Determination of the conformations and relative configurations of exocyclic amines

Article abstract of DOI:10.1002/mrc.2693

The conformations and relative configurations of 20 amines, classified according to the following labeling scheme, were analyzed. Series a comprised compounds derived from N-(1-phenylethyl)cyclohexanamine, b comprised derivatives of N-[1-(naphthalen-2-yl)ethyl]cyclohexanamine, c comprised derivatives of N-(diphenylmethyl)cyclohexanamine, and d comprised derivatives of N-(propan-2-yl)cyclohexanamine. The compounds were labeled as follows: 1 indicates cyclohexanamine, 2 indicates 2-methylcyclohexanamines, 3 indicates 3-methylcyclohexanamines, 4 indicates 4-methylcyclohexanamines, and 5 indicates 4-tert-butylcyclohexanamines. These compounds were prepared without the use of stereoselective induction and, therefore, all expected stereoisomers were observed. Structural assignments were established by ¹H, ¹³C, and ¹⁵N NMR.

Full text of DOI:10.1002/mrc.2693

Research Article
Received: 6 August 2010
Revised: 27 September 2010
Accepted: 1 October 2010
Published online in Wiley Online Library: 28 October 2010
(wileyonlinelibrary.com) DOI 10.1002/mrc.2693
Determination of the conformations
and relative configurations of exocyclic amines
´
´
J. Ascencion Montalvo-Gonzalez, María Guadalupe Iniestra-Galindo
and Armando Ariza-Castolo∗
The conformations and relative configurations of 20 amines, classified according to the following labeling scheme, were
analyzed. Series a comprised compounds derived from N-(1-phenylethyl)cyclohexanamine, b comprised derivatives of N-[1-
(naphthalen-2-yl)ethyl]cyclohexanamine, c comprised derivatives of N-(diphenylmethyl)cyclohexanamine, and d comprised
derivatives of N-(propan-2-yl)cyclohexanamine. The compounds were labeled as follows: 1 indicates cyclohexanamine, 2
indicates 2-methylcyclohexanamines, 3 indicates 3-methylcyclohexanamines, 4 indicates 4-methylcyclohexanamines, and 5
indicates 4-tert-butylcyclohexanamines. These compounds were prepared without the use of stereoselective induction and,
therefore, all expected stereoisomers were observed. Structural assignments were established by 1H, 13C, and 15N NMR.
c
Copyright ꢀ 2010 John Wiley & Sons, Ltd.
Keywords: 1H; 13C; and 15N NMR; conformation; configuration; exocyclic amine
Introduction
indicated the environment of each hydrogen, and the coupling
patterns provided evidence for the conformation. The 13C NMR
spectra displayed known γanti/γgauche effects that allowed for the
elucidation of the absolute orientation of the electronegative
groups. The 15N NMR was a valuable method of analysis for
determining conformation because the difference between the
chemical shifts of the equatorial and axial positions was at least
7 ppm.[6]
Knowledge of the absolute configuration and conformation
of exocyclic amines is of great importance, particularly for
compounds with biological activity. Also, determination of
the stereoselectivity of a reaction is important for both the
pharmaceutical and agricultural industries. The exocyclic amines
are a key group of compounds because they are the source of
many interesting substances in these industries.
Some of the amines reported here have been used as chiral
inductors, particularly the derivatives of 1-phenylethylamine[1]
and 1-(naphthalen-2-yl)ethylamine.[2] The cyclohexanamines and
their N-substituted derivatives form a group of secondary amines
with a variety of basicities that can be used in the synthesis of
complex molecules; currently, N-(propan-2-yl)cyclohexanamine[3]
isusedasabaseforthedeprotonationofslightlyacidiccompounds
through the preparation of a lithium amide.
This paper reports the structural analysis of 20 amines: the
symmetric secondary cyclohexanamines 1c, 1d, 4c, 4d, 5c, and
5d; compounds 1a, 1b, 4a, 4b, 5a, and 5b, which contain one
asymmetric atom; compounds 2c, 2d, 3c, and 3d, which have two
stereogenic atoms; and compounds 2a, 2b, 3a, and 3b which have
three stereogenic atoms (Fig. 1).
These compounds were assigned as diastereomeric mixtures
and presented all the expected stereoisomers. Analysis of the
mixtures allowed determination of the additive effects of the NMR
chemical shifts.
