Palladium-catalyzed imidoylative cyclization of α-isocyanoacetamides: Efficient access to c2-diversified oxazoles

Article abstract of DOI:10.1002/chem.201403033

A novel procedure for the synthesis of C2-diversified oxazoles, through palladium-catalyzed imidoylative cyclization of α-isocyanoacetamides with aryl, vinyl, alkynyl halides, or triflates, was developed. Migratory insertion of isocyanide into a C sp 3-palladium(II) intermediate in a cascade process was also realized, generating alkyl-substituted oxazoles. Therefore, oxazoles functionalized at the C2 position with sp, sp², and sp³ hybridized carbon atoms are accessible by applying this method.

Full text of DOI:10.1002/chem.201403033

DOI: 10.1002/chem.201403033
Full Paper
&
Organic Synthesis
Palladium-Catalyzed Imidoylative Cyclization of a-
Isocyanoacetamides: Efficient Access to C2-Diversified Oxazoles
Jian Wang, Shuang Luo, Jinbo Huang, Tingting Mao, and Qiang Zhu*[a]
Abstract: A novel procedure for the synthesis of C2-diversi-
fied oxazoles, through palladium-catalyzed imidoylative cyc-
lization of a-isocyanoacetamides with aryl, vinyl, alkynyl hal-
ides, or triflates, was developed. Migratory insertion of isocy-
anide into a Csp3-palladium(II) intermediate in a cascade pro-
cess was also realized, generating alkyl-substituted oxazoles.
Therefore, oxazoles functionalized at the C2 position with
sp, sp2, and sp3 hybridized carbon atoms are accessible by
applying this method.
Introduction
dates could also be obtained by condensation of bisnucleo-
philes with aryl halides in the presence of a palladium catalyst
and isocyanide, in which the amino moiety in isocyanide was
released as a byproduct.[9] Owing to our long-standing interest
in palladium-catalyzed isocyanide insertion reactions and new
synthetic methods directed towards heterocycle synthesis,[7a,10]
a new class of imidoylative cyclization reactions leading to het-
erocycles is designed by using an isocyanide substrate contain-
ing an internal nucleophile thanks to the ability to functional-
ize isocyanide compared with carbon monoxide. a-Isocyanoa-
cetamides, easily accessible by amidation of the corresponding
a-isocyanoesters, salts of a-isocyanocarboxylic acid, or by de-
hydration of the related formamides, are ideal molecules of
this kind (Scheme 1).[11]
Compared with palladium-catalyzed carbonylation reactions,[1]
the related imidoylative process using isocyanide (RNC) rather
than carbon monoxide (CO) as a C1 source has received far
less attention.[2] In carbonylation reactions, large excesses of
toxic gaseous CO are normally required, which may limit prac-
tical applications in laboratories and industry. However, in the
imidoylative reactions reported, only stoichiometric amounts
of isocyanide (typically a liquid) are needed, highlighting its
great advantage in this context. The key step of an imidoyla-
tive reaction involves migratory insertion of isocyanide into
a palladium(II) intermediate, generated either by oxidative ad-
dition of organohalides to a Pd0 species[3] or by PdII-catalyzed
CÀH activation.[4] Upon nucleophilic substitution and subse-
quent reductive elimination, the corresponding amidines,[3a]
amides,[3b,4] ketimines,[5] imidates, or thioimidates[6] have been
obtained depending on the nucleophiles used. In addition, pal-
ladium-catalyzed imidoylative cyclization provides a novel
strategy to construct various highly functionalized heterocyclic
compounds. By linking a nucleophile to the substrate contain-
ing the CÀhalogen or CÀH bond to be activated, cyclic imidoy-
lated products can be formed.[7] For example, we developed
an efficient synthesis for 4-aminoquinazolines through a PdII-
catalyzed CÀH activation/isocyanide insertion/cyclization se-
quence.[7a] Recently, Maes, Orru, and Ruijter et al. reported a pal-
ladium-catalyzed aerobic oxidation reaction between bisnu-
cleophiles and aliphatic isocyanides to produce cyclic guani-
dine-containing (and related) heterocycles.[8a] Cyclic (thio)imi-
Scheme 1. Palladium-catalyzed imidoylative reactions.
