Efficient and stereodivergent electrochemical synthesis of optically pure menthylamines

Article abstract of DOI:10.1002/anie.201101330

The cathode directs the way to the epimeric menthylamines. The reduction of menthone oxime on a Hg cathode generates (-)-menthylamine as the major product, whereas a Pb cathode gives access to (+)-neomenthylamine (see scheme). Insitu decoration of the Pb cathode by small amounts of additives results in clean and quantitative conversions. Furthermore, Pb corrosion is completely prevented in this practical method. Copyright

Full text of DOI:10.1002/anie.201101330

Communications
DOI: 10.1002/anie.201101330
Electrochemical Amine Synthesis
Efficient and Stereodivergent Electrochemical Synthesis of Optically
Pure Menthylamines**
Jꢀrn Kulisch, Martin Nieger, Florian Stecker, Andreas Fischer, and Siegfried R. Waldvogel*
Dedicated to Professor Dieter Hoppe on the occasion of his 70th birthday
Enantiomerically enriched amines with stereogenic informa-
tion at the a position to the primary amino group represent an
important class of compounds. They serve as building blocks
in the synthesis of drug molecules,[1] as auxiliaries,[2] and as
ligands for homogeneous catalysis.[3] Many a-chiral amines
Scheme 1. Steric influence on the amino group in a-chiral primary
amines.
are derived from the chiral pool, for example, amino alcohols,
or are made synthetically, such as phenethylamines.[1a,4]
Compared to these a-chiral amines, terpene-derived primary
amines have attracted little attention; only fenchyl, bornyl,
and dehydroabietylamine are widely available and have been
used in applications.[5] While menthol and 8-substituted
congeners play a significant role in stereoselective synthesis,[6]
the corresponding menthylamines have only rarely been
utilized. Their poor availability has resulted in them being an
almost neglected class of chiral amines.[2]
The unique character of menthylamines is expressed by
the strong influence of the substituent close to the amino
group and leads to a superb transfer of stereogenic informa-
tion. Compared to simple a-chiral amines 1, for example,
phenethylamines, a stronger steric effect on the amino moiety
is created in cyclohexylamine 2 (Scheme 1). A prominent
example is represented by trans-2-phenylcyclohexylamine
(2a), in which a significant influence of the Ph group on the
functional group exists because of the conformational rigidity.
The synthesis of 2a requires a multistep synthesis, including
resolution of a racemic intermediate in most cases.[7] Inter-
estingly, the cis diastereomer of 2a has found application in
the construction of inhibitors for the glycine transporter I.[8]
The additional substituent R in 3 leads to enhanced con-
formational stability and even stronger steric influence
around the amino function. Appropriate functional groups
R result in a molecular U turn.
Optically pure menthylamines have found applications as
structural elements of supramolecular receptors suitable for
enantiofacial discrimination[9] and show efficient binding of
electron-deficient aromatic compounds, such as caffeine and
1,3,5-trinitrotoluene (TNT).[10,11] (+)-Neomenthylamine has
been used as a building block for a stationary phase for high-
performance column chromatography.[12–15] This stationary
phase was used for the racemic resolution of a cervastatin
precursor.[16,17] Some menthylamides, such as the cyclopropa-
necarboxamide of (+)-neomenthylamine, also show a strong
umami taste.[18]
All the synthetic pathways to menthylamines rely on
terpenoic starting materials such as (À)-menthone. Optically
enriched (À)-menthone is available from natural sources and
its reductive amination leads to the synthesis of menthyl-
amines. An isomeric mixture of all the menthylamines (3a–
3c) is obtained under Leuckart–Wallach conditions.[19] An
alternative approach is the reduction of the corresponding
oxime 4 to the amine. A Bouveault–Blanc reduction was
established, which led to the desired amines in good yields
and suitable diastereoselectivities (Scheme 2).[20] The draw-
back of this method is the necessity of 30 equivalents of
sodium metal. The potential hazard and low atom efficiency
thus necessitates a new and innovative approach. Further-
more, both 3a and 3b are needed for applications. We report
here a novel electrochemical method which can be used as a
stereodivergent synthesis. A related approach was demon-
strated for the electrochemical reduction of isomeric men-
thones.[21]
[*] Dr. J. Kulisch, Prof. Dr. S. R. Waldvogel
Kekulꢀ Institute for Organic Chemistry and Biochemistry
Bonn University
Gerhard-Domagk-Strasse 1, 53121 Bonn (Germany)
Dr. M. Nieger
Laboratory of Inorganic Chemistry
University of Helsinki
00014 Helsinki (Finland)
Dr. F. Stecker, Dr. A. Fischer
BASF SE, GCI/E—M311, 67056 Ludwigshafen (Germany)
Prof. Dr. S. R. Waldvogel
Institute for Organic Chemistry
Johannes-Gutenberg University Mainz
Duesbergweg 10–14, 55128 Mainz (Germany)
E-mail: waldvogel@uni-mainz.de
[**] Support from SFB 813 “Chemistry at Spin Centers” (DFG) and
BASF SE is highly appreciated.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201101330.
