Light Induced C-C Coupling of 2-Chlorobenzazoles with Carbamates, Alcohols, and Ethers

Article abstract of DOI:10.1021/acs.joc.6b00715

A light induced, transition-metal-free C-C coupling reaction of 2-chlorobenzazoles with aliphatic carbamates, alcohols, and ethers is presented. Inexpensive reagents, namely sodium acetate, benzophenone, water, and acetonitrile, are employed in a simple reaction protocol using a cheap and widely available 25 W energy saving UV-A lamp at ambient temperature.

Full text of DOI:10.1021/acs.joc.6b00715

Note
pubs.acs.org/joc
Light Induced C−C Coupling of 2‑Chlorobenzazoles with
Carbamates, Alcohols, and Ethers
Alexander Lipp, Gunther Lahm, and Till Opatz*
̈
Institute of Organic Chemistry, University of Mainz, Duesbergweg 10-14, D-55128 Mainz, Germany
S
* Supporting Information
ABSTRACT: A light induced, transition-metal-free C−C
coupling reaction of 2-chlorobenzazoles with aliphatic carba-
mates, alcohols, and ethers is presented. Inexpensive reagents,
namely sodium acetate, benzophenone, water, and acetonitrile,
are employed in a simple reaction protocol using a cheap and
widely available 25 W energy saving UV-A lamp at ambient
temperature.
enzimidazoles,1−4 benzothiazoles,5−8 and benzoxa-
corresponding C−C coupled products via a radical recombi-
nation mechanism.30 These authors reacted ethers with
benzoxazoles, benzimidazoles, and benzothiazoles whereas the
use of alcohols as alkylating agents was only demonstrated with
benzothiazoles. Recently, Ji and co-workers disclosed a protocol
for the light induced amidation and alkylation of heteroarenes
including benzothiazoles and benzimidazoles with formalde-
hyde, amides, or ethers (Scheme 1).31 The C−C coupled
products were accessed using ammonium persulfate, stoichio-
metric quantities of benzaldehyde, and an excess of the
corresponding substrate. The authors proposed a radical
mechanism based on a peroxodisulfate decomposition medi-
ated by photoexcited benzaldehyde. However, benzoxazoles
turned out to be incompatible with the reaction protocol.
Secondary amines (protected as carbamates) and alcohols
would represent highly attractive coupling components since
the resulting C−C coupled products could be further
incorporated into other building blocks via esterification or
reductive amination (for applications of these two reactions in
the formation of sophisticated structures see for example refs
32−34). Therefore, this study aimed to develop a safe
procedure for the mild and metal-free C−C coupling of
benzazoles with carbamates, alcohols, and ethers. To avoid the
use of aggressive and harmful stoichiometric oxidants, the
process should be redox neutral. To the best of our knowledge,
a coupling reaction with these characteristics has not been
previously reported.
9−11
Bzoles
represent prominent structural motifs in a wide
range of biologically active molecules and are attractive target
structures in medicinal chemistry. The benzoxazole moiety
occurs in various compounds with antimicrobial,12 antitumor,13
herbicidal,14 antiretroviral,15 or protein inhibitory16 properties
and is found in numerous ligands for biochemical receptors.17,18
Furthermore, it was shown to be a valuable activating and
directing group for the C(sp3)−H α-alkylation of amines.19
Therefore, methodologies for the synthesis of substituted
benzazoles are attractive for various areas of chemical research.
For the functionalization of (benz)azoles, a variety of
transition-metal-catalyzed C−C and C−N coupling reactions
have been developed including for example the copper, nickel,
or palladium catalyzed arylation,20 benzylation,20,21 allylation,21
alkylation,22 alkenylation,20,23 alkynylation,24 amination,25 or
amidation26 at the C-2 position. MacMillan and co-workers
recently reported the α-arylation of tertiary arylamines with
various chlorinated heteroarenes including 2-chloro-
benzoxazole, 2-chlorobenzothiazole, and Boc-protected 2-
chloro-1H-benzimidazole via an iridium-catalyzed photoredox
reaction.27 Weaver and co-workers also used an iridium-
catalyzed photoredox approach for the α-arylation of tertiary,
sterically hindered (non-nucleophilic) amines with 2-chloro-
(benz)azoles.28 However, only very few metal-free systems for
the C-2 functionalization of benzazoles were reported which are
particularly attractive in view of the very expensive transition
metal catalysts and ligands. For example, Nachtsheim and co-
workers used a combination of catalytic tetrabutylammonium
iodide (TBAI) and H2O2 or tert-butyl hydroperoxide (TBHP)
as co-oxidants and HOAc as an additive to achieve the first
metal-free direct C-2 amination of various benzoxazoles.29
Simultaneously, He et al. developed a metal-free alkylation of
benzazoles with alcohols and ethers (reacting adjacent to the
heteroatom) using excess TBHP at 120 °C to access the
It is well-known that photoexcited benzophenone readily
abstracts H atoms from substrate molecules to form ketyl
radicals.35−37 The potential use of benzophenone as a
photosensitizer38−40 for radical reactions has for example
been studied by Inoue and co-workers.41−43 Carbamates are
Received: April 3, 2016
© XXXX American Chemical Society
A
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Note
Scheme 1. Selected Previous and Current Photoredox C−C
Coupling Approaches to the C-2 Functionalization of
Benzazoles
Scheme 2. Hypothetical Mechanism for the Photoinduced
C−C Coupling
to be shortened, Boc-piperidine was subjected to the standard
reaction protocol using a 400 W UV-A lamp and a reduced
reaction time of 14 h. However, the yield was lower than in the
case of the simple and inexpensive 25 W energy saving UV-A
bulb (1b). The reaction of Boc-pyrrolidine and Boc-azepane
with Boc-protected 2-chloro-1H-benzimidazole provided the
corresponding cross-coupled products 1d and 1f in appreciable
yields, whereas Boc-piperidine was repeatedly found to furnish
only trace amounts of product 1e. This unexpected result is
particularly surprising because the formation of compound 1b
indicates that H-abstraction from the Boc-piperidine core is
feasible. Since NMR-analysis suggested that most of the
carbamate remained unreacted, the formed amino radical
might be able to reabstract a hydrogen atom instead of reacting
with tert-butyl 2-chloro-1H-benzimidazole-1-carboxylate which
appears to be an electronically or sterically unfavorable process.
The coupling of 2-chlorobenzothiazole proceeded very slowly
yielding only 11% of compound 1g after 24 h. An increase of
the reaction time to 120 h was required to obtain the C−C
coupled product 1g in moderate yield. The reaction protocol
also proved suitable for the α-functionalization of open-chain
carbamates (1h), but the benzylic position in Boc-protected
1,2,3,4-tetrahydroisoquinoline turned out to be inaccessible for
the developed coupling reaction (1i).
Next, the utility of this method for alcohols and ethers as
coupling partners was investigated. Open-chain aliphatic
alcohols such as ethanol, n-propanol, or n-butanol reacted
with 2-chlorobenzoxazole to furnish the desired products 2a−
2c in appreciable yields. However, further increasing the chain
length to n-octanol led to a decrease in the yield (2d).
Interestingly, ethanol did not react with 2-chlorobenzothiazole
and only trace amounts of the product were formed. This is in
line with previous findings for carbamates (1g) which also
showed significantly reduced reactivity toward the benzothia-
zole compared to the benzoxazole moiety. This is particularly
noteworthy in view of the complementary selectivity of the
thermal TBHP mediated radical recombination route employ-
ing alcohols to alkylate benzothiazoles but not benzoxazoles.30
The developed reaction protocol is also suitable for cyclic
alcohols providing the C−C coupled product of cyclohexanol
and 2-chlorobenzoxazole in 61% yield (2e). Furthermore, the
method could be extended to cyclic and open-chain ethers.
THF reacted smoothly to give the desired cross-coupled
much less susceptible to oxidations via a single electron transfer
(SET) process than tertiary amines due to the adjacent
alkoxycarbonyl group. Therefore, an electron transfer mecha-
nism including the oxidation of a carbamate (which typically
have oxidation potentials above 1.70 V)44,45 by the excited state
of benzophenone (whose reduction potential can be approxi-
mated46 based on the ground-state reduction potential
Ered(BP/BP−1) and the triplet energy ET as Ered(BP*/BP−1) =
Ered(BP/BP−1) + ET = −1.83 V37,47,48 + 3.00 V37,48 = 1.17 V) is
not feasible. Nevertheless, benzophenone mediated H-
abstraction in α-position to carbamate nitrogens can generate
the corresponding α-amino radicals.41,42
Our working hypothesis, deduced from a mechanistic
proposal for the iridium-catalyzed photoredox α-arylation of
tertiary arylamines with chlorinated heteroarenes,27 is that the
reaction proceeds via a radical substitution pathway (Scheme
2).
