Pd-catalyzed directed ortho -C-H alkenylation of phenylalanine derivatives

Article abstract of DOI:10.1021/jo502912m

A practical Pd-catalyzed ortho-olefination of enantioenriched N-(SO₂Py)-protected aryl-alanine and norephedrine derivatives with electron-deficient alkenes has been developed using N-fluoro-2,4,6-trimethylpyridinium triflate as the terminal oxidant. The reaction occurs efficiently with excellent monosubstitution selectivity and without loss of enantiopurity. This cross-coupling proved to be broad in scope, tolerating a variety of steric and electronic changes to both coupling partners. Removal of the directing group under mild conditions provides access to optically active tetrahydroisoquinoline-3-carboxylic acid derivatives (Tics) with good diastereocontrol and with very small erosion of enantiomeric purity.

Full text of DOI:10.1021/jo502912m

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Note
Pd-catalyzed directed ortho-C-H alkenylation of phenylalanine derivatives
Alfonso Garcia-Rubia, Eduardo Laga, Carlos Cativiela, Esteban P.
Urriolabeitia, Ramon Gomez Arrayas, and Juan Carlos Carretero
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502912m • Publication Date (Web): 12 Feb 2015
Downloaded from http://pubs.acs.org on February 15, 2015
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The Journal of Organic Chemistry
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Pdꢀcatalyzed directed orthoꢀC−H alkenylation of
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phenylalanine derivatives
Alfonso GarcíaꢀRubia,† Eduardo Laga,†,‡ Carlos Cativiela,‡ Esteban P. Urriolabeitia,‡ Ramón Gómezꢀ
Arrayás†* and Juan C. Carretero†*
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† Departamento de Química Orgánica, Facultad de Ciencias, Universidad Autónoma de Madrid,
Cantoblanco, 28049 Madrid, Spain. ‡ Instituto de Síntesis Química y Catálisis Homogénea (ISQCH),
CSICꢀUniversidad de Zaragoza, Pedro Cerbuna 12, Eꢀ50009 Zaragoza, Spain.
ramon.gomez@uam.es; juancarlos.carretero@uam.es
ABSTRACT: A practical Pdꢀcatalyzed orthoꢀolefination of enantioenriched Nꢀ(SO2Py)ꢀprotected arylꢀ
alanine and norephedrine derivatives with electron deficient alkenes has been developed using Nꢀfluoroꢀ
2,4,6ꢀtrimethylpyridinium triflate as the terminal oxidant. The reaction occurs efficiently with excellent
monoꢀsubstitution selectivity and without loss of enantiopurity. This cross coupling proved to be broad
in scope, tolerating a variety of steric and electronic changes to both coupling partners. Removal of the
directing group under mild conditions provides access to optically active tetrahydroisoquinolineꢀ3ꢀ
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carboxylic acid derivatives (Tics) with good diastereocontrol and with very small erosion of
enantiomeric purity.
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Keywords: Palladium; C−H Olefination; Phenylalanine; Norephedrine; 2ꢀPyridylsulfonyl;
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Tetrahydroisoquinoline.
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The direct functionalization of C−H bonds is an area of great interest because of its potential to
streamline synthetic routes.1 The use of directing groups has become a common strategy to address the
challenge of achieving predictable selectivity in substrates that lack strong steric or electronic biases or
to override the inherent substrate biasing elements. 1ꢀ3
Coordinationꢀdirected C−H bond functionalization of nitrogenꢀcontaining compounds, such as αꢀ
amino acids, is particularly attractive given their prevalence in natural products and therapeutic agents.4ꢀ
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Moreover, the incorporation of flexible functional handles into the amino acid skeleton provide
products that offer high versatility as building blocks for their diversification into valuable heterocyclic
frameworks.9 Despite their significance, catalytic metalꢀcontrolled direct functionalization of αꢀamino
acids remain underdeveloped.5,7,8 An important challenge is to find a suitable directing function capable
of preventing interference by the potentially coordinating proximal αꢀester group and overcoming the
increased steric restriction caused by the already installed αꢀstereocenter. An added requirement of such
methods is mild functionalization/deprotection conditions tolerant of sensitive functional groups and the
easily racemizable α−stereocenter. Most of the reported procedures are suited for Nꢀprotected NHꢀamino
acid derivatives,5ꢀ8 due to the participation of active metal amide intermediate complexes, whereas
catalytic direct functionalization of Nꢀsubstituted substrates (instead of NHꢀamino acid derivatives)
remains an important ongoing challenge. Additionally, controlling monoꢀ vs. disubstitution selectivity is
often problematic in this type of processes.10
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Within this field, the PdIIꢀcatalyzed oxidative coupling between arenes and olefins (FujiwaraꢀMoritani
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reaction) is arguably one of the most important reactions in this field.11,12 Recently, our group introduced
the use of the Nꢀ(2ꢀpyridyl)sulfonyl (SO2Py) moeity as an easily installable and removable
protecting/directing group in a variety of Pdꢀcatalyzed C–H functionalization reactions.13 In particular, it
showed a high directing ability, as well as structural flexibility, in the PdIIꢀcatalyzed aryl C−H ortho
alkenylation of anilines, benzylamines and phenethylamines with electronꢀdefficient alkenes.13c
Subsequently, Yu and coꢀworkers demonstrated the suitability of this NꢀSO2Pyꢀstrategy for PdIIꢀ
catalyzed intramolecular C−H amination of phenethylamine derivatives, including optically active
phenylalanine derivatives.7h Herein, we report a practical and efficient PdIIꢀcatalyzed monoꢀorthoꢀ
olefination of enantioenriched phenylalanine derivatives. The use of the NꢀSO2Pyꢀprotecting group
allows for facile deprotection and subsequent cyclization via azaꢀMichael addition of the free amino
group to the acrylate moiety to form disubstituted tetrahydroisoquinolines with good diastereocontrol.
On the basis of the knowledge acquired in our previous contribution,13c the enantiomerically pure Nꢀ
methylꢀNꢀ(SO2Py)ꢀprotected phenylalanine ethyl ester derivative (S)ꢀ1 was probed for its potential in the
olefination reaction with butyl acrylate (2.0 equiv) using Pd(OAc)2 as catalyst (10 mol%) and Nꢀfluoroꢀ
2,4,6ꢀtrimethylpyridium triflate [F+] as stoichiometric oxidant,14 at 110 ºC for 18 h. The results of this
optimization study are shown in Table 1. The reaction in DCE showed poor conversion (40%, entry 1),
while changing the solvent to AcOH resulted in a slightly higher conversion (entry 2). Despite the low
conversions, the reactions were very clean and in the latter case the desired orthoꢀolefination product
(S)ꢀ2 was isolated in 45% yield. It is important to note that the stereochemical information present in the
starting phenylalanine derivative (S)ꢀ1 was preserved in the olefinꢀbearing product (S)ꢀ2 with minimal
erosion in the enantiomeric purity (97% ee, entry 2; the starting (S)ꢀ1 was prepared from commercially
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available Lꢀphenylalanine of ≥98% ee). The use of hexafluoroisopropanol (HFIP), a solvent that proved
to be highly effective in C−H functionalization of αꢀamino acid derivatives,8i resulted in a boost in
conversion up to 94%. However, this increase in reactivity (83% yield of the desired product 2) came at
the cost of a loss of enantiomeric purity (88% ee, entry 3).
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Table 1. Optimization of reaction conditions.a
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Entry Solvent [F+] (equiv) Conversion(%)b ee(%)c
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6e
DCE
2.0
2.0
2.0
2.5
3.0
3.0
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−
AcOH
HFIP
53 (45)d
94 (83)d
72
97
88
−
AcOH
AcOH
AcOH
>98
−
>98 (84)d
97
a Conditions: (−)ꢀ1 (0.15 mmol), Pd(OAc)2 (0.015 mmol), [F+] (0.45 mmol), AcOH (1 mL) at 110 ºC,
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butyl acrylate (0.30 mmol). By H NMR from the crude mixture, measuring the relative ratio of 2 to
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starting 1 by integration of charasterictic, baseline separated signals. Enantiomeric excess of (S)ꢀ2,
d
e
dtermined by chiral stationary phase HPLC. In parenthesis, isolated yield after chromatography.
Reaction time: 6 hours.
To our satisfaction, the solution to the problem of low reactivity without compromising the
stereochemical integrity was found by increasing the amount of the oxidant. Thus, the model reaction of
1a with butyl acrylate in AcOH in the presence of 2.5 equivalents of [F+] led to 72% conversion of 2
(entry 4), while further increase of [F+] to 3.0 equivalents allowed for complete conversion (entry 5).
Furthermore, under these latter conditions complete conversion was observed after only 6 hours,
affording the acrylate 2 in good yield (84%) without appreciable loss of enantiopurity (97% ee, entry 6).
It should be noted that, in contrast to literature precedents,11 in which monoꢀolefination selectivity is
often difficult to control, complete monoꢀsubstitution selectivity was observed under our reaction
conditions.
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After the optimal reaction parameters had been established, the effect of electronic and structural
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variations on the alkene was studied. For that purpose, a variety of monosubstituted electrophilic alkenes
were surveyed in the reaction with the parent substrate 1 (Scheme 1). For this study, racemic (±)ꢀ1 was
used in most cases. Not only acrylates (products 2 and 3), but also dimethyl vinyl phosphonate (4),
phenyl vinyl sulfone (5) and phenyl vinyl sulfonate (6) coupled efficiently with 1 to give the
corresponding orthoꢀalkenylated products with excellent regioselectivity, monoꢀsubstitution selectivity
and Eꢀstereoselectivity in synthetically useful yields (68–84%). Other carbonyl derivatives such as
methyl vinyl ketone (7) or acrolein (8) resulted less efficient coupling partners (43% and 25% yield,
respectively). Interestingly, styrene derivatives bearing electronꢀwithdrawing substituents (pentafluoro,
NO2 or CF3) at the phenyl ring were found to be also capable reactants for the alkenylation reaction,
affording the corresponding products in acceptable yields (products 9ꢀ11, 37ꢀ56% yield). Unfortunately,
styrene itself provided poor reactivity (<10% conversion, not shown). We confirmed again that the
alkenylation reaction takes place with no appreciable racemization, as demonstrated in the reaction with
phenyl vinyl sulfone (product (S)ꢀ5, 79% yield, >98% ee).
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Scheme 1. Scope with regard to the olefin coupling partner.
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EtO2C
Page 6 of 40
EtO2C
EtO2C
EtO2C
Me
Me
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8
Pd(OAc)2 (10 mol%)
[F+] (3.0 equiv)
N-SO2Py
N-SO2Py
EWG
EWG
AcOH, 110 ºC, 18 h
(2 equiv)
1
3-11
EtO2C
EtO2C
Me
Me
Me
N-SO2Py
SO2Ph
N-SO2Py
N-SO2Py
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CO2Me
P(O)(OMe)2
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(S)-5, 79%
(>98% ee)a
3, 77%
4, 68%
EtO2C
CO2Et
F
Me
Me
F
F
F
PySO2-N
N-SO2Py
N-SO2Py
COR
Me
SO3Ph
F
7, R = Me, 43%
8, R = H, 25%
6, 73%
CO2Et
9, 56%
CO2Et
CF3
NO2
PySO2-N
Me
PySO2-N
Me
10, 49%
11, 37%
The starting (S)ꢀ1 was prepared from commercially available Lꢀphenylalanine of ≥98% ee. [F+]=Nꢀ
fluoroꢀ2,4,6ꢀtrimethylpyridinium triflate. EWG=electronꢀwithdrawing functional group.
a
Encouraged by the good tolerance of our catalyst system towards different functional groups,
structurally diverse phenylalanine derivatives were subjected to the catalytic olefination with butyl
acrylate in order to evaluate the scope and limitations with regard to the aromatic substitution of the
amino acid counterpart. This scope study was limited by the number of commercially available arylꢀ
alanines. The results are presented in Scheme 2. Both electronꢀrich such as (OMe and Me), and electronꢀ
deficient groups (F, Cl, Br) were tolerated, although substrates with electronꢀreleasing groups are
generally more reactive. Thus, the pꢀOMe product 12 (a derivative of tyrosine) was obtained with 71%
yield, whereas no reactivity was observed in the substrate holding a pꢀNO2 group (<10% conversion,
result not shown in Scheme 2). Nevertheless, a number of mono orthoꢀolefinated phenylalanine
derivatives were isolated in acceptable yields (24ꢀ72%). It should be noted that in the case of pꢀCl or pꢀ
Br substituted substrates, the incomplete conversions and the difficulty in the complete chromatographic
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separation of the products from the starting material and trace amount of unidentified byproducts
resulted in low yields upon isolation (products 15 and 16, 24% and 29% yield, respectively).15 Despite
these shortcomings, the partial tolerance to halogenꢀcontaining substrates is useful for subsequent
product derivatization since it provides orthogonal reactivity relative to the Pd0ꢀcatalyzed crossꢀcoupling
chemistry.
