Regioselective hydration of terminal halo-substituted propargyl carboxylates by gold catalyst: Synthesis of α-acyloxy α'-halo ketones

Article abstract of DOI:10.1021/jo4027319

Regioselective hydration of the terminal halo-substituted propargyl carboxylate by gold(I) catalyst is reported. The mild catalytic conditions tolerate common acid-labile protecting groups, and a wide variety of α-acyloxy α'-halo ketones are efficiently synthesized within a short reaction time. The α-acyloxy α'-halo ketones are used for the synthesis of 2-aminothiazoles.

Full text of DOI:10.1021/jo4027319

Article
pubs.acs.org/joc
Regioselective Hydration of Terminal Halo-Substituted Propargyl
Carboxylates by Gold Catalyst: Synthesis of α‑Acyloxy α′-Halo
Ketones
Nayan Ghosh, Sanatan Nayak, B Prabagar, and Akhila K. Sahoo*
School of Chemistry, University of Hyderabad, Hyderabad 500046, India
S
* Supporting Information
ABSTRACT: Regioselective hydration of the terminal halo-
substituted propargyl carboxylate by gold(I) catalyst is
reported. The mild catalytic conditions tolerate common
acid-labile protecting groups, and a wide variety of α-acyloxy
α′-halo ketones are efficiently synthesized within a short
reaction time. The α-acyloxy α′-halo ketones are used for the
synthesis of 2-aminothiazoles.
The presence of easily modifiable multifunctional groups
such as halo, keto, and carboxylate makes the compound 2 an
important building block in the fabrication of complex
molecules.10 Inspired by the results of Zhang’s group,8 and
considering the broad synthetic utility of 2, we are interested in
establishing an efficient and gram scale synthetic procedures for
2 via the regioselective hydration of 1 by applying our
previously developed gold-catalyzed conditions.11a Herein, we
report an atom-economical hydration of readily accessible halo-
substituted propargyl carboxylate 1 under the catalytic
conditions comprising of Ph3PAuCl/AgSbF6 (3.0 mol %) and
H2O (3.0 equiv) in 1,4-dioxane/CH3NO2 (20:1) at room
temperature to the efficient synthesis of wide array of α-acyloxy
α′-halo ketones.
INTRODUCTION
■
The hydration of alkynes results in the incorporation of an
easily modifiable carbonyl functional moiety in the molecules.1
Despite the numerous findings available on the acid-mediated
attack of water on unactivated alkynes,2 the use of gold catalyst
for the regioselective hydration of alkynes is noteworthy.3,4
Moreover, the presence of a neighboring ester moiety in
alkynes, e.g., propargyl carboxylates, would induce the
regioselective incorporation of the carbonyl functional group.5
In general, the structure of the propargyl carboxylates
determines the 1,2- and 1,3-migration of the carboxylate
group in the gold-catalyzed transformations.6,7 Recently, the
Zhang group demonstrated the gold-catalyzed regioselective
1,2-acyloxy migration of terminally halogenated propargyl
carboxylates to the synthesis of 1-halo-2-carboxy-1,3-dienes (3
in Scheme 1).8 Interestingly, the presence of an electronegative
RESULTS AND DISCUSSION
■
We first examined the regioselective hydration of 4-bromo-1-
phenylbut-3-yn-2-yl acetate (1a) under various gold catalyst-
s.11a,12,13 The optimization studies are detailed in Table 1. The
combination of Ph3PAuCl (3.0 mol %), AgSbF6 (3.0 mol %),
and H2O (3.0 equiv) in 1,4-dioxane at room temperature
furnished the desired 4-bromo-3-oxo-1-phenylbutan-2-yl ac-
etate (2a) in 75% yield with the complete consumption of 1a
within 4 h (entry 1). Screening of other Au catalysts such as
AuCl3 or AuCl along with AgSbF6 yielded 2a in up to 51% yield
(entries 2 and 3). The yield of 2a was improved to 67% when
solvents THF, acetone, dichloromethane, and acetonitrile were
employed instead of dioxane (entries 4−7). The combinations
of AgOTf or AgBF4 with Ph3PAuCl were found to be
moderate; the reaction did not undergo completion even
with prolonged time (entries 8 and 9). The reaction of 1a with
water under Zhang’s catalytic conditions produced 2a in only
46% yield,8 recovering the unreacted precursor 1a (52%) (entry
Scheme 1. Mode of Rearrangements of Terminal Halo-
Substituted Propargyl Carboxylate
halo group at the alkyne terminus enhances the polarization of
the alkynes and facilitates activating the alkyne moiety by gold;9
this in turn induces the regioselective nucleophilic attack of the
neighboring acyloxy group (A in Scheme 1). Surprisingly, the
Zhang group observed the formation of a trace amount of
hydration product α-acyloxy α′-halo ketone (2) along with 3 in
the optimization studies (Scheme 1).8
Received: December 9, 2013
Published: March 4, 2014
© 2014 American Chemical Society
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a
Table 1. Optimization of Reaction Conditions
Table 2. Effect of Aryl Substituents at the Propargyl Position
toward Hydration of 1
a,b
catalyst
(3.0 mol %)
cocatalyst
(3.0 mol %)
time
(h) yield (%)
b
entry
solvent
1
2
3
4
5
6
7
8
9
10
Ph3PAuCl
AuCl3
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgOTf
AgBF4
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
4
4
4
4
4
4
4
4
4
4
4
75
c
51 (21)
trace
67
AuCl
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
Ph3PAuNTf2
Ph3PAuCl
acetone
61
CH2Cl2
32
CH3CN
42
c
c
c
1,4-dioxane
1,4-dioxane
CH2Cl2
49 (36)
39 (45)
46 (52)
93
d
11
AgSbF6
AgSbF6
AgSbF6
AgSbF6
1,4-dioxane/
CH3NO2
12
13
14
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
1,4-dioxane/
DMSO
4
4
4
trace
trace
67
1,4-dioxane/
DMF
CH3NO2
a
Reactions were carried out using 1 (1.0 mmol), Ph3PAuCl/AgSbF6
a
Reactions were carried out using 1a (0.5 mmol) and solvent (1.0 mL)
(0.03 mmol), H2O (3.0 mmol), and 1,4-dioxane/CH3NO2 (2.0 mL,
20:1) at 0 °C to rt. Isolated yields.
b
c
b
at rt. Isolated yields. Yield of recovered 1a is given in the
parentheses. 1a was added at 0 °C in a mixture of solvent (1.0 mL,
d
20:1) and then stirred at rt.
Table 3. Effect of Alkyl Group at the Propargyl Position
toward Hydration of 1
a,b
10). We next examined the effect of mixture of solvents on the
reaction outcome. Gratifyingly, 2a was isolated in 93% yield,
when a solvent mixture 1,4-dioxane and CH3NO2 (20:1) was
employed (entry 11), while 1,4-dioxane with DMSO/DMF
mixture were ineffective (entries 12 and 13). The reaction in
wet nitromethane produced 2a in 67% yield (entry 14). Thus,
different catalytic conditions allow in accessing two distinct products
from the precursor 1a.8
Reaction Scope. The optimal reaction conditions
[Ph3PAuCl, AgSbF6, and H2O in 1,4-dioxane/CH3NO2
(20:1); entry 11, Table 1] were surveyed to investigate the
generality of the hydration of the terminal halo-substituted
propargyl acetates (Tables 2 and 3). The stereoelectronic effect
of substituents on the aryl moiety at the propargyl position was
explored at first, and the results are summarized in Table 2. The
hydration of 3-bromo-1-phenylprop-2-ynyl acetate 1b gave 86%
isolated yield of 2b. The electron-withdrawing and -donating
groups at the 4/3/2 positions on the aryl moiety reacted
efficiently, and the desired keto products were obtained in good
to excellent yields (2c−g). The o-O-allyl moiety on aromatic
ring in 1h did not affect the reaction outcome, producing 2h in
81% yield. The 1-naphthyl-bearing hydration product 2i was
cleanly obtained from 1i. Gratifyingly, the di-ortho-substituted
sterically demanding substrate 1j efficiently hydrated, delivering
90% of 2j.
We next investigated the hydration of alkyl moieties bearing
Br-propargyl acetates (Table 3). As observed in the
optimization reaction conditions (entry 11, Table 1), the α-
benzyl-substituted α-acyloxy-α′-bromo ketone 2a was isolated
in 92% yield from 1a. Similarly, hydration of N-Boc-protected
3-indolyl-substituted bromo propargyl acetate 1k gave 79% of
2k within 1.5 h. The easily modifiable functional groups (Br
and N3) as well as the -NHBoc, -OTHP, and -OBn protecting
groups on alkyl chain are well-tolerated and the desired
a
Reactions were carried out using 1 (1.0 mmol), Ph3PAuCl/AgSbF6
(0.03 mmol), H2O (3.0 mmol), and 1,4-dioxane/CH3NO2 (2.0 mL,
20:1) at 0 °C−rt. Isolated yields. Reaction of 1a (1.0 g, 3.76 mmol)
under the optimized conditions gave 2a (779 mg, 73%). O-TBDMS
b
c
d
bond of 1q cleaved under optimized conditions and produced 2q.
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products 2l−p are obtained in lucrative yields, demonstrating
the mild nature of the catalytic conditions. The Au-catalyzed
hydration of O-TBDMS-protected 1q gave the desilylated 2q in
92% yield. The sterically demanding cyclic-substituted acetates
1r and 1s did not affect the hydration, affording 2r and 2s in
good yields with the survival of the acid-sensitive 1,3-dioxolane
moiety in 2s. The O-pivolate group also directs the hydration of
bromoalkyne 1t, generating the desired product 2t in 85% yield.
The reaction of N-SO2Ph-protected indole-3-susbtituted
bromopropargyl acetate 1u under the optimized conditions
was found to be complex, although a trace amount of the
synthesis of heterocycles. The α-halo ketones are successfully
used for the construction of large varieties of heterocycles.9a
Gratifyingly, the condensation of 2b and 2e with thiourea in
EtOH independently delivered 4-benzyl-substituted 2-amino-
thiazole 9a and 9b in good yields (eq 1, Scheme 3); the acetate
Scheme 3. Synthetic Utility of α-Acyloxy α′-Halo Ketones
1
desired hydration product was detected in crude H NMR;
however, our effort in obtaining the pure product 2u failed.
Next, the hydration of terminal chloro- and iodo-substituted
propargyl acetates were examined (Scheme 2). The chloro-
Scheme 2. Effect of Chloro and Iodo Groups at Alkyne
Terminus on Propargyl Acetates to the Gold-Catalyzed
Hydration Reaction
group at the benzylic position is replaced with an ethoxy moiety
during the reaction. However, the reaction between α-alkyl α-
acyloxy α′-halo ketones 2a and thiourea did not affect the
acetate moiety, affording 10 in 65% yield (eq 2, Scheme 3).
We then investigated the effect of different protecting groups
on the O-propargyl alcohol for the hydration reaction (Table
4). A trace amount of hydration product 12a was noticed when
a,b
Table 4. Effect of Directing Group
b
entry
11/1a/1t
R
time (h)
12/2a/2t
yield (%)
1
2
3
4
5
11a
11b
11c
1a
H
4
4
4
4
4
12a
12b
12c
2a
trace
NR
83
Me
substituted propargyl acetate 4a underwent hydration effi-
ciently, and the desired product 6a was isolated in 81% yield
(Scheme 2). The pivolate group is equally effective, producing
6b from the hydration of 4b (Scheme 2). The sterically
encumbered and 1,3-dioxolane-protected cyclohexane bearing
α-acyloxy-α′-chloro ketone 6c was produced from 4c in 81%
yield (Scheme 2). Pleasingly, the substrate with iodo
substitution at the alkyne terminus in 5 underwent hydration
easily, forming 4-iodo-3-oxo-1-phenylbutan-2-yl acetate (7) in
77% yield (Scheme 2).
