Selectivity control in one-pot myrtenol amination over Au/ZrO2 by molecular hydrogen addition

Article abstract of DOI:10.1016/j.molcata.2016.10.034

The one-pot myrtenol amination was studied over Au (3 wt.%)/ZrO₂ catalyst under mixed N₂/H₂ atmosphere (9 bar). The effect of hydrogen addition was explored with the aim to increase selectivity to the target amines. Hydrogen addition timing depending on myrtenol conversion and hydrogenation temperature affected selectivity to the reaction products. Hydrogen addition (1 bar) after almost complete myrtenol conversion at 100 °C increased the yield to amine up to 68% preserving C[dbnd]C bond in the initial myrtenol structure. Hydrogen addition at 180 °C irrespective of the myrtenol conversion level provoked reduction of both C[dbnd]C and C[dbnd]N bonds with formation of two diastereomers (yield up to 93%), with trans-isomer formation being preferred when hydrogen was added at almost complete myrtenol conversion. It was shown, that in the presence of a gold catalyst controlled hydrogenation of competitive C[dbnd]C and C[dbnd]N groups can be performed during one-pot alcohol amination by regulation of the reaction conditions.

Full text of DOI:10.1016/j.molcata.2016.10.034

Accepted Manuscript
Title: Selectivity control in one-pot myrtenol amination over
Au/ZrO2 by molecular hydrogen addition
Author: Yu.S. Demidova E.V. Suslov I.L. Simakova E.S.
Mozhajcev D.V. Korchagina K.P. Volcho N.F. Salakhutdinov
A. Simakov D.Yu. Murzin
PII:
S1381-1169(16)30435-6
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.molcata.2016.10.034
MOLCAA 10097
To appear in:
Journal of Molecular Catalysis A: Chemical
Received date:
Revised date:
Accepted date:
20-8-2016
10-10-2016
12-10-2016
Please cite this article as: Yu.S.Demidova, E.V.Suslov, I.L.Simakova,
E.S.Mozhajcev, D.V.Korchagina, K.P.Volcho, N.F.Salakhutdinov, A.Simakov,
D.Yu.Murzin, Selectivity control in one-pot myrtenol amination over Au/ZrO2
by molecular hydrogen addition, Journal of Molecular Catalysis A: Chemical
http://dx.doi.org/10.1016/j.molcata.2016.10.034
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Selectivity control in one-pot myrtenol amination over Au/ZrO2 by molecular
hydrogen addition
Yu.S. Demidova1,2, E.V. Suslov3, I.L. Simakova1,2,*, E.S. Mozhajcev3, D.V. Korchagina3,
K.P. Volcho2,3, N.F. Salakhutdinov2,3, A. Simakov4, D.Yu. Murzin5
1Boreskov Institute of Catalysis, pr. Lavrentieva, 5, 630090, Novosibirsk, Russia
2Novosibirsk State University, Pirogova 2, 630090, Novosibirsk, Russia
3Novosibirsk Institute of Organic Chemistry, pr. Lavrentieva, 9, 630090, Novosibirsk, Russia
4Universidad Nacional Autónoma de México, Centro de Nanociencias y Nanotecnología, km.
107 carretera Tijuana a Ensenada, C.P. 22860, Ensenada, Baja California, México
5Process Chemistry Centre, Åbo Akademi University, FI-20500, Turku/Åbo, Finland
*E-mail: simakova@catalysis.ru
Graphical abstract
1

