Design, preparation, X-ray crystal structure, and reactivity of o-alkoxyphenyliodonium bis(methoxycarbonyl)methanide, a highly soluble carbene precursor

Article abstract of DOI:10.1021/ol301268j

The preparation, X-ray structure, and reactivity of new, highly soluble, and reactive iodonium ylides derived from malonate methyl ester and bearing an ortho substituent on the phenyl ring are reported. These new reagents show higher reactivity than common phenyliodonium ylides in the Rh-catalyzed cyclopropanation, C-H insertion, and transylidation reactions under homogeneous conditions.

Full text of DOI:10.1021/ol301268j

ORGANIC
LETTERS
2012
Vol. 14, No. 12
3170–3173
Design, Preparation, X-ray Crystal
Structure, and Reactivity of
o-Alkoxyphenyliodonium
Bis(methoxycarbonyl)methanide, a Highly
Soluble Carbene Precursor
Chenjie Zhu,†,‡ Akira Yoshimura,† Lei Ji,† Yunyang Wei,‡ Victor N. Nemykin,*,† and
Viktor V. Zhdankin*,†
Department of Chemistry and Biochemistry, University of Minnesota;Duluth, Duluth,
Minnesota 55812, United States, and School of Chemical Engineering,
Nanjing University of Science and Technology, Nanjing 210094, China
vnemykin@d.umn.edu; vzhdanki@d.umn.edu
Received May 8, 2012
ABSTRACT
The preparation, X-ray structure, and reactivity of new, highly soluble, and reactive iodonium ylides derived from malonate methyl ester and
bearing an ortho substituent on the phenyl ring are reported. These new reagents show higher reactivity than common phenyliodonium ylides in
the Rh-catalyzed cyclopropanation, CꢀH insertion, and transylidation reactions under homogeneous conditions.
Within the rapidly growing field of hypervalent iodine
chemistry,1 phenyliodonium ylides2 occupy a special and
important place as efficient carbene precursors, alternative
to the diazo compounds,3 but without major drawbacks,
such as explosiveness and toxicity. Phenyliodonium ylides
(1, Figure 1) are prepared by the reaction of CꢀH acidic
compounds (e.g., 1,3-dioxo derivatives) with hypervalent
iodine(III) reagents such as PhI(OAc)2. The nitrogen
analogs of phenyliodonium ylides, phenyliodonium imides
2, are synthesized similarly from arylsulfonamides and
PhI(OAc)2.
† University of Minnesota;Duluth.
‡ Nanjing University of Science and Technology.
(1) For books and selected reviews on hypervalent iodine chemistry, see:
(a) Varvoglis, A. Hypervalent Iodine in Organic Synthesis; Academic Press:
London, 1997. (b) Hypervalent Iodine Chemistry; Wirth, T., Ed.; Springer-
Verlag: Berlin, 2003. (c) Wirth, T. Angew. Chem., Int. Ed. 2005, 44, 3656–3665.
(d) Koser, G. F. Adv. Heterocycl. Chem. 2004, 86, 225–292. (e) Moriarty,
R. M. J. Org. Chem. 2005, 70, 2893–2903. (f) Quideau, S.; Pouysegu, L.;
Deffieux, D. Synlett 2008, 467–495. (g) Ladziata, U.; Zhdankin, V. V.
