Intramolecular iodine-mediated oxygen transfer from nitro groups to C≡C bonds

Article abstract of DOI:10.1002/ejoc.201200100

Highly regioselective oxygen transfer from nitro groups to C≡C bonds has been achieved by employment of iodine monochloride or molecular iodine. The precursors are heterocyclic, aromatic or acyclic compounds, each bearing a nitro group ortho to an interna

Full text of DOI:10.1002/ejoc.201200100

FULL PAPER
DOI: 10.1002/ejoc.201200100
Intramolecular Iodine-Mediated Oxygen Transfer from Nitro Groups to CϵC
Bonds
Inga Cikotiene*[a]
Keywords: Cycloisomerization / Cyclization / Regioselectivity / Nitro compounds / Alkynes / Iodine
Highly regioselective oxygen transfer from nitro groups to
CϵC bonds has been achieved by employment of iodine
monochloride or molecular iodine. The precursors are hetero-
cyclic, aromatic or acyclic compounds, each bearing a nitro
tion in the isoxazole ring. It is very important to note that the
outcomes of the cycloisomerizations are not dictated by the
natures of the heterocycle or alkyne substituents. Moreover,
this is a unique example of iodine-mediated ring closure of
group ortho to an internal alkyne. The developed methodol- internal alkynes without introduction of halogen into the
ogy is general for the preparation of a wide range of fused
isoxazoles, each bearing a carbonyl function in the fifth posi-
newly formed rings.
Introduction
Cyclization of alkynes containing adjacent nucleophilic butylammonium fluoride (TBAF),[4c] nitrosobenzene,[4e,5]
centers is currently of considerable interest and developing or UV light.[6]
into one of the most effective strategies for heterocyclic ring
Usually these classic reactions take long times and re-
construction. This chemistry provides a straightforward ap- quire high temperatures. On the other hand, nitro-alkyne
proach to the synthesis of functionalized carbo- and hetero- cycloisomerization can be effectively catalyzed by metal cat-
cycles through regio- and stereoselective addition of a nu- alysts under relatively mild reaction conditions. In metal-
cleophile to an unsaturated carbon unit across the carbon- mediated nitro-alkyne cycloisomerizations, however, forma-
carbon triple bond.[1] A variety of transition-metal- or elec- tion of two products – isatogens B and/or anthranils C
trophile-induced 5-exo-dig or 6-endo-dig cyclization reac- (Scheme 1) – is possible. o-Alkynylnitrobenzenes thus selec-
tions have been reported.[2] ortho-Alkynyl nitrobenzenes A tively formed isatogens B in the presence of a catalytic
(Scheme 1) are well known as precursors for the prepara- amount of Pd(CH3CN)2Cl2,[7] whereas o-arylalkynylnitro-
tion of isatogens B. Since Baeyer’s pioneering work,[3]
a
benzenes formed mixtures of isatogens B and anthranils C
variety of intramolecular cyclizations of o-alkynylnitro- in the presence of gold(III) bromide.[8] On the other hand,
benzenes have been reported. The classical cycloisomeriza- o-alkylalkynylnitrobenzenes were converted selectively into
tions of starting compounds A to afford isatogens B can be anthranils C in the presence of gold(III) bromide[8] or irid-
initiated by concentrated sulfuric acid,[3] pyridine,[4] tetra- ium hydride complex.[9]
Scheme 1. Literature results.
Several years ago we developed a concise and high-yield-
[a] Department of Organic Chemistry, Faculty of Chemistry,
ing route to pyrrolo[3,2-d]pyrimidin-7-one 5-oxides E
Vilnius University,
(Scheme 2) through smooth cycloisomerization of 2,4-di-
substituted 6-arylethynyl-5-nitropyrimidines D in the pres-
ence of pyridine. We showed that the triple bonds in the
starting compounds are electron-poor, so cycloisomeriza-
Naugarduko 24, 03225 Vilnius, Lithuania
Fax: +370-5-233-09-87
E-mail: inga.cikotiene@chf.vu.lt
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200100.
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Eur. J. Org. Chem. 2012, 2766–2773

Intramolecular Oxygen Transfer
tion takes only few minutes and does not require transition-
metal catalysts, UV initiation, or harsh conditions.[10] It was
also shown by us that electron-rich 2-alkynyl-3-nitrothio-
phenes F (Scheme 2) underwent smooth regioselective in-
tramolecular cycloisomerization to afford thieno[2,3-c][1,2]-
oxazoles G in the presence of gold(III) chloride or silver(I)
trifluoroacetate. It is notable that the outcomes of the cycli-
zations of 2-alkynyl-3-nitrothiophenes F were not dictated
by the natures of the alkyne substituents.[11]
Figure 1. Nitro-alkyne precursors. 1: R = Ph (a), Bu (b), 4-
CH3C6H4 (c), 4-C2H5C6H4 (d), 2-Py (e), tBu (f), H (g). 2: R =
Ph (a), c-Pr (b). 3: R = Ph, RЈ = OCH3 (a), R = c-Pr, RЈ = H (b).
4: R = Ph (a), Bu (b), 4-CH3C6H4 (c), 4-C2H5C6H4 (d), c-Pr (e),
H (f). 5: R = Ph (a), Bu (b).
Scheme 2. Our previous results.
phenes 1a, 1b, and 2a, benzenes 3a and 3b, pyridines 4a and
4b, and pyrimidines 5a and 5b under the different condi-
tions are presented in Table 1.
Molecular iodine has recently been reported to function
as a Lewis acid and to impart high regio- and chemoselec-
tivity in various transformations.[12] Use of iodine as a
Lewis acid has been increasing exponentially for the last
decade, due to its high tolerance to air and moisture, low
cost, and high catalytic activity both under dilute and under
highly concentrated conditions, as well as under solvent-
free reaction conditions. It is also known that I+ is a soft
electrophilic reagent that can promote the intramolecular
attack of carbon, oxygen, and nitrogen nucleophiles on al-
kynes.[13] In continuation of our research into cycloisomer-
izations of various substrates containing various functional
groups and alkynyl moieties in close proximity to one an-
other, it was envisioned that electrophilic iodine could well
activate CϵC bonds in nitro-alkyne cycloisomerizations.
Indeed, highly regioselective iodine-mediated nitro-alkyne
cycloisomerizations of various substrates were observed.
Here we report the results of our investigations.
Scheme 3. Cycloisomerization of nitro-alkyne precursors.
The feasibility of the nitro-alkyne cycloisomerization was
examined with the catalysts most commonly described in
the literature: gold(III) bromide (Table 1, Method A),
PdCl2(CH3CN)2 (Table 1, Method B) and pyridine (Table 1,
Method C). Moreover, the potential for the use of iodine
monochloride to initiate nitro-alkyne cycloisomerization
was also studied (Table 1, Method D).
