Gold catalysis: One-pot alkylideneoxazoline synthesis/Alder-ene reaction

Article abstract of DOI:10.1002/asia.201200046

Based on the gold-catalyzed synthesis of methyleneoxazolines, a one-pot combination with an Alder-ene reaction was developed. For azodicarboxylates, good to very good yields (51-99%) of the oxazolemethylhydrazinedicarboxylates were achieved with 3 mol% of the Gagosz catalyst, [Ph₃PAuNTf ₃]. In a less-selective reaction, 4-phenyl-3H-1,2,4-triazol-3,5(4H)- dione gave lower yields (41-49%) of the corresponding oxazolemethylphenyltriazolidinediones. Overall, five new bonds were formed. Tetracyanoethylene afforded a cyclobutane derivative through a [2+2] cycloaddition reaction at -40°C, but only 45% of the spiro compound was obtained. The less-readily available KITPHOS ligands on gold gave even higher yields at lower catalyst loadings (2a mol%), but longer reaction times were required. Copyright

Full text of DOI:10.1002/asia.201200046

DOI: 10.1002/asia.201200046
Gold Catalysis: One-Pot Alkylideneoxazoline Synthesis/Alder-Ene Reaction
A. Stephen K. Hashmi* and Anna Littmann[a]
Abstract: Based on the gold-catalyzed
synthesis of methyleneoxazolines,
dione gave lower yields (41–49%) of
the corresponding oxazolemethylphe-
nyltriazolidinediones. Overall, five new
bonds were formed. Tetracyanoethy-
lene afforded a cyclobutane derivative
through a [2+2] cycloaddition reaction
at À408C, but only 45% of the spiro
compound was obtained. The less-read-
ily available KITPHOS ligands on gold
gave even higher yields at lower cata-
lyst loadings (2 mol%), but longer re-
action times were required.
a one-pot combination with an Alder-
ene reaction was developed. For azodi-
carboxylates, good to very good yields
(51–99%) of the oxazolemethylhydra-
zinedicarboxylates were achieved with
3 mol% of the Gagosz catalyst,
[Ph3PAuNTf3]. In a less-selective reac-
Keywords: alkynes · amides · gold ·
heterocycles · oxazoles
tion, 4-phenyl-3H-1,2,4-triazol-3,5ACTHNUGRTNEUNG(4H)-
Introduction
the van Leusen oxazole synthesis.[4g,h] N-Propargylcarboxa-
mides have long been recognized as precursors to oxazoles,
and initially sulfuric acid or mercury(II) acetate were used
for their conversion.[6] In 1989, Hacksell and co-workers dis-
covered a conversion that was catalyzed by strong bases.[7]
N-Propargylimidates were also reported to be suitable start-
ing materials,[8] although neither of these methods had good
functional-group tolerance.
The oxazole ring,[1] 5-methyloxazoles,[2] and functionalized
5-methyloxazoles[3] are prevalent in many natural products
and pharmaceutically active compounds. Thus, an efficient
synthesis of such compounds is very important.
One of the classical routes to synthesize oxazoles is the
Robinson–Gabriel synthesis (Scheme 1)[4a–c] by using acylat-
ed aminoketones and dehydrating reagents, such as PCl5,
SOCl2, or even concentrated sulfuric acid. Other routes in-
clude the Fischer oxazole synthesis,[4d] the methods devel-
oped by Theilig[5] and by Bredereck and co-workers,[4e,f] and
The first transition metal-catalyzed oxazole syntheses with
high functional-group tolerance were published by Cacchi
and co-workers in 2001[9] and by Costa and co-workers in
2002,[10] both of them used palladium catalysis. Several sub-
sequent syntheses were reported by Mꢀller and co-workers,
among others.[11] In 2004, we reported the conversion of N-
propargylcarboxamides (1) into 5-methyloxazoles (3) by
using 2 mol% goldACTHNUTRGNEUNG
(III) chloride (Scheme 2);[12] this method
has since been applied in academic[13] and industrial re-
search.[14] Alkylideneoxazolines (2) were determined to be
intermediates in the reaction, and an initial anti-oxyauration
step was observed after the coordination of the triple bond
to the gold catalyst (Scheme 2).[12] At the same time,
Scheme 1. Different known routes to oxazole heterocycles.
[a] Prof. Dr. A. S. K. Hashmi, Dipl.-Chem. A. Littmann
Organisch-Chemisches Institut
Ruprecht-Karls-Universitꢁt Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax : (+49)6221-54-4205
Scheme 2. Mechanism of the gold-catalyzed conversion of compound
E-mail: hashmi@hashmi.de
1 into compound 3.
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Uemura and co-workers also published a gold-catalyzed syn-
thesis of oxazoles[15] from a one-pot reaction that included
the ruthenium-catalyzed formation of the N-propargylcar-
boxamides from carboxamides and propargylic alcohols;
however, 20 mol% of goldACTHUNRGTNE(NUG III) chloride was required in this
process. In 2006, we showed that the use of gold(I) catalysts
stopped the reaction at the alkylideneoxazoline stage;[16] this
result has also found broad application in the screening of
new catalysts.[17]
Although the conditions for the gold-catalyzed pathway
are intrinsically mild, and neither oxygen nor humidity need
to be excluded,[18] there is still a major drawback: all of the
oxazoles that were formed as
Scheme 3. The direct halogenation reaction as a route to functionalized
oxazoles was unselective.
the final products contained
simple methyl groups; in the
Table 1. Gold-catalyzed reactions of substrates 1 with enophiles E.
presence of more-complex sub-
stituents, oxazines were prefer-
entially formed instead.[17e,19]
However, the rapid and easy
access to compounds
2 by
[a]
[b]
[c]
Entry 1 (R1)
E (R2)
t1
t2
Yield (method A)
[%]
t3
Yield (method B)
[%]
Product
gold(I) catalysis made the use
of these versatile building
blocks more feasible. Hence,
their functionalization should
be possible.
In 1981, Caristi and co-work-
ers reported the preparation of
halomethyloxazolines
(Scheme 3), which are potential
synthetic intermediates in the
synthesis of functionalized oxa-
zoles.[20] The reaction of com-
pound 1a with a Br+ or I+
donor gave halomethyloxazo-
line 4. Heating compound 4 af-
forded compound 5 when X=
Br, whereas the reaction with
1
1b (tBu)
Ea (Et)
Eb (iPr)
0.5 h 1.5 h 91
0.5 h 7 h
Ec (tBu) 0.5 h 3 d
Ea (Et) 14 h
Eb (iPr) 14 h
Ec (tBu) 14 h
Ed (Bn) 14 h
4 h 89
1 d 95
3 d 81
14 h 81
2 d 92
3 d 86
20 h 88
3 h 96
13 h 99
40 h 86
3 d 66
45 h 85
6a
6b
6c
6d
6e
6 f
6g
6h
6i
2
3
4
1b (tBu)
1b (tBu)
1c (Bn)
96
87
66
88
96
51
98
95
98
53
–
5 h
27 h
3 d
16 h
2 h
10 h
1 d
2 d
5
1c (Bn)
6
1c (Bn)
7
1c (Bn)
8
9
10
11
12
1d (thienyl)
1d (thienyl)
1d (thienyl)
Ea (Et)
Eb (iPr)
1 h
1 h
Ec (tBu) 1 h
6j
6k
6l
1e (cyclopropyl) Ea (Et) 10 h
1 f (adamantyl) Ec (tBu)
–
–
[a] Reaction time after addition of the catalyst; [b] reaction time after addition of the enophile; [c] reaction
time according to method B.
