Room-Temperature Chemoselective Reductive Alkylation of Amines Catalyzed by a Well-Defined Iron(II) Complex Using Hydrogen

Article abstract of DOI:10.1021/acs.joc.9b00581

A transition-metal frustrated Lewis pair approach has been envisaged to enhance the catalytic activity of tricarbonyl phosphine-free iron complexes in reduction of amines. A new cyclopentadienyl iron(II) tricarbonyl complex has been isolated, fully characterized, and applied in hydrogenation. This phosphine-free iron complex is the first Earth-abundant metal complex that is able to catalyze chemoselective reductive alkylation of various functionalized amines with functionalized aldehydes. Such selectivity and functionality tolerance (alkenes, esters, ketones, acetals, unprotected hydroxyl groups, and phosphines) have been demonstrated also for the first time at room temperature with an Earth-abundant metal complex. This alkylation reaction was also performed without any preliminary condensation and generated only water as a byproduct. The resulting amines provided rapid access to potential building blocks, metal ligands, or drugs. Density functional theory calculations highlighted first that the formation of the 16 electron species, via the activation of the tricarbonyl complex Fe3, was facilitated and, second, that the hydrogen cleavage did not follow the same pathway as bond breaking, usually described with the known cyclopentadienone iron tricarbonyl complexes (Fe1 and Fe4). These calculations highlighted that the new complex Fe3 does not behave as a bifunctional catalyst, in contrast to its former congeners.

Full text of DOI:10.1021/acs.joc.9b00581

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Article
Room Temperature Chemoselective Reductive Alkylation of Amines
Catalyzed by a Well-Defined Iron(II) Complex using Hydrogen.
Alexis Lator, Quentin Gaignard Gaillard, Delphine S. Mérel, Jean-
François Lohier, Sylvain Gaillard, Albert Poater, and Jean-Luc Renaud
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00581 • Publication Date (Web): 09 May 2019
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The Journal of Organic Chemistry
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Room Temperature Chemoselective Reductive Alkylation of Amines
Catalyzed by a Well-Defined Iron(II) Complex using Hydrogen.
Alexis Lator,a Quentin Gaignard Gaillard,a Delphine S. Mérel,a Jean-François Lohier,a Sylvain Gail-
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lard,a Albert Poater,b* Jean-Luc Renauda*
a Normandie Univ., LCMT, ENSICAEN, UNICAEN, CNRS, 6 boulevard du Maréchal Juin,14000 Caen, France.
b Departament de Química, Institut de Química Computacional i Catàlisi (IQCC), University of Girona, c/Mª Aurèlia Cap-
many 69, 17003 Girona, Catalonia, Spain.
ABSTRACT: A transition metal frustrated Lewis pair approach has been envisaged to enhance the catalytic activity of tricarbonyl
phosphine-free iron complexes in reduction. A new cyclopentadienyl iron(II) tricarbonyl complex has been isolated, fully charac-
terized and applied in hydrogenation. This phosphine-free iron complex is the first Earth-abundant metal complex able to catalyze
chemoselective reductive alkylation of various functionalized amines with functionalized aldehydes. Such selectivity and function-
ality tolerance (alkenes, esters, ketones, acetals, unprotected hydroxyl group, phosphine) have been demonstrated also for the first
time at room temperature with an Earth-abundant metal complex. This alkylation reaction was also performed without any prelimi-
nary condensation and generated only water as by-product. The resulting amines provided a rapid access to potential building
blocks, metal ligands or drugs. DFT calculations highlighted first that the formation of the 16 electron species, via the activation of
the tricarbonyl complex Fe3, was facilitated and, second, that the hydrogen cleavage did not follow the same pathway than the
bond breaking usually described with the known cyclopentadienone iron tricarbonyl complexes (Fe1 and Fe4). These calculations
highlighted that the new complex Fe3 does not behave as a bifunctional catalyst, in contrast to its former congeners.
tion of enones into saturated ketones in the presence of a
phosphine-free bifunctional iron(0) complex.7 However, che-
moselective reduction of aldehydes in the presence of ketones
has been scarcely reported.8-12 Dupau et al. reported in 2015 a
general base-free hydrogenation of aldehydes in the presence
INTRODUCTION
The demand for complex molecules is increasing in organic
synthesis. Control of the stereoselectivity is often a key step
and undoubtedly one of the case studies in homogeneous
catalysis and in organic synthesis.1 This research was mainly
driven by the growing demand for optically pure compounds.
But, while several new efficient catalysts and catalytic meth-
odologies for such stereoselective control have been devel-
oped in the last two decades, these achievements were made to
the detriment of the reaction scope, the regio- and/or the che-
moselectivity. B. M. Trost introduced in a pioneer work, and
conceptualized later in a seminal review, the importance of the
chemoselectivity in synthesis.2 Moreover, he pointed out also:
"The degree of difficulty of chemoselectivity depends on the
similarity of two or more functional groups. Thus, discrimina-
tion is simpler if the functional groups belong to two different
classes, such as a C=O and a C=C, than if they are members of
the same class, such as two different C=O groups in the same
molecule." More recently, Baran stated also that chemoselec-
tivity is a key factor in the synthesis of complex molecules.3
Indeed, the control of the chemoselectivity may avoid some
tedious protection/deprotection steps and shorten the synthe-
ses. Regarding the "simplest" case (discrimination between
C=O and C=C bonds), chemoselective reductions of carbonyl
functions over alkenes or alkynes have been reported in litera-
ture in the presence of noble metals4 or Earth-abundant met-
als.5 Similarly, chemoselective reduction of alkenes over car-
bonyl functions has also been described.6 As example, our
group has recently disclosed a general chemoselective reduc-
of
ketones
catalyzed
by
a
[Ru(diamine)(diphosphine)(carboxylate)2] complex.9 More
recently, a phosphine-containing iron complex,10a and pincer-
type ligand containing Earth-abundant metal complexes
(Fe,10b-d Co,11 Mn12) were introduced for such a chemoselec-
tive hydrogenation of aldehydes. Albeit these studies demon-
strated its feasability with Earth-abundant metal complexes,
the scope was rather limited to some non-functionalized aro-
matic carbonyl derivatives.
Moreover, and quite surprisingly, no report to date has ap-
peared on the catalytic chemoselective reductive alkylation of
amines with aldehydes, while amines are important com-
pounds in organic chemistry, chemical industry and biological
processes, as well. As examples, they are present in amino
acids, various biological compounds, or organic building
blocks.13-14 Synthesis of amine derivatives is widely reported
in the literature. Among the different strategies to prepare
alkylated amines, the reduction of imines and the reductive
amination are well documented.15-21 The use of stoichiometric
reducing agent and the consequently formation of stoichiomet-
ric amount of waste led academic researchers to develop eco-
friendly pathways. Recent development using molecular hy-
drogen,17 formic acid,18 hydride transfer19 or hydrogen borrow-
ing transfer20 has emerged in the last decade. These reactions
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were initially reported with platinum metals (rhodium, palla- from
Page 2 of 17
1,4-dimethyl-5,7-diphenyl-3,4-dihydro-1H-
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3
4
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dium, ruthenium or iridium). Due to economic pressure and
sustainability concerns, the quest for efficient Earth abundant-
based metals has led to the development of new complexes,
and iron chemistry is at the forefront of this intensive research
area.17c-d, 19c-f, 20c-l, 21 But reductive alkylation with functional-
ized amines and/or carbonyl derivatives has been scarcely
reported in literature.22 We report in this work that a new
phosphine-free iron(II) complex catalyzes chemoselectively
the reductive alkylation of various functionalized amines with
functionalized aldehydes at room temperature.
cyclopenta[b]pyrazin-6-(2H)-one 1 in a 51 % overall yield
(steps (i) and (ii), Scheme 1). A simple heating of this ligand
with [Fe2(CO)9] in toluene provided, not the expected cy-
clopentadienone iron(0) tricarbonyl complex Fe2, but the
cyclopentadienyl iron(II) complex Fe3 in 49 % yield, through
a redox process (Scheme 1). To unambiguously establish the
atom connectivity in complexes Fe3, single crystals were
grown by slow diffusion of pentane in a dichloromethane
solution of Fe3. Suitable single crystals were obtained and
subjected to X-ray diffraction (XRD). Thermal ellipsoid repre-
sentations are shown in Figure 1. This structure presents a
slight distortion of the piperazine-type ring. The phenyl ring
and the cyclopentadienyl ring are not coplanar (torsion angle =
63.28(19)°), like in complex Fe1, maintaining steric hindrance
around the metal center.22 The C-N bonds are also a relevant
feature of this complex. The C1-N1 bond length was measured
(1.341(6) Å) and was comparable to the Csp2-N bond lengths
of the piperazine ring (1.324(6) and 1.360(6) Å). This length is
also comparable to the Csp2-N bond length reported by Casey
in an aminocyclopentadienyl ruthenium complex.29 These
observations confirm the η5-coordination of the ancillary
ligand.
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RESULTS AND DISCUSSION
Within this context, our group had described the first reductive
amination between aliphatic or aromatic aldehydes, ketones
and various primary and secondary amines catalyzed by cy-
clopentadienone iron carbonyl complexes.23-24 A careful struc-
tural analysis highlighted that variation of the substituents on
the cyclopentadienone motif controlled the reactivity of the
iron catalyst. First, the steric hindrance of R1 groups was es-
sential to prevent dimerization of the iron complex.23b Second,
these complexes could be seen as a transition metal frustrated
Lewis pair.25 Considering the unsaturated 16-electron interme-
diate and the cyclopentadienone ligand, the iron metal center
would be the Lewis acid site while the carbonyl function
would be the Lewis base site (Chart 1). Modifications of the
electron density on both sites led to a more or less easy hydro-
gen cleavage.23-24, 26 Based on these results, and in order to
synthesize an iron complex exhibiting noble-metal reactivities,
the replacement of the oxygen atom by a more basic atom,
namely a nitrogen atom, was targeted to enhance the Lewis
base character of the cyclopentadienone iron tricarbonyl com-
plex. To achieve this goal, we conceptually designed the iron
complex Fe2 as suitable candidate (Chart 1).
To investigate the electron density on the cyclopentadienyl
motif in Fe3, CO-bond IR stretching frequencies were investi-
gated and compared both with the known [(η5-C5H5)Fe(CO)3]+
and with our previous complex Fe1.24, 30 The CO stretching
frequencies were at 2042, 1992 and 1965 cm-1 in complex
Fe3, while they were at 2120 and 2068 cm-1 in [(η5-
C5H5)Fe(CO)3]+ and at 2027, 1962, and 1947 cm-1 in Fe1. The
experimentally measured frequencies indicated a more impor-
tant back donation of the iron center to carbonyl ligand in Fe3
compared to [(η5-C5H5)Fe(CO)3]+, and consequently a more
important electron density on the Fe(II) metal center. Further-
more, these analyses highlighted also that the electron density
was similar in complexes Fe3 and Fe1, albeit the oxidation
numbers are not identical.
Condensation of iso-propylamine on the N,N'-dimethyl-3,4-
ethylenediamino-substituted cyclopentadienone, following the
Katzenellenbogen's procedure,27 in the presence of a Lewis
acid led to a complex mixture. Such reactivity might be asso-
ciated to the electron-richness of the cyclopentadienone. Fi-
nally, following a procedure reported by Gompper,28 the ami-
nocyclopentadienylium ligand 2 was prepared in two steps
Chart 1. Cyclopentadienone iron tricarbonyl complexes: Transition Metal Frustrated Lewis Pairs.
Previous Work:
Ph
Ph
TMS
TMS
O
Ph
I
N
O
O
O
N
TsN
N
TMS
Ph
TMS
<<
<<
Fe
CO
CO
Fe
Fe
CO
CO
Fe
CO
CO
CO
OC
OC
OC
OC
CO
Increase of the electronic density on the cyclopentadienone ligand => Higher reactivity
Our strategy for this work via a frustrated Lewis Pair approach:
Lewis base
R1
Ph
Ph
Fe
O
Ph
N
Ph
X
R1
R2
R2
N
N
iPr
steric hindrance
Lewis acid site
N
N
Fe
Fe
CO
CO
OC
OC
OC
CO
CO
OC
Fe1
Fe2
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Scheme 1. Synthesis of cationic iron complex Fe3
2
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Figure 1. Thermal ellipsoid representations (50 % prob-
ability) of complex Fe3. Hydrogen atoms, except for the
NHiPr group, and BF4 anion were omitted for clarity.
Such trend might be due to some catalyst decomposition or
inhibition during the course of the reductive alkylation.
Table 1. Fe-catalyzed reductive alkylation of N-methyl
benzylamine with citronellala
entry
catalyst
(x mol %)
Fe4 (5)
Fe5 (5)
Fe1 (2.5)
Fe3 (2)
Fe1 (2)
Fe3 (2)
Fe3 (2)
Fe3 (1)
Me3NO
(y mol %)
7.5
temp. (°C)
yieldb (%)
1
2
85
85
45
45
r.t.
r.t.
r.t.
r.t.
67
83
83 (100d)
(100d)
N. R.
(100d)
91 (100d)
74
7.5
3
3.75
3.0
4
5
6c
3.0
3.0
7
3.0
8
1.5
a
General conditions: aldehyde (0.5 mmol, 1 equiv.), amine (0.6 mmol, 1.2
equiv.), under 5 bar of hydrogen in ethanol (1 mL) for 16 h. b Isolated yields. c 10 bar
of hydrogen. d Conversion determined by 1H-NMR spectroscopy.
The catalytic activity of this new iron complex Fe3 was ini-
tially evaluated in a model reductive amination between citro-
nellal and N-methylbenzylamine and compared with previous
catalysts (Fe1, Fe4 and Fe5, see Table 1).23-24 The Knölker's
complex Fe4 and the modified Knölker's type Fe5 required
high temperature (85 °C, entries 1-2, Table 1) while Fe3 (un-
der 10 bar of molecular hydrogen) was as active as our previ-
ous complex Fe1 at 45 °C in ethanol (100 % conversion in
both cases, entries 3-4, Table 1). But, to our delight, Fe3 was
also active at room temperature, unlike Fe1 (entries 5-6, Table
1). When the catalyst loading was lowered to 1 mol %, the
chemical yield in alkylated amine reduced a little from 91 to
74 % (entries 7-8, Table 1). A rapid monitoring of the conver-
sion over time showed that the reaction started rapidly (20 %
conversion after 1 h) but the reaction rate decreased in time
(36 % conversion after 3 h, and 60 % conversion after 6 h).
