Hypervalent iodine(III): selective and efficient single-electron-transfer (SET) oxidizing agent

Article abstract of DOI:10.1016/j.tet.2009.10.040

In 1994, we first determined the single-electron-transfer (SET) oxidation ability of phenyliodine(III) bis(trifluoroacetate) (PIFA) toward phenyl ethers, affording the corresponding aromatic cation radicals. Since then, hypervalent iodine(III) has been utilized as a selective and efficient SET oxidizing agent that enables a variety of direct C-H functionalizations of aromatic rings in electron-rich arenes under mild conditions. We have now extended the original method to work in a series of heteroaromatic compounds such as thiophenes, pyrroles, and indoles. The investigations and results obtained since the start of this century are summarized in this article.

Full text of DOI:10.1016/j.tet.2009.10.040

Tetrahedron 65 (2009) 10797–10815
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Hypervalent iodine(III): selective and efficient single-electron-transfer (SET)
oxidizing agent
,
Toshifumi Dohi a b, Motoki Ito b, Nobutaka Yamaoka a, Koji Morimoto a, Hiromichi Fujioka b,
,
Yasuyuki Kita a
*
a College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577, Japan
b Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
In 1994, we first determined the single-electron-transfer (SET) oxidation ability of phenyliodine(III)
bis(trifluoroacetate) (PIFA) toward phenyl ethers, affording the corresponding aromatic cation radicals.
Since then, hypervalent iodine(III) has been utilized as a selective and efficient SET oxidizing agent that
enables a variety of direct C–H functionalizations of aromatic rings in electron-rich arenes under mild
conditions. We have now extended the original method to work in a series of heteroaromatic compounds
such as thiophenes, pyrroles, and indoles. The investigations and results obtained since the start of this
century are summarized in this article.
Received 31 July 2009
Received in revised form
29 September 2009
Accepted 9 October 2009
Available online 10 November 2009
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
Hypervalent iodine
Single-electron-transfer
Heteroaromatic compound
Oxidation
1. Introduction
syntheses of biologically important natural products and their
pivotal intermediates,2 PIDA and PIFA play particularly important
With the recent increasing impetus for developing greener
synthetic processes, hypervalent iodine reagents are gaining
much attention in modern organic synthesis.1 A number of tri-
valent and pentavalent iodine reagents, e.g., phenyliodine(III)
diacetate (PIDA), phenyliodine(III) bis(trifluoroacetate) (PIFA),
[hydroxy(tosyloxy)iodo]benzene (HTIB, Koser’s reagent), iodoso-
benzene, Dess–Martin periodinane (DMP), and 2-iodoxybenzoic
acid (IBX), are now commercially available, and they serve as
a useful synthetic tool due to their low toxicity, high stability,
ready availability, easy handling, and unique reactivities similar
to that of a series of heavy metals, such as leadIV, mercuryII,
cadmiumIV, and thalliumIII-based agents. These beneficial fea-
tures as safe and non-toxic organo-oxidants make them universal
agents to perform environmentally friendly oxidations, replacing
the classical methods that use highly toxic oxidizers. Extensive
research studies have been found to date in the literature for
investigating the basic reactivities of both iodine(III) and iodi-
ne(V) compounds. Based on their contributions for the total
roles to reproduce the biomimetic phenolic oxidation processes
under mild conditions.3–6 The pentavalent DMP and its precursor,
IBX, are also known as mild and highly selective reagents
showing a broad scope of functional group tolerance for alcohol
oxidations.7,8
In most cases, the reactivities of hypervalent iodine(III)
reagents are typically explained by the two-electron-transfer
processes involving the initial ligand exchange of substrates at
the iodine centers and successive reductive elimination step to
release the iodoarene co-product.9 For example, the oxidation of
phenols 1 with PIDA or PIFA could proceed via a mechanism
involving the Type I intermediate, in which the phenolic oxygen
initially reacts with the iodine center of the reagents (Eq. 1).
Following attack of the nucleophiles (alcohols,3a,5a–d amides,3b
carboxylic acids,3a,5e–g water,3c,5h oximes,5i,j alkenes and alky-
nes4a,b,j,k or enamides,3d,e electron-rich aromatic rings,3f,g,4b–g,l,m
fluoride ion,6 etc.) at the para- or ortho-positions of the phenol
rings, various cyclohexadienones 2 would be produced, together
with the iodobenzene co-product. On the other hand, the
hypervalent iodine(III) reagents shown in Figure 1 are also
known to act as selective and efficient single-electron-transfer
(SET) oxidizing agents for electron-rich aromatic compounds if
treated under specific reaction conditions.
* Corresponding author. Tel./fax: þ81 77 561 5829.
E-mail address: kita@ph.ritsumei.ac.jp (Y. Kita).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.040

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T. Dohi et al. / Tetrahedron 65 (2009) 10797–10815
Type I
Ph
I
OH
O
O
OCOR
OCOR
ligand exchange
I
(1)
OCOR
R'
R'
R'
Nu
HO2CR
Nu
R = CH3 (PIDA)
R = CF3 (PIFA)
PhI
Nu
2
1
Nu = Nucleophiles
Type II
OR
OR
OR
-OCOCF3
Nu-
Nu
+
SET
PIFA
Ph
OCOCF3
I
(2)
+
(CF3)2CHOH
(HFIP)
RO
R'
PhI
R'
3
R'
4
R'
cation radical
CT-complex
Nu = N3, OAc, SAr, SCN,
O
O
etc.
I
O
*
*
OCOR
I
OH
I
been further modified for broader synthetic applications in our
laboratory.11–14 The strategies for generating aromatic cation radi-
cals with hypervalent iodine(III) reagents are mainly classified by
the following two methods:
OCOR
OTs
R = CH3 (PIDA)
R = CF3 (PIFA)
Koser's reagent
(HTIB)
iodosobenzene
1. Use of the fluoroalcohol solvents.
Figure 1. Hypervalent iodine(III) reagents as single-electron-transfer (SET) oxidizing
agents for electron-rich aromatic rings.
HFIP and TFE are unique alcohol solvents that exhibit high
ionizing powers with low nucleophilicities, which would effec-
tively stabilize in situ generated reactive aromatic cation radical
species.15 Therefore, the formation of aromatic cation radicals by
the action of the hypervalent iodine(III) reagents should be facili-
tated in this media.
Regarding this, we reported in 1990 the novel and direct nu-
cleophilic substitution of p-substituted phenyl ethers 3 by azide
(Nꢀ3 ) using a hypervalent iodine(III) reagent, PIFA, in the highly
polar, but low nucleophilic fluoroalcohol solvents, 1,1,1,3,3,3-
hexafluoro-2-propanol (HFIP) or 2,2,2-trifluoroethanol (TFE) (Eq.
2).10a It was quite surprising as phenyl ethers 3 (R¼alkyl) are
generally inert to iodine(III) reagents and would not react via the
reaction mechanism with the Type I phenoxy iodine(III) in-
termediates. This unusual phenomenon clearly indicated that
a new mechanism leading to the substitution products 4 should be
involved in the reaction. Based on detailed UV and ESR spectro-
scopic studies, the generation of Type II aromatic cation radicals
induced by the SET oxidation through the charge-transfer (CT)
complex of phenyl ethers 3 and PIFA could be determined.10b The
reactive intermediate was then effectively trapped by the azide
nucleophile, resulting in the formation of 4. Interestingly, the
umpolung of the aromatic rings occurred without the use of any
metal agent. That is the first case confirming the presence of
a cation radical intermediate during the hypervalent iodine-me-
diated oxidations, and the organoiodine compounds, specifically
PIFA, were determined to have an excellent SET oxidation ability
toward electron-rich aromatic rings.
2. Addition of the appropriate Lewis acids.
By coordination to the ligand at the iodine atoms, the acid ad-
ditives could enhance the SET oxidizing ability of the reagents to-
ward aromatic compounds and thus assist in the smooth
generation of aromatic cation radical species. Typical examples
include the classically-used BF3$Et2O11 and TMSOTf12 as well as the
soft solid acids, such as heteropoly acids (HPAs)13 and other series
of solid clay catalysts.14
As already shown in Eq. 2, the former enables the selective at-
tack of general nucleophiles (Nꢀ3 , AcOꢀ, ArSꢀ [Ar¼aryl], SCNꢀ, and
b-dicarbonyl compounds, etc.) at the ortho-positions of the cation
radical intermediates, furnishing the oxidative aromatic sub-
stitution of a variety of p-substituted electron-rich phenyl ethers 3
in good yields.11 Hence, this process has appeared, even recently, in
the synthetic courses of non-natural and naturally-occurring mol-
ecules having important and diverse biological actions.16
Meanwhile, the latter method has significant advantages in
controlling the reactivity of the oxidants and the reaction course. As
a result, PIFA showed a wide array of reactivities depending on the
As such, the reactivity of hypervalent iodine species highly de-
pends on the employed reaction conditions, and the reagents are
now extensively utilized as an efficient and selective SET oxidizing
agent. In this decade, the original method for phenyl ethers 3 has

T. Dohi et al. / Tetrahedron 65 (2009) 10797–10815
10799
added Lewis acids, and became a versatile SET oxidizing agent
OMe
compatible for more extensive applications. First, we found that the
PIFA–BF3$Et2O and PIFA–TMSOTf combinations are particularly ef-
fective as the intramolecular variant for the substitution reactions
of Eq. 2. For example, the synthesis of pyrroloiminoquinones 5 via
intramolecular cyclization of the N-protected indoles having the
azide side chain was the most successful with the PIFA–TMSOTf
system (Eq. 3).12 A similar cyclization process of sulfide to dihy-
drobenzothiophene 6, on the other hand, smoothly proceeded
when the reaction was conducted with PIFA–BF3$Et2O in CH2Cl2
(Eq. 4).11a The functionalized dihydrobenzothiophene 60 was then
R
O
R'
R''
OMe
7
PIFA
(by M-K10)
M-K10 or H4[SiW12O40
]
R
or
O
(5)
OH
conditions
R'
R''
obtained after azidation a- to the sulfur atom of 6 and the following
R
deprotection of the acetoxy group. Coupling of 5 and 60 led to
completion of the first total synthesis of a natural product,
(ꢁ)-makaluvamine F and its analogs (Scheme 1),17a,b the key pre-
cursors of which were also used in our laboratory for the asym-
metric total syntheses of the related sulfur-containing antitumor
marine alkaloids, the discorhabdins.17c,d
R = H, alkyl, alkoxy
R', R'' = H, alkyl,
O
R'
R''
8
and other functional groups
(by H4[SiW12O40])
Although the phenolic-type couplings using hypervalent iodine
reagents through the Type I intermediates are known,3f,g,4e–j the
biaryl coupling of phenyl ether compounds has never been repor-
ted. The biaryl substructure is a central building block in not only
a large number of bioactive natural products, such as polyketides,
terpenes, lignanes, coumarins, flavonoids, tannins, and many al-
kaloids, but also the ligand of metal catalysts in asymmetric syn-
thesis.18 Thus, we then extended the above methods to the
intramolecular oxidative biaryl coupling process. In particular, our
newly developed biaryl synthetic method utilizing the oxygen-,
sulfur-, and silicon-tethered templates could provide a practical
route for multi-substituted biaryls 9 (Eq. 6).11b,c With the activated
PIFA, each substrate afforded products 9 in excellent yields by the
SET process. The dibenzoheterocyclic structures of 9 were finally
cleaved by known general procedures to give the symmetrical or
unsymmetrical biaryls 10.
N
HO
Br
+
MeO
N
H
HN
coupling
reaction
O
5
S
+
N
N
H
H
Br
O
makaluvamine F
HO
S
N3
6'
Scheme 1. Final coupling step of 5 and 60 in the total synthesis of (ꢁ)-makaluvamine F.
N3
N
PIFA-TMSOTf
HFIP/H2O
(3)
MeO
N
R
MeO
N
O
R1
R'
R'
MeO
PIFA
BF3•Et2O
R
R
5
R = COCH3 ,COPh
Ts, Cbz
+
(47-61%)
R1 = H, Ts, Cbz
CH2Cl2
Y
Y
Y
Y
X
X
X = O, S(O)n (n = 1, 2), Si(t-Bu2)
Y = CH2, O
R or R' = H, OMe, OCH2O, OTBS
Br
Br
RO
PIFA-BF3•Et2O
(4)
R'
R'
CH2Cl2
then, aq. MeNH2
BnO
BnS
S
R
R
6
remove X
(6)
1) BF3•Et2O
EtSH
R = Bn (66%)
R = Ac
Y
Z
2) Ac2O
Y
Z
10
X
9
Br
RO
(Z = OH, CHO, CH3)
[PhIO]n-TMSN3
CH3CN
biaryls
S
N3
6'
R = Ac (46%)
R = H
Interestingly, the use of HPAs as an activator of PIFA showed
a remarkable difference to BF3$Et2O in the reactions of the methoxy-
substituted bisaryl substrates 11 (Eq. 7). The treatment of 11a with
a combination of PIFA and BF3$Et2O should typically deliver the
biaryl compound 13a.11b,c While the spirodienone 12a was only
obtained from the same substrate 11a when using HPAs instead of
BF3$Et2O, the coupling site of the reaction was controlled at the p-
position by the methoxy group.13a,b The application of this novel
method was most distinct for the non-phenolic coupling of the
NaOH
MeOH
For the intramolecular attack of hydroxyl groups, the combi-
nation of PIFA-M-K10 (montmorillonite K10) clay or HPAs was
employed to afford chromans 7 or spirocyclized products 8, re-
spectively (Eq. 5).13e,14

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T. Dohi et al. / Tetrahedron 65 (2009) 10797–10815
benzyltetrahydroisoquinolines for the construction of the morphi-
nandienone-type alkaloid skeletons,13c,d which are the important
precursors of many pharmaceutical compounds,19 for example, O-
methyl flavinantine 12b. Generally, the chemical oxidation of lau-
danosine 11b (and its derivatives) results in the formation of glaucine
13b, not the morphinandienones.20 In contrast to the other chemical
oxidants, the exclusive formation of the morphinandienone-type
product 12b should occur by using the new reagent combination
(PIFA–HPAs) from 11b.
This type of biaryl coupling reaction was also successful in an
intermolecular fashion. Under the optimized conditions with the
activated PIFA, the oxidative biaryl coupling of electron-rich aro-
matic compounds, that is, phenyl ethers and alkylarenes, directly
gave the self-coupling products, the biphenyl and binaphthyl di-
mers 14, in high yields (Eq. 8).11e,f Here, replacement of PIFA with
recyclable alternatives is also possible and could improve the re-
actions for more practical ones.
Ph
Ph
O
O
O
O
O
O
O
O
O
O
PIFA
BF3 Et2O
R
R
OMe
OMe
O
O
O
O
CH2Cl2
R
OMe
OMe
MeO
R =
2
15
MeO
OMe
(>99% de)
OMe
OMe
HO
OMe
OMe
LiAlH4
(9)
MeO
MeO
OH
16
OMe
The PIFA-induced intermolecular oxidative coupling was further
used for the synthesis of the optically pure chiral biaryls. Utilizing
(>99% ee)
a-D-glucose frameworks as inexpensive chiral templates, the biar-
yls 15 were generally obtained with high diastereomeric exces-
ses.11d Especially, the synthesis of 16, a potent precursor leading to
ellagitannin, was achieved with an extremely high ee value through
15, which was obtained by the stereo-selective intermolecular ox-
idative coupling (Eq. 9). Removal of the sugar template by LiAlH4 in
the product 15 yielded the optically pure biphenyl 16 (>99% ee).
As exemplified by these transformations,10–14 hypervalent
iodine(III) reagents, obviously PIFA, as well as their related in situ
activated species are promising for reproducing SET oxidation
processes that were classically promoted by highly toxic heavy-
metal oxidants. Although the initial prospective of the user-friendly
O
O
MeO
MeO
NMe
MeO
MeO
H4[SiW12O40
]
or
H3[PW12O40
]
N
OMe
MeO
COCF3
OMe
MeO
MeO
12a: 74%
(from 11a)
12b: 70%
(from 11b)
NMe
PIFA
MeO
MeO
or
(7)
or
OMe
MeO
N
MeO
MeO
MeO
COCF3
Et2O
BF3
NMe
11b
MeO
MeO
11a
N
MeO
COCF3
13a: 89%
13b: 58%
(from 11b)
(from 11a)
organo-oxidants seems to be a simple replacement of these heavy
metals, this changes rapidly as the unique reactivities and selec-
tivities are revealed. In our study, we have recently extended our
original methods using phenyl ethers 3 and related compounds to
work even in a series of heteroaromatic compounds such as thio-
phenes, pyrroles, and indoles, by choosing a suitable Lewis acid
additive and reaction conditions (Eq. 10).21–24 The use of hyper-
valent iodine(III) reagents was indispensable for success of each
reaction, and notably, other typical organic and inorganic oxidants
were unsatisfactory in terms of the reaction yields and product
selectivities in these cases.
PIFA
BF3 Et2O
R
R
+
CH2Cl2
R = alkoxy, alkyl
R
self-coupling
(8)
We now summarize our accomplishment on this theme and
report the results obtained since the start of this century. Through
this research, hypervalent iodine(III) reagents have become
a unique and efficient SET oxidizing agent not only for the conver-
sions of electron-rich benzene rings, but also of heteroaromatics.
R
14
biaryls

