One-pot synthesis of benzoxazoles via the metal-free ortho-C-H functionalization of phenols with nitroalkanes

Article abstract of DOI:10.1039/c5ra15128g

PPA-activated nitroalkanes are employed in the design of a one-pot cascade transformation involving metal-free and oxidant-free direct ortho-C-H functionalization, followed by Beckman rearrangement and intramolecular cyclocondensation to produce benzoxazoles and benzobisoxazoles directly from easily available phenols.

Full text of DOI:10.1039/c5ra15128g

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V. Aksenov, O. N. Nadein, D. A. Aksenov, A. N. Smirnov and M. Rubin, RSC Adv., 2015, DOI:
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ARTICLE
One-pot synthesis of benzoxazoles via the metal-free ortho-C-H
functionalization of phenols with nitroalkanes†
Nicolai A. Aksenov,a Alexander V. Aksenov,*a Oleg N. Nadein,a Dmitrii A. Aksenov,a
Alexander N. Smirnov,a and Michael Rubin*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
PPA-activated nitroalkanes are employed in the design of a one-pot cascade transformation involving metal-free and
oxidant-free direct ortho-C-H functionalization, followed by Beckman rearrangment and intramolecular cyclocondensation
to produce benzoxazoles and benzobisoxazoles directly from easily available phenols.
www.rsc.org/
Introduction
Benzoxazole is one of the most privileged scaffolds in natural
product chemistry1 and modern drug design.2,3 Benzoxazole
derivatives are also versatile ligands for transition metal and
Lewis acid catalysis.4 Development of polybenzobisoxazoles
led to the discovery of a new generation of organic polymers
for electronics and novel high tensile materials.5 Not surprise-
ingly, vast efforts are put into the development of efficient
methods for their synthesis.6 The most straightforward appro-
aches to benzoxazoles involve various cyclocondensations
between o-aminophenols and different carbonyl derivatives:
aldehydes,7 imines,8 carboxylic acids,9 acyl halides,10 esters,11
orthoesters,12 N-alkylnitrilium salts,13 isocyanides,14 or carbon
monoxide.15 Alternatively, benzoxazoles can be accessed by
catalytic annulation of ortho-haloanilines with acylchlorides16
or 1,2-dihalobenzenes with primary amides.16 All of the above-
mentioned protocols, however, require 1,2-disubstituted
benzene precursors for which there are only a handful of
methods that allow for the direct ortho-C-H functionalization
of phenol derivatives. Subsequent annulation provides benz-
oxazole products. One of these methods involves the intra-
molecular Cu-catalyzed ring closure of O-aryl oximes.17
Intermolecular approaches, involving the condensation of N-
nitro-O-arylhydroxylamines18 or aryloxenium ions19 with
nitriles and oxidative coupling of phenols with primary
amines20 or nitriles21 were also demonstrated. Many of them,
however, are rather inefficient, have limited scope, and
Scheme 1
require addition of an external oxidant, such as MnO2, DDQ, or
K3Fe(CN)6. Herein we wish to report a new, direct approach to
benzoxazoles and benzobisoxazoles via the ortho-CH function-
alization of readily available phenols with PPA-activated
nitroalkanes.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Results and discussion
Our team has been investigating the reactivity of nitro-compounds
in a polyphosphoric acid (PPA) medium in application to synthesis
of medicinally relevant heterocyclic compounds.22 In the frame of
this program we have previously reported the synthesis of benzox-
azoles 2 proceeding via the cyclocondensation of ortho-amino-
phenols 1 with nitroalkanes 3 (Scheme 1, eq. 1).23 The mechanism
of this transformation involves umpolung of nitroalkane upon
formation of a strong Lewis acid – Lewis base complex with PPA.
The resulting highly electrophilic phosphorylated aci form 4 under-
goes nucleophilic attack by aniline moiety in 1 to afford protonated
imidamide species 5. Subsequent acid-assisted cyclocondensation
with elimination of hydroxylamine provided benzoxazole 2 (Scheme
1, eq. 1).23 We proposed that ortho-aminophenols 1 can potentially
be substituted with much more accessible phenols 6 to obtain the
same benzoxazole products 2 by combining the described above
methodology with our recent finding that unprotected phenols can
undergo PPA-promoted acetamidation with nitroalkanes (Scheme
2, eq. 3).24a Thus, it was anticipated that aci species 4 would serve
as an electrophile in the SEAr-type reaction with electron-rich
phenols to produce phosphorylated oxime 7 which, as demonstr-
ated previously, could participate in a Beckman rearrangement to
yield benzamide 8.24 The latter would undergo a PPA-promoted
cyclocondensation into benzoxazole 2 producing water as the only
by-product. It should be mentioned that acetamidation of phenol
was shown to be highly para-selective,24a and this would limit the
proposed transformation to substrates with substituted or sterically
encumbered para-position to ensure the electrophilic attack at the
ortho-position of phenols.