With these conditions in hands and to validate our initial hy-
pothesis, we decided to explore the scope and limitations of
the reductive amination, initially between simple amines and
aldehydes (amines 3-12, Table 2), secondly with functional-
ized ones (amines 13-22, Table 2). Reaction of citronellal, 3-
phenylpropanal and cyclohexyl carboxaldehyde with various
amines led to the corresponding alkylated amines 3-11 in good
yields (79-99 %, Table 2). On a gram scale, as example, com-
pound 3 was isolated in 88% yield, showing the robustness of
this procedure. Neither the reduction of isolated alkene nor a
cyclopropyl ring opening has been observed (amines 3-6, 10-
11 Table 2). Both secondary and primary amines could be
used, albeit the latter led to lower yields (amines 3-6, Table 2).
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Table 2. Fe3-catalyzed reductive alkylation of aminesa
As limitation of the scope, unlike the reactivity observed with
1
2
3
4
Fe1, no reductive amination occurs with pyridine carboxalde-
hyde in the presence of our new complex Fe3. As observed by
1H-NMR analysis, pyridine moiety reacts with the iron centre
and leads to decomposition of the complex.
R2
O
H
Fe3 (2 mol %), Me3NO (3 mol %)
+
N
N
H
R2 R3
R1
R1
R3
H2 (5 atm.), EtOH, r.t., 16 h.
Next, we turned our attention to more functionalized amines
and aldehydes. Remarkably, unprotected phenol and acetal
were tolerated (amines 15-16, Table 2). Whereas phosphines
are known to coordinate cyclopentadienyl iron(0) dicarbonyl
complexes,26a the 2-diphenylphosphinebenzaldehyde could be
used as alkylating agent with this new iron(II) complex and
the functionalized amino-phosphine 17 was isolated in 70 %
yield. No reaction occurred at 45 °C in the presence of Fe1,
demonstrating the higher efficiency of the new catalyst over
its previous congeners. It is also worth to note that a chiral
aminoester such as (S)-proline ester could also be used with
aliphatic and aromatic aldehydes and the corresponding alky-
lated amines 18-19 were obtained in 73-86% yield. Similarly,
chiral amino-alcohols (such as (S)-prolinol)) or amino-amide
(such as cytisine) could be alkylated in high yield and the
corresponding alkylayed amines 20-21 were isolated in 81-85
%. Finally, a PNNP ligand 22 was prepared in 62 % yield in
5
6
7
8
N
N
N
O
4 (79 %)
5 (82 %)
3 (91 %)
9
N
H
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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O
6 (47 %)b
7 (87 %)
8 (96 %)
N
N
N
O
9 (90 %)
10 (87 %)
11 (99 %)
Ph
N
S
N
Ph
N
Fe
MeOOC
O
13 (92 %)
12 (98 %)
14 (94 %)
one
step
from
the
commercially
and
available
(2R, 2'R)-2,2'-
2-
N
Ph
diphenylphosphinebenzaldehyde
O
O
N
bipyrrolidine.31
N
O
O
HO
PPh2
16 (70 %)
17 (70 %)
15 (99 %)
O
O
Scheme 2. Fe3-catalyzed reductive alkylation of primary
aminesa
HO
N
O
O
1) MeOH, r.t. , 4h
N
PPh2
19 (86 %)c
N
O
N
NH2
O
H
R
H
Ph
R
2) Fe3 (2 mol %), Me3NO (3 mol %)
18 (73 %)
20 (85 %)
PTSA (50 mol %), H2 (20 bar), 16h
PPh2
H
F3C
N
N
N
N
H
N
H
N
H
N
N
MeO2C
O2N
Fe
CF3
24, (67%)b
O
22 (62 %)c
Ph2P
21 (81 %)
26, (54%)b
25, (77%)b
23 (96%)b
a
a
General conditions: aldehyde (0.5 mmol, 1 equiv.), amine (0.6 mmol, 1.2
General conditions: aldehyde (0.5 mmol, 1 equiv.), amine (0.6 mmol, 1.2
equiv.), Fe3 (2 mol %), Me3NO (3 mol %), under 5 bar of hydrogen in ethanol (1
b
equiv.), PTSA (50 mol%) under 20 bar of hydrogen in ethanol (1 mL) for 16 h.
b
Isolated yields.
mL) for 16 h at room temperature. Yield was based on isolated product. 20 bar of
c
hydrogen. when Fe1 (2.5 mol %) was used instead of Fe3 with Me3NO (3.75 mol
%), under 5 bar of hydrogen in ethanol (1 mL) for 16 h at 45 °C, no reaction occured.
As mentioned previously, selectivity is a key factor not only in
organic synthesis but also for the development of sustainable
chemical processes. Catalysts exhibiting complete selectivity
Aromatic aldehydes bearing either electron donating or elec-
tron withdrawing substituents could also be engaged in this
reductive amination without noticeable decrease of the chemi-
cal yields (amines 12-15, 92-99 %, Table 2). In the same reac-
tion conditions (2 mol % of Fe3, 3 mol % of Me3NO at room
temperature under 5 bar of hydrogen), neither aliphatic nor
aromatic ketones underwent reductive amination. Other re-
ducible function, such as ester, remained intact and the amine
14 was isolated in 94 % yield. As mentioned above, benzy-
lamine was used in the reductive amination but the corre-
sponding alkylated amine was isolated in moderate yield. To
extend this protocol to other primary amines, a modification of
the reaction conditions has to be set up and a substoichiomet-
ric amount of an acid has to be added to generate an iminium
intermediate. In these conditions, alkylated amines were iso-
lated in moderate to excellent yields (54-96 %, Scheme 2).
Other reducible functions, such as ester, nitro group or
trifluoromethyl substituent, were tolerated (Scheme 2).
for aldehydes over ketones are still under estimated and even
32
rather unexplored.8-12,
We showed that ketones remained
non-reactive in the reaction conditions (vide supra), so a che-
moselective reductive amination of aldehyde in the presence
of a ketone function should be feasible and would bring a
breakthrough not only in catalysis but also in organic synthe-
sis. For this study, three keto-aldehydes, representing the two
different classes (aliphatic and aromatic) of carbonyl func-
tions, were engaged in the reductive amination conditions.
Reductive alkylation of amines with keto-aldehydes furnished,
in the presence of the new phosphine-free iron(II) complex
Fe3 under hydrogen pressure at room temperature, exclusively
the aminoketones 27-41. Neither reductive amination of the
ketone functions, nor direct reduction of ketones was noticed
(Table 3).
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was engaged in this alkylation as a model substrate (Table 3).
Table 3. Fe3-catalyzed chemoselective reductive alkyla-
tion of amines.a
The corresponding alkylated amine 41 was isolated chemose-
lectively in 60 % yield. Finally, the reductive amination be-
tween propylamine and 4-acetylbenzaldehyde led to com-
pound 40 in 86% yield (Table 3). In the presence of Fe1 in-
stead of Fe3, the reductive alkylation of N-methylbenzylamine
with 4-acetylbenzaldehyde and 3-(propen-2'-yl)-6-oxo-
heptanal occurred at 45 °C albeit in much lower yields (40 and
22 %, respectively, Table 3) and no reaction was observed at
room temperature. To highlight the robustness of our protocol,
the reductive alkylation of N-methylamino acetaldehyde di-
methyl acetal with 3-(propen-2'-yl)-6-oxo-heptanal was car-
ried out on a 5 mmol scale and the corresponding alkylated
amine 37 was isolated in 88 % yield.
1
2
3
4
5
6
7
8
9
O
O
O
N
N
O
28 (89 %)
27 (93 %)
HO
O
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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40
41
42
43
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N
O
29 (88 %)
30 (94 %, 40 %b)
HO
N
In order to have some mechanistic insights, both deuterium-
labeling experiment (Table 4, Scheme 3) and DFT calculations
were undertaken (Figures 2-5).33
O
N
O
O
Full deuterium incorporation was observed at the C1 position
(the former carbonyl function, compound 3-d1) under D2 pres-
sure in methanol, while an incomplete incorporation was no-
ticed at the C2 atom (compound 3-d2) under hydrogen pres-
sure in deuterated methanol (entries 1-2, Table 4). Finally the
deuterated compound 3-d3 was obtained in deuterated metha-
nol under D2 pressure (again a full incorporation at the C1
position and a partial one at the C2, entry 3, Table 4). When 3-
(propen-2'-yl)-6-oxo-heptanal and N-methylbenzylamine were
engaged in the reduction process in deuterated methanol, the
amino derivative 27-d was isolated in 75 % yield (Scheme 3).
Incorporation of deuterium occurred only at the β-position of
the amino group and at the α-positon of the ketone (Scheme
3). All these deuterium-labeling experiments underline first
the presence of iminium/enamine equilibrium and second the
exclusive reduction of the iminium intermediate.
32 (99 %)
31 (79 %)
O
N
N
N
O
O
34 (89 %, 22 %b)
O
33 (74 %)
OH
N
N
O
O
35 (81 %)
36 (88 %)
OH
OH
O
N
N
O
O
O
OH
38 (65 %)
37 (78 %)
HO
N
N
H
Table 4. Deuteration reactiona
40 (86 %c)
O
O
39 (80 %)
N
N
O
41 (60 %)
General conditions: aldehyde (0.5 mmol, 1 equiv.), amine (0.6 mmol, 1.2
a
entry
solvent
CH3OH
CD3OD
CD3OD
reductant
product
3-d1 (100% at C1)
3-d2
equiv.), Fe3 (2 mol %), Me3NO (3 mol %), under 5 bar of hydrogen in ethanol (1
b
mL) for 16 h at room temperature. Yield was based on isolated product. Fe1
1
2
D2
H2
D2
(2.5 mol %) was used instead of Fe3, with Me3NO (3.75 mol %), under 5 bar of
hydrogen in ethanol (1 mL) for 16 h at 45 °C. c Reductive amination procedure as
described in Scheme 2.
3
3-d3 (100% at C1)
a
General conditions: aldehyde (0.5 mmol, 1 equiv.), amine (0.6 mmol, 1.2
equiv.), under 5 bar of a reductant gas (H2 or D2) in solvent (1 mL) for 16 h. Yield
was based on isolated product.
In more details, with the 6-phenyl-6-oxo-hexanal, alkylated
amines 27-29 were isolated in 88-93 % yield. Non-protected
alcohol, benzyl or acetal function, were tolerated (Table 3).
With the same amines in the presence of 4-
acetylbenzaldehyde, the same conclusions could be drawn and
the corresponding alkylated amines 30-33 were obtained in
79-99 % yield (Table 3). Cytisine reacted with this keto-
aldehyde to furnish the alkylated amine 33 in 74 % yield (Ta-
ble 3). With the more challenging 3-(propen-2'-yl)-6-oxo-
heptanal having both aliphatic carbonyl functions, the reduc-
tive alkylation of substituted amines provided the correspond-
ing compounds 34-39 in high yields (65-88 %, Table 3).
Again, non-protected phenol and alcohols (such as in prolinol,
N-methylaminoethanol, adrenaline), and acetal could be intro-
duced without any depletion of the chemical yields. As many
drugs contain a piperazine framework, N-methylpiperazine
Scheme 3. Deuteration reaction of ketoaldehydea
CH2 0%
CHD 30%
CD2 70%
O
Fe3 (2 mol%)
Me3NO (3 mol%)
O
O
Ph
N
Ph
Bn
+
H
2 (5 Bar), CD3OD, r.t., 16h
H
N
27-D
75%
Bn
CH2 25%
CHD 50%
CD2 25%
a
General conditions: aldehyde (0.5 mmol, 1 equiv.), amine (0.6 mmol, 1.2
equiv.), under 5 bar H2 in CD3OD (1 mL) for 16 h. Yield was based on isolated
product.
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The second possible pathway implied an external amine mole-
1
2
3
4
5
6
7
8
cule to deprotonate one of the hydrogen atoms on the metal
centre in intermediate III (see Figures 3 and 4). The latter step
is kinetically disfavored by 5.8 kcal/mol with respect to the
traditional III-IV step (see Figures 2-4), but the deprotonated
intermediate III’ is somewhat thermodynamically favored,
especially if BF4 anion was not included (12.5 kcal/mol).
To unveil how the reaction pathway is modified, switching
from the relatively high temperature demanding cyclopentadi-
enone iron tricarbonyl complexes Fe4 or Fe5 to the new cati-
onic Fe3 (see Figures 2-5), we underwent DFT calculations.
The activation of catalyst Fe3, that generated a vacant site
through the release of a carbon dioxide molecule, was more
facile compared to the CO removing previously described for
Fe1 and Fe4 (see Figure 4).23b, 24 This step was for Fe3 3.3 and
6.2 kcal/mol less kinetically demanding than with Fe1, taking
into account or not the BF4 anion, respectively; thus, improv-
ing significantly the generation of the catalytic active species
(Figure 4 and Table 5 for the energy barriers for the sake of
comparison). The next step leading to intermediate III was the
coordination of a hydrogen molecule to iron and did not re-
quire a high barrier of energy. Then, two competing pathways
could be suggested. In the first one, ethanol could be involved
as a proton shuttle and participate to the hydrogen bond cleav-
age (III to IV, Figure 2 and Figure 4). This step required an
energy barrier of 23.7 and 20.6 kcal/mol, taking into account
or not the BF4 anion, respectively.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 5. Energy barriers for Fe1, Fe3 and Fe4.a
Fe3
Figure 3. Transition states III-III’ for Fe3 (main distances
in Å).
Step
Fe1
Fe3
Fe4
(without BF4)
Regarding the mechanism for Fe1 and Fe4, this deprotonation
mechanism is even more favored kinetically, however the
equilibrium is displaced towards the previously described non-
deprotonated intermediate III, by 12.1 and 7.2 kcal/mol, re-
spectively (Figure 5), and III’ is again disfavored by 19.5 and
14.8 kcal/mol, respectively, with respect to intermediate IV.
Consequently this deprotonation mechanism might potentially
only slow down the catalytic activity for both neutral com-
plexes. Based on these calculations, the new complex Fe3
seems also to not act as a bifunctional complex.
I-II
20.7
6.0
14.5
3.7
17.4
4.9
19.6
4.0
II-III
III-III’
7.2
8.4
27.9
13.8
10.8
11.6
III’-V -5.8 (6.3)a
0.3 (7.6)a
18.9
(13.0)a
III-IV 15.2
20.6
33.7
a in parenthesis calculated from III
Finally, the last step of the reaction mechanism led to the
organic product once protonated the methylidene moiety of the
cationic organic moiety overcoming a rather low energy bar-
rier for all catalysts. However this step becomes generously
displaced towards the product with Fe3 by 8.5 kcal/mol,
whereas it is nearly isoenergetic for Fe1, and particularly
rather disfavored for Fe4 by 6.4 kcal/mol. This trend is in
perfect agreement with experiments. Alternatively the other
two other nitrogen atoms of the ligand in Fe3 were also tested
in the hydrogen cleavage, taking into consideration an isomer
of intermediate III, where both carbonyls on the iron center
have rotated of 120º (see SI). Thus, the H2 moiety was placed
below any of both amines of the six-member ring of the cy-
clopentadienyl ring. Since the homologous species III, IV and
V, and the transition states that link them displayed close
energy values to the ones in Figure 4, the potential active role
of this pathway could not be ruled out.
