Metal-Free Synthesis of 2-N,N-Dialkylaminobenzoxazoles Using Tertiary Amines as the Nitrogen Source

Article abstract of DOI:10.1021/acs.joc.9b00797

The unprecedented reaction of tertiary amines with 2(3H)-benzoxazolones has been investigated. In the presence of the Ph₃P-I₂ reagent system, the reaction of both acyclic and cyclic aliphatic tertiary amines led to the formation of 2-N,N-dialkylaminobenzoxazoles with the selective cleavage of an alkyl group. Especially, N-(2-iodoethyl)piperazinyl derivatives were rapidly produced in good yields when using DABCO as the nitrogen source. Only in the cases when the nucleophilicity of the substrates exceeds that of the amine, competitive self-condensation of benzoxazolones then proceeds preferentially. ³¹P{¹H}-NMR study suggested the involvement of an aryloxyphosphonium intermediate and/or possibly 2-iodobenzoxazole which activates the C-2 position of benzoxazolones toward nucleophilic aromatic substitution.

Full text of DOI:10.1021/acs.joc.9b00797

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Note
Metal-Free Synthesis of 2-N,N-Dialkylaminobenzoxazoles
using Tertiary Amines as the Nitrogen Source
Mookda Pattarawarapan, Dolnapa Yamano, nittaya wiriya, and Wong Phakhodee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00797 • Publication Date (Web): 24 Apr 2019
Downloaded from http://pubs.acs.org on April 24, 2019
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Metal-Free Synthesis of 2-N,N-Dialkylaminobenzoxazoles using Tertiary Amines as the
Nitrogen Source
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9
Mookda Pattarawarapana,b, Dolnapa Yamanoa, Nitaya Wiriyaa, and Wong Phakhodee*a,b
aDepartment of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200,
Thailand
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bResearch Center on Chemistry for Development of Health Promoting Products from Northern
Resources, Faculty of Science, Chiang Mai University, Chiang Mai, 50200, Thailand
X
R1
N
R3
H
N
Ph3P, I2,
R1
R2
N
O
N
O
R2
CH2Cl2, 25 o
Ph3P, I2, Et3N
CH2Cl2, 25 o
X
N
N
X
O
X
O
O
C
C
O
X = Me, OMe
X = H, Cl, Br, NO2, Me, OMe
EWG & EDG
MILD SELECTIVE



Abstract
The unprecedented reaction of tertiary amines with 2(3H)-benzoxazolones has been
investigated. In the presence of Ph3P-I2 reagent system, the reaction of both acyclic and cyclic
aliphatic tertiary amines led to the formation of 2-N,N-dialkylaminobenzoxazoles with the
selective cleavage of an alkyl group. Especially, N-(2-iodoethyl)piperazinyl derivatives were
rapidly produced in good yields when using DABCO as the nitrogen source. Only in the cases
when the nucleophilicity of the substrates exceeds that of the amine, competitive self-
condensation of benzoxazolones then proceeds preferentially. 31P{1H}-NMR study suggested
the involvement of an aryloxyphosphonium intermediate and/or possibly 2-iodobenzoxazole
which activates the C-2 position of benzoxazolones toward nucleophilic aromatic substitution.
Keywords Tertiary amines; Benzoxazolones; Aminobenzoxazoles; Triphenylphosphine;
Iodine
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Tertiary amines are commonly used as base in organic reactions due to their solubility in
several organic solvents, stability, and inertness. Nevertheless, the unusual role of tertiary
amine as a secondary amine surrogate has already been observed under appropriate reaction
conditions. While a number of metal-catalyzed aminations toward N,N-disubstituted products
reported to date have been carried out with several substrates such as carboxylic acids, esters,
sulfonyl chlorides, alkenes, alkynes, benzynes, and benzoxazoles,1 the metal-free reaction of
tertiary amines has rarely been explored. Most of which requires highly reactive substrates
including anhydrides,2 acyl chloride,3 acyl iodide4 and heteroaromatic halides (X = Cl),5
otherwise harsh reaction conditions are strictly required.6
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2-Aminobenzoxazoles are interesting structural motifs often found to be incorporated
in a number of therapeutically important molecules.7 A wide range of biological activities have
already been observed. Particularly, 2-(N-alkylpiperazyl)benzoxazoles were described as
potent 5-HT3-receptor agonists.7h Owing to their pharmaceutical importance, several
approaches toward the synthesis of 2-aminobenzoxazoles have been introduced including SNAr
9
displacement of 2-substituted benzoxazoles (Cl8and CCl3 ), metal-catalyzed oxidative C–H
bond amination of benzoxazoles10 condensation of 2-aminophenol with iso(thio)cyanate,11
isocyanide,12 or dithiocarbamates,13 as well as microwave-assisted direct amination of
2‑mercaptobenzoxazoles.14
Despite numerous studies on the application of primary and secondary amines as the
common nucleophile, there are only three reports on the synthesis of 2-aminobenzoxazoles
using tertiary amines. Two of these studies involve SNAr reaction of 2-chlorobenzoxazoles
with N-alkyl tertiary amines (Scheme 1a).5d,6b Another study relies on Cu-catalyzed oxidative
amination of benzoxazoles (Scheme 1b).1h Nevertheless, harsh conditions, long reaction times,
and narrow substrate scope remain the major issues to be overcome. While the synthesis
starting from 2-chlorobenzoxazoles requires extra preparation step toward the reactive
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precursors using highly toxic POCl3 or PCl5,15 the costs associated with residual catalyst
removal in the metal–catalyzed reaction have prompted a great interest in developing metal-
free reaction that enables the use of simple reagents as well as relatively low cost and highly
abundant tertiary amines as the nitrogen source.
