Facile monoprotection of trans-1,2-diaminocyclohexane

Article abstract of DOI:10.1016/S0957-4166(03)00308-2

A new method of monoprotection of C₂-symmetric trans-1,2-diaminocyclohexane as the N-phthaloyl, N-tetrachlorophthaloyl or N-1,8-naphthaloyl derivative is presented. The first two derivatives are obtained with high yields and can be readily transformed into other unsymmetrical derivatives of trans-1,2-diaminocyclohexane.

Full text of DOI:10.1016/S0957-4166(03)00308-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1559–1563
Facile monoprotection of trans-1,2-diaminocyclohexane
M. Kaik and J. Gawron´ski*
Department of Chemistry, A. Mickiewicz University, Poznan´, Poland
Received 19 February 2003; accepted 3 April 2003
Abstract—A new method of monoprotection of C2-symmetric trans-1,2-diaminocyclohexane as the N-phthaloyl, N-tetra-
chlorophthaloyl or N-1,8-naphthaloyl derivative is presented. The first two derivatives are obtained with high yields and can be
readily transformed into other unsymmetrical derivatives of trans-1,2-diaminocyclohexane. © 2003 Elsevier Science Ltd. All rights
reserved.
1. Introduction
intramolecular hydrogen bonding by the acylamino
group.10 Monoprotected derivative 1b was obtained
directly from 1a (1 equiv.) with the yield 30%, by using
2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile as
the acylating agent.11 Likewise, 1b was obtained from
di-t-butyl dicarbonate and 1a (3 equiv.) with the claimed
yield 73%; yield based on 1a was only 24%.12
Non-racemic trans-1,2-diaminocyklohexane (DACH),
1a, is readily available in both enantiomeric forms by
simple resolution of the crude commercial racemate with
tartaric acid.1 In the past ten years DACH has received
much interest as a starting material for making enan-
tiomerically pure reagents, scaffolds and ligands.2 Exam-
ples include the preparation of Jacobsen’s salen ligands
for asymmetric epoxidation3 and asymmetric epoxide
ring-opening reactions,4 Trost’s ligand for enantioselec-
tive allylic alkylations5 and the synthesis of chiral
oligomeric diimines6 and diimides.7 Other uses involve
controlled formation of hybrid organic–inorganic struc-
tures with helical morphology.8,9
Since commercial enantiomerically pure 1a and its enan-
tiomer are expensive, the direct method may not be
practical for large-scale applications.
The majority of reported derivatives of DACH are
symmetrically N,N%-disubstituted. Nevertheless there is a
demand for its unsymmetrically substituted derivatives,
for example to prepare hybrid ligands. To meet this goal,
monoprotection of DACH has been used as the initial
synthetic step. Several methods for monoprotection of 1a
have been reported. The versatile mono-N-Boc protected
derivative 1b was obtained in three steps, first by dipro-
tection of DACH with the Cbz groups (2a), followed by
monoprotection with the Boc group (2b) and finally by
hydrogenolytic removal of both Cbz groups. The overall
yield of the three-step sequence was high (89%), in
contrast to the failed attempts to directly monoprotect
1a with 1 equiv. of the acylating reagent which gave the
diacylated derivative as the major product. This finding
was ascribed to a higher reactivity of the monoacylated
derivative, compared to the reactivity of the parent
diamine 1a, as a result of a general base catalysis through
* Corresponding author. Tel.: +48-61-8291313; fax: +48-61-8658008;
e-mail: gawronsk@amu.edu.pl
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00308-2

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M. Kaik, J. Gawron´ski / Tetrahedron: Asymmetry 14 (2003) 1559–1563
the formation of salt with p-toluenesulfonic acid. In a
similar way, related monoprotected DACH derivatives,
7·p-TsOH and 8·p-TsOH, were obtained with the use
of, correspondingly, tetrachlorophthalic anhydride
(yield 95%) or 1,8-naphthalic anhydride (yield 67%).
