Palladium-Catalyzed Aminocarbonylation Reaction to Access 1,3,4-Oxadiazoles using Chloroform as the Carbon Monoxide Source

Article abstract of DOI:10.1002/adsc.201500778

A palladium-catalyzed aminocarbonylation reaction of aryl halides with chloroform and tetrazoles has been developed, where chloroform was employed as the carbon monoxide (CO) source in the presence of cesium hydroxide. The in situ generated N-acylated tetrazoles were unstable and easily decomposed to afford 2,5-disubstituted 1,3,4-oxadiazoles. A wide range of tetrazoles and aryl halides reacted smoothly under the optimized reaction conditions to give the corresponding products in moderate to good yields.

Full text of DOI:10.1002/adsc.201500778

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DOI: 10.1002/adsc.201500778
Palladium-Catalyzed Aminocarbonylation Reaction to Access
1,3,4-Oxadiazoles using Chloroform as the Carbon Monoxide
Source
Zhengyi Lia and Liang Wanga,*
a
School of Petrochemical Engineering, Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology,
Changzhou University, Gehu Raod 1, Wujin, Changzhou 213164, Peopleꢀs Republic of China
Fax: (+86)-519-8633-0251; e-mail: lwcczu@126.com
Received: August 19, 2015; Revised: September 12, 2015; Published online: November 12, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500778.
Abstract: A palladium-catalyzed aminocarbonyla-
tion reaction of aryl halides with chloroform and
tetrazoles has been developed, where chloroform
was employed as the carbon monoxide (CO) source
in the presence of cesium hydroxide. The in situ
generated N-acylated tetrazoles were unstable and
easily decomposed to afford 2,5-disubstituted 1,3,4-
oxadiazoles. A wide range of tetrazoles and aryl
halides reacted smoothly under the optimized reac-
tion conditions to give the corresponding products
in moderate to good yields.
also showed promising application in carbonylation
reactions as CO source.[7] However, the generated
phenol could act as a strong nucleophile in these reac-
tions.
Chloroform is an inexpensive and readily available
solvent in organic synthesis. It can be hydrolyzed to
release CO in the presence of strongly basic aqueous
hydroxide solutions,[8] albeit the yield of CO was
poor.[9] Just recently, Gockel et al. reported a Pd-cata-
lyzed aminocarbonylation reaction by using chloro-
form as CO source.[10] Gu and co-workers also dis-
closed palladium-catalyzed Heck-type domino cycliza-
tion and carboxylation reactions to synthesize carbox-
ylic acids with chloroform in aqueous system,[11]
where chloroform showed superior performance over
CO gas and phenyl formate.
Keywords: aminocarbonylation; carbon monoxide;
chloroform; 1,3,4-oxadiazoles; tetrazoles
Inspired by these pioneering works, we wondered
whether this kind of catalytic system could be em-
Ever since the pioneering work of Heck and co-work- ployed for the one-pot aminocarbonylation of aryl
ers in the early 1970s,[1] transition metal-catalyzed car- halides with tetrazoles. If so, the in situ generated N-
bonylative coupling reactions have become one of the acylated tetrazoles could be decomposed under high
most powerful tools to construct carbonyl com- temperature to afford 2,5-disubstituted 1,3,4-oxadia-
pounds.[2] Although carbon monoxide (CO) is widely zoles (Scheme 1).[12] To the best of our knowledge,
applied in carbonylative reactions since it is cheap there is only one example of an aminocarbonylation
and readily available on a large scale, the high toxicity reaction using chloroform as the CO source.[10] The
and explosiveness severely limits its practical use in N-containing heterocycles such as tetrazoles, however,
laboratories. Thus, the development of safe, effective, have not been tried yet. Given that 1,3,4-oxadiazoles
and operationally simple carbonylation reactions
without the use of external CO gas is highly desirable.
