Transition-metal-free oxidative iodination of 1,3,4-oxadiazoles

Article abstract of DOI:10.1002/ejoc.201403352

Transition-metal-free oxidative iodination of 2-substituted 1,3,4-oxadiazoles was achieved by using sodium iodide as the halide source and Selectfluor as the oxidant. Variously substituted products were obtained in moderate to good yields under operationa

Full text of DOI:10.1002/ejoc.201403352

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201403352
Transition-Metal-Free Oxidative Iodination of 1,3,4-Oxadiazoles
Carl Albrecht Dannenberg,[a] Vincent Bizet,[a] Liang-Hua Zou,[a] and Carsten Bolm*[a]
Keywords: Synthetic methods / Iodine / Oxidation / Nitrogen heterocycles / Oxadiazoles
Transition-metal-free oxidative iodination of 2-substituted
1,3,4-oxadiazoles was achieved by using sodium iodide as
the halide source and Selectfluor as the oxidant. Variously
substituted products were obtained in moderate to good
yields under operationally straightforward conditions. Com-
pared to existing methods for analogous conversions, the
newly developed protocol appears synthetically attractive.
gent and an alkali salt additive under inert and anhydrous
conditions followed by an iodo–metal exchange.[11] Finally,
iodinated heterocycles can also be accessed by Finkelstein-
type substitution reactions of aryl halides[12] and Sandme-
yer reactions.[13]
Recently, we reported the functionalization of 1,3,4-oxa-
diazoles to give products with new C–P, C–S, and C–C
bonds (compounds A–C, Scheme 1).[14] To our surprise, we
noted that analogous iodination reactions were essentially
unexplored, although the resulting 2-halogenated products
appeared rather attractive for further functionalization.[15]
In fact, to the best of our knowledge, only a single example
of the direct iodination of an 1,3,4-oxadiazole has been re-
Introduction
1,3,4-Oxadiazoles are important heterocycles in medici-
nal chemistry that exhibit a broad array of bioactivities, and
they are used, for example, as antimicrobial, fungicidal, and
antibacterial agents.[1–4] Two representative bioactive com-
pounds are the antibiotic Furamizole and the antihyperten-
sive agent Nesapidil (Figure 1).[5] In material science, 1,3,4-
oxadiazoles have extensively been applied in organic light-
emitting diodes.[6]
Figure 1. 1,3,4-Oxadiazoles with pharmaceutical relevance.
Iodinated heteroarenes are common products in the
pharmaceutical industry, in medicine, and in crop protec-
tion, and furthermore, they serve as useful intermediates
in transition-metal-catalyzed cross-coupling reactions and
allow rapid access to diversified compound libraries.[7,8]
Several selective iodination methods are known. Owing to
the electron-deficient nature of many heterocycles, electro-
philic iodination reactions are often difficult to achieve;
they require strong, highly reactive iodinating agents such
as N-iodosuccinimide, N-iodosaccharin, iodine mono-
chloride, or iodonium salts such as IPy2BF4 (Barluenga’s
reagent, Py = pyridine).[7,9,10] A more effective method is
iododemetalation, which involves initial deprotonation of
the heteroarene with combination of an organometallic rea-
[a] Institute of Organic Chemistry, RWTH Aachen University,
Landoltweg 1, 52056 Aachen, Germany
E-mail: Carsten.Bolm@oc.rwth-aachen.de
http://bolm.oc.rwth-aachen.de/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403352.
Scheme 1. Functionalization of 2-substituted 1,3,4-oxadiazoles.
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C. A. Dannenberg, V. Bizet, L.-H. Zou, C. Bolm
SHORT COMMUNICATION
ported to date. Therein, Knochel and co-workers obtained (Table 1, entries 4–7). The most promising results were ob-
2a from 2-phenyl-1,3,4-oxadiazole (1a) in 80% yield by ap- tained with K2S2O8, NFSI, and Selectfluor, all of which
plying a deprotonative metalation strategy with 3 followed provided 2a in yields up to 45% (Table 1, entries 8–10).[18]
by halogenation of the resulting metalated intermediate The formation of 4a was still observed, but to a lower ex-
with molecular iodine (Scheme 1).[11a] On the basis of the tent. Assuming that the degradation pathways could be
expertise gained in our previous studies,[14] we wondered if minimized by lowering the reaction temperature, iodination
we could develop an alternative approach towards products with the latter three oxidants was also performed at 100 °C
such as 2a by circumventing the use of complex metal- and instead of 130 °C (Table 1, entries 11–13). To our delight,
salt-rich reagent mixtures such as 3. Herein, we report on the outcome was positive, and with NFSI and Selectfluor
the success of this study and describe the site-selective io- improved yields (of 51 and 58%, respectively) of 2a were
dination of 2-substituted 1,3,4-oxadiazoles by oxidative observed. Byproduct 4a was still formed, but to an accept-
halogenation reactions.[7,16,17]
able extent. As Selectfluor showed the best reactivity, it was
chosen as the oxidant for subsequent optimizations.