Finally, the acetate group in the hydration product 2a was
successfully deacetylated with Sc(OTf)3 (20 mol %) in
CH3OH/H2O (4:1) at rt (eq 1). The α-hydroxy α′-bromo
ketone 8 was obtained in 83% yield.11a,14 The compound 8 is
useful for the construction of various molecular fragments.10
benzoyl
acetyl
pivaloyl
92
1t
2t
85
a
Reactions were carried out using 1/11 (1.0 mmol), Ph3PAuCl/
AgSbF6 (0.03 mmol), H2O (3.0 mmol), and 1,4-dioxane/CH3NO2
(2.0 mL, 20:1) at 0 °C to rt. Isolated yields. NR = no reaction.
b
propargyl alcohol 11a reacted under the optimization catalytic
conditions (entry 1). The methyl-protected propargyl ethers
11b did not undergo hydration (entry 2). The benzoyl-
protected propargyl ester 11c furnished the hydration product
12c in 83% yield (entry 3). As shown previously, the substrates
1a and 1t having acetyl and pivaloyl protecting groups on
propargyl alcohol produced the desired hydration products 2a
and 2t in 92% and 85% yields, respectively (entries 4 and 5).
These results reveal that the O-directing group is mandatory in
assisting the regioselective hydration of the alkyne moiety at an
ambient temperature.
On the basis of our previous studies and the effect of O-
directing group to the hydration of alkyne moiety shown in
Table 4,11a the plausible reaction mechanism11b is sketched in
Scheme 4. The reaction initiates with the activation of alkyne
triple bond by carbophilic Au catalyst, forming the transient co-
ordination complex I. The intramolecular 5-exo-dig attack of
acetate carbonyl group to activated alkyne would lead to the 5-
Thus, the Au-catalyzed hydration of terminal-halo-substi-
tuted propargyl acetates provides an efficient access to a broad
range of multifunctional groups such as halo, keto, and
carboxylate bearing α-substituted α-acyloxy α′-halo ketones
(2). We next envisaged exploring the utility of 2 toward the
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Methanol was dried over a magnesium cake. Analytical and spectral
data of all of the known compounds matched the reported values.
Proton and carbon nuclear magnetic resonance spectra (1H NMR,
13C NMR, and 19F NMR) were recorded on 400 MHz (1H NMR, 400
MHz; 13C NMR, 101 MHz; 19F NMR, 376 MHz) and 500 MHz
spectrometers (1H NMR, 500 MHz; 13C NMR, 126 MHz; 19F NMR,
470 MHz) with the solvent resonance as internal standard (1H NMR,
CHCl3 at 7.26 ppm; 13C NMR, CDCl3 at 77.0 ppm). In a few cases,
tetramethylsilane (TMS) at 0.00 ppm was used as the reference
standard. IR spectra were recorded and reported in cm−1. LC−MS
spectra were obtained (EI positive/negative mode) with an ionization
voltage of 70 eV; data are reported in the form of m/z (intensity
relative to base peak 100). Elemental (C, H, N) analysis was carried
out using an EA 1112 analyzer. HRMS were obtained in ESI mode.
TOF and quadrupole mass analyzers were used for the HRMS
measurements. Melting points were determined on an electrothermal
melting point apparatus and are uncorrected.
Scheme 4. Plausible Mechanism
Preparation of 1 and 5: General Procedure (GP-1). Following
the known synthetic methods,11a the O-acetylation of 1″ and 5′ gave 1
and 5, respectively, in excellent yields. The first step involves the
addition of TMS-acetylide to aldehydes (1′) followed by K2CO3-
assisted desilylation to provide 3.8,11a Next, the Ag-catalyzed Br/I
insertion to the alkyne terminus in 3 delivered the desired 1″ and 5′
(Scheme 5).8 The spectral data of compounds 1″ and 5′ match the
reported values.8 The aldehydes 1′l−q were prepared following the
literature procedures.13
membered electrophilic vinyl-Au species II.11c The nucleophilic
attack of H2O to II then generates the species III.
Protodemetalation11d and isomerization of III finally delivers
the desired α-acyloxy α′-halo ketone 2. To validate the mode of
water attack to alkyne,15 hydration of 1b with oxygen-18-
enriched water was performed under the optimized conditions.
As anticipated, the 18O-incorporated product 2b′ was obtained
from 1b; molecular mass [272.9973 (M + H)+] confirms the
formation of 2b′.16 Finally, Sc(OTf)3-catalyzed deacetylation of
2b′ gave 2b″ [250.9684 (M + Na)+] with the loss of 18O.14,16
This observation supports the intramolecular assistance of
carbonyl oxygen of the −OAc moiety to the hydration of alkyne
(eq 1, Scheme 4).
4-Bromo-1-phenylbut-3-yn-2-yl acetate (1a): yellow oil (957 mg,
1
43% yield); Rf = 0.55 (19:1 hexane/EtOAc) (silica, UV, and I2); H
NMR (400 MHz, CDCl3) δ 7.36−7.21 (m, 5H), 5.54 (t, J = 4.0 Hz,
1H), 3.08 (d, J = 8.0 Hz, 2H), 2.05 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 169.7, 135.5, 129.6, 128.4, 127.1, 77.2, 65.1, 47.0, 41.0, 20.8;
IR (neat) νmax 3065, 3030, 2934, 2218, 1745, 1496, 1454, 1371, 1228,
1022, 702 cm−1; MS (EI) m/z 268 (M+ + 2, 100), 156 (15). Anal.
Calcd for C12H11BrO2: C, 53.96; H, 4.15. Found: C, 53.86; H, 4.21.
3-Bromo-1-phenylprop-2-ynyl acetate (1b): pale yellow oil (1.11
1
g, 46% yield); Rf = 0.26 (9:1 hexane/EtOAc) (silica, UV, and I2); H
NMR (400 MHz, CDCl3) δ 7.51 (d, J = 6.8 Hz, 2H), 7.40 (d, J = 5.6
Hz, 3H), 6.46 (s, 1H), 2.12 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
169.7, 136.4, 129.1, 128.8, 127.7, 76.9, 66.1, 48.1, 21.0; IR (neat) νmax
2222, 1739, 1454, 1373, 1228, 1018 cm−1; MS (EI) m/z 254 (M+ + 2,
19), 253 (M+ + 1, 100). Anal. Calcd for C11H9BrO2: C, 52.20; H, 3.58.
Found: C, 52.36; H, 3.51.
CONCLUSION
■
In summary, the combination of commercially available catalyst
[Ph3PAuCl and AgSbF6] in dioxane/CH3NO2 hydrates a wide
range of readily accessible terminal halo-substituted propargyl
carboxylates (Br, Cl, and I), delivering a series of α-acyloxy α′-
halo ketones in good to excellent yields. Various acid-sensitive
protecting groups survived, and the reaction conditions did not
affect the common functional groups. The hydration products
α-acyloxy α′-bromo ketones have been used for the synthesis of
substituted 2-aminothiazole derivatives. Current efforts are
directed toward unraveling the synthetic potential of this
strategy.
3-Bromo-1-(4-fluorophenyl)prop-2-ynyl acetate (1c): colorless
solid (857 mg, 39% yield); mp = 49−50 °C; Rf = 0.56 (30:1
1
hexane/EtOAc) (silica, UV, and I2); H NMR (400 MHz, CDCl3) δ
7.49 (br t, J = 5.6 Hz, 2H), 7.08 (t, J = 8.8 Hz, 2H), 6.42 (s, 1H), 2.11
(s, 3H). 13C NMR (101 MHz, CDCl3) δ 169.6, 163.1 (d, J = 249 Hz),
132.4, 129.7 (d, J = 8.4 Hz), 115.7 (d, J = 21.8 Hz), 76.5, 65.5, 48.4,
21.0. 19F NMR (470 MHz, CDCl3) δ −110.72 (q, J = 5.2 Hz). IR
(KBr) νmax 2220, 1732, 1604, 1512, 1369, 1226, 1059 cm−1. MS (EI)
m/z 273 (M+ + 3, 92), 271 (M+ + 1, 100), 243 (34), 130 (18). Anal.
Calcd for C11H8BrFO2: C, 48.74; H, 2.97. Found: C, 48.85; H, 2.91.
3-Bromo-1-p-tolylprop-2-ynyl acetate (1d). pale yellow oil (925
mg, 42% yield). Rf = 0.62 (19:1 hexane/EtOAc) (silica, UV, and I2);
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.0 Hz, 2H), 7.21 (d, J =
7.6 Hz, 2H), 6.43 (s, 1H), 2.38 (s, 3H), 2.11 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 169.7, 139.2, 133.5, 129.4, 127.7, 76.9, 66.1, 47.9,
21.2, 21.0; IR (neat) νmax 2928, 1745, 1516, 1373, 1230, 1022 cm−1;
EXPERIMENTAL SECTION
■
General Information. Unless otherwise noted, all of the reagents
and intermediates were obtained commercially and used without
purification. Dichloromethane (CH2Cl2), acetonitrile (CH3CN),
acetone, nitromethane (CH3NO2), dimethyl sulfoxide (DMSO), and
dimethylformamide (DMF) were distilled over CaH2. THF was freshly
distilled over sodium/benzophenone ketyl under dry nitrogen.
Scheme 5. General Procedure for the Synthesis of Precursors 1, 4, and 5
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MS (EI) m/z 265 (M+ − 1, 5), 235 (34), 192 (100), 151 (40). Anal.
Calcd for C12H11BrO2: C, 53.96; H, 4.15. Found: C, 53.91; H, 4.23.
3-Bromo-1-(3-methoxyphenyl)prop-2-ynyl acetate (1e): pale
yellow oil (1.10 g, 53% yield); Rf = 0.34 (19:1 hexane/EtOAc) (silica,
UV, and I2); 1H NMR (400 MHz, CDCl3) δ 7.31 (t, J = 8.0 Hz, 1H),
7.08 (d, J = 7.6 Hz, 1H), 7.04 (s, 1H), 6.91 (d, J = 8.0 Hz, 1H), 6.42
(s, 1H), 3.83 (s, 3H), 2.12 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
169.6, 159.8, 137.8, 129.8, 119.9, 114.6, 113.2, 76.7, 66.0, 55.3, 48.1,
21.0; IR (neat) νmax 3472, 2942, 1743, 1602, 1228, 1037 cm−1; MS
(EI) m/z 284 (M+ + 2, 100), 270 (29), 183 (5). Anal. Calcd for
C12H11BrO3: C, 50.91; H, 3.92. Found: C, 51.06; H, 3.85.
1,8-Dibromooct-1-yn-3-yl acetate (1l): colorless oil (825 mg, 45%
yield); Rf = 0.70 (10:1 hexane/EtOAc) (silica, UV, and I2); H NMR
1
(400 MHz, CDCl3) δ 5.35 (t, J = 6.8 Hz, 1H), 3.41 (t, J = 6.8 Hz, 2H),
2.08 (s, 3H), 1.93−1.84 (m, 2H), 1.81−1.73 (m, 2H), 1.53−1.40 (m,
4H); 13C NMR (101 MHz, CDCl3) δ 169.8, 77.5, 64.4, 46.0, 34.3,
33.5, 32.5, 27.6, 24.1, 20.9; IR (neat) νmax 2937, 2216, 1745, 1371,
1230, 1020 cm−1; MS (EI) m/z 326 (M+ + 2, 81), 324 (M+, 100), 246
(13), 234 (12). Anal. Calcd for C10H14Br2O2: C, 36.84; H, 4.33.