Some of these compounds have been prepared by stereoselec-
tive reduction of imines[4]; the 1-phenylethanamine has been used
as an asymmetric inductor. They have been used as models for
absolute configuration, recognized by means of chiroptical tech-
niques because of their capacity to form host/guest complexes.[5]
For this reason, determination of their geometry was interesting,
and NMR was used because it is the most robust and facile method
for elucidating a conformation in the solution state.
Results and Discussion
The compounds studied in the present work were pre-
pared by reduction of the corresponding cyclohexylidene-
N-(1-arylethyl)amine, cyclohexylidene-N-(isopropyl)amine, or
cyclohexylidene-N-(diphenylmethyl)amine derivatives by NaBH4.
Since the reduction reaction was not stereoselective, all possible
isomers were obtained in the reaction mixture. The NMR spectral
assignments were made based on one- and two-dimensional (1D
and 2D, respectively) techniques. Connectivity was established
using heteronuclear and homonuclear correlation spectroscopies
(COSY, NOESY, and HETCOR 13C–1H), and the type of carbon was
determined by APT (attached proton test) or DEPT (distortionless
enhancement by polarization transfer) spectra.
The secondary cyclohexanamines preferred a chair conforma-
tion,andtheaminegroupsinthecompoundswithoutsubstituents
(1a–1d) were present in the equatorial position. The 1H NMR spec-
tra (Table 1) provided robust information about the conformation
of the six-member rings as well as the relative positions of the
amine groups. In the case of the cyclohexane anchored by the
∗
Correspondence to: Armando Ariza-Castolo, Departamento de Química,
Cinvestav, Av. IPN 2508, Zacatenco, Mexico D.F., 07360 Mexico.
E-mail: aariza@cinvestav.mx
The relative position of each substituent on the cyclohexane
was determined using 1H, 13C, and 15N NMR. The 1H chemical shift
Departamento de Química, Cinvestav, Av. IPN 2508, Zacatenco, Mexico
c
Magn. Reson. Chem. 2010, 48, 938–944
Copyright ꢀ 2010 John Wiley & Sons, Ltd.

Conformation and configuration of cyclohexanamines
Table 1. 1H NMR of the amine series a (1a, 2a, 3a, 4a, and 5a)
Compounds
Isomers
–
1
2
3
4
5
6
7
R
–
1a
2.29
1.72
1.13
1.20
1.66
1.13
1.06
1.69
1.06
1.69
1.35
1.60
1.43
1.55
1.66
1.13
1.41
1.68
1.32
1.41
1.28
1.63
1.38
1.58
1.38
1.48
1.40
1.48
1.34
1.72
1.34
1.70
1.27
1.43
0.81
1.62
1.27
1.51
0.85
1.70
1.06
1.63
1.22
1.72
0.93
1.72
1.20
1.63
1.30
1.55
1.54
1.64
1.54
1.64
1.17
1.72
1.22
1.71
1.33
1.50
0.78
1.64
1.37
1.57
0.87
1.72
1.25
1.78
1.50
1.68
1.99
1.13
1.01
1.83
1.22
1.83
1.14
1.20
1.51
1.65
1.18
1.72
1.30
1.63
0.95
2.00
0.72
2.00
1.46
1.56
1.01
2.01
1.27
1.85
0.95
2.09
1.1
3.96
2a
lu
2.06
1.85
2.52
2.50
2.69
2.69
2.27
2.29
2.51
2.21
2.68
2.23
2.40
2.20
1.94
2.65
2.57
2.89
2.88
2.49
2.50
2.67
2.37
2.81
2.33
2.50
2.66
1.24
1.62
1.38
1.57
1.35
1.54
1.41
1.66
1.54
1.58
1.42
1.58
0.82
1.02
0.82
1.02
1.29
3.90
3.90
3.91
4.00
3.98
3.98
3.87
3.87
3.89
3.95
3.98
3.84
4.85
4.79
4.79
4.79
4.79
4.82
4.83
4.95
4.95
4.80
4.86
4.72
4.86
5.13
5.04
0.98
0.97
1.09
0.93
0.82
0.85
0.88
0.86
0.81
0.92
0.79
