Chiral amino and imino-alcohols based on (R)-limonene

Article abstract of DOI:10.21577/0103-5053.20190201

Derivatives of the natural occurring and inexpensive terpene (R)-limonene were synthetized and completely characterized. Starting from internal olefin epoxidation, followed by epoxide opening with sodium azide and azide reduction with LiAlH4, two chiral amino-alcohols were obtained. The amino-alcohols were reacted with three different aldehydes, generating six new imino-alcohols, two of them yielding crystals suitable for X-ray diffraction characterization. The reduction of four of these compounds with LiAlH4 led to new amino-alcohols. All derivatives were obtained with good overall yields through simple reaction protocols.

Full text of DOI:10.21577/0103-5053.20190201

http://dx.doi.org/10.21577/0103-5053.20190201
J. Braz. Chem. Soc., Vol. 00, No. 00, 1-9, 2019
Printed in Brazil - ©2019 Sociedade Brasileira de Química
Article
Chiral Amino and Imino-Alcohols Based on (R)-Limonene
Rodrigo S. Fuscaldo,a Eduam O. Boeira,a Rafael Stieler,a Diogo S. Lüdtkea
and José R. Gregório *,a
aInstituto de Química, Universidade Federal do Rio Grande do Sul,
91501-970 Porto Alegre-RS, Brazil
Derivatives of the natural occurring and inexpensive terpene (R)-limonene were synthetized and
completely characterized. Starting from internal olefin epoxidation, followed by epoxide opening
with sodium azide and azide reduction with LiAlH4, two chiral amino-alcohols were obtained. The
amino-alcohols were reacted with three different aldehydes, generating six new imino-alcohols,
two of them yielding crystals suitable for X-ray diffraction characterization. The reduction of four
of these compounds with LiAlH4 led to new amino-alcohols. All derivatives were obtained with
good overall yields through simple reaction protocols.
Keywords: natural products, N,O ligands, Schiff bases, sustainable chemistry, renewable
sources
Introduction
LiPPh3 to perform previously reported selective epoxide
opening in limonene oxides,20 generating phosphine-
alcohols that induced low selectivity in Rh-catalyzed
C–H insertion and cyclopropanation reactions. Since then,
there was a narrow development in the ligand synthesis
starting from limonene, having excellent results in terms
of yield and stereoselectivity, however distributed into two
main reactions: organozinc additions21-25 and ruthenium
catalyzed asymmetric hydrogen transfer reactions.26-28
Usually, its internal cis and trans-oxides are used as
substract for selective epoxide opening with amines in order
to produce secondary or tertiary chiral amino-alcohols,
although there are some divergent methodologies using
amino-oximes26,29,30 or aziridines.28
Natural asymmetric molecules are excellent starting
points for the synthesis of chiral compounds since they are
usually enantiomerically pure, obtained from renewable
sources and, for most of them, inexpensive. Terpenes are
great natural asymmetric building blocks: mainly produced
by a variety of plants, some exemplars can be transformed
into more complex compounds with high aggregated value,
used as ligands or catalyst for asymmetric reactions, for
instance.1 One good example of this type of compound is
(R)-limonene (Scheme 1), which is present in high quantities
on citric fruits, especially in orange peel. Since Brazil is the
world top producer of orange and its juice (having the peel
as a side product),2 it is economically interesting to give
(R)-limonene nobler applications compared to solvent for
paint, additive to food, hygiene products or cosmetics and
other classical uses of this terpene.3
(R)-Limonene has two chemically distinct double bonds
that make possible a large number of chemical modifications
in order to synthesize more complex molecules4-6 with
applications spread over medicinal chemistry,7-13 total
synthesis of natural products,14-18 and others, including
applications in catalysis. The first use of limonene-
derived chiral ligands in catalytic systems was published
by Lahuerta et al.19 in 2000, where the researchers used
In order to increase structure variety, hoping this would
widen the application of limonene-based chiral molecules,
we present herein the synthesis of new amino- and imino-
alcohols based on (R)-limonene through simple and high
yielding reactions as epoxidation, epoxide opening, azide
reduction, imine formation and reduction (Scheme 1).
Results and Discusion
In order to produce (R)-limonene based imines, it was
necessary to synthesize its primary amines. We performed
the epoxidation of the internal double bond using H2O2
as oxidant and methyltrioxorhenium (MeReO3, MTO)
as catalyst, as described by Rudler et al.,31 producing a
*e-mail: jrg@ufrgs.br

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Chiral Amino and Imino-Alcohols Based on (R)-Limonene
J. Braz. Chem. Soc.
Scheme 1. Present work overview.
mixture of cis and trans-limonene oxides 1 in good yield
(Scheme 2). This mixture was then reacted with NaN3,
using an adaptation of the methodology of Cimarelli et
al.32 As described by these researchers, the reaction was
highly stereosselective and yielded only two products, the
azido-alcohols 2a and 2b, bearing trans carbon substituents
in the cyclohexyl ring, which could be separated by flash
column chromatography. This reaction pattern is very
common for limonene oxide ring opening by nucleophiles
and is due to the ring strain during the transition state
and therefore is used for the kinetic separation of these
oxides.33,34 Through the reduction of the azide group with
LiAlH4 in tetrahydrofuran (THF), primary amines 3a and
3b were obtained in high yields. These derivatives were
1
characterized by H and 13C nuclear magnetic resonance
(NMR) and the spectra matched very well the ones of their
enantiomers, which are described in the literature.32
With the primary amines 3a-b in hands, we proceeded
to the imine formation reaction with three different
OH-substituted aromatic aldehydes. These reactions
produced the desired Schiff bases (4-6a and 4-6b) in
excellent yields and in short reaction times (Scheme 3). It
is worth pointing out that the acidity of the phenolic group
itself was the catalyst for this reaction and provided an
optimum pH for the reaction to take place, since there was
no need to use another catalyst or water removal to dislocate
Scheme 2. Chiral amino-alcohol synthesis using (R)-limonene as starting material.