Recently, “CO-free” carbonylation reactions have
received much attention. It was found that aromatic
aldehydes could serve as efficient CO sources in rho-
dium-catalyzed
Pauson–Khand-type
reactions.[3]
Skrydstrup and co-workers reported two new tech-
niques for the ex situ generation of CO from tertiary
acid chlorides[4] or carbon dioxide[5] in the presence of
a catalytic amount of a palladium complex or base.
Similarly, silacarboxylic acid was utilized to generate
CO assisted by potassium fluoride.[6] Aryl formate Scheme 1. Working plan.
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Zhengyi Li and Liang Wang
Table 1. Optimization of reaction conditions.[a]
are of great importance due to their wide applications
in pharmaceutical chemistry[13] and material sci-
ence,[14] and in continuation of our interest in hetero-
cycles,[12g] herein, we report a palladium-catalyzed
aminocarbonylation reaction to access 1,3,4-oxadia-
zoles by using chloroform as the carbon monoxide
source.
Initially, iodobenzene 1a and 5-phenyl-2H-tetrazole
2a were selected as the model substrates to optimize
the reaction conditions. A variety of reaction condi-
tions including catalyst, ligand, amount of chloroform,
solvent as well as temperature were explored (see the
Supporting Information, Tables S1–S6). The solvents
showed big influence on this transformation. No de-
sired product was observed in solvents such as di-
methyl sulfoxide (DMSO), N,N-dimethylformamide
(DMF), 1,2-dichloroethane (DCE), dioxane, acetoni-
trile and tetrahydrofuran (THF). Reaction in chloro-
benzene gave product 3a in 24% yield. Encouragingly,
a 49% yield of 3a was obtained when the reaction
was conducted in toluene (Supporting Information,
Table S1, entry 4). Different ligands were also exam-
ined. Xantphos turned out to be the superior ligand
providing 3a in 65% yield whereas Cy3P, Ph3P, dppp,
and dppf led to trace amounts of the desired product
(Table 1, entries 1–6). Bases are vital for the reaction.
It was reported that CO could be rapidly generated in
high yield from chloroform under the assistance of
CsOH·H2O, which allowed the carbonylation reaction
to outcompete non-carbonylative couplings.[10] As ex-
pected, CsOH·H2O showed good activity to release
CO from chloroform, while KOH, t-BuOK, Et3N, and
pyridine resulted in either the failure of the reaction
or much lower yields (Table 1, entries 7–10).
Entry Ligand
Base
CHCl3 (equiv.) Yield [%][b]
1
2
DPEphos CsOH·H2O
Xantphos CsOH·H2O
3
3
3
3
3
3
3
3
3
3
1
5
3
3
3
49
65 (42)[c]
trace
trace
trace
trace
13
3
4
5
6
Cy3P
Ph3P
dppp
dppf
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
7
Xantphos KOH
8
9
Xantphos t-BuOK
Xantphos Et3N
NR
NR
NR
16
10
11
12
13
14
15
Xantphos pyridine
Xantphos CsOH·H2O
Xantphos CsOH·H2O
Xantphos CsOH·H2O
Xantphos CsOH·H2O
Xantphos CsOH·H2O
60
37[d]
46[e]
43,[f] 57[g]
[a]
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol),
Pd(OAc)2 (2.5 mol%), ligand (10 mol%) [DPEphos=
bis(2-diphenylphosphinophenyl) ether, Xantphos=4,5-
Bis(diphenylphosphino)-9,9-dimethylxanthene,
1,3-Bis(diphenylphosphino)propane, dppf=1,1’-Bis(di-
phenylphosphino)ferrocene], CHCl3, base (10 equiv.),
dppp=
toluene (1 mL), 1208C, N2, 24 h.
Isolated yields.
Under air.
5 mol% of Pd(OAc)2.
5 mol% of Xantphos.
1008C.