Figure 2. Transition states III-IV for Fe3 (main distances
in Å).
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The Journal of Organic Chemistry
Ph
H
1
2
3
4
5
6
7
8
N
N
Ph
H
Ph
R2
H
N
N
N
N
Ph
H
Ph
-50.7
-52.9
H
Fe
N
N
H
N
OC
Ph
H
CO
Fe
R1
N
H
O
OC
H
R2
-39.9
-50.4
CO
H
Fe
Ph
H
H
OC
-57.8
-58.8
N
N
N
H
H2O
CO
H2
H2
Ph
N
III
CO
O
R2
H
Fe
Ph
H
N
OC
N
Ph
CO
N
H
-34.1
-38.2
N
9
-56.4
-64.2
Me3N
Fe
10
11
12
13
14
15
16
17
18
19
20
21
Ph
Me3NO
H
H
OC
N
CO
Ph
N
H
Ph
III'
N
N
N
Ph
H
Ph
H
Ph
N
Ph
N
17.4
14.5
N
Ph
H
N
Fe
N
H
H
OC
R1
N
Fe
N
R2
N
CO
CO
CO2
O
-55.9
-51.7
OC
H
Fe
CO
-55.6
-56.6
Fe
II
H
OC
0.0
0.0
OC
H
CO
CO
I
IV
Ph
Ph
H
H
N
N
N
-44.8
-53.4
N
N
H
Ph
H
Ph
H
N
R1
R2
N
R2
N
N
-64.9
-65.7
Fe
CO
Fe
CO
R2
OC
H
OC
H
R1
R1
V
Figure 4. Energy profile for Fe3-catalyzed chemoselective reductive alkylation of amines (R1 = CH2CH3, R2 = CH2(Ph);
Gibbs free energies in solvent in kcal/mol for Fe3 in blue, and BF4 anion was omitted for clarity; in light blue without in-
cluding BF4 anion in the calculations.
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Y
O
Y
X
Y
R1
X
O
Y
X
Y
N
-48.7
-46.2
H
Fe
X
O
H2
X
OC
H
Y
CO
Fe
R2
X
H
O
OC
H
R1
-48.6
-44.0
CO
Fe
Y
H
H
OC
NH3
O
-55.8
-57.8
N
H
H2O
CO
H2
Y
N
III
H
CO
Fe
R1
Y
OC
-40.6
-38.9
O
CO
NH2
X
O
Y
H
X
-43.7
-50.5
Me3N
CO2
Fe
Ph
Me3NO
OC
O
CO
Y
X
Ph
Y
III'
O
Y
X
X
O
Y
H
Y
H
O
X
X
20.7
19.6
O
Y
Fe
CO
II
X
X
H
X
H
-63.2
-65.3
OC
R2
Fe
N
R1
CO
Fe
OC
CO
OC
Fe
-54.7
-50.2
H
H
CO
0.0
0.0
OC
CO
I
IV
X = NCH3, Y = Ph, Fe1
X = CH2, Y = TMS, Fe4
Y
Y
O
Y
O
Y
X
H
-49.5
-50.2
X
R1
X
X
R2
R1
N
R1
N
HN
-63.4
-58.9
Fe
Fe
R2
H
OC
OC
H
CO
CO
R2
R2
V
Figure 5. Energy profile for Fe1 and Fe4-catalyzed reductive alkylation of amines (R1 = CH2CH3, R2 = CH2(Ph); Gibbs free
energies in solvent in kcal/mol for Fe1 and Fe4 in red and violet, respectively.
only demonstrated through the reductive alkylation of func-
tionalized amines with a broad range of carbonyl derivatives
CONCLUSIONS
(other reducible functions, unprotected alcohols, phosphine
moiety, etc… were tolerated on both partners of this reaction)
but also through the chemoselectivity of this process. Amines
were isolated in moderate to high yields at room temperature.
To the best of our knowledge, these examples represent the
In summary, we have synthesized and fully characterized a
well-defined phosphine free iron(II) complex bearing an elec-
tron-rich cyclopentadienyl framework. Its efficiency was not
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solid was solubilized in methylene chloride (30 mL) and filtrated over
first chemoselective reductive amination of aldehydes with an
®
a pad of Celite and organics were evaporated. The crude product was
purified by flash column chromatography on silica (ethyl acetate) and
the pure complex Fe3 was isolated as a gold orange powder (295 mg,
45 %). 1H-NMR (CDCl3, 400 MHz) δ 7.60-7.50 (m, 10H), 3.69 (ddd,
J = 10.6; 6.8; 3.6 Hz, 2H), 3.03 (d, J = 9.2 Hz, 1H), 2.88 (ddd, J =
10.6; 6.8; 3.6 Hz, 2H), 3.83-2.77 (m, 1H), 2.35 (s, 6H), 0.69 (d, J =
6.4 Hz, 6H) ppm. 11B-NMR (CDCl3, 128 MHz) δ -0.85 ppm. 19H-
NMR (CDCl3, 400 MHz) δ -152.9 ppm. 13C{1H}-NMR (CDCl3, 100
MHz) δ 208.5 (3C), 138.1, 130.4 (6C), 129.8 (4C), 128.5 (2C), 118.2
(2C), 67.5 (2C), 49.7 (2C), 45.5, 40.2 (2C), 23.1 (2C) ppm. IR (neat):
3372, 2042, 1992, 1965, 1570, 1539, 1506, 1483, 1445, 1418, 1367,
1277, 1048, 1032, 754, 704 cm-1. HRMS (ESI+) m/z: [M-BF4]+ Calcd
for C27H28FeN3O3 498.1480; Found 498.1492. HRMS (ESI-) m/z
1
2
3
4
5
6
7
8
Earth abundant metal complex or a FLP catalyst at room tem-
perature under hydrogen pressure. Moreover, compared to the
most recent work in reductive alkylation,17c, 22 no molecular
sieves is required. Mechanistically, DFT calculations rational-
ized the trend of reactivity Fe4 < Fe1 << Fe3, and highlighted
the active role of the base (amine) in the activation of hydro-
gen in the presence of the cationic Fe3. This base facilitated
also the protonation and release of the product, not basically
by kinetics, but thermodynamics. These results open a route to
environmentally acceptable atom-efficient procedure to func-
tionalized amines. Further work will be dedicated first to ex-
tend and apply such transition metal in the activation of hy-
drogen, and other small molecules, in the presence of various
unsaturated compounds, second to develop new chemoselec-
tive processes.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
-
[BF4] Calcd for BF4 87.0029; Found 87.0033.
Preparation of keto-aldehyde 42:34 In a 100 mL round bottom flask
equipped with a stirring bar, (R)-Limonene (15 mmol, 1 equiv, 2.3
mL) was solubilized in dry methylene chloride (50 mL) and cooled
down to 0 °C with an ice bath. 3-Chloroperbenzoic acid (16 mmol,
1.05 equiv, 2.76 g) was added slowly by portion over 10 minutes. The
reaction was stirred 1 hour at 0 °C, then quenched by NaHCO3 aque-
ous saturated solution (20 mL). Organic phase was separated and
aqueous phase was washed twice with dichloromethane (2x20 mL).
Organics were combined, dried over MgSO4, filtrated and concen-
trated in vacuo. Purification of the crude by silica flash column chro-
matography, afforded the pure epoxide intermediate, which was
directly engaged in the next step. The crude epoxide was solubilized
in a 1/1 mixture of THF/H2O (20 mL). Sodium periodate (22.5 mmol,
1.5 equiv, 4.8 g) was added and the reaction was stirred at room
temperature for 1 hour. The mixture was extracted with dichloro-
methane (3x20 mL) and the organic layers were dried over Na2SO4,
filtrated and concentrated in vacuo. The crude product was purified by
silica flash column chromatography (Pentane/Et2O 9:1) and the pure
Experimental Part
General Considerations: All air- and moisture-sensitive manipulations
were carried out using standard vacuum line Schlenk tubes tech-
niques. Dry toluene was dried using a solvent purification system
from Innovative Technologies, by passage through towers containing
activated alumina. Xylene was purchased from Carlo Erba and was
distillated over sodium and stocked over 4Å molecular sieves. Both
were deglazed prior to use by bubbling argon gas directly in the
solvent. Other solvents and chemicals were purchased from different
suppliers and used as received. Neutral alumina was purchased from
Alfa Aesar (Brockmann Grade I, 58 Angstroms, -60 Mesh Powder,
S.A. 150 m2/g) and silica from Carlo Erba (60Å 40-63µ). Deuterated
solvents for NMR spectroscopy were purchased from Sigma Aldrich
and used as received. NMR spectra were recorded on a 500 MHz
Brücker spectrometer. Proton (1H) NMR information is given in the
following format: multiplicity (s, singlet; d, doublet; t, triplet; q,
quartet; qui, quintet; sept, septet; m, multiplet), coupling constant(s)
(J) in Hertz (Hz), number of protons. The prefix app is occasionally
applied when the true signal multiplicity was unresolved and br
indicates the signal in question broadened. Carbon (13C or DEPTQ)
NMR spectra are reported in ppm (δ) relative to CDCl3 unless noted
otherwise. Infrared spectra were recorded over a PerkinElmer Spec-
trum 100 FT-IR Spectrometer using neat conditions. HRMS analyses
were performed with Acquity UPLC H-Class Xevo G2-XS QTof
(WATERS) by Laboratoire de Chimie Moléculaire et Thioorganique
analytical Facilities Optical rotation was measured in chloroform, at
25 °C over a Jasco P-2000 polarimeter using a sodium lamp (589 nm)
with a concentration of 3.5 10-3g.mL-1. The ligand 1 was prepared
according to the previously reported procedure.20l
1
keto-aldehyde 42 was obtained as a colorless oil (1.96 g, 78 %). H-
NMR (CDCl3, 500 MHz) δ 9.67 (s, 1H), 4.84-4.81 (m, 1H), 4.77-4.76
(m, 1H), 2.70-2.64 (m, 1H), 2.45 (dd, J = 7.9; 2.5 Hz, 1H), 2.43 (dd, J
= 7.9; 2.5 Hz, 1H), 2.39 (t, J = 7.4 Hz, 2H), 2.13 (s, 3H), 1.75-1.67
(m, 1H), 1.63 (br. s, 3H), 1.61-1.57 (m, 1H) ppm. 13C{1H}-NMR
(CDCl3, 125 MHz) δ 208.3, 201.8, 145.1, 113.3, 47.5, 40.9, 40.8,
30.1, 26.4, 18.4 ppm. [α]D25 = -3.2 (C = 3.5 10-3g.mL-1 CHCl3).
Synthesis of 6-Oxo-6-phenylhexanal 43:35 In a 100 mL round bottom
flask equipped with a stirring bar, 2-phenylcyclohexene (20 mmol, 1
equiv, 3.18 mL) was solubilized in dry methylene chloride (50 mL)
and cooled down to 0 °C with an ice bath. 3-Chloroperbenzoic acid
(50 % wt) (22 mmol, 1. equiv, 7.6 g) was added slowly by portion
over 10 minutes. The reaction was stirred for 1 hour at 0 °C, then
quenched by a saturated aqueous solution of NaHCO3 (20 mL). The
organic phase was separated and the aqueous phase was extracted
twice with dichloromethane (2x20 mL). The organic phases were
combined, dried over MgSO4, filtrated and concentrated under vac-
uum. The crude product was purified by flash column chromatogra-
phy on silica (Pentane/Et2O 95:5), the pure epoxide intermediate was
then directly engaged in the next step. The epoxide intermediate was
solubilized in a 1/1 mixture of THF/H2O (30 mL ). Sodium periodate
(30 mmol, 1.5 equiv, 6.41 g) was added and the reaction was stirred at
room temperature for 18 hours. The mixture was extracted with di-
chloromethane (3x20 mL) and the organic layers were dried over
Na2SO4, filtrated and concentrated under vacuum. The crude product
was purified by flash column chromatography on silica (Pentane/Et2O
8:2) and the pure keto-aldehyde 43 was obtained as a white solid
(1.81 g, 48 %). 1H-NMR (CDCl3, 500 MHz) δ 9.78 (s, 1H), 7.95 (d, J
= 7.5 Hz, 2H), 7.56 (t, J = 7.5 Hz, 1H), 7.46 (t, J = 7.3 Hz, 2H), 3.00
(t, J = 7.0 Hz, 2H), 2.51 (t, J = 7.0 Hz, 2H), 1.82-1.69 (m, 4H) ppm.
13C{1H}-NMR (CDCl3, 125 MHz) δ 202,0, 199.7, 136.9, 133.0, 128.6
(2C), 127.9 (2C), 43.8, 38.1, 23.6, 21.7 ppm.
N-(1,4-dimethyl-5,7-diphenyl-3,4-dihydro-1H-cyclopenta[b]pyrazine-
6(2H)-ylidene)propan-2-aminium tetrafluroborate 2: According to the
procedure previously reported by Gompper,28 starting from ligand 1
(3.13 mmol, 1 equiv, 1.0 g) in presence of triethyloxonium tetra-
fluoroborate (3.16 mmol, 1 equiv, 900 mg) and isopropylamine (3.16
mmol, 1 equiv, 0.27 mL), the cationic ligand 2 was obtained as a deep
1
blue powder (647 mg, 51 %). H-NMR (CDCl3, 400 MHz) δ 7.40-
7.26 (m, 8H), 7.22-7.17 (m, 2H), 5.61 (d, J = 9.8 Hz, 1H), 3.53 (ddd,
J = 12.6; 8.5; 5.6 Hz, 4H), 3.29 (dhept, J = 9.8; 6.3 Hz, 1H), 2.65 (s,
3H), 2.64 (s, 3H), 0.78 (d, J = 6.3 Hz, 6H) ppm. 11B-NMR (CDCl3,
128 MHz) δ -0.91 ppm. 19H-NMR (CDCl3, 400 MHz) δ -153.7 ppm.
13C{1H}-NMR (CDCl3, 100 MHz) δ 172.8, 154.6, 145.9, 133.2, 132.9
(2C), 132.4 (2C), 130.0, 129.3 (2C), 129.1 (2C), 129.0 (2C), 96.1,
90.5, 50.7, 49.3, 47.0, 41.9, 41.6, 23.3 (2C) ppm. IR (neat) 3328,
2977, 1625, 1569, 1513, 1465, 1367, 1335, 1335, 1157, 1101, 1053,
954, 732, 706, 520 cm-1. HRMS (ESI+) m/z: [M-BF4]+ Calcd for
C24H28N3 358.2283; Found 358.2288.
