Enantiomerically pure isophorone diamine [3-(aminomethyl)-3,5,5- trimethylcyclohexylamine]: A chiral 1,4-diamine building block made available on large scale

Article abstract of DOI:10.1021/jo0613737

(Chemical Equation Presented) Isophorone diamine [IPDA, 3-(aminomethyl)-3,5,5-trimethylcyclohexylamine] is a chiral non-C ₂-symmetric 1,4-diamine which is produced industrially on large scale as the mixture of all four stereoisomers (cis/ trans

Full text of DOI:10.1021/jo0613737

Enantiomerically Pure Isophorone Diamine
[3-(Aminomethyl)-3,5,5-trimethylcyclohexylamine]: A Chiral
1,4-Diamine Building Block Made Available on Large Scale
Albrecht Berkessel,* Katrin Roland, Michael Schro¨der, Jo¨rg M. Neudo¨rfl, and Johann Lex
Institut fu¨r Organische Chemie, UniVersita¨t zu Ko¨ln, Greinstrasse 4, D-50939 Ko¨ln, Germany
berkessel@uni-koeln.de
ReceiVed July 2, 2006
Isophorone diamine [IPDA, 3-(aminomethyl)-3,5,5-trimethylcyclohexylamine] is a chiral non-C2-symmetric
1,4-diamine which is produced industrially on large scale as the mixture of all four stereoisomers (cis/
trans ca. 3:1). Starting from this industrial bulk product, the preparation of the bis-tosyl, bis-Fmoc, bis-
Boc and bis-Z derivatives of cis-IPDA, the preparation of the pure cis enantiomers by HPLC on chiral
stationary phase, and the assignment of absolute configurations to the isolated enantiomers are described.
We furthermore report an efficient method for the optical resolution of IPDA by salt formation with
dibenzoyl tartaric acid. The latter method conveniently affords enantiomerically pure cis-IPDA in 100 g
quantities. A number of salen ligands have been prepared from this enantiomerically pure 1,4-diamine
and fully characterized. The nickel complex of one of the salen ligands was prepared and analyzed by
X-ray crystallography. The crystal structure of the Ni4L4 complex illustrates the pronounced preference
of cis-IPDA for adopting the chair conformation in which both the amino- and the aminomethyl substituents
occupy equatorial positions. As a consequence, the two salicylidene imine moieties of one ligand molecule
do not converge on one metal ion, but act as bridging ligands between two nickel ions.
Introduction
enantiomerically pure form from the commercial mixture of all
three stereoisomers by crystallization with tartaric acid. We have
recently reported the successful application of chromium-salen
complexes of endo,endo-2,5-diaminonorbornane (DIANANE)
2 in the asymmetric Nozaki-Hiyama-Kishi addition of allylic
In recent years, chiral diamines have become ever more
important as building blocks for chiral salen ligands1 and metal
complexes derived thereof, for the synthesis of chiral organo-
catalysts,2 and for many other applications.3 One of the most
prominent chiral diamine building blocks is trans-1,2-diami-
nocyclohexane 1.4 The optical resolution of rac-1 was reported
by Galsbøl et al. in 1972 and later modified by Jacobsen and
co-workers.5 The trans-1,2-diamine 1 is readily obtained in
(3) (a) Collins, A. N., Sheldrake, G. N., Crosby, J., Eds. Chirality in
Industry; John Wiley & Sons Ltd.: Chichester, U.K., 1992. (b) Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds. ComprehensiVe Asymmetric Catalysis;
Springer-Verlag: Berlin, Heidelberg, Germany, 1999. (c) Lucet, D.; Le Gall,
T.; Mioskowski, C. Angew. Chem. 1998, 110, 2724-2772. Angew. Chem.,
Int. Ed. 1998, 37, 2580-2627. (d) Mun˜iz, K. Angew. Chem. 2005, 117,
6780-6785. Angew. Chem., Int. Ed. 2005, 44, 6622-6627.
(4) Bennani, Y. L.; Hanessian, S. Chem. ReV. 1997, 97, 3161-3195.
(5) (a) Galsbøl, F.; Steenbøl, P.; Sørensen, B. S. Acta Chem. Scand. 1972,
26, 3605-3611. (b) Larrow, J. F.; Jacobsen, E. N. J. Org. Chem. 1994, 59,
1939-1942. (c) Larrow, J. F; Jacobsen, E. N. Org. Synth. 1997, 75, 1-11.
(1) Cozzi, P. G. Chem. Soc. ReV. 2004, 33, 410-421.
(2) (a) Berkessel, A.; Gro¨ger, H. Asymmetric Organocatalysis; Wiley-
VCH: Weinheim, Germany, 2005. (b) Dalko, P. I.; Moisan, L. Angew.
Chem. 2004, 116, 5248-5286. Angew. Chem., Int. Ed. 2004, 43, 5138-
5175.
10.1021/jo0613737 CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/15/2006
9312
J. Org. Chem. 2006, 71, 9312-9318

Enantiomerically Pure Isophorone Diamine
FIGURE 2. (a) Stereoisomers of isophorone diamine (IPDA, 3); (b)
preferred ee conformation of cis-IPDA 3-cis.
FIGURE 1. The C2-symmetric diamines trans-1,2-diaminocyclohexane
(DACH, 1), endo,endo-2,5-diaminonorbornane (DIANANE, 2), and
salen ligands derived thereof.
and vinylic electrophiles to aldehydes.6 DIANANE (2) is a C2-
symmetric 1,4-diamine. Compared to salen ligands prepared
from trans-1,2-diaminocyclohexane (1), those derived from
DIANANE (2) have a significantly larger N-N distance (Figure
1).7
FIGURE 3. IPDA derivatives rac-4-7-cis.
