New highly soluble dimedone-derived iodonium ylides: Preparation, X-ray structure, and reaction with carbodiimide leading to oxazole derivatives

Article abstract of DOI:10.1039/c2cc35708a

Highly soluble dimedone-derived o-alkoxyphenyliodonium ylides have been prepared and characterized by single crystal X-ray diffraction. These new iodonium ylides are useful reagents for the preparation of oxazole derivatives by reaction with carbodiimides. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc35708a

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New highly soluble dimedone-derived iodonium ylides: preparation, X-ray
structure, and reaction with carbodiimide leading to oxazole derivativesw
Chenjie Zhu,ab Akira Yoshimura,a Pavlo Solntsev,a Lei Ji,a Yunyang Wei,b
Victor N. Nemykin*a and Viktor V. Zhdankin*a
Received 6th August 2012, Accepted 24th August 2012
DOI: 10.1039/c2cc35708a
Highly soluble dimedone-derived o-alkoxyphenyliodonium ylides have
been prepared and characterized by single crystal X-ray diffraction.
These new iodonium ylides are useful reagents for the preparation of
oxazole derivatives by reaction with carbodiimides.
Surprisingly, to the best of our knowledge, there were no
reports on the reaction of ylide 1 with carbodiimides, which
seems ideal to provide a method for the synthesis of the
previously unknown oxazoles 2.
Herein, we report the design, preparation, structural investiga-
tion, and reactivity of new highly soluble dimedone-derived
o-alkoxyphenyliodonium ylides and their reactions with carbo-
diimide leading to the oxazole derivatives 2. Initial experiments
were carried out using the known ylide 1 and diisopropylcarbo-
diimide (DIC) as a model substrate. A strong solvent dependence
was observed in this reaction. Numerous solvents including
CH2Cl2, CHCl3, PhH, PhF, PhCl, PhMe, 4-MeC6H4F, hexafluoro-
benzene, nitromethane, dimethoxyethane, tetrachloroethane,
pentane, hexane, TFE (trifluoroethanol), and HFIP (hexafluoro-
isopropanol) were tested (see for details Table S1 in ESIw). All
these solvents were found to be unacceptable choices for this
reaction because of the low reactant or catalyst solubility,
formation of byproducts, and overall low yields of product 2.
Among all the solvent we tested, PhCF3 was the optimal, giving
the highest yield of product 2 (up to 62%) and the lowest yield of
byproducts. Further optimization of this reaction was limited by
the insolubility of ylide 1 in aromatic solvents, particularly in
PhCF3, resulting in heterogeneous reaction conditions. Recently,
we have found that the solubility and reactivity of a noncyclic
iodonium ylide, PhIC(CO2CH3)2, can be significantly improved
by the introduction of an o-alkoxy group into the phenyl ring of
the phenyliodonium moiety.12 Based on this work, we attempted
to synthesize a modified, o-alkoxy-substituted ylide 1, in order to
improve its solubility in aromatic hydrocarbons and other
common organic solvents.
Within the rapidly growing field of hypervalent iodine reagents,1
phenyliodonium ylides2 occupy an important place as efficient
carbene precursors and safe alternative to the diazo compounds.3
Particularly useful is 5,5-dimethyl-1,3-cyclohexanedione phenyl-
iodonium ylide 1 (Scheme 1), a relatively stable iodonium ylide
synthesized by condensation of PhI(OAc)2 with dimedone under
basic conditions.4 Under catalytic, thermal, or photochemical
conditions, ylide 1 serves as an excellent carbenoid precursor;5
the transfer of such a carbenoid moiety to a suitable acceptor
has found wide application in the synthesis of 5-membered
cycles or heterocycles (Scheme 1). Cycloadditions are typically
observed in the reactions of ylide 1 with acetylenes,6 ketenes,4a
nitriles,6,7 isocyanates,4a,8 isothiocyanates,9 thiones,10 and dienes.11
The o-alkoxyphenyliodonium dimedonide ylides 5a–d were
synthesized according to the procedure shown in Scheme 2.
Reaction of commercially available 2-iodophenol with appropriate
alkyl bromide or alkyl iodide afforded 2-iodophenol ethers 3a–d in
excellent yields (Scheme 2). Subsequent oxidation to diacetoxyiodo
derivatives 4a–d was accomplished using freshly prepared peracetic
acid. Finally, diacetates 4a–d were converted to o-alkoxyphenyl-
iodonium dimedonides 5a–d by treatment with dimedone under
basic conditions (Scheme 2). Products 5 are quite stable and can be
stored at room temperature for several months without any
degradation. More important from the point of view of applica-
tion, ylides 5a–d all have good solubility in common organic and
aromatic solvents (e.g. the solubility of 5b in PhCF3 is 0.67 g mLÀ1).
