An efficient copper catalyzed one-pot, four-component, and diastereoselective synthesis of highly functionalized ferrocenyl azetidinimines

Article abstract of DOI:10.1016/j.tetlet.2013.04.002

An efficient, facile, and diastereoselective synthesis of highly functionalized ferrocenyl azetidinimines from copper catalyzed one-pot, four-component reaction of ferrocenealdehyde, aromatic amines, tosyl azide, and aryl alkynes in high yield has been accomplished. A plausible reaction mechanism is provided.

Full text of DOI:10.1016/j.tetlet.2013.04.002

Tetrahedron Letters 54 (2013) 3007–3010
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An efficient copper catalyzed one-pot, four-component,
and diastereoselective synthesis of highly functionalized ferrocenyl
azetidinimines
Siddan Gouthaman a, Ponnusamy Shanmugam a, , Asit Baran Mandal b
⇑
a Organic Chemistry Division, CSIR–Central Leather Research Institute (CLRI), Adyar, Chennai 600020, India
b Chemical Laboratory, CSIR–Central Leather Research Institute (CLRI), Adyar, Chennai 600020, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, facile, and diastereoselective synthesis of highly functionalized ferrocenyl azetidinimines
from copper catalyzed one-pot, four-component reaction of ferrocenealdehyde, aromatic amines, tosyl
azide, and aryl alkynes in high yield has been accomplished. A plausible reaction mechanism is provided.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 17 January 2013
Revised 30 March 2013
Accepted 1 April 2013
Available online 8 April 2013
Keywords:
Multicomponent reaction
Azetidinimines
Ferrocene
Copper catalyst
Ligands
Ferrocene1 molecule has drawn the attention of chemists owing
to its applications in organic synthesis,2,3 development of new mate-
rials,4 bio-organometallic chemistry,5 and asymmetric catalysis.6
Nitrogen heterocyclic compounds of ferrocene are in the current
scenario, especially in asymmetric synthesis7 and in the develop-
ment of novel therapeutics8 (Fig. 1). Azetidines9 and azetidinones10
are important class of small ring nitrogen heterocyclic compounds
found in many natural products and exhibit interesting biological
and pharmacological properties.11 Azetidines have been success-
fully utilized as ligands,12 catalysts in various asymmetric synthe-
ses13 and in ring opening reactions to prepare nitrogen-containing
organic compounds.14 Multicomponent reactions15,16 (MCRs) are
considered as a powerful tool to generate complex molecular archi-
tectures from simple and readily available substrates in a one-pot
manner. In recent years, the transition-metal-catalyzed MCRs are
of high importance because they have excellent catalytic efficiency
in most cases. Nevertheless, it requires harsh conditions; mean-
while, protocolsthat allowmuch milderconditionshave been devel-
oped. Copper (I) catalyzed17 MCRs concerning sulfonyl azides and
alkynes have been extensively used.18 Fokin et al and Xu et al
described a Cu-catalyzed, three-component cascade reaction to gen-
erate an impressive array of N-sulfonylazetidin-2-imine18a and
2-(sulfonylimino)-4-(alkylimino) azetidine derivatives,19 respec-
tively. However, no reports are available in the literature on the
O
R1
2
R
S
H
N
S
HN
Fe
Fe
S
N
O
N
O
CO2H
O
A
B
CO2H
R1
R2
H
N
Fe
O
N
CH2OCOMe
CO2H
O
C
Figure 1. Structure of ferrocenyl–penicillin A and ferrocenyl–penicillin B, and a
ferrocenyl–cephalosporin C.
Cl
O
N
S
H
O
S
O
O
N
Table 1
82%
N
N3
H
H
Fe
Fe
Cl
3a
1a
2
4a
⇑
Corresponding author. Tel.: +91 044 24437129; fax: +91 44 24911589.
E-mail address: shanmu196@rediffmail.com (P. Shanmugam).
Scheme 1. Synthesis of ferrocenyl azetidinimine 4a.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.002

3008
S. Gouthaman et al. / Tetrahedron Letters 54 (2013) 3007–3010
Table 1
synthesis of ferrocenyl azetidinimines. Therefore, in continuation of
our work on the challenge existed for ferrocene derivatives,20 herein
we report an efficient synthesis of ferrocenyl azetidine-2-imines via
copper catalyzed alkyne–azide cascade reaction as a key step.