Monoacetyl derivative 1c was obtained from DACH
with 90% yield by the reaction with the Pinner salt,
MeC(OEt)ꢀNH·HCl, followed by hydrolysis of the
intermediate imidazoline 3. Monoprotected 1c was fur-
ther converted to the N,N-dimethyl derivative 4a by
reductive amination, followed by acidic hydrolysis of
the acetamide group under rather harsh conditions.13
Further substitution reactions of the amino group in 5a
led to products 5b, 5c, 5d, 9a and 9b. Orthogonally
protected diamine 5b was obtained by the reaction of
5a with benzaldehyde, with subsequent reduction of the
isolated imine 6 with sodium cyanoborohydride (overall
yield 70%). Sulfonylation of 5a gave products 5c or 5d
with yields 83–87%. Dialkylated derivatives 9a and 9b
were obtained correspondingly by the Eschweiler–Clark
methylation (yield 86%) or by alkylation with benzyl
bromide (yield 72%). The phthaloyl group in 5b, 5c, 5d,
9a and 9b was removed by a standard reaction with
hydrazine to yield the monoprotected DACH deriva-
tives 1d, 1e, 1f, 4a and 4b with yields 90–95%. The
products were fully characterized (see Experimental
Section).
Direct monoderivatization of DACH with 1 equiv. of
aryl sulfonyl chloride has been reported to proceed with
moderate yield (55–65%).14 Monotoluenesulfonyl
derivative 1d was alternatively prepared using 3 equiv.
of 1a.15 More conveniently monosulfonamide deriva-
tives of DACH, free of bis-sulfonamides, can be
obtained from the salt of 1a with tartaric acid, which is
a less expensive and more stable commercial source of
DACH, but again 1a had to be used in a three-fold
excess (yield of 1d 31%).16a An improved procedure
requires 1.5-fold excess 1a and the yields of monosul-
fonamide derivatives are around 40%.16b
We have found that DACH derivatives can be conve-
niently identified by the position of the 1H NMR
signals of the protons adjacent to the CꢁN bonds.
These signals appear as doublets of triplets, with two
vicinal axial/axial couplings (J=10.4–11.7 Hz) and one
axial/equatorial coupling (J=3.2–4.1 Hz), when there is
no proton on the adjacent nitrogen atom. The chemical
shifts of the signals, relative to those of the parent
DACH molecule (l=2.20), depend on the nature of
substituents on both nitrogen atoms. Remarkable is a
large shielding effect of both axial a and b protons due
to the protecting imide group. For example, monoph-
thaloylation 5a brings about a large downfield shift of
Monourea and monothiourea derivatives were obtained
from DACH hydrochloride by the reaction with iso-
cyanates or isothiocyanates at −30°C. The yields were
below 50%, based on the used DACH.17 Monoalkyla-
tion of
2
equiv. of DACH with (3-chloro-
propyl)triethoxysilane was reported to proceed with
70% yield.18 Similarly, palladium-catalyzed monoaryla-
tion of DACH with aryl bromides afforded the prod-
ucts with low to moderate yields.19
Finally, we note that monoimine derivatives of DACH
were prepared by reacting derivatives of salicylaldehyde
with a slight excess of 1a at 0°C. These intermediates
were used for the subsequent preparation of unsymmet-
rical Schiff bases of 1a with good to high yields.20 The
ratio of mono- to diimine products apparently
depended on the structure of the salicylaldehyde and
the solvent used. It was found21 that the mono-Schiff
base derivative of DACH could be separated from the
equilibrium mixture by precipitation of its salt with
(+)-O,O%-dibenzoyltartaric acid.
the CH
6 N(imide) signal (Dl=1.60), as well as the vicinal
CH
6
NH2 signal (Dl=1.20). Actual positions of the rele-
vant resonance signals of 5a are 3.80 and 3.41. Bis-1,8-
naphthaloylation of DACH shifts the signals of the
CH6 N protons by as much as 4.2 ppm, from l=2.2 to
l=6.4.22 More detailed data are collected in Table 1.
3. Conclusion
Monoprotection of DACH with either phthalic or
tetrachlorophthalic anhydride is a high yield and conve-
nient procedure, opening a way to numerous unsym-
metrically substituted and synthetically useful deriva-
tives of DACH.
2. Results and discussion
Herein we present a practical method of monoprotec-
tion of DACH which was developed in the course of
the synthesis of oligoimides of DACH.7a The method is
based on monophthaloylation of DACH, a process that
is simple to carry out and requires only cheap reagents.
