Catalytic hydrogenation of esters. Development of an efficient catalyst and processes for synthesising (R)-1,2-propanediol and 2-(l-Menthoxy)ethanol

Article abstract of DOI:10.1021/op200234j

A ruthenium catalyst for the reduction of esters by hydrogenation has been developed. Processes for the hydrogenation of esters have also been developed for (R)-1,2-propanediol and 2-(l-menthoxy)ethanol. The catalyst shows good catalytic activity for the hydrogenation of esters in methanol. Methyl lactate was reduced at 30 °C and gave turnover numbers (TON) up to 4000. The optical purity of the (R)-1,2-propanediol made by the hydrogenation of methyl (R)-lactate was higher than that via the asymmetric hydrogenation of hydroxyacetone. A hydrogenation process to replace the lithium aluminum hydride (LAH) reduction used in the production of 2-(l-menthoxy)ethanol was developed.

Full text of DOI:10.1021/op200234j

Technical Note
pubs.acs.org/OPRD
Catalytic Hydrogenation of Esters. Development of an Efficient
Catalyst and Processes for Synthesising (R)-1,2-Propanediol and
2-(l-Menthoxy)ethanol
Wataru Kuriyama,* Takaji Matsumoto, Osamu Ogata, Yasunori Ino, Kunimori Aoki, Shigeru Tanaka,
Kenya Ishida, Tohru Kobayashi, Noboru Sayo, and Takao Saito
Takasago International Corporation, Corporate Research and Development Division, 4-11, Nishiyawata 1-chome, Hiratsuka City,
Kanagawa 254-0073, Japan
S
* Supporting Information
ABSTRACT: A ruthenium catalyst for the reduction of esters by hydrogenation has been developed. Processes for the
hydrogenation of esters have also been developed for (R)-1,2-propanediol and 2-(l-menthoxy)ethanol. The catalyst shows good
catalytic activity for the hydrogenation of esters in methanol. Methyl lactate was reduced at 30 °C and gave turnover numbers
(TON) up to 4000. The optical purity of the (R)-1,2-propanediol made by the hydrogenation of methyl (R)-lactate was higher
than that via the asymmetric hydrogenation of hydroxyacetone. A hydrogenation process to replace the lithium aluminum
hydride (LAH) reduction used in the production of 2-(l-menthoxy)ethanol was developed.
and carbonylation (Scheme 1). [RuCl2(H2NCH2CH2PPh2)2]
was reported to catalyze the reduction of isopropyl benzoate
INTRODUCTION
■
Hydrogenation and hydride reduction are used for industrial
scale ester reductions.1 Hydrogenation reductions, employing a
heterogeneous catalyst at high temperature and high pressure
are used in the manufacture of structurally simple chemicals
such as fatty alcohols.1a,b On the other hand, hydride reductions
are used in pharmaceutical processes that form more structurally
complex compounds.1c While hydride reagents are versatile,2
their hazardous nature, complex postreaction workup proce-
dures, and high level of residual waste are matters of concern in
industrial operations.1c Replacing hydride reductions with
hydrogenations enables companies involved in pharmaceutical
intermediate production, which have expertise in hydrogenation
reactions, to implement simple and convenient processes. For
this purpose, catalysts which work under mild conditions would
have significant industrial advantages. Herein we describe a
catalyst for the hydrogenation of esters and its use in the
production of (R)-1,2-propanediol and 2-(l-menthoxy)ethanol.
Scheme 1. Possible deactivation pathway
more efficiently than methyl benzoate. The authors of that report
reasoned that the methanol produced during the reduction of
methyl benzoate deactivated the catalyst through carbonylation3i.
Therefore, carbonylation resistant catalysts should show higher
performance.
The lability of the second carbonyl ligand on ruthenium has
also been reported.5 In the example used, one of two carbonyl
ligands on a ruthenium with a potentially tridentate ligand
dissociated to form a monocarbonyl complex. Thus [Ru(CO)-
(triphos-κ3P)Cl2] was synthesized from [Ru(CO)2(triphos-
κ2P)Cl2] via decarbonylation. This result encouraged our
synthesis of new [Ru(CO)(P^NH^P)] complexes. Carbonylation
and decarbonylation of the complex should be reversible and any
dicarbonyl species produced during reaction should be converted
back into the original monocarbonyl species (Scheme 2).