Scheme 2
completely consumed within 2 h and produced intermediate
amide 8aa, which was not isolated but further heated for 3 h
at 135 oC to enable heteroannulation into benzoxazole 2aa
(Scheme 2, eq. 4; Table 1, entry 1).25 Inspired by the successful
result, we screened a few other nitroalkanes (3b-e) in the
reaction with phenol, all of which afforded the corresponding
benzoxazoles (2ab-2ae) in good yields under the same reaction
conditions (entries 2-5).
Analogously, other para-substituted phenols, p-ethyl-
phenol (6b) and p-cumenol (6c), reacted with nitroethane to
give benzoxazoles 2ba and 2ca, respectively (entries 6, 7). 3,4-
Xylenol (6d) afforded trisubstituted products 2da and 2de
,
with nitroethane (3a) and 2-phenylnitroethane (3e) (entries 8-
9). The structure of 2da was unambiguously confirmed by X-
ray crystallography (Figure 1). A strong M+ meta-substituent,
such as fluorine, also efficiently directed the SEAr-attack ortho
to the OH group affording benzoxazole 2ea in reasonable yield
(entry 10). Resorcinols 6f and 6g also reacted selectively
showing a strong preference for the electrophilic attack at only
one of the ortho-positions (C-6), governed by steric factors
(entries 1-12).
To test this idea, we attempted the reaction between p-
cresol (6a) and nitroethane (3a), which was carried out in the
80% solution of PPA at 100-105 oC. At this temperature 6a was
Table 1
#
6
3
R1
R2
H
R3
H
R4
2
Yield, %a
67
1
6a
6a
6a
6a
6a
6b
6c
6d
6d
6e
6f
3a
3b
3c
3d
3e
3a
3a
3a
3e
3a
3a
3a
3a
Me
Me
Me
Me
Me
Et
Me
2aa
2ab
2ac
2ad
2ae
2ba
2ca
2da
2de
2ea
2fa
2ga
2ha
2
H
H
Et
74
3
H
H
n-C5H11
Ph
74
4
H
H
72
5
H
H
PhCH2
Me
69
6
H
H
78
7
i-Pr
Me
Me
H
H
H
Me
72
8
Me
Me
F
H
Me
76
9
H
PhCH2
Me
71
10
11
12
13
H
62
H
OH
OH
H
H
Me
78
6g
6h
H
Me
H
Me
70
OH
Me
34
a) Isolated yields of purified benzoxazole products
2 | J. Name., 2012, 00, 1-3
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Figure 1. ORTEP drawing of 2,5,6-trimethylbenzo[d]oxazole (2da, CCDC 1410546)
showing 50% probability amplitude displacement ellipsoids. Oxygen and nitrogen
atoms are shown disordered as this planar molecule can pack in two different ways
occupying practically the same space in the crystalline lattice.
Hydroquinone (6h) was also considered as an illustrative
substrate for the described transformations due to symmetry,
which renders all possible directions for electrophilic attack
identical. However, the reaction of 6h was complicated by
concurrent aerobic oxidation of the material under employed
reaction conditions and only provided benzoxazole 2ha in
modest yield (entry 13).
Scheme 3
We were also inspired by the idea of using diphenols for
simultaneous or stepwise installation of two benzoxazole rings
en route to benzobisoxazoles (BBOs), the key building blocks
for a new generation of organic semiconducting materials.26
The possibility to obtain BBOs in a single step from abundant
and inexpensive diphenols provides clear advantages over the
currently used approaches that rely on tetrasubstituted
aromatic substrates.26 To probe this idea, we carried out the
reaction of resorcinols 6f
initial annulation into benzoxazole (2fa
entfully; however, subsequent cyclization required prolonged
heating to afford benzobisoxazoles 9a (Scheme 3, eq. 6). The
,
g
with excess nitroethane (3a). The
Scheme 4
,
2ga) occurred unev-
This one-pot cascade transformation is made possible
through the use of polyphosphoric acid, which plays an
important role in each step, including: a) umpolung of
nitroalkane rendering the nitro group an efficient electrophile
and oxidant for the electron-rich aromatic C-H bond; b)
promoting Beckman rearrangement through phosphorylation
of the oxime moiety; c) facilitating the condensation step by
efficient removal of water; and d) in-situ reversible protection
of the phenol group at the initial stages of the reaction.
,b
same one-pot transformation can also be carried out with
successive addition of two different nitroalkanes to resorcinol
(Scheme 3, eq. 8). Alternatively, isolated benzoxazole 2fa
subjected to a second fold cyclization with 2-phenylnitro-
ethane (3e) cleanly afforded non-symmetric benzobisoxazole
9c (Scheme 3, eq. 7).
To gain additional support for the mechanism and prop-
osed reaction intermediates (Scheme 1, eq. 2), we subjected p-
cresol (6a) to the reaction with various nitroalkanes at lower
temperatures. Treatment of 6a with nitroethane at 90 oC for 2
h provided oxime 10aa as a sole product after a standard
aqueous work up. (Scheme 5). In contrast, the reaction carried
o
out at 105 C in the presence of 1-nitrohexane, provided the
Beckman rearrangement product, amide 8ac, in good yield.