Scheme 2. Potential stereoisomers on reduction of (À)-menthone
oxime.
5564
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 5564 –5567

rearrangement of this substrate[25] was not detected under
these conditions. The pronounced selectivity obtained by
direct reduction on a metal surface can be attributed to the
formation of a covalently bound intermediate in such a
transformation (see the Supporting Information).[26]
Table 1: Screening for cathode materials.
Entry
Cathode
Current
density
Yield [%]
Faradaic
yield [%]
d.r.
3a/3b
[mAcmÀ2
]
1[a]
2[b]
3[b]
4[b]
5[b]
Hg
Cd
Pb
Pb/5% Cu
BDD
46
25
25
25
31
68
40
66
41
<2
24
31
11
16
<1
2.4:1
2.7:1
1.0:1
1.5:1
3.4:1
The corrosion commonly found when lead is used as the
cathode material can be explained by the anticipated lead
intermediates on the cathode surface. The formation of a
white precipitate (PbSO4) over the course of the electrolysis
confirms this undesired side reaction. Although sulfuric acid
is a strong electrolyte, the addition of a small quantity of a
tetraalkylammonium salt improves the situation dramatically
(Table 3). The conversions are clean and with a slight
preference for the epimer 3b. The small and relatively rigid
cations 5–8 effect almost quantitative conversions (Table 3,
entries 1–4). Changing the counterions had no influence on
the efficiency and the stereoselectivity (see the Supporting
Information). Of the additives tested, the best result was
obtained with triethylmethylammonium methylsulfate (6),
which is environmentally benign and the least expensive
additive (Table 3, entry 2). The yield of the isolated product in
the absence of an additive is only 88%, but it is formed with a
comparable stereoselectivity (Table 3, entry 5). However,
[a] Conditions: catholyte 0.5m H2SO4 in MeOH/H2O 1:1, 208C. [b] Con-
ditions: catholyte 0.5m H2SO4 in DME/H2O 6:1, 208C. DME=1,2-
dimethoxyethane.
Oximes are most reliably reduced in acidic media.[22] The
À
cleavage of the N O bond represents the first part of the
sequence (for the mechanistic rationale, see the Supporting
Information). Since the evolution of molecular hydrogen is a
strongly competing reaction, specific attention was given to
the cathode material. An extensive screening of potential
cathode materials showed the desired transformation was
only possible on metals exhibiting a high overpotential for the
evolution of molecular hydrogen (see the Supporting Infor-
mation). A selection of optimized conditions is displayed in
Table 1. The use of mercury or cadmium as the cathodes
resulted in a pronounced selectivity for (À)-menthylamine
(3a; Table 1, entries 1 and 2), whereas lead or a copper/lead
alloy gave either no selective transformation or only a slight
preference for 3a (Table 1, entries 3 and 4). Recently, boron-
doped diamond (BDD) electrodes were used successfully for
the reduction of oximes.[23,24] Although a high stereoselectiv-
ity was found with the BDD cathode, only traces of menthyl-
amines could be isolated, because of a low conversion
(Table 1, entry 5). Thus, this electrode material was not
considered further.
Table 3: Quaternary ammonium salts as additives for the reduction on a
lead cathode.
Entry
Additive
[0.5%]
Yield [%]
Faradaic
yield [%]
d.r. 3a/3b
1[a]
>99
>99
40
41
0.8:1
0.6:1
2[a]
Mercury turned out to be the best cathode material in
respect to stereoselectivity, but it exhibits a strong temper-
ature dependence (Table 2). Menthylamine is favored at low
temperature, but the chemical yield of the isolated product
could not be increased above 76%. Only moderate current
densities could be applied because of the slow mass transport
between the bulk phase and the electrode surface (Table 2,
entries 1 and 2). Higher temperatures resulted in the stereo-
selectivity for 3a dropping; the best conversion was obtained
at 08C (Table 2, entry 3). A further increase in the electrolysis
temperature caused a decrease in the yield, since hydrolysis of
the oxime occurred (Table 2, entries 4 and 5). Beckmann
3[a]
>99
40
0.7:1
4[a]
5[a]
6[a]
99
88
78
40
36
31
0.8:1
0.6:1
0.5:1
–
7[a]
89
33
36
14
0.6:1
0.9:1
Table 2: Effect of temperature on the reduction of menthone oxime on a
mercury cathode.
