Photoredox-Enabled Synthesis of β-Substituted Pyrroles from Pyrrolidines

Article abstract of DOI:10.1021/acs.joc.0c00459

The merger of photoredox-initiated enamine-imine tautomerization and nucleophilic addition processes to access β-substituted pyrroles from pyrrolidines has been achieved. The significant advantage of this method is suppressing the Friedel-Crafts reaction,

Full text of DOI:10.1021/acs.joc.0c00459

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Article
Photoredox-Enabled Synthesis of #-Substituted Pyrroles from Pyrrolidines
Xiao-De An, Shuo Yang, Bin Qiu, Ting-Ting Yang, Xian-Jiang Li, and Jian Xiao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00459 • Publication Date (Web): 22 Jun 2020
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Photoredox-Enabled Synthesis of β-Substituted Pyrroles from
Pyrrolidines
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Xiao-De An,†, § Shuo Yang,†, § Bin Qiu,† Ting-Ting Yang,† Xian-Jiang Li, ┴ Jian Xiao*, †, ‡
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† College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao 266109, China
‡ School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China
┴Shandong Kangqiao Biotechnology Co. Ltd., Binzhou, 256500, China
Corresponding author: Jian Xiao
E-mail address: chemjianxiao@163.com
Graphic Abstract
Abstract: The merger of photoredox-initiated enamine-imine tautomerization and nucleophilic
addition processes to access -substituted pyrroles from pyrrolidines has been achieved. The
significant advantage of this method is suppressing the Friedel-Crafts reaction, which usually
occurs between N-aryl pyrrolidines and the highly electrophilic ketoesters. The good functional
group tolerance, high atom-economy and high regioselectivity as well as easy handling conditions
make it appealing alternative to synthesize -substituted pyrroles.
INTRODUCTION
The pyrrole ring represents not only an essential motif of natural products and biologically
important molecules,1 but also one kind of significant precursors for synthesis of pharmaceutical
molecules and functional materials.2 Meanwhile, the introduction of trifluoromethyl group into
pharmaceutical molecules would significantly improve their bio-receptor selectivity.3 As a
consequence, the synthesis of pyrrole derivatives containing trifluoromethyl group would open an
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access to the new drug discovery.
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The electrophilic substitution reaction provides the classic method towards various pyrrole
derivatives.4 However, due to the intrinsic α-reactivity of the five-membered heterocycles, the
electrophilic CH functionalization of pyrroles preferentially occurs at α-position, leading to
α-substituted pyrroles (Scheme 1a).5 On account of this, the development of novel strategies to
access -substituted pyrroles, which usually display special biological activities,6 has received
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significant attention.7
In recent years, visible-light promoted transformations has attracted special interest from
chemists.8 Among them, visible-light photoredox catalysis has emerged as a powerful tool for
functionalization of cyclic amines with high efficiency.9 Nevertheless, much attention has been
focused on the α-functionalization of cyclic amines via Mannich-type reaction of iminium, using
various nucleophiles as coupling partners (Scheme 1b).10 In sharp contrast, only one example was
reported to construct -substituted pyrroles via photoredox -functionalization of cyclic amines
(Scheme 1b).11 Mechanistically, the single electron oxidation rendered the in situ generation of
enamine intermediate, which was engaged in the subsequent radical addition and dehydrogenative
aromatization to furnish -substituted sulfonyl pyrroles. However, up to till now, there is no work
merging the photoredox catalysis with enamine-involved ionic reaction to synthesize -substituted
pyrroles. Theoretically, the -position of enamine could serve as a competent nucleophilic site in
ionic reaction.12 Inspired by our recent success on the redox-neutral CH functionalization of
cyclic amines,13 now we report the visible-light-promoted -CH functionalization and
aromatization of pyrrolidines with fluorinated ketoesters. This protocol provides a rapid access to
a variety of -substituted pyrroles with trifluoromethyl group from readily available pyrrolidine
precursors (Scheme 1b).
Scheme 1. Approaches towards Substituted Pyrrole Derivatives.
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RESULTS AND DISCUSSION
We first explored this protocol using the challenging N-aryl pyrrolidine 1a as the starting
material, which might undergo Friedel-Crafts reactions with electrophiles.14 Ethyl
trifluoropyruvate 2a was employed as an alkylating reagent and a range of photocatalysts (PC)
were evaluated at ambient temperature (see the Supporting Information). To our delight, with
Ir(ppy)2(dtbbpy)PF6 as a photocatalyst (PC) and DMSO as a solvent, the desired product 3a was
produced in 53% yield without any Friedel-Crafts product 3a detected (Table 1, entry 1). In sharp
contrast, only Friedel-Crafts product 3a was observed in 66% yield in the absence of
photocatalyst, indicating the essential of photoredox initiation in this transformation (Table 1,
entry 2). Unfortunately, the other solvents didn’t lead to a superior result and CH3CN afforded 3a
as the major product (Table 1, entries 3-7). In order to improve the yield, various bases were
introduced as additives to facilitate the enamine-imine tautomerization15 (Table 1, entries 8-12). To
our delight, when NaH2PO4 was added as an additive, the desired product was furnished in 72%
yield (Table 1, entry 10). And the yield could be improved to 78% after screening the dosages of
the base and 2a (Table 1, entries 13-16). Unfortunately, the next decreasing or increasing the
amount of 2a did not improve the yield (Table 1, entries 15-16). Consequently, the optimal
reaction condition was indicated as entry 14.
Table 1. Optimization of the Reaction Conditionsa
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yield of 3a
yield of 3a
(%)b
trace
66
entry
base
solvent
(%)b
1
2c
-
DMSO
DMSO
DMF
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-
trace
48
3
-
trace
trace
trace
trace
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4
-
1,4-dioxane
THF
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-
38
6
-
DME
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7
-
CH3CN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
<10
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KH2PO4
K2HPO4
NaH2PO4
Na2HPO4
NaHCO3
NaH2PO4
NaH2PO4
NaH2PO4
NaH2PO4
8
12
9
31
21
10
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12
13d
14e
15e, f
16e, g
72
<10
<10
19
63
38
75
<10
12
78
58
12
78
12
aReaction conditions: a solution of 1a (0.1 mmol), 2a (0.25 mmol), base (0.1 mmol) and Ir(ppy)2(dtbbpy)PF6
b
(0.001 mmol) was irradiated by blue LED strips in the solvent (1.0 mL) for 24 h under an air atmosphere. The
yield was determined by crude 1H NMR using dibromomethane as the internal standard. cWithout
Ir(ppy)2(dtbbpy)PF6. d1.5 equiv (0.15 mmol) NaH2PO4. 2.0 equiv (0.20 mmol) NaH2PO4. f2.0 equiv (0.20 mmol)
e
2a. g3.5 equiv (0.35 mmol) 2a.
