Regio- and stereoselective iodoacyloxylations of alkynes

Article abstract of DOI:10.1021/acs.joc.5b00250

A new method for the regioselective and stereoselective iodoacyloxylation of alkynes has been developed. This protocol utilizes a combination of an iodobenzene dicarboxylate and iodine to functionalize a series of activated and unactivated alkynes in an entirely selective and predictable fashion. The resultant iodo-enol esters were subsequently coupled with boronic acids to afford tetrasubstituted alkene derivatives, which could be further converted to the corresponding 1,1-disubstituted acetophenone.

Full text of DOI:10.1021/acs.joc.5b00250

Article
pubs.acs.org/joc
Regio- and Stereoselective Iodoacyloxylations of Alkynes
Daniel L. Priebbenow,*,† Robert. W. Gable,‡ and Jonathan Baell*,†
†Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia
‡School of Chemistry, University of Melbourne, Melbourne, Victoria 3010, Australia
S
* Supporting Information
ABSTRACT: A new method for the regioselective and
stereoselective iodoacyloxylation of alkynes has been devel-
oped. This protocol utilizes a combination of an iodobenzene
dicarboxylate and iodine to functionalize a series of activated
and unactivated alkynes in an entirely selective and predictable
fashion. The resultant iodo-enol esters were subsequently
coupled with boronic acids to afford tetrasubstituted alkene
derivatives, which could be further converted to the
corresponding 1,1-disubstituted acetophenone.
and terminal alkynes using a combination of Koser’s reagent
and iodine.8
INTRODUCTION
■
Multisubstituted alkenes (of which enol esters are an important
subclass) have been utilized as key intermediates in the
synthesis of natural products and applied as reagents in
numerous synthetic transformations including cycloadditions,
heterocycle formation and aldol-type reaction processes.1 The
synthesis, however, of multisubstituted alkenes (including enol
esters), in an efficient and predictable manner still presents a
significant challenge to the modern organic chemist.2 One
recent example that elegantly addressed this issue was the Rh/
Cu catalyzed multicomponent synthesis of enol esters from
dialkyl alkynes reported by Pham and Cramer involving the
CH-activation of heterocycles.3
More recently, Yanada and co-workers reported the
cohalogenation of alkynes to afford vinylic iodo esters 2 using
a combination of acetic acid and N-iodosuccinimide (NIS).9
Although a range of vinyl iodides were accessible using these
conditions, the reaction conditions were only applicable to
polarized alkynes possessing an electron donating group on one
end of the triple bond. To enhance the utility of the
cohalogenation reactions and expand the scope to include
unactivated alkynes, a new method was required to facilitate the
rapid preparation of a range of vinylic iodo enol esters using
common reagents and mild conditions that provides predictable
control over both regio- and stereochemistry.
Alkenes and enol esters that contain a halide substituent are
particularly valuable substrates in organic synthesis, applicable
to subsequent cross-coupling reactions to provide access to
various tri- and tetra-substituted alkene derivatives.4 Okamoto
and Yanada recently demonstrated that iodo-enol esters could
undergo a Sonogashira cross-coupling to afford alkynylated
enol esters that subsequently cyclized to yield tetra-substituted
furans.1g Geary and Hultin described the preparation of dienes,
trienes and enynes from chloro-substituted enol esters,4g and
Shimizu and co-workers showed that tetra-substituted alkenes
containing a trifluoromethyl substituent could be accessed from
bromo-substituted enol sulfonates.4h As such, the synthesis of
halo-substituted enol esters using methodology that allows
control over both the regio- and stereochemistry is highly
desirable. In 1971, Ogata and Urasaki reported the conversion
of diphenylacetylene (1a) to (E)-2-iodo-1,2-diphenylvinyl
acetate (2a) following the in situ generation of iodine
monoacetate (IOAc) from a combination of per-acetic acid
and iodine in acetic acid.5,6 Subsequently, the Barluenga
research group reported a similar cohalogenation of alkynes
using I(Py)2·BF4 and an appropriate nucleophile in the
presence of tetrafluoroboric acid.7 In 1999, Togo and co-
workers described the iodo-tosyloxylation of various internal
RESULTS AND DISCUSSION
■
Initially, the conditions reported by Yanada using acetic acid
and NIS in 1,2-dichloroethane (DCE) at 40 °C were trialed for
the functionalization of diphenylacetylene (1a) but failed to
afford the desired product 2a (Table 1, entry 1).9 Inspired by a
recent publication from the Yu group whereby iodine
monoacetate was generated in situ from the reaction of silver
acetate or iodobenzene diacetate with molecular iodine,10 the
iodoacetoxylation of diphenylacetylene was further explored.
