A mild and efficient one-pot synthesis of 2-aminated benzoxazoles and benzothiazoles

Article abstract of DOI:10.1021/jo900308t

Previous syntheses of the biologically active 2-aminated benzoxazoles have relied on forcing thermal conditions to generate the products directly from the corresponding thiols. The resulting yields have ranged from moderate to poor. A mild and high-yielding alternative one-pot chlorination-amination procedure is described. Compounds with a variety of substitution patterns are reported and the methodology has been successfully extended to benzothiazoles. Palladium catalysis on suitably activated examples has been employed to generate the desired compounds of interest.

Full text of DOI:10.1021/jo900308t

facile and efficient synthesis of these compounds is therefore
highly desirable. During the course of a recent project we
became interested in the synthesis of such compounds. Herein
we wish to report a mild and efficient one-pot synthesis of
2-aminated benzoxazoles and benzothiazoles. In addition,
halogenated variants of these core motifs are shown to be
excellent substrates for palladium-catalyzed reactions, allowing
for the rapid construction of complex compounds.
A Mild and Efficient One-Pot Synthesis of
2-Aminated Benzoxazoles and Benzothiazoles
Gavin W. Stewart,* Carl A. Baxter, Ed Cleator, and
Faye J. Sheen
Department of Process Research, Merck Sharp & Dohme
Research Laboratories, Hertford Road, Hoddesdon,
Hertfordshire, EN11 9BU, United Kingdom
gaVin_stewart@merck.com
ReceiVed February 13, 2009
FIGURE 1. Serotonin (5-HT).
Existing methods toward 2-aminated benzoxazoles and ben-
zothiazoles have involved nucleophilic displacement of the thiol
moiety with an appropriate amine at elevated temperature
(refluxing toluene, Scheme 1). We discounted this approach as
the yields ranged from moderate to poor. Moreover, hydrogen
sulfide is liberated, which is both highly toxic and flammable.
Previous syntheses of the biologically active 2-aminated
benzoxazoles have relied on forcing thermal conditions to
generate the products directly from the corresponding thiols.
The resulting yields have ranged from moderate to poor. A
mild and high-yielding alternative one-pot chlorination-
amination procedure is described. Compounds with a variety
of substitution patterns are reported and the methodology
has been successfully extended to benzothiazoles. Palladium
catalysis on suitably activated examples has been employed
to generate the desired compounds of interest.
SCHEME 1. Typical Existing Literature Routes to
2-Aminated Benzoxazoles
5-Hydroxytryptamine (1, serotonin, 5-HT, Figure 1) is an
important compound that is involved in several biological
pathways.1 Selective 5-HT3 receptor antagonists effectively
prevent radiation- and chemotherapy-induced emesis.2,3 They
have also been used successfully as a novel therapeutic agents
for diarrhea-predominant irritable bowel syndrome (IBS).4
However, up to 30% of IBS patients have reported significant
side effects. It has been proposed that 5-HT3 receptor partial
agonists may alleviate these side effects by the control of
gastroenteric motility.5-7 Benzoxazole derivatives with a nitrogen-
containing heterocyclic substituent at the 2-position have been
A more indirect route to these compounds is preparation of
the chloride followed by displacement with an amine to form
the compounds of interest (Scheme 1). However, the literature
examples with this strategy rely on the use of PCl5 at elevated
temperatures. These forcing conditions often necessitate that the
chloride intermediate is isolated prior to the displacement
reaction. Unfortunately, in many cases, these chlorides are
unstable once isolated. We hypothesized that if it was possible
to prepare this chloride using a milder set of reaction conditions,
the amine could be added to the reaction mixture and potentially
generate the desired product in a one-pot procedure.
