Cyclization of propargylic amides: Mild access to oxazole derivatives

Article abstract of DOI:10.1002/chem.200902472

The substrate scope, the mechanistic aspects of the gold-catalyzed oxazole synthesis, and substrates with different aliphatic, aromatic, and functional groups in the side chain were investigated. Even molecules with several propargyl amide groups could easily be converted, delivering di- and trioxazoles with interesting optical properties. Furthermore, the scope of the gold(I)-catalyzed alkylidene synthesis was investigated. Further functionalizations of these isolable intermediates of the oxazole synthesis were developed and chelate ligands can be obtained. The use of Barluenga's reagent offers a new and mild access to the synthetically valuable iodoalkylideneoxazoles from propargylic amides, this reagent being superior to other sources of halogens.

Full text of DOI:10.1002/chem.200902472

DOI: 10.1002/chem.200902472
Cyclization of Propargylic Amides: Mild Access to Oxazole Derivatives
Jan P. Weyrauch,[b] A. Stephen K. Hashmi,*[a] Andreas Schuster,[a] Tobias Hengst,[a]
Stefanie Schetter,[b] Anna Littmann,[a] Matthias Rudolph,[a] Melissa Hamzic,[a]
Jorge Visus,[b] Frank Rominger,[a] Wolfgang Frey,[b] and Jan W. Bats[c]
In memorial of Dr. Jan P. Weyrauch
Abstract: The substrate scope, the
mechanistic aspects of the gold-cata-
lyzed oxazole synthesis, and substrates
with different aliphatic, aromatic, and
functional groups in the side chain
were investigated. Even molecules with
several propargyl amide groups could
easily be converted, delivering di- and
trioxazoles with interesting optical
properties. Furthermore, the scope of
the gold(I)-catalyzed alkylidene syn-
thesis was investigated. Further func-
tionalizations of these isolable inter-
mediates of the oxazole synthesis were
developed and chelate ligands can be
obtained. The use of Barluengaꢀs re-
agent offers a new and mild access to
the synthetically valuable iodoalkyli-
AHCTUNGTRENNdGUN eneoxazoles from propargylic amides,
this reagent being superior to other
sources of halogens.
Keywords: cyclization
cence gold catalysis
·
fluores-
· methyl-
·
AHCTUNGTRENNUNG
Introduction
cles. The first evidence for this reaction pattern was contrib-
uted by Utimoto et al. in 1987 who investigated an intramo-
lecular hydroamination of alkynes, which delivered tetrahy-
dropyridines after a subsequent isomerization.[2] In 2000, our
group published the gold-catalyzed transformation of furans
by a 5-endo-trig cyclization of allenyl ketones, which provid-
ed evidence that even carbonyl oxygen atoms can serve as
nucleophiles in gold-catalyzed rearrangements.[3] Based on
these findings, a large family of gold-catalyzed heterocycle
syntheses was developed by different groups.[4]
The utilization of gold catalysts in the field of organic
chemistry is one of the hot topics in current research.[1]
Most of these reactions are atom economical and in compar-
ison to other transition-metal catalysts the reaction condi-
tions are remarkably mild in most cases. Among these trans-
formations, the intramolecular addition of heteroatom nu-
cleophiles to carbon–carbon triple bonds plays an important
role as powerful tool for the synthesis of various heterocy-
Inspired by Arcadi, Cacchi, and co-workers, who pub-
lished a Pd0-catalyzed coupling–cyclization sequence for the
synthesis of disubstituted oxazoles,[5] in 2004 we contributed
the gold-catalyzed synthesis of oxazoles 2 formed by a 5-
[a] Prof. Dr. A. S. K. Hashmi, Dipl.-Chem. A. Schuster,
Dipl.-Chem. T. Hengst, Dipl.-Chem. A. Littmann, Dr. M. Rudolph,
Dr. M. Hamzic, Dr. F. Rominger+
Organisch-Chemisches Institut
exo-dig cyclization of N-propargyl carboxamides
1
Ruprecht-Karls-Universitꢁt Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax : (+49)6221-544205
(Scheme 1).[6] This transformation is of high importance, as
the motif of disubstituted oxazoles can often be found in
natural products and plenty of these compounds exhibit in-
teresting pharmaceutical potential, for example, as antitu-
mor agents, antifungal agents, herpes simplex virus type 1
E-mail: hashmi@hashmi.de
[b] Dr. J. P. Weyrauch, S. Schetter, J. Visus, Dr. W. Frey+
Institut fꢂr Organische Chemie, Universitꢁt Stuttgart
Pfaffenwaldring 55, 70569 Stuttgart (Germany)
[c] Dr. J. W. Bats+
Institut fꢂr Organische Chemie und Chemische Biologie
Johann Wolfgang Goethe-Universitꢁt Frankfurt
Marie-Curie-Str. 11, 60439 Frankfurt (Germany)
[+] Crystallographic investigation.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902472.
