Zinc bromide promoted coupling of isonitriles with carboxylic acids to form 2,4,5-trisubstituted oxazoles

Article abstract of DOI:10.1002/anie.201305506

Deviant behavior: In a deviation from "normal" reactivity, isocyanides underwent co-trimerization with carboxylic acids in the presence of ZnBr₂ to smoothly provide oxazoles (see scheme). The reaction is thought to occur by initial nucleophilic

Full text of DOI:10.1002/anie.201305506

Angewandte
Chemie
DOI: 10.1002/anie.201305506
Domino Reactions
Zinc Bromide Promoted Coupling of Isonitriles with Carboxylic Acids
To Form 2,4,5-Trisubstituted Oxazoles**
Yann Odabachian, Shuo Tong, Qian Wang, Mei-Xiang Wang,* and Jieping Zhu*
Dedicated to Professor Pierre Vogel on the occasion of his 70th birthday
[
5]
The carbene-like reactivity of the divalent carbon atom of
isonitriles makes these compounds ideal starting materials for
N-formylamide 3 through a sequence involving a-addition
[6,7]
followed by a 1,3-acyl shift [Eq. (2), Scheme 1].
The divalent carbon atom of isonitriles has pronounced
nucleophilicity and readily undergoes nucleophilic addition to
[
1]
the development of multicomponent reactions, insertion
[
2]
[3]
reactions, and oligo-/polymerization processes. Saegusa,
Ito, and co-workers pioneered the field of transition-metal-
catalyzed reactions of isonitriles and demonstrated that
a copper salt is able to catalyze the insertion of isonitriles
into amines, alcohols, thiols, silanes, and phosphines [Eq. (1),
[
8,9]
electrophiles.
electrophilicity are rare.
on the development of isonitrile-based novel transforma-
On the contrary, reactions initiated by its
[
10,11]
As a continuation of our studies
[
12]
tions,
we became interested in Lewis acid mediated
reactions between isonitriles and nucleophiles. We report
[4]
[13]
Scheme 1]. Formally, these reactions correspond to the a-
herein that in the presence of ZnBr , the reaction between
2
isonitriles 1 and carboxylic acids 2 deviated completely from
the a-addition/1,3-acyl-shift sequence [Eq. (2)] to a complex
but ordered reaction manifold that led to 2,4,5-trisubstituted
oxazoles 4 in good to excellent yields [Eq. (3), Scheme 1].
We began our studies by using tert-butyl isocyanide (1a)
and p-toluic acid (2a) as test substrates. The heating of an
equimolar amount of 1a and 2a in toluene in the presence of
ZnBr (0.2 equiv) afforded N-(tert-butyl)-N-formyl-4-methyl-
2
benzamide (3a) together with a small amount of an unknown
compound whose structure was determined by X-ray crystal-
structure analysis to be the 5-aminooxazole 4a (see the
Supporting Information). Constitutionally, 4a is composed of
one molecule of 2a and three molecules of 1a with the loss of
a tert-butyl group. Intrigued by the mechanism of this
unprecedented reaction and further motivated by the impor-
tance of oxazoles in natural products and medicinal chemis-
Scheme 1. Insertion reactions of isonitriles.