1
2 was detected by H NMR spectroscopy. Then, the enophile
the iodo-derivative of compound 4 failed.
(E, an azodicarboxylate) was added and, after reaction time
t2, the conversion was complete and the product was isolat-
ed. All of the conversion reactions were conducted under
mild conditions at room temperature. The reaction times
strongly depended on the substrate and on the enophile. For
both steps, that is, the gold-catalyzed cycloisomerization and
Alder-ene reactions, the rates of reaction varied significantly
and there was no clear trend in terms of substrate 1. Com-
pound 1b (Table 1, entries 1–3) reacted faster than com-
pound 1d (Table 1, entries 8–10), whilst compound 1c was
the slowest of the substrates tested (Table 1, entries 4–7).
We could not detect any influence of the gold catalyst on
the Alder-ene reaction; from the observed rates of reaction,
there was no evidence for a participation of gold as a catalyst
in the pericyclic reaction. For enophiles (E) with increasing
steric bulk, longer reaction times were observed for the re-
actions with compounds 1b (Table 1, entries 1–3) and 1c
(Table 1, entries 4–7); for the planar-thienyl-substituted sub-
strate (1d), quite similar reaction times were detected. How-
ever, apart from these details, the yields were good to excel-
The reaction of compound 1a with N-bromosuccinimide
also gave compound 5.[21] Whilst these halogen derivatives
are potential candidates for the preparation of methyl-func-
tionalized derivatives of compound 3, their synthesis is still
troublesome and they are very sensitive, even if prepared by
combining gold catalysts and halogenation reagents.[22,23]
Herein, we report the first reactions of alkylideneoxazo-
lines 2 with nitrogen electrophiles in Alder-ene reactions.
Results and Discussion
Substrates 1b–1 f, which contained R=tBu, Bn, thienyl, cy-
clopropyl, and adamantly substituents, respectively, were
prepared according to literature procedures.[12,16,23] First, we
tested the stepwise addition of the substrates in a one-pot
procedure (Table 1, method A): substrate 1 and gold catalyst
[Ph3PAuNTf2] (Gagoszꢃs catalyst)[24] were mixed together.
After reaction time t1, complete conversion into compound
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One-Pot Alkylideneoxazoline Synthesis/Alder-Ene Reaction
lent, the only exception being cyclopropyl derivative 1e
(Table 1, entry 11), which did not react selectively, and in-
stead formed unidentified oligomeric side-products.
Next, we conducted the same reactions by mixing com-
pounds 1, enophiles E, and the catalyst altogether (Table 1,
method B). Experiments with only the substrate and eno-
phile showed that there was no direct reaction between
these two components; the
at higher polarity. Because compounds 7 are less interesting
from a synthetic point of view than compounds 6,[26] we did
not investigate this point in detail.
Further experiments to prepare substituted oxazoles by
using Alder-ene reactions were performed with compound
1b and tetracyanoethylene (Ef), as well as with compound
1c and electrophiles Eg–Ei (Scheme 4).
Alder-ene reaction was not ob-
served until after the cycloiso-
merization reaction to afford
compound 2. We were delight-
ed to see that the enophiles (E)
did not inhibit the gold cata-
lysts, which once more demon-
strated a weak AuI–N interac-
Scheme 4. Other enophiles tested.
tion.[25] However, the overall re-
action time (t3) was clearly
slower (compared to t1+t2); thus, the presence of the eno-
phile slightly inhibited the catalysis. With regard to the
yield, in most cases, the results of the step-wise addition
from method A could almost be matched (Table 1, en-
tries 1–3, 6, 8, and 10). In five cases, slightly higher yields
were obtained (Table 1, entries 4, 5, 7, 9, and 11). This result
was due, in part, to the more-sensitive intermediate (2)
being exposed to the enophile immediately, which reduced
the opportunity for competing side-reactions to occur. For
Table 1, entries 7, 9, and 11, the longer overall reaction
times might also contribute to the higher yield. For com-
pounds 1 f and Ec, only method B was used, and a very
good yield (85%) was obtained (Table 1, entry 12).
The addition of enophile Ef to intermediate 2b, which
had previously been generated from the cyclization of com-
pound 1b, was conducted at À408C. If the addition was
done at room temperature, a fast and unselective decompo-
sition of the reaction mixture was observed, and a black tar
was formed. For the reaction with enophile Ei, 1 equivalent
of tetrabutylammonium periodate was added to in situ oxi-
dize compound 8 into enophile tert-butylnitrosoformate (Ei;
Scheme 4).
The only successful conversion was the reaction with eno-
phile Ef, in which a moderate yield of spiro compound 9
was obtained (Scheme 5). A [2+2]-cycloaddition pathway
with the enol ether-like substructure of compound 2b
Next, we tested amides 1b–1d with [Ph3PAuNTf2] and the
very reactive dienophile 4-phenyl-3H-1,2,4-triazol-3,5ACTHNUTRGNEU(GN 4H)-
dione (Ee; Table 2).
Unlike the reactions with azodicarboxylates Ea–Ed, the
reactions with enophile Ee afforded only moderate yields.
The very high reactivity of enophile Ee led to a loss of selec-
tivity, owing to competing side-reactions and subsequent re-
actions of Ee, as indicated by a large number of TLC spots
Scheme 5. The formation of a four-membered ring was observed with
enophile Ef.
Table 2. Yields and reaction times for the gold-catalyzed reactions of compounds 1a–
1c and enophile Ee to afford compounds 7a–7c.
seemed to be preferred with this reagent. Once
more, the reaction was unselective, thereby provid-
ing several unidentified polar side-products.
Even after heating at 1008C for 2 hours, the reac-
tion between compound 1c and enophile Eg did
not show any conversion into product 2b in the
1H NMR spectrum. On the other hand, in the reac-
tion of compound 1c with either enophile Eh or Ei,
complete consumption of compound 2c was ob-
served. However, only complex mixtures of prod-
ucts were formed, and no defined product could be
isolated and characterized.
To compare the catalytic efficiency of
[Ph3PAuNTf2] with that of other catalysts, we used
compound 1c and enophile Ec in the reaction with
gold(I) complexes K1 and K2 (Scheme 6). These
[a]
[b]
[c]
Entry 1 (R1)
t1
t2
Yield (meth-
od A) [%]
t3
Yield (meth-
od B) [%]
Product
1
2
3
1b (tBu)
1c (Bn)
0.5 h 1.5 h
14 h
1d (thienyl) 1 h
89
22
41
3 d
4 d
11 d
46
41
49
7a
7b
7c
1.5 h
2 h
[a] Reaction time after addition of the catalyst; [b] reaction time after addition of the
enophile; [c] reaction time according to method B.
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A. Stephen K. Hashmi and Anna Littmann
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plete selectivity was not achieved, with the formation of
some side-products, such as [2+2]-cycloaddition products.
