Regioselective Arylative Ring-Closing Reaction of 2-Alkynylphenyl Derivatives: Formation of Arylated Benzoxazin-2-ones, Benzoxazin-2-amines and 2,3-Disubstituted Indoles

Article abstract of DOI:10.1002/ejoc.201601162

Copper-catalysed arylative ring-closing reactions of 2-alkynylphenylcarbamates and 2-alkynylphenylureas with diaryliodonium salts gave C,N-double-arylated benzoxazin-2-ones and C-arylated benzoxazin-2-amines, respectively, both bearing fully substituted e

Full text of DOI:10.1002/ejoc.201601162

A Journal of
Accepted Article
Title: Regioselective Arylative Ring-Closing Reaction of 2-Alkynylphenyl Derivati-
ves: Formation of Arylated Benzoxazin-2-ones, Benzoxazin-2-amines and 2,3-
Disubstituted Indoles
Authors: Reiko Yanada; Hideki Minami; Takuya Kanayama; Reishi Tanaka; Noriko
Okamoto; Takuya Sueda
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601162
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European Journal of Organic Chemistry
10.1002/ejoc.201601162
FULL PAPER
Regioselective Arylative Ring-Closing Reaction of 2-Alkynylphenyl
Derivatives: Formation of Arylated Benzoxazin-2-ones, Benzoxazin-2-
amines and 2,3-Disubstituted Indoles
Hideki Minami,[a] Takuya Kanayama,[a] Reishi Tanaka,[a] Noriko Okamoto,[a] Takuya Sueda,[a] and Reiko
Yanada*[a]
Abstract: Copper-catalyzed arylative ring-closing reactions of 2-alkynylphenylcarbamates and 2-alkynylphenylureas with diaryliodonium salts
were achieved to afford C, N-double arylated benzoxazin-2-ones and C-arylated benzoxazin-2-amines bearing fully substituted exo olefins,
respectively. On the other hand, palladium-catalyzed arylative ring-closing reaction of 2-alkynylphenylcarbamates interestingly afforded C-
arylated 2,3-disubstituted indoles.
Introduction
A carbon-carbon triple bond is one of the most important functional
groups in current organic chemistry. Due to the useful and interesting
reactivity of carbon-carbon triple bonds, many investigations have
focused on their synthetic utilities.[1-3] In regard to this, metal-
catalyzed syntheses of substituted aromatics and heteroaromatics
derived from 2-alkynylaryl compounds have attracted much
attention.[4] We have also reported tandem cyclization reactions of 2-
alkynylaryl compounds to produce heteroaromatics.[5] On the other
hand, metal-catalyzed carboarylations with hypervalent aryliodonium
reagents have recently been developed in organic syntheses.[6] Among
them, studies on tandem carboarylation-closing strategies have
recently been increasing.[7] In 2013, Novák et al. reported copper-
catalyzed C-arylation-ring closing reaction of 2-alkynylanilides with
diaryliodonium salts to afford benzoxazines.[8] C-Arylation reaction
with iodonium salts is now a useful method, but there have not been
many studies on various N-arylation reactions.[9] Recently, we have
also reported that copper-catalyzed N-arylation ring-closing reaction
of 2-alkynylbenzamides produced iminoisocoumarin derivatives. The
arylation occurred at the nitrogen atom rather than the oxygen atom of
the amide group, alkynyl carbon, or benzene ring.[10] As part of our
continuous interest in the difference of reactivity caused by the subtle
Scheme 1. Utilization of arylative ring-closing strategy.
difference of electron density of triple bonds, we have focused on the
reaction of 2-alkynylphenylcarbamates possessing a carbamate motif
and 2-alkynylphenylureas possessing a urea motif. Because of the
Results and Discussion
different properties of substituents such as carbamates, ureas,
anilides,[8] and amides,[10] we envisaged that they would show
differences in the nucleophilic site and cyclization pattern. We report
here the first example of regioselective metal-catalyzed C- and N- or
C-arylation ring-closing reaction using 2-alkynylphenylcarbamates
and 2-alkynylphenylureas to produce benzoxazin-2-ones and
benzoxazin-2-amines bearing fully substituted exo olefins by 6-exo-
dig cyclization. Furthermore, we also report that the switch of the
selectivity toward the indole formation by aryltative 5-endo-dig
cyclization reaction only using Pd-catalyst instead of Cu-catalyst
(Scheme 1). They are attractive frameworks from the point of view of
biological activities. Benzoxazin-2-ones 1 have osteoclast differential
induction inhibitory activity,[11] and benzoxazin-2-amines 2 show
various activities as a human chymase inhibitor, cathepsine G
inhibitor, and human leukocyte elastase inhibitor.[12] Indoles 3 are
We initially focused our studies on metal-catalyzed tandem
arylative cyclization of 2-hexynylphenylcarbamate 5a with Ph2IOTf
in the presence of copper salts (Table 1). The best result was obtained
when 2.2 equiv of Ph2IOTf was used in combination with 2,6-di-tert-
butylpyridine (DTBP) and CuBr in 1,2-dichloroethane (DCE) at 80°C
(entry 1). The stereoselectivity of 6a was slightly reduced by
replacing CuBr with CuCl (entry 2). No significant effect was
observed when stoichiometric amount of CuBr was used (entry 3). No
reaction was observed at 40 °C (entry 4). Screening of the iodonium
salts [X=OTf, PF6, BF4] showed that OTf was the superior
counteranion (entries 1, 5 and 6). The absence of DTBP resulted in a
very low yield of 6a (entry 7). Further screening of the reaction media
revealed that DCE was the best solvent for this reaction (entries 1, 8–
10). The geometry of (E)- and (Z)-6a was established by X-ray
crystallographic analyses.[15] 1H NMR of (E)-6a revealed higher field
shifts of protons on phenyl ring A owning to the anisotropic effect of
phenyl ring B, which seemed to be nearly perpendicular to phenyl
ring A (Figure 1).
well-known skeletons that exist in
a variety of bioactive
compounds[13] and medicines such as indomethacin 4.[14]
[a]
Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-
1-1 Hirokoshingai, Kure, Hiroshima 737-0112, Japan
E-mail: ryanada@ps.hirokoku-u.ac.jp
http://www.hirokoku-u.ac.jp/pharm/
Supporting information for this article is given via a link at the end of the
document.((Please delete this text if not appropriate))
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European Journal of Organic Chemistry
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FULL PAPER
Table 1. Optimization results for Cu-catalyzed C- and N-arylation.
Table 2. Oxazin-2-one synthesis accompanied by N- and C-arylation.
entry
1
2
3
X
catalyst
CuBr
CuCl
CuBr
(100 mol%)
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
temp
(°C)
80
80
80
time
(h)
20
20
20
solvent
DCE
DCE
DCE
E:Z[a] 6a yield[b]
%
OTf
OTf
OTf
4.0:1
80
entry
5
R1
R2
R
Ar
temp time
(°C) (h)
6
E:Z[a] yield[b]
3.5:1
3.8:1
81
81
(%)
1
2
3
4
5
6
7
8
9
5b
5c
5a
5a
5d
5d
Bu
Bu
Bu
Bu
Ph
Ph
H
H
H
H
H
H
H
H
Me
tBu
Ph
Ph
80
80
80
70
80
70
70
70
80
80
80
20 6a
20 6a
46 6b
24 6c
43 6d
2.3:1
1.0:1
4.3:1
3.1:1
–
60
8
4
5
6
7[f]
8
OTf
PF6
40
80
80
80
80
20
20
20
20
22
20
24
DCE
DCE
DCE
–
0[c]
31[d]
38[e]
9[g]
Et 4-(Me)C6H4
Et
Et
Et 4-(Me)C6H4
Et 4-(Me)C6H4
Et
74
1.1:1
1.5:1
1.3:1
–
4-(F)C6H4
Ph
70[c]
77
BF4
OTf
OTf
OTf
OTf
DCE
24 6e (1.6:1)[d]
24 6f
60
dioxane
toluene
DCB
0[h]
5e 4-(Me)C6H4
5f 4-(OMe)C6H4
5g
–
62[e]
9
10
100
100
5.5:1
5.4:1
71
50[i]
Ph
Ph
Ph
Ph
31 6g (1.7:1)[d] 51[f]
27 6h 5.8:1
48 6i
27 6j
Bu
Ph
Bu
Me Et
Me Et
F
88
79
79
All reactions were run with 5a (0.2 mmol) and Ph2IX (0.44 mmol). [a] Determined
on the basis of isolated yields. [b] Total isolated yields of E- and Z-isomers. [c]
Recovery of starting material (quant.). [d] Recovery of starting material (65%). [e]
Recovery of starting material (56%). [f] Absence of DTBP. [g] Recovery of starting
material (30%). [h] Recovery of starting material (52%). [i] Recovery of starting
material (31%).
10 5h
11 5i
–
Et
3.2:1
[a] Determined on the basis of isolated yields. [b] Total isolated yields of E- and Z-
isomers. [c] Recovery of starting material (20%). [d] E/Z ratios could not be
determined. [e] 3-H Indole (6%) and starting material (25%) were also isolated. [f] 3-
Ph-Indole (39%) was also isolated.
Figure 1. 1H NMR spectra of (E)- and (Z)-6a.
Instead of 2-alkynylphenylcarbamates, the arylative cyclization was
applied to 2-alkynylphenylureas 7. After examining some reaction
conditions, it was found that arylative cyclization proceeded well
without DTBP at 40 °C (Table 3). We investigated this reaction with
several types of 2-alkynylphenylureas 7. In this case, N-arylation did
not occur at al. All reactions with 7a–7g provided oxazin-2-amines
8a–8i in good to moderate yields except for 7g (entries 1–9). It was
thought that decreased electron density on the nitrogen atom adjacent
to the phenyl carbon atom in urea 7g caused the difficulty in reaction
(entry 9). Stereostructures of (E)-8a and (Z)-8c were determined by
X-ray crystallographic analyses.[15] The same high field aromatic
higher field shifts
1
(E)-6a
(Z)-6a
proton shift phenomena were observed in H NMR spectra of (E)-8a–
8g and 8i. Novák also reported that C-arylated oxazin-2-amines was
produced from 2- alkynylanilides,[8] which are thought to be similar to
7 in electronic system.
Having established the reaction conditions, we examined the scope
of this novel C, N-double arylative 6-exo-dig cyclization reaction by
using various aromatic carbamates 5 with diaryliodonium triflates
(Table 2). It was found that methyl carbamate 5b also gave 6a in
moderate yield, but the reaction with tbutyl carbamate did not proceed
well (entries 1 and 2). Diaryliodonium salts bearing a methyl group
and a fluorine atom on the phenyl ring also reacted well (entries 3 and
4). Carbamates having aromatic substituent R1 on the alkynyl carbon
5d–5f also cyclized successfully accompanied by C- and N-arylations
(entries 5–8). Carbamates having electron donating and electron
withdrawing groups at the para-position to the alkynyl substituent
also provided the desired products (entries 9–11). The anisotropic
effects mentioned above were also observed in the 1H NMR spectra of
6b, 6c, 6h, 6j, which revealed the orientation of the phenyl ring B.
The reason for the remarkable differences in the reactivity between 2-
alkynylphenylcarbamate and 2-alkynylbenzamide[10] is thought to be
the difference in electron density of the triple-bond in them. 2-
Alkynylphenylcarbamate would have higher electron density of the
triple bond than that of 2-alkynylbenzamide. Consequently, it is
thought that C-arylation of alkynyl carbon occurred in the case of 2-
alkynylphenylcarbamate accompanied by further N-arylation and
ring-closing reaction.