[RuHCl(CO)(HN(CH2CH2PPh2)2)]6 was therefore synthe-
sized to catalyze the hydrogenation of esters7 more efficiently.
RESULT AND DISCUSSION
■
Ru-MACHO: A Catalyst for the Hydrogenation of
Esters. Catalytic hydrogenation reductions of esters under
relatively mild conditions have been reported by many research
groups in recent decades.3 Among them, catalytic
[RuCl2(H2NCH2CH2PPh2)2] with NaOMe showed excellent
activity in THF.3i We have also reported that [RuX1X2(dppp)-
(dpen)] (dppp: diphenylphosphinopropane, dpen: 1,2-diphe-
nylethylenediamine, X1 = X2 = Cl, or X1 = H, X2 = BH4), which
possesses similar Ru/NH biofunctionality.4 These complexes
catalyze the hydrogenation of benzoic acid esters and optically
active esters without loss of optical purity, however they have
only moderate activities (TON ≈ 100 to 500). Therefore, we
have focused our efforts toward the development of a more
effective catalyst for industrial applications. We hypothesized that
catalyst deactivation was caused by irreversible ligand dissociation
Received: August 26, 2011
Published: November 29, 2011
© 2011 American Chemical Society
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Organic Process Research & Development
Technical Note
a
Scheme 2. Possible equilibrium between monocarbonyl and
dicarbonyl species
Table 1. Hydrogenation of esters in methanol
The primary merit of the catalyst is that it shows good
catalytic activity even in methanol, while [RuCl2-
(H2NCH2CH2PPh2)2] gives almost no reaction in the solvent.3i
This means that the catalyst is not deactivated by methanol8a
and is less prone to alcohol inhibition in general.8b This
property is advantageous for the reduction of methyl esters,
because methanol is necessarily produced during methyl ester
reduction. In addition, solvent recycling is much easier as it is
unnecessary to separate byproduct methanol from the solvent
(Scheme 3). In pharmaceutical processes, the use of solvents
Scheme 3. Advantages of [RuHCl(CO)(HN(CH2CH2PPh2)2)]
has high environmental impacts, and hence, improving solvent
recycling is important.9
The complex is readily synthesized from [RuHCl(CO)-
(PPh3)3] and HN(CH2CH2PPh2)2 and has been named Ru-
MACHO because of its structure, which resembles a brawny
athlete holding the ruthenium (Figure 1).
a
Standard reaction conditions: substrate (200 mmol), Ru-MACHO
(0.2 mmol), NaOMe (28% in MeOH, 20.0 mmol), MeOH (160 mL),
b
c
H2 (5 MPa), 100 °C, 16 h. Isolated yield after distillation. GC area %.
d
Substrate (10 mmol), Ru-MACHO (0.01 mmol), NaOMe
(28% in MeOH, 1.0 mmol), MeOH (8 mL), H2 (5 MPa), 100 °C,
e
1
16 h. Yield based on H NMR (internal standard; 2-methoxynaph-
thalene)
Figure 1. Ru-MACHO.
(entries 6 and 7). iPr and tBu esters also gave the corresponding
alcohol in good yield (entries 8 and 9).
