Iron-catalysed carbene-transfer reactions of diazo acetonitrile

Article abstract of DOI:10.1039/c8ob01991f

A continuous-flow protocol for the synthesis of diazo acetonitrile was developed. It was further applied in iron-catalysed insertion reactions of diazo acetonitrile into N-H and S-H bonds to yield valuable α-substituted acetonitrile, including gram-scale synthesis.

Full text of DOI:10.1039/c8ob01991f

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Iron-catalysed carbene-transfer reactions of diazo acetonitrile
a
a
a
Claire Empel, Katharina J. Hock and Rene M. Koenigs*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
1
1-13
A continuous-flow protocol for the synthesis of diazo acetonitrile safe and scalable solutions to chemical synthesis.
In
For
was developed. It was further applied in iron-catalysed insertion particular, the generation of diazoalkanes in continuous-flow
1
2,13
reactions of diazo acetonitrile into N—H and S—H bonds to yield has received significant interest in the past years.
valuable α-substituted acetonitrile, including gram-scale synthesis. example, the aqueous diazotisation reaction of glycine ethyl
ester hydrochloride with sodium nitrite using microreactor
Against the background of limited resources, toxicity and
increasing commodity prices of precious metal catalysts, the
development of novel transformations based on cheap, earth-
abundant metals is of prime importance in the development of
technology easily outperforms current industrial scale
3h
1
preparation methods of ethyl diazoacetate.
As part of our on-going interest in highly reactive diazoalkanes
4
c,9
and their application in carbene-transfer reactions, we got
intrigued in studying the continuous-flow synthesis of diazo
acetonitrile. In the presence of an appropriate metal catalyst,
diazo acetonitrile would provide an access to a nitrile-
substituted metal-carbene intermediate. The latter should
undergo insertion reactions into X—H bonds to furnish
α-heteroatom-substituted acetonitrile derivatives and thus
provide an alternative synthetic method to cross
dehydrogenative coupling reactions. The latter is an important
method for the synthesis α-amino acetonitriles, though limited
1,2
new synthetic methods. Iron is the second-most abundant
metal on earth (following aluminium) and features a broad
spectrum of oxidation and spin states that can assist in the
stabilisation
of
a
transition
states
or
high-energy
2
intermediates.
It is thus considered as an attractive
alternative to replace common precious metal catalysts based
2b
on palladium, rhodium, iridium or copper.
Iron-heme
complexes are a privileged structural motif and consist of a
central iron cation coordinated by a tetra-dentate porphyrin
ligand and are the central co-factor of, for example,
14
in substrate scope with regards to the amine component.
3
haemoglobin, myoglobin or P450 enzymes. In organic
synthesis iron-heme complexes are important catalysts for Scheme 1. Catalytic X—H insertion reactions with diazo acetonitrile.
2
a,3
oxidation and coupling reactions.
In particular, iron-heme
Previous work
complexes recently emerged as attractive catalysts for carbene
transfer reactions derived from acceptor-substituted
introduction of a nitrile group
2
a,3,4
diazoalkanes.
Diazo acetonitrile was first described by T. Curtius in 1898.
+
CN-
N
Ph
5
N
Ph
[
Oxidant]
Although it is a very close analogue of ethyl diazoacetate, it
possesses significantly altered properties and is associated to
CN
via iminium ion
H
this work
5
,6
high risks of explosions.
Till now, there is only little
introduction of a cyanomethylene group
precedence on applications of diazo acetonitrile in organic
7
-10
synthesis
and recently, P. Mykhailiuk and our group
+
NC
N
Ph
N
2
[
N-H insertion]
N
H
Ph
reported on two distinct protocols to access diazo acetonitrile
8
,9
CN
in situ.
Today, flow chemistry is as a versatile tool to access highly
reactive reagents and is an important technology to provide The carbene reactivity of diazo acetonitrile is surprisingly
9
,10
underdeveloped.