SCHEME 1. Preparation of Enantiomerically Pure IPDA
3-cis and ent-3-cis by Hydrogenolytic Deprotection of
Bis-Z-IPDA 7-cis and ent-7-cis
Our positive results achieved with the 1,4-diamine DIANANE
(2) raised the question whether other chiral 1,4-diamines might
be available as building blocks for novel salen-type ligands.
We realized that 3-aminomethyl-3,5,5-trimethylcyclohexylamine
(isophorone diamine, IPDA; 3, Figure 2) might be a suitable
candidate: IPDA (3) is a chiral 1,4-diamine which is produced
industrially on large scale as a ca. 3:1 mixture of the racemic
cis- and trans-diastereomers (rac-3-cis + rac-3-trans). The bis-
isocyanate derivative of IPDA (3) is produced on a ca. 10 000
t/a scale, and it is used for polyurethane synthesis.8-10 We
reasoned that IPDA (3) itselfsas a cheap and readily available
chiral diaminescould find use as a novel building block in
asymmetric catalysis (e.g. for the synthesis of novel salen
ligands, or as building block for chiral organocatalysts). A
particularly interesting feature of cis-IPDA is the fact that this
1,4-diamine, as a cyclohexane derivate, largely prefers the bis-
equatorial arrangement of its amino- and aminomethyl substit-
uents (Figure 2b).10b In other words, organocatalysts derived
from IPDA could be expected to have nonconvergent and thus
independently acting functional groups. Similarly, the two
binding sites of salen ligands derived from cis-IPDA could be
anticipated to not bind simultaneously to one metal ion. Instead,
the formation of metal complexes of higher nuclearity should
result. In this article, we report a practical method for the
preparation of enantiomerically pure cis-IPDA (3-cis, ent-3-cis)
on large scale, the assignment of absolute configuration, the
preparation of IPDA-salen ligands, and the structural features
of a nickel complex derived from one of the novel cis-IPDA
salen ligands.
Results and Discussion
The separation of the four stereoisomers of the industrial
product (“3-mix”) was first attempted by derivatization to the
bis-tosylamide-, bis-Fmoc-, bis-Boc-, and bis-Z-derivative and
subsequent preparative HPLC on chiral stationary phase.11 In
fact, recrystallization of the crude mixture of the tosylamide
and the carbamates already furnished the diastereomerically pure
cis-stereoisomers rac-4-cis, rac-5-cis, rac-6-cis, and rac-7-cis
(see Figure 3). The separation of the cis-enantiomers of
compounds rac-4-cis and rac-7-cis was readily achieved by
preparative HPLC on Chiralpak AD. The separated enantiomers
of the cis-bis-tosylamides (4-cis and ent-4-cis) were again
crystallized and subjected to X-ray structural analysis. The
absolute configurations for 4-cis (1S,3R) and ent-4-cis (1R,3S)
could be assigned by anomalous dispersion (see Supporting
Information). By cleavage of the Z-protective group in 7-cis
(or ent-7-cis) with H2/Pd-C, enantiomerically pure cis-IPDA
3-cis (or ent-3-cis) was obtained for the first time, albeit in small
quantities only, because of the limitations imposed by the HPLC
separation (Scheme 1).
(6) (a) Berkessel, A.; Menche, D.; Sklorz, C. A.; Schro¨der, M.; Paterson,
I. Angew. Chem. 2003, 115, 1062-1065; Angew. Chem., Int. Ed. 2003, 42,
1032-1035. (b) Paterson, I.; Bergmann, H.; Menche, D.; Berkessel, A. Org.
Lett. 2004, 6, 1293-1295.
(7) Berkessel, A.; Schro¨der, M.; Sklorz, C. A.; Tabanella, S.; Vogl, N.;
Lex, J.; Neudo¨rfl, J. M. J. Org. Chem. 2004, 69, 3050-3056.
(8) For the preparation of IPDA with high cis/trans ratio, see (a) Funke,
F.; Hill, T.; Melder, J.-P.; Schwab, E.; Himmel, W.; Henkes, E.; Petersen,
H.; Ko¨rner, R. Int. Patent WO 2003020421 A1, 2003. (b) Haas, T.; Arntz,
D.; Most, D. Eur. Patent EP 659733 A1, 1995. (c) Haas, T.; Arntz, D.
Chem. Eng. Technol. 1996, 68, 161-165.
(9) For examples see (a) Hoenel, M.; Pfeil, A.; Budnick, T.; Schwan,
H. German Patent DE 4344510 A1, 1995. (b) Tillack, J.; Schmalstieg, L.;
Puetz, W.; Ruttmann, G. German Patent DE 19935329 A1, 2001. (c)
Schmitt, K.; Disteldorf, J.; Hu¨bel, W. U.S. Patent US 3352913, 1967.
(10) (a) Wendisch, D.; Reiff, H.; Dieterich, D. Angew. Makromol. Chem.
1986, 141, 173-183. (b) Auf der Heyde, W.; Hu¨bel, W.; Boese, R. Angew.
Makromol. Chem. 1987, 153, 1-13. (c) Born, L.; Wendisch, D.; Reiff, H.;
Dieterich, D. Angew. Makromol. Chem. 1989, 171, 213-231.
For the large scale preparation of enantiomerically pure IPDA,
we performed a screening of chiral carboxylic acids that were
hoped to form diastereomeric salts with IPDA (either cis or
trans). Attempts in this direction using tartaric acid, mandelic
acid, or amino acids such as glutamic or aspartic acid failed
(11) For the preparation of stereoisomeric mixtures of IPDA-carbamates
see (a) Butler, D. C. D.; Alper, H. Chem. Commun. 1998, 2575-2576. (b)
Valli, V. L. K.; Alper, H. J. Org. Chem. 1995, 60, 257-258. (c) Afonso,
C. A. M. Synth. Commun. 1998, 28, 261-276.
J. Org. Chem, Vol. 71, No. 25, 2006 9313

Berkessel et al.
