Iron-catalyzed intramolecular O-arylation: Synthesis of 2-aryl benzoxazoles

Article abstract of DOI:10.1021/ol800744y

(Chemical Equation Presented) A practical iron-catalyzed intramolecular O-arylation reaction and its application in the synthesis of benzoxazole derivatives, starting from the readily available 2-haloanilines, is presented. The key cyclization step involves the use of a combination of the cheap and environmentally friendly FeCl₃ and 2,2,6,6-tetramethyl-3,5 heptanedione (TMHD) as the catalyst system.

Full text of DOI:10.1021/ol800744y

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2665-2667
Iron-Catalyzed Intramolecular
O-Arylation: Synthesis of 2-Aryl
Benzoxazoles
Julien Bonnamour and Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen UniVersity, Landoltweg 1,
D-52056 Aachen, Germany
carsten.bolm@oc.rwth-aachen.de
Received April 2, 2008
ABSTRACT
A practical iron-catalyzed intramolecular O-arylation reaction and its application in the synthesis of benzoxazole derivatives, starting from the
readily available 2-haloanilines, is presented. The key cyclization step involves the use of a combination of the cheap and environmentally
friendly FeCl3 and 2,2,6,6-tetramethyl-3,5 heptanedione (TMHD) as the catalyst system.
Benzoxazoles are privileged organic compounds of medicinal
significance due to their recognized biological and therapeutic
activities.1 As such, these heterocycles constitute key struc-
tural motifs in a wide range of natural products and are thus
appealing targets in drug synthesis.2 Commonly, the prepara-
tion of 2-substituted benzoxazoles starts from ortho-ami-
nophenols, and often it implies the use of either highly toxic
reagents or harsh reaction conditions such as those involving
strong acids in combination with high temperatures.3 Some
of these drawbacks have recently been overcome by the
development of novel and more sustainable processes, which
allow the efficient assembly of the target heterocycles under
comparatively milder reaction conditions.4 Among those
protocols, copper-catalyzed intramolecular O-arylations of
ortho-haloanilides represent an elegant and straightforward
means for the preparation of the benzoxazole ring system.5
(1) For examples in medicinal chemistry, see: (a) McKee, M. L.; Kerwin,
S. M. Bioorg. Med. Chem. 2008, 16, 1775. (b) Oksuzoglu, E.; Tekiner-
Gulbas, B.; Alper, S.; Temiz-Arpaci, O.; Ertan, T.; Yildiz, I.; Diril, N.;
Sener-Aki, E.; Yalcin, I. J. Enzyme Inhib. Med. Chem. 2008, 23, 37. (c)
Oksuzoglu, E.; Temiz-Arpaci, O.; Tekiner-Gulbas, B.; Eroglu, H.; Sen, G.;
Alper, S.; Yildiz, I.; Diril, N.; Aki-Sener, E.; Yalcin, I. Med. Chem. Res.
2007, 16, 1. (d) Potashman, M. H.; Bready, J.; Coxon, A.; DeMelfi, T. M.,
Jr.; DiPietro, L.; Doerr, N.; Elbaum, D.; Estrada, J.; Gallant, P.; Germain,
J.; Gu, Y.; Harmange, J.-C.; Kaufman, S. A.; Kendall, R.; Kim, J. L.; Kumar,
G. N.; Long, A. M.; Neervannan, S.; Patel, V. F.; Polverino, A.; Rose, P.;
Van der Plas, S.; Whittington, D.; Zanon, R.; Zhao, H. J. Med. Chem. 2007,
50, 4351. (e) Huang, S.-T.; Hsei, I-J.; Chen, C. Bioorg. Med. Chem. 2006,
14, 6106.
(3) For example, see: (a) Hein, D. W.; Alheim, R. J.; Leavitt, J. J. J. Am.
Chem. Soc. 1957, 79, 427. (b) Terashima, M.; Ishii, M.; Kanaoka, Y.
Synthesis 1982, 484. (c) Bougrin, K.; Loupy, A.; Soufiaoui, M. Tetrahedron
Lett. 1998, 54, 8055. (d) Chang, J.; Zhao, K.; Pan, S. Tetrahedron Lett.
