Stereochemical analysis of N-cyclohexylidene-N-(1-phenylethyl)amine derivatives

Article abstract of DOI:10.1002/mrc.1666

The configurational properties of a series of cyclohexylidene imines are discussed on the basis of their ¹H, ¹³C and ¹⁵N NMR spectral data. Copyright

Full text of DOI:10.1002/mrc.1666

MAGNETIC RESONANCE IN CHEMISTRY
Magn. Reson. Chem. 2005; 43: 975–978
Published online 22 August 2005 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/mrc.1666
Stereochemical analysis of N-cyclohexylidene-
N-(1-phenylethyl)amine derivatives
1
Armando Ariza-Castolo,1∗ J. Ascencion Montalvo-Gonzalez
´
´
2
´
´
and Ruben Montalvo-Gonzalez
1
Centro de Investigacio´ n y de Estudios Avanzados del IPN, Apartado Postal, 14-740, 07000 Me´ xico D.F., Mexico.
2
´
´
Unidad Acade´ mica de Ciencias e Ingenierıas, Universidad Autonoma de Nayarit, Tepic Nayarit, Mexico
Received 2 May 2005; Revised 15 June 2005; Accepted 6 July 2005
The configurational properties of a series of cyclohexylidene imines are discussed on the basis of their 1H,
13C and 15N NMR spectral data. Copyright  2005 John Wiley & Sons, Ltd.
KEYWORDS: 1H NMR; 13C NMR; 15N NMR; configuration; N-cyclohexylidene-1-phenylethylamine derivatives
In contrast, the four-substituted derivatives 4 and 5 are
conformationally fixed because the methyl and the tert-butyl
group, respectively, strongly prefer the equatorial position
(steric anchor). Thereby, the interconversion of the E/Z
diastereomers is blocked and two diastereomeric pairs of
enantiomers exist permanently. As a consequence, two NMR
signal sets are observed for each compound.
In each of the imines 2 and 3, a new stereogenic center
is introduced (C-2 and C-3, respectively) giving rise to four
diastereomeric pairs of enantiomers so that four signal sets
emerge. In order to assign the configurations of compound 3
with its equatorial methyl group, (R)-3-methylcyclohexanone
as well as optically pure (R)- or (S)-1-phenylethylamine were
used as precursors.
It was not possible to assign compound 2 with the strategy
used for 3 because 2-methylcyclohexanone has a tautomeric
ketone-enol equilibrium that restrains working with opti-
cally pure compounds. However, Fraser et al. prepared the
isomers Z of imine 2 by stereoselective methylation via opti-
cally active lithioenamine.1b They elucidated their structure
and found that the methyl group of cyclohexane occupies
the axial position. In our observations, the assignment is
in agreement to their report1b with the difference that the
E isomers with less hindrance are the most abundant (9 : 1
ratio).
INTRODUCTION
Imines are important intermediates which have been used
in deracemizing alkylation,1 acylation,2 lactams and oxaziri-
dine preparations3 as well as in Michael additions.4 Iminium
salts have also been proposed as intermediates in the prepa-
ration of amines obtained by reductive amination of ketones
with reducing agents,5 but this intermediate has never been
detected nor isolated. Eventhough imines have been widely
used for the last 20 years their structures have not been
completely analyzed by means of spectroscopic methods.
To our knowledge, only the absolute configurations of N-
cyclohexylidene-1-phenylethylamine (1) and some isomers
of N-(2-methylcyclohexylidene)-1-phenylethylamine (2) pre-
pared by stereoselective alkylation, have been determined
by means of chiroptical methods6 and their relative configu-
ration established by NMR.7
In this paper we report the 1H, 13C and 15N NMR assign-
ment of imines 1–5 (Scheme 1). Although the structures of
these compounds have been described as simple, they pos-
sess some symmetry elements that require more detailed
analysis.8
RESULTS AND DISCUSSION
Stereochemical analysis
First, the chiral center C-7 produces a pair of enantiomers.
Secondly, The C N double bond gives rise to two diastere-
omers (E and Z) which can easily be differentiated by NMR
methods if the cyclohexane ring is conformationally fixed.
In 1, the cyclohexane ring can undergo ring inversion by
which these E/Z diastereomers interconvert. Therefore, only
one signal set is observed for this compound at room tem-
perature, whereas coalescence is observed on lowering the
NMR spectra
We describe herein our investigations concerning the
NMR spectral analysis of cyclohexylidene derivatives 1–5.
The compounds were prepared by reaction of 2-methyl,
3-methyl, 4-methyl and 4-tert-butylcyclohexanoens with 1-
phenylethylamine (both racemic and optically pure samples).
Detailed spectral analysis presents a great challenge due
to the complexity of the 1H NMR spectra (Table 1) of the
cyclohexyl fragment and the similarity of many of the
chemical shift both in 1H and 13C NMR for the isomers.
Only, it is possible to distinguish a doubled triplet signal for
temperature; two signal sets appear at 203 K (see also foot-
note a of Table 2); Gc D 46.9 š 1.2 kJ molꢀ1
.
Ł
ŁCorrespondence to: Armando Ariza-Castolo, Centro de
Investigacio´n y de Estudios Avanzados del IPN, Apartado Postal,
14-740, 07000 Me´xico D.F., Mexico. E-mail: aariza@cinvestav.mx
Copyright  2005 John Wiley & Sons, Ltd.