The reaction using silver acetate and iodine in DCE provided
2a in modest yield (58%, entry 2) with a significant amount of
benzil (3) also identified from over oxidation. The use of
iodobenzene diacetate and iodine to generate the reactive
iodine monoacetate led to the formation of 2a in excellent yield
of 82% with the trans-isomer formed as the major product
(Table 1, entry 3).11
By lowering the reaction temperature to ambient temper-
atures, formation of the trans-isomer was favored (entry 4) and
Received: February 2, 2015
Published: April 13, 2015
© 2015 American Chemical Society
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Table 1. Optimization of the Iodoacetyloxylation of Diphenylacetylene
a
entry
conditions
cis:trans (%)
yield (%)
0
1
AcOH, NIS, DCE, 40 °C, 16 h
Ag(OAc), I2, DCE, 40 °C, 16 h
PhI(OAc)2, I2, DCE, 40 °C, 16 h
PhI(OAc)2, I2, DCE, 25 °C, 4 h
−
b
2
22:78
29:71
12:88
0:100
8:92
−
−
−
−
−
58 (36)
b
3
82 (16)
b
4
85 (10)
b
5
PhI(OAc)2, I2, DCE, 4Å MS, 25 °C, 4 h
PhI(OAc)2, I2, CH2Cl2, 4Å MS, 25 °C, 16 h
PhI(OAc)2, I2, CHCl3, 4Å MS, 25 °C, 16 h
PhI(OAc)2, I2, THF, 4Å MS, 25 °C, 16 h
PhI(OAc)2, I2, DMF, 4Å MS, 25 °C, 16 h
PhI(OAc)2, I2, MeCN, 4Å MS, 25 °C, 16 h
PhI(OAc)2, I2, 1,4-dioxane, 4Å MS, 25 °C, 16 h
PhI(OAc)2, I2, PhMe, 4Å MS, 25 °C, 16 h
PhI(OAc)2, TBAI, DCE, 4Å MS, 25 °C, 16 h
PhI(OAc)2, NIS, DCE, 4Å MS, 25 °C, 16 h
PhI(OAc)2, ICl, DCE, 4Å MS, 25 °C, 16 h
PhI(OAc)2, NaI, DCE, 4Å MS, 25 °C, 16 h
91 (trace)
6
95
0
7
8
0
9
0
10
11
12
13
14
15
16
0
0
b
10:90
85 (10)
−
−
−
−
0
0
0
0
a
b
To suppress formation of di-iodostilbene, all reactions were conducted in the dark by wrapping the reaction flask in aluminum foil. Yield of benzil
(3) in brackets.
the inclusion of 4Å molecular sieves suppressed the side
reaction, the oxidation of diphenylacetylene to 3 (entry 5).
Following a very simple workup procedure, the product 2a was
readily obtained after recrystallization from ethanol to afford
exclusively the trans-isomer in excellent yield of 91%. The use
of alternative solvents was then investigated. When performed
in dichloromethane, vinyl iodide 2a was obtained in excellent
yield; however, a slight loss in stereoselectivity was observed
(Table 1, entry 6). The reaction failed to proceed when
conducted in other solvents including chloroform, acetonitrile,
THF, 1,4-dioxane and DMF (Table 1, entries 7−11). Good
yields and selectivities were obtained when toluene was applied
as the solvent (entry 12). Other iodine sources including
sodium iodide, iodine monochloride, tetrabutylammonium
iodide and NIS did not react to form the desired product 2a
(entries 13−16), and the use of molecular bromine instead of
iodine afforded only α,α′-dibromostilbene.
Scheme 1. Exploration of the Scope of Alkynes Tolerated in
This Reaction Process
With a new protocol in-hand employing a combination of
iodine and iodobenzene diacetate for the high-yielding
stereoselective iodoacetoxylation of alkynes, a range of diaryl,
dialkyl and aryl-alkyl substituted internal alkynes were subjected
to the previously optimized reaction conditions (Scheme 1). It
was observed that for the diaryl alkynes, electronically neutral
and electron deficient alkynes reacted well to afford almost
exclusively the trans-isomer of the corresponding vinylic iodides
2a−2d where the acetate group added to the most electron
deficient end of the alkyne (Scheme 1). Both the
regiochemistry and the trans-stereochemistry were confirmed
by X-ray crystallography of cyano-derivative 2c (Figure S1).12
Reactions performed with terminal alkynes failed to afford
synthetically useful yields of the corresponding vinyl acetate.
When a strongly electron-donating group was present on one
of the aryl groups, the cis-isomer was the major stereoisomer
formed with the acetate group adding to the end of the alkyne
closest to the EDG (Scheme 1, 2f,g). Aryl-alkyl substituted
alkynes and dialkyl substituted alkynes also performed well in
this reaction process to afford predominantly the trans-isomer
of the corresponding vinyl iodides in excellent yield (Scheme 1,
2e,h−j). For unsymmetrically substituted diaryl acetylenes
containing only moderately electron-withdrawing or electron-
donating groups such as chloro- and fluoro-substituted
diphenylacetylene, the reaction proceeded well; however, a
mixture of regioisomers was obtained with the trans-stereo-
isomer still favored in each case (2k−m, Figure 1).12
To further explore the scope of this reaction process, a range
of substituted iodobenzene dicarboxylate derivatives were
investigated. The iodobenzene dicarboxylate reagents were
prepared by azeotroping off the acetic acid from iodobenzene
diacetate in the presence of the desired carboxylic acid in
chlorobenzene.13 In a one-pot process, the iodobenzene
dicarboxylates were synthesized and subsequently reacted
with iodine and diphenylacetylene to afford a series of iodo-
enol ester stilbenes (Scheme 2). Using this approach, both aryl
(2n−p) and alkyl (2q−t) substituted carboxylic acids could be
added across diphenylacetylene to afford a range of previously
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Scheme 3. Iodine Monoacetate Addition to Ynamides
S-phenylsulfoximine and oxazolidinone-based ynamides derived
from 1-hexyne and 3,5-dimethoxyphenylacetylene failed to
afford to the corresponding iodo-substituted enolamides.
To further understand this reaction process, a mechanism
based on the results presented herein and of others is
proposed.5,7,15 When an electronically neutral or electron-
deficient alkyne is applied to the standard reaction conditions,
following activation of the alkyne by iodine monoacetate,
pathway A ensues (R = CN, Scheme 4), where the kinetic
process involving an SN2-type attack of a secondary acetate
anion affords vinyl iodide 2c as a single regioisomer with very
high selectivity for the trans-stereoisomer. In the case of
electron-rich alkynes (R = OMe, Scheme 4), pathway B
prevails, whereby following alkyne activation, fragmentation of
the iodine monoacetate takes place to afford an iodo-allenic
cation which is resonance stabilized by the electron-rich aryl
group. It is proposed that pathway B proceeds via a six-
membered transition state in what could be considered a near-
concerted fashion in which the acetate anion released from the
iodine monoacetate during the fragmentation process forms an
ion pair with the allenic cation facilitating rapid syn-addition of
the acetoxy group to afford tetrasubstituted alkene 2f as the cis-
stereoisomer with the opposite regiochemistry to that observed
in pathway A (Scheme 4).