Vol. 00, No. 00, 2019
Fuscaldo et al.
3
the reaction equilibrium to the products. The phenolic
OH group present in these compounds could be useful in
catalysis or medicinal chemistry, by providing an additional
number of possible interactions to metals or biomolecules
active sites. All of these compounds were characterized
by mass spectroscopy, polarimetry, infrared spectroscopy
(IR), 1H and 13C NMR. The most important change on the
1H NMR spectra of these compounds was the appearance
of the imine N=C−H signal at about 8.5 ppm, along with
the incorporation of the aromatic and phenolic hydrogens.
Single crystals of 5a and 6a suitable to X-ray diffraction
studies were grown by slow evaporation of the solvent from
a concentrated dichloromethane (DCM)/hexane solution
of the compounds and provided additional information
about their molecular structures. The molecular structures
of 5a and 6a are shown in Figures 1 and 2, respectively.
The main crystallographic data and structure refinement
parameters are reported in the Supplementary Information
(SI) section. Compound 5a (Figure 1) has three stereogenic
centers and the absolute configuration was determined to
be C13(S), C14(S), C16(R) by considering the synthetic
pathway and confirmed by the X-ray diffraction study.
Moreover, the solid-state structure of 5a reveals that the
imine group are in E configuration and the torsion angle
between C6–C12–N–C13 is 176.55(32). Compound 6a
(Figure 2) has also three chiral centers with the absolute
configuration determined as C12(S), C15(R), C17(S), which
is consistent with the synthetic pathway and confirmed by
the X-ray diffraction analysis. Like 5a, the imine group in
6a are in E configuration and the torsion angle between
C12–N1–C11–C10 is 175.38(14).
To increase the structural variation of the compounds,
we performed the reduction of the imines with LiAlH4
(Scheme 4). Although the reaction occurred in good yield
with imines 4-5a and 4-5b, it was not the case for the
naphtyl derivatives, which produced a complex mixture
Scheme 3. Synthesis of limonene-derived aromatic imines.

4
Chiral Amino and Imino-Alcohols Based on (R)-Limonene
J. Braz. Chem. Soc.
Figure 1. Molecular structure of 5a with the key atoms labelled (thermal
ellipsoids drawn at 50% probability level).
Figure 2. Molecular structure of 6a with the key atoms labelled (thermal
along with some unreacted starting material. All of these
compounds were characterized by mass spectroscopy,
polarimetry, infrared spectroscopy, 1H and 13C NMR. The
ellipsoids drawn at 50% probability level).
(R)-limonene, through simple reactions with good overall
yields.
1
most important change on the H NMR spectra of these
derivatives was disappearance of the imine N=C–H signal
at about 8.5 ppm.
Conclusions
In summary, we obtained 4 enantiomers of compounds
that were previously described in the literature (2a-b and
3a-b).32 We also described the synthesis of 6 new imino-
alcohols and 4 new amino-alcohols, all based on the terpene
Primary amino-alcohol ligands were obtained by
epoxidation of (R)-limonene with MTO/H2O2, followed by
epoxy-opening reactions with sodium azide and reduction
Scheme 4. Imine reduction reactions.

Vol. 00, No. 00, 2019
Fuscaldo et al.
5
with LiAlH4. From these, imines were formed by reacting
with three aromatic salicylaldehydes in excellent yields.
Some imines were reduced to secondary amino-alcohols.
The compounds were extensively characterized by NMR,
IR, high resolution mass spectroscopy (HRMS) and
polarimetry, and it was possible to solve the crystal structure
of two of them through single crystal X-ray diffraction
(XRD). The reactions proceeded smoothly and with great
yields. With these procedures, we were able to achieve
new imino- and amino-alcohols, which could be useful in
catalysis, medicinal chemistry or even in other applications.
This study is under way.
(4R)-1-Methyl-4-(prop-1-en-2-yl)-7-oxabicyclo
[4.1.0]heptane
¹H NMR (300 MHz, CDCl3) d 4.76-4.53 (m, 4H,
cis + trans), 3.01 (t, 1H, J 2.0, cis), 2.95 (d, 1H, J 5.3,
trans), 2.15-1.92 (m, 5H, cis + trans), 1.89-1.76 (m, 4H,
cis + trans), 1.73-1.58 (m, 9H, cis + trans), 1.56-1.44 (m,
1H, cis + trans), 1.39-1.30 (m, 2H, cis + trans), 1.28 (s,
3H, cis), 1.27 (s, 3H, trans).