A detailed screening of reaction conditions using 2-
chlorobenzoxazole and either Boc-pyrrolidine or ethanol as a
model system was initially undertaken (see Supporting
Information, Tables S1 and S2). It was decided to employ
the inexpensive and effective combination of benzophenone
and sodium acetate in acetonitrile/water mixtures as the
standard conditions for the coupling of 2-chlorobenzazoles with
aliphatic carbamates, alcohols, or ethers. Using this reaction
protocol, a series of C−C coupled products were prepared
(Table 1).
As anticipated, cyclic carbamates reacted readily with 2-
chlorobenzoxazole to produce the C−C coupled products 1a−
1c in high yields. To determine whether an increase in the
intensity of the UV-A irradiation would allow the reaction times
B
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Note
a
Table 1. Scope of the Presented C−C Coupling Reaction
a
For all reactions: 2-chlorobenzazole (0.90 mmol, 1.0 equiv), benzophenone (0.90 mmol, 1.0 equiv, unless stated otherwise), 15 mL of degassed
b
solvent and either 2.0 equiv of carbamate or 50 equiv of alcohol/ether, 25 W UV-A lamp. Isolated yields after chromatographic purification. 24 h
irradiation. K2CO3, 24 h irradiation. 400 W UV-A lamp, 14 h irradiation. 0.50 equiv of benzophenone and 36 h irradiation. 36 h irradiation. 72 h
irradiation. 120 h irradiation. Multigram scale using 18 mmol of 2-chlorobenzoxazole and 50 equiv of THF, 60 h irradiation (see Experimental
Section). 48 h irradiation.
c
d
e
f
g
h
i
j
products of all three tested 2-chlorobenzazoles in high yields
(2f−h). A multigram scale reaction of THF with 2-
chlorobenzoxazole proceeded equally well furnishing the
desired product 2f in high yield by simply irradiating the
reaction mixture with two inexpensive 25 W energy saving UV-
A lamps (Table 1). While diethyl ether smoothly reacted with
2-chlorobenzoxazole to 2i in high yield, allyl alcohol and benzyl
alcohol could not be transformed to the C−C cross-coupled
products 2j and 2k. This finding is in line with the lacking
formation of the arylated benzylic carbamate 1i and might be
attributable to the low reactivity of the involved well-stabilized
radicals in the C−C bond formation. A similar inaccessibility of
allylic and benzylic positions has been observed by He et al. in
their thermal TBHP mediated procedure.30 In contrast to
primary alcohols, methanol failed to give the respective
coupling product 2l. The regioselectivity of the α-arylation of
methyl propyl ether which provided a regioisomeric mixture
with a ratio of 6.25/1.00 in favor of the internal product in 69%
combined yield (2m, 2n) provides further evidence that
primary radicals are less suitable intermediates in the process.
As in other photochemical H-abstractions,41,42 stoichiometric
amounts of benzophenone are employed. Although this cheap
reagent is no cost factor, reduction of the loading of the
sensitizer was investigated. Ethanol and 2-chlorobenzoxazole
were chosen as model substrates. Even though the best results
were obtained with 1.0 equiv of benzophenone, a reduction to
25 mol % still afforded appreciable yields (55% instead of 57%)
while a loading of 1 mol % only resulted in a moderate turnover
(22% under identical conditions; see Supporting Information,
Table S3). The benzophenone loading of 25 mol % was
successfully applied to the preparative C−C coupling reaction
with Boc-azepane, ethanol, and THF (Table 2).
The addition of increasing amounts of the radical scavenger
2,6-bis(1,1-dimethylethyl)-4-methylphenol (butylated hydrox-
C
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Note
The sealed reaction mixture was stirred and irradiated with a 25 W
UV-A lamp for the indicated amount of time (lamp−sample distance
approximately 6 cm; see further specifications in the Supporting
Information). The volatiles were removed under reduced pressure, and
the residue was redissolved in chloroform (50 mL), dried over sodium
sulfate, and filtered. After the removal of the solvent under reduced
pressure, the crude product was purified by flash chromatography on
silica using eluent mixtures composed of cyclohexane and ethyl
acetate.
Table 2. C−C Coupling with Reduced Benzophenone
a
Loading
b
reactant
ethanol
product
time (h)
yield (%)
As expected, all reported cross-coupled products with Boc-protected
amines were obtained as mixtures of rotamers which can be
distinguished by NMR spectroscopy.
2a
2f
24
24
36
52
65
51
THF
Boc-azepane
1c
Multigram Scale Experiment (Compound 2f, Table 1). Under
an argon atmosphere, benzophenone (3.28 g, 18.0 mmol, 1.0 equiv),
sodium acetate (3.69 g, 45.0 mmol, 2.5 equiv), THF (64.9 g, 900
mmol, 50 equiv), acetonitrile (260 mL), and deionized water (40 mL)
were combined in a 500 mL Schlenk flask. The mixture was degassed
by bubbling a stream of argon through the stirred reaction medium for
10 min. 2-Chlorobenzoxazole (2.76 g, 18.0 mmol, 1.0 equiv) was
added to the vessel in an argon counterflow. The vessel was sealed, and
the mixture was stirred and irradiated for 60 h with two 25 W UV-A
lamps (lamps placed at opposite sides of the reaction vessel in order to
increase the irradiated surface; lamp−sample distance approximately 6
cm; see specifications in the Supporting Information). A solution of
sodium metabisulfite (5% in water, 50 mL, recommended in order to
destroy peroxides (if formed) in ether multigram scale experiments)
was added before THF and acetonitrile were removed under reduced
pressure. The remaining aqueous layer was extracted with ethyl acetate
(3 × 100 mL). The combined organic phases were dried over sodium
sulfate and filtered. After removal of the solvent under reduced
pressure, the crude mixture was purified by flash chromatography on
silica (cHex/EtOAc = 10/1). The pure product was obtained as an
orange oil (2.48 g, 13.1 mmol, 73%). Characterization data as given for
2f.
a
For all reactions: 2-chlorobenzoxazole (0.90 mmol, 1.0 equiv),
benzophenone (0.225 mmol, 0.25 equiv), 15 mL of degassed solvent
and either 2.0 equiv of carbamate or 50 equiv of alcohol/ether, 25 W
UV-A lamp. Isolated yields after chromatographic purification.
b
ytoluene, BHT) led to a dramatic decrease in the yield,
underlining the key role of radical intermediates in the reaction
mechanism (see Supporting Information, Table S3).
In summary, a mild, transition-metal-free and scalable
photochemical, redox-neutral C−C coupling of ethers, alcohols,
and carbamates with 2-chlorobenzazoles at ambient temper-
ature has been developed. The inexpensive reagents sodium
acetate, benzophenone, water, and acetonitrile were employed
in combination with UV-A light from cheap and widely
available energy saving lamps.
