Novel and direct oxidative cyanation reactions of heteroaromatic compounds mediated by a hypervalent iodine(III) reagent

Article abstract of DOI:10.1021/ol0476826

(Chemical Equation Presented) The hypervalent iodine(III) reagent phenyliodine bis(trifluoroacetate) (PIFA) mediates the selective cyanation reactions of a wide range of electron-rich heteroaromatic compounds such as pyrroles, thiophenes, and indoles unde

Full text of DOI:10.1021/ol0476826

ORGANIC
LETTERS
2005
Vol. 7, No. 4
537-540
Novel and Direct Oxidative Cyanation
Reactions of Heteroaromatic
Compounds Mediated by A Hypervalent
Iodine(III) Reagent
Toshifumi Dohi, Koji Morimoto, Yorito Kiyono, Hirofumi Tohma, and
Yasuyuki Kita*
Graduate School of Pharmaceutical Sciences, Osaka UniVersity, 1-6 Yamada-oka,
Suita, Osaka, 565-0871 Japan
kita@phs.osaka-u.ac.jp
Received November 11, 2004
ABSTRACT
The hypervalent iodine(III) reagent phenyliodine bis(trifluoroacetate) (PIFA) mediates the selective cyanation reactions of a wide range of
electron-rich heteroaromatic compounds such as pyrroles, thiophenes, and indoles under mild conditions. These reactions proceed via a
cation radical intermediate, and the key for the successful transformation presumably depends on the oxidation
−reduction potential of the
substrates used. The synthetic utility has been demonstrated through the conversion of these biologically important pyrroles 2f and 2g.
Heteroaromatic cyanides such as pyrroles, indoles, and
thiophenes are of substantial interest for a wide range of
researchers from organic and pharmaceutical chemistries to
material science due to their ubiquity of natural products1
and unique physical properties in polymer form.2 On the basis
of these considerations, effective methods for the introduction
of the cyanide functionality into these heteroaromatic
compounds are considered to be very important, because
nitriles are valuable intermediates in organic synthesis for
yielding a broad spectrum of compounds.3 To date, two
representative methodologies have already been reported
(Scheme 1). One of them is a stepwise approach (method
A); though prefunctionalized substrates are needed, the
transition-metal-catalyzed cyanation of aryl halides4 and the
electrophilic cyanation of metalated aryls5 have attracted
widespread interest for organic synthesis in terms of high
selectivity and versatility of substrates. However, introduction
of cyanide into a pyrrole ring is difficult using such methods
because the starting halogenated pyrroles are very unstable.6
Therefore, another approach such as direct introduction of
unfunctionalized pyrroles is important to obtain these cyan-
ated compounds. The direct introduction of cyanide into
(1) (a) Jones, R. A. Pyrroles, Chemistry of Heterocyclic Compounds;
Wiley: New York, 1990; Vol. 48. (b) Kleemann, A.; Engel, J.; Kutscher,
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4th ed.; Georg Thieme: Stuttgart, 2001. (c) Gilchrist, T. L. J. Chem. Soc.,
Perkin Trans. 1 1999, 2849.
Scheme 1
(2) (a) Roncali, J. Chem. ReV. 1992, 92, 711. (b) Mu¨llen, K., Wegner,
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Verlag GmbH, 1998. (c) McCullough, R. D. AdV. Mater. 1998, 10, 93.
(3) (a) Rappoport, Z. The Chemistry of the Cyano Group; Interscience
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Transformations. A Guide to Functional Group Preparations; VCH
Publishers: New York, 1989.
10.1021/ol0476826 CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/19/2005

