One-pot synthesis of hydroxybenzo[d]- oxazole-2-aliphatic acid derivatives by Meerwein's reagent

Article abstract of DOI:10.1080/00397911.2011.567435

(Chemical Equation Presented) A general one-pot synthesis of hydroxylbenzo[d]oxazole-2-aliphatic acid esters and hydroxylbenzo[d]oxazole-2- amino acid esters was successfully achieved in good yield by using Meerwein's reagent. Copyright Taylor & Francis G

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One-Pot Synthesis of Hydroxybenzo[d]-
oxazole-2-aliphatic Acid Derivatives by
Meerwein's Reagent
Wei Zhang a , Wenlu Liu a , Xizhen Jiang a , Faqin Jiang a & Lei Fu a
a School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
Accepted author version posted online: 31 Oct 2011.Version of
record first published: 29 May 2012.
To cite this article: Wei Zhang, Wenlu Liu, Xizhen Jiang, Faqin Jiang & Lei Fu (2012): One-Pot
Synthesis of Hydroxybenzo[d]-oxazole-2-aliphatic Acid Derivatives by Meerwein's Reagent, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
42:18, 2772-2779
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Synthetic Communications1, 42: 2772–2779, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.567435
ONE-POT SYNTHESIS OF HYDROXYBENZO[d]-
OXAZOLE-2-ALIPHATIC ACID DERIVATIVES BY
MEERWEIN’S REAGENT
Wei Zhang, Wenlu Liu, Xizhen Jiang, Faqin Jiang, and Lei Fu
School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
GRAPHICAL ABSTRACT
Abstract A general one-pot synthesis of hydroxylbenzo[d]oxazole-2-aliphatic acid esters
and hydroxylbenzo[d]oxazole-2-amino acid esters was successfully achieved in good yield
by using Meerwein’s reagent.
Keywords 2-Aminophenol; benzo[d]oxazole; Meerwein’s reagent; triethyloxonium tetra-
fluoroborate
INTRODUCTION
Benzoxazole derivatives were found to have biological activities. In cancer
research, benzoxazoles have been explored as VEGFR-2 inhibitors,[1] CSF-1 R inhi-
bitors,[2] LPAAT-b inhibitors,[3] EDGR inhibitors,[4] Janus kinases inhibitors[5], and
GnRH receptor inhibitors.[6] In the mean time, benzoxoazole fragments have drawn
Received November 23, 2010.
Address correspondence to Lei Fu, School of Pharmacy, Shanghai Jiao Tong University, Dong
Chuan Road 800, MinHang District, Shanghai 200240, China. E-mail: leifu@sjtu.edu.cn
2772

HYDROXYBENZO[d]OXAZOLE-2-ALIPHATIC ACID
2773
considerable attention over the past few years for their antimicrobial activities, and
antibiotics containing benzoxoazole modules have been developed.[7,8]
The synthesis of benzo[d]oxazole has been reported and promoted in many
articles. Generally, benzo[d]oxazole has been formed from various 2-aminophenols
with acid anhydride,[9] carboxylic acid,[10] acylchloride,[11] amide,[12] or carboxylic
ether.[13] These common methods were usually applied to synthesize simple and
stable benzo[d]oxazole derivatives, as they require high temperature
(100–300 ꢀC)[12,14] and=or stong acidic catalysts (e.g., p-TsOH[11], P2O5,[15] PPTS[16]
and POCl3[17]). A gentle method was therefore developed, in which 2-aminophenols
was condensed with imidate esters under reflux conditions in methanol or ethanol to
complete cyclization, giving benzo[d]oxazole in good yields.[18,19] However, the imi-
date esters generally existed in hydrochloride salt form and were presynthesized from
nitriles and alcohols in ether or hexane solution by bubbling with dry hydrogen
chloride gas.[20,21] Furthermore, the imidate esters are usually water sensitive and
unstable, and hence difficult to handle.[22]
Meyers et al.[23] and Hall et al.[24] utilized aromatic imidate esters from aromatic
amide by Meerwein’s reagent, triethyloxonium tetrafluoroborate ðEt3OþBF4ꢁÞ, to
Scheme 1. Synthesis of hydroxybenzo[d]oxazol-2-aliphatic acid esters 4a–e and 5a and b.