Scheme 1. Gold-catalyzed oxazole synthesis (R=alkyl, vinyl, aryl).
956
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2010, 16, 956 – 963

FULL PAPER
Table 1. Substrate scope of the gold-catalyzed oxazole synthesis with AuCl3.
(HSV-1) inhibitors, serine–
threonine phosphate inhibitors,
and antibacterials.[7]
Entry Starting
material
Solvent
CH2Cl2
CH2Cl2
Time Product
Yield
of 2 [%]
As most of the above-men-
tioned compounds are highly
functionalized, the mild condi-
tions[8] of the gold-catalyzed ox-
azole synthesis make it ex-
tremely attractive in compari-
son to the classical routes
through condensation reactions,
which often demand harsh reac-
tion conditions.[7] Hence, this
protocol has even attracted in-
dustrial chemists and patents
containing the gold-catalyzed
transformation as the key step
can be found.[9]
1
2
21 h
21 h
100[a]
70
3
4
CH2Cl2
CH2Cl2
21 h
63
97
5 min
In the meantime, there are
several reports in the literature
concerning the use of different
ligand systems at the gold
center,[10] the use of other tran-
sition metals as catalysts,[11] as
well as a Brønsted acid-cata-
lyzed variant (under reflux con-
ditions).[12] Herein, we report
our latest results in this impor-
tant field, on both synthetic as
well as further mechanistic as-
pects of this fascinating and
useful reaction.
5
6
CH2Cl2
CH2Cl2
5 min
12 h
94
99
7
CH3CN
5 h[b]
45
8
9
CH3CN
CH2Cl2
72 h
no conversion
–
6 h[b]
60
Results and Discussion
10
11
CH2Cl2
12 h
no conversion[c]
–
Our first goal was to extend our
methodology to a broader array
of starting materials including
substrates bearing even several
propargylic moieties for multi-
ple reactions. Table 1 shows the
results of these cyclizations. For
the substrates containing only
one propargylic amide side
chain, all substrates underwent
a smooth reaction to furnish
tert-butyl- (2a), benzyl- (2b),
thiophenyl-substituted oxazoles
CH2Cl2 or CH3CN 12 h[b]
86
[a] NMR conversion; product too volatile to be isolated. [b] Reaction at 508C. [c] This is most probably
caused by the insolubility of the starting material.
2c (Table 1, entries 1–3) as well as the bulky anthracenyl-
substituted oxazole 2d (Table 1, entry 4) and the biphenyl
substrate 2e, most of them in excellent yields. Concerning
the interesting optical abilities of aryl-substituted oxazoles
and their application as luminophores,[13] we investigated the
reactions of substrates containing up to three proACTHNUGRTNEUNGpargylic
moieties in one molecule. To our delight, most of these sub-
strates showed full conversion to the corresponding oxazoles
(Table 1, entries 6, 7, 9) for the bifunctionalized, and even
substrate 1k (Table 1, entry 11), which contains three prop-
argylic moieties, delivered 2k as a single product in a re-
markable yield of 86%. The X-ray crystal structure analysis
of compound 2 f (Figure 1) provides unambiguous proof for
the formation of the two oxazole moieties.[14] All of the reac-
tions with substrates containing more than one propargylic
tether were carried out at slightly elevated temperature,
Chem. Eur. J. 2010, 16, 956 – 963
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
957

A. S. K. Hashmi et al.
termediate propargyl amides 1, which after isomerization to
the allene intermediates A (Scheme 2, path a) finally give
the oxazole products 2 with 10 mol% of AuCl3 in a one-pot
Figure 1. Plot of the structure of 2 f in the solid state.
which was essential because of the low solubility of the
starting materials. In the case of substrate 1j (Table 1,
entry 10) this is most probably the reason for the lack of
conversion; the compound was neither soluble in dichloro-
methane nor in CH3CN even at boiling temperatures.
Scheme 2. Possible mechanistic pathways for the oxazole formation.
By decreasing the electron density of the central aromatic
systems in 1g and 1h (Table 1, entries 7 and 8), it could be
demonstrated that the limitations of this methodology are
electron-poor substrates (in the case of electron-poor pyri-
dine substrate 1h no conversion at all took place).
