Direct cyanation of heteroaromatic compounds mediated by hypervalent iodine(III) reagents: In situ generation of PhI(III)-CN species and their cyano transfer

Article abstract of DOI:10.1021/jo061820i

Hypervalent iodine(III) reagents mediate the direct cyanating reaction of a wide range of electron-rich heteroaromatic compounds such as pyrroles 1, thiophenes 3, and indoles 5 under mild conditions (ambient temperature), without the need for any prefunctionalization. Commercially available trimethylsilylcyanide is usable as a stable and effective cyanide source, and the reaction proceeds in a homogeneous system. The N-substituent of pyrroles is crucial to avoid the undesired oxidative bipyrrole coupling process, and thus a cyano group was introduced selectively at the 2-position of N-tosylpyrroles 1 in good yields using the combination of phenyliodine bis(trifluoroacetate) (PIFA), TMSCN, and BF₃·Et₂O at room temperature. In the reaction mechanism, cation radical intermediates of heteroaromatic compounds are involved as a result of single electron oxidation, and the key to successful transformations seems to depend on the oxidation potential of the substrates used. Thus, the reaction was also successfully extended to other heteroaromatic compounds having oxidation potentials similar to that of N-tosylpyrroles such as thiophenes 3 and indoles 5. However, regioisomeric mixtures of the products derived from the reaction at the 2- and 3-positions were obtained in the case of N-tosylindole 5a. Further investigation performed in our laboratory provided insights into the real active iodine(III) species during the reaction; the reaction is induced by an active hypervalent iodine(III) species having a cyano ligand in situ generated by ligand exchange reaction at the iodine(III) center between trifluoroacetoxy group in PIFA and TMSCN, and effective cyanide introduction into heteroaromatic compounds is achieved by means of the high cyano transfer ability of the hypervalent iodine(III)-cyano intermediates. In fact, the reaction of N-tosylpyrrole 1a with a hypervalent iodine(III)-cyano compound (e.g., (dicyano)iodobenzene 8), in the absence of TMSCN, took place to afford the 2-cyanated product 2a in good yield, and an effective preparation of the intermediates is of importance for successful transformation. 1,3,5,7-Tetrakis[4-{bis(trifluoroacetoxy)-iodo}phenyl]adamantane 12, a recyclable hypervalent iodine(III) reagent, was also comparable in the cyanating reactions as a valuable alternative to PIFA, affording a high yield of the heteroaromatic cyanide by facilitating isolation of the cyanated products with a simple workup. Accordingly, after preparing the active hypervalent iodine(III)-CN species by premixing of a recyclable reagent 12, TMSCN, and BF₃· Et₂U for 30 min in dichloromethane, reaction of a variety of pyrroles 1 and thiophenes 3 provided the desired cyanated products 2 and 4 in high yields. The iodine compound 13, recovered by filtration after replacement of the reaction solvent to MeOH, could be reused without any loss of activity (the oxidant 12 can be obtained nearly quantitatively by reoxidation of 13 using m-CPBA).

Full text of DOI:10.1021/jo061820i

Direct Cyanation of Heteroaromatic Compounds Mediated by
Hypervalent Iodine(III) Reagents: In Situ Generation of
PhI(III)-CN Species and Their Cyano Transfer
Toshifumi Dohi, Koji Morimoto, Naoko Takenaga, Akihiro Goto, Akinobu Maruyama,
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 September 1, 2006
Hypervalent iodine(III) reagents mediate the direct cyanating reaction of a wide range of electron-rich
heteroaromatic compounds such as pyrroles 1, thiophenes 3, and indoles 5 under mild conditions (ambient
temperature), without the need for any prefunctionalization. Commercially available trimethylsilylcyanide
is usable as a stable and effective cyanide source, and the reaction proceeds in a homogeneous system.
The N-substituent of pyrroles is crucial to avoid the undesired oxidative bipyrrole coupling process, and
thus a cyano group was introduced selectively at the 2-position of N-tosylpyrroles 1 in good yields using
the combination of phenyliodine bis(trifluoroacetate) (PIFA), TMSCN, and BF3‚Et2O at room temperature.
In the reaction mechanism, cation radical intermediates of heteroaromatic compounds are involved as a
result of single electron oxidation, and the key to successful transformations seems to depend on the
oxidation potential of the substrates used. Thus, the reaction was also successfully extended to other
heteroaromatic compounds having oxidation potentials similar to that of N-tosylpyrroles such as thiophenes
3 and indoles 5. However, regioisomeric mixtures of the products derived from the reaction at the 2- and
3-positions were obtained in the case of N-tosylindole 5a. Further investigation performed in our laboratory
provided insights into the real active iodine(III) species during the reaction; the reaction is induced by an
active hypervalent iodine(III) species having a cyano ligand in situ generated by ligand exchange reaction
at the iodine(III) center between trifluoroacetoxy group in PIFA and TMSCN, and effective cyanide
introduction into heteroaromatic compounds is achieved by means of the high cyano transfer ability of
the hypervalent iodine(III)-cyano intermediates. In fact, the reaction of N-tosylpyrrole 1a with a
hypervalent iodine(III)-cyano compound (e.g., (dicyano)iodobenzene 8), in the absence of TMSCN,
took place to afford the 2-cyanated product 2a in good yield, and an effective preparation of the
intermediates is of importance for successful transformation. 1,3,5,7-Tetrakis[4-{bis(trifluoroacetoxy)-
iodo}phenyl]adamantane 12, a recyclable hypervalent iodine(III) reagent, was also comparable in the
cyanating reactions as a valuable alternative to PIFA, affording a high yield of the heteroaromatic cyanide
by facilitating isolation of the cyanated products with a simple workup. Accordingly, after preparing the
active hypervalent iodine(III)-CN species by premixing of a recyclable reagent 12, TMSCN, and BF3‚
Et2O for 30 min in dichloromethane, reaction of a variety of pyrroles 1 and thiophenes 3 provided the
desired cyanated products 2 and 4 in high yields. The iodine compound 13, recovered by filtration after
replacement of the reaction solvent to MeOH, could be reused without any loss of activity (the oxidant
12 can be obtained nearly quantitatively by reoxidation of 13 using m-CPBA).
10.1021/jo061820i CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/09/2006
J. Org. Chem. 2007, 72, 109-116
109

Dohi et al.