EXPERIMENTAL SECTION
■
All reagents and solvents were received from commercial suppliers and
used without further purification unless stated otherwise. Diethyl ether
and THF were freshly distilled from sodium/potassium. Acetonitrile
(HPLC grade) and deionized water were used without further
purification. When used as solvents for cross-coupling reactions,
acetonitrile and water were degassed by argon bubbling during
ultrasonication (20 min). Flash chromatography was performed on
silica gel (35−70 μm) using the specified eluent mixtures given as a
volumetric ratio of components. NMR spectra were recorded on a 300
( )-tert-Butyl 2-Chloro-1H-benzimidazole-1-carboxylate. To a
solution of di-tert-butyl-dicarbonate (2.71 g, 12.4 mmol, 1.1 equiv)
in acetonitrile (50 mL), 2-chloro-1H-benzimidazole (1.70 g, 11.1
mmol, 1.0 equiv) and 4-dimethylaminopyridine (DMAP, 150 mg, 1.23
mmol, 0.11 equiv) were added at 0 °C. The reaction mixture was
stirred for 14 h at room temperature. Water (50 mL) and ethyl acetate
(50 mL) were added, the phases were separated, and the organic layer
was washed with brine (50 mL), dried over sodium sulfate, and
filtered. The volatiles were removed under reduced pressure, and the
obtained crude product was purified by flash chromatography (cHex/
EtOAc = 12/1) furnishing the title compound as a colorless solid (2.65
MHz (300 MHz H NMR, 75.5 MHz 13C NMR), 400 MHz (400
1
MHz H NMR, 100.6 MHz 13C NMR), or 600 MHz (600 MHz H
1
1
NMR, 151 MHz 13C NMR) spectrometer. All 13C NMR spectra were
1
broad-band H-decoupled. The chemical shifts are reported in ppm
c
g, 10.5 mmol, 95%). Mp 65.0−66.5 °C. Rf = 0.33 (SiO2, Hex/EtOAc
and are referenced to the residual solvent (e.g., for CDCl3: δ = 7.26
12:1). IR (ATR): ν [cm−1] = 2982, 1761, 1494, 1449, 1346, 1327,
ppm for H and δ = 77.16 ppm for 13C NMR spectra). Coupling
1
̅
1
1151, 1116, 1081, 759. H NMR, COSY (300 MHz, CDCl3): δ/ppm
constants (J) are given in Hz using the conventional abbreviations (br
= broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet
and combinations thereof). FT-IR spectra were recorded using a
diamond ATR unit and are reported in terms of frequency of
absorption ν [cm−1]. Melting points were determined in open capillary
tubes using a digital electrothermal apparatus. HPLC-ESI-MS
measurements were performed on an HPLC system with a UV
diode array detector coupled with an ion trap mass spectrometer using
acetonitrile/water (with 0.1% v/v formic acid) mixtures as eluent.
High-resolution masses were recorded on an ESI/QTOF-instrument
with a suitable external calibrant. tert-Butyl pyrrolidine-1-carboxylate,
tert-butyl piperidine-1-carboxylate, tert-butyl azepane-1-carboxylate,
tert-butyl diethylcarbamate, and tert-butyl 3,4-dihydroisoquinoline-
2(1H)-carboxylate were prepared according to known proce-
dures.49−51
General Procedure for the Preparation of Cross-Coupled
Products (Table 1). Acetonitrile and deionized water were degassed
as described above. Under an argon atmosphere, benzophenone (164
mg, 0.900 mmol, 1.0 equiv), sodium acetate (185 mg, 2.26 mmol, 2.5
equiv), the required 2-chlorobenzazole (0.900 mmol, 1.0 equiv),
acetonitrile (13 mL), deionized water (2 mL), and either the
corresponding carbamate (1.80 mmol, 2.0 equiv) or the alcohol/
ether (45.0 mmol, 50 equiv) were combined in a 25 mL Schlenk flask.
= 7.94−7.86 (m, 1H, H−Ar), 7.70−7.61 (m, 1H, H−Ar), 7.40−7.30
(m, 2H, 2 × H−Ar), 1.72 (s, 9H, C(CH3)3). 13C NMR, HSQC,
t
HMBC (75.5 MHz, CDCl3): δ/ppm = 147.3 (CO2 Bu), 141.1 (Cq−
Ar), 139.8 (C-2), 133.5 (Cq−Ar), 125.2 (CH−Ar), 124.8 (CH−Ar),
119.7 (CH−Ar), 114.9 (CH−Ar), 86.8 (C(CH3)3), 28.2 (C(CH3)3).
ESI-MS: m/z (%) = 152.9 (100) [M − Boc + H]+, 169.6 (31) [M −
tBu + H]+. ESI-HRMS: calcd for [C12ClH13N2NaO2]+, m/z =
275.0563; found, 275.0562.
( )-tert-Butyl 2-(1,3-Benzoxazol-2-yl)pyrrolidine-1-carboxylate
(1a). Prepared according to the general procedure using Boc-
pyrrolidine (308 mg, 1.80 mmol, 2.0 equiv), 2-chlorobenzoxazole
(138 mg, 0.900 mmol, 1.0 equiv) and a reaction time of 24 h. After
purification by flash chromatography (cHex/EtOAc = 5/1) the title
compound was obtained as a colorless solid (202 mg, 0.701 mmol,
78%). Mixture of rotamers with A/B = 0.36/0.64. Mp 91.0−93.0 °C
(Lit.:52 65−70 °C). Rf = 0.23 (SiO2, Hex/EtOAc 4:1). IR (ATR): ν
c
̅
[cm−1] = 2977, 2932, 2880, 1698, 1455, 1392, 1367, 1242, 1163, 748.
1H NMR, COSY, NOESY (600 MHz, CDCl3): A, δ/ppm = 7.71−7.65
(m, 1H, H−Ar), 7.51−7.45 (m, 1H, H−Ar), 7.35−7.25 (m, 2H, 2 ×
H−Ar), 5.15 (br d, J = 7.9 Hz, 1H, H-2), 3.77−3.66 (m, 1H, Ha-5),
3.53−3.44 (m, 1H, Hb-5), 2.44−2.26 (m, 1H, Ha-3), 2.22−2.07 (m,
2H, Hb-3, Ha-4), 2.02−1.92 (m, 1H, Hb-4), 1.44 (br s, 9H, C(CH3)3);
D
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Note
B, δ/ppm = 7.71−7.65 (m, 1H, H−Ar), 7.51−7.45 (m, 1H, H−Ar),
7.35−7.25 (m, 2H, 2 × H−Ar), 5.01 (dd, J = 8.2, 4.4 Hz, 1H, H-2),
3.76−3.66 (m, 1H, Ha-5), 3.58 (dt, J = 10.5, 7.1 Hz, 1H, Hb-5), 2.44−
2.26 (m, 1H, Ha-3), 2.22−2.07 (m, 2H, Hb-3, Ha-4), 2.02−1.92 (m,
1H, Hb-4), 1.19 (br s, 9H, C(CH3)3). 13C NMR, HSQC, HMBC (151
procedure using Boc-pyrrolidine (308 mg, 1.80 mmol, 2.0 equiv), tert-
butyl 2-chloro-1H-benzimidazole-1-carboxylate (227 mg, 0.898 mmol,
