Synthesis and Characterization of Enantiomerically Pure Menthylamines and Their Isocyanates

Article abstract of DOI:10.1055/s-2003-42432

A synthetic protocol for optically pure (-)-menthylamine, (-)-8-methylmenthylamine, and the novel (-)-8-phenylmenthylamine is presented including a detailed characterization of these compounds and their isocyanates.

Full text of DOI:10.1055/s-2003-42432

PAPER
2689
Synthesis and Characterization of Enantiomerically Pure Menthylamines and
Their Isocyanates
E
nantiomerically Pure
a
Menthylam
t
ines an
t
d Thei
h
r
Isocyanate
s
ias C. Schopohl,a Klaus Bergander,a Olga Kataeva,b Roland Fröhlich,a Siegfried R. Waldvogel*a
a
Westfälische Wilhelms-Universität Münster, Org.-Chem. Institut, Corrensstr. 40, 48149 Münster, Germany
Fax +49(251)8339772; E-mail: waldvog@uni-muenster.de
b
H. E. Arbuzov Institute, Arbuzov Street 8, Kazan 420088, Russia
Received 31 July 2003
CH3
Abstract: A synthetic protocol for optically pure (–)-menthyl-
amine, (–)-8-methylmenthylamine, and the novel (–)-8-phenylmen-
thylamine is presented including a detailed characterization of these
compounds and their isocyanates.
CH3
H3C
H3C
R2
R1
NH2
CH3 H3C
R
NH2
CH3 NH2
Key words: amines, aminations, asymmetric synthesis, chirality,
1
2
3
chiral auxiliaries
Figure 1 Steric demand of -chiral amines
Enantiomerically pure -chiral amines 1 are important
building blocks and auxiliaries in synthetic organic chem-
istry.1 Several methodologies are established for the enan-
tioselective synthesis of these compounds.2 If very bulky
substituents on the -stereogenic center are involved,
common procedures like the conversion of enantiopure
sulfinimines suffer from low yields and are consequently
less attractive.3 For our supramolecular investigations, -
chiral amines with far-projecting substituents (R2) larger
than tert-butyl groups (e.g. 2) were required. The chiral
information should be addressed by steric means in the vi-
cinity of the nitrogen. In addition, the rigidity of the cyclo-
hexane skeleton will provide conformational stability
with locating the substituents appropriately and resulting
in different steric demands on both sides of the nitrogen.4
All these molecular features are excellently combined in
3 (Figure 1).
RMgX, CuI, Et2O
O
O
R
4 (+)-pulegone
5b: R = CH3; 43 %
5c: R = Ph; 72 %
Scheme 1
to be prepared first. Therefore, we used (+)-pulegone (4)
and installed the appropriate moiety by cuprate addition,
providing 5b/c (Scheme 1).8 Employment of (+)-pule-
gone in practical grade (92%) is recommended since the
impurities and the by-products of the 1,4-addition are eas-
ily removed after the transformation. The 1,2-addition oc-
curred in a side reaction forming the intermediate
alcohols, which undergo elimination upon work-up. The
menthanones 5b/c were purified by a single distillation
and consisted of an epimeric mixture due to the configu-
rationally labile -carbon.
Optically pure menthylamine or 8-substituted derivatives
3 seemed to be the compounds of choice since an ex chiral
pool synthesis can be exploited and should be feasible on
a multi-gram scale. 8-Substituted (–)-menthol derivatives
are widely used auxiliaries e.g. in the Diels–Alder reac-
tion.5 In contrast, the corresponding menthylamines are
either not known or only sparingly described in the litera-
ture.6,7
Subsequent oxime formation (Scheme 2) was performed
under standard conditions.9 Analytically pure product was
only obtained after column chromatography on silica
yielding 6a–c as colorless crystals. At the beginning, the
eluent contains pure (E)-oxime; only the last 20% of the
eluent consists of an E/Z-mixture. Therefore, all analytical
data refer to the (E)-oxime. While the menthyl and 8-phe-
nylmenthyl oxime resulted in excellent yields, the 8-me-
thylmenthyl derivative 6b was obtained only in less
quantity. The known physical data for 6a/b are restricted
to their melting points,6,7 which was confirmed for 6a. For
the oxime 6b we found a quite different melting point.10
The significant impact of the substitution pattern in the 8-
position of the menthane skeleton is revealed in different
yields when a chemical reaction is performed directly on
the cyclohexane moiety. Consequently, the reduction of
We describe a reliable protocol for the synthesis of enan-
tiopure menthyl-, 8-methylmenthyl-, and 8-phenylmenth-
ylamine, as well as their isocyanates, including the full
analytical characterization. All transformations can be ap-
plied to multi-gram quantities.
The synthesis of the parent menthylamine started directly
with the commercially available (–)-menthone. For the 8-
substituted derivatives the corresponding menthones had
SYNTHESIS 2003, No. 17, pp 2689–2694
x
x.
x
x
.
2
0
0
3
Advanced online publication: 14.10.2003
DOI: 10.1055/s-2003-42432; Art ID: T08303SS
© Georg Thieme Verlag Stuttgart · New York

2690
M. C. Schopohl et al.
PAPER
Remarkably, all menthyl derivatives, except 6b and 9,
show a negative optical rotation in the measured light
range (365–589 nm). The absolute configurations of the
menthyl isocyanates 8a/b were confirmed by X-ray anal-
yses after installing them onto receptor moieties.4 The ex-
pected (1R,3R,4S)-configuration was verified.11 Since the
8-phenylmenthyl isocyanate 8c and its precursors did not
gave any suitable crystal for X-ray analysis, we converted
7c to the 4-nitrobenzoic amide (Scheme 3), which gave
excellent crystals for determining the solid state structure
(Figure 2). The anticipated – -interaction between the
phenyl and the 4-nitrophenyl system is not observed in the
crystal. In the solid state the electron poor nitro arene is
embedded by two cyclohexane moieties, which is most
likely caused by packing effects.
H2NOH.HCl,
NaOH, EtOH
N
Na/EtOH,
toluene, reflux
OH
NH2
O
R
R
R
5a: R = H
3a: 59 %
3b: 67 %
3c: 93 %
6a: 90 %
6b: 70 %
6c: 90 %
5b: R = CH3
5c: R = Ph
phosgene,
toluene, reflux
HCl/Et2O
NH3Cl
NCO
R
R
7a: 66 %
7b: 64 %
7c: 74 %
8a: 90 %
8b: 90 %
8c: 91 %
Scheme 2 Synthesis of (–)-menthylamines and their derivatives
O
4-nitrobenzoyl
chloride, NEt3
7c
N
H
NO2
the oximes followed by a Beauvault–Blanc reaction pro-
vided the amines 3a/c in good yields, but the transforma-
tion of the 8-methylmenthyloxime 6b required prolonged
reaction times. The individual amines 3 were formed as
single products when using sodium and alcohol as a re-
ductive mixture. Unfortunately, the conversion stops
when the resulting salts precipitate. Furthermore, apply-
ing larger amounts of sodium metal is difficult and dan-
gerous since encrustation of metallic material will occur.
