DMAP-catalyzed regel-type direct C-2 (Hetero)aroylation of oxazoles and thiazoles derivatives with acid chlorides

Article abstract of DOI:10.1055/s-0033-1339858

A Regel-type transition-metal-free direct C-2 aroylation of (benzo)oxazoles, (benzo)thiazoles and 1,3,4-oxadiazoles with acid chlorides catalyzed by N,N-dimethyl-4-aminopyridine (DMAP) is described. This methodology is effective with several aroyl and het

Full text of DOI:10.1055/s-0033-1339858

LETTER
▌2233
lDettMer AP-Catalyzed Regel-Type Direct C-2 (Hetero)Aroylation of Oxazoles and
Thiazoles Derivatives with Acid Chlorides
Direct C-2 (Hetero)Aroylation of Azoles with Acid Chlorides
Pierrik Lassalas, Francis Marsais, Christophe Hoarau*
Normandie Université, COBRA, UMR 6014 et FR 3038, Université de Rouen, INSA de Rouen, CNRS, 1 rue Tesnière,
76821 Mont-Saint-Aignan Cedex, France
Fax +33(235)522962; E-mail: christophe.hoarau@insa-rouen.fr
Received: 18.07.2013; Accepted after revision: 27.08.2013
8
b
displayed a poor to modest reactivity (Scheme 1). In this
letter, we reinvestigate Regel’s base-mediated electro-
philic aroylation methodology and we demonstrate that
the use of DMAP as catalyst may dramatically improve
Abstract: A Regel-type transition-metal-free direct C-2 aroylation
of (benzo)oxazoles, (benzo)thiazoles and 1,3,4-oxadiazoles with
acid chlorides catalyzed by N,N-dimethyl-4-aminopyridine
(
DMAP) is described. This methodology is effective with several
aroyl and heteroaroyl chlorides affording the corresponding 2-keto- the effectiveness of the initial procedure on a broad panel
azoles in moderate to excellent yields.
of 1,3-diazoles (Scheme 1).
Key words: acylation, azoles, C–H functionalization, heterocycles,
metal-free, regioselectivity
O
O
Ar
Ar
Cl
N
X
N+
Cl–
N
X
O
(1–2 equiv)
Y
Y
Y
1
,3-Diazoles are common features of a wide range of bio-
1
Et3N (1–3 equiv)
MeCN, 15–24 h
X
Ar
logically active natural products and drugs. Among the
diverse synthetic strategies to prepare substituted 1,3-dia-
zoles, efficient methods for direct C-2 substitution have
Y = CH, N; X = O, S
7 examples (5–68%)
• without co-catalyst (Regel's work)
with DMAP (30 mol%) (this work)
2
attracted much interests. The commonly employed meth-
•
31 examples (52–97%)
odology for C-2 acylation, including aroylation, consists
in preparing 2-metallated 1,3-diazoles intermediates,
which are either condensed or engaged in cross-coupling
reactions with acyl chlorides or Weinreb’s amides.2 The
Scheme 1 Former and new Regel-type direct aroylation of 1,3-dia-
zoles with aroyl chlorides
,3
current development of transition-metal-catalyzed C–H As first set of experiments, benzothiazole (1a) was al-
functionalization reactions, which avoid the prior prepara- lowed to react with one equivalent of benzoyl chloride in
4
tion of heteroaryl metals, has also drawn much attention. acetonitrile using a stoichiometric amount of triethyl-
8b
In this context, Beller recently improved the palladium- amine, strictly following Regel’s protocol. The expected
catalyzed C–H arylation methodologies of 1,3-diazoles 2-benzoylbenzothiazole (2a) was isolated in a low 25%
with halides to propose a novel carbonylative coupling yield (Table 1, entry 1). The production of 2a was then
process, by use of carbon monoxide as carbonylative significantly improved to 63% yield when two equiva-
5
agent. Metal-free processes present a more valuable and lents of benzoyl chloride were employed, along with in-
challenging alternative, and thus spark considerable inter- creasing the amount of triethylamine (3 equiv) as well as
6
est. Notably, Wu recently disclosed a direct ring-opening the reaction temperature (Table 1, entries 2 and 3). There-
7
aroylation of benzothiazole with aryl ketones. Paradoxi- fore, a longer time of reaction (72 h) did not improve the
cally, the most famous metal-free strategy of selective C- conversion of starting material 1a, which remains the
2
aroylation of 1,3-diazoles was reported by Regel and main limitation of the yield (Table 1, entry 3). Surprising-
8
Büchel thirty years ago. Hence they highlighted that the ly, stronger bases such as Hünig’s base or DBU, which are
treatment of 1,3-diazoles with acyl chlorides in the pres- expected to facilitate the formation of the ylide, could not
ence of a smooth base did not undergo the expected elec- achieve the direct aroylation of 1a (Table 1, entries 5 and
trophilic aromatic acylation at the most nucleophilic site. 6). We then focused directly on various means to improve
In fact, a more valuable base-mediated electrophilic sub- the reactivity of the aroyl chloride. Pleasingly, one of the
stitution takes place at the most acidic C-2 site, involving most available activating agents (DMAP) immediately
the formation of a 1,3-diazolium ylide rapidly trapped proved to be efficient, affording 2a in a good 82% yield
with acyl chlorides. Although this methodology proved to (Table 1, entry 7). The best performance was observed in
be highly efficient for the C-2 aroylation of imidazole de- the presence of 30 mol% of DMAP catalyst and two
8
a
rivatives, less electron-rich 1,3-diazole such as (ben- equivalents of benzoyl chloride in acetonitrile. Indeed, all
zo)oxazoles, (benzo)thiazoles and 1,3,4-oxadiazoles have direct benzoylations of 1a conducted in optimal condi-
tions using less or more polar solvents, such as 1,4-diox-
ane, 1,2-DCE and DMF, respectively, afforded 2a in
lower yields (Table 1, entries 9–11). At this stage, two
other acylating agents were evaluated, benzoic anhydride
and benzyl chloroformate. Nevertheless, both reactions
SYNLETT 2013, 24, 2233–2240
Advanced online publication: 23.09.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339858; Art ID: ST-2013-B0670-L
Georg Thieme Verlag Stuttgart · New York
©

2
234
P. Lassalas et al.
LETTER
Table 1 Study of Direct Aroylation of Benzothiazole 1aa
yield (Table 2, entry 6). Furthermore, a broad panel of ar-
oyl chlorides bearing either electron-donating or electron-
withdrawing groups were successfully coupled (Table 2,
entries 5–10), with a poor influence of the electronic ef-
fect. The results are even sometimes slightly better than
those obtained with benzothiazole analogue (Table 2, en-
tries 7–9).
PhCOCl (2 equiv)
base (3 equiv)
N
S
N
S
O
additive, solvent
Ph
80 °C, 24 h
1a
2a
Entry Solvent
Base
Additive (%)
Yield (%) of 2ab
Encouraged by this first success, the direct aroylation pro-
cedure was then evaluated on less electron-rich 1,3-di-
azoles.
1
2
3
4
5
6
7
8
9
0
1
2
3
MeCN
MeCN
MeCN
Et N
–
25c
3
Et N
–
48d
3
Et N
–
63 (64)e
Table 2 Scope of the Direct C-2 Aroylation of Benzoxazole and
3
Benzothiazole with Various Aroyl Chloridea
Et N
–
–
59 (63)e
3
Et3N (3 equiv)
O
N
X
O
25e
N
X
DMAP (30 mol%)
MeCN
MeCN
MeCN
MeCN
1,4-dioxane
1,2-DCE
DMF
DIPEA
DBU
–
+
Cl
MeCN (0.5 M)
–
n.r.
Het
80 °C, 24 h
Het
1a
X = S
X = O
2
3
X = S
X = O
Et N
DMAP (30)
DMAP (10)
DMAP (30)
DMAP (30)
DMAP (30)
DMAP (30)
DMAP (30)
82 (54)f
75
1b
(2 equiv)
3
Et N
Yield (%)b
3
Entry Product
X
R
Et N
48
3
N
S
O
1
1
1
Et N
70
1
2
3
4
CH OMe
CH CN
CH Cl
2b 64
2c 66
2d 65
3
Et N
68
3
n.r.g
X
N
Cl
2e
58
MeCN
MeCN
Et N
3
R
1
Et N
n.r.h
3
N
S
O
a
Unless otherwise specified, reactions were carried out at 0.5 M on 1-
5
–
Cl
2f
76
mmol scale. 1,2-DCE = 1,2-dichloroethane; DIPEA = diisopropyle-
thylamine; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; DMAP =
N,N-dimethyl-4-aminopyridine.
Yield based on isolated product after flash chromatography; n.r. =
no reaction.