2002, 43, 951. (e) Kawashita, Y.; Nakamichi, N.; Kawabata, H.; Hayashi,
M. Org. Lett. 2003, 5, 3713. (f) Seijas, J. A.; Va´zquez-Tato, M. P.;
Carballido-Reboredo, M. R.; Crecente-Campo, J.; Romar-Lo´pez, L. Synlett
2007, 313. (g) Seijas, J. A.; Va´zquez-Tato, M. P.; Carballido-Reboredo,
M. R.; Crecente-Campo, J.; Romar-Lo´pez, L. Synlett 2007, 313.
(4) Selected examples: (a) Sezen, B.; Sames, D. Org. Lett. 2003, 5, 3607.
(b) Lewis, J. C.; Wiedemann, S. H.; Bergman, R. G.; Ellman, J. A. Org.
Lett. 2004, 6, 35. (c) Lewis, J. C.; Wu, J. Y.; Bergman, R. G.; Ellman,
J. A. Angew. Chem., Int. Ed. 2006, 45, 1589. (d) Do, H.-Q.; Daugulis, O.
J. Am. Chem. Soc. 2007, 129, 12404. (e) Downer-Riley, N. K.; Jackson,
Y. A. Tetrahedron 2007, 61, 10276.
(2) For example: (a) Easmon, J.; Purstinger, G.; Thies, K.-S.; Heinisch,
G.; Hofmann, J. J. Med. Chem. 2006, 49, 6343. (b) Sun, L.-Q.; Chen, J.;
Cruce, M.; Deskus, J. A.; Epperson, J. R.; Takaki, K.; Johnson, G.; Iben,
L.; Malhe, C. D.; Ryan, E.; Xu, C. Bioorg. Med. Chem. Lett. 2004, 14,
3799. (c) Kumar, D.; Jacob, M. R.; Reynolds, M. B.; Kerwin, S. M. Bioorg.
Med. Chem. 2002, 10, 3997.
(5) (a) Altenhoff, G.; Glorius, F. AdV. Synth. Catal. 2004, 346, 1661.
(b) Evindar, G.; Batey, R. A. J. Org. Chem. 2006, 71, 1802. (c) Barbero,
N.; Carril, M.; SanMartin, R.; Dom´ınguez, E. Tetrahedron 2007, 63, 10425.
(d) Viirre, R. D.; Evindar, G.; Batey, R. A. J. Org. Chem. 2008, 73, 3452.
10.1021/ol800744y CCC: $40.75
Published on Web 05/29/2008
2008 American Chemical Society

Despite the recent findings of various iron-catalyzed orga-
nic transformations,6 the challenging field of carbon-hetero-
atom bond formations has remained largely undeveloped.7
Along these lines, we have recently reported novel and
practical C-N, C-O, and C-S cross-couplings of aryl
halides with nitrogen,8 oxygen,9 and sulfur nucleophiles,10
respectively, utilizing catalyst systems comprised of FeCl3
in combination with appropriately chosen ligands. More
specifically, N- and S-arylations efficiently proceeded in the
presence of catalytic amounts of FeCl3 and N,N′-dimethyl-
ethylendiamine (DMEDA), whereas O-arylations required
the use of a combination of FeCl3 and 2,2,6,6-tetramethyl-
3,5-heptanedione (TMHD). In connection with these en-
couraging results, we report herein an iron-catalyzed in-
tramolecular O-arylation reaction, which yields synthetically
valuable 2-substituted benzoxazoles.
