Preparation of enantiomers of 1-(1-naphthyl)-2,2-dimethylpropylamine and their behaviour as chiral solvating agents: Study of diastereochemic association by Job's plots and intermolecular NOE measurements

Article abstract of DOI:10.1016/S0957-4166(00)00334-7

Enantiomers of 1-(1-naphthyl)-2,2-dimethylpropylamine have been obtained and considered as chiral solvating agents against several compounds. The formed complexes have been studied with the aid of the nuclear Overhauser effect and its stoichiometry by the

Full text of DOI:10.1016/S0957-4166(00)00334-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3747–3757
Preparation of enantiomers of
1-(1-naphthyl)-2,2-dimethylpropylamine and their behaviour
as chiral solvating agents: study of diastereochemic
association by Job’s plots and intermolecular NOE
measurements
A. Port, A. Virgili,* A. Alvarez-Larena and J. F. Piniella
Unitat de Qu´ımica Orga`nica, Departament de Qu´ımica and Departament de Geologia,
Universitat Auto`noma de Barcelona, 08193 Bellaterra, Barcelona, Spain
Received 27 July 2000; accepted 22 August 2000
Abstract
Enantiomers of 1-(1-naphthyl)-2,2-dimethylpropylamine have been obtained and considered as chiral
solvating agents against several compounds. The formed complexes have been studied with the aid of the
nuclear Overhauser effect and its stoichiometry by the method of continuous variations. Two diastereoiso-
meric complexes present similar geometry of association by p–p-stacking of the aromatic rings and by
hydrogen bonding of the functional groups. © 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
The rotational barrier of a bond is one of the essential factors in the chiral discriminatory
ability in complex formation. In demonstrating this, the preparation1,2 of 9-anthryl-tert-butyl-
carbinol as a chiral solvating agent and its behaviour were recently reported showing the
importance of the t-butyl group to study the complex structure. The intermolecular nuclear
Overhauser effect (NOE) was used to analyze2,3 in a qualitative way the proximity of various
parts of the chiral molecules for which enantiodifferentiation occurred.
Optically active amines have been used extensively as chiral solvating agents (CSA) in the
NMR determination of the enantiomeric excess of chiral carboxylic acids.4 Anisotropic groups
in chiral amines have given rise to chemical non-equivalence in the diastereomeric complexes
formed between amine and acid compounds. The preparation of enantiomers of 9-(1-amino-2,2-
dimethylpropyl)-9,10-dihydroanthracene and their behaviour as chiral solvating agent have been
described.5
* Corresponding author. E-mail: albert.virgili@uab.es
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00334-7

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A. Port et al. / Tetrahedron: Asymmetry 11 (2000) 3747–3757
1-(1-Naphthyl)ethylamine was reported, firstly, by Pirkle et al. to assign the absolute
configuration of alkylarylcarbinols and acids.6 In order to study the effect of a higher rotational
barrier, and to increase the possibility of obtaining intermolecular NOEs, a t-butyl group was
introduced and the 1-(1-naphthyl)-2,2-dimethylpropylamine 1 was synthesised. The enantiomers
were separated by chiral HPLC and tested against several chiral molecules as acids and alcohols.
2. Results and discussion
Racemic 1-(1-naphthyl)-2,2-dimethylpropylamine 1 was obtained by reducing 1-(1-naphthyl)-
2,2-dimethylpropylimine 2, which was prepared by reaction of the lithium derivative of
1-bromonaphthalene with pivalonitrile (Fig. 1).
Figure 1. Scheme of synthesis of 1
Separation of the enantiomers of 1 was achieved by direct chromatography using a Whelk-O1
semi-preparative chiral column. Hexane/i-PrOH (9:1) was used as elution solvent with a 3.5 ml
min−1 flow rate. K(S)=3.2; K(R)=5.9; h=1.85. The first enantiomer eluted was (+)-1 and the
second (−)-1. Their absolute configuration was assigned ((S)-(+)-1 and (R)-(−)-1) by X-ray
diffraction of the amide derivative of (−)-1: 1N-[1-(1-naphthyl)-2,2-dimethyl-(1R)-propyl]-3,3,3-
trifluoro-2-methoxy-2-phenyl-(2R)-propylamide, 3, (Fig. 2) obtained by reaction of (R)-1 with
(R)-(−)-a-methoxy-a-(trifluoromethyl)-phenylacetyl chloride.
2.1. Conformational studies
Restricted rotation about the sp2–sp3 bond in carbinols of the type ArRR%COH has been
studied extensively in recent years.7 Lunazzi et al. employed dynamic nuclear magnetic reson-
ance to study atropisomers generated by this rotation. Although imines,8 sulfoxides,9 sulfones,10
ketones11 and phosphines12 bearing naphthyl as an aromatic group were also examined, no
references exist when an amine is present on the sp3 carbon. Dynamic HPLC was also useful in
detecting these isomers.13
Here, a complete study was performed on 1-(1-naphthyl)-2,2-dimethylpropylamine 1, where a
pair of conformational atropisomers exists owing to the simultaneous presence of a stereogenic
center (the carbon atom) and a stereogenic axis (sp2–sp3) (Figs. 3 and 4).