A solvent screening confirmed that acetonitrile was the
optimal solvent for the reaction. Only with 1,4-dioxane was
a comparable reactivity observed. Protic, polar solvents
(water, methanol, DMF) decomposed the starting mate-
rial.[19]
Table 2 summarizes the impact of the halide source on
the oxidative iodination of 1a. As the data show, the coun-
terion had a significant effect on the product yield. Among
ammonium, lithium, sodium, potassium, and cesium, only
the latter three led to moderate yields of 2a (Table 2, en-
tries 1–5). In all cases, 4a was formed as a byproduct. The
use of molecular iodine as the halide source (in varying
amounts) with and without Selectfluor afforded 2a in very
low yields (Table 2, entries 6–9).[20] In these reactions, up to
22% of 4a was obtained. Guided by the results of Jiao and
co-workers,[17] the oxidative iodination was performed with
the addition of various bases to improve the yield of 2a
(Table 2, entries 10–12). None of those attempts, however,
were successful. Apparently, the combination of sodium
iodide (1.2 equiv.) and Selectfluor (1.5 equiv. in the absence
of a base) were optimal and provided 2a under straightfor-
Results and Discussion
The investigation was initiated by an oxidant and tem-
perature screening with 2-phenyl-1,3,4-oxadiazole (1a) as
the model substrate and potassium iodide as the halogen
source. The results are summarized in Table 1.
Table 1. Oxidant and temperature screening.[a]
Entry
Oxidant[b]
Temp. [°C]
Yield of 2a [%][c]
1
2
O2
PIDA
130
130
130
130
130
130
130
130
130
130
100
100
100
n.d. (5)
n.d. (n.d)
n.d. (n.d.)
6 (10)
10 (22)
8 (24)
10 (38)
45 (11)
47 (5)
34 (6)
7 (17)
51 (1)
58 (8)
3
4
PIFA
DTBP
5
6
7
8
K3[Fe(CN)6]
NaIO4
Oxone®
K2S2O8
NFSI
Table 2. Screening of the iodine source.[a]
9
10
11
12
13
Selectfluor
K2S2O8
NFSI
Selectfluor
[a] The reaction was performed in a sealed tube on a 0.2 mmol scale
by using the oxidant (1.5 equiv.) and KI (1.2 equiv.) in acetonitrile
(3 mL). [b] PIDA: [bis(acetoxy)iodo]benzene. PIFA: [bis(trifluoro-
acetoxy)iodo]benzene. DTBP: di-tert-butyl peroxide. NFSI: N-
fluorodibenzenesulfonimide. Selectfluor: 1-chloromethyl-4-fluoro-
1,4-diazoniabicyclo[2.2.2]octane. [c] Determined by 1H NMR spec-
troscopy. n.d.: not detected. The values in parentheses refer to the
yield of 4a.
Entry
Iodine source
Base[b]
Yield 2a [%][c]
1
2
3
4
5
6
NH4I
LiI
NaI
KI
CsI
I2
I2
I2
I2
–
–
–
–
–
–
–
–
6 (15)
16 (8)
69 (8)
58 (8)
62 (12)
10 (22)
8 (20)
4 (12)
4 (22)
7 (23)
15 (5)
n.d. (n.d.)
7[d]
8[e]
9[e]
10
11
12
As hypothesized, target compound 2a was indeed formed
under these oxidative conditions (at 130 °C) and most oxi-
dants exhibited activity. Unfortunately, however, in many
cases the yields of 2a were low, mainly because of the lack
of conversion of 1a, decomposition of the starting material,
and the formation of hydrolysis product 4a. Dioxygen,
PIFA, and PIDA proved unsuitable oxidants, and at best,
trace amounts of 4a were detected (Table 1, entries 1–3).
The use of DTBP, K3[Fe(CN)]6, NaIO4, and Oxone gave 2a
NaHCO3
LiOtBu
NaHCO3
Et3N
NaI
NaI
NaI
[a] The reaction was performed in a sealed tube on a 0.2 mmol scale
by using Selectfluor (1.5 equiv.) and the iodine source (1.2 equiv.) in
acetonitrile (3 mL). [b] Use of 1.5 equiv. of base. [c] Determined by
1H NMR spectroscopy. n.d.: not detected. The values in parenthe-
ses refer to the yield of 4a. [d] Without Selectfluor. [e] Use of
in very low yields, and the formation of 4a dominated 0.6 equiv. of iodine.
