Reaction of triflyl-imidazole with aldoximes: Facile synthesis of nitriles and formation of novel aldoxime-bis(N-triflyl)-imidazole adducts

Article abstract of DOI:10.1016/j.tetlet.2011.07.135

The synthetic utility of N-triflylimidazole as an in situ reagent for facile, high yielding, synthesis of various aliphatic, aromatic, and heteroaromatic nitriles from the corresponding aldoximes has been demonstrated. With benzaldoximes, in the presence of certain substitutents (2-F; 2-OMe; 3-CF₃; 2-Me-5-F) a different course of reaction was observed, leading instead to novel 1:1 aldoxime-bis(N-triflyl)imidazole covalent adducts, in which the aldoxime oxygen atom is bonded to the imidazole C-2 ring carbon. For these aldoximes, conversion to nitrile could be effected by reaction with Tf₂O in the absence of imidazole. The molecular structure of the adduct formed from 2-methyl-5-fluoro-benzaldoxime was confirmed by X-ray analysis. Plausible mechanisms for the formation of 1:1 covalent adducts have been considered. Various attempts to isolate such adducts via the reaction of an authentic sample of bis(N-triflyl)imidazolium trifate with aldoxime were unsuccessful. Remarkably, whereas isolated benzaldoxime adducts undergo deprotonation/methylation with NaH/MeI, an authentic sample of bis(N-triflyl)imidazolium triflate did not undergo H/Me exchange under these conditions. These transformations are discussed.

Full text of DOI:10.1016/j.tetlet.2011.07.135

Tetrahedron Letters 52 (2011) 5184–5187
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Tetrahedron Letters
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Reaction of triflyl-imidazole with aldoximes: facile synthesis of nitriles
and formation of novel aldoxime-bis(N-triflyl)-imidazole adducts
Rajesh G. Kalkhambkar a, Scott D. Bunge b, Kenneth K. Laali a,
⇑
a Department of Chemistry, University of North Florida, 1 UNF Drive, Jacksonville, FL 32224, USA
b Department of Chemistry, Kent State University, Kent, OH 44242, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthetic utility of N-triflylimidazole as an in situ reagent for facile, high yielding, synthesis of var-
ious aliphatic, aromatic, and heteroaromatic nitriles from the corresponding aldoximes has been demon-
strated. With benzaldoximes, in the presence of certain substitutents (2-F; 2-OMe; 3-CF3; 2-Me-5-F) a
different course of reaction was observed, leading instead to novel 1:1 aldoxime-bis(N-triflyl)imidazole
covalent adducts, in which the aldoxime oxygen atom is bonded to the imidazole C-2 ring carbon. For
these aldoximes, conversion to nitrile could be effected by reaction with Tf2O in the absence of imidazole.
The molecular structure of the adduct formed from 2-methyl-5-fluoro-benzaldoxime was confirmed by
X-ray analysis. Plausible mechanisms for the formation of 1:1 covalent adducts have been considered.
Various attempts to isolate such adducts via the reaction of an authentic sample of bis(N-triflyl)imidazo-
lium trifate with aldoxime were unsuccessful. Remarkably, whereas isolated benzaldoxime adducts
undergo deprotonation/methylation with NaH/MeI, an authentic sample of bis(N-triflyl)imidazolium tri-
flate did not undergo H/Me exchange under these conditions. These transformations are discussed.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 7 July 2011
Revised 27 July 2011
Accepted 28 July 2011
Available online 4 August 2011
Keywords:
Triflylimidazole
Aldoximes to nitriles
Triflic anhydride
Aldoxime-bis (N-triflyl)imidazole adducts
X-ray and NMR
Mechanistic insights
Due to its widespread presence in natural products, pharmaceu-
ticals, and functional materials, and its high versatility for conver-
sion to other functional groups, the cyano moiety occupies a
position of paramount importance in chemistry. The –CN group
can be synthesized from a wide range of precursors using a large
number of methods and reagents that have been discussed and
summarized earlier in several authoritative reviews.1a–g Among
these, one of the most extensively studied methods is by dehydra-
tion of aldoximes. Some of the more recently reported synthetic
methods/reagents for the preparation of nitriles from aldoximes
include bromodimethylsulfonium bromide,2 Pd(OAc)2/PPh3,3
Ru(Ph3P)3(CO)H2/Xantphos,4 ClSO3H/toluene,5 (EtO)2POCl/tolu-
ene,6 dry or wet alumina,7 CuCl2/MeCN/ultrasound,8 silica sul-
CF3
O
O
N
S
H
O
S
O
O
S
O
DCM
0-5 o
N
N
2
F3C
O
CF3
+
+
OTf
C
N
H
N
N
H
1
Scheme 1. Synthesis of triflylimidazole 1 according to Ref. 16.
