Tetrahedron Letters 55 (2014) 4424–4426

Contents lists available at ScienceDirect

Tetrahedron Letters

journal homepage: www.elsevier .com/ locate / tet let

Ionic liquid-induced conversion of methoxymethyl-protectedalcohols into nitriles and iodides using [Hmim][NO3]

http://dx.doi.org/10.1016/j.tetlet.2014.06.0160040-4039/� 2014 Elsevier Ltd. All rights reserved.

⇑ Corresponding author. Tel.: +98 311 650 6276 (J. Noei).⇑⇑ Co corresponding author.

E-mail address: noei0655@yahoo.com (J. Noei).

RO O

+ N4

X

R= ArCH2, alkyl, allylX= CN, I

MW

[Hmim][NO3]R X

NHN

NO3-

[Hmim][NO3] =

Scheme 1. Direct conversion of MOM-ethers into nitriles and iodid[Hmim][NO3].

Jalil Noei a,⇑, Arsalan Mirjafari b,⇑⇑a Department of Chemistry, Islamic Azad University, Mahshahr Branch, Mahshahr 63519, Iranb Department of Chemistry and Physics, Florida Gulf Coast University, Fort Myers, FL 33965, USA

a r t i c l e i n f o a b s t r a c t

Article history:Received 15 January 2014Revised 15 May 2014Accepted 5 June 2014Available online 12 June 2014

Keywords:[Hmim][NO3]MOM-ethersNitrilesIodidesMicrowaveBrønsted acidic ionic liquids

This Letter reports a one-pot efficient conversion of methoxymethyl-ethers into their correspondingnitriles and iodides using the ionic liquid, 1-methyl-3H-imidazolium nitrate ([Hmim][NO3]) undermicrowave irradiation. A variety of products were prepared in high yields using this method.

� 2014 Elsevier Ltd. All rights reserved.

One-pot reactions represent effective strategies in terms ofeconomic and environmental aspects. They typically consist oftwo or more steps, that are performed without isolation of anyintermediates, which minimizes waste, solvent use, reaction times,and energy consumption.1,2 Nitriles are important organicmolecules because they are easily converted into carboxylic acids,esters, amides, amines, amidines, aldehydes, and ketones. Applica-tions involving nitriles have been widely used for the preparationof nitrogen-containing heterocycles such as tetrazoles, imidazoles,oxazoles, and thiazoles, which are important classes of compoundsin the pharmaceutical and agrochemical industries.3–8 Thesynthesis of aliphatic nitriles is usually accomplished by nucleo-philic substitution of alkyl halides with inorganic cyanides.9–11

Additionally, organic halides and especially iodides, are importantclasses of chemicals used extensively in organic synthesis, whiletheir transformations into useful compounds are widely docu-mented in the literature.12–16

Methoxymethyl ethers (MOM-ethers) are important intermedi-ates, which are stable under both basic and moderately acidicconditions.17 The MOM group is often used to protect alcohols.Due to the fact that the nitrile functionality is extensively appliedas a building block in the pharmaceutical and chemical industries,and the importance of iodide compounds in organic synthetic

chemistry, improved procedures for the preparation of thesecompounds are highly desired. Therefore, the direct transforma-tion of methoxymethyl-protected alcohols into nitriles and halidescan be considered important in organic synthesis.18

Ionic liquids (ILs) have been found to serve as interesting greenreaction media which can act as a catalyst or reagent whileremaining easy to recycle.19–21 Recently, Brønsted acidic ionicliquids have been deemed as promising alternatives for acid-catalyzed reactions and play the dual role of solvent and catalystfor a variety of reactions including esterification of carboxylicacids, protection of alcohols and carbonyl groups, conversion ofalcohols into oximes, oxidation of alcohols, alcohol dehydrodimer-ization, pinacol/benzopinacol rearrangement in Mannich reactions,and the cleavage of ethers.22–27

Herein, we report a one-pot and facile process for the directsynthesis of nitriles and iodides from MOM-ethers using1-methyl-3H-imidazolium nitrate ([Hmim][NO3]) as a Brønstedacid ionic liquid (Scheme 1).

es using

Table 1One-pot conversion of benzylmethoxymethyl ether into benzyl nitrile under variousconditionsa

+ N4

CNOMOM CN

Entry IL Conditions Yieldb (%)

1 — MW 02 [bmim][Br] MW 03 [bmim][BF4] MW 104 [bmim][PF6] MW 105 [bmim][FeCl4] MW 316 [bmim][AlCl4] MW 227 [Hmim][NO3] MW 898 [Hmim][NO3] Thermal Trace

Bold values significance the optimized reaction conditions.a Reaction conditions: MOM-ether (1 equiv), [Bu4N][CN] (2 equiv), IL (0.4 equiv).b Isolated yields.