ARKIVOC 2006, No. ix, 26–58. (h) Ciufolini, M. A.; Braun, N. A.; Canesi,
S.;Ousmer, M.;Chang, J.;Chai, D.Synthesis 2007, 3759–3772. (i) Zhdankin,
V. V. Sci. Synth. 2007, 31a, 161–234 (Chapter 31.4.1). (j) Zhdankin, V. V.;
Stang, P. J. Chem. Rev. 2008, 108, 5299–5358. (k) Ladziata, U.; Zhdankin,
V. V. Synlett 2007, 527–537. (l) Dohi, T.; Kita, Y. Chem. Commun. 2009,
2073–2085. (m) Ochiai, M.; Miyamoto, K. Eur. J. Org. Chem. 2008, 4229–
4239. (n) Zhdankin, V. V. ARKIVOC 2009, No. i, 1–62. (o) Yusubov, M. S.;
Maskaev, A. V.; Zhdankin, V. V. ARKIVOC 2011, No. i, 370–409. (p)
Uyanik, M.; Ishihara, K. Chem. Commun. 2009, 2086–2099. (q) Liang, H.;
Ciufolini, M. A. Angew. Chem., Int. Ed. 2011, 50, 11849–11851. (r) Yusubov,
M.S.;Nemykin, V. N.;Zhdankin, V. V.Tetrahedron 2010,66, 5745–5752. (s)
Quideau, S.; Wirth, T. Tetrahedron 2010, 66, 5737–5738. (t) Uyanik, M.;
Ishihara, K. Aldrichimica Acta 2010, 43, 83–91. (u) Merritt, E. A.; Olofsson,
B. Angew. Chem., Int. Ed. 2009, 48, 9052–9070. (v) Merritt, E. A.; Olofsson,
B. Synthesis 2011, 517–538. (w) Zhdankin, V. V. J. Org. Chem. 2011, 76,
1185–1197. (x) Silva, J. L. F.; Olofsson, B. Nat. Prod. Rep. 2011, 28, 1722–
1754. (y) Turner, C. D.; Ciufolini, M. A. ARKIVOC 2011, No. i, 410–428.
(z) Yusubov, M. S.; Zhdankin, V. V. Curr. Org. Synth. 2012, 9, 247–272.
Under catalytic, thermal, or photochemical conditions,
both reagents 1 and 2 serve as excellent progenitors for
generation of singlet carbene (or carbenoid)4 and nitrene
€
(2) For selected reviews on phenyliodonium ylides, see: (a) Muller,
P.; Fernandez, D.; Nury, P.; Rossier, J.-C. J. Phys. Org. Chem. 1998, 11,
€
321–333. (b) Muller, P. Acc. Chem. Res. 2004, 37, 243–251. (c) Li, A.-H.;
Dai, L.-X. Chem. Rev. 1997, 97, 2341–2372. (d) Ochiai, M.; Tada, N.;
Miyamoto, K.; Shiro, M. Heteroatom. Chem. 2011, 22, 325–330. (e)
Neilands, O. Latv. J. Chem 2002, 27–59. (f) Moriarty, R. M.; Vaid, R. K.
Synthesis 1990, 431–447. (g) Malamidou-Xenikaki, E.; Spyroudis, S.
Synlett 2008, 2725–2740.
(3) (a) Regitz, M.; Maas, G. Diazo Compounds: Properties and
Synthesis; Academic Press: London, 1986. (b) Bollinger, F. W.; Tuma,
L. D. Synlett 1996, 407–413. (c) Bretherick, L. In Hazards in the Chemical
Laboratory, 4th ed.; Royal Society of Chemistry, Burlington House:
London, 1986.
r
10.1021/ol301268j
Published on Web 05/24/2012
2012 American Chemical Society

phenyl ring of the phenyliodonium moiety.10a Herein, we
report the design, preparation, structural investigation,
and reactivity of new highly soluble and stable iodonium
ylides 5, which are derived from o-alkoxyiodobenzene and
malonatemethylester. The choice of thisstructuralmotifis
based on our previous research10 and that of Protasiewicz
et al.11
o-Alkoxyphenyliodonium bis(methoxycarbonyl)
methanides 5aꢀd were synthesized according to the pro-
cedure shown in Scheme 1. Reaction of commercially
available 2-iodophenol with appropriate alkyl bromide
or alkyl iodide afforded 2-iodophenol ethers 3aꢀd in
excellent yields. Subsequent oxidation to diacetoxyiodo
derivatives 4aꢀd was accomplished using freshly prepared
peracetic acid. At last, diacetates 4aꢀd were converted to
the final o-alkoxyphenyliodonium bis(methoxycarbonyl)
methanides 5aꢀd by treatment with malonate methyl
ester under basic conditions. Products 5 are relatively
stable at rt and can be stored for several months in a
refrigerator without significant degradation, which is
clearly advantageous in comparison to the original 1a.
