Iron-Catalyzed Reductive Ethylation of Imines with Ethanol

Article abstract of DOI:10.1002/anie.201800328

The borrowing hydrogen strategy has been applied to the ethylation of imines with an air-stable iron complex as precatalyst. This approach opens new perspectives in this area as it enables the synthesis of unsymmetric tertiary amines from readily available substrates and ethanol as a C₂ building block. A variety of imines bearing electron-rich aryl or alkyl groups at the nitrogen atom could be efficiently reductively alkylated without the need for molecular hydrogen. The mechanism of this reaction, which shows complete selectivity for ethanol over other alcohols, has been studied experimentally and by means of DFT computations.

Full text of DOI:10.1002/anie.201800328

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Accepted Article
Title: Iron-Catalyzed Reductive Ethylation of Imines Using Ethanol
Authors: Marie Vayer, Sara Patricia Morcillo, Jennifer Dupont, Vincent
Gandon, and Christophe Bour
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201800328
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10.1002/anie.201800328
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COMMUNICATION
Iron-Catalyzed Reductive Ethylation of Imines Using Ethanol
Marie Vayer,[a] Sara P. Morcillo,[a] Jennifer Dupont,[a] Vincent Gandon*[a,b] and Christophe Bour*[a]
been recognized as one of the most practical methods to
substitute amines by alkyl groups.[1] The broad availability of
amines and alcohols, combined with the fact that water is the
only by-product, are the reasons for its large-scale
implementation in the industry. It was first reported with simple
2nd and 3rd row late transition metal complexes, which were
rapidly followed by more elaborated well-defined species (Ru,[8]
Rh,[9] Ir,[10] or Os[11]). The current trend is to replace these noble
elements by more abundant 1st row transition metals. In that
respect, significant improvements have been made by using
Mn ,[12] Fe-[13] and Co-based catalysts.[14]
Abstract: The borrowing hydrogen strategy has been applied to the
ethylation of imines, using an air-stable iron complex as precatalyst.
This approach opens new perspectives in this area, as it allows the
synthesis of unsymmetric tertiary amines from readily available
substrates and ethanol as C2-building block. A variety of imines
bearing electron-rich aromatic or alkyl groups at the nitrogen atom
could be efficiently reductively alkylated, without requiring the use of
molecular hydrogen. The mechanism of this reaction, which shows a
complete selectivity for ethanol, has been studied experimentally
and by means of DFT computations.
R1
R2
R1
R2
M cat.
OH
+
H2N R3
NHR3 + H2O
MH2
+
Tertiary amines have
a wide range of applications as
pharmaceuticals and in material science.[1] Among them, some
mono ethyl amines show prominent biological properties and are
exploited as drugs and crop protecting agents. This framework
can be found in a variety of compounds, such as non-steroidal
drugs for breast cancer treatment,[2] novel anti-HCV agents,[3] or
synthetic plant growth regulators (Figure 1). These tertiary N-
ethyl amines are also frequently encountered in molecular
thermal-transfer dyes,[4] or in pigments.[5]
M
R1
R2
R1
R2
MH2
O
NR3
+ H2O
Scheme 1. Metal-catalyzed amination of alcohols.
Despite these advances, access to tertiary amines is mainly
limited to products bearing two or three identical substituents
(see Scheme 2a in the case of ethyl groups). Using two different
alcohols usually leads to mixtures, as shown in Scheme 2b.[13d]
In 2015, Shi et al reported an alcohol amination strategy for
providing unsymmetric tertiary amines from primary amines via
the use of aluminum oxide catalysts doped with copper.[ 15 ]
Despite its flexibility, this approach requires harsh conditions
and high catalyst loadings. A few unsymmetric tertiary amines
have been synthesized by direct amination of readily oxidizable
benzyl alcohols using secondary amines.[13d] Given the above
considerations, methodologies allowing practical synthesis of
unsymmetric tertiary amines remain highly desirable. Herein, we
report an efficient and straightforward reductive ethylation of
imines using ethanol as C2 building block and an iron complex
as catalyst (Scheme 2c).[16] An example of one-pot sequential 3-
component reaction where the imine is generated in situ is also
provided.
