A facile and clean direct cyanation of heteroaromatic compounds using a recyclable hypervalent iodine(III) reagent

Article abstract of DOI:10.1248/cpb.54.1608

The facile and clean direct cyanating reaction of pyrroles and thiophenes has been achieved using a recyclable hypervalent iodine(III) reagent 1b by a simple solid-liquid separation of the products and the reagent.

Full text of DOI:10.1248/cpb.54.1608

1608
Notes
Chem. Pharm. Bull. 54(11) 1608—1610 (2006)
Vol. 54, No. 11
A Facile and Clean Direct Cyanation of Heteroaromatic Compounds
Using a Recyclable Hypervalent Iodine(III) Reagent
Toshifumi DOHI, Koji MORIMOTO, Naoko TAKENAGA, Akinobu MARUYAMA, and Yasuyuki KITA*
Graduate School of Pharmaceutical Sciences, Osaka University; 1–6 Yamada-oka, Suita, Osaka 565–0871, Japan.
Received July 19, 2006; accepted September 2, 2006; published online September 5, 2006
The facile and clean direct cyanating reaction of pyrroles and thiophenes has been achieved using a recycla-
ble hypervalent iodine(III) reagent 1b by a simple solid-liquid separation of the products and the reagent.
Key words cyanation; hypervalent iodine(III) reagent; recycle; heteroaromatic compound; direct method
Heteroaromatic compounds are often significant compo- adamantane core,17) instead of PIFA with the combination of
nents of natural compounds and pharmaceuticals.1,2) The cya- BF3·Et2O in the presence of TMSCN. The present method
nating reaction of heteroaromatic compounds is one of the not only directly produces the heteroaromatic cyanides in
important organic transformations in organic synthesis, since high yields, but also facilitates the isolation of the cyanated
the cyano group is readily converted into a variety of other products utilizing the insolubility of 2 in MeOH.
functional groups through carboxy groups, amines, etc.3)
With a 0.5 eq of 1b (200 mol% iodine(III) atom),
Therefore, several synthetic methods, both stepwise4,5) and BF3·Et2O (4 eq) and TMSCN (3 eq) in dichloromethane, we
direct6—9) ones have already been developed. Among them, first examined the cyanating reaction of N-tosyl pyrrole 3a
the latter methods seem to be convenient, especially in elec- (Table 1, Eq. 1). In accord with our expectation, the reaction
tron-rich heteroaromatic compounds, such as pyrroles, that smoothly proceeded under homogeneous conditions to give
are unstable in their halogenated or metallated forms. The the 2-cyanated product 4a in 85% yield without the forma-
direct introduction of the cyano functionality into these tion of other regioisomers by reaction at the 3-position (entry
heteroaromatic compounds was usually achieved by elec- 1). To set up the reaction, premixing of all the reagents is es-
trophilic substitution reactions, but it is not a widely accepted sential in order to generate the active iodine(III) species be-
method due to the necessity of using ‘unstable cyano cation fore adding 3a; the iodine(III) reagent 1b, TMSCN and
equivalents.’
BF3·Et2O should be pre-mixed for 30 min, otherwise 4a
From this point of view, the direct cyanating reaction using would be obtained in lower yields. Similar to the previous re-
a stable cyanide (CNꢀ) under oxidative conditions is consid- sult, 4a was not formed by treatment of 1a having acetoxy
ered to be an alternative and attractive method.10) We have re- group.
cently developed a novel and direct oxidative cyanating reac-
As shown in Table 1, 1b gave a variety of corresponding
tion of heteroaromatic compounds induced by a hypervalent a-cyanated products 4 in good to excellent yields. It is noted
iodine(III) reagent, phenyliodine bis(trifluoroacetate) (PIFA), that the sterically demanding pyrrole 3d also afforded the 2-
with BF3·Et2O (Chart 1) at room temperature.11) The present cyanated product 4d (entry 4). The reaction proceeded in the
method has significant advantages; i.e., availability of a low presence of some functional groups, which are available for
toxic, readily accessible and easy handling hypervalent further transformations after the reactions (entries 5, 7, 8).