Table 3. Oxazin-2-amine synthesis accompanied by C-arylation.
entry
7
R1
R2
R
R’
Ar
8
E:Z[a] yield[b]
(%)
1
2
3
4
5
6
7
8
9
7a Bu
7b Bu
7c Bu
7a Bu
7a Bu
H
H
H
H
H
H
H
CH2Ph
CH2CHPh2
Ph
Ph
Ph
8a 1.3:1
8b 2.5:1
8c 2.0:1
63
77
87
88
86
96
69
92
19
–(CH2)2O(CH2)2–
H
H
H
H
H
H
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
Ph
4-(Me)C6H4 8d 1.5:1
4-(F)C6H4 8e 2.0:1
7d Bu Me
Ph
Ph
Ph
Ph
8f 1.0:1
8g 1.5:1
7e Bu
7f Ph
7g Bu
F
H
H
8h
–
8i 1:2.0
[a] Ratios were determined by 1H NMR. [b] Total isolated yields of E- and Z-
isomers.
A plausible reaction mechanism for the formation of oxazin-2-ones
6 from 2-alkynylphenylcarbamates 5 and oxazin-2-amines 8 from 2-
alkynylphenylureas 7 is depicted in Scheme 2. The CuBr is oxidized
by Ar2I(OTf) resulting the formation of ArCu(III) reagent which
coordinates to the triple bond of 2-alkynylphenyl derivatives 5 and 7.
Vinylcation intermediate A might break down to C-arylated vinyl
cation B by reductive elimination of CuBr from vinyl cation A. The
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European Journal of Organic Chemistry
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FULL PAPER
formation of (E)- and (Z)-6 was thought to be partly caused by the
vinyl cation intermediate[7f] and and isomerization[8] of (E)- and (Z)-6.
Then isomerization studies were carried out using (E)-6a with 2.2
equiv of DTBP•TfOH salt in DCE at 80 °C for 20 h to afford (E)-6a :
(Z)-6a = 9:1. Isomerization product (E)-6a : (Z)-6a = 1:7 was obtained
from (Z)-6a. Similarly isomerization study with (E)-8a and 1.1 equiv
of TfOH in DCE at 40 °C for 24 h afforded (E)-8a : (Z)-8a = 3:1.
Therefore isomerization and carbocation intermediate formation is
speculated during the arylative cyclization because of the product
ratios (Table 1, entry 1 and Table 3, entry 1). The nucleophilic attack
of trifluoromethanesulfonate anion to the alkyl substituent of 5A (path
a) and N-arylation would result in the formation of oxazin-2-ones 6.
Table 4. Optimization results and scope of arylated indole synthesis.
entry
5
R1
R2
R
Ar temp time solv.
(°C) (h)
10
yield[a]
(%)
1
2
3
4
5
5a
5a
5b
5c
5a
Bu
Bu
Bu
Bu
Bu
H
H
H
H
H
Et
Et
Me
tBu
Ph
Ph
Ph
Ph
70
36 DCE 10a
75
72
68
0
64
150 48 DCB 10a
150 70 DCB 10b
70
24 DCE 10a
Et 4-(Me) 150 48 DCB 10c
On
the
other
hand,
the
nucleophilic
attack
of
C6H4
trifluoromethanesulfonate anion to the nitrogen proton of 7A would
produce oxazin-2-amines 8 (path b), althouth although the reason is
unclear.
6
5a
Bu
H
Et
4-(F) 80
C6H4
68 DCE 10d
74
7
8
5d
Ph
H
H
Et
Et
Ph
Ph
80
70
45 DCE 10e
30 DCE 10f
62
73
5f 4-(OMe)
C6H4
9
5h
Bu
Bu
Me Et
Et
Ph
Ph
80
70
24 DCE 10g
48 DCE 10h
92
68
10 5i
F
[a] Isolated yields.
We speculated that 2,3-disubstituted indoles 10 would be arisen
from oxidative arylation of indole palladium(II) intermediates
(Scheme 3). However redox chemistry involving Pd(IV) is much less,
the oxidation of Pd(II) intermedate intermediate to
a Pd(IV)
intermediate by diaryl iodonium(III) salts is relatively known.[19]
There might be in equilibrium between indole palladium (II)
intermediates and 3-H indles indoles 9, because 3-H indoles
sometimes were isolated during the optimization experiments. Then
the examination was done using 3-H indole 9a synthesized from 2-
alkynylphenylcarbamate 5a and 0.1 equiv. of Cu(OTf)2 catalyst.[18d]
The reaction with 9a, Pd(OAc)2, and Ph2I(OAc) in DCE afforded 2,3-
disubstituted indole 10a in 83% yield (Scheme 4). Therefore it is to
say that 3-H indole 9 might be an intermediate of the reaction from 2-
alkynylphenylcarbamate 5 to 2,3-disubstituted indole 10. Furthermore
the reaction of 5a with Pd(OAc)2 and PhI was studied under the same
reaction conditions in order to deny the possibility of the arylation
verify that the reaction does not involve an arylation mediated by PhI
derived from the decomposed iodonium salt. The reaction did not
afford 10a at all but only 3-H indole 9a in 76% yield. These results
support the proposed reaction mechanism.[20]
Scheme 2. Plausible reaction mechanism for the synthesis of oxazin-
2-ones and oxazin-2-amines.
Interestingly, indoles were obtained as byproducts apparently
arising from 5-endo-dig cyclization of the reaction of compounds 5e
and 5f (Table 2, entries 7 and 8).[16] Then we paid attention to C-
arylative 5-endo-dig cyclization using 2-alkynylarylcarbamate. There
are several reports on arylations of indoles with diaryliodonium
salts.[9d,17] On the other hand, transition metal-catalyzed indole
syntheses through 5-endo-dig cyclization of 2-alkynylarylcarbamate
are relatively well known.[18] We were pleased to find the first
example of Pd(II)-catalyzed regioselective arylative ring-closing
reaction of 2-alkynylarylcarbamate with diaryliodonium salts to
produce C3-arylated indoles. Diphenyliodonium salt was resistant to a
high temperature (Table 4, entries 1 and 2). In order to complete the
Scheme 3. Plausible reaction mechanism for the synthesis of 2,3-
disubstituted indoles.
indole formation starting from methylcarbamate 5b,
a higher
t
temperature (150 °C) was needed (entry 3). Butylcarbamate 5c did
not furnish the desired product (entry 4). The reaction of compound
5a
with
bis(4-methylphenyl)iodonium
triflate
or
bis(4-
fluorophenyl)iodonium triflate also gave the desired products (entries
5 and 6). The reaction of 5d and 5f, bearing phenyl and p-anisyl
substituents as R1, proceeded smoothly to give 10e and 10f (entries 7
and 8). Carbamates 5h and 5i, having an electron donating methyl
group and an electron withdrawing fluorine atom at the para-position
to the alkynyl substituent also provided the desired indoles (entries 9
and 10). The reaction with 2-alkynyphenylureas 7 instead of 2-
alkynylphenylcarbamates 5 did not proceed well.
Scheme 4. Experimental supports for the reaction mechanism.
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European Journal of Organic Chemistry
10.1002/ejoc.201601162
FULL PAPER
1240, 1196, 1063, 812, 758, 694. MS (EI): m/z = 259 (M+). HRMS (EB, EI):
m/z calcd for C16H21NO2: 259.1572; found: 259.1569.
Ethyl N-(5-methyl-2-phenylethynylphenyl)carbamate (5h): Yield: 770 mg,
92%; pale yellow oil. 1H-NMR (CDCl3) δ: 8.03 (1H, s), 7.55 (2H, d, J = 7.6
Hz), 7.40–7.35 (5H, m), 6.84 (1H, d, J = 8.2 Hz), 4.27–4.24 (2H, m), 2.38 (3H,
s), 1.34 (3H, t, J = 7.2 Hz). 13C-NMR (CDCl3) δ: 153.3, 140.3, 138.9, 131.5,
131.5, 128.6, 128.5, 123.4, 122.7, 118.3, 108.4, 95.5, 84.5, 61.4, 22.0, 14.6. IR
(CHCl3, cm-1) 3403, 1731, 1597, 1570, 1528, 1492, 1468, 1443, 1244, 1061,
812, 682. MS (EI): m/z = 279 (M+). HRMS (EB, EI): m/z calcd for C18H17NO2:
279.1259; found: 279.1256.
Conclusions
In summary, we have developed new regioselective Cu-catalyzed C,
N-double arylative 6-exo-dig ring-closing reaction with 2-
alkynylphenylcarbamates providing benzoxazin-2-ones, C-arylative 6-
exo-dig ring-closing reaction with 2-alkynylphenylureas providing
benzoxazin-2-amines, and regioselective Pd-catalyzed C-arylative 5-
endo-dig ring-closing reaction with 2-alkynylphenylcarbamates
providing 2,3-disubstituted indoles. It is thought that copper bromide
and palladium acetate act as both ring-closing catalysts and active
arylating reagents formed in situ with diaryliodonium salts.
Ethyl N-(5-fluoro-2-hexynylphenyl)carbamate (5i): Yield: 710 mg, 90%;
pale yellow oil. 7.95 (1H, br), 7.46 (1H, s), 7.30–7.26 (1H, m), 6.66 (1H, ddd, J
= 8.2, 8.2, 2.1 Hz), 4.27–4.23 (2H, m), 2.49 (2H, t, J = 7.2 Hz), 1.65–1.60 (2H,
m), 1.54–1.48 (2H, m), 1.34 (3H, t, J = 7.2 Hz), 0.97 (3H, t, J = 7.2 Hz). 13C-
NMR (CDCl3) δ: 162.6 (d, JC,F = 247.1 Hz), 153.0, 140.6 (d, JC,F = 13.0 Hz),
132.7 (d, JC,F = 10.1 Hz), 109.2 (d, JC,F = 23.1 Hz), 107.8, 105.0 (d, JC,F = 28.9
Hz), 97.3, 74.9, 61.5, 30.6, 22.0, 19.2, 14.5, 13.6. IR (CHCl3, cm-1) 3396, 3036,
2962, 2935, 1733, 1593, 1528, 1467, 1291, 1239, 1197, 1058, 811. MS (EI):
m/z = 263 (M+). HRMS (EB, EI): m/z calcd for C15H18NO2F: 263.1322; found:
263.1321.
Experimental Section
General: 1H NMR and 13C NMR spectra were recorded on 600 MHz
spectrometer. Chemical Shifts are reported in δ (ppm) from tetramethylsilane as
an internal standard. Data are reported as follows: chemical shifts, relative
integration value, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
br = broad, m = multiplet), coupling constants (Hz). Infrared spectra were
obtained using an FT spectrometer. HRMS experiments were measured on a
double-focussing mass spectrometer (EB). Analytical thin layer
chromatography was performed on Merck silica gel 60 F254 TLC plates.
General procedure for the synthesis of 4-methylene-4H-benzoxazin-2-ones:
To a solution of alkyne (0.2 mmol) in DCE (2 mL) was added Ar2I(OTf) (0.44
mmol), CuBr (0.02mmol), and 2,6-di-tert-butylpyridine (0.44 mmol) and
stirred at the indicated temperature under argon. The reaction was monitored by
TLC to establish the completion. The reaction mixture was diluted with AcOEt,
washed twice with saturated sodium bicarbonate solution, the aqueous solution
was extracted with AcOEt, and the combined organic solution was washed with
brine, dried over anhydrous Na2SO4, and concentrated at the reduced pressure.
Column chromatography on silica gel using hexane/ethyl acetate as an eluent
afforded coupling product.
General procedure for the preparation of 2-alkynylarylcarbamate:
Alkynes 5a,[18d] 5b,[21] 5c,[22]and 5d[18d] are all known compounds. To a solution
of 2-iodophenylcarbamate (3 mmol) in Et3N (0.2 M) was added Pd(OAc)2 (0.05
eq), PPh3 (0.1 eq), CuI (0.05 eq) and terminal alkyne (1.3 eq) and stirred at
room temperature under nitrogen. The reaction was monitored by TLC to
establish completion. Saturated aqueous NH4Cl solution was added to the
reaction mixture and extracted with AcOEt (three times). The combined
organic solution was washed with brine, dried over anhydrous MgSO4, and
concentrated at the reduced pressure. Column chromatography on silica gel
using hexane/ethyl acetate as an eluent afforded coupling products.
