Synthesis of cis-TMCDA: Optimization and characterization of a key intermediate

Article abstract of DOI:10.1016/j.ica.2011.06.008

We report optimized synthetic procedures to cis-TMCDA and cis-cyclohexane-1,2-diamine. Our new two-step approach is an efficient and low-cost method for synthesizing the ligand cis-TMCDA. In the preparation of cis-cyclohexane-1,2-diamine, the crystallization of the unexpected intermediate cis-cyclohexane-1,2-diammonium hydrogensulfate ethylsulfate made the subsequent reactions easier in their workup, as nickel(II) chloride impurities were eliminated.

Full text of DOI:10.1016/j.ica.2011.06.008

Inorganica Chimica Acta 376 (2011) 634–637
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Inorganica Chimica Acta
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Note
Synthesis of cis-TMCDA: Optimization and characterization of a key intermediate
⇑
Prisca K. Eckert, Verena Schill, Carsten Strohmann
Anorganische Chemie, TU Dortmund, Otto-Hahn-Str. 6, 44227 Dortmund, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
We report optimized synthetic procedures to cis-TMCDA and cis-cyclohexane-1,2-diamine. Our new
two-step approach is an efficient and low-cost method for synthesizing the ligand cis-TMCDA. In the
preparation of cis-cyclohexane-1,2-diamine, the crystallization of the unexpected intermediate cis-
cyclohexane-1,2-diammonium hydrogensulfate ethylsulfate made the subsequent reactions easier in
their workup, as nickel(II) chloride impurities were eliminated.
Received 3 February 2011
Received in revised form 25 May 2011
Accepted 2 June 2011
Available online 13 June 2011
Ó 2011 Elsevier B.V. All rights reserved.
Keywords:
cis-Tetramethylcyclohexane-1,2-diamine
cis-Cyclohexane-1,2-diamine
Ligands
Nickel
1. Introduction
tms]: Bruker DPX 300 (300.1 MHz), Bruker DRX 400 (400.1 MHz),
Bruker DRX 500 (500.1 MHz), Varian Inova 500 (499.8 MHz). 13C
Chiral diamines such as tetramethylcyclohexane-1,2-diamine
(TMCDA) are useful ligands for asymmetric synthesis [1–3]. The
C2-symmetrical diastereomer (R,R)-TMCDA, an important ligand
in organolithium chemistry [4–6] is easily obtained from a mixture
of cis–trans-cyclohexane-1,2-diamine (1) via the tartrate salt of
(R,R)-cyclohexane-1,2-diamine [7]. (R,S)- or cis-TMCDA, the
meso-form, can be synthesized from cyclohexene [8]. A less
time-consuming method, however, is the preparative separation
of (R,S)- or cis-cyclohexane-1,2-diamine (cis-1) from the commer-
cially available mixture of diastereomers reported by Saito and
Kidani in 1976 [9]. As cyclohexane-1,2-diamine (1) is a by-product
of hexane-1,6-diamine (a reagent necessary for nylon synthesis)
and thus readily available, this method is also less expensive.
We present two optimized syntheses to cis-TMCDA (5): in a first
approach, the method of Saito and Kidani was rendered less time-
consuming. We were also able to obtain crystal structures of two
intermediates (3 and 4). In a second approach, a straight-forward
two-step synthesis starting again from the mixture of cis- and
trans-cyclohexane-1,2-diamine (1) was established.
NMR [internal standard CDCl3 (d 77.16), external standard tms]:
Bruker DPX 300 (111.9 MHz), Bruker DRX 400 (100.6 MHz), Bruker
DRX 500 (125.8 MHz), Varian Inova 500 (125.7 MHz). Assignment
of all signals was supported by DEPT and HSQC experiments.
Elemental analysis: Leco Instrument CHNS-932. ESI(+)-MS:
Thermo TSQ, 250 °C, 4.5 kV. GC–MS: gas chromatography: HP
6890 [column: J. & W. Scientific, 25 m length, ID 0.2; gas: helium,
2.06 bar; temperature program: 50 °C (1 min) – 40 °C/min –
300 °C (5 min)], EI-MS: HP Selective Detector 5973 (70 eV). The
selected m/z values refer to the isotopes 1H, 12C, 14N, 16O and 32S.
FIA-(+)ESI-FTMS (exact mass): LTQ Orbitrap, 275 °C, source voltage
3.8 kV, capillary voltage 41 V, tube lens voltage 140 V. cis–trans-
Cyclohexane-1,2-diamine was used as a 90% mixture of diastereo-
mers from Acros. The diastereomeric ratio was shown to be
cis/trans 35:65 (by integration of the methyl peaks of the 1H
NMR spectrum of TMCDA synthesized from the mixture of
diastereomers).