Switching to other proton sources like tert-butanol, 2-pro-
panol or amyl alcohol did not ameliorate the problems.
The crude amines 3 were purified by vacuum distillation
wherein the corresponding oxime was reisolated. We
made efforts to substitute the Beauvault–Blanc reaction
by catalytic reductions. When 6b was treated with hetero-
geneous transition metal catalysts, like CoCl2–NaBH4,
NiCl2–NaBH4, PtO2–H2, Raney-Ni, or Pd/C–H2, either no
conversion was found or the corresponding amine 3b was
accompanied by an equal amount of a diastereomeric
amine. The separation of these epimeric amines did not
succeed on a preparative scale.
Ph
9: 87 %
Scheme 3
For the preparation of the isocyanates, the amines were
converted into the ammonium salts and subsequently
treated with phosgene. For analytical purposes, all ammo-
nium salts were recrystallized from dioxane, which ren-
dered a lower yield given in Scheme 2 as first crop.
Subsequent crops from the mother liquor indicated small
impurities and were not used further. For various reac-
tions and as a stable form for storage the solid hydrochlo-
rides turned out to be ideal and were consequently used
for detailed analytical studies. When applying the crude
ammonium salts to the phosgenation, a significantly high-
er yield was observed. All isocyanates 8b were colorless,
viscous liquids. The unusually high steric hindrance of the
nitrogen in the 8-methylmenthyl system is demonstrated
in the isocyanate 8b which reacts very slowly and is there-
fore less prone to hydrolysis.
Figure 2 Crystal structure of 9
When locating bulky groups in the vicinity of functional
groups and studying secondary interactions between these
systems a correct assignment of the individual NMR sig-
nals is crucial. Therefore, we performed a complete analy-
tical characterization by NMR including multi-
1
dimensional techniques. For the assignment of all H
NMR signals we started with the well-separated signal set
on C-1 and C-3, respectively. The combination of charac-
teristic coupling patterns and correlated spectra identified
the remaining signals. Heteronuclear correlation provided
a clear assignment for the 13C signals. Both, the functional
group in the 3-position and the substituent on the exocy-
clic moiety have a significant impact on the spectra. Con-
sequently, the corresponding multiplets differ strongly in
Synthesis 2003, No. 17, 2689–2694 © Thieme Stuttgart · New York

PAPER
Enantiomerically Pure Menthylamines and Their Isocyanates
Oxime Formation (6); General Procedure
2691
the chemical shifts as well as in their shape. A complete
set of correlated spectra is given in detail for 3a and 8a,
which can be exemplarily employed for the spectral as-
signment of the other compounds. Sufficient NMR reso-
lution was achieved on a 600 MHz instrument.
The menthone derivatives 5 (32 mmol) were dissolved in EtOH–
H2O (1:1, 80 mL). Hydroxylammonium chloride (6.67 g, 96 mmol)
and NaOH (7.68 g, 192 mmol) were added and the suspension was
stirred at 25 °C for 3–4 d. EtOH was removed under reduced pres-
sure and the mixture was diluted with H2O (50 mL) and extracted
with Et2O (4 × 100 mL). The combined organic layers were washed
with brine, dried (MgSO4) and concentrated under vacuum. The
crude products were purified by column chromatography yielding
colorless oils that form crystalline solids.
In conclusion, we developed reliable protocols for the
synthesis of (–)-menthylamine, (–)-8-methylmenthyl-
amine and the novel (–)-8-phenylmenthyl system. These
very bulky optically pure -chiral amines are readily ac-
cessible on a multi-gram scale, starting from (–)-mentho-
ne or (+)-pulegone, respectively. Furthermore, the
corresponding isocyanates were established as highly re-
active equivalents of these particular amines. For the first
(–)-(E)-(1R,4S)-Menthyl Oxime (5a)
Yield: 4.87 g (29 mmol, 90%); mp 55–57 °C; TLC Rf 0.54 (cyclo-
hexane–EtOAc, 8:2); [ ]58920 –39. 4, [ ]57820 –41.1, [ ]54620 –47.2,
[ ]43620 –84.1, [ ]36520 –140.9 (c 1.32, EtOH).
time, a comprehensive analytical study for this class of 1H NMR (400 MHz, CDCl3): = 0.91 (d, 3 H, 10-H, 3J = 6.8 Hz),
compounds was performed. NMR spectroscopy and X-
0.94 (d, 3 H, 9-H, 3J = 6.4 Hz), 0.98 (d, 3 H, 7-H, 3J = 6.8 Hz), 1.10–
1.20 (m, 1 H, 2-Ha), 1.32–1.41 (m, 1 H, 5-Ha), 1.64–1.94 (m, 5 H,
ray analysis gave a consistent stereochemical picture. All
2-He, 4-Ha, 5-He, 6-Ha, 6-He), 2.13 (m, 1 H, 8-H), 3.04–3.08 (m, 1
NMR signals for the primary amines 3 and its derivatives
H, 1-Ha), 9.46 [s(w), 1 H, NOH].
6–8 were assigned. The use of these particular auxiliaries
13C NMR (100 MHz, CDCl3): = 19.0 (C-10), 21.4 (C-7), 21.7 (C-
will be reported in due course.
9), 26.3 (C-8), 26.8 (C-5), 31.9 (C-1), 32.3 (C-2/-6), 32.8 (C-2/-6),
48.7 (C-4), 161.2 (C-3).
All reagents were used in analytical grades. Solvents were desiccat-
MS (EI, 70 eV): m/z (%) = 169.1 (14) [M+], 154.1 (15) [M+ – CH3],
ed if necessary by standard methods. Column chromatography was
127.0 (100) [M+ – C3H6], 110.1 (8) [127+ – OH], 95 (22) [127+ –
performed on silica gel (particle size 63–200 m, Merck, Darm-
NHOH].
stadt) using mixtures of cyclohexane and EtOAc as eluents. TLC
Anal. Calcd for C10H19NO (169.26): C, 70.96; H, 11.31; N, 8.28.
Found: C, 70.87; H, 11.35; N, 8.13.
was done on silica gel 60 F254 on glass (Merck, Darmstadt). Mps
were determined on a Melting Point Apparatus SMP3 (Stuart Sci-
entific, Watford Herts, UK) and were uncorrected. Microanalysis
was performed using a Vario EL III (Elementar-Analysensysteme,
Hanau). NMR spectra were recorded on a Bruker AMX 400 or on a
Varian 600 Unity Plus using TMS as internal standard or = 2.49
(+)-(E)-(1R,4S)-8-Methylmenthyl Oxime (6b)
Yield: 4.11 g (22 mmol, 70%); mp 45–47 °C; TLC Rf 0.42 (cyclo-
hexane–EtOAc, 9:1); [ ]58920 +11.4, [ ]57820 +12.0, [ ]54620 +13.6,
[ ]43620 +21.0, [ ]36520 +29.1 (c 1.50, EtOH).
for DMSO-d6 (GCOSY, Gradient-Selected COrrelation Spectros-
1H NMR (400 MHz, CDCl3): = 0.97 (d, 3 H, 7-H, 3J = 6 Hz), 1.02
(s, 9 H, 9-H), 1.05–1.12 (m, 1 H, 6-Ha), 1.36–1.46 (m, 1 H, 5-Ha),
1.61–1.84 (m, 3 H, 1-Ha, 2-Ha, 6-He), 1.91–2.01 (m, 2 H, 4-Ha, 5-
He), 3.06–3.11 (m, 1 H, 2-He), 8.39 [s(w), 1 H, NOH].
