Iron-catalyzed reductive strecker reaction

Article abstract of DOI:10.1016/j.jcat.2021.01.003

Strecker reaction is widely applied for the synthesis of amino acids from aldehydes, amines and cyanides. Herein, we report the FeI₂-catalyzed reductive Strecker type reaction of formamides instead of aldehydes to produce amino acetonitriles. The challenging capture of carbinolamine intermediates by CN^? was achieved via Fe catalysis. This approach afforded better yields than the use of Ir- or Rh-catalysts. The application ability of this methodology is demonstrated by 1) one-pot construction of (¹³C labeled) complex molecules from CO₂ via amino acetonitrile intermediates and 2) convenient production of homologated carboxylic acids from aldehydes.

Full text of DOI:10.1016/j.jcat.2021.01.003

Journal of Catalysis 395 (2021) 188–194
Contents lists available at ScienceDirect
Journal of Catalysis
journal homepage: www.elsevier.com/locate/jcat
Iron-catalyzed reductive strecker reaction
Fachao Yan a,b,1, Zijun Huang a,c,1, Chen-Xia Du d, Jian-Fei Bai a, Yuehui Li a,
⇑
a State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute of LICP, Center for Excellence in Molecular Synthesis, Lanzhou Institute of Chemical
Physics (LICP), Chinese Academy of Sciences, Lanzhou 730000, PR China
b University of Chinese Academy of Sciences, Beijing 100049, PR China
c College of Chemistry and Chemical Engineering, Hunan Institute of Engineering, Xiangtan 411104, PR China
d College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Strecker reaction is widely applied for the synthesis of amino acids from aldehydes, amines and cyanides.
Herein, we report the FeI2-catalyzed reductive Strecker type reaction of formamides instead of aldehydes
to produce amino acetonitriles. The challenging capture of carbinolamine intermediates by CNꢀ was
achieved via Fe catalysis. This approach afforded better yields than the use of Ir- or Rh-catalysts. The
application ability of this methodology is demonstrated by 1) one-pot construction of (13C labeled)
complex molecules from CO2 via amino acetonitrile intermediates and 2) convenient production of
homologated carboxylic acids from aldehydes.
Received 4 November 2020
Revised 28 December 2020
Accepted 4 January 2021
Available online 12 January 2021
Keywords:
Reduction
Strecker reaction
Iron catalysis
Amino acetonitriles
Ó 2021 Elsevier Inc. All rights reserved.
1. Introduction
rocycles [5]. Besides, AANs can easily form carbanion species
through C-H deprotonation to give the key intermediate formalde-
The Strecker reaction is a well-known practical synthetic
method for -aminonitriles, widely used for the preparation of
hyde iminium ion with cyanomethyl group regarded as the amine
protecting group [6]. Hence, AANs are amenable to further trans-
formation with their structural motif prevalent in an array of trans-
formation with their structural motif prevalent in an array of
natural products, pharmaceuticals and drug candidates such as
Balicatib, Luliconazole, Girgensohnine (Fig. 1c) [7]. As a conse-
quence, selective construction of amino acetonitriles has received
considerable attention in recent years.
Other than the traditional methods via substitution reaction of
organic halides, transition-metal-catalyzed direct cyanation of C-H
bonds by oxidative cross dehydrogenative coupling methods has
emerged as an attractive approach to AANs derivatives [8]. Notable
reported examples feature metal-based catalysts such as Ru [9], Fe
[10], V [11], Au [12], Mo [13] and metal-organic frameworks [14],
in the presence of oxidants O2, H2O2, or TBHP. Furthermore, AANs
derivatives have also recently been obtained under photochemical
conditions [15]. However, these procedures involve excess use of
oxidants and often have problems of limited chemo-selectivity
and functional-group tolerance.
a
amino acids [1]. The classical Strecker reaction described by the
German chemist Adolph Strecker (1822–1871) in 1850, and makes
use of aldehydes, amines and hydrogen cyanide as starting materi-
als (Fig. 1a) [2]. Notably, the reaction of formaldehyde with ammo-
nia and cyanide to form amino acids is believed to be the essence of
the origin of life [3]. Alternatively and unprecedentedly, substitu-
tion of formaldehyde reactant with formamides instead in the
presence of reductants, Strecker-type products amino-
acetonitriles (AANs) could be generated (Fig. 1b). The challenge is
how to rationally design the catalyst and suppress the over-
reduction of the active iminium/carbinolamine intermediates.
Aminoacetonitrile is used as the key intermediate to many her-
bicide and pharmaceuticals. Molecules with at least two functional
groups are highly valuable and generally used for diverse synthe-
ses of polymeric materials and bio-active products [4]. Accordingly,
AANs are recognized as versatile intermediates in organic synthe-
sis, and can readily be transformed into numerous valuable prod-
ucts such as amino acids,
compounds, nitrogen containing thiadiazoles and imidazoles hete-
a
-amino alcohols,
a
-amino carbonyl
Straightforward procedures to prepare AANs derivatives using
readily available and more stable starting materials are highly
desirable. Recent progress in the reductive cyanation of amides
into AANs derivatives has been demonstrated as ideal pathway
albeit challenging [16]. Sato group [17] and Huang group [18] have
developed cyanations of tertiary amides employing stoichiometric
⇑
Corresponding author.
E-mail address: yhli@licp.cas.cn (Y. Li).
These authors contributed equally.
1
https://doi.org/10.1016/j.jcat.2021.01.003
0021-9517/Ó 2021 Elsevier Inc. All rights reserved.

