Preparation of trans-1,2-diaminocyclohexane derivatives by lithium perchlorate catalyzed ring opening of aziridines

Article abstract of DOI:10.1081/SCC-100106039

N,N′-Dialkylated trans-1,2-diaminocyclohexane derivatives were synthesized with good overall yield via reaction of the corresponding N-alkylated cyclohexene aziridine with amines, in the presence of lithium perchlorate as catalyst.

Full text of DOI:10.1081/SCC-100106039

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PREPARATION OF TRANS-1,2-DIAMINOCYCLOHEXANE
DERIVATIVES BY LITHIUM PERCHLORATE CATALYZED
RING OPENING OF AZIRIDINES
C. Anaya de Parrodi a , V. Vázquez a , L. Quintero b & E. Juaristi c
a Departamento de Química y Biología , Universidad de las Américas-Puebla , Santa
Catarina Mártir, Cholula, Puebla, 72780, México
b Centro de Investigación de la Facultad de Ciencias Químicas , Universidad Autónoma de
Puebla , Puebla, 72570, México
c Departamento de Química , Centro de Investigación y de Estudios Avanzados del
Instituto Politécnico Nacional , Apartado Postal 14-740, México, D.F., 07000, México
Published online: 20 Aug 2006.
To cite this article: C. Anaya de Parrodi , V. Vázquez , L. Quintero & E. Juaristi (2001) PREPARATION OF TRANS-1,2-
DIAMINOCYCLOHEXANE DERIVATIVES BY LITHIUM PERCHLORATE CATALYZED RING OPENING OF AZIRIDINES, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 31:21, 3295-3302,
DOI: 10.1081/SCC-100106039
To link to this article: http://dx.doi.org/10.1081/SCC-100106039
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SYNTHETIC COMMUNICATIONS, 31(21), 3295–3302 (2001)
PREPARATION OF TRANS-1,2-
DIAMINOCYCLOHEXANE
DERIVATIVES BY LITHIUM
PERCHLORATE CATALYZED
RING OPENING OF AZIRIDINES
1,
V. Vazquez,1
*
C. Anaya deParrodi,
*
L. Quintero,2, and E. Juaristi3
1Departamento de Quımica y Biologıa,
Universidad de las Americas-Puebla, 72780,
Santa Catarina Martir, Cholula, Puebla, Mexico
2Centro de Investigacion de la Facultad de
Ciencias Quımicas, Universidad Autonoma de
Puebla, 72570, Puebla, Mexico
3Departamento de Quımica, Centro de
Investigacion y de Estudios Avanzados del
Instituto Politecnico Nacional, Apartado Postal
14-740, 07000 Mexico, D.F., Mexico
ABSTRACT
N,N0-Dialkylated trans-1,2-diaminocyclohexane derivatives
were synthesized with good overall yield via reaction of the
corresponding N-alkylated cyclohexene aziridine with amines,
in the presence of lithium perchlorate as catalyst.
*Corresponding authors. E-mail: anaya@mail.udlap.mx
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Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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DE PARRODI ET AL.
INTRODUCTION
There are numerous recent examples of the use of chiral 1,2-diamines
in the field of asymmetric synthesis and molecular recognition.1 Some of the
most widely used ligands incorporating a vicinal diamine moiety are deri-
vatives of trans-1,2-diaminocyclohexane, 1.2 In addition, N,N 0-dialkylated
derivatives 2 have been recently exploited as stereodirecting reagents or
ligands in asymmetric synthesis, with applications continuing to increase
(Scheme 1).2
Scheme 1.
One of the classical synthetic procedures for the formation of 1,2-
diamines is the ring opening of aziridines with amines; nevertheless, this
method has limited application due to the low nucleophilicity of amines
and the relative scarcity of aziridine starting materials.3,4
Interestingly, Crotti et al.5 reported the ring opening reaction of epo-
xides and oxetanes in the presence of various metal based-salts, such as
LiClO4, LiBF4 and lanthanide(III) triflates. In particular, Yamamoto et al.7
studied the aminolysis of N-Boc, N-Ts, and N-Bn-protected aziridines cat-
alyzed by lanthanoid triflates. Besides, other reports of the use of lithium
salts to facilitate the opening of epoxides have recently appeared.6–8
This paper describes a useful extension of the above idea, the LiClO4-
catalyzed aminolysis of aziridines conveniently prepared from ubiquitous
epoxides.9
RESULTS AND DISCUSSION
The synthesis of several vicinal diamines was carried via the LiClO4-
catalyzed aminolysis of N-alkylated aziridines derived from cyclohexene
oxide (Table 1).