0.84
–
ll
1.30
2.05
1.71
ul
uu
3a
RRR
SRS
RRS
SRR
cis
1.39
1.39
1.18
1.42
0.79
1.75
0.98
1.55
1.4
1.73
1.73
1.26
1.30
4a
5a
1.27
1.43
0.85
1.62
1.27
1.51
0.95
1.67
1.12
1.66
0.93
1.74
0.93
1.74
1.32
1.45
1.45
1.45
1.86
1.47
1.11
1.70
1.34
1.7
trans
cis
1.29
0.99
0.94
trans
–
1.17
1.89
1.12
1.84
1.32
1b
2b
1.55
1.55
1.29
1.69
1.29
1.60
1.34
1.43
1.34
1.66
1.07
1.64
1.07
1.64
0.83
1.55
0.83
1.55
1.36
1.99
0.93
2.01
0.93
2.01
1.46
1.46
1.46
1.62
1.10
1.70
1.49
1.64
0.99
2.10
0.82
2.10
1.55
1.55
1.09
2.03
1.29
1.90
0.91
2.09
1.20
2.04
1.50
1.65
lu
1.04
1.07
1.13
1.00
0.91
0.93
0.95
0.93
0.95
0.82
0.87
0.78
–
ll
1.32
2.01
1.82
ul
uu
3b
RRR
SRS
RRS
SRR
cis
1.62
1.62
1.31
1.69
0.91
1.95
1.03
1.95
1.50
1.63
1.18
1.87
1.48
1.80
1.09
1.93
1.20
2.04
1.97
1.86
1.31
1.26
4b
5b
1.33
1.50
0.86
1.65
1.29
1.55
0.87
1.72
1.24
1.78
1.45
1.45
trans
cis
1.34
0.97
0.87
trans
–
1c
2c
1.23
1.61
1.42
1.61
cis
1.05
c
Magn. Reson. Chem. 2010, 48, 938–944
Copyright ꢀ 2010 John Wiley & Sons, Ltd.
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J. A. Montalvo-Gonza´lez, M. G. Iniestra-Galindo and A. Ariza-Castolo
Table 1. (Continued)
Compounds
Isomers
1
2
3
4
5
6
7
R
trans
2.07
1.22
1.09
1.73
1.41
1.69
1.69
1.10
1.69
1.59
1.69
1.41
1.78
1.78
1.29
1.79
1.59
1.69
1.58
1.76
1.40
1.58
1.57
1.61
0.90
1.74
1.00
1.65
1.19
1.48
1.13
1.58
1.17
1.61
1.37
1.37
1.35
1.35
1.11
1.30
1.05
1.45
0.96
1.70
1.03
2.27
0.93
1.68
1.08
2.12
1.20
2.12
0.97
1.76
1.37
1.93
1.12
2.13
1.55
1.83
1.21
1.32
0.88
1.79
0.74
1.51
0.93
1.77
0.90
1.72
0.80
1.52
1.30
1.76
0.92
1.90
5.13
1.15
3c
4c
5c
cis
2.51
2.93
2.78
2.46
2.84
2.38
2.47
2.53
1.90
2.40
2.78
2.55
2.29
2.83
2.39
0.84
2.12
1.29
1.79
1.20
2.12
0.97
1.76
1.37
1.93
1.12
2.13
1.55
1.83
1.76
5.05
5.18
5.07
5.16
4.97
5.10
2.94
2.75
2.75
2.87
2.78
2.73
2.80
2.78
2.92
1.00
0.97
1.02
0.95
0.91
0.86
–
trans
cis
1.87
1.58
1.76
1.40
1.58
1.57
1.61
0.90
1.74
1.00
1.65
1.27
1.37
1.58
1.58
1.29
trans
cis
1.61
1.02
1.02
trans
–
1d
2d
1.19
1.65
1.13
1.24
1.10
1.48
1.00
1.49
–
cis
0.74
0.82
0.79
0.79
0.74
0.71
0.77
0.77
trans
cis
1.08
3d
4d
5d
0.56
1.77
1.17
1.42
0.90
1.72
0.80
1.52
1.30
1.76
0.92
1.90
trans
cis
1.61
1.35
1.35
1.11
1.30
1.05
1.45
0.96
1.70
1.42
1.15
0.81
0.85
trans
cis
trans
3J (1Hax, 1Heq) = 3.7 0.4 Hz; 3J (1Heq, 1Heq) = 4.2 1 Hz; 3J (1Hax, 1Hax) = 10.4 1 Hz.
The strategy for assigning the configuration of compounds 3a
and 3b was to prepare the ketimines using the optically pure (R) or
(S) 3-methylcyclohexanone and (R) or (S) 1-phenylethanamine,
which were used to identify the epimers present in these
compounds since the absolute configuration at C-3 and C-7 were
known. This method provided only the cis and trans isomers. For
instance, the trans isomer of compound 3a, with a configuration
RRR, in which the amine group was in the axial position, displayed
the 1H as a pseudo-quintet signal (δH = 2.69, 3JH,H = 4.5); the cis
isomer (SRR), with the amine group in the equatorial position, split
the same hydrogen as a triplet of triplets (δH = 2.29, 3JH,H = 10.9
and 4.0). The same observations were made for the epimers SRS
and RRS as well as for compound 3b.
