Fe(Cp)2PF6 catalyzed efficient Strecker reactions of ketones and aldehydes under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2007.11.136

The synthesis of α-aminonitriles of ketones and aldehydes was performed in very short reaction times (20 min) with excellent yields in the presence of 5 mol % of Fe(Cp)₂PF₆ under solvent-free conditions.

Full text of DOI:10.1016/j.tetlet.2007.11.136

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Tetrahedron Letters 49 (2008) 640–644
Fe(Cp)2PF6 catalyzed efficient Strecker reactions of ketones
and aldehydes under solvent-free conditions
a,
a
a
a
*
Noor-ul H. Khan , Santosh Agrawal , Rukhsana I. Kureshy , Sayed H.R. Abdi ,
Surendra Singh a, Eringathodi Suresh b, Raksh V. Jasra a
a Discipline of Inorganic Materials and Catalysis, Central Salt and Marine Chemicals Research Institute (CSMCRI), Bhavnagar 364 002, Gujarat, India
b Analytical Science Discipline, Central Salt and Marine Chemicals Research Institute (CSMCRI), Bhavnagar 364 002, Gujarat, India
Received 8 October 2007; revised 15 November 2007; accepted 22 November 2007
Abstract
The synthesis of a-aminonitriles of ketones and aldehydes was performed in very short reaction times (20 min) with excellent yields in
the presence of 5 mol % of Fe(Cp)2PF6 under solvent-free conditions.
Ó 2007 Published by Elsevier Ltd.
Keywords: Strecker reaction; Aldehydes; Ketones; Fe(Cp)2PF6; Solvent-free
a-Aminonitriles are valuable intermediates for the syn-
thesis of a-amino acids1 and a variety of nitrogen-contain-
ing heterocycles2 such as imidazoles and thiadiazoles.
These are versatile synthons in organic chemistry3. In gen-
eral, a-aminonitriles are prepared4 by the reaction of alde-
hydes/ketones with amines in the presence of a cyanide
source such as HCN,3 KCN,5a TMSCN,5b, (EtO)2-
P(O)CN,5c Et2AlCN5d and Bu3SnCN,5e which are often
hazardous, toxic and involve harsh reaction conditions.6
Lewis acids such as Cu(OTf)2,7 BiCl3,8 NiCl2,9 InCl3,10
RuCl3,11 Sc(OTf)3,12 La(NO3)3Á6H2O or GdCl3Á6H2O13
workers20 used Ga(III) triflate in dichloromethane. Water
as reaction medium was also reported for preparing a-
aminonitriles,5f but due to the reversible nature of the reac-
tion, unreacted starting materials remained along with cya-
nohydrins as by-products. This made the isolation of pure
a-aminonitriles difficult under aqueous conditions. There-
fore, a system devoid of solvent21 or using a non-hazardous
solvent, for the synthesis of a-aminonitriles in good yields
using ketones as substrates and short reaction times would
Table 1
14
and I2 in stoichiometric or catalytic amounts have been
The effect of catalyst loading on the one-pot synthesis of a-aminonitriles
under solvent-free conditionsa
used to catalyze the Strecker reaction under milder condi-
tions with aldehydes, and there are also a few reports not
using these as a catalyst.15 Solid catalysts such as, hetero-
poly acids,16 Montmorillonite KSF clay,17 and guanidine
O
NC
NH2
Fe(Cp)2PF6
(1-5 mol %)
N
H
TMSCN
+
+
rt, neat, 20 min
18
hydrochloride have been employed with aldehydes only
Entry
Mol [%]
Yieldb [%]
for the synthesis of a-aminonitriles. For ketones, Matsum-
oto19 reported the synthesis of a-aminonitriles at very high
pressure in long reaction times, while Olah and co-
1
2
3
a
1
2.5
5
78
86
94c
Fe(Cp)2PF6 (1–5 mol %), acetophenone (1 mmol), aniline (1 mmol)
and TMSCN (1.3 mmol); reaction time 20 min.
*
Corresponding author. Tel.: +91 0278 2567760; fax: +91 0278
b
Isolated yields.
2566970.
c
Complete conversion on TLC.
E-mail address: khan2593@yahoo.co.in (N.H. Khan).
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.11.136

