PD(II)-Catalyzed ligand-controlled synthesis of 2,3-dihydroisoxazole-4-carboxylates and bis(2,3-dihydroisoxazol-4-Yl)methanones

Article abstract of DOI:10.3987/COM-15-S(T)22

Pd(II)-catalyzed ligand-controlled switching between cyclization-carbonylation and cyclization-carbonylation-cyclization-coupling(CCC-coupling) reactions of propargylic N-hydroxylamines was investigated. The use of a [Pd(tfa)2(box)] catalyst in MeOH affor

Full text of DOI:10.3987/COM-15-S(T)22

512
HETEROCYCLES, Vol. 93, No. 2, 2016
HETEROCYCLES, Vol. 93, No. 2, 2016, pp. 512 - 528. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 25th August, 2015, Accepted, 30th September, 2015, Published online, 28th October, 2015
DOI: 10.3987/COM-15-S(T)22
PD(II)-CATALYZED
LIGAND-CONTROLLED
SYNTHESIS
OF
2,3-DIHYDROISOXAZOLE-4-CARBOXYLATES
BIS(2,3-DIHYDROISOXAZOL-4-YL)METHANONES
AND
Tomohiro Ariyama, Taichi Kusakabe,* Keita Sato, Mifuyu Funatogawa,
Dong Lee, Keisuke Takahashi, and Keisuke Kato*
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi,
Chiba
274-8510,
Japan.
E-mail:
taichi.kusakabe@phar.toho-u.ac.jp,
kkk@phar.toho-u.ac.jp
Dedicated to Professor Dr. Lutz F. Tietze on the occasion of his 75th birthday
Abstract
–
Pd(II)-catalyzed
ligand-controlled
switching
between
cyclization–carbonylation and cyclization–carbonylation–cyclization-coupling
(CCC-coupling) reactions of propargylic N-hydroxylamines was investigated. The
use of a [Pd(tfa)2(box)] catalyst in MeOH afforded symmetric ketones bearing two
2,3-dihydroisoxazoles in good yields; replacing the catalyst and solvent with
Pd(tfa)2 and MeOH/DMSO led to the formation of methyl 2,3-dihydroisoxazole-
4-carboxylates in good yields.
INTRODUCTION
2,3-Dihydroisoxazoles (4-isoxazolines) are versatile heterocycles known for their potent biological
activities1 as well as being useful building blocks for synthesis2 (Figure 1). Diarylketones are also
frequently present in natural products and pharmaceuticals,3 e.g., raloxifene (selective estrogen receptor
modulator used for treatment of osteoporosis), benzbromarone (antipodagric), and amiodarone
(antiarrhythmic). The importance of 2,3-dihydroisoxazoles in both chemistry and biology has led to
various approaches2 for their synthesis: (i) [3+2] cycloadditions between nitrones and alkynes,2,4 (ii)
oxaziridine ring opening,5 (iii) addition of N-hydroxylamines to a 1,3-conjugated enyne6 or an
,-dicyanoolefin,7 and (iv) a one-pot multicomponent approach by the reaction of an aldehyde with
acetohydroxamic acid and malononitrile or methyl cyanoacetate.8 A variety of heterocycles can be
synthesized by transition-metal-catalyzed cyclization of unsaturated systems.9 Propargylic

HETEROCYCLES, Vol. 93, No. 2, 2016
513
N-hydroxylamines are a good precursor for the synthesis of 2,3-dihydroisoxazoles,10 but the
cyclization–carbonylation reaction of propargylic N-hydroxylamines has not been investigated.
Me
N O
Me
N O
F
SO2Me
F
mitotic kinesin inhibitor
COX-2 inhibitor
O
HO
O
O
I
Br
S
O(CH2)2N
O
O
nBu
OH
O(CH2)2NEt2
Et
Br
I
OH
raloxifene
benzbromarone
amiodarone
Figure 1. Structures of biologically active 2,3-dihydroisoxazoles and diarylketones
Recently, we reported a cyclization–carbonylation–cyclization-coupling reaction (CCC-coupling
reaction) of propargyl acetates,11a amides,11a -propynyl-1,3-diketones,11b N-propargylanilines,11c
o-alkynylphenols, 11c and propargyl ureas11d catalyzed by palladium(II)-bisoxazoline (box) complexes.
We also very recently reported Pd(II)-catalyzed ligand-controlled switching between
cyclization–carbonylation and CCC-coupling reactions of ,-alkynic hydrazones,11e,h (o-alkynylphenyl)
(methoxymethyl) sulfides,11f,h and 2-alkynylanilines11g (Scheme 1). In this transformation, the triple bond
of the substrate coordinates to palladium(II) and undergoes nucleophilic attack by the intramolecular
nucleophile X, followed by CO insertion to produce the acyl palladium intermediate A. Coordination of
the triple bond of a second molecule induces the second cyclization,12 then reductive elimination leads to
the formation of a ketone bearing two heterocyclic groups. Methanolysis of the acyl palladium
intermediate A gives the ester product as a result of cyclization–carbonylation. If the intramolecular
cyclization reactions of propargylic N-hydroxylamine could be expanded to include carbonylative
(coupling) reactions, the process would be a synthetically valuable method for direct preparation of
ketones bearing two 2,3-dihydroisoxazole groups and 2,3-dihydroisoxazole-4-carboxylates. Herein, we
investigated Pd(II)-catalyzed ligand-controlled switching between cyclization–carbonylation and
CCC-coupling reactions of propargylic N-hydroxylamines.

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HETEROCYCLES, Vol. 93, No. 2, 2016
Scheme 1. Reaction courses of cyclization–carbonylation and
cyclization–carbonylation–cyclization-coupling (CCC-coupling) in propargylic compounds
RESULTS AND DISCUSSION
Initially, we selected 1a as a standard substrate to search for potential catalysts and solvents (Table 1). The
reaction of 1a with Pd(tfa)2 (5 mol%) and p-benzoquinone (1.5 equiv.) in methanol under a carbon
monoxide atmosphere (balloon) at 0 ºC afforded the 2,3-dihydroisoxazole-4-carboxylate derivative 3a in
77% yield (Table 1, entry 1). The use of [PdCl2(PPh3)2] was ineffective, affording 3a in low yield along
with recovery of substrate 1a (74%) (Table 1, entry 2). The use of [PdCl2(CH3CN)2] and [Pd(tfa)2(bipy)]
generated the dimeric ketone 2a in 37-56% yield along with 5-38% yield of ester 3a (Table 1, entries 3 and
4). Next, an attempt was made to use the box-PdII complexes according to our previous results11 (Table 1,
entries 5-7). Although the use of [Pd(tfa)2(L1)] resulted in the formation of 2a in 33% yield together with
54% yield of 3a, [Pd(tfa)2(L2)] accelerated the reaction, and the yield of dimeric ketone 2a improved to
89%. It is conceivable that the steric hindrance of L1 inhibited the coordination of the second substrate to
palladium, and thus the yield of 2a was decreased. The nature of the counteranion of the palladium
complexes somewhat influenced catalytic activity (Table 1, entry 8). Next, according to our previous
findings,11g,h mixed solvent (MeOH/DMSO) was tested in the carbonylation reaction of 1a (Table 1, entries
9-13). The best result was obtained using a 5/1 ratio of MeOH/DMSO, affording 3a in 88% yield (Table 1,
entry 11). PdCl2 and Pd(OAc)2 were found to be unsuitable catalysts for this reaction (Table 1, entries 12
and 13).