976
A. Ariza-Castolo, J. A. Montalvo-Gonzalez and R. Montalvo-Gonzalez
the axial H-2 in 3 to 5 which has a vicinal coupling of 4.5 Hz
(axial with equatorial protons) as well as a geminal plus a
vicinal coupling (axial with axial proton) of 13 Hz each. This
proves the chair conformation.
The atomic connectivity was established by heteronuclear
and homonuclear correlation spectroscopy (COSY and
13C–1H HETCOR). 15N NMR spectra were recorded using
a single pulse 1H-decoupled experiment (no NOE). The 13C
and 15N NMR reveal systematic substituent effects which
support the signal assignment.
(c)
(b)
The assignment of the configuration originated by the
double bond (E, Zꢀ is based on 13C NMR data (Table 2).
The 1-phenylethylamine substituent induces a diamagnetic
ꢁ effect at the carbon in Z-position shifting its signal by
10 ppm to low frequency compared to the E-positioned
carbon. The introduction of a methyl group gives rise to
a deshielding of ˛ carbons by 6.5 š 0.5 ppm (C-3 and C4
for imine 3 and 4, respectively); its effect for ˇ carbons is
8.0 š 0.5 ppm deshielding. In contrast, the methyl effect on
C-2 in compound 2 is only C2 to C4 ppm; the ꢁ bond effect
is less than 1.2 ppm. The tert-butyl group shifts the ˛ signal
(C-4) by C22 ppm and its ˇ effect is less than C2 ppm. This
assignment is in agreement with previous reports.7,8,10
The 15N NMR chemical shifts (Table 3) reflect a depen-
dence on the configuration of the molecules; however, the
shift difference between isomers is less than 0.4 ppm (Scheme
2). In derivative 2, only the signals for the main isomers
product were observed.
(a)
−60
−61.25
−62.5
−63.75
−65
Scheme 2. 15N NMR spectra of 3; (a) spectrum of the diastere-
omeric mixture, (b) E and Z isomers of the (3R,7R)-ketimine 3,
and (c) E and Z isomers of the (3R,7S)-ketimine 3.
15Nf Hg NMR spectra were obtained at 40.51 MHz using
1
a single pulse 1H-decoupled without NOE method11, spectral
width was 16 216 Hz, 16 384 data points 2024 scans, recycle
delay 2 s.
EXPERIMENTAL
The NMR spectra were recorded at room temperature with
a Jeol eclipse C400, equipped with a 5-mm multinuclear
autotuning probe and a variable temperature unit using
5-mm od tubes. The chemical shifts are referenced to
internal Me4Si [υ(1H) and υ(13C) 0 ppm] and neat MeNO2
[υ(15N) 0 ppm for (15N) D 10.136 767 MHz]. CDCl3 solutions
containing 0.8 mmol of the samples in natural abundance
were used for 13C and 15N NMR experiments while 1H data
were determined using 20 mg in 0.7 ml.
H,H–COSY spectra were obtained with the dqf-COSY
pulse sequence11 using a 1024 ð 512 data point matrix and
a 3522.4 ð 3522.4 Hz, the recycle delay was 1 s. Fourier
transformations were carried out using a sine-bell function
for F1 and F2, in the absolute value mode.
The 13C,1H–COSY spectra11 were obtained for the
aliphatic region using a 1024 ð 512 data point matrix and
a 5026 ð 1958 Hz frequency matrix, pulse time intervals 1
and 2 were set as 2 ð 1/4 J D 1.85 ms, respectively, and
recycle delay was 1 s. Fourier transformations were carried
out using a sine-bell function for F1 and F2, in the absolute
value mode.
The MS were determined in a Hewlett-Packard 5890
spectrometer coupled with a gas chromatograph in electron
ionization mode (EI).
The Schiff bases were prepared from the corresponding
cyclohexanones and 1-phenylethylamine in toluene solution
at reflux for 24 h in a Dean-Stark water separator. Both the
cyclohexanones and the amines are commercially available
products. The physical and spectroscopic properties are
in good agreement with previous reports: 1,6,7 2,7 3,12
4,12c 5.3a
1H NMR spectra were recorded at 399.65 MHz (spectral
width 3915.4 Hz, acquisition time 4.2 s, 16 384 data points,
°
equivalent 45 pulse duration, 16 scans, recycle delay 3 s).
1
13Cf Hg NMR spectra were recorded at 100.53 MHz,
spectral width 25 181 Hz, 32 768 data points, recycle delay
of 0.8 s, 32 scans. Similar conditions were used for APT and
INEPT spectra11. 13C1H NMR spectra of 1 were recorded at
low temperature as well and the coalescence temperature TC
was determined for the carbon para of phenyl group.
N-[3-methylcyclohexylidene]-1-phenylethylamine
(3)
was prepared from (R)-(C)-3-methylcyclohexanone and the
optically pure (R)- or (S)-1-phenylethylamine as well as
the racemic mixtures of both. We used (R)- or (S)-1-
phenylethylamine for the preparation of compounds 4 and 5
Scheme 1. Structures of the imines 1–5.
Copyright  2005 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2005; 43: 975–978