After careful experimentation, we discovered that preparation
of the Vilsmeier reagent in situ by addition of oxalyl chloride
((COCl)2, 1.5 equiv) to a solution of 2-mercaptobenzoxazole
in dichloromethane (CH2Cl2), followed by dropwise addition
of N,N-dimethylformamide (DMF), led to complete conversion
to the corresponding 2-chlorobenzoxazole within 1 h at room
temperature. It is noteworthy that employing solely (COCl)2 or
thionyl chloride (SOCl2) in the absence of DMF led to
found to act as selective 5-HT3 receptor partial agonists.5-7
A
(1) Kilpatrick, G. J.; Bunce, K. T.; Tyers, M. B. Med. Res. ReV. 1990, 10,
441–475, and references cited therein.
(2) Sanger, G. J.; Nelson, D. R. Eur. J. Parmacol. 1989, 159, 113–124.
(3) Butler, A.; Hill, J. M.; Ireland, S. J.; Jordan, C. C.; Tyers, M. B. Br. J.
Pharmacol. 1988, 94, 397–412.
(4) Camilleri, M.; Northcutt, A. R.; Kong, S.; Dukes, G. E.; McSorley, D.;
Mangel, A. W. Lancet 2000, 355, 1035–1040.
(5) Yasuo, S.; Megumi, Y.; Satoshi, Y.; Tomoko, S.; Midori, I.; Tetsutaro,
N.; Kokichi, S.; Fukio, K. J. Med. Chem. 1998, 41, 3015–3021.
(6) Sato, Y.; Imai, M.; Amano, K.; Iwamatsu, K.; Konno, F.; Kurata, Y.;
Sakakibara, S.; Hachisu, M.; Izumi, M.; Matski, X.; Saito, H. Biol. Pharm. Bull.
1997, 20, 752–755.
(7) Yoshida, S.; Shiokawa, S.; Kawano, K.; Ito, T.; Murakami, H.; Suzuki,
H.; Sato, Y. J. Med. Chem. 2005, 48, 7075–7079.
10.1021/jo900308t CCC: $40.75
Published on Web 03/24/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 3229–3231 3229

TABLE 1. Substituted Benzoxazoles/Benzothiazoles
SCHEME 2. Chlorination/Amination of Substituted
Benzoxazoles/Benzothiazoles
SCHEME 3. Proposed Mechanism
Bearing these important points in mind, stirring this reaction
mixture for 2 h led to complete amination at the 2-position.
The reaction was found to be general for a number of substituted
benzoxazoles and benzothiazoles with selected primary (Table
1, entries 2, 3, 4, and 5) and secondary amines (Table 1, entries
1, 6, 7, 8, 9, and 10) affording aminated products in good to
excellent yields (Scheme 2, Table 1).
The proposed mechanism for chloride formation (Scheme 3)
involves the generation of Vilsmeier reagent 2 that then reacts
with the thiol 3 to give the activated sulfide 4. Breakdown of 4
leads to the chlorinated product 5 with concomitant formation
of N,N-dimethylthioformamide 6, which is observed as a
byproduct in the final reaction mixture.
With the mild one-pot chlorination/amination in hand atten-
tion was turned to further elaboration of the heterocyclic core.
We surmised that the substituted benzoxazoles and benzothia-
zoles bearing an aryl halide could be aminated under conditions
developed by Buchwald (Scheme 4).11 Applying these condi-
tions to our system and using XPhos as the ligand of choice,
both the 5- and 6-chloro compounds were found to generate
the desired coupled product in excellent yields (Table 2). In
addition, both primary and secondary amines were found to be
well tolerated in this reaction.
Finally, these halides were also found to be amenable to
Suzuki couplings. Treatment of 5-chlorobenzoxazole 7 with
pyridine-3-boronic acid 8 gave access to cross-coupled product
9 in 65% yield under standard conditions12 (Scheme 5).
In summary, we have developed a mild and high-yielding
one-pot chlorination/amination of substituted 2-mercaptoben-
zoxazoles and benzothiazoles. This method obviates the need
a Analytical samples were obtained by chromatography and/or
recrystallization.
unsuccessful reactions. Likewise, a combination of SOCl2 and
DMF also gave disappointing results at room temperature. The
order of addition of the reagents was found to be critical to the
success of the reaction. If the (COCl)2 was added to a mixture
of the 2-mercaptobenzoxazole in CH2Cl2/DMF, incomplete
reactions were observed which were attributed to the poor
mobility of the reaction mixture (viscous slurries were formed).