Benzothiazole (1 equiv), benzoyl chloride (1 equiv), Et N (1 equiv)
in MeCN at r.t. for 15 h.
Benzothiazole (1 equiv), benzoyl chloride (1.2 equiv), Et N (2
R
b
N
O
O
c
6
7
8
H
OMe
Cl
3a
3b 83
3c 72
66
3
–
d
3
equiv) in MeCN at r.t. for 15 h.
R
e
Reaction time was extended to 72 h.
Amount of benzoyl chloride used: 1.2 equiv.
Benzoic anhydride (2 equiv) was employed as the coupling partner.
Benzyl chloroformate (2 equiv) was employed as the coupling part-
N
O
O
O
f
g
h
9
–
–
Cl
3d 77
R
ner.
N
O
R
failed and starting material 1a was completely recovered
1
0
OMe
3e
56
(
Table 1, entries 12 and 13).
With the optimal conditions in hands (Table 1, entry 7),
the scope of the direct aroylation of benzothiazole 1a with
several acid chlorides was first investigated. The results
are summarized in Table 2. Aroyl chlorides bearing either
electron-donating or electron-withdrawing groups, such
as highly valuable chlorine, cyano and methoxy groups,
were suitable electrophiles, providing the expected aro-
ylated benzothiazoles 2b–d and 2f in fair yields (Table 2,
entries 1–3, and 5). Heteroaroylation of 1a was also suc-
cessfully achieved through the production of nicotinoyl-
benzoxazole 2e in 58% yield (Table 2, entry 4).
Interestingly, the protocol remains highly efficient for the
benzoylation of the less electron-rich benzoxazole, yield-
ing the desired 2-benzoylbenzoxazole 3a in a modest 66%
a
Reaction conditions: azole (1 mmol), aroyl chloride (2 equiv), Et N
3 equiv), DMAP (30 mol%) in MeCN (2 mL), 80 °C, 24 h.
Yield based on isolated product after flash chromatography.
3
(
b
We first engaged unsubstituted thiazole (4a) and oxazole
4b) in the aroylation reaction under optimized condi-
(
tions. The results depicted in Table 3 clearly showed that
both substrates were excellent candidates for aroylation
under this newly developed procedure, using either ben-
zoyl chloride (Table 3, entries 1 and 5) or variously sub-
stituted aroyl chlorides (Table 3, entries 2, 3, 6 and 8).
According to the electrophilic substitution mechanism
initially proposed by Regel, all conducted aroylations of
Synlett 2013, 24, 2233–2240
© Georg Thieme Verlag Stuttgart · New York

LETTER
Direct C-2 (Hetero)Aroylation of Azoles with Acid Chlorides
2235
4
a and 4b occurred selectively at the most acidic C-2 po- We first observed that 5-aryloxazoles 4c–4f, including
9
sition, without any influence of the aromatic substitution. models bearing highly electron-donating and electron-
The procedure remains also effective for the C-2 heteroar- withdrawing groups, displayed a remarkable reactivity
oylation of 4a and 4b with 6-chloronicotinoyl chloride and the expected 2-benzoylated 5-aryloxazoles 7a–10a
and 2-furanoyl chloride, leading to the corresponding di- were isolated in excellent yields (Table 4, entries 1–4). In
heteroaryl ketones 5d, 6c and 6e in good yields (Table 3, addition, this protocol successfully achieved the benzo-
entries 4, 7 and 9). The bisoxazol-2-yl ketone (6f) was fi-
Table 4 Direct Benzoylation of Azoles under Standard Conditionsa
nally prepared in a modest 59% yield (Table 3, entry 10),
in a ‘single flask’ procedure starting from commercially
available oxazole 5-carboxylic acid (see experimental part
for details). This diheteroaryl ketone constitutes, in partic-
ular, a precursor to the main heterocyclic core of
Et N (3 equiv)
DMAP (30 mol%)
R1
3
R1
O
N
X
N
X
O
Y
Y
+
Cl
Ph
MeCN (0.5 M)
R2
R2
X = O, S
Y = N, CH
c–4l
Ph
80 °C, 24 h
(2 equiv)
7
a–16a
1
0
bengazoles.
4
Table 3 Scope of the Direct C-2 Aroylation of Oxazole and Thia-
zole
Entry SMb Product
Yield (%)c
89
a
Et3N (3 equiv)
O
N
N
X
DMAP (30 mol%)
N
X
O
O
+
1
4c
7a
Cl
O
MeCN (0.5 M)
Het
2 equiv)
Ph
80 °C, 24 h
Het
4
4
a
b
X = S
X = O
5
6
X = S
X = O
(
N
O
2
3
4
4d
4e
4f
8a
9a
90
80
96
O
Entry Product
X
R
H
Yield (%)b
O2N
Ph
N
O
O
O
1
2
N
N
–
–
5a
93
90
O
OMe
Ph
5
b
MeO
S
S
R
N
O
10a
11a
O
R
Me2N
Ph
3
4
–
–
Cl
5c
69
88
O
O
O
t-BuO
N
O
5
4g
53
N
N
–
5d
6a
S
Ph
S
O
N
O
O
6
7
4h
4i
12a
13a
79
76
O
5
6
7
CH
CH
N
H
92
90
92
EtO
Ph
OMe 6b
Cl
O
6c
N
S
O
X
R
R
O
O
Ph
N
N
O
8
–
Cl
6d
97
EtO
O
O
N
O
8
9
4j
14a
52
O
Ph
O
6
e
9
1
CH
N
83
59
MeO
0
X
6f
O
TBSO
N
N
a
Reaction conditions: azole (1 mmol), aroyl chloride (2 equiv), Et N
3
4k
4l
15a
16a
54
80
(
3 equiv), DMAP (30 mol%) in MeCN (2 mL), 80 °C, 24 h.
Yield based on isolated product after flash chromatography.
O
b
Ph
N
O
To conclude the scope evaluation of the direct aroylation 10
procedure in 1,3-diazoles series, several substituted 1,3-
O
Ph
diazoles were evaluated, including the deactivated 4- and
a
Reaction conditions: azole (1 mmol), benzoyl chloride (2 equiv),
5
-oxa(thia)zolecarboxylates and the even more challeng-
Et N (3 equiv), DMAP (30 mol%) in MeCN (2 mL), 80 °C, 24 h.
3
ing 2-phenyl-1,3,4-oxadiazole.
b
c
SM = Starting material.
Yield based on isolated product after flash chromatography.
©
Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2233–2240

2
236
P. Lassalas et al.
LETTER
ylation of thiazole-4-carboxylate (4g), oxazole-5-carbox- CDCl
): δ = 8.65 (app d, J = 9.0 Hz, 2 H), 8.21–8.24 (m, 1 H), 7.98–
3
8
3
1
1
4
.02 (m, 1 H), 7.49–7.60 (m, 2 H), 7.04 (app d, J = 9.0 Hz, 2 H),
ylate (4h) and 4,5-dimethylthiazole (4i) in fair to high
yields (Table 4, entries 5–7). However, an exception to
this excellent reactivity was noticed when the reaction
was carried out with ethyl oxazole-4-carboxylate, which
1
3
.91 (s, 3 H). C NMR (75 MHz, CDCl ): δ = 183.5 (C), 168.0 (C),
64.5 (C), 154.0 (C), 137.0 (C), 134.0 (CH), 127.9 (C), 127.5 (CH),
26.9 (CH), 125.6 (CH), 122.2 (CH), 114.0 (CH), 55.7 (Me).
3
12
-(Benzothiazole-2-carbonyl)benzonitrile (2c): Prepared ac-
led only to an inseparable mixture of benzoylated product cording to the general procedure, using benzothiazole (110 μL, 1
and benzoic anhydride in a poor yield. Interestingly, this mmol), 4-cyanobenzoyl chloride (331 mg, 2 mmol), Et N (420 μL,
equiv) and DMAP (37 mg, 30 mol%) in MeCN (2 mL). Purifica-
3
3
modest reactivity could be restored by increasing the elec-
tron-richness of the oxazole ring. Thus, introducing a 4-
methoxyphenyl group on position C-5 or reducing the es-
ter function to a less electron-withdrawing silylated meth-
tion by flash column chromatography (PE–EtOAc, 8:2) afforded 2c
1
as a colorless solid (174 mg, 66%). H NMR (300 MHz, CDCl ): δ
3
=
1
8.67 (app d, J = 8.7 Hz, 2 H), 8.23–8.26 (m, 1 H), 8.02–8.05 (m,
H), 7.86 (app d, J = 8.7 Hz, 2 H), 7.56–7.65 (m, 2 H). 1 C NMR
3
yl alcohol group, resulted in a clean formation of (75 MHz, CDCl ): δ = 184.1 (C), 166.1 (C), 153.9 (C), 138.3 (C),
3
1
37.3 (C), 132.3 (CH), 131.7 (CH), 128.3 (CH), 127.4 (CH), 126.0
benzoylated products 14a and 15a in 52% and 54% yield,
respectively (Table 4, entries 8 and 9). The much better
performance of this novel DMAP-catalyzed aroylation
methodology against the initial Regel’s procedure was fi-
(
CH), 122.4 (CH), 118.2 (C), 117.0 (C).