Highlights
 H2 addition enhances selectivity to target amines in one-pot amination over Au/ZrO2
 H2 insertion at 100⁰C provides selective C=N saturation without hydrogenating C=C
bond
 H2 addition at 180⁰C provokes saturation of both C=C and C=N bonds
 Higher trans-amine selectivity after H2 addition at 180⁰C at full myrtenol conversion
ABSTRACT
The one-pot myrtenol amination was studied over Au (3 wt.%) /ZrO2 catalyst under mixed N2/H2
atmosphere (9 bar). The effect of hydrogen addition was explored with the aim to increase
selectivity to the target amines. Hydrogen addition timing depending on myrtenol conversion and
hydrogenation temperature affected selectivity to the reaction products. Hydrogen addition (1
bar) after almost complete myrtenol conversion at 100⁰C increased the yield to amine up to 68%
preserving C=C bond in the initial myrtenol structure. Hydrogen addition at 180⁰C irrespective
of the myrtenol conversion level provoked reduction of both C=C and C=N bonds with
formation of two diastereomers (yield up to 93%), with trans-isomer formation being preferred
when hydrogen was added at almost complete myrtenol conversion. It was shown, that in the
presence of a gold catalyst controlled hydrogenation of competitive C=C and C=N groups can be
performed during one-pot alcohol amination by regulation of the reaction conditions.
Keywords: one-pot alcohol amination, hydrogen borrowing, gold, biomass, selectivity control,
competitive hydrogenation, monoterpenoid.
Introduction
Amines are important chemicals per se and as building blocks for the production of
valuable compounds in a number of industries. Bio-derived natural extractives such as terpenes
2

due to their molecular structure represent very attractive starting materials for producing fine and
specialty chemicals [1,2] Utilization as platform molecules of natural terpenoids, which often
possess biological activities, can provide new opportunities for the synthesis of efficacious
chemicals for human disease prevention and therapy. In particular, terpene amines, synthesized
from renewable raw materials, were shown to exhibit specific physiological properties and can
be used as intermediates of potential drugs for neurological diseases [3,4,5 -6].On the other hand,
terpenoids are highly reactive. There is a variety of different transformations such as, for
example, isomerization that can occur along with the target reaction resulting in selectivity
decrease [7,8,9,10,11,12,13,14] Thus, selective synthesis of terpenoid amines is a challenging
task.
One-pot alcohol amination is considered as an effective approach for C-N bond
formation and for the synthesis of complicated amines .[15] The overall reaction generally
proceeds through three consecutive steps: alcohol activation (dehydrogenation) to a more
reactive carbonyl compound, which then reacts with an amine to form condensation products,
and finally transfer of hydrogen subtracted from the alcohol during first step to the imine with
the target amine formation. This approach in theory allows selective production of secondary
amines without formation of a tertiary amine.
In our previous work interactions of widespread monoterpenoid myrtenol with aniline
leading to formation of a corresponding amine were studied (Figure 1). It was shown that gold
catalysts exhibited promising catalytic activity along with a low impact of such side reactions as
reduction of the reactive C=C group of myrtenol by hydrogen formed in the first step (Figure 1)
[16,17,18] Basicity of catalyst support strongly affects effectivity of gold catalysts in alcohols
activation [19] Indeed, the catalytic performance in myrtenol amination was shown to depend on
acid–base properties of the selected catalyst supports [Error! Bookmark not defined.] as well
as on the catalyst redox pretreatment [Error! Bookmark not defined.]. Based on these
experimental data a detailed analysis of the reaction in terms of catalytic sites required for direct
3

one-pot alcohol amination was performed. Among the catalysts tested in our studies Au/ZrO2
pre-treated under oxidizing atmosphere was found to be optimal in terms of the target amine
yield [Error! Bookmark not defined.].
Based on kinetic data of myrtenol amination with aniline earlier published in [Error!
Bookmark not defined.] it can be tentatively proposed that hydrogenation of imine is somewhat
slower than other steps, therefore debottlenecking of this step by introducing addition hydrogen
is beneficial for the overall process. Such approach is of general interest for so-called hydrogen
borrowing reactions, when hydrogen generated in a dehydrogenation step is transferred to an
intermediate imine.
In the current study, therefore the effect of molecular hydrogen addition into the reaction
system on the products selectivity was studied with the main aim to develop approaches for the
direct terpene amines production minimizing influence of the side reactions.
2. Experimental/methodology
2.1. Catalysts preparation and characterization
The same sample of Au/ZrO2 catalyst described well in our previous work was used
[Error! Bookmark not defined.]. Commercial monoclinic ZrO2 (Alfa Aesar) with surface area
110 m2/g, pore volume 1.21 cm3/g and pore diameter 6.6 nm was selected as a support, which in
the powder form with the particles size below 40 μm was used for catalyst preparation. Au/ZrO2
catalyst (3 wt.% according to ICP) was synthesized by deposition-precipitation technique using
HAuCl4 (Alfa-Aesar) as a gold precursor and urea as a precipitating agent similar to the
procedure described elsewhere [20] In order to remove the excess of chloride after gold
deposition, the sample was washed with a solution of NH4OH (pH ca. 10), as in [21,22]
Thereafter the catalyst was washed with deionized water, filtered and dried at room temperature
for 24 h. Before the catalytic tests, the sample was oxidized in air flow under a temperature
increase to 350oC with a ramp rate of 20oC/min.
4

