Phosphine ligands in the ruthenium-catalyzed reductive amination without an external hydrogen source

Article abstract of DOI:10.1016/j.jorganchem.2021.121806

A systematic study of the phosphine additives influence on the activity of a ruthenium catalyst in reductive amination without an external hydrogen source was carried out. [CymeneRuCl₂]₂ was used as a reference catalyst, and a broad set of phosphines including Alk₃P, Alk₂ArP, Ar₃P and X₃P was screened. Three complexes of general formula (Cymene)RuCl₂PR₃ were isolated in a pure form, and their catalytic activity was compared with the in situ generated complexes. Nonhindered triarylphosphines with electron acceptor groups were found to be the most perspective activating agents, increasing the activity of the catalyst approx. six times, Alk₂ArP ligands have less noticeable influence, while trialkylphosphines strongly deactivate the ruthenium catalyst.

Full text of DOI:10.1016/j.jorganchem.2021.121806

Journal of Organometallic Chemistry 941 (2021) 121806
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Phosphine ligands in the ruthenium-catalyzed reductive amination
without an external hydrogen source
Maria Makarovaa, Oleg I. Afanasyeva, Fedor Kliuevb, Yulia V. Nelyubinaa,
Maria Godovikovaa, Denis Chusova,b,∗
a A.N.Nesmeyanov Institute of Organoelement Compounds of Russian Academy of Sciences, Vavilova St. 28, 119991 Moscow, Russia
b National Research University Higher School of Economics, Miasnitskaya Str. 20, Moscow 101000, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
A systematic study of the phosphine additives influence on the activity of a ruthenium catalyst in re-
ductive amination without an external hydrogen source was carried out. [CymeneRuCl2]2 was used as a
reference catalyst, and a broad set of phosphines including Alk3P, Alk2ArP, Ar3P and X3P was screened.
Three complexes of general formula (Cymene)RuCl2PR3 were isolated in a pure form, and their catalytic
activity was compared with the in situ generated complexes. Nonhindered triarylphosphines with elec-
tron acceptor groups were found to be the most perspective activating agents, increasing the activity of
the catalyst approx. six times, Alk2ArP ligands have less noticeable influence, while trialkylphosphines
strongly deactivate the ruthenium catalyst.
Received 19 February 2021
Revised 23 March 2021
Accepted 29 March 2021
Available online 3 April 2021
Keywords:
Ruthenium
Phosphines
Reductive amination
Carbon monoxide
Catalysis
© 2021 Elsevier B.V. All rights reserved.
1. Introduction
this context, development of alternative reducing systems without
such disadvantages is highly desirable.
Development of new approaches towards rapid and atom-
efficient build-up of molecular complexity is a global aim of the
synthetic community. [1–9] As catalytic reactions are highly im-
portant to solve the titled fundamental task, understanding of the
factors, influencing the activity of the particular catalyst is a key
to optimize preparation of desirable compounds. Herein we con-
sider the influence of phosphine ligands on the activity of the
ruthenium catalysts in the reductive amination without an exter-
nal hydrogen source. This reaction allows a direct preparation of
secondary and tertiary amines from carbonyl compounds utilizing
carbon monoxide as a reducing agent. Amines are a crucial class of
organic molecules with a great variety of applications in multiple
fields. [10–16] However, synthesis of secondary and tertiary amines
still remains challenging. [17–18] One of the highly prospective ap-
proaches towards amines is reductive amination: during 2019 and
2020 three huge reviews considering this reaction were published
[19–21] However, the correct choice of a reducing agent is not so
straightforward as it seems to be. Classical reductants such as hy-
drogen or different types of borohydrides are not enough selective
or efficient for the reductive amination of challenging substrates
with high sterical hindrance or reducible functional groups. [22] In
Carbon monoxide was demonstrated to be a very powerful
reducing agent in organic transformations. Despite the fact that
CO is a toxic gas and one should take necessary safety precau-
tions working with this reagent (first of all, good ventilation is re-
quired), it is a highly desirable reagent in organic chemistry. It is
widely used for nitro group reductions [23,15,24] or as an indirect
reducing agent working via the water-gas shift reaction (WGSR)
[25,26,27,28,29]. Hence, carbon monoxide or its synthetic equiv-
alents could be considered as a good alternative to classical re-
ducing agents. Such reducing systems achieve high selectivity to-
wards reducible functional groups [30,31] and high efficiency in
preparation of sterically hindered substrates [32,33]. They also al-
low to solve some special problems like amine methylation [34] or
Vasicinone-like alkaloids preparation [35].
One of the most popular ligands, used in catalysis, are phos-
phines. [36,37] To the best of our knowledge there was no sys-
tematic study on the influence of phosphine ligands on the out-
come of reductive amination without an external hydrogen source.