MeO
NH
O
Pharmaceuticals or crop proctection agents
Cl
NO2
N
N
O2N
flumetralin
F
CF3
O2N
elacestrant
HCV protease inhibitor
Material Science
N
-
SO3
2Na+
N
N
S
N
+
NH
N
N
NC
O
MSA5480
thermal transfer dye
Brilliant BLUE FCF
food colorant (E133)
-
-
SO3
SO3
R2
R2
metal-based catalysts:
N
H2N
Figure 1. Selected biologically active compounds or molecular materials
featuring N-ethyl unsymmetric tertiary amine.
Ru Beller, Williams, Milstein
previous work
or
Grützmacher
Yamaguchi, Kempe, Martin-Matute
Feringa, Barta, Wills, Zhao
Rh
Ir
or
+
OH
OH
N
NH3
a)
Fe
Classical methods for amine ethylation rely on the use of toxic
reagents such as acetaldehyde, ethyl halides or their
equivalents (diethylsulfate or sulfonate).[6] Among the alternative
strategies, one could think about the direct amination of alcohols
through borrowing hydrogen catalysis (Scheme 1),[7] which has
Mn Milstein, Kirchner, Beller
via hydrogen borrowing
Co
Kempe, Zeng, Milstein
strategy
R2
H2N
R2
+
R2 R2
+
N
N
R3
N
+
b)
c)
R3 OH
R3
R3
this work
R2
Umpolung ethylation of imines*
R2
N
N
[a]
[b]
M. Vayer, Dr. S. P. Morcillo, J. Dupont, Prof. V. Gandon, Dr. C. Bour
ICMMO, CNRS UMR 8182, Univ Paris-Sud, Université Paris-Saclay,
Bât. 420, 91405 Orsay cedex, France.
E-mail: vincent.gandon@u-psud.fr; christophe.bour@u-psud.fr
Prof. V. Gandon, Laboratoire de Chimie Moléculaire, CNRS UMR
9168, Ecole Polytechnique, Université Paris-Saclay, route de
Saclay, 91128 Palaiseau cedex, France.
+
access to unsym-
metric tertiary amines
OH
R3
Fe cat.
R3
R2
R3
H2N
+
O
* or one-pot sequential 3-component reaction
Scheme 2. N-Ethyl tertiary amine synthesis via the hydrogen borrowing
strategy.
Supporting information for this article is given via a link at the end of
the document.
More specifically, we were attracted by (cyclopentadienone)iron
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10.1002/anie.201800328
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COMMUNICATION
carbonyl complexes,[17] which have been used as catalysts for
imines[ 18 ] or ketones hydrogenation,[ 19 ] as well as alcohol
oxidation,[20] via the borrowing hydrogen mechanism. We found
that the right combination of an iron carbonyl precatalyst and
ethanol allowed the title reaction. To the best of our knowledge,
no reports mention this type of Umpolung catalytic imine
alkylation reaction.[21] Moreover, this method is complimentary to
the amine methylation procedure with CO2,[22] since ethanol can
be produced sustainably.[23] After evaluation of different reaction
parameters (see Tables S1-3 in the Supporting Information), we
found that imine 1a could be fully converted into ethyl amine 3a
in 99% yield in the presence of the Knölker-type iron complex A
as precatalyst (5 mol%),[24] Me3NO as activator (5 mol%)[19a] in
EtOH (0.2 M) at 110 °C in 24 h (Table 1, entry 1).
whatever the precatalyst used, the alkylation was not oberved
with other primary alcohols which mostly led to the
hydrogenation product 2a (entry 11, see Table S4 for details).[18f]
The complete selectivity for EtOH in this alkylative process
raised questions regarding its mechanism. A tentative one is
shown in Scheme 3. The reaction to form 3a starts with the
coordination of EtOH to iron to give complex X and then
concerted oxidation of EtOH generates the Fe(II) hydride Y and
acetaldehyde.[19a-b] Hydrogen transfer from Y to imine 1a leads
to amine 2a, while regenerating the unsaturated Fe(0) complex
X. Amine 2a then reacts with acetaldehyde to give hemiaminal
4a[27] and then enamine 4a’. Hydrogen transfer from Y to 4a’
delivers the final product 3a. Apart from the last one, all steps
are presumably equilibrated.