The prepared Au/ZrO2 catalyst was analyzed with an inductively coupled plasma atomic
emission spectroscopy (ICP-AES) using a Varian Liberty 110 ICP Emission Spectrometer.
Specific surface area and pores of the samples were determined with the BET method by
physisorption of nitrogen in a Tristar II 3020 Micromeritics equipment. Prior to measurements,
the samples were treated in vacuum (0.05 mbar) at 350°C for 12 hours.
Transmission electron microscopy (TEM) was performed with a JEOL 2010 microscope.
Before TEM measurements the samples were dispersed in isopropanol and dropped on a copper
grid coated with a carbon film. To estimate the value of a mean diameter of Au nanoparticles
more than 250 particles were counted. The mean diameter (dm) of particles was calculated using
( x d )

i
i
i
the following equation:
, where xi is the number of particles with diameter di.
d m

xi

i
The electronic state of gold species was studied by X-ray photoelectron spectroscopy
(XPS) with Kratos AXIS 165 photoelectron spectrometer using monochromatic AlKα radiation
(hv = 1486.58 eV) and fixed analyzer pass energy of 20 eV. All measured binding energies (BE)
were referred to the C1s line of adventitious carbon at 284.8 eV. The spectra fitting was done
using Shirley background estimation over the energy range of the fit.
2.2. Catalytic experiments
Liquid-phase (-)-myrtenol amination was performed in a stainless steel reactor, equipped
with an electromagnetic stirrer (1100 rpm) and the sampling system. A mixture of (-)-myrtenol
(1 mmol), aniline (1 mmol) and the catalyst (92 mg) in toluene (10 ml) was typically used.
Generally two types of experiments were carried out depending on when addition of molecular
hydrogen in the reaction system was performed, before or after initial (-)-myrtenol conversion.
For the former case of hydrogen being initially added to the system, the reaction was performed
at 180°C under N2/H2 atmosphere with H2 partial pressure 1-2 bar and total pressure 9 bar. In the
later case when hydrogen was introduced at almost complete (-)-myrtenol conversion hydrogen
5

partial pressure was 1 bar (total N2/H2 9 bar) and the temperature was 100 or 180⁰C, while prior
to hydrogen addition the reaction was carried out at 180°C under N2 atmosphere.
(-)-Myrtenol conversion was studied separately both in the presence or absence of
molecular hydrogen. In a typical experiment, a mixture of (-)-myrtenol (1 mmol), Au/ZrO2
catalyst (92 mg) in toluene (10 ml) was intensively stirred at 180°C under N2 or N2/H2 (8/1)
atmosphere with the total pressure 9 bar. N-(((1R,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-en-2-
yl)methyl)aniline (imine (1)) was hydrogenated using 1 mmol of the substrate and 92 mg of
Au/ZrO2 catalyst in 10 ml of toluene at 180°C under N2/H2 (8/1) pressure 9 bar.
The measurements of catalytic activity were performed in the kinetic regime. The impact
of internal diffusion was determined through estimation of the Weisz-Prater criterion [Error!
Bookmark not defined.]. The impact of external diffusion and namely mass transfer limitation
through the liquid-solid interface was evaluated by the corresponding criterion calculation
[23,24]
N-(((1R,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-en-2-yl)methyl)aniline (imine (1)) was
synthesized from (-)-myrtenal and aniline. (-)-Myrtenal (0.15 g, 0.1 mmol) was added to a
solution of aniline (0.093 g, 0.1 mmol) in methanol (3 mL). The mixture was stirred for 2 h, and
1
then the solvent was distilled off, giving imine (1) (0.216 g (95%)). H NMR and 13C NMR
spectra of imine (1) were in good agreement with the ones described earlier [Error! Bookmark
not defined.].
4-bromo-N-(((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methyl)aniline
was
synthesized from (-)-myrtenal and 4-bromoaniline. (-)-Myrtenal (0.155 g, 1.03 mmol) was added
to a solution of p-bromoaniline (0.175 g, 1.02 mmol) in methanol (3 mL). The mixture was
stirred for 3 h, then sodium borohydride powder (0.236 g, 6.24 mmol) was added to the solution.
The resulting suspension was stirred at room temperature for 12 h, then methanol was distilled
off and the residue was suspended in brine (15 mL). The solution was treated with ethyl acetate
(3×15 mL), combined organic solutions were dried over Na2SO4, then drying agent was filtered
6