SCHEME 1. Direct Oxidative Introduction of Nucleophiles
Introduction
into Phenyl Ethers and Alkylarenes via Cation Radical
Intermediates
Heteroaromatic compounds constitute general motifs in
natural compounds and pharmaceuticals and are of substantial
interest in a wide range of research studies from organic and
pharmaceutical chemistries to material sciences due to their
unique physical properties.1,2 Along with these considerations,
heteroaromatic cyanides are one of the important classes of
compounds to build up complex molecules, because the cyano
group is readily converted to a variety of other functional groups
through the carboxylic acids and the amines, and so forth.3
Therefore, it is important to develop efficient methods to
introduce the cyano group into heteroaromatic compounds, and
several synthetic methods have been reported thus far.4-10
The reported cyanating reactions of heteroaromatic com-
pounds are generally classified into two representative meth-
odologies; namely, a stepwise approach or a direct method.
Despite the need for prefunctionalized substrates, the former
approach involving a transition-metal-catalyzed cyanation of
heteroaromatic halides4 and electrophilic cyanation of metalated
heteroaromatics using cyano electrophiles5 has attracted wide-
spread interest for organic synthesis in terms of the high
selectivity and versatility of substrates. However, introduction
of a cyano functionality into a pyrrole ring, an electron-rich
heteroaromatic ring, is difficult when using such an approach,
because the requisite functionalized pyrroles are relatively
unstable.11 Therefore, the latter method enabling direct introduc-
tion of a cyano group into pyrroles is important and desirable
especially for an electron-rich heteroaromatic ring, but it is not
a widely accepted method due to problems concerning the
preparation of unstable cyano cation equiValents (+CN) and the
difficulty of the reaction control.6-9 In this view, a direct
cyanating reaction using stable cyanide ion (-CN) under
oxidative conditions10 would become an alternative attractive
method for the synthesis of these compounds because facile
and effective methods had not yet appeared.
Hypervalent iodine(III) reagents have mild oxidation abilities,
similar to the highly toxic heavy metal oxidizers such as Pb-
(IV), Tl(III), and Hg(II), and have been recognized recently as
a useful synthetic tool due to their low toxicity, ready avail-
ability, and easy handling.12 Over the past decade, we have
focused on a new, efficient, and mild oxidative transformation
of electron-rich aromatic compounds using hypervalent iodine-
(III) reagents and have developed phenyliodine(III) bis(trifluo-
roacetate) (PIFA)-induced direct oxidative nucleophilic substi-
tutions of phenyl ethers and alkylarenes by a variety of
nucleophilessuchas-N3,13a,e -OAcandâ-dicarbonylcompounds,13b
-SAr,13d,e and -SCN13e under mild conditions (Scheme 1). The
oxidative transformation could be rationalized by the formation
of cation radical intermediates, which are generated by single
electron transfer (SET) of phenyl ethers to PIFA.13d Subsequent
intermolecular attack of nucleophiles followed by a further one-
electron oxidation and deprotonation completes the oxidative
aromatic substitution to give the observed products. Encouraged
by these results, we have now examined the possibility of direct
oxidative substitution of heteroaromatic compounds by cyanide
ion (-CN) as a stable nucleophilic cyanide source. Fortunately,
our attempts have been realized successfully and have given
rise to the direct oxidative introduction of cyanide into a wide
(1) (a) Jones, R. A. In The chemistry of heterocyclic compounds: A series
of monographs; Wiley: New York, 1992; Vol. 48. (b) Kleemann, A.; Engel,
J.; Kutscher, B.; Reichert, D. Pharmaceutical Substance: Synthesis, Patents,
Applications, 4th ed.; Georg Thieme: Stuttgart, 2001. (c) Gilchrist, T. L.
J. Chem. Soc., Perkin Trans. 1 1999, 2849.
(2) (a) Roncali, J. Chem. ReV. 1992, 92, 711. (b) Electronic Materials:
The Oligomer Approach; Mu¨llen, K., Wegner, G., Eds.; Wiley-VCH: New
York, 1998. (c) McCullough, R. D. AdV. Mater. 1998, 10, 93.
(3) (a) Rappoport, Z. The Chemistry of the Cyano Group; Interscience
Publishers: London, 1970. (b) Larock, R. C. ComprehensiVe Organic
Transformations. A Guide to Functional Group Preparations; VCH
Publishers: New York, 1989.
(4) (a) Takagi, K.; Okamoto, T.; Sakakibara, Y.; Oka, S. Chem. Lett.
1973, 471. (b) Sekiya, A.; Ishikawa, N. Chem. Lett. 1975, 277. For reviews,
see: (c) Sundermeier, M.; Zapf, A.; Beller, M. Eur. J. Inorg. Chem. 2003,
3513. (d) Grushin, V. V.; Alper, H. Chem. ReV. 1994, 94, 1047. (e) Ellis,
G. P.; Romney-Alexander, A. F. Chem. ReV. 1987, 87, 779.
(5) (a) Sato, N.; Yue, Q. Tetrahedron 2003, 59, 5831 and references
therein. (b) Sato, N. Tetrahedron Lett. 2002, 43, 6403. (c) Wu, Y.-q.;
Limburg, D. C.; Wilkinson, D. E.; Hamilton, G. S. Org. Lett. 2000, 2, 795.
(d) Hughes, T. V.; Cava, M. P. J. Org. Chem. 1999, 64, 313. (e) Klement,
I.; Lennick, K.; Tucker, C. E.; Knochel, P. Tetrahedron Lett. 1993, 34,
4623. (f) Foulger, N. J.; Wakefield, B. J. Tetrahedron Lett. 1972, 13, 4169.
(g) Van Leusen, A. M.; Jagt, J. C. Tetrahedron Lett. 1970, 11, 967.
(6) Chlorosulfonyl isocyanate: (a) Graf, R. Chem. Ber. 1956, 89, 1071.
(b) Lohaus, G. Chem. Ber. 1967, 100, 2719. (c) Lohaus, G. Org. Synth.
1970, 50, 52. (d) Barnett, G. H.; Anderson, H. J.; Loader, C. E. Can. J.
Chem. 1980, 58, 409.
(7) Isocyanatophosphoric acid dichloride: (a) Kirsanov, A. V. Zh.
Obshch. Khim. 1954, 24, 1033. (b) Smaliy, R. V.; Chaikovskaya, A. A.;
Pinchuk, A. M.; Tolmachev, A. A. Synthesis 2002, 2416.
(8) (Ethoxycarbonylimino)triphenylphosphorane: von der Bru¨ck, D.;
Tapia, A.; Riechel, R.; Plieninger, H. Angew. Chem. 1968, 80, 397.
(9) Triphenyphosphine thiocyanogen: (a) Tamura, Y.; Kawasaki, M.;
Adachi, M.; Tanio, M.; Kita, Y. Tetrahedron Lett. 1977, 18, 4417. (b)
Tamura, Y.; Adachi, M.; Kawasaki, T.; Yasuda, H.; Kita, Y. J. Chem. Soc.,
Perkin Trans. 1 1980, 1132.