2774
W. ZHANG ET AL.
synthesize aryl-substituted oxazoline cycles. Their successful application had
prompted us to explore the synthesis of benzo[d]oxazole by Meerwein’s reagent.
In this communication, we reported the synthesis of a family of more complex
hydroxybenzo[d]oxazole-2-aliphatic acid derivatives 4a-e and hydroxybenzo[d]oxazole-
2-amino acid derivatives 5a and b as shown in Scheme 1. In general, Meerwein’s
reagent ðEt3OþBFꢁ4 Þ was prepared according to the modified methods reported by
Table 1. Yields of hydroxylbenzo[d]oxazole-2-aliphatic acid esters (4a–e) and hydroxylbenzo[d]oxazole-
2-amino acid esters (5a and b)
Reactant 1
Reactant 2
Products
Yield (%)
80
75
70
60
73
60
55

HYDROXYBENZO[d]OXAZOLE-2-ALIPHATIC ACID
2775
Hall et al.[24] and Kern.[25] Succinamic acid ethyl ester (1a), malonamic acid ethyl
ester (1b), or N0-Boc-L-argininate ethyl ester (1c) was treated with freshly prepared
Meerwein’s reagent ðEt3OþBF4ꢁÞ in 1, 2-dichloroethane at room temperature for
24 h. The imidate ethyl esters tetrafluoroborate salts 2a–c were formed, and they
were sequentially reacted in situ with solutions of various hydroxyl-2-aminophenols
(3a–d) in absolute ethanol at reflux temperature (85 ꢀC). This one-pot reaction
yielded hydroxylbenzo[d]oxazole-2-aliphatic acid esters (4a–d) and hydroxylbenzo[d]-
oxazole-2-amino acid esters (5a and b) in reasonable yields. All reaction conditions,
including the reactants, products, and yields are listed in Table 1, and all compounds
1
4a–d and 5a and b were characterized by H NMR, electrospray ionization (ESI),
and elemental analyses.
Specifically, in this one-pot procedure, solutions of air-sensitive 2-aminophe-
nols (3a–d) in dry alkyl alcohol prepared from the stable 2-nitrobenzenediol by
hydrogenation were introduced directly into the reaction system without further
purification of imidate alkyl esters. The alcoholic solvents (e.g., ethanol, methanol)
we utilized could quench the excess amount of Meerwein’s reagent, thus no alky-
lation side products of 2-aminophenols were formed. After addition of aqueous
NaHCO3 solution, the excess imidate alkyl esters were transferred into less polar die-
sters (e.g., diethyl succinate from 1a) and conveniently removed by using a flash
chromatographic column. The unreacted 2-aminophenols could be removed by
washing with diluted mineral acids (e.g., 1 N HCl).
In summary, we have successfully developed an efficient and facile one-pot
method to prepare a series of hydroxylbenzo[d] oxazole-2-aliphatic acid derivatives
via Meerwein’s reagent ðEt3OþBF4ꢁÞ. This new procedure avoids the use of vigorous
temperature and strong acidic catalysts, and it can be readily utilized to synthesize
more complex benzo[d]oxazole derivatives.
EXPERIMENTAL
All commercial chemicals and solvents are analytical grade and were used with-
out further purification unless otherwise specified. All reactions except those in aque-
ous media were carried out with the use of standard techniques for the exclusion of
moisture. Reactions were monitored by thin-layer chromatography (TLC) under
1
254-nm ultraviolet light. H NMR and 13C NMR spectra were recorded on either
a Brucker 300 MHz Avance DPX or a Bruker 500-MHz Avance DRX instrument.
Chemical shifts are reported in parts per million (d), and coupling constants (J)
are in hertz (Hz). Mass spectroscopy was conducted using a Shimadzu QP5000 mass
spectrometer. Elemental analyses were performed with a Perkin-Elmer CHNS=O
analyzer. Optical rotations were obtained using Jasco polarimeter P-2000.
Meerwein’s Reagent: Et3OþBF4ꢁ
Under nitrogen protection, at room temperature, epichlorohydrin (30 mL,
0.38 mmol) was added dropwise into a mixture of freshly distilled Et2O ꢂ BF3
(63 mL, 0.5 mmol) in 125 mL ether at a rate sufficient to maintain vigorous boiling.
After addition of epichlorohydrin, the resulting mixture was kept refluxing for
another 1.0 h. Sequentially, it was cooled to room temperature and left stand for