All ylides 5aꢀd have good solubility in dichloro-
methane, chloroform, or acetone (e.g., the solubility
of 5b in dichloromethane is 0.56 g/mL). Thus, the new
ylides 5 have a significant advantage over previously
known iodonium ylides.
Figure 1. Phenyliodonium ylides and imides.
species, respectively. Particularly important and well-
developed are the nitrene transfer reactions using imides
2 in the presence of Cu(I) or Rh(II) catalysts.5 In contrast,
similar catalytic carbene (or carbenoid) transfer reactions
using ylides 1 have been less investigated due to the
following reasons: ylides 1 usually are unstable and diffi-
cult to purify, and many of them, especially the acyclic
compounds, have very low solubility in common organic
solvents. For example, phenyliodonium bis(methoxy-
carbonyl) methanide 1a, a most common iodonium ylide
derived from malonate methyl ester, has found synthetic
applications in the cyclopropanation of alkenes,6 CꢀH
insertion reactions,7 epoxidation,8 and asymmetric
synthesis.9 However, despite its importance, 1a is not a
perfect reagent. The main challenges are its poor solubility
(insoluble in most organic solvents except DMSO) and low
stability (should be stored ꢀ20 °C).2,6c,6d In view of the
innocuous and eco-friendly attributes of iodonium ylides,
the quest for modified ylides 1 that are more stable and
soluble in common organic solvents is particularly attractive.
Recently, we have found that the solublility and reactiv-
ity of phenyliodonium imides 2 can be significantly im-
proved by the introduction of an o-alkoxy group in the
Scheme 1. Synthesis of Iodonium Ylides 5aꢀd
(4) (a) Camacho, M. B.; Clark, A. E.; Liebrecht, T. A.; Deluca, J. P.
J. Am. Chem. Soc. 2000, 122, 5210–5211. (b) Moriarty, R. M.; Tyagi, S.;
Kinch, M. Tetrahedron 2010, 66, 5801–5810.
€
(5) (a) Muller, P. Transition metal-catalyzed nitrene transfer: aziridi-
nation and insertion; Doyle, M. P., Ed.; JAI Press: London, 1997. (b) M€uller,
P.; Fruit, C. Chem. Rev. 2003, 103, 2905–2919. (c) Dauban, P.; Dodd,
R. H. Synlett 2003, 1571–1586.
(6) (a) Moriarty, R. M.; Prakash, O.; Vaid, R. K.; Zhao, L. J. Am.
Chem. Soc. 1989, 111, 6443–6444. (b) Camacho, M. B.; Clark, A. E.;
Liebrecht, T. A.; Deluca, J. P. J. Am. Chem. Soc. 2000, 122, 5210–5211.
(c) Goudreau, S. R.; Marcoux, D.; Charette, A. B. J. Org. Chem. 2009,
74, 470–473. (d) Goudreau, S. R.; Marcoux, D.; Charette, A. B. Org.
Synth. 2010, 87, 115–125. (e) Ghanem, A.; Lacrampe, F.; Schurig, V.
Helv. Chim. Acta 2005, 88, 216–239. (f) Georgakopoulou, G.; Kalogiros,
C.; Hadjiarapoglou, L. P. Synlett 2001, 1843–1846. (g) Batsila, C.;
Kostakis, G.; Hadjiarapoglou, L. P. Tetrahedron Lett. 2002, 43, 5997–
6000.
All new ylides 5aꢀd were identified by NMR spectro-
scopy, IR, and elemental analysis, and the structure of 5a
was unambiguously established by a single crystal X-ray
diffraction analysis. To the best of our knowledge, this is
the first single crystal X-ray analysis of a malonate ester
derived iodonium ylide since the discovery of this class of
ylides in 1965.12 The X-ray crystal structure of 5a, showing
(7) (a) Batsila, C.; Gogonas, E. P.; Kostakis, G.; Hadjiarapoglou,
L. P. Org. Lett. 2003, 5, 1511–1514. (b) Telu, S.; Durmus, S.; Koser,
G. F. Tetrahedron Lett. 2007, 48, 1863–1866. (c) Muller, P.; Bolea, C.
€
ꢀ
(10) (a) Yoshimura, A.; Nemykin, V. N.; Zhdankin, V. V. Chem.;
Eur. J. 2011, 17, 10538–10541. (b) Yoshimura, A.; Banek, C. T.;
Yusubov, M. S.; Nemykin, V. N.; Zhdankin, V. V. J. Org. Chem.