Attempts to reinitiate stalled reaction streams were unsuccessful.
However, if the DMF was added last, the chlorination was
complete within 1 h at room temperature. It was necessary to
maintain a reaction temperature of less than 25 °C during the
addition of DMF to avoid generating the corresponding 2-dim-
ethylamino derivative (decomposition of DMF generates dim-
ethylamine).8 After complete chlorination, the reaction mixture
was then treated with triethylamine (3 equiv) and a primary or
secondary amine (1.2 equiv). Temperature control was also
found to be important during the addition of triethylamine to
avoid formation of the corresponding diethylamino derivative.10
(8) Sharpe, C. J.; Palmer, P. J.; Evans, D. E.; Brown, G. R.; King, G.;
Shadbolt, R. S.; Trigg, R. B.; Ward, R. J. J. Med. Chem. 1972, 15, 523–529.
(9) Sato, Y.; Yamada, M.; Yoshida, S.; Soneda, T.; Ishikawa, M.; Nizato,
T.; Suzuki, K.; Konno, F. J. Med. Chem. 1998, 41, 3015–3021.
(11) Charles, M. D.; Schultz, P.; Buchwald, S. L. Org. Lett. 2005, 7, 3965–
3968.
(12) Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3358–
3366.
(10) Advani, S. P.; Sam, J. J. Pharm. Sci. 1968, 1693–1696.
3230 J. Org. Chem. Vol. 74, No. 8, 2009

SCHEME 4. Amination of Aryl Halides
(5 mL). The combined organics assayed for 560 mg of the title
compound (77%). A pure analytical sample was obtained by
recrystallization from acetonitrile/water. Mp 109-111 °C; 1H NMR
(400 MHz, CDCl3) δH 7.32 (1 H, d, J ) 2.0 Hz), 7.17 (1 H, d, J
) 8.6 Hz), 7.01 (1 H, dd, J ) 2.0, 8.6 Hz), 3.83 (4 H, m), 3.70 (4
H, m); 13C NMR (100 MHz, CDCl3) δC 162.8, 147.4, 144.3, 129.4,
120.7, 116.6, 109.3, 66.1, 45.6; HRMS (ESI+) calcd for
C11H11ClN2O2 239.0587, found 239.0595.
General Procedure 1 for the Pd-Catalyzed Amination of
Benzoxazoles and Benzothiazoles. To a flask containing a
magnetic stir bar was added the aryl halide, sodium tert-butoxide,
Pd2dba3 ·CHCl3, ligand A, and amine in cases where this was solid.
The flask was evacuated and backfilled with nitrogen twice. The
amine was added with a syringe in cases where this was liquid
followed by toluene. The flask was evacuated and backfilled with
nitrogen twice, then heated to 90 °C for 16 h. The reaction mixture
was cooled to room temperature, then purified by silica gel
chromatography (100% hexane to 80% ethyl acetate in hexane) to
provide the products.
TABLE 2. Aminated Benzoxazoles/Benzothiazoles
(2-Morpholin-4-yl-benzothiazol-5-yl)-p-tolylamine (Table 2,
Entry 1). Following general procedure 1, 5-chloro-2-morpholin-
4-yl-benzothiazole (70 mg, 0.28 mmol), 4-methylaniline (35 mg,
0.33 mmol), sodium tert-butoxide (37 mg, 0.39 mmol),
Pd2dba3 ·CHCl3 (5.0 mg, 0.0055 mmol, 2 mol %), ligand A (10.5
mg, 0.0220 mmol, 8 mol %), and toluene (2 mL) were stirred at
90 °C for 16 h. After silica gel chromatography the title compound
was isolated as a pale brown solid (75.4 mg, 85%). Mp 163-168
1
°C; H NMR (400 MHz, CDCl3) δH 7.43 (1H, d, J ) 8.4 Hz),
7.29-7.26 (1H, m), 7.07 (2H, d, J ) 8.4 Hz), 7.01 (2H, d, J ) 8.4
Hz), 6.79 (1H, dd, J ) 8.4, 2.0 Hz), 5.67 (1H, br s), 3.84-3.80
(4H, m), 3.62-3.58 (4H, m), 2.30 (3H, s); 13C NMR (100 MHz,
CDCl3) δC 170.1, 153.9, 143.1, 140.7, 130.8, 130.0, 122.1, 121.2,
118.8, 112.9, 107.8, 66.4, 48.5, 20.8; HRMS (ESI+) calcd for
C18H19N3OS 326.1327, found 326.1313.
