Derivatization of a tris-oxazole using Pd-catalyzed coupling reactions of a 5-bromooxazole moiety

Article abstract of DOI:10.1016/j.tetlet.2010.01.064

Modification at the C5 position of an oxazole ring contained in a 2,4-concatenated tris-oxazole by Pd-catalyzed coupling reactions was performed. Novel Pd-catalyzed amination and alkoxylation of a 5-bromooxazole derivative as well as Suzuki-Miyaura coupling and Migita-Stille coupling have been demonstrated. A wide variety of functional groups, including aryl, heteroaryl, primary and secondary amines, and phenol, were introduced in the 5-bromooxazole moiety in moderate to excellent yields using Pd(OAc)₂/S-PHOS or Pd(OAc)₂/X-PHOS as a catalyst.

Full text of DOI:10.1016/j.tetlet.2010.01.064

Tetrahedron Letters 51 (2010) 1674–1677
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Derivatization of a tris-oxazole using Pd-catalyzed coupling reactions
of a 5-bromooxazole moiety
a,
Kazuaki Shibata a, Masahito Yoshida b, Takayuki Doi a,b, , Takashi Takahashi
*
*
a Department of Applied Chemistry, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro, Tokyo 152-8552, Japan
b Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Modification at the C5 position of an oxazole ring contained in a 2,4-concatenated tris-oxazole by Pd-cata-
lyzed coupling reactions was performed. Novel Pd-catalyzed amination and alkoxylation of a 5-bromoox-
azole derivative as well as Suzuki–Miyaura coupling and Migita–Stille coupling have been demonstrated.
A wide variety of functional groups, including aryl, heteroaryl, primary and secondary amines, and phenol,
were introduced in the 5-bromooxazole moiety in moderate to excellent yields using Pd(OAc)2/S-PHOS or
Pd(OAc)2/X-PHOS as a catalyst.
Received 14 December 2009
Revised 15 January 2010
Accepted 20 January 2010
Available online 25 January 2010
Keywords:
Oxazoles
Ó 2010 Elsevier Ltd. All rights reserved.
Pd-catalyzed reaction
Amination
Alkoxylation
Cross-coupling
Oxazole-containing natural products are attracting attention for
their fascinating structures and broad range of biological activity.1
Many researchers have investigated their total synthesis and that
of their derivatives.2 These natural products consist of not only a
single oxazole but also two or more oxazoles concatenated at the
2- and 4-positions3 such as in telomestatin (1),4,5 YM-216391
(2),6,7 and ulapualide A (3)8,9 (Fig. 1). Since the oxazoles in these
natural products possess a hydrogen, a methyl, or a phenyl group
at the C5 position, these substituents may affect their biological
activities. To elucidate the structure–activity relationships on the
basis of the substituents on the 2,4-concatenated oxazoles, we
need to develop an efficient synthetic method for introducing a
wide variety of functional groups at the C5 position of an oxazole
moiety.
Our strategy is therefore to introduce a 5-bromooxazole moiety
in a 2,4-concatenated tris-oxazole in advance and selectively acti-
vate the bromide by Pd-catalyzed coupling reactions in the later
stage of synthesis toward efficient diversification (Fig. 2). Herein,
we report the synthesis and Pd-catalyzed coupling reactions of
5-bromooxazole-containing tris-oxazole that corresponds to the
synthetic intermediate of the natural product telomestatin.10–12
Preparation of tris-oxazole 11 containing a 5-bromooxazole
moiety is shown in Scheme 1. Commercially available Boc–Cys(t-
Bu)–OH (4) was converted to 4-cyanooxazole 5 by the modified
Harran procedure.13 Boc protection of the carbamate with (Boc)2O,
followed by treatment with NH3/MeOH and aqueous H2O2, pro-
vided amide 6 (68%) in two steps. After conversion of 6 to tetra-
carbamate with (Boc)2O, methanolysis at the C terminus with
K2CO3/MeOH, followed by a selective removal of the Boc group
S
N
O
N
O
O
N
N
H
O
O
O
N
N
N
NH
NH
N
N
O
N
O
O
O
N
O
N
N
O
N
O
O
S
Ph
Telomestatin (1)
YM-216391 (2)
O
N
O
OAc O
OMe O
OMe
O
OH
N
N
O
N
Ulapualide A (3)
O
* Corresponding authors. Fax: +81 3 5734 2884.
E-mail addresses: doi_taka@mail.pharm.tohoku.ac.jp (T. Doi), ttak@apc.titech.
ac.jp (T. Takahashi).
O
Figure 1. Tris-oxazole-containing natural products.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.064