8[a]
Entry
T [8C] Current
density
Yield [%] Faradaic yield [%] d.r.
3a/3b
[mAcmÀ2
]
9[b]
>99
>99
41
41
0.5:1
0.3:1
1[a]
2[b]
3[a]
4[a]
5[a]
À14–À18 23
À10 10
46
56
76
86
68
17
34
31
56
24
16
3.8:1
4.1:1
2.4:1
2.4:1
2.0:1
10[c]
0
20 46
50 51
[a] Conditions: catholyte 2% H2SO4 in MeOH, 208C. [b] Conditions:
catholyte 2% H2SO4 in MeOH, 08C. [c] Conditions: catholyte 2% H2SO4
in MeOH, À108C.
[a] Conditions: catholyte 0.5m H2SO4 in DME/H2O 1:1. [b] Conditions:
catholyte 2% H2SO4 in DME with 10% H2O.
Angew. Chem. Int. Ed. 2011, 50, 5564 –5567
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5565

Communications
Table 4: Polycationic ammonium salts as additives for the reduction on
lead cathode.
preventing the undesired lead corrosion makes the use of
additives attractive from a technical point of view.
The addition of either more lipophilic or hydrophilic
cations does not improve the situation significantly (Table 3,
entries 6–8). Small cations which are capable of forming a
compact salt layer seem to efficiently block the access of
protons to the cathode surface. This prevents the drain of
electric current by evolution of molecular hydrogen. More
lipophilic cations (9 and 10) might form a softer decoration
(Table 3, entries 6 and 7). The strongly hydrated cation of 11
allows fast access of the protons to the lead electrode and
causes inferior results (Table 3, entry 8). A further parameter
for tuning the selectivity towards 3b is the electrolysis
temperature (Table 3, entries 9 and 10). Lowering the tem-
perature to 08C already improves the diastereomeric ratio.
When the electrolysis is performed at À108C the yield is still
excellent, but the generated amine contains almost 75% (+)-
neomenthylamine (3b; Table 3, entry 10). The use of even
lower temperatures results in no further benefit (see the
Supporting Information).
In the absence of additive the transformation is not clean
and a mixture of several products is obtained (Figure 1a). In
contrast, decoration by these additive cations results in the
formation of the compact salt layer and effects a smooth
electrochemical transformation (Figure 1b). A significant
amount of menthylimine is formed which can undergo
hydrolysis to menthone. After the calculated current of
4 Faradays per oxime, 88% of menthylamine is formed. The
conversion is complete after an additional 2 Faradays of
current, which facilitates the workup tremendously. The best
results allow more than 99% conversion to the product with a
current efficiency of 66%.
Entry Additive
Conc
[%]
Yield Faradaic
[%] yield [%]
d.r.
3a/3b
1[a]
0.5
>99 40
1.0:1
2[a]
3[a]
4[a]
5[a]
<0.1
96
39
0.6:1
0.6:1
0.6:1
0.6:1
0.5 + 10%
H2O
>99 40
>99 40
>99 40
<0.1
0.5 + 10%
H2O
6[a]
!0.1
>99 40
0.5:1
0.6:1
0.5 + 20%
H2O
7[a]
84
34
[a] Conditions: catholyte 2% H2SO4 in MeOH, 208C, 12.5 mAcmÀ2
.
Similar to chelating effects, polycationic species should
enhance the decoration of the cathode. The dicationic salt 12
obtained from the Baizer process[27,28] shows the anticipated
effect. Although 12 comprises approximately two subunits of
9, the oxime reduction is quantitative (Table 4, entry 1).
Remarkably, the electrolysis conditions result in a completely
unselective menthylamine. We synthesized harder oligo(me-
thylammonium) derivatives by standard methods (see the
Supporting Information) and tested them in this cathodic
process to elucidate the power of the concept. The yield is
slightly decreased, but a preference for 3b is observed
(Table 4, entry 2) when the amount of additive 13 is present
in the electrolyte at less than 0.1% by weight. The use of a
little more of the additive 13 allows the electrolysis to be
carried out in the presence of 10% water without affecting the
excellent performance (Table 4, entry 3). Tricationic additive
14 can be used in the presence of water or concentrations of
far less than 0.1% (Table 4, entries 4 and 5).[29] An additive
with four quaternary ammonium moieties exhibits an even
higher performance. The solubility of 15 in acidic methanol is
very poor but the amount is sufficient to decorate the cathode
with high efficiency (Table 4, entry 6). A clear solution with
0.5% additive is achieved with a water content of 20%. The
performance is decreased under these conditions but still
much better than without additive (Table 4, entry 7).