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Scheme 1. Tertiary Amine as Nitrogen Source in the Synthesis of 2-Aminobenzoxazoles
Previous works;
R1
N
R3
R1
R2
N
O
N
O
R2
N
Cl
(a)
+
R3Cl
0.8 GPa,100 oC,4 days
or THF, reflux, 3 h
or neat,130 oC, 3 h
R1
N
CH R3
, CuBr2
2
R1
R2
R2
N
O
N
O
+
R3CHO
H
N
N
(b)
(c)
CH3CO2H, O2 (1 atm)
dioxane, 120 oC, 16 h
This work;
R1
H
N
N
R3
R1
R2
Ph3P, I2,
N
O
R2
+
R3I
O
O
CH2Cl2, 25 o
C
In our continuing work with Ph3P-I2-mediated synthesis,16 we have unexpectedly
isolated N,N-diethylsubstituted benzoxazole while performing amination reaction of 2(3H)-
benzoxazolone using triethylamine as base. To the best of our knowledge, the direct amination
of heterocyclic carbamate with tertiary amines has never been previously explored. This result
thus encourages us to further investigate the scope and generality of the reaction of
benzoxazolones with tertiary amines as shown in Scheme 1(c).
To establish the optimum conditions, amination of benzoxazolone 1a with
triethylamine (Et3N) was chosen as a model reaction. Various set of reaction conditions were
screened as summarized in Table 1. Using three equivalents of Et3N in the presence of a 1:1
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mixture of iodine and Ph3P (1.5 equiv) in dichloromethane gave the corresponding diethyl
substituted product 2aa in 35% together with recovered starting material (entry 1). When the
reaction was performed with 1.2 equivalents of Et3N in the presence of other commonly used
bases such as N,N-diisopropylethylamine (i-Pr2NEt) and N,N-dimethylaminopyridine
(DMAP), only low yield or trace amount of the desired product was obtained (entries 2-3).
Interestingly, using imidazole led to a competitive formation of 2ab in high yield indicating
the greater nucleophilicity of this base relative to Et3N (entry 4). To our delight, the yield of
the respective product was improved when increasing the amount of Et3N (entry 5).
Unfortunately, longer reaction times, raising the temperature, or increasing the equivalents of
the reagents did not further improve the product yield (entries 6-9).
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Table 1. Optimization of the Reaction Conditionsa
H
N
N
N
Ph3P, I2, Et3N
N
O
N
CH2Cl2, 25 o
C
N
O
O
O
2aa
2ab
1a
entry Ph3P:I2
(equiv)
Et3N
base
(equiv)
-
conditions
%yield
(equiv)
1
2
3
4
5
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7
8
9
1.5:1.5
1.5:1.5
1.5:1.5
1.5:1.5
1.5:1.5
1.5:1.5
1.5:1.5
1.5:1.5
2.5:2.5
3
1.2
1.2
1.2
5
CH2Cl2, 25 oC, 8 h
CH2Cl2, 25 oC, 8 h
CH2Cl2, 25 oC, 8 h
CH2Cl2, 25 oC, 8 h
CH2Cl2, 25 oC, 8 h
CH2Cl2, 25 oC, 16 h
toluene, 110 oC, 8 h
35
19
i-Pr2NEt (3)
DMAP (3)
trace
trace (72)b
52
imidazole (3)
-
-
-
-
-
5
48
5
15
5
1,2-dichloroethane, 80 oC, 8 h
CH2Cl2, 25 oC, 8 h
38
6
44
aReaction conditions: 1a (0.37 mmol) in 2 mL of solvent. bYield of 2ab.
Since both electronic nature of the substrate, basicity and nucleophilicity of tertiary
amine are important factors determining the product yield and reaction rate, we next explored
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the scope and limitations of the process with respect to substituted benzoxazolones and types
of tertiary amines using the partially optimized reaction conditions (Table 1, entry 5).