Being re-subjected to the standard reaction conditions (2 h at
o
135 C), 8ac cleanly afforded benzoxazole 2ac (Scheme 4). It
should be emphasized that, unlike other heteroannulations
proceeding via C-H functionalization of arenes,20,21 our method
does not require any external oxidative agents and produces
water as the only by-product.
Figure 2. ORTEP drawing of 2,6-Dimethylbenzo[1,2-d:5,4-d']bis(oxazole) (9a, CCDC
1415173) showing 50% probability amplitude displacement ellipsoids. Oxygen and
nitrogen atoms are shown disordered as this planar molecule can pack in two different
ways occupying practically the same space in the crystalline lattice.
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J = 8.3 Hz, 1H), 2.92 (q, J = 7.6 Hz, 2H), 2.43 (s, 3H), 1.42 (t, J =
7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.3, 149.1, 141.7,
133.8, 125.5, 119.6, 109.6, 22.3, 21.5, 11.0; HRMS (ES TOF)
calc`d for C10H12NO (M+H)+: 162.0919, found 162.0918 (0.6
ppm).
Conclusions
We have developed a new cascade transformation combining
a direct ortho-acetamidation of phenols and intramolecular
cyclocondensation of the intermediate 2-hydroxyanilides into
benzoxazoles. This reaction involves successive formation of
the C-N and C-O bonds, with the former proceeding via a PPA-
assisted C-H functionalization of the arene. This method offers
a direct, atom-economic, metal-free, external oxidant-free,
one-pot route to benzoxazoles and benzobisoxazoles from
easily available phenols, producing water as the only by-
product.
2-Hexyl-5-methylbenzo[d]oxazole
ing to the typical procedure employing p-cresol (6a) (108 mg,
1.00 mmol) and 1-nitrohexane (3c) (167 L, 157 mg, 1.20
(2ac). Prepared accord-
ꢀ
mmol). Titled compound was isolated as yellowish oil, Rf 0.44
(hexane/EtOAc 10:1). Yield 150 mg (0.74 mmol, 74%). 1H
NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.34 (d, J = 8.3 Hz, 1H),
7.09 (d, J = 8.2 Hz, 1H), 2.90 (t, J = 7.6 Hz, 2H), 2.45 (s, 3H),
1.93-1.83 (m, 2H), 1.42-1.35 (m, 4H), 0.91 (t, J = 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 167.6, 149.2, 141.8, 141.7, 134.0,
125.5, 119.6, 109.7, 31.5, 28.8, 26.7, 22.4, 21.6, 14.0; HRMS
(ES TOF) calc`d for C13H18NO (M+H)+: 204.1388, found
204.1391 (1.5 ppm).
Experimental Part
1H and 13C NMR spectra were recorded on a Bruker Avance-III
spectrometer (400 or 100 MHz, respectively) equipped with
BBO probe in CDCl3 using TMS as internal standard. High
resolution mass spectra were registered with Bruker Maxis
spectrometer (electrospray ionization, in MeCN, using
5-Methyl-2-phenylbenzo[d]oxazole
ording to the typical procedure employing p-cresol (6a) (108
mg, 1.00 mmol) and -nitrotoluene (3d) (165 mg, 1.20 mmol).
(
2ad).29 Prepared acc-
α
HCO2Na-HCO2H for calibration).
Melting points were
Titled compound was isolated as colorless crystals, mp 101-
102 oC (benzene), Rf 0.69 (hexane/EtOAc 6:1). Yield 150 mg
(0.72 mmol, 72%). 1H NMR (400 MHz, DMSO-d6) δ 8.18 (dd, J =
7.4, 2.0 Hz, 2H), 7.67-7.56 (m, 5H), 7.23 (d, J = 7.4 Hz, 1H), 2.43
(s, 3H); 13C NMR (DMSO-d6) δ 162.3, 148.4, 141.7, 134.2,
131.8, 129.3 (2C), 127.2 (2C), 126.5, 126.5, 119.6, 110.3, 21.0;
IR (NaCl, film, cm-1) 3050, 2924, 1551, 1482, 1449, 1333, 1271,
1198, 1056, 1023, 924, 825, 795; HRMS (ES TOF) calc`d for
C14H12NO (M+H)+: 210.0913, found 210.0916 (1.4 ppm).
measured with Stuart smp30 apparatus. All reactions were
performed in oven-dried drum vials open to the atmosphere
employing overhead stirring. Reaction progress and purity of
isolated compounds were monitored by TLC on Silufol UV-254
plates, eluting with EtOAc. Flash column chromatography was
performed on Silica gel (32-63 ꢀm, 60 Å pore size). All
reagents and solvents were purchased from commercial
vendors and used as received.