Table 2 shows the luminescence abilities of some repre-
sentative examples (see also Figure 1). The UV absorption
of the compounds was in the 300–400 nm region, depending
reaction. They claimed the observation of intermediate A
by in situ H NMR spectroscopy. A similar reaction pattern
1
was reported by Hacksell et al., who reported a base-cata-
lyzed isomerization of propargylic amides through allenic in-
1
termediates.[16] But the H NMR data reported by Uemura
et al. did not match the symmetry of intermediate A, which
should show only one resonance for the allenic CH2 group,
but two different resonances were reported in footnote 7 of
the publication. Furthermore, such an intermediate would
contradict our mechanistic findings:[6] As we considered the
participation of intermediate dihydrooxazoles (Scheme 2,
path b) in our publication, further experimental clarification
of the mechanism was required. For a direct comparison, we
synthesized the propargylic amide 1l, which was also gener-
ated in situ during Uemuraꢀs one-pot version of this reaction
Table 2. Luminescence data of some representative aryloxazoles.
Entry
2
lmax (Abs.)
[nm]
emax
[LmolÀ1 cmÀ1
log emax lmax (Em.)
Dn˜
[cmÀ1
]
]
[nm]
1
2
3
4
d
e
i
376
302
324
290
6343
3.80
4.51
4.68
4.73
469
359
387
369
5274
5257
5024
7382
32452
47400
53166
k
1
and had been studied by in situ H NMR spectroscopy by
Uemura et al. The low-temperature DEPT NMR spectra of
the reaction mixture (Figure 2) clearly reveal that only
path b is operating for the gold-catalyzed cyclization, unam-
biguously proven by the tertiary carbon atom at d=
70.7 ppm (the allenic intermediate does not contain any me-
thine carbon atom).
on the grade of conjugation. While compound 2d (Table 2,
entry 1) showed a maximum absorption at 376 nm, com-
pound 2i had a maximum absorption at 324 nm due to a
hypsochromic shift induced by the loss of conjugation be-
tween the two phenyl rings. The absorption at the lowest
wavelength of 2k (Table 2, entry 4) clearly indicates that the
three attached oxazole rings are not coplanar to the central
aromatic core. Even 2i with three single bonds between the
four aromatic moieties showed a higher maximum absorp-
tion at 324 nm.
The fluorescence spectra of 2d showed a maximum emis-
sion at 469 nm that was visible as a green luminescence,
whereas the other compounds showed blue luminescence
with maximum emissions between 359–387 nm. The highest
stokes shift of 7382 cmÀ1 was monitored for compound 2k,
initiated by the three oxazole moieties.
Mechanistic aspects: Contemporaneous to our initial publi-
cation on the gold-catalyzed oxazole synthesis, Uemura
et al. contributed
a highly innovative Ru/Au-catalyzed
tandem sequence of propargylic alcohols and amides to the
corresponding oxazoles.[15] Their mechanistic concept consid-
ered a ruthenium-catalyzed condensation (5 mol% of a di-
Figure 2. a) 13C{1H} NMR spectrum, b) DEPT 135 NMR spectrum, and
c) DEPT 90 NMR spectrum. All spectra were taken during the conver-
sion of 1l with 5.0 mol% AuCl3 at À208C.
ACHTUNGTRENNUNGruthenium complex) of the starting material to form the in-
958
www.chemeurj.org
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 956 – 963

Cyclization of Propargylic Amides
FULL PAPER
From a mechanistic point of view, it is obvious, that a
proton is needed for the regeneration of the active catalyst.
With this in mind, we prepared substrates 1m and 1n
(Scheme 3) containing a methyl-substituted nitrogen, and
turned out to be very broad. Entries 1–5 in Table 3 present
substrates which contain aliphatic moieties in the side chain.
Apart from substrate 1q (Table 3, entry 4), all of the sub-
strates underwent smooth conversion. Here the presence of
an additional alkynyl moiety led to a loss of selectivity of
the reaction and only 8% of the fairly unstable product 8q
could be isolated. Even substrate 1r (Table 3, entry 5) with
the sterically demanding adamantyl substituent delivered re-
markable yields. The high functional group tolerance of this
reaction could be demonstrated with an array of different
ester substrates (Table 3, entries 6–8). Interestingly, the di-
rectly attached ester moiety in substrate 1s (Table 3,
entry 6) led to aromatization, while the other ester sub-
strates (Table 3, entries 7 and 8) delivered the methyleneox-
azolines in high yields. Next we investigated aryl-containing
substrates. To our delight all of the tested substrates deliv-
ered the corresponding methyleneoxazolines in good to ex-
cellent yields, independent of the electronic properties of
the aromatic systems (Table 3, entries 9–13). Figure 3a
shows the results of the X-ray crystal structure analysis of
compound 8v.[14] The fully conjugated system of the mole-
cule leads to a planar alignment in the solid state. Substrates
containing aromatic heterocycles as substituents showed a
dependency on the electronic properties of the aromatic
system. While thiophene substrate 1c (Table 3, entry 14)
and furan substrates 1z and 1aa (Table 3, entries 15 and 16)
furnished good to excellent yields, only poor yields were ac-
complished with the electron-poor furan substrate 1ab
(Table 3, entry 17) as well as the pyridine derivative 1ac
(Table 3, entry 18). We then tested substrates that contained
two propargylic moieties. The same tendencies mentioned
above were visible for these compounds as well (Table 3, en-
tries 19–23). The limits lay once again in electron-poor sub-
strates like 1h (Table 3, entry 23). Here the position of the
heteroatom of the central pyridine led to a differentiation
between the two alkynyl moieties. Only the electron-richer
side chain reacted to form dihydrooxazole 8 f. Two of the
products formed single crystals suitable for X-ray structure
analysis. The illustrations of the X-ray structure data of 8ad
and 8 f in Figure 3b and c respectively, once more reveal the
high chemoselectivity of these transformations.[14] The prod-
ucts 8ac and 8ad can only be formed with the AuI catalysts,
as these products are chelating ligands and poison the
square planar AuIII complexes by product inhibition, but not
the linear AuI complexes.