T. Dohi et al. / Tetrahedron 65 (2009) 10797–10815
10801
coupling conditions (Scheme 3). Although the observed product
distribution of the dimers 18 and 19 was nearly equal in the PIFA–
BF3$Et2O combination, further screening of the Lewis acid im-
proved the regioselectivity. Thus, by using the weak TMSOTf, the
H–T dimer 18a was preferentially formed (18a/19a¼94:6). The
yield was also increased by changing the reagent to 2-MeC6H4-
I(OCOCF3)2, and the bithiophene mixture of 18a and 19a was
obtained in better yield with an acceptable selectivity.
A similar product distribution was observed in the series of 3-
alkylthiophenes (Table 1). Thiophenes having longer alkyl chains
produced dimers with a higher H–T dimer selectivity under these
conditions, albeit in lower product yields (Entries 2 and 3). On the
other hand, the smaller the alkyl chains, the lower the observed
regioselectivity (Entries 4 and 5). The sterically demanding sec-
ondary substituents seem to more preferentially force the forma-
tion of the H–T dimers 18 compared to the primary alkyl groups
(Entries 6 and 7). However, 3-tert-butyl thiophene did not give
either 18 or 19, but a tail-to-tail (T–T) dimer was formed (the result
is not shown). The bromo-containing thiophene gave the dimers
18h and 19h, which could be further modified utilizing the
remaining bromo functionality (Entry 8). With respect to the
Hypervalent Iodine(III)
reagent
R
X
R
+
X
SET
e-
X = heteroatoms
cation radical
R
in situ trapping
e-
Nu
(10)
X
Nu = Nucleophiles
2. Result and discussion
2.1. Oxidative biaryl coupling reactions of thiophenes using
PIFA–BF3$Et2O or PIFA–TMSOTf21
The treatment of 2,4-dimethylthiophene with 0.5 equiv of PIFA
in the presence of BF3$Et2O in CH2Cl2 at ꢀ78 ꢂC gave a corre-
sponding dimer 17a in moderate yield (Scheme 2). In fluoroalcohol
solvents, TFE and HFIP, the dimer 17a was not obtained, while the
formation of diaryliodonium(III) salts 35 usually occurred instead
(see below, Section 2.4).24 The reaction of other di- or tri-alkyl
derivatives also proceeded in similar ways. This method could
products, the polymerization of 18 can yield the corresponding a-
linked H–T-type regioregular polymers having an excellent degree
of co-planarity compared to that prepared from the thiophene
monomer.27 Therefore, the H–T dimers 18 have been the focus of
much attention as useful precursors of high-quality electro-
conductive organic materials.28
provide the
linked regioisomers of 17a and 17b were not detected in each case.
a,a a, -
0-linked dimer as the sole coupling product and b0
R1
R2
R3
PIFA (0.5 equiv.)
BF3 Et2O (1 equiv.)
R2
R3
R1
S
R3
Table 1
S
CH2Cl2
3 h, -78 °C
Preferential H–T dimer formation of 3-alkylthiophenesa
S
R1
17
R2
R1
R1
R1
2-MeC6H4I(OCOCF3)2
S
S
TMSOTf
R1 = R3 = Me, R2 = H (17a): 44% (65%)
+
S
CH2Cl2, -78 °C
3 h
S
R1 = hexyl , R2 = H, R3 = Me (17b): 45% (68%)
R1 = R2 = R3 = Me (17c): 36% (65%)
S
R1
19
(H-H)
R1
18
(H-T)
Scheme 2. Oxidative coupling reaction of alkylthiophenes with PIFA–BF3$Et2O to give
symmetrical 2,20-bithiophenes 17. Yield based on consumed substrates are shown in
parenthesis.
Entry
R1
Product
Yieldb
72 (90)d
52
30
72
88
98
67
62
The direct oxidative coupling of 3-alkylthiophenes seems to be
more difficult, as the forming dimers, 18 or 19, might be further
1
Hexyl
Heptyl
Octyl
Methyl
Butyl
i-Butyl
c-Hexyl
(CH2)6Br
18aþ19a (81:19)
18bþ19b (92:8)
18cþ19c (95:5)
18dþ19d (80:20)
18eþ19e (77:23)
18fþ19f (87:13)
18gþ19g (90:10)
18hþ19h (82:18)
2
3c
4
oxidized and react at the free a-positions due to their lower oxi-
dation potentials than the initial monomers.25
5
Therefore, no direct oxidative coupling method of the 3-alkyl-
thiophenes, to our knowledge, has yet appeared in the literature,
though the strategy is a very straightforward and convenient
route. In fact, the electro-chemical conditions and metal oxidants,
such as FeIII, TlIII, RuIII, and MoV, have not been utilized for di-
merization of these 3-alkylthiophenes, but for oligomerization and
polymerization processes.26 However, surprisingly, the corre-
6
7c
8
a
The molar ratio of thiophene, iodine(III), and TMSOTf is 3:1:2. The excess
amounts of thiophene (1 equiv relative to iodine(III)) were recovered by silica gel
column chromatography after the reactions.
b
Isolated yield calculated from the amount of iodine(III) used.
PIFA was used as oxidant.
Yield based on consumed starting material.
c
sponding a-free bithiophenes 18a [head to tail (H–T) dimer] and
19a [head to head (H–H) dimer] were directly obtained from 3-
d
hexylthiophene when the reaction was conducted using our
The reaction mechanism for the direct
a,a
0-bithiophene syn-
thesis is represented by the oxidative coupling of the 3-alkylthio-
phenes (Scheme 4). Analogous to those of our originally developed
PIFA-induced SET oxidation processes for phenyl ethers 3 and
alkylarenes,10–14 the thiophene cation radicals should be formed by
the action of PIFA–Lewis acids through the CT-complex. The formed
radicals then react with the neutral thiophene molecules. We have
confirmed that this process to furnish the biaryl C–C bond of
bithiophenes could selectively occur at the 2-position of the cation
radicals rather than at the 5-position (see also Section 2.3).29 Thus,
the selective coupling between the 2-position of the cation radicals
and the 5-position of the neutral thiophenes accounts for the for-
Hex
Hex
PIFA
Hex
Lewis acid
S
S
+
CH2Cl2
1.5 ~ 6 h, -78 °C
S
S
S
Hex
19a
Hex
18a
Lewis acid: BF3 Et2O 68% (18a/19a = 46/54)
Bu2BOTf 71% (64/36)
41% (94/6)
72% (81/19)a)
TMSOTf
TMSOTf
mation of the H–T linked
dimers 19 were obtained. Finally, the reactions were completed by
a,a
0-bithiophenes 18, otherwise the H–H
Scheme 3. Effect of Lewis acid additive on regioselectivity; (a) 2-Me(C6H4) I(OCOCF3)2
was used instead of PIFA.

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T. Dohi et al. / Tetrahedron 65 (2009) 10797–10815
recognition and self-assembly systems.32 As the valuable precursor
OCOCF3
R1 PIFA
TMSOTf
of electroactive organic materials, some electron-rich bipyrroles
have recently found new applications due to their high conduc-
tivities in the oligomer and polymer forms.33 However, the syn-
thetic methods for the preparation of these electron-rich bipyrroles
are quite limited,34 and the majorities are the indirect approaches
that require multistep transformations involving decarboxylation
steps.35 The direct oxidative coupling of pyrrole themselves is
a more attractive way to prepare these bipyrroles,36 but little at-
tention has currently been paid to this method because of the dif-
ficulty in suppressing the formation of byproducts and the need to
use stoichiometric amounts of expensive transition metals.
Ph
S
I
OCOCF3
R1
SET
S
R = alkyl
CT-complex
S
R1
H
R1
H
R1
R1
S
S
or
R1
S
H
S
H
S
R1
(for 19)
cation radical
(for 18)
Considering the situation, we then planned to apply the SET
strategy using hypervalent iodine reagents as a new straightfor-
ward synthetic method for the formation of bipyrroles from 1H-
pyrroles. Accordingly, the reactions of 1H-pyrroles were first ex-
amined under the above mentioned conditions with PIFA–BF3$Et2O
or PIFA–TMSOTf (Scheme 6). However, these combinations were
less effective for the present pyrrole coupling since the pyrroles
caused acid-catalyzed oligomerizations by treatment with
BF3$Et2O and TMSOTf even in the absence of PIFA. Due to the se-
rious background side reactions, the selection of other suitable
activators of PIFA was essential to realize the planned reaction.
Fortunately, further screening of the Lewis acid led to finding
a more appropriate activator, TMSBr; it functions as an efficient
promoter not only to activate PIFA for inducing the desired SET
oxidation process, but also to suppress the oligomerization of the
pyrroles during the coupling reactions. Using 2 equiv of TMSBr
relative to PIFA, the desired coupling of the pyrroles proceeded
R1
R1
PIFA
S
S
+
S
S
R1
R1
e-, 2H+
18
(H-T)
19
(H-H)
Scheme 4. Reaction mechanism.
the further one-electron oxidation and successive deprotonation to
afford the H–T dimers 18 and H–H dimers 19. Over-oxidations of
the dimers would not occur when using the hypervalent iodine
reagents, probably because the reactivity of the reagent combina-
tions is high enough to complete the initial SET oxidation process
before yielding the dimers.
The addition of the Lewis acids was essential for inducing the
effective SET oxidation process. Both BF3$Et2O and TMSOTf could
enhance the electrophilicity of the iodine center of PIFA by co-
ordinating to the trifluoroacetoxy ligand.30 The added Lewis acids
thus seem to facilitate the initial interaction of PIFA with thio-
phenes to form the CT-complex before inducing SET. On the other
hand, the precise role of the added Lewis acids on the product se-
lectivity is still unclear, but the persistent radicals are thought to be
confined in the coordination sphere of the iodine(III)–Lewis acid
complex, by which the product distribution might be controlled.31
In contrast to the above cases, the reaction of 3-iodo or 3-trime-
thylsilyl thiophenes selectively offered the H–H dimer 19i and T–T
dimer 20j under the same reaction conditions (Scheme 5). The for-
mation of 19i is probably due to the electronic character of the halo-
genatom, while thelatterisapparentlyduetostericreasons. Basedon
the existence of the numerous transformations for the C–halogen and
C–Si bonds, these products should be the potential useful precursors
for other various H–H or T–T type bithiophene derivatives.
within 1 h to afford the
a,
a
0-bipyrroles 21a–d in good yields. The
0-bipyrrole 21a among the
pyrrole itself produced only the
a,a
possible three regioisomers, the 2,20-, 2,30-, and 3,30-bipyrroles. It
should be noted that protection of the nitrogen atom of the pyrroles
was not necessary and the 1H-pyrroles were usable in the reactions.
As mentioned from a mechanistic point of view (see Scheme 4 for
thiophenes), half the amount of the reagent relative to the pyrroles
was rationally required for full conversion of the substrates in the
oxidative coupling strategy, and thus ca. 1 equiv of the starting
materials could be recovered after the reactions by the usual
chromatographic workup.
R
R
PIFA
TMSBr
R
R
H
N
CH2Cl2
-78 °C to -40 °C
N
H
N
H
R
21
R
I
I
R = H (21a): 78%
2-MeC6H4I(OCOCF3)2
R = Et (21b): 75% (69%)a)
R = i-Bu (21c): 60%
S
TMSOTf
CH2Cl2, -78 °C
3 h
S
S
R,R = -(CH2)4- (21d): 61%
I
19i
Scheme 6. Direct oxidative coupling of pyrroles and 3,4-disubstituted pyrroles. (a)
(36%)
Yield based on the consumed pyrrole.
TMS
TMS
The C–C bond formation in the coupling reaction of the 3-
substituted pyrroles also occurred at each a-position (Table 2). The
as above
S
S
S
observed regioselectivity of the coupling products 22 and 23 was
similar in extent to the 3-alkylthiophenes (see Table 1). Thus, the
crude bipyrrole products typicallycontained two regioisomers, the
unsymmetrical H–T dimers 22 and symmetrical H–H dimers 23. In
the present bipyrrole synthesis, this would not be a problem for
obtaining each type of pure bipyrrole 22 and 23, as these products
were separable by purification using typical chromatographic
techniques (see the Experimental section). No H–T and H–H dimer
was formed from 3-tert-butyl thiophene because of the steric re-
pulsion between the two bulky groups (Eq. 11).37 Although the
TMS
20j
(46%)
Scheme 5. Selective formation of functionalized H–H dimer 19i or T–T dimer 20j.
2.2. Oxidative biaryl coupling reactions of pyrroles and
indoles using PIFA–TMSBr22
Bipyrrole structures are ubiquitous in natural products, pig-
ments, porphyrin mimics, and components for molecular

T. Dohi et al. / Tetrahedron 65 (2009) 10797–10815
10803
electron-deficient pyrroles, such as the N-tosylpyrrole, were still
unreactive as expected, the presence of several functional groups
(ester, arene, ether, halogen, etc.) in the side chains of the pyrroles
was acceptable (Entries 3–6). Therefore, the present method has
the potential to provide a practical route for constructing a new
class of bipyrroles.
25aa–ad were produced by the coupling of the N-substituted pyrrole
derivatives, while the 1H-pyrrole mainly gave the
0-bipyrrole 21a.
The benzyl groups showed the highest
0-bipyrrole selectivities
a,a
a,b
among those examined, which could be removed after the coupling
reactions according to standard deprotection procedures. Since the
N-substituted pyrroles are exceptionally stable even in the presence
of the strong Lewis acid, BF3$Et2O, its use is plausible here for
Table 2
Synthesis of
obtaining the
erwise TMSBr tends to produce certain amounts of
a
,
b
0-bipyrrole products 25aa–ad in good yields, oth-
0-bipyrroles
a
-linked bipyrroles using PIFAa
a,a
R1
R1
R1
21aa–ad similar to the results observed for the 1H-pyrroles. The
N-substituent of the pyrroles was thus an important factor for
the reactions regarding both the product selectivity and stability of
the starting substrates. Unfortunately, the method is quite case-
sensitive and was not applicable to other ring-substituted pyrrole
derivatives, such as the 3-alkyl and aryl pyrroles. However, consid-
ering the absence of an alternative facile approach to obtain these
PIFA
TMSBr
H
N
H
N
and/or
R1
CH2Cl2
N
H
N
H
N
H
-78 oC to -40 oC
3 h
R1
23
22
Entry
R1
Yieldb
unique molecules,40 the
ent method appear to be usable as the common component for other
a,b
0-bipyrroles 25 prepared from the pres-
1
2
3
4
5
6
Methyl
Heptyl
(CH2)3CO2Me
Phenyl
4-MeOC6H4
4-BrC6H4
58% (22a)
60% (22b)
82% (22c)
70% (22d)
52% (22e)
68% (22f)
12% (23a)
9% (23b)
13% (23c)
13% (23d)
<1% (23e)
8% (23f)
modified compounds having the
a,b
0-bipyrrole frameworks.
PIFA
a
X
N
The molar ratio of pyrroles, PIFA, and TMSBr is 3:1:2. The excess amount of
remaining substrates (0.5–1 equiv relative to PIFA) were recovered after the re-
actions by column chromatography on neutral alumina.
Et2O
BF3
and/or
N
X
N
X
CH2Cl2
-78 °C to r.t.
N
X
b
NX
Isolated yield calculated from the amount of PIFA.
21a
25a
α, β'-bipyrrole
α, α'-bipyrrole
t
t
Bu
PIFA
TMSBr
Bu
H
N
65% (21a)
28% (25a)
85% (25aa)
62% (25ab)
74% (25ac)
24% (25ad)
(11)
X: H
: Bn
CH2Cl2
N
H
<1% (21aa)
<1% (21ab)
24% (21ac)
<3% (21ad)
N
H
-78 oC to -40 oC
3 h
: PMB
: Ph
t
Bu
24g
: Me
(34%)
Scheme 8. Influence of N-substituent for
methoxybenzyl.
a,
b
0-bipyrrole synthesis. PMB¼p-
When the reaction was applied to 3-methylindole, dihy-
droindole 27 was formed together with the bisindole 26 (Scheme
7). As the isolated 27 did not produce the bisindole 26 under the
reaction conditions, a stepwise mechanism involving the addition
product 27 was excluded for the formation of 26. Rather, the
production of 27 should be regarded as the result of an acid-in-
duced background side reaction of the indole via the iminium
ion.38 Our persistent attempts to detect intermediates in the
pyrrole coupling also suggested the absence of an alternative
stepwise reaction pathway through addition-type intermediates
like the dihydroindole 27. Based on these experiments as well as
our continuous studies, we considered the involvement of the
pyrrole cation radicals,39 which were generated by SET from the
pyrroles toward PIFA–TMSBr.
2.3. Introduction of nucleophiles for heteroaromatic
compounds using PIFA by oxidative substitution
During the reaction of heteroaromatic compounds with
hypervalent iodine(III) reagents, the formation of diaryliodonium
(III) salts 35 is accelerated in HFIP and TFE (see Section 2.4).24 Due
to this remarkable solvent effect for producing reactions for the
condensation products 35, the aromatic substitution shown in Eq.
2 fairly occurred in heteroaromatic compounds in the fluo-
roalcohol solvents10 and typically resulted in failure. Despite the
limitation, several nucleophiles could be introduced in standard
solvents by utilizing the second strategy with the Lewis acid-
activated PIFA. In 3-hexylthiophene, halogens were introduced by
treatment with PIFA and TMSX (X¼Cl or Br) in CH2Cl2 (Scheme 9).
We have examined the other silicon-based nucleophiles, TMSNCS
and TMSCN, for thiocyanation and cyanation in the same
Modification of the steric environment around the nitrogen atom
of the pyrrole allows control of the product selectivity (Scheme 8). In
all instances, any substituent at the nitrogen atom of the pyrrole
would contribute to the production of the a,b
0-bipyrroles 25, and
PIFA
TMSBr
H
N
H
N
+
N
H
CH2Cl2
-78 °C to -40 °C
3 h
N
H
N
H
26 (74%)
27 (29%)
conditions
X
Scheme 7. Oxidative coupling reaction of 3-methylindole.