(E)-1-Phenyl-4-(1-phenylpentylidene)-1H-benzo[d][1,3]oxazin-2(4H)-one
(6a): Yield: 47.2 mg, 64%; colorless prisms; mp 125–126 °C. 1H-NMR
(CDCl3) δ: 7.57–7.24 (10H, m), 6.94 (1H, dd, J = 7.6, 7.6 Hz), 6.61 (1H, dd, J
= 7.6, 7.6 Hz), 6.52 (1H, d, J = 8.2 Hz), 6.26 (1H, d, J = 8.2 Hz), 2.75 (2H, t, J
= 6.5 Hz), 1.40 (4H, s), 0.88 (3H, t, J = 5.8 Hz). 13C-NMR (CDCl3) δ: 149.9,
139.6, 139.5, 139.1, 137.0, 130.0, 129.2, 129.1, 128.9, 128.8, 128.6, 127.5,
127.4, 126.6, 122.5, 118.3, 115.2, 32.4, 29.6, 22.5, 14.0. IR (CHCl3, cm-1) 3009,
1730, 1700, 1607, 1596, 1507, 1435, 1348, 1252, 1239, 1196, 812. MS (EI):
m/z = 387 (M++H2O). HRMS (EB, EI): m/z calcd for C25H23NO2: 387.1834;
found: 387.1835.
Ethyl N-[2-(p-tolylethynyl)phenyl]carbamate (5e): Yield: 762 mg, 91%; pale
yellow oil. 1H-NMR (CDCl3) δ: 8.17 (1H, br), 7.47–7.44 (4H, m), 7.33 (1H, dd,
J = 8.2, 7.6 Hz), 7.19 (2H, d, J = 7.6 Hz), 7.01 (1H, dd, J = 7.6, 7.6 Hz), 4.25
(2H, q, J = 6.9 Hz), 2.39 (3H, s), 1.34 (3H, t, J = 6.9 Hz). 13C-NMR (CDCl3) δ:
153.3, 139.1, 139.0, 131.7, 131.5, 129.6, 129.3, 122.4, 119.4, 117.6, 111.5, 96.4,
83.6, 61.4, 21.6, 14.6. IR (CHCl3, cm-1) 3402, 3037, 3009, 1734, 1581, 1521,
1307, 1238, 1196, 1062. MS (EI): m/z = 279 (M+). HRMS (EB, EI): m/z calcd
for C18H17NO2: 279.1259; found: 279.1263.
(Z)-1-Phenyl-4-(1-phenylpentylidene)-1H-benzo[d][1,3]oxazin-2(4H)-one
1
(6a): Yield: 11.8 mg, 16%; colorless prisms; mp 83–84 °C. H-NMR (CDCl3)
δ: 7.57 (1H, d, J = 7.6 Hz), 7.51 (2H, dd, J = 7.6, 7.6 Hz), 7.44 (1H, dd, J = 7.6,
7.6 Hz), 7.39–7.36 (6H, m), 7.30–7.28 (1H, m), 7.16 (2H, ddd, J = 7.6, 7.6, 6.9
Hz), 6.37 (1H, d, J = 8.2 Hz), 2.72 (2H, t, J = 7.9 Hz), 1.48–1.34 (4H, m), 0.88
(3H, t, J = 7.2 Hz). 13C-NMR (CDCl3) δ: 150.0, 140.0, 138.6, 137.8, 137.0,
129.9, 129.2, 129.0, 128.8, 128.7, 128.2, 127.5, 127.2, 126.5, 123.0, 119.3,
115.3, 32.5, 30.7, 22.7, 13.8. IR (CHCl3, cm-1) 3036, 3009, 1729, 1700, 1602,
1496, 1460, 1344, 1252, 1238, 1196, 809. MS (EI): m/z = 369 (M+). HRMS
(EB, EI): m/z calcd for C25H23NO2: 369.1729; found: 369.1732.
Ethyl N-[2-(4-methoxyphenylethynyl)phenyl]carbamate (5f): Yield: 584 mg,
66%; pale yellow oil. 1H-NMR (CDCl3) δ: 8.17 (1H, br), 7.49 (2H, d, J = 8.2
Hz), 7.45 (2H, d, J = 7.6 Hz), 7.32 (1H, dd, J = 8.2, 7.6 Hz), 7.01 (1H, dd, J =
7.6, 7.6 Hz), 6.91 (2H, d, J = 8.2 Hz), 4.25 (2H, q, J = 6.9 Hz), 3.83 (3H, s),
1.34 (3H, t, J = 6.9 Hz). 13C-NMR (CDCl3) δ: 160.0, 153.3, 138.9, 133.1, 131.6,
129.4, 122.4, 117.6, 114.5, 114.2, 111.7, 96.2, 83.0, 61.4, 55.4, 14.6. IR (CHCl3,
cm-1) 3402, 3008, 1734, 1580, 1526, 1516, 1305, 1289, 1254, 1196, 1061, 833.
MS (EI): m/z = 295 (M+). HRMS (EB, EI): m/z calcd for C18H17NO3: 295.1208;
found: 295.1214.
(E)-1-(p-Tolyl)-4-(1-p-tolylpentylidene)-1H-benzo[d][1,3]oxazin-2(4H)-one
(6b): Yield: 47.7 mg, 60%; colorless prisms; mp 124–126 °C. 7.35 (2H, d, J =
7.6 Hz), 7.27 (2H, d, J = 8.2 Hz), 7.14 (4H, dd, J = 8.2, 8.2 Hz), 6.93 (1H, dd, J
= 7.6, 7.6 Hz), 6.62 (1H, dd, J = 7.6, 7.6 Hz), 6.57 (1H, d, J = 7.6 Hz), 6.28 (1H,
d, J = 8.2 Hz), 2.71 (2H, t, J = 6.5 Hz), 2.44 (3H, s), 2.38 (3H, s), 1.36 (4H, m),
0.87 (3H, t, J = 6.5 Hz). 13C-NMR (CDCl3) δ: 150.1, 139.5, 139.2, 138.8, 137.1,
136.4, 134.3, 130.7, 129.6, 129.0, 128.8, 128.5, 127.4, 126.4, 122.4, 118.4,
115.1, 32.4, 29.6, 22.5, 21.3, 21.3, 14.0. IR (CHCl3, cm-1) 3009, 2929, 1724,
1700, 1601, 1514, 1490, 1460, 1351, 1319, 1313, 1303, 1258, 1099, 807, 759,
Ethyl N-(2-hexynyl-5-methylphenyl)carbamate (5g): Yield: 699 mg, 90%;
pale yellow oil. 1H-NMR (CDCl3) δ: 7.97 (1H, br), 7.38 (1H, s), 7.22 (1H, d, J
= 7.6 Hz), 6.77 (1H, d, J = 7.6 Hz), 4.24 (2H, q, J = 6.9 Hz), 2.49 (2H, t, J =
6.9 Hz), 2.33 (3H, s), 1.65–1.60 (2H, m), 1.53–1.49 (2H, m), 1.33 (3H, t, J =
6.9 Hz), 0.97 (3H, t, J = 7.2 Hz). 13C-NMR (CDCl3) δ: 153.3, 139.2, 138.8,
131.3, 123.1, 117.9, 109.2, 96.9, 75.9, 61.2, 30.8, 22.0, 21.9, 19.3, 14.6, 13.6.
IR (CHCl3, cm-1) 3396, 2961, 2935, 1730, 1574, 1560, 1529, 1467, 1430, 1295,
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European Journal of Organic Chemistry
10.1002/ejoc.201601162
FULL PAPER
716, 705, 682. MS (EI): m/z = 397 (M+). HRMS (EB, EI): m/z calcd for
C27H27NO2: 397.2042; found: 397.2047.
Hz), 6.68 (1H, dd, J = 7.6, 7.6 Hz), 6.31 (1H, d, J = 8.2 Hz), 2.43 (3H, s), 2.37
(3H, s). 13C-NMR (CDCl3) δ: 149.1, 140.2, 139.7, 138.9, 137.6, 137.1, 134.2,
130.8, 130.7, 130.3, 129.6, 129.1, 128.7, 128.7, 128.2, 127.9, 127.3, 125.6,
122.5, 118.5, 115.2, 21.3, 21.3. IR (CHCl3, cm-1) 3036, 3009, 1726, 1700, 1601,
1514, 1460, 1350, 1196, 1176 MS (EI): m/z = 417 (M+). HRMS (EB, EI): m/z
calcd for C29H23NO2: 417.1729; found: 417.1722.
(Z)-1-(p-Tolyl)-4-(1-p-tolylpentylidene)-1H-benzo[d][1,3]oxazin-2(4H)-one
(6b): Yield: 11.1 mg, 14%; colorless prisms; mp 160–162 °C. 1H-NMR
(CDCl3) δ: 7.54 (1H, d, J = 6.9 Hz), 7.31–7.28 (4H, m), 7.22–7.11 (6H, m),
6.39 (1H, d, J = 8.2 Hz), 2.70 (2H, t, J = 8.2 Hz), 2.41 (3H, s), 2.36 (3H, s),
1.47–1.320 (4H, m), 0.88 (3H, t, J = 7.2 Hz). 13C-NMR (CDCl3) δ: 150.2,
140.1, 138.7, 138.4, 136.9, 134.7, 134.3, 130.6, 129.1, 128.9, 128.7, 127.3,
126.4, 122.8, 119.3, 115.3, 32.4, 30.8, 22.7, 21.3, 21.2, 13.8. IR (CHCl3, cm-1)
3009, 2960, 2929, 1726, 1602, 1514, 1489, 1460, 1344, 1316, 1304, 1250, 1119,
1094, 820, 481. MS (EI): m/z = 397 (M+). HRMS (EB, EI): m/z calcd for
C27H27NO2: 397.2042; found: 397.2043
4-(Di-p-tolylmethylene)-1-(p-tolyl)-1H-benzo[d][1,3]oxazin-2(4H)-one (6f):
Yield: 53.4 mg, 62%; colorless prisms; mp 175–176 °C. 1H-NMR (CDCl3) δ:
7.34–7.30 (4H, m), 7.26–7.23 (2H, m), 7.13–7.12 (6H, m), 6.97 (1H, dd, J =
8.2, 7.6 Hz), 6.74 (1H, d, J = 7.6 Hz), 6.67 (1H, dd, J = 8.2, 7.6 Hz), 6.29 (1H,
d, J = 8.2 Hz), 2.42 (3H, s), 2.37 (3H, s), 2.34 (3H, s). 13C-NMR (CDCl3) δ:
149.2, 139.9, 139.6, 138.9, 137.5, 137.1, 136.0, 134.2, 130.8, 130.7, 130.2,
129.6, 128.9, 128.7, 128.6, 128.2, 125.6, 122.4, 118.6, 115.2, 21.3, 21.3, 21.3.
IR (CHCl3, cm-1) 3036, 3009, 1723, 1719, 1700, 1514, 1459, 1236, 1196. MS
(EI): m/z = 431 (M+). HRMS (EB, EI): m/z calcd for C30H25NO2: 431.1885;
found: 431.1883.
(E)-1-(p-Fluorophenyl)-4-(1-p-fluorophenylpentylidene)-1H-
benzo[d][1,3]oxazin-2(4H)-one (6c): Yield: 42.9 mg, 53%; pale yellow oil.