Monophthaloylation has been achieved by heating in
toluene 1a with 1 equiv. of each phthalic anhydride and
p-toluenesulfonic acid. The product, the salt 5a·p-
TsOH, was directly obtained as a crystalline solid in
92% yield. Free monoprotected diamine 5a was isolated
from the salt by simple carbonate treatment. The suc-
cess of this monoprotection reaction can be ascribed to
the steric effect the phthaloyl group which is exerted on
the vicinal amino group, combined with the effect of
removal of the product from the reaction medium by
4. Experimental
4.1. General methods
1H NMR spectra were determined at 298 K in CDCl3,
if not stated otherwise; chemical shifts are reported in
ppm relative to TMS. IR spectra were measured in KBr
pellets. EI mass spectra were taken on an AMD 402
spectrometer. Optical rotations were measured with a
Perkin Elmer 243 B polarimeter. Elemental analyses
were obtained with a Vario EL III instrument. Melting
points are uncorrected.

M. Kaik, J. Gawron´ski / Tetrahedron: Asymmetry 14 (2003) 1559–1563
1561
Table 1. Dl of Ra and Rb to the chemical shift of Ha in derivatives of trans-1,2-diaminocyclohexane
š
Substituenta
NMe2
NHBn
NBn2
NH3
NHTs
NHMs
Ra
Rb
−0.1
0.3
−0.1
0.2
−0.1
0.5
0.5
0.4
0.4
0.1
0.6
0.2
Substituenta
NꢀCHPhb
NHBocc
NHAc
NHBzd
NHPhte
NNphf
Ra
Rb
1.0
0.2
1.0
0.1
1.1
0.2
1.3
0.3
1.6
1.2
2.5
1.7
a Basal value for Ha in DACH: 2.20 ppm (CDCl3).
b Similar values were obtained for p-substituted benzylidene derivatives.
c Data from Ref. 11.
d Data from Ref. 23.
e Identical values were obtained for tetrachlorophthalimide substituent.
f NNph=1,8-naphthalenedicarboximide.
4.2. (1R,2R)-N-Phthaloyl-1,2-diaminocyclohexane 5a
and (1R,2R)-N-tetrachlorophthaloyl-1,2-diaminocyclo-
hexane 7
5a: yield 83%, mp 123–125°C; [h]2D0 −79.3 (c 1, CHCl3);
1H NMR l 1.1–1.5 (m, 5H), 1.7–1.9 (m, 3H), 2.0–2.1
(m, 1H), 2.1–2.3 (m, 1H), 3.42 (dt, J=4.0, 11.0 Hz,
1H), 3.81 (dt, J=4.0, 10.6 Hz, 1H), 7.70–7.75 (m, 2H),
7.80–7.85 (m, 2H). IR w (cm−1) 3058, 2937, 2862, 1710,
1642, 1556, 1372, 842, 829, 713. Anal. calcd for
C14H16N2O2: C, 68.83; H, 6.60; N, 11.47. Found: C,
68.74; H, 6.55; N, 11.49%.
A solution of p-TsOH·H2O (1.92 g, 0.01 mol) in xylenes
(50 mL) was dehydrated by azeotropic distillation.
After cooling to room temperature to the solution was
added DACH (1a, 1.14 g, 0.01 mol) followed by
phthalic anhydride (1.48 g, 0.01 mol) or tetra-
chlorophthalic anhydride (2.86 g, 0.01 mol). The mix-
ture was heated with stirring until homogeneous
solution was obtained and the product begun to crystal-
lize. The product was collected by filtration, washed
with xylene–hexane and air-dried.
7: yield 92%, mp 132–134°C (from ethanol–diethyl
ether); [h]2D0 −24.2 (c 0.5, MeOH); 1H NMR (CD3OD) l
1.2–1.5 (m, 3H), 1.7–1.9 (m, 3H), 2.0–2.2 (m, 2H), 3.40
(dt, J=3.2, 11.5 Hz, 1H), 3.86 (dt, J=3.8, 11.3 Hz,
1H). IR w (cm−1) 3268, 3060, 2940, 2860, 1658, 1555,
1406, 1338, 1285, 1020, 914, 742, 659, 649, 618. Anal.
calcd for C14H12Cl4N2O2: C, 44.01; H, 3.17; N, 7.33.