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When a substrate having blocked the meta position was employed, as in the case of the 2ꢀnaphthyl
derivative, the reaction occurred at a sterically more accessible site (Cꢀ3’) to avoid the steric congestion
(product 18, 52% yield). However, metaꢀfluoroꢀsubstitution caused the formation of a mixture of the
two orthoꢀolefination regioisomers (17a and 17b were isolated with 72% yield in a 43:57 relative ratio),
probably arising from the low steric discrimination of the two ortho positions by the small fluoro
substituent. The 1ꢀnaphthyl derivative underwent clean olefination at the available Cꢀ2’ position (19,
69% yield).
Scheme 2. Scope with regard to the substitution at the aromatic ring.a
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EtO2C
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EtO2C
Me
Me
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8
Pd(OAc)2 (10 mol%)
[F+] (3.0 equiv)
N SO2Py
N SO2Py
CO2Bu
CO2Bu
AcOH, 110 ºC, 18 h
R
R
(2 equiv)
12-19
EtO2C
EtO2C
EtO2C
Me
N SO2Py
CO2Bu
Me
Me
N SO2Py
CO2Bu
N SO2Py
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CO2Bu
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12, 71%
13, 43%
14, 40%
OMe
Me
EtO2C
F
EtO2C
EtO2C
Me
N SO2Py
CO2Bu
Me
Me
N SO2Py
CO2Bu
N SO2Py
CO2Bu
17a
17b
F
F
15, X = Cl, 24%
16, X = Br, 29%
X
72% (17a/17b = 43:57)
EtO2C
Me
N SO2Py
EtO2C
Me
N SO2Py
CO2Bu
BuO2C
18, 52%
19, 69%
a[F+]=Nꢀfluoroꢀ2,4,6ꢀtrimethylpyridinium triflate.
Notably, this method can be further extended to chiral enantiomerically pure α,βꢀdisubstituted
phenethylamines, such as the norephedrine derivative 20 (Scheme 3). Compound 20 was smoothly
alkenylated under the standard reaction conditions with butyl acrylate or phenyl vinyl sulfone (1.0 equiv)
1
to give the corresponding products in good yields (74%ꢀ78%) without epimerization , according to H
NMR.
Scheme 3. Extension to norephedrine derivatives
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The easy reductive removal of the Nꢀ(2ꢀpyridyl)sulfonyl protecting/directing group under smooth
conditions (Zn powder, 1:1 THF/sat. aq NH4Cl, 65 ºC) without affecting the sensitive acrylate moiety
enabled the direct access to valuable 1,2,3,4ꢀtetrahydroisoquinolineꢀ3ꢀcarboxylic acid (Tic)16 skeletons
in synthetically useful yields (Scheme 4). For example, Nꢀdeprotection of product (±)ꢀ2 simultaneously
triggers the cyclization of the free amine under the reaction conditions to afford 23 in 71% yield and
good diastereoselectivity (anti/syn = 80:20).17 When the enantiomerically pure product (S)ꢀ5 (>98% ee)
was submitted to identical conditions, the same Nꢀdeprotection/intramolecular azaꢀMichael sequence
was produced, affording the corresponding bicyclic product 24 in similar yield (74%) and
diastereocontrol (anti/syn = 80:20), albeit with a small degree of racemization (95% ee in the major anti
diastereomer).
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Scheme 4. Nꢀdeprotection/cyclization to afford tetrahydroisoquinolines
In conclusion, we have demonstrated that the directing ability of the easily removable Nꢀ(2ꢀ
pyridyl)sulfonyl group can be extended to the PdIIꢀcatalyzed direct orthoꢀolefination of Nꢀsubstituted
phenylalanine and norephedrine derivatives in acceptable yields and with preservation of enantiopurity
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of the starting substrate. This protocol features good structural versatility in both alkene and nitrogen
arene components. The smooth Nꢀdeprotection without affecting the acrylate moiety enables rapid
access to enantioenriched tetrahydroisoquinoline derivatives.
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EXPERIMENTAL SECTION
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1.1 General methods
Solvents were used as received from commercial sources. They were not distilled nor subjected to
additional purification. All reactions were carried out without special protections against air and
moisture. Column liquid chromatography was performed on silica gel (70ꢀ230 mesh). The 1H, 13C{1H},
31
19F and P{1H} NMR spectra were recorded in CDCl3 solutions at 25 °C on 300, 400 or 500 MHz
spectrometers (δ, ppm; J, Hz); H and 13C{1H} spectra were referenced using the solvent signal as
1
internal standard, while 19F and 31P NMR spectra were referenced to CFCl3 and H3PO4 (85%),
respectively. HRMS and ESI (ESI+) mass spectra were recorded using an MicroToF Q, APIꢀQꢀToF ESI
with a mass range from 20 to 3000 m/z and mass resolution 15000 (FWHM). HPLC experiments were
conducted on an Agilent 1100 instrument, using Daicel Chiralpak IA, AD, ASꢀH and Chiralcel OJꢀH
columns as chiral stationary phase. Optical rotations were measured on a polarimeter and they are
temperature
reported as follows: [α]wavelenght
(c, solvent). Melting points were determined in openꢀend
capillary tubes.
Synthesis of the starting N-(2-pyridyl)sulfonyl phenylalanine ethyl ester derivatives from aryl-
alanines
Step 1: Protection of the carboxylic acid group as ethyl ester
Typical procedure: synthesis of (S)-ethyl 2-amino-3-phenylpropanoate (S)-I. To an iceꢀcooled
solution (−5 °C) of (S)ꢀphenylalanine (2.00 g, 12.11 mmol; ≥98% ee) in ethanol (10 mL) was added
thionyl chloride (1.32 mL, 18.16 mmol). The resulting mixture was heated to reflux for 3 hours, it was
allowed to reach room temperature and the solvent was evaporated. The solid residue was treated with a
sat. aq solution of sodium hydrogen carbonate (10 mL) and extracted with ethyl acetate (3×10 mL). The
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combined organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to give
(S)-I as a clear yellow oil; yield: 1.82 g (78%)
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1H NMR (300 MHz, CDCl3): δ 7.29 – 7.10 (m, 5H), 4.09 (q, J = 7.1 Hz, 2H), 3.63 (t, br, J = 5.3 Hz,
1H), 3.01 (dd, J = 13.5, 5.3 Hz, 1H), 2.81 (dd, J = 13.5, 7.6 Hz, 1H), 1.58 (s, br, 2H), 1.17 (t, J = 7.2 Hz,
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3H). C{1H} NMR (75 MHz, CDCl3): δ 174.7, 137.1, 129.0, 128.2, 126.4, 60.5, 55.5, 40.9, 13.9. ESIꢀ
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HRMS: Calcd for C11H16NO2 [M+H]+: 194.1176. Found: 194.1185. [α]D298 = −7.04 (c 1.09, CHCl3).
(±)-Ethyl 2-amino-3-(4-methoxyphenyl)propanoate [(±)-II]. Following the typical procedure,
thionyl chloride (445.9 ꢁL, 6.15 mmol) reacted with Oꢀmethyltyrosine (800.0 mg, 4.10 mmol) in ethanol
(5 mL) to give, after workup, (±)-II as a pale yellow oil; yield: 694.4 mg (76%).
1H NMR (300 MHz, CDCl3): δ 6.96 (d, J = 8.6 Hz, 2H), 6.68 (d, J = 8.6 Hz, 2H), 4.00 (q, J = 7.2 Hz,
2H), 3.60 (d, J = 1.0 Hz, 3H), 3.50 (dd, J = 7.5, 5.5 Hz, 1H), 2.85 (dd, J = 13.6, 5.4 Hz, 1H), 2.67 (dd, J
= 13.6, 7.5 Hz, 1H), 1.74 (s, br, 2H), 1.09 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ 174.6,
158.0, 129.8, 128.8, 113.4, 60.3, 55.4, 54.6, 39.7, 13.7. ESIꢀHRMS: Calcd for C12H18NO3 [M+H]+:
224.1281. Found: 224.1276.
(±)-Ethyl 2-amino-3-(p-tolyl)propanoate [(±)-III]. Following the typical procedure, thionyl chloride
(242.9 ꢀL, 3.35 mmol) reacted with pꢀmethylphenylalanine (400.0 mg, 2.23 mmol) in ethanol (10 mL)
to give, after workup, (±)-III as a pale yellow oil; yield: 461.0 mg (99%).
1H NMR (300 MHz, CDCl3): δ 7.14 – 7.01 (m, 4H), 4.15 (q, J = 7.2 Hz, 2H), 3.66 (dd, J = 7.8, 5.2 Hz,
1H), 3.02 (dd, J = 13.5, 5.2 Hz, 1H), 2.80 (dd, J = 13.5, 7.8 Hz, 1H), 2.30 (s, 3H), 1.49 (s, 2H), 1.23 (t, J
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= 7.1 Hz, 3H). C{1H} NMR (75 MHz, CDCl3): δ 175.0, 136.2, 134.1, 129.1, 129.1, 60.8, 55.8, 40.6,
21.0, 14.1. ESIꢀHRMS: Calcd for C12H18NO2 [M+H]+: 208.1332. Found: 208.1327.
(±)-Ethyl 2-amino-3-(4-fluorophenyl)propanoate [(±)-IV]. Following the typical procedure, thionyl
chloride (475.2 ꢀL, 6.55 mmol) reacted with pꢀfluorophenylalanine (800.0 mg, 4.37 mmol) in ethanol (5
mL) to give, after workup, (±)-IV as a pale yellow oil; yield: 851.0 mg (92%).
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1H NMR (300 MHz, CDCl3): δ 7.11 – 6.99 (m, 2H), 6.92 – 6.81 (m, 2H), 4.03 (q, J = 7.1 Hz, 2H), 3.56
(s, br, 1H), 2.91 (dd, J = 13.5, 5.3 Hz, 1H), 2.74 (dd, J = 13.6, 7.4 Hz, 1H), 1.51 (s, br, 2H), 1.11 (t, J =
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7.1 Hz, 3H). C{1H} NMR (75 MHz, CDCl3): δ 174.6, 161.5 (d, JCꢀF = 244.6 Hz), 132.9 (d, JCꢀF = 3.2
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Hz), 130.5 (d, JCꢀF = 7.9 Hz), 115.0 (d, JCꢀF = 21.2 Hz), 60.6, 55.5, 40.0, 13.9. δF: ꢀ115.88. ESIꢀHRMS
Calcd for C11H15FNO2 [M+H]+: 212.1081. Found: 212.1080.
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(±)-Ethyl 2-amino-3-(4-chlorophenyl)propanoate [(±)-V]. Following the typical procedure, thionyl
chloride (545.1 ꢀL, 7.51 mmol) reacted with pꢀchlorophenylalanine (1.00 g, 5.01 mmol) in ethanol (10
mL) to give, after workup, (±)-V as a pale yellow oil; yield: 1.12 g (99%).