HETEROCYCLES, Vol. 93, No. 2, 2016
515
Table 1. Optimization of CCC-coupling and cyclization–carbonylation reactions of 1a
Time
(h)
52
Yield of Yield of Recovery
Entry
1
Pd II
Pd(tfa)2
Solvent
MeOH
2a (%)
3a (%) of 1a (%)
-
77
-
74
-
2
[PdCl2(PPh3)2]
[PdCl2(MeCN)2]
[Pd(tfa)2(bipy)]
[Pd(tfa)2(L1)]
[Pd(tfa)2(L2)]
[Pd(tfa)2(L2)]
[PdCl2(L2)]
Pd(tfa)2
MeOH
96
96
48
96
24
48
96
72
48
61
72
74
-
56
37
33
87
89
42
-
7
3
MeOH
38
5
4
MeOH
29
-
5
MeOH
54
13
9
6
71
MeOH
-
MeOH
-
8
MeOH
-
43
23
31
-
9
MeOH / DMSO = 3 / 1
MeOH / DMSO = 1 / 1
MeOH / DMSO = 5 / 1
MeOH / DMSO = 5 / 1
MeOH / DMSO = 5 / 1
63
57
88
28
11
10
11
12
13
Pd(tfa)2
-
Pd(tfa)2
-
PdCl2
-
37
75
Pd(OAc)2
-
1) –20 ~ –10 ºC
Having elucidated the optimum conditions for both reactions, we then employed a variety of propargylic
N-hydroxylamines 1 in the CCC-coupling reaction (Table 2, entries 1-10, condition A). The influence of
aryl substituents at the propargylic position (R1 = aryl) was investigated first (Table 2, entries 1-8). The
substrate 1b gave good results, similar to that of the parent substrate 1a (Table 2, entry 2). The substrates
1c–1g, bearing an electron-donating or halogen (F, Cl) group at the para or ortho position, afforded good
to excellent yields of 2c-2g (Table 2, entries 3-7). A good yield was obtained by using 1h, containing an
alkyl group instead of an aryl group at the propargylic position (Table 2, entry 8). The substrate 1i,
bearing an aryl substituent at the propargylic position and at the alkyne terminus, afforded a slightly lower
yield (70%) of 2i (Table 2, entry 9). However, terminal alkyne 1j was ineffective under the optimized
conditions (entry 10). The reaction pathways were switched by using condition B. Substrates bearing aryl
substituents at the propargylic position were investigated; the substrate 1b gave good results (Table 2,
entry 12). Propargylic N-hydroxylamines 1c-1g, containing an electron-donating or halogen (F, Cl) group
at the para or ortho position, were transformed to the corresponding methyl

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HETEROCYCLES, Vol. 93, No. 2, 2016
2,3-dihydroisoxazole-4-carboxylates 3c-3g in good yield (Table 2, entries 11-17). The substrates 1h-1i,
bearing alkyl or aryl substituents at the propargylic position and alkyne terminus, afforded good yields of
3h-3i (Table 2, entries 18 and 19). In contrast, terminal alkyne 1j gave a complex mixture (Table 2, entry
20).
Table 2. Substrate scope of CCC-coupling (condition A) and
cyclization–carbonylation reactions (condition B)
Yield of
Yield of
3 (%)
Entry
R1
R2
Temp (ºC)
Time (h)
23 (%)
1
2
Ph
Ph
n-Bu
cyclopropyl
n-Bu
–20 ~ –10
48
24
46
76
72
47
44
24
69
19
61
35
72
65
62
73
72
38
71
43
2a : 89
2b : 89
2c : 86
2d : 82
2e : 81
2f : 94
2g : 85
2h : 86
2i : 70
3a : 9
3b : 4
3c : 5
3d : 9
3e : 10
-
0
3
4-MeOC6H4
4-FC6H4
4-ClC6H4
2-FC6H4
2-ClC6H4
C6H5-(CH2) 2
Ph
–20 ~ –10
4
n-Bu
–20 ~ –10
5
n-Bu
–20 ~ –10
6
n-Bu
–10 ~ 0
7
Me
–10 ~ 0
3g : 8
3h : 13
3i : 17
8
n-Bu
–10
91
10
11
12
131
14
15
16
172
18
191
20
4-MeC6H4
H
–5
Ph
–20
Recovery of 1j : 44%
Ph
n-Bu
0
-
-
3a : 88
3b :83
3c : 81
3d : 85
3e : 88
3f : 88
3g : 89
3h : 88
3i : 86
Ph
cyclopropyl
n-Bu
0
-
-
-
-
-
-
-
4-MeOC6H4
4-FC6H4
4-ClC6H4
2-FC6H4
2-ClC6H4
C6H5-(CH2) 2
Ph
0
n-Bu
0
n-Bu
0
n-Bu
0
10
Me
n-Bu
0
4-MeC6H4
H
5
Ph
0 ~ 10
complex mixture
1) 1,4-Benzoquinone (2.5 equiv) was used. 2) 1,4-Benzoquinone (3.0 equiv) was used.
3) Mixture of diastereomers (ratio = 1:1~3:1)

HETEROCYCLES, Vol. 93, No. 2, 2016
517
Isoxazoles are a major class of five-membered heterocycles and are used for a variety of pharmaceutical
and agrochemical products (Figure 2).13 Accordingly, the synthetic utility of the obtained
2,3-dihydroisoxazoles was shown by conversion to isoxazoles (Scheme 2). Deprotection14 of 2a and 3g,
followed by oxidation, afforded the corresponding isoxazoles in 49-86% yield (2 steps).
Cl
N O
N O
N O
Me
Me
Me
O
O
NH
N
O
NH
S
SO2NH2
CF3
O
OH
valdecoxib
leflunomide
cloxacillin
Figure 2. Structures of biologically active isoxazoles
Scheme 2. Synthesis of isoxazoles
A plausible mechanism for the CCC-coupling and cyclization–carbonylation reactions of 1 is shown in
Scheme 3. Nucleophilic attack by the oxygen atom at the electrophilically activated triple bond is
followed by CO insertion to produce the acyl palladium intermediate I-1. Under condition A (L = box),
coordination of the triple bond of a second molecule (I-2) induces the second cyclization, and reductive
elimination then leads to the formation of a ketone bearing two 2,3-dihydroisoxazole groups. We believe
that the box ligand enhances the -electrophilicity of palladium(II),12 thus promoting coordination of the
second triple bond to the acyl palladium intermediate I-1 and leading to the dimerization reaction. Under