Found: C, 43.93; H, 3.21; N, 7.12%.
5a·p-TsOH: yield 92%, mp 249–252°C (from dioxane–
1
toluene); [h]2D0 −15.8 (c 1, CHCl3); H NMR l 1.1–2.1
(m, 8H), 3.93 (m, 1H), 4.18 (dt, J=3.8, 11.3 Hz, 1H),
6.99 (d, J=8.2 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H),
7.4–7.5 (m, 2H), 7.5–7.6 (m, 2H), 7.84 (bs, 3H). IR w
(cm−1) 3387, 3026, 2949, 2887, 1774, 1707, 1496, 1386,
1214, 816, 684.
4.3. (1R,2R)-N-1%,8%-Naphthaloyl-1,2-diaminocyclohex-
ane 8
To a solution of 1,8-naphthaloyl anhydride (1.98 g,
0.01 mol) in DMF (20 mL), stirred at 90°C, was added
1a (1.14 g, 0.01 mol) and p-TsOH·H2O (1.92 g, 0.01
mol). Stirring at 120–130°C was continued for 4 h.
After cooling to room temperature, water was added to
precipitate the unreacted anhydride. The mixture was
filtered, the solution evaporated in vacuo and the
residue crystallized from methanol–diethyl ether to give
8·p-TsOH: yield 67%, mp 280–282°C; [h]2D0 +3.2 (c 0.5,
7·p-TsOH: yield 95%, mp 320–323°C (from ethanol–
toluene); [h]2D0 −20.0 (c 0.5, CHCl3); 1H NMR (CD3OD)
l 1.4–1.6 (m, 3H), 1.85–1.95 (m, 3H), 2.15–2.30 (m,
2H), 2.37 (s, 3H), 3.94 (dt, J=3.8, 11.3 Hz, 1H), 4.18
(dt, J=3.8, 11.3 Hz, 1H), 7.21 (d, J=8.2 Hz, 2H), 7.65
(d, J=8.1 Hz, 2H). IR w (cm−1) 3083, 3055, 3022, 2960,
2934, 2857, 2835, 2810, 1765, 1707, 1494, 1453, 1390,
1103, 1075, 976, 746, 718, 698.
1
CHCl3); H NMR (CD3OD) l 1.4–1.6 (m, 3H), 1.8–2.0
(m, 2H), 2.2–2.3 (m, 1H), 2.37 (s, 3H), 2.5–2.6 (m, 1H),
4.39 (dt, J=3.8, 10.4 Hz, 1H), 5.12 (dt, J=3.8, 10.0 Hz,
1H), 7.23 (d, J=8.0 Hz, 2H), 7.70 (d, J=8.0 Hz, 2H),
7.84 (t, J=7.1 Hz, 2H), 8.39 (d, J=7.1 Hz, 2H), 8.60
(m, 2H). IR w (cm−1) 3387, 3026, 2949, 2887, 1774,
1707, 1496, 1386, 1214, 816, 684.
A solution of either 5a·p-TsOH or 7·p-TsOH (1 mmol)
in dichloromethane (25 mL) was stirred overnight with
saturated NaHCO3 solution (5 mL). The organic solu-
tion was separated, dried over MgSO4 and the solvent
removed to give either 5a or 7.

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M. Kaik, J. Gawron´ski / Tetrahedron: Asymmetry 14 (2003) 1559–1563
The salt was converted to 8 as described for 5a and 7.
Yield 87%, mp 205–210°C (from benzene–hexane);
CHCl3); 1H NMR l 1.4–1.6 (m, 2H), 1.7–1.95 (m,
5H), 2.2–2.35 (m, 1H), 4.07 (dt, J=4.1, 10.4 Hz, 1H),
4.45 (dt, J=3.9, 10.4 Hz, 1H), 7.31 (m, 3H), 7.57 (m,
2H), 7.6–7.7 (m, 2H), 7.7–7.8 (m, 2H), 8.20 (s, 1H). IR
w (cm−1) 3063, 2943, 2862, 2674, 2559, 1769, 1707,
1602, 1583, 1496, 1453, 1424, 1327, 1292, 1128, 1097,
934, 752, 716, 624. Anal. calcd for C21H20N2O2: C,
75.88; H, 6.06; N, 8.43. Found: C, 75.79; H, 6.17; N,
8.40%.