Stereochemical analysis of cyclohexylidene derivatives 977
Copyright  2005 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2005; 43: 975–978

978
A. Ariza-Castolo, J. A. Montalvo-Gonzalez and R. Montalvo-Gonzalez
Table 2. 13C NMR chemical shift of the imines 1–5
2
Major
Minorb
3
C-
1a,b
E-2SŁ,7RŁ E-2SŁ,7SŁ Z-2SŁ,7RŁ Z-2SŁ,7SŁ E-3R,7R E-3R,7S Z-3R,7R Z-3R,7S
4
5
1
171.97
40.13
27.72
25.97
27.00
29.40
57.64
24.99
173.45
42.38
36.08
24.50
27.92
28.20
57.57
25.81
147.26
126.84
128.31
126.36
17.65
173.76
42.38
35.96
24.62
27.92
28.26
57.66
25.66
147.17
126.72
128.31
126.30
17.56
175.93
31.59
32.78
20.47
27.46
35.77
57.14
25.44
146.53
126.85
128.47
126.92
16.86
175.38
31.87
33.33
20.37
27.46
36.30
57.14
25.44
146.53
126.36
128.47
125.80
17.50
171.87
48.50
34.56
26.15
34.60
28.21
58.25
25.59
146.48
126.57
128.44
126.39
22.06
172.04
48.43
34.59
26.38
34.47
28.93
58.17
24.87
146.48
126.57
128.44
126.39
22.02
171.54
37.48
34.08
26.38
34.47
39.77
58.44
25.71
146.20
126.52
128.30
126.33
22.68
171.81 171.72 171.52 172.42 172.21
2
3
4
5
6
7
8
37.61
33.43
25.68
34.47
39.72
58.33
24.95
39.08 39.05 39.75 39.71
35.56 35.53 29.02 28.97
31.94 31.90 47.72 47.64
34.55 34.51 28.34 28.31
28.19 28.19 32.45 32.16
57.76 57.63 58.01 57.85
25.06 24.72 25.30 24.95
Ci 146.24
Co 126.61
Cm 128.18
Cp 126.43
146.26 146.21 145.95 146.53 146.21
126.54 126.65 126.59 126.61 126.57
128.30 128.35 128.35 128.33 128.33
126.38 126.43 126.43 126.40 126.38
R
–
22.59
21.28 21.17 27.62 27.57
a At 203 K: υ(Co) 127.09, 126.90 ppm; υ(Cm) 128.47, 128.26 ppm, υ(Cp) 126.62, 126.43 ppm.
b The chemical shift data for 1 and the Z-2SŁ,7RŁ and Z-2SŁ,7SŁ isomers of 2 are in agreement with Ref. 7.
Table 3. 15N NMR chemical
shifts of the imines 1–5
(d) Thominiaux C, Rousse´ S, Desmae¨le D, d’Angelo J, Riche C.
Tetrahedron: Asymmetry 1999; 10: 2015; (e) Jabin I, Revial G,
¨
Pfau M, Netchitaılo P. Tetrahedron: Asymmetry 2002; 13: 563;
(f) Camara C, Joseph D, Dumas F, d’Angelo J, Chiaroni A.
Tetrahedron Lett. 2002; 43: 1445; (g) d’Angelo J, Desmae¨le D,
Dumas F, Guingant A. Tetrahedron: Asymmetry 1992; 3: 459.
5. (a) Sato S, Sakamoto T, Miyazawa E, Kikugawa Y. Tetrahedron
2004; 60: 7899; (b) Hajipour AR, Mohammadpoor-Baltork I,
υ(15N)
1
2
ꢀ63.3
ꢀ60.8
ꢀ60.6
ꢀ62.2
ꢀ62.3
ꢀ62.5
ꢀ62.5
ꢀ62.3
ꢀ62.4
ꢀ64.1
ꢀ64.3
E-2SŁ,7RŁ
E-2SŁ,7SŁ
E-3R,7R
E-3R,7S
Z-3R,7R
Z-3R,7S
Noroallhi M. Indian J. Chem., Sect.
B 2001; 40B: 152;
(c) Fernandez E, Maeda K, Hooper MW, Brown JM. Chem. Eur.
J. 2000; 6: 1840; (d) Hajipour AR, Mohammadpoor-Baltork I,