heteroaromatic compounds has also been reported using
chemical agents7 and photo- or electrochemical operations
(method B).8 The latter approach is believed to be desirable
in nature by not requiring any functionality, but the utility
has usually been limited to practical applications perhaps
because of problems concerning the cyanation reagents. All
reported cyanation procedures need the highly electrophilic
cyano cation equivalent (+CN) as cyanation sources, which
are relatively unstable and difficult to prepare and handle
and even in some cases possess reactivity too high to allow
for selective control of the reactions. Therefore, new
methodologies and reagents for enabling the direct cyanation
have been strongly desired.
(PIFA)-mediated reaction that allows the direct oxidative
conversion of a wide range of heteroaromatic compounds
into cyanides using trimethylsilyl cyanide at room temper-
ature.
We first examined the cyanation of pyrrole 1a by PIFA
in (CF3)2CHOH or a combination of PIFA and BF3‚Et2O in
dichloromethane at ambient temperature, which did not give
any cyanation product under such conditions but instead
afforded mainly oxidative biaryl coupling products (Table
1, entry 1).11 This result shows the high nucleophicity of
Table 1. Direct Cyanation of N-Protected Pyrroles
Recently, hypervalent iodine(III) reagents have been
recongnized as useful synthetic tools due to their low toxicity,
ready availability, and ease of handling.9 As a continuation
of our study on hypervalent iodine chemistry, we have
previously reported the hypervalent iodine(III)-induced mild
and efficient direct nucleophilic substitutions of phenyl
ethers10 and alkylarenes10e in the presence of various nu-
-
cleophiles such as SCN,10a -SAr,10a,b -OAc, â-dicarbonyl
entry
R
yield of 2 (%)a
10c-e
compounds,10d and -N3
(Scheme 2). These results
1
2
3
4
5b
H (1a)
Boc (1b)
Me (1c)
Ts (1d)
(1d)
trace
trace
20 (2c)
59 (2d)
83
Scheme 2
a Isolated yields. b Performed with 2 equiv of PIFA and 4 equiv of
BF3‚Et2O.
the pyrrole ring itself. After a number of unsuccessful
attempts, we finally found that the protecting group of the
pyrrole nitrogen atom plays a crucial role (entries 2-4).
Thus, N-tosyl pyrrole 1d was selectively converted to
2-cyano-N-tosyl pyrrole 2d in 83% yield by the combination
of PIFA and BF3‚Et2O in CH2Cl2 at room temperature (entry
5). The regiochemistry of the cyanation products was
encouraged us to examine the cyanide anion (-CN) as a
stable nucleophilic cyanide source for direct oxidative
cyanation. We now report a phenyliodine bis(trifluoroacetate)
1
determined from the H NMR measurement or by leading
the cyanation products to the known compounds which have
been reported before. Trimethylsilyl cyanide produced the
best result as a cyanide source among those examined,12
probably due to its good solubility in organic solvents. Other
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538
Org. Lett., Vol. 7, No. 4, 2005