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Transition-Metal-Free Oxidative Iodination of 1,3,4-Oxadiazoles
ward conditions in 69% yield (Table 2, entry 3). The 2m was studied. Although the yield of 2m was only 39%,
amount of 4a remained at 8%. this positive result represented a promising basis for future
Next, the substrate scope was examined by using 1,3,4- investigations. To our delight, the iodination of 2-phenyl-
oxadiazoles with various substituents at the C2 atom. The 1,3,4-thiadiazole (1n) proceeded well to afford the corre-
results are summarized in Table 3. The use of aryl-substi- sponding product in 87% yield.[21]
tuted substrates with electron-withdrawing groups led to
Performing the oxidative iodination of 1a on a 4 mmol
the corresponding products (i.e., 2a–e) in yields ranging scale gave 2a in 60% yield (together with 17% of unreacted
from 62 to 69%. Having electron-donating substituents on 1a and 15% of 4a), which confirmed the scalability of the
the connected arene lowered the reactivity, and the iodin- process.[22]
ated oxadiazoles (i.e., 2i–f) were obtained in yields between
Attempts to use the same methodology for the introduc-
32 and 59%. The position of the substituent had a negligi- tion of a bromo or chloro substituent onto 1,3,4-oxadiazole
ble effect, as revealed by the results for para- and ortho- 1a were unsatisfying. With NaBr (instead of NaI), corre-
methyl-substituted products 2g and 2h, which were ob- sponding brominated product 5 was only observed in trace
tained in yields of 57 and 59%, respectively. 2-Naphthyl- quantities, and to our surprise, chlorination of 1a occurred.
1,3,4-oxadiazole (1j) reacted well to provide product 2j in Apparently, Selectfluor served as a halide source, and as a
54% yield. Neither pyridinyl-containing 2k nor para-di- result chlorinated 1,3,4-oxadiazole 6 was formed in 30%
methylamino-substituted 2l could be obtained by this pro- yield.[23] Substituting NaI with NaCl led to the same prod-
cedure, presumably as a result of two factors: one, the pres- uct (i.e., 6) in 33% yield.[24]
ence of basic nitrogen atoms hampers the iodination pro-
cess; two, their pronounced sensitivity towards the oxidants
present in the reaction mixture. As a representative example
of 2-alkyl-substituted 1,3,4-oxadiazoles, the formation of
Conclusions
In summary, we developed the oxidative iodination of
1,3,4-oxadiazoles by using NaI as the halogen source and
Selectfluor as the oxidant. Although in some cases the
product yields were only moderate, the protocol is attractive
because it circumvents the use of complex metal mixtures
and does not require an inert atmosphere or anhydrous re-
action conditions. Its applicability to 1,3,4-thiadiazoles was
exemplified. Further iodination reactions of other heterocy-
clic compounds are currently under investigation in our
laboratories.
Table 3. Substrate scope under optimized reaction conditions.[a]
Experimental Section
Procedure for the Synthesis of 2-Substituted 5-Iodo-1,3,4-oxadi-
azoles: A sealed tube, equipped with a magnetic stir bar, was
charged with 2-substituted-1,3,4-oxadiazole
1
(0.5 mmol,
1.0 equiv.), NaI (89.9 mg, 0.6 mmol, 1.2 equiv.), Selectfluor
(265.7 mg, 0.75 mmol, 1.5 equiv.), and acetonitrile (5 mL). Then,
the mixture was stirred at 100 °C for 24 h. After cooling to room
temperature, the mixture was diluted with CH2Cl2 (10 mL) and
washed with a saturated aqueous solution of Na2S2O3 (10 mL).
After extracting the aqueous phase with CH2Cl2 (2ϫ 10 mL) the
organic phases were combined, dried with MgSO4, and filtered.
The mixture was evaporated under reduced pressure, and the resi-
due was purified by column chromatography (n-pentane/ethyl acet-
ate, 11:1) to yield iodinated product 2.
Acknowledgments
V. B. and L.-H. Z. acknowledge the Alexander von Humboldt
Foundation and the China Scholarship Council (CSC), respec-
tively, for fellowships. The authors thank Jakob Mottweiler
(RWTH Aachen University) for fruitful discussions and proofread-
ing the manuscript.
[a] Performed in sealed tubes on a 0.5 mmol scale in acetonitrile
(5 mL). [b] Use of NaBr for 5 and NaCl for 6 instead of NaI.
[1] G. Majji, S. K. Rout, S. Guin, A. Gogoi, B. K. Patel, RSC Adv.
2014, 4, 5357–5362.
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SHORT COMMUNICATION
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Received: October 15, 2014
Published Online: ᭿
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Transition-Metal-Free Oxidative Iodination of 1,3,4-Oxadiazoles
Metal-Free Iodination
C. A. Dannenberg, V. Bizet, L.-H. Zou,
C. Bolm* ........................................... 1–5
Transition-Metal-Free Oxidative Iodin-
ation of 1,3,4-Oxadiazoles
The transition-metal-free oxidative iodin-
ation of 2-substituted 1,3,4-oxadiazoles is
developed to provide products in moderate
to good yields with NaI as the halogen
source and Selectfluor as the oxidant.
Neither anhydrous conditions nor an inert
atmosphere is required, which renders this
process synthetically attractive.
Keywords: Synthetic methods / Iodine /
Oxidation / Nitrogen heterocycles / Oxa-
diazoles
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