Synthesis of iron complex Fe3: In a 100 mL Schlenk tube, equipped
with a stirring bar, under argon, cationic ligand (1.12 mmol, 1 equiv,
500 mg) and iron nonacarbonyl (2.35 mmol, 2.1 equiv, 860 mg) were
suspended in dry free-O2 toluene (20 mL). The mixture was heated at
110 °C for 18 hours. The black mixture was cooled down to room
temperature and concentrated to dryness under vacuum. The dark
Reductive amination
General Procedure A: In a 10 mL autoclave equipped with a stirring
bar, under argon, aldehyde (0.5 mmol, 1 equiv), secondary amine (0.6
mmol, 1.2 equiv), Fe3 (0.01 mmol, 2 mol %, 5.86 mg) and trimethy-
lamine N-oxide (0.015 mmol, 3 mol %, 1.2 mg) were solubilized in
free-O2 ethanol (1 mL). The autoclave was sealed and pressurized
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The Journal of Organic Chemistry
with hydrogen (5 bar), and the mixture was stirred for 16 hours at
room temperature. The reaction was extracted with dichloromethane
(10 mL) and washed with a saturated aqueous solution of NaHCO3
(10 mL), dried over MgSO4, filtrated and the solvent was removed
under vacuum. The crude product was purified by flash column
chromatography on silica.
124.8, 56.7, 56.4, 51.2, 37.3, 34.3, 31.1, 29.2, 25.8, 25.6, 19.8, 17.7
ppm.
1
2
3
4
5
6
7
8
N-Benzyl-3,7-dimethyl-6-octenylamine (6):39 According to general
procedure B, starting from (±)-citronellal (0.5 mmol, 1 equiv, 90 µL)
and N-benzylamine (0.75 mmol, 1.5 equiv, 90 µL), 6 was isolated,
after purification by silica flash column chromatography (Dichloro-
1
General Procedure B: In a 10 mL autoclave equipped with a stirring
bar, under argon, aldehyde (0.5 mmol, 1 equiv), benzylamine (0.6
mmol, 1.2 equiv), Fe3 (0.01 mmol, 2 mol %, 5.86 mg) and trimethy-
lamine N-oxide (0.015 mmol, 3 mol %, 1.2 mg) were solubilized in
free-O2 ethanol (1 mL). The autoclave was sealed and pressurized
with hydrogen (10 bar), and the mixture was stirred for 16 hours at
room temperature. The reaction was extracted with dichloromethane
(10 mL) and washed with a saturated aqueous solution of NaHCO3
(10 mL), dried over MgSO4, filtrated and solvent was removed under
vaccum. The crude product was purified by flash column chromatog-
raphy on silica.
General Procedure C: In a 10 mL autoclave equipped with a stirring
bar, under argon, aldehyde (0.5 mmol, 1 equiv), primary amine (0.6
mmol, 1.2 equiv), Fe3 (0.01 mmol, 2 mol %, 5.86 mg) were solubi-
lized in free-O2 ethanol (1 mL) and stirred at room temperature for 4h.
Then trimethylamine N-oxide (0.015 mmol, 3 mol %, 1.2 mg) and p-
toluenesulfonic acid (0.25 mmol, 50 mol %, 43 mg) were added. The
autoclave was sealed and pressurized with hydrogen (20 bar), and the
mixture was stirred for 16 hours at room temperature. The reaction
was extracted with dichloromethane (10 mL) and washed with a
saturated aqueous solution of NaHCO3 (10 mL), dried over MgSO4,
filtrated and solvent was removed under vacuum. The crude product
was purified by flash column chromatography on silica gel.
methane/MeOH 97/3), as a yellowish oil (58 mg, 47 %). H-NMR
(CDCl3, 500 MHz) δ 7.34-7.31 (m, 4H), 7.28-7.23 (m, 1H), 5.08 (tt, J
= 7.2; 1.4 Hz, 1H), 3.82-3.77 (m, 2H), 2.71-2.60 (m, 2H), 2.09-1.89
(m, 2H), 1.68 (s, 3H), 1.59 (s, 3H), 1.59-1.51 (m, 1H), 1.50-1.44 (m,
1H), 1.38-1.27 (m, 2H), 1.19-1.11 (m, 1H), 0.87 (d, J = 6.8 Hz, 3H)
ppm. 13C{1H}-NMR (CDCl3, 125 MHz) δ 140.1, 131.2, 128.4 (2C),
128.3 (2C), 127.0, 124.9, 54.0, 47.3, 37.2, 37.1, 30.6, 25.7, 25.5, 19.6,
17.7 ppm.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-(3-Phenylpropyl)morpholine (7):40 According to the general proce-
dure A, starting from 3-phenylpropionaldehyde (0.5 mmol, 1 equiv,
70 µL) and morpholine (0.6 mmol, 1.2 equiv, 55 µL), 7 was isolated,
®
after filtration with pentane over a pad of Celite , as a yellowish oil
1
(89 mg, 87 %). H-NMR (CDCl3, 500 MHz) δ 7.31-7.25 (m, 2H),
7.21-7.16 (m, 3H), 3.72 (q, J = 4.6 Hz, 4H), 2.65 (t, J = 7.7 Hz, 2H),
2.47-2.40 (br. s, 4H), 2.37 (t, J = 7.7 Hz, 2H), 1.82 (quint, J = 7.7 Hz,
2H) ppm. 13C{1H}-NMR (CDCl3, 125 MHz) δ 142.1, 128.4 (2C),
128.4 (2C), 125.8, 67.1 (2C), 58.4, 53.8 (2C), 33.7, 28.3 ppm.
1,2,3,4-tetrahydro-2-(3-phenylpropyl)-isoquinoline (8):41 According
to the general procedure A, starting from 3-phenylpropionaldehyde
(0.5 mmol, 1 equiv, 70 µL) and morpholine (0.6 mmol, 1.2 equiv, 55
µL), 8 was isolated, after purification by silica flash column chroma-
1
tography (Pentane/Et2O 9/1), as a colorless oil (120 mg, 96 %). H-
NMR (CDCl3, 500 MHz) δ 7.29-7.25 (m, 2H), 7.22-7.15 (m, 3H),
7.13-7.06 (m, 3H), 7.02-6.98 (m, 1H), 3.61 (s, 2H), 2.89 (t, J = 5.5
Hz, 2H), 2.73-2.65 (m, 4H), 2.53 (t, J = 7.5 Hz, 2H), 1.92 (quint, J =
7.5 Hz, 2H) ppm. 13C{1H}-NMR (CDCl3, 125 MHz) δ 142.3, 134.9,
134.4, 128.7 (2C), 128.5, 128.4, 126.7, 126.1, 125.9, 125.8, 125.6,
57.9, 56.2, 51.0, 33.8, 29.2, 28.9ppm.
N-Benzyl-N-3,7-trimethyloct-6-en-1-amine (3):36 According to the
general procedure A, starting from (±)-citronellal (0.5 mmol, 1 equiv,
90 µL) and N-benzylmethylamine (0.6 mmol, 1.2 equiv, 80 µL), 3
was obtained as a colorless oil after purification by silica flash column
chromatography (Pentane/EtOAc 95/5) (118 mg, 91 %). 1H-NMR
(CDCl3, 500 MHz) δ 7.29-7.17 (m, 5H), 5.04 (t, J = 7.1 Hz, 1H), 3.44
(q, J = 13.0 Hz, 1H), 2.35 (t, J = 7.6 Hz, 2H) ppm. 13C{1H}-NMR δ
139.3, 131.1, 129.1 (2C), 128.2 (2C), 126.9, 124.9, 62.4, 55.6, 42.3,
37.3, 34.4, 30.9, 25.8, 25.5, 19.7, 17.7 ppm.
4-(Cyclohexylmethyl)morpholine (9):42 According to the general
procedure A, starting from cyclohexanecarboxaldehyde (0.5 mmol, 1
equiv, 60 µL) and morpholine (0.6 mmol, 1.2 equiv, 55 µL), 9 was
®
isolated, after filtration with pentane over a pad of Celite , as a yel-
lowish oil (83 mg, 90 %). 1H-NMR (CDCl3, 500 MHz) δ 3.69 (t, J =
4.0 Hz, 4H), 2.41-2.33 (br. s, 4H), 2.11 (d, J = 7.0 Hz, 2H), 1.84-1.63
(m, 4H), 1.52-1.43 (m, 1H), 1.27-1.10 (m, 4H), 0.91-0.81 (m, 2H)
ppm. 13C{1H}-NMR (CDCl3, 125 MHz) δ 67.1 (2C), 66.2, 54.2 (2C),
34.7, 31.8 (2C), 26.8, 26.2 (2C) ppm.
Scale up for 3: In a 10 mL autoclave equipped with a stirring bar,
under argon, (±)-citronellal (5 mmol,
1 equiv, 0.9 mL), N-
benzylmethylamine (6 mmol, 1.2 equiv, 0.8 mL), Fe3 (0.1 mmol, 2
mol %, 58.6 mg) and trimethylamine oxide (0.15 mmol, 3 mol %, 12
mg) were solubilized in free-O2 ethanol (5 mL). The autoclave was
sealed and pressurized with hydrogen (5 bar), and the mixture was
stirred 18 hours at room temperature. The reaction was extracted with
dichloromethane (30 mL) and washed twice with a saturated NaHCO3
aqueous solution (2 x 20 mL), dried over MgSO4, filtrated and solvent
was removed in vacuo. The crude product was purified by silica flash
column chromatography (Pentane/EtOAc 95/5) to afford the pure
product 3 as a colorless oil (1.11 g, 86 %).
2‐({bicyclo[2.2.1]hept‐5‐en‐2‐yl}methyl)‐1,2,3,4‐tetrahydroisoquinoli
ne (10): According to general procedure A starting from (0.5 mmol,
60 µL) and 1,2,3,4-tetrahydroisoquinoline (0.6 mmol, 1.2 equiv, 76
µL), 10 was isolated, after purification by flash column chromatogra-
phy on silica gel (Pentane/Et2O: 9/1), as a mixture of two diastereoi-
somers endo and exo in a 1:1 ratio (103 mg, 87 %). Diastereoisomer 1
1H-NMR (CDCl3, 500 MHz) δ 7.14-7.07 (m, 3H), 7.04-6.99 (m, 1H),
6.14-6.10 (m, 1H), 6.09-6.05 (m, 1H), 3.64 (q, J = 14.8 Hz, 2H), 2.90
(t, J = 5.8 Hz, 2H), 2.83 (s, 1H), 2.80-2.69 (m, 3H), 2.58-2.48 (m,
2H), 1.76-1.69 (m, 1H), 1.35 (s, 2H), 1.34-1.24 (m, 2H) ppm.
13C{1H}-NMR (CDCl3, 125 MHz): δ 136.8, 136.7, 135.1, 134.5,
128.7, 126.6, 126.0, 125.5, 64.5, 56.5, 51.3, 45.3, 45.2, 41.9, 36.5,
31.9, 29.0 ppm. IR (neat): ν 3059, 2959, 2757, 2760, 1498, 1455,
1378, 1334, 1127, 1097, 936, 740, 708 cm-1. HRMS (ESI+) m/z:
[M+H]+ Calcd for C17H22N 240.1752; Found 240.1753. [α]D25= -
280.2 (C = 3.5 10-3g.mL-1 CHCl3). Diastereoisomer 2 1H-NMR
(CDCl3, 500 MHz) δ 7.14-7.07 (m, 3H), 7.04-6.98 (m, 1H), 6.17-6.11
(m, 1H), 5.99-5.95 (m, 1H), 3.62 (q, J = 11.9 Hz, 2H), 2.97-2.86 (m,
3H), 2.79-2.77 (m, 1H), 2.77-2.72 (m, 1H), 2.70-2.63 (m, 1H), 2.32-
2.25 (m, 1H), 2.19-2.13 (m, 1H), 1.89 (td, J = 10.0; 4.4 Hz, 1H), 1.42
(d, J = 8.1 Hz, 1H), 0.66-0.60 (m, 1H) ppm. 13C{1H}-NMR (CDCl3:
125 MHz) δ 137.0, 135.2, 134.5, 132.7, 128.6, 126.6, 126.0, 125.5,
63.0, 56.6, 51.1, 49.5, 45.2, 42.5, 36.6, 31.6, 29.0 ppm. IR (neat): ν
2957, 2935, 2865, 2763, 1498, 1453, 1340, 1265, 1095, 936, 739, 718
cm-1. HRMS (ESI+) m/z: [M+H]+: calcd for C17H22N 240.1752;
Found 240.1751. [α]D25 = +267.3 (C = 3.5 10-3g.mL-1 CHCl3).
Morpholino-4-(3,7-dimethyl-6-octen-1-yl) (4):37 According to the
general procedure A, starting from (±)-citronellal (0.5 mmol, 1 equiv,
90 µL) and morpholine (0.6 mmol, 1.2 equiv, 55 µL) 4 was isolated,
®
after filtration with pentane over a pad of Celite , as a yellowish oil
1
(89 mg, 79 %). H-NMR (CDCl3, 500 MHz) δ 5.02 (t, J = 7.0 Hz,
1H), 3.65 (t, J = 4.0 Hz, 4H), 2.42-2.32 (br. s, 4H), 2.32-2.22 (m, 2H),
1.98-1.83 (m, 2H), 1.61 (s, 3H), 1.53 (s, 3H), 1.50-1.42 (m, 1H), 1.40-
1.35 (m, 1H), 1.29-1.17 (m, 2H), 1.14-1.06 (m, 1H), 0.82 (d, J = 7.0
Hz, 3H) ppm. 13C{1H}-NMR (CDCl3, 125 MHz) δ 131.2, 124.9, 67.1,
57.3, 52.9, 37.2, 33.6, 31.1, 25.9, 25.8, 19.7, 17.7 ppm.
2-(3,7-dimethyloct-6-en-1-yl)-1,2,3,4-tetrahydroisoquinoline
(5):38
According to the general procedure A, starting from (±)-citronellal
(0.5 mmol, 1 equiv, 90 µL) and 1,2,3,4-tetrahydroisoquinoline (0.6
mmol, 1.2 equiv, 76 µL), 5 was isolated after purification by silica
flash column chromatography (Pentane/Et2O 9/1), as a yellowish oil
1
(111 mg, 82 %). H-NMR (CDCl3, 500 MHz) δ 7.14-7.07 (m, 3H),
7.04-6.99 (m, 1H), 5.11 (t, J = 7.5 Hz, 1H), 3.63 (s, 2H) 2.91 (t, J =
6.0 Hz, 2H), 2.76-2.70 (m, 2H), 2.57-2.47 (m, 2H), 2.07-1.93 (m,
2H), 1.69 (s, 3H), 1.68-1.62 (m, 1H), 1.61 (s, 3H), 1.56-1.47 (m, 1H),
1.46-1.16 (m, 4H), 0.92 (d, J = 7.0 Hz, 3H) ppm. 13C{1H}-NMR
(CDCl3, 125 MHz) δ 135.0, 134.4, 131.2, 128.7, 126.6, 126.1, 125.6,
Benzyl(cyclopropylmethyl)methylamine (11): According to general
procedure A starting from cyclopropane carboxaldehyde (0.5 mmol,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 17
37 µL) and N-benzylmethylamine (0.6 mmol, 1.2 equiv, 80 µL), 11
2784, 1456, 1377, 1194, 1128, 1076, 968 cm-1. HRMS (ESI+) m/z:
was isolated, after purification by flash column chromatography on
(M+H)+ Calcd for C15H32NO2 258.2433; Found 258.2434.