SCHEME 2. Reaction of IPDA 3-Mix to Afford the
Crystalline Carbamic Acid rac-8-cis.
crystallography was identified as the [4× Ni + 4× 10c]-
aggregate rac-11 (Figure 4). Inspection of the crystal structure
reveals that two of the four nickel centers are coordinated in a
(distorted) square-planar fashion, whereas the other two are
octahedral. In the latter cases, the coordination spheres around
the nickel ions are completed by water. As already observed
for the cis-IPDA bis-salicylidene imines (such as 10c, Scheme
4), the cis-IPDA core maintains the bis-equatorial orientation
of the amine substituents, thus preventing the simultaneous
binding of both salicylidene imine substituents to the same nickel
ion. As a consequence, the four IPDA-derived salen ligands
10c in the complex rac-11swithout exceptionscoordinate two
different nickel ions.
completely12 and invariably led to the isolation of the crystalline
carbamic acid rac-8-cis which is readily formed upon exposition
of IPDA to air (Scheme 2).
The resolution could eventually be achieved by reaction of
IPDA with (R,R)-dibenzoyl tartaric acid (DBTA) to yield, after
one recrystallization, the diastereomerically pure salt 9 in 56%
yield (with respect to the amount of 3-cis present in 3-mix) and
with a dr of >99:1 (Scheme 3). For the determination of the
dr, the amine component was liberated from the salt 9, and its
enantiomeric purity was measured (as the bis-Z-derivative 7-cis,
ent-7-cis) by HPLC on chiral stationary phase. Furthermore,
the DBTA salt 9 was subjected to X-ray analysis. As the
configuration of the dibenzoyl tartrate (DBTA) employed in the
separation was known, the relative and absolute configuration
of the amine component (3-cis, 1R,3S) could be deduced from
the X-ray structure. Clearly, the enantiomeric IPDA ent-3-cis
is obtained when (S,S)-dibenzoyl tartaric acid is used in the
crystallization. The enantiomerically pure IPDA 3-cis is easily
liberated from its DBTA-salt by addition of base (NaOH) and
extraction with CH2Cl2. After Kugelrohr distillation, the enan-
tiomerically pure diamine 3-cis was routinely obtained in
quantitative yield. By this procedure, the separation of crude
IPDA 3-mix can easily be carried out in 100 g batches. On the
other hand, care has to be taken when handling small quantities
of IPDA in air, because carbamate formation rapidly takes place
(vide supra).
Upon combination with salicylic aldehydes, IPDA readily
forms the corresponding diimines. As shown in Scheme 4, the
bis-salicylidene imines 10a-g can be prepared even more
conveniently directly from the IPDA-DBTA salt 9 (or ent-9,
respectively) in the presence of potassium carbonate as base.
Scheme 4 also shows the X-ray crystal structure of a typical
IPDA-salen, namely 10c. As anticipated, the IPDA cyclohexane
ring adopts a chair conformation, and both amine substitutents
are oriented equatorially. In more commonly used salen ligands,
for example, those incorporating DACH (1) as the diamine
component, the salicylidene imine moieties can converge to bind
a metal ion in a tetradentate fashion.13 In the case of the IPDA
salens, this converging of the two salicylidene units would
require an energetically unfavorable bis-axial arrangement of
the two amine substituents. As a consequence, coordination
geometries different from “regular” salens may be expected for
the metal complexes of the tetradentate ligands 10a-g.
To test this assumption, we chose nickel(II) as a metal ion
known to form square-planar complexes with various salen
ligands. Indeed, the reaction of preformed nickel(II) bis-4-
chlorosalicylic aldehyde complex with the mixture of IPDA
stereoisomers (3-mix) did not afford a simple 1:1 salen complex.
Instead, a crystalline material was obtained which by X-ray
As the first application of enantiomerically pure IPDA in
asymmetric organocatalysis, we recently described the IPDA-
based bis(thio)ureas 12 (Figure 5) as highly efficient and
enantioselective catalysts for the Morita-Baylis-Hillman reac-
tion (up to quant. yield and 96% ee).14
Conclusions
The aim of the current study was to elaborate a method for
the large-scale and practical preparation of IPDA 3-cis (or ent-
3-cis). We have shown that this goal can be achieved, starting
from the industrial bulk product IPDA 3-mix by salt formation
with (R,R)- or (S,S)-dibenzoyl tartaric acid (DBTA). The
absolute configurations of the resulting IPDA enantiomers 3-cis
and ent-3-cis were assigned. Seven bis-salicylidene imine ligands
(10a-g) were prepared directly from the IPDA-DBTA salt 9
by treatment with salicylic aldehydes in the presence of base.
The X-ray structural analyses of a number of cis-IPDA
derivatives confirmed the pronounced preference of both amine
substituents to occupy the equatorial positions at IPDA’s
cyclohexane core. As a consequence, and as expected, coordina-
tion of the ligand rac-10c to Ni(II) afforded the tetranuclear Ni
complex rac-11, and not a mononuclear coordination compound
typical, for example, for DACH-salens. Future work will address
the synthesis of chiral and bifunctional IPDA-based catalysts,
taking advantage of the different reactivity of the two amino
moieties of IPDA 3.14
Experimental Section
1-Toluenesulfonylamido-3-toluenesulfonylamidomethyl-3,5,5-
trimethylcyclohexane rac-4-cis.15 A solution of isophorone diamine
3-mix (technical mixture of stereoisomers, ca. 70% rac-3-cis, 5.53
mL, 30.0 mmol) in CH2Cl2 (100 mL) was cooled to -78 °C, and
toluenesulfonyl chloride (12.0 g, 63.0 mmol) in CH2Cl2 (50.0 mL)
and NEt3 (8.85 mL, 63.0 mmol) were added in a dropwise manner.