[b]
[c]
[d]
[e]
[f]
Other parameters such as reaction atmosphere,
CHCl3 equivalencies, catalyst and ligand loadings, and
palladium precursors were also investigated. It was
found that reaction under an air atmosphere led to
[g]
1308C.
a lower yield (42%, Table 1, entry 2). Decreasing the tion system. Meanwhile, since secondary amines were
amount of CHCl3 to 1 equiv. afforded the desired less active than primary amines in this aminocarbony-
product in only 16% yield, while increasing the lation reaction, more equivalents of Xantphos were
amount of CHCl3 to 5 equiv. gave an inferior result thus required to accelerate the reaction. Other palla-
(Table 1, entry 12). It was worth noting that a high dium precursors including PdCl2, Pd(dppe)Cl2,
Pd/ligand ratio (1:4) was required, and relatively Pd(PPh3)4, and Pd(dppf)Cl2 were also evaluated and
lower yields were obtained on decreasing the amount relatively lower yields were obtained (Supporting In-
of Xantphos to 5 mol% (Table 1, entry 14). For this formation, Table S3). Finally, the survey of the reac-
phenomenon, 31P NMR spectroscopy and kinetic ex- tion temperature showed that 1208C was the opti-
periments were undertaken by Hullꢀs group during mum. Thus, the optimized reaction conditions are as
their experiments.[10] They hypothesized that the follows: 1.0 equiv. of iodobenzene, 1.5 equiv. of tetra-
active catalyst was generated via oxidation of an zole, 2.5 mol% Pd(OAc)2, 10 mol% Xantphos,
equivalent of the ligand to generate Xantphos mono- 3.0 equiv. of CHCl3, and 10 equiv. of CsOH·H2O in
oxide and Pd(0). Similarly, there are three kinds of toluene (0.2M) under N2 in a sealed vial at 1208C. It
different Pd(0) complexes that could exist in the reac- should be mentioned that although a moderate yield
tion mixture, including: [(Xantphos)Pd], [(Xantphos (6%) was obtained under the optimized reaction con-
mono-oxide)Pd], and [(Xantphos mono-oxide)2Pd]. ditions, the reaction was very clean and no arylation
This result unavoidably led to a lower concentration product was observed. Compared with the yield from
of the real active catalyst [(Xantphos)Pd] in the reac- aliphatic amines such as morpholine, the lower yield
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Palladium-Catalyzed Aminocarbonylation Reaction
Table 2. Reaction scope for aryl halides.[a]
obtained in this reaction system may be attributed to
the relatively lower nucleophilicity of aromatic secon-
dary amines, which is consistent with the previous
report.[10]
With the optimized conditions in hand, a series of
aryl halides was employed to explore the generality
of this protocol (Table 2). Generally, all of the investi-
gated aryl halides coupled with 5-phenyl-2H-tetrazole
2a smoothly to provide the 1,3,4-oxadiazoles in mod-
erate to good yields (44–75%). Diverse functional
groups survived well under the reaction conditions.
Aryl halides with electron-withdrawing groups at the
para-position afforded better yields. Aryl bromides
bearing strong electron-withdrawing groups such as
nitro and cyano also showed good reactivities to give
the desired products in satisfactory yields (Table 2,
entries 8 and 9). Aryl chlorides, however, were inac-
tive towards the reaction. Notably, chemoselectivity
was observed in the aminocarbonylation of halo-sub-
stituted iodobenzene, providing 3d–3f in good yields
(Table 2, entries 4–6). The remaining halogen groups
thereby can be further modified to form complex
Entry
R1
X
Product
Yield [%]
1
2
3
4
5
6
7
8
C6H5
I
I
I
I
I
I
Br
Br
Br
I
I
I
I
I
I
I
I
I
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
65
63
56
70
66
64
62
75
72
61
55
68
51
45
44
69
61
64
trace
52
4-CH3C6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-CF3C6H4
4-NO2C6H4
4-CNC6H4
4-MeSC6H4
2-CH3C6H4
3-CH3C6H4
2-ClC6H4
2-BrC6H4
2-MeOC6H4
1-naphthyl
2-furyl
9
10
11
12
13
14
15
16
17
18
19
20
À
compounds through classical C C coupling strategies.
2-thienyl
4-CHOC6H4
4-EtOOCC6H4
Steric hindrance was observed for ortho-substituted
aryl halides, and relatively lower yields were obtained
(3k, 55%; 3m, 51%; 3n, 45%; 3o, 44%, respectively).