According to Scheme 2, benzoxazolones having different substituents, especially those bearing
electron-withdrawing group, could be involved in the amination reaction. The reaction of
triethylamine with electron-deficient substrates such as those containing chloro or nitro
substituent proceeds in a faster rate and produces the corresponding diethylamino derivatives
in higher yields when comparing with those without substituent or having bromo group. The
ease of substitution could be attributed to the increase in electrophilicity of the benzoxazolone
ring. Unfortunately, electron-rich substrates such as those having -Me or -OMe group failed
to react with triethylamine under the applied reaction conditions. Instead, only self-condensed
products 3g and 3h were isolated in high yields, respectively, indicating that these substrates
once converted to the more reactive intermediates could undergo hydrolysis and coupling with
each other. It should be noted that similar coupling product has been reported in the reaction
involving 2-chlorobenzoxazole.17
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The reaction of 1a was further investigated with a variety of tertiary amines and the
results were summarized in Table 2. Other aliphatic amines were found to behave similarly to
triethylamine which provided the corresponding 2-dialkylaminobenzoxazoles in moderate to
good yields. For symmetrical substituted amines, the deoxygenative amination was found to
be dependent on the alkyl chain lengths as the reaction with trimethylamine proceeded more
readily than that using tributylamine (entry 1 vs entry 2). Surprisingly, despite the ease of
removal of the tentative benzyl iodide, tribenzylamine failed to react under the applied
conditions (entry 3) or even upon prolong heating at 80 oC in 1,2-dichloroethane. These results
suggested that either its weak basicity or the steric hindrance of the three benzyl groups may
be responsible for the lack of reactivity of this amine.
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Scheme 2. Scope of Reaction of 2(3H)-Benzoxazolones with Triethylaminea
5
6
7
8
H
N
Et
Et
N
Ph3P, I2
O
+
Et3N
N
Z
Z
CH2Cl2, 0-25 o
C
O
O
9
1
2
10
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NO2
Et
N
Et
N
Et
Et
N
O
N
N
N
O
Et
O2N
O
Et
O2N
2ca
(4 h, 75%)
2aa
(8 h, 52%)
2ba
(4 h, 79%)
Et
Et
N
O
Cl
Et
Et
N
N
O
Et
N
O
N
N
Br
Et
Cl
2fa
(8 h, 54%)
Z
2da
(4 h, 61%)
2ea
(4 h, 65%)
MeO
Et
Et
N
O
Me
Et
Et
N
O
N
N
Z
N
N
O
2ha
(16 h, -)
2ga
(16 h, -)
O
O
3g
3h
, Z = Me (16 h, 80%)
, Z = OMe (16 h, 76%)
aReaction conditions: 1 (0.74 mmol), Et3N (3.70 mmol), Ph3P (1.11 mmol), I2 (1.11 mmol) in
5 mL CH2Cl2, 0-25 oC.
When using mixed tertiary acyclic amine such as N,N-diethylbenzylamine,
debenzylation proceeded exclusively to give product 2aa in moderate yield (entry 4).
However, no reaction was observed with the more sterically hindered dibenzylethylamine
(entry 5). The reaction with various N-substituted cyclic amines was also investigated and the
expected products was obtained without detectable endocyclic C–N bond cleavage (see entries
6-10). Unfortunately, arylamines failed to undergo deoxygenative amination suggesting that
the reaction is incompatible with amines having the C(sp2)-N bond (entries 11-13).
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Table 2. Amination of 1a with Various Tertiary Aminesa
5
6
7
H
N
R1
R1
N
Ph3P, I2
R3
O
+
N
N
CH2Cl2, 0-25 o
C
R2
R2
O
O
8
2
1a
9
entry
1
amine
Me3N
product
N
N
O
time (h)
4
Yield (%)b
70
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2ac
Bu
Bu
N
O
2
3
Bu3N
Bn3N
16
16
16
16
4
45
NR
41
N
2ad
Bn
N
O
N
Bn
2ae
2aa
Et
Et2NBn
EtNBn2
N
O
4
5
N
Et
NR
66
2ae
N
O
6
N
N
2af
7
8
59
2af
N
N
8
8
63
N
O
N
O
O
2ag
9
16
16
16
16
61
2ag
N
O
Ph
N
10
11
12
57
N
N
Ph
O
2ah
2ai
N
Me2NPh
NR
NR
N
O
Ph
N
N
N
N
O
N
N
2aj
N
O
13
16
3
NR
N
N
N
N
2ab
14b
72
15
N
N
N
N
O
2ak
2ac
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15b
3
67
N
N
N
N
N
O
2al
5
6
7
8
9
aReaction conditions: 1 (0.74 mmol), amine (3.70 mmol), Ph3P (1.11 mmol), I2 (1.11 mmol) in
b
5 mL CH2Cl2, 0-25 oC. amine (2.22 mmol).
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Further studies with tertiary amines containing two nitrogen atoms such as N,N,N’,N’-
tetramethylethylenediamine (TMEDA) and 1,4-dimethylpiperazine revealed another problem
involving insoluble salt formation. Thus, to improve the product yields, it is necessary to
decrease the amount of the amines used in the reaction. According to Table 2 (entries 14 and
15), an interesting selectivity was observed. Among the two possible N-dealkylation, the
demethylated product 2ak was isolated as a major product when 1a was treated with TMEDA
(entry 14). Monosubstituted product 2al was also obtained exclusively when using 1,4-
dimethylpiperazine as a nucleophile (entry 15).