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Table 1. Aminolysis of Cyclohexene Oxide, 3
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Aminolysis of cyclohexene oxide 3 with primary amines, (S)-a-phenyl-
ethylamine, 4a, benzylamine, 4b, and cyclopentylamine, 4c, in the presence
of an equivalent of lithium perchlorate in acetonitrile, heating to reflux for
ca. 20 h, afforded in excellent yield (95–98%) the corresponding trans-N-
alkyl-1,2-aminocyclohexanols 5a–c (Table 1).
b-Aminoalcohols 5a–c were then converted into the corresponding
N-alkyl-cyclohexene aziridines 6a–c via in-situ intramolecular SN2displace-
ment of the mesylated alcohol by the amine, in 68–70% yields (Table 2).9
Finally, ring opening of aziridines 6a–c was achieved by aminolysis
with primary amines 4a–c as well as piperidine, 4d, catalyzed by lithium
perchlorate (equimolar amount, heating to reflux in acetonitrile). As
expected, the ring opening of the aziridines is completely stereoselective,
leading to trans (enantiomeric) 7b, 7c, and 7d, and trans (diastereomeric)
7a, with no evidence for cis products (Table 3).
In summary, the present procedure for the synthesis of trans-1,2-di-
aminocyclohexane derivatives from cyclohexene oxide in the presence of
lithium perchlorate as catalyst proceeds in good yield (52–60% overall).
EXPERIMENTAL
Melting points were recorded on a Melt–Temp apparatus and are
uncorrected. Optical rotations [a]D were measured at room temperature in

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Table 2. Synthesis of N-Alkyl Cyclohexene Aziridines, 6a–c
Table 3. Aminolysis of Aziridines 6a–c to Give 1,2-Diamines 7a–d
0.1 dm cells, using a Perkin–Elmer 241 spectrophotometer. All reagents were
purchased from Aldrich Chemical Co. Analytical TLC plates and silica gel
(230–400 mesh) were purchased from Merck.
All operations were carried under a nitrogen atmosphere. All glass-
ware was dried in an oven at 120ꢀC and cooled to room temperature under
nitrogen atmosphere before use. 1H and 13C NMR spectra were recorded in