1H NMR (300 MHz, CDCl3): δ 7.21 (d, J = 7.9 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 4.10 (q, J = 7.2 Hz,
2H), 3.62 (t, J = 6.9 Hz, 1H), 2.97 (dd, J = 13.4, 5.4 Hz, 1H), 2.78 (dd, J = 13.6, 7.7 Hz, 1H), 1.43 (s, br,
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2H), 1.19 (t, J = 7.0 Hz, 3H). C{1H} NMR (75 MHz, CDCl3): δ 174.7, 135.8, 132.5, 130.6, 128.5,
60.9, 55.6, 40.3, 14.1. ESIꢀHRMS: Calcd for C11H15ClNO2 [M+H]+: 228.0786. Found: 228.0772.
(±)-Ethyl 2-amino-3-(4-bromophenyl)propanoate [(±)-VI]. Following the typical procedure, thionyl
chloride (445.8 ꢀL, 6.14 mmol) reacted with pꢀbromophenylalanine (1.00 g, 4.10 mmol) in ethanol (10
mL) to give, after workup, (±)-VI as a pale yellow oil; yield: 1.04 g (93%).
1H NMR (300 MHz, CDCl3): δ 7.45 – 7.34 (m, 2H), 7.13 – 7.02 (m, 2H), 4.14 (q, J = 7.1 Hz, 2H), 3.65
(dd, J = 7.8, 5.4 Hz), 3.00 (dd, J = 13.6, 5.4 Hz, 1H), 2.80 (dd, J = 13.6, 7.7 Hz, 1H), 1.43 (s, 2H), 1.22
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(t, J = 7.1 Hz, 3H). C{1H} NMR (75 MHz, CDCl3): δ 174.87, 136.46, 131.62, 131.10, 120.77, 61.07,
55.73, 40.53, 14.27. ESIꢀHRMS: Calcd for C11H15BrNO2 [M+H]+: 272.0286. Found: 272.0269.
(±)-Ethyl 2-amino-3-(3-fluorophenyl)propanoate [(±)-VII] Following the typical procedure, thionyl
chloride (207.1 ꢁL, 2.85 mmol) reacted with mꢀfluor phenylalanine (366.4 mg, 2.00 mmol) in ethanol (5
mL) to give, after workup, (±)-VII as a pale yellow oil; yield: 333.5 mg (79%).
1H NMR (300 MHz, CDCl3): δ 8.82 (s, br, 2H), 7.29 (m, 1H), 7.12 (t, J = 8.1 Hz, 2H), 6.95 (t, J= 7.8
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Hz, 1H), 4.44 (m, 1H), 4.13 (m, 2H), 3.51 (m, 1H), 3.36 (m, 1H), 1.15 (t, J = 6.8 Hz, 3H). C{1H}
NMR (75 MHz, CDCl3): δ 168.8, 162.0 (d, JCꢀF = 46.5 Hz), 136.9 (d, JCꢀF = 7.8 Hz), 130.3 (d, JCꢀF = 8.2
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Hz), 125.4 (d, JCꢀF = 2.9 Hz), 116.7 (d, JCꢀF = 21.4 Hz), 114.5 (d, JCꢀF = 20.9 Hz), 62.5, 54.2, 36.0, 13.8.
19F{1H} NMR (282 MHz, CDCl3): δ ꢀ112.7. ESIꢀHRMS: Calcd for C11H15FNO2 [M+H]+: 212.1081.
Found: 212.1088.
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(±)-Ethyl 2-amino-3-(naphthalen-1-yl)propanoate [(±)-VIII]. Following the typical procedure,
thionyl chloride (207.1 ꢁL, 2.85 mmol) reacted with 1ꢀnaphtylalanine (430.3 mg, 2.00 mmol) in ethanol
(5 mL) to give, after workup, (±)-VIII as a pale yellow oil; yield: 340.6 mg (70%).
1H NMR (300 MHz, CDCl3): δ 8.07 (d, J = 7.9 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 8.1 Hz,
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1H), 7.40ꢀ7.18 (m, 6H), 4.43 (m, 1H), 3.97 (m, 1H), 3.64 (m, 3H), 0.63 (t, J = 7.0 Hz, 3H). C{1H}
NMR (75 MHz, CDCl3): δ 169.5, 133.8, 131.9, 131.0, 128.7, 128.5, 128.1, 126.5, 125.7, 125.5, 123.6,
62.1, 53.9, 34.0, 13.3. ESIꢀHRMS: Calcd for C15H18NO2 [M+H]+: 244.1332. Found: 244.1335.
(±)-Ethyl 2-amino-3-(naphthalen-2-yl)propanoate [(±)-IX]. Following the typical procedure,
thionyl chloride (207.1 ꢁL, 2.85 mmol) reacted with 2ꢀnaphtylalanine (430.3 mg, 2.00 mmol) in ethanol
(5 mL) to give, after workup, (±)-IX as a pale yellow oil; yield: 384.4 mg (79%).
1H NMR (300 MHz, CDCl3): δ 8.88 (s, br, 2H), 7.80ꢀ7.74 (m, 4H), 7.44ꢀ7.39 (m, 3H), 4.52 (t, J = 7.1
Hz, 1H), 3.97 (m, 2H), 3.67 (dd, J = 5.4, 14.1 Hz, 1H), 3.50 (dd, J = 7.9, 13.9 Hz, 1H), 0.96 (t, J = 7.0
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Hz, 3H). C{1H} NMR (75 MHz, CDCl3): δ 169.0, 133.4, 132.6, 131.9, 128.7, 128.3, 127.8, 127.6,
127.4, 126.1, 125.8, 62.3, 54.3, 36.6, 13.7. ESIꢀHRMS: Calcd for C15H18NO2 [M+H]+: 244.1332.
Found: 244.1338.
Step 2: N-sulfonylation reaction
Typical procedure: synthesis of (S)-ethyl 3-phenyl-2-(pyridine-2-sulfonamido)propanoate [(S)-
X]. To a solution of (S)ꢀI (1.82 g, 9.43 mmol) and pyridine (2.7 mL, 33.96 mmol) in dry THF (20 mL),
cooled to −5 °C and under Ar atmosphere, was added dropꢀwise a solution of 2ꢀpyridylsulfonyl chloride
(2.01 g, 11.32 mmol) in dry THF (5 mL). The resulting mixture was allowed to reach room temperature
and stirred for further 18 h before it was filtered and concentrated to dryness. The resulting solid residue
was triturated in a 1:1 mixture of hexane:water (20 mL) and then filtered to give compound (S)ꢀX as a
white solid; yield: 2.69 g (85%); mp: 131 – 133 ºC.
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1H NMR (300 MHz, CDCl3): δ 8.59 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 7.90 (dt, J = 7.8, 1.1 Hz, 1H), 7.84
(td, J = 7.7, 1.7 Hz, 1H), 7.43 (ddd, J = 7.5, 4.7, 1.4 Hz, 1H), 7.26 – 7.16 (m, 3H), 7.15 – 7.09 (m, 2H),
5.57 (d, J = 8.9 Hz, 1H), 4.58 (dt, J = 8.8, 6.0 Hz, 1H), 3.98 (qq, J = 7.1, 3.6 Hz, 2H), 3.10 (d, J = 6.1
Hz, 2H), 1.10 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ 170.9, 157.8, 149.8, 138.0, 135.2,
129.6, 128.5, 127.2, 126.7, 121.7, 61.7, 57.6, 39.8, 14.0. ESIꢀHRMS: Calcd for C16H19N2O4S [M+H]+:
335.1060. Found: 335.1052. [α]D298 = −9.75 (c = 1.11, CHCl3).
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(±)-Ethyl 3-(4-methoxyphenyl)-2-(pyridine-2-sulfonamido)propanoate [(±)-XI]. Following the
typical procedure, (±)-II (694.4 mg, 3.11 mmol) and pyridine (905.6 ꢁL, 11.20 mmol) in THF (20 mL)
reacted with a soln of 2ꢀpyridylsulfonyl chloride (662.9 mg, 3.73 mmol) in THF (5 mL) to give (±)-XI
as a white solid; yield: 829.4 g (73%); mp: 125 – 128 ºC.
1H NMR (300 MHz, CDCl3): δ 8.59 (d, J = 4.6 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.84 (td, J = 7.7, 1.7
Hz, 1H), 7.43 (ddd, J = 7.4, 4.7, 1.3 Hz, 1H), 7.03 (d, J = 8.6 Hz, 2H), 6.75 (d, J = 8.6 Hz, 2H), 5.53 (d,
J = 8.8 Hz, 1H), 4.53 (dt, J = 8.8, 5.9 Hz, 1H), 3.98 (m, 2H), 3.75 (s, 3H), 3.04 (d, J = 5.9 Hz, 2H), 1.12
(t, J = 7.1 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ 170.9, 158.8, 157.9, 149.8, 138.0, 130.6, 127.1,
126.7, 121.7, 113.9, 61.6, 57.7, 55.3, 38.9, 14.1. ESIꢀHRMS: Calcd for C17H20N2O5S [M+H]+:
365.1166. Found: 365.1143.
(±)-Ethyl 2-(pyridine-2-sulfonamido)-3-(p-tolyl)propanoate [(±)-XII]. Following the typical
procedure, (±)ꢀIII (461.0 mg, 2.22 mmol) and pyridine (647.6 ꢀL, 8.00 mmol) in THF (20 mL) reacted
with a soln of 2ꢀpyridylsulfonyl chloride (474.0 mg, 2.67 mmol) in THF (5 mL) to give (±)ꢀXII as a
yellow solid. Further purification by column chromatography (hexaneꢀEtOAc, 2:3) provided (±)ꢀXII as
a white powder; yield: 389.3 mg (50%); mp: 129 – 131 ºC.
1H NMR (300 MHz, CDCl3): δ 8.59 (dq, J = 4.7, 1.3 Hz, 1H), 7.89 (dt, J = 7.8, 1.3 Hz, 1H), 7.84 (td, J
= 7.6, 1.7 Hz, 1H), 7.43 (ddd, J = 7.3, 4.7, 1.5 Hz, 1H), 7.05 – 6.98 (m, 4H), 5.46 (d, J = 8.9 Hz, 1H),
4.56 (dt, J = 8.8, 5.9 Hz, 1H), 3.99 (qd, J = 7.1, 2.2 Hz, 2H), 3.06 (d, J = 5.9 Hz, 2H), 2.28 (s, 3H), 1.12
(t, J = 7.1 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ 170.9, 157.8, 149.8, 138.0, 136.7, 131.9, 129.4,
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129.2, 126.6, 121.7, 61.6, 57.6, 39.3, 21.1, 14.0. ESIꢀHRMS: Calcd for C17H21N2O4S [M+H]+:
349.1217. Found: 349.1212.
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(±)-Ethyl 3-(4-fluorophenyl)-2-(pyridine-2-sulfonamido)propanoate [(±)-XIII]. Following the
typical procedure, (±)ꢀIV (851.0 mg, 4.03 mmol) and pyridine (1170 ꢀL, 14.50 mmol) in THF (20 mL)
reacted with a soln of 2ꢀpyridylsulfonyl chloride (858.7 mg, 4.835 mmol) in THF (5 mL) to give (±)ꢀ
XIII as a white solid. Yield: 1.24 g (87%); mp: 132 – 134 ºC.
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1H NMR (300 MHz, CDCl3): δ 8.59 (ddd, J = 4.8, 1.7, 1.0 Hz, 1H), 7.90 (dt, J = 7.8, 1.3 Hz, 1H), 7.85
(td, J = 7.6, 1.7 Hz, 1H), 7.45 (ddd, J = 7.4, 4.7, 1.4 Hz, 1H), 7.11 (m, 2H), 6.91 (m, 2H), 5.60 (d, J =
8.7 Hz, 1H), 4.55 (dt, J = 8.7, 6.0 Hz, 1H), 4.00 (qd, J = 7.1, 3.1 Hz, 2H), 3.10 (dd, J = 13.8, 6.0 Hz,
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1H), 3.05 (dd, J = 13.6, 6.1 Hz, 1H), 1.12 (t, J = 7.1 Hz, 3H). C{1H} NMR (75 MHz, CDCl3): δ
170.84, 162.13 (d, J = 245.5 Hz), 157.88, 149.91, 138.14, 131.20 (d, JC-F = 8.1Hz), 131.05 (d, JC-F = 3.3
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Hz), 126.81, 121.76, 115.43 (d, JC-F = 21.3 Hz), 61.86, 57.71 (d, JC-F = 1.4 Hz), 39.05, 14.12. F{1H}
NMR: δ ꢀ115.55 (s). ESIꢀHRMS: Calcd for C16H18FN2O4S [M+H]+: 353.0966. Found: 353.0991.