2776
W. ZHANG ET AL.
2 h for the product to crystallize. Ether was cannulated off, and dry ether was added
to wash the crystals three times, and then the washing ether was batchwise cannu-
lated off. After drying in vacuum, a white crystal, Meerwein’s reagent, was obtained
(70 g, yield 97%).
Ethyl 3-(4-Hydroxybenzo[d]oxazol-2-yl)propanoate (4a)
Succinamic acid ethyl ester (1a) (0.2 g, 1.38 mmol) was dissolved in 10 mL 1,
2-dichloroethane, and then freshly prepared Meerwein’s reagent Et3OþBF4ꢁ
(0.262 g, 1.38 mmol) was added in portions under nitrogen. The resulting mixture
was stirred for 24 h at rt. A newly prepared solution of 2-aminobenzene-1,3-diol
(3a) (0.19 g, 1.52 mmol, prepared from 2-nitrobenzene-1,3-diol and 10%Pd=C in
absolute ethanol under hydrogen at 1 atm) in 20 mL ethanol was transferred into
the solution through a syringe. The mixture was heated to reflux for 4 h and cooled
to rt. Next, 20 mL saturated aqueous NaHCO3 solution was added, and then the
aqueous layer was extracted with 30 mL dichloromethane. The organic layer was
washed with brine and dried with anhydrous Na2SO4. After filtration and concen-
tration, the crude product was then purified on silica gel, eluting with petroleum
ether–EtOAc (2: 1) to give a pure compound 4a, brownþceraceous solid, 277 mg,
80% yield, mp 44–46 ꢀC. MS (ESI), m=z: 236 [M þ H] . 1H NMR (300 MHz,
CDCl3), d: 8.52 (br, 1H, OH), 7.20 (t, J ¼ 8.1 Hz, 1H, ArH), 7.04 (d, J ¼ 8.1 Hz,
1H, ArH), 6.86 (d, J ¼ 8.1 Hz, 1H, ArH), 4.15 (q, J ¼ 7.2 Hz, 2H, CH2), 3.30 (t,
J ¼ 7.8 Hz, 2H, CH2), 2.91 (t, J ¼ 7.2 Hz, 2H, CH2), 1.23 (t, J ¼ 7.0 Hz, 3H, CH3).
13C NMR (125 MHz, CDCl3), d: 171.22, 164.15, 151.46, 147.50, 128.57, 125.45,
110.55, 101.69, 60.49, 30.52, 23.35, 13.64. Anal. calcd. for C12H13NO4: C, 61.27;
H, 5.57; N, 5.95. Found: C, 61.30; H, 5.52; N, 6.01.
Ethyl 3-(7-Hydroxybenzo[d]oxazol-2-yl)propanoate (4b)
Brown ceraceous solid, 75% yield, mp 22–25 ꢀC. MS (ESI), m=z: 236
[M þ H]þ.1H NMR (300 MHz, CDCl3), d: 7.44 (br, 1H, OH), 7.21 (dd, J ¼ 8.1 Hz,
J ¼ 0.6 Hz, 1H, ArH), 7.13 (t, J ¼ 8.0 Hz, 1H, ArH), 6.84 (dd, J ¼ 7.5 Hz, J ¼ 1.2 Hz,
1H, ArH), 4.15 (q, J ¼ 7.1 Hz, 2H, CH2), 3.25 (t, J ¼ 7.2 Hz, 2H, CH2), 2.92 (t,
J ¼ 7.3 Hz, 2H, CH2), 1.23 (t, J ¼ 7.2 Hz, 3H, CH3). 13C NMR (125 MHz, CDCl3),
d: 171.75, 164.78, 147.42, 142.30, 124.47, 120.21, 111.24, 96.51, 60.56, 30.32, 23.38,
13.66. Anal. calcd. for C12H13NO4: C, 61.27; H, 5.57; N, 5.95. Found: C, 61.32;
H, 5.61; N, 5.93.
Ethyl 3-(6-Hydroxybenzo[d]oxazol-2-yl)propanoate (4c)
Yellow solid, 70% yield, mp 39–42 ꢀC. MS (ESI), m=z: 236 [M þ H]þ. 1H NMR
(300 MHz, CDCl3), d: 7.46 (d, J ¼ 8.8 Hz, 1H, ArH), 6.96 (d, 1H, J ¼ 2.4 Hz, ArH),
6.80 (dd, J ¼ 8.4 Hz, J ¼ 2.0 Hz, 1H, ArH), 4.17 (q, J ¼ 7.2 Hz, 2H, CH2), 3.21 (t, 2H,
J ¼ 7.4 Hz, CH2), 2.90 (t, J ¼ 7.6 Hz, 2H, CH2), 1.25 (t, J ¼ 7.4 Hz, 3H, CH3). 13C
NMR (125 MHz, CDCl3), d: 171.66, 164.01, 154.17, 151.08, 133.51, 118.86,
112.55, 97.23, 60.61, 30.29, 23.32, 13.62. Anal. calcd. for C12H13NO4: C, 61.27; H,
5.57; N, 5.95. Found: C, 61.35; H, 5.59; N, 5.96.

