Iodocyclization of hydroxylamine derivatives based on the control of oxidative aromatization leading to 2,5-dihydroisoxazoles and isoxazoles

Article abstract of DOI:10.1021/jo200407b

An efficient method for the synthesis of 2,5-dihydroisoxazoles and isoxazoles using iodocyclization of N-alkoxycarbonyl O-propargylic hydroxylamines has been developed. 2,5-Dihydro-4-iodoisoxazole underwent the cross-coupling reactions without aromatization to afford polyfunctionalized 2,5-dihydroisoxazoles. This process was applied to the preparation of valdecoxib and its 2,5-dihydro-derivative.

Full text of DOI:10.1021/jo200407b

ARTICLE
pubs.acs.org/joc
Iodocyclization of Hydroxylamine Derivatives Based on the Control
of Oxidative Aromatization Leading to 2,5-Dihydroisoxazoles
and Isoxazoles
Takashi Okitsu, Kana Sato, Taterao M. Potewar, and Akimori Wada*
Department of Organic Chemistry for Life Science, Kobe Pharmaceutical University, 4-19-1, Motoyamakita-machi, Higashinada-ku,
Kobe 658-8558, Japan
S Supporting Information
b
ABSTRACT: An efficient method for the synthesis of 2,5-
dihydroisoxazoles and isoxazoles using iodocyclization of N-alko-
xycarbonyl O-propargylic hydroxylamines has been developed.
2,5-Dihydro-4-iodoisoxazole underwent the cross-coupling reac-
tions without aromatization to afford polyfunctionalized 2,5-
dihydroisoxazoles. This process was applied to the preparation
of valdecoxib and its 2,5-dihydro-derivative.
Scheme 1. Previous Method for the Synthesis of Isoxazoles
and 2,5-Dihydroisoxazoles by Iodocyclization
’ INTRODUCTION
Isoxazoles and their dihydro-derivatives are well-known to
possess widespread biological activities.1,2 Due to their attractive
properties, numerous synthetic approaches for the construction
of the isoxazole framework have been reported.3 Although the
preparation of 2,3- and 4,5-dihydroisoxazoles has been well
established,4 that of 2,5-dihydoroisoxazoles (3-isoxazolines) is
rare and only monosubstituted variants have been synthesized.5
Therefore, alternative methods for the preparation of polysub-
stituted 2,5-dihydroisoxazoles are desirable.
Iodocyclization, one of the most useful methods for the
construction of functionalized ring systems,6,7 creates cyclic
architectures along with an iodo-functionality in the same mole-
cule so that the reaction products can undergo further transfor-
mations. Iodine reagents have recently attracted much attention
by organic chemists due to their environmentally friendly proper-
ties and low cost as applied toward eco-technologies.
Larock and colleagues reported an efficient synthesis of
4-iodoisoxazoles via iodocyclization from 2-alkyn-1-one O-methyl
oximes (Scheme 1, eq 1).8 The requisite 2-alkyn-1-one required for
their methodology can be readily synthesized, and demonstrated
iodocyclizations proceeded in mild conditions. Recently, Knight
and co-workers presented an elegant approach toward 2,5-dihydro-
4-iodoisoxazoles by iodocyclization of O-propargylic N-tosyl hy-
droxylamines (Scheme 1, eq 2).9 During the palladium-catalyzed
coupling reactions toward the iodine atom bonded to an sp2-
carbon, N-tosyl-2,5-dihydroisoxazoles were easily aromatized to
isoxazoles along with the elimination of the p-tosyl group due to
their basic conditions. Therefore, this method could be adapted to
the construction of a compound library of isoxazoles, however,
that of 2,5-dihydro-derivatives has not been achieved yet.
Consequently, we sought an efficient approach to both iso-
xazoles and dihydroisoxazoles with enhanced potential for
functionalizaions.
We recently reported a switchable access to 2,5-dihydropyr-
azoles and pyrazoles through the iodocyclization of propargylic
hydrazides as common substrates (Scheme 2, eq 1).10 Our
methodology is based on the control of oxidative aromatization
by the iodocyclization reaction conditions so that diverse ap-
proaches to the desired cyclic compounds are allowed.11 We
thought that this strategy could be adapted to other substrates if
appropriate precursors and reaction conditions for cyclization
were designed. Herein we wish to report an iodocyclization of
N-alkoxycarbonyl O-propargylic hydroxylamine derivatives lead-
ing to 2,5-dihydroisoxazoles and isoxazoles in connection with our
recent explorations of the 5-endo-dig type iodocyclizations
(Scheme 2, eq 2).12 Our developed strategy have some advantages
over previous method: first, switchable access to 2,5-dihydroisox-
azole and isoxazole was enabled, second, the cross-coupling
Received: February 23, 2011
Published: March 30, 2011
r
2011 American Chemical Society
3438
dx.doi.org/10.1021/jo200407b J. Org. Chem. 2011, 76, 3438–3449
|

The Journal of Organic Chemistry
ARTICLE
Scheme 2. Our Strategy for the Synthesis of Isoxazole and 2,5-Dihydroisoxazole by Iodocyclization
Scheme 3. Preparation of the Precursors
Table 2. Optimization of Carbamate Groups
entry substrate
R
conditiona time (min) product yield (%)
1
2
1a
1b
1c
1d
1e
1a
1b
1c
1d
1e
Bn
A
A
A
A
A
B
B
B
B
B
30
30
30
30
20
15
20
20
15
15
2a
2b
2c
2d
2e
3a
3a
3a
3a
3a
97
<29b
87
Et
3
i-Pr
t-Bu
Fmc
Bn
4
67
Table 1. Optimization of Reaction Conditionsa
5
94
6
48
7
Et
56
8
9
i-Pr
t-Bu
Fmc
63
57
10
38
a Condition A: I(coll)2PF6 (1.5 equiv), CH2Cl2 (0.1 M), rt; Condition
B: NIS (2.5 equiv), BF3 OEt2 (2.5 equiv), CH2Cl2 (0.1 M), 0 °C.
3
b Product 2b was unstable. c Fm = 9-fluorenylmethyl.
yield (%)
entry [Iþ] source (equiv) additiveb T (°C) time (min) 2a
3a
from propargylic alcohols (Scheme 3).13 In brief, the respective
four steps comprising bromination of propargylic alcohols, O-
alkylation of N-hydroxyphthalimide, removal of phthalimide, and
protection of the nitrogen atom by carbamate were performed to
give 1 in good yields.
We first scrutinized the reaction of 1a toward the iodinating
reagents (Table 1). According to our previous work,10 bis(2,4,6-
collidine)iodonium(I) hexafluorophosphate [I(coll)2PF6]14 was
examined as the first choice for an iodinating reagent to give 2,5-
dihydroisoxazole 2a in excellent yield (entry 1). I(coll)2PF6 (1.5
equiv) alone was sufficient for the synthesis of 2a, and the use of an
1
2
3
4
5
6
7
8
I(coll)2PF6 (1.5) none
rt
rt
rt
rt
rt
0
30
15
97
90
35
69
0
0
0
I(coll)2PF6 (2.5) none
I(coll)2PF6 (2.5) BF3 OEt2
60
9
3
NIS (2.5)
NIS (2.5)
NIS (2.5)
I2 (2.5)
none
60
0
BF3 OEt2
15
39
48
43
21
3
BF3 OEt2
15
120
15
0
3
NaHCO3
rt
0
ICl (2.5)
none
rt
0
a Reaction was performed in CH2Cl2 (0.1 M) under argon atmosphere.
b Equivalents of additive are the same as that of [Iþ].
activator of the iodinating reagent such as BF3 OEt2 or N-iodosucci-
nimide (NIS) in place of I(coll)2PF6 caused a diminishment of the
3
reactions of2,5-dihydro-4-iodoisoxazoles wereunderwent without
aromatization to afford polyfunctionalized 2,5-dihydroisoxazoles.
This process was applied to the preparation of valdecoxib and its
2,5-dihydro-derivatives.
yields of 2a (entries 2ꢀ4). Notably, the combination of NIS/
BF3 OEt2 afforded isoxazole 3a as the sole product in moderate
3
yield (entry 5). When the reaction temperature was decreased to 0 °C,
the yield of 3a improved to 48% (entry 6). We examined other
iodinating reagents, but lower yields of 3a were observed (entries 7, 8).
Next, we investigated the effect of the carbamate groups
(Table 2). Among the carbamate groups, benzyloxycarbonyl
(Cbz, R = Bn) was the most suitable for the synthesis of
’ RESULTS AND DISCUSSION
The N-alkoxycarbonyl O-propargylic hydroxylamines 1 re-
quired for our studies were prepared in the four-step sequence
3439
dx.doi.org/10.1021/jo200407b |J. Org. Chem. 2011, 76, 3438–3449

The Journal of Organic Chemistry
ARTICLE
Table 3. Synthesis of 2,5-Dihydroisoxazole 2 by Iodocycli-
zation of 1a
Table 4. Synthesis of Isoxazole 3 by Iodocyclization of 1a
substrate
R1
R2 time (min) product yield (%)
substrate
entry
1
1
1s
1t
o-MeC6H4
H
H
H
H
H
H
H
H
H
H
H
H
Me
15
15
15
15
15
45
45
45
30
15
15
30
15
3s
71
59
80
58
70
50
71
62
79
45
66
53b
96
entry
1
R1
R2 time (min) product yield (%)
2
p-MeC6H4
3t
1
1f
1g
1h
1i
o-MeC6H4
H
H
H
H
H
H
H
H
H
H
H
H
Me
20
20
20
20
20
20
20
30
20
30
20
30
20
2f
93
89
3
1u
1v
1w
1x
1y
1z
o-MeOC6H4
m-MeOC6H4
p-MeOC6H4
o-NO2C6H4
m-NO2C6H4
p-NO2C6H4
3u
2
p-MeC6H4
2g
2h
2i
4
3v
3
o-MeOC6H4
m-MeOC6H4
p-MeOC6H4
o-NO2C6H4
m-NO2C6H4
95
5
3w
3x
4
98
6
5
1j
2j
80
7
3y
6
1k
1l
2k
2l
75
8
3z
7
81
9
1aa 1-naphthyl
1ab 2-thienyl
1ac 1-cyclohexenyl
1ad n-Bu
3aa
3ab
3ac
3ad
3ae
8
1m p-NO2C6H4
2m
2n
2o
2p
2q
2r
87
10
11
12
13
9
1n
1o
1p
1q
1r
1-naphthyl
2-thienyl
1-cyclohexenyl
n-Bu
95
10
11
12
13
96
80
1ae Ph
94
<96b
a Conditions: NIS (2.5 equiv), BF3 OEt2 (2.5 equiv), CH2Cl2 (0.1 M),
3
Ph
0 °C. b Product 3ad0 was also obtained in 16% yield and could not be
separated from 3ad.
a Conditions: I(coll)2PF6 (2 equiv), CH2Cl2 (0.1 M), rt. b Product 2r
was unstable.
2,5-dihydroisoxazole 2 under condition A (I(coll)2PF6, CH2Cl2, rt;
entries 1ꢀ5). In contrast, isopropyloxycarbonyl (R = iPr) was the
best choice for producing isoxazole 3 under condition B (NIS,
BF3 OEt2, CH2Cl2, 0 °C; entries 6ꢀ10).
3
Once the optimized conditions and N-protecting groups were
established as in entries 1 and 8 (Table 2), various substrates were
examined. The transformations from N-benzyloxycarbonyl O-pro-
pargylic hydroxylamines 1fꢀr to 2,5-dihydroisoxazoles 2fꢀr are
summarized in Table 3. Our investigated conditions permitted a
variety of substituents R1 on the alkyne to afford the corresponding
cyclized products in high yields. The presence of electron-donating
or withdrawing substituents on the aromatic core did not influence
the iodocyclizations (entries 1ꢀ9). As other sp2-carbon centers for
the substituent on the alkyne, heteroaromatic and vinylic groups
were allowed (entries 10ꢀ11). It is noteworthy that alkyl- (sp3
carbon center) substituted alkyne 1q was also applicable in these
conditions (entry 12). In addition, the iodocyclization proceeded in
the presence of substituent R2 at the propargylic position, however,
cyclized product 2r was unstable and slowly decomposed (entry
13). To our delight, N-isopropyloxycarbonyl O-propargylic hydro-
xylamines 1sꢀae, analogs of 1fꢀr, also behaved as applicable
substrates for the construction of isoxazoles 3sꢀae (Table 4).
Compounds 1sꢀae cleanly underwent electrophilic cyclization to
provide the respective products 3sꢀae in moderate to good yields.
The presence of a nitro group on the aromatic core substituted at the
alkynes required prolongation of reaction time to consume the
substrates 1xꢀz (entries 6ꢀ8, Table 4). Although iodocyclization
of n-butyl-substituted alkyne 1ad afforded 3ad in 53% yield, further
iodinated product 3ad0 was formed in 16% yield as inseparable
mixture from 3ad (entry 12).
Scheme 4. Halonium Ion-Mediated Oxidation of 2,5-Dihy-
droisoxazole 2a to Isoxazole 3a and 4a
isoxazole 3a in 51% yield (Scheme 4). This result indicated that
the formation of isoxazole 3 from precursor 1 underwent via 2,5-
dihydroisoxazole 2. To understand precise mechanism of oxida-
tive aromatization, we next examined the treatment of 2a with the
N-bromosuccinimide (NBS)/BF3 OEt2 combination instead of
3
NIS to afford 4-bromoisoxazole 4a accompanied with 3a in low
yields due to its dirty reaction. However, this observation
suggested that isoxazole 3 was formed via electrophilic addition
of halonium ion to 2,5-dihydroisoxazole 2.
Based on the outcomes of these reactions, we devised a plausible
reaction mechanism for the iodocyclization (Scheme 5). The
electrophilic 5-endo-dig cyclization of iodonium ion A gives dihy-
droisoxazole 2. When more acidic conditions, NIS/BF3 OEt2
3
To clarify the reaction mechanism, 2,5-dihydroisoxazole 2a
system, are employed, more reactive Iþ species react on the π
CꢀC double bond of the enecarbamate moiety to produce
was treated with the combine reagent NIS/BF3 OEt2 to afford
3
3440
dx.doi.org/10.1021/jo200407b |J. Org. Chem. 2011, 76, 3438–3449