With the optimized reaction conditions in hand, the synthetic potential with respect to the N-aryl
pyrrolidines was firstly evaluated (Table 2). Gratifyingly, either electron-donating or -withdrawing
substituents on the aryl ring were fully tolerable in this transformation, furnishing the desired
products in good yields. For instance, the alkyl (3b, 3c), phenyl (3d), halides (3e-g),
trifluoromethyl (3h), cyano (3i) and acetyl (3j) substituted substrates were all good reaction
partners to afford the corresponding products in 52-78% yields. Besides, the success of bulky
2,4,6-trimethylphenyl group (3k) indicated that the steric hindrance of the substituent did not
influence the productivity. Remarkably, this reaction exhibited excellent functional group
tolerance and a variety of functional groups survived, such as cyano (3i), acetyl (3j), formyl (3m)
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and double bond (3n) moieties, yielding the products in good yields. Particularly, both the acetyl
(3j) and formyl (3m) groups containing electrophilic sites were tolerable in this nucleophilic
addition process. These appealing results demonstrate the great practicability of this new protocol
and hold great potential for further application. Changing the chlorine from 4-position (3e) to
3-position (3l) showed positive influence on the reaction productivity, leading to product 3l in 84%
yield. Notably, when 2-methylpyrrolidine was subjected to the reaction, 2,4-disubstituted pyrrole
3p could also be obtained in 82% yield. A lower yield (64%) of 3a was obtained under the
catalysis of 2 mol % Ir-catalyst in 1.0 mmol scale.
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Table 2. Substrate Scope for the Synthesis of 3 a
aReaction conditions: a solution of 1 (0.2 mmol), 2a (0.5 mmol), NaH2PO4 (0.4 mmol) and Ir(ppy)2(dtbbpy)PF6
(0.002 mmol) in DMSO (2.0 mL) was irradiated by blue LED strips under an air atmosphere. The yields are
c
isolated yields after purification. bThe reaction was performed on a 1.0 mmol scale. The amount of 2a was 3.5
equiv (0.7 mmol).
To further explore the substrate scope, diethyl 2-oxomalonate 2b was also tested under the
standard reaction conditions (Table 3). Generally, an array of N-aryl pyrrolidines could engage in
this cascade -functionalization/aromatization with 2b as an alkylating agent. As expected, either
electron-donating or -withdrawing substituents, such as alkyl (4b), phenyl (4c), methoxy (4d),
halides (4e, 4f), trifluoromethyl (4g) groups on para-position of the N-phenyl moiety, could
tolerate in this reaction with good efficiencies (45-84% yield). The sterically hindered pyrrolidine
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with two methyl groups at the ortho-position delivered the corresponding product 4i in 66% yield.
Same as the above observations, substrate modified with ketone (4h), double bond (4k), ester (4l)
fragment still exhibited appealing efficiency in this transformation. Identically,
2-methylpyrrolidine afforded the pyrrole 4m in 80% yield. Interestingly, for reactions with diethyl
2-oxomalonate 2b, alcohol 5 was observed as a by-product, implying that the reduction of
ketoester occurred in this reaction. As a comparison, the failure of detecting alcohol of ethyl
trifluoropyruvate 2a might be ascribed to the lower boiling point of ethyl
3,3,3-trifluoro-2-hydroxypropanoate.16
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Table 3. Substrate Scope for the Synthesis of 4 a
aReaction conditions: a solution of 1 (0.2 mmol), 2b (0.7 mmol), NaH2PO4 (0.4 mmol) and Ir(ppy)2(dtbbpy)PF6
(0.002 mmol) in the DMSO (2.0 mL) was irradiated by blue LED strips under an air atmosphere. The yields are
isolated yields after purification.
To get a deep insight into this transformation, the mechanistic study was conducted using
diethyl 2-oxomalonate 2b as a reaction partner (Scheme 2a). When TEMPO was added to the
reaction system, this reaction failed to produce the desired product, pointing toward a radical
mechanism. In addition, the control experiments indicated that the iridium (III) complex
photocatalyst was essential for the initiation of this radical reaction (Table 1, entry 2). Therefore,
our previously reported hydride transfer pathway was excluded in this transformation.13b The
detection of by-product 5 suggested that ketoester 2b served as an oxidant in the dehydrogenation
of pyrrolidine,17 which also gave an explanation on the necessity of excess amount (2.5 - 3.5 eq)
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of ketoesters. This assumption was further supported by the production of 4a in 88% yield under
N2 atmosphere. However, this reaction could be quenched under a pure oxygen atmosphere.
Besides, treatment of 1-phenylpyrrolidine with 2a under the standard conditions failed to give the
Friedel-Crafts product (Scheme 2b). Therefore, the direct Friedel-Crafts alkylation of pyrrole was
excluded in the mechanism.
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Based on the above control experiments and our precedent work,13a a plausible mechanism is
proposed as shown in Scheme 2c. Visible-light excitation of the Ir(III) leads to an excited-state
species Ir(III)*, which oxidizes the redox-active amine I via single-electron transfer. The resultant
Ir(II) complex would subsequently reduce the ketoester to an anion radical intermediate III,18
which would trap a hydrogen atom from amine cation radical II to produce an iminium
intermediate
V.
Followed
by
the
enamine-imine
tautomerization/nucleophilic
addition/enamine-imine tautomerization sequence, the -substituted -unsaturated amine VIII
was furnished. Eventually, the atmospheric oxidation delivers the -substituted pyrroles, which
was supported by the mechanistic study (see the Supporting Information). Alternatively, the
aromatization could also be achieved by the photoredox dehydrogenation.
Scheme 2. Mechanistic Study
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CONCLUSION
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In conclusion, we have developed an efficient method for the synthesis of -substituted pyrroles
from pyrrolidines in one step through single electron oxidation/hydrogen atom
transfer/enamine-imine tautomerization/nucleophilic addition sequence. This work merges
photoredox catalysis-initated enamine-imine tautomerization and nucleophilic addition, and it
does not require strong oxidants and high temperature. Remarkably, the Friedel-Crafts reaction is
suppressed, which usually occurs between N-aryl pyrrolidines and highly electrophilic ketoesters.