Found: C, 36.85; H, 4.39.
8-Azido-1-bromooct-1-yn-3-yl acetate (1m): colorless oil (925
mg, 46% yield); Rf = 0.73 (4:1 hexane/EtOAc) (silica, UV, and I2); 1H
NMR (400 MHz, CDCl3) δ 5.36 (t, J = 6.8 Hz, 1H), 3.28 (t, J = 6.8
Hz, 2H), 2.08 (s, 3H), 1.83−1.74 (m, 2H), 1.69−1.58 (m, 2H), 1.52−
1.35 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 169.8, 77.5, 64.4, 51.3,
46.0, 34.4, 28.7, 26.2, 24.5, 20.9; IR (neat) νmax 3391, 2941, 2096,
1745, 1456, 1228, 1020 cm−1; MS (EI) m/z 289 (M+ + 2, 83), 288
(M+ + 1, 100), 170 (13), 119 (10). Anal. Calcd for C10H14BrN3O2: C,
41.68; H, 4.90; N, 14.58. Found: C, 41.75; H, 4.86; N, 14.45.
1-Bromo-8-(tert-butoxycarbonylamino)oct-1-yn-3-yl acetate
(1n): colorless oil (708 mg, 42% yield); Rf = 0.58 (4:1 hexane/
EtOAc) (silica, UV, and I2); 1H NMR (400 MHz, CDCl3) δ 5.33 (t, J
= 6.4 Hz, 1H), 4.54 (br s, 1H), 3.10 (br d, J = 5.6 Hz, 2H), 2.07 (s,
3H), 1.82−1.79 (m, 2H), 1.55−1.40 (m, 13H), 1.39−1.27 (m, 2H);
13C NMR (101 MHz, CDCl3) δ 169.9, 156.0, 79.1, 77.5, 64.5, 45.9,
3-Bromo-1-(2-chlorophenyl)prop-2-ynyl acetate (1f): colorless
solid (777 mg, 38% yield); mp = 66−67 °C; Rf = 0.49 (19:1
1
hexane/EtOAc) (silica, UV, and I2); H NMR (400 MHz, CDCl3) δ
7.73 (br d, J = 6.4 Hz, 1H), 7.41 (br d, J = 6.8 Hz, 1H), 7.39−7.25 (m,
2H), 6.75 (s, 1H), 2.13 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
169.3, 133.8, 133.3, 130.4, 129.8, 129.3, 127.2, 75.7, 63.3, 48.5, 20.7; IR
(KBr) νmax 2224, 1741, 1440, 1217, 1047 cm−1; MS (EI) m/z 288 (M+
+ 2, 100), 270 (11), 232 (8), 200 (10). Anal. Calcd for C11H8BrClO2:
C, 45.95; H, 2.80. Found: C, 46.08; H, 2.85.
3-Bromo-1-o-tolylprop-2-ynyl acetate (1g): pale yellow oil (835
mg, 38% yield); Rf = 0.56 (30:1 hexane/EtOAc) (silica, UV, and I2);
1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.0 Hz, 1H), 7.33−7.25
(m, 2H), 7.20 (d, J = 8.0 Hz, 1H), 6.57 (s, 1H), 2.42 (s, 3H), 2.13 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 169.6, 136.2, 134.4, 130.9,
129.1, 127.9, 126.4, 76.5, 64.2, 47.9, 20.9, 19.0; IR (neat) νmax 2934,
2218, 1743, 1369, 1226, 1016 cm−1; MS (EI) m/z 266 (M+, 23), 265
(M+ − 1, 100), 205 (38), 175 (46), 143 (69), 79(15). Anal. Calcd for
C12H11BrO2: C, 53.96; H, 4.15. Found: C, 54.10; H, 4.08.
40.4, 34.5, 29.9, 28.4, 26.3, 24.6, 20.9; IR (neat) νmax 3373, 2934, 1743,
1699, 1521, 1234, 1020 cm−1; MS (EI) m/z 363 (M+ + 2, 24), 362
(M+ + 1, 24), 361 (M+, 24), 339 (100), 306 (59), 164 (30). Anal.
Calcd for C15H24BrNO4: C, 49.73; H, 6.68; N, 3.87. Found: C, 49.65;
H, 6.73; N, 3.80.
1-Bromo-8-(tetrahydro-2H-pyran-2-yloxy)oct-1-yn-3-yl acetate
(1o): pale yellow oil (750 mg, 43% yield); Rf = 0.26 (9:1 hexane/
EtOAc) (silica, UV, and I2); 1H NMR (400 MHz, CDCl3) δ 5.35 (t, J
= 6.8 Hz, 1H), 4.57 (br t, J = 4.4 Hz, 1H), 3.92−3.79 (m, 1H), 3.77−
3.69 (m, 1H), 3.56−3.44 (m, 1H), 3.42−3.31 (m, 1H), 2.08 (s, 3H),
1.89−1.69 (m, 3H), 1.68−1.48 (m, 7H), 1.47−1.34 (m, 4H); 13C
NMR (101 MHz, CDCl3) δ 169.9, 98.9, 77.6, 67.4, 64.6, 62.3, 45.8,
34.5, 30.8, 29.5, 25.8, 25.5, 24.8, 20.9, 19.7; IR (neat) νmax 2941, 1745,
1371, 1230, 1024 cm−1; MS (EI) m/z 348 (M+ + 2, 70), 347 (M+,
100), 276 (56), 219 (98). Anal. Calcd for C15H23BrO4: C, 51.88; H,
6.68. Found: C, 51.76; H, 6.75.
8-(Benzyloxy)-1-bromooct-1-yn-3-yl acetate (1p): yellow oil (757
mg, 44% yield); Rf = 0.33 (6:1 hexane/EtOAc) (silica, UV, and I2); 1H
NMR (400 MHz, CDCl3) δ 7.36−7.33 (m, 4H), 7.31−7.27 (m, 1H),
5.36 (t, J = 6.8 Hz, 1H) 4.51 (s, 2H), 3.48 (t, J = 6.4 Hz, 2H), 2.08 (s,
3H), 1.84−1.73 (m, 2H), 1.68−1.59 (m, 2H), 1.52−1.37 (m, 4H); 13C
NMR (101 MHz, CDCl3) δ 169.8, 138.6, 128.4, 127.6, 127.5, 77.7,
72.9, 70.2, 64.6, 45.8, 34.6, 29.6, 25.8, 24.8, 20.9; IR (neat) νmax 3466,
2937, 2860, 2216, 1745, 1371, 1230, 1022 cm−1; MS (EI) m/z 354
(M+ + 2, 92), 353 (M+ + 1, 16), 352 (M+, 100), 197 (15). Anal. Calcd
for C17H21BrO3: C, 57.80; H, 5.99. Found: C, 57.69; H, 5.92.
1-Bromo-8-(tert-butyldimethylsilyloxy)oct-1-yn-3-yl acetate (1q):
colorless oil (635 mg, 39% yield); Rf = 0.70 (9:1 hexane/EtOAc)
(silica, UV, and I2); 1H NMR (400 MHz, CDCl3) δ 5.35 (br t, J = 6.4
Hz, 1H), 3.61 (br t, J = 6.4 Hz, 2H), 2.08 (s, 3H), 1.81−1.72 (m, 2H),
1.58−1.30 (m, 6H), 0.90 (s, 9H), 0.05 (s, 6H); 13C NMR (101 MHz,
CDCl3) δ 169.9, 77.6, 64.6, 62.9, 45.8, 34.6, 32.6, 26.0, 25.4, 24.7, 20.9,
18.4, −5.3; IR (neat) νmax 2932, 2858, 1749, 1371, 1230, 1101, 1022
cm−1; MS (EI) m/z 378 (M+ + 2, 100), 377 (M+ + 1, 94), 317 (38),
187 (38), 105 (38). Anal. Calcd for C16H29BrO3Si: C, 50.92; H, 7.75.
Found: C, 50.88; H, 7.69.
1-(2-(Allyloxy)phenyl)-3-bromoprop-2-ynyl acetate (1h): pale
yellow oil (695 mg, 37% yield); Rf = 0.73 (9:1 hexane/EtOAc)
1
(silica, UV, and I2); H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 7.6
Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 6.89 (d, J =
8.4 Hz, 1H), 6.85 (s, 1H), 6.10−5.95 (m, 1H), 5.41 (d, J = 17.2 Hz,
1H), 5.28 (d, J = 10.4 Hz, 1H), 4.58 (br d, J = 4.4 Hz, 2H), 2.10 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 169.6, 155.6, 132.8, 130.5,
128.9, 124.7, 120.8, 117.3, 112.0, 76.7, 68.9, 61.2, 47.2, 20.9; IR (neat)
νmax 2218, 1741, 1602, 1043 cm−1; MS (EI) m/z 309 (M+ + 1, 18),
307 (25), 251 (90), 249 (100), 141 (25), 100 (94), 83 (41). Anal.
Calcd for C14H13BrO3: C, 54.39; H, 4.24. Found: C, 54.28; H, 4.35.
3-Bromo-1-(naphthalen-1-yl)prop-2-ynyl acetate (1i): brown oil
(884 mg, 45% yield); Rf = 0.51 (19:1 hexane/EtOAc) (silica, UV, and
I2); 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 7.6 Hz, 1H), 7.90 (br
t, J = 4.0 Hz, 2H), 7.80 (d, J = 7.2 Hz, 1H), 7.63−7.45 (m, 3H), 7.08
(s, 1H), 2.13 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.8, 134.0,
131.7, 130.4, 130.1, 128.9, 126.8, 126.6, 126.1, 125.2, 123.5, 77.1, 64.5,
48.6, 21.0; IR (neat) νmax 3055, 2935, 2220, 1938, 1747, 1597, 1512,
1371, 1217, 777 cm−1; MS (EI) m/z 301 (M+ − 1, 16), 229 (59), 212
(38), 197 (100). Anal. Calcd for C15H11BrO2: C, 59.43; H, 3.66.
Found: C, 59.23; H, 3.61.
3-Bromo-1-(2,6-dimethoxyphenyl)prop-2-ynyl acetate (1j): color-
less solid (820 mg, 43% yield); mp = 116−117 °C; Rf = 0.42 (9:1
1
hexane/EtOAc) (silica, UV, and I2); H NMR (400 MHz, CDCl3) δ
7.28 (d, J = 8.0 Hz, 1H), 7.10 (s, 1H), 6.58 (d, J = 8.4 Hz, 2H) 3.88 (s,
6H), 2.08 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 170.0, 158.7,
130.8, 112.9, 104.6, 77.2, 57.5, 56.3, 44.2, 21.1; IR (KBr) νmax 2214,
1743, 1597, 1479, 1255, 1224, 1109 cm−1; MS (EI) m/z 314 (M+ + 2,
13), 313 (M+ + 1, 100). Anal. Calcd for C13H13BrO4: C, 49.86; H,
4.18. Found: C, 49.96; H, 4.12.
tert-Butyl 3-(2-acetoxy-4-bromobut-3-ynyl)-1H-indole-1-carbox-
ylate (1k): pale yellow oil (715 mg, 46% yield); Rf = 0.45 (12:1
1-(Bromoethynyl)cyclopentyl acetate (1r): pale yellow oil (1.25 g,
1
1
hexane/EtOAc) (silica, UV, and I2); H NMR (400 MHz, CDCl3) δ
45% yield); Rf = 0.43 (19:1 hexane/EtOAc) (silica, UV, and I2); H
8.15 (d, J = 7.2 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.53 (s, 1H), 7.34 (t,
J = 7.6 Hz, 1H), 7.28 (t, J = 6.8 Hz, 1H), 5.62 (t, J = 6.8 Hz, 1H), 3.20
(d, J = 6.4 Hz, 2H), 2.06 (s, 3H), 1.69 (s, 9H); 13C NMR (101 MHz,
CDCl3) δ 169.7, 149.6, 135.3, 130.5, 124.5, 124.4, 122.5, 119.0, 115.3,
114.6, 83.6, 77.4, 64.5, 47.0, 30.6, 28.2, 20.9; IR (neat) νmax 2980,
2220, 1734, 1454, 1373, 1018, 7463 cm−1; MS (EI) m/z 407 (M+ + 2,
100), 389 (06), 221 (10). Anal. Calcd for C19H20BrNO4: C, 56.17; H,
4.96; N, 3.45. Found: C, 56.25; H, 4.92; N, 3.43.