The Journal of Organic Chemistry
ARTICLE
Scheme 5. Plausible Reaction Mechanism
iodonium ion B. The ring-opening of B followed by elimination of
HI from C affords N-alkoxycarbonyl isoxazolium ion D. Finally,
H2O-workup would cause hydrolysis to obtain isoxazole 3. We
considered that I(coll)2PF6 or NIS alone, weak iodonium sources,
could not react with enecarbamate group of 2 so that their
conditions afforded 2 as a sole product (Table 1, entries 1ꢀ6).
As discussed above, preparing substituted 2,5-dihydroisoxa-
zoles was a challenging process due to the scope of substrates5 or
their tendency to easily oxidize to isoxazoles under cross-
coupling conditions.9 This rare class of heterocycles, the 2,5-
dihydroisoxazoles, would be attractive for drug discovery, so we
attempted the functionalization at the CꢀI bond of 2a by using
three palladium-catalyzed CꢀC bond forming reactions
(Scheme 6). We performed Sonogashira coupling,15 Suzukiꢀ
Miyaura cross-coupling,16 and MizorokiꢀHeck reaction17 to
afford the respective carbo-skeleton-assembled 2,5-dihydroi-
soxazoles 5, 6, and 7 in good yields without aromatization.
Particularly, the Cbz group of 2a was well tolerated under these
conditions to prevent the 2,5-dihydroisoxazole from aromatizing.
In addition, the unstable 2r could also use in subsequent
reaction to obtain polysubstituted 2,5-dihydroisoxazole 8 as the
stable product in 52% yield from 1r for two steps (Scheme 7).
With the general approach for the highly functionalized
isoxazoles, the application of this method to the switchable
synthesis of valdecoxib (9) and its 2,5-dihydro-derivative 10
was next examined (Scheme 8). Valdecoxib is a cyclooxigenase-2
(COX-2) selective inhibitor and was used for a nonsteroidal anti-
inflammatory drug (NSAID) to treat osteoarthritis, rheumatoid
Scheme 6. Transformation of 2,5-Dihydroisoxazole 2a
Scheme 7. Two-Step Preparation of Polysubstituted 2,5-Dihydroisoxazole 8
Scheme 8. Synthesis of Valdecoxib (9) and its 2,5-Dihydro Derivative 10
3441
dx.doi.org/10.1021/jo200407b |J. Org. Chem. 2011, 76, 3438–3449

The Journal of Organic Chemistry
ARTICLE
arthritis, and painful menstruation.18 Valdecoxib (9) was easily
accessed from N-isopropyloxycarbonyl-O-propargylic hydroxy-
solution of 2% H2SO4 (17 mL/mol), added CH2Cl2 (4.4 mL/mol), and
stirred for 15ꢀ20 min. The mixture was filtered through a short Celite pad
to remove the precipitate and the filter cake was washed with an aqueous
solution of 2% H2SO4. The filtrate was extracted with CH2Cl2 and the
remaining aqueous layer was neutralized with the addition of crystals
NaHCO3. The neutralized aqueous solution was then again extracted with
CH2Cl2 and the combined organic layer was dried over Na2SO4 and
evaporated in vacuo. The residue was purified by flash column chroma-
tography on silica gel to give O-propargylic hydroxylamine. Step 3:
According to literature,22 NaHCO3 (2 equiv) was added to a solution of
O-propargylic hydroxylamine (1 equiv) in 1,4-dioxane/H2O (1/1; 0.17
M) at rt and the mixture was stirred for 30 min. Then, alkyl chloroformate
orBoc2O (1.2 equiv) was added dropwise and stirred for 1 h. After reaction
completed, the mixture was evaporated to its half volume in vacuo. The
mixture was diluted with water and extracted with AcOEt. The organic
layer was dried over Na2SO4, filtered and evaporated in vacuo. The residue
was purified by flash column chromatography on silica gel to give N-
alkoxycarbonyl O-propargylic hydroxylamine 1.
lamine 1ae in two steps; NIS/BF3 OEt2-mediated tandem
3
iodocyclization/oxidation process of 1ae produced isoxazole
3ae in 96% yield, and subsequent Suzuki-Miyaura cross-
coupling16 with commercially available 4-sulphamoylbenzene-
boronic acid afforded valdecoxib (9) in 54% yield. Similarly, N-
Cbz-2,5-dihydro-vardecoxib (10) was synthesized in 40% overall
yield from the precursor 1r by I(coll)2PF6-promoted electro-
philic iodocyclization and palladium-catalyzed cross-coupling
sequence. As our methodology allowed not only the substituent
diversity but also the choice of skeleton, a wide variety of analogs
of valdecoxib (9) could be provided.
’ CONCLUSION
In summary, we developed an alternative method for the
preparation of 2,5-dihydroisoxazoles and isoxazoles by iodocy-
clization of N-alkoxycarbonyl O-propargylic hydroxylamines.
Our strategy takes advantage of the dual nature of iodine as both
an iodinating and an oxidizing agent. Therefore, the control of
the oxidative aromatization by the reaction conditions enabled
‘product switch’ and enhanced the flexibility of the synthetic
route. In addition, the iodo moiety of the cyclized product 2
could create a variety of 2,5-dihydroisoxazoles, which may be
difficult to prepare by other reported methods. As our metho-
dology could be applied for the synthesis of valdecoxib and its
2,5-dihydro-analog, this research would be a valuable tool for
drug discovery.
Benzyl(3-phenyl-2-propynyl)oxycarbamate (1a). According to step
2, O-(3-phenyl-2-propynyl)hydroxylamine (2.16 g, 71% in 2 steps) was
obtained from 3-bromo-1-phenyl-1-propyne20 (4.00 g, 20.5 mmol).
Eluent: hexane/Et2O = 1/1. Colorless oil; IR νmax: 3331, 3018,
1580 cmꢀ1
;
1H NMR (300 MHz, CDCl3) δ 7.48ꢀ7.45 (m, 2H),
7.32ꢀ7.28 (m, 3H), 5.62 (br s, 2H), 4.53 (s, 2H); 13C NMR (75 MHz,
CDCl3) δ 131.2, 128.4, 128.2, 122.4, 86.2, 84.7, 64.0; EI-HRMS calcd for
C9H9NO (Mþ) 147.0684. Found 147.0679. According to step 3, 1a (185
mg, 96%) was obtained from O-(3-phenyl-2-propynyl)hydroxylamine
(100 mg, 0.679 mmol). Eluent: hexane/Et2O = 3/2. Colorless crystals;
mp 82ꢀ83 °C (hexane/CH2Cl2); IR νmax: 3384, 3023, 2958, 1748,
1599 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.63 (br s, 1H), 7.45ꢀ7.42
(m, 2H), 7.37ꢀ7.30 (m, 8H), 5.21 (s, 2H), 4.72 (s, 2H); 13C NMR (75
MHz, CDCl3) δ 157.0, 135.4, 131.8, 128.8, 128.6, 128.4, 128.3, 122.0, 87.7,
83.0, 67.7, 64.7; EI-HRMS calcd for C17H15NO3 (Mþ) 281.1052. Found
281.1067.
’ EXPERIMENTAL SECTION
General. IR spectra were measured using CHCl3. Chemical shifts
(δ) of 1H NMR and 13C NMR spectra are reported in ppm relative to
tetramethylsilane as internal reference (CDCl3: δ = 0 ppm for 1H) and
residual solvent signals (CDCl3: δ = 77 ppm for 13C; CD3OD: δ = 3.31
and 49.0 ppm for 1H and 13C). J-Values are given in Hz.
Isopropyl(3-phenyl-2-propynyl)oxycarbamate (1c). According to
step 3, 1c (154 mg, 98%) was obtained from O-(3-phenyl-2-propy-
nyl)hydroxylamine (100 mg, 0.679 mmol). Eluent: hexane/Et2O = 3/2.
Colorless crystals; mp 39 °C (hexane); IR νmax: 3386, 2986, 1743,
1600 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.50 (br s, 1H), 7.48ꢀ7.44
(m, 2H), 7.35ꢀ7.29 (m, 3H), 5.02 (sept, J = 6.3 Hz, 1H), 4.72 (s, 2H),
1.28 (d, J = 6.3 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 157.0, 131.8,
128.7, 128.3, 122.1, 87.4, 83.2, 70.0, 64.6, 21.9; EI-HRMS calcd for
C13H15NO3 (Mþ) 233.1052. Found 233.1070.
Benzyl(3-(2-methylphenyl)-2-propynyl)oxycarbamate (1f). Accord-
ing to step 1, 3-bromo-1-(2-methylphenyl)-1-propyne (1.68 g, 88%) was
obtained from 3-(2-methylphenyl)-2-propyn-1-ol20 (1.33 g, 9.09 mmol).
Eluent: hexane. Colorless oil; IR νmax: 2954, 2218, 1601 cmꢀ1; 1H NMR
(300 MHz, CDCl3) δ 7.40 (dd, J = 7.5, 1.2 Hz, 1H), 7.26ꢀ7.09 (m, 3H),
4.20 (s, 2H), 2.42 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 140.7, 132.1,
129.5, 128.9, 125.5, 121.9, 88.0, 85.8, 20.6, 15.4; EI-HRMS calcd for
C10H9Br (Mþ) 207.9888. Found 207.9891. According to step 2, O-(3-(2-
methylphenyl)-2-propynyl)hydroxylamine (424 mg, 34% in 2 steps) was
obtained from 3-bromo-1-(2-methylphenyl)-1-propyne (1.65 g, 7.88
mmol). Eluent: hexane/Et2O = 1/1. Colorless oil; IR νmax: 3330, 3016,
1579 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.42 (d, J = 7.5 Hz, 1H),
7.23ꢀ7.09 (m, 3H), 5.62 (br s, 2H), 2.45 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 140.3, 132.1, 129.4, 128.5, 125.5, 122.2, 88.5, 85.2, 64.2, 20.6;
EI-HRMS calcd for C10H11NO (Mþ) 161.0841. Found 161.0829.
According to step 3, 1f (174 mg, 89%) was obtained from O-(3-(2-
methylphenyl)-2-propynyl)hydroxylamine (106 mg, 0.657 mmol). Elu-
ent: hexane/Et2O = 3/2. Colorless crystals; mp 55ꢀ56 °C (hexane/
CH2Cl2); IR νmax: 3385, 3022, 1748, 1601 cmꢀ1; 1H NMR (300 MHz,
CDCl3) δ 7.68 (s, 1H), 7.41ꢀ7.30 (m, 6H), 7.25ꢀ7.09 (m, 3H), 5.20 (s,
2H), 4.76 (s, 2H), 2.41 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 157.0,
General Procedure for the Preparation of N-Alkoxycarbo-
nyl O-Propargylic Hydroxylamine 1. Step 1: According to
literature,19 CBr4 (1.2 equiv) was added in one portion to a solution of
propargylic alcohol (1 equiv) in dry CH2Cl2 (0.6 M) at 0 °C and the
reaction was stirred at 0 °C. After 10 min, a solution of Ph3P (1.5 equiv) in
CH2Cl2 (1.5 M) was added via cannula and stirred at 0 °C for 10 min.
Then the reaction mixture was allowed to warm at rt and further stirred for
1ꢀ1.5 h. After reaction completed, the mixture was evaporated in vacuo.
The residue was purified by flash column chromatography on silica gel to
give propargylic bromide. 3-Bromo-1-(2-methoxyphenyl)-1-propyne (for
1h and 1u) and 3-bromo-1-(1-naphthyl)-1-propyne (for1n and 1aa) were
prepared according to ref.19. 3-Bromo-1-phenyl-1-propyne (for 1aꢀe),
3-bromo-1-(3-methoxyphenyl)-1-propyne (for 1i and 1v), and 1-bromo-
2-heptyne (for 1q and 1ad) were prepared by the reaction of 3-phenyl-2-
propyn-1-ol, 3-(3-methoxylphenyl)-2-propyn-1-ol, and 2-heptyn-1-ol with
Br2 and Ph3P according to literature.20,21 Step 2: According to literature,13
DBU (1 equiv) was added dropwise to a solution of N-hydroxyphthalimide
(1 equiv) and propargylic bromide (1 equiv) in DMF (0.2 M) at rt and
stirred for 20ꢀ60 min. After reaction completed, the reaction mixture was
poured into 1 M HCl (16.1 mL/mol), stirred for further 20 min. The
resulting precipitated crystals were filtered, washed with water and the
residue was dried to afford O-propargylic phthalimide, which was used
without further purification for next reaction. Hydrazine monohydrate
(1.05 equiv) was added to a solution of O-propargylic phthalimide
(1 equiv) in MeOH/CH2Cl2 (1/1; 0.17 M) at rt, and stirred for 2.5ꢀ3 h.
After reaction completed, the reaction mixture was poured into an aqueous
3442
dx.doi.org/10.1021/jo200407b |J. Org. Chem. 2011, 76, 3438–3449