2.2. Synthetic procedures
2. Experimental
2.2.1. Bis(cis-tetramethylcyclohexane-1,2-diamine)nickel(II) chloride
(2)
2.1. Instruments, measurements and chemicals
cis–/trans-Cyclohexane-1,2-diamine (1) [22.5 mL, corresponds
to 6.59 g (57.7 mmol) cis-cyclohexane-1,2-diamine (cis-1)] was
added to a solution of NiCl2ꢀ6H2O (24.0 g, 101 mmol) in methanol
(550 mL). The solution turned dark green and was stirred for 1 h.
The yellow solid 2 was then filtered and washed carefully with
methanol (150 mL in small portions) until the washings turned a
yellowish green. Yield: 9.35 g (26.1 mmol, 90%); mp 344 °C
Melting points: Büchi B-545. 1H NMR [internal standards CHCl3
(d 7.26) for CDCl3, and HDO (d 4.79) for D2O, external standard
⇑
Corresponding author. Tel.: +49 231 755 3807; fax: +49 231 755 5048.
E-mail address: mail@carsten-strohmann.de (C. Strohmann).
0020-1693/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.ica.2011.06.008

P.K. Eckert et al. / Inorganica Chimica Acta 376 (2011) 634–637
635
(decomp.). Anal. Calc. C, 40.26; H, 7.88; N, 15.65. Found: C, 40.2; H,
7.8; N, 15.6%.
pure cis-TMCꢃD2A (5). Yield: 11.0 g (64.6 mmol, 58%); bp
50 ꢄC=9:5 ꢁ 10 mbar; d.r. >99% (see Section 2.1).
2.2.2. cis-Cyclohexane-1,2-diammonium sulfate (4)
2.3. X-ray structure determinations
Ethanol (250 mL in two portions) was quickly added to a solu-
tion of 2 (10.0 g, 27.9 mmol) in sulfuric acid (100 mL), resulting
in a boiling, clear green solution (adding the sulfuric acid solution
to ethanol or adding the ethanol more slowly results in direct pre-
cipitation). Using a 1 L round-bottom flask prevents the solution
from boiling over. After 23 h, colorless needles of cis-cyclohex-
ane-1,2-diammonium hydrogensulfate ethylsulfate (3) had
formed, which started to decompose at once upon filtration. Wash-
ing with ethanol (3 ꢁ 80 mL), resulted in a white powder of 4.
Yield: 10.1 g (47.7 mmol, 85%); mp 268 °C (decomp.). 1H NMR
ðD2OÞ: d 1.40–2.06 (m, 8H; CH2 aliph.), 3.62–3.81 (b, 2H; CHN).
2.3.1. X-ray structure determination of 3 (colorless needles from
sulfuric acid/ethanol)
Crystallographic data: C8H22N2O8S2, M = 338.40, monoclinic,
space group P21; a ¼ 9:5011ð7Þ; b ¼ 7:6370ð4Þ; c ¼ 11:0521ð10Þ
Å;b ¼ 113:816ð11Þ;V ¼ 733:65ð10ÞÅ3;Z ¼ 2;Dc ¼ 1:532mg=m3, type
of radiation Mo Ka, k = 0.71073 Å, l
= 0.115 mmꢃ1. Measurements:
Oxford Diffraction XcaliburS, T = 173 K. Programs used for data col-
lection: CrysAlis (Oxford, 2008), CrysAlis RED (Oxford, 2008). The
structure was solved using direct methods (SHELXS90), structural
refinement was done with SHELXL97; 5484 reflections measured
within h = 2.34–27°, 3152 independent reflections, anisotropic
thermal parameters for all non-H atoms, the H atoms were refined
on a riding model in their ideal geometric positions, except for H1,
H6, H1a–d, and H2a–c, which were refined isotropically,
13C NMR ðD2OÞ: d 20.1 ðCH2 aliph.), 25.6 ðCH2 aliph.), 49.7 (CHN).
ESI(+)-MS: m/z 115 ½ðC6 H10ÞðNH2ÞðNH3Þþ; 98ꢂ; 98 ½ðC6H8ÞNH
;
þ
2
100ꢂ. Anal. Calc. C, 33.95; H, 7.60; N, 13.20. Found: C, 33.6; H,
7.7; N, 12.7%.
R = 0.0397, 3152 independent reflections, [I > 2r(I)], wR2 = 0.0632
(all data).
