile parts of the mixture were
evaporated by RVE. The crude product was distilled to yield 3a.
Yield: 4.18 g, 16.6 mmol (95%).
Major Diastereoisomer (4R*,7R*)-(4a)
Mp 80–83 °C (hexane).
IR (CHCl3): 3030 (m), 2980 (m), 2935 (m), 2880 (w), 2860 (w),
1680 (br s, C=O), 1590 (m, C=C), 1435 (m), 1418 (m), 1358 (m),
1320 (w), 1300 (w), 1225 (m), 1138 (m), 1118 (m), 1100 (w), 1070
(w), 1053 (m), 1005 (w), 965 (w), 923 (w), 875 (m), 835 (w), 813
(m), 620 (w) cm–1.
1H NMR (300 MHz, CDCl3): = 4.88 [dd, 1 H, J(4,5) = 6.3,
J(4,5) = 1.4, H–C(4)], 3.33 [ddq, 1 H, J(6,7) = 10.8, J(6,7) = 8.0,
J(Me,7) = 6.3, H–C(7)], 2.14–2.33 [m, 2 1 H, in order
HH–C(7)–C(6), H–C(5)], 2.19 [s, 3 H, Me–C(3)], 2.01 [m, 1 H,
H–C(5)], 1.50–1.60 [m, 1 H shielded by influence of C(2)=C(3),
HCl–C(6)], 1.18 [d, 3 H, J(Me,7) = 6.3, Me-C(7)].
Yield: 5.26 g, 30.5 mmol (85%); light yellow oil; bp 95 °C/0.1mbar.
IR (CHCl3): 3040 (m), 3020 (m), 2984 (m), 2940 (s), 2875 (m),
1690 (s, C=O), 1680 (br s, C=O), 1608 (s, C=C), 1460 (s), 1445 (m),
1430 (m), 1380 (s), 1325 (w), 1245 (m), 1140 (s), 1090 (m), 1080
(w), 1040 (m), 980 (w), 908 (s), 845 (m), 660 (w) cm–1.
1H NMR (300 MHz, CDCl3): = 2.82 {ddq, 1 H, J(6Cl,7) = 10.9,
J(Me,7) = 6.5, J[6H–C(7),7] = 6.3, H-C(7)}, 2.60 {ddddm, 1 H,
Jgem = 17.6, J[4,5H–C(4)] = 10.5, J(4,5C=O) = 3.0, J[4,6H-C(7)
]
1,
among others J[Me–C(3), 4], HMe–C(3)–C(4)}, 2.49 {ddd, 1H,
Jgem = 17.6, J(4,5C=O) = 6.1, J[4,5H–C(4)] = 3.2, HMe–C(7)–C(4)},
2.15 [s, 3 H, Me-C(3)], 1.82–2.01 [m, 2 H, in order HH–C(4)–C(5) and
HH–C(7)–C(6)], 1.45–1.65 [m, 2 H shielded by influence of
C(2)=C(3) and C=O, in order HC=O–C(5) and HCl–C(6), respective-
ly], 1.17 [d, 3 H, J(Me,7) = 6.5, Me–C(7)].
13C NMR (75 MHz, CDCl3): = 199.09 (s, C=O), 152.31 [s, C(3)],
131.30 [s, C(2)], 44.84 [d, C(7)], 35.64 [t, C(4)], 31.67 [t, C(6)],
25.08 [t, C(5)], 25.43 [q, Me–C(3)], 16.91 [q, Me-C(7)].
13C NMR (75 MHz, CDCl3): = 199.23 (s, C=O), 177.56 [s, C(3)],
134.47 [s, C(2)], 54.29 [d, C(4)], 44.14 [d, C(7)], 32.25 [t, C(5)],
30.01 [t, C(6)], 22.75 [q, Me-C(3)], 16.42 [q, Me-C(7)].
