FeCl3 mediated one-pot route to nitriles

Article abstract of DOI:10.1016/j.tetlet.2013.06.134

A new and convenient protocol for the transformation of aldehydes into nitriles using hydroxylamine hydrochloride by iron III chloride is presented. The protocol offers a very simple, cost efficient, and environmentally benign procedure with good to excellent yield of nitrile.

Full text of DOI:10.1016/j.tetlet.2013.06.134

Accepted Manuscript
FeCl mediated one-pot route to nitriles
3
Pranab Ghosh, Raju Subba
PII:
S0040-4039(13)01119-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.06.134
TETL 43187
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
15 May 2013
25 June 2013
26 June 2013
Please cite this article as: Ghosh, P., Subba, R., FeCl mediated one-pot route to nitriles, Tetrahedron Letters (2013),
3
doi: http://dx.doi.org/10.1016/j.tetlet.2013.06.134
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FeCl mediated one-pot route to nitriles
3
*
Pranab Ghosh and Raju Subba
Natural Product and Polymer Chemistry Laboratory, Department of Chemistry, University of
North Bengal, Darjeeling 734013, India.
Ph.No. 0353-2776381 Fax: (0353) 2699001
Email: pizy12@yahoo.com
Abstract
A new and convenient protocol for the transformation of aldehydes to nitriles using
hydroxylamine hydrochloride by iron III chloride is presented. The protocol offers a very
simple, cost efficient and environmentally benign procedure with good to excellent yield of
nitrile.
3
Keywords: Aldehydes, hydroxyl amine, FeCl , nitriles.
Nitriles are industrially important intermediate for the production of agrochemicals,
1
pharmaceutical, polymers, dyes and pigments. In addition, they serve as potential synthon
2
3
for the functional group transformation and heterocyclic synthesis. Classical methods for
4
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the nitrile synthesis comprises Sandmeyer reaction, ammoxidation of aldehydes, Kolbe
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7
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nitrile synthesis, hydrocyanation of alkenes and Rosenmund-von Braun reaction. During
the last decades, use of various catalytic systems have been established for the oxidative
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transformation of nitrile from the substrates like alcohols, amines, amides, oximes and
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3
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azides. The direct oxidative rearrangement of alkene, methyl arenes and benzyl or allyl
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6
halides into nitrile are also known but in such cases elongation of one carbon in parent
compound takes place. The transformation of carbonyl to nitriles using hydroxyl amine is an
alternative attractive approach without elongation of carbon chain. The literature survey
reveals that a host of catalytic systems were applied for the one-pot transformation of
1
7
aldehydes into nitriles. Although a plethora of synthetic strategies have been developed, the

use of expensive catalyst, various oxidants, prolong reaction time, hazardous metal salts,
work-up difficulties made the various existing methodologies non desirable under the aspect
of sustainable synthesis. Because of wide application of nitriles as a potent bioactive
1
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material as well as synthon for designing the molecules, there is demand for less expensive,
straightforward and environmentally friendly protocols for their synthesis.
(
Please insert fig.1 here)
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It is well documented that iron is one of the most versatile highly abundant transition metal
which is environmentally benign, low toxic and inexpensive. It plays key roles in
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0
fundamental biological processes and remarkable roles in wide area of organic synthesis.
Being a Lewis acid and mild oxidising agent, iron III chloride can easily form an adduct with
Lewis bases and thereby activate organic substrates. The high catalytic activity and functional
group tolerance, low toxicity and inexpensiveness makes iron salt a versatile reagent and
have gained special attention in modern organic chemistry, such as oxidative radical cross-
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coupling, Sonogashira reactions of terminal alkynes and aryl halides, Prins cyclization,
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catalytic oxidation of alkane, heterocyclic synthesis by C-H, C-X bond activation and
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condensation, alkenylation of arenes, synthesis of amide, Friedel-Crafts reaction, Aldol
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reactions and pinacol-pinacolone rearrangement. Behbahani et al and Desai et al have
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1
already reported the use of iron III salt for the transformation of oximes to nitriles.
However, to the best of our knowledge, the direct transformation of carbonyl to nitrile using
hydroxylamine hydrochloride by iron III chloride as a sole mediator has never been reported
so far. With these backgrounds of iron salt, and in view of our present attempt to search for a
milder reaction condition coupled with use of environment-friendly, cost efficient, high
functional group tolerance and high yielding reagent for nitrile synthesis, we have chosen
ferric chloride as ideal reagent for the one step conversion of aldehyde to nitrile.