1
2
3
4
5
6
7
8
1
silica (Dichloromethane/MeOH 9:1), as an oil (88 mg, 99 %). H-
(2,2‐dimethoxyethyl)({[2‐(diphenylphosphanyl)phenyl]methyl})methyl
amine (17): According to general procedure A starting from 2-
(diphenylphosphino)benzaldehyde (0.5 mmol, 145 mg) and N-
methylaminoacetaldehyde dimethyl acetal (0.6 mmol, 1.2 equiv, 65
µL), 17 was isolated, after purification by flash column chromatogra-
phy on silica (Pentane/Et2O 9/1), as a white solid (136 mg, 70 %). 1H-
NMR (CDCl3, 500 MHz): δ 7.50-7.46 (m, 1H), 7.28-7.23 (m, 7H),
7.22-7.16 (m, 4H), 7.09 (t, J = 7.7 Hz, 1H), 6.85-6.81 (m, 1H), 4.22
(t, J = 5.0 Hz, 1H), 3.72 (d, J = 2.0 Hz, 2H), 3.20 (s, 6H), 2.45 (d, J =
5.0 Hz, 2H), 2.07 (s, 3H) ppm. 13C{1H}-NMR (CDCl3, 125 MHz): δ
144.0 (d, J = 22.8 Hz, 1C), 137.5 (d, J = 10.3 Hz, 2C), 136.4 (d, J =
14.9, 1C), 138.8, 133.7 (d, J = 19.7 Hz, 2C), 129.2 (d, J = 5.1 Hz,
1C), 128.6 (2C), 128.4 (2C), 128.3 (d, J = 5.1 Hz, 2C), 127.1, 103.1,
60.6 (d, J = 20 Hz, 1C), 58.1, 53.2 (2C), 42.2 ppm. 31P-NMR (CDCl3,
203 MHz): δ -15.6 ppm. IR (neat): ν 3052, 2927, 2829, 1585, 1433,
1364, 1192, 1122, 1067, 1026, 965, 743, 695, 502 cm-1. HRMS
(ESI+) m/z: [M+H]+ Calcd for C24H29NO2P 394.1936; Found
394.1937.
NMR (CDCl3, 500 MHz): δ 7.29-7.22 (m, 4H), 7.20-7.15 (m, 2H),
3.48 (s, 3H), 2.22 (s, 3H), 2.21 (d, J = 6.7 Hz, 2H), 0.90-0.81 (m,
1H), 0.48-0.42 (m, 2H), 0.03 (q, J = 4.8 Hz, 2H) ppm. 13C{1H}-NMR
(CDCl3: 125 MHz) δ 139.2, 129.1 (2C), 128.2 (2C), 126.8, 62.4, 62.3,
42.4, 8.9, 3.9 (2C) ppm. IR (neat): ν 3077, 3002, 2941, 2775, 1495,
1453, 1365, 1026, 737, 698 cm-1. HRMS (ESI+) m/z: [M+H]+: Calcd
for C12H18N 176.1439; Found 176.1440.
4-(2-thienylmethyl)-morpholine (12):43 According to the general
procedure A, starting from 2-thiophene carboxaldehyde (0.5 mmol, 1
equiv, 47 µL) and morpholine (0.6 mmol, 1.2 equiv, 55 µL), 12 was
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
®
isolated, after filtration with pentane over a pad of Celite , as a yel-
1
lowish oil (89 mg, 98 %). H-NMR (CDCl3, 500 MHz): δ 8.53-8.50
(m, 1H), 7.61 (td, J = 7.6; 1.9 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.14-
7.10 (m, 1H), 3.69 (t, J = 4.9 Hz, 4H), 3.61 (s, 2H), 2.46 (t, J = 4.9
Hz, 4H) ppm. 13C{1H}-NMR (CDCl3, 125 MHz): δ 159.6, 149.3,
136.6, 123.3, 122.2, 66.9 (2C), 64.9, 55.8 (2C) ppm.
(N,N-Benzylmethylaminomethyl)ferrocene (13): According to general
procedure A, starting from ferrocene carboxaldehyde (0.5 mmol, 1
equiv, 107 mg) and N-benzylmethylamine (0.6 mmol, 1 equiv, 90
µL), 13 was isolated, after purification by flash column chromatogra-
phy on silica (pentane/Et2O 8/2), as a yellow oil (146 mg, 92 %). 1H-
NMR (CDCl3, 500 MHz): δ 7.29-7.18 (m, 5H), 4.14 (t, J = 1.9 Hz,
2H), 4.08 (t, J = 1.9 Hz, 2H), 4.04 (s, 4H), 3.39 (s, 4H), 2.10 (s, 3H)
ppm. 13C{1H}-NMR (CDCl3, 125 MHz): δ 139.3, 129.1 (2C), 128.3
(2C), 126.9, 83.2, 70.3 (2C), 68.6 (5C), 67.9 (2C), 61.0, 56.9, 41.8
ppm. IR (neat): ν 3086, 3027, 2930, 2835, 2780, 1494, 1453, 1105,
1022, 1000, 858, 818, 734, 698, 520, 481 cm-1. HRMS (ESI+) m/z:
[M+H] Calcd for C19H21NFe 319.1023; found 319.1023.
Ethyl-(2S)‐1‐(3‐phenylpropyl)pyrrolidine‐2‐carboxylate (18): Accord-
ing to general procedure A starting from 3-phenylpropionaldehyde
(0.5 mmol, 85 mg) and (S)-proline methyl ester 5 (0.6 mmol, 1.2
equiv, 90 mg), 18 was isolated, after purification by flash column
chromatography on silica (Pentane/Et2O 8/2), as yellowish oil (95 mg,
1
73 %). H-NMR (CDCl3, 500 MHz): δ 7.29-7.25 (m, 2H), 7.19-7.15
(m, 3H), 4.23-4.12 (m, 2H), 3.22-3.17 (m, 1H), 3.13-3.09 (m, 1H),
2.75-2.98 (m, 3H), 2.45-2.39 (m, 1H), 2.32 (q, J = 8.5 Hz, 1H), 2.14-
2.07 (m, 1H), 1.96-1.88 (m, 2H), 1.87-1.77 (m, 3H), 1.24 (t, J = 7.2
Hz, 3H) ppm. 13C{1H}-NMR (CDCl3, 125 MHz): δ 174.9, 142.1,
128.4 (2C), 128.3 (2C), 125.9, 66.3, 60.6, 54.7, 53.6, 51.8, 33.7, 30.2,
23.2, 14.3 ppm. IR (neat): ν 2940, 1728, 1496, 1454, 1371, 1174,
1128, 1030, 746, 699 cm-1. HRMS (ESI+) m/z: [M+H]+ Calcd for
Methyl 4‐(benzyl(methyl)amino)methyl)benzoate (14): According to
the general procedure A, starting from methyl 4-formylbenzoate (0.5
mmol, 1 equiv, 82 mg) and N-benzylmethylamine (0.6 mmol, 1.2
equiv, 80 µL), 14 was isolated, after purification by flash column
chromatography on silica (Pentane/Et2O 8/2), as a colorless oil (127
25
C16H24NO2 262.1807; Found 262.1813. [α]D = -47.3 (C = 3.5 10-
3g.mL-1 CHCl3).
Ethyl(2S)‐1‐[2‐(diphenylphosphanyl)phenyl]pyrrolidine‐2‐carboxylat
1
mg, 95 %). H-NMR (CDCl3, 500 MHz): δ 7.91 (d, J = 8.0 Hz, 2H),
e
(19): According to general procedure A starting from 2-
7.36 (d, J = 8.0 Hz, 2H), 7.30-7.22 (m, 4H), 7.19-7.15 (m, 1H), 3.83
(s, 3H), 3.48 (s, 2H), 3.45 (s, 2H), 2.11 (s, 3H) ppm. 13C{1H}-NMR
(CDCl3, 125 MHz): δ 167.1, 145.0, 139.1, 129.6 (2C), 128.9 (2C),
128.7 (2C), 128.3 (2C), 127.1, 62.0, 61.5, 52.1, 42.4 ppm. IR (neat): ν
2819, 2840, 2787, 1719, 1616, 1453, 1434, 1274, 1191, 1173, 1108,
1099, 1018, 757, 749, 698 cm-1. HRMS (ESI+) m/z [M+H]+ Calcd for
C17H20NO2 270.1494; Found 270.1497.
4‐((benzyl(methyl)amino)methyl)‐2‐methoxyphenol (15): According to
the general procedure A, starting from vanillin (0.5 mmol, 1 equiv, 75
mg) and N-benzylmethylamine (0.6 mmol, 1.2 equiv, 80 µL), 15 was
isolated, after purification by flash column chromatography on silica
(Dichloromethane/MeOH 98/2), as a yellowish solid ( 127 mg, 99 %).
1H-NMR (CDCl3, 500 MHz): δ 7.28-7.20 (m, 4H), 7.18-7.13 (m, 1H),
6.85-6.83 (m, 1H), 6.78-6.70 (m, 2H), 6.18-5.29 (br. s, 1H), 3.79 (s,
3H), 3.42 (s, 2H), 3.38 (s, 2H), 2.09 (s, 3H) ppm. 13C{1H}-NMR
(CDCl3, 125 MHz): δ 146.6, 144.7, 139.2, 131.1, 129.1 (2C), 128.3
(2C), 127.0, 121.9, 113.9, 111.4, 61.9, 61.6, 55.9, 42.2 ppm. IR
(neat): ν 3526, 3398, 3027, 2938, 2835, 2784, 1601, 1512, 1495,
1463, 1451, 1430, 1364, 1271, 1234, 1206, 1152, 1118, 1033, 870,
816, 796, 739, 698, 568 cm-1. HRMS (ESI+) m/z: [M+H]+ Calcd for
C16H20NO2 258.1494; Found 258.1497.
(diphenylphosphino)benzaldehyde (0.5 mmol, 145 mg) and (S)-
proline methyl ester (0.6 mmol, 1.2 equiv, 90 mg), 19 was isolated,
after purification by flash column chromatography on silica (Pen-
tane/Et2O 95/5), as white solid (180 mg, 86 %). 1H-NMR (CDCl3, 500
MHz): δ 7.51-7.47 (m, 1H), 7.33-7.26 (m, 6H), 7.23-7.18 (m, 4H),
7.15 (t, J = 7.8 Hz, 1H), 6.90-6.86 (m, 1H), 4.11 (q, J =7.1 Hz, 2H),
4.02 (s, 2H), 3.35-3.30 (m, 1H), 2.84-2.78 (m, 1H), 2.42 (q, J = 7.0
Hz, 1H), 1.73-1.50 (m, 4H), 1.35-1.27 (m, 1H), 1.23 (t, J = 7.1 Hz,
3H) ppm. 13C{1H}-NMR (CDCl3, 125 MHz): δ 174.4, 144.4 (d, JC-P
=
23.8 Hz), 137.9 (d, JC-P= 13.9 Hz), 137.8 (d, JC-P= 13.9 Hz), 136.2 (d,
J
C-P= 15.3 Hz), 134.2, 133.7 (d, JC-P= 5.8 Hz, 2C), 133.5 (d, JC-P= 5.8
Hz, 2C), 129.3 (d, JC-P= 5.5 Hz), 128.7 (2C), 128.4, 128.3, 128.2,
127.2 ppm. 31P-NMR (CDCl3, 203 MHz): δ -15.8 ppm. IR (neat): ν
3053, 2977, 2833, 1729, 1586, 1434, 1177, 1144, 1027, 744, 697, 905
cm-1. HRMS (ESI+) m/z: [M+H]+ Calcd for C26H29NO2P 418.1936;
Found 418.1938. [α]D25 = + 56.7 (C = 3.5 10-3g.mL-1 CHCl3).
[(2S)‐1‐(cyclopropylmethyl)pyrrolidin‐2‐yl]methanol (20): According
to general procedure A starting from cyclopropane carboxaldehyde
(0.5 mmol, 37 µL) and L-prolinol (0.6 mmol, 1.2 equiv, 60 µL), 20
was isolated, after purification by flash column chromatography on
silica (Dichloromethane/Methanol 95/5), as a yellowish oil (67 mg, 86
1
(2,2‐dimethoxyethyl)(3,7‐dimethyloct‐6‐en‐1‐yl)methylamine
(16):
%). H-NMR (CDCl3, 500 MHz): δ 3.62 (dd, J = 10.3; 3.8 Hz, 1H),
According to the general procedure A, starting from (±)-citronellal
(0.5 mmol, 1 equiv, 90 µL) and N-methylaminoacetaldehyde dimethyl
acetal (0.6 mmol, 1.2 equiv, 65 µL), 7 was isolated, after purification
by flash column chromatography on silica (Pentane/Et2O 9/1) as a
yellowish oil (90 mg, 70 %). 1H-NMR (CDCl3, 500 MHz): δ 5.09 (t, J
= 6.8 Hz, 1H), 4.49 (t, J = 5.2 Hz, 1H), 3.36 (s, 6H), 2.55-2.47 (m,
2H), 2.47-2.37 (m, 2H), 3.07 (s, 3H), 2.01-1.95 (m, 2H), 1.68 (s, 3H),
1.60 (s, 3H), 1.56-1.47 (m, 1H), 1.45-1.39 (m, 1H), 1.36-1.23 (m,
2H), 1.19-1.11 (m, 1H), 0.89 (d, J = 6.8 Hz, 3H) ppm. 13C{1H}-NMR
(CDCl3, 125 MHz): δ 131.1, 124.8, 102.8, 58.9, 56.6, 53.3 (2C), 43.2,
37.2, 33.9, 30.9, 25.7, 19.6, 17.6 ppm. IR (neat): ν 2953, 2916, 2848,
3.38 (dd, J = 10.3; 2.6 Hz, 1H), 3.34-3.28 (m, 1H), 2.64 (dd, J = 12.5;
6.4 Hz, 1H), 2.60-2.54 (m, 1H), 2.31 (q, J = 8.5 Hz, 1H), 2.06 (dd, J
= 12.5 Hz; 7.1 Hz, 1H), 1.91-1.81 (m, 1H), 1.80-1.69 (m, 3H), 0.93-
0.84 (m, 1H), 0.57-0.43 (m, 2H), 0.16-0.06 (m, 2H) ppm. 13C{1H}-
NMR (CDCl3, 125 MHz) :δ 64.3, 61.9, 59.2, 54.7, 27.7, 23.7, 10.2,
4.7, 3.1 ppm. IR (neat): ν 3370, 3077, 2960, 2874, 2806, 1657, 1461,
1399, 1200, 1092, 1046, 1020, 829 cm-1. HRMS (ESI+) m/z: [M+H]+
Calcd for C9H18NO 156.1388; Found 156.1394. [α]D25 = + 35.1 (C =
3.5 10-3g.mL-1 CHCl3).