F. Yan, Z. Huang, Chen-Xia Du et al.
Journal of Catalysis 395 (2021) 188–194
Fig. 1. The choice of CO2 utilization for AANs intermediates. (a) Strecker reaction. (b) Reductive Strecter reaction from CO2. (c) Biologically-active natural products featuring
AANs derivatives.
amounts of activating agents (eg. Tf2O/2-F-Py or [Cp2ZrHCl]/TFA).
Dixon group [19] and Adolfsson group [20] reported the elegant
metal’s coordination sphere. As part of our continuing efforts on
transition-metal-catalyzed cyanation reactions and CO2 utilization
[27], we describe here FeI2-catalyzed reductive cyanation of for-
mamides with TMSCN to access AANs products. Using iodide as
the ligand showed unexpected substrate reactivity and selectivity
for Fe(II)-catalyzed reductive Strecker reaction of formamides.
synthesis of
a-amino nitriles from tertiary amides catalyzed by
IrCl(CO)[P(C6H5)3]2 (Vaska’s catalysts) and Mo(CO)6, respectively.
Moreover, Huang and co-workers reported the reductive function-
alization of secondary amides catalyzed by [IrCl(COE)2]2 [21]. How-
ever, in these cases, the efficiency for the reactions of formamides was
not explored or rather limited [19].
On the other hand, the use of CO2 as C1 synthon holds promise
for sustainable synthesis. Generally employed methods rely largely
on the use of organometallic species [22] (Grignard reagents, orga-
noboron, organolithium and organozinc reagents), reductants [23],
and unsaturated compounds [24]. These methods exploit the elec-
trophilicity of CO2 to successfully, prepare alcohols, carboxylic
acids and derivatives as well as cyclic compounds [25]. More
recently, nucleophilic radical anion CO2 was generated as key
intermediate in photo/electrochemical reductive transformations
[26]. Nevertheless, these strategies were mainly based on one-
step linear synthesis and only one type of functional group was
introduced in the final product. Converting CO2 into valuable com-
plex molecules is still challenging.
2. Results and discussion
Aromatic formamides are intermediates in the methanogenesis
cycle, involving CO2 as terminal electron acceptor [28]. Therefore,
we have chosen N-methylformanilide 1a as starting material in
our initial study to react with TMSCN for reaction condition opti-
mization (Table 1). Reaction optimization considered a variety of
parameters such as metal precursors, ligands, reducing agents,
additives and solvents. Satisfyingly, we were pleased to find that
reductive cyanation of 1a proceeded to afford 2-(methyl(phenyl)a
mino)acetonitrile 2a exclusively in 94% yield at room temperature
in the presence of 10 mol% of FeI2 in MeCN without additional
ligands (Table 1, entry 1). FeI2 catalyst was found essential for good
reactivity, and no reaction occurred in the absence of this catalyst
(Table 1, entry 2). The Vaska’s catalyst [19] and [RhCl(COD)]2 were
also tested leading to target product 2a in lower yields of 49% and
37%, respectively (Table 1, entries 3-4). Significant amounts of
To the best of our knowledge, there is no report on general
reductive Strecker cyanation of CO2-derived formamides to amino
acetonitriles. It is well recognized that ligand association and dis-
sociation from metal centers involves significant change in the
189