2-Benzyl-5-methylbenzo[d]oxazole
ording to the typical procedure employing p-cresol (6a) (108
mg, 1.00 mmol) and 2-phenylnitroethane (3e) (162 L, 181 mg,
(
2ae).30 Prepared acc-
27
2,5-Dimethylbenzo[d]oxazole
(
2aa
)
(Typical procedure).
Oven-dried vial was charged with p-cresol (108 mg, 1.00
mmol), nitroethane (85 L, 90 mg, 1.20 mmol), and 80% poly-
ꢀ
ꢀ
1.20 mmol). Titled compound was isolated as yellowish oil, Rf
1
0.61 (hexane/EtOAc 4:1). Yield 154 mg (0.69 mmol, 69%). H
phosphoric acid (2.0 g). The mixture was stirred at 105 oC for 2
h before all p-cresol was consumed. Then the temperature
was raised to 135 oC and the stirring was continued for 3 h.
Hot mixture was poured into solution of Na2CO3 (3.0 g) in cold
water (27 mL), the product was extracted with petroleum
NMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 7.18-7.34 (m, 6H), 7.04
(d, J = 8.5 Hz, 1H), 4.20 (s, 2H), 2.39 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 165.5, 149.4, 141.2, 134.9, 134.3, 129.1 (2C), 129.0
(2C), 127.4, 126.0, 119.7, 110.0, 35.4, 21.6; IR (NaCl, film, cm-1)
3078, 1742, 1616, 1553, 1453, 1242, 1052, 742, 704; HRMS
(ES TOF) calc`d for C15H14NO (M+H)+: 224.1070, found
224.1067 (1.3 ppm).
ether (4 x 25 mL) (for extraction of products 2fa, 2ha, 2ha, 2ia
petroleum ether should be replaced with CH2Cl2). Combined
extracts were concentrated in vacuum and the titled
compound was isolated by column chromatography (eluting
with mixture petroleum ether-EtOAc, applying gradient from
10:1 to 1:1) as yellowish oil, Rf 0.71 (hexane/EtOAc 1:1). Yield
99 mg (0.67 mmol, 67%). 1H NMR (400 MHz, CDCl3) δ 7.43 (1H,
d, J = 7.9 Hz), 7.08 (1H, d, J = 7.9 Hz), 7.32 (1H, s), 2.61 (3H, s),
2.44 (3H, s); 13C NMR (100 MHz, CDCl3) δ 164.1, 149.3, 141.6,
134.1, 125.6, 119.4, 109.7, 21.5, 14.6; IR (NaCl, film, cm-1)
2926, 1616, 1580, 1489, 1435, 1261, 1118, 1044, 922, 872,
841, 798; HRMS (ES TOF) calc`d for C9H10NO (M+H)+:
148.0767, found 148.0767 (0.0 ppm).
5-Ethyl-2-methylbenzo[d]oxazole
ording to the typical procedure employing p-ethylphenol (6b
(136 mg, 1.00 mmol) and nitroethane (3a) (85 L, 90 mg, 1.20
(
2ba).31 Prepared acc-
)
ꢀ
mmol). Titled compound was isolated as yellowish oil, Rf 0.63
(hexane/EtOAc 4:1). Yield 126 mg (0.78 mmol, 78%). 1H NMR
(400 MHz, CDCl3) δ 7.43 (d, J = 0.9 Hz, 1H), 7.30 (d, J = 8.3 Hz,
1H), 7.06 (dd, J = 8.3, 1.6 Hz, 1H), 2.70 (q, J = 7.6 Hz, 2H), 2.56
(s, 3H), 1.23 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
163.8, 149.3, 141.7, 140.4, 124.4, 118.2, 109.6, 28.8, 16.2,
14.4. IR (NaCl, film, cm-1) 2964, 2937, 2878, 1620, 1584, 1479,
1439, 1376, 1323, 1257, 1175, 1125, 1063, 1036, 914, 875,
842, 805, 756, 733, 670, 630; HRMS (ES TOF) calc`d for
C10H12NO (M+H)+: 162.0913, found 162.0918 (3.1 ppm).