Table 1. Catalyst screening and optimization for the N-ethylation of imine 1a
H
Ar
H
Ar
Ar
N
H
N
OH
Ar
3a
OMe
OMe
OMe
2a
H
A (5 mol%)
H
TBDMS
O
TBDMS
O
Me3NO (5 mol%)
+
TsN
TsN
N
N
N
H
EtOH
TBDMS
OH
TBDMS
OH
Fe
Fe
MeO
110 °C, 24 h MeO
MeO
CO
CO
1a
2a
3a
CO
CO
X
X
H
H
Deviation from above
conditions[a]
Ratio [%][b]
(1a/2a/3a)
Entry
TBDMS
O
TBDMS
O
TsN
TsN
H
H
TBDMS
TBDMS
1
2
3
4
5
none
0/0/100 (97)[c]
Fe
Fe
H
H
Y
Y
CO
CO
with 1 mol% of A instead of 5 mol%
K2CO3 instead of Me3NO
91/9/-
CO
CO
Ar
Ar
N
1a
HO
H
100/-/-
Ar
N
+
+ H2O
Ar
N
O
Ar
Ar
4a’
THF/EtOH (1/1 v/v, 0.2 M) instead of EtOH
THF/EtOH (0.2 M/3 equiv) instead of EtOH
5/23/72
27/65/8
H
4a
H
Scheme 3. Mechanistic proposal (Ar = 4-MeOC6H4).
CPME/EtOH (0.2 M/3 equiv) instead of
EtOH
6
20/80/0
This rationale is supported by previous contributions,[7,18] and by
the following experiments. The reaction progress was monitored
by GC (see Figure S1), which revealed that 2a is the precursor
of 3a. However, when the reaction was carried out with amine
2a as starting material, only traces of 3a were formed (Scheme
4a).
7
8
9
precatalyst B instead of A
precatalyst C instead of A
precatalyst D instead of A
38/28/34
43/52/5
100/0/0
precatalyst
Me3NO
E instead of A and without
10
11
0/0/100 (99)
other alcohols instead of EtOH
mostly 2a
[a] Standard conditions: in a sealed tube, imine 1a (0.2 M), iron complex A (5
mol%), Me3NO (5 mol%) in EtOH at 110 °C for 24 h. [b] Determined by GC. [c]
Isolated yield.
Remarkably, the hydrogenation product 2a was not observed.
Decreasing the catalyst loading to 1 mol%, or treating A with
K2CO3 instead of Me3NO inhibited the reaction (entries 2 and 3).
Adding THF or CPME in the reaction mixture strongly
encouraged the formation of 2a (entries 4-6).[25] Precatalysts B-
D proved poorly efficient (entries 7-9). Gratifyingly, when the air-
stable iron-dicarbonyl-nitrile complexes E was used,[18b,26 ] 3a
was isolated in 99% yield, without activation with Me3NO (entry
10). As noted previously, the TBDMS groups can enhance the
reactivity by preventing iron dimers formation.[19b, 20c] Importantly,
Scheme 4. Mechanistic investigations (Ar = 4-MeOC6H4).
A low amount of imine 1a was also detected, indicating the
reversibility of the process. Interestingly, after adding a catalytic
amount of acetaldehyde or imine 1a, full conversion into 3a was
reached (Scheme 4b). This result clearly reveals the
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10.1002/anie.201800328
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COMMUNICATION
E (5 mol%)[a]
interdependence of the two catalytic cycles and that
acetaldehyde is a likely intermediate. When Et3SiH was used as
competitive reducing agent, only the hydrogenation product 2a
was observed, thus confirming that ethanol is both the hydrogen
transfer and the alkylating agent (Scheme 4c).[28] Using C2D5OD,
only a low amount of hydrogenated imine was isolated. The
formation of the Fe(II) complex seems to be severely slowed
down,[19a] as well as the capture of acetaldehyde-d4 and the
reduction of the corresponding adducts. On the other hand,
using EtOD led to 3a-d3 as major product, showing complete
deuterium incorporation at the β-ethyl position (Scheme 4d).
This suggests that the produced acetaldehyde undergoes rapid
H/D exchange[29] in C2H5OD to become D3CCHO prior to be
trapped by 2a. Thus, the combination of a rapid trapping of the
formed aldehyde (which rules out larger alcohols)[30] and of the
reduction of resulting enamine (which rules out MeOH), might be
at the origin of the complete selectivity for EtOH.[31] We decided
to investigate the ability of a complex such as Y to transfer its
two hydrogen atoms to a model enamine by DFT computations
(Figure 2, see the Supporting Information for details). The
hydrogenation was predicted as straightforward, requiring only
8.0 kcal/mol of free energy of activation. It is moderately
exergonic, but the dissociation of the complex and its reoxidation
should ensure an overall irreversibility. Of note, with an
additional methyl group at the double bond terminus, the
hydrogenation is slower but still very reasonable in energy
(ΔG‡298 10.1 kcal/mol). Thus, it is not only this step that would
account for the absence of alkylation when n-PrOH is used, but
also the rate of the trapping of propanal and that of the formation
of the enamine.
