Palladium-Catalyzed Regioselective C-H Alkenylation of Arylacetamides via Distal Weakly Coordinating Primary Amides as Directing Groups

Article abstract of DOI:10.1021/acs.joc.7b02618

Herein we disclose the efficient Pd(II)-catalyzed and regioselective ortho C-H alkenylation of arylacetamide derivatives, viz. weakly coordinating aliphatic primary amides. This protocol utilizes ubiquitous free primary amides as the directing group and c

Full text of DOI:10.1021/acs.joc.7b02618

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Article
Palladium-Catalyzed Regioselective C-H Alkenylation of Arylacetamides
via Distal Weakly Coordinating Primary Amide as Directing Group
Yogesh Jaiswal, Yogesh Kumar, and Amit Kumar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02618 • Publication Date (Web): 25 Dec 2017
Downloaded from http://pubs.acs.org on December 25, 2017
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PalladiumꢀCatalyzed Regioselective CꢀH Alkenylation of Arylacetamides via
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Distal Weakly Coordinating Primary Amide as Directing Group
Yogesh Jaiswal, Yogesh Kumar and Amit Kumar*
Department of Chemistry, Indian Institute of Technology Patna, Bihta 801106, Bihar, India
*Eꢀmail: amitkt@iitp.ac.in or amitktiitk@gmail.com
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Graphical Abstract
Abstract
Herein, we disclose the Pd(II)ꢀcatalyzed efficient and regioꢀselective ortho CꢀH alkenylation of
arylacetamide derivatives viz weakly coordinating aliphatic primary amide. This protocol utilizes
ubiquitous free primary amide as the directing group and circumventing two troublesome steps
of installation and removal of an external auxiliary. This strategy directly enables the
incorporation of a synthetically versatile olefin in the products in moderate to good yields with
regio and distereoꢀselective fashion. The alkenylated acetamides can be easily manipulated and
further transformed into a variety of useful derivatives.
Introduction
Amide bonds are the key structural unit that is present in many physiologically active
compounds (Figure 1) beside their ubiquitous presence in biopolymers, for instance, proteins and
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glycoproteins.1 The amide functionality also serves as an important building block in organic
synthesis and in recent year extensively utilized as a directing group for direct CꢀH bond
activation viz cyclopalladation.2 In this context, pioneer work has been done by Yu, Miura,
Daugulis, Glorius, Ackermann, and Dong et al. where Nꢀsubstituted secondary3 and tertiary
amides4 have been used as a directing group for chemo and regioꢀselective CꢀH bond
functionalization. In spite of these significant progresses, free form of amide, in particularly,
aliphatic primary amide group (ꢀCH2CONH2) has been rarely utilized as directing group for CꢀH
bond transformation.5 Moreover, the primary amide group is more venerable for further
functional group interꢀconversion after the desired installation. Therefore, an important challenge
in the area of direct CꢀH bond functionalization is to find out a simple and ubiquitous functional
group, which can be used as directing group for distal CꢀH bond activation reaction, without the
need of preꢀinstallation, which eventually increases the atom and step economy.
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Figure 1: Biologically active molecules containing phenylacetamide motif.
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Carbonꢀcarbon bond formation viz transition metal catalyzed twoꢀfold CꢀH activation (Fujiwaraꢀ
Moritani reaction), in particular, the directing group assisted σꢀchelation control reactions have
emerged as economical and handful tools in organic synthesis.6 A range of the directing groups
has been introduced on aryl motifs, which control the regioꢀselectivity. However, a major
limitation of these strategies lies in requirements of preꢀinstallation of directing groups followed
by their uninstallation after the desired operation.7 Recently Yu et al.8a (Scheme 1a) and Maity
and coworkers8b (Scheme 1b) elegantly demonstrated the application of Nꢀsubstituted secondary
and tertiary acetamide as an effective distal directing group for orthoꢀCꢀH olefination of
phenylacetamide derivatives. While these σꢀchelationꢀassisted reactions were quite effective for
CꢀC bond formation, Pdꢀcatalyzed oxidative alkenylation with the prevalent functional group,
such as aliphatic primary acetamide as a weak coordinating group has never been reported.
Recently, our group introduced the use of aliphatic primary acetamide as a versatile directing
group for regioꢀselective orthoꢀCꢀH arylation of phenylacetamides derivatives.9 Substantial
advantage of this distal and weakly coordinating directing group is due to the presence of free
amide moiety, which can be easily manipulated by the different functional groups. In our
continued efforts to synthesize multifunctionalized arenes,10 herein we disclose, an efficient
Pd(II)ꢀcatalyzed monoꢀorthoꢀolefination of phenylacetamides derivatives via distal CꢀH bond
activation (Scheme 1c). The generality of this protocol is demonstrated by preparing a
commendable set of Eꢀalkenylated compounds.
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Scheme 1. Weakly coordinating directing group assisted alkenylation of arylacetamides.
Result and Disscussion
Excited form our recent finding, we were further interested to explore the distal directing ability
for twoꢀfold CꢀH activation (FujiwaraꢀMoritani reaction) on arylacetamides without installing
any additional auxiliary. However, to utilize the aliphatic primary amide as a directing group for
distal CꢀH bond activation is by no means routine transformation and not comparable to primary
benzamide as a directing group. The presence of free rotating methylene group (ꢀCH2) between
amide group and aryl ring of phenylacetamides increases the challenges in the manifold.
Considering this fact, we commenced our studies by selecting phenylacetamide 1a as model
substrate and electron deficient ethyl acrylate 2a as a coupling partner and palladium (II) salt as a
choice of metal catalyst. Other reaction parameters such as solvent, oxidant and reaction
temperature (for detailed information see Supporting Information) were optimized for regioꢀ
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selective orthoꢀalkenylation of phenylacetamides and results are tabulated in Table 1. To our
delight, 43% of desired product 3a was obtained using 10 mol% Pd(OAc)2 in presence of
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Ag2CO3 in AcOH solvent at 100 C for 36 h (Table 1, entry1). Among a broad range of solvents
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surveyed TFA, AcOH, HIFA, ACN, DMF, and TFE, TFA provided the desired product in
superior yield (Table 1, entry 6). Next, the effects of various oxidants were also investigated and
it was found the efficiency of the desired transformation increased when benzoquinone (BQ)
(entry 12) was used as oxidant under a molecular oxygen atmosphere. Interestingly, we observed
that loading of benzoquinone (BQ) plays a significant effect on the efficiency of the overall
process (see SI). For example, when the reaction was carried out with 1.0 equiv. of
benzoquinone (BQ) under standard conditions, afforded the olefinated product 3a in 72% yield
(entry 13). The yield of the transformation was almost unaffected by increasing the reaction
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temperature (100 C to 120 C) and time (see SI). Similarly, the use of excess amount of ethyl
acrylate (3.0 equiv.) does not affect the product yield considerably. It must be noted that
throughout this optimization there was no evidence of Nꢀalkenylated product formation, which
was a primary concern as primary amide is vulnerable precursor to undergo intermolecular Nꢀ
alkenylation.11 Finally, the reaction conditions described in entry 13, Tableꢀ1 were selected as the
standard reaction conditions for further exploration.