2-Ethyl-5-methylbenzo[d]oxazole
ording to the typical procedure employing p-cresol (6a) (108
mg, 1.00 mmol) and nitropropane (3b) (109 L, 107 mg, 1.20
(
2ab).28 Prepared acc-
ꢀ
mmol). Titled compound was isolated as yellowish oil, Rf 0.38
1
(hexane/EtOAc 8:1). Yield 119 mg (0.74 mmol, 74%). H NMR
5-Isopropyl-2-methylbenzo[d]oxazole
ording to the typical procedure employing p-cumenol (6c) (108
mg, 1.00 mmol) and nitroethane (3a) (85 L, 90 mg, 1.20
(2ca). Prepared acc-
(400 MHz, CDCl3) δ 7.44 (s, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.06 (d,
ꢀ
4 | J. Name., 2012, 00, 1-3
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o
mmol). Titled compound was isolated as yellowish oil, Rf 0.65 178-181 C (benzene), Rf 0.25 (hexane/EtOAc 4:1). Yield 114
(hexane/EtOAc 4:1). Yield 126 mg (0.72 mmol, 72%). 1H NMR mg (0.70 mmol, 70%). 1H NMR (400 MHz, DMSO) δ 8.61 (s,
(400 MHz, CDCl3) δ 7.48 (d, J = 1.0 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 6.35 (d, J = 8.5 Hz, 1H), 5.93 (d, J = 8.5 Hz, 1H), 1.65 (s,
1H), 7.12 (dd, J = 8.4, 1.6 Hz, 1H), 3.03-2.93 (m, 1H), 2.57 (s, 3H), 1.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.7, 152.8,
3H), 1.26 (d, J = 6.9 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 163.9, 150.6, 133.2, 115.5, 111.8, 106.3, 14.1, 9.1; HRMS (ES TOF)
149.4, 145.2, 141.7, 123.1, 116.7, 109.6, 34.2, 24.5, 14.5 (2С); calc`d for C9H10NO2 (M+H)+: 164.0706, found 164.0706 (0.0
IR (NaCl, film, cm-1) 2964, 2865, 1739, 1614, 1581, 1482, 1452, ppm).
1436, 1383, 1366, 1310, 1267, 1188, 1165, 1129, 1046, 921,
881, 844, 805, 733, 667, 637; HRMS calc`d for C11H14NO to the typical procedure employing hydroquinone (6h) (110
(M+H)+: 176.1070, found 176.1070 (0.0 ppm). mg, 1.00 mmol) and nitroethane (3a) (85 L, 90 mg, 1.20
2,5,6-Trimethylbenzo[d]oxazole
2da).32 Prepared accord- mmol). Titled compound was isolated as colorless crystals, mp
ing to the typical procedure employing 3,4-xylenol (6d) (122 164-165 oC (acetonitrile), Rf 0.28 (hexane/EtOAc 1:1). Yield 51
mg, 1.00 mmol) and nitroethane (3a) (85
L, 90 mg, 1.20 mg (0.34 mmol, 34%). 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J =
2-Methylbenzo[d]oxazol-5-ol (
2ha).33 Prepared according
ꢀ
(
ꢀ
mmol). Titled compound was isolated as colorless crystals, mp 8.8 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 6.87 (dd, J = 8.8, 2.4 Hz,
93 oC (hexane), Rf 0.42 (hexane/EtOAc 4:1). Yield 122 mg (0.76 1H), 2.66 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.3, 153.8,
mmol, 76%). 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 1H), 7.23 (s, 145.4, 141.0, 113.6, 110.8, 104.9, 14.6; HRMS (ES TOF) calc`d
1H), 2.60(s, 3H), 2.34 (s, 3H), 2.33 (s, 3H); 13C NMR (CDCl3) δ for C8H8NO2 (M+H)+: 150.0550, found 150.0550 (0.0 ppm)
163.2, 149.7, 139.5, 133.6, 132.9, 119.5, 110.7, 20.5, 20.2,
N-(2-Hydroxy-5-methylphenyl)hexanamide (8ac). Oven-
14.6; HRMS (ES TOF) calc`d for C10H12NO (M+H)+: 162.0913, dried vial was charged with p-cresol (108 mg, 1.00 mmol), 1-
found 162.0913 (0.0 ppm).
nitrohexane (3c) (167
2de). Prepared phosphoric acid (2.0 g). The mixture was stirred at 105 oC for 3
h before all p-cresol was consumed. Then the hot mixture was
L, poured into solution of Na2CO3 (3.0 g) in cold water (27 mL),
ꢀL, 157 mg, 1.20 mmol), and 80% poly-
2-Benzyl-5,6-dimethylbenzo[d]oxazole
(
according to the typical procedure employing 3,4-xylenol (6d
(122 mg, 1.00 mmol) and 2-phenylnitroethane (3e) (162
)
ꢀ
181 mg, 1.20 mmol). Titled compound was isolated as yellow- the product was extracted with petroleum ether (4 x 25 mL).