1.0 equiv), and a reaction time of 36 h. After purification by flash
chromatography (cHex/EtOAc = 12.5/1 → 8.33/1 → 7.14/1) the title
compound was obtained as a yellowish oil (171 mg, 0.441 mmol,
49%). Mixture of rotamers with A/B = 0.49/0.51. Rf = 0.13 (SiO2,
t
MHz, CDCl3): A, δ/ppm = 167.2 (C-2′), 154.5 (CO2 Bu), 150.8 (Cq−
Ar), 141.3 (Cq−Ar), 124.7 (CH−Ar), 124.2 (CH−Ar), 120.2 (CH−
Ar), 110.8 (CH−Ar), 80.1 (C(CH3)3), 55.1 (C-2), 46.9 (C-5), 31.6
(C-3), 28.5 (C(CH3)3), 24.5 (C-4); B, δ/ppm = 167.5 (C-2′), 154.0
cHex/EtOAc 6:1). IR (ATR): ν [cm−1] = 2977, 2933, 2879, 1745,
̅
1
1699, 1453, 1393, 1350, 1153, 1119. H NMR, COSY, NOESY (600
MHz, CDCl3): A, δ/ppm = 7.91−7.85 (m, 1H, H−Ar), 7.73−7.68 (m,
1H, H−Ar), 7.33−7.29 (m, 1H, H−Ar), 7.29−7.25 (m, 1H, H−Ar),
5.70 (dd, J = 8.5, 1.9 Hz, 1H, H-2), 3.89−3.82 (m, 1H, Ha-5), 3.60−
3.45 (m, 1H, Hb-5), 2.47−2.34 (m, 1H, Ha-3), 2.16−1.97 (m, 2H, Hb-
3, Ha-4), 1.95−1.88 (m, 1H, Hb-4), 1.69 (br s, 9H, C′(C′H3)3), 1.45
(br s, 9H, C(CH3)3); B, δ/ppm = 7.91−7.85 (m, 1H, H−Ar), 7.73−
7.68 (m, 1H, H−Ar), 7.33−7.29 (m, 1H, H−Ar), 7.29−7.25 (m, 1H,
H−Ar), 5.61 (dd, J = 8.3, 3.3 Hz, 1H, H-2), 3.89−3.82 (m, 1H, Ha-5),
3.60−3.45 (m, 1H, Hb-5), 2.47−2.34 (m, 1H, Ha-3), 2.16−1.97 (m,
2H, Hb-3, Ha-4), 1.95−1.88 (m, 1H, Hb-4), 1.71 (br s, 9H,
C′(C′H3)3), 1.14 (br s, 9H, C(CH3)3). 13C NMR, HSQC, HMBC
t
(CO2 Bu), 150.5 (Cq−Ar), 141.2 (Cq−Ar), 124.9 (CH−Ar), 124.4
(CH−Ar), 120.0 (CH−Ar), 110.6 (CH−Ar), 80.1 (C(CH3)3), 55.5
(C-2), 46.6 (C-5), 32.7 (C-3), 28.2 (C(CH3)3), 23.9 (C-4). ESI-MS:
m/z (%) = 189.3 (21) [M − Boc + H]+, 233.1 (100) [M − tBu + H]+,
289.1 (37) [M + H]+. ESI-HRMS: calcd for [C16H20N2NaO3]+, m/z =
311.1372; found, 311.1382. The spectroscopic data are in accordance
with those reported in the literature.52
( )-tert-Butyl 2-(1,3-Benzoxazol-2-yl)piperidine-1-carboxylate
(1b). Prepared according to the general procedure using Boc-
piperidine (334 mg, 1.80 mmol, 2.0 equiv), 2-chlorobenzoxazole
(138 mg, 0.900 mmol, 1.0 equiv), and a reaction time of 24 h. After
purification by flash chromatography (cHex/EtOAc = 20/1) the title
compound was obtained as a colorless solid (165 mg, 0.546 mmol,
t
(151 MHz, CDCl3): A, δ/ppm = 157.1 (C-2′), 154.6 (CO2 Bu), 148.9
t
(C′O2 Bu), 142.3 (Cq−Ar), 132.9 (Cq−Ar), 124.3 (CH−Ar), 124.0
(CH−Ar), 120.1 (CH−Ar), 115.0 (CH−Ar), 85.6 (C′(C′H3)3), 79.6
(C(CH3)3), 56.7 (C-2), 47.1 (C-5), 32.1 (C-3), 28.7 (C(CH3)3), 28.2
61%). Mixture of rotamers with A/B ≈ 1/1. Mp 139.0−141.0 °C. Rf =
c
0.17 (SiO2, Hex/EtOAc 15:1). IR (ATR): ν [cm−1] = 3004, 2974,
t
(C′(C′H3)3), 23.5 (C-4); B, δ/ppm = 158.2 (C-2′), 154.1 (CO2 Bu),
̅
2862, 1695, 1455, 1409, 1242, 1122, 745. 1H NMR, COSY (600 MHz,
CDCl3): δ/ppm = 7.74−7.68 (m, 1H, H−Ar), 7.51−7.47 (m, 1H, H−
Ar), 7.34−7.28 (m, 2H, 2 × H−Ar), 5.89−5.36 (m, 1H, H-2), 4.11 (br
s, 1H, Ha-6), 3.15−2.78 (m, 1H, Hb-6), 2.50−2.44 (m, 1H, Ha-3),
1.96−1.87 (m, 1H, Hb-3), 1.79−1.57 (m, 2H, Ha-4, Ha-5), 1.58−1.38
(m, 11H, Hb-4, Hb-5, C(CH3)3). 13C NMR, HSQC, HMBC (151
t
149.0 (C′O2 Bu), 142.3 (Cq−Ar), 133.5 (Cq−Ar), 124.4 (CH−Ar),
124.3 (CH−Ar), 120.1 (CH−Ar), 114.8 (CH−Ar), 85.8 (C′(C′H3)3),
79.2 (C(CH3)3), 56.3 (C-2), 46.7 (C-5), 32.9 (C-3), 23.2 (C-4), 28.2
(C(CH3)3) and C′(C′H3)3). ESI-MS: m/z (%) = 232.1 (10) [M −
Boc − tBu + H]+, 282.2 (100) [M − Boc + H]+, 388.1 (86) [M + H]+.
ESI-HRMS: calcd for [C21H30N3O4]+, m/z = 388.2236; found,
388.2251.
t
MHz, CDCl3): δ/ppm = 165.7 (C-2′), 155.5 (CO2 Bu), 151.0 (Cq−
Ar), 141.4 (Cq−Ar), 124.9 (CH−Ar), 124.3 (CH−Ar), 120.1 (CH−
Ar), 110.7 (CH−Ar), 80.4 (C(CH3)3), 50.9 and 49.5 (C-2, rotamers A
and B), 42.1 and 41.0 (C-6, rotamers A and B), 28.5 (C(CH3)3), 27.6
(C-3), 25.1 (CH2), 20.3 (CH2). ESI-MS: m/z (%) = 203.2 (91) [M −
Boc + H]+, 247.2 (100) [M − tBu + H]+, 303.2 (51) [M + H]+, 325.2
(49) [M + Na]+. ESI-HRMS: calcd for [C17H22N2NaO3]+, m/z =
325.1528; found, 325.1539.
( )-tert-Butyl 2-(tert-Butyl 1,3-Benzimidazol-1-carboxylate-2-yl)-
azepane-1-carboxylate (1f). Prepared according to the general
procedure using Boc-azepane (359 mg, 1.80 mmol, 2.0 equiv), tert-
butyl 2-chloro-1H-benzimidazole-1-carboxylate (227 mg, 0.898 mmol,
1.0 equiv), and a reaction time of 36 h. After purification by flash
chromatography (cHex/EtOAc = 12/1) the title compound was
obtained as a yellowish and highly viscous oil (180 mg, 0.433 mmol,
48%). Mixture of rotamers with A/B = 0.42/0.58. Rf = 0.13 (SiO2,
( )-tert-Butyl 2-(1,3-Benzoxazol-2-yl)azepane-1-carboxylate (1c).
Prepared according to the general procedure using Boc-azepane (359
mg, 1.80 mmol, 2.0 equiv), 2-chlorobenzoxazole (138 mg, 0.900
mmol, 1.0 equiv), benzophenone (82 mg, 0.45 mmol, 0.50 equiv), and
a reaction time of 36 h. After purification by flash chromatography
(cHex/EtOAc = 15/1) the title compound was obtained as a colorless
solid (211 mg, 0.667 mmol, 74%). Mixture of rotamers with A/B =
cHex/EtOAc 12:1). IR (ATR): ν [cm−1] = 2976, 2929, 2854, 1744,
̅
1
1690, 1452, 1320, 1151, 1118. H NMR, COSY (400 MHz, CDCl3):
A, δ/ppm = 7.92−7.84 (m, 1H, H−Ar), 7.72−7.66 (m, 1H, H−Ar),
7.34−7.24 (m, 2H, 2 × H−Ar), 5.98 (dd, J = 11.9, 5.9 Hz, 1H, H-2),
4.11−4.02 (m, 1H, Ha-7), 3.55−3.42 (m, 1H, Hb-7), 2.53 (ddd, J =
14.3, 8.4, 5.9 Hz, 1H, Ha-3), 2.05−1.25 (m, 7H, Hb-3, H-4, H-5, H-6),