13C NMR (100 MHz, CDCl3): = 22.1 (C-7), 27.8 (C-5), 28.4 (C-
9), 32.9 (C-1), 33.0 (C-2), 34.1 (C-6), 36.8 (C-8), 52.8 (C-4), 161.6
(C-3).
copy; GHSQC, Gradient-Selected Heteronuclear Single Quantum
Coherence; GHMBC, Gradient-Selected Heteronuclear Multiple
Bond Correlation; APT, Attached Proton Test; DEPT, Distortion-
less Enhancement by Polarization Transfer). Mass spectra were ob-
tained on a MAT8200 (Finnigan-MAT, Bremen) employing EI and
on a QUATTRO LCZ (Waters-Micromass, Manchester) for ESI
(ES+). Optical rotary power was determined in a 10 cm cell on a
Polarimeter 341 (Perkin–Elmer GmbH, Überlingen).
MS (EI, 70 eV): m/z (%) = 183.2 (5) [M+], 168.1 (8) [M+ – CH3],
+
127.1 (100) [M+ – C4H8], 85.0 (32) [C6H13+], 57.0 (37) [C4H9 ].
8-Substituted Menthone Derivatives (5b/c); General Procedure
In a well dried flask equipped with condenser, dropping funnel and
argon inlet, magnesium turnings (4.2 g, 173 mmol) were placed and
the Grignard reagent was prepared in anhyd Et2O (60 mL) with me-
thyl iodide (24.5 g, 10.8 mL, 173 mmol) or bromobenzene (27.1 g,
18.0 mL, 173 mmol), respectively. Remaining pieces of magnesium
were removed by filtration under inert atmosphere. CuI (2.32 g, 12
mmol) was added to the chilled filtrate (0 °C) and stirred for 30 min.
After dropwise addition of (+)-pulegone (15.0 g, 99 mmol) in anhyd
Et2O (15 mL), the reaction mixture was stirred overnight and al-
lowed to warm up to r.t. At 0 °C, H2O (20 mL) was cautiously add-
ed, followed by sat. aq NH4Cl solution (78 mL) and concd aq HCl
(11 mL). The mixture was extracted with Et2O (3 × 100 mL). The
combined organic layers were washed with sat. aq Na2S2O3- and
NaHCO3-solution (each 2 × 200 mL), dried (MgSO4) and concen-
trated under reduced pressure. Purification by distillation under vac-
uum yielded colorless liquids.
Anal. Calcd for C11H21NO (183.29): C, 72.08; H, 11.55; N, 7.64.
Found: C, 71.97; H, 11.62; N, 7.43.
(–)-(E)-(1R,4S)-8-Phenylmenthyl Oxime (6c)
Yield: 7.07 g (29 mmol, 90%); mp 61–63 °C; TLC Rf 0.28 (cyclo-
hexane–EtOAc, 9:1); [ ]58920 –39.2, [ ]57820 –41.3, [ ]54620 –47.7,
[ ]43620 –90.4, [ ]36520 –164.9 (c 1.06, EtOH).
3
1H NMR (400 MHz, CDCl3): = 0.93 (d, 3 H, 7-H, J = 6.4 Hz),
0.94–0.98 (m, 1 H, 6-Ha), 1.31–1.37 (m, 1 H, 5-Ha), 1.41 (s, 3 H, 10-
H), 1.47 (s, 3 H, 9-H), 1.59–1.70 (m, 4 H, 1-Ha, 2-Ha, 5-He, 6-He),
2.53 (ddd, 1 H, 4-Ha, 3Jae = 5.6, 3Jaa = 10.6 Hz), 2.94–3.01 (m, 1 H,
2-He), 7.13–7.17 (m, 1 H, Ar-H), 7.24–7.36 (m, 4 H, Ar-H).
13C NMR (100 MHz, CDCl3): = 22.1 (C-7), 25.2 (C-10), 27.2 (C-
9), 27.9 (C-5), 32.5 (C-1), 32.8 (C-2), 33.8 (C-6), 40.3 (C-8), 52.4
(C-4), 125.4 (C-Ar), 125.9 (C-Ar), 127.8 (C-Ar), 150.0 (C-Ar),
160.9 (C-3).
(1R)-8-Methylmenthone (5b)8c,d
Yield: 7.16 g (43 mmol, 43%); bp 98–101 °C (29–31 mbar).
MS (EI, 70 eV): m/z (%) = 245.3 (9) [M+], 228.2 (21) [M+ – OH],
+
127.1 (51) [M+ – C9H10], 119.1 (100) [C6H5C(CH3)2 ], 91.1 (35)
+
+
[C7H7 ], 77.1 (4) [C6H5 ].
(1R)-8-Phenylmenthone (5c)8a,b
Yield: 16.4 g (71 mmol, 72%); bp 93 °C (1 × 10–2 mbar).
Anal. Calcd for C16H23NO (245.36): C, 78.32; H, 9.45; N, 5.71.
Found: C, 78.32; H, 9.52; N, 5.61.
Synthesis 2003, No. 17, 2689–2694 © Thieme Stuttgart · New York

2692
M. C. Schopohl et al.
PAPER
Reduction to (–)-Menthylamines (3); General Procedure
A 500 mL two-necked flask equipped with a metal condenser, argon
inlet and septum was charged with sodium (8.5 g, 368 mmol) and
anhyd toluene (200 mL). The mixture was refluxed for 15 min form-
ing a finely dispersed system to which the oxime 6 (18.4 mmol) was
injected as a toluene solution. After 15 min, EtOH (30 mL) was add-
ed dropwise. The reaction was monitored by GC and additional so-
dium and EtOH were added if necessary. After all metallic sodium
has been dissolved, the reaction mixture was acidified to pH 1 at
0 °C (caution!) using concd aq HCl. Subsequently, the solvents
were removed under reduced pressure. With NaOH-solution (20%)
the pH was adjusted to 12 and the aq layer was extracted with Et2O
(6 × 100 mL). After drying (NaOH), the organic layer was concen-
trated and purified by distillation yielding the amines 3 as colorless
oils. A higher boiling fraction consisted of the corresponding start-
ing materials 6.