Synthesis of (1S,2S,4R)-2-azido-1-methyl-4-(pro-1-en-
2-yl)cyclohexanol (2a) and (1S,2S,5R)-2-azido-2-methyl-
5-(prop-1-en-2-yl)cyclohexanol (2b)
Experimental
The procedure was based on the literature.25 1.52 g
of 1 (10 mmol), 1.3 g of NaN3 (20 mmol) and 0.54 g of
NH4Cl (10 mmol) were refluxed in 4 mL of methanol
(MeOH) until all limonene oxide was consumed according
to TLC (about 32 h). The mixture was allowed to cool to
room temperature and the solvent removed. Then, DCM
was added, and the mixture was filtered through Na2SO4
and evaporated. The azido-alcohols were separated by
silica flash column chromatography using 10-30% ether
in hexane as gradient elutant (TLC: tR = 0.45 (2a) and
0.3 (2b), KMnO4 as developer). After solvent removal, the
azido-alcohols were obtained as pale-yellow oils.Yield: 2a
594 mg (37%) and 2b 822 mg (50%).
General
Unless otherwise stated, all reagents and solvents were
usedasreceived.THFwasdriedthroughdistillationfromNa-
benzophenone. NMR experiments were performed in a 300
or 400 MHzVarian spectrometer. Fourier-transform infrared
spectroscopy/attenuated total reflection (FTIR/ATR)
analyses were performed in a Bruker alpha-P apparatus
in ATR mode or Shimazdu IR Prestige-21 as thin films
between KBr crystals. The NMR chemical shifts are given
in ppm relatively to tetramethylsilane (TMS) and the FTIR
wavenumbers are given in cm−1. Mass spectra were recorded
on a Micromass Q-TOF Micro operating in electrospray
mode. Polarimetry analyses were performed in a Jasco
P2000 polarimeter in chloroform.
Compound 2a
¹H NMR (300 MHz, CDCl3) d 4.76-4.70 (m, 2H), 3.64
(t, 1H, J 3.3), 2.25 (tt, 1H, J 10.8, 3.3), 1.95-1.40 (m, 10H),
1.36 (s, 3H); ¹³C NMR (75 MHz, CDCl3) d 149.0, 109.1,
71.9, 63.1, 37.1, 34.1, 30.8, 26.4, 22.6, 20.8.
Synthesis of cis- and trans-(+)-limonene oxides (1)
The procedure was based on the literature.24 To
15.4 mg of MTO (0.0613 mmol), in an ice bath, 5 mL of
dichloromethane (DCM) and 0.99 mL of (R)-limonene
(6.13 mmol) were added. Then 2.90 mL of a 3.18 M
aqueous H2O2 (1.5 eq.) were added and the reaction was
stirred in an ice bath for 1 h. Then, the oxidant excess was
destroyed with a small amount of MnO2. The organic phase
was separated, and the aqueous layer was extracted with
1 × 10 mL and 2 × 5 mL of DCM. The organic layers were
combined, dried with Na2SO4 and the solvent removed
under vacuum. The product was purified by silica flash
column chromatography using 5% ethyl acetate (EtOAc)
in hexane as elutant (thin layer chromatography (TLC),
tR = 0.5, 5% EtOAc in hexane, using KMnO4 basic solution
as developer). The solvent was carefully evaporated in a
rotatory evaporator to give 1 as a colourless volatile oil.
Yield: 746 mg (80%).
Compound 2b
¹H NMR (400 MHz, CDCl3) d 4.77 (s, 2H), 3.54 (s,
1H), 2.20 (ddd, 1H, J 14.8, 9.8, 3.9), 2.00 (ddd, 1H, J 14.8,
11.9, 3.0), 1.90-1.81 (m, 1H), 1.76 (s, 3H), 1.72- 1.61 (m,
1H), 1.62-1.36 (m, 5H), 1.30 (s, 3H); 13C NMR (101 MHz,
CDCl3) d 148.7, 109.2, 70.9, 66.4, 37.9, 33.9, 30.7, 27.6,
25.92, 20.95.
Synthesis of (1S,2S,5R)-2-amino-2-methyl-5-(prop-1-en-
2-yl)cyclohexanol (3a)
The procedure was based on the literature.25 Under
argon atmosphere, 2 mL of dry THF were added on 200 mg
of LiAlH4 (5.26 mmol) in an ice bath. Then, a solution of
699 mg of 2a (3.58 mmol) in 3 mL of dry THF was slowly
added, causing N2 evolution, and the mixture was stirred
for 1 h in room temperature. The reaction was quenched
with saturated Na2SO4 (aq), then 10 mL of DCM were

6
Chiral Amino and Imino-Alcohols Based on (R)-Limonene
J. Braz. Chem. Soc.
added, along with MgSO4. The mixture was filtered and
the solid washed with 5 × 5 mL of DCM. The filtrate was
dried under vacuum to give 3a as a white crystalline solid.
Yield: 488 mg (81%).
EtOAc in hexane as elutant (TLC: 15% EtOAc in hexane,
tR = 0.35, vanillin as developer). Yield: 139 mg (100%) of
a bright yellow oil.
25
[α]D −166.3° (c 0.325, CHCl3); 1H NMR (400 MHz,
¹H NMR (400 MHz, CDCl3) d 4.68 (s, 2H), 3.47 (s, 1H),
2.23 (ddd, 1H, J 14.7, 10.0, 3.9), 1.79 (dddd, 1H, J 13.8, 10.9,
3.0,1.3),1.72-1.49(m,9H+H2O),1.49-1.36(m,1H),1.36-1.24
(m, 1H), 1.07 (d, 3H, J 1.3); C NMR (75 MHz, CDCl3)
d 149.1, 109.1, 71.9, 55.4, 37.5, 34.4, 33.7, 26.2, 25.8, 21.2.