1.71 (br s, 9H, C′(C′H3)3), 1.44 (br s, 9H, C(CH3)3); B, δ/ppm =
7.92−7.84 (m, 1H, H−Ar), 7.72−7.66 (m, 1H, H−Ar), 7.34−7.24 (m,
2H, 2 × H−Ar), 5.72 (dd, J = 12.0, 5.2 Hz, 1H, H-2), 4.32−4.21 (m,
1H, Ha-7), 3.55−3.42 (m, 1H, Hb-7), 2.42 (ddd, J = 14.1, 8.5, 5.2 Hz,
1H, Ha-3), 2.05−1.25 (m, 7H, Hb-3, H-4, H-5, H-6), 1.71 (br s, 9H,
C′(C′H3)3), 1.22 (br s, 9H, C(CH3)3). 13C NMR, HSQC, HMBC
c
0.43/0.57. Mp 94.5−96.5 °C. Rf = 0.34 (SiO2, Hex/EtOAc 15:1). IR
(ATR): ν [cm−1] = 2975, 2930, 2856, 1694, 1455, 1407, 1227, 1162,
̅
749. 1H NMR, COSY (300 MHz, CDCl3): A, δ/ppm = 7.73−7.66 (m,
1H, H−Ar), 7.53−7.45 (m, 1H, H−Ar), 7.35−7.27 (m, 2H, 2 × H−
Ar), 5.22 (dd, J = 11.7, 6.2 Hz, 1H, H-2), 4.08−3.95 (m, 1H, Ha-7),
3.16 (ddd, J = 14.7, 11.1, 1.6 Hz, 1H, Hb-7), 2.58−2.36 (m, 1H, Ha-3),
2.12−1.20 (m, 7H, Hb-3, H-4, H-5, H-6), 1.37 (br s, 9H, C(CH3)3); B,
δ/ppm = 7.73−7.66 (m, 1H, H−Ar), 7.53−7.45 (m, 1H, H−Ar),
7.35−7.27 (m, 2H, 2 × H−Ar), 5.53 (dd, J = 11.7, 6.9 Hz, 1H, H-2),
3.92−3.79 (m, 1H, Ha-7), 3.05 (ddd, J = 14.8, 11.6, 1.8 Hz, 1H, Hb-7),
2.58−2.36 (m, 1H, Ha-3), 2.12−1.20 (m, 7H, Hb-3, H-4, H-5, H-6),
1.49 (br s, 9H, C(CH3)3). 13C NMR, HSQC, HMBC (75.5 MHz,
t
(100.6 MHz, CDCl3): A, δ/ppm = 158.8 (C-2′), 156.1 (CO2 Bu),
t
148.8 (C′O2 Bu), 142.5 (Cq−Ar), 133.1 (Cq−Ar), 124.0 (2C, 2 ×
CH−Ar), 119.9 (CH−Ar), 115.0 (CH−Ar), 85.7 (C′(C′H3)3), 79.5
(C(CH3)3), 54.6 (C-2), 44.4 (C-7), 33.3 (C-3), 30.0 (CH2), 29.6
(CH2), 28.6 (C(CH3)3), 28.2 (C′(C′H3)3), 26.0 (CH2); B, δ/ppm =
t
t
159.7 (C-2′), 155.5 (CO2 Bu), 148.9 (C′O2 Bu), 142.5 (Cq−Ar), 132.6
(Cq−Ar), 124.3 (2C, 2 × CH−Ar), 120.1 (CH−Ar), 114.9 (CH−Ar),
85.7 (C′(C′H3)3), 79.5 (C(CH3)3), 56.2 (C-2), 44.0 (C-7), 33.3 (C-
3), 30.4 (CH2), 29.5 (CH2), 28.4 (C(CH3)3), 28.2 (C′(C′H3)3), 26.8
t
CDCl3): A, δ/ppm = 167.4 (C-2′), 155.3 (CO2 Bu), 150.6 (Cq−Ar),
141.2 (Cq−Ar), 124.9 (CH−Ar), 124.4 (CH−Ar), 120.1 (CH−Ar),
110.6 (CH−Ar), 80.4 (C(CH3)3), 54.9 (C-2), 43.5 (C-7), 32.6 (C-3),
29.5 (CH2), 29.4 (CH2), 28.4 (C(CH3)3), 25.7 (CH2); B , δ/ppm =
t
(CH2). ESI-MS: m/z (%) = 260.1 (8) [M − Boc − Bu + H]+, 316.2
t
(77) [M − Boc + H]+, 416.2 (100) [M + H]+. ESI-HRMS: calcd for
167.1 (C-2′), 156.1 (CO2 Bu), 150.9 (Cq−Ar), 141.2 (Cq−Ar), 124.9
[C23H33N3NaO4]+, m/z = 438.2369; found, 438.2360.
(CH−Ar), 124.3 (CH−Ar), 120.1 (CH−Ar), 110.9 (CH−Ar), 80.2
(C(CH3)3), 52.9 (C-2), 43.7 (C-7), 32.3 (C-3), 29.7 (CH2), 29.3
(CH2), 28.6 (C(CH3)3), 25.0 (CH2). ESI-MS: m/z (%) = 217.2 (28)
[M − Boc + H]+, 261.2 (100) [M − tBu + H]+, 317.2 (65) [M + H]+,
339.2 (17) [M + Na]+. ESI-HRMS: calcd for [C18H24N2NaO3]+, m/z
= 339.1685; found, 339.1684.
( )-tert-Butyl 2-(1,3-Benzothiazol-2-yl)pyrrolidine-1-carboxylate
(1g). Prepared according to the general procedure using Boc-
pyrrolidine (308 mg, 1.80 mmol, 2.0 equiv), 2-chlorobenzothiazole
(153 mg, 0.902 mmol, 1.0 equiv), and a reaction time of 120 h. After
purification by flash chromatography (cHex/EtOAc = 6/1) the title
compound was obtained as a colorless solid (97 mg, 0.32 mmol, 35%).
Mixture of rotamers with A/B = 0.35/0.65. Mp 97.0−99.0 °C. Rf =
( )-tert-Butyl 2-(tert-Butyl 1,3-benzimidazol-1-carboxylate-2-yl)-
pyrrolidine-1-carboxylate (1d). Prepared according to the general
E
DOI: 10.1021/acs.joc.6b00715
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
c
0.18 (SiO2, Hex/EtOAc 6:1). IR (ATR): ν [cm−1] = 2976, 2879,
( )-1-(1,3-Benzoxazol-2-yl)propan-1-ol (2b). Prepared according
to the general procedure using n-propanol (2.70 g, 44.9 mmol, 50
equiv), 2-chlorobenzoxazole (138 mg, 0.900 mmol, 1.0 equiv), and a
reaction time of 36 h. After purification by flash chromatography
(cHex/EtOAc = 8/1 → 6/1) the title compound was obtained as a
̅
1699, 1437, 1386, 1367, 1244, 1166, 1112, 760. 1H NMR, COSY (600
MHz, CDCl3): A, δ/ppm = 7.96 (d, J = 8.1 Hz, 1H, H−Ar), 7.89−7.80
(m, 1H, H−Ar), 7.50−7.39 (m, 1H, H−Ar), 7.39−7.30 (m, 1H, H−
Ar), 5.36−5.30 (m, 1H, H-2), 3.71−3.61 (m, 1H, Ha-5), 3.53−3.44
(m, 1H, Hb-5), 2.47−2.22 (m, 2H, H-3), 2.06−1.92 (m, 2H, H-4),
1.49 (br s, 9H, C(CH3)3); B, δ/ppm = 7.96 (d, J = 8.1 Hz, 1H, H−
Ar), 7.89−7.80 (m, 1H, H−Ar), 7.50−7.39 (m, 1H, H−Ar), 7.39−7.30
(m, 1H, H−Ar), 5.22 (dd, J = 8.3, 3.2 Hz, 1H, H-2), 3.71−3.61 (m,
1H, Ha-5), 3.61−3.53 (m, 1H, Hb-5), 2.47−2.22 (m, 2H, H-3), 2.06−
1.92 (m, 2H, H-4), 1.30 (br s, 9H, C(CH3)3). 13C NMR, HSQC,
HMBC (151 MHz, CDCl3): A, δ/ppm = 176.3 (C-2′), 154.9
c
yellow oil (77 mg, 0.43 mmol, 48%). Rf = 0.10 (SiO2, Hex/EtOAc
6:1). IR (ATR): ν [cm−1] = 3316, 2969, 2936, 2879, 1613, 1568, 1455,
̅
1242, 1125, 1103, 840, 744. 1H NMR, COSY (400 MHz, CDCl3): δ/
ppm = 7.71−7.65 (m, 1H, H−Ar), 7.51−7.45 (m, 1H, H−Ar), 7.34−
7.27 (m, 2H, 2 × H−Ar), 4.96−4.88 (m, 1H, CH2CHOH), 4.47 (br s,
1H, CHOH), 2.15−1.93 (m, 2H, CH2CHOH), 1.04 (t, J = 7.4 Hz,
3H, CH3CH2). 13C NMR, HSQC, HMBC (100.6 MHz, CDCl3): δ/
ppm = 168.1 (C-2′), 150.8 (Cq−Ar), 140.4 (Cq−Ar), 125.2 (CH−Ar),
124.6 (CH−Ar), 120.0 (CH−Ar), 110.8 (CH−Ar), 69.2 (CHOH),
28.8 (CH2CHOH), 9.6 (CH3CH2). ESI-MS: m/z (%) = 160.1 (74)
[M − OH]+, 178.0 (100) [M + H]+. ESI-HRMS: calcd for
[C10H11NNaO2]+, m/z = 200.0687; found, 200.0679. This compound
has been described in the literature,54 but detailed analytical data are
not available.