1H NMR (600 MHz, CDCl3): = 0.82 (dddd, 1 H, 6-Ha, 3Jae = 3.6,
3
3
3Jaa = 12.6, Jaa = 13.2 Hz), 0.87 (d, 3 H, 7-H, J = 6.6 Hz), 0.88–
3
0.93 (m, 2 H, 2-Ha, 4-Ha), 0.97 (dddd, 1 H, 5-Ha, Jae = 3.6,
3Jaa = 13.2 Hz), 1.00 (s, 9 H, 9-H), 1.17 [s(w), 2 H, NH], 1.35–1.44
(m, 1 H, 1-Ha), 1.66 (dddd, 1 H, 6-He, 3Jee = 3, 3Jae = 3.6, 2J = 12.6
3
3
2
Hz), 1.71 (ddd, 1 H, 2-He, Jae = 3, Jae = 3.6, J = 12.6 Hz), 1.78
(dddd, 1 H, 5-He, 3Jee = 3, 3Jae = 3.6, 2J = 13.2 Hz), 2.63 (ddd, 1 H,
3-Ha, 3Jae = 3.6, 3Jaa = 10.2 Hz).
13C NMR (150 MHz, CDCl3): = 22.2 (C-7), 27.3 (C-5), 29.7 (C-
9), 31.9 (C-1), 33.1 (C-8), 35.3 (C-6), 48.1 (C-2), 53.3 (C-3/-4).
MS (EI, 70 eV): m/z (%) = 169.2 (7) [M+], 154.1 (7) [M+ – CH3],
112.1 (4) [C7H14N+], 95.0 (3) [112+ – NH3], 70.0 (100) [C5H10+],
+
57.0 (6) [C4H9 ].
Anal. Calcd for C11H23N (169.31): C, 78.03; H, 13.69; N, 8.27.
Found: C, 77.82; H, 13.65; N, 8.21.
(–)-(1R,3R,4S)-Menthylamine (3a)
(–)-(1R,3R,4S)-8-Phenylmenthylamine (3c)
Yield: 3.96 g (17.1 mmol, 93%); bp 92–96 °C (2 × 10–2 mbar);
Yield: 1.7 g (10.9 mmol, 59%); bp 74–77 °C (11–13 mbar);
[ ]58920 –35.7, [ ]57820 –37.1, [ ]54620 –41.9, [ ]43620 –67.6, [ ]365
20
[ ]58920 –26.9, [ ]57820 –27.8 (c 0.8, CHCl3).
–98.9 (c 1.39, CHCl3).
1H NMR (600 MHz, CDCl3): = 0.76 (m, 1 H, 2-Ha), 0.86 (d, 3 H,
7-H, 3J = 6.6 Hz), 0.89–0.97 (m, 1 H, 6-Ha), 1.10 (dddd, 1 H, 5-Ha,
3Jae = 3.6, 2J = 13.2, 3Jaa = 13.8 Hz), 1.21 (s, 3 H, 10-H), 1.38 (s, 3
H, 9-H), 1.39–1.42 (m, 1 H, 1-Ha), 1.62–1.65 (m, 1 H, 4-Ha), 1.66–
1.74 (m, 2 H, 2-He, 6-He), 1.82 (dddd, 1 H, 5-He, J = 3, J = 3.6,
2J = 13.2 Hz), 2.63 (ddd, 1 H, 3-Ha, 3Jae = 3.6, 3Jaa = 9.6 Hz), 7.14–
7.17, 7.28–7.31, 7.37–7.39 (m, 5 H, Ar-H).
1H NMR (600 MHz, CDCl3): = 0.78 (d, 3 H, 9-H, J = 6.6 Hz),
3
0.81–0.88 (m, 2 H, 2-Ha, 6-Ha), 0.89 (d, 3 H, 7-H, 3J = 6.6 Hz), 0.93
(d, 3 H, 10-H, 3J = 7.2 Hz), 0.94–0.99 (m, 2 H, 4-Ha, 5-Ha), 1.38–
1.46 (m, 1 H, 1-Ha), 1.60 (ddd, 1 H, 5-He, 3J = 3, 3J = 9.6 Hz), 1.68–
1.70 (m, 1 H, 6-He), 1.82–1.84 (m, 3 H, 2-He, NH), 2.09–2.14 (m, 1
H, 8-H), 2.53 (ddd, 1 H, 3-Ha, 3Jae = 4.2, 3J = 10.8 Hz).
3
3
13C NMR (150 MHz, CDCl3): = 15.3 (C-9), 21.2 (C-10), 22.3 (C-
7), 23.1 (C-5), 25.9 (C-8), 31.9 (C-1), 34.8 (C-6), 45.5 (C-2), 50.3
(C-4), 51.5 (C-3).
13C NMR (150 MHz, CDCl3): = 22.2 (C-7), 22.7 (C-9), 27.0 (C-
5), 30.6 (C-10), 31.9 (C-1), 35.3 (C-6), 39.9 (C-8), 46.7 (C-2), 53.2
(C-3), 54.2 (C-4), 125.3, 128.3, 152.9 (C-Ar).
GCOSY (600 MHz/600 MHz, CDCl3): (1H)/ (1H) = 0.78 (9-H)/
2.09–2.14 (8-H), 0.81–0.88 (2-Ha, 6-Ha)/0.94–0.99 (4-Ha, 5-Ha)/
1.60 (5-He), 1.68–1.70 (6-He)/1.82–1.84 (2-He, NH)/2.53 (3-Ha),
0.89 (7-H)/1.38–1.46 (1-Ha), 0.93 (10-H)/2.09–2.14 (8-H), 0.94–
0.99 (4-Ha, 5-Ha)/1.60 (5-He)/1.68–1.70 (6-He)/2.53 (3-Ha), 1.82–
1.84 (2-He, NH)/2.53 (3-Ha).
MS (EI, 70 eV): m/z (%) = 231.2 (26) [M+], 214.2 (94) [M+ – NH3],
+
199.1 (42) [C15H19+], 171.1 (41) [C13H15+], 91.0 (100) [C7H7 ], 77.0
+
(24) [C6H5 ].
Anal. Calcd for C16H25N (231.38): C, 83.06; H, 10.89; N, 6.05.
Found: C, 82.75; H, 11.00; N, 5.49.
GHSQC (150 MHz/600 MHz, CDCl3): (13C)/ (1H) = 15.3 (C-9)/
0.78 (9-H), 21.2 (C-10)/0.93 (10-H), 22.3 (C-7)/0.89 (7-H), 23.1
(C-5)/0.94–0.99 (4-Ha, 5-Ha)/1.60 (5-He), 25.9 (C-8)/2.09–2.14 (8-
H), 31.9 (C-1)/1.38–1.46 (1-Ha), 34.8 (C-6)/0.81–0.88 (2-Ha, 6-Ha)/
1.68–1.70 (6-He), 45.5 (C-2)/0.81–0.88 (2-Ha, 6-Ha)/1.82–1.84 (2-
He, NH), 50.3 (C-4)/0.94–0.99 (4-Ha, 5-Ha), 51.5 (C-3)/2.53 (3-Ha).
(–)-Menthylammonium Chlorides (7); General Procedure
The menthylamines 3 (40 mmol) were dissolved in anhyd Et2O (50
mL) and treated at 0 °C with HCl–Et2O (10 equiv). The resulting
solids were recrystallized from boiling 1,4-dioxane (80 mL) yield-
ing the products as colorless crystals. Only the first crop provided
analytically pure 7.