Owing to the strong electron-donating nature of the amino
group in a-isocyanoacetamide, the carbonyl oxygen atom of
the amide is nucleophilic enough to attack the intramolecular
nitrilium intermediate generated by initial nucleophilic addition
of the terminal carbon of isocyanide to imines or aldehydes in
Ugi- or Passerini-type reactions, respectively. In pioneering
work by Zhu et al. in 2001, 2-aminoalkyl oxazole derivatives
were prepared by using a-isocyanoacetamides in a Ugi-type
three-component reaction.[12] Later on, the same group suc-
cessfully applied the strategy to the enantioselective synthesis
[a] J. Wang, S. Luo, J. Huang, T. Mao, Q. Zhu
State Key Laboratory of Respiratory Disease
Guangzhou Institutes of Biomedicine and Health
Chinese Academy of Sciences
190 Kaiyuan Avenue, Guangzhou 510530 (P.R. China)
Fax: (+86)20-3201-5299
E-mail: zhu_qiang@gibh.ac.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403033.
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of 2-aminoalkyl oxazoles[13] and its cascade reactions using the
in situ generated oxazoles as key intermediates.[14] Very recent-
ly, Zhu et al. reported a ZnBr2 promoted reaction of a-isocya-
noacetamides with tertiary propargyl amines, used as synthetic
equivalents of vinyl cations, for the synthesis of 2-alkenyl oxa-
zoles.[15] We thus envisioned that a-isocyanoacetamides could
also participate in palladium-catalyzed imidoylative cyclization
reactions, affording a novel approach to multisubstituted oxa-
zoles. As shown in Scheme 2, an initial oxidative addition of or-
Results and Discussion
Optimization studies
The study was initiated by investigating the reaction between
2-isocyano-2-phenyl-1-(piperidin-1-yl)ethanone, 1a, and iodo-
benzene, 2a, in MeCN (Table 1). When a range of inorganic
Table 1. Optimization of the reaction conditions.[a]
Entry
Solvent
Base
Catalyst
Yield (%)[b]
1
2
3
4
5[c]
6c]
7[c]
8[c]
9[c]
10[d]
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMSO
DMF
Cs2CO3
K2CO3
Et3N
Et3N
Et3N
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)2Cl2]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
<10
<10
10
6
26
59
56
53
30
Scheme 2. Proposed scenario of Pd-catalyzed imidoylative cyclization of a-
isocyanoacetamides.
DMA
MeCN
96
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.30 mmol), [Pd(PPh3)4]
(0.01 mmol, 5 mol%), base (0.22 mmol), solvent (2 mL), 708C, 1 h, under
Ar. [b] Isolated yield. [c] A solution of 1a in solvent (1 mL) was added
slowly over 30 min. [d] A solution of 1a in solvent (1 mL) was added by
syringe pump within 1 h.
ganohalides to Pd0, and a subsequent migratory insertion of
the isocyanide moiety to the palladium(II) intermediate II gives
an imidoyl palladium(II) intermediate, III. Nucleophilic substitu-
tion of the intramolecular carbonyl oxygen atom on palladiu-
m(II) generates a key six-membered palladacycle, IV. Following
this, reductive elimination and deprotonative aromatization de-
livers 2,4,5-trisubstituted oxazoles. Theoretically, various palla-
dium(II) intermediates in the form of RÀPdÀX can be applied
in this strategy, giving tremendous diversity to the C2 position
of the oxazole products. Herein, we report a general method
for the synthesis of C2-diversified multisubstituted oxazoles by
palladium-catalyzed imidoylative cyclization of a-isocyanoace-
tamides with aryl, vinyl, alkynyl halides, and triflates. Further-
more, the Csp3-palladium(II) intermediate generated from carbo-
palladation of alkenes could also be applied in this process,
leading to diversified oxazoles, which are ubiquitous in natural
products, pharmaceutical agents, and functional materials
(Figure 1).[16]
and organic bases were screened, the desired C2-phenylated
oxazole 3a was indeed formed, albeit in no more than 10%
yield in the presence of [Pd(PPh3)4] (entries 1–3). Other cata-
lysts such as [Pd(PPh3)2Cl2] gave lower yields. These low yields
were due to the decomposition of starting material 1a in the
reaction mixture. The yield of 3a was increased to 26% by
adding a MeCN solution of 1a over 30 min with Et3N as a base
(entry 5). The cyclization efficiency was further improved in the
presence of DIPEA (diisopropylethylamine; entry 6, 59%).
Other solvents, such as DMSO, DMF, and DMA, gave similar or
worse results (entry 7–9). Satisfyingly, when a solution of 1a
was added with a syringe pump within 1 h, 3a was obtained
in 96% yield.
Scope and limitations
With the optimized reaction conditions in hand, we first
screened the scope of aryl iodides (Scheme 3). Aryl iodides
containing various substituents were converted smoothly to
give the corresponding arylated products in moderate to ex-
cellent yields. ortho-Methyl iodobenzene gave a much lower
yield than its meta- and para-methyl iodobenzene counterparts
(3b vs. 3c and 3d), indicating that the reaction was sensitive
to the steric hindrance of aryl iodides. Ester (3 f) and bromide
(3h), valuable functionalities for further transformations, sur-
vived the reaction conditions.
