Improved method for the iodination of sydnones

Article abstract of DOI:10.1080/00397911.2013.779713

Iodination at the sydnone C-4 position has been achieved in good yields for a series of 3-arylsydnones using N-iodosuccinimide in acetic acid. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2013.779713

This article was downloaded by: [University of Chicago Library]
On: 30 July 2013, At: 02:33
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
An Improved Method for the Iodination of Sydnones
Daniel C. Brown a & Kenneth Turnbull a
a Chemistry Department , Wright State University , Dayton , Ohio , USA
Accepted author version posted online: 03 Jul 2013.
To cite this article: Synthetic Communications (2013): An Improved Method for the Iodination of Sydnones,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI:
10.1080/00397911.2013.779713
To link to this article: http://dx.doi.org/10.1080/00397911.2013.779713
Disclaimer: This is a version of an unedited manuscript that has been accepted for publication. As a service
to authors and researchers we are providing this version of the accepted manuscript (AM). Copyediting,
typesetting, and review of the resulting proof will be undertaken on this manuscript before final publication of
the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the
content, and all legal disclaimers that apply to the journal relate to this version also.
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

ACCEPTED MANUSCRIPT
An Improved Method for the Iodination of Sydnones
Daniel C. Brown1, Kenneth Turnbull2,*
1Chemistry Department, Wright State University, Dayton, Ohio, USA
Kenneth Turnbull, Chemistry Department, Wright State University, Dayton, Ohio 45435,
U.S.A. E-mail: kenneth.turnbull@wright.edu
Abstract
Iodination at the sydnone C-4 position has been achieved in high yields for a series of 3-
arylsydnones using N-iodosuccinimide in acetic acid.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications® for the following free supplemental resource(s):
Full experimental and spectral details.]
KEYWORDS: iodination; mesoionic compounds; sydnones
INTRODUCTION
Sydnones are the most studied members of the class of heterocyclic compounds known as
mesoionic.[1] They undergo a wide range of transformations including electrophilic
aromatic substitution,[2] metalation,[3] 1,3-dipolar cycloaddition,[4] and cleavage with
ACCEPTED MANUSCRIPT
1

ACCEPTED MANUSCRIPT
aqueous acids to afford hydrazines[5] or heterocycles.[6] Halogenation of the sydnone ring
at the C4 position has been achieved by a number of methods, however, of those
reported, iodination remains the most problematic. For the latter, indirect routes
involving 4-chloromercuri[7] and Grignard intermediates[8] have been described, however,
such avenues suffer from toxicity or stability issues. One report of the use of N-
iodosuccinimide (NIS) for the iodination of 3-(3-pyridyl)sydnone has been
forthcoming,[9] however, the yield of the 4-iodo product was low and the generality of the
process was unclear. To date, the most effective route to the preparation of 4-iodo
sydnones 2 from the unsubstituted precursors 1 has been with iodine monochloride in
acetic acid and, in general, very good yields of the iodinated products result.[2b,e]
However, for another study, we required 4-iodosydnones and, while the ICl approach did
provide the desired compounds, we had issues with the instability of the reagent.
Accordingly, we elected to explore further the NIS methodology first reported by Greco
in 1979 for the preparation of a single compound,[9] since NIS is a stable, crystalline
compound.
RESULTS & DISCUSSION
For our initial test, we treated 3-phenylsydnone (1) with NIS (1.1 equivalents) in
methanol at room temperature and, even after 36 hours of stirring, no reaction was
observed and the starting material was recovered unchanged. Gratifyingly, changing the
solvent to acetic acid resulted in an 89% yield of the corresponding 4-iodo species 2 after
4 hours at room temperature and we now report that this method is a general process for
the iodination of 3-arylsydnones (Scheme 1).
ACCEPTED MANUSCRIPT
2