With weak dienophiles, no reaction was observed.
This first successful organic transformation of alkylidene–
oxazolines into functionalized oxazoles will form the basis
for a detailed study of the use of other synthetically impor-
tant enophile building blocks, including in the analogous
asymmetric reactions.
Scheme 6. Catalysts K1 and K2, which contained ligands from the KIT-
PHOS family.
Experimental Section
General Procedure for the Cyclization of Propargylamides into
Methylenedihydrooxazoles, Followed by the Addition of Electrophiles
catalysts had been used in the synthesis of alkylideneoxazo-
lines with great success.[16a–c]
Method A: In an NMR tube, a solution of propargylcarboxamide in
CD2Cl2 (600 mL) was treated with [Ph3PAuNTf2]. When the cyclization
was complete (t1), as monitored by 1H NMR spectroscopy, the enophile
was added. The progress of the second step was also monitored by
1H NMR spectroscopy, and, when the reaction was complete (t2), the sol-
vent was evaporated under reduced pressure. The crude product was pu-
rified by column chromatography on silica gel.
All reactions were performed in an NMR tube. Com-
pound 1c and enophile Ec were dissolved in CD2Cl2; then,
2 mol% of catalyst [Ph3PAuNTf2], K1, or K2 was added.
The reactions in the presence of catalysts K1 and K2 were
slower than with [Ph3PAuNTf2], although they were more
long-living with regards to their activity. After 7 days, no fur-
ther conversion was detectable by 1H NMR spectroscopy.
The yields were determined by using 1,3,5-tri-tert-butylben-
zene as an internal standard (Table 3).
Method B: In an NMR tube, the catalyst [Ph3PAuNTf2] was added to
a solution of the propargylcarboxamide and the electrophile in CD2Cl2
1
(600 mL). After the reaction was complete (t3), as monitored by H NMR
spectroscopy, the solvent was evaporated under reduced pressure, and
the crude product was purified by column chromatography on silica gel.
Table 3. A comparison of different gold catalysts.
Diethyl-1-((2-tert-butyloxazol-5-yl)methyl)hydrazine-1,2-dicarboxylate
(6a)
Diethyl-1-((2-tert-butyloxazol-5-yl)methyl)hydrazine-1,2-dicarboxylate
was prepared according to methods A (t1 =30 min, t2 =1.5 h) and B (t3 =
4 h). In method A, compound 1b (27.0 mg, 194 mmol), enophile Ea
(33.8 mg, 194 mmol), and [Ph3PAuNTf2] (3.41 mg, 4.61 mmol) were used.
In method B, compound 1b (15.0 mg, 108 mmol), enophile Ea (19.0 mg,
109 mmol), and [Ph3PAuNTf2] (2.37 mg, 3.21 mmol) were used. Column
chromatography on silica gel (petroleum ether/EtOAc, 2:1) afforded
compound 6a (method A: 55.0 mg, 176 mmol, 91%; method B: 30.0 mg,
95.7 mmol, 89%) as a colorless oil.
1
Entry
Catalyst
Yield of 6 f [%]
Rf (petroleum ether/EtOAc, 2:1): 0.15; H NMR (300 MHz, CD2Cl2): d=
1.12–1.18 (m, 6H), 1.25 (s, 9H), 4.03–4.14 (m, 4H), 4.57 (s, 2H), 6.73 (s,
1H), 6.80 ppm (brs, 1H); 13C NMR (75 MHz, CD2Cl2): d=14.4 (q), 14.7
(q), 28.6 (q, 3C), 34.0 (s), 45.0 (t), 62.4 (t), 63.2 (t), 125.7 (d), 146.8 (s),
156.2 (s), 171.1 (s), 171.2 ppm (s); IR (film): n˜ =3293, 2977, 2935, 1720,
1555, 1515, 1467, 1414, 1383, 1336, 1266, 1201, 1148, 1115, 1096, 1061,
1029, 992, 762, 670 cmÀ1; MS (ESI): m/z (%): 627 (35) [M2+H]+, 314
(100) [M+H]+, 110 (4), 101 (6), 96 (5), 89 (5); HRMS (ESI): m/z calcd
for [C14H24N3O5]+: 314.1711; found: 314.1709; elemental analysis calcd
(%) for C14H23N3O5: C 53.66, H 7.40, N 13.41; found: C 53.32, H 7.44,
N 13.04.
1
2
3
[Ph3PAuNTf2]
84
92
98
K1
K2
A loading of 2 mol% of [Ph3PAuNTf2] gave a lower yield
of the product than with 3 mol% (84% versus 86%;
Table 1, entries 1 and 6). Catalyst K1 gave a higher yield
(Table 3, entry 2), but the best catalyst was K2. However,
because the differences were not significant, and because
catalyst K1 is commercially available whilst K2 had to be
prepared, for most applications, catalyst K1 is probably the
more-convenient catalyst.
Diisopropyl-1-((2-tert-butyloxazol-5-yl)methyl)hydrazine-1,2-
dicarboxylate (6b)
Diisopropyl-1-((2-tert-butyloxazol-5-yl)methyl)hydrazine-1,2-dicarboxy-
late was prepared according to methods A (t1 =0.5 h, t2 =7 h) and B (t3 =
1 d). In method A, compound 1b (33.5 mg, 241 mmol), enophile Eb
(68.2 mg, 337 mmol), and [Ph3PAuNTf2] (4.91 mg, 6.64 mmol) were used.
In method B, compound 1b (22.4 mg, 161 mmol), enophile Eb (44.5 mg,
220 mmol), and [Ph3PAuNTf2] (3.58 mg, 4.84 mmol) were used. Column
chromatography on silica gel (petroleum ether/EtOAc, 3:1) afforded
compound 6b (method A: 79.0 mg, 231 mmol, 96%; method B: 52.0 mg,
152 mmol, 95%) as a colorless oil.
Conclusions
The combination of the gold-catalyzed alkylidene–oxazoline
synthesis and the Alder-ene reaction allowed the synthesis
of functionalized oxazoles in a two-component, one-pot re-
action. Neither the enophile nor the hydrazine-type prod-
ucts, both of which were potential ligands, significantly in-
hibited the catalyst. With highly reactive enophiles, com-
1
Rf (petroleum ether/EtOAc, 2:1): 0.27; H NMR (300 MHz, CD2Cl2): d=
1.19–1.29 (m, 12H), 1.32 (s, 9H), 4.62 (s, 2H), 4.82–4.99 (m, 2H), 6.53–
6.71 (brs, 1H), 6.79 ppm (s, 1H); 13C NMR (75 MHz, CD2Cl2): d=22.1
(q, 2C), 22.2 (q, 2C), 28.7 (q, 3C), 34.0 (s), 43.8 (t), 70.2 (d), 71.0 (d),
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One-Pot Alkylideneoxazoline Synthesis/Alder-Ene Reaction
125.6 (d), 147.0 (s), 155.7 (s), 171.7 ppm (s, 2C); IR (film): n˜ =3300, 2196,
1715, 1555, 1468, 1410, 1386, 1375, 1263, 1227, 1206, 1181, 1146, 1108,
1036, 996, 956, 864, 797, 713, 679 cmÀ1; MS (ESI): m/z (%): 705 (100),
683 (13) [M2+H]+, 342 (93) [M+H]+, 108 (6), 101 (8), 89 (4); HRMS
(ESI): m/z calcd for [C16H28N3O5]+: 342.2024 [M+H]+; found: 342.2024.