CDCl3) d 13.49 (s, 1H), 8.29 (s, 1H), 7.28-7.16 (m, 2H),
6.89 (d, 1H, J 8.2), 6.81 (td, 1H, J 7.5, 1.1), 4.68-4.61 (m,
2H), 3.20 (t, 1H, J 3.1), 2.33-2.21 (m, 1H), 2.08 (ddd, 1H,
J 13.3, 12.2, 3.3), 1.89-1.75 (m, 1H), 1.22-1.54 (m, 6H), 1.50
(ddt, 1H, J 13.3, 3.7. 2.2) 1.03 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 164.1, 161.1, 149.4, 132.4, 131.4, 118.8, 118.8,
117.0, 109.0, 74.3, 70.8, 38.2, 34.9, 34.8, 28.3, 26.5, 21.1;
IR (KBr) ν / cm−1 3425, 2929, 2864, 1631, 1496, 1276, 756,
433; HRMS (FTMS + pESI) m/z, calculated for C17H23NO2H
[MH]+: 274.1807, found: 274.1807.
13
Synthesis of (1S,2S,4R)-2-amino-1-methyl-4-(prop-1-en-
2-yl)ciclohexanol (3b)
The procedure was identical to the synthesis of 3a,
using 717 mg of 2b (3.67 mmol). Yield: 519 mg (84%).
The product was obtained as a pale-yellow solid.
1H NMR (400 MHz, CDCl3) d 4.68 (s, 2H), 3.52-3.44
(m, 1H), 2.22 (td, 1H, J 10.3, 5.0), 1.85-1.50 (m, 9H + H2O),
1.49-1.39 (m, 1H), 1.33 (dddd, 1H, J 13.3, 4.9, 3.6, 1.1),
1.08 (s, 3H); 13C NMR (75 MHz, CDCl3) d 149.1, 109.1,
74.5, 51.6, 37.6, 34.5, 33.7, 26.4, 26.1, 21.3.
Synthesis of 2-(tert-butyl)-6-((E)-(((1S,2S,4R)-2-hydroxy-
1-methyl-4-(prop-1-en-2-yl)cyclohexyl)imino)methyl)-
4-methylphenol (5a)
83 mg of 3a (0.48 mmol) and 96 mg of 3-(tert-butyl)-
2-hydroxy-5-methylbenzaldehyde (0.5 mmol) were stirred
in 2 mL of EtOH until all 3a was consumed according to
TLC (1 h 30 min). The mixture was vacuum dried and
purified by silica flash column chromatography using
0-10% EtOAc in hexane as elutant.Yield: 167.9 mg (99%)
of a yellow crystalline solid.
Synthesis of 2-((E)-(((1S,2S,4R)-2-hydroxy-1-methyl-
4-(prop-1-en-2-yl)cyclohexyl)imino)methyl)phenol (4a)
86.3 mg of 3a (0.51 mmol) and 55 µL of salicylaldehyde
(0.51 mmol) were stirred in 2 mL of EtOH at room
temperature until 3a was completely consumed according
to TLC (20 min, 20% MeOH in DCM, tR = 0.5, KMnO4
as developer). The solvent was removed and the product
purified with silica flash column chromatography using
gradient elution with 5-20% EtOAc in hexane (TLC: 15%
EtOAc in hexane, tR = 0.35, using vanillin acidic solution
as developer). Yield: 137 mg (98%) of a bright yellow oil.
25
[α]D −17.0° (c 0.456, CHCl3); ¹H NMR (400 MHz,
CDCl3) d 4.23 (s, 1H), 8.40 (s, 1H), 7.13 (d, 1H, J 2.2), 6.95
(d, 1H, J 1.5), 4.78-4.68 (m, 2H), 3.83 (s, 1H), 2.47-2.33
(m, 1H), 2.29 (s, 3H), 2.02-1.85 (m, 2H), 1.78-1.74 (m,
1H), 1.57 (m, 7H), 1.43 (s, 9H), 1.30 (s, 3H); 13C NMR
(101 MHz, CDCl3) d 162.5, 158.3, 14.5, 137.3, 130.4,
129.8, 126.4, 118.6, 109.2, 74.4, 61.5, 37.5, 34.8, 34.1,
32.3, 29.4, 26.1, 23.9, 20.7, 20.6; IR (KBr) ν / cm−1 3508,
2939, 2858, 1620, 1440, 876; HRMS (FTMS + pESI)
m/z, calculated for C22H33NO2H [MH]+: 344.2589, found:
344.2586; melting point: 110 ºC.
25
[α]D +31.7º (c 0.427, CHCl3); ¹H NMR (400 MHz,
CDCl3) d 14.13 (s, 1H), 8.46 (s, 1H), 7.40-7.23 (m, 2H), 6.99
(d, 1H, J 8.2), 6.91 (t, 1H, J 7.4), 4.75 (s, 2H), 3.82 (s, 1H),
2.42 (tt, 1H, J 11.9, 3.9), 1.95 (ddt, 2H, J 14.4, 12.8, 2.2), 1.80
(td, 1H, J 3.9, 1.8), 1.78-1.70 (m, 5H), 1.69-1.47 (m, 2H),
1.34 (s, 3H); 13C NMR (100 MHz, CDCl3) d 161.9, 161.6,
149.1, 132.3, 131.5, 118.9, 118.4, 117.2, 109.2, 74.2, 61.7,
37.4, 34.1, 32.4, 26.1, 23.8, 20.8; FTIR ν / cm−1 3421, 3075,
2938, 1625, 889, 755; HRMS (FTMS + pESI) m/z, calculated
for C17H23NO2H [MH]+: 274.1807, found: 274.1807.