K. Shibata et al. / Tetrahedron Letters 51 (2010) 1674–1677
1675
O
O
N
N
Transition metal-catalyzed
cross coupling reaction
N
N
Br
R
O
O
Suzuki-Miyaura reaction
Migita-Stille reaction
Amination, Alkoxylation
N
N
O
O
R = Aryl, Alkyl,
Amino, Alkoxy group
Figure 2. Our synthetic strategy for 5-functionalized tris-oxazole derivatives by Pd-catalyzed coupling reactions.
t-BuS
Table 1
t-BuS
a)
b)
Pd-catalyzed and Cu-mediated cross-coupling reactions of 5-bromooxazole 7
N
CN
Br
OH
BocHN
t-BuS
t-BuS
BocHN
O
O
O
Conditions
O
N
N
BocHN
BocHN
OMe
OMe
4
5
O
O
Br
R
7
12
t-BuS
t-BuS
BocHN
O
O
c)
d)
Entry
R
Nucleophile
Catalyst
Additive Product Yield
(%)
N
N
BocN
Boc
NH2
OMe
O
O
1a
2b
3c
4d
5e
Ph
Me
Ph
PhSnBu3
Me4Sn
PhB(OH)2
PdCl2(CH3CN)2
POPd
PdCl2(PPh3)2
Pd(OAc)2
—
—
CuI
KF
K3PO4
CuI
12a
12b
12a
12c
12d
94
85
90
80
81
Br
Br
6
7
C8H17NH C8H17NH2
CF3 FSO2CF2CO2Me
t-BuS
BocHN
HMPA
Reagents and conditions: (a) PdCl2(CH3CN)2 (5 mol %), PhSnBu3 (1.5 equiv), DMF
(0.2 M), 80 °C, 12 h; (b) POPd (5 mol %), CuI (15 mol %), Me4Sn (1.5 equiv), DMF
(0.2 M), 80 °C, 12 h; (c) PdCl2(PPh3)2 (5 mol %), PhB(OH)2 (1.5 equiv), KF (2 equiv),
dioxane (0.2 M), 60 °C, 12 h; (d) Pd(OAc)2 (5 mol %), X-PHOS (10 mol %), C8H17NH2
(2 equiv), K3PO4 (3 equiv), DME (0.2 M), 60 °C, 24 h; (e) CuI (1.2 equiv), FSO2CF2-
CO2Me (5 equiv), HMPA (5 equiv), DMF (0.05 M), 70 °C, 12 h. POPd = PdCl2[(t-
Bu)2P(OH)]2, X-PHOS = 2-Dicyclohexylphosphino-20,40,60-triisopropylbiphenyl.
O
t-BuS
O
N
e)
Br
N
BocHN
OH
O
O
HN
OH
Br
O
N
8
O
MeO
10
Table 2
t-BuS
BocHN
Suzuki–Miyaura cross-coupling of 11 with phenyl boronic acid
t-BuS
t-BuS
O
HO
N
N
f)
O
Br
BocHN
BocHN
O
O
9 =
N
N
N
N
N
Pd cat., PhB(OH)2
Base, dioxane
OMe
H2N
Br
Ph
O
O
O
N
O
O
O
O
O
N
N
MeO
11
O
O
MeO
MeO
11
13
Scheme 1. Reagents and conditions: (a) (i) aminomalononitrile p-toluenesulfonate,
EDCI, Py., rt, 20 h, (ii) t-BuONO, CuBr2, CH3CN, 0 °C to rt, 2 h, 28% (two steps); (b) (i)
(Boc)2O, NEt3, DMAP, CH2Cl2, rt, 24 h, (ii) NH3/MeOH, aq H2O2, dioxane, rt, 2 h, 68%
(two steps); (c) (i) (Boc)2O, DMAP, CH3CN, rt, 2 h, (ii) K2CO3, THF–MeOH, rt, 3 h, (iii)
TFA (2.0 equiv), CH2Cl2, rt, 6 h, 90% (three steps); (d) Me3SnOH, (CH2Cl)2, 80 °C, 6 h,
92%; (e) 9, PyBrop, DIEA, CH2Cl2, rt, 3 h, 90%; (f) (i) Burgess reagent, THF, 70 °C, 12 h,
(ii) DBU, BrCCl3, CH2Cl2, rt, 12 h, 76% (two steps).
Entry
Pd cat.
Base
Temp (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
PdCl2(PPh3)2
Pd(Pt-Bu3)2
KF
KF
KF
KF
KF
KF
K3PO4
60
60
60
60
60
16
16
16
16
16
0.5
16
Trace
Trace
62
73
92
Pd(OAc)2, L-1
Pd(OAc)2, L-2
Pd(OAc)2, L-3
Pd(OAc)2, L-3
Pd(OAc)2, L-3
110
60
95
79
with 2 equiv of TFA, afforded the desired 5-bromooxazole 7 (90%
overall). Although hydrolysis of 7 with LiOH in THF–MeOH–H2O
gave a complex mixture, methyl ester 7 was converted to acid 8
by treatment with trimethyltin hydroxide (92%).14 Amidation of
8 with amine 9 using PyBrop/DIEA provided bis-oxazole amide
10 (90%). Finally, cyclodehydration of 10 using Burgess reagent,15
followed by a treatment with BrCCl3/DBU,16 afforded the expected
tris-oxazole 11 (76%).
In our initial attempt at modification at the C5 position of an
oxazole, we investigated various Pd-catalyzed coupling reactions
of 5-bromooxazole 7. Results are summarized in Table 1. Migita–
Stille coupling of 7 with PhSnBu3 in the presence of PdCl2(CH3CN)2
proceeded at 80 °C to give 12a in 94% (entry 1). Coupling reaction
Reagents and conditions: Pd catalyst (10 mol %) or Pd(OAc)2 (10 mol %)/ligand
(20 mol %), PhB(OH)2 (1.5 equiv), base (KF or K3PO4) (2 equiv), dioxane (0.2 M).
L-1 = 2-(Di-t-butylphosphino)-20-methylbiphenyl, L-2 = 2-(Dicyclohexylphosphino)-
20-methylbiphenyl, L-3 = 2-Dicyclohexylphosphino-20,60-dimethoxybiphenyl (S-
PHOS).
with Me4Sn in the presence of POPd17/CuI yielded 12b (85%; entry
2). Suzuki–Miyaura reaction of 7 with PhB(OH)2 in the presence of
PdCl2(PPh3)2/KF afforded the expected 12a in excellent yield (90%;
entry 3). Racemization at the
a-position of the modified cysteine
residue is suppressed (<2%) under the reaction conditions (See
Supplementary data).18

