Synthesis of 2,4- and 2,5-disubstituted oxazoles via metal-catalyzed cross-coupling reactions

Article abstract of DOI:10.1002/adsc.201000668

The rapid synthesis of 2,4- and 2,5-disubstituted oxazoles via metal-catalyzed cross-coupling reactions is reported. The 4- or 5-position of the corresponding 4- or 5-halogenated 2-butylthiooxazoles was successfully functionalized via Suzuki-Miyaura, Sono

Full text of DOI:10.1002/adsc.201000668

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DOI: 10.1002/adsc.201000668
Synthesis of 2,4- and 2,5-Disubstituted Oxazoles via Metal-
Catalyzed Cross-Coupling Reactions
Carla M. Counceller,a Chad C. Eichman,a Nicolas Proust,a and James P. Stambulia,*
a
Department of Chemistry, The Ohio State University, Evans Laboratories, Columbus, Ohio 43210, USA
Fax : (+1)-614-292-1685; phone: (+1)-614-688-8082; e-mail: stambuli@chemistry.ohio-state.edu
Received: August 27, 2010; Published online: December 30, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000668.
Abstract: The rapid synthesis of 2,4- and 2,5-disub-
stituted oxazoles via metal-catalyzed cross-coupling
reactions is reported. The 4- or 5-position of the
corresponding 4- or 5-halogenated 2-butylthiooxa-
zoles was successfully functionalized via Suzuki–
Miyaura, Sonogashira and Stille cross-coupling re-
actions. The 2-position of the 2-butylthiooxazoles
obtained was further coupled to various organozinc
reagents through palladium- or nickel-mediated
cross-coupling reactions.
the 2- or the 4-position of 2,4-diiodooxazole can be
controlled by the ancillary ligand.[8] One drawback to
metal-catalyzed cross-coupling reactions of oxazoles
is that many methods require the use of the parent
oxazole compound to prepare the requisite starting
materials.
Oxazole is commercially available, but expensive,
and its laboratory preparation is tedious and low-
yielding.[9] Although there have been a number of im-
portant contributions to cross-coupling reactions of
oxazoles, most of these reactions employ the parent
oxazole compound. To avoid the use of oxazole, we
developed a cross-coupling reaction that produces
substituted oxazoles by coupling 2-alkylthiooxazoles
with organozinc reagents in the presence of a catalytic
Keywords: cross-coupling; homogeneous catalysis;
nickel; nitrogen heterocycles; palladium
amount of NiCl
thiooxazole starting material can be prepared on a
(PPh3)2.[10] Importantly, the 2-alkyl-
2ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
Oxazoles are an important class of nitrogen heterocy- large scale by reacting the diethyl acetal of glycolalde-
cle that exhibit diverse biological activities.[1] A large hyde with potassium thiocyanate, followed by alkyla-
number of oxazole-containing natural products that tion of the resulting thiol.[11] These coupling reactions
exhibit anticancer, antifungal, or antibacterial proper- provided a variety of alkyl-, alkynyl-, aryl-, and heter-
ties have been isolated and many of these compounds oaryloxazoles solely substituted at the 2-position. Al-
have been synthesized.[2] Because of the sheer though we reported a few examples of 2,5-disubstitut-
number of biologically relevant oxazole natural prod- ed oxazoles starting from the corresponding 2,5-dime-
ucts and pharmaceuticals that have emerged in the thylthiooxazole, there were no examples of 2,4-disub-
last twenty years, this class of compound has begun to stituted oxazoles.
