Novel ferrocene-labeled propargyl amines via CuI multicomponent amination/alkynylation

Article abstract of DOI:10.1039/c9nj00538b

An efficient synthesis of ferrocene-tagged propargyl amine derivatives via one-pot three-component domino amination/alkynylation in water is reported. The synthesis involves a single Cu(i) catalyst without addition of a ligand, has broad substrate applicability and gives excellent yields.

Full text of DOI:10.1039/c9nj00538b

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Novel
Ferrocene-labeled
Propargyl
amines
via
CuI
Multicomponent Amination/Alkynylation
Suman Srivastava*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
An efficient synthesis of Ferrocene-tagged Propargyl Amine derivatives via one-pot three-component domino
amination/alkynylation in water is reported. The synthesis involves single Cu(I) catalyst without the addition of ligand with
broad substrate applicability and excellent yields.
www.rsc.org/
The Multicomponent diversity oriented reactions (MCRs) context, heterocycles containing a Ferrocene moiety show
are of great interest to organic chemists due to their use in interesting features that make them attractive for use as
medicinal chemistry as fast and selective methods for the biologically active compounds. Recently, we have reported
synthesis of large libraries of organic molecules.1 In these some procedures for the synthesis of Ferrocene based
reactions the products are formed in a single step by thiopropanone12 and furan13 derivatives. Considering the
simultaneous reaction of several reagents and the molecular above reports, and as part of our program aimed at developing
diversity required for such combinatorial libraries can be new ecofriendly and green methodologies for the preparation
achieved by simply varying each component through a chain of of bioactive heterocyclic compounds,14 We are currently
consecutive elementary transformations.
Propargyl amines are versatile structural units present ferrocene tagged Propargyl amine via a facile, atom-
in various important natural products which exhibit interesting economical, diversity oriented one pot three-component
investigating the Copper(I) catalysed synthesis of various
2
3
4
biological activities. For example Pargyline, Rasagyline, and reaction in water.
5
Selegiline have found direct application in the treatment of
neurodegenerative diseases, such as Parkinson’s6 and
7
Alzheimer’s diseases (Figure 1). Several methods have been
developed for the preparation of Propargyl amines, among
which simplest and most straightforward method involves the
addition of alkynyl metal reagents to imines. 8
Scheme 1. Propargyl amine synthesis in water
Despite the extensive use of Propargyl amines in organic
synthesis, to the best of our knowledge, no report describing
the synthesis of Ferrocene tagged propargyl amine has been
reported in the literature so far.
Figure1. Bioactive Propargyl amines
In last past years there has been an increasing interest in
the design of new compounds incorporating the Ferrocene
The catalytic activity of various copper salts such as CuI,
CuBr, CuCl was examined for the coupling of Ferrocene
carboxaldehyde, piperidine and Phenylacetylene because they
are readily available and much cheaper than silver, gold,
ruthenium, or other additives. Initially, a mixture of Ferrocene
carboxaldehyde, Piperidine and Phenylacetylene in acetonitrile
was stirred in the presence of 20 mol% of CuX (I, Br, and Cl) at
room temperature for 24 h and the product was not observed
and reaction stopped after the formation of iminium
intermediate (Table 1, Entry 2), leading to the assumption that
more temp may be needed. To focus on the effect of
temperature, the reaction was carried out at 80°C in
9
skeleton , due to its easy chemical modification, small size,
relative lipophilicity, and stability in aqueous and aerobic
media. Several examples of Ferrocene derivatives of drug
moiety such as antibiotics (penicillin or cephalosporins)10 and
cancer drugs (tamoxifen)11 have also been synthesized. In this
aDepartment of Applied Aciences, National Institute of Technology, Delhi, NILERD
campus, Sec –A-7, Narela, Delhi, India, 110040
Corresponding author: Dr Suman Srivastava
E-mail address: sumansrivastava@nitdelhi.ac.in
Electronic Supplementary Information (ESI) available: [General experimental
procedure and characterisation spectra of all the compounds are included in
supplementary information]. See DOI: 10.1039/x0xx00000x
*
a.
This journal is © The Royal Society of Chemistry 20xx
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acetonitrile as solvent, which allowed the product to form with
Journal Name
Towards this objective initially the Ethynyl ferVrioewceAnrtiecl 1e 5Ownlianes
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a 22, 35, and 75% yield for CuCl CuBr, and CuI respectively synthesized from Acetyl ferrocene (SchDeOmI:e10.310).39I/nC9tNhJe00n53e8xBt
Table 1, Entry 3, 4 and 5). The coupling process proceeded stage of the study the attention was focused towards synthesis
(
well in the presence of 20 mol% of CuI to give Ferrocene of Propargyl amine, employing Ethynyl ferrocene.
tagged Propargylamines in 75% conversion (Table 1, Entry 5).