Only single experiments with phosphines were reported. For ex-
ample, Kolesnikov et al. demonstrated a strong decrease of the
reaction yield after addition of triphenylphosphine to ruthenium
chloride-catalyzed reductive amination without an external hydro-
gen source.[38] Later Makarova et al. demonstrated an increase of
the reaction rate with SPhos if [CymeneRuCl2]2 was used as a pre-
catalyst. [39]
∗
Corresponding author.
E-mail address: chusov@ineos.ac.ru (D. Chusov).
https://doi.org/10.1016/j.jorganchem.2021.121806
0022-328X/© 2021 Elsevier B.V. All rights reserved.

M. Makarova, O.I. Afanasyev, F. Kliuev et al.
Journal of Organometallic Chemistry 941 (2021) 121806
Table 1
Phosphine ligands comparison under the standard conditions.
Phosphine
Yield of 1a
50%
No ligand
Fig. 1. Trialkylphosphines tested.
Alk3P
PCy3 2a
40%
19%
PnBu3 2b
Alk2PAr
RuPhos 3a
25%
33%
42%
43%
51%
64%
83%
XPhos 3b
BrettPhos 3c
DavePhos 3d
tBuXPhos 3e
SPhos 3f
CyJohnPhos 3g
Ar3P
P(2-MeOC6H4)3 4a
P(2,6-(MeO)2C6H3)3 4b
P(oTol)3 4c
32%
43%
46%
48%
66%
72%
96%
91%
96%
96%
96%
P(4-MeOC6H4)3 4d
PMes3 4e
JackiePhos 4f
PPh3 4g
P(pTol)3 4h
P(3-MeOC6H4)3 4i
P(4-FC6H4)3 4j
P(4-ClC6H4)3 4k
Bidentate
Fig. 2. Dialkylarylphosphines tested.
XantPhos 5a
BINAP 5b
56%
47%
52%
Bis(dicyclohexylphosphinophenyl) ether 5c
Other ligands
PCl3 5d
RuPhos, SPhos, DavePhos, XPhos, tBuXPhos, CyJohnPhos), tri-
arylphosphines Ar3P 4, bidentate ligands (XantPhos, BINAP,
Bis(dicyclohexylphosphinophenyl) ether), and three additional
phosphine and phosphite ligands P(OEt)3, PCl3, and PBr3 to
achieve a comprehensive study of the sterical and electronical
parameters influencing the reaction outcome. Structures of these
ligands are provided below (Figs. 1, 2, 3, 4). Initially all ligands
were compared under the standard conditions (Table 1).
49%
71%
50%
PBr3 5e
P(OEt)3 5f
a
Reaction conditions: 0.33 mmol scale, 2 equiv. p-anisidine, 1 equiv. p-
anisaldehyde, 0.25 mol% [CymeneRuCl2]2 (0.5 mol% Ru), 0.5 mol% ligand, 300
μL MeCN, 140°C, 50 bar CO, 22 h. Yields were determined by GC using an
external calibration. At least two replicate runs for each ligand were carried
out.
Here are two factors with a crucial impact on the reaction per-
formance: electronic and sterical properties of the ligand. Electron-
rich ligands with low sterical hindrance form very stable com-
plexes that do not catalyze the reaction. Ligands with high sterical
hindrance either do not form complexes (in this case, yield of the
reaction is the same as without ligand) or form stable complexes
and block the coordination with substrates (this is the case of ster-
ically hindered electron-rich ligands). In the intermediate cases,
these two factors can compensate each other. These considerations
are illustrated below.
2. Results and discussion
Herein we report
a study of the ligand influence on the
ruthenium-catalyzed reductive amination, as this metal is compa-
rably cheap and known to form stable phosphine complexes.[40]
[CymeneRuCl2]2 was used as a ruthenium precatalyst. This is a
stable well-defined ruthenium source, often used in organometal-
lic chemistry. Ruthenium chloride, known to catalyze the titled
reaction [38], is much cheaper, however it does not have any
well-defined structure, and an amount of crystalline water might
impact the formation of the organometallic complexes. [41]. The
goal of this study is identification of ligand parameters influencing
the catalytic activity, therefore all other factors interfering the re-
producibility and performance of the reaction should be avoided.
Hence [CymeneRuCl2]2 was chosen as the preferable ruthenium
source.
Trialkylphosphines (Fig. 1) are very strong ligands, inhibiting
the activity of the ruthenium catalyst. However, tricyclohexylphos-
phine 2a decreases the reaction yield only by 1.25 times (40% vs
50%), while tributylphosphine 2b has a stronger influence reducing
the reaction rate by 2.5 times (19% vs 50%). Cy3P is characterized
with a bigger Tolman cone angle then nBu3P (170 vs 132)[42]. As
electronic properties of these ligands are almost the same, nBu3P
forms a much more stable ruthenium complex which catalyzes the
reaction poorly. Electronic deactivation in the case of Cy3P is com-
pensated by increased sterical hindrance, so the resulting complex
works better than the one with nBu3P.