approach the forefront of important nitrogen hetero-
2,4-Disubstituted oxazoles are prevalent in nature
and 2,5-disubstituted oxazoles are important in the
cycles.[3]
Current methods to produce 1,3-oxazoles include pharmaceutical industry. To expand on the use of
cyclodehydrations,[4] oxidations of oxazolines,[5] direct thio
ACTHNUTRGNEoNUG xazoles as partners in metal-catalyzed cross-cou-
metallation of the parent oxazole,[6] and, most recent- pling reactions of oxazoles and to demonstrate the
ly, metal-catalyzed cross-coupling reactions.[7] The versatility of the alkylthiooxazolyl group, we set out
most common methods used to prepare oxazoles are to prepare 2,4- and 2,5-disubstituted oxazoles. In
cyclodehydration reactions. However, this method order to access 2,4-disubstituted oxazoles using our
does not allow the preparation of all oxazole substitu- coupling chemistry, a large quantity of 2,4-dialkyl-
tion patterns in high yields, nor does it allow direct
ACHTUNGTRENtNGNU hiooxazole was needed. However, the traditional syn-
functionalization at oxazole. Metal-catalyzed cross- thetic approach to 2,4-dialkylthiooxazole requires
coupling reactions have emerged as a useful approach many steps, mostly because the oxazole hydrogen at
to functionalize oxazoles. Earlier this year, a group at C-5 is more acidic than the hydrogen at C-4, which
Merck reported that the selective coupling at either disallows selective deprotonation of the oxazole at C-
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Carla M. Counceller et al.
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Table 1. Suzuki–Miyaura reactions of disubstituted ox-
AHCTUNGTRENNUNG
azoles.[a]
Entry
1[b]
Substrate
Product
Yield [%]
68
Scheme 1. Synthesis of 2-butylthio-5-bromooxazole (2), 2-
butylthio-5-iodooxazole (4), 2-butylthio-4-bromooxazole (3)
and 2-butylthio-4-iodooxazole (5).
2[b]
92
86
4. Because of this type of chemical scenario, we decid-
ed to perform the halogen dance rearrangement of 2-
butylthio-5-bromooxazole.[12]
3[b]
2-Butylthiooxazole (1) was deprotonated at the 5-
position with n-BuLi and quenched with CBr4 to pro-
vide the corresponding 2-butythio-5-bromooxazole
(2) (Scheme 1). The 5-bromooxazole (2) was reacted
with LDA to provide 2-butylthio-4-bromooxazole (3)
in 77% yield. However, the reactivity of 2-butylthio-
4-bromooxazole was sluggish (vide infra) and prepara-
tion of the corresponding iodide was undertaken by
replacing CBr4 above with I2. To the best of our
knowledge, this is the first report of the halogen
dance of an iodooxazole. The yield of 2-butylthio-4-
iodooxazole (5) was lower than that of the corre-
sponding bromide (41%, along with 39% of thiooxa-
zole 1). This dramatic difference in yield between bro-
mooxazole 3 and iodooxazole 5 is currently the sub-
ject of a more detailed investigation. With the desired
oxazoles in hand, we examined Suzuki–Miyaura, So-
nogashira, and Stille coupling reactions of these com-
pounds. The use of 2-butylthio-4-bromooxazole (3)
provided good yields in some cases, but the more re-
4[c]
83
72
82
5[c]
6[c]
[a]
Refer to the Supporting Information for complete exper-
imental details. The reported yields are an average of
two reactions (one mmol scale).
[b]
[c]
Reaction conducted in dioxane:water (1:1).
Reaction conducted in THF.
The cross-coupling methodology was also extended
active 2-butylthio-4-iodooxazole (5) consistently gave to the Sonogashira reaction (Table 2). The 4- and 5-
superior results. For example, the reaction of 2-bu- iodooxazoles were combined with a variety of al-
tylthio-4-bromooxazole (3) and 2-butylthio-4-iodooxa- kynes, catalytic amounts of PdCl
zole (5) with phenylboronic acid in the presence of NEt3 and acetonitrile to produce the corresponding
2.5 mol% of Pd(dba)2/DPEphos in dioxane:water pro- substituted oxazoles in good yields. Once again, the
2ACHTUNGTREN(UNNG PPh3)2 and CuI, in
ACHTUNGTRENNUNG
vided 68% and 92% yields, respectively (Table 1, en- C-4 iodooxazole required 608C, while reactions of the
tries 1 and 2). This disparity in yield may be caused C-5 iodooxazole proceeded at ambient temperature,
by the faster rate of the oxidative addition of aryl io- except for the outlying nitrile example in entry 4.