After it was stirred at -78 °C for 3 h, the mixture was allowed to
warm to room temperature overnight. The resulting suspension was
extracted with 3 × 40.0 mL of 2 M aqueous HCl, 2 × 40.0 mL of
H2O, and 40.0 mL of brine and dried over MgSO4. After the extract
was concentrated in vacuo, a colorless semisolid was obtained. This
crude product was washed several times with a Et2O/pentane
mixture (1/1, v/v) and crystallized from MeOH to yield 10.1 g
(71%) of the bistosylamide rac-4-cis as a colorless solid, containing
traces of the trans-isomer. Further purification was achieved by
slow recrystallization from EtOH to give colorless crystals suitable
for X-ray crystallography. HPLC (Daicel Chiralpak AD 4.60 mm
(14) Berkessel, A.; Roland, K.; Neudo¨rfl, J. M. Org. Lett. 2006, 8, 4195-
4198.
(15) Mixtures of the stereoisomers of 4 appear to be commercially
available as components of screening libraries, e.g., Princeton Gold
Collection I or Aurora Screening Library. No report on their preparation or
assignment of configuration appears to exist.
(12) Kozma, D., Ed. Optical Resolutions Via Diastereomeric Salt
Formation; CRC Press: Boca Raton, FL, 2002.
(13) For examples of tetradentate salen complexes see Jacobsen, E. N.;
Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng, L. J. Am. Chem. Soc. 1991,
113, 7063-7064.
9314 J. Org. Chem., Vol. 71, No. 25, 2006

Enantiomerically Pure Isophorone Diamine
SCHEME 3a
a Preparation of the (R,R)-dibenzoyl tartrate 9 of 3-cis from the IPDA mixture of stereoisomers 3-mix (a); conversion of 9 to enantiomerically pure
(1R,3S)-IPDA 3-cis (b); X-ray crystal structure of the tartrate salt 9 (c).
SCHEME 4a
a
Preparation of the bissalicylidene imine ligands 10a-g from the IPDA-DBTA Salt 9 (a); X-ray crystal structure of the ligand 10c (b).
i.d. × 250 mm length; n-hexane/2-propanol 70/30, 0.5 mL/min;
80 min; UV, 220-400 nm) τR 44.0, 46.5 min (trans isomers), 57.3
min [4-cis (1S,3R)], 74.2 min [ent-4-cis (1R,3S)]; mp 201 °C. IR
(CsI): 3448, 3272, 2957, 2361, 2358, 1598, 1348, 1323, 1157, 1153,
1096, 1072, 821, 668, 551 cm-1. 1H NMR (300 MHz, d6-DMSO):
δ 7.72-7.61 (m; 4H), 7.52-7.42 (m; 2H), 7.42-7.33 (m; 4H),
3.26-3.10 (m; 1H), 2.38 (s; 3H), 2.37 (s; 3H), 2.29 (d; J ) 6.7
Hz, 2H), 1.32-1.13 (m; 2H), 1.03-0.82 (m; 4H), 0.81 (s; 3H),
0.79 (s; 3H), 0.75 (s; 3H). 13C NMR (75 MHz, d6-DMSO): δ 142.3
(s), 142.2 (s), 139.0 (s), 137.3 (s), 129.4 (d), 126.4 (d), 126.2 (d),
56.0 (t), 46.7 (d), 45.9 (t), 45.7 (t), 41.8 (t), 35.3 (s), 34.6 (q), 31.3
(s), 27.1 (q), 23.2 (q), 20.9 (q). Anal. Calcd for C24H34N2O4S2: C,
60.22; H, 7.16; N, 5.85. Found: C, 60.16; H, 7.18; N, 5.86.
(1S,3R)- and (1R,3S)-1-Toluenesulfonylamido-3-toluenesulfo-
nylamidomethyl-3,5,5-trimethylcyclohexane 4-cis (1S,3R)- and
ent-4-cis (1R,3S). The enantiomers of the bistosylamide rac-4-cis
were separated by chiral preparative HPLC on a Daicel Chiralpak
AD column (50 mm i.d. × 500 mm length) with n-hexane/i-PrOH
(70/30), p 12 bar, flow 80 mL/min. τR 45.0-55.0 min [4-cis], 57.0-
72.0 min [ent-4-cis]. A total of 100 mg of rac-4-cis in 10.0 mL of
EtOH (dissolved by sonication) were injected per run. The fractions
were concentrated in vacuo, and the residue was recrystallized from
J. Org. Chem, Vol. 71, No. 25, 2006 9315

Berkessel et al.
FIGURE 4. (a) X-ray crystal structure of the nickel(II)-IPDA salen complex rac-11 (stereoscopic view); (b) schematic diagram of complex
rac-11: green, (1R,3S)-configuration; red, (1S,3R)-configuration.
mixture was stirred for 10 h. The aqueous phase was brought to
pH 5 by the addition of 10% hydrochloric acid and extracted with
3 × 20.0 mL of ethyl acetate. The organic phase was dried over
MgSO4, and the solvent evaporated under reduced pressure.
Repeated crystallization of the resulting yellow residue from ethanol
yielded 353 mg (41%) cis-(9H-fluoren-9-ylmethyl)-N-(3-{[(9H-
fluoren-9-ylmethoxycarbonyl)amino]methyl}-3,5,5-
trimethylcyclohexyl}carbamate rac-6-cis as pale yellow crystals,
FIGURE 5. Organocatalysts 12 derived from enantiomerically pure
suitable for X-ray crystallography: mp 90 °C. IR (CsI): 3331, 3066,
IPDA 3-cis.