2-Morpholin-4-yl-5-pyridin-3-yl-benzoxazole (9). To a flask
containing a magnetic stir bar was added the 5-chloro-2-morpholin-
4-ylbenzoxazole (50 mg, 0.21 mmol), pyridine-3-boronic acid (39
mg, 0.31 mmol), potassium phosphate tribasic (89 mg, 0.42 mmol),
Pd2dba3 ·CHCl3 (1.9 mg, 0.0021 mmol, 1 mol %), and ligand A
(4.0 mg, 0.0084 mmol, 4 mol %). The flask was evacuated and
backfilled with nitrogen twice. n-Butanol (2 mL) was added then
flask was evacuated and backfilled with nitrogen twice and then
heated to 100 °C for 18 h. The reaction mixture was cooled to
room temperature, then filtered through a pad of Celite, eluting
with EtOAc. The solution was concentrated, then purified by silica
gel chromatography (100% hexane to 80% ethyl acetate in hexane)
to provide the title compound as a white solid (38.5 mg, 65%).
SCHEME 5. Suzuki coupling
for forcing conditions and/or the isolation of the unstable
chloride intermediates. Products bearing an aryl halide can be
further elaborated by using palladium-mediated reactions to
generate compounds of biological interest in a short and efficient
manner.
1
Mp 150-155 °C; H NMR (400 MHz, CDCl3) δH 8.85 (1H, d, J
) 1.6 Hz), 8.57 (1H, dd, J ) 4.8, 1.2 Hz), 7.87 (1H, dt, J ) 7.6,
1.6 Hz), 7.56 (1H, d, J ) 1.6 Hz), 7.38-7.34 (2H, m), 7.25 (1H,
dd, J ) 8.0, 1.6 Hz), 3.86-3.82 (4H, m), 3.74-3.71 (4H, m); 13
C
NMR (100 MHz, CDCl3) δC 162.8, 149.2, 147.7, 147.4, 144.1,
137.6, 135.4, 134.1, 124.0, 120.4, 115.3, 109.4, 66.3, 45.9; HRMS
(ESI+) calcd for C16H15N3O2 282.1243, found 282.1238.
Experimental Section
5-Chloro-2-morpholin-4-yl-1,3-benzoxazole (Table 1, Entry
1). To a mixture of 5-chloro-2-mercaptobenzoxazole (564 mg, 3.04
mmol) in dichloromethane (5 mL) was added oxalyl chloride (0.40
mL, 4.56 mmol). The reaction was cooled to 0 °C and N,N-
dimethylformamide (2 mL) was added dropwise at 0-5 °C. The
reaction was warmed to 20 °C, aged for 1 h, then recooled to 0 °C.
Triethylamine (1.27 mL, 9.12 mmol) was added dropwise at 0-10
°C followed by morpholine (0.29 mL, 3.34 mmol). The reaction
was warmed to 20 °C and aged for 1 h. The reaction was diluted
with water (5 mL) and dichloromethane (5 mL). The phases were
separated and the aqueous layer was extracted with dichloromethane
Acknowledgment. We thank Simon Hamilton and Alexia
Bertrand for mass spectrometry work.
Supporting Information Available: Experimental proce-
1
dures, characterization data, and copies of H and 13C NMR
spectra for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO900308T
J. Org. Chem. Vol. 74, No. 8, 2009 3231