off and the solvent was distilled off, giving 4-bromo-N-(((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-
2-en-2-yl)methyl)aniline (0.310 g (98%)).
2.3. Product analysis
Aliquots were withdrawn from the reactor at appropriate time intervals and analyzed by
gas chromatography using a SLB-5ms column (length 30 m, inner diameter 0.25 mm and film
thickness 0.25 μm, gas carrier He, 40 ml/min) and a flame ionization detector operating at
300°C. Additionally the products structure was confirmed by analysis with gas chromatograph-
mass spectrometer (Agilent 7000 GC/MS Triple Quad, HP-5MS column) as well as 1H- and 13C-
NMR.
13
1H- and C-NMR spectra: Bruker DRX-500 spectrometer (500.13 MHz (1H) and 125.76
MHz (13C)) in the CDCl3 solutions of the substances; chemical shifts  in ppm rel. to residual
chloroform [(H) 7.24, (C) 76.90 ppm], J in Hz. The structure of the compounds was elucidated
1
by analyzing the NMR spectra of H and 13C with the attraction of the spectra of the dual
resonance of 1H – 1H, two-dimensional spectra of the heteronuclear of 13C – 1H of correlation on
1
the straight constants of spin-spin interaction (C – H COSY, JC,H 160 Hz). The signal
13
multiplicity in the C NMR spectra was determined from the J modulation (JMOD). Elemental
composition was determined by data of mass spectra recorded on a Agilent 7200 Accurate Mass
Q-TOF GC/MS with ionization by electron impact 70 eV (HP-5MS column).
The structure of compounds 1 and 4 (Figure 1) was established in our previous work by
1H- and 13C-NMR [Error! Bookmark not defined.]. Amine (2) was earlier described in [25] In
1
13
the current work trans- and cis-isomers of amine (4) were characterized by H- and C-NMR.
NMR and HR-MS data of compounds (trans-(4) and cis-(4)) are presented in the supplementary
materials.
1H
NMR
and
13C
NMR
spectra
of
4-bromo-N-(((1R,5S)-6,6-
dimethylbicyclo[3.1.1]hept-2-en-2-yl)methyl)aniline are also presented in the supplementary
materials.
7

The selectivity to the product was calculated based on the following equation: selectivity
= yield of the product/total yield of all products. Diastereomeric excess (de) was defined as the
absolute difference between the mole fractions (%) of each diastereomer.
3. Results and discussion
3.1. Catalytic results
Au/ZrO2 catalyst used in this study was selected as an optimal one based on our previous
research, where the catalyst characterization was presented in detail [Error! Bookmark not
defined., Error! Bookmark not defined.]. Au (3 wt. %)/ZrO2 catalyst with the gold particle
size 2.5 nm estimated from TEM images was obtained by deposition-precipitation method using
urea followed by the catalyst pre-treatment under oxidizing atmosphere [Error! Bookmark not
defined.]. The gold nanoparticles found by TEM in the studied sample were characterized with a
semispherical shape practically without any well detectable crystallographic planes. According
to XPS data the catalyst was characterized by the presence of mainly metallic gold species (76%)
and some fraction of gold cations (24%) seem to be located in the gold-support surface interface
[Error! Bookmark not defined., Error! Bookmark not defined.]. It is worth to note that
along with effect of gold oxidation state studied by XPS other aspects, such as gold
nanoparticles size and effect of the support have been addressed in detail in [Error! Bookmark
not defined.].
First myrtenol amination with aniline was studied over Au/ZrO2 catalyst under
N2 atmosphere at 180°C [Error! Bookmark not defined.]. During the reaction besides
generation of expected products, myrtenal and its imine (1) and amine (2), additionally formation
of myrtanol as well as myrtanal with the saturated C-C bond and the corresponding imine (3) and
amine (4) occurred (Figure 1). Nevertheless, Au/ZrO2 catalyst favored rather C=N that C=C
bond hydrogenation under inert atmosphere when only a stoichiometric amount of hydrogen
8