Use of gold(III) bromide in dichloromethane at room
temperature (Table 1, Method A, Entries 1–3) led to the se-
lective formation of (thieno[2,3-c][1,2]oxazol-3-yl)-meth-
anones 9a and 9b (Figure 2, below) and phenyl(thieno[2,3-
c][1,2]oxazol-3-yl)methanone (10a). Treatment of benzene
Results and Discussion
The starting compounds, each bearing a nitro group and derivative 3a with AuBr3 (5 mol-%) in dichloromethane at
an ethynyl moiety in close proximity (Figure 1), were syn- room temperature gave the mixture of isatogen 6a and the
thesized by classical Sonogashira coupling[14] between halo- 2,1-benzoxazol 11a (Table 1, Method A, Entry 4). On the
gen derivatives and terminal acetylenes. 2-Alkynyl-3-nitro- other hand, 1-cyclopropylethynyl-2-nitrobenzene (3b) was
thiophenes 1a–g, 3-alkynyl-2-nitrothiophenes 2a, 2b, 2-alk- selectively converted into 2,1-benzoxazol 11b in the pres-
ynylnitrobenzenes 3a, 3b, 2-alkynyl-3-nitropyridines 4a–f, ence of AuBr3 (Table 1, Method A, Entry 5). However, pyr-
and 4-alkynyl-5-nitropyrimidines 5a, 5b were prepared.
idine and pyrimidine systems 4a/4b and 5a/5b with nitro-
The prepared heteroaryl and aryl substrates, each bear- alkyne substrates were completely unreactive toward cyclo-
ing a nitro group and an alkynyl substituent in close prox- isomerization conditions on exposure to AuBr3. In all these
imity to one another, can undergo cycloisomerization reac- cases (Table 1, Method A, Entries 6–9) the starting materi-
tions into products containing either pyrrol-3-one 1-oxide als were recovered after workup of the reaction mixtures.
or isoxazole rings (Scheme 3), so the scope of nitro-alkyne
Next, the scope of the cycloisomerization described by
cycloisomerization of various substrates bearing both Ramana et al. (Table 1, Method B)[7] was studied.
phenyl and alkyl substituents on their alkyl moieties was Pd(CH3CN)2Cl2 worked well with benzene substrates 3a
explored first. The results of cycloisomerizations of thio- and 3b. Both compounds were converted selectively into
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I. Cikotiene
FULL PAPER
Table 1. Study of cycloisomerization of selected nitro-alkyne precursors.
Entry Starting
compound
R
Products of cycloisomerization reactions (yield, %)
Method A[a]
Method B[b]
Method C[c]
Method D[d]
[e]
1
2
3
4
5
6
7
8
9
1a
Ph
Bu
Ph
9a (97%)
9a (33%)
no reaction
no reaction
no reaction
no reaction
no reaction
7 (82%)
no reaction
8 (96%)
no reaction
9a (98%)
9b (99%)
10a (88%)
[e]
1b
2a
3a
3b
4a
4b
5a
5b
9b (91%)
9b (37%)
10a (45%)[e]
10a (15%)[e]
6a (55%)
Ph (RЈ = OCH3) 6a (60%) and 11a (29%)
c-Pr (RЈ = H)
Ph
Bu
Ph
Bu
6a (3%) and 11a (87%)
11b (99%)
11b (76%)
no reaction
no reaction
no reaction
no reaction
6b (49%)[e]
no reaction
no reaction
no reaction
no reaction
12a (92%)
12b (93%)
13 (69%)
complicated[f]
[a] Reaction conditions: AuBr3 (5 mol-%), DCM, r.t., 2 h. [b] Reaction conditions: PdCl2(CH3CN)2 (5 mol-%), CH3CN, r.t., 6 h. [c] Reac-
tion conditions: heating of the starting material at reflux in dry pyridine (20 min for 5a and 2 h for 4a). [d] Reaction conditions: ICl
(3 mol-%), DCE, reflux (30 min for 1–3, 1 h for 4, 4 h for 5). [e] Incomplete conversion of the starting material after 24 h. [f] A lot of
byproducts were formed.
3H-indol-3-one 1-oxides 6a and 6b (Table 1, Method B, En-
After these intriguing results, the best conditions for trig-
tries 4 and 5). However, the palladium complex gave dif- gering iodine-mediated regioselective oxygen transfer from
ferent selectivity with thiophene substrates 1a, 1b, and 2a, nitro groups to alkyne moieties were optimized. First of all,
which were converted into methanones 9a, 9b, and 10a in some other sources of iodine were also studied. It should
low yields (Table 1, Method B, Entries 1–3). It should be be noted that iodine monochloride gave the best results in
also noted that the conversions of the starting thiophenes terms of yields, amount of the catalyst, and reaction time.
were incomplete after prolonged heating of the reaction Another good catalyst for nitro-alkyne cycloisomerization
mixtures. Pyridine and pyrimidine derivatives 4a/4b and 5a/ is molecular iodine. To determine its effectiveness, reactions
5b remained unchanged on treatment with Pd(CH3CN)2Cl2 were run with different concentrations of it (1 mol-%,
(Table 1, Method B, Entries 6–9).
5 mol-%, 10 mol-%, 20 mol-%, and 50 mol-%). The reaction
The pyridine-initiated cycloisomerization was successful took place at all concentrations, but 20 mol-% of iodine was
only in cases of electron-poor heterocycles bearing phenyl- found to be the best. Bis(pyridine)iodonium tetrafluorobor-
ethynyl moieties in close proximity to their nitro groups. ate, however, did not promote the cycloisomerization effec-
The pyridine derivative 4a and the pyrimidine 5a were con- tively.
verted into the corresponding heterocyclic isatogen ana-
logues 7 and 8 on heating at reflux in dry pyridine (Table 1, solvent in comparison with acetonitrile, methanol, tetra-
Method C, Entries 6 and 8). hydrofuran, dimethylformamide, and 1,4-dioxane. The iod-
1,2-Dichloroethane was found to be the most suitable
It was therefore possible to conclude at this stage of the ine-mediated cycloisomerization reactions of the starting ni-
investigation that metal catalysts AuBr3 and Pd(CH3- tro-alkyne precursors proceeded readily and in the most
CN)2Cl2 gave satisfactory results only in the cases of cases showed excellent regioselectivity independently of alk-
benzene derivatives and electron-rich thiophene heterocy- yne substituent and the nature of the heterocycle (Figure 2).
cles. Whereas gold(III) bromide usually leads to the forma- However, it should be noted that 2-ethynyl-3-nitrothio-
tion of isoxazoles, the palladium complex catalyzes the cy- phene (1g) and 2-ethynyl-3-nitropyridine (4f) did not un-
cloisomerization of o-alkynylnitrobenzenes to 3H-indol-3- dergo cycloisomerization on heating at reflux in dichloro-
one 1-oxides 6a and 6b, but also leads to the formation of ethane in the presence of molecular iodine. In these two
thieno-isoxazoles 9a, 9b, and 10a in low yields. The nucleo- cases the slow formation of diiodo compounds 14 and 15
philic initiation of nitro-alkyne cycloisomerization by pyr- took place. Probably, the absence of a substituent on the
idine is possible only in cases of electron-poor heterocycles alkyne moiety favors electrophilic 1,2-addition of iodine to
bearing aryl substituents on their alkyne moieties.
the triple bond. On the other hand, the presence of an alkyl
Next the possibility of using iodine monochloride as a or aryl substituent on the alkyne moiety and of the nitro
mild Lewis acid for the promotion of nitro-alkyne cyclo- group in the ortho-position sterically disfavor 1,2-addition,
isomerization was studied. The starting nitro-alkyne sub- and intramolecular oxygen transfer from the nitro group
strates were heated at reflux in dichloroethane in the pres- takes place.
ence of ICl (3 mol-%). A pleasant surprise was to see that
A possible mechanism of the cycloisomerization reaction
the regioselective cycloisomerization reactions of com- is presented in Scheme 4. It seems that the iodine catalyst
pounds 1–5 into products 9–13, containing isoxazole rings, behaves in a way very similar to that in related gold-cata-
took place in almost all cases (Table 1, Method D, En- lyzed oxygen functionality transfer reactions.[15] After the
tries 1–8). The exception was the cycloisomerization of 6- direct iodonium activation (intermediate I) of the triple
(hex-1-ynyl)-4-morpholinyl-5-nitropyrimidine 5b. The reac- bond, the intramolecular 6-endo-dig nucleophilic attack of
tion behavior of compound 5b was complicated, leading to the oxygen of the nitro group takes place, leading to the
a mixture of various products (Table 1, Method D, En- formation of the intermediate II. Cleavage of the N–O bond
try 9).
gives the intermediate III, which undergoes recyclization to
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Eur. J. Org. Chem. 2012, 2766–2773

Intramolecular Oxygen Transfer
Figure 2. Compounds prepared through iodine-mediated cycloisomerization of various nitro-alkyne precursors.