In particular, X—H insertion reactions of
diazo acetonitrile have never been studied although they
would pave the way towards the efficient synthesis of
α-heteroatom-substituted acetonitriles. The majority of
studies focus on applications of ester-substituted diazoalkanes
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or trifluoromethyl-substituted diazoalkanes using different and catalyst loading (table 1, entry 15) revealing that a
1
5,16
Cu(I), Rh(II), Co(II) and Ir(III) catalysts.
combination of 4 eq. of diazo acetonitrile, toluene as solvent
The acetonitrile moiety represents an important functional and 1 mol-% FeTPPCl is optimal in this transformation (table 1,
group and is of high importance in the synthesis of biologically entry 16).
1
7,18
active molecules and total synthesis.
acetonitriles find prominent application in agrochemical batch protocol, we conducted the iron-catalysed N—H
For example, α-amino As proof of principle studies and for comparison with the flow-
1
7c
research
inhibitors (
are employed as nucleophilic warheads of irreversible covalent added to a biphasic mixture of N-benzyl-aniline, FeTPPCl and
(1) or as an electrophilic warhead of protease insertion reaction with in situ generated diazo acetonitrile. In
1
7d
2
). Contrarily, α-mercapto acetonitrile derivatives this batch-protocol, an aqueous solution of sodium nitrite was
1
7e
inhibitors of protein kinases
(
3
).
The nitrile moiety amino acetonitrile hydrochloride, yet 7a could only be isolated
furthermore provides direct access to tetrazoles by in significantly reduced yield (table 1, entry 17).
cycloaddition reactions and thus represents an important
Table 1. Reaction Optimisation.
precursor in the synthesis of biologically active compounds
1
(4).
8
Figure 1. Applications α-amino and α-mercapto acetonitrile derivatives in
pharmaceutical and agrochemical research.
1
Entry
Catalyst
Solvent
Eq. 6
% yield
1
2
3
4
5
6
7
8
9
FeTPPCl
FePcCl
FePc
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
THF
8
8
8
8
8
8
8
8
8
8
8
8
8
2
2
4
4
66
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
7
Fe(OTf)
2
CuPF (MeCN)
6
4
Co(II)MeO-TPP
Co(salen)
Rh
Rh
2
esp
2
2
OAc
4
15
1
1
1
1
1
0
1
2
3
4
FeTPPCl
FeTPPCl
FeTPPCl
FeTPPCl
FeTPPCl
FeTPPCl
FeTPPCl
FeTPPCl
69
EtOAc
toluene
78
Following this rationale, diazo acetonitrile is generated in a
continuous-flow reaction by mixing a stream of an aqueous
solution of amino acetonitrile hydrochloride and an aqueous
solution of sodium nitrite. The outlet of the flow reactor is
connected to a standard reaction vessel. This flow-batch
protocol was then used to investigate the N—H insertion
reaction of diazo acetonitrile with different catalysts using
80
CHCl
3
65
toluene
toluene
toluene
toluene
66
2
15
49
3
4
16
98
17
22
1
1
9
Reaction conditions: Flow Conditions: 0.2 mmol 5a (1 eq.) and catalyst (1 mol-%)
were dissolved in 100 µL solvent; 1.6 M (8.0 eq.) 100 µL/min amino acetonitrile
hydrochloride; 1.92 M (9.6 eq.) NaNO 100 µL/min; 55 °C, 200 µL reactor volume;
addition time: 10 min and 1 h additional reaction time; 3mol-% FeTPPCl;
N-benzyl-aniline as a substrate.
2
Scheme 2. Reaction setup.
2
3
4
0
.4 mmol scale; Reactions Conditions: Batch protocol: 0.4 mmol substrate,
catalyst (1 mol-%) and amino acetonitrile hydrochloride (4.0 eq.) were dissolved
in 200 µL toluene and 1 mL H O; 0.8 M (4.8 eq.) and NaNO (4.8 eq.) dissolved in
mL H O is added over a period of 3 h.
2
2
1
2
In further experiments, we evaluated the applicability of this
N—H insertion reaction and investigated different amines.
