Direct Mannich reaction mediated by Fe(Cp)2PF6 under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2009.11.022

Fe(Cp)₂PF₆ (5 mol %) efficiently catalyzed Mannich reaction of aldehydes, anilines, and ketones under solvent-free condition to give β-amino-ketones in high yield (up to 94%) within 30 min with anti-isomer in excess. Simple experimental conditions and product isolation procedure makes this protocol potential for the development of clean and environment-friendly strategy for the synthesis of β-amino-ketones.

Full text of DOI:10.1016/j.tetlet.2009.11.022

Tetrahedron Letters 51 (2010) 489–494
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Direct Mannich reaction mediated by Fe(Cp)2PF6 under solvent-free conditions
a
a
a
a
Rukhsana I. Kureshy a, , Santosh Agrawal , S. Saravanan , Noor-ul H. Khan , Arpan K. Shah ,
*
Sayed H. R. Abdi a, Hari C. Bajaj a, E. Suresh b,
a Discipline of Inorganic Materials and Catalysis, Central Salt and Marine Chemicals Research Institute (CSMCRI), Council of Scientific and Industrial Research (CSIR), G.B. Marg,
Bhavnagar 364 002, Gujarat, India
b Analytical Science Discipline, Central Salt and Marine Chemicals Research Institute (CSMCRI), Council of Scientific and Industrial Research (CSIR), G.B. Marg, Bhavnagar 364 002,
Gujarat, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Fe(Cp)2PF6 (5 mol %) efficiently catalyzed Mannich reaction of aldehydes, anilines, and ketones under sol-
vent-free condition to give b-amino-ketones in high yield (up to 94%) within 30 min with anti-isomer in
excess. Simple experimental conditions and product isolation procedure makes this protocol potential for
the development of clean and environment-friendly strategy for the synthesis of b-amino-ketones.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 17 August 2009
Revised 4 November 2009
Accepted 6 November 2009
Available online 12 November 2009
Keywords:
Mannich reaction
Carbonyl compounds
Fe(Cp)2PF6
Solvent-free synthesis
Catalysis
The Mannich reaction is an important carbon–carbon bond
forming reaction in organic synthesis1 for the preparation of
b-amino carbonyl compounds which are vital intermediates in
pharmaceuticals and natural products.2 Attempts have been made
in the past to improve methodologies based on two-component
reactions, where the imine as electrophile is pre-formed and then
reacted with nucleophiles such as enolates, enol ethers, and enam-
ines.3 However, in most cases these protocols use hazardous or-
ganic solvents4 and suffer from long reaction time with low
yields and poor selectivity. Therefore, the development of modern
versions5 of the reaction that work under mild conditions is of
great importance. A more appropriate version of Mannich reaction
involved the one-pot three-component approach that allowed a
wide range of structural variations in the reactants—aldehydes,
anilines, and ketones to give Mannich product using an appropriate
catalyst such as organo-catalyst6 and transition metal-based Lewis
acid catalysts7 in hazardous solvents such as CH2Cl2, CH3CN,
DMSO, NMP, and THF. Nevertheless, few recent reports have suc-
cessfully used organic molecules as catalysts under aqueous med-
ium8 or under solvent-free conditions. However, in these cases the
organo-catalysts produce colloidal dispersion or form emulsion
where phase separation is often difficult.9 The use of iron-based
catalyst is of particular interest because of its abundance in nature,
less toxicity, and environmentally benign nature.10
Due to the attributes described above for the use of iron in
catalysis and our current interest in developing solvent-free11,12
and environmentally benign synthetic protocols for different
organic transformations,11–13 here we have demonstrated sol-
vent-free protocol for the Mannich reaction using Fe(Cp)2PF6 as a
catalyst in the preparation of b-amino ketones (yields up to 94%)
at room temperature in short time (ꢀ30 min). To the best of our
knowledge Fe(Cp)2PF6 was used for the first time as a catalyst to
carry out Mannich reaction.
Initially, in order to find out optimal catalyst loading the three-
component Mannich reaction was carried out using benzaldehyde,
aniline, and cyclohexanone as a representative reactants with
1–5 mol % of Fe(Cp)2PF6. The best result in terms of yield (94%)
for the formation of b-amino ketone was achieved within 30 min
with the catalyst loading of 5 mol % (Table 1, entry 3).
With this catalyst loading (5 mol %), the Mannich reaction of
benzaldehyde and cyclohexanone with various amines viz., aniline,
2-MeO aniline, 4-Me aniline, 2-Cl aniline, and 4-Cl aniline was
carried out and the data are presented in Table 2. The product yield
was excellent in all the cases however the selectivity for anti-
isomer was highest in the case of unsubstituted aniline as evident
from 1H NMR results. Barring 4-methyl aniline (entry 3) where the
diastereoselectivity for the anti product was more, the syn:anti
ratio was near 1 for other substituted anilines used in the present
study.
* Corresponding author. Tel.: +91 0278 2567760; fax: +91 0278 2566970.
E-mail address: rukhsana93@yahoo.coin (R.I. Kureshy).
Tel.: +91 0278 2567760, Fax: +91 0278 2566970.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.022

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R. I. Kureshy et al. / Tetrahedron Letters 51 (2010) 489–494
Table 1
The effect of catalyst loading on three-component Mannich reaction of benzaldehyde with aniline and cyclohexanonea
Entry
Catalyst mol (%)
Time (min)
Yieldb (%)
1
2
3
1
3
5
30
30
30
61
86
94
a
All reactions were carried out at room temperature using benzaldehyde (1 mmol), aniline (1 mmol), cyclohexanone (2 mmol).
Isolated yield.
b
Table 2
Data for the Mannich reaction of various aniline with benzaldehyde and cyclohexanonea
Entry
1
Amine
Product
Yieldb,c [syn:anti]
94 (24:76)
2
89 (44:56)
3
90 (37:63)
4
85 (49:51)
(Fig. 1)
5
88 (48:52)
a
b
c
All reactions were carried out at room temperature using, benzaldehyde (1 mmol), amine (1 mmol) cyclohexanone (2 mmol), and Fe(Cp)2PF6 (5 mol %).
Isolated yield.
Syn/anti ratio has been calculated by 1H NMR spectroscopy.