IV. Finally, abstraction of iodine by an anion leads to the out the introduction of halogen or oxygen from the solvent
aromatization of the isoxazole moiety and regeneration of into the newly formed ring. Moreover, the developed
the catalyst.
method can be used broadly for the preparation of fused
isoxazoles through nitro-alkyne cycloisomerization of either
electron-rich or electron-poor substrates. The reaction con-
ditions employed are catalytic in nature and mild, accom-
modating both aryl and alkyl substituents on the alkyne
moieties.
Conclusions
The first examples of iodine-mediated regioselective ni-
tro-alkyne cycloisomerization have been demonstrated. The
method has several advantages over metal-mediated reac-
tions, such as low cost, tolerance to air and moisture, and
high regioselectivity. The outcomes of the cycloisomeriza-
tions are not dictated by the natures of the heterocycles or
the alkyne substituents. Moreover, they represent unique ex-
amples of iodine-mediated ring closure of internal alkynes
without introduction of halogen into the newly formed
rings, and constitute the first report of highly regioselective
nitro-alkyne cycloisomerization through a 6-endo-dig pro-
cess. A new, simple, and high-yielding synthetic route to a
range of compounds containing the isoxazole framework is
therefore presented.
Scheme 4. Possible mechanism for the iodine-mediated nitro-alkyne
cycloisomerization.
It is well known from the literature that various intramo-
lecular transformations of functionally substituted alkynes
can be carried out either with gold catalysts or with iodine
electrophiles to access the same core unit in an analogous
manner.
In almost all cases electrophilic cyclization results in in-
corporation of iodine in the final product,[13] whereas gold
catalysis typically results in hydrogen at the same position,
due to the protodeauration step required for catalyst regen-
eration.[15,16] The method presented here is a unique exam-
Experimental Section
IR spectra were measured with a Perkin–Elmer FT Spectrum BX II
ple of iodine-mediated ring closure of internal alkynes with- spectrophotometer (KBr discs). 1H and 13C NMR spectra were re-
Eur. J. Org. Chem. 2012, 2766–2773
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I. Cikotiene
FULL PAPER
corded with a Varian Unity INOVA spectrometer (300 MHz) with
use of residual solvent peaks as internal standards. HRMS spectra
were obtained with a Dual-ESI Q-TOF 6520 mass spectrometer
(Agilent Technologies). All reactions and the purities of the synthe-
sized compounds were monitored by TLC with silica gel 60 F254
aluminum plates (Merck). Visualization was accomplished by use
of UV light.
tBu), 7.31 [d, J = 6.0 Hz, 1 H, C(4)-H], 7.55 [d, J = 6.0 Hz, 1 H,
C(5)-H] ppm. 13C NMR (75 Hz, CDCl3, 25 °C): δ = 28.2, 30.5,
70.2, 100.3, 120.3, 124.3, 126.2, 143.6 ppm. IR (KBr): νmax = 2224
˜
(CϵC) cm–1. HRMS (ES): calcd. for C10H12NO2S [M + H]+
210.0583; found 210.0570.
2-Ethynyl-3-nitrothiophene (1g): Compound 1g was prepared from
the intermediate 3-nitro-2-trimethylsilylthiophene (obtained by
Sonagashira coupling) by treatment with potassium fluoride in
methanol solution at room temperature for 20 min. Purification
was accomplished by column chromatography. Yellowish solid;
General Procedure for the Preparation of Compounds 1–5: A mix-
ture of the appropriate nitroaryl halide (5 mmol), PdCl2(PPh3)2
(5 mol-%), and Et3N (1.01 g; 10 mmol) was suspended in anhy-
drous THF (8 mL). The appropriate acetylene (1.1 equiv.) was then
injected under argon, followed by addition of CuI (2.5 mol-%). The
reaction mixture was stirred under argon at 40 °C temperature until
full completion (normally 1–3 h, completion observed by TLC).
Solvent was evaporated under the reduced pressure; the crude resi-
due was purified by column chromatography (elution by mixtures
of hexane and ethyl acetate).
1
yield 85%; m.p. 89–90 °C. H NMR (300 MHz, CDCl3, 25 °C): δ
= 3.90 (s, 1 H, ϵC–H), 7.25 [d, J = 5.7 Hz, 1 H, C(4)-H], 7.58 [d,
J = 5.7 Hz, 1 H, C(5)-H] ppm. 13C NMR (75 Hz, CDCl3, 25 °C):
δ = 73.1, 90.7, 123.5, 123.7, 126.1, 139.3 ppm. IR (KBr): ν
=
˜
max
3268 (ϵC–H), 2104 (CϵC) cm–1. HRMS (ES): calcd. for
C6H4NO2S [M + H]+ 153.9957; found 153.9966.
2-Nitro-3-(phenylethynyl)thiophene (2a): Yellowish oil; yield 80%.
1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.15 [d, J = 5.4 Hz, 1 H,
C(4)-H], 7.38–7.41 (m, 3 H, ArH), 7.45 [d, J = 5.4 Hz, 1 H, C(5)-
H], 7.61–7.64 (m, 2 H, ArH) ppm. 13C NMR (75 Hz, CDCl3,
25 °C): δ = 82.3, 99.4, 121.9, 128.5, 129.2, 129.6, 130.1, 131.3,
3-Nitro-2-(phenylethynyl)thiophene (1a): Yellowish solid; yield 69%;
1
m.p. 62–64 °C. H NMR (300 MHz, CDCl3, 25 °C): δ = 7.25 [d, J
= 6.0 Hz, 1 H, C(4)-H], 7.42–7.45 (m, 3 H, ArH), 7.63–7.66 (m, 2
H, ArH), 7.64 [d, J = 6.0 Hz, 1 H, C(5)-H] ppm. 13C NMR (75 Hz,
CDCl3, 25 °C): δ = 79.6, 102.8, 121.7, 123.7, 125.2, 125.4, 128.5,
132.1, 132.4 ppm. IR (KBr): ν
= 2205 (CϵC) cm–1. HRMS
˜
max
129.7, 131.9, 147.9 ppm. IR (KBr): ν
= 2207 (CϵC) cm–1.
(ES): calcd. for C12H8NO2S [M + H]+ 230.0270; found 230.0275.
˜
max
HRMS (ES): calcd. for C12H8NO2S [M + H]+ 230.0270; found
3-(Cyclopropylethynyl)-2-nitrothiophene (2b): Yellowish oil; yield
230.0269.
1
84%. H NMR (300 MHz, CDCl3, 25 °C): δ = 0.94–1.01 (m, 4 H,
2-(Hex-1-ynyl)-3-nitrothiophene (1b): Yellow oil; yield 90%. 1H
NMR (300 MHz, CDCl3, 25 °C): δ = 0.93 (t, J = 7.5 Hz, 3 H,
CH2CH2CH2CH3), 1.44–1.52 (m, 2 H, CH2CH2CH2CH3), 1.58–
1.67 (m, 2 H, CH2CH2CH2CH3), 2.53 (t, J = 7.5 Hz, 2 H,
CH2CH2CH2CH3), 7.10 [d, J = 5.7 Hz, 1 H, C(4)-H], 7.50 [d, J =
5.7 Hz, 1 H, C(5)-H] ppm. 13C NMR (75 Hz, CDCl3, 25 °C): δ =
13.5, 19.8, 21.9, 30.0, 71.1, 105.9, 123.2, 124.1, 126.4, 147.5 ppm.
c-Pr), 1.51–1.59 (m, 1 H, c-Pr), 7.00 [d, J = 5.7 Hz, 1 H, C(4)-H],
7.38 [d, J = 5.7 Hz, 1 H, C(5)-H] ppm. 13C NMR (75 Hz, CDCl3,
25 °C): δ = 0.9, 9.6, 69.3, 105.9, 124.3, 129.9, 131.6, 147.8 ppm. IR
(KBr):
ν
=
2220 (CϵC) cm–1. HRMS (ES): calcd. for
˜
max
C9H8NO2S [M + H]+ 194.0270; found 194.0272.