Benzyl-protected anilines reacted efficiently to the desired
α-amino nitriles in excellent yield (table 2, 7a-7c). Similarly,
different aliphatic substituted anilines and substituted N-
We were delighted to observe that the flow-batch protocol
was very efficient and we could achieve the desired N—H
methyl anilines underwent the N—H insertion reaction in good
2
0
to excellent isolated yields (table 2, 7d-7i). Similarly,
insertion reaction with FeTPPCl as catalyst in good yield.
Different phthalocyanine based iron catalysts, copper or
cobalt- catalysts did not provide the reaction product.
Similarly, Rh(II) catalysts only gave minor amounts of the
desired α-amino nitrile. In further optimisation steps, we
tested different solvents and equivalents of diazo acetonitrile
heterocyclic substrates, such as tetrahydroquinoline (7j) or
piperazine (7k) reacted smoothly under the present reaction
conditions. In a scale-up of this flow-batch transformation, 7a
was obtained on a gram-scale without the necessity to isolate
or to handle diazo acetonitrile. Notably, primary amines such
2
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as aniline (5l) or benzylamine did not react under the present byproduct (table 3, entry 9g to 9i). Heterocyclic, aromatic
reaction conditions. Similarly, diphenylamine (5m) did not thiols (8o), did not undergo the desired insertion reaction. We
provide the desired reaction product. We additionally tested furthermore investigated the batch-protocol, yet as in the case
primary or secondary benzamides (5n, 5o), though no product of N—H insertion reactions, the S—H insertion reactions
formation was observed. Moreover, the batch-protocol was operated most efficiently using the flow-batch protocol.
further investigated with two different examples (7d and 7j),
Table 3. Catalytic S—H insertion reactions with diazo acetonitrile.
which both underline the high efficiency of the flow-batch
setup.
Table 2. Catalytic N—H insertion reactions with diazo acetonitrile.
Values in parantheses indicate yields from in situ reactions. Reaction conditions:
Flow Conditions: 0.4 mmol 8a-n (1 eq.) and catalyst (1 mol-%) were dissolved in
Values in parantheses indicate yields from in situ reactions. Reaction conditions:
2
0
00 µL toluene; 0.8 M (4.0 eq.) 100 µL/min aminoacetonitrile hydrochloride;
Flow Conditions: 0.4 mmol 5a-n (1 eq.) and FeTPPCl (1 mol-%) were dissolved in
2
.96 M (4.8 eq.) NaNO 100 µL/min; flow reaction: 55 °C, 200 µL reactor volume;
2
0
00 µL toluene; 0.8 M (4.0 eq.) 100 µL/min amino acetonitrile hydrochloride;
.96 M (4.8 eq.) NaNO 100 µL/min; flow reaction: 55 °C, 200 µL reactor volume;
addition time: 20 min and 3 h additional reaction time. Reactions Conditions:
2
Batch conditions: 0.4 mmol thiol, FeTPPCl (1 mol-%) and aminoacetonitrile
addition time: 20 min and 1 h additional reaction time. Reactions Conditions:
hydrochloride (4.0 eq.) were dissolved in 200 µL toluene and 1 mL H
2 2
O; NaNO
Batch conditions: 0.4 mmol amine, FeTPPCl (1 mol-%) and amino acetonitrile
(
4.8 eq.) dissolved in 1 mL H O is added over a period of 3 h.
2
hydrochloride (4.0 eq.) were dissolved in 200 µL toluene and 1 mL H
2 2
O; NaNO
(
4.8 eq.) dissolved in 1 mL H O is added over a period of 3 h.
2
We then turned our attention towards the insertion reaction
into different X—H bonds and evaluated the reactivity of
phenol (10), benzoic acid (11), silanes (12) and phenyl sulfinate
In further experiments we evaluated different X—H insertion
reaction precursors. We set out these investigations using
thiols as nucleophiles for the interception of the iron-carbene
intermediate (table 3). To our delight, thiophenol smoothly
reacted to the desired insertion product in moderate yield
(
13) in this iron-catalysed insertion reaction. Yet, no product
formation was observed in crude NMR (figure 2).