(10) By electrochemical oxidation: (a) Yoshida, K. J. Am. Chem. Soc.
1977, 99, 6111. (b) Yoshida, K. J. Am. Chem. Soc. 1979, 101, 2116. (c)
Atobe, M.; Aoyagi, T.; Fuchigami, T.; Nonaka, T. Electrochemistry 2004,
72, 821. (d) Liu, W.; Ma, Y.; Yin, Y.-W.; Zhao, Y.-F. J. Heterocycl. Chem.
2006, 43, 681.
(11) (a) Gossauer, A. Die Chemie der Pyrrole; Springer: New York,
1974; pp 326-332. (b) Jones, R. A.; Bean, G. P. In The Chemistry of
Pyrroles. Organic Chemistry. A Series of Monographs; Blomquist, A. T.,
Wasserman, H. H., Eds.; Academic Press: New York, 1977; p 129.
(12) For recent reviews, see: (a) Stang, P. J.; Zhdankin, V. V. Chem.
ReV. 1996, 96, 1123. (b) Kita, Y.; Takada, T.; Tohma, H. Pure Appl. Chem.
1996, 68, 627. (c) Varvoglis, A. HyperValent Iodine in Organic Synthesis;
Academic Press: San Diego, CA, 1997. (d) Kitamura, T.; Fujiwara, Y.
Org. Prep. Proced. Int. 1997, 29, 409. (e) Ochiai, M. In Chemistry in
HyperValent Compounds; Akiba, K., Ed.; Wiley-VCH: New York, 1999;
Chapter 12. (f) Zhdankin, V. V.; Stang, P. J. Chem. ReV. 2002, 102, 2523.
(g) HyperValent Iodine Chemistry; Wirth, T., Ed.; Springer-Verlag: Berlin,
Heidelberg, 2003. (h) Moriarty, R. M. J. Org. Chem. 2005, 70, 2893. (i)
Wirth, T. Angew. Chem., Int. Ed. 2005, 44, 3656.
(13) (a) Kita, Y.; Tohma, H.; Inagaki, M.; Hatanaka, K.; Yakura, T.
Tetrahedron Lett. 1991, 32, 4321. (b) Kita, Y.; Tohma, H.; Hatanaka, K.;
Takada, T.; Fujita, S.; Mitoh, S.; Sakurai, H.; Oka, S. J. Am. Chem. Soc.
1994, 116, 3684. (c) Kita, Y.; Tohma, H.; Takada, T.; Mitoh, S.; Fujita, S.;
Gyoten, M. Synlett 1994, 427. (d) Kita, Y.; Takada, T.; Mihara, S.; Tohma,
H. Synlett 1995, 211. (e) Kita, Y.; Takada, T.; Mihara, S.; Whelen, B. A.;
Tohma, H. J. Org. Chem. 1995, 60, 7144.
110 J. Org. Chem., Vol. 72, No. 1, 2007

Direct Cyanation of Heteroaromatic Compounds
TABLE 1. Optimization of Reaction Conditions: Effect of
N-Substituents in Direct Oxidative Cyanation of Pyrrole (Eq 1)
SCHEME 2. Direct Oxidative Cyanation of Various
Heteroaromatic Compounds Induced by PIFA
yield of cyanated
product (%)b
range of heteroaromatic compounds such as pyrroles 1, thiophenes
3, and indoles 5 (Scheme 2).14
entrya
R
additive
solvent
1
2
3
4
5
6
7
8
H
H
none
(CF3)2CHOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
(CF3)2CHOH
CH2Cl2
CH2Cl2
CH2Cl2
trace
trace
complex
59
55
20
Herein, we wish to report in full detail the novel oxidative
cyanating reaction of heteroaromatic compounds by the com-
bination of PIFA, TMSCN, and BF3‚Et2O at room temperature.
The further investigation described herein revealed that the
reaction would be mediated by hypervalent iodine(III) species
having cyano ligands,15,16 in situ generated from PIFA, TMSCN,
and BF3‚Et2O, and involves the cyano transfer from the active
PhI(III)-CN species to heteroaromatic compounds. A facile and
clean cyanating reaction has also been demonstrated using a
recyclable hypervalent iodine(III) reagent as a useful alternative
to PIFA.
BF3‚Et2O
BF3‚Et2O
BF3‚Et2O
BF3‚Et2O
BF3‚Et2O
none
TMSOTf
BF3‚Et2O
BF3‚Et2O
Boce
Ts (1a)
TIPSe
Me
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
no reaction
34
35
83
9c
10d
a Reactions were performed using 3 equiv of TMSCN, 1 equiv of PIFA,
and 2 equiv of additive otherwise noted. b Isolated yield of the pure cyanated
compounds. c Iodosobenzene was used instead of PIFA. d Two equivalents
of PIFA and 4 equiv of BF3‚Et2O were used. e Boc ) t-butoxycarbonyl,
TIPS ) tri(isopropyl)silyl.
Results and Discussion
Direct Cyanating Reaction of Pyrroles Using PIFA.
Consulting our previous results on oxidative nucleophilic
substitution reactions of phenyl ethers and alkylarenes, we first
examined cyanation of 1H-pyrrole by PIFA in (CF3)2CHOH or
the combination of PIFA and BF3‚Et2O in dichloromethane at
ambient temperature using TMSCN as a soluble cyanide source,
which gave only disappointing results; only trace amounts of
cyanation products were detected by TLC and GC with
unidentified byproducts (Table 1, entries 1 and 2). We then
conducted the reaction at lower temperature (-78 °C). Similarly
to the preliminary results, no introduction of cyanide into 1H-
pyrrole was observed in this case, but instead mainly oxidative
coupling products were obtained.17 These results are clearly
attributed to the excessive nucleophilicity of the pyrrole ring
itself, and so we attempted to survey suitable N-substituents of
pyrroles that can modulate nucleophilicity of the pyrrole ring.
Accordingly, we tried the reactions of pyrroles with electron-
withdrawing groups at their N-position. After a number of
unsuccessful attempts of the reactions at -78 °C, we finally
found that the cyanating reaction would proceed at room
temperature by choosing a tosyl group (Ts) as a suitable
N-protecting group. Thus, N-tosylpyrrole 1a was selectively
converted to 2-cyano-N-tosylpyrrole 2a in 59% yield with some
extent of unreacted starting 1a by the combination of PIFA and
BF3‚Et2O in CH2Cl2 at room temperature (entry 4). The
corresponding 2-cyanated products were also obtained with other
N-substituents (entries 5 and 6), but the methyl group caused a
more remarkable polymerization than the Ts and TIPS groups.