Synthesis of 2-(tert-butyl)-6-((E)-(((1S,2S,5R)-2-hydroxy-
2-methyl-5-(prop-1-en-2-yl)cyclohexyl)imino)methyl)-
4-methylphenol (5b)
The procedure was identical to the synthesis of 6a,
using 3b. The product was purified by silica flash column
chromatography using 10-30% EtOAc in hexane as elutant.
(tR = 0.5, 20% EtOAc in hexane, vanillin as developer).
Yield: 158 mg (94%) of a yellow viscous material.
Synthesis of 2-((E)-(((1S,2S,5R)-2-hydroxy-2-methyl-
5-(prop-1-en-2-yl)cyclohexyl)imino)methyl)phenol (4b)
25
1
[α]D −24.8° (c 0.584, CHCl3); H NMR (300 MHz,
CDCl3) d 13.50 (s, 1H), 8.33 (s, 1H), 7.14 (d, 1H, J 1.8),
6.94 (d, 1H, J 1.8), 4.76-4.69 (m, 2H), 3.25 (t, 1H, J 2.9),
2.49-2.32 (m, 1H), 2.29 (s, 3H), 2.13 (ddd, 1H, J 13.2, 12.2,
The procedure was identical to the synthesis of 4a, using
3b as substract. The product was purified with silica flash
column chromatography using gradient elution with 5-20%

Vol. 00, No. 00, 2019
Fuscaldo et al.
7
3.3), 1.81-1.51 (m, 9H), 1.44 (s, 9H), 1.12 (s, 3H); 13C NMR
(101 MHz, CDCl3) d 178.1, 153.7, 148.3, 137.9, 134.0,
129.3, 128.0, 126.0, 125.5, 122.7, 117.5, 109.7, 106.5,
73.0, 59.7, 37.2, 34.1, 32.4, 25.8, 23.8, 21.0; IR (KBr)
ν / cm−1 3428, 2947, 1620, 1432, 888, 753; HRMS
(FTMS + pESI) m/z, calculated for C22H33NO2H [MH]+:
344.2589, found: 344.2589.
Synthesis of 2-((((1S,2S,4R)-2-hydroxy-1-methyl-4-(prop-
1-en-2-yl)cyclohexyl)amino)methyl)phenol (7a)
Under Ar atmosphere, 16 mg of LiAlH4 (0.42 mmol)
were suspended in 1 mL of dry THF and to this 58.1 mg
of 4a (0.17 mmol) were added. The reaction was stirred
at reflux temperature for 1 h and allowed to cool to room
temperature. The reaction was quenched with saturated
Na2SO4 (aq), then 10 mL of DCM were added, along with
MgSO4, the mixture was filtered and the solid washed with
5 × 5 mL of DCM. The filtrate was dried under vacuum to
give 7a. Yield: 36 mg (77%) of a yellow viscous material.
Synthesis of 1-((E)-(((1S,2S,4R)-2-hydroxy-1-methyl-
4-(prop-1-en-2-yl)cyclohexyl)imino)methyl)naphtalen-2-ol
(6a)
25
130.8 mg of 3a (0.773 mmol) and 137.1 mg of
2-hydroxy-1-naphtaldehyde (0.77 mmol) were solubilized
in 5 mL of EtOH and stirred at room temperature until
all 3a was consumed (about 15 min). The mixture was
dried in vacuum and then purified by silica flash column
chromatography using 20-40% EtOAc in hexane as elutant.
Yield: 242 mg (97%) of an orange crystalline solid.
[α]D +20.4° (c 1.632, CHCl3); ¹H NMR (400 MHz,
CDCl3) d 7.17 (td, 1H, J 7.9, 1.7), 7.01 (dd, 1H, J 7.4,
1.7), 6.84 (dd, 1H, J 7.9, 1.2), 6.78 (td, 1H, J 7.4, 1.2),
4.80-4.72 (m, 2H), 3.96-3.83 (m, 2H), 3.77-3.71 (m, 1H),
2.35 (tt, 1H, J 10.9, 4.0), 1.92-1.81 (m, 1H), 1.81-1.56 (m,
8H), 1.54-1.39 (m, 1H), 1.26 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 158.0, 148.7, 128.8, 128.2, 123.2, 119.2, 116.5,
109.4, 72.1, 55.6, 44.8, 37.4, 33.8, 30.2, 25.7, 21.8, 21.1;
IR (KBr) ν / cm−1 3424, 3015, 2929, 1277, 765, 667, 466;
HRMS (FTMS + pESI) m/z, calculated for C17H25NO2H
[MH]+: 276.1964, found: 276.1964.