With the success in the use of both acyclic and cyclic amines, we next explore the
reaction with bicyclic amine using DABCO as the representative. Again, it was found that
reducing the amount of DABCO leads to better yields as the formation of the tentative
quaternary ammonium salts comprising substituted N-ethylpiperazinyl moiety18 was
minimized. According to Scheme 3, a range of benzoxazolones either those containing
electron-withdrawing group or donating group underwent rapid amination with DABCO
leading to the desired products 2am-2hm in good yields under short reaction times. Notably,
in the cases of using 1g or 1h, no trace of self-condensed product was detected indicating that
DABCO is highly reactive as base and nucleophile. The scope of the reaction could also be
extended to the synthesis of N-(2-iodoethyl)piperazinylbenzothiazoles using 2(3H)-
benzothiazolones as the substrates (see compounds 2im and 2jm). The practical utility of the
method was further demonstrated in a gram-scale synthesis of 2em. In this case, no significant
deteriorated effect on the product yield was observed when using only 1.2 equivalents of
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DABCO with the addition of Et3N as base. It is worth mentioning that this observation is
highly useful since the monoarylated piperazines are promising candidates for the treatment of
irritable bowel syndrome (IBS), dyspepsia, pain, anxiety, and psychosis.7f,19 Additionally, the
reported SNAr-based approach using DABCO still suffers from very high temperature, long
reaction times which is restricted to only electron-poor substrates.5e,6c,18,20
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Scheme 3. Reaction of 2(3H)-Benzoxazolones with DABCOa
H
I
N
X
N
Ph3P, I2
N
N
N
N
Z
O
Z
+
CH2Cl2, 0-25 oC, 0.5-2 h
X
2
1
(X = O, S)
NO2
N
Cl
I
N
I
I
N
N
O
N
N
N
N
N
O
O
O2N
b
2em
(78%, 70% )
2am
(74%)
2bm
(87%)
Z
I
N
S
Me
MeO
I
I
N
O
N
N
N
N
N
N
N
O
2i
2j
m; Z = H (72%)
m; Z = Cl (76%)
2gm
(71%)
2hm
(69%)
aReaction conditions: 1 (0.74 mmol), DABCO (2.22 mmol), Ph3P (1.11 mmol), I2 (1.11 mmol)
in 5 mL CH2Cl2, 0-25 oC. bYield using 7.4 mmol of 1e.
Based on the results obtained and previous reports by other related studies,5d,6b,21 the
reaction presumably proceeds via SNAr process involving the initial formation of the activated
aryloxyphosphonium intermediate I or possibly 2-iodobenzoxazole II generated in-situ
(Scheme 4). Subsequent attacks by tertiary amine then gives rise to the formation of quaternary
ammonium salts III (route a). Final, N-dealkylation by the action of iodide at the least steric
C-N bond then provides the N,N-disubstituted products 2. Provided that nucleophilicity of 1
is greater than that of the amine, competitive formation of 3 would be feasible (route b). To
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gain insight into the role of phosphonium intermediates, 31P-NMR study on the progress of the
reaction between 1a and Et3N was carried out. According to Figure S1, addition of 1a to the
mixture of Ph3P-I2 containing Et3N showed an appearance of a high intensity signal at p 38.68
ppm suggesting the formation of I. An increase in the intensity of the triphenylphosphine oxide
signal at p -28.96 ppm with a simultaneous decrease of the phosphonium’s signal upon
prolonged reaction time indicated further reaction of I with nucleophiles which could be iodide
or the remaining amine. It should be noted that no significant change in the phosphorous
signals was observed when adding Et3N to the Ph3P/I2 mixture suggesting that the possibility
for the initial formation of diethylaminophosphonium iodide could be ruled out (see Figures
S2 and S3 in ESI).
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Scheme 4. Proposed Mechanism for the Reaction of Benzoxazolones with Tertiary
Amine
R1
I
N
R3
H
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R1
R2
PPh3
O
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R3
R2
Ph3P-I2, NR1R2R3
-NR1R2R3 HI
N
O
R2
N
N
O
Z
N
I
Z
O
Z
-R3I
-Ph3PO
route a
O
O
I
III
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2
-Ph3PO
H
N
Z
Z
O
N
N
O
O
-NR1R2R3 HI
route b
Z
I
N
Z
O
O
O
II
3
In summary, we have disclosed for the first time an efficient metal-free procedure for
the synthesis of 2-N,N-dialkylaminobenzoxazoles through the Ph3P-I2 activation of
benzoxazolones toward SNAr reaction with tertiary amines. The method is compatible with a
broad range of substrates which enables rapid access to various 2-aminobenzoxazoles under
mild conditions. Given the abundance, low cost, and relatively low toxicity of the tertiary
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amines, the developed protocol is potentially useful as an alternative process toward interesti
ng synthetic targets where other known amination methods are limited or ineffective. The ease
of introducing of the N-(2-iodoethyl)piperazinyl group could also lead to further development
toward more structural diversity and interesting bioactivity. Studies to expand the scope of
reaction and to understand the mechanism underlying the Ph3P-I2 mediated reaction of
heterocyclic amides, ureas, and other alicyclic carbamates are underway which will be reported
in due course.
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EXPERIMENTAL SECTION
Material and methods
All reagents including most of the 2(3H)-benzoxazolone precurors 1 (1a, 1c-1g, 1i and
1j) were purchased from Sigma-Aldrich or TCI and used without further purification.