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T. Dohi et al. / Tetrahedron 65 (2009) 10797–10815
substrate. With PIFA–BF3$Et2O, both trials could provide the
substitution products 30a or 31a in good yields. In particular, the
last case became a unique and efficient method to selectively
introduce the cyano functionality into a wide range of electron-
rich heteroaromatic compounds, without the need for any pre-
functionalization.23
appropriate protecting group of the pyrrole nitrogen atom that can
modulate the stability and nucleophilicity of the pyrrole ring was
evaluated. Among the series of N-protected pyrroles, the oxidation
potential of N-tosylpyrrole [Eopx (V vs SCE)¼1.96],43 which lies be-
tween the values of the 3-alkylthiophenes44 and alkylbenzenes,45
seems to be the most suitable for this transformation. Indeed, N-
tosylpyrrole was fully converted to 2-cyano-N-tosylpyrrole 32a in
83% yield (Table 3, Entry 1). The corresponding 2-cyanated products
were obtained in poorer yields with other N-substituents (Bn, PMB,
Ph, Me, Boc, etc.). The tosyl groups in the product 32a was remov-
able by the standard deprotection protocols.46
Hex
X
S
28a (X = Cl): 78%
TMSX
29a (X = Br): 81%
Table 3
Direct
Hex
Hex
a
-cyanation of N-tosylpyrroles induced by PIFA–BF3$Et2Oa
PIFA
CH2Cl2
r.t.
TMSNCS
SCN
30a: 84%
Hex
Entry
a
-Cyano pyrrole
Product
Yieldb
S
S
R
TMSCNa)
CN
N
Ts
CN
31a: 65%
S
1
2
3
4
5
6
7
8
R¼H
32a
32b
32c
32d
32e
32f
83
70
71
86
94
97
90
45
R¼Methyl
R¼Heptyl
Scheme 9. Oxidative introduction of several nucleophiles toward thiophene using
PIFA–Lewis acids in dichloromethane. (a) In the presence of BF3$Et2O.
R¼(CH2)3CO2Me
R¼t-Butyl
R¼2-BrC6H4
R¼4-BrC6H4
R¼4-OMeC6H4
The reported methods for direct introduction of the cyano group
into heteroaromatic compounds mostly rely on the use of highly
reactive and unstable cyano cation equivalents (þCN),41 by which
the difficulty of the reaction control and preparation of unstable
reagents were sometimes encountered. From this view point, a di-
rect cyanating method under oxidative conditions using the stable
cyanide anion (ꢀCN) is very attractive.42 This results in a series of
thiophenes that support the versatility of this new method with
PIFA–BF3$Et2O and TMSCN (Scheme 10). All reactions occurred at
32g
32h
Et
Et
CN
9
32i
32j
73
58
N
Ts
Et
10
the a-position of the thiophenes. In the 3-substituted thiophenes,
CN
N
the 2-cyanated products 31a–e were selectively obtained. Likewise,
the reaction is quite sensitive relative to the electronic character
of the thiophenes. The presence of some donating groups, e.g.,
OMe, on the thiophene ring was acceptable, but no cation radicals
were formed at all in the thiophenes possessing electron-with-
drawing groups such as an ester or cyano functionality. This fact
suggests that over-oxidation of the cyanated products 31 would not
occur during the reactions, which is responsible for the observed
high product selectivity. Therefore, no detectable side products
derived from the over-oxidations of 31 were obtained even when
using an excess amount of PIFA (2 equiv).
Ts
11
32k
43
CN
N
Ts
a
All reactions were carried out by using 3 equiv of TMSCN, 2 equiv of PIFA, and
4 equiv of BF3$Et2O for 3 h at room temperature.
b
Isolated yield.
The cyanating reaction was applicable for a wide range of
substituted pyrroles as summarized in Table 3. The reaction of
pyrroles having aliphatic or aromatic substituents at their 3-posi-
tion afforded the corresponding 2-cyanated products 32b–h (En-
tries 2–8). The steric difference in the substituent did not affect the
regioselectivity and yield (Entry 5). 1H NMR measurement of the
crude cyanated products revealed that the selectivity of the re-
action position is high enough to produce less than 3% of other
regioisomeric products. The observed yield of 32h was lower be-
cause of the competitive oxidations by PIFA attributed to the
electron-rich phenyl ether ring (Entry 8).
R1
CN
R1
PIFA - BF3 Et2O
TMSCN
R2
R2
S
31
CH2Cl2
r.t., 3 h
S
R1 = Hex, R2 = H (31a): 65%
R1 = Me, R2 = H (31b): 79%
R1 = c-Hex, R2 = H (31c): 59%
R1 = OMe, R2 = H (31d): 42%
This cyanation protocol was also available for the N-tosyl in-
doles, despite the slightly problematic yield and regioselectivity
R
1 = Ph, R2 = H (31e): 68%
R1 = H, R2 = Me (31f): 62%a)
Scheme 10. PIFA-induced direct
source. (a) GC yield.
a
-cyanation of thiophenes using TMSCN as cyanide
Me
CN
CN
Me
CN
N
N
N
Considering the results in Scheme 10, we extended the new
cyanating method to other heteroaromatic compounds having
oxidation potentials similar to those of the thiophenes. Since the
1H-pyrroles caused the acid-promoted oligomerization as a back-
ground reaction by the persistent BF3$Et2O (Section 2.2), an
Ts
33b
Ts
33a
Ts
34c
(46%)a)
(64%)
(37%)
Scheme 11. Reaction of indole derivatives. (a) The product included small amount of
-cyano isomer.
b

T. Dohi et al. / Tetrahedron 65 (2009) 10797–10815
10805
(Scheme 11). For the N-tosylindole, the
duced, but a small amount of the regioisomeric isomer derived
from the reaction at the -position was also detected. 2-Methyl-N-
tosylindole gave the -cyanated product 33b, and 3-methyl-N-
tosylindole reacted at the 3-position in turn, as anticipated by the
N-tosylindole result.
a
-cyanated 33a was pro-
2.4. Direct dehydrative approach for heteroaromatic
iodonium(III) salts in fluoroalcohol solvents24
b
a
The use of fluoroalcohol media is promising for aromatic
cation radical generation in the iodine(III)-induced SET oxida-
tion.10 This principle should be available for heteroaromatic
compounds, and indeed, the thiophenes produced the corre-
sponding cation radical in HFIP or TFE like the previous trans-
formations described in Section 2.3, the presence of which was
also detectable by ESR and UV spectroscopy.49 If a good leaving
group effectively accommodating the anion charge was present
in a ligand, the reaction with heteroaromatic compounds typi-
cally resulted in the formation of diaryliodonium(III) salts having
it as a counterion, as exemplified in Eq. 12. The present dehy-
drative condensation is very facile and clean, only producing
water as the co-product.50
The reaction mechanism to introduce the cyanide should be
considered to be similar to that of the previous oxidative sub-
stitution of phenyl ethers 3 and alkylarenes by oxygen, nitrogen,
sulfur, and carbon nucleophiles, including the cation radical in-
termediates.10,11 However, premixing of all reagents was essential
in the order of PIFA, TMSCN, and BF3$Et2O to produce the best
performance in this system. They were mixed for 30 min before
adding the substrates, otherwise the yield of the cyanated products
was slightly lower. This appears to imply that the real oxidant for
the reaction was not just PIFA. As an alternative species for initi-
ating the cyanation, we focused on the hypervalent iodine reagents
having a cyano ligand. These types of compounds were previously
synthesized from [PhIO]n or PIFA and TMSCN through ligand ex-
change.47 With this perspective, we prepared (dicyanoiodo)-
benzene (PhI(CN)2) according to the literature method,47a and used
it with BF3$Et2O for the reaction (Scheme 12). Although PhI(CN)2
was inherently not reactive to N-tosylpyrrole, it gradually started
the reaction after activation by BF3$Et2O, and the cyanated product
32a was produced, without the addition of the external cyanide
source, TMSCN. Therefore, the rapid transfer of the cyano ligand
from the iodine(III) atom to the cation radicals, not directly from
TMSCN, seem to be one of the important driving forces of the
present reaction.
PIFA
(12)
TFE
I
Ph
S
S
S
0 oC to r.t.
3 h
OCOCF3
cation radical
35a-OCOCF3
(81%)
The chemical and physical properties of the diaryliodonium(III)
salts highly depend on the nature of the anionic counterpart.
Modification of the counterions was easily attainable using an-
other reagent, that is, [PhIO]n (Scheme 14). A variety of Brønsted
acids were conveniently introduced to the products 35a as the
counterions, X, by this strategy.
PhI(CN)2 - BF3 Et2O
CN
N
CH2Cl2, r.t.
20 h
N
Ts
Ts
32a
[PhIO]n
HX
(53%)
I
Ph
TFE
0 °C to r.t.
3 h
S
S
X
35a-X
Scheme 12. Direct cyanating reaction using (dicyanoiodo)benzene PhI(CN)2 with
BF3$Et2O.
X = OTf (56%)
= ClO4 (61%)
= NO3 (42%)
= OTs (80%)
To summarize, a plausible mechanism of the cyanating reaction
is depicted in Scheme 13. Initially, PIFA reacted with TMSCN to
produce PhI(CN)2 or its analog (Y¼OCOCF3) by facile ligand ex-
change between the cyanide and trifluoroacetoxy group at the
iodine(III) center. The formed iodine(III)–CN species was then
activated by the Lewis acid to induce the SET oxidation of the
heteroaromatic compounds, generating the cation radical in-
termediates. The reactive cation radical intermediates could be
directly measured by electron spin resonance (ESR) spectroscopy
in this system.23b The regioselective cyano-transfer toward the
intermediates48 followed by a further one-electron oxidation and
deprotonation gave the products 31 or 32 along with an iodo-
benzene co-product.
Scheme 14. Thienyl iodonium(III) salts having differential X.
A significant number of Koser’s-type reagents are now readily
available,51 and variation of the reagents in the reaction could ex-
pand the structural diversity of the obtained products. The selected
examples are shown in Scheme 15. Iodonium salts 35–37 having
differential aryl rings and counterions X were obtained from a sin-
gle thiophene substrate, after precipitation of the products 35–37
by replacement of the reaction solvent, TFE, to the non-polar Et2O.
A significant advantage of using fluoroalcohol solvents is what
various types of reagents can be usable in these ways.
PIFA - BF3 Et2O
TMSCN
in situ
Y
PhI(CN)Y - BF3 Et2O
(Y = CN or OCOCF3)
Ph
X
I
R
PhI(CN)Y
CN
R
R
CN
SET
cyanotransfer
X
X
X
R
e-, H+
PhI
X = heteroatom
31 (X = S)
or
cation radical
CT-complex
32 (X = NTs)
Scheme 13. A plausible reaction mechanism for direct cyanating reaction of heteroaromatic compounds.

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T. Dohi et al. / Tetrahedron 65 (2009) 10797–10815
A unique selectivity was observed in the organosilicon com-
pound. In the competitive reaction of the C–H and C–Si bonds in 3-
ArI(OH)X
TFE, r.t.
3 h
I
Ar
S
trimethylsilylthiophene, an ipso-substitution product 38 as a result
S
of electrophilic substitution via the Wheland type of s
-complex50
X
35a-37a
was not obtained, but instead produced a dehydrative condensa-
tion product 35j-OTs (Scheme 16).54 Therefore, the present direct
and waste-free approach based on the cation radical strategy55 has
a broad range of versatility for the synthesis of various diary-
liodonium(III) salts56 as well as a unique selectivity not available by
other methods.
X
Ar
Ph
OTs
OTs
OTs
OMs
OCs
35a-OTs (98%)
36a-OTs (78%)
37a-OTs (70%)
35a-OMs (89%)
35a-OCs (92%)
mesityl
C6F5
Ph
Ph
Scheme 15. Formation of iodonium(III) sulfonates. Ms¼methanesulfonyl, Cs¼(ꢁ)-10-
OTs
TMS
TMS
camphorsulfonyl.
I
Ph
PhI(OH)OTs
Ph
I
Table 4 represents the versatility of the thiophene substrates
when using PhI(OH)OTs. Based on our expectation, the scope and
selectivity of the reactions were similar to those of the trans-
formations having already appeared in Tables 1–3 and Scheme 5.
TFE
H
S
S
r.t., 3 h
S
OTs
38
35j-OTs
(not observed)
(71%)
The condensation preferentially occurred at the
a-position of
Scheme 16. Competitive reaction between C–H and C–Si bonds.
thiophene atom, among which the 2-position was more reactive
in the 3-substituted thiophenes (Entries 1–6). In all cases, no other
iodine(III) impurities and regioisomeric products were contami-
3. Conclusion
nated in the products 35. On the other hand, the
a-disubstituted
In this article, we describe our continuous effort regarding the
use of hypervalent iodines as a selective and efficient SET oxidizing
agent, especially emphasizing the extension of the original method
in phenyl ethers 3 to the heteroaromatic compounds. As a result,
several new facile and useful oxidative transformations of thio-
phenes, pyrroles, and indoles, have been developed by choosing the
appropriate Lewis acids or fluoroalcohol solvents. The use of
hypervalent iodines as an oxidant was essential for each reaction
progress, hence the success of which apparently relies on the ex-
cellent SET oxidation ability of the reagents as well as their mild
nature of reactivity to only permit the desired oxidations.
thiophenes could afford the -thienyl iodonium salt 35i-OTs
b
(Entry 9). A remarkable solvent effect was clearly observed in each
case, and the reactions finished within a shorter reaction time
(3 h) when compared to other solvents, such as CH2Cl2.50b These
thienyliodonium(III) salts 35-OTs show a wide range of applica-
bility as photoacid generator (PAG) for cationic polymerization
processes,52a active bactericides,52b,c and as arylating agents in
organic synthesis.53
Table 4
Scope of thiophene substratesa
After discovering that PIFA works as an excellent SET oxidizing
agent for affording aromatic cation radicals,10 it has been playing
a main role in exploiting the new field of chemistry. Due to their
activity, a variety of other iodine reagents such as [PhIO]n and HTIB
are now being used. In particular, utilization of the adamantane-
type reagents (Fig. 2),57 which were originally developed by us as
useful recyclable alternatives to PIFA and HTIB, is the next prom-
ising step for making these reactions greener and more practical.58
Entry
Thiophene
Product (35-OTs)
Yieldb
R
R
I
Ph
S
S
OTs
1
2
3
4
5
6
R¼Methyl
R¼i-Butyl
R¼c-Hexyl
R¼OMe
35a-OTs
98
93
74
89
95
98
35b-OTs
35c-OTs
35d-OTs
35e-OTs
35f-OTs
X
R¼Br
R¼4-MeO2CC6H4
I
Ph
S
7
93
OTs
S
35g-OTs
X
X
O
O
X = I(OCOCF3)2
X = I(OH)OTs
X
O
O
MeO2C
I
Ph
Figure 2. Adamantane-type recyclable alternatives to PIFA and HTIB.
8
88
62
S
OTs
MeO2C
S
35h-OTs
In closing, the innovative research front of this area that has
appeared in the past few years should be noted. One is that the
biaryl coupling methods illustrated in Eq. 8 have been successfully
extended to the unprecedented selective and high-yield in-
termolecular cross-coupling processes.59 More recently, a novel
and metal-free cross-coupling method of heteroaromtatic com-
pounds has been developed utilizing the diaryliodonium(III) salts
in Section 2.4, which can partially replace conventional biaryl
syntheses that require multi-steps and use of transition metals.60
Surprisingly, the competitive formation of homodimers would not
OTs
I
Ph
9
S
S
35i-OTs
a
Reactions were performed using equimolar amount of thiophenes and PhI(O-
H)OTs in TFE (0.20 M) for 3 h at room temperature.
b
Isolated yield of pure product after precipitation.