t
(CO2 Bu), 153.9 (Cq−Ar), 135.1 (Cq−Ar), 125.9 (CH−Ar), 124.8
(CH−Ar), 123.0 (CH−Ar), 121.7 (CH−Ar), 80.3 (C(CH3)3), 59.6
(C-2), 47.2 (C-5), 33.1 (C-3), 28.6 (C(CH3)3), 24.2 (C-4); B, δ/ppm
t
= 177.1 (C-2′), 154.4 (CO2 Bu), 153.6 (Cq−Ar), 134.7 (Cq−Ar),
126.1 (CH−Ar), 124.9 (CH−Ar), 122.9 (CH−Ar), 121.8 (CH−Ar),
80.5 (C(CH3)3), 60.1 (C-2), 46.8 (C-5), 34.3 (C-3), 28.4 (C(CH3)3),
23.5 (C-4). ESI-MS: m/z (%) = 205.4 (16) [M − Boc + H]+, 249.2
(99) [M − Bu + H]+, 305.1 (100) [M + H]+. ESI-HRMS: calcd for
t
( )-1-(1,3-Benzoxazol-2-yl)butan-1-ol (2c). Prepared according to
the general procedure using n-butanol (3.34 g, 45.1 mmol, 50 equiv),
2-chlorobenzoxazole (138 mg, 0.900 mmol, 1.0 equiv), and a reaction
time of 24 h. After purification by flash chromatography (cHex/EtOAc
= 10/1 → 6/1) the title compound was obtained as an orange oil (86
[C16H20N2NaO2S]+, m/z = 327.1143; found, 327.1156.
( )-tert-Butyl (1-(1,3-Benzoxazol-2-yl)ethyl)ethylcarbamate (1h).
Prepared according to the general procedure using tert-butyl
diethylcarbamate (312 mg, 1.80 mmol, 2.0 equiv), 2-chlorobenzox-
azole (138 mg, 0.900 mmol, 1.0 equiv), and a reaction time of 72 h.
After purification by flash chromatography (cHex/EtOAc = 15/1) the
title compound was obtained as a colorless solid (134 mg, 0.461 mmol,
mg, 0.45 mmol, 50%). Rf = 0.14 (SiO2, cHex/EtOAc 6:1). IR (ATR): ν
̅
[cm−1] = 3328, 2961, 2935, 2874, 1612, 1568, 1456, 1243, 1128, 746.
1H NMR, COSY (400 MHz, CDCl3): δ/ppm = 7.71−7.64 (m, 1H,
H−Ar), 7.51−7.45 (m, 1H, H−Ar), 7.34−7.28 (m, 2H, 2 × H−Ar),
5.02−4.94 (m, 1H, CH2CHOH), 4.31 (d, J = 6.0 Hz, 1H, CHOH),
2.07−1.90 (m, 2H, CH2CHOH), 1.59−1.43 (m, 2H, CH3CH2), 0.96
(t, J = 7.4 Hz, 3H, CH3CH2). 13C NMR, HSQC, HMBC (100.6 MHz,
CDCl3): δ/ppm = 168.3 (C-2′), 150.8 (Cq−Ar), 140.4 (Cq−Ar),
125.2 (CH−Ar), 124.6 (CH−Ar), 120.0 (CH−Ar), 110.9 (CH−Ar),
67.8 (CHOH), 37.7 (CH2CHOH), 18.5 (CH3CH2), 13.9 (CH3CH2).
ESI-MS: m/z (%) = 174.0 (23) [M − OH]+, 192.0 (100) [M + H]+.
ESI-HRMS: calcd for [C11H14NO2]+, m/z = 192.1025; found,
192.1033.
51%). Mixture of rotamers with A/B = 0.44/0.56. Mp 53.0−54.5 °C.
Rf = 0.14 (SiO2, Hex/EtOAc 15:1). IR (ATR): ν [cm−1] = 2976,
c
̅
2936, 1690, 1455, 1407, 1378, 1288, 1149, 765, 743. 1H NMR, COSY
(600 MHz, CDCl3): A, δ/ppm = 7.74−7.68 (m, 1H, H−Ar), 7.53−
7.46 (m, 1H, H−Ar), 7.35−7.28 (m, 2H, 2 × H−Ar), 5.01 (br s, 1H,
NCHCH3), 3.56−2.95 (m, 2H, NCH2CH3), 1.81−1.63 (m, 3H,
NCHCH3), 1.62−1.20 (m, 9H, C(CH3)3), 1.19−0.89 (m, 3H,
NCH2CH3); B, δ/ppm = 7.74−7.68 (m, 1H, H−Ar), 7.53−7.46 (m,
1H, H−Ar), 7.35−7.28 (m, 2H, 2 × H−Ar), 5.68 (br s, 1H,
NCHCH3), 3.56−2.95 (m, 2H, NCH2CH3), 1.81−1.63 (br s, 3H,
NCHCH3), 1.62−1.20 (m, 9H, C(CH3)3), 1.19−0.89 (m, 3H,
NCH2CH3). 13C NMR, HSQC, HMBC (151 MHz, CDCl3): A, δ/
( )-1-(1,3-Benzoxazol-2-yl)octan-1-ol (2d). Prepared according to
the general procedure using n-octanol (5.86 g, 45.0 mmol, 50 equiv),
2-chlorobenzoxazole (138 mg, 0.900 mmol, 1.0 equiv) and a reaction
time of 36 h. After removal of excess n-octanol in fine vacuum and
subsequent purification by flash chromatography (cHex/EtOAc = 10/1
→ 6/1) the title compound was obtained as a yellow oil (78 mg, 0.32
t
ppm = 166.3 (C-2′), 154.6 (CO2 Bu), 150.9 (Cq−Ar), 141.1 (Cq−Ar),
125.2 (CH−Ar), 124.4 (CH−Ar), 120.1 (CH−Ar), 110.8 (CH−Ar),
80.3 (C(CH3)3), 51.0 (NCHCH3), 41.0 (NCH2CH3), 28.5 (C-
(CH3)3), 17.1 (NCHCH3), 14.5 (NCH2CH3); B, δ/ppm = 166.6 (C-
t
mmol, 36%). Rf = 0.20 (SiO2, cHex/EtOAc 6:1). IR (ATR): ν [cm−1]
2′), 155.6 (CO2 Bu), 150.9 (Cq−Ar), 141.1 (Cq−Ar), 125.2 (CH−Ar),
̅
1
124.4 (CH−Ar), 120.1 (CH−Ar), 110.8 (CH−Ar), 80.3 (C(CH3)3),
48.9 (NCHCH3), 38.8 (NCH2CH3), 28.5 (C(CH3)3), 16.7
(NCHCH3), 15.3 (NCH2CH3). ESI-MS: m/z (%) = 191.0 (44) [M
= 3329, 2925, 2856, 1613, 1568, 1456, 1243, 1105, 745. H NMR,
COSY (300 MHz, CDCl3): δ/ppm = 7.74−7.62 (m, 1H, H−Ar),
7.59−7.47 (m, 1H, H−Ar), 7.36−7.28 (m, 2H, 2 × H−Ar), 5.00 (br s,
1H, CH2CHOH), 3.61 (br s, 1H, CHOH), 2.15−1.88 (m, 2H,
CH2CHOH), 1.57−1.41 (m, 2H, CH2CH2CHOH), 1.39−1.16 (m,
8H, 4 × CH2), 0.86 (t, J = 7.0 Hz, 3H, CH3). 13C NMR, HSQC,
HMBC (151 MHz, CDCl3): δ/ppm = 168.1 (C-2′), 151.0 (Cq−Ar),
140.6 (Cq−Ar), 125.3 (CH−Ar), 124.6 (CH−Ar), 120.1 (CH−Ar),
110.9 (CH−Ar), 68.1 (CHOH), 35.8 (CH2CHOH), 31.9 (CH2), 29.4
(CH2), 29.3 (CH2), 25.2 (CH2), 22.8 (CH3CH2), 14.2 (CH3). ESI-
MS: m/z (%) = 230.0 (10) [M − OH]+, 248.1 (100) [M + H]+, 270.1
(4) [M + Na]+. ESI-HRMS: calcd for [C15H21NNaO2]+, m/z =
270.1470; found, 270.1477.
− Boc + H]+, 235.0 (100) [M − Bu + H]+, 291.1 (48) [M + H]+,
t
313.1 (15) [M + Na]+. ESI-HRMS: calcd for [C16H22N2NaO3]+, m/z
= 313.1528; found, 313.1524.