1718, 1562, 1497, 1468, 1455, 1409, 1386, 1376, 1265, 1198, 1181, 1145,
1108, 1038, 998, 165, 728, 697 cmÀ1; MS (EI(+), 70 eV): m/z (%): 375 (2)
[M]+, 316(5), 274 (15), 273 (69), 272 (57), 246 (7), 231 (27), 230 (7), 229
(7), 214 (44), 187 (45), 186 (16), 181 (16), 174 (11), 173 (90), 172 (100),
117 (13), 91 (44); HRMS (EI(+), 70 eV): m/z calcd for [C19H25N3O5]+:
375.1794; found: 375.1779; elemental analysis calcd (%) for C19H25N3O5:
C 60.79, H 6.71, N 11.19; found: C 60.44, H 6.81, N 10.76.
Di-tert-butyl-1-((2-tert-butyloxazol-5-yl)methyl)hydrazine-1,2-
dicarboxylate (6c)
Di-tert-butyl-1-((2-benzyloxazol-5-yl)methyl)hydrazine-1,2-dicarboxylate
(6 f)
Di-tert-butyl-1-((2-tert-butyloxazol-5-yl)methyl)hydrazine-1,2-dicarboxy-
late was prepared according to methods A (t1 =0.5 h, t2 =3 d) and B (t3 =
3 d). In method A, compound 1b (30.6 mg, 220 mmol), enophile Ec
(51.5 mg, 224 mmol), and [Ph3PAuNTf2] (4.76 mg, 6.44 mmol) were used.
In method B, compound 1b (20.1 mg, 144 mmol), enophile Ec (35.6 mg,
155 mmol), and [Ph3PAuNTf2] (3.56 mg, 4.82 mmol) were used. Column
chromatography on silica gel (petroleum ether/EtOAc, 2:1) afforded
compound 6c (method A: 71.0 mg, 192 mmol, 87%; method B: 43.0 mg,
116 mmol, 81%) as a colorless oil.
Di-tert-butyl-1-((2-benzyloxazol-5-yl)methyl)hydrazine-1,2-dicarboxylate
was prepared according to methods A (t1 =14 h, t2 =3 d) and B (t3 =3 d).
In method A, compound 1c (29.0 mg, 167 mmol), enophile Ec (41.2 mg,
179 mmol), and [Ph3PAuNTf2] (3.71 mg, 5.02 mmol) were used. In meth-
od B, compound 1c (40.0 mg, 231 mmol), enophile Ec (55.7 mg,
242 mmol), and [Ph3PAuNTf2] (5.18 mg, 7.00 mmol) were used. Column
chromatography on silica gel (petroleum ether/EtOAc, 3:1) afforded
compound 6 f (method A: 59.0 mg, 160 mmol, 96%; method B: 80.0 mg,
198 mmol, 86%) as a pale yellow oil.
1
Rf (petroleum ether/EtOAc, 2:1): 0.12; H NMR (300 MHz, CD2Cl2): d=
1.31 (s, 9H), 1.42 (s, 9H), 1.44 (s, 9H), 4.57 (s, 2H), 6.76 (s, 1H), 6.92–
7.06 ppm (brs, 1H); 13C NMR (75 MHz, CD2Cl2): d=28.3 (q, 3C), 28.3
(q, 3C), 28.7 (q, 3C), 34.0 (s), 45.6 (t), 81.3 (s), 81.9 (s), 125.3 (d), 147.4
(s), 155.2 (s), 171.5 ppm (s, 2C); IR (film): n˜ =3122, 2974, 2934, 2361,
2305, 2196, 1775, 1715, 1555, 1503, 1475, 1424, 1365, 1270, 1224, 1145,
993, 955, 771, 744, 712, 694, 677 cmÀ1; MS (EI(+), 70 eV): m/z (%): 369
(2) [M]+, 293 (3), 281 (3), 269 (42), 257 (17), 253 (5), 242 (5), 241 (9), 240
(70), 213 (49), 212 (16), 197 (34), 196 (11), 170 (8), 169 (81), 168 (9), 156
(5), 153 (89), 152 (26), 140 (14), 139 (100), 121 (14), 118 (6); HRMS
(EI(+), 70 eV): m/z calcd for [C18H31N3O5]+: 369.2264; found: 369.2300.
1
Rf (petroleum ether/EtOAc, 2:1): 0.30; H NMR (300 MHz, CD2Cl2): d=
1.44 (s, 18H), 4.05 (s, 2H), 4.57 (s, 2H), 6.59 (s, 1H), 6.85 (s, 1H), 7.22–
7.34 ppm (m, 5H); 13C NMR (75 MHz, CD2Cl2): d=28.3 (q, 6C), 34.6
(t), 43.9 (t), 81.5 (s), 82.1 (s), 126.0 (d), 127.3 (d), 129.0 (d, 2C), 129.2 (d,
2C), 136.1 (s), 148.3 (s), 155.2 (s), 163.5 ppm (s); IR (film): n˜ =3307,
2979, 2932, 2305, 1715, 1562, 1496, 1479, 1455, 1393, 1368, 1278, 1255,
1154, 1110, 998, 956, 856, 759, 727, 712, 697 cmÀ1; MS (ESI): m/z (%):
807 (27) [M2+H]+, 404 (100) [M+H]+, 244 (5), 101 (8); HRMS (ESI): m/
z calcd for [C21H30N3O5]+: 404.2180 [M+H]+; found: 404.2181.
Diethyl-1-((2-benzyloxazol-5-yl)methyl)hydrazine-1,2-dicarboxylate (6d)
Dibenzyl-1-((2-benzyloxazol-5-yl)methyl)hydrazine-1,2-dicarboxylate
(6g)
Diethyl-1-((2-benzyloxazol-5-yl)methyl)hydrazine-1,2-dicarboxylate was
prepared according to methods A (t1 =14 h, t2 =5 h) and B (t3 =14 h). In
method A, compound 1c (19.0 mg, 110 mmol), enophile Ea (21.0 mg,
110 mmol), and [Ph3PAuNTf2] (2.43 mg, 3.29 mmol) were used. In meth-
od B, compound 1c (12.9 mg, 74.5 mmol), enophile Ea (17.0 mg,
97.6 mmol), and [Ph3PAuNTf2] (1.84 mg, 2.49 mmol) were used. Column
chromatography on silica gel (petroleum ether/EtOAc, 1:1) afforded
compound 6d (method A: 25.0 mg, 72.0 mmol, 66%; method B: 21.0 mg,
60.5 mmol, 81%) as a colorless oil.