ACCEPTED MANUSCRIPT
In general, the yields are very good for a range of aryl substituents [Table 1, entries 1-9],
though for 1g the reaction required heating at 50°C for 5 hours for completion and a
lower than expected yield of 2i was obtained from 1i. In these cases it is likely that the
resonance withdrawing effect of the nitro group (in 1g) and the steric encumbrance
afforded by the 2-iodo substituent (in 1i) are controlling factors. However, given the
limited number of such examples available, further study will be necessary to determine
any such trends. The 4-iodo products 2a-i were identified by comparison with authentic
samples (for 2a,c,d and i) or from their infrared, proton and carbon nmr spectra. For the
latter, attachment of an iodine atom at the sydnone C-4 position shifted the signal from
~95 ppm to ~55 ppm, allowing ready assessment of product identity.
In conclusion, we have developed an effective iodination methodology for 3-
arylsydnones using 1.1 equivalents of N-iodosuccinimide in acetic acid at room
temperature. In general, the product yields are high and work-up is straightforward,
though strongly electron-withdrawing or sterically hindering groups may hamper the
process. The further scope and limitations of this approach will be reported in due course.
EXPERIMENTAL
General Notes
3-Phenylsydnone (1a) and its substituted analogs 1b-1i were synthesized according to
reported procedures.[4a,10,11] All other starting reagents were purchased from commercial
sources and used without further purification. Melting points were determined on a Mel-
Temp melting point apparatus and are uncorrected. Infrared spectra were acquired on a
Mattson Genesis II FTIR. NMR spectra were acquired on a Bruker 300MHz NMR
ACCEPTED MANUSCRIPT
3

ACCEPTED MANUSCRIPT
spectrometer and are reported relative to tetramethylsilane as an internal standard.
Combustion analyses were performed by Midwest Microlab, Indianapolis.
General Procedure For The Synthesis Of 4-Iodo-3-Aryl Sydnones 2 From 3-
Arylsydnones 1 With N-Iodosuccinimide In Acetic Acid.
N-iodosuccinimide (NIS) (1.1 equiv) was added to a stirred solution of the 3-arylsydnone
1 (0.200 g) in acetic acid (3 mL). The mixture was allowed to stir at room temperature for
4 hours after which time water (10 mL) was added. The resultant precipitate was isolated
by filtration and the filtrate was extracted with dichloromethane (3x 3 mL). The
combined extracts were washed with aqueous NaOH (10%), separated then dried with
magnesium sulfate, filtered and evaporated. The combined solids were then
recrystallized from dichloromethane / hexanes.
Supporting Information: Full experimental detail, 1H and 13C NMR spectra. This material
can be found via the “Supplementary Content” section of this article’s webpage.
REFERENCES
1.
P.A. Recent developments in the chemistry of sydnones. Tetrahedron. 2010, 66, 553-568.
2. (a) Mahoney, J.; Turnbull, K.; Cubberley, M. Bismuth triflate-catalyzed Friedel-
For a comprehensive review of sydnone chemistry, see: Browne, D. L.; Harrity, J.
Crafts acylations of sydnones. Synth. Commun. 2012, 42, 3220-29; (b) Dumitrascu, F.;
Mitan, C. I.; Dumitrescu, D.; Draghici, M. T.; Caproiu, M. T. Steric effects on the
sydnones reactivity. New sydnones and pyrazoles. Arkivoc. 2002, 2, 80-86; (c) Zhang, Z.
ACCEPTED MANUSCRIPT
4

ACCEPTED MANUSCRIPT
B.; Wu, Y. R.; Yin, C. L. The efficient synthesis of new sydnones containing fused ring.
Synth. Commun. 2002, 32, 2203-7; (d) Turnbull, K.; Gross, K. C.; Hall, T. A. Direct
carboxamidation of sydnones with chlorosulfonyl isocyanate. Synth. Commun. 1998, 28,
931-7; (e) Dumitrascu, F.; Draghici, M. T.; Dumitrescu, D.; Tarko, L.; Raileanu, D.
Direct iodination of sydnones and their cycloadditions to form 5-iodo-pyrazoles. Liebigs
Ann./Rec. 1997, 2613-16; (f) Turnbull, K.; Ito, S. Chlorination of 3-substituted sydnones
with dichloroiodobenzene. Synth. Commun. 1996, 26, 1441-6; (g) Turnbull, K.;
Blackburn, T. L.; McClure, D. B. Reactions of activated aryl sydnones with electrophiles.
J. Heterocycl. Chem. 1994, 31, 1631-6; (h) Tien, H.-J.; Yeh, J.-C.; Wu, S.-J. Acetylation
and debromination of sydnones accelerated by ultrasound. J. Chin. Chem. Soc. 1992, 39,
443-7; (i) Turnbull, K.; Blackburn, T. L.; Esterline, D. T. Bromination of sydnones. III.
Bromination of 3-(2-substituted phenyl)- sydnones and subsequent side chain
modification. J. Heterocycl. Chem. 1990, 27, 1259-63; (j) Turnbull, K. Bromination of
sydnones. I. Reaction with 3-arylsydnones containing electron-donors on the aryl ring. J.
Heterocycl. Chem. 1985, 22, 965-8; (k) Hodson, S. J.; Turnbull, K. Bromination of
sydnones. II. Bromination of 3-(2-aminophenyl)sydnone and related compounds. J.
Heterocycl. Chem. 1985, 22, 1223-7.
3.
(a) Turnbull, K.; Nashashibi, I. F. 4-Substituted ortho-(silylated phenyl)sydnones
via a lithiation-induced silicon migration and subsequent reaction with electrophiles.
Synth. Commun. 2007, 37, 915-9; (b) Turnbull, K.; Krein, D. M. ortho-(Substituted
silyl)phenylsydnones via a novel sydnone to phenyl ring, lithiation-induced silicon
migration. Synth. Commun. 2003, 33, 2061-7; (c) Turnbull, K.; Sun, C.; Krein, D. M. The
sydnone ring as an ortho-director of lithiation. 2. Dilithiation of 3-phenylsydnone and
ACCEPTED MANUSCRIPT
5