Table 1. Iron-Catalyzed O-Arylations of Amide 1aa
entry
base
solvent
temp (°C)
2ab (%)
1
2
3
4
5
6
7
8
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
K2CO3
NaOt-Bu
none
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
135
120
110
80
98 (42)
88 (traces)
66 (0)
22 (0)
0 (0)
56
60
120
120
120
120
120
120
120
120
54
13
9
DMF
0
10
11
12
13
dioxane
DME
toluene
CH3CN
72
40
N-(2-Bromophenyl)benzamide (1a), which can easily be
synthesized by benzoylation of commercially available
2-bromoaniline, was selected as a model substrate for the
optimization of the reaction conditions. Taking into account
the observations made in the intermolecular O-arylations,9
a reagent combination of FeCl3, TMHD, Cs2CO3, and DMF
was tested (Table 1, entry 1). To our delight, benzamide 1a
cyclized smoothly at 135 °C to give benzoxazole 2a in 98%
yield. Noteworthy was the fact that in this case the bromo
derivative reacted so well, whereas the intermolecular
coupling processes required the use of the more reactive
iodoarenes. There, bromo derivatives reacted slowly, needing
prolonged reaction times to ensure acceptable yields.9 A
reaction performed in the absence of FeCl3/TMHD afforded
2a in only 42% yield, suggesting that in the initial experiment
both an iron-catalyzed cyclization as well as a nucleophilic
substitution led to the high yield of 2a. Consequently, the
subsequent reactions were carried out at lower temperatures
to minimize the annulation Via aromatic substitution.11 Thus,
at 120 °C benzoxazole 2a was obtained in 88% yield, and
the blank experiment (without the iron catalyst) confirmed
that those results corresponded predominantly to the iron-
0
65
a Reaction conditions: 1a (1 equiv), FeCl3 (0.1 equiv), TMHD (0.2
equiv), base (2.0 equiv), solvent (1 mL/mmol of 1a), 20 h. b Yield of product
after chromatography; in parentheses, results from experiments performed
in the absence of FeCl3/TMHD.
catalyzed arylation reaction (Table 1, entry 2). At lower
temperatures, the yield of 2a significantly dropped (entries
3-5).
Another set of experiments revealed the crucial role of
the base and the solvent. Thus, use of Cs2CO3 led to the
best results, and other bases such as K3PO4, K2CO3 and
NaOt-Bu (Table 1, entries 6-8) furnished the target
benzoxazole 2a in lower yields. In the absence of the base
no product was obtained (entry 9). Also the use of solvents
other than DMF resulted in lower yields of 2a (entries
10-13).
Table 2. Influence of the Nature of the Catalyst in the
Intramolecular Cyclization of 1a to give Benzoxazole 2aa
(6) For general overviews on iron catalyses, see: (a) Bolm, C.; Legros,
J.; PaihJ. L.; Zani L, Chem. ReV. 2004, 104, 6217. (b) Fu¨rstner, A.; Martin,
R. Chem. Lett. 2005, 624.
entry
iron source
ligand
2a (%)b
1
2
3
FeCl3
none
FeCl3
TMHD
TMHD
none
88
0
0
25
77
75
85
80
86
75
(7) For selected recent iron-catalyzed carbon-heteroatom bond forming
processes, see: (a) Komeyama, K.; Morimoto, T.; Takaki, K. Angew. Chem.,
Int. Ed. 2006, 45, 2938. (b) Plietker, B. Angew. Chem., Int. Ed. 2006, 45,
6053. (c) Nakanishi, M.; Bolm, C. AdV. Synth. Catal. 2007, 349, 861. (d)
Chen, M. S.; White, C. Science 2007, 318, 783. (e) Gelalcha, F. G.;
Bitterlich, B.; Anilkumar, G.; Tse, M. T.; Beller, M. Angew. Chem., Int.
Ed. 2007, 46, 7293. (f) Kawatsura, M.; Komatsu, Y.; Yamamoto, M.;
Hayase, S.; Itoh, T. Tetrahedron Lett. 2007, 48, 6480. (g) Jana, U.; Maiti,
S.; Biswas, S. Tetrahedron Lett. 2008, 49, 858.
4
5
6
FeCl3
FeCl3
Fe2O3
DMEDA
N,N′-dimethylglycine
TMHD
7
8
FeCl3·6H2O
FeBr2
TMHD
TMHD
(8) (a) Correa, A.; Bolm, C. Angew. Chem., Int. Ed. 2007, 46, 8862.
(b) Correa, A.; Bolm, A. AdV. Synth. Catal. 2008, 350, 391. (c) Correa, A.;
Elmore, S.; Bolm, C. Chem.-Eur. J. 2008, 14, 3527.
9
10
Fe(OAc)2
Fe(ClO4)2
TMHD
TMHD
a Reaction conditions: 1a (1 equiv), [Fe] (0.10 equiv), ligand (0.20
equiv), Cs2CO3 (2.0 equiv), DMF (1 mL/mmol of 1a), 120 °C, 20 h. b Yield
of isolated product after chromatography.