1H-NMR (CDCl3) δ: 7.38 (2H, dd, J = 8.2, 4.8 Hz), 7.26–7.20 (4H, m), 7.06
(2H, dd, J = 8.2, 8.2 Hz), 6.99 (1H, dd, J = 7.6, 7.6 Hz), 6.67 (1H, dd, J = 7.6,
7.6 Hz), 6.53 (1H, d, J = 8.2 Hz), 6.27 (1H, d, J = 8.2 Hz), 2.72 (2H, t, J = 6.2
Hz), 1.39–1.37 (4H, m), 0.88 (3H, t, J = 6.2 Hz). 13C-NMR (CDCl3) δ: 163.2 (d,
JC,F = 248.5 Hz), 162.2 (d, JC,F = 247.1 Hz), 149.8, 139.8, 139.1, 135.2 (d, JC,F
1-(p-Methoxyphenyl)-4-[(p-methoxyphenyl)phenylmethylene]-1H-
benzo[d][1,3]oxazin-2(4H)-one (major-6g): Yield: 23.7 mg, 32%; pale yellow
1
oil. H-NMR (CDCl3) δ: 7.54 (2H, dd, J = 7.6, 7.6 Hz), 7.46 (1H, dd, J = 7.6,
= 2.9 Hz), 132.8 (d, JC,F = 4.3 Hz), 130.9 (d, JC,F = 10.1 Hz), 130.9 (d, JC,F
=
7.6 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.37 (2H, d, J = 7.6 Hz), 7.33 (2H, dd, J = 7.6,
7.6 Hz), 7.25 (1H, m), 7.16 (2H, d, J = 8.9 Hz), 6.99 (1H, dd, J = 8.2, 7.6 Hz),
6.86 (2H, d, J = 8.9 Hz), 6.80 (1H, d, J = 8.2 Hz), 6.71 (1H, dd, J = 8.2, 7.6 Hz),
6.28 (1H, d, J = 8.2 Hz) 3.83 (3H, s). 13C-NMR (CDCl3) δ: 159.2, 149.0, 140.0,
139.6, 138.9, 136.9, 132.1, 132.1, 130.4, 130.0, 129.1, 129.0, 128.9, 128.2,
127.9, 127.4, 125.4, 122.6, 118.6, 115.3, 114.3, 55.24. IR (CHCl3, cm-1) 1729,
1602, 1511, 1498, 1461, 1350, 1320, 1302, 1289, 1246, 1173, 1069, 1036. MS
(EI): m/z = 419 (M+). HRMS (EB, EI): m/z calcd for C28H21NO3: 419.1521;
found: 419.1525.
8.7 Hz), 128.9, 127.4, 125.7, 122.8, 118.2, 117.1 (d, JC,F = 23.1 Hz), 116.0 (d,
JC,F = 21.7 Hz), 115.1, 32.3, 30.0, 22.4, 14.0. IR (CHCl3, cm-1) 3021, 1723,
1601, 1510, 1490, 1461, 1350, 1258, 1240, 1153, 841, 720, 701, 529. MS (EI):
m/z = 405 (M+). HRMS (EB, EI): m/z calcd for C25H21NO2F: 405.1540; found:
405.1544.
(Z)-1-(p-Fluorophenyl)-4-(1-p-fluorophenylpentylidene)-1H-
benzo[d][1,3]oxazin-2(4H)-one (6c): Yield: 13.8 mg, 17%; pale yellow oil.
1H-NMR (CDCl3) δ: 7.56 (1H, d, J = 6.9 Hz), 7.37–7.32 (4H, m), 7.22–7.15
(4H, m), 7.08 (2H, dd, J = 8.9, 8.2 Hz), 6.37 (1H, d, J = 8.2 Hz), 2.70 (2H, t, J
= 7.9 Hz), 1.46–1.41 (2H, m), 1.39–1.33 (2H, m), 0.89 (3H, t, J = 7.2 Hz). 13C-
NMR (CDCl3) δ: 162.4 (d, JC,F = 248.5 Hz), 162.0 (d, JC,F = 245.6 Hz), 150.0,
1-(p-Methoxyphenyl)-4-[(p-methoxyphenyl)phenylmethylene]-1H-
benzo[d][1,3]oxazin-2(4H)-one (minor-6g): Yield: 13.9 mg, 19%; pale yellow
oil. 1H-NMR (CDCl3) δ: 7.54 (2H, dd, J = 7.6, 7.6 Hz), 7.47 (1H, d, J = 7.6 Hz),
7.38–7.32 (7H, m), 7.26 (2H, dd, J = 8.9, 6.2 Hz), 6.97 (1H, d, J = 7.6 Hz),
6.87 (2H, d, J = 8.9 Hz), 6.66 (2H, dd, J = 8.2, 8.2 Hz), 6.27 (1H, d, J = 8.2 Hz),
3.82 (3H, s). 13C-NMR (CDCl3) δ: 158.8, 149.1, 140.1, 139.6, 139.5, 136.9,
131.7, 131.0, 130.0, 129.0, 128.9, 128.9, 128.2, 127.8, 125.4, 122.5, 118.7,
115.2, 113.3, 55.22. IR (CHCl3, cm-1) 3009, 1728, 1717, 1605, 1512, 1497,
1460, 1349, 1319, 1303, 1248, 1174, 1123, 1069, 1036, 831. MS (EI): m/z =
419 (M+). HRMS (EB, EI): m/z calcd for C28H21NO3: 419.1521; found:
419.1521.
139.8, 138.7, 133.4 (d, JC,F = 2.9 Hz), 132.7 (d, JC,F = 2.9 Hz), 130.8 (d, JC,F
8.7 Hz), 130.5 (d, JC,F = 7.2 Hz), 129.5, 126.6, 123.2, 119.1, 117.0 (d, JC,F
=
=
23.1 Hz), 115.2 (d, JC,F = 20.2 Hz), 115.2, 32.5, 30.7, 22.6, 13.8. IR (CHCl3,
cm-1) 2961, 2930, 1729, 1717, 1603, 1510, 1460, 1345, 1316, 1118, 1093, 839.
MS (EI): m/z = 405 (M+). HRMS (EB, EI): m/z calcd for C25H21NO2F:
405.1540; found: 405.1545.
4-(Diphenylmethylene)-1-phenyl-1H-benzo[d][1,3]oxazin-2(4H)-one (6d):
Yield: 60.0 mg, 77%; pale yellow oil. 1H-NMR (CDCl3) δ: 7.54 (2H, dd, J =
7.6, 7.6 Hz), 7.47 (1H, dd, J = 7.6, 6.9 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.37 (2H,
d, J = 8.2 Hz), 7.34–7.32 (5H, m), 7.27–7.25 (3H, m), 6.99 (1H, dd, J = 7.6, 7.6
Hz), 6.72 (1H, d, J = 7.6 Hz), 6.67 (1H, d, J = 7.6 Hz), 6.28 (1H, d, J = 8.2 Hz).
13C-NMR (CDCl3) δ: 148.9, 140.4, 140.0, 139.6, 138.6, 136.8, 130.9, 130.3,
130.1, 129.2, 129.0, 128.9, 128.3, 127.9, 127.8, 127.4, 125.7, 122.6, 118.3,
115.2. IR (CHCl3, cm-1) 3036, 3009, 1730, 1700, 1461, 1350, 1236, 1196, 502.
MS (EI): m/z = 389 (M+). HRMS (EB, EI): m/z calcd for C27H19NO2: 389.1416;
found: 389.1421.
(E)-7-Methyl-1-phenyl-4-(1-phenylpentylidene)-1H-benzo[d][1,3]oxazin-
2(4H)-one (6h): Yield: 57.5 mg, 75%; light yellow powder; mp 125–127 °C.
1H-NMR (CDCl3) δ: 7.56 (2H, dd, J = 7.6, 7.6 Hz), 7.49 (1H, d, J = 7.6 Hz),
7.39–7.31 (5H, m), 7.24 (2H, d, J = 7.6 Hz), 6.43–6.38 (2H, m), 6.04 (1H, s),
2.73 (2H, t, J = 6.9 Hz), 2.06 (3H, s), 1.40–1.36 (4H, m), 0.88 (3H, t, J = 6.5
Hz). 13C-NMR (CDCl3) δ: 149.9, 139.8, 139.7, 139.1, 137.0, 130.0, 129.3,
129.1, 128.9, 128.8, 127.4, 127.3, 125.4, 123.5, 115.6, 32.3, 30.0, 22.5, 21.4,
14.0. IR (CHCl3, cm-1) 3009, 2960, 2929, 1723, 1647, 1615, 1578, 1492, 1456,
1424, 1349, 1262, 1182, 1099. MS (EI): m/z = 383 (M+). HRMS (EB, EI): m/z
calcd for C26H25NO2: 383.1885; found: 383.1891.
4-(Phenyl(p-tolyl)methylene)-1-(p-tolyl)-1H-benzo[d][1,3]oxazin-2(4H)-one
(major-6e): Yield: 30.8 mg, 37%; light yellow powder; mp 223–225 °C. 1H-
NMR (CDCl3) δ: 7.34–7.31 (6H, m), 7.26–7.24 (5H, m), 7.14 (2H, d, J = 7.6
Hz), 6.97 (1H, dd, J = 8.2, 6.9 Hz), 6.69–6.63 (2H, m), 6.30 (1H, d, J = 8.2 Hz),
2.43 (3H, s), 2.34 (3H, s). 13C-NMR (CDCl3) δ: 149.1, 140.2, 140.1, 139.7,
138.9, 137.2, 135.8, 134.2, 131.0, 130.7, 130.2, 129.0, 128.9, 128.7, 128.7,
128.2, 127.7, 125.6, 122.4, 118.5, 115.2, 21.3, 21.3. IR (CHCl3, cm-1) 3036,
3009, 1727, 1700, 1513, 1460, 1236, 1196, 807. MS (EI): m/z = 417 (M+).
HRMS (EB, EI): m/z calcd for C29H23NO2: 417.1729; found: 417.1730.
4-(Phenyl(p-tolyl)methylene)-1-(p-tolyl)-1H-benzo[d][1,3]oxazin-2(4H)-one
(minor-6e): Yield: 19.2 mg, 23%; light yellow powder; mp 141–142 °C. 1H-
NMR (CDCl3) δ: 7.41 (2H, d, J = 8.2 Hz), 7.32 (3H, dd, J = 8.2, 8.2 Hz), 7.25–
7.22 (4H, m), 7.13 (4H, s), 6.98 (1H, dd, J = 8.2, 7.6 Hz), 6.77 (1H, d, J = 8.2
(Z)-7-Methyl-1-phenyl-4-(1-phenylpentylidene)-1H-benzo[d][1,3]oxazin-
2(4H)-one (6h): Yield: 9.9 mg, 13%; light yellow powder; mp 115–117 °C.
1H-NMR (CDCl3) δ: 7.52 (2H, dd, J = 7.6, 7.6 Hz), 7.46 (2H, dd, J = 8.2, 4.8
Hz), 7.38–7.34 (6H, m), 7.27 (1H, d, J = 4.8 Hz), 6.95 (1H, d, J = 8.2 Hz), 6.15
(1H, s), 2.71 (2H, t, J = 8.2 Hz), 2.23 (3H, s), 1.46–1.32 (4H, m), 0.88 (3H, t, J
= 7.2 Hz). 13C-NMR (CDCl3) δ: 150.1, 139.9, 139.8, 138.7, 137.9, 137.0, 129.9,
129.0, 128.9, 128.7, 128.1, 127.1, 126.4, 126.4, 124.0, 116.5, 115.8, 32.5, 30.7,
22.7, 21.6, 13.8. IR (CHCl3, cm-1) 2961, 2929, 1729, 1714, 1614, 1344, 1318,
1179, 1169, 1118, 1098, 1072, 1040. MS (EI): m/z = 383 (M+). HRMS (EB,
EI): m/z calcd for C26H25NO2: 383.1885; found: 383.1885.
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European Journal of Organic Chemistry
10.1002/ejoc.201601162
FULL PAPER
4-(Diphenylmethylene)-7-methyl-1-phenyl-1H-benzo[d][1,3]oxazin-2(4H)-
one (6i): Yield: 63.7 mg, 79%; light yellow powder; mp 188–190 °C. 1H-NMR
(CDCl3) δ: 7.54 (2H, dd, J = 7.6, 6.9 Hz), 7.48–7.41 (3H, m), 7.37–7.22 (10H,
m), 6.58 (1H, d, J = 7.6 Hz), 6.48 (1H, d, J = 7.6 Hz), 6.06 (1H, s), 2.09 (3H, s).