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HETEROCYCLES, Vol. 93, No. 2, 2016
condition B, DMSO acts as a neutral ligand instead of a box.11g,h Methanolysis of the acyl palladium
intermediate I-1 should be facilitated, giving 2,3-dihydroisoxazole-4-carboxylates 3 in good yields.
R2
OH
R1
L
L
Pd
-
tfa = CF3CO2
N
tfa
tfa
Cbz
OH
TFA = CF3CO2H
L = box or DMSO
1
OH
O
CO
Cyclization
2TFA +
O
C
TFA
R1
-Carbonylation
OMe
O
N
Cbz
R2
O
L
L
3
Methanolysis
Condition B
L = DMSO
Pd
O
N
O
O
tfa
C
N
L'
R2
R1
PdL'4
Pd
L'
N O
L' = MeOH or DMSO
TFA
MeOH
L' = MeOH
Cbz
I-1
+
Condition A
L = box
tfa
O
O
R1
R1
O
C
N
N
Cbz
Cbz
N
O
R2
R2
N
O
O
Pd
R1
R1
C
R2 R2
R1
+ TFA
N
Cbz
OH
N
2
Cbz
R2
O
OH
N
Cyclization-Coupling reaction
1
I-2
Cbz
Scheme 3. Plausible mechanism for the CCC-coupling and cyclization–carbonylation reactions of 1
In conclusion, we developed an efficient way of switching between CCC-coupling and
cyclization–carbonylation reactions of propargylic N-hydroxylamines (1) catalyzed by PdII. The use of
[Pd(tfa)2(box)] as a catalyst in MeOH afforded symmetric ketones bearing two 2,3-dihydroisoxazoles in
good to excellent yields, whereas replacing the catalyst and solvent with Pd(tfa)2 and MeOH/DMSO led
to the formation of methyl 2,3-dihydroisoxazole-4-carboxylates in good yields. These reactions were
general for a wide range of propargylic N-hydroxylamines. We have shown that these products can serve
as precursors for the preparation of isoxazoles. We are currently investigating additional cascade
reactions based on the reaction strategy of CCC-coupling and cyclization–carbonylation presented here
for the synthesis of ketones containing two heterocyclic groups and heterocycles-carboxylates.
EXPERIMENTAL
The propargylic N-hydroxylamines 1 were prepared by FeCl3-catalyzed nucleophilic substitution of
corresponding propargylalcohol with Cbz-NHOH according to known literature procedures15 except 1h.
The propargylic N-hydroxylamine 1a, 1d, 1e, 1f, 1i were all known compounds.16

HETEROCYCLES, Vol. 93, No. 2, 2016
519
Benzyl (3-cyclopentyl-1-phenylprop-2-yn-1-yl)(hydroxy)carbamate (1b): colorless solid; mp 89-91
1
ºC; H-NMR (400 MHz, CDCl3) δ 0.72-0.82 (4H, m), 1.29-1.36 (1H, m), 5.23 (2H, s), 5.86 (1H, br-s),
6.08 (1H, d, J = 2.0 Hz), 7.25-7.37 (8H, m), 7.49-7.50 (2H, m); 13C-NMR (100 MHz, CDCl3) δ -0.5, 8.4,
8.4, 55.7, 68.4, 69.8, 90.5, 127.9 (2C), 128.2 (2C), 128.2, 128.4 (3C), 128.7 (2C), 135.6, 136.2, 157.1; IR
(KBr): 3375, 3017, 2241, 1665, 1597, 1413, 1348, 1290, 753, 691 cm-1; HRMS-ESI: calcd for
C20H19NNaO3 [M+Na]+: 344.1263; found: 344.1269.
1
Benzyl hydroxy(1-(4-methoxyphenyl)hept-2-yn-1-yl)carbamate (1c): brown oil; H-NMR (400 MHz,
CDCl3) δ 0.91 (3H, t, J = 7.2 Hz), 1.38-1.56 (4H, m), 2.27 (2H, dt, J = 7.2, 2.0 Hz), 3.78 (3H, s), 5.23 (2H,
s), 5.83 (1H, br-d), 6.06 (1H, t, J = 2.0 Hz), 6.84-6.87 (2H, m), 7.25-7.45 (7H, m); 13C-NMR (100 MHz,
CDCl3) δ 13.6, 18.5, 22.0, 30.7, 55.2, 55.3, 68.3, 74.9, 87.3, 113.7 (2C), 128.2 (2C), 128.4, 128.4, 128.6
(2C), 129.3 (2C), 135.7, 157.1, 159.5; IR (KBr): 3335, 2961, 2220, 1707, 1612, 1509, 1248, 1099, 746
cm-1; HRMS-ESI: calcd for C22H25NNaO4 [M+Na]+: 390.1681; found: 390.1654.
1
Benzyl hydroxy(1-(2-chlorophenyl)but-2-yn-1-yl)carbamate (1g): colorless oil; H-NMR (400 MHz,
CDCl3) δ 1.90 (3H, d, J = 2.4 Hz), 5.25 (2H, s), 5.86 (1H, br-d), 6.40 (1H, q, J = 2.4 Hz), 7.26-7.40 (8H,
13
m), 7.86-7.89 (1H, m); C-NMR (100 MHz, CDCl3) δ 3.7, 53.2, 68.4, 73.6, 83.1, 126.6, 128.1 (2C),
128.3, 128.5 (2C), 129.5, 129.8, 131.5, 133.6, 133.7, 135.7, 157.0; IR (KBr): 3299, 2234, 1704, 1582,
1407, 1286, 1101, 749 cm-1; HRMS-ESI: calcd for C18H16NNaO3 [M+Na]+: 352.0716; found: 352.0696.
Benzyl hydroxy(1-phenylnon-4-yn-3-yl)carbamate (1h)
To a solution of 1-phenyl-4-nonyn-3-ol17 (0.50 g, 2.31 mmol) and Ph3P (1.21 g, 4.62 mmol) in MeCN (15
mL) was added CBr4 (1.53 g, 4.62 mmol) at 0 ºC. The solution was stirred at 0 ºC for 1.5 h, then filtered,
rinsed with AcOEt (20 mL), and dried over MgSO4. Concentration by rotary evaporation furnished a
crude mixture that was purified by silica gel chromatography (hexane) to afford
3-bromo-4-nonyn-1-yl-benzene (90%). Yellow oil; 1H-NMR (400 MHz, CDCl3) δ 0.92 (3H, t, J = 7.6 Hz),
1.39-1.55 (4H, m), 2.25-2.30 (4H, m), 2.83-2.87 (2H, m), 4.48-4.52 (1H, m), 7.19-7.30 (5H, m);
13C-NMR (100 MHz, CDCl3) δ 13.6, 18.6, 21.9, 30.5, 33.5, 37.8, 41.7, 79.0, 88.8, 126.2, 128.5 (2C),
128.6 (2C), 140.3; IR (KBr): 2958, 2933, 2233, 1724, 1709, 1603, 1453, 748, 699 cm-1; HRMS-EI: calcd
for C15H19Br [M+]: 278.0670; found: 278.0668.
To a solution of 3-bromo-4-nonyn-1-yl-benzene (0.50 g, 1.79 mmol) in 1-methyl-2-pyrrolidone (6 mL)
was added NH2OH (50% in water, 2 mL), and the mixture was stirred at rt for 18 h. The mixture was
diluted with AcOEt (40 mL), washed with water and brine, dried over MgSO4, and concentrated in vacuo.
The crude product was dissolved in dioxane (8 mL) and sat. a.q. NaHCO3 (8 mL). Benzyl chloroformate
(611 mg, 3.58 mmol) was added dropwise to the mixture at rt and stirred for 1 h. The mixture was diluted
with AcOEt (20 mL) and washed with water (20 mL). The organic layer was dried over MgSO4 and
concentrated in vacuo. The crude product was purified by flash chromatography. The fraction eluted with