1
[h]2D0 +2.4 (c 0.5, CHCl3); H NMR l 1.2–1.4 (m, 3H),
1.4–1.6 (m, 2H), 1.7–1.9 (m, 3H), 2.0–2.1 (m, 1H),
2.4–2.6 (m, 1H), 3.78 (dt, J=3.8, 10.4 Hz, 1H), 4.79
(dt, J=3.8, 10.4 Hz, 1H), 7.76 (t, J=7.4 Hz, 2H), 8.20
(d, J=8.3 Hz, 2H), 8.60 (bs, 2H). IR w (cm−1) 3055,
3022, 2935, 2810, 1765, 1707, 1612, 1494, 1310, 746,
718, 699. Anal. calcd for C18H18N2O2: C, 73.45; H,
6.16; N, 9.52. Found: C, 73.53; H, 6.01; N, 9.62%.
4.7. (1R,2R)-N-Benzyl-N%-phthaloyl-1,2-diaminocyclo-
hexane 5b
4.4. (1R,2R)-N,N-Dimethyl-N%-phthaloyl-1,2-diamino-
cyclohexane 9a
To a solution of imine 6 (325 mg, 0.97 mmol) in
acetonitrile (7 mL) stirred in an ice bath (0 to −5°C)
for 15 min was added NaBH3CN (126 mg, 2 mmol)
followed by a few drops of acetic acid. Stirring was
continued for additional 3 h at room temperature.
After solvent removal and extractive work-up
(dichloromethane–saturated NaHCO3) product 5b was
crystallized from benzene–hexane, yield 75%, mp 92–
A mixture of 5a (709 mg, 2.9 mmol), 80% formic acid
(1.2 mL) and 36% formaldehyde solution (0.5 mL, 6.4
mmol) was stirred under reflux (oil bath 120°C) for 6
h. The solvents were removed in vacuo and the
product was extracted with dichloromethane and satu-
rated NaHCO3 solution. The organic solution was
dried over MgSO4 and evaporated to give crude
product. After crystallization from benzene–hexane 9a
was obtained as colorless crystals, yield 679 mg (86%),
1
94°C; [h]2D0 −53.7 (c 1, CHCl3); H NMR l 1.05–1.2
(m, 1H), 1.3–1.45 (m, 3H), 1.7–1.9 (m, 3H), 2.2–2.3
(m, 2H), 3.25 (dt, J=3.8, 11.0 Hz, 1H), 3.60 (d, J=
13.7 Hz, 1H), 3.81 (d, J=13.2 Hz, 1H), 3.96 (dt,
J=3.8, 11.0 Hz, 1H), 7.0–7.1 (m, 5H), 7.65–7.75 (m,
2H), 7.8–7.9 (m, 2H). IR w (cm−1) 3450, 3334, 3087,
3063, 3030, 2938, 2855, 1766, 1699, 1465, 1371, 1072,
717. Anal. calcd for C21H22N2O2: C, 75.42; H, 6.63; N,
8.38. Found: C, 75.44; H, 6.53; N, 8.32%.
1
mp 117–120°C; [h]D20 −32.5 (c 1, CHCl3); H NMR l
1.1–1.4 (m, 3H), 1.7–2.0 (m, 5H), 2.14 (s, 6H), 3.30
(dt, J=3.4, 11.7 Hz, 1H), 4.11 (dt, J=3.7, 11.7 Hz,
1H), 7.65–7.70 (m, 2H), 7.80–7.82 (m, 2H). IR w
(cm−1) 3451, 2929, 2861, 1761, 1706, 1468, 1461, 1138,
1078, 1042, 717 cm−1. Anal. calcd for C16H20N2O2: C,
70.56; H, 7.40; N, 10.29. Found: C, 70.41; H, 7.12; N,
10.28%.