GHMBC (150 MHz/600 MHz, CDCl3): (13C)/ (1H) = 21.2 (C-
10), 25.9 (C-8), 50.3 (C-4)/0.78 (9-H), 23.1 (C-5), 31.9 (C-1), 34.8
(C-6), 50.3 (C-4), 51.5 (C-3)/0.81–0.88 (2-Ha, 6-Ha), 31.9 (C-1),
34.8 (C-6), 45.5 (C-2)/0.89 (7-H), 15.3 (C-9), 25.9 (C-8), 50.3 (C-
4)/0.93 (10-H), 34.8 (C-6), 50.3 (C-4)/0.94–0.99 (4-Ha, 5-Ha), 31.9
(C-1), 34.8 (C-6), 50.3 (C-4), 51.5 (C-3)/1.60 (5-He), 23.1 (C-5),
31.9 (C-1)/1.68–1.70 (6-He), 31.9 (C-1), 50.3 (C-4), 51.5 (C-3)/
1.82–1.84 (2-He, NH), 15.3 (C-9), 21.2 (C-10), 23.1 (C-5), 50.3 (C-
4), 51.5 (C-3)/2.09–2.14 (8-H), 23.1 (C-5), 45.5 (C-2), 50.3 (C-4)/
2.53 (3-Ha).
(–)-(1R,3R,4S)-Menthylammonium Chloride (7a)
20
Yield: 5.1 g (26.4 mmol, 66%); mp 187 °C (sublimation); [ ]589
–38.1, [ ]57820 –39.6, [ ]54620 –44.9, [ ]43620 –74.2, [ ]36520 –112.6
(c 0.99, MeOH).
1H NMR (600 MHz, DMSO-d6): = 0.71 (d, 3 H, 10-H, J = 6.6
3
Hz), 0.78 (dddd, 1 H, 6-Ha, 3J = 3, 2J = 12.6 Hz), 0.85 (d, 3 H, 7-H,
3J = 6.6 Hz), 0.86 (d, 3 H, 9-H, 3J = 6.6 Hz), 0.94 (dddd, 1 H, 5-Ha,
3J = 3, 2J = 12.6 Hz), 0.98 (ddd, 1 H, 2-Ha, 3Jaa = 12 Hz), 1.32–1.40
(m, 2 H, 1-Ha, 4-Ha), 1.57–1.64 (m, 2 H, 5-He, 6-He), 1.98–2.04 (m,
2 H, 2-He, 8-H), 2.81–2.84 (m, 1 H, 3-Ha), 8.19 [s(w), 3 H, NH].
APT (100 MHz, CDCl3): (CH/CH3) = 15.3 (C-9), 21.2 (C-10),
22.3 (C-7), 25.9 (C-8), 31.9 (C-1), 50.3 (C-4), 51.5 (C-3). (CH2/
Cq) = 23.1 (C-5), 34.8 (C-6), 45.5 (C-2).
MS (EI, 70 eV): m/z (%) = 155.1 (12) [M+], 140.1 (5) [M+ – CH3],
138.1 (5) [M+ – NH3], 127.0 (5) [M+ – C2H4], 98.0 (8) [140+ –
C3H6], 70.0 (100) [C5H10+].
13C NMR (150 MHz, DMSO-d6): = 15.6 (C-10), 21.1 (C-9), 22.1
(C-7), 22.5 (C-5), 25.0 (C-8), 30.9 (C-1), 33.8 (C-6), 39.7 (C-2),
45.4 (C-4), 51.0 (C-3).
MS (ESI): m/z (%) = 156.1 [M – Cl–].
Anal. Calcd for C10H22ClN (191.74): C, 62.64; H, 11.56; N, 7.31.
Found: C, 62.24; H, 11.49; N, 7.23.
Anal. Calcd for C10H21N (155.28): C, 77.35; H, 13.63; N, 9.02.
Found: C, 76.95; H, 13.69; N, 8.92.
(–)-(1R,3R,4S)-8-Methylmenthylammonium Chloride (7b)
20
(–)-(1R,3R,4S)-8-Methylmenthylamine (3b)
Yield: 5.3 g (25.6 mmol, 64%); mp 192 °C (sublimation); [ ]589
–26.6, [ ]57820 –27.9, [ ]54620 –31.5, [ ]43620 –52.8, [ ]36520 –81.4
Yield: 2.1 g (12.3 mmol, 67%); bp 98–102 °C (28–30 mbar);
[ ]58920 –47.4, [ ]57820 –49.5, [ ]54620 –56.2 (c 1.09, CHCl3).
(c 1.04, MeOH).
Synthesis 2003, No. 17, 2689–2694 © Thieme Stuttgart · New York

PAPER
Enantiomerically Pure Menthylamines and Their Isocyanates
2693
1H NMR (600 MHz, DMSO-d6): = 0.78 (dddd, 1 H, 6-Ha,
3Jae = 3.6, 3Jaa = 12.6, 3Jaa = 13.2 Hz), 0.85 (d, 3 H, 7-H, 3J = 6 Hz),
0.94 (s, 9 H, 9-H), 0.99 (dddd, 1 H, 5-Ha, 3Jae = 3.6, 3Jaa = 12.6 Hz),
1.04 (ddd, 1 H, 2-Ha, 3Jaa = 12 Hz), 1.29 (ddd, 1 H, 4-Ha, 3Jae = 3.6,
3Jaa = 12 Hz), 1.35–1.44 (m, 1 H, 1-Ha), 1.62 (dddd, 1 H, 6-He,
13C NMR (150 MHz, CDCl3): = 15.5 (C-10), 20.8 (C-9), 21.8 (C-
7), 23.2 (C-5), 27.1 (C-8), 31.8 (C-1), 34.1 (C-6), 44.7 (C-2), 49.3
(C-4), 56.3 (C-3), 121.9 (NCO).
GCOSY (600 MHz/600 MHz, CDCl3): (1H)/ (1H) = 0.72 (10-H)/
2.05 (8-H), 0.81 (6-Ha)/1.57 (5-Ha)/1.62 (6-He), 0.85 (7-H)/1.30–
1.38 (1-Ha)/1.62 (6-Ha)/2.01 (2-He), 0.86 (9-H)/2.02–2.08 (8-H),
0.90 (3-Ha)/1.11–1.16 (4-Ha)/1.57 (5-He), 1.09 (2-Ha)/1.30–1.38 (1-
Ha)/2.01 (2-He), 1.11–1.16 (4-Ha)/1.57 (5-He)/3.13 (3-Ha), 2.01 (2-
He)/3.13 (3-Ha).
GHSQC (150 MHz/600 MHz, CDCl3): (13C)/ (1H) = 15.5 (C-
10)/0.72 (10-H), 20.8 (C-9)/0.86 (9-H), 21.8 (C-7)/0.85 (7-H), 23.2
(C-5)/0.90 (5-Ha)/1.57 (5-He), 27.1 (C-8)/2.02–2.08 (8-H), 31.8 (C-
1)/1.30–1.38 (1-H), 34.1 (C-6)/0.81 (6-Ha)/1.62 (6-He), 44.7 (C-2)/
1.09 (2-Ha)/2.01 (2-He), 49.3 (C-4)/1.11–1.16 (4-Ha), 56.3 (C-3)/
3.13 (3-Ha).