Moreover, the good functional group tolerance, high regioselectivity and atom-economy as well as
easy handling conditions make it a more appealing alternative to construct -substituted pyrroles.
The resultant -substituted pyrroles containing trifluoromethyl group will find wide application in
medicinal chemistry community.
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EXPERIMENTAL SECTION
All commercially available reagents, unless otherwise indicated, were used without further
purification. All solvents were purified and dried according to standard methods prior to use.
Molecular sieves were activated at 550 °C for 6 h before use. Reactions were monitored by thin
layer chromatography (TLC) with 0.2 mm silica gel-coated HSGF 254 plates, visualized by UV
light at 254 or 365 nm. Products were isolated and purified by column chromatography on
200-300 mesh silica gel. 1H, 13C and 19F NMR spectra were recorded on a Bruker AMX 500 (500
MHz for 1H, 126 MHz for 13C and 471 MHz for 19F NMR) spectrometer at room temperature. The
chemical shifts (δ) were reported in ppm with respect to an internal standard, tetramethylsilane (0
ppm), and the solvent (CDCl3, 1H: δ = 7.26 ppm, 13C: δ = 77.16 ppm). Coupling constants (J) are
given in Hertz. Splitting patterns of apparent multiplets associated with an averaged coupling
constants were designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd
(doublet of doublets) and br (broadened). All 13C spectra were recorded with broadband proton
decoupling. HRMS were performed on a Waters XEVO QTOF mass spectrometer. Starting
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material pyrrolidines 1 were synthesized according to the literature.12b
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General Procedure: Synthesis of -Substituted Pyrroles.
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A 20-mL reaction tube was equipped with a rubber stopper and magnetic stir bar and was
charged with 1 (0.2 mmol), NaH2PO4 (0.4 mmol), and Ir(ppy)2(dtbbpy)PF6 (0.002 mmol). DMSO
(2.0 mL) and ketoesters 2 were then added with syringe. The mixture was then irradiated by blue
LED strips under an air atmosphere. After the reaction was completed (as judged by TLC
analysis), the mixture was poured into a separatory funnel containing 20 mL of saturated NaCl and
20 mL of EtOAc. The organic layers were dried over Na2SO4 and concentrated under reduced
pressure after filtration. The crude product was purified by flash chromatography on silica gel to
afford the desired product.
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Scale-up Experiment.
An 50-mL sealed tube equipped with and magnetic stir bar was charged with 1a (1 mmol),
NaH2PO4 (2.0 mmol), and Ir(ppy)2(dtbbpy)PF6 (0.02 mmol). DMSO (10.0 mL) and ketoester 2a
(2.5 mmol) were then added with syringe. The mixture was then irradiated by blue LED strips
under an air atmosphere. After the reaction was completed (as judged by TLC analysis), the
mixture was poured into a separatory funnel containing 50 mL of saturated NaCl and 50 mL of
EtOAc. The organic layers were dried over Na2SO4 and concentrated under reduced pressure after
filtration. The residue was directly purified by flash column chromatography on silica gel (eluent:
ethyl acetate/petroleum ether = 1:30) to afford 3a with 64% yield (198.9 mg).
ethyl 3,3,3-trifluoro-2-hydroxy-2-(1-phenyl-1H-pyrrol-3-yl)propanoate (3a): yellow oil, 48.7 mg,
78% yield, purification on silica gel (EtOAc : hexane = 1:20). 1H NMR (500 MHz, CDCl3) δ 7.36
(dd, J = 8.5, 7.2 Hz, 2H), 7.32 – 7.29 (m, 2H), 7.24 (t, J = 2.1 Hz, 1H), 7.22 – 7.19 (m, 1H), 6.97
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(t, J = 2.7 Hz, 1H), 6.45 (dt, J = 2.1, 1.0 Hz, 1H), 4.41 – 4.28 (m, 3H), 4.19 (s, 1H), 1.32 (t, J = 7.2
Hz, 4H). 19F NMR (376 MHz, CDCl3) δ -78.05. 13C{1H} NMR (126 MHz, CDCl3) δ 169.4, 140.2,
129.6, 126.2, 123.1 (q, J = 285.6 Hz), 120.7, 119.9, 119.0, 118.7, 109.7, 75.8 (q, J = 31.7 Hz),
64.0, 14.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for C15H15F3NO3: 314.0999; found: 314.0997.
ethyl 3,3,3-trifluoro-2-hydroxy-2-(1-(4-isopropylphenyl)-1H-pyrrol-3-yl)propanoate (3b): yellow
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1
oil, 54.6 mg, 77% yield, purification on silica gel (EtOAc : hexane = 1:20). H NMR (500 MHz,
CDCl3) δ 7.30-7.25 (m, 1H), 7.00 (t, J = 2.7 Hz, 1H), 6.50 (t, J = 2.2 Hz, 1H), 4.49 – 4.33 (m, 2H),
4.27 (s, 1H), 2.97-2.89 (m, 1H), 1.38 (t, J = 7.1 Hz, 3H), 1.26 (d, J = 7.0 Hz, 6H). 19F NMR (471
MHz, CDCl3) δ -78.03. 13C{1H} NMR (126 MHz, CDCl3) δ 169.5, 147.0, 138.2, 127.5, 124.3 (q,
J = 285.5 Hz), 120.8, 119.9, 119.1, 118.3, 109.3, 75.8 (q, J = 31.3 Hz), 64.0, 33.6, 24.0, 13.9.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for C18H21F3NO3: 356.1468; found: 356.1467.
ethyl 2-(1-(4-(tert-butyl)phenyl)-1H-pyrrol-3-yl)-3,3,3-trifluoro-2-hydroxypropanoate (3c):
yellow oil, 57.5 mg, 78%, purification on silica gel (EtOAc : hexane = 1:30). 1H NMR (500 MHz,
CDCl3) δ 7.35 (d, J = 8.6 Hz, 2H), 7.25 – 7.18 (m, 3H), 6.92 (t, J = 2.7 Hz, 1H), 6.42 (t, J = 2.1
Hz, 1H), 4.42 – 4.26 (m, 2H), 4.19 (s, 1H), 1.30 (t, J = 7.1 Hz, 3H), 1.26 (s, 9H). 19F NMR (471
MHz, CDCl3) δ -78.01. 13C{1H} NMR (126 MHz, CDCl3) δ 169.5, 149.4, 137.8, 126.5, 123.2 (q,
J = 285.5 Hz), 120.4, 119.9, 119.1, 118.4, 109.4, 75.8 (q, J = 31.2 Hz), 64.0, 34.5, 31.4, 14.0.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for C19H23F3NO3: 370.1625; found: 370.1624.