Scheme 3. Conversion of N-methyl propargylic amides.
added external proton sources such as p-TsOH or HBF4.
The AuCl3-catalyzed conversion of these substrates did not
form oxazoles, instead addition of water to the intermediate
dihydrooxazonium salts 3 and a subsequent ring opening de-
livered vinylesters 4a–c with allylamine substructures. Inter-
estingly, no aromatization of the intermediates was moni-
tored, indicating that the intermolecular water addition
seems to be faster than the aromatization step.
The experiment aimed at generating a possible 6-exo-dig
cyclization of the aniline-derived substrate 5 (Scheme 4)
showed only traces of the desired product. In this case, the
Scheme 4. Intermolecular water addition versus intramolecular 6-exo-dig
cyclization.
competing water addition leading to 6 turned out to be
much faster.
Dihydrooxazoles: In our previous report on the gold-cata-
lyzed cyclization of trichloroacetimidates to the correspond-
ing oxazoles by hydroamination,[17] AuI salts turned out to
be very effective for the conversion to the alkylidene oxa-
zoles, previously only known as reactive intermediates. In-
spired by these results, we looked into one example for an
AuI-catalyzed conversion of propargylic amides as well.
Under these conditions we were able to isolate the methyl-
ene dihydrooxazole as a stable compound even after purifi-
cation on silica. To further explore the scope of this isomeri-
zation, we converted a series of different propargylic amides
by using AuI catalysts (Table 3). The scope of this reaction
Further functionalization: Our next aim was to further func-
tionalize the methyleneoxazolines. Inspired by literature re-
ports on the trapping of intermediate vinylgold com-
pounds[18] with electrophilic reagents,[19] we reacted different
propargylic amides in the presence of electrophilic N-halo-
succinimides and the gold catalyst (Table 4). The results
demonstrate that the expected halomethyleneoxazolines 10
were not formed in the reaction of the gold intermediate
with the electrophile before the proto-demetalation step
(Scheme 5). Instead, the formation of halogen-substituted
halomethyloxazoles 9 occurred, unfortunately in low yields,
Chem. Eur. J. 2010, 16, 956 – 963
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
959

A. S. K. Hashmi et al.
Table 3. AuI-catalyzed formation of methylendihydrooxazoles.
Entry
Starting
material
1
Catalyst
Solvent
CH2Cl2
Time
36 h
Product
8
Yield
of 8 [%]
2 mol%
AHCTUNTGRENN[GNU PPh3Au]NTf2
1
o
o
76
2 mol%
[PPh3Au]NTf2
complete
2
3
4
a
p
q
CH2Cl2
CH2Cl2
CH2Cl2
4 h
a
p
q
N
conversion[a]
2 mol%
A
complete
34 h
36 h
conversion[a]
3 mol%
AHCTUNTGRENN[GNU PPh3Au]NTf2
8
1 mol%
AHCTUNGTRENNUNG
[PPh3 Au]NTf2
5
6
r
s
CH2Cl2
CH2Cl2
18 h
r
s
95
5 mol%
AHCTUNGRTENN[GUN PPh3Au]OTs
2 days
81
5 mol%
AHCTUNGRTENN[GUN PPh3Au]OTs
7
8
9
t
CH2Cl2
CH2Cl2
CH2Cl2
2 days
2 days
24 h
t
87
5 mol%
AHCTUNGRTENN[GUN PPH3Au]OTs
u
b
u
b
81[b]
92
5 mol%
AHCTUNGRTENN[GUN PPh3Au]OTs
1 mol%
AHCTUNTGRENN[GNU PPh3Au]NTf2
10
11
12
v
CH2Cl2
CH2Cl2
CHCl3
36 h
36 h
48 h
v
91
79
74
68
1 mol%
AHCTUNTGRENN[GNU PPh3Au]NTf2
w
x
w
x
4 mol%
AHCTUNTGRENN[GNU Mes3Au]NTf2
5 mol%
AHCTUNTGRENN[GNU PPh3Au]NTf2
13
14
y
c
CHCl3
3 h
y
c
2 mol%
[PPh3Au]NTf2
complete
CH2Cl2
34 h
G
conversion[a]
5 mol%