Dibenzyl-1-((2-benzyloxazol-5-yl)methyl)hydrazine-1,2-dicarboxylate was
prepared according to methods A (t1 =14 h, t2 =16 h) and B (t3 =20 h). In
method B, CH2Cl2 (25 mL) and a flask were used instead of an NMR
tube. In method A, compound 1c (81.7 mg, 470 mmol), enophile Ed
(155 mg, 521 mmol), and [Ph3PAuNTf2] (17.4 mg, 23.5 mmol) were used. In
method B, compound 1c (206 mg, 1.19 mmol), enophile Ed (385 mg,
1.29 mmol), and [Ph3PAuNTf2] (44.0 mg, 59.5 mmol) were used. Column
chromatography on silica gel (petroleum ether/EtOAc, 2:1) afforded
compound 6g (method A: 113 mg, 240 mmol, 51%; method B: 495 mg,
1.05 mmol, 88%) as a colorless oil.
1
Rf (petroleum ether/EtOAc, 4:1): 0.14; H NMR (300 MHz, CD2Cl2): d=
1.17–1.26 (m, 6H), 4.05 (s, 2H), 4.08–4.20 (m, 4H), 4.64 (s, 2H), 6.73–
6.80 (brs, 1H), 6.86 (s, 1H), 7.21–7.31 ppm (m, 5H); 13C NMR (75 MHz,
CD2Cl2): d=14.5 (q), 14.5 (q), 34.8 (t), 45.1 (t), 62.4 (t), 63.2 (t), 126.3
(d), 127.3 (d), 128.9 (d, 2C), 129.1 (d, 2C), 136.0 (s), 147.6 (s, 2C), 156.5
(s), 163.6 ppm (s); IR (film): n˜ =3283, 2983, 2933, 1717, 1561, 1497, 1468,
1455, 1426, 1383, 1263, 1227, 1197, 1111, 1061, 1028, 996, 764, 729,
697 cmÀ1; MS (EI(+), 70 eV): m/z (%): 347(3) [M]+, 260 (19), 259 (100),
258 (74), 214 (17), 187 (19), 186 (11), 173 (79), 172 (100), 171 (24), 167
(68), 144 (20), 117 (27), 103 (11), 91 (88); HRMS (EI(+), 70 eV): m/z
calcd for [C17H21N3O5]+: 347.1481; found: 347.1436.
1
Rf (petroleum ether/EtOAc, 2:1): 0.14; H NMR (300 MHz, CD2Cl2): d=
3.99 (s, 2H), 4.69 (s, 2H), 5.14 (s, 4H), 6.81 (s, 1H), 7.22–7.33 ppm (m,
15H); 13C NMR (75 MHz, CD2Cl2): d=34.8 (t), 44.4 (t), 68.0 (t), 68.7 (t),
125.3 (d), 126.2 (d), 127.1 (d, 2C), 127.2 (d, 2C), 127.4 (d), 127.5 (d),
127.7 (d, 4C), 127.8 (d, 2C), 128.0 (d, 2C), 134.8 (s), 135.1 (s, 2C), 146.3
(s), 154.8 (s), 162.6 (s), 170.1 ppm (s); IR (film): n˜ =3032, 1721, 1561,
1497, 1454, 1410, 1349, 1264, 1221, 1194, 1111, 1049, 1029, 1001, 975, 733,
697, 645, 576, 504 cmÀ1; MS (FAB(+)): m/z (%): 562 (8), 472 (100)
[M+H]+; HRMS (FAB(+)): m/z calcd for [C27H26N3O5]+: 472.1872
[M+H]+; found: 472.1915.
Diisopropyl-1-((2-benzyloxazol-5-yl)methyl)hydrazine-1,2-dicarboxylate
(6e)
Diethyl-1-((2-(thiophen-2-yl)oxazol-5-yl)methyl)hydrazine-1,2-
dicarboxylate (6h)
Diisopropyl-1-((2-benzyloxazol-5-yl)methyl)hydrazine-1,2-dicarboxylate
was prepared according to methods A (t1 =14 h, t2 =27 h) and B (t3 =
2 d). In method A, compound 1c (21.0 mg, 121 mmol), enophile Eb
(27.8 mg, 137 mmol), and [Ph3PAuNTf2] (2.62 mg, 3.54 mmol) were used.
In method B, compound 1c (30.6 mg, 177 mmol), enophile Eb (49.5 mg,
245 mmol), and [Ph3PAuNTf2] (3.70 mg, 5.00 mmol) were used. Column
chromatography on silica gel (petroleum ether/EtOAc, 2:1) afforded
compound 6e (method A: 40.0 mg, 107 mmol, 88%; method B: 61.0 mg,
162 mmol, 92%) as a colorless oil.
Diethyl-1-((2-(thiophen-2-yl)oxazol-5-yl)methyl)hydrazine-1,2-dicarboxy-
late was prepared according to methods A (t1 =1 h, t2 =2 h) and B (t3 =
3 h). In method A, compound 1d (45.3 mg, 274 mmol), enophile Ea
(59.6 mg, 342 mmol), and [Ph3PAuNTf2] (10.8 mg, 14.6 mmol) were used.
In method B, compound 1d (28.4 mg, 172 mmol), enophile Ea (43.7 mg,
251 mmol), and [Ph3PAuNTf2] (6.35 mg, 8.59 mmol) were used. Column
chromatography on silica gel (petroleum ether/EtOAc, 2:1) afforded
compound 6h (method A: 91.0 mg, 268 mmol, 98%; method B: 56.0 mg,
165 mmol, 96%) as a colorless oil.
1
Rf (petroleum ether/EtOAc, 1:1): 0.25; H NMR (300 MHz, CD2Cl2): d=
1.22 (d, 2J=6.9 Hz, 12H), 4.05 (s, 2H), 4.62 (s, 2H), 4.82–5.00 (m, 2H),
6.61–6.79 (brs, 1H), 6.85 (s, 1H), 7.22–7.34 ppm (m, 5H); 13C NMR
(75 MHz, CD2Cl2): d=22.1 (q, 2C), 22.2 (q, 2C), 34.9 (t), 44.7 (t), 70.2
(d), 71.0 (d), 126.2 (d), 127.4 (d), 129.0 (d, 2C), 129.2 (d, 2C), 136.1 (s),
147.9 (s, 2C), 155.8 (s), 163.6 ppm (s); IR (film): n˜ =3302, 2982, 2937,
Rf (petroleum ether/EtOAc, 2:1): 0.16; H NMR (300 MHz, CD2Cl2): d=
1
1.25 (s, 6H), 4.08–4.21 (m, 4H), 4.72 (s, 2H), 6.63–6.88 (brs, 1H), 6.99 (s,
1H), 7.08 (dd, 3J=4.8 Hz, 3J=3.0 Hz, 1H), 7.42 (d, 3J=4.8 Hz, 1H),
7.58 ppm (d, 3J=3.0 Hz, 1H); 13C NMR (75 MHz, CD2Cl2): d=13.4 (q),
13.6 (q), 43.7 (t), 61.4 (t), 62.2 (t), 126.4 (d), 126.9 (d), 127.2 (d), 127.6
Chem. Asian J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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A. Stephen K. Hashmi and Anna Littmann
FULL PAPERS
1
(d), 129.0 (s), 146.1 (s), 155.0 (s), 157.2 ppm (s, 2C); IR (film): n˜ =3294,
2982, 1717, 1584, 1507, 1493, 1468, 1425, 1382, 1266, 1197, 1121, 1095,
1060, 1020, 987, 853, 764, 726, 711 cmÀ1; MS (FAB(+)): m/z (%): 340
(100) [M+H]+, 266 (6), 261 (4), 251 (6), 250 (7); HRMS (FAB(+)): m/z
calcd for [C14H18N3O5S]+: 340.0967 [M+H]+; found: 340.0923; elemental
analysis calcd (%) for C14H17N3O5S: C 49.55, N 12.38, H 5.05, S 9.45;
found C 49.49, N 11.89, H 5.26, S 9.30.