25
[α]D +83.1° (c 0.596, CHCl3); ¹H NMR (400 MHz,
CDCl3) d 14.99 (s, 1H), 8.80 (d, 1H, J 8.4), 7.81 (d, 1H,
J 8.4), 7.66 (d, 1H, J 9.3), 7.58 (d, 1H, J 7.8), 7.41 (ddd, 1H,
J 8.3, 7.1, 1.2), 7.25-7.17 (m, 1H), 6.90 (d, 1H, J 9.3 Hz),
4.76 (d, 2H, J 5.7), 3.89 (s, 1H), 3.34- 2.93 (m, 1H), 2.44
(ddd, 1H, J 14.5, 10.8, 3.6), 2.11-1.90 (m, 2H), 1.90-1.78
(m, 2H), 1.78-1.55 (m, 5H), 1.49 (s, 3H); 13C NMR
(101 MHz, CDCl3) d 178.1, 153.7, 148.3, 137.9, 134.0,
129.3, 128.0, 126.0, 125.5, 122.7, 117.5, 109.7, 106.5,
73.0, 59.7, 37.2, 34.1, 32.4, 25.8, 23.8, 21.0; IR (KBr)
ν / cm−1 3258, 2925, 2852, 1616, 1341, 759; HRMS
(FTMS + pESI) m/z, calculated for C21H25NO2H [MH]+:
324.1964, found: 324.1963; melting point: 138 ºC.
Synthesis of 2-((((1S,2S,5R)-2-hydroxy-2-methyl-5-(prop-
1-en-2-yl)cyclohexyl)amino)methyl)phenol (7b)
The procedure was identical to the synthesis of 7a,
starting from 81 mg (0.31 mmol) of 4b.Yield: 56 mg (76%)
of a light yellow viscous material.
25
[α]D +26.4° (c 1.028, CHCl3); ¹H NMR (400 MHz,
CDCl3) d 7.18 (td, 1H, J 8.0, 1.2), 7.01 (dd, 1H, J 7.4, 0.7),
6.84 (dd, 1H, J 8.0, 0.7), 6.79 (td, 1H, J 7.4, 1.2), 4.76 (d,
2H, J 7.5), 4.07 (d, 1H, J 13.6), 3.87 (d, 1H, J 13.6), 2.69 (t,
1H, J 4.0), 2.17-2.02 (m, 1H), 1.96 (ddd, 1H, J 14.0, 10.8,
3.3), 1.78-1.50 (m, 9H), 1.30 (s, 3H); 13C NMR (101 MHz,
CDCl3) d 158.0, 148.4, 128.9, 128.3, 123.0, 119.3, 116.4,
109.6, 71.5, 61.8, 51.0, 37.8, 35.0, 29.9, 28.8, 26.0, 21.2; IR
(KBr) ν / cm−1 3425, 3012, 2933, 1215, 761, 486; HRMS
(FTMS + pESI) m/z, calculated for C17H25NO2H [MH]+:
276.1964, found: 276.1962.
Synthesis of 1-((E)-(((1S,2S,5R)-2-hydroxy-2-methyl-
5-(prop-1-en-2-yl)cyclohexyl)imino)methyl)naphtalen-2-ol
(6b)
The procedure was identical to the synthesis of 5a, using
84.7 mg (0.50 mmol) of 3b. Yield: 156.9 mg (97%) of an
orange viscous material.
25
1
[α]D +33.0° (c 0.562, CHCl3); H NMR (400 MHz,
CDCl3) d 15.17 (s, 1H), 8.88 (s, 1H), 7.93 (d, 1H, J 8.3), 7.72
(d, 1H, J 9.2), 7.64 (d, 1H, J 7.9), 7.46 (t, 1H, J 7.7), 7.26 (t,
1H, J 7.4), 6.99 (d, 1H, J 9.2), 4.77 (d, 2H, J 4.6), 3.49 (s,
1H), 2.43-2.30 (m, 1H), 2.23 (td, 1H, J 12.4, 3.2), 1.99-1.62
(m, 9H + H2O), 1.22 (s, 3H); 13C NMR (101 MHz, CDCl3)
d 173.9, 157.9, 148.6, 136.9, 133.4, 129.3, 128.0, 126.5,
123.7, 123.0, 118.1, 109.5, 107.1, 70.7, 69.7, 38.2, 34.8,
33.7, 27.7, 26.2, 21.2; IR (KBr) ν / cm−1 3319, 3058, 2950,
1616, 1027, 746; HRMS (FTMS + pESI) m/z, calculated for
C21H25NO2H [MH]+: 324.1964, found: 324.1964.
Synthesis of 2-(tert-butyl)-6-((((1S,2S,4R)-2-hydroxy-
1-methyl-4-(prop-1-en-2-yl)cyclohexyl)amino)methyl)-
4-methylphenol (8a)
The procedure was identical to the synthesis of 7a,
starting from 58 mg (0.16 mmol) of 5a.Yield: 45 mg (77%)
of a light yellow solid.
25
1
[α]D +15.3° (c 0.180, CHCl3); H NMR (400 MHz,
CDCl3) d 6.99 (s, 1H), 6.71 (s, 1H), 4.76 (s, 2H), 3.85

8
Chiral Amino and Imino-Alcohols Based on (R)-Limonene
J. Braz. Chem. Soc.
(m, 2H), 3.74 (s, 1H), 2.43-2.29 (m, 1H), 2.24 (s, 3H),
1.95-1.79 (m, 2H), 1.72-1.45 (m, 10H), 1.40 (s, 9H), 1.26
(s, 3H); 13C NMR (101 MHz, CDCl3) d 154.7, 148.9, 136.8,
127.2, 126.9, 126.6, 123.5, 109.5, 72.3, 55.4, 45.2, 37.6,
34.6, 33.8, 30.2, 29.6, 25.8, 22.1, 20.9, 20.8; IR (KBr)
ν / cm−1 3508, 2938, 1425, 1075, 1017, 859; HRMS
(FTMS + pESI) m/z, calculated for C22H35NO2H [MH]+:
346.2746, found: 346.2745; melting point: 104 ºC.
