Practical synthesis of optically pure menthylamines starting from racemic neomenthol

Article abstract of DOI:10.1055/s-0030-1258295

A reliable and scalable route to racemic and highly enantiomerically enriched menthylamines exploits the technical product rac-neomenthol as the starting material. The elaborated protocol is based on nucleophilic substitution of the hydroxy moiety by azide. Subsequent reduction and resolution with tartaric acid provides the desired optically enriched menthylamines.

Full text of DOI:10.1055/s-0030-1258295

3596
PRACTICAL SYNTHETIC PROCEDURES
Practical Synthesis of Optically Pure Menthylamines Starting from Racemic
Neomenthol
Optically Pure
M
e
i
nthylam
n
ines a Welschoff,a Siegfried R. Waldvogel*a,b
a
Kekulé Institute for Organic Chemistry and Biochemistry, University of Bonn, Gerhard-Domagk-Str. 1, 53121 Bonn, Germany
Institute for Organic Chemistry, Johannes-Gutenberg University Mainz, Duesberg 10–24,
55128 Mainz, Germany
b
Fax +49(6131)3926777; E-mail: waldvogel@uni-mainz.de
Received 20 August 2010; revised 20 September 2010
PSP
No195
Abstract: A reliable and scalable route to racemic and highly enantiomerically enriched menthylamines exploits the technical product rac-
neomenthol as the starting material. The elaborated protocol is based on nucleophilic substitution of the hydroxy moiety by azide. Subse-
quent reduction and resolution with tartaric acid provides the desired optically enriched menthylamines.
Key words: amines, azides, chiral resolution, reduction, terpenoids
NaN3, DMF
NMI, Et3N, MsCl, toluene
r.t., 2 h, quant.
40 °C, 2 d, 70%
N3
OMs
OH
( )-1
( )-3
( )-2
resolution:
L-(+)- or D-(–)-tartaric acid
Raney-Ni, THF
H2, r.t., 3 d, 98%
MeOH–H2O, 10 °C, 3 d
NH2
NH2
H2N
( )-4
(+)-4
(−)-4
Scheme 1
Here, we report a fast synthetic access to optically pure All pathways for the synthesis of menthylamine take ad-
menthylamines starting from racemic neomenthol includ- vantage of terpenoic starting materials providing the full
ing a resolution on the final step (Scheme 1). Menthyl- carbon skeleton for the desired products. A pathway for
amines (–)-4–6 are unique a-chiral amines, which exhibit the synthesis of menthylamines proceeds from menthol
an asymmetric environment in the vicinity of the amino derivatives. Most reactions in the literature start with
group. Due to the conformational stability of the all-equa- (–)-menthol (10) to obtain the undesired diastereoisomer
torial substituted cyclohexane scaffold a superb transfer (+)-neomenthylamine [(+)-6] (Scheme 3).
of stereogenic information is guaranteed. Recently, this
Initially, an efficient leaving group has to be installed,
building block has been applied to the construction of su-
mostly a mesylate [Scheme 3; 1) (a)–(d)].13–16 In a subse-
pramolecular receptors 7 that allow enantiofacial discrim-
quent nucleophilic substitution reaction the configuration-
ination of single substrates1–3 and an efficient binding of
ally inverted azide was obtained. Alkali salts usually
caffeine4 and explosives.5–7 Epimeric mixtures of optical-
served as azide sources [Scheme 3; 2) (a), (b)].13,16 Reduc-
ly enriched menthylamine and neomenthylamine have
tion could be conducted by CeCl3/NaI mixtures17 or by
been used in the synthesis of high performance stationary
LiAlH4 to form (+)-neomenthylamine [(+)-6].16 In a
Mitsunobu-type transformation employing diisopropyl
azodicarboxylate and triphenylphosphine, the substrate
phase like 8 for column chromatography.8–10 Such a reso-
lution material was employed for the resolution of ceriv-
astatin, a precursor of a formerly top-selling drug.11
10 reacted with a zinc azide derivative in a one-pot proce-
Specific amides of (+)-neomenthylamine [(+)-6] turned
dure to form the desired azide 12 (Scheme 3).18
out to exhibit a strong capacity for umami flavor
(Scheme 2).12
There is no previous report for the synthesis of (–)-menth-
ylamine starting from neomenthol. Only the mesylation of
(+)-neomenthol [(+)-1] in pyridine is known
(Scheme 4).19 However, no details about the purity of the
SYNTHESIS 2010, No. 21, pp 3596–3601
x
x.