1-Iodonaphthalene also showed good reactivity to de-
liver 3p in 69% yield. Pleasingly, both 2-iodofuran
and 2-iodothiophene survived the reaction conditions
and were successfully transformed to the correspond-
ing products 3q and 3r in good yields. Finally, 4-iodo-
I
I
3s
3t
[a]
Reaction conditions:
1 (0.2 mmol), 2a (0.3 mmol),
Pd(OAc)2 (2.5 mol%), Xantphos (10 mol%), CHCl3
(3 equiv.), CsOH·H2O (10 equiv.), toluene (1 mL), 1208C,
N2, 24 h, isolated yields.
benzaldehyde and ethyl 4-iodobenzoate were utilized amount of product 3s was observed. The aldehyde
to check the compatibilities of aldehyde and ester was easily attacked by chloroform under strongly
groups (Table 2, entries 19 and 20). Only a trace basic condition as determined by GC-MS analysis. In
Table 3. Aminocarbonylation of iodobenzene with tetrazoles and chloroform.[a]
[a]
Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), Pd(OAc)2 (2.5 mol%), Xantphos (10 mol%), CHCl3 (3 equiv.),
CsOH·H2O (10 equiv.), toluene (1 mL), 1208C, N2, 24 h, isolated yields.
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contrast, the ester group was more stable and the cor- Experimental Section
responding product 3t was obtained in 52% yield.
To further explore the scope of this protocol, General Procedure for One-Pot Synthesis of 2,5-
a series of aryl iodides and aryltetrazoles were then Diaryl-1,3,4-oxadiazoles
investigated. The results are summarized in Table 3.
We were pleased to find that aryltetrazoles with dif-
ferent substituents such as methyl, methoxy, fluoro,
A 10-mL reaction vial equipped with a stir bar was charged
with Pd(OAc)2 (1.2 mg, 5.0 mmol, 2.5 mol%), Xantphos
(11.6 mg, 20 mmol, 10 mol%), CsOH·H2O (336 mg,
chloro, and trifluoromethyl survived well under the
reaction conditions, giving the desired 2,5-diaryl-1,3,4-
oxadiazoles in 44–69% yields. Steric hindrance from
the aryltetrazole showed only a negligible influence
on the reaction (3k, 64%). A series of symmetrical
and unsymmetrical 2,5-aryl 1,3,4-oxadiazoles could
also be obtained in good yields via the present proto-
col. Again, no arylation products of tetrazoles as well
as self-coupling products of aryl iodides were ob-
served.
With respect to the reaction mechanism, initially,
palladium acetate is reduced to Pd(0).[15] Subsequent-
ly, aryl halide undergoes oxidative addition with
Pd(0). After coordination and insertion of CO which
is generated from chloroform under the assistance of
CsOH·H2O, an acyl palladium complex is generated.
This key intermediate is then attacked by aryltetra-
zole to give the acylated tetrazole, and Pd(0) is regen-
erated in the presence of a base. The unstable N-acy-
2.0 mmol, 10 equiv.), toluene (1 mL), aryl halide (0.20 mmol,
1.0 equiv.), tetrazole (0.30 mmol, 1.5 equiv.), and chloroform
(0.60 mmol, 3.0 equiv.). The reaction mixture was heated at
1208C under nitrogen for 24 h. After reaction, the mixture
was cooled to room temperature and the solvent was re-
moved under reduced pressure. The residue was purified by
silica gel chromatography to afford the desired product 3.
Acknowledgements
We gratefully acknowledge financial support from the Na-
tional Natural Science Foundation of China (21302014), the
Jiangsu Key Laboratory of Advanced Catalytic Materials and
Technology (BM2012110) and Advanced Catalysis and
Green Manufacturing Innovation center of Changzhou Uni-
versity.
lated tetrazole is then decomposed under high tem- References
perature to afford the 2,5-disubstituted 1,3,4-oxadia-
zoles (Scheme 2).
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