(
Please insert scheme 1 here)
In an endeavour to start our present investigation we have chosen vanillin as our model
compound for the desired transformation.
The model reaction comprising vanillin (1 mmol), hydroxylamine hydrochloride (1.5 mmol)
and ferric chloride anhydrous (1 mmol) at room temperature furnished only aldoxime instead
of nitrile. We started raising the reaction temperature when only trace amount of nitrile was
o
formed at 100 C. The reaction was then set up under reflux condition when it was found to
yield the corresponding nitrile by more than 90% in 3 h. Finally we could optimize the
quantity of reactants as 1.2 mmol hydroxylamine hydrochloride and 0.5 mmol ferric chloride
(anhydrous) per mmol of aldehyde and found 98% yield of nitrile in 3 h in DMF under reflux
condition (Table 1, entry 2). It was also found that 5 ml solvent is sufficient for complete
transformation. The similar reactions were carried out with other iron salts but found not
efficient for the desired transformation. The results with other iron salts are reported in (Table
1
). For the generalization of our scheme, the aldehydes 1a-k was treated under optimized
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2
reaction condition and the nitriles 2a-k were obtained in 76-98% yields (Table 2). It was
evident from Table 2 that the aldehydes without substituent (entry 1j-k) and having electron-
donating groups like –OMe, -OH, -N(Me)
electron-withdrawing groups (entry 1d-e) furnished lower yield.
Please insert table 1 here)
2
furnished higher yield whereas aldehydes with
(
(Please insert table 2 here)
In conclusion, we have developed an easy and one pot route to nitrile from aldehyde (1
mmol), hydroxylamine hydrochloride (1.2 mmol) and ferric chloride (0.5 mmol). Excellent
yield, cost efficient, environmental benign, high functional group tolerance and simple work-
up process are the added advantages of this protocol.

Acknowledgments
One of the authors (R.S) is thankful to CSIR New Delhi for financial support.
References and notes
1
2
3
. (a) Larock, R. C. Comprehensive Organic Transformations; 1989; pp 819–995; (b)
Grundmann, C. Houben-Weyl: Methodender Organischen Chemie. Falbe; 1985, E5;
pp 1313–1527.
. (a) Muñoz, J. M.; Alcázar, J.; Hoz, A.; Díaz-Ortiz, A. Tetrahedron Lett. 2011, 52,
6058-6060; (b) Caddick, S.; Haynes, A. K. K.; Judd, D. B.; Williams M. R. V.
Tetrahedron Lett. 2000, 41, 3513-3516.
. (a) Heller, B.; Sundermann, B.; Buschmann, H.; Drexler, H-J.; You, J.; Holzgrabe, U.;
Heller, E.; Oehme. G. J. Org. Chem. 2002, 67, 4414-4422; (b) Bosch, L.; Vilarrasa, J.
Angew. Chem. Int. Ed. 2007, 46, 3926-3930; (c) Aureggi, V.; Sedelmeier, G. Angew.
Chem. Int. Ed. 2007, 46, 8440-8444; (d) Aldhoun, M.; Massi, A.; Dondoni, A. J. Org.
Chem. 2008, 73, 9565-9575; (e) Bokach, N. A.; Kuznetsov, M. L.; Haukka, M.;
Ovcharenko, V. I.; Tretyakov, E. V.; Kukushkin, V. Y. Organometallics. 2009, 28,
1406-1413.
4. Beletskaya, I. P.; Sigeev, A. S.; Peregudov, A. S.; Petrovskii, P. V. J. Organometallic.
Chem. 2004, 689, 3810–3812.
5. Ellis, G. P.; Romney-Alexander, T. M. Chem. Rev. 1987, 87, 779–794.
6. Friedman, L.; Shechter, H. J. Org. Chem. 1960, 25, 877–879.
7. Bini, L.; Muller, C.; Wilting, J.; Chrzanowski, L.; Spek, A. L.; Vogt, D. J. Am. Chem.
Soc. 2007, 129, 12622–12623.
8
9
1
. Lindley, J. Tetrahedron. 1984, 40, 1433–1456.
. Chen, F-E.; Li, Y-Y.; Xu, M.; Jia. H-Q. Synthesis, 2002, 1804-1806.
0. (a) Yamaguchi, K.; Mizuno, N. Angew. Chem. Int. Ed. 2003, 42, 1480-1483. (b)