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K. Shibata et al. / Tetrahedron Letters 51 (2010) 1674–1677
Table 3
Scope of the boronic acids in Suzuki–Miyaura reaction of 11 and other Pd-catalyzed cross-coupling reactions
t-BuS
t-BuS
BocHN
BocHN
O
O
N
N
N
N
Br
R1
(i) Pd(OAc)2 (10 mol%)
S-PHOS (20 mol%)
O
O
R1 = Aryl, Alkyl
Amino, Alkoxy
O
O
N
N
(ii)−(v) Pd(OAc)2 (10 mol%)
X-PHOS (20 mol%)
O
O
MeO
R2
11
15
Product
Entry
1
Nucleophile
Conditions
i
R1
Yield (%)
91
(HO)2B
14a
14b
15a (R2 = OMe)
15b (R2 = OMe)
OMe
F
OMe
F
(HO)2B
(HO)2B
2
3
i
i
80
74
15c (R2 = OMe)
15d (R2 = OMe)
OMe
OMe
14c
14d
O
O
O
O
(HO)2B
H
H
4
i
62
(HO)2B
(HO)2B
5
6
14e
14f
i or ii
i or ii
15e (R2 = OMe)
15f (R2 = OMe)
i: 53 ii: 84
i:30 ii:91
OH
OH
S
S
(HO)2B
(HO)2B
7
8
14g
14h
ii
ii
15g (R2 = OMe)
15h (R2 = OMe)
63
68
N
N
N
N
O
O
Bu3Sn
9
10
11
14i
14j
14k
iii
iv
iv
15i (R2 = OMe)
16j (R2 = NHC8H17
15k (R2 = OMe)
70
70
65
TMS
TMS
H2N
HN
6
N
)
6
H
N
O
O
HN
HO
N
O
12
13
141
iv
v
151 (R2 = OMe)
15m (R2 = OMe)
69
43
14m
OMe
OMe
Reagents and conditions: (i) KF (2 equiv), dioxane (0.2 M), 110 °C (MW), 0.5 h; (ii) KF (2 equiv), DME (0.2 M), 80 °C, 16 h; (iii) dioxane (0.2 M), 60 °C, 16 h; (iv) K3PO4 (3 equiv),
DME (0.2 M), 80 °C, 24 h; (v) K3PO4 (2 equiv), dioxane (0.2 M), 80 °C, 16 h; nucleophile was used as 1.5 equiv (entries 1–9, and 13), 4 equiv (entry 10) and 2 equiv (entries 11
and 12).
Furthermore, we introduced an amino group at the C5 position
of the oxazole by Pd-catalyzed amination.19 Amination of 7 with
octylamine in the presence of Pd(OAc)2/X-PHOS at 60 °C provided
the desired 5-(octylamino)oxazole 12c (80%; entry 4). The methyl
we also examined trifluoromethylation. Cu(I)-mediated nucleo-
philic substitution of 7 with FSO2CF2CO2Me provided 5-(trifluoro-
methyl)oxazole 12d (81%; entry 5).21
According to the above result (Table 1, entry 3), we investigated
the Suzuki–Miyaura coupling reaction of tris-oxazole 11 with
PhB(OH)2. Results are summarized in Table 2. Reaction in the pres-
ence of PdCl2(PPh3)2/KF (entry 1) did not proceed; nor did reaction
in the presence of Pd(Pt-Bu3)2 (entry 2). In view of the difficulty of
ester remains intact and racemization at the
a-position of the
modified cysteine residue is suppressed (<3%) under the reaction
conditions.18 Fluorinated small molecules are attractive com-
pounds for medicinal chemistry and drug discovery.20 Therefore,