Table 2 (continued)

Entry R MOM-ether yield, %b (time, min)

X = CN X = I

10MeO

84 (4.5) 82 (4.5)

11MeO

93 (3) 91 (3)

12BnO

90 (3) 88 (3)

13H3C

92 (3) 89 (3)

14tBu

92 (3) 89 (3)

15 90 (3) 90 (3)

16 91 (3) 86 (3)

17 5 87 (4) 83 (4)

a Reaction conditions: MOM-ether (1 equiv), [Bu4N][X] (2 equiv), [Hmim][NO3](0.4 equiv).

b Isolated yields.

J. Noei, A. Mirjafari / Tetrahedron Letters 55 (2014) 4424–4426 4425

Initially, we examined the reaction under different conditionsfor the formation of benzyl nitrile (Table 1). The reaction was notsuccessful in the absence of a catalyst or microwave irradiation(Table 1, entries 1 and 8). Classical ionic liquids such as [bmim][Br],[bmim][BF4], and [bmim][PF6] (Table 1, entries 2–4) and Lewisacidic ionic liquids such as [bmim][FeCl4] and [bmim][AlCl4](Table 1, entries 5 and 6) did not show high efficiency. Amongthe investigated IL/conditions, [Hmim][NO3], exhibited the highestefficiency (Table 1, entry 7) and was selected as the catalyst for thistransformation.

The Brønsted acidic IL, [Hmim][NO3], was obtained simply by aneutralization reaction. The combination of 1-methylimidazolewith HNO3 (67% w/w) in a 1:1 M ratio produced a white solid

Table 2One-pot synthesis of nitriles and iodides from R-OMOM ethers using [Hmim][NO3]under MW irradiationa

Entry R MOM-ether yield, %b (time, min)

X = CN X = I

1 89 (3) 88 (3)

2

Cl

83 (4.5) 84 (4.5)

3Cl

88 (4.5) 88 (4.5)

4

Cl

Cl

82 (4.5) 80 (4.5)

5

OH

84 (4.5) 81 (4.5)

6

Br

82 (5) 81 (5)

7Br

88 (3) 90 (3.5)

8O2N

85 (4.5) 85 (4.5)

9O2N

87 (4) 85 (4)

(Tm = 69.6 �C) after water removal which was identified as 1-methyl-3H-imidazolium nitrate. This IL is air-stable, hydrophilic,and its physicochemical properties have been studied. It has beenused as a solvent and promoter in oxidation reactions and hasconsiderable potential as a reaction medium.27–30 According topreviously reported results, the mechanism can be explained onthe basis of the potential oxidative ability of [Hmim][NO3] in thepresence of atmospheric oxygen.28

For the ultimate goal of applying this reaction in a diversity-generating strategy, we examined the one-pot conversion ofMOM-ethers into their corresponding nitriles and iodides undermicrowave irradiation conditions (Table 2).31 A wide range ofsubstituted and structurally diverse primary benzylic, allylic, andaliphatic MOM-ethers containing electron-withdrawing or elec-tron-donating groups (chloro, bromo, nitro, methoxy, hydroxy,tert-butyl, and benzyloxy) underwent the conversion with [Bu4N][X] (X = CN and I) in the presence of [Hmim][NO3]. Under MWirradiation, the corresponding nitriles and iodides were obtainedin good to excellent yields (80–93%) and in short reaction times(3–5 min). It is worth noting that by-products from methanolsubstitution as a possible side reaction, were not observed andthe desired nitriles or iodides were formed as the only products.

In conclusion, [Hmim][NO3] can be considered as an efficientBrønsted acidic ionic liquid for the synthesis of nitriles and iodidesstarting from MOM-ethers under MW irradiation. The use of this ILprovides a novel, efficient, eco-friendly, and chemoselective proce-dure for the preparation of nitriles and halides in high yields andshort reaction times.

Supplementary data

Supplementary data associated with this article can be found, inthe online version, at http://dx.doi.org/10.1016/j.tetlet.2014.06.016.

References and notes

1. Katritzky, A. R.; Meth-Cohn, O.; Rees, C. W. Comprehensive Organic FunctionalGroup Transformations; Pergamon: Oxford, 1995.

4426 J. Noei, A. Mirjafari / Tetrahedron Letters 55 (2014) 4424–4426

2. Larock, R. C. Comprehensive Organic Transformations: A Guide to Functional GroupPreparations, 2nd ed.; Wiley-VCH, 1999.