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x
.
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Advanced online publication: 13.10.2010
DOI: 10.1055/s-0030-1258295; Art ID: T16610SS
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Optically Pure Menthylamines
3597
MeSO2Cl, pyridine
−10 °C, 30 min then
OMs
OH
HN
O
2 °C, 15 h, quant.19
HN
(+)-1
(+)-2
O
all-syn
Scheme 4
O
3
7
NH2
(–)-4
receptor for TNT, caffeine
Ph3P, DEAD, nicotinoyl azide
THF, 0 °C to r.t., 3 h, 65%20
OH
N3
NH
ent-10
ent-12
O
Ph
Scheme 5
HN
NH2
5
O
H2
C
therefore elaborated into a reliable procedure.26 The draw-
back of this method consisted in the required large excess
of sodium metal. Consequently, a more sustainable and
electroorganic process was developed for the oxime re-
duction.27
n
8
high performance stationary phase
Racemic neomenthol [( )-1] is a technical by-product
which is obtained in the synthesis of menthol starting
from thymol.28 This particular diastereomer is usually re-
cycled by dehydrogenation/hydrogenation sequences.
Consequently, rac-neomenthol represents an attractive
starting material for the preparation of optically enriched
menthylamines. This pathway (Scheme 1) circumvents
the separation of menthyl- and neomenthylamines.
HN
O
NH2
(+)-6
9
novel umami flavor
Scheme 2
crude product were given and therefore, the conversion
was claimed to be quantitative.19
The substitution of the alcohol moiety in ( )-1 by a nitro-
gen functionality was challenging since the axially posi-
tioned leaving group was prone to elimination processes.
For the mesylation step, we tested different bases, K2CO3,
Et3N, pyridine, 1-methylimidazole (NMI), and mixtures
thereof. Table 1 displays the optimized conditions for the
individual reagent mixtures. No reaction occurred em-
ploying insoluble bases in 1,4-dioxane (entry 1), or using
triethylamine (entry 2) in dichloromethane at ambient
conditions. Using pyridine as solvent and base gave sig-
nificantly more of the desired product (entry 3). The less
basic 1-methylimidazole turned out to be beneficial for
this transformation. If 1-methylimidazole was applied as
reaction medium, the mesylate ( )-2 was obtained in 89%
yield (entry 4). Performing this conversion in THF at low-
er temperature slowed the reaction rate down, but provid-
Another direct conversion of a menthol derivative to the
corresponding azide was reported for (+)-menthol using
Mitsunobu conditions (Scheme 5).20
Alternatively, menthone could be converted by standard
transformations into the corresponding oximes. Prelimi-
nary results of the synthesis of menthylamine were pub-
lished in 1891 by Wallach et al.21 They reported a
Leuckert amination of menthone to obtain the desired
menthylamine.21–23 Detailed investigation of this product
in our lab indicated the formation of a mixture of several
stereoisomers.24 Another pathway was a subsequent Bou-
veault–Blanc-type reduction, which provided the menthyl-
amine in acceptable stereochemistry. However, the
original protocol lacked in reproducibility25 and was
4) Mitsunobu-type reaction
1) mesylation
3) reduction
2) substitution
OMs
N3
OH
NH2
6
11
12
13
10
Scheme 3 Reaction conditions: 1) (a) MeSO2Cl, pyridine, 0 °C;13 (b) MeSO2Cl, Et3N, CH2Cl2, 0 °C, 1 h, quant.;14 (c) MeSO2Cl, NMI, Et3N,
toluene, 20–25 °C, 1 h, 99%;15 (d) (MeSO2)2O, pyridine, DMAP, CH2Cl2, r.t., 19 h, quant;16 2) (a) LiN3, DMF, 90 °C, 20 h, 12: 63%, 13: 11%;13
(b) NaN3, DMF, 80 °C, 42 h, 12: 59%;16 3) (a) CeCl3·7H2O, NaI, MeCN, 100 °C, 24 h, 75%;17 (b) LiAlH4, Et2O, 40 °C, 2 h, then r.t., 21 h,
51%;16 4) Zn(N3)2·2Py, Ph3P, N2(CO2CHMe2), toluene, r.t., 2 h, 76%.18
Synthesis 2010, No. 21, 3596–3601 © Thieme Stuttgart · New York

3598
N. Welschoff, S. R. Waldvogel
PRACTICAL SYNTHETIC PROCEDURES
ed the target compound in excellent yield (entry 5). A
mixture of Et3N and NMI in toluene15 led to the best result
(Table 1, entry 6). These mild conditions suppressed com-
pletely the elimination reaction to menth-2-ene. Switch-
ing to other leaving functionalities, for example, 4-
tolylsulfonate to obtain rac-neomenthyl-4-tolylsulfonate
[( )-14], gave far inferior results (entry 7).