3039, 2954, 2924, 1696, 1539, 1450, 1302, 1257, 1241, 1143, 1034,
1
EtOH. The products were obtained quantitatively as colorless
1012, 996, 757, 739 cm-1. H NMR (300 MHz, CDCl3): δ 7.76
(d; J ) 7.3 Hz, 4H), 7.60 (d; J ) 7.3 Hz, 4H), 7.39 (t; J ) 7.3 Hz,
4H), 7.31 (t; J ) 7.3 Hz, 4H), 4.92-4.79 (m; 1H), 4.67-4.52 (m;
1H), 4.51-4.34 (m; 4H), 4.28-4.14 (m; 2H), 3.93-3.76 (m; 1H),
crystals, suitable for X-ray crystallography. 4-cis: mp 173 °C; [R]20
D
-36.0 (c 1.00, CHCl3). Anal. Calcd for C24H34N2O4S2: C, 60.22;
H, 7.16; N, 5.85. Found: C, 60.26; H, 7.13; N, 5.83. ent-4-cis:
mp 173 °C; [R]20 +36.0 (c 1.00, CHCl3). Anal. Calcd for
3.02-2.82 (m; 2H), 1.84-1.58 (m; 2H), 1.26-0.66 (m; 13H). 13
C
D
C24H34N2O4S2: C, 60.22; H, 7.16; N, 5.85. Found: C, 60.13; H,
7.12; N, 5.80.
NMR (75 MHz, CDCl3): δ 156.8 (s), 155.6 (s), 144.1 (s), 144.0
(s), 141.3 (s), 127.6 (d), 127.0 (d), 124.9 (d), 119.9 (d), 66.4 (t),
54.8 (t), 47.3 (d), 47.0 (t), 46.3 (t), 44.7 (d), 41.7 (t), 36.4 (s), 35.0
(q), 31.8 (s), 27.6 (q), 23.2 (q). HRMS (ESI): calcd for
C40H42N2O4+Na+, 637.3043; found, 637.3050. Anal. Calcd for
C40H42N2O4: C, 78.15; H, 6.89; N, 4.56. Found: C, 77.97; H, 6.92;
N, 4.60. HPLC (anal., Daicel Chiralpak AD (4.60 mm i.d. × 250
mm), n-hexane/ethanol (93/7, v/v), flow 1.10 mL/min) τR 45.5 min,
49.5 min [trans isomers], τR 81.4 min [6-cis], 101.9 min [ent-6-
cis] (absolute configuration of the two cis-enantiomers was assigned
arbitrarily).
cis-tert-Butyl-N-{3-[(tert-butoxycarbonylamino)methyl]-3,5,5-
trimethylcyclohexyl}carbamate rac-5-cis. To a solution of di-
tert-butyl-dicarbonate (5.45 g, 25.0 mmol) and K2CO3 (6.90 g, 50.0
mmol) in dioxane/water (2:1, 100 mL) was added at room
temperature 3-aminomethyl-3,5,5-trimethylcyclohexylamine 3-mix
(1.85 mL, 10.0 mmol) and stirred for 12 h. The aqueous phase
was brought to pH 7 by the addition of 10% hydrochloric acid and
extracted with 3 × 20.0 mL of ethyl acetate. The organic phase
was dried over MgSO4, and the solvent evaporated under reduced
pressure. Repeated crystallization of the resulting residue from
ethanol yielded 1.70 g (46%) cis-tert-butyl-N-{3-[(tert-butoxycar-
bonylamino)methyl]-3,5,5-trimethylcyclohexyl}carbamate rac-5-cis
as colorless crystals, suitable for X-ray crystallography: mp 127
°C. IR (CsI): 3386, 3326, 2979, 2957, 2924, 1692, 1678, 1525,
1456, 1392, 1367, 1308, 1288, 1276, 1173, 1047, 1023, 1008, 956,
cis-Benzyl-N-{3-[(benzyloxycarbonylamino)methyl]-3,5,5-tri-
methylcyclohexyl}carbamate rac-7-cis.16 To a suspension of
benzyl chloroformate (4.50 mL, 31.5 mmol) and K2CO3 (6.20 g,
45.0 mmol) in water (100 mL) at 0 °C was added 3-aminomethyl-
3,5,5-trimethylcyclohexylamin 3-mix (2.80 mL, 15.0 mmol) and
stirred at that temperature for 3 h. The aqueous phase was brought
to pH 5 by the addition of 10% hydrochloric acid and extracted
with 3 × 30.0 mL of ethyl acetate. The organic phase was dried
over MgSO4, and the solvent evaporated under reduced pressure.
Repeated crystallization of the resulting residue from methanol
yielded 2.93 g (44%) cis-benzyl-N-{3-[(benzyloxycarbonylamino)-
methyl]-3,5,5-trimethylcyclohexyl}carbamate rac-7-cis as colorless
crystals, suitable for X-ray crystallography: mp 103 °C. IR (CsI):
3346, 3034, 2985, 2953, 1707, 1686, 1536, 1457, 1307, 1246,
1
648 cm-1. H NMR (300 MHz, CDCl3): δ 4.66-4.47 (m; 1H),
4.38-4.19 (m; 1H), 3.84-3.55 (m; 1H), 2.91-2.67 (m; 2H), 1.76-
1.57 (m; 2H), 1.41 (s; 18H), 1.19-1.07 (m; 1H), 1.05-0.67 (m;
12H). 13C NMR (75 MHz, CDCl3): δ 156.3 (s), 155.2 (s), 79.1
(s), 78.7 (s), 54.6 (t), 47.2 (t), 46.5 (t), 44.1 (d), 42.1 (t), 36.4 (s),
35.1 (q), 31.8 (s), 28.5 (q), 28.4 (q), 27.7 (q), 23.2 (q). HRMS
(ESI): calcd for C20H38N2O4+Na+, 393.2729; found, 393.2730.
Anal. Calcd for C20H38N2O4: C, 64.83; H, 10.34; N, 7.56. Found:
C, 64.82; H, 10.23; N, 7.59.