Ar
Ar
R
N
R
N
EtOH, 110 °C, 24 h
1
3
OMe
OMe
OMe
R
O
O
N
N
N
3k 71% (70%)
3l 78%
3b (R= H), 68%
3c (R= p-Me), 55%
R
R2
3d (R= p-SMe), 85%
3e (R= p-Cl), 74%
3f (R= p-Br), 68%
3g (R= p-F), 44%[b]
3h (R= o-OMe) 55%
3i (R= m-OMe) 78%
R1
N
N
MeO
3m (R= H), 30%
3n (R= p-Me), 88% 3q (R1= p-Me, R2= p-Me), 78%
3o (R= p-I), 21%
3p (R1= H, R2= H), 30%
3j (R= o-Me, p-Me), 70%
OMe
OMe
OMe
Ph
N
N
N
3r, 67%
3s, 48%
3t, 54%
Scheme 5. Reductive N-ethylation of aromatic imines with ethanol. [a]
Reaction conditions: in a sealed tube, imine (0.1-0.2 mmol, 0.2 M), E (5 mol%)
in EtOH, 110 °C, 24 h. Yields of isolated products are given. [b] At 130 °C.
E (5 mol%)[a]
R’
R’
R
N
R
N
EtOH, 110 °C, 24 h
6
5
R
R
N
N
N
MeO
6a (R= H), 57%
6h (R= n-Pr), 85%
6i (R= n-Bu), 85%
6j (R= C5H9), 75%
6k (R = CH2Cy), 51%
MeO
6b (R= p-OMe), 85%
6c (R= p-Me), 38%
6d (R= p-Br), 88%
6e (R= o-Br), 72%
6f (R= p-CF3), 55%
8.0
6l, 47%
N
n
N
6g (R= p-CO2Me), 76%
O
0.0
TBDMS
MeO
MeO
-1.8
6m (n = 1), 71%
6n (n = 2), 53%
6o, 80%
TsN
O
TBDMS
O
H
TsN
TBDMS
Fe
H
TBDMS
H
H
CO
Fe
Scheme 6. Reductive N-ethylation of alkyl imines with ethanol. [a] Reaction
conditions: in a sealed tube, imine (0.1-0.2 mmol, 0.2 M), E (5 mol%) in EtOH,
110 °C, 24 h. Yields of isolated products are given.
CO
CO
CO
N
Y·enamine
N
X·amine
Ph
Ph
A multi-component approach where the imine is generated in
situ was also briefly investigated (Scheme 7). A mixture of p-
anisaldehyde and p-anisidine was converted into the desired
product 3a, accompanied in equal amount by the diethylation
product 7. Since this product results from the ethylation of the
starting aniline, we decided to wait for the imine to be formed
prior to adding the iron catalyst. Although the imine formation
proved to be complete within 1 h, the presence of water in the
reaction medium disrupted the equilibria and the diethylation
product 7 was again observed by GC analysis. The hydrolysis of
the imine is probably encouraged by the fast ethylation of the
resulting primary amine and of the subsequent secondary
one.[33] Nevertheless, the desired product could be isolated in
65% yield, showing the feasibility of a one-pot process.
Figure 2. Computed transition state for the hydrogenation of a model enamine
(left, some hydrogen atoms have been ommited for clarity, distances in Å) and
corresponding free energy profile (right, ΔG298, kcal/mol).
To demonstrate the effectiveness of this novel catalytic
ethylation, various aromatic imines were tested (Scheme 5).
Yields are mostly good to high, provided the aromatic group at
the nitrogen atom is electron-rich. Interestingly, while iron
hydrides are known to promote the isomerization of alkenes, no
C=C bond migration was observed with 1r-t.[16a] We next
explored the applicability of the reductive N-ethylation reaction
with a series of alkyl imines (Scheme 6). Such substrates proved
also compatible with the title reaction and provided the desired
unsymmetric tertiary amines with high chemoselectivity. Imines
exhibiting short chains (C3, C4) or cycloalkanes at the nitrogen
were also successfully ethylated to give unsymmetric tertiary
benzylamines, which are of major interest to the industry of
surfactants, flotation agents, gasoline detergents, rubber
processing additives, etc.[ 32 ] The fact that electron-rich aryl
imines (Scheme 5) and alkyl imines (Scheme 6) work well in this
chemistry is consistent with the proposed trapping of
acetaldehyde (Scheme 3), which requires the most nucleophilic
amines to displace the equilibrium.
