A Gold-Catalyzed Acid-Assisted Regioselective Cyclization for the Synthesis of Polysubstituted Oxazoles

Article abstract of DOI:10.1002/ejoc.201900699

Polysubstituted oxazole derivatives are obtained through a regioselective gold-catalyzed reaction of α-alkynylamides and alkynoates in the presence of nitriles. The intermediary obtained gold carbenes are generated by alkyne oxidation with a pyridine N-oxide. Acidic conditions ensure that only one of the two carbonyl oxygen atoms in these intermediates selectively cyclizes to the products in excellent yields.

Full text of DOI:10.1002/ejoc.201900699

A Journal of
Accepted Article
Title: Synthesis of Poly-Substituted Oxazoles by a Gold-Catalyzed
Acid-Assisted Regioselective Cyclization
Authors: Quian Wang, Stephanie Hoffmann, Jasmin Schiessl, Matthias
Rudolph, Frank Rominger, and A. Stephen K. Hashmi
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900699
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900699
Supported by

10.1002/ejoc.201900699
European Journal of Organic Chemistry
COMMUNICATION
Synthesis of Poly-Substituted Oxazoles by a Gold-Catalyzed Acid-
Assisted Regioselective Cyclization
Qian Wang,[a] Stephanie Hoffmann,[a] Jasmin Schießl,[a] Matthias Rudolph,[a] Frank Rominger,[a] and A.
Stephen K. Hashmi*[a]
Abstract: Poly-substituted oxazole derivatives are obtained via a
regioselective gold-catalyzed reaction of α-alkynylamides and
alkynoates in the presence of nitriles. The intermediary obtained gold
carbenes are generated by an alkyne oxidation with a pyridine-N-
oxide. Acidic conditions ensure that only one of the two carbonyl
oxygen atoms in these intermediates selectively cyclizes to the
products in excellent yields.
First we decided to use alkynones as test substrates (see the
Supporting Information for details). The obtained mixture of
isomeric products gave a hint that other functional groups might
be feasible to switch the selectivity of the reaction. Inspired by that
[14]
result we discovered that alkynamide derivatives
in addition
with acid and alkynoates[15] (Scheme 1, b) as the starting
materials deliver single products in perfect selectivity. The solid
state molecular structure of the desired product 3d is depicted in
Figure 1. Based on the many applications of amide and ester[16]
groups in medical compounds,[17] this protocol towards
polysubstituted oxazoles offers a meaningful synthetic method.
Introduction
Poly-substituted oxazoles are important motifs in natural products
and pharmaceuticals, especially for the purpose of curing allergic
diseases.[1] Many strategies for the synthesis of oxazoles have
been established,[2] including the intermolecular reaction of α-
diazo ketones with nitriles.[3] However, these approaches require
a multi-step synthesis and/or harsh reaction conditions. In
addition, often toxic metal salts such as mercury(II) compounds
have to be used.[4] Therefore, the synthesis of poly-substituted
oxazoles, from simple and commercially available substrates
under mild reaction conditions, is of high priority. In the recent
decades, gold complexes were established as powerful soft Lewis
acids that efficiently activates alkynes towards the addition of
nucleophiles.[5] Series of transformations such as 1,2-migrations[6]
or X-H insertions[7] (X=O or N) with α-oxo gold carbenes became
available. These species can be formed by an oxygen transfer
from nucleophilic oxygen-atom donor groups onto π-activated
alkynes.[8] Especially N-oxides in combination with alkynes turned
out to be suitable alternatives for hazardous α-diazo ketones.[9,10]
Herein, we report a gold-catalyzed annulation to give 2,4,5-
trisubstituted oxazoles under mild conditions.
a) Zhang's work:
from the N-oxide
O
[Au], N-oxide
[Au]
R
R
CH3CN
R
without a competing
carbonyl group:
addition of the ketone
O
N
b) This work:
O
O
O
[Au], N-oxide
R2
R1
R2
R1
[Au]
CH3CN
R2 = NHBn
or OEt
O
O
N
O
R
R2
O
[Au]
Acid
R2
N
R1
with a competing,
more nucleophilic
carbonyl group:
addition of the ketone
can still be achieved
Scheme 1. Gold-catalyzed oxidative oxazole synthesis: a) without competing
carbonyl group, b) with a competing, more nucleophilic group.
Liming Zhang and co-worker’s ground-breaking synthesis of
gold carbene intermediates from pyridine-N-oxides and alkynes
completely avoids the use of diazo reagents (Scheme 1, a).[11] In
such reactions, the intermediary formed α-oxo gold carbenes are
intercepted by nitriles,[12] followed by a selective cyclization via the
carbonyl moiety. The overall reaction offers a desirable [2+2+1]
annulation as an expansion of the pioneering work of Zhang’s
group.[13] If the key carbenoid intermediate is derived from α-acyl
alkynes, two carbonyl moieties are present. As a consequence
two possible pathways leading to differently substituted oxazoles
are reasonable. Controlling the selectivity of the reaction in the
presence of additional functional groups attracted our attention.
Figure 1. Solid-state molecular structure of 3d.
[a]
Dr. Q. Wang, B.Sc. S. Hoffmann, Dr. J. Schießl, Dr. M. Rudolph, Dr.
F. Rominger, Prof. Dr. A. S. K. Hashmi
Organisch-Chemisches Institut, Heidelberg University
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
E-mail: hashmi@hashmi.de
Results and Discussion
When alkynamide 1a was treated with 3,5-dibromopyridine N-
Homepage: http://www.hashmi.de
oxide (1.5 equiv.) in the presence of [IPrAuCl]/AgNTf2 in
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201900699
European Journal of Organic Chemistry
COMMUNICATION
acetonitrile as solvent we still got a mixture of products 3a and 4a
(Table 1, entry 1). However, to our surprise, only
11). Even KAuBr4 could not catalyze this reaction (Table 1, entry
9). TsOH and TfOH as additives were also effective leading to a
single product 3a in 55 % and 58 % respectively (Table 1, entry
12 and 13). A testing of different silver salts revealed only a minor
effect of the counter ion onto the reaction (Table 1, entry 14 and
15). Increasing the amount of pyridine N-oxide to two equivalents
significantly increased the yield to 76% (Table 1, entry 16). We
also tested 0.2 equiv. MsOH as additives resulting in 37% yield
(Table 1, entry 17). Other Lewis acids such as Zn(OTf)2 and
Sc(OTf)3 as additives showed only poor activities (Table 1, entry
18 and 19). A control experiment demonstrated that the role of
gold was pivotal for the reaction (Table 1, entry 20).
Table 1. Optimization of the reaction conditions.[a]
Entry
1
Catalyst
Acid
Temp.
80 oC
80 oC
50 oC
50 oC
50 oC
50 oC
50 oC
50 oC
50 oC
50 oC
50 oC
50 oC
50 oC
50 oC
50 oC
3a/4a(%)[b]
26/17
51/0
[IPrAuCl]/AgNTf2
[IPrAuCl]/AgNTf2
[IPrAuCl]/AgNTf2
[IPrAuCl]/AgNTf2
[IPrAuCl]/AgNTf2
[IPrAuCl]/AgNTf2
[IPrAuCl]/AgNTf2
[PPh3AuCl]/AgNTf2
KAuBr4
-
Under the optimized reaction conditions, we explored different
N-substituted alkynamides 1 as precursor for polysubstituted
oxazoles (Table 2). First, different substituents on the benzene
core connected to the alkyne were examined. The effect of either
electron-donating substituents like methyl- and methoxy-groups
(3b and 3c) or electron-withdrawing substituents like -F, -Cl, or -
CF3 (3d, 3e, 3f) were only minor with yields ranging from 64% to
75%. An only moderate effect of the substitution pattern onto the
reaction was also observed for differently substituted benzylic
moieties at the amide. Most of the products were gained in
moderate yields (3g-3k) except of the electron-deficient
trifluoromethyl-substituted 3l, which was obtained in only 61 %.
Notably, thiophene- and furan-substituted alkyneamides also
performed well in this reaction (3m and 3n). Moreover, an N-
methyl amide derivative converted to the corresponding product
3o in 53 % yield.
2
MsOH
MsOH
MsOH
MsOH
MsOH
MsOH
MsOH
MsOH
MsOH
MsOH
TsOH
TfOH
MsOH
MsOH
MsOH
3
54/0
4
35/0
5
65/0
6
50/0
7
21/0
8
22/0
9
trace
31/0
10
11
12
13
14
15
16
17
[SPhosAuCl]/AgNTf2
[Cy3PAuCl]/AgNTf2
[IPrAuCl]/AgNTf2
[IPrAuCl]/AgNTf2
[IPrAuCl]/AgOTf
[IPrAuCl]/AgSbF6
[IPrAuCl]/AgNTf2
[IPrAuCl]/AgNTf2
30/0
Table 2. Scope of the reaction from N-substituted alkynylamides.[a]
55/0
O
N
58/0
O
O
NHR2
IPrAuCl (5 mol%), AgNTf2 (5 mol%)
NHR2
53/0
2b
MsOH (2 equiv),
(2 equiv), CH3CN
R1
1
51/0
R1
3
50 o
C
76 (72 )[d]/0
37/0
N
N
O
N
N
O
O
O
O
O
O
O
NHBn
NHBn
NHBn
50 oC
50 oC
50 oC
50 oC
NHBn
MsOH
(0.2 eq.)
3a
, 72%
3b
, 70%
3c
3d
, 70%
, 65%
O
F
N
18
19
20
[IPrAuCl]/AgNTf2
[IPrAuCl]/AgNTf2
AgNTf2
Zn(OTf)2
(2 eq.)
11/0
trace
n.d.
N
O
O
O
O
O
N
N
H
N
NHBn
O
NHBn
H
N
O
Sc(OTf)3
(2 eq.)
Ph
O
Ph
O
Cl
CF3
F
3h
, 79%
3g
3f
, 70%
Cl
, 64%
3e
, 75%
MsOH
Br
N
N
N
H
H
H
N
O
O
O
N
N
[a] Unless otherwise noted, the reactions were carried out on a 0.1 mmol scale,
[Au] (5 mol%), [Ag] (5 mol%), acid (2 equiv.) in 1 mL of CH3CN with 1.5 equiv
N-oxides overnight, entry 1-3 (2c), entry 4 (2a), entry 5 (2b), entry 6 (2d), entry
7 (2e), entry 8-20 (2b). [b] Yield was determined by 1H NMR analysis using
1,3,5-trimethoxybenzene as the internal standard. Isolated yield of product in
parentheses. [c] 2b 2 equiv. [d] Isolated yield.
Ph
Ph
Ph
O
3j
O
O
, 75%
3i
, 75%
3k
, 73%
CF3
N
N
H
N
N
N
H
O
H
O
H
O
O
N
N
N
S
O
Ph
O
Ph
O
3m
Ph
Ph
O
O
3n
, 65%
3o
, 53%
3l
, 71%
, 61%
polysubstituted oxazole 3a was obtained in 51% yield with MsOH
(2 equiv) as an additive under the same conditions (Table 1, entry
2). Encouraged by this result, we further optimized the conditions.
At first, different N-oxides were tested at 50 oC (Table 1, entry 3-
7). 3,5-Dichloropyridine N-oxide 2b was the best oxidant while
quinoline N-oxide 2e reached only 21 % yield. A small screening
of other gold catalysts did not improve the yield (Table 1, entry 8-
[a] 1 (0.1 mmol), [Au] (5 mol%), [Ag] (5 mol%), acid (2 equiv.), N-oxides (2
equiv.), 1 mL CH3CN, 50 oC, overnight, yield of isolated product. [b] 80 oC, 16
h, MsOH (2 equiv.).
Table 3. Scope of the reaction for alkynoate starting materials.[a]
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10.1002/ejoc.201900699
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COMMUNICATION
Other nitriles were also used under the same reaction conditions.
4-Methoxybenzonitrile and 4-chlorobenzonitrile, led to a moderate
yield of the desired products (9f and 9g) which improves the
diversity for an aryl substituent in the 2-position of the obtained
oxazoles. Phenylacetonitrile and hexanenitrile also reacted with
ethyl phenylpropiolate to generate 9h and 9i in good yield.
N
O
O
O
O
O
IPrAuCl (5 mol%), AgNTf2 (5 mol%)
8-ethyl quinoline N-oxide (1.5 equiv), CH3CN
R3
5
R3
6
N
N
O
N
O
O
N
O
O
O
O
O
O
O
Based on the above results, we propose a mechanism as
shown in Scheme 2. Alkynylamide 1a undergoes a protonation
leading to intermediate I. After that, in the presence of gold and
N-oxide, an α-oxo gold carbene intermediate II is generated. Then
the gold carbene intermediate II is captured by the nitrile to
produce intermediate III. With the assistance of acid, the
nucleophilicity of the amide decreases which promotes the ketone
to react with the nitrile leading to the formation of intermediate IV.
Furthermore, the final product 3a is obtained by the loss of a
proton.
O
O
O
F
6a
6b
6c
6d
, 99%
, 95%
, 90%
, 95%
O
N
O
O
N
N
O
O
N
O
O
O
O
O
O
O
Cl
O
O2N
6g
, 85%
6h
, 93%
O
6e
, 97%
6f
, 87%
[a] 1 (0.2 mmol), [Au] (5 mol%), [Ag] (5 mol%), N-oxide (1.5 equiv), 1 mL CH3CN,
80 oC, 3 h, yield of isolated product.
O
OH
NHBn
O
OH
NHBn
To our delight, alkynoates also reacted selectively.
Noteworthy, even in the absence of an acid, a selective
incorporation of the oxygen derived from the N-oxide was
observed while the ester group remained in the final product
(Table 3). 8-Ethylquinoline N-oxide (2f) was the best among the
examined oxidants (see the Supporting Information for details).
Phenylbenzoates bearing either electron-donating or electron-
withdrawing groups afforded the corresponding products in
excellent yield and perfect selectivity (6a-6f). Even with the strong
electron-withdrawing effect of a nitro group, 6g was still formed in
85 % yield. Furthermore, an alkyl alkynoate 5h afforded product
6h in 93 % yield.
NHBn
[Au]
acid
[Au]
N-oxide
I
II
1a
N
O
OH
OH
BnHN
BnHN
N
O
N
O
NHBn
O
N
[Au]
III
IV
3a
Scheme 2. Proposed mechanism.
Table 4. Scope of the reaction for various nitriles.[a]
R5
O
Conclusions
N
IPrAuCl (5 mol%), AgNTf2 (5 mol%)
O
R4
N
R5
O
+
Ph
N-oxides, nitriles
R4
Ph
7
8
In conclusion, we have developed a one-step synthesis for
polysubstituted oxazoles from alkynylamide derivatives and
alkynoates. Acid as an additive was essential to give a selective
reaction in the case of amides while esters reacted selectively
even in the absence of an acid. The obtained products might
serve as versatile building blocks as they represent substructures
of biologically active compounds. The methodology could be
useful for the synthesis of biologically or pharmaceutically active
compounds. Further studies to expand the synthetic scope of this
reaction are ongoing in our laboratories.
9
N
N
N
N
O
O
O
O
O
O
Ph
O
N
O
O
NHBn
Ph
NHBn
Ph
Ph
O
O
O
Ph
9ed
O
9dc
9bb
63%
9ab
77%
Cl
9cc
83%
87%
70%
O
N
O
O
N
N
N
O
O
O
O
O
Ph
O
O
Ph
Ph
Ph
O
O
O
9fd
9gd
9id
9hd
71%
Experimental Section
73%
68%
69%
[a] 7 (0.1 mmol), [Au] (5 mol%), [Ag] (5 mol%) yield of isolated product. [b] 8 (1
mL), 2b 2 equiv, 50 oC, overnight. [c] 8 (1 mL), 2f 1.5 equiv, 80 oC, 3 h. [d] 8 3
equiv., toluene (0.5 mL), 2f 1.5 equiv, 80 oC, 3 h.
Alkynamide 1 (0.10mmol), [IPrAuCl]/AgNTf2 (0.005 mmol), N-oxide (0.15
mmol), and MsOH (0.20mmol) were mixed in nitriles (1 mL). The resulting
mixture was heated in a closed flask at 50oC for 12 h. Then the solvent
was removed under vacuum to give a residue, which was purified by silica
gel chromatography (petroleum ether/ethyl acetate = 8:1) to yield the
corresponding products 3.
Next, we evaluated different nitriles in the reaction (Table 4).
When propionitrile and isobutyronitrile were used as the reaction
solvent, the proposed oxazoles were obtained in moderate to
good yields (9a–9d). For expensive nitriles or nitriles with a high
melting point, a different procedure was considered. With only
three equivalents of benzonitrile in 0.5 mL toluene as the solvent
(alkynoate concentration 0.4 M), 5a performed an acceptable
yield (9e, 63%) and the remaining benzonitrile could be recovered.
Acknowledgments
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10.1002/ejoc.201900699
European Journal of Organic Chemistry
COMMUNICATION
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Q.W. is grateful for the fellowships from China Scholarship
Council (CSC). The authors thank Umicore AG&Co. KG
for the generous donation of gold salts.
Keywords: alkynes • gold • carbene • oxazoles • N-oxides
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[16] Recently a publication also basing on oxidative gold-caalysis with
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10.1002/ejoc.201900699
European Journal of Organic Chemistry
COMMUNICATION
COMMUNICATION
Gold Carbene
Qian Wang, Stephanie Hoffmann,
Jasmin Schießl, Matthias Rudolph,
Frank Rominger, and A. Stephen K.
Hashmi*
Page No. – Page No.
Poly-substituted oxazole derivatives are obtained via a regioselective gold-catalyzed
reaction of α-alkynylamides and alkynoates in the presence of nitriles. The
intermediary obtained gold carbenes are generated by an alkyne oxidation with a
pyridine-N-oxide. Acidic conditions ensure that only one of the two carbonyl oxygen
atoms in these intermediates selectively cyclizes to the products in excellent yields.
Synthesis of Poly-Substituted
Oxazoles by a Gold-Catalyzed Acid-
Assisted Regioselective Cyclization
This article is protected by copyright. All rights reserved.