HYDROXYBENZO[d]OXAZOLE-2-ALIPHATIC ACID
2777
Ethyl 3-(5-Hydroxybenzo[d]oxazol-2-yl)propanoate (4d)
Brown ceraceous solid, 60% yield, mp 76–79 ꢀC. MS (ESI), m=z: 236 [M þ H]þ.
1H NMR (300 MHz, CDCl3), d: 7.33 (d, J ¼ 9.0 Hz, 1H, ArH), 7.11 (d, J ¼ 2.1 Hz,
1H, ArH), 6.83 (dd, J ¼ 8.7 Hz, J ¼ 2.7 Hz, 1H, ArH), 5.16 (s, 1H, OH), 4.18 (q,
J ¼ 7.2 Hz, 2H, CH2), 3.24 (t, J ¼ 7.2 Hz, 2H, CH2), 2.93 (t, J ¼ 7.3 Hz, 2H, CH2),
1.27 (t, J ¼ 7.2 Hz, 3H, CH3). 13C NMR (125 MHz, CDCl3), d: 171.45, 166.10,
153.13, 144.72, 140.96, 112.92, 110.07, 104.72, 60.55, 30.23, 23.47, 13.63. Anal. calcd.
for C12H13NO4: C, 61.27; H, 5.57; N, 5.95. Found: C, 61.26; H, 5.55; N, 5.93.
Ethyl 2-(4-Hydroxybenzo[d]oxazol-2-yl)acetate (4e)
1
White solid, 73% yield, mp 102–104 ꢀC. MS (ESI), m=z: 222 [M þ H]þ. H
NMR (300 MHz, CDCl3), d: 7.26 (t, J ¼ 8.1 Hz, 1H, ArH), 7.08 (dd, J ¼ 8.1 Hz,
J ¼ 0.6 Hz, 1H, ArH), 6.89 (dd, J ¼ 8.1 Hz, J ¼ 0.8 Hz, 1H, ArH), 4.22 (q, J ¼ 7.2 Hz,
Hz, 2H, CH2), 4.10 (s, 2H, CH2), 1.26 (t, J ¼ 7.3 Hz, 3H, CH3). 13C NMR (125 MHz,
CDCl3), d: 166.15, 158.53, 151.67, 147.77, 126.25, 110.79, 61.62, 34.33, 13.58. Anal.
calcd. for C11H11NO4: C, 59.73; H, 5.01; N, 6.33. Found: C, 59.88; H, 4.97; N, 6.31.
(S)-Ethyl 2-(tert-Butoxycarbonylamino)-3-(4-hydroxybenzo[d]oxazol-
2-yl)propanoate (5a)
Yellow sticky oil, 60% yield. ½aꢃ1D5 p¼ ꢁ14 (c ¼ 0.22 in acetone). MS (ESI), m=z:
351 [M þ H]þ. 1H NMR (300 MHz, CDCl3), d: 7.23 (t, J ¼ 8.1 Hz, 1H, ArH), 7.05 (d,