NMR (400 MHz, CDCl3) δ 2.25−2.11 (m, 4H), 2.04 (s, 3H), 1.81−
1.68 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 169.5, 81.0, 80.3, 45.1,
40.2, 23.2, 21.6; IR (neat) νmax 3470, 2962, 2876, 2208, 1745, 1439,
1367, 1240, 1016 cm−1; MS (EI) m/z 232 (M+ + 2, 21), 231 (M+ + 1,
100). Anal. Calcd for C9H11BrO2: C, 46.78; H, 4.80. Found: C, 46.71;
H, 4.87.
8-(Bromoethynyl)-1,4-dioxaspiro[4.5]decan-8-yl acetate (1s):
colorless oil (863 mg, 44% yield); Rf = 0.48 (19:1 hexane/EtOAc)
2457
dx.doi.org/10.1021/jo4027319 | J. Org. Chem. 2014, 79, 2453−2462

The Journal of Organic Chemistry
Article
1
(silica, UV, and I2); H NMR (400 MHz, CDCl3) δ 3.95 (s, 4H),
flask under an argon atmosphere for 20 min an ambient temperature.
This freshly prepared light pink colored gold−silver complex mixture
was added to another Schlenk flask containing a solution of 1 (1.0
mmol) in CH3NO2 (100 μL) followed by the addition of deionized
water (54 μL, 3.0 mmol) at 0 °C. The resulting reaction mixture was
slowly warmed to room temperature and stirred for the time shown in
the respective tables at an ambient temperature. Upon complete
consumption of precursor, the reaction mixture was diluted with
dichloromethane (10 mL), and filtered through a small pad of Celite.
The solvent was evaporated under reduced pressure, and the crude
reaction mixture was purified using column chromatography on silica
gel.
2.26−2.11 (m, 4H), 2.05 (s, 3H), 1.83−1.67 (m, 4H); 13C NMR (101
MHz, CDCl3) δ 169.3, 107.4, 79.1, 74.4, 64.4, 64.3, 46.5, 34.2, 30.9,
21.7; IR (neat) νmax 3470, 2959, 2883, 2206, 1743, 1444, 1371, 1226,
1168, 1103 cm−1; MS (EI) m/z 303 (M+ + 1, 100), 282 (12). Anal.
Calcd for C12H15BrO4: C, 47.54; H, 4.99. Found: C, 47.65; H, 5.06.
4-Bromo-1-phenylbut-3-yn-2-yl pivalate (1t): pale yellow oil (1.21
g, 47% yield); Rf = 0.66 (30:1 hexane/EtOAc) (silica, UV, and I2); 1H
NMR (400 MHz, CDCl3) δ 7.31 (br t, J = 8.0 Hz, 2H), 7.25 (t, J = 8.0
Hz, 3H), 5.53 (t, J = 8.0 Hz, 1H), 3.09 (d, J = 8.0 Hz, 2H), 1.15 (s,
9H); 13C NMR (101 MHz, CDCl3) δ 177.2, 135.7, 129.7, 128.3,
127.0, 64.9, 46.4, 41.1, 38.7, 27.0; IR (neat) νmax 2974, 2218, 1732,
1479, 1278, 1143, 1033 cm−1; MS (EI) m/z 310 (M+ + 2, 100). Anal.
Calcd for C15H17BrO2: C, 58.27; H, 5.54. Found: C, 58.15; H, 5.63.
3-Bromo-1-(1-(phenylsulfonyl)-1H-indol-3-yl)prop-2-yn-1-yl ace-
tate (1u): pale yellow oil (55 mg, 20% yield); Rf = 0.12 (9:1 hexane/
EtOAc) (silica, UV, and I2; 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J =
8.4 Hz, 1H), 7.93 (d, J = 7.6 Hz, 2H), 7.76 (s, 1H), 7.65 (d, J = 8.0 Hz,
1H), 7.58 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 8.0 Hz, 2H), 7.37 (t, J = 7.6
Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.94 (s, 1H), 2.10 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 169.7, 138.0, 135.2, 134.1, 129.4, 128.0,
127.0, 125.7, 125.3, 123.7, 120.1, 118.1, 113.7, 75.5, 59.1, 47.9, 20.9; IR
(neat) νmax 2931, 2224, 1747, 1451, 1369, 1232, 1177, 1128 cm−1;
HRMS (ESI) for C19H14BrNO4SNa (M + Na)+ calcd 453.9725, found
453.9727.
4-Bromo-3-oxo-1-phenylbutan-2-yl acetate (2a): pale yellow oil
(262 mg, 92% yield); Rf = 0.56 (9:1 hexane/EtOAc) (silica, UV, and
1
I2); H NMR (400 MHz, CDCl3) δ 7.38−7.25 (m, 3H), 7.21 (d, J =
6.8 Hz, 2H), 5.45 (dd, J = 6.4, 4.4 Hz, 1H), 3.93 (d, J = 11.2 Hz, 1H),
3.87 (d, J = 11.2 Hz, 1H), 3.21 (dd, J = 11.2, 4.4 Hz, 1H), 3.11 (dd, J =
11.6, 6.4 Hz, 1H), 2.11 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
198.7, 170.2, 135.2, 129.3, 128.7, 127.3, 77.0, 37.3, 32.4, 20.5; IR
(neat) νmax 2939, 1743, 1726, 1496, 1373, 1232, 1049, 702 cm−1; MS
(EI) m/z 286 (M+ + 2, 65), 285 (M+ + 1, 100), 156 (33). Anal. Calcd
for C12H13BrO3: C, 50.55; H, 4.60. Found: C, 50.42; H, 4.71.
3-Bromo-2-oxo-1-phenylpropyl acetate (2b): pale yellow oil (233
mg, 86% yield); Rf = 0.30 (9:1 hexane/EtOAc) (silica, UV, and I2); 1H
NMR (400 MHz, CDCl3) δ 7.43 (br s, 5H), 6.30 (s, 1H), 4.02 (d, J =
13.6 Hz, 1H), 3.94 (d, J = 13.6 Hz, 1H), 2.20 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 195.6, 170.1, 132.4, 129.9, 129.3, 128.3, 78.3, 31.1,
20.6; IR (neat) νmax 2937, 1747, 1720, 1375 cm−1; MS (EI) m/z 27
(M+ + 1, 100), 156 (62), 127 (28). Anal. Calcd for C11H11BrO3: C,
48.37; H, 4.09. Found: C, 48.62; H, 4.15.
4-Iodo-1-phenylbut-3-yn-2-yl acetate (5): colorless oil (1.31 g,
50% yield); Rf = 0.50 (9:1 hexane/EtOAc) (silica, UV, and I2); H
1
NMR (400 MHz, CDCl3) δ 7.48−7.22 (m, 5H), 5.64 (br t, J = 6.8 Hz,
1H), 3.07 (d, J = 7.4 Hz, 2H), 2.05 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 169.7, 135.6, 129.7, 128.4, 127.1, 91.3, 77.2, 65.7, 41.2, 20.9;
IR (neat) νmax 2930, 1745, 1371, 1128, 1018, 750 cm−1; MS (EI) m/z
316 (M+ + 2, 29), 315 (M+ + 1, 100). Anal. Calcd for C12H11IO2: C,
45.88; H, 3.53. Found: C, 45.76; H, 3.61.
Preparation of 4 from 3: General procedure (GP-2). Following
the known synthetic procedures,8 compounds 4 were prepared from 4′
through O-acetylation in excellent yields. The reaction of 3 with n-
BuLi (2.0 equiv) followed by quenching with NCS allowed access to
4′ in good yields. Spectral data of compound 4′ match reported
values.8
4-Chloro-1-phenylbut-3-yn-2-yl acetate (4a): pale yellow oil (785
mg, 42% yield); Rf = 0.58 (19:1 hexane/EtOAc) (silica, UV, and I2);
1H NMR (400 MHz, CDCl3) δ 7.31 (t, J = 7.6 Hz, 2H), 7.25 (t, J =
7.6 Hz, 3H), 5.53 (t, J = 6.8 Hz, 1H), 3.07 (d, J = 6.8 Hz, 2H), 2.05 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 169.7, 135.5, 129.6, 128.4,
127.1, 66.4, 65.1, 64.6, 41.0, 20.9; IR (neat) νmax 2934, 2245, 1749,
1496, 1454, 1228, 1024 cm−1; MS (EI) m/z 224 (M+ + 2, 10), 223
(M+ + 1, 100), 209 (09), 177 (22). Anal. Calcd for C12H11ClO2: C,
64.73; H, 4.98. Found: C, 64.87; H, 4.92.
4-Chloro-1-phenylbut-3-yn-2-yl pivalate (4b): pale yellow oil (815
mg, 36% yield); Rf = 0.81 (19:1 hexane/EtOAc) (silica, UV, and I2);
1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 7.2 Hz, 2H), 7.24 (d, J =
8.0 Hz, 3H), 5.51 (t, J = 7.2 Hz, 1H), 3.08 (d, J = 6.8 Hz, 2H), 1.15 (s,
9H); 13C NMR (101 MHz, CDCl3) δ 177.2, 135.7, 129.6, 128.3,
127.0, 66.7, 64.6, 64.4, 41.1, 38.7, 27.0; IR (neat) νmax 2974, 2245,
1736, 1479, 1280, 1143, 1032 cm−1; MS (EI) m/z 265 (M+ + 1, 23),
264 (M+, 100). Anal. Calcd for C15H17ClO2: C, 68.05; H, 6.47. Found:
C, 68.15; H, 6.38.
3-Bromo-1-(4-fluorophenyl)-2-oxopropyl acetate (2c): colorless
oil (237 mg, 82% yield); Rf = 0.24 (9:1 hexane/EtOAc) (silica, UV,
and I2); 1H NMR (400 MHz, CDCl3) δ 7.46−7.38 (m, 2H), 7.12 (t, J
= 8.4 Hz, 2H), 6.28 (s, 1H), 3.99 (d, J = 13.6 Hz, 1H), 3.97 (d, J =
13.6 Hz, 1H), 2.19 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 195.6,
170.0, 163.5 (d, J = 251 Hz), 130.2 (d, J = 8.5 Hz), 128.4, 116.4 (d, J =
21.9 Hz), 77.4, 30.8, 20.6. 19F NMR (376 MHz, CDCl3) δ −110.72 (q,
J = 2.6 Hz); IR (neat) νmax 2934, 1755, 1620, 1512, 1221, 1078 cm−1;
MS (EI) m/z 289 (M+ + 1, 100), 287 (62), 269 (18), 201 (27), 81
(97). Anal. Calcd for C11H10BrFO3: C, 45.70; H, 3.49. Found: C,
45.61; H, 3.55.