[14]
try,
we set out to investigate this reaction in detail. To
addition of the heteroatom–hydrogen bond to the carbon
atom of the isonitrile functional group. In 2008, Danishefsky
and co-workers reported that in the absence of an external
reagent (catalyst), the reaction of an isonitrile 1 with a car-
boxylic acid 2 under microwave irradiation (MW) afforded an
channel the reaction towards the formation of 4a, we carried
out a systematic survey of the reaction conditions by varying
the Lewis acid (LA), the solvent, the temperature, and the
reaction time, and investigating various additives. Some
representative results are summarized in Table 1. Of the
Lewis acids examined [ZnBr , Zn(OTf) , Yb(OTf) , Cu-
2
2
3
(
OTf) , Ga(OTf) ], only Yb(OTf) displayed discernable
2
3
3
[
*] Dr. Y. Odabachian, Dr. S. Tong, Dr. Q. Wang, Prof. Dr. J. Zhu
Ecole Polytechnique Fꢀdꢀrale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@epfl.ch
catalytic activity (Table 1, entry 7). However, the yield of 4a
was low, and the reaction was accompanied by the formation
of the N-formylamide 3a. Furthermore, the yield of 4a
Homepage: http://lspn.epfl.ch
decreased with an increased loading of Yb(OTf) , probably as
3
Prof. Dr. M.-X. Wang
Key Laboratory of Bioorganic Phosphorous and Chemical Biology
a result of concurrent decomposition of the product (Table 1,
entry 8). Although ZnBr was incapable of catalyzing the
2
(
Ministry of Education), Tsinghua University
desired reaction, the yield of 4a increased significantly when
a stoichiometric amount of this Lewis acid was used (Table 1,
entry 10) and reached 81% with 1.5 equivalents of ZnBr2
Beijing 100184 (China)
E-mail: wangmx@mail.tsinghua.edu.cn
[
**] We thank the EPFL (Switzerland), the Swiss National Science
Foundation (SNSF), the Swiss National Centres of Competence in
Research (NCCR), and the National Natural Science Foundation of
China (NNSFC) for financial support.
(
entry 11). The addition of an extra proton source (tBuOH)
[15]
had no impact on the reaction efficiency (Table 1, entry 12),
whereas the addition of molecular sieves led to a lower yield
of 4a (entry 13). Overall, the optimum conditions found
consisted of heating a solution of 1a (1.7 equiv) and 2a
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201305506.
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Table 1: Lewis acid catalyzed reaction between tert-butyl isocyanide (1a)
and p-toluic acid (2a).
Entry
LA (mol%)
Solvent
T [8C]
Additive
–
4a [%]
[
[
[
b]
b]
b]
1
2
3
4
5
6
7
8
9
ZnBr (20)
toluene
toluene
toluene
toluene
100
100
100
100
RT
RT
RT
RT
RT
100
100
100
100
trace
trace
trace
10
2
ZnBr (20)
Et N
2
3
Zn(OTf) (20)
–
–
–
–
–
2
Yb(OTf) (20)
3
ZnBr (10)
CH Cl2
trace
2
2
[
c]
Cu(OTf) (10)
CH Cl2
<5
2
2
[
d]
Yb(OTf) (10)
CH Cl2
34
17
3
2
[
d]
Yb(OTf) (50)
CH Cl2
3
2
Ga(OTf) (10)
CH Cl2
–
–
–
trace
3
2
[
d]
10
11
12
13
ZnBr (100)
toluene
toluene
toluene
toluene
65
81
80
73
2
[
d]
ZnBr (150)
2
ZnBr (150)
tBuOH
4 ꢁ MS
2
[
d]
ZnBr (150)
2
[
a] Reaction conditions: 1a (1.7 equiv), 2a (1.0 equiv), solvent (solution
concentration: 0.1m), argon atmosphere, 30 min. [b] The N-formylamide
a was the major product. [c] The yield was determined by NMR
3
spectroscopy. [d] Yield of the isolated product. Tf=trifluoromethane-
sulfonyl.
(
(
1.0 equiv, 0.1m) in toluene in the presence of ZnBr2
1.5 equiv relative to 2a) for 30 min. Under these conditions,
compound 4a was isolated in 81% yield.
The scope of the reaction was examined under these
optimum conditions (Scheme 2). Aromatic acids regardless of
their electronic nature participated in the reaction efficiently
to afford biaryls 4a–h in good to excellent yields. Cyano (in
4
c), ester (in 4d), nitro (in 4e), trifluoromethyl (in 4 f), and
bromine functional groups (in 4h) at positions ortho, meta,
and para to the carboxylic acid functionality were tolerated
well. The heteroaromatic compounds 1H-indole-2-carboxylic
acid, furan-2-carboxylic acid, and thiophene-2-carboxylic acid
underwent co-trimerization with 1a to furnish the bis(hetero-
arenes) 4i–k in good yields. Our method thus provides
a useful alternative for the construction of biaryl compounds
Scheme 2. Scope of the reaction with respect to the carboxylic acid
substrate. [a] Reaction conditions: 1a (1.7 equiv), 2 (1.0 equiv, 0.1m),
ZnBr (1.5 equiv), toluene, 608C, 30 min. The products were purified
2
on silica gel unless otherwise specified. [b] The reaction was performed
at 1008C. [c] The reaction was finished in 5 min. [d] The product was
purified on an alumina support (Brockmann type IV). [e] The ee value
was not determined owing to the instability of 4q under HPLC
conditions.