Figure 2. Substrates that did not undergo X—H insertion reaction
(
9a). In a next step different aromatic and aliphatic thiols were
investigated in the S—H insertion reaction (table 3). Different
substituents at the aromatic ring were well tolerated and the
desired α-mercapto nitriles were isolated in moderate to good
yield (table 3, entry 9a to 9k). Notably, ortho-substituted
thiophenols provided significantly improved yield of the
α-mercapto nitrile, which might be attributed to steric
hindrance and concomitant slower oxidation to the disulphide
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In summary, FeTPPCl was found to be an efficient catalyst for
N—H and S—H insertion of diazo acetonitrile. A flow protocol
was applied to generate hazardous diazo acetonitrile in a safe
and continuous fashion. The subsequent insertion reaction can
be readily performed in a consecutive batch transformation
providing an efficient access towards α-substituted acetonitrile
derivatives.
7
(a) F. Roelants and A. Bruylants, Tetrahedron, 1978, 34
,
,
,
2
6
4
229; (c) J. Hooz and S. Linke, J. Am. Chem. Soc., 1968, 90
891; (d) D. T. Witiak and M. C. Lu, J. Org. Chem., 1970, 35
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9
P. K. Mykhailiuk, Eur. J. Org. Chem., 2015, 7235.
(a) K. J. Hock, L. Mertens, R. Hommelsheim, R. Spitzner and
R. M. Koenigs, Chem. Commun., 2017, 53, 6577; (b) K. J. Hock
and R. M. Koenigs, Angew. Chem. Int. Ed., 2017, 56, 13566;
(
c) K. J. Hock, A. Knorrscheidt, R. Hommelsheim, J. Ho, M. J.
Weissenborn and R. M. Koenigs, ChemRxiv, 2018, DOI:
chemrxiv.6011096.v1;
Conflicts of interest
1
1
0 Selected articles on the carbene reactivity of diazo
acetonitrile: (a) C. V. Galliford and K. A. Scheidt, J. Org.
Chem., 2007, 72, 1811-1813; (b) Y. Ferrand, P. Le Maux and
G. Simmoneaux, Tetrahedron: Asymmetry, 2005, 16, 3829-
3836; (c) F.-X. Felpin, E. Doris, A. Wagner, A. Valleix, B.
Rousseau and C. Mioskowski, J. Org. Chem., 2001, 66, 305.
1 Selected recent review articles on flow chemistry: (a) M. B.
Plutschack, B. Pieber, K. Gilmore and P. H. Seeberger, Chem.
Rev., 2017, 117, 11796; (b) M. Movsisyan, E. I. P. Delbeke, J.
K. E. T. Berton, C. Battilocchio, S. V. Ley, and C. V. Stevens,
Chem. Soc. Rev., 2016, 45, 4892; (c) V. Hessel, D. Kralisch, N.
There are no conflicts to declare.
Acknowledgements
Funded by the Deutsche Forschungsgemeinschaft (DFG,
German Research Foundation) – project no. 408033718. RMK
gratefully thank the Fonds der Chemischen Industrie for
generous support (Sachkostenbeihilfe).
Kockmann, T. Noel, and Q. Wang, ChemSusChem, 2013,
46.
2 Selected review articles for diazo compounds in continuous-
6,
7
Notes and references
1
1
Selected articles on catalysis with non-precious metals: (a) K.
Gao and N. Yoshikai, Acc. Chem. Res., 2015, 47, 1208; (b) P. J.
Chirik, Acc. Chem. Res., 2015, 47, 1687; (c) Y.-Y. Li, S.-L. Yu,
W.-Y. Shen and J.-X. Gao, Acc. Chem. Res., 2015, 47, 2587; (d)
J. R. Carney, B. R. Dillon and S. P. Thomas, Eur. J. Org. Chem.,
flow: (a) S. T. R. Mueller and T. Wirth, ChemSusChem, 2015,
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Chem. Eur. J., 2015, 21, 2298; (c) M. Movsisyan, E. I. P.