Figure 1. An inseparable mixture of regio-isomers was obtained from
some reaction attempts.
Scheme 2. Extending the Scope of the Iodoacyloxylation of
Diphenylacetylene Using Various Iodobenzene
Dicarboxylates
For the iodoacetoxylation of the ynamide derivative 4a, at
elevated temperatures the thermodynamic pathway was favored
leading to formation of a higher portion of the cis-isomer 5a′;
however, at 0 °C the kinetic pathway predominates to afford
almost exclusively the trans-isomer 5a. To further probe the
effect of temperature on this reaction process, the iodoacetox-
ylation of 1c was performed at elevated temperature (60 °C) in
an attempt to generate the cis-adduct; however, once again the
trans-isomer of 2c was formed as the major product (83% yield,
E/Z = 40:1). The iodoacetoxylation of 1f was then conducted
at −20 °C to observe if the kinetic pathway to form the trans-
isomer could be favored; however, the cis-isomer of 2f was
again isolated as the major product (86% yield, E/Z = 1:12).
Thus, the electronic characteristics of the diaryl alkynes
predetermine the regio- and stereoselectivity of the product
formed, whereas in the case of the ynamides, formation of
either the cis- or trans-stereoisomer can be favored by
controlling the reaction temperature. This proposed mecha-
nism (Scheme 4) involving electronic factors to determine the
regio- and stereochemistry differs to those previously described
where only steric interactions were proposed to be the cause of
the observed stereo- and regioselectivity.5,15
inaccessible trans-substituted iodo enol esters in high-yield and
with very high stereoselectivity (Scheme 2). The structure and
stereochemistry of the products obtained from this inves-
tigation were confirmed through X-ray crystal analysis of
benzoyl derivative 2n, which again clearly shows the trans-
orientation of the iodine and benzoyloxy groups (Figure S2).12
Ynamides are key molecular building blocks that have found
application in numerous synthetic transformations.14 To
enhance the utility of the methodology described herein, the
iodo-acetoxylation of ynamides was then pursued. Using the
previously optimized reaction conditions, chiral ynamides 4a−c
were readily converted in good yield to the corresponding iodo-
enolamides 5a−c, a previously unreported class of tetrasub-
stituted alkenes (Scheme 3). It was observed that at elevated
temperatures a mixture of stereoisomers was obtained with
formation of the cis-isomer favored; however, when the reaction
was performed at 0 °C, the trans-stereoisomer was almost
exclusively formed. The regio- and stereochemistry of the
products obtained were further confirmed by X-ray crystallog-
raphy of enolamide derivative 5b (Figure S3),12 which shows
the acetoxy group added to the side of the alkyne closest to the
oxazolidinone moiety and oriented trans to the iodine atom.
Additional reaction attempts using N-phenylethynyl-S-methyl-
To further highlight the value of the products obtained using
the method described herein, vinyl iodide 2a was subjected to
Suzuki cross-coupling with 3,5-dimethylphenyl boronic acid to
afford tetrasubstituted alkene 6 which was subsequently
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Scheme 4. Proposed Mechanism to Account for the Observed Regio- And Stereo-Selectivity of This Process
(CDCl3: 7.26 [1H] or 77.16 [13C]). Proton resonances are annotated
as chemical shift (d), multiplicity (s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; br, broad), coupling constant (J, Hz), and
number of protons. High resolution MS was performed on a TOF
LC−MS. All data were acquired and reference mass corrected via a
dual-spray electrospray ionization (ESI) source. Each scan or data
point on the total ion chromatogram (TIC) is an average of 13 700
transients, producing a spectrum every second. Mass spectra were
created by averaging the scans across each peak and subtracting the
background from first 10 s of the TIC. Acquisition parameters: mode,
ESI; drying gas flow, 11 L/min; nebulizer pressure, 45 psi; drying gas
temperature, 325 °C; voltages: capillary, 4000 V; fragmentor, 160 V;
skimmer, 65 V; octapole RF, 750 V; scan range, 100−1500 m/z;
positive ion mode internal reference ions, m/z 121.050873 and
922.009798.
hydrolyzed to afford the 1,1-disubstituted acetophenone
derivative 7 (Scheme 5). This synthetic strategy utilizing aryl-
Scheme 5. Additional Functionalization of the Vinyl Iodides
boronic acids to incorporate the second aryl moiety provides a
complementary approach to that recently reported by Taillefer
and co-workers for the synthesis of 1,1-disubstituted
acetophenone derivatives where aryl halides were applied.16
In summary, a highly regio- and stereoselective method for
the functionalization of activated and unactivated alkynes has
been developed under mild conditions. This reaction process
provides access to a series of useful iodo-enol ester derivatives
with predictable control over both the regio- and stereo-
chemistry. In addition, this method has facilitated the synthesis
of halo-substituted enolamides from ynamides, a previously
unreported class of tetrasubstituted alkenes. To further
understand this transformation, additional synthetic and
theoretical studies are ongoing in our laboratory.
General Procedure 1 for the Iodo-acetoxylation of Alkynes.
To a solution of PhI(OAc)2 (1.0 mmol) in DCE (5 mL) containing
4Å molecular sieves (∼1.0 g) was added I2 (1.0 mmol). After stirring
for 10 min, the alkyne (1.2 mmol) was added in one portion, and the
resultant solution stirred at room temperature for 4 h. After this time,
the molecular sieves were filtered off, and the reaction quenched by
the addition of Na2S2O3 (10% w/w aqueous, 10 mL). The aqueous
phase was extracted with CH2Cl2 (3 × 5 mL). The combined organic
fractions were dried over MgSO4 and filtered, and the solvent
evaporated. The product was purified by either recrystallization or
flash column chromatography as stated.