(±)-Ethyl 3-(4-chlorophenyl)-2-(pyridine-2-sulfonamido)propanoate [(±)-XIV]. Following the
typical procedure, (±)ꢀV (1.12 g, 4.93 mmol) and pyridine (718.2 ꢀL, 8.88 mmol) in THF (20 mL)
reacted with a soln of 2ꢀpyridylsulfonyl chloride (1.05 g, 5.92 mmol) in THF (5 mL) to give (±)ꢀXIV as
a white solid; yield: 1.42 g (78%); mp: 129 – 131 ºC.
1H NMR (300 MHz, CDCl3): δ 8.59 (dt, J = 4.8, 1.3 Hz, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.85 (td, J = 8.0,
1.5 Hz, 1H), 7.45 (ddd, J = 6.9, 4.8, 1.8 Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 5.47
(d, J = 8.6 Hz, 1H), 4.58 (dt, J = 8.6, 6.0 Hz, 1H), 4.03 (qd, J = 7.1, 1.7 Hz, 2H), 3.12 (dd, J = 13.9, 5.9
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Hz, 1H), 3.04 (dd, J = 13.9, 6.2 Hz, 1H), 1.15 (t, J = 7.1 Hz, 3H). C{1H} NMR (75 MHz, CDCl3): δ
170.7, 149.9, 138.1, 133.8, 133.2, 131.0, 128.7, 126.8, 121.7, 61.9, 57.6, 39.2, 14.1 [The quaternary C
atom of the pi fragment was not observed, in spite of the use of long accumulation periods]. ESIꢀHRMS:
Calcd for C16H18ClN2O4S [M+H]+: 369.0670. Found: 369.0663.
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(±)-Ethyl 3-(4-bromophenyl)-2-(pyridine-2-sulfonamido)propanoate [(±)-XV]. Following the
typical procedure, (±)ꢀVI (1.04 g, 3.82 mmol) and pyridine (556.4 ꢀL, 6.88 mmol) in THF (5 mL)
reacted with a soln of 2ꢀpyridylsulfonyl chloride (814.5 mg, 4.59 mmol) in THF (20 mL) to give (±)ꢀXV
as a white solid; yield: 1.217 g (77%); mp: 126 – 128 ºC.
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1H NMR (300 MHz, CDCl3): δ 8.58 (dt, J = 4.6, 1.3 Hz, 1H), 7.88 (d, J = 7.0 Hz, 1H) 7.84 (td, J = 7.9,
1.4 Hz, 1H), 7.45 (ddd, J = 6.8, 4.8, 2.1 Hz, 1H), 7.33 (d, J = 8.3 Hz, 2H), 7.01 (d, J = 8.3 Hz, 2H), 5.59
(d, J = 8.7 Hz, 1H), 4.56 (dt, J = 8.7, 6.1 Hz, 1H), 4.03 (qd, J = 7.1, 1.5 Hz, 2H), 3.09 (dd, J = 13.9,
5.8 Hz, 1H), 3.01 (dd, J = 13.8, 6.4 Hz, 1H), 1.14 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3):
δ 170.7, 157.8, 149.9, 138.1, 134.4, 131.6, 131.3, 126.7, 121.7, 121.3, 61.9, 57.5, 39.2, 14.1. ESIꢀ
HRMS: Calcd for C16H18BrN2O4S [M+H]+: 413.0165. Found: 413.0159.
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(±)-Ethyl 3-(3-fluorophenyl)-2-(pyridine-2-sulfonamido)propanoate [(±)-XVI]. Following the
typical procedure, (±)ꢀVII (316.8 mg, 1.50 mmol) and pyridine (548.8 ꢀL, 6.78 mmol) in THF (20 mL)
reacted with a soln of 2ꢀpyridylsulfonyl chloride (401.7 mg, 2.26 mmol) in THF (5 mL) to give (±)ꢀXVI
as a white solid; yield: 422.8 mg (80%); mp: 144 – 146 ºC.
1H NMR (300 MHz, CDCl3): δ 8.53 (dt, J = 0.7, 4.7 Hz, 1H), 7.85 (dd, J = 0.7, 7.5 Hz, 1H), 7.80 (dt, J
= 1.6, 8.9 Hz, 1H), 7.39 (m, 1H), 7.16 (m, 1H), 6.88ꢀ6.74 (m, 3H), 5.27 (d, J = 8.5 Hz, 1H), 4.52 (m,
1H), 3.95 (dc, J = 5.5, 7.0 Hz, 2H), 3.04 (d, J = 5.8 Hz, 2H), 1.07 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (75
MHz, CDCl3): δ 170.6, 164.2 (d, JCꢀF = 245.9 Hz), 157.8, 149.8, 138.0, 137.7 (d, JCꢀF = 7.1 Hz), 130.0
(d, JCꢀF = 8.2 Hz), 126.7, 125.3 (d, JCꢀF = 2.7 Hz), 121.6, 116.4 (d, JCꢀF = 20.0 Hz), 114.1 (d, JCꢀF = 20.9
Hz), 61.8, 57.4, 39.5, 14.0. 19F{1H} NMR (282 MHz, CDCl3): δ ꢀ113.0. ESIꢀHRMS: Calcd for
C16H18FN2O4S [M+H]+: 353.0966. Found: 353.0961.
(±)-Ethyl 3-(naphthalen-1-yl)-2-(pyridine-2-sulfonamido)propanoate [(±)-XVII]. Following the
typical procedure, (±)ꢀVIII (364.9 mg, 1.50 mmol) and pyridine (548.8 ꢀL, 6.78 mmol) in THF (20 mL)
reacted with a soln of 2ꢀpyridylsulfonyl chloride (401.7 mg, 2.26 mmol) in THF (5 mL) to give (±)ꢀ
XVII as a colorless oil; yield: 409.5 mg (71%).
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1H NMR (300 MHz, CDCl3): δ 8.53 (m, 1H), 7.85ꢀ7.72 (m, 5H), 7.59 (s, 1H), 7.48ꢀ7.49 (m, 2H), 7.34ꢀ
7.25 (m, 3H), 4.70 (m, 1H), 4.05 (c, J = 7.0 Hz, 2H), 3.31ꢀ3.27 (m, 2H), 1.13 (t, J = 7.2 Hz, 3H).
13C{1H} NMR (75 MHz, CDCl3): δ 171.0, 157.6, 149.7, 137.8, 133.3, 133.0, 132.5, 128.4, 128.1, 127.7,
127.6, 127.5, 126.4, 126.0, 125.8, 121.5, 61.7, 57.8, 39.8, 14.0. ESIꢀHRMS: Calcd for C20H21N2O4S
[M+H]+: 385.1217. Found: 385.1211.
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(±)-Ethyl 3-(naphthalen-2-yl)-2-(pyridine-2-sulfonamido)propanoate [(±)-XVIII]. Following the
typical procedure, (±)ꢀIX (364.9 mg, 1.50 mmol) and pyridine (548.8 ꢀL, 6.78 mmol) in THF (20 mL)
reacted with a soln of 2ꢀpyridylsulfonyl chloride (401.7 mg, 2.26 mmol) in THF (5 mL) to give (±)ꢀ
XVIII as a white solid; yield: 440.0 mg (77%); mp: 53 – 55 ºC.
1H NMR (300 MHz, CDCl3): δ 8.36 (d, J = 4.6 Hz, 1H), 7.95 (d, J = 7.2 Hz, 1H), 7.75ꢀ7.64 (m, 5H),
7.44ꢀ7.39 (m, 2H), 7.28ꢀ7.20 (m, 2H), 5.42 (d, J = 8.8 Hz, 1H), 4.61 (c, J = 7.0 Hz, 1H), 3.83 (m, 2H),
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3.46 (d, J = 7.1 Hz, 2H), 0.90 (t, J = 7.0 Hz, 3H) C{1H} NMR (75 MHz, CDCl3): δ 171.3, 157.7,
149.6, 137.7, 133.8, 131.8, 131.6, 128.8, 128.1, 128.0, 126.4, 126.3, 125.7, 125.3, 123.5, 121.4, 61.6,
57.2, 37.2, 13.8. ESIꢀHRMS: Calcd for C20H21N2O4S [M+H]+, 385.1217. Found: 385.1215.
Step 3: N-methylation
Typical
procedure:
synthesis
of
(S)-ethyl
2-(N-methylpyridine-2-sulfonamido)-3-
phenylpropanoate [(S)-1]. To a solution of (S)ꢀX (2.69 g, 8.05 mmol) and K2CO3 (2.23 g, 16.11 mmol)
in MeCN (20 mL), was added methyl iodide (1.5 mL, 24.16 mmol). The reaction mixture was refluxed
for 16 h before it was cooled to room temperature and concentrated to dryness. The residue was purified
by flash chromatography (nꢀhexaneꢀEtOAc 9:1) to give compound (S)ꢀ1. Furhter purification by
trituration in a 1:2 mixture nꢀhexaneꢀEt2O gave (S)ꢀ1 as a white solid; yield: 2.21 g (79%); mp: 119 –
121 ºC.
1H NMR (300 MHz, CDCl3): δ 8.61 (dt, J = 4.7, 1.6 Hz, 1H), 7.85 – 7.75 (m, 2H), 7.42 (ddd, J = 6.1,
4.7, 2.6 Hz, 1H), 7.25 – 7.15 (m, 5H), 4.96 (dd, J = 8.3, 7.3 Hz, 1H), 3.95 (q, J = 7.1 Hz, 2H), 3.24 (dd,
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J = 14.0, 7.3 Hz, 1H), 3.07 (s, 3H), 2.96 (dd, J = 14.0, 8.3 Hz, 1H), 1.05 (t, J = 7.1 Hz, 3H). C{1H}
NMR (75 MHz, CDCl3): δ 170.1, 157.5, 149.8, 137.7, 136.3, 129.1, 128.6, 126.9, 126.4, 122.1, 61.2,
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61.0, 35.9, 31.3, 14.0. ESIꢀHRMS: Calcd for C17H21N2O4S [M+H]+: 349.1217. Found: 349.1190.
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[α]D298 = −19.12 (c 1.00, CHCl3).
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(±)-Ethyl
3-(4-methoxyphenyl)-2-(N-methylpyridine-2-sulfonamido)propanoate
[(±)-XIX].
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Following the typical procedure, (±)ꢀXI (829.4 mg, 2.28 mmol) reacted with MeI (425.1 ꢀL, 6.828
mmol) in the presence of K2CO3 (629.1 mg, 4.55 mmol) in MeCN (10 mL) to give, after column
chromatography (nꢀhexaneꢀEtOAc 8:2), (±)ꢀXIX as a white solid; yield: 669.9 mg (78%); mp: 115 –
117 ºC.
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1H NMR (300 MHz, CDCl3): δ 8.56 (d, J = 4.7 Hz, 1H), 7.84 – 7.67 (m, 2H), 7.39 (t, J = 5.7 Hz, 1H),
7.05 (d, J = 8.3 Hz, 2H), 6.71 (d, J = 8.2 Hz, 2H), 4.87 (t, J = 7.8 Hz, 1H), 3.92 (q, J = 7.1 Hz, 2H), 3.71
(s, 3H), 3.14 (dd, J = 14.2, 7.1 Hz, 1H), 3.03 (s, 3H), 2.85 (dd, J = 14.1, 8.5 Hz, 1H), 1.02 (t, J = 7.1 Hz,
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3H). C{1H} NMR (75 MHz, CDCl3): δ 170.0, 158.3, 157.3, 149.7, 137.6, 129.9, 128.1, 126.3, 121.9,
113.8, 61.0, 60.9, 55.0, 34.8, 31.1, 13.9. ESIꢀHRMS: Calcd for C18H23N2O5S [M+H]+: 379.1328.