1128, 1033, 998, 752, 742, 699 cm-1 1H NMR (300 MHz,
.
cis-(9H-Fluoren-9-ylmethyl)-N-(3-{[(9H-fluoren-9-ylmethoxy-
carbonyl)amino]methyl}3,5,5-trimethylcyclohexyl}carbamate rac-
6-cis. To a solution of 9-fluorenylmethyl-N-succinimidyl carbonate
(1.00 g, 2.96 mmol) and NaHCO3 (200 mg, 2.12 mmol) in dioxane/
water (2:1, 50 mL) was added at room temperature 3-aminomethyl-
3,5,5-trimethylcyclohexylamine 3-mix (260 µl, 1.41 mmol), and the
CDCl3): δ 7.48-7.27 (m; 10H), 5.07 (s; 2H), 5.06 (2s; 2H), 4.86-
4.73 (m; 1H), 4.55-4.46 (m; 1H), 3.91-3.68 (m; 1H), 2.96-
(16) rac-7-cis was mentioned previously, but no procedure for its
preparation was reported: Takata, M.; Hisamatsu, N. German Patent
19910363 A1, 1999.
9316 J. Org. Chem., Vol. 71, No. 25, 2006

Enantiomerically Pure Isophorone Diamine
2.85 (m; 2H), 1.78-1.61 (m; 2H), 1.27-0.78 (m; 4H), 0.90 (s;
3H), 1.04 (s; 6H). 13C NMR (75 MHz, CDCl3): δ 156.7 (s), 155.5
(s), 136.5 (s), 128.4 (d), 128.1 (d), 128.0 (d), 66.7 (t), 66.4 (t),
54.8 (t), 46.2 (t), 46.9 (t), 44.6 (d), 41.7 (t), 36.3 (s), 34.9 (q), 31.7
(s), 27.5 (q), 23.2 (q). HRMS (ESI): calcd for C26H34N2O4+Na+,
461.2416; found, 461.2420. Anal. Calcd for C26H34N2O4: C, 71.21;
H, 7.81; N, 6.39. Found: C, 71.13; H, 7.79; N, 6.44. HPLC (anal.,
Daicel Chiralpak AD (4.60 mm i.d. × 250 mm), n-hexane/2-
propanol (80/20, v/v), flow 1.00 mL/min) τR 9.8 min, 11.1 min
[trans isomers], τR 12.6 min [7-cis (1R,3S)], 18.2 min [ent-7-cis
(1S,3R)]. The two enantiomers of carbamate rac-7-cis were
separated by chiral preparative HPLC on a Daicel Chiralpak AD
column (50 mm i.d. × 500 mm length) with n-hexane/2-propanol
(60/40, v/v), flow 60 mL/min; τR 27 min [7-cis], 47 min [ent-7-
cis] (strong tailing). A total of 250 mg of rac-7-cis dissolved in 10
mL of hot EtOH were injected per run. The fractions were
extraction with 500 µL of ethyl acetate and evaporation of the
solvent, the sample was analyzed by HPLC on chiral stationary
phase. HPLC (anal., Daicel Chiralpak AD (4.60 mm i.d. × 250
mm) column, n-hexane/2-propanol (80/20, v/v), flow 1.00 mL/min)
τR 12.6 min [7-cis (1R,3S)], 18.2 min [ent-7-cis (1S,3R)].
(1R,3S)-3-Aminomethyl-3,5,5-trimethylcyclohexylamine 3-cis.
(2R,3R)-2,3-Bis(benzoyloxy)butanedioic acid (1S,5R)-(5-amino-
1,3,3-trimethylcyclohexyl)-methaneamine salt (1:1) 9 (5.28 g 10.0
mmol) was dissolved in 5 M sodium hydroxide solution (25.0 mL).
The clear solution was extracted with 4 × 50.0 mL of dichlo-
romethane, the organic phase was dried over Na2SO4, and the main
part of the solvent evaporated. Vacuum distillation gave (1R,3S)-
3-aminomethyl-3,5,5-trimethylcyclohexylamine 3-cis as a clear
liquid (to be stored under argon) in quantitative yield: bp 120 °C
(0.5 mbar). HR-MS (EI): calcd for C10H22N2+, 170.1783; found,
1
171.1780. H NMR (300 MHz, CDCl3): δ 2.96 (tt; J ) 11.7 Hz,
concentrated in vacuo. 7-cis [R]20 +10.7 (CHCl3, c 0.98). ent-7-
J ) 3.8 Hz, 1H), 2.30 (s; 2H), 1.65-1.40 (m; 2H), 1.19-1.09 (m;
1H), 1.07-0.66 (m; 16H). 13C NMR (75 MHz, CDCl3): δ 58.0
(t), 50.9 (t), 47.6 (d), 46.2 (t), 44.5 (q), 36.9 (s), 35.6 (q), 32.4 (s),
D
cis [R]20 -10.7 (c 1.14, CHCl3).
D
(1R,3S)- and (1S,3R)-3-Aminomethyl-3,5,5-trimethylcyclo-
hexylamine 3 [3-cis and ent-3-cis]. (1R,3S)- or (1S,3R)-cis-Benzyl-
N-{3-[(benzyloxycarbonylamino)methyl]-3,5,5-trimethylcyclohexyl}-
carbamate 7-cis or ent-7-cis (120 mg, 274 µmol), obtained by
preparative HPLC, were dissolved in 5.00 mL of absolute MeOH,
and Pd-C (5%; 20.0 mg) was added. The mixture was stirred at
room temperature under H2 atmosphere (1 bar) for 12 h. The solid
catalyst was filtered off over Celite, and the solvent was removed
under reduced pressure to yield (1R,3S)- or (1S,3R)-3-aminomethyl-
3,5,5-trimethylcyclohexylamine 3-cis or ent-3-cis as clear liquids
in quantitative yield. See below for the characterization of 3-cis.