PPh3Au]OTs
15
16
z
CH2Cl2
CH2Cl2
24 h
24 h
z
67
82
5 mol%
AHCTUNGRTENN[GUN PPh3Au]OTs
aa
aa
5 mol%
AHCTUNGRTENN[GUN PPh3Au]OTs
17
18
ab
ac
CH2Cl2
CH2Cl2
4 days
6 days
ab
ac
30[c]
37
5 mol%
AHCTUNGRTENN[GUN PPh3Au]OTs
5 mol%
AHCTUNGRTENN[GUN PPh3Au]OTs
19
ad
CH2Cl2
24 h
ad
80
960
www.chemeurj.org
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 956 – 963

Cyclization of Propargylic Amides
Table 3. (Continued)
FULL PAPER
Entry
Starting
material
1
Catalyst
5 mol%
Solvent
CH2Cl2
Time
Product
8
Yield
of 8 [%]
20
21
22
23
ae
f
3 days
12 h
5 h
ae
f
41
74
46
64
AHCTUNGRTENN[GUN PPh3Au]OTs
3 mol%
AHCTUNTGRENN[GNU PPh3Au]NTf2
[d]
CH2Cl2
2 mol%
AHCTUNTGRENN[GNU PPh3Au]NTf2
g
CH3CN[e]
CH3CN
g
5 mol%
AHCTUNTGRENN[GNU PPh3Au]NTf2
h
5 h
h
[a] Determined by NMR spectroscopic measurements (highly volatile). [b] 2:1 mixture of alkylideneoxazoline/oxazole. [c] Mixture of 56% of starting
material, 11% of aromatized oxazole, and 32% of 8ab. [d] Reaction temperature=508C. [e] Reaction temperature 708C.
Scheme 5. Formation of halomethyloxazoles 9.
independent of the oxidation state of the metal catalysts
(Table 4, entries 1–4). Control experiments without gold cat-
alyst (Table 4, entries 5 and 6) showed no conversion in the
case of N-chlorosuccinimide (NCS) and a slow decomposi-
tion of the starting material in the case of N-bromosuccini-
mide (NBS).
Not unexpectedly, the isolated methyleneoxazolines 8
could be converted with the electrophilic reagents too, indi-
cating that during the gold-catalyzed version first the vinyl
gold species gets proto-demetalated and then in a subse-
quent uncatalyzed step the final products are formed.
Table 5 summarizes the results of the uncatalyzed conver-
sion of the methylenedihydrooxazoles 8. As for the data in
Table 4, the yields of the transformations presented in
Table 5 were not satisfying in most cases. Only the adaman-
tyl-substituted substrate (Table 5, entry 4) showed a clean
reaction in the case of NBS, while all the other substrates
showed significant amounts of byproduct formation during
the reaction. Besides the formation of the halogenated prod-
uct, simple aromatization to oxazoles 2 also took place,
leading to inseparable mixtures. Especially in the case of the
iodination, substrates turned out to be fairly unstable.
Figure 3. Solid-state structure of methyleneoxazolines 8v (a), 8ad (b),
and 8 f (c).
Table 4. Formation of halomethyloxazoles 9 from propargylic amides 1.
Entry
R
Catalyst
NXS[a] (equiv) Temp.
9
Yield
Finally, we used a different halide source, Barluengaꢀs re-
agent (bisACHTNUGRTNEUNG(pyridyl)iodonium(I) tetrafluoroborate (Py2IBF4)),
[8C]
of 9 [%]
1
2
3
4
5
6
N
G
40
20
40
20
40
20
a
b
a
–
–
–
7
9
29
which is well known for its ability to activate triple bonds
for the attack of different nucleophiles.[20] Table 6 demon-
strates the higher effectiveness of this reagent. All the em-
ployed substrates showed clean conversion under mild con-
ditions regardless of whether aliphatic (Table 6, entries 1
and 2) or aromatic moieties (Table 6, entries 3–5) were em-
ployed, even the alkene in entry 3 was tolerated. As in the
NCS (1.2)
NBS (1.2)
NCS (1.2)
NBS (1.2)
[b]
–
nc[c]
[b]
–
[a] NBS=N-bromosuccinimide, NCS=N-chlorosuccinimide. [b] Unse-
lective reaction. [c] nc=no conversion.