2011, 76, 3812–3819. (c) Zhdankin, V. V.; Koposov, A. Y.; Litvinov,
D. N.; Ferguson, M. J.; McDonald, R.; Luu, T.; Tykwinski, R. R.
J. Org. Chem. 2005, 70, 6484–6491. (d) Koposov, A. Y.; Karimov, R. R.;
Geraskin, I. M.; Nemykin, V. N.; Zhdankin, V. V. J. Org. Chem. 2006,
71, 8452–8458.
(11) (a) Macikenas, D.; Jankun, E. S.; Protasiewicz, J. D. J. Am.
Chem. Soc. 1999, 121, 7164–7165. (b) Macikenas, D.; Jankun, E. S.;
Protasiewicz, J. D. Angew. Chem., Int. Ed. 2000, 39, 2007–2010. (c)
Meprathu, B. V.; Protasiewicz, J. D. Tetrahedron 2010, 66, 5768–5774.
(12) Neilands, O. Zh. Org. Khim. 1965, 1, 1858–1862.
€
ꢀ
Molecules 2001, 6, 258–266. (d) Muller, P.; Bolea, C. Helv. Chim. Acta
€
2002, 85, 483–494. (e) Muller, P.; Tohill, S. Tetrahedron 2000, 56, 1725–
1731. (f) Lee, Y. R.; Cho, B. S. Bull. Korean Chem. Soc. 2002, 23, 779–
782.
(8) (a) Ochiai, M.; Kitagawa, Y.; Yamamoto, S. J. Am. Chem. Soc.
1997, 119, 11598–11604. (b) March, P.; Huisgen, R. J. Am. Chem. Soc.
1982, 104, 4952. (c) Fairfax, D. J.; Austin, D. J.; Xu, S. L.; Padwa, A.
J. Chem. Soc., Perkin Trans. 1 1992, 2837–2844.
€
(9) (a) Ghanem, A.; Enein, H. Y. A.; Muller, P. Chirality 2005, 17,
€
ꢀ
44–50. (b) Muller, P.; Bolea, C. Helv. Chim. Acta 2001, 84, 1093–1111. (c)
€
Muller, P.; Allenbach, Y. F.; Chappellet, S.; Ghanem, A. Synthesis 2006,
1689–1696.
Org. Lett., Vol. 14, No. 12, 2012
3171

Scheme 2. Cyclopropanation Reactions of Alkenesa and Phe-
nylacetylene Using 5a
Figure 2. X-ray crystal structure of 5a showing intra- and
intermolecular interactions with the hypervalent iodine center.
Table 1. Comparison of Rectivity of 5, 1a, and Dimethyl
2-Diazomalonate (DDAM) in Cyclopropanation of Styrenea
temp
time
yield
(%)b
a The cyclopropanation of alkenes was conducted in CH2Cl2 at rt by
stirring 5a (1 equiv), alkene (5 equiv), and Rh2(OAc)4 (0.05 equiv) unless
otherwise noted. bCu(acac)2 was used instead of Rh2(OAc)4 under reflux
conditions. cThe reaction was conducted under reflux conditions. dThe
yield shown in parentheses corresponds to the use of 5c instead of 5a.
entry
reagent
catalyst
(°C)
(min)
ref
1
1a
Rh2(OAc)4
rt
30
120
1
80
91
80
39
90
88
74
72
57
5
6c
6c
6f
6c
c
2
1a
Rh2(esp)2
rt
3
1a
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
CuOTf
120
rt
d
4
DDAM
5a
ꢀ
catalysts in comparison with reactions of the common
carbene precursors, ylide 1a and dimethyl 2-diazomalo-
nate (Table 1). In general, the reactions of ylides 5 with
alkenes proceed under mild conditions and afford higher
yields of cyclopropanation products compared to ylide 1a
and dimethyl malonate, which can be explained by the
better solubility of 5a.
