AuBr3-Catalyzed Chemoselective Annulation of Isocyanates with 2H-Azirine

Article abstract of DOI:10.1002/chem.201804765

The chemoselective cyclization of isocyanates with 2H-azirine was achieved with AuBr₃ as catalyst. This transfer sets the stage for the synthesis of aromatic oxazole-ureas in a tandem process. The addition of a catalytic amount of phosphite enhances the process enormously. The reaction can also be performed in a one-pot process using benzoyl azide instead of isocyanate under the same conditions. A detailed study on the role of the phosphite that was applied as an additive revealed that only non-coordinated phosphite can reduce gold(III) and that gold(I) coordinated phosphite is not oxidized. Accompanied by the reduction of gold, HBr is generated in situ, which turned out to be the actual promotor in combination with the remaining AuBr₃. The positive effect of acid can be explained by a strong N–Au coordination, which tends to break more easily in the presence of small amount of protic acid in the reaction solution.

Full text of DOI:10.1002/chem.201804765

A Journal of
Accepted Article
Title: AuBr3-Catalyzed Chemoselective Annulation of Isocyanates with
2H-Azirine
Authors: Yufeng Wu, Tian Bing, Sina Witzel, Hongming Jin, Xianhai
Tian, Matthias Rudolph, Frank Rominger, and A. Stephen K.
Hashmi
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Chem. Eur. J. 10.1002/chem.201804765
Link to VoR: http://dx.doi.org/10.1002/chem.201804765
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AuBr
3
-Catalyzed Chemoselective Annulation of Isocyanates with
2
H-Azirine
[
a]
[a]
[a]
[a]
[a]
[a]
Yufeng Wu, Bing Tian, Sina Witzel, Hongming Jin, Xianhai Tian, Matthias Rudolph, Frank
[
a]
[a], [b]
Rominger, and A. Stephen K. Hashmi*
Abstract: The chemoselective cyclization of isocyanates with 2H-
azirine was achieved with AuBr as catalyst. This transfer sets the
allenes contain a cumulene substructure, were not investigated
so far.
3
stage for the synthesis of aromatic oxazol-ureas in a tandem process.
The addition of a catalytic amount of phosphite enhances the process
enormously. The reaction can also be performed in a one-pot process
using benzoyl azide instead of isocyanate under the same conditions.
A detailed study on the role of the phosphite that was applied as an
additive revealed that only non-coordinated phosphite can reduce
gold(III) and that gold(I) coordinated phosphite is not oxidized.
Accompanied by the reduction of gold, HBr is generated in situ, which
turned out to be the actual promotor in combination with the remaining
Scheme 1. Reactivity of isocyanates.
known reactions of isocyanates
R'
N
X
H
X
+
R
NCO
R NCO
+ M X
R
O
transition-metal catalyzed
"C-H activation"
M= Co, Ni, Ru, Rh, Re, Pd ...
X = C, O, N...
R' = H, M
3
AuBr . The positive effect of acid can be explained by a strong N-Au
this work
O
coordination, which tends to break more easily in the presence of
small amount of protic acid in the reaction solution.
formal [2+3]
Ph
N
NH
Ph
Ph
N
N
[Au]
Ph
C
+
O
Ph
Ph
Ph
O
N
O
Introduction
chemoselective
Ph
NH
N
Ph
In addition to massive industrial application, academic research
on the versatile isocyanates has increased over the past years.