Here, it should be noted that premixing of all reagents is
essential in the order of PIFA, TMSCN, and BF3‚Et2O; they
were mixed for 30 min before adding 1a for performing
successful transformations. Otherwise, 2a was obtained in poorer
yields. In contrast, no reaction was observed in (CF3)2CHOH,
a most effective solvent in the oxidative nucleophilic substitution
of phenyl ethers.13 Other Lewis acids and iodine(III) compounds
such as phenyliodine diacetate (PIDA) and [hydroxyl(tosyloxy)-
iodo]benzene (HTIB) did not produce any cyanation products
except for iodosobenzene with BF3‚Et2O (entry 9).18 Using an
excess of PIFA and BF3‚Et2O improved the yield of cyanated
product 2a without any detectable side products derived from
over-oxidations of 2a.19 Thus, N-tosylpyrrole 1a was added to
the stirred solution including 2 equiv of PIFA, 4 equiv of BF3‚
Et2O, and 3 equiv of TMSCN in dichloromethane. After reacting
for 3 h, all starting 1a was consumed and 2a was obtained in
83% yield (entry 10).
To confirm the scope of the reaction, we attempted to apply
the reaction to a variety of pyrroles using the optimized
condition. As a result, the present reaction is applicable to a
wide range of substituted pyrroles, and these results are
summarized in Table 2. The cyanating reaction of pyrroles,
having aliphatic substituents at their 3-position, smoothly
proceeded and afforded the corresponding 2-cyanated products
(entries 2-5). The structure of the cyanation product 2b was
determined from the 1H NMR measurement (coupling constant,
JH4-H5 ) 3.0 Hz) or by converting the cyanation product to the
(14) For a preliminary communication, see: Dohi, T.; Morimoto, K.;
Kiyono, Y.; Tohma, H.; Kita, Y. Org. Lett. 2005, 7, 537.
(15) (a) Zhdankin, V. V.; Tykwinski, R.; Williamson, B. L.; Stang,
P. J.; Zefirov, N. S. Tetrahedron Lett. 1991, 32, 733. (b) Zhdankin, V. V.;
Kuehl, C. J.; Krasutsky, A. P.; Bolz, J. T.; Mismash, B.; Woodward, J. K.;
Simonsen, A. J. Tetrahedron Lett. 1995, 36, 7975.
(16) Cyanophenyl iodonium(III) salts: (a) Stang, P. J.; Zhdankin, V. V.
J. Am. Chem. Soc. 1990, 112, 6437. (b) Zhdankin, V. V.; Crittell, C. M.;
Stang, P. J. Tetrahedron Lett. 1990, 31, 4821. (c) Zhdankin, V. V.; Scheuller,
M. C.; Stang, P. J. Tetrahedron Lett. 1993, 34, 6853. (d) Zhdankin, V. V.;
Kuehl, C. J.; Bolz, J. T.; Formaneck, M. S.; Simonsen, A. J. Tetrahedron
Lett. 1994, 35, 7323.
(17) (a) Dohi, T.; Morimoto, K.; Maruyama, A.; Kita, Y. Org. Lett. 2006,
8, 2007. (b) Dohi, T.; Morimoto, K.; Kiyono, Y.; Maruyama, A.; Tohma,
H.; Kita, Y. Chem. Commun. 2005, 2930. (c) Tohma, H.; Iwata, M.;
Maegawa, T.; Kiyono, Y.; Maruyama, A.; Kita, Y. Org. Biomol. Chem.
2003, 1, 1647.
(18) Among the cyanide sources, trimethylsilyl cyanide gave the best
yield compared with other compounds such as diethyl cyanophosphonate,
tributyltin cyanide, and a combination of potassium cyanide and 18-crown-
6.
(19) It was reported that the oxidation potentials of N-tosylpyrrole 1a
ox
and 2-cyano-N-tosylpyrrole 2a are 1.96 and 2.56 {Ep (V vs SCE)},
respectively: Tajima, T.; Nakajima, A.; Fuchigami, T. J. Org. Chem. 2006,
71, 1436.
J. Org. Chem, Vol. 72, No. 1, 2007 111

Dohi et al.
TABLE 2. PIFA-Mediated Direct Oxidative Cyanating Reaction of Pyrroles 1
a Reactions were performed using 3 equiv of TMSCN, 2 equiv of PIFA, and 4 equiv of BF3‚Et2O for 3 h at room temperature. b Isolated yield of the pure
cyanated compounds.
known unprotected 2-cyano 1H-pyrrole.20 Although trace amounts
of 5-cyanated products were detected by H NMR (less than
product (entry 8). Polyalkylated pyrroles 1i-k gave the desired
products as the less substituted pyrroles, but the yields were
decreased probably due to the considerable acid-catalyzed
oligomerization of 1i-k. (entries 9-11). In all cases, the
products did not lead to further oxidation and polycyanated
products were not observed. The tosyl groups in the products 2
were easily removable by the standard procedures such as NaOH
in MeOH or EtOH.22
1
3%), high regioselectivities were observed in each case. Thus,
3-methylpyrrole 1b gave 2b in 71% isolated yield after column
chromatography (entry 2). More sterically demanding pyrroles
with higher alkyl groups 1c and 1d were also applicable to the
reaction, and notably, a t-butyl group did not affect the
regioselectivity and yield (entries 3 and 4). The 3-aryl pyrroles
also gave 2-cyanated pyrroles selectively as a single isomer
(entries 6-8). The reaction worked in the presence of some
functional groups, which are convenient for further transforma-
tions toward more complex molecules (entries 5-7).21 Appar-
ently, 2f and 2g are hardly accessible not only by a stepwise
approach such as the palladium-catalyzed cyanation of an aryl
halide but also by the selective introduction of a bromide into
aryl rings after cyanation. In pyrrole 1h, the yield was slightly
decreased because of the competitive undesired oxidation
attributed to the electron-rich phenyl ether ring, though the
cyanated product 2h was obtained as a sole isolable cyanated
Direct Oxidative Cyanation of Other Heteroaromatic
Compounds. Next, we planned to extend the present cyanating
reaction to other heteroaromatic compounds having oxidation
(21) Recent publications on the utility of 3-arylpyrroles: (a) Pavri,
N. P.; Trudell, M. L. J. Org. Chem. 1997, 62, 2649. (b) Kimpe, N. D.;
Tehrani, K. A.; Stevens, C.; Cooman, P. D. Tetrahedron 1997, 53, 3693.