The present study focuses on reactions of 1 with aldoximes as a
convenient, high yielding, method for the synthesis of various
nitriles, and on the formation of novel 1:1 aldoxime-bis(N-triflyl)
imidazole adducts with certain substituted benzaldoximes. Struc-
ture of these adducts and the mechanistic implications of this
transformation are discussed.
Given the potential of triflylimidazole as a triflyl transfer agent,
we reasoned that it might serve as a convenient reagent for the
dehydration of aldoximes according to Scheme 2. Initial studies
sought to employ isolated 1, but the isolated yields proved to be
rather low despite the fact that the reaction proceeded efficiently
and in good yields, judging from the amount of the imidazolium
triflate byproduct that was formed and isolated. Subsequent work
focused on employing this reagent in situ without isolation, and
this proved successful.
fate/acetone,9
enzymatic
method,10
NH2OHÁHCl/red-mud/
microwave,11 Ph3P/Tf2O,12 1-pentyl-3-methylimidazolium tetra-
fluoroborate,13 2,4,6-trichloro[1,3,5]triazine in DMF,14 and BOP/
DBU or Bt-OTS/DBU.15
In a short Letter published in 1970, Effenberger and Mack16
introduced a new reagent trifluoromethanesulfonic imidazolide
(triflylimidazole) 1, by reacting imidazole with Tf2O (in 2:1 ratio),
and isolated this compound as a low boiling liquid (Scheme 1).
The utility of 1 as a triflyl-transfer reagent was briefly shown in
reaction with phenols, forming aryl triflates, but its potential to ef-
fect other transformations remained unexplored.
A variety of aliphatic, aromatic, and heteroaryl oximes were con-
verted to nitriles in respectable isolated yields at room tempera-
ture.17 The results are summarized in Table 1. Given the mild
⇑
Corresponding author. Tel.: +1 904 620 1503; fax: +1 904 620 3535.
E-mail address: kenneth.laali@UNF.edu (K.K. Laali).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.135

R. G. Kalkhambkar et al. / Tetrahedron Letters 52 (2011) 5184–5187
5185
CF3
O
O
N
OH
H
S
R
N
N
DCM
R
N
2
Tf2O
R
N
O
0-5 oC
N
N
H
N
DCM, rt
SO2CF3
N
H
1
R = Alkyl, Aryl, Heteroaryl
Scheme 2. Aldoxime to nitrile conversion via the in situ generated triflylimidazole.
Table 1
Conversion of aldoximes to nitriles with N-triflylimidazole
Entry
Oximes
Product
Oxime:Tf2O ratio
0.7
Time (h)
16
Isolated yieldc (%)
H
N
N
1
61
OH
H
N
N
2
3
0.5
1
12
18
70
78
OH
N
OH
OH
N
N
NO2
NO2
N
4
5
6
0.5
0.75
1
12
12
4
65
N
OH
N
O2N
76
O2N
O
O
O
N
N
OH
83a
N
OH
N
OH
N
7
8
1
4.3
12
67b,19
OH
N
O
0.55
88
O
F
N
OH
82a
71a
N
N
9
1
1
6
F
N
OH
N
10
12
F3C
N
F3C
N
N
OH
11
12
1
12
12
74
78
N
OH
N
0.66
O
O
N
N
OH
OH
N
N
13
14
15
0.4
1
12
12
2.5
84
72
87
N
H
N
H
S
S
CN
OH
OH
N
0.7
E,E isomer
CN
N
16
0.7
2.5
85
E,Z isomer
a
b
c
Product obtained in the absence of imidazole.