Table 1. Optimization of Reaction Conditionsa
Entry
Solvent
Oxidant
Yield b (%)
1
AcOH
Ag2CO3
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HFIP
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2O
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40
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0
TFE
ACN
DMF
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
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CH3CO2Ag
AgBF4
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CF3CO2Ag
AgNO3
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72c
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BQ/O2
BQ/O2
Cu(OAc)2/O2
aReaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), Pd(OAc)2 (10 mol%), oxidant (2.0 equiv.)
solvent (2.0 mL), at 100 C for 36 h. bIsolated yield after column chromatography. cOxidant (1.0
o
equiv.). BQ = Benzoquinone
With these optimized reaction conditions in hand, we explored the reaction scope with a variety
of substituted alkenes and results are summarized in Table 2. With the parent system 1 an array
of acrylates were examined to furnish Eꢀalkenylated products. For example, differentially
substituted acrylic esters such as methyl to nꢀbutyl all afforded the corresponding orthoꢀ
olefinated products (3aꢀ3d) and yields were in the range of 56ꢀ72% with excellent regioꢀ
selectivity. Fortunately, when the reaction was carried out with other electron deficient alkenes,
for instance, phenyl vinyl sulfone (2e), diethyl vinylphosphonate (2f) and phenoxyethyl acrylate
(2g) as a coupling partner, desired products (3eꢀ3g) were isolated in good to moderate yields
(70%ꢀ32%). However, we observed that when the reactions were carried out with unactivated
alkenes such as styrene (2h) and 4ꢀfluoro styrene (2i) under optimized reaction conditions, the
desired products were isolated in trace amount along with the formation of polymerized products
and some starting material was also recovered. Surprisingly, by changing the solvent from
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trifluoroacetic acid to acetic acid afforded the corresponding products (3h and 3i) albeit in low
yields 37% and 33% respectively.
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Table 2. Scope of Alkene Derivativesa
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aReaction conditions: see entry 13, Table 1. bAcOH was used as a solvent.
Next, we extended the scope of the alkenylation reaction using a range of substituted
arylacetamides with various alkenes (Table 3). Electron donating group such as methoxy, methyl
and 3,4ꢀdioxy at meta and para positions of aryl ring underwent smooth alkenylation reaction
with activated acrylates to give regioꢀselective mono alkenylated products in good yields (53ꢀ
62%, 4aꢀ4d). Furthermore, when moderate electron withdrawing group such as fluorine was
introduced at meta-position of an aryl ring, desired product 4e was procured in lower yield
(34%). It is worth to mention that, meta-substituted substrates such as 1c, 1d and 1e containing
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two possible sites for CꢀH bond alkenylation proceeded selectively at the least sterically hindered
position to afford 4c, 4d and 4e as the sole products. When 4ꢀmethyl phenylacetamide was
employed to couple with diethyl vinyl phosphonate desired olefinated product (4f) was obtained
in moderate yield (42%). Reaction of phenyl vinyl sulfone with paraꢀmethyl and paraꢀmethoxy
substituted arylacetamide underwent smooth conversion to give alkenylated products in good
yield 68% and 65% respectively (4gꢀ4h). Pleasingly, halogen substituted arylacetamide were
also compatible with phenyl vinyl sulfone to give orthoꢀalkenylated products in acceptable yields
(33%ꢀ38%, 4i and 4j), which could provide a handle for further synthetic elaboration.
Delightfully, styrene was successfully coupled with paraꢀmethyl and methoxy substituted
phenylacetamides (4k and 4l).
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Table 3. Scope with regard to the arylacetamides and alkenesa
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aReaction conditions: see entry 13, Table 1.bAcOH was used as a solvent.
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Further, we became interested to check the scope of αꢀmethyl phenylacetamide as directing
group for orthoꢀolefination reaction under the optimized reaction conditions (Table 4).
Interestingly, ethyl acrylate and phenyl vinyl sulfone reacted well to afford the corresponding
monoꢀolefinated products in good yields (61ꢀ64%, 6a and 6b). Similarly, other alkenes such as
diethyl vinylphosphonate and styrene were also coupled to give the corresponding products in
moderate yields (42ꢀ45%, 6c and 6d).
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Table 4. Scope of olefins withαꢀmethyl phenylacetamidea
aReaction conditions: see entry 13, Table 1.bAcOH was used as a solvent.
To demonstrate the synthetic utility, we performed scaleꢀup experiment with 4.0 mmole of
phenylacetamide 1a with ethyl acrylate 2a under standard conditions. The olefinated product 3a
was isolated in 57% yield and there was a slight drop in the yield in scaleꢀup reaction (Scheme
2).
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Scheme 2. Preparative Scale Experiment
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After this primary acetamide directed orthoꢀalkenyaltion strategy was established, the further
synthetic transformation of alkenylated phenylacetamide product 3a was explored. Amide group
can be easily manipulated to different functional groups as per requirements under given
conditions. Treatment of 3a with a catalytic amount of PdCl2 in the mixture of CH3CN and
water led to dehydration to afford 7a in 82% yield without affecting ester group. Similarly, when
3a was treated with iodobenzene and oxone in presence of methanol, amide group was converted
to ester via trans esterification to give 7b in 70% yield. Furthermore, the functionalizable
primary amide and ester groups can be easily hydrolyzed to the corresponding dicarboxylic acid
7c by treating with 20% H2SO4 at 100 oC for 6h (Scheme 3).
Scheme 3. Functional Group Transformation of 3a
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In order to obtain desired information about the electronic preference of reaction, the
intermolecular competition experiments were performed. When an equimolar amount of meta
substituted electron rich 1d and electron deficient 1e were allowed to compete under standard
conditions in coupling with ethyl acrylate, result highlighted that electron donating 1d shows
higher reactivity with conversion ratio 3.6:1 over 1e (Scheme 4a, eq. 1). Similarly, when
phenylacetamide 1a reacted with an equimolar amount of ethyl acrylate and phenyl vinyl sulfone
under standard conditions, approximately equal amount of product was isolated (1:1) (Scheme
4a, eq. 2). This result demonstrates that both types of alkene have similar reactivity toward the
acetamide derivatives. Next, we performed a control experiment in the presence of radical
scavenger 2,2,6,6ꢀtetramethylpiperidine Nꢀoxide (TEMPO) (Scheme 4b). There was no
significant drop in yield of product formation, the observed results implied that the reaction is
likely not to involve a single electron pathway. To gain further insight into the reaction
mechanism, intermolecular isotope kinetic experiment was performed between 1a and 1aꢀd5. An
isotope kinetic effect (KIE) of 4.0 was disclosed, thus suggesting that the palladium mediated Cꢀ
H bond cleavage could potentially be involved in the rateꢀlimiting step (RLS) in the catalytic
cycle (Scheme 4c).12 Notably, when Nꢀsubstituted phenylacetamide 8 was subjected under
optimal reaction conditions for orthoꢀalkenylation, the desired product 9 was obtained, albeit in
low yield (25%, yield was not optimized at this stage with Nꢀsubstituted phenylacetamides,
Scheme 4d).
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Scheme 4. Mechanistic Study
(a) Intermolecular competition experiment
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F
NH2
H3C
NH2
R
NH2
Std. Conditions
+
(1)
O
O
Ethyl acrylate (3.0 equiv)
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O
1d, R = CH3
1e, R = F
CO2Et
NH2
CO2Et
NH2
4e,13%
4d, 48%
Std. Conditions
NH2
+
O
O
(2)
Ethyl acrylate (3.0 equiv)
Phenyl vinyl sulphone (3.0 equiv)
O
SO2Ph
CO2Et
1a
3g, 48 %
3a, 43%
(b) Radical trapping experiment
(c) Competition experiment between 1a and 1aꢀd5
d) Reaction with Nꢀbenzyl phenylacetamide
H
N
Ph
H
N
Ph
Std. Condition
Ethyl acrylate (3.0 equiv)
O
O
8
9, 25%
CO2Et
On the basis of earlier literature reports13 and aforementioned results, we propose the plausible
reaction mechanism for the orthoꢀalkenylation reaction via weakly coordinating directing group
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(Scheme 5). The initial step is likely to be an ortho C−H bond activation directed by the carbonyl
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oxygen9, 14 of phenylacetamide, thus affording sixꢀmembered cyclometalated intermediate A by
the elimination of trifluoroacetic acid. Next, alkene coordinates and insert into PdꢀC bond to
form eightꢀmembered palladacycle C. Finally, βꢀhydrogen elimination of C leads to the desired
product and Pd(0) species, which is oxidized to Pd(II) by benzoquinone and completing the
catalytic cycle.
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Scheme 5. Proposed Mechanism
In summary, we have demonstrated that aliphatic primary acetamides (ꢀCH2CONH2) are
effective distal directing groups in transition metal catalyzed CꢀH activation. A variety of
alkenyl groups have been remotely incorporated at orthoꢀpositions of aryacetamide derivatives
selectively via weakly coordinating primary amide as directing groups. Furthermore, this
strategy avoids troublesome two extra steps of installation and removal of external directing
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groups, which eventually decrease the overall cost in terms of time, waste and economy and
evade the formation of Nꢀalkenylated acetamide derivatives. We anticipate that wide availability
of starting materials and high importance of primary aliphatic amides in the field of medicines,
this developed strategy will find a broad applications in organic synthesis.
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EXPERIMENTAL SECTION
General Consideration:
Unless otherwise noted, all reagents were purchased from a commercial supplier and used
without further purification. All the starting material, aryl acetamides were prepared by
following known literature procedure.15 All the reactions were run under oxygen and indicated
temperature was that of an oil bath. H NMR spectra were recorded at 400 MHz and C{1H}
1
13
NMR spectra were recorded at 100 MHz, CDCl3 and DMSOꢀd6 were used as a solvent. Chemical
1
shifts are reported in δ ppm referenced to CDCl3 (δ 7.26), DMSOꢀd6 (δ 2.50) for H NMR and
CDCl3 (δ 77.0), DMSOꢀd6 (δ 39.5) for 13C NMR. The following abbreviations were used to
explain multiplicities: (s, singlet; d, doublet; t, triplet; q, quartet; m, multiple, brs, broad singlet),
coupling constant (Hertz). Infrared spectra were recorded by FTꢀIR apparatus. Highꢀresolution
mass spectra (HRMS) spectra were obtained on ESIꢀTOF (electron spray ionizationꢀtime of
flight) spectrometer and methanol was used to dissolve the sample. Column chromatography was
performed on silica gel (100ꢀ200) mesh using ethyl acetate and hexanes or ethyl acetate/DCM as
eluent in different ratio.
General procedure for olefination rection (GPꢀA): To a clean ovenꢀdried 25 mL round bottom
flask equipped with magnetic stir bar was sequentially added aryl acetamide (0.4 mmol),
Pd(OAc)2 (10 mol %, 8.9 mg), benzoquinone (0.4 mmol, 1.0 equiv, 43.2 mg). Then ethyl
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acrylate (1.2 mmol, 3.0 equiv, 127.8 µL ) followed by trifluoroacetic acid ( 4.0 mL) was added to
the reaction mixture. The reaction mixture was purged with oxygen thrice. The flask was
connected to oxygen ballon through condenser. The reaction mixture was placed in pre heated oil
bath of 100 oC and vigorously stirred for 36 h. After completion, the reaction mixture was cooled
to room temperature and solvent was evaporated under reduced pressure and diluted with ethyl
acetate followed by neutralization with saturated solution of sodium bicarbonate. After extraction
with ethyl acetate (15 mL x 3) organic layer was washed with brine solution and passed through
short pad of celite and dried over sodium sulphate. After evaporation of solvent, the crude
mixture was purified by column chromatograophy silica gel and ethyl acetate/hexanes or ethyl
acetate/DCM as eluent.
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(E)ꢀEthyl 3ꢀ(2ꢀ(2ꢀaminoꢀ2ꢀoxoethyl)phenyl)acrylate (3a): Following GPꢀA the title
compound was isolated as white solid (67 mg, 72% yield); Rf (6:4 Hexanes/EtOAc) = 0.35; Mp
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110ꢀ112 C; IR(ATR) 3389, 3188, 2927, 1711, 1659, 1626, 1398 cmꢀ1; H NMR (400 MHz,
CDCl3) δ 7.91 (d, J = 16.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.39ꢀ7.29 (m, 3H), 6.37 (d, J =
16.0 Hz, 1H), 5.87 (brs, 1H), 5.61 (brs, 1H), 4.25 (q, J = 8.0 Hz, 2H), 3.72 (s, 2H), 1.32 (t, J =
8.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.6, 166.6, 141.0, 134.2, 134.0, 131.4, 130.5,
128.2, 127.2, 121.0, 60.7, 40.6, 14.3; HRMS (ESIꢀTOF) m/z Calcd for C13H16NO3 [M + H]+
234.1125, found 234.1141.
(E)ꢀMethyl 3ꢀ(2ꢀ(2ꢀaminoꢀ2ꢀoxoethyl)phenyl)acrylate (3b): Following GPꢀA the title
compound was isolated as white solid (53 mg, 61% yield); Rf (6:4 Hexanes/EtOAc) = 0.3; Mp
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152ꢀ154 C; IR (ATR) 3392, 3181, 2923, 1705, 1658, 1393, 763 cmꢀ1; H NMR (400 MHz,
CDCl3) δ 7.91 (d, J = 16.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.38ꢀ7.29 (m, 3H), 7.38 (d, J =
16.0 Hz, 1H), 5.88 (brs, 1H), 5.55 (brs, 1H), 3.79 (s, 3H), 3.72 (s, 2H); 13C{1H} NMR (100
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MHz, CDCl3) δ 172.6, 167.0, 141.3, 134.2, 134.0, 131.3, 130.5, 128.2, 127.2, 120.6, 51.8, 40.5;
HRMS (ESIꢀTOF) m/z Calcd for C12H14NO3 [M + H]+ 220.0981, found 220.0968.
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(E)ꢀPropyl 3ꢀ(2ꢀ(2ꢀaminoꢀ2ꢀoxoethyl)phenyl)acrylate (3c): Following GPꢀA the title
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compound was isolated as white solid (62 mg, 63% yield); Rf (6:4 Hexanes/Acetone) = 0.35; Mp
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111ꢀ113 C; IR (ATR), 3351, 3185, 1701, 1654, 1631, 1408, 1183, 745 cmꢀ1; H NMR (400
MHz, CDCl3) δ 7.92 (d, J = 16.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.38ꢀ7.30 (m, 3H), 6.40 (d,
J= 16.0 Hz, 1H), 5.60 (brs, 1H), 5.45 (brs, 1H), 4.16 (t, J = 8.0 Hz, 2H), 3.73 (s, 2H), 1.75ꢀ1.70
(m, 2H), 0.99 (t, J = 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.6, 166.7, 141.0,
134.10, 134.08, 131.3, 130.5, 128.2, 127.2, 121.1, 66.3, 40.5, 22.0, 10.4; HRMS (ESIꢀTOF) m/z
Calcd for C14H18NO3 [M + H]+ 248.1281, found 248.1294.
(E)ꢀButyl 3ꢀ(2ꢀ(2ꢀaminoꢀ2ꢀoxoethyl)phenyl)acrylate (3d): Following GPꢀA the title compound
was isolated as white solid (58 mg, 56 % yield); Rf (6:4 Hexanes/Acetone) = 0.4; Mp 112ꢀ114
oC; IR (ATR) 3352, 3180, 1708, 1657, 1630, 1413, 1172, 765 cmꢀ1; 1H NMR (400 MHz, CDCl3)
δ 7.91 (d, J = 16.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.40ꢀ7.29 (m, 3H), 6.39 (d, J = 16.0 Hz,
1H), 5.67 (brs, 1H), 5.54 (brs, 1H), 4.20 ( t, J = 6.8 Hz, 1H), 3.73 (s, 2H), 1.72ꢀ1.65 (m, 2H),
1.47ꢀ1.38 (m, 2H), 0.96 (t, J = 8.0 Hz, 3H),13C{1H} NMR (100 MHz, CDCl3) δ 172.4, 166.7,
140.9, 134.1, 131.3, 130.5, 128.2, 127.3, 121.2, 66.7, 40.5, 30.7, 19.2, 13.7; HRMS (ESIꢀTOF)
m/z Calcd for C15H19NNaO3 [M + Na]+ 284.1275, found 284.1285.
(E)ꢀ2ꢀ[2ꢀ(2ꢀBenzenesulfonylꢀvinyl)ꢀphenyl]ꢀacetamide (3e): Following GPꢀA the title
compound was isolated as brownish solid (76 mg, 70% yield); Rf (6:4 Hexanes/EtOAc) = 0.25;
Mp 147ꢀ149 oC; IR (ATR) 3395, 3207, 2924, 1711, 1623, 1306, 1142 cmꢀ1; 1H NMR (400 MHz,
DMSOꢀd6 + CDCl3) δ 7.94ꢀ7.89 (m, 3H), 7.76ꢀ7.70 (m, 2H), 7.67ꢀ7.61 (m, 3H), 7.48 (d, J =
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16.0 Hz), 7.38ꢀ7.26 (m, 3H), 3.64 (s, 2H); 13C NMR (400 MHz, DMSO + CDCl3) δ 171.4,
140.7, 140.0, 136.6, 133.1, 131.6, 131.2, 130.5, 129.2, 128.3, 127.1, 127.0, 126.9, 39.4; HRMS
(ESIꢀTOF) m/z Calcd for C16H16NO3S[M + H]+302.0845, found 302.0860.
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(E)ꢀ2ꢀ{2ꢀ[2ꢀ(Diethylꢀphosphinoyl)ꢀvinyl]ꢀphenyl}ꢀacetamide (3f): Following GPꢀA the title
compound was isolated as brownish sticky solid (51 mg, 43 % yield); Rf ( EtOAc) = 0.2;
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IR(ATR) 3343, 3194, 2987, 1671, 1391, 1219, 1018, 958; H NMR (400 MHz, CDCl3) δ 7.76
(dd, J = 16.0 Hz, 8.0 Hz, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.36ꢀ7.33 (m, 3H), 6.26ꢀ6.16 (m, 2H),
5.81 (brs, 1H), 4.13ꢀ4.10 (m, 4H), 3.69 (s, 2H), 1.34 (t, J = 6.8 Hz, 6H); 13C{1H} NMR (100
MHz, CDCl3) δ 172.7, 145.8, 134.5 and 134.3 (d, JCꢀP = 22.0 Hz), 134.1, 131.5, 130.5, 128.0,
126.7, 117.6 and 115.7 (d, JCꢀP = 189.0 Hz), 62.13, 62.08,40.2, 16.39, 16.33; HRMS (ESIꢀTOF)
m/z Calcd for C14H20NNaO4P [M + Na]+ 320.1022, found 320.1029.
(E)ꢀ2ꢀPhenoxyethyl 3ꢀ(2ꢀ(2ꢀaminoꢀ2ꢀoxoethyl)phenyl)acrylate (3g): Following GPꢀA the title
compound was isolated as white solid (43 mg, 32% yield); Rf (6:4 Hexanes/EtOAc) = 0.3; Mp
136ꢀ138 oC; IR(ATR) 3395, 3199, 2925, 1712, 1651, 1395, 1217, 1045, 745 cmꢀ1; 1H NMR (400
MHz, CDCl3) δ 7.96 (d, J = 16 Hz, 1H), 7.62 (d, J = 4.0 Hz, 1H), 7.41ꢀ7.23 (m, 5H), 7.0ꢀ6.93
(m, 3H), 6.44 (d, J = 16 Hz, 1H), 5.47 (brs, 1H), 5.39 (brs, 1H), 4.57 (t, J = 4.8 Hz, 2H), 4.25 (t,
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J = 4.8 Hz, 2H), 3.72 (s, 2H), C{1H} NMR (100 MHz, CDCl3) δ 172.8, 166.5, 158.5, 141.8,
143.1, 133.9, 131.4, 130.7, 129.6, 128.3, 127.3, 121.2, 120.4, 114.7, 65.9, 63.1, 40.4; HRMS
(ESIꢀTOF) m/z Calcd for C19H19NNaO4 [M + Na]+ 348.1206, found 348.1202.
(E)ꢀ2ꢀ(2ꢀstyrylphenyl)acetamide (3h): Following GPꢀA the title compound was isolated as
white solid (35 mg, 37% yield); Rf (6:4 Hexanes/EtOAc) = 0.5; Mp 147ꢀ149 oC; IR (ATR) 3397,
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3205, 1657, 1404, 964, 762 cmꢀ1; H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.0 Hz, 1H), 7.51
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(d, J = 8.0 Hz, 2H), 7.38ꢀ7.26 (m, 7H), 7.04 (d, J = 16.0 Hz, 1H), 5.53 (brs, 1H), 5.35 (brs, 1H),
3.74 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.4, 137.1, 137.0, 132.5, 131.9, 131.0,
128.8, 128.3, 128.2, 128.0. 126.8, 126.4, 124.9, 41.4; HRMS (ESIꢀTOF) m/z Calcd for
C16H15NaNO [M + Na]+ 260.1046, found 260.1046.
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(E)ꢀ2ꢀ(2ꢀ(4ꢀFluorostyryl)phenyl)acetamide (3i): Following GPꢀA the title compound was
o
isolated as white solid (34 mg, 33% yield); Rf (6:4 Hexanes/EtOAc) = 0.3; Mp 161ꢀ163 C; IR
(ATR) 3386, 3194, 2921, 1653, 1505, 1398, 760 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J =
8.0 Hz, 1H), 7.55 (t, J = 5.4 Hz, 2H), 7.43ꢀ7.30 (m, 4H), 7.14ꢀ7.05 (m, 3H), 5.61 (brs, 1H), 5.44
(brs, 1H), 3.81 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.2, 163.83 and 161.37 ( d, JCꢀF
=
246.0 Hz), 137.0, 133.22 and 133.19 (d, JCꢀF = 3.0 Hz), 132.5, 131.1, 130.6, 128.36 and 128.31
(d, JCꢀF = 5.0 Hz), 128.3, 126.3, 124.8, 115.85 and 115.63 (d, J = 22.0 Hz), 41.5; HRMS (ESIꢀ
TOF) m/z Calcd for C16H15FNO[M + H]+ 256.1132, found 256.1138.
(E)ꢀ3ꢀ(2ꢀCarbamoylmethylꢀ5ꢀmethoxyꢀphenyl)ꢀacrylic acid methyl ester (4a): Following
GPꢀA the title compound was isolated as white solid (53 mg, 53% yield); Rf (6:4
Hexanes/EtOAc) = 0.25; Mp 153ꢀ155oC; IR (ATR) 3385, 3199, 2916, 1710, 1651, 1428, 1177
cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 16.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.10 (s,
1H), 6.93 (d, J = 8.0 Hz, 1H), 6.36 (d, J = 16.0 Hz, 1H)5.87 (brs, 1H), 5.53 (brs, 1H), 3.82 (s,
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3H), 3.79 (s, 3H), 3.65 (s, 2H); C{1H} NMR (100 MHz, CDCl3) δ 173.6, 167.0, 159.3, 141.3,
135.0, 132.5, 126.2, 120.8, 116.5, 112.1, 55.4, 51.9, 39.5; HRMS (ESIꢀTOF) m/z Calcd for
C13H16NO4 [M + H]+ 250.1074, found 250.1084.
(E)ꢀEthyl 3ꢀ(2ꢀ(2ꢀaminoꢀ2ꢀoxoethyl)ꢀ5ꢀmethylphenyl)acrylate (4b): Following GPꢀA the title
compound was isolated as white solid (60 mg, 61% yield); Rf (6:4 Hexanes/EtOAc) = 0.3;
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Mp130ꢀ132 C; IR (ATR) 3377, 3187, 2922, 1712, 1655, 1404, 1177, 1040, 653 cmꢀ1; 1H NMR
(400 MHz, CDCl3) δ 7.98 (d, J = 12.0 Hz, 1H), 7.53 (s, 1H), 7.29 (s, 2H), 6.48 (d, J = 12 Hz,
1H), 6.06 (brs, 1H), 5.64 (brs, 1H), 4.35 (q, J = 7.2 Hz, 2H), 3.78 (s, 2H), 2.46 (s, 3H), 1.43 (t, J
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= 6.8 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 173.0, 166.7, 141.1, 137.9, 133.8, 131.33,
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131.26, 131.24, 129.7, 129.3, 127.7, 120.7, 60.6, 40.1, 21.0, 14.3; HRMS (ESIꢀTOF) m/z Calcd
for C14H17NNaO3 [M + Na]+ 270.1101, found 270.1104.
(E)ꢀ3ꢀ(6ꢀCarbamoylmethylꢀbenzo[1,3]dioxolꢀ5ꢀyl)ꢀacrylic acid ethyl ester (4c): Following
GPꢀA the title compound was isolated as white solid (68 mg, 62% yield); Rf ( 6:4
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Hexanes/EtOAc) = 0.3; Mp 167ꢀ169 C; IR (ATR) 3391, 3190, 2921, 1693, 1655, 1448, 1255,
1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 16.0 Hz, 1H), 6.82ꢀ6.76 (m, 3H), 6.08 (s, 2H), 5.43
(brs, 1H), 5.39 (brs, 1H), 4.26 (q, J = 8.0 Hz, 2H), 3.67 (s, 2H), 1.33 (t, J = 8.0 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 172.8, 167.2, 147.50, 147.47, 135.5, 127.8, 124.4, 123.7, 116.8,
109.5, 101.7, 60.7, 40.3, 14.3; HRMS (ESIꢀTOF) m/z Calcd for C14H15NNaO5 [M + Na]+
300.0842, found 300.0833.
(E)ꢀEthyl 3ꢀ(2ꢀ(2ꢀaminoꢀ2ꢀoxoethyl)ꢀ4ꢀmethylphenyl)acrylate (4d): Following GPꢀA the title
compound was isolated as white solid (57 mg, 58% yield); Rf ( 6:4 Hexanes/EtOAc) = 0.3; Mp
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142ꢀ144 C; IR (ATR) 3386, 3194, 2976, 1711, 1651, 1312, 1175 cmꢀ1; H NMR (400 MHz,
CDCl3) δ 7.87 (d, J = 16.0 Hz, 1H), 7.53 (d, J = 7.2 Hz, 1H), 7.15ꢀ7.11 (m, 2H), 6.35 (d, J = 16.0
Hz, 1H), 5.49 (brs, 1H), 5.42 (brs, 1H), 4.25 (d, J = 6.8 Hz, 2H), 3.70 (s, 2H), 2.36 (s, 3H), 1.33
(t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.7, 166.9, 140.95, 140.87, 134.1,
132.1, 131.1, 129.1, 127.1, 119.9, 60.6, 40.5, 21.3, 14.3; HRMS (ESIꢀTOF) m/z Calcd for
C14H17NNaO3 [M + Na]+ 270.1101, found 270.1108.
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(E)ꢀ3ꢀ(2ꢀCarbamoylmethylꢀ4ꢀfluoroꢀphenyl)ꢀacrylic acid ethyl ester (4e): Following GPꢀA
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0.3; Mp 144ꢀ146 C; IR (ATR) 3388, 3199, 1711, 1650, 1462, 1180, 657 cmꢀ1; H NMR (400
MHz, CDCl3) δ 7.69 (d, J = 16.0 Hz, 1H), 7.33ꢀ7.32 (m, 1H), 7.13ꢀ7.08 (m, 2H), 6.58 (d, J =
16.0 Hz, 1H), 5.51 (brs, 2H), 4.25 (q, J = 8.0 Hz, 2H), 3.72 (s, 2H), 1.33 (t, J = 8.0 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 171.9, 166.9, 163.08 and 160.56 (JCꢀF = 252.0 Hz), 136.53
and 136.50 (d, JCꢀF = 3.0 Hz), 134.9, 130.86 and 130.77 (d, JCꢀF = 9.0 Hz), 127.0, 125.42 and
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125.29 (d, JCꢀF = 13.0 Hz), 122.43 and 122.31 (d, JCꢀF = 12.0 Hz), 115.72 and 115.49 (d, JCꢀF
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23.0 Hz), 60.8, 40.6, 14.3; HRMS (ESIꢀTOF) m/z Calcd for C13H14FNNaO3 [M + Na]+
274.0850, found 274.0850.
(E)ꢀDiethyl 2ꢀ(2ꢀaminoꢀ2ꢀoxoethyl)ꢀ5ꢀmethylstyrylphosphonate (4f): Following GPꢀA the
title compound was isolated as brownish sticky solid (52 mg, 42% yield); Rf (EtOAc) = 0.2; IR
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(ATR) 3352, 3199 , 2986, 1668, 1198, 1021, 965; H NMR (400 MHz, CDCl3) δ 7.72 (t, J =
16.0 Hz, 1H), 7.38 (s, 1H), 7.18 (s, 2H), 6.19 (t, J = 16.0 Hz, 1H), 5.79 (brs, 2H), 4.12 (m, 4H),
3.65 (s, 2H), 2.35 (s, 3H), 1.33 (t, J = 8.0 Hz, 6H); C{1H} NMR (100 MHz, CDCl3) δ 172.9,
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145.8, 137.7, 134.22 and 134.00 (d, J = 22.0 Hz), 131.4, 131.3, 131.2, 127.3, 117.18 and 115.23
(d, J = 189.0 Hz), 62.12, 62.07, 39.9, 21.0, 16.39, 16.32; HRMS (ESIꢀTOF) m/z Calcd for
C15H22NNaPO4 [ M + Na]+ 334.1179, found 334.1185.
(E)ꢀ2ꢀ[2ꢀ(2ꢀBenzenesulfonylꢀvinyl)ꢀ4ꢀmethylꢀphenyl]ꢀacetamide (4g): Following GPꢀA the
title compound was isolated as brownish solid (86 mg, 68% yield); Rf (6:4 Hexanes/EtOAc) =
0.25; Mp 172ꢀ174 oC; IR(ATR) 3429, 3302, 3187, 2926, 1662, 1298, 1139; H NMR (400 MHz,
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(m, 2H), 7.60 (s, 1H), 7.56 (brs, 1H), 7.45 (d, J = 16.0 Hz, 1H), 7.20 (s, 2H), 7.00 (brs, 1H), 3.58
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(s, 2H), 2.26 (s, 3H); C{1H} NMR (100 MHz, DMSOꢀd6) δ 171.7, 140.8, 140.0, 136.4, 134.0,
133.5, 131.5, 131.4, 131.3, 129.5, 128.9, 127.6, 127.2, 39.0, 20.4; HRMS (ESIꢀTOF) m/z Calcd
for C17H18NO3S [M + H]+ 316.1002, found 316.1025.
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(E)ꢀ2ꢀ[2ꢀ(2ꢀBenzenesulfonylꢀvinyl)ꢀ4ꢀmethoxyꢀphenyl]ꢀacetamide (4h): Following GPꢀA the
title compound was isolated as brownish solid (77 mg, 61% yield); Rf (6:4 Hexanes/EtOAc) =
0.25; Mp 153ꢀ155 oC; IR (ATR) 3394, 3177, 2922, 1654, 1402, 1143 cmꢀ1; 1H NMR (400 MHz,
DMSOꢀd6 + CDCl3) δ 7.93ꢀ7.91 (m, 2H), 7.86 (d, J = 15.2 Hz, 1H), 7.72ꢀ7.63 (m, 1H), 7.65ꢀ7.61
(m, 2H), 7.54 (s, 1H), 7.50 (s, 1H), 7.28 (d, J = 2.8 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6.95ꢀ6.92
(m, 2H), 3.76 (s, 3H), 3.55 (s, 2H); 13C{1H} NMR (400 MHz, DMSOꢀd6 + CDCl3) δ 171.8,
158.2, 140.8, 139.9, 133.4, 132.43, 132.38, 129.4, 129.2, 128.5, 127.2, 117.4, 111.2, 55.3, 38.6;
HRMS (ESIꢀTOF) m/z Calcd for C17H18NO4S [ M + H]+ 332.0951, found 332.0951.
(E)ꢀ3ꢀ(2ꢀCarbamoylmethylꢀ5ꢀbromoꢀphenyl)ꢀacrylic acid ethyl ester (4i): Following GPꢀA
the title compound was isolated as brownish solid (58 mg, 38% yield); Rf (6:4 Hexanes/EtOAc)
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= 0.3; Mp 158ꢀ160 C; IR(ATR) 3458, 3301, 1682, 1292, 1143, 609 cmꢀ1; H NMR (400 MHz,
DMSOꢀd6) δ 8.0 ( s, 1H), 7.93 (d, J = 7.6 Hz, 2H)), 7.82ꢀ7.73 (m, 2H), 7.69ꢀ7.65 (m, 3H), 7.62
(brs, 1H), 7.50ꢀ7.56 (m, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.07 (brs, 1H), 3.63 (s, 2H); 13C{1H}
NMR (100 MHz, DMSOꢀd6) δ 171.1, 140.5, 138.2, 136.1, 134.0, 133.6, 133.4, 133.2, 129.9,
129.5, 127.2, 120.3, 38.8; HRMS (ESIꢀTOF) m/z Calcd for C16H15BrNO3S [ M + H]+ 379.9951,
found 379.9956.
(E)ꢀ3ꢀ(2ꢀCarbamoylmethylꢀ5ꢀchloroꢀphenyl)ꢀacrylic acid ethyl ester (4j): Following GPꢀA
the title compound was isolated as brownish solid (44 mg, 33% yield); Rf (6:4 Hexanes/EtOAc)
= 0.3; Mp199ꢀ201 oC; IR(ATR) 3427, 3190, 2921, 1661, 1304, 1143, cmꢀ1; 1H NMR (400 MHz,
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DMSOꢀd6) δ 7.93 (d, J = 7.2 Hz, 2H), 7.87 (s, 1H), 7.82ꢀ7.72 (m, 2H), 7.68ꢀ7.64 (m, 3H), 7.61
(brs, 1H), 7.45ꢀ7.43 (m, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.06 (brs, 1H), 3.64 (s, 2H); 13C{1H}
NMR (100 MHz, DMSOꢀd6) δ 171.6, 141.0, 138.8, 136.2, 134.1, 133.7, 132.4, 130.7, 130.4,
130.0, 127.7, 127.1, 39.3; HRMS (ESIꢀTOF) m/z Calcd for C16H15ClNO3S [ M + H]+ 336.0456,
found 336.0445
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(E)ꢀ2ꢀ(4ꢀmethylꢀ2ꢀstyrylphenyl)acetamide (4k): Following GPꢀA the title compound was
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isolated as white solid (35 mg, 35% yield); Rf (6:4 Hexanes/EtOAc) = 0.35; Mp 194ꢀ196 C; IR
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(ATR) 3406, 3197, 2913, 1651, 1403 cmꢀ1; H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 6.4 Hz,
3H), 7.38 (t, J = 8.0 Hz, 2H), 7.31ꢀ7.26 (m, 2H), 7.17ꢀ7.11 (m, 2H), 7.06 (d, J = 16.0 Hz, 1H),
5.68 (brs, 1H), 5.45 (brs, 1H), 3.72 (s, 2H), 2.41 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
173.6, 137.9, 137.0, 136.8, 131.5, 131.0, 129.6, 129.0, 128.7, 128.0, 126.9, 126.7, 125.0, 41.0,
21.2; HRMS (ESIꢀTOF) m/z Calcd for C17H18NO [ M + H]+ 252.1383, found 252.1376.
(E)ꢀ2ꢀ(4ꢀmethoxyꢀ2ꢀstyrylphenyl)acetamide (4l): Following GPꢀA the title compound was
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isolated as white solid (38 mg, 36% yield); Rf (6:4 Hexanes/EtOAc) = 0.35; Mp 151ꢀ153 C; IR
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(ATR) 3386, 3196, 2924, 1651, 1500, 1400 cmꢀ1; H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 6.4
Hz, 2H), 7.38ꢀ7.35 (m, 2H), 7.30 (s, 1H), 7.22ꢀ7.16 (m, 3H), 7.03 (d, J = 16.4 Hz, 1H), 6.85ꢀ6.33
(m, 1H), 5.48 (brs, 1H), 5,39 (brs, 1H), 3.86 (s, 3H), 3.68 (s, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 173.7, 159.4, 138.2, 136.9, 132.2, 131.9, 128.8, 128.2, 126.8, 125.0, 113.9, 111.5, 55.4,
40.6; HRMS (ESIꢀTOF) m/z Calcd for C17H18NO2 [ M + H]+ 268.1332, found 268.1333.
(E)ꢀ3ꢀ[2ꢀ(1ꢀCarbamoylꢀethyl)ꢀphenyl]ꢀacrylic acid ethyl ester (6a): Following GPꢀA the title
compound was isolated as white solid (62 mg, 64 % yield); Rf (6:4 Hexanes/EtOAc) = 0.35; Mp
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CDCl3) δ 8.03 (d, J = 16.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.43ꢀ7.37 (m, 2H), 7.31ꢀ7.28 (m,
1H), 6.35 (s, J = 8.0 Hz, 1H), 5.70 (brs, 1H), 5.50 (brs, 1H), 4.26 (q, J = 8.0 Hz, 2H), 3.99 (q, J =
8.0 Hz, 1H), 1.51 (d, J = 8.0 Hz, 3H), 1.34 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 176.0, 166.7, 141.3, 140.4, 133.3, 130.6, 127.7, 127.3, 127.5, 60.8, 42.2, 18.5, 14.3; HRMS
(ESIꢀTOF) m/z Calcd for C14H17NNaO3 [ M + Na]+ 270.1101, found 270.1095.
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(E)ꢀ2ꢀ[2ꢀ(2ꢀBenzenesulfonylꢀvinyl)ꢀphenyl]ꢀpropionamide (6b): Following GPꢀA the title
compound was isolated as brownish solid (77 mg, 61% yield); Rf ( 6:4 Hexanes/EtOAc) = 0.25;
Mp 149ꢀ151 oC; IR(ATR) 3428, 3310, 1666, 1299, 1140, 745 cmꢀ1; 1H NMR (400 MHz, DMSOꢀ
d6 + CDCl3) δ 8.04 (d, J = 16 Hz, 1H), 7.95ꢀ7.93 (m, 2H), 7.73ꢀ7.69 (m, 1H), 7.67ꢀ7.62 (m, 3H),
7.46 (brs, 1H), 7.44ꢀ7.40 (m, 2H), 7.39ꢀ7.36 (m, 1H), 7.27ꢀ7.22 (m, 1H), 6.96 (brs, 1H), 3.98 (q,
J = 8.0 Hz, 1H), 1.31 (d, J = 8.0 Hz, 3H); 13C{1H} NMR (400 MHz, DMSOꢀd6 + CDCl3) δ
174.8, 142.3, 140.6, 139.4, 133.4, 130.8, 130.6, 129.45, 129.38, 127.5, 127.4, 127.1, 126.8, 41.3,
19.0; HRMS (ESIꢀTOF) m/z Calcd for C17H18NO3S [ M + H]+ 316.1002, found 316.0995.
(E)ꢀDiethyl 2ꢀ(1ꢀaminoꢀ1ꢀoxopropanꢀ2ꢀyl)styrylphosphonate (6c): Following GPꢀA the title
compound was isolated as brownish sticky solid (56 mg, 45% yield); Rf (EtOAc) = 0.2; IR(ATR)
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3350, 3197, 2980, 1671, 1222, 1018, 958; H NMR (400 MHz, CDCl3) δ 7.95ꢀ7.85 (m, 1H),
7.52ꢀ7.44 (m, 2H), 7.39ꢀ7.35 (m, 1H), 7.29ꢀ7.25 (m, 1H), 6.22ꢀ6.17 (m, 1H), 6.13 (brs, 1H), 5.92
(brs, 1H), 4.15ꢀ4.06 (m, 4H), 4.01 (q, J = 8.0 Hz, 1H), 1.47 (d, J = 8.0 Hz, 3H), 1.35ꢀ1.31 (m,
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6H); C{1H} NMR (100 MHz, CDCl3) δ 176.2, 146.10, 140.13, 133.81 and 133.59 (d, JCꢀP
=
22.0 Hz), 130.6, 127.7, 127.5, 126.5, 126.8, 118.01 and 116.12 (d, JCꢀP = 189.0 Hz), 62.08,
62.03, 41.7, 18.6, 16.38, 16.32; HRMS (ESIꢀTOF) m/z Calcd for C15H22NNaPO4 [ M + Na]+
334.1179, found 334.1183.
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(E)ꢀ2ꢀ(2ꢀStyrylꢀphenyl)ꢀpropionamide (6d): Following GPꢀA the title compound was isolated
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as white solid (42 mg, 42% yield); Rf (6:4 Hexanes/EtOAc) = 0.4; Mp 114ꢀ116 C; IR(ATR)
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3397, 3202, 2921, 1621, 1461, 762 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.52 (d, J =
6.4 Hz, 2H), 7.40ꢀ7.31 (m, 7H), 7.99 (d, J = 16.0 Hz, 1H), 5.49 (brs, 1H), 5.30 (brs, 1H), 3.97 (q,
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J = 7.2 Hz, 1H), 1.57 (d, J = 6.8 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 176.7, 138.6,
137.1, 136.6, 132.2, 128.8, 128.4, 128.0, 127.7, 127.5, 126.8, 126.7, 125.4, 43.1, 17.8; HRMS
(ESIꢀTOF) m/z Calcd for C17H18NO [ M + H]+ 252.1383, found 252.1392.
Procedure for preparative scale synthesis: In an oven dried 100 mL round bottom flask
equipped with magnetic stir bar was sequentially added phenylacetamide (4.0 mmol, 1 equiv,
540 mg), Pd(OAc)2 (10 mol %, 89.8 mg), benzoquinone ( 0.4 mmol, 1equiv, 432 mg). Then ethyl
acrylate (12 mmol, 3.0 equiv,1.27 mL) followed by trifluoroacetic acid ( 40 mL) was added to
reaction mixture. The reaction mixture was purged with oxygen thrice. The flask was connected
to oxygen balloon through the condenser. The reaction mixture was placed in preheated oil bath
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of 100 C and vigorously stirred for 36 h. After cooling to room temperature, thesolvent was
evaporated under reduced pressure and diluted with ethyl acetate followed by neutralization with
asaturated solution of sodium bicarbonate. After extraction with ethyl acetate (100 mL x 3)
organic layer was washed with brine solution and filtered through ashort pad of celite and dried
over sodium sulfate and concentrated under vaccum. The crude mixture was purified by silica gel
column chromatography and ethyl acetate/hexanes as eluent to give 3a 57% (530 mg) of
alkenylated derivative.
Synthesis of (E)ꢀethyl 3ꢀ(2ꢀ(Cyanomethyl)phenyl)acrylate (7a) By following a reported
procedure16a 3a (0.2 mmol, 46 mg) in a mixture of CH3CN/H2O (1:1) was treated with PdCl2 (10
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was purified by column chromatography.
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(E)ꢀ3ꢀ(2ꢀCyanomethylꢀphenyl)ꢀacrylic acid ethyl ester (7a): white solid (35 mg, 82% yield);
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Rf (1:10 Hexanes/EtOAc) = 0.5; Mp 69ꢀ71 C; IR(ATR) 2941, 2220, 1703, 1632, 3112, 1175,
765 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 16.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.51
(d, J = 8.0 Hz, 1H), 7.44ꢀ7.36 (m, 2H), 6.39 (d, J = 16.0 Hz, 1H), 4.28 (q, J = 7.2 Hz, 2H), 3.86
(s, 2H), 1.34 (t, J = 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.3, 139.7, 133.3, 130.6,
129.3, 128.90, 128.86, 127.4, 122.1, 117.1, 60.9, 21.8, 14.3; HRMS (ESIꢀTOF) m/z Calcd for
C13H13NNaO2 [M + Na]+ 238.0838, found 238.0851.
3ꢀ[2ꢀ(Methoxycarbonylaminoꢀmethyl)ꢀphenyl]ꢀacrylic acid methyl ester (7b) By following a
reported procedure16b a mixture of oxone (0.4 mmol, 122.8 mg) and iodobenzene (0.2 mmol, 33
µL) was prepared in methanol (2.0 mL), 3a (0.2 mmol, 46 mg) was added in reaction mixture
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and stir for 24 h at 100 C. After completion reaction mixture solvent was evaporated in vacuo
and extracted with ethyl acetate (10 mL x 3). Solvent was removed in vacuum and crude product
was purified by column chromatography.
3ꢀ[2ꢀ(Methoxycarbonylaminoꢀmethyl)ꢀphenyl]ꢀacrylic acid methyl ester (7b): colorless
liquid Rf (10:1 Hexanes/EtOAc) = 0.4;(35 mg, 70% yield); IR (ATR) 2952, 1714, 1634, 1434,
1318, 1167, 765 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 16.0 Hz, 1H), 7.59 (d, J = 8.0
Hz, 1H), 7.34ꢀ7.28 (m, 3H), 6.37 (d, J = 16.0 Hz, 1H), 3.80 (s, 3H), 3.78 (s, 2H). 3.69 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 171.4, 167.2, 141.9, 134.0, 133.6, 131.1, 130.2, 127.9,
126.9, 120.1, 52.2, 51.8, 38.6. HRMS (ESIꢀTOF) m/z Calcd for C13H14NaO4 [M +Na]+ 257.0784,
found 257.0797.
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3ꢀ(2ꢀCarboxymethylꢀphenyl)ꢀacrylic acid (7c) By following a reported procedure16c a mixture
of 3a (0.2 mmol, 46 mg) was prepared in 20% (v/v) H2SO4 (2.5 mL) and heated at 100 oC for 6 h.
After completion of reaction, mixture was cooled to room temperature and diluted with water
then extracted with ethylacetate (15 mL x 3). Organic layer was dried in vacuum.
Recrystallization with dichloromethane and hexane produced white solid.
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3ꢀ(2ꢀCarboxymethylꢀphenyl)ꢀacrylic acid (7c) white solid (30 mg, 73 %), Mp 130ꢀ132 C
IR(ATR) 2925 (br), 1682, 1619, 1220, 974; 1H NMR (400 MHz, DMSOꢀd6) δ 7.78ꢀ7.74 (m, 2H),
7.38ꢀ7.29 (m, 3H), 6.43 (d, J = 16.0 Hz, 2H), 3.75 (s, 2H); 13C{1H} NMR (100 MHz, DMSOꢀd6)
δ 172.3, 167.5, 141.1, 134.8, 133.6, 131.5, 130.0, 127.6, 126.7, 38.5; HRMS (ESIꢀTOF) m/z
Calcd for C11H10NaO4 [M + Na]+ 229.0471, found 229.0501.
(E)ꢀethyl 3ꢀ(2ꢀ(2ꢀ(benzylamino)ꢀ2ꢀoxoethyl)phenyl)acrylate (9): Following GPꢀA the title
compound was isolated as white solid (16 mg, 25% yield); Rf (7:3 Hexanes/EtOAc) = 0.4; Mp
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105ꢀ107 C; IR(ATR) 3285, 2924, 1708, 1640, 1542, 1316, cmꢀ1; H NMR (400 MHz, CDCl3)
δ7.92 (d, J = 16.0 Hz, 1H), 7.59 (m, 1H), 7.35ꢀ7.26 (m, 6H), 7.26ꢀ7.16 (m, 2H), 6.35 (d, J = 16.0
Hz, 1H), 5.70 (brs, 1H), 4.40(d, J = 4.0 Hz, 2H), 4.26 (q, J = 8/0 Hz, 2H), 3.77 (s, 2H), 1.33 (t, J
= 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ168.9, 166.5, 140.9, 137.0, 134.1, 131.4,
130.5, 128.6, 128.2, 127.5, 127.4, 127.2, 121.1, 60.7, 43.6, 41.2; HRMS (ESIꢀTOF) m/z Calcd
for C20H21NNaO3 [M + Na]+ 346.1414, found 346.1459.
Procedure for intermolecular competition experiment between 1d and 1e: A suspension of
Pd(OAc)2 (10 mol %, 3.5 mg) BQ ( 1 equiv, 16.2 mg) ethyl acrylate ( 3 equiv, 48 µL), 1d (0.15
mmol, 22.3 mg, 1 equiv) and 1e (0.15 mmol, 23 mg, 1 equiv) was stirred in TFA (2.0 mL) under
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oxygen for 36 h at 100 C. After cooling to room temperature, solvent was evaporated in
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vacuum. Reaction mixture was dilute with ethyl acetate, followed by neutralization with aqueous
solution of sodium bicarbonate. After extraction with ethyl acetate organic layer was washed
with brine solution and filtered through short pad of celite and dried over sodium sulphate.
Combined organic layer was concentrated under vacuum. The crude mixture was purified by
column chromatography using ethyl acetate/hexanes as eluent. Compounds 4d and 4e were
obtained in 48% and 13% respectively.
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Procedure for intermolecular competition experiment between 2a and 2g: A suspension of
1a (0.2 mmol, 27 mg), Pd(OAc)2 (10 mol%, 4.5 mg) BQ (1 equiv, 21.6 mg), ethyl acrylate (3
equiv, 64 µL) and phenyl vinyl sulfone (3.0 equiv, 100 mg) was stirred in TFA (3.0 mL) under
oxygen for 36 h at 100oC. After cooling to room temperature, thesolvent was evaporated in
vacuum. The reaction mixture was diluted with ethyl acetate and followed by neutralization with
anaqueous solution of sodium bicarbonate. After extraction with ethyl acetate organic layer was
washed with brine solution and passed through ashort pad of celite and dried over sodium
sulfate. Combined organic layer was concentrated under vacuum. The crude mixture was
purified by column chromatography using ethyl acetate/hexanes as eluent. Compounds 3a and 3g
were obtained in 43% and 48% respectively.
Kinetic isotope effect experiment:Procedure for intermolecular competitive experiment
between 1a and 1aꢀd5: A mixture of 1a (0.15 mmol) and 1aꢀd5(0.15 mmol), Pd(OAc)2 (10 mol
%, 6.7 mg), BQ ( 1 equiv, 32.4 mg), (3 equiv, 48 µL) was strirred in TFA (3.0 mL) under oxygen
for 3 h at 100 oC. After cooling to room temperature, thesolvent was evaporated in vacuum. The
reaction mixture was diluted with ethyl acetate, followed by neutralization with anaqueous
solution of sodium bicarbonate. After extraction with ethyl acetate organic layer was washed
with brine solution and filtered through ashort pad of celite and dried over sodium sulfate.
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Combined organic layer was concentrated under vacuum. The crude mixture was purified by
column chromatography using ethyl acetate/hexanes as eluent to give 3a/3aꢀd4 (15 mg, 24%).
The ratio of 3a and 3aꢀd4 was determined by 1H NMR. The kinetic isotope effect of the reaction
was determined to be kH/kD = 4.0 (see SI for details).
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Additional screening data, mechanistic experimental details, H and 13C NMR spectra of all new
1
products
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail:amitkt@iitp.ac.in or amitktiitk@gmail.com
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Authors gratefully acknowledge Indian Institute of Technology (IIT) Patna and CSIR, New
Delhi (02(0229)/15/EMRꢀII), for financial support. Y. Jaiswal and Y. Kumar thank IIT Patna for
an Institute Research Fellowship. The authors also acknowledge SAIFꢀPunjab University for
providing NMR facilities and SAIFꢀIIT Patna for HRMS facilities.
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REFERENCES
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