(c) Franc, C.; Denonne, F.; Cuisinier, C.; Ghosez, L. Tetrahedron Lett. 1999,
40, 4555 and references therein. (d) Amira, R.; Evan, T.; Aknin, M.;
Kashman, Y. J. Nat. Prod. 2000, 63, 832. (e) Dannhardt, G.; Kiefer, W.;
Kramer, G.; Maehrlein, S.; Nowe, U.; Fiebich, B. Eur. J. Med. Chem. 2000,
35, 499. (f) Di Santo, R.; Costi, R.; Artico, M.; Massa, S.; Ragno, R.;
Marshall, G. R.; La Colla, P. Bioorg. Med. Chem. 2002, 10, 2511. (g)
Fujikawa, N.; Ohta, T.; Yamaguchi, T.; Fukuda, T.; Ishibashi, F.; Iwao,
M. Tetrahedron 2006, 62, 594.
(20) Abramovitch, R. A. J. Am. Chem. Soc. 1976, 98, 1478.
112 J. Org. Chem., Vol. 72, No. 1, 2007

Direct Cyanation of Heteroaromatic Compounds
TABLE 3. PIFA-Mediated Direct Oxidative Cyanation of 3- or 2-Substituted Thiophenes 3
a All reactions were performed using 3 equiv of TMSCN, 2 equiv of PIFA, and 4 equiv of BF3‚Et2O for 3 h at room temperature. b Isolated yield of the
pure products after purification. c No reaction. d Yield was determined by GC.
SCHEME 3. Cyanating Reaction of Indole Derivatives 5 with
PIFA
potentials similar to that of N-tosylpyrroles 1. In the wake of
our recent success in alkylthiophene oxidations using PIFA,17b,c
we next examined the reaction for thiophenes 3. Consequently,
it became clear that 2-cyanated thiophenes 4 were obtained in
acceptable yields from a wide range of thiophenes 3 having
different oxidation potentials (Table 3).23 Similar to pyrroles,
1° and 2° alkyl thiophenes 3a-c selectively gave 2-cyanation
products in good to moderate yields (entries 1-3). These
reactions are quite sensitive relative to the electronic character
of thiophenes, but a donating group is acceptable in this reaction
(entry 4). Thiophenes 3e were also converted to 2-cyano biaryl
derivative 4e in a similar manner (entry 5). Meanwhile,
thiophenes 3f and 3g having electron-withdrawing groups did
not react at all under the present reaction conditions (entries 6
and 7). 2-Methylthiophene 3h also reacted at the position
adjacent to the sulfur atom to give 2-cyano-5-methylthiophene
4h selectively (entry 8).
This cyanation protocol is also extendable to indoles 5, despite
before adding substrates for the successful transformations in
the present case; this might imply the formation of alternative
iodine(III) species before starting the cyanating reaction, and
the real oxidant is not just PIFA. To clarify the precise reaction
mechanism for the direct oxidative cyanating reaction, we have
challenged the isolation and spectroscopic detection of the real
hypervalent iodine(III) species by 1H and 13C NMR, but all these
efforts failed due to their instability. Next, assuming ligand
exchange at the iodine(III) center between the trifluoroacetoxy
group in PIFA and the cyanide in TMSCN, we focused on
hypervalent iodine(III) compounds having cyano ligands. These
compounds have previously been reported by Stang and
Zhdankin,15,16 and therefore, we synthesized (dicyanoiodo)-
benzene 8 according to the literature method15a and performed
the cyanating reaction of 1a using 8 with BF3‚Et2O under similar
reaction condition, but without TMSCN, to confirm the involve-
ment of such hypervalent iodine(III)-CN species in the direct
oxidative cyanating reaction (Scheme 4). Although the solid 8
itself is not reactive, it gradually started the reaction after
activation by BF3‚Et2O and cyanated product 2a was produced
in an acceptable yield, according to our expectation.24
being slightly problematic in yields and regioselectivities
(Scheme 3). Thus, for indole 5a, 6a was produced, but a small
amount of the regioisomeric isomer 7a derived from the reaction
at the â-position was also detected (eq 2), though introduction
of cyanide into the â-position of the nitrogen atom was not
observed at all in the cases of pyrroles 1. 3-Methylindole 5b
sufficiently gave 2-cyanated product 6b (eq 3); otherwise, 5c
reacted at the 3-position to give the corresponding cyanation
product 6c in turn (eq 4), as anticipated by the result of eq 2.
Mechanistic Consideration. The reaction mechanism of the
cyanating reaction of heteroaromatic compounds with PIFA is
considered to be similar to that of the previous oxidative
substitution reactions of phenyl ethers and alkylarenes by
oxygen, nitrogen, sulfur, and carbon nucleophiles, including a
cation radical intermediate involving SET by the action of PIFA.
However, as noted above, premixing of all reagents is essential
(22) (a) Anderson, H. J.; Loader, C. E.; Xu, R. X.; Le, N.; Gogan, N. J.;
McDonald, R.; Edwards, L. G. Can. J. Chem. 1985, 63, 896 (b) Masaguer,
C. F.; Ravina, E.; Rueyo, J. Heterocycles 1992, 34, 1303.
(23) In our measurements, the representative oxidation potentials of
thiophenes 3 are as follows: 1.64 for 3a, 1.68 for 3b, 1.70 for 3c, 1.55 for
ox
3d, and 1.35 for 3e {Ep (V vs SCE)}.
J. Org. Chem, Vol. 72, No. 1, 2007 113

Dohi et al.
SCHEME 4. Cyanating Reaction Using a Hypervalent
Iodine(III) Compound 8 Having Cyano Ligands
TABLE 4. Effect of the Aryliodine(III) Structures in Direct
FIGURE 1. Low-molecular recyclable hypervalent iodine(III) bis-
(trifluoroacetate) 12 having an adamantane structure.
Oxidative Cyanation of N-Tosyl-3,5-dimethylpyrrole 1i
a
entry
ArI(OCOCF3)2
time (h)
yield of 2i (%)b
electrolytic oxidations10,27 yielding aromatic or heteroaromatic
cation radicals. The cation radical formation was sufficiently
supported by direct measurement of electron spin resonance
spectroscopy (see Supporting Information, Chart 1) and effective
inhibition of their reaction by a radical scavenger, galvinoxyl.