The ligand impact was compared using the model reaction of p-
anisidine and p-anisaldehyde (Table 1). Catalyst loading and other
reaction conditions (temperature, CO pressure, solvent, reaction
time, reagents ratio) were chosen to provide 50% yield of 1 without
any phosphine additives. Such yield allows catching both activation
and deactivation of the catalytic system.
Alk2PAr are generally less nucleophilic than Alk3P. It is the rea-
son why in this case (Fig. 2) a balance between electronic and ster-
ical properties should be found. For example, RuPhos 3a led to a
two-fold decrease of the reaction yield while SPhos 3f increased it
1.3 times. While electronic properties are almost the same, RuPhos
has a higher sterical hindrance, which in this case decreases the
reaction yield. This trend is opposite to the one detected for tri-
All available phosphine ligands were divided into few
classes according to their structure: trialkylphosphines Alk3P
2
(nBu3P, Cy3P), Dialkylarylphosphines Alk2PAr 3 (BrettPhos,
2

M. Makarova, O.I. Afanasyev, F. Kliuev et al.
Journal of Organometallic Chemistry 941 (2021) 121806
Table 2
Impact of the most active ligands on the reaction yield at reduced tempera-
ture.
Phosphine
Yielda
10%
21%
24%
27%
56%
63%
No ligand
PPh3 4g
P(pTol)3 4h
P(3-MeOC6H4)3 4i
P(4-FC6H4)3 4j
P(4-ClC6H4)3 4k
a
Reaction conditions: 0.33 mmol scale, 2 equiv. p-anisidine, 1 equiv. p-
anisaldehyde, 0.25 mol% [CymeneRuCl2]2 (0.5 mol% Ru), 0.5 mol% ligand, 300
μL MeCN, 120°C, 50 bar CO, 22 h. Yields were determined by GC using an
external calibration. At least two replicate runs for each ligand were carried
out.
strong donating properties. Strong donation leads to formation of
strong coordinating bonds while sterical hindrance blocks the coor-
dination of substrates and inhibits the reaction. Both these ligands
more or less deactivate the catalyst. P(oTol)3 4c is less electron-
donating ligand with less sterical hindrance, and its impact on
the reaction yield is negligible. P(4-MeOC6H4)3 4d is a strong do-
nating ligand with low sterical hindrance. It also has no influ-
ence on the reaction. The last two cases illustrate the compensa-
tion of electronic and sterical factors to zero. Combination of elec-
tronic and sterical properties of P(Mes)3 4e provides slight activa-
tion of the catalyst. JackiePhos 4f has strong acceptor groups in its
structure thus activating the catalyst. The most perspective results
were achieved using m- and p- substituted triarylphosphines with
electron-neutral or electron-withdrawing groups. PPh3, P(pTol)3,
P(3-MeOC6H4)3, P(4-FC6H4)3, P(4-ClC6H4)3 provided almost quan-
titative yields. To enable accurate comparison of these ligands we
set up the reaction at reduced temperature 120°C (Table 2). PPh3
4g, P(pTol)3 4h, and P(3-MeOC6H4)3 4i increased the yield of the
target molecule two times (with reference to experiment without
ligand). Halogen-substituted phosphines increased it approx. six
times. P(4-FC6H4)3 4j provides slightly lower yield of the product
as mesomeric effect of fluorine is much higher than of chlorine. So
P(4-FC6H4)3 supposed to be a little bit more electron-rich in com-
parison with P(4-ClC6H4)3 4k.
Fig. 3. Triarylphosphines tested.
To obtain the whole picture of the phosphine ligands influ-
ence, we tested few bidentate ligands (Fig. 4) and other mon-
odentate phosphines PCl3, PBr3, and P(OEt)3. The tested bidentate
phosphines showed almost no influence on the reaction outcome.
This might indicate a balance of opposite sterical and electronic ef-
fects in these cases, however to detect any trends more data is re-
quired. PCl3, PBr3 and P(OEt)3 demonstrate more countable effects.
As sterical hindrance for these phosphines is very low, all effects
could be assigned to the electronic effects. PBr3 has a slight ac-
tivation mode while PCl3 and P(OEt)3 do not change the reaction
yield. This indicates that too strong electron withdrawing groups
also deactivate the catalyst.
Fig. 4. Bidentate ligands and other ligands.
alkylphosphines. In the case of Alk3P the coordination was too
strong. Sterical factors used to decrease deactivation of the cata-
lyst. For Alk2PAr coordination is not so strong, and the sterical hin-
drance interferes the target reaction. tBuXPhos 3e seems to have
very high sterical hindrance so we suppose that it does not form
a ruthenium complex and does not influence the catalytic activ-
ity. To confirm this an NMR experiment was carried out. tBuXPhos
was added to a solution of [CymeneRuCl2]2 in CDCl3 in NMR tube
followed by registration of 1H, 13C, and 31P NMR spectra after two
hours. No phosphine complex formation was noted (Scheme 1).
