Cyclic Vinyl(aryl)iodonium Salts: Synthesis and Reactivity

Article abstract of DOI:10.1021/acs.orglett.9b02540

A convenient, highly regioselective synthesis of five-membered cyclic vinyl(aryl)iodonium salts directly from β-iodostyrenes is presented. An X-ray crystal structure confirms the identity of these heterocycles. These λ³-iodanes can be converted

Full text of DOI:10.1021/acs.orglett.9b02540

Letter
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Cyclic Vinyl(aryl)iodonium Salts: Synthesis and Reactivity
Konrad Kepski, Craig R. Rice, and Wesley J. Moran*
Department of Chemistry, University of Huddersfield, Queensgate, Huddersfield HD1 3DH, U.K.
S
* Supporting Information
ABSTRACT: A convenient, highly regioselective synthesis of
five-membered cyclic vinyl(aryl)iodonium salts directly from
β-iodostyrenes is presented. An X-ray crystal structure
confirms the identity of these heterocycles. These λ3-iodanes
can be converted rapidly into functionalized arylacetylenes by
treatment with mild base or undergo SNV reactions with
nonbasic nucleophiles.
iodonium salts have received much less attention than
ypervalent iodine compounds continue to attract
Hattention from the synthetic chemistry community diaryliodonium salts,13 and the corresponding five-membered
cyclic vinyl(aryl)iodonium salts have received almost no
attention at all. In 1972, Beringer reported the synthesis of
one example in 15% yield by the low-temperature addition of
butyllithium to diphenylacetylene followed by addition to
trans-2-chlorovinyliododichloride (Figure 1b).14 Notably, they
obtained a single-crystal X-ray structure of this intriguing λ3-
iodane. We predicted that a general, facile access to five-
membered cyclic vinyl(aryl)iodonium salts could be revealed
by the oxidation of cis-β-iodostyrenes (Figure 1c). It was
envisaged that a simple preparation of these λ3-iodanes would
open up their use to scientists in various disciplines.15
It was anticipated that cis-β-iodostyrene 2a would be
converted into the cyclic iodonium salt 3a upon addition of
an oxidant employing experimental conditions similar to those
reported for the preparation of other λ3-iodanes. Iodide 2a was
readily prepared in one step from benzaldehyde using a Wittig
reaction, and the conversion of this into 3a was investigated
(Table 1). Pleasingly, stirring 2a in dichloromethane at 0 °C
with m-CPBA and triflic acid led to cyclic iodonium salt
formation (entry 1); however, the yield was suboptimal.
Increasing the amount of oxidant and acid did not lead to an
improvement in yield (entry 2). Lowering the temperature of
the reaction vessel to −10 and −78 °C led to a diminishment
in yield in each case (entries 3 and 4). Allowing the reaction to
occur at room temperature resulted in an increase in yield to
48% (entry 5), but a further increase to 40 °C had a
detrimental effect (entry 6). Changing solvent to 1,2-
dichloroethane or ethyl acetate led to poorer yields (entries
8 and 9); however, acetonitrile was found to give superior
results (entry 10). Finally, reducing the amount of acid gave a
slightly diminished yield (entry 11). In addition, replacing
trifluoromethanesulfonic acid with trifluoroacetic acid or p-
toluenesulfonic acid did not lead to any isolable λ3-iodanes.
With our optimized conditions in hand, we looked at the
scope of this reaction with a range of substituted cis-β-
because of their useful, often novel, reactivity and their
relatively environmentally benign nature.1 Iodonium salts are a
class of hypervalent iodine compounds that have found
applications in synthesis2 as well as in positron emission
tomography,3 in pharmaceutical applications,4 and as radical
initiators.5 As such, investigations into new iodonium salts and
of novel reactivity with iodonium salts are worthwhile
endeavors.