[
16]
from aryl carboxylic acids.
Cinnamic acids were also
accepted as substrates to afford the 2-vinyl-substituted
oxazoles 4l and 4m. Finally, aliphatic acids, including
benzylic, functionalized, and sterically demanding substrates,
reacted equally well with 1a to furnish the 2-alkyl-substituted
oxazoles 4n–q. The oxazoles derived from aliphatic acids
(
4n–q) are acid-labile and should be purified on an alumina
The reaction of authentic N-(tert-butyl)-N-formyl-4-
methylbenzamide (3a) with 1a under standard conditions
failed to produce even a trace amount of oxazole 4a, thus
indicating that 3a is not an intermediate in the formation of
4a. To gain insight into the reaction mechanism, we synthe-
sized the complex (tBuNC) ZnBr (5) by heating a solution of
support. Besides tBuNC, other tertiary alkyl isocyanides,
including functionalized substrates, participated in this reac-
tion to afford the corresponding oxazoles in good to excellent
yields (Scheme 3). Use of the primary isocyanide 5-
(
isocyanomethyl)benzo[d][1,3]dioxole led to the correspond-
2
2
ing oxazole 4v in moderate yield (33%; Scheme 3). However,
reactions involving other primary and secondary alkyl
isocyanides (PhCH NC, p-MeOC H CH NC, iPrNC, c-
tBuNC (3.0 equiv) and ZnBr2 in toluene at 1008C. This
complex was fully characterized for the first time, including by
[17]
X-ray crystal-structure analysis (Scheme 4).
It is mono-
2
6
4
2
C H NC) and phenyl isocyanide (PhNC) afforded a complex
meric with a distorted tetrahedral coordination geometry
around the zinc atom. The isonitrile–zinc moiety is linear (N-
C-Zn 170.118, C-N-C 174.878), which indicates that both the
carbon atom and the nitrogen center are sp-hybridized. The
6
11
reaction mixture, whereas 2,2-bis(4’-methoxyphenyl)methyl-
isocyanide underwent clean isomerization to furnish 2,2-
bis(4’-methoxyphenyl)acetonitrile.
2
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isocyanide and zinc bromide is a dynamic process, and that
the reaction most probably takes place in the ligand sphere of
the complex.
The formation of an oxazole 4 from an isonitrile 1 and
a carboxylic acid 2 implies a complex reaction manifold. To
determine the source of the two oxygen atoms in 4, we carried
out an isotopic-labeling experiment. The treatment of
1
8
18
[20]
PhC O OH with tert-butyl isocyanide (1a) under standard
1
8
18
conditions afforded a double- O-labeled oxazole 4b- O , as
2
evidenced by mass spectrometry (Scheme 5). The upfield shift
Scheme 5. Isotopic-labeling experiment.
1
3
18
of the C NMR signal of the amide carbonyl group in 4b- O
2
relative to that for 4b (dC=18 Àd =16 = À2.9 Hz) is in agree-
O
C
O
Scheme 3. Scope of the reaction with respect to the isocyanide
substrate. [a] Reaction conditions: 1 (1.7 equiv), 2a (1.0 equiv, 0.1m),
[21]
ment with previous reports. The same shielding effect of
18
O was observed for carbon atoms C2 and C5 in accordance
ZnBr (1.5 equiv), toluene, 1008C, 2 h.