2.2.3. cis-Cyclohexane-1,2-diamine (cis-1)
A solution of 4 (9.60 g, 45.2 mmol) in sodium hydroxide
(150 mL, 2 M aqueous solution), was stirred for 70 min, and then
extracted with dichloromethane (6 ꢁ 150 mL). The combined or-
ganic phases were dried over magnesium sulfate, filtered and the
solvent was removed. The resulting product cis-1 was purified by
Kugelrohr distillation and immediately stored under argon at
ꢃ30 °C as it is unstable in air. Yield: 3.48 g, (30.5 mmol, 67%); bp
80 °C/20 mbar. 1H NMR ðCDCl3Þ: d 0.96–1.10 (s, 4H; NH2Þ, 1.13–
1.26, 1.31–1.46 (m, 8H; CH2 aliph.), 2.66–2.77 (m, 2H; CHN). 13C
NMR ðCDCl3Þ: d 21.8 ðCH2 aliph.), 31.0 ðCH2 aliph.), 51.9 (CHN).
GC(+)-MS: tr = 3.43 min; m/z 114 [MÅ+, 24], 97 ½ðC6H10Þ
NHÅþ; 82ꢂ; 82 ½C6H Åþ; 22ꢂ; 69 ðC5H Åþ; 90Þ; 56½C4H Åþ; 100ꢂ. Exact
2.3.2. X-ray structure determination of 4 (colorless plates from water)
Crystallographic data: C6H16N2O4S, M = 212.27, monoclinic,
space group Pn, a = 6.4255(3), b = 11.0260(5), c = 6.6327(3) Å,
b = 100.484(4), V = 462.07(4) Å3, Z = 2, Dc = 1.526 mg/m3, type of
radiation MoKa, k = 0.71073 Å, l
= 0.338 mm3. Measurements:
Oxford Diffraction XcaliburS, T = 173 K. Programs used for data col-
lection: CrysAlis (Oxford, 2008), CrysAlis RED (Oxford, 2008). The
structure was solved using direct methods (SHELXS90), structural
refinement was done with SHELXL97; 2281 reflections measured
within h = 3.63–27°, anisotropic thermal parameters for all non-H
atoms, the H atoms were refined on a riding model in their ideal
geometric positions, except for H1a–c, and H2c–e, which were re-
fined isotropically, R = 0.0262, 1996 independent reflections,
10
10
8
mass (ESI): Calc. m/z [M+H]+: 115.12298. Found: 115.12244.
Immediate reaction of cis-1 in air prevented elemental analysis.
cis-1 synthesized by this procedure is not only less expensive but
also purer than when bought directly (the purity of the bought
product ranges from 96% to 98%).
[I > 2r(I)], wR2 = 0.0631 (all data).
3. Results and discussion
2.2.4. cis-TMCDA (5)
cis-Cyclohexane-1,2-diamine (3.11 g, 27.2 mmol) (cis-1) was di-
luted in formaldehyde (19.4 mL, 40% aqueous solution) and formic
acid (15.4 mL) and refluxed gently for 29 h. Sodium hydroxide was
added until the reaction mixture was basic and the mixturewas then
extracted with diethyl ether (10 ꢁ 50 mL). The combined organic
phases were dried over magnesium sulfate. After filtering, the sol-
vent was removed and the crude product purified by Kugelrꢃo2hr dis-
tillation. Yield: 3.62 g (21.3 mmol, 78%); bp 50 ꢄC=9:5 ꢁ 10 mbar
d.r. >99% (see Section 2.1). 1H NMR ðCDCl3Þ: d 1.23–1.35, 1.41–
1.54, 1.58–1.71, 1.75–1.87 (m, 8H; CH2 aliph.), 2.14–2.22 (m, 2H;
CHN), 2.27 [s, 12H; NðCH3Þ2]. 13C NMR ðCDCl3Þ: (d 23.3 CH2 aliph.),
26.8 ðCH2 aliph:Þ; 44:5 ½NðCH3Þ2ꢂ; 65:5ðCHNÞ:GCðþÞ—MS : tr ¼ 4:08
min; m=z 170 ½MÅþ; 71ꢂ; 124 ½ðC6H8Þ NHNMeÅþ; 24ꢂ; 110 ½ðC6H10Þ-
, 66]. Anal. Calc. C, 70.53; H, 13.50; N, 16.45. Found: C, 70.3; H, 13.7; N,
16.5%.
cis-Cyclohexane-1,2-diamine (cis-1) was separated from a mix-
ture of diastereomers by crystallization with NiCl2ꢀ6H2O to give
bis(cis-tetramethylcyclohexane-1,2-diamine)nickel(II) chloride (2)
[9] (Scheme 1). Crystals of 2 obtained from water confirmed the
structure already reported in the literature [10–12].