A. Port et al. / Tetrahedron: Asymmetry 11 (2000) 3747–3757
3749
Figure 2. Representation of X-ray diffraction of amide 3
Figure 3. Numbering of compound 1
MM3 calculations14 (Fig. 5) were used to estimate the barriers of rotation about the sp2–sp3
axis. Two atropisomers, ac and sc, are of differing stability, with the ac atropisomer being more
stable with a 3.45 kcal mol−1 energy difference, which means that ac atropisomer is predominant
in a 99.3 to 0.7 population. Interconversion of the more abundant (ac) into the less abundant
atropisomer (sc) can be achieved following two different pathways: tert-butyl group rotation

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Figure 4. R or S nomenclature used for chiral centre and nomenclature for atropisomers sp2–sp3 used for the chiral
axis
over proton H8 or over H2, where the latter has the lowest energy pathway. Hence the
corresponding calculated free energy of activation can be derived (DG*=15 kcal mol−1). The
variable temperature NMR experiment did not afford changes in the signal shape nor any
chemical shift of any proton in the amine. The X-ray structure confirms that only the ac
atropisomer is present in the solid state (Fig. 6).
Figure 5. Steric energy plot for atropisomer conversion of 1. Diedric angles used for the study were W1=N–C9–C1–C2
and W2=CH3–C10–C9–C1. Lowest energy conversion pathway between atropisomers is shown.

A. Port et al. / Tetrahedron: Asymmetry 11 (2000) 3747–3757
3751
Figure 6. Molecular structure obtained by X-ray diffraction for (S)-1
2.2. Chiral induction activity
A mixture of a racemic and non-racemic chiral compound (Fig. 7) (methoxy mandelic acid 4,
1-phenyl-1,2-ethanediol 5, 3-phenylbutyric acid 6, ibuprofen 7, 2-bromopropionic acid 8,
2,2,2-trifluoro-1-(9-anthryl)-ethanol 9 and trans-1,2-diphenylethylene oxide 10) with between one
and two equivalents of one enantiomer (R or S) of 1 gave diastereomeric complexes in which 1H
NMR chemical shift non-equivalence was observed. Integration of the separate anisochronous
resonances allowed measurement of enantiomeric purity. All experiments were carried out in a
400 MHz spectrometer at 298 K and using CDCl3 as a solvent. Results are shown in Table 1.
Figure 7. Compounds 4–10