HR GC-MS (EI, 70eV, TInjector < 150 °C otherwise thermal decom-
position): m/z (%) Calcd for C9H12BrClO (250.00): 255 (M+· + 5,
0.03), 254 (M+· + 4, 0.19), 253 (M+· + 3, 0.11), 252 (M+· + 2, 0.76),
251 (M+· + 1, 0.05), 250 (M+·, 0.59), 173 (M+· + 2 – Br, 20), 171 (M+·
– Br, 51), 143 (16), 143 (C8H12Cl+, 44), 129 (16), 107 (C7H7O+,
+
+
100), 105 (14), 101 (18), 91 (C7H7 , 45), 79 (C6H7 , 32), 77 (24), 65
+
+
HR GC-MS (EI, 70eV): m/z (%) Calcd for C9H13ClO (172.07): 175
(M+· + 3, 1), 174 (M+· + 2, 12), 173 (M+· + 1, 4), 172 (M+·, 37), 143
(16), 137 (M+· –Cl, 87), 131 (33), 130 (15), 129 (C7H10Cl+, 100),
118 (40), 116 (C6H9Cl+, 64), 109 (C8H13+, 76), 102 (16), 95 (21), 93
(C5H5 , 53), 55 (C3H3O+, 27), 51 (C4H3 , 18).
Minor Diastereoisomer (4R*,7S*)-(4b)
1H NMR (300 MHz, CDCl3): = 5.27 [dd, 1 H, J(4,5) = 6.3,
J(4,5) = 1.9, H–C(4)], 3.03 [m, 1 H, H-C(7)] and 1.21 [d, 3 H,
J(Me,7) = 6.8, Me-C(7)] significant assignment only from the
mixed spectrum of the diastereoisomers.
+
(40), 91 (C7H7 , 21), 88 (42), 81 (39), 79 (30), 77 (32), 68 (18), 67
+
(C5H7 , 76), 65 (36), 55 (C3H3O+, 94), 53 (70), 51 (23).
2-Chloro-3,7-dimethyl-1-trimethylsilyloxycyclohepta-1,3-diene
(3b)
2,6-Dimethyltropone (2,6-Dimethylcyclohepta-2,4,6-trien-1-
one) (5)
HR GC-MS (EI, 70eV): m/z (%) Calcd for C12H21ClOSi
(244.11): 249 (M+· + 5, 0.05), 248 (M+· + 4, 0.38), 247 (M+· + 3,
1.65), 246 (M+· + 2, 10), 245 (M+· + 1, 4.7), 244 (M+·, 26), 229 (11),
215 (20), 209 (13), 203 (12), 202 (10), 119 (25), 95 (C7H11+,11), 93
A mixture of 4 (2.70 g, 10.7 mmol, 1.0 mol equiv) and Li2CO3
(873 mg, 11.81 mmol, 1.1 mol equiv) in anhyd DMF (50 mL) was
stirred at 120 °C for 45 min under a nitrogen atmosphere. After the
reaction, DMF was removed in vacuo and the crude mixture was
distilled to yield 5.
+
(41), 91 (19), 79 (12), 77 (C6H5 ,10), 75 (C2H7OSi+,19), 73 (Me3Si+,
+
100), 65 (C5H5 ,10).
Yield: 991.9 mg, 7.39 mmol (69%); yellow oil; bp 120 °C/0.12
mbar.
Table 2 Comparison of Calculated and Observed Molecular Ion In-
tensities for C12H21ClOSi
IR (CHCl3): 3040 (m), 3015 (s, =CH), 1635 (m, C=C), 1600 (m,
C=C), 1565 (br s, C=O), 1520 (m),1478 (m), 1440 (w), 1430 (w),
1400 (w), 1375 (w), 1360 (w), 1290 (w), 1165 (m), 1120 (w), 1090
(w), 1040 (w), 960 (w), 925 (w), 880 (w), 595 (w) cm–1.
1H NMR (300 MHz, CDCl3): = 7.21 [ddq, 1 H, J(3,4) = 5.4, J(3,5)
1.5, J(Me-C(2),3) = 1.1, H-C(3)], 7.01 {dq, 1 H, J[Me–
C(6),7] = 1.1, J(5,7) 1, H–C(7)}, 6.78–6.80 [m, 2 H, H–C(4) and
H–C(5)], 2.31 {d, 3 H, J[Me–C(6),7] = 1.1, Me–C(6)}, 2.25 {d, 3
H, J[Me-C(2),3] = 1.1, Me-C(2)}.
13C NMR (75 MHz, CDCl3): = 186.37 (s, C=O), 152.03 and
146.41 [2 s, C(2) and C(6)], 131.94 [d, C(7)], 134.32 [d, C(4) or
C(5)], 135.99 [d, C(3)], 139.11 [d, C(5) or C(4)], 22.68 [q, Me–
C(6)], 26.47 [q, Me-C(2)].