could be formed during the reaction resulting in a small amount of products with the saturated C-
C bond (<10%) (Figure 2a). The only limitation for selective secondary amine production
without changes in the initial myrtenol structure was slow C=N bond hydrogenation after
complete initial myrtenol conversion which was providing hydrogen. Amine (2) was formed
with about 54% selectivity at nearly complete myrtenol conversion reaching 98% (Figure 2a).
In order to enhance selectivity towards the desired product, the influence of hydrogen
addition was explored. First, the reaction was studied under mixed N2/H2 atmosphere at initial
H2 partial pressure 1-2 bar and total pressure 9 bar at 180°C. In this case temperature decrease
was considered not to be appropriate since the initial step of alcohol dehydrogenation to
aldehyde requires elevated temperature [Error! Bookmark not defined.]. It was found that the
excess of hydrogen at 180°C provoked fast hydrogenation of both unsaturated C=C and C=N
bonds leading to selective formation of amine (4) (Figure 2 b). Selectivity to amine (4) reached
93% in 7 h under 1 bar H2 partial pressure. Note that the reaction rate at H2 partial pressure 1
bar was about 1.5 fold higher compared to the reaction performed only under inert atmosphere.
Hydrogen addition can lead to less prominent deactivation caused by imine oligomerization or
polymerization [26]. At the same time, the reaction rate was also shown to be affected by
hydrogen pressure. Thus, an increase in hydrogen pressure from 1 to 2 bar supressed the initial
step of myrtenol dehydrogenation, while favoring C=C bond hydrogenation in myrtenol and
myrtenal (Figure 2c). Since hydrogenation of C=C bond in myrtenol results in creation of a new
1
asymmetric center, the different diastereomers can be formed. In the present case, based on H
and 13C NMR data (Supplementary materials), trans- and cis-isomers were detected, with
predominant formation of amine (4) with trans-orientation of phenyl group to gem-dimethyl
fragment. Diastereomeric excess was shown to depend on the reaction condition (Table 1). The
increase of hydrogen pressure from 1 to 2 bar (line 1 and 2) led to a decrease in diastereomeric
excess from 30% to 24% at complete myrtenol conversion, respectively. In both cases
diastereomeric excess decreased along the reaction starting from 75% and 40% at myrtenol
9