Supplementary Information
Crystallographic data for the structures in this
work (Table S1) were deposited in the Cambridge
Crystallographic Data Centre as supplementary publication
number CCDC 1585565 and 1585568. Copies of the
data can be obtained free of charge at http://www.ccdc.
cam.ac.uk/conts/retrieving.html or from the Cambridge
Crystallographic Data Centre, CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033. E-mail:
deposit@ccdc.cam.ac.uk.
Synthesis of 2-(tert-butyl)-6-((E)-(((1S,2S,5R)-2-hydroxy-
2-methyl-5-(prop-1-en-2-yl)cyclohexyl)imino)methyl)-
4-methylphenol (8b)
The full characterization spectra of new compounds
are available free of charge at http://jbcs.sbq.org.br as a
PDF file.
The procedure was identical to the synthesis of 7a,
starting from 103 mg (0.30 mmol) of 5b. Yield: 76 mg
(74%) of a yellow viscous material.
Acknowledgments
25
1
[α]D +30.8° (c 1.478, CHCl3); H NMR (400 MHz,
CDCl3) d 7.00 (d, 1H, J 2.2), 6.71 (d, 1H, J 2.2), 4.80-4.73
(m, 2H), 4.04 (d, 1H, J 13.2), 3.81 (d, 1H, J 13.2), 3.78-3.68
(m, 1H), 2.65 (t, 1H, J 3.8), 2.24 (s, 3H), 2.06 (t, 1H,
J 10.4 Hz), 1.97-1.86 (m, 1H), 1.67-1.53 (m, 11H), 1.41
(s, 9H), 1.30 (s, 3H); 13C NMR (101 MHz, CDCl3) d 154.5,
148.6, 136.7, 127.3, 127.1, 126.8, 123.1, 109.5, 71.6, 62.7,
61.2, 51.1, 37.8, 34.8, 34.6, 29.9, 29.6, 28.7, 26.9, 26.1,
21.2, 20.8; IR (KBr) ν / cm−1 3406, 2951, 1639, 1436, 1213,
887, 767, 501; HRMS (FTMS + pESI) m/z, calculated for
C22H35NO2H [MH]+: 346.2746, found: 346.2744.
The authors thank E. A. Cechinatto for the HRMS
analysis, Prof B. Tirloni for the XRD analysis and CNPq,
FAPERGS and PROPESQ/UFRGS for financial support
and fellowships to RSF and EOB.
References
1. Samir, M.; Alami, I. E.; Amin, M.; Amrani, E.; Agbossou-
Niedercorn, F.; Suisse, I.; Mortreux, A.; Chem. Eur. J. 2015,
21, 1398.
2. United States Department ofAgriculture (USDA); Citrus:World
Market and Trades, ForeignAgricultural Services, Washington,
USA, 2019. Avaliable at https://apps.fas.usda.gov/psdonline/
circulars/citrus.pdf accessed on August 13, 2019.
Single crystal X-ray diffraction studies
Single crystal of 5a and 6a suitable for X-ray diffraction
studies were grown by slow evaporation of the solvent from
a concentrated DCM/hexane solution of the compounds.A
Bruker D8Venture dual source diffractometer equipped with
a Photon 100 complementary metal-oxide-semiconductor
(CMOS) detector was used to collect X-ray data for the
structural analysis of the compounds. Data were collected
using Cu-Kα (5a) and Mo-Kα (6a) radiation, and a
combination of ϕ and ω scans was carried out to obtain
at least one unique data set. The crystal structures were
solved using direct methods in the SHELXS program.35
The final structures were refined using SHELXL,35 where
the remaining atoms were located from difference Fourier
synthesis in which anisotropic displacement parameters
were applied to all non-hydrogen atoms, followed by full-
matrix least-squares refinement based on F2. All hydrogen
atoms were placed in ideal positions and refined as riding
atoms with relative isotropic displacement parameters.
Additional structural information for 5a and 6a are provided
in SI section.
3. World Health Organization (WHO); Some Naturally Occurring
Substances: Food Items and Constituents, Heterocyclic
Aromatic Amines and Mycotoxins; IARC: Lyon, 1993, 56, 135.
4. Ciriminna, R.; Lomeli-Rodriguez, M.; Demma Carà, P.; Lopez-
Sanchez, J.A.; Pagliaro, M.; Chem. Commun. 2014, 50, 15288.
5. Sanseverino, A. M.; Silva, F. M.; Jones, J.; Mattos, M. C. S.;
J. Braz. Chem. Soc. 2000, 11, 381.
6. Mattos, M. C. S.; Bernini, R. B.; J. Braz. Chem. Soc. 2007, 18,
1068.
7. Bachi, M. D.; Korshin, E. E.; Hoos, R.; Szpilman, A. M.;
Ploypradith, P.; Xie, S.; Shapiro, T. A.; Posner, G. H.; J. Med.
Chem. 2003, 46, 2516.
8. Hamann, L. G.; Meyer, J. H.; Ruppar, D. A.; Marschke, K. B.;
Lopez, F. J.; Allegretto, E. A.; Karanewsky, D. S.; Bioorganic
Med. Chem. Lett. 2005, 15, 1463.