(E)-2-Iodo-1,2-diphenylvinyl acetate (2a).5 General procedure 1
was followed using diphenylacetylene. Purification by recrystallization
from ethanol afforded the title compound as a pale yellow solid (331
EXPERIMENTAL SECTION
■
1
mg, 91%): mp = 142.8−145.3 °C; H NMR (400 MHz, CDCl3) δ =
General Experimental. Iodobenzene diacetate, iodine and the
solvents used in reaction extractions and chromatography were
supplied by commercial vendors without further purification or drying.
Diphenylacetylene and 3-hexyne were supplied by commercial
vendors, all other alkynes were prepared by palladium-catalyzed
Sonogashira cross-coupling reaction following a literature procedure.17
Chiral ynamides 4a−c were also prepared using a literature method.18
All reactions were performed under an inert atmosphere of anhydrous
N2. 1,2-Dichloroethane (DCE) was purchased in anhydrous form and
stored under nitrogen. Petroleum spirits with a boiling point range of
40−60 °C were used in chromatography. Column (flash) chromatog-
raphy was performed on 40−60 μm silica gel. 1H and 13C NMR
spectra were recorded at 400.13 and 100.62 MHz, respectively.
Chemical shifts (d, ppm) are reported relative to the solvent peak
7.67−7.69 (m, 2H), 7.42−7.47 (m, 4H), 7.36−7.41 (m, 2H), 7.30 (tt,
J = 1.4 and 7.4 Hz, 1H), 1.86 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3) δ = 168.6, 147.3, 140.7, 137.1, 129.7, 129.3, 128.5, 128.4,
128.3, 128.1, 89.1, 20.4 ppm; HRMS (m/z) = [C16H13O2I + H]+ calcd
365.0033, found 365.0030.
(E)-2-Iodo-2-(4-nitrophenyl)-1-phenylvinyl acetate (2b). General
procedure 1 was followed using 1-nitro-4-(phenylethynyl)benzene.
Purification by column chromatography (1:1 PhMe/Pet. Sp. → 100%
PhMe) afforded the title compound as a pale yellow amorphous solid
(331 mg, 81%): 1H NMR (400 MHz, CDCl3) δ = 8.21 (d, J = 9.0 Hz,
2H), 7.62−7.65 (m, 2H), 7.59 (d, J = 9.0 Hz, 2H), 7.41−7.44 (m,
3H), 1.87 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ = 168.2,
149.1, 147.3, 136.3, 129.83, 129.76, 129.5, 128.3, 123.6, 85.2, 20.4
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ppm; HRMS (m/z) = [C16H12NO4I + H]+ calcd 409.9884, found
409.9888.
chromatography (1:2 PhMe/Pet. Sp.) afforded the title compound
as a pale yellow oil (304 mg, 85%): 1H NMR (400 MHz, CDCl3) δ =
7.46−7.49 (m, 2H), 7.32−7.38 (m, 3H), 2.53 (t, J = 7.4 Hz, 2H), 2.11
(s, 3H), 1.55−1.63 (m, 2H), 1.32−1.38 (m, 4H), 0.92 (t, J = 7.4 Hz,
3H) ppm; 13C NMR (100 MHz, CDCl3) δ = 168.3, 146.3, 137.6,
129.8, 128.9, 127.9, 96.9, 38.1, 30.7, 28.6, 22.4, 20.6, 14.0 ppm; HRMS
(m/z) = [C15H19O2I + Na]+ calcd 381.0322, found 381.0317.
(E)-2-Iodo-2-(4-cyanophenyl)-1-phenylvinyl acetate (2c). General
procedure 1 was followed using 4-(phenylethynyl)benzonitrile.
Purification by column chromatography (1:1 PhMe/Pet. Sp. →
100% PhMe) afforded the title compound as a pale yellow solid (339
1
mg, 87%): mp = 132.0−133.7 °C; H NMR (400 MHz, CDCl3) δ =
7.61−7.66 (m, 4H), 7.54 (d, J = 8.6 Hz, 2H), 7.40−7.44 (m, 3H), 1.86
(s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ = 168.2, 148.8, 145.4,
136.4, 132.1, 129.8, 129.5, 128.2, 118.4, 112.0, 85.7, 20.4 ppm; HRMS
(m/z) = [C17H12NO2I + H]+ calcd 389.9985, found 389.9987.
(E)-2-Iodo-2-phenyl-1-(p-tolyl)vinyl acetate (2d).15 General pro-
cedure 1 was followed using 1-methyl-4-(phenylethynyl)benzene.
Purification by column chromatography (1:1 PhMe/Pet. Sp.) afforded
the title compound as a white solid (321 mg, 85%): mp = 78.5−81.0
°C; 1H NMR (400 MHz, CDCl3) δ = 7.46 (d, J = 8.1 Hz, 2H), 7.33−
7.35 (m, 2H), 7.23−7.28 (m, 2H), 7.18−7.20 (m, 1H), 7.11 (d, J = 7.9
Hz, 2H), 2.29 (s, 3H), 1.72 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3) δ = 168.7, 147.4, 140.9, 139.4, 134.3, 129.5, 128.8, 128.5,
128.30, 128.26, 88.6, 21.5, 20.5 ppm; HRMS (m/z) = [C17H15O2I +
H]+ calcd 379.0189, found 379.0184.
General Procedure 2 for the Iodo-acyloxylation of Alkynes.