The Journal of Organic Chemistry
ARTICLE
140.5, 135.4, 132.2, 129.4, 128.8, 128.6, 128.4, 128.3, 125.5, 121.8, 86.7,
86.6, 67.7, 64.9, 20.6; ESI-HRMS calcd for C18H18NO3 (M þ Hþ)
296.1287. Found 296.1275.
88%) was obtained from 3-(4-methoxylphenyl)-2-propyn-1-ol20 (600 mg,
3.70 mmol). Eluent: hexane/Et2O = 19/1. Colorless oil; 1H NMR (300
MHz,CDCl3) δ7.38 (dt, J= 9.0, 2.1 Hz, 2H), 6.84 (dt, J= 9.0, 2.1 Hz, 2H),
4.17 (s, 2H), 3.81 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.0, 133.4,
114.2, 113.9, 86.7, 82.9, 55.3, 15.8. According to step 2, O-(3-(4-
methoxyphenyl)-2-propynyl)hydroxylamine (297 mg, 48% in 2 steps)
was obtained from 3-bromo-1-(4-methoxyphenyl)-1-propyne (788 mg,
3.50 mmol). Eluent: hexane/Et2O = 2/3. Colorless oil; IR νmax: 3539,
3016, 1606 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ7.40 (d, J= 6.9 Hz, 2H),
Benzyl(3-(4-methylphenyl)-2-propynyl)oxycarbamate (1g). Accor-
ding to step 1, 3-bromo-1-(4-methylphenyl)-1-propyne (1.75 g, 76%) was
obtained from 3-(4-methylphenyl)-2-propyn-1-ol20 (1.59 g, 10.9 mmol).
Eluent: hexane/Et2O = 19/1. Colorless oil; IR νmax: 3016, 2219,
1
1608 cmꢀ1; H NMR (300 MHz, CDCl3) δ 7.33 (d, J = 8.4 Hz, 2H),
7.11 (d, J = 8.4 Hz, 2H), 4.16 (s, 2H), 2.34 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 139.1, 131.8, 129.1, 119.0, 87.0, 83.5, 21.5, 15.8; EI-HRMS calcd
for C10H9Br (Mþ) 207.9888. Found 207.9900. According to step 2,
O-(3-(4-methylphenyl)-2-propynyl)hydroxylamine (0.980 g, 74% in 2
steps) was obtained from 3-bromo-1-(4-methylphenyl)-1-propyne (1.71
g, 8.17 mmol). Eluent: hexane/Et2O = 1/1. Colorless oil; IR νmax: 3331,
3015, 1580 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.35 (d, J = 8.1 Hz, 2H),
6.83 (d, J = 6.9 Hz, 2H), 5.61 (br s, 2H), 4.51 (s, 2H), 3.80 (s, 3H); 13
C
NMR (75 MHz, CDCl3) δ159.7, 133.3, 114.5, 113.9, 86.3, 83.2, 64.2, 55.2;
EI-HRMS calcd for C10H11NO2 (Mþ) 177.0790. Found 177.0804.
According to step 3, 1j (174 mg, 99%) was obtained from O-(3-(4-
methoxyphenyl)-2-propynyl)hydroxylamine (100 mg, 0.564 mmol). Elu-
ent: hexane/Et2O = 3/2. Colorless crystals; mp 63ꢀ64 °C (hexane/
CH2Cl2); IR νmax: 3590, 3384, 3022, 2222, 1747, 1606 cmꢀ1; 1H NMR
(300 MHz, CDCl3) δ 7.74 (br s, 1H), 7.38ꢀ7.32 (m, 7H), 6.82 (d, J = 9.0
Hz, 2H), 5.19 (s, 2H), 4.69 (s, 2H), 3.79 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 159.9, 157.0, 135.4, 133.4, 128.54, 128.48, 128.40, 128.3, 126.9,
114.0, 113.9, 87.7, 81.7, 67.6, 64.9, 55.2; EI-HRMS calcd for C18H17NO4
(Mþ) 311.1158. Found 311.1168.
7.10 (d, J = 8.1 Hz, 2H), 5.61 (br s, 2H), 4.51 (s, 2H), 2.33 (s, 3H); 13
C
NMR (CDCl3, 75 MHz) δ 138.6, 131.7, 129.0, 119.3, 86.4, 83.9, 64.1, 21.3;
EI-HRMS calcd for C10H11NO (Mþ) 161.0841. Found 161.0861. Accord-
ing to step 3, 1g (226 mg, 92%) was obtained from O-(3-(4-methylphenyl)-
2-propynyl)hydroxylamine (133 mg, 0.825 mmol). Eluent: hexane/Et2O =
1/1. Colorless crystals; mp 82 °C (hexane/CH2Cl2); IR νmax: 3385, 3022,
1
1748, 1606 cmꢀ1; H NMR (300 MHz, CDCl3) δ 7.70 (br s, 1H),
Benzyl(3-(2-nitrophenyl)-2-propynyl)oxycarbamate (1k). Accord-
ing to step 1, 3-bromo-1-(2-nitrophenyl)-1-propyne (1.97 g, 94%) was
obtained from 3-(2-nitrophenyl)-2-propyn-1-ol (1.54 g, 8.69 mmol).
Eluent: hexane/AcOEt = 9/1. Brown crystals; mp 199ꢀ200 °C
(MeOH); IR νmax: 3015, 2293, 1602 cmꢀ1; 1H NMR (300 MHz, CDCl3)
δ 8.05 (dd, J = 8.1, 1.2 Hz, 1H), 7.66ꢀ7.57 (m, 2H), 7.52ꢀ7.46 (m, 1H),
4.20 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 149.7, 134.9, 132.9, 129.3,
124.6, 117.5, 91.7, 81.5, 14.4; CI-HRMS calcd for C9H7BrNO2 (MþHþ)
239.9660. Found 239.9651. According to step 2, O-(3-(2-nitrophenyl)-2-
propynyl)hydroxylamine (754 mg, 49% in 2 steps) was obtained from
3-bromo-1-(2-nitrophenyl)-1-propyne (1.92 g, 7.98 mmol). Eluent: hex-
ane/AcOEt = 13/7. Yellow crystals; mp 41ꢀ42 °C (hexane/Et2O); IR
νmax: 3570, 3330, 1609, 1573, 1347 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ
8.05 (dd, J = 8.1, 1.2 Hz, 1H), 7.67ꢀ7.56 (m, 2H), 7.51ꢀ7.45 (m, 1H),
4.74 (br s, 2H), 4.58 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 149.7, 134.6,
132.8, 128.8, 124.6, 117.9, 93.3, 81.6, 63.9; CI-HRMS calcd for C9H9N2O3
(M þ Hþ) 193.0613. Found 193.0607. According to step 3, 1k (200 mg,
79%) was obtained from O-(3-(2-nitrophenyl)-2-propynyl)hydroxyla-
mine (149 mg, 0.775 mmol). Eluent: hexane/AcOEt = 7/3. Pale brown
crystals; mp 75ꢀ76 °C (hexane/CH2Cl2); IR νmax: 3580, 3381, 3024,
1746, 1609, 1529, 1346 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 8.05 (dd,
J = 8.1, 0.9 Hz, 1H), 7.87 (br s, 1H), 7.63ꢀ7.54 (m, 2H), 7.51ꢀ7.45 (m,
1H), 7.40ꢀ7.29 (m, 5H), 5.21 (s, 2H), 4.77 (s, 2H); 13C NMR (75 MHz,
CDCl3) δ 156.9, 149.6, 135.4, 134.7, 133.0, 129.1, 128.5, 128.4, 128.3,
124.7, 117.6, 91.4, 83.0, 67.6, 64.6; ESI-HRMS calcd for C17H15N2O5
(M þ Hþ) 327.0981. Found 327.0975.
7.39ꢀ7.31 (m, 7H), 7.10 (d, J = 7.8 Hz, 2H), 5.19 (s, 2H), 4.70 (s, 2H),
2.33 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 157.0, 139.0, 135.4, 131.8,
129.0, 128.6, 128.4, 128.3, 118.9, 87.8, 82.3, 67.6, 64.9, 21.4; ESI-HRMS
calcd for C18H18NO3 (M þ Hþ) 296.1287. Found 296.1277.
Benzyl(3-(2-methoxylphenyl)-2-propynyl)oxycarbamate (1h). Acc-
ording to step 2, O-(3-(2-methoxyphenyl)-2-propynyl)hydroxylamine (857
mg, 99% in 2 steps) was obtained from 3-bromo-1-(2-methoxyphenyl)-1-
propyne19 (1.10 g, 4.88 mmol). Eluent: hexane/Et2O = 3/2. Colorless oil; IR
νmax: 3331, 3018, 1581 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.43 (dd, J =
7.5, 1.8 Hz, 1H), 7.32ꢀ7.27 (m, 1H), 6.93ꢀ6.86 (m, 2H), 5.64 (br s, 2H),
4.57 (s, 2H), 3.87 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.1, 133.7,
129.9, 120.3, 111.54, 110.49, 88.6, 82.8, 64.4, 55.7; CI-HRMS calcd for
C10H12NO2 (MþHþ) 178.0863. Found 178.0870. According to step 3, 1h
(293 mg, 88%) was obtained from O-(3-(2-methoxyphenyl)-2-propy-
nyl)hydroxylamine (189 mg, 1.07 mmol). Eluent: hexane/Et2O = 3/2.
Colorless crystals; mp 77ꢀ78 °C (hexane/CH2Cl2); IR νmax: 3385, 3021,
1
1746, 1597 cmꢀ1; H NMR (300 MHz, CDCl3) δ 7.83 (br s, 1H),
7.40ꢀ7.27 (m, 7H), 6.92ꢀ6.85 (m, 2H), 5.19 (s, 2H), 4.76 (s, 2H), 3.84 (s,
3H); 13CNMR(75MHz, CDCl3) δ160.2, 156.9, 135.5, 133.5, 130.3, 128.6,
128.4, 128.2, 120.4, 111.1, 110.5, 87.1, 84.4, 67.6, 64.9, 55.6; ESI-HRMS
calcd for C18H18NO4 (M þ Hþ) 312.1230. Found 312.1223.
Benzyl(3-(3-methoxylphenyl)-2-propynyl)oxycarbamate (1i). Acc
ording to step 2, O-(3-(3-methoxyphenyl)-2-propynyl)hydroxylamine
(976 mg, 78% in 2 steps) was obtained from 3-bromo-1-(3-meth-
oxyphenyl)-1-propyne21 (1.59 g, 7.06 mmol) Eluent: hexane/Et2O = 3/2.
1
Colorless oil; IR νmax: 3528, 3017, 1582 cmꢀ1; H NMR (300 MHz,
Benzyl(3-(3-nitrophenyl)-2-propynyl)oxycarbamate (1l). According
to step 1, 3-bromo-1-(3-nitrophenyl)-1-propyne (1.77 g, 97%) was
obtained from 3-(3-nitrophenyl)-2-propyn-1-ol24 (1.34 g, 7.55 mmol).
Eluent: hexane/AcOEt = 9/1. Yellow crystals; mp 62ꢀ63 °C (MeOH/
CDCl3) δ 7.21 (t, J = 7.8 Hz, 1H), 7.06 (d, J = 7.8 Hz, 1H), 7.00ꢀ6.99 (m,
1H), 6.88 (dd, J = 8.1, 1.8 Hz, 1H), 5.64 (br s, 2H), 4.52 (s, 2H), 3.79 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 159.2, 129.3, 124.3, 123.4, 116.6,
115.1, 86.2, 84.5, 64.1, 55.2; CI-HRMS calcd for C10H12NO2 (MþHþ)
178.0868. Found 178.0869. According to step 3, 1i (344 mg, 87%) was
obtained from O-(3-(3-methoxyphenyl)-2-propynyl)hydroxylamine (223
mg, 1.26 mmol). Eluent: hexane/Et2O = 3/2. Colorless crystals; mp
1
H2O); IR νmax: 3025, 1574, 1532, 1352, cmꢀ1; H NMR (300 MHz,
CDCl3) δ 8.29 (t, J = 1.5 Hz, 1H), 8.19 (ddd, J = 7.8, 2.1, 1.2 Hz, 1H), 7.74
(dt, J = 7.8, 1,5 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 4.16 (s, 2H); 13C NMR
(75 MHz, CDCl3) δ 148.0, 137.5, 129.4, 126.7, 123.9, 123.5, 86.8, 83.9,
14.1; EI-HRMS calcd for C9H6BrNO2 (Mþ) 238.9582. Found 238.9570.
According to step 2, O-(3-(3-nitrophenyl)-2-propynyl)hydroxylamine
(919 mg, 67% in 2 steps) was obtained from 3-bromo-1-(3-
nitrophenyl)-1-propyne (1.70 g, 7.09 mmol). Eluent: hexane/AcOEt =
13/7. Pale yellow crystals; mp 37ꢀ38 °C (hexane/Et2O); IR νmax: 3571,
3331, 3014, 1531, 1351 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 8.31 (t,
J = 1.8 Hz, 1H), 8.17 (ddd, J = 7.8, 2.4, 1.2 Hz, 1H), 7.76 (dt, J = 7.8, 1.5 Hz,
1H), 7.51 (t, J = 7.8 Hz, 1H), 5.40 (br s, 2H), 4.55 (s, 2H); 13C NMR (75
MHz, CDCl3) δ 148.0, 137.4, 129.3, 126.6, 124.3, 123.2, 87.3, 83.6, 63.7;
1
62ꢀ63 °C (hexane); IR νmax: 3539, 3386, 3023, 1748, 1597 cmꢀ1; H
NMR (300 MHz, CDCl3) δ 7.70 (br s, 1H), 7.37ꢀ7.32 (m, 5H), 7.21 (t,
J = 7.8 Hz, 1H), 7.03 (dt, J = 7.8, 1.2 Hz, 1H), 6.98ꢀ6.96 (m, 1H), 6.89
(ddd, J = 7.8, 2.7, 1.2 Hz, 1H), 5.20 (s, 2H), 4.71 (s, 2H), 3.78 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 159.3, 157.0, 135.4, 129.4, 128.6, 128.5, 128.3,
124.4, 123.0, 116.6, 115.4, 87.6, 82.8, 67.7, 64.8, 55.2,; ESI-HRMS calcd for
C18H18NO4 (M þ Hþ) 312.1230. Found 312.1232.
Benzyl(3-(4-methoxylphenyl)-2-propynyl)oxycarbamate (1j). Acc-
ording to step 1, 3-bromo-1-(4-methoxylphenyl)-1-propyne23 (738 mg,
3443
dx.doi.org/10.1021/jo200407b |J. Org. Chem. 2011, 76, 3438–3449

