Unprecedentedly mild direct Pd-catalyzed arylation of oxazolo[4,5-b] pyridine

Article abstract of DOI:10.1016/j.tetlet.2006.02.117

Pd-catalyzed C-2 arylation of oxazolo[4,5-b]pyridine proceeds efficiently at 30°C and tolerates a variety of aryl halides, including derivatized amino acids for which no racemization was observed during the reaction. Experimental evidence for facile depro

Full text of DOI:10.1016/j.tetlet.2006.02.117

Tetrahedron Letters 47 (2006) 2929–2932
Unprecedentedly mild direct Pd-catalyzed arylation
of oxazolo[4,5-b]pyridine
Fedor A. Zhuravlev*
Technical University of Denmark, Building 201, Kemitorvet, DK-2800 Kgs. Lyngby, Denmark
Received 5 January 2006; revised 9 February 2006; accepted 17 February 2006
Available online 10 March 2006
Abstract—Pd-catalyzed C-2 arylation of oxazolo[4,5-b]pyridine proceeds efficiently at 30 °C and tolerates a variety of aryl halides,
including derivatized amino acids for which no racemization was observed during the reaction. Experimental evidence for facile
deprotonation of oxazolo[4,5-b]pyridine under the reaction conditions is presented and the nature of the anionic intermediates is
computationally examined.
Ó 2006 Elsevier Ltd. All rights reserved.
Inhibition of fatty acid amide hydrolaze (FAAH) is
emerging as a promising therapeutic strategy for pain
intervention, anxiety management, and treatment of
sleep disorders.1 Several new classes of reversible FAAH
inhibitors based on azole heterocycles have been recently
disclosed.2,3 Among those, oxazolo[4,5-b]pyridines
functionalized at C-2 showed exceptionally high levels
of potency and selectivity. The introduction of carbon-
based substituents at the C-2 position of azoles, however,
remains a demanding task often requiring fully stoichio-
metric pre-functionalization, such as metalation. This
significantly limits functional group compatibility and
increases the length of the reaction sequence. The devel-
opment of a mild and general methodology allowing for
direct catalytic carbon–carbon functionalization of
azoles is, therefore, of great importance. In recent years,
significant progress has been made toward the develop-
ment of direct arylation of a wide variety of substrates,
including oxazoles,4,5 thiazoles,4–7 imidazoles,4,6,8,9
indoles,9–13 pyrroles,9,12 indolizines,14 imidazo[1,2-a]pyri-
midines,7,15 imidazo[1,2-b][1,2,4]triazines,16 and purine.9
The majority of these reactions use palladium catalysis
although some success was also reported with cobalt5
and rhodium-based12 catalytic systems. All these exam-
ples, however, require forcing reaction conditions with
temperatures typically in the range of 100–140 °C. Ex-
tended reaction times are often necessary for achieving
good yields. This letter reports the first example of the
Pd-catalyzed arylation of oxazolo[4,5-b]pyridine, which
readily proceeds at ambient temperature and accommo-
dates a variety of aryl halides including those with sensi-
tive functionalities.
Initial attempts to effect the arylation of oxazolo[4,5-
b]pyridine with phenyl iodide under conditions most
frequently found in the literature (Pd(OAc)2/PPh3/
Cs2CO3, DMF, 140 °C) indicated rapid consumption
of the starting material and the formation of 2-phenyl-
oxazolo[4,5-b]pyridine, also prepared independently.17
Optimization of the reaction temperature revealed that
ambient temperatures were adequate for efficient aryl-
ation: at 30 °C the product was obtained in 68% isolated
yield (Table 1, entry 1). Using this reaction as a platform
for further screening, the choice of solvent and base was
addressed. In accordance with previous reports polar
solvents performed well; acetone, in particular, was
found to have an advantage over DMF in terms of
yields and ease of work-up. Cesium carbonate proved
to be the base of choice as other common inorganic
bases, including potassium carbonate failed to give any
product. Two equivalents of base were needed since
the yield dropped to 32% with 1 equiv of Cs2CO3.
Next, the effect of ligand and Pd source was examined.
As expected, the combination Pd(OAc)2/PPh3 worked
well giving a 72% yield. A 4:1 molar ratio of PPh3/
Pd(OAc)2 was found to be important for maintaining
catalytic efficiency as lowering the amount of triphenyl-
phosphine from 20 to 10 mol % decreased the reaction
Keywords: Direct Pd-catalyzed arylation; Oxazolopyridine; Oxaz-
olo[4,5-b]pyridine; Azole functionalization.
*
Tel.: +45 45252101; fax: +45 45883136; e-mail: fedorz@kemi.dtu.dk
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.117