In a 100 mL RBF was combined iodobenzene diacetate (1.0 mmol),
the carboxylic acid (2.0 mmol) and chlorobenzene (20 mL). The
solution was then stirred on the rotary evaporator for 10 min at 50 °C,
after which time the solvent was slowly evaporated over 30 min under
reduced pressure. The resultant iodobenzene dicarboxylate was further
dried on the high vacuum for an additional 30 min and then dissolved
in DCE (5 mL) containing 4Å molecular sieves (∼1.0 g), and I2 (1.0
mmol) added. After stirring for 10 min, diphenylacetylene (1.2 mmol)
was added in one portion, and the resultant solution stirred at rt for 4
h. After this time, the molecular sieves were filtered off, and the
reaction quenched by the addition of Na2S2O3 (10% w/w aqueous, 10
mL). The aqueous phase was extracted with CH2Cl2 (3 × 5 mL). The
combined organic fractions were dried over MgSO4 and filtered, and
the solvent evaporated. The product was purified by either
recrystallization or flash column chromatography as stated.
(E)-4-Iodohex-3-en-3-yl acetate (2e).7 General procedure 1 was
followed using 3-hexyne. Purification by column chromatography
(1:19 EtOAc/Pet. Sp.) afforded the title compound as a pale yellow oil
(217 mg, 81%): 1H NMR (400 MHz, CDCl3) δ = 2.48 (q, J = 7.5 Hz,
2H), 2.26 (q, J = 7.4 Hz, 2H), 2.10 (s, 3H), 0.94 (t, J = 7.5 Hz, 3H),
0.93 (t, J = 7.4 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ = 168.4,
148.7, 96.1, 31.1, 29.8, 20.4, 14.0, 10.9 ppm; HRMS (m/z) =
[C8H13O2I]+ calcd 267.9955, found 267.9958.
(E)-2-Iodo-1,2-diphenylvinyl benzoate (2n). General procedure 2
was followed using benzoic acid and diphenylacetylene. Purification by
recrystallization from ethanol afforded the title compound as a white
1
solid (358 mg, 84%): mp = 106.2−110.4 °C; H NMR (400 MHz,
CDCl3) δ = 7.82 (dd, J = 1.3 and 8.4 Hz, 2H), 7.75 (dd, J = 1.4 and 8.2
Hz, 2H), 7.48−7.53 (m, 3H), 7.40−7.44 (m, 3H), 7.33−7.38 (m, 2H),
7.26−7.30 (m, 2H), 7.19 (dt, J = 1.3 and 8.7 Hz, 1H) ppm; 13C NMR
(100 MHz, CDCl3) δ = 164.3, 147.3, 140.6, 137.1, 133.5, 129.9, 129.8,
129.4, 128.9, 128.6, 128.4, 128.3, 128.2, 128.1, 89.3 ppm; HRMS (m/
z) = [C21H15O2I + H]+ calcd 427.0189, found 427.0182.
(Z)-2-Iodo-1-(4-methoxyphenyl)-2-phenylvinyl acetate (2f).9
General procedure 1 was followed using 1-methoxy-4-(phenyl-
ethynyl)benzene. Purification by column chromatography (1:1
PhMe/Pet. Sp. → 100% PhMe) afforded the title compound as a
1
pale yellow solid (367 mg, 93%): mp = 125.6−128.3 °C; H NMR
(E)-2-Iodo-1,2-diphenylvinyl 3-(trifluoromethyl)benzoate (2o).
General procedure 2 was followed using 3-trifluoromethylbenzoic
acid and diphenylacetylene. Purification by column chromatography
(1:1 PhMe/Pet. Sp.) afforded the title compound as a yellow solid
(351 mg, 71%): mp = 120.2−121.9 °C; 1H NMR (400 MHz, CDCl3)
δ = 8.04 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.72−7.76 (m, 3H), 7.37−
7.50 (m, 6H), 7.29 (t, J = 7.3 Hz, 2H), 7.19 (dt, J = 1.3 and 6.7 Hz,
1H) ppm; 13C NMR (100 MHz, CDCl3) δ = 163.0, 146.9, 140.4,
136.7, 133.0, 129.9 (q, J = 3.6 Hz), 129.5, 129.1, 128.5, 128.4, 128.3,
128.2, 126.7 (q, J = 3.8 Hz), 89.6 ppm; 19F NMR (400 MHz, CDCl3)
δ = −62.90 ppm; HRMS (m/z) = [C22H14F3O2I + H]+ calcd
495.0063, found 495.0050.
(400 MHz, CDCl3) δ = 7.27−7.30 (m, 2H), 7.17−7.23 (m, 3H), 7.08
(d, J = 9.0 Hz, 2H), 6.64 (d, J = 9.0 Hz, 2H), 3.72 (s, 3H), 2.29 (s,
3H) ppm; 13C NMR (100 MHz, CDCl3) δ = 168.0, 159.6, 149.9,
140.8, 130.21, 130.17, 128.4, 128.1, 125.8, 113.5, 89.9, 55.2, 21.4 ppm;
HRMS (m/z) = [C17H15O3I + Na]+ calcd 416.9958, found 416.9959.
(Z)-1-(4-((Ethoxycarbonyl)amino)phenyl)-2-iodo-2-phenylvinyl
acetate (2g). General procedure 1 was followed using 1-
(ethoxycarbonyl)amino-4-(phenylethynyl)benzene. Purification by
recrystallization from ethanol afforded the title compound as a pale
1
yellow solid (320 mg, 71%): mp = 161.4−164.6 °C; H NMR (400
MHz, CDCl3) δ = 7.18−7.22 (m, 2H), 7.10−7.16 (m, 3H), 7.07 (d, J
= 8.8 Hz, 2H), 6.99 (dt, J = 2.2 and 8.8 Hz, 2H), 6.46 (brs, 1H), 4.12
(q, J = 7.1 Hz, 2H), 2.22 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H) ppm; 13C
NMR (100 MHz, CDCl3) δ = 168.0, 153.2, 149.6, 140.6, 138.2, 130.2,
129.6, 128.4, 128.3, 117.7, 90.7, 61.4, 21.4, 14.5 ppm; HRMS (m/z) =
[C19H18NO4I + H]+ calcd 452.0353, found 452.0358.