The Journal of Organic Chemistry
ARTICLE
EI-HRMS calcd for C9H8N2O3 (Mþ) 192.0535. Found 192.0536. Accord-
ing to step 3, 1l (280 mg, 90%) was obtained from O-(3-(3-nitrophenyl)-
2-propynyl)hydroxylamine (183 mg, 0.952 mmol). Eluent: hexane/Et2O =
1/1. Colorless crystals; mp 95ꢀ96 °C (hexane/CH2Cl2); IR νmax: 3591,
3025, 1750, 1532, 1351 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 8.27 (t,
J = 1.5 Hz, 1H), 8.17 (dd, J = 8.4, 1.5 Hz, 1H), 7.77 (s, 1H), 7.71 (d, J = 7.8
Hz, 1H), 7.49 (t, J = 8.4 Hz, 1H), 7.37ꢀ7.32 (m, 5H), 5.21 (s, 2H), 4.74 (s,
2H); 13C NMR (75 MHz, CDCl3) δ 157.2, 148.0, 137.4, 135.3, 129.4,
128.6, 128.5, 128.3, 126.6, 123.9, 123.4, 85.9, 85.0, 67.8, 64.4; ESI-HRMS
calcd for C17H15N2O5 (M þ Hþ) 327.0981. Found 327.0983.
3-bromo-1-(1-naphthyl)-1-propyne (1.61 g, 8.02 mmol. Eluent: hex-
ane/Et2O = 1/1. Yellow oil; IR νmax: 3571, 3331, 3017, 2223,
1581 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.27ꢀ7.23 (m, 2H), 6.97
(dd, J = 5.1, 3.9 Hz, 1H), 5.63 (br s, 2H), 4.53 (s, 2H); 13C NMR (75
MHz, CDCl3) δ 132.6, 127.4, 126.9, 122.3, 88.8, 79.5, 64.1; EI-HRMS
calcd for C7H7NOS (Mþ) 153.0248. Found 153.0257. According to
step 3, 1o (225 mg, 81%) was obtained from O-(3-(2-thienyl)-2-
propynyl)hydroxylamine (148 mg, 0.966 mmol). Eluent: hexane/
Et2O = 7/3. Colorless crystals; mp 82ꢀ83 °C (hexane/CH2Cl2); IR
νmax: 3680, 3384, 3022, 2225, 1747, 1601 cmꢀ1; 1H NMR (300 MHz,
CDCl3) δ 7.61 (br s, 1H), 7.38ꢀ7.33 (m, 5H), 7.28 (dd, J = 5.1, 1.2 Hz,
1H), 7.24 (dd, J = 3.6, 1.2 Hz, 1H), 6.97 (dd, J = 5.1, 3.6 Hz, 1H), 5.21 (s,
2H), 4.73 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 157.0, 135.4, 133.0,
128.6, 128.4, 128.3, 127.9, 127.0, 121.9, 87.1, 80.9, 67.7, 64.8; EI-HRMS
calcd for C15H13NO3S (Mþ) 287.0616. Found 287.0601.
Benzyl(3-(4-nitrophenyl)-2-propynyl)oxycarbamate (1m). Accord-
ing to step 1, 3-bromo-1-(4-nitrophenyl)-1-propyne (1.36 g, 91%) was
obtained from 3-(4-nitrophenyl)-2-propyn-1-ol25 (1.10 g, 6.20 mmol).
Eluent: hexane/AcOEt = 9/1. Yellow crystals; mp 70ꢀ71 °C (MeOH/
H2O); IR νmax: 3024, 1593 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 8.19
(d, J = 9.0 Hz, 2H), 7.59 (d, J = 8.7 Hz, 2H), 4.17 (s, 2H); 13C NMR
(75 MHz, CDCl3) δ 147.4, 132.6, 128.9, 123.6, 89.3, 84.3, 14.0; EI-
HRMS calcd for C9H6BrNO2 (Mþ) 238.9582. Found 238.9592.
According to step 2, O-(3-(4-nitrophenyl)-2-propynyl)hydroxylamine
(762 mg, 79% in 2 steps) was obtained from 3-bromo-1-(4-nitro-
phenyl)-1-propyne (1.20 g, 4.99 mmol). Eluent: hexane/AcOEt = 3/
2. Colorless crystals; mp 104ꢀ105 °C (hexane/AcOEt); IR νmax: 3570,
Benzyl(3-(1-cyclohexenyl)-2-propynyl)oxycarbamate (1p). Accord-
ing to step 1, 3-bromo-1-(1-cyclohexenyl)-1-propyne27 (1.99 g, 73%) was
obtained from 3-(1-cyclohexenyl)-2-propyn-1-ol28 (1.86 g, 13.7 mmol).
Eluent: hexane. The spectral data of this compound were identical with
those of the literature.27 Colorless oil; 1H NMR (300 MHz, CDCl3) δ 6.15
(quint, J = 3.0 Hz, 1H), 4.07 (s, 2H), 2.13ꢀ2.08 (m, 4H), 1.66ꢀ1.56 (m,
4H); 13C NMR (75 MHz, CDCl3) δ 136.7, 120.0, 88.8, 81.6, 28.8, 25.6,
22.1, 21.3, 15.9. According to step 2, O-(3-(1-cyclohexenyl)-2-propy-
nyl)hydroxylamine (680 mg, 53% in 2 steps) was obtained from 3-bromo-
1-(1-cyclohexenyl)-1-propyne (1.72 g, 8.54 mmol). Eluent: hexane/
AcOEt = 4/1. Colorless oil; IR νmax: 3684, 3331, 2936, 2220,
1
3332, 3019, 1594, 1520, 1344 cmꢀ1; H NMR (300 MHz, CDCl3) δ
8.19 (d, J = 9.0 Hz, 2H), 7.60 (d, J = 9.0 Hz, 2H), 5.71 (s, 2H), 4.55 (s,
2H); 13C NMR (75 MHz, CDCl3) δ 147.2, 132.5, 129.4, 123.5, 90.5,
84.2, 63.8; EI-HRMS calcd for C9H8N2O3 (Mþ) 192.0535. Found
192.0534. According to step 3, 1m (207 mg, 82%) was obtained from
O-(3-(4-nitrophenyl)-2-propynyl)hydroxylamine (150 mg, 0.780 mmol).
Eluent: hexane/Et2O = 1/1. Colorlesscrystals;mp 114ꢀ115 °C (hexane/
CH2Cl2); IR νmax: 3594, 3381, 3030, 1749, 1595, 1520, 1343 cmꢀ1; 1H
NMR (300 MHz, CDCl3) δ 8.16 (d, J = 9.0 Hz, 2H), 7.74 (br s, 1H), 7.55
(d, J = 9.0 Hz, 2H), 7.38ꢀ7.33 (m, 5H), 5.21 (s, 2H), 4.75 (s, 2H); 13C
NMR (75 MHz, CDCl3) δ 157.2, 147.4, 135.3, 132.5, 128.9, 128.6, 128.5,
128.3, 123.5, 88.4, 85.5, 67.8, 64.6; CI-HRMS calcd for C17H15N2O5
(M þ Hþ) 327.0981. Found 327.0977.
1
1642 cmꢀ1; H NMR (300 MHz, CDCl3) δ 6.15 (quint, J = 3.0 Hz,
1H), 5.53 (br s, 2H), 4.41 (s, 2H), 2.15ꢀ2.08 (m, 4H), 1.65ꢀ1.56 (m,
4H); 13C NMR (75 MHz, CDCl3) δ 135.8, 120.0, 81.7, 64.3, 63.0, 29.1,
25.6, 22.2, 21.4; ESI-HRMS calcd for C9H14NO (M þ Hþ) 152.1075.
Found 152.1069. According to step 3, 1p (441 mg, quant) was obtained
from O-(3-(1-cyclohexenyl)-2-propynyl)hydroxylamine (200 mg, 1.32
mmol). Eluent: hexane/AcOEt
= 4/1. Colorless crystals; mp
49.5ꢀ51.5 °C (hexane/AcOEt); IR νmax: 3671, 3386, 2936, 2223, 1748,
1629 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.54 (br s, 1H), 7.39ꢀ7.35
(m, 5H), 6.15 (quint, J = 1.8 Hz, 1H), 5.19 (s, 2H), 4.61 (m, 2H),
2.12ꢀ2.08 (m, 4H), 1.64ꢀ1.56 (m, 4H); 13C NMR (75 MHz, CDCl3) δ
157.0, 136.4, 135.5, 128.6, 128.5, 128.3, 119.8, 89.7, 80.2, 67.6, 64.9, 28.9,
25.6, 22.2, 21.3; ESI-HRMS calcd for C17H19NNaO3 (M þ Naþ)
308.1263. Found 308.1256.
Benzyl(3-(1-naphthyl)-2-propynyl)oxycarbamate (1n). According
to step 2, O-(3-(1-naphthyl)-2-propynyl)hydroxylamine (1.02 g, 72%
in 2 steps) was obtained from 3-bromo-1-(1-naphthyl)-1-propyne19
(1.76 g, 7.17 mmol). Eluent: hexane/Et2O = 1/1. Pale yellow oil; IR
1
νmax: 3673, 3017, 2226, 1582 cmꢀ1; H NMR (300 MHz, CDCl3) δ
Benzyl(2-heptyn-1-yl)oxycarbamate (1q). 1-Bromo-2-heptyne29
(3.90 g, 89%) was prepared according to ref.20 Colorless oil; bp
70 °C/12 mmHg; 1H NMR (300 MHz, CDCl3) δ 3.93 (t, J = 2.4 Hz,
2H), 2.28ꢀ2.21 (m, 2H), 1.55ꢀ1.37 (m, 4H), 0.91 (t, J = 7.2 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 88.2, 75.2, 30.4, 21.9, 18.6, 15.7, 13.5.
According to step 2, O-(2-heptyn-1-yl)hydroxylamine (727 mg, 81% in
2 steps) was obtained from 1-bromo-2-heptyne (1.23 g, 7.03 mmol).
Eluent: hexane/Et2O = 2/3. Pale yellow oil; IR νmax: 3672, 3518, 3330,
2960, 2224 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 5.51 (br s, 2H), 4.29
(t, J = 2.1 Hz, 2H), 2.27ꢀ2.21 (m, 2H), 1.56ꢀ1.37 (m, 4H), 0.91 (t, J =
7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 87.3, 75.3, 63.9, 30.5, 21.8,
18.3, 13.4; ESI-HRMS calcd for C7H14NO (M þ Hþ) 128.1075. Found
128.1068. According to step 3, 1q (186 mg, 83%) was obtained from
O-(2-heptyn-1-yl)hydroxylamine (109 mg, 0.860 mmol). Eluent: hex-
ane/Et2O = 4/1. Colorless oil; IR νmax: 3684, 3387, 2935, 1748,
8.35 (d, J = 8.1 Hz, 1H), 7.81 (dd, J = 8.1, 3.9 Hz, 2H), 7.69 (dd, J = 7.2,
1.2 Hz, 1H), 7.58ꢀ7.46 (m, 2H), 7.42ꢀ7.37 (m, 1H), 5.68 (s, 2H), 4.66
(s, 2H); 13C NMR (75 MHz, CDCl3) δ 133.3, 133.0, 130.7, 129.0,
128.2, 126.8, 126.4, 126.0, 125.1, 120.1, 89.7, 84.3, 64.2; EI-HRMS calcd
for C13H11NO (Mþ) 197.0841. Found 197.0858. According to step 3,
1n (257 mg, 95%) was obtained from O-(3-(1-naphthyl)-2-propy-
nyl)hydroxylamine (160 mg, 0.811 mmol). Eluent: hexane/Et2O = 3/
2. Colorless crystals; mp 64ꢀ65 °C (hexane); IR νmax: 3507, 3382, 3012,
2227, 1747, 1587 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 8.29 (dt, J = 7.8,
0.9 Hz, 1H), 7.83 (dd, J = 7.2, 1.2 Hz, 2H), 7.74 (br s, 1H), 7.67 (dd,
J = 7.2, 1.2 Hz, 1H), 7.58ꢀ7.48 (m, 2H), 7.43ꢀ7.29 (m, 6H), 5.21 (s,
2H), 4.87 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 157.1, 135.4, 133.3,
133.1, 131.0, 129.3, 128.6, 128.4, 128.29, 128.27, 126.9, 126.5, 126.0,
125.1, 119.7, 87.8, 85.8, 67.7, 65.0; EI-HRMS calcd for C21H17NO3
(Mþ) 331.1208. Found 331.1225.
Benzyl(3-(2-thienyl)-2-propynyl)oxycarbamate (1o). According to
step 1, 3-bromo-1-(2-thienyl)-1-propyne (1.70 g, 96%) was obtained
from 3-(2-thienyl)-2-propyn-1-ol26 (1.20 g, 8.68 mmol). Eluent: hexane.
Brown oil; IR νmax: 3018, 2226 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ
7.28 (dd, J = 5.1, 0.9 Hz, 1H), 7.24 (dd, J = 3.9, 0.9 Hz, 1H), 6.97 (dd, J =
5.1, 3.9 Hz, 1H), 4.17 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 133.0,
128.0, 127.0, 122.0, 88.1, 80.1, 15.3; EI-HRMS calcd for C7H5BrS (Mþ)
199.9295. Found 199.9306. According to step 2, O-(3-(2-thienyl)-2-
propynyl)hydroxylamine (751 mg, 61% in 2 steps) was obtained from
1
1604 cmꢀ1; H NMR (300 MHz, CDCl3) δ 7.62 (s, 1H), 7.38ꢀ7.33
(m, 5H), 5.18 (s, 2H), 4.72 (t, J = 2.4 Hz, 2H), 2.42ꢀ2.18 (m, 2H),
1.53ꢀ1.32 (m, 4H), 0.90 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 156.9, 135.5, 128.5, 128.4, 128.2, 88.9, 73.9, 67.5, 64.6, 30.4,
21.8, 18.4, 13.5; ESI-HRMS calcd for C15H20NO3 (M þ Hþ) 262.1443.
Found 262.1441.
Benzyl(4-phenyl-3-butyn-2-yl)oxycarbamate (1r). According to step
1, 2-bromo-4-phenyl-3-butyne (2.30 g, quant) was obtained from 4-phen-
yl-3-bytyn-2-ol (1.50 g, 10.3 mmol). Eluent: hexane. Colorless oil; IR νmax
:
3444
dx.doi.org/10.1021/jo200407b |J. Org. Chem. 2011, 76, 3438–3449