J ¼ 8.1 Hz, 1H, ArH), 6.87 (d, J ¼ 8.1 Hz, 1H, ArH), 5.66 (d, J ¼ 8.1 Hz, 1H, NH),
4.86–4.82 (m, 1H, CH), 4.22 (q, J ¼ 7.2 Hz, 2H, CH2), 3.50 (d, J ¼ 5.4 Hz, 2H,
CH2), 1.39 (s, 9H, 3CH3), 1.22 (t, J ¼ 7.2 Hz, 3H, CH3). 13C NMR (125 MHz,
CDCl3), d: 170.37, 161.47, 154.74, 151.59, 147.39, 128.44, 125.71, 110.37, 101.85,
79.80, 61.57, 51.04, 31.09, 27.78, 13.54. Anal. calcd. for C17H22N2O6: C, 58.28; H,
6.33; N, 8.00. Found: C, 58.43; H, 6.28; N, 7.99.
(S)-Ethyl 2-(tert-Butoxycarbonylamino)-3-(5-hydroxybenzo[d]
oxazol-2-yl)propanoate (5b)
15
Yellow sticky oil, 55% yield. ½aꢃD ¼ ꢁ6.6 (c ¼ 0.30 in acetone). MS (ESI), m=z:
351 [M þ H]þ. 1H NMR (300 MHz, CDCl3), d: 7.30 (d, J ¼ 8.4 Hz, 1H, ArH), 7.10 (s,
1H, ArH), 6.83 (dd, J ¼ 8.4 Hz, J ¼ 1.5 Hz, 1H, ArH), 5.68 (m, 1H, NH), 4.82–4.79
(m, 1H, CH), 4.20 (q, J ¼ 7.0 Hz, 2H, CH2), 3.43 (dd, dd, J ¼ ꢁ15.9 Hz, J ¼ 5.1 Hz,
J ¼ 4.5 Hz, 2H, CH2), 1.41 (s, 9H, 3CH3), 1.19 (t, J ¼ 7.0 Hz, 3H, CH3). 13C NMR
(125 MHz, CDCl3), d: 170.35, 163.36, 154.90, 152.99, 144.91, 141.19, 112.99,
110.08, 104.98, 79.93, 61.54, 50.81, 31.23, 27.78, 13.51. Anal. calcd. for
C17H22N2O6: C, 58.28; H, 6.33; N, 8.00. Found: C, 58.30; H, 6.35; N, 8.02.
ACKNOWLEDGMENT
We thank the National Comprehensive Technology Platforms for Innovative
Drug Research and Development, 2009ZX09301-007, for the financial support.

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W. ZHANG ET AL.
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