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CDCl3 as solvent with tetramethylsilane (TMS) as an internal standard on a
400 MHz JEOL spectrometer. Chemical shifts are given as d values (ppm).
Mass Spectra were recorded on a Varian Saturn II spectrometer.
Aminolysis of Ciclohexene Oxide. General Procedure
In a dry two necked flask provided with addition funnel condenser and
magnetic stirrer, was placed with stirring and under argon an equimolar
mixture of cyclohexene oxide (3, 10 mmol) and anhydrous lithium perchlo-
rate (10 mmol) in freshly distilled acetonitrile (ca. 10 ml) until complete
dissolution of the lithium salt. The reaction mixture was cooled in an ice
water bath before the dropwise addition of the amine (4a–c, 10 mmol). The
resulting solution was then heated to reflux until the reaction was complete
(ca. 20 h). Water (25 ml) was added to the reaction mixture and the organic
phase was extracted with CH2Cl2 (3 Â 25 ml). The combined organic
extracts were dried over anhydrous Na2SO4, filtered and concentrated in
vacuo to afford the b-aminoalcohols 5a–c.
trans-(10S )2-N-[(a-Phenylethyl)amino]cyclohexanols, 5a. See ref. 8
rac-trans-2-N-[(Benzyl)amino]cyclohexanols, 5b.10 1H NMR: 0.99 (m,
1H), 1.25 (m, 3H), 1.68 (m, 2H), 1.99 (m, 1H), 2.15 (m, 1H), 2.29 (m, 1H),
2.56 (broad, 2H), 3.20 (m, 1H), 3.67 (d, 1H, J ¼ 12.8), 3.93 (d, 1H, J ¼ 12.8),
7.21–7.40 (m, 5H). 13C NMR: 24.4, 25.2, 30.5, 33.5, 50.8, 63.1, 73.8, 127.1,
128.2, 128.5, 140.4. m/z: 205 (Mþ).
1
rac-trans-2-N-[(Cyclopentyl)amino]cyclohexanols, 5c. H NMR: 0.86
(m, 2H), 1.18 (m, 4H), 1.46 (m, 3H), 1.60 (m, 4H), 1.77 (m, 1H), 1.93 (m,
1H), 2.05 (m, 1H), 2.14 (m, 1H), 2.77 (broad, 2H), 3.00 (m, 1H), 3.13 (q, 1H,
J ¼ 6.6). 13C NMR: 23.7, 23.8, 24.4, 25.2, 30.7, 32.9, 33.5, 34.3, 56.2, 61.9,
73.5. m/z: 183 (Mþ.). Anal. calcd. C11H21ON (183.3) C 72.09%, H 11.54%;
found C 71.81%, H 11.59%.
Preparation of N-Alkyl-cyclohexene Aziridines.
General Procedure
In a two necked flask provided with an addition funnel, condenser and
a magnetic stirrer, under argon the mixture of b-aminoalcohols (10 mmol,
5a–c) and dry triethylamine (5 ml) were dissolved in dry CH2Cl2 (20 ml). To
the ice cooled mixture was added dropwise a solution of methanesulfonyl