3-Aminomethyl-3,5,5-trimethylcyclohexylamine carbamic acid
rac-8-cis. Exposition of 3-aminomethyl-3,5,5-trimethylcyclohexyl-
amine 3-mix to air led to gradual precipitation of colorless crystals
of the carbamic acid rac-8-cis which were subjected to X-ray
crystallography: mp 142 °C dec. IR (CsI): 3385, 2948, 2738, 2617,
1597, 1473, 1465, 1455, 1376, 1326, 1213.
28.4 (q), 23.8 (q). [R]20 +3.1 (c 1.51, CHCl3).
D
General Procedure for the Preparation of IPDA Schiff-Base
Ligands 10a, 10c, and 10g. To a solution of (2R,3R)-2,3-bis-
(benzoyloxy)butanedioic acid (1S,5R)-(5-amino-1,3,3-trimethyl-
cyclohexyl)-methaneamine salt (1:1) 9 (1.00 equiv) and K2CO3
(2.00 equiv) in water was added EtOH and a solution of the salicylic
aldehyde (2.00 equiv) in EtOH. A yellow precipitation was formed
immediately. The reaction mixture was allowed to stir at room
temperature for an additional hour, then water was added, and the
mixture was cooled to 5 °C for 1 h. The solid was filtered off,
washed with EtOH and water, and then dissolved in CH2Cl2. The
organic layer was washed with water and brine, dried over Na2SO4,
and filtered, and the solvent was removed under reduced pressure.
2-((E)-(((1S,5R)-5-((E)-2-Hydroxybenzylideneamino)-1,3,3-tri-
methylcyclohexyl)methylimino)methyl)phenol 10a. The bis-Schiff
base was crystallized from EtOH/CH2Cl2 to yield 90.0 mg (63%)
of the product 10a as bright yellow needles, which were subjected
to X-ray crystallography: mp 145 °C. IR (CsI): 3406, 2964, 1630,
1605, 1501, 1476, 1378, 1347, 1280, 892, 769 cm-1. 1H NMR (300
MHz, CDCl3): δ 13.58 (s(br); 2H), 8.41 (s; 1H), 8.31 (s; 1H), 7.36-
7.19 (m; 4H), 7.00-6.81 (m; 4H), 3.59 (tt; J ) 11.6 Hz, J ) 3.9
Hz, 1H), 3.43-3.28 (m; 2H), 1.70-1.56 (m; 2H), 1.48-1.34 (m;
2H), 1.24-1.26 (m; 2H), 1.21 (s; 3H), 1.12, (s; 3H), 1.00 (s; 3H).
13C NMR (75 MHz, CDCl3): δ 165.3 (d), 163.0 (d), 161.2 (s),
161.1 (s), 132.2 (d), 132.0 (d), 131.3 (d), 131.1 (d), 118.7 (s), 118.5
(d), 118.4 (d), 117.0 (d), 75.1 (t), 62.0 (d), 48.0 (t), 47.3 (t), 43.8
(t), 36.0 (s), 31.5 (s), 35.0 (q), 28.0 (q), 24.4 (q). HRMS (EI): calcd
for C24H30N2O2+, 378.2307: found, 378.2305. Anal. Calcd for
C24H30N2O2: C, 76.16; H, 7.99; N, 7.40. Found: C, 76.06; H, 8.01;
(2R,3R)-2,3-Bis(benzoyloxy)butanedioic Acid (1S,5R)-(5-
Amino-1,3,3-trimethylcyclohexyl)-methaneamine Salt (1:1) 9.
3-Aminomethyl-3,5,5-trimethylcyclohexylamine 3-mix (200 mL,
1.08 mol) was added at room temperature to R,R-dibenzoyl tartaric
acid (155 g, 432 mmol) suspended in distilled water (2.00 L) with
vigorous stirring. During the exothermic reaction the solution
cleared, and then the precipitation of the product started after about
5 min. The reaction mixture was cooled to 0 °C and left at this
temperature for 1.5 h. The solid was filtered off, washed with 3 ×
200 mL of 2-propanol, and dried under reduced pressure over
phosphorus pentoxide. One recrystallization from 2-propanol/water
(2:1, 1.00 L) yielded 120 g (21% corresponding to the amount of
3-mix used, 56% based on the amount of (1R,3S)-3-cis present in
3-mix) of (2R,3R)-2,3-bis(benzoyloxy)butanedioic acid (1S,5R)-
(5-amino-1,3,3-trimethylcyclohexyl)-methaneamine salt (1:1) 9 as
colorless crystals with dr > 99:1, suitable for X-ray crystal-
lography: mp 205 °C. IR (CsI): 3428, 2954, 2713, 1723, 1607,
1407, 1333, 1280, 1122, 1025, 736, 716. 1H NMR (300 MHz, d6-
DMSO): δ 8.04-7.96 (m; 4H), 7.66-7.57 (m; 2H), 7.56-7.46
(m; 4H), 5.53 (s; 2H), 4.31 (s(br); 6H), 3.25-3.03 (m; 1H), 2.16 (s;
2H), 1.60-1.41 (m; 2H), 1.08-0.98 (m; 2H), 0.96-0.87 (m; 2H),
0.84 (s; 3H), 0.82 (s; 3H), 0.81 (s; 3H). 13C NMR (75 MHz, d6-
DMSO): δ 169.8 (s), 165.2 (s), 132.6 (d), 131.2 (s), 129.2 (d),
128.3 (d), 76.0 (d), 55.4 (t), 46.3 (t), 43.9 (d), 44.6 (t),41.1 (t),
34.6 (q), 35.4 (s), 34.6 (q), 31.1 (s), 22.8 (q). HRMS (ESI): calcd
for C10H22N2+H+, 171.1861; found, 171.1860. Anal. Calcd for
C28H36N2O8: C, 63.62; H, 6.86; N, 5.30. Found: C, 63.22; H, 6.98;
N, 5.24. 9 [R]20D -74.1 (c 0.51, H2O). Application of S,S-dibenzoyl
tartaric acid gave the DBTA salt of the (1S,3R)-amine ent-9,
N, 7.38. [R]20 -42.5 (c 1.05, CHCl3).