Hydrogenation of Esters with Ru-MACHO. The reduc-
tion of esters in methanol using Ru-MACHO is summarized in
Table 1. Various kinds of esters were reduced with good
conversion and selectivity in the presence of NaOMe (entries
1−5, 8, and 9). Aromatic and alkanoic acid methyl esters were
successfully reduced (entries 1 and 2). The reduction of a
diester (entry 3) using 0.1 mol % of the complex (0.05 mol %
per ester group) was also completed with the diol produced in
good yield. Oxygen- and nitrogen-containing functional groups
at the α-position of ester groups did not impact the activity
(entries 4 and 5), however substrates with those groups at
β-position gave low yield with decomposition of substrates
(R)-1,2-Propanediol Production with Ru-MACHO. To
assess potential industrial applications of the catalyst, we first
focused on the reduction of methyl lactate. Nonracemic 1,2-
propanediol is a useful chiral building block for pharmaceuticals,10
and has been produced via the asymmetric hydrogenation of
hydroxyacetone since 1992 at Takasago.11 Ru-SEGPHOS
complex is a good catalyst for this reaction. The TON is
up to 10,000, and the optical purity of the product is 98.5%
ee. However, products with an ee greater than 99% can be re-
quired as pharmaceutical intermediates. The optical purity can
be improved by recrystallization after p-nitrobenzoylation
(Scheme 4).11a In this process, additional steps (p-nitorobenzoylation,
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Organic Process Research & Development
Technical Note
Ru-MACHO afforded a good yield of 1,2-propanediol with a
loss of less than 1% ee (entry 3).
Scheme 4. Process for increasing optical purity of 1,2-
propanediol
A large-scale methyl lactate hydrogenation was carried out with
0.05 mol % of Ru-MACHO on a multiton scale per batch
(Scheme 6). After distillation, 1477 kg of (R)-1,2-propanediol was
a
Scheme 6. Large-scale hydrogenation of methyl (R)-lactate
recrystallization) are required to obtain 1,2-propanediol with the
required ee.
A better solution for us would be to catalyze the
hydrogenation of methyl lactate, which starts at >99% ee,
without the decrease in optical purity (Scheme 5). The shorter
process could reduce energy, lead-time, and cost.
a
Reaction conditions: substrate (2200 kg, 21,133 mol), Ru-MACHO
(6.4 kg, 10.6 mol), NaOMe (28% in MeOH, 51.0 kg, 256.2 mol),
MeOH (6369.2 kg), H2 (4.0 to 4.2 MPa), 26 to 28 °C, 12 h.
Scheme 5. Comparison of 1,2-propanediol processes
produced with 99.2% ee from 2200 kg of methyl (R)-lactate with
99.6% ee.
2-(l-Menthoxy)ethanol Production with Ru-MACHO.
2-(l-Menthoxy)ethanol is a cooling agent.12 It has a mild odor
and a longer-lasting cooling action than menthol. The reduction
of l-menthoxyacetic acid with LAH to produce 2-(l-menthoxy)-
ethanol has been reported by Takasago.13 However, large-scale
LAH reductions are troublesome, particularly because of the
exothermic postreaction hydride quench step. Using a Ru-
MACHO-catalyzed hydrogenation reduction would eliminate
these issues. The reaction would allow the use of a common
intermediate, l-menthoxyacetic acid (after methyl esterifica-
tion), and would have the additional benefits of employing this
hydrogenation technique with its simple methodology and
reduction of waste (Scheme 7).
Scheme 7. Comparison of 2-(l-menthoxy)ethanol processes
Our research indicated that reaction temperature is
important in the optical purity (Table 2). The optical purity
Table 2. Hydrogenation of methyl (R)-lactate
c
diol
c
d
entry
S/C
temp.
ester
(yield)
ee
a
1
1000
1000
4000
80
40
30
<1
2
99 (−)
98 (−)
− (87)
35.9
98.6
98.6
a
2
b
3
−
a
Reaction conditions: Substrate (10 mmol), Ru-MACHO (0.01
mmol), NaOMe (2 M in MeOH, 0.5 mmol), MeOH (5.5 mL), H2
b
(5 MPa), 16 h. Reaction conditions: Substrate (48 mmol), Ru-
MACHO (0.012 mmol), NaOMe (2 M in MeOH, 0.96 mmol),
c
d
MeOH (5 mL), H2 (4 to 6 MPa), 24 h. GC area %. Isolated yield
after silica gel column chromatography.
decreased from 99.2% ee to 35.9% ee at 80 °C (entry 1), but
the loss of optical purity was less than 1% ee at 40 °C (entry 2).
