Application of the reetz reagent, dichlorodimethyltitanium, to develop sterically congested quaternary centers. The synthesis of herbertene

Article abstract of DOI:10.1055/s-1998-2089

A general protocol for conversion of a tetrasubstituted alkene to a highly methylated hydrocarbon is tested with a concise synthesis of the natural product, herbertene. The conversion: alkene → 1,2-diol → 1,2- dimethylated hydrocarbon should find application in a number of synthesis designs.

Full text of DOI:10.1055/s-1998-2089

832
Short Papers
SYNTHESIS
Application of the Reetz Reagent, Dichlorodimethyltitanium, to Develop Sterically
Congested Quaternary Centers. The Synthesis of Herbertene
Thomas Poon,*1 Bradford P. Mundy,*2 Frank G. Favaloro,3 Christina A. Goudreau,4 Andrew Greenberg, Ryan Sullivan
Chemistry Department, Colby College, Waterville, ME 04901, USA
E-mail: tpoon@rmc.edu; bpmundy@colby.edu
Received 8 July 1997; revised 1 December 1997
Abstract: A general protocol for conversion of a tetrasubstituted
alkene to a highly methylated hydrocarbon is tested with a concise
synthesis of the natural product, herbertene. The conversion:
alkene ® 1,2-diol ® 1,2-dimethylated hydrocarbon should find
application in a number of synthesis designs.
Key words: herbertene, Reetz reagent, dichlorodimethyltitanium,
methylation, quaternary centers
Reetz has shown that a tertiary hydroxy group can be re-
placed by a methyl group using dichlorodimethyltitani-
um.5 As part of our program designed to develop
protocols for the rapid development of complex mole-
cules, we envisioned a simultaneous replacement of the
two adjacent hydroxy groups of a 1,2-diol with two meth-
yl groups. An obvious test for this was found in her-
bertene.
Herbertene, isolated from the liverwort, Herberta adun-
ca,6 has the structure described by 1. Our focus is apparent
in the retrosynthetic analysis (Scheme 1).
Scheme 1
While a number of syntheses for herbertene have been re-
ported,7 the ability to convert the diol 2 to the title com-
pound would provide a relatively concise route to this and
other naturally occurring terpenoids.8 We report here two
total syntheses of (±)-herbertene.
A summary of the synthesis of herbertene is provided in
Scheme 2.
Reagents and conditions: (a) (i) Mg, Et2O, 22°C, 1.5 h. (ii) 2-methyl-
cyclopentanone, 22°C, 3 h. (b) TsOH (cat.), toluene, 110°C, 3 h. (c)
MCPBA, CH2Cl2, 0 °C, 1 h. (d) HClO4, H2O, THF, 22°C, 1 week. (e)
AlMe3 (5 equiv), hexane, 0°C, 8 h. (f) pyrolysis, 200°C. (g)
Me2TiCl2 (10 equiv), CH2Cl2, 0°C, 8 h.
Readily available 3-bromotoluene was converted to a
Grignard reagent, which when followed by addition of 2-
methylcyclopentanone provided 5. Without purification,
the crude product was dehydrated with a catalytic amount
Scheme 2
of p-toluenesulfonic acid in toluene. The dehydration ini-
tially gave the kinetically controlled less substituted
The diol precursor 2 was obtained in 48% yield by per-
chloric acid catalyzed hydrolysis10 of 7. This product was
prone to dehydration, even under conditions of mild silica
gel chromatography. Other methods11 of forming 1,2-di-
ols from 6 or from 3 were of limited success. Because of
the labile nature of 2, an alternate route to 1 was devised
from 8. The homobenzylic alcohol 8 was prepared from
the reaction of five equivalents of trimethylaluminum
alkene, [5-methyl-1-(3-methylphenyl)cyclopentene (6)],
as major product. However, heating the reaction mixture
under reflux for 6 hours affected the isomerization to the
desired 3 [ratio 3/6 91:9].9 This alkene mixture was
subjected to MCPBA epoxidation in dichloromethane,
and the corresponding epoxide isomers were readily
separated by flash column chromatography to give 7 in
51% yield.