M+· + 5 M+· + 4 M+· + 3 M+· + 2 M+· + 1 M+·
Calcd11 0.03
Found 0.05
0.34
0.38
1.7
1.7
9.6
4.8
4.7
26.0
26.0
10.0
4-Bromo-2-chloro-3,7-dimethylcyclohept-2-ene-1-one (4)
A mixture of 3 (3.00 g, 17.4 mmol, 1.0 mol equiv), NBS (3.87 g,
21.7 mmol, 1.3 mol equiv) and AIBN (57 mg, 0.35 mmol, 2.0
mol%) in CCl4 (100 mL) was stirred and heated under nitrogen at
60 °C for 2.5 h. After this time, a yellow solution of the reaction
mixture turned colorless. The precipitate was filtered off by suction.
The resulting solution was extracted with a sat. aq NaHCO3 (3 30
mL) and then extracted with sat. aq NaCl (2 50 mL). All water
fractions were extracted with CCl4 (3 30 mL). The combined or-
ganic solution was dried (Na2SO4) and evaporated by RVE to yield
product (4.18 g, 16.6 mmol, 95%) as crystals in yellow oil. The
HR GC-MS (EI, 70eV): m/z (%) Calcd for C9H10O (134.07): 134
+
(M+·, 21), 106 (M+· –CO, 24), 105 (C7H5O+, 19), 91 (C7H7 , 100), 77
+
+
+
(C6H5 ,12), 70 (9), 65 (C5H5 ,9), 61 (13), 51 (C4H3 ,9).
Synthesis 2002, No. 12, 1695–1700 ISSN 0039-7881 © Thieme Stuttgart · New York

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2,6-Dimethyltropone – A Convenient Methodology from 2,6-Dimethylcyclohexanone
1699
(3) (a) Shono, T.; Nozoe, T.; Yamaguchi, Y.; Ishifune, M.;
Sakaguchi, M.; Masuda, H.; Kashimura, S. Tetrahedron
Lett. 1991, 32, 1051. (b) Franck-Neumann, M.; Brion, F.;
Martina, D. Tetrahedron Lett. 1978, 5033. (c) Cavazza, M.;
Pietra, F. J. Chem. Soc., Perkin Trans. 1 1985, 2283.
(d) Cavazza, M.; Guerriero, A.; Pietra, F. J. Chem. Soc.,
Perkin Trans. 1 1986, 2005. (e) Akroyd, P.; Haworth, R. D.;
Jefferies, P. R. J. Chem. Soc. 1954, 286. (f) Akroyd, P.;
Haworth, R. D.; Jefferies, P. R. J. Chem. Soc. 1951, 3427.
(g) Schreiber, J.; Pesaro, M.; Leimgruber, W.; Eschenmoser,
A. Helv. Chim. Acta 1958, 41, 2103. (h) Nikanorov, V. A.;
Gavrilova, G. V.; Rozenberg, V. I.; Reutov, O. A. Russ.
Chem. Bull. 1987, 36, 2174. (i) Miller, J.; Ponte, C. D. J.
Chem. Res. Miniprint 1988, 3, 914. (j) Nikanorov, V. A.;
Gavrilova, G. V.; Yur’ev, A. V.; Rozenberg, V. I.; Reutov,
O. A. Russ. Chem. Bull 1995, 44, 1767. (k) Itoh, A.; Saito,
T.; Oshima, K.; Nozaki, H. Bull. Chem. Soc. Jpn. 1981, 54,
1456. (l) Shono, T.; Naekawa, H.; Nozoe, T.; Kashimura, S.
Tetrahedron Lett. 1990, 31, 895. (m) Wenkert, E.;
Acknowledgement
Financial support by Tempus S-JEP-09101-95 Project New Curri-
culum in Chiral Chemistry and the Slovak Grant Agency VEGA 1/
4167/97, VEGA 1/7013/20, VEGA 1/9124/02, also by grants of
The Comenius University, UK/3723/99, PRIFUK 7/1999, UK/88/
2000, UK/55/2001 is also gratefully acknowledged.