R. I. Kureshy et al. / Tetrahedron Letters 51 (2010) 489–494
491
Table 3
Data for the Mannich reaction of various aldehydes with aniline and cyclohexanonea
Entry
Aldehydes (R)
Product
Yieldb,c [syn:anti]
1
94 (24:76)
2
88 (33:67)
3
90 (32:68)
4
5
93(30:63)
92 (35:65)
6
89 (44:56)
7
90 (24:76)
(Fig. 2)
8
79(33:67)
(continued on next page)

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R. I. Kureshy et al. / Tetrahedron Letters 51 (2010) 489–494
Table 3 (continued)
Entry
Aldehydes (R)
Product
Yieldb,c [syn:anti]
9
76 (39:61)
10
11
80 (34:66)
77(34:66)
12
13
89 (34:66)
85 (55:45)
14*
81 (48:52)
*
The reaction was conducted with benzaldehyde, aniline, and cyclooctanone under the present reaction conditions.
a
All reactions were carried out at room temperature using aldehyde (1 mmol), aniline (1 mmol) cyclohexanole (2 mmol), and Fe(Cp)2PF6 (5 mol %).
Isolated yield.
b
c
Syn/anti ratio has been calculated by 1H NMR spectroscopy.
Figure 1. ORTEP diagram of the compound (Table 2, entry 4) with atom numbering
Figure 2. ORTEP diagram of the compound (Table 3, entry7) with atom numbering
scheme (30% probability factor for the thermal ellipsoids).
scheme (30% probability factor for the thermal ellipsoids).

R. I. Kureshy et al. / Tetrahedron Letters 51 (2010) 489–494
493
Table 4
Data for the Mannich reaction of various aniline with benzaldehyde and acetonea
Entry
Amine
Product
Yieldb
1
89
86
2
3
4
82
88
a
All reactions were carried out at room temperature using, aldehyde (1 mmol), aniline (1 mmol) acetone (2 mmol), and Fe(Cp)2PF6 (5 mol %).
Isolated yield.
b
Based on the above observations we varied aldehydes namely,
ring of aldehyde moiety had significant effect on overall yield of
the product b-amino ketone. The aldehydes with electron-donating
groups (–OMe, –Me) gave higher yield of b-amino ketone (entries
2–7) than the aldehydes having electron-withdrawing groups (en-
tries 8–11). Relatively, the aldehydes with electron-withdrawing
groups favored the formation of anti-isomer as against respective
aldehydes with electron-withdrawing groups, nevertheless
4-Me benzaldehyde, 3-Me benzaldehyde, 2-Me benzaldehyde, 4-
MeO benzaldehyde, 3-MeO benzaldehyde, 2-MeO benzaldehyde,
4-F benzaldehyde, 4-Cl benzaldehyde, 4-Br benzaldehyde, 4-NO2
benzaldehyde, 2-thiophene-carboxaldehyde, and hydrocinnamal-
dehyde while retaining other reactant (aniline and cyclohexanone)
(Table 3). The electronic effect of substituents present on benzene
Scheme 1. Probable path for the product formation in three-component Mannich reaction.

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case of hydrocinnamaldehyde 89% product yield was obtained
with syn:anti ratio of 34:66 whereas in the case of 2-thiophene-
carboxaldehyde 85% yield of b-amino ketone was achieved with
marginally higher syn diastereoselectivity. On conducting the Man-
nich reaction with benzaldehyde and cyclooctanone with aniline
under the identical reaction conditions the Mannich product was
obtained in 81%, however in this case the syn:anti ratio was near
1 (entry 14).
The present Mannich protocol worked well under the identical
reaction condition even with less reactive ketone such as acetone
to give the Mannich product in 82–89% isolated yield with various
anilines and benzaldehyde (Table 4).
Scheme 1 depicts a probable route for the formation of b-amino
ketone. To understand this we conducted a series of experiments
with benzaldehyde, aniline, and cyclohexanone in the presence
and absence of Fe(Cp)2PF6 as catalyst. The reaction mixture when
stirred for 6 h in the absence of the catalyst showed no sign of
the product formation on TLC at room temperature. In an another
experiment, a mixture of benzaldehyde and cyclohexanone was
stirred in the presence of Fe(Cp)2PF6 for 6 h which failed to give
any aldol condensation product. This rules out the path-A for the
product formation. However, when pre-formed imine (a condensa-
tion product of benzaldehyde and aniline) was allowed to react
with cyclohexanone in the presence of Fe(Cp)2PF6 at room temper-
ature the product b-amino-ketone formed in a similar manner with
similar syn:anti ratio as in the case of reaction conducted as per the
condition given in Table 2 (entry 1). Based on these observations it
can be concluded that path-B is operative in the present catalytic
protocol.
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In conclusion we have developed a very simple, efficient, and
eco-friendly protocol for the synthesis of b-amino ketone using
easily commercially available Fe(Cp)2PF6 as a catalyst under sol-
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Acknowledgements
S.A. thanks CSIR for awarding the Senior Research Fellowship.
R.I.K. is thankful to DST and CSIR, Net Work project for financial
assistance and also to ‘Analytical Discipline’ for providing instru-
mentation facility.
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