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DE PARRODI ET AL.
chloride (10 mmol) in dry CH2Cl2 (5 ml). The reaction mixture was stirred at
0ꢀC until no more b-aminoalcohols 5a–c were detected by TLC (ca. 24 h),
and then the in situ mesylated compounds were allowed to warm to rt for ca.
8 h to give the desired product. The cool reaction mixture was poured over
ice cooled 1 N HCl (30 ml) and the organic layer was extracted with CH2Cl2
(3 Â 25 ml). The combined organic extracts were dried over Na2SO4, filtered
and concentrated in vacuo. The crude products were purified by flash chro-
matography to provide aziridine 6a–c as a liquid. Vacuum distillation
afforded pure aziridines as colorless liquid.
(1R,2S,10S )N-(a-Phenylethyl)cyclohexene aziridine, 6a. 1H NMR9
13C NMR9[a]D ¼ ꢁ42.4(c ¼ 1.0,CHCl3),[Lit.9[a]D ¼ ꢁ42.4(c ¼ 1.4,CHCl3)].
N-(Benzyl)cyclohexene aziridine, 6b.7a,c 1H NMR: 1.17 (m, 2H), 1.39
(m, 2H), 1.58 (s, 2H), 1.75 (m, 2H), 1.86 (m, 2H), 3.43 (s, 2H), 7.09–7.45
(m, 5H). 13C NMR: 20.7, 24.6, 38.6, 64.4, 126.6, 127.5, 128.3, 140.1. m/z:
187 (MþE).
N-(Cyclopentyl)cyclohexene aziridine, 6c. 1H NMR: 1.02 (m, 2H), 1.21
(m, 2H), 1.35 (m, 5H), 1.47 (m, 2H), 1.58 (m, 8H). 13C NMR: 20.6, 24.4,
24.8, 32.2, 37.3, 72.06. m/z: 165 (Mþ.). Anal. calcd C11H19N (165.2)
C 79.95%, H 11.58%; found C 80.17%, H 11.49%.
Aminolysis of N-Alkyl-cyclohexene Aziridines 6a–c.
General Procedure
In a dry two necked flask provided with an addition funnel, condenser
and a magnetic stirrer, was placed with stirring and under argon an equi-
molar mixture of N-alkyl-cyclohexene aziridine 6a–c (10 mmol) and anhy-
drous lithium perchlorate (10 mmol) in freshly dried acetonitrile (ca. 10 ml)
until complete dissolution of the lithium salt. The reaction mixture was
cooled in an ice-water bath to 0ꢀC before the dropwise addition of the
amine (10 mmol, 4a–d). The resulting solution was then heated to reflux
until the reaction was complete, ca. 30 h. Water was added to the reaction
mixture and the organic phase was extracted with CH2Cl2 (3 Â 25 ml). The
combined organic extracts were dried over anhydrous Na2SO4, filtered and
concentrated in vacuo affording the 1,2-diamines 7a–d.
trans-(10S )-[N-(a-Phenylethyl)-N 0-benzyl]-1,2-cyclohexanediamine 7a.
1H NMR: 0.85 (m, 1H), 1.20 (m, 3H), 1.35 (d, 3H, J ¼ 6.6), 1.65 (m, 3H),
1.92 (m, 2H), 2.18 (m, 2H), 2.38 (m, 1H), 3.66 (d, 1H, J ¼ 13.2), 3.82 (q, 1H,
J ¼ 6.6), 3.91 (d, 1H, J ¼ 13.2), 7.15–7.44 (m, 10H). 13C NMR: 23.9, 24.9,
25.0, 25.4, 31.6, 32.7, 32.6, 51.1, 54.1, 55.8, 57.8, 59.7, 61.4, 61.5, 126.6,
.
126.9, 128.0, 128.1, 128.4, 141.3, 146.0, 147.6. m/z: 308 (Mþ ). Anal. calcd
C21H28N2 (308.4) C 81.78%, H 9.14%; found C 81.53%, H 9.17%.

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Rac-trans-N,N0-Bis(benzyl)-1,2-cyclohexanediamine 7b.
See ref. 11
rac-trans-N,N 0-bis(cyclopentyl)-1,2-cyclohexanediamine 7c. H NMR:
0.86 (m, 2H), 1.28 (m, 4H), 1.42 (m, 4H), 1.64 (m, 9H), 1.92 (m, 6H), 2.39
(m, 2H), 3.06 (m, 1H), 3.81 (m, 1H), 4.47 (m, 1H). 13C NMR: 23.7, 23.8,
24.6, 28.9, 30.0, 30.1, 31.4, 35.9, 52.7, 53.5, 58.5, 59.8, 63.2. m/z: 250 (MþE).
Anal. calcd C16H30N2 (250.4) C 76.75%, H 12.07%; found C 76.28%, H
11.98%.
1
trans-[N-(cyclopentyl)-N 0-(piperidinyl)]-1,2-cyclohexanediamine 7d.
1H NMR: 1.18 (m, 6H), 1.52 (m, 16H), 1.90 (m, 2H), 2.27 (m, 2H), 2.38
(m, 1H), 2.56 (m, 2H), 3.07 (m, 1H). 13C NMR: 22.0, 23.6, 23.7, 24.8, 25.1,
27.0, 32.5, 34.6, 49.5, 56.2, 57.9, 68.2. m/z: 250 (MþE). Anal. calcd C16H30N2
(250.4) C 76.75%, H 12.07%; found C 76.92%, H 12.12%.
ACKNOWLEDGMENTS
We thank CONACYT for financial support (Project 3983-E).
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Received in the USA January 10, 2001

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