References
(1) Monoalkyltropones: 2-Me;2a–k,2u 2-Et;2a,b,2l–n,2u 2-n-Pr; 2b,o 2-
i-Pr; 2b,g,m,n,2p–s 2-n-Bu; 2b,2r,2t–v 2-i-Bu; 2g 2-t-Bu; 2w 2-n-
octyl;2b 3-Me; 2x,y 3-i-Pr; 2q–s,2y,3a,b 3-n-Bu3c,d; 4-Me; 2i,j,x,3d–k
4-i-Pr(Nezukon); 2h,q,r,o,3d,3k–s 4-n-Bu.3l Dialkyltropones: 2-
Me-3-Me; 2l,3t,u 2-Me-4-Me; 2j,3v 2-Me-5-Me; 2b,j,3t,w,x 2-Me-
7-Me; 2r,3u,y,3a–e 3-Me-5-Me;4g 3-Me-6-Me; 2y 2-Et-7-Et;4c 2-
i-Pr-5-Me; 2b,3v,x 4-i-Pr-2-Me;4f 5-i-Pr-2-Me; 2l,3v 2-i-Pr-7-i-
Pr; 2r,4h 4-n-Bu-2-Me;4f 4-n-Bu-2-Et;4f 2-t-Bu-7-t-Bu.4e
Trialkyltropones: 2-Me-3-Me-5-Me; 2l 2-Me-3-Me-7-Me;4i
2-Me-4-Me-7-Me; 2r,4h,j,k 2-i-Pr-7-i-Pr-4-Me; 2r,4h 2-t-Bu-7-t-
Bu-4-Me;4j,m 2-t-Bu-4-t-Bu-6-t-Bu.4l Tetraalkyltropones: 2-
Me-4-Me-5-Me-7-Me; 2r,4h 2-i-Pr-7-i-Pr-4-Me-5-Me. 2r,4h
Pentaalkyltropone: 2-Me-3-Me-4-Me-6-Me-7-Me. 4n–p
(2) (a) Mukai, T. Nippon Kagaku Zasshi 1958, 79, 1547; Chem.
Abstr. 1960, 23846. (b) Brady, W. T.; Hieble, J. P. J. Am.
Chem. Soc. 1972, 94, 4278. (c) Schuster, D. I.; Wang, L.;
van der Veen, J. M. J. Am. Chem. Soc. 1985, 107, 7045.
(d) Gavrilova, G. V.; Nikanorov, V. A.; Shiryaevskaya, I.
A.; Galakhov, M. V.; Rozenberg, V. I.; Reutov, O. A. Russ.
Chem. Bull. 1987, 36, 2676. (e) Wang, L.; Schuster, D. I.;
van der Veen, J. M. Tetrahedron Lett. 1983, 24, 2627.
(f) Shono, T.; Nozoe, T.; Maekawa, H.; Kashimura, S.;
Masuda, H.; Okada, T.; Kashimura, S. Tetrahedron Lett.
1988, 29, 555. (g) Shono, T.; Nozoe, T.; Maekawa, H.;
Yamaguchi, Y.; Kanetaka, S.; Masuda, H.; Okada, T.;
Kashimura, S. Tetrahedron 1991, 47, 593. (h) Asao, T.;
Yagihara, M.; Kitahara, Y. Heterocycles 1981, 15, 985.
(i) Rosenblum, M.; Watkins, J. C. J. Am. Chem. Soc. 1990,
112, 6316. (j) Zbiral, E.; Jaz, J.; Wessely, F. Monatsh Chem.
1961, 92, 1155. (k) Morita, N.; Kurita, M.; Ito, S.; Asao, T.;
Sotokawa, H.; Tajiri, A. Tetrahedron: Asymmetry 1995, 6,
35. (l) Zbiral, E.; Takacs, F.; Wessely, F. Monatsh. Chem.
1964, 95, 402. (m) Maatschappij, N. V. Shell International
Res., French Patent 1342142, 1963; Chem. Abstr. 1964, 60,
13199. (n) ter Borg, A. P.; van Helden, R.; Bickel, A. F.
Recl. Trav. Chim. Pays-Bas 1962, 81, 591. (o) Jones, G. J.
Chem. Soc. C 1970, 1230, 1232. (p) Childs, R. F.;
Greenberg, R. S.; Kim, H.-S. Helv. Chim. Acta 1987, 70,
2159. (n) Davies, H. M. L.; Clark, T. J.; Kimmer, G. F. J.
Org. Chem. 1991, 56, 6440. (o) Banwell, M. G.; Cowden,
C. J.; Gravatt, G. L.; Rickard, C. E. F. Aust. J. Chem. 1993,
46, 1941. (p) Banwell, M. G.; Gravatt, G. L.; Rickard, C. E.