N. H. Khan et al. / Tetrahedron Letters 49 (2008) 640–644
641
Table 2
One-pot synthesis of a-aminonitriles from various ketones catalyzed by Fe(Cp)2PF6 under solvent-free conditionsa
O
R1 CN
Fe(Cp)2PF6
(5 mol %)
R-NH2
TMSCN
R1
R2
rt, neat, 20 min.
R2
NH
R
Entry
1
Ketone
Amine
Product
Yieldb[%]
94
O
CN
H3C
NH2
CH3
N
H
CH3
O
NH2
NH2
NH2
NH2
CN
2
3
4
5
6
92
82
86
81
90
N
H
CH3
O
CN
H3C
CH3
N
H
F
F
O
CN
H3C
N
H
CH3
H3C
H3C
O
CN
H3C
CH3
N
H
Br
O
Br
CN
H3C
NH2
N
H
CH3
CH3
O
CN
NH2
7
89
N
H
CH3
O
CN
H3C
H3C
NH2
8
9
CH3
CH3
79
88
N
H
O2N
O2N
O
CN
NH2
N
H
O
O
NH2
CN
10
68
N
H
CN
NH2
Cl
H3C
11
12
73
78
CH3
N
H
Cl
O
NH2
CN
H3C
CH3
O
N
H
CN
H3C
NH2
13
90c
CH3
N
H
a
Fe(Cp)2PF6 (5 mol %), ketone (1 mmol), aniline (1 mmol) and TMSCN (1.3 mmol); reaction time 20 min.
Isolated yield.
Using 10 mmol ketone.
b
c

642
N. H. Khan et al. / Tetrahedron Letters 49 (2008) 640–644
Table 3
One-pot synthesis of a-aminonitriles from various aldehydes catalyzed by Fe(Cp)2PF6 under solvent-free conditionsa
O
R1 CN
Fe(Cp)2PF6
(5 mol%)
R-NH2
TMSCN
R1
H
rt, neat, 20 min.
NH
R
H
Entry
1
Aldehyde
Amine
Product
Yieldb [%]
94
CN
NH2
CHO
N
H
CN
CHO
NH2
NH2
NH2
NH2
NH2
2
3
4
5
6
85
86
82
68
84
N
H
MeO
S
MeO
S
H
N
CHO
CHO
CN
H
N
O
O
CN
NC
CHO
CHO
N
H
CN
N
H
H3C
H3C
CN
CHO
NH2
NH2
N
7
8
9
87
84
80
H
OMe
OMe
CN
H3C
H3C
H3C
H3C
CH2CHO
CHO
N
H
CH2
CN
NH2
N
H
CN
NH2
NH2
NH2
10
11
12
93
81
65
N
CHO
S
H
S
CN
CHO
N
H
MeO
H3CO
CN
CHO
6
N
6
H