3-Bromo-2-oxo-1-p-tolylpropyl acetate (2d): pale yellow oil (237
mg, 83% yield); Rf = 0.38 (9:1 hexane/EtOAc) (silica, UV, and I2); 1H
NMR (400 MHz, CDCl3) δ 7.31(br d, J = 8.0 Hz, 2H), 7.23 (br d, J =
8.0 Hz, 2H), 6.26 (s, 1H), 4.01 (d, J = 14.0 Hz, 1H), 3.92 (d, J = 13.6
Hz, 1H) 2.37 (s, 3H), 218 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
195.7, 170.2, 140.0, 130.0, 129.4, 128.3, 78.2, 31.2, 21.3, 20.6; IR
(neat) νmax 2934, 1738, 1725, 1514, 1371, 1230, 1024 cm−1; MS (EI)
m/z 285 (M+ + 1, 64), 283 (M+ − 1, 55), 220 (33), 193 (55), 161
(100). Anal. Calcd for C12H13BrO3: C, 50.55; H, 4.60. Found: C,
50.65; H, 4.53.
3-Bromo-1-(3-methoxyphenyl)-2-oxopropyl acetate (2e): pale
yellow oil (235 mg, 78% yield); Rf = 0.23 (9:1 hexane/EtOAc)
(silica, UV, and I2); 1H NMR (400 MHz, CDCl3) δ 7.34 (t, J = 8.0 Hz,
1H), 7.01 (d, J = 7.6 Hz, 1H), 6.94 (br s, 2H) 6.26 (s, 1H), 4.02 (d, J =
13.6 Hz, 1H), 3.93 (d, J = 13.6 Hz, 1H), 3.83 (s, 3H), 2.20 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 195.4, 170.1, 160.2, 133.7, 130.4,
120.4, 115.5, 113.5, 78.2, 55.4, 31.0, 20.6; IR (neat) νmax 2941, 1745,
1668, 1601, 1373, 1228, 1039 cm−1; MS (EI) m/z 302 (M+ + 2, 54),
301 (M+ + 1, 100). Anal. Calcd for C12H13BrO4: C, 47.86; H, 4.35.
Found: C, 47.92; H, 4.31.
8-(Chloroethynyl)-1,4-dioxaspiro[4.5]decan-8-yl acetate (4c):
colorless oil (890 mg, 54% yield); Rf = 0.28 (30:1 hexane/EtOAc)
1
(silica, UV, and I2); H NMR (400 MHz, CDCl3) δ 3.93 (s, 4H),
2.28−2.15 (m, 4H), 2.06 (s, 3H), 1.85−1.69 (m, 4H); 13C NMR (101
MHz, CDCl3) δ 169.2, 107.4, 73.8, 68.4, 64.7, 64.4, 34.2, 30.9, 21.7; IR
(neat) νmax 2957, 2229, 1747, 1444, 1371, 1116, 1105, 1022 cm−1; MS
(EI) m/z 256 (M+ − 2, 16), 225 (M+ − 3, 100), 229 (27), 169 (29).
Anal. Calcd for C12H15ClO4: C, 55.71; H, 5.84. Found: C, 55.61; H,
5.92.
3-Bromo-1-(2-chlorophenyl)-2-oxopropyl acetate (2f): colorless
oil (262 mg, 86% yield); Rf = 0.30 (9:1 hexane/EtOAc) (silica, UV,
1
and I2); H NMR (400 MHz, CDCl3) δ 7.52−7.28 (m, 4H), 6.70 (s,
1H), 4.13 (d, J = 14.0 Hz, 1H), 4.03 (d, J = 13.6 Hz, 1H), 2.19 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 195.1, 169.9, 133.9, 131.1,
130.8, 130.2, 130.1, 127.7, 74.8, 31.6, 20.5; IR (neat) νmax 2941, 1745,
1637, 1477, 1371, 1224, 1032 cm−1; MS (EI) m/z 305 (M+ + 1, 100),
303 (M+ − 1, 70), 285 (21), 261 (32), 181 (86). Anal. Calcd for
C11H10BrClO3: C, 43.24; H, 3.30. Found: C, 43.37; H, 3.26.
Gold-Catalyzed Hydration of 1, 4, 5, and 11 for the
Preparation of 2, 6, 7, and 12, Respectively: General Procedure
(GP-3). A mixture of PPh3AuCl (14.7 mg, 0.03 mmol) and AgSbF6
(10.2 mg, 0.03 mmol) in dioxane (2.0 mL) was stirred in a Schlenk
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3-Bromo-2-oxo-1-o-tolylpropyl acetate (2g): colorless oil (251
mg, 88% yield); Rf = 0.39 (9:1 hexane/EtOAc) (silica, UV, and I2); 1H
NMR (400 MHz, CDCl3) δ 7.36−7.22 (m, 4H), 6.57 (s, 1H), 3.96 (d,
J = 13.6 Hz, 1H), 3.89 (d, J = 13.6 Hz, 1H), 2.46 (s, 3H), 2.19 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 195.8, 170.0, 137.4, 131.5, 131.1,
129.9, 128.8, 126.8, 75.8, 30.9, 20.7, 19.5; IR (neat) νmax 2943, 1741,
1730, 1371, 1228, 1030 cm−1; MS (EI) m/z 286 (M+ + 2, 62), 285
(M+ + 1, 100), 156 (21). Anal. Calcd for C12H13BrO3: C, 50.55; H,
4.60. Found: C, 50.67; H, 4.54.
1-(2-(Allyloxy)phenyl)-3-bromo-2-oxopropyl acetate (2h): color-
less oil (265 mg, 81% yield); Rf = 0.47 (9:1 hexane/EtOAc) (silica,
UV, and I2); 1H NMR (400 MHz, CDCl3) δ 7.43−7.29 (m, 2H), 7.01
(br t, J = 7.6 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.64 (s, 1H), 6.12−
5.97 (m, 1H), 5.43 (d, J = 16.8 Hz, 1H), 5.34 (d, J = 10.4 Hz, 1H),
4.69−4.52 (m, 2H), 4.14 (d, J = 14.0 Hz, 1H), 4.05 (d, J = 14.0 Hz,
1H), 2.18 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 195.9, 170.1,
155.8, 132.4, 131.0, 130.1, 121.8, 121.4, 118.5, 112.4, 77.4, 73.3, 69.4,
32.0, 20.7; IR (neat) νmax 3468, 2939, 1743, 1715, 1601, 1493, 1226,
1026, 756 cm−1; MS (EI) m/z 327 (M+ + 1, 16), 326 (M+, 100), 292
(24), 256 (32). Anal. Calcd for C14H15BrO4: C, 51.40; H, 4.62. Found:
C, 51.36; H, 4.71.
C10H16BrN3O3: C, 39.23; H, 5.27; N, 13.73. Found: C, 39.36; H, 5.22;
N, 13.65.
1-Bromo-8-(tert-butoxycarbonylamino)-2-oxooctan-3-yl acetate
(2n): colorless oil (331 mg, 87% yield); Rf = 0.39 (4:1 hexane/EtOAc)
1
(silica and I2); H NMR (400 MHz, CDCl3) δ 5.23 (dd, J = 8.0, 4.4
Hz, 1H), 4.53 (br s, 1H), 4.06 (d, J = 13.6 Hz, 1H), 4.01 (d, J = 13.6
Hz, 1H), 3.09 (br t, J = 6.0 Hz, 2H), 2.15 (s, 3H), 1.92−1.77 (m, 2H),
1.55−1.29 (m, 15H); 13C NMR (101 MHz, CDCl3) δ 198.9, 170.5,
156.0, 79.1, 76.5, 40.3, 31.4, 30.9, 29.8, 28.4, 26.3, 24.8, 20.6; IR (neat)
νmax 3375, 2934, 1745, 1695, 1520, 1367, 1242, 1168 cm−1; MS (EI)
m/z 381 (M+ + 2, 100). Anal. Calcd for C15H26BrNO5: C, 47.38; H,
6.89; N, 3.68. Found: C, 47.45; H, 6.82; N, 3.61.
1-Bromo-2-oxo-8-(tetrahydro-2H-pyran-2-yloxy)octan-3-yl ace-
tate (2o): colorless oil (263 mg, 72% yield); Rf = 0.37 (9:1 hexane/
1
EtOAc) (silica and I2); H NMR (400 MHz, CDCl3) δ 5.22 (dd, J =
8.0, 4.0 Hz, 1H), 4.54 (br t, J = 4.0 Hz, 1H), 4.05 (d, J = 13.6 Hz, 1H),
4.01 (d, J = 13.6 Hz, 1H), 3.87−3.79 (m, 1H), 3.71 (dt, J = 8.0, 4.0 Hz,
1H), 3.52−3.44 (m, 1H), 3.37 (dt, J = 8.0, 4.0 Hz, 1H), 2.13 (s, 3H),
1.89−1.75 (m, 3H), 1.63−1.46 (m, 6H), 1.45−1.34 (m, 5H); 13C
NMR (101 MHz, CDCl3) δ 198.9, 170.5, 98.9, 76.6, 67.3, 62.4, 31.5,
30.9, 30.7, 29.4, 25.9, 25.5, 25.0, 20.6, 19.7; IR (neat) νmax 2930, 1743,
1722, 1373, 1234, 1032 cm−1; MS (EI) m/z 366 (M+ + 2, 76), 365
(M+ + 1, 76), 276 (31), 141 (21). Anal. Calcd for C15H25BrO5: C,
49.32; H, 6.90. Found: C, 49.38; H, 6.85.
3-Bromo-1-(naphthalen-1-yl)-2-oxopropyl acetate (2i): thick
brown oil (247 mg, 77% yield); Rf = 0.56 (9:1 hexane/EtOAc)
1
(silica, UV, and I2); H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.4
8-(Benzyloxy)-1-bromo-2-oxooctan-3-yl acetate (2p): colorless oil
(349 mg, 94% yield); Rf = 0.35 (4:1 hexane/EtOAc) (silica, UV, and
I2); 1H NMR (400 MHz, CDCl3) δ 7.39−7.27 (m, 5H), 5.23 (dd, J =
8.4, 4.8 Hz, 1H), 4.50 (s, 2H), 4.05 (d, J = 13.2 Hz, 1H), 4.02 (d, J =
13.2 Hz, 1H), 3.47 (t, J = 6.4 Hz, 2H), 2.14 (s, 3H), 1.92−1.77 (m,
2H), 1.71−1.58 (m, 2H), 1.47−1.38 (m, 4H); 13C NMR (101 MHz,
CDCl3) δ 198.9, 170.5, 138.6, 128.4, 127.6, 127.5, 76.6, 72.9, 70.1,
31.5, 30.9, 29.5, 25.9, 25.0, 20.6; IR (neat) νmax 2937, 1741, 1725,
1371, 1234, 1101, 738 cm−1; MS (EI) m/z 372 (M+ + 2, 79), 371 (M+
+ 1, 32), 370 (M+, 100), 352 (30), 340 (98), 326 (13). Anal. Calcd for
C17H23BrO4: C, 55.00; H, 6.24. Found: C, 55.16; H, 6.29.
1-Bromo-8-hydroxy-2-oxooctan-3-yl acetate (2q): colorless oil
(258 mg, 92% yield); Rf = 0.73 (4:1 hexane/EtOAc) (silica and I2); 1H
NMR (400 MHz, CDCl3) δ 5.23 (dd, J = 8.0, 4.4 Hz, 1H), 4.06 (d, J =
13.6 Hz, 1H), 4.02 (d, J = 13.6 Hz, 1H), 3.09 (t, J = 6.4 Hz, 2H), 2.13
(s, 3H), 2.05 (br s, 1H), 1.92−1.73 (m, 2H), 1.55 (t, J = 6.4 Hz, 2H),
1.51−1.29 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 199.1, 170.6,
76.6, 62.5, 32.3, 31.6, 30.9, 25.3, 24.9, 20.6; IR (neat) νmax 3413, 2942,
1742, 1375, 1243 cm−1; MS (EI) m/z 282 (M+ + 2, 84), 281 (M+ + 1,
16), 280 (M+, 100). Anal. Calcd for C10H17BrO4: C, 42.72; H, 6.09.