ethyl 2-(1-([1,1'-biphenyl]-4-yl)-1H-pyrrol-3-yl)-3,3,3-trifluoro-2-hydroxypropanoate (3d):
yellow oil, 45.2 mg, 58% yield，purification on silica gel (EtOAc : hexane = 1:20). 1H NMR (500
MHz, CDCl3) δ 7.65 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 7.4 Hz, 2H), 7.49 – 7.42 (m, 4H), 7.40 –
7.32 (m, 2H), 7.08 (t, J = 2.8 Hz, 1H), 6.55 (t, J = 2.2 Hz, 1H), 4.49 – 4.36 (m, 2H), 4.28 (s, 1H),
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1.40 (t, J = 7.1 Hz, 3H). 19F NMR (471 MHz, CDCl3) δ -78.03. 13C{1H} NMR (126 MHz, CDCl3)
δ 169.4, 140.0, 139.4, 139.2, 128.9, 128.3, 127.5, 126.7, 123.2 (q, J = 285.5 Hz), 120.9, 119.8,
119.0, 118.8, 109.8, 75.8 (q, J = 31.1 Hz), 64.1, 14.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for
C21H19F3NO3: 390.1312; found: 390.1310.
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ethyl 2-(1-(4-chlorophenyl)-1H-pyrrol-3-yl)-3,3,3-trifluoro-2-hydroxypropanoate (3e): yellow
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oil, 41.3 mg, 60% yield, purification on silica gel (EtOAc : hexane = 1:20). H NMR (500 MHz,
CDCl3) δ 7.40 (d, J = 8.7 Hz, 2H), 7.31 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 3.3 Hz, 1H), 6.99 (t, J =
2.8 Hz, 1H), 6.53 (t, J = 2.2 Hz, 1H), 4.53 – 4.33 (m, 2H), 4.27 (s, 1H), 1.38 (t, J = 7.1 Hz, 3H).
19F NMR (471 MHz, CDCl3) δ -78.09. 13C{1H} NMR (126 MHz, CDCl3) δ 169.3, 138.8, 131.8,
129.7, 123.1 (q, J = 285.3 Hz), 121.8, 119.8, 119.1, 119.0, 110.1, 75.7 (q, J = 31.4 Hz), 64.1, 14.0.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for C15H14ClF3NO3: 348.0609; found: 348.0610.
ethyl 2-(1-(4-bromophenyl)-1H-pyrrol-3-yl)-3,3,3-trifluoro-2-hydroxypropanoate (3f): yellow oil,
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47.3 mg, 60% yield, purification on silica gel (EtOAc : hexane = 1:25). H NMR (500 MHz,
CDCl3) δ 7.54 (d, J = 8.8 Hz, 2H), 7.28-7.25 (m, 3H), 6.99 (t, J = 2.7 Hz, 1H), 6.53 (t, J = 2.2 Hz,
1H), 4.53 – 4.33 (m, 2H), 4.29 (s, 1H), 1.38 (t, J = 7.1 Hz, 3H). 19F NMR (471 MHz, CDCl3) δ
-78.07. 13C{1H} NMR (126 MHz, CDCl3) δ 169.3, 139.2, 132.7, 123.1 (q, J = 285.3 Hz), 122.1,
119.8, 119.4, 119.2, 118.9, 110.1, 75.7 (q, J = 31.2 Hz), 64.2, 14.0. HRMS (ESI-TOF) m/z:
[M+H]+ Calcd. for C15H14BrF3NO3: 392.0104; found: 392.0109.
ethyl 3,3,3-trifluoro-2-hydroxy-2-(1-(4-iodophenyl)-1H-pyrrol-3-yl)propanoate (3g): yellow oil,
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53.2 mg, 61% yield, purification on silica gel (EtOAc : hexane = 1:30). H NMR (500 MHz,
CDCl3) δ 7.73 (d, J = 8.7 Hz, 2H), 7.27 (t, J = 2.1 Hz, 1H), 7.13 (d, J = 8.7 Hz, 2H), 6.99 (t, J =
2.7 Hz, 1H), 6.53 (t, J = 2.2 Hz, 1H), 4.50 – 4.33 (m, 2H), 4.29 (s, 1H), 1.38 (t, J = 7.1 Hz, 3H).
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19F NMR (471 MHz, CDCl3) δ -78.05. 13C{1H} NMR (126 MHz, CDCl3) δ 169.3, 139.9, 138.6,
123.1 (q, J = 285.3 Hz), 122.3, 119.7, 119.2, 118.8, 110.2, 90.2, 75.7 (q, J = 31.3 Hz), 64.2, 14.0.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for C15H14F3INO3: 439.9965; found: 439.9967.
ethyl 3,3,3-trifluoro-2-hydroxy-2-(1-(4-(trifluoromethyl)phenyl)-1H-pyrrol-3-yl)propanoate (3h):
yellow oil, 42.8 mg, 56% yield, purification on silica gel (EtOAc : hexane = 1:20). 1H NMR (500
MHz, CDCl3) δ 7.69 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.36 (t, J = 2.1 Hz, 1H), 7.09 (t,
J = 2.8 Hz, 1H), 6.58 (t, J = 2.2 Hz, 1H), 4.48 – 4.37 (m, 2H), 4.32 (d, J = 6.6 Hz, 1H), 1.39 (t, J =
7.1 Hz, 3H). 19F NMR (471 MHz, CDCl3) δ -62.32, -78.07. 13C{1H} NMR (126 MHz, CDCl3) δ
169.2, 142.7, 128.2 (q, J = 33.0 Hz), 127.0 (q, J = 3.7 Hz), 123.9 (q, J = 277.2 Hz), 123.1 (q, J =
285.3 Hz), 120.3, 119.8, 119.7, 118.9, 110.7, 75.7 (q, J = 31.3 Hz), 64.2, 14.0. HRMS (ESI-TOF)
m/z: [M+H]+ Calcd. for C16H14F6NO3: 382.0872; found: 382.0876.