iodine(III) organo-oxidant12—16) and a stable trimethylsilyl However, with the pyrrole 3i, the yield of 4i was slightly de-
cyanide (TMSCN), high selectivity and versatility of het- creased due to the undesired competitive oxidation of the
eroaromatic compounds (i.e., pyrroles, thiophenes and in- electron-rich phenyl ether ring (entry 9). The polysubstituted
doles). Therefore, it might become a powerful method to pyrroles 3j and 3k gave the desired products in similar ways
synthesize these useful heteroaromatic cyanides. However, in (entries 10, 11). Interestingly, 1b showed sufficiently high re-
this reaction, a large amount of volatile and inseparable activities to give the cyanated products in a yield comparable
iodobenzene (PhI), the reduced form of PIFA, was co-pro- to or better than PIFA. In contrast, the conventional polymer-
duced after the reactions, which makes isolation of the reac- supported reagents,18,19) poly(diacetoxyiodo)styrene (PDAIS)
tion products troublesome. For these reasons, we decided to and poly[bis(trifluoroacetoxy)iodo]styrene (PBTIS), also
find another suitable hypervalent iodine(III) alternative for provided the cyanated products, but the yields were consider-
the oxidative cyanating reaction.
ably lower than those of 1b due to the insolubility of PDAIS
We now report the reaction using 1,3,5,7-tetrakis[4- and PBTIS.
{bis(trifluoroacetoxy)iodo}phenyl]adamantane (1b, Fig. 1),
a recyclable hypervalent iodine(III) reagent bearing an
Fig. 1. Recyclable Hypervalent Iodine(III) Reagents Based on an
Adamantane Structure
Chart 1
∗ To whom correspondence should be addressed. e-mail: kita@phs.osaka-u.ac.jp
© 2006 Pharmaceutical Society of Japan

November 2006
1609
Table 1. Direct Oxidative Cyanating Reaction of Pyrroles Using a Recy-
clable Hypervalent Iodine(III) Reagent 1b (Eq. 1)
tively recovered and the recycling of 1 was achieved without
any loss of activity by reoxidation of the recovered 2 using
m-chloroperbenzoic acid (mCPBA) in acetic acid/dichloro-
methane.17) From the combined MeOH filtrate, the crude
cyanated product 4 was obtained along with a small amount
of impurities, which were subjected to further purification,
e.g., short column chromatography on silica gel, if required.
As already described, the present protocol is quite simple,
clean and versatile, and consequently, is a facile and conven-
ient method for the introduction of the cyano group into elec-
tron-rich heteroaromatic compounds.
Substrate 3
Time
(h)
Yield of 4
Entrya)
(%)b)
R1
R2
R3
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
H
Et
H
H (3a)
H (3b)
H (3c)
H (3d)
H (3e)
H (3f)
H (3g)
H (3h)
H (3i)
H (3j)
Me (3k)
6
6
6
6
6
6
6
6
4
6
6
85 (4a)
71 (4b)
72 (4c)
98 (4d)
85 (4e)
92 (4f)
95 (4g)
90 (4h)
45 (4i)
75 (4j)
70 (4k)
Me
Hep
t-Bu
(CH2)3CO2Me
C6H5
2-BrC6H4
4-BrC6H4
4-MeOC6H4
Et
Experimental
General The 1H- and 13C-NMR spectra were recorded by a JEOL JMN-
300 spectrometer operating at 300 MHz in CDCl3 at 25 °C with tetramethyl-
silane as the internal standard. Data are reported as follows: chemical shift
in ppm (d), integration, multiplicity (sꢁsinglet, dꢁdoublet, tꢁtriplet,
qꢁquartet, brꢁbroad singlet, mꢁmultiplet), coupling constant (Hz) and in-
terpretation. The infrared spectra (IR) were obtained using a Hitachi 270-50
spectrometer; absorptions are reported in reciprocal centimeters with the fol-
lowing relative intensities: s (strong), m (medium) or w (weak). The mass
spectra were obtained using a Shimadzu GCMS-QP 5000 instrument with
ionization voltages of 70 eV. The high resolution mass spectra were per-
formed by the Elemental Analysis Section of Osaka University. Column
chromatography and TLC were carried out on Merck Silica gel 60 (230—
400 mesh) and Merck Silica gel F254 plates (0.25 mm), respectively. The
spots and bands were detected by UV irradiation (254, 365 nm).