Scheme 1 Reactions of ylide 1.
a Department of Chemistry and Biochemistry, University of Minnesota
Duluth, Duluth, USA. E-mail: vzndanki@d.umn.edu
b School of Chemical Engineering, Nanjing University of Science and
Technology, Nanjing 210094, China
w Electronic supplementary information (ESI) available: Full experi-
mental details and spectral data of all compounds. CCDC
894817–894819 (2b, 5a, and 5b). For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c2cc35708a
c
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Chem. Commun.

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Table 1 Comparison of reactivity of ylides 5b and 1 in the reaction
with DICa
Scheme 2 Reaction conditions: (a) RBr or RI, K2CO3, DMF, 50 1C
(88–95%). (b) AcOOH–AcOH (57–84%). (c) Dimedone, KOH,
MeOH, 0 1C (82–93%).
Entry Reagent Catalyst
Temp (1C) Time (h) Yieldb (%)
1
2
3
4
5
6
7
8
9
5b
1
5b
1
5b
5b
5b
5b
1
Rh2(OAc)4 80
Rh2(OAc)4 80
Rh2(OAc)4 r.t.
Rh2(OAc)4 r.t.
Cu(OTf)2
CuOTfd
BF3ÁEt2O
Cu(acac)2
Cu(acac)2
0.5
3
79
62
Given all that, the modified new ylides 5 have a significant
advantage over the common ylide 1. All products were identified
by NMR spectroscopy, IR, and elemental analysis, and structures
of 5a and 5b were unambiguously established by single crystal
X-ray diffraction analysis.
12
81
24
12
12
12
12
48
37 (22c)
46
17
r.t.
r.t.
r.t.
r.t.
r.t.
—
78
The X-ray crystal structure of 5b, showing intra- and
intermolecular interactions with the hypervalent iodine center,
is given in Fig. 1. I–C(Ar) bond distances in 5a and 5b (B2.12 A)
are significantly longer compared to I–C(Alk) distances (B2.06 A)
with the C–I–C bond angles (B971) reflective of the pseudo
T-shape at the iodine center. In addition, there are one strong
O3–I (B2.98 A) and two weak O1–I and O2–I (B3.14–3.18 A)
intramolecular contacts observed in 5a and 5b. Molecules of 5a
form dimers in a solid state using the I1A–O2B (B3.02 A)
intermolecular interactions. Molecules 5b crystallize in the poly-
meric chains formed by the I1A–O1B close (B2.75 A) contacts.
We tested the reactivity of new iodonium ylides 5 towards DIC
in comparison with the original ylide 1 (Table 1). Due to
improved solubility in aromatic solvents, the modified analogues
5 have shown much higher reactivity than the original ylide 1.
For example, the reaction of 5b with DIC was complete in 0.5 h
to afford product 2a in 79% yield, whereas a similar reaction
of ylide 1 afforded product 2a in 62% yield and required 3 h
for completion (Table 1, entries 1 and 2). Motivated by this
encouraging result, we then optimized other reaction condi-
tions, such as catalyst, temperature, and time (see for details
Table S2 in ESIw). We were pleased to find that the reaction
could even be performed at room temperature, with a prolonged
23 (15c)
a
Reaction conditions: 1 or 5b (1 equiv.), DIC (1.5 equiv.), catalyst
(0.05 equiv.), PhCF3 (3 mL) and argon protect unless otherwise noted.
b
c
d
Isolated yields. Yield after 12 h. (CuOTf)2ÁC6H6 was used as the
source of CuOTf.
reaction time (entry 3). The higher reactivity of 5b permits the use
of a less reactive copper-based catalyst in this reaction (entry 8).
For comparison, the use of the original ylide 1 under the same
conditions did not give satisfactory results, even after longer
reaction time up to 24 h (entries 4 and 9).
In order to determine the scope and limitations of synthetic
applications of this new carbenoid precursor, we tested ylide
5b in the Rh- or Cu-catalyzed reactions with carbodiimides
bearing different substituents (Table 2). As shown in Table 2,
most carbodiimides underwent transformation to afford the
corresponding products in moderate to excellent yields.
The structure of product 2b was unambiguously established
by single crystal X-ray diffraction analysis (see ESIw for
details). Bis(2,6-diisopropylphenyl)carbodiimide exhibited
low reactivity towards this transformation, which may be
explained by the steric hindrance effect of the four isopropyl
groups (entries 7 and 8). When the substrate changed from
symmetrical carbodiimide to unsymmetrical, two isomers 2f
and 2g were formed and isolated as an inseparable mixture
(entries 11 and 12).
Possible reaction pathways are summarized in Scheme 3.