K. Shibata et al. / Tetrahedron Letters 51 (2010) 1674–1677
1677
oxidative addition of 11 onto Pd(0) catalyst, we used more elec-
References and notes
tron-rich ligands in this cross-coupling reaction because Buchwald
and co-workers have reported that biaryl monophosphine ligands
are highly effective for Suzuki–Miyaura reaction of heteroaryl ha-
lides with aryl boronic acids; reaction using Pd(OAc)2/Buchwald
monophosphine ligands (L-1, L-2, and L-3 in the Table)22 pro-
ceeded to yield the desired 13 (entries 3–7). In particular, the use
of L-3 (S-PHOS) yielded 13 in 92% yield (entry 5). After further opti-
mization, cross-coupling reaction was completed within 30 min
under microwave irradiation to yield 13 (95%; entry 6).
With optimized reaction conditions for Suzuki–Miyaura reac-
tion of 11 in hand, we next examined a range of boronic acids
and other cross-coupling reactions such as ethynylation, amina-
tion, and alkoxylation. Results are summarized in Table 3. p-Substi-
tuted aryl boronic acids 14a–d yielded the corresponding products
15a–d (62–91%; entries 1–4). p-Hydroxyphenyl derivative 14e re-
acted incompletely (53%) even under microwave irradiation (entry
5). However, reaction in the presence of Pd(OAc)2/X-PHOS/KF un-
der conventional heating (80 °C, 16 h) was completed to yield
15e (84%). When p-formylphenyl boronic acid 14d was used for
the coupling reaction, a small amount of debrominated product
15n (R1 = H, R2 = OMe) was observed (<5%). Turning from micro-
wave irradiation to conventional heating (DME, 80 °C, 16 h) in
the presence of Pd(OAc)2/X-PHOS provided the desired coupling
products 15f–h in acceptable yields (entries 6–8). Ethynylation of
11 by Migita–Stille coupling (entry 9) proceeded at 60 °C in the
presence of Pd(OAc)2/X-PHOS to yield 15i (70%).
Amination of 11 with primary and secondary amines (entries
10–12) using K3PO4 at 80 °C afforded the corresponding coupling
products 16j, 15k, and 15l (65–70%). In entry 10, 16j was obtained
as a sole product formed by transamidation of the methyl ester
with the less-hindered primary amine 14j. In alkoxylation of 11,
coupling reaction of phenol 14m with K3PO4 in the presence of
Pd(OAc)2/X-PHOS provided the expected 15m (43%; entry 13). In
this reaction, b-elimination of the St-Bu group was observed.23
In summary, we have demonstrated the modification of the C5
position of an oxazole ring contained in a 2,4-concatenated tris-oxa-
zole derivative by means of Pd-catalyzed cross-coupling reactions.
Novel Pd-catalyzed amination and alkoxylation of 5-bromooxazole
as well as Suzuki-Miyaura coupling have been achieved. In the pres-
ence of Pd(OAc)2/S-PHOS or Pd(OAc)2/X-PHOS, a wide variety of
functional groups, such as aryl, heteroaryl, primary and secondary
amines, and phenol, were introduced in the 5-bromooxazole moiety
in moderate to excellent yields. These modifications could be ap-
plied to diversification of natural products containing a 2,4-concat-
enated tris-oxazole. The synthesis of telomestatin derivatives
utilizing this method is underway in our laboratory.
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Acknowledgments
This work was supported by the New Energy and Industrial
Technology Development Organization. We also thank the partial
support by the Global COE Program (Chemistry, TokyoTech).
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Supplementary data
23. b-Elimination of the St-Bu group was also observed in the total synthesis of
telomestatin. Cs2CO3 promoted b-elimination in the construction of oxazoline.
See Ref. 5.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.01.064.