Even at a substrate/catalyst molar ratio (S/C) of 4000 at 30 °C,
Ru-MACHO showed good catalytic activity for the reduction
of methyl menthoxyacetate. The reaction was completed in 5 h
at 80 °C with a S/C ratio of 2000. 2-(l-Menthoxy)ethanol was
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Organic Process Research & Development
Technical Note
obtained in 87% yield after distillation without exothermic
postreaction hydride quench (Scheme 8).
stainless steel autoclave equipped with a mechanical stirrer. The
atmosphere was replaced with nitrogen gas, and then MeOH
(160 mL), substrate (200 mmol), and NaOMe (28% in MeOH,
3.86 mL, 20 mmol) were added. The vessel was purged three
times with hydrogen gas (0.5 MPa) and pressurized with
hydrogen (5 MPa). The mixture was stirred at 100 °C for 16 h,
cooled to 25 °C, and then the hydrogen gas released. The
mixture was analyzed by GC, concentrated in vacuo, and the
residue was distilled.
a
Scheme 8. Hydrogenation of methyl l-menthoxyacetate
Entry 1: 19.5 g (180.3 mmol, 90%) of benzyl alcohol
obtained as a colorless oil. 1H NMR (300 MHz, CDCl3) δ: 1.81
(br s, 1H), 4.67 (s, 2H), 7.20−7.40 (m, 5H); 13C NMR (75
MHz, CDCl3) δ: 64.6, 126.8, 127.3, 128.3, 140.7. bp: 90 °C (14
mmHg)
a
Reaction conditions: Substrate (160 mmol), Ru-MACHO (0.08
mmol), NaOMe (28% in MeOH, 1.55 g, 8 mmol), MeOH (73.2 mL),
H2 (4.5 MPa), 80 °C, 5 h.
Entry 2: 33.6 g (180.3 mmol, 90%) of dodecan-1-ol
obtained as a colorless oil. H NMR (300 MHz, CDCl3) δ:
0.88 (t, J = 6.8 Hz, 3H), 1.20−1.40 (m, 18H), 1.50−1.60 (m,
2H), 3.64 (t, J = 6.8 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ:
14.0, 22.6, 25.7, 29.3, 29.4, 29.6, 29.6, 31.9, 32.7, 62.8. bp: 108 °C
(2.0 mmHg)
CONCLUSIONS
■
1
This study describes a catalyst for the hydrogenation of esters, Ru-
MACHO, and its utility in the production of (R)-1,2-propanediol
and 2-(l-menthoxy)ethanol. The most notable feature of the cata-
lyst is its high catalytic activity in methanol. For the production of
(R)-1,2-propanediol, using Ru-MACHO results in a better quality
product. The optical purity was 99.2% ee compared with less than
99% ee made via the asymmetric hydrogenation of hydroxyace-
tone. Ru-MACHO produced 2-(l-menthoxy)ethanol in satisfactory
yield via hydrogenation without an undesirable exothermic, post-
reaction, hydride quench. The Ru-MACHO catalyst enables us to
take advantage of existing hydrogenation expertise for the reduc-
tion of esters and develop alternative processes. Ru-MACHO is
commercially available from Strem Chemicals and Sigma Aldrich.