10
11
Me
a) The molar ratio of 3, 1b, BF3·Et2O and TMSCN is 1 : 2ꢂ1/4 : 4 : 3. b) Isolated
yields after purification.
Table 2. Direct Oxidative Cyanating Reaction of Thiophenes Using 1b
(Eq. 2)
Preparation of 1b To
a stirred solution of 1,3,5,7-tetrakis(4-
iodophenyl)adamantane 2 (1.42 g, 1.5 mmol) in CH2Cl2 (150 ml)–AcOH
(150 ml) was added mCPBA (69% purity, 3.12 g, 18 mmol) at room tempera-
ture. The mixture was stirred for 12 h under the same reaction conditions,
while the cloudy solution became clear. The resultant mixture was filtered,
and CH2Cl2 was removed from the filtrate using a rotary evaporator. Hexane
was added to the residue to precipitate 1,3,5,7-tetrakis[4-(diacetoxyiodo)-
phenyl]adamantane 1a. After filtration, the crude product was washed sev-
eral times with hexane, and then dried in vacuo to give 1a (2.09 g, 97%).
1a (1.01 g, 0.71 mmol) was dissolved in CHCl3 (15 ml), then trifluoro-
acetic acid (15 ml) was slowly added to the solution at room temperature.
The mixture was stirred for 1.5 h under the same reaction conditions. After
removal of the CHCl3 under reduced pressure, hexane–Et2O (10 : 1) was
added. The precipitate was filtered and washed with hexane–Et2O (10 : 1)
several times, and dried in vacuo to give 1b (1.17 g, 89%) as a solid.
Substrate 5
Time
(h)
Yield of 6
Entrya)
(%)b)
R4
Me
R5
1
2
3
4
5
6
H (5a)
H (5b)
H (5c)
H (5d)
H (5e)
Me (5f)
15
15
15
4
7
6
79 (6a)
68 (6b)
75 (6c)
77 (6d)
75 (6e)
64 (6f)
Hex
c-Hex
OMe
C6H5
H
1b:
A slightly yellow crystals. mp (decomp.) 196—203 °C (from
CF3CO2H–CH2Cl2–hexane). 1H-NMR (CDCl3/CF3CO2Hꢁ10/1) d: 8.24
(8H, d, Jꢁ8.7 Hz, ArH), 7.73 (8H, d, Jꢁ8.7 Hz, ArH), 2.30 (12H, s, CH2).
19F-NMR (200 MHz, CDCl3/CF3CO2Hꢁ10/1, hexafluorobenzene (ꢀ162.9
ppm)) d: ꢀ74.51 (24F, s, OCOCF3). Anal. Calcd for C50H28F24I4O16: C,
32.49; H, 1.53. Found: C, 32.82; H, 1.86.
a) The molar ratio of 5, 1b, BF3·Et2O and TMSCN is 1 : 2ꢂ1/4 : 4 : 3. b) Isolated
yields after purification.
Typical Procedure for Direct Oxidative Cyanating Reaction Using 1b
To a stirred solution of 1b (462 mg, 0.25 mmol) and BF3·Et2O (0.25 ml,
2 mmol) in CH2Cl2 was slowly added TMSCN (0.20 ml, 1.5 mmol) at room
temperature. The mixture was stirred for 30 min, while the yellow color of
the solution gradually changed to white. N-Tosylpyrrole 3a (111 mg,
0.5 mmol) was then added to the solution in one portion and stirred for an
additional 6 h. Saturated NaHCO3 aq. and solid Na2S2O3·5H2O were succes-
sively added to the reaction mixture. After being stirred for 5 min, the or-
ganic layer was separated and evaporated. MeOH (10 ml) was added to the
reaction mixture, and it was filtered. The solid residue was washed several
times with MeOH, and the residue was recovered as tetraiodide 2 (confirmed
by 1H-NMR analysis and TLC). The filtrate including 4a was evaporated and
subjected to column chromatography (SiO2, hexane/AcOEt) to give 2-cyano-
N-tosylpyrrole 4a (105 mg, 85 %) as a white powder.