Ph
Recently, 2H-azirines, readily accessible within two synthetic
steps, have attracted great attention from organic chemists for the
They are extensively applied in foams,[1] elastomers, coatings,
[2]
facile synthesis of azacyclic compounds.[
18]
Utilizations in
adhesives,[3] in the polymers industry, as membranes,[5] as
[4]
[
19]
[20]
[
4b,6]
and photonic crystal materials.[7] Further,
transition-metal catalysis, including gold-catalyzed reactions
were reported. Due to its mild nucleophilicity and the compatibility
with Au catalysts, we concluded that 2H-azirines might be a good
reactant with isocyanates. Indeed in the presence of gold
catalysts oxazoles were formed chemoselectively and no
competing lactam product was observed (Scheme 1). Since its
first report in 1840 by Zinin, oxazoles are extensively utilized in
organic synthesis,[ medicinal chemistry and drug discovery
(Figure 1).[23] Due to the importance of 2-amino-oxazoles as
structural motif, various synthetic strategies are already
established.[ Firstly, -X carbonyl compounds (X = Cl, Br, OH)
biomedical materials,
isocyanates are applied in synthetic organic chemistry where they
react with diverse nucleophiles (Scheme 1).[
4a,4d,8]
Especially,
isocyanates serve as efficient starting materials in transition-metal
catalysis. For instance, Ackermann and Ellman et al. developed a
series of cobalt catalysis in which isocyanates are used as an
[
21]
amidation reagent to form aromatic amides.[9] By using nickel-
22]
based catalysts, N-heterocyclic rings are formed from
[10]
isocyanates after insertion and decarbonylation. An amide part
can be elegantly introduced into compounds from isocyanates
22]
after C-H functionalization by ruthenium,[
11]
[12]
or rhenium.
[
24]
are common precursors together with ureas or cyanides.
Rhodium, nickel and palladium can also assist the construction of
amide bonds in the presence of isocyanates.[11b,13,14] However, so
far no gold-catalyzed direct isocyanate activations are reported.[15]
Carbenes derived from diazocarbonyl compounds reacted with
cyanides also deliver the target compounds.[ Other special
substrates, like N-(tosylmethyl) thiourea, cyano-pendent urea or
cyano azides also serve as precursors.[ Practically, the chlorine
atom from 2-chlorooxazoles can be substituted by amine to get 2-
amino-oxazoles.[ Herein we report an alternative gold catalyzed
chemoselective synthesis of 2-amino-oxazole derivates
generated from isocyanate and 2H-azirine in a cascade manner.
25]
One important feature of gold catalysts is their -acidity, which
26]
enables activation of C-C multiple bonds, such as alkynes,
[
16]
alkenes and allenes. While we have been working on allene
chemistry for almost two decades,[17] isocyanates, which like
27]
[
[
a]
b]
M. Sc. Y. Wu, M. Sc. S. Witzel, M. Sc. X. Tian, M. Sc. B. Tian, M.
Sc. H. Jin, Dr. M. Rudolph, Dr. F. Rominger, Prof. Dr. A. S. K.
Hashmi
Organisch-Chemisches Institut, Universität Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
E-mail: hashmi@hashmi.de
Prof. Dr. A. S. K. Hashmi
Chemistry Department, Faculty of Science, King Abdulaziz
University (KAU), 21589 Jeddah (Saudi Arabia)
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Chemistry - A European Journal
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H
H
N
H
N
N
N
Ph
Ph
N
N
Ph
Ph
N
Ph
O
O
O
O
2
Ph
C
Ph
N
O
Ph
O
O
Ph
Ph dry DCE Ph NH
Ph
anti-infective ,
anti-inflammatory agent
anti-infective agent
antiobesity agent
1a
2a
3aa
Ph
H
N
o
Yield[f]
Entry
Catalyst /
mol %
Additive
-
T [ C]
5
H
H
N
N
N
N
N
OH
1
2
3
4
5
PPh AuCl
60
60
60
60
80
trace
8%
Ph
3
F
O
O
N
OH
PPh
KAuBr4
KAuBr
3
AuCl
AgSbF
-
6
O
Ph
F
OH OH
14%
22%
36%
immunomodulator
antiviral agent
4
10 mol % PPh
3
3
KAuBr4
KAuBr4
10 mol % PPh
Figure 1. Selected bioactive 2-amino-oxazoles derivates.