2
3
3
3Jee = 3, J = 13.2 Hz), 1.78 (dddd, 1 H, 5-He, Jee = 3, Jae = 3.6,
3
2J = 13.8 Hz), 2.09 (ddd, 1 H, 2-He, Jae = 3.6, 2J = 12.6 Hz), 2.93
(ddd, 1 H, 3-Ha, 3J = 9 Hz), 8.08 [s(w), 3 H, NH].
13C NMR (150 MHz, DMSO-d6): = 21.9 (C-7), 26.5 (C-5), 29.0
(C-9), 30.8 (C-1), 32.8 (C-8), 34.2 (C-6), 41.1 (C-2), 49.4 (C-4),
52.0 (C-3).
MS (ESI): m/z = 170.1 [M – Cl–].
Anal. Calcd for C11H24ClN (205.77): C, 64.21; H, 11.76; N, 6.81.
Found: C, 64.02; H, 11.68; N, 6.69.
(–)-(1R,3R,4S)-8-Phenylmenthylammonium Chloride (7c)
GHMBC (150 MHz/600 MHz, CDCl3): (13C)/ (1H) = 20.8 (C-9),
27.1 (C-8), 49.3 (C-4)/0.72 (10-H), 23.2 (C-5), 31.8 (C-1)/0.81 (6-
Ha), 31.8 (C-1), 34.1 (C-6), 44.7 (C-2)/0.85 (7-H), 15.5 (C-10), 27.1
(C-8), 49.3 (C-4)/0.86 (9-H), 34.1 (C-6), 49.3 (C-4)/0.90 (5-Ha),
21.8 (C-7), 31.8 (C-1), 56.3 (C-3)/1.09 (2-Ha), 56.3 (C-3)/1.11–1.16
(4-Ha), 21.8 (C-7)/1.30–1.38 (1-Ha), 34.1 (C-6), 49.3 (C-4), 56.3
(C-3)/1.57 (5-He), 23.2 (C-5)/1.62 (6-He), 31.8 (C-1), 49.3 (C-4),
56.3 (C-3)/2.01 (2-He), 15.5 (C-10), 20.8 (C-9), 23.2 (C-5), 49.3 (C-
4), 56.3 (C-3)/2.02–2.08 (8-H), 27.1 (C-8), 44.7 (C-2), 49.3 (C-4)/
3.13 (3-Ha).
Yield: 7.93 g (29.6 mmol, 74%); mp 198 °C (sublimation);
[ ]58920 –18.3, [ ]57820 –19.1, [ ]54620 –21.6, [ ]43620 –34.7, [ ]365
20
–49.0 (c 1.02, MeOH).
1H NMR (400 MHz, DMSO-d6): = 0.60 (ddd, 1 H, 6-Ha,
3
3
3
3Jae = 2.8, Jaa = 12.4, Jaa = 12.8 Hz), 0.80 (d, 3 H, 7-H, J = 6.4
Hz), 0.90 (m, 1 H, 5-Ha), 1.05–1.15 (m, 2 H, 2-Ha, 5-He), 1.26 (s, 3
H, 9-H), 1.31–1.39 (m, 2 H, 1-Ha, 6-He), 1.44 (s, 3 H, 10-H), 1.96
(ddd, 1 H, 4-Ha, 3Jae = 2.8, 3Jaa = 11.6, 3Jaa = 13.2 Hz), 2.09 (ddd, 1
H, 2-He, 2J = 11.2 Hz), 3.09 (m, 1 H, 3-Ha), 7.13–7.17 (m, 1 H, Ar-
H), 7.26–7.30 (m, 4 H, Ar-H), 8.04 [s(w), 3 H, NH].
APT (100 MHz, CDCl3): (CH/CH3) = 15.5 (C-10), 20.8 (C-9),
21.8 (C-7), 27.1 (C-8), 31.8 (C-1), 49.3 (C-4), 56.3 (C-3). (CH2/
Cq) = 23.2 (C-5), 34.1 (C-6), 44.7 (C-2), 121.9 (NCO).
13C NMR (100 MHz, DMSO-d6): = 21.8 (C-7), 22.6 (C-9), 27.3
(C-5), 29.2 (C-10), 30.9 (C-1), 33.9 (C-6), 40.5 (C-2), 41.2 (C-8),
49.6 (C-4), 51.9 (C-3), 125.5, 125.7, 128.4, 150.8 (C-Ar).
MS (EI): m/z (%) = 181.2 (47) [M+], 166.2 (9) [M+ – CH3], 138.2
(20) [166+ – CO], 124.1 (88) [C9H16+], 95.1 (100) [C7H11+], 81.0
MS (ESI): m/z = 232.2 [M – Cl–].
+
+
(95) [C6H9 ], 55.1 (63) [C4H7 ].
Anal. Calcd for C16H26ClN (267.84): C, 71.75; H, 9.78; N, 5.23.
Found: C, 71.56; H, 9.62; N, 5.12.
Anal. Calcd for C11H19NO (181.27): C, 72.88; H, 10.56; N, 7.73.
Found: C, 72.51; H, 10.43; N, 7.62.
Phosgenation; General Procedure
(–)-(1R,3R,4S)-8-Methylmenthyl Isocyanate (8b)
The menthylammonium chlorides 7 (52 mmol) were suspended in
anhyd toluene (60 mL). The employed flask was equipped with a
condenser operating at –10 °C. A phosgene (25.7 g, 260 mmol) so-
lution in toluene (ca. 20%) was added through the condenser and the
suspension was refluxed until the mixture cleared (4–5 h). The so-
lution was concentrated to a third of its volume under reduced pres-
sure. Excess phosgene, hydrogen chloride and toluene were trapped
in a cooling device operating with liquid N2. Removal of the re-
maining toluene was done by distillation at ambient pressure. The
purification of the crude isocyanate can be performed by distillation
in vacuum yielding the isocyanates 8 as colorless oils.
20
Yield: 9.1 g (47 mmol, 90%); bp 120–123 °C (23 mbar); [ ]589
–59.4, [ ]57820 –62.0, [ ]54620 –70.4, [ ]43620 –119.9, [ ]36520 –188.6
(c 1.79, benzene).
1H NMR (600 MHz, CDCl3): = 0.79 (dddd, 1 H, 6-Ha, 3Jae = 3.6,
3Jaa = 12, 2J = 13.2 Hz), 0.84 (d, 3 H, 7-H, 3J = 6.6 Hz), 0.85–0.90
3
3
(ddd, 1 H, 5-Ha, Jae = 3.6, Jaa = 12 Hz), 0.92 (s, 9 H, 9-H), 1.06
(ddd, 1 H, 4-Ha, 3Jae = 3.6, 3Jaa = 10.8, 3Jaa = 12 Hz), 1.17 (ddd, 1 H,
2-Ha, 3Jaa = 12 Hz), 1.29–1.38 (m, 1 H, 1-Ha), 1.61 (dddd, 1 H, 6-He,
2
3
2
3Jae = 3.6, J = 13.2 Hz), 1.76 (dddd, 1 H, 5-He, J = 3.6, J = 13.2
Hz), 2.01 (dddd, 1 H, 2-He, 3Jae = 3.6, 2J = 12 Hz), 3.14 (ddd, 1 H,
3-Ha, 3Jae = 3.6, 3Jaa = 10.8 Hz).