4.5. (1R,2R)-N,N-Dibenzyl-N%-phthaloyl-1,2-diamino-
cyclohexane 9b
4.8. (1R,2R)-N-p-Toluenesulfonyl-N%-phthaloyl-1,2-
diaminocyclohexane 5c and (1R,2R)-N-methanesul-
fonyl-N%-phthaloyl-1,2-diaminocyclohexane 5d
To a solution of 5a (244 mg, 1 mmol) in acetonitrile
(5 mL) was added at room temperature K2CO3 (320
mg, 2.3 mmol) and benzyl bromide (0.3 mL, 2.5
mmol). The mixture was refluxed with stirring for 4 h.
The solvent was removed in vacuo and the mixture
extracted with dichloromethane and saturated
NaHCO3 solution. The organic solution was dried
over MgSO4 and evaporated. Product 9b was crystal-
lized from benzene–hexane, yield 72%, mp 123–127°C;
To a solution of 5a (244 mg, 1 mmol) and diisopropyl-
ethylamine (0.26 mL, 1.5 mmol) at 0°C was added
appropriate sulfonyl chloride (1 mmol) and the mix-
ture was stirred at room temperature for 6 h. Extrac-
tion with dichloromethane–1N HCl followed by
washing with brine and drying over MgSO4 afforded
products 5c or 5d.
1
[h]2D0 −27.3 (c 1, CHCl3); H NMR l 1.2–1.4 (m, 3H),
5c: crystallized from benzene–hexane, yield 89%, mp
1
1.7–1.9 (m, 3H), 2.1–2.3 (m, 2H), 3.30 (m, 1H), 3.33
(d, J=13.4 Hz, 2H), 3.75 (d, J=13.2 Hz, 2H), 4.31
(dt, J=3.7, 11.7 Hz, 1H), 7.0–7.2 (m, 10H), 7.7–7.9
(br m, 4H). IR w (cm−1) 3456, 3083, 3056, 3022, 2935,
2858, 2810, 1765, 1705, 1612, 1600, 1583, 1494, 1468,
1453, 1389, 1358, 1244, 1104, 1075, 1019, 976, 907,
872, 850, 746, 718, 638. Anal. calcd for C28H28N2O2:
C, 79.22; H, 6.65; N, 6.60. Found: C, 79.25; H, 6.44;
N, 6.42%.
198–202°C; [h]2D0 −19.9 (c 1, CHCl3); H NMR l 1.1–
1.6 (m, 4H), 1.7–1.9 (m, 3H), 2.13 (s, 3H), 2.3–2.45
(m, 1H), 3.83 (m, 2H), 4.44 (d, J=9.3 Hz, 1H), 6.88
(d, J=8.0 Hz, 2H), 7.48 (d, J=8.2 Hz, 2H), 7.7 (bs,
4H). IR w (cm−1) 3449, 3223, 2953, 2921, 2856, 1760,
1695, 1447, 1391, 1326, 1153, 1087, 921, 723, 661
cm−1. Anal. calcd for C21H22N2O4S: C, 63.29; H, 5.56;
N, 7.03; S, 8.05. Found: C, 63.19; H, 5.63; N, 7.06; S
8.11%.
1
4.6. (1R,2R)-N-Benzylidene-N%-phthaloyl-1,2-diamino-
5d: oil, yield 83%, [h]2D0 −48.9 (c 0.5, CHCl3), H NMR
cyclohexane 6
l 1.3–1.5 (m, 3H), 1.8–1.9 (m, 3H), 2.2–2.5 (m, 2H),
2.75 (s, 3H), 3.95 (m, 2H), 4.50 (d, J=9.1 Hz, 1H),
7.7–7.75 (m, 2H), 7.8–7.9 (m, 2H). IR (film) w (cm−1)
3406, 3228, 3076, 2933, 2860, 1581, 1447, 1325, 1447,
1325, 1152, 1072, 980, 817 cm−1. Anal. calcd for
C15H18N2O4S: C, 55.88; H, 5.63; N, 8.69; S 9.95.
Found: C, 55.47; H, 5.28; N, 8.72, S 9.67%.