ish oil, Rf 0.65 (hexane/EtOAc 4:1). 1H NMR (400 MHz, CDCl3) δ Combined extracts were concentrated in vacuum and the
7.45 (s, 1H), 7.39-7.30 (m, 6H), 4.26 (s, 2H), 2.36 (s, 6H); 13C titled compound was isolated by column chromatography
NMR (101 MHz, CDCl3) δ 164.4, 149.7, 139.4, 135.0, 133.7, (eluting with mixture petroleum ether-EtOAc, applying grad-
132.8, 128.9 (2С), 128.7 (2С), 127.2, 119.7, 110.7, 35.2, 20.4, ient from 10:1 to 1:1) as yellowish oil, Rf 0.38 (hexane/EtOAc
20.1. IR (NaCl, film, cm-1) 2924, 1571, 1469, 1449, 1267, 1152, 8:1). Yield 170 mg (0.77 mmol, 77%). 1H NMR (400 MHz,
1129, 1000, 954, 868, 716; HRMS (ES TOF) calc`d for C16H16NO CDCl3) δ 0.92 (t, J = 6.2 Hz, 3H), 1.43-1.32 (m, 4H), 1.58 (s, 1H),
(M+H)+: 238.1226, found 238.1230 (1.7 ppm);
6-Fluoro-2-methylbenzo[d]oxazole
2ea).33 Prepared acc- 6.27 (s, 1H), 6.88 (d, J = 8.4 Hz, 1H), 7.11 (s, 1H), 7.19 (d, J = 8.4
ording to the typical procedure employing 3-fluorophenol (6e
Hz, 1H), 12.16 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 170.1,
(112 mg, 1.00 mmol) and nitroethane (3a) (85 L, 90 mg, 1.20 159.5, 135.1, 127.8, 125.3, 118.6, 114.1, 39.8, 29.4, 29.2, 22.5,
1.68-1.59 (m, 2H), 2.29 (s, 3H), 3.44 (dd, J = 13.5, 6.7 Hz, 2H),
(
)
ꢀ
mmol). Titled compound was isolated as yellowish oil, Rf 0.42 20.7, 14.1; IR (NaCl, film, cm-1): 2982, 2942, 2924, 1574, 1483,
(hexane/EtOAc 6:1). Yield 94 mg (0.62 mmol, 62%). 1H NMR 1454, 1429, 1261, 1175, 1165, 926, 833, 800, 667, 598; HRMS
(400 MHz, CDCl3) δ 7.55 (dd, J = 8.7, 4.9 Hz, 1H), 7.18 (dd, J = (ES TOF) calc`d for C13H20NO2 (M+H)+: 222.1490, found
8.0, 2.4 Hz, 1H), 7.06-6.99 (m, 1H), 2.61 (m, 1H); 13C NMR (100 222.1494 (1.8 ppm).
MHz, CDCl3) δ 164.5 (d, J = 3.0 Hz), 160.4 (d, J = 242 Hz), 151.0
2-Hexyl-5-methylbenzo[d]oxazole (2ac) from amide 8ac.
(d, J = 14 Hz), 137.8 (d, J = 2 Hz), 119.7 (d, J = 10 Hz), 112.0 (d, J Oven-dried vial was charged with amide 8ac (170 mg, 0.77
= 25 Hz), 98.5 (d, J = 28 Hz), 14.6; HRMS (ES TOF) calc`d for mmol) and 80% polyphosphoric acid (2.0 g). The mixture was
C8H7FNO (M+H)+: 152.0506, found 152.0505 (0.7 ppm).
2-Methylbenzo[d]oxazol-6-ol
to the typical procedure employing resorcinol (6f) (110 mg, acted with petroleum ether (4 x 25 mL). Combined extracts
1.00 mmol) and nitroethane (3a) (85 L, 90 mg, 1.20 mmol). were concentrated in vacuum and the titled compound was
stirred at 135 oC for 2 h, and then poured into solution of
(
2fa).34 Prepared according Na2CO3 (3.0 g) in cold water (27 mL). The product was extr-
ꢀ
Titled compound was isolated as colorless crystals, mp 194- isolated by column chromatography (eluting with mixture
196 oC (acetonitrile), Rf 0.52 (hexane/EtOAc 1:1). Yield 116 mg petroleum ether-EtOAc, applying gradient from 10:1 to 1:1) as
(0.78 mmol, 78%). 1H NMR (400 MHz, DMSO) δ 9.64 (s, 1H), colorless oil, identical to the material obtained in reaction of p-
7.40 (d, J = 8.5 Hz, 1H), 6.95 (d, J = 1.9 Hz, 1H), 6.75 (dd, J = 8.5, cresol and 1-nitrohexane (vide supra).
2.0 Hz, 1H), 2.52 (s, 3H); 13C NMR (100 MHz, DMSO) δ 161.8,
155.3, 151.3, 133.6, 118.9, 112.5, 96.9, 14.0; HRMS (ES TOF) dried vial was charged with resorcinol (6f) (110 mg, 1.00
calc`d for C8H8NO2 (M+H)+: 150.0550, found 150.0560 (6.7 mmol), nitroethane (3a) (85
L, 90 mg, 1.20 mmol), and 80%
ppm) polyphosphoric acid (4.0 g). The mixture was stirred for 1 h at
2,7-Dimethylbenzo[d]oxazol-6-ol
ing to the typical procedure employing 2-methylresorcinol (6g
(124 mg, 1.00 mmol) and nitroethane (3a) (85 L, 90 mg, 1.20 2.00 mmol) was injected. The resulting mixture was stirred at
mmol). Titled compound was isolated as colorless crystals, mp 105 C for 2 h, and then at 135 C for 2 h. After this the hot
2,6-Dimethylbenzo[1,2-d:5,4-d']bis(oxazole) (
9a).36 Oven-
ꢀ
o
o
(
2ga).35 Prepared accord- 100-105 C, then for 1 h at 135 C. The mixture was cooled
)
down and additional amount of nitroethane (142 L, 150 mg,
ꢀ
ꢀ
o
o
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Journal Name
1
See, for example: (a) G. Daletos, N. J. de Voogd, W. E.