ACCEPTED MANUSCRIPT
regiospecific o-aryl acylation using N-methoxy-N-methylamides. Tetrahedron Lett. 1998,
39, 1509-12; (d) Turnbull, K.; Krein, D. M. The sydnone ring as an ortho-director of
lithiation. Dilithiation of 3-phenylsydnone and trapping by electrophiles. Tetrahedron
Lett. 1997, 38, 1165-8; (e) Turnbull, K.; Krein, D. M. Formation of 4-hydroxy-4-
substituted sydno[3,4-a](4H)indoles via dilithiation of 3-(2-bromophenyl)sydnone.
Synthesis. 1996, 1183-4; (f) Kalinin, V. N.; Min, S. F. Synthesis of aryl- and
vinylsydnones. Cross-coupling of 4-copper-3-phenylsydnone with aryl and vinyl halides
catalyzed by palladium complexes. J. Organomet. Chem. 1988, 352, C34-6; (g)
Fuchigami, T.; Chen, C.-S.; Nonaka, T.; Yeh, M.-Y.; Tien, H.-J. Preparation of sydnone
compounds substituted by thio and seleno functional groups at the 4-positions. Bull.
Chem. Soc. Jpn. 1986, 59, 487-91; (h) Greco, C. V.; Pesce, M.; Franco, J. M. The direct
lithiation of 3-phenylsydnone. J. Heterocycl. Chem. 1966, 3, 391-2; (i) Greco, C. V.;
O’Reilly, B. P. Mesoionic Compounds VI: Metalation of sydnones: An estimate of
acidity. J. Heterocycl. Chem. 1970, 7, 1433-4.
4.
(a) Fang, Y.; Wu, C.; Larock, R. C.; Shi, F. Synthesis of 2H-indazoles by the [3 +
2] dipolar cycloaddition of sydnones with arynes. J. Org. Chem. 2011, 76, 8840-51; (b)
Browne, D. L.; Taylor, J. B.; Plant, A.; Harrity, J. P. A. Alkyne [3 + 2] Cycloadditions of
iodosydnones toward functionalized 1,3,5-trisubstituted pyrazoles. J. Org. Chem. 2010,
75, 984-7; (c) Delaunay, T.; Pierre, G.; Mazen, E-S.; Jean-Pierre, V.; Nuno, M.;
Genevieve, B. A modular sydnone cycloaddition/Suzuki-Miyaura cross-coupling strategy
to unsymmetrical 3,5-bis(hetero)aromatic pyrazoles. Org. Lett. 2010, 12, 3328-31; (d)
Browne, D. L.; Vivat, J. F.; Plant, A.; Gomez-Bengoa, E.; Harrity, J. P. A. Investigation
of the scope and regiochemistry of alkynylboronate cycloadditions with sydnones. J. Am.
ACCEPTED MANUSCRIPT
6