Table 2 Conditions for the SN2 Reaction
Entry
NaN3 (equiv) Conditions
Yield (%)a
70b
1
2
3
4
5
6
7
8
9
1.5
2
DMF, 40 °C, 2 d
DMF, 40 °C, 2 d
DMF, 40 °C, 2 d
DMF, 40 °C, 2 d
DMF, 40 °C, 30 h
DMSO, 40 °C, 2 d
NMP, 40 °C, 2 d
DMF, 30 °C, 4 d
acetone, 40 °C, 7 d
65b
3
78b
4
58c
Table 1 Introduction of Leaving Functionality
Yield (%)a
5
57c
Entry Base
Conditions
1.5
1.5
1.5
3
63b
1
2
3
4
5
6
7
K2CO3
MsCl, 1,4-dioxane, r.t., 5 d
MsCl, CH2Cl2, r.t., 5 d
MsCl, 0 °C to r.t., 14 h
MsCl, 0 °C, 1 h
–
70b
Et3N
–
63b
pyridine
NMI
81b
89b
95
–
a Yield of isolated product.
NMI
MsCl, THF, –20 °C to r.t., 5 d
b By-product menth-2-ene determined by 1H NMR spectroscopy for a
5 mmol scale; ca. 5%. For scaled-up processes (250 mmol); ca. 20%.
c By-product menth-2-ene determined by 1H NMR spectroscopy for a
5 mmol synthesis; ca. 20%.
NMI, Et3N MsCl, toluene, r.t., 2 h
pyridine TsCl, 0 °C, 70 h
quant
c
–
a Yield of isolated product.
b By-product menth-2-ene determined by 1H NMR spectroscopy (5–
Table 3 Reduction of rac-Menthyl Azide
10%).
c Reaction did not go to completion; a mixture of ( )-1, 13, and ( )-14
Entry
Reducing agent
FeCl3/Zn
Conditions
Yield (%)
(1:1:1) was obtained.
1
2
3
4
5
EtOH, 0 °C to r.t., 7 d
EtOH, 0 °C to r.t., 7 d
MeOH, r.t., 4 d
–
NaBH4
trace
61
92
98
Since the SN2 reaction was not preferred on a six-mem-
bered carbocycle and the leaving group was preset for the
elimination reaction, a very good and low basic nitrogen
nucleophile was required. A pronounced solvent effect
was anticipated and therefore, aprotic reaction media were
tested (Table 2): DMF, DMSO, and NMP (entries 1, 6, 7)
gave very similar results, whereas acetone as solvent led
to no conversion at all (entry 9). However, DMF seemed
to be the superior solvent for the substitution reaction. The
azide ( )-3 was contaminated with 20% of the by-product
13 if the synthesis was performed on large-scale (up to
0.25 mol starting material). In test reactions of 5 mmol
scale, only a little elimination process was detected (not
exceeding 5%). Remarkably, an excess of 1.5 equivalents
NaN3 seemed to be crucial (entry 1); 3 equivalents offered
slightly better results (entry 3). Exposure to an excess of
nucleophile gave lower yield and produced an increased
amount of elimination product (entries 4, 5).