Figure 1. Oxazole-containing natural and bioactive molecules.
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Scheme 4. Scope of reaction with vinyl/alkynyl halides/triflates. Reaction
conditions: 1 (0.20 mmol), 2 (0.30 mmol), [Pd(PPh3)4] (0.01 mmol), base
(0.22 mmol), MeCN (2 mL), Ar, syringe pump addition within 1 h. [a] Vinyl
bromides are mixtures of E,Z-isomers. The E/Z ratio ranged from 1:1 to 10:1.
The equivalent of 2 was based on E-isomer. [b] X=Br. [c] X=OTf.
tively (Scheme 4). It is worth noting that when mixtures of E-
and Z-vinyl bromides (E/Z=1:1 to 10:1) were used as starting
materials, only the E-isomers reacted, affording the corre-
sponding E-alkenylated products in good yields. The Z-vinyl
bromides remained unreacted. For example, a 1:1 mixture of
(E/Z)-(2-bromovinyl)benzene reacted with 1a to deliver the de-
sired (E)-4-phenyl-5-(piperidin-1-yl)-2-styryloxazole, 4a, in 66%
yield as the only product. Electron-withdrawing Cl and Br sub-
stituents on the phenyl ring enhanced the reactivity of vinyl
bromides, providing 4b and 4c in 93% and 89% yields, re-
spectively. It was intriguing that during the formation of 4c,
the bromo group on the phenyl ring remained unreacted,
demonstrating excellent chemoselectivity in favor of the vinyl
bromide over the aromatic bromide. The reaction is also appli-
cable to conjugated dienyl bromide. Thus, ((1E,3E)-4-bromobu-
ta-1,3-dien-1-yl)benzene gave the desired product in moderate
yield (4d). Cyclohexenyl-substituted oxazole 4e was also ac-
cessible from the corresponding vinyl triflate, which was easily
accessible from cyclohexanone (67%). Furthermore, alkynyl
bromides were another class of substrates suitable for this imi-
doylative cyclization reaction. Functionalities including OMe,
Br, COOMe, Ac, and CHO on the phenyl ring of (bromoethynyl)-
benzene were compatible with the reaction conditions, giving
the corresponding alkynylated oxazoles 4 f–4k in moderate to
good yields. Again, the alkynyl bromide reacted preferentially
over the aromatic bromide (4h). Alkyl-substituted alkynyl bro-
mide was also compatible with this process, affording the
product 4l in 36% yield. To the best of our knowledge, migra-
tory insertion of isocyanide to a CspÀPdII intermediate is
unprecedented.
Scheme 3. Scope of reactions with aryl halides/triflates. Reaction conditions:
1 (0.20 mmol), 2 (0.30 mmol), [Pd(PPh3)4] (0.01 mmol, 5 mol%), base
(0.22 mmol), MeCN (2 mL), Ar, syringe pump addition within 1 h. [a] base=
DIPEA, 708C. [b] base=CsF, 908C. [c] 0.5 equiv of 1,4-dibromobenzene. [d]
X=OTf, 10 mol% of [Pd(PPh3)4] (0.02 mmol), base=DIPEA, 708C.
No desired product was obtained with aryl bromides as the
coupling partner at 708C. When the reaction temperature was
raised to 908C, 3a was generated with DIPEA as a base, albeit
in relatively low yield (72%). After a screening a series of
bases, CsF was found to be the optimal base, producing 3a in
86% yield. Aryl bromides substituted with electron-neutral or
-donating groups provided the same products in lower yields
than the corresponding aryl iodides (Scheme 3, 3a, 3d, and
3e). Electron-withdrawing substituents on aryl bromides, such
as chloro (3g, 3k), cyano (3l), formyl (3m), acetyl (3n), trifluor-
omethyl (3o), and fluoro groups (3p), generated excellent
yields in most cases. Heterocycles, including benzodioxole (3q)
and benzothiophene (3r), could also be introduced into the
C2 position of oxazole by using the corresponding bromides.
To our delight, when 1,4-dibromobenzene was used as the
coupling partner, double imidoylative cyclization took place to
produce a highly conjugated symmetric molecule, 3s, in good
yield. In addition, phenyl triflate could also be used as an elec-
trophile in this process, although it gave a relatively low yield
(30%).