The observed regioselectivity of the introduction of the cyano
group into the 3-substituted heteroaromatic compounds is also
consistent with the result of the calculated spin density of the
intermediates.10b,28 During the reaction, room temperature is
required not only to prepare active iodine(III)-cyano species
but also to generate the cation radicals A by SET, and therefore,
the premier PhI(III)-CN compounds have weaker SET oxida-
tion ability compared to that of PIFA. The regioselective cyano
transfer toward A followed by oxidation and deprotonation gave
the observed cyanation products along with an iodobenzene
coproduct. From the present reaction mechanism, it is obvious
that effective generation of the real iodine(III)-cyano active
intermediate, the ability of one-electron oxidation, and succes-
sive cyano transfer determine the efficiency of the transforma-
tion. The precise reason for hypervalent iodine(III) reagents as
effective oxidants in the cyanating reaction over heavy metal
oxidizers (and/or electrolytic oxidations) is yet unclear, but mild
and effective generation of cation radical intermediates A as
well as rapid transfer of cyanide from the iodine(III) atom into
A seem to be important.
Facile and Clean Cyanating Reaction Using a Recyclable
Hypervalent Iodine(III) Reagent 12. Although the present
cyanating reaction is applicable to various types of electron-
rich heteroaromatic compounds and therefore might become a
powerful method for synthesizing these useful heteroaromatic
cyanides, excess PIFA was required for the successful trans-
formation, and the products were usually contaminated with a
large amount of coproduct iodoarenes after the reactions. The
limitation causes a difficulty concerning isolation of the reaction
products and stands in the way of practical applications. In an
effort to improve the system, we employed 1,3,5,7-tetrakis[4-
{bis(trifluoroacetoxy)iodo}phenyl]adamantane (12, Figure 1),
a recyclable hypervalent iodine(III) reagent having reactivity
similar to that of PIFA,29 instead of PIFA in the cyanating
reaction (Table 5).
1
2
3
4
Ar ) C6H5 (PIFA)
) 4-Me (9)
3
3
3
43
54
50
6
) 4-Cl (10)
) C6F5 (11)
24
a Two equivalents of ArI(OCOCF3)2 were used. b Isolated yields of the
pure cyanated compound 2i after silica gel column chromatography.
From the results, it is clear that one of the important steps is
an effective generation of real iodine(III)-cyano active inter-
mediate. With this perspective, we decided to examine several
aryliodine bis(trifluoroacetate) compounds modulating the sta-
bility and reactivity in our cyanating reaction. Table 4 shows
the results in N-tosyl-3,5-dimethylpyrrole 1i using PIFA and
other aryliodine(III) bis(trifluoroacetate) compounds 9-11
bearing some functional groups. Because the iodine atoms of
hypervalent iodine(III) compounds have a certain degree of
Lewis acidity, it is thought that selection of electron-rich aryl
moieties contribute to make the iodine(III) more stable, whereas
electron-deficient aryl moieties enhance their reactivity; in other
words, decrease their stability. As a result, a direct oxidative
cyanating reaction of 1i using PIFA and aryliodine bis-
(trifluoroacetate) compounds 9-11 showed clear distinctions
according to their oxidant structures; 4-methyl- and 4-chloro-
substituted 9 and 10 afforded the cyanated product 2i in yields
higher than PIFA, while a strong oxidation reagent 1125 having
an electron-withdrawing group did not work like the former
two compounds in our system (low conversion of 1i, only 6%
yield of 2i), apparently suggesting that both effective generation
and stability of the iodine(III)-cyano intermediates are highly
important.
A plausible reaction mechanism of the cyanating reaction is
depicted in Scheme 5. First, PIFA reacts with TMSCN with or
without the assistance of BF3‚Et2O to generate hypervalent
iodine(III) species having cyano ligands by ligand exchange
reaction at the iodine(III) center between trifluoroacetoxy group
in PIFA and TMSCN. The activated iodine(III)-CN by BF3‚
Et2O induces SET oxidation of heteroaromatic compounds to
produce their cation radicals A via a CT complex under reaction
conditions analogous to those of our previously developed PIFA-
induced reactions,13 typical heavy metal oxidations,26 and
Using 12 (0.5 equiv, 200 mol % iodine atom), BF3‚Et2O (4
equiv), and TMSCN (3 equiv), we performed the cyanating
reaction of N-tosylpyrrole 1a. As expected, 2-cyanated product
2a was obtained in 85% yield with the same regioselectivity
(24) In contrast, a cyanoaryliodonium salt, PhI+(CN) -OTf, did not afford
cyanated product 2a in the presence of BF3‚Et2O (only 3% isolated yield)
when using 1a. This result implies that our oxidative cyanating reaction
involves tricoordinate neutral cyanoaryliodine(III) species.
(25) (a) Schmeisser, M.; Dahmen, K.; Sartori, P. Chem. Ber. 1967, 100,
1633. (b) Moriarty, R. M.; Prakash, I.; Penmasta, R. J. Chem. Soc., Chem.
Commun. 1987, 202.
(26) (a) Julia´, L.; Davies, A. G.; Rueda, D. R.; Calleja, F. J. B. Chem.
Ind. 1989, 78. (b) Tormo, J.; Moreno, F. J.; Ruiz, J.; Fajar´ı, L.; Julia´, L.
J. Org. Chem. 1997, 62, 878. (c) Yoshino, K.; Nakajima, S.; Sugimoto, R.
Jpn. J. Appl. Phys. 1987, 26, L1038. (d) Souto, R.; Maior, M.; Hinkelmann,
K.; Eckert, H.; Wudl, F. Macromolecules 1990, 23, 1268.
(27) (a) Avila, D. V.; Davies, A. G. J. Chem. Soc., Perkin Trans. 2 1991,
1111. (b) Shichiri, T.; Toriumi, M.; Tanaka, K.; Yamabe, T.; Yamauchi,
J.; Deguchi, Y. Synth. Met. 1989, 33, 389. (c) Andrieux, C. P.; Audebert,
P.; Hapiot, P.; Saveant, J. M. J. Am. Chem. Soc. 1990, 112, 2439. (d) Davies,
A. G.; Julia, L.; Yazdi, S. N. J. Chem. Soc., Perkin Trans. 2 1989, 239.
(28) Ando, S.; Ueda, M. Synth. Met. 2002, 129, 207.
(29) Tohma, H.; Maruyama, A.; Maeda, A.; Maegawa, T.; Dohi, T.;
Shiro, M.; Morita, T.; Kita, Y. Angew. Chem., Int. Ed. 2004, 43, 3595.