Found: 379.1322.
(±)-Ethyl 2-(N-methylpyridine-2-sulfonamido)-3-(p-tolyl)propanoate [(±)-XX]. Following the
typical procedure, (±)ꢀXII (389.3 mg, 1.12 mmol) reacted with MeI (208.6 ꢀL, 3.35 mmol) in the
presence of K2CO3 (308.8 mg, 2.23 mmol) in MeCN (10 mL) to give, after column chromatography (nꢀ
hexaneꢀEtOAc 8:2), (±)ꢀXX as a white solid; yield: 387.3 mg (96%); mp: 121 – 123 ºC.
1H NMR (300 MHz, CDCl3): δ 8.60 (dt, J = 4.7, 1.5 Hz, 1H), 7.87 – 7.73 (m, 2H), 7.42 (ddd, J = 6.7,
4.7, 2.3 Hz, 1H), 7.09 – 7.00 (m, 4H), 4.93 (dd, J = 8.6, 7.0 Hz, 1H), 3.96 (q, J = 7.1 Hz, 2H), 3.20 (dd,
J = 14.1, 7.0 Hz, 1H), 3.07 (s, 3H), 2.90 (dd, J = 14.0, 8.5 Hz, 1H), 2.29 (s, 3H), 1.07 (t, J = 7.1 Hz,
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3H). C{1H} NMR (75 MHz, CDCl3): δ 170.2, 157.6, 149.8, 137.7, 136.4, 133.2, 129.3, 129.0, 126.3,
122.1, 61.2, 61.0, 35.5, 31.3, 21.2, 14.0. ESIꢀHRMS: Calcd for C18H23N2O4S [M+H]+: 363.1373.
Found: 363.1388.
(±)-Ethyl 3-(4-fluorophenyl)-2-(N-methylpyridine-2-sulfonamido)propanoate [(±)-XXI]. Following
the typical procedure, (±)ꢀXIII (1.24 g, 3.51 mmol) reacted with MeI (656.3 ꢀL, 10.54 mmol) in the
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presence of K2CO3 (971.4 mg, 7.03 mmol) in MeCN (10 mL) to give, after column chromatography (nꢀ
hexaneꢀEtOAc 8:2), (±)ꢀXXI as a white solid; yield: 1.027 g (80%); mp: 121 – 123 ºC.
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1H NMR (300 MHz, CDCl3): δ 8.53 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 7.76 (td, J = 7.7, 1.7 Hz, 1H), 7.71
(ddd, J = 7.9, 1.5, 0.9 Hz, 1H), 7.37 (ddd, J = 7.4, 4.7, 1.5 Hz, 1H), 7.14 – 7.04 (m, 2H), 6.83 (t, J = 8.7
Hz, 2H), 4.85 (dd, J = 8.7, 6.9 Hz, 1H), 3.88 (q, J = 7.1 Hz, 2H), 3.14 (dd, J = 14.2, 6.9 Hz, 1H), 2.99 (s,
3H), 2.86 (dd, J = 14.2, 8.7 Hz, 1H), 0.97 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ 169.6,
161.5 (d, JCꢀF = 244.8 Hz), 157.1, 149.6, 137.6, 131.9 (d, JCꢀF = 0.7 Hz), 130.4 (d, JCꢀF = 8.0 Hz), 126.3,
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121.8, 115.1 (d, JCꢀF = 21.3 Hz), 61.0, 60.8 (d, JCꢀF = 1.3 Hz), 34.7, 31.00, 13.7. F{1H} NMR: δ ꢀ
115.99 (s). ESIꢀHRMS: Calcd for C17H20FN2O4S [M+H]+: 367.1122. Found: 367.1113.
(±)-Ethyl
3-(4-chlorophenyl)-2-(N-methylpyridine-2-sulfonamido)propanoate
[(±)-XXII].
Following the typical procedure, (±)ꢀXIV (1422 mg, 3.85 mmol) reacted with MeI (719.9 ꢀL, 11.56
mmol) in the presence of K2CO3 (1.07 g, 7.71 mmol) in MeCN (10 mL) to give, after column
chromatography (nꢀhexaneꢀEtOAc 8:2), (±)ꢀXXII as a white solid; yield: 145 mg (98%); mp: 122 – 124
ºC.
1H NMR (300 MHz, CDCl3): δ 8.58 (ddd, J = 4.7, 1.7, 0.9 Hz, 1H), 7.81 (ddd, J = 7.8, 7.3, 1.7 Hz, 1H),
7.75 (ddd, J = 7.9, 1.5, 0.9 Hz, 1H), 7.43 (ddd, J = 7.3, 4.7, 1.5 Hz, 1H), 7.19 – 7.07 (m, 4H), 4.92 (dd, J
= 8.8, 6.8 Hz, 1H), 3.98 (q, J = 7.1 Hz, 2H), 3.21 (dd, J = 14.2, 6.8 Hz, 1H), 3.05 (s, 3H), 2.92 (dd, J =
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14.2, 8.8 Hz, 1H), 1.08 (t, J = 7.1 Hz, 3H). C{1H} NMR (75 MHz, CDCl3): δ 169.9, 157.5, 149.8,
137.7, 134.9, 132.8, 130.5, 128.7, 126.4, 122.0, 61.4, 60.9, 35.1, 31.3, 14.0. ESIꢀHRMS: Calcd for
C17H20ClN2O4S [M+H]+: 383.0832. Found: 383.0827.
(±)-Ethyl 3-(4-bromophenyl)-2-(N-methylpyridine-2-sulfonamido)propanoate [(±)-XXIII]
Following the typical procedure, (±)ꢀXV (1.22 g, 2.94 mmol) reacted with MeI (549.8 ꢀL, 8.83
mmol) in the presence of K2CO3 (813.7 mg, 5.89 mmol) in MeCN (10 mL) to give, after column
chromatography (nꢀhexaneꢀEtOAc 8:2), (±)ꢀXXIII as a white solid; yield: 1.19 g (95%); mp: 118 – 120
ºC.
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1H NMR (300 MHz, CDCl3): δ 8.57 (ddd, J = 4.7, 1.8, 0.9 Hz, 1H), 7.80 (ddd, J = 7.9, 7.4, 1.7 Hz, 1H),
7.73 (ddd, J = 7.9, 1.4, 0.9 Hz, 1H), 7.43 (ddd, J = 7.4, 4.7, 1.4 Hz, 1H), 7.33 – 7.27 (m, 2H), 7.07 –
6.99 (m, 2H), 4.91 (dd, J = 8.9, 6.7 Hz, 1H), 3.98 (q, J = 7.1 Hz, 2H), 3.18 (dd, J = 14.2, 6.7 Hz, 1H),
3.04 (s, 3H), 2.89 (dd, J = 14.2, 8.9 Hz, 1H), 1.07 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3):
δ 169.8, 157.4, 149.8, 137.7, 135.4, 131.6, 130.8, 126.4, 121.9, 120.8, 61.4, 60.8, 35.2, 31.2, 14.0. ESIꢀ
HRMS: Calcd for C17H20BrN2O4S [M+H]+: 427.0322. Found: 427.0314.
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(±)-Ethyl
3-(3-fluorophenyl)-2-(N-methylpyridine-2-sulfonamido)propanoate
[(±)-XXIV].
Following the typical procedure, (±)ꢀXVI (352.4 mg, 1.00 mmol) reacted with MeI (186.8 ꢀL, 3.00
mmol) in the presence of K2CO3 (276.3 mg, 2.00 mmol) in MeCN (10 mL) to give, after column
chromatography (nꢀhexaneꢀEtOAc 8:2), (±)ꢀXXIV as a colorless oil; yield: 311.4 mg (85%).
1H NMR (300 MHz, CDCl3): δ 8.66 (d, J = 4.7 Hz, 1H), 7.86 (m, 2H), 7.48 (m, 1H), 7.24 (m, 1H), 7.03
(d, J = 7.7 Hz, 1H), 6.93 (m, 2H), 4.99 (t, J = 8.0 Hz, 1H), 4.01 (c, J = 7.1 Hz, 2H), 3.27 (dd, J = 7.2,
14.0 Hz, 1H), 3.10 (s, 3H), 3.00 (dd, J = 8.3, 14.0 Hz, 1H), 1.12 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (75
MHz, CDCl3): δ 169.8, 162.7 (d, JCꢀF = 46.0 Hz), 157.3, 149.8, 138.9 (d, JCꢀF = 7.1 Hz), 137.8, 130.0 (d,
JCꢀF = 9.2 Hz), 126.5, 124.8 (d, JCꢀF = 3.0 Hz), 121.9, 115.9 (d, JCꢀF = 21.4 Hz), 113.8 (d, JCꢀF = 20.9 Hz),
61.2, 60.8, 35.5, 31.2, 13.9. 19F{1H} NMR (282 MHz, CDCl3): δ ꢀ113.0. ESIꢀHRMS: Calcd for
C17H20FN2O4S [M+H]+: 367.1122. Found: 367.1128.
(±)-Ethyl
2-(N-methylpyridine-2-sulfonamido)-3-(naphthalen-1-yl)propanoate
[(±)-XXV].
Following the typical procedure, (±)ꢀXVII (384.5 mg, 1.00 mmol) reacted with MeI (186.8 ꢀL, 3.00
mmol) in the presence of K2CO3 (276.3 mg, 2.00 mmol) in MeCN (10 mL) to give, after column
chromatography (nꢀhexaneꢀEtOAc 8:2), (±)ꢀXXV as a colorless oil; yield: 354.6 mg (89%).
1H NMR (300 MHz, CDCl3): δ 8.46 (d, J = 4.3 Hz, 1H), 7.81 (m, 1H), 7.73 (m, 2H), 7.65 (d, J = 7.9 Hz,
1H), 7.59ꢀ7.51 (m, 2H), 7.50ꢀ7.46 (m, 2H), 7.35 (dd, J= 1.1, 8.6 Hz, 1H), 7.20 (m, 1H), 5.12 (dd, J =
6.8, 8.9 Hz, 1H), 4.05 (c, J = 7.2 Hz, 2H), 3.44 (dd, J = 6.7, 14.0 Hz, 1H), 3.18 (s, 3H), 3.13 (dd, J = 9.8,
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14.0 Hz, 1H), 1.13 (t, J = 7.2 Hz, 3H). C{1H} NMR (75 MHz, CDCl3): δ 170.0, 157.3, 149.5, 137.3,
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133.9, 133.3, 132.4, 128.2, 127.8, 127.6, 127.1, 126.0, 125.7, 121.5, 61.3, 61.1, 35.9, 31.3, 14.0. ESIꢀ
HRMS: Calcd for C21H23N2O4S [M+H]+: 399.1379. Found: 399.1372.
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(±)-Ethyl
2-(N-methylpyridine-2-sulfonamido)-3-(naphthalen-2-yl)propanoate
[(±)-XXVI].
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Following the typical procedure, (±)ꢀXVIII (384.5 mg, 1.00 mmol) reacted with MeI (186.8 ꢀL, 3.00
mmol) in the presence of K2CO3 (276.3 mg, 2.00 mmol) in MeCN (10 mL) to give, after column
chromatography (nꢀhexaneꢀEtOAc 8:2), (±)ꢀXXVI as a colorless oil; yield: 318.8 mg (80%).