A solution of 5a (244 mg, 1 mmol) and benzaldehyde
(122 mL, 1.2 mmol) in benzene was refluxed with
azeotropic removal of water for 6 h. After removal of
solvents product 6 was crystallized from benzene–hex-
ane, yield 93%, mp 135–137°C; [h]2D0 −24.2 (c 1,

M. Kaik, J. Gawron´ski / Tetrahedron: Asymmetry 14 (2003) 1559–1563
1563
4.9. (1R,2R)-N-Acetyl-N%-phthaloyl-1,2-diaminocyclo-
3. (a) Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J. R.;
Deng, L. J. Am. Chem. Soc. 1991, 113, 7063–7064; (b)
Larrow, J. F.; Jacobsen, E. N.; Gao, Y.; Hong, Y.; Nie,
X.; Zepp, C. M. J. Org. Chem. 1994, 59, 1939–1942.
4. (a) Jacobsen, E. N.; Wu, M. H. In Comprehensive Asym-
metric Catalysis; Jacobsen, E. N.; Pfalz, A.; Yamamoto,
H., Eds.; Springer-Verlag: New York, 1999; pp. 1309–1326;
(b) Jacobsen, E. N. Acc. Chem. Res. 2000, 33, 421–431; (c)
Ready, J. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123,
2687–2688.
5. (a) Trost, B. M.; Hachiya, I. J. Am. Chem. Soc. 1998, 120,
1104–1105; (b) Trost, B. M.; Hildbrand, S.; Dogra, K. J.
Am. Chem. Soc. 1999, 121, 10416–10417; (c) Trost, B. M.;
Dogra, K.; Hachiya, I.; Emura, T.; Hughes, D. L.; Krska,
S.; Reamer, R. A.; Palucki, M.; Yasuda, N.; Reider, P. J.
Angew. Chem., Int. Ed. 2002, 41, 1929–1932.
6. Gawronski, J.; Kolbon, H.; Kwit, M.; Katrusiak, A. J.
Org. Chem. 2000, 65, 5768–5773.
hexane 5e
A sample of 5a (50 mg) was refluxed with acetic anhy-
dride (0.2 mL) until all substrate reacted. The anhy-
dride was removed in vacuo and the residue crystallized
from toluene–hexane, mp 180–182°C, [h]2D0 −37.2 (c 0.5,
1
CHCl3), H NMR l 1.2–1.6 (m, 3H), 1.7–1.9 (m, 3H),
1.74 (s, 3H), 2.1–2.2 (m, 1H), 2.5–2.65 (m, 1H), 3.92
(dt, J=3.9, 11.0 Hz, 1H), 4.51 (ddd, J=4.4, 8.8, 11.0
Hz, 1H), 5.30 (d, J=8.8 Hz, 1H), 7.7–7.75 (m, 2H),
7.8–7.9 (m, 2H). IR w (cm−1) 3416, 3323, 2925, 2862,
1777, 1706, 1655, 1547, 1373, 719. Anal. calcd for
C16H18N2O3: C, 67.12; H, 6.34; N, 9.78. Found: C,
67.13; H, 6.28; N, 9.72%.
4.10. Removal of the phthaloyl protecting group
7. (a) Gawronski, J.; Gawronska, K.; Grajewski, J.;
Kacprzak, K.; Rychlewska, U. J. Chem. Soc. Chem.
Commun. 2002, 00, 582–583; (b) Gawronski, J.; Brzos-
towska, M.; Gawronska, K.; Koput, J.; Rychlewska, U.;
Skowronek, P.; Norde`n, B. Chem. Eur. J. 2002, 8, 2484–
2494.
8. Jung, J. H.; Ono, Y.; Hanabusa, K.; Shinkai, S. J. Am.
Chem. Soc. 2000, 122, 5008–5009.
9. Moreau, J. J. E.; Vellutini, L.; Wong Chi Man, M.; Bied,
C. J. Am. Chem. Soc. 2001, 123, 1509–1510.
10. Kim, Y. K.; Lee, S. J.; Ahn, K. H. J. Org. Chem. 2000,
65, 7807–7813.
A sample of 5b, 5c, 5d, 9a or 9b (1 mmol) was refluxed
with hydrazine hydrate (0.12 mL) in ethanol (2 mL) for
2 h. After cooling the solution was diluted with diethyl
ether to precipitate phthaloyl hydrazide. The mixture
was filtered and the filtrate evaporated to dryness. The
products were purified either by extraction into the
dilute HCl, followed by neutralization with saturated
NaHCO3 solution and back extraction with
dichloromethane, or by crystallization. Yields were in
the range 85–95%.