June 1998
SYNTHESIS
833
1,2-Epoxy-1-methyl-2-(3-methylphenyl)cyclopentane (7):
with 7 in hexane at 0 °C under argon. Aqueous workup
followed by radial thin layer chromatography gave 8 in
38% yield.
A solution of the alkenes 3 and 6 (2.56 g, 0.0148 mol) in CH2Cl2
(20 mL) was added slowly to a solution of MCPBA (4.29 g, 0.0249
mol) in CH2Cl2 (100 mL) at 0°C. The reaction was allowed to warm up
to r.t. ovemight. The resultant milky white mixture was washed with dil
NaHCO3 (3 ´) and the organic layer was then washed with water and
dried (Na2SO4). Removal of the solvent under reduced pressure and
flash column chromatography (silica gel) gave 1.41 g (51% yield) of 7.
1H NMR (400 MHz): d = 7.22–7.08 (m, 4H), 2.36 (s, 3H), 2.28–2.01
(m, 3H), 1.80–l.48 (m, 3H), 1.17 (s, 3H).
The precursors, 2 and 8, were readily converted to 1 by re-
action with excess dichlorodimethyltitanium in dichlo-
romethane at 0°C under an argon atmosphere. Separation
of 1 from unreacted starting material was accomplished
by preparative GC. Isolated yields were 41% from 2 and
60% from 8. Herbertene was characterized by a combina-
tion of HRMS and NMR spectra (both 1H and 13C). Data
were in accord with those previously reported.4
13C NMR (100 MHz): d = 138.3, 138.01, 128.6, 128.5, 127.7, 124.1,
73.3, 71.0, 33.3, 32.4, 21.6, 19.0, 15.3.
HRMS (EI): m/z calcd 188.1201, found 188.1202.
An interesting result was noted when we attempted to iso-
late 7 by preparative GC. The conditions of the GC chro-
matograph (see experimental section) resulted in the
pyrolysis of 7 to 9. Since cuparene has been synthesized
using the Reetz methylation of 2-methyl-2-(4-methyl-
phenyl)cyclopentanone, we expect, by analogy, that 9
might also be able to undergo a similar transformation.
1-Methyl-2-(3-methylphenyl)cyclopentane-1,2-diol (2):
To THF/H2O (1:1, 35 mL) containing 7 (0.210 g, 0.00112 mol) was
added 65–85% HClO4 (4 drops). The reaction was allowed to stir at
r.t. for one week. The solvent was removed under reduced pressure
and the crude product was washed with hexane to yield a white pow-
der (110 mg) in 48% yield.
13C NMR (100 MHz): d = 140.0, 136.4, 127.6, 127.5, 127.4, 126.5,
83.2, 81.9, 38.0, 35.8, 24.4, 21.0, 18.9.
The unique utility of the Reetz methylation protocol to
generate methylated centers from tertiary diols has been
illustrated via the synthesis of (±)-herbertene. In addition,
a second method for generating the title compound from
epoxides has been presented. Both syntheses are charac-
terized by a simplicity for developing vicinal methylated
quaternary centers. This method should provide a synthet-
ically useful route to a number of sesquiterpenes isolated7
from the class of Bryophytes known as liverworts.
1,2-Dimethyl-2-(3-methylphenyl)cyclopentan-1-o1 (8):
To a solution of 7 (0.266 g, 0.00141 mol) in hexane (2 mL) at 0°C was
added 2 M AlMe3 (3.5 mL, 0.00700 mol) under argon. The reaction
was allowed to proceed overnight before being quenched with water.
The mixture was extracted with several small portions of hexane, and
the combined hexane layers were dried (Na2SO4) and concentrated
under reduced pressure. Purification by radial chromatography using
Et2O/hexane (1:1) gave 8 (0.11 g, 38% yield) as a colorless liquid.
1H NMR (400 MHz): d = 7.32–6.96 (m, 4H), 2.34 (s, 3H), 2.29 (m,
1H), 1.94–1.67 (m, 3H), 1.36 (s, 3H), 1.28 (m, 2H), 0.93 (s, 3H).
13C NMR (100 MHz): d = 147.4, 137.1, 127.9, 127.7, 126.3, 123.5,
82.1, 50.9, 39.0, 35.1, 25.8, 24.1, 21.9, 18.0.
Toluene and anhyd Et2O were used as purchased from Fisher, while
THF and CH2Cl2 were distilled from Na/benzophenone and CaH2, re-
spectively. Routine GC/MS analyses were performed on a Hewlett–
Packard 5890 gas chromatogram coupled to a 5970 series mass selec-