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1H NMR (300 MHz, CDCl3): δ 8.58 (d, J = 4.5 Hz, 1H), 8.13 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 7.8 Hz,
1H), 7.74ꢀ7.69 (m, 3H), 7.61ꢀ7.50 (m, 2H), 7.39 (m, 1H), 7.32ꢀ7.28 (m, 2H), 5.17 (t, J = 7.3 Hz, 1H),
3.98 (c, J = 7.0 Hz, 2H), 3.74 (dd, J = 8.0, 14.0 Hz, 1H), 3.50 (dd, J = 7.3, 14.0 Hz, 2H), 3.26 (s, 3H),
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1.03 (t, J = 7.0 Hz, 3H). C{1H} NMR (75 MHz, CDCl3): δ 170.2, 157.3, 149.6, 137.6, 133.8, 132.2,
131.8, 128.9, 127.9, 127.7, 126.4, 126.3, 125.7, 125.3, 123.4, 121.8, 61.1, 60.0, 33.4, 31.2, 13.9. ESIꢀ
HRMS: Calcd for C21H23N2O4S [M+H]+: 399.1379. Found: 399.1375.
N-((1R,2S)-1-Methoxy-1-phenylpropan-2-yl)-N-methylpyridine-2-sulfonamide [(−)-20]
Potassium hydride (1.04 g of a 35 % suspension in oil, 364 mg, 9.1 mmol) was weighted into a 100 ml
3 neck round bottom flask. The KH was washed with hexane (3 x 4 mL) to remove the mineral oil and
THF (7 mL) was added to the dry KH powder. To the resulting suspension, cooled to 0 ºC, was added
dropꢀwise (over 10 min) a soln of Lꢀnorpseudoephedrine (1.37 g, 9.1 mmol) in THF (15 mL). The
reaction was stirred at room temperature for 10 min before MeI (0.567 mL, 9.1 mmol) was added. The
mixture was stirred for 1.5 h before a 2 N soln of sodium thiosulfate (25 mL) was added. The mixture
was extracted with diethyl ether (3 x 50 mL) and the combined organic phase was dried (MgSO4) and
concentrated to dryness. The resulting methyl ether intermediate [(1R,2S)ꢀXXVII] was of sufficient
purity for use in the next step.
To a solution of crude (1R,2S)ꢀXXVII (9.1 mmol) and pyridine (1.08 mL, 13.65 mmol) in dry THF
(20 mL), cooled to −5 ºC and under Ar atmosphere, was added dropꢀwise a solution of 2ꢀpyridylsulfonyl
chloride (2.4 g, 13.65 mmol) in dry THF (5 mL). The mixture was stirred at room temperature for 18 h
and then it was filtered through a small pad of silica gel and the filtrate concentrated to dryness. The
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resulting solid residue was triturated in a 1:1 mixture of nꢀhexaneꢀwater (20 mL) and filtered, to give
(1R,2S)ꢀXXVIII as a white solid that was used in the next step without further purification.
To a solution of (1R,2S)ꢀXXVIII (9.1 mmol) and K2CO3 (2.51 g, 18.2 mmol) in MeCN (20 mL) at
room temperature was added methyl iodide (1.0 mL, 16.1 mmol). The reaction mixture was refluxed for
16 h before it was concentrated to dryness. The residue was purified by column chromatography (nꢀ
hexaneꢀEtOAc 8:2) to afford the desired compound (1R,2S)ꢀ20 as a colorless oil; yield: 2.011g (69%).
1H NMR (300 MHz, CDCl3): δ 8.45 (d, J = 4.8 Hz, 1H), 7.83–7.51 (m, 2H), 7.23 (ddd, J = 7.4, 4.7, 1.4
Hz, 1H), 7.18–6.88 (m, 5H), 4.29 (d, J = 3.5 Hz, 1H), 4.00 (dd, J = 7.0, 3.4 Hz, 1H), 3.05 (s, 3H), 2.83
(s, 3H), 0.79 (d, J = 7.0 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ 155.6, 147.6, 136.8, 135.4, 125.9,
125.2, 124.3, 123.9, 120.0, 85.3, 56.1, 54.8, 28.6, 8.1. ESIꢀHRMS: Calcd for C16H21N2O3S (M+H)+:
321,1267. Found: 321,1261. [α]D298 = −68.23 (c 0.68, CHCl3).
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Typical procedure for the C−H activation reaction: Synthesis of (S,E)-Butyl 3-(2-(3-ethoxy-2-(N-
methylpyridine-2-sulfonamido)-3-oxopropyl) phenyl)acrylate [(S)-2] A screwꢀcapped test tube was
charged with Nꢀ(2ꢀpyridyl)sulfonyl phenylalanine ethyl ester derivative (S)ꢀ1 (52.3 mg, 0.15 mmol), 1ꢀ
fluoroꢀ2,4,6ꢀtrimethylpyridinium triflate (130.2 mg, 0.45 mmol) and Pd(OAc)2 (3.4 mg, 0.015 mmol).
The tube was sealed with a rubber septum and then evacuated and backfilled with nitrogen (3x) before
acetic acid (1 mL) and butyl acrylate (43.0 ꢀL, 0.30 mmol) were successively added. The septum was
replaced with a Teflonꢀcoated screw cap and the resulting solution was heated and vigorously stirred at
110 °C for 6 hours. Then, it was cooled to room temperature and diluted with CH2Cl2 (5 mL). The
resulting suspension was filtered through a plug of Celite (washed with CH2Cl2). The clear solution was
washed with sat. aq soln of NaHCO3 (2×10 mL), dried with anhydrous MgSO4 and then concentrated to
dryness. The residue was then purified by column chromatography (nꢀhexaneꢀEtOAc 85:15) to afford
(S)ꢀ2 as a yellow oil; yield: 59.8 mg (84%).
[α]D20= −13.7 (c 0.89, CHCl3); 1H NMR (300 MHz, CDCl3): δ 8.57 (dd, J = 0.6, 7.5 Hz, 1H), 7.98 (d,
J = 15.0 Hz, 1H), 7.75ꢀ7.70 (m, 2H), 7.55ꢀ7.40 (m, 1H), 7.40ꢀ7.35 (m, 2H), 7.30ꢀ7.10 (m, 2H), 6.73 (d,
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J = 15.0 Hz, 1H), 4.80 (t, J = 8.0 Hz, 1H), 3.95ꢀ3.80 (m, 2H), 3.33 (dd, J = 7.3 Hz, 1H), 3.10 (dd, J =
7.3 Hz, 1H), 3.01 (s, 3H), 1.73 (m, 2H), 1.48 (m, 2H), 1.10 (t, J = 7.0 Hz, 3H), 0.98 (t, J = 7.1 Hz, 3H).
13C{1H} NMR (75 MHz, CDCl3): δ 169.7, 166.8, 157.4, 149.8, 141.3, 137.6, 135.8, 133.8, 130.6, 130.0,
127.5, 126.9, 126.3, 122.0, 120.8, 64.5, 61.3, 60.7, 32.6, 31.4, 30.8, 19.2, 13.9, 13.8. ESIꢀHRMS: Calcd
for C24H31N2O6S [M+H]+: 475.1897. Found: 475.1891. HPLC: Daicel Chiralpak AD, hexaneꢀ
isopropanol 90ꢀ10, flow rate 0.7 mL/min (ë = 254 nm), tR: 28.0 min (3R)ꢀ2 and 33.8 min (3S)ꢀ2.
(±)-(E)-methyl 3-(2-(3-ethoxy-2-(N-methylpyridine-2-sulfonamido)-3-oxopropyl)phenyl)acrylate
[(±)-3] Following the typical procedure, (±)ꢀ1 (52.3 mg, 0.15 mmol) reacted with methyl acrylate (27.0
ꢀL, 0.30 mmol) in the presence of Pd(OAc)2 (3.4 mg, 0.015 mmol), and 1ꢀfluoroꢀ2,4,6ꢀ
trimethylpyridinium triflate (130.2 mg, 0.45 mmol) in acetic acid (1 mL), to afford, after purification by
column chromatography (nꢀhexaneꢀEtOAc 85:15), product (±)ꢀ3 as yellow oil; yield: 49.5 mg (77%).
1H NMR (300 MHz, CDCl3): δ 8.55 (d, J = 4.5 Hz, 1H), 7.96 (d, J = 15.9 Hz, 1H), 7.80ꢀ7.70 (m, 3H),
7.45 (d, J = 7.7 Hz, 1H), 7.35 (m, 1H), 7.25ꢀ7.15 (m, 2H), 6.29 (d, J = 15.9 Hz, 1H), 4.84 (m, 1H), 3.88
(dc, J = 2.2, 7.0 Hz, 2H), 3.70 (s, 3H), 3.31 (dd, J = 7.0, 14.0 Hz, 1H), 3.06 (dd, J = 7.0, 14.0 Hz, 1H),
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3.01 (s, 3H), 0.99 (t, J = 7.1 Hz, 3H). C{1H} NMR (75 MHz, CDCl3): δ 169.7, 167.1, 157.4, 149.8,
141.6, 137.7, 135.9, 133.8, 130.7, 130.1, 127.6, 126.9, 126.3, 122.1, 120.4, 61.3, 60.8, 51.7, 32.7, 31.4,
13.9. ESIꢀHRMS: Calcd for C21H25N2O6S [M+H]+: 433.1428. Found: 433.1420.
(±)-(E)-Ethyl
3-(2-(2-(dimethoxyphosphoryl)vinyl)phenyl)-2-(N-methylpyridine-2-
sulfonamido)propanoate [(±)-4]. Following the typical procedure, (±)ꢀ1 (52.3 mg, 0.15 mmol) reacted
with dimethyl vinylphosphonate (35.6 ꢀL, 0.30 mmol) in the presence of Pd(OAc)2 (3.4 mg, 0.015
mmol), and 1ꢀfluoroꢀ2,4,6ꢀtrimethylpyridinium triflate (130.2 mg, 0.45 mmol) in acetic acid (1 mL), to
afford, after purification by column chromatography (nꢀhexaneꢀEtOAc 50:50), product (±)ꢀ4 as yellow
oil, yield: 49.3 mg (68%).
1H NMR (300 MHz, CDCl3): δ 8.56 (m, 1H), 7.82ꢀ7.74 (m, 3H), 7.44 (dd, J = 1.9, 7.7 Hz, 1H), 7.36
(m, 1H), 7.25ꢀ7.15 (m, 3H), 6.12 (t, J = 7.7 Hz, 1H), 4.88 (m, 1H), 3.73 (d, J = 5.0 Hz, 2H), 3.71 (d, J =
4.8 Hz, 6H), 3.31 (dd, J = 6.6, 14.2 Hz, 1H), 3.07 (dd, J = 8.5, 14.2 Hz, 1H), 3.01 (s, 3H), 0.98 (t, J =
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7.3 Hz, 3H). C{1H} NMR (75 MHz, CDCl3): δ 169.7, 157.3, 149.9, 146.3 (d, Jc-p = 5.0 Hz), 137.7,
135.5, 134.4 (d, Jc-p = 43.7 Hz), 130.7, 130.2, 127.6, 126.8, 126.4, 122.1, 115.5 (d, Jc-p = 160.6 Hz),
61.3, 60.7, 52.6, 32.7, 31.4, 13.9. ESIꢀHRMS: Calcd for C21H28N2O7PS [M+H]+: 483.1349. Found:
483.1356.
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(S,E)-ethyl
2-(N-methylpyridine-2-sulfonamido)-3-(2-(2-(phenylsulfonyl)vinyl)phenyl)-
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propanoate [(S)-5]. Following the typical procedure, (S)ꢀ1 (52.3 mg, 0.15 mmol) reacted with phenyl
vinyl sulfone (50.46 mg, 0.30 mmol) in the presence of Pd(OAc)2 (3.4 mg, 0.015 mmol), and 1ꢀfluoroꢀ
2,4,6ꢀtrimethylpyridinium triflate (130.2 mg, 0.45 mmol) in acetic acid (1 mL), to afford, after
purification by column chromatography (nꢀhexaneꢀEtOAc 80:20), product (S)ꢀ5 as yellow oil, yield:
61.1 mg (79%).