Thiophenes 5 have similar oxidation potentials as N-tosyl
pyrroles,20,21) and thus are applicable for the cyanating reac-
tion (Table 2). The 2-cyano thiophenes 6 were obtained from
a wide range of thiophenes 5 having different oxidation po-
tentials (entries 1—5), and 2-methylthiophene 5f also reacted
at the a-position of the sulfur atom to give the 2-cyano-5-
methylthiophene 6f (entry 6).
In all these transformations, 1b could be easily separated
from the reaction mixtures as the tetraiodide 2, a reduced
form of 1b, by a simple solid-liquid separation, i.e., filtration.
Thus, after the reactions were completed, the remaining 1b
was reduced to 2 by the sequential treatment of saturated
NaHCO3 aq. and solid Na2S2O3·5H2O. The organic layer was
then separated and evaporated under reduced pressure. To the
resulting oily mixture, MeOH was added to precipitate 2.
Since 2 is only slightly soluble in MeOH, it was simultane-
ously precipitated as a fine powder. The solution was then fil-
tered to remove 2 and the solid residue was washed several
2-Cyano-N-tosylpyrrole (4a)22): Colorless crystals. mp 114—115 °C.
Rfꢁ0.51 (hexane/EtOAcꢁ4/1). 1H-NMR (CDCl3) d: 2.44 (3H, s, CH3), 6.32
(1H, t, Jꢁ3.4 Hz, pyrrole), 6.95 (1H, dd, Jꢁ3.4, 1.6 Hz, pyrrole), 7.37 (2H,
d, Jꢁ8.7 Hz, Ts), 7.47 (1H, dd, Jꢁ3.4, 1.6 Hz, pyrrole), 7.93 (2H, d,
Jꢁ8.7 Hz, Ts). 13C-NMR (CDCl3) d: 21.69, 103.74, 111.63, 112.30, 126.56,
126.57, 127.85, 130.36, 134.12, 146.52. IR (KBr) cmꢀ1: 2225 (CN, s).
4-(2-Cyano-N-tosylpyrrole-3-yl)butyric Acid Methyl Ester (4e): Colorless
crystals. mp 110—112 °C. Rfꢁ0.41 (hexane/EtOAcꢁ2/1). 1H-NMR
times with MeOH. In this way, 2 could be nearly quantita- (CDCl3) d: 1.81 (2H, quint, Jꢁ7.5 Hz, CH2), 2.22 (2H, t, Jꢁ7.5 Hz,

1610
Vol. 54, No. 11
5) Electrophilic cyanations of metallated aryls: Sato N., Yue Q., Tetrahe-
dron, 59, 5831—5836 (2003) and references cited therein.
6) Chlorosulfonyl isocyanate: Graf R., Chem. Ber., 89, 1071—1079
(1956).
7) Isocyanatophosphoric acid dichloride: Smaliy R. V., Chaikovskaya A.
A., Pinchuk A. M., Tolmachev A. A., Synthesis, 2002, 2416—2420
(2002).
8) (Ethoxycarbonylimino)triphenylphosphorane: von der Brück D., Tapia
A., Riechel R., Plieninger H., Angew. Chem. Int. Ed., 7, 377 (1968).
9) Triphenyphosphine-thiocyanogen: Tamura Y., Adachi M., Kawasaki
T., Yasuda H., Kita Y., J. Chem. Soc., Perkin Trans. 1, 1980, 1132—
1135 (1980).
CH2CO2Me), 2.37 (3H, s, CH3), 2.50 (2H, t, Jꢁ7.5 Hz, CH2(CH2)2CO2CH3),
3.58 (3H, s, CO2CH3), 6.16 (1H, d, Jꢁ3.0 Hz, pyrrole 4-H), 7.28—7.33 (3H,
m), 7.83 (2H, d, Jꢁ8.1 Hz, Ts). 13C-NMR (CDCl3) d: 21.72, 24.65, 25.79,
33.00, 51.62, 101.69, 111.46, 112.91, 126.46, 127.76, 130.33, 134.14,
142.49, 146.33, 173.27. IR (KBr) cmꢀ1: 2220 (CN, m). HR-FAB-MS: m/z
347.1043 [MꢃH]ꢃ (Calcd for C17H18N2O4S: 347.1065).