T. Dohi et al. / Tetrahedron 65 (2009) 10797–10815
10807
occur in these cases by using hypervalent iodines(III), while other
oxidants (VV, MnIII, MoV, FeIII, TlIII, and PbIV-based heavy metals in
strong acids, nitric acid-based oxidants, anodic oxidations, combi-
nation of palladium catalysts and oxidants, etc.) were invalid, based
on our studies, for obtaining the cross-coupling products due to the
difficulty in suppressing the self-dimerization process of aromatic
substrates to produce undesired homobiaryls. Thus, these methods
involving the hypervalent iodine-induced SET oxidation processes
as the key step have become unique and valuable new metal-free
direct C–H functionalization processes of electron-rich aromatic
compounds.
CDCl3) d 0.81–0.91 (m, 6H), 1.18–1.34 (m, 12H), 1.43–1.56 (m, 4H),
2.41 (t, 4H, J¼8.1 Hz), 2.44 (s, 6H), 6.59 (s, 2H) ppm. 13C NMR
(67.8 MHz, CDCl3)
d 14.0, 15.3, 22.5, 28.8, 29.1, 30.6, 31.6, 126.5,
126.8, 139.1, 142.0 ppm. Anal. Calcd for C22H34S2: C, 72.86; H, 9.45;
S, 17.68. Found: C, 73.07; H, 9.38; S, 17.41.
4.2.3. 3,30,4,40,5,50-Hexamethyl-2,20-bithiophene (17c). A colorless
solid, mp 165–167 ꢂC (EtOH) (lit.63 mp 163–165 ꢂC (EtOH)). IR (KBr)
cmꢀ1: 2914, 2852, 1444, 912, 742. 1H NMR (270 MHz, CDCl3)
d
2.00
(s, 6H), 2.05 (s, 6H), 2.34 (s, 6H) ppm. 13C NMR (67.8 MHz, CDCl3)
12.7, 13.3, 14.0, 132.3, 133.3, 136.2 ppm. MS m/z 250 [M]þ.
d
By these contributions, hypervalent iodines will continue to
make an impact as unique and efficient SET oxidizing agents in the
21st century. We hope that the summarized principles and the
results provided herein should provide seminal guidance for un-
derstanding the versatility of these reagents in the SET oxidations
and for promising their future development in a variety of new SET
oxidizing chemical processes.
4.3. General procedure for regioselective oxidative coupling
of 3-alkylthiophenes with PIFA–TMSOTf
TMSOTf (0.36 mL, 2.0 mmol) and PIFA (430 mg, 1.0 mmol) were
sequentially added to a stirred solution of 3-hexylthiophene
(0.50 g, 3.0 mmol) in CH2Cl2 (2.5 mL) at ꢀ78 ꢂC under a nitrogen
atmosphere. The mixture was stirred for 3 h under the same re-
action condition. An aqueous workup with saturated NaHCO3 at
0 ꢂC followed by column chromatography (SiO2/n-hexane) gave the
corresponding 2,20-bithiophenes 18a and 19a in 41% yield as
a mixture. The formation of two regioisomers, H–T and H–H, was
confirmed by using a previously reported procedure.64
4. Experimental
4.1. General
Melting points (mp) are uncorrected. The 1H NMR (and 13C
NMR) spectra were recorded by a JEOL JMN-300 spectrometer op-
erating at 300 MHz (75.3 MHz for 13C NMR) in CDCl3 at 25 ꢂC with
tetramethylsilane as the internal standard. The data are reported as
4.3.1. 3,40-Dihexyl-2,20-bithiophene (18a)20 and 3,30-dihexyl-2,20-bi-
thiophene (19a)21. A yellow oil. IR (KBr) cmꢀ1: 2950, 2850, 1457,
follows: chemical shift in parts per million (d), integration, multi-
plicity (s¼singlet, d¼doublet, t¼triplet, q¼quartet, brs¼broad sin-
glet, m¼multiplet), and coupling constant (Hz). The infrared
spectra (IR) were obtained using a Hitachi 270-50 spectrometer.
The mass spectra were obtained using a Shimadzu GCMS-QP 5000
instrument with ionization voltages of 70 eV. The high resolution
mass spectra and elemental analysis were performed by the Ele-
mental Analysis Section of Osaka University. The column chroma-
tography 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).
PhI(OCOCF3)2 (PIFA) is prepared according to the literature pro-
cedure.61 PhI(OH)OTs (HTIB, Koser’s reagent), [PhIO]n, BF3$Et2O,
TMSOTf, and TMSBr are commercially available compounds and
were used as received. N-Tosylated pyrroles and indoles were
prepared from corresponding 1H-pyrroles and p-toluenesulfonyl
chloride as the usual N-tosylation procedures.46b Solvents and all
other starting materials were obtained from commercial suppliers
and were used without further purification.
1377. 1H NMR (300 MHz, CDCl3)
d 0.84–0.92 (m, 6H, for 18a and
19a), 1.15–1.37 (m, 12H, for 18a and 19a), 1.46–1.70 (m, 4H, for 18a
and 19a), 2.49 (4H, t, J¼7.5 Hz, for 19a), 2.63 (t, 2H, J¼8.4 Hz, for
18a), 2.74 (t, 2H, J¼8.4 Hz, for 18a), 6.90–6.94 (m, for 18a and 19a),
7.03 (s, 1H, for 18a), 7.12 (d, 1H, J¼5.5 Hz, for 18a), 7.27 (d, 2H,
J¼5.1 Hz, for 19a) ppm. 13C NMR (75.3 MHz, CDCl3)
d 14.1, 22.5, 22.6,
28.7, 29.0, 29.1, 29.2, 29.7, 30.4, 30.5, 30.6, 30.7, 31.6, 31.7, 119.9,
123.4, 125.2, 127.3, 128.5, 128.7, 129.9, 130.9, 135.8, 139.3, 142.3,
143.5 ppm. HRMS (FAB) Calcd for C20H30S2 [M]þ 334.1789, found
334.1784.
4.3.2. 3,40-Diheptyl-2,20-bithiophene (18b) and 3,30-diheptyl-2,20-bi-
thiophene (19b). A colorless oil. 1H NMR (300 MHz, CDCl3)
d 0.86
(m, 6H, for 18b and 19b), 1.23–1.45 (m, 16H, for 18b and 19b), 1.48–
1.68 (m, 4H, for 18b and 19b), 2.49 (t, 4H, J¼7.8 Hz, for 19b), 2.60 (t,
2H, J¼7.8 Hz, for 18b), 2.74 (t, 2H, J¼7.8 Hz, for 18b), 6.86–6.98 (m,
for 18b and 19b), 7.14 (d,1H, J¼5.4 Hz, for 18b), 7.27 (d, 2H, J¼5.1 Hz,
for 19b) ppm. HRMS (FAB) Calcd for C22H34S2 [M]þ 362.2102, found
362.2087.
4.2. General procedure for oxidative biaryl coupling of
thiophenes using PIFA–BF3$Et2O
4.3.3. 3,40-Dioctyl-2,20-bithiophene (18c) and 3,30-dioctyl-2,20-bi-
thiophene (19c). A colorless oil. IR (KBr) cmꢀ1: 2923, 2853, 1464,
BF3$Et2O (0.26 mL, 2.0 mmol) and PIFA (430 mg, 1.0 mmol) were
added sequentially to a stirred solution of 2,4-dimethylthiophene
(224 mg, 2.0 mmol) in CH2Cl2 (3 mL) at ꢀ78 ꢂC under a nitrogen
atmosphere. The mixture was stirred for 3 h under the same re-
action condition. Aqueous workup with saturated NaHCO3 at 0 ꢂC
followed by column chromatography (SiO2/n-hexane) gave the
corresponding bithiophene 17a (98 mg, 0.44 mmol) in 44% yield.
1377, 1200, 1086, 831, 721, 652. 1H NMR (300 MHz, CDCl3)
d 0.83–
0.96 (m, 6H, for 18c and 19c), 1.16–1.42 (m, 20H, for 18c and 19c),
1.47–1.70 (m, 4H, for 18c and 19c), 2.48 (t, 4H, J¼7.8 Hz, for 19c),
2.59 (t, 2H, J¼7.8 Hz, for 18c), 2.73 (t, 2H, J¼7.8 Hz, for 18c), 6.87–
6.95 (m, for 18c and 19c), 7.12 (d, 1H, J¼5.1 Hz, for 18c), 7.26 (d, 2H,
J¼5.1 Hz, for 19c) ppm. 13C NMR (75.3 MHz, CDCl3)
d 14.1, 15.2, 22.6,
28.7, 29.1, 29.2, 29.3, 29.4, 29.5, 30.4, 30.5, 30.7, 31.8, 119.8, 123.3,
125.2, 127.3,128.5,128.7,129.8,130.9,135.8, 139.3,142.3,143.5 ppm.
Anal. Calcd for C24H38S2: C, 73.78; H, 9.80; S, 16.42. Found: C, 73.83;
H, 9.82; S, 16.13.
4.2.1. 3,30,5,50-Tetramethyl-2,20-bithiophene (17a). Colorless crys-
tals, mp 61–62 ꢂC (EtOH). (lit.62 mp 61 ꢂC (EtOH)). IR (KBr) cmꢀ1
:
2916, 2856, 1440, 1211, 1132, 914, 825. 1H NMR (300 MHz, CDCl3)
2.09 (s, 6H), 2.43 (s, 6H), 6.56 (s, 2H) ppm. 13C NMR (75.3 MHz,
CDCl3)
14.6, 15.2, 127.2, 128.3, 136.0, 138.9 ppm. MS m/z 222 [M]þ.
d
4.3.4. 3,40-Dimethyl-2,20-bithiophene (18d)65 and 3,30-dimethyl-2,20-
bithiophene (19d). A yellow oil. IR (KBr) cmꢀ1: 2950, 2850, 1457,
d
1377. 1H NMR (300 MHz, CDCl3)
d 2.17 (s, 6H, for 19d), 2.28 (s, 3H,
4.2.2. 3,30-Dihexyl-5,50-dimethyl-2,20-bithiophene (17b). A colorless
for 18d), 2.38 (s, 3H, for 18d), 6.86–6.93 (m, for 18d and 19d), 7.11 (d,
oil. IR (KBr) cmꢀ1: 2923, 2854, 1454, 912, 742. 1H NMR (270 MHz,
1H, J¼5.1 Hz, for 18d), 7.24 (d, 2H, J¼5.1 Hz, for 19d) ppm. 13C NMR

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T. Dohi et al. / Tetrahedron 65 (2009) 10797–10815
(75.3 MHz, CDCl3)
d
14.6, 15.3, 15.7, 120.4, 123.0, 124.9, 127.8, 129.3,
After the reaction completion, saturated aqueous NaHCO3 (ca.
130.0, 131.3, 133.7, 136.3, 136.4, 138.0, 141.32 ppm.
20 mL) was added to the mixture, and then stirred for an additional
10 min at ambient temperature. The organic layer was separated
and the aqueous phase was extracted with CH2Cl2. The combined
extract was dried with Na2SO4 and evaporated. The residue was
purified by column chromatography (SiO2 (neutral)/n-hexane–
AcOEt) to give the pure 2,20-bipyrrole 21a (56 mg, 75%) as a color-
less oil. The less polar fractions gave unreacted pyrrole as a pure
form (31 mg).
4.3.5. 3,40-Dibutyl-2,20-bithiophene (18e) and 3,30-dibutyl-2,20-bi-
thiophene (19e). A yellow oil. IR (KBr) cmꢀ1: 3051, 2930, 2858,1732,
1456, 1377, 1263, 1088, 831, 748, 652. 1H NMR (300 MHz, CDCl3)
d
0.85–0.97 (m, 6H, for 18e and 19e), 1.20–1.45 (m, 4H, for 18e and
19e), 1.46–1.68 (m, 4H, for 18e and 19e), 2.50 (t, 4H, J¼7.8 Hz, for
19e), 2.60 (t, 2H, J¼7.8 Hz, for 18e), 2.75 (t, 2H, J¼7.8 Hz, for 18e),
6.87–6.96 (m, for 18e and 19e), 7.13 (d, 1H, J¼5.4 Hz, for 18e), 7.26
(d, 2H, J¼5.1 Hz, for 19e) ppm. 13C NMR (75.3 MHz, CDCl3)
d
13.8,
4.4.1. 2,20-Bi-1H-pyrrole (21a). A colorless solid, mp 187–189 ꢂC
(hexane/AcOEt). IR (KBr) cmꢀ1: 3366, 3123, 3103, 1574, 1518, 1454,
1425, 1404, 1261, 1097, 1032, 912, 891, 775, 743, 658. 1H NMR
13.9, 22.3, 22.4, 22.6, 28.4, 28.8, 30.1, 30.2, 32.5, 32.8, 119.8, 123.3,
125.1, 127.3, 128.5, 128.7, 129.8, 130.9, 134.1, 139.3, 142.2, 143.9 ppm.
Anal. Calcd for C16H22S2: C, 69.01; H, 7.96; S, 23.03. Found: C, 69.01;
H, 7.93; S, 22.74.
(300 MHz, CDCl3)
d
6.05–6.19 (m, 4H), 6.70–6.72 (m, 2H), 8.23 (br s,
103.5, 109.4, 117.6,
2H) ppm. 13C NMR (75.3 MHz, CDCl3)
d
125.9 ppm. Anal. Calcd for C8H8N2: C, 72.70; H, 6.10; S, 20.92.
Found: C, 72.41; H, 6.22; S, 20.92.
4.3.6. 3,40-Diisobutyl-2,20-bithiophene (18f) and 3,30-diisobutyl-2,20-
bithiophene (19f). A yellow oil. 1H NMR (300 MHz, CDCl3)
d 0.79–
0.92 (m, 12H, for 18f and 19f), 1.79–1.91 (m, 2H, for 18f and 19f),
2.34 (d, 4H, J¼8.1 Hz, for 19f), 2.43 (d, 2H, J¼7.8 Hz, for 18f), 2.58 (d,
2H, J¼7.8 Hz, for 18f), 6.81–6.92 (m, for 18f and 19f), 7.09 (1H, d,
J¼5.4 Hz, for 18f), 7.24 (d, 2H, J¼5.1 Hz, for 19f) ppm. HRMS (FAB)
Calcd for C16H22S2 [M]þ 278.1163, found 278.1152.
4.4.2. 3,30,4,40-Tetraethyl-2,20-bi-1H-pyrrole (21b)67. A colorless
solid, mp 90–92 ꢂC (hexane/AcOEt). IR (KBr) cmꢀ1: 3373, 2963,
2867, 1553, 1435, 1371, 1327, 1259, 1190, 1086, 1063, 1038, 947, 912,
742, 650. 1H NMR (300 MHz, CDCl3)
d
1.05 (t, 6H, J¼7.8 Hz), 1.25 (t,
6H, J¼7.8 Hz), 2.42 (q, 4H, J¼7.8 Hz), 2.52 (q, 4H, J¼7.8 Hz), 6.53 (br
s, 2H), 7.58 (br s, 2H) ppm. 13C NMR (75.3 MHz, CDCl3)
d 14,1, 16.0,
4.3.7. 3,40-Dicyclohexyl-2,20-bithiophene (18g) and 3,30-dicyclo-
hexyl-2,20-bithiophene (19g). Ayellowoil. IR (KBr) cmꢀ1: 2923, 2851,
1728, 1448, 1263, 1124, 943, 833, 731, 708, 650. 1H NMR (300 MHz,
17.9, 18.6, 113.8, 121.1, 122.9, 125.2 ppm. MS m/z 244 [M]þ.
4.4.3. 3,30,4,40-Tetrakis(2-methylpropyl)-2,20-bi-1H-pyrrole
(21c). yellow oil. IR (KBr) cmꢀ1: 3477, 3379, 2866, 1464, 1433, 1381,
1364, 1339, 1167, 1091, 912, 743, 650. 1H NMR (300 MHz, CDCl3)
CDCl3)
d 1.15–1.56 (m, for 18g and 19g), 1.65–1.87 (m, for 18g and
19g), 1.99–2.02 (m, 2H, for 18g), 2.57–2.65 (m, for 18g and 19g),
2.96–3.01 (m,1H, for 18g), 6.91 (s,1H, for 18g), 6.97–7.05 (m, for 18g
and 19g), 7.15 (d,1H, J¼5.4 Hz, for 18g), 7.31 (d, 2H, J¼5.1 Hz, for 19g)
d
0.78 (d, 12H, J¼6.6 Hz), 0.93 (d, 12H, J¼6.6 Hz), 1.60–1.69 (m, 2H),
1.76–1.85 (m, 2H), 2.23 (d, 4H, J¼7.2 Hz), 2.30 (d, 4H, J¼7.2 Hz), 6.48
(s, 2H), 7.66 (br s, 2H) ppm. 13C NMR (75.3 MHz, CDCl3)
22.6, 22.7,
ppm. 13C NMR (75.3 MHz, CDCl3)
d
26.1, 26.6, 26.7, 34.1, 34.4, 34.5,
d
38.1, 38.2, 39.6, 118.5, 123.8, 125.4, 126.1, 126.4, 127.3, 127.5, 130.1,
135.5,144.8,147.5,149.26 ppm. Anal. Calcd for C20H26S2: C, 72.67; H,
7.93; S, 19.40. Found: C, 72.66; H, 7.86; S,19.09.
29.2, 29.3, 34.3, 35.1, 114.6, 120.5, 122.0, 122.7 ppm. HRMS (FAB)
Calcd for C24H40N2 [M]þ 356.3191, found 356.3189.
4.4.4. 4,40,5,50,6,60,7,70-Octahydro-1,10-bi-1H-isoindole (21d). A yel-
low oil. IR (KBr) cmꢀ1: 3442, 3371, 2930, 2847, 1560, 1435, 1387,
1317, 1256, 1184, 1132, 1076, 1032, 955, 916, 822, 733, 650. 1H NMR
4.3.8. 3,40-Bis(6-bromohexyl)-2,20-bithiophene (18h) and 3,30-bisꢀ(61-
bromohexyl)-2,20-bithiophene (19h). A yellow oil. IR (KBr) cm
:
2931, 1726, 1556, 1529, 1456, 1257, 1219, 1085, 1037, 831, 725, 644.
(300 MHz, CD2Cl2)
d
1.72–1.78 (m, 8H), 2.58–2.63 (m, 8H), 6.46 (br
21.8, 22.6,
1H NMR (300 MHz, CDCl3)
d
1.14–1.88 (m, 8H, for 18h and 19h), 2.45
s, 2H), 7.92 (br s, 2H) ppm. 13C NMR (75.3 MHz, CDCl3)
d
(t, 4H, J¼7.8 Hz, for 19h), 2.56 (t, 2H, J¼7.8 Hz, for 18h), 2.70 (t, 2H,
J¼7.8 Hz, for 18h), 3.29–3.39 (m, 4H, for 18h and 19h), 6.81–6.92
(m, for 18h and 19h), 7.09 (d, 1H, J¼5.4 Hz, for 18h), 7.24 (d, 2H,
J¼5.1 Hz, for 19h) ppm. HRMS (FAB) Calcd for C20H28Br2S2 [M]þ
489.9999, found 489.9988.
23.5, 23.9, 112.0, 114.7, 120.1, 120.2 ppm. HRMS (FAB) Calcd for
C16H20N2 [M]þ 240.1626, found 240.1641.
In the reaction of 3-substituted 1H-pyrroles, two regioisomers
[head to tail dimers (22, major products)] and [head to head dimers
(23, minor products)] were formed. These regioisomers were sep-
arable by usual column chromatography techniques (SiO2 (neu-
tral)/n-hexane–AcOEt), the regiochemistry of which was
determined according to the literature.33a
4.3.9. 3,30-Diiodo-2,20-bithiophene (19i). A yellow solid, mp 49–
50 ꢂC (hexane/AcOEt). IR (KBr) cmꢀ1: 3097, 2924, 1759, 1595, 1473,
1437, 1390, 1332, 1261, 1139, 1082, 900, 850, 796, 713. 1H NMR
(300 MHz, CDCl3)
d
7.18 (d, 2H, J¼5.4 Hz), 7.41 (d, 2H, J¼5.4 Hz)
ppm. 13C NMR (75.3 MHz, CDCl3)
d
85.1, 129.3, 134.9, 135.6 ppm.
4.4.5. 3,40-Dimethyl-2,20-bi-1H-pyrrole (22a)33a. A yellow oil. IR
(KBr) cmꢀ1: 3377, 3096, 2924, 2866, 1562, 1504, 1435, 1381, 1261,
1207, 1173, 1097, 1063, 1030, 972, 912, 889, 793, 741, 689. 1H NMR
HRMS (FAB) Calcd for C8H4S2I2 [M]þ 417.7844, found 417.7850.
4.3.10. 4,40-Bis(trimethylsilyl)-2,20-bithiophene (20j)66. A gray solid,
mp 75–78 ꢂC (MeOH). IR (KBr) cmꢀ1: 2953, 2895, 1654, 1485, 1377,
1249, 1182, 1105, 935, 833, 748, 692. 1H NMR (300 MHz, CDCl3)
(300 MHz, CDCl3)
d 2.14 (s, 3H), 2.20 (s, 3H), 6.00–6.04 (m, 1H), 6.07
(t, 1H, J¼2.4 Hz), 6.49–6.53 (m, 1H), 6.59 (t, 1H, J¼2.4 Hz), 7.93 (br s,
2H) ppm. 13C NMR (75.3 MHz, CDCl3)
d 11.8, 12.0, 106.7, 111.3, 114.5,
d
0.26 (s, 18H), 7.17 (d, 2H, J¼1.2 Hz), 7.26 (d, 2H, J¼1.2 Hz) ppm. 13
C
115.4, 116.5, 119.6, 122.1, 125.6 ppm. MS, m/z: 160 [M]þ.
NMR (75.3 MHz, CDCl3)
d
ꢀ0.70, 128.4, 130.4, 138.0, 142.9 ppm.
4.4.6. 3,30-Dimethyl-2,20-bi-1H-pyrrole (23a)33a. A yellow oil. 1H
4.4. General procedure for direct oxidative coupling of
pyrroles using a combination of PIFA and TMSBr
NMR (300 MHz, CD2Cl2)
d
2.16 (s, 6H), 6.14 (t, 2H, J¼2.4 Hz), 6.72 (t,
2H, J¼2.4 Hz), 7.95 (br s, 2H). MS, m/z: 160 [M]þ.
To a stirred solution of 1H-pyrrole (111 mg, 0.9 mmol) in CH2Cl2
(15 mL), PIFA (0.3 mmol) and TMSBr (0.6 mmol) were quickly
added at ꢀ78 ꢂC. The reaction mixture was then stirred for 1 h,
while the reaction temperature was maintained below ꢀ40 ꢂC.
4.4.7. 3,40-Diheptyl-2,20-bi-1H-pyrrole (22b). A yellow oil. IR (KBr)
cmꢀ1: 3371, 2924, 2853, 1684, 1437, 1377, 1107, 976, 891. 1H NMR
(300 MHz, CDCl3)
d 0.80–0.95 (m, 6H), 1.22–1.38 (m, 16H), 1.53–1.64
(m, 4H), 2.48 (t, 2H, J¼7.5 Hz), 2.56 (t, 2H, J¼7.5 Hz), 5.97–6.12 (m,