2930
F. A. Zhuravlev / Tetrahedron Letters 47 (2006) 2929–2932
Table 1. Screening studies
yield (entry 3). Further investigations into the effect of
ligand indicated that steric factors appeared to be one
of the essential control elements. Tri-2-furylphosphine18
was found to be as efficient as the marginally larger PPh3
(cone angles 133° and 145°). Spatially constrained dppf
led to a lower yield (entry 6) while the use of P(Cy)3 and
P(o-Tol)3 (cone angles 170° and 194°, respectively) gave
no reaction. A recent report7 on direct arylation of p-
excessive aromatics catalyzed by palladium leached
from the solid support led to an attempt to use palla-
dium nanoparticles encapsulated in polyurea matrix as
an alternative source of Pd(0). This gave no arylated
product (entry 8). A number of inorganic additives were
also tested. Among these, CuI was reported to promote
direct arylation of thiazole and thiophene derivatives.4
In the present case, addition of CuI had a deleterious
effect on the reaction yield (entry 9). Neither Pd(OAc)2
nor CuI alone were able to catalyze direct arylation.
O
O
N
PhI, catalyst / ligand
Cs2CO3, solvent,
30 oC, 24 h
Ph
N
N
N
Entry
Solvent
Catalysta/ligandb
Yield (%)
1
2
3
4
5
6
7
8
9
DMF
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/10 mol % PPh3
Pd(PPh3)4
Pd(OAc)2/P(2-furyl)3
Pd(OAc)2/dppf
68
72
42
76
71
52
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
DMF
c
Pd(OAc)2/P(o-Tol)3 or P(Cy)3
Pd(0) EnCat NP30d
—
—
35f
DMF
Pd(OAc)2/PPh3/CuIe
a 5 mol %.
b 20 mol %.
c Below TLC detection limit (<0.5%).
d Available from Aldrich.
e 25 mol %.
The optimized conditions were applied to investigate the
scope of arylation (Table 2). Phenyl iodide proved to be
f 45% in acetone.
Table 2. Reaction scope
ArX, Pd(OAc)2/PPh3
O
O
N
Ar
Cs2CO3, acetone,
30 oC, 24 h
N
N
N
Entry
1
Aryl halide
Producta
Yield (%)
52
O
Br
Ph
N
N
O
N
N
N
N
N
N
N
Cl
N
2
3
4
5
6
7
33
52
67
74
39
61
N
O
H3C
CH3
N
O
I
H3CO
H2N
Cl
OCH3
NH2
Cl
N
O
I
N
O
I
N
O
I
NC
CN
N
O
N
I
O
O
OLeu(L)NBoc
NHBoc
NHBoc
8b
41
48
N
I
O
O
O
N
OLeu(D)NBoc
I
9c
N
a Conditions: 2 equiv aryl halide, 1 equiv heterocycle, 5 mol % Pd(OAc)2, 20 mol % PPh3, 2 equiv Cs2CO3.
b 1 equiv aryl halide, heterocycle.
c 1 equiv aryl halide, 2 equiv heterocycle.