2
18
with the oxazole structure of 4b- O2 (dC2À18 Àd À16
=
O
C2
O
À2.9 Hz, d À18 Àd À16 = À2.5 Hz). These results indicate
C5
O
C5
O
clearly that both oxygen atoms in oxazole 4 come from the
carboxylic acid, and that adventitious water or dioxygen are
not involved in the formation of 4.
On the basis of the aforementioned structural analysis and
the results of control experiments, a possible reaction path-
way leading to 4 is depicted in Scheme 6. Nucleophilic
addition of the carboxylic acid to the ligated isonitrile affords
Scheme 4. Synthesis and X-ray crystal structure of (tBuNC) ZnBr (5).
2
2
[22]
6, which upon migratory insertion provides intermediate 7.
[23]
NꢀC bond length of the coordinated isonitrile ligand is
.136 ꢀ, which is shorter than that of the uncoordinated
Coordination of another molecule of the isonitrile to 7,
1
[18]
isonitrile, whereas the Zn–C bond length is 2.072 ꢀ and
thus longer than that in the dimethyl terpyridine zinc complex
[
19]
(
2.028 ꢀ). The shortened NꢀC bond length is also evident
from the increased NꢀC vibrational frequency of this
À1
À1
bond [ n¯ (NꢀC)
= 2230 cm , n¯ (NꢀC) = 2134 cm : D n¯ =
coord
free
À1
9
6 cm ]. These spectroscopic data indicate that, unlike most
[13]
other RNC–transition-metal complexes, 5 is a s complex
with very weak back-donation from the metal, and that
the ligated isonitrile is activated towards nucleophilic addi-
tion.
Mixing of equimolar amounts of 1,1,3,3-tetramethylbutyl
isocyanide (the Walborsky reagent) and 5 provided a mixture
1
3
of several zinc bromide complexes, as evidenced by C NMR
spectra. Mixing of the Walborsky reagent with 5 and 2a
afforded a complex mixture, from which three different
aminooxazoles corresponding to the statistical distribution of
the four possible constitutional isomers (two of which have
the same molecular weight) were detected by LC/MS analysis
[
15]
(
see the Supporting information).
On the other hand,
heating of
a
solution of p-toluic acid (2a) with
(
tBuNC) ZnBr (5) in toluene at 608C for 2 h afforded the
2 2
oxazole 4a in 56% yield. The results of all these control
experiments indicate that complex formation between the
Scheme 6. Possible reaction mechanism.
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3
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.
Angewandte
Communications
followed by a second migratory insertion, furnishes 9 via 8.
[4] a) T. Saegusa, Y. Ito, S. Kobayashi, K. Hirota, H. Yoshioka,
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The elimination of ZnBr delivers ketenimine 10, which is
2
predisposed for the subsequent Mumm rearrangement to
afford 11. Intramolecular nucleophilic addition of the amide
oxygen atom to the ketenimine affords 12, which upon
dealkylation provides the observed 2,4,5-trisubstituted oxa-
1967, 8, 521 – 524; d) T. Saegusa, S. Kobayashi, K. Hirota, Y.
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zole 4. The reaction should be catalytic in ZnBr according to
2
the proposed reaction pathway. The need for a stoichiometric
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amount of ZnBr is probably due to product inhibition, as
2
2
+
[24]
oxazole 4 might chelate strongly to the Zn ion. We stress
that cationic isomerization/oligomerization is completely
[
25,26]
suppressed under our reaction conditions.
In summary, we have developed an unprecedented zinc
bromide mediated co-trimerization of isonitriles with carbox-
ylic acids as an efficient synthesis of 2,4,5-trisubstituted
[
6] a) G. O. Jones, X. C. Li, A. E. Hayden, K. N. Houk, S. J.
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[
27]
oxazoles.
A broad range of carboxylic acids, including
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of (tBuNC) ZnBr2 was fully characterized and provided
2
useful hints regarding the reaction mechanism. Experimental
results indicated that the reaction might be initiated by
nucleophilic addition of the carboxylic acid to the ligated
isonitrile, followed by a double-migratory-insertion/metal-
salt-elimination/acyl-migration/cyclization/dealkylation
sequence.
814; e) L. Banfi, R. Riva, A. Basso, Synlett 2010, 23 – 41; f) A. V.