(9) Bistri, O.; Correa, A.; Bolm, C. Angew. Chem., Int. Ed. 2008, 47,
586.
(10) Correa, A.; Carril, M.; Bolm, C. Angew. Chem., Int. Ed. 2008, 47,
2880.
(11) For examples of benzoxazole formations that proceeded Via either
aryne intermediates or aromatic substitutions, see: (a) Hrutford, B. F.;
Bunnett, J. F. J. Am. Chem. Soc. 1958, 80, 2021. (b) El-Sheikh, M. I.; Marks,
A.; Biehl, E. R. J. Org. Chem. 1981, 46, 3256. (c) Reavill, D. R.; Richardson,
S. K. Synth. Commun. 1990, 20, 1423. (d) Inukai, Y.; Sonoda, T.; Kobayashi,
H. Bull. Chem. Soc. Jpn. 1979, 52, 2657.
Next, the effect of the catalyst composition on the
benzoxazole formation with Cs2CO3 in DMF at 120 °C
was studied (Table 2). Reactions performed in the absence
2666
Org. Lett., Vol. 10, No. 13, 2008

superior to those involving FeCl3 together with DMEDA
or N,N′-dimethylglycine (entries 1 vs 4, and 5). Further-
more, the process proved compatible with the use of other
iron(III) sources such as Fe2O3 and FeCl3·6H2O (entries
6 and 7). Iron in the oxidation state +2 was also applicable
as shown by the successful use of FeBr2, Fe(OAc)2 and
Fe(ClO4)2 (entries 8-10). In all cases benzoxazole 2a was
obtained in good to high yields. Balancing all results it
was concluded that the optimal conditions for the in-
tramolecular O-arylation involved the use of FeCl3,
TMHD, and Cs2CO3 in DMF at 120 °C.
Table 3. Iron-Catalyzed Synthesis of Benzoxazole Derivatives
2a
Finally, the scope of the iron-catalyzed intramolecular
O-arylation was explored. As summarized in Table 3,
several ortho-halobenzamides provided the corresponding
2-substituted benzoxazole derivatives in good to excellent
yields. Also the iodo analogue of 1a cyclized well
affording benzoxazole 2a in high yield (entry 2). Con-
versely, the chloro derivative proved unreactive under
those conditions (entry 3). The nature of the substituent
R2 directly linked to the carbonyl moiety was of major
importance. Thus, various substrates bearing differently
substituted aromatic motifs at that position were converted
to the desired benzoxazoles 2 in satisfactory to high yields
(entries 1-13). In contrast, halobenzamides with aliphatic
or vinylic substituents R2 did not cyclize at all (entries
14-16). Steric hindrance hampered the reaction and hence
benzoxazoles 2f and 2g were obtained in comparatively
lower yields, despite performing the cyclization for longer
reaction times or using the iodo-arene as electrophilic
coupling partner. Aromatic amides bearing additional
substituents (R1) on the bromoarene portion of the
molecule furnished the corresponding benzoxazoles in
good yields (entry 12 and 13).
In summary, we have developed an efficient iron-catalyzed
intramolecular O-arylation, which represents a practical and
straightforward approach toward 2-aryl substituted benzox-
azole derivatives. The key cyclization step involves the use
of cheap, easy-to-handle and environmentally benign FeCl3
in combination with TMHD. The use of a simple iron salt
as catalyst renders the protocol suitable for large-scale
synthesis, providing a valuable synthetic tool for industrial
applications.
Acknowledgment. We are grateful to the Fonds der
Chemischen Industrie for financial support. We also thank
Dr. A. Correa (RWTH Aachen University) for the sup-
porting ideas and help during the preparation of this
manuscript.
a 1 (1 equiv), FeCl3 (0.10 equiv), TMHD (0.20 equiv), Cs2CO3 (2.0
equiv), DMF (1 mL/mmol of 1), 20 h. b Yield of isolated product after
chromatography. c Reaction time: 72 h.
Supporting Information Available: Experimental pro-
cedures and spectral data for all compounds. This material
isavailablefreeofchargeviatheInternethttp://pubs.acs.org.
of either FeCl3 or the ligand confirmed that the presence
of both was required for amide cyclization (entries 2 and
3). The combination of the iron salt with TMHD proved
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