N. H. Khan et al. / Tetrahedron Letters 49 (2008) 640–644
643
Table 3 (continued)
Entry
Aldehyde
Amine
Product
Yieldb [%]
CN
NH2
Cl
CHO
13
14
90
N
H
Cl
CN
CHO
CHO
NH2
NH2
91
89
N
H
Cl
F
Cl
F
CN
15
N
H
a
Fe(Cp)2PF6 (5 mol %), aldehyde (1 mmol), aniline (1 mmol) and TMSCN (1.3 mmol); reaction time 20 min.
isolated yields.
b
be of interest.22 Previously, we reported the use of
line and TMSCN gave a 78% yield of a-aminonitrile within
20 min (Table 2, entry 12).
Fe(Cp)2PF6 as a catalyst for the cyanosilylation of car-
bonyl compounds under solvent-free conditions23 and here
we report the utility of Fe(Cp)2PF6 as a catalyst to produce
a-aminonitriles of ketones in high yields under solvent-free
conditions at room temperature with various amines. To
establish the generality of the reaction, we have also
extended this protocol to aldehydes.
Fe(Cp)2PF6 (1–5 mol %) with acetophenone, TMSCN
and aniline as a representative substrate, gave the corre-
sponding a-aminonitrile in 94% yield with a catalyst load-
ing of 5 mol % within 20 min (Table 1, entry 3) under
solvent-free conditions at room temperature. Reducing
the catalyst loading to 1 mol % gave a 78% yield of
;a-aminonitrile under identical reaction conditions
(Table 1, entry 1). No cyanohydrin trimethylsilyl ether
(from the ketone and trimethylsilyl cyanide) was detected,
perhaps due to the rapid formation and activation of the
imines by the Fe(Cp)2PF6 catalyst.
The synthesis of a-aminonitriles was also investigated by
the reaction of a variety of aromatic, aliphatic and hetero-
cyclic aldehydes with various amines using Fe(Cp)2PF6
(5 mol %) under identical reaction conditions. 4-Substi-
tuted benzaldehydes with an electron-donating group
(OCH3, CH3) gave poorer conversions (Table 3, entries 2
and 6) than those with electron-withdrawing groups (F,
Cl) (entries 14 and 15). 2-Thiophene-carboxaldehyde and
2-furan-carboxaldehyde gave good yields (entries 3 and
4), while an a,b-unsaturated aldehyde gave a somewhat
poorer yield (entry 5). Using benzylamine, yields varied
from 65% to 93%.
Scheme 1 depicts a probable mechanism for the forma-
tion of a-aminonitriles, which is based on the fact that no
cyanohydrin trimethylsilylether was detected. The amines
used are better nucleophiles than trimethylsilylcyanide,
hence, they react first with the carbonyl compound to
We extended our studies using a variety of aromatic and
aliphatic ketones and different amines using Fe(Cp)2PF6
(5 mol %). The data in Table 2 shows that substituents
on the aromatic ring of the ketone play a crucial role in
product formation. A 4-substituted acetophenone with an
electron-donating group (–CH3) gave a higher conversion
(Table 2, entry 4) than with an electron-withdrawing group
(–F, NO2) (entries 3 and 8). Furthermore, conducting the
reaction with an o-substituted acetophenone such as 2-bro-
moacetophenone gave an 81% yield of a-aminonitrile
within 20 min (Table 2, entry 5), and with 2-acetonaph-
thone and benzophenone, the former gave a good yield
(88%) of a-aminonitrile and the latter 68% (Table 2, entries
9 and 10). When benzylamine was used in combination
with acetophenone or propiophenone, good yields of the
corresponding a-aminonitriles were obtained. Reaction of
2-chloroaniline with acetophenone gave a yield of 73%
(Table 2, entry 11). Furthermore, reaction of an aliphatic
ketone versus 3-methyl-2-butanone as a substrate with ani-
R1
R2
R
R1
R2
-H2O
+
O
NH2
R
N
Substrate
R1
R
H
Fe
CN
PF 6
N
Catalyst
R2
Product
Catalytic
Cycle
R2
R1
HO Si
H2O
R1
NC Si
N
R
R
CN
Fe
N
PF6
Si
R2
Intermediate
Scheme 1. Probable mechanism of the formation of a-aminonitriles.