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Experimental Section
Typical procedure: A suspension of a carboxylic acid (1.0 equiv,
0
.1m), an isonitrile (1.7 equiv), and zinc bromide (1.5 equiv) in
2
2
005, 7, 3697 – 3699; e) J. D. Winkler, S. M. Asselin, Org. Lett.
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2
3
Hyodo, M. Oshita, N. Chatani, J. Am. Chem. Soc. 2007, 129,
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solution was then added to the mixture, and the resulting solution was
stirred for 30 min. The reaction mixture was extracted with dichloro-
methane, and the combined organic layers were washed with brine,
dried over Na SO , and concentrated in vacuo. The crude mixture was
1
Wang, J. Am. Chem. Soc. 2013, 135, 4708 – 4711; for Lewis acid
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2
4
then purified by flash chromatography to give the desired oxazole.
Compound 4a (isolated by flash chromatography on silica gel
(
petroleum ether/EtOAc 95:5) as colorless crystals in 81% yield):
1
m.p.: 81–858C; H NMR (400 MHz, CDCl ): d = 7.76 (d, J = 8.1 Hz,
3
2
1
1
H), 7.22 (d, J = 8.1 Hz, 2H), 6.51 (s, 1H), 6.36 (s, 1H), 2.39 (s, 3H),
1
3
.47 ppm (s, 18H); C NMR (100 MHz, CDCl ): d = 164.0, 156.9,
3
49.6, 139.4, 129.5, 125.1, 124.6, 108.1, 52.7, 50.8, 30.0, 29.4, 21.5 ppm;
IR: n¯ = 3413, 3351, 2983, 2872, 1647, 1623, 1526, 1365, 1246, 1205,
À1
+
1
3
109, 1046, 874 cm ; HRMS (ESI): m/z calcd for C H N O :
19 28 3 2
+
30.2176 [M+H] ; found: 330.2173.
Received: June 26, 2013
Published online: && &&, &&&&
[
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Keywords: domino reactions · isocyanides · Lewis acids ·
.
oxazoles · rearrangement
[
3
353; see also: b) M. Suginome, T. Fukuda, Y. Ito, Org. Lett.
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4
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Angewandte
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[
[
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[
[
15] We thank one of the referees for proposing this control
experiment.
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2
2
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[
17] (tBuNC) ZnBr2 has been reported previously without full
2
characterization: B. L. Holman, A. G. Jones, J. Lister-James, A.
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[
[
[
18] The estimated NꢀC bond length in MeNC is 1.167 ꢀ: M. Kessler,
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m1325.
1
8
18
18
2
20] PhC O OH was synthesized from PhCCl and H O by slight
3
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1
8
13
[
[
[
22] The formation of p-toluic acid–ZnBr with concurrent liberation
2
of HBr was not observed in an NMR spectroscopic titration
experiment (see the Supporting Information).
23] The reaction may also start from the polycoordinated (RNC)n–
ZnBr complex. Indeed, the mixing of (tBuNC) ZnBr (d =
1
2
2
2
NC
30.7 ppm, s) with different amounts of tBuNC (1.0–5.0 equiv;
dNC = 153.6 ppm, t, J = 4.5 Hz] in CD Cl2 led rapidly to the
2
formation of a new species (see the Supporting Information).
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Domino Reactions
Y. Odabachian, S. Tong, Q. Wang,
M.-X. Wang,* J. Zhu*
&&&& — &&&&
Zinc Bromide Promoted Coupling of
Isonitriles with Carboxylic Acids To Form
Deviant behavior: In a deviation from
“normal” reactivity, isocyanides under-
went co-trimerization with carboxylic
nucleophilic addition of the carboxylic
acid to a ligated isonitrile molecule,
followed by a sequence involving double
migratory insertion, metal-salt elimina-
tion, acyl migration, cyclization, and
dealkylation.
2
,4,5-Trisubstituted Oxazoles
acids in the presence of ZnBr to
2
smoothly provide oxazoles (see scheme).
The reaction is thought to occur by initial
6
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Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!