Initially, we investigated a cascade reaction of an equimolar
mixture of ferrocenylimine 1a, p-toluenesulfonyl azide 2, phenyl
acetylene 3a, and activated 5 Å molecular sieves in acetonitrile
stirred with 20 mol % CuI and 2.0 equiv of Et3N under nitrogen
atmosphere at room temperature (Scheme 1). The imine 1a was
prepared from ferrocenealdehyde and 4-chloroaniline in toluene
at reflux temperature. Thin layer chromatography (TLC) analysis
showed the progress of the cascade four-component reaction oc-
curred in 13 h. The reaction afforded a single product of ferrocenyl
azetidinimine 4a in 75% yield after purification by column chroma-
tography (Table 1, entry 1).
Optimization of synthesis of 4a
Entry
CuI (mol %)
Solvent
Base (equiv)
Time (h)
% Yield of 4aa,b
1
2
3
4
20
20
20
20
20
15
10
10
10
10
10
5
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCM
Et3N (2)
Py
DABCO
13
14
14
14
13
13
13
14
14
14
13
15
75
65
45
0
80
82
82
60
43
72
65
50
K2CO3
5
Et3N (1.5)
Et3N (1.5)
Et3N (1.5)
Et3N (1.5)
Et3N (1.5)
Et3N (1.5)
Et3N (1)
Et3N (1.5)
6
7c
8
9
THF
10
11
12
Toluene
CH3CN
CH3CN
a
b
c
All the reactions were performed at room temperature.
Isolated yield after column purification.
Optimized condition.
The structure of the compound 4a was assigned based on spec-
troscopic analysis such as Fourier transform infrared (FTIR), 1H nu-
clear magnetic resonance (NMR), 13C NMR, and high resolution
mass spectrometry (HRMS). The relative stereochemistry of com-
pound 4a was derived from single crystal X-ray analysis (Fig. 2).21
To optimize the reaction conditions, variables such as base,
mol % of Cu catalyst and solvent have been considered. Among
the screened bases such as Et3N, pyridine, DABCO, and K2CO3,
Et3N proved to be the most effective for this transformation and
provided compound 4a in 75% yield (Table 1, entries 1–4). Further
reducing equivalent of base to 1.5 afforded a marginally improved
yield (Table 1, entry 5), while with 1 equiv provided lesser yield
(Table 1, entry 11). Loading of CuI was reduced from 20 mol % to
15 mol % and to 10 mol % which had no adverse effect on the prod-
uct yield (Table 1, entries 5–7). Further decrease in catalyst load
(5 mol %) had an inferior product yield (Table 1, entry 12). The
reaction in solvents such as CH2Cl2, CHCl3, THF and toluene was
surveyed and found to provide lesser yield (Table 1, entries 8–
10). An optimum yield was obtained when the reaction was carried
out in CH3CN with 10% of CuI and 1.5 equiv of Et3N at ambient
temperature (Table 1, entry 7).
Figure 2. ORTEP diagram of ferrocenyl azetidinimine 4a.
Table 2
Synthesis of ferrocenyl azetidinimines 4a–p
R2
R3
O
N
S
10 mol % CuI, TEA
CH3CN, N2, RT,
H
O
S
O
N
R1
O
3
N3 + R
N
+
R1
Fe
Fe
R2
13-15h
R3=C6H5 3a;
CF3-4-C6H4
SiMe3
1a-x
4a-p
2
3b;
3c
Entry
Imine
Alkyne 3
Azetidine imine 4
% Yielda
drc
R1
R2
1
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4-Cl-C6H4
4-Me-C6H4
4-OMe-C6H4
4-NMe2-C6H4
C6H5
4-Br-C6H4
4-F-C6H4
4F-3Cl-C6H3
3-Br-C6H4
3-F-C6H4
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1b
1m
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3a
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
82
84
83
86b
82
79
73
69
72
60
73
81
73
63
91:9
92:8
91:9
97:3
95:5
95:5
94:6
97:3
94:6
97:3
95:5
96:4
94:6
95:5
9
10
11
12
13
14
4-CF3-C6H4
Napthyl
4-Me-C6H4
2-Br-C6H4

S. Gouthaman et al. / Tetrahedron Letters 54 (2013) 3007–3010
3009
Table 2 (continued)
Entry
Imine
Alkyne 3
Azetidine imine 4
% Yielda
drc
R1
R2
1
15
16
17
18
19
20
21
22
23
24
H
CH3
H
H
H
H
H
H
H
Cyclohexyl
4-OMe-C6H4
5-quinolin
4-prydyl
3-NO2-C6H4
4-NO2-C6H4
4-CN-C6H4
tosyl
1n
1o
1p
1q
1r
1s
1t
1u
1v
1w
3c
3a
3a
3a
3a
3a
3a
3a
3a
3a
4o
4p
4q
4r
4s
4t
4u
4v
4w
4x
76
76
0d
0d
0d
0d
0d
0d
0d
0d
94:6
97:3
––
––
––
––
––
––
––
2,6-di-Cl-C6H3
2,6-dimethyl-C6H3
H
––
a
All the reactions were performed using 10% of CuI and 1.5 equiv of Et3N and CH3CN as solvent at rt.