(-)-N-cyclopropylmethyl-1,2,3,4,5,6-hexahydro-1,5-methano-
pyrido[1,2α][1,5]diazocin-8-one (21):44 According to general proce-
dure A starting from cyclopropane carboxaldehyde (0.5 mmol, 37 µL)
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The Journal of Organic Chemistry
and cytisine (0.6 mmol, 1.2 equiv, 115 mg), 21 was isolated, after
benzylmethylamine (0.6 mmol, 1.2 equiv, 80 µL), 27 was isolated,
evaporation of the solvent and filtration with diethyl ether over a pad
of Celite , as a white solid (99 mg, 81 %). H-NMR (CDCl3, 500
after purification by flash column chromatography on silica (Di-
chloromethane/MeOH 9/1), as a yellowish oil (137 mg, 93 %). H-
1
2
3
4
5
6
7
8
1
1
®
NMR (CDCl3, 500 MHz): δ 7.90 (d, J = 7.9 Hz, 2H), 7.49 (t, J = 7.2
Hz, 1H), 7.40 (t, J = 7.9 Hz, 2H), 7.29-7.23 (m, 4H), 7.21-7.16 (m,
1H), 3.46 (s, 3H), 2.91 (t, J = 7.3 Hz, 2H), 2.36 (t, J = 7.3 Hz, 2H),
2.16 (s, 3H), 1.70 (quint, J = 7.6 Hz, 2H), 1.54 (quint, J = 7.3 Hz,
2H), 1.36 (quint, J = 7.6 Hz, 2H) ppm. 13C{1H}-NMR (CDCl3, 125
MHz): δ 200.3, 138.6, 137.0, 129.1 (2C), 128.5 (2C), 128.2 (2C),
127.9 (2C), 126.9, 62.2, 57.1, 42.0, 38.4, 27.1, 24.1 ppm. IR (neat): ν
2936, 2786, 1683, 1597, 1449, 1363, 1213, 1074, 1027, 796, 690 cm-
1. HRMS (ESI+) m/z: [M+H]+ Calcd for C20H26NO 296.2014 Found
296.2018.
MHz): δ 7.24 (dd, J = 9.1; 6.8 Hz, 1H), 6.40 (dd, J = 9.1; 1.3 Hz,
1H), 5.96 (dd, J = 6.8; 1.3 Hz, 1H), 3.87 (dd, J = 15.1; 6.6 Hz, 1H),
3.08-3.03 (m, 1H), 2.99-2.95 (m, 1H), 2.93-2.89 (m, 1H), 2.42-2.37
(m, 1H), 2.30 (dd, J = 10.7; 2.1 Hz, 1H), 2.27-2.23 (m, 1H), 2.13 (dd,
J = 12.7; 6.3 Hz, 1H), 2.08-2.02 (m, 1H), 1.86-1.82 (m, 1H), 1.75-
1.70 (m, 1H), 0.66-0.57 (m, 1H), 0.39-0.34 (m, 2H), -0.06 (qd, J =
4.9; 0.7 Hz, 2H) ppm. 13C{1H}-NMR (CDCl3, 125 MHz): δ 166.6,
151.8, 138.5, 116.4, 104.5, 62.8, 60.4, 59.8, 49.9, 35.5, 27.9, 25.9,
7.9, 3.7, 3.5 ppm.
9
(2R,2'R)‐1,1'‐bis({[2‐(diphenylphosphanyl)phenyl]methyl})‐2,2'‐bipyr
rolidine (22):45 According to general procedure A starting from 2-
(diphenylphosphino)benzaldehyde (0.34 mmol, 1.2 equiv, 100 mg)
and (2R,2′R)-2,2′-bipyrrolidine (0.14 mmol, 20mg), 22 was isolated,
after purification by flash column chromatography on silica (Di-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6‐[(2,2‐dimethoxyethyl)(methyl)amino]‐1‐phenylhexan‐1‐one
(28):
According to general procedure A starting from 42 (0.5 mmol, 95 mg)
and N-methylaminoacetaldehyde dimethyl acetal (0.6 mmol, 1.2
equiv, 65 µL), 28 was isolated, after purification by flash column
chromatography on silica (Dichloromethane/MeOH 9/1), as a color-
1
chloromethane/MeOH 99/1), as white solid (60mg, 62 %). H-NMR
1
less oil (130 mg, 89 %). H-NMR (CDCl3, 500 MHz): δ 7.93 (d, J =
(CDCl3, 500 MHz): δ 7.52-7.50 (m, 2H), 7.31-7.27 (m, 14H), 7.25-
7.19 (m, 8H), 7.10 (t, J = 7.3 Hz, 2H), 6.83-6.81 (m, 2H), 4.06 (d, J =
13.6 Hz, 2H), 3.53(dd, J = 2.2, 13.8 Hz, 2H), 2.73-2.68 (m, 4H),
1.97-1.91 (m, 2H), 1.73-1.26 (m, 8H) ppm. 31P-NMR (CDCl3, 200
MHz): δ -16.4 ppm. 13C{1H}-NMR (CDCl3, 125 MHz): δ 145.2 (d, J
= 23.2 Hz, 2C), 137.7 (d, J = 11.6 Hz, 2C), 137.0 (d, J = 10.4 Hz,
2C), 135.4 (d, J = 14.7 Hz, 2C), 133.9 (d, J = 19.9 Hz, 6C), 133.7 (d,
J = 19.3 Hz, 6C), 133.5 (2C), 128.9 (d, J = 5.7 Hz, 2C), 128.7 (2C),
128.4 (d, J = 6.7 Hz, 6C), 128.3 (d, J = 6.8 Hz, 4C), 126.7 (2C), 65.0
(2C), 57.4 (d, J = 20.5 Hz, 2C), 54.7 (2C), 25.8 (d, J = 1.7 Hz, 2C),
23.57 (2C) ppm. [α]D25 = + 44.1 (C = 3.5 10-3g.mL-1 CHCl3).
7.9 Hz, 2H), 7.53 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 4.46 (t,
J = 5.1 Hz, 1H), 3.34 (s, 6H), 2.95 (t, J = 7.3 Hz, 2H), 2.49 (d, J =
5.1, 2H), 2.39 (t, J = 7.2 Hz, 2H), 2.27 (s, 3H), 1.74 (quint, J = 7.5
Hz, 2H), 1.51 (quint, J = 7.5 Hz, 2H), 1.37 (quint, J = 7.7 Hz, 2H)
ppm. 13C{1H}-NMR (CDCl3, 125 MHz): δ 200.3, 136.9, 132.8, 128.5
(2C), 127.9 (2C), 102.7, 58.8, 58.3, 53.2 (2C), 43.2, 38.4, 27.1, 26.9,
24.1 ppm. IR (neat): ν 2935, 2830, 1683, 1448, 1368, 1125, 1065,
968, 749, 691 cm-1. HRMS (ESI+) m/z: [M+H]+ Calcd for C17H28NO3
294.2069 Found 294.2072.
6‐[(2S)‐2‐(hydroxymethyl)pyrrolidin‐1‐yl]‐1‐phenylhexan‐1‐one (29):
According to general procedure A starting from ketoaldehyde 42 (0.5
mmol, 95 mg) and L-prolinol (0.6 mmol, 1.2 equiv, 60 µL), 29 was
isolated, after purification by flash column chromatography on silica
(Dichloromethane/Methanol 95/5), as a yellowish oil (120 mg, 88 %).
1H-NMR (CDCl3, 500 MHz): δ 7.97-7.93 (m, 2H), 7.55 (t, J = 7.3 Hz,
1H), 7.46 (t, J = 7.6 Hz, 2H), 3.61 (dd, J = 10.5; 3.6 Hz, 1H), 3.37 (d,
J = 10.5 Hz, 1H), 3.18-3.13 (m, 1H), 2.97 (t, J = 7.3 Hz, 2H), 2.84
(br. s, 1H), 2.71 (dt, J = 12.0; 8.0 Hz, 1H), 2.57-2.52 (m, 1H), 2.28-
2.17 (m, 2H), 1.91-1.81 (m, 1H), 1.80-1.65 (m, 6H), 1.54 (quint, J =
6.9 Hz, 2H), 1.49-1.33 (m, 2H) ppm. 13C{1H}-NMR (CDCl3, 125
MHz): δ 200.3, 137.0, 132.9, 128.5 (2C), 128.0 (2C), 64.9, 61.7, 54.2,
54.1, 38.5, 28.8, 27.6, 27.1, 24.1, 23.6 ppm. IR (neat): ν 3357, 2936,
2863, 2801, 1682, 1597, 1580, 1448, 1358, 1225, 1203, 1044, 751,
691 cm-1. HRMS (ESI+) m/z: [M+H]+ Calcd for C17H26NO2 276.1964
Found 276.1967. [α]D25 = +27.2 (C = 3.5 10-3g.mL-1 CHCl3).
Methyl 4-(Propylaminomethyl)benzoate (23):46 According to the
general procedure C, starting from methyl 4-formylbenzoate
(0.5mmol, 1 equiv, 80 mg) and propylamine (0.6 mmol, 1.2 equiv, 49
µL), 23 was isolated, after filtration with pentane over a pad of Celite,
as yellow oil (100 mg, 96 %).1H-NMR (CDCl3, 500 MHz): δ 7.98 (d,
J = 8.3 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 3.9 (s, 3H), 3.84 (s, 2H),
2.58 (t, J = 7.1 Hz, 2H), 1.52 (sext, J = 7.3 Hz, 2H), 0.92 (t, J = 7.3
Hz, 3H) ppm. 13C{1H}-NMR (CDCl3, 125 MHz): δ 167.1, 146.0,
129.7 (2C), 128.7, 126.8 (2C), 53.7, 52.0, 51.4, 23.2, 11.8 ppm.
N-[[3,5-bis(trifluoromethyl)phenyl]methyl]propan-1-amine
(24):
According to the general procedure C, starting from 3,5-
bis(trifluoromethyl)benzaldehyde (0.5mmol, 1 equiv, 121 mg) and
propylamine (0.6 mmol, 1.2 equiv, 49 µL), 24 was isolated, after
filtration with pentane over a pad of Celite, as yellow oil (96 mg, 67
%).1H-NMR (CDCl3, 500 MHz): δ 7.81 (s, 2H), 7.75 (s, 1H), 3.91 (s,
2H), 2.60 (t, J = 7.1 Hz, 2H), 1.54 (sext., J = 7.2 Hz, 2H), 0.94 (t, J =
7.3 Hz, 3H) ppm. 13C{1H}-NMR (CDCl3, 125 MHz): δ 143.4, 131.5
(q, J = 33.2 Hz, 2C), 128.0 (dd, J = 1.1, 3.6 Hz, 2C), 124.3, 122.5,
120.9 (quint, J = 3.9 Hz, 1C), 53.0, 51.4, 23.2, 11.7 ppm. 19F-NMR
(CDCl3, 500 MHz): δ -62.8 ppm. IR (neat): ν 2964, 2936, 2879, 1623,
1461, 1376, 1275, 1168, 1123, 898, 843, 706, 682 cm-1. HRMS
(ESI+) m/z: [M+H]+ Calcd for C12H14NF6 286.1030 Found 286.1034.
N-(4-Nitrobenzyl)propylamine (25):47 According to the general pro-
cedure C, starting from 4-nitrobenzaldehyde (0.5mmol, 1 equiv, 76
mg) and propylamine (0.6 mmol, 1.2 equiv, 49 µL), 25 was isolated,
after a purification by flash column chromatography on silica
(CH2Cl2/MeOH 98/2), as yellow oil (75 mg, 77 %).1H-NMR (CDCl3,
500 MHz): δ 8.17 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.5Hz, 2H), 3.01
(s, 2H), 2.59 (t, J = 7.1 Hz, 2H), 1.54 (sext, J = 7.2 Hz, 2H), 0.92 (t, J
= 7.3 Hz, 3H) ppm. 13C{1H}-NMR (CDCl3, 125 MHz): δ 148.2,
147.0, 128.7 (2C), 123.6 (2C), 53.1, 51.4, 23.1, 11.7 ppm.
4-(N-Benzyl-N-methylaminomethyl)acetophenone (30):49
According to the general procedure A, starting from 4-
acetylbenzaldehyde (0.5 mmol,
1
equiv, 75 mg) and N-
benzylmethylamine (0.6 mmol, 1.2 equiv, 80 µL), 30 was isolated,
after purification by flash column chromatography on silica (Pen-
1
tane/Et2O 8/2), as a colorless oil (119 mg, 94 %). H-NMR (CDCl3,
500 MHz): δ 7.81 (d, J = 8.7 Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 7.29-
7.14 (m, 5H), 3.49 (s, 2H), 3.45 (s, 2H), 2.51 (s, 3H), 2.08 (s, 3H)
ppm. 13C{1H}-NMR (CDCl3, 125 MHz): δ 197.9, 145.3, 139.0, 136.1,
128.9 (2C), 128.8 (2C), 128.4 (2C), 128.3 (2C), 127.2, 62.1, 61.4,
42.4, 26.7 ppm.
1‐(4‐{[(2,2‐dimethoxyethyl)(methyl)amino]methyl}phenyl)ethan‐1‐one
(31): According to general procedure
A starting from 4-
acetylbenzaldehyde (0.5 mmol, equiv, 75 mg) and N-
1
methylaminoacetaldehyde dimethyl acetal (0.6 mmol, 1.2 equiv, 65
µL), 31 was isolated, after purification by flash column chromatogra-
1
(N-Propylaminomethyl)ferrocene (26):48 According to the general
procedure C, starting from ferrocene carboxaldehyde (0.5mmol, 1
equiv, 107mg) and propylamine (0.6 mmol, 1.2 equiv, 49 µL), 26 was
isolated, after a purification by flash column chromatography on silica
phy on silica (Pentane/Et2O 1/1), as an oil (99 mg, 79 %). H-NMR
(CDCl3, 500 MHz): δ 7.91 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 8.3 Hz,
2H), 4.51 (t, J = 5.0 Hz, 1H), 3.61 (s, 2H), 3.32 (s, 6H), 2.58 (s, 3H),
2.54 (d, J = 5.0 Hz, 2H), 2.28 (s, 3H) ppm. 13C{1H}-NMR (CDCl3,
125 MHz): δ 197.9, 136.0, 128.9 (2C), 128.5 (2C), 126.5, 102.8, 62.4,
58.5, 53.3 (2C), 43.2, 26.6 ppm. IR (neat): ν 2930, 2831, 1681, 1507,
1412, 1359, 1267, 1125, 1073, 1015, 967, 815 cm-1. HRMS (ESI+)
m/z: [M+H]+ Calcd for C14H22NO3 252.1600; found 252.1602.