Found: C, 42.58; H, 6.15.
Hz, 1H), 7.94 (t, J = 8.8 Hz, 2H), 7.63−7.45 (m, 4H), 7.02 (s, 1H),
3.94 (d, J = 13.2 Hz, 1H), 3.80 (d, J = 12.8 Hz, 1H), 2.23 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 195.9, 170.0, 134.2, 131.1, 130.9, 129.1,
128.5, 127.5, 126.5, 125.4, 123.5, 76.8, 30.8, 20.7; IR (neat) νmax 2937,
1743, 1725, 1510, 1369, 1230, 1020 cm−1; MS (EI) m/z 323 (M++ 3,
100), 322 (M+ + 2, 70), 321 (M+ + 1, 21), 292 (19). Anal. Calcd for
C15H13BrO3: C, 56.10; H, 4.08. Found: C, 56.18; H, 3.96.
3-Bromo-1-(2,6-dimethoxyphenyl)-2-oxopropyl acetate (2j): col-
orless liquid (299 mg, 90% yield); Rf = 0.28 (19:1 hexane/EtOAc)
(silica, UV, and I2); 1H NMR (400 MHz, CDCl3) δ 7.35 (t, J = 8.0 Hz,
1H), 6.91 (s, 1H), 6.59 (d, J = 8.0 Hz, 2H), 4.03 (d, J = 14.0 Hz, 1H),
3.96 (d, J = 14.0 Hz, 1H), 3.82 (s, 6H), 2.17 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 196.6, 170.1, 158.9, 131.8, 111.3, 104.3, 69.6, 56.1,
31.8, 20.9. IR (neat) νmax 2939, 1753, 1736, 1597, 1479, 1230, 1105,
1022, 783 cm−1; MS (EI) m/z 332 (M+ + 2, 100). Anal. Calcd for
C13H15BrO5: C, 47.15; H, 4.57. Found: C, 47.23; H, 4.51.
tert-Butyl 3-(2-acetoxy-4-bromo-3-oxobutyl)-1H-indole-1-car-
boxylate (2k): thick yellow oil (335 mg, 79% yield); Rf = 0.47 (9:1
1
hexane/EtOAc) (silica, UV, and I2); H NMR (400 MHz, CDCl3) δ
8.14 (br d, J = 7.2 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.46 (s, 1H), 7.34
(t, J = 7.2 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 5.51 (t, J = 5.2 Hz, 1H),
3.95 (s, 2H), 3.30 (dd, J = 14.8, 5.2 Hz, 1H), 3.22 (dd, J = 14.8, 7.2
Hz, 1H), 2.10 (s, 3H), 1.68 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
198.9, 170.3, 149.5, 135.3, 130.1, 124.7, 124.5, 122.7, 118.9, 115.4,
114.2, 83.9, 76.1, 32.4, 28.2, 26.9, 20.6; IR (neat) νmax 3449, 2974,
1734, 1715, 1608, 1452, 1385, 1255, 937, 765 cm−1; MS (EI) m/z 425
(M+ + 2, 26), 424 (M+ + 1, 100). Anal. Calcd for C19H22BrNO5: C,
53.79; H, 5.23; N, 3.30. Found: C, 53.71; H, 5.28; N, 3.36.
1-(2-Bromoacetyl)cyclopentyl acetate (2r): colorless solid (217
mg, 87% yield); mp = 42−43 °C; Rf = 0.52 (9:1 hexane/EtOAc) (silica
1
and I2); H NMR (400 MHz, CDCl3) δ 4.05 (s, 2H), 2.32−2.21 (m,
2H), 2.11 (s, 3H), 2.02−1.97 (m, 2H), 1.86−1.69 (m, 4H); 13C NMR
(101 MHz, CDCl3) δ 199.5, 171.3, 93.1, 36.6, 30.6, 24.7, 21.0; IR
(KBr) νmax 2964, 1728, 1715, 1431, 1373, 1024, 621 cm−1; MS (EI)
m/z 251 (M+ + 3, 95), 250 (M+ + 2, 10), 249 (M+ + 1, 100), 221 (29),
189 (23), 171 (21), 143 (18), 109 (12). Anal. Calcd for C9H13BrO3:
C, 43.39; H, 5.26. Found: C, 43.36; H, 5.21.
1,8-Dibromo-2-oxooctan-3-yl acetate (2l): pale yellow oil (306
1
mg, 89% yield); Rf = 0.66 (19:1 hexane/EtOAc) (silica and I2); H
8-(2-Bromoacetyl)-1,4-dioxaspiro[4.5]decan-8-yl acetate (2s):
NMR (400 MHz, CDCl3) δ 5.24 (dd, J = 8.0, 4.4 Hz, 1H), 4.06 (d, J =
13.6 Hz, 1H), 4.01 (d, J = 13.6 Hz, 1H), 3.40 (t, J = 6.8 Hz, 2H), 2.16
(s, 3H), 1.94−1.77 (m, 4H), 1.55−1.38 (m, 4H); 13C NMR (101
MHz, CDCl3) δ 198.9, 170.5, 76.5, 33.5, 32.3, 31.4, 30.8, 27.6, 24.3,
20.6; IR (neat) νmax 2939, 1739, 1713, 1373, 1028 cm−1; MS (EI) m/z
344 (M+ + 2, 16), 343 (M+ + 1, 92), 342 (M+, 100), 282 (13). Anal.
Calcd for C10H16Br2O3: C, 34.91; H, 4.69. Found: C, 34.85; H, 4.58.
8-Azido-1-bromo-2-oxooctan-3-yl acetate (2m): yellow liquid
(272 mg, 89% yield); Rf = 0.44 (6:1 hexane/EtOAc) (silica and I2); 1H
NMR (400 MHz, CDCl3) δ 5.24 (dd, J = 8.4, 4.4 Hz, 1H), 4.06 (d, J =
13.6 Hz, 1H), 4.01 (d, J = 13.6 Hz, 1H), 3.27 (t, J = 6.8 Hz, 2H), 2.15
(s, 3H), 1.95−1.77 (m, 2H), 1.69−1.57 (m, 2H) 1.50−1.34 (m, 4H);
13C NMR (101 MHz, CDCl3) δ 198.9, 170.5, 76.5, 51.2, 31.4, 30.8,
28.6, 26.3, 24.7, 20.6; IR (neat) νmax 2934, 2100, 1747, 1718, 1371,
1234, 1028 cm−1; MS (EI) m/z 307 (M+ + 2, 100). Anal. Calcd for
colorless solid (250 mg, 78% yield); mp = 43−44 °C; Rf = 0.31
1
(9:1 hexane/EtOAc) (silica and I2); H NMR (400 MHz, CDCl3) δ
4.07 (s, 2H), 3.99−3.88 (m, 4H), 2.23−2.05 (m, 7H), 1.84−1.74 (m,
2H), 1.73−1.64 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 199.7,
170.7, 107.3, 83.3, 64.6, 64.4, 30.1, 29.7, 29.6, 20.8; IR (neat) νmax
2957, 1732, 1722, 1446, 1373, 1230, 1097, 1033, 727 cm−1; MS (EI)
m/z 321 (M+ + 1, 23), 263 (86), 261 (100). Anal. Calcd for
C12H17BrO5: C, 44.88; H, 5.34. Found: C, 44.96; H, 5.31.
4-Bromo-3-oxo-1-phenylbutan-2-yl pivalate (2t): colorless oil
(278 mg, 85% yield); Rf = 0.59 (10:1 hexane/EtOAc) (silica, UV,
and I2); 1H NMR (400 MHz, CDCl3) δ 7.35−7.24 (m, 3H), 7.21 (br
d, J = 8.0 Hz, 2H), 5.41 (dd, J = 8.0, 4.0 Hz, 1H), 3.90 (s, 2H), 3.23
(dd, J = 12.0, 8.0 Hz, 1H), 3.11 (dd, J = 12.0, 8.0 Hz, 1H), 1.17 (s,
9H); 13C NMR (101 MHz, CDCl3) δ 199.0, 177.8, 135.4, 129.4,
128.6, 127.3, 76.9, 38.6, 37.5, 32.4, 26.9; IR (neat) νmax 2974, 1728,
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1715, 1479, 1396, 1280, 1149, 700 cm−1; MS (EI) m/z 328 (M+ + 2,
19), 327 (M+ + 1, 73), 326 (M+, 100). Anal. Calcd for C15H19BrO3: C,
55.06; H, 5.85. Found: C, 55.16; H, 5.79.
4-(Ethoxy(phenyl)methyl)thiazol-2-amine (9a): brown oil (36 mg,
63% yield); Rf = 0.61 (3:2 hexane/EtOAc) (silica, UV, and I2); H
1
NMR (400 MHz, CDCl3) δ 7.45−7.41 (m, 2H), 7.39−7.34 (m, 2H),
7.31 (dt, J = 7.2, 1.6 Hz, 1H), 6.31 (s, 1H), 5.29 (s, 1H), 5.09 (brs,
2H), 3.62−3.46 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 167.9, 153.1, 140.5, 128.3, 127.8, 127.4, 105.1, 80.2,
64.7, 15.3; IR (neat) νmax 3413, 2926, 1605, 1528 cm−1; HRMS (ESI)
for C12H14N2OSNa (M + Na)+ calcd 257.0725, found 257.0728.
4-(Ethoxy(3-methoxyphenyl)methyl)thiazol-2-amine (9b): yellow
oil (44 mg, 67% yield); Rf = 0.54 (3:2 hexane/EtOAc) (silica, UV, and
4-Chloro-3-oxo-1-phenylbutan-2-yl acetate (6a): colorless oil
(195 mg, 81% yield); Rf = 0.52 (9:1 hexane/EtOAc) (silica, UV,
and I2); 1H NMR (400 MHz, CDCl3) δ 7.34−7.25 (m, 3H), 7.20 (d, J
= 6.8 Hz, 2H), 5.39 (dd, J = 7.6, 5.6 Hz, 1H), 4.12 (d, J = 16.4 Hz,
1H), 3.99 (d, J = 16.4 Hz, 1H), 3.15 (dd, J = 14.0, 5.2 Hz, 1H), 3.11
(dd, J = 14.0, 8.0 Hz, 1H), 2.10 (s, 3H); 13C NMR (101 MHz, CDCl3)
δ 199.2, 170.3, 135.0, 129.3, 128.8, 127.4, 77.2, 47.1, 37.1, 20.5; IR
(neat) νmax 2935, 1741, 1732, 1496, 1373, 1051, 702 cm−1; MS (EI)
m/z 241 (M+ + 1, 23), 240 (M+, 21), 239 (M+ − 1, 68), 219 (51), 161
(100), 143 (18). Anal. Calcd for C12H13ClO3: C, 59.88; H, 5.44.
Found: C, 59.75; H, 5.51.
1
I2); H NMR (400 MHz, CDCl3) δ 7.25 (br s, 1H), 6.99 (br s, 2H),
6.84 (d, J = 8.0 Hz, 1H), 6.25 (s, 1H), 5.59 (br s, 2H), 5.25 (s, 1H),
3.81 (s, 3H), 3.62−3.46 (m, 2H), 1.26 (t, J = 6.0 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ 168.5, 159.7, 151.4, 141.5, 129.4, 119.8, 113.6,
112.7, 104.8, 79.6, 64.9, 55.3, 15.3; IR (neat) νmax 3287, 2926, 1600,
1517, 1260 cm−1; HRMS (ESI) for C13H17N2O2S (M + H)+: calcd
265.101, found 265.1013.