PtO2, H2
LiAlH4
THF, 0 °C to r.t., 22 h
THF, r.t., 3 d
Raney-Ni, H2
agents like (–)-O,O¢-dibenzoyl-L-tartaric acid, L-(–)-mal-
ic acid, (+)-camphorsulfonic acid, or Brown’s acid gave
no resolvable diastereomeric salts. Only L-(+)-tartaric
acid separated the enantiomers in low but acceptable
yields (Table 4). At first different concentrations of EtOH
(entries 1–6) and MeOH solutions (entries 7–12) at differ-
ent conditions (temperature and water content) were stud-
ied. Best results were achieved with a 1.25 mmol/mL
concentration in MeOH, which contained 5% water (entry
10). The crystallization had to be conducted at 10 °C.
With these conditions in hand it should be possible to use
L-(+)- and D-(–)-tartaric acid in an alternate way making
both antipodes accessible in high optical purity and en-
hanced efficiency (Figure 1). Starting the resolution of the
enantiomers with L-(+)-tartaric acid, (–)-menthylamine
formed a crystalline salt with the chiral acid. The salt was
dissolved in NaOH and extracted with tert-butyl methyl
ether to obtain the desired amine (13%, >95% ee). The fil-
trate, which was enriched with (+)-menthylamine, was
isolated and formed a diastereomeric salt with D-(–)-tar-
taric acid. After a two-fold crystallization with D-(–)-tar-
taric acid of this enriched filtrate and the mentioned
workup, (+)-menthylamine was obtained in good yields
and high optical purity (27%, >95% ee, 2 steps). Further-
Table 3 displays possible reagents for the reduction of
rac-menthyl azide [( )-3]. Neither a mixture of FeCl3 with
Zn nor NaBH4 were reactive enough to synthesize the
amine ( )-4 (entries 1, 2). When employing LiAlH4 in
THF ( )-4 was obtained in good yields (entry 4). For a
multigram approach of the menthylamine, Raney-Ni in
THF turned out to be the method of choice (entry 5). Com-
pared to LiAlH4, the workup with Raney-Ni was more
practical and provided better yields.
Finally, the racemic menthylamine ( )-4 had to be re-
solved by optically pure acids. The resolution turned out
to be more difficult than anticipated. Common resolving
Synthesis 2010, No. 21, 3596–3601 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Optically Pure Menthylamines
3599
receptors.5–7 For this purpose the isocyanates had been
prepared and reported.26 We also synthesized the (–)-men-
thyl isothiocyanate by reacting (–)-menthylamine [(–)-4]
with thiophosgene in a biphasic mixture of CH2Cl2 and
aqueous sodium bicarbonate (Scheme 6).29 The isothiocy-
anate (–)-15 might also find application as building block
in supramolecular chemistry or organocatalysis.
Table 4 Resolution with L-(+)-Tartaric Acida
20
Entry Solvent
H2O
Temp Time [a]D
Yield
(%)b
(c [mmol/mL]) (%)
(°C)
r.t.
r.t.
10
(d)
1
2
EtOH (0.5)
EtOH (0.5)
EtOH (0.5)
EtOH (1.0)
EtOH (1.5)
EtOH (2.0)
MeOH (1.25)
MeOH (1.25)
MeOH (1.25)
MeOH (1.25)
MeOH (1.5)
MeOH (2.0)
–
6
–33.8
–28.2
– 1.3
– 6.6
– 4.0
– 3.7
–20.3
–36.1
–23.8
–36.5
–26.9
–27.3
10
13
29
42
48
49
23
10
17
13
7
2.5
–
6
3
1
CSCl2, NaHCO3, CH2Cl2
r.t., 30 min, 86%
4
–
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
10
1
5
–
1
NH2
NCS
6
–
1
(–)-4
(–)-15
7
2.5
5
8
Scheme 6
8
3
In conclusion, a fast and reliable procedure to optically
enriched menthylamine was elaborated. The method ex-
ploited as starting material a technical by-product rac-
neomenthol. For an efficient installation of the amino
moiety, the elimination reaction was suppressed by using
1-methylimidazole. Application of these elaborated reac-
tion conditions essentially avoided by-products. After re-
duction with Raney-nickel in a hydrogen atmosphere,
resolution was achieved by the formation of diastereomer-
ic salts with tartaric acid. Crystallization from aqueous
methanol provided essentially enantiopure menthylamine
salt.