F. Yan, Z. Huang, Chen-Xia Du et al.
Journal of Catalysis 395 (2021) 188–194
Table 1
With the optimized conditions in hand, we tested the one-pot
reaction from CO2 for the synthesis of amino acetonitrile products.
In this case PhSiH3 was used for CO2 reduction to AAN 2a in the
presence of N-Me aniline (Eq. (1)). To our delight, the reaction pro-
ceeded smoothly even at gram-scale and 1.34 g of AAN 2a was
obtained at room temperature in high yield (92%) [29]. In addition,
this one-pot approach was applied for the synthesis of isotope-
labelled melatonin receptor ligand (MLT) intermediate 8 in high
yield using 13C-CO2 (Eq. (2)) [30]. The production of one-carbon
homologated carboxylic acids from aldehydes is valuable but only
limited methods are known [31]. Using the product of reductive
Strecker reaction 2a, homologated bio-active carboxylic acids 10
or 2-(1-methyl-1H-indol-3-yl)acetic acid were prepared conve-
niently from benzaldehyde and indole-3-carboxaldehyde in 81%
and 86% yields, respectively (Eq. (3)).
N-Methylformanilide derivatives bearing a methyl group at the
meta or para position converted smoothly under the optimized
conditions and afforded the corresponding AANs derivatives in
good yields (2b and 2c, 80% and 88%, Table 2). Cyclo-formamides
(1d and 1e) were also compatible delivering the desired products
in good yields (2d and 2e, 61% and 78%). Notably, the method tol-
erates substrates bearing halide groups such as chloro and bromo
at meta or para positions (2f and 2g, 70% and 75%), providing the
opportunity for further transformations. Furthermore, formamides
with various alkyl groups on N-atom such as Et, nBu, iPr, C12H25 or
cyclohexyl groups were examined (2h-2l) and the reaction
afforded the corresponding products in appreciable yields, 64%-
80%. Sterically hindered N-naphthyl-substituted formanilide were
converted smoothly to 2-(naphthalen-2-yl(phenyl)amino)acetoni
trile 2o in 56% yield under elevated temperature of 80 °C. Excellent
yields were observed for formamides bearing benzyl or phenyl
group (2m and 2n). Moreover, N-benzyl-N-methylformamide 1p
was also tolerated and the target product 2p was obtained in
59% yield. These examples show the application potential and sub-
strate tolerance of the method using this iron-catalyzed reductive
cyanation strategy. Unfortunately, dialkyl formamides were not
Optimization of the reaction conditions.a
Entry
Variation of standard conditions
Yield (%)b
1
2
3
4
5
6
7
8
none
Without FeI2
94
n.r.
49 [19]
37
n.r. [20]
n.d.
n.d.
n.d.
n.d.
53
Vaska’s Cata. instead of FeI2
[RhCl(COD)]2 instead of FeI2
Mo(CO)6 instead of FeI2
Ni(COD)2 instead of FeI2
MnBr(CO)5 instead of FeI2
CuI instead of FeI2
FeCl2 instead of FeI2
FeBr2 instead of FeI2
FeBr2 and KI instead of FeI2
PhSiH3 instead of TMDS
Toluene instead of MeCN
DMF instead of MeCN
9
10
11
12
13
14
91
78
46
trace
a
Reaction conditions: 1a (0.3 mmol), catalyst (10 mol%), solvent (2.0 mL),
additive (10 mol%), N2, r.t., 12 h.
b
Isolated yields were shown. n.d. no detected. n.r. no reaction.
over-reduction product N,N-dimethylaniline were generated in
both cases. Attempts to use other transition metal catalysts such
as Mo(CO)6 [20], Ni(COD)2 and MnBr(CO)5 to replace FeI2 were
all unsuccessful (Table 1, entries 5–7). We also investigated a vari-
ety of different iron salts in an effort to explore the anion effect,
and only analogous FeBr2 resulted in 53% yield of 2a (Table 1,
entries 9–10). In this case, the addition of KI (10 mol%) as iodide
source improved the yield significantly (Table 1, entry 11). These
results indicate that iodide anion ligand plays an important role
in promoting the reaction. The screening of other iodide salts such
as CuI was ineffective to generate the desired product 2a, indicat-
ing the crucial role of iron metal center for this transformation
(Table 1, entry 8). Exploring other silane reducing agents such as
PhSiH3 resulted in lower yields (Table 1, entry 12). Furthermore,
solvents screening showed that only MeCN was more suitable sol-
vent compared to toluene or DMF (Table 1, entries 13–14).
Table 2
Substrate scope of tertiary formamides.a,b
ð1Þ
ð2Þ
ð3Þ
aReaction conditions for tertiary amines: substrate 1 (0.3 mmol), TMDS (2.0 equiv.),
TMSCN (2.0 equiv.), FeI2 (10 mol%), MeCN (2 mL), r.t., 12 h.
bYield of isolated product.
cDetermined by GC, n-dodecane was used as an internal standard.
d80 oC, 20 h.
190