T. Dohi et al. / Tetrahedron 65 (2009) 10797–10815
10809
1H), 6.12 (t, 1H, J¼2.7 Hz), 6.47–6.65 (m, 1H), 6.68 (t, 1H, J¼2.7 Hz),
J¼2.7 Hz), 7.21 (d, 4H, J¼8.4 Hz), 7.39 (d, 4H, J¼8.4 Hz), 8.00 (br s,
2H) ppm. MS, m/z: 439 [M]þ.
7.91 (br s, 1H), 7.95 (br s, 1H) ppm. 13C NMR (75.3 MHz, CDCl3)
d
14.1(ꢃ2), 22.7, 26.5, 27.0, 29.2(ꢃ2), 29.5, 29.6, 31.1, 31.2, 31.8, 31.9,
106.0, 109.8, 114.6, 116.6, 120.4, 121.7, 125.4, 125.6 ppm. HRMS (FAB)
Calcd for C22H36N2 [M]þ 328.2878, found 328.2862.
4.4.16. 4,40-Bis(1,1-dimethylethyl)-2,20-bi-1H-pyrrole (24g)37a. A col-
orless solid, mp 162–164 ꢂC (hexane/AcOEt). IR (KBr) cmꢀ1: 3473,
3360, 2966, 1783, 1555, 1444, 1359, 1292, 1107, 912, 742. 1H NMR
4.4.8. 3,30-Diheptyl-2,20-bi-1H-pyrrole (23b). A yellow oil. 1H NMR
(300 MHz, CD2Cl2)
(300 MHz, CDCl3) d 1.26 (s, 18H), 6.08 (s, 2H), 6.45 (s, 2H), 7.64 (br s,
d
0.80–0.92 (m, 6H), 1.22–1.30 (m, 16H), 1.57–
2H). 13C NMR (75.3 MHz, CDCl3)
d 30.5, 31.7, 102.3, 112.2,125.9, 136.4.
1.55 (m, 4H), 2.39 (t, 4H, J¼7.8 Hz), 6.12 (t, 2H, J¼2.7 Hz), 6.74 (t, 2H,
MS, m/z: 244 [M]þ.
J¼2.7 Hz), 7.97 (br s, 2H) ppm. MS, m/z: 328 [M]þ.
4.4.17. 2,30-Bi-1H-pyrrole (25a)23. A colorless solid, mp 102–103 ꢂC
4.4.9. [2,20-Bi-1H-pyrrole]-3,40-dibutanoic acid dimethyl ester
(22c). A yellow oil. IR (KBr) cmꢀ1: 3377, 2949, 2853, 1713, 1556,
1537, 1504, 1454, 1433, 1140, 1101, 1003, 912, 797, 743. 1H NMR
(hexane/AcOEt). IR (KBr) cmꢀ1: 3402, 3124, 2252, 1793, 1608, 1525,
1427, 1111, 912, 792. 1H NMR (300 MHz, CDCl3)
d 6.22–6.24 (m, 2H),
6.31–6.32 (m, 1H), 6.68–6.78 (m, 2H), 6.80–6.81 (m, 1H), 8.07 (br s,
(300 MHz, CDCl3)
d
1.82–2.03 (m, 4H), 2.33–2.46 (m, 4H), 2.54 (t,
2H) ppm. 13C NMR (75.3 MHz, CDCl3)
116.6, 117.5, 118.6, 128.3 ppm.
d 103.6, 105.8, 109.1, 113.2,
2H, J¼7.8 Hz), 2.61 (t, 2H, J¼7.8 Hz), 3.67 (s, 3H), 3.70 (s, 3H), 6.02–
6.04 (m, 1H), 6.07 (t, 1H, J¼2.7 Hz), 6.62–6.64 (m, 1H), 6.67 (t, 1H,
J¼2.7 Hz), 8.09 (br s, 1H), 9.03 (br s, 1H) ppm. 13C NMR (75.3 MHz,
4.4.18. 1,10-Dibenzyl-2,30-bipyrrole (25aa). A colorless oil. IR (KBr)
CDCl3)
d
25.7, 26.2, 26.3, 26.4, 32.9, 33.6, 51.5, 51.7, 104.9, 109.9,
cmꢀ1: 3063, 3028, 2922, 1497, 1452, 1339, 1282, 1078, 1028, 918,
115.4, 116.6, 118.3, 122.3, 123.6, 125.4, 174.4, 175.2 ppm. HRMS (FAB)
708, 623. 1H NMR (300 MHz, CDCl3)
d 4.98 (s, 2H), 5.18 (s, 2H), 6.14
Calcd for C18H24N2O4Na [MþNa]þ 355.1634, found 355.1628.
(dd, 1H, J¼3.0, 2.1 Hz), 6.18–6.21 (m, 2H), 6.55 (t, 1H, J¼2.1 Hz), 6.60
(t, 1H, J¼3.0 Hz), 6.67 (dd, 1H, J¼3.0, 2.1 Hz), 6.98–7.07 (m, 4H),
4.4.10. [2,20-Bi-1H-pyrrole]-3,30-dibutanoic acid dimethyl ester
7.21–7.31 (m, 6H) ppm. 13C NMR (75.3 MHz, CDCl3)
d 50.6, 53.4,
(23c). A yellow oil. 1H NMR (300 MHz, CDCl3)
d
1.82–1.99 (m, 4H),
106.9,107.9,109.0,116.2,119.4,121.2,121.4,126.2,126.9,127.6,128.5,
128.6, 129.7, 137.7, 139.2 ppm. HRMS(FAB) Calcd for C22H20N2Na
[MþNa]þ 335.1532, found 335.1528.
2.35 (t, 4H, J¼7.3 Hz), 2.52 (t, 4H, J¼7.3 Hz), 3.64 (s, 6H), 6.12 (t, 2H,
J¼2.7 Hz), 6.78 (t, 2H, J¼2.7 Hz), 8.61 (br s, 2H). MS, m/z: 332 [M]þ.
4.4.11. 3,40-Diphenyl-2,20-bi-1H-pyrrole (22d). A colorless solid, mp
4.4.19. 1,10-Bis(4-methoxybenzyl)-2,30-bipyrrole (25ab). A colorless
60–62 ꢂC (hexane/CH2Cl2). IR (KBr) cmꢀ1: 3379, 2855, 1790, 1682,
oil. IR (KBr) cmꢀ1: 2926, 1612, 1514, 1462, 1247, 1174, 1033, 916, 819,
1177, 912, 743, 650. 1H NMR (300 MHz, CDCl3)
d
6.35 (t, 1H,
773, 709. 1H NMR (300 MHz, CDCl3)
d 3.77 (s, 3H), 3.79 (s, 3H), 4.92
J¼2.7 Hz), 6.50–6.52 (m, 1H), 6.74 (t, 1H, J¼2.7 Hz), 6.85–6.87 (m,
(s, 2H), 5.10 (s, 2H), 6.14–6.19 (m, 3H), 6.55 (t, 1H, J¼1.5 Hz), 6.60 (t,
1H, J¼1.5 Hz), 6.64 (t, 1H, J¼1.5 Hz), 6.80 (d, 2H, J¼6.6 Hz), 6.83 (d,
2H, J¼6.6 Hz), 6.93 (d, 2H, J¼6.6 Hz), 7.03 (d, 2H, J¼6.6 Hz) ppm. 13C
1H), 7.09–7.51 (m, 10H), 7.98 (br s, 1H), 8.14 (br s, 1H) ppm. 13C
NMR (75.3 MHz, CDCl3)
d 103.5, 109.8, 110.2, 114.6, 117.9, 120.8,
121.0, 124.90, 125.20, 125.60, 125.80, 126.1, 128.1, 128.6, 135.3,
136.2 ppm. HRMS (FAB) Calcd for C14H16N2 [M]þ 284.1313, found
284.1299.
NMR (67.8 MHz, CDCl3) d 50.1, 52.9, 55.2, 55.3, 106.9, 107.8, 109.0,
113.9, 114.0, 116.2, 119.3, 121.0, 121.2, 127.6, 128.6, 129.7, 129.8, 131.3,
158.6, 159.2 ppm. HRMS (FAB) Calcd for C24H24N2O2 [M]þ 372.1838,
found C24H24N2O2 372.1834.
4.4.12. 3,30-Diphenyl-2,20-bi-1H-pyrrole (23d). A yellow oil. 1H NMR
(300 MHz, CDCl3)
d
6.46 (t, 2H, J¼2.7 Hz), 6.74 (t, 2H, J¼2.7 Hz),
4.4.20. 1,10-Diphenyl-2,20-bipyrrole (21ac). A colorless solid, mp:
102–105 ꢂC (hexane/CH2Cl2). IR (KBr) cmꢀ1: 3064, 2924,1599,1500,
1454,1410,1344,1211,1166,1070,1035,122, 761. 1H NMR (300 MHz,
7.14–7.22 (m, 2H), 7.23–7.36 (m, 4H), 7.38–7.45 (m, 4H), 8.00 (br s,
2H) ppm. MS, m/z: 284 [M]þ.
CDCl3)
d
6.31 (dt, 2H, J¼2.1, 0.6 Hz), 6.43–6.44 (m, 2H), 6.56–6.58
4.4.13. 3,40-Bis(4-methoxyphenyl)-2,20-bi-1H-pyrrole (22e). A yel-
low oil. IR (KBr) cmꢀ1: 3369, 3002, 2937, 2909, 2835, 1611, 1556,
1526, 1510, 1493, 1464, 1441, 1425, 1391, 1288, 1244, 1178, 1109,
1096, 1076, 1030, 912, 833, 793, 743, 698, 650. 1H NMR (300 MHz,
(m, 4H), 6.75–6.77 (m, 2H), 6.99–7.04 (m, 6H) ppm. 13C NMR
(75.3 MHz, CDCl3)
d 109.0, 112.4, 122.2, 123.7, 125.0, 125.4, 128.4,
140.1 ppm. MS, m/z: 284 [M]þ.
CDCl3)
d
3.82 (s, 3H), 3.83 (s, 3H), 6.32 (t, 1H, J¼2.7 Hz), 6.48–6.49
4.4.21. 1,10-Diphenyl-2,30-bipyrrole (25ac). A yellow oil. IR (KBr)
(m, 1H), 6.81 (t, 1H, J¼2.7 Hz), 6.83–6.85 (m, 1H), 6.86–6.94 (m, 4H),
7.35 (d, 2H, J¼8.4 Hz), 7.44 (d, 2H, J¼8.4 Hz), 8.04 (br s, 1H), 8.27 (br
cmꢀ1: 3058, 1599, 1504, 1462, 1352, 1319, 1184, 1074, 1036, 912, 743,
694, 650. 1H NMR (300 MHz, CDCl3)
d
6.07 (dd, 1H, J¼3.3, 1.7 Hz),
s, 1H) ppm. 13C NMR (75.3 MHz, CDCl3)
d
55.2, 55.3, 102.9, 110.4,
6.31–6.40 (m, 2H), 6.63–6.66 (m, 1H), 6.83–6.86 (m, 1H), 6.90–6.94
113.7, 114.0, 114.1, 117.6, 120.4, 120.8, 125.1, 126.0, 126.1, 128.2, 128.7,
129.4, 157.8, 158.1 ppm. HRMS (FAB) Calcd for C22H20N2O2 [M]þ
344.1525, found 344.1519.
(m, 1H), 7.16–7.28 (m, 4H), 7.31–7.40 (m, 6H) ppm. 13C NMR
(75.3 MHz, CDCl3)
d 107.85, 108.73, 110.50, 116.16, 118.35, 118.82,
119.83,122.75,125.30,126.45, 126.94,128.70,128.99, 129.39,140.21,
140.74 ppm. HRMS (FAB) Calcd for C20H17N2 [MþH]þ 285.1392,
found 285.1394.
4.4.14. 3,40-Bis(4-bromophenyl)-2,20-bi-1H-pyrrole (22f). A yellow
oil. IR (KBr) cmꢀ1: 3450, 3369, 1591, 1514, 1494, 1479, 1441, 1410,
1385, 1261, 1175, 1105, 1070, 1009, 912, 829, 800, 743, 650. 1H NMR
4.4.22. 1,10-Dimethyl-2,30-bipyrrole (25ad). A colorless oil. IR (KBr)
(300 MHz, CDCl3)
1H, J¼2.7 Hz), 6.95–6.97 (m, 1H), 7.25–7.52 (m, 8H), 8.02 (br s, 1H),
8.26 (br s, 1H) ppm. 13C NMR (75.3 MHz, CDCl3)
103.8, 110.2, 115.0,
d
6.36 (t, 1H, J¼2.7 Hz), 6.52–6.54 (m, 1H), 6.83 (t,
cmꢀ1: 3099, 2943, 1595, 1510, 1417, 1356, 1284, 1186, 1087, 995, 742.
1H NMR (300 MHz, CDCl3)
d 3.64 (s, 6H), 6.10–6.12 (m, 2H), 6.21 (t,
d
1H, J¼2.1 Hz), 6.57–6.60 (m, 2H), 6.63 (t, 1H, J¼1.8 Hz). 13C NMR
118.2, 119.2, 119.9, 120.0, 120.9, 124.5, 125.7,126.5, 129.6, 131.7, 131.8,
134.1, 135.0 ppm. HRMS (FAB) Calcd for C20H14N2Br2 [M]þ
439.9524, found 439.9529.
(75.3 MHz, CDCl3) d 34.8, 36.1, 106.4, 107.1, 108.5, 116.4, 119.6, 121.7,
121.8, 129.7. HRMS (EI) Calcd for C10H12N2 [M]þ 160.1001, found
160.1000.
4.4.15. 3,30-Bis(4-bromophenyl)-2,20-bi-1H-pyrrole (23f). A oil. 1H
4.4.23. 3,30-Dimethyl-2,20-biindole (26)68. A yellow solid, mp 158–
NMR (300 MHz, CDCl3)
d
6.45 (t, 2H, J¼2.7 Hz), 6.79 (t, 2H,
161 ꢂC (hexane/CH2Cl2). IR (KBr) cmꢀ1: 3406, 3057, 2918, 2860,