Figure 1. Structures of the amine derivatives analyzed. For 1, R = H; 2, R =
CH3 at C2; 3, R = CH3 at C3; 4, R = CH3 at C4; 5, R = tert-butyl at C4.
tert-butyl group, the amine group was present in the equatorial
1
Compounds 3c and 3d contained two stereogenic atoms (C1
and C3); therefore, each compound mixture included a pair of
diastereomers, which was evident in the NMR spectra. These
compounds were identified by the relative position of the cis/trans
isomers (l and u, respectively). The cis isomers of compound 3c
contained the amine group in the equatorial position, and the
resonance of the hydrogen bond to C1 was displayed as a triplet
or the axial position. If the H was present in the equatorial po-
sition, its multiplicity was a quintet and the magnitudes of the
axial–equatorial and equatorial–equatorial coupling constants
were the same (3JH,H = 3.6 Hz). For the case of the 1H in the axial
position, the resonance appeared as a triplet of triplets, with two
axial–axial coupling constants of 10 Hz and two axial–equatorial
coupling constants of 3.6 Hz. The equatorial hydrogen atoms were
high-frequency shifted by 0.59 0.18 ppm with respect to the
axial hydrogen atoms.
3
of triplets with two coupling constants (δH = 2.51, JH,H = 10.8
and 3.9). The trans isomers preferred to position the amine group
c
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Copyright ꢀ 2010 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2010, 48, 938–944

Conformation and configuration of cyclohexanamines
Figure 2. 1H NMR spectrum of 4a. At the chemical shift positions 3.95 and 3.88 ppm, two quartets were assigned to the CH of the phenylethanamine,
and their corresponding CH3 groups partially overlapped at 1.323 and 1.319 ppm. The methyl groups of the cyclohexane appeared at 0.9 and 0.81 ppm.
The expanded view (inset) shows the triple–triple (3JH,H = 3.8 and 5.1) at 2.53 for the cis isomer (amine group in the axial position) and the triplet of
triplets (3JH,H = 3.9 and 11) at 2.23 for the trans isomer (amine group in equatorial position).
axially, as was evident in the resonance of the hydrogen on C1,
which was observed as a quintet signal (δ 1H = 2.93, 3JH,H = 3.9).
A similar observation was made for compound 3d (ꢀδH = 0.32).
The amines 5a–5d were used as ananchomeric models because
thesecompoundscontainedatert-butylgroupattheC4equatorial
1
position. The H NMR showed evidence that the six-membered
ring preferred the chair conformation with the two connectivity
isomers (cis/trans). In general, the vicinal coupling constants
‘axial–equatorial’ and ‘equatorial–equatorial’ were almost of the
same magnitude, 3.9 and 2.9 0.2 Hz, respectively, whereas the
‘axial–axial’ constants were 10.8 0.1 Hz. The hydrogen in the
equatorial position was high-frequency shifted by 0.4 ppm with
respecttotheaxialhydrogen.Compounds4a–4dshowedasimilar
coupling pattern, providing evidence for the same preferential
conformation with both isomers present; for instance, the ratio
between the cis/trans isomers in compound 4a was 3 : 1 (Fig. 2).
The chemical shift difference for the hydrogens at C2 and C6
1
in the H NMR spectra permitted assignment of the substituent
of the exocyclic amine derivative due to the aromatic ring current
effect[7] (Fig. 3). Thedeshieldingeffectofthearomaticring allowed
Figure 3. Ananchomeric models (5a, 5b, 5c, and 5d) with a δH for the
hydrogen atoms α to the amine group, in agreement with the NOESY
spectra.
determination of the correct assignment of the C2 or C6 carbons
in the cyclohexyl derivative.
conformation as 2a. This was confirmed by the chemical shift
and coupling constants determined by 1H, 13C, and 15N NMR
spectra.