D
2-((E)-(((1S,5R)-5-((E)-5-Chloro-2-hydroxybenzylideneamino)-
1,3,3-trimethylcyclohexyl)methylimino)methyl-4-chlorophenol
10c. The bis-Schiff base was crystallized from EtOH/CH2Cl2 to
yield 138 mg (82%) of the product 10c as yellow needles, which
were subjected to X-ray crystallography: mp 220 °C. IR (CsI):
1
3423, 2959, 1633, 1605, 1481, 1382, 1346, 1279 cm-1. H NMR
(300 MHz, CDCl3): δ 13.52 (s(br); 2H), 8.34 (s; 1H), 8.24 (s; 1H),
7.30-7.18 (m; 2H), 6.95-6.82 (m; 4H), 3.60 (tt; J ) 11.6 Hz, J
) 3.8 Hz, 1H), 3.43-3.29 (m; 2H), 1.68-1.56 (m; 2H), 1.48-
1.34 (m; 2H), 1.29-1.23 (m; 2H), 1.20 (s; 3H), 1.12, (s; 3H), 1.00
(s; 3H). 13C NMR (75 MHz, CDCl3): δ 164.3 (d), 161.9 (d), 159.9
(s), 132.2 (d), 132.0 (d), 130.5 (d), 130.3 (d), 123.1 (s), 123.0 (d),
119.4 (d), 118.6 (d), 74.9 (t), 62.0 (d), 47.9 (t), 47.1 (t), 43.6 (t),-
36.0 (s), 35.1 (q), 31.5 (s), 28.0 (q), 24.5 (q). HRMS (EI): calcd
for C24H28Cl2N2O2+, 446.1528; found, 446.1523. Anal. Calcd for
C24H28Cl2N2O2: C, 64.43; H, 6.31; N, 6.26. Found: C, 64.06; H,
respectively: ent-9 [R]20 +74.1 (c 0.51, H2O). To determine the
D
6.33; N, 6.17. [R]20 -6.3 (c 1.10, CHCl3).
enantiomeric composition of the diamine 3-cis present in the salt 9, a
sample of the crystalline product and K2CO3 were dissolved in 1.00
mL of distilled water. An amount of 500 µl of benzyl chloroformate
was added, and the suspension was heated thoroughly. After
D
2-((E)-(((1S,5R)-5-((E)-2-Hydroxy-3-methoxybenzylidene-
amino)-1,3,3-trimethylcyclohexyl)methylimino)methyl-6-meth-
oxyphenol 10g. The bis-Schiff base was crystallized from EtOH/
J. Org. Chem, Vol. 71, No. 25, 2006 9317

Berkessel et al.
CH2Cl2 to yield 1.00 g (67%) of the product 10g as yellow
crystals: mp 62 °C. IR (ATR): 2949, 2910, 2835, 1625, 1461,
then suspended in ethanol (5.00 mL), and IPDA 3-mix (140 µl,
758 µmol) was added. The mixture was heated to 80 °C for 1 h,
then water (20.0 mL) was added, and the dark green precipitation
was isolated by filtration. A crystal suitable for X-ray crystal-
lography was obtained by recrystallization from CHCl3/EtOH/H2O.
1439, 1416, 1248, 1168, 1079, 1047, 974, 838, 777, 732, 664 cm-1
.
1H NMR (300 MHz, CDCl3): δ 14.22 (s(br); 1H), 14.06 (s(br);
1H), 8.44-8.35 (m; 1H), 8.35-8.25 (m; 1H), 6.98-6.73 (m; 6H),
3.96-3.85 (m; 6H), 3.69-3.53 (m; 1H), 3.45-3.27 (m; 2H), 1.72-
1.58 (m; 2H), 1.54-1.31 (m; 3H), 1.30-0.92 (m; 10H). 13C NMR
(75 MHz, CDCl3): δ 165.4 (d), 163.0 (d), 152.3 (s), 148.6 (s),
122.9 (d), 118.6 (s), 118.4 (s), 117.7 (d), 117.6 (d), 114.0 (d), 113.7
(d), 74.5 (t), 61.4 (d), 56.2 (q), 56.0 (q), 47.9 (t), 47.2 (t), 43.8 (t),
36.0 (s), 35.1 (q), 31.5 (s), 28.0 (q), 24.4 (q). HRMS (EI): calcd
for C26H34N2O4+, 438.2518; found, 438.2515.
Acknowledgment. This work was supported by the Fonds
der Chemischen Industrie. We thank the BASF AG for a
donation of technical IPDA (3-mix).
Supporting Information Available: Preparation of the IPDA-
salen ligands 10b,d-f; 1H and 13C NMR spectra for all new
compounds, Crystallographic information files (CIF) for compounds
rac-4-cis, 4-cis, ent-4-cis, rac-5-cis, rac-6-cis, rac-7-cis, rac-8-cis,
9, 10a,c and rac-11; X-ray crystallographic data and crystal
structures for compounds rac-4-cis, 4-cis, ent-4-cis, rac-5-cis, rac-
6-cis, rac-7-cis, rac-8-cis, 9, 10a,c and rac-11. This material is
available free of charge via the Internet at http://pubs.acs.org.
Nickel Complex rac-11. Nickel acetate (378 mg, 1.52 mmol)
was dissolved in water (5.00 mL) and heated to 50 °C with 5-chloro-
2-hydroxybenzaldehyde (238 mg, 1.52 mmol) in ethanol (5.00
mL).17 A green solid precipitated which was filtered off, dried, and
(17) Pfeiffer, P.; Breith, E.; Lu¨bbe, E.; Tsumaki, T. Liebigs Ann. Chem.
1933, 503, 84-130.
JO0613737
9318 J. Org. Chem., Vol. 71, No. 25, 2006