Compound 1b22 and 1h23 were synthesized according to the reported procedures. The reaction
was monitored by thin-layer chromatography carried out on silica gel plates (60F254, MERCK,
Germany) and visualized under UV light (254 nm). Column chromatography was performed
over silica gel 60 (70–230 mesh, MERCK, Germany). Melting points were determined using
o
Mettler Toledo DSC equipment at a heating rate of 6 C/min and were uncorrected. NMR
spectra were recorded using a Bruker AVANCETM (400 and 500 MHz for 1H). Chemical shifts
were reported in parts per million (ppm, δ) downfield from tetramethylsilane (TMS). Splitting
patterns are described as singlet (s), doublet (d), triplet (t), quartet (q), quintet (qui), sextet
(sex), multiplet (m), broad (br), doublet of doublets (dd), triplet of doublets (td) and doublet of
doublet of doublets (ddd). High-resolution mass spectra (HRMS) were recorded using time-
of-flight (TOF) via the atmospheric pressure chemical ionization (APCI) or electrospray
ionization (ESI).
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General procedure for the synthesis of 2-N,N-Dialkylaminobenzoxazoles 2
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To a solution of iodine (280 mg, 1.11 mmol) in freshly distilled dichloromethane (5
mL) was added triphenylphosphine (288 mg, 1.11 mmol) at 0 oC under N2. After that, amine
(3.70 mmol) was added, followed by the addition of benzoxazolone 1 (0.74 mmol). The
mixture was stirred at 0 oC for 5 min before warming up to room temperature. Upon
completion of the reaction, the crude mixture was concentrated under reduced pressure then
purified by column chromatography (CC) using ethyl acetate/hexanes as the eluent.
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N,N-Diethylbenzo[d]oxazol-2-amine (2aa).24 Colorless oil; (0.0734 g, 52% yield); Rf 0.35
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(10% EtOAc/hexanes); H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 7.2 Hz, 1H), 7.26 (d, J =
7.6 Hz, 1H), 7.16 (td, J = 7.6, 1.2 Hz, 1H), 7.00 (td, J = 7.6, 1.2 Hz, 1H), 3.61 (q, J = 7.2 Hz,
4H), 1.30 (t, J = 7.2 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.3, 148.9, 143.7, 123.8,
120.0, 115.8, 108.5, 43.0, 13.5.
2-(1H-Imidazol-1-yl)benzo[d]oxazole (2ab).25 Yellow solid; (0.0992 g, 72% yield); mp 110-
112 °C (lit. 25 mp 112 oC); Rf 0.26 (30% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 8.40
(s, 1H), 7.73 (t, J = 1.5 Hz, 1H), 7.69 (dd, J = 7.5, 2.0 Hz, 1H), 7.55 (dd, J = 7.5, 2.0 Hz, 2H),
7.39 (td, J = 7.5, 2.0 Hz, 1H), 7.36 (td, J = 7.5, 2.0 Hz, 1H), 7.25 (d, J = 1.5 Hz, 1H); 13C{1H}
NMR (125 MHz, CDCl3) δ 152.0, 149.0, 140.5, 135.9, 131.4, 125.5, 125.1, 119.7, 116.8, 110.5.
N,N-Diethyl-4,6-dinitrobenzo[d]oxazol-2-amine (2ba). Yellow oil; (0.1635 g, 79% yield);
Rf 0.44 (20% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 8.98 (d, J = 2.0 Hz, 1H), 8.28
(d, J = 2.0 Hz, 1H), 3.84 (br s, 2H), 3.70 (br s, 2H), 1.38 (t, J = 7.2 Hz, 6H); 13C{1H} NMR
(125 MHz, CDCl3) δ 166.8, 150.7, 146.3, 138.9, 133.3, 117.7, 107.8, 44.6, 43.1, 13.6, 12.9;
TOF-HRMS calcd for C11H12N4NaO5 (M+Na)+ 303.0705, found 303.0709.
N,N-Diethyl-6-nitrobenzo[d]oxazol-2-amine (2ca).26 Yellow solid; (0.1309 g, 75% yield);
mp 110-112 °C (lit.26 mp 112-114 oC); Rf 0.43 (20% EtOAc/hexanes); 1H NMR (400 MHz,
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CDCl3) δ 8.16 (dd, J = 8.8, 2.4 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 3.64
(q, J = 7.2 Hz, 4H), 1.33 (t, J = 7.2 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.9, 150.6,
147.9, 140.9, 121.4, 114.4, 104.8, 43.4, 13.4.
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6-Chloro-N,N-diethylbenzo[d]oxazol-2-amine (2da).1h Off-white solid; (0.1021 g, 61%
yield); mp 60-62 °C; Rf 0.35 (10% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J
= 2.0 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.10 (dd, J = 8.4, 2.0 Hz, 1H), 3.55 (q, J = 7.2 Hz, 4H),
1.26 (t, J = 7.2 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.5, 148.9, 142.5, 124.9, 124.0,
116.0, 109.3, 43.0, 13.4.