4-Chloro-3-oxo-1-phenylbutan-2-yl pivalate (6b): colorless oil
(238 mg, 73% yield); Rf = 0.26 (9:1 hexane/EtOAc) (silica, UV, and
1
I2); H NMR (400 MHz, CDCl3) δ 7.37−7.28 (m, 3H), 7.22 (d, J =
1-(2-Aminothiazol-4-yl)-2-phenylethyl acetate (10): yellow oil (42
mg, 65% yield); Rf = 0.61 (3:2 hexane/EtOAc) (silica, UV, and I2); 1H
NMR (400 MHz, CDCl3) δ 7.30−7.24 (m, 2H), 7.22 (dt, J = 6.8, 1.2
Hz, 1H), 7.16 (dd, J = 6.8, 1.6 Hz, 2H), 6.31 (s, 1H), 5.87 (t, J = 6.8
Hz, 1H), 5.38 (br s, 2H), 3.22 (d, J = 7.2 Hz, 2H), 2.04 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 170.2, 168.1, 149.5, 137.0, 129.4, 128.3,
126.6, 106.2, 72.6, 40.3, 21.2; IR (neat) νmax 3386, 3156, 1709, 1638,
1523 cm−1; HRMS (ESI) for C13H14N2O2SNa (M + Na)+ calcd
285.0656, found 285.0675.
(4-Bromo-2-methoxybut-3-yn-1-yl)benzene (11b): pale yellow oil
(130 mg, 83% yield); Rf = 0.66 (9:1 hexane/EtOAc) (silica, UV, and
I2); 1H NMR (400 MHz, CDCl3) δ 7.31 (t, J = 6.8 Hz, 2H), 7.26 (d, J
= 7.2 Hz, 3H), 4.17 (t, J = 6.8 Hz, 1H), 3.41 (s, 3H). 3.03 (dd, J = 8.8,
4.0 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 136.9, 129.6, 128.3,
126.7, 78.7, 73.1, 56.8, 46.3, 42.0, 29.7; IR (neat) νmax 2931, 2213,
1500, 1456, 1330 cm−1; HRMS (ESI) for C11H11BrONa (M + Na)+
calcd 260.9891, found 260.9890.
6.4 Hz, 2H), 5.38 (dd, J = 7.6, 5.6 Hz, 1H), 4.13 (d, J = 16.4 Hz, 1H),
4.04 (d, J = 16.4 Hz, 1H), 3.15 (dd, J = 14.0, 4.8 Hz, 1H), 3.09 (dd, J =
14.0, 7.6 Hz, 1H), 1.17 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
199.3, 177.8, 135.2, 129.4, 128.7, 127.3, 76.9, 47.0, 38.6, 37.1, 26.9; IR
(neat) νmax 2928, 1730, 1682, 1606, 1458, 1151, 1045, 750 cm−1; MS
(EI) m/z 284 (M+ + 2, 26), 283 (M+ + 1, 70), 245 (100). Anal. Calcd
for C15H19ClO3: C, 63.71; H, 6.77. Found: C, 63.85; H, 6.71.
8-(2-Chloroacetyl)-1,4-dioxaspiro[4.5]decan-8-yl acetate (6c):
colorless solid (224 mg, 81% yield); mp = 64−65 °C; Rf = 0.5 (4:1
1
hexane/EtOAc) (silica and I2); H NMR (400 MHz, CDCl3) δ 4.27
(br s, 2H), 3.99−3.90 (m, 4H), 2.23−2.15 (m, 2H), 2.13 (s, 3H),
2.13−2.05 (m, 2H), 1.86−1.75 (m, 2H), 1.73−1.66 (m, 2H); 13C
NMR (101 MHz, CDCl3) δ 199.7, 170.6, 107.2, 83.2, 64.6, 64.4, 44.3,
30.0, 29.3, 20.8; IR (neat) νmax 2947, 1736, 1728, 1442, 1377, 1236,
1095, 1033, 746 cm−1; MS (EI) m/z 278 (M+ + 2, 31), 277 (M+ + 1,
100), 247 (47), 219 (34). Anal. Calcd for C12H17ClO5: C, 52.09; H,
6.19. Found: C, 52.16; H, 6.23.
4-Bromo-1-phenylbut-3-yn-2-yl benzoate (11c): pale yellow oil
(170 mg, 58% yield); Rf = 0.54 (9:1 hexane/EtOAc) (silica, UV, and
I2); 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.6 Hz, 2H), 7.58 (t, J
= 7.2 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.36−7.30 (m, 4H), 7.28−7.25
(m, 1H), 5.80 (t, J = 6.8 Hz, 1H), 5.38 (dd, J = 6.8, 3.6 Hz, 2H); 13C
NMR (101 MHz, CDCl3) δ 165.3, 135.6, 133.3, 129.8, 129.7, 129.6,
128.5, 127.1, 77.2, 65.7, 47.3, 41.1; IR (neat) νmax 2920, 2219, 1725,
1451, 1254, 1111 cm−1; HRMS (ESI) for C17H13BrO2Na (M + Na)+
calcd 350.9997, found 350.9999.
4-Iodo-3-oxo-1-phenylbutan-2-yl acetate (7): yellow oil (256 mg,
77% yield); Rf = 0.37 (9:1 hexane/EtOAc) (silica, UV and I2); H
1
NMR (400 MHz, CDCl3) δ 7.38−7.25 (m, 3H), 7.21 (d, J = 6.8 Hz,
2H), 5.49 (dd, J = 7.6, 4.8 Hz, 1H), 3.82 (d, J = 11.2 Hz, 1H), 3.76 (d,
J = 11.2 Hz, 1H), 3.21 (dd, J = 14.0, 4.8 Hz, 1H), 3.11 (dd, J = 14.0,
8.0 Hz, 1H), 2.11 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 200.0,
170.1, 135.5, 129.4, 128.7, 127.3, 76.7, 37.9, 20.6, 2.8; IR (neat) νmax
2934, 1745, 1715, 1496, 1373, 1236, 1045, 750 cm−1; MS (EI) m/z
334 (M+ + 2, 65), 333 (M+ + 1, 100). Anal. Calcd for C12H13IO3: C,
43.39; H, 3.95. Found: C, 43.29; H, 4.05.
4-Bromo-3-oxo-1-phenylbutan-2-yl benzoate (12c): yellow oil
(287 mg, 83% yield); Rf = 0.34 (9:1 hexane/EtOAc) (silica, UV, and
I2); 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 7.6 Hz, 2H), 7.61 (t, J
= 7.2 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.36−7.24 (m, 5H), 5.67 (dd, J
= 7.2, 5.2 Hz, 1H), 3.97 (s, 2H), 3.38−3.24 (m, 2H); 13C NMR (101
MHz, CDCl3) δ 198.8, 165.9, 135.3, 133.8, 129.9, 129.5, 128.8, 128.6,
127.4, 77.7, 37.7, 32.8; IR (neat) νmax 2925, 1714, 1445, 1265 cm−1;
HRMS (ESI) for C17H16BrO3 (M + H)+ calcd 347.0283, found
347.0283.
4-Iodo-3-oxo-1-phenylbutan-2-yl Acetate (8). To a stirred
solution of 2a (70 mg, 0.25 mmol) in CH3OH/H2O (1 mL, 4:1)
was added Sc(OTf)3 (24 mg, 0.05 mmol) at room temperature. The
reaction mixture was stirred overnight at an ambient temperature.
Progress of the reaction was monitored by TLC. After complete
consumption of starting material, the solvent was evaporated under
reduced pressure. The crude material was diluted with diethyl ether
(20 mL). The organic layer was washed with brine, dried over Na2SO4,
and concentrated under reduced pressure. The crude reaction mixture
was purified by column chromatography on silica gel eluting with
hexane/ethyl acetate (10:1) to accomplish 8:11 yellow oil (49 mg, 83%
3-Bromo-2-oxo-1-phenylpropyl Acetate (18O-Labeled, 2b′). Fol-
lowing the general procedure GP-3, hydration of 1b (200 mg, 0.80
mmol) under the optimized conditions in the presence of H218O (48
μL, 2.40 mmol) gave 2b′ (180 mg, 84% yield) as a pale yellow oil: Rf =
1
yield); Rf = 0.37 (9:1 hexane/EtOAc) (silica, UV, and I2); H NMR
1
0.33 (9:1 hexane/EtOAc) (silica, UV, and I2); H NMR (400 MHz,
(400 MHz, CDCl3) δ 7.44−7.16 (m, 5H), 4.70 (t, J = 6.0 Hz, 1H),
4.02 (s, 2H), 3.17 (dd, J = 14.4, 4.8 Hz, 1H), 2.95 (dd, J = 14.0, 7.6
Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 203.4, 135.8, 129.3, 128.9,
127.3, 76.1, 40.4, 31.4; IR (neat) νmax 3468, 1737, 1232, 1946 cm−1.
HRMS (ESI) for C10H12BrO2 (M + H)+: calcd 243.002, found
243.0023.
CDCl3) δ 7.43 (br s, 5H), 6.30 (s, 1H), 3.97 (q, J = 13.6 Hz, 2H), 2.20
(s, 3H); 13C NMR (101 MHz, CDCl3) δ 195.6, 170.1, 132.4, 129.9,
129.3, 128.3, 78.3, 31.1, 20.6; IR (neat) νmax 2936, 1736, 1720, 1500,
1347, 1221 cm−1; HRMS (ESI) for C11H12BrO2O18 (M + H)+ calcd
272.997, found 272.9973.
3-Bromo-1-hydroxy-1-phenylpropan-2-one (2b″). To a stirred
solution of 2b′ (100 mg, 0.37 mmol) in CH3OH/H2O (1.0 mL, 4:1)
was added Sc(OTf)3 (36 mg, 0.07 mmol) at room temperature. The
reaction mixture was stirred overnight an ambient temperature. The
solvent was evaporated under reduced pressure. The crude material
was diluted with diethyl ether (20 mL). The organic layer was washed
with brine (5.0 mL), dried over Na2SO4, and concentrated under
reduced pressure. The crude mixture was purified by column
Synthesis of 2-Aminothiazole 9 and 10: General Procedure
(GP-4). A mixture of α-acyloxy α′-halo ketones 2 (0.25 mmol) and
thiourea (0.37 mmol) was stirred in EtOH (1.0 mL) at 80 °C
overnight. Progress of the reaction was monitored by TLC. After
complete consumption of 2, the reaction mixture was extracted with
CH2Cl2 (2 × 10 mL), and the organic layers were washed with brine,
dried over Na2SO4, and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel.9a
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The Journal of Organic Chemistry
Article
chromatography on silica gel eluting with hexane/ethyl acetate (10:1)
Synlett 2010, 692. (c) Correa, A.; Marion, N.; Fensterbank, L.;
Malacria, M.; Nolan, S. P.; Cavallo, L. Angew. Chem., Int. Ed. 2008, 47,
718. (d) Marion, N.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46,
2750.
(6) For recent examples of gold-catalyzed 1,2-rearrangement of
propargylic carboxylate and further transformations, see: (a) Retten-
meier, E.; Schuster, A. M.; Rudolph, M.; Rominger, F.; Gade, A.;
Hashmi, A. S. K. Angew. Chem., Int. Ed. 2013, 52, 5880. (b) Rao, W.;
Koh, M. J.; Li, D.; Hirao, H.; Chan, P. W. H. J. Am. Chem. Soc. 2013,
to obtain 2b″:11 pale yellow oil (27 mg, 33% yield); Rf = 0.43 (4:1
1
hexane/EtOAc) (silica, UV, and I2); H NMR (400 MHz, CDCl3) δ
7.45−7.32 (m, 5H), 5.52 (s, 1H), 3.81 (d, J = 13.2 Hz, 1H), 3.94 (d, J
= 13.2 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 200.6, 134.6, 131.7,
130.3, 129.3, 128.9, 127.3, 26.4; IR (neat) νmax 3479, 2920, 1714, 1599,
1445 cm−1; HRMS (ESI) for C9H9BrO2Na (M + Na)+ calcd 250.9684,
found 250.9684.