F. J. Chem. Soc., Chem. Commun. 1985, 514. (q) Birch, A.
J.; Keeton, R. J. Chem. Soc. C 1968, 109. (r) Hatakawa, Y.;
Sakai, M.; Noyori, R. Chem. Lett. 1975, 509.
(s) Froehlisch, B.; Korfant, H.; Meining, H.; Frey, W. Eur. J.
Org. Chem. 2000, 7, 1335. (t) Sato, T. Nippon Kagaku
Zasshi 1959, 80, 1347; Chem. Abstr. 1961, 4525.
(u) Trahanovsky, W. S.; Emeis, S. L.; Lee, A. S. J. Org.
Chem. 1976, 41, 4043. (v) Kato, M.; Yamamoto, S.;
Nomura, S.; Miwa, T. Bull. Chem. Soc. Jpn. 1990, 63, 64.
(w) Feldman, K. S.; Wu, M.-J.; Rotella, D. P. J. Am. Chem.
Soc. 1989, 111, 6457. (x) Brady, W. T. Synthesis 1971, 415.
(y) Muehlstaedt, M. Naturwissenschaft 1958, 45, 240. (z)
Muehlstaedt, M. Chem. Ber. 1960, 93, 2638.
(4) (a) Mayor, C.; Jones, W. M. J. Org. Chem. 1978, 43, 4498.
(b) Stohrer, I.; Hoffmann, H. M. R. Tetrahedron 1992, 48,
6021. (c) Foehlisch, B.; Sendelbach, S.; Bauer, H. Liebigs
Ann. Chem. 1987, 1. (d) Noyori, R.; Baba, Y.; Makino, S.;
Takaya, H. Tetrahedron Lett. 1973, 1741. (e) Closs, C. J.
Am. Chem. Soc. 1961, 83, 599. (f) Shono, T.; Okada, T.;
Furuse, T.; Kashimura, S.; Nozoe, T.; Maekawa, H.
Tetrahedron Lett. 1992, 33, 4337. (g) Yamaga, H.; Fujise,
Y.; Ito, S. Tetrahedron Lett. 1987, 28, 585. (h) Noyori, R.;
Makino, S.; Takaya, H. J. Am. Chem. Soc. 1971, 93, 1272.
(i) Baldwin, J. E.; Broline, B. M. J. Am. Chem. Soc. 1982,
104, 2857. (j) Barbier, M.; Barton, D. H. R.; Devys, M.;
Topgi, R. S. Tetrahedron 1987, 43, 5031. (k) Barbier, M.;
Barton, D. H. R.; Devys, M.; Topgi, R. S. J. Chem. Soc.,
Chem. Commun. 1984, 743. (l) Rieker, A.; Renner, R.;
Mueller, E. Justus Liebigs Ann. Chem. 1969, 730, 67.
(m) Hiyama, T.; Ozakiano, Y.; Nozaki, H. Tetrahedron
1974, 30, 2661. (n) Salakhutdinov, N. F.; Detsina, A. N.;
Koptyug, V. A. Russ. J. Org. Chem. 1981, 1312.
Varadarajan, A. Can. J. Chem. 1981, 59, 3252. (q) Noyori,
R.; Hayakawa, Y. Tetrahedron 1985, 41, 5879. (r) Takaya,
H.; Hayakawa, Y.; Makino, S.; Noyori, R. J. Am. Chem. Soc.
1978, 100, 1778. (s) Noyori, R.; Makino, S.; Okita, T.;
Hayakawa, Y. J. Org. Chem. 1975, 40, 806. (t) Doering, H.
J. Am. Chem. Soc. 1952, 74, 5688. (u) Brady, W. T.; Hieble,
J. P. Tetrahedron Lett. 1970, 3205. (v) Cavazza, P. J. Chem.
Soc., Chem. Commun. 1974, 501. (w) Berger, C.; Dietrich,
S.; Dilger, U.; Geuenich, D.; Helios, H.; Herges, R.;
Kirchmer, P.; Rottele, H.; Schroder, G. Angew. Chem. Int.
Ed. 1998, 37, 1854. (x) Sendelbach, S.; Schwetzler-
Raschke, R.; Radi, A.; Kaiser, R.; Henie, G. H.; Korfant, H.;
Reiner, S.; Foehlisch, B. J. Org. Chem. 1999, 64, 3398.
(y) Lee, C. J.; Cho, S. Y.; Cha, J. K. Tetrahedron Lett. 1999,
40, 7675.