The Journal of Organic Chemistry
ARTICLE
3017, 1606 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.45ꢀ7.41 (m, 2H),
7.31 (dd, J = 5.1, 2.1 Hz, 3H), 5.86 (q, J = 6.9 Hz, 1H), 2.00 (d, J = 6.9 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 131.7, 128.7, 128.2, 122.1, 89.2, 31.9,
27.5; HR-EIMS calcd for C10H9Br (Mþ) 207.9888. Found 207.9880.
According to step 2, O-(4-phenyl-3-butyn-2-yl)hydroxylamine (660 mg,
43% in 2 steps) was obtained from 2-bromo-4-phenyl-3-butyne (2.00 g,
9.57 mmol). Eluent: hexane/AcOEt = 3/1. Colorless oil; IR νmax: 3670,
3331, 2997, 2233, 1582 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.48ꢀ7.44
(m, 2H), 7.34ꢀ7.28 (m, 3H), 5.51 (br s, 2H), 4.60 (qd, J = 6.6, 1.2 Hz,
1H), 1.49 (dd, J = 6.6, 1.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 131.8,
128.3, 128.2, 122.5, 88.6, 84.9, 71.2, 20.3; ESI-HRMS calcd for C10H12NO
(M þ Hþ) 162.0919. Found 162.0913. According to step 3, 1r (445 mg,
quant) was obtained from O-(4-phenyl-3-butyn-2-yl)hydroxylamine (200
mg, 1.24 mmol). Eluent: hexane/AcOEt = 5/1. Colorless crystals; mp
Eluent: hexane/Et2O = 3/2. Colorless crystals; mp 83ꢀ84 °C (hexane/
AcOEt); IR νmax: 3691, 2931, 1743, 1606 cmꢀ1; 1H NMR (300 MHz,
CDCl3) δ 7.54 (br s, 1H), 7.39 (dd, J = 6.6, 2.1 Hz, 2H), 6.83 (dd, J = 6.6,
2.1 Hz, 2H), 5.02 (sept, J = 6.3 Hz, 1H), 4.70 (s, 2H), 3.81 (s, 3H), 1.28
(d, J = 6.3 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 156.0, 156.9, 133.4,
114.2, 113.9, 87.5, 81.8, 70.0, 64.8, 55.3, 21.9; CI-HRMS calcd for
C14H18NO4 (M þ Hþ) 264.1236. Found 264.1220.
Isopropyl(3-(2-nitrophenyl)-2-propynyl)oxycarbamate (1x). Ac-
cording to step 3, 1x (315 mg, 79%) was obtained from O-(3-(2-
nitrophenyl)-2-propynyl)hydroxylamine (275 mg, 1.43 mmol). Eluent:
hexane/Et2O = 7/3. Colorless crystals; mp 80ꢀ81 °C (hexane); IR
νmax: 3672, 3382, 3022, 1741, 1609, 1528, 1346 cmꢀ1; 1H NMR (300
MHz, CDCl3) δ 8.07 (dd, J = 8.1, 1.2 Hz, 1H), 7.76 (s, 1H), 7.67ꢀ7.58
(m, 2H), 7.52ꢀ7.47 (m, 1H), 5.02 (sept, J = 6.3 Hz, 1H), 4.78 (s, 2H),
1.28 (d, J = 6.3 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 156.8, 149.6,
134.7, 132.9, 129.1, 124.6, 117.6, 91.6, 82.8, 70.0, 64.4, 21.9; CI-HRMS
calcd for C13H15N2O5 (M þ Hþ) 279.0981. Found: 279.0986.
Isopropyl(3-(3-nitrophenyl)-2-propynyl)oxycarbamate (1y). Ac-
cording to step 3, 1y (329 mg, 74%) was obtained from O-(3-(3-
nitrophenyl)-2-propynyl)hydroxylamine (307 mg, 1.60 mmol). Eluent:
hexane/AcOEt = 7/3. Colorless crystals; mp 111ꢀ112 °C (hexane/
72ꢀ74 °C (hexane/AcOEt); IRνmax: 3388, 3022, 2230, 1749, 1643 cmꢀ1
;
1H NMR (300 MHz, CDCl3) δ 7.62 (br s, 1H), 7.44ꢀ7.41 (m, 2H),
7.37ꢀ7.29 (m, 8H), 5.19 (d, J = 2.1 Hz, 2H), 4.88 (q, J = 6.9 Hz, 1H), 1.56
(d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 157.0, 135.6, 131.8,
128.6, 128.4, 128.3, 128.2, 122.1, 87.2, 86.0, 72.3, 67.6; ESI-HRMS calcd
for C18H18NO3 (M þ Hþ) 296.1287. Found 296.1278; Anal. calcd for
C18H17NO3: C, 73.20; H, 5.80; N, 4.74. Found C, 73.40; H, 5.72; N, 4.81.
Isopropyl(3-(2-methylphenyl)-2-propynyl)oxycarbamate (1s). Ac-
cording to step 3, 1s (220 mg, 82%) was obtained from O-(3-(2-
methylphenyl)-2-propynyl)hydroxylamine (175 mg, 1.08 mmol). Elu-
ent: hexane/Et2O = 7/3. Colorless oil; IR νmax: 3549, 3385, 2968,
1743 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.56 (s, 1H), 7.42 (d, J = 7.2
Hz, 1H), 7.27ꢀ7.13 (m, 3H), 5.02 (sept, J = 6.3 Hz, 1H), 4.76 (s, 2H),
2.44 (s, 3H), 1.28 (d, J = 6.3 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ
157.0, 140.4, 132.2, 129.4, 128.7, 125.5, 121.9, 86.9, 86.4, 70.0, 64.7, 21.9,
20.6; CI-HRMS calcd for C14H18NO3 (M þ Hþ) 248.1286. Found
248.1276.
1
Et2O); IR νmax: 3688, 3384, 3023, 1746, 1532, 1443, 1351 cmꢀ1; H
NMR (300 MHz, CDCl3) δ 8.31 (t, J = 1.5 Hz, 1H), 8.19 (ddd, J = 8.1, 2.4,
1.5 Hz, 1H), 7.76 (dt, J = 7.8, 1.5 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.50 (br
s, 1H), 5.04 (sept, J = 6.3 Hz, 1H), 4.74 (s, 2H), 1.29 (d, J = 6.0 Hz, 6H);
13C NMR (75 MHz, CDCl3) δ 157.1, 148.0, 137.4, 129.4, 126.6, 124.0,
123.4, 86.1, 84.8, 70.2, 64.4, 21.9; EI-HRMS calcd for C13H14N2O5 (Mþ)
278.0903. Found 278.0911.
Isopropyl(3-(4-nitrophenyl)-2-propynyl)oxycarbamate (1z). Ac-
cording to step 3, 1z (242 mg, 83%) was obtained from O-(3-(4-
nitrophenyl)-2-propynyl)hydroxylamine (200 mg, 1.04 mmol). Eluent:
hexane/AcOEt = 3/1. Colorless crystals; mp 100ꢀ101 °C (hexane/
Isopropyl(3-(4-methylphenyl)-2-propynyl)oxycarbamate (1t). Ac-
cording to step 3, 1t (243 mg, 93%) was obtained from O-(3-(4-
methylphenyl)-2-propynyl)hydroxylamine (168 mg, 1.04 mmol). Eluent:
1
Et2O); IR νmax: 3691, 3383, 2928, 1745, 1596, 1521, 1343 cmꢀ1; H
NMR (300 MHz, CDCl3) δ 8.19 (d, J = 9.0 Hz, 2H), 7.61 (d, J = 9.0 Hz,
2H), 7.58 (s, 1H), 5.03 (sept, J = 6.3 Hz, 1H), 4.75 (s, 2H), 1.29 (d, J =
6.3 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 157.1, 147.4, 132.5, 129.0,
123.5, 88.7, 85.3, 70.2, 64.5, 21.9; EI-HRMS calcd for C13H14N2O5
(Mþ) 278.0903. Found 278.0920.
Isopropyl(3-(1-naphthyl)-2-propynyl)oxycarbamate (1aa). Accord-
ing to step 3, 1aa (364 mg, 89%) was obtained from O-(3-(1-naphthyl)-2-
propynyl)hydroxylamine (285 mg, 1.44 mmol). Eluent: hexane/Et2O = 1/
1. Colorless crystals; mp 67ꢀ68 °C (hexane/AcOEt);IRνmax: 3688, 3385,
3021, 2228, 1741, 1590 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 8.31 (d, J =
8.1 Hz, 1H), 7.84 (d, J = 8.1 Hz, 2H), 7.69 (dd, J = 7.2, 1.2 Hz, 1H), 7.64 (s,
1H), 7.60ꢀ7.49 (m, 2H), 7.44ꢀ7.39 (m, 1H), 5.03 (sept, J = 6.3 Hz, 1H),
4.87 (s, 2H), 1.28 (d, J = 6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ
157.0, 133.3, 133.0, 130.9, 129.2, 128.3, 126.9, 126.5, 126.0, 125.1, 119.8,
88.0, 85.6, 70.1, 64.8, 21.9; EI-HRMS calcd for C17H17NO3 (Mþ)
283.1208. Found 283.1223.
Isopropyl(3-(2-thienyl)-2-propynyl)oxycarbamate (1ab). According
to step 3, 1ab (311 mg, 97%) was obtained from O-(3-(2-thienyl)-2-
propynyl)hydroxylamine (205 mg, 1.33 mmol). Eluent: hexane/Et2O = 3/
2. Colorless crystals; mp 32ꢀ33 °C (hexane); IR νmax: 3676, 3384, 2986,
2226, 1742, 1607 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.56 (s, 1H), 7.28
(dd, J = 5.1, 1.2 Hz, 1H), 7.25 (dd, J = 3.6, 1.2 Hz, 1H), 6.97 (dd, J = 5.1, 3.6
Hz, 1H), 5.02 (sept, J = 6.3 Hz, 1H), 4.72 (s, 2H), 1.28 (d, J = 6.3 Hz, 6H);
13CNMR(75MHz,CDCl3) δ157.0, 132.9, 127.8, 127.0, 122.0, 87.3, 80.8,
70.1, 64.7, 21.9; EI-HRMS calcd for C11H13NO3S (Mþ) 239.0616. Found
239.0630.
Isopropyl(3-(1-cyclohexenyl)-2-propynyl)oxycarbamate (1ac). Ac-
cording to step 3, 1ac (441 mg, quant) was obtained from O-(3-(1-
cyclohexenyl)-2-propynyl)hydroxylamine (180 mg, 1.19 mmol). Eluent:
hexane/AcOEt = 4/1. Colorless oil; IR νmax: 3386, 2939, 2223, 1743,
1631 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.43 (br s, 1H), 6.16 (quint,
hexane/Et2O = 3/2. Colorless crystals; mp 73ꢀ74 °C (hexane); IR νmax
:
3687, 2928, 1743, 1604 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.56 (br s,
1H), 7.35 (d, J = 7.8 Hz, 2H), 7.12, (d, J = 7.8 Hz, 2H), 5.02 (sept, J = 6.3
Hz, 1H), 4.70 (s, 2H), 2.35 (s, 3H), 1.28 (d, J = 6.6 Hz, 6H); 13C NMR
(CDCl3, 75 MHz) δ 156.9, 138.9, 131.7, 129.0, 119.0, 87.6, 82.5, 70.0, 64.7,
21.9, 21.4; CI-HRMS calcd for C14H18NO3 (M þ Hþ) 248.1286. Found
248.1268.
Isopropyl(3-(2-methoxyphenyl)-2-propynyl)oxycarbamate (1u). Ac-
cording to step 3, 1u (208 mg, 92%) was obtained from O-(3-(2-
methoxylphenyl)-2-propynyl)hydroxylamine (152 mg, 0.857 mmol). Elu-
ent: hexane/Et2O = 3/2. Colorless crystals; mp 82ꢀ83 °C (hexane/
1
Et2O); IR νmax: 3386, 2985, 1742, 1598 cmꢀ1; H NMR (300 MHz,
CDCl3) δ 7.66 (s, 1H), 7.41 (dd, J = 7.8, 1.8 Hz, 1H), 7.34ꢀ7.27 (m, 1H),
6.94ꢀ6.87 (m, 2H), 5.02 (sept, J = 6.3 Hz, 1H), 4.76 (s, 2H), 3.89 (s, 3H),
1.28 (d, J = 6.3 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 160.8, 156.7,
133.5, 130.2, 120.4, 111.2, 110.5, 87.2, 84.1, 69.8, 64.7, 55.6, 21.9; EI-
HRMS calcd for C14H17NO4 (Mþ) 263.1158. Found 263.1172.
Isopropyl(3-(3-methoxyphenyl)-2-propynyl)oxycarbamate (1v). Ac-
cording to step 3, 1v (176 mg, 87%) was obtained from O-(3-(3-
methoxylphenyl)-2-propynyl)hydroxylamine (135 mg, 0.761 mmol). Elu-
ent: hexane/Et2O = 3/2. Colorless crystals; mp 43ꢀ44 °C (hexane); IR
νmax: 3674, 3385, 2986, 1743, 1598 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ
7.78 (s, 1H), 7.21 (t, J = 8.4 Hz, 1H), 7.07ꢀ6.98 (m, 2H), 6.89 (ddd, J =
8.4, 2.1, 0.9 Hz, 1H), 5.01 (sept, J = 6.3 Hz, 1H), 4.71 (s, 2H), 3.78 (s, 3H),
1.27 (d, J = 6.3 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 159.2, 157.0,
129.3, 124.3, 123.0, 116.6, 115.3, 87.2, 83.0, 69.9, 64.5, 55.1, 21.8; EI-
HRMS calcd for C14H17NO4 (Mþ) 263.1158. Found 263.1141.
Isopropyl(3-(4-methoxyphenyl)-2-propynyl)oxycarbamate (1w).
According to step 3, 1w (148 mg, 98%) was obtained from O-(3-(3-
methoxylphenyl)-2-propynyl)hydroxylamine (100 mg, 0.564 mmol).
3445
dx.doi.org/10.1021/jo200407b |J. Org. Chem. 2011, 76, 3438–3449

