An efficient preparation of 2-alkyl-oxazoles from 2-iodooxazoles

Article abstract of DOI:10.1016/j.tetlet.2013.05.088

An efficient synthesis toward 2-alkyl substituted oxazoles has been achieved through Suzuki cross-coupling reaction. Treatment of various alkyl iodides with 9-MeO-BBN, followed by in situ palladium-catalyzed carbon-carbon formation with 2-iodooxazoles obt

Full text of DOI:10.1016/j.tetlet.2013.05.088

Tetrahedron Letters 54 (2013) 4045–4048
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An efficient preparation of 2-alkyl-oxazoles from 2-iodooxazoles
Xing Zhang a,b, Jun Liu a, Yi Liu b, Yuguo Du a,b,
⇑
a State Key Laboratory of Environmental Chemistry and Eco-toxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
b School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis toward 2-alkyl substituted oxazoles has been achieved through Suzuki cross-cou-
pling reaction. Treatment of various alkyl iodides with 9-MeO-BBN, followed by in situ palladium-cata-
lyzed carbon–carbon formation with 2-iodooxazoles obtained the 2-alkyl substituted oxazoles in good to
excellent yields. Regioselective C2-alkylation on 2,4-di-iodooxazole under the same reaction conditions
was firstly disclosed.
Received 25 March 2013
Revised 15 May 2013
Accepted 20 May 2013
Available online 24 May 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Iodooxazole
2-Alkyl oxazoles
Suzuki reaction
Regioselective alkylation
Oxazoles are widely distributed in natural products, and many
of them possess significant biological activities including anti-
fungal, cytotoxic, and anthelmintic properties.1 Oxazoles have also
been utilized as important building blocks in organic syntheses and
drug developments.2,3 The potent biological activity and the prev-
alence of oxazoles in natural products and drug candidates have
stimulated intensive interests in the synthesis of these heterocy-
cles.2b,2d–g
As an important structural motif, 2-alkyl substituted oxazole
ring has been found in many oxazole-containing natural products,
including the phenoxan,1g noricumazoles,4 hennoxazoles,1f and lei-
odolides A & B.1d Conventional synthesis of 2-alkyl oxazoles was
conducted in multistep reaction,2f,5 and to the best of our knowl-
edge, direct alkylation at the C2 position is challenging and has
very limited success to date.6 Due to the structural significance
in drug development, it has a strong demanding to explore new
synthetic methodologies to access this highly functionalized het-
erocycles in a straightforward and efficient way. Herein, we wish
to report our result for the synthesis of 2-alkyl-oxazole via Suzu-
ki–Miyaura cross-coupling reaction between 2-iodooxazoles and
alkylboronates.
required a method for the facile assembly of this densely function-
alized 2-alkyl-substitution oxazole derivative, exemption from
multistep construction of the oxazole ring.
The exploration started from a direct alkylation on oxazole C-2
position through C-2 lithiation and a subsequent quenching with
an electrophile, using ethyl oxazole-4-carboxylate (3) and iodo-
methane (4) as the testing system. Treatment of 3 with lithium
base (LiHMDS or t-BuLi) in anhydrous THF, with or without 1,3-di-
methyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), resulted
in the recovery of major starting materials. In order to exclude
the electron-withdrawing effect of carboxylate at C4-position,
TBS group protected substrate 4-(tert-butyl-dimethylsilyl-
oxy)methyloxazole (5) was applied, unfortunately, no desired
product was observed. Attempted C-2 alkylation on oxazole
through lithium-halogen exchange for ethyl 2-iodooxazole-4-car-
boxylate (6)8 in the presence of lithium reagent and 4 also failed
to generate the desired 2-methyl oxazole-4-carboxylate. It seems
that trapping 2-lithiooxazole with 4 was more difficult than we ex-
pected due to the mobile equilibrium9 between oxazole anion 7a
and a-isocyano enolate 7b (Scheme 1).
We then turned our attention to the palladium-catalyzed B-al-
kyl Suzuki–Miyaura cross-coupling, as shown in Table 1.10 Initial
studies were focused on the screening of a suitable coupling condi-
tion between 1-iodobutane (8a) and oxazolyl substrate 6. Several
common palladium catalyst precursors, such as Pd(PPh3)4,
Pd(PPh3)2Cl2, and Pd(dba)2 were tested, and did not give encourag-
ing results under the standard Suzuki coupling conditions (entries
1–3). Fortunately, we found that Pd(OAc)2 in the presence of AsPh3
and K3PO4 provided the desired product 9a in 37% yield (entry 6).
Inspired by this finding, we next investigated other coupling
reagents and conditions, and were pleased to find that Pd(dppf)Cl2
In our efforts toward the total synthesis of leiodolides (Fig. 1),
showing potential cytotoxicity against HCT-116 human colon car-
cinoma cells,1d we have recently reported the stereoselective syn-
thesis of the C22–C31 fragment of leiodolide A employing a
diastereoselective Seebach alkylation and
a Brown’s P2-Ni
catalyzed cis-alkyne semihydrogenation in the presence of a vinyl
iodide.7 To build fragments C1–C17 of leiodolide A, we eagerly
⇑
Corresponding author. Tel./fax: +86 10 62849126.
E-mail address: duyuguo@rcees.ac.cn (Y. Du).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.088