Benzisoxazole19 was obtained both with and without imidazole.
Reported yields are based on quantity of aldoximes taken.
conditions and absence of high boiling solvents, the method is supe-
rior to a recently reported method using N-tosylimidazole/DBU in
refluxing DMF or DMSO.18 With substituted benzaldoximes variable
outcomes were observed depending on the substituents. Thus
whereas the 2-NO2, 4-NO2, and 4-OMe derivatives gave nitriles,
unexpected products were isolated from 2-F, 2-OMe, 2-Me/5-F,

5186
R. G. Kalkhambkar et al. / Tetrahedron Letters 52 (2011) 5184–5187
F3CO2S
Turning our attention to the adducts, suitable crystals were ob-
tained from 2-Me/5-F derivative (3c) for X-ray analysis, establish-
ing the formation of novel 1:1 aldoxime-bis(N-triflyl)imidazole
covalent adducts, in which the aldoxime oxygen atom is bonded
to the imidazole C-2 ring carbon (see Scheme 3). The ORTEP plot
for 3c is shown in Figure 1. The ArCH@N, CHN–O, and the
CHNO–CH bond length are 1.278, 1.447, and 1.381 Å, respectively.
The molecular structures of all four compounds were fully estab-
lished by multinuclear 1D (1H, 13C, 19F) and by 2D NMR correlation
(HMQC; see experimental and Supplementary data).
N
H
N
N
O
OH
N
Imidazole / Tf2O
DCM, rt
SO2CF3
R
R
(2a-d)
(3a-d)
a
b
c
d
( )
R = 2-F ( ), 2-OMe ( ), 2-Me-5F ( ), 3-CF3
Scheme 3. Formation of covalent adducts (3a–d).
As depicted in Scheme 4, formation of the covalent adducts 3
may be explained by equilibrium formation of N-heterocyclic car-
bene (NHC) derived from bis(triflyl)imidazolium triflate as a key
intermediate. Alternatively, the imidazolium triflate may undergo
nucleophilic attack by the conjugate base of benzaldoxime.
Subsequent studies focused on gathering information in con-
nection to the mechanistic hypothesis outlined in Scheme 4. The
proposed bis(N-triflyl)imidazolium triflate 4 was independently
synthesized and isolated in good yield by further reaction of 1 with
Tf2O. With 4 at hand, several reactions, employing various bases,
were performed in an effort to synthesize covalent adducts with
benzaldoximes, but no such adducts could be isolated and the
aldoximes remained unreacted (Scheme 5).
In a recent report from Beller et al.20 BuLi/MeI was used to
introduce a methyl at C-2 in diphenyl-substituted imidazolium
salts. Contrary to our expectation that presence of –Tf groups
should lower the pKa of salt 4 allowing a milder base to be used
for deprotonation, in a control experiment, 4 could not be methyl-
ated with NaH/MeI to give 5 (Scheme 5).
Returning to the isolated 1:1 covalent adducts, we reasoned
that deprotonation may trigger the break-up of the C–O bond,
forming an NHC which could possibly be trapped with RX. Remark-
ably reaction with NaH/MeI resulted in H/Me exchange and this
was shown with three different adducts (Scheme 6). Attempts to
install R groups larger than methyl were unsuccessful, and reac-
tions with adamantly-, isopropyl- and ethyl bromide as well as
ethyl iodide resulted in the recovery of intact adducts.