Rf (petroleum ether/EtOAc, 2:1): 0.17; H NMR (300 MHz, CD2Cl2): d=
0.95 (s, 2H), 0.97 (s, 2H), 1.07–1.25 (m, 6H), 1.98 (s, 1H), 4.07–4.20 (m,
4H), 4.59 (s, 2H), 6.72 (s, 1H), 7.45 ppm (s, 1H); 13C NMR (75 MHz,
CD2Cl2): d=7.1 (t, 2C), 7.9 (d), 13.4 (q), 13.5 (q), 42.9 (t), 62.0 (t), 62.2
(t), 124.9 (d), 145.3 (s), 155.1 (s), 165.6 (s), 170.2 ppm (s); IR (film): n˜ =
3290, 2984, 2937, 1719, 1572, 1518, 1468, 1421, 1383, 1349, 1303, 1262,
1201, 1139, 1096, 1061, 1030, 992, 765, 732 cmÀ1; MS (ESI): m/z (%): 595
(9) [M2+H]+, 542 (37), 493 (31), 393 (100), 298 (30) [M+H]+, 108 (5),
101 (5), 96 (4); HRMS (ESI): m/z calcd for [C13H20N3O5]+: 298.1398
[M+H]+; found: 298.1398.
Diisopropyl-1-((2-(thiophen-2-yl)oxazol-5-yl)methyl)hydrazine-1,2-
dicarboxylate (6i)
Diisopropyl-1-((2-(thiophen-2-yl)oxazol-5-yl)methyl)hydrazine-1,2-dicar-
boxylate was prepared according to methods A (t1 =1 h, t2 =10 h) and B
(t3 =13 h). In method A, compound 1d (35.9 mg, 217 mmol), enophile Eb
(52.4 mg, 259 mmol), and [Ph3PAuNTf2] (8.60 mg, 11.6 mmol) were used.
In method B, compound 1d (26.2 mg, 159 mmol), enophile Eb (46.0 mg,
227 mmol), and [Ph3PAuNTf2] (5.48 mg, 7.42 mmol) were used. Column
chromatography on silica gel (petroleum ether/EtOAc, 2:1) afforded
compound 6i (method A: 76.0 mg, 207 mmol, 95%; method B: 58.0 mg,
158 mmol, 99%) as a colorless solid.
M.p.: 28C; Rf (petroleum ether/EtOAc, 2:1): 0.25; 1H NMR (500 MHz,
CD2Cl2): d=1.24 (s, 12H), 4.71 (s, 2H), 4.80–4.95 (m, 2H), 6.86 (s, 1H),
7.00 (s, 1H), 7.09 (dd, 3J=5.0 Hz, 3J=3.0 Hz, 1H), 7.43 (d, 3J=5.0 Hz,
1H), 7.59 ppm (d, 3J=3.0 Hz, 1H); 13C NMR (125 MHz, CD2Cl2): d=
22.1 (q, 2C), 22.2 (q, 2C), 45.4 (t), 70.2 (d), 71.1 (d), 127.5 (d), 128.0 (d),
128.3 (d), 128.7 (d), 130.3 (s), 147.4 (s), 155.8 (s), 158.3 ppm (s, 2C); IR
(film): n˜ =3289, 3119, 2983, 2360, 2305, 2196, 1713, 1493 , 1468, 1426,
1407, 1386, 1376, 1341, 1316, 1267, 1203, 1181, 1145, 1108, 1041, 990, 955,
711, 678 cmÀ1; MS (FAB(+)): m/z (%): 340 (100) [M+H]+, 266 (6), 261
(4), 251 (6), 250 (7); HRMS (FAB(+)): m/z calcd for [C16H21N3O5S]+:
368.1280 [M+H]+; found: 368.1248; elemental analysis calcd (%) for
C16H21N3O5S: C 52.30, H 5.76, N 11.44, S 8.73; found: C 52.39, H 5.87,
N 11.25, S 9.02.
Di-tert-butyl-1-((2-adamantyloxazol-5-yl)methyl)hydrazine-1,2-
dicarboxylate (6l)
Di-tert-butyl-1-((2-adamantyloxazol-5-yl)methyl)hydrazine-1,2-dicarboxy-
late was prepared according to method B (t3 =45 h). Compound 1g
(105 mg, 483 mmol), enophile Ec (121 mg, 525 mmol), and [Ph3PAuNTf2]
(12.9 mg, 17.4 mmol) were used. Column chromatography on silica gel
(petroleum ether/EtOAc, 2:1) afforded compound 6l (183 mg, 409 mmol,
85%) as a colorless solid.
1
Rf (petroleum ether/EtOAc, 2:1): 0.44; H NMR (300 MHz, CD2Cl2): d=
1.42 (s, 18H), 1.76 (s, 6H), 1.99 (m, 6H), 2.06 (brs, 3H), 4.57 (s, 2H),
6.55 (brs, 1H), 6.79 ppm (s, 1H); 13C NMR (75 MHz, CD2Cl2): d=28.3
(q, 6C), 28.5 (d, 3C), 36.0 (s), 36.8 (t, 3C), 40.7 (t, 3C), 60.6 (t), 81.5 (s),
81.9 (s), 125.3 (d), 147.0 (s), 155.13 (s), 177.2 (s), 177.3 ppm (s); IR (film):
n˜ =3311, 3199, 2979, 2909, 2853, 1731, 1551, 1478, 1454, 1393, 1368, 1346,
1313, 1275, 1254, 1155, 1120, 1103, 1052, 996, 956, 712 cmÀ1; MS (ESI):
m/z (%): 933 (2) [M2+K]+, 917 (6) [M2+Na]+, 895 (3) [M2+H]+, 486 (22)
[M+K]+, 470 (47) [M+Na]+, 448 (100) [M+H]+; HRMS (ESI): m/z calcd
for [C24H38N3O5]+: 448.2806 [M+H]+; found: 448.2809.
1-((2-tert-Butyloxazol-5-yl)methyl)-4-phenyl-1,2,4-triazolidine-3,5-dione
(7a)
1-((2-tert-Butyloxazol-5-yl)methyl)-4-phenyl-1,2,4-triazolidine-3,5-dione
was prepared according to methods A (t1 =0.5 h, t2 =1.5 h) and B (t3 =
3 d). In method A, compound 1b (39.6 mg, 284 mmol), enophile Ee
(54.1 mg, 309 mmol), and [Ph3PAuNTf2] (6.47 mg, 8.75 mmol) were used.
In method B, compound 1b (20.1 mg, 144 mmol), enophile Ee (33.4 mg,
191 mmol), and [Ph3PAuNTf2] (4.52 mg, 6.11 mmol) were used. Column
chromatography on silica gel (petroleum ether/EtOAc, 1:4) afforded
compound 7a (method A: 79.5 mg, 253 mmol, 89%; method B: 21.0 mg,
66.8 mmol, 46%) as a yellow oil.