9
7.5
5
8
10
11
12
3
5
10
6
5
10
6
9
a Optical rotation of liberated amine from crystallized diastereomeric
salt is given.
b Yields of isolated products.
more, the filtrates were recycled for further resolutions so
that no menthylamine was wasted. The sequential resolu-
tion strategy allowed a fast access to significant amounts After one recrystallization, (–)-menthylamine and (+)-
of both antipodes. Since the manipulations were easy to menthylamine were obtained in 13% and 44% yield with
perform, a scale up was readily achieved.
an enantiomeric excess of >95% ee and 81% ee, respec-
tively. With this procedure (–)-menthylamine and its anti-
pode are readily available. The protocols are scalable and
The optically enriched menthylamines had to be attached
on scaffolds to exploit their unique stereodirecting capa-
bilities as previously mentioned for the supramolecular
Figure 1 Flow chart depicting the resolution process of menthylamine with tartaric acid
Synthesis 2010, No. 21, 3596–3601 © Thieme Stuttgart · New York

3600
N. Welschoff, S. R. Waldvogel
PRACTICAL SYNTHETIC PROCEDURES
MS (EI, 70 eV): m/z (%) = 138.1 (72, [M – HN3]+), 123.1 (30, [M –
will allow a broad application of these unique optically
pure amines.
HN3 – CH3]+), 95.0 (100, [C7H11]+), 81.0 (78, [C6H9]+).
All reagents used were of analytical grade. Solvents for extractions
were technical grade and distilled prior to use. Column chromatog-
raphy was performed on silica gel (particle size 63–200 mm, Acros
Organics BVBA, Geel, Belgium) using mixtures of cyclohexane
and EtOAc as eluents. TLC was done on silica gel 60 F254 on glass
(Merck KGaA, Darmstadt). GC analysis was obtained on a GC-
2010 of Shimadzu, Japan with a HP 5 column of Agilent Technolo-
gies, USA, (length: 30 m, bore diameter: 0.25 mm, thickness of
rac-Menthylamine [( )-4]
Raney-Ni: Raney-nickel was synthesized from Al/Ni alloy (25.4 g
alloy, 46.4 g NaOH, 250 mL H2O) and was stored under H2O. For
the reaction, the slurry was washed and decanted several times with
THF.
Reduction with Raney-Ni: A flask was charged with rac-menthyl
azide [( )-3; 32.4 g, 0.18 mol], THF (100 mL), and a slurry of
Raney-Ni (10.0 g) in THF. The flask was carefully evacuated and
flushed three times with H2. The mixture was shaken under a reser-
voir of H2 (balloon) at r.t. for 3 d. The Raney-Ni was then carefully
filtered off, washed with THF (250 mL), and the solvent was re-
moved in vacuo [Caution! The filter paper with the Raney-Ni is
highly pyrophoric, controlled incineration is recommended]. rac-
Menthylamine ( )-4 (27.0 g, 98%) was obtained as a colorless oil.
1H NMR (400 MHz, CDCl3): d = 2.51 (m, 1 H, 3-H), 2.10 (m, 1 H,
8-H), 1.81 (m, 1 H, 2-H), 1.67 (m, 1 H, 6-H), 1.58 (m, 1 H, 5-H),
1.39 (m, 1 H, 1-H), 0.96 (m, 2 H, 4-H, 5-H), 0.91 (d, J = 6.9 Hz,
3 H, 10-H), 0.87 (d, J = 6.5 Hz, 3 H, 7-H), 0.82 (m, 2 H, 2-H, 6-H),
0.76 (d, J = 7.0 Hz, 3 H, 9-H).