1,2-Dimethoxy-4-nitro-5-(phenylethynyl)benzene (3a): Yellow solid;
1
= 2225 (CϵC) cm–1. HRMS (ES): calcd. for
yield 67%; m.p. 117–118 °C. H NMR (300 MHz, CDCl3, 25 °C):
IR (KBr): ν
˜
max
C10H12NO2S [M + H]+ 210.0583; found 210.0566.
δ = 4.02 (s, 3 H, OCH3), 4.04 (s, 3 H, OCH3), 7.12 (s, 1 H, ArH),
7.40–7.43 (m, 3 H, ArH), 7.63–7.65 (m, 2 H, ArH), 7.73 (s, 1 H,
ArH) ppm. 13C NMR (75 Hz, CDCl3, 25 °C): δ = 56.3, 56.5, 85.7,
95.8, 107.6, 115.0, 127.5, 128.3, 128.4, 128.9, 131.8, 142.5, 148.7,
2-[(4-Methylphenyl)ethynyl]-3-nitrothiophene (1c): Yellow solid;
1
yield 74%; m.p. 70–71 °C. H NMR (300 MHz, CDCl3, 25 °C): δ
= 2.39 (s, 3 H, CH3), 7.18–7.21 [m, 3 H, ArH and C(4)-H], 7.49
(d, J = 8.1 Hz, 2 H, ArH), 7.60 [d, J = 5.7 Hz, 1 H, C(5)-H] ppm.
13C NMR (75 Hz, CDCl3, 25 °C): δ = 21.9, 79.6, 103.7, 118.9,
152.7 ppm. IR (KBr): ν
= 2211 (CϵC) cm–1. HRMS (ES):
˜
max
calcd. for C16H14NO4 [M + H]+ 284.0917; found 284.0930.
1-(Cyclopropylethynyl)-2-nitrobenzene (3b): Yellowish oil; yield
91%. H NMR (300 MHz, CDCl3, 25 °C): δ = 0.90–0.98 (m, 4 H,
123.9, 125.3, 126.1, 129.6, 132.2, 140.6, 148.1 ppm. IR (KBr): ν
=
˜
max
1
2196 (CϵC) cm–1. HRMS (ES): calcd. for C13H10NO2S
[M + H]+ 244.0427; found 244.0439.
c-Pr), 1.48–1.57 (m, 1 H, c-Pr), 7.38 (td, J = 7.1, 2.1 Hz, 1 H, ArH),
7.49–7.58 (m, 2 H, ArH), 7.96–7.99 (m, 1 H, ArH) ppm. 13C NMR
(75 Hz, CDCl3, 25 °C): δ = 0.6, 9.1, 71.1, 102.6, 119.3, 124.3, 127.5,
2-[(4-Ethylphenyl)ethynyl]-3-nitrothiophene (1d): Yellow solid; yield
88%; m.p. 72–74 °C. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.25
(t, J = 7.5 Hz, 3 H, CH3), 2.68 (q, J = 7.5 Hz, 2 H, CH2), 7.18–
7.24 [m, 3 H, ArH and C(4)-H], 7.53 (d, J = 8.1 Hz, 2 H, ArH),
7.59 [d, J = 5.7 Hz, 1 H, C(5)-H] ppm. 13C NMR (75 Hz, CDCl3,
25 °C): δ = 14.8, 28.5, 78.8, 99.5, 102.9, 118.4, 123.1, 124.5, 127.7,
132.5, 134.5, 149.8 ppm. IR (KBr): ν
= 2232 (CϵC) cm–1.
˜
max
HRMS (ES): calcd. for C11H10NO2 [M + H]+ 188.0706; found
188.0711.
3-Nitro-2-(phenylethynyl)pyridine (4a): Beige solid; yield 82%; m.p.
107–109 °C (propan-2-ol). 1H NMR (300 MHz, CDCl3, 25 °C): δ
= 7.42–7.51 (m, 4 H, ArH), 7.70–7.73 (m, 2 H, ArH), 8.42 [dd, J
= 8.1, 1.2 Hz, 1 H, C(4)-H], 8.84 [d, J = 3.6, 1 H, C(6)-H] ppm.
13C NMR (75 Hz, CDCl3, 25 °C): δ = 85.0, 97.8, 121.3, 122.6,
131.5, 132.0, 146.0 ppm. IR (KBr): ν
= 2203 (CϵC) cm–1.
˜
max
HRMS (ES): calcd. for C14H12NO2S [M + H]+ 258.0583; found
258.0577.
2-[(3-Nitrothien-2-yl)ethynyl]pyridine (1e): Yellow solid; yield 71%;
1
128.5, 130.1, 132.5, 132.6, 137.5, 146.2, 153.5 ppm. IR (KBr): ν
=
˜
m.p. 112–114 °C. H NMR (300 MHz, CDCl3, 25 °C): δ = 7.30 [d,
max
2223 (CϵC) cm–1. HRMS (ES): calcd. for C13H9N2O2
[M + H]+ 225.0659; found 225.0666.
J = 5.7 Hz, 1 H, C(4)-H], 7.30–7.34 (m, 1 H, ArH), 7.61 [d, J =
5.7 Hz, 1 H, C(5)-H], 7.64 (dt, J = 7.8, 1.2 Hz, 1 H, ArH), 7.71–
7.78 (m, 1 H, ArH), 8.64–8.66 (m, 1 H, ArH) ppm. 13C NMR
(75 Hz, CDCl3, 25 °C): δ = 79.0, 100.3, 123.7, 123.9, 125.1, 126.7,
2-(Hex-1-ynyl)-3-nitropyridine (4b): Brownish oil; yield 89%. 1H
NMR (300 MHz, CDCl3, 25 °C): δ = 0.90 (t, J = 7.2 Hz, 3 H,
CH2CH2CH2CH3), 1.40–1.50 (m, 2 H, CH2CH2CH2CH3), 1.57–
1.66 (m, 2 H, CH2CH2CH2CH3), 2.50 (t, J = 6.9 Hz, 2 H,
CH2CH2CH2CH3), 7.34–7.38 [m, 1 H, C(5)-H], 8.24 [dd, J = 8.25;
128.0, 136.6, 141.9, 148.8, 150.1 ppm. IR (KBr): ν
= 2211
˜
max
(CϵC) cm–1. HRMS (ES): calcd. for C11H7N2O2S [M + H]+
231.0223; found 231.0218.