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A. Port et al. / Tetrahedron: Asymmetry 11 (2000) 3747–3757
Table 1
Measurement of the maximum induced chemical shift on racemic compounds 4–9 using (R)-1 or (S)-1 as CSA
Substrate
Observed resonance
Stoichiometry 1:chiral solut
DlH (ppm)
4
H1
H2
H3/H4/H5
H2
H3
H2
H3
H3%
H5
H6
H2
H11
H10
1.5
1.5
1.5
1.5
1.5
1a
0.10
0.09
0.09
0.01
0.01
0.02
0.02
0.01
0.02
0.03
0.09
0.07
0.01
5
6
1a
1a
1.5
1.5
1a
1.5
1.5
7
8
9
a Salt formation.
Fig. 8 shows a part of the NMR spectrum corresponding to the addition of 1.5 equivalents
of (S)-1 to the racemic compound and to the one enriched enantiomer of compound 4. The
observed non-equivalence of the methyne (H1) and methyl (H2) signals increased at higher
concentrations of the amine (S)-1, with a maximum being recorded at 1.5 equivalents of amine.
1
Figure 8. Evolution of aliphatic DlH for acid 4; (a) pure 4; (b) 400 MHz H NMR spectrum of 4 with 0.5 equivalents
of (S)-1; (c) with 1.5 equivalents of (S)-1; (d) addition of 1 equivalent of (S)-1 to a one enantiomer enriched
(1R/1S=1/3) of 4

A. Port et al. / Tetrahedron: Asymmetry 11 (2000) 3747–3757
3753
Compound 4 shows the greatest shift in non-equivalence between enantiomers. Different
hydrogen bonds between the acidity sites in the acid and between the basic sites in the amine
together with p–p-stacking interactions between aromatic rings provides the force for chiral
recognition.15
Two complexes were examined in order to study the interactions between the solvating agent
and the chiral solute in greater detail: the two enantiomers of the methoxy mandelic acid 4 with
(S)-1 (called S1S4 and S1R4). First we examined the chemical shifts between complexes in 1:1
mixtures of (S)-1 with each enantiomer of 4. Table 2 shows the results of the NMR experiments.
The differences in chemical shift for each enantiomer with respect to the free compound in the
presence of the amine 1 were measured. The influence of the chiral compound was markedly
different; while the behaviour of the protons of 1 are similar for two complexes, the H1, H3 and
H4 of the (R)-4 enantiomer was shifted to higher fields than was the (S)-4 enantiomer. These
results explained that energetically and/or geometrically the two complexes, S1R4 and S1S4,
must be different.
Table 2
Chemical shift changes (ppm) for 1:1 mixtures of (S)-1 with each enantiomer of 4
Proton
1 or 4
S1S4
S1R4
l
Dl
l
Dl
DDl
H2-1
H3-1
H4-1
H5-1
H6-1
H7-1
H8-1
H9-1
H11-1
H1-4
H2-4
H3-4
H4-4
H5-4
7.68
7.45
7.74
7.84
7.45
7.45
8.19
4.78
0.97
4.77
3.40
7.42
7.35
7.35
7.61
7.36
7.72
7.79
7.41
7.41
7.89
4.83
0.85
4.28
3.01
7.24
7.15
7.15
−0.07
−0.09
−0.02
−0.05
−0.04
−0.04
−0.30
+0.05
−0.12
−0.49
−0.39
−0.18
−0.20
−0.20
7.67
7.40
7.76
7.82
7.43
7.43
7.93
4.83
0.79
4.03
3.07
6.95
7.05
7.10
−0.01
−0.05
+0.02
−0.02
−0.02
−0.02
−0.26
+0.05
−0.18
−0.74
−0.33
−0.47
−0.30
−0.25
−0.06
−0.04
−0.04
−0.03
−0.02
−0.02
−0.04
0.00
+0.06
+0.25
−0.06
+0.29
+0.10
+0.05
2.3. NOE measurements
Intermolecular NOE values were obtained for the two complexes S1S4 and S1R4. High
quality NOE spectra were obtained using gradients techniques as DPFGNOE.16 Diverse
intermolecular NOE was observed between protons of 1 and 4 indicating the short distance
between the two components. Fig. 9 shows several intermolecular 1D spectra observed in the
S1R4 complex. Similar results were found when analogous 2D sequences were applied. When H9
of 1S was saturated an important NOE effect on the methoxy protons of 4 appears. When the
last methoxy group was irradiated, several proton signals of the naphthyl ring were present in
the spectra, those nearest to the chiral centre, indicating the proximity of the substituted ring of
the naphthyl group to the methoxy group of 4.