5-chloro-N,N-diethylbenzo[d]oxazol-2-amine (2ea).1h White solid; (0.1078 g, 65% yield);
mp 60-62 °C; Rf 0.35 (10% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.22 (d, J = 2.0
Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.10 (dd, J = 8.4, 2.0 Hz, 1H), 3.55 (q, J = 7.2 Hz, 4H),
1.26 (t, J = 7.2 Hz, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ 162.5, 148.9, 142.5, 124.9,
124.0, 116.0, 109.3, 43.0, 13.4.
5-Bromo-N,N-diethylbenzo[d]isoxazol-3-amine (2fa). Colorless solid; (0.1073 g, 54%
yield); mp 54-56 °C; Rf 0.27 (10% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J
= 2.0 Hz, 1H), 7.25 (dd, J = 8.4, 2.0 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 3.56 (q, J = 7.2 Hz,
4H), 1.27 (t, J = 7.6 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.4, 149.3, 143.0, 126.8,
116.6, 112.0, 111.8 ,43.0, 13.4; TOF-HRMS calcd for C11H14N2O81Br (M+H)+, 271.0270,
found 271.0286, for C11H14N2O79Br (M+H)+, 269.0290, found 269.0301.
5,5'-Dimethyl-2'H-[2,3'-bibenzo[d]oxazol]-2'-one (3g). White solid; (0.0832 g, 80% yield);
mp 156-157 °C; Rf 0.35 (5% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.94 (s, 1H),
7.56 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.19 (dd, J = 8.2, 1.0 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H),
7.10 (dd, J = 8.2, 1.0 Hz, 1H) 2.50 (s, 3H), 2.49 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ
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151.2, 149.5, 146.9, 140.4, 140.1, 135.2, 135.0, 127.2, 126.0, 125.5, 119.7, 114.2, 110.2,
109.9, 21.7, 21.6; TOF-HRMS calcd for C16H12N2NaO3 (M+Na)+ 303.0746, found 303.0743.
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5,5'-Dimethoxy-2'H-[2,3'-bibenzo[d]oxazol]-2'-one (3h). White solid; (0.1148 g, 76%
yield); mp 160-162 °C; Rf 0.41 (20% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.75
(d, J = 2.5 Hz, 1H), 7.52 (d, J = 9.0 Hz, 1H), 7.25 (d, J = 2.5 Hz, 1H), 7.20 (d, J = 9.0 Hz,
1H), 6.96 (dd, J = 9.0, 2.5 Hz, 1H), 6.82 (dd, J = 9.0, 2.5 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 157.8, 157.2, 151.6, 149.6, 143.2, 140.8, 136.4, 127.9,
113.1, 111.0, 110.7, 110.3, 103.2, 100.6, 56.2 56.0; TOF-HRMS calcd for C16H12N2NaO5
(M+Na)+ 335.0644, found 335.0647.
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N,N-Dimethylbenzo[d]oxazol-2-amine (2ac).27 White solid; (0.0842 g, 70% yield); mp 89-
90 oC (lit. 27 mp 90-91oC); Rf 0.46 (20% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.35
(d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.15 (td, J = 8.0, 1.0 Hz, 1H), 7.00 (td, J = 8.0,
1.0 Hz, 1H), 3.20 (s, 6H). 13C{1H} NMR (125 MHz, CDCl3) δ 163.1, 149.1, 143.5, 123.9,
120.3, 116.0, 108.6, 37.7.
N,N-dibutylbenzo[d]oxazol-2-amine (2ad).10e Yellow oil; (0.0540 g, 45% yield); Rf 0.36 (5%
EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 7.6 Hz, 1H), 7.25 (d, J = 7.6 Hz,
1H), 7.15 (td, J = 7.6, 1.2 Hz, 1H), 6.99 (td, J = 7.6, 1.2 Hz, 1H), 3.53 (t, J = 7.6 Hz, 4H), 1.68
(quin, J = 7.6 Hz, 4H), 1.40 (sex, J = 7.6 Hz, 4H), 0.98 (t, J = 7.6 Hz, 6H); 13C{1H} NMR (100
MHz, CDCl3) δ 162.6, 148.7, 143.7, 123.7, 119.8, 115.8, 108.4, 48.3, 30.1, 20.0, 13.9.
2-(Piperidin-1-yl)benzo[d]oxazole (2af).24 Pale yellow solid; (0.0994 g, 66% yield); mp 70-
73 oC (lit.24 mp 72-75 oC); Rf 0.35 (10% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.34
(d, J = 7.5 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 6.98 (td, J = 7.5 Hz, 1H),
3.66 (s, 4H), 1.68 (s, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ 162.5, 148.7, 143.4, 123.8,
120.3, 116.0, 108.6, 46.6, 25.3, 24.1.
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2-Morpholinobenzo[d]oxazole (2ag).24 White solid; (0.0951 g, 63% yield); mp 90-92 °C
(lit.24 mp 90-94 oC); Rf 0.20 (50% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.37 (d,
J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.04 (t, J = 8.0 Hz, 1H),
3.82 (t, J = 4.5 Hz, 4H), 3.70 (t, J = 4.5 Hz, 4H); 13C{1H} NMR (125 MHz, CDCl3) δ 162.1,
148.8, 142.9, 124.1, 121.0, 116.5, 108.8, 66.2, 45.7.