The Journal of Organic Chemistry
ARTICLE
J = 2.1 Hz, 1H), 5.01 (sept, J = 6.3 Hz, 1H), 4.60 (s, 2H), 2.12ꢀ2.09 (m,
4H), 1.65ꢀ1.57 (m, 4H), 1.28 (d, J = 6.3 Hz, 6H); 13C NMR (75 MHz,
CDCl3) δ 156.9, 136.3, 119.9, 89.5, 80.4, 69.9, 64.8, 29.0, 25.6, 22.2, 21.9,
21.4; ESI-HRMS calcd for C13H20NO3 (M þ Hþ) 238.1443. Found
238.1436.
5.04 (s, 2H), 5.02 (s, 2H), 3.69 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
157.1, 152.2, 138.6, 135.0, 130.90, 130.86, 128.3, 128.0, 127.9, 120.1,
118.9, 111.1, 80.5, 67.9, 67.5, 55.4; ESI-HRMS calcd for C18H17INO4
(M þ Hþ) 438.0202. Found 438.0187.
Benzyl 2,5-Dihydro-4-iodo-3-(3-methoxylphenyl)-2H-isoxazole-2-
carboxylate (2i). 2i (138 mg, 98%) was obtained from 1i (100 mg,
0.321 mmol). Eluent: hexane/Et2O = 7/3. Pale yellow crystals; mp
Isopropyl(2-heptyn-1-yl)oxycarbamate (1ad). According to step 3,
1ad (290 mg, 87%) was obtained from O-(2-heptyn-1-yl)hydroxylamine
(198 mg, 1.56 mmol). Eluent: hexane/Et2O = 4/1. Colorless oil; IR
1
79ꢀ80 °C (hexane/CH2Cl2); IR νmax: 3022, 1730, 1597 cmꢀ1; H
1
νmax: 3677, 3386, 2936, 1743 cmꢀ1; H NMR (300 MHz, CDCl3) δ
NMR (300 MHz, CDCl3) δ 7.31ꢀ7.20 (m, 4H), 7.15 (dt, J = 7.5, 1.5
Hz, 1H), 7.07 (dd, J = 8.1, 1.5 Hz, 1H), 7.00ꢀ6.97 (m, 2H), 6.93 (ddd,
J = 8.1, 2.7, 1.5 Hz, 1H), 5.07 (s, 2H), 4.99 (s, 2H), 3.76 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 159.2, 154.6, 141.0, 134.7, 131.1, 129.2,
128.3, 128.2, 127.8, 121.2, 115.4, 113.9, 81.5, 68.4, 67.9, 55.2; ESI-
HRMS calcd for C18H17INO4 (M þ Hþ) 438.0202. Found 438.0202.
Benzyl 2,5-Dihydro-4-iodo-3-(4-methoxylphenyl)-2H-isoxazole-2-
carboxylate (2j). 2j (99.1 mg, 80%) was obtained from 1j (89.0 mg,
0.285 mmol). Eluent: hexane/Et2O = 7/3. Colorless crystals; mp
7.48 (s, 1H), 5.01 (sept, J = 6.3 Hz, 1H), 4.47 (t, J = 2.4 Hz, 2H),
2.26ꢀ2.20 (m, 2H), 1.53ꢀ1.37 (m, 4H), 1.28 (d, J = 6.3 Hz, 6H), 0.91
(t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 156.8, 88.7, 74.0,
69.8, 64.4, 30.4, 21.9, 21.8, 18.3, 13.4; ESI-HRMS calcd for C11H20NO3
(M þ Hþ) 214.1443. Found 214.1433.
Isopropyl(4-phenyl-3-butyn-2-yl)oxycarbamate (1ae). According
to step 3, 1ae (274 mg, 89%) was obtained from O-(4-phenyl-3-
butyn-2-yl)hydroxylamine (200 mg, 1.24 mmol). Eluent: hexane/
AcOEt = 4/1. Colorless crystals; mp 61ꢀ62 °C (hexane/AcOEt); IR
νmax: 3692, 2988, 2230, 2744, 1600 cmꢀ1; 1H NMR (300 MHz, CDCl3)
δ 7.55 (br s, 1H), 7.47ꢀ7.43 (m, 2H), 7.31 (dd, J = 5.1, 2.1 Hz, 3H), 5.00
(sept, J = 6.3 Hz, 1H), 4.87 (q, J = 6.6 Hz, 1H), 1.57 (d, J = 6.6 Hz, 3H),
1.27 (d, J = 6.3 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 157.0, 131.8,
128.6, 128.2, 122.2, 87.4, 85.8, 72.1, 69.8, 21.92, 21.88, 19.9; ESI-HRMS
calcd for C14H18NO3 (M þ Hþ) 248.1287. Found 248.1277; Anal.
Calcd for C14H17NO3: C, 68.00; H, 6.93; N, 5.66. Found C, 68.06; H,
6.85; N, 5.63.
1
98ꢀ99 °C (hexane/CH2Cl2); IR νmax: 3021, 1727, 1607 cmꢀ1; H
NMR (300 MHz, CDCl3) δ 7.49 (d, J = 8.7 Hz, 2H), 7.25ꢀ7.21 (m,
3H), 7.02ꢀ6.99 (m, 2H), 6.88 (d, J = 8.4 Hz, 2H), 5.07 (s, 2H), 4.96 (s,
2H), 3.82 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.3, 154.7, 140.8,
134.8, 130.2, 128.3, 128.1, 127.8, 122.1, 113.5, 81.3, 68.3, 66.0, 55.2; EI-
HRMS Calcd for C18H16INO4 (Mþ) 437.0124. Found 437.0111.
Benzyl 2,5-Dihydro-4-iodo-3-(2-nitrophenyl)-2H-isoxazole-2-car-
boxylate (2k). 2k (95.0 mg, 75%) was obtained from 1k (91.4 mg,
0.280 mmol). Eluent: hexane/Et2O = 3/2. Brown amorphous solid; IR
νmax; 3024, 1723, 1608, 1531, 1349 cmꢀ1; 1H NMR (300 MHz, CDCl3)
δ 8.01 (dd, J = 8.1, 1.2 Hz, 1H), 7.63 (td, J = 7.5, 1.5 Hz, 1H), 7.53ꢀ7.41
(m, 2H), 7.28ꢀ7.23 (m, 3H), 7.06ꢀ7.03 (m, 2H), 5.10 (br d, J = 10.5
Hz, 2H), 4.98 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 151.6, 147.8,
138.2, 134.4, 133.4, 132.0, 130.4, 128.4, 128.3, 125.7, 124.8, 80.7, 68.5,
66.3; ESI-HRMS calcd for C17H14IN2O5 (M þ Hþ) 452.9942. Found
452.9952.
General Procedure for the Preparation of 2,5-Dihydroi-
soxazole 2. To a solution of 1 (1 equiv) in dry CH2Cl2 (0.1 M) was
added I(coll)2PF6 (1.5ꢀ2 equiv) at rt and the reaction mixture was stirred
for 20ꢀ30 min. The reaction mixture was quenched with a saturated
aqueous solution of Na2S2O3, and was extracted with CH2Cl2. The
organic layer was dried over Na2SO4, filtered, and evaporated in vacuo.
The residue was purified by flash column chromatography on silica gel to
give 2.
Benzyl 2,5-Dihydro-4-iodo-3-phenyl-2H-isoxazole-2-carboxylate
(2a). 2a (114 mg, 97%) was obtained from 1a (80.0 mg, 0.284 mmol).
Eluent: hexane/Et2O = 5/2. Yellow amorphous solid; IR νmax: 2926,
1729, 1561 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.56ꢀ7.53 (m, 2H),
7.38ꢀ7.36 (m, 3H), 7.24ꢀ7.21 (m, 3H), 6.97ꢀ6.94 (m, 2H), 5.05 (s,
2H), 4.99 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 154.5, 141.0, 134.7,
129.9, 129.3, 128.7, 128.3, 128.1, 127.7, 81.4, 68.3, 67.5; EI-HRMS calcd
for C17H14INO3 (Mþ) 407.0018. Found 407.0026.
Benzyl 2,5-Dihydro-4-iodo-3-(3-nitrophenyl)-2H-isoxazole-2-car-
boxylate (2l). 2l (106 mg, 81%) was obtained from 1l (94.2 mg, 0.288
mmol). Eluent: hexane/Et2O = 13/7. Yellow crystals; mp 75ꢀ76 °C
1
(hexane/CH2Cl2); IR νmax; 3025, 1734, 1612, 1532, 1348 cmꢀ1; H
NMR (300 MHz, CDCl3) δ 8.39 (t, J = 1.8 Hz, 1H), 8.18ꢀ8.15 (m, 1H),
7.84 (d, J = 7.8 Hz, 1H), 7.51 (t, J = 8.1 Hz, 1H), 7.29ꢀ7.22 (m, 3H), 7.05
(dd, J = 7.5, 1.8 Hz, 2H), 5.05 (s, 4H); 13C NMR (75 MHz, CDCl3) δ
154.4, 147.9, 139.2, 134.5, 134.2, 131.7, 129.1, 128.6, 128.5, 128.2, 123.9,
123.8, 81.7, 70.2, 68.9; ESI-HRMS calcd for C17H14IN2O5 (M þ Hþ)
452.9942. Found 452.9954.
Benzyl 2,5-Dihydro-4-iodo-3-(4-nitrophenyl)-2H-isoxazole-2-car-
boxylate (2m). 2m (72.6 mg, 87%) was obtained from 1m (60.2 mg,
0.184 mmol). Eluent: hexane/Et2O = 13/7. Yellow crystals; mp
111ꢀ113 °C (hexane/CH2Cl2); IR νmax: 3026, 1735, 1599, 1523,
1346 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 8.16 (d, J = 8.7 Hz, 2H),
7.68 (d, J = 8.7 Hz, 2H), 7.28ꢀ7.21 (m, 3H), 7.04 (br d, J = 6.3 Hz, 2H),
5.05 (s, 2H), 5.04 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 154.4, 147.8,
139.5, 136.3, 134.2, 129.6, 128.7, 128.4, 128.3, 123.4, 81.9, 70.9, 69.0; EI-
HRMS calcd for C17H13IN2O5 (Mþ) 451.9869. Found 451.9881.
Benzyl 2,5-Dihydro-4-iodo-3-(1-naphthyl)-2H-isoxazole-2-carbox-
ylate (2n). 2n (134 mg, 95%) was obtained from 1n (102 mg, 0.307
Benzyl 2,5-Dihydro-4-iodo-3-(2-methylphenyl)-2H-isoxazole-2-car-
boxylate (2f). 2f (120 mg, 93%) was obtained from 1f (90.0 mg, 0.304
mmol). Eluent: hexane/Et2O = 7/3. Brown oil; IR νmax: 3023, 1722,
1563 cmꢀ1
;
1H NMR (300 MHz, CDCl3) δ 7.35ꢀ7.14 (m, 7H),
6.96ꢀ6.93 (m, 2H), 5.04 (s, 2H), 5.00 (s, 2H), 2.22 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 152.2, 141.0, 137.2, 134.7, 130.2, 129.8, 129.5,
129.4, 128.3, 128.1, 127.9, 125.5, 80.3, 68.1, 67.4, 19.6; ESI-HRMS calcd
for C18H17INO3 (M þ Hþ) 422.0253. Found 422.0242.
Benzyl 2,5-Dihydro-4-iodo-3-(4-methylphenyl)-2H-isoxazole-2-car-
boxylate (2g). 2g (57.0 mg, 89%) was obtained from 1g (45.0 mg, 0.152
mmol). Eluent: hexane/Et2O = 7/3. Pale yellow crystals; mp 61ꢀ62 °C
(hexane/CH2Cl2); IR νmax: 3018, 1727, 1637 cmꢀ1; H NMR (300
1
mmol). Eluent: hexane/Et2O = 7/3. Yellow amorphous solid; IR νmax
:
MHz, CDCl3) δ 7.44 (dd, J = 6.6, 1.5 Hz, 2H), 7.26ꢀ7.16 (m, 5H),
7.00ꢀ6.96 (m, 2H), 5.06 (s, 2H), 4.98 (s, 2H), 2.38 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 154.6, 141.1, 139.4, 134.8, 128.9, 128.7, 128.2,
128.1, 127.8, 127.0, 81.4, 68.4, 66.7, 21.5; EI-HRMS calcd for
C18H16INO3 (Mþ) 421.0175. Found 421.0160.
3020, 1724, 1596 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.93ꢀ7.90 (m,
1H), 7.86ꢀ7.82 (m, 2H), 7.51ꢀ7.40 (m, 4H), 7.19ꢀ7.05 (m, 3H), 6.62
(d, J = 7.2 Hz, 2H), 5.16 (d, J = 4.2 Hz, 2H), 4.83 (s, 2H); 13C NMR (75
MHz, CDCl3) δ 152.5, 140.2, 134.4, 133.4, 131.1, 129.9, 128.4, 128.1,
128.0, 127.7, 127.5, 126.7, 126.2, 125.1, 124.9, 80.8, 68.9, 68.2; EI-
HRMS calcd for C21H16INO3 (Mþ) 457.0175. Found 457.0195.
Benzyl 2,5-Dihydro-4-iodo-3-(2-thienyl)-2H-isoxazole-2-carboxy-
late (2o). 2o (124 mg, 96%) was obtained from 1o (90.1 mg, 0.313
Benzyl 2,5-Dihydro-4-iodo-3-(2-methoxylphenyl)-2H-isoxazole-2-
carboxylate (2h). 2h (124 mg, 95%) was obtained from 1h (92.2 mg,
0.296 mmol). Eluent: hexane/Et2O = 3/2. Yellow amorphous solid; IR
νmax; 3018, 1720, 1596 cmꢀ1 1H NMR (300 MHz, CDCl3) δ
;
mmol). Eluent: hexane/Et2O = 4/1. Yellow amorphous solid; IR νmax
:
7.38ꢀ7.22 (m, 5H), 6.99ꢀ6.94 (m, 3H), 6.08 (d, J = 8.1 Hz, 1H),
3446
dx.doi.org/10.1021/jo200407b |J. Org. Chem. 2011, 76, 3438–3449