The formation of a compact salt layer is evident from two
major findings: The reduction is not stereoselective at
ambient conditions since the contact to the electrode surface
is missing, but, most importantly, the corrosion of the lead
cathode is completely avoided. The electrodes stay intact with
a shiny surface and no lead sulfate is formed.
Figure 1. Menthyl derivatives monitored during the course of the
&
electrolysis. a) Without additive; b) with 0.5% 6 ( : menthylamines 3a
*
and 3b; : menthylimine; ꢁ: menthone oxime 4).
5566
www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 5564 –5567

[4] a) A. S. Bommarius, M. Schwarm, K. Stingl, M. Kottenhahn, K.
Huthmacher, K. Drauz, Tetrahedron: Asymmetry 1995, 6, 2851 –
2888.
[5] a) G. M. Rishton, D. M. Retz, P. A. Tempest, J. Novotny, S.
Kahn, J. J. S. Treanor, J. D. Lile, M. Citron, J. Med. Chem. 2000,
43, 2297 – 2299; b) M. Yildirim, H. C. Wals, B. J. Van Vliet,
J. H. M. Lange, PCT Int. Appl. WO 2008152086A2, 2008;
c) P. H. Boyle, Q. Rev. 1971, 25, 323 – 341; d) I. M. Malkowsky,
M. Nieger, O. Kataeva, S. R. Waldvogel, Synthesis 2007, 773 –
778.
[6] H. Oertling, A. Reckziegel, H. Surburg, H.-J- Bertram, Chem.
Rev. 2007, 107, 2136 – 2164.
Scheme 3. Separation of diastereomeric menthylamines by exploiting
the different solubility of the hydrochlorides.
[7] a) C. M. Nachtsheim, A. W. Frahm, Arch. Pharm. 1989, 322,
187 – 197; b) G. Knupp, A. W. Frahm, Chem. Ber. 1984, 117,
2076 – 2098; c) A. G. Schultz, M. Macielag, D. E. Podhorez, J. C.
Suhadolnik, R. K. Kullnig, J. Org. Chem. 1988, 53, 2456 – 2464;
d) N. Welschoff, S. R. Waldvogel, Synthesis 2010, 3596 – 3601.
[8] E. Pinard, S. M. Ceccarelli, H. Stalder, D. Alberati, Bioorg. Med.
Chem. Lett. 2006, 16, 349 – 353.
[9] M. C. Schopohl, C. Siering, O. Kataeva, S. R. Waldvogel, Angew.
Chem. 2003, 115, 2724 – 2727; Angew. Chem. Int. Ed. 2003, 42,
2620 – 2623.
[10] M. Bomkamp, C. Siering, K. Landrock, H. Stephan, R. Frꢂhlich,
S. R. Waldvogel, Chem. Eur. J. 2007, 13, 3724 – 3732.
[11] R. Orghici, U. Willer, M. Gierszecwska, S. R. Waldvogel, W.
Schade, Appl. Phys. B 2008, 90, 355 – 360.
[12] R. Grosser, W. Lange, B. Boehmer, D. Arlt, D. Bielefeldt, Ger.
Offen. DE 40 21 108A1, 1990.
The separation of the epimers 3a and 3b can be
performed by chromatographic means (see the Supporting
Information). This is not practical since it is very time
consuming and costly. After conversion into the correspond-
ing hydrochlorides 16a and 16b, respectively, the different
solubility in tert-butylmethylether can be exploited for a
viable separation (Scheme 3, for details see the Supporting
Information). Starting from a 1:1 ratio of diastereomers, a
35% yield of 16a with a stereochemical purity of 90% is
obtained. By this approach, 16b can be obtained in a highly
isomerically enriched manner. Both hydrochlorides are ideal
derivatives for storage.
In conclusion, we have found a reliable method for the
electrochemical synthesis of menthylamines from menthone
oxime. The cathodic conversion on the mercury pool provides
a selective reduction to (À)-menthylamine. When lead is used
as the cathode material it can be decorated with a small
amount of quaternary ammonium salts, which allows quanti-
tative conversions and prevents corrosion of the toxic cathode
metal. The stereoselectivity can be shifted to the technically
relevant (+)-neomenthylamine by lowering the electrolysis
temperature. In addition, a very practicable way for the
separation of the epimeric menthylamines has been estab-
lished. These unique optically pure amines are highly
accessible by using this stereodivergent process and will find
future applications. Moreover, a novel concept for the
cathodic use of lead has been found which could eliminate
concerns of employing it as an electrode material. This will
open up a new possibility for sustainable reductions by
electrosynthesis.