ASSOCIATED CONTENT
135, 7926. (c) Lauterbach, T.; Gatzweiler, S.; Nosel, P.; Rudolph, M.;
̈
■
S
Rominger, F.; Hashmi, A. S. K. Adv. Synth. Catal. 2013, 355, 2481.
* Supporting Information
Figures giving the 1H and 13C spectra of new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org
(d) Garayalde, D.; Kruger, K.; Nevado, C. Angew. Chem., Int. Ed. 2011,
̈
50, 911. (e) Watson, I. D. G.; Ritter, S.; Toste, F. D. J. Am. Chem. Soc.
2009, 131, 2056. (f) Uemura, M.; Watson, I. D. G.; Katsukawa, M.;
Toste, F. D. J. Am. Chem. Soc. 2009, 131, 3464. (g) Zou, Y.; Garayalde,
D.; Wang, Q.; Nevado, C.; Goeke, A. Angew. Chem., Int. Ed. 2008, 47,
10110. (h) Shapiro, N. D.; Toste, F. D. J. Am. Chem. Soc. 2008, 130,
9244. (i) Cordonnier, M.-C.; Blanc, A.; Pale, P. Org. Lett. 2008, 10,
AUTHOR INFORMATION
Corresponding Author
*E-mail: akhilchemistry12@gmail.com.
■
́
1569. (j) Gorin, D. J.; Dube, P.; Toste, F. D. J. Am. Chem. Soc. 2006,
128, 14480. (k) Shi, X.; Gorin, D. J.; Toste, F. D. J. Am. Chem. Soc.
2005, 127, 5802.
Notes
The authors declare no competing financial interest.
(7) For recent examples of gold-catalyzed 1,3-rearrangement of
propargylic carboxylate and further transformations, see: (a) Yu, Y.;
Wang, W.; Rominger, F.; Hashmi, A. S. K. Angew. Chem., Int. Ed. 2013,
52, 7586. (b) Hashmi, A. S. K.; Yang, W.; Yu, Y.; Hansmann, M. M.;
Rudolph, M.; Rominger, F. Angew. Chem., Int. Ed. 2013, 52, 1329.
(c) Rao, W.; Sally, M.; Koh, J.; Chan, P. W. H. J. Org. Chem. 2013, 78,
ACKNOWLEDGMENTS
■
We gratefully acknowledge the University of Hyderabad,
ACRHEM, and the DST (Grant No. SR/S1/OC-34/2009)
for support. N.G and S.N. thank CSIR, India, for graduate
fellowship.
3183. (d) Yang, W.; Yu, Y.; Zhang, T.; Hansmann, M. M.; Pflasterer,
̈
D.; Hashmi, A. S. K. Adv. Synth. Catal. 2013, 355, 2037. (e) Nosel, P.;
̈
REFERENCES
■
Comprido, L. N. d. S.; Lauterbach, T.; Rudolph, M.; Rominger, F.;
Hashmi, A. S. K. J. Am. Chem. Soc. 2013, 135, 15662. (f) Rao, W.; Koh,
M. J.; Kothandaraman, P.; Chan, P. W. H. J. Am. Chem. Soc. 2012, 134,
10811. (g) Rao, W.; Susanti, D.; Chan, P. W. H. J. Am. Chem. Soc.
2011, 133, 15248. (h) Zhang, D.-H.; Yao, L.-F.; Wei, Y.; Shi, M.
Angew. Chem., Int. Ed. 2011, 50, 2583. (i) Zheng, H.; Zheng, J.; Yu, B.;
Chen, Q.; Wang, X.; He, Y.; Yang, Z.; She, Y. J. Am. Chem. Soc. 2010,
132, 1788. (j) Teng, T.-M.; Liu, R.-S. J. Am. Chem. Soc. 2010, 132,
(1) (a) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104,
3079. (b) Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem., Int.
Ed. 2004, 43, 3368. (c) Hintermann, L.; Labonne, A. Synthesis 2007,
1121.
(2) (a) Kribber, T.; Labonne, A.; Hintermann, L. Synthesis 2007,
2809. (b) Chang, H.-K.; Datta, S.; Das, A.; Odedra, A.; Liu, R.-S.
Angew. Chem., Int. Ed. 2007, 46, 4744. (c) Chang, H.-K.; Lioa, Y.-C.;
Liu, R.-S. J. Org. Chem. 2007, 72, 8139. (d) Ackermann, L.; Kaspar, L.
T. J. Org. Chem. 2007, 72, 6149. (e) Bras, G. L.; Provot, O.; Peyrat, J.-
F.; Alami, M.; Brion, J.-D. Tetrahedron Lett. 2006, 47, 5497. (f) Wan,
Z.; Jones, C. D.; Mitchell, D.; Pu, J. Y.; Zhang, Y. T. J. Org. Chem.
2006, 71, 826. (g) Vasudevan, A.; Verzal, M. K. Synlett 2004, 631.
(h) Nishizawa, M.; Skwarczynski, M.; Imagawa, H.; Sugihara, T. Chem.
Lett. 2002, 12. (i) Baidossi, W.; Lahav, M.; Blum, J. J. Org. Chem. 1997,
62, 669. (j) Imi, K.; Imai, K.; Utimoto, K. Tetrahedron Lett. 1987, 28,
3127.
(3) For recent reviews on gold catalysis, see: (a) Rudolph, M.;
Hashmi, A. S. K. Chem. Soc. Rev. 2012, 41, 2448. (b) Garayalde, D.;
́
Nevado, C. ACS Catal. 2012, 2, 1462. (c) Corma, A.; Leyva-Perez, A.;
Sabater, M. J. Chem. Rev. 2011, 111, 1657. (d) Rudolph, M.; Hashmi,
A. S. K. Chem. Commun. 2011, 47, 6536. (e) Hashmi, A. S. K.; Buhrle,
M. Aldrichimica Acta 2010, 43, 27. (f) Sohel, S. M. A.; Liu, R.-S. Chem.
Soc. Rev. 2009, 38, 2269. (g) Li, Z.; Brower, C.; He, C. Chem. Rev.
́
9298. (k) Mauleon, P.; Krinsky, J. L.; Toste, F. D. J. Am. Chem. Soc.
2009, 131, 4513. (l) Marion, N.; Nolan, S. P. Chem.Eur. J. 2009, 15,
3243. (m) Li, G.; Zhang, G.; Zhang, L. J. Am. Chem. Soc. 2008, 130,
́ ́
3740. (n) Marion, N.; Díez-Gonzalez, S.; de Fremont, P.; Noble, A. R.;
Nolan, S. P. Angew. Chem., Int. Ed. 2006, 45, 3647. (o) Wang, S.;
Zhang, L. J. Am. Chem. Soc. 2006, 128, 8414. (p) Zhang, L.; Wang, S.
Z. J. Am. Chem. Soc. 2006, 128, 1442. (q) Buzas, A.; Gagosz, F. J. Am.
Chem. Soc. 2006, 128, 12614. (r) Zhang, L. J. Am. Chem. Soc. 2005,
127, 16804.
(8) Wang, Y.; Lu, B.; Zhang, L. Chem. Commun. 2010, 46, 9179.
(9) (a) Xie, L.; Wu, Y.; Yi, W.; Zhu, L.; Xiang, J.; He, W. J. Org. Chem.
2013, 78, 9190. (b) Leyva-Perez, A.; Rubio-Marques, P.; Al-Deyab, S.
́ ́
S.; Al-Resayes, S. I.; Corma, A. ACS Catal. 2011, 1, 601. (c) Buzas, A.
K.; Istrate, F. M.; Gagosz, F. Tetrahedron 2009, 65, 1889.
(10) (a) Esteve, J.; Larente, A.; Romea, P.; Urpí, F.; Ríos-Luci, C.;
́
Padrοn, J. M. Eur. J. Org. Chem. 2011, 960. (b) Nebot, J.; Romea, P.;
2008, 108, 3239. (h) Jimenez-Nunez, E.; Echavarren, A. M. Chem. Rev.
́
́
̃
Urpí, F. J. Org. Chem. 2009, 74, 7518. (c) Ritson, D. J.; Spiteri, C.;
Moses, J. E. J. Org. Chem. 2011, 76, 3519.
2008, 108, 3326. (i) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. Rev.
2008, 108, 3351. (j) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180.
(k) Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem., Int. Ed. 2006, 45,
7896.
(11) (a) Ghosh, N.; Nayak, S.; Sahoo, A. K. J. Org. Chem. 2011, 76,
500. (b) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2010, 49, 5232.
(c) Dopp, R.; Lothschutz, C.; Wurm, T.; Pernpointner, M.; Keller, S.;
̈
̈
(4) For selected gold-catalyzed hydration of alkynes, see: (a) Wang,
D.; Shi, X. J. Am. Chem. Soc. 2012, 134, 9012. (b) Wang, W.; Jasinski,
J.; Hammond, G. B.; Xu, B. Angew. Chem., Int. Ed. 2010, 49, 7247.
(c) Wang, W.; Xu, B.; Hammond, G. B. J. Org. Chem. 2009, 74, 1640.
Rominger, F.; Hashmi, A. S. K. Organometallics 2011, 30, 5894.
(d) Krauter, C. M.; Hashmi, A. S. K.; Pernpointner, M. ChemCatChem
2010, 2, 1226.
(12) Hattori, G.; Matsuzawa, M.; Miyake, Y.; Nishibayashi, Y. Angew.
Chem., Int. Ed. 2008, 47, 3781.
(d) Marion, N.; Ramon
́
, R. S.; Nolan, S. P. J. Am. Chem. Soc. 2009,
131, 448. (e) Ramon, R. S.; Marion, N.; Nolan, S. P. Tetrahedron 2009,
́
(13) (a) Trost, B. M.; Warner, R. W. J. Am. Chem. Soc. 1982, 104,
6112. (b) Shaikh, T. M.; Sudalai, A. Eur. J. Org. Chem. 2010, 3437.
(c) Halim, M.; Tremblay, M. S.; Jockusch, S.; Turro, N. J.; Sames, D. J.
Am. Chem. Soc. 2007, 129, 7704. (d) Nishitani, K.; Yamakawa, K.
Tetrahedron Lett. 1987, 28, 655. (e) Chang, M.-Y.; Chen, C.-Y.; Chen,
65, 1767. (f) Yang, C.-Y.; Lin, G.-Y.; Liao, H.-Y.; Datta, S.; Liu, R.-S. J.
Org. Chem. 2008, 73, 4907. (g) Fukuda, Y.; Utimoto, K. J. Org. Chem.
1991, 56, 3729.
(5) (a) Oh, C. H.; Kim, J. H.; Oh, B. K.; Park, J. R.; Lee, J. H.
Chem.Eur. J. 2013, 19, 2592. (b) Wang, S.; Zhang, G.; Zhang, L.
2461
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Article
S.-T.; Chang, N.-C. Tetrahedron 2003, 59, 7547. (f) Kaiser, F.;
Schwink, L.; Velder, J.; Schmalz, H.-G. J. Org. Chem. 2002, 67, 9248.
(14) Kajiro, H.; Mitamura, S.; Mori, A.; Hiyama, T. Tetrahedron Lett.
1999, 40, 1689.
(15) The reaction of bromoalkyne 13, having no α-acyloxy group,
under the optimized conditions produced the hydration product 14 in
27% and 39% yields in 4 and 14 h, respectively.
(16) See the Supporting Information for details.
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