F. Yan, Z. Huang, Chen-Xia Du et al.
Journal of Catalysis 395 (2021) 188–194
Table 3
formed with the results summarized in Fig. 2. The hydrolysis of
nitrile group provided the corresponding amide 6a in 68% yield.
N-Boc-protected amine 6b could be obtained by a Ni-catalyzed
reduction reaction in 73% yield. Moreover, the nitrile group was
hydrolyzed to the carboxylic acid 6c in high yield. Surprisingly,
2-(methyl(phenyl)amino)-acetonitrile 2a was selectively con-
verted into 2-(methyl(phenyl)amino)-1-phenylethan-1-one 6d in
Substrate scope of secondary formamides.a,b
70% yield. The
a-cyanoenamines 6f and 6g can be conveniently
obtained from the reactions with ketones or aldehydes [32]. More-
over, thienyl-substituted acetonitrile 6e as versatile reagents in
electrophilic reactions, nucleophilic and radical reactions, can be
gram-scale obtained in 90% yield [33]. Additionally, the reaction
of
a-cyanoenamines 6f with methyl isocyanoacetate provided
the cyclic product methyl 4-(methyl(phenyl)amino)-3-phenyl-
1H-pyrrole-2-carboxylate 7 [34].
CO2 as C1 linker of functional groups, this synthesis strategy
based on amino-acetonitrile intermediates involves cleavage of
the four C-O bonds in CO2 and formation of 12 kinds of chemical
bonds (including C-H, CAC, C@C, CAO, C@O, CAN, CAS etc.) on
the same carbon center. Notably, in contrast to traditional methods
that are based on the electrophilicity of CO2, tuning the property of
C to a nucleophile was achieved by the Fe-catalyzed selective for-
mation of key amino-acetonitrile intermediates. Beyond the pre-
sented synthesis of different types of organic molecules, the
newly developed strategy might inspire the utilization of CO2 as
a versatile synthon, and enable the design and synthesis of com-
plex chemicals with the desired functional group on the C atom.
3. Mechanistic studies
a Reaction conditions for secondary formamides: substrate 3 (0.3 mmol), TMDS (2.0
To gain insights into the reaction mechanism, NMR measure-
ments and control experiments were conducted. 1H NMR of N-
methylformanilide interaction with metal iodides showed the peak
at 8.057 ppm shifting downfield to 8.133 ppm after addition of KI
(10 mol%), which suggests that H-I is engaged in hydrogen bonding
interactions (Fig. S1). Additionally, the reaction of N-
methylformanilide was carried out in the presence of N,N-
dimethylbenzamide. After the reaction, 2-(methyl(phenyl)amino)
acetonitrile was detected as the only product accompanied by
the recovery of N,N-dimethylbenzamide (>98%) (Eq. (4)). Next,
we moved to intramolecular competing reactions for different type
of amide bonds. Gratifyingly, 5a was obtained in excellent yields
with benzamide moiety (A) remaining unaltered (Eq. (5)). There-
fore, we conclude that N-formyl group is crucial for the reaction
and the acidic C-H proton probably acts as significant activator
(Fig. S2).
equiv.), TMSCN (2.0 equiv.), FeI2 (10 mol%), MeCN (2 mL), r.t., 12 h.
b
Yield of isolated product.
Determined by GC, n-dodecane was used as an internal standard.
80 °C, 20 h.
c
d
suitable substrates and no desired product could be generated
(Fig. S4).
To further investigate the synthetic generality of the reaction,
substrate scope was extended to secondary amides to produce
AANs derivatives (Table 3). Secondary amino acetonitriles are
important building blocks in organic synthesis due to the presence
of a synthetically versatile NH group. To our delight, the presence
of NH group tolerated the reaction conditions with the desired
products obtained in moderate to good yields. N-phenyl for-
mamides bearing methoxy or alkyl groups performed well to deli-
ver the corresponding products 4b-4l in 49–90% yields. Steric
effect ortho to N-H was noticeable and 4k was obtained in moder-
ate yield. To our satisfaction, electron-deficient substrates were
transformed to products 4m-4q smoothly in 58–75% yields. Fur-
thermore, heterocyclic and nitro derivatives were applicable under
our reaction conditions affording the corresponding products 4r
and 4s in 62% and 69%, respectively. Noteworthy, the vinyl moiety
remained intact, highlighting the chemoselectivity of this method
(4u). The 2-(naphthalen-1-ylamino)acetonitrile 4v was also
obtained in good yield and benzylamines were also suitable sub-
strates with the chirality retained in 4x.
ð4Þ
ð5Þ
To understand the high efficiency of FeI2, we performed the FT-
IR and UV–vis measurement for the mixture of FeI2 and TMSCN.
The band at 2080 cmꢀ1 was observed (Fig. 3). Considering that
K4[Fe(CN)6] has the vibrational frequencies at around 2050 cmꢀ1
[35]. This result suggests that weaker coordination occurs between
FeI2 and TMSCN compared to ionic Fe2+/CNꢀ coordination. Using
1:1 mol ratio of FeI2 and TMSCN, significant amounts of free (or
weakly-influenced) TMSCN was still shown in the IR spectrum
(1250 cmꢀ1). Besides, weak interaction between FeI2 and 1a was
Our approach deployed CO2 utilization for the construction of
valuable molecules is noteworthy. Accordingly, we have demon-
strated general synthesis of functionalized compounds via reduc-
tive Strecker-type cyanation of formamides from CO2, providing
access to amino acetonitriles, olefins, amino ketones, diamines,
carboxylic acids and pyrroles etc. Specifically, synthetic diversifica-
tion from 2a, which could be synthesized at gram-scale, were per-
191