The most active catalytic system was achieved using CyJohn-
Phos 3g. It has low sterical hindrance with moderate donating
properties which indicates that the decrease of the sterical factor
has a crucial influence on the catalyst activity.
In addition, to demonstrate the correctness of the assump-
tion that ruthenium phosphine complexes form in situ, three well-
defined complexes of general formula CymeneRuCl2PR3 were syn-
thesized and their catalytic activities were compared with activ-
ities of the in situ generated complexes. P(4-ClC6H4)3 providing
highest activation, the most available PPh3 providing moderate ac-
tivation, and inactive P(OEt)3 were applied. The latter did not af-
fect the yield of 1, so an attempt to obtain a well-defined complex
with P(OEt)3 allows to distinguish either no complex formation oc-
Ortho-substituted triarylphosphines with methoxy groups (4a,
4b) (Fig. 3) have very high sterical hindrance in combination with
3

M. Makarova, O.I. Afanasyev, F. Kliuev et al.
Journal of Organometallic Chemistry 941 (2021) 121806
Table 3
Comparison of the well-defined complexes vs
in situ generated.
Catalyst
Yielda
PPh3 + [CymeneRuCl2]2
CymeneRuCl2PPh3 6a
96%
94%
50%
49%
96%
96%
P(OEt)3 + [CymeneRuCl2]2
CymeneRuCl2P(OEt)3 6b
P(4-ClC6H4)3+ [CymeneRuCl2]2
CymeneRuCl2P(4-ClC6H4)3 6c
a
Reaction conditions: 0.33 mmol scale,
2
equiv. p-anisidine,
1
equiv. p-anisaldehyde,
0.25 mol% [CymeneRuCl2]2 or 0.5 mol% ruthe-
nium complex, 0.5 mol% ligand (if required),
300 μL MeCN, 140°C, 50 bar CO, 22 h. Yields
were determined by GC using an external cal-
ibration. At least two replicate runs for each
ligand were carried out.
Fig. 5. General view of compound CymeneRuCl2P(4-ClC6H4)3 (6c) in representa-
˚
tion of atoms via thermal ellipsoids (p=50%). Selected bond lengths (A): Ru(1)-Cl(1)
2.4130(8), Ru(1)-Cl(2) 2.4141(8), Ru(1)-P(1) 2.3614(9), Ru(1)-C(1) 2.230(3), Ru(1)-
C(2) 2.201(3), Ru(1)-C(3) 2.188(3), Ru(1)-C(4) 2.231(3), Ru(1)-C(5) 2.237(3), Ru(1)-
C(6) 2.242(3).
Scheme 1. NMR experiment demonstrating that tBuXPhos does not form any com-
plex with ruthenium.
Scheme 2. Synthesis of CymeneRuPR3Cl2 complexes. Isolated yields.
curs is this case or the catalytic activity of CymeneRuCl2(POEt)3 is
equivalent to that of [CymeneRuCl2]2.
Titled complexes were prepared according to the literature pro-
tocols (Scheme 2) [43,44,45]. All the complexes were character-
ized using NMR, and the structure of CymeneRuCl2P(4-ClC6H4)3
(6c) was confirmed using X-ray analysis for the first time (Fig. 5).
The results of the catalytic activity comparison are provided in the
Table 3. One can see that in all cases the activity is the same, so
the comparison provided above is representative.
Afterwards, the catalyst activation was checked on substrates of
different types (Scheme 3). Aromatic amines demonstrate at least
two-fold activation in reactions with an aromatic aldehyde (1),
aliphatic (7, 8) and aromatic ketones (10, 11). In case of acetophe-
none (10), activation with phosphine reached 2.9 times, and with
tetralone (11) only traces of the product were obtained without
Scheme 3. Substrate scope for the reductive amination. NMR yields with DMF as an
a
internal standard. Second yield value corresponds to the reaction at 120°C b160°C.
4

M. Makarova, O.I. Afanasyev, F. Kliuev et al.
Journal of Organometallic Chemistry 941 (2021) 121806
phosphine. Reaction of aniline with p-methoxybenzaldehyde (9)
led to the good yields both with and without phosphine at 140°C,
however decreasing the temperature to 120°C allowed to catch the
activation effect. In the case of reaction between piperidine and
benzylacetone (13) the yield was almost the same. Even slight de-
crease of the yield was noted (84% vs 90%). Similarly no activation
was detected in the case of morpholine (12). This trend could be
explained by the fact that aliphatic amines are much more nucle-
ophilic then aromatic ones. So, piperidine and morpholine could
dramatically change the catalyst structure decreasing the activation
extent.