1
coating: 0.25 mm). H NMR spectra were recorded at 25 °C on
Bruker DPX 300 or 400 instruments (Analytische Messtechnik
Karlsruhe, Germany). Chemical shifts (d) are reported in parts per
million (ppm) relative to TMS as internal standard or traces of
CHCl3 in the deuterated solvent. IR spectra were measured on a
Bruker Ifs 28 spectrometer and reported in cm–1. Mass spectra were
obtained on a MAT95XL (Finnigan, Bremen, Germany) employing
EI. Optical rotations were measured using a polarimeter P-2000 of
Jasco, Labor- und Datentechnik GmbH, Gross-Umstadt, in a 10 cm
cell at ambient conditions.
rac-Neomenthyl Methanesulfonate [( )-2]
To a solution of rac-neomenthol [( )-1; 40.0 g, 0.25 mol], Et3N
(32.0 mL, 0.38 mol), and 1-methylimidazole (30.0 mL, 0.38 mol)
in toluene (250 mL) was added MeSO2Cl (29.4 mL, 0.38 mol) dis-
solved in toluene (400 mL) dropwise over 15 min. After stirring the
mixture for 2 h at r.t., H2O (200 mL) was added. The layers were
separated and the aqueous layer was extracted with tert-butyl meth-
yl ether (2 × 200 mL). The combined organic layers were washed
with sat. aq NH4Cl (500 mL) and brine (500 mL), dried (MgSO4)
and the solvent was removed in vacuo to afford a colorless oil
(59.5 g, quant), which turned to be analytically pure.
1H NMR (300 MHz, CDCl3): d = 5.14 (s, 1 H, 3-H), 3.00 (s, 3 H,
11-H), 2.17 (dq, J = 3.5, 14.6 Hz, 1 H, 2-H), 1.70 (m, 3 H, 5-H, 6-
H, 8-H), 1.48 (m, 1 H, 1-H), 1.25 (m, 1 H, 5-H), 1.09 (m, 1 H, 2-H),
1.01 (m, 1 H, 4-H), 0.97 (d, J = 6.6 Hz, 3 H, 10-H), 0.91 (d,
J = 6.5 Hz, 3 H, 7-H), 0.89 (m, 4 H, 9-H, 6-H).
13C NMR (100 MHz, CDCl3): d = 51.6 (C-3), 50.4 (C-4), 45.7 (C-
2), 34.9 (C-6), 32.0 (C-1), 26.0 (C-8), 23.2 (C-5), 22.4 (C-7), 21.3
(C-10), 15.5 (C-9).
MS (EI, 70 eV): m/z (%) = 155.1 (6, [M]+), 140.1 (5, [M – CH3]+),
138.1 (5, [M – NH3]+), 98.0 (8, [140 – C3H6]+), 70.0 (100, [C5H10]+).
(–)-Menthylamine [(–)-4]
L-(+)-Tartaric acid (0.94 g, 6.25 mmol) was dissolved in aq MeOH
(5 mL, 5% H2O) and rac-menthylamine [( )-4; 0.97 g, 6.25 mmol]
was added. With a seed crystal, the solution was stored at 10 °C for
3 d. The precipitate was filtered off and dried. The residue was sus-
pended in a mixture of tert-butyl methyl ether (20 mL) and aq 10%
NaOH (20 mL) and stirred until dissolution occurred. The aqueous
layer was extracted with tert-butyl methyl ether (2 × 50 mL). The
combined organic layers were dried with CaO powder and concen-
trated in vacuo to obtain the (–)-menthylamine [(–)-4] (0.13 g, 13%,
>95% ee); [a]D20 –36.1 (c 0.5, CHCl3) {Lit.26 [a]D20 –35.7 (c 1.39,
CHCl3)}.
13C NMR (75 MHz, CDCl3): d = 81.3 (C-3), 47.5 (C-4), 40.2 (C-2),
39.2 (C-11), 34.4 (C-6), 28.8 (C-1), 26.0 (C-8), 24.2 (C-5), 22.0 (C-
7), 20.7 (C-10), 20.6 (C-9).