6
7
5 mol % PPh
3
80
80
80
40%
47%
55%
KAuBr
KAuBr
4
4
5 mol % A
5 mol % A
5 mol % A

b]
8
Results and Discussion
9[b,c]
HAuBr .xH O
80
63%
4
2

b]
Y(OTf)3
Pd(dba)
10
11
-
-
-
-
-
80
80
80
80
80
trace
We initiated our studies by using phenyl isocyanate (1a) and 2H-
azirine (2a) as a model reaction. After screening a diverse
spectrum of catalysts in DCE, we found that Au(III) selectively
delivers the product in better yield, than cationic gold(I) complexes

b]
2
-
-
-
-
2[b]
6 5 3 3
Rh(I)Cl[(C H ) P]
1
1
1
b]
3
4
InF
3
(Table 1, entry 1-3 and Table S1). Various other solvents were
b]
Pd(OAc)2
also screened, however the yield did not improve (Table S2 and
Table S3). Inspired by reports about the positive effects of an
Rhodium(II) aceta t- e
dimer dihydrate
5[b]
80
-
1
[
28]
[29]
b]
PtCl2
-
80
80
80
80
80
trace
62%
53%
61%
-
additive on gold catalyzed oxidations,
hydrosilylation,
we
16
17[b,d]
A
envisioned that a phosphorous-based additive might prompt the
transfer by stabilizing the catalyst. By using triphenylphosphine as
an additive, the yield of the desired product increased to 22%
AuBr
3
5 mol %
18[b,e]
19[b,e]
A
AuBr
3
9.5 mol %
AuBr3
-
9.3 mol % A
(
entry 4). Raising the temperature from 60 °C to 80 °C had a
0[b,e]
1[b,e]
2[b,e]
-
2
2
2
beneficial effect on the reaction (entry 5). When the amount of
triphenylphosphine with respect to gold was decreased to a ratio
of 1:1, a further increase in yield was observed (entry 6).
Compared to the phosphine ligand, the less electron-donating
-
9.3 mol % A
80
80
-
AuBr
3
-
44%
[
a] If not noted otherwise, 1a (0.4 mmol, 4 equiv.), 2a (0.1 mmol, 1 equiv.) in dry
DCE (1 ml) overnight. [b] Addition of 40 mg of 3 Å molecular sieves under N
2
phosphite A was beneficial for the system (entry 7). Upon addition
atmosphere. [c] 2H-azirine was fully consumed within 5 h. [d] 2H-Azirine was
fully consumed within 8 h. [e] 1a (0.8 mmol, 4 equiv.), 2a (0.2 mmol, 1 equiv.),
.
of molecular-sieves, we could isolate 63% yield with HAuBr
4
xH
2
O
3
for entry 18, 19, 22, 10 mol % AuBr was used, column after 5 h. [f] Yield of
as catalyst (entry 8-9). Other Lewis acids, such as Y-, Rh-, Pd-,
In-, Pt-based Lewis acid, instead of [Au], showed almost no
isolated products by column.
transfer (entry 10-16). Though HAuBr .
AuBr
solubility, less hygroscopic; entry 17). By upscaling to a 0.2 mmol
xH
was preferred due to the easier handling of the catalyst
4
2
O was more effective,
3
A (phosphite):
(
scale the yield unexpectedly decreased. To restore the optimal
yield, we further varied the phosphite to gold ratio and found that
with less than 1:1, the yield increased from 53% to 61% (entry 18-
19 and Table S6). The control experiment, in the absence of the
gold catalyst, showed no conversion (entry 20-21), and without
the addition of phosphite A the yield decreased significantly (entry
With the optimized reaction conditions in hand, we next turned our
focus on the substrate scope with respect to the isocyanates.
Generally, a large range of oxazole derivatives bearing different
substituents was accessible in moderate to excellent yields (Table
22).
Table 1. Optimization of the reaction conditions[a]
.
2
). Interestingly, isocyanates bearing chloro-, bromo- and iodo-
substituents led to the formation of halogen-containing oxazoles
ga, 3ha, 3ia, 3wa, potential substrates for further cross coupling
3
reactions. Products with fluoride or methylthio moieties, usually
used in the field of medicine and pharmacy,[
30]
were also
accessible in 3fa, 3ja, 3ka, 3qa, 3ta, 3ua. Naphthyl isocyanate
was transformed into compound 3xa in 39% yield. Notably, as
shown in Table 2, substrates containing electron-withdrawing
groups provided the desired products in higher yields and shorter
reaction times than substrates bearing electron-donating groups.
Unfortunately, acetyl- and ester-substituted phenyl isocyanate
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3
oa, 3pa and aliphatic isocyanates failed to afford the respective
By considering the higher activation energy of alkyl isocyanates
compared to aromatic isocyanates, the reaction temperature was
raised to 120 °C. Fortunately, the reaction proceeded and gave
ethyl, propyl, n-hexyl and benzyl-substituted oxazoles in
moderate to good yields of 50-63% (Table 3). Cyclohexyl
isocyanate only afforded 11% of the desired product, which can
be explained by the steric bulk adjacent to the nitrogen. For the
further study about the effect of increased sterical bulk at the
isocyanate, see Supporting Information, section 5.
oxazole derivatives under the given conditions.
Table 2. Scope with respect to aromatic isocyanates 1[a]
.
R
1
0 mol % AuBr
3
,
N
N
9.3 mol % A
O
N
O
C
2
R
O
+
Ph
Ph
Ph
DCE, 3 Å MS, N2
NH
N
0 o
We next examined the scope with respect to 2H-azirines. First,
we varied the substituents on the C=N double bond moiety of the
8
C
1
2a
R
3
Ph
R
2
H-azirine. Electron-donating groups (Table 4, 3ab), as well as
R
electron-withdrawing groups (3ac-3ae) were tolerated well. Next,
R
2
2
H-azirines possessing different groups R were studied; these
O
N
O
O
N
O
O
N
Ph
gave the products 3af, 51% and 3ag, 52%, respectively. However,
2H-azirines bearing a 1- or 2-naphthyl group only produced 3ah
and 3ai in 19% and 40% yield, respectively. The reason for the
decrease in yield could be the steric hindrance, which is more
severe in 3ah than in 3ai. A furyl-based heterocyclic 2H-azirine
O
NH
N
Ph
NH
N
Ph
NH
N
R
Ph
R
R
Ph
3
3
3
3
3
3
3
3
3
3
3
3
3
3
aa R = H
5 h
61%
3
ga R = Cl 11 h 58%
3qa R = F
3ra R = Me 24 h 50%
20 h 53%
ba R = Me
ca R = Et
21 h 50%
21 h 50%
21 h 52%
11 h 53%
20 h 64%
6.5 h 53%
5 h 72%
3ia R = I
21 h 44%
(
3aj) could be obtained in a yield of 56%. The molecular structure
i
R
F
da R = Pr
of 3ha and 3ag was unambiguously determined by an X-ray
single crystal structure analysis (see Supporting Information).[31]
The conversion is limited to diaryl-2H-azirines, all tests with other
2H-azirines only gave completely unselective conversion due to
the sensitivity of these substrates.
ea R = MeO
fa R = F
O
F
N
O
ha R = Br
O
N
Ph
NH
N
O
ja R = CF3
ka R = MeS
Ph
NH
N
29 h 31%
13 h 36%[
Ph
la R = phenyl
ma R = Benzyl
na R = PhO
b]
Ph
R
F
F
21 h 42%
5 h
5 h
5 h
60%
0%
3
sa R = Me
3ta R = MeS
15 h 53%
21 h 40%
Table 4. Reaction scope with respect to 2H-azirine 2[a]
3ua
21 h 52%
.
oa R = acetyl
pa R = CO
2
Et
0%
Cl
Me
Cl
Me
Ph
N
O
O
N
O
N
O
O
O
N
3
10 mol % AuBr ,
9.3 mol % A
N
O
O
Cl
Ph
N
NH
N
R2
NH
Ph
2
+ R1
O
R2
Ph
Me
Ph
N
NH
Ph
C
NH
N
N
DCE, 3 Å MS, N2
80
Ph
1a
2
o
C
3
Ph
Cl
R1
Me
Ph
N
Ph
Ph
O
O
3va 22 h 57%
3wa
6.5 h 46%
3xa
43 h 39%
O
O
N
N
O
O
NH
N
R
NH
Ph
Ph
NH
Ph
N
N
[
a] If not noted otherwise, 1 (0.8 mmol, 4 equiv.), 2a (0.2 mmol, 1 equiv.) in 1
mL dry DCE, 40 mg 3 Å molecular sieves was used. [b] Reaction in 1 mL dry
toluene.
R
3
ab R = Me 7 h 64%
3af R = Me 7 h 52%
3ag R = Br
3ah 40 h 19%
brsm 60%[b]
Table 3. Scope with respect to aliphatic isocyanates 4[a]
.
3ac R = F
5 h 66%
7 h 62%
19 h 51%
5 h 51%
3
3
ad R = Cl
ae R = Br
Ph
O
N
Ph
alkyl
O
1
0 mol % AuBr
3
,
O
N
N
A
NH
O
N
9.3 mol %
O
N
O
O
Ph
N
2
alkyl
C
+
Ph
NH
N
O
Ph
Ph toluene, 3 Å MS, N2
Ph
NH
N
1
20 o
C
alkyl
O
4
2a
5
Ph
ai 46 h 40%, brsm 68%[b]
3aj
19 h 56%
3
5
O
N
O
O
O
N
N
O
Ph
[a] If not noted otherwise, 1a (0.8 mmol, 4 equiv.), 2 (0.2 mmol, 1 equiv.) in 1
mL dry DCE, 40 mg 3 Å molecular sieves was used. [b] yields “based on
recovered starting material” (brsm).
NH
N
Ph
NH
Ph
NH
N
N
5
Ph
Ph
Ph
5
a 44 h 54%
5b 46 h 52%
5c 19 h 50%
Cy
To get a better understanding of the elementary steps involved in
the developed cascade reaction, a series of control experiments
was conducted. First, 1a (1.0 equiv.) was reacted with 2a (5.0
equiv.) under the optimized reaction conditions (Scheme 2a).
However, no 6 but only 3aa was detected, which suggested that
a dimer of the isocyanate might be the key intermediate. Thus,
the dimer 7 was prepared but no target compound was formed
after 5 hours which excludes this possibility (Scheme 2b). It was
Ph
O
N
O
N
O
O
Ph
Ph
NH
N
NH
Cy
N
Ph
5e 24 h 11%
Ph
Ph
5d 19 h 63%
[
a] If not noted otherwise, 4 (0.8 mmol, 4 equiv.), 2a (0.2 mmol, 1 equiv.) in 1
mL dry toluene, 40 mg 3 Å molecular sieves was used.
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Chemistry - A European Journal
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FULL PAPER
also speculated that the second step was faster than the first step.
Thus the intermediate product 6 is quickly intercepted by another
isocyanate, even when an excess 2a is used to the first step. To
verify the assumption, inert 1e and most active 1j were mixed with
N
H
R
C
O
O
O
N
Ph
Ph
N
R
R
R
C
R
N
O
1 or 4
[
Au]
V
R
[
Au]
N
O
N
O
[Au]
2
8
H-azirine in the formal reaction. Four different oxazoles (3ea, 3ja,
a, 8b) were expected for this transformation and that 6a and 6b
H
Ph
NH
N
R
Ph
N
N
C
O
3
or 5 Ph
IV
I
would prefer to combine with electron-deficient isocyanate 1j. In
fact, the observed results (yields: 3ja > 8b, 8a > 3ea) support our
expectation (Scheme 2c). Overall, the reaction performs better for
electron-deficient isocyanate and the second step proceeds far
faster than the first step.
Ph
N
H
Ph
Ph
2a
[
Au]
N
[Au]
N
O
O
H
R
R
Ph
N
N
Scheme 2. Mechanistic study.
III
Ph
Ph
Ph
II
The efficacy of phosphite spurred us to study its role for the
catalytic system. First, in the absence of phosphite, a lower yield
of 44% 3aa was obtained (Table 1, entry 22). In addition a color
change from light yellow (with phosphite) to red was visible. This
suggested that phosphite might stabilize 2H-azirine in the
presence of the catalyst. But after 5 hours the amount of
recovered 2H-azirine was almost the same in the case of added
phosphite 49% as in its absence 45% (Scheme 4a). In order to
obtain insight into the active catalytic species a stoichiometric
3
amount of AuBr was applied in the presence of a base to pretend
from a protometallation step (Scheme 4b). Under these conditions,
the Au(I) phosphite complex 9 could be isolated, the structure was
confirmed by X-ray structural analysis (see Supporting
Information).[ A control experiment with 9 under the standard
reaction conditions (Scheme 4c) after 5 hours delivered only trace
of the desired product 3aa, hence this species cannot be the
active catalyst. Even upon addition of gold complex 9 and
phosphite, again only traces of 3aa were formed after 5 hours
31]
(Scheme 4d).
Based on the experiments described above, we propose the
following mechanism (Scheme 3). The first step of the catalytic
cycle is the coordination of isocyanate to the gold catalyst. Then,
Scheme 4. The first studies on the role of phosphite.
2
a acting as a nucleophile, attacks the Au-activated cumulene
5
h, returned 2H-azirine
bond under the formation of zwitterionic intermediate II.
Subsequently, the carbonyl oxygen opens up the strained aza-
heterocycle in the next step to generate intermediate III. The
aromatic oxazole scaffold is generated by deprotonation. Finally,
the Au complex is liberated by protodemetallation under formation
of the intermediate product V, which reacts with another
isocyanate to give the final product.
N
80
o
C, DCE (1 mL)
A
a1 phosphite 9.3 mol %
49%
+
Ph
AuBr
3
(a)
Ph
Ph
N
2
a2 no phosphite A
45%
[Au]
2a
1
eq
10 mol %
N
O
Ph
Ph
8
0 o
DCE (1 mL)
3 Å MS, N
C
N
IV
N
N
Ph
P
C
+
Ph
+
AuBr3
1 eq
+
NaCHO
1 eq
3
+
A
(b)
O
Ph
2
tBu
1
a
2a
1
eq
1 eq
0.93 eq
O
AuBr
3
Scheme 3. Proposed mechanism for AuBr -catalyzed chemoselective
annulation.
tBu
3
9
Ph
N
N
80 oC, DCE (1 mL)
3 Å MS, N
O
O
N
Ph
Ph
C
+
+
+
[Au]
Ph
(c)
(d)
O
O
Ph
Ph
2
N
3aa
NH
Ph
1
a
2a
1 eq
9
Ph
4
eq
10 mol %
trace
Ph
80 oC, DCE (1 mL)
3 Å MS, N
O
N
O
N
N
Ph
C
+
[Au]
+
A
NH
N
Ph
Ph
2
Ph
1a
2a
1 eq
9
3aa
trace
Ph
4
eq
10 mol % 10 mol %
3
The formation of the gold complex 9 from AuBr can be explained
by the reduction with phosphite in solution. To proof this
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Chemistry - A European Journal
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FULL PAPER
assumption, equal amounts of AuBr
3
and phosphite were reacted
Next, a potential variant of this methodology was exploited. Acyl
azides are known to be good precursors for isocyanates.32 Indeed
when benzoyl azide 10 was exposed to our optimized conditions,
the 3aa was obtained in good yield following a one-pot process
(Scheme 6). A scission of the urea group for the formation of 2-
amino-oxazole 6 was possible in 65% yield.
in a time resolved NMR experiment. 3 hours of monitoring (by 31P
NMR) show that the ratio of A : 9 is always about 1:1 (Figure 2).