Reaction was performed using 10% of CuI and 1 equiv of Et3N.
Diastereomeric ratio was determined using 1H NMR of the crude products.
Decomposed.
b
c
d
(Table 2, entries 19–22). It should be noted that reactions of 2,6-
disubstituted ferrocenyl imine 1v and 1w became sluggish pre-
sumably due to steric factors (Table 2, entries 23 and 24). The
structure of all the new compounds was assigned based on spec-
troscopic analysis (FTIR, 1H NMR, 13C NMR and HRMS).22
A plausible mechanism for the formation of ferrocenyl azetidi-
nimine 4 is shown in Scheme 2. Initially alkyne 3 reacts with sul-
fonyl azide 2 in the presence of Et3N and CuI through two
possible pathways I and II to form intermediates B and D, respec-
tively. Both the intermediates B and D afforded the ketenimine
intermediate C with regeneration of copper catalyst. The interme-
diate C then reacts with ferrocenyl imine 1 through a [2+2]-cyclo-
addition17 to afford the observed product 4.
In conclusion, the studies have led to the development of four-
component synthesis of novel nitrogen heterocyclic substituted ri-
gid ferrocenyl azetidinimine in good yield. The reaction has been
demonstrated with an ample scope of the substrate and good func-
tionality tolerance. The process opens a new pathway toward di-
rect formation of N-heterocyclic substituted ferrocenyl derivative.
Further work in this area is under investigation.
[CuLn]
i
-[CuLn]
H
N
SO2R4
-N2
R3
SO2R4
B
N
N
[CuLn],
N
H
N
2
N
R3
N SO2 R4
[CuLn]
B(base)
-BH
N
R1
1
R3
C
NSO2R4
Fe
R3
H
C
3
N
N
-[CuLn]
N SO2R4
[CuLn]
H
R3
-N2
ii
R3
NSO2R4
Fe
N
R1
R2
4
Scheme 2. Plausible mechanism for the formation of ferrocenyl azitidinimines 4.
In order to demonstrate the scope and limitation for this cas-
cade reaction, under optimized condition, experiments with num-
ber of substituted ferrocenylimines 1a–x, p-toluenesulfonyl azide 2
and alkynes 3a–c had been carried out. All the reactions proceeded
smoothly and provided corresponding ferrocenyl azetidinimines
4a–p in good yield and the results are summarized in Table 2.
Electron releasing and withdrawing groups at 3- and 4-posi-
tions of the benzene ring of ferrocenyl imines 1a–x were employed
as substrates in this reaction. It has been observed that electron
rich ferrocenyl imines afforded corresponding products 4b–e in
excellent yield (Table 2, entries 2–5). Ferrocenyl imines 1a, 1f–j
having halogen substituent at the 3 and 4 positions of the benzene
ring afforded the desired products 4a, 4f–j in good yield (Table 2,
entries 1 and 6–10). We then examined with N4, N4-dimethyl de-
rived ferrocenyl imine 1d and the reaction proceeded smoothly
to provide corresponding ferrocenyl azetidinimine 4d. Extending
Acknowledgment
S.G. thanks CSIR (New Delhi) for the award of a Junior Research
Fellowship. Funding support from CSIR-12th five year plan project
‘‘STRAIT’’ is acknowledged.
Supplementary data
Supplementary data (general experimental procedure, com-
plied spectroscopic data of new compounds and scanned copies
of spectra) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2013.04.002.
the scope of 4-ethynyl-a,a,a-trifluoro toluene 3b and trimethylsi-
lylacetylene 3c as an alkyne counterpart furnished very good yield
References and notes
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Tetrahedron Lett. 2006, 47, 2205–2208; (e) Golding, P.; Millar, R. W.; Paul, N. C.;
Richards, D. H. Tetrahedron 1995, 51, 5073–5082.