ACCEPTED MANUSCRIPT
Chem. Soc. 2009, 131, 7762-9; (e) Gao, D.; Zhai, H.; Parvez, M.; Back, T. G. 1,3-Dipolar
cycloadditions of acetylenic sulfones in solution and on solid supports. J. Org. Chem.
2008, 73, 8057–68; (f) Gonzalez-Nogal, A. M.; Calle, M.; Cuadrado, P.; Valero, R. 1,3-
Dipolar cycloadditions of silicon and tin alkynes and alkenes. Regiospecific synthesis of
silyl and stannylpyrazoles and pyrazolines. Tetrahedron. 2007, 63, 224-31; (g) Croce, P.
D.; La Rosa, C.; Zecchi, G. 1,3-Dipolar cycloadditions with alkynyl phenyl sulphones. J.
Chem. Soc., Perkin Trans. 1. 1985, 2621-2624; (h) Padwa, A.; Burgess, E. M.; Gingrich,
H. L.; Roush, D. M. On the problem of regioselectivity in the 1,3-dipolar cycloaddition
reaction of munchnones and sydnones with acetylenic dipolarophiles. J. Org. Chem.
1982, 47, 786-91.
5.
(a) Chang, H-T.; Chiang, K-C.; Wong, F. F.; Huang, C-S.; Liao, Y-M.; Kuo, W-
F.; Won, S-B.; Yeh, Y. Synthesis of 4-(5-aryl-1,3,4-oxadiazol-2-yl)phenyl-hydrazine
derivatives from 3-(4-hydrazinocarbonyl-phenyl)sydnones. Heteroatom Chem. 1997, 18,
438-42; (b) Saljoughian, M.; Turnbull, K. Acid induced reactions of a sydnone ketoxime.
J. Heterocycl. Chem. 1988, 25, 1817-1819; (c) Aziz, S.; Tillett, J. G. Hydrolysis of some
3-alkylsydnones. Tetrahedron Lett. 1969, 33, 2855-8; (c) Staley. J.; Clark, D. D. Acid
hydrolysis of 3-phenylsydnone-2-15N. J. Org. Chem. 1964, 29, 2483-4; (d) Baker, W.;
Ollis, W. D.; Poole, V. D. Cyclic mesoionic compounds. I. The structure of the sydnones
and related compounds. J. Chem. Soc. 1949, 307-14.
6.
(a) Marx, J.A.; Turnbull, K. Formation of 1-bromocarbonylindazoles via cleavage
of 4-bromo ortho-substituted arylsydnones with HBr. Tetrahedron Lett. 1993, 34, 239-41;
(b) Gelvin, C. R.; Turnbull, K. Sydnones as masked hydrazines for heterocycle
ACCEPTED MANUSCRIPT
7

ACCEPTED MANUSCRIPT
formation: Reactions of 3-(2-substituted phenyl)sydnones with HCl. Helv. Chim. Acta.
1992, 75, 1931-43.
7.
phenylsydnone. Nippon Kagaku Zasshi. 1956, 77, 1306-8.
8. Ohta, M.; Kato, H. Studies on mesoionic compounds. VII. Reactivities of 4-
Nakahara, K.; Kato, H. Mesoionic compounds II. Mercuration of 3-
halosydnones and the reactions of their Grignard reagent. Nippon Kagaku Zasshi. 1957,
78, 1653-6.
9.
3-(3-pyridyl)sydnones. J. Heterocycl. Chem. 1979, 16, 1059-60.
10. Weisner, A. J.; Cooper, T. M.; Turnbull, K. Routes to sydnone-containing
oligomeric areneynes. Synth. Commun. 2005, 35, 639-51.
11. (a) Baumgarten, H. E. 3-Phenylsydnone. Org. Synth., 1973, Coll. Vol. 5, 962-5;
Greco, C. V.; Mehta, J. R. Mesoionic compounds. XI. Photochromic 4-halogeno-
(b) Berk, H.C.; Franz, J. E. Periselective addition of mesoionic compounds to
tetracyanoethylene. Preparation of [(dicyanovinyl)hydrazono]-malononitriles. J. Org.
Chem. 1979, 44, 2395-400.
ACCEPTED MANUSCRIPT
8

ACCEPTED MANUSCRIPT
Table 1. Reaction of 3-arylsydnones 1a-i with N-iodosuccinimide / acetic acid to afford
the corresponding 4-iodo congeners 2a-i
Entry R in 1 & 2
Yield of mp °C
Lit. mp
°C
2 (%)
1
2
3
4
5
6
7
8
9
a, H
89
77
76
84
87
79
73
76
64
163-5
168-9
158-60
159-61
161-3
203-5
208-10
103-4
183-5
164-5[2e]
b, 4-Me
c, 4-MeO
d, 4-Br
e, 4-Cl
f, 4-I
---
160-2[4b]
160-2[4a]
---
---
g, 4-NO2
h, 3-CF3
i, 2-I
205-8[4b]
---
190-1[3d]
ACCEPTED MANUSCRIPT
9

ACCEPTED MANUSCRIPT
Scheme I. Iodination of 3-arylsydnones 1
ACCEPTED MANUSCRIPT
10