13C-NMR (CDCl3) δ: 148.9, 140.6, 140.2, 139.8, 139.5, 138.8, 136.8, 130.9,
130.3, 130.2, 130.0, 129.0, 128.9, 128.1, 127.9, 127.7, 127.3, 124.6, 123.6,
115.6, 115.5, 21.5. IR (CHCl3, cm-1) 3009, 1728, 1614, 1599, 1577, 1492, 1444,
1349, 1263, 1248, 1186, 1063, 703. MS (EI): m/z = 403 (M+). HRMS (EB, EI):
m/z calcd for C28H21NO2: 403.1572; found: 403.1577.
N-(2-(Hex-1-ynyl))phenyl)morpholine-4-carboxamide (7c): Yield: 255 mg,
89%; pale yellow solid; mp 84–85 °C. 1H-NMR (CDCl3) δ: 8.18 (1H, d, J = 8.2
Hz), 7.40 (1H, s), 7.33 (1H, d, J = 7.6 Hz), 7.28–7.26 (1H, m), 6.93 (1H, dd, J
= 7.6, 7.6 Hz), 3.76 (4H, t, J = 4.8 Hz), 3.52 (4H, t, J = 4.8 Hz), 2.49 (2H, t, J =
7.2 Hz), 1.63–1.58 (2H, m), 1.52–1.46 (2H, m), 0.96 (3H, t, J = 7.2 Hz). 13C-
NMR (CDCl3) δ: 154.4, 139.9, 131.4, 129.0, 121.9, 118.1, 111.9, 97.4, 76.5,
66.5, 44.1, 31.0, 22.1, 19.3, 13.6. IR (CHCl3, cm-1) 3413, 3009, 2964, 2931,
2902, 2863, 1663, 1653, 1607, 1581, 1521, 1517, 1448, 1364, 1336, 1309, 1278,
1265, 1238, 1119, 998, 495, 489, 483, 472, 464, 414. MS (EI): m/z = 286 (M+).
HRMS (EB, EI): m/z calcd for C17H22N2O2: 286.1681; found: 286.1684.
1-Benzyl-3-(2-(hex-1-ynyl)-5-methyl)phenylurea (7d): Yield: 80.0 mg, 25%;
(E)-7-Fluoro-1-phenyl-4-(1-phenylpentylidene)-1H-benzo[d][1,3]oxazin-
1
2(4H)-one (6j): Yield: 46.6 mg, 60%; light yellow powder; mp 84–85 °C. H-
1
NMR (CDCl3) δ: 7.50 (2H, dd, J = 7.6, 7.6 Hz), 7.43 (1H, dd, J = 7.6, 7.6 Hz),
7.32–7.24 (5H, m), 7.17 (2H, dd, J = 13.8, 7.6 Hz), 6.40 (1H, dd, J = 8.9, 6.2
Hz), 6.24 (1H, ddd, J = 8.9, 6.2, 2.1 Hz), 5.89 (1H, dd, J = 10.3, 2.1 Hz), 2.65
(2H, t, J = 7.2 Hz), 1.32–1.27 (4H, m), 0.81 (3H, t, J = 6.9 Hz). 13C-NMR
(CDCl3) δ: 162.3 (d, JC,F = 248.5 Hz), 149.5, 140.8 (d, JC,F = 10.1 Hz), 139.3,
138.9, 136.6, 130.2, 129.2 (d, JC,F = 10.1 Hz), 129.0 (d, JC,F = 21.7 Hz), 127.6,
126.3, 114.4, 109.6 (d, JC,F = 23.1 Hz), 102.9, 102.8, 32.2, 29.6, 22.5, 14.0. IR
(CHCl3, cm-1) 2960, 2931, 1730, 1647, 1607, 1596, 1507, 1492, 1435, 1348,
1254, 1239, 1195, 1179, 1170, 1099, 1072, 855. MS (EI): m/z = 387 (M+).
HRMS (EB, EI): m/z calcd for C25H22NO2F: 387.1635; found: 387.1642.
(Z)-7-Fluoro-1-phenyl-4-(1-phenylpentylidene)-1H-benzo[d][1,3]oxazin-
2(4H)-one (6j): Yield: 14.6 mg, 19%; light yellow powder; mp 139–140 °C.
1H-NMR (CDCl3) δ: 7.55–7.51 (3H, m), 7.47 (1H, dd, J = 7.6, 6.9 Hz), 7.41–
7.33 (6H, m), 7.30 (1H, d, J = 6.9 Hz), 6.85 (1H, d, J = 6.9 Hz), 6.09 (1H, d, J
= 9.6 Hz), 2.68 (2H, t, J = 7.9 Hz), 1.45–1.43 (2H, m), 1.37–1.33 (2H, m), 0.88
(3H, t, J = 7.2 Hz). 13C-NMR (CDCl3) δ: 162.9 (d, JC,F = 248.5 Hz), 149.6,
141.8 (d, JC,F = 10.1 Hz), 137.8, 137.5, 136.5, 130.1, 129.1, 128.8, 128.8, 128.2,
pale yellow solid; mp 168–169 °C. H-NMR (DMSO-d6) δ: 7.95 (1H, s), 7.75
(1H, s), 7.65 (1H, dd, J = 5.5 Hz), 7.36–7.31 (4H, m), 7.26 (1H, dd, J = 6.9, 6.2
Hz), 7.17 (1H, d, J = 7.6 Hz), 6.71 (1H, d, J = 7.6 Hz), 4.31 (2H, d, J = 5.5 Hz),
2.50–2.47 (2H, m), 2.25 (3H, s), 1.58–1.54 (2H, m), 1.46–1.39 (2H, m), 0.91
(3H, t, J = 7.2 Hz). 13C-NMR (DMSO-d6) δ: 154.8, 140.6, 140.1, 138.0, 131.6,
128.4, 127.3, 126.9, 122.0, 119.0, 108.7, 96.3, 76.3, 42.8, 30.3, 21.6, 18.9, 13.5.
IR (CHCl3, cm-1) 3386, 3009, 2960, 2933, 1701, 1570, 1530, 1507, 1456, 1430,
1294, 1282, 477, 448, 435, 400. MS (EI): m/z = 320 (M+). HRMS (EB, EI):
m/z calcd for C21H24N2O: 320.1889; found: 320.1885.
1-Benzyl-3-(2-fluoro-6-(hex-1-ynyl))phenylurea (7e): Yield: 243 mg, 75%;
pale yellow solid; mp 133–134 °C. 1H-NMR (CDCl3) δ: 8.03 (1H, dd, J = 11.7,
2.1 Hz), 7.36–7.26 (6H, m), 7.15 (1H, s), 6.62 (1H, ddd, J = 9.2, 9.2, 2.1 Hz),
5.06 (1H, s), 4.46 (2H, d, J = 6.2 Hz), 2.40 (2H, t, J = 7.2 Hz), 1.59–1.54 (2H,
m), 1.47–1.41 (2H, m), 0.92 (3H, t, J = 7.6 Hz). 13C-NMR (CDCl3) δ: 162.6 (d,
JC,F = 245.6 Hz), 154.2, 141.4 (d, JC,F = 11.6 Hz), 138.3, 132.8 (d, JC,F = 10.1
Hz), 128.8, 127.6, 108.9 (d, JC,F = 21.7 Hz), 107.6, 105.8, 105.6, 97.0, 75.4,
44.5, 30.8, 22.1, 19.2, 13.6. IR (CHCl3, cm-1) 2933, 2360, 1696, 1593, 1528,
1518, 1506, 1458, 1439, 1291, 1170, 719, 690, 672, 495, 491, 460, 450, 439,
423, 418. MS (EI): m/z = 324 (M+). HRMS (EB, EI): m/z calcd for
C20H21N2OF: 324.1638; found: 324.1642.
128.1 (d, JC,F = 10.1 Hz), 127.3, 127.3, 115.2 (d, JC,F = 2.9 Hz), 109.9 (d, JC,F
=
21.7 Hz), 103.2 (d, JC,F = 27.5 Hz), 32.5, 30.7, 22.7, 13.8. IR (CHCl3, cm-1)
3009, 1734, 1609, 1597, 1506, 1436, 1344, 1239, 1196. MS (EI): m/z = 387
(M+). HRMS (EB, EI): m/z calcd for C25H22NO2F: 387.1635; found: 387.1640.
General procedure for the preparation of 2-Alkynylphenylurea: To a
solution of 2-alkynylbenzamide (1.0 mmol) in 1,2-dichlorobenzene was added
phenyliodo(1.10 mmol) and stirred at 70 °C under argon. Next, solution was
added terminal amine (1.10 mmol) and stirred at r.t.. The reaction was
monitored by TLC to establish completion. The combined solution was
concentrated at the reduced pressure. Column chromatography on silica gel
using hexane/ethyl acetate as an eluent afforded 2-alkynylphenylurea.
1-Benzyl-3-(2-(hex-1-ynyl))phenylurea (7a): Yield: 275 mg, 90%; pale
yellow solid; mp 151–152 °C. 1H-NMR (CDCl3) δ: 8.08 (1H, d, J = 8.2 Hz),
7.35–7.22 (7H, m), 7.06 (1H, s), 6.93 (1H, dd, J = 7.6, 7.6 Hz), 5.10 (1H, br),
4.46 (2H, d, J = 6.2 Hz), 2.41 (2H, t, J = 7.2 Hz), 1.59–1.54 (2H, m), 1.45–1.42
(2H, m), 0.92 (3H, t, J = 7.2 Hz). 13C-NMR (CDCl3) δ: 154.8, 139.7, 138.6,
131.9, 128.9, 128.7, 127.6, 127.5, 122.1, 118.7, 112.7, 97.4, 76.2, 44.5, 30.8,
22.1, 19.3, 13.6. IR (CHCl3, cm-1) 3441, 3388, 3036, 3009, 2961, 2935, 1685,
1581, 1521, 1497, 1454, 1447, 1306, 1238, 1196, 809, 506, 499, 467. MS (EI):
m/z = 306 (M+). HRMS (EB, EI): m/z calcd for C20H22N2O: 306.1732; found:
306.1737.
1-Benzyl-3-(2-phenylethynyl))phenylurea (7f): Yield: 251 mg, 77%; pale
yellow solid; mp 184–185 °C. 1H-NMR (CDCl3) δ: 8.12 (1H, d, J = 8.2 Hz),
7.49–7.45 (3H, m), 7.36–7.23 (9H, m), 7.08 (1H, s), 6.99 (1H, dd, J = 7.4, 6.9
Hz), 5.20 (1H, br), 4.43 (2H, d, J = 5.5 Hz). 13C-NMR (CDCl3) δ: 154.7, 139.8,
138.5, 132.0, 131.6, 129.7, 128.7, 128.7, 128.4, 127.6, 127.5, 122.5, 122.4,
119.2, 112.0, 95.8, 84.7, 44.5. IR (CHCl3, cm-1) 3440, 3393, 3009, 1701, 1691,
1681, 1581, 1521, 1516, 1490, 1459, 1444, 1303, 1281, 479, 448, 435. MS
(EI): m/z = 326 (M+). HRMS (EB, EI): m/z calcd for C22H18N2O: 326.1419;
found: 326.1415.
1-(2-(Hex-1-ynyl)phenyl)-3-phenylurea (7g): Yield: 134 mg, 46%; pale
yellow solid; mp 137–138 °C. 1H-NMR (CDCl3) δ: 8.21 (1H, d, J = 8.2 Hz),
7.59 (1H, s), 7.36–7.17 (7H, m), 6.98–6.93 (2H, m), 2.23 (2H, t, J = 6.9 Hz),
1.45–1.35 (4H, m), 0.90 (3H, t, J = 6.9 Hz). 13C-NMR (CDCl3) δ: 153.1, 139.4,
137.6, 131.7, 129.5, 128.8, 125.1, 122.8, 122.4, 118.8, 112.8, 97.5, 75.9, 30.7,
22.1, 19.2, 13.6. IR (CHCl3, cm-1) 3423, 3367, 3009, 2961, 2935, 1684, 1600,
1582, 1521, 1517, 1498, 1449, 1307, 1271, 1240, 1196, 450. MS (EI): m/z =
292 (M+). HRMS (EB, EI): m/z calcd for C19H20N2O: 292.1576; found:
292.1577.