9. Ferrarini, S. R.; Graebin, C. S.; Limberger, J.; Canto, R. F.;
Dias, D. O.; Rosa, R. G.; Madeira, M. F.; Eifler-Lima, V. L.;
Mem. Inst. Oswaldo Cruz 2008, 103, 773.
10. Graebin, C. S.; Madeira, M. F.;Yokoyama-Yasunaka, J. K. U.;
Miguel, D. C.; Uliana, S. R. B.; Benitez, D.; Cerecetto, H.;

Vol. 00, No. 00, 2019
Fuscaldo et al.
9
González, M.; Rosa, R. G.; Eifler-Lima, V. L.; Eur. J. Med.
25. Le, T. M.; Csámpai, A.; Fülöp, F.; Szakonyi, Z.; Chem. - Eur.
J. 2018, 51, 13607.
Chem. 2010, 45, 1524.
11. Vandresen, F.; Falzirolli, H.; Almeida Batista, S. A.; Silva-
Giardini, A. P. B.; Oliveira, D. N.; Catharino, R. R.; Ruiz,
A. L. T. G.; Carvalho, J. E.; Foglio, M. A.; Silva, C. C.; Eur.
J. Med. Chem. 2014, 79, 110.
26. Ibn El Alami, M. S.; El Amrani, M. A.; Dahdouh, A.; Roussel,
P.; Suisse, I.; Mortreux, A.; Chirality 2012, 24, 675.
27. Watts, C. C.; Thoniyot, P.; Cappuccio, F.; Verhagen, J.;
Gallagher, B.; Singaram, B.; Tetrahedron: Asymmetry 2006,
17, 1301.
12. Figueiredo, I. M.; Santos, L. V.; Costa, W. F.; Carvalho, J. E.;
Silva, C. C.; Sacoman, J. L.; Kohnb, L. K.; Sarragiotto, M. H.;
J. Braz. Chem. Soc. 2006, 17, 954.
28. Roszkowski, P.; Maurin, J. K.; Czarnocki, Z.; Tetrahedron:
Asymmetry 2013, 24, 643.
13. Almeida Batista, S. A.; Vandresen, F.; Falzirolli, H.; Britta, E.;
Oliveira, D. N.; Catharino, R. R.; Gonçalves, M. A.; Ramalho,
T. C.; Porta, F.A.; Nakamura, C. V.; Silva, C. C.; J. Mol. Struct.
2019, 1179, 252.
29. Kokina, T. E.; Glinskaya, L.A.; Klevtsova, R. F.; Boguslavskii,
E. G.; Sheludyakova, L. A.; Bizyaev, S. N.; Tkachev, A. V.;
Larionov, S. V.; Russ. J. Coord. Chem. 2009, 35, 200.
30. Kokina, T. E.; Tkachev, A. V.; Myachina, L. I.; Bizyaev,
S. N.; Sheludyakova, L. A.; Glinskaya, L. A.; Korol’kov, I. V.;
Boguslavskii, E. G.; Larionov, S.V.; Russ. J. Gen. Chem. 2013,
83, 336.
14. Wender, P. A.; Zhang, L.; Org. Lett. 2000, 2, 2323.
15. Srikrishna, A.; Dethe, D. H.; Org. Lett. 2003, 5, 2295.
16. Mehta, G.; Shinde, H. M.; Tetrahedron Lett. 2003, 44, 7049.
17. Mattos, M. C. S.; Elias, S. M.; J. Braz. Chem. Soc. 1995, 6, 377.
18. Pisoni, D. S.; Silva, D. B.; Schenato, R. A.; Ceschi, M. A.;
J. Braz. Chem. Soc. 2004, 15, 652.
31. Rudler, H.; Gregorio, J. R.; Denise, B.; Bregeault, J.-M.;
Deloffre, L.; J. Mol. Catal. A: Chem. 1998, 133, 255.
32. Cimarelli, C.; Fratoni, D.; Palmieri, G.; Tetrahedron: Asymmetry
2009, 20, 2234.
19. Lahuerta, P.; Moreno, E.; Monge, A.; Muller, G.; Sanau, M.;
Pe, J.; Eur. J. Inorg. Chem. 2000, 2, 2481.
33. Royals, E. E.; Leffingwell, J. C.; J. Org. Chem. 1966, 31, 1937.
34. Steiner, D.; Ivison, L.; Goralski, C. T.;Appell, R. B.; Gojkovic,
J. R.; Singaram, B.; Tetrahedron: Asymmetry 2002, 13, 2359.
35. Sheldrick, G. M.; Acta Cryst. 2008, A64, 112.
20. Muller, G.; Sainz, D.; J. Organomet. Chem. 1995, 495, 103.
21. Steiner, D.; Sethofer, S. G.; Goralski, C. T.; Singaram, B.;
Tetrahedron: Asymmetry 2002, 13, 1477.
22. Watts, C. C.; Thoniyot, P.; Hirayama, L. C.; Romano, T.;
Singaram, B.; Tetrahedron: Asymmetry 2005, 16, 1829.
23. Rachwalski, M.; Tetrahedron Asymmetry 2014, 25, 219.
24. Wujkowska, Z.; Jarzyński, S.; Pieczonka, A. M.; Leśniak, S.;
Rachwalski, M.; Tetrahedron: Asymmetry 2016, 27, 1238.
Submitted: January 8, 2019
Published online: August 23, 2019
This is an open-access article distributed under the terms of the Creative Commons Attribution License.