conversion 25% for 1 to 2 bar of H2, respectively. According to the thermodynamic calculations
performed by using molecular modeling program HyperChem 8.0 (semi-empirical PM3 method)
for both imine (3) and amine (4) trans-isomer was detected to be slightly more stable, with the
energy difference between diastereomers being 11 and 6 kJ/mol, respectively. Thus, in this case
predominant trans-isomer formation seems to occur because of thermodynamic but not kinetic
control. Note that selective formation of diastereomers is considered to be of interest,
particularly, for synthesis of biologically active compounds.
An alternative approach to improve selectivity to amine was to introduce molecular hydrogen in
the system after complete conversion of initial myrtenol with the aim to diminish an impact of
C=C bond hydrogenation at least on the first stage. The second part of the reaction in the
presence of hydrogen was carried out at 100 and 180⁰C to explore the effect of temperature on
selectivity to the reaction products. As can be seen from Figure 3a hydrogen addition at 100⁰C
resulted in controlled hydrogenation of the C=N bond and amine (2) yield increase up to 68%
compared to 54% for the reaction performed only under nitrogen atmosphere. The temperature
increase to 180⁰C favored hydrogenation of both C=N and C=C bonds (Figure 3b) as it was
observed prior to reaction initiation. A profound difference between the experiments was
associated with diastereomeric excess of amine (4). Formation of the trans-isomer was more
selective with the de value being about two fold higher when hydrogen was added after myrtenol
consumption (Table 1, line 3). Interestingly, when aniline was replaced by 4-bromaniline the
impact of C=C bond hydrogenation was noticeable even under nitrogen atmosphere and only
formation of products with the saturated C-C bond was detected. At the same time the initial
reaction rate increased 1.7 fold compared to aniline.
Selectivity to the corresponding imine and amine with the saturated C-C bond was 49 and 22%
under nitrogen atmosphere, respectively, while the corresponding values of 29% and 43% were
observed after hydrogen addition at 100oC in 3 h. Worth to note that in the presence of Au/ZrO2
catalyst even under hydrogen atmosphere hydrodehalogenation of 4-bromaniline previously
10

reported in the literature [27] was suppressed. Unexpected activity in C=C bond hydrogenation
seems to be related to the catalyst modification by the reaction substrates or with the electronic
effect of the substituent. These results clearly demonstrate that although Au/ZrO2 can be used
with other amines not only aniline, optimal conditions should be carefully defined depending on
the substrate structure.
At the same time, generally hydrogenation of compounds containing pinane fragment in
the presence of metal catalysts mainly resulted in corresponding cis-isomer formation because of
steric hindrance [Error! Bookmark not defined., Error! Bookmark not defined.]. Thus, in
our case predominant formation of trans-isomer demonstrated that the C=C hydrogenation can
occur via more complicated mechanism such as intermolecular hydrogen transfer from C-N to
C=C bond. Apparently a separate study is required to the clarify hydrogenation mechanism.
Previously amine (2) was only obtained with the yield of 60% via allylic amination
catalyzed by [Cp*Fe(CO)2]2 [28]. The synthesis of amine (4) was not published before, whereas
the cis-isomers of compounds with the similar structure containing methyl and methoxy
functional groups in phenyl fragment were obtained with yield about 91% and 67%, respectively
[29,30].
The obtained results suggest that diastereoselectivity for amine (4) can be regulated at the
steps of myrtenol/myrtenal hydrogenation and corresponding imine (3) formation. To elucidate
regularities of the products formation hydrogenation of myrtenol and imine (1) was studied at
180⁰C under N2/H2 atmosphere (9 bar) at H2 partial pressure of 1 bar. In the case of myrtenol
formation of the corresponding alcohol and aldehyde with the saturated C-C bond in the
presence of hydrogen occurred, with the diastereomeric excess for myrtanol and myrtanal being
about 84% and 76%, respectively (Figure 4a). Relatively selective formation of trans-myrtanol
and trans-myrtanal during myrtenol transformation under hydrogen was observed. Worth to
note, that hydrogen addition in small amounts (1 bar) did not prevent initial alcohol
dehydrogenation in the presence of Au/ZrO2 catalyst. Under nitrogen pressure myrtenol was
11