NH2
OMe
OMe
O
E (5 mol%)
+
N
+
N
EtOH
MeO
MeO
OMe
110 °C, 24 h
3a, 42%[a]
68%[b] (65%)[c]
7, 41%[a]
32%[b]
Scheme 7. One-pot synthesis of an unsymmetric tertiary amine. [a] Reaction
conditions: aldehyde (0.37 mmol), amine (0.40 mmol), E (5 mol%) in EtOH
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10.1002/anie.201800328
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COMMUNICATION
(2 mL) at 110 °C, 24 h. GC conversion. [b] Same as [a] but E is added after 1
h of stiring at 110 °C. GC conversion [c] Isolated yield.
Rawlings, L. J. Diorazio, M. Wills, Org. Lett. 2015, 17, 1086; c) H.-J.
Pan, T. W. Ng, Y. Zhao, Chem. Commun. 2015, 51, 11907; d) T. Yan,
B. L. Feringa, K. Barta, ACS Catal. 2015, 6, 381; e) T. J. Brown, M.
Cumbes, L. J. Diorazio, G. J. Clarkson, M. Wills, J. Org. Chem. 2017,
82, 10489; f) T. Yan, B. L. Feringa, K. Barta, Sci. Adv. 2017, 3, DOI
10.1126/sciadv.aao6494.
In conclusion, we have disclosed a general catalytic approach
for the reductive ethylation of imines, using ethanol as a
sustainable C2 building block. This transformation proceeds with
good chemoselectivity with an air-stable iron complex as
precatalyst. This straightforward method eases the synthesis of
unsymmetric ethylated tertiary amines and is complemetary to
the aforementioned methylation procedure.[22]
[14] For selected examples of Co-catalyzed amination of alcohols, see: a) S.
Rösler, M. Ertl, T. Irrgang, R. Kempe, Angew. Chem. Int. Ed. 2015, 54,
15046; b) G. Zhang, Z. Yin, S. Zheng, Org. Lett. 2016, 18, 300; c) P.
Daw, Y. Ben-David, D. Milstein, ACS Catal. 2017, 7, 7456.
[15] S. Pang, Y. Deng, F. Shi, Chem. Commun. 2015, 51, 9471.
[16] For general reviews on iron-catalysis, see: a) C. Bolm, J. Legros, J. Le
Paih, L. Zani, Chem. Rev. 2004, 104, 6217; b) K. Junge, K. Schröder,
M. Beller, Chem. Commun. 2011, 47, 4849.
Acknowledgements
[17] For a review on their catalytic activity, see: A. Quintard, J. Rodriguez,
Angew. Chem. Int. Ed. 2014, 53, 4044.
We thank CNRS, MESRI, Université Paris-Sud, Ecole Polytechnique and
IUF.
[18] For selected examples of imine reduction, see: a) S. Fleischer, S.
Werkmeister, S. Zhou, K. Junge, M. Beller, Chem. Eur. J. 2012, 18,
9005; b) A. Pagnoux-Ozherelyeva, N. Pannetier, M. D. Mbaye, S.
Gaillard, J.-L. Renaud, Angew. Chem. Int. Ed. 2012, 51, 4976; c) S.
Moulin, H. Dentel, A. Pagnoux-Ozherelyeva, S. Gaillard, A. Poater, L.
Cavallo, J.-F. Lohier, J.-L. Renaud, Chem. Eur. J. 2013, 19, 17881; d)
D. S. Mérel, M. Elie, J.-F. Lohier, S. Gaillard, J.-L. Renaud,
ChemCatChem 2013, 5, 2939; e) T. T. Thai, D. S. Mérel, A. Poater, S.
Gaillard, J.-L. Renaud, Chem. Eur. J. 2015, 21, 7066; f) H.-J. Pan, T.
W. Ng, Y. Zhao, Org. Biomol. Chem. 2016, 14, 5490.
Keywords: amines • borrowing hydrogen • ethylation • catalysis
• iron
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10.1002/anie.201800328
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Marie Vayer, Sara Patricia Morcillo,
Jennifer Dupont, Vincent Gandon* and
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Iron-Catalyzed Reductive Ethylation
of Imines Using Ethanol
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