( )-1-(1,3-Benzoxazol-2-yl)ethan-1-ol (2a). Prepared according to
the general procedure using ethanol (2.07 g, 44.9 mmol, 50 equiv), 2-
chlorobenzoxazole (138 mg, 0.900 mmol, 1.0 equiv), and a reaction
time of 24 h. After purification by flash chromatography (cHex/EtOAc
= 6/1 → 7/3) the title compound was obtained as a yellowish oil
which slowly crystallized to provide a colorless solid (87 mg, 0.53
mmol, 59%). Mp 33.0−34.5 °C (Lit.:53 29.0−31.0 °C). Rf = 0.23
(SiO2, Hex/EtOAc 7:3). IR (ATR): ν [cm−1] = 3327, 2985, 1613,
c
( )-1-(1,3-Benzoxazol-2-yl)cyclohexan-1-ol (2e). Prepared accord-
ing to the general procedure using cyclohexanol (4.51 g, 45.0 mmol,
50 equiv), 2-chlorobenzoxazole (138 mg, 0.900 mmol, 1.0 equiv), and
a reaction time of 36 h. After purification by flash chromatography
(cHex/EtOAc = 20/1 → 10/1) the title compound was obtained as a
̅
1
1569, 1456, 1243, 1121, 1100, 817, 748. H NMR, COSY (400 MHz,
CDCl3): δ/ppm = 7.71−7.64 (m, 1H, H−Ar), 7.50−7.44 (m, 1H, H−
Ar), 7.34−7.27 (m, 2H, 2 × H−Ar), 5.14 (q, J = 6.7 Hz, 1H,
CH3CHOH), 4.75 (br s, 1H, OH), 1.71 (d, J = 6.7 Hz, 3H,
CH3CHOH). 13C NMR, HSQC, HMBC (100.6 MHz, CDCl3): δ/
ppm = 168.7 (C-2′), 150.8 (Cq−Ar), 140.4 (Cq−Ar), 125.3 (CH−Ar),
124.6 (CH−Ar), 120.0 (CH−Ar), 110.8 (CH−Ar), 64.1
(CH3CHOH), 21.5 (CH3CHOH). ESI-MS: m/z (%) = 146.0 (28)
[M − OH]+, 164.0 (100) [M + H]+, 185.9 (4) [M + Na]+. ESI-
HRMS: calcd for [C9H9NNaO2]+, m/z = 186.0531; found, 186.0535.
The analytical data are in accordance with those reported in the
literature.53
c
colorless solid (120 mg, 0.552 mmol, 61%). Rf = 0.18 (SiO2, Hex/
EtOAc 6:1). Mp 88.0−90.0 °C. IR (ATR): ν [cm−1] = 3377, 2936,
̅
2858, 1562, 1455, 1244, 1152, 1040, 749. 1H NMR, COSY (400 MHz,
CDCl3): δ/ppm = 7.74−7.68 (m, 1H, H−Ar), 7.55−7.48 (m, 1H, H−
Ar), 7.36−7.30 (m, 2H, 2 × H−Ar), 2.96 (br s, 1H, OH), 2.21−2.08
(m, 2H, Ha-2, Ha-6), 2.00−1.90 (m, 2H, Hb-2, Hb-6), 1.90−1.76 (m,
2H, Ha-3, Ha-5), 1.72−1.57 (m, 3H, Hb-3, Ha-4, Hb-5), 1.47−1.35 (m,
1H, Hb-4). 13C NMR, HSQC, HMBC (100.6 MHz, CDCl3): δ/ppm =
F
DOI: 10.1021/acs.joc.6b00715
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
170.6 (C-2′), 150.9 (Cq−Ar), 140.8 (Cq−Ar), 125.2 (CH−Ar), 124.5
(CH−Ar), 120.2 (CH−Ar), 110.9 (CH−Ar), 71.3 (COH), 36.5 (2C,
C-2 and C-6), 25.3 (C-4), 21.7 (2C, C-3 and C-5). ESI-MS: m/z (%)
= 200.1 (44) [M − OH]+, 218.0 (100) [M + H]+, 240.4 (4) [M +
Na]+. ESI-HRMS: calcd for [C13H15NNaO2]+, m/z = 240.1000; found,
240.1002.
( )-2-(Oxolan-2-yl)-1,3-benzoxazole (2f). Prepared according to
the general procedure using THF (3.24 g, 44.9 mmol, 50 equiv), 2-
chlorobenzoxazole (138 mg, 0.900 mmol, 1.0 equiv), and a reaction
time of 24 h. After purification by flash chromatography (cHex/EtOAc
= 10/1) the title compound was obtained as an orange oil (119 mg,
15:1). IR (ATR): ν [cm−1] = 3059, 2980, 2936, 2896, 2872, 1568,
̅
1455, 1320, 1241, 1179, 1114, 751. 1H NMR, COSY (300 MHz,
CDCl3): δ/ppm = 7.76−7.68 (m, 1H, H−Ar), 7.58−7.50 (m, 1H, H−
Ar), 7.38−7.29 (m, 2H, 2 × H−Ar), 4.76 (q, J = 6.7 Hz, 1H,
OCHCH3), 3.58 (qd, J = 7.0, 0.9 Hz, 2H, OCH2CH3), 1.67 (d, J = 6.7
Hz, 3H, OCHCH3), 1.23 (t, J = 7.0 Hz, 3H, OCH2CH3). 13C NMR,
HSQC, HMBC (75.5 MHz, CDCl3): δ/ppm = 166.4 (C-2), 150.9
(Cq−Ar), 140.9 (Cq−Ar), 125.3 (CH−Ar), 124.5 (CH−Ar), 120.4
(CH−Ar), 111.0 (CH−Ar), 71.5 (OCHCH3), 65.5 (OCH2CH3), 19.8
(OCHCH3), 15.4 (OCH2CH3). ESI-MS: m/z (%) = 146.0 (48) [M −
EtO]+, 192.0 (100) [M + H]+, 214.0 (3) [M + Na]+. The obtained
spectroscopic data are in accordance with those reported in the
literature.55
c
0.629 mmol, 70%). Rf = 0.20 (SiO2, Hex/EtOAc 6:1). IR (ATR): ν
̅
[cm−1] = 3059, 2980, 2955, 2875, 1614, 1569, 1455, 1242, 1059, 748.
1H NMR, COSY (400 MHz, CDCl3): δ/ppm = 7.73−7.66 (m, 1H,
H−Ar), 7.54−7.47 (m, 1H, H−Ar), 7.35−7.27 (m, 2H, 2 × H−Ar),
5.19 (t, J = 6.8 Hz, 1H, H-2′), 4.11 (ddd, J = 8.3, 7.2, 6.4 Hz, 1H, Ha-
5′), 3.99 (ddd, J = 8.3, 7.3, 6.1 Hz, 1H, Hb-5′), 2.42−2.34 (m, 2H, H-
3′), 2.22−1.98 (m, 2H, H-4′). 13C NMR, HSQC, HMBC (100.6 MHz,
CDCl3): δ/ppm = 166.3 (C-2), 150.9 (Cq−Ar), 140.9 (Cq−Ar), 125.2
(CH−Ar), 124.4 (CH−Ar), 120.2 (CH−Ar), 110.8 (CH−Ar), 74.0
(C-2′), 69.4 (C-5′), 30.8 (C-3′), 25.8 (C-4′). ESI-MS: m/z (%) =
190.1 (100) [M + H]+, 212.0 (16) [M + Na]+. ESI-HRMS: calcd for
[C11H11NNaO2]+, m/z = 212.0687; found, 212.0678. The obtained
spectroscopic data are in accordance with those reported in the
literature.55
( )-2-(1-Methoxypropyl)-1,3-benzoxazole (2m). Prepared accord-
ing to the general procedure using methyl propyl ether (3.34 g, 45.1
mmol, 50 equiv), 2-chlorobenzoxazole (138 mg, 0.900 mmol, 1.0
equiv), and a reaction time of 24 h. After purification by flash
chromatography (cHex/EtOAc = 25/1) the title compound and its
regioisomer 2n were obtained as a pale orange oil (119 mg, 0.622
mmol, 69%) with a regioisomeric ratio of 6.25/1.00 in favor of 2m. Rf
c
= 0.38 (SiO2, Hex/EtOAc 6:1). IR (ATR): ν [cm−1] = 2970, 2936,
̅
2879, 2827, 1568, 1455, 1242, 1130, 1097, 839, 749. 1H NMR, COSY
(300 MHz, CDCl3): δ/ppm = 7.77−7.69 (m, 1H, H−Ar), 7.58−7.50
(m, 1H, H−Ar), 7.38−7.29 (m, 2H, 2 × H−Ar), 4.42 (t, J = 6.7 Hz,
1H, OCHCH2), 3.41 (s, 3H, OCH3), 2.13−1.92 (m, 2H,
OCHCH2CH3), 0.98 (t, J = 7.5 Hz, 3H, OCHCH2CH3). 13C NMR,
HSQC, HMBC (75.5 MHz, CDCl3): δ/ppm = 165.5 (C-2), 150.9
(Cq−Ar), 140.8 (Cq−Ar), 125.3 (CH−Ar), 124.5 (CH−Ar), 120.3
(CH−Ar), 111.0 (CH−Ar), 78.8 (OCHCH2), 57.9 (OCH3), 27.1
(OCHCH2), 9.7 (OCHCH2CH3). ESI-HRMS: calcd for
[C11H13NNaO2], m/z = 214.0844; found, 214.0835.