This indicates that phosphite which is coordinated to the gold(I)
center cannot be oxidized by the remaining gold(III) salt. Hence,
3
if the applied ratio of AuBr to phosphite (10 : 9.3) under the
optimized reaction conditions is used, a redox equation as
depicted in Scheme 5a should result. This led to the conclusion
Scheme 6. Synthetic applications.
that residual AuBr
together. To confirm our speculation, AuBr
3
and in situ formed HBr catalyze this transfer
and concentrated HBr
3
Ph
solution were added into the reaction using the ratio rationalized
from the equation of Scheme 5a in the absence of phosphite.
Indeed, 55% of 3aa were obtained after 6 hours (Scheme 5b)
10 mol % AuBr3,
.3 mol % phosphite
O
O
N
O
N
9
Ph
(a)
+
Ph
N
3
Ph
O
Ph DCE, 3 Å MS, N2
NH
N
Ph
0 o
C
Ph
8
10
2a
3aa, 54%
compared to a yield of 44% with AuBr
In contrast, if complex 9 was applied together with HBr as additive
Scheme 5c) only 13% of 3aa were formed, suggesting that 9 is
3
alone (Table 1, entry 22).
Ph
N
H
O
O
N
Ph
(
reflux in sat. KOH (0.05 M)
Ph
Ph
(b)
just a side-product and that a small amount of protic acid is helpful
to the transfer. In the absence of a gold catalyst and phosphite
but using only concentrated HBr, the desired product 3aa was
yielded with 16%, 22% respectively (Scheme 5d, 5e). In summary,
NH
N
N
Ph
Ph
Ph
3aa
6, 65%
3
in the presence of phosphite, part of AuBr is reduced to gold(I)
along with the formation of complex 9 and HBr. The acidic additive Conclusions
then might play a benefitial role for the deauration step to
complete the reaction.
In conclusion, a gold(III)-catalyzed C,O-selective annulation of
general isocyanate with 2H-azirine has been achieved. Due to the
commercial access to a wide array of isocyanates, various
oxazole derivatives were obtained from both aryl and aliphatic
isocyanates in moderate to excellent yields. Different substituted
2
H-azirines were transformed in moderate to very good yields. An
additional catalytic amount of phosphite is necessary to promote
the transfer. Preliminary mechanistic studies suggest that the
unique coordination of N to Au, leads to the C,O selectivity in the
annulation. The studies of the role of phosphite indicate that in
situ generated HBr favours the deauration step to complete the
catalytic cycle. Phenyl isocyanate can also be displaced with
benzoyl azide using the optimized reaction conditions. Also, the
amide group can easily be cleaved to form 2-amino-oxazoles.
Figure 2. 8.8 mg AuBr
at room temperature, 31P NMR spectra were measured in CD
for 3 h. The horizontal axis stands for time (min). The vertical axis stands for the
3
and 12.1 mg A were dissolved into 1 mL CD
2 2
Cl . Then,
2
2
Cl consecutively
31
ratio value of A : 9 (the ratio of Integral Area in P spectra).
Scheme 5. The second studies on the role of phosphite.
Acknowledgements
tBu
tBu
Y. Wu, B. Tian, X. Tian, H. Jin is grateful for a Ph.D. fellowship
from the China Scholarship Council (CSC). Sina Witzel is grateful
for the support by the Landesgraduiertenförderung of the state of
Baden-Württemberg.
O
P
O
P
O
+
AuBr
3
+
+ H
2
O
AuBr3
+
[Au]
+
(a)
2 HBr
tBu
3
tBu
3
A
9
10 mol %
9.3 mol %
5.35 mol % 4.65 mol % 4.65 mol %
9.30 mol %
Ph
N
80 oC, DCE (1 mL) O
+ conc. HBr solution
O
N
N
Ph
Ph
C
+
+ AuBr
3
(b)
(c)
Keywords: gold catalysis • isocyanates • 2H-azirines • oxazoles
O
O
Ph
Ph
NH
N
3
Å MS, N
2
Ph
Ph
1
a
2a
3aa
6 h, 55%
Ph
• heterocycles
4
eq
1 eq
5 mol %
8.7 mol %
[
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(d)
(e)
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