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HETEROCYCLES, Vol. 93, No. 2, 2016
hexane/AcOEt (6 /1) afforded 1h (66%, 2 steps). Colorless oil; 1H-NMR (400 MHz, CDCl3) δ 0.89 (3H, t,
J = 7.2 Hz), 1.35-1.50 (4H, m), 2.04-2.20 (4H, m), 2.71 (2H, t, J = 7.6 Hz), 4.74-4.78 (1H, m), 5.17 (1H,
13
d, J = 12.4 Hz), 5.20 (1H, d, J = 12.4 Hz), 6.21 (1H, br-d), 7.15-7.37 (10H, m); C-NMR (100 MHz,
CDCl3) δ 13.6, 18.3, 21.9, 30.7, 32.2, 34.5, 51.8, 68.2, 76.2, 85.6, 126.0, 128.1 (2C), 128.3, 128.4 (2C),
128.5 (2C), 128.5 (2C), 135.7, 141.0, 157.6; IR (KBr): 3276, 2952, 2235, 1704, 1596, 1102, 747, 698
cm-1; HRMS-ESI: calcd for C23H27NNaO3 [M+Na]+: 388.1889; found: 388.1886.
1
Benzyl hydroxy(1-phenylprop-2-yn-1-yl)carbamate (1j): yellow oil; H-NMR (400 MHz, CDCl3) δ
2.56 (1H, d, J = 2.4 Hz), 5.24 (2H, s), 5.94 (1H, br-s), 6.14 (1H, d, J = 2.4 Hz), 7.34-7.55 (10H, m);
13C-NMR (100 MHz, CDCl3) δ 55.3, 68.6, 74.8, 78.6, 128.0 (2C), 128.3 (2C), 128.5, 128.6 (3C), 128.6
(2C), 135.1, 135.4, 157.1; IR (KBr): 3288, 2118, 1705, 1286, 1100, 752, 722, 697 cm-1; HRMS-ESI:
calcd for C17H15NNaO3 [M+Na]+: 304.0950; found: 304.0936.
Typical
hydroxy(1-phenylhept-2-yn-1-yl)carbamate (1a): condition A
30 mL two-necked round-bottom flask containing
procedure
for
the
CCC-coupling
reaction
of
benzyl
A
a
magnetic stir bar, benzyl
hydroxy(1-phenylhept-2-yn-1-yl)carbamate (1a) (135 mg, 0.40 mmol), p-benzoquinone (64.9 mg, 0.60
mmol), and MeOH (5 mL) was fitted with a rubber septum and a three-way stopcock connected to a
balloon filled with carbon monoxide. The apparatus was purged with carbon monoxide by pump-filling
via the three-way stopcock. A MeOH (1 mL) suspension of [Pd(tfa)2(L2)] (10.3 mg, 0.02 mmol) was
added to the stirred solution using a syringe at −20 ºC. The remaining [Pd(tfa)2(L2)] was washed in
MeOH (1 mL) twice and stirred for 48 h at −20 to −10 ºC. The mixture was diluted with CH2Cl2 (50 mL)
and washed with 5% a.q. NaOH (40 mL). The aqueous layer was extracted with CH2Cl2 (25 mL) and the
combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude product was
purified by column chromatography on silica gel. The fraction eluted with hexane–ethyl acetate (40/1)
afforded dimeric ketone 2a as a diasteromixture (ratio 1.5:1) (monomeric ester 3a, hexane–AcOEt =
50/1).
1
Compound 2a: inseparable mixture of diastereomers (ratio = 1.5:1); yellow oil; H-NMR (400 MHz,
CDCl3) δ 0.76 (12/5H, t, J = 7.2 Hz), 0.84 (18/5H, t, J = 7.2 Hz), 1.02-1.57 (8H, m), 2.23-2.50 (4H, m),
13
5.14-5.22 (4H, m), 5.89 (6/5H, s), 6.25 (4/5H, s), 7.13-7.35 (20H, m); C-NMR (100 MHz, CDCl3) δ
13.6 (4/5C), 13.6 (6/5C), 22.3 (4/5C), 22.4 (6/5C), 25.3 (4/5C), 25.6 (6/5C), 28.9 (4/5C), 29.0 (6/5C),
68.5 (4/5C), 68.5 (4/5C), 68.6 (6/5C), 69.2 (6/5C), 113.9 (6/5C), 114.7 (4/5C), 126.6 (8/5C), 126.7
(12/5C), 128.1 (8/5C), 128.2 (12/5C), 128.2 (4/5C), 128.3 (6/5C), 128.4 (4/5C), 128.5 (6/5C), 128.5
(8/5C), 128.6 (12/5C), 128.6 (12/5C), 128.7 (8/5C), 135.1 (2C), 139.4 (4/5C), 139.5 (6/5C), 156.3 (6/5C),
156.4 (4/5C), 162.1 (4/5C), 162.5 (6/5C), 182.3 (2/5C), 182.7 (3/5); IR (KBr): 2961, 1729, 1606, 1390,