Caution! The defrosting of the trapped contents should be per-
formed in the presence of ammonia. All glassware was treated thor-
oughly with ammonia in order to deactivate remaining phosgene.
13C NMR (150 MHz, CDCl3): = 21.6 (C-7), 26.5 (C-5), 28.8 (C-
9), 31.8 (C-1), 32.9 (C-8), 34.6 (C-6), 46.7 (C-2), 52.0 (C-4), 55.6
(C-3), 121.9 (NCO).
(–)-(1R,3R,4S)-Menthylisocyanate (8a)
MS (EI): m/z (%) = 195.2 (9) [M+], 180.1 (8) [M+ – CH3], 138.1 (4)
Yield: 8.48 g (47 mmol, 90%); bp 92–95 °C (12–13 mbar);
[ ]58920 –60.0, [ ]57820 –62.4, [ ]54620 –70.7, [ ]43620 –117.6,
[ ]36520 –178.6 (c 1.31, benzene).
1H NMR (600 MHz, CDCl3): = 0.72 (d, 3 H, 10-H, 3J = 6.6 Hz),
0.81 (dddd, 1 H, 6-Ha, 3J = 3, 2J = 12 Hz), 0.85 (d, 3 H, 7-H, 3J = 6.6
Hz), 0.86 (d, 3 H, 9-H, 3J = 7.2 Hz), 0.90 (dddd, 1 H, 5-Ha, 3J = 3,
2J = 13.2 Hz), 1.09 (ddd, 1 H, 2-Ha, 2J = 12 Hz), 1.11–1.16 (m, 1 H,
+
+
[M+ – C4H9 ], 96.1 (20) [C7H12+], 81.1 (18) [C7H12 – CH3], 57.1
+
(100) [C4H9 ].
Anal. Calcd for C12H21NO (195.30): C, 73.80; H, 10.84; N, 7.17.
Found: C, 73.84; H, 11.03; N, 7.12.
(–)-(1R,3R,4S)-8-Phenylmenthyl Isocyanate (8c)
Yield: 12.2 g (47 mmol, 91%); bp 108–112 °C (2–3 × 10–2 mbar);
3
4-Ha), 1.30–1.38 (m, 1 H, 1-Ha), 1.57 (dddd, 1 H, 5-He, J = 3,
20
[ ]58920 –32.2, [ ]57820 –33.5, [ ]54620 –37.8, [ ]43620 –61.1, [ ]365
3
2
2J = 13.2 Hz), 1.62 (dddd, 1 H, 6-He, J = 3, J = 13.2 Hz), 2.01
–88.7 (c 1.56, anhyd toluene).
3
2
(ddd, 1 H, 2-He, Jae = 3.6, J = 12 Hz), 2.02–2.08 (m, 1 H, 8-H),
3
1H NMR (600 MHz, CDCl3): = 0.83 (dddd, 1 H, 6-Ha, Jae = 3,
3.13 (ddd, 1 H, 3-Ha, 3Jae = 4.2, 3Jaa = 11.4 Hz).
3
3
3Jaa = 12, Jaa = 12.6 Hz), 0.87 (d, 3 H, 7-H, J = 6.6 Hz), 0.93
(dddd, 1 H, 5-Ha, 3Jae = 3, 3Jaa = 12.6, 2J = 13.2 Hz), 1.19 (ddd, 1 H,
2-Ha, Jaa = 11.4, Jaa = 12 Hz), 1.30 (s, 3 H, 9-/10-H), 1.32–1.40
3
3
Synthesis 2003, No. 17, 2689–2694 © Thieme Stuttgart · New York

2694
M. C. Schopohl et al.
PAPER
(m, 1 H, 1-H a), 1.42 (s, 3 H, 9-/10-H), 1.54–1.62 (m, 2 H, 5-He, 6-
reduction Denzo-SMN,12 absorption correction SORTAV,13 struc-
ture solution SHELXS-97,14 structure refinement SHELXL-97 (G.
M. Sheldrick, Universität Göttingen, 1997), graphics DIAMOND
V2.1c (Crystal Impact GbR).
He), 1.72 (ddd, 1 H, 4-Ha, 3Jae = 3, 3Jaa = 10.8 Hz), 2.02 (ddd, 1 H,
3
2
3
2-He, Jae = 3.6, J = 12.6 Hz), 3.16 (ddd, 1 H, 3-Ha, Jae = 4.2,
3Jaa = 10.8 Hz), 7.14–7.17, 7.29–7.33 (m, 5 H, Ar-H).
13C NMR (150 MHz, CDCl3): = 21.6 (C-7), 26.4, 26.7 (C-9/-10),
26.9 (C-5), 31.8 (C-1), 34.5 (C-6), 40.3 (C-8), 46.4 (C-2), 52.7 (C-
4), 55.5 (C-3), 125.4, 125.6, 128.0, 150.4 (C-Ar).
Crystallographic data (excluding structure factors) for the structures
reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication CCDC
215853. Copies of the data can be obtained free of charge on appli-
cation to: The Director, CCDC, 12 Union Road, Cambridge CB2
MS (EI): m/z (%) = 257.2 (9) [M+], 119.1 (100) [C6H5C(CH3)2 ],
+
+
+
91.1 (15) [C7H7 ], 77.0 (4) [C6H5 ].
1EZ,
UK
[fax:
+44(1223)336033,
e-mail:
depos-
Anal. Calcd for C17H23NO (257.37): C, 79.33; H, 9.01; N, 5.44.
Found: C, 79.20; H, 9.04; N, 5.43.
it@ccdc.cam.ac.uk].
(+)-N-[(1R,3R,4S)-8-Phenylmenthyl]-4-nitrobenzamide (9)
(–)-8-Phenylmenthylammonium chloride (7c) (600 mg, 2.24 mmol)
was dissolved in anhyd CH2Cl2 (30 mL) at 0 °C. Et3N (0.63 mL,
4.48 mmol) and p-nitrobenzoyl chloride (830 mg, 4.48 mmol) in an-
hyd CH2Cl2 (10 mL) were added and the solution was allowed to
warm up to r.t. overnight. Extraction with aq NaOH (2 M; 60 mL),
washing with brine (50 mL), drying (MgSO4) and concentration
yielded a yellow oil which was purified by column chromatography
(cyclohexane–EtOAc, 9:1 to 6:4), providing a pale yellow solid
(740 mg, 1.94 mmol, 87%). Crystals were obtained by evaporation
from a CH2Cl2–n-hexane mixture (1:8).
Acknowledgment
The work was supported by the Deutsche Forschungsgemeinschaft,
the State Nordrhein-Westfalen and the Sonderforschungsbereich
424. We particularly thank Prof. Dr. Dieter Hoppe for the fruitful
discussions and the support in this project.
References
(1) Seyden-Penne, J. Chiral Auxiliaries and Ligands in
Asymmetric Synthesis; Wiley Inter-Science: New York,
1995, 57–58.
(2) (a) James, B. R. Catal. Today 1997, 37, 209. (b) Denmark,
S. E.; Nicaise, O. J.-C. Chem. Commun. 1996, 999.
(c) Beak, P.; Zajdel, W. J.; Reitz, D. B. Chem. Rev. 1984, 84,
471. (d) Ellman, J. A. Pure Appl. Chem. 2003, 75, 39.
(3) Zhou, P.; Chen, B.; Davis, F. A. In Advances in Sulfur
Chemistry, Vol. 2; JAI Press: New York, 2000, 249–282;
and literature cited therein.
(4) Schopohl, M. C.; Siering, C.; Kataeva, O.; Waldvogel, S. R.
Angew. Chem. Int. Ed. 2003, 42, 2620.
(5) (a) Corey, E. J. Angew. Chem. Int. Ed. 2002, 41, 1650.
(b) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.;
Vassilikogiannakis, G. E. Angew. Chem. Int. Ed. 2002, 41,
1668.
(6) Hueckel, W.; Sommer, W. Liebigs Ann. Chem. 1965, 687,
102.
(7) (a) Feltkamp, H.; Koch, F.; Thanh, T. N. Liebigs Ann. Chem.
1967, 707, 78. (b) Cope, A. C.; Acton, E. M. J. Am. Chem.
Soc. 1958, 80, 355.
(8) (a) Ort, O. Org. Synth. 1987, 65, 203. (b) Fernández, F.;
García-Mera, X.; López, C.; Rodríguez-Borges, J. E.
Tetrahedron: Asymmetry 2000, 11, 4805. (c) Flemming, S.;
Kabbara, J.; Nickisch, K.; Neh, H.; Westermann, J. Synthesis
1995, 317. (d) Costello, D. P.; Geraghty, N. W. A. Synth.
Commun. 1999, 29, 3083.
(9) (a) Eck, J. C.; Marvel, C. S. Org. Synth., Coll. Vol. 2; Wiley:
London, 1943, 76. (b) Bousquet, E. W. Org. Synth., Coll.
Vol. 2; Wiley: London, 1943, 314.
Mp 157 °C; TLC Rf 0.38 (cyclohexane–EtOAc, 8:2); [ ]58920 +41.5,
[ ]57820 +44.7, [ ]54620 +55.0, [ ]43620 +136.6 (c 1.01, CH2Cl2).
1H NMR (400 MHz, CDCl3): = 0.84 (ddd, 1 H, 2-Ha, 3Jaa = 12.4
Hz), 0.89 (d, 3 H, 7-H, 3J = 6.4 Hz), 1.02 (dddd, 1 H, 6-Ha,
3
3Jae = 3.6, Jaa = 13.2 Hz), 1.14 (s, 3 H, 10-H), 1.32 (s, 3 H, 9-H),
1.34 (dddd, 1 H, 5-Ha, 3Jae = 3.6, 3Jaa = 13.2 Hz), 1.54–1.63 (m, 1 H,
1-Ha), 1.85 (dddd, 1 H, 6-He, 3Jae = 3.6, 2J = 12.8 Hz), 2.01 (ddd, 1
H, 2-He, 3Jae = 3.6, 2J = 12 Hz), 2.07–2.13 (m, 2 H, 4-Ha, 5-He), 4.01
(ddd, 1 H, 3-Ha, 3Jae = 3.6, 3Jaa = 11.2, 3Ja,NH = 8.8 Hz), 5.29 (d, 1 H,
3
NH, J = 8.8 Hz), 7.01–7.09 (m, 3 H, 14-H, 17-H), 7.18 (dd, 2 H,
13-H, 3J13,12/14 = 7.6 Hz), 7.32 (d, 2 H, 12-H, 3J12,13 = 7.6 Hz), 8.02
(d, 2 H, 18-H, 3J18,17 = 8.4 Hz).
13C NMR (100 MHz, CDCl3): = 20.2 (C-9), 21.8 (C-7), 26.8 (C-
5), 31.6 (C-10), 32.2 (C-1), 35.0 (C-6), 39.7 (C-8), 43.5 (C-2), 50.0
(C-4), 51.8 (C-3), 123.0 (C-18), 125.0 (C-12), 125.3 (C-14), 127.7
(C-17), 129.0 (C-13), 139.4 (C-16), 149.1 (C-19), 153.1 (C-11),
162.9 (C-15).
MS (EI): m/z (%) = 380.2 (4) [M+], 262.1 (39) [M+ – C9H11+], 167.1
+
+
+
(27) [O2NC6H4CONH3 ], 119.1 [C6H5C(CH3)2 ], 91.1 (17) [C7H7 ].
Anal. Calcd for C23H28N2O3 (380.48): C, 72.60; H, 7.42; N, 7.36.
Found: C, 72.50; H, 7.20; N, 7.34.
X-Ray Crystal Structure Analysis
C23H28N2O3:
colorless
crystals,
crystal
dimension
0.40 × 0.40 × 0.30 mm3; M = 380.48; orthorhombic, space group
P212121 (No. 19); a = 9.674(1), b = 9.762(1), c = 22.502(1) Å,
V = 2125.0(3) Å3, Z = 4, = 1.54178 Å, T = 223 K, calc = 1.189 g
(10) Despite the analytical purity and different ways to produce
the crystalline material, our melting point was 35 °C below
the reported datum in the reference.6
(11) The stereochemical assignment refers to the systematic
numbering of the menthane skeleton and corresponds to
(1R,2S,5R)-cyclohexylamine.
(12) Otwinowski, Z.; Minor, W. Methods in Enzymology 1997,
276, 307.
(13) (a) Blessing, R. H. Acta Cryst. 1995, A51, 33. (b) Blessing,
R. H. J. Appl. Cryst. 1997, 30, 421.
cm–3, = 6.29 cm–1, empirical absorption correction (0.787
T
0.834), and scans, 10713 reflections collected ( h, k, l),
[(sin )/ ] = 0.59 Å–1, 3564 independent (Rint = 0.043) and 3009 ob-
served reflections [I
2 (I)], 260 refined parameters, R = 0.038,
wR2 = 0.094, max. residual electron density 0.25 (–0.20) eÅ–3,
Flack parameter 0.2(3), hydrogen atom at N17 from difference Fou-
rier map, refined free with isotropic thermal displacement parame-
ter, other hydrogen atoms calculated and refined as riding atoms.
Data set was collected with Nonius KappaCCD diffractometer. Pro-
grams used: data collection COLLECT (Nonius B.V., 1998), data
(14) Sheldrick, G. M. Acta Cryst. 1990, A46, 467.
Synthesis 2003, No. 17, 2689–2694 © Thieme Stuttgart · New York