[α]D20= −11.0 (c 2.0, CHCl3); 1H NMR (300 MHz, CDCl3): δ 8.57 (dd, J = 0.6, 4.5 Hz, 1H), 7.98 (d, J
= 15.0 Hz, 1H), 7.93 (d, J = 7.9 Hz, 2H), 7.75ꢀ7.70 (m, 2H), 7.55ꢀ7.40 (m, 3H), 7.40ꢀ7.35 (m, 2H), 7.30ꢀ
7.10 (m, 3H), 6.73 (d, J = 15.0 Hz, 1H), 4.80 (t, J = 8.0 Hz, 1H), 3.95ꢀ3.80 (m, 2H), 3.33 (dd, J = 7.3
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Hz, 1H), 3.10 (dd, J = 7.3 Hz, 1H), 3.01 (s, 3H), 0.98 (t, J = 7.1 Hz, 3H). C{1H} NMR (75 MHz,
CDCl3): δ 169.5, 157.2, 149.9, 140.5, 139.4, 137.7, 136.6, 133.8, 131.7, 131.1, 131.0, 129.6, 129.4,
127.9, 127.7, 127.4, 126.5, 122.1, 61.4, 61.0, 32.7, 31.4, 13.9. ESIꢀHRMS: Calcd for C25H27N2O6S2
[M+H]+: 515.1305. Found: 515.1310. HPLC: Daicel Chiralpak AD, hexaneꢀisopropanol 85ꢀ15, flow
rate 0.7 mL/min (ë = 254 nm), tR: 87.0 min (3S)ꢀ5 and 93.4 min (3R)ꢀ5.
(±)-(E)-ethyl
2-(N-methylpyridine-2-sulfonamido)-3-(2-(2-(phenoxysulfonyl)vinyl)phenyl)-
propanoate [(±)-6]. Following the typical procedure, (±)ꢀ1 (52.3 mg, 0.15 mmol) reacted with phenyl
vinyl sulfonate (55.2 mg, 0.30 mmol) in the presence of Pd(OAc)2 (3.4 mg, 0.015 mmol), and 1ꢀfluoroꢀ
2,4,6ꢀtrimethylpyridinium triflate (130.2 mg, 0.45 mmol) in acetic acid (1 mL), to afford, after
purification by column chromatography (nꢀhexaneꢀEtOAc 80:20), product (±)ꢀ6 as yellow oil, yield:
58.1 mg (73%).
1H NMR (300 MHz, CDCl3): δ 8.55 (m, 1H), 7.83 (d, J = 15.1 Hz, 1H), 7.76ꢀ7.48 (m, 2H), 7.45ꢀ7.20
(m, 10H), 6.73 (d, J = 15.1 Hz, 1H), 4.77 (dd, J = 6.3, 8.8 Hz, 1H), 3.88 (dc, J = 1.6, 7.6 Hz, 2H), 3.21
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(dd, J = 6.3, 14.5 Hz, 1H), 2.99ꢀ2.90 (m, 4H), 0.98 (t, J = 7.1 Hz, 3H). C{1H} NMR (75 MHz,
CDCl3): δ 169.3, 157.2, 149.8, 149.6, 143.3, 137.7, 136.9, 131.4, 131.3, 131.0, 129.9, 127.9, 127.4,
127.2, 126.4, 123.1, 122.5, 122.1, 61.5, 60.9, 32.4, 31.9, 13.9. ESIꢀHRMS: Calcd for C25H27N2O7S2
[M+H]+: 531.1254. Found: 531.1259.
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(±)-(E)-ethyl 2-(N-methylpyridine-2-sulfonamido)-3-(2-(3-oxobut-1-en-1-yl)phenyl)propanoate
[(±)-7]. Following the typical procedure, (±)ꢀ1 (52.3 mg, 0.15 mmol) reacted with 3ꢀbutenꢀ2ꢀone (24.3
ꢀL, 0.30 mmol) in the presence of Pd(OAc)2 (3.4 mg, 0.015 mmol), and 1ꢀfluoroꢀ2,4,6ꢀ
trimethylpyridinium triflate (130.2 mg, 0.45 mmol) in acetic acid (1 mL), to afford, after purification by
column chromatography (diethyl etherꢀhexane 50:50), product (±)ꢀ7 as yellow oil, yield: 26.5 mg (43%).
1H NMR (300 MHz, CDCl3): 8.62 (dt, J = 4.7, 1.4 Hz, 1H), 7.94 (d, J = 16.1 Hz, 1H), 7.87 – 7.81 (m,
2H), 7.61 – 7.55 (m, 1H), 7.44 (q, J = 4.6 Hz, 1H), 7.31 – 7.22 (m, 2H), 6.64 (d, J = 16.1 Hz, 1H), 4.90
(dd, J = 8.3, 6.9 Hz, 1H), 3.90 (q, J = 7.1 Hz, 2H), 3.40 (dd, J = 14.0, 8.3 Hz, 1H), 3.23 (dd, J = 14.0,
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6.9 Hz, 1H), 3.09 (s, 3H), 2.44 (s, 3H), 0.98 (t, J = 7.2 Hz, 3H). C{1H} NMR (75 MHz, CDCl3): δ
199.1, 169.6, 157.3, 149.9, 140.3, 137.9, 136.0, 134.1, 131.3, 130.2, 130.1, 127.9, 127.0, 126.6, 122.4,
61.3, 60.7, 33.7, 31.4, 27.4, 14.0. ESIꢀHRMS: Calcd for C21H24N2O5S [M+H]+: 417.1479. Found:
417.1510.
(±)-(E)-ethyl 2-(N-methylpyridine-2-sulfonamido)-3-(2-(3-oxoprop-1-en-1-yl)phenyl)propanoate
[(±)-8]. Following the typical procedure, (±)ꢀ1 (52.3 mg, 0.15 mmol) reacted with acrolein (20.1 ꢀL,
0.30 mmol) in the presence of Pd(OAc)2 (3.4 mg, 0.015 mmol), and 1ꢀfluoroꢀ2,4,6ꢀtrimethylpyridinium
triflate (130.2 mg, 0.45 mmol) in acetic acid (1 mL), to afford, after purification by column
chromatography (diethyl etherꢀhexane 50:50), product (±)ꢀ8 as yellow oil, yield: 15.3 mg (25%).
1H NMR (300 MHz, CDCl3): 9.77 (d, J = 7.7 Hz, 1H), 8.63 (d, J = 4.3 Hz, 1H), 8.05 (d, J = 15.7 Hz,
1H), 7.91 – 7.84 (m, 2H), 7.66 – 7.60 (m, 1H), 7.46 (td, J = 5.1, 3.0 Hz, 1H), 7.36 – 7.27 (m, 3H), 6.69
(dd, J = 15.7, 7.7 Hz, 1H), 4.90 (dd, J = 8.9, 6.1 Hz, 1H), 3.92 (qd, J = 7.1, 1.0 Hz, 2H), 3.43 (dd, J =
13.9, 8.9 Hz, 1H), 3.28 (dd, J = 13.9, 6.2 Hz, 1H), 3.08 (s, 3H), 0.98 (t, J = 7.1 Hz, 3H). 13C{1H} NMR
(75 MHz, CDCl3): δ 94.3, 169.5, 157.3, 149.9, 149.4, 137.9, 136.3, 133.5, 131.6, 131.0, 130.8, 128.0,
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127.2, 126.7, 122.5, 61.4, 60.8, 33.8, 31.4, 14.0. ESIꢀHRMS: Calcd for C20H23N2O5S [M+H]+:
403.1328. Found: 403.1322.
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2-(N-methylpyridine-2-sulfonamido)-3-(2-(2-(perfluorophenyl)vinyl)phenyl)-
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propanoate [(±)-9]. Following the typical procedure, (±)ꢀ1 (52.3 mg, 0.15 mmol) reacted with 2,3,4,5,6ꢀ
pentafluorostyrene (41.4 ꢀL, 0.30 mmol) in the presence of Pd(OAc)2 (3.4 mg, 0.015 mmol), and 1ꢀ
fluoroꢀ2,4,6ꢀtrimethylpyridinium triflate (130.2 mg, 0.45 mmol) in acetic acid (1 mL), to afford, after
purification by column chromatography (diethyl etherꢀhexane 50:50), product (±)ꢀ9 as yellow oil, yield:
45.0 mg (56%).
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1H NMR (300 MHz, CDCl3): 8.58 (s, 1H), 7.83 – 7.71 (m, 2H), 7.76 (d, J = 16.5 Hz, 1H), 7.56 (dd, J
= 6.9, 1.8 Hz, 1H), 7.44 – 7.37 (m, 1H), 7.29 – 7.20 (m, 3H), 6.86 (d, J = 16.5 Hz, 1H), 4.94 (dd, J =
8.5, 6.7 Hz, 1H), 3.96 (q, J = 7.1 Hz, 2H), 3.42 (dd, J = 14.3, 6.7 Hz, 1H), 3.11 (dd, J = 14.3, 6.7 Hz,
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1H), 3.11 (s, 3H), 1.06 (t, J = 7.1 Hz, 3H). C{1H} NMR (75 MHz, CDCl3): δ 169.8, 157.3, 149.6,
144.8 (q, JC-F = 252.12 Hz), 139.8 (q, JC-F = 252.12 Hz), 137.6, 137.6 (q, JC-F = 252.12 Hz), 136.0,
134.7, 134.5 (td, JC-F = 8.1, 2.4 Hz), 130.6, 128.8, 127.6, 126.3, 126.1, 121.9, 115.3 (d, JC-F = 3.2 Hz),
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112.43 (m), 61.2, 60.5, 33.2, 31.3, 13.8. F{1H} NMR: δ ꢀ142.55 (dd, JC-F = 21.2, 7.6 Hz, 2F), ꢀ156.30
(t, JC-F = 20.8 Hz, 1F), ꢀ162.94 (td, JC-F = 21.2, 7.6 Hz, 2F). ESIꢀHRMS: Calcd for C25H22F5N2O4S
[M+H]+: 541.1215. Found: 541.1251.
(±)-(E)-Ethyl 2-(N-methylpyridine-2-sulfonamido)-3-(2-(3-nitrostyryl)phenyl)propanoate [(±)-
10]. Following the typical procedure, (±)ꢀ1 (52.3 mg, 0.15 mmol) reacted with 3ꢀnitrostyrene (41.8 ꢀL,
0.30 mmol) in the presence of Pd(OAc)2 (3.4 mg, 0.015 mmol), and 1ꢀfluoroꢀ2,4,6ꢀtrimethylpyridinium
triflate (130.2 mg, 0.45 mmol) in acetic acid (1 mL), to afford, after purification by column
chromatography (diethyl etherꢀhexane 50:50), product (±)ꢀ10 as yellow oil, yield: 36.3 mg (49%).
1H NMR (300 MHz, CDCl3): 8.58 (dt, J = 4.7, 1.4 Hz, 1H), 8.38 (t, J = 2.1 Hz, 1H), 8.10 – 8.05 (m,
1H), 7.95 (dt, J = 8.0, 1.5 Hz, 1H), 7.84 – 7.80 (m, 2H), 7.71 (d, J = 16.0 Hz, 1H), 7.63 (d, J = 7.6 Hz,
1H), 7.49 (t, J = 7.9 Hz, 1H), 7.45 – 7.38 (m, 1H), 7.30 – 7.24 (m, 1H), 7.22 – 7.18 (m, 2H), 7.08 (d, J =
15.8 Hz, 1H), 5.00 (dd, J = 8.5, 6.7 Hz, 1H), 3.94 (q, J = 7.1 Hz, 2H), 3.40 (dd, J = 13.8, 8.5 Hz, 1H),
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3.28 (dd, J = 13.8, 6.7 Hz, 1H), 3.10 (s, 3H), 1.00 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3):
δ 169.8, 157.2, 149.8, 148.9, 139.3, 137.8, 136.0, 134.5, 132.6, 131.1, 129.6, 129.0, 128.7, 128.4, 127.8,
126.6, 126.2, 122.5, 122.2, 121.7, 61.2, 60.5, 34.0, 31.2, 14.0. ESIꢀHRMS: Calcd for C25H26N3O6S
[M+H]+: 496.1537. Found: 496.1541.