mainly converted to myrtenal with a low yield of products with the saturated C-C bond, with the
reaction rate being 1.5 fold lower compared to myrtenol conversion in the presence of aniline.
The results for imine (1) hydrogenation demonstrated that in the presence of Au/ZrO2
catalyst the consecutive hydrogenation of C=N bond followed by C=C bond hydrogenation
occurred (Figure 4b). The obtained data additionally demonstrate that the gold catalyst is active
rather in C=N than C=C bond hydrogenation. At the same time, the diastereomeric excess was
close to 60% at total imine consumption, with this value being decreased up to 50% in 10
hours (Figure 4b). Thus, since trans-isomer formation is thermodynamically controlled, in this
case direct trans-cis isomerization is not favorable as, for example, was shown in [31,32,33] for
several cases of C=C double bond hydrogenation in olefins or cycloalkenes. Therefore, other
explanations should be invoked to account for rather moderate, but not negligible changes in
stereoselectivity. Such explanations can include for example involvement of hydrogen transfer,
faster side reactions of the trans-isomer, or changes in the geometry of adsorbed imine (3)
favoring cis-formation. In the latter case such changes depend on coverage of other species
which certainly is influenced by the liquid-phase composition. It is apparently clear that a
separate theoretical study is needed to reveal the origin of this intriguing and unusual
stereoselectivity.
In summary, in the current work approaches for controlled selective synthesis of complicated
terpene amines via one-pot alcohol amination were presented. Addition of hydrogen into the
reaction system allowed an increase of selectivity to the final product amine. Hydrogen addition
at 100⁰C resulted in controlled hydrogenation of the C=N bond and amine (2) yield increase up
to 68% compared to 54% for the reaction performed only under nitrogen atmosphere. The
temperature increase up to 180⁰C led to both C=C and C=N bonds hydrogenation with formation
of two diastereomers. Trans-isomer of amine (4) was formed more selectively when hydrogen
was added after myrtenol consumption. It should be emphasized that the values of
diastereoselectivity are rather modest keeping in mind that higher diastereoselectivity is
12

desirable for potential industrial applications. At the same time it should be mentioned that in
organic synthesis there are plenty of different approaches to enrich diastereoselectivity including
separation based on differences in physicochemical properties of diastereomers. Typically,
separation is performed using crystallization relying on the fact that diastereomeric excess in the
crystallized phase is different from the initial composition [34]. Such approaches will be
apparently required also in the current case to obtain the desired diastereoselectivity.
Furthermore, for the initial substrates, containing a reactive C=C bond, such as myrtenol,
controlled synthesis of both amines with saturated and unsaturated C=C bonds can be performed
by regulation of the reaction condition namely temperature and timing of hydrogen addition.
Regarding these results the next step to increase the process efficiency is considered to be using
of more safe and often more readily available in fine chemicals industry hydrogen sources such
as alcohols, formic acid etc.
At the same time it is worth to note that external hydrogen addition was proposed to
compensate insufficient hydrogen formation on the surface of gold particles due to non-specific
myrtenol dehydrogenation involving both support active sites and gold nanoparticles. Earlier it
was clearly demonstrated that alcohol dyhydrogenation can occur both in the presence and
absence of gold nanoparticles, while hydrogen formation was observed only in the presence of
gold [Error! Bookmark not defined., [35,36]]. Despite the initial alcohol activation on the
basic sites of the support, alcohol dehydrogenation proceeding only on the support active sites
did not produce hydrogen species needed for further hydrogenation.
4. Conclusions
In this work the effect of hydrogen addition on one-pot myrtenol amination in the presence of
Au/ZrO2 catalyst was studied with the aim to remove limitations on the last step of imine
hydrogenation to amine and to control selectivity to the target product. Bio-based alcohol
myrtenol with a competiting C=C functional group was used to develop approaches for the
13

synthesis of amines with different structure on gold catalyst. Depending on the time of hydrogen
addition or hydrogenation temperature predominant hydrogenation of either C=N bond or both
C=N and C=C bonds in the presence of Au/ZrO2 catalyst was observed. Thus, hydrogen addition
(1 bar) after almost complete myrtenol conversion at 100⁰C led to an increase in the amine yield
up to 68% with preservation of C=C bond in the initial myrtenol structure compared to 54% for
the reaction performed only under nitrogen atmosphere. Addition of hydrogen at 180⁰C
irrespective of the myrtenol conversion level provoked reduction of both C=C and C=N bonds
1
13
with formation of two diastereomers. According to H and C NMR data mainly trans-isomer
was produced. Hydrogen addition at the start of reaction at 180⁰C led to a faster formation of the
target amine accompanied by two fold decrease in diastereomeric excess from 60% to 30%
compared to hydrogen introduction after myrtenol consumption. The results demonstrate that in
the presence of the gold catalyst controlled competitive hydrogenation of C=C and C=N groups
can be performed during one-pot alcohol amination by regulation of the reaction conditions. In
particular, amines with different structures can be synthesized starting from one initial biomass-
derived myrtenol.
Acknowledgements
The authors acknowledge the financial support of RFBR (Russia) through grant No 16-
33-60028. Prof. Andrey Simakov expresses his gratitude to CONACyT (México) for the
financial support through Grant 179619. The authors are grateful to S. Beloshapkin, M. Estrada
for their help in carrying out this work.
14