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ethyl 2-(1-(4-cyanophenyl)-1H-pyrrol-3-yl)-3,3,3-trifluoro-2-hydroxypropanoate (3i): yellow oil,
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41.7 mg, 62% yield, purification on silica gel (EtOAc : hexane = 1:15). H NMR (500 MHz,
CDCl3) δ 7.73 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H), 7.38 (s, 1H), 7.10 (t, J = 2.8 Hz, 1H),
6.59 (s, 1H), 4.50 – 4.36 (m, 2H), 4.32 (s, 1H), 1.39 (t, J = 7.2 Hz, 3H). 19F NMR (471 MHz,
CDCl3) δ -78.10. 13C{1H} NMR (126 MHz, CDCl3) δ 169.0, 143.1, 133.9, 123.0 (q, J = 285.6 Hz),
120.4, 120.3, 119.5, 118.7, 118.3, 111.3, 109.5, 75.6 (q, J = 31.4 Hz), 64.3, 14.0. HRMS
(ESI-TOF) m/z: [M+H]+ Calcd. for C16H14F3N2O3: 339.0951; found: 339.0954.
ethyl 2-(1-(4-acetylphenyl)-1H-pyrrol-3-yl)-3,3,3-trifluoro-2-hydroxypropanoate (3j): yellow oil,
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36.7 mg, 52% yield, purification on silica gel (EtOAc : hexane = 1:10). H NMR (500 MHz,
CDCl3) δ 8.04 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 7.40 (s, 1H), 7.13 (s, 1H), 6.59 (s, 1H),
4.51 – 4.36 (m, 2H), 4.33 (s, 1H), 2.62 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). 19F NMR (471 MHz,
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CDCl3) δ -78.07. 13C{1H} NMR (126 MHz, CDCl3) δ 196.7, 169.2, 143.5, 134.6, 130.2, 123.1 (q,
J = 285.7 Hz), 119.9, 119.6, 118.8, 110.8, 75.7 (q, J = 31.1 Hz), 64.2, 26.6, 14.0. HRMS
(ESI-TOF) m/z: [M+H]+ Calcd. for C17H17F3NO4: 356.1104; found: 356.1109.
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ethyl 3,3,3-trifluoro-2-hydroxy-2-(1-mesityl-1H-pyrrol-3-yl)propanoate (3k): yellow oil, 48.9 mg,
68% yield, purification on silica gel (EtOAc : hexane = 1:30). 1H NMR (500 MHz, CDCl3) δ 6.93
(s, 2H), 6.81 (t, J = 2.0 Hz, 1H), 6.54 (t, J = 2.6 Hz, 1H), 6.48 (t, J = 2.2 Hz, 1H), 4.48 – 4.35 (m,
2H), 4.22 (s, 1H), 2.32 (s, 3H), 1.97 (d, J = 3.7 Hz, 6H), 1.35 (t, J = 7.1 Hz, 3H). 19F NMR (471
MHz, CDCl3) δ -78.29. 13C{1H} NMR (126 MHz, CDCl3) δ 169.7, 138.1, 136.9, 135.7, 135.7,
128.7, 123.3 (q, J = 285.6 Hz), 122.0, 121.2, 116.9, 107.9, 75.9 (q, J = 31.1 Hz), 63.8, 21.0, 17.2,
17.2, 13.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for C18H21F3NO3: 356.1468; found: 356.1465.
ethyl 2-(1-(3-chlorophenyl)-1H-pyrrol-3-yl)-3,3,3-trifluoro-2-hydroxypropanoate (3l): yellow oil,
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58.0 mg, 84% yield, purification on silica gel (EtOAc : hexane = 1:15). H NMR (500 MHz,
CDCl3) δ 7.41 – 7.37 (m, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.30 – 7.24 (m, 3H), 7.02 (t, J = 2.8 Hz,
1H), 6.54 (t, J = 2.2 Hz, 1H), 4.48 – 4.36 (m, 2H), 4.29 (s, 1H), 1.39 (t, J = 7.1 Hz, 3H). 19F NMR
(471 MHz, CDCl3) δ -78.08. 13C{1H} NMR (126 MHz, CDCl3) δ 169.3, 141.2, 135.3, 130.7,
126.3, 123.1 (d, J = 285.5 Hz), 120.8, 119.8, 119.3, 118.9, 118.6, 110.2, 75.7 (q, J = 31.5 Hz),
64.2, 14.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for C15H14ClF3NO3: 348.0609; found:
348.0613.
ethyl 3,3,3-trifluoro-2-(1-(2-formylphenyl)-1H-pyrrol-3-yl)-2-hydroxypropanoate (3m): yellow
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oil, 64.8 mg, 80% yield, purification on silica gel (EtOAc : hexane = 1:25). H NMR (500 MHz,
CDCl3) δ 9.80 (d, J = 0.8 Hz, 1H), 8.01 (dd, J = 7.8, 1.6 Hz, 1H), 7.71 – 7.66 (m, 1H), 7.55 – 7.49
(m, 1H), 7.45 (dd, J = 8.0, 1.2 Hz, 1H), 7.17 (t, J = 2.0 Hz, 1H), 6.89 (t, J = 2.7 Hz, 1H), 6.59 (t, J
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= 2.2 Hz, 1H), 4.53 – 4.34 (m, 2H), 4.29 (s, 1H), 1.39 (t, J = 7.1 Hz, 3H). 19F NMR (471 MHz,
CDCl3) δ -78.19. 13C{1H} NMR (126 MHz, CDCl3) δ 189.5, 169.3, 143.2, 134.8, 130.8, 128.4,
128.2, 126.6, 124.1, 123.1 (q, J = 285.3 Hz), 123.1, 119.1, 109.9, 75.6 (q, J = 31.3 Hz), 64.2, 14.0.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for C16H15F3NO4: 342.0948; found: 342.0949.
ethyl 3,3,3-trifluoro-2-hydroxy-2-(1-(2-vinylphenyl)-1H-pyrrol-3-yl)propanoate (3n): yellow oil,
41.4 mg, 61% yield, purification on silica gel (EtOAc : hexane = 1:20). 1H NMR (500 MHz,
CDCl3) δ 7.64 (dd, J = 7.6, 1.7 Hz, 1H), 7.35 (dtd, J = 17.9, 7.4, 1.6 Hz, 2H), 7.28-7.25 (m, 1H),
7.03 (t, J = 2.1 Hz, 1H), 6.77 (t, J = 2.6 Hz, 1H), 6.54 – 6.43 (m, 2H), 5.71 (dd, J = 17.5, 1.1 Hz,
1H), 5.28 (dd, J = 11.0, 1.1 Hz, 1H), 4.50 – 4.34 (m, 2H), 4.23 (s, 1H), 1.38 (t, J = 7.1 Hz, 3H).