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2-(N-methylpyridine-2-sulfonamido)-3-(2-(3-(trifluoromethyl)styryl)phenyl)-
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propanoate [(±)-11]. Following the typical procedure, (±)ꢀ1 (52.3 mg, 0.15 mmol) reacted with 3ꢀ
(trifluoromethyl)styrene (44.5 ꢀL, 0.30 mmol) in the presence of Pd(OAc)2 (3.4 mg, 0.015 mmol), and
1ꢀfluoroꢀ2,4,6ꢀtrimethylpyridinium triflate (130.2 mg, 0.45 mmol) in acetic acid (1 mL), to afford, after
purification by column chromatography (diethyl etherꢀhexane 50:50), product (±)ꢀ11 as yellow oil,
yield: 28.7 mg (37%).
1H NMR (300 MHz, CDCl3): 8.56 (s, 1H), 7.86 – 7.73 (m, 4H), 7.62 (d, J = 15.6 Hz, 1H), 7.61 (d, J =
8.4 Hz, 1H), 7.52 – 7.48 (m, 1H), 7.48 – 7.43 (m, 1H), 7.43 – 7.35 (m, 1H), 7.31 – 7.23 (m, 1H), 7.21 –
7.16 (m, 2H), 7.05 (d, J = 16.1 Hz, 1H), 5.00 (dd, J = 8.3, 6.9 Hz, 1H), 3.93 (q, J = 7.1 Hz, 2H), 3.39
(dd, J = 13.9, 8.3 Hz, 1H), 3.26 (dd, J = 13.8, 6.8 Hz, 1H), 3.11 (s, 3H), 1.00 (t, J = 7.1 Hz, 3H).
13C{1H} NMR (75 MHz, CDCl3): δ 169.93, 157.30, 149.83, 138.29, 137.79), 136.38, 134.33, 131.09 (q,
JC-F = 32.24 Hz), 131.05, 129.99, 129.20, 128.14, 127.71, 127.52, 126.54, 126.17, 124.25 (q, JC-F = 3.8
Hz), 123.77 (q, JC-F = 3.77 Hz), 122.44, 61.23, 60.47, 33.93, 31.31, 13.97. The CF3 carbon was not
observed, in spite of the use of long accumulation trials. 19F{1H} NMR: δ ꢀ62.75. ESIꢀHRMS: Calcd for
C26H25F3N2O4S [M+H]+: 519.1560. Found: 519.1578.
(±)-(E)-Butyl
3-(2-(3-ethoxy-2-(N-methylpyridine-2-sulfonamido)-3-oxopropyl)-5-
methoxyphenyl)-acrylate [(±)-12]. Following the typical procedure, sulfonamide (±)ꢀXIX (56.8 mg,
0.15 mmol) reacted with butyl acrylate (43.0 ꢀL, 0.30 mmol) in the presence of Pd(OAc)2 (3.4 mg,
0.015 mmol), and 1ꢀfluoroꢀ2,4,6ꢀtrimethylpyridinium triflate (130.2 mg, 0.45 mmol) in acetic acid (1
mL), to afford, after purification by column chromatography (nꢀhexaneꢀEtOAc 80:20), product (±)ꢀ12 as
yellow oil, yield: 53.7 mg (71%).
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1H NMR (300 MHz, CDCl3): δ = 8.54 (d, J = 4.5 Hz, 1H), 7.90 (d, J = 15.6 Hz, 1H), 7.80ꢀ7.65 (m,
2H), 7.35 (m, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.94 (d, J = 2.6 Hz, 1H), 6.75 (dd, J = 2.6, 8.3 Hz, 1H), 6.26
(d, J = 15.6 Hz, 1H), 4.79 (dd, J = 2.8, 8.7 Hz, 1H), 4.14 (t, J = 6.6 Hz, 2H), 3.90 (dc, J = 1.0, 7.9 Hz,
2H), 3.73 (s, 3H), 3.25 (dd, J = 6.6, 14.1 Hz, 1H), 3.01 (m, 4H), 1.62 (m, 2H), 1.36 (m, 2H), 1.00 (t, J =
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7.1 Hz, 3H), 0.89 (t, J = 7.1 Hz, 3H). C{1H} NMR (75 MHz, CDCl3): δ 169.7, 166.7, 158.7, 157.5,
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149.7, 141.3, 137.6, 134.8, 131.8, 128.1, 126.2, 122.0, 120.8, 116.1, 111.5, 64.5, 61.2, 60.9, 55.3, 31.9,
31.4, 30.8, 19.2, 13.9, 13.7. ESIꢀHRMS: Calcd for C25H33N2O7S [M+H]+, 505.2003. Found 505.2009.
(±)-(E)-Butyl
3-(2-(3-ethoxy-2-(N-methylpyridine-2-sulfonamido)-3-oxopropyl)-5-
methylphenyl)-acrylate [(±)-13]. Following the typical procedure, sulfonamide (±)ꢀXX (54.5 mg, 0.15
mmol) reacted with butyl acrylate (43.0 ꢀL, 0.30 mmol) in the presence of Pd(OAc)2 (3.4 mg, 0.015
mmol), and 1ꢀfluoroꢀ2,4,6ꢀtrimethylpyridinium triflate (130.2 mg, 0.45 mmol) in acetic acid (1 mL), to
afford, after purification by column chromatography (nꢀhexaneꢀEtOAc 80:20), product (±)ꢀ13 as yellow
oil; yield: 31.3 mg (43%).
1H NMR (300 MHz, CDCl3): δ 8.61 (dt, J = 4.8, 1.5 Hz, 1H), 7.98 (d, J = 15.7 Hz, 1H), 7.85 – 7.75
(m, 2H), 7.42 (ddd, J = 6.7, 4.7, 2.1 Hz, 1H), 7.33 (d, J = 1.8 Hz, 1H), 7.13 (d, J = 7.8 Hz, 1H), 7.08
(dd, J = 7.8, 1.8 Hz, 1H), 6.34 (d, J = 15.7 Hz, 1H), 4.89 (dd, J = 8.8, 6.6 Hz, 1H), 4.21 (t, J = 6.7 Hz,
2H), 3.97 (qd, J = 7.1, 1.4 Hz, 2H), 3.35 (dd, J = 14.4, 6.6 Hz, 1H), 3.08 (s, 3H), 3.07 (dd, J = 14.4, 8.8
Hz, 1H), 2.32 (s, 3H), 1.73 – 1.64 (m, 2H), 1.48 – 1.40 (m, 2H), 1.07 (t, J = 7.1 Hz, 3H), 0.96 (t, J = 7.4
13
Hz, 3H). C{1H} NMR (75 MHz, CDCl3): δ 169.9, 167.0, 157.5, 149.8, 141.5, 137.7, 137.1, 133.6,
133.0, 131.0, 130.7, 127.5, 126.3, 122.1, 120.5, 64.6, 61.4, 60.9, 32.3, 31.5, 30.9, 21.2, 19.3, 14.0, 13.9.
ESIꢀHRMS: Calcd for C25H32N2NaO6S [M+Na]+: 511.1873. Found: 511.1867.
(±)-(E)-Butyl 3-(2-(3-ethoxy-2-(N-methylpyridine-2-sulfonamido)-3-oxopropyl)-5-fluorophenyl)-
acrylate [(±)-14]. Following the typical procedure, sulfonamide (±)ꢀXXI (55.0 mg, 0.15 mmol) reacted
with butyl acrylate (43.0 ꢀL, 0.30 mmol) in the presence of Pd(OAc)2 (3.4 mg, 0.015 mmol), and 1ꢀ
fluoroꢀ2,4,6ꢀtrimethylpyridinium triflate (130.2 mg, 0.45 mmol) in acetic acid (1 mL), to afford, after
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The Journal of Organic Chemistry
purification by column chromatography (nꢀhexaneꢀEtOAc 80:20), product (±)ꢀ14 as yellow oil; yield:
29.6 mg (40%).
1
2
3
4
5
6
7
8
9
1H NMR (300 MHz, CDCl3): δ 8.65 (d, J = 3.7 Hz, 1H), 7.98 (d, J = 15.8 Hz, 1H), 7.90ꢀ7.80 (m, 2H),
7.47 (m, 1H), 7.30ꢀ7.13 (m, 2H), 7.01 (m, 1H), 6.37 (d, J = 15.8 Hz, 1H), 4.91 (m, 1H), 4.25 (t, J = 6.8
Hz, 2H), 4.01 (m, 2H), 3.40 (dd, J = 6.4, 14.5 Hz, 1H), 3.16ꢀ3.10 (m, 4H), 1.73 (m, 2H), 1.48 (m, 2H),
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11
12
13
14
15
16
17
18
19
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26
27
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32
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34
35
36
37
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40
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43
44
45
46
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48
49
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52
53
54
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56
57
58
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60
13
1.11 (t, J = 7.2 Hz, 3H), 1.00 (t, J = 7.2 Hz, 3H). C{1H} NMR (75 MHz, CDCl3): δ 169.5, 166.4,
157.4, 149.8, 140.1 (2C), 137.7, 135.7 (d, JC-F = 7.3 Hz), 132.4 (d, JC-F = 7.3 Hz), 131.7, 126.3, 122.0,
121.9, 116.9 (d, JC-F = 22.0 Hz), 113.2 (d, JC-F = 22.6 Hz), 64.7, 61.4, 60.9, 32.0, 31.4, 30.7, 19.2, 13.9,
13.7. 19F{1H} NMR (282 MHz, CDCl3): δ ꢀ114.7. ESIꢀHRMS: Calcd for C24H30FN2O6S [M+H]+:
493.1803. Found: 493.1805.
(±)-(E)-Butyl 3-(5-chloro-2-(3-ethoxy-2-(N-methylpyridine-2-sulfonamido)-3-oxopropyl)phenyl)-
acrylate [(±)-15]. Following the typical procedure, sulfonamide (±)ꢀXXII (57.5 mg, 0.15 mmol) reacted
with butyl acrylate (43.0 ꢀL, 0.30 mmol) in the presence of Pd(OAc)2 (3.4 mg, 0.015 mmol), and 1ꢀ
fluoroꢀ2,4,6ꢀtrimethylpyridinium triflate (130.2 mg, 0.45 mmol) in acetic acid (1 mL), to afford, after
purification by column chromatography (nꢀhexaneꢀEtOAc 80:20), product (±)ꢀ15 as yellow oil; yield:
18.2 mg (24%). It should be noted that he difficulty in the complete chromatographic separation of the
products from the starting material and trace amount of unidentified byproducts resulted in low yields
upon isolation.
1H NMR (300 MHz, CDCl3): δ 8.60 (ddd, J = 4.7, 1.7, 0.9 Hz, 1H), 7.91 (d, J = 15.7 Hz, 1H), 7.82
(td, J = 7.7, 1.7 Hz, 1H), 7.76 (tt, J = 7.9, 1.0 Hz, 1H), 7.46 (d, J = 2.1 Hz, 1H), 7.44 (ddd, J = 7.6, 4.7,
1.2 Hz, 1H), 7.20 (dd, J = 8.3, 2.1 Hz, 1H), 7.17 – 7.15 (m, 1H), 6.34 (d, J = 15.7 Hz, 1H), 4.87 (dd, J =
9.0, 6.4 Hz, 1H), 4.21 (t, J = 6.7 Hz, 2H), 4.03 – 3.98 (m, 2H), 3.35 (dd, J = 14.5, 6.4 Hz, 1H), 3.08 (dd,
J = 14.5, 9.0 Hz, 1H), 3.07 (s, 3H), 1.71 – 1.65 (m, 2H), 1.46 – 1.40 (m, 2H), 1.09 (t, J = 7.1 Hz, 3H),
0.96 (t, J = 7.4 Hz, 3H). 13C{1H} NMR: δ 169.5, 166.5, 157.4, 149.9, 139.9, 137.8, 135.6, 134.4, 133.4,
132.1, 129.9, 126.8, 126.4, 122.1, 122.0, 64.7, 61.6, 60.8, 32.1, 31.5, 30.8, 19.3, 14.0, 13.8. ESIꢀHRMS:
Calcd for C24H30ClN2O6S [M+H]+: 509.1508. Found: 509.1499.
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