Di-tert-butyl-1-((2-(thiophen-2-yl)oxazol-5-yl)methyl)hydrazine-1,2-
dicarboxylate (6j)
Di-tert-butyl-1-((2-(thiophen-2-yl)oxazol-5-yl)methyl)hydrazine-1,2-dicar-
boxylate was prepared according to methods A (t1 =1 h, t2 =1 d) and B
(t3 =40 h). In method A, compound 1d (45.3 mg, 274 mmol), enophile Ec
(59.6 mg, 342 mmol), and [Ph3PAuNTf2] (10.8 mg, 14.6 mmol) were used.
In method B, compound 1d (28.3 mg, 171 mmol), enophile Ec (56.5 mg,
245 mmol), and [Ph3PAuNTf2] (8.37 mg, 11.3 mmol) were used. Column
chromatography on silica gel (petroleum ether/EtOAc, 2:1) afforded
compound 6j (method A: 91.0 mg, 268 mmol, 98%; method B: 58.0 mg,
147 mmol, 86%) as a colorless solid.
1
Rf (petroleum ether/EtOAc, 1:2): 0.17; H NMR (300 MHz, CD2Cl2): d=
1.30 (s, 9H), 4.73 (s, 2H), 6.92 (s, 1H), 7.38–7.52 ppm (m, 6H); 13C NMR
(75 MHz, CD2Cl2): d=28.6 (q, 3C), 34.2 (s), 42.5 (t), 126.1 (d, 2C), 126.4
(d), 128.8 (d), 129.5 (d, 2C), 131.7 (s), 145.1 (s), 154.2 (s), 172.8 ppm (s,
2C); IR (film): n˜ =3318, 3213, 2978, 2934, 2873, 1718, 1556, 1478, 1458,
1393, 1368, 1253, 1154, 1050, 1022, 994, 957, 859, 742, 705 cmÀ1; MS
(FAB(+)): m/z (%): 315 (100) [M+H]+, 314 (18), 289 (5), 283 (6), 282
(10), 281 (31), 279 (26), 267 (15), 261 (13), 239 (5), 221 (29); HRMS
(FAB(+)): m/z calcd for [C16H19N4O3]+: 315.1457 [M+H]+; found:
315.1476.
1
M.p.: 1498C; Rf (petroleum ether/EtOAc, 2:1): 0.25; H NMR (300 MHz,
CD2Cl2): d=1.43 (s, 9H), 1.47 (s, 9H), 4.66 (s, 2H), 6.59 (s, 1H), 7.00 (s,
1H), 7.10 (dd, 3J=5.1 Hz, 3J=3.9 Hz, 1H), 7.43 (dd, 3J=5.1 Hz, 4J=
1.2 Hz, 1H), 7.61 ppm (dd, 3J=3.9 Hz, 4J=1.2 Hz, 1H); 13C NMR
(75 MHz, CD2Cl2): d=28.3 (q, 6C), 44.1 (t), 81.6 (s), 82.2 (s), 127.3 (d),
127.9 (d), 128.3 (d), 128.6 (d), 129.7 (s), 130.45 (s), 147.9 (s), 155.2 (s),
158.2 ppm (s); IR (film): n˜ =3311, 2980, 2933, 1715, 1507, 1493, 1478,
1456, 1425, 1394, 1368, 1320, 1277, 1255, 1154, 1051, 989, 955, 853, 760,
712, 678 cmÀ1; MS (ESI): m/z (%): 396 (100) [M+H]+, 305 (4), 101 (2);
HRMS (ESI): m/z calcd for [C18H26N3O5S]+: 396.1588 [M+H]+; found:
396.1595; elemental analysis calcd (%) for C18H25N3O5S: C 54.67, H 6.37,
N 10.63, S 8.11; found: C 54.64, H 6.40, N 10.35, S 7.85.
1-((2-Benzyloxazol-5-yl)methyl)-4-phenyl-1,2,4-triazolidine-3,5-dione (7b)
1-((2-Benzyloxazol-5-yl)methyl)-4-phenyl-1,2,4-triazolidine-3,5-dione was
prepared according to methods A (t1 =14 h, t2 =1.5 h) and B (t3 =4 d). In
method A, compound 1c (35.6 mg, 206 mmol), enophile Ee (37.3 mg,
213 mmol), and [Ph3PAuNTf2] (4.56 mg, 6.17 mmol) were used. In meth-
od B, compound 1c (58.9 mg, 3.40 mmol), enophile Ee (60.1 mg,
343 mmol), and [Ph3PAuNTf2] (13.4 mg, 18.1 mmol) were used. Column
chromatography on silica gel (petroleum ether/EtOAc, 1:2) afforded
compound 7b (method A: 16.0 mg, 45.9 mmol, 22%; method B: 49.0 mg,
141 mmol, 41%) as a dark-yellow oil.
Diethyl-1-((2-cyclopropyloxazol-5-yl)methyl)hydrazine-1,2-dicarboxylate
(6k)
Diethyl-1-((2-tert-butyloxazol-5-yl)methyl)hydrazine-1,2-dicarboxylate
was prepared according to methods A (t1 =10 h, t2 =2 d) and B (t3 =3 d).
In method A, compound 1e (42.7 mg, 347 mmol), enophile Ea (71.3 mg,
574 mmol), and [Ph3PAuNTf2] (13.2 mg, 17.9 mmol) were used. In meth-
od B, compound 1e (40.2 mg, 327 mmol), enophile Ea (84.4 mg,
485 mmol), and [Ph3PAuNTf2] (12.6 mg, 17.0 mmol) were used. Column
chromatography on silica gel (petroleum ether/EtOAc, 1:1) afforded
compound 6k (method A: 55.0 mg, 185 mmol, 53%); method B: 64.0 mg,
215 mmol, 66%) as a colorless oil.
1
Rf (petroleum ether/EtOAc, 1:2): 0.21; H NMR (300 MHz, CD2Cl2): d=
4.04 (s, 2H), 4.69 (s, 2H), 6.23 (brs, 1H), 7.20–7.35 (m, 5H), 7.37–
7.51 ppm (m, 5H); 13C NMR (75 MHz, CD2Cl2): d=33.7 (t), 41.2 (t),
124.9 (d, 2C), 125.8 (d), 126.4 (d), 127.6 (d), 127.9 (d, 2C),128.0 (d, 2C),
128.3 (d, 2C), 130.5 (s), 134.4 (s), 147.7 (s), 152.9 (s), 153.0 (s), 163.5 ppm
(s); IR (film): n˜ =3064, 3032, 2924, 1773, 1713, 1600, 1560, 1502, 1455,
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ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!

One-Pot Alkylideneoxazoline Synthesis/Alder-Ene Reaction
1423, 1359, 1262, 1111, 997, 955, 770, 729, 711, 696, 638 cmÀ1; MS
(FAB(+)): m/z (%): 349 (83) [M+H]+, 347 (66), 326 (11), 307 (12), 305
(15), 289 (17), 281 (17), 279 (21), 136 (100); HRMS (FAB(+)): m/z calcd
for [C19H17N4O3]+: 349.2301 [M+H]+; found: 349.1287.