Iodonium ylide 5 serves as the source of initial carbene
(or carbenoid), which is transferred to the double bond of
carbodiimide via rhodium complexes 6 and 7. The formation
of 2 may involve a 1,3-dipolar cycloaddition of the carbenoid
(path B) or initial aziridination to 8 followed by ring cleavage
to give zwitterion 9 (path A). The third possible route (path C)
involves the nitrogen ylide 10 as an intermediate product.11b,13
We were able to isolate the intermediate 10 as a relatively
stable compound (see ESIw), which provides strong support
towards path C. A special experiment has shown that under
reaction conditions [Rh2(OAc)4 (0.05 equiv.), PhCF3, r.t.]
intermediate 10 completely rearranges to the final product 2
in 30 min.
In summary, we have reported the preparation, X-ray
structure, and reactivity of new iodonium ylides 5 derived
from dimedone and bearing an ortho substituent in the phenyl
ring. These new reagents have better solubility in common
organic solvents, especially in aromatic solvents, and afford
Fig. 1 X-ray crystal structure of 5b dimer showing intra- and inter-
molecular interactions with the hypervalent iodine center.
c
Chem. Commun.
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Table 2 Reactions of ylide 5b with carbodiimidesa
This work was supported by research grants from the NSF
(CHE-1009038; MRI CHE-0922366). Chenjie Zhu thanks the
China Scholarship Council for supporting his visit to the University
of Minnesota Duluth and the Research and Innovation Plan for
Graduate Students of Jiangsu Higher Education Institutions for
project support (No. CXZZ11_0266).
Notes and references
1 For books and selected reviews on hypervalent iodine chemistry,
see: (a) A. Varvoglis, Hypervalent Iodine in Organic Synthesis,
Academic Press, London, 1997; (b) Hypervalent Iodine Chemistry-
Modern Developments in Organic Synthesis, ed. T. Wirth, Springer,
Berlin, 2003; (c) T. Dohi and Y. Kita, Chem. Commun., 2009, 2073;
(d) M. Ochiai, Chemistry of Hypervalent Compounds, ed. K.-Y.
Akiba, Wiley-VCH, New York, 1999; (e) M. Uyanik and
K. Ishihara, Chem. Commun., 2009, 2086; (f) J. P. Brand,
Yieldb
Product (%)
Entry R1 and R2
Catalyst
1
2
3
4
5
6
7
i-Pr and i-Pr
i-Pr and i-Pr
Rh2(OAc)4 2a
81
78
84
Cu(acac)2
Rh2(OAc)4 2b
Cu(acac)2 2b
Rh2(OAc)4 2c
Cu(acac)2 2c
Rh2(OAc)4 2d
2a
c-C6H11 and c-C6H11
c-C6H11 and c-C6H11
p-Tol and p-Tol
p-Tol and p-Tol
2,6-(i-Pr)2C6H3 and
2,6-(i-Pr)2C6H3
76
77c
72c
28 (34d)
D. F. Gonzalez, S. Nicolai and J. Waser, Chem. Commun., 2011,
´
47, 102; (g) V. V. Zhdankin and P. J. Stang, Chem. Rev., 2008,
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8
2,6-(i-Pr)2C6H3 and
2,6-(i-Pr)2C6H3
Cu(acac)2
2d
25
9
Me3Si and Me3Si
Me3Si and Me3Si
Rh2(OAc)4 2e
Cu(acac)2 2e
88
86
10
11
12
C2H5 and (CH3)2N(CH2)3 Rh2(OAc)4 2f + 2g 37 + 56e
2 For selected reviews on phenyliodonium ylides, see: (a) P. Muller,
¨
D. Fernandez, P. Nury and J.-C. Rossier, J. Phys. Org. Chem.,
C2H5 and (CH3)2N(CH2)3 Cu(acac)2
2f + 2g 30 + 53e
a
1998, 11, 321; (b) P. Muller, Acc. Chem. Res., 2004, 37, 243;
¨
Reaction conditions: 5b (1 equiv.), carbodiimide (1.5 equiv.), catalyst
(0.05 equiv.), PhCF3 (3 mL), under argon at room temperature for
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b
12 h unless otherwise noted. Isolated yields. The reaction was
c
d
conducted at 60 1C for 2 h. The reaction was conducted at 80 1C
for 4 h. Yields of 2f and 2g were determined by NMR using 1,1,2,2-
tetrachloroethane as an internal standard.
e
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Scheme 3 Proposed reaction mechanism.
12 C. Zhu, A. Yoshimura, L. Ji, Y. Wei, V. N. Nemykin and
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higher yields of oxazole derivatives than the original ylide 1 in
the reaction with carbodiimides under milder homogeneous
conditions.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun.