Base-mediated stereospecific synthesis of aryloxy and amino substituted ethyl acrylates

Article abstract of DOI:10.1021/jo201948e

The stereospecific synthesis of aryloxy and amino substituted E- and Z-ethyl-3-acrylates is of interest because of their potential in the polymer industry and in medicinal chemistry. During work on a copper-catalyzed cross-coupling reaction of ethyl (E)- and (Z)-3-iodoacrylates with phenols and N-heterocycles, we discovered a very simple (nonmetallic) method for the stereospecific synthesis of aryloxy and amino substituted acrylates. To study this long-standing problem on the stereoselectivity of aryloxy and amino substituted acrylates, a series of O- and N-substituted nucleophiles was allowed to react with ethyl (E)- and (Z)-3-iodoacrylates. Screening of different bases indicated that DABCO (1,4-diazabicyclo[2.2.2]octane) afforded successful conversion of ethyl (E)- and (Z)-3-iodoacrylates into aryloxy and amino substituted ethyl acrylates in a stereospecific manner. Herein are the details of this DABCO-mediated stereospecific synthesis of aryloxy and amino substituted E- or Z-acrylates.

Full text of DOI:10.1021/jo201948e

Article
pubs.acs.org/joc
Base-Mediated Stereospecific Synthesis of Aryloxy and Amino
Substituted Ethyl Acrylates
M. Shahjahan Kabir,*,† Ojas A. Namjoshi,† Ranjit Verma,† Michael Lorenz,†
V. V. N. Phani Babu Tiruveedhula,† Aaron Monte,‡ Steven H. Bertz,§ Alan W. Schwabacher,*,†
and James M. Cook*,†
†Department of Chemistry and Biochemistry, University of Wisconsin−Milwaukee, Milwaukee, Wisconsin 53201, United States
‡Department of Chemistry, University of Wisconsin−La Crosse, La Crosse, Wisconsin 54601, United States
§Complexity Study Center and University of North Carolina−Charlotte, Charlotte, North Carolina 28223, United States
S
* Supporting Information
ABSTRACT: The stereospecific synthesis of aryloxy and
amino substituted E- and Z-ethyl-3-acrylates is of interest
because of their potential in the polymer industry and in
medicinal chemistry. During work on a copper-catalyzed cross-
coupling reaction of ethyl (E)- and (Z)-3-iodoacrylates with
phenols and N-heterocycles, we discovered a very simple
(nonmetallic) method for the stereospecific synthesis of
aryloxy and amino substituted acrylates. To study this long-
standing problem on the stereoselectivity of aryloxy and amino substituted acrylates, a series of O- and N-substituted nucleophiles
was allowed to react with ethyl (E)- and (Z)-3-iodoacrylates. Screening of different bases indicated that DABCO (1,4-
diazabicyclo[2.2.2]octane) afforded successful conversion of ethyl (E)- and (Z)-3-iodoacrylates into aryloxy and amino
substituted ethyl acrylates in a stereospecific manner. Herein are the details of this DABCO-mediated stereospecific synthesis of
aryloxy and amino substituted E- or Z-acrylates.
INTRODUCTION
RESULTS AND DISCUSSION
Synthesis of Aryloxy and Amino Substituted E-
■
■
Vinyl ethers are important intermediates in organic and
medicinal chemistry and as raw materials for the polymer
industry.1−5 Indeed, vinyl aryl ethers constitute useful
intermediates in a wide range of reactions, for example,
cycloadditions, cyclopropanations, metathesis reactions, natural
product analogues, and polymers.2 N-Vinyl amines are widely
used in the preparation of polymeric dyes, catalysts and ion-
exchange resins, while the vinyl group can also act as an
efficient protecting group of phenol derivatives.1 Vinyl aryl
ether moieties are found in numerous biologically active
molecules, for example 1-phenoxy-3-triazolyl-1-hexene deriva-
tives are plant growth regulators.2 In particular, acrylate ester
derivatives are used as the base acrylic monomer in a wide
range of coatings, adhesives, as well as finishes for paper, leather
and textiles. In addition, they are used in floor and wood
polishes, acrylic resins, and powder coatings. Acrylic acid-
derived polymers are widely used in everyday life including
super adsorbent polymers (SAPs).6 Recent reports indicate that
classes of alkoxy acrylates are potently active against drug
resistant strains of tuberculosis7,8 and N-azolyl acrylates inhibit
CRM1(Chromosome Region Maintenance)-mediated nucleo-
cytoplasmic transport, a selective congener which inhibits the
HIV-1 production in latently infected cells.9
Acrylates from Ethyl (Z)-3-Iodoacrylates. The past decade
has shown significant progress in the development of Cu-
catalyzed cross-coupling processes and other methods10,11 for
the synthesis of aryl ethers, aryl thioethers, aryl amines, and
their respective vinyl analogues of synthetic, polymeric, and
biological importance.10−33 The use of copper-catalysis in the
formation of C−N, C−O and C−S bonds including aryl and
vinyl substituted derivatives covering a broad spectrum of
amines, ethers, and thioethers in good to excellent yields has
been reported.7,8,34 It has now been shown that the formation
of vinylic C−N and C−O bonds by a Cu-catalytic method7 is
ineffective with the functionalized ethyl iodoacrylate substrates,
for both phenols and N-heterocycles as nucleophiles.1 These
products obtained from an ethyl (Z)-3-iodoacrylate substrate,
presumably, resulted from the conjugate addition, which
produced only the E- isomers of the desired products of ethers
or amines from an ethyl (Z)-3-iodoacrylate instead of giving the
previously reported7 copper mediated stereospecific cross-
coupled Z- products at the 40 °C optimized reaction
temperature. This previous result reported from our laboratory
with ethyl (Z)-3-iodoacrylate employing a copper catalytic
method for the synthesis of aryloxy and amino substituted Z-
Received: September 21, 2011
Published: November 10, 2011
© 2011 American Chemical Society
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Table 1. Aryloxy and Amino Substituted Trans Acrylates from the Starting Cis Acrylates Are Believed to Be from a Conjugate
Addition
a
b
c
Isolated yields, the average of at least two runs. The reaction was carried out at 40 °C and was stirred for 2 h. The reaction was carried out at 40
°C and was stirred for 3 h.
acrylates yielded exclusively the E-isomers (as shown in Table
1)1 and were inadvertently assigned as the Z-isomers.7,8 The
coupling constants for arylthio substituted Z-acrylates were in
the range of 10−12 Hz according to the literature.35,36 In this
case the coupling constants for aryloxy and amino substituted
E-acrylates were also in the range of 10−12 Hz, which led us to
assign the E-isomers as Z-isomers when compared to the
arylthio derivatives of Z-acrylates.1,7,8,36 Hence, in order to
correct the error due to miss-assignment in the previous
communications7,8 as well as develop an efficient method for
the stereospecific synthesis of phenoxy- and amino- E- and Z-
ethyl acrylates, it was decided to investigate the reaction
conditions step-by-step.
Role of a Base for the Synthesis of Aryloxy and Amino
Substituted E-Acrylates from Ethyl (Z)-3-Iodoacrylate.
To investigate this reaction a series of experiments were
performed and the results are summarized in Scheme 1. The
optimized reaction conditions with a copper catalyst in
combination with an inorganic base, Cs2CO3, at 40 °C was
applied to ethyl-Z-3-iodoacrylate1,7,8 with a phenol or an amine
and yielded only the E-products 2 and 9, respectively. With a
copper catalyst in the presence of Cs2CO3 at room temper-
ature, this yielded mixtures of E- and Z-isomers in an
approximately 3:2 ratio for both aryloxy substituted acrylates
(2, 16) and amino substituted acrylates (9, 22). The use of
Cs2CO3 without a copper catalyst at room temperature yielded
the same results obtained with a copper catalyst. At 0 °C, the
reaction did not proceed with or without the catalyst. The
copper catalyst was clearly not necessary in this process.1,7
The use of inorganic bases Cs2CO3, K3PO4 and K2CO3 at
elevated temperature (40 °C) yielded exclusively E-isomers of
ethers and amines from the Z-acrylate exclusively, but at room
temperature they gave mixtures of Z- and E-isomers, indicating
the lack of stereospecificity.
The results presented in Scheme 1 suggested that in the
presence of an inorganic base, a conjugate addition took place
between the acrylate iodide and nucleophiles1 instead of a
copper-catalyzed cross-coupling process.7
Optimization of Base-Mediated Stereospecific Syn-
thesis of Aryloxy and Amino Substituted Acrylates from
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Scheme 1. Role of a Base for the Synthesis of Aryloxy and Amino Substituted E-Acrylates from Z-Ethyl-iodoacrylate
Ethyl-3-iodoacrylate. These findings prompted us to inves-
tigate the long-standing problem of stereoselectivity with ethyl
(Z)-3-iodoacrylate from different approaches. Since it was now
known that the reaction proceeded without a copper catalyst1
and only a base was essential, it was decided to screen different
organic bases, such as strong bases (HMDS, LiHMDS),
nucleophilic hindered bases (DABCO and DBU), the
unhindered nucleophilic base (DMAP), and a commonly
used simple amine base (Et3N). The results indicated that a
nucleophilic hindered base, DABCO, efficiently promoted the
conversion of ethyl (Z)-3-iodoacrylates into aryloxy and amino
substituted Z-acrylates in a stereospecific fashion. The authors
are unaware of any published reports for such a DABCO-
mediated stereospecific addition of O- or N-nucleophiles to
ethyl iodoacrylates for the stereospecific synthesis of bio-
logically important aryloxy and amino substituted acrylates.
As mentioned earlier, various inorganic bases (Cs2CO3,
K2CO3, K3PO4) were screened with and without a copper
catalyst at ambient and elevated (40 °C) temperatures. None of
the conditions were effective in controlling the stereochemistry
of the ether and amine products. The prototypical base
employed by us and others for the synthesis of vinyl ethers and
amines from vinyl iodide substrates was Cs2CO3.36 Treatment
of 1 with the inorganic bases K2CO3 or K3PO4 with the
nucleophile 1A produced almost the same results as with
Cs2CO3, either with or without a copper catalyst. The results
obtained with Cs2CO3 under various conditions are summar-
ized in Table 2, entries 1−7. None of these conditions provided
the desired stereospecificity and in most cases yielded mixtures
of the Z- and E-isomers 16 and 2 in a 2:3 ratio. We next
screened the DBU, DABCO, DMAP, Et3N, HMDS, LiHMDS
in various solvents at room temperature. The results are
summarized in Table 1. With DBU, DMAP and Et3N in DMF
either with or without a copper catalyst the process did not
proceed (Table 2, entries 24−29). However, it was found that
treatment of 1 with 1A and 2 equiv of DABCO in DMF in the
absence of a copper catalyst at room temperature for 1 h
afforded exclusively Z-isomer 16 in nearly quantitative yield
with full retention of stereochemistry (Table 2, entry 15). The
use of 1.1 equiv of DABCO under the same conditions required
longer reaction times to finish and resulted in somewhat lower
yield (Table 2, entry 16). The use of a catalytic amount of
DABCO did not provide full conversion of the starting material
(Table 1, entries 17−19) into product. To summarize, the
optimized conditions for the stereospecific conversion of 1 to
16 were 1 equiv of 1 when stirred for 1 h with 1.5 equiv of 1A
and 2 equiv of DABCO in DMF at room temperature and
afforded Z-isomer 16 stereospecifically.
Application of DABCO-Mediated Stereospecific Syn-
thesis of Aryloxy and Amino Substituted Z-Acrylates
from Ethyl (Z)-3-Iodoacrylate. With optimized conditions
in hand, it was decided to determine the scope of this process.
To ensure the coupling reaction proceeded in a regio- and
stereospecific fashion, the coupling reaction was investigated
using 1 with various electron-poor and electron-rich substituted
aromatic phenols and N-heterocycles. Examination of the
results (summarized in Table 3) indicated that the DABCO-
mediated system worked well when the Z-vinyl iodide was
subjected to the coupling with aryl- or heterocyclic-substituted
phenols (Table 3, entries 1−6). Electron-rich, electron poor,
and ortho-substituted hindered aromatic phenols gave excellent
yields with full retention of stereochemistry (16−19) when the
process was carried out at room temperature for 1−2 h. As
expected, the 3-hydroxypyridine substrate (Table 3, entry 6)
gave the corresponding vinyl ether 21, but this reaction took 3
h to go to completion. This demonstrated that the scope of the
reaction can be extended to the synthesis of heterocyclic
substituted vinyl ethers in excellent yields.
Encouraged by these results, the DABCO-mediated reaction
conditions were employed for the coupling of 1 with various N-
heterocycles, including pyrazole, indazole, benzotriazole, and
triazoles (Table 3, entries 8−13). Interestingly, 1 gave the
desired Z-vinyl amines (22−27, Table 3, entries 8−13), but
required somewhat longer reaction times as compared to
oxygen nucleophiles. No reaction between 1 and indole took
place, presumably because of the unique character of the indole
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Table 2. Stereospecific Cross-Coupling of Ethyl (Z)-3-Iodoacrylate with 3,5-Dimethoxyphenol
a
entry
catalyst
equiv. base
solvent
temp. (°C)
time (h)
yield (%)
Z/E
1
CuI, L
CuI, L
CuI
2.0 Cs2CO3
2.0 Cs2CO3
2.0 Cs2CO3
2.0 Cs2CO3
2.0 Cs2CO3
2.0 Cs2CO3
2.0 Cs2CO3
2.0 K2CO3
2.0 K2CO3
2.0 K3PO4
2.0 K3PO4
2.0 HMDS
2.0 HMDS
2.0 LiHMDS
2.0 DABCO
1.1 DABCO
0.5 DABCO
0.2 DABCO
0.1 DABCO
2.0 DABCO
2.0 DABCO
2.0 DABCO
2.0 DABCO
2.0 DMAP
2.0 DMAP
2.0 Et3N
DMF
DMF
DMF
DMF
DMF
DMF
toluene
DMF
toluene
DMF
toluene
DMF
toluene
DMF
DMF
DMF
DMF
DMF
DMF
DMF
toluene
DMF
toluene
DMF
DMF
DMF
DMF
DMF
DMF
40
rt
rt
rt
40
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0.5
0.5
0.5
0.5
0.5
0.5
6
95
94
95
95
94
95
88
91
75
93
60
10
10
0
0:100
40:60
40:60
40:60
0:100
40:60
70:30
40:60
65:35
40:60
65:35
100:0
100:0
N/A
2
3
4
L
5
6
7
8
0.5
6
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
0.5
10
6
15
6
1.0
6.0
2.5
2.5
2.5
0.5
12
0.5
12
6
95
84
50
20
10
95
87
95
84
0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
N/A
CuI, L
CuI, L
CuI
CuI
CuI, L
CuI, L
CuI, L
6
0
N/A
6
0
N/A
2.0 Et3N
6
0
N/A
2.0 DBU
6
0
N/A
2.0 DBU
6
0
N/A
a
The starting aryl vinyl halides contained ∼3−9% Z-isomer; this resulted in ∼3−9% of the cis-isomer, included in the overall yield.
N−H bond (pKa = 19). The pKas of the nucleophiles that
worked well in this study ranged from 9.5 to 15 for both
phenols and N-heterocycles.
9−15). As expected, 29 afforded the desired amino substituted
E-acrylates 9−15 in excellent yield when stirred at room
temperature for a 2−3 h period.
Application of DABCO-Mediated Stereospecific Syn-
thesis of Aryloxy and Amino Substituted E-Acrylates
from Ethyl (E)-3-Iodoacrylate. To investigate whether or
not the stereochemistry of aryloxy and amino substituted
acrylates was retained regardless of the E- or Z-configuration of
the starting ethyl iodoacrylate, a series of experiments was
conducted which employed the DABCO-mediated reaction
conditions using ethyl (E)-3-iodoacrylate 29 in the presence of
the same phenols and N-heterocycles, as shown previously with
1 (Table 3). The results of the DABCO-mediated coupling
between 29 with various phenols and N-heterocycles are
summarized in Table 4. Examination of the results indicated
that reaction of 29 with nucleophiles proceeded in a
stereospecific fashion and yielded exclusively the aryloxy
substituted E-acrylates with electron-rich, electron poor, and
ortho substituted, as well as heterocyclic substituted aromatic
phenols in excellent yields (2−6) over a 1−3 h period (Table 4
entries 1−5). To test the hypothesis and to further extend the
scope of the reaction, E-isomer 29 was subjected to the
optimized reaction conditions with N-heterocycles, including
pyrazole, indazole, triazole, and benzotriazole (Table 4, entries
Potential Mechanism for the Stereospecificity. Key
points that were observed from the experiments:
(a) Ethyl iodoacrylate substrates reacted with oxygen and
nitrogen nucleophiles in stereospecific fashion in the
absence of a copper catalyst.
(b) The hindered, nucleophilic base DABCO was required to
control the stereospecificity.
(c) At least 1.1 equiv of DABCO was necessary for efficient
conversion.
On the other hand, the stereospecific nature of sulfur
substitution was unusual (Scheme 2, 30) and gave the reported
arylthio derivatives of Z-acrylates stereospecifically, in contrast
to most oxygen and nitrogen nucleophiles (2, 16 and 9, 22).1,7
Hence, it was speculated that an addition−elimination
mechanism may be involved in these types of substitution
reactions with oxygen and nitrogen nucleophiles.
In the case of thiolate or DABCO, addition to ethyl (Z)- or
(E)-3-iodoacrylate 1 or 29 would lead to 33 or 34, respectively
(Scheme 3). In order to give distinct products by this
mechanism, loss of iodide must be faster than rotation about
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Table 3. DABCO-Mediated Stereospecific Cross-Coupling of Ethyl (Z)-3-Iodoacrylate 1
a
b
Isolated yields, the average of at least two runs. The reaction was carried out at rt and was stirred for 3 h.
the C−C bond to interconvert 33 and 34. Consequently, these
may be transition states rather than intermediates, which is
reasonable, given the leaving group ability of iodide.37 Both
product isomers are stable to the reaction conditions, so that
loss of stereochemistry in the earlier cases (Scheme 1; 2, 16 and
9, 22) was not due to a stereospecific reaction followed by
interconversion. The other possible distinction between these
reactions involves enolate stereochemistry, which will be
discussed below.
If the rate of iodide loss were the only determinant of
stereospecific substitution, then DABCO must function as a
base, rather than a nucleophilic catalyst. This was in question
because the other amine bases were found to be much less
effective at mediating substitution (Table 2, entries 16−21).
The nucleophilic catalytic behavior of DABCO in the process
was proven as follows:
Treatment of ethyl (E)- and (Z)-3-iodoacryate 1 or 29 with a
stoichiometric amount of DABCO was monitored by 1H NMR
spectroscopy. Examination of the data in Figure 1 indicates that
each acrylate reacts to form a distinct product, 31 and 32
respectively, and the proton NMR coupling constants indicate
that ethyl (Z)-3-iodoacrylate (Figure 1, 1) gave the
intermediate Z-adduct (Figure 1, 31) and ethyl (E)-3-
iodoacrylate (Figure 1, 29) gave the E-adduct (Figure 1, 32).
Subsequent treatment of these intermediates with nucleophile
stereospecifically led to the product (see Figure 1). While
reaction of iodoacrylates plausibly proceeds through a single
transition state, substitution of these ammonium ions almost
certainly does not. Presumably intermediates 35 and 37
(Scheme 4) have a sufficient lifetime that they could
interconvert with their respective rotamers before elimination.
While it is certainly true that a barrier exists to slow
interconversion of rotamers, it is not expected to be sufficient
to cause the observed results. Thus, the observed stereospecific
substitution of both 31 and 32 requires some other distinction
between their intermediates than the rotamer formed.
There is another distinction besides rotamers that is possible:
enolate stereochemistry. Nucleophilic attack on Z-ammonium
acrylate 31 (Scheme 4) could proceed so as to allow close
approach of the ammonium species with the nascent oxyanion
of 35. This requires formation of the E-enolate (assuming an
ester with a higher CIP priority than the oxyanion). In contrast,
the E-ammonium acrylate 32 cannot bring the nascent
oxyanion of 37 into close proximity to the ammonium ion,
so E-enolate is not favored. Charge repulsion between anionic
nucleophile and the forming oxyanion may explain Z-enolate
geometry in 37, which also would allow better solvation of the
oxyanion. Note that s-cis versus s-trans conformational
preference of 31 and 32 is likely to be small, transition state
stability should overwhelm minor preferences. Rotation about
the single bond interconverts 37 and 38; however, 37, with the
smaller H eclipsing the OEt group, is preferred over 38.
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Table 4. DABCO-Mediated Stereospecific Cross-Coupling of Ethyl (Z)-3-Iodoacrylate with Phenols and N-Heterocycles
a
b
Isolated yields, the average of at least two runs. The reaction was carried out at rt and was stirred for 3 h.
corresponding Z-product through the reaction pathway that
retains closest approach of oppositely charged atoms and Z-
enolate 37 leading to the corresponding E-product through the
pathway of lowest steric repulsion with H eclipsing OEt.
Intermediate 37 has a larger distance between charged atoms
and little variation depending on the rotamer.
Scheme 2. Cs2CO3-Mediated Stereospecific Formation of
Arylthio Substituted Z-Acrylates from Ethyl-Z-iodoacrylate
This mechanism provides a self-consistent picture, but does
not answer all questions. Among others, the direct thiolate
substitution, and the initial formation of ammonium acrylate
intermediates cannot be controlled by these factors. We fall
back on the extremely rapid loss of β iodide from the enolate,
faster than rotameric interconversion. With smaller nucleo-
Intermediates 35 and 37 are distinct, and would remain so
throughout their reactions: E-enolate 35 leading to the
a
Scheme 3. Schematic Representation of Possible Mechanistic Pathways of Ethyl Iodoacrylate with Thiols or DABCO
a
b
In the case of ethyl-3-iodo-acrylate starting material, no considerable preference for the s-cis or the s-trans conformation is expected. Rotation
along the single bond in 33 and 34 (indicated by red color) must be slower than elimination of iodide.
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Figure 1. Experimental evidence for the formation of a stereospecific acrylate−DABCO adduct.
philes, bond making proceeds to a different extent in the
transition state and rotation competes with elimination, even
with the iodide leaving group.
DABCO in DMF at room temperature for 1 h provided Z-
isomer 16 in nearly quantitative yield.
This is our preferred explanation, but other possibilities
remain. Despite our efforts to exclude them, adventitious
transition metal catalysts may be present. A mechanism that
does not involve loss of double bond integrity is possible via
SRN1. Electron transfer to acrylate would form a radical anion
that loses iodide, and reaction of the resulting vinyl radical with
nucleophile forms a radical anion that can transfer an electron
to form product and propagate the reaction. The iodoacrylates
would cleave more readily as the radical anion, but the
ammonium acrylate intermediates could accept an electron
more readily. While this mechanism is mentioned, we consider
it less likely because of the range of nucleophiles that function
in this process.
EXPERIMENTAL SECTION
■
General Considerations. The N,N-dimethylformamide (DMF,
anhydrous, 99.8% purity), cesium carbonate (99.98% purity),
DABCO, phenols, and N-heterocyclic compounds were used as
received without further purification. Silica gel (230−400 mesh)
1
chromatography was utilized for purification of the products. H and
13C NMR spectra were obtained on a 300 or 500 MHz NMR
instrument with chemical shifts reported relative to TMS.
General Procedure A: DABCO-Mediated Synthesis of
Aryloxy and Amino Substituted Acrylates from Ethyl-Z-3-
iodo-acrylate and Ethyl (E)-3-Iodoacrylate (Tables 3 and 4). An
oven-dried round-bottom flask containing a magnetic stir bar was
sealed with a rubber septum and then evacuated and backfilled with
argon while cooling to rt. The round-bottom flask was then charged
with anhydrous DABCO (2.0 equiv), ethyl (E)- or (Z)-3-iodoacrylate
(1.0 equiv) and dry DMF (2 mL). The solution which resulted was
stirred for 5−10 min at rt. The appropriate phenol or N-heterocycle
(0.75 mmol, 1.5 equiv) in 0.5 mL of dry DMF was added to the
reaction mixture through a rubber septum and the mixture stirred for
an additional 0.5−3 h at rt depending on the structure of the substrate.
The reaction mixture was then filtered through a pad of silica gel to
remove insoluble residues. The pad of silica gel was washed with ethyl
acetate and hexane (40:60, 100 mL). The combined filtrate was
washed with brine (5 × 50 mL), dried (Na2SO4) and concentrated in
vacuo on a rotary evaporator. The concentrated crude oil was purified
by flash column chromatography on silica gel using the eluent (2−
20%) ethyl acetate and hexane (depending on the substrate) to obtain
the pure products (81−98%).
SUMMARY
■
An efficient DABCO-mediated stereospecific synthesis of
aryloxy and amino substituted ethyl acrylates has been achieved
in good to excellent yields. The DABCO-mediated system
tolerates a wide range of functional groups which gives it wide
applicability. The generality and simplicity of the system
permits open air reactions without special precautions or
metals.1 This stereospecific process should have many
applications in the polymer and resin industries. The optimized
conditions are as illustrated for the synthesis of Z-isomer 16
(Table 2, entry 15). Treatment of 1 with 1A and 2 equiv of
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7.78 (1H, d, J = 12.2 Hz), δ 6.30 (1H, t, J = 2.2 Hz), δ 6.25−6.24 (2H,
m), δ 5.59 (1H, d, J = 12.2 Hz), δ 4.22 (2H, q, J = 3.6 Hz, J = 10.7
Hz), δ 3.80 (6H, s), δ 1.31 (3H, t, J = 7.1 Hz) ppm. 13C NMR (75
MHz, CDCl3): δ 167.1, 161.6, 158.4, 157.5, 102.3, 96.9, 96.5, 60.0,
55.4, 14.2 ppm. HRMS (EI), calcd. for C13H16O5 252.0998; found
252.1007.
Scheme 4. Schematic Representation of Probable
Mechanistic Pathways of Ethyl-3-iodo-acrylate with Oxygen
and Nitrogen Nucleophiles
(E)-Ethyl-3-(4-tert-butyl-phenoxy)-acrylate (Tables 1 and 4; 3).
General procedure A was followed (rt, 3 h). E-Vinyl iodide 29 (100
mg, 0.44 mmol), DABCO (98.7 mg, 0.88 mmol), tert-butylphenol
(99.1 mg, 0.66 mmol) and DMF (2.0 mL) were stirred to obtain the
crude product. Column chromatography on silica gel (5% EtOAc in
hexane) provided 3 (101.6 mg, 0.409 mmol, 93% yield) as a colorless
oil. 1H NMR (300 MHz, CDCl3): δ 7.81 (1H, d, J = 12.2 Hz), δ 7.43−
7.38 (2H, m), δ 7.04−6.99 (2H, m), δ 5.54 (1H, d, J = 12.2 Hz), δ
4.21 (2H, q, J = 3.6 Hz, J = 10.7 Hz); δ 1.34 (9H, s), δ 1.30 (3H, t, J =
7.1 Hz) ppm. 13C NMR (75 MHz, CDCl3): δ 166.2, 158.5, 152.6,
147.2, 126.5, 117.4, 101.6, 60.1, 35.3, 32.6, 15.5 ppm. HRMS (ESI),
calcd. for C15H21O3 (M + H)+:249.1491; found 249.1502.
(E)-Ethyl-3-(4-fluorophenoxy)-acrylate (Tables 1 and 4; 4).
General procedure A was followed (rt, 3 h). E-Vinyl iodide 29 (100
mg, 0.44 mmol), DABCO (98.7 mg, 0.88 mmol), 4-fluorophenol (74
mg, 0.66 mmol) and DMF (2.0 mL) were stirred to obtain the crude
product. Column chromatography on silica gel (5% EtOAc in hexane)
1
provided 4 (77.8 mg, 0.370 mmol, 84% yield) as a colorless oil. H
NMR (300 MHz, CDCl3): δ 7.75 (1H, d, J = 12.2 Hz), δ 7.12−7.02
(4H, m), δ 5.52 (1H, d, J = 12.2 Hz), δ 4.21 (2H, q, J = 3.6 Hz, J =
10.7 Hz), δ 1.30 (3H, t, J = 7.1 Hz) ppm. 13C NMR (75 MHz,
CDCl3): δ 161.3, 159.2, 119.7, 119.6, 116.6, 116.3, 102.1, 60.0, 14.2
ppm. HRMS (EI), calcd. for C11H11O3F: 210.0692; found 210.0690.
(E)-Ethyl-3-(2-isopropylphenoxy)-acrylate (Table 1; 5). General
procedure B was followed (rt, 6 h or 40 °C, 30 min). Z-Vinyl iodide 1
(100 mg, 0.44 mmol), CuI (4.2 mg, 0.022 mmol), Cs2CO3 (260 mg,
0.80 mmol), L (4.3 mg, 0.022 mmol), 2-isopropylphenol (119.9 mg,
0.88 mmol) and DMF (2.0 mL) were stirred to obtain the crude
product. Column chromatography on silica gel (5% EtOAc in hexane)
General Procedure B: Cu-Catalyzed Cross-Coupling of Z-
Ethyl-2-iodo-acrylate l with Phenols and N-Heterocycles
(Table 1). An oven-dried round-bottom flask containing a magnetic
stir bar was sealed with a rubber septum and evacuated and backfilled
with argon (the sequence was repeated three times) while cooling to
rt. The round-bottom flask was then charged with anhydrous cesium
carbonate (2.0 equiv), copper(I) iodide (5 mol %), L (5 mol %) and
dry DMF (2 mL). The solution which resulted was stirred for 5−10
min at rt. The reaction mixture turned a light green color within 3−5
min. The reaction vessel was evacuated and backfilled with argon once
more before adding the N-heterocycle or phenol. The appropriate N-
heterocycle or phenol (0.75 mmol, 1.5 equiv) was added to the
reaction mixture through a rubber septum and the mixture stirred for
an additional 5 min at rt. Then, ethyl (Z)-3-iodoacrylate 1 (0.5 mmol,
1.0 equiv) of choice was added in a minimum amount of dry DMF to
the resulting reaction mixture through a rubber septum. The contents
of the reaction mixture were heated from rt to 40 to 80 °C for 0.5−4 h
depending on the substrate. The reaction mixture was then cooled to
rt and filtered through a pad of silica gel to remove insoluble residues.
The pad of silica gel was washed with ethyl acetate and hexane (40:60)
(100 mL). The combined filtrate was washed with brine (5 × 50 mL),
dried (Na2SO4) and concentrated in vacuo on a rotatory evaporator.
The concentrated crude oil was purified by flash column
chromatography on silica gel using the eluent ethyl acetate and
hexane to obtain the pure product (81−95%). With oxygen and
nitrogen nucleophiles this gave a mixture of Z- and E- products. With
sulfur nucleophiles it gave the desired Z-isomer, but this is not a
copper-mediated process.
1
provided 5 (97.9 mg, 0.418 mmol, 95% yield) as a colorless oil. H
NMR (300 MHz, CDCl3): δ 7.80 (1H, d, J = 12.3 Hz), δ 7.34−7.30
(1H, m), δ 7.26−7.16 (2H, m), δ 7.02−6.99 (1H, m), δ 5.46 (1H, d, J
= 12.3), δ 4.20 (2H, q, J = 3.6 Hz, J = 10.7 Hz), δ 3.22 (1H, hep), δ
1.35−1.23 (9H, m) ppm. 13C NMR (75 MHz, CDCl3): δ 167.3, 160.3,
152.9, 139.2, 127.0, 125.5, 118.5, 101.2, 59.9, 27.0, 22.8, 14.2 ppm.
HRMS (ESI), calcd. for C14H19O3 (M + H)+: 235.1334; found
235.1334.
(E)-Ethyl-3-(naphtalen-1-yloxy)-acrylate (Tables 1 and 4; 6).
General procedure A was followed (rt, 3 h). E-Vinyl iodide 29 (100
mg, 0.44 mmol), DABCO (98.7 mg, 0.88 mmol), naphthalene-1-ol
(95.2 mg, 0.66 mmol) and DMF (2.0 mL) were stirred to obtain the
crude product. Column chromatography on silica gel (5% EtOAc in
hexane) provided 6 (102.3 mg, 0.422 mmol, 96% yield) as a colorless
oil. 1H NMR (300 MHz, CDCl3): δ 8.12−8.09 (1H, m) δ 7.97 (1H, d,
J = 12.2 Hz), δ 7.92−7.87 (1H, m), δ 7.73−7.70 (1H, m), δ 7.63−7.56
(2H, m), δ 7.46 (1H, t, J = 7.8 Hz), δ 7.17−7.15 (1H, m), δ 5.65 (1H,
d, J = 12.2 Hz), δ 4.25 (2H, q, J = 6.0 Hz J = 15.4 Hz) δ 1.31 (3H, t, J
= 7.1 Hz) ppm. 13C NMR (75 MHz, CDCl3): δ 167.1, 159.6, 151.7,
134.6, 127.7, 126.8, 126.4, 125.7, 125.4, 125.0, 121.3, 112.7, 102.4,
60.0, 14.2 ppm. HRMS (ESI), calcd. for C15H15O3 (M +
H)+:243.1021; found 243.1013.
(E)-Ethyl-3-(benzo[d]thiazol-2-yloxy)-acrylate (Table 1; 7). Gen-
eral procedure B was followed (40 °C 30 min-2 h). Z-Vinyl iodide 1
(100 mg, 0.44 mmol), CuI (4.2 mg, 0.022 mmol), Cs2CO3 (260 mg,
0.80 mmol), L3 (4.3 mg, 0.022 mmol), benzothiazol-2-ol (133.0 mg,
0.88 mmol) and DMF (2.0 mL) were stirred to obtain the crude
product. Column chromatography on silica gel (10% EtOAc in
hexane) provided 7 (100.9 mg, 0.405 mmol, 92% yield) as a colorless
oil. 1H NMR (300 MHz, CDCl3): δ 7.94 (1H, d, J = 14.3 Hz), δ 7.48−
7.36 (3H, m), δ 7.31−7.26 (1H, m), δ 6.95 (1H, d, J = 14.3 Hz), δ
4.30 (2H, q, J = 3.6 Hz, J = 10.7 Hz), δ 1.36 (3H, t, J = 7.2 Hz) ppm.
13C NMR (75 MHz, CDCl3): δ 168.8, 167.1, 134.8, 133.5, 126.8,
124.7, 122.9, 122.0, 111.5, 110.4, 60.7, 14.2 ppm. HRMS (ESI), calcd.
for C12H12NO3S (M + H)+: 250.0538; found 250.0540.
Characterization Data for Products Shown in Tables 1 and
4. (E)-Ethyl-3-(3,5-dimethoxy-phenoxy)-acrylate (Tables 1 and 4;
2). General procedure A was followed (rt, 1 h). E-Vinyl iodide 29
(100 mg, 0.44 mmol), DABCO (98.7 mg, 0.88 mmol), 3,5-
dimethoxyphenol (101.8 mg, 0.66 mmol) and DMF (2.0 mL) were
stirred to obtain the crude product. Column chromatography on silica
gel (5% EtOAc in hexane) provided pure E-ether 2 (108.8 mg, 0.431
1
mmol, 98% yield) as a colorless oil. H NMR (300 MHz, CDCl3): δ
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(E)-Ethyl-3-(pyridin-3-yloxy)-acrylate (Tables 1 and 4; 8). General
procedure A was followed (rt, 3 h). E-Vinyl iodide 29 (100 mg, 0.44
mmol), DABCO (98.7 mg, 0.88 mmol), pyridine-3-ol (62.8 mg, 0.66
mmol) and DMF (2.0 mL) were stirred to obtain the crude product.
Column chromatography on silica gel (15% EtOAc in hexane)
yield) as a white crystalline solid. 1H NMR (300 MHz, CDCl3): δ 8.55
(1H, d, J = 14.3 Hz), δ 8.17 (d, 1H, J = 8.3 Hz), δ 7.77 (1H, d, J = 8.3
Hz), δ 7.66 (1H, t, J = 7.4 Hz), δ 7.50 (1H, t, J = 7.4 Hz), δ 6.79 (1H,
d, J = 14.3 Hz), δ 4.36 (2H, q, J = 7.1 Hz), δ 1.39 (3H, t, J = 7.1 Hz)
ppm. 13C NMR (75 MHz, CDCl3): δ 165.8, 146.5, 135.0, 131.4, 129.2,
125.3, 120.7, 110.0, 108.1, 60.9, 14.1 ppm. HRMS (EI), calcd. for
C11H11N3O2: 217.0851; found: 217.0832.
(E)-Ethyl-3-(1H-imidazol-1-yl)-acrylate (Tables 1 and 4; 14).
General procedure A was followed (rt, 2 h). E-Vinyl iodide 29 (100
mg, 0.44 mmol), DABCO (98.7 mg, 0.88 mmol), 1H-imidazole (34
mg, 0.66 mmol) and DMF (2.0 mL)) were stirred to obtain the crude
product. Column chromatography on silica gel (10% EtOAc in
hexane) provided 14 (70 mg, 0.42 mmol, 96% yield) as a colorless oil.
1H NMR (300 MHz, CDCl3): δ 7.93 (1H, d, J = 14.2 Hz), δ 7.81 (1H,
s), δ 7.26 (1H, s), δ 7.20 (1H, s), δ 6.10 (1H, d, J = 14.2 Hz), δ 4.30
(2H, q, J = 7.1 Hz), δ 1.33 (3H, t, J = 7.1 Hz) ppm. 13C NMR (75
MHz, CDCl3): δ 166.1, 137.7, 136.2, 131.6, 116.1, 107.1, 60.8, 14.1
ppm. HRMS (EI), calcd. for C8H10N2O2: 166.0742; found: 166.0769.
(E)-Ethyl-3-(1H-1,2,4-triazol-1-yl)-acrylate (Tables 1 and 4; 15).
General procedure A was followed (rt, 2 h). E-Vinyl iodide 29 (100
mg, 0.44 mmol), DABCO (98.7 mg, 0.88 mmol), 1H-1,2,4-triazole
(45.6 mg, 0.66 mmol) and DMF (2.0 mL)) were stirred to obtain the
crude product. Column chromatography on silica gel (5% EtOAc in
hexane) provided 15 (67.6 mg, 0.40 mmol, 92% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ 8.35 (1H, s), 8.08 (1H, s), 8.03 (1H,
1
provided 8 (73.0 mg, 0.378 mmol, 86% yield) as a colorless oil. H
NMR (300 MHz, CDCl3): δ 8.48 (2H, m), δ 7.78 (1H, d, J = 12.2
Hz), δ 7.46−7.41 (1H, m), δ 7.37−7.33 (1H, m), δ 5.62 (1H, d, J =
12.2 Hz), δ 4.22 (2H, q, J = 3.6 Hz, J = 10.7 Hz), δ 1.30 (3H, t, J =
7.1) ppm. 13C NMR (75 MHz, CDCl3): δ 166.6, 157.8, 152.2, 146.2,
140.7, 125.1, 124.2, 103.6, 60.2, 14.2 ppm. HRMS (ESI), calcd. for
C10H12NO3 (M + H)+: 194.0817; found 194.0819.
(E)-Ethyl-3-(1H-pyrazol-1-yl)-acrylate (Tables 1 and 4; 9).
General procedure A was followed (rt, 2 h). E-Vinyl iodide 29 (100
mg, 0.44 mmol), DABCO (98.7 mg, 0.88 mmol), 1H-pyrazole (34 mg,
0.66 mmol) and DMF (2.0 mL) were stirred to obtain the crude
product. Column chromatography on silica gel (5% EtOAc in hexane)
1
provided 9 (67.3 mg, 0.405 mmol, 92% yield) as a white solid. H
NMR (300 MHz, CDCl3): δ 8.03 (1H, d, J = 13.9 Hz), δ 7.74 (1H, s,
br), δ 7.68 (1H, d, J = 2.5 Hz), δ 6.46 (1H, m), δ 6.39 (1H, d, J = 13.9
Hz), δ 4.29 (2H, q, J = 7.1), δ 1.32 (3H, t, J = 7.1 Hz) ppm. 13C NMR
(75 MHz, CDCl3): δ 166.4, 143.3, 139.4, 129.8, 108.9, 105.7, 60.5,
14.1 ppm; HRMS (EI), calcd. for C8H10N2O2: 166.0742; found
166.0716.
E-Ethyl-3-(5-(methylthio)-1H-tetrazol-1-yl)-acrylate (Table 1;
10). General procedure B was followed (40 °C, 3 h). Z-vinyl iodide
1 (100 mg, 0.44 mmol), CuI (4.2 mg, 0.022 mmol), Cs2CO3 (73 mg,
0.88 mmol), L (4.3 mg, 0.022 mmol), 5-(methylsulfanyl)-1H-
tetraazole (76.6 mg, 0.66 mmol) and DMF (2.0 mL) were stirred to
obtain the crude product. Column chromatography on silica gel (5%
EtOAc in hexane) provided 10 (77 mg, 0.36 mmol, 81% yield) as a
d, J = 13.8 Hz), δ 6.63 (1H, d, J = 13.8 Hz), δ 4.31 (2H, q, J = 7.1 Hz),
δ 1.35 (3H, t, J = 7.1 Hz) ppm. 13C NMR (75 MHz, CDCl3): δ 165.5,
153.5, 144.5, 134.9, 110.4, 61.0, 14.1 ppm. HRMS (EI), calcd. for
C7H9N3O2: 167.0694; found: 167.0666.
Characterization Data for Products Shown in Table
3.38 (Z)-Ethyl-3-(3,5-dimethoxyphenoxy)-acrylate (16). General
procedure A was followed (rt, 1 h). Z-Vinyl iodide 1 (100 mg, 0.44
mmol), DABCO (98.7 mg, 0.88 mmol), 3,5-dimethoxyphenol (101.8
mg, 0.66 mmol) and DMF (2.0 mL) were stirred to obtain the crude
product. Column chromatography on silica gel (5% EtOAc in hexane)
1
yellowish semisolid. H NMR (300 MHz, CDCl3): δ 7.94 (1H, d, J =
14.1 Hz, HC(N)CH), δ 6.77 (1H, d, J = 14.1 Hz HC|CH(N)), δ
4.34 (2H, q, J = 7.1 Hz, H2CCH3), δ 1.37 (3H, t, J = 7.1 Hz, H3C−
CH2) ppm; HRMS (EI), calcd. for C7H10N4O2S: 214.0524; found:
214.0515.
1
provided 16 (108.8 mg, 0.431 mmol, 98% yield) as a colorless oil. H
(E)-Ethyl-3-(1H-indol-1-yl)-acrylate (Table 1; 11). General proce-
dure B was followed (40 °C, 3 h). Z-Vinyl iodide 1 (100 mg, 0.44
mmol), CuI (4.2 mg, 0.022 mmol), Cs2CO3 (73 mg, 0.88 mmol), L
(4.3 mg, 0.022 mmol), indole (77.3 mg, 0.66 mmol) and DMF (2.0
mL)) were stirred to obtain the crude product. Column chromatog-
raphy on silica gel (5% EtOAc in hexane) provided 11 (88 mg, 0.41
mmol, 93% yield) as an off-white solid. 1H NMR (300 MHz, CDCl3):
δ 8.33 (1H, d, J = 14 Hz), δ 7.64 (d, 1H, J = 3.3 Hz), δ 7.61 (1H, m), δ
7.41 (1H, d, J = 3.5 Hz), δ 7.35 (1H, m), 7.25 (1H, m), δ 6.75 (1H, d,
J = 3.5 Hz), δ 6.00 (1H, d, J = 14 Hz), δ 4.31 (2H, q, J = 7.1 Hz), δ
1.37 (3H, t, J = 7.1 Hz) ppm. 13C NMR (75 MHz, CDCl3): δ 167.3,
137.0, 136.0, 129.7, 123.8, 123.4, 122.3, 121.4, 109.9, 108.6, 100.5,
103.2, 60.2, 14.3 ppm. Elemental analysis calcd. for C13H13NO2·0.27
H2O: C, 70.95; H, 6.20; N, 6.36; found: C, 70.95; H, 6.10; N, 6.32.
(E)-Ethyl-3-(1H-indazol-1-yl)-acrylate (Tables 1 and 4; 12).
General procedure A was followed (rt, 2 h). E-Vinyl iodide 29 (100
mg, 0.44 mmol), DABCO (98.7 mg, 0.88 mmol), 1H-indazole (78 mg,
0.66 mmol)and DMF (2.0 mL)) were stirred to obtain the crude
product. Column chromatography on silica gel (5% EtOAc in hexane)
provided 12 (80 mg, 0.37 mmol, 84% yield) as a white solid. 1H NMR
(300 MHz, CDCl3): δ 8.38 (1H, d, J = 13.7 Hz), δ 8.22 (s, 1H), δ 7.79
(1H, d, J = 8 Hz), δ 7.69 (1H, d, J = 8.4 Hz), δ 7.54 (1H, t, J = 7.5
Hz), δ 7.32 (1H, t, J = 7.5 Hz), δ 6.55 (1H, d, J = 13.7 Hz), δ 4.32
(2H, q, J = 7.1 Hz), δ 1.37 (3H, t, J = 7.1 Hz) ppm. 13C NMR (75
MHz, CDCl3): δ 167.2, 139.5, 138.9, 136.5, 128.2, 125.5, 123.1, 121.5,
109.5, 103.2, 60.3, 14.1 ppm. Elemental analysis calcd. for
C12H12N2O2: C, 66.65; H, 5.59; N, 12.96; found: C, 66.51; H, 5.65;
N, 12.85.
NMR (300 MHz, CDCl3): δ 6.89 (1H, d, J = 7.0 Hz), δ 6.30 (3H, s), δ
5.17 (1H, d, J = 7.0 Hz), δ 4.23 (2H, q, J = 10.7 Hz, J = 3.6 Hz), δ 3.80
(6H, s), δ 1.33 (3H, t, J = 7.1 Hz) ppm. 13C NMR (75 MHz, CDCl3):
δ 161.5, 158.7, 153.5, 100.1, 96.8, 96.1, 59.8, 55.4, 14.2 ppm. HRMS
(EI), calcd. for C13H16O5: 252.0998; found: 252.1007.
(Z)-Ethyl-3-(4-tert-butylphenoxy)-acrylate (17). General proce-
dure A was followed (rt, 3 h). Z-Vinyl iodide 1 (100 mg, 0.44
mmol), DABCO (98.7 mg, 0.88 mmol), 4-tert-butylphenol (99.2 mg,
0.66 mmol) and DMF (2.0 mL) were stirred to obtain the crude
product. Column chromatography on silica gel (5% EtOAc in hexane)
1
provided 17 (101.6 mg, 0.409 mmol, 93% yield) as a colorless oil. H
NMR (300 MHz, CDCl3): δ 7.40 (2H, d, J = 8.7 Hz), δ 7.06 (2H, d, J
= 8.7 Hz), δ 6.88 (1H, d, J = 7.2 Hz), δ 5.15 (1H, d, J = 7.0 Hz), δ 4.23
(2H, q, J = 10.7 Hz, J = 3.6 Hz); δ 1.35−1.30 (12H, m) ppm. 13C
NMR (75 MHz, CDCl3): δ 164.8, 155.0, 154.5, 147.7, 126.6, 117.1,
99.6, 59.9, 34.4, 31.4, 14.3 ppm. HRMS (ESI), calcd. for C15H21O3 (M
+ H)+: 249.1491; found: 249.1490.
(Z)-Ethyl-3-(4-fluorophenoxy)-acrylate (18). General procedure A
was followed (rt, 3 h). Z-Vinyl iodide 1 (100 mg, 0.44 mmol),
DABCO (98.7 mg, 0.88 mmol), 4-fluorophenol (74.0 mg, 0.66 mmol)
and DMF (2.0 mL) were stirred to obtain the crude product. Column
chromatography on silica gel (5% EtOAc in hexane) provided 18 (77.8
1
mg, 0.370 mmol, 84% yield) as a colorless oil. H NMR (300 MHz,
CDCl3): δ 7.11−7.04 (4H, m), δ 6.81 (1H, d, J = 7.0 Hz), δ 5.18 (1H,
d, J = 7.0 Hz), δ 4.23 (2H, q, J = 10.7 Hz, J = 3.6 Hz), δ 1.33 (3H, t, J
= 7.1) ppm. 13C NMR (75 MHz, CDCl3): δ 164.5, 161.1, 157.8, 154.1,
119.1, 116.5, 100.2, 59.9, 14.2 ppm. HRMS (EI), calcd. for
C11H11O3F: 210.0692; found: 210.0690.
(Z)-Ethyl-3-(2-isopropyl-phenoxy)-acrylate (19). General proce-
dure A was followed (rt, 3 h). Z-Vinyl iodide 1 (100 mg, 0.44
mmol), DABCO (98.7 mg, 0.88 mmol), 2-isopropylphenol (90 mg,
0.66 mmol) and DMF (2.0 mL)) were stirred to obtain the crude
product. Column chromatography on silica gel (5% EtOAc in hexane)
(E)-Ethyl-3-(1H-benzo[d][1,2,3]triazol-1-yl)-acrylate (Tables 1
and 4; 13). General procedure A was followed (rt, 2 h). E-Vinyl
iodide 29 (100 mg, 0.44 mmol), DABCO (98.7 mg, 0.88 mmol), 1H-
1,2,3-benzotriazole (59 mg, 0.66 mmol) and DMF (2.0 mL)) were
stirred to obtain the crude product. Column chromatography on silica
gel (5% EtOAc in hexane) provided 13 (80.3 mg, 0.37 mmol, 84%
1
provided 19 (97.9 mg, 0.418 mmol, 95% yield) as a colorless oil. H
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NMR (300 MHz, CDCl3): δ 7.33−7.30 (1H, m), δ 7.25−7.16 (2H,
m), δ 6.98 (1H, d, J = 1.2 Hz), δ 6.87 (1H, d, J = 6.9 Hz), δ 5.15 (1H,
d, J = 6.9 Hz), δ 4.25 (2H, q, J = 10.7 Hz, J = 3.6 Hz), δ 3.40 (1H,
hep), δ 1.36−1.21 (9H, m) ppm. 13C NMR (75 MHz, CDCl3): δ
165.0, 154.9, 154.6, 139.0, 127.0, 125.0, 116.8, 99.6, 59.9, 27.5, 22.8,
14.4 ppm. HRMS (ESI), calcd. for C14H19O3 (M + H)+: 235.1334;
found: 235.1326.
(Z)-Ethyl-3-(1H-benzo[d][1,2,3]triazol-1-yl)-acrylate (25). General
procedure A was followed (rt, 3 h). Z-Vinyl iodide 1 (90 mg, 0.4
mmol), DABCO (90. mg, 0.8 mmol), 1H-benzotriazole (71.3 mg, 0.6
mmol) and DMF (2.0 mL) were stirred to obtain the crude product.
Column chromatography on silica gel (20% EtOAc in hexane)
provided pure Z-vinyl amine 25 (79 mg, 91% yield) as a yellowish
1
brown liquid. H NMR (300 MHz, CDCl3): δ 8.13 (1H, d, J = 9.0
(Z)-Ethyl-3-(naphtalen-1-yloxy)-acrylate (20). General procedure
A was followed (rt, 3 h). Z-Vinyl iodide 1 (100 mg, 0.44 mmol),
DABCO (98.7 mg, 0.88 mmol), naphthalene-1-ol (95.2 mg, 0.66
mmol) and DMF (2.0 mL) were stirred to obtain the crude product.
Column chromatography on silica gel (5% EtOAc in hexane) provided
Hz), δ 7.58 (t, 2H, J = 7.8 Hz), δ 7.46 (2H, t, J = 7.8 Hz), δ 6.10 (1H,
d, J = 9.0 Hz), δ 4.20 (2H, q, J = 7.2 Hz), δ 1.14 (3H, t, J = 7.2 Hz)
ppm; 13C NMR (75 MHz, CDCl3): δ 164.3, 145.6, 132.4, 129.2, 128.3,
124.6, 120.3, 114.4, 110.4, 61.3, 13.8 ppm; HRMS (ESI) calcd. for
C11H12N3O2 (M + H)+: 218.0930; found: 218.0931.
(Z)-Ethyl-3-(3-methyl-1H-pyrazol-1-yl)-acrylate (26). General
procedure A was followed (rt, 3 h). Z-vinyl iodide 1 (90 mg, 0.4
mmol), DABCO (90. mg, 0.8 mmol), 3-methylpyrazole (49.5 mg, 0.6
mmol) and DMF (2.0 mL) were stirred to obtain the crude product.
Column chromatography on silica gel (10% EtOAc in hexane)
provided pure Z-vinyl amine 26 (54 mg, 75% yield) as a light yellow
liquid. 1H NMR (300 MHz, CDCl3): δ 9.04 (1H, d, J = 2.7 Hz), δ 7.22
(1H, d, J = 11.1 Hz), δ 6.23 (1H, d, J = 2.7 Hz), δ 5.33 (1H, d, J =
11.1), δ 4.23 (2H, q, J = 7.2 Hz), δ 1.33 (3H, t, J = 7.2 Hz) ppm. 13C
NMR (75 MHz, CDCl3): δ 165.2, 151.9, 137.7, 139.9, 109.2, 100.7,
60.4, 14.2, 13.4 ppm; HRMS (ESI) calcd. for C9H13N2O2 (M + H)+:
181.0977; found: 181.0975.
1
20 (102.3 mg, 0.422 mmol, 96% yield) as a colorless oil. H NMR
(300 MHz, CDCl3): δ 8.39−8.36 (1H, m), δ 7.88−7.85 (1H, m), δ
7.67 (1H, d, J = 8.2 Hz), δ 7.60−7.55 (2H, m), δ 7.42 (1H, t, J = 7.8
Hz), δ 7.11−7.08 (2H, m), δ 5.28 (1H, d, J = 6.9 Hz), δ 4.31 (2H, q, J
= 10.7 Hz J = 3.6 Hz), δ 1.39 (3H, t, J = 7.1 Hz) ppm. 13C NMR (75
MHz, CDCl3): δ 164.9, 153.8, 153.0, 134.5, 127.4, 126.9, 126.3, 125.9,
125.3, 124.4, 121.9,110.4, 100.3, 59.9, 14.4 ppm. HRMS (ESI), calcd.
for C15H15O3 (M + H)+: 243.1021; found: 243.1013.
(Z)-Ethyl-3-(pyridin-3-yloxy)-acrylate (21). General procedure A
was followed (rt, 3 h). Z-Vinyl iodide 1 (100 mg, 0.44 mmol),
DABCO (98.7 mg, 0.88 mmol), pyridine-3-ol (62.8 mg, 0.66 mmol)
and DMF (2.0 mL) were stirred to obtain the crude product. Column
chromatography on silica gel (15% EtOAc in hexane) provided 21
(Z)-Ethyl-3-(1H-1,2,4-triazol-1-yl)-acrylate (27). General proce-
dure A was followed (rt, 3 h). Z-vinyl iodide 1 (90 mg, 0.4 mmol),
DABCO (90. mg, 0.8 mmol), 1,2,4-triazole (41.3 mg, 0.6 mmol) and
DMF (2.0 mL) were stirred to obtain the crude product. Column
chromatography on silica gel (20% EtOAc in hexane) provided pure
1
(73.0 mg, 0.378 mmol, 86% yield) as a colorless oil. H NMR (300
MHz, CDCl3): δ 8.49−8.42 (2H, m), δ 7.45−7.41 (1H, m), δ 7.33−
7.29 (1H, m), δ 6.83 (1H, d, J = 6.9 Hz), δ 5.25 (1H, d, J = 6.9 Hz), δ
4.21 (2H, q, J = 3.5 Hz, J = 10.7 Hz), δ 1.30 (3H, t, J = 7.2 Hz) ppm.
13C NMR (75 MHz, CDCl3): δ 164.3, 153.5, 152.7, 146.0, 140.1,
124.8, 124.2, 101.8, 60.1, 14.3 ppm. HRMS (ESI), calcd. for
C10H12NO3 (M + H)+: 194.0817; found: 194.0821.
1
Z-vinyl amine 27 (61.5 mg, 92% yield) as a colorless liquid. H NMR
(300 MHz, CDCl3): δ 9.68 (1H, s), δ 8.01 (1H, s), δ 7.26 (1H, d, J =
11.1 Hz), δ 5.71 (1H, d, J = 11.1 Hz), δ 4.26 (2H, q, J = 7.2 Hz), δ
1.33 (3H, t, J = 7.2 Hz) ppm. 13C NMR (75 MHz, CDCl3): δ 164.3,
152.0, 146.7, 133.5, 107.5, 61.2, 14.1 ppm; HRMS (ESI) calcd. for
C7H10N3O2 (M + H)+: 168.0773; found: 168.0783.
(Z)-Ethyl-3-(1H-pyrazol-1-yl)-acrylate (22). General procedure A
was followed (rt, 1 h). Z-Vinyl iodide 1 (90 mg, 0.4 mmol), DABCO
(90 mg, 0.8 mmol), 1H-pyrazole (40.5 mg, 0.6 mmol) and DMF (2.0
mL) were stirred to obtain the crude product. Column chromatog-
raphy on silica gel (10% EtOAc in hexane) provided pure Z- vinyl
(Z)-Ethyl-3-(4-tert-butylphenylsulfanyl)-acrylate (30) (Scheme
2). To a suspension of Cs2CO3 (286.3 mg 0.88 mmol) in 5 mL of
DMF, vinyl iodide 1 (100 mg, 0.44 mmol) and 4-tert-butyl-
benzenethiol (88 mg, 0.53 mmol) were added respectively at rt. The
reaction mixtures were stirred either for 30 min at 45 °C or at room at
room temperature for 2 h to obtain 30 (114 mg, 98% yield) as a
colorless oil. Column chromatography solvent (2−3% EtOAc in
1
amine 22 (60 mg, 90% yield) as a colorless liquid. H NMR (300
MHz, CDCl3): δ 9.13 (1H, d, J = 2.7 Hz), δ 7.68 (1H, d, J = 1.5 Hz), δ
7.32 (1H, d, J = 11.1 Hz), δ 6.59 (1H, t, J = 2.1 Hz), δ 5.44 (1H, d, J =
11.1 Hz), δ 4.24 (2H, q, J = 7.2 Hz), δ 1.34 (3H, t, J = 7.2 Hz) ppm.
13C NMR (75 MHz, CDCl3): δ 165.0, 142.2, 137.8, 133.0, 108.6,
102.2, 60.6, 14.2 ppm; HRMS (ESI) calcd. for C8H11N2O2 (M + H)+:
167.0821; found: 167.0830.
1
hexane) provided pure 30. The HNMR, 13CNMR and HRMS data
for compound 30 is in agreement according to the reported
36
1
literature. = H NMR (300 MHz, CDCl3): δ 7.43 (4H, q, J = 13.4,
8.5 Hz), δ 7.28 (1H, d, J = 10.1 Hz), δ 5.90 (1H, d, J = 10.1 Hz), δ
4.27 (2H, q, J = 14.3, 7.1 Hz), δ 1.34 (12H, t, J = 7.9 Hz); 13C NMR
(75 MHz, CDCl3): δ 166.5, 151.5, 150.4, 132.6, 131.0,126.3, 112.9,
60.2, 34.5, 31.1, 14.3. HRMS (ESI) (M + H)+, Calcd. for C15H21O2S
265.1262; Found 265.1259.
(Z)-Ethyl-3-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-acrylate (23).
General procedure A was followed (rt, 1 h). Z-Vinyl iodide 1 (90
mg, 0.4 mmol), DABCO (90. mg, 0.8 mmol), 3-(trifluoromethyl)
pyrazole (81.8 mg, 0.6 mmol) and DMF (2.0 mL) were stirred to
obtain the crude product. Column chromatography on silica gel (10%
EtOAc in hexane) provided pure Z-vinyl amine 23 (87 mg, 93% yield)
1
as a white solid; mp 36.1−37.1 °C. H NMR (300 MHz, CDCl3): δ
ASSOCIATED CONTENT
9.11 (1H, m), δ 7.27 (1H, d, J = 11.1 Hz), δ 6.65 (1H, d, J = 3.0 Hz), δ
5.62 (1H, d, J = 11.1 Hz), δ 4.26 (2H, q, J = 7.2), δ 1.34 (3H, t, J = 7.2
Hz) ppm. 13C NMR (75 MHz, CDCl3): δ 164.4, 145.0, 144.5, 136.7,
134.7, 122.5, 119.0, 106.3, 106.2, 61.0, 14.1 ppm; Anal. Calc. for
C9H9N2O2F3·0.07 CH3(CH2)4CH3: C, 47.12; H, 4.19; N, 11.66;
found: C, 47.18; H, 3.90; N, 11.54; HRMS (ESI) calcd. for
C9H10N2O2F3 (M + H)+: 235.0694; found: 235.0717.
■
S
* Supporting Information
Copies of 1H NMR and 13C NMR are provided in the
Supporting Information sections. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: capncook@uwm.edu. Phone: 414-229-5856. Fax: 414-
229-5530.
■
(Z)-Ethyl-3-(1H-indazol-1-yl)-acrylate (24). General procedure A
was followed (rt, 2 h). Z-Vinyl iodide 1 (90 mg, 0.4 mmol), DABCO
(90. mg, 0.8 mmol), indazole (70.5 mg, 0.6 mmol) and DMF (2.0 mL)
were stirred to obtain the crude product. Column chromatography on
silica gel (15% EtOAc in hexane) provided pure Z- vinyl amine 24 (77
1
mg, 89% yield) as a colorless liquid. H NMR (300 MHz, CDCl3): δ
ACKNOWLEDGMENTS
■
8.18 (1H, s), δ 7.76 (1H, dd, J1 = 8.1 Hz, J1 = 1.2 Hz), δ 7.46 (2H, m),
δ 7.33 (1H, d, J = 9.9 Hz), δ 7.29 (1H, m), δ 5.70 (1H, d, J = 9.9), δ
4.28 (2H, q, J = 7.2 Hz), δ 1.26 (3H, t, J = 7.2 Hz) ppm. 13C NMR (75
MHz, CDCl3): δ 166.1, 139.5, 137.4, 129.7, 127.5, 124.8, 122.5, 121.4,
109.9, 106.7, 60.8, 14.1 ppm; HRMS (ESI) calcd. for C12H13N2O2 (M
+ H)+: 217.0977; found: 217.1004.
We thank Dr. Douglas Stafford, Director, Milwaukee Institute
for Drug Discovery, for technical advice and the NIH and the
Research Growth Initiative of the University of Wisconsin-
Milwaukee for financial support. We also thank Professor Wim
Dehaen (Department of Chemistry, University of Leuven,
309
dx.doi.org/10.1021/jo201948e | J. Org. Chem. 2012, 77, 300−310

The Journal of Organic Chemistry
Article
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Tables 2 and 4 in ref 7 to us.
Org. Lett. 2004, 6, 5005.
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