3. Sundermeier, M.; Zapf, A.; Mutyala, S.; Baumann, W.; Sans, J.; Weiss, S.; Beller,M. Chem. Eur. J. 2003, 9, 1828.

4. Rappoport, Z. The Chemistry of the Cyano Group; Interscience Publishers:London, 1970.

5. Yang, C.; Williams, J. M. Org. Lett. 2004, 6, 2837.6. Kukushkin, V. Y.; Pombeiro, A. J. L. Chem. Rev. 2002, 102, 1771.7. Wipf, P.; Yokokawa, F. Tetrahedron Lett. 1998, 39, 2223.8. Fabiani, M. E. Drug News Perspect. 1999, 12, 207.9. Ouchaou, K.; Georgin, D.; Taran, F. Synlett 2010, 2083.

10. Mowry, D. T. Chem. Rev. 1948, 42, 189.11. Kiefel, M. J. In Comprehensive Organic Functional Group Transformations;

Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.; Pergamon: Cambridge, UK,1995; p 641.

12. Chambers, R. D.; James, S. R. In Comprehensive Organic Chemistry; Barton, D. H.R., Ollis, W. D., Eds.; Pergamon: Oxford, 1979; pp 493–575.

13. Bohlmann, R. In Comprehensive Organic Chemistry; Trost, B. M., Fleming, I., Eds.;Pergamon: Oxford, 1991; pp 203–223.

14. Hudlicky, M.; Hudlicky, T. In The Chemistry of Functional Groups; Supplement,D., Patai, S., Rappoport, Z., Eds.; Wiley: New York, 1983; p 1021.

15. Khumraksa, B.; Phakhodee, W.; Pattarawarapan, M. Tetrahedron Lett. 2013, 54,1983.

16. Soleiman-Beigi, M.; Mohammadi, F. Tetrahedron Lett. 2012, 53, 7028.17. Greene’s Protective Groups in Organic Synthesis; Greene, T. W., Wuts, P. G. M.,

Eds.; Wiley Interscience: New York, 2006.18. Mirjafari, A.; Mohammadpoor-Baltork, I.; Moghadam, M.; Tangestaninejad, S.;

Mirkhani, V.; Khosropour, A. R. Tetrahedron Lett. 2010, 51, 3274.

19. Yadav, L. D. S.; Awasthi, C.; Rai, A. Tetrahedron Lett. 2008, 49, 6360.20. Bao, W.; Wang, Z. Green Chem. 2006, 8, 1028.21. Dupont, J.; de Souza, R. F.; Suarez, P. A. Z. Chem. Rev. 2002, 102, 3667.22. Welton, T. Chem. Rev. 1999, 99, 2071.23. Zhao, G.; Jiang, T.; Gao, H.; Han, B.; Huang, J.; Sun, D. Green Chem. 2004, 6, 75.24. Sheldon, R. Chem. Commun. 2001, 2399.25. Zhu, H. P.; Yang, F.; Tang, J.; He, M. Y. Green Chem. 2003, 5, 38.26. Cole, A. C.; Jensen, J. L.; Ntai, I.; Tran, K. L. T.; Weaver, K. J.; Forbes, D. C.; Davis, J.

H., Jr. J. Am. Chem. Soc. 2002, 124, 5962.27. Mirjafari, A.; Mobarrez, M.; O’Brien, R. A.; Davis, J. H., Jr.; Noei, J. C.R. Chim.

2011, 14, 1065.28. Chiappe, C.; Leandri, E.; Tebano, M. Green Chem. 2006, 8, 742.29. Emel’yanenko, V. N.; Verevkin, S. P.; Heintz, A.; Voss, K.; Schulz, A. J. Phys. Chem.

B 2009, 113, 9871.30. Mirjafari, A. Environ. Chem. Lett. 2014, 12, 177.31. General procedure: a mixture of MOM-ether (1 mmol), [Bu4N][X] (2 mmol), and

[Hmim][NO3] (0.4 mmol) was exposed to MW irradiation. All reactions werecarried out at 135–140 �C with 170 W applied power. After completion of thereactions (monitored by TLC, eluent: n-hexane/EtOAc, 5:1), the mixture wasextracted with Et2O (3 � 10 mL). The organic phase was dried over anhydrousNa2SO4 and rotary evaporation afforded a residue, which was then passedthrough a short pad of neutral alumina (n-hexane/EtOAc, 5:1, 75 mL) to givehighly pure products.The Micro-SYNTH microwave system was used for these experiments. Duringexperiments, power, temperature, and time were monitored and controlledwith the easyCONTROL software. The temperature was monitored with the aidof an ATCFO sensor (TS3517), which was inserted directly into the reactionvessel.