644
N. H. Khan et al. / Tetrahedron Letters 49 (2008) 640–644
Toru, T. Tetrahedron: Asymmetry 2004, 15, 1513–1516; (e) Vachal, P.;
Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012–10014; (f)
Suginome, M.; Yamamoto, A.; Ito, Y. Chem. Commun. 2002, 1392–
1393.
produce the corresponding imine. The in situ generated
imine was polarized by the catalyst making the imine car-
bon more prone to the attack by cyanide producing the
TMS-derivative of the a-aminonitrile, which was readily
hydrolyzed with water to give the product a-aminonitrile
(Scheme 1).
In conclusion, we have developed a clean and environ-
mentally friendly protocol for the one-pot synthesis of a-
aminonitriles in up to 94% yields, from ketones/aldehydes
in combination with an amine using readily available
Fe(Cp)2PF6 as catalyst and TMSCN as cyanide source
under solvent-free conditions.
6. (a) Martinez, R.; Ramon, D. J.; Yus, M. Tetrahedron Lett. 2005, 46,
8471–8474; (b) De, S. K. Synth. Commun. 2005, 35, 653–656; (c)
Sakurai, R.; Suzuki, S.; Hashimoto, J.; Baba, M.; Itoh, O.; Uchida,
A.; Hattori, T.; Miyano, S.; Yamaura, M. Org. Lett. 2004, 6, 2241–
2244; (d) Kobayashi, S.; Ishitani, H.; Ueno, M. Synlett 1997, 115–116;
(e) Mulzer, J.; Meier, A.; Buschmann, J.; Luger, P. Synthesis 1996,
123–132; (f) Horenstein, B. A.; Nakanishi, K. J. Am. Chem. Soc. 1989,
111, 6242–6246.
7. Paraskar, S.; Sudalai, A. Tetrahedron Lett. 2006, 47, 5759–5762.
8. De, S. K.; Gibbs, R. A. Tetrahedron Lett. 2004, 45, 7407–7408.
9. De, S. K. J. Mol. Catal. A: Chem. 2005, 225, 169–171.
10. Ranu, B. C.; Dey, S. S.; Hajra, A. Tetrahedron 2002, 58, 2529–2532.
11. (a) North, M. Angew. Chem., Int. Ed. 2004, 43, 4126–4128; (b)
Murahashi, S. I.; Komiya, N.; Terai, H.; Nakae, T. J. Am. Chem. Soc.
2003, 125, 15312–15313.
Acknowledgements
N.H.K. thanks the DST and CSIR Network project on
catalysis for financial assistance and also Dr. P. K. Ghosh,
the Director of the Institute for providing instrumentation
facilities.
12. Kobayashi, S.; Busujima, T.; Nagayama, S. Chem. Commun. 1998,
981–982.
13. Narasimhulu, M.; Reddy, T. S.; Mahesh, K. C.; Reddy, S. M.; Reddy,
A. V.; Venkateswarlu, Y. J. Mol. Catal. A: Chem. 2007, 264, 288–292.
14. Royer, L.; De, S. K.; Gibbs, R. A. Tetrahedron Lett. 2005, 46, 4595–
4597.
Supplementary data
15. (a) Yadav, J. S.; Reddy, B. V. S.; Eeshwaraiah, B.; Srinivas, M.;
Vishnumurthy, P. New J. Chem. 2003, 27, 462–465; (b) Martinez, R.;
Ramon, D. J.; Yus, M. Tetrahedron Lett. 2005, 46, 8471–8474.
16. Fetterly, B. M.; Jana, N. K.; Verkade, J. G. Tetrahedron 2006, 62,
440–456.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2007.
11.136.
17. Yadav, J. S.; Subba Reddy, B. V.; Eeshwaraian, B.; Srinivas, M.
Tetrahedron 2004, 60, 1767–1771.
References and notes
18. Arefi, H. A.; Khaksar, S.; Shiroodi, R. K. J. Mol. Catal. A: Chem.
2007, 271, 142–144.
1. Shafran, Y. M.; Bakulev, V. A.; Mokrushin, V. S. Russ. Chem. Rev.
1989, 58, 148–162.
2. Matier, W. L.; Owens, D. A.; Comer, W. T.; Deitchman, D.;
Ferguson, H.; Seidehamel, R. J.; Young, J. R. J. Med. Chem. 1973,
16, 901–908.
3. Enders, D.; Shilvock, J. P. Chem. Soc. Rev. 2000, 29, 359–373.
4. (a) Groger, H. Chem. Rev. 2003, 103, 2795–2827; (b) Spino, C. Angew.
Chem., Int. Ed. 2004, 43, 1764.
19. (a) Matsumoto, K.; Kim, J. C.; Hayashi, N.; Jenner, G. Tetrahedron
Lett. 2002, 43, 9167; (b) Jenner, G.; Salem, R. B.; Kim, J. C.;
Matsumoto, K. Tetrahedron Lett. 2003, 44, 447–449.
20. Prakash, G. K. S.; Mathew, T.; Panja, C.; Alconcel, S.; Vaghoo, H.;
Do, C.; Olah, G. A. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 3703–
3706.
´
21. Baeza, C.; Najera, J.; Sansano, M. Synthesis 2007, 1230–1234.
22. Mojtahedi, M. M.; Saed Abaee, M.; Abbasi, H. Can. J. Chem. 2006,
84, 429–432.
23. Khan, N. H.; Agrawal, S.; Kureshy, R. I.; Abdi, S. H. R.; Singh, S.;
Jasra, R. V. J. Organomet. Chem. 2007, 692, 4361–4366.
5. (a) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069–1094; (b)
Bhanu Prasad, B. A.; Bisai, A.; Singh, V. K. Tetrahedron Lett. 2004,
45, 9565–9567; (c) Harusawa, S.; Hamada, Y.; Shioiri, T. Tetrahedron
Lett. 1979, 20, 4663–4666; (d) Nakamura, S.; Sato, N.; Sugimoto, M.;