MS (EI, 70 eV): m/z (%) = 138.1 (62, [M – HOMs]+), 123.1 (32, [M
1H NMR (400 MHz, CDCl3): d = 2.51 (m, 1 H, 3-H), 2.10 (m, 1 H,
8-H), 1.81 (m, 1 H, 2-H), 1.67 (m, 1 H, 6-H), 1.58 (m, 1 H, 5-H),
1.39 (m, 1 H, 1-H), 0.96 (m, 2 H, 4-H, 5-H), 0.91 (d, J = 6.9 Hz,
3 H, 10-H), 0.87 (d, J = 6.5 Hz, 3 H, 7-H), 0.82 (m, 2 H, 2-H, 6-H),
0.76 (d, J = 7.0 Hz, 3 H, 9-H).
– HOMs – CH3]+), 95.0 (100, [C7H11]+), 81.0 (68, [C6H9]+).
rac-Menthyl Azide [( )-3]
Mesylate ( )-2 (61.0 g, 0.26 mol) was dissolved in DMF (200 mL)
and NaN3 (25.4 g, 0.39 mol) was added. The suspension was stirred
for 2 d at 40 °C. After this time, GC analysis showed complete con-
version. The mixture was poured onto ice and extracted with tert-
butyl methyl ether (3 × 150 mL). The combined organic layers were
washed with H2O (3 × 200 mL) and brine (200 mL), and dried
(MgSO4). Evaporation of the solvent in vacuo afforded the menthyl
azide (32.8 g, 70%) as a pale yellow liquid, which was used without
further purification (NMR spectra showed the presence of 20%
menth-2-ene). Analytically pure azide was obtained by removal of
menth-2-ene by solvent distillation. Caution! This should only be
carried out in small quantities because of potential explosions.
(+)-Menthylamine [(+)-4]
D-(–)-Tartaric acid (4.10 g, 26.5 mmol) was dissolved in aq MeOH
(21.2 mL, 5% H2O) and the filtrate of the chiral resolution of rac-
menthylamine, which is enriched with (+)-menthylamine (3.97 g,
26.5 mmol) was added. With a seed crystal, the solution was stored
at 10 °C for 3 d. The precipitate was filtered off and dried. The
workup is done as described above. After the first resolution with D-
(–)-tartaric acid, (+)-menthylamine (1.80 g, 44%, 81% ee) was iso-
lated; [a]D20 +28.9 (c 0.5, CHCl3).
1H NMR (400 MHz, CDCl3): d = 3.05 (ddd, J = 4.1, 11.2, 11.2 Hz,
1 H, 3-H), 2.10 (m, 2 H, 2-H, 8-H), 1.68 (m, 2 H, 5-H, 6-H), 1.43
(m, 1 H, 1-H), 1.16 (m, 1 H, 4-H), 1.09 (m, 1 H, 2-H), 1.02 (m, 1 H,
5-H), 0.94 (d, J = 6.6 Hz, 3 H, 10-H), 0.91 (d, J = 7.0 Hz, 3 H, 7-
H), 0.83 (m, 1 H, 6-H), 0.79 (d, J = 6.9 Hz, 3 H, 9-H).
13C NMR (100 MHz, CDCl3): d = 62.5 (C-3), 47.2 (C-4), 40.4 (C-
2), 34.2 (C-6), 31.9 (C-1), 26.9 (C-8), 23.6 (C-5), 22.0 (C-7), 20.8
(C-10), 15.9 (C-9).
(–)-Menthyl Isothiocyanate [(–)-15]
A solution of (–)-menthylamine [(–)-4; 0.40 g, 2.58 mmol] in
CH2Cl2 (16 mL) was charged with a solution of sat. aq NaHCO3
(16 mL). Thiophosgene (0.22 mL, 2.84 mmol) was added via sy-
ringe to the organic layer. The biphasic mixture was stirred vigor-
ously for 30 min at r.t. After the separation of the two layers, the
aqueous fraction was extracted with CH2Cl2 (2 × 25 mL). The com-
bined organics were washed with brine (50 mL) and dried
(Na2SO4). The solvent was removed and the crude product was sub-
Synthesis 2010, No. 21, 3596–3601 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Optically Pure Menthylamines
3601
jected to column chromatography (cyclohexane) to afford the
isothiocyanate as a colorless liquid (0.44 g, 86%); Rf = 0.67 (cyclo-
hexane–EtOAc, 95:5); [a]D20 –74.2 (c 0.52, CHCl3).