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521
1308, 1221, 1103, 745, 696 cm-1; HRMS-EI: calcd for C43H44N2O7 [M+]: 700.3149; found: 700.3151.
1
Compound 2b: inseparable mixture of diastereomers (ratio = 1.2:1); yellow oil; H-NMR (400 MHz,
CD2Cl2) δ 0.84-1.24 (8H, m), 2.06-2.20 (2H, m), 5.14-5.20 (4H, m), 6.08 (12/11H, s), 6.23 (10/11H, s),
7.18-7.37 (20H, m); 13C-NMR (100 MHz, CD2Cl2) δ 8.1 (12/11C), 8.2 (10/11C), 8.4 (10/11C), 8.6
(12/11C), 8.7 (10/11C), 9.2 (12/11C), 68.8 (10/11C), 68.9 (12/11C), 70.1 (10/11C), 70.3 (12/11C), 114.2
(12/11C), 115.5 (10/11C), 127.1 (24/11C), 127.2 (20/11C), 128.3 (20/11C), 128.4 (24/11C), 128.5
(10/11C), 128.5 (12/11C), 128.7 (10/11C), 128.8 (12/11C), 128.9 (4C), 128.9 (20/11C), 128.9 (24/11C),
135.7 (2C), 140.1 (12/11C), 140.1 (10/11C), 157.2 (10/11C), 157.4 (12/11C), 162.7 (10/11C), 164.3
(12/11C), 181.9 (5/11C), 182.6 (6/11C); IR (KBr): 3033, 1732, 1624, 1596, 1456, 1392, 1306, 904, 750,
697 cm-1; HRMS-EI: calcd for C41H36N2O7 [M+]: 668.2523; found: 668.2523.
1
Compound 2c: inseparable mixture of diastereomers (ratio = 1:1); yellow oil; H-NMR (400 MHz,
CDCl3) δ 0.79 (3H, t, J = 7.2 Hz), 0.85 (3H, t, J = 7.2 Hz), 1.01-1.60 (8H, m), 2.33-2.57 (4H, m), 3.75
(3H, s), 3.76 (3H, s), 5.14-5.22 (4H, m), 5.84 (1H, s), 6.18 (1H, s), 6.72-6.74 (2H, m), 6.77-6.79 (2H, m),
13
7.07-7.09 (2H, m), 7.12-7.14 (2H, m), 7.26-7.36 (10H, m); C-NMR (100 MHz, CDCl3) δ 13.6 (1C),
13.7 (1C), 22.3 (1C), 22.4 (1C), 25.5 (1C), 25.7 (1C), 29.0 (1C), 29.1 (1C), 55.2 (1C), 55.2 (1C), 68.1
(1C), 68.5 (1C), 68.5 (1C), 68.7 (1C), 113.8 (1C), 114.0 (2C), 114.0 (2C), 114.4 (1C), 128.1 (4C),
128.1(2C), 128.4 (2C), 128.5 (2C), 128.5 (2C), 128.6 (2C), 131.4 (1C), 131.6 (1C), 135.2 (2C), 156.3
(1C), 156.4 (1C), 159.5 (1C), 159.5 (1C), 162.5 (1C), 162.6 (1C), 182.6 (1/2C), 183.0 (1/2C); IR (KBr):
2961, 1726, 1606, 1509, 1311, 1176, 1004, 1030, 741 cm-1; HRMS-EI: calcd for C45H48N2O9 [M+]:
760.3360; found: 760.3360.
Compound 2d: diastereomeric ratio = 1.5:1
major diastereomer: yellow oil; 1H-NMR (400 MHz, CDCl3) δ 0.85 (6H, t, J = 7.2 Hz), 1.19-1.28 (4H, m),
1.39-1.60 (4H, m), 2.44-2.48 (4H, m), 5.17 (2H, d, J = 12.0 Hz), 5.21 (2H, d, J = 12.0 Hz), 5.90 (2H, s),
13
6.91-6.97 (4H, m), 7.10-7.15 (4H, m), 7.26-7.36 (10H, m); C-NMR (100 MHz, CDCl3) δ 13.6 (2C),
2
22.4 (2C), 25.7 (2C), 29.0 (2C), 68.5 (2C), 68.7 (2C), 113.6 (2C), 115.6 (4C, d, JC-F = 20.9 Hz), 128.2
3
4
(4C), 128.5 (4C, d, JC- F = 8.6 Hz), 128.6 (6C), 135.0 (2C), 135.4 (2C, d, JC-F = 2.8 Hz), 156.3 (2C),
1
162.6 (2C, d, JC-F = 246.0 Hz), 162.9 (2C), 182.6 (1C); IR (KBr): 2965, 1728, 1608, 1507, 1386, 1306,
1224, 1100, 744 cm-1; HRMS-EI: calcd for C43H42N2O7F2 [M+]: 736.2960; found: 736.2964.
1
minor diastereomer: colorless solid, mp 111-112 ºC; H-NMR (400 MHz, CDCl3) δ 0.79 (6H, t, J = 7.2
Hz), 0.84-1.48 (8H, m), 2.30-2.38 (2H, m), 2.46-2.54 (2H, m), 5.16 (2H, d, J = 12.0 Hz), 5.21 (2H, d, J =
13
12.0 Hz), 6.20 (2H, s), 6.85-6.91 (4H, m), 7.16-7.29 (4H, m), 7.25-7.36 (10H, m); C-NMR (100 MHz,
CDCl3) δ 13.6 (2C), 22.3 (2C), 25.4 (2C), 28.9 (2C), 67.9 (2C), 68.7 (2C), 114.3 (2C), 115.6 (4C, d, 2JC-F
3
4
= 21.0 Hz), 128.2 (4C), 128.4 (4C, d, JC-F = 8.6 Hz), 128.6 (6C), 135.0 (2C), 135.2 (2C, d, JC-F = 2.9
1
Hz), 156.4 (2C), 162.4 (2C), 162.6 (2C, d, JC-F = 246.0 Hz), 182.2 (1C); IR (KBr): 2957, 1727, 1644,