Figure 1. X-ray structure, ORTEP diagram of compound 3c (thermal ellipsoid plot;
In summation, the present study has demonstrated interesting
new applications for triflylimidazole 1, a reagent first reported by
Effenberger and Mack16 in 1970 for the synthesis of ArOTf from
phenols. Whereas the in-situ formed 1 proved efficient for nitrile
synthesis from a variety of aldoximes under mild conditions in
respectable isolated yields, more remarkable was the formation
of novel covalent adducts with certain substituted benzaldoximes.
Although formation of covalent adducts via the corresponding NHC
or by direct nucleophilic attack of benzaldoxime seems plausible,
our attempts to independently generate covalent adducts by react-
ing the bis(N-triflyl)imidazolium triflate 4 with benzaldoximes in
the presence of various bases have been unsuccessful. The isolated
adducts undergo H/Me exchange with NaH/MeI to give the meth-
ylated analogs in good yields but this reaction appears to be highly
ellipsoids are drawn at the 30% level. H atoms are omitted for clarity).
and 3-CF3 benzaldoximes (2a–d). However by excluding imidazole
from the reaction, and in DCM as solvent, these benzaldoximes
reacted ‘normally’ to give nitriles (Table 1; entries 6, 9, and 10).
To gauge the influence of aldoxime stereochemistry on the ease
of dehydration, and in concert with the work of Singh and Laksh-
man,15 we studied the reaction of E,E- and E,Z-cinnamaldoximes
with 1 in side-by-side experiments. TLC monitoring the progress
of the reactions indicated that both isomers reacted to the same
extent, forming E-nitrile in near equal overall yields, suggesting
that aldoxime stereochemistry did not influence the ease of
dehydration.
O
-
N
H
OTf
SO2CF3
H
SO2CF3
Tf2O
DCM
N
NH
N
N
R
N
N
N
H
F3CO2S
SO2CF3
N
N
N
N
O
R
SO2CF3
SO2CF3
4
SO2CF3
1
3
O
N
H
SO2CF3
N
R
-
3
OTf
N
pyridine
4
SO2CF3
Scheme 4. Suggested mechanisms for the formation of covalent adducts (3a–d).

R. G. Kalkhambkar et al. / Tetrahedron Letters 52 (2011) 5184–5187
5187
N
N
OH
OH
F3CO2S
F3CO2S
N
H
N
R
R
SO2CF3
OTf
N
O
N
O
N
N
N
H
SO2CF3
SO2CF3
N
NaH, C2H4Cl2
imidazole
or TEA
or DBU
F3CO2S
R
R
4
3
3
NaH
MeI
C2H4Cl2
SO2CF3
N
OTf
N
F3CO2S
5
Scheme 5. Exploring adduct formation from 4.
3. Kim, H. S.; Kim, S. H.; Kim, J. N. Tetrahedron Lett. 2009, 50, 1717.
4. Anand, N.; Owston, N. A.; Parker, A. J.; Slatford, P. A.; Williams, J. M. J.
Tetrahedron Lett. 2007, 48, 7761.
5. Li, D.; Shi, F.; Guo, S.; Deng, Y. Tetrahedron Lett. 2005, 46, 671.
6. Sardarian, A. R.; Shahsavari-Fard, Z.; Shahsavari, H. R.; Ebrahimi, Z. Tetrahedron
Lett. 2007, 48, 2639.
F3CO2S
F3CO2S
N
H
N
N
O
N
O
N
N
Me
SO2CF3
SO2CF3
NaH
DCM 40-50 o
H3C
I
R
R
7. Sharghi, H. M.; Sarvari, H. Tetrahedron 2002, 58, 10323.
8. Jiang, N. A.; Ragauskas, J. Tetrahedron Lett. 2010, 51, 4479.
C
9. Li, Z.; Ding, R.; Lu, Z.; Xiao, S.; MaZheng, X. M. J. Mol. Catal A: Chem. 2006, 250,
100.