2-Cyano-3-(4-methoxyphenyl)-N-tosylpyrrole (4i): Colorless crystals. mp
1
85—88 °C. Rfꢁ0.41 (hexane/EtOAcꢁ2/1). H-NMR (CDCl3) d: 2.37 (3H,
s, CH3), 3.75 (3H, s, OCH3), 6.45 (1H, d, Jꢁ3.3 Hz, pyrrole 4-H), 6.86 (2H,
d, Jꢁ8.4 Hz), 7.30 (2H, d, Jꢁ8.4 Hz), 7.43 (1H, d, Jꢁ3.0 Hz, pyrrole 5-H),
7.50 (2H, d, Jꢁ8.4 Hz), 7.89 (2H, d, Jꢁ8.4 Hz). 13C-NMR (CDCl3) d: 21.75,
55.32, 98.56, 111.66, 112.96, 114.36, 123.16, 126.75, 127.98, 128.48,
130.36, 134.15, 141.11, 146.41, 160.20. IR (KBr) cmꢀ1: 2216 (CN, s). HR-
FAB-MS: m/z 375.0793 [MꢃNa]ꢃ (Calcd for C18H14N2O2BrSNa:
375.0779).
10) Under electrochemical operations: Yoshida K., J. Am. Chem. Soc., 99,
6111—6113 (1977).
11) Dohi T., Morimoto K., Kiyono Y., Tohma H., Kita Y., Org. Lett., 7,
537—540 (2005).
12) Wirth T., Angew. Chem. Int. Ed., 44, 3656—3665 (2005).
13) “Hypervalent Iodine Chemistry,” ed. by Wirth T., Springer-Verlag,
Berlin, Heidelberg, 2003.
14) Zhdankin V. V., Stang P. J., Chem. Rev., 102, 2523—2584 (2002).
15) “Hypervalent Iodine in Organic Synthesis,” ed. by Varvoglis A., Acad-
emic Press, San Diego, 1997.
Acknowledgements This work was supported by a Grant-in-Aid for
Scientific Research (A) and for Encouragement of Young Scientists, and by
a Grant-in-Aid for Scientific Research on Priority Areas “Advanced Molecu-
lar Transformations of Carbon Resources” from the Ministry of Education
Culture, Sports, Science, and Technology, Japan. T. D. also thanks the Indus-
trial Technology Research Grant Program from the New Energy and Indus-
trial Technology Development Organization (NEDO) of Japan.
16) Kita Y., Takada T., Tohma H., Pure Appl. Chem., 68, 627—630
(1996).
17) Tohma H., Maruyama Y., Maeda A., Maegawa T., Dohi T., Shiro M.,
Morita T., Kita Y., Angew. Chem. Int. Ed., 43, 3595—3598 (2004).
18) Togo H., Sakuratani K., Synlett, 2002, 1966—1975 (2002).
19) Tohma H., Kita Y., Yuki Gosei Kagaku Kyokaishi, 62, 116—127
(2004).
20) Tajima T., Nakajima A., Fuchigami T., J. Org. Chem., 71, 1436—1441
(2006).
21) “Conducting Polymers, Fundamentals and Applications,” ed. by Chan-
drasekhar P., Kluwer Academic Publisher, Boston, 1999.
22) Highs T. V., Cava M. O., J. Org. Chem., 64, 313—315 (1999).
References
1) Jones R. A., “The Chemistry of Heterocyclic Compounds: a Series of
Monographs,” Vol. 48, Wiley, New York, 1992.
2) Kleemann A., Engel J., Kutscher B., Reichert D., “Pharmaceutical
Substance: Synthesis, Patents, Applications,” 4th ed., Georg Thieme,
Stuttgart, 2001.
3) Friedrich K., Wallensfels K., “The Chemistry of the Cyano Group,”
ed. by Rappoport Z., Interscience Publishers, London, 1970.
4) Review of transition-metal-catalyzed substitution reactions of aryl
halides: Sundermeier M., Zapf A., Beller M., Eur. J. Inorg. Chem.,
2003, 3513—3526 (2003).