4046
X. Zhang et al. / Tetrahedron Letters 54 (2013) 4045–4048
20
Me
Me
30
HO
Me
O
15
Me
13
O
O
11
17
OMe
OMe
28
O
O
HO
Me
HO
Me
22
N
N
O
O
Br
9
O
O
OH
OH
7
1
4
Me
Me
19
OH
OH
18
Me
Me
Leiodolide B, (2)
Leiodolide A , (1)
Figure 1. Structures of leiodolides A and B.
Me
N
R1
N
(Table 2). Coupling of 6 with alkyl iodides, with or without
branched chain structures, afforded the products in good to excel-
lent yields (entries 1–6) under the above optimized reaction condi-
4
CH3I ( )
O
O
lithium reagent
R2
R2
tions. Previously failed coupling reaction between
6 and
iodomethane through lithium-halogen exchange was also achieved
in moderate yield (61%, entry 3). More importantly, the valuable
building block 8f11 in our synthesis of leiodolide A also accom-
plished the corresponding alkyl oxazole 9f in 92% yield (entry 6).
However, reaction of the alkyl or benzyl bromide (entries 7–8),
as well as the secondary iodide (entry 9), with oxazole 6 was
proved to be inefficient under current conditions.12 The same pro-
cedure performed on other functionalized iodooxazole substrates,
such as oxazolyl compound 10, also furnished good results sug-
gesting a wide substrate adaptability of this method (entry10).
Recently, Strotman et al.13 reported a direct arylation on di-
substituted 2,4-di-iodo-oxazole (11) to prepare bis- and tris-oxa-
zole molecules and demonstrated the possibility of catalyst-con-
trolled regioselective Suzuki couplings at 2- or 4-position of 11.
Inspired by their elegant pioneer work, we studied the alkylation
of 11 with different alkyl iodides under our conditions. We were
pleased to find that the cross-coupling reaction was carried out
smoothly affording 2-alkyl-4-iodooxazole as the only coupling
product in good yields (entries 11–14). Confirmation of this selec-
tivity was exemplified by lithiation of 4-iodooxazole 9j with n-
BuLi, and quenching with H2O to obtain the known compound 2-
butyloxazole.14 To the best of our knowledge, there is no literature
precedent about the regioselective 2-alkylation on 2,4-di-iodo-
oxazole. This result implies that the current method is applicable
to the synthesis of differentially substituted 2,4-di-alkyl-oxazoles,
3 R1 = H, R2 = COOEt
5 R1 = H, R2 = CH2OTBS
6 R1 = I, R2 = COOEt
Li
N
2
O
OLi
Lithium reagent
N
O
N
H
5
H
4
H
H
H
7b
H
7a
Scheme 1. Attempted C-2 alkylation on oxazole using lithium reagents.
could generate the desired product 9a in 75% yield (entry 7). Thus
an optimized coupling reaction was established as follows: To a
solution of alkyl iodide (1.3 equiv) and 9-methoxy-BBN
(3.42 equiv) in Et2O (1 mL) at À78 °C was added t-BuLi (3.0 equiv)
rapidly. After 5 min, THF (1 mL) was added. The solution was stir-
red for 30 min at À78 °C and then allowed to warm to room tem-
perature over 1 h. In a separate flask, 2-iodooxazole (0.094 mmol,
1.0 equiv) was taken up in 1 mL of DMF to which Pd(dppf)Cl2
(10%,), AsPh3(15%), Cs2CO3(4.0 equiv), and H2O (24.0 equiv) were
added sequentially. Then the ethereal solution of alkyl boronate
was transferred into the DMF solution, and the resulting mixture
was stirred for 12 h (entry 9).
We also investigated the scope and limitation of this reaction by
treatment of various alkyl halides with iodooxazole derivatives
Table 1
Optimization for one-pot B-alkyl Suzuki cross-coupling
n-C4H9
n-C4H9
O
6
t-BuLi, 9-MeO-BBN
N
n-C3H7CH2-I
8a
B
MeO
Et2O, THF
B-Alkyl Suzuki Coupling
Li
O
OEt
9a
Entry
Reagent sources and solventa
T (°C)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
Pd(PPh3)2Cl2, K3PO4, H2O, DMF
Pd(PPh3)4, NaOH, H2O, THF
rt to reflux
12
24
24
24
12
12
12
12
12
Trace
NDc
ND
ND
5
37
75
85
91
rt
rt
rt
rt
rt
rt
rt
rt
Pd(dba)2, AsPh3, Cs2CO3, H2O, DMF
Pd(OAc)2, AsPh3, Cs2CO3, H2O, DMF
Pd(dppf)Cl2, K3PO4, H2O, DMF
Pd(OAc)2, AsPh3, K3PO4, H2O, DMF
Pd(dppf)Cl2 (5%), AsPh3, Cs2CO3, H2O, DMF
Pd(dppf)Cl2, AsPh3, K3PO4, H2O, DMF
Pd(dppf)Cl2, AsPh3, Cs2CO3, H2O, DMF
a
Unless otherwise noted, 2-iodooxazole (0.094 mmol, 1.0 equiv), n-C3H7CH2-I (1.3 equiv), t-BuLi (3.0 equiv), 9-methoxy-BBN (3.42 equiv), Et2O (1 mL), DMF (1 mL), the
palladium catalyst precursors (10%), AsPh3 (15%), Cs2CO3 (4.0 equiv), K3PO4 (3.0 equiv), NaOH (4.0 equiv), and H2O (24.0 equiv) were used.
b
Isolated yield.
No desired product.
c