Chem. Eur. J. 2010, 16, 956 – 963
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
961

A. S. K. Hashmi et al.
Table 5. Formation of halomethyloxazoles 9 from methylenedihydrooxa-
zoles 8.
anistically, this transformation shows significant parallels to
the gold-catalyzed pathway (Scheme 6). Here the initial step
is the coordination of the electrophilic iodine cation, which
activates the alkyne triple bond for the anti attack of the
carbonyl oxygen. The difference lies in the next reaction
step, when, after the loss of the proton, the halogen stays in
the product; therefore, stoichiometric amounts of the halide
source are needed. The E configuration of the double bond
could be verified by the X-ray crystal structure data of com-
pounds 10c and 10e (see Figure 4).[14]
Entry
R
NXS[a] (equiv) Time Temp. [8C]
9
Yield
of 9 [%]
1
2
3
4
5
NCS (1.5)
NBS (1.5)
NIS (1.5)
NBS (1.5)
NIS (1.5)
48 h
48 h
24 h
24 h
24 h
50
20
20
20
20
a
b
c
d
e
9[b]
43
49
86
34
ACHTUNGTRENNUNG
6
7
8
9
10
11
12
13
14
NCS (3)
48 h
24 h
24 h
48 h
24 h
24 h
40
20
20
40
20
20
f
39
39
34
16
44
Ph
NBS (1.5)
NIS (1.5)
NCS (3)
NBS (1.5)
NIS (1.5)
NIS (1.1)
NIS (1.1)
NIS (1.1)
g
h
i
j
[c]
–
k
l
–
tBu
Bn
thiophenyl
16 h[d] 20
16 h[d] 20
16 h[d] 20
41
35
16
m
[a] NBS=N-bromosuccinimide, NCS=N-chlorosuccinimide, NIS=N-io-
dosuccinimide. [b] Inseparable mixture with 23% of the oxazole without
halogen. [c] Unselective reaction. [d] The methylenedihydrooxazole was
generated in situ, after 16 h NIS was added and the reaction was contin-
ued for additional 30 min. (Bn=benzyl).
Table 6. Iodination with Barluengaꢀs reagent.
Figure 4. Solid-state structures of iodomethyleneoxazolines 10c (a) and
10e (b).
Entry
1
R
10
a
Yield of 10 [%]
(CH2)6CH3
50
Conclusions
2
b
65
In our study of the gold-catalyzed conversion of propargylic
amides we demonstrated that depending on the oxidation
state of the gold catalyst, oxazoles (AuIII catalysis) or meth-
ylenedihydrooxazoles (AuI catalysis) can reliably be ob-
tained with high chemoselectivities. For both of the applied
protocols, a broad range of substrates could be converted,
regardless of whether aromatic or aliphatic side chains were
used. Furthermore, even substrates with up to three propar-
gylic moieties could be converted in high yields, delivering
access to a class of compounds with interesting optical prop-
erties. The limitations for both of these methodologies lie in
substrates in which electron-deficient substituents decrease
the nucleophilicity of the carbonyl oxygen.
3
4
c
71
69
Ph
d
5
e
63
case of the AuI-catalyzed cyclization, no aromatization to
the oxazoles occurred and the iodomethylenedihydrooxa-
zoles 10 could be isolated as pure E diastereoisomers. Mech-
Efforts to functionalize the vinylgold intermediates by
trapping with N-halosuccinimides as electrophiles were not
successful; instead a further transformation of the proto-de-
metalated methylenedihydrooxazoles took place that finally
led to halomethyloxazoles. Nevertheless, by using Barluen-
gaꢀs reagent we were able to establish a mild access to the
synthetically useful iodomethylenedihydrooxazoles under
very mild reaction conditions. The cycloisomerization of
substrates with internal alkynes is also under detailed inves-
Scheme 6. Formation of iodomethyleneoxazolines 10.
962
www.chemeurj.org
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 956 – 963

Cyclization of Propargylic Amides
FULL PAPER
[8] For a review on the application of gold catalysis in total synthesis,
see: A. S. K. Hashmi, M. Rudolph, Chem. Soc. Rev. 2008, 37, 1766–
1775.
tigation, preliminary results have just been communi-
ACHTUNGTRENNUNG
cated.[21]
[9] a) D. Dorsch, L. T. Burgdorf, R. Gericke, N. Beier, W. Mederski,
WO 2005123688A2, 2005; [Chem. Abstr. 2005, 144, 69837]; b) D.
Dorsch, O. Schadt, A. Blaukat, F. Stieber, WO 2008/017361A2;
[Chem. Abstr. 2008, 148, 190536].
Experimental Section
[10] a) D. Aguilar, M. Contel, R. Navarro, T. Soler, P. E. Urriolabeitia, J.