The Journal of Organic Chemistry
ARTICLE
3028, 1733, 1626 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.45 (dd, J =
3.6, 1.2 Hz, 1H), 7.41 (dd, J = 4.8, 1.2 Hz, 1H), 7.29ꢀ7.27 (m, 3H),
7.14ꢀ7.11 (m, 2H), 7.06 (dd, J = 4.8, 3.6 Hz, 1H), 5.15 (s, 2H), 4.93 (s,
2H); 13C NMR (75 MHz, CDCl3) δ 155.8, 137.4, 134.8, 129.8, 128.4,
128.3, 127.9, 127.6, 126.8, 81.6, 69.0, 68.7; EI-HRMS calcd for C15H12I-
NO3S (Mþ) 412.9583. Found 412.9572.
13C NMR (75 MHz, CDCl3) δ 163.0, 161.4, 157.2, 131.7, 131.2, 120.6,
116.8, 111.1, 61.5, 55.3; EI-HRMS calcd for C10H8INO2 (Mþ)
300.9600. Found: 300.9616.
4-Iodo-3-(3-methoxylphenyl)isoxazole (3v). 3v (45.5 mg, 58%) was
obtained from 1v (68.0 mg, 0.258 mmol). Eluent: hexane/Et2O = 9/1.
Colorless crystals; mp 54ꢀ55 °C (hexane); IR νmax: 3018, 1591 cmꢀ1
;
Benzyl 2,5-Dihydro-4-iodo-3-(1-cyclohexenyl)-2H-isoxazole-2-car-
boxylate (2p). 2p (25.5 mg, 80%) was obtained from 1p (22.0 mg,
1H NMR (300 MHz, CDCl3) δ 8.46 (s, 1H), 7.42ꢀ7.40 (m, 2H), 7.35
(d, J = 1.8 Hz, 1H), 7.06ꢀ7.02 (m, 1H), 3.87 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 162.6, 161.9, 159.6, 129.7, 128.9, 120.9, 116.3, 113.6,
58.0, 55.3; EI-HRMS calcd for C10H8INO2 (Mþ) 300.9600. Found
300.9621.
0.0771 mmol). Eluent: hexane/AcOEt = 4/1. Colorless oil; IR νmax
:
2973, 1723 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.37ꢀ7.33 (m, 5H),
6.01 (quint, J = 2.1 Hz, 1H), 5.18 (s, 2H), 4.85 (s, 2H), 2.10ꢀ2.09 (m,
4H), 1.55ꢀ1.51 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 153.6, 142.7,
135.1, 132.4, 128.53, 128.49, 128.2, 80.5, 68.5, 64.5, 26.9, 25.2, 22.1,
21.6; ESI-HRMS calcd for C17H19INO3 (M þ Hþ) 412.0410. Found
412.0404.
4-Iodo-3-(4-methoxylphenyl)isoxazole (3w). 3w (80.9 mg, 70%)
was obtained from 1w (100 mg, 0.379 mmol). Eluent: hexane/Et2O =
9/1. Colorless crystals; mp 64ꢀ65 °C (hexane); IR νmax: 3018,
1612 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 8.43 (s, 1H), 7.78 (d, J =
8.7 Hz, 2H), 7.01 (d, J = 8.7 Hz, 2H), 3.86 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 162.4, 161.6, 161.1, 129.9, 120.1, 114.0, 58.0, 55.3; EI-HRMS
calcd for C10H8INO2 (Mþ) 300.9600. Found 300.9613.
4-Iodo-3-(2-nitrophenyl)isoxazole (3x). 3x (49.0 mg, 50%) was
obtained from 1x (86.1 mg, 0.309 mmol). Eluent: hexane/Et2O = 3/
2. Yellow crystals; mp 108ꢀ109 °C (hexane/Et2O); IR νmax: 3014,
1576, 1533, 1350 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 8.50 (s, 1H),
8.25 (dd, J = 8.1, 1.5 Hz, 1H), 7.81ꢀ7.70 (m, 2H), 7.53 (dd, J = 7.2, 2.1
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 162.9, 161.6, 148.2, 133.6,
132.5, 131.3, 125.1, 123.6, 60.3; EI-HRMS calcd for C9H5IN2O3 (Mþ)
315.9345. Found 315.9366.
4-Iodo-3-(3-nitrophenyl)isoxazole (3y). 3y (73.0 mg, 70%) was
obtained from 1y (90.8 mg, 0.326 mmol). Eluent: hexane/Et2O = 17/
3. Pale yellow crystals; mp 131ꢀ132 °C (hexane); IR νmax: 3022, 1606,
1534, 1352 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 8.76 (t, J = 1.8 Hz,
1H), 8.55 (s, 1H), 8.37 (ddd, J = 8.1, 2.4, 1.2 Hz, 1H), 8.19 (ddd, J = 8.1,
1.5, 1.2 Hz, 1H), 7.71 (t, J = 8.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
163.2, 160.3, 148.2, 134.3, 129.8, 129.6, 124.9, 123.6, 57.4; EI-HRMS
calcd for C9H5IN2O3 (Mþ) 315.9345. Found 315.9333.
4-Iodo-3-(4-nitrophenyl)isoxazole (3z). 3z (71.9 mg, 62%) was
obtained from 1z (100 mg, 0.359 mmol). Eluent: hexane/Et2O = 4/1.
Pale yellow crystals; mp 172ꢀ173 °C (hexane/CH2Cl2); IR νmax: 3024,
2927, 1605, 1526, 1349 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 8.55 (s,
1H), 8.37 (d, J = 9.0 Hz, 2H), 8.05 (d, J = 9.0 Hz, 2H); 13C NMR (75
MHz, CDCl3) δ 163.3, 160.5, 148.9, 134.1, 129.6, 123.8, 57.4; EI-HRMS
calcd for C9H5IN2O3 (Mþ) 315.9345. Found 315.9357.
4-Iodo-3-(1-naphthyl)isoxazole (3aa). 3aa (89.2 mg, 79%) was
obtained from 1aa (100 mg, 0.353 mmol). Eluent: hexane/Et2O =
19/1. Colorless crystals; mp 101ꢀ102 °C (hexane); IR νmax: 3017,
1542 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.01ꢀ7.90 (m,
2H), 7.78 (dd, J = 6.9, 2.1 Hz, 1H), 7.58ꢀ7.50 (m, 4H); 13C NMR (75
MHz, CDCl3) δ 163.5, 161.9, 133.6, 131.3, 130.5, 128.6, 128.4, 126.9,
126.4, 125.6, 125.1, 124.9, 61.8; EI-HRMS calcd for C13H8INO (Mþ)
320.9651. Found 320.9664.
4-Iodo-3-(2-thienyl)isoxazole (3ab). 3ab (58.5 mg, 45%) was obtained
from 1ab (108 mg, 0.451 mmol). Eluent: hexane/Et2O = 19/1. Colorless
crystals; mp 33ꢀ35 °C (hexane/CH2Cl2); IR νmax: 3018, 1558 cmꢀ1; 1H
NMR (300 MHz, CDCl3) δ8.45 (s, 1H), 7.91 (dd, J= 3.6, 1.2 Hz, 1H), 7.49
(dd, J = 5.1, 1.2 Hz, 1H), 7.18 (dd, J = 5.1, 3.6 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 162.8, 157.3, 129.0, 128.6, 128.5, 127.6, 56.9; EI-HRMS calcd for
C7H4INOS (Mþ) 276.9058. Found 276.9065.
4-Iodo-3-(1-cyclohexenyl)isoxazole (3ac). 3ac (23.6 mg, 66%) was
obtained from 1ac (31.0 mg, 0.131 mmol). Eluent: hexane/AcOEt = 5/
1. Colorless crystals; mp 62ꢀ63 °C (hexane/AcOEt); IR νmax: 2934,
1602 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 8.31 (s, 1H), 6.67 (quint, J =
1.8 Hz, 1H), 2.45ꢀ2.44 (m, 2H), 2.29ꢀ2.23 (m, 2H), 1.81ꢀ1.64 (m,
4H); 13C NMR (75 MHz, CDCl3) δ 161.9, 161.8, 133.0, 126.8, 56.3,
26.7, 25.5, 22.3, 21.6; ESI-HRMS calcd for C9H11INO (M þ Hþ)
275.9885. Found 275.9880.
Benzyl 3-Butyl-2,5-dihydro-4-iodo-2H-isoxazole-2-carboxylate (2q).
2q (28.5 mg, 94%) was obtainedfrom 1q (20.4 mg, 0.0781 mmol). Eluent:
hexane/AcOEt = 4/1. Colorless oil; IR νmax: 2962, 1713, 1644 cmꢀ1; 1H
NMR (300 MHz, CDCl3) δ 7.42ꢀ7.31 (m, 5H), 5.23 (s, 2H), 4.82
(t, J = 1.2 Hz, 2H), 2.63 (tt, J = 7.5, 1.2 Hz, 2H), 1.55ꢀ1.45 (m, 2H),
1.37ꢀ1.25 (m, 2H), 0.89 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 151.7, 141.5, 135.2, 128.6, 128.50, 128.46, 79.2, 68.1, 63.7, 29.4, 28.0,
22.2, 13.8; ESI-HRMS calcd for C15H19INO3 (M þ Hþ) 388.0410. Found
388.0405.
Benzyl 2,5-Dihydro-4-iodo-3-phenyl-5-methyl-2H-isoxazole-2-car-
boxylate (2r). 2r (38.2 mg, 96%) was obtained from 1r (28.0 mg,
0.0948 mmol). Eluent: hexane/AcOEt = 3/1. This product was unstable
under concentrated condition and gradually decomposed so that the
selected data of 2r were shown as below. Brown oil; 1H NMR (300 MHz,
CDCl3) δ 7.39ꢀ7.30 (m, 5H), 7.26ꢀ7.19 (m, 3H), 6.98ꢀ6.94 (m, 2H),
5.23 (q, J = 6.3 Hz, 1H), 5.06 (s, 2H), 1.50 (d, J = 6.3 Hz, 3H).
General Procedure for the Preparation of Isoxazole 3. To a
solution of 1 (1 equiv) in dry CH2Cl2 (0.1 M) was added NIS (2.5
equiv) followed by BF3 OEt2 (2.5 equiv) at 0 °C and the reaction
3
mixture was stirred for 15ꢀ45 min. The reaction mixture was quenched
with a saturated aqueous solution of Na2S2O3, and was extracted with
CH2Cl2. The organic layer was dried over Na2SO4, filtered, and
evaporated in vacuo. The residue was purified by flash column chroma-
tography on silica gel to give 3.
4-Iodo-3-phenylisoxazole (3a). 3a (36.8 mg, 63%) was obtained
from 1c (50.0 mg, 0.214 mmol). Eluent: hexane/Et2O = 19/1. Colorless
crystals; mp 92ꢀ93 °C (hexane); IR νmax: 3018, 1542 cmꢀ1; 1H NMR
(300 MHz, CDCl3) δ 8.46 (s, 1H), 7.83ꢀ7.80 (m, 2H), 7.51ꢀ7.48 (m,
3H); 13C NMR (75 MHz, CDCl3) δ 162.5, 162.1, 130.2, 128.6, 127.8,
58.0; EI-HRMS calcd for C9H6INO (Mþ) 270.9494. Found 270.9506.
4-Iodo-3-(2-methylphenyl)isoxazole (3s). 3s (49.0 mg, 71%) was
obtained from 1s (59.2 mg, 0.239 mmol). Eluent: hexane/Et2O = 19/1.
Colorless crystals; mp 53ꢀ54 °C (hexane); IR νmax: 3019, 1606 cmꢀ1
;
1H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H), 7.42ꢀ7.29 (m, 4H), 2.28
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.3, 161.6, 137.4, 130.5,
130.0, 129.9, 127.3, 125.7, 61.2, 20.0; EI-HRMS calcd for C10H8INO
(Mþ) 284.9651. Found 284.9674.
4-Iodo-3-(4-methylphenyl)isoxazole (3t). 3t (68.7 mg, 59%) was
obtained from 1t (101 mg, 0.407 mmol). Eluent: hexane/Et2O = 19/1.
Colorless crystals; mp 57ꢀ58 °C (hexane); IR νmax: 3017, 2928,
1614 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 8.43 (s, 1H), 7.71 (d, J =
8.1 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 2.42 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 162.4, 162.0, 140.3, 129.3, 128.4, 124.9, 58.1, 21.4; EI-HRMS
calcd for C10H8INO (Mþ) 284.9651. Found 284.9651.
4-Iodo-3-(2-methoxylphenyl)isoxazole (3u). 3u (59.7 mg, 80%) was
obtained from 1u (65.1 mg, 0.247 mmol). Eluent: hexane/Et2O = 17/3.
Pale yellow crystals; mp 60ꢀ61 °C (hexane/Et2O); IR νmax: 3017,
1606 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 8.43 (s, 1H), 7.51ꢀ7.45 (m,
1H), 7.36 (dd, J = 7.5, 1.8 Hz, 1H), 7.08ꢀ6.99 (m, 2H), 3.84 (s, 3H);
3447
dx.doi.org/10.1021/jo200407b |J. Org. Chem. 2011, 76, 3438–3449

The Journal of Organic Chemistry
ARTICLE
3-Butyl-4-iodoisoxazole (3ad) and 3-(1-Iodobutyl)-4-iodoisoxazole
(3ad0). 3ad (26.4 mg, 53%) and 3ad0 (11.6 mg, 16%) were obtained as
unseparatable mixture from 1ad (42.0 mg, 0.197 mmol). Eluent:
hexane/AcOEt = 5/1. Selected data of 3ad: 1H NMR (300 MHz,
CDCl3) δ 8.30 (s, 1H), 2.66 (t, J = 7.5 Hz, 2H), 1.70 (quint, J = 7.5 Hz,
2H), 1.42 (sext, J = 7.5 Hz, 2H), 0.96 (t, J = 7.5 Hz, 3H); ESI-HRMS
calcd for C7H11INO (M þ Hþ) 251.9880. Found 251.9879. Selected
data of 3ad0: 1H NMR (300 MHz, CDCl3) δ 8.36 (s, 1H), 4.97 (dd, J =
8.4, 7.2 Hz, 1H), 2.46ꢀ2.32 (m, 1H), 2.27ꢀ2.14 (m, 1H), 1.62ꢀ1.30
(m, 2H), 0.98 (t, J = 7.2 Hz, 3H); ESI-HRMS calcd for C7H10I2NO
(M þ Hþ) 377.8846. Found 377.8845.
(60 μL, 0.414 mmol) in dry CH3CN (1.5 mL) was added PdCl2(PPh3)2
(5.8 mg, 8.30 μmol). The reaction mixture was refluxed for 3 h. After
reaction completed, the mixture was quenched with a saturated aqueous
solution of NH4Cl, extracted with Et2O. The organic layer was dried
over Na2SO4, filtered and evaporated in vacuo. The residue was purified
by flash column chromatography on silica gel eluting with hexane/
AcOEt = 2/1 to give 7 (41.8 mg, 83%) as a yellow oil. IR νmax: 3023,
1720, 1619 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.44ꢀ7.36 (m, 5H),
7.33 (d, J = 15.6 Hz, 1H), 7.27ꢀ7.25 (m, 3H), 7.05ꢀ7.02 (m, 2H), 5.58
(d, J = 15.6 Hz, 1H), 5.19 (s, 2H), 5.08 (s, 2H); 13C NMR (75 MHz,
CDCl3) δ 166.9, 152.6, 142.2, 134.6, 134.4, 129.9, 129.1, 128.45, 128.39,
128.3, 128.0, 118.6, 115.9, 74.4, 68.5, 51.6; ESI-HRMS calcd for
C21H18NO5 (M ꢀ Hꢀ) 364.1185. Found 364.1189.
4-Iodo-3-phenyl-5-methylisoxazole (3ae):8a. 3ae (33.7 mg, 96%)
was obtained from 1ae (40.0 mg, 0.162 mmol). Eluent: hexane/AcOEt =
1
5/1. Pale yellow crystals; mp 97ꢀ99 °C (hexane/AcOEt); H NMR
Benzyl 2,5-Dihydro-4-((E)-2-(methoxycarbonyl)ethenyl)-
3-phenyl-5-methyl-2H-isoxazole-2-carboxylate (8). Accord-
ing to general procedure for the preparation of 2,5-dihydroisoxazole 2,
2r was obtained from 1r (40.0 mg, 0.135 mmol). Eluent: hexane/Et2O =
3/1. And then, to a solution of 2r, methyl acrylate (46 μL, 0.513 mmol),
Et3N (56 μL, 0.405 mmol) in dry CH3CN (1.5 mL) was added
PdCl2(PPh3)2 (5.7 mg, 8.10 μmol). The reaction mixture was refluxed
for 3 h. After reaction completed, the mixture was quenched with a
saturated aqueous solution of NH4Cl, extracted with Et2O. The organic
layer was dried over Na2SO4, filtered and evaporated in vacuo. The
residue was purified by flash column chromatography on silica gel
eluting with hexane/AcOEt = 2/1 to give 8 (26.4 mg, 52%) as a yellow
oil. IR νmax: 3023, 1720, 1618 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ
7.44ꢀ7.35 (m, 5H), 7.27 (d, J = 16.0 Hz, 1H), 7.27ꢀ7.22 (m, 3H), 7.12
(dd, J = 4.5, 2.0 Hz, 2H), 5.70 (d, J = 16.0 Hz, 1H), 5.43 (q, J = 6.0 Hz,
1H), 5.07 (q, J = 9.5 Hz, 2H), 3.70 (s, 3H), 1.52 (d, J = 6.5 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 167.1, 153.0, 142.3, 134.9, 134.8, 130.0,
129.3, 128.6, 128.5, 128.4, 128.3, 127.9, 120.7, 117.7, 81.9, 68.4, 51.7,
19.8; ESI-HRMS calcd for C22H22NO5 (M þ Hþ) 380.1498. Found
380.1490.
(300 MHz, CDCl3) δ 7.80ꢀ7.77 (m, 2H), 7.49ꢀ7.47 (m, 3H), 2.55 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 171.4, 162.8, 130.0, 128.7, 128.5,
128.4, 57.8, 12.9.
4-Bromo-3-phenylisoxazole (4a). To a solution of 2a (39.0 mg,
0.0958 mmol) in dry CH2Cl2 (0.96 mL) was added NBS (25.6 mg, 0.144
mmol) followed by BF3 OEt2 (18 μL, 0.144 mmol) at 0 °C and the
3
reaction mixture was stirred for 15 min. The reaction mixture was
quenched with a saturated aqueous solution of Na2S2O3, and was
extracted with CH2Cl2. The organic layer was dried over Na2SO4,
filtered, and evaporated in vacuo. The residue was purified by flash
column chromatography on silica gel eluting with hexane/AcOEt = 4/1
to give 3a (1.2 mg, 5%) and 4a (2.4 mg, 11%). Colorless crystals; mp
53ꢀ54 °C (hexane/AcOEt); IR νmax: 3018, 1554 cmꢀ1; 1H NMR (300
MHz, CDCl3) δ 8.52 (s, 1H), 7.88ꢀ7.85 (m, 2H), 7.53ꢀ7.48 (m, 3H);
13C NMR (75 MHz, CDCl3) δ 160.0, 158.1, 130.3, 128.7, 128.3, 127.1,
93.3; ESI-HRMS calcd for C9H6BrNO (Mþ Hþ) 223.9711. Found
223.9708.
Benzyl 2,5-Dihydro-3-phenyl-4-((trimethylsilyl)ethynyl)-
2H-isoxazole-2-carboxylate (5). A solution of 2a (67.0 mg, 0.165
mmol), ethynyltrimethylsilane (26 μL, 0.181 mmol), PdCl2(PPh3)2 (1.2
mg, 1.65 μmol), CuI (0.6 mg, 3.29 μmol) in Et3N (3.0 mL) was stirred
for 27 h at rt. After reaction completed, the mixture was diluted with
AcOEt, washed with 10% HCl aq., dried over Na2SO4, filtered and
evaporated in vacuo. The residue was purified by flash column chroma-
tography on silica gel eluting with hexane/AcOEt = 5/1 to give 5 (36.9
mg, 59%) as a yellow oil. IR νmax: 3422, 1754, 1656 cmꢀ1; 1H NMR (300
MHz, CDCl3) δ 7.71ꢀ7.64 (m, 2H), 7.35ꢀ7.33 (m, 3H), 7.25ꢀ7.22
(m, 3H), 7.04ꢀ7.01 (m, 2H), 5.10 (s, 2H), 4.93 (s, 2H), 0.17 (s, 9H);
13C NMR (75 MHz, CDCl3) δ 155.1, 144.0, 134.9, 129.5, 129.3, 128.4,
128.23, 128.18, 127.8, 103.9, 103.0, 95.9, 76.0, 68.4, ꢀ0.4; ESI-HRMS
calcd for C22H24NO3Si (M þ Hþ) 378.1526. Found 378.1523.
4-(5-Methyl-3-phenyl-isoxazol-4-yl)benzenesulfonamide
(Valdecoxib) (9)18. 3ae (20.0 mg, 0.0700 mmol), 4-sulphamoylben-
zeneboronic acid (19.7 mg, 0.0980 mmol), Pd(dba)2 (2.0 mg, 3.50
μmol), and Ph3P (3.7 mg, 0.0140 mmol) were placed into the Schlenk-
flask with reflux condenser and bubble-counter. After THF (3.7 mL) and
20% Na2CO3 aq. (3.7 mL) were added, the mixture was refluxed for 13
h. It was diluted with AcOEt, and organic layer was separated and
evaporated in vacuo. The residue was purified by flash column chroma-
tography on silica gel eluting with hexane/AcOEt = 5/1 to give 9 (11.8
mg, 54%) as colorless crystals. mp 172ꢀ173 °C (hexane/AcOEt); IR
νmax: 3379, 3372, 2993, 1359, 1159 cmꢀ1 1H NMR (300 MHz,
;
CD3OD) δ 7.91 (d, J = 8.7 Hz, 2H), 7.46ꢀ7.36 (m, 5H), 7.38 (d, J =
8.7 Hz, 2H), 4.88 (s, 2H), 2.49 (s, 3H); 13C NMR (75 MHz, CD3OD) δ
169.1, 162.6, 144.5, 135.6, 131.4, 130.9, 130.0, 129.8, 129.6, 127.6, 116.0,
11.5; ESI-HRMS calcd for C16H15N2O3S (M þ Hþ) 315.0803. Found
315.0804.
Benzyl 2,5-Dihydro-3-phenyl-4-(2-thienyl)-2H-isoxazole-
2-carboxylate (6). 2a (94.1 mg, 0.231 mmol), 2-thiopheneboronic
acid (41.4 mg, 0.324 mmol), Pd(dba)2 (6.6 mg, 11.6 μmol), and Ph3P
(12.1 mg, 0.462 mmol) were placed into the Schlenk-flask with reflux
condenser and bubble-counter. After THF (1 mL) and 20% Na2CO3 aq.
(1 mL) were added, the mixture was refluxed for 15 h. It was diluted with
AcOEt, and organic layer was separated and evaporated in vacuo. The
residue was purified by flash column chromatography on silica gel
eluting with hexane/AcOEt = 5/1 to give 6 (53.8 mg, 64%) as a yellow
oil. IR νmax: 3021, 1716, 1598 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ
7.45ꢀ7.36 (m, 5H), 7.26ꢀ7.24 (m, 3H), 7.07ꢀ7.01 (m, 3H), 6.88 (dd, J
= 5.4, 3.6 Hz, 1H), 6.70 (dd, J = 3.6, 1.2 Hz, 1H), 5.35 (s, 2H), 5.06 (s,
2H); 13C NMR (75 MHz, CDCl3) δ 153.3, 135.0, 132.9, 132.2, 129.7,
129.6, 129.4, 128.6, 128.3, 128.1, 128.0, 126.6, 125.2, 125.0, 112.9, 76.0,
68.0; ESI-HRMS calcd for C21H16NO3S (M ꢀ Hꢀ) 362.0851. Found
362.0855.
Benzyl 2,5-Dihydro-4-(4-sulfamoylphenyl)-3-phenyl-5-
methyl-2H-isoxazole-2-carboxylate
(N-Cbz-2,5-dihydro-
valdecoxib) (10). According to general procedure for the preparation
of 2,5-dihydroisoxazole 2, 2r was obtained from 1r (25.0 mg, 0.0847
mmol). Eluent: hexane/Et2O = 3/1. And then, to a solution of 2r,
4-sulphamoylbenzeneboronic acid (23.8 mg, 0.119 mmol), Pd(dba)2
(2.4 mg, 4.23 μmol), and Ph3P (4.4 mg, 0.0169 mmol) were placed into
the Schlenk-flask with reflux condenser and bubble-counter. After THF
(3.6 mL) and 20% Na2CO3 aq. (3.6 mL) were added, the mixture was
refluxed for 13 h. It was diluted AcOEt, and organic layer was separated
and evaporated in vacuo. The residue was purified by flash column
chromatography on silica gel eluting with hexane/AcOEt = 5/1 to give
10 (15.3 mg, 40%) as a colorless oil. IR νmax: 3346, 3276, 3031, 1724,
1597, 1340, 1167 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J = 8.7
Hz, 2H), 7.36ꢀ7.21 (m, 8H), 7.10 (d, J = 8.4 Hz, 2H), 5.80 (q, J = 6.3
Benzyl 2,5-Dihydro-4-((E)-2-(methoxycarbonyl)ethenyl)-
3-phenyl-2H-isoxazole-2-carboxylate (7). To a solution of 2a
(56.0 mg, 0.138 mmol), methyl acrylate (45.0 mg, 0.523 mmol), Et3N
3448
dx.doi.org/10.1021/jo200407b |J. Org. Chem. 2011, 76, 3438–3449