With the aim to develop and define the scope and limita-
tion of the reactions, the new ylide 5a was first tested as a
reagent in typical Rh-catalyzed cyclopropanations with a
wide range of unsaturated compounds, including benzylic,
allylic, heterocyclic, alicyclic, aliphatic alkenes, dienes, and
an alkyne (Scheme 2).
Diversely substituted styrene-type derivatives under-
went smooth cycloaddition to afford the corresponding
cyclopropanedicarboxylates in excellent yields without
any evidence of CꢀH insertion at the benzylic positions
(6aꢀ6j). Cyclic, alicyclic, and aliphatic alkenes also reacted
smoothly rendering cyclopropanation adducts in moder-
ate to good yields (6kꢀ6o). Interestingly, the outcome of
the reaction of β-methylstyrenes depended on the stereo-
chemistry of the alkene. The cis-isomer afforded exclu-
sively the cis-cyclopropane product in high yield, while the
trans-isomer led to a complex mixture of products, from
which the trans-cyclopropane was isolated in only 21%
yield (6s vs 6t). This very high degree of stereospecificity
indicates that the steric hindrance effect is much more
important than the influence of electronic effect in the
present system. The cyclopropanation seems to be electro-
philic in nature, but the steric factor is dominant, which
5
rt
60
60
60
60
6
5b
rt
7
5c
rt
8
5d
rt
d
9
1a
rt
ꢀ
6c
6c
d
10
11
12
13
14f
DDAM
5a
CuOTf
CuOTfe
rt
ꢀ
rt
120
10
77
57
74
27
1a
Cu(acac)2
Cu(acac)2
Rh2(OAc)4
80
80
rt
6f
5a
10
4a
300
a Reactions were performed by stirring styrene (5 equiv) with appro-
priate catalyst (0.05 equiv) in CH2Cl2 unless otherwise noted. b Isolated
yields. c esp = R,R,R0,R0-tetramethyl-1,3-benzenedipropanoate. d Reac-
tion time is not provided in the reference. e (CuOTf)2 C6H6 was used as
3
the source of CuOTf. f In situ formation of the ylide 5a using 4a, dimethyl
˚
malonate, MgO, and 4 A molecular sieves.
intra- and intermolecular interactions with the hypervalent
iodine center, is given in Figure 2. In the solid state 5a has a
polymeric, asymmetrically bridged structure with a hex-
acoordinated geometry around the iodine centers formed
˚
˚
by two short CꢀI bonds [2.117 A for IꢀC(Ph) and 2.039 A
for IꢀC(malonate)] and two relatively long IꢀO intramo-
˚
lecular interactions between IꢀO1 (2.928 A) and IꢀO2
˚
(3.087 A). In addition, a relatively weak intermolecular
˚
IꢀO4 secondary interaction (2.933 A) is also present in the
solid state structure of 5a. Because the intermolecular
interaction between molecules of 5a is weak, this com-
pound is highly soluble in organic solvents.
The reactivity of iodonium ylides 5 was tested in a
cyclopropanation reaction with styrene using various
3172
Org. Lett., Vol. 14, No. 12, 2012

Scheme 3. Transylidation Reactions of 5aa
Table 2. CꢀH Insertion Reactions Using Iodonium Ylide 5a
a The transylidation was conducted in CH2Cl2 at rt using 5a (1.2
equiv), the appropriate heteroatom nucleophile (1.0 equiv), and Rh2-
(OAc)4 (0.01 equiv) unless otherwise noted. bThe yield shown in par-
entheses corresponds to catalyst-free reflux conditions. cCu(acac)2 was
used instead of Rh2(OAc)4 under reflux conditions.