1-(2,2-Diphenylethyl)-3-(2-(hex-1-ynyl))phenylurea (7b): Yield: 317 mg,
General procedure for the synthesis of oxazin-2-amines: To a solution of 2-
alkynylphenylurea (0.2 mmol) in DCE was added Ar2I(OTf) (0.22 mmol) and
CuBr (0.02 mmol) and stirred at 40 °C under argon. The reaction was
monitored by TLC to establish completion. Column chromatography on silica
gel using hexane/ethyl acetate as an eluent afforded oxazin-2-amine.
1
80%; pale yellow solid; mp 141–142 °C. H-NMR (CDCl3) δ: 7.83 (1H, d, J =
7.6 Hz), 7.33–7.16 (12H, m), 6.90–6.88 (2H, m), 4.67 (1H, br), 4.25 (1H, t, J =
7.9 Hz), 3.91–3.89 (2H, m), 2.38 (2H, t, J = 6.9 Hz), 1.54–1.50 (2H, m), 1.43–
1.37 (2H, m), 0.90 (3H, t, J = 7.2 Hz). 13C-NMR (CDCl3) δ: 154.6, 141.8,
139.6, 131.8, 128.8, 128.8, 128.1, 126.8, 122.1, 118.7, 112.8, 97.3, 76.2, 50.9,
44.9, 30.7, 22.0, 19.2, 13.5. IR (CHCl3, cm-1) 3034, 2931, 1704, 1581, 1517,
1507, 1449, 1306, 1233, 800, 784, 751, 742, 726, 70 3034, 2931, 1704, 1581,
1517, 1507, 1449, 1306, 1233, 800, 784, 751, 742, 726, 705, 692, 685, 663, 501,
471, 467, 456, 409. MS (EI): m/z = 396 (M+). HRMS (EB, EI): m/z calcd for
C27H28N2O: 396.2202; found: 396.2200.
(4E)-N-Benzyl-4-(1-phenylpentylidene)-4H-benzo[d][1,3]oxazin-2-amine
(8a): Yield: 26.7 mg, 35%; pale yellow solid; mp 166–167 °C.1H-NMR
(CDCl3) δ: 7.33–7.12 (11H, m), 6.97 (1H, dd, J = 7.6 Hz), 6.87 (1H, d, J = 7.6
Hz), 6.44 (1H, dd, J = 7.6 Hz), 6.27 (1H, d, J = 7.6 Hz), 4.54 (2H, s), 2.43 (2H,
t, J = 7.2 Hz), 1.25–1.18 (4H, m), 0.76 (3H, t, J = 6.9 Hz). 13C-NMR (CDCl3)
δ: 153.4, 143.5, 141.2, 140.5, 138.4, 129.4, 129.2, 128.9, 128.7, 127.6, 127.1,
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European Journal of Organic Chemistry
10.1002/ejoc.201601162
FULL PAPER
126.5, 122.6, 122.0, 121.1, 119.6, 45.5, 32.6, 29.7, 29.6, 22.6, 14.0. IR (CHCl3,
cm-1) 3443, 2960, 2931, 2860, 1628, 1594, 1570, 1472, 1457, 1289, 1258, 1096,
705, 487, 477, 472, 448, 437. MS (EI): m/z = 382 (M+). HRMS (EB, EI): m/z
calcd for C26H26N2O: 382.2045; found: 382.2049.
s), 2.48 (2H, t, J = 7.6 Hz), 2.37 (3H, s), 1.36–1.25 (4H, m), 0.83 (3H, t, J = 6.9
Hz). 13C-NMR (CDCl3) δ: 153.4, 143.4, 141.0, 138.4, 137.3, 136.7, 129.6,
129.2, 128.7, 127.6, 127.5, 126.5, 122.6, 122.1, 121.1, 45.5, 32.6, 29.6, 22.6,
21.3, 14.0. IR (CHCl3, cm-1) 2958, 2927, 2856, 1653, 1628, 1594, 1457, 1214,
718, 692, 491, 471, 466, 458, 425, 408. MS (EI): m/z = 396 (M+). HRMS (EB,
EI): m/z calcd for C27H28N2O: 396.2202; found: 396.2206.
(4Z)-N-Benzyl-4-(1-phenylpentylidene)-4H-benzo[d][1,3]oxazin-2-amine
(8a): Yield: 21.4 mg, 28%; pale yellow solid; mp 129–130 °C. 1H-NMR
(CDCl3) δ: 7.43 (1H, d, J = 7.6 Hz), 7.32–7.02 (14H, m), 4.20 (2H, s), 2.64 (2H,
t, J = 7.9 Hz), 1.47–1.42 (2H, m), 1.38–1.32 (2H, m), 0.88 (3H, t, J = 7.2 Hz).
13C-NMR (CDCl3) δ: 154.3, 154.2, 144.5, 140.3, 139.6, 138.3, 129.8, 128.8,
128.5, 128.0, 127.3, 126.6, 125.6, 122.4, 122.3, 120.4, 53.4, 45.1, 32.6, 30.8,
22.8, 13.9. IR (CHCl3, cm-1) 2959, 2929, 2859, 2358, 1653, 1646, 1623, 1616,
1594, 1457, 1288, 692, 682, 674, 504, 490, 458, 450, 426, 400. MS (EI): m/z =
382 (M+). HRMS (EB, EI): m/z calcd for C26H26N2O: 382.2045; found:
382.2044.
(4Z)-N-Benzyl-4-(1-p-tolylpentylidene)-4H-benzo[d][1,3]oxazin-2-amine
(8d): Yield: 27.7mg, 35%; pale yellow solid; mp 119–121 °C. 1H-NMR
(CDCl3) δ: 7.43–7.23 (7H, m), 7.16–7.02 (7H, m), 4.22 (2H, d J = 5.7 Hz), 2.62
(2H, t, J = 7.9 Hz), 2.33 (3H, s), 1.45–1.41 (2H, m), 1.37–1.30 (2H, m), 0.88
(3H, t, J = 7.2 Hz). 13C-NMR (CDCl3) δ: 167.8, 144.4, 140.1, 138.3, 136.5,
136.2, 130.9, 129.7, 128.7, 128.6, 128.5, 127.3, 125.6, 122.3, 68.1, 45.2, 38.7,
32.5, 30.8, 22.8, 21.2, 13.9. IR (CHCl3, cm-1) 2960, 2929, 2862, 1653, 1646,
1628, 1593, 1569, 1457, 1289, 1242, 1090, 479, 475, 462, 448, 437. MS (EI):
m/z = 396 (M+). HRMS (EB, EI): m/z calcd for C27H28N2O: 396.2202; found:
396.2200.
(4E)-N-(2,2-Diphenylethyl)-4-(1-phenylpentylidene)-4H-
benzo[d][1,3]oxazin-2-amine (8b): Yield: 51.9 mg, 55%; pale yellow solid;
mp 124–125 °C. 1H-NMR (CDCl3) δ: 7.35–7.18 (16H, m), 7.04 (1H, dd, J =
7.6, 6.9 Hz), 6.93 (1H, d, J = 6.9 Hz), 6.51 (1H, dd, J = 7.6, 7.6 Hz), 6.33 (1H,
d, J = 7.6 Hz), 4.34 (1H, t, J = 7.6 Hz), 4.04 (2H, d, J = 8.2 Hz), 2.47 (2H, t, J =
7.2 Hz), 1.29–1.19 (4H, m), 0.77 (3H, t, J = 7.2 Hz). 13C-NMR (CDCl3) δ:
153.2, 143.5, 141.7, 141.2, 140.5, 129.4, 129.2, 128.9, 128.8, 128.1, 127.1,
126.9, 126.5, 122.6, 122.0, 121.0, 50.7, 45.8, 32.5, 29.7, 29.5, 22.4, 14.0. IR
(CHCl3, cm-1) 2929, 1653, 1628, 1593, 1235, 782, 773, 765, 753, 744, 730, 723,
714, 694, 679, 666, 458, 439, 417. MS (EI): m/z = 472 (M+). HRMS (EB, EI):
m/z calcd for C33H32N2O: 472.2515; found: 472.2518.
(4E)-N-Benzyl-4-(1-(4-fluorophenyl)pentylidene)-4H-benzo[d][1,3]oxazin-
2-amine (8e): Yield: 45.6 mg, 57%; pale yellow solid; mp 172–174 °C. 1H-
NMR (CDCl3) δ: 7.39–6.95 (14H, m), 6.56 (1H, dd, J = 7.6, 7.6 Hz), 6.35 (1H,
d, J = 8.2 Hz), 4.61 (2H, s), 2.48 (2H, t, J = 6.5 Hz), 1.29–1.257 (4H, m), 0.83
(3H, t, J = 6.2 Hz). 13C-NMR (CDCl3) δ: 162.8, 143.6, 141.5, 138.3, 136.2,
131.0, 130.2 (d, JC,F = 238.4 Hz), 128.8, 128.6, 127.6, 127.5, 126.4, 122.8,
122.1, 119.9, 115.9(d, JC,F = 21.7 Hz), 45.5, 32.5, 29.7, 29.5, 22.5, 14.0. IR
(CHCl3, cm-1) 1653, 1646, 1628, 1624, 1594, 1517, 1507, 1457, 725, 709, 701,
450, 448, 441, 439, 433, 400. MS (EI): m/z = 400 (M+). HRMS (EB, EI): m/z
calcd for C26H25N2OF: 400.1951; found: 400.1953.
(4Z)-N-(2,2-Diphenylethyl)-4-(1-phenylpentylidene)-4H-
benzo[d][1,3]oxazin-2-amine (8b): Yield: 20.8 mg, 22%; pale yellow solid;
mp 148–149 °C. 1H-NMR (CDCl3) δ: 7.35 (1H, d, J = 7.6 Hz), 7.23–6.89 (19H,
m), 3.68 (3H, br), 2.56 (2H, t, J = 7.9 Hz), 1.36–1.18 (4H, m), 0.80 (3H, t, J =
7.2 Hz). 13C-NMR (CDCl3) δ: 154.2, 144.6, 141.6, 140.2, 139.6, 129.8, 128.7,
128.6, 128.1, 128.0, 128.0, 126.7, 126.6, 125.6, 123.5, 122.1, 50.6, 45.2, 32.4,
30.8, 29.7, 22.7, 13.9. IR (CHCl3, cm-1) 2960, 2929, 2860, 1653, 1646, 1628,
1617, 1592, 1569, 1496, 1457, 1288, 1115, 1094, 693, 489, 485, 455, 408. MS
(EI): m/z = 472 (M+). HRMS (EB, EI): m/z calcd for C33H32N2O: 472.2515;
found: 472.2520.
(4Z)-N-Benzyl-4-(1-(4-fluorophenyl)pentylidene)-4H-benzo[d][1,3]oxazin-
2-amine (8e): Yield: 23.2 mg, 29%; pale yellow solid; mp 122–124 °C. H-
NMR (CDCl3) δ: 7.43–6.97 (15H, m), 4.20 (1H, s), 2.66–2.60 (2H, m), 1.43–
1.25 (4H, m), 0.89 (3H, t, J = 6.9 Hz). 13C-NMR (CDCl3) δ: 161.5 (d, JC,F
=
244.2 Hz), 140.5, 138.2, 135.3, 131.0, 130.8, 130.4 (d, JC,F = 7.2 Hz), 130.0
129.3, 128.8, 128.6, 127.6, 127.4 (d, JC,F = 4.3 Hz), 125.6, 122.4, 116.1, 116.0,
115.0 (d, JC,F = 20.2 Hz), 32.6, 30.7, 22.7, 13.9. IR (CHCl3, cm-1) 3438, 2960,
2931, 2874, 2862, 1730, 1653, 1628, 1593, 1570, 1508, 1497, 1468, 1458, 1399,
1354, 1289, 1157, 1114, 1090, 840, 495, 474, 437. MS (EI): m/z = 400(M+).
HRMS (EB, EI): m/z calcd for C26H25N2OF: 400.1951; found: 400.1954.