1‐(4‐{[(2S)‐2‐(hydroxymethyl)pyrrolidin‐1‐yl]methyl}phenyl)ethan‐1‐
one (32): According to general procedure A starting from 4-
acetylbenzaldehyde (0.5 mmol, 1 equiv, 75 mg) and L-prolinol (0.6
1
(CH2Cl2/MeOH 98/2), as yellow powder (70 mg, 54 %). H-NMR
(CDCl3, 500 MHz): δ 4.24 (app. t, J= 1.7Hz, 2H), 4.12 (s, 7H), 3.60
(s, 2H), 2.61 (t, J = 7.3 Hz, 2H), 1.56 (sext, J = 7.2 Hz, 2H), 0.92 (t, J
= 7.3 Hz, 3H) ppm. 13C{1H}-NMR (CDCl3, 125 MHz): δ 67.0 ( 2C),
68.5 ( 6C), 68.1 ( 2C), 50.7, 48.6, 22.4, 11.7 ppm.
6‐[benzyl(methyl)amino]‐1‐phenylhexan‐1‐one (27): According to
general procedure A starting from 42 (0.5 mmol, 95 mg) and N-
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mmol, 1.2 equiv, 60 µL), 32 was isolated, after purification by flash
113.2, 59.0, 57.9, 55.8, 44.5, 41.5, 41.2, 30.1, 29.9, 26.7, 17.4 IR
column chromatography on silica (Dichloromethane/MeOH 98/2), as
an oil (117 mg, 99 %). H-NMR (CDCl3, 500 MHz): δ 7.92 (d, J =
(neat): ν 3386, 2939, 2876, 2801, 1711, 1644, 1450, 1412, 1366,
1
2
3
4
5
6
7
8
1
1163, 1063, 1037, 890 cm-1. HRMS (ESI+) m/z: [M+H]+ Calcd for
25
8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 4.08 (d, J = 13.8 Hz, 1H), 3.66
(dd, J = 10.5; 3.1 Hz, 1H), 3.44 (t, J = 13.2 Hz, 2H), 2.99-2.94 (m,
1H), 2.79-2.73 (m, 1H), 2.69-2.61 (m, 1H), 2.60 (s, 3H), 2.28 (q, J =
8.0 Hz, 1H), 1.99-1.90 (m, 1H), 1.89-1.81 (m, 1H), 1.77-1.67 (m, 2H)
ppm. 13C{1H}-NMR (CDCl3, 125 MHz): δ 197.8, 145.1, 136.1 (2C),
128.7 (2C), 128.5, 64.5, 61.8, 58.3, 54.6, 27.6, 26.6, 23.5 ppm. IR
(neat): ν 3419, 2949, 2806, 1681, 1607, 1413, 1358, 1267, 1017, 819,
732 cm-1. HRMS (ESI+) m/z: [M+H]+ Calcd for C14H20NO2 234.1494;
found 234.1500. [α]D25 = + 31.5 (C = 3.5 10-3g.mL-1 CHCl3).
C13H26NO2 228.1964; Found 228.1966. [α]D = -25.2 (C = 3.5 10-
3g.mL-1 CHCl3).
(5R)‐5‐{2‐[(2,2‐dimethoxyethyl)(methyl)amino]ethyl}‐6‐methylhept‐6‐
en‐2‐one (37): According to general procedure A starting from ke-
toaldehyde 43 (0.5 mmol, 85 mg) and N-methylaminoacetaldehyde
dimethyl acetal (0.6 mmol, 1.2 equiv, 65 µL), 37 was isolated, after
purification by flash column chromatography on silica (Dichloro-
methane/Methanol 98/2), as a colorless oil (106 mg, 78 %). 1H-NMR
(CDCl3, 500 MHz): δ 4.76 (s, 1H), 4.67 (s, 1H), 4.47 (t, J = 5.0 Hz,
1H), 3.35 (s, 6H), 2.49 (d, J = 5.0 Hz, 2H), 2.33 (q, J = 7.3 Hz, 4H),
2.28 (s, 3H), 2.10 (s, 3H), 2.05-1.98 (m, 1H), 1.70-1.61 (m, 1H), 1.56
(s, 3H), 1.55-1.47 (m, 3H) ppm. 13C{1H}-NMR (CDCl3, 125 MHz): δ
208.9, 146.2, 112.7, 102.7, 58.9, 56.6, 53.3, 44.8, 43.2, 41.5, 30.4,
30.0, 26.9, 17.5 cm-1. IR (neat): ν 2937, 2831, 1715, 1644, 1448,
1366, 1191, 1124, 1064, 968, 889 cm-1. HRMS (ESI+) m/z: [M+H]+
Calcd for C15H30NO3 272.2226 Found 272.2226 . [α]D25 = -21.2 (C =
3.5 10-3g.mL-1 CHCl3).
Scale up for 37: In a 10 mL autoclave equipped with a stirring bar,
under argon, ketoaldehyde 43 (5 mmol, 1 equiv, 0.85 mL), N-
methylaminoacetaldehyde dimethyl acetal (6 mmol, 1.2 equiv, 0.65
mL), Fe3 (0.1 mmol, 2 mol %, 58.6 mg) and trimethylamine N-oxide
(0.15 mmol, 3 mol %, 12 mg) were solubilized in free-O2 ethanol (5
mL). The autoclave was sealed and pressurized with hydrogen (5 bar),
and the mixture was stirred for 18 hours at room temperature. The
reaction was extracted with dichloromethane (30 mL) and washed
twice with a saturated NaHCO3 aqueous solution (2 x 20 mL). The
organic phases were dried over MgSO4, filtrated and the solvent was
removed in vacuum. Crude product was purified by flash column
chromatography on silica (Dichloromethane/Methanol 98/2) to afford
the pure product 37 as a colorless oil (1.2 g, 88 %).
9
(1R,9S)‐11‐[(4‐acetylphenyl)methyl]‐7,11‐diazatricyclo[7.3.1.02,7]trid
eca‐2,4‐dien‐6‐one (33) : According to general procedure A starting
from 4-acetylbenzaldehyde (0.5 mmol, 74 mg) and cytisine (0.6
mmol, 1.2 equiv 100mg), 33 was isolated, after purification by flash
column chromatography on silica (Dichloromethane/MeOH 99/1), as
yellowish oil (120mg, 74 %). 1H-NMR (CDCl3, 500 MHz): δ 7.77 (d,
J = 6.2 Hz, 2H), 7.31-7.29 (m, 1H), 7.06 (d, J = 8.0 Hz, 2H), 6.51 (d,
J = 8.8 Hz, 1H), 5.91 (d, J = 6.7 Hz, 1H), 4.13 (d, J = 15.3 Hz, 1H),
3.89 (dd, J = 6.3, 15.3, 1H), 3.52 (d, J = 14.3 Hz, 1H), 3.43 (d, J =
14.3 Hz, 1H), 2.95-2.92 (m, 2H), 2.81 (d, J = 10.5 Hz, 1H), 2.55 (s,
3H), 2.47-2.42 (m, 2H), 2.33 (d, J = 10.6 Hz, 1H), 1.95-1.91 (m, 1H),
1.83-1.79 (m, 1H) ppm. 13C{1H}-NMR (CDCl3, 125 MHz): δ 198.0,
163.7, 151.2, 143.9, 138.7, 136.1, 128.4 (2C), 128.2 (2C), 116.7,
104.8, 61.6, 60.2, 60.1, 50.0, 35.5, 28.2, 26.6, 25.9 ppm. IR (neat): ν
2937, 2792, 1678, 1648, 1606, 1585, 1546, 1358, 1266, 1140, 1102,
1060, 909, 729, 644, 582, 552, 507. HRMS (ESI+) m/z: [M+H]+
Calcd for C20H22N2O2 323.1760, found 323.1766. [α]D25 = +43.42 (C
= 3.5 10-3g.mL-1 CHCl3).
(5R)‐5‐{2‐[benzyl(methyl)amino]ethyl}‐6‐methylhept‐6‐en‐2‐one (34):
According to general procedure A starting from ketoaldehyde 42 (0.5
mmol, 85 mg) and N-benzylmethylamine (0.6 mmol, 1.2 equiv, 80
µL), 34 was isolated, after purification by flash column chromatogra-
phy on silica (Pentane/Et2O 1/1), as yellowish oil (112 mg, 89 %). 1H-
NMR (CDCl3, 500 MHz): δ 7.32-7.27 (m, 4H), 7.26-7.21 (m, 1H),
4.75-4.73 (m, 1H), 4.66-4.64 (m, 1H), 3.45 (s, 2H), 2.36-2.26 (m,
4H), 2.16 (s, 3H), 2.11 (s, 3H), 2.10-2.04 (m, 1H), 1.69-1.61 (m, 1H),
1.56 ‘s, 3H), 1.59-1.50 (m, 4H) ppm. 13C{1H}-NMR (CDCl3, 125
MHz): δ 209.1, 146.5, 129.1 (2C), 128.2 (2C), 126.9, 112.6, 62.5,
55.7, 44.9, 42.6, 41.6, 31.1, 30.4, 30.1, 26.9, 17.2 ppm. IR (neat): ν
3026, 2937, 2789, 1717, 1644, 1453, 1365, 1161, 1027, 890, 738, 699
cm-1. HRMS (ESI+) m/z: [M+H]+: calculated C18H28NO 274.2171;
Found 274.2176. [α]D25 = -5.5 (C = 3.5 10-3g.mL-1 CHCl3).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(5R)‐5‐(2‐{[(2R)‐2‐(3,4‐dihydroxyphenyl)‐2‐hydroxyethyl](methyl)ami
no}ethyl)‐6‐methylhept‐6‐en‐2‐one (38): According to general proce-
dure A starting from ketoaldehyde 43 (0.5 mmol, 80 mg) and adrena-
line (0.6 mmol, 1.2 equiv, 110 mg), 38 was isolated, after purification
by flash column chromatography on silica (Dichloromethane/MeOH
1
8/2), as an oil (110 mg, 65 %). H-NMR (CD3OD, 500 MHz): δ 6.82
(s, 2H), 6.73 (d, J = 7.6 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 4.82 (s,
1H), 4.72 (s, 1H), 4.68 (d, J = 7.1 Hz, 1H), 2.77 (t, J = 9.7 Hz, 1H),
2.68-2.57 (m, 2H), 2.57-2.49 (m, 1H), 2.48 (s, 3H), 2.44-2.35 (m,
2H), 2.10 (s, 3H), 2.11-2.03 (m, 1H), 1.69-1.51 (m, 5H), 1.61 (s, 3H)
ppm. 13C{1H}-NMR (CD3OD, 125 MHz): δ 211.9, 147.3, 146.4,
146.0, 135.3, 118.6, 116.2, 114.3, 113.7, 70.9, 65.6, 56.9, 46.0, 42.5,
30.2, 29.9, 29.6, 27.9, 17.3 ppm. IR (neat): ν 3355, 2938, 1698, 1447,
1275, 1204, 114, 1067, 887, 815, 759 cm-1. HRMS (ESI-) m/z: [M-H]-
Calcd for C19H28NO4 334.2018 Found 334.2011. [α]D25 = -15.1 (C =
3.5 10-3g.mL-1 CHCl3).
(5R)‐6‐methyl‐5‐[2‐(1,2,3,4‐tetrahydroisoquinolin‐2‐yl)ethyl]hept‐6‐e
n‐2‐one (35): According to general procedure A starting from ketoal-
dehyde 43 (0.5 mmol, 85 mg) and 1,2,3,4-tetrahydroisoquinoline (0.6
mmol, 1.2 equiv, 80 µL) 35 was isolated, after purification by flash
column chromatography on silica (Dichloromethane/Methanol 99/1),
1
(5R)‐5‐[2‐[(2S)‐2‐(hydroxymethyl)pyrrolidin‐1‐yl]ethyl]‐6‐methylhept
‐6‐en‐2‐one (39): According to general procedure A starting from
ketoaldehyde 43 (0.5 mmol, 85 mg) and L-prolinol (0.6 mmol, 1.2
equiv, 60 µL), 39 was isolated, after purification by flash column
chromatography on silica (Dichloromethane/MeOH 99/1), as yel-
as light purple oil (116 mg, 81 %). H-NMR (CDCl3, 500 MHz): δ
7.13-7.07 (m, 3H), 7.03-6.99 (m, 1H), 4.79-4.78 (m, 1H), 4.71-4.69
(m, 1H), 3.67-3.59 (m, 1H), 2.90 (t, J = 5.8 Hz, 2H), 2.73 (t, J = 5.8
Hz, 2H), 2.44 (t, J = 8.3 Hz, 2H), 2.36 (t, J = 8.3 Hz, 2H), 2.12 (s,
3H), 2.16-2.07 (m, 1H), 1.75-1.54 (m, 5H), 1.61 (s, 3H) ppm.
13C{1H}-NMR (CDCl3, 125 MHz): δ 208.1, 145.2, 133.5, 133.1,
127.6, 125.7, 125.1, 124.6, 11.8, 55.5, 55.1, 50.1, 43.9, 40.4, 29.6,
29.1, 27.9, 25.9 ppm. IR (neat): ν 2932, 2804, 1714, 1643, 1453,
1368, 1192, 1161, 1097, 890, 711 cm-1. HRMS (ESI+) m/z: [M+H]+
Calcd for C19H28NO 286.2171; Found 286.2177. [α]D25 = -7.3 (C =
3.5 10-3g.mL-1 CHCl3).
1
lowish oil (100mg, 79 %). H-NMR (CDCl3, 500 MHz): d 4.79 (s,
1H), 4.70 (d, J = 1.6 Hz, 1H), 3.59 (dd, J = 2.9, 10.6 Hz, 1H), 3.36
(d, J = 10.6, 1H), 3.21-3.15 (br. s, 1H), 2.68-2.63 (m, 1H), 2.60-2.55
(m, 1H), 2.35 (t, J = 7.5 Hz, 2H), 2.21-2.12 (m, 2H), 2.11 (s, 3H),
1.89-1.81 (m, 1H), 1.80-1.71 (m, 4H), 1.68-1.61 (m, 2H), 1.59-1.51
(m, 6H ) ppm. 13C{1H}-NMR (CDCl3, 125 MHz): d 209.0, 146.1,
113.2, 65.1, 61.8, 54.1, 52.5, 44.8, 41.5, 32.80, 30.1, 27.5, 27.1, 23.6,
17.2 ppm. IR (neat): ν 3386, 2938, 2873, 1712, 1644, 1447, 1365,
1162, 1044, 891, 539 cm-1. HRMS (ESI+) m/z: [M+H]+ Calcd for
C15H27NO2 254.2120 Found 254.2122. [a]D25 = +25.14 (C = 3.5 10-
3g.mL-1 CHCl3).