Entry 3: 16.0 g (177.5 mmol, 89%) of 1,4-butanediol
1
obtained as a colorless oil. H NMR (300 MHz, CDCl3) δ:
1.60−1.76 (m, 4H), 2.40−2.60 (m, 2H), 3.60−3.80 (m, 4H);
13C NMR (75 MHz, CDCl3) δ: 29.7, 62.4. bp: 88 °C (1.0
mmHg)
Entry 4: 28.1 g (184.6 mmol, 92%) of 2-(benzyloxy)ethanol
obtained as a colorless oil. 1H NMR (300 MHz, CDCl3) δ: 1.90
(br s, 1H), 3.56−3.61 (m, 2H), 3.72−3.77 (m, 2H), 4.55 (s,
2H), 7.28−7.40 (m, 5H); 13C NMR (75 MHz, CDCl3) δ: 61.4,
71.3, 72.9, 127.4, 127.5, 128.1, 137.8. bp: 85 °C (0.3 mmHg)
Entry 5: 22.2 g (171.8 mmol, 86%) of piperidine ethanol
EXPERIMENTAL SECTION
■
General Information. All reactions and manipulations
were conducted under a nitrogen atmosphere in commercial
solvents unless otherwise noted. NMR spectra were obtained
on Varian Mercury Plus 300 spectrometer. NMR chemical
shifts are reported in ppm relative to CHCl3 (7.26 ppm for 1H,
1
obtained as a colorless oil. H NMR (300 MHz, CDCl3) δ:
1.36−1.52 (m, 2H), 1.52−1.70 (m, 4H), 2.32−2.58 (m, 6H),
2.58−3.20 (br, 1H), 3.59 (t, J = 5.4 Hz, 2H); 13C NMR (75
MHz, CDCl3) δ: 24.0, 25.6, 54.3, 57.7, 60.3. bp: 78 °C (8.0
mmHg)
and 77.0 ppm for 13C), DMF (2.91 ppm for H), and H3PO4
1
General Procedure for Hydrogenation of Methyl
Esters in Methanol Summarized in Table 1 (entries 6−9).
Ru-MACHO (6.1 mg, 0.01 mmol) was placed in a 100-mL
stainless steel autoclave equipped with a Teflon-coated stir bar.
The atmosphere was replaced with nitrogen gas, and then
MeOH (8 mL), substrate (10 mmol), and NaOMe (28% in
MeOH, 193 μL, 1 mmol) were added. The vessel was purged
three times with hydrogen gas (0.5 MPa) and pressurized with
hydrogen (5 MPa). The mixture was stirred at 100 °C for 16 h
and cooled to 25 °C, and the excess hydrogen gas was released.
The mixture was analyzed by 1H NMR or GC. See Supporting
Information.
GC Conditions for Reactions in Table 1. Neutra Bond-1
(df = 0.40 μm, 0.25 mm i.d. × 30 m, GL-Sciences), Carrier gas:
helium, Injection temp.: 200 °C, Detector temp.: 280 °C,
Oven: 40 °C → 100 °C (5 °C/min)−100 °C (5 min hold) →
280 °C (10 °C/min)−280 °C (5 min hold).
General Procedure for Hydrogenation of Methyl (R)-
Lactate Summarized in Table 2. Ru-MACHO was placed
in a stainless steel autoclave equipped with a Teflon-coated stir
bar. The atmosphere was replaced with nitrogen gas, followed
by the addition of MeOH, methyl (R)-lactate (99.2% ee), and
NaOMe (2 M in MeOH). The autoclave was purged three
times with hydrogen gas (0.5 MPa) and pressurized with
hydrogen (5 MPa). The mixture was stirred and cooled to
25 °C, and the excess hydrogen gas was released.
(0 ppm for 31P as an external reference). Optical rotations were
obtained on a JASCO P-1020 polarimeter. Mass spectra were
recorded on a SHIMADZU LCMS-IT-TOF instrument.
Synthesis of Ru-MACHO. Under a N2 atmosphere,
14
toluene (183 kg), HCl·HN(CH2CH2PPh2)2 (42 kg, 87.9
mol), water (42 kg), and NaOH (10.5 kg, 262.5 mol) were
added to a stainless steel vessel. The mixture was stirred at
44 °C for 15 min. The two phases were separated, and the organic
layer was washed with water (2 × 42 kg). The organic layer was
concentrated to recover 74 kg of toluene. [RuHCl(CO)-
(PPh3)3]15 (72 kg, 75.6 mol) in toluene (111 kg) was added to
the solution. The mixture was stirred at reflux for 2 h, then
cooled to 40 °C, and stirred for an additional 1.7 h. The re-
sulting precipitate was filtered, washed with toluene (3 × 72 kg),
and dried in vacuo to produce Ru-MACHO (38.8 kg, 63.9
mol, 85% based on [RuHCl (CO)(PPh3)3]) as a pale-yellow
solid. Ru-MACHO was obtained as a mixture of the two
1
possible isomers. H NMR (300 MHz, DMF-d7) δ: −15.01 (t,
J = 19.8 Hz, 0.6H), −14.30 (t, J = 20.7 Hz, 0.4H), 2.20−3.78 (m,
8H), 4.39 (br, 0.6H), 5.58 (brt, J = 11.4 Hz, 0.4H), 7.08−7.60
(m, 12H), 7.65−8.20 (m, 8H); 31P NMR (121 MHz, DMF-d7)
δ: 53.7 and 57.0. MS (ESI, m/z) calculated for C29H30NOP2Ru
([M − Cl]+) 572.0846, found 572.0829; mp: 308 °C (dec).