yield Rf = 0.50; mp = 176–178 °C, FTIR (KBr)
m
max: 3088, 3035, 2934, 1615,
1590, 1573, 1494, 1314, 1243, 1115, 893, 734. 688 cmꢁ1
;
1H NMR (CDCl3/TMS,
500.1 MHz): d 7.51 (s, 1H), 7.50 (s, 1H), 7.38 (m, 5H), 7.24 (d, J = 8.5 Hz, 2H),
7.12 (d, J = 8.5 Hz, 2H), 7.01 (d, J = 10.0 Hz, 2H), 5.08 (d, J = 2.5 Hz, 1H), 5.05 (d,
J = 2.5 Hz, 1H), 4.43 (s, 1H), 4.29 (m, 2H), 4.25 (s, 1H), 4.14 (s, 5H), 2.31 (s, 3H)
ppm; 13C NMR (CDCl3/TMS, 125.7 MHz): d 165.1, 142.2, 139.3, 137.0, 135.4,
129.1, 129.1, 128.9, 128.5, 128.2, 126.6, 125.4, 119.1, 82.1, 70.8, 68.8, 68.5,
66.5, 58.5, 21.5 ppm; ESI mass: calcd for C32H27ClN2SO2Fe2+ m/z = 594.936;
found 594.802 (M+1). 4d Pale yellow powder, 0.252 g 86% yield; Rf = 0.45
(hex:EtOAc = 7:3); mp= 158–160 °C, FTIR (KBr)
mmax: 3066, 3030, 1725, 1618,
1526, 1295, 1154, 684 cmꢁ1 1H NMR (CDCl3/TMS, 500.1 MHz): d 7.68 (d,
;
J = 8.5 Hz, 2H), 7.32 (d, J = 7.5 Hz, 2H), 7.09 (m, 1H), 6.99 (m, 4H), 6.86 (d,
J = 7.0 Hz, 2H), 6.78 (d, J = 8.5 Hz, 2H), 5.71(d, J = 5 Hz,1H), 5.11(d,
J = 5.5 Hz,1H), 3.96 (s, 5H), 3.86 (s, 2H), 3.78 (s, 1H), 3.50 (s, 1H), 2.96 (s, 6H),
2.29 (s, 3H) ppm; 13C NMR (CDCl3/TMS, 125.7 MHz): d 164.9, 149.0, 142.0,
139.7, 129.7, 128.9, 127.8, 127.2, 126.7, 126.5, 122.8, 112.3, 83.1, 69.1, 68.5,
67.0, 66.4, 65.0, 56.6, 40.7, 21.6; ESI mass: calcd for C34H33N3O2SFe m/z:
604.58; found 604.58(M+1). 4l Pale yellow powder, 0.234 g, 82% yield; Rf = 0.65
15. For a monograph see Multicomponent Reactions; Zhu, J., Bienaymé, H., Eds.;
Wiley-VCH: Weinheim, Germany, 2005.
16. (a) Sunderhaus, J. D.; Martin, S. F. Chem. Eur. J. 2009, 15, 1300–1308; (b)
Isambert, N.; Lavilla, R. Chem. Eur. J. 2008, 14, 8444–8454; (c) Dömling, A. Chem.
Rev. 2006, 106, 17–89; (d) Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471–
1499; (e) Bienaymé, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6,
3321–3329; (f) Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210;
(g) Ugi, I.; Dömling, A.; Werner, B. J. Heterocycl. Chem. 2000, 37, 647–658; (h)
Weber, L.; Illgen, Kü.; Almstetter, M. Synlett 1999, 366–374; (i) Armstrong, R.
W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res.
1996, 29, 123–131; (j) Ugi, I.; Dömling, A.; Hörl, W. Endeavour 1994, 18, 115–
122; (k) Posner, G. H. Chem. Rev. 1986, 86, 831–844.
(hex:EtOAc = 7:3); mp = 184–186 °C, FT IR (KBr)
m
max: 3060, 2924, 1616, 1595,
1500, 1457, 1416, 1304, 1151, 1089, 1043, 897, 687 cmꢁ1
;
1H NMR (CDCl3/
TMS, 500.1 MHz) 7.93 (d, J = 9.0 Hz, 1H), 7.79–7.85 (m, 1H), 7.79 (t, J = 4.5 Hz,
1H), 7.55–7.53 (m, 2H), 7.50–7.49 (m, 2H), 7.43–7.39 (m, 5H), 7.13 (d,
J = 8.0 Hz, 2H), 6.97 (d, J = 2.5 Hz, 2H), 5.29 (d, J = 1.5 Hz, 1H), 5.05 (d, J = 2.0 Hz,
1H), 4.40(s, 1H), 4.24 (s, 1H), 4.09 (s, 1H), 3.92 (s, 5H), 3.90 (s, 1H), 3.32 (s, 3H)
ppm; 13C NMR (CDCl3/TMS, 125.7 MHz): d 168.0, 129.3, 128.8, 128.7, 128.3,
128.1, 126.8, 126.5, 125.3, 123.7, 123.2, 82.17, 72.7, 69.7, 69.2, 69.1 68.6, 66.0,
58.8, 21.5 ppm; ESI mass: calcd for
611.2098 (M+1).
C36H30FeN2O2S m/z: 611.20; found