Products 1d,16a 1e,16b and 4a13,24 were previously
reported. We note, however, that 1e is a crystalline
solid, mp 112–113°C (from benzene–hexane).
11. Hu, K.; Bradshaw, J. S.; Dalley, N. K.; Krakowiak, K. E.;
Wu, N.; Lee, M. L. J. Heterocyclic Chem. 1999, 36,
381–387.
12. Lagriffoule, P.; Wittung, P.; Eriksson, M.; Jensen, K. K.;
Norde´n, B.; Buchardt, O.; Nielsen, P. E. Chem. Eur. J.
1997, 3, 912–919.
13. Mitchell, J. M.; Finney, N. S. Tetrahedron Lett. 2000, 41,
8431–8434.
4.10.1. (1R,2R)-N-Benzyl-1,2-diaminocyclohexane 1f.
1
Oil, [h]2D0 −87.4 (c 1, CHCl3); H NMR l 0.9–1.4 (m,
4H), 1.6–1.9 (m, 6H), 2.05–2.2 (m, 2H), 2.41 (m, 1H),
3.68 (d, J=13.2 Hz, 2H), 3.94 (d, J=13.4 Hz, 2H),
7.2–7.4 (m, 5H). IR (film) w (cm−1) 3271, 3060, 2932,
2857, 1495, 1451, 1089, 972, 697 cm−1. HRMS found
204.16104 C13H20N2 requires 204.16264.
14. Pu3 ntener, K.; Schwink, L.; Knochel, P. Tetrahedron Lett.
1996, 37, 8165–8168.
15. Neumann, W. L.; Franklin, G. W.; Sample, K. R.; Aston,
K. W.; Weiss, R. H.; Riley, D. P. Tetrahedron Lett. 1997,
38, 779–782.
16. (a) Balsells, J.; Mejorado, L.; Phillips, M.; Ortega, F.;
Aguire, G.; Somanathan, R.; Walsh, P. J. Tetrahedron:
Asymmetry 1998, 9, 4135–4142; (b) Balsells, J.; Walsh, P.
J. J. Org. Chem. 2000, 65, 5005–5008.
4.10.2. (1R,2R)-N,N-Dibenzyl-1,2-diaminocyclohexane
1
4b. Oil, [h]2D0 −42.5 (c 0.36, CHCl3); H NMR l 0.8–1.0
(m, 1H), 1.05–1.3 (m, 3H), 1.6–1.7 (m, 3H), 1.7–1.85
(m, 1H), 1.9–2.05 (m, 2H), 2.13 (m, 1H), 2.68 (dt,
J=3.8, 10.4 Hz, 1H), 3.38 (d, J=13.5 Hz, 2H), 3.82 (d,
J=13.4 Hz, 2H), 7.2–7.4 (m, 10H). IR (film) w (cm−1)
3060, 3026, 2928, 2855, 1494, 1452, 748, 698. HRMS
found 294.20959 C20H26N2 requires 294.20892.
17. Bied, C.; Moreau, J. J. E.; Man, M. W. C. Tetrahedron:
Asymmetry 2001, 12, 329–336.
18. Adima, A.; Moreau, J. J.; Man, M. W. C. Chirality 2000,
12, 411–420.
19. Frost, C. G.; Mendonca, P. Tetrahedron: Asymmetry 1999,
10, 1831–1834.
Acknowledgements
20. (a) Lopez, J.; Mintz, E. A.; Hsu, F.-L.; Bu, X. R.
Tetrahedron: Asymmetry 1998, 9, 3741–3744; (b) Lopez, J.;
Liang, S.; Bu, X. R. Tetrahedron Lett. 1998, 39, 4199–4202.
21. Daly, A. M.; Dalton, C. T.; Renehan, M. F.; Gilheany, D.
G. Tetrahedron Lett. 1999, 40, 3617–3620.
22. Gawron´ski, J.; Gawron´ska, K.; Skowronek, P.; Holme´n,
A. J. Org. Chem. 1999, 64, 234–241.
We thank the Committee for Scientific Research for
financial support.
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