10810
T. Dohi et al. / Tetrahedron 65 (2009) 10797–10815
1551, 1454, 1420, 1333, 1240, 1176, 1152, 1115, 1099, 1011, 912, 745,
650. 1H NMR (300 MHz, CDCl3)
2.37 (s, 6H), 7.17 (t, 2H, J¼7.2 Hz),
7.25 (t, 2H, J¼7.2 Hz), 7.35 (d, 2H, J¼7.2 Hz), 7.61 (d, 2H, J¼7.2 Hz),
The combined extract was dried with Na2SO4 and evaporated. The
residue was purified by column chromatography (SiO2/n-hexane–
Et2O) to give pure 32a (205 mg, 83%).
d
7.92 (br s, 2H) ppm. 13C NMR (75.3 MHz, CDCl3)
d 9.7, 110.7, 118.9,
119.6, 120.1, 122.5, 126.6, 129.1, 136.1 ppm. MS, m/z: 260 [M]þ.
4.6.1. 3-Hexylthiophene-2-carbonitrile (31a). A slightly yellow oil.
IR (KBr) cmꢀ1: 2214. 1H NMR (300 MHz, CDCl3)
d 0.89 (t, 3H,
4.4.24. 3-Methyl-2-(3-methylindol-2-yl)indoline (27)69. A colorless
solid, mp 126–129 ꢂC (hexane/CH2Cl2¼1:1). IR (KBr) cmꢀ1: 3353,
3030, 2862, 1614, 1485, 1469, 1452, 1290, 1203, 1153, 1084, 1003,
J¼6.9 Hz), 1.20–1.48 (m, 6H), 1.51–1.73 (m, 2H), 2.79 (t, 2H,
J¼7.5 Hz), 6.97 (d,1H, J¼5.1 Hz), 7.26 (d,1H, J¼5.1 Hz) ppm. 13C NMR
(75.3 MHz, CDCl3)
d 14.0, 22.5, 28.8, 29.8, 30.1, 31.5, 105.4, 114.3,
912, 743, 650. 1H NMR (300 MHz, CDCl3)
d
1.35 (d, 3H, J¼6.6 Hz),
128.5, 131.6, 154.8 ppm. Anal. Calcd for C11H15NS: C, 68.35; H, 7.82;
N, 7.25. Found: C, 68.56; H, 7.87; N, 6.98.
2.31 (s, 3H), 3.16–3.26 (m, 1H), 4.68 (d, 1H, J¼10.5 Hz), 6.65 (d, 1H,
J¼7.8 Hz), 6.81 (t, 1H, J¼7.5 Hz), 7.02–7.18 (m, 3H), 7.22 (d, 1H,
J¼7.8 Hz), 7.52 (d, 1H, J¼7.5 Hz), 8.30 (br s, 1H) ppm. 13C NMR
4.6.2. 3-Methylthiophene-2-carbonitrile (31b)70. A slightly yellow
(75.3 MHz, CDCl3)
d
8.7, 16.4, 45.2, 64.2, 108.3, 109.5, 110.7, 118.4,
oil. IR (KBr) cmꢀ1: 2214. 1H NMR (300 MHz, CDCl3)
d 2.45 (3H, s),
119.4, 119.6, 121.8, 123.2, 127.7, 129.2, 132.9, 134.4, 135.2, 149.7 ppm.
6.94 (1H, d, J¼5.1 Hz), 7.46 (1H, d, J¼5.1 Hz) ppm. 13C NMR
MS, m/z: 262 [M]þ.
(75.3 MHz, CDCl3): d 15.2, 105.8, 114.2, 129.5, 131.5, 149.5 ppm.
4.5. General procedure for oxidative introduction of
nucleophiles using PIFA
4.6.3. 3-Cyclohexylthiophene-2-carbonitrile (31c). A slightly yellow
oil. IR (KBr) cmꢀ1: 2220. 1H NMR (300 MHz, CDCl3)
1.05–1.98 (m,
10H), 2.84–2.86 (m, 1H), 6.93 (d, 1H, J¼5.1 Hz), 7.40 (d, 1H, J¼5.1 Hz)
ppm. 13C NMR (75.3 MHz, CDCl3)
25.8, 26.3, 33.6, 39.8, 104.2,
114.4, 126.5, 131.8, 159.9 ppm. Anal. Calcd for C11H13NS: C, 69.07; H,
6.85; N, 7.32. Found: C, 69.05; H, 6.98; N, 7.03.
d
To a stirred solution of 3-hexylthiophene (168 mg, 1.0 mmol) in
CH2Cl2 (10 mL), PIFA (430 mg, 1.0 mmol) and TMSCl (0.25 mL,
2.0 mmol) were quickly added at 0 ꢂC. The reaction mixture was
then stirred for 3 h. After the reaction completion, saturated
aqueous NaHCO3 was added to the mixture, and then stirred for an
additional 10 min at ambient temperature. The organic layer was
separated and the aqueous phase was extracted with CH2Cl2. The
combined extract was dried with Na2SO4 and evaporated. The
residue was purified by column chromatography (SiO2/n-hexane)
to give the pure chlorothiophene 28a (158 mg, 78%) as a colorless
oil.
d
4.6.4. 3-Methoxythiophene-2-carbonitrile (31d)71. A colorless oil. IR
(KBr) cmꢀ1: 2214. 1H NMR (300 MHz, CDCl3)
d 4.02 (s, 3H), 6.72 (d,
1H, J¼5.1 Hz), 7.36 (d, 1H, J¼5.1 Hz) ppm. 13C NMR (75.3 MHz,
CDCl3)
d 59.1, 86.7, 113.5, 116.1, 131.6, 165.6 ppm.
4.6.5. 3-Phenylthiophene-2-carbonitrile (31e). A slight yellow oil. IR
(KBr) cmꢀ1: 2214. 1H NMR (300 MHz, CDCl3)
7.23 (d,1H, J¼5.1 Hz),
7.23–7.50 (m, 3H), 7.54 (d, 1H, J¼5.1 Hz), 7.65 (dd, 2H, J¼8.4, 1.8 Hz)
ppm. 13C NMR (75.3 MHz, CDCl3)
104.3, 114.7, 127.7, 128.2, 129.0,
d
4.5.1. 2-Chloro-3-hexylthiophene (28a). A colorless oil. IR (KBr)
d
cmꢀ1: 2930, 2858, 2253, 1028, 912, 650. 1H NMR (300 MHz, CDCl3)
129.1, 131.8, 133.0, 151.4 ppm. Anal. Calcd for C11H7NS: C, 71.32; H,
3.81; N, 7.56. Found: C, 71.05; H, 4.06; N, 7.44.
d
0.89 (t, 3H, J¼6.9 Hz), 1.15–1.43 (m, 6H), 1.52–1.59 (m, 2H), 2.56 (t,
2H, J¼7.5 Hz), 6.79 (d, 1H, J¼5.4 Hz), 7.02 (d, 1H, J¼5.4 Hz) ppm. 13C
NMR (75.3 MHz, CDCl3)
d
14.1, 22.6, 27.9, 28.9, 29.6, 31.6, 121.0,
4.6.6. 5-Methylthiophene-2-carbonitrile (31f)72. A colorless oil. IR
124.4, 127.9, 139.2 ppm. HRMS (EI) Calcd for C10H15SCl [M]þ
202.0583, found 202.0611.
(KBr) cmꢀ1: 2220. 1H NMR (300 MHz, CDCl3)
d 2.55 (s, 3H), 6.79 (d,
1H, J¼4.8 Hz), 7.44 (d, 1H, J¼4.8 Hz) ppm. 13C NMR (75.3 MHz,
CDCl3):
d 15.4, 107.0, 114.5, 126.0, 137.8, 148.2 ppm.
4.5.2. 2-Bromo-3-hexylthiophene (29a). A colorless oil. IR (KBr)
cmꢀ1: 2928, 2856, 2251, 1466, 1408, 1377, 912, 743. 1H NMR
4.6.7. 2-Cyano-1-tosylpyrrole (32a)73. Colorless crystals, mp 114–
115 ꢂC. IR (KBr) cmꢀ1: 2225. 1H NMR (300 MHz, CDCl3)
2.44 (s,
(300 MHz, CDCl3)
d
0.89 (t, 3H, J¼6.9 Hz), 1.30–1.37 (m, 6H), 1.52–
d
1.59 (m, 2H), 2.56 (t, 2H, J¼7.5 Hz), 6.79 (d,1H, J¼5.4 Hz), 7.18 (d,1H,
3H), 6.32 (t, 1H, J¼3.4 Hz), 6.95 (dd, 1H, J¼3.4, 1.6 Hz), 7.37 (d, 2H,
J¼5.4 Hz) ppm. 13C NMR (75.3 MHz, CDCl3)
d 14.1, 22.6, 28.9, 29.4,
J¼8.7 Hz), 7.47 (dd,1H, J¼3.4,1.6 Hz), 7.93 (d, 2H, J¼8.7 Hz) ppm. 13C
29.7, 31.6, 108.8, 125.1, 128.2, 141.7 ppm. HRMS (EI) Calcd for
NMR (75.3 MHz, CDCl3)
130.4, 134.1, 146.5 ppm.
d 21.7, 103.7, 111.6, 112.3, 126.5, 126.6, 127.9,
C10H15SBr [M]þ 246.0077, found 246.0092.
4.5.3. 2-Thiocyanato-3-hexylthiophene (30a). A colorless oil. IR
4.6.8. 2-Cyano-3-methyl-1-tosylpyrrole (32b). Colorless crystals,
(KBr) cmꢀ1: 2928, 2858, 2253, 2158, 1466, 1393, 912, 743, 650. 1H
mp 114–117 ꢂC. IR (KBr) cmꢀ1: 2222. 1H NMR (300 MHz, CDCl3)
NMR (300 MHz, CDCl3)
d
0.92 (t, 3H, J¼6.9 Hz), 1.29–1.41 (m, 6H),
d
2.11 (s, 3H), 2.37 (s, 3H), 6.11 (d, 1H, J¼3.0 Hz), 7.28–7.30 (m, 3H),
1.55–1.69 (m, 2H), 2.79 (t, 2H, J¼7.5 Hz), 7.00 (d, 1H, J¼5.4 Hz), 7.50
7.83 (d, 2H, J¼8.1 Hz) ppm. 13C NMR (75.3 MHz, CDCl3)
d 12.1, 21.7,
(d, 1H, J¼5.4 Hz) ppm. 13C NMR (75.3 MHz, CDCl3)
d
14.0, 22.5, 29.0,
102.1, 111.7, 114.2, 126.2, 127.8, 130.3, 134.3, 139.1, 146.2 ppm. HRMS
29.2, 30.1, 31.5, 110.5, 112.3, 129.4, 131.9, 152.1 ppm. HRMS (EI) Calcd
for C11H15NS2 [M]þ 248.0542, found 248.0543.
(FAB) Calcd for C13H12N2O2S [MþH]þ, 261.0683, found 261.0690.
4.6.9. 2-Cyano-3-heptyl-1-tosylpyrrole (32c). A colorless oil. IR
4.6. General procedure for direct cyanation of heteroaromatic
compounds
(KBr) cmꢀ1: 2220. 1H NMR (300 MHz, CDCl3)
1.02–1.30 (m, 8H), 1.54–1.61 (m, 2H), 2.44 (s, 3H) 2.51 (t, 2H,
d
0.86 (t, 3H, J¼7.5 Hz),
J¼7.8 Hz), 6.20 (d, 1H, J¼3.3 Hz), 7.34–7.37 (m, 3H), 7.91 (d, 2H,
To a stirred solution of PIFA (860 mg, 2.0 mmol) and BF3$Et2O
(0.49 mL, 4.0 mmol) in CH2Cl2 (1 mL) added trimethylsilyl cyanide
(0.38 mL, 3.0 mmol) at room temperature. After stirring 30 min, N-
tosylpyrrole (221 mg,1 mmol) was added in one portion and stirred
for additional 3 h. After the reaction completed, saturated aqueous
sodium thiosulfate (ca. 5 mL) was added to the mixture. The organic
layer was separated and aqueous phase was extracted with CH2Cl2.
J¼8.1 Hz) ppm. 13C NMR (75.3 MHz, CDCl3)
d 14.0, 21.7, 22.5, 26.6,
28.8, 28.9, 29.5, 31.6, 101.5, 111.7, 113.1, 126.3, 127.7, 130.3, 134.4,
144.1, 146.2 ppm. Anal. Calcd for C19H24N2O2S: C, 66.25; H, 7.02; N,
8.13. Found: C, 66.17; H, 7.01; N, 8.32.
4.6.10. 2-Cyano-1-tosylpyrrole-3-butanoic acid methyl ester (32d). Col-
orless crystals, mp 113–115 ꢂC (hexane/EtOAc). IR (KBr) cmꢀ1: 2220.