F. A. Zhuravlev / Tetrahedron Letters 47 (2006) 2929–2932
2931
acetone-d6, 30 oC
Cs2CO3
a better coupling partner then phenyl bromide (entry 1),
O
N
O
N
which in turn was superior to 2-chloropyridine. Both
electron-rich (entries 3–5) and electron poor aryl halides
(entries 6 and 7) were similarly reactive giving moderate
to good yields of arylated products.
D
N
N
1
Scheme 1. Deuterium exchange.
Given the success of arylation with a set of conventional
aryl halides, it was intriguing to see whether more
complex and potentially biologically relevant substances
such as terminally modified peptides could be success-
fully coupled. For these, potential epimerization of
stereogenic centers becomes an additional concern. To
test whether the stereochemical integrity is conserved
during the reaction, the L and D enantiomers of N-Boc
protected p-iodobenzylleucinate19 were subjected to
arylation with 1 and 2 equivalents of oxazolo[4,5-b]pyri-
dine. Both experiments resulted in similar yields (entries
8 and 9) and gave enantiomerically pure compounds
within the limits of NMR detection.20
and characterize the deprotonated species in anhydrous
solvents using a variety of bases, however, were frus-
trated by extensive decomposition.
To obtain further insight into the nature of the deproto-
nated species, calculations (B3LYP/6-31G*+) were per-
formed.23 Two minima on the potential energy surface
were located (Fig. 1). 2-Isocyanopyridinolate 2 origi-
nates from the ring opening of the oxazolo[4,5-b]pyridi-
nide 3 and is the more stable of the two. This is expected:
previous experimental and computational studies dem-
onstrated that Li oxazolyl anions strongly favor ring-
opened structures.24,25 Compared to the 20 kcal/mol
that lithiated oxazole gains upon ring-opening, oxaz-
olo[4,5-b]pyridinide is unusually stable being only
8.8 kcal/mol uphill in energy from 2.
The high reactivity of oxazolo[4,5-b]pyridine opens the
question of whether the inherent electronic properties
of the substrate are responsible for the unusually high
rates of arylation or whether some other factors inter-
vene.21 A competition experiment, in which an equi-
molar mixture of oxazolo[4,5-b]pyridine and benzoxazole
was reacted with two equivalents of phenyl iodide
yielded exclusively 2-phenyloxazolo[4,5-b]pyridine.
This stability can be rationalized by suggesting that the
structure of the ring-closed form 3 can be better de-
scribed as an anionic carbene (Fig. 1, structure on the
right). In the anionic carbene structure, the negative
charge can be delocalized onto both the pyridine and
oxazole nitrogen atoms while retaining the aromaticity
of the oxazolopyridine moiety. The NBO charge distri-
bution supports this description: À0.71 at the oxazole
N, À0.55 at the pyridine N, and 0.08 at C-2. The p-dona-
tion from the oxygen and nitrogen atoms into the car-
bene p orbital is an additional important stabilization
factor. The deuterium quench will occur under Curtin–
Hammett conditions, where the stronger but less stable
base 3, is deuterated either at C-2 or at the oxazole nitro-
gen by the solvent. In the latter case, the resulting neutral
carbene will undergo a 1,2-deuterium shift giving 1.
The competition experiment has important mechanistic
ramifications. Electrophilic pathways have been recur-
rently implicated in Pd-catalyzed arylation of
azoles,4,8,15,16 including benzoxazole.4 Despite apparent
structural similarities between benzoxazole and oxaz-
olo[4,5-b]pyridine the electronics of the two are signifi-
cantly different: the presence of an electron-withdrawing
pyridine ring deactivates oxazolo[4,5-b]pyridine toward
electrophilic processes. The combination of high reactiv-
ity and electron-deficiency might suggest that arylation of
oxazolo[4,5-b]pyridine proceeds via a non-electrophilic
pathway. The C–H acidity of benzoxazole was measured
at <15.7 (THF);22 oxazolo[4,5-b]pyridine is expected to
be even more acidic. Thus, the involvement of an anionic
reaction manifold appears to be a viable mechanistic
alternative. Kinetic studies provided further support for
this hypothesis. Running the arylation in deuteroacetone
under otherwise standard conditions and monitoring the
progress by 1H NMR revealed a rapid disappearance of
the oxazolo[4,5-b]pyridine C-2 proton signal. Impor-
tantly, neither the position nor the absolute intensity of
the remaining protons on the pyridine ring of the starting
material significantly changed. The rate of product
formation substantially lagged behind the rate of depro-
tonation. These observations pointed to facile deutera-
tion of the C-2 position of the heterocycle under the
reaction conditions.
The results presented above invite speculation concern-
ing the overall mechanism of the Pd-catalyzed arylation
of oxazolo[4,5-b]pyridine. One can hypothesize that the
transmetalation of ArPd(PPh3)2I by ambidently nucleo-
philic 2 and 3 leads to intermediates 4 and 5, which
reductively eliminate to give the arylated product
(Scheme 2). Under this scenario, the transmetalation
step is expected to be rate determining and would ratio-
nalize the ligand steric requirements observed for this
reaction (vide supra). Metalation of oxazole to oxazol-
2ylzinc followed by Pd-catalyzed cross-coupling with
O
N
N
O
N
O
N
C:
2.0 kcal/mol
N
N
This was further examined by reacting 1 equiv of oxa-
3
O
zolo[4,5-b]pyridine with 2 equiv of Cs2CO3 in acetone-
1
d6. H NMR showed that within several hours the
8.8 kcal/mol
N
NC
starting material was consumed and the product,
characterized as 2-deutero-oxazolo[4,5-b]pyridine 1 was
isolated in 42% yield (Scheme 1). Attempts to generate
2
Figure 1. B3LYP/6-31G*+ (energy levels drawn not to scale).