114 J. Org. Chem., Vol. 72, No. 1, 2007

Direct Cyanation of Heteroaromatic Compounds
SCHEME 5. Plausible Mechanism of Oxidative Cyanation Induced by a Hypervalent Iodine(III) Reagent
TABLE 5. Direct Oxidative Cyanation of Pyrroles 1 and
Thiophenes 3 Using a Recyclable Hypervalent Iodine(III) Reagent
12
Conclusions
We have described a direct oxidative cyanation of electron-
rich pyrroles, thiophenes, and indoles using a combination of
hypervalent iodine(III) reagents with TMSCN at room temper-
ature. Our novel cyanation protocol has the following charac-
teristic features: (i) direct and selective cyanation of unfunc-
tionalized heteroaromatic compounds under mild conditions, (ii)
use of the stable organocyanide source, (iii) applicability of
various types of heteroaromatic compounds, and (iv) aryl halide
function that is maintained, which is beneficial for further
transformations of the cyanation products. From a mechanistic
point of view, the cyanating reaction is induced by active
hypervalent iodine(III) species having cyano ligands in situ
generated from PIFA and TMSCN, and the effective cyanide
introduction into heteroaromatic compounds might occur with
the aid of rapid transfer of the cyano ligands in the hypervalent
iodine(III)-CN species into a cation radical intermediate of
heteroaromatic compounds. An extensive survey on hypervalent
iodine(III) compounds has led to successful utilization of a
recyclable hypervalent iodine(III) reagent, 1,3,5,7-tetrakis[4-
{bis(trifluoroacetoxy)iodo}phenyl]adamantane 12. Utilization of
this reagent confidently leads to the practicability of the
cyanating reaction due to the ease of separation of the cyanated
products and recovery of the oxidation reagent. From these
advantages, our novel procedure described herein will provide
a new efficient alternative method to introduce cyano function-
ality into electron-rich heteroaromatic compounds.
time yield
(h)
time yield
(h)
entrya substrate
(%)b entrya substrate
(%)b
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
6
6
6
6
6
6
6
4
85
71
72
98
85
90
95
45
9
10
11
12
13
14
15
16
1i
1j
6
6
15
15
15
4
70
75
79
68
75
77
75
64
3a
3b
3c
3d
3e
3h
1g
1h
7
6
a 12 [0.5 equiv, 200 mol % of I(III)], TMSCN (3 equiv), and BF3‚Et2O
(4 equiv) were used. b Isolated yield of the pure cyanated compounds after
silica gel column chromatography.
(Table 5, entry 1). With a variety of pyrroles 1 and thiophenes
3, 12 gave excellent results (∼98% yields) compatible with
PIFA as shown in Table 5. Interestingly, the reagent gave better
yields than PIFA in several cases, which is probably due to the
electronic effect of the adamantyl group.
In all these transformations, 12 could be separated easily from
the reaction mixtures as tetraiodide 13, a reduced form of 12,
by a simple solid-liquid separation (i.e., filtration). Thus, after
completion of the reactions, saturated NaHCO3 aqueous and
solid sodium thiosulfate were sequentially added to the reaction
mixtures to reduce the excess 12 to tetraiodide 13. The organic
layer was then separated and evaporated under reduced pressure.
To the resulting oily mixture, MeOH was added. As 13 is hardly
soluble in MeOH, it was simultaneously precipitated as a white
powder. The solution was filtered, and the solid 13 was washed
several times with MeOH. In this way, 13 could be recovered
nearly quantitatively (checked by 1H NMR analysis and TLC),
and it could be reoxidized to 12 in high yield by treatment with
m-chloroperbenzoic acid (m-CPBA) in acetic acid/dichlo-
romethane, followed by the treatment of trifluoroacetic acid.29
Evaporation of the combined MeOH filtrate afforded crude
cyanated products with a small amount of impurities, which
were subjected to further purification (e.g., short column
chromatography on silica gel) when required. As mentioned
above, the present method is quite simple, clean, and versatile
and consequently is a facile and convenient method to introduce
a cyano group into heteroaromatic compounds.
Experimental Section
General Procedure for PIFA-Mediated Cyanating Reaction
of Heteroaromatic Compounds. In a flame-dried two-necked
round-bottomed flask, under nitrogen, to a stirred solution of PIFA
(2 mmol) and BF3‚Et2O (4 mmol) in CH2Cl2 (1 mL), we added
trimethylsilyl cyanide (3 mmol) at room temperature. After being
stirred for 30 minutes, N-tosylpyrrole 1a (1 mmol) was added in
one portion and stirred for an additional 3 h under the same
conditions while the reaction progress was evaluated by GC or TLC.
After the reaction was completed, saturated NaHCO3 aqueous (ca.
10 mL) and sodium thiosulfate aqueous (ca. 5 mL) were succes-
sively added to the mixture. The organic layer was separated, and
the aqueous phase was extracted with CH2Cl2. The combined extract
was dried with Na2SO4 and evaporated to dryness. The residue was
purified by column chromatography (SiO2/n-hexane/AcOEt) to give
pure 2a (83%).
J. Org. Chem, Vol. 72, No. 1, 2007 115

Dohi et al.
N-Tosylpyrrole-2-carbonitrile (2a):30 Colorless crystals, mp
114-115 °C, Rf ) 0.51 (hexane/EtOAc ) 4/1); H NMR (300
Typical Procedure for Cyanating Reaction Using Recyclable
Hypervalent Iodine(III) Reagent 12. To a mixture of 12 (462
mg, 0.25 mmol) and TMSCN (0.20 mL, 1.5 mmol) in CH2Cl2 (1
mL) was slowly added BF3‚Et2O (0.25 mL, 2 mmol) at room
temperature. The mixture was then stirred for 30 min, while the
solution changed gradually to become homogeneous and yellow
in color. N-Tosyl-3,5-dimethylpyrrole 1i (124 mg, 0.5 mmol) was
then added to the solution in one portion and stirred for an additional
6 h. Saturated NaHCO3 aqueous and solid sodium thiosulfate (ca.
1 g) were successively added to the reaction mixture. After being
stirred for 5 min, the organic layer was separated, dried with Na2-
SO4, and evaporated to remove the solvent. MeOH (10 mL) was
added to the residue to precipitate tetraiodide 13, and then it was
filtered. The solid was washed with MeOH several times to recover
tetraiodide 13 nearly quantitatively (checked by 1H NMR analysis
and TLC, quant.). The filtrate including 2i was evaporated and
subjected to short column chromatography (SiO2, hexane/AcOEt)
to give 3,5-dimethyl-N-tosylpyrrole-2-carbonitrile 2i (124 mg, 70%)
as a white powder.
1
MHz, CDCl3) δ 2.44 (3H, s), 6.32 (1H, t, J ) 3.4 Hz), 6.95 (1H,
dd, J ) 3.4, 1.6 Hz), 7.37 (2H, d, J ) 8.7 Hz), 7.47 (1H, dd, J )
3.4, 1.6 Hz), 7.93 (2H, d, J ) 8.7 Hz); 13C NMR (300 MHz, CDCl3)
δ 21.7, 103.7, 111.6, 112.3, 126.6, 126.6, 127.9, 130.4, 134.1, 146.5;
IR (KBr, cm-1): υ 2225.