19F NMR (471 MHz, CDCl3) δ -78.11. 13C{1H} NMR (126 MHz, CDCl3) δ 169.5, 138.5, 133.5,
132.2, 128.4, 127.9, 126.5, 126.4, 123.2 (q, J = 285.3 Hz), 123.1, 122.2, 117.5, 116.5, 108.4, 75.6
(q, J = 31.3 Hz), 64.0, 13.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for C17H17F3NO3: 340.1155;
found: 340.1158.
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ethyl
2-chloro-4-(3-(3-ethoxy-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)-1H-pyrrol-1-yl)benzoate
(3o): yellow oil, 59.0 mg, 80% yield, purification on silica gel (EtOAc : hexane = 1:20). 1H NMR
(500 MHz, CDCl3) δ 7.90 (d, J = 8.5 Hz, 1H), 7.42 (d, J = 2.3 Hz, 1H), 7.28 (t, J = 2.0 Hz, 1H),
7.26 (dd, J = 8.5, 2.3 Hz, 1H), 7.01 (t, J = 2.8 Hz, 1H), 6.51 (t, J = 2.3 Hz, 1H), 4.41 – 4.33 (m,
2H), 4.23 (s, 1H), 3.88 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H). 19F NMR (471 MHz, CDCl3) δ -78.10.
13C{1H} NMR (126 MHz, CDCl3) δ 169.1, 165.2, 143.0, 135.7, 133.3, 126.7, 123.1 (q, J = 285.3
Hz), 122.2, 120.3, 119.6, 118.7, 117.6, 111.1, 75.6 (q, J = 31.1 Hz), 64.3, 52.5, 14.0. HRMS
(ESI-TOF) m/z: [M+Na]+ Calcd. for C18H17ClF3NNaO5: 442.0640; found: 442.0634.
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ethyl 3,3,3-trifluoro-2-hydroxy-2-(5-methyl-1-phenyl-1H-pyrrol-3-yl)propanoate (3p): yellow oil,
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53.8 mg, 82% yield, purification on silica gel (EtOAc : hexane = 1:25). H NMR (500 MHz,
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CDCl3) δ 7.46-7.41 (m, 2H), 7.38 – 7.33 (m, 1H), 7.30 – 7.26 (m, 2H), 6.96 (d, J = 2.0 Hz, 1H),
6.21 (s, 1H), 4.48-4.32 (m, 2H), 4.20 (s, 1H), 2.17 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H). 19F NMR (471
MHz, CDCl3) δ -77.87. 13C{1H} NMR (126 MHz, CDCl3) δ 169.6, 139.8, 129.7, 129.1, 127.3,
125.8, 123.3 (q, J = 285.4 Hz), 120.8, 116.3, 107.3, 75.8 (q, J = 31.2 Hz), 63.9, 14.0, 12.9. HRMS
(ESI-TOF) m/z: [M+H]+ Calcd. for C16H17F3NO3: 328.1155; found: 328.1161.
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diethyl 2-hydroxy-2-(1-phenyl-1H-pyrrol-3-yl)malonate (4a): yellow oil, 53.3 mg, 84% yield,
purification on silica gel (EtOAc : hexane = 1:20). 1H NMR (500 MHz, CDCl3) δ 7.44 – 7.35 (m,
5H), 7.31 (t, J = 2.1 Hz, 1H), 7.24 (t, J = 7.2 Hz, 1H), 7.04 (t, J = 2.7 Hz, 1H), 6.49 (t, J = 2.3 Hz,
1H), 4.39 – 4.26 (m, 5H), 4.18 (s, 1H), 1.32 (t, J = 7.1 Hz, 7H). 13C{1H} NMR (126 MHz, CDCl3)
δ 170.1, 140.5, 129.5, 125.9, 121.8, 120.5, 119.5, 118.4, 110.0, 90.0, 62.8, 14.0. HRMS (ESI-TOF)
m/z: [M+H]+ Calcd. for C17H20NO5: 318.1336; found: 318.1339.
diethyl 2-hydroxy-2-(1-(4-isopropylphenyl)-1H-pyrrol-3-yl)malonate (4b): yellow oil, 45.2 mg,
63% yield, purification on silica gel (EtOAc : hexane = 1:20). 1H NMR (500 MHz, CDCl3) δ 7.29
(d, J = 8.6 Hz, 2H), 7.28 – 7.23 (m, 3H), 7.00 (t, J = 2.7 Hz, 1H), 6.47 (dd, J = 3.0, 1.7 Hz, 1H),
4.36 – 4.27 (m, 4H), 4.18 (s, 1H), 2.93 (p, J = 6.9 Hz, 1H), 1.32 (t, J = 7.1 Hz, 6H), 1.26 (d, J =
7.0 Hz, 6H). 13C{1H} NMR (126 MHz, CDCl3) δ 170.2, 146.6, 138.4, 127.4, 121.4, 120.6, 119.5,
118.5, 109.7, 90.0, 62.8, 33.6, 24.0, 14.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for C20H26NO5:
360.1805; found: 360.1809.
diethyl 2-(1-([1,1'-biphenyl]-4-yl)-1H-pyrrol-3-yl)-2-hydroxymalonate (4c): yellow oil, 63.2 mg,
80% yield, purification on silica gel (DCM). 1H NMR (500 MHz, CDCl3) δ 7.65 – 7.61 (m, 2H),
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7.61 – 7.57 (m, 2H), 7.48 – 7.42 (m, 4H), 7.38 – 7.33 (m, 2H), 7.08 (t, J = 2.7 Hz, 1H), 6.52 (dd, J
= 3.0, 1.7 Hz, 1H), 4.39 – 4.26 (m, 4H), 4.21 (s, 1H), 1.33 (t, J = 7.1 Hz, 6H). 13C{1H} NMR (126
MHz, CDCl3) δ 170.1, 140.1, 139.6, 138.8, 128.9, 128.2, 127.4, 126.9, 121.9, 120.7, 119.4, 118.3,
110.2, 62.8, 14.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for C23H24NO5: 394.1649; found:
394.1653.