T. Dohi et al. / Tetrahedron 65 (2009) 10797–10815
10811
1H NMR (300 MHz, CDCl3)
d
1.89 (q, 2H, J¼7.5 Hz), 2.28 (t, 2H,
130.8, 135.0, 137.2, 137.5, 145.6 ppm. HRMS (FAB) Calcd for
C
J¼7.2 Hz), 2.44 (s, 3H), 2.58 (t, 2H, J¼7.5 Hz) 3.65 (s, 3H), 6.22 (d, 1H,
14H15O2N2S [MþH]þ; 275.0884, found 275.0871.
J¼3.3 Hz), 7.38–7.40 (m, 3H), 7.92 (d, 2H, J¼8.1 Hz) ppm. 13C NMR
(75.3 MHz, CDCl3)
d
21.7, 24.7, 25.8, 33.0, 51.6, 101.7, 111.5, 112.9,
4.6.18. 1-Tosylindole-2-carbonitrile (33a)73. Colorless crystals, mp
160–162 ꢂC (hexane/EtOAc). IR (KBr) cmꢀ1 2224. 1H NMR
(300 MHz, CDCl3)
126.5, 127.8, 130.3, 134.1, 142.5, 146.3, 173.3 ppm. HRMS (FAB) Calcd
:
for C17H18N2O4S [MþH]þ; 347.1065, found 347.1066.
d
2.37 (s, 3H), 7.27 (d, 2H, J¼7.4 Hz), 7.34 (d, 1H,
J¼5.6 Hz), 7.36 (s, 1H), 7.54 (t, 1H, J¼7.4 Hz), 7.58 (d, 1H, J¼8.1 Hz),
4.6.11. 3-tert-Butyl-1-tosylpyrrole-2-carbonitrile
(32e). Colorless
7.90 (d, 2H, J¼8.4 Hz), 8.22 (d, 1H, J¼8.1 Hz) ppm. 13C NMR
crystals, mp 65–67 ꢂC. IR (KBr) cmꢀ1: 2220. 1H NMR (300 MHz,
(75.3 MHz, CDCl3) d 21.6,109.0,112.2,114.6,122.5,123.0,124.7,127.1,
CDCl3)
d
1.31 (s, 9H), 2.45 (s, 3H), 6.26 (d, 1H, J¼3.0 Hz), 7.36–7.40
127.6, 128.6, 130.2, 134.4, 136.6, 146.1 ppm.
(m, 3H), 7.92 (d, 2H, J¼8.4 Hz) ppm. 13C NMR (75.3 MHz, CDCl3)
d
21.7, 30.3, 31.9, 99.3, 111.1, 112.9, 125.6, 127.8, 130.3, 134.2, 146.2,
4.6.19. 3-Methyl-1-tosylindole-2-carbonitrile (33b). Colorless crys-
152.5 ppm. Anal. Calcd for C16H18N2O2S: C, 63.55; H, 6.00; N, 9.26.
Found: C, 63.42; H, 6.08; N, 9.26.
tals, mp 160–168 ꢂC (hexane/EtOAc). IR (KBr) cmꢀ1: 2224. 1H NMR
(300 MHz, CDCl3)
d
2.36 (s, 3H), 2.43 (s, 3H), 7.25 (d, 2H, J¼8.4 Hz),
7.35 (t, 1H, J¼7.5 Hz), 7.54 (d, 2H, J¼8.4 Hz), 7.86 (d, 2H, J¼8.4 Hz),
4.6.12. 3-(2-Bromophenyl)-1-tosylpyrrole-2-carbonitrile
8.20 (d, 1H, J¼8.7 Hz) ppm. 13C NMR (75.3 MHz, CDCl3)
d 10.0, 21.6,
(32f). Colorless crystals, mp 132–134 ꢂC (hexane/EtOAc). IR (KBr)
107.0, 112.1, 114.7, 120.7, 124.4, 127.0, 128.6, 128.7, 130.1, 134.3, 134.4,
136.6, 145.8 ppm. HRMS (FAB) Calcd for C17H15N2O2S [MþH]þ;
311.0854, found 311.0850.
cmꢀ1: 2220. 1H NMR (300 MHz, CDCl3)
d 2.44 (s, 3H), 6.56 (d, 1H,
J¼3.4 Hz), 7.17–7.23 (m, 1H), 7.27–7.45 (m, 4H), 7.50 (d, 1H,
J¼3.4 Hz), 7.62 (d, 1H, J¼8.7 Hz), 7.96 (d, 2H, J¼8.4 Hz) ppm. 13C
NMR (75.3 MHz, CDCl3)
d
21.8, 102.1, 111.5, 114.5, 122.8, 125.6, 127.7,
4.6.20. 2-Methyl-1-tosylindole-3-carbonitrile (34c). Colorless crys-
128.0, 130.4, 131.3, 131.9, 133.5, 134.1, 140.7, 146.6 ppm. Anal. Calcd
for C18H13BrN2O2S: C, 53.88; H, 3.27; N, 6.98. Found: C, 53.65; H,
3.27; N, 6.81.
tals, mp 146–148 ꢂC (hexane/EtOAc). IR (KBr) cmꢀ1: 2224. 1H NMR
(300 MHz, CDCl3)
(dd, 1H, J¼7.1, 1.4 Hz), 7.74 (d, 2H, J¼8.4 Hz), 8.20 (dd, 1H, J¼7.1,
1.4 Hz) ppm. 13C NMR (75.3 MHz, CDCl3)
15.0, 21.7, 94.5, 114.6,
d 2.39 (s, 3H), 2.81 (s, 3H), 7.21–7.45 (m, 4H), 7.58
d
4.6.13. 3-(4-Bromophenyl)-1-tosylpyrrole-2-carbonitrile
119.1, 124.7, 125.7, 126.6, 126.8, 127.8, 129.7, 130.2, 135.1, 135.4,
146.0 ppm. HRMS (FAB) Calcd for C17H15N2O2S [MþH]þ; 311.0854,
found 311.0853.
(32g). Colorless crystals, mp 161–163 ꢂC (hexane/EtOAc). IR (KBr)
cmꢀ1: 2220. 1H NMR (300 MHz, CDCl3)
d 2.37 (s, 3H), 6.46 (d, 1H,
J¼3.1 Hz), 7.31 (d, 2H, J¼8.7 Hz), 7.37–7.55 (m, 5H), 7.89 (d, 2H,
J¼8.7 Hz) ppm. 13C NMR (75.3 MHz, CDCl3)
d
21.8, 99.5, 111.6, 112.4,
4.7. General procedure for direct cyanation of N-tosylpyrrole
by (dicyanoiodo)benzene [PhI(CN)2]
123.3, 126.9, 128.1, 128.7, 129.8, 130.5, 132.2, 134.0, 139.9, 146.7 ppm.
Anal. Calcd for C18H13BrN2O2S: C, 53.88; H, 3.27; N, 6.98. Found: C,
53.71; H, 3.30; N, 6.98.
To a stirred solution of PhI(CN)2 (512 mg, 2.0 mmol) and
BF3$Et2O (0.49 mL, 4.0 mmol) in CH2Cl2 (1 mL), N-tosylpyrrole
(221 mg, 1 mmol) was added under nitrogen atmosphere. The so-
lution was then stirred for 20 h at room temperature. TLC analysis
of the reaction indicated that the cyanated 32a was present as
major product with a small amount remaining starting substrate.
The product 32a was separated and purified according to the
general experimental procedure mentioned in Section 4.6.
4.6.14. 3-(4-Methoxyphenyl)-1-tosylpyrrole-2-carbonitrile
(32h). Colorless crystals, mp 85–88 ꢂC (hexane/EtOAc). IR (KBr)
cmꢀ1: 2216. 1H NMR (300 MHz, CDCl3)
d 2.37 (s, 3H), 3.75 (s, 3H),
6.45 (d, 1H, J¼3.3 Hz), 6.86 (d, 2H, J¼8.4 Hz), 7.30 (d, 2H, J¼8.1 Hz),
7.43 (d, 1H, J¼3.0 Hz), 7.50 (d, 2H, J¼8.7 Hz), 7.89 (d, 2H, J¼8.1 Hz)
ppm. 13C NMR (75.3 MHz, CDCl3)
d 21.8, 55.3, 98.6,111.7,113.0,114.4,
123.2, 126.8, 128.0, 128.5, 130.4, 134.2, 141.1, 146.4, 160.2 ppm. Anal.
Calcd for C19H16N2O3S: C, 64.76; H, 4.58; N, 7.95. Found: C, 64.49; H,
4.78; N, 7.72.
4.8. General procedure for dehydrative condensation of
thiophenes and hypervalent iodine(III) reagents
4.6.15. 3,4-Diethyl-1-tosylpyrrole-2-carbonitrile
(32i). Colorless
To a stirred solution of 3-methylthiophene (98 mg, 1.0 mmol) in
2,2,2-trifluoroethanol (5 mL), iodosobenzene (220 mg, 1.0 mmol)
crystals, mp 120–122 ꢂC (hexane/EtOAc). IR (KBr) cmꢀ1: 2220. 1H
NMR (300 MHz, CDCl3)
d
1.11–1.25 (m, 6H), 2.33–2.61 (m, 7H),
and perchloric acid aqueous solution (60%, 334 mL) were added at
7.16 (s, 1H), 7.35 (d, 2H, J¼8.1 Hz), 7.90 (d, 2H, J¼8.1 Hz) ppm. 13C
0 ꢂC under air, and it was stirred for 2 h at room temperature. After
the reaction completed, CH2Cl2 was added to the mixture. The or-
ganic layer was separated and aqueous phase was extracted with
CH2Cl2. The combined extract was dried with Na2SO4 and evapo-
rated. The resulting oily crude product 35a-ClO4 was precipitated by
adding Et2O with stirring. The precipitate was filtered off and dried
in vacuo to give 35a-ClO4 (245 mg, 61%) as a slightly black powder.
NMR (75.3 MHz, CDCl3)
d 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 ppm. Anal. Calcd for
C16H18N2O2S: C, 63.55; H, 6.00; N, 9.26. Found: C, 63.55; H, 5.99;
N, 9.26.
4.6.16. 4-Ethyl-3,5-dimethyl-1-tosylpyrrole-2-carbonitrile
(32j)74. Colorless crystals, mp 153–156 ꢂC (hexane/EtOAc). IR (KBr)
cmꢀ1: 2214. 1H NMR (300 MHz, CDCl3)
d
0.98 (t, 3H, J¼7.5 Hz), 2.13
4.8.1. (3-Methyl-2-thienyl)(phenyl)iodonium trifluoroacetate (35a-
(s, 3H), 2.29 (q, 2H, J¼7.5 Hz), 2.39 (s, 3H), 2.43 (s, 3H), 7.34 (d, 2H,
OCOCF3). A colorless solid, mp 137–139 ꢂC (ether). IR (KBr) cmꢀ1
:
J¼8.1 Hz), 7.85 (d, 2H, J¼8.1 Hz) ppm. 13C NMR (75.3 MHz, CDCl3)
3049,1672,1440,1176, 991, 725. 1H NMR (300 MHz, CDCl3)
d 2.48 (s,
d
10.4, 12.1, 14.4, 17.4, 21.7, 102.1, 112.9, 127.2, 127.7, 130.2, 133.2,
3H), 6.97 (d,1H, J¼5.1 Hz), 7.27–7.43 (m, 2H), 7.49–7.54 (m,1H), 7.61
135.5, 137.5, 145.6 ppm.
(d, 1H, J¼5.1 Hz), 7.90 (dd, 2H, J¼8.4, 0.9 Hz) ppm. 13C NMR
(75.3 MHz, CDCl3)
d 17.3, 99.9, 115.5, 119.4, 130.1, 131.5, 131.8, 133.1,
4.6.17. 3,5-Dimethyl-1-tosylpyrrole-2-carbonitrile (32k). Colorless
crystals, mp 148–151 ꢂC (hexane/EtOAc¼3:1). IR (KBr) cmꢀ1: 2214.
135.6, 148.3, 162.0 ppm. HRMS (FAB) Calcd for C11H10IS
[MꢀOCOCF3]þ 300.9548, found 300.9548.
1H NMR (300 MHz, CDCl3)
d 2.08 (s, 3H), 2.37 (s, 3H), 2.38 (s, 3H),
5.80 (s, 1H), 7.28 (d, 2H, J¼8.4 Hz), 7.80 (d, 2H, J¼8.4 Hz) ppm. 13C
4.8.2. (3-Methyl-2-thienyl)(phenyl)iodonium trifluoromethanesꢀu1l-
:
NMR (75.3 MHz, CDCl3)
d
11.9, 15.0, 21.7, 112.6, 115.0, 127.0, 130.0,
fonate (35a-OTf). A gray solid, mp 128 ꢂC (ether). IR (KBr) cm

10812
T. Dohi et al. / Tetrahedron 65 (2009) 10797–10815
3057, 2924, 1440, 1273, 1161, 1030, 991, 738. 1H NMR (300 MHz,
CDCl3)
2.54 (s, 3H), 7.08 (d, 1H, J¼5.1 Hz), 7.52 (t, 2H, J¼7.8 Hz),
7.67 (t, 1H, J¼7.8 Hz), 7.86 (d, 1H, J¼5.1 Hz), 8.08 (d, 2H, J¼7.8 Hz)
ppm. 13C NMR (100.53 MHz, CDCl3)
17.5, 98.4, 118.5, 121.8 (q,
742. 1H NMR (300 MHz, CDCl3)
d 2.51 (s, 3H), 2.52 (s, 3H), 6.97 (d,
d
1H, J¼5.1 Hz), 7.40 (t, 2H, J¼7.5 Hz), 7.51 (t,1H, J¼7.5 Hz), 7.62 (d,1H,
J¼5.1 Hz), 7.94 (d, 2H, J¼7.5 Hz) ppm. 13C NMR (75.3 MHz, CDCl3)
d
d 17.5, 39.0, 98.3, 1178.0, 129.8, 131.3, 131.5, 133.6, 135.7, 148.4 ppm.
J¼319 Hz), 131.1, 133.2, 133.6, 135.5, 137.8, 150.1 ppm.
HRMS (FAB) Calcd for C11H10IS [MꢀOMs]þ 300.9548, found
300.9550.
4.8.3. (3-Methyl-2-thienyl)(phenyl)iodonium perchlorate (35a-
ClO4). A slightly black solid, mp 148–149 ꢂC (ether). IR (KBr) cmꢀ1
3049, 2912, 1708, 1683, 1562, 1467, 1438, 1375, 1157, 1085, 991, 823,
:
4.9.5. (3-Methyl-2-thienyl)(pheny)iodonium (ꢁ)-10-camphor-sulfo-
nate (35a-OCs). A colorless solid, mp 145 ꢂC (ether). IR (KBr) cmꢀ1
:
746. 1H NMR (300 MHz, DMSO)
d
2.49 (s, 3H), 7.11 (d, 1H, J¼5.4 Hz),
3458, 2956, 1732, 1562, 1469, 1373, 1192, 1051, 918, 732. 1H NMR
(400 MHz, CDCl3) 0.77 (s, 3H), 1.01 (s, 3H), 1.26–1.32 (m, 1H), 1.52–
7.53 (t, 2H, J¼7.5 Hz), 7.67 (t, 1H, J¼7.5 Hz), 7.97 (d, 1H, J¼5.4 Hz),
d
8.18 (d, 2H, J¼7.5 Hz) ppm. 13C NMR (75.3 MHz, DMSO)
d
17.0, 99.8,
1.59 (m,1H),1.83 (d,1H, J¼18.4 Hz),1.89–2.00 (m, 2H), 2.25–2.32 (m,
1H), 2.51(s, 3H), 2.54–2.62(m,1H), 2.68(d,1H,J¼14.8 Hz), 3.21(d,1H,
J¼14.8 Hz), 6.98 (d, 1H, J¼5.2 Hz), 7.40 (t, 2H, J¼8.0 Hz), 7.50 (t, 2H,
J¼8.0 Hz), 7.63 (d,1H, J¼5.2 Hz), 7.96 (d, 2H, J¼8.0 Hz) ppm. 13C NMR
118.7, 129.9, 131.8, 132.0, 134.5, 136.6, 147.7 ppm. HRMS (FAB) Calcd
for C11H10IS [MꢀClO4]þ 300.9548, found 300.9555.
4.8.4. (3-Methyl-2-thienyl)(phenyl)iodonium nitrate (35a-NO3). A
(100.5 MHz, CDCl3) d 17.5, 19.7, 19.9, 24.3, 27.0, 42.6, 42.8, 47.2, 47.7,
yellow solid, mp 151 ꢂC (ether). IR (KBr) cmꢀ1: 3099, 1410, 1300,
58.5, 98.3, 118.6, 130.0, 131.3, 131.6, 133.6, 135.7, 148.7, 217.0 ppm.
HRMS (FAB): Calcd for C11H10IS [MꢀOCs]þ: 300.9548, found
300.9570.
1028, 993, 732. 1H NMR (300 MHz, DMSO)
d 2.49 (s, 3H), 7.10 (d, 1H,
J¼5.4 Hz), 7.53 (t, 2H, J¼7.5 Hz), 7.66 (t, 1H, J¼7.5 Hz), 7.97 (d, 1H,
J¼5.4 Hz), 8.17 (d, 2H, J¼7.5 Hz) ppm. 13C NMR (75.3 MHz, DMSO)
d
17.0, 100.0, 118.9, 129.9, 131.7, 131.9, 134.5, 136.6, 147.5 ppm. HRMS
4.9.6. (3-Isobutyl-2-thienyl)(phenyl)iodonium tosylate (35b-OTs). A
(FAB) Calcd for C11H10IS [MꢀNO3]þ 300.9548, found 300.9550.
colorless amorphous. IR (KBr) cmꢀ1: 3045, 2951, 1464, 1438, 1384,
1190,1132,1045, 912, 815, 731, 696.1H NMR (400 MHz, CDCl3)
d 0.84
4.9. General procedure for the preparation of
diaryliodonium(III) tosylates 35-OTs
(d, 6H, J¼4.8 Hz), 1.86 (m, 1H), 2.33 (s, 3H), 2.62 (d, 2H, J¼4.8 Hz),
6.96 (d, 1H, J¼5.6 Hz), 7.11 (d, 2H, J¼8.4 Hz), 7.36 (t, 2H, J¼8.0 Hz),
7.49 (t,1H, J¼8.0 Hz), 7.63 (d, 2H, J¼8.0 Hz), 7.68 (1H, J¼5.6 Hz), 7.89
To a stirred solution of 3-methylthiophene (98 mg, 1.0 mmol) in
2,2,2-trifluoroethanol (5 mL), [hydroxyl(tosyloxy)iodo]benzene
(392 mg, 1.0 mmol) was added in one portion at room temperature
under air, and it was stirred for 2 h. MeOH was then added to the
reaction mixture when the solvents were removed under vacuum.
The resulting oily crude product 35a-OTs was precipitated by
adding Et2O with stirring. The precipitate was filtered off and dried
in vacuo to give 35a-OTs (396 mg, 84%) as a gray powder.
(d, 2H, J¼8.4 Hz) ppm.13C NMR (100.5 MHz, CDCl3)
d 21.3, 22.2, 29.8,
40.6, 97.5, 118.6, 126.0, 128.7, 129.4, 131.6, 131.8, 133.2, 136.4, 140.0,
141.8,152.8 ppm. HRMS (FAB) Calcd for C14H16IS [M-OTs]þ 343.0017,
found 343.0015.
4.9.7. (3-Cyclohexyl-2-thienyl)(phenyl)iodonium tosylate (35c-
OTs). A colorless solid, mp 128–130 ꢂC (ether). IR (KBr) cmꢀ1: 3053,
2926, 2850, 1564,1469,1440, 1190, 1132, 1045, 991, 914, 815, 732. 1H
NMR (400 MHz, CDCl3)
d 1.22–1.77 (m, 10H), 2.33 (s, 3H), 2.76 (m,
4.9.1. (3-Methyl-2-thienyl)(phenyl)iodonium tosylate (35a-OTs)50b. A
gray solid. Mp 165 ꢂC (ether). IR (KBr) cmꢀ1: 3051, 1575, 1469, 1440,
1377, 1191, 1132, 1045, 1014, 991, 815, 746, 680. 1H NMR (300 MHz,
1H), 6.97 (d, 1H, J¼5.6 Hz), 7.09 (d, 2H, J¼8.0 Hz), 7.35 (t, 2H,
J¼8.0 Hz), 7.48 (t, 1H, J¼8.0 Hz), 7.61 (d, 2H, J¼8.0 Hz), 7.68 (d, 1H,
J¼5.6 Hz), 7.88 (d, 2H, J¼8.0 Hz) ppm. 13C NMR (100.5 MHz, CDCl3)
CD3OD)
d
2.33 (s, 3H), 2.49 (s, 3H), 7.03 (d, 1H, J¼5.1 Hz,), 7.19 (d, 2H,
d 21.3, 25.6, 26.1, 34.1, 42.0, 96.4, 118.9, 126.0, 127.0, 128.7, 131.5,
J¼7.2 Hz), 7.46–7.49 (m, 2H), 7.59–7.67(m, 3H), 7.83 (d, 1H,
131.8, 133.3, 136.6, 139.9, 141.9, 158.4 ppm. HRMS (FAB) Calcd for
J¼5.1 Hz,), 8.05 (d, 2H, J¼7.8 Hz) ppm. 13C NMR (75.3 MHz, CD3OD)
C16H18IS [M-OTs]þ 369.0174, found 369.0165.
d
17.5, 21.3, 98.4, 118.4, 126.9, 129.8, 131.0, 133.0, 133.1, 133.4, 135.4,
137.7, 141.6, 150.0 ppm.
4.9.8. (3-Methoxy-2-thienyl)(phenyl)iodonium tosylate (35d-OTs). A
blue solid, mp 49 ꢂC (ether). IR (KBr) cmꢀ1: 3014, 1554, 1471, 1379,
1217, 1132, 1070, 1043, 1014, 771, 694. 1H NMR (300 MHz, CD3OD)
4.9.2. (3-Methyl-2-thienyl)(2,4,6-trimethylphenyl)iodonium tosylate
(36a-OTs). A colorless solid, mp 145 ꢂC (ether). IR (KBr) cmꢀ1
:
d
2.35 (s, 3H), 4.02 (s, 3H), 7.08 (d, 1H, J¼6.0 Hz), 7.21 (d, 2H,
3637, 3466, 3061, 2953, 1923, 1600, 1450, 1377, 1300, 1215, 1132,
J¼7.8 Hz), 7.46–7.51 (m, 2H), 7.61–7.69 (m, 3H), 7.97 (d, 1H,
1043, 815, 758. 1H NMR (300 MHz, CDCl3)
d
2.27 (s, 3H), 2.30 (s, 3H),
J¼6.0 Hz), 8.03 (d, 2H, J¼7.8 Hz) ppm. 13C NMR (75.5 MHz, CD3OD)
2.47 (s, 3H), 2.67 (s, 6H), 6.84 (d, 1H, J¼5.4 Hz), 6.93 (s, 2H), 7.00 (d,
d 21.3, 60.4, 77.4, 116.5, 118.7, 126.9, 129.8, 133.0, 133.4, 135.5, 138.7,
2H, J¼7.8 Hz), 7.40 (d, 2H, J¼7.8 Hz), 7.48 (d, 1H, J¼5.4 Hz) ppm. 13C
141.6, 143.6, 165.1 ppm. HRMS (FAB): Calcd for C11H10IOS [M-OTs]þ:
316.9497, found 316.9504.
NMR (75.3 MHz, CDCl3)
d 17.7, 20.9, 21.2, 27.1, 96.9, 125.8, 126.4,
128.3, 129.6, 129.7, 134.3, 139.2, 141.2, 142.3, 143.1, 147.2 ppm. HRMS
(FAB): Calcd for C14H16IS [MꢀOTs]þ: 343.0017, found 343.0026.
4.9.9. (3-Bromo-2-thienyl)(phenyl)iodonium tosylate (35e-OTs). A
colorless solid, mp 49 ꢂC (ether). IR (KBr) cmꢀ1: 3045, 1562, 1469,
1438, 1373, 1330, 1191, 1130, 1043, 1014, 860, 815, 740, 692. 1H NMR
4.9.3. (3-Methyl-2-thienyl)(pentafluorophenyl)iodonium tosylate
(37a-OTs). A colorless solid, mp 140–141 ꢂC (ether). IR (KBr) cmꢀ1
:
(300 MHz, CD3OD) d 2.35 (s, 3H), 7.19–7.24 (m, 3H), 7.53 (t, 2H,
3091, 1633, 1487, 1390, 1195, 1078, 974, 908, 815, 756, 696. 1H NMR
(300 MHz, CDCl3)
2.35 (s, 3H), 2.49 (s, 3H), 6.81 (d, 1H, J¼5.4 Hz),
7.08 (d, 2H, J¼7.8 Hz), 7.37 (d, 2H, J¼7.8 Hz), 7.46 (d, 1H, J¼5.4 Hz)
ppm.13C NMR (75.3 MHz, CDCl3)
17.5, 21.2, 93.7,100.0,125.7,128.6,
J¼7.8 Hz), 7.67 (d, 3H, J¼7.8 Hz), 7.98 (d, 1H, J¼5.7 Hz), 8.16 (d, 2H,
d
J¼7.8 Hz) ppm. 13C NMR (75.5 MHz, CD3OD)
d 21.3, 119.2, 125.6,
126.9, 129.8, 132.1, 133.2, 133.9, 135.9, 139.8, 141.4, 141.7, 143.5 ppm.
HRMS (FAB): Calcd for C10H7BrIS [MꢀOTs]þ: 364.8497, found
364.8501.
d
129.4, 135.5, 138.0, 140.4, 140.6, 144.3, 146.8, 149.1 ppm. HRMS
(FAB): Calcd for C11H5F5IS [MꢀOTs]þ: 390.9077, found 390.9095.
4.9.10. [3-(4-Methoxycarbonyl)phenyl-2-thienyl](phenyl)-iodonium
tosylate (35f-OTs). A yellow solid, mp 126–128 ꢂC (ether). IR (KBr)
cmꢀ1: 3051, 1722, 1608, 1438, 1280, 1188, 1116, 1045, 1016, 912, 734.
4.9.4. (3-Methyl-2-thienyl)(phenyl)iodonium methanesulfonate (35a-
OMs). A colorless solid, mp 144 ꢂC (ether). IR (KBr) cmꢀ1: 3047,
1562, 1525, 1469, 1440, 1377, 1327, 1222, 1053, 991, 912, 825, 785,
1H NMR (400 MHz, CDCl3)
d 2.30 (s, 3H), 3.98 (s, 3H), 7.03 (d, 2H,