2-(3,3-Dimethylbut-1-ynyl)-3-nitrothiophene (1f): Yellowish oil; 1.5 Hz, 1 H, C(4)-H], 8.73 [brs, 1 H, C(6)-H] ppm. 13C NMR
1
yield 69%. H NMR (300 MHz, CDCl3, 25 °C): δ = 1.35 (s, 9 H,
(75 Hz, CDCl3, 25 °C): δ = 13.4, 19.4, 21.9, 29.8, 76.5, 100.8, 122.2,
2770
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2766–2773

Intramolecular Oxygen Transfer
128.2, 132.1, 137.5, 153.0 ppm. IR (KBr): νmax = 2228 (CϵC) cm–1. Palladium(II)-Mediated Cycloisomerization: The palladium(II)-me-
˜
HRMS (ES): calcd. for C11H13N2O2 [M + H]+ 205.0972; found diated cycloisomerization was performed by the method reported
205.0992.
by Ramana et al.[7]
5,6-Dimethoxy-2-phenyl-3H-indol-3-one 1-Oxide (6a): Violet solid;
yield 55%; m.p. 200–202 °C. H NMR (300 MHz, CDCl3, 25 °C):
2-[(4-Methylphenyl)ethynyl]-3-nitropyridine (4c): Beige solid; yield
83%; m.p. 88–90 °C. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 2.38
(s, 3 H, CH3), 7.20 (d, J = 7.8 Hz, 2 H, ArH), 7.41 [dd, J = 8.4,
4.8 Hz, 1 H, C(5)-H], 7.56 (d, J = 7.8 Hz, 2 H, ArH), 8.39 [dd, J
= 8.4, 1.5 Hz, 1 H, C(4)-H], 8.82 [dd, J = 4.8, 1.5 Hz, 1 H, C(6)-
H] ppm. 13C NMR (75 Hz, CDCl3, 25 °C): δ = 21.9, 84.9, 98.7,
118.5, 122.7, 129.6, 132.7, 132.8, 137.9, 140.9, 146.0, 153.7 ppm.
1
δ = 4.01 (s, 3 H, OCH3), 4.08 (s, 3 H, OCH3), 7.17 (s, 1 H, ArH),
7.30 (s, 1 H, ArH), 7.48–7.53 (m, 3 H, ArH), 8.63–8.66 (m, 2 H,
ArH) ppm. 13C NMR (75 Hz, CDCl3, 25 °C): δ = 56.7, 56.9, 98.6,
104.3, 114.4, 126.1, 127.5, 128.5, 130.1, 130.4, 143.1, 151.0, 154.3,
186.6 ppm. IR (KBr): νmax = 1701 (C=O) cm–1. HRMS (ES): calcd.
˜
for C16H14NO4 [M + H]+ 284.0917; found 284.0922.
IR (KBr): ν
= 2217 (CϵC) cm–1. HRMS (ES): calcd. for
˜
max
C14H11N2O2 [M + H]+ 239.0815; found 239.0823.
2-Cyclopropyl-3H-indol-3-one 1-Oxide (6b): Orange solid; yield
49%; m.p. 137–139 °C. 1H NMR (300 MHz, CDCl3, 25 °C): δ =
1.08–1.15 (m, 2 H, c-Pr), 1.53–1.58 (m, 2 H, c-Pr), 2.15–2.25 (m, 1
H, c-Pr), 7.41–7.48 (m, 2 H, ArH), 7.52–7.57 (m, 1 H, ArH), 7.60–
7.63 (m, 1 H, ArH) ppm. 13C NMR (75 Hz, CDCl3, 25 °C): δ =
6.5, 6.9, 113.1, 120.7, 122.6, 130.3, 134.3, 138.8, 146.8, 185.9 ppm.
2-[(4-Ethylphenyl)ethynyl]-3-nitropyridine (4d): Beige solid; yield
81%; m.p. 90–92 °C. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.19
(t, J = 7.8 Hz, 3 H, CH3), 2.52 (q, J = 7.8 Hz, 2 H, CH2), 7.19 (d,
J = 7.8 Hz, 2 H, ArH), 7.40 [dd, J = 8.4, 4.8 Hz, 1 H, C(5)-H],
7.52 (d, J = 7.8 Hz, 2 H, ArH), 8.40 [dd, J = 8.4, 1.5 Hz, 1 H,
C(4)-H], 8.81 [dd, J = 4.8, 1.5 Hz, 1 H, C(6)-H] ppm. 13C NMR
(75 Hz, CDCl3, 25 °C): δ = 14.3, 28.9, 85.9, 97.7, 117.5, 121.7,
IR (KBr): ν
= 1708 (C=O) cm–1. HRMS (ES): calcd. for
˜
max
C11H10NO2 [M + H]+ 188.0706; found 188.0700.
General Procedure for the Pyridine-Mediated Cycloisomerization: A
solution of the alkyne 4a or 5a (1 mmol) in pyridine (5 mL) was
heated at reflux for 30 min. After the system had cooled to room
temperature, the precipitate was filtered off and recrystallized to
give the product as a dark red (7) or violet (8) solid.
129.5, 132.2, 132.9, 136.9, 140.5, 146.4, 153.9 ppm. IR (KBr): ν
=
˜
max
2216 (CϵC) cm–1. HRMS (ES): calcd. for C15H13N2O2
[M + H]+ 253.0972; found 253.0980.
1
2-Cyclopropyl-3-nitropyridine (4e): Brown oil; yield 79%. H NMR
(300 MHz, CDCl3, 25 °C): δ = 0.98–1.01 (m, 4 H, c-Pr), 1.52–1.60
(m, 1 H, c-Pr), 7.37 [dd, J = 8.25, 4.5 Hz, 1 H, C(5)-H], 8.28 [dd,
J = 8.25, 1.5 Hz, 1 H, C(4)-H], 8.74 [brs, 1 H, C(6)-H] ppm. 13C
NMR (75 Hz, CDCl3, 25 °C): δ = 0.9, 9.8, 72.4, 104.7, 122.2, 128.8,
2-Phenyl-3H-pyrrolo[3,2-b]pyridin-3-one 1-Oxide (7): Dark red so-
lid; yield 92%; m.p. 190–192 °C (propan-2-ol). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 7.50–7.53 (m, 3 H, ArH), 7.57 [dd,
J = 7.8, 5.1 Hz, 1 H, C(6)-H], 8.00 [dd, J = 7.8, 1.2 Hz, 1 H, C(7)-
H], 8.63–8.67 (m, 2 H, ArH), 8.81 [dd, J = 5.1, 1.4 Hz, 1 H, C(5)-
H] ppm. 13C NMR (75 Hz, CDCl3, 25 °C): δ = 121.6, 125.2, 126.4,
127.4, 128.0, 128.7, 131.4, 142.9, 143.6, 152.2, 185.3 ppm. IR
132.5, 137.9, 153.5 ppm. IR (KBr): ν
= 2226 (CϵC) cm–1.
˜
max
HRMS (ES): calcd. for C10H9N2O2 [M + H]+. 189.0658; found
189.0670.
1726 (C=O) cm–1. HRMS (ES): calcd. for
2-Ethynyl-3-nitropyridine (4f): Compound 4f was prepared from the
intermediate 3-nitro-2-(trimethylsilyl)pyridine (obtained by Sona-
gashira coupling) by treatment with potassium fluoride in meth-
anol solution at room temperature for 20 min. Purification was ac-
complished by column chromatography. Brownish solid; yield 53%;
(KBr):
ν
=
˜
max
C13H9N2O2 [M + H]+ 225.0659; found 225.0666.