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17

Fig. 1. Myrtenol amination with aniline over Au catalysts [Error! Bookmark not defined.].
18

o
a)
9 bar N2, 180 C
100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
(1) C=C C=N
(2) C=C C-N
(3)C-C C-N
(4) C-C C=N
0
2
4
6
8
10
12
14
16
18
Time, h
1 bar H2/8 bar N , 180oC
2
b)
100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
(1) C=C C=N
(2) C=C C-N
(3) C-C C=N
(4) C-C C-N
0
2
4
6
8
Time, h
o
c)
2 bar H2/7 bar N2, 180 C
100
100
90
80
70
60
50
40
30
20
10
0
90
80
70
60
50
40
30
20
10
0
(1) C=C C=N
(2) C=C C-N
(3) C-C C=N
(4) C-C C-N
0
2
4
6
8
10
12
Time, h
Fig. 2. The effect of hydrogen presence and it partial pressure (without hydrogen (a), 1 bar (b)
and 2 bar (c)) on myrtenol conversion and selectivity to the reaction products. The reaction
conditions: T = 180°C, myrtenol 1 mmol, aniline 1 mmol, toluene 10 ml, catalyst 1.4 mol. % Au,
9 bar N2/H2.
19

o
1 bar H2/8 bar N , 100oC
a)
9 bar N2, 180 C
2
100
90
80
70
60
50
40
30
20
10
0
70
60
50
(1) C=C C=N
(2) C=C C-N
(3) C-C C=N
(4) C-C C-N
40
30
20
10
0
0
2
4
6
8
10
12
14
16
18
20
Time, h
1 bar H2/8 bar N , 180oC
o
b)
9 bar N2, 180 C
2
100
90
80
70
60
50
40
30
20
10
0
70
60
50
(1) C=C C=N
40
(2) C=C C-N
(3) C-C C=N
30
(4) C-C C-N
20
10
0
0
2
4
6
8
10
12
14
16
18
20
Time, h
Fig. 3. The effect of hydrogen addition on selectivity to the reaction products at 100 (a) and
180⁰C (b) after almost complete myrtenol conversion. The reaction conditions: 1) T = 180°C,
myrtenol 1 mmol, aniline 1 mmol, toluene 10 ml, catalyst 1.4 mol. % Au, 9 bar N2; 2) T = 100
and 180°C, 9 bar N2/H2.
20

a)
100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
trans:cis = 92:8
trans:cis = 88:12
Myrtanol
Myrtanal
Myrtenal
Myrtenol
Myrtanal
Myrtanol
0
2
4
6
8
10
12
Time, h
b)
60
100
90
80
70
60
50
40
30
20
10
0
trans:cis = 80:20
50
40
30
20
10
0
trans:cis = 75:25
(1) C=C C=N
(2) C=C C-N
(3) C-C C=N
(4) C-C C-N
0
2
4
6
8
10
12
Time, h
Fig. 4. The products distribution and diastereomeric excess (de) as a function of the reaction time
during myrtenol and N-((6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methyl)aniline (imine (1))
hydrogenation. The reaction conditions: T = 180°C, initial substrate 1 mmol, toluene 10 ml,
catalyst 1.4 mol. % Au, 9 bar total, N2/H2 = 8/1.
21

Table 1. Effect of the reaction conditions on the content of amine (4) diastereomers and
diastereomeric excess value at complete myrtenol conversion.
Conditions
trans-, % cis-, % de, % Figure
1 bar H2, 8 bar N2, 180°C
2 bar H2, 7 bar N2, 180°C
65
62
35
38
20
30
24
60
2b
2c
3b
9 bar N2, 180°C/ 1 bar H2, 8 bar N2, 180°C 80
22