Organomet. Chem. 2009, 694, 486–493; b) G. Verniest, A. Padwa,
Org. Lett. 2008, 10, 4379–4382; c) G. Verniest, A. Padwa, Org. Lett.
2008, 10, 4379–4382.
See the Supporting Information for experimental details.
[11] a) E. Merkul, T. J. J. Mꢂller, Chem. Commun. 2006, 4817–4819;
b) E. Merkul, O. Grotkopp, T. J. J. Mꢂller, Synthesis 2009, 502–507;
c) E. M. Beccalli, E. Borsini, G. Broggini, G. Palmisano, S. Sottocor-
nola, J. Org. Chem. 2008, 73, 4746–4749; d) M. Harmata, C. Huang,
Synlett 2008, 1399–1401.
Acknowledgements
Gold salts were provided by Umicore AG & Co. KG. J. V. is grateful for
an Erasmus fellowship of the European Union. We thank the Fonds der
Chemischen Industrie for fellowships for J. P. W. and S. S..
[12] Y.-M. Pan, F.-J. Zheng, H.-X. Lin, Z.-P. Zhan, J. Org. Chem. 2009,
74, 3148–3151.
[13] a) B. M. Krasovitskij, B. M. Bolotin, Organic Luminescent Materials,
VCH, Weinheim, 1988; b) K. Buttke, H. Baumgaertel, J. Prakt.
Chem. 1997, 339, 721–728.
[14] CCDC-746778 (1b), CCDC-746779 (1c), CCDC-746780 (1 f),
CCDC-746781 (1ab), CCDC-746782 (1ac), CCDC-746783 (1ad),
CCDC-746784 (2 f), CCDC-746785 (8 f), CCDC-746786 (8ad),
CCDC-746787 (8v), CCDC-746788 (10c), CCDC-746789 (10e), and
[1] For representative reviews on gold catalysis, see: a) A. S. K. Hashmi,
Gold Bull. 2003, 36, 3–9; b) A. S. K. Hashmi, Gold Bull. 2004, 37,
51–65; c) A. S. K. Hashmi, G. J. Hutchings, Angew. Chem. 2006,
118, 8064–8105; Angew. Chem. Int. Ed. 2006, 45, 7896–7936; d) A.
Fꢂrstner, P. W. Davis, Angew. Chem. 2007, 119, 3478–3519; Angew.
Chem. Int. Ed. 2007, 46, 3410–3449; e) D. J. Gorin, F. D. Toste,
Nature 2007, 446, 395–403; f) A. S. K. Hashmi, Chem. Rev. 2007,
107, 3180–3211; g) A. Arcadi, Chem. Rev. 2008, 108, 3266–3325;
h) E. Jimꢄnez-Nfflnez, A. M. Echavarren, Chem. Rev. 2008, 108,
3326–3350; i) Z. G. Li, C. Brouwer, C. He, Chem. Rev. 2008, 108,
3239–3265.
CCDC-746790
(5,5-diethyl-1,3-di(prop-2-yn-1-yl)pyrimidine-
2,4,6(1H,3H,5H)-trione) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
[2] a) Y. Fukuda, K. Utimoto, H. Nozaki, Heterocycles 1987, 25, 297–
300; b) Y. Fukuda, K. Utimoto, Synthesis 1991, 975–978.
[15] M. D. Milton, Y. Inada, Y. Nishibayashi, S. Uemura, Chem.
Commun. 2004, 2712–2713.
[3] a) A. S. K. Hashmi, L. Schwarz, J.-H. Choi, T. M. Frost, Angew.
Chem. 2000, 112, 2382–2385; Angew. Chem. Int. Ed. 2000, 39, 2285–
2288; see also discussion in: b) A. S. K. Hashmi, Angew. Chem.
2000, 112, 3737–3740; Angew. Chem. Int. Ed. 2000, 39, 3590–3593.
[4] a) T. Yao, X. Zhang, R. C. Larock, J. Am. Chem. Soc. 2004, 126,
11164–11165; b) S. Shin, Bull. Korean Chem. Soc. 2005, 26, 1925–
1926; c) T. Yao, X. Zhang, R. C. Larock, J. Org. Chem. 2005, 70,
7679–7685; d) J.-E. Kang, E.-S. Lee, S.-I. Park, S. Shin, Tetrahedron
Lett. 2005, 46, 7431–7433; e) J.-E. Kang, S. Shin, Synlett 2006, 717–
720; f) J.-E. Kang, H.-B. Kim, J.-W. Lee, S. Shin, Org. Lett. 2006, 8,
3537–3540; g) R. Robles-Machin, J. Adrio, J. C. Carretero, J. Org.