4.2.2. [(p-cymene)Ru(PPh3)Cl2] (6a)
A solution of [(p-cymene)RuCl2]2 (100 mg, 100 mol%, 0.16
mmol) and PPh3 (90 mg, 210 mol%, 0.34 mmol) in CH2Cl2 (6 ml)
was stirred at room temperature in Schlenk tube under argon at-
mosphere for 17 h. After this time the solution was reduced in vac-
uum to ~1,5 ml. Hexanes (~8 ml) were added to yield an orange
precipitate. Then it was filtered through a funnel with fritted disc.
The solid was washed with hexanes (3 ml 3 times) and dried in
vacuum to yield a red-brown solid (169.6 mg, 91.3% yield).
1H NMR (400 MHz, CDCl3) δ 7.87 – 7.73 (m, 6H), 7.42 – 7.28 (m,
9H), 5.18 (d, J = 5.9 Hz, 2H), 4.98 (d, J = 5.9 Hz, 2H), 2.84 (sept,
J = 6.9 Hz, 1H), 1.85 (s, 3H), 1.08 (d, J = 6.9 Hz, 6H).
13C NMR (101 MHz, CDCl3) δ 134.4 (d, J = 9.3 Hz), 133.9 (d,
J = 45.6 Hz), 130.3 (d, J = 2.4 Hz), 128.0 (d, J = 10.0 Hz), 111.2,
96.0, 89.1 (d, J = 3.2 Hz), 87.2 (d, J = 5.5 Hz), 30.3, 21.9, 17.8.
31P NMR (162 MHz, CDCl3) δ 24.2.
3. Conclusions
Finally, the first systematic study of the phosphine additives in-
fluence on the catalytic activity of cymene ruthenium chloride in
the reductive amination without an external hydrogen source was
provided. Different phosphines including Alk3P, Alk2PAr, and Ar3P
were compared. Generally the most prominent activation is pro-
vided by triarylphoshines with low sterical hindrance and electron-
withdrawing groups in aromatic rings structure. This activation
was studied on different amines. In the case of aromatic amines
yield increased at least twice, while in the case of aliphatic amines
the activation was not so powerful. This might be related to the
high nucleophilicity of aliphatic amines.
NMR spectra are in agreement with the literature data.[47,48]
4.2.3. [(p-cymene)Ru(P(OEt)3)Cl2] (6b)
A solution of [(p-cymene)RuCl2]2 (50 mg, 100 mol%, 0.08 mmol)
and POEt3 (70 μL, 500 mol%, 0.41 mmol) in CH2Cl2 (5.5 mL) was
stirred at room temperature in a Schlenk tube under argon atmo-
sphere overnight. Then the solvent was evaporated in vacuum to
yield an oil. Hexanes (~10 ml) were added and the mixture was
triturated to yield a red precipitate. Then it was filtered through a
funnel with fritted disc. The precipitate was washed with hexanes
(10 ml 3 times) and dried in vacuum to yield an orange-brown
solid (35 mg, 45.5% yield).
4. Experimental section
1H NMR (400 MHz, CDCl3) δ 5.49 (d, J = 6.0 Hz, 2H), 5.35 (d,
J = 6.0 Hz, 2H), 4.13 (dq (appears as a quint), J = 6.8 Hz, 6H), 2.89
(sept, J = 6.9 Hz, 1H), 2.13 (s, 3H), 1.25 (t, J = 6.8 Hz, 9H), 1.21 (d,
J = 6.9 Hz, 6H).
4.1. General information
Unless otherwise stated, all reagents were purchased from com-
mercial suppliers and used without further purification. CH2Cl2
and CH3CN were distilled over calcium hydride.
13C NMR (101 MHz, CDCl3) δ 109.0, 100.6, 89.3 (d, J = 6.1 Hz),
88.8 (d, J = 6.1 Hz), 63.1 (d, J = 6.4 Hz), 30.4, 22.1, 18.4, 16.3 (d,
J = 6.2 Hz).
1H, 13C and 31P spectra were recorded in CDCl3 on Bruker
Avance 300, Bruker Avance 400 and Varian Inova-400 spectrom-
eters. Chemical shifts are reported in parts per million relative to
CHCl3 (7.26 and 77.16 ppm for 1H and 13C respectively). Chemical
shifts δ are reported in ppm relative to the solvents resonance sig-
nal as an internal standard. The following abbreviations were used
to designate chemical shift multiplicities: s = singlet, d = doublet,
t = triplet, q = quartet, quint = quintet, sept = septet, dq = dou-
blet of quartets, m = multiplet, br s= broad singlet; coupling con-
stants are given in Hertz (Hz).
31P NMR (162 MHz, CDCl3) δ 112.3.