F. Yan, Z. Huang, Chen-Xia Du et al.
Journal of Catalysis 395 (2021) 188–194
Fig. 2. Synthetic application based on derivatizations of 2a.
detected with carbonyl group’s signal red-shifted by 19.4 cmꢀ1
(Fig. S3). In UV–vis spectra, the formation of Fe-I bond was
detected when adding KI to the solution of FeCl2 in MeCN. Thus,
other than iodide ion, formamide molecules might behave as weak
ligands, which allows for a better dissolution of FeI2 in toluene to
give moderate reactivity (Table S1, entry 42; 49% yield).
Based on the above results, we propose the following mecha-
nism for this Fe-catalyzed reductive Stecker reaction (see SI,
Scheme 1). The catalyst FeI2 interacts firstly with the solvent or for-
mamides to dissolve followed by formation of FeAH species via
SiAH cleavage [36]. Concerted activation of formamides via FeAO
and HAI interactions occurs to have the hydride attack on the car-
bonyl group. However, the other reaction pathway via the forma-
the reduced acetal intermediate reacts with CNꢀ to give the desired
product via similar concerted activation, with the generation of the
Fe-CN type species. The hydridic attack on the carbonyl group of
formamides to form the acetal type species, followed by the SN2
type cyanation reaction to give the desired amino-acetonitrile
products. SiAC bond activation might be achieved by the concerted
SN2-type attack of the nucleophilic siloxide ion to Si atom and
active species will be regenerated by ligand exchange of cyanide
and iodide.
4. Conclusions
tion of
a
-siloxy nitrile intermediates followed by reduction to
In conclusion, we have developed Fe-catalyzed reductive cyana-
tion of formamides to access AANs with excellent chemoselectiv-
generate amino acetonitrile products could not be excluded. Then,
192

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Journal of Catalysis 395 (2021) 188–194
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Declaration of Competing Interest
catalysed sequential reaction towards a-aminonitriles from secondary amines,
primary alcohols and trimethylsilyl cyanide, Chem. Commun. 52 (2016) 2776–
2779.
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
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Acknowledgements
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Appendix A. Supplementary material
(b) P. Kumar, S. Varma, S.L. Jain, A TiO2 immobilized Ru(II) polyazine complex:
a visible-light active photoredox catalyst for oxidative cyanation of tertiary
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Supplementary data to this article can be found online at
https://doi.org/10.1016/j.jcat.2021.01.003.
(c) V. Panwar, P. Kumar, A. Bansal, S.S. Ray, S.L. Jain, PEGylated magnetic
nanoparticles (PEG@Fe3O4) as cost effective alternative for oxidative cyanation
of tertiary amines via C-H activation, Appl. Catal. A 498 (2015) 25–31;
(d) S. Verma, R.B.N. Baig, C. Han, M.N. Nadagouda, R.S. Varma, Magnetic
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