By reducing the catalyst amount by 20 to 10 % yield remains
almost same (Table 1, Entry 6). No reaction occurred in the
absence of catalyst (Table 1, Entry 1). In addition, no other
additive was needed for this system, and the experimental
process was quite simple and easy.
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Table 1: Optimisation of reaction conditiona
Scheme 3. Reagents and conditions: (i) POCl
, DMF, CH COONa,
3
3
0oC to rt, 3h; (ii) aqueous NaOH, dioxane, reflux, 10 min.
S.no Reaction conditiona
y
Mol (%)
b
(yield) %
No catalyst, 80˚C, CH CN
3
1
2
3
4
5
6
7
-
-
Scheme 4. Reagent and Conditions: (i) CuI (10mol %), refluxed in
water.
Table 2. Substrate scope of ferrocene tagged propargyl aminea
CuX, Rt, CH
CuCl, 80˚C, CH
CuBr, 80˚C, CH
3
CN, 24h
CN, 24h
CN, 24h
20
20
20
20
10
10
-
3
22
35
75
78
92
3
CuI, 80˚C, CH
3
CN, 6h
CN, 6h
CuI, 80˚C, CH
3
CuI, Water, 100˚C, 4h
Ent product
ry
R
1
(a-l)
R
2
Amine
Time (h)
Yieldb
%)
(
a
Reaction Conditions: Ferrocene caboxaldehyde, (1.0 mmol)), Piperidine
b
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9
5
Fc
Fc
Ph
Ph
Ph
Fc
Fc
Fc
Fc
Fc
Fc
Fc
Fc
Fc
Fc
Fc
Piperidine
Morpholine
Piperidine
Morpholine
Piperidine
Piperidine
Morpholine
Piperidine
Morpholine
Piperidine
Morpholine
Morpholine
Piperidine
4
92
(1.5mmol) and Phenylacetylene (1.2 mmol), Isolated yield, CuX (X=Br, Cl, I)
6
4
91
87
76
78
75
90
92
82
89
79
92
84
After optimisation of temperature and catalyst, the
establishment of the reaction conditions was undertaken by
investigating the effect of different solvents, and reaction
times. The choice of an appropriate reaction media is also of
crucial importance for successful synthesis. Our attention then
moved on to investigate the effect of solvents on the product
yields, and acetonitrile was replaced by water. Water
produced the desired Propargyl amine in a significantly higher
yield (92%) in less time (Table 1, Entry 7).
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2,5-OCH
4-OCH
2,5-OCH
4-NO
4-NO
3
C
6
H
4
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2.5
2.5
2
3
C
6
H
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3
C
6
H
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C
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H
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2
C
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H
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2.5
1.5
2.5
2
Napthyl
1
0
1
2
3
4-FC
6
H
5
1
1
1
4-OCH
3
C
6
H
5
Butyraldehyde
Fc
1.0
2.5
Scheme 2. Reagent and Conditions: (i) CuI (10mol %), refluxed in water
aReaction Conditions: Substituted aldehyde (Aromatic, Aliphatic and
Ferrocene carboxaldehyde, 1.0 mmol)), Piperidine/Morpholine (1.5mmol)
Having successfully optimized the reaction conditions for
b
and Phenylacetylene/ Ethynyl ferrocene (1.2 mmol), CuI (10 mol%), Isolated
preparation
of Propargyl amine using
Ferrocene
yield.
carboxaldehyde (Table 2, entry 1,2) Next to expand the
structural diversity, propargyl amine using Ethynyl ferrocene
was synthesized.
The same standardized protocol was used by refluxing
Piperidine, Benzaldehyde, with Ethynyl Ferrocene in the presence
2
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of CuI in water (Scheme 4). As compared to the scheme 2, it was
observed that the reaction between Piperidine, Ethynyl ferrocene
and Benzaldehyde completed within 2h (Table 2, entry 3).
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Acknowledgements
View Article Online
DOI: 10.1039/C9NJ00538B
SS is thankful to DST for the financial assistance through
Inspire Faculty Award No IFA-13-CH-123. IIT Mandi and CSIR-
CDRI was acknowledged for providing the spectral analytical
data.
Notes and references
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(a) B. B. Shingate, Organic Chem Current Res, 2012, 1(2), e107;
b) J. E. Biggs-Houck, A. Younai, and J. T. Shaw, Current Opinion
in Chemical Biology, 2010, 14(3), 371-382; (c) H. Eckert,
(
Scheme5. Reagent and Conditions: (i) CuI (10mol %), refluxed in
water
Molecules, 2012, 17, 1074-1102.
Subsequently, various Aldehydes, Alkynes, and Amines
were coupled and the results were summarized in Table 2.