(E)-2-Iodo-1,2-diphenylvinyl 3,4-dimethylbenzoate (2p). General
procedure 2 was followed using 3,4-dimethylbenzoic acid and
diphenylacetylene. Purification by column chromatography (1:1
PhMe/Pet. Sp.) afforded the title compound yellow oil that solidified
1
upon standing (341 mg, 75%): H NMR (400 MHz, CDCl3) δ =
(E)-2-Iodo-1-phenylpent-1-en-1-yl acetate (2h). General proce-
dure 1 was followed using 1-phenylpentyne. Purification by column
chromatography (1:2 PhMe/Pet. Sp.) afforded the title compound as a
7.64−7.67 (m, 2H), 7.51 (s, 1H), 7.46 (dd, J = 1.7 and 7.9 Hz, 1H),
7.40−7.43 (m, 2H), 7.28−7.32 (m, 3H), 7.17−7.21 (m, 2H), 7.09 (tt,
J = 1.3, 6.7, and 8.2 Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H), 2.17 (s, 3H),
2.14 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ = 164.6, 147.4,
143.0, 140.7, 137.3, 136.8, 131.0, 129.75, 129.66, 129.3, 128.7, 128.23,
128.17, 128.0, 127.5, 126.4, 89.1, 20.0, 19.6 ppm; HRMS (m/z) =
[C23H19O2I + H]+ calcd 455.0502, found 455.0500.
1
pale yellow oil (258 mg, 78%): H NMR (400 MHz, CDCl3) δ =
7.38−7.40 (m, 2H), 7.21−7.26 (m, 3H), 2.43 (t, J = 7.4 Hz, 2H), 2.00
(s, 3H), 1.52 (sext, J = 7.4 Hz, 2H), 0.88 (t, J = 7.4 Hz, 3H) ppm; 13C
NMR (100 MHz, CDCl3) δ = 168.3, 146.6, 137.6, 129.8, 128.9, 127.9,
96.7, 40.0, 22.4, 20.6, 13.2 ppm; HRMS (m/z) = [C13H15O2I + Na]+
calcd 353.0009, found 353.0008.
(E)-2-Iodo-1-phenylhex-1-en-1-yl acetate (2i). General procedure
1 was followed using 1-phenylhexyne. Purification by column
chromatography (1:2 PhMe/Pet. Sp.) afforded the title compound
as a pale yellow oil (289 mg, 84%): 1H NMR (400 MHz, CDCl3) δ =
7.46−7.49 (m, 2H), 7.31−7.37 (m, 3H), 2.54 (t, J = 7.4 Hz, 2H), 2.11
(s, 3H), 1.53−1.61 (m, 2H), 1.33−1.43 (sext., J = 7.5 Hz, 2H), 0.96 (t,
J = 7.4 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ = 168.3, 146.3,
137.6, 129.8, 128.9, 127.9, 96.9, 37.8, 31.1, 21.7, 20.6, 13.9 ppm;
HRMS (m/z) = [C14H17O2I + Na]+ calcd 367.0165, found 367.0161.
(E)-2-Iodo-1-phenylhept-1-en-1-yl acetate (2j). General procedure
1 was followed using 1-phenylheptyne. Purification by column
(E)-2-Iodo-1,2-diphenylvinyl 3-phenylpropanoate (2q). General
procedure 2 was followed using 3-phenylpropanoic acid and
diphenylacetylene. Purification by column chromatography (1:1
PhMe/Pet. Sp.) afforded the title compound as a clear oil (350 mg,
1
77%): H NMR (400 MHz, CDCl3) δ = 7.52−7.55 (m, 2H), 7.31−
7.34 (m, 4H), 7.20−7.25 (m, 2H), 7.17−7.19 (m, 2H), 7.07−7.12
(3H), 6.91−6.93 (m, 2H), 2.57 (t, J = 7.5 Hz, 2H), 2.31−2.35 (m,
2H) ppm; 13C NMR (100 MHz, CDCl3) δ = 170.5, 147.2, 140.7,
139.9, 137.0, 129.7, 129.3, 128.54, 128.48, 128.4, 128.3, 128.14,
128.10, 126.3, 88.9, 35.2, 30.3 ppm; HRMS (m/z) = [C23H19O2I +
H]+ calcd 455.0502, found 455.0495.
(E)-2-Iodo-1,2-diphenylvinyl 2-((1S,4R)-bicyclo[2.2.1]heptan-2-
yl)acetate (2r). General procedure 2 was followed using 2-
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Article
norbornaneacetic acid and diphenylacetylene. Purification by column
chromatography (1:1 PhMe/Pet. Sp.) afforded the title compound as a
clear oil (321 mg, 70%): 1H NMR (400 MHz, CDCl3) δ = 7.63−7.66
(m, 2H), 7.32−7.44 (m, 7H), 7.24−7.29 (m, 1H), 2.09 (s, 1H), 2.05
(dd, J = 8.0 and 15.2 Hz, 1H), 1.90 (dd, J = 7.6 and 15.2 Hz, 1H),
1.55−1.62 (m, 2H), 1.36−1.40 (m, 2H), 1.20−1.26 (m, 1H), 1.10 (dt,
J = 1.8 and 9.9 Hz, 1H), 1.01−1.05 (m, 2H), 0.95−1.00 (m, 1H),
0.73−0.79 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ = 170.6,
147.4, 140.9, 137.2, 129.7, 129.2, 128.6, 128.3, 128.2, 128.0, 88.7,
40.85, 40.76, 38.0, 37.5, 36.6, 35.0, 29.7, 28.4 ppm; HRMS (m/z) =
[C23H23O2I + H]+ calcd 459.0815, found 459.0811.