1
1
Benzothiazol-2-yl-(4-chlorophenyl)methanone (2d): Prepared
according to the general procedure, using benzothiazole (110 μL, 1
mmol), 4-chlorobenzoyl chloride (256 μL, 2 mmol), Et N (420 μL,
3
nally evidenced through the successful benzoylation of 3 equiv) and DMAP (37 mg, 30 mol%) in MeCN (2 mL). Purifica-
the highly deactivated 2-phenyl-1,3,4-oxadiazole (4l), af- tion by flash column chromatography (PE–EtOAc, 95:5) afforded
1
2
d as a colorless solid (178 mg, 65%). H NMR (300 MHz, CDCl ):
fording the expected benzoylated product 16a in 80%
yield (Table 4, entry 10).
3
δ = 8.53 (app d, J = 8.7 Hz, 2 H), 8.19–8.22 (m, 1 H), 7.96–7.99 (m,
H), 7.54 (app qd, J = 7.2, 1.5 Hz, 2 H), 7.50 (app d, J = 8.7 Hz, 2
1
1
3
In summary, we have developed a novel DMAP-mediated H). C NMR (75 MHz, CDCl ): δ = 184.1 (C), 166.9 (C), 153.9 (C),
3
1
40.7 (C), 137.1 (C), 133.3 (C), 132.8 (CH), 129.0 (CH), 127.9
Regel-type direct C-2 aroylation of various 1,3-diazoles
with a broad panel of aroyl chlorides. This general and ef-
ficient methodology allows the metal-free preparation of
valuable diheteroaryl ketones, which are found in natural
products and pharmaceuticals.
(CH), 127.2 (CH), 125.9 (CH), 122.3 (CH).
Benzothiazol-2-yl-(6-chloropyridin-3-yl)methanone (2e): Pre-
pared according to the general procedure, using benzothiazole (110
μL, 1 mmol), 6-chloronicotinoyl chloride (352 mg, 2 mmol), Et N
(420 μL, 3 equiv) and DMAP (37 mg, 30 mol%) in MeCN (2 mL).
Purification by flash column chromatography (PE–EtOAc, 96:4) af-
forded 2e as a colorless solid (159 mg, 58%); mp 120–121 °C (PE–
3
All commercially available reagents were used as received, except
otherwise specified. MeCN, DMF and 1,4-dioxane were obtained
from Acros Organics® in sealed bottles over 3 Å or 4 Å molecular
sieves under N , and were used without further purification. Et N
1
CH Cl ). H NMR (300 MHz, CDCl ): δ = 9.62 (d, J = 2.1 Hz, 1 H),
2
2
3
8
.81 (dd, J = 8.4, 2.1 Hz, 1 H), 8.23 (dd, J = 6.6, 1.8 Hz, 1 H), 8.02
13
(
dd, J = 6.9, 2.4 Hz, 1 H), 7.51–7.64 (m, 3 H). C NMR (75 MHz,
2
3
CDCl ): δ = 183.1 (C), 166.0 (C), 156.4 (C), 153.9 (C), 153.0 (CH),
3
was distilled from CaH . DIEA was distilled over KOH and stored
2
1
41.0 (CH), 137.2 (C), 129.7 (C), 128.4 (CH), 127.5 (CH), 126.1
over 4 Å molecular sieves under N . Liquid or low-melting solid
2
(
CH), 124.4 (CH), 122.4 (CH). IR (neat): 3105, 3060, 3000, 1654,
acyl chlorides were purified by distillation under reduced pressure
before each use.
–1
1
642, 1575, 1551, 1459, 1302, 1101 cm . HRMS (ESI+): m/z calcd
+
for C H ClN OS : 275.0046; found: 275.0038.
1
3
8
2
General Procedure: DMAP (37 mg, 30 mol%), aroyl chloride (if
solid; 2 mmol, 2 equiv) and azole (if solid; 1 mmol, 1 equiv) were
weighed in a sealable tube. The tube was sealed and flushed with a
stream of dry N . MeCN (2 mL) was added, followed by Et N (420
Benzothiazol-2-yl-(3-chlorophenyl)methanone (2f): Prepared ac-
cording to the general procedure, using benzothiazole (110 μL, 1
mmol), 3-chlorobenzoyl chloride (256 μL, 2 mmol), Et N (420 μL,
3
3
2
3
equiv) and DMAP (37 mg, 30 mol%) in MeCN (2 mL). Purifica-
μL, 3 equiv). Azole (1 mmol, 1 equiv) and aroyl chloride (2 mmol,
tion by flash column chromatography (PE–EtOAc, 95:5) afforded
2
equiv) were added dropwise to the reaction mixture, and stirred
○
2
e as a colorless solid (207 mg, 76%); mp 96–97 C (PE–CH Cl ).
2 2
for 24 h at 80 °C. The mixture was then cooled to r.t., diluted with
1
H NMR (300 MHz, CDCl ): δ = 8.55 (t, J = 2.1 Hz, 1 H), 8.48 (tt,
3
EtOAc and sat. aq NaHCO , and extracted with EtOAc (2 ×). Com-
3
J = 7.8, 1.2 Hz, 1 H), 8.23–8.26 (m, 1 H), 7.99–8.02 (m, 2 H), 7.53–
7
δ = 184.1 (C), 166.5 (C), 153.9 (C), 137.1 (C), 136.5 (C), 134.8 (C),
1
1
1
bined organic layers were washed with brine, dried over MgSO and
13
4
.65 (m, 3 H), 7.50 (t, J = 7.8 Hz, 1 H). C NMR (75 MHz, CDCl3):
concentrated in vacuo. Purification by flash column chromato-
graphy (SiO ) afforded the desired product.
Benzothiazol-2-yl-(phenyl)methanone (2a): Prepared according
to the general procedure, using benzothiazole (110 μL, 1 mmol),
2
33.9 (CH), 131.2 (CH), 129.9 (CH), 129.6 (CH), 128.0 (CH),
27.2 (CH), 126.0 (CH), 122.3 (CH). IR (neat): 3086, 1651, 1637,
1
1
–1
586, 1564, 1485, 1462, 1423, 1293, 1265, 1132, 1122 cm .
benzoyl chloride (230 μL, 2 equiv), Et N (420 μL, 3 equiv) and
+
3
HRMS (ESI+): m/z calcd for C H ClNOS : 274.0093; found:
1
4
9
DMAP (37 mg, 30 mol%) in MeCN (2 mL). Purification by flash
2
74.0092.
column chromatography (PE–EtOAc, 96:4) afforded 2a as a color-
5
Benzoxazol-2-yl-(phenyl)methanone (3a): Prepared according to
1
less solid (197 mg, 82%). H NMR (300 MHz, CDCl ): δ = 8.55–
3
the general procedure, using benzoxazole (119 mg, 1 mmol), ben-
zoyl chloride (230 μL, 2 equiv), Et N (420 μL, 3 equiv) and DMAP
8
.56 (m, 2 H), 8.23–8.26 (m, 1 H), 7.99–8.03 (m, 1 H), 7.64–7.70
1
3
3
(
(
(
(
m, 1 H), 7.51–7.61 (m, 4 H). C NMR (75 MHz, CDCl ): δ = 185.4
C), 167.2 (C), 154.0 (C), 137.1 (C), 135.1 (C), 134.0 (CH), 131.4
CH), 128.6 (CH), 127.7 (CH), 127.0 (CH), 125.8 (CH), 122.3
3
(
37 mg, 30 mol%) in MeCN (2 mL). Purification by flash column
chromatography (PE–EtOAc, 9:1) afforded 3a as a colorless solid
1
(
167 mg, 66%). H NMR (300 MHz, CDCl ): δ = 8.54–8.57 (m, 2
3
CH).