Vinyl and alkynyl bromides were also suitable reactants for
this coupling reaction under higher catalyst-loading conditions,
furnishing C2-alkenylated and -alkynylated oxazoles, respec-
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Changing
the
piperidinyl
group in a-isocyanoacetamide
1a to other amino groups, such
as pyrrolidinyl, dimethylamino,
N-methylethylamino, and diethy-
lamino, all resulted in moderate
to good yields (5a–5d). Altering
the phenyl group in 1a to
a benzyl group (5e) gave an ex-
cellent yield of 91%. Unfortu-
nately, secondary a-isocyanoace-
tamide failed to form the corre-
sponding cyclized product 5 f
(Scheme 5).
A domino process involving
oxidative addition of N-(2-iodo-
phenyl)methacrylamide deriva-
tive
6
to Pd0, intramolecular
alkene insertion, and imidoyla-
tive cyclization of the resulting Scheme 6. Large scale synthesis and further transformations.
Csp3ÀPdII intermediate with a-iso-
uct through the palladium-catalyzed partial hydrogenation of
4 f (Scheme 6c).[18] This transformation provides a complemen-
tary approach to current imidoylative cyclizations with vinyl
bromides to configurationally defined alkenylated oxazoles.
Generally, C2-alkyl-substituted oxazoles could be synthesized
easily by hydrogenation of alkenylated derivatives, as exempli-
fied by the synthesis of 10 from 4a (Scheme 6d).
Mechanistic study
A control reaction between 4-phenyl-5-(piperidin-1-yl)oxazole,
11, and iodobenzene under the standard conditions resulted
in no formation of the desired product, with 93% of 11 recov-
ered (Equation 2). A possible pathway involving direct arylation
Scheme 5. Scope of reaction with isocyanides. Reaction conditions:
1 (0.20 mmol), 2a (0.30 mmol), [Pd(PPh3)4] (0.01 mmol, 5 mol%), DIPEA
(0.22 mmol), MeCN (2 mL), Ar, syringe pump addition within 1 h.
cyanoacetamide 1a, was realized to install an oxindole moiety
on the oxazole with a methylene tether (Equation 1, 7a and
7b). Isocyanide insertion into a Csp3ÀPdII intermediate is rare.[3b]
of in situ generated oxazole was thus ruled out. Therefore, iso-
cyanide insertion into PdII intermediates is believed to be the
key step of this reaction, as shown in Scheme 3.
Conclusion
We have developed a novel procedure for the synthesis of C2-
functionalized oxazoles through palladium-catalyzed imidoyla-
tive cyclizations of a-isocyanoacetamides with the correspond-
ing aryl, vinyl, alkynyl halides, or triflates. Migratory insertion of
isocyanide into a CspÀpalladium(II) intermediate is reported for
the first time, affording C2-alkynylated oxazoles. Both E- and Z-
isomers of alkenylated oxazoles can be accessed by the current
imidoylative cyclization with vinyl bromides or by selective hy-
drogenation of alkynylated precursors, respectively. Migratory
Gram-scale preparation of 3a was equally efficient
(Scheme 6a). Further diversifications of the obtained function-
alized oxazole products were also performed. For example,
a Diels–Alder reaction of oxazole 3a with dimethyl but-2-yne-
dioate afforded tetra-substituted furan
8 in 62% yield
(Scheme 6b).[17] (Z)-4-Phenyl-5-(piperidin-1-yl)-2-styryloxazole 9,
a configurational isomer of 4a, was accessed as a major prod-
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tion with sp, sp2, and sp3 hybridized carbon atoms are accessi-
ble by this method. Further studies on extending this transfor-
mation and the evaluation of the biological activity of these
compounds are currently underway in our laboratory.
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Experimental Section
Representative procedure
An oven-dried 25 mL Schlenk tube was charged with [Pd(PPh3)4]
(0.01 mmol, 11.6 mg), and was evacuated and refilled with Ar three
times. A solution of DIPEA (0.22 mmol, 38.4 mL) and iodobenzene
(2a, 0.3 mmol) in MeCN (1.0 mL) was added by syringe and the
tube was placed in an oil bath at 708C. A solution of 2-isocyano-2-
phenyl-1-(piperidin-1-yl)ethanone (1a, 0.2 mmol) in MeCN (1.0 mL)
was added to the reaction mixture with a syringe pump within 1 h.
The crude reaction mixture was extracted with CH2Cl2 (20 mLꢁ3)
and washed with brine (20 mL). The organic phase was concentrat-
ed in vacuo and the purified product 3a was isolated as a white
solid by flash chromatography using petroleum ether and ethyl
acetate (50:1 to 15:1) as the eluent.
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We are grateful for financial support from the Chinese Acade-
my of Sciences, and National Science Foundation of China
(21072190, 21202167).
Keywords: heterocycles
·
imidoylative cyclization
·
a-
isocyanoacetamide · oxazoles · palladium
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Published online on August 5, 2014
Chem. Eur. J. 2014, 20, 11220 – 11224
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