4-(4-Morpholinyl)-6-phenyl-7H-pyrrolo[3,2-d]pyrimidin-7-one 5-Ox-
ide (8): Dark violet solid; yield 96%; m.p. 184–186 °C. 1H NMR
(300 MHz, [D6]DMSO, 25 °C): δ = 3.89–3.92 [m, 4 H, N(CH2)2],
4.02–4.05 [m, 4 H, O(CH2)2], 7.50–7.54 (m, 3 H, ArH), 8.48–8.52
(m, 2 H, ArH), 8.89 [s, 1 H, C(2)-H] ppm. 13C NMR (75 Hz,
[D6]DMSO, 25 °C): δ = 49.7, 66.9, 125.0, 127.7, 128.6, 130.5, 130.9,
1
m.p. 65–67 °C. H NMR (300 MHz, CDCl3, 25 °C): δ = 3.69 (s, 1
H, ϵC–H), 7.53 [dd, J = 8.25, 4.5 Hz, 1 H, C(5)-H], 8.39 [dd, J =
8.25, 1.5 Hz, 1 H, C(4)-H], 8.87 [dd, J = 4.5, 1.5 Hz, 1 H, C(6)-
H] ppm. 13C NMR (75 Hz, CDCl3, 25 °C): δ = 78.2, 85.4, 123.4,
132.8, 150.9, 151.3, 159.7, 186.4 ppm. IR (KBr): ν
= 1710
˜
max
132.1, 133.9, 136.0, 153.2 ppm. IR (KBr): ν
= 3264 (ϵC–H),
˜
max
(C=O) cm–1. HRMS (ES): calcd. for C16H15N4O3 [M + H]+
2214 (CϵC) cm–1. HRMS (ES): calcd. for C7H5N2O2 [M + H]+
311.1139; found 311.1145.
149.0346; found 149.0364.
General Procedure for the Iodine-Mediated Cycloisomerization:
Iodine monochloride (2.44 mg, 0.015 mmol) or iodine (25 mg,
0.1 mmol) was added to a solution of the appropriate compound
1–5 (0.5 mmol) in 1,2-dichloroethane (10 mL), and the resulting
solution was heated at reflux until full completion (1–4 h.). The
reaction mixture was diluted with dichloromethane and washed
with saturated aqueous Na2S2O3 solution (2ϫ40 mL) and then
with water (2ϫ30 mL). The organic layer was dried with anhy-
drous sodium sulfate and concentrated, and the obtained residue
was purified by column chromatography (ethyl acetate in hexane)
to afford the corresponding compound 9–13.
4-Morpholinyl-5-nitro-6-(phenylethynyl)pyrimidine (5a): Yellow so-
lid; yield 62%; m.p. 142–144 °C (propan-2-ol). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 3.63–3.66 [m, 4 H, N(CH2)2], 3.79–
3.83 [m, 4 H, O(CH2)2], 7.39–7.48 (m, 3 H, ArH), 7.63–7.67 (m, 2
H, ArH), 8.60 [s, C(2)-H] ppm. 13C NMR (75 Hz, CDCl3, 25 °C):
δ = 46.4, 66.3, 82.7, 99.6, 120.5, 128.5, 130.5, 132.8, 144.2, 144.4,
153.6, 157.3 ppm. IR (KBr): ν
= 2219 (CϵC) cm–1. HRMS
˜
max
(ES): calcd. for C16H15N4O3 [M + H]+ 311.1139; found 311.1145.
6-(Hex-1-ynyl)-4-morpholinyl-5-nitropyrimidine (5b): Brownish oil;
yield 74%. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 0.90 (t, J =
7.2 Hz,
3
H, CH2CH2CH2CH3), 1.37–1.48 (m,
2
H, Phenyl(thieno[2,3-c][1,2]oxazol-3-yl)methanone (9a): White solid;
1
CH2CH2CH2CH3), 1.52–1.62 (m, 2 H, CH2CH2CH2CH3), 2.44 (t, yield 98%; m.p. 114–115 °C. H NMR (300 MHz, CDCl3, 25 °C):
J = 6.9 Hz, 2 H, CH2CH2CH2CH3), 3.52–3.56 [m, 4 H, N(CH2)2], δ = 7.15 [d, J = 5.4 Hz, 1 H, C(6)-H], 7.57–7.63 (m, 2 H, ArH),
3.70–3.73 [m, 4 H, O(CH2)2], 8.47 [s, 1 H, C(2)-H] ppm. 13C NMR
7.68–7.73 (m, 1 H, ArH), 7.70 [d, J = 5.4 Hz, 1 H, C(5)-H], 8.35–
(75 Hz, CDCl3, 25 °C): δ = 13.4, 19.3, 21.8, 29.6, 46.2, 66.2, 74.4, 8.38 (m, 2 H, ArH) ppm. 13C NMR (75 Hz, CDCl3, 25 °C): δ =
102.9, 133.6, 144.5, 153.3, 157.1 ppm. IR (KBr): ν
= 2223 112.0, 127.0, 128.8, 130.1, 134.0, 135.0, 143.1, 158.2, 170.5,
˜
max
(CϵC) cm–1. HRMS (ES): calcd. for C14H19N4O3 [M + H]+
179.3 ppm. IR (KBr): νmax = 1635 (C=O) cm–1. HRMS (ES): calcd.
˜
291.1452; found 291.1459.
for C12H8NO2S [M + H]+ 230.0270; found 230.0279.
Eur. J. Org. Chem. 2012, 2766–2773
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2771

I. Cikotiene
FULL PAPER
1-(Thieno[3,2-c][1,2]oxazol-3-yl)pentan-1-one (9b): White solid;
yield 99%; m.p. 62–63 °C. H NMR (300 MHz, CDCl3, 25 °C): δ
25 °C): δ = 3.99 (s, 3 H, OCH3), 4.00 (s, 3 H, OCH3), 6.88 (s, 1
H,ArH), 7.31 (s, 1 H, ArH), 7.53–7.56 (m, 2 H, ArH), 7.61–7.68
1
= 0.95 (t, J = 7.5 Hz, 3 H, CH2CH2CH2CH3), 1.44 (sext., J = (m, 1 H,ArH), 8.28–8.31 (m, 2 H, ArH), ppm. 13C NMR (75 Hz,
7.5 Hz, 2 H, CH2CH2CH2CH3), 1.76 (pent., J = 7.5 Hz, 2 H, CDCl3, 25 °C): δ = 56.3, 56.5, 91.7, 96.3, 119.2, 127.5, 128.6, 130.0,
CH2CH2CH2CH3), 3.04 (t, J = 7.5 Hz, 2 H, CH2CH2CH2CH3), 133.5, 136.2, 153.5, 155.2, 155.3, 181.6 ppm. IR (KBr): νmax = 1650
˜
7.09 [d, J = 5.4 Hz, 1 H, C(6)-H], 7.63 [d, J = 5.4 Hz, 1 H, C(5)-
(C=O) cm–1. HRMS (ES): calcd. for C16H14NO4 [M + H]+
H] ppm. 13C NMR (75 Hz, CDCl3, 25 °C): δ = 13.8, 22.3, 25.5, 284.0917; found 284.0929.
39.3, 111.9, 123.4, 142.7, 157.4, 170.9, 188.6 ppm. IR (KBr): ν
˜
max
(2,1-Benzisoxazol-3-yl)cyclopropylmethanone (11b): Yellowish solid;
yield 99%; m.p. 79–80 °C. H NMR (300 MHz, CDCl3, 25 °C): δ
= 1.23–1.28 (m, 2 H, c-Pr), 1.40–1.43 (m, 2 H, c-Pr), 3.04–3.13 (m,
1 H, c-Pr), 7.24–7.29 (m, 1 H, ArH), 7.39–7.44 (m, 1 H, ArH), 7.74
(d, J = 9.0 Hz, 1 H, ArH), 8.04 (d, J = 8.7 Hz, 1 H, ArH) ppm.
13C NMR (75 Hz, CDCl3, 25 °C): δ = 12.8, 18.9, 115.8, 118.6,
=
1681 (C=O) cm–1. HRMS (ES): calcd. for C10H12NO2S
1
[M + H]+ 210.0583; found 210.0577.