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft (HA
1932/11-1). We thank Umicore AG & Co. KG for the generous donation
of noble-metal salts.
4-Phenyl-1-((2-(thiophen-2-yl)oxazol-5-yl)methyl)-1,2,4-triazolidine-3,5-
dione (7c)
4-Phenyl-1-((2-(thiophen-2-yl)oxazol-5-yl)methyl)-1,2,4-triazolidine-3,5-
dione was prepared according to methods A (t1 =1 h, t2 =2 h) and B (t3 =
11 d). In method A, compound 1d (34.6 mg, 209 mmol), enophile Ee
(37.0 mg, 211 mmol), and [Ph3PAuNTf2] (7.50 mg, 10.1 mmol) were used.
In method B, compound 1d (50.1 mg, 303 mmol), enophile Ee (53.5 mg,
305 mmol), and [Ph3PAuNTf2] (11.0 mg, 14.9 mmol) were used. Column
chromatography on silica gel (petroleum ether/EtOAc, 1:1) afforded
compound 7c (method A: 29.0 mg, 85.2 mmol, 41%; method B: 51.0 mg,
150 mmol, 49%) as a colorless solid.
[1] a) D. C. Palmer, S. Venkatraman in The Chemistry of Heterocyclic
Compounds, A Series of Monographs, Oxazoles: Synthesis Reactions,
and Spectroscopy, Part A (Ed.: D. C. Palmer), Wiley, New York,
2003; b) S. Lang-Fugmann in Methoden der Organischen Chemie
(Houben-Weyl) (Ed.: E. Schaumann), Thieme, Stuttgart, 1993; c) R.
Lakhan, B. Ternai, Adv. Heterocycl. Chem. 1974, 17, 99–211; d) G. J.
Pattenden, Heterocycl. Chem. 1992, 29, 607–618.
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1
M.p.: 1638C; Rf (petroleum ether/EtOAc, 1:1): 0.24; H NMR (300 MHz,
[D6]DMSO): d=4.84 (s, 2H), 7.22 (dd, 3J=5.1 Hz, 3J=3.6 Hz, 1H), 7.32
(s, 1H), 7.38–7.54 (m, 6H), 7.69 (dd, 3J=3.6 Hz, 4J=1.2 Hz, 1H),
7.80 ppm (dd, 3J=5.1 Hz, 4J=1.2 Hz, 1H); 13C NMR (75 MHz, CD2Cl2):
d=41.8 (t), 126.5 (d, 2C), 128.2 (d), 128.4 (d), 128.5 (d), 128.9 (d), 129.2
(s), 129.3 (d, 2C), 130.1 (d), 131.9 (s), 146.0 (s), 153.1 (s), 154.0 (s),
157.7 ppm (s); IR (KBr): n˜ =3432, 3117, 2926, 1708, 1627, 1542, 1502,
1454, 1419, 1311, 1255, 1134, 1047, 767, 728, 693, 646, 617, 583, 508 cmÀ1
;
MS (FAB(+)): m/z (%): 413 (100), 363 (18), 341 (50) [M+H]+, 331 (5),
279 (4); HRMS (FAB(+)): m/z calcd for [C16H13N4O3S]+: 341.0708
[M+H]+.
6-tert-Butyl-5-oxa-7-azaspiroACHTNUTRGNEUNG[3.4]oct-6-ene-1,1,2,2-tetracarbonitrile (8)
To a solution of compound 1b (105 mg, 750 mmol) in CH2Cl2 (20 mL),
was added catalyst [Ph3PAuNTf2] (28.7 mg, 38.8 mmol). After 1.5 h, the
mixture was cooled to À408C. Tetracyanoethylene enophile Ef (110 mg,
859 mol) was added dropwise and the resulting solution was stirred at
À408C for 2 h, before being slowly warmed to room temperature. The
solvent was evaporated under reduced pressure and the crude product
was purified by column chromatography on silica gel (petroleum ether/
EtOAc, 3:1) to furnish compound
a brown solid.
8 (91.0 mg, 340 mmol, 45%) as
M.p.: 1268C (dec.); Rf (petroleum ether/EtOAc, 2:1): 0.38; 1H NMR
(300 MHz, CD2Cl2): d=1.27 (s, 9H), 3.44 (d, 2J=14.1, 1H), 3.63 (d, 2J=
14.1, 1H), 4.09 (d, 2J=17.1, 1H), 4.55 ppm (d, 2J=17.1, 1H); 13C NMR
(75 MHz, CD2Cl2): d=27.5 (s), 27.8 (q, 3C), 32.0 (s), 34.2 (s), 45.4 (t),
64.8 (t), 85.51 (s), 108.0 (s), 108.9 (s), 110.7 (s), 111.0 (s), 173.0 ppm (s);
IR (KBr): n˜ =3444, 3025, 2976, 2933, 2874, 1691, 1637, 1601, 1557, 1482,
1461, 1427, 1368, 1285, 1229, 1112, 1037, 1007, 920, 855 cmÀ1; MS (EI(+),
70 eV): m/z (%): 268 [M+H]+ (8), 241 (7), 236 (6), 110 (6), 108 (11), 101
(7), 96 (4), 89 (5); HRMS (EI(+), 70 eV): m/z calcd for [C14H14N5O]+:
268.1193 [M+H]+; found: 268.1196.
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Comparison of Different AuI CatalystsDi-tert-butyl-1-((2-benzyloxazol-5-
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In an NMR tube, compound 1c, enophile Ec, and 1,3,5-tri-tert-butylben-
zol (2 mg) as a standard were dissolved in CD2Cl2 (600 mL) and the cata-
1
lyst was added (Table 4). The yield was determined by H NMR spectros-
copy.
Table 4. Comparison of different catalysts for the reaction of compound
1c to form compound 6 f.
Reactant 1c
18.8 mg, 109 mmol 26.3 mg, 114 mmol [Ph3PAuNTf2]
(1.61 mg, 2.18 mmol)
16.4 mg, 94.7 mmol 22.9 mg, 99.4 mmol K1
(1.54 mg, 1.62 mmol)
Enophile Ec
Catalyst
Yield [%]
84
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c) E. M. Beccalli, E. Borsini, G. Broggini, G. Palmisano, S. Sottocor-
92
98
14.0 mg, 80.8 mmol 19.5 mg, 84.7 mmol K2
(1.84 mg, 1.87 mmol)
Chem. Asian J. 2012, 00, 0 – 0
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A. Stephen K. Hashmi and Anna Littmann
FULL PAPERS
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[18] The tolerance to water and oxygen has already been reported in ear-
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Received: January 13, 2012
Revised: February 18, 2012
Published online: && &&, 0000
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ÝÝ These are not the final page numbers!

FULL PAPERS
Oxazoles
A. Stephen K. Hashmi,*
Anna Littmann
&&&& — &&&&
Gold Catalysis: One-Pot Alkylide-
neoxazoline Synthesis/Alder-Ene
Reaction
The famous five: The one-pot reaction
of readily available N-propargylamides
and azodicarboxylates provided func-
tionalized oxazoles through a five-step
cycloisomerization/Alder-ene reaction
pathway.
Chem. Asian J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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