H), 7.94–7.97 (m, 1 H), 7.70–7.74 (m, 1 H), 7.69 (tt, J = 7.4, 1.4 Hz,
5
Benzothiazol-2-yl-(4-methoxyphenyl)methanone (2b): Prepared
according to the general procedure, using benzothiazole (110 μL, 1
13
1
H), 7.45–7.60 (m, 4 H). C NMR (75 MHz, CDCl ): δ = 180.7
3
(
(
(
C), 157.2 (C), 150.6 (C), 140.9 (C), 135.1 (CH), 134.5 (CH), 131.1
CH), 128.8 (CH), 128.6 (CH), 125.9 (CH), 122.5 (CH), 112.0
CH).
mmol), 4-methoxybenzoyl chloride (270 μL, 2 mmol), Et N (420
3
μL, 3 equiv) and DMAP (37 mg, 30 mol%) in MeCN (2 mL). Puri-
fication by flash column chromatography (PE–EtOAc, 9:1) afford-
5
Benzoxazol-2-yl-(4-methoxyphenyl)methanone (3b): Prepared
according to the general procedure, using benzoxazole (119 mg, 1
1
ed 2b as a colorless solid (175 mg, 64%). H NMR (300 MHz,
Synlett 2013, 24, 2233–2240
© Georg Thieme Verlag Stuttgart · New York

LETTER
Direct C-2 (Hetero)Aroylation of Azoles with Acid Chlorides
2237
mmol), 4-methoxybenzoyl chloride (270 μL, 2 mmol), Et N (420
μL, 3 equiv) and DMAP (37 mg, 30 mol%) in MeCN (2 mL). Puri-
8.54 (app d, J = 9.1 Hz, 2 H), 8.03 (d, J = 3.3 Hz, 1 H), 7.65 (d, J =
3.3 Hz, 1 H), 6.97 (app d, J = 9.1 Hz, 2 H), 3.85 (s, 3 H). C NMR
3
1
3
fication by flash column chromatography (PE–EtOAc, 85:15) af-
forded 3b as a colorless solid (209 mg, 83%). H NMR (300 MHz,
(75 MHz, CDCl ): δ = 182.3 (C), 168.6 (C), 164.1 (C), 144.6 (CH),
3
1
133.7 (CH), 127.9 (C), 125.8 (CH), 113.8 (CH), 55.5 (Me).
1
3
CDCl ): δ = 8.60 (app d, J = 9.0 Hz, 2 H), 7.91–7.94 (m, 1 H), 7.68–
(3-Chlorophenyl)(thiazol-2-yl)methanone (5c): Prepared ac-
cording to the general procedure, using thiazole (71 μL, 1 mmol), 3-
3
7
3
1
1
.71 (m, 1 H), 7.42–7.55 (m, 2 H), 7.03 (app d, J = 9.0 Hz, 2 H),
.91 (s, 3 H). 13C NMR (75 MHz, CDCl ): δ = 178.9 (C), 164.8 (C),
chlorobenzoyl chloride (256 μL, 2 mmol), Et N (420 μL, 3 equiv)
3
3
57.5 (C), 150.4 (C), 140.9 (C), 133.7 (CH), 128.2 (CH), 128.1 (C),
25.7 (CH), 122.3 (CH), 114.1 (CH), 111.9 (CH), 55.7 (Me).
and DMAP (37 mg, 30 mol%) in MeCN (2 mL). Purification by
flash column chromatography (PE–EtOAc, 9:1) afforded 5c as a
1
Benzoxazol-2-yl-(4-chlorophenyl)methanone (3c): Prepared ac-
colorless solid (165 mg, 69%). H NMR (300 MHz, CDCl ): δ =
3
cording to the general procedure, using benzoxazole (119 mg, 1
8.49 (t, J = 1.8 Hz, 1 H), 8.38 (ddd, J = 7.9, 1.2, 1.2 Hz, 1 H), 8.10
(d, J = 3.1 Hz, 1 H), 7.75 (d, J = 3.1 Hz, 1 H), 7.60 (ddd, J = 7.9,
2.2, 1.2 Hz, 1 H), 7.46 (t, J = 7.9 Hz, 1 H). C NMR (75 MHz,
mmol), 4-chlorobenzoyl chloride (256 μL, 2 mmol), Et N (420 μL,
3
1
3
3
equiv) and DMAP (37 mg, 30 mol%) in MeCN (2 mL). Purifica-
tion by flash column chromatography (PE–EtOAc, 95:5) afforded
c as a colorless solid (186 mg, 72%); mp 100–101 °C (PE–
CDCl ): δ = 182.8 (C), 167.3 (C), 145.2 (CH), 136.7 (C), 134.7 (C),
3
3
133.6 (CH), 131.2 (CH), 129.8 (CH), 129.3 (CH), 126.8 (CH).
Furan-2-yl-(thiazol-2-yl)methanone (5d): Prepared according to
the general procedure, using thiazole (71 μL, 1 mmol), 2-furoyl
1
CH Cl ). H NMR (300 MHz, CDCl ): δ = 8.55 (app d, J = 9.0 Hz,
2
2
3
2
7
H), 7.92–7.95 (m, 1 H), 7.69–7.72 (m, 1 H), 7.45–7.59 (m, 2 H),
1
3
.53 (app d, J = 9.0 Hz, 2 H). C NMR (75 MHz, CDCl ): δ = 179.2
chloride (200 μL, 2 mmol), Et N (420 μL, 3 equiv) and DMAP (37
3
3
(
(
(
C), 156.9 (C), 150.5 (C), 141.2 (C), 140.7 (C), 133.4 (C), 132.6
CH), 129.1 (CH), 128.8 (CH), 126.0 (CH), 122.5 (CH), 112.0
CH). IR (neat): 3102, 3064, 3028, 1657, 1582, 1523, 1477, 1381,
mg, 30 mol%) in MeCN (2 mL). Purification by flash column chro-
matography (PE–EtOAc, 8:2) afforded 5d as a colorless solid (157
1
mg, 88%); mp 77–78 °C (Et O). H NMR (300 MHz, CDCl ): δ =
2
3
–
1
+
1
2
208, 1154, 1093 cm . HRMS (ESI+): m/z calcd for C H ClNO :
8.19 (dd, J = 3.6, 0.9 Hz, 1 H), 8.05 (d, J = 3.0 Hz, 1 H), 7.77 (dd, J
= 1.5, 0.6 Hz, 1 H), 7.70 (d, J = 3.0 Hz, 1 H), 6.63 (dd, J = 3.6, 1.8
1
4
9
58.0322; found: 258.0320.
1
3
Benzoxazol-2-yl-(3-chlorophenyl)methanone (3d): Prepared ac-
Hz, 1 H). C NMR (75 MHz, CDCl ): δ = 171.2 (C), 166.7 (C),
3
cording to the general procedure, using benzoxazole (119 mg, 1
150.0 (C), 148.7 (CH), 145.0 (CH), 126.1 (CH), 124.4 (CH), 112.9
(CH). IR (neat): 3138, 3099, 3079, 2923, 1622, 1553, 1487, 1480,
mmol), 3-chlorobenzoyl chloride (256 μL, 2 mmol), Et N (420 μL,
3
–
1
3
equiv) and DMAP (37 mg, 30 mol%) in MeCN (2 mL). Purifica-
tion by flash column chromatography (PE–EtOAc, 96:4) afforded
d as a colorless solid (199 mg, 77%); mp 135.5–136.5 °C (PE–
1459, 1400, 1129, 1014 cm . HRMS (ESI+): m/z calcd for
+
C H NO : 180.0119; found: 180.0119.
8
6
3
Oxazol-2-yl-(phenyl)methanone (6a): Prepared according to the
general procedure, using oxazole (66 μL, 1 mmol), benzoyl chloride
1
CH Cl ). H NMR (300 MHz, CDCl ): δ = 8.57 (t, J = 1.7 Hz, 1 H),
2
2
3
8
.50 (dt, J = 7.8, 1.3 Hz, 1 H), 7.96–7.99 (m, 1 H), 7.71–7.74 (m, 1
(230 μL, 2 equiv), Et N (420 μL, 3 equiv) and DMAP (37 mg, 30
mol%) in MeCN (2 mL). Purification by flash column chromatog-
3
1
3
H), 7.66 (ddd, J = 8.0, 2.2, 1.1 Hz, 1 H), 7.47–7.61 (m, 3 H).
C
NMR (75 MHz, CDCl ): δ = 179.3 (C), 156.8 (C), 150.6 (C), 140.8
raphy (PE–EtOAc, 9:1) afforded 6a as a colorless solid (160 mg,
3
1
(
1
(
1
2
C), 136.5 (C), 135.0 (C), 134.4 (CH), 131.0 (CH), 130.1 (CH),
29.4 (CH), 128.9 (CH), 126.1 (CH), 122.7 (CH), 112.1 (CH). IR
neat): 3291, 3096, 3071, 3019, 1661, 1610, 1601, 1590, 1523,
92%); mp 64–65 °C (PE–CH Cl ). H NMR (300 MHz, CDCl ): δ
2
2
3
= 8.41–8.45 (m, 2 H), 7.88 (d, J = 0.3 Hz, 1 H), 7.60 (tt, J = 6.3, 1.2
Hz, 1 H), 7.45–7.50 (m, 2 H), 7.38 (d, J = 0.3 Hz, 1 H). 1 C NMR
3
–1
+
304, 1208 cm . HRMS (ESI+): m/z calcd for C H ClNO :
(75 MHz, CDCl ): δ = 178.8 (C), 157.8 (C), 141.6 (CH), 134.9 (C),
1
4
9
3
58.0322; found: 258.0320.