dides over aryl bromides in the presence of palladi- Again, the butylthio group did not appear to be af-
um.[13] We also observed that the C-4 iodooxazole is fected under these conditions.
less reactive than the corresponding C-5 iodooxazole,
However, the cause of the mass balance in these re-
and the former reactions were conducted at higher actions is not clear as we did not detect any apprecia-
temperatures in a more polar solvent. Various aryl- ble amounts of side-products. We have shown in
boronic acids provide the corresponding 2,4- or 2,5- Table 1 that the butylthio group is stable to palladium,
disubstituted products regardless of substitution at the and Marino has previously shown that the methylthio
aryl group. Most importantly, the butylthio group re- group is stable to copper.[14] Moreover, submission of
mained untouched, which allowed an additional cou- the butylthio product to the reaction conditions did
pling without needing to employ blocking groups.
not cause noticeable decomposition.
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Synthesis of 2,4- and 2,5-Disubstituted Oxazoles via Metal-Catalyzed Cross-Coupling Reactions
Table 2. Sonogashira reactions of disubstituted oxazoles.[a] Table 3. Stille reactions of disubstituted oxazoles.[a]
Entry
1[b]
Substrate
Product
Yield [%]
81
Entry
1[b]
Substrate
Product
Yield [%]
62
2[b]
75
2[c]
77
3[c]
63
66
[a]
Refer to the Supporting Information for complete exper-
imental details. The reported yields are an average of
two reactions (one mmol scale).
Reaction conducted at 908C.
Reaction conducted at 608C.
4[b]
[b]
[c]
5[c]
77
duced in good yields. The remaining butylthio group
at the C-2 position can now be coupled with the cor-
responding organozinc product to set the substitution
pattern seen in leiodelide A.
After successfully completing the Suzuki–Miyaura,
Songashira, and Stille coupling reactions, several of
these products were coupled at the 2-butylthio group
[a]
See Supporting Information for complete experimental
details. The reported yields are an average of two reac-
tions (one mmol scale).
Reaction conducted at 608C.
Reaction conducted at 238C.
[b]
[c]
One application of this methodology will be as a with a variety of organozinc reagents, using conditions
key step in the synthesis of the natural product leio- we described previously (Table 4). The reactions pro-
delide A (Figure 1).[15]
duced the desired 2,4- or 2,5-oxazole products in good
Leiodelide A contains a macrocyclic ring containing to high yields. More importantly, these reactions dem-
a 2,4-disubstituted oxazole. More specifically, an alkyl onstrate the modularity of employing 2-butylthio-4-
chain is at the C-2 position of the oxazole, while a tri- halooxazoles to prepare 2,4- and 2,5-disubstituted ox-
substituted olefin occupies the C-4 position. Since we azoles.
have previously coupled an alkyl group to the C-2 po-
The use of zinc bromide in Table 4, entry 2 deserves
sition of oxazole, we investigated the more challeng- comment. In our previous work, the coupling of oxa-
ing coupling of the trisubstituted olefin to the C-4 po- zoles with alkylzinc reagents required 2.5 equivalents
sition. After some experimentation, the Stille cross- of alkylzinc reagent and provided low yields of the 2-
coupling reaction (Table 3) provided the best results alkyloxazole product (~60%). During the course of
to install the olefin.[16] Using 5 mol% PdCl
2ACHTNUTRGNE(NUG MeCN)2 this research, we began a careful investigation to ac-
as catalyst with excess LiCl in DMF at elevated tem- count for the lower yields. The protonated organozinc
peratures, the C-4 and C-5 vinyloxazoles were pro- reagent was identified as a major side-product of the
reaction. In order to investigate the origin of the
proton that was quenching the organozinc reagent, 2-
methylthiooxazole was deuterated at the C-5 position
(22) and at the alkylthio position at C-2 (SCD3, 23) as
these two hydrogens are the most acidic in the sub-
strate. Submitting the monodeuterated oxazole (22)
to the standard reactions conditions did not provide
an appreciable amount of deuterated propylbenzene
(Scheme 2). However, reacting the deuterated thioox-
Figure 1. Leiodelide A.