Two signals corresponding to the hydrogen atoms at C1
were observed in the 1H NMR spectrum of compound 2a:
one at 1.85 and another at 2.06 ppm, which were expected
for the two trans diequatorial isomers epimeric at C7 (ll
and lu, respectively), with two different coupling constants,
3JHax–Hax = 10.1 and 3JHax–Heq = 4.2. The corresponding signals
The trans isomers of 2c and 2d have the two substituents
of the cyclohexane in the ‘equatorial’ positions, as evidenced
by the splitting pattern of H1 in the 1H NMR spectra which is
observed as a doublet of triplets with two ‘axial–axial’ and one
‘equatorial–axial’spin–spincouplingconstants(δH = 2.07and1.9
for the compound 2c and 2d, respectively, 3JH,H = 10.0 and 3.7).
The cis isomers displayed one signal, a doublet–doublet–doublet,
with two vicinal coupling constants corresponding to the
‘axial–equatorial’ interaction and one corresponding to the
‘axial–axial’ interaction (δH = 2.66 and 2.53, for the compounds
of H1 in the cis isomers (ul and uu) appeared at 2.50 and
3
2.52 ppm, each one with two coupling constants: JHeq–Heq
=
3
3
3
4.2, JHax–Heq = 6.7, JHeq–Heq = 3.7, and JHax–Heq = 3.7,
respectively. It was possible to identify four doublets at 1.09,
0.98, 0.97, and 0.93 ppm, with coupling constants of 6.4, 7.1,
7.1, and 6.4, respectively, which were assigned to the methyl
group in the cyclohexane. The resonances corresponding to
H7 were observed at 3.9, 3.9, 3.91, and 4.0 ppm, each with a
coupling constant of 6.6 Hz. The compound 2b had the same
3
2c and 2d, respectively; JH,H = 8.7, 4.3 and 3.9). The 1H NMR
spectra of compound 2c displayed two singlet signals at 5.04 and
c
Magn. Reson. Chem. 2010, 48, 938–944
Copyright ꢀ 2010 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/mrc

J. A. Montalvo-Gonza´lez, M. G. Iniestra-Galindo and A. Ariza-Castolo
Table 2. 13C chemical shifts of the amine series a (1a, 2a, 3a, 4a, and 5a)
Compounds
Isomers
1
2
3
4
5
6
7
R = CH3
1a
2a
–
53.62
61.12
59.42
54.79
55.42
49.28
53.68
49.28
53.86
50.76
53.83
48.46
54.12
54.06
61.37
59.51
55.03
55.66
49.76
54.17
49.53
53.94
51.09
54.20
50.47
54.38
54.08
55.05
59.89
54.23
49.70
50.46
54.26
48.81
54.69
53.18
55.01
60.27
53.59
48.63
50.57
53.62
47.75
53.86
34.59
39.39
38.44
34.31
32.40
32.23
34.15
40.57
43.54
30.52
34.63
32.01
34.60
34.73
39.33
38.76
34.52
32.03
32.19
34.34
40.65
43.60
30.61
34.61
32.03
34.95
34.08
33.52
39.26
43.11
39.55
34.04
34.21
30.85
34.54
33.88
32.42
38.55
43.19
39.68
34.19
34.28
30.67
34.21
25.27
34.83
34.83
30.81
31.20
27.06
31.68
26.88
31.95
30.09
34.25
21.55
26.29
25.50
34.84
34.84
30.91
31.22
27.05
31.75
27.23
32.07
30.23
34.36
21.68
26.41
25.24
30.88
34.95
31.99
26.97
29.67
29.87
21.55
26.45
25.07
31.26
34.76
31.97
26.98
29.50
29.97
21.23
26.31
26.22
26.02
26.23
22.90
21.92
34.27
34.92
34.27
34.92
32.60
32.60
48.28
47.82
26.36
26.03
26.16
23.00
21.85
34.24
34.97
34.24
34.97
32.63
32.63
48.27
47.89
26.37
23.11
26.19
34.49
30.66
31.06
32.58
48.39
48.03
25.99
21.90
25.97
33.89
31.33
30.24
32.59
48.16
47.79
25.07
25.88
25.74
23.42
24.44
20.59
25.08
20.31
25.08
29.79
33.97
21.21
26.05
25.20
25.86
25.56
21.85
24.53
20.73
25.24
20.47
24.99
29.95
34.08
21.36
26.13
25.24
23.33
25.78
25.17
20.58
29.67
29.87
21.55
26.45
25.07
24.24
25.68
25.12
20.29
29.50
29.97
21.23
26.31
33.23
34.05
34.05
28.05
29.24
38.49
42.37
29.90
32.96
28.49
33.26
29.52
33.15
33.87
33.89
32.74
28.29
29.18
39.08
42.96