NMR spectra are in agreement with the literature data.[44]
4.2.4. [(p-cymene)Ru(P(p-ClPh)3)Cl2] (6c)
A solution of [(p-cymene)RuCl2]2 (33 mg, 100 mol%, 0.053
mmol) and P(p-ClPh)3 (50 mg, 256 mol%, 0.137 mmol) in CH2Cl2
(8 ml) was stirred at room temperature in Schlenk tube under ar-
gon atmosphere for 14 h. Then the solvent was evaporated in vac-
uum to yield an oil. Hexanes (~5 ml) were added and the mixture
was triturated to yield a white-red precipitate. The precipitate was
filtered through a funnel with fritted disc. The solid was washed
with hexanes (10 mL 3 times) and dried in vacuum to yield a dark-
orange solid (68 mg, 94% yield). Crystals were prepared by diffu-
sion crystallization in CHCl3 – hexane system.
1H NMR (400 MHz, CDCl3) δ 7.72 (t, J = 9.1 Hz, 6H), 7.35 (d,
J = 8.1 Hz, 6H), 5.24 (d, J = 6.0 Hz, 2H), 4.97 (d, J = 6.0 Hz, 2H),
2.88 (sept, J = 7.0 Hz, 1H), 1.86 (s, 3H), 1.14 (d, J = 7.0 Hz, 6H).
13C NMR (101 MHz, CDCl3) δ 137.4 (d, J = 3.2 Hz), 135.6 (d,
J = 10.3 Hz), 131.7 (d, J = 46.3 Hz), 128.7 (d, J = 10.4 Hz), 112.2
(d, J = 3.6 Hz), 96.5, 88.9 (d, J = 3.0 Hz), 87.7 (d, J = 5.7 Hz), 30.5,
22.0, 18.1.
Analytical gas chromatography (GC) was performed using a
Chromatec Crystal 5000.2 Gas Chromatograph fitted with a flame
ionization detector. GC yields were calculated using external cali-
bration, NMR yields were calculated using DMF as an internal stan-
dard. More details are provided in SI.
4.2. Synthesis of ruthenium complexes
4.2.1. [(p-cymene)RuCl2]2
To a solution of RuCl3•4H2O (1.65 g, 100 mol%, 5.9 mmol)
in EtOH (50 mL) in a 250 mL round-bottom Schlenk flask, α-
phellandrene (5.67 mL, 600 mol%, 35.2 mmol) was added. The re-
action mixture was refluxed for 24 h and then cooled to 0°C. The
resulting red precipitate was filtered, washed with Et2O and dried
in vacuo to yield a red solid (1.12 g, 62% yield).
1H NMR (400 MHz, CDCl3) δ 5.45 (d, J = 5.7 Hz, 2H), 5.31 (d,
J = 5.7 Hz, 2H), 2.88 (sept, J = 6.9 Hz, 1H), 2.13 (s, 3H), 1.25 (d,
J = 6.9 Hz, 6H).
31P NMR (121 MHz, CDCl3) δ 23.82.
NMR spectra are in agreement with the literature data.[45]
4.3. General procedure for reductive amination
Caution: carbon monoxide used as a reagent in this protocol is
a toxic gas. Corresponding safety precautions should be taken.
A glass vial in a 10 mL stainless steel autoclave was charged
with 0.5 mol% [(p-cymene)RuCl2]2, 0.5 mol% of the indicated lig-
and, and CH3CN. Then, 2 equivalents of amine and 1 equivalent of
13C NMR (101 MHz, CDCl3) δ 101.2, 96.7, 81.3, 80.5, 30.6, 22.2,
19.0.
NMR spectra are in agreement with the literature data.[46]
5

M. Makarova, O.I. Afanasyev, F. Kliuev et al.
Journal of Organometallic Chemistry 941 (2021) 121806
carbonyl compound were added. The autoclave was sealed, flushed
three times with 10 bar of CO, and then charged with 50 bar of CO.
The reactor was placed into a preheated to 140°C oil bath. After 22
h of heating, the reactor was cooled to room temperature and de-
pressurized. Its content was analyzed using NMR or GC, and the
product was isolated using chromatography (column chromatog-
raphy on silica gel or using flash chromatograph InterChim Puri-
Flash).
using preparative flash chromatograph InterChim PuriFlash in hex-
ane – ethyl acetate binary system (gradient 5% to 10% ethyl acetate
in hexane for 12 min, Rf=0.25 in 10:1 hexane:ethyl acetate) to af-
ford 51 mg (69 %) of the product as a yellow oil.
1H NMR (300 MHz, CDCl3) δ 7.44 – 7.17 (m, 5H), 6.71 (d, J = 8.8
Hz, 2H), 6.49 (d, J = 8.8 Hz, 2H), 4.43 (q, J = 6.6 Hz, 1H), 3.71 (s,
3H), 1.52 (d, J = 6.6 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 152.0, 145.6, 141.8, 128.7, 126.9,
126.0, 114.9, 114.7, 55.9, 54.4, 25.3.