Rahi A. Indian J. Chem., Sect. B 2000; 39B: 239; (e) Ranu BC,
Majee A, Sarkar A. J. Org. Chem. 1998; 63: 370; (f) Abdel-
Magid AF, Carson KG, Harris BD, Maryanoff CA, Shah RD. J.
Org. Chem. 1996; 61: 3849; (g) Kotsuki H, Yoshimura N, Kadota I.
Synthesis 1990; 5: 401; (h) Abdel-Magid AF, Maryanoff CA,
Carson KG. Tetrahedron Lett. 1990; 31: 5595; (i) Morales H, Perez-
Juarez M, Cuellar L, Mendoza L, Fernandez H, Contreras R.
Synth. Commun. 1984; 14: 1213.
3
4
5
6. Knupp G, Frahm AW. Chem. Ber. 1984; 117: 2076.
7. Fraser RR, Banville J, Akiyama F, Chuanqui-Offermanns N. Can.
J. Chem. 1981; 59: 705.
8. (a) Ariza-Castolo A, Paz-Sandoval MA, Contreras R. Magn.
Reson. Chem. 1992; 30: 520; (b) Montalvo-Gonza´lez R, Ariza-
Castolo A. J. Mol. Struct. 2003; 665: 375.
9. (a) Carroll FA. Perspective on Structure and Mechanism in
Organic Chemistry. Brookes Cole: Thompson Learning; 1998;
(b) http://www.chem.qmul.ac.uk/iupac/stereo/RS.html#14,
(last accessed August 2005).
as well; both products showed NMR spectra identical with
the one prepared from the racemic mixture.
REFERENCES
1. (a) Pfau M, Revial G, Guingant A, d’Angelo J. J. Am. Chem. Soc.
1985; 107: 273; (b) Fraser RR, Akiyama F, Banville J. Tetrahedron
Lett. 1979; 41: 3929.
10. (a) Jennings WB, Wilson VE, Boyd DR, Coulter PB. Org. Magn.
Reson. 1983; 21: 279; (b) Solladie´-Cavallo A, Solladie´ G. Org.
Magn. Reson. 1977; 15: 235; (c) Kalinowski HO, Berger S, Braun S.
Carbon-13 NMR Spectroscopy (1st edn). Wiley: Chichester, 1991.
11. Braun S, Kalinowski HO, Berger S. 150 and More Basic NMR
Experiments. Wiley-VCH: Weinheim, 1998.
12. (a) Kuznetsov VV, Lantsetov SV, Aliev AE, Barlanov AV,
Prostakov NS. Zh. Org. Khim. 1992; 28: 74; (b) Knupp G,
Frahm AW. Arch. Pharm. 1985; 318: 535; (c) Knupp G,
Frahm AW. J. Chem. Res. (S) 1981; 164.
2. (a) Merla B, Grumbach HJ, Risch N. Synthesis 1998; 11: 1609;
(b) Bartoli G, Cimarelli C, Dalpozzo R, Palmieri G. Tetrahedron
1995; 51: 8613.
3. (a) Lattes A, Oliveros E, Rivie`re M, Belzecki C, Mostowicz D,
Abramskj W, Piccinni-Leopardi C, Germain G, Van Meerss-
che M. J. Am. Chem. Soc. 1982; 104: 3929; (b) Belzecki C, Mostow-
icz D. J. Org. Chem. 1975; 40: 3878; (c) Mostowicz D, Belzecki C.
J. Org. Chem. 1977; 42: 3917.
4. (a) Cave´ C, Desmae¨le D, d’Angelo J. J. Org. Chem. 1996; 61:
4361; (b) Jung ME, Nishimura N. Org. Lett. 2001; 3: 2113;
(c) Lim S, Jabin I, Revial G. Tetrahedron Lett. 1999; 40: 4180;
Copyright  2005 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2005; 43: 975–978