tive detector using a Supelco 2-4026 15 m ´ 0.25 mm capillary col-
umn packed with SPBM-1 (0.25 mm). NMR spectra were recorded at
400 MHz for 1H and 100 MHz for 13C on a Jeol GSX-400/54 high res-
olution NMR spectrometer. CDCl3 was used as the NMR solvent un-
less otherwise noted. Preparative GC separations were performed on
a Gow-Mac Series 350 gas chromatograph using a 8¢ ´ 0.25² 20%
Carbowax 20M on Chrom-P 80/100 mesh column (injector port, ov-
en, detector, and outlet port set to 200°C; He flow rate = 6 mL/min).
Radial TLC was performed using a Harrison Research Chromatotron
fitted with a 1 mm silica gel rotor.
HRMS (EI): m/z calcd 204.1514, found 204.1518.
2-Methyl-2-(3-methylphenyl)cyclopentanone (9):
A sample of 7 (25 mL) was analyzed by preparative GC under the con-
ditions described above. The largest fraction (tR 12 min) was collected
and combined with two other collections obtained in the same way.
GC/MS analysis showed the product to be over 99% pure.
1H NMR (400 MHz): d = 7.22–7.04 (m, 4H), 2.55 (m, 1H), 2.34 (s,
3H), 2.02–1.86 (m, 5H), 1.38 (s, 3H).
13C NMR (100 MHz, benzene-d6): d = 218.1, 143.1, 138.2, 128.8,
128.1, 127.6, 123.6, 52.9, 37.8, 37.3, 25.6, 21.5, 18.8.
Dichlorodimethyltitanium:
The methylating reagent was prepared by adding 2 M Me2Zn in tolu-
ene (1 equiv) to TiCl4 (1 equiv) in CH2Cl2 at 0 °C under argon. The
reagents are allowed to react with stirring for 10 min before addition
of substrate.
1-Methyl-2-(3-methylphenyl)cyclopentene (3):
A solution of 3-bromotoluene (10.7 g, 0.0626 mol) in Et2O (10 mL)
was added slowly to a mixture of Mg (1.53 g, 0.0630 mol) in Et2O
(25 mL) under argon. The mixture was allowed to reflux under its own
heat until most of the Mg was consumed. A solution of 2-methylcyclo-
pentanone (6.08 g, 0.062 mol) in Et2O (10 mL) was then added slowly
to the resulting Grignard solution and allowed to reflux for 3 h. The
mixture was quenched with 1 M HCl, and the organic layer was then
washed with water and dried (Na2SO4). The Et2O was removed under
reduced pressure to give a clear yellow liquid. Without purification, the
crude product 5 was dissolved in toluene (40 mL), and TsOH (1.5 g)
was added to this solution. The resulting solution was refluxed for 3 h,
whereupon the solution turned from slightly yellow to deep purple in
color. The toluene solution was then washed with sat. NaHCO3, dried
(MgSO4), and reduced under pressure to yield a thick, purple liquid.
The alkene product was collected as a clear, colorless liquid by Kugel-
rohr distillation (120°C/3.2 Torr). The product (2.56 g, 29% yield) was
found, by GC/MS, to consist of 3 (91%) and 6 (9%).
(±)-Herbertene (1) from 2:
A solution of 2 (0.025 g, 0.000123 mol) in CH2Cl2 (1 mL) was added
to Me2TiCl2 soln (10 equiv) at 0°C under argon. The reaction was al-
lowed to proceed overnight, after which it was quenched by careful
addition of water at 0°C. The mixture was then extracted with several
small portions of CH2Cl2, and the combined organic layers were dried
(MgSO4). Removal of the solvent under reduced pressure followed by
preparative TLC separation gave 1 (0.010 g, 4l% yield).
1H NMR (400 MHz): d = 7.20–7.00 (m, 4H), 2.51 (m, 1H), 2.34 (s,
3H), 1.81–1.52 (m, 5H), 1.26 (s, 3H), 1.07 (s, 3H), 0.56 (s, 3H).
13C NMR (100 MHz): d = 136.7, 127.8, 127.3, 126.0, 124.1, 50.4,
44.2, 39.7, 36.7, 26.5, 24.4, 24.3, 21.8, 19.7.
HRMS (EI): m/z calcd 202.1721, found 202.1717.

834
Short Papers
SYNTHESIS
(±)-Herbertene (1) from 8:
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Support by way of a Bristol–Myers Squibb Award of Research Cor-
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the Camille and Henry Dreyfus Foundation for their generous sup-
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