G. Mueller, V. Wray, W. Lin, D. Feger, M. Kubbutat, A.
H. Aly, Amal H.; P. Proksch, J. Nat. Prod. 2014, 77, 218.
(b) G. Genta-Jouve, N. Francezon, A. Puissant, P.
Auberger, J. Vacelet, T. Perez, A. Fontana, A. Al
mixture was poured into solution of Na2CO3 (6 g) in cold water
(54 mL), and the crude product was extracted with CH2Cl2 (4 x
25 mL). Combined organic extracts were concentrated in
vacuum, and the residue was purified by column chromateogr-
aphy (eluting with mixture petroleum ether-EtOAc, applying
gradient from 10:1 to 1:1), and then by re-crystallization from
hexane as colorless crystals, mp 128-131°С (hexane), Rf 0.23
(hexane/ EtOAc 1:1). Yield 43 mg (0.23 mmol, 23%). 1H NMR
(400 MHz, CDCl3) δ 7.89 (s, 1H), 7.58 (s, 1H), 2.68 (s, 6H); 13C
NMR (CDCl3) δ 164.8 (2C), 148.6 (2C), 138.6 (2C), 108.8 (2C),
93.0 (2C), 14.8 (2C); IR (NaCl, film, cm-1) 2931, 1620, 1429,
1386, 1267, 1247, 1145, 1109, 914, 874; HRMS (ES TOF) calc`d
for C10H9N2O2 (M+H)+: 189.0659, found 189.0659 (0.0 ppm).
Mourabit, O. P. Thomas, Magn. Reson. Chem. 2011, 49
,
533. (c) S. P. B. Ovenden, J. L. Nielson, C. H. Liptrot, R.
H. Willis, D. M. Tapiolas, A. D. Wright, C. A. Motti, J.
Nat. Prod. 2011, 74, 65. (d) C. Hohmann, K. Schneider,
C. Bruntner, E. Irran, G. Nicholson, A. T. Bull, A. L.
Jones, R. Brown, J. E. M. Stach, M. Goodfellow, W. Beil,
M. Krämer, J. F. Imhoff, R. D Süssmuth, H.-P. Fiedler, J.
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2
3
For recent reviews, see: (a) C. S. Demmer, L. Bunch,
Eur. J. Med. Chem. 2015, 97, 778. (b) M. K. Gautam,
Sonal, N. K. Sharma, Priyanka, K. K. Jha, Int. J.
2,6,8-trimethylbenzo[1,2-d:5,4-d']bis(oxazole) (9b). Was
obtained according to procedure described for preparation of
9a, substituting resorcinol with 2-methylresorcinol (6g) (124
mg, 1.00 mmol). Titled compound was isolated as colorless
ChemTech Res. 2012,
4, 640. (c) B. Shrivastava, V.
Sharma, P. Lokwani, Pharmacologyonline 2011, 236.
See, for most recent reports: (a) C. Yang, X. Zhi, H. Xu,
Bioorg. Med. Chem. Lett. 2015, 25, 2217. (b) P.
o
crystals, mp 176-177 C (hexane), Rf 0.21 (hexane/EtOAc 1:1).
Yield 85 mg (0.42 mmol, 42%). 1H NMR (400 MHz, CDCl3) δ
7.63 (s, 1H), 2.60 (s, 6H), 2.58 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 164.1 (2C), 147.7 (2C), 138.2 (2C), 105.8, 103.7, 14.8
(2C), 9.5; IR (NaCl, film, cm-1) 2924, 1594, 1432, 1376, 1360,
1304, 1185, 1149, 1079, 921, 845; HRMS (ES TOF) calc`d for
C11H11N2O2 (M+H)+: 203.0815, found 203.0818 (1.5 ppm).
Anusha, J. V. Rao, Int. J. Pharm. Biol. Sci. 2014,
(c) A. Kaur, S. Wakode, D. P. Pathak, Int. J. Pharm.
Pharm. Sci. 2015, , 16. (d) C. Yang, X. Zhi, H. Xu,
4, 83.
7
Bioorg. Med. Chem. Lett. 2015, 25, 2217. (e) A.
Srivastava, L. Aggarwal, N. Jain, ACS Comb. Sci. 2015,
17, 39.
L. Fu, Top. Heterocycl. Chem. 2012, 29, 103.
(a) K. Fukukawa, M. Ueda, J. Photopol. Sci. Technol.
2009, 22, 761. (b) G. A. Holmes, K. Rice, C. R. Snyder, J.
Mater. Sci. 2006, 41, 4105.
For selected reviews, see: (a) G. V. Boyd, Science of
Synthesis 2002, 11, 481. (b) R. V. Kumar, Asian J. Chem.
2004, 16, 1241. (c) M. Schnurch, J. Hammerle, P.