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diethyl 2-hydroxy-2-(1-(4-methoxyphenyl)-1H-pyrrol-3-yl)malonate (4d): yellow oil, 37.4 mg,
55% yield, purification on silica gel (DCM). 1H NMR (500 MHz, CDCl3) δ 7.31 – 7.27 (m, 2H),
7.21 (dd, J = 2.4, 1.7 Hz, 1H), 6.96 – 6.90 (m, 3H), 6.46 (dd, J = 2.9, 1.7 Hz, 1H), 4.41 – 4.21 (m,
4H), 4.16 (s, 1H), 3.83 (s, 3H), 1.32 (t, J = 7.1 Hz, 6H). 13C{1H} NMR (126 MHz, CDCl3) δ 170.2,
157.8, 134.2, 122.2, 121.2, 119.8, 118.7, 114.6, 109.5, 62.8, 55.6, 14.0. HRMS (ESI-TOF) m/z:
[M+H]+ Calcd. for C18H22NO6: 348.1442; found: 348.1442.
diethyl 2-(1-(4-fluorophenyl)-1H-pyrrol-3-yl)-2-hydroxymalonate (4e): yellow oil, 57.0 mg, 84%
yield, purification on silica gel (EtOAc : hexane = 1:15). 1H NMR (500 MHz, CDCl3) δ 7.36 –
7.30 (m, 2H), 7.24 (t, J = 2.1 Hz, 1H), 7.10 (t, J = 8.5 Hz, 2H), 6.96 (t, J = 2.7 Hz, 1H), 6.52 –
6.46 (m, 1H), 4.39 – 4.27 (m, 4H), 4.20 (s, 1H), 1.32 (t, J = 7.1 Hz, 6H). 13C{1H} NMR (126 MHz,
CDCl3) δ 170.1, 160.7 (d, J = 245.1 Hz), 136.8 (d, J = 2.9 Hz), 122.3 (d, J = 8.2 Hz), 121.9, 119.7,
118.6, 116.3 (d, J = 23.0 Hz), 110.1, 62.8, 14.0. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd. for
C17H18FNNaO5: 358.1061; found: 358.1061.
diethyl 2-hydroxy-2-(1-(4-iodophenyl)-1H-pyrrol-3-yl)malonate (4f): yellow oil, 40.0 mg, 45%
yield, purification on silica gel (DCM : hexane = 1:1). 1H NMR (500 MHz, CDCl3) δ 7.71 (d, J =
8.4 Hz, 2H), 7.27 (t, J = 2.0 Hz, 1H), 7.13 (d, J = 8.6 Hz, 2H), 7.00 (t, J = 2.7 Hz, 1H), 6.50 (s,
2H), 4.45 – 4.25 (m, 4H), 4.19 (s, 1H), 1.32 (t, J = 7.1 Hz, 6H). 13C{1H} NMR (126 MHz, CDCl3)
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δ 170.0, 140.1, 138.5, 122.3, 122.1, 119.2, 118.1, 110.6, 89.7, 62.9, 14.0. HRMS (ESI-TOF) m/z:
[M+H]+ Calcd. for C17H19INO5: 444.0302; found: 444.0308.
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diethyl 2-hydroxy-2-(1-(4-(trifluoromethyl)phenyl)-1H-pyrrol-3-yl)malonate (4g): yellow oil,
49.6 mg, 64% yield, purification on silica gel (DCM). 1H NMR (500 MHz, CDCl3) δ 7.68 (d, J =
8.1 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 7.37 (t, J = 2.4 Hz, 1H), 7.09 (t, J = 3.0, 1H), 6.55 (dd, J =
3.1, 1.7 Hz, 1H), 4.41 – 4.26 (m, 4H), 4.21 (s, 1H), 1.33 (t, J = 7.1 Hz, 6H). 13C{1H} NMR (126
MHz, CDCl3) δ 169.9, 142.9, 127.7 (q, J = 32.8 Hz), 126.9 (q, J = 3.9 Hz), 123.9 (q, J = 270.8 Hz),
122.9, 120.0, 119.3, 118.1, 111.1, 62.9, 14.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for
C18H19F3NO5: 386.1210; found: 386.1216.
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diethyl 2-(1-(4-acetylphenyl)-1H-pyrrol-3-yl)-2-hydroxymalonate (4h): yellow oil, 36.3 mg, 51%
yield, purification on silica gel (EtOAc : hexane = 1:5). 1H NMR (500 MHz, CDCl3) δ 8.02 (d, J =
8.7 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 7.40 (t, J = 2.4, 1H), 7.12 (t, J = 3.1 Hz, 1H), 6.55 (dd, J =
3.1, 1.7 Hz, 1H), 4.39 – 4.27 (m, 4H), 4.21 (s, 1H), 2.61 (s, 3H), 1.33 (t, J = 7.1 Hz, 6H). 13C{1H}
NMR (126 MHz, CDCl3) δ 196.8, 169.9, 143.7, 134.2, 130.2, 123.0, 119.4, 119.2, 118.0, 111.2,
62.9, 26.6, 14.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for C19H22NO6: 360.1442; found:
360.1447.
diethyl 2-hydroxy-2-(1-mesityl-1H-pyrrol-3-yl)malonate (4i): yellow oil, 47.8 mg, 66% yield,
purification on silica gel (DCM). 1H NMR (500 MHz, CDCl3) δ 6.85 (s, 2H), 6.72 (t, J = 2.0 Hz,
1H), 6.45 (t, J = 2.5 Hz, 1H), 6.37 (dd, J = 2.8, 1.7 Hz, 1H), 4.23 (q, J = 7.1 Hz, 4H), 4.05 (s, 1H),
2.25 (s, 3H), 1.92 (s, 6H), 1.22 (t, J = 7.1 Hz, 7H). 13C{1H} NMR (126 MHz, CDCl3) δ 170.4,
137.9, 137.1, 135.8, 128.6, 121.6, 120.8, 120.0, 107.9, 62.5, 21.0, 17.3, 14.0. HRMS (ESI-TOF)
m/z: [M+H]+ Calcd. for C20H26NO5: 360.1805; found: 360.1808.