iodine(III) compounds such as phenyliodine diacetate (PIDA)
and [hydroxy(tosyloxy)iodobenzene] (HTIB), gave poor
results.
The present reaction is applicable for a wide range of
substituted pyrroles as well as thiophenes having various
types of aliphatic, aromatic, and ether substituents. These
results are summarized in Table 2.13 Although it has been
yields (entries 7-9). These reactions are quite sensitive to
the electronic character of the thiophene (entry 10). The
thiophenes 3e are also converted to useful 2-cyano derivatives
having 3-aryl groups in the same manner (entry 11).
Despite some slightly problematic yields, this cyanation
protocol is available for indoles 5 (Table 3). 2-Methyl indole
5a reacted at the 3-position to give the corresponding
cyanation product 6a (entry 1), and 3-methyl indole 5b and
5c reacted at the 2-position in turn (entries 2 and 3).
Table 2. PIFA-Mediated Direct Oxidative Cyanation of
Pyrroles and Thiophenes
Table 3. PIFA-Mediated Direct Oxidative Cyanation of Indole
Derivatives
a All products were characterized by 1H NMR, 13C NMR, and IR.
b Isolated yields after purification by chromatography on silica gel.
To demonstrate the synthetic utility of this novel direct
oxidative cyanation reaction, we conducted transformations
of the cyanation products 2f and 2g because these 3-aryl
pyrroles are physiologically very important (Scheme 3).14
Thus, deprotection of the tosyloxy group of 2f and 2g
followed by treatment with 2-amino-2-methyl-1-propanol
gave the 2-dihydrooxazole compounds 7a and 7b, respec-
tively (eq 1). Apparently, these products are hardly accessible
not only by a stepwise approach such as the palladium-
catalyzed cyanation of aryl halides but also by the selective
a All products were characterized by 1H NMR, 13C NMR, and IR.
b Isolated yields after purification by chromatography on silica gel.
widely recognized that the synthesis of 2-substituted 3-aryl
pyrroles is quite difficult and only a few methods have been
reported and they give low yields and lack of generality,14a
3-(4-bromophenyl)pyrrole 1f and 1g gave 2-cyanation prod-
ucts 2f and 2g, respectively, in excellent yields (entries 3
and 4). On the other hand, disubstituted pyrroles 1h gave
somewhat poor results due to the competitive formation of
bipyrroles (entry 5). Trisubstituted pyrrole 1i is applicable
(entry 6). Similar to pyrroles, alkyl thiophenes 3a-c
selectively gave 2-cyanation products in good to moderate
Scheme 3
(12) Among the cyanide sources, trimethylsilyl cyanide gave the best
yield compared with other reagents such as diethyl cyanophosphonate,
tributyltin cyanide, and a combination of potassium cyanide and 18-crown-
6.
(13) Typical Experimental Procedure. To a stirred solution of PIFA
(2 mmol) and BF3‚AcOEt (4 mmol) in CH2Cl2 (1 mL) was added
trimethylsilyl cyanide (3 mmol) at room temperature. After stirring for 30
min, N-tosyl pyrrole 1d (1 mmol) was added in one portion, and the mixture
was stirred for additional 3 h under the same condition while checking the
reaction progress by GC or TLC. After the reaction was complete, saturated
aqueous sodium thiosulfate (ca. 5 mL) was added to the mixture. The organic
layer was separated, and the aqueous phase was extracted with CH2Cl2.
The combined extract was dried with MgSO4 and evaporated to dryness.
The residue was purified by column chromatography (SiO2/n-hexanes-
Et2O) to give pure 2d (83%).
Org. Lett., Vol. 7, No. 4, 2005
539

introduction of a bromide into aryl rings after cyanation. It
is thought that aryl bromide functions in compounds 7a and
7b are advantageous for construction of more complex
molecules via C-C, C-N, and C-O bond formations.
A plausible mechanism of the present reaction is depicted
in Scheme 4. Cation radical B is initially formed from the
is still unclear, but the mild and effective generation of cation
radical B induced by PIFA-BF3‚Et2O might be important.
In summary, we have developed the direct oxidative
cyanation of heteroaromatic compounds using a hypervalent
iodine(III) reagent. Our novel cyanation protocol has the
following characteristic features: (i) direct cyanation of
unfunctionalized heteroaromatic compounds under mild
conditions, (ii) a stable organocyanide source is usable, (iii)
various types of heteroaromatic compounds are applicable,
and (iv) the aryl halide function is maintained, which is
beneficial for further transformations of the cyanation
products. From these points of view, our novel cyanation
procedure described herein will provide a new alternative
method. Application of this cyanation reaction will be
presented in the near furture.
Scheme 4
heteroaromatic compounds with PIFA-BF3‚Et2O via CT-
complex A under the reaction conditions analogous to those
of our previously developed PIFA-induced reactions10,11 or
typical heavy metal oxidations,15 yielding aromatic cation
radicals. The cation radical B then reacts with the cyanide
anion by an one-electron oxidation followed by deprotonation
to give the observed cyanation product. The formation of B
was supported by the effective inhibition of the reaction in
the presence of the radical scavenger, galvinoxyl. The precise
reason PIFA is an effective oxidizer in this cyanation reaction
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research (S) (No. 13853010) from the
Ministry of Education, Culture, Sports, Science, and Tech-
nology, Japan.
Supporting Information Available: Experimental details
for preparation and detailed spectroscopic data of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0476826
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