(o) Salakhutdinov, N. F.; Detsina, A. N.; Korobeinicheva, I.
K.; Koptyug, V. A. Russ. J. Org. Chem. 1979, 15, 1310.
(p) Salakhutdinov, N. F.; Korobeinicheva, I. K.; Detsina, A.
N.; Koptyug, V. A. Bull. Chem. Russ. 1978, 27, 1937.
(q) Cavazza, M.; Morganti, G.; Pietra, F. J. Chem. Soc.,
Perkin Trans. 1 1984, 4, 727.
(5) Yoshitake, Y.; Nakagawa, H.; Eto, M.; Harano, K.
Tetrahedron Lett. 2000, 41, 4395.
(6) Saito, K.; Ando, S.; Kondo, Y. Heterocycles 2000, 53, 2601.
Synthesis 2002, No. 12, 1695–1700 ISSN 0039-7881 © Thieme Stuttgart · New York

1700
A. Almássy et al.
PAPER
(7) (a) Nitta, M.; Tajima, Y. J. Chem. Res., Synop. 1999, 6, 372.
(b) Kumar, K.; Kapur, A.; Ishar, M. P. S. Org. Lett. 2000, 2,
787.
(8) Kashman, Y.; Hirsch, S.; Koehn, F.; Cross, S. Tetrahedron
Lett. 1987, 28, 5461.
Matuzaki, N.; Nishigama, T.; Hiroka, S. Bull. Chem. Soc.
Jpn. 1981, 54, 1893. (c) Patwardran, S. A.; Dev, S.
Tetrahedron 1972, 28, 1075. (d) Sato, M.; Tanaka, T.;
Tsunetsugu, J.; Ebine, S. Bull. Chem. Soc. Jpn. 1975, 48,
2395.
(9) Rosenblum, M.; Watkins, J. C. J. Am. Chem. Soc. 1990, 112,
6316.
(10) (a) Hirao, T.; Masunaga, T.; Hayashi, K.; Ohshiro, Y.;
Agawa, T. Tetrahedron Lett. 1983, 24, 399. (b) Amice, P.;
Blanco, L.; Conia, J. M. Synthesis 1976, 196.
(14) (a) Hudson, A.; Bona, M. A. D.; Waterman, D.; Alberti, A.;
Benaglia, M.; Macciantelli, D. J. Chem. Soc., Perkin Trans.
2 1997, 12, 2487. (b) Tan, Q.; Lou, J.; Borhan, B.;
Karnaukhova, E.; Berova, N.; Nakanishi, K. Angew. Chem.
Int. Ed. Engl. 1997, 36, 2089.
(11) Pretsch, E.; Clerc, T.; Seibl, J.; Simon, W. Tables of Spectral
Data for Structure Determination of Organic Compounds;
Springer-Verlag: Berlin, 1983, M90.
(15) The superscripts indicate toward which C-atom
(a substituent or H-atom) is assigned hydrogen oriented [for
example HCl–C(6) means the hydrogen at C(6) oriented
toward to Cl].
(16) Takaya, H.; Hayakawa, Y.; Noyori, R. J. Am. Chem. Soc.
1978, 100, 1778.
(17) Jones, G. J. Chem. Soc. C 1970, 1230.
(18) (a) Almeida, W. P.; Correia, C. R. D. Tetrahedron Lett.
1994, 35, 1367; (82%, Et3N, NaI, TMSCl). (b) Duhamel,
P.; Hennequin, L.; Poirier, J. M.; Tavel, G.; Vottero, C.
Tetrahedron 1986, 42, 4777.
(12) (a) Wenkert, E.; Arrhenius, T. S.; Bookser, B.; Gwo, M.;
Manici, P. J. Org. Chem. 1990, 55, 1185. (b) Birch, A. J.;
Brown, J. M.; Stansfield, F. J. Chem. Soc. 1964, 5343.
(c) Patwarden, S. A.; Dev, S. Tetrahedron 1972, 28, 1075.
(d) Taylor, R. T.; Paquette, L. A. In Org. Synth., Coll. Vol.
7; John Wiley and Sons: New York, 1990, 200.
(13) (a) Birch, A. J.; Brown, J. M.; Stansfield, F. J. Chem. Soc.
1964, 5343. (b) Kuroda, S.; Sugimori, M.; Kawahigashi, S.;
Synthesis 2002, No. 12, 1695–1700 ISSN 0039-7881 © Thieme Stuttgart · New York