(E)-2-Iodo-1,2-diphenylvinyl cyclopentanecarboxylate (2s). Gen-
eral procedure 2 was followed using cylopentane carboxylic acid and
diphenylacetylene. Purification by column chromatography (1:2
PhMe/Pet. Sp.) afforded the title compound as a pale yellow solid
(289 mg, 69%): mp = 105.9−109.3 °C; 1H NMR (400 MHz, CDCl3)
δ = 7.64−7.67 (m, 2H), 7.35−7.43 (m, 5H), 7.32−7.34 (m, 2H),
7.24−7.29 (m, 1H), 2.49−2.57 (m, 1H), 1.58−1.63 (m, 2H), 1.39−
1.49 (m, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ = 174.1, 147.5,
140.9, 137.1, 129.6, 129.2, 128.5, 128.3, 128.2, 128.0, 88.3, 43.3, 29.3,
25.6 ppm; HRMS (m/z) = [C20H19O2I + H]+ calcd 419.0502, found
419.0494.
(S,E)-1-(4-Benzyl-2-oxooxazolidin-3-yl)-2-iodo-2-phenylvinyl ace-
tate (5b). General procedure 3 was followed using (S)-4-benzyl-3-
(phenylethynyl)oxazolidin-2-one. Purification by column chromatog-
raphy (1:19 EtOAc/PhMe) followed by recrystallization from ethanol
afforded the title compound as white needle-like crystals (366 mg,
79%): mp = 121.4−123.1 °C; 1H NMR (400 MHz, CDCl3) δ = 7.30−
7.32 (m, 2H), 7.22−7.25 (m, 4H), 7.18−7.20 (m, 2H), 7.12−7.15 (m,
2H), 4.22−4.26 (m, 1H), 4.20 (t, J = 8.0 Hz, 1H), 4.11 (dd, J = 6.4
and 8.0 Hz, 1H), 3.46 (dd, J = 3.4 and 13.2 Hz, 1H), 2.86 (dd, J = 10.0
and 13.2 Hz, 1H), 1.80 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ
= 167.9, 153.8, 138.9, 136.8, 135.6, 129.1, 129.0, 128.9, 128.7, 128.3,
127.3, 92.6, 68.2, 57.6, 39.2, 20.1 ppm; HRMS (m/z) = [C20H18NO4I
+ H]+ calcd 464.0353, found 464.0358.
(S,E)-2-Iodo-1-(4-phenyl-2-oxooxazolidin-3-yl)-2-phenylvinyl ac-
etate (5c). General procedure 3 was followed using (S)-4-phenyl-3-
(phenylethynyl)oxazolidin-2-one. Purification by column chromatog-
raphy (1:19 EtOAc/PhMe) afforded the title compound as a pale
1
yellow oil that solidified on standing (364 mg, 81%): H NMR (400
MHz, CDCl3) δ = 7.42−7.50 (m, 5H), 7.21−7.30 (m, 5H), 5.12 (dd, J
= 6.5 and 8.7 Hz, 1H), 4.80 (t, J = 8.7 Hz, 1H), 4.32 (dd, J = 6.5 and
8.7 Hz, 1H), 1.57 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ =
166.6, 153.3, 138.7, 137.3, 137.1, 129.3, 129.1, 128.7, 128.2, 127.4,
90.3, 70.7, 60.3, 19.5 ppm; HRMS (m/z) = [C19H16NO4I + H]+ calcd
450.0197, found 450.0178.
(E)-2-Iodo-1,2-diphenylvinyl (S)-2-phenylpropanoate (2t). Gen-
eral procedure 2 was followed using (S)-2-phenylpropanoic acid and
diphenylacetylene. Purification by column chromatography (1:1
PhMe/Pet. Sp.) afforded the title compound as a pale yellow oil
(372 mg, 82%): 1H NMR (400 MHz, CDCl3) δ = 7.54−7.56 (m, 2H),
7.35−7.39 (m, 5H), 7.26−7.31 (m, 3H), 7.20−7.25 (m, 3H), 6.99−
7.01 (m, 2H), 3.55 (q, J = 7.2 Hz, 1H), 1.28 (d, J = 7.2 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl3) δ = 171.8, 147.1, 140.7, 139.0, 136.7,
(E)-2-(3,5-Dimethylphenyl)-1,2-diphenylvinyl acetate (6). To a
degassed solution of vinyl iodide 2a (728 mg, 2.0 mmol) in THF (10
mL) in a sealed tube was added Pd(PPh3)4 (5 mol %), Cs2CO3 (2.0
equiv. 5 M aqueous solution) and 3,5-dimethylphenyl boronic acid
(450 mg, 3.0 mmol). The resultant solution was heated to 100 °C for
16 h. After this time the reaction mixture was diluted with EtOAc (10
mL) and washed with NH4Cl (10 mL, sat. aq. solution) and brine (10
mL, sat. aq. solution). The organic phase was separated, dried over
MgSO4 and concentrated. Purification by column chromatography
(1:1 PhMe/Pet. Sp.) afforded the title compound as a pale yellow oil
129.6, 129.2, 128.6, 128.5, 128.24, 128.19, 127.9, 127.5, 127.1, 88.6,
45.1, 18.0 ppm; HRMS (m/z) = [C23H19O2I + H]+ calcd 455.0502,
found 455.0492.
1
General Procedure 3 for the Iodo-acetoxylation of
Ynamides. To a solution of PhI(OAc)2 (1.0 mmol) in DCE (5
mL) containing 4Å molecular sieves (∼1.0 g) was added I2 (1.0
mmol). After stirring for 10 min, ynamide (1.2 mmol) was added in
one portion, and the resultant solution stirred at 0 °C for 16 h. After
this time, the molecular sieves were filtered off, and the reaction
quenched by the addition of Na2S2O3 (10% w/w aqueous, 10 mL).