134.0 (CH), 130.8 (CH), 129.1 (CH), 128.5 (CH). IR (neat): 3149,
3130, 3059, 1662, 1598, 1574, 1538, 1472, 1445, 1375, 1293, 1179,
Benzoxazol-2-yl-(2-methoxyphenyl)methanone (3e): Prepared
according to the general procedure, using benzoxazole (119 mg, 1
–
1
+
1187 cm . HRMS (ESI+): m/z calcd for C H NO : 174.0555;
10 8
mmol), 2-methoxybenzoyl chloride (300 μL, 2 mmol), Et N (420
found: 174.0557.
(4-Methoxyphenyl)(oxazol-2-yl)methanone (6b): Prepared ac-
cording to the general procedure, using oxazole (66 μL, 1 mmol), 4-
methoxybenzoyl chloride (270 μL, 2 mmol), Et N (420 μL, 3 equiv)
3
μL, 3 equiv) and DMAP (37 mg, 30 mol%) in MeCN (2 mL). Puri-
fication by flash column chromatography (PE–EtOAc, 85:15) af-
forded 3e as a colorless solid (142 mg, 56%); mp 92–93 °C (PE–
3
1
CH Cl ). H NMR (300 MHz, CDCl ): δ = 7.85–7.88 (m, 1 H), 7.74
and DMAP (37 mg, 30 mol%) in MeCN (2 mL). Purification by
2
2
3
(
dd, J = 7.6, 1.8 Hz, 1 H), 7.64–7.66 (m, 1 H), 7.39–7.59 (m, 3 H),
flash column chromatography (PE–CH Cl , 2:8) afforded 6b as a
2
2
1
7
.09 (td, J = 7.5, 0.8 Hz, 1 H), 7.0 (d, J = 8.4 Hz, 1 H), 3.75 (s, 3 H).
colorless solid (183 mg, 90%); mp 113–114 °C (PE–Et O). H
2
1
3
C NMR (75 MHz, CDCl ): δ = 183.1 (C), 159.1 (C), 158.4 (C),
NMR (300 MHz, CDCl ): δ = 8.47 (app d, J = 9.3 Hz, 2 H), 7.85 (d,
3
3
1
50.6 (C), 140.9 (C), 134.5 (CH), 131.0 (CH), 128.1 (CH), 126.3
J = 0.6 Hz, 1 H), 7.34 (d, J = 0.6 Hz, 1 H), 6.93 (app d, J = 9.3 Hz,
1
3
(C), 125.6 (CH), 122.3 (CH), 120.7 (CH), 112.1 (CH), 111.8 (CH),
2 H), 3.82 (s, 3 H). C NMR (75 MHz, CDCl ): δ = 177.2 (C), 164.4
3
5
1
2
6.0 (Me). IR (neat): 3070, 2960, 2933, 1669, 1596, 1578, 1535,
(C), 158.0 (C), 141.3 (CH), 133.4 (CH), 128.8 (CH), 127.8 (C),
–
1
+
462, 1245, 1160 cm . HRMS (ESI+): m/z calcd for C H NO :
113.8 (CH), 55.5 (Me). IR (neat): 3149, 3125, 2999, 2961, 2844,
1
5
12
–
1
54.0817; found: 254.0818.
1641, 1598, 1570, 1541, 1511, 1487, 1426, 1373, 1254, 1027 cm .
9
+
Phenyl(thiazol-2-yl)methanone (5a): Prepared according to the
HRMS (ESI+): m/z calcd for C H NO : 204.0661; found:
1
1
10
general procedure, using thiazole (71 μL, 1 mmol), benzoyl chloride
204.0664.
(
230 μL, 2 equiv), Et N (420 μL, 3 equiv) and DMAP (37 mg, 30
mol%) in MeCN (2 mL). Purification by flash column chromatog-
(6-Chloropyridin-3-yl)(oxazol-2-yl)methanone (6c): Prepared
according to the general procedure, using oxazole (66 μL, 1 mmol),
3
raphy (PE–EtOAc, 8:2) afforded 5a as a colorless solid (175 mg,
6-chloronicotinoyl chloride (352 mg, 2 mmol), Et N (420 μL, 3
equiv) and DMAP (37 mg, 30 mol%) in MeCN (2 mL). Purification
3
1
9
3%). H NMR (300 MHz, CDCl ): δ = 8.44–8.48 (m, 2 H), 8.05 (d,
3
J = 3.0 Hz, 1 H), 7.68 (d, J = 3.0 Hz, 1 H), 7.59 (tt, J = 6.3, 1.2 Hz,
by flash column chromatography (CH Cl ) afforded 6c as a color-
2
2
1
3
1
1
H), 7.46–7.51 (m, 2 H). C NMR (75 MHz, CDCl ): δ = 184.0
less solid (192 mg, 92%); mp 95–96 °C (MeCN–Et O). H NMR
3
2
(
1
C), 167.8 (C), 144.8 (CH), 135.1 (C), 133.6 (CH), 131.0 (CH),
28.4 (CH), 126.3 (CH).
(300 MHz, CDCl ): δ = 9.50 (d, J = 2.1 Hz, 1 H), 8.74 (dd, J = 8.4,
3
2.1 Hz, 1 H), 7.95 (s, 1 H), 7.48 (d, J = 8.4 Hz, 1 H), 7.45 (s, 1 H).
1
3
5
C NMR (75 MHz, CDCl
52.6 (CH), 142.4 (CH), 140.7 (CH), 129.6 (CH), 129.5 (C), 124.4
CH). IR (neat): 3154, 3133, 3076, 1667, 1650, 1571, 1556, 1479,
3
): δ = 176.2 (C), 157.2 (C), 156.5 (C),
(
4-Methoxyphenyl)(thiazol-2-yl)methanone (5b): Prepared ac-
1
(
1
(
cording to the general procedure, using thiazole (71 μL, 1 mmol), 4-
methoxybenzoyl chloride (270 μL, 2 mmol), Et N (420 μL, 3 equiv)
and DMAP (37 mg, 30 mol%) in MeCN (2 mL). Purification by
flash column chromatography (PE–EtOAc, 8:2) afforded 5b as a
3
–1
468, 1451, 1381, 1359, 1286, 1186, 1104, 1026 cm . HRMS
ESI+): m/z calcd for C H ClN O : 209.0118; found: 209.0122.
+
9 6 2
1
colorless solid (197 mg, 90%). H NMR (300 MHz, CDCl ): δ =
3
©
Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2233–2240

2
238
P. Lassalas et al.
LETTER
(
3-Chlorophenyl)(oxazol-2-yl)methanone (6d): Prepared accord-
[5-(4-Methoxyphenyl)oxazol-2-yl](phenyl)methanone (9a): Pre-
ing to the general procedure, using oxazole (66 μL, 1 mmol), 3-
chlorobenzoyl chloride (256 μL, 2 mmol), Et N (420 μL, 3 equiv)
pared according to the general procedure, using 5-(4-methoxyphe-
1
4
nyl)oxazole (175 mg, 1 mmol), benzoyl chloride (230 μL, 2
3
and DMAP (37 mg, 30 mol%) in MeCN (2 mL). Purification by
equiv), Et N (420 μL, 3 equiv) and DMAP (37 mg, 30 mol%) in
MeCN (2 mL). Purification by flash column chromatography (PE–
3
flash column chromatography (PE–EtOAc, 8:2) afforded 6d as a
1
pale yellow solid (200 mg, 97%); mp 106–107 °C (PE–CH Cl ). H
CH Cl , 3:7) afforded 9a as a yellow solid (222 mg, 80%); mp 133–
2
2
2
2
1
NMR (300 MHz, CDCl ): δ = 8.50 (t, J = 1.8 Hz, 1 H), 8.41 (ddd, J
134 °C (MeCN–Et O). H NMR (300 MHz, CDCl ): δ = 8.48–8.44
3
2
3
7.8, 1.2, 1.2 Hz, 1 H), 7.93 (d, J = 0.6 Hz, 1 H), 7.62 (ddd, J = 7.8,
(m, 2 H), 7.75 (app d, J = 9.0 Hz, 2 H), 7.63 (tt, J = 6.3, 1.2 Hz, 1
H), 7.49–7.53 (m, 2 H), 7.49 (s, 1 H), 6.98 (app d, J = 9.0 Hz, 2 H),
13
C NMR (75 MHz, CDCl ): δ = 177.5 (C), 157.5 (C), 142.0 (CH),
3.85 (s, 3 H). C NMR (75 MHz, CDCl ): δ = 178.7 (C), 161.1 (C),
3
3
1
36.5 (C), 134.9 (C), 134.1 (CH), 130.9 (CH), 130.0 (CH), 129.4
156.7 (C), 154.5 (C), 135.6 (C), 133.7 (CH), 130.8 (CH), 128.5
(CH), 127.2 (CH), 122.7 (CH), 119.4 (C), 114.7 (CH), 55.5 (Me).