Aromatic aldehydes carrying both electron-withdrawing and
electron-releasing substituents were also converted to their
corresponding Propargyl amine derivatives in relatively similar 4. J. J. Chen, D. M. Swope, J. Clin. Pharmacol. 2005, 45, 878-894.
times and yields (Table 2, entries 3-11). Aliphatic aldehyde also 5. J. Birks, L. Flicker, Selegiline for Alzheimer’s disease. Cochrane
gave excellent yield in less time as compared to aromatic
aldehyde (Table 2, entry 12). The Ferrocene carboxaldehyde,
was used for this transformation and gave very good yields
2
. K. Lauder, A. Toscani, N. Scalacci, and D. Castagnolo, Chem. Rev.
017, 117, 14091−14200.
. J. W. Langston, I. Irwin, E. B. Langston, L. S. Forno, Science, 1984,
225, 1480-1482.
2
3
Database of Systematic Reviews; John Wiley & Sons, Ltd:
Chichester, UK, 2003; Vol. 1,
CD00044210.1002/14651858.CD000442.
. M. Baranyi, P. F. Porceddu, F. Gol ncser, S. Kulcsa
. Kittel, A. Pinna, L. Frau, P. B. Huleatt, M.-L. Khoo, C. L. L. Chai,
P. Dunkel, P. Matyus, M. Morelli, B. Sperlagh, Mol.
Neurodegener , 2016, 11, 1-21.
. I. Bolea, A. Gella, M. Unzeta, J. Neural. Transm. 2013, 120, 893-
02.
p
6
̈
ö
́
́
r, L. Otrokocsi,
(Table 2, entry 13).
Aꢀ
́
́
7
8
9
. A. F. Abdel-Magid, K. G. Carson, B. D. Harris, C. A. Maryanoff,
and R. D. Shah, J. Org. Chem. 1996, 61, 3849-3862.
9. (a) D. R. van Staveren and N. Metzler-Nolte, Chem.
Rev., 2004, 104 (12), 5931-5986; (b) F. A. Larik, A. Saeed, T. A.
Fattah, U. Muqadar, P. A. Channar, Applied Organometallic
Chemistry, 2016, 1-22.; (c) M. F. R. Fouda , M. M. Abd‐Elzaher ,
R. A. Abdelsamaia, A. A. Labib, 2007, 21 (8), 613-625.
0. E. I. Edwards, R. Epton, G. Marr, J. Organomet. Chem. 1976, 107,
51-357.
1
3
Figure 2: Proposed Mechanistic pathway
1
1. S. Top, J. Tang, A. Vessieres, D. Carrez, C. Provote, and G.
Jaouen, Chem. Commun. 1996, 955-956.
A plausible mechanism is also proposed. The generated Copper 12. A. Kumar, S. Srivastava, G. Gupta, P. Kumar, and J. Sarkar, RSC
acetylide intermediate can react with the iminium ion prepared in-
Advances, 2013, 3, 3548-3552.
situ from the Aldehyde and the Secondary amines, to form the 13. A. Kumar, S. Maurya, K., and Suman Srivastava, Chem.
corresponding Propargylamine. Commun., 2016, 52, 2795-2798.
An efficient synthesis of Ferrocenyl tagged Propargylamines 14. (a) A. Kumar, S. Srivastava and G. Gupta, Green Chemistry, 2012,
through three-component coupling of Aldehydes, Secondary
amines and Alkynes in water is described by using copper iodide as
catalyst and to the best of our knowledge this is the first report of
the CH activation on Ethynyl ferrocene. This new method offers the
following competitive advantages: (i) Use of readily available, cheap
copper iodide as catalyst; (ii) Broad substrate applicability; (v) high
yields attained in short reaction times; (vi) simple and easy
operation. The protocol may find application in the diversity
oriented synthesis of chemoprobes with structural complexity.
Further the biological activity is underway.
14, 3269-3272; (b) A. Kumar, P. kumar, V D. Tripathi, S.
Srivastava, RSC Advances, 2012, 2, 11641-11644; (c) A. Kumar,
S. Srivastava, G. Gupta, V. Chaturvedi, S. Sinha, and R.
Srivastava, ACS. Combinatorial Science, 2011, 13, 65-71; (d) A.
Kumar, G. Gupta and S. Srivastava, Green Chemistry, 2011, 13,
459-2463; (e) A. Kumar, S. Srivastava, G. Gupta, Tetrahedron
Letters 2010, 51, 517-520; (f) A. Kumar, G. Gupta, and S.
Srivastava, J. Comb. Chem. 2010, 12, 458-462.
2
1
5. Submitted by Johann Polin and Herwig Schottenberger. Checked
by Bruce Anderson and Stephen F. Martin,.Organic Syntheses,
Coll. Vol. 9, p.411 (1998); Vol. 73, p.262 (1996).
Conflicts of interest
“
There are no conflicts to declare”.
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Novel Ferrocene-labeled Propargyl amines via CuI Multicomponent
Amination/Alkynylation
An efficient synthesis of ferrocene-tagged Propargyl Amine derivatives via one-pot three-component domino amination/alkynylation in water is
reported.
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R2 = Ar, Fc