(4E)-N-Benxyl-7-methyl-4-(1-phenylpentylidene)-4H-benzo[d][1,3]oxazin-
2-amine (8f): Yield: 38.0 mg, 48%; pale yellow solid; mp 165–166 °C. 1H-
NMR (CDCl3) δ: 7.33 (9H, m), 7.21 (2H, d, J = 6.9 Hz), 6.78 (1H, s), 6.35 (1H,
d, J = 8.2 Hz), 6.22 (1H, d, J = 7.6 Hz), 4.61 (2H, s), 2.49 (2H, t, J = 6.9 Hz),
2.18 (3H, s), 1.36–1.25 (4H, m), 0.83 (3H, t, J = 6.9 Hz). 13C-NMR (CDCl3) δ:
153.4, 143.3, 141.3, 140.7, 139.4, 138.4, 129.4, 128.9, 128.7, 127.6, 127.0,
126.3, 123.1, 119.9, 116.7, 45.5, 32.5, 30.8, 29.6, 22.6, 21.2, 14.0. IR (CHCl3,
cm-1) 3685, 3671, 3666, 3440, 3036, 1648, 1636, 1603, 1559, 1507, 732, 722,
717, 713, 678, 526, 502, 499, 480, 450, 447. MS (EI): m/z = 396(M+). HRMS
(EB, EI): m/z calcd for C27H28N2O: 396.2202; found: 396.2208.
(4E)-2-Morpholino-4-(1-phenylpentylidene)-4H-benzo[d][1,3]oxazine (8c):
1
Yield: 42.0 mg, 58%; pale yellow solid; mp 113–114 °C. H-NMR (CDCl3) δ:
7.35–7.29 (3H, m), 7.20 (2H, d, J = 6.9 Hz), 7.03 (1H, d, J = 6.9 Hz), 6.93 (1H,
d, J = 8.2 Hz), 6.51 (1H, t, J = 7.6 Hz), 6.33 (1H, d, J = 7.6 Hz), 3.78 (4H, t, J =
4.8 Hz), 3.69 (4H, t, J = 4.8 Hz), 2.54 (2H, t, J = 7.6 Hz), 1.40–1.30 (4H, m),
0.87 (3H, t, J = 7.2 Hz). 13C-NMR (CDCl3) δ: 152.9, 143.7, 141.5, 140.4, 129.3,
129.3, 128.9, 127.1, 126.4, 122.8, 122.1, 121.0, 119.1, 66.5, 44.5, 33.1, 29.7,
22.8, 14.0. IR (CHCl3, cm-1) 2961, 2927, 2861, 1653, 1646, 1616, 1587, 1569,
1474, 1457, 1420, 1303, 1291, 1255, 1118, 1096, 493, 483, 472, 464, 403. MS
(EI): m/z = 362 (M+). HRMS (EB, EI): m/z calcd for C23H26N2O2: 362.1994;
found: 362.2000.
(4Z)-2-Morpholino-4-(1-phenylpentylidene)-4H-benzo[d][1,3]oxazine (8c):
Yield: 21.0 mg, 29%; pale yellow solid; mp 82–83 °C. 1H-NMR (CDCl3) δ:
7.43 (1H, d, J = 7.6 Hz), 7.34 (2H, t, J = 7.6 Hz), 7.25–7.22 (4H, m), 7.01 (2H,
t, J = 6.9 Hz), 3.46 (4H, t, J = 4.5 Hz), 3.15 (4H, br), 2.63 (2H, t, J = 7.9 Hz),
1.51–1.46 (2H, m), 1.38–1.35 (2H, m), 0.89 (3H, t, J = 7.2 Hz). 13C-NMR
(CDCl3) δ: 153.6, 144.8, 140.5, 140.0, 129.8, 128.9, 128.1, 126.7, 125.4, 123.9,
122.6, 122.2, 120.2, 66.4, 44.3, 32.5, 30.8, 22.8, 13.9. IR (CHCl3, cm-1) 2962,
2927, 2862, 1617, 1586, 1569, 1474, 1449, 1430, 1303, 1290, 1253, 1115, 703,
494, 487, 482, 479, 474, 465, 450, 416. MS (EI): m/z = 362 (M+). HRMS (EB,
EI): m/z calcd for C23H26N2O2: 362.1994; found: 362.1999.
(4Z)-N-Benxyl-7-methyl-4-(1-phenylpentylidene)-4H-benzo[d][1,3]oxazin-
2-amine (8f): Yield: 38.0 mg, 48%; pale yellow solid; mp 93–94 °C. 1H-NMR
(CDCl3) δ: 7.34–7.22 (11H, m), 7.12 (1H, s), 6.87 (2H, d, J = 6.2 Hz), 4.17 (2H,
s), 2.63 (2H, t, J = 7.9 Hz), 2.33 (3H, s), 1.46–1.41 (2H, m), 1.36–1.32 (2H, m),
0.88 (3H, t, J = 7.2 Hz). 13C-NMR (CDCl3) δ: 140.3, 140.1, 139.7, 138.2, 128.8,
128.7, 128.5, 128.0, 127.3, 126.6, 125.5, 123.4, 45.1, 32.6, 31.6, 30.7, 29.7,
22.8, 21.4, 14.1, 13.9. IR (CHCl3, cm-1).2960, 2927, 2860, 1628, 1601, 1560,
1456, 1173, 1115, 1097, 479, 448, 437, 400. MS (EI): m/z = 396(M+). HRMS
(EB, EI): m/z calcd for C27H28N2O: 396.2202; found: 396.2203.
(4E)-N-Benxyl-7-fluoro-4-(1-phenylpentylidene)-4H-benzo[d][1,3]oxazin-2-
amine (8g): Yield: 32.8 mg, 41%; pale yellow solid; mp 146–147 °C.1H-NMR
(CDCl3) δ: 7.39–7.26 (9H, m), 7.18 (2H, d, J = 6.9 Hz), 6.62 (1H, d, J = 8.2
Hz), 6.29–6.20 (2H, m), 4.60 (2H, s), 2.49 (2H, t, J = 6.9 Hz), 1.36–1.25 (4H,
m), 0.83 (3H, t, J = 6.5 Hz). 13C-NMR (CDCl3) δ: 163.3(d, JC,F = 247.1 Hz),
(4E)-N-Benzyl-4-(1-p-tolylpentylidene)-4H-benzo[d][1,3]oxazin-2-amine
(8d): Yield: 42.0 mg, 53%; pale yellow solid; mp 168–170 °C. 1H-NMR
(CDCl3) δ: 7.43–7.36 (4H, m), 7.31 (1H, t, J = 7.2 Hz), 7.16–7.03 (6H, m), 6.94
(1H, d, J = 7.6 Hz), 6.54 (1H, t, J = 7.6 Hz), 6.40 (1H, d, J = 8.2 Hz), 4.61 (2H,
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European Journal of Organic Chemistry
10.1002/ejoc.201601162
FULL PAPER
145.9, 140.6, 140.3, 138.1, 129.3, 129.1, 129.0, 128.8, 128.1, 128.0, 127.9,
127.6(d, JC,F = 20.2 Hz), 127.2, 120.7, 109.2, 109.0, 45.5, 32.4, 29.6, 22.6, 14.0.
IR (CHCl3, cm-1) 2960, 2929, 1653, 1628, 1623, 1594, 1497, 1489, 1456, 1437,
1256, 1162, 1115, 1094, 973, 499, 479, 473, 448, 400. MS (EI): m/z = 400
(M+). HRMS (EB, EI): m/z calcd for C26H25N2OF: 400.1951 ; found: 400.1949.
(4Z)-N-Benxyl-7-fluoro-4-(1-phenylpentylidene)-4H-benzo[d][1,3]oxazin-2-
amine (8g): Yield: 22.4 mg, 28%; pale yellow solid; mp 108–110 °C. 1H-NMR
(CDCl3) δ: 7.39–7.08 (12H, m), 6.73 (2H, dd, J = 8.9, 8.2 Hz), 4.40 (2H, br),
2.60 (2H, t, J = 7.9 Hz), 1.42–1.25 (4H, m), 0.88 (3H, t, J = 7.2 Hz). 13C-NMR
(CDCl3) δ: 163.8(d, JC,F = 247.1 Hz), 139.7, 139.4, 138.0, 129.3, 129.0, 128.8,
128.8, 128.6, 128.6, 128.1, 127.7, 127.4, 127.2, 126.9 (d, JC,F = 10.1 Hz), 126.7,
109.2 (d, JC,F = 21.7 Hz), 45.1, 32.5, 30.7, 22.7, 13.9. IR (CHCl3, cm-1) 2958,
2931, 2860, 1593, 1164, 1115, 1096, 977, 726, 475, 472, 456, 447, 439, 400.
MS (EI): m/z = 400 (M+). HRMS (EB, EI): m/z calcd for C26H25N2OF:
400.1951 ; found: 400.1953.
127.1, 124.0, 123.1, 121.9, 119.1, 115.6, 53.5, 32.6, 26.8, 22.6, 13.8. IR (CHCl3,
cm-1) 2958, 1734, 1458, 1444, 1383, 1356, 1329, 1303, 1258, 1238, 1194, 1123,
717, 693, 692, 683, 670, 663, 502. MS (EI): m/z = 307 (M+). HRMS (EB, EI):
m/z calcd for C20H21NO2: 307.1572; found: 307.1574.
Ethyl 2-butyl-3-(p-tolyl)-1H-indole-1-carboxylate (10c): Yield: 42.9 mg,
1
64%; light yellow oil. H-NMR (CDCl3) δ: 8.16 (1H, d, J = 8.2 Hz), 7.39 (1H,
d, J = 8.2 Hz), 7.31–7.26 (5H, m), 7.20 (1H, t, J = 7.6 Hz), 4.55–4.52 (2H, m),
3.01 (2H, t, J = 7.6 Hz), 2.42 (3H, t, J = 7.9 Hz), 1.62–1.50 (5H, m), 1.31–1.27
(2H, m), 0.84 (3H, t, J = 7.6 Hz). 13C-NMR (CDCl3) δ: 152.0, 138.1, 136.8,
135.8, 130.8, 130.1, 130.0, 129.2, 123.8, 122.9, 121.6, 119.1, 115.6, 63.0, 32.7,
26.9, 22.6, 21.3, 14.4, 13.9. IR (CHCl3, cm-1) 3007, 2962, 1728, 1458, 1398,
1375, 1347, 1326, 1302, 1295, 1240, 1194, 1188, 1123, 1072, 708, 701, 695,
692. MS (EI): m/z = 335 (M+). HRMS (EB, EI): m/z calcd for C22H25NO2:
335.1885; found: 335.1888.
Ethyl 2-butyl-3-(4-fluorophenyl)-1H-indole-1-carboxylate (10d): Yield:
50.2 mg, 74%; light yellow oil. 1H-NMR (CDCl3) δ: 8.17 (1H, d, J = 8.9 Hz),
7.38–7.15 (7H, m), 4.54 (2H, q, J = 7.1 Hz), 2.99 (2H, t, J = 7.9 Hz), 1.60–1.50
(5H, m), 1.28 (2H, q, J = 7.2 Hz), 0.83 (3H, t, J = 7.2 Hz). 13C-NMR (CDCl3)
δ: 162.1(d, JC,F = 247.1 Hz), 152.0, 138.4, 135.8, 131.7(d, JC,F = 8.7 Hz), 129.9,
129.8(d, JC,F = 12.9 Hz), 124.0, 123.1, 120.7, 118.8, 115.7, 115.5(d, JC,F = 21.7
Hz), 63.1, 32.6, 26.8, 22.6, 14.4, 13.8. IR (CHCl3, cm-1) 3036, 3009, 1730,
1509, 1458, 1398, 1375, 1347, 1326, 1240, 1188, 1157, 837. MS (EI): m/z =
339 (M+). HRMS (EB, EI): m/z calcd for C21H22NO2F: 339.1635; found:
339.1631.