(8) Schwartz, U.; Großer, R.; Piejko, K.-E.; Bömer, B.; Arlt, D.
German Patent DE3532356A1, 1987; Chem. Abstr. 1987,
107, 40614.
(9) Grose-Bley, M.; Bömer, B.; Großer, R.; Arlt, D.; Lange, W.
German Patent DE4120695, 1992; Chem. Abstr. 1993, 119,
139964.
(10) Bömer, B.; Großer, R.; Lange, W.; Zweering, U.; Köhler, B.;
Sirges, W.; Grose-Bley, M. DE19546136A1, 1997; Chem.
Abstr. 1997, 127, 96037.
(11) Lange, W.; Grosser, R.; Köhler, B.; Michel, S.; Bömer, B.;
Zweering, U. DE19714343A1, 1998; Chem. Abstr. 1998,
129, 290016.
(12) Looft, J.; Vössing, T.; Ley, J.; Backes, M.; Blings, M.
European Patent EP1989944A1, 2008; Chem. Abstr. 2008,
149, 532086.
(13) Shimizu, T.; Ohzeki, T.; Hiramoto, K.; Hori, N.; Nakata, T.
Synthesis 1999, 1373.
(14) Albrecht, S.; Defoin, A.; Tarnus, C. Synthesis 2006, 1635.
(15) Nakatsuji, H.; Ueno, K.; Misaki, T.; Tanabe, Y. Org. Lett.
2008, 10, 2131.
IR (neat): 2956m, 2924m, 28970w, 2127s, 2066s, 1455m, 720m
cm–1.
1H NMR (400 MHz, CDCl3): d = 3.42 (ddd, J = 4.0, 11.1 Hz, 1 H,
3-H), 2.12 (m, 2 H, 2-H, 8-H), 1.68 (m, 2 H, 5-H, 6-H), 1.38 (m,
2 H, 1-H, 4-H), 1.27 (m, 1 H, 2-H), 1.00 (m, 1 H, 5-H), 0.94 (d,
J = 7.2 Hz, 3 H, 10-H), 0.92 (d, J = 6.6 Hz, 3 H, 7-H), 0.88 (m, 1 H,
6-H), 0.80 (d, J = 6.9 Hz, 3 H, 9-H).
13C NMR (100 MHz, CDCl3): d = 58.8 (C-3), 48.5 (C-4), 42.9 (C-
2), 33.9 (C-6), 31.6 (C-1), 27.5 (C-8), 23.3 (C-5), 21.7 (C-7), 20.7
(C-10), 15.7 (C-9).
MS (EI 70 eV): m/z (%) = 197.2 (100, [M]+), 182.2 (40, [M –
CH3]+), 139.2 (25, [M – NCS]+), 97.1 (15), 83.1 (72), 69.1 (18), 55.1
(24, [C4H7]+).
HRMS (EI): m/z [M]+ calcd for C11H19NS: 197.1241; found:
197.1238.
(16) Jumaryatno, P.; Rands-Trevor, K.; Blanchfield, J. T.;
Garson, M. J. ARKIVOC 2007, (vii), 157.
(17) Bartoli, G.; Di Antonio, G.; Giovannini, R.; Giuli, S.;
Lanari, S.; Paoletti, M.; Marcantoni, E. J. Org. Chem. 2008,
73, 1919.
(18) Viaud, M. C.; Rollin, P. Synthesis 1990, 130.
(19) Gansäuer, A.; Narayan, S.; Schiffer-Ndene, N.; Bluhm, H.;
Oltra, J. E.; Cuerva, J. M.; Rosales, A.; Nieger, M.
J. Organomet. Chem. 2006, 691, 2327.
Acknowledgment
The donations of rac-neomenthol by Symrise (Germany) and
1-methylimidazole by BASF SE (Germany) are highly appreciated.
We thank Dr. J. Toräng for previous studies in menthylamine
chemistry.
(20) Papeo, G.; Posteri, H.; Vianello, P.; Varasi, M. Synthesis
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Synthesis 2010, No. 21, 3596–3601 © Thieme Stuttgart · New York