Diaryliodonium salts have commanded the majority of
attention in this field,6 and in recent years, five-membered
cyclic diaryliodonium salts have appeared as reagents and,
more recently, as halogen-bonding organocatalysts (Figure
1a).7 Their transformation into a range of useful heterocycles,8
carbocycles,9 and other molecules is testament to their
synthetic utility.10 The simplest example, dibenziodolium
chloride 1 (a.k.a. diphenyleneiodonium chloride or DPI), has
found wide application in biological studies as it exhibits
potent activity as, for example, a NADPH oxidase inhibitor11
and as a hypoglycaemic agent.12 In contrast, vinyl(aryl)-
Received: July 21, 2019
Figure 1. Synthetic approaches to cyclic iodonium salt formation.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02540
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Table 1. Optimization Studies on the Formation of Cyclic
Vinyl(aryl)iodonium Salt 3a
Scheme 1. Formation of Cyclic Vinyl(aryl)iodonium Salts 3
entry
n
m
solvent
T (°C)
yield (%)
1
2
3
4
5
6
7
8
1.4
2.1
1.4
1.4
1.4
1.4
1
1
1
1
1
2
3
2
2
2
2
2
3
3
3
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1,2-DCE
EtOAc
0
0
−10
−78
20
40
20
20
20
27
25
17
4
48
38
21
31
14
53
45
9
10
11
MeCN
MeCN
20
20
iodostyrenes 2 (Scheme 1). The alkenes obtained from the
Wittig reaction contained up to 10% of the trans-isomers, but
these isomeric mixtures were subjected directly to the reaction
conditions and the iodonium salts obtained were pure. Methyl-
substituted substrates 2b, 2c, and 2d led to clean conversion to
the iodonium salts in all cases, and importantly, only one
regioisomer of 3c was observed. m-Methoxy-bearing substrate
2f was converted into 3f selectively as one regioisomer.
Notably, this is not the same regioisomer obtained with 2c.
However, the presence of the o- or p-methoxy substituents in
2e and 2g led to rapid decomposition of the iodanes at room
temperature, and no identifiable compounds could be isolated.
Piperonal-derived iodide 2h could be converted to iodane 3h
and isolated. The presence of the strongly electron-with-
drawing trifluoromethyl group in 2i led to regioselective
formation of 3i. Styrene 2j with a m-fluoro group also cyclized
to one regioisomer of product, 3j, in the same fashion as 2f.
Styrene 2k with an m-chloro substituent also cyclized para to
the chlorine in an analogous fashion to 2f. In this case, a very
small amount of the alternative regioisomer could be observed
in the NMR spectrum (ca. 32:1 relative ratio). Cyclization of
naphthyl substrate 2l occurred preferentially at C1 with no
trace of the other regioisomer. Introduction of substituents on
the alkene were also tolerated, and λ3-iodanes 3m, 3n, and 3o
were readily prepared.
The yields quoted here are reproducible in our hands;
however, changes to the standard reaction conditions can lead
to augmented or diminished yields which differ from substrate
to substrate. For example, increased reaction times lead to
lower yields for some substrates but higher yields for others.
These λ3-iodanes typically precipitate out of solution as
powders or very fine crystals, however, crystals suitable for X-
ray diffraction were obtained for 3a after some experimentation
(Figure 2).16 In accord with related examples, the crystal
structure indicates that the whole molecule is not aromatic and
exists as a dimer in the solid state with two loosely bound
triflate anions binding together the two iodine(III) centers.14
The CC bond is 1.34 Å, which is typical for an alkene. The
adjacent C(6)−C(7) bond is slightly short at 1.45 Å,
compared to 1.54 Å for a typical single bond, but is longer
that the phenyl aromatic bonds which are between 1.38 and
1.40 Å.
Figure 2. Crystal structure of 3a showing the dimeric nature of the
cyclic iodonium salt. Selective distances and angles: C(1)−I(1) =
2.085 Å, C(8)−I(1) = 2.063 Å, C(7)−C(8) = 1.340 Å, C(2)−C(7) =
1.451 Å, C(1)−I(1)−C(8) = 82.5°, I(I)−C(8)−C(7)−H(7) =
179.93°.
The isolated λ3-iodanes are stable and can be stored at room
temperature under air without any signs of decomposition for
B
DOI: 10.1021/acs.orglett.9b02540
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Letter
several weeks at least. However, treatment with base leads to
facile conversion into the alkynes (Scheme 2). In all cases,
Scheme 3. Effect of C2 and C3 Substitution on Alkyne
formation
Scheme 2. Conversion of Cyclic Vinyl(aryl)iodonium Salts
3 into Alkynes 4
alkyne 4m must proceed through α-elimination via formation
of a vinylidene intermediate followed by aryl migration, and
this is a slower process.