N-Benzyl-4-(diphenylmethylene)-4H-benzo[d][1,3]oxazin-2amine
(8h):
1
Yield: 74.0 mg, 92%; pale yellow solid; mp 155–158 °C. H-NMR (CDCl3) δ:
8.06 (1H, d, J = 8.2 Hz), 7.42–7.19 (16H, m), 6.99–6.92 (2H, m), 5.05 (1H, s),
4.38 (2H, d, J = 6.2 Hz). 13C-NMR (CDCl3) δ: 154.7, 139.8, 138.5, 132.0,
131.6, 129.8, 128.8, 128.7, 128.5, 127.6, 127.5, 1225, 122.4, 119.2, 112.0, 95.8,
84.7, 44.6. IR (CHCl3, cm-1) 3170, 3064, 3036, 3306, 2955, 2875, 2790, 1691,
1685, 1592, 1297, 1285, 1238, 1175, 1025, 637, 475, 448, 433, 400. MS (EI):
m/z = 402(M+). HRMS (EB, EI): m/z calcd for C28H22N2O: 402.1732; found:
402.1734.
(4E,Z)-N-Phenyl-4-(1-phenylpentylidene)-4H-benzo[d][1,3]oxazin-2-amine
(8i): E- and Z-isomers could not be separated and some impurities
contaminated 8i. Yield: 14.0 mg, 19%; pale yellow oil. 1H-NMR (CDCl3) δ:
7.65–7.07 (14H, m), 7.02–6.83 (1H, m), 2.68–2.49 (2H, m), 1.46–1.25 (4H, m),
0.92–0.79 (3H, m). 13C-NMR (CDCl3) δ: 155.7, 151.0, 140.2, 139.6, 137.7,
129.9, 129.7, 129.3, 129.3, 129.0, 128.9, 128.9, 128.8, 128.7, 128.4, 128.3,
127.2, 127.1, 126.9, 126.9, 126.8, 125.7, 124.1, 123.2, 123.0, 122.9, 122.8,
120.7, 120.6, 120.5, 119.4, 119.3, 118.4, 115.3, 33.0, 32.7, 30.6, 29.6, 22.8,
22.6, 14.0, 13.9. IR (CHCl3, cm-1) 3429, 3036, 3009, 2960, 2931, 2862, 1636,
1628, 1593, 1569, 1539, 1533, 1474, 1445, 1306, 1291, 1238, 1196, 1092. MS
(EI): m/z = 368(M+). HRMS (EB, EI): m/z calcd for C25H24N2O: 368.1889;
found: 368.1892.
Ethyl 2,3-diphenyl-1H-indole-1-carboxylate (10e): Yield: 42.3 mg, 62%;
light yellow oil. 1H-NMR (CDCl3) δ: 8.28 (1H, d, J = 8.2 Hz), 7.60 (1H, d, J =
8.2 Hz), 7.40 (1H, t, J = 7.9 Hz), 7.29–7.21 (11H, m), 4.20 (2H, q, J = 7.2 Hz),
1.02 (3H, t, J = 7.2 Hz). 13C-NMR (CDCl3) δ: 151.8, 136.3, 135.8, 133.4, 133.2,
130.4, 130.1, 129.5, 128.2, 127.6, 127.6, 126.7, 124.9, 123.3, 122.4, 119.7,
115.5, 62.8, 13.6. IR (CHCl3, cm-1) 3008, 1728, 1454, 1445, 1398, 1375, 1345,
1323, 1263, 1238, 1192, 1056. MS (EI): m/z = 341 (M+). HRMS (EB, EI): m/z
calcd for C23H19NO2: 341.1416; found: 341.1421.
Ethyl 2-(4-methoxyphenyl)-3-phenyl-1H-indole-1-carboxylate (10f): Yield:
54.2 mg, 73%; light yellow oil. 1H-NMR (CDCl3) δ: 8.27 (1H, d, J = 8.2 Hz),
7.58 (1H, d, J = 7.6 Hz), 7.39 (1H, dd, J = 8.2, 6.9 Hz), 7.30–7.25 (6H, m),
7.16 (2H, d, J = 8.2 Hz), 6.82 (2H, d, J = 8.2 Hz), 4.19 (2H, q, J = 6.9 Hz), 3.78
(3H, s), 1.02 (3H, t, J = 6.9 Hz). 13C-NMR (CDCl3) δ: 158.3, 151.8, 136.2,
135.5, 133.6, 131.1, 130.4, 129.7, 127.6, 127.5, 125.3, 124.8, 123.2, 122.1,
119.7, 115.4, 113.7, 62.8, 55.1, 13.6. IR (CHCl3, cm-1) 3008, 1728, 1515, 1456,
1400, 1375, 1323, 1305, 1240, 1194, 1178, 1057, 501. MS (EI): m/z = 371 (M+).
HRMS (EB, EI): m/z calcd for C24H21NO3:371.1521; found: 371.1523.
Ethyl 2-butyl-6-methyl-3-phenyl-1H-indole-1-carboxylate (10g): Yield: 61.6
mg, 92%; light yellow oil. 1H-NMR (CDCl3) δ: 8.02 (1H, s), 7.48–7.37 (5H, m),
7.26 (1H, dd, J = 8.2, 7.6 Hz), 7.04 (1H, d, J = 7.6 Hz), 4.53 (2H, q, J = 7.1 Hz),
2.99 (2H, t, J = 7.9 Hz), 2.49 (3H, s), 1.60–1.49 (5H, m), 1.27 (2H, q, J = 7.6
Hz), 0.82 (3H, t, J = 7.6 Hz). 13C-NMR (CDCl3) δ: 152.1, 137.4, 136.3, 134.1,
133.8, 130.1, 128.4, 127.7, 127.0, 124.3, 121.6, 118.6, 115.9, 63.0, 32.7, 26.9,
22.5, 22.0, 14.3, 13.8. IR (CHCl3, cm-1) 3036, 3009, 1727, 1398, 1375, 1344,
1332, 1320, 1302, 1196, 1189, 1130. MS (EI): m/z = 335 (M+). HRMS (EB,
EI): m/z calcd for C22H25NO2: 335.1885; found: 335.1891.
General procedure for the synthesis of 2,3-disubstituted-1H-indole-1-
carboxylates: To a solution of alkyne (0.2 mmol) in DCE (2 mL) was added
Ar2I(OTf) (0.22 mmol) and Pd(OAc)2 (0.02mmol), and stirred at the indicated
temperature under argon. The reaction was monitored by TLC to establish the
completion. The reaction mixture was diluted with AcOEt, washed twice with
saturated sodium bicarbonate solution, the aqueous solution was extracted with
AcOEt, and the combined organic solution was washed with brine, dried over
anhydrous Na2SO4, and concentrated at the reduced pressure. Column
chromatography on silica gel using hexane/ethyl acetate as an eluent afforded
coupling product.
Ethyl 2-butyl-3-phenyl-1H-indole-1-carboxylate (10a): Yield: 48.2 mg,
1
75%; light yellow oil. H-NMR (CDCl3) δ: 8.17 (1H, d, J = 8.2 Hz), 7.48 (2H,
dd, J = 8.2, 7.6 Hz), 7.42–7.39 (4H, m), 7.29 (1H, dd, J = 8.2, 6.9 Hz), 7.21
(1H, dd, J = 7.6, 6.9 Hz), 4.54 (2H, q, J = 6.5 Hz), 3.02 (2H, t, J = 7.6 Hz),
1.62–1.60 (2H, m), 1.52 (3H, t, J = 6.5 Hz), 1.31–1.27 (2H, m), 0.83 (3H, t, J =
7.2 Hz). 13C-NMR (CDCl3) δ: 152.0, 138.3, 135.8, 133.9, 130.1, 130.0, 128.5,
127.1, 123.9, 123.0, 121.7, 119.0, 115.7, 63.1, 32.7, 26.9, 22.6, 14.4, 13.8. IR
(CHCl3, cm-1) 3036, 3009, 1729, 1458, 1325, 1239, 1199, 742, 709, 692, 502.
MS (EI): m/z = 321 (M+). HRMS (EB, EI): m/z calcd for C21H23NO2: 321.1729;
found: 321.1736.
Ethyl 2-butyl-6-fluoro-3-phenyl-1H-indole-1-carboxylate (10h): Yield: 46.1
1
mg, 68%; light yellow oil. H-NMR (CDCl3) δ: 7.91 (1H, d, J = 10.3 Hz), 7.48
(2H, dd, J = 7.6, 6.9 Hz), 7.39 (3H, d, J = 7.6 Hz), 7.30–7.26 (1H, m), 6.96 (1H,
dd, J = 8.9, 8.2 Hz), 4.54 (2H, q, J = 7.1 Hz), 2.99 (2H, t, J = 7.9 Hz), 1.62–
1.51 (5H, m), 1.31–1.25 (2H, m), 0.84 (3H, t, J = 7.2 Hz). 13C-NMR (CDCl3) δ:
160.7(d, JC,F = 238.4 Hz), 151.8, 138.4(d, JC,F = 4.3 Hz), 135.9(d, JC,F = 13.0
Hz), 133.6, 130.0, 128.6, 127.2, 126.3, 121.3, 119.5(d, JC,F = 10.1 Hz), 111.0(d,
JC,F = 24.6 Hz), 103.2(d, JC,F = 28.9 Hz), 63.3, 32.7, 27.0, 22.6, 14.3, 13.8. IR
(CHCl3, cm-1) 3009, 1734, 1482, 1441, 1398, 1375, 1348, 1327, 1303, 1269,
Methyl 2-butyl-3-phenyl-1H-indole-1-carboxylate (10b): Yield: 41.8 mg,
68%; light yellow oil. 8.14 (1H, d, J = 8.2 Hz), 7.49–7.20 (8H, m), 4.08 (3H, s),
3.01 (2H, t, J = 7.9 Hz), 1.58 (2H, m), 1.31–1.27 (2H, m), 0.84 (3H, t, J = 7.2
Hz). 13C-NMR (CDCl3) δ: 152.5, 138.3, 135.7, 133.9, 130.1, 130.0, 128.5,
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601162
FULL PAPER
1238, 1194, 1185, 692. MS (EI): m/z = 339 (M+). HRMS (EB, EI): m/z calcd
Chem. Soc. 2013, 135, 12532-12535; g) S. Tang, P. Peng, P. Zhong, J.-H. Li,
J. Org. Chem. 2008, 73, 5476-5480.
for C21H22NO2F: 339.1635; found: 339.1634.
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Supporting Information (see footnote on the first page of this article): Copies
of the1H, 13C NMR spectra for all know compounds, crystal data and structure
refinement, thermal ellipsoid plot of the crystallographic structure of
compounds (E)-6a, (Z)-6a, (E)-8a, and (Z)-8c.
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Acknowledgements
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We gratefully acknowledge a Grant-in-Aid for Scientific Research (C)
from JSPS KAKENHI (23590032 26460025 to R. Y. and 15K07881
to T. S.). We are grateful to Dr. Shoji Yamaguchi at Setsunan
University for obtaining LRMS and HRMS data.
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Keywords: regioselective/ arylative cyclization/ indoles/
benzoxazines/ diaryliodonium/ 5-endo-dig
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European Journal of Organic Chemistry
10.1002/ejoc.201601162
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Tandem Arylation and Cyclization
Hideki Minami, Takuya Kanayama] Reishi
Tanaka, Noriko Okamoto, Takuya Sueda,
and Reiko Yanada*
Page No. – Page No.
Regioselective Arylative Ring-Closing
Reaction of 2-Alkynylphenyl Derivatives:
Formation of Arylated Benzoxazin-2-
ones, Benzoxazin-2-amines and 2,3-
Disubstituted Indoles
Copper-catalyzed arylative ring-closing reactions of 2-alkynylphenylcarbamates and 2-
alkynylphenylureas with diaryliodonium salts were achieved to afford C, N-double arylated
benzoxazin-2-ones and C-arylated benzoxazin-2-amines bearing fully substituted exo
olefins, respectively. On the other hand, palladium-catalyzed arylative ring-closing reaction
of 2-alkynylphenylcarbamates interestingly afforded C-arylated 2,3-disubstituted indoles.
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