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1605, 1509, 1391, 1225, 733 cm-1; HRMS-EI: calcd for C43H42N2O7F2 [M+]: 736.2960; found: 736.2959.
Compound 2e: diastereomeric ratio = 1.3:1
major diastereomer: colorless solid; mp 50-52 ºC; 1H-NMR (400 MHz, CDCl3) δ 0.79 (6H, t, J = 7.2 Hz),
0.87-1.47 (8H, m), 2.28-2.35 (2H, m), 2.43-2.50 (2H, m), 5.16 (2H, d, J = 12.0 Hz), 5.21 (2H, d, J = 12.0
13
Hz), 6.19 (2H, s), 7.12-7.34 (18H, m); C-NMR (100 MHz, CDCl3) δ 13.6 (2C), 22.3 (2C), 25.4 (2C),
29.0 (2C), 68.0 (2C), 68.7 (2C), 114.3 (2C), 127.9 (4C), 128.2 (4C), 128.6 (6C), 128.9 (4C), 134.2 (2C),
134.9 (2C), 137.9 (2C), 156.3 (2C), 162.3 (2C), 182.0 (1C); IR (KBr): 2960, 1726, 1594, 1492, 1305,
1390, 1217, 1090, 755 cm-1; HRMS-EI: calcd for C43H42N2O7Cl2 [M+]: 768.2369; found: 768.2366.
minor diastereomer: yellow oil; 1H-NMR (400 MHz, CDCl3) δ 0.84 (6H, t, J = 7.2 Hz), 1.18-1.26 (4H, m),
1.36-1.57 (4H, m), 2.42-2.46 (4H, m), 5.17 (2H, d, J = 12.0 Hz), 5.22 (2H, d, J = 12.0 Hz), 5.91 (2H, s),
13
7.07-7.11 (4H, m), 7.22-7.36 (14H, m); C-NMR (100 MHz, CDCl3) δ 13.6 (2C), 22.4 (2C), 25.7 (2C),
29.1 (2C), 68.5 (2C), 68.8 (2C), 113.5 (2C), 128.1 (4C), 128.2 (4C), 128.6 (4C), 128.6 (2C), 128.8 (4C),
134.2 (2C), 134.9 (2C), 138.0 (2C), 156.2 (2C), 163.0 (2C), 182.3 (1C); IR (KBr): 2959, 1727, 1605,
1493, 1386, 1092, 752, 697 cm-1; HRMS-EI: calcd for C43H42N2O7Cl2 [M+]: 768.2369; found: 768.2363.
1
Compound 2f: inseparable mixture of diastereomers (ratio = 2:1); colorless oil; H-NMR (400 MHz,
CDCl3) δ 0.80 (2H, t, J = 7.2 Hz), 0.85 (4H, t, J = 7.2 Hz), 1.10-1.63 (8H, m), 2.35-2.64 (4H, m),
5.14-5.23 (4H, m), 6.13 (4/3H, s), 6.51 (2/3H, s), 6.90-7.07 (4H, m), 7.15-7.35 (14H, m); 13C-NMR (100
MHz, CDCl3) δ 13.6 (4/3C), 13.7 (2/3C), 22.3 (2/3C), 22.4 (4/3C), 25.3 (2/3C), 25.6 (4/3C), 28.9 (4/3C),
3
3
28.9 (2/3), 63.7 (4/3C, d, JC-F = 2.9 Hz), 63.7(2/3C, d, JC-F = 2.9 Hz), 68.6 (2/3C), 68.6 (4/3C), 112.7
(4/3C), 113.4 (2/3C), 115.7 (4/3C, d, 2JC-F = 21.0 Hz), 115.8 (2/3C, d, 2JC-F = 21.0 Hz), 124.4 (2C, d, 4JC-F
2
= 2.9 Hz), 126.3 (2/3C, d, JC-F = 12.4 Hz), 126.6 (4/3C, d, 2JC-F = 12.4 Hz), 128.1 (4/3C), 128.2 (8/3C),
3
3
128.4 (2/3C ), 128.5 (4/3C ), 128.6 (4C ), 128.8 (4/3, d, JC-F = 3.8 Hz), 129.4 (2/3C, d, JC-F = 3.8 Hz),
3
3
130.1 (2/3C, d, JC-F = 8.6 Hz), 130.1 (4/3C, d, JC-F = 8.6 Hz), 135.0 (2C), 156.1 (2/3C), 156.2 (4/3C),
1
1
160.1 (4/3C, d, JC-F = 247.9 Hz), 160.3 (2/3C, d, JC-F = 247.9 Hz), 162.9 (2/3C), 163.0 (4/3C), 181.5
(1/3C), 182.1 (2/3C); IR (KBr): 2964, 1730, 1607, 1387, 1307, 1223, 1102, 897, 754 cm-1; HRMS-EI:
calcd for C43H42N2O7F2 [M+]: 736.2960; found: 736.2960.
Compound 2g: inseparable mixture of diastereomers (ratio = 2:1); colorless solid; mp 43-45 ºC;
1H-NMR (400 MHz, CDCl3) δ 2.15 (6H, s), 5.11-5.25 (4H, m), 6.22 (4/3H, s), 6.66 (2/3H, s), 7.05-7.34
(18H, m); 13C-NMR (100 MHz, CDCl3) δ 11.8 (2/3C), 11.8 (4/3C), 66.1 (4/3C), 66.5 (2/3C), 68.8 (2/3C),
68.9 (4/3C), 114.0 (4/3C), 114.6 (2/3C), 127.4 (2/3C), 127.6 (4/3C), 128.5 (4/3C), 128.6 (10/3C), 128.7
(8/3C), 128.7 (4/3C), 128.7 (4/3C), 129.2 (4/3C), 129.7 (2/3C), 129.8 (4/3C), 129.9 (4/3C), 129.9 (2/3C),
130.2 (2/3C), 132.8 (4/3C), 133.1 (2/3C), 135.1 (2/3C), 135.1 (4/3C), 136.2 (2/3C), 136.8 (4/3C), 155.6
(2/3C), 155.8 (4/3C), 159.1 (2/3C), 159.1 (4/3C), 181.4 (1/3C), 182.2 (2/3C); IR (KBr): 1741, 1603, 1390,
1317, 1218, 1099, 896, 751 cm-1; HRMS-EI: calcd for C37H30N2O7Cl2 [M+]: 684.1430; found: 684.1434.

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1
Compound 2h: inseparable mixture of diastereomers (ratio = 1.5:1); yellow oil; H-NMR (400 MHz,
CDCl3) δ 0.80 (12/5H, t, J = 7.2 Hz), 0.81 (18/5H, t, J = 7.2 Hz), 1.19-1.29 (4H, m), 1.42-1.58 (4H, m),
13
1.78-2.18 (4H, m), 2.37-2.74 (8H, m), 5.17-5.33 (6H, m), 7.07-7.37 (20H, m); C-NMR (100 MHz,
CDCl3) δ 13.6 (4/5C), 13.6 (6/5C), 22.3 (4/5C), 22.4 (6/5C), 25.7 (6/5C), 25.7 (4/5C), 29.0 (2C), 31.4
(2C), 36.8 (4/5C), 37.2 (6/5C), 65.9 (6/5C), 66.9 (4/5C), 68.7 (2C), 113.5 (4/5C), 113.6 (6/5C), 125.9
(6/5C), 125.9 (4/5C), 128.3 (8/5C), 128.3 (6C), 128.3 (8/5C), 128.4 (16/5C), 128.6 (8/5C), 128,7 (4C),
135.1 (2C), 141.1 (6/5C), 141.3 (4/5C), 157.9 (4/5C), 158.0 (6/5C), 163.9 (6/5C), 164.2 (4/5C), 182.7
(3/5C), 183.4 (2/5C); IR (KBr): 2958, 1722, 1600, 1385, 1308, 1105, 1036, 744, 697 cm-1; HRMS-EI:
calcd for C47H52N2O7 [M+]: 756.3775; found: 756.3772.
1
Compound 2i: inseparable mixture of diastereomers (ratio = 3:1); yellow amorphous; H-NMR (400
MHz, CDCl3) δ 2.34 (9/2H, s), 2.36 (3/2H, s), 5.06-5.22 (4H, m), 6.08 (3/2, s), 6.22 (1/2H, s), 6.95-7.04
13
(8H, m), 7.23-7.35(20H, m); C-NMR (100 MHz, CDCl3) δ 21.6 (2C), 68.3 (1/2C), 68.4 (3/2C), 70.3
(3/2C), 70.4 (1/2C), 112.2 (3/2C), 112.5 (1/2C), 122.6 (3/2C), 122.7 (1/2C), 127.0 (3C), 127.3 (1C), 127.9
(3C), 128.2 (1/2C), 128.3 (3/2C), 128.4 (1/2C), 128.5 (5/2C), 128.5 (1C), 128.6 (4C), 128.6 (3C), 128.8
(1C), 128.9 (3C), 129.1 (3C), 129.1 (1C), 135.1 (1/2C), 135.2 (3/2C), 138.9 (1/2C), 139.2 (3/2C), 141.8
(1/2C), 142.0 (3/2C), 155.9 (1/2C), 156.2 (3/2C), 158.8 (1/2C), 159.1 (3/2C), 182.0 (1/4C), 182.4 (3/4C);
IR (KBr): 3033, 1724, 1607, 1508, 1386, 1307, 1104, 744, 697 cm-1; HRMS-ESI: C49H41N2O7 [M+H]+:
769.2914; found: 769.2883.
Typical
hydroxy(1-phenylhept-2-yn-1-yl)carbamate (1a): condition B
30 mL two-necked round-bottom flask containing
procedure
for
the
cyclization–carbonylation
reaction
of
benzyl
A
a
magnetic stir bar, benzyl
hydroxy(1-phenylhept-2-yn-1-yl)carbamate (1a) (100 mg, 0.40 mmol), p-benzoquinone (64.9 mg, 0.60
mmol), and MeOH/DMSO = 5/1 (5 mL) was fitted with a rubber septum and a three-way stopcock
connected to a balloon filled with carbon monoxide. The apparatus was purged with carbon monoxide by
pump-filling via the three-way stopcock. A MeOH/DMSO = 5/1 (1 mL) solution of Pd(tfa)2 (6.6 mg, 0.02
mmol) was added to the stirred solution using a syringe at 0 °C. The remaining Pd(tfa)2 was washed in
MeOH/DMSO = 5/1 (1 mL) twice and stirred for 72 h at 0 °C. The mixture was diluted with CH2Cl2 (40
mL) and washed with 5% a.q. NaOH (40 mL). The aqueous layer was extracted with CH2Cl2 (20 mL) and
the combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude product was
purified by column chromatography on silica gel. The fraction eluted with hexane–AcOEt (50/1) afforded
monomeric ester 3a.
Compound 3a: colorless oil; 1H-NMR (400 MHz, CDCl3) δ 0.94 (3H, t, J = 7.2 Hz), 1.38-1.47 (2H, m),
1.64-1.69 (2H, m), 2.79-2.83 (2H, m), 3.60 (3H, s), 5.21 (2H, s), 6.08 (1H, s), 7.26-7.36 (10H, m);