(5R)‐5‐{2‐[(2‐hydroxyethyl)(methyl)amino]ethyl}‐6‐methylhept‐6‐en‐2
‐one (36): According to general procedure A starting from ketoalde-
hyde 43 (0.5 mmol, 85 mg) and N-methylaminoethanol (0.6 mmol,
1.2 equiv, 60 µL), 36 was isolated, after purification by flash column
chromatography on silica (Dichloromethane/Methanol 9/1), as a
1
4‐(propylaminomethyl)acetophenone (40): According to the general
procedure C, starting from 4-acetylbenzaldehyde (0.5mmol, 1 equiv,
75 mg) and propylamine (0.6 mmol, 1.2 equiv, 49 µL), 40 was iso-
lated, after filtration with pentane over a pad of Celite, as yellow oil
colorless oil (100 mg, 88 %). H-NMR (CDCl3, 500 MHz): δ 4.78 (s,
1H), 4.67 (s, 1H), 3.93-3.74 (br. s, 1H), 3.63 (t, J = 4.7 Hz, 2H), 2.68-
2.58 (m, 2H), 2.49-2.38 (m, 2H), 2.37-2.31 (m, 2H), 2.34 (s, 3H),
2.10 (s, 3H), 2.08-2.03 (m, 1H), 1.71-1.62 (m, 1H), 1.57 (s, 3H), 1.59-
1.49 (m, 3H) ppm. 13C{1H}-NMR (CDCl3, 125 MHz): δ 208.8, 145.8,
1
(82 mg, 86 %). H-NMR (CDCl3, 500 MHz): δ 7.91 (d, J = 8.3 Hz,
2H), 7.41 (d, J = 8.3 Hz, 2H), 3.84 (s, 2H), 2.59-2.57 (m, 5H), 1.52
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(sext, J = 7.3 Hz, 2H), 0.91 (t, J = 7.5 Hz, 3H) ppm. 13C{1H}-NMR
(s, 3H), 1.59 (s, 3H), 1.46 (sextuplet, J = 6.6 Hz, 1H), 1.36-1.27 (m,
1H), 1.19-1.10 (m, 1H), 0.87 (d, J = 6.6 Hz, 3H) ppm. 13C{1H}-NMR
(CDCl3, 125 MHz): δ 139.3, 131.1, 129.1 (2C), 128.1 (2C), 126.8,
124.9, 62.4, 55.2 (t, J = 20 Hz, 1C), 42.2, 37.2, 34.1-33.5 (m, 1C),
30.8, 25.7, 25.5, 19.7, 17.6 ppm. HRMS (ESI+) m/z: [M+H]+ Cacld
for C18H26D3N 263.2567; found 263.2565.
(CDCl3, 125 MHz): δ 197.9, 146.3, 135.9, 128.5 (2C), 128.1 (2C),
53.6, 51.4, 26.7, 23.2, 11.8 ppm. IR (neat): ν 3345, 2958, 2930, 2873,
2814, 1678, 1607, 1357, 1265, 1122, 1017, 955, 816, 597 cm-1.
HRMS (ESI+) m/z: [M+H]+ Calcd for C12H18NO 192.1388 Found
192.1383.
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4
5
6
7
8
9
1‐{4‐[(4‐benzylpiperazin‐1‐yl)methyl]phenyl}ethan‐1‐one (41): Ac-
cording to general procedure A starting from 4-acetylbenzaldehyde
(0.5 mmol, 1 equiv., 75 mg) and benzylpiperazine (0.6 mmol, 1.2
equiv., 105 µL), 41 was isolated, after purification by silica flash
column chromatography (Dichloromethane/MeOH 98:2), as a yellow
6‐[benzyl(methyl)amino]‐1‐phenylhexan‐1‐one (27-D): In a 10mL
autoclave equipped with a stirring bar, under argon ketoaldehyde 41
(0.5 mmol, 95 mg) and N-benzylmethylamine (0.6 mmol, 1.2 equiv,
80 µL), Fe3 (0.01 mmol, 2 mol%, 5.86 mg) and trimethylamine N-
oxide (0.015 mmol, 3 mol%, 1.2 mg) were solubilized in free-O2
deuterated methanol (CD3OD; 1 mL). The autoclave was sealed and
pressurized with hydrogen (5 bar), and the mixture was stirred for 16
hours at room temperature. The reaction mixture was extracted with
dichloromethane (10 mL) and washed with a saturated aqueous solu-
tion of NaHCO3 (10 mL), dried over MgSO4, filtrated and concen-
trated under vacuum. The pure product was isolated after purification
by flash column chromatography on silica (Dichloromethane/MeOH
9/1) as a yellowish oil (110 mg, 75 %). 1H-NMR (CDCl3, 500 MHz):
δ 7.88 (d, J = 7.9 Hz, 2H), 7.49 (tt, J = 7.2, 1.4 Hz, 1H), 7.39 (t, J =
7.9 Hz, 2H), 7.26-7.23 (m, 4H), 7.20-7.18 (m, 1H), 3.46 (s, 3H), 2.90
(t, J = 7.3 Hz, 0.5 H), 2.87 (tt, J = 7.0, 2.0 Hz, CDH), 2.35 (s, 2H),
2.16 (s, 3H), 1.70-1.66 (m, 2H), 1.50 (m, 0.3H), 1.36-132 (m, 2H)
ppm. 13C{1H}-NMR (CDCl3, 125 MHz): δ 200.6, 200.5, 200.4, 137,
133, 129.2, 128.6, 128.3, 128.0, 127.2, 62.2, 57.0, 42.1, 38.5, 38.2 (t,
J = 19.2 Hz), 37.8 (quint, J = 18.4 Hz), 27.0-26.9 (m), 26.7 (t, J =
19.6 Hz), 26.3 (quint, J = 18.6 Hz), 24.2-24.1 (m) ppm. IR (neat): ν
3061, 3027, 2932, 2839, 2784, 1682, 1448, 1267, 1025, 736, 690 cm-
1. HRMS (ESI+) m/z: [M+H]+ Calcd for C20H25DNO 297.2077 Found
297.2073, C20H24D2NO calculated 298.2140 Found 298.2134,
C20H23D3NO calculated 299.2203 Found 299.2193, C20H22D4NO
calculated 300.2265 Found 300.2248.
1
solid (92 mg, 60 %). H-NMR (CDCl3, 500 MHz) δ 7.90 (d, J = 8.3
Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H), 7.31-7.28 (m, 5H), 3.55 (s, 2H),
3.52 (s, 2H), 2.58 (s, 3H), 2.56 – 2.41 (br. s, 8H) ppm. 13C{1H}-NMR
(CDCl3, 125 MHz) δ 197.9, 136.1, 129.26 (2C), 129.2 (2C), 128.4
(2C), 128.2 (2C), 127.1, 126.7, 63.1, 62.6, 53.2, 53.0 (2C), 26.7 (2C)
ppm. IR (neat) ν 3064, 3029, 3005, 2948, 2908, 2797, 2762, 1678,
1605, 1267, 1160, 1129, 1010, 836, 727, 696, 591 cm-1. HRMS
(ESI+) m/z: [M+H]+ Calcd for C20H25N2O 309.1967; Found 309.1971.
Deuterium Labeling:
Benzyl[3,7‐dimethyl(2‐deuterium)oct‐6‐en‐1‐yl]methylamine (3-D2):
In a 10 mL autoclave equipped with a stirring bar, under argon, (±)-
citronellal (0.5 mmol, 1 equiv, 90 µL), N-benzylmethylamine (0.6
mmol, 1.2 equiv, 80 µL), Fe3 (0.01 mmol, 2 mol %, 5.86 mg) and
trimethylamine N-oxide (0.015 mmol, 3 mol %, 1.2 mg) were solubi-
lized in free-O2 deuterated methanol (CD3OD; 1 mL). The autoclave
was sealed and pressurized with hydrogen (5 bar), and the mixture
was stirred for 16 hours at room temperature. The solvent was re-
moved under vacuum and the crude product was purified by flash
column chromatography on silica (Penatne/Et2O 9/1). 3-D2 was ob-
tained as a colorless oil (105 mg, 81 %). 1H-NMR (CDCl3, 500 MHz):
δ 7.32-7.29 (m, 4H), 7.26-7.21 (m, 1H), 5.09 (tt, J = 7.1; 1.3 Hz, 1H),
3.52-3.46 (q, J = 12.0 Hz, 2H), 2.39-2.35 (m, 2H), 2.17 (s, 3H), 2.04-
1.89 (m, 2H), 1.67 (s, 3H), 1.59 (s, 3H), 1.46 (sextuplet, J = 6.6 Hz,
1H), 1.36-1.27 (m, 1H), 1.19-1.10 (m, 1H), 0.87 (d, J = 6.6 Hz, 3H)
ppm. 13C{1H}-NMR (CDCl3, 125 MHz): δ 139.3, 131.1, 129.1 (2C),
128.1 (2C), 126.8, 124.9, 62.4, 55.4, 42.3, 37.2, 34.1-33.5 (m, 1C),
30.7, 25.7, 25.5, 19.7, 17.6 ppm. HRMS (ESI+) m/z: [M+H]+ Calcd
for C18H28D2N 262.2504 ; found 262.2502.
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28
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Spectroscopic details of the catalytic reactions; DFT calcu-
lations
Data for C27H28BF4N3O3Fe (CIF) - CCDC: 1857379
Benzyl[3,7‐dimethyl(1‐deuterium)oct‐6‐en‐1‐yl]methylamine (3-D1):
In a 10 mL autoclave equipped with a stirring bar, under argon, (±)-
citronellal (0.5 mmol, 1 equiv, 90 µL), N-benzylmethylamine (0.6
mmol, 1.2 equiv, 80 µL), Fe3 (0.01 mmol, 2 mol %, 5.86 mg) and
trimethylamine N-oxide (0.015 mmol, 3 mol %, 1.2 mg) were solubi-
lized in free-O2 methanol (1 mL). The autoclave was sealed and
pressurized with deuterium (5 bar), and the mixture was stirred for 16
hours at room temperature. The solvent was removed under vacuum
and the crude product was purified by flash column chromatography
on silica (Penatne/Et2O 9/1). 3-D1 was obtained as a colorless oil (121
AUTHOR INFORMATION
Corresponding Author
* E-mail: jean-luc.renaud@ensicaen.fr.
* E-mail: albert.poater@udg.edu
Present Addresses
1
mg, 93 %). H-NMR (CDCl3, 500 MHz): δ 7.32-7.29 (m, 4H), 7.26-
†If an author’s address is different than the one given in the af-
filiation line, this information may be included here.
7.21 (m, 1H), 5.09 (tt, J = 7.1; 1.3 Hz, 1H), 3.52-3.42 (m, 2H), 2.37-
2.31 (m, 1H), 2.17 (s, 3H), 2.04-1.89 (m, 2H), 1.67 (s, 3H), 1.59 (s,
3H), 1.58-1.52 (m, 1H), 1.46 (sextuplet, J = 6.6 Hz, 1H), 1.36-1.27
(m, 2H), 1.19-1.10 (m, 1H), 0.87 (d, J = 6.6 Hz, 3H) ppm. 13C{1H}-
NMR (CDCl3, 125 MHz): δ 139.3, 131.1, 129.1 (2C), 128.1 (2C),
126.8, 124.9, 62.4, 55.2 (t, J = 20 Hz, 1C), 42.2, 37.2, 34.3, 30.8,
25.7, 25.5, 19.7, 17.6 ppm. HRMS (ESI+) m/z: [M+H]+ Calcd for
C18H28DN 261.2441; found 261.2444.
Author Contributions
All authors have given approval to the final version of the manu-
script.
ORCID
Jean-Luc Renaud: 0000-0001-8757-9622
Albert Poater: 0000-0002-8997-2599
Sylvain Gaillard: 0000-0003-3402-2518
Alexis Lator: 0000-0002-6992-5795
Benzyl[3,7‐dimethyl(1,2,2‐deuterium)oct‐6‐en‐1‐yl]methylamine (3-
D3): In a 10 mL autoclave equipped with a stirring bar, under argon,
(±)-citronellal (0.5 mmol, 1 equiv, 90 µL), N-benzylmethylamine (0.6
mmol, 1.2 equiv, 80 µL), Fe3 (0.01 mmol, 2 mol %, 5.86 mg) and
trimethylamine N-oxide (0.015 mmol, 3 mol %, 1.2 mg) were solubi-
lized in free-O2 deuterated methanol (CD3OD; 1 mL). The autoclave
was sealed and pressurized with deuterium (5 bar), and the mixture
was stirred for 16 hours at room temperature. Solvent was removed
under vacuum and the crude product was purified by flash column
chromatography on silica (Penatne/Et2O 9/1). 3-D3 was obtained as a
Quentin Gaignard Gaillard: 0000-0002-9424-1264
ACKNOWLEDGMENT
We gratefully acknowledge financial support from the "Ministère
de la Recherche et des Nouvelles Technologies" (for a grant for
D. S. M.), Normandie Université, CNRS, Region Normandie (for
a PhD grant for Q. G. G.) and the LABEX SynOrg (ANR-11-
LABX-0029, PhD grant for A. L.). A. P. thanks the Spanish
1
colorless oil (107 mg, 82 %). H-NMR (CDCl3, 500 MHz): δ 7.32-
7.29 (m, 4H), 7.26-7.21 (m, 1H), 5.09 (tt, J = 7.1; 1.3 Hz, 1H), 3.52-
3.42 (m, 2H), 2.37-2.31 (m, 1H), 2.17 (s, 3H), 2.04-1.89 (m, 2H), 1.67
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Page 14 of 17
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Alkylation: Rapid Access to α-Methylated Substituted Ketones. Org.
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Propyl)-Aminomethyl Ferrocene,
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1
Table Of Content
2
3
4
H2
5
6
7
8
[BF4]
[BF4]
H
H
iPr
H
iPr
iPr
Ph
Ph
Ph
N
N
N
N
N
N
N
Ph
Ph
Ph
N
N
H
Fe
Fe
Fe
H
OC
OC
OC
CO
CO
CO
H
R'
9
H
H2
N
H
FG
N
N
FG
R'
R'
H
FG
FG
FG
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[BF4]
O
yield = 47-99 %
room temperature,
EtOH
FG
FG
unprotected ketones, free phosphine, Aliphatic, aromatic, heteroaromatic,
acetal, free alcohol, chiral secondary amine, Aliphatic, benzylic, heterocycle,
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