3-Methyl-1-(toluene-4-sulfonyl)pyrrole-2-carbonitrile (2b).31
This product was obtained following the general procedure
mentioned above. Colorless crystals, mp 114-117 °C; Rf ) 0.41
1
(hexane/EtOAc ) 4/1); H NMR (300 MHz, CDCl3): 2.11 (3H,
s), 2.37 (3H, s), 6.11 (1H, d, J ) 3.0 Hz), 7.29 (3H, m), 7.83 (2H,
d, J ) 8.1 Hz); 13C NMR (300 MHz, CDCl3): 12.1, 21.7, 102.1,
111.7, 114.2, 126.2, 127.8, 130.3, 134.3, 139.1, 146.2; IR (KBr,
cm-1): ν 2222; HRFABMS Calcd for C13H12N2O2S (M + H)+,
261.0683. Found, 261.0690.
Cyanating Reaction of 1a Using (Dicyanoiodo)benzene (8).
To a stirred solution of 8 (2 mmol) and BF3‚Et2O (4 mmol) in
CH2Cl2 (1 mL), we added N-tosylpyrrole 1a (1 mmol) under
nitrogen atmosphere. The solution was then stirred for 20 h at room
temperature. TLC analysis of the reaction indicated that formation
of cyanated product 2a was a major product with a small amount
remaining as 1a. The cyanated product 2a was separated and
purified according to the general experimental procedure using PIFA
mentioned above.
Preparation of 1,3,5,7-Tetrakis[4-bis(trifluoroacetoxyiodo)-
phenyl]adamantane (12). To a stirred solution of 1,3,5,7-tetrakis-
(4-iodophenyl)adamantane 13 (1.42 g, 1.5 mmol) in CH2Cl2 (150
mL)/AcOH (150 mL) was added m-CPBA (3.12 g, 12.4 mmol,
69% purity) at room temperature. The mixture was stirred for 12
h under the same reaction conditions, as the clear solution became
clouded. The resultant mixture was filtered, and CH2Cl2 was
removed from the filtrate using a rotary evaporator. Hexane was
added to the AcOH solution when white solid was immediately
precipitated. After filtration, the crude product was washed with
hexanes several times and was dried in vacuo to give 1,3,5,7-
tetrakis[4-(diacetoxyiodo)phenyl]adamantane (2.09 g, 97%).
Then, 1,3,5,7-tetrakis[4-(diacetoxyiodo)phenyl]adamantane (1.01
g, 0.71 mmol) was dissolved in CHCl3 (15 mL). To the solution,
trifluoroacetic acid (15 mL) was slowly added at room temperature.
The mixture was stirred for an additional 1.5 h under the same
reaction conditions. After removal of the solvent under reduced
pressure, hexane/Et2O ()10:1) was added to precipitate 12. The
precipitate was filtered and washed with hexane/Et2O ()10:1)
several times and dried in vacuo to give 12 (1.17 g, 89%) as a
slightly yellow solid.
3,5-Dimethyl-N-tosylpyrrole-2-carbonitrile (2i):32 Colorless
1
crystals; mp 148-151 °C, Rf ) 0.38 (hexane/EtOAc ) 4/1); H
NMR (300 MHz, CDCl3): δ 2.08 (3H, s), 2.37 (3H, s), 2.38 (3H,
s), 5.80 (1H, s), 7.28 (2H, d, J ) 8.4 Hz), 7.80 (2H, d, J ) 8.4
Hz); 13C NMR (300 MHz, CDCl3): δ 11.9, 15.0, 21.7, 112.6, 115.0,
127.0, 130.0, 130.8, 135.0, 137.2, 137.5, 145.5; IR (KBr, cm-1):
υ 2214; HRFABMS Calcd for C14H15O2N2S (M + H)+, 275.0884.
Found, 275.0871.
3,4-Diethyl-1-(toluene-4-sulfonyl)pyrrole-2-carbonitrile (2k).33
This product was obtained following the general procedure
mentioned above. Colorless crystals, mp 120-122 °C; Rf ) 0.41
1
(hexane/EtOAc ) 4/1); H NMR (300 MHz, CDCl3): δ 1.11-
1.25 (6H, m), 2.33-2.61 (7H, m), 7.16 (1H, s), 7.35 (2H, d, J )
8.1 Hz), 7.90 (2H, d, J ) 8.1 Hz); 13C NMR (300 MHz, CDCl3):
δ 13.5, 14.2, 18.1, 18.7, 21.8, 101.2, 111.9, 122.9, 127.6, 129.2,
130.1, 134.5, 144.1, 145.8; IR (KBr, cm-1): ν 2220; Anal. Calcd
for C16H18N2O2S: C, 63.55; H, 6.00; N, 9.26. Found: C, 63.55;
H, 5.99; N, 9.26.
Acknowledgment. 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 Molecular Transformations of
Carbon Resources” from the Ministry of Education Culture,
Sports, Science, and Technology, Japan. T.D. also thanks the
Industrial Technology Research Grant Program from the New
Energy and Industrial Technology Development Organization
(NEDO) of Japan.
12: A slightly yellow solid; mp 196-203 °C dec (from CF3-
1
CO2H/CH2Cl2/hexane); H NMR (300 MHz, CDCl3/CF3CO2H )
10/1) δ 2.30 (12H, s), 7.73 (8H, d, J ) 8.7 Hz), 8.24 (8H, d, J )
8.7 Hz); 19F NMR (200 MHz, CDCl3/CF3CO2H ) 10/1, hexafluo-
robenzene (-162.9 ppm))
δ -74.5 (s); Anal. Calcd for
Supporting Information Available: General experimental
C50H28F24I4O16: C, 32.49; H, 1.53. Found: C, 32.82; H, 1.86.
procedure and detailed spectroscopic data for all new materials,
1
reagents, and products including H and 13C NMR spectra charts.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(30) Hughes, T. V.; Cava, M. P. J. Org. Chem. 1999, 64, 313.
(31) Abramovitch, R. A. J. Am. Chem. Soc. 1976, 98, 1478.
(32) Cheng, L.; Lightner, D. A. Synthesis 1999, 46.
(33) Bru¨ckner, C.; Xie, L. Y.; Dolphin, D. Tetrahedron 1998, 54, 2021.
JO061820I
116 J. Org. Chem., Vol. 72, No. 1, 2007