Delbeke, J. K. E. T. Berton, C. Battilocchio, S. V. Ley and C. V.
Stevens, Chem. Soc. Rev., 2016, 45, 4892; (d) K. J. Hock and
R. M. Koenigs, Chem. Eur. J., 2018, 24, 10571.
8
2
016, 3912.
2
Selected review articles on iron catalysis: (a) S.-F. Zhu and Q.- 13 Selected articles for diazo compounds in continuous-flow: (a)
L. Zhou, Natl. Sci. Rev., 2014,
1
, 580; (b) H.-J. Knölker and I.
L. Mertens, K. J. Hock and R. M. Koenigs, Chem. Eur. J., 2016,
22, 9542; (b) K. J. Hock, L. Mertens, F. K. Metze, C.
Schmittmann and R. M. Koenigs, Green Chem., 2017, 19, 905;
(c) J. Britton and T. F. Jamison, Angew. Chem. Int. Ed., 2017,
56, 8823 (d) E. Levesque, S. T. Laporte and A. B. Charette,
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Feist, A. Hafner, M. Simon, D. N. Tran, D. M. Allwood, D. C.
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E. Nakamura, Chem. Rev., 2017, 117, 9086; (d) L.-X. Liu, Curr.
Org. Chem., 2010, 14, 1099; (e) C. Bolm, J. Legros, J. LePaih
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Catalysis in Organic Chemistry: Reactions and applications,
2
nd ed., Wiley-VCH, Weinheim, 2008; (g) W. M. Czaplik, M.
Mayer, J. Cvengros and A. Jacobi von Wangelin,
ChemSusChem, 2009, , 396.
Selected review articles on iron-heme complexes in catalysis:
a) O. F. Brandenberg, R. Fasan and F. H. Arnold, Curr. Opin.
Blakemore and S. V. Ley, Nat. Chem., 2016,
E. Delville, J. C. M. van Hest and F. Rutjes, Beilstein J. Org.
Chem., 2013, , 1813; (g) K. J. Hock, L. Mertens and R. M.
8, 360; (f) M. M.
2
3
9
(
Koenigs, Chem. Commun., 2016, 52, 13783; (h) H. Lehmann,
Green Chem., 2017, 19, 1449; (i) F. Mastronardi, B. Gutmann
and C. O. Kappe, Org. Lett., 2013, 15, 5590; (j) B. Pieber and
C. O. Kappe, Org. Lett., 2016, 18, 1076; (k) S. T. R. Müller, A.
Murat, D. Maillos, P. Lesimple, P. Hellier and T. Wirth, Chem.
Eur. J., 2015, 21, 7016; (l) S. M. Nicolle, C. J. Hayes and C. J.
Moody, Chem. Eur. J., 2015, 21, 4576; (m) E. Rossi, P. Woehl
and M. Maggini, Org. Proc. Res. Dev., 2012, 16, 1146; (n) R.
A. Maurya, C. P. Park, J. H. Lee and D.-P. Kim, Angew. Chem.
Int. Ed., 2011, 50, 5952; (o) P. G. McCaw, N. M. Buckley, K. S.
Eccles, S. E. Lawrence, A. R. Maguire and S. G. Collins, J. Org.
Chem., 2017, 82, 3666.
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Am. Chem. Soc., 2016, 138, 11410; (c) L. Que Jr and W. B.
Tolman, Nature, 2008, 455, 333; (d) W. Nam, Acc. Chem.
Res., 2007, 40, 522; (e) E. I. Solomon, A. Decker and N.
Lehnert, Proc. Natl. Acad. Sci. U.S.A., 2003, 100, 3589; (f) M.
T. Gladwin, R. Grubina and M. P. Doyle, Acc. Chem. Res.,
2
008, 42, 157.