Ghorbani-Vaghei, R.; Veisi, H. Synthesis, 2009, 945-950.
1
1
1
1. Zhou, S.; Junge, K.; Addis, D.; Das, S.; Beller, M. Org. Lett. 2009, 11, 2461-2464.
2. Li, D.; Shi, F.; Guo, S.; Deng, Y. Tetrahedron Lett. 2005, 46, 671–674
3. (a) Lamani, M.; Prabhu, K. R. Angew. Chem. Int. Ed. 2010, 49, 6622-6625; (b) He, J.;
Yamaguchi, K.; Mizuno, N. J. Org. Chem. 2011, 76, 4606-4610.
1
1
1
1
4. Qin, C.; Jiao, N. J. Am. Chem. Soc. 2010, 132, 15893-15895.
5. Zhou, W.; Zhang, L.; Jiao, N. Angew. Chem. Int. Ed. 2009, 48, 7094-7097.
6. Zhou, W.; Xu, J.; Zhang, L.; Jiao, N. Org. Lett. 2010, 12, 2888-2891.
7. (a) Shargi, H.; Sarvari, M. H. Synthesis, 2003, 243-246; (b) Zhu, J-L.; Lee, F-Y.; Wu,
J-D.; Kuo, C-W.; Shia, K-S. Synlett. 2007, 1317-1319; (c) Augustine, J. K.; Atta, R.
N.; Ramappa, B. K.; Boodappa, C. Synlett, 2009, 3378-3382; (d) Sridhar, M.; Reddy,
M. K. K.; Sairam, V. V.; Raveendra, J.; Godala, K. R.; Narsaiah, C.; Ramanaiah B.
C.; Reddy, C. S. Tetrahedron Lett. 2012, 53, 3421–3424; (e) Coşkun, N.; Arikan, N.
Tetrahedron. 1999, 55, 11943-11948; (f) Erman, M. B.; Snow, J. W.; Williams, M. J.
Tetrahedron Lett. 2000, 41, 6749-6752; (g) Carmeli, M.; Shefer, N.; Rozen, S.
Tetrahedron Lett. 2006, 47, 8969–8972; (h) Telvekar, V. N.; Patel, K. N.; Kundaikar,
H. S.; Chaudhari, H. K. Tetrahedron Lett. 2008, 49, 2213–2215; (i) Sharghi, H.;
Sarvari, M. H. Tetrahedron. 2002, 58, 10323–10328; (j) Reddy, K. R.; Maheswari, C.
U.; Venkateshwar, M.; Prashanthi, S.; Kantam, M. L. Tetrahedron Lett. 2009, 50,
2
050–2053
8. (a) Fleming, F. F.; Yao, L.; Ravikumar, P. C.; Funk, L.; Shook, B. C. J. Med. Chem.
010, 53, 7902–7917; (b) Zhang, Z.; Yang, H.; Wu, G.; Li, Z.; Song, T.; Li, X. q. Eur. J.
Med. Chem. 2011, 46, 3909-3916; (c) Barsoum, F. F. Eur. J. Med. Chem. 2010, 45,
1
2
5
176-5182; (d) Tarleton, M.; Gilbert, J.; Sakoff, J. A.; McCluskey, A. Eur. J. Med. Chem.
2012, 57, 65-73; (e) Altmann, E.; Cowan-Jacob, S. W.; Missbach, M. J. Med. Chem.