30.44
33.55
29.02
33.8
54.46
56.71
54.64
54.35
54.64
54.51
54.84
54.44
54.84
54.77
54.66
54.92
54.70
49.73
51.57
50.01
49.37
50.01
50.40
49.59
50.25
49.76
50.27
49.90
48.78
49.75
63.79
63.71
64.00
64.05
63.66
63.99
63.85
64.10
63.97
44.38
44.59
46.00
44.70
44.70
44.73
44.86
44.68
44.93
–
lu
13.43
19.57
15.44
19.87
21.65
22.78
21.81
22.69
20.83
22.43
–
ll
ul
uu
3a
RRR
SRS
RRS
SRR
cis
4a
5a
trans
cis
trans
–
–
1b
2b
–
lu
13.51
19.80
15.52
19.93
21.82
22.78
21.82
22.78
20.95
22.46
–
ll
ul
uu
3b
RRR
SRS
RRS
SRR
cis
4b
5b
trans
cis
30.08
34.12
34.08
28.42
32.88
34.99
33.81
34.04
34.21
30.85
34.54
33.88
28.79
33.54
34.90
33.89
34.19
34.28
30.67
34.21
trans
–
–
1c
2c
–
cis
15.14
19.96
22.80
22.11
21.37
22.45
–
trans
cis
3c
4c
5c
trans
cis
trans
cis
trans
–
–
1d
2d
–
cis
13.33
19.37
22.65
21.39
20.56
22.41
–
trans
cis
3d
4d
5d
trans
cis
trans
cis
trans
–
tert-butyl group: δC = 32.53 0.13, δCH3 = 27.65 0.08. NCCH3: δC = 24.37 0.75. In the series a phenyl group: δCi = 146.54 0.49,
δCo = 126.63 0.10, δCm = 128.12 1.11, δCp = 126.75 0.07. In the series b naphthyl group: δC1 = 142.28 0.45, δC2 = 129.07 0.04,
δC3 = 125.46 0.18, δC4 = 127.06 0.04, δC5 = 123.03 0.31, δC6 = 125.80 0.07, δC7 = 125.83 0.04, δC8 = 123.09 0.33, δC9 = 134.09 0.04,
δC10 = 131.43 0.1. In the c phenyl group: δCi = 144.93 0.31, δCo = 126.91 0.05, δ,Cm = 128.49 0.04, δCp = 127.58 0.11.
5.13 ppm corresponding to the hydrogen atom of the exocyclic
methine at C7 in each isomer present (cis and trans, respectively),
as well as the doublet signal for the methyl group at δH = 1.05
average of the coupling constants, as observed in the 1H NMR
spectrum of 4a. In this compound, the ratio of the amine groups
in the axial and equatorial positions of the cis isomer was 5 : 1.
These data provide evidence that the methyl group preferred the
equatorial conformation, as demonstrated by the 15N NMR.
The 13C NMR spectra of the epimers of 3a and3b (1-R,3-R,7-R;
1-S,3-R,7-R; 1-R,3-R,7-S; 1-S,3-R,7-S) were completely different and
were assigned by the 1D and 2D spectra, including the 13C–1H
3
(cis) and 1.15 (trans) with JH,H = 7.1 and 6.1, respectively. The
cis/trans ratio was 4 : 1 in compounds 2c and 2d.
The isomers of compounds 2a–2d, which included a methyl
group on the C2 of the cyclohexane in the cis position with respect
to the amine group, displayed spectra similar to 5a due to the
c
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Copyright ꢀ 2010 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2010, 48, 938–944

Conformation and configuration of cyclohexanamines
Table 3. 15N chemical shifts of the amines
Compounds Isomers
δN
Compounds Isomers
δN
1a
2a
–
−309.09
−311.37
−312.70
−318.91
−322.32
−315.70
−316.71
−307.35
−307.56
−315.78
−308.68
−320.88
−309.28
−310.53
−323.38
−313.56
−309.33
−318.51
−318.53
−310.16
−322.38
−310.18
−308.54
−309.80
−309.95
−311.95
1b
2b
–
−311.91
−313.79
−315.55
−322.3
−325.27
−319.03
−320.02
−310.97
−311.10
−318.92
−311.54
−324.20
−311.28
−305.45
−319.04
−309.93
−304.91
−313.90
−313.29
−305.52
−319.24
−305.77
–
lu
lu
ll
ll
ul
ul
uu
uu
3a
RRR
RRS
SRR
SRS
cis
3b
RRR
RRS
SRR
SRS
cis
4a
5a
4b
5b
trans
cis
trans
cis
Figure 4. A model of compound 5a with the data for the cyclohexane C1
and C3 chemical shifts. The Newman projection is shown on the right.
trans
–
trans
–
1c
2c
1d
2d
long-range correlation spectrum, which allowed the quaternary
carbon assignments.