IR (neat): 3113, 3011, 2920, 2846, 1649, 1610, 1576, 1564, 1477,
(
CH), 129.2 (CH). IR (neat): 3154, 3135, 3095, 3071, 1651, 1566,
–
1
1
481, 1374, 1291, 1274, 1124 cm . HRMS (ESI+): m/z calcd for
+
–1
C H ClNO : 208.0165; found: 208.0173.
Furan-2-yl-(oxazol-2-yl)methanone (6e): Prepared according to
1426, 1367, 1248, 1172 cm . HRMS (ESI+): m/z calcd for
1
0
7
+
C H NO : 280.0974; found: 280.0973.
1
7
14
the general procedure, using oxazole (66 μL, 1 mmol), 2-furoyl
{5-[4-(Dimethylamino)phenyl]oxazol-2-yl}(phenyl)methanone
chloride (200 μL, 2 mmol), Et N (420 μL, 3 equiv) and DMAP (37
(10a): Prepared according to the general procedure, using 5-[4-(di-
3
1
4
mg, 30 mol%) in MeCN (2 mL). Purification by flash column chro-
methylamino)phenyl]oxazole (188 mg, 1 mmol), benzoyl chloride
matography (PE–CH Cl , 8:2) afforded 6e as a colorless solid (135
(230 μL, 2 equiv), Et N (420 μL, 3 equiv) and DMAP (37 mg, 30
mol%) in MeCN (2 mL). Purification by flash column chromatog-
2
2
3
1
mg, 83%); mp 124–125 °C (Et O). H NMR (300 MHz, CDCl ): δ
2
3
=
8.08 (dd, J = 3.6, 0.6 Hz, 1 H), 7.88 (s, 1 H), 7.76 (dd, J = 1.5, 0.6
raphy (PE–EtOAc, 7:3) afforded 10a as an orange solid (281 mg,
1
3
1
Hz, 1 H), 7.37 (s, 1 H), 6.61 (dd, J = 3.6, 1.5 Hz, 1 H). C NMR (75
96%); mp 144–145 °C (MeCN–Et O). H NMR (300 MHz, CDCl ):
2
3
MHz, CDCl ): δ = 165.9 (C), 157.1 (C), 150.2 (C), 149.1 (CH),
δ = 8.44–8.47 (m, 2 H), 7.69 (app d, J = 9.0 Hz, 2 H), 7.60–7.65 (m,
1 H), 7.52 (app t, J = 7.8 Hz, 2 H), 7.41 (s, 1 H), 6.73 (app d, J = 9.0
3
1
41.8 (CH), 129.3 (CH), 124.4 (CH), 113.0 (CH). IR (neat): 3145,
1
3
3
124, 2922, 1643, 1554, 1541, 1485, 1454, 1398, 1298, 1222, 1025
Hz, 2 H), 3.03 (s, 6 H). C NMR (75 MHz, CDCl ): δ = 178.5 (C),
3
–
1
+
cm . HRMS (ESI+): m/z calcd for C H NO : 164.0348; found:
156.3 (C), 155.7 (C), 151.4 (C), 135.9 (C), 133.5 (CH), 130.8 (CH),
128.5 (CH), 126.9 (CH), 121.6 (CH), 114.3 (C), 112.1 (CH), 40.2
(Me). IR (neat): 3130, 3070, 2905, 2816, 1641, 1610, 1597, 1575,
8
6
1
64.0341.
Oxazol-2-yl-(oxazol-5-yl)methanone (6f): To a solution of oxa-
–
1
zole-5-carboxylic acid (226 mg, 2 mmol) in anhyd CH Cl (2 mL)
1552, 1474, 1360, 1230, 1167 cm . HRMS (ESI+): m/z calcd for
2
2
+
was added dropwise oxalyl chloride (343 μL, 4 mmol), followed by
a drop of DMF. The reaction mixture was stirred for 3.5 h (until no
effervescence was observed by addition of a drop of anhyd DMF)
and the solvent was evaporated. The crude acid chloride (4 mmol)
C H N O : 293.1290; found: 293.1289.
1
8
17
2
tert-Butyl 2-Benzoylthiazole-4-carboxylate (11a): Prepared ac-
cording to the general procedure, using tert-butyl thiazole-4-
1
5
carboxylate (185 mg, 1 mmol), benzoyl chloride (230 μL, 2
was allowed to react with oxazole (66 μL, 2 mmol), Et N (420 μL,
equiv), Et N (420 μL, 3 equiv) and DMAP (37 mg, 30 mol%) in
MeCN (2 mL). Purification by flash column chromatography (PE–
3
3
3
equiv) and DMAP (37 mg, 30 mol%) in MeCN (2 mL) according
to the general procedure. Purification by flash column chromatog-
EtOAc, 8:2) afforded 11a as a colorless solid (152 mg, 53%); mp
1
raphy (PE–EtOAc, 7:3) afforded 6f as a colorless solid (96 mg,
82–83 °C (PE–CH Cl ). H NMR (300 MHz, CDCl ): δ = 8.58–8.62
2
2
3
1
5
9%); mp 128–129 °C (MeCN–Et O). H NMR (300 MHz, CDCl ):
(m, 2 H), 8.35 (s, 1 H), 7.61–7.67 (m, 1 H), 7.50–7.55 (m, 2 H), 1.63
2
3
1
3
13
δ = 8.60 (s, 1 H), 8.18 (s, 1 H), 7.94 (s, 1 H), 7.42 (s, 1 H). C NMR
(s, 9 H). C NMR (75 MHz, CDCl ): δ = 183.5 (C), 168.0 (C),
3
(
1
1
75 MHz, CDCl ): δ = 165.4 (C), 156.4 (C), 154.9 (CH), 147.6 (C),
160.0 (C), 150.2 (C), 134.5 (C), 134.1 (CH), 132.6 (CH), 131.5
(CH), 128.7 (CH), 82.7 (C), 28.3 (Me). IR (neat): 3093, 2990, 2929,
3
42.5 (CH), 138.6 (CH), 129.6 (CH). IR (neat): 3148, 3122, 1665,
–
1
–1
650, 1638, 1560, 1458, 1401, 1320, 1224, 1138, 1090 cm .
1717, 1651, 1596, 1586, 1470, 1287, 1241, 1102 cm . HRMS
+
+
HRMS (ESI+): m/z calcd for C H N O : 165.0300; found:
(ESI+): m/z calcd for C H NO S : 290.0851; found: 290.0845.
7
5
2
15 16
3
1
65.0297.
Ethyl 2-Benzoyloxazole-5-carboxylate (12a): Prepared according
to the general procedure, using ethyl oxazole-5-carboxylate (152
3
a
Phenyl(5-phenyloxazol-2-yl)methanone (7a): Prepared accord-
ing to the general procedure, using 5-phenyloxazole (145 mg, 1
1
4
mg, 1 mmol), benzoyl chloride (230 μL, 2 equiv), Et N (420 μL, 3
3
mmol), benzoyl chloride (230 μL, 2 equiv), Et N (420 μL, 3 equiv)
and DMAP (37 mg, 30 mol%) in MeCN (2 mL). Purification by
equiv) and DMAP (37 mg, 30 mol%) in MeCN (2 mL). Purification
3
by flash column chromatography (CH Cl ) afforded 12a as a pale
2
2
1
flash column chromatography (PE–EtOAc, 9:1) afforded 7a as a
yellow oil (193 mg, 79%). H NMR (300 MHz, CDCl ): δ = 8.40–
3
1
pale yellow solid (222 mg, 89%). H NMR (300 MHz, CDCl ): δ =
8.44 (m, 2 H), 7.94 (s, 1 H), 7.65 (tt, J = 6.6, 1.2 Hz, 1 H), 7.49–7.55
3
1
3
8
.46–8.49 (m, 2 H), 7.79–7.82 (m, 2 H), 7.63 (tt, J = 7.3, 2.2 Hz, 1
(m, 2 H), 4.43 (q, J = 7.2 Hz, 2 H), 1.40 (t, J = 7.2 Hz, 3 H). C
1
3
H), 7.60 (s, 1 H), 7.40–7.54 (m, 5 H). C NMR (75 MHz, CDCl3):
NMR (75 MHz, CDCl ): δ = 178.6 (C), 158.3 (C), 157.2 (C), 144.2
3
δ = 178.6 (C), 157.0 (C), 154.1 (C), 135.3 (C), 133.8 (CH), 130.8
(C), 134.6 (C), 134.5 (CH), 134.4 (CH), 131.0 (CH), 128.7 (CH),
(
CH), 130.0 (CH), 129.1 (CH), 128.5 (CH), 126.7 (C), 125.4 (CH),
24.0 (CH).