a Method A: The reaction was performed by heating a mixture of the
iodonium ylide 5a (1.5 equiv), substrate (1.0 equiv), Rh2(OAc)4 (0.01
equiv), and CH2Cl2 (3 mL) under reflux. Method B: Cu(acac)2 was used
instead of Rh2(OAc)4 in method A. Method C: The reaction was
performed using a mixture of the iodonium ylide 5a (1.5 equiv), substrate
(1.0 equiv), BF3 Et2O (3 equiv), and CH2Cl2 (3 mL) at 0ꢀ5 °C. Method
3
D: Heating a mixture of ylide 5a (1.5 equiv), substrate (1.0 equiv), and
CH2Cl2 (3 mL) under reflux. b Isolated yield. c Cu(OTf)2 was used as
catalyst. d Reaction was performed at rt.
which is well-known to form in the reactions using a diazo
compound.14
We have also found that iodonium ylide 5a is highly
reactive in transylidation reactions with a wide range of
heteroatom nucleophiles involving sulfides, sulfoxides,
phosphines, and nitrogen heterocycles; the results are
summarized in Scheme 3. Structures of sulfonium ylide
8d and phosphonium ylide 8i were established by X-ray
diffraction (see Supporting Information).
In summary, we have reported the preparation, X-ray
structure, and reactivity of new, highly soluble, and reac-
tive iodonium ylides 5 derived from malonate methyl ester
and bearing an ortho substituent in the phenyl ring. These
new reagents afford higher yields of products than com-
mon phenyliodonium bis(methoxycarbonyl) methanide 1a
inthe Rh-catalyzedcyclopropanation, CꢀH insertion, and
transylidation reactions under homogeneous conditions.
could be further supported by the fact that using 5c instead
of 5a in the cyclopropanation of 6t also led to a lower yield.
Heating the ylide 5a with a diene in the presence of Rh2-
(OAc)4 led to the isolation of vinylcyclopropanes in mod-
erate yields (6r and 6u). Again, the reaction with 6,6-
dimethylfulvene indicates that the addition of an ylide to
a diene is also rather more sensitive to the steric effect than the
electronic effect (6u). Another remarkable feature of 5a was
observed upon reaction of phenylacetylene, with the corre-
sponding cyclopropene 7being obtained as the major product.
Next we investigated the direct insertion reactions of
reagent 5a into CꢀH bonds of aromatic hydrocarbons,
which is a challenging synthetic goal that has previously
been achieved by using various transition-metal catalysts.13
We were pleased to find that reagent 5a readily reacts with
hydrocarbons to give the corresponding CꢀH insertion pro-
duct under metal-free (method C) or catalyst-free (method D)
conditions (Table 2). For example, the reaction with 1,4-
dimethoxybenzene proceeds even at rt to afford the product
of CꢀH insertion in 32% yield, without any catalyst, but
with a prolonged reaction time (entry 12). Presumably, this
reaction proceeds via a cation-radical7b (or carbene) path-
way rather than a carbenoid pathway. Excellent chemos-
electivity was also observed using this system. In the reaction
with N-methylpyrrole, the R-isomer was the only product;
there was no evidence for the formation of the β-isomer,
Acknowledgment. C.Z. 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 In-
stitutions for project support (No. CXZZ11_0266). This
work was supported by research grants from the NSF
(CHE-1009038; MRI CHE-0922366).
Supporting Information Available. Experimental pro-
cedures, spectral data for key compounds, and cif files for
products 5a, 8d, and 8i. This material is available free of
charge via the Internet at http://pubs.acs.org.
(14) (a) Maryanoff, B. E. J. Org. Chem. 1982, 47, 3000–3002. (b)
Cuffe, J.; Gillespie, R. J.; A. Porter, E. A. J. Chem. Soc., Chem. Commun.
1978, 641–642.
(13) (a) Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103,
2861–2903. (b) Davies, H. M. L.; Dick, A. R. Top. Curr. Chem. 2010,
292, 303–345. (c) Slattery, C. N.; Ford, A.; Maguire, A. R. Tetrahedron
2010, 66, 6681–6705.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 12, 2012
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