[13] M. Grosse-Bley, B. Bꢂmer, R. Grosser, D. Arlt, W. Lange, Ger.
Offen. DE 41 20 695A1, 1991.
[14] M. Grosse-Bley, B. Bꢂmer, R. Grosser, W. Lange, F. P. Hoever,
D. Arlt, Ger. Offen. DE 42 21 711A1, 1992.
[15] B. Bꢂmer, R. Grosser, W. Lange, U. Zweering, B. Koehler, W.
Sirges, M. Grosse-Bley, Ger. Offen. DE 195 46 136A1, 1995.
[16] W. Lange, R. Grosser, B. Kꢂhler, S. Michel, U. Zweering, B.
Bꢂmer, Ger. Offen. DE 197 14 343A1, 1997.
[17] R. Angerbauer, R. Grosser, W. Hinsken, J. Rehse, Eur. Pat.
Appl. EP 0 617 019A1, 1994.
[18] J. Looft, T. Vꢂssing, J. Ley, M. Backes, M. Blings, Eur. Pat. Appl.
EP 1 989 944A1, 2008.
[19] O. Wallach, Ber. Dtsch. Chem. Ges. 1891, 24, 3992 – 3993.
[20] M. C. Schopohl, K. Bergander, O. Kataeva, R. Frꢂhlich, S. R.
Waldvogel, Synthesis 2003, 2689 – 2694.
[21] N. D. Zubavera, A. A. Vedenyapin, E. I. Klabunovskii, Russ. J.
Appl. Chem. 2009, 82, 1234 – 1237.
[22] J. Tafel, E. Pfeffermann, Ber. Dtsch. Chem. Ges. 1902, 35, 1510 –
1518.
[23] U. Griesbach, D. Zollinger, H. Pꢀtter, C. Comminellis, J. Appl.
Electrochem. 2005, 35, 1265 – 1270.
[24] S. R. Waldvogel, S. Mentizi, A. Kirste, Top. Curr. Chem. 2011,
DOI: 10.1007/128_2011_125.
[25] N. Komatsu, S. Simizu, T. Sugita, Synth. Commun. 1992, 22, 277 –
279.
Received: February 22, 2011
Published online: May 12, 2011
Keywords: amines · cations · chiral pool · electrochemistry · lead
[26] A. J. Fry, J. H. Newberg, J. Am. Chem. Soc. 1967, 89, 6374.
[27] The compound was provided by BASF SE. The corresponding
bisulfate is formed immediately in the electrolyte.
[28] a) H. Pꢀtter in Organic Electrochemistry, 4th ed. (Eds.: H. Lund,
O. Hammerich), Marcel Dekker, New York, 2001, pp. 1259 –
1308; b) D. Sopher, A. Gieseler, H. Hibst, K. Harth, Ger.
Offen. DE 43 19 951A1, 1993; c) M. M. Baizer, J. Electrochem.
Soc. 1964, 111, 215 – 222; d) M. M. Baizer, C. R. Campbell, R. H.
Fariss, R. Johnson, U.S. Patent 3 193 480, 1965; e) M. M. Baizer,
U.S. Patent 3 250 690, 1960.
.
[1] a) M. Breuer, K. Ditrich, T. Habicher, B. Hauer, M. Keßeler, R.
Stꢀrmer, T. Zelinski, Angew. Chem. 2004, 116, 806 – 843; Angew.
Chem. Int. Ed. 2004, 43, 788 – 824; b) U. Kraatz, G. Hꢁnssler,
Eur. Pat. Appl. EP 0 341 475A2, 1989.
[2] J. Seyden-Penne, Chiral Auxiliaries and Ligands in asymmetric
Synthesis, Wiley, New York, 1995.
[3] a) S. Hashiguchi, A. Fujii, J. Takehara, T. Ikariya, R. Noyori,
J. Am. Chem. Soc. 1995, 117, 7562 – 7563; b) A. Fujii, S.
Hashiguchi, N. Uematsu, T. Ikariya, R. Noyori, J. Am. Chem.
Soc. 1996, 118, 2521 – 2522.
[29] Compound 14 is poorly soluble in 2% sulfuric acid in methanol
and, therefore, the concentration might be less than 0.01%.
Angew. Chem. Int. Ed. 2011, 50, 5564 –5567
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5567