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2-(Pyrrolidin-1-yl)benzo[d]oxazole (2ah).28 White solid; (0.0795 g, 57% yield); mp 135-137
oC (lit.28 mp 136-137 oC); Rf 0.30 (30% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.35
(d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H), 6.99 (t, J = 8.0 Hz, 1H),
3.65 (s, 4H), 2.03 (s, 4H); 13C{1H} NMR (125 MHz, CDCl3) δ ) δ 161.0, 148.9, 143.4, 123.9,
120.2, 115.8, 108.7, 47.4, 25.6.
N1-(Benzo[d]oxazol-2-yl)-N1,N2,N2-trimethylethane-1,2-diamine (2ak).28 Yellow solid;
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(0.1167 g, 72% yield); mp 110-111 C; Rf 0.28 (10% MeOH/EtOAc); H NMR (500 MHz,
DMSO-d6) δ 7.42 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.16 (td, J = 7.8, 1.2 Hz, 1H),
7.03 (td, J = 7.8, 1.2 Hz, 1H), 3.87 (t, J = 6.2 Hz, 2H), 3.33 (t, J = 6.2 Hz, 2H), 3.16 (s, 3H),
2.82 (s, 6H); 13C{1H} NMR (125 MHz, DMSO-d6) δ 162.8, 149.0, 143.5, 124.5, 120.8, 116.2,
109.4, 54.5, 45.8, 43.5, 35.6.
2-(4-Methylpiperazin-1-yl)benzo[d]oxazole (2al).24 White solid; (0.1085 g, 67% yield); mp
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36-38 C (lit.24 mp 36-38 oC); Rf 0.26 (10% MeOH/EtOAc); H NMR (500 MHz, CDCl3) δ
7.36 (dd, J = 8.0, 1.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.16 (td, J = 8.0, 1.0 Hz, 1H), 7.02 (td,
J = 8.0, 1.5 Hz, 1H), 3.74 (t, J = 5.0 Hz, 4H), 2.54 (t, J = 5.0 Hz, 4H), 2.36 (s, 3H); 13C{1H}
NMR (125 MHz, , CDCl3) δ 162.2, 148.8, 143.1, 124.0, 120.7, 116.3, 108.7, 54.2, 46.2, 45.5.
2-(4-(2-Iodoethyl)piperazin-1-yl)benzo[d]oxazole (2am). Pale yellow oil; (0.1966 g, 74%
yield); Rf 0.23 (20% EtOAc/hexane); 1H NMR (500 MHz, CDCl3) δ 7.30 (d, J = 7.8 Hz, 1H),
7.24 (d, J = 7.8 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 7.02 (t, J = 7.8 Hz, 1H), 3.70 (br s, 4H), 3.23
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(t, J = 7.5 Hz, 2H), 2.80 (t, J = 7.5 Hz, 3H), 2.63 (br s, 4H); 13C{1H} NMR (125 MHz, CDCl3)
δ 165.9, 152.4, 146.3 , 128.1, 125.0 , 124.9, 119.9, 112.8, 64.4, 55.6, 49.2, 33.6; TOF-HRMS
calcd for C13H17IN3O (M+H)+ 358.0416, found 358.0419.
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2-(4-(2-Iodoethyl)piperazin-1-yl)-5,7-dinitrobenzo[d]oxazole (2bm). Yellow oil; (0.2870
g, 87% yield); Rf 0.28 (30% EtOAc/Hexane); 1H NMR (500 MHz, CDCl3) δ 9.01 (d, J = 2.0
Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 3.95 (br s, 4H), 3.25 (t, J = 7.5 Hz, 2H), 2.83 (t, J = 7.5 Hz,
2H), 2.70 (t, J = 5.0 Hz, 4H); 13C{1H} NMR (125 MHz, CDCl3) δ 164.8 , 149.1, 144.4, 138.1,
132.2, 116.4, 107.0, 58.7, 50.2, 29.5; TOF-HRMS calcd for C13H14IN5NaO5 (M+Na)+
469.9937, found 469.9935.
5-Chloro-2-(4-(2-iodoethyl)piperazin-1-yl)benzo[d]oxazole (2em). Pale yellow solid;
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(0.2253 g, 78% yield); mp 109-110 C; Rf 0.31 (30% EtOAc/Hexane); H NMR (500 MHz,
CDCl3) δ 7.30 (d, J = 2.0 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 6.98 (dd, J = 8.4, 2.0 Hz, 1H), 3.72
(t, J = 5.0 Hz, 4H), 3.23 (t, J = 8.0 Hz, 2H), 2.79 (t, J = 8.0 Hz, 2H), 2.62 (t, J = 5.0 Hz, 4H);
13C{1H} NMR (125 MHz, CDCl3) δ 161.0, 145.6, 142.7, 127.6, 118.7, 114.6, 107.5, 58.7, 49.9,
43.7; TOF-HRMS calcd for C13H1637ClIN3O (M+H)+ 393.9997, found 393.9993, for
C13H1635ClIN3O (M+H)+ 392.0027, found 392.0024.