5-(4-Nitrophenyl)oxazol-2-yl](phenyl)methanone (8a): Pre-
62.3 (CH ), 14.3 (Me). IR (neat): 3151, 3072, 2984, 1724, 1667,
2
–
1
1
[
1598, 1577, 1563, 1448, 1360, 1280, 1262 cm . HRMS (ESI+): m/z
calcd for C H NO : 246.0753; found: 246.0766.
+
1
3
12
pared according to the general procedure, using 5-(4-nitrophe-
(4,5-Dimethylthiazol-2-yl)(phenyl)methanone (13a): Prepared
according to the general procedure, using 4,5-dimethylthiazole (106
nyl)oxazole14 (14; 190 mg, 1 mmol), benzoyl chloride (230 μL, 2
equiv), Et N (420 μL, 3 equiv) and DMAP (37 mg, 30 mol%) in
MeCN (2 mL). Purification by flash column chromatography
μL, 1 mmol), benzoyl chloride (230 μL, 2 equiv), Et N (420 μL, 3
equiv) and DMAP (37 mg, 30 mol%) in MeCN (2 mL). Purification
3
3
(
CH Cl –MeCN, 249:1) afforded 8a as a colorless solid (266 mg,
by flash column chromatography (PE–Et O, 9:1) afforded 13a as a
2
2
2
1
9
1
8
1
0%); mp 192–193 °C (PE–CH Cl ) (melts/resolidifies); second mp
colorless solid (166 mg, 76%); mp 90–91 °C (MeCN–Et O). H
2
2
2
1
97–198 °C. H NMR (300 MHz, CDCl ): δ = 8.47–8.51 (m, 2 H),
NMR (300 MHz, CDCl ): δ = 8.42–8.425 (m, 2 H), 7.59 (tt, J = 7.3,
3
3
1
3
.35 (app d, J = 9.0 Hz, 2 H), 8.00 (app d, J = 8.7 Hz, 2 H), 7.80 (s,
1.3 Hz, 1 H), 7.46–7.52 (m, 2 H), 2.46 (s, 3 H), 2.45 (s, 3 H). C
H), 7.68 (tt, J = 6.3, 1.2 Hz, 1 H), 7.53–7.58 (m, 2 H). 1 C NMR
3
NMR (75 MHz, CDCl ): δ = 184.0 (C), 162.6 (C), 151.8 (C), 136.0
3
(
75 MHz, CDCl ): δ = 178.7 (C), 158.0 (C), 151.8 (C), 148.3 (C),
(C), 135.6 (C), 133.3 (CH), 131.1 (CH), 128.3 (CH), 15.2 (Me),
3
1
35.0 (C), 134.4 (CH), 132.5 (C), 131.0 (CH), 128.8 (CH), 126.7
12.0 (Me). IR (neat): 3065, 2919, 2854, 1628, 1594, 1574, 1520,
–
1
(
CH), 126.1 (CH), 124.7 (CH). IR (neat): 3139, 3113, 3084, 1637,
1449, 1423, 1374, 1291, 1133 cm . HRMS (ESI+): m/z calcd for
–
1
+
1
602, 1573, 1516, 1473, 1447, 1416, 1325, 1297 cm . HRMS
C H NOS : 218.0640; found: 218.0633.
1
2
12
+
(
ESI+): m/z calcd for C H N O : 295.0719; found: 295.0709.
16 11 2
Synlett 2013, 24, 2233–2240
© Georg Thieme Verlag Stuttgart · New York

LETTER
Direct C-2 (Hetero)Aroylation of Azoles with Acid Chlorides
2239
Ethyl
2-Benzoyl-5-(4-methoxyphenyl)oxazole-4-carboxylate
Supporting Information for this article is available online at
(
14a): Prepared according to the general procedure, using ethyl 5-
4-methoxyphenyl)oxazole-4-carboxylate (124 mg, 0.5 mmol),
http://www.thieme-connect.com/ejournals/toc/synlett. SupIpnf oiogtrm rat
i
o
tnnrfmo at
o
1
6
(
benzoyl chloride (120 μL, 2 equiv), Et N (210 μL, 3 equiv) and
3
DMAP (18 mg, 30 mol%) in MeCN (1 mL). Purification by flash References and Notes
column chromatography (PE–EtOAc, 95:5) afforded 14a as a col-
1
(1) (a) Grimmett, M. R. In Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R.; Rees, C. W.; Scriven, E. F.
V., Eds.; Pergamon: Oxford, 1996, 77–220. (b) Myllymäki,
M. J.; Saario, S. M.; Kataja, A. O.; Castillo-Melendez, J. A.;
Nevalainen, T.; Juvonen, R. O.; Järvinen, T.; Koskinen, A.
M. P. J. Med. Chem. 2007, 50, 4236. (c) Janssens, F.;
Leenaerts, J.; Diels, G.; De Boeck, B.; Megens, A.; Langlois,
X.; van Rossem, K.; Beetens, J.; Borgers, M. J. Med. Chem.
2005, 48, 2154. (d) Lee, J.; Kim, H.; Yu, H.; Chung, J. Y.;
Oh, C.-H.; Yoo, K. H.; Sim, T.; Hah, J.-M. Bioorg. Med.
Chem. Lett. 2010, 20, 1573.
orless solid (91 mg, 52%); mp 119–120 °C (MeCN–Et O). H NMR
2
(
300 MHz, CDCl ): δ = 8.49 (app d, J = 7.5 Hz, 2 H), 8.19 (app d,
3
J = 9.0 Hz, 2 H), 7.65 (app t, J = 7.5 Hz, 1 H), 7.54 (app t, J = 7.5
Hz, 2 H), 7.00 (app d, J = 9.0 Hz, 2 H), 4.45 (q, J = 6.9 Hz, 2 H),
1
3
3
.87 (s, 3 H), 1.42 (t, J = 6.9 Hz, 3 H). C NMR (75 MHz, CDCl3):
δ = 178.6 (C), 162.1 (C), 162.0 (C), 157.6 (C), 154.3 (C), 134.9 (C),
34.2 (CH), 131.1 (CH), 131.0 (CH), 128.7 (CH), 127.2 (C), 118.5
C), 114.1 (CH), 61.7 (CH ), 55.5 (Me), 14.4 (Me). IR (neat): 3067,
1
(
2
2
974, 2933, 2841, 1713, 1655, 1607, 1596, 1579, 1565, 1504, 1170
–
1
+
cm . HRMS (ESI+): m/z calcd for C H NO : 352.1185; found:
2
0
18
3
4
52.1169.
-{[(tert-Butyldimethylsilyl)oxy]methyl}-5-phenyloxazole (4k):
(2) (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry; John
Wiley & Sons: New York, 2010, 5th ed., 763. (b) Zificsak,
C. A.; Hlasta, D. J. Tetrahedron 2004, 60, 8991.
To a mixture of (5-phenyloxazol-4-yl)methanol (200 mg, 1.14
mmol) in anhyd CH Cl (4.2 mL) were added dropwise distilled
2
2
2
,6-lutidine (330 μL, 2.85 mmol) and TBSOTf (400 μL, 1.71
(c) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007,
107, 174.
(3) (a) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.;
Pedrini, P. J. Org. Chem. 1987, 52, 3413. (b) Harn, N. K.;
Gramer, C. J.; Anderson, B. A. Tetrahedron Lett. 1995, 36,
mmol), and the reaction was stirred for 2.5 h at r.t. The mixture was
diluted with sat. aq NaHCO and extracted with CH Cl (3 ×). The
organic layers were washed with brine, dried over MgSO and con-
3
2
2
4
centrated in vacuo. Purification by flash column chromatography
1
(
PE–EtOAc, 95:5) afforded 4k as a colorless oil (302 mg, 92%). H
9453. (c) Pippel, D. J.; Mapes, C. M.; Mani, N. S. J. Org.
NMR (300 MHz, CDCl ): δ = 7.84 (s, 1 H), 7.75–7.78 (m, 2 H),
3
Chem. 2007, 72, 5828. (d) Rohbogner, C. J.; Wunderlich, S.