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13C-NMR (100 MHz, CDCl3) δ 13.7, 22.4, 25.4, 29.1, 51.2, 68.0, 68.5, 104.3, 127.2 (2C), 128.2 (2C),
128.2, 128.5, 128.5 (2C), 128.6 (2C), 135.2, 139.9, 156.4, 163.4, 167.0; IR (KBr): 2957, 1714, 1658,
1223, 1113, 1031, 695 cm-1; HRMS-EI: calcd for C23H25NO5 [M+]: 395.1733; found: 395.1732.
1
Compound 3b: colorless solid; mp 120-122 ºC; H-NMR (400 MHz, CDCl3) δ 1.03-1.31 (4H, m),
13
2.71-2.76 (1H, m), 3.63 (3H, s), 5.19 (2H, s), 6.09 (1H, s), 7.30-7.36 (10H, m); C-NMR (100 MHz,
CDCl3) δ 7.8, 7.9, 9.0, 51.2, 68.6, 68.6, 104.2, 127.1 (2C), 128.1, 128.2 (2C), 128.5 (2C), 128.5 (2C),
128.6, 135.2, 139.9, 156.9, 164.1, 167.6; IR (KBr): 1712, 1643, 1335, 1122, 1055, 700 cm-1; HRMS-EI:
calcd for C22H21NO5 [M+]: 379.1420; found: 379.1422.
Compound 3c: colorless oil; 1H-NMR (400 MHz, CDCl3) δ 0.94 (3H, t, J = 7.6 Hz), 1.38-1.47 (2H, m),
1.61-1.71 (2H, m), 2.78-2.82 (2H, m), 3.60 (3H, s), 3.79 (3H, s), 5.21 (2H, s), 6.04 (1H, s), 6.84-6.86 (2H,
m), 7.24-7.33 (7H, m); 13C-NMR (100 MHz, CDCl3) δ 13.7, 22.4, 25.4, 29.1, 51.2, 55.3, 67.6, 68.5, 104.3,
113.9 (2C), 128.2 (2C), 128.4 (2C), 128.4, 128.5 (2C), 132.1, 135.2, 156.4, 159.5, 163.5, 166.8; IR (KBr):
2956, 1714, 1658, 1512, 1248, 1227, 1113, 1033, 697 cm-1; HRMS-EI: calcd for C24H27NO6 [M+]:
425.1838; found: 425.1838.
Compound 3d: colorless oil; 1H-NMR (400 MHz, CDCl3) δ 0.94 (3H, t, J = 7.6 Hz), 1.37-1.46 (2H, m),
1.63-1.71 (2H, m), 2.78-2.82 (2H, m), 3.60 (3H, s), 5.21 (2H, s), 6.06 (1H, s), 6.98-7.02 (2H, m),
13
7.31-7.34 (7H, m); C-NMR (100 MHz, CDCl3) δ 13.7, 22.4, 25.4, 29.1, 51.3, 67.4, 68.6, 104.1, 115.4
2
3
(2C, d, JC-F = 21.0 Hz), 128.3 (2C), 128.6 (2C, d, JC-F = 5.7 Hz), 128.9, 129.0 (2C), 135.1, 135.8 (d,
4JC-F = 3.8 Hz), 156.3, 162.6 (d, 1JC-F = 245.0 Hz), 163.3, 167.0; IR (KBr): 2958, 1717, 1655, 1510, 1227,
1114, 674 cm-1; HRMS-EI: calcd for C23H24NO5F [M+]: 413.1638; found: 413.1638.
Compound 3e: colorless oil; 1H-NMR (400 MHz, CDCl3) δ 0.93 (3H, t, J = 7.2 Hz), 1.37-1.46 (2H, m),
1.62-1.70 (2H, m), 2.77-2.83 (2H, m), 3.61 (3H, s), 5.21 (2H, s), 6.04 (1H, s), 7.26-7.36 (9H, m);
13C-NMR (100 MHz, CDCl3) δ 13.7, 22.4, 25.4, 29.1, 51.3, 67.4, 68.7, 104.0, 128.3 (2C), 128.5 (2C),
128.6 (3C), 128.7 (2C), 134.0, 135.0, 138.5, 156.2, 163.2, 167.1; IR (KBr): 2957, 1717, 1658, 1345, 1222,
1113, 1032, 697 cm-1; HRMS-EI: calcd for C23H24NO5Cl [M+]: 429.1343; found:429.1345.
Compound 3f: colorless oil; 1H-NMR (400 MHz, CDCl3) δ 0.94 (3H, t, J = 7.2 Hz), 1.38-1.48 (2H, m),
1.62-1.72 (2H, m), 2.79-2.84 (2H, m), 3.59 (3H, s), 5.21 (2H, s), 6.39 (1H, s), 7.00-7.13 (2H, m),
13
3’
7.26-7.33 (7H, m); C-NMR (100 MHz, CDCl3) δ 13.7, 22.4, 25.4, 29.0, 51.3, 62.3 (d, JC-F = 3.9 Hz),
2
3
2
68.5, 103.3, 115.7 (d, JC-F = 21.9 Hz), 124.3 (d, JC-F = 3.8 Hz), 127.0 (d, JC-F = 12.4 Hz), 128.2 (2C),
4
3
128.4, 128.5 (2C), 129.1 (d, JC-F = 3.8 Hz), 130.0 (d, JC-F = 8.6 Hz), 135.2, 156.0, 160.5, 163.2, 167.4;
IR (KBr): 2957, 1715, 1659, 1222, 1114, 1035, 757 cm-1; HRMS-EI: calcd for C23H24NO5F [M+]:
413.1638; found: 413.1640.
Compound 3g: colorless solid; mp 163-164 ºC; 1H-NMR (400 MHz, CDCl3) δ 2.39 (3H, d, J = 1.2 Hz),
3.59 (3H, s), 5.15 (1H, d, J = 12.0 Hz), 5.22 (1H, d, J = 12.0 Hz), 6.59 (1H, d, J = 1.2 Hz), 7.20-7.33 (9H,