T. Dohi et al. / Tetrahedron 65 (2009) 10797–10815
10813
Ochiai, M.; Zhdankin, V. V.; Koser, G. F.; Tohma, H.; Kita, Y. Top. Curr. Chem.: Hy-
pervalent Iodine ChemistrydModern Developments in Organic Synthesis; Springer:
Berlin, 2003; (h) Tohma, H.; Kita, Y. Adv. Synth. Catal. 2004, 346, 111; (i) Moriarty,
R. M. J. Org. Chem. 2005, 70, 2893; (j) Wirth, T. Angew. Chem., Int. Ed. 2005, 44,
3656; (k) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299; (l) Ochiai, M.
Synlett 2009, 159; (m) Dohi, T.; Kita, Y. Chem. Commun. 2009, 2073.
2. For reviews, see: (a) Tohma, H.; Kita, Y. Top. Curr. Chem. 2003, 224, 209; (b)
Ciufolini, M. A.; Braun, N. A.; Canesi, S.; Ousmer, M.; Chang, J.; Chai, D. Synthesis
2007, 3759; (c) Quideau, S.; Pouysegu, L.; Deffieux, D. Synlett 2008, 467; (d)
Nicolaou, K. C.; Chen, J. S.; Edmonds, D. J.; Estrada, A. A. Angew. Chem., Int. Ed.
2009, 48, 660.
3. (a) Tamura, Y.; Yakura, T.; Haruta, J.; Kita, Y. J. Org. Chem. 1987, 52, 3927; (b) Kita,
Y.; Tohma, H.; Kikuchi, K.; Inagaki, M.; Yakura, T. J. Org. Chem. 1991, 56, 435; (c)
Tamura, Y.; Yakura, T.; Tohma, H.; Kikuchi, K.; Kita, Y. Synthesis 1989, 126; (d)
Kita, Y.; Yakura, T.; Tohma, H.; Kikuchi, K.; Tamura, Y. Tetrahedron Lett. 1989, 30,
1119; (e) Kita, Y.; Tohma, H.; Inagaki, M.; Hatanaka, K.; Kikuchi, K.; Yakura, T.
Tetrahedron Lett. 1991, 32, 2035; (f) Kita, Y.; Takada, T.; Ibaraki, M.; Gyoten, M.;
Mihara, S.; Fujita, S.; Tohma, H. J. Org. Chem. 1996, 61, 223; (g) Kita, Y.; Arisawa,
M.; Gyoten, M.; Nakajima, M.; Hamada, R.; Tohma, H.; Takada, T. J. Org. Chem.
1998, 63, 6625.
J¼7.6 Hz), 7.09 (d, 1H, J¼5.6 Hz), 7.18 (t, 2H, J¼7.6 Hz), 7.39 (t, 1H,
J¼7.6 Hz), 7.49 (m, 6H), 7.72 (d, 1H, J¼5.6 Hz), 8.08 (d, 2H, J¼7.6 Hz)
ppm. 13C NMR (100.5 MHz, CDCl3)
d 21.3, 52.3, 99.7, 118.9, 120.1,
126.0, 128.6, 129.2, 130.2, 130.5, 131.3, 131.4, 133.9, 136.3, 138.7,
140.1, 141.4, 150.4, 166.5 ppm. HRMS (FAB) Calcd for C18H14IO2S
[MꢀOTs]þ 420.9759, found 420.9778.
4.9.11. (5-Methyl-2-thienyl)(phenyl)iodonium tosylate (35g-OTs). A
brown solid, mp 89–92 ꢂC (ether). IR (KBr) cmꢀ1: 3053, 1440, 1193,
1128, 1039, 1012, 817, 792, 738, 680. 1H NMR (400 MHz, CDCl3)
d
2.30 (s, 3H), 2.51 (s, 3H), 6.65 (d, 1H, J¼3.6 Hz), 7.05 (d, 2H,
J¼8.4 Hz), 7.30 (t, 2H, J¼8.0 Hz), 7.46 (t, 1H, J¼8.0 Hz), 7.54 (d, 2H,
J¼8.4 Hz), 7.64 (d, 1H, J¼3.6 Hz), 7.93 (d, 2H, J¼8.0 Hz) ppm. 13C
NMR (100.5 MHz, CDCl3) d 15.4, 21.3, 93.5, 118.3, 126.0, 128.1, 128.7,
131.5, 131.6, 134.0, 140.3, 140.9, 141.7, 152.2 ppm. HRMS (FAB) Calcd
for C11H10S [MꢀOTs]þ 300.9548, found 300.9548.
4. (a) Callinan, A.; Chen, Y.; Morrow, G. W.; Swenton, J. S. Tetrahedron Lett. 1990, 31,
4551; (b) Mizutani, H.; Takayama, J.; Honda, T. Tetrahedron Lett. 2002, 43, 2411; (c)
ˆ
ˆ
ˆ
ˆ
`
SzaAntay, C.; BlaskoA, G.; BaArczai-Beke, M.; PeAchy, P.; DoErnyei, G. Tetrahedron
Lett.1980, 21, 3509; (d) White, J. D.; Chong, W. K. M.; Thirring, K. J. Org. Chem.1983,
48, 2300; (e) Lewis, N.; Wallbank, P. Synthesis 1987, 1103; (f) Rama Krishna, K. V.;
Sujatha, K.; Kapil, R. S. Tetrahedron Lett.1990, 31,1351; (g) Gates, B. D.; Dalidowicz,
P.; Tebben, A.; Wang, S.; Swenton, J. S. J. Org. Chem. 1992, 57, 2135; (h) Murakata,
M.; Tamura, M.; Hoshino, O. J. Org. Chem.1997, 62, 4428; (i) Pelter, A.; Hussain, A.;
Smith, G.; Ward, R. S. Tetrahedron 1997, 53, 3879; (j) Sabot, C.; Commare, B.;
Duceppe, M.-A.; Nahi, S.; Guerard, K. C.; Canesi, S. Synlett 2008, 3226; (k) Sabot, C.;
Guerard, K. C.; Canesi, S. Chem. Commun. 2009, 2941; (l) Sabot, C.; Berard, D.;
Canesi, S. Org. Lett. 2008,10, 4629; (m) Guerard, K. C.; Sabot, C.; Racicot, L.; Canesi,
S. J. Org. Chem. 2009, 74, 2039.
4.9.12. (7-Methoxycarbonyl-2,3-dihydro-thieno[3,4-b][1,4]dioxin-5-
yl)(phenyl)iodonium tosylate (35h-OTs). A colorless solid, mp 169 ꢂC
(ether). IR (KBr) cmꢀ1: 3520, 3051, 2949,1712,1573,1487,1444,1359,
1274, 1193, 1089, 912, 740. 1H NMR (400 MHz, CDCl3)
d 2.31 (s, 3H),
3.83 (s, 3H), 4.28–4.32 (m, 4H), 7.02 (d, 2H, J¼7.6 Hz), 7.32 (t, 2H,
J¼7.6 Hz), 7.45 (m, 3H), 7.96 (d, 2H, J¼7.6 Hz) ppm. 13C NMR
(100.53 MHz, CDCl3)
d 21.2, 52.2, 65.0, 65.1, 83.8, 99.9, 116.0, 118.6,
125.8, 128.4, 131.4, 134.5, 139.7, 141.9, 144.1, 146.4, 160.2 ppm. HRMS
(FAB): Calcd for C14H12IO4S [MꢀOTs]þ: 402.9501, found 402.9508.
5. (a) Lewis, N.; Wallbank, P. Synthesis 1987, 1103; (b) Pelter, A.; Elgendy, S. Tetra-
hedron Lett.1988, 29, 677; (c) Pelter, A.; Elgendy, S. M. A. J. Chem. Soc., PerkinTrans.
1 1993, 1891; (d) Mitchell, A. S.; Russell, R. A. Tetrahedron Lett. 1993, 34, 545; (e)
Rama Rao, A. V.; Gurjar, M. K.; Sharma, P. A. Tetrahedron Lett. 1991, 32, 6613; (f)
Wipf, P.; Kim, Y. Tetrahedron Lett.1992, 33, 5477; (g) Hara, H.; Inoue, T.; Nakamura,
H.; Endoh, M.; Hoshino, O. Tetrahedron Lett. 1992, 33, 6491; (h) McKillop, A.;
4.9.13. (2,5-Dimethyl-3-thienyl)(phenyl)iodonium tosylate (35i-
OTs). A colorless solid, mp 111–112 ꢂC (ether). IR (KBr) cmꢀ1: 3539,
3047, 2918, 1562, 1469, 1193, 1132, 1045, 912, 815, 740. 1H NMR
¨
McLaren, L.; Taylor, R. J. K. J. Chem. Soc., Perkin Trans. 11994, 2047; (i) KacEan, M.;
(400 MHz, CDCl3)
d 2.31 (s, 3H), 2.36 (s, 3H), 2.52 (s, 3H), 6.87 (s,
Koyuncu, D.; McKillop, A. J. Chem. Soc., PerkinTrans.11993,1771; (j) Murakata, M.;
Yamada, K.; Hoshino, O. J. Chem. Soc., Chem. Commun. 1994, 443.
6. (a) Karam, O.; Jacquesy, J.-C.; Jouannetaud, M.-P. Tetrahedron Lett. 1994, 35, 2541
application to sulfonamide; (b) Basset, L.; Martin-Mingot, A.; Jouannetaud, M.-
P.; Jacquesy, J.-C. Tetrahedron Lett. 2008, 49, 1551.
7. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155; (b) Dess, D. B.; Martin, J.
C. J. Am. Chem. Soc. 1991, 113, 7277; (c) Hartmann, C.; Meyer, V. Chem. Ber. 1893,
26, 1727; (d) Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J. Org.
Chem. 1995, 60, 7272.
1H), 7.04 (d, 2H, J¼8.0 Hz), 7.31 (t, 2H, J¼7.6 Hz), 7.44 (t, 1H,
J¼7.6 Hz), 7.50 (d, 2H, J¼8.0 Hz), 7.84 (d, 2H, J¼7.6 Hz) ppm. 13C
NMR (100.5 MHz, CDCl3)
d 15.2, 17.0, 21.2, 99.6, 115.9, 125.9, 128.4,
129.5, 131.0, 131.4, 133.9, 139.3, 141.2, 142.6, 145.5 ppm. HRMS
(FAB): Calcd for C12H12IS [MꢀOTs]þ: 314.9704, found 314.9703.
4.9.14. Phenyl(4-trimethylsilyl-2-thienyl)iodonium tolsylate (35j-
OTs). A colorless solid, mp 121 ꢂC (ether). IR (KBr) cmꢀ1: 3051,
2954, 1566, 1469, 1440, 1253, 1199, 1132, 1103, 1043, 1014, 991, 883,
8. See Ref. 1h and other reviews: (a) Wirth, T. Angew. Chem., Int. Ed. 2001, 40, 2812;
(b) Nicolaou, K. C.; Mathison, C. J. N. Angew. Chem., Int. Ed. 2005, 44,
Ladziata, U.; Zhdankin, V. V. ARKIVOC 2006, 9, 26.
5992; (c)
9. (a) Moriarty, R. M.; Prakash, O. Acc. Chem. Res. 1986, 19, 244; (b) Ligand Cou-
pling Reaction with Heteroatomic Compounds; Finet, P., Ed.Tetrahedron Organic
Chemistry Series; Pergamon: Oxford, 1998; Vol. 18; (c) Ozanne-Beaudenon,
A.; Quideau, S. Angew. Chem., Int. Ed. 2005, 44, 7065 and references cited
therein.
10. (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.; Takada, T.;
Mihara, S.; Tohma, H. Synlett 1995, 211; (d) Kita, Y.; Takada, T.; Mihara, S.;
Whelan, B. A.; Tohma, H. J. Org. Chem. 1995, 60, 7144; (e) Arisawa, M.; Ramesh,
N. G.; Nakajima, M.; Tohma, H.; Kita, Y. J. Org. Chem. 2001, 66, 59; (f) Kita, Y.;
Takada, T.; Tohma, H. Pure Appl. Chem. 1996, 68, 627.
842, 750, 680. 1H NMR (300 MHz, CDCl3)
d 0.32 (s, 9H), 2.40 (s, 3H),
7.26 (d, 2H, J¼7.8 Hz), 7.54 (t, 2H, J¼7.5 Hz), 7.67–7.74 (m, 3H), 7.99
(s, 1H), 8.11 (s, 1H), 8.19 (d, 2H, J¼7.8 Hz) ppm. 13C NMR (75.5 MHz,
CD3OD)
d
ꢀ0.59, 21.6, 119.1, 127.2, 130.1, 133.4, 133.9, 136.1, 136.4,
141.9, 143.8, 144.4, 146.5, 147.0 ppm. HRMS (FAB): Calcd for
C13H16ISSi [MþH]þ: 358.9781, found 358.9792.
Acknowledgements
11. (a) Kita, Y.; Egi, M.; Ohtsubo, M.; Saiki, T.; Takada, T.; Tohma, H. Chem. Commun.
1996, 2225; (b) Kita, Y.; Gyoten, M.; Ohtsubo, M.; Tohma, H.; Takada, T. Chem.
Commun.1996, 1481; (c) Takada, T.; Arisawa, M.; Gyoten, M.; Hamada, R.; Tohma,
H.; Kita, Y. J. Org. Chem. 1998, 63, 7698; (d) Arisawa, M.; Utsumi, S.; Nakajima, M.;
Ramesh, N. G.; Tohma, H.; Kita, Y. Chem. Commun. 1999, 469; (e) Tohma, H.;
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M.; Saiki, T.; Okajima, A.; Takada, T.; Tohma, H. Chem. Pharm. Bull. 1999, 47, 241.
13. (a) Hamamoto, H.; Anilkumar, G.; Tohma, H.; Kita, Y. Chem. Commun. 2002, 450;
(b) Hamamoto, H.; Anilkumar, G.; Tohma, H.; Kita, Y. Chem.dEur. J. 2002, 8,
5377; (c) Hamamoto, H.; Shiozaki, Y.; Hata, K.; Tohma, H.; Kita, Y. Chem. Pharm.
Bull. 2004, 52, 1231; (d) Hamamoto, H.; Shiozaki, Y.; Nambu, H.; Hata, K.;
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Shiozaki, Y.; Kita, Y. Chem. Commun. 2005, 2465.
This work was partially supported by a Grant-in-Aid for Scien-
tific Research (S and A) and for Young Scientists (B), and a grant for
Scientific Research on Priority Areas ‘Advanced Molecular Trans-
formations of Carbon Resources’ from the Ministry of Education,
Culture, Sports, Science and Technology, Japan. T.D. also acknowl-
edges support from the Industrial Technology Research Grant
Program from the New Energy and Industrial Technology De-
velopment Organization (NEDO) of Japan. M.I. thanks research
fellowship of J.S.P.S. for Young Scientists.
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