azole (23) under the same conditions showed the pro-
Adv. Synth. Catal. 2011, 353, 79 – 83
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Carla M. Counceller et al.
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Table 4. Alkylthiooxazole couplings with organozinc rea-
ed a higher yield of product (76–84%, Scheme 2 vs.
56%[10]).
ACHTUNGTRENNUNG
gents.[a]
In summary, the metal-catalyzed cross-coupling re-
actions of 2-butylthio-4-iodooxazole and 2-butylthio-
5-iodooxazole produced the corresponding cross-cou-
pling products in good to high yields for the Suzuki–
Miyaura, Sonogashira, and Stille coupling reactions.
This work demonstrates that 2,4- and 2,5-disubstituted
oxazoles can be prepared in a modular fashion with-
out the necessity to use protecting groups. Moreover,
this research, along with our previously reported oxa-
zole chemistry, allows rapid access to the synthesis of
mono- and disubstituted oxazoles. Finally, the inclu-
sion of ZnBr2 improves the reaction yield and lowers
the amount of the stoichiometric organozinc reagent
required in coupling reactions of oxazoles.
Entry R2
Product
Yield [%]
85
1[b]
2[c]
3
BnCH2-
hexyl-
78
88
p-F-C6H4
Experimental Section
4
p-MeO-C6H4
90
General Procedure for the Cross-Coupling Reactions
of Oxazoles
[a]
Refer to the Supporting Information for complete exper-
imental details. The reported yields are an average of
two reactions (one mmol scale).
To a round-bottom flask equipped with a stir bar and a
reflux
condenser,
Pd(dba)2
(2.5 mol%),
DPEPhos
(2.5 mol%), the boronic acid (1.2 mmol), and K3PO4
(3 mmol) were added. The flask was then evacuated and
flushed with nitrogen. The oxazole (1 mmol) was then
added to the flask followed by THF (5 mL) or a 1:1 (v/v) of
dioxane (2.5 mL) and water (2.5 mL). The reaction mixture
was heated to reflux for 12 h. After this time, water was
added and the reaction was extracted with Et2O (3ꢁ20 mL),
dried over MgSO4, and concentrated under vacuum. The re-
maining crude residue was purified via flash chromatogra-
phy.
[b]
[c]
NiCl
2ACHTUNGTRENNUNG(PPh3)2 was used as catalyst.
1 equivalent of ZnBr2 was used as an additive.
duction of deuterated propylbenzene. We hypothe-
sized that zinc was coordinating to the oxazole nitro-
gen, which assisted the deprotonation of the methyl-
thio group and ultimately, the protonation of the or-
ganozinc reagent. Therefore, the addition of zinc bro-
mide should compete with the organozinc reagent
from the oxazole nitrogen and thus, the organozinc
reagent would not get protonated. Although we have
no direct evidence for this coordination event, the ad-
dition of 1 equivalent of ZnBr2 allowed a lesser
Supporting Information
Supporting information for this article including the synthe-
sis of all starting materials, reaction procedures, compound
amount of organozinc reagent (1.5 equiv.) and provid- characterization and NMR spectra is available.
Scheme 2. 2H NMR spectroscopic study of alkylzinc coupling reactions.
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Synthesis of 2,4- and 2,5-Disubstituted Oxazoles via Metal-Catalyzed Cross-Coupling Reactions
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try data.
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