HETEROCYCLES, Vol. 93, No. 2, 2016
525
13
m); C-NMR (100 MHz, CDCl3) δ 11.6, 51.3, 64.8, 68.6, 104.8, 127.2, 128.4 (2C), 128.5, 128.5 (2C),
129.3, 129.4, 129.7, 133.4, 135.0, 137.2, 155.4, 163.1, 163.2; IR (KBr): 2952, 1719, 1655, 1405, 1337,
1230, 1119, 750, 701 cm-1; HRMS-EI: calcd for C20H18NO5Cl [M+]: 387.0873; found: 387.0874.
1
Compound 3h: yellow oil; H-NMR (400 MHz, CDCl3) δ 0.90 (3H, t, J = 7.6 Hz), 1.32-1.41 (2H, m),
1.54-1.61 (2H, m), 1.88-1.97 (1H, m), 2.11-2.18 (1H, m), 2.67-2.80 (4H, m), 3.71(3H, s), 5.20-5.30 (3H,
m), 7.16-7.39 (10H, m); 13C-NMR (100 MHz, CDCl3) δ 13.7, 22.3, 25.4, 29.0, 31.1, 35.9, 51.3, 65.4, 68.6,
103.3, 125.8, 128.3 (4C), 128.4 (2C), 128.5, 128.6 (2C), 135.2, 141.6, 158.0, 163.7, 168.0; IR (KBr):
2955, 1716, 1658, 1373, 1310, 1215, 1111, 1034, 698 cm-1; HRMS-EI: calcd for C25H29NO5 [M+]:
423.2046; found: 423.2048.
Compound 3i : colorless oil; 1H-NMR (400 MHz, CDCl3) δ 2.41 (3H, s), 3.59 (3H, s), 5.27 (2H, s), 6.30
13
(1H, s), 7.24-7.26 (2H, m), 7.31-7.37 (8H, m), 7.44-7.46 (2H, m), 7.80-7.82 (2H, m); C-NMR (100
MHz, CDCl3) δ 21.7, 51.4, 68.7, 69.3, 103.8, 122.6, 127.2 (2C), 128.2 (2C), 128.3, 128.5 (2C), 128.6
(3C), 128.8 (2C), 130.0 (2C), 135.2, 139.9, 142.4, 157.1, 162.1, 163.0; IR (KBr): 3033, 1718, 1640, 1232,
1084, 821, 753, 698 cm-1; HRMS-EI: calcd for C26H23NO5 [M+]: 429.1576; found: 429.1576.
Preparation of bis(5-butyl-3-phenylisoxazol-4-yl)methanone (4a)
To a solution of 2a (91.7 mg, 0.131 mmol) in THF/MeOH/H2O = 4/1/1 (3 mL) was added LiOH·H2O
(33.0 mg, 0.786 mmol), and the mixture was stirred at rt. After 20 min, the mixture was neutralized with
5% a.q. citric acid. Sodium hypochlorite solution (0.5 mL) was then added to the mixture at rt, and stirred
for 20 min. The mixture was diluted with CH2Cl2 (20 mL) and 10% a.q. Na2S2O3 (20 mL). The organic
layer was separated, the aqueous layer was extracted with CH2Cl2 (20 mL) twice, and the combined
organic layers were dried over MgSO4 and concentrated in vacuo. The crude product was purified by
flash chromatography. The fraction eluted with hexane/AcOEt (20/1-4/1) afforded 4a (22.7 mg, 49%, 2
1
steps). Yellow oil; H-NMR (400 MHz, CDCl3) δ 0.97 (6H, t, J =7.6 Hz), 1.38-1.47 (4H, m), 1.71-1.79
13
(4H, m), 2.89-2.93 (4H, m), 7.15-7.17 (4H, m), 7.26-7.30 (4H, m), 7.36-7.40 (2H, m); C-NMR (100
MHz, CDCl3) δ 13.7 (2C), 22.5 (2C), 26.6 (2C), 29.3 (2C), 116.6 (2C), 127.2 (2C), 128.2 (4C), 128.8
(4C), 130.1 (2C), 160.9 (2C), 177.8 (2C), 183.2; IR (KBr): 2960, 1652, 1590, 1570, 1410, 886, 768, 697
cm-1; HRMS-EI: calcd for C27H28N2O3 [M+]: 428.2100; found: 428.2102.
Preparation of methyl 3-(2-chlorophenyl)-5-methylisoxazole-4-carboxylate (5g)
To a solution of 3g (115.9 mg, 0.299 mmol) in THF/MeOH/H2O = 4/1/1 (9 mL) was added LiOH·H2O
(37.6 mg, 0.897 mmol), and the mixture was stirred at rt. After 20 min, the mixture was neutralized with
5% a.q. citric acid. Sodium hypochlorite solution (0.5 mL) was then added to the mixture at rt, and stirred
for 20 min. The mixture was diluted with CH2Cl2 (20 mL) and 10% a.q. Na2S2O3 (20 mL). The organic

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HETEROCYCLES, Vol. 93, No. 2, 2016
layer was separated, the aqueous layer was extracted with CH2Cl2 (20 mL) twice, and the combined
organic layers were dried over MgSO4 and concentrated in vacuo. The crude product was purified by
flash chromatography. The fraction eluted with hexane/AcOEt (20/1-4/1) afforded 5g (64.4 mg, 86%, 2
1
steps). Colorless solid; mp 58-59 ºC. (lit.18 mp 58-59 ºC); H-NMR (400 MHz, CDCl3) δ 2.76 (3H, s),
13
3.70 (3H, s), 7.35-7.47 (4H, m); C-NMR (100 MHz, CDCl3) δ 13.3, 51.7, 109.7, 126.6, 128.4, 129.4,
130.9, 130.9, 134.0, 160.8, 162.1, 175.2; IR (KBr):1728, 1607, 1450, 1318, 1107, 762 cm-1;
HRMS-APCI: calcd for C12H11ClNO3 [M+H]+: 252.0428; found: 252.0437.
ACKNOWLEDGEMENTS
This work was supported by a JSPS KAKENHI grant (No.15K078771).
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