Upon addition of ethanol to a solution of 2 in concentrated sul-
furic acid, crystals of cis-cyclohexane-1,2-diammonium hydrogen-
sulfate ethylsulfate (3) were obtained as colorless needles. These
decomposed readily upon filtration and formed a powder of
cis-cyclohexane-1,2-diammonium sulfate (4) when washed with
ethanol. The growth of crystals of 3 is a key intermediate in the
synthesis of cis-TMCDA (5) as the reaction gets a lot easier (no
evaporation of sulfuric acid is required anymore) and the final
product 4 does not contain traces of nickel(II) chloride. This elim-
inates problems in later reaction steps.
cis-Cyclohexane-1,2-diammonium hydrogensulfate ethylsulfate
(3) crystallizes from sulfuric acid/ethanol in the monoclinic crystal
system, space group P21 (Fig. 1). The two carbon–nitrogen bond
lengths C(1)–N(1) and C(6)–N(2) are similar with 1.501(4) Å and
1.495(4) Å, respectively. In the ester group, the bond length S(2)–
O(8) amounts to 1.570(2) Å with an angle of 117.9(2) [S(2)–O(8)–
C(7)] (Table 1).
Crystals of 4 were obtained upon recrystallization from water,
as proposed by Sakata et al. [13]. cis-Cyclohexane-1,2-diammo-
nium sulfate (4) crystallizes in the monoclinic crystal system,
space group Pn (Fig. 2). The two carbon–nitrogen bond lengths
2.2.5. Direct synthesis of cis-TMCDA (5) starting from 2
Bis(cis-tetramethylcyclohexane-1,2-diamine)nickel(II) chloride
(2) (20.00 g, 55.9 mmol) was diluted in formic acid (66 mL) and
formaldehyde (85 mL, 37% aqueous solution) and the reaction mix-
ture was refluxed gently for 30 h, filtered and washed with water.
The resulting clear solution was made basic with sodium hydrox-
ide (2 M aqueous solution, 400 mL) as well as solid sodium hydrox-
ide and extracted with diethyl ether (3 ꢁ 500 mL). The combined
organic phases were dried over sodium sulfate, filtered and the sol-
vent was removed. Kugelrohr distillation of the crude oil afforded

636
P.K. Eckert et al. / Inorganica Chimica Acta 376 (2011) 634–637
H2
N
H2
N
N2
NH
2NiCl2(aq)
Cl2
N
N
NH2
N1
H2
H2
C6
2
1
O2
cis : trans
35:65
C5
C1
H2SO4,
EtOH
O3
S1
O1
C4
C2
2+
O4
NH3
− HSO4
−
EtOSO3
C3
NH3
Fig. 2. Molecular structure of 4.
3
EtOH
Table 2
Selected bond lengths (Å) and angles (°) for 4.
H2CO,
HCO2H
2+
NH3
NH3
C(1)–N(1)
C(6)–N(2)
S(1)–O(1)
S(1)–O(2)
S(1)–O(3)
S(1)–O(4)
1.491(2)
1.495(2)
1.4683(13)
1.4843(14)
1.4832(14)
1.4609(13)
O(4)–S(1)–O(1)
O(4)–S(1)–O(3)
O(4)–S(1)–O(2)
O(1)–S(1)–O(3)
O(1)–S(1)–O(2)
O(3)–S(1)–O(2)
111.19(7)
109.04(9)
109.87(8)
109.88(7)
108.33(8)
108.49(7)
2−
SO4
4
NaOH
NH2
H2CO,
HCO2H
NMe2
NMe2
111.19(7), O(4)–S(1)–O(3) 109.04(9), O(4)–S(1)–O(2) 109.87(8),
O(1)–S(1)–O(3) 109.88(7), O(1)–S(1)–O(2) 108.33(8), O(3)–S(1)–
O(2) 108.49(7)] (Table 2).
NH2
Efforts to methylate 4 directly did not result in satisfying yields
of 5. Therefore, cis-cyclohexane-1,2-diammonium sulfate (4) was
deprotonated with sodium hydroxide, yielding cis-cyclohexane-
1,2-diamine (cis-1), which is unstable in air. Subsequent Eshweil-
er–Clarke reaction with formic acid and formaldehyde gave
cis-TMCDA (5) with a d.r. of >99%. Thus, the diamine 5 was pre-
pared from a mixture of diastereomers with 40% overall yield.