Chem. 2006, 71, 5023–5026; h) E. Genin, P. Y. Tullec, S. Antoniotti,
C. Brancour, J.-P. GenÞt, V. Michelet, J. Am. Chem. Soc. 2006, 128,
3112–3113; i) S. Ritter, Y. Horino, J. Lex, H.-G. Schmalz, Synlett
2006, 3309–3313; j) A. Buzas, F. Gagosz, Org. Lett. 2006, 8, 515–
518; k) A. Buzas, F. Gagosz, Synlett 2006, 2727–2730; l) C.-Y. Zhou,
P. W. H. Chan, C.-M. Che, Org. Lett. 2006, 8, 325–328; m) E.-S. Lee,
H.-S. Yeom, J.-H. Hwang, S. Shin, Eur. J. Org. Chem. 2007, 3503–
3507; n) A. S. K. Hashmi, R. Salathꢄ, W. Frey, Synlett 2007, 1763–
1766; o) Y. Xia, A. S. Dudnik, V. Gevorgyan, Y. Li, J. Am. Chem.
Soc. 2008, 130, 6940–6941; p) N. T. Patil, Y. Yamamoto, Chem. Rev.
2008, 108, 3395–3442; q) S. F. Kirsch, Synthesis 2008, 3183; r) V.
Belting, N. Krause, Org. Biomol. Chem. 2009, 7, 1221–1225.
[5] A. Arcadi, S. Cacchi, L. Cascia, G. Fabrizi, F. Marinelli, Org. Lett.
2001, 3, 2501–2504.
[16] a) B. M. Nilsson, U. Hacksell, J. Heterocycl. Chem. 1989, 26, 269–
275; b) B. M. Nilsson, H. M. Vargas, B. Ringdahl, U. Hacksell, J.
Med. Chem. 1992, 35, 285–294.
[17] a) A. S. K. Hashmi, M. Rudolph, S. Schymura, J. Visus, W. Frey, Eur.
J. Org. Chem. 2006, 4905–4909; compare also one other example
observed in: b) C. Ferrer, A. M. Echavarren, Angew. Chem. 2006,
118, 1123–1127; Angew. Chem. Int. Ed. 2006, 45, 1105–1109.
[18] A. S. K. Hashmi, C. Lothschꢂtz, R. Dçpp, M. Rudolf, T. D. Rama-
murthi, F. Rominger, Angew. Chem. 2009, 121, 8392–8395; Angew.
Chem. Int. Ed. 2009, 48, 8243–8246.
[19] a) A. Buzas, F. Gagosz, Org. Lett. 2006, 8, 515–518; b) A. Buzas, F.
Gagosz, Synlett 2006, 2727–2730; c) A. Buzas, F. Istrate, F. Gagosz,
Org. Lett. 2006, 8, 1958–2006; d) S. F. Kirsch, Angew. Chem. 2007,
119, 2360–2363; Angew. Chem. Int. Ed. 2007, 46, 2310–2313; e) L.
Zhang, Org. Lett. 2007, 9, 2147–2150; f) B. Crone, S. F. Kirsch, J.
Org. Chem. 2007, 72, 5435–5438M; g) m: Yu, G. Zhang, L. Zhang,
Org. Lett. 2007, 9, 2147–2150; for a study of this elemental step,
see: h) A. S. K. Hashmi, T. Dondeti Ramamurthi, F. Rominger, J.
Organomet. Chem. 2009, 694, 592–597.
[20] For representative examples of the use of Barluengaꢀs reagent, see:
a) J. Barluenga, M. A. Rodríguez, J. M. Gonzµlez, P. J. Campos, Tet-
rahedron Lett. 1990, 31, 4207–4210; b) J. Barluenga, H. Vµzquez-
Villa, A. Ballesteros, J. M. Gonzµlez, J. Am. Chem. Soc. 2003, 125,
9028–9029; c) J. Barluenga, M. Trincado, M. Marco-Arias, A. Bal-
lesteros, E. Rubido, J. M. Gonzµlez, Chem. Commun. 2005, 2008–
2010; for a review, see: J. Barluenga, Pure Appl. Chem. 1999, 71,
431–436.
[6] A. S. K. Hashmi, J. P. Weyrauch, W. Frey, J. W. Bats, Org. Lett. 2004,
6, 4391–4394.
[7] 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.
Lakham, B. Ternai, Adv. Heterocycl. Chem. 1974, 17, 99–211;
d) G. J. Pattenden, Heterocycl. Chem. 1992, 29, 607–618.
[21] A. S. K. Hashmi, A. Schuster, F. Rominger, Angew. Chem. 2009,
121, 8396–8398; Angew. Chem. Int. Ed. 2009, 48, 8247–8249.
Received: September 8, 2009
Published online: November 24, 2009
Chem. Eur. J. 2010, 16, 956 – 963
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
963