2004, 47, 5833-5836.
19. Shi, F.; Tse, M. N.; Li, Z.; Beller, M. Chem. Eur. J. 2008, 14, 8793-8797.
20. Bolm, C.; Legros, J.; Paih, J. L.; Zani, L. Chem. Rev. 2004, 104, 6217-6254.
21. Huang, Z.; Jin, L.; Feng, Y.; Peng, P.; Yi, H.; Lei, A. Angew. Chem. Int. Ed. 2013, 52,
1–6.
22. Carril, M.; Correa, A.; Bolm, C. Angew. Chem., Int. Ed. 2008, 47, 4862-4865.
23. Zheng, K.; Liu, X.; Qin, S.; Xie, M.; Lin, L.; Hu, C.; Feng, X. J. Am. Chem. Soc.
2
012, 134, 17564−17573.
4. Yiu, S-M.; Wu, Z-B.; Mak, C-K.; Lau, T-C. J. Am. Chem. Soc. 2004, 126, 14921-
4929.
2
1
2
5. (a) Guo, X.; Yu, R.; Li, H.; Li, Z. J. Am. Chem. Soc. 2009, 131, 17387–17393; (b)
Roy, B.; Ansary, I.; Samanta, S.; Majumdar, K. C. Tetrahedron Lett. 2012, 53, 5119–
5
122; (c) Zhang, Y.; Wang, M.; Li, P.; Wang, L. Org. Lett. 2012, 14, 2206-2209; (d)
Liang, Z.; Hou, W.; Du, Y.; Zhang, Y.; Pan, Y.; Mao, D.; Zhao, K. Org. Lett., 2009,
1, 4978-4981; (e) Bonnamour, J.; Bolm, C. Org. Lett. 2008, 10, 2665-2667.
1
26. Li, R.; Wang, S. R.; Lu, W. Org. Lett. 2007, 9, 2219-2222.
27. (a) Anxionnat, B.; Guérinot, A.; Reymond, S.; Cossy, J. Tetrahedron Lett. 2009, 50,
3470–3473; (b) Khodaei, M. M.; Meybodi, F. A.; Rezai, N.; Salehi, P. Synth.
Commun, 2001, 31, 2047–2050.
2
8. (a) Wang, B-Q.; Xiang, S-K.; Sun, Z-P.; Guan, B-T.; Hu, P.; Zhao, K-Q.; Shi, Z-J.
Tetrahedron Lett. 2008, 49, 4310–4312; (b) Wang, J.; Zhang, L.; Jing, Y.; Huang, W.;
Zhou, X. Tetrahedron Lett. 2009, 50, 4978–4982; (c) Liu, J.; He, T.; Wang, L.
Tetrahedron. 2011, 67, 3420-3426.
2
9. (a) Li, H.; Li, W.; Li, Z. Chem. Commun. 2009, 3264-3266; (b) Lecomte, V.; Bolm,
C. AdV. Synth. Catal. 2005, 347, 1666-1672

3
0. Shinde, A. B.; Shrigadi, N. B.; Bhat, R. P.; Samant, S. D. Synth. Commun. 2004, 34,
09-314.
1. (a) Behbahani, F. K.; Heravi, M. M.; Oskooie, H. A. Adv. Chem. Res. 2011, 7, 253-
3
3
257; (b) Desai, D. G.; Swami, S. S.; Mahale, G. D. Synth. Commun. 2000, 30, 1623-
1625.
3
2. General procedure for the synthesis of nitrile from aldehyde: Aldehyde (1 mmol) and
hydroxylamine hydrochloride (1.2 mmol) were added successively to a solution of
anhydrous ferric chloride (0.5 mmol) in 5 ml dry DMF. The mixture was reflux for
appropriate time (Table 2). The progress of the reaction was monitored by TLC. After
completion of the reaction, the solution was poured into 100 ml water and extract with
ethyl acetate washed several times with water. The combined organic mixture was
2 4
dried over anhydrous Na SO , concentrated and the residue was purified by column
chromatography on silica gel 60-120 mesh using petroleum ether/ethyl acetate (96:4)
1
as eluent to afford the pure nitrile. All the products were characterized by IR, H
1
3
NMR and C NMR.

Figure 1
N
HO
N
NH
NC
O
N
N
NC
CN
Letrozole
Vildagliptin
CN
N
CN
N
N
O
Me N
2
O
N
F
Escitalopram
Zaleplon
Fig. 1.Biologically potent nitrile derivatives

Scheme 1
Synthesis of nitriles by the reaction of aldehyde, hydroxylamine hydrochloride and FeCl
under reflux condition.
3
FeCl /reflux
3
R CHO + NH OH.HCl
R CN (76-98%)
2
Dry DMF-5ml
1a-k
2a-k
.

Legends
1. Fig. 1 Biologically potent nitrile derivatives
2
. Scheme 1 Synthesis of nitriles by the reaction of aldehyde, hydroxylamine
hydrochloride and FeCl under reflux condition.
3

FeCl Mediated One-pot Route to Nitriles
3
*
Pranab Ghosh and Raju Subba
Natural Product and Polymer Chemistry Laboratory, Department of Chemistry, University of
North Bengal, Darjeeling 734013, India.