General Procedure for Hydrogenation of Methyl
Esters in Methanol Summarized in Table 1 (entries 1−5).
Ru-MACHO (121.4 mg, 0.2 mmol) was placed in a 1000-mL
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Organic Process Research & Development
Technical Note
GC Conditions. For conversion: Inert Cap Pure-Wax (df =
0.25 μm, 0.25 mm i.d. × 30 m), Carrier gas: helium, Injection
temperature: 250 °C, Detector temperature: 280 °C, Oven
program: 60 to 250 °C (10 °C/min) to 250 °C (1 min hold).
For product ee (analyzed after acetonization): CP-Chirasil-
DEX CB (df = 0.25 μm, 0.25 mm i.d. × 25 m), Carrier gas:
helium, Injection temperature: 250 °C, Detector temperature:
250 °C, Oven program: 60 °C (30 min). Acetonization
procedure: Amberlyst-15 (∼1 mg) was added to a solution of
the diol (10 mg) in acetone (1 mL). The mixture was stirred at
room temperature for 1 h. The reaction mixture was analyzed
directly.
62.1, 69.4, 79.5; bp: 85 °C (1.5 mmHg) ; [α]20.3D −91.1 (c 1.03,
CHCl3)
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR spectra, 13C NMR spectra, and GC analytical data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Author for correspondence. E-mail: wataru_kuriyama@
takasago.com. Telephone: +81-463-25-2187.
■
Entries 1 and 2. The reaction mixture was analyzed by GC.
Entry 3. The mixture was concentrated in vacuo. The
residual oil was purified by silica gel column chromatography
(CHCl3/MeOH = 20/1 to 10/1). The diol was obtained as a
REFERENCES
■
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1
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99.6% ee) and MeOH (2,384.6 kg) were added to a 14,000-L
stainless steel autoclave equipped with a mechanical stirrer.
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mixture, and the input line was washed with MeOH (160 kg).
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(320 kg) was added to the mixture, and the input line was
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(7) Catalytic hydrogenation of esters with pincer ruthenium carbonyl
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Alcohol (product) inhibition for hydrogenation of methyl benzoate at
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(en)] was reported in ref 3m.
1
(1477.0 kg, 19,410 mol, 92%, 99.2% ee). H NMR (300 MHz,
CDCl3) δ: 1.15 (d, J = 6.3 Hz, 3H), 2.75 (s, 2H), 3.38 (dd, J =
7.8, 11.1 Hz, 1H), 3.61 (dd, J = 3.0, 11.1 Hz, 1H), 3.83−3.96
(m, 1H); 13C NMR (75 MHz, CDCl3) δ: 18.5, 67.5, 68.1; bp:
45 °C (0.15 mmHg); [α]20.3 −30.3 (c 0.99, CHCl3), [lit.
D
[α]24.4 −28.6 (CHCl3)].16
D
Reduction of Methyl l-Menthoxyacetate in Scheme 8.