X. Zhang et al. / Tetrahedron Letters 54 (2013) 4045–4048
4047
Table 2
Pd-catalyzed B-alkyl Suzuki cross-coupling of iodooxazoles with halidesa
I
O
R1
N
R1
O
R2
N
t-BuLi, 9-MeO-BBN
Li
R1CH2-X
B
MeO
Et2O, THF
B-Alkyl Suzuki Coupling
R2
X = Br, I
8
9
Entry
1
Iodooxazole
Alkyl halide
Product
Yieldb (%)
I
O
n-C3H7CH2-I (8a)
9a6c
91
N
EtO2C
6
2
3
6
6
n-C6H13CH2-I (8b)
MeI (8c)
9b
89
61
9c6c
Me
I
4
5
6
6
9d
9e
83
91
Me
(8d)
TBDPSO
I
3
(
)
8e
Me
6
6
9f
92
I
Me
Me
(8f)
7
8
6
6
PhCH2-Br (8g)
n-C3H7CH2-Br (8h)
9g6c
9a
7
Trace
I
9
6
9h
NDc
Me
Me
(8i)
I
O
N
10
n-C3H7CH2-I (8a)
9i
79
Me
10
HO
I
O
N
11
n-C3H7CH2-I (8a)
n-C6H13CH2-I (8b)
9j
76d
I
11
12
13
11
9k
9l
73d
71d
Me
I
11
Me
Me
(8d)
14
11
9m
76d
I
Me
Me
(8f)
a
Unless otherwise noted, the Pd(dppf)Cl2 (10%), AsPh3 (15%), Cs2CO3 (4.0 equiv), and H2O (24.0 equiv) were used, then the alkyl boronate solution was added and stirred
for 12 h at room temperature.
b
Isolated yield.
No desired product.
No 2,4-disubstituted or 4-substituted product was observed.
c
d
and is a good complement to the existing methods for oxazole
syntheses.
and application of this methodology to the total synthesis of lei-
odolides are currently underway in our group.
In conclusion, we have developed an efficient method toward
2-alkyl substituted oxazoles through alkylborane mediated
Suzuki cross-coupling in good to excellent yields. The first
example of palladium-catalyzed regioselective alkylation on
2,4-diiodooxazole is also disclosed. This method could provide
a new facile synthetic approach toward 2,4-disubstituted oxaz-
olyl natural product synthesis. Expansion of the protocol scope
Acknowledgments
This work was supported by the MOST of China (Projects
2012ZX09502001-001 and 2012CB822101) and NNSF of China
(Projects 21072217 and 21202193).

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X. Zhang et al. / Tetrahedron Letters 54 (2013) 4045–4048
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