The 13C NMR spectra (Table 2) showed that the amine group
in the equatorial position displayed a C1 chemical shift at higher
frequencies compared to the amine group in the axial position. In
these compounds, C3 and C5 were shifted by 5 ppm for the case
cis
cis
trans
cis
trans
cis
3c
3d
4d
5d
trans
cis
trans
cis
4c
trans
cis
trans
cis
in which the amine group was in the equatorial position (γanti
)
5c
compared to the chemical shift when the amine group was in the
axial position (γgauche) (Fig. 4).
trans
lu
trans
–
2 aH+
–
–
–
–
The preferred conformation of compound 1a was the chair,
with the amine group in the equatorial position. In addition to
the diastereotopic resonances of C2 and C6, which had been
previously reported,[8] we found that the C3 and C5 resonances
also differed.
ll
–
–
ul
–
–
uu
–
–
The 15N NMR spectrum (Table 3) agreed with the other
NMR data.[9] Compounds 1a–1d displayed a preference for the
equatorial position (δN = −309 3). In addition, it was observed
that ꢀδeq–ax = 9 3.
because mixtures allow the determination of substitution effects.
The main conformation of the cyclohexane was the chair; the
alkyl groups in the amines were predominantly in the equatorial
position. The evidence obtained by 1H NMR indicated that the
substitution effect of the aryl group was larger than that of the
methyl groups. In contrast with previous reports, we established
that the amine group preferred the equatorial position, including
cases in which steric hindrance of the methyl group in the β
position was present, as demonstrated by 15N NMR.
Compound1ashowedaδN = −309.1. Thiscorrespondedtothe
amine group in the equatorial position because two isomers were
observed in the 15N NMR spectrum in the compound anchored
with the tert-butyl group; the cis isomer with the amine group in
the axial position displayed δN = −320.9 and the trans isomer
with nitrogen in the equatorial position displayed δN = −309.3.
In contrast with previous reports,[8,10] the isomers of 2a
preferentially positioned the methyl groups in the equatorial
position, as demonstrated by the 15N NMR spectrum, because
ꢀδN = 10.95 for the lu and uu isomers. The isomers ll and
ul displayed ꢀδN = 6.2. This difference is very narrow to be
accepted as evidence for the presence of both the axial and
equatorial nitrogen positions. Additional evidence was gathered
by preparing the hydrochloride derivatives (labeled in the table
as 2 aH+). These isomers included the ammonium group in the
equatorial position and yielded a value of ꢀδN = 1.8 0.4 ppm for
the epimers. Formation of the ammonium hydrochloride shifted
the peak corresponding to the nitrogen in the equatorial position
by 2.9 ppm, whereas the isomers that preferentially positioned
the amine group in the axial position presented a difference of
9.7 0.7 ppm due to the change in the conformation.
Experimental
The NMR spectra of compounds 1a–5d were recorded at room
temperature (21 2 ◦C) using Jeol 270 GSX-Delta (6.345 T), Jeol
Eclipse 400 (9.390 T), and Jeol ECA-500 (11.7 T) spectrometers
equipped with 5 mm multinuclear probes. All spectra were
obtained using natural abundance samples in CDCl3 (0.9 mmol
of each compound per 0.4 ml solvent). The unified scale[11] was
used as primary reference, the 1H resonance of TMS in dilute
solution (volume fraction, ϕ < 1%) in chloroform. (CH3)4Si (δ 1H =
0, δ 13C = 0) and neat CH3NO2 (δ 15N for ꢁ 15N = 10.136767 MHz).