Ru-MACHO (48.6 mg, 0.08 mmol) was placed in a 200-mL
stainless steel autoclave equipped with a mechanical stirrer. The
atmosphere was replaced with nitrogen gas, followed by the
addition of MeOH (73.2 mL), methyl l-menthoxyacetate13,17
(36.6 g, 160 mmol), and NaOMe (28% in MeOH, 1.55 g,
8 mmol). The vessel was purged three times with hydrogen gas
(0.5 MPa) and was pressurized with hydrogen (4.5 MPa). The
mixture was stirred at 80 °C for 5 h and cooled to 25 °C, and
the excess hydrogen gas was purged. The reaction mixture was
concentrated in vacuo. Toluene (73 mL) was added to the
residue, and the mixture was washed with water (3 × 74 mL)
and concentrated in vacuo. The residue was purified by
distillation to produce 2-(l-menthoxy)ethanol (27.9 g, 139.3
(9) Butters, M.; Catterick, D.; Craig, A.; Curzons, A.; Dale, D.;
Gillmore, A.; Green, S. P.; Marziano, I.; Sherlock, J.-P.; White, W.
Chem. Rev. 2006, 106, 3002 and references cited therein.
(10) Examples of pharmaceutical processes using nonracemic 1,2-
propanediol or its derivatives. (a) Levofloxacine : Fujiwara, T.; Ebata,
T. (Daiichi Seiyaku Co., Ltd.). U.S. Pat. 5,312,999, 1994. (b)
Tenofovir: Ripin, D. H. B.; Teager, D. S.; Fortunak, J.; Basha,
S. M.; Bivins, N.; Boddy, C. N.; Byrn, S.; Catlin, K. K.; Houghton, S. R.;
1
mmol, 87%). H NMR (300 MHz, CDCl3) δ: 0.78 (d, J = 7.2
Hz, 3H), 0.80−1.10 (m, 9H), 1.18−1.30 (m, 1H), 1.30−1.45
(m, 1H), 1.57 −1.70 (m, 2H), 1.85 (br s, 1H), 2.04 −2.14 (m,
1H), 2.14 −2.28 (m, 1H), 3.38 (dt, J = 3.9, 10.5 Hz, 1H),
3.36 −3.48 (m, 1H), 3.63 −3.80 (m, 3H); 13C NMR (75 MHz,
CDCl3) δ: 16.1, 20.8, 22.2, 23.2, 25.6, 31.4, 34.4, 40.3, 48.1,
170
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Organic Process Research & Development
Technical Note
Jagadeesh, S. T.; Kumar, K. A.; Melton, J.; Muneer, S.; Rao, L. N.; Rao,
R. V.; Ray, P. C.; Reddy, N. G.; Reddy, R. M.; Shekar, K. C.; Silverton,
T.; Smith, D. T.; Stringham, R. W.; Subbaraju., G. V.; Talley, F.;
Williams, A. Org. Process Res. Dev. 2010, 14, 1194. (c) MK-0941:
Yoshikawa, N.; Xu, F.; Arredondo, J. D.; Itoh, T. Org. Process Res. Dev.
2011, 15, 824.
(11) (a) Kumobayashi, H.; Sayo, N.; Akutagawa, S.; Sakaguchi, T.;
Tsuruta, H. J. Chem. Soc. Jpn., Chem. Ind. Chem. 1997, 835. (b) Saito,
T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura, T.;
Kumobayashi, H. Adv. Synth. Catal. 2001, 343, 264. (c) Sumi, K.;
Kumobayashi, H. Top. Organomet. Chem. 2004, 6, 63.
(12) For menthol and related cooling compounds see: Eccles, R.
J. Pharm. Pharmacol. 1994, 46, 618.
(13) Green, C. B.; Nakatsu, T.; Ishizaki, T.; Lupo, A. T. (Takasago
International Corporation). U.S. Pat. Appl. 2002/0198412 A1, 2002.
(14) Nuzzo, R. G.; Haynie, S. L.; Wilson, M. E.; Whitesides, G. M.
J. Org. Chem. 1981, 46, 2861.
(15) Ahmad, N.; Levison, J. J.; Robinson, S. D.; Uttley, M. F. Inorg.
Synth. 1974, 15, 45.
(16) Shieh, N; Price, C. C. J. Org. Chem. 1959, 24, 1169.
(17) Soper, Q. F.; Whitehead, C. W.; Behrens, O. K.; Corse, J. J.;
Jones, R. G. J. Am. Chem. Soc. 1948, 70, 2849.
171
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