Gram-scale synthesis of 5-Chloro-2-(4-(2-iodoethyl)piperazin-1-yl)benzo[d]oxazole (2em)
To a solution of iodine (2.80 g, 11.1 mmol) in freshly distilled dichloromethane (25 mL) was
added triphenylphosphine (2.88 g, 11.1 mmol) at 0 oC under N2. After that, DABCO (0.9961
g, 8.8 mmol) and triethylamine (3.00 mL, 22.2 mmol) were sequentially added, followed by
the addition of chlorzoxazone (1e, 1.2540 g, 7.4 mmol). The mixture was stirred at 0 oC for 5
min before warming up to room temperature. After completion of the reaction, the reaction
was filtered and washed with ethyl acetate. The concentrated crude product was then purified
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2-(4-(2-Iodoethyl)piperazin-1-yl)-5-methylbenzo[d]oxazol (2gm).
Pale yellow solid;
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(0.1957 g, 71% yield); mp 110-112 oC; Rf 0.33 (30% EtOAc/Hexane); 1H NMR (500 MHz,
CDCl3) δ 7.15 (d, J = 1.5 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.82 (dd, J = 8.0, 1.5 Hz, 1H), 3.71
(t, J = 5.0 Hz, 4H), 3.24 (t, J = 8.0 Hz, 2H), 2.78 (t, J = 8.0 Hz, 2H), 2.62 (t, J = 5.0 Hz, 4H),
13
2.39 (s, 3H); C{1H} NMR (125 MHz, CDCl3) δ 160.5, 145.1, 141.3, 131.9, 119.6, 114.9,
106.3, 58.7, 50.0, 43.7, 19.7; TOF-HRMS calcd for C14H19IN3O (M+H)+ 372.0573, found
372.0572.
2-(4-(2-iodoethyl)piperazin-1-yl)-5-methoxybenzo[d]oxazole (2hm). White solid; (0.1042
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g, 69% yield); mp 105 -106 °C; Rf 0.38 (30% EtOAc/hexanes); H NMR (500 MHz, CDCl3)
δ 7.12 (d, J = 8.6 Hz, 1H), 6.93 (d, J = 2.4 Hz, 1H), 6.59 (dd, J = 8.6, 2.4 Hz, 1H), 3.81 (s, 3H),
3.73 (t, J = 5.0 Hz, 4H), 3.25 (t, J = 7.5 Hz, 2H), 2.81 (t, J = 7.5 Hz, 2H), 2.64 (t, J = 5.0 Hz,
4H); 13C{1H} NMR (125 MHz, CDCl3) δ 162.8, 157.1, 144.0, 143.3, 108.6, 107.3, 101.4, 60.5,
55.9, 51.8, 45.4; TOF-HRMS calcd for C14H19IN3O2 (M+H)+ 388.0522, found 388.0521.
2-(4-(2-Iodoethyl)piperazin-1-yl)benzo[d]thiazole (2im). Pale purple solid; (0.1993 g, 72%
yield); mp 159-160 °C; Rf 0.32 (20% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.60 (d,
J = 8.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 3.66
(t, J = 5.5 Hz,, 4H), 3.22 (t, J = 7.5 Hz, 2H), 2.79 (t, J = 7.5 Hz, 2H), 2.62 (t, J = 5.5 Hz,, 4H);
13C{1H} NMR (125 MHz, CDCl3) δ 166.8, 150.8, 128.9, 124.2, 119.6, 118.9, 117.3, 58.6, 50.0,
46.4; TOF-HRMS calcd for C13H17IN3S (M+H)+ 374.0188, found 374.0185.
5-Chloro-2-(4-(2-iodoethyl)piperazin-1-yl)benzo[d]thiazole (2jm). Pale yellow solid;
(0.2294 g, 76% yield); mp 133-135 °C; Rf 0.35 (20% EtOAc/hexanes); 1H NMR (500 MHz,
CDCl3) δ 7.52 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.04 (dd, J = 8.4, 2.0 Hz, 1H),
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3.65 (t, J = 5.0 Hz, 4H), 3.23 (t, J = 7.5 Hz, 2H), 2.79 (t, J = 7.5 Hz, 2H), 2.63 (t, J = 5.0 Hz,
4H); 13C{1H} NMR (125 MHz, CDCl3) δ 167.8, 152.0, 130.1, 127.2, 119.8, 119.5, 117.3,
58.6, 50.0, 46.5; TOF-HRMS calcd for C13H1637ClN3S (M+H)+ 409.9768, found 409.9763,
for C13H1635Cl N3S (M+H)+ 407.9798, found 407.9796.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
DOI:
Copies of 1H NMR and 13C NMR spectra for all products.
AUTHOR INFORMATION
Corresponding Author
*E-mail: wongp2577@gmail.com. Phone: +66 877286472. Fax: (+) 66-53-892277.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
Financial support from The Thailand Research Fund through the Royal Golden Jubilee Ph.D.
Program to D.Y (Grant No. PHD/0023/2559) and N.W. (Grant No. PHD/0072/2559) is
gratefully acknowledged. This work is also partially supported by Chiang Mai University,
Thailand. Special appreciation to Chulabhorn Research Institute (CRI), Thailand for the
HRMS analysis.
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