H.; Clososki, G. C.; Knochel, P. Eur. J. Org. Chem. 2009,
1781. (e) Couture, A.; Grandclaudon, P.; Hoarau, C.;
Cornet, J.; Hénichart, J.-P.; Houssin, R. J. Org. Chem. 2002,
67, 3601.
7
0
.42–7.47 (m, 2 H), 7.33–7.39 (m, 1 H), 4.78 (s, 2 H), 0.91 (s, 9 H),
.13 (s, 6 H). 13C NMR (75 MHz, CDCl ): δ = 148.9 (CH), 148.6
3
(
C), 134.4 (C), 128.8 (CH), 128.6 (CH), 128.2 (C), 126.4 (CH), 58.2
(CH ), 26.0 (Me), 18.4 (C), –5.0 (Me). IR (neat): 2953, 2928, 2884,
2
–
1
2
856, 1509, 1471, 1463, 1254, 1076, 1058 cm . HRMS (ESI+): m/z
(
4) (a) Bellina, F.; Rossi, R. Adv. Synth. Catal. 2010, 352, 1223.
+
calcd for C H NO Si : 290.1576; found: 290.1568.
16
24
2
(b) Roger, J.; Gottumukkala, A. L.; Doucet, H.
[
4-{[(tert-Butyldimethylsilyl)oxy]methyl}-5-phenyloxazol-2-
ChemCatChem 2010, 2, 20. (c) McGlacken, G. P.; Bateman,
L. M. Chem. Soc. Rev. 2009, 38, 2447. (d) Ackermann, L.;
Vicente, R.; Kapdi, A. R. Angew. Chem. Int. Ed. 2009, 48,
yl](phenyl)methanone (15a): Prepared according to the general
procedure, using 4k (146 mg, 0.5 mmol), benzoyl chloride (120 μL,
2
equiv), Et N (210 μL, 3 equiv) and DMAP (18 mg, 30 mol%) in
3
9792. (e) Campeau, L.-C.; Fagnou, K. Chem. Soc. Rev.
MeCN (1 mL). Purification by flash column chromatography (PE–
EtOAc, 95:5) afforded 15a as a colorless solid (106 mg, 54%); mp
6
H), 7.94–7.97 (m, 2 H), 7.65 (tt, J = 6.3, 1.2 Hz, 1 H), 7.42–7.56 (m,
5
CDCl ): δ = 178.8 (C), 155.2 (C), 151.5 (C), 137.2 (C), 135.4 (C),
1
1
2007, 36, 1058. (f) Seregin, I. V.; Gevorgyan, V. Chem. Soc.
Rev. 2007, 36, 1173.
1
7–68 °C (Et O). H NMR (300 MHz, CDCl ): δ = 8.51–8.54 (m, 2
2
3
(
5) Wu, X.-F.; Anbarasan, P.; Neumann, H.; Beller, M. Angew.
Chem. Int. Ed. 2010, 49, 7316.
6) (a) Sun, C.-L.; Li, H.; Yu, D.-G.; Yu, M.; Zhou, X.; Lu, X.-
Y.; Huang, K.; Zheng, S.-F.; Li, B.-J.; Shi, Z.-J. Nat. Chem.
1
3
H), 4.89 (s, 2 H), 0.94 (s, 9 H), 0.17 (s, 6 H). C NMR (75 MHz,
(
3
33.8 (CH), 131.0 (CH), 129.9 (CH), 129.0 (CH), 128.5 (CH),
2010, 2, 1044. (b) Popov, I.; Do, H.-Q.; Daugulis, O. J. Org.
27.3 (CH), 127.3 (C), 58.3 (CH ), 26.0 (Me), 18.5 (C), –4.9 (Me).
2
Chem. 2009, 74, 8309. (c) Shirakawa, E.; Itoh, K.-I.;
Higashino, T.; Hayashi, T. J. Am. Chem. Soc. 2010, 132,
IR (neat): 3073, 3059, 2952, 2928, 2856, 1653, 1598, 1588, 1577,
1
3
–1
+
447, 1325, 1176 cm . HRMS (ESI+): m/z calcd for C H NO Si :
23 28 3
15537. (d) Vechorkin, O.; Hirt, N.; Hu, X. Org. Lett. 2010,
94.1838; found: 394.1838.
1
7
12, 3567. (e) Verrier, C.; Lassalas, P.; Théveau, L.;
Quéguiner, G.; Trécourt, F.; Marsais, F.; Hoarau, C.
Beilstein J. Org. Chem. 2011, 7, 1584.
Phenyl(5-phenyl-1,3,4-oxadiazol-2-yl)methanone (16a): Pre-
pared according to the general procedure, using 2-phenyl-1,3,4-
oxadiazole18 (146 mg, 1 mmol), benzoyl chloride (230 μL, 2 equiv),
(
(
7) Gao, Q.; Wu, X.; Jia, F.; Liu, M.; Zhu, Y.; Cai, Q.; Wu, A.
J. Org. Chem. 2013, 78, 2792.
8) (a) Regel, E. Justus Liebigs Ann. Chem. 1977, 159.
(b) Regel, E.; Büchel, K.-H. Justus Liebigs Ann. Chem.
1977, 145.
Et N (420 μL, 3 equiv) and DMAP (37 mg, 30 mol%) in MeCN (2
mL). Purification by flash column chromatography (PE–EtOAc,
8
3
1
5:15) afforded 16a as a pale yellow oil (201 mg, 80%). H NMR
(300 MHz, CDCl ): δ = 8.57–8.60 (m, 2 H), 8.22–8.26 (m, 2 H),
3
1
3
7
.72 (tt, J = 7.4, 1.4 Hz, 1 H), 7.54–7.66 (m, 5 H). C NMR (75
MHz, CDCl ): δ = 177.6 (C), 166.0 (C), 161.0 (C), 134.9 (CH),
(9) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.;
Pedrini, P. J. Org. Chem. 1988, 53, 1748.
3
1
34.3 (C), 132.9 (CH), 131.0 (CH), 129.3 (CH), 128.9 (CH), 127.9
(
CH), 122.9 (C).
(10) (a) Bull, J. A.; Balskus, E. P.; Horan, R. A. J.; Langner, M.;
Ley, S. V. Angew. Chem. Int. Ed. 2006, 45, 6714. (b) Bull, J.
A.; Balskus, E. P.; Horan, R. A. J.; Langner, M.; Ley, S. V.
Chem. Eur. J. 2007, 13, 5515. (c) Mulder, R. J.; Shafer, C.
M.; Molinski, T. F. J. Org. Chem. 1999, 64, 4995. (d) Searle,
P. A.; Richter, R. K.; Molinski, T. F. J. Org. Chem. 1996, 61,
Acknowledgment
This work has been supported by CNRS, the IS:CE-Chem Interreg
program, INSA of Rouen and the University of Rouen. P.L. thanks
the ‘Région Haute Normandie’ for a doctoral fellowship. The au-
thors thank C. Carne for his contribution to this work.
4073. (e) Shioiri, T.; Chittari, P.; Hamada, Y. Heterocycles
2003, 59, 465.
(
11) Boga, C.; Stengel, R.; Abdayem, R.; Del Vecchio, E.;
Forlani, L.; Todesco, P. E. J. Org. Chem. 2004, 69, 8903.
©
Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2233–2240

2
240
P. Lassalas et al.
LETTER
(14) Van Leusen, A. M.; Hoogenboom, B. E.; Siderius, H.
(
12) Fan, X.; He, Y.; Zhang, X.; Guo, S.; Wang, Y. Tetrahedron
011, 67, 6369.
2
Tetrahedron Lett. 1972, 2369.
(
13) Gemma, S.; Campiani, G.; Butini, S.; Kukreja, G.; Coccone,
S. S.; Joshi, B. P.; Persico, M.; Nacci, V.; Fiorini, I.;
Novellino, E.; Fattorusso, E.; Taglialatela-Scafati, O.;
Savini, L.; Taramelli, D.; Basilico, N.; Parapini, S.; Morace,
G.; Yardley, V.; Croft, S.; Coletta, M.; Marini, S.;
Fattorusso, C. J. Med. Chem. 2008, 51, 1278.
(15) Martin, T.; Verrier, C.; Hoarau, C.; Marsais, F. Org. Lett.
2008, 10, 2909.
(16) Schröder, R.; Schöllkopf, U.; Blume, E.; Hoppe, I. Liebigs
Ann. Chem. 1975, 533.
(17) Kudelko, A. Tetrahedron 2011, 67, 8502.
(18) Kawano, T.; Hirano, K.; Satoh, T.; Miura, M. J. Am. Chem.
Soc. 2010, 132, 6900.
Synlett 2013, 24, 2233–2240
© Georg Thieme Verlag Stuttgart · New York