The aqueous phase was extracted with CH2Cl2 (3 × 5 mL). The
combined organic fractions were dried over MgSO4 and filtered, and
the solvent evaporated. The product was purified by flash column
chromatography.
that solidified upon standing (493 mg, 72%): H NMR (400 MHz,
CDCl3) δ = 7.12−7.21 (m, 7H), 7.0−7.06 (m, 3H), 6.69 (s, 1H), 6.60
(brs, 2H), 2.019 (s, 3H), 2.018 (s, 3H), 1.85 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3) δ = 169.9, 143.6, 140.4, 139.5, 137.5, 136.0, 132.3,
129.1, 129.0, 128.9, 128.6, 128.2, 128.0, 127.9, 127.4, 21.2, 21.0 ppm;
HRMS (m/z) = [C24H22O2 + H]+ calcd 343.1693, found 343.1696.
2-(3,5-Dimethylphenyl)-1,2-diphenylethan-1-one (7).18 To a
solution of acetate 6 (342 mg, 1.0 mmol) in methanol (5 mL) was
added NaOH (2.0 mmol, 2 M aqueous solution), and the resultant
mixture stirred at room temperature for 16 h. After this time the
volatiles were evaporated. The aqueous solution was then acidified to
pH 5 using 1 M HCl and then extracted with EtOAc (4 × 5 mL). The
combined organic phases were dried over MgSO4 and concentrated.
Purification by column chromatography (1:1 PhMe/Pet. Sp.) afforded
the title compound as a clear oil (291 mg, 97%): 1H NMR (400 MHz,
CDCl3) δ = 7.98 (dd, J = 1.4 and 8.5 Hz, 2H), 7.48 (dt, J = 1.3 and 6.8
Hz, 1H), 7.36−7.41 (m, 2H), 7.21−7.32 (m, 5H), 6.88 (s, 2H), 6.87
(s, 1H), 5.95 (s, 1H), 2.250 (s, 3H), 2.249 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3) δ = 198.4, 139.3, 138.8, 138.3, 137.0, 133.0, 129.2,
128.99, 128.97, 128.64, 128.61, 127.1, 126.9, 59.4, 21.4 ppm; HRMS
(m/z) = [C22H20O + H]+ calcd 301.1587, found 301.1591.
(S,E)-2-Iodo-1-(4-isopropyl-2-oxooxazolidin-3-yl)-2-phenylvinyl
acetate (5a). General procedure 3 was followed using (S)-4-isopropyl-
3-(phenylethynyl)oxazolidin-2-one. Purification by column chroma-
tography (1:19 EtOAc/PhMe) afforded the title compound as a pale
1
yellow oil (299 mg, 72%): H NMR (400 MHz, CDCl3) δ = 7.44−
7.47 (m, 2H), 7.29−7.33 (m, 2H), 7.25−7.27 (m, 1H), 4.38 (t, J = 8.8
Hz, 1H), 4.19 (dd, J = 5.9 and 8.8 Hz, 1H), 4.07 (ddd, J = 4.0, 5.9, and
8.8 Hz, 1H), 2.11−2.19 (m, 1H), 1.87 (s, 3H), 1.06 (d, J = 6.8 Hz,
3H), 0.99 (d, J = 7.0 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ =
166.8, 154.0, 139.1, 137.6, 128.8, 128.7, 128.3, 89.7, 64.0, 60.4, 29.7,
20.1, 18.3, 15.8 ppm; HRMS (m/z) = [C16H18NO4I + H]+ calcd
416.0353, found 416.0359.
ASSOCIATED CONTENT
* Supporting Information
■
(S,Z)-2-Iodo-1-(4-isopropyl-2-oxooxazolidin-3-yl)-2-phenylvinyl
acetate (5a′). General procedure 3 was followed using (S)-4-
isopropyl-3-(phenylethynyl)oxazolidin-2-one; however, the reaction
was performed at 60 °C. Purification by column chromatography
(1:19 EtOAc/PhMe) afforded the title compound as a pale yellow oil
S
NMR spectra for all compounds and crystallographic data for
compounds 2c, 2n and 5b.19 This material is available free of
charge via the Internet at http://pubs.acs.org.
1
(266 mg, 64%, E/Z = 1:3). Major isomer (cis-5a′): H NMR (400
AUTHOR INFORMATION
Corresponding Authors
*E-mail: daniel.priebbenow@monash.edu.
*E-mail: jonathan.baell@monash.edu.
MHz, CDCl3) δ = 7.37−7.40 (m, 2H), 7.28−7.36 (m, 3H), 4.00 (t, J =
8.9 Hz, 1H), 3.93 (dd, J = 5.8 and 8.9 Hz, 1H), 3.40 (ddd, J = 3.3, 5.8,
and 8.9 Hz, 1H), 2.28 (s, 3H), 1.93−2.04 (m, 1H), 0.72 (d, J = 7.0 Hz,
3H), 0.53 (d, J = 6.8 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ =
167.1, 155.6, 138.9, 138.3, 129.2, 128.8, 128.6, 91.0, 63.6, 60.5, 28.4,
21.1, 18.1, 14.2 ppm; HRMS (m/z) = [C16H18NO4I + H]+ calcd
416.0353, found 416.0357. Minor-isomer (trans-5a): see above.
■
Notes
The authors declare no competing financial interest.
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Article
(19) The crystallographic data for compounds 2c, 2n and 5b have
been deposited with the Cambridge Crystallographic Data Centre with
reference numbers 1046658, 1046659 and 1046660, respectively.
Copies of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, U.K. (fax: +44 (0)
1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
ACKNOWLEDGMENTS
■
Funding from the Australian Research Council
(DP140103996) is acknowledged. The authors also thank
Assoc. Prof. Bernie Flynn for valuable discussions.
REFERENCES
■
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1
of the H NMR spectra, whereby the chemical shift of the −CH3 of
the acetoxy group of the trans-isomer is observed at 1.86 ppm and the
cis-isomer at 2.32 ppm.
(12) Refer to the Supporting Information for more details.
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