(4-Methylphenyl)(thieno[2,3-c][1,2]oxazol-3-yl)methanone
(9c):
White solid; yield 92%; m.p. 117–118 °C. 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 2.49 (s, 3 H, CH3), 7.14 [d, J = 5.7 Hz, 1 H,
C(6)-H], 7.39 (d, J = 8.1 Hz, 2 H, ArH), 7.69 [d, J = 5.7 Hz, 1 H,
C(5)-H], 8.27 (d, J = 8.1 Hz, 2 H, ArH) ppm. 13C NMR (75 Hz,
CDCl3, 25 °C): δ = 21.8, 111.9, 126.8, 129.6, 130.2, 132.5, 143.0,
121.4, 128.4, 131.3, 157.6, 160.1, 190.1 ppm. IR (KBr): νmax = 1671
˜
(C=O) cm–1. HRMS (ES): calcd. for C11H10NO2 [M + H]+
188.0706; found 188.0752.
145.2, 158.5, 170.4, 178.9 ppm. IR (KBr): νmax = 1636 (C=O) cm–1.
˜
(Isoxazolo[4,3-b]pyridin-3-yl)phenylmethanone (12a): Beige solid;
HRMS (ES): calcd. for C13H10NO2S [M + H]+ 244.0427; found
244.0439.
1
yield 92%; m.p. 95–96 °C. H NMR (300 MHz, CDCl3, 25 °C): δ
= 7.37 [dd, J = 9.15, 3.6 Hz, 1 H, C(6)-H], 7.54–7.59 (m, 2 H,
ArH), 7.66–7.71 (m, 1 H, ArH), 7.14 [dd, J = 9.15, 1.5 Hz, 1 H,
C(7)-H], 8.20–8.23 (m, 2 H, ArH), 8.84 [dd, J = 3.6, 1.5 Hz, 1 H,
C(5)-H] ppm. 13C NMR (75 Hz, CDCl3, 25 °C): δ = 124.2, 125.8,
128.0, 128.7, 130.4, 134.2, 135.8, 151.4, 155.6, 160.4, 181.1 ppm.
(4-Ethylphenyl)(thieno[2,3-c][1,2]oxazol-3-yl)methanone (9d): White
solid; yield 95%; m.p. 69–70 °C. 1H NMR (300 MHz, CDCl3,
25 °C): δ = 1.29 (t, J = 7.8 Hz, 3 H, CH3), 2.75 (q, J = 7.8 Hz, 2
H, CH2), 7.10 [d, J = 5.7 Hz, 1 H, C(6)-H], 7.38 (d, J = 8.1 Hz, 2
H, ArH), 7.66 [d, J = 5.7 Hz, 1 H, C(5)-H], 8.27 (d, J = 8.1 Hz, 2
H, ArH) ppm. 13C NMR (75 Hz, CDCl3, 25 °C): δ = 14.9, 28.9,
111.8, 126.7, 128.3, 130.3, 132.5, 143.0, 151.2, 158.4, 170.3,
IR (KBr): ν
= 1661 (C=O) cm–1. HRMS (ES): calcd. for
˜
max
C13H9N2O2 [M + H]+ 225.0659; found 225.0677.
1-([1,2]Oxazolo[4,3-b]pyridin-3-yl)pentan-1-one (12b): White solid;
178.8 ppm. IR (KBr): νmax = 1637 (C=O) cm–1. HRMS (ES): calcd.
˜
1
yield 93%; m.p. 73–74 °C. H NMR (300 MHz, CDCl3, 25 °C): δ
for C14H12NO2S [M + H]+ 258.0583; found 258.0569.
= 0.95 (t, J = 7.5 Hz, 3 H, CH2CH2CH2CH3), 1.45 (sext., J =
7.5 Hz, 2 H, CH2CH2CH2CH3), 1.79 (pent., J = 7.5 Hz, 2 H,
CH2CH2CH2CH3), 3.32 (t, J = 7.5 Hz, 2 H, CH2CH2CH2CH3),
7.32 [dd, J = 9.15; 3.6 Hz, 1 H, C(6)-H], 8.09 [dd, J = 9.15; 1.5 Hz,
1 H, C(7)-H], 8.81 [dd, J = 3.6; 1.5 Hz, 1 H, C(5)-H] ppm. 13C
NMR (75 Hz, CDCl3, 25 °C): δ = 13.8, 22.3, 25.8, 40.7, 124.4,
(2-Pyridinyl)(thieno[2,3-c][1,2]oxazol-3-yl)methanone (9e): White
solid; yield 88%; m.p. 195–196 °C. 1H NMR (300 MHz, CDCl3,
25 °C): δ = 7.15 [d, J = 5.7 Hz, 1 H, C(6)-H], 7.59–7.64 (m, 1 H,
ArH), 7.61 [d, J = 5.7 Hz, 1 H, C(5)-H], 7.95–8.00 (m, 1 H, ArH),
8.31–8.34 (m, 1 H, ArH), 8.85 (ddd, J = 4.5, 1.8, 0.9 Hz, 1 H,
ArH) ppm. 13C NMR (75 Hz, CDCl3, 25 °C): δ = 112.6, 123.7,
127.9, 128.9, 137.6, 143.2, 148.3, 151.9, 154.8, 170.3, 176.4 ppm.
125.6, 132.6, 151.6, 155.4, 159.5, 188.7 ppm. IR (KBr): νmax = 1687
˜
(C=O) cm–1. HRMS (ES): calcd. for C11H13N2O2 [M + H]+
205.0972; found 205.0970.
IR (KBr): ν
= 1656 (C=O) cm–1. HRMS (ES): calcd. for
˜
max
C11H7N2O2S [M + H]+ 231.0223; found 231.0233.
(4-Methylphenyl)([1,2]oxazolo[4,3-b]pyridin-3-yl)methanone (12c):
Beige solid; yield 87%; m.p. 117–119 °C. 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 2.49 (s, 3 H, CH3), 7.35–7.41 (m, 3 H, ArH),
8.14–8.18 (m, 3 H, ArH), 8.85–8.86 [m, 1 H, C(5)-H] ppm. 13C
NMR (75 Hz, CDCl3, 25 °C): δ = 21.8, 124.2, 125.7, 129.4, 130.5,
2,2-Dimethyl-1-thieno[2,3-c][1,2]oxazol-3-ylpropan-1-one (9f): White
1
solid; yield 99%; m.p. 75 °C. H NMR (300 MHz, CDCl3, 25 °C):
δ = 1.44 (s, 9 H, tBu), 7.06 [d, J = 5.4 Hz, 1 H, C(6)-H], 7.63 [d, J
= 5.4 Hz, 1 H, C(5)-H] ppm. 13C NMR (75 Hz, CDCl3, 25 °C): δ
= 25.9, 43.6, 111.9, 126.5, 143.2, 157.7, 170.1, 193.6 ppm. IR
133.2, 133.4, 145.4, 151.3, 155.4, 160.7, 180.7 ppm. IR (KBr): ν
˜
max
1664 (C=O) cm–1. HRMS (ES): calcd. for
=
1648 (C=O) cm–1. HRMS (ES): calcd. for C14H11N2O2
(KBr):
ν
=
˜
max
C10H12NO2S [M + H]+ 210.0583; found 210.0575.
[M + H]+ 239.0815; found 239.0874.
Phenyl(thieno[2,3-c][1,2]oxazol-3-yl)methanone (10a): Beige solid;
yield 88%; m.p. 53–55 °C. H NMR (300 MHz, CDCl3, 25 °C): δ
(4-Ethylphenyl)([1,2]oxazolo[4,3-b]pyridin-3-yl)methanone (12d): Be-
ige solid; yield 88%; m.p. 91–92 °C. H NMR (300 MHz, CDCl3,
1
1
= 7.14 [d, J = 5.4 Hz, 1 H, C(5)-H], 7.40 [d, J = 5.4 Hz, 1 H, C(4)-
H], 7.54–7.60 (m, 2 H, ArH), 7.67–7.70 (m, 1 H, ArH), 8.23–8.26
(m, 2 H, ArH) ppm. 13C NMR (75 Hz, CDCl3, 25 °C): δ = 115.0,
128.8, 130.0, 132.8, 133.9, 135.6, 136.8, 148.6, 156.3, 180.3 ppm.