4
Selected articles on carbene transfer reactions with iron
catalysts: (a) P. Le Maux, S. Juillard and G. Simmoneaux,
Synthesis, 2006, 1701; (b) B. Morandi and E. M. Carreira,
Angew. Chem. Int. Ed., 2010, 49, 938; (c) K. J. Hock, R.
Spitzner and R. M. Koenigs, Green Chem., 2017, 19, 2118; (d) 14 Selected articles on C-H cyanation reactions: (a) M. Rueping,
M. S. Holzwarth, I. Alt and B. Plietker, Angew. Chem. Int. Ed.,
S. Zhou and R. M. Koenigs, Chem. Commun., 2011, 47
012, 51, 5351; (e) J. Day, B. McKeever-Abbas and J.
,
2
12709; (b) L. Ma, W. Chen and D. Seidel, J. Am. Chem. Soc.,
2012, 134, 15305; (c) S.-I. Murahashi, N. Komiya, H. Terai and
T. Nakae, J. Am. Chem. Soc., 2003, 125, 15312; (d) D. P. Hari
and B. König, Org. Lett., 2011, 13, 3852; (E) A. Wagner and A.
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S.-C. Zhao F. Yu and Y.-P. He, J. Org. Chem., 2017, 82, 12786.
15 Selected review articles on X—H insertion reactions: (a) D.
Gillingham and N. Fei, Chem. Soc. Rev., 2013, 42, 4918; (b)
M. P. Doyle and T. Ye, Modern Catalytic Methods for Organic
Synthesis with Diazo Compounds, Wiley, New York, 1998.
Dowden, Angew. Chem. Int. Ed., 2016, 55, 5809; (f) J. R.
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and Y. Pan, Chem. Commun., 2017, 53, 6219; (h) D. M.
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L. Legnani and E. Gallo, Chem. Eur. J., 2016, 22, 13599.
T. Curtius, Ber. Dtsch. Chem. Ges., 1898, 31, 2489.
5
6
D. D. Phillips and W. C. Champion, J. Am. Chem. Soc., 1956,
78, 5452.
4
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1
6 Selected recent articles on iron-catalysed X—H insertion
reactions of acceptor-only diazoalkanes: (a) L. K. Baumann,
H. M. Mbuvi, G. Du and L. L. Woo, Organometallics, 2007, 26
,
3
5
995; (b) H. Keipour and T. Ollevier, Org. Lett., 2017, 19,
736; (c) J. Yoo, N. Park, J. H. Park, J. H. Park, S. Kang, S. M.
Lee, J. J. Kim, H. Jo, J.-G. Park and S. U. Son, ACS Catal., 2015,
5, 350; (d) X. Xu, C. Li, Z. Tao and Y. Pan, Adv. Synth. Catal.,
2
015, 357, 3341; (e) Z. J. Wang, N. E. Peck, H. Renata and F.
Arnold, Chem. Sci., 2014, 5, 598; (f) I. Aviv and Z. Gross,
Chem. Eur. J., 2008, 14, 3995.
7 Selected references on α-aminonitriles: (a) V. V. Kouznetsov,
and G. E. P. Galvis, Tetrahedron, 2018, 74, 773; (b) C. K. Prier,
D. A. Rankic and D. W. C. MacMillan, Chem. Rev., 2013, 113,
1
1
5
5
322; (c) S. Ito, S. Wakamori, I. Kimura and K. Takita, JP
0077532, 1975, (Kumiai Chemical Industry); (d) K. Ohmoto
and I. Itagaki, WO 2001055118, 2001, (Ono Pharmaceutical);
References on α-thionitriles: (e) Kate S. Carroll,
WO2014089546, 2014, (Scripps Research Inst.).
8 L.-L. Dai, H.-Z. Zhang, S. Nagarajan, S. Rhasheed and C.-H.
Zhou, Med. Chem. Commun., 2015, 6, 147.
1
2
9 for details, please see the supporting information.
0 TPP = meso-tetraphenyl porphyrin.
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