4
5
2-Benzyl-6-methylbenzo[1,2-d:5,4-d']bis(oxazole)
(9c).
Was obtained according to procedure described for prepar-
ation of 9a, when second portion of nitroethane (3a) was
6
7
replaced with 2-phenylnitroethane (3e) (270 ꢀL, 302 mg, 2.00
mmol). Titled compound was isolated as yellowish oil, solidif-
ying upon standing to give colorless amorphous solid, Rf 0.43
1
(hexane/EtOAc 1:1). H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H),
Stanetty, Science
Updates 2010, 153.
of
Synthesis,
Knowledge
7.49 (s, 1H), 7.34-7.26 (m, 5H), 4.22 (s, 2H), 2.58 (s, 3H). 13C
NMR (101 MHz, CDCl3) δ 166.0, 164.8, 148.8, 148.7, 138.9,
138.7, 134.7, 129.2 (2C), 129.0 (2C), 127.6, 109.3, 93.1, 35.5,
14.8; IR (NaCl, film, cm-1) 3030, 2931, 1624, 1587, 1558, 1436,
1386, 1112, 1046, 881; HRMS calc`d for C16H13N2O2 (M+H)+
265.0972, found 265.0978 (2.3 ppm);
(a) Y.-X. Chen, L.-F. Qian, W. Zhang, B. Han, Angew.
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F. Su, S. C. Mathew, L. Möhlmann, M. Antonietti, X.
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657.
(a) Y. Wang, K. Sarris, D. R. Sauer, S. W. Djuric,
Tetrahedron Lett. 2006, 47, 4823. (b) M. Terashima, M.
Ishii, Y. Kanaoka, Synthesis 1982, 484. (c) J. A. Seijas,
M. P. Vazquez-Tato, M. R. Carballido-Reboredo, J.
Crecente-Campo, L. Romar-Lopez, Synlett 2007, 313.
(d) C. O. Kangani, D. E. Kelley, B. W. Day, Tetrahedron
Lett. 2006, 47, 6497. (e) D. Kumar, S. Rudrawar, A. K.
Chakraborti, Austral. J. Chem. 2008, 61, 881.
8
9
1-(2-Hydroxy-5-methylphenyl)ethan-1-one oxime (10aa) Rf
0.63 (hexane/AcOEt 2:1); 1H NMR (400 MHz, CDCl3) δ 11.46
(br. s, 1H), 8.13 (br. s, 1H), 7.23 (d, J = 2.0 Hz, 1H), 7.08 (dd, J =
8.2, 2.0 Hz, 1H), 6.89 (d, J = 8.0 HZ, 1H), 2.34 (s, 3H), 2.27 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 159.6, 155.2, 131.6, 128.4,
128.0, 118.4, 117.1, 20.8, 10.9; IR (NaCl, film, cm-1) 3327,
1636, 1503, 1391, 1369, 1321, 1285, 1252, 1036, 816, 783,
743, 669; HRMS calc`d for C9H12NO2 (M+H)+ 166.0863, found
166.0857 (3.6 ppm);
10 C. Chen, Y.-J. Chen, Tetrahedron Lett. 2004, 45, 113.
11 (a) H. J. Lim, D. Myung, I. Y. C. Lee, M. H. Jung, J. Comb.
Chem. 2008, 10, 501. (b) R. Kumar, C. Selvam, G. Kaur,
A. K. Chakraborti, Synlett 2005, 1401.
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2010, 75, 7942. (b) G. Bastug, C. Eviolitte, I. E. Marko,
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Acknowledgements
13 B. L. Booth, K. O. Jibodu, M. F. Proenca, J. Chem. Soc.,
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14 P. J. Boissarie, Z. E. Hamilton, S. Lang, J. A. Murphy, C. J.
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15 K. T. Neumann, A. T. Lindhardt, B. Bang-Andersen, T.
Skrydstrup, Org. Lett. 2015, 17, 2094.
Financial support for this work was provided by Russian
Foundation for Basic Research (grant #14-03-31288 Mol/A),
Russian Science Foundation (grant #14-23-00068), and
President Grant for Government Support of Young Russian
Scientists (grant #МК-5733.2015.3).
16 R. D. Viirre, G. Evindar, R. A. Batey, J. Org. Chem. 2008,
73, 3452.
Notes and references
6 | J. Name., 2012, 00, 1-3
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Journal Name
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DOI: 10.1039/C5RA15128G
One-pot synthesis of benzoxazoles via the metal-free ortho-C-H
functionalization of phenols with nitroalkanes†
Nicolai A. Aksenov, Alexander V. Aksenov,* Oleg N. Nadein, Dmitrii A. Aksenov,
Alexander N. Smirnov, and Michael Rubin*a
Graphical Abstract
Abstract: PPA-activated nitroalkanes are employed in the design of a one-pot cascade
transformation involving ortho-C-H functionalization, by Beckman rearrangment, and
condensation to produce benzoxazoles and benzobisoxazoles directly from easily available
phenols.