25 °C): δ = 1.28 (t, J = 7.8 Hz, 3 H, CH3), 2.74 (q, J = 7.8 Hz, 2
H, CH2), 7.32–7.39 (m, 3 H, ArH), 8.11–8.16 (m, 3 H, ArH), 8.81–
8.83 [m, 1 H, C(5)-H] ppm. 13C NMR (75 Hz, CDCl3, 25 °C): δ =
14.9, 29.0, 124.2, 125.7, 127.3, 128.2, 130.6, 133.4, 151.3, 151.5,
= 1652 (C=O) cm–1. HRMS (ES): calcd. for
155.4, 160.7, 180.7 ppm. IR (KBr): ν
= 1646 (C=O) cm–1.
IR (KBr): ν
˜
max
˜
max
C12H8NO2S [M + H]+ 230.0270; found 230.0266.
HRMS (ES): calcd. for C15H13N2O2 [M + H]+ 253.0972; found
253.0971.
Cyclopropyl(thieno[2,3-c][1,2]oxazol-3-yl)methanone (10b): Beige so-
lid; yield 91%; m.p. 61–63 °C. 1H NMR (300 MHz, CDCl3, 25 °C):
δ = 1.17–1.23 (m, 2 H, c-Pr), 1.33–1.39 (m, 2 H, c-Pr), 2.84–2.92
(m, 1 H, c-Pr), 7.10 [d, J = 5.4 Hz, 1 H, C(5)-H], 7.36 [d, J =
5.4 Hz, 1 H, C(4)-H] ppm. 13C NMR (75 Hz, CDCl3, 25 °C): δ =
12.9, 18.7, 114.6, 116.3, 129.5, 136.6, 155.9, 188.9 ppm. IR (KBr):
Cyclopropyl([1,2]oxazolo[4,3-b]pyridin-3-yl)methanone (12e): Beige
solid; yield 94%; m.p. 129–130 °C. 1H NMR (300 MHz, CDCl3,
25 °C): δ = 1.20–1.27 (m, 2 H, c-Pr), 1.43–1.46 (m, 2 H, c-Pr), 3.44–
3.53 (m, 1 H, c-Pr), 7.33 [dd, J = 9.15, 3.9 Hz, 1 H, C(6)-H], 8.10
[dd, J = 9.15, 1.5 Hz, 1 H,C(7)-H], 8.81 [dd, J = 3.9, 1.5 Hz, 1 H,
C(5)-H] ppm. 13C NMR (75 Hz, CDCl3): δ = 13.3, 19.6, 124.4,
ν
max = 1663 (C=O) cm–1. HRMS (ES): calcd. for C9H8NO2S [M +
˜
H]+ 194.0270; found 194.0288.
125.5, 132.7, 151.5, 155.3, 159.6, 188.4 ppm. IR (KBr): νmax = 1672
˜
(5,6-Dimethoxy-2,1-benzisoxazol-3-yl)phenylmethanone (11a): Beige
(C=O) cm–1. HRMS (ES): calcd. for C10H9N2O2 [M + H]+
189.0658; found 189.0666.
solid; yield 87%; m.p. 165–166 °C. 1H NMR (300 MHz, CDCl3,
2772
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2766–2773

Intramolecular Oxygen Transfer
2001, 42, 1339; n) N. Monteiro, A. Arnold, G. Balme, Synlett
1998, 1111; o) R. C. Larock, P. Pace, H. Yang, C. E. Russell,
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Chem. 1997, 62, 527 and references cited therein r) G. Balme,
D. Bouyssi, Tetrahedron 1994, 50, 403.
[7-(4-Morpholinyl)-[1,2]oxazolo[4,3-d]pyrimidin-3-yl]phenyl-
methanone (13): Yellow solid; yield 69%; m.p. 139–140 °C. 1H
NMR (300 MHz, CDCl3, 25 °C):
δ = 3.92–3.94 [m, 4 H,
N(CH2)2], 4.21 (brs, 2 H,OCH2), 4.24 (brs, 2 H, OCH2), 7.57–7.62
(m, 2 H, ArH), 7.69–7.74 (m, 1 H, ArH), 8.22 (d, J = 7.5 Hz, 1 H,
ArH), 8.47 [s, 1 H, C(2)-H] ppm. 13C NMR (75 Hz, CDCl3, 25 °C):
δ = 44.8, 48.9; 66.7, 66.9, 128.7, 130.3, 134.2, 135.7, 135.9, 145.8,
[2] a) A. Takeda, S. Kamijo, Y. Yamamoto, J. Am. Chem. Soc.
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152.5, 157.7, 158.3, 180.8 ppm. IR (KBr): νmax = 1645 (C=O) cm–1.
˜
HRMS (ES): calcd. for C16H15N4O3 [M + H]+ 311.1139; found
311.1178.
General Procedure for the 1,2-Addition of Iodine: Iodine (0.132 g,
0.52 mmol) was added to a solution of compound 1g or 4f
(0.5 mmol) in 1,2-dichloroethane (10 mL) and the resulting solu-
tion was heated at reflux for 2 h. The reaction mixture was diluted
with dichloromethane and washed with saturated aqueous
Na2S2O3 solution (2ϫ40 mL) and then with water (2ϫ30 mL).
The organic layer was dried with anhydrous sodium sulfate and
concentrated, and the obtained residue was purified by column
chromatography (ethyl acetate in hexane) to afford compound 14
or 15.
[3] a) A. Baeyer, Ber. Dtsch. Chem. Ges. 1881, 14, 1741; b) A.
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2-[(E)-1,2-Diiodoethenyl]-3-nitrothiophene (14): Yellowish solid;
1
yield 72%; m.p. 80–81 °C. H NMR (300 MHz, CDCl3, 25 °C): δ
= 7.40 [, J = 5.7 Hz, 1 H, d C(5)-H], 7.56 [s, 1 H, C(sp2)-H], 7.58
[d, J = 5.7 Hz, 1 H, C(4)-H] ppm. 13C NMR (75 Hz, CDCl3): δ =
80.6; 89.9, 124.0, 125.7, 143.0, 145.9 ppm. HRMS (ES): calcd. for
C6H4I2NO2S [M + H]+ 407.8047; found 407.8039.
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2-[(E)-1,2-Diiodoethenyl]-3-nitropyridine (15): Yellowish wax; yield
71%. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.37 [s, 1 H, C(sp2)-
H], 7.59 [dd, J = 8.4, 4.8 Hz, 1 H, C(5)-H], 8.46 [dd, J = 8.4, 1.5 Hz,
1 H, C(4)-H], 8.97 [dd, J = 4.8, 1.5 Hz, 1 H, C(6)-H] ppm. 13C
NMR (75 Hz, CDCl3): δ = 83.8, 89.6, 124.4, 133.2, 152.4, 153.8,
154.1 ppm. HRMS (ES): calcd. for C7H5I2N2O2 [M + H]+
402.8435; found 402.8444.
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Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra of final products 6–15.
Acknowledgments
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The research was funded by the European Social Fund under the
Global Grant measure (grant number VP1-3.1-SMM-07-K-01-
002).
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Received: January 28, 2012
Published Online: March 27, 2012
Eur. J. Org. Chem. 2012, 2766–2773
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2773