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diethyl 2-(1-(3-chlorophenyl)-1H-pyrrol-3-yl)-2-hydroxymalonate (4j): yellow oil, 49.7 mg, 71%
yield, purification on silica gel (DCM) 1H NMR (500 MHz, CDCl3) δ 7.38 (t, J = 2.1 Hz, 1H),
7.34 (t, J = 8.0 Hz, 1H), 7.30 (t, J = 2.0 Hz, 1H), 7.28 – 7.26 (m, 1H), 7.24 – 7.19 (m, 1H), 7.02 (t,
J = 2.8 Hz, 1H), 6.51 (s, 1H), 4.40 – 4.25 (m, 4H), 4.19 (s, 1H), 1.32 (t, J = 7.1 Hz, 6H). 13C{1H}
NMR (126 MHz, CDCl3) δ 169.9, 141.4, 135.2, 130.6, 125.8, 122.4, 120.6, 119.3, 118.4, 118.2,
110.6, 62.9, 14.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for C17H19ClNO5: 352.0946; found:
352.0946.
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diethyl 2-hydroxy-2-(1-(2-vinylphenyl)-1H-pyrrol-3-yl)malonate (4k): yellow oil, 44.0 mg, 65%
1
yield, purification on silica gel (DCM). H NMR (500 MHz, CDCl3) δ 7.63 (dd, J = 7.3, 1.9 Hz,
1H), 7.37 – 7.29 (m, 2H), 7.29 – 7.27 (m, 1H), 7.03 (t, J = 2.3, 1H), 6.76 (t, J = 2.9, 1H), 6.55 (dd,
J = 17.5, 11.0 Hz, 1H), 6.46 (dd, J = 2.9, 1.7 Hz, 1H), 5.70 (dd, J = 17.6, 1.2 Hz, 1H), 5.27 (dd, J
= 11.0, 1.2 Hz, 1H), 4.41 – 4.25 (m, 4H), 4.15 (s, 1H), 1.32 (t, J = 7.1 Hz, 6H). 13C{1H} NMR
(126 MHz, CDCl3) δ 170.2, 138.8, 133.4, 132.5, 128.3, 127.6, 126.5, 126.4, 122.8, 121.7, 120.6,
116.2, 108.6, 62.7, 14.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for C19H22NO5: 344.1492; found:
344.1497.
diethyl 2-(1-(3-chloro-4-(ethoxycarbonyl)phenyl)-1H-pyrrol-3-yl)-2-hydroxymalonate (4l):
1
yellow oil, 52.0 mg, 64% yield, purification on silica gel (DCM). H NMR (500 MHz, CDCl3) δ
7.95 (d, J = 8.6 Hz, 1H), 7.48 (d, J = 2.3 Hz, 1H), 7.36 (dd, J = 2.4, 1.7 Hz, 1H), 7.32 (dd, J = 8.6,
2.3 Hz, 1H), 7.08 (t, J = 3.1, 1H), 6.55 (dd, J = 3.1, 1.7 Hz, 1H), 4.40 – 4.24 (m, 4H), 4.21 (s, 1H),
3.94 (s, 3H), 1.32 (t, J = 7.1 Hz, 6H). 13C{1H} NMR (126 MHz, CDCl3) δ 169.8, 165.2, 143.2,
135.7, 133.2, 126.2, 123.3, 121.9, 119.1, 118.0, 117.4, 111.6, 63.0, 52.5, 14.0. HRMS (ESI-TOF)
m/z: [M+H]+ Calcd. for C20H22ClNNaO7: 446.0977; found: 446.0981.
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diethyl 2-hydroxy-2-(5-methyl-1-phenyl-1H-pyrrol-3-yl)malonate (4m): yellow oil, 52.8 mg, 80%
yield, purification on silica gel (DCM). 1H NMR (500 MHz, Chloroform-d) δ 7.44-7.40 (m, 2H),
7.35 – 7.31 (m, 1H), 7.31 – 7.28 (m, 2H), 6.95 (d, J = 2.0 Hz, 1H), 6.18 (dd, J = 2.0, 1.0 Hz, 1H),
4.40 – 4.25 (m, 4H), 4.10 (s, 1H), 2.18 (d, J = 1.0 Hz, 3H), 1.37 – 1.25 (m, 6H). 13C{1H} NMR
(126 MHz, CDCl3) δ 170.2, 140.0, 129.0, 127.0, 125.7, 120.3, 119.4, 107.7, 62.7, 14.1, 13.0.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for C18H22NO5: 332.1492; found: 332.1494.
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1
ethyl 3,3,3-trifluoro-2-hydroxy-2-(4-(pyrrolidin-1-yl)phenyl)propanoate (3a’): H NMR (500
MHz, CDCl3) δ 7.58 (d, J = 8.3 Hz, 2H), 6.59 – 6.52 (m, 2H), 4.46 – 4.32 (m, 2H), 4.19 (d, J = 2.0
Hz, 1H), 3.28 (q, J = 4.2 Hz, 4H), 2.06 – 1.90 (m, 4H), 1.40 – 1.33 (m, 3H). 13C{1H} NMR (126
MHz, CDCl3) δ 169.5, 148.4, 123.4 (q, J = 285.5 Hz), 118.9, 111.2, 77.7 (d, J = 30.1 Hz), 64.0,
47.6, 25.5, 13.9.
diethyl 2-hydroxymalonate (5):19 1H NMR (500 MHz, CDCl3) δ 4.62 (d, J = 8.3 Hz, 1H),
4.27-4.19 (m, 4H), 3.33 (d, J = 8.3 Hz, 1H), 1.25 (t, J = 7.1 Hz, 6H). 13C{1H} NMR (126 MHz,
CDCl3) δ 168.5, 71.5, 62.6, 14.0.
Supporting Information
Structural proofs and NMR spectra of products. This material is available free of charge via the
Internet at http://pubs.acs.org.
ORCID
Jian Xiao: 0000-0003-4272-6865
Notes
§These authors contribute equally to this work. The authors declare no competing financial
interest.
ACKNOWLEDGMENTS
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We are grateful to The Taishan Scholars Construction Projects of Shandong
(tsqn201909131) and NSFC (21878167). The Key Research and Development Program of
Shandong Province (2017GSF218073) and Qingdao Special Research Foundation of Science
and Technology (19-6-1-38-nsh) as well as the First Class Fishery Discipline Programme of
Shandong Province are also gratefully acknowledged. We thank Dr. Feng-Ying Dong
(Central Laboratory of Qingdao Agricultural University) for NMR determination.
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