10. Kato, Y.; Ooi, R.; Kato, Y. A. J. Mol. Catal B: Enzym. 1999, 6, 249.
11. Khezri, S. H.; Azimi, N.; Mohammed-Vali, M.; Eftekhari-Sis, B. M.; Hashemi, M.;
Baniasadi, M. H.; Khezri, F. T. H. Arkivoc 2007, 15, 162.
(3b-d)
R = 2-OMe, 3-CF3, 2-Me-5-F
Scheme 6. Synthesis of methylated adducts (6b–d).
(6b-d)
12. Moussa, Z.; Ahmed, S. A.; ElDouhaibi, S.; Al-Raqa, S. Y. Tetrahedron Lett. 2010,
51, 1826.
13. Saha, D.; Saha, A.; Ranu, B. C. Tetrahedron Lett. 2009, 50, 6088.
14. Luca, L. D.; Giacomelli, G.; Porcheddu, A. J. Org. Chem. 2002, 67, 6272.
15. Singh, M. K.; Lakshman, M. K. J. Org. Chem. 2009, 74, 3079.
16. Effenberger, F.; Mack, K. E. Tetrahedron Lett. 1970, 3947.
sensitive to steric affects, since R groups larger than CH3 could not
be installed by this method.
17. General procedure for synthesis of nitriles from oximes (1–16): A mixture of
aldoximes (1 mmol) and imidazole (3 mmol) in anhydrous DCM (10–15 mL)
was charged into an oven-dried round-bottom flask under nitrogen and the
reaction mixture was stirred at r.t. for 20 min, after which triflic anhydride
(0.4–1.0 mmol) was added dropwise via syringe under nitrogen, and the
reaction mixture was allowed to stir at r.t. for a specific time (Table 1). Progress
of the reaction was monitored by TLC and/or by GC–MS. Upon completion, the
reaction mixture was quenched with dilute NaHCO3 solution and the product
mass was extracted in DCM. The solvent was removed under reduced pressure
to yield the crude product which was purified by prep TLC (ethyl acetate–
hexane mixture) (80:20), to give the corresponding nitrile (61–88% yield). The
structure of the products was confirmed by comparison of their mp or bp, TLC,
IR, GC–MS, 1H NMR and 13C NMR data with authentic samples obtained
commercially or prepared by literature methods.
Acknowledgments
We thank University of North Florida for support of this re-
search and Dr. Nelson Zhao for NMR assistance. We also thank a
referee for helpful remarks concerning the suggested mechanism.
Supplementary data
Supplementary data (X-ray data collection parameters, (exclud-
ing structure factors) for the structures have been deposited with
the Cambridge Crystallographic Data Centre as supplementary
publication No. CCDC 822706. Copies of the data can be obtained,
free of charge, via http://www.pubs.acs.org or on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44 (0)1223
336033; or e-mail: deposit@ccdc.cam.ac.uk) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2011.07.135.
General procedure for the synthesis of adducts (3a–d): A mixture of aldoximes
(2a–d) (1 mmol) and imidazole (3 mmol) was added to anhydrous DCM (10–
15 mL) in an oven-dried round bottom flask under nitrogen and stirred at r.t.
for 20 min. Triflic anhydride (0.4–1 mmol) was then introduced dropwise via
syringe under nitrogen and the reaction mixture was allowed to stir at r.t.
overnight. The progress of reaction was monitored by TLC and by GC–MS. Upon
completion the reaction mixture was quenched with dilute NaHCO3 solution,
and the product mass was extracted in DCM, removal of solvent gave the crude
product, which was purified by Prep-TLC (ethyl acetate–hexane mixture)
(80:20) and column chromatography (ethyl acetate–hexane mixture) (80:20)
to give the corresponding adducts (65–90% yield), whose structures were
confirmed by NMR (1H, 13C and HMQC; see below), and by X-ray analysis in the
case of 3c. GC–MS analysis of adducts 3 consistently exhibited an intense m/z
333 ion corresponding to the bis(N-triflyl)imidazolium cation, and the intact
molecular ions were not detected even at 20 eV.
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