The Journal of Organic Chemistry
ARTICLE
Hz, 1H), 5.09 (s, 2H), 4.89 (s, 2H), 1.47 (d, J = 6.3 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 154.5, 140.2, 137.1, 137.0, 134.9, 129.5, 129.3,
129.1, 128.6, 128.3, 128.2, 127.9, 126.7, 121.6, 84.0, 77.2, 68.2, 19.3; ESI-
HRMS calcd for C24H23N2O5S (M þ Hþ) 451.1328. Found 451.1325.
Lett. 2008, 10, 1967–1970. (d) Barluenga, J.; Palomas, D.; Rubio, E.;
Gonzꢀalez, J. M. Org. Lett. 2007, 9, 2823–2826. (e) Garud, D. R.;
Koketsu, M. Org. Lett. 2008, 10, 3319–3322. (f) Bi, H.-P.; Guo, L.-N.;
Duan, X.-H.; Gou, F.-R.; Huang, S.-H.; Liu, X.-Y.; Liang, Y.-M. Org. Lett.
2007, 9, 397–400. (g) Barluenga, J.; Trincado, M.; Rubio, E.; Gonzꢀalez,
J. M. Angew. Chem., Int. Ed. 2006, 45, 3140–3143. (h) Yue, D.; Yao, T.;
Larock, R. C. J. Org. Chem. 2005, 70, 10292–10296. (i) Barluenga, J.;
Trincado, M.; Rubio, E.; Gonzꢀalez, J. M. Angew. Chem., Int. Ed. 2003,
42, 2406–2409. (j) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2006,
71, 62–69. (k) Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 1432–1437.
(l) Yao, T.; Campo, M. A.; Larock, R. C. J. Org. Chem. 2005,
70, 3511–3517. (m) Khan, Z. A.; Wirth, T. Org. Lett. 2009,
11, 229–231. (n) Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2005,
127, 12230–12231. (o) Barluenga, J.; Trincado, M.; Rubio, E.; Gonzꢀalez,
J. M. Angew. Chem., Int. Ed. 2003, 42, 2406–2409. (p) Mehta, S.; Waldo,
J. P.; Larock, R. C. J. Org. Chem. 2009, 74, 1141–1147. (q) Mehta, S.;
Larock, R. C. J. Org. Chem. 2010, 75, 1652–1658. (r) Verma, A. K.;
Aggarwal, T.; Rustagi, V.; Larock, R. C. Chem. Commun. 2010, 46,
4064–4066.
(8) (a) Waldo, J. P.; Larock, R. C. Org. Lett. 2005, 7, 5203–5205.
(b) Waldo, J. P.; Larock, R. C. J. Org. Chem. 2007, 72, 9643–9647.
(c) Waldo, J. P.; Mehta, S.; Neuenswander, B.; Lushington, G. H.;
Larock, R. C. J. Comb. Chem. 2008, 10, 658–663.
(9) Foot, O. F.; Knight, D. W.; Low, A. C. L.; Li, Y. Tetrahedron Lett.
2007, 48, 647–650.
(10) Okitsu, T.; Sato, K.; Wada, A. Org. Lett. 2010, 12, 3506–3509.
(11) Crone, B.; Kirsch, S. F.; Umland, K.-D. Angew. Chem., Int. Ed.
2010, 49, 4661–4664.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra for
S
b
all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: a-wada@kobepharma-u.ac.jp.
’ ACKNOWLEDGMENT
This work was supported by a Grant-in Aid for Encourage-
ment of Young Scientists form the Ministry of Education,
Culture, Sports, Science and Technology and by grant from
the Science Research Promotion Fund of the Japanese Private
School Promotion Foundation.
’ REFERENCES
(12) (a) Okitsu, T.; Nakazawa, D.; Taniguchi, R.; Wada, A. Org. Lett.
2008, 10, 4967–4970. (b) Okitsu, T.; Nakazawa, D.; Kobayashi, A.;
Mizohata, M.; In, Y.; Ishida, T.; Wada, A. Synlett 2010, 203–206.
(13) (a) Koenig, S. G.; Miller, S. M.; Leonard, K. A.; L€owe, R. S.;
Chen, B. C.; Austin, D. J. Org. Lett. 2003, 5, 2203–2206. (b) Jackson,
S. K.; Karadeolian, A.; Driega, A. B.; Kerr, M. A. J. Am. Chem. Soc. 2008,
130, 4196–4201.
(14) Homsi, F.; Robin, S.; Rousseau, G. Org. Synth. 2000, 77, 206–211.
(15) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46–49.
(16) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
(17) Heck, R. F. Org. React. 1982, 27, 345–390.
(18) Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.; Koboldt,
C. M.; Masferrer, J. L.; Perkins, W. E.; Rogers, R. S.; Shaffer, A. F.; Zhang,
Y. Y.; Zweifel, B. S.; Seibert, K. J. Med. Chem. 2000, 43, 775–777.
(19) Crich, D.; Wu, B. Org. Lett. 2006, 8, 4879–4882.
(20) Kwong, F. Y.; Li, Y. M.; Lam, W. H.; Qiu, L.; Lee, H. W.; Yeung,
C. H.; Chan, K. S.; Chan, A. S. C. Chem.—Eur. J. 2005, 11, 3872–3880.
(21) Carpino, L. A.; Han, G. Y. J. Org. Chem. 1972, 37, 3404–3409.
(22) Zhang, W.; Luo, Z.; Chen, C. H.-T.; Curran, D. P. J. Am. Chem.
Soc. 2002, 124, 10443–10450.
(1) For isoxazoles, see: (a) Alsalameh, S.; Burian, M.; Mahr, G.;
Woodcock, B. G.; Geisslinger, G. Aliment. Pharmacol. Ther. 2003,
17, 489–501. (b) Niho, N.; Kitamura, T.; Takahashi, M.; Mutoh, M.;
Sato, H.; Matsuura, M.; Sugimura, T.; Wakabayashi, K. Cancer Sci. 2006,
97, 1011–1014. (c) Mangold, U.; Dax, C. I.; Saar, K.; Schwab, W.;
Kirschbaum, B.; M€ullner, S. Eur. J. Biochem. 1999, 266, 1184–1191.
(d) Rowley, M.; Broughton, H. B.; Collins, I.; Baker, R.; Emms, F.;
Marwood, R.; Patel, S.; Ragan, C. I.; Freedman, S. B.; Leeson, P. D. J. Med.
Chem. 1996, 39, 1943–1945.
(2) For dihydroisoxazoles, see: (a) Pulkkinen, J. T.; Honkakoski, P.;
Per€akyl€a, M.; Berczi, I.; Laatikainen, R. J. Med. Chem. 2008,
51, 3562–3571. (b) Maksimovic-Ivanic, D.; Mijatovic, S.; Harhaji, L.;
Miljkovic, D.; Dabideen, D.; Cheng, K. F.; Mangano, K.; Malaponte, G.;
Al-Abed, Y.; Libra, M.; Garotta, G.; Nicoletti, F.; Stosic-Grujicic, S. Mol.
Cancer Ther. 2008, 7, 510–520. (c) Dallannoce, C.; Magrone, P.; Bazza,
P.; Grazioso, G.; Rizzi, L.; Riganti, L.; Gotti, C.; Clementi, F.; Frydenvang,
K.; De Amici, M. Chem. Biodiv. 2009, 6, 244–259. (d) Conti, P.; di
Ventimiglia, S. J.; Pinto, A.; Tamborini, L.; Menniti, F. S.; Lazzaro, J. T.;
De Micheli, C. Chem. Biodiv. 2008, 5, 657–663. (e) Hentschel, F.; Lindel,
T. Synthesis 2010, 181–204 and references therein.
(23) Yi, X.-H.; Meng, Y.; Hua, X.-G.; Li, C.-J. J. Org. Chem. 1998, 63,
7472–7480.
(3) For a review, see: Wakefield, B. J. In Science of Synthesis: Houben-Weyl
Methods of Molecular Transformations; Shaumann, E., Ed.; Georg Thieme
Verlag: Stuttgart, 2001; Vol. 11, pp 229ꢀ288.
(24) Moreau, E.; Fortin, S.; Desjardins, M.; Rousseau, J. L. C.;
ꢀ
Petitclerc, E.; C.-Gaudreault, R. Bioorg. Med. Chem. 2005, 13, 6703–6712.
(4) (a) Zhu, M.-K.; Zhao, J.-F.; Loh, T.-P. J. Am. Chem. Soc. 2010,
132, 6284–6285. (b) Yu, X.; Du, B.; Wang, K.; Zhang, J. Org. Lett. 2010,
12, 1876–1879. (c) Debleds, O.; Zotto, C. D.; Vrancken, E.; Campagne,
J.-M.; Retailleau, P. Adv. Synth. Catal. 2009, 351, 1991–1998. (d) Suga,
H.; Adachi, Y.; Fujimoto, K.; Furihata, Y.; Tsuchida, T.; Kakehi, A.; Baba,
T. J. Org. Chem. 2009, 74, 1099–1113. (e) Cecchi, L.; De Sarlo, F.;
Machetti, F. Chem.—Eur. J. 2008, 14, 7903–7912 and references therein.
(5) Yeom, H.-S.; Lee, E.-S.; Shin, D. Synlett 2007, 2292–2294.
(6) For reviews, see: (a) French, A. N.; Bissmire, S.; Wirth, T. Chem.
Soc. Rev. 2004, 33, 354–362. (b) Larock, R. C. Acetylene Chem.
2005, 51–99. (c) Togo, H.; Iida, S. Synlett 2006, 2159–2175.
(d) Mphahlele, M. J. Molecules 2009, 14, 4814–4837.
(25) Sudeshna, S.; Dipankar, S.; Piyali, D.; Rima, L.; Amitabha, S.
Tetrahedron 2009, 65, 4367–4374.
(26) Franks, M. A.; Schrader, E. A.; Pietsch, E. C.; Pennella, D. R.;
Torti, S. V.; Welker, M. E. Bioorg. Med. Chem. 2005, 13, 2221–2233.
(27) Doutheau, A.; Gorg, J.; Diab, J. Tetrahedron 1985, 41, 329–338.
(28) Tessier, P. E.; Nguyen, N.; Clay, M. D.; Fallis, A. G. Org. Lett.
2005, 7, 767–770.
(29) Tirpak, M. R.; Hollingsworth, C. A.; Wotiz, J. H. J. Org. Chem.
1960, 25, 687–690.
(7) For selected papers on the iodocyclizations of alkynes, see:
(a) Fischer, D.; Tomeba, H.; Pahadi, N. K.; Patil, N. T.; Yamamoto,
Y. Angew. Chem., Int. Ed. 2007, 46, 4764–4766. (b) Worlikar, S. A.;
Kesharwani, T.; Yao, T.; Larock, R. C. J. Org. Chem. 2007,
72, 1347–1353. (c) Halim, R. H.; Scammells, P. J.; Flynn, B. L. Org.
3449
dx.doi.org/10.1021/jo200407b |J. Org. Chem. 2011, 76, 3438–3449