Another useful reactivity of vinyliodonium salts is the
vinylation of nucleophiles.23 Accordingly, treatment of 3a with
weakly basic tetrabutylammonium iodide and bromide led to
conversion to the trans-haloalkenes 5 and 6, respectively, with
no evidence of cis-alkene or alkyne formation by NMR analysis
of the crude reaction mixtures (Scheme 4). It is likely that this
is an example of an SNV process due to the powerful leaving
group ability of the iodine moiety.24
complete conversion was observed in moments as the poorly
soluble iodonium salts were converted into the perfectly
soluble products. Triethylamine was found to be an
appropriate base for this process, while pyridine was
completely ineffective. This elimination is known with acyclic
vinyl(aryl)iodonium salts;17 however, with these cyclic salts the
iodine atom is not lost as it remains attached to the aromatic
ring within the products. This two-step process from β-
halostyrenes into arylacetylenes via the iodonium salt is fast
and efficient. Literature methods for the conversion of β-
halostyrenes into arylacetylenes typically require treatment
with strong bases, such as sodamide or LiHMDS,18 although
weaker bases such as potassium tert-butoxide in THF,19
DBU,20 and tetrabutylammonium fluoride21 have also been
shown to be effective. Critically, the halide is lost from the
molecule in these examples. Phenylacetylene derivatives are
extremely useful compounds, and our method allows rapid
access into a range of novel examples ready for cross-coupling
at two or more positions.
Scheme 4. Stereoselective Ring-Opening of Cyclic Iodane
The facile preparation of cyclic vinyl(aryl)iodonium salts is
presented. These λ3-iodanes can be converted into substituted
phenylacetylenes upon treatment with base or undergo SNV
reactions with nonbasic nucleophiles. Future work in our
laboratory will concentrate on developing new reactions with
these cyclic λ3-iodanes.
ASSOCIATED CONTENT
* Supporting Information
■
λ3-Iodanes 3m and 3o contain a substituent at positions 2
and 3, respectively, which could act as a blocking group
preventing conversion to the alkyne. Research with acyclic
vinyliodonium salts reported by Ochiai and co-workers
suggests that removal of the proton at either C2 or C3 is
possible but that the former is preferred.17 In our hands, λ3-
iodane 3m with a phenyl substituent at C3 underwent
incomplete conversion to alkyne 4m after 1 h upon treatment
with base in solvent (Scheme 3). Conversely, λ3-iodane 3o
with a methyl group at C2 underwent spontaneous conversion
to alkyne 4o upon standing in various solvents, including
acetone and methanol, without addition of any base being
necessary. Unsurprisingly, treatment of 3o under our standard
conditions resulted in very rapid conversion to 4o.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02540.
Experimental procedures, characterization data, and
NMR spectra of novel compounds (PDF)
Accession Codes
CCDC 1908034 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
These results suggest that an E2 elimination process is the
preferred mechanistic route to the alkyne. Indeed, the I(I)−
C(8)−C(7)−H(7) dihedral angle is 180°; i.e., it is in perfect
alignment for the elimination. Calculations by Apeloig and co-
workers have shown that a methyl group significantly stabilizes
a vinyl cation;22 therefore, the methyl in 3o speeds up the
elimination to 4o by stabilization of developing positive charge
in the transition state. Conversion of compound 3m into
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: w.j.moran@hud.ac.uk.
ORCID
Craig R. Rice: 0000-0002-0630-4860
Wesley J. Moran: 0000-0002-5768-3629
C
DOI: 10.1021/acs.orglett.9b02540
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
(e) Liu, C.; Zhang, W.; Dai, L.-X.; You, S.-L. Org. Lett. 2012, 14,
4525.
(16) Deposition of data at CCDC: 1908034.
Notes
The authors declare no competing financial interest.
(17) Ochiai, M.; Takaoka, Y.; Nagao, Y. J. Am. Chem. Soc. 1988, 110,
6565.
ACKNOWLEDGMENTS
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We thank the University of Huddersfield for funding, Dr. Neil
McLay (University of Huddersfield) for assistance with NMR
spectroscopy, and Dr. Robert Faulkner (University of
Huddersfield) for assistance with recrystallization.
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