NMR spectra are in agreement with the literature data.[51]
N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalen-1-amine (11)
Synthesized according to the general procedure. 56% yield by
NMR with DMF as an internal standard. The residue was puri-
fied using preparative flash chromatograph InterChim PuriFlash in
dichloromethane – hexane – ethyl acetate ternary system (gra-
dient 30% to 100% dichloromethane in hexane for 8 min then
to 50% ethylacetate in dichloromethane for 8 min, Rf=0.52 in
dichloromethane) to afford 42 mg (51 %) of the product as a brown
oil.
4.4. Characterization of the products of the reductive amination
4-methoxy-N-(4-methoxybenzyl)aniline (1)
Synthesized according to the general procedure. 96% yield by
GC. The residue was purified using preparative flash chromato-
graph InterChim PuriFlash in hexane – ethyl acetate binary system
(gradient 3% to 15% ethyl acetate in hexane for 30 min, Rf=0.30
in 10:1 hexane:ethyl acetate) to afford 68 mg (86%) of the product
as a white solid. Melting point 89-91°C is in agreement with the
literature data[38] (89-90°C).
1H NMR (400 MHz, CDCl3) δ 7.56 – 7.48 (m, 1H), 7.30 – 7.18
(m, 3H), 6.90 (d, J = 8.6 Hz, 2H), 6.73 (d, J = 8.6 Hz, 2H), 4.64 (m,
1H), 3.85 (s, 3H), 3.66 (brs, 1H), 3.00 – 2.70 (m, 2H), 2.13 – 1.79
(m, 4H).
1H NMR (300 MHz, CDCl3) δ 7.30 (d, J = 8.4 Hz, 2H), 6.89 (d,
J = 8.4 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H), 6.62 (d, J = 8.8 Hz, 2H),
4.22 (s, 2H), 3.81 (s, 3H), 3.75 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 158.9, 152.3, 142.6, 131.8, 128.9,
13C NMR (101 MHz, CDCl3) δ 151.9, 141.8, 138.5, 137.6, 129.3,
129.0, 127.1, 126.1, 115.1, 114.3, 55.9, 52.0, 29.4, 28.7, 19.4.
NMR spectra are in agreement with the literature data.[52]
4-(4-methoxybenzyl)morpholine (12)
115.0, 114.2, 114.1, 55.9, 55.4, 48.8.
NMR spectra are in agreement with the literature data.[38]
N-isopropyl-4-methoxyaniline (7)
Synthesized according to the general procedure. 97% yield by
NMR with DMF as an internal standard. The residue was purified
by column chromatography (eluent: hexane:ethyl acetate 10:1 Rf
=0.37) to afford 48 mg (90%) of the product as a yellow oil.
1H NMR (300 MHz, CDCl3) δ 6.79 (d, J = 8.8 Hz, 2H), 6.58 (d,
J = 8.8 Hz, 2H), 3.75 (s, 3H), 3.55 (sept, J = 6.1 Hz, 1H), 3.16-3.10
(br s, 1H), 1.19 (d, J = 6.1 Hz, 6H).
Synthesized according to the general procedure except for addi-
tion of phosphine. 50% yield by NMR with DMF as an internal stan-
dard. The residue was purified by column chromatography (eluent:
hexane:ethyl acetate:triethylamine 4:1:0.05 Rf =0.17) to afford 33
mg (48%) of the product as a yellow oil.
1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.5 Hz, 2H), 6.91 (d,
J = 8.5 Hz, 2H), 3.86 (s, 3H), 3.76 (t, J = 4.6 Hz, 4H), 3.49 (s, 2H),
2.48 (t, J = 4.6 Hz, 4H).
13C NMR (101 MHz, CDCl3) δ 152.0, 141.9, 115.0 (2C), 55.9, 45.3,
23.2.
13C NMR (101 MHz, CDCl3) δ 158.8, 130.4, 129.7, 113.6, 67.0,
62.9, 55.3, 53.5.
NMR spectra are in agreement with the literature data.[49]
N-(4-methoxyphenyl)adamantan-2-amine (8)
NMR spectra are in agreement with the literature data. [53]
1-(4-phenylbutan-2-yl)piperidine (13)
Synthesized according to the general procedure. 92% yield by
NMR with DMF as an internal standard. The residue was puri-
fied by column chromatography (eluent: hexane:ethyl acetate 6:1
Rf =0.44) to afford 73 mg (87%) of the product as a grey solid.
Melting point 102-103°C is in agreement with the literature data
(100-102°C).