The method described above is also very useful for cis-TMCDA
derivatives, which can be synthesized from diastereomerically
pure cis-cyclohexane-1,2-diamine (cis-1).
In order to make the synthesis of cis-TMCDA (5) even less
time-consuming, a direct methylation of the nickel salt 2 was
established. Compound 2 was reacted with formic acid and formal-
dehyde solution to yield cis-TMCDA (5) with a d.r. of >99% and an
overall yield of 52%.
5
cis-1
Scheme 1. Synthesis of cis-TMCDA (5).
C4
O8
O7
C8
C5
O6
C7
S2
C3
C2
C6
O5
N2
O1
N1
C1
4. Conclusions
O2
S1
O4
This work has shown two optimized synthetic approaches to
diastereomerically pure cis-TMCDA (5). The two-step approach al-
lows a straight-forward synthesis of cis-TMCDA (5), thus clearing
the path for its use in preparative synthesis. The preparation of
cis-cyclohexane-1,2-diamine (cis-1) via crystals of cis-cyclohex-
ane-1,2-diammonium hydrogensulfate ethylsulfate (3) greatly
facilitates workup in the subsequent reaction steps. Studies con-
cerning the coordination behavior of 5 towards different metals
are currently in progress.
O3
Fig. 1. Molecular structure of 3.
Table 1
Selected bond lengths (Å) and angles (°) for 3.
C(1)–N(1)
O(8)–S(2)
1.501(4)
1.570(2)
C(6)–N(2)
S(2)–O(8)–C(7)
1.495(4)
117.9(2)
Acknowledgements
The authors thank Cornelia Werner for her valuable assistance
in testing the optimized synthetic procedures and Sarah Baumert
for synthesizing the nickel salt 2 many times. Additional thanks
goes to FCI (Fonds der Chemischen Industrie) and DFG (Deutsche Fors-
chungsgemeinschaft) for financial support.
are similar to those in 3 [C(1)–N(1) 1.491(2), C(6)–N(2) 1.495(2)]
and the sulfate anion shows only a slight deviation from tetrahe-
dral symmetry [S(1)–O(1) 1.4683(13), S(1)–O(2) 1.4843(14),
S(1)–O(3) 1.4832(14), S(1)–O(4) 1.4609(13), O(4)–S(1)–O(1)

P.K. Eckert et al. / Inorganica Chimica Acta 376 (2011) 634–637
[3] J.-C. Kizirian, Chem. Rev. 108 (2008) 104.
637
Appendix A. Supplementary material
[4] C. Strohmann, V.H. Gessner, Angew. Chem. 119 (2007) 8429.
[5] C. Strohmann, V.H. Gessner, J. Am. Chem. Soc. 129 (2007) 8952.
[6] C. Strohmann, V.H. Gessner, J. Am. Chem. Soc. 130 (2008) 11719.
[7] J.F. Larrow, E.N. Jacobsen, Org. Synth. 75 (1998) 1.
[8] G. Swift, D. Swen, J. Org. Chem. 32 (1967) 511.
CCDC 810696 and 810697 for compounds 3 and 4, respectively,
contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crys-
tallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.ica.2011.06.008.
[9] R. Saito, Y. Kidani, Chem. Lett. (1976) 123.
[10] K. Toriumi, H. Okamoto, T. Mitani, S. Bandow, M. Yamashita, Y. Wada, Y. Fujii,
R.J.H. Clark, D.J. Michael, A.J. Edward, D. Watkin, M. Kurmuro, P. Day, Mol.
Cryst. Liq. Cryst. 181 (1990) 333.
[11] S. Garcia-Granda, M.R. Diaz, F. Gomez-Beltran, Acta Crystallogr., Sect. C Cryst.
Struct. Commun. 47 (1991) 181.
[12] K.J. Gerard, J. Morgan, P.J. Steel, D.A. House, Inorg. Chim. Acta (1997)
27.
References
[13] K. Sakata, T. Odamura, Y. Kanbara, T. Nibu, M. Hashimoto, A. Tsuge, Y.
Moriguchi, Polyhedron 17 (1998) 1463.
[1] D. Stead, P. O’Brien, A. Sanderson, Org. Lett. 10 (2008) 1409.
[2] N. Cabello, J.-C. Kizirian, S. Gille, A. Alexakis, G. Bernadinelli, L. Pinchard, J.-C.
Caille, Eur. J. Org. Chem. (2005) 4835.