( )-2-(Oxolan-2-yl)-1,3-benzothiazole (2g). Prepared according to
the general procedure using THF (3.24 g, 44.9 mmol, 50 equiv), 2-
chlorobenzothiazole (138 mg, 0.900 mmol, 1.0 equiv), and a reaction
time of 120 h. After purification by flash chromatography (cHex/
EtOAc = 12/1 → 11/1) the title compound was obtained as a yellow
oil (109 mg, 0.531 mmol, 59%). Rf = 0.27 (SiO2, cHex/EtOAc 6:1). IR
(ATR): ν [cm−1] = 3061, 2978, 2950, 2873, 1520, 1456, 1437, 1312,
̅
( )-2-(Propoxymethyl)-1,3-benzoxazole (2n). Prepared according
to the general procedure using methyl propyl ether (3.34 g, 45.1
mmol, 50 equiv), 2-chlorobenzoxazole (138 mg, 0.900 mmol, 1.0
equiv), and a reaction time of 24 h. After purification by flash
chromatography (cHex/EtOAc = 25/1) the title compound and its
regioisomer 2m were obtained as a pale orange oil (119 mg, 0.622
1063, 760, 731. 1H NMR, COSY (300 MHz, CDCl3): δ/ppm = 7.99−
7.94 (m, 1H, H−Ar), 7.90−7.85 (m, 1H, H−Ar), 7.48−7.41 (m, 1H,
H−Ar), 7.38−7.31 (m, 1H, H−Ar), 5.34 (dd, J = 7.8, 5.3 Hz, 1H, H-
2′), 4.15 (dt, J = 8.3, 6.5 Hz, 1H, Ha-5′), 3.99 (dt, J = 8.3, 7.0 Hz, 1H,
Hb-5′), 2.58−2.43 (m, 1H, Ha-3′), 2.33−2.19 (m, 1H, Hb-3′), 2.08−
1.96 (m, 2H, H-4′). 13C NMR, HSQC, HMBC (75.5 MHz, CDCl3):
δ/ppm = 176.4 (C-2), 153.8 (Cq−Ar), 134.8 (Cq−Ar), 126.0 (CH−
Ar), 124.9 (CH−Ar), 122.9 (CH−Ar), 121.9 (CH−Ar), 78.9 (C-2′),
69.9 (C-5′), 33.5 (C-3′), 25.8 (C-4′). ESI-MS: m/z (%) = 206.1 (100)
[M + H]+, 228.0 (3) [M + Na]+. ESI-HRMS: calcd for [C11H12NOS]+,
m/z = 206.0640; found, 206.0635. The obtained spectroscopic data
are in accordance with the literature.30
mmol, 69%) with a regioisomeric ratio of 6.25/1.00 in favor of 2m. Rf
c
= 0.38 (SiO2, Hex/EtOAc 6:1). IR (ATR): ν [cm−1] = 2970, 2936,
̅
2879, 2827, 1568, 1455, 1242, 1130, 1097, 839, 749. 1H NMR, COSY
(300 MHz, CDCl3): δ/ppm = 7.77−7.69 (m, 1H, H−Ar), 7.58−7.50
(m, 1H, H−Ar), 7.38−7.29 (m, 2H, 2 × H−Ar), 4.74 (s, 2H, OCH2-
Azol), 3.57 (t, J = 6.7 Hz, 2H, OCH2CH2CH3), 1.75−1.59 (m, 2H,
OCH2CH2CH3), 0.94 (t, J = 7.4 Hz, 3H, OCH2CH2CH3). 13C NMR,
HSQC, HMBC (75.5 MHz, CDCl3): δ/ppm = 163.1 (C-2), 151.0
(Cq−Ar), 141.0 (Cq−Ar), 125.4 (CH−Ar), 124.5 (CH−Ar), 120.3
(CH−Ar), 111.0 (CH−Ar), 73.5 (OCH2CH2), 66.5 (OCH2-Azol),
22.9 (OCH2CH2), 10.5 (OCH2CH2CH3). ESI-HRMS: calcd for
[C11H13NNaO2]: m/z = 214.0844; found, 214.0835.
( )-tert-Butyl 2-(oxolan-2-yl)-1H-benzimidazole-1-carboxylate
(2h). Prepared according to the general procedure using THF (3.24
g, 44.9 mmol, 50 equiv), tert-butyl 2-chloro-1H-benzimidazole-1-
carboxylate (227 mg, 0.898 mmol, 1.0 equiv), and a reaction time of
48 h. After purification by flash chromatography (cHex/EtOAc = 6/1)
the title compound was obtained as a yellow oil (173 mg, 0.600 mmol,
67%). Rf = 0.15 (SiO2, cHex/EtOAc 6:1). IR (ATR): ν [cm−1] = 2978,
̅
2874, 1744, 1453, 1370, 1350, 1154, 1121, 767. 1H NMR, COSY (400
MHz, CDCl3): δ/ppm = 7.93−7.87 (m, 1H, H−Ar), 7.78−7.72 (m,
1H, H−Ar), 7.35−7.28 (m, 2H, 2 × H−Ar), 5.71 (dd, J = 7.8, 5.1 Hz,
1H, H-2′), 4.25−4.17 (m, 1H, Ha-5′), 4.04−3.96 (m, 1H, Hb-5′),
2.51−2.40 (m, 1H, Ha-3′), 2.34−2.23 (m, 1H, Hb-3′), 2.15−1.94 (m,
2H, H-4′), 1.70 (br s, 9H, OC(CH3)3). 13C NMR, HSQC, HMBC
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b00715.
t
NMR spectra of all compounds, detailed reports of the
performed screening reactions, loading experiments and
radical scavenger studies as well as precise descriptions of
the used light sources. (PDF)
(100.6 MHz, CDCl3): δ/ppm = 156.7 (C-2), 148.8 (CO2 Bu), 142.1
(Cq−Ar), 133.3 (Cq−Ar), 124.7 (CH−Ar), 124.3 (CH−Ar), 120.4
(CH−Ar), 114.9 (CH−Ar), 85.8 (C(CH3)3), 75.3 (C-2′), 69.2 (C-5′),
31.5 (C-3′), 28.2 (C(CH3)3), 25.5 (C-4′). ESI-MS: m/z (%) = 189.0
(100) [M − Boc + H]+, 233.0 (28) [M − tBu + H]+, 289.1 (27) [M +
H]+. ESI-HRMS: calcd for [C16H20N2NaO3]+, m/z = 311.1372; found,
311.1382.
AUTHOR INFORMATION
■
( )-2-(1-Ethoxyethyl)-1,3-benzoxazole (2i). Prepared according to
the general procedure using diethyl ether (3.34 g, 45.1 mmol, 50
equiv), 2-chlorobenzoxazole (138 mg, 0.900 mmol, 1.0 equiv), and a
reaction time of 24 h. After purification by flash chromatography
(cHex/EtOAc = 30/1) the title compound was obtained as a pale
Corresponding Author
*E-mail: opatz@uni-mainz.de.
Notes
c
yellow oil (117 mg, 0.612 mmol, 68%). Rf = 0.19 (SiO2, Hex/EtOAc
The authors declare no competing financial interest.
G
DOI: 10.1021/acs.joc.6b00715
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(33) Frederick, M. O.; Frank, S. A.; Vicenzi, J. T.; LeTourneau, M. E.;
Berglund, K. D.; Edward, A. W.; Alt, C. A. Org. Process Res. Dev. 2014,
18, 546−551.
ACKNOWLEDGMENTS
■
We thank Dr. J. C. Liermann (Mainz) for NMR spectroscopy
and Dr. N. Hanold (Mainz) for mass spectrometry.
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