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A. Port et al. / Tetrahedron: Asymmetry 11 (2000) 3747–3757
Figure 9. 400 MHz NOE spectra of a 1:1 mixture S1R4. DPFGNOE method was used with a mixing time of 400 ms.
Intermolecular signals are encircled
No intermolecular cross relaxation is present when H1 of 4 is inverted demonstrating that this
proton is outside of the complex. Similar results were obtained for the S1S4 complex, indicating
a similar geometry of the association: the involvement of the substituted ring of the naphthyl
group and the stereogenic center of 1 in front of the benzene ring, the acidic function and
methoxyl group of the 4.
A knowledge of the stoichiometry of the associate is basic data in determining the structure
of the complexes. As the chemical shift of a nucleus is a mean value of the several species
presents in the solution, when its solubility is complete, Job’s method17 (method of continuous
variations18) can be applied to calculate the stoichiometry of the complexes in solution. The two
complexes, S1S4 and S1R4, were analysed: seventeen samples of a constant total concentration
were prepared containing variable ratios of the two components. Only complex S1S4 is
described here.
1
The H NMR spectra of seventeen samples were recorded at 300 K and chemical shift
variations were observed for protons of amine 1 and the acid 4. The plot of the variation of the
chemical shift of the H2 and H3 of 4 and amine protons H2, H8, and H9 versus the ratio between
the concentration of each compound (1 or 4) and the total concentration (0.04 M) are reflected
in Figs. 10 and 11.
The X coordinate of the parabolic curve maximum represents stoichiometry. In the case being
examined here, a completely different behaviour is observed when the signal from the one or
other components are considered. For acid protons H2 and H3 and amine proton H9 the
maximum corresponds to a 4/1 ratio of 2/1, that is, each amine 1 has two acids 4 surrounding
it. Moreover when amine protons H8 and H2 are studied, the stoichiometry of the complex is
1/1, indicating that these protons are only influenced by one acid molecule, (S)-4. This

A. Port et al. / Tetrahedron: Asymmetry 11 (2000) 3747–3757
3755
Figure 10. Job’s plots of variation of chemical shift for acid protons H2 and H3 in S1S4 complex
Figure 11. Job’s plots of variation of chemical shift for amine protons H9, H8 and H2 in the S1S4 complex
anomalous behaviour might be induced by the presence of other processes. It has been
described19 that when other (or more than one, dimerization, etc.) interactions are present the
Job’s plots obtained might be strongly affected giving incorrect stoichiometries. Only NMR
(involving the observation of each of the components separately) can provide this type of
differential information.
If we consider that logical processes such as the dimerization of the acid compounds might be
responsible for the abnormal behaviour and that conditions such as the low concentrations used
here where trimer species is statistically unlikely, a 1/1 association can be assumed. The same
results were obtained for complex S1R4.
3. Experimental
3.1. Synthesis: 1-(1-naphthyl)-2,2-dimethylpropylimine 2
A solution (1.6 M) of butyllithium (15.7 ml, 25.11 mmol) was slowly added to a diethyl oxide
(60 ml) solution of 1-bromonaphthalene (4 g, 19.32 mmol) kept under N2 at 0°C with
continuous stirring. The reaction was completed after two hours and pivalonitrile (2.78 ml, 25.11
mmol) was added dropwise, keeping temperature at 0°C. After 90 minutes at room temperature,
the reaction was quenched and the organic layer was separated, dried and concentrated. The
residue was filtered and a white solid (85% yield) was obtained. Mp: 50–52°C. IR (KBr) cm−1:

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A. Port et al. / Tetrahedron: Asymmetry 11 (2000) 3747–3757
1
3240, 3051, 2966, 2868, 1609, 1476, 1391, 1216, 1159, 906, 780. H NMR (CDCl3) (ppm): 1.29
(s), 7.22 (d), 7.41 (t), 7.46 (m), 7.72 (m), 7.79 (d), 7.83 (m), 9.2 (broad). 13C NMR (CDCl3)
(ppm): 28.5, 40.7, 123.1, 124.4, 125.9, 126.2, 127.9, 128.2, 130.4, 133.6, 139.5, 189.4. EM m/z
(%): 211 (21), 196 (23), 155 (13), 154 (100), 127 (27).
3.2. 1-(1-Naphthyl)-2,2-dimethylpropylamine 1
A diethyl oxide solution (10 ml) of 1-(1-naphthyl)-2,2-dimethylpropylimine (1 g, 4.77 mmol)
was slowly added to a diethyl oxide (20 ml) solution of AlLiH4 (543 mg, 14.32 mmol) kept under
N2 with continuos stirring and refluxed for 22 hours. The reaction was quenched and the organic
layer separated, dried and concentrated. A white solid was obtained with an 80% yield, mp:
44–46°C. (S)-1: [h]2D0=+54.2; c=1.01; CH2Cl2. (R)-1: [h]2D0=−58.5; c=1.06; CH2Cl2. IR (KBr)
1
cm−1: 3388, 3051, 2945, 2868, 1595, 1511, 1476, 1398, 1363, 801, 780. H NMR (CDCl3) (ppm):
0.97 (s, tBu), 1.61 (s, HNH), 4.78 (s, H9), 7.45 (m, H6/H7), 7.48 (t, H3, JAB=6.72 Hz), 7.68 (d, H2),
7.74 (d, H4, JAB=7.92 Hz), 7.84 (dd, H5, JAB=7.92 Hz), 8.19 (d, H8, JAB=8.52 Hz). 13C NMR
(CDCl3) (ppm): 26.9, 36.4, 57.2, 123.8, 125.0, 125.1, 125.4, 127.2, 128.8, 132.4, 133.4, 140.6. EM
m/z (%): 213 (2), 157 (13), 156 (100), 129 (29), 128 (11). C15H19N, calcd: C, 84.46%; H, 8.98%;
N, 6.57%; found: 84.29%; H, 9.04%; N, 6.57%.
3.3. 1N-[1-(1-Naphthyl)-2,2-dimethyl-(1R)-propyl]-3,3,3-trifluoro-2-methoxy-2-phenyl-(2R)-
propylamide 3
(R)-(−)-a-Methoxy-a-(trifluoromethyl)-phenylacetyl chloride (100 mg, 0.4 mmol) was slowly
added to a methylene chloride (2 ml) solution of 1(R)-(1-naphthyl)-2,2-dimethylpropylamine
(R)-1 (64 mg, 0.3 mmol) and triethylamine (0.06 ml, 0.4 mmol) kept under N2 with continuous
stirring. After 2 hours, the reaction was quenched and the organic phase dried and concentrated.
A white powder was obtained (115 mg) in 89% yield. Mp: 108–109°C. [h]2D0=−30.8; c=0.585;
1
CH2Cl2. IR (KBr) cm−1: 3437, 2966, 1687, 1511, 1265, 1166, 1096, 1005, 780, 702. H NMR
(CDCl3) (ppm): 0.90 (s, 9H), 3.40 (s, 3H), 5.86 (d, H9, JAB=9.1 Hz), 7.31 (d, H2, JAB=7.0 Hz),
7.36 (d, NH), 7.40 (m, H11, JAB=7.3 Hz), 7.44 (t, H3, JAB=8.2 Hz), 7.45 (m, H6, JAB=7.9 Hz),
7.50 (m, H7, JAB=8.5 Hz), 7.60 (m, H10, JAB=2.0 Hz), 7.76 (d, H4), 7.83 (d, H5), 8.31 (d, H8).
13C NMR (CDCl3) (ppm): 26.9, 36.1, 54.8, 55.3, 84, 124, 124.3, 124.5, 125.5, 126.1, 127.5, 127.9,
128.5, 128.7, 129.4, 132.3, 132.9, 133.6, 136.6, 165.5. EM m/z (%): 429 (1), 373 (18), 372 (44),
189 (100), 155 (19), 154 (18), 141 (25), 127 (15), 119 (12), 105 (15), 69 (12), 41 (13).
C25H26F3NO2, calcd: C, 69.92%; H, 6.10%; N, 3.26%; found: 69.92%; H, 6.01%; N, 3.14%.
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