Synthesized according to the general procedure except for addi-
tion of phosphine. 90% yield by NMR with DMF as an internal stan-
dard. The residue was purified by column chromatography (eluent:
hexane:ethyl acetate:triethylamine 15:1:0.1 Rf =0.31) to afford 52
mg (73%) of the product as a yellow oil.
1H NMR (400 MHz, CDCl3) δ 7.34 – 7.14 (m, 5H), 2.73-2.60 (m,
2H), 2.61 – 2.48 (m, 3H), 2.45 – 2.35 (m, 2H), 1.93-1.84 (m, 1H),
1.67 – 1.53 (m, 5H), 1.50 – 1.38 (m, 2H), 1.01 (d, J = 6.5 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 143.1, 128.6, 128.3, 125.6, 59.0,
49.4, 35.7, 33.4, 26.7, 25.2, 13.9.
1H NMR (400 MHz, CDCl3) δ 6.78 (d, J = 8.8 Hz, 2H), 6.59 (d,
J = 8.8 Hz, 2H), 3.75 (s, 3H), 3.48 (s, 1H), 2.14 – 1.69 (m, 13H), 1.59
(d, J = 12.8 Hz, 2H).
13C NMR (101 MHz, CDCl3) δ 151.8, 141.8, 115.1, 114.7, 57.8, 56.0,
37.9, 37.6, 31.8, 31.7, 27.7, 27.5.
NMR spectra are in agreement with the literature data.[38]
N-(4-methoxybenzyl)aniline (9)
NMR spectra are in agreement with the literature data.[22]
Crystallographic data: Crystals of 6c (C28H26Cl5PRu,
Synthesized according to the general procedure except for addi-
tion of phosphine. 85% yield by NMR with DMF as an internal stan-
dard. The residue was purified using preparative flash chromato-
graph InterChim PuriFlash in hexane – ethyl acetate binary system
(gradient 5% to 20% ethyl acetate in hexane for 20 min, Rf=0.33 in
10:1 hexane:ethyl acetate) to afford 56 mg (80%) of the product as
a yellowish oil.
1H NMR (400 MHz, CDCl3) δ 7.33-7.31 (m, 2H), 7.22-7.19 (m,
2H), 6.92-6.90 (m, 2H), 6.76-6.73 (m, 1H), 6.67-6.65 (m, 2H), 4.27
(s, 2H), 3.97 (br s, 1H), 3.83 (s, 3H).
M
K:
=
671.78) are monoclinic, space group P21/n, at 120
˚
a
=
9.7252(6),
b
=
16.3057(10),
˚
c
=
17.8645(11) A,
3
β = 91.7160(10)°, V = 2831.6(3) A , Z = 4 (Z’ = 1), dcalc = 1.576
gcm–3, μ(MoKα) = 10.99 сm−1, F(000) = 1352. Intensities of
32307 reflections were measured with a Bruker APEX2 DUO CCD
˚
0.71073 A, ω-scans, 2θ<56°], and
diffractometer [λ(MoKα)
=
6836 independent reflections [Rint = 0.0656] were used in further
refinement. Using Olex2 [54], the structure was solved with the
ShelXT structure solution program [55] using Intrinsic Phasing and
refined with the XL refinement package [56] using Least Squares
minimisation. Positions of hydrogen atoms were calculated, and
they were refined in the isotropic approximation within the
riding model. The refinement converged to wR2 = 0.0896 and
GOF = 1.022 for all the independent reflections (R1 = 0.0364 was
calculated against F for 5169 observed reflections with I>2σ(I)).
13C NMR (101 MHz, CDCl3) δ 158.9, 148.3, 131.5, 129.4, 128.9,
117.6, 114.1, 112.9, 55.4, 47.9.
NMR spectra are in agreement with the literature data. [50]
4-methoxy-N-(1-phenylethyl)aniline (10)
Synthesized according to the general procedure. 69% yield by
NMR with DMF as an internal standard. The residue was purified
6

M. Makarova, O.I. Afanasyev, F. Kliuev et al.
Journal of Organometallic Chemistry 941 (2021) 121806
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Declaration of Competing Interest
[16] R. Hrdina, F.M. Metz, M. Larrosa, J.-P. Berndt, Y.Y. Zhygadlo, S. Becker,
J. Becker, Intramolecular C–H amination reaction provides direct access to 1,2-
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doi:10.1002/ejoc.201500691.
The authors declare that they have no known competing finan-
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influence the work reported in this paper.
[17] T. Schönauer, S.L.J. Thomä, L. Kaiser, M. Zobel, R. Kempe, General synthesis of
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Acknowledgments
This work was supported by Russian Science Foundation (Grant
No. 20-73-00010). Characterization of compounds using NMR spec-
troscopy was performed with the financial support from Ministry
of Science and Higher Education of the Russian Federation using
the equipment of Center for molecular composition studies of IN-
EOS RAS.
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