1
The H NMR spectra were recorded at 500 MHz (spectral width:
9384 Hz; acquisition time: 6.984 s, 65536 data points, pulse width
45◦, 16 scans, recycle delay: 1 s). 13C{ H} NMR spectra were
1
recorded at 100.525 MHz (spectral width: 39.3 kHz; acquisition
time:0.834 s, 32768datapoints, pulsewidth30◦, 256scans, recycle
delay: 1 s). 15N NMR spectra were recorded at 50.7 MHz using a
single pulse decoupling experiment with nOe,[12] considering that
the ηmax = −4.93 with a Waltz-16 composite pulse decoupling
Conclusions
The assignment of the stereochemistry at each amine center of the
compounds examined was enabled by analysis of the mixtures,
c
Magn. Reson. Chem. 2010, 48, 938–944
Copyright ꢀ 2010 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/mrc

J. A. Montalvo-Gonza´lez, M. G. Iniestra-Galindo and A. Ariza-Castolo
(spectral width: 25406 Hz; 32768 data points, from 1024 to 30 000
scans, depending on the solubility; recycle delay: 1 s).
13C NMR APT spectra were recorded at 67.94 MHz (spectral
width: 17006.8 Hz; acquisition time: 0.963 s, 16384 data points,
1JC,H = 145 using the modulation of J, 1024 scans, recycle delay:
1 s).
13C NMR DEPT spectra were recorded at 100.523 MHz (spectral
width: 25 189 Hz; acquisition time: 1.3 s, 32768 data points, setting
90◦ and 135◦ versions, 1/(2JC,H) = 3.5 ms, 512 scans, recycle delay:
2 s).
described[14]; the reactants were dissolved in methanol at room
temperature (26 3 ◦C), equilibrated for 96 h, and the pH of
each solution was adjusted to 1 using HCl. The compounds
were washed with an aqueous alkaline solution (NaOH, pH =
11) and extracted with CH2Cl2 at neutral pH. The solutions were
evaporated to dryness under vacuum and purified by column
chromatography(ethylacetate/hexane9 : 1,silicagel).Thephysical
andspectroscopicpropertiesoftheamines1a,[1c,4a,8,15b] 2a,[8,10,15c]
3a,[1a,b,15a] 4a,[15a] 5a,[15e] 1b,[2] 1d,[3] 2d,[15f] and 5d[15d,e] were in
good agreement with previous reports.
1H–1H COSY spectra were obtained at 399.78 MHz with the
DQF–COSYpulsesequence[12] usinga1024×512datapointmatrix
and a 3299 × 3299 Hz frequency matrix. The recycle delay was 1 s
and a total of 16 scans were performed. Fourier transformations
were carried out for F1 and F2 using a sine function in the absolute
value mode.
1H–1H NOESY[12] spectra were obtained at 399.78 MHz using
a 1024 × 512 data point matrix and a 3299 × 3299 Hz frequency
matrix. The 1 s mixing time recycle delay was 1 s, and 16 scans
were performed. Fourier transformations were carried out for F1
and F2 using a sine function in the absolute value mode.
13C–1H HETCOR spectra[12] were obtained at 100.525 MHz to
yield a high resolution in the aliphatic region using a 2048 × 512
data point matrix and a 13 190 × 3299 Hz frequency matrix. The
pulse time intervals 1 and 2 were set as 2 × 1/4J = 1.85 ms.
The recycle delay was 1 s, and 16 scans were performed. Fourier
transformations were carried out using a square-sine function for
F1 and F2 in the absolute value mode.
The 13C–1H long-range correlation spectrum was recorded at
100.525 MHz with the g-HMBC pulse sequence using a 2048×512
data point matrix and 4251 × 20 750 Hz frequency matrix. The
delaysweresetbasedonthe1JC,H = 140 Hzandthe2/3JC,H = 8 Hz.
The recycle delay was 1.5 s, and 16 scans were performed. Fourier
transformations were carried out using a square-sine function for
F1 and F2 in the absolute value mode.
Mass spectrometry (MS) studies of compounds 2a–5d were
carried out using a Hewlett-Packard (HP) 5890 spectrometer
coupled to a gas chromatograph in the electron ionization
(EI) mode (at 70 eV). No mass spectra could be obtained for
compounds 1a–5a because of their instability at their respective
boiling temperatures.
Acknowledgements
Funding for this research was provided by CONACyT (Research
grant no. 56604) and J. A. M-G is grateful to CONACyT for the
scholarship. Thanks are due to Prof. Rosa Santillan for her critical
reading.
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The imines were obtained according to previous reports[13] by
the condensation of equimolar amounts of the corresponding
amines and cyclohexanones in pentane or toluene solutions. The
reactions were carried out under reflux (for 12 h) in a Dean–Stark
water separator. The compounds were purified by low-pressure
distillation.TheiminegroupswerereducedbyNaBH4,aspreviously
c
wileyonlinelibrary.com/journal/mrc
Copyright ꢀ 2010 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2010, 48, 938–944