2932
F. A. Zhuravlev / Tetrahedron Letters 47 (2006) 2929–2932
2. Boger, D. L.; Miyauchi, H.; Du, W.; Hardouin, C.; Fecik,
PPh3
Ph
Ph
C
Ph3P
O
PPh3
O
R. A.; Cheng, H.; Hwang, I.; Hedrick, M. P.; Leung, D.;
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Pd
Pd
O
N
N
Ph
N
B
A
N
N
N
+
4. Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.;
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Pd(PPh3)n
4
5
Scheme 2. Suggested key intermediates in the catalytic cycle.
aryl halides and triflates was reported to give 2-aryloxaz-
ole at room temperature.26,27 The documented proclivity
of oxazol-2ylzinc to form ring closed structures25 lends
support for the suggested intermediate 4. The suggested
pathway B and the palladacycle 5 for which any experi-
mental support is lacking appears to be both kinetically
and thermodynamically competitive from the DFT cal-
culations currently being studied.
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In conclusion, the Pd-catalyzed C-2 arylation of oxa-
zolo[4,5-b]pyridine is reported. The reaction efficiently
proceeds at 30 °C and tolerates a variety of aryl halides,
including D- and L-p-iodobenzylleucinates for which no
racemization was observed. A facile deuteration of the
C-2 position of oxazolo[4,5-b]pyridine is likely to occur
via deprotonation. DFT calculations indicated that the
resulting anionic intermediates exist as a rapidly equili-
brating mixture of open and closed forms. Either one
or both have been suggested to enter the catalytic cycle
as key intermediates.
17. Doise, M.; Dennin, F.; Blondeau, D.; Sliwa, H. Tetra-
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Acknowledgments
19. See Supplementary data.
The Danish Technical University is acknowledged for
the support of this work.
20. Enantiomeric purity was determined using a lanthanide
chiral shift reagent; see Supplementary data.
21. An alternative mechanistic scenario might include, for
example, an in situ catalyst modification by potentially
ligating oxazolo[4,5-b]pyridine.
22. Fraser, R. R.; Mansour, T. S.; Savard, S. Can. J. Chem.
1985, 63, 3505–3509.
23. Jaguar 4.2 Schrodinger, Portland, OR, 1991–2000. All
calculations included treatment of solvation using acetone
as solvent. See Supplementary data for computational
details.
Supplementary data
Experimental procedures and spectroscopic data for all
new compounds and computational details are pre-
sented. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2006.02.117.
24. Hilf, C.; Bosold, F.; Harms, K.; Marsch, M.; Boche, G.
Chem. Ber. Recl. 1997, 130, 1213–1221.
25. Boche, G.; Bosold, F.; Hermann, H.; Marsch, M.; Harms,
K.; Lohrenz, J. C